WE WELCOME YOU TO THE 14TH
SESSION OF THE 23RD YEAR OF THE
COURSE IN DEMYSTIFYING MEDICINE
CONDUCTED AT THE NATIONAL
INSTITUTES OF HEALTH IN
BETHESDA, MARYLAND.
THE PROGRAM FOR THIS YEAR AND
THE PREVIOUS YEAR WAS VIRTUAL,
BUT WE MAY BE MOVING NOW INTO A
MORE HYBRID MODE IN 2024.
WE CERTAINLY HOPE SO.
THE PURPOSE OF THIS COURSE IS TO
BRIDGE, BRIDGE EXCITING
DEVELOPMENTS IN BIOLOGY AND
ENGINEERING WITH MEDICINE.
AND THE RAPID DEVELOPMENTS IN
BIOLOGICAL SCIENCE, ENGINEERING
SCIENCE, METHODOLOGIES, HAS
CREATED AN ENORMOUS GAP BETWEEN
WHAT IS USED AND PRACTICED IN
THE DIAGNOSIS AND TREATMENT OF
HUMAN DISEASE.
SO THE LOGO FOR OUR COURSE SHOWN
IN THE UPPER RIGHT IS THE WORLD
FAMOUS BROOKLYN BRIDGE, WHICH WE
HAVE SHOWN 412 TIMES FOR
SESSIONS IN THIS COURSE, A LONG
TIME.
TODAY, THE INDIVIDUALS ON THE
CATWALK REPRESENT A UNIQUE KIND
OF BRIDGING, ALL CONCERNS
DIABETES.
WE'LL GET TO THAT IN A MOMENT.
BUT WE HAVE THE BRIDGING BETWEEN
A CHANGE IN CAREER FROM A
LEADING DEVELOPMENTAL BIOLOGIST
INTO A PATHOBIOLOGICALLY -- CELL
BIOLOGIST.
AND A YOUNG WOMAN WHO HAS TYPE .
AND HAS MADE ENORMOUS PROGRESS
IN HER LIFE, WHICH SHE'S GOING
TO SHARE WITH US.
SO OUR CONCERN IS THAT MUCH OF
THE PROGRESS IN THE MORE BASIC
SCIENCES AND IN MEDICINE
CONSTITUTE LIKE SILOS OF
INFORMATION.
THEY BECOME SO SPECIALIZED THAT
THERE'S LIMITED BRIDGING BETWEEN
THEM.
SO THE PURPOSE OF THIS COURSE IS
ESSENTIALLY TO CONVERT SILOS OF
KNOWLEDGE AND EXPERIENCE INTO
BRIDGES FOR THE BETTERMENT OF AN
UNDERSTANDING OF BIOLOGY AND
MEDICINE.
SO THE SPEAKERS HAVE NO
FINANCIAL RELATIONSHIPS.
THE CME CREDIT IS 45394.
THE PHONE NUMBTODAY THE TOPIC IT
PROGRESS IN DIABETES.
NOW IT'S BEEN OVER 100 YEARS
SINCE THE DISCOVERY OF INSULIN.
AND YET THE CURE OF DIABETES AND
THE TREATMENT REMAINS
CHALLENGING.
AT THE SAME TIME, BOTH THE
FREQUENCY OF TYPE 1 AND TYPE
2 DIABETES GLOBALLY CONTINUES T.
MANY QUESTIONS ARISE, AND SOME
THAT I WILL MENTION HERE ARE
ONES THAT WILL BE THE TOPIC OF
TODAY'S PRESENTATIONS.
IS METICULOUS CONTROL OF BLOOD
SUGAR POSSIBLE, THEREBY
PREVENTING MANY OF THE LONG-TERM
COMPLICATIONS OF DIABETES, SUCH
AS CARDIOVASCULAR DISEASE,
INFECTION, CANCER, BLINDNESS,
NEUROPATHY, NEPHROPATHY, AND
OTHERS.
WHAT'S THE PATHOGENESIS OF TYPE
1 DIABETES?
CAN PANCREATIC BETA CELL BIOLOGY
BE USED AS TREATMENT TO PROVIDE
ESSENTIALLY IN VIVO FUNCTION IN
MAN?
AND HOW CAN DIABETICS "LIVE
WITH" THEIR DISEASE AND FUNCTION
NORMALLY?
THESE ARE THE BIG TOPICS TO BE
PRESENTED TODAY BY OUR SPEAKERS
SO LET ME INTRODUCE THEM TO YOU.
SO THE FIRST SPEAKER IS COURTNEY
DUCKWORTH.
WHO GRADUATED FROM THE
UNIVERSITY OF VIRGINIA,
RECEIVING HER MEDICAL DEGREE IN
2022.
AND SHE IS PRESENTLY A FIRST
YEAR PEDIATRIC RESIDENT AT
BOSTON CHILDREN'S HOSPITAL.
IN 2003, COURTNEY WAS DIAGNOSED
WITH TYPE 1 DIABETES.
IN A FRIGHTENING CLINICAL
SITUATION.
FROM 2015 TO '17, SHE WAS AT THE
NATIONAL INSTITUTES OF HEALTH AS
A POSTBAC, AN IRTA RESEARCH
FELLOW.
AND THERE, SHE WORKED WITH AARON
SIPUS AND OTHERS PRIMARILY ON
STUDIES IN VIVO OF BROWN FAT
METABOLISM.
IN 2018, SHE WAS A RESEARCH
ASSISTANT IN GENETICS AND
METABOLISM AT THE CHILDREN'S
NATIONAL HEALTH SYSTEM.
NOW ASIDE FROM THIS CHEVY -- ASE
FROM THIS HEAVY ACADEMIC
RESPONSIBILITY, COURTNEY DOES
NOT LET GRASS GROW UNDER HER
FEET.
SHE IS A FIGURE SKATING COACH.
SHE WAS A FIGURE SKATING
CHEERLEADER WITH THE WASHINGTON
CAPITALS, THE PROFESSIONAL
HOCKEY TEAM.
SHE IS A MARATHON RUNNER.
HAS RUN THE BOSTON MARATHON AT
LEAST TWICE, AND SHE'S A FITNESS
AND DANCE INSTRUCTOR, AND
PROBABLY A FEW OTHER THINGS.
BUT MOST NOTABLY, FOR TODAY'S
PRESENTATION, SHE'S AN AUTHOR.
AND HER BOOK ENTITLED "THE
MARATHON WE LIVE: TRAINING FOR
A PERSONAL BEST IN LIFE WITH
TYPE 1 DIABETES," IS, IN MY
VIEW, A CLASSIC THAT PEOPLE
SHOULD READ TO UNDERSTAND WHAT
REALLY CAN BE DONE IN THE WAY OF
TREATMENT AND MANAGEMENT OF THIS
DISEASE.
NOW OUR SECOND SPEAKER WHO WILL
BE WITH US THROUGH THE COURTESY
OF MAKING A VIDEO AS A
LAST-MINUTE CONFLICT PREVENTED
HIM FROM BEING IN PERSON WITH
US, IS DOUG MELTON.
NOW DOUG RECEIVED A BACHELO
BACHELOR'S DEGREE IN BIOLOGY
FROM THE UNIVERSITY OF ILLINOIS
AND A SECOND DEGREE IN
PHILOSOPHY AND SCIENCE AT
CAMBRIDGE, AND THEN A PH.D. IN
MOLECULAR BIOLOGY AT TRINITY
COLLEGE THERE IN THE FAMOUS
MEDICAL RESEARCH COUNCIL
LABORATORY OF MOLECULAR BIOLOGY.
AFTER THAT TRAINING, THERE WAS
NO POSTDOC FOR DOUG.
HE WAS RECRUITED AT WH HARVARD N
1981 AND LEFT IN 2022, WHERE HE
WAS THE XANDER UNIVERSITY
PROFESSOR AND HOWARD HUGHES
INVESTIGATOR AND CO-DIRECTOR OF
THE HARVARD STEM CELL INSTITUTE.
IN 2022, HE MOVED TO THE VERTEX
FAPHARMACEUTIC COMPANY, AND HE
WILL EXPLAIN THE REASONS FOR
THIS CHANGE.
DOUG HAS RECEIVED NUMEROUS
AWARDS, INCLUDING ELECTION TO
THE NATIONAL ACADEMY OF MEDIC
MEDICINE.
IN HIS EARLIER CAREER AT
HARVARD, HE WAS A LEADING
DEVELOPMENTAL BIOLOGIST, AND
THEN RATHER DRAMATICALLY CHANGED
HIS FOCUS TO DEVELOP TREATMENT
FOR DIABETES BY INSULIN
PRODUCING PANCREATIC BETA CELL
TRANSPLANTS, MAINLY FROM STEM
CELLS.
USING IPS CELLS FROM TYPE
1 JUVENILE DIABETICS, HE STUDIED
THE BASIS OF AUTOIMMUNITY AND
HIS LABORATORY HAS ALSO DONE
ELEGANT STUDIES IN TYPE
2 DIABETES.
SO WE WILL BEGIN WITH
DR. DUCKWORTH, AND COURTNEY,
IT'S A PLEASURE TO HAVE YOU WITH
US.
>>THANK YOU FOR THAT KIND
INTRODUCTION, WIN.
THANK YOU, EVERYONE, FOR YOUR
TIME TODAY, AND FOR ATTENDING
THIS LECTURE IN DEMYSTIFYING
MEDICINE.
AS WIN SAID, MY NAME IS COURTNEY
DUCKWORTH.
I'M CURRENTLY A RESIDENT
PHYSICIAN AT BOSTON CHILDREN'S
HOSPITAL AND BOSTON MEDICAL
CENTER, CALLING IN FROM THE CALL
ROOM HERE AT THE BRIGHAM AND
WOMEN'S NICU.
TODAY WE'RE GOING TO BE TALKING
ABOUT HOW IN MANY WAYS DIABETES
IS ONE OF THE GREAT MARATHONS OF
LIFE.
I HAVE NO FINANCIAL DISCLOSURES
OR CONFLICTS OF INTEREST WITH
THE MATERIAL IN THIS
PRESENTATION.
AND PRIOR TO MEDICAL SCHOOL, I
WAS A POSTBAC RESEARCH FELLOW AT
THE NIH AND BEFORE CONTINUING
THIS PRESENTATION, I FIRST HAVE
TO THANK EVERYONE WHO BROUGHT ME
THERE, INCLUDING DR. CHEN, MY
P.I., DR. CYPESS, DR. BRYCHTA,
MY COLLEAGUES DR. LEITNE R & B
ASKIN AS WELL AS THE COUNTLESS
MENTORS I MEANT ALONG THE WAY
INCLUDES DRS. ARIAS AND DRS.
COLLINS AND COUNTLESS OTHERS.
MY INTRODUCTION TO MEDICINE CAME
IN THE FORM OF DIAGNOSIS WITH
TYPE 1 DIABETES AT THE AGE OF
10.
I'VE LIVED WITH THIS DISEASE NOW
FOR ABOUT TWO DECADES,
EXPERIENCING THE COMPLEXITIES OF
THIS CHRONIC ILLNESS, THE
PHYSICAL AS WELL AS PSYCHOSOCIAL
IMPACTS, AS WELL AS THE
INCREDIBLE CHANGES IN DIABETES
TECHNOLOGY THAT HAVE HAPPENED IN
THIS PERIOD OF TIME.
WHEN I WAS FIRST DIAGNOSED, I
WAS USING MPH AND REGULAR
INSULIN.
I HAVE ALSO EXPERIENCED A NUMBER
OF MULTIPLE DAILY INJECTION
THERAPIES TO INSULIN PUMPS, NOW
CGMs AND ON THE HORIZON ARE
INSULIN-PRODUCING CELL
TRANSPLANTS, LARGELY LY A PART F
DR. MELTON'S WORK WHICH WE'LL
HEAR ABOUT LATER IN HIS
PRESENTATION.
I HOPE TO CONTRIBUTE MY
PERSPECTIVE AS BOTH A PATIENT
AND AS A PHYSICIAN AS WE DISCUSS
THE FOLLOWING OBJECTIVES.
FIRST, GAINING AN UNDERSTANDING
OF THE MULTIFACETED NATURE OF
MANAGING TYPE 1 DIABETES.
APPRECIATING HOW ADVANCEMENTS IN
TREATMENT IMPROVE DIABETES
MANAGEMENT AND QUALITY OF LIFE.
RECOGNIZING EXPANDING HEALTHCARE
DISPARITIES IN THE CONTEXT OF
NEW DIABETES TREATMENTS.
FIRST TOUCHING ON
PATHOPHYSIOLOGY AND PREVALENCE
OF TYPE 1 DIABETES, AS MANY
PEOPLE IN THIS AUDIENCE ARE
FAMILIAR WITH, TYPE 1 DIABETES
IS AN AUTOIMMUNE CONDITION
CHARACTERIZED BY T-CELL MEDIATED
ATTACK ON PANCREATIC BETA CELLS
LEADING TO LACK OF INSULIN
SECRETION.
CURRENTLY 8.8 MILLION PEOPLE IN
THE WORLD ARE ESTIMATED TO HAVE
TYPE 1 DIABETES, WITH 1.5 BEING
IN THE U.S. ALONE.
OVERALL, TYPE 1 DIABETES
ACCOUNTS FOR ABOUT 5 TO 10% OF
ALL DIABETES CASES.
THERE'S AN ESTIMATED INCREASE OF
ABOUT 2 TO 3% IN INCIDENCE PER
YEAR, AND WHILE THERE'S MANY
THEORIES BEHIND THIS, ONE
UNDOUBTED THEORY IS THAT THERE'S
BETTER PUBLIC EDUCATION AROUND
DIABETES AND DIAGNOSIS IN
GENERAL.
THERE'S ALSO AN INCREASE IN
PREVALENCE AS TREATMENTS
CONTINUE TO PROGRESS.
AND WHILE TYPE 1 DIABETES IS
TRADITIONALLY THOUGHT TO BE A
DISEASE OF CHILDHOOD, ABOUT 50%
OF NEW CASES ARE DIAGNOSED IN
ADULTHOOD.
DIABETES HAS FAR REACHING
PHYSICAL, PSYCHOSOCIAL AND
FINANCIAL IMPACTS.
PHYSICALLY FOR EVERY TWO PEOPLE
WITH TYPE 1 ALIVE TODAY, ONE IS
LOST TO DIRECT CAUSES.
ABOUT 22 HEALTHY LIFE YEARS ARE
LOST IF DIAGNOSED IN CHILDHOOD
IN THE UNITED STATES, WHICH IS A
LITTLE BIT HIGHER THAN THAT OF
OTHER COMPARABLE HIGH INCOME
COUNTRIES.
PSYCHOLOGICALLY, DIABETES IS A
VERY INTERESTING CONDITION IN
THAT SO MUCH OF THE OUTCOMES OF
THIS DISEASE DEPEND ON
INDIVIDUAL ACTION.
EVERYTHING YOU DO OR DON'T DO
CAN AFFECT YOUR GLUCOSE LEVELS,
WHICH IS AN INCREDIBLE AMOUNT OF
PRESSURE.
PERHAPS NOT SURPRISINGLY, PEOPLE
WITH DIABETES ARE TWO TO THREE
TIMES MORE LIKELY TO DEVELOP
DEPRESSION.
ABOUT 20% MORE LIKELY TO
EXPERIENCE ANXIETY.
AND WOMEN WITH TYPE 1 ARE ABOUT
TWICE AS LIKELY TO DEVELOP AN
EATING DISORDER.
AND IMPORTANTLY, PHYSICAL HEALTH
AND MENTAL HEALTH ARE A
BIDIRECTIONAL RELATIONSHIP, AND
FOR MENTAL HPOOR MENTAL HEALTH N
NEGATIVELY AFFECT GLUCOSE LEVELS
AND VICE VERSA.
FINANCIALLY, PEOPLE WITH
DIABETES ARE ESTIMATED TO SPEND
AN ADDITIONAL $9,600 A YEAR
DIRECTLY DUE TO DIABETES
TREATMENTS.
AND ABOUT 5.5 DAYS OF WORK ARE
MISSED A YEAR ON AVERAGE, AND IN
TOTAL, IT'S ESTIMATED THAT ABOUT
14 DAYS OF PRODUCTIVITY AT WORK
ARE MISSED, AND THIS CAN BE DUE
TO THE TIME IT TAKES TO CARE FOR
DIABETES, AS WELL AS THE MENTAL
ENERGY IT TAKES TO CONTROL THIS
DISEASE AS WELL.
ILLUSTRATING THIS BURDEN OF
DISEASE ON AN INDIVIDUAL LEVEL,
MY CRASH COURSE IN MEDICINE
BEGAN OCTOBER 27TH, 2003, WHEN I
WAS DIAGNOSED WITH DIABETES, AND
ENDED OCTOBER 30TH, 2003, WHEN I
LEFT THE HOSPITAL AT CHILDREN'S
NATIONAL.
PRIOR TO DIAGNOSIS, I WOULD HAVE
DESCRIBED MY LIFE AS A
COMBINATION OF VARIOUS
ACTIVITIES, MOSTLY SCHOOL,
FRIENDS, AND FIGURE SKATING.
AND AFTER DIAGNOSIS, I WOULD
STILL DESCRIBE MY LIFE AS A
COMBINATION OF THESE ACTIVITIES.
JUST NOW WITH MULTIPLE
INJECTIONS, FINGER STICKS, AND
CARB COUNTING AS WELL AS AN A
CONSTANT INTERNAL DIALOGUE OF
WHAT MY GLUCOSE LEVELS WERE
DOING AT ANY TIME PRIOR TO DO
THE BEING A TIINGTHE ACTIVITIES.
THE FIRST YEAR WAS ESPECIALLY
DIFFICULT BECAUSE THE LEARNING
CURVE WAS VERY DEEP.
MY FAMILY AND I BARELY KNEW WHAT
A CARB WAS MUCH LESS HOW TO
COUNT THEM.
WE FOUND THERE WAS A LOT OF
SOCIAL STIGMA BEHIND THE WORD
"DIABETES."
THIS SLIDE IS BUSY ON PURPOSE,
REPRESENTING ALL OF THE
ADDITIONAL ACTIVITY THAT WERE
NOW ADDED TO MY DAY, SUCH AS
TESTING GLUCOSE ANYWHERE BETWEEN
6 TO 14 TIMES A DAY, TAKING
ANYWHERE FROM 6 TO 8 SHOTS, AS
WELL AS SOME OF THE
INCONVENIENCES THAT COULD HAPPEN
AT ANY TIME OF THE DAY, SUCH AS
GETTING AN EPISODE OF
HYPOGLYCEMIA, AND HAVING TO GO
TO THE NURSE'S OFFICE, AS WELL
AS THE VERY METICULOUS CARB
COUNTING AS WELL AS THE TIMING
OF CARBOHYDRATES IN MY DAY.
ON
AVERAGE, IT'S ESTIMATED THAT
DIABETES CARE TASKS ALONE TAKE
ABOUT AN HOUR AND 15 MINUTES A
DAY.
AND IF SOMEONE WITH DIABETES
WERE TO PERFORM ALL RECOMMENDED
HEALTHCARE TASKS SUCH AS GOING
TO THE DOCTOR, DOING THEIR FOOT
EXAM, FOR EXAMPLE, YOU KNOW,
CHANGING OUT THEIR INSULIN, ALL
OF THESE TASKS THAT CAN ADD UP,
IT CAN TAKE UPWARDS OF FIVE
HOURS A DAY.
WITH DIABETES TREATMENT, I
LEARNED A FEW UNDERLYING
PRINCIPLES EARLY ON.
FIRST, THAT FOLLOWING DIRECTIONS
PERFECTLY DIDN'T NECESSARILY
MAKE FOR PERFECT RESULTS.
DIABETES THRIVES ON CONSISTENCY.
AND PEOPLE'S ACTIVITIES CHANGE
FROM DAY TO DAY, ESPECIALLY WHEN
YOU'RE VERY YOUNG AND YOU DON'T
HAVE ANY AGENCY OVER YOUR
SCHEDULE, AND DIABETES ALSO
DEPENDS ON THE CONDITIONS WITHIN
YOUR OWN BODY, WHICH ALSO CHANGE
FROM DAY TO DAY, ESPECIALLY WHEN
YOU'RE YOUNG AND YOUR BODY IS
GROWING VERY RAPIDLY.
SECOND, I LEARNED THAT LOW BLOOD
SUGAR KILLS YOU IN MINUTES, HIGH
BLOOD PRESSURE KILLS YOU IN
YEARS.
OFTENTIMES, IT FELT SAFER TO RUN
MY BLOOD SUGARS A LITTLE HIGHER
AND BE ABLE TO PARTICIPATE IN
ACTIVITIES WITH MY PEERS.
IT WAS EXTREMELY SCARY TO HAVE
LOW BLOOD SUGAR, ESPECIALLY WHEN
I DIDN'T KNOW HOW RAPIDLY IT WAS
DROPPING, AND ALSO WHEN I WAS IN
ENVIRONMENTS WHERE I FELT THAT
PEOPLE WERE NOT EDUCATED ON
DIABETES AND THAT I WAS TAKING
CARE OF IT BY MYSELF.
HOWEVER, I KNEW BEING IN RANGE
HELPED ME LIVE TO MY FULLEST
POTENTIAL.
WHEN MY BLOOD SUGAR WAS LOW I
FELT SHAKY AND LIGHT-HEADED AND
OFTEN COULDN'T PARTICIPATE IN
THE ACTIVITIES I WAS SUPPOSED TO
BE DOING.
HOWEVER, WHEN MY BLOOD SUGAR WAS
HIGH, I WOULD FEEL SLEEPY, AND
LIKE I COULD LOSE MY FOCUS VERY
EASILY.
AND I KNEW THAT BEING SOMEWHERE
IN THE MIDDLE HELPED ME TO LIVE
MY LIFE TO MY FULLEST POTENTIAL.
AND FINALLY, DIABETES IS A TEAM
SPORT.
ESPECIALLY WHEN YOU'RE YOUNG, SO
MUCH OF CARRYING OUT DAILY
MANAGEMENT TASKS DEPENDS ON THE
ADULTS AROUND YOU.
MY MOM WOULD WAKE UP EVERY NIGHT
TO TEST MY GLUCOSE TO MAKE SURE
THAT I WOULD WAKE UP THE NEXT
MORNING, AND I ALSO HAD AN
EXCELLENT CARE TEAM AT
CHILDREN'S NATIONAL, INCLUDING
DR. COGAN, WHO ALWAYS GOT TO
KNOW ME AS A PERSON BEFORE WE
TRIED TO TACKLE THE PROBLEMS OF
DIABETES TOGETHER.
IN MY FIRST 10 YEARS OF LIVING
WITH TYPE 1 DIABETES, AGAIN, I
EXPERIENCED A NUMBER OF
DIFFERENT TREATMENTS, BUT FACED
SIMILAR CHALLENGES.
AGAIN, GOING FROM MPH AND
REGULAR INSULIN TO BASAL/BOLUS
REGIMES, AND INSULIN PUMP IN
2013.
DURING THIS TIME, I HAD ALSO
BECOME A COLLEGE STUDENT AT
WILLIAM AND MARY, AND I DID
PRETTY WELL AS A PRE-MED, AND
GAVE MORE HEALTHCARE LITERACY.
AND THESE BETTER
TREATMENTS AND INCREASE IN
HEALTHCARE LITERACY, I FOUND IT
WAS EXTREMELY CHALLENGING TO
MEET THE GOALS SET FORTH BY THE
AMERICAN DIABETES ASSOCIATION
AND THE GLYCEMIC GOALS I KNEW I
WAS CAPABLE.
CURRENTLY THE ADA RECOMMENDS
THAT A1Cs BE BELOW 7% FOR BOTH
YOUTH AND ADULTS.
HOWEVER, THIS IS A FAIRLY NEW
RECOMMENDATION, AND PREVIOUSLY,
A1Cs WERE RECOMMENDED TO BE
BELOW 7.5% FOR YOUTH AND YOUNG
ADULTS.
IN 2015, WE CAN SEE IN THIS
FIGURE ON THE RIGHT THAT EVEN
WITH THE 7.5%, ABOUT 86% OF
TEENS AND YOUNG ADULTS WERE NOT
MEETING THIS RECOMMENDATION,
MEANING THAT I WAS IN THE VAST
MAJORITY.
DURING THIS TIME, I HAD ALSO
TAKEN ON AN EXTRA CHALLENGE IN
THE FORM OF RUNNING MARATHONS
WHEN A FRIEND AND I DISCOVERED
THAT WE BOTH SHARED RUNNING A
MARATHON ON OUR BUCKET LIST.
IN MY VERY FIRST MARATHON
WITHOUT EVER HAVING TRAINED FOR
SPEED, I WAS ABOUT 3 MINUTES
AWAY FROM QUALIFYING FOR THE
BOSTON MARATHON.
SO NATURALLY, MY GOAL CHANGED
FROM RUN A MARATHON TO RUN THE
BOSTON MARATHON.
AND ABOUT A YEAR LATER, A VERY
STRATEGIC TRAINING AND A COUPLE
OF MARATHONS, I WAS ABLE TO
QUALIFY.
AND I THOUGHT TO MYSELF, IF I
CAN TRAIN TO BECOME A BETTER
RUNNER IN THE SPAN OF JUST ONE
YEAR AND EVEN QUALIFY FOR THE
BOSTON MARATHON, SURELY I CAN
TRAIN TO BE BETTER IN A DISEASE
THAT I'VE HAD FOR OVER A DECADE.
AND THIS LED TO THE THOUGHT,
WHAT IF I APPROACHED DIABETES
CARE LIKE I APPROACHED TRAINING
FOR MARATHONS?
THIS WOULD BECOME THE FRAMEWORK
FOR MY BOOK, "THE MARATHON WE
LIVE," AND IT'S HOW WE TALK
ABOUT THE MULTIFACETED NATURE OF
DIABETES CARE FOR THE REST OF
THIS TALK.
OVERALL, MY MARATHON TRAINING
STRATEGY CONSISTED OF FOUR
PARTS.
KNOWING WHAT YOU'RE TRAINING FOR
AND WHY YOU'RE TRAINING,
LEARNING HOW TO TRAIN, FORMING
STRATEGIES, AND BUILDING
ENDURANCE.
FIRST, KNOWING WHAT YOU'RE
TRAINING FOR.
IN RUNNING, IT'S EXCEEDINGLY
DIFFICULT TO CONVINCE YOURSELF
TO GET UP AND RUN 20 MILES FOR
NO GOOD REASON.
YOU HAVE TO HAVE A LONG-TERM
EVENT IN MIND.
AND YOU HAVE TO HAVE A TARGET.
LIKEWISE IN DIABETES, WE HAVE TO
KNOW WHAT WE'RE TRAINING FOR.
ANECDOTALLY AS A PHYSICIAN AND A
PATIENT, I'VE NOTICED THAT
CONVERSATIONS AROUND GLYCEMIC
GOALS OFTEN GO OVERLOOKED.
AGAIN, A1C GOALS ARE RECOMMENDED
TO BE BELOW 7%, WITH POST
PRANDIAL GLUCOSE LEVELS BEING
BELOW 180, AND FOR THOSE WHO USE
CONTINUOUS GLUCOSE MONITOR OR
CGM TECHNOLOGY, TIME AND RANGE
IS RECOMMENDED TO BE AT LEAST
70%, WITH 4% BELOW TARGET.
IN THIS GRAPH HERE FROM DIABETES
CARE ON THE RIGHT, WE CAN SEE
TIME AND RANGE REPRESENTED IN
THE GREEN HERE.
TIME ABOVE RANGE REPRESENTED IN
THE YELLOW, AND TIME BELOW RANGE
REPRESENTED IN THE RED.
NEXT YOU HAVE TO KNOW WHY YOU'RE
TRAINING, WHAT ARE YOUR BENEF
BENEFITS.
IN RUNNING, MY LONG TERM BIG
PICTURE BENEFITS WERE CROSSING
AN ITEM OFF MY BUCKET LIST,
WHILE THERE WERE ALSO DAY TO DAY
BENEFITS, AND THIS COULD BE
ANYTHING FROM EXPLORING A NEW
PART OF TOWN ON A RUN TO HAVING
BANANA AND PEANUT BUTTER AFTER A
RUN.
LIKEWISE, IN DIABETES, WE GAIN
BOTH LONG TERM AND SHORT TERM
BENEFITS.
LONG TERM, WE GAIN PROTECTION
FROM RETINOPATHY, NEUROPATHY,
NEPHROPATHY, AS WELL AS MACRO
VASCULAR EVENTS.
HOWEVER, THIS LONG TERM
PROTECTION CAN SEEM VAGUE,
ESPECIALLY FOR YOUNG PEOPLE WHO
PROBABLY FEEL RELATIVELY
INVINCIBLE, AND PROBABLY HAVE AN
EASIER TIME RELATING TO THESE
DAY TO DAY BENEFITS THAT THEY
GET FROM BETTER GLUCOSE CONTROL.
THIS INCLUDES INCREASED ENERGY,
FOCUS, SATIETY, IMMUNITY, MENTAL
HEALTH, AND SOCIAL RELATIONSHIPS
WITH THEIR PEERS.
NEXT, YOU HAVE TO KNOW HOW TO
TRAIN FOR THE TASK AT HAND.
WHAT ARE YOUR TOOLS AND WHAT ARE
THE SKILLS THAT YOU'RE TRYING TO
DEVELOP?
IN RUNNING, TRAINING FOR A
50-YARD DASH IS GOING TO LOOK A
LOT DIFFERENT THAN TRAINING FOR
A MARATHON.
LIKEWISE, IN DIABETES, WE HAVE
TO KNOW EXACTLY WHAT WE'RE
TRYING TO ACCOMPLISH.
QUITE SIMPLY, THIS IS REALLY
JUST TWO THINGS: SENSING
GLUCOSE CHANGES AND STAYING
WITHIN A RELATIVELY TIGHT RANGE.
AND WE HAVE MULTIPLE TOOLS TO DO
BOTH OF THESE THINGS.
FOR SENSING GLUCOSE CHANGES WE
USE GLUCOSE MONITORS AS WELL AS
CONTINUOUS GLUCOSE MONITORS, AND
TO STAY WITHIN A TIGHT RANGE, WE
CAN USE INSULIN, NUTRITION, AND
EXERCISE, WITH THE CAVEAT THAT
WHILE EXERCISE CAN BE GREAT FOR
INCREASING INSULIN SENSITIVITY,
IT CAN BE REALLY HARD TO CONTROL
GLUCOSE LEVELS DURING EXERCISE.
AND IN FACT, PHYSICAL ACTIVITY
HAS NOT SHOWN TO BE ASSOCIATED
WITH LOWER A1C LEVELS.
EACH OF THESE TOOLS COME WITH
THEIR OWN SET OF SKILLS THAT
NECESSITATE THE NEED FOR
CONTINUOUS EDUCATION AND VERY
STRATEGIC PRACTICE.
FOR EXAMPLE, USING INSULIN TO
ITS UTMOST EFFECT REQUIRES THAT
ONE KNOWS HOW TO DOSE THEIR
INSULIN CORRECTLY, AS WELL AS
TIME THEIR INSULIN CORRECTLY,
ADMINISTER SAFELY, AND STORE
EFFECTIVELY.
NEXT, WE FORM STRATEGIES.
IN RUNNING, YOU MIGHT SIT DOWN
16 WEEKS BEFORE A RACE AND PLAN
OUT EVERY SINGLE WORKOUT THAT
YOU DO WITH THE REALIZATION THAT
THIS IS EXTREMELY FLEXIBLE.
YOU HAVE TO TRY YOUR STRATEGIES,
SEE IF THEY'RE WORKING, AND THEN
ADAPT ALONG THE WAY.
LIKEWISE IN TYPE 1 DIABETES,
EVERY DAY YOU'RE YOUR OWN
SCIENTIFIC EXPERIMENT AND WE'RE
CONSTANTLY DESIGNING STRATEGIES
FOR INDIVIDUAL SITUATIONS,
WHETHER THIS IS HAVING BETTER
GLYCEMIC CONTROL AT BEDTIME, OR
IF THIS IS DEVELOPING SKILLS
SUCH AS LEARNING HOW TO DOSE
INSULIN CORRECTLY.
IN MEDICINE, WE OFTEN TALK ABOUT
THE PDSA CYCLE, PLAN, DO, STUDY
ACT, WHEN WE TALK ABOUT QUALITY
IMPROVEMENT, WHICH IS A
RECENT -- FIRST WE PROACTIVELY
DECIDE THE ACTIONS THAT WILL
TARGET A CERTAIN AREA OF
IMPROVEMENT.
WE PERFORM THESE ACTIONS AND
COLLECT OUR DATA.
WE ANALYZE OUR DATA.
AND FINALLY, WE IDENTIFY AREAS
FOR IMPROVEMENT AND BEGIN A NEW
CYCLE.
AND STUDYING OUR DATA AS WELL AS
ACTING ON OUR DATA AND
IDENTIFYING AREAS FOR
IMPROVEMENT IS WHERE OUR SECOND
LEARNING OBJECTIVE COMES IN.
APPRECIATING THE CHANGES THAT
HAVE COME ABOUT WITH BETTER
DIABETES TECHNOLOGY TO HELP US
IN BOTH OF THESE DOMAINS.
LARGELY, THIS IS DUE TO
CONTINUOUS GLUCOSE MONITORS.
CGMs TAKE A READING OF THE
GLUCOSE IN THE INTERSTITIAL
FLUID EVERY FIVE MINUTES.
THIS GIVES US 284 ADDITIONAL
DATA POINTS A DAY.
AND SO WE CAN SEE THE EFFECTS OF
OUR STRATEGIES IN REALTIME AND
ADAPT AS NEEDED.
BELOW, THIS IS ONE OF MY GLUCOSE
READOUTS.
IN A TWO-WEEK PERIOD OF TIME.
SO LOOKING AT OUR DATA, WE CAN
SEE THAT WHILE 86% OF THE TIME I
WAS IN RANGE FOR THESE TWO
WEEKS, WHICH IS QUITE GOOD, 7%
OF THE TIME I WAS SPENDING BELOW
RANGE, WHICH IS ABOVE THE
RECOMMENDED 4% FROM THE ADA.
SO THAT'S A POTENTIAL AREA FOR
IMPROVEMENT.
LOOKING AT THIS GRAPH ON THE
BOTTOM, WE CAN SEE THE TIMES OF
THE DAY WHERE I WAS TENDING TO
GO LOW.
ONE BEING AFTER DINNER, FOR
EXAMPLE.
AND I CAN BACKTRACK AND ASK
MYSELF QUESTIONS ABOUT WHY THAT
MIGHT HAPPEN SUCH AS TAKING TOO
MUCH INSULIN AND DINNER AND THEN
BREAKING THAT DOWN EVEN FURTHER
INTO INSULIN DOSE AND INSULIN TO
CARB RATIO AND TRYING TO CHANGE
THAT, AND THEN LOOKING AT THE
DATA THAT I HAVE FROM THE NEXT
TWO WEEKS AFTER IMPLEMENTING A
CHANGE.
OR EVEN SOONER.
OVERALL, CGM TECHNOLOGY HAS BEEN
SHOWN TO INCREASE TIME IN RANGE.
FOR YOUTH UNDER 26 YEARS OLD,
THIS CAN BE AS MUCH AS 0.7 TO 1%
IMPROVEMENT IN A1C LEVELS.
CGM TECHNOLOGY HAS ALSO BEEN
SHOWN TO DECREASE EPISODES OF
DKA, AS WELL AS HYPOGLYCEMIC
EVENTS, WHICH ARE SOME OF THE
LEADING CAUSES OF MORBIDITY AND
MORTALITY WI FOR PEOPLE WITH TY.
CGMs HAVE ALSO BEEN SHOWN TO
PROVIDE PSYCHOSOCIAL BENEFITS.
THIS INCLUDES INCREASED EFFICACY
AND CARE, CONFIDENCE THAT YOU
CAN HAVE GREAT GLYCEMIC CONTROL,
AND THAT FOLLOWING THROUGH ON
THE ACTIONS IN MANAGEMENT
PRODUCES THE RESULTS THAT YOU
WANT.
IT'S ALSO BEEN SHOWN TO DECREASE
LEVELS OF ANXIETY AND DEPRESSION
FOR PEOPLE WITH DIABETES,
INCREASED RESTFUL SLEEP, PROVIDE
GREATER PARTICIPATION IN PEER
ACTIVITIES, AND INCREASED
COMFORT WITH NON-GUARDIAN
CAREGIVERS.
THIS BRINGS US TO OUR THIRD
LEARNING OBJECTIVE, WHICH IS
APPRECIATING THE DISPARITIES IN
THE CONTEXT OF NEW TREATMENTS.
THIS CONVERSATION IS ESPECIALLY
IMPORTANT, ESPECIALLY WITH
RECENT IMPROVEMENTS IN ACCESS TO
INSULIN.
IT'S IMPORTANT THAT WE CARRY OUT
THIS CONVERSATION IN ALL ASPECTS
OF DIABETES CARE.
CURRENTLY ABOUT 30% OF PEOPLE
WITH TYPE 1 HAVE ACCESS TO
CGMs, MEANING THAT THE VAST
MAJORITY DO NOT.
THOSE WHO PERHAPS NEED CGMs
THE MOST INCLUDING ADOLESCENTS,
MINORITY GROUPS, AND THOSE OF
LOWER SOCIOECONOMIC STATUS WHO
ON AVERAGE TEND TO HAVE HIGHER
A1C LEVELS AND INCREASED RATES
OF DKA AND HYPOGLYCEMIA ARE ALSO
THOSE WHO HAVE THE LOWEST RATES
OF CGM USE.
CURRENTLY THE NUMBER ONE BARRIER
TO CGM USE IS COST AND INSURANCE
COVERAGE.
NOT ALL STATES' MEDICAID
CURRENTLY COVER CGMs, AND FOR
THOSE WHO DO, THERE'S OFTEN AN
EXTENSIVE PROCESS TO PROVE
MEDICAL NEED.
FOR THOSE WHO DO HAVE INSURANCE
LIVING 133% ABOVE POVERTY LEVEL,
THEY OFTEN PAY HUNDREDS OF
DOLLARS OUT OF POCKET.
THIS CAN BE ANYWHERE FROM 200 TO
$500 A MONTH.
WHICH IS SIMPLY NOT POSSIBLE FOR
MOST FAMILIES.
HOWEVER, STUDIES HAVE SHOWN OVER
AND OVER AGAIN
COST-EFFECTIVENESS EVEN WHEN
ACCOUNTING FOR ONLY A FEW COST
SAVING VARIABLES, SUCH AS
ADMISSION TO THE HOSPITAL FROM
DKA, BUT THEY'RE NOT COUNTING
ALL OF THE COST SAVING
VARIABLES.
THERE'S ALSO ADDITIONAL BARRIERS
TO CGM ACCESS IN THE FORM OF THE
WAY THAT PROVIDERS OFFER CGMs
TO PATIENTS.
AS WELL AS THE WAY THAT CGMs
ARE PERCEIVED BY INDIVIDUAL
PATIENTS, WHICH IS A CURRENT
AREA OF STUDY HERE AT BOSTON
CHILDREN'S THAT WE'RE TRYING TO
ELUCIDATE FURTHER.
FINALLY, THE LAST STEP OF
MARATHON TRAINING IS BUILDING
ENDURANCE.
AND THIS IS NOT NECESSARILY JUST
PHYSICAL ENDURANCE BUT ALSO THE
MENTAL ENDURANCE TO KEEP GOING.
WHEN YOU'RE TRAINING FOR A
MARATHON, THERE ARE MANY DAYS
WHERE YOU WAKE UP AND YOU SIMPLY
DON'T WANT TO RUN.
IT'S DARK OUTSIDE, IT'S COLD,
ESPECIALLY HERE IN BOSTON, AND
YOU JUST NEED TO FIND STRATEGIES
TO KEEP GOING ONE MORE DAY.
THERE'S MANY WAYS THAT WE CAN DO
THIS.
IN DIABETES, SIMILARLY, WE CAN
FACE BURNOUT, BUT WE CAN EMPLOY
STRATEGIES TO, AGAIN, KEEP GOING
AND JUST TAKE IT ONE DAY AT A
TIME.
ONE STRATEGY IS LEANING IN TO
THE SUPPORT FROM THOSE O ON THE
SIDELINES.
IF YOU'RE SUPPORTING SOMEONE
WITH TYPE 1, IT REALLY HELPS TO
LISTEN, ENCOURAGE, LEND
PERSPECTIVE, ADVOCATE, AND OFFER
INSPIRATION, WHICH CAN COME FROM
ANYONE AT ANY TIME.
NEXT, WE CAN SHARE THE RACE WITH
OTHER PEOPLE WHO ARE IN A
SIMILAR SITUATION.
HAVING CAMARADERIE IS INCREDIBLY
HELPFUL IN BOTH SHARING
CHALLENGES AND FINDING
SOLUTIONS.
AND THIS MEANS GETTING INVOLVED
IN THE DIABETES COMMUNITY AND
GIVING BACK, WHICH WILL CIRCLE
AROU -- WHICHWE'LL CIRCLE AROUNN
A SECOND.
AND FINALLY, AGAIN, TRYING TO
BUILD MENTAL STRENGTH, WHICH IS
JUST AS MUCH A SKILL AS BUILDING
PHYSICAL STRENGTH AND SOMETHING
THAT NEEDS TO BE PRACTICED DAI
DAILY.
THIS INCLUDES PRACTICING A
PROBLEM-SOLVING MINDSET, AS WELL
AS GRATITUDE, ESPECIALLY IN THE
CONTEXT OF THE INCREDIBLE
CHANGES THAT HAVE NOT ONLY
HAPPENED IN THE LAST 20 YEARS,
BUT AS WIN ALLUDED TO AT THE
BEGINNING OF THIS LECTURE, HAVE
HAPPENED IN THE PAST HUNDRED
YEARS.
AND THE FACT THAT WE'RE ABLE TO
MANAGE DIABETES AT ALL AND LIVE
WITH THIS DISEASE IS AN
INCREDIBLE BLESSING.
ALSO REMEMBERING OUR WINS, EVEN
THE SMALL ONES.
TRANSIENCE.
THAT GOOD OR BAD, SITUATIONS ARE
NOT PERMANENT.
KINDNESS TO OUR FUTURE SELVES,
ALL THE BENEFIT THAT WE'RE
RECEIVING BY WORKING SO HARD,
AND JUST TRYING TO BE 1% BETTER
EVERY SINGLE DAY, NOT TRYING TO
CHANGE TOO MUCH TOO SOON.
GIVING BACK IS ESPECIALLY
IMPORTANT.
I FIND THAT A LOT OF PEOPLE IN
THE DIABETES COMMUNITY WANT TO
FIND MEANING IN THEIR
EXPERIENCES, AND I BELIEVE
THAT'S WHY SO MANY PEOPLE WITH
DIABETES BECOME PART OF
HEALTHCARE PROFESSIONS.
FINALLY, IF THIS LIFE WITH
DIABETES IS A MARATHON, WE CAN
CREATE A BETTER RACE THROUGH
INNOVATION, PATIENT CARE, AND
ADVOCACY.
INNOVATION TO CONTINUE TO FIND
BETTER TREATMENTS, AND IMPROVE
QUALITY OF LIFE, PATIENT CARE,
ALWAYS GETTING TO KNOW A PATIENT
AND THEIR VALUES BEFORE THEIR
ILLNESS, AND FINALLY, ADVOCACY.
SHARING DATA AND STORIES, SO
THAT WE WORK IN A HEALTHCARE
SYSTEM WHERE INNOVATION AND
PATIENT CARE CAN BE USED TO
THEIR UTMOST EFFECT.
AND THANK YOU TO EVERYONE IN
THIS AUDIENCE WHO ARE WORKING IN
THESE DOMAINS TO CREATE A BETTER
RACE FOR THOSE LIVING WITH
DIABETES TODAY AND THOSE WHO
LIVE WITH IT IN THE FUTURE.
HERE ARE MY REFERENCES.
AND THANK YOU SO MUCH AGAIN FOR
YOUR ATTENTION AND FOR ATTENDING
THIS LECTURE.
IF YOU HAVE ANY REMAINING
QUESTIONS AFTER THE END OF THIS
TALK, I CAN BE REACHED AT
COURTNEY.DUCKWORTH AT
CHILDREN'S.HARVARD.EDU.
THANK YOU.
>>THANK YOU, THANK YOU VERY
MUCH, COURTNEY, FOR REALLY AN
EXCELLENT, INSPIRING AND
INFORMATIVE.
NOW WE'RE GOING TO MOVE TO THE
OTHER SIDE OF THE BRIDGE.
AND WELCOME DOUG MELTON, WHO
WILL BE WITH US IN A MOMENT.
AS SOON AS THE ELECTRONICS ARE
CONNECTED, FOR HIS VIDEO
PRESENTATION.
>>HELLO.
MY NAME IS DOUG MELTON, AND I'M
HAPPY TO TALK TO YOU THIS
AFTERNOON ABOUT TYPE 1 DIABETES
AND STEM CELLS.
I'M ESPECIALLY GRATEFUL TO
DR. WIN ARIAS AND DRS. COURTNEY
DUCKWORTH, WHO ARE JOINING ME IN
TODAY'S PRESENTATION ON
DEMYSTIFYING MEDICINE.
I'LL SHARE MY SCREEN AND THEN
SPEAK FOR ABOUT A HALF AN HOUR
ABOUT THIS PROJECT.
SO WHAT YOU CAN SEE HERE THEN IN
MY FIRST SLIDE IS I'M GOING TO
TALK TO YOU TODAY ABOUT CELLS AS
LIVING MEDICINES, A NEW APPROACH
TO TREAT TYPE 1 DIABETES.
AS IT SAYS HERE ON THIS SLIDE,
I'M NOW A FELLOW, A RESEARCH
FELLOW AT VERTEX
PHARMACEUTICALS.
I'M ON LEAVE FROM HARVARD
UNIVERSITY.
BUT I'M A FULL TIME EMPLOYEE OF
VERTEX, AND, THEREFORE, I WANT
TO SHOW THIS DISCLAIMER.
WHAT YOU SEE HERE IS THAT I AM
AN EMPLOYEE, I OWN SOME STOCK,
AND THIS WILL BE RELEVANT AT THE
END, NOT THE BEGINNING, OF MY
TALK.
THE BEGINNING OF MY TALK, I'M
GOING TO FOCUS ENTIRELY ON WORK
DONE FOR MANY YEARS AT HARVARD
UNIVERSITY, AND THIS IS A
RESEARCH PROJECT AND IT WON'T BE
UNTIL THE END WHERE I'LL MAKE
CLEAR THINGS THAT HAVE BEEN DONE
AT VERTEX.
SO IF I CAN ADVANCE THE SLIDES
HERE.
I DON'T PROBABLY NEED TO REMIND
THIS AUDIENCE THAT FOR MORE THAN
100 YEARS NOW, DIABETES,
PARTICULARLY TYPE 1 DIABETES AND
AUTOIMMUNE DISEASE, HAS BEEN
TREATED BY THE INJECTION OF
INSULIN.
THIS REQUIRES PATIENTS MOB TORE
TMONITORTHEIR BLOOD SUGARS.
AS SHOWN HERE, IT'S BEING
MONITORED IN TWO WAY, ONE WITH A
FINGER PRICK AND A LITTLE DROP
OF BLOOD TO MEASURE ON THEIR
MONITOR, OR WITH A CONTINUOUS
GLUCOSE MONITOR SHOWN AT THE
BOTTOM RIGHT.
AND THEN INSULIN IN RESPONSE TO
THOSE BLOOD GLUCOSE MEASUREMENTS
IS INJECTED WITH SYRINGES RE ATE
BOTTOM LEFT OR AN INSULIN PUMP.
WHAT I WANT TO POINT OUT HERE IS
THAT WHILE THERE HAVE BEEN VAST
IMPROVEMENTS IN MEASURING BLOOD
GLUCOSE LEVELS AND PROVIDING
INSULIN BY MECHANICAL MEANS,
FUNDAMENTALLY, IT'S BEEN THE
SAME APPROACH FOR MORE THAN A
HUNDRED YEARS.
NAMELY, FIGURE OUT YOUR BLOOD
SUGAR, ADJUST YOUR MEALS AND
YOUR EXERCISE, AND THEN INJECT A
BOLUS OF INSULIN TO TRY TO
CONTROL YOUR BLOOD SUGARS AND
KEEP THEM WITHIN A NORMAL RANGE.
BY RANGE, I MEAN A RANGE OF
BLOOD GLUCOSE LEVEL IN THE
BLOOD, BECAUSE TOO LOW BLOOD
GLUCOSE WILL LEAD TO PROBLEMS AS
WELL AS TOO HIGH, SO THERE'S
HYPOGLYCEMIA, WHICH CAN LEAD TO
UNCONSCIOUSNESS AND OTHER SEVERE
PROBLEMS, AND TO HIGH BLOOD
SUGARS, WHICH LEADS TO THE
COMPLICATIONS THAT ARE WELL
DOCUMENTED IN THE TREATMENT OF
DIABETES.
I'M GOING TO PRESENT TODAY AN
IDEA THAT THERE MAY BE A BETTER
WAY TO DO THIS, NAMELY, REPLACE
THE MISSING BETA CELLS.
YOU CAN SEE HERE THAT BETA CELLS
READ BLOOD GLUCOSE EVERY
MILLISECOND, AND THEY RELEASE
JUST THE RIGHT AMOUNT OF INSULIN
TO CONTROL GLUCOSE UPTAKE.
AND I PUT THOSE SIMPLE FACTS
THERE TO CONTRAST THEM WITH
WHAT'S DONE BY TRYING TO ADJUST
BLOOD GLUCOSE LEVELS
MECHANICALLY.
BLOOD GLUCOSE MONITORS IN THE
BEST CASES READ INTERSTITIAL
BLOOD GLUCOSE LEVELS ABOUT EVERY
FIVE MINUTES, WHICH WOULD MEAN
5,000 TIMES OR ABOUT 3,000 TIMES
LESS FREQUENTLY THAN A BETA
CELL.
SIMILARLY, AN INSULIN PUMP
INJECTS A LARGE AMOUNT OF
INSULIN TO CONTROL GLUCOSE
UPTAKE, WHEREAS THE BETA CELL
SQUEAKS OUT OR SECRETES JUST THE
RIGHT AMOUNT CONSTANTLY TO
CONTROL BLOOD GLUCOSE LEVELS.
SO THIS MAKES IT PRETTY OBVIOUS
THAT WHAT ONE WOULD WANT TO DO
MAYBE IS TO TRY A DIFFERENT
APPROACH, AND WHILE THIS SLIDE
MIGHT SEEM RATHER SIMPLE-MINDED,
IT IS ADMITTEDLY HOW I THINK
ABOUT THE PROBLEM.
THE CHALLENGES FOR TYPE
1 DIABETES ARE TWOFOLD.
THERE'S THE LOSS OF BETA CELLS
MAKING THE PATIENT
INSULIN-DEPENDENT, AND THERE'S
AN AUTOIMMUNE ATTACK, WHICH IS
THE PRIMARY CAUSE OF THE LOSS OF
THE BETA CELLS.
AND SO ONE WAY TO THINK ABOUT
THIS IS COULD WE DISCOVER AND
DEVELOP REPLACEMENT BETA CELLS?
I'M GOING TO FOCUS MOST OF MY
TALK ON THAT TODAY.
AND THEN SECONDLY, IF ONE IS
ABLE TO SOLVE THE FIRST HALF OF
THE PROBLEM, WHAT WOULD WE DO
ABOUT AUTOIMMUNE ATTACK OF BETA
CELLS?
HERE I'LL TALK ABOUT AN APPROACH
TO MODULATE THE IMMUNE ATTACK TO
REDUCE TOLERANCE TO THE STEM
CELL DERIVED ISLETS.
AS A DISCLAIMER AT THE
BEGINNING, I'LL TELL YOU WE'VE
COME QUITE A LONG WAY ON NUMBER
ONE AND WE'RE JUST STARTING ON
NUMBER TWO.
SO OUR APPROACH TO THE FIRST
PROBLEM, THE ABSENCE OF
PANCREATIC INSULIN PRODUCING
BETA CELLS, WAS TO TRY TO
RECAPITULATE WHAT HAPPENS IN
NORMAL DEVELOPMENT, AND TO DO
THAT IN VITRO, USING EMBRYONIC
OR PLURIPOTENT STEM CELLS.
AS MANY WELL KNOW, EMBRY OH TICK
OR PLUR POTENT STEM CELLS SHOWN
HERE, INFORM IN PRINCIPLE ANY
CELL TYPE IN THE BODY, AND SO IT
SEEMED OBVIOUS THAT WHAT ONE
WOULD TRY TO DO IS TO INSTRUCT
THOSE CELLS TO BECOME FULLY
FUNCTIONAL PANCREATIC BETA CELLS
SHOWN HERE ON THE FAR RIGHT IN
PURPLE, AS A BETA.
SO THE IDEA HERE IS TO REPEAT
WHAT HAPPENS IN NORMAL
DEVELOPMENT BUT OF COURSE DO IT
IN HUMAN CELLS OUTSIDE THE BODY.
AND I MIGHT NOTE THAT MY LAB
MAKES FUN OF ME BECAUSE THIS
SKITTLE DIAGRAM AS IT'S KNOWN
HAS BEEN SHOWN FOR MANY YEARS.
WE FIRST TELL THE CELLS HOW TO
BECOME DEFINITIVE ENDODERM, DE,
THEN TELL THEM -- THEN
PANCREATIC PROGENITORS OF TWO
FORMS, THEN FINALLY AN ENDOCRINE
PROGENITOR SHOWN HERE AS EN, AND
LASTLY, THE PANCREATIC BETA
CELL.
A COUPLE THINGS I'D LIKE TO SAY
HERE.
FIRST OF ALL, YOU CAN SEE THAT
THIS TAKES MANY DAYS, SEVERAL
WEEKS, IN ORDER TO DO THIS, AND
THERE ARE DIFFERENT FACTORS
ADDED AT EACH STAGE.
SO IN SOME SENSE, I COULD
SUMMARIZE IT BY SAYING ONE HAD
TO JUST FIGURE OUT WHICH FACTORS
TO ADD AT WHICH CONCENTRATION AT
WHAT TIME IN ORDER TO ACHIEVE
THIS GOAL, AND NAIVELY, I
THOUGHT WHEN WE BEGAN THIS, THIS
WOULD BE RELATIVELY
STRAIGHTFORWARD.
IT TURNED OUT TO BE MUCH MORE
DIFFICULT THAN I THOUGHT IT WAS,
OR THOUGHT IT WOULD BE.
I THINK IT'S FAIR TO SAY THAT
IT'S NOT SO COMPLICATED TO TURN
PLPLURIPOTENT STEM CELLS INTO
NEURONS.
THE PARTICULAR TYPE OF NEURON
ONE WANTS TO MAKE, BECAUSE, OF
COURSE, SPECIFIC ADJUSTMENTS.
IT'S ALSO BEEN DEMONSTRATED TO
MAKE CARDIOMYOCYTES.
IT JUST REQUIRES MANY MORE
SIGNALS.
AND THIS SLIDE HERE SUMMARIZES
MORE THAN 15 YEARS OF RESULTS
WITH ABOUT 50 STUDENTS AND
POSTDOCS, WHO I'M GLAD TO SAY
JOINED IN ON THIS PROJECT TO
HELP MAKE THIS POSSIBLE.
ON THE BOTTOM LEFT, YOU SEE WHAT
OUR TARGET GOAL WAS, IS ORGAN
DONOR ISLETS, AND THEY'RE
STAINED WITH TWO MARKERS,
INSULIN, THE GOAL BEING STAINED
IN THE CYTOPLASM AS GREEN AND
THE RED IMPORTANT TRANSCRIPTION
FACTOR IN RED STAINING IN THE
NUCLEUS.
ON THE RIGHT, WHERE IT SAYS
SC-BETA, THAT'S FOR STEM CELL
DERIVED ISLETS FOR BETA CELLS,
YOU SEE WHAT AT THIS LEVEL A
RESOLUTION LOOKS TO BE
INDISTINGUISHABLE FROM THE ORGAN
DONOR ISLETS.
THE IMPORTANT TRANSCRIPTION
FACTOR IS EXPRESSED IN THE
NUCLEUS AND THE INSULIN IN THE
CYTOPLASM.
YOU MIGHT SAY A BIT MORE THIS
TRANSCRIPTION FACTOR IS KNOWN TO
BE ABSOLUTELY REQUIRED FOR BETA
CELL DEVELOPMENT, INDEED IT'S
REQUIRED FOR PANCREATIC
DEVELOPMENT, AND THAT'S WHY WE
USED IT AS ONE OF THE MARKERS TO
TELL US GOING ALONG EACH STAGE
HERE, HOW FAR WE WERE GETTING.
NOW THE RESULT OF THIS WAS WE
MADE THESE CELLS, THESE CLUSTERS
OF CELLS IN A SPINNER FLASK IN
THREE DIMENSIONS, AND WE WERE
ABLE TO MAKE CLUSTERS THAT ARE
NOT ONLY HOMO GENIUS IN CELL
COMPOSITION BUT THEY WERE THE
SAME SIZE AT HUMAN ISLETS.
SO HERE YOU SEE A CONFOCAL IMAGE
THROUGH A SLICE OF THE CLUSTERS,
AND THIS IS A TYPICAL EXAMPLE OF
WHAT WE WERE ABLE TO ACHIEVE AT
THE BEGINNING, WHICH IS ABOUT
16 1/2% IT SHOWS HERE OF THE
CELLS WHE WERE THE CELLS WE WAN,
THAT IS, THE PANCREATIC BETA
CELLS.
I'LL SHOW YOU IN A FEW MINUTES
THAT THE OTHER CELLS ARE OTHER
ENDOCRINE CELLS AND SOME CELLS
WE DIDN'T WANT, BUT OUR GOAL
INITIALLY WAS TO MAKE INSULIN
PRODUCING CELLS SHOWN HERE BY C
PEPTIDE PROTEIN AND THE
TRANSCRIPTION FACTOR NKX6.1,
WHICH IS SPECIALIZED IN THE BETA
CELL IN HUMANS.
I COULD SHOW YOU A LOT OF
MOLECULAR DETAIL AND WE'LL COME
TO THAT LATER.
BUT THE QUESTION WOULD BE USING
MOLECULAR AND CELL BIOLOGY AND
HISTOLOGY, DID WE REALLY MAKE A
FUNCTIONAL BETA CELL.
AND INSTEAD OF JUST SHOWING YOU
A LOT OF TRANSCRIPTIONAL DATA, I
LIKE THIS KIND OF OLD-FASHIONED
METHOD WHICH IS A TRANSMISSION
EM PICTURE.
FOR THOSE WHO HAVE STUDIED CELL
BIOLOGY, YOU'LL REMEMBER THAT
THE BETA CELL IS WELL-KNOWN,
CONTAINING VACUOLES THAT HAVE
CRYSTALLIZED INSULIN IN THEM.
YOU SEE THAT HERE ON THE UPPER
RIGHT, WHERE YOU SEE A SINGLE
VACUOLE WITH A CRYSTALLIZED
INSULIN COMPLEX.
IT'S A ZINC KRAIS CRIST TALLIZED
WITH MANY MOLECULES OF
CRYSTALLINE.
ON THE BOTTOM YOU SEE OUR STEM
CELL DERIVED BETA SELL, LOOKS TO
BE INDISTINGUISHABLE, AGAIN,
VACUOLES WITH CRYSTALLIZED
INSULIN.
MY POINT IN SHOWING THIS SLIDE
IS THAT IN ORDER FOR A CELL TO
MAKE THESE STRUCTURES, THE
PLURIPOTENT STEM CELL HAD TO
TURN ON AND TURN OFF THOUSANDS
OF GENES TO GET TO THIS POINT.
AND YOU CAN'T MAKE THESE
STRUCTURES IF YOU ARE ONLY HALF
OF A BETA CELL, OR IF YOU'RE A
MIXED UP CELL MAKING OTHER KINDS
OF THINGS.
WELL, IN ADDITION TO, LET'S SAY,
THE ANATOMY, THE HISTOLOGY OF
THE CELLS, LET'S HAVE A LOOK AT
FUNCTION.
THIS IS ONE OF THE FIRST
EXAMPLES THAT LED US TO BELIEVE
THAT WE WERE SUCCESSFUL, AND
THAT IS, WE SHOW THAT IN VITRO,
WE COULD OBTAIN SEQUENTIAL HUMAN
INSULIN SECRETION FOLLOWING
GLUCOSE CHALLENGES.
I'LL EXPLAIN THIS BY FOCUSING ON
THE GRAPH HERE ON THE LEFT, THIS
HISTOGRAM.
ON THE Y AXIS IS THE AMOUNT OF
HUMAN INSULIN BEING SECRETED AND
ON THE X AXIS ARE THREE
SEQUENTIAL CHALLENGES WITH
GLUCOSE.
I SOMETIMES LIKE TO JOKE AND
DESCRIBE THIS AS LIKE BREAKFAST,
LUNCH AND DINNER.
THERE'S 2 MILLIMOLAR OF GLUCOSE
FOLLOWED BY 20.
2 MILLIMOLAR, 20.
AND THEN DEPOLARIZATION OF THE
MEMBRANE WITH POTASSIUM
CHLORIDE.
YOU SEE IN EACH SEQUENTIAL
TREATMENT, WE'RE OBSERVING AN
INCREASE IN INSULIN SECRETION,
WHICH IS WHAT WOULD HAPPEN IN A
PATIENT'S PANCREAS IF THEY DID
NOT HAVE TYPE 1 DIABETES.
SO A CONTROL PATIENT.
IN THE MIDDLE OF IS A CONTROL
DIFFERENTIATION.
I WON'T TALK MUCH ABOUT THIS BUT
THESE WERE THE CELLS THAT HAD
BEEN WORKED ON BY OTHERS, AND
THE MAIN POINT BEING THAT THOSE
PROGENITOR CELLS WERE NOT
CAPABLE OF THIS KIND OF
SEQUENTIAL SECRETION OF INSULIN.
ON THE FAR RIGHT ARE ISLETS
KNOWN TO BE ABLE TO CONTROL
BLOOD SUGARS WHEN TRANSPLANTED
INTO TYPE 1 DIABETICS ALONG WITH
IMMUNOSUPPRESSION, AND YOU SEE
HERE AGAIN THE SEQUENTIAL
SECRETION OF INSULIN.
THIS WAS A GOOD PREPARATION OF
THE CAT VAIRK ISLETS BUT THEY
VARY QUITE A BIT AS YOU WOULD
EXPECT, SINCE THEY HAVE TO COME
FROM A CADAVER AND HAVE TO BE
ENZYMATICALLY OBTAINED BY -- THE
PANCREAS THROUGH A COMPLEX
PROCEDURE.
HERE IS A SLIDE I LIKE TO SHOW
FOR A COUPLE OF REASONS.
ONE IS IT SHOWS THE TOTAL MASS
OR VOLUME OF ISLETS FOUND IN A
PERSON WITH TYPE 1 DIABETES.
SAID ANOTHER WAY, THESE ARE
HUMAN ISLETS MADE FROM STEM
CELLS.
THE ISLETS HAVE BEEN STAINED
DARK BLUE FOR INSULIN, SO IT
LOOKS AS IF EVERY CELL IN THOSE
DOTS IS AN INSULIN CELL.
THAT'S NOT TRUE AS I SHOWED YOU
BEFORE, ONLY A PORTION OF THOSE
CELLS ARE, BUT THIS STAIN IS SO
STRONG, THE INSULIN SIZE
CLUSTERS ALL LOOK DARK BLUE.
EACH DOT THERE CONTAINS ABOUT
5 TO 10,000 CELLS, AND THE TOTAL
NUMBER OF BETA CELLS IN THAT
VIAL IS WHAT IT WOULD TAKE TO
TREAT EFFECTIVELY A TYPE
1 DIABETIC BY OUR CALCULATIONS.
AND SO THIS IS JUST TO GIVE YOU
AN IDEA OF THIS SIZE OF THE
CELLS YOU COULD SAY WHICH CAUSE
SO MUCH TROUBLE.
I HAVEN'T TALKED TODAY A LOT
ABOUT HOW MUCH TROUBLE THEY
CAUSE, YOU'LL HEAR MORE ABOUT
THAT FROM DR. DUCKWORTH, BUT LET
ME JUST SAY THAT FROM WHAT I
UNDERSTAND THIS YEAR IN 2023,
ABOUT $30 BILLION WILL BE SPENT
INJECTING INSULIN AND
CONTROLLING BLOOD GLUCOSE REALLY
BECAUSE OF THE DEFICIENCY IN
THOSE CELLS.
SO THAT'S REALLY TAKING IT FROM
A KIND OF DEVELOPMENTAL BIOLOGY
PERSPECTIVE TO THE EFFECT IT HAS
ON PATIENTS.
SO WE'VE BEEN ABLE TO MAKE STEM
CELL DERIVED ISLETS.
WE'RE GOING TO SPEND THE NEXT
FEW MINUTES ON WHAT'S NEXT.
AGAIN I WANT TO EMPHASIZE THE
EXPERIMENTS I'VE SHOWN YOU THUS
FAR AND WHAT I'LL SHOW YOU NOW
WERE DONE WITH A RESEARCH GRADE
CELL LINE DONE AT HARVARD.
THESE ARE NOT THE CELLS THAT
I'LL DESCRIBE LATER THAT VERTEX
USES IN THEIR CLINICAL TRIALS.
SO SORRY.
WHAT I WANT TO TALK ABOUT THEN
IS, COULD WE GET COMPLETE
CONTROL OR MASTERY OVER THE CELL
COMPOSITION OF THESE IN VITRO
DERIVED CELLS, AND THEN WHAT ARE
WE GOING TO DO ABOUT WHAT I SEE
AS THE NEED TO ELIMINATE THIS
REQUIREMENT SO FAR OF SYSTEMIC
IMMUNE SUPPRESSION.
I'LL COME BACK TO THE IMMUNE
SUPPRESSION PROBLEM IN A MOMENT.
SO FIRST THING WE DID, AND I'M
GOING TO SHOW THIS BECAUSE IT
DIDN'T PRODUCE THE RESULT I
WANTED, WAS TO SAY BECAUSE WE
MAKE THESE CELLS IN VITRO, COULD
WE DO A DEEP DIVE INTO ALL OF
THE TRANS KRIPTIONAL CHANGES AND
THE CHROMATIN CHANGES THAT OCCUR
FROM THE DEVELOPMENT OF A
PLURIPOTENT STEM CELL SHOWN HERE
ON THE LEFT ALL THE WAY TO A
STEM CELL DERIVED BETA CELL, AND
COMPARE THAT TO WHAT I CALL
PRIMARY OR CADAVERIC ALPHA AND
BETA CELLS, ALPHA CELLS BEING
THOSE PRODUCING GLUCAGON AND THE
BETA CELLS PRODUCING INSULIN.
SO WE PREPARED MANY TIMES THIS
IN VITRO DIFFERENTIATION, AND
THEN STUDIED CHROMATIN CHANGES
LOOKING AT CHANGES IN HISTONE
MODIFICATIONS USING ATTACK SEQ,
LOOKING AT DNA METHYLATION, AND
THEN WE DID TRANSCRIPTIONAL
CHANGES USING SINGLE CELL
SEQUENCING.
THAT'S QUITE COMMON NOW.
WHEN WE DID THIS, IT WAS JUST AT
THE BEGINNING OF THIS SO WE USE
THE A TECHNIQUE CALLED SINGLE
CELL SEQUENCING, AND WE DID THIS
FOR A COUPLE OF REASONS.
ONE IS I THINK IT'S IMPORTANT TO
KNOW AS MUCH AS ONE CAN ABOUT --
YOU COULD CALL IT THE DRUG
PRODUCT OF THE THING WE WANT AT
THE END.
BUT FRANKLY, THE MAIN REASON WE
DID IT WAS I WAS HOPING THAT WE
WOULD DISCOVER SIGNALING
MOLECULES OR RECEPTORS AT
VARIOUS STAGES, WHICH WOULD GIVE
US GREATER CONTROL OVER THE
PROCESS.
THIS WAS A VERY DIFFICULT,
EXPENSIVE AND TIME-CONSUMING
EXPERIMENT, AND FRANKLY IT
PRODUCED INTEREST IN INFORMATION
BUT IT DID NOT PRODUCE WHAT I
WANTED, WHICH WAS SON IMPORTANT
NEW CLUES ABOUT HOW TO BETTER
CONTROL THE PROCESS.
LET'S LOOK AT THE POSITIVE AND
SEE WHAT WE DID LEARN FROM IT.
FIRST IMPORTANT THING WE LEARNED
BY DOING SINGLE CELL SEQUENCING
IS THAT THERE WERE THE CELLS WE
WANTED, BUT THERE WERE ALSO
SURPRISING CELLS WHICH WE DIDN'T
WANT.
SO LET ME DESCRIBE THIS
PRESENTATION HERE TO YOU NOW.
THIS IS AT THE END OF OUR
PROCESS, WHAT WE CALLED STAGE 6,
AND WE'RE LOOKING AT 37,000
CELLS IN THOSE CLUSTERS THAT I
SHOWED YOU ALREADY.
THIS IS A SO-CALLED TSNE PLOT,
STATISTICAL REPRESENTATION OF
THE DATA, AND THE CELLS WE
WANTED ARE SHOWN HERE IN PURPLE.
THEY'RE IN THE MIDDLE.
I LIKE TO SHOW THIS PLOT BECAUSE
YOU CAN SHOW THESE PLOTS KIND OF
BY MANIPULATING THE PRESENTATION
IN A NUMBER OF WAYS.
I LIKE THIS ONE BECAUSE I THINK
IT LOOKS LIKE A LOBSTER, AND
SINCE I LIVE IN BOSTON AND I
LIKE LOBSTER, I CHOSE THIS WAY
TO SHOW YOU THE DATA.
HERE YOU SEE IN PURR PULL THE
CELLS WE WANTED.
THEY'RE STEM CELL DERIVED BETA
CELLS.
IN RED ARE OTHER CELLS WE DIDN'T
AIM FOR BUT WE WERE HAPPY TO
FIND.
THESE ARE STEM CELL DERIVED
ALPHA CELLS.
THE CELLS THAT MAKE GLUCAGON, AS
I'VE SAID THE -- REGULATORY
HORMONE.
BEFORE I GET TO THE SURPRISE,
THE BROWN CELLS WERE
PROGENITORS, WE WEREN'T
SURPRISED TO LEARN THAT NOT ALL
OF THE CELLS RECEIVED THE
INSTRUCTIONS THE WAY WE WANTED.
AND THEN THERE WERE SOME
NON-ENDOCRINE CELLS, CELLS WHICH
DIDN'T BECOME ENDOCRINE.
THE BIG SURPRISE WERE THESE BLUE
CELLS HERE ON THE BOTTOM RIGHT,
ENTEAR A CHROMAFFIN CELLS.
THESE SECRETE SA SEROTONIN IN TE
GUT.
THEY'RE NORMALLY FOUND IN THE
GUT BUT THEY ARE NOT FOUND IN
ADULT PANCREATIC ISLETS.
THERE ARE A COUPLE OF
PUBLICATIONS SUGGESTING, WITH
EVIDENCE, THAT THOSE CELLS ARE
FOUND DURING FETAL DEVELOPMENT
IN THE PANCREAS, BUT EVERYONE
AGREES THEY ARE NOT FOUND IN THE
ADULT ISLET AND THEY'RE NOT A
CELL WE REALLY WANT TO HAVE IN
OUR END PRODUCT.
ON THE BOTTOM, IT SHOWS YOU THE
KIND OF POPULATION RATIOS.
YOU MIGHT REMEMBER AT THE
BEGINNING THERE WAS ABOUT 16%
BETA CELLS, THAT'S PROBABLY
CLOSE TO WHAT WE GOT HERE AS WE
WERE IMPROVING THE PROTOCOL, SO
IT'S THESE PURPLE AND RED CELLS
THAT ARE THE ONES WE WANT WHICH
MAKE UP MORE THAN, SAY, 50% OF
THE TOTAL.
BUT THESE ENTERIC CHROMAFFIN
CELLS AND THE OTHER ONES ARE
ONES WE DON'T WANT.
SO ONE OTHER THING WE LEARNED
FROM THIS KIND OF SINGLE CELL
ANALYSIS, WHICH I SUPPOSE WE
COULD HAVE THOUGHT OF AHEAD OF
TIME BUT FRANKLY WE DIDN'T, IT
WAS KIND OF AN INTERESTING
OUTCOME OF THE RESULTS, WAS THAT
WHEN WE LOOKED AT ALL OF THE
GENES EXPRESSED, WE FOUND THAT
THE CELLS WERE EXPRESSING ALL OF
THE GENES FOR THE CIRCADIAN
CLOCK.
THAT IS, ALL OF THE CELLS HAD
THEIR CIRCADIAN CLOCK GENES ON
AND WERE ON A CIRCADIAN RHYTHM.
BUT WHAT WE NOTICED, OF COURSE,
WAS -- AND NOT SURPRISINGLY --
THEY WERE NOT ALL KIND OF
STARTING AT THE SAME TIME.
THEY WERE ALL KIND OF MARCHI
MARCHING -- SOMETHING LIKE AT A
FOOTBALL GAME, YOU THINK OF A
HALF TIME, THE MARCHING BAND,
EVERYONE STARTS AT THE SAME TIME
AND THEN MARCHES AND PLAYS IN
STEP.
WELL IN THIS CASE, IT WOULD BE
LIKE IF ALL THE FOOTBALL
PLAYERS -- SORRY, IF ALL OF THE
BAND MEMBERS WERE LISTENING TO
MUSIC THAT STARTED AT A
DIFFERENT TIME, WHILE THEY WERE
MARCHING, THEY WERE COMPLETELY
UNSYNCHRONIZED.
I DON'T KNOW IF THAT HELPS
DESCRIBE THIS EXPERIMENT, BUT
THAT'S SORT OF ONE WAY TO THINK
ABOUT IT.
SO WHAT WE LOOKED AT THEN, IF I
CAN DRAWL YOUR ATTENTION TO THE
BOTTOM LEFT, IS GLUCOSE
STIMULATED INSULIN SECRETION,
AND IN GREY BARS ARE WHAT I
SHOWED YOU EARLIER, WHICH IS
OVER SEVERAL DAYS, THESE CELLS
ARE SECRETE INSULIN RESPONSE TO
GLUCOSE WITH THAT STIMULATION
INDENTION OF ABOUT 1 OR 2.
BUT IF WE SYNCHRONIZE THE CELLS
AS SHOWN HERE IN RED, AND WE DID
THAT BY GIVING THEM SHOCKS AND
ALLOWING THEM TO RECOVER OVER A
THREE-DAY PERIOD, WE DID THIS
THREE TIMES, GIVE THEM EITHER
ARGININE, INSULIN OR GLUCOSE FOR
12 HOURS AND THEN TAKE IT AWAY,
THIS IS ALL TO KIND OF GET THEM
SYNCHRONIZED.
YOU SEE THE MUCH BETTER RESPONSE
HERE IN GLUCOSE STIMULATED
INSULIN SECRETION IN RED.
YOU SEE THE GSIS, AS IT'S
CALLED, GO FROM ABOUT 1 1/2 TO
ABOUT 3 1/2 HERE.
THIS IS VERY REMINISCENT OF WHAT
YOU SEE IN CADAVERIC ISLETS.
SO YOU SEE HERE CADAVERIC
ISLETS, WHICH HAVE OF COURSE
GROWN UP AND BEEN IN A PERSON
THAT HAD DAILY CYCLE, CIRCADIAN
CYCLE.
AND SO THIS IS, I THINK, A
GRATIFYING RESULT THAT WE CAN
TAKE THE STEM CELL DERIVED
ISLETS AND MAKE THEM WORK EVEN
BETTER IN VITRO BY SYNCHRONIZING
THEIR CIRCADIAN RHYTHM.
SO HERE'S THE CHALLENGE WE HAVE
NOW.
WE ARE ABLE TO TAKE EMBRYONIC
STEM CELLS AND TELL THEM TO
BECOME ISLET-LIKE STRUCTURES BUT
THEY DON'T HAVE ALL OF THE CELLS
WE WANT, THEY HAVE SOME CELLS WE
DON'T WANT, AND SO COULD WE GAIN
COMPLETE CONTROL OVER THE
COMPOSITION?
THE WAY I'M GOING TO DESCRIBE
DOING THAT IS TO USE GENETIC
MODIFICATION.
SO WHAT I'M SHOWING YOU HERE IN
THIS LITTLE CARTOON IS I WANT TO
USE GENETIC MODIFICATION WHICH
WOULD PREVENT THE FORMATION OF
ENTERIC -- CELLS, PREVENT THE
FORMATION OF THE NON-ENDOCRINE
CELLS, THE CELLS YOU COULD SAY
DIDN'T GET WITH THE PROGRAM, AND
THEN MAKE ONLY THESE THREE CELL
TYPES.
THAT WOULD BE THE IDEAL GOAL.
INSULIN PRODUCING CELLS,
GLUCAGON PRODUCING CELLS, AND
SOMATOSTATIN PRODUCING CELLS.
THEN WITH THIS LITTLE CARTOON
HERE, WE'RE ALSO TAKING ON THE
IDEA WITH THESE LIKE SHIELDS
THAT COULD WE MAKE CELLS WHICH
DID NOT -- WERE NOT EASILY
REMOVED BY THE PATIENT'S IMMUNE
SYSTEM.
SO LET ME PAUSE THERE AND TALK
ABOUT SOMETHING I HAVEN'T REALLY
EMPHASIZED.
I MENTIONED THAT TYPE 1 DIABETES
IS AN AUTOIMMUNE DISEASE, WHICH
MEANS THAT THE PATIENT'S IMMUNE
SYSTEM RECOGNIZES THEIR VERY OWN
BETA CELLS AND KILLS THEM.
ELIMINATES THEM.
IT DOESN'T ELIMINATE THE ALPHA
OR DELTA OR OTHER ISLET-LIKE
CELLS, JUST THE BETA CELLS.
BUT IN THIS CASE, WE ARE
PRODUCING ALLO CELLS, CELLS FROM
AN EMBRYONIC STEM CELLS OR
PLURIPOTENT STEM CELLS AND,
THEREFORE, THEY ARE NON-CELL, SO
ALL OF THE CELLS WOULD BE KILLED
IN A PATIENT'S -- A PATIENT
RECEIVING A TRANSPLANT BECAUSE
THEIR IMMUNE SYSTEM WOULD
RECOGNIZE THEM AS FOREIGN.
ANOTHER WAY TO EMPHASIZE THAT IS
THE PATIENTS WE'RE AIMING FOR
HERE NOT ONLY WOULD SEE OUR DRUG
PRODUCT AS FOREIGN BECAUSE
THEY'RE ALLO CELLS BUT THEY ALSO
HAVE AUTOIMMUNITY BECAUSE
THEY'RE PARTICULARLY INCLINED TO
RECOGNIZE THE BETA CELL.
SO BACK TO THESE EXPERIMENTS I'M
GOING TO DESCRIBE, WHAT WE WOULD
LIKE TO DO IS TO SAY COULD WE
MODIFY THE GENES IN OUR STARTING
MATERIAL SUCH THAT AS THEY GO
THROUGH THE DIFFERENTIATION
PROCESS, THERE ARE DOORS BEING
CLOSED, THEY CANNOT BECOME
ENTEROCHROMAFFIN CELLS OR
NON-ENDOCRINE CELLS.
THEY CAN ONLY, AS THEY'RE
WALKING DOWN THE HALL THE ONLY
DOORS OPEN TO THEM ARE TO BECOME
DELTA CELLS THAT MAKE
SOMATOSTATIN, ALPHA CELLS THAT
MAKE GLUCAGON OR BETA CELLS THAT
MAKE INSULIN.
THAT'S SORT OF LOGIC OF WHAT
WE'RE TRYING TO DO.
IN ADDITION, WE WANT AS I SAID
TO MODIFY GENES WHICH ARE NOT
REQUIRED FOR THE FORMATION OF
ENDOCRINE CELLS, BUT INSTEAD
MIGHT BE GENES THAT ALLOW THE
CELLS TO BE RECOGNIZED AS
FOREIGN AND, THEREFORE, KILLED
OFF BY THE PATIENT'S IMMUNE
SYSTEM.
COULD WE MAKE KIND OF OPAQUE OR
HIDDEN CELLS THAT EVADE IMMUNE
ATTACK?
SO I'M GOING TO DESCRIBE IN SOME
DETAIL HOW WE'VE GONE ABOUT
THIS.
THIS WORK HASN'T YET BEEN
PUBLISHED.
AND IT'S TAKEN US A LONG TIME TO
FIGURE OUT HOW TO DO THIS, WHICH
IS WHY I THOUGHT IT MIGHT BE
INTERESTING TO DESCRIBE IT.
ONE OF THE ADVANTAGES WE HAVE
HERE IS THAT WE GROW HUNDREDS OF
MILLIONS OF CELLS IN THESE
SPINNER FLASKS.
THIS DIAGRAM HERE, THIS CARTOON
IS INTENDED TO SHOW A KIND OF
THREE-DIMENSIONAL SPAIN SPINNER.
BECAUSE WE GROW HUNDREDS OF
MILLIONS OF CELLS, WE COULD
KNOCK OUT GENES ONE AT A TIME,
THAT IS KNOCKING OUT ONE GENE
PER CELL, AND THEN LOOK FOR THE
PHENOTYPE, THAT IS, DOES IT
AFFECT THE COMPOSITION AND THE
ABILITY OF THE CELL TO AVOID
IMMUNE ATTACK?
THIS SLIDE SHOWS HOW WE DO THAT.
WE INFECT THE STARTING MATERIAL,
THE PLURIPOTENT STEM CELLS, WITH
A LENTIVIRAL LIBRARY CONTAINING
CRISPR AND GUIDE RNAs.
IT ALSO CONTAINS A DRUG
SELECTION, SO AS SHOWN HERE WITH
THE ASTERISK, WE INFECT THE
CELLS AT A LOW MULTIPLICITY OF
INFECTION THEN SELECT WITH
PUREMYCIN SO THE ONLY CELLS THAT
SURVIVE ARE THOSE THAT HAVE
RECEIVED A GENE MODIFYING VIRUS.
WE ALLOW THE CELLS TO RECOVER,
WE THEN SEED THEM FOR
DIFFERENTIATION AND GO THROUGH
THAT SIX-STAGE PROTOCOL I
DESCRIBED AND HERE THE COLOR
CODING IS RELEVANT TO WHAT I'M
GOING TO SHOW YOU SO WE'RE NOW
LOOKING SOME 40 DAYS LATER.
PURPLE WERE THE BETA CELLS, THE
CELLS THAT WE WANT, RED ARE THE
ALPHA CELLS, THE CELLS WE WANT,
BLUE ARE THE ENTEROCHROMAFFIN
CELLS, THE CELLS WE DO NOT WANT
AND THEN GREEN HERE IS JUST
TRIPLE NEGATIVE MEANING IT'S
CELLS THAT DIDN'T RESPOND AT ALL
OR BECAME SOMETHING DIFFERENT.
WE THEN DISASSOCIATE THE
CLUSTER, STAIN FOR THESE
MARKERS, SORT OUT THE
POPULATIONS, UNDUE THE FIXATION,
AND THEN SEQUENCE THE GUIDE DNA
TO TELL US WHICH GENE WAS
KNOCKED OUT.
SO AT THE END, WE HAVE FOUR CELL
POPULATIONS, BETA, ALPHA,
ENTEROCHROMAFFIN AND TRIPLE
NEGATIVE, AND WE'RE LOOKING TO
SEE WHAT SURVIVED ALL OF THIS
PROCESS.
ONE OF THE THINGS I LIKE ABOUT
THIS APPROACH IS THAT WHEN WE
KNOCK OUT GENES THAT ARE
HOUSEKEEPING GENES LIKE FOR DNA
PRELIMINPOLYMERASE, YOU NEED THE
HOUSEKEEPING GENES TO GROW, BUT
WE'RE NOT INTERESTED IN THOSE
GENES ANYWAY.
WE'RE NOT TRYING TO KNOCK OUT
HOUSEKEEPING GENES THAT CELLS
NEED FOR LIVING.
WE'RE ONLY INTERESTED IN THOSE
THAT AFFECT DIFFERENTIATION AND
FUNCTION.
SO IN OTHER WORDS, WE GET RID OF
A LOT OF UNINTERESTING GENES
FROM THE POINT OF VIEW OF OUR
GOAL.
HERE'S HOW WE DID IT, THESE
GENETIC SCREENS.
I'M SHOWING YOU LOTS OF DETAIL
HERE MOSTLY TO CONVINCE YOU THAT
THE RESULTS I SHOW YOU ARE
LIKELY TO BE IMPORTANT AND
ACCURATE.
WE USE A LIN TEE VIRAL LIBRARY
PROVIDED BY THE BROAD INSTITUTE
WHICH EXPRESSES CAS # ALONG WITH
THE GUIDES.
THE PRIMARY GENOME-WIDE SCREEN
WAS DONE THREE TIMES, USING
19,000 TARGETS, THAT IS, FOUR
GUIDE RNAs FOR A TOTAL OF
80,000 GUIDE RNAs.
WE HAD A THOUSAND NON-TARGETING
CONTROLS AND WE DID THIS THREE
TIMES TO IDENTIFY TOP CANDIDATES
FOR RESCREENING.
WE THEN DID THE RESCREENING
AIMING AT 800 GENES WE FOUND IN
THE FIRST THREE DIFFERENTIA
DIFFERENTIATIONS, AGAIN USING
MULTIPLE TARGETS, GUIDES, SORRY,
MULTIPLE GUIDES FOR EACH GENE,
AND IMPORTANTLY, WE DID THIS 18
DIFFERENT TIMES.
SO THIS IS A VERY EXTENSIVE
EXPERIMENT THAT ALLOWED US TO
IDENTIFY 200 GENETIC
PERTURBATIONS WITH STATISTICALLY
SIGNIFICANT EFFECTS.
THE REASON WE HAD TO DO IT THIS
WAY, I'LL POINT OUT, IS THAT
WE'RE NOT USING MONOCLONAL CELL
LINES AT THIS POINT, WE'RE
LOOKING AT POPULATIONS, SO WE
HAD TO HAVE STATISTICALLY
SIGNIFICANT RESULTS IN ORDER TO
DRAW ANY CONCLUSIONS.
AND WHAT YOU SEE HERE THEN IS
TWO WAYS OF SHOWING YOU THE
CONCLUSIONS WE WERE ABLE TO
ACHIEVE.
I'M SHOWING YOU THE DATA IN TWO
DIFFERENT FORMS.
THESE ARE CONTROLS IN SOME WAYS.
LET'S LOOK AT THE TOP LEFT.
I'D ALREADY MENTIONED EARLIER ON
IN MY TALK THIS PANCREATIC DUO
DEENL HOMEOBOX GENE NUMBER 1,
AND YOU SEE THAT WHEN WE KNOCKED
IT OUT, EACH DOT HERE REPRESENTS
A KNOCKOUT, IT REDUCES THE
PROBABILITY THAT THE CELLS COULD
BECOME BETA CELLS.
SO YOU SEE THESE WERE
STATISTICALLY INSIGNIFICANT,
DOWN HERE IS PDX.
THESE CELLS ARE MORE LIKELY TO
BE ABLE TO BECOME ALPHA OR
ENTEROCHROMAFFIN BUT NOT BETA.
AND THIS JUST SHOWS FOUR GENES
IN TWO DIFFERENT WAYS.
THIS SHOWS YOU BY KIND OF A BAR
PLOT, AND HERE IS A CIRCULAR
DIAGRAM, WHERE YOU SEE THE X IS
OPPOSITE PRO BETA, MEANING THAT
IF YOU KNOCK OUT PDX, YOU'RE
MUCH LESS LIKELY TO BECOME A
BETA CELL.
I'LL JUST SHOW ONE OTHER EXAMPLE
HERE.
ARX HAD BEEN SHOWN BY MANY
OTHERS IN MICE TO BE REQUIRED
FOR ALPHA CELLS, AND WHEN WE
KNOCKED THIS GENE OUT, WE SEE
AGAIN YOU'RE NOT -- YOU'RE MUCH
LESS LIKELY TO BECOME A GLUCAGON
PRODUCING CELL THAN YOU ARE
OTHER CELL TYPES.
I DON'T HAVE A SLIDE TO SHOW YOU
BUT I CAN TELL YOU THERE ARE A
NUMBER OF GENES THAT MAKE YOU
MUCH MORE LIKELY TO BECOME BETA
CELLS, LIKE THIS ONE.
AND ONE OF THE ONES WE'RE
PARTICULARLY INTERESTED IN IS A
GENE CALLED F BOX L14, WHICH IS
IN THE UBIQUITIN PATHWAY, AND
WHAT WE THINK IS GOING ON THERE,
WE'RE NOW TRYING TO PROVE THAT
WITH MONOCLONAL CELL LINES, IS
THAT THAT PROTEIN, THAT ENZYME
IS REQUIRED TO MARK CELLS FOR
DEGRADATION, AND IF WE DEGRADE
THEM, THEN THE CELLS ARE MORE
LIKELY TO BECOME BETA CELL,
MEANING THE PROTEINS IT PROBABLY
MARKS ARE INCLINED TO MAKE THE
CELLS BECOME ENTEROCHROMAFFIN
CELLS WHICH WE DON'T WANT.
SO THE POINT OF THIS SLIDE IS TO
SHOW YOU THAT A GENETIC SCREEN
CAN GIVE US CLUES NOW ABOUT WHAT
MODIFICATIONS WE COULD MAKE TO
ACHIEVE THE GOAL OF MAKING
PRIMARILY IF NOT EXCLUSIVELY
ALPHA CELLS, BETA CELLS, AND
DELTA CELLS.
INSULIN PRODUCING GLUCAGON
PRODUCING, AND SOMATOSTATIN
CELLS.
I DIDN'T TELL YOU WHY WE WOULD
WANT TO MAKE THE DELTA CELLS,
THE SOMATOSTATIN PRODUCING CELLS
BUT THE MAIN REASON FOR THAT IS
EXPERIMENTS IN MICE SHOW THAT
KNOCKING OUT DELTA CELLS MAKES
THE ALPHA AND BETA CELLS WORK A
LITTLE LESS WELL.
LAST THING, AND I'M ALMOST DONE
HERE, IS TO TELL BUT THIS
CHALLENGE OF ALLO INJECTION.
I'M NOT AN IMMUNOLOGIST SO I'M
GOING TO GIVE YOU -- WHAT I
WOULD SAY IS KIND OF MY
UNDERGRADUATE VIEW OF WHAT WE
CAN ACLEAVE.
ACHIEVE.
SHOWN HERE IN PURPLE COULD BE
DEGRADED BY A NUMBER OF CELL
TYPES AND I WON'T GO THROUGH
THESE IN DETAIL, MAINLY I JUST
WANT TO SHOW YOU HOW COMPLICATED
IT IS.
THAT THESE CELLS COULD BE KILLED
BY CYTOACTIVE T-CELLS,
CD8 POSITIVE T-CELLS, BY NATURAL
KILLER CELLS, BY COMPLEMENT
FIXATION, BY CYTOKINES, BY
MACROPHAGE ENGULFMENT.
AND THE POINT OF THIS SLIDE IS
THAT THERE'S A LOT KNOWN FROM
THE WORK OF IMMUNOLOGISTS AND
OTHERS ABOUT THE MOLECULAR
SIGNALS INVOLVED IN THERE, AND
SO WE ARE THINKING THAT WE CAN
KNOCK THOSE GENES OUT OR ADD
GENES TWHA WOULD PR THAT WOULD S
KIND OF IMMUNE ATTACK.
I'M NOT GOING INTO DETAIL HERE
BECAUSE WE HAVEN'T ACHIEVED THAT
GOAL.
I'M GOING TO SHOW YOU ONE
EXAMPLE, MORE TO JUST SHOW YOU
WHAT THE CHALLENGE AHEAD IS.
AND HERE IS THE ONE EXAMPLE I
WANTED TO DESCRIBE.
THE STEM CELL DERIVED ISLETS IN
THIS CASE WERE GENETICALLY
MODIFIED TO EXPRESS IL10, TGF
BETA AND A MODIFIED IL2.
WHAT WE SHOW HERE AND IF YOU
LOOK AT THE BOTTOM RIGHT IS IF
WE TAKE UNMODIFIED CELLS, WHILED
TYPE CELLS AND PUT THEM INTO A
HUMANIZED MOUSE WHICH WE THEN
CAN INJECT WITH HUMAN PBMCs OR
FROM XENOREJECTION IN THE MOUSE
THAT THESE GENETICALLY MODIFIED
CELLS CAN SURVIVE FOR UP TO NINE
WEEKS.
I DON'T WANT TO IMPLY THAT THIS
IS THE SOLUTION TO THE PROBLEM.
I SIMPLY WANT TO SAY THAT BY
GENETICALLY MODIFYING THE CELLS,
I THINK WE CAN INCREASE THEIR
SURVIVAL IN PATIENTS.
NOW LET ME FINISH WITH THIS
QUESTION OF PATIENTS.
WHAT I'VE TOLL YOU A TOLD YOU SS
ABOUT RESEARCH WORK DONE IN LAB.
I WANT TO FINISH UP BY SAYING
WHAT ARE THE CHALLENGES OF GOING
FROM THESE KIND OF RESEARCH
DERIVED CELLS TO ACTUALLY A
CLINICAL TRIAL AND EVENTUALLY, I
HOPE, TREATING PATIENTS.
THIS REQUIRES LOTS OF THINGS
WHICH WE CANNOT AND ONE CANNOT
GENERALLY SPEAKING DO IN A
UNIVERSITY ENVIRONMENT.
SO WHERE I TEACH AT HARVARD
COLLEGE AND THE HARVARD MEDICAL
SCHOOL, WE COULD WORK ON
REPRODUCIBILITY, WHICH WE DID,
BUT SCALING, GETTING CLINICALLY
COMPLIANT CELLS, DEALING WITH
REGULATORY ISSUES, DESIGNING AND
EXECUTING A CLINICAL TRIAL,
FINDING PATIENT ELIGIBILITY FOR
THIS AND OF COURSE THE FINANCES
ARE REALLY BEYOND OF SCOPE OF
WHAT ONE DOES AT THE UNIVERSITY.
SO THIS LITTLE SLIDE HERE SHOWS
MY PATH OR MY LAB'S PATH TO A
CLINICAL TRIAL, WE BEGAN THE
WORK I DESCRIBED FOR YOU IN
ABOUT 1998 AT HARVARD.
WE THEN DETERMINED ONCE WE WERE
ABLE TO MAKE STEM CELL DERIVED
ISLETS AND PATENTED THAT
PROTOCOL, THAT THE THINGS I JUST
DESCRIBED WOULD BE BETTER DONE
OUTSIDE OF THE UNIVERSITY OR
ENABLED OUTSIDE OF THE
UNIVERSITY, SO WE STARTED A
COMPANY IN 2015 CALLED SEMMA
THERAPEUTICS, AND IT INDUSTRIAL
IZED THE PROTOCOL, USED
CLINICALLY COMPLIANT CELLS,
DEMONSTRATED EFFICACY IN A MORE
ANIMAL MODELS THAN WE HAD DONE,
STUDIED THESE CELLS IN A DEVICE
IN PIGS, AND THAT COMPANY WAS
ACQUIRED A FEW YEARS AGO BY
VERTEX PHARMACEUTICALS, AND I'M
NOW GOING TO SWITCH TO
DESCRIBING WHAT VERTEX HAS DONE.
SO A CLINICAL TRIAL WITH STEM
CELL DERIVED ISLETS BEGAN IN
2021, BY VERTEX PHARMACEUTICALS.
SO HERE'S WHAT WAS DONE.
THEY USE ADD MODIFIED VERSION OF
THE PROTOCOL WITH A DIFFERENT
CELL LINE TO MAKE THESE STEM
CELL DERIVED ISLETS AND THEN
FOLLOWED WHAT HAD BEEN DONE WITH
CADAVERIC ISLETS BY TRANSPORTING
THEM TO THE PORTAL VEIN,
IMPORTANTLY HERE ALONG WITH
NONSTEROIDAL IMMUNOSUPPRESSANTS.
I THINK I'VE SAID IT CLEARLY
ENOUGH ALREADY, THAT THESE ARE
ALLO CELLS WHICH WOULD BE
REJECTED BY THE PATIENT SO THE
STEM CELL DERIVED ISLETS ARE
PROVIDED WITH NONSTEROIDAL
IMMUNOSUPPRESSANTS.
AND I'M ALLOWED TO SHOW THESE
DATA, WHICH HAVE BEEN MADE
PUBLIC, AND THERE'S LOTS OF DATA
HERE ON THIS SLIDE BUT IT WOULD
BE PRETTY EASY FOR ME TO AT THE
ME TODESCRIBE WHY I'M EXCITED AT
THIS.
WE CALCULATED HOW MANY STEM CELL
DERIVED ISLETS A PATIENT WOULD
NEED AND THE FDA WISELY
SUGGESTED THAT INITIALLY WE JUST
USE HALF OF THAT DOSE.
SO I'M SHOWING YOU HERE ON THE
LEFT, LET'S LOOK AT THE
PATIENTS' BLOOD GLUCOSE LEVELS,
25 DAYS BEFORE TRANSPLANTATION.
MEASURED BY A CONTINUOUS GLUCOSE
MONITOR.
AND THE DETAIL HERE ISN'T SO
IMPORTANT TO LOOK AT ALL THE
NUMBERS, BUT JUST TO SAY LOOK IN
THE GREY REGION, WHICH IS WHAT A
NON-DIABETIC'S BLOOD GLUCOSE
LEVELS WOULD BE, A SO-CALLED
TIME IN RANGE.
AND YOU SEE THIS POOR PATIENT
SUFFERS FROM MANY PERIODS OF
TIME WHERE THEY HAD HIGH BLOOD
SUGARS AND IMPORTANTLY THEY ALSO
HAD VERY LOW AND DANGEROUS LOW
BLOOD SUGAR SHOWN HERE AT THE
BOTTOM AN IN SORT OF ORANGE AND
PURPLE.
270 DAYS, OR 240 TO 270 DAYS
AFTER RECEIVING HALF A DOSE OF
STEM CELL DERIVED ISLETS, LOOK
AT HOW GOOD THIS LOOK.
S.
THEIR TIME IN RANGE IS 99.9%,
THEIR DAILY INSULIN REQUIREMENTS
WENT FROM 34 UNITS OF INSULIN
EVERY DAY TO ZERO.
AND THEIR HEMOGLOBIN A1C, A
MEASUREMENT OF BLOOD GLUCOSE
CONTROL, WENT FROM 8.6 TO
ESSENTIALLY NORMAL.
THIS IS FRANKLY A RESULT BETTER
THAN I COULD HAVE HOPED FOR,
WITH JUST HALF A DOSE, AND IN MY
VIEW IS A VERY EXCITING RESULT
SHOWING FOR THE FIRST TIME THAT
STEM CELL DERIVED ISLETS CAN
CONTROL A PATIENT'S BLOOD
SUGARS, ALBEIT IN THE PRESENCE
OF IMMUNOSUPPRESSION BUT
NEVERTHELESS THESE STEM CELL
DERIVED ISLETS WORKED AS WELL AS
CADAVERIC ISLETS.
AS IT'S NOT SURPRISING, THIS
RESULT ISN'T ALWAYS THE CASE.
THE SECOND PATIENT WITH HALF A
DOSE HAD AN IMPROVEMENT, 25
UNITS TO 18, 35% HIGH RANGE TO
MORE THAN 50%, A LOWERING OF THE
HEMOGLOBIN A1C, BUT CLEARLY NOT
AS GOOD A RESULT AS THE FIRST
PATIENT.
THERE ARE MORE PATIENTS NOW THAT
HAVE BEEN PROVIDED WITH STEM
CELL DERIVED ISLETS AND THOSE
RESULTS WILL READ OUT IN THE
NEXT FEW MONTHS.
BUT IN MY VIEW, I WOULD JUST SAY
THAT THE FIRST RESULTS WERE
MAYBE EVEN BETTER THAN I COULD
HAVE HOPED FOR, AND I FEEL LIKE
THIS SHOWS WE'RE ON THE RIGHT
TRACK FOR FINDING A NEW
TREATMENT FOR TYPE 1 DIABETES.
SO I'LL CONCLUDE T CONCLUDE THEG
WHERE I THINK WE ARE.
THIS IS AN INVESTIGATION TALL
AFROACH USING STEM CELL DERIVED
ISLETS FOR TRANSPLANTATION INTO
TYPE 1 DIABETICS.
IF I GO BACK TO MY SIMPLE MINDED
DIVISION OF THE PROBLEM CAN WE
MAKE THE ISLETS, THERE ARE
IMPROVEMENTS WHICH CAN BE MADE
ON THAT, BUT I THINK WE'VE
SOLVED IN PRINCIPLE THE FIRST
HALF OF THE PROBLEM.
WE'RE NOW DOSING WITH
IMMUNOSUPPRESSION AND THAT'S
GOING WELL.
I DIDN'T HAVE TIME TODAY TO TELL
YOU ABOUT AN ENS CAPS LAITION
DEVICE DEVELOPED AT SEMMA AND
VERTEX AND THAT'S NOW BEEN
APPROVED FOR A CLINICAL TRIAL
WHICH IS ONGOING BUT AT THE END
I DESCRIBED FOR YOU MY VIEW THAT
MAYBE EVENTUALLY, WE CAN GET TO
NAKED OR GENETICALLY MODIFIED
CELLS, WHICH WOULD NOT BE PUT IN
A DEVICE.
SO TO BE OPTIMISTIC ABOUT THE
FUTURE, I LIKE TO THINK ABOUT A
TIME WHEN A POOR YOUNG GIRL OR
BOY IS DIAGNOSED WITH TYPE
1 DIABETES AND THEY'RE TALKING
TO THEIR ENDOCRINOLOGIST, SHE
SAYS TO THEM, WELL, THIS IS NOT
A GOOD DISEASE TO HAVE, BUT IT'S
POSSIBLE THAT WE CAN INJECT YOU
OR TRANSPLANT YOU WITH STEM CELL
DERIVED ISLETS, WHICH WON'T BE
REJECTED BY YOUR OWN IMMUNE
SYSTEM, AND WHICH WILL CONTROL
YOUR BLOOD SUGARS.
SO AS LONG AS YOU RECEIVE THESE
ISLETS, YOUR BLOOD SUGARS AND
YOUR METABOLISM WILL BE
CONTROLLED.
I FINISH BY SHOWING A PICTURE OF
THE LUCKY TEAM I'VE HAD TO WORK
WITH ME ON THIS PROBLEM OVER A
NUMBER OF YEARS AND I'D ALSO
LIKE TO THANK THE FUNDING
AGENCIES AND OUR COLLABORATORS.
IN BLACK ON THE LEFT ARE THE
PEOPLE WHO ARE STILL IN MY
HARVARD LAB, ALTHOUGH IT IS
CLOSING DOWN.
IN BLUE ARE THE COLLABORATORS
WE'VE ENJOYED WORKING WITH FOR
MANY YEARS, AND IN BLACK AT THE
BOTTOM ARE THE FUNDING AGENCIES
INCLUDING THE NIH, JDRF, PICOWER
FOUNDATION, HARVARD STEM CELL
INSTITUTE, IN GREEN, SEMMA
ACQUIRED BY VERTEX, WHERE I NOW
WORK AS A RESEARCH FELLOW.
SO THANK YOU FOR YOUR ATTENTION,
AND I HOPE THE REST OF THE
DISCUSSION GOES WELL.
>>THANK YOU VERY MUCH, DOUG,
AND WE GREATLY APPRECIATE YOUR
TAKING THE TIME TO PREPARE THIS
VIDEO, GIVEN THE CIRCUMSTANCES
THAT YOU COULD UNFORTUNATELY NOT
BE WITH US.
WE HAVE A VARIETY OF QUESTIONS
HERE.
AND SO I'M GOING TO DIRECT THE
FIRST GROUP TO COURTNEY.
SO COURTNEY, WE HAVE A QUESTION
FROM JIM TAYLOR WHO SAYS HIS
WIFE WAS ON METFORMIN FOR MANY
YEARS TO LOWER HER BLOOD SUGAR.
WHEN HER BLOOD SUGAR STARTED
MEASURING LESS THAN 100, SHE WAS
REMOVED FROM METFORMIN AND HER
BLOOD SUGAR LEVELS HAVE REMAINED
STABLE WITHIN THE NORMAL LIMITS.
IS THIS A COMMON PHENOMENA?
AND SHOULD SHE STILL BE
CONSIDERED AS A DIABETIC?
WHAT MIGHT HAVE HAPPENED TO
CAUSE HER TO NO LONGER NEED
MEDICATION?
WEL
>>THAT'S AN EXCELLENT QUESTION.
METFORMIN HAS A LOT OF WONDERFUL
BENEFITS FOR PEOPLE WITH INSULIN
RESISTANCE.
INCLUDING LOWERING THAT INSULIN
RESISTANCE AND YOU CAN DO THAT A
NUMBER OF WAYS.
YOU CAN DO THAT THROUGH
MEDICATION, LIFESTYLE IS ALSO AN
EXCELLENT CHOICE, SO I'D BE
CURIOUS TO LEARN WHAT LIFESTYLE
INTERVENTIONS THAT SHE
UNDERTOOK, WHETHER IT WAS
CHANGING DIET, CHANGING EXERCISE
OR SOMETHING ELSE IN HER LIFE
THAT COULD HAVE ALSO LOWERED
THAT INSULIN RESISTANCE.
AS FAR AS THE DIAGNOSIS OF
DIABETES, AN A1C OF 6.5 OR
HIGHER IS JUST ONE CRITERIA THAT
CAN BE USED FOR DIAGNOSIS.
SO WHILE THERE IS A SPECTRUM OF
INSULIN SENSITIVITY, USUALLY THE
CUTOFFS ARE PRETTY BLACK AND
WHITE AS TO WHETHER OR NOT
SOMEONE IS CONSIDERED DIABETIC
OR PREDIABETIC OR SOMEONE WHO
DOES NOT HAVE DIABETES AT ALL
AND HAS NORMAL GLUCOSE LEVELS.
>>WE HAVE A SERIES OF SOMEWHAT
PERSONAL QUESTIONS, SO --
>>THAT'S FINE.
>>OKAY.
SO, ONE, WHAT IS THE MOST
DIFFICULT DECISION YOU HAD TO
MAKE IN THE LAST 20 YEARS SINCE
YOU WERE DIAGNOSED WITH TYPE
1 DIABETES?
AND SORT OF A SECOND PART, DO
YOU THINK THAT RUNNING LONG
DISTANCES IS BETTER THAN OTHER
FORMS OF EXERCISE TO CONTROL
BLOOD SUGAR?
>>BOTH GOOD QUESTIONS.
IN REGARDS TO THE FIRST
QUESTION, IS THIS A DECISION
REGARDING DIABETES MANAGEMENT
SPECIFICALLY?
>>I'M SORRY.
>>THE QUESTION REGARDING
DIABETES MANAGEMENT
SPECIFICALLY, THE MOST DIFFICULT
DECISION WITHIN MANAGEMENT?
>>IT JUST SAID WHAT IS THE MOST
DIFFICULT DECISION YOU HAD TO
MAKE IN YOUR LIFE IN THE PAST 20
YEARS SINCE YOU WERE DIAGNOSED
WITH TYPE 1 DIABETES.
>>WOW, WHAT A GOOD QUESTION.
I DON'T KNOW IF THERE'S ANY ONE
SPECIFIC DECISION THAT COMES TO
MIND.
I THINK RECENT DECISIONS ARE
EASIER TO REMEMBER.
AND CERTAINLY AS A RESIDENT,
KNOWING THAT SOMETIMES YOUR OWN
HEALTHCARE CAN GET PUT ON THE
BACK BURNER, WHICH IS AN
UNFORTUNATE TRUTH WHEN YOU
DECIDE TO PURSUE A CAREER IN
MEDICINE, HAS DEFINITELY BEEN A
DIFFICULT DECISION AND ONE THAT
HAS TAKEN A LITTLE BIT MORE
STRATEGIZING.
ESPECIALLY AS A FIRST YEAR
RESIDENT.
AGAIN WITH LITTLE AUTONOMY
SOMETIMES IN MY OWN SCHEDULE.
BUT I THINK IT'S A WORTHWHILE
DECISION.
IT'S DIFFICULT BUT WORTHWHILE.
>>FOLKS HAVE ASKED WHETHER
DIABETES IS PRESENT IN YOUR
FAMILY.
>>IT'S NOT, NOT TO MY KNOWLE
KNOWLEDGE.
WHICH DOESN'T MEAN THAT IT
WASN'T PRESENT IN PREVIOUS
GENERATIONS AND JUST WENT
UNDIAGNOSED BUT NO CASES I KNOW
OF SPECIFICALLY, NO.
>>SO TURNING A WHRIT BIT MORE E
TO THE SCIENCE OF IT, WHAT'S
YOUR FEELING ABOUT THE
UNDERLYING AUTOIMMUNE PROCESS?
DOLL YOU THINK IT'S POSSIBLE TO
DETECT EVIDENCE OF THAT PROCESS
BEFORE THERE IS ANY
MANIFESTATION OF HYPOINSULIN?
>>I DO.
THERE'S A LOT OF THEORIES ABOUT
THE TRIGGERS FOR AUTOIMMUNITY
AND A LOT OF GOOD TRIALS RIGHT
NOW LOOKING AT SPECIFIC
ANTIBODIES THAT CAN BE PICKED UP
YEARS BEFORE A DIAGNOSIS.
I KNOW FOR EXAMPLE WHEN I WAS
YOUNGER AND MY FAMILY WENT TO A
DIABETES CAMP, THERE WAS THE
OPTION FOR SIBLINGS TO BE TESTED
FOR THESE ANTIBODIES.
MY SISTER CHOSE TO NOT BE TESTED
SO I THINK THAT THIS IS ALSO
HIGHLY PERSONAL, WHETHER OR NOT
SOMEONE CHOOSES TO KNOW THAT
THEY'RE PREDISPOSED OR NOT.
>>THERE HAVE BEEN A SERIES OF
PAPERS IN THE PAST, I DON'T
KNOW, SIX MONTHS OR A YEAR, MORE
FROM SORT OF THE TECHNICAL
STANDPOINT OF DEVELOPMENTS OF
DIFFERENT WAYS OF MONITORING
BLOOD SUGAR.
SOME ACTUALLY SUGGESTING A KIND
OF AI APPROACH OR A COMPUTER
BASED APPROACH.
DO YOU HAVE COMMENTS ABOUT
THOSE?
>>COMPUTER AI APPROACH AS IN
CLOSED LOOP TECHNOLOGY OR ALONG
THE LINES OF CLOSED LOOP
TECHNOLOGY?
>>WELL, THE QUESTION IS WHAT
ABOUT THE RECENT METHODS FOR
MONITORING BLOOD GLUCOSE?
IS THERE ROOM FOR IMPROVEMENT
THERE?
>>OH, ABSOLUTELY.
EVEN WITHIN THE -- GOODNESS, I
GUESS IT'S BEEN SEVEN YEARS NOW
SINCE THE FDA-APPROVED CGMs AS
A REPLACEMENT FOR BLOOD GLUCOSE
MONITORING.
AND EVEN IN THAT TIME, CGMs
HAVE BECOME INCREASINGLY
ACCURATE.
HOWEVER, THEY'RE STILL NOT
PERFECT.
THEY ONLY LAST FOR ABOUT 10 DAYS
ON AVERAGE, 10 TO 14 DAYS, AND
WHILE ACCURACY IS INCREASING,
IT'S STILL NOT PERFECT AND THERE
ARE A NUMBER OF VARIABLES THAT
CAN AFFECT A READING, ONE BEING
PRESSURE THAT'S APPLIED TO THE
OUTSIDE OF THE SENSOR THAT CAN
AFFECT MEASUREMENTS AS WELL AS
CERTAIN MEDICATIONS.
AS FAR AS TECHNOLOGY IN THE
FUTURE, THERE'S ALSO BEEN WORK
ON CONTINUOUS MONITORS THAT ARE
IMPLANTED THAT NEED TO SCAN AND
LAST FOR LONGER PERIODS OF TIME.
I'M NOT PERSONALLY AS FAMILIAR
WITH THOSE YET.
AND THEN THERE'S ALSO A LOT OF
WORK BEING DONE WITH THE WAY
THAT THE CONTINUOUS GLUCOSE
MONITORS CAN TALK IN A SENSE
WITH THE INSULIN PUMPS AND THE
INSULIN PUMPS CAN EITHER GIVE
MORE OR LESS INSULIN DEPENDING
ON THOSE READINGS.
>>IT'S APROPOS THE INFORMATION
YOU PROVIDED WAS RATHER
DEVASTATING AS TO WHAT THE
DEFICITS ARE IN OUR HEALTHCARE
SYSTEM, WHICH ARE PRIMARILY OR
TO A GREATER EXTENT FELT BY
PEOPLE WHO ARE NOT VERY WELL
INFORMED AND ARE AT THE LOWER
END OF THE SOCIOECONOMIC SCALE.
SO I'M CURIOUS, WHAT ABOUT IN
OTHER COUNTRIES, WHERE THE
SYSTEM IS MORE BASED ON SINGLE
INSURANCE OR NATIONAL HEALTH, DO
COUNTRIES LIKE THE UNITED
KINGDOM, CANADA, THE
NETHERLANDS, DO THEY PROVIDE
GLUCOSE MONITORS AND INJECTORS
AS PART OF THEIR HEALTH POLICY,
DO YOU KNOW?
>>IN THE FEW PAPERS THAT I'VE
READ, IT SEEMS LIKE THERE'S
BETTER COVERAGE AND FEWER
DISPARITIES BETWEEN DIFFERENT
SOCIOECONOMIC GROUPS, SO AS
WHERE THE U.S. MIGHT HAVE A
DIFFERENCE IN A1C OF AROUND --
BETWEEN THE HIGHEST AND LOWEST
SOCIOECONOMIC GROUPS, THAT
DIFFERENCE DOESN'T EXIST IN
COUNTRIES WITH SINGLE PAYOR
SYSTEMS TYPICALLY IN WHAT I'VE
READ SO FAR.
>>CAN ANYONE, FOR EXAMPLE, WHO
BECOMES A DIABETIC IN ANY --
TYPE 1, DIABETES, LET'S SAY, IN
ANY OF THOSE COUNTRIES, CAN THEY
AUTOMATICALLY APPLY FOR AND
RECEIVE GLUCOSE MONITORS AND
INSULIN INJECTORS, OR OR DOES T
STILL REQUIRE SOME PRIVATE
INSURANCE OPERATION, DO YOU
KNOW?
>>I DON'T KNOW ABOUT ALL
COMPARABLE HIGH INCOME
COUNTRIES, BUT GERMANY COMES TO
MIND AS ONE THAT DOES COVER
PRETTY WELL.
AND I THINK THE UK AND FRANCE
ALSO COVER PRETTY WELL.
BUT I WOULD HAVE TO READ A
LITTLE BIT MORE ABOUT OTHER
COUNTRIES TO GIVE A MORE
THOROUGH ANSWER TO THAT QUEST
QUESTION.
>>IN THE UNITED STATES, IS THIS
EQUIPMENT AND TREATMENT
AVAILABLE THROUGH MEDICARE AND
MEDICAID PATIENTS?
>>IT'S COVERED UNDER MEDICAID
IN MOST STATES BUT NOT ALL
STATES.
I THINK THAT A LOT OF STATES
HAVE GOTTEN ON BOARD AND THEY DO
UNDERSTAND THAT THIS IS BECOMING
A MEDICAL NECESSITY FOR PEOPLE
WITH DIABETES AND WITHOUT IT,
YOU'RE EFFECTIVELY LIVING IN THE
80s OR THE 90s, AS FAR AS
DIABETES TREATMENTS GO.
HOWEVER, THERE'S A LONG WAY TO
GO.
THE PROCESS TO PROVE MEDICAL
NECESSITY CAN MAKE YOU JUMP
THROUGH A LOT OF HOOPS AND I
THINK THAT FOR MANY PEOPLE, THAT
CAN PROVIDE A LARGE OBSTACLE
ESPECIALLY FOR THOSE WITH LOWER
LEVELS OF HEALTHCARE LITERACY.
>>LET'S PUSH THIS JUST A LITTLE
BIT FURTHER.
IS THIS A PART OF A FEDERAL
MANDATE AS IT WERE OR IS THIS
SOMETHING THAT IS DECIDED AT THE
INDIVIDUAL STATE LEVEL, WHETHER
A PERSON CAN RECEIVE MONITORING
AND INSULIN INJECTORS?
>>FROM WHAT I GATHER, IT'S
MOSTLY DEPENDENT STATE TO STATE.
>>IT'S A STATE -- PREDOMINANTLY
A STATE ISSUE?
>>PREDOMINANTLY A STATE ISSUE,
FROM WHAT I CAN TELL.
>>ALL RIGHT.
HERE'S AN INTERESTING QUESTION.
WHAT IS THE BEST ADVICE FROM
YOUR BOOK?
YOU COVERED ALL OF IT, I DON'T
KNOW WHY SOMEONE WANTS TO KNOW
THE ABSOLUTE BEST, BUT I GUESS
THE ADVICE IS TO READ THE BOOK,
RIGHT?
>>WELL, THERE'S NOTHING BETTER
THAN READING THE ENTIRE BOOK,
BUT GOODNESS.
I THINK THE BIGGEST REVELATION
FOR ME, AT LEAST WHEN I WAS
DOING THE RESEARCH FOR THE BOOK
AND WRITING THE BOOK, WAS THAT
THE STRUGGLES I WAS FACING WERE
NOT UNCOMMON AND I THINK THAT
OFTENTIMES THE LOUDEST VOICES IN
THE DIABETES COMMUNITY ARE FROM
THOSE WHO TEND TO DO VERY WELL,
AND IT CREATES THIS PICTURE THAT
EVERYONE WITH DIABETES IS DOING
WELL, AND I THINK THAT CAN
REALLY DECREASE MENTAL HEALTH OF
PEOPLE WHO ARE LIVING WITH
DIABETES AND STRUGGLING.
AND I THINK THAT NORMALIZING
THOSE STRUGGLES IS VERY
IMPORTANT IN TALKING ABOUT THE
ISSUES VERY OPENLY CAN REALLY
NOT ONLY BUILD CAMARADERIE BUT
ALSO BUILD HOPE IN THAT YOU
DON'T HAVE TO EITHER BE,
QUOTE-UNQUOTE, LIKE A PERFECT
DIABETIC OR LIKE A BAD DIABETIC,
THERE'S NO SUCH THING AS EITHER
ONE OF THOSE.
IT IS ALL JUST A CONTINUOUS
PROCESS OF IMPROVEMENT AND I
THINK THAT FRAMING IT IN THAT
LENS WAS VERY HELPFUL.
>>SO YOU ALLUDED TO IN YOUR
REALLY ELEGANT DESCRIPTION OF
HOW A PATIENT CAN RELATE TO THE
DISEASE AND ONE OF THE
APPROACHES, THE STANDARDS, THE
GOALS YOU SET FOR YOURSELF, SO
THIS PROMPTS THE QUESTION FROM
YOUR UNDERSTANDING, HOW
METICULOUS DOES REGULATION OF
BLOOD GLUCOSE HAVE TO BE?
IDEALLY, I GUESS IT SHOULD BE
MAYBE A STEM CELL MEDIATED THING
THAT'S NORMAL, BUT WITHIN THE
RANGE OF WHAT WE CURRENTLY DEAL
WITH, DO YOU STRUGGLE TO KEEP IT
WITHIN A NORMAL RANGE OR IS IT A
LITTLE BIT OF VARIATION GIVEN
YOUR ACTIVITIES AND GIVEN YOUR
OTHER THINGS PERMISSIBLE, AND IF
ISTHAT GOOD FOR YOU, IS IT BAD R
YOU, DO WE KNOW WHETHER MODEST
CHANGES IN THE BLOOD GLUCOSE
CURVE PERHAPS WITH SOME
FREQUENCY HAVE ANY DELETERIOUS
HEALTH EFFECTS?
>>I THINK IN AN IDEAL WORLD, WE
WOULD BE ABLE TO MIMIC WHAT THE
BODY DOES PERFECTLY, WHICH IS
IMPOSSIBLE.
THE BODY IS SMARTER THAN ANY
REGIMEN COULD EVER HOPE TO MIM
MIMIC.
ALSO THE GOALS FOR EACH PERSON
HAVE TO BE INDIVIDUALIZED.
SO WHILE WE DO HAVE THESE
CUTOFFS OF AN A1C LESS THAN 7%,
THAT'S NOT NECESSARILY THE GOAL
FOR EVERY PERSON.
FOR EXAMPLE, WHEN PEOPLE ARE
OLDER AND THEY'RE LIVING WITH
DIABETES, IT IS PERMISSIBLE
SOMETIMES TO HAVE A HIGHER A1C
LEVEL BECAUSE EPISODES OF
HYPOGLYCEMIA CAN LEAD TO REALLY
TRAGIC EVENTS.
LIKEWISE IF YOU'RE DEALING WITH
SOMEONE WHO'S INCREDIBLY YOUNG,
SOMETIMES A HIGHER A1C MIGHT BE
MORE PERMISSIBLE IN THE SETTING
OF THEM GOING TO SCHOOL AND NOT
WANTING TO RISK LOW BLOOD
SUGARS, SO AGAIN IT DEPENDS ON
EACH INDIVIDUAL AND
CONVERSATIONS WITH THEIR DOCTORS
IDEALLY WE RANGE FOR A RANGE IN
DIABETES FROM 170 TO 180, 180
MOSTLY AFTER MEALS AND SOMEWHERE
IN BETWEEN WITH AS FEW
VARIATIONS AS POSSIBLE, WHICH
CAN BE KIND OF DIFFICULT, AS
FAR AS TIME IN RANGE AND KIND OF
THE LEVELS THAT YOU SWING IN
BETWEEN, YOU SHOULD BE ABOUT --
GOODNESS, I'M FORGETTING THE
RIGHT WORD FOR IT, I WOULD HAVE
TO LOOK AT MY MONITOR, BUT
STANDARD DEVIATION, STANDARD
DEVIATION.
YOUR STANDARD DEVIATION SHOULD
BE ABOUT A THIRD OF YOUR AVERAGE
GLUCOSE.
>>WHY ARE ADOLESCENTS ON THE
LIST OF NOT TAKING FULL
ADVANTAGE OF THE BEST THERAPIES?
IS THAT ADOLESCENCE OR IS
THAT -- WHAT'S YOUR --
>>I HAVE A LOT OF THEORIES.
IT DEPENDS ON THE ADOLESCENT.
I THINK IT'S IMPORTANT TO
RECOGNIZE THAT AT THIS AGE,
DEVELOPMENTALLY WHAT'S VERY
IMPORTANT FOR ADOLESCENTS IS
FITTING IN WITH YOUR PEERS.
THAT'S PERHAPS THEIR NUMBER ONE,
TWO AND THREE PRIORITY WHEN IT
COMES TO CONSIDERING DIABETES
TREATMENTS.
THEY JUST WANT TO BE ABLE TO FIT
IN AND DO WHATEVER THEIR PEERS
ARE DOING.
AND BY WEARING A CGM, YOU HAVE
SOMETHING EXTRA ON YOUR BODY, SO
ALREADY YOU'RE SETTING YOURSELF
APART FROM YOUR PEERS, SAME WITH
AN INSULIN PUMP.
WHEN I WAS IN HIGH SCHOOL, I WAS
SUPPOSED TO TRY PUMP AND I PUT
IT ON MY BODY, I TRIED TO
SITUATE IT, I TRIED TO PUT IT IN
MY POCKET, I TRIED TO STUFF IT
INTO MY CLOTHES IN VARIOUS
PLACES AND BECAUSE IT LOOKED SO
DIFFERENT, I COULD NOT DO IT IN
HIGH SCHOOL, AND IN COLLEGE, I
FELT LIKE IT WAS MORE
ACCEPTABLE, PEOPLE DIDN'T
QUESTION AS MUCH WHAT IT WAS,
AND I WAS FINALLY ABLE TO START,
BUT AS FAR AS BEING ABLE TO FIT
IN WITH YOUR PEERS, I THINK
IMPORTANCE CAN BE IMPORTANT AND
THAT'S ALSO A BARRIER TO
TECHNOLOGY.
>>THERE IS LITERATURE, QUITE A
BIT ACTUALLY, ON THE EFFECT OF
MARIJUANA ON INTERMEDIARY
METABOLISM, PARTICULARLY
CARBOHYDRATE METABOLISM.
IS THERE ANY SPINOFF ON THIS IN
TERMS OF ITS EFFECT IN A
DIABETIC PATIENT?
HAS THAT BEEN STUDIED OR IS IT
NOT A SIGNIFICANT FACTOR AS FAR
AS YOU KNOW?
>>OH, I THINK IT SHOULD
ABSOLUTELY BE STUDIED MORE,
ESPECIALLY AS MARIJUANA BECOMES
MORE LEGALIZED ACROSS THE UNITED
STATES.
I THINK THERE NEEDS TO BE MORE
REGULATED STUDIES ON THIS, AND
PERHAPS LESS STIGMA AROUND THIS
CONVERSATION.
THINGS THAT ARE IMPORTANT TO
TALK ABOUT PATIENTS DO INCLUDE
YOUR TYPICAL SEX, DRUGS AND ROCK
AND ROLL AND THESE THINGS CANNOT
HAVE ANY SORT OF BARRIERS TO
STUDYING BECAUSE YOU HAVE TO
GIVE THE RIGHT ANTICIPATORY
GUIDANCE TO PATIENTS IN THOSE
SITUATIONS, ESPECIALLY IF THEY
CHANGE METABOLISM, CAN BE
DANGEROUS FOR PEOPLE WITH
DIABETES.
SO HAVING THOSE CONVERSATIONS
AND HAVING THE DATA TO BACK IT
UP AND KNOW WHAT TO TELL
PATIENTS TO EXPECT WOULD BE
INCREDIBLY HELPFUL IN GUIDING
THOSE CONVERSATIONS.
>>VERY GOOD.
WELL, WE HAVE A SERIES OF
QUESTIONS THAT ARE SORT OF
PRIMARILY DIRECTED TO DOUG.
BUT LET ME RUN A FEW OF THEM BY
AND SEE, MAYBE YOU HAVE SOME
COMMENTS ABOUT IT.
SO HERE IS ONE.
FROM MARK SAYING, TO DR. MELTON,
YOU ARE INDUCING TOLERANCE BY
KNOCKING OUT GENES THAT WOULD
ORDINARILY ELICIT AN IMMUNE
RESPONSE.
WHY ISN'T THAT DONE FOR ORGAN
TRANSPLANT PATIENTS IN GENERAL?
DOES THIS HAVE SOME BROAD
APPLICATION TO THE WHOLE
QUESTION OF AUTOIMMUNITY?
OR IS IT SOMEWHAT RESTRICTED TO
INSULIN?
>>THAT'S AN EXCELLENT QUESTION.
AND I SEE WHY THEY'RE ASKING.
I THINK THAT, YOU KNOW, MAYBE
THIS COULD EVENTUALLY CROSS OVER
INTO ORGAN TRANSPLANTATION.
OF COURSE I DON'T KNOW AS MUCH
ABOUT CELL BIOLOGY AS DOUG AND
HE WOULD BE ABLE TO GIVE A MORE
THOROUGH ANSWER, BUT WOULDN'T
THAT BE EXCITING IF IT WERE ABLE
TO BETTER BOTH FIELDS.
>>WELL, IT IS OF INTEREST THAT,
YOU KNOW, ISLET CELL
TRANSPLANTATION IS IN AND OF
ITSELF NOT A NEW PHENOMENON.
IT WAS ACTUALLY ATTEMPTED, I
NING IN THINK IN THE 80s, AND TE
WAS QUITE A FLURRY OF ACTIVITY,
GRANT SUPPORT AND SO FORTH FOR
IT.
ONE OF THE GREAT PROBLEMS WAS
THE ISLETS WERE ADMINISTERED
EITHER BY INJECTION INTO THE
PORTAL VEIN OR IN SOME FORM OF
ENCAPSULATED MATERIAL THAT WAS
PLACED USUALLY IN THE ABDOMINAL
CAVITY.
BUT THOSE CELLS DON'T LAST VERY
LONG AND THEY'RE EITHER ATTACKED
IMMUNOLOGICALLY OR PERHAPS
THEY'RE BEREFT OF THEIR BLOOD
SUPPLY, I DON'T KNOW, BUT AT ANY
RATE, THAT WHOLE OPERATION USING
THOSE KINDS OF ISLET CELL
PREPARATIONS HAS, I THINK,
COMPLETELY ENDED.
I DON'T BELIEVE IT'S SUPPORTED
ANYMORE.
SO WHAT DOUG IS PROPOSING IS
USING THOSE SAME METHODS FOR
ADMINISTRATION, AND IT'S TOO BAD
HE'S NOT WITH US SO HE CAN
COMMENT ABOUT WHETHER THERE ARE
SOME DEVELOPMENTS THAT
FACILITATE THAT FORM OF
ADMINISTRATION ASIDE FROM THE
NATURE OF THE CELLS THEMSELVES
AND THEIR ORIGIN.
SO WE'LL FORWARD THAT QUESTION
TO HIM ALONG WITH A GOOD MANY
OTHERS IN THE ANIMALS, HOW LONG
CAN THESE CELLS WORK?
IS IT REALLY NECESSARY TO HAVE
IMMUNOSUPPRESSION?
WELL, CAN YOU INDUCE TOLERANCE?
ALL THE BASIC QUESTIONS OF
IMMUNOLOGY HAVE POPPED UP, AND
WE'LL REFER THEM TO HIM UNLESS
YOU WANT TO MAKE SOME COMMENT
ABOUT IT.
>>NO, REFERRAL SOUNDS GREAT.
WE CAN REFER TO DOUG.
>>I THINK WE'D BOTH BE VERY
INTERESTED IN HIS REPLY.
>>MM-HMM.
>>SO LISTEN, I WANT TO THANK
YOU ON BEHALF OF -- I TOLD YOU
THIS PROGRAM GOES GLOBALLY, AND
WE FREQUENTLY HAVE PEOPLE IN
SOMETHING LIKE 38 DIFFERENT
COUNTRIES.
SO HOPEFULLY YOU'LL RECEIVE SOME
RESPONSES WHERE YOU'LL BE ABLE
TO HELP PEOPLE.
BUT IT'S REALLY BEEN A PLEASURE,
AND WE ALL CONGRATULATE YOU ON
YOUR SUCCESSES AND LOOK FORWARD
TO EVEN BRIGHTER DAYS.
>>WELL THANK YOU AGAIN SO MUCH
FOR HAVING ME AND FOR EVERYONE
WHO JOINED THE VIDEOCAST TODAY.
WE REALLY APPRECIATE IT.
>>OKAY.
SO I GUESS YOU GO BACK TO WORK,
AND CONTINUE YOUR GOOD WORK.
BYE.
>>THANK YOU, WIN.