>> GOOD AFTERNOON, EVERYONE, AND
WELCOME TO THE EIGHTH ANNUAL
VIVIAN PINN SYMPOSIUM.
I'M DR. JANINE CLAYTON, THE
ASSOCIATE DIRECTOR FOR RESEARCH
ON WOMEN'S HEALTH AND IN THAT
CAPACITY I DIRECT THE OFFICE OF
RESEARCH ON WOMEN'S HEALTH AND
WE'RE DELIGHTED TO HAVE YOU
HERE.
WE HAVE A FULL LINEUP FOR YOU
SCHEDULED, AND AN AWESOME
AGENDA, AND SO PLEASE DO STAY
WITH US FOR THE FULL AFTERNOON
FOR THIS FANTASTIC PROGRAM.
IF SOMEBODY COULD PULL UP THE
AGENDA VERY BRIEFLY THERE AND
THEN MY SLIDES, THAT WOULD BE
FANTASTIC.
GREAT.
AND NEXT?
WONDERFUL.
I'M GOING TO JUST GIVE SOME
BRIEF OPENING REMARKS ABOUT HOW
IMPORTANT IT IS TO BRIDGE THE
GAP AND CHART THE PATH FOR
WOMEN'S AUTOIMMUNE DISEASE
RESEARCH.
THIS IS SOME AMAZING SCIENCE, SO
I ALWAYS LOVE TO BEGIN WITH THE
DATA AND THE SCIENCE THAT WAS
RECENTLY IN THE LITERATURE.
WE KNOW THAT FOUR OUT OF FIVE
PATIENTS WITH AUTOIMMUNE DISEASE
ARE FEMALE.
WORK DONE BY DIANA DU AND HER
COLLEAGUES RECENTLY PUBLISHED IN
SELF HIGHLIGHTED WHAT THEY
BELIEVE IS ONE OF THE MAJOR
REASONS WHY WE SEE THAT SEX BI
BIAS.
XIST IS A LONG CODING RNA
EXPRESSED ONLY IN FEMALES TO
RANDOMLY INACTIVATE ONE OF THE
2X CHROMOSOMES TO ACHIEVE GENE
DOSAGE COMPENSATION.
IN THIS STUDY, THEY POSITED THAT
XIST RIBONUCLEAR PROTEIN
COMPLEXES COULD ACT AS ANTIGENIC
TRIGGERS, AND THAT THIS
UNDERLIES THE GREATER PREVALENCE
OF AUTOIMMUNE DISEASES IN
FEMALES.
THEY CONDUCTED ELEGANT STUDIES
WITH TRANSGENIC MOUSE MODELS
INDUCING EXPRESSION OF XIST IN
MALE ANIMALS AND THAT EXPRESSION
IN MALES AND THROUGH TRANSGENIC
EXPRESSION INDUCED
AUTOANTIBODIES AS WELL AS
AUTOIMMUNE PATHOLOGY IN THOSE
MALE MICE.
FURTHER, THAT XIST EXPRESSION
REPROGRAMMED T AND B CELL
POPULATIONS TO LOOK MORE LIKE
FEMALE POPULATIONS.
SO CLEARLY, XIST IS PLAYING A
CRITICAL ROLE.
AND ONCE AGAIN, DR. MONICA
BERTAGNOLLI, THE NEW NIH
DIRECTOR, FEATURED THIS STUDY IN
HER BLOG.
SHE'S BEEN VERY -- SHE HAS
FOCUSED A LOT ON WOMEN'S HEALTH
IN HER SHORT TIME WITH US, AND
SHE FEATURED IN THIS BLOG THIS
NEW RESEARCH.
SO AT NIH, AUTOIMMUNE DISEASE
RESEARCH HAS BEEN SOMETHING THAT
HAS BEEN IMPORTANT TO US FOR
MANY, MANY YEARS.
AND I WANT TO HIGHLIGHT THAT IN
FISCAL YEAR 2021 AND 2022, WHICH
ARE THE MOST RECENT YEARS FOR
FULL INFORMATION AVAILABLE, NIH
SUPPORTED OVER 1400 GRANTS AND
ADMINISTRATIVE SUPPLEMENTS THAT
WERE CODED AS AUTOIMMUNE DISEASE
RESEARCH.
AND IN TERMS OF THE AMOUNT OF
FUNDING, THE AMOUNT OF FUNDING
FOR AUTOIMMUNE DISEASE RESEARCH
HAS INCREASED AND HAS REACHED
NEARLY A BILLION DOLLARS IN FY
21.
THE OFFICE OF AUTOIMMUNE DISEASE
RESEARCH WITHIN ORWH HAS
UNDERTAKEN A PORTFOLIO ANALYSIS
TO BE ABLE TO ESTABLISH A
BASELINE, AND FOR THE PURPOSES
OF THAT PORTFOLIO ANALYSIS, WE
ARE LOOKING AT THE 144 DISEASES
AND CONDITIONS THAT WERE LISTED
IN THE NATIONAL ACADEMIES OF
SCIENCE, ENGINEERING AND
MEDICINE REPORT ENTITLED
"ENHANCING NIH RESEARCH ON
AUTOIMMUNE DISEASE" AS EITHER
CONSIDERED AUTOIMMUNE OR
CO-EXISTING WITH OTHER
AUTOIMMUNE DISEASES SUGGESTING
POTENTIAL COMMONALITIES IN
PATHOGENESIS.
IT'S VERY IMPORTANT FOR US TO
UNDERSTAND OUR AUTOIMMUNE
DISEASE RESEARCH PORTFOLIO AT
THIS TIME BECAUSE THAT'S GOING
TO INFORM THE DEVELOPMENT OF THE
FIRST NIH-WIDE STRATEGIC PLAN
FOR AUTOIMMUNE DISEASE RESEARCH.
AS I MENTIONED, AUTOIMMUNE
DISEASE HAS BEEN IMPORTANT --
1SEC.
I LOST VIEW OF THE SLIDE THERE.
ARE THEY STILL SHOWING FOR YOU
ALL?
>> YES.
>> I'M NOT ABLE TO SEE THEM.
CAN YOU LET ME KNOW WHICH SLIDE
WE'RE ON?
>> OMNIBUS LANGUAGE.
>> GREAT.
OKAY.
THANKS SO MUCH.
SO IN FISCAL YEAR '23, CONGRESS
CREATED THE OFFICE OF AUTOIMMUNE
DISEASE RESEARCH WITHIN ORWH BY
THIS CONGRESSIONAL DIRECTIVE.
THEY APPROPRIATED $10 BILLION IN
FUNDS TO COORDINATE A MULTI-IC
STRATEGIC RESEARCH PLAN TO
IDENTIFY EMERGING AREAS OF
INNOVATION AND RESEARCH
OPPORTUNITY, COORDINATING AND
EVALUATING THE PORTFOLIO,
PROVIDING RESOURCES TO SUPPORT
PLANNING, COLLABORATION AND I
OVATION AND TO DEVELOP PUBLICLY
ACCESSIBLE CENTRAL REPOSITORY
FOR AUTOIMMUNE DISEASE RESEARCH.
I AM THRILLED TO TELL YOU IN OUR
VERY FIRST YEAR OF EXISTENCE,
THE AUTOIMMUNE DISEASE RESEARCH
OFFICE FUNDED 41 APPLICATIONS
FROM 12 INSTITUTES AND CENTERS
AND WE WERE ABLE TO COVER 17
DISEASES IN THAT VERY FIRST
YEAR.
THE VERY FIRST FUNDING
OPPORTUNITY THAT WE'RE ABLE TO
DELIVER IS THE EXACT PLAN,
STANDS FOR EXPOSOME IN
AUTOIMMUNE DISEASE COLLABORATING
TEAMS PLANNING AWARDS.
IN COLLABORATION WITH THE
NATIONAL INSTITUTE OF ARTHRITIS,
MUSCULOSKELETAL AND SKIN
DISEASES AS WELL AS THE NATIONAL
INSTITUTE OF ENVIRONMENTAL
HEALTH SCIENCES, THE EXACT PLAN
NOTICE OF SPECIAL INTEREST WAS
ISSUED AND HERE ARE THE SIX
FIRST COMPACT-PLAN AWARDEE
REACCEPT YENTS.
YOU'RE GOING TO HEAR FROM
DR. BUCKNER SHORTLY, BUT THE
EXACT NETWORK IS DESIGNED TO BE
A NATIONAL RESEARCH
COLLABORATIVE TEAM TO CONDUCT
RESEARCH TO DISCOVER THE
ENVIRONMENTAL EXPOSURES THAT
INFLUENCE AUTOIMMUNE DISEASE
SUSCEPTIBILITY, ONSET AND
OUTCOMES, AND WILL DEVELOP A
SYSTEMS-LEVEL APPROACH TO
UNDERSTANDING THE MECHANISMS
RELATED TO PERTURBATIONS THAT
CROSS AUTOIMMUNE DISEASES.
WE WORKED ALSO WITH DR. LINDSAY
CRISWELL, DR. BOB CARTER, THE
LEADERSHIP OF THE NATIONAL
INSTITUTE OF ARTHRITIS,
MUSCULOSKELETAL AND SKIN
DISEASES TO CREATE A NEW PROGRAM
ALONG WITH THE OFFICE OF DAY A
SCIENCE STRATEGY.
THIS PROGRAM IS FOCUSED ON
LEADERSHIP DEVELOPMENT AND TEAM
SCIENCE IN THE AREAS OF WOMEN'S
HEALTH SPECIFICALLY AUTOIMMUNE
AND IMMUNE MEDIATED DISEASES.
THROUGH THIS LEADERSHIP SCHOLAR
PROGRAM OR LSP, WE ARE
SUPPORTING MID CAREER SCIENTISTS
WHO ARE WORKING IN THE WOMEN'S
HEALTH SPACE AND THEY HAVE THE
OPPORTUNITY TO WORK WITH THE
ACCELERATING MEDICINES
PARTNERSHIP, AUTOIMMUNE AND
IMMUNE-MEDIATED DISEASES
PUBLIC-PRIVATE PARTNERSHIP OR
AMP AIM.
THROUGH THAT LARGE
PUBLIC-PRIVATE PARTNERSHIP WITH
THE FOUNDATION FOR NIH, THESE
SIX INVESTIGATORS ARE WORKING ON
TOPICS THAT RANGE FROM
MULTI-OMIC APPROACHES TO EARLY
DISEASE PATHOGENESIS IN LUPUS
NEPHRITIS, AT THE
TRANSCRIPTIONAL AND EPIGENETIC
LEVELS AND TO A TOPIC NEAR AND
DEAR TO MY HEART, PERSONALIZED
USE OF METHOTREXATE FOR THE
TREATMENT OF JUVENILE IDIOPATHIC
ARTHRITIS-ASSOCIATED UVEITIS.
ORWH WAS ASKED BY CONGRESS TO
EXAMINE THE NIH PORTFOLIO AROUND
THREE AREAS.
MATERNAL MO MORBIDITY AND
MORTALITY, STALLED CERVICAL
CANCER SURVIVAL RATES IN THE
UNITED STATES AND RISING RATES
OF CHRONIC DISEASES IN WOMEN IN
THE U.S.
AS A RESULT OF THAT REQUEST, WE
HOSTED AN NIH-WIDE ADVISORY
COMMITTEE LED CONFERENCE ON
WOMEN'S HEALTH RELATED TO THOSE
TOPICS, AND WE IDENTIFIED
CHRONIC CONDITIONS UNDER WOMEN
AS A RESEARCH GAP.
WE PARTNERED WITH FIVE
INSTITUTES AND CENTERS
IDENTIFIED HERE ON THE SLIDE TO
CREATE THESE TWO RFAs FOCUSING
ON UNDERSTUDIED CHRONIC
CONDITIONS IN WOMEN, AN R01 AND
AN R21.
HERE OUR SPECIAL AREAS OF
INTEREST WERE IDENTIFIED AS
FEMALE-SPECIFIC CONDITIONS,
CONDITIONS MORE COMMON IN WOMEN.
HERE'S WHERE WE CALLED OUT
SPECIFICALLY AUTOIMMUNE
DISEASES, POSITIONS POTENTIALLY
UNDERSTUDIED IN WOMEN AND THOSE
WITH HIGH MORBIDITY IN WOMEN.
THE NEXT ROUND OF APPLICATIONS
WILL CLOSE ON JUNE 20TH AND
WE'RE LOOKING FORWARD TO SHARING
NEWS WITH YOU THOSE FUNDING
APPLICATIONS IN THE FUTURE.
ON NOVEMBER 13TH, I WAS
ABSOLUTELY HONORED TO BE ABLE TO
JOIN THE PRESIDENT AND FIRST
LADY ALONG WITH DR. MONICA
BERTAGNOLLI, WHO HAD JUST BEEN
NAMED NIH DIRECTOR, SECRETARY
BECERRA AND OTHERS IN THE OVAL
OFFICE FOR THE SIGNING OF THE
HISTORIC WHITE HOUSE INITIATIVE
ON WOMEN'S HEALTH RESEARCH.
IN THAT INITIATIVE, THE
PRESIDENT AND THE FIRST LADY
TALKED ABOUT HOW IMPORTANT
WOMEN'S HEALTH RESEARCH IS TO
THEM AND CHALLENGED ALL THE
AGENCIES INVOLVED TO IDENTIFY
CONCRETE ACTIONS THAT WE COULD
TAKE WITHIN 45 DAYS TO MAXIMIZE
THE ADMINISTRATION'S INVESTMENTS
IN WOMEN'S HEALTH RESEARCH,
INCLUDING ADDRESSING HEALTH
DISPARITIES AND HEALTH
INEQUITIES.
THE INITIATIVE IS DESIGNED TO
FUNDAMENTALLY CHANGE THE WAY WE
DO WOMEN'S HEALTH RESEARCH.
WHETHER THAT'S IDENTIFYING
OPPORTUNITIES FOR ADDITIONAL
INVESTMENTS, INTEGRATING
RESEARCH EFFORTS AND
FACILITATING INTERDISCIPLINARY
RESEARCH, DEVELOPING
PUBLIC-PRIVATE PARTNERSHIPS, AND
INCREASING PUBLIC AWARENESS OF
THE NEED FOR GREATER INVESTMENT
AND ATTENTION TO WOMEN'S HEALTH
RESEARCH.
YOU'RE GOING TO NEED TO CLICK
NEXT A COUPLE TIMES UNTIL THREE
RED BARS ARE UP.
OKAY.
AND THEN PLEASE GO FORWARD TO
THE NEXT SLIDE, WHERE I AM
TALKING ABOUT THIS AMAZING
EXECUTIVE ORDER 14120.
THIS EXECUTIVE ORDER IS
HIGHLIGHTING THE IMPORTANCE OF
ADVANCING WOMEN'S HEALTH
RESEARCH.
SO FIRST THE PRESIDENT SIGNED A
PRESIDENTIAL MEMO AND THEN THIS
WAS FILED WITH AN EXECUTIVE
ORDER THAT HIGHLIGHTS FOUR
AREAS: THE IMPORTANCE OF
PRIORITIZING INVESTMENT IN
WOMEN'S HEALTH RESEARCH,
INTEGRATING WOMEN'S HEALTH
ACROSS THE FEDERAL RESEARCH
PORTFOLIO, IN MULTIPLE AGENCIES
AND DEPARTMENTS, GALVANIZING NEW
RESEARCH ON WOMEN'S MID LIFE
HEALTH, AND THEN ASSESSING UNMET
NEEDS TO SUPPORT WOMEN'S HEALTH
RESEARCH.
AND I'M LOOKING FORWARD TO
SHARING NEWS WITH YOU ABOUT ALL
OF THE AMAZING STEPS WE ARE
TAKING TO ALIGN WITH THIS
EXECUTIVE ORDER.
THE NEXT SLIDE HIGHLIGHTS A
NOTICE OF SPECIAL INTEREST WHICH
IS ONE OF NIH'S VERY FIRST STEPS
WE ARE TAKING TO ADDRESS AND
ALIGN WITH THE EXECUTIVE ORDER.
WE HAVE ISSUED A NOTICE OF
SPECIAL INTEREST RELATED TO
WOMEN'S HEALTH RESEARCH EVERY
SINGLE INSTITUTE AND CENTER
SIGNED ON TO THIS NOSI.
IT IS LINKED TO ALL OF THE NIH
PARENT FUNDING OPPORTUNITIES
REGARDLESS OF MECHANISM OR
INSTITUTE, SO ALL THE PARENT
FUNDING OPPORTUNITIES, THE
RPGs, THE Ts, THE Ks, THE
Fs, THE SMALL BUSINESS
INNOVATION, THE TECH TRANSFER,
EVERYBODY SINGLE FUNDING
OPPORTUNITY THAT'S APPARENT IS
LINKED TO THIS.
AND WHAT THAT DOES IS THAT GIVES
APPLICANTS MANY PATHWAYS TO
WOMEN'S HEALTH RESEARCH.
IT INDICATES OUR INTEREST IN
RECEIVING APPLICATIONS ON
WOMEN'S HEALTH RESEARCH ACROSS A
WIDE RANGE OF TOPICS.
CERTAINLY CONDITIONS THAT
PREDOMINANTLY AFFECT WOMEN AND,
AGAIN, AUTOIMMUNE DISEASES WERE
EXPRESSLY CALLED OUT HERE ALONG
WITH DEPRESSIVE DISORDERS,
ALZHEIMER'S DISEASE AND OTHER
DISEASES THAT PRESENT OR
PROGRESS DIFFERENTLY IN WOMEN
AND THEN THOSE THAT ARE
FEMALE-SPECIFIC.
SO WE ARE VERY EXCITED ABOUT
THIS NEW OPPORTUNITY.
TODAY WE LAUNCHED THE NEW
NIH-WIDE STRATEGIC PLAN FOR
RESEARCH ON THE HEALTH OF WOMEN
FOR 2024 TO 2028, A ROAD MAP TO
THE FUTURE.
I AM DELIGHTED TO BE HERE TODAY
WITH YOU TO ANNOUNCE THIS
NIH-WIDE STRATEGIC PLAN THAT
WILL SET OUT OUR GOALS FOR THE
NEXT FIVE YEARS AND WILL BE THE
ROAD MAP THAT ALL OF US WILL
FOLLOW ACROSS THE 27 INSTITUTES
AND CENTERS HERE AT NIH TO
ADDRESS WHAT WAS IDENTIFIED
COLLECTIVELY WITH KEY INTERESTED
PARTNERS, FEDERAL PARTNERS, OUR
ADVISORY COMMITTEE AND OTHERS,
SCIENTISTS, CLINICIANS IN THE
FIELD, WHO'VE IDENTIFIED
RESEARCH GAPS AND WE HAVE
ARTICULATED GOALS AND OBJECTIVES
TO ADDRESS THOSE GAPS.
WE HAVE TAKEN A DATA-DRIVEN
ITERATIVE APPROACH AND WE ARE
COMMITTED TO HEARING FROM THE
INDIVIDUALS AFFECTED BY THE
DISEASES UNDER STUDY WOMEN IN
OUR COMMUNITY AND FROM THE
PUBLIC IN GENERAL.
SO I'M DELIGHTED TO BE ABLE TO
ANNOUNCE THAT TO YOU AND WE'LL
REFER YOU TO A VIDEO THAT HAS
BEEN LAUNCHED TODAY WHERE THE
NIH DIRECTOR, DR. MONICA
BERTAGNOLLI, ARTICULATES HER
VISION FOR WOMEN'S HEALTH
RESEARCH IN THE FUTURE.
THIS SLIDE IS A THANK YOU SLIDE.
I WANTED TO ARTICULATE ON THIS
SLIDE SO MANY THINGS WE ARE
GRATEFUL FOR TO DR. PINN, BUT I
DECIDED JUST TO SAY THAT WE ARE
THANKFUL FOR EVERYTHING THAT
SHE'S DONE IN TERMS OF CREATING
THE VERY FIRST NIH-WIDE
STRATEGIC PLAN FOR WOMEN'S
HEALTH RESEARCH, TO CREATING THE
BIRCH PROGRAM AND THE SCORE
PROGRAM AND THE RE-ENTRY
SUPPLEMENT PROGRAM AND ADVANCING
INCLUSION POLICY AND OTHER
PROGRAMS FOR THE RECRUITMENT
RE-ENTRY AND SUSTAINED
ADVANCEMENT OF WOMEN IN SCIENCE
CAREERS.
WE REALLY WANT TO ACKNOWLEDGE
YOU, DR. PINN, FOR ALL OF YOUR
EFFORTS THAT HAVE HELPED US GET
TO WHERE WE ARE TODAY, AND THAT
IS WHY THIS SYMPOSIUM IS NAMED
IN YOUR HONOR, SO THANK YOU, DR.
I ALSO WANT TO THANK DR
DR. SHANMUGAM AND THE TEAM FOR
PLANNING THIS EVENT, THE OFFICE
OF AUTOIMMUNE DISEASE RESEARCH,
THEIR VERY FIRST NIH-WIDE VIVIAN
PINN SYMPOSIUM TYPE OF EVENT,
THE ORWT COMMUNICATIONS TEAM,
OUR PARTNERS AND THE NIH
INSTITUTES AND CENTERS,
CONTRACTORS AND COLLEAGUES
ACROSS THE ICs WHO WORKED ON
THE PROGRAM, ALL OF THE
SPEAKERS, ALL OF THE MODERATORS,
FOR PARTICIPATING TODAY, AND I
ALSO WANT TO ACKNOWLEDGE ALL OF
THE WOMEN AND INDIVIDUALS WHO
HAVE PARTICIPATED IN THE
RESEARCH THAT WE'RE ABLE TO
PRESENT TO YOU TODAY.
YOU ARE THE REASON WHY WE ARE
DOING THIS AND WE LOOK FORWARD
TO CONTINUED EFFORTS IN THIS
REGARD.
IF YOU GO TO THE NEXT SLIDE, YOU
WILL SEE THE SPEAKERS WE WILL BE
HAVING, OUR TWO KEY NOTES.
TODAY'S SYMPOSIUM IS ENTITLED
SYNERGY IN SCIENCE, INNOVATIONS
IN AUTOIMMUNE DISEASE RESEARCH
AND CARE.
FIRST YOU'LL BE HEARING FROM DRL
HEAR AT THE END FROM OUR
CAPSTONE SPEAKER, DR. GAIL KARR.
SO PLEASE STAY WITH US FOR THIS
FULL EVENT.
I'M GOING TO WELCOME OUR KEYNOTE
SPEAKER, DR. JANE BUCKNER.
DR. BUCKNER IS THE PRESIDENT OF
THE BENAROYA RESEARCH INSTITUTE
IN SEATTLE, WASHINGTON.
SHE ALSO SERVES AS AFFILIATE
PROFESSOR IN THE DEPARTMENT OF
MEDICINE, DEPARTMENT OF
RHEUMATOLOGY AND DEPARTMENT OF
IMMUNOLOGY AT THE UNIVERSITY OF
WASHINGTON.
HER FULL BUY Y BIYO IS AVAILABLN
THE PROGRAM BOOKLET LINKED IN
THE CHAT.
DR. BUCKNER IS KNOWN FOR HER
RESEARCH IN TRANSLATIONAL
IMMUNOLOGY, COMBINING GENETICS,
IMMUNOLOGY AND CLINICAL MEDICINE
TO ADVANCE THE UNDERSTANDING OF
THE CAUSES OF AUTOIMMUNE
DISEASES.
SHE HAS BEEN INSTRUMENTAL IN
DEVELOPING THE TRANSLATIONAL
IMMUNOLOGY RESEARCH PROGRAM AND
ESTABLISHING THE BENAROYA
RESEARCH INSTITUTE
BIOREPOSITORY, WHICH CURRENTLY
INCLUDES OVER 350,000 SAMPLES
FROM 14,000 PARTICIPANTS.
DR. BUCKNER HAS MADE SIGNIFICANT
CONTRIBUTIONS TO OUR
UNDERSTANDING OF HOW HUMAN T
CELLS ARE DISREGULATED IN TYPE D
ARTHRITIS AND HAS BEEN A PIONEER
IN THE DEVELOPMENT OF
ANTIGEN-SPECIFIC T REG
THERAPIES.
WE LOOK FORWARD TO LEARNING FROM
HER DURING THIS KEYNOTE ADDRESS.
WELCOME, DR. BUCKNER.
>> THANK YOU.
THANK YOU SO MUCH FOR THAT KIND
INTRODUCTION, AND THIS IS REALLY
AN EXCITING SYMPOSIUM TO BE
PART.
AND TODAY I'M GOING TO TRY TO
GIVE AN OVERVIEW OF HOW WE CAN
LOOK AND UNDERSTAND -- LOOK AT
AUTOIMMUNE DISEASES, UNDERSTAND
THEM, AND ULTIMATELY HOW ARE OUR
STUDIES AND SCIENCE GOING TO
TRANSFORM PATIENTS' LIVES.
ALL RIGHT.
BRIEFLY JUST WANTED TO SHARE MY
DISCLOSURES.
I WILL BE TALKING ABOUT
ENGINEERED REGULATORY T CELLS
DURING THIS TALK.
SO STARTING WITH THE TOP POINT
OF VIEW IS JUST SOME TAKE HOME
MESSAGES TODAY.
IMPORTANTLY, AUTOIMMUNITY
AFFECTS A LARGE MERS TAJ PERCENF
OUR POPULATION.
I PUT TODAY IN PARENTHESES
BECAUSE MY GOAL AND HOPE IS THAT
THIS WILL CHANGE TOMORROW.
THIS HAS ALREADY BEEN MENTIONED,
WOMEN ARE DISPROPORTIONATELY
IMPACTED BY AUTOIMMUNITY, AND
WHEN WE THINK ABOUT AUTOIMMUNE
DISEASES, I'M GOING TO TALK
TODAY ABOUT HOW THE IMMUNE
SYSTEM IS CENTRAL TO AUTOIMMUNE
DISEASES AND THE FACTORS THAT
ARE DRIVING AUTOIMMUNITY
INCLUDING OUR GENETICS AS WELL
AS ENVIRONMENTAL EXPOSURES.
AND WHEN WE THINK OF THOSE
INFLUENCES, THEY'RE BOTH
INFLUENCING THE ULTIMATE
DEVELOPMENT OF AUTOIMMUNITY, BUT
ALSO THE OUTCOMES CLINICALLY FOR
OUR PATIENTS WHO HAVE AUTOIMMUNE
DISEASES.
I'D LIKE TO TALK ON SOME NEW
APPROACHES IN TERMS OF TREATING
AUTOIMMUNITY AND HOW WE CAN
TARGET DISEASE SPECIFICALLY.
AND THEN AT THE END OF THE DAY,
HOW DO WE PREDICT AND PREVENT
THESE DISEASES, BECAUSE THAT'S
THE ULTIMATE FORM OF CURE.
SO I THOUGHT I'D START WITH WHAT
IS AUTOIMMUNITY, AND IT IS --
THESE ARE DISEASES THAT SHARE IN
COMMON THE FACT THAT THE IMMUNE
SYSTEM IS ATTACKING HEALTHY
TISSUE.
THIS IS A LIST OF SOME
AUTOIMMUNE DISEASE, CERTAINLY
NOT ALL OF THEM.
THEY LOOK DIFFERENT TO THE
PHYSICIANS CARING FOR THESE
PATIENTS AND MANY TIMES WHEN I
TALK TO THE PUBLIC, PEOPLE
AREN'T AWARE THAT SOME OF THESE
DISEASES ARE TRULY AUTOIMMUNE.
THINGS LIKE AUTOIMMUNE THYROID
DISEASE, TYPE 1 DIABETES,
PSORIASIS AND ANY NUMBER OF
DISEASES.
I'M A RHEUMATOLOGIST SO I THINK
A LOT ABOUT JOINT DISEASES AND
RHEUMATOID ARTHRITIS BUT TODAY
YOU'LL HEAR ME TALKING ABOUT
TYPE 1 DIABETES AND HOPEFULLY
YOU'LL UNDERSTAND BY THE END OF
MY TALK WHY A RHEUMATOLOGIST IS
THINKING ABOUT TYPE 1 DIABETES.
SO WHAT I'D LIKE TO EMPHASIZE IS
ALTHOUGH THESE DISEASES LOOK
DIFFERENT, THEY REALLY SHARE
SOME COMMON FEATURES.
BUT BEFORE I GET INTO THE IMMUNE
SYSTEM AND HOW IT'S INVOLVED,
JUST WANT TO AGAIN RE-EMPHASIZE
THAT AUTOIMMUNE DISEASES ARE
CHRONIC, DEBILITATING, COSTLY,
AND CURRENTLY INCURABLE.
THERE'S OVER 110 DIFFERENT
AUTOIMMUNE DISEASES.
THAT NUMBER CHANGES AND KEEPS
GOING UP.
BUT I THINK WHAT'S REALLY
IMPORTANT TO UNDERSTAND IS THAT
MEANS 1 IN 15 AMERICANS HAS AN
AUTOIMMUNE DISEASE AND OF COURSE
THAT MEANS MANY MORE PEOPLE ARE
IMPACTED BY THEM AS THEIR
FAMILIES AND PEOPLE WHO CARE FOR
THEM AND LOVE THEM ARE ALSO
IMPACTED.
THESE ARE COSTLY DISEASES
BECAUSE OF THE CHRONICITY OF THE
DISEASES AND THEY'RE COSTLY BOTH
IN TERMS OF OUR CARE FOR OUR
PATIENTS, BUT CLEARLY THEY'RE
DEBILITATING FOR INDIVIDUALS AS
WELL.
AS WAS ALREADY MENTIONED, WOMEN
ARE MUCH MORE FREQUENTLY
AFFECTED BY AUTOIMMUNITY THAN
MEN.
AND I'D ALSO LIKE TO POINT OUT
THAT THESE DISEASES AFFECT ALL
AGE GROUPS FROM EARLY CHILDHOOD
TO WOMEN WHO MAY BE IN THEIR
20s AND 30s TO THOSE THAT
CAN EVEN BEGIN LATER IN LIFE.
SO REALLY CROSSING THE WHOLE
CONTEXT OF HUMAN HEALTH.
SO WHEN I TALK ABOUT AUTOIMMUNE
DISEASES, WE REALLY HAVE TO
THINK ABOUT HOW IS THE IMMUNE
SYSTEM INVOLVED AND SO FOR
IMMUNOLOGISTS LIKE MYSELF, WE
NEED TO THINK ABOUT THE
STRUCTURES THAT ARE DRIVING
AUTOIMMUNITY.
I'M A T-CELL IMMUNOLOGIST SO I'M
SHOWING YOU A FIGURE THAT
EMPHASIZES T CELLS AND CLEARLY
THAT'S NOT THE ONLY THING
INVOLVED, BUT WHAT WE THINK
ABOUT IS WE KNOW THAT T CELLS
ARE REALLY KIND OF THE GUIDING
FORCE OF THE IMMUNE RESPONSE,
GIVING US A VERY TARGETED
SPECIFIC RESPONSE, HELPING
PROTECT US FROM VIRUSES,
BACTERIA, CANCERS.
AND WHAT HAPPENS IN AUTOIMMUNITY
IS THAT THESE T CELLS THAT ARE
SPECIFIC FOR SELF ANTIGEN BECOME
ACTIVATED AND THEN START DRIVING
THE AUTOIMMUNE RESPONSE.
IT HELPS PROMOTE THE DEVELOPMENT
OF AUTOANTIBODIES, WHICH ARE THE
COMMON MARKER WE USE FOR
AUTOIMMUNITY AND WHICH CAN
DIRECTLY DRIVE DISEASE, BUT ALSO
THESE T CELLS MAY PROMOTE
INFLAMMATION, BRINGING OTHER
CELLS TO A TISSUE AND THEN
CAUSING DAMAGE.
SO TODAY WE'RE GOING TO TALK A
LITTLE BIT ABOUT CERTAIN ASPECTS
OF THIS PATHWAY AND HOW WE CAN
UNDERSTAND IT BETTER.
NOW, WHEN WE THINK ABOUT
AUTOIMMUNITY AS A FAILURE OF
IMMUNE TOLERANCE, ONE OF THE
ISSUES IS THAT THESE ARE
DISEASES THAT OCCUR OVER TIME.
SO THE MAJORITY OF PEOPLE ARE
HEALTHY INITIALLY, BUT THEN AT
SOME POINT, THERE IS A TRIGGER
THAT LEADS TO IMMUNE
DYSREGULATION.
WE TYPICALLY IDENTIFY THOSE
INDIVIDUALS AS HAVING
AUTOANTIBODIES.
THEY DO NOT YET FEEL ILL, THEY
DO NOT YET HAVE INFLAMMATION IN
ANY OF THEIR TISSUES, BUT THEN
THEY WILL GO ON TO START
DEVELOPING DISEASE, DEVELOP
TISSUE INFLAMMATION, AND THEN
OVER TIME, BECAUSE THESE ARE
CHRONIC DISEASES, THERE'S A
PERPETUATION OF THAT
INFLAMMATION, TISSUE
DESTRUCTION, AND EVEN SOMETIMES
MORE SYSTEMIC EFFECTS.
SO THERE'S REALLY A TIMELINE IN
TERMS OF DEVELOPING AUTOIMMUNE
DISEASES.
THEN WHEN WE TRY TO UNDERSTAND
WHAT ARE THE FACTORS THAT ARE
PARTICIPATING IN THE
DEVELOPMENT, WHY DO SOME PEOPLE
GET THESE DISEASES AND OTHERS
NOT, WE KNOW GENETICS IS A
FACTOR.
AUTOIMMUNE DISEASES RUN IN
FAMILIES, SOMETIMES IT'S THE
SAME DISEASE, BUT FREQUENTLY
WE'LL SEE FAMILIES WHERE ONE
INDIVIDUAL MIGHT HAVE RHEUMATOID
ARTHRITIS, A CHILD OF THAT
PARENT MIGHT HAVE TYPE
1 DIABETES AND SOMEONE'S SISTER
HAS THYROID DISEASE.
WHEN I'M IN CLINIC, I HEAR THIS
STORY EVERY WEEK.
SO WE KNOW GENETICS IS
IMPORTANT, IT SETS YOU UP
POTENTIALLY FOR AUTOIMMUNITY.
WE ALSO KNOW IT'S NOT THE ONLY
FACTOR.
IDENTICAL TWINS, ONLY ABOUT 50%
WILL BOTH HAVE AN AUTOIMMUNE
DISEASE.
SO OTHER FACTORS ARE INVOLVED
AND WE KNOW THOSE TEND TO BE
ENVIRONMENTAL FACTORS.
EXPOSURES TO INFECTIONS,
INJURIES, LIFESTYLE STRESS,
CHEMICALS, A CLASSIC EXAMPLE IS
CIGARETTE SMOKING WHERE IF YOU
HAVE THE GENETIC RISK FOR
RHEUMATOID ARTHRITIS, YOU HAVE A
50% GREATER CHANCE OF GETTING
R.A. IF YOU'RE A SMOKER.
SO THE ENVIRONMENT IS REALLY
IMPORTANT.
AND THEN I ALWAYS ADD IN TIME,
BECAUSE AGE, MATURATION, AND
OTHER COMORBIDITIES ALSO
INFLUENCE THE DEVELOPMENT OF
AUTOIMMUNITY AND THEN OF COURSE
THE OUTCOME OF THOSE DISEASES.
SO THE KEY QUESTIONS WE NEED TO
ASK TO UNDERSTAND AUTOIMMUNITY
IS REALLY WHAT FACTORS INITIATE
AND PERPETUATE AUTOIMMUNE
DISEASES.
AND TO DO THAT, WE CAN LOOK AT
THE IMMUNE FEATURES THAT
DIFFERENTIATE INDIVIDUALS WITH
AUTOIMMUNITY FROM THOSE WITHOUT
AUTOIMMUNITY.
THEN ONCE WE IDENTIFY WHAT'S
DIFFERENT, ASK WHAT MECHANISMS
ARE LEADING TO THESE DIFFERENCES
AND THEN ULTIMATELY CAN WE
INTERVENE TO TREAT THESE
MECHANISMS, PREVENT AND CURE
DISEASE.
SO OVER THE LAST 20 YEARS SINCE
I'VE BEEN STUDYING AUTOIMMUNE
DISEASES, I THINK WE'VE
DEVELOPED A PARADIGM FOR
ADVANCING OUR UNDERSTANDING OF
THESE DISEASES AND PARTICULARLY
A PARADIGM THAT ALLOWS US TO
MOVE INTO PATIENTS.
AS A PHYSICIAN, MY GOAL HAS
ALWAYS BEEN TO UNDERSTAND MY
PATIENTS AND WHAT'S DRIVING
THEIR DISEASE.
SO THERE'S CHALLENGES AROUND
THAT BECAUSE STUDYING HUMAN
BEINGS IS COMPLICATED.
SO THIS PARADIGM REALLY STARTS
WITH THE GENERATION OF
HYPOTHESES.
MODEL SYSTEMS CAN BE REALLY
POWERFUL IN HELPING US DEVELOP A
BETTER UNDERSTANDING OF THE
IMMUNE SYSTEM AND THEN
UNDERSTAND HOW CHANGES IN THE
IMMUNE SYSTEM COULD DRIVE
AUTOIMMUNITY.
ADDITIONALLY, WE CAN STUDY
UNIQUE POPULATIONS.
POPULATIONS WHERE THERE MAY BE A
SINGLE GENE MUTATION THAT DRIVES
AUTOIMMUNITY OR GROUPS THAT WE
KNOW HAVE INCREASED RISK FOR
AUTOIMMUNITY.
THEN AS WE LEARN MORE ABOUT
GENES AND THE GENETIC RISK, THAT
HAS BEEN AN AREA THAT HAS REALLY
HELPED US DEVELOP HYPOTHESES
THAT WE CAN THEN GO AND TEST
GROUPS OF PATIENTS.
SO DEVELOPING COHORTS IS REALLY
IMPORTANT.
AND ONE OF THE THINGS THAT IS
VERY IMPORTANT HERE IS NOT JUST
GETTING GROUPS OF PATIENTS WITH
A DISEASE YOU'RE INTERESTED IN,
BUT HAVING A CONTROL POPULATION
TO LOOK AT TO COMPARE THEM TO.
PEOPLE WHO ARE SIMILAR IN AGE,
IN SEX, IN THEIR BACKGROUND AS
WELL,, IS IMPORTANT FOR US SO
DEVELOPING THESE COHORTS HAS
BEEN A PROJECT MANY OF US HAVE
BEEN ENGAGED IN OVER THE LAST 20
YEARS AND I THINK IT BECOME VERY
NOTABLE IN HOW IT HELPS US STUDY
HUMAN DISEASE.
SO WE HAVE A HYPOTHESIS, WE HAVE
A COHORT OF INDIVIDUALS TO STUDY
AND THEN WE CAN ASSESS DIFFERENT
IMMUNOLOGIC PATHWAYS TO
UNDERSTAND IF THESE -- THIS
HYPOTHESIS WE HAVE IS TRUE.
THEN WHAT'S REALLY USEFUL ONCE
WE IDENTIFY PATHWAYS THAT ARE
ALTERED IN INDIVIDUALS WITH AN
AUTOIMMUNE DISEASE IS TO ASK
SOME ADDITIONAL QUESTIONS.
AND ONE OF MY FAVORITE QUESTIONS
IS TO SAY, IS THIS FEATURE
SHARED ACROSS AUTOIMMUNE
DISEASES?
IS THIS SOMETHING THAT WE CAN
EXPAND BEYOND?
SO HAVING OTHER POPULATIONS TO
COMPARE TO, AND THAT HELPS US
THINK DOWN THE ROAD ABOUT WHO TO
TREAT.
WE CAN LOOK AT DISEASE
EVOLUTION.
LOOKING AT INDIVIDUALS WHO ARE
AT RISK, MAYBE FAMILY MEMBERS OF
INDIVIDUALS WITH AUTOIMMUNITY,
AND FOLLOW THEM OVER TIME AS
THEY DEVELOP AN AUTOIMMUNE
DISEASE.
THAT HELPS US KNOW ONCE WE HAVE
A TREATMENT WHEN TO TREAT
PATIENTS.
AND THEN WE ALSO CAN NOW TAKE
ADVANTAGE OF WHAT I CALL IN VIVO
INTERVENTIONS.
THAT MAY BE A CLINICAL TRIAL
WHERE WE DRAW EXTRA SAMPLES AND
TRY TO LOOK AT HOW WE'RE
CHANGING THE IMMUNE SYSTEM.
OR IT MAY BE A STUDY WHERE WE
VERY SPECIFICALLY ASK
INDIVIDUALS TO PARTICIPATE WHERE
WE CAN INTERVENE, GIVE A
VACCINATION, USE A SPECIFIC
DRUG, AND SEE HOW WE'VE CHANGED
THEIR IMMUNE RESPONSE.
AND THAT REALLY HELPS US START
THINKING ABOUT HOW TO TREAT.
I'M GOING TO TRY TO TOUCH ON
EACH OF THESE APPROACHES TODAY.
SO TO START WITH, I THOUGHT I'D
TALK ABOUT REALLY HOW GENETICS
CAN TEACH US ABOUT AUTOIMMUNITY.
AND FOLLOW THIS PATHWAY AND SHOW
YOU HOW UNDERSTANDING ONE SET OF
GENES HAS LED MY GROUP ACTUALLY
TO DEVELOPING A THERAPEUTIC.
SO THE GENOME-WIDE ASSOCIATION
STUDIES WERE PERFORMED IN THE
EARLY 2000s.
AND THOSE STUDIES DEMONSTRATED A
WHOLE SERIES OF GENE OR GENE
REGIONS THAT WERE ASSOCIATED
WITH AUTOIMMUNITY.
SOME PEOPLE WERE DISAPPOINTED
BECAUSE THERE WEREN'T JUST A FEW
GENES, THERE WERE ACTUALLY
HUNDREDS OF GENES.
BUT ONE COULD LOOK AT THE
GENETIC RISK AND HERE'S SHOWING
SOME OF THE GENES THAT WERE
ASSOCIATED WITH TYPE 1 DIABETES.
IN PURPLE, THOSE WERE GENES
INVOLVED THE IN THE IMMUNE SYSM
AND ITS FUNCTION.
SO I WAS PLEASED TO SEE AS AN
EARLY INVESTIGATOR THAT BEING AN
IMMUNOLOGIST AND STUDYING
AUTOIMMUNITY MADE SENSE.
SO THIS IS A STORY ABOUT ONE
GENE CALLED PTPN2.
THEY'RE ALL INVOLVED IN
IL2 SIGNALING.
SO THE GWAS IN TYPE 1 DIABETES
BASICALLY PUT AN ARROW POINTING
AT IL2 AND WE NEEDED TO
UNDERSTAND IT.
SO PTPN2 IS ACTUALLY INVOLVED IN
THE INHIBITION OF THE
IL2 SIGNALING PATHWAY, AND
IL2 IS VITAL TO THE GROWTH AND
SURVIVAL O OF T CELLS BUT
SPECIFICALLY TO REGULATORY T
CELLS.
SO WE CAN STUDY THE ROLE OF
IL2 SIGNALING AND HOW THE
VARIANTS ARE INVOLVED BY LOOKING
AT SIGNALING IN T CELLS.
SO WHAT WE DID EARLY ON WAS WE
HAD A GROUP OF WHAT WE
CONSIDERED HEALTHY CONTROL
INDIVIDUALS.
THESE INDIVIDUALS DID NOT HAVE
ANY CHRONIC CONDITIONS, DID NOT
HAVE ANY AUTOIMMUNE DISEASES,
AND IMPORTANTLY, DIDN'T HAVE ANY
FIRST DEGREE RELATIVES WITH
AUTOIMMUNITY.
SO THEY WERE NOT GENETICALLY
ENRICHED FOR AUTOIMMUNITY.
BUT WE WERE ABLE TO LOOK FOR
THESE GENETIC VARIANTS THAT WERE
ASSOCIATED WITH AUTOIMMUNITY IN
THESE INDIVIDUALS, BECAUSE
THEY'RE COMMON VARIANTS.
SO WHAT I'M SHOWING HERE ON THE
LEFT IS LOOKING AT THE RESPONSE
TO IL2, WE MEASURE THAT AS
PERCENT OF PHOSPHORYLATED STAT5
IN THIS COHORT OF HEALTHY
CONTROLS.
AND WHEN WE LOOK AT THIS, THE
C/C WITH THE STARS ARE
INDIVIDUALS HOMOZYGOUS FOR THE
RISK VARIANT.
AND WE CAN COMPARE THEM TO THE
TT GRO/T GROUP IN BLACK, HOMOZYS
FOR THE NON-RISK.
YOU CAN SEE THERE'S A VERY
SIGNIFICANT DIFFERENCE IN THE
ABILITY TO RESPOND TO
IL2 BETWEEN THE NON-RISK GROUP
AND THE RISK GROUP, AND THEN THE
INDIVIDUALS WHO WERE
HETEROZYGOUS FOR RISK SHOWED AN
INTERMEDIATE PHENOTYPE.
SO SUGGESTING THAT IMPAIRED
RESPONSES TO IL2 IN T CELLS IS
ASSOCIATED WITH THIS GENETIC
RISK VARIANT.
NOW, WHEN WE STUDY
CHARACTERISTICS OF THE IMMUNE
SYSTEM IN INDIVIDUALS, SOME
THINGS VARY WIDELY, DEPENDING ON
THE DAY, THE WEEK AND WHAT
INFECTION YOU HAD RECENTLY.
AND THINGS THAT ARE GENETICALLY
DRIVEN SHOULD ACTUALLY BE VERY
CONSISTENT OVER TIME.
SO WHAT WE'RE ABLE TO DO WITH
OUR COHORTS WHERE WE HAVE
SAMPLES DRAWN AT TWO DIFFERENT
TIME POINTS, IN THIS CASE,
MONTHS TO YEARS APART, WE CAN DO
THE SAME ASSAY WITH THOSE TWO
SAMPLES FROM THE SAME
INDIVIDUALS AND AS YOU CAN SEE
THERE'S A REALLY BEAUTIFUL
LINEAR CORRELATION FOR THE
RESPONSE TO IL2 AND VERY
CONSISTENT IN AN INDIVIDUAL BUT
DIFFERENT BASED ON GENOTYPE.
SO THIS SUGGESTED TO US THAT
IMPAIRED IL2 RESPONSES MAY BE
IMPORTANT IN TYPE 1 DIABETES.
SO TO ASK THAT QUESTION, WE TOOK
OUR CONTROL COHORT WITH A GROUP
OF INDIVIDUALS WITH TYPE
1 DIABETES AND LACKED AT THEIR
LOOKED AT THEIRABILITY TO RESPO.
ON THE LEFT YOU CAN SEE THE SAME
MEASURE, PERCENT OF PHOSPHO
STAT5 IN RESPONSE TO IL2 AND THE
CONTROLS ARE IN BLACK AND THE
TYPE 1 DIABETIC INDIVIDUALS ARE
IN BLUE.
NOW THERE'S A SIGNIFICANTLY
LOWER RESPONSE TO IL2 OVERALL
THAT BUT YOU CAN SEE ACROSS
INDIVIDUALS THERE'S QUITE A
VARIATION.
SO THEN WE WANTED TO SAY HOW
MUCH OF THIS IS DUE TO THE GENE
PTPN2, SO THEN WE'RE ABLE TO
COMPARE THE T/T CONTROLS, THOSE
ARE HEALTHY INDIVIDUALS WHO
DON'T CARRY THE RISK, SO
INDIVIDUALS WHO ARE T/T
DIABETICS, AND YOU CAN SEE THAT
THEY'RE ALREADY DIFFERENT, EVEN
THOUGH THAT GENETIC RISK IS NOT
THERE.
WHEN WE LOOK WITHIN THE
DIABETICS, WE CAN TELL THAT
PTPN2 DOES EVEN FURTHER BLUNT
IL2 SIGNALING, BUT BY DOING THE
STUDY IN THIS WAY, WE'RE ABLE TO
KNOW THAT NOT THIS ONE SINGLE
GENE ALONE IS CAUSING THE
BLUNTED IL2 SIGNALING, BUT IT'S
A MORE COMMON CHARACTERISTIC
LIKELY DUE TO A COMBINATION OF
GENETIC RISK VARIANTS, ALL OF
WHICH AFFECT THE IL2 PATHWAY.
SO GENETICS IS GREAT, SHOWING
YOU PHOSPHO STAT5 SIGNALING IS
NICE, BUT IT REALLY DOESN'T TELL
US WHAT'S GOING ON IN THE IMMUNE
SYSTEM, AND SINCE AS I NOTED
BEFORE THAT IL2 IS REALLY VITAL
TO THE SURVIVAL AND FUNCTION OF
REGULATORY T CELLS, WHICH WE
KNOW ARE VITAL TO CONTROLLING
AUTOIMMUNITY, WE WANTED TO ASK
NEXT, WHAT HAPPENS IF YOU'RE AN
INDIVIDUAL WHO HAS IMPAIRED
IL2 RESPONSES?
SO WE LOOKED AT REGULATORY T
CELLS THAT WE TOOK FROM THE
BLOOD OF INDIVIDUALS WITH TYPE E
HERE, OR HEALTHY CONTROLS.
AND IF YOU LOOK AT THE FIGURE
AND LOOK AT THE -- WHERE NO
IL2 IS PRESENT WE CAN SEE A LOSS
OF REGULATORY T CELLS OVER TIME
IN BOTH CONTROLS AND TYPE
1 DIABETICS.
BUT WHAT'S REALLY THE MOST
IMPRESSIVE THING IS THAT IF YOU
INCUBATE WITH IL2, WE LOSE THE
REGULATORY T CELLS EVEN IN THE
PRESENCE OF IL2 IF AN INDIVIDUAL
HAS TYPE 1 DIABETES.
IT'S SHOWN ON THE LEFT, FOR MANY
INDIVIDUALS ON THE RIGHT IT
SHOWED A COMPENDIUM OF
INDIVIDUALS WITH TYPE
1 DIABETES.
SO WHAT THIS SUGGESTS IS THAT IN
TYPE 1 DIABETES, THERE MAY BE AN
IMBALANCE WHERE THE EFFECTOR T
CELLS THAT CAN TARGET THE BETA
CELL, CAUSE TYPE 1 DIABETES, MAY
NOT BE REGULATED AND THERE MAY
BE AN INADEQUATE NUMBER OF
REGULATORY T CELLS OR THOSE
CELLS MAY NOT FUNCTION WELL.
SO BEGINNING WITH A SET OF GENES
THAT POINTED TO IL2, WE WERE
THEN ABLE TO FIND
CHARACTERISTICS THAT CHANGE THE
IMMUNE SYSTEM AND SUGGEST THAT
THERE MAY BE FAILED T REG
FITNESS IN INDIVIDUALS WITH TYPE
1 DIABETES.
SO THAT RAISES THE QUESTION,
COULD WE TREAT TYPE 1 DIABETES
BY INCREASING REGULATORY T
CELLS?
AND THIS IS AN AREA WHERE MANY
PEOPLE HAVE BEEN INTERESTED IN
ADDRESSING THE QUESTION AND
BECAUSE OF THE BRIEF TIME I HAVE
TODAY, I'M ONLY GOING TO TALK
ABOUT ONE AREA.
THERE'S ONE APPROACH PEOPLE HAVE
TAKEN, IS TO GIVE IL2 TO
INDIVIDUALS WITH TYPE
1 DIABETES, THIS HAS ALSO BEEN
DONE IN OTHER AUTOIMMUNE
DISEASES.
AND WHAT WE KNOW FROM THOSE
STUDIES, IN FACT, ONE STUDY MY
GROUP WAS INVOLVED IN IS THAT IF
YOU GIVE INDIVIDUALS IL2 WITH
DIABETES, YOU CAN INCREASE THE
NUMBER OF REGULATORY T CELLS
THAT THEY HAVE, AND IN FACT, YOU
CAN NORMALIZE THEIR RESPONSE TO
IL2.
THE BAD NEWS IS THAT IL2 AFFECTS
MORE CELL TYPES THAN T-REGS
ALONE SO WE ACTUALLY WERE NOT
ABLE TO IMPROVE THE BETA CELL
FUNCTION IN THE INDIVIDUALS WE
TESTED AND IN FACT IT
TRANSIENTLY BECAME WORSE.
SO THAT CLINICAL STUDY WAS
REALLY USEFUL, BECAUSE WHAT IT
TAUGHT US WAS WE HAVE TO BE
CAREFUL ABOUT HOW WE GIVE IL2
THERAPY AND JUST INCREASING
T-REGS ALONE WITH HAVING
BLINDERS ON EVERYTHING ELSE IS
NOT REALLY WHERE WE NEED TO GO.
IT'S LED -- THIS NEGATIVE STUDY
HAS LED TO MANY NEW DEVELOPMENTS
IN TRYING TO CREATE A NOVEL,
BETTER WAY TO ENHANCE T-REGS.
SO THE OTHER APPROACH WOULD BE
TO GIVE PEOPLE MORE REGULATORY T
CELLS.
AND THAT'S ALSO BEEN DONE WITH
THE IDEA OF TAKING AN
INDIVIDUAL'S CELLS, ISOLATING
REGULATORY T CELLS, EXPANDING
THEM, AND THEN GIVING THEM BACK
TO THE PATIENT.
AND SO THIS IS AN EXAMPLE OF TWO
DIFFERENT STUDIES.
ON THE TOP, WHAT WAS DONE IS
EXACTLY WHAT I'VE DESCRIBED.
AND WE WERE ABLE TO SHOW THAT
THOSE REGULATORY T CELLS
ACTUALLY HAD BETTER FUNCTION
AFTER THEY WERE EXPANDED IN
CULTURE AND IN THE PRESENCE OF
IL2, BEFORE THEY WERE GIVEN BACK
TO THESE INDIVIDUALS.
AND ALL OF THESE INDIVIDUALS HAD
NEW ONSET TYPE 1 DIABETES.
WHAT'S SHOWN ON THE RIGHT IS
THAT THERE WAS NO ACTUALLY IMOF
IMPROVEMENT IN THEIR BETA CELL
FUNCTION.
THE GOOD NEWS IS THESE WERE
SAFE, SO THEN A SECOND TRIAL WAS
DONE, AND IN THIS TRIAL, AGAIN,
T-REGS WERE TAKEN FROM PATIENTS,
EXPANDED AND GIVEN BACK, BUT
THEY WERE ALSO IL2 AT THE SAME
TIME.
WITH THE HOPE THAT THAT WOULD
KEEP THOSE CELLS GOES IN VIVO.
BUT THIS ONE AGAIN WAS SAFE, BUT
DID NOT SHOW EFFICACY.
SO WHAT'S WRONG HERE?
WHY ISN'T THIS WORKING?
WHAT I WOULD SAY IS WE ARE MAYBE
NOT GIVING THE T-REGS IN THE
RIGHT WAY.
OUR CURRENT THERAPIES FOR
AUTOIMMUNE DISEASES ARE TO
GENERALLY STUNT THE IMMUNE
RESPONSE.
IF WE BLOCK THE IMMUNE RESPONSE,
WE CAN ACTUALLY TREAT PEOPLE
WITH AUTOIMMUNITY, BUT WE ALSO
LEAVE THEM OPEN TO INFECTION,
COMPLICATIONS DUE TO CANCER, SO
THERE'S NO SPECIFICITY.
NOW WHAT REGULATORY T CELLS HAVE
THAT OTHER APPROACHES DON'T HAVE
IS THAT THEY ARE ACTUALLY VERY
SPECIFIC.
REGULATORY T CELLS ARE DESIGNED
TO IDENTIFY HEALTHY TISSUE THAT
IS -- AND TO BLOCK ANY IMPACT OF
EFFECTOR CELLS TO ATTACK THAT
HEALTHY TISSUE.
AND THEY'RE SPECIFIC BY THE FACT
THAT THEY HAVE A T-CELL RECEPTOR
THAT RECOGNIZES SELF ANTIGENS
AND STOPS INFLAMMATION.
AND I'VE HIGHLIGHTED THAT T-CELL
RECEPTOR INTERACTION WITH CLASS
2 AND PEPTIDE HERE IN THE
FIGURE.
SO IF WE TOOK ADVANTAGE OF THE
SPECIFICITY OF T-REGS, COULD WE
DO BETTER?
SO OUR GROUP TOOK ON THIS
QUESTION AFTER TRYING FOR QUITE
A FEW YEARS WITH SOME SUCCESS.
SO WHY CONSIDER GIVING THESE --
THIS T REG THERAPY?
WELL, WE KNOW IN MOUSE MODELS
THAT IF YOU GIVE
ANTIGEN-SPECIFIC T-REGS, YOU CAN
ACTUALLY PREVENT OR CURE
DIABETES.
AND WE ALSO KNOW THE ANTIGENS
THAT ARE BEING TARGETED IN
DIABETES BY T CELLS, SO WE COULD
ACTUALLY IDENTIFY OR MAKE A
REGULATORY T-CELL THAT WAS
SPECIFIC, BUT THERE'S A LOT OF
CHALLENGES.
ISLET-SPECIFIC T CELLS ARE
REALLY RARE IN DIABETES.
GETTING A PURE POPULATION OF
ISLET-SPECIFIC REGULATORY T
CELLS WOULD BE VERY DIFFICULT
BECAUSE THEY'RE QUITE RARE IN
THE PERIPHERAL BLOOD.
THERE'S OTHER PROBLEMS.
REGULATORY T CELLS CAN CHANGE,
AND THEY CAN BECOME EFFECTORS.
AND THAT'S SCARY IF YOU MAKE AN
ANTIGEN-SPECIFIC CELL AND THEN
IT DOESN'T REGULATE ANYMORE.
AND OF COURSE AS I'VE SHOWN YOU,
THERE'S LESS SENSITIVITY TO IL2
IN TYPE 1 DIABETES SO THESE
CELLS MAY NOT BE STABLE.
SO KNOWING THAT THESE ARE
PROBLEMS, WE WERE ABLE TO WORK
WITH A COLLEAGUE TO DEVELOP A
NEW FORM OF LEG REGULATORY T-CE.
IN THIS CASE WHAT WE WOULD DO IS
TAKE CELLS FROM A PATIENT,
TRANSFORM THOSE CELLS INTO
REGULATORY CELLS, AND HAVE THEM
EXPRESS T-CELL RECEPTOR THAT IS
SPECIFIC FOR THE ISLET, AND THE
ISLET ANTIGENS THAT WE KNOW ARE
TARGETED IN TYPE 1 DIABETES.
WE CAN THEN EXPAND THOSE CELLS
AND GIVE THEM BACK TO THE
PATIENT.
SO THAT'S THE IDEA.
SO HOW DO WE DO THAT?
WELL, WE TRIED TO DO THAT FOR 15
YEARS, AND BECAUSE THE
REGULATORY T CELLS WERE RARE AND
UNSTABLE AND SPECIFICITY WAS
HARD TO GET, WE WERE REALLY
STYMIED.
BUT THEN WITH THE DEVELOPMENT OF
GENE EDITING THROUGH CRISPR/CAS
9, WE HAD A WAY OUT OF THIS
PROBLEM.
AND THE WAY OUT OF THE PROBLEM
WAS TO TAKE CELLS THAT WERE JUST
RUN OF THE MILL CONVENTIONAL
CELLS, EXPRESS A T-CELL RECEPTOR
DIRECTED TO THE ISLET, WHICH WE
CAN USE DOING GENE EDITING OR
USING SOMETHING CALLED -- THEN
WE WERE ABLE TO USE GENE EDITING
TO EXPRESS THE GENE FOXP3, AND
FOXP3 IS CENTRAL TO THE
STABILITY AND FUNCTION OF
REGULATORY T CELLS, AND IN DOING
THAT, WE'VE NOW CREATED A CELL
THAT IS SUPPRESSIVE AND IS
SPECIFIC FOR THE ISLET.
SO WHEN WE DO THESE EXPERIMENTS,
THESE ARE NOW IN VITRO
EXPERIMENTS WHERE WE'VE ASKED
SEVERAL QUESTIONS.
IF WE TAKE A T-CELL THAT WE KNOW
TARGETS AN ISLET ANTIGEN, THAT'S
SHOWN IN BLUE ON THE LEFT -- OR
IT'S SHOWN IN GREEN ON THE LEFT,
AND WE USE A REGULATORY T-CELL
THAT CAN SEE THE SAME ANTIGEN,
WE CAN ACTUALLY SHOW, AND IT'S
SHOWN BELOW WITH A RED CIRCLE --
RED SQUARE AROUND IT, THAT WE
CAN SUPPRESS THE PROLIFERATION
OF THOSE T CELLS.
AND THE SUPPRESSION ONLY OCCURS
WHEN THE ENGINEERED REGULATORY
T-CELL IS THERE IN THE PRESENCE
OF ITS ANTIGEN.
THIS IS IMPORTANT.
WE DON'T WANT THESE CELLS TO GET
ACTIVATED ANY OLD PLACE.
WE WANT THEM ACTIVATED WHEN
THEY'RE IN THE ISLET AND THEY
HAVE A REASON TO BE ACTIVATED.
WE'VE ALSO SHOWN THAT THESE
CELLS CAN SUPPRESS BYSTANDERS.
THAT MEANS ANOTHER CELL IN THE
AREA THAT MAY SEE ANOTHER ISLET
ANTIGEN.
IN THE MIDDLE, WE HAVE A T-CELL
THAT CAN SEE TID5-1, THAT'S A
SPECIFIC PEPTIDE THAT'S SEEN IN
THE ISLET, AND NOW WE HAVE A
REGULATORY CELL THAT WE'VE
ENGINEERED TO SEE A DIFFERENT
ANTIGEN, AND AGAIN, IT ABLE TO
SUPPRESS THAT IN A BYSTANDARD
MANNER.
SO YOU DON'T HAVE TO KNOW EVERY
ANTIGEN THAT'S BEING TARGETED IN
THIS AUTOIMMUNE DISEASE, YOU
ONLY NEED TO SEE ONE.
BUT WHEN WE DO THESE EXPERIMENTS
THE WAY I'VE SHOWN THEM IN THE
TWO LEFT FIGURES, WE'VE ACTUALLY
ENGINEERED THE EFFECTOR CELLS AS
WELL AND THE QUESTION IS, CAN WE
ACTUALLY SUPPRESS AUTO REACTIVE
T CELLS FROM PATIENTS WHO HAVE
DIABETES?
SO WHAT WE'RE ABLE TO DO IS TAKE
BLOOD SAMPLES FROM THOSE
PATIENTS, AND GROW UP THE ONES
THAT SEE ISLET ANTIGENS AND
THERE WILL BE MANY DIFFERENT T
CELLS WITH VERY MANY DIFFERENT
SPECIFICITIES, THEN WE
CO-CULTURE THOSE WITH A SINGLE
ENGINEERED T REG SPECIFICITY AND
WHAT WE'VE BEEN ABLE TO SHOW IS
WE CAN SUPPRESS THOSE.
SO THE BEAUTY OF THIS IS THAT
WE'RE ABLE TO BE VERY SPECIFIC,
ONLY SUPPRESS IN THE PRESENCE OF
AN ISLET ANTIGEN, SO THESE
REGULATORY T CELLS SHOULDN'T
SUPPRESS ANY OTHER IMMUNE
RESPONSES.
BUT YET WE'RE ABLE TO SUPPRESS
MORE BROADLY AN IMMUNE RESPONSE
TARGETING THE ISLET.
NOW THAT IS ONE APPROACH, AN
APPROACH WE DEVELOPED FOR TYPE D
ABOUT, BECAUSE I'M A
RHEUMATOLOGIST, IS THAT YOU CAN
DO THIS FOR OTHER ANTIGENS IN
OTHER TISSUE-SPECIFIC DISEASES.
SO IN THE LOWER FIGURE, I'VE
SHOWN AN ENGINEERED T REG THAT
WE MADE AGAINST AN EPITOPE, ONE
OF THE ANTIGENS WE THINK DRIVES
THE T-CELL RESPONSE IN
RHEUMATOID ARTHRITIS.
SO THIS IS ONE EXAMPLE.
OBVIOUSLY YOU COULD THINK OF
MORE EXAMPLES SO WE'RE EXCITED
TO THINK ABOUT WHERE YOU COULD
TAKE THIS MOVING FORWARD.
SO JUST IN SUMMARY BY
ENGINEERING A REGULATORY CELL
AND MAKING IT ANTIGEN-SPECIFIC,
YOU CAN SPECIFICALLY TARGET A
TISSUE.
YOU CAN GET A STABLE REGULATORY
CELL THAT CONTINUOUSLY EXPRESSES
FOXP3, AND WE CAN ALSO ENGINEER
OTHER FEATURES INTO THESE CELLS.
AND CURRENTLY WE'RE TRYING TO
ENGINEER ENHANCED RESPONSES TO
IL2, BUT ALSO ENGINEER THE
ABILITY TO SECRETE FACTORS THAT
MAY ENHANCE HEALING IN THE
TISSUE.
BUT THERE'S LIMITATIONS WITH
THIS APPROACH.
FIRST OF ALL FOR THE ANTIGEN
SPECIFICITY, WE USE ONLY -- THIS
IS VERY TARGETED TO HLA, SO IN
THE CASE OF A TYPE 1 DIABETIC,
WE MAY BE ABLE TO COVER ALL 40%
WITH TYPE 1 DIABETES, WE'D HAVE
TO GENERATE A DIFFERENT
REGULATORY CELL FOR SOME OF THE
OTHER INDIVIDUALS.
CURRENTLY THESE REQUIRE
AUTOLOGOUS T CELLS SO THAT'S A
MUCH MORE EXPENSIVE PROCEDURE
WHERE WE NEED TO GET CELLS FROM
THE PATIENT TO GIVE THEM BACK.
AND IT'S EXPENSIVE.
SO REALLY, THE HOPE IS TO SHOW
THAT THIS TYPE OF APPROACH
WORKS, BUT THEN WE NEED TO
DEVELOP AN OFF THE SHELF
THERAPY.
THEN ALSO NOTE I'VE SHOWED YOU
ONE APPROACH, THE APPROACH WE'VE
TAKEN.
OTHERS ARE TAKING OTHER
APPROACHES INCLUDING PUTTING
CARS INTO REGULATORY T CELLS,
AND OTHER APPROACHES TO ENGINEER
CELLS THAT COULD DO THIS.
SO I THINK THERE'S A GREAT DEAL
OF HOPE RIGHT NOW.
THE FIRST CLINICAL TRIALS ARE
BEING STARTED WITH
ANTIGEN-SPECIFIC REGULATORY
CELLS.
SO WE'LL LEARN MORE IN THE NEXT
FEW YEARS.
SO I'VE TALKED A LITTLE BIT
ABOUT HOW WE CAN TAKE THIS
PARADIGM STARTING WITH GENETICS,
IDENTIFY A PATHWAY THAT'S
ALTERED IN AN AUTOIMMUNE
DISEASE, AND THEN THINK ABOUT
HOW DO WE CREATE THERAPEUTICS,
BUT I'D LIKE TO SHARE THE OTHER
TWO PART OF THIS APPROACH, WHICH
IS LOOKING AT WHO TO TREAT AND
WHEN TO TREAT.
AND SO WHAT WE WERE ABLE TO DO
ONCE WE'D IDENTIFIED THIS
ALTERATION IN IL2 SIGNALING WAS
RIGHT OUT TO THE TRIAL NET
CONSORTIUM, WHICH IS A GROUP
FUNDED BY THE NIH AND HAS BEEN
OVER THE YEARS IDENTIFYING
COHORTS OF FAMILIES WHERE
INDIVIDUALS HAVE TYPE 1 DIABETES
AND THEN FOLLOWING SIBLINGS WHO
ARE AT HIGH RISK OVER TIME.
SO WE CAN IDENTIFY THOSE
INDIVIDUALS WHO NEVER GO ON TO
GET DIABETES, WE'RE CALLING THEM
FDRs HERE, INDIVIDUALS WHO
DEVELOP AUTOANTIBODIES, AND THEN
FOLLOW THEM OVER TIME AS THEY
MOVE TOWARDS DEVELOPMENT OF
DIABETES.
THESE COHORTS HAVE BEEN
EXCEPTIONALLY USEFUL IN HELPING
US DEVELOP A PREDICTION PARADIGM
FOR TYPE 1 DIABETES, BUT FOR ME
AS AN IMMUNOLOGIST, I WAS ABLE
TO LOOK AT SAMPLES FROM
INDIVIDUALS WHO WE FOLLOWED OVER
TIME AND ASKED, DID THE PEOPLE
WHO WERE RELATED WHO NEVER GOT
AN AUTO ANTIBODY, DID THEY HAVE
ILLINOIS DEFECTS AS COMPARED TO
THE INDIVIDUAL WHO HAD AUTO
ANTIBODIES?
AS YOU CAN SEE ON THE LEFT,
PEOPLE WHO ARE RELATED TO A TYPE
1 DIABETIC BUT NEVER GOT
AUTOANTIBODIES HAVE NORMAL IL2
RESPONSES.
WHEREAS THOSE INDIVIDUALS WHO
HAD AUTOANTIBODIES BUT DID NOT
YET HAVE TYPE 1 DIABETES HAD
BLUNTED IL2 RESPONSES.
SO WHEN DOES THAT HAPPEN?
AND SO WHAT WE LOOKED AT WAS THE
NUMBER OF AUTOANTIBODIES AN
INDIVIDUAL HAD, AND WE KNOW THEY
ACQUIRE AU AUTOANTIBODIES OVER
TIME.
AS YOU CAN SEE ON THE RIGHT,
INDIVIDUALS WHO HAVE ANY
AUTOANTIBODIES DIRECTED TO
THE -- SUGGESTING THAT THIS
IMPAIRMENT IN IL2 SIGNALING MAY
BE IMPORTANT EARLY IN THE LOSS
OF TOLERANCE AND IN THE
DEVELOPMENT OF AUTOANTIBODIES.
SO TREATING ILLINOIS 28 AND
IL2 AND MAYBE EVENT-REGS MAY NEN
MY MIND.
THE OTHER THING WE CAN ASK IS,
IS THIS IL2 STORY IMPORTANT IN
OTHER DISEASES?
SO WE CAN LOOK ACROSS COHORTS,
AND THIS IS WHERE DEVELOPMENT OF
COHORTS IS VERY IMPORTANT,
BECAUSE WE WANT TO BE ABLE TO
COMPARE OUR STUDIES AND OUR
ASSAYS BETWEEN INDIVIDUALS.
SO WE HAVE THE GOOD FORTUNE OF
HAVING OUR BIOREPOSITORY HAVE
MULTIPLE DIFFERENT AUTOIMMUNE
DISEASES BUT ALL THE SAMPLES ARE
HANDLED IN AN IDENTICAL MANNER.
SO HERE WHAT WE DID IS WE TOOK A
GROUP OF OUR CONTROLS,
INDIVIDUALS WITH TYPE
1 DIABETES, INDIVIDUALS WITH
RELAPSE -- WITH MULTIPLE
SCLEROSIS, AND INDIVIDUALS WITH
LUPUS.
AND WE ASKED THIS SAME QUESTION
ABOUT THE RESPONSE TO IL2 AND
THEIR REGULATORY T-CELLS.
WHAT YOU CAN SEE FROM THIS GRAPH
IS THAT INDIVIDUALS WITH
MULTIPLE SCLEROSIS SIMILAR TO
DIABETES HAVE IMPAIRED IL2
SIGNALING, WHEREAS INDIVIDUALS
WITH LUPUS DO NOT.
NOW THIS MAKES SENSE BECAUSE WE
KNOW SOME OF THE SAME GENES
ASSOCIATED WITH TYPE 1 DIABETES
ARE ALSO ASSOCIATED WITH M.S.
AND INVOLVE THE IL2 PATHWAY.
IT ALSO MAKES SENSE FOR LUPUS
BECAUSE WE ACTUALLY KNOW IN
LUPUS THAT THERE'S NOT ENOUGH
IL2 MADE, BUT THAT THOSE CELLS
RESPOND TO IL2.
SO THAT HAS -- IT INFLUENCES THE
WAY WE WOULD THINK ABOUT
TARGETING THE IL2 PATHWAY IN
LUPUS AS COMPARED TO IN TYPE
1 DIABETES AND M.S.
BUT IT ALSO MEANS AS WE START
THINKING ABOUT INTERVENTIONS, IT
HELPS US NOT LEARN -- LEARN MORE
FROM ONE DISEASE THAN JUST THAT
DISEASE ALONE.
SO I'D LIKE TO END WITH SOME
COMMENTS ABOUT USING A UNIQUE
POPULATION TO HELP UNDERSTAND
AUTOIMMUNITY, AND NOT ONLY
UNDERSTANDING THEIR DISEASE
RISK, BUT ALSO OTHER DISEASES.
AND THE POPULATION THAT WE HAVE
BECOME VERY INTERESTED IN
STUDYING IS INDIVIDUALS WHO HAVE
DOWN SYNDROME.
THIS WORK HAS BEEN SUPPORTED BY
THE NIH INCLUDE PROJECT AND HAS
BEEN REALLY AN EXCITING AREA FOR
US.
SO DOWN SYNDROME IS TRISOMY
21 AND IT OCCURS IN 1 IN 800
BIRTHS.
INDIVIDUALS WITH DOWN SYNDROME
HAVE BEEN KNOWN FOR A LONG TIME
TO HAVE IMMUNE DYSREGULATION.
THEY HAVE POOR RESPONSES TO
VACCINES, THEY HAVE INCREASED
SUSCEPTIBILITY TO INFECTION.
BUT AS THE LIFESPAN OF
INDIVIDUALS WITH DOWN SYNDROME
HAS EXTENDED BECAUSE OF MUCH
BETTER ABILITY TO CARE FOR THEIR
OTHER HEALTH ISSUES, IT'S BECOME
VERY CLEAR THAT THESE
INDIVIDUALS ARE AT A MARKED
INCREASED RISK FOR
TISSUE-SPECIFIC AUTOIMMUNITY.
AND I'VE JUST LISTED A FEW HERE.
TYPE 1 DIABETES ARE 4.5 TIMES
MORE LIKELY TO HAVE THAT.
26 FOLD INCREASED RISK OF
HASHIMOTO'SHASHIMOTO'S THYROIDI6
TIMES CELIAC DISEASE.
SO THIS GROUP OF INDIVIDUALS, WE
THINK IT'S IMPORTANT TO
UNDERSTAND WHY THEY HAVE
AUTOIMMUNITY SO WE CAN
POTENTIALLY TARGET THERAPEUTICS
THAT COULD PREVENT THIS IN THIS
GROUP OF INDIVIDUALS, BUT IT
ALSO MAY BE A WAY FOR US TO
LEARN MORE ABOUT AUTOIMMUNITY IN
GENERAL.
SO WHAT WE HAVE BEEN ABLE TO DO
IS DEVELOP A COHORT OF
INDIVIDUALS WITH DOWN SYNDROME,
RANGING FROM VERY EARLY
CHILDHOOD INTO THE 50s, AND
NOW WITH THE HELP OF THE INCLUDE
PROJECT, HAVE OVER 200
INDIVIDUALS IN THAT REGISTRY,
AND WE CAN COMPARE WHAT THEIR
IMMUNE SYSTEM LOOKS LIKE TO OUR
TYPICAL CONTROLS, WHO ARE AGE-
AND SEX-MATCHED AND INDIVIDUALS
WITH DIABETES WHO ARE ALSO AGE-
AND SEX-MATCHED.
AND JUST BRIEFLY, SOME OF OUR
DATA, THIS HAS BEEN PUBLISHED IN
SCIENCE TRANSLATIONAL MEDICINE
IN 2022.
WHAT WE WERE ABLE TO SHOW SOME
OF THE T-CELL POPULATIONS THAT
WE ASSOCIATE WITH AUTOIMMUNITY
ARE MARKEDLY INCREASED IN
INDIVIDUALS WITH DOWN SYNDROME.
THAT INCLUDES GAMMA INTERFERING
SECRETE TH1 CELLS, GAMMA AND
TH17 SECRETE TH17.1 CELLS, AND
THEN STEM CELL MEMORY IN CD4 AND
CD8, AND THEY'RE THOUGHT TO BE
THE PRECURSORS OF AUTOIMMUNITY.
NOW WHEN YOU LOOK AT THE
DIFFERENCES BETWEEN TYPICAL
CONTROLS IN DOWN SYNDROME ARE
VERY OBVIOUS, THESE ARE QUITE
EXAGGERATED CHANGES.
AND WHEN WE LOOK IN TYPE
1 DIABETES, WE SEE MUCH MORE
MUTED CHANGES BUT THOSE CHANGES
ARE THERE, AND WE GET
SIGNIFICANCE WHEN WE LOOK AT THE
CD8 POPULATION STEM CELLS.
IF WE LOOK AT ALL OF THE
DISREGULATED SUBSETS THAT HAVE
BEEN DESCRIBED IN MULTIPLE
AUTOIMMUNE DISEASES LIKE
CROHN'S, M.S., PSORIASIS, R.A.
AND LUPUS, WE ALSO SEE THOSE
SAME POPULATIONS ARE, IN FACT,
DISREGULATED IN DOWN SYNDROME.
SO THERE ARE SOME COMMON
PATHWAYS HERE AND IN DOWN
SYNDROME, THEY APPEAR TO BE MORE
EXAGGERATED.
SO MY COLLEAGUE BERNARD KORR WAS
VERY INTERESTED IN THIS QUESTION
OF IMMUNE AGING AND SO HE
DEVELOPED -- HE LOOKED AT THE
CELL POPULATIONS COMPARING
TYPICAL CONTROLS TO DOWN
SYNDROME, AND DEVELOPED AP WAY
TO LOOK AT IMMUNE AGE.
AND WHEN WE TAKE TYPICAL
CONTROLS AND CREATE THAT MODEL,
WE CAN SEE DOWN SYNDROME HAS A
MODEST INCREASE IN IMMUNE AGE.
BUT IN THE ACTUAL THE DS
FILTERED MODEL, USING HEALTHY
CONTROLS BUT FOCUSED ON THE
SUBSETS OR POPULATIONS ALTERED
IN DOWN SYNDROME, WE ACTUALLY
HAVE A MODEL OF IMMUNE AGING
THAT'S QUITE GOOD IN HEALTHY
INDIVIDUALS BUT IT DEMONSTRATES
THE EXTREME CHANGE IN IMMUNE AGE
IN DOWN SYNDROME.
WHEN WE LOOK THEN AT INDIVIDUALS
WITH DOWN SYNDROME WHO HAVE
AUTOIMMUNITY, WE SEE A MUCH MORE
EXAGGERATED IMMUNE AGE.
BUT WHAT I FOUND HERE IS THAT
WHEN WE NOW TAKE THIS MODEL THAT
WE'VE LEARNED FROM DOWN SYNDROME
AND APPLY TO TYPE 1 DIABETES, IN
THE RIGHT LOWER AREA, YOU CAN
SEE THAT WE NOW SEE THAT
INDIVIDUAL WITH TYPE 1 DIABETES
HAVE ENHANCED IMMUNE AGING AS
WELL, SOMETHING WE WOULDN'T HAVE
PICKED UP VERY WELL WITH THE
UNFILTERED MODEL.
SO SHOWING THAT IMMUNE AGE AND
INFLA MINFLAMMATION ARE IMPORTAN
BOTH OF THESE SETTINGS.
SO THIS PARADIGM CAN HELP US
UNDERSTAND DOWN SYNDROME AS WELL
AS MECHANISMS THAT MAY BE
IMPORTANT IN DIABETES AS WELL AS
OTHER AUTOIMMUNE DISEASES, AND
HELP US IDENTIFY THERAPEUTIC
TREATMENTS.
SO IN THE LAST FEW MINUTES, I
JUST THOUGHT I'D WIND UP BY
BRINGING US BACK TO THIS FIGURE,
AND IT IS A FIGURE I'VE STARTED
WITH FOR YEARS, TALKING ABOUT
HOW PEOPLE MOVE FROM HEALTH TO
DISEASE PERPETUATION.
AND OF COURSE I'VE SPENT MURCH
OF MY CAREER TALKING ABOUT THE
GENETIC FACTORS THAT DRIVE THIS.
AND I'VE ALWAYS HAD
ENVIRONMENTAL FACTORS LISTED,
AND HAVE VERY RARELY BEEN ABLE
TO SPEAK TO THEM BECAUSE WE
THINK OF THE ENVIRONMENTAL
FACTORS AS BEING VERY -- VERY
DIFFICULT TO MEASURE AND THERE
ARE SO MANY OF THEM.
BUT I THINK THE GREAT NEWS IS
THAT -- WELL, AND I THOUGHT I'D
BRING OUT THIS SLIDE BECAUSE
I'VE BEEN TALKING ABOUT THIS FOR
YEARS USING THAT FIGURE.
BUT YOU CAN LOOK AT MULTIPLE
FIGURES FROM OTHER DISEASES.
TYPE 1 DIABETES HAS THAT
ENVIRONMENTAL TRIGGER.
SYSTEMIC LUPUS HAS AN
ENVIRONMENTAL TRIGGER.
AND RHEUMATOID ARTHRITIS HAS AN
ENVIRONMENTAL TRIGGER.
AND NOW IT'S REALLY TIME FOR US
AS WE UNDERSTAND THE IMMUNE
SYSTEM MUCH BETTER, WE
UNDERSTAND SOME OF THE DRIVERS
OF YOU A AUTOIMMUNITY AND THE C
UNDERPINNINGS TO ACTUALLY TACKLE
THIS QUESTION OF ENVIRONMENTAL
RISK FACTORS AND AS WAS DI
DESCRIBED BEFORE, HOW DO WE ASK
THIS QUESTION, HOW DO WE USE THE
TOOLS THAT OTHER PEOPLE IN
ENVIRONMENTAL HEALTH HAVE
DEVELOPED, PEOPLE IN OTHER
FIELDS OF MEDICINE HAVE STARTED
LOOKING AT AND APPLY TO
AUTOIMMUNITY, SO I'M REALLY
EXCITED TO BE PART OF THAT GROUP
TO START FILLING IN THE BLANK
THAT I'VE LEFT FOR SO MANY
YEARS.
AND THEN FINALLY, AS WE MOVE
FORWARD, WE THINK ABOUT
DISEASES, REALLY THE ULTIMATE
GOAL SHOULD BE TO PREVENT
DISEASES BECAUSE IT IS THE
ULTIMATE CURE.
AND WE ARE GETTING TO THE POINT
IN AUTOIMMUNITY THAT WE CAN
START THINKING ABOUT PREDICTING,
AND IN TYPE 1 DIABETES, WE
ACTUALLY CAN NOW PREDICT THE
DEVELOPMENT OF CLINICAL
DIABETES.
AS I'VE ALREADY DESCRIBED,
INDIVIDUALS WHO WERE AT HIGH
RISK FROM FAMILY MEMBER, WE KNOW
THEY DEVELOP AUTOANTIBODIES BUT
WHAT WE ALSO KNOW NOW IS IF YOU
HAVE TWO AUTOANTIBODIES, YOU
WILL GET DIABETES.
IF YOU HAVE TWO AUTOANTIBODIES
AND IMPAIRED GLUCOSE TOLERANCE,
YOU WILL GET DIABETES MUCH
SOONER SO WE CALL THAT STAGE
TWO, AND STAGE THREE IS WHEN YOU
REQUIRE INSULIN.
SO BY HAVING STAGES AND KNOWING
WE CAN PREDICT IT, WE'VE NOW
BEEN ABLE TO DO CLINICAL TRIALS
WHERE WE CAN INTERVENE PRIOR TO
DEVELOPMENT OF CLINICAL DISEASE.
AND SO TRIALNET DID ONE SUCH
TRIAL WITH A DRUG CALLED
TEPLIZUMAB SEVERAL YEARS AGO,
IT'S ANTI-CD3 AND IT WAS SHOWN
FIRST TO BE EFFECTIVE IN STAGE
III, BUT THEN MOVED TO STAGE II.
SO INDIVIDUALS WHO DO NOT YET
REQUIRE INSULIN.
AND IT WAS SHOWN TO DELAY THE
TYPE OF TYPE 1 DIABETES BY AT
LEAST TWO YEARS.
SOME INDIVIDUALS STILL HAVE NOT
DEVELOPED DIABETES.
SO IT'S A DRUG THAT WE'VE NOW
SHOWN COULD DELAY ONSET OF
DIABETES.
AND WHAT'S SO EXCITING IS IT'S
FDA-APPROVED NOW TO TREAT STAGE
II.
SO WE HAVE REASON TO GO TO THE
CLINIC, PREDICT WHO WILL GET
DIABETES AND SO THAT WE CAN GET
THEM THIS THERAPY.
SOME STUDYS ARE NOW GOING ON IN
ROOM TIED ARTHRITIS WHERE WE
HAVE AUTOANTIBODIES THAT CAN
PREDICT DEVELOPMENT OF DISEASE
AND TRIALS ARE STARTING TO SHOW
DELAY OF DISEASE.
SO WE'VE TALKED ABOUT THIS AND
DREAMED ABOUT IT FOR YEARS.
WE'RE NOW AT A PLACE WHERE WE
CAN MOVE FORWARD.
AND THEN FINALLY WE'RE AT AN ERA
WITH GROWING TECHNOLOGIES THAT
ARE GOING TO CHANGE IN MANY WAYS
HOW WE THINK AND LEARN ABOUT
AUTOIMMUNITY, FROM MULTI-OMICS
WHICH ALLOW US TO LOOK VERY
DEEPLY INTO THE REGULATION OF
THE GENOME, AND THE MULTIPLE
CELL TYPES AND TR TRANSCRIPTIONL
EXPRESSION, TO LOOKING IN THE
TISSUES AND LOOKING AT CELL-CELL
INTERACTIONS.
AND I THINK THIS IS GOING TO BE
A GREAT STEP FORWARD.
WE'VE ALREADY LEARNED SO MUCH
FROM PROJECTS LIKE AMP AIM.
BUT I'D ALSO SAY THAT THE RULES
WON'T CHANGE, AND WE STILL --
ONCE WE DEVELOP -- GENERATE
HYPOTHESES FROM THESE NEW
TECHNOLOGIES, WE WILL THEN AGAIN
NEED TO APPLY THEM TO WELL
CHARACTERIZED COHORTS ANGD BE
ABLE TO MOVE FORWARD TO
UNDERSTAND HOW TO INTERVENE,
WHEN TO INTERVENE AND WHO TO
INTERVENE WITH.
SO MY TAKE-HOME MESSAGES,
AUTOIMMUNE IT AFFECTS A LARGE
PERCENTAGE OF OUR POPULATION.
AS OF TODAY, IT'S CHRONIC,
DEBIDEBILITATING AND INCURABLE T
TOMORROW, I DON'T THINK IT WILL
BE.
IMPORTANTLY FOR WOMEN IS THAT IT
REALLY DISPROPORTIONATELY
IMPACTS WOMEN AND I WILL SAY IT
IMPACTS WOMEN AT RELATIVELY
YOUNG AGES, SO THEY HAVE A LIFE
OF LIVING WITH THESE DISEASES.
SO I THINK IT'S REALLY VITAL AS
WE THINK ABOUT TREATING WOMEN
AND GIVING THEM BETTER HEALTH TO
FOCUS ON AUTOIMMUNITY.
I'VE TALKED ABOUT HOW THE IMMUNE
CENTRAL IS CENTRAL AND ITS
DYSFUNCTION IS DRIVEN BY
GENETICS AND ENVIRONMENT.
AND I THINK IF WE COULD
UNDERSTAND THESE PATHWAYS EVEN
BETTER THAN WE DO TODAY, WE
COULD TREAT AUTOIMMUNE DISEASES
BETTER AND I BELIEVE NEW
THERAPIES ARE COMING DOWN THE
PIPE THAT ARE GOING TO LET US
USE A TARGETED FORM OF THERAPY
SO WE DON'T GLOBALLY
IMMUNOSUPPRESS PEOPLE.
WE ARE REALLY KNOCKING AT THE
DOOR AT PREDICTION AND
PREVENTION.
WE NEED TO INVEST HERE.
WE NEED TO BRING THIS INTO
REALITY INTO THE CLINIC SO THAT
PATIENTS ARE GETTING SCREENED
JUST LIKE WE SCREEN FOR HIGH
BLOOD PRESSURE AND HIGH
CHOLESTEROL, WE COULD SCREEN FOR
AUTOIMMUNE DISEASES AND PREVENT
THEM, THAT WOULD BE THE ULTIMATE
CURE.
AND JUST FINALLY, MY
ACKNOWLEDGMENTS.
INCLUDING THE MEMBERS OF MY LAB
TEAM, MY INVESTIGATORS BRI, AND
I HAVE MANY COLLABORATORS.
I'VE PICTURED SOME OF THE KEY
PEOPLE HERE WHO HELPED ME WITH
THIS WORK OVER THE YEARS, AND
DAVID RAWLINGS IS MY
LONG-STANDING COLLEAGUE WHO IS
AN EXPERT IN GENE EDITING AND
HELPS WITH ENGINEERED REGULATORY
T CELLS.
OF COURSE FUNDING IS ALWAYS
VITAL TO DOING OUR WORK.
>> THANK YOU, DR. BUCKNER, FOR
THAT INCREDIBLE WHIRLWIND
PRESENTATION, REALLY ELEGANT
EXPLANATION OF HOW YOU THOUGHT
THROUGH ALL OF THE PATHWAYS AND
WE'RE CLOSE TO TIME BUT I THINK
I WANT TO ASK YOU ONE QUESTION.
CAN YOU TALK A LITTLE BIT ABOUT
WHERE YOU THINK I NFL AMMAGING
IS GOING TO LEAD US AND BROADER
APPLICATIONS OF THAT CONCEPT?
>> SO I THINK MY COLLEAGUE
BERNARD ALWAYS TALKS ABOUT
LOOKING AT OUR PATIENTS AGE,
THEIR IMMUNE AGE AS OPPOSED TO
THEIR AGE ON THEIR DRIVER'S
LICENSE.
AND SO HOW WE WOULD TREAT PEOPLE
MAY DEPEND A BIT ON THEIR IMMUNE
AGE, AND I THINK IT WILL, ONE,
HELP US THINK ABOUT THEIR RISK
FOR DISEASE, AND AN IMPORTANT
EXAMPLE OF THIS IS WE GIVE A
DIFFERENT VACCINE TO PEOPLE WHO
ARE OLDER FOR FLU.
WELL, WE JUST PICK A NUMBER
TODAY, BUT REALLY SHOULD WE BE
PICKING THAT NUMBER BASED ON
YOUR IMMUNE AGE?
SO ONE OF THE STUDIES BERNARD IS
DOING RIGHT NOW IN INDIVIDUALS
WITH DOWN SYNDROME IS TO TEST
WHETHER WE SHOULD BE GIVING THEM
A DIFFERENT VACCINE BECAUSE
THEIR IMMUNE AGE IS REALLY 15
YEARS OLDER.
SO THAT'S A SIMPLE EXPLANATION.
BUT I THINK RISK OF CHRONIC
ILLNESS AND HOW DO WE DO
VACCINATIONS WOULD BE ONE EASY
AND VERY STRAIGHTFORWARD
APPROACH.
AND I ALSO -- ONE MORE THING, I
ACTUALLY THINK THAT BECAUSE WE
ARE NOT ONLY IDENTIFYING WAYS TO
IDENTIFY IMMUNE AGE BUT THE
FACTORS THAT DRIVE IMMUNE AGE,
WE COULD SLOW IT DOWN WITH
INTERVENTIONS THAT TARGET THOSE
DRIVERS.
>> OKAY.
WELL, WE ALWAYS WANT TO SLOW
DOWN AGING OF ALL KINDS, SO
THANK YOU FOR THAT FASCINATING
NUGGET THAT YOU LEFT US WITH.
AGAIN, THANK YOU SO MUCH FOR
SERVING AS OUR EIGHTH ANNUAL
VIVIAN PINN SYMPOSIUM KEYNOTE
SPEAKER.
YOU'VE GIVEN US SO MUCH TO THINK
ABOUT, AND WE WILL LOOK FORWARD
TO ALL THE FOLLOW-UP ON THE
EXACT PLAN AS WELL, AS YOU'RE
TAKING A LEADERSHIP ROLE THERE
TOO, SO THANK YOU SO MUCH, ON
BEHALF OF OADR AND ORWH,
DR. BUCKNER, FOR THAT AMAZING
KEYNOTE SPEECH.
>> THANK YOU.
>> AND WITH THAT, WE WILL
TRANSITION OVER TO DR. VICTORIA
SHANMUGAM.
I WANT TO EXHIB INTRODUCE THE FT
DIRECTOR OF THE OFFICE OF
AUTOIMMUNE DISEASE RESEARCH IN
THE OFFICE OF RESEARCH ON
WOMEN'S HEALTH.
SHE PREVIOUSLY SERVED AS
DIRECTOR OF RHEUMATOLOGY AT THE
GEORGE WASHINGTON UNIVERSITY AND
NOW SERVES AS OUR FIRST DIRECTOR
OF THE NIH OFFICE OF AUTOIMMUNE
DISEASE RESEARCH WITHIN THE
OFFICE OF RESEARCH ON WOMEN'S
HEALTH.
DR. SHANMUGAM TOOK A LEADERSHIP
ROLE IN DEVELOPING THIS YEAR'S
VIVIAN PINN SYMPOSIUM PROGRAM,
SO I WANT TO THANK YOU FOR YOUR
LEADERSHIP THERE, VICKIE, AND
I'LL TURN IT OVER TO YOU.
>> THANK YOU SO MUCH.
THANK YOU, DR. BUCKNER, FOR THAT
WONDERFUL TALK AND INTRODUCING
US AND SETTING THE STAGE AND
THANK YOU, DR. CLAYTON, FOR THAT
KIND INTRODUCTION.
IT'S NOW MY GREAT PLEASURE TO
KICK OFF OUR INSIDE INNOVATION
SESSION FOCUSED ON SOME OF THE
INTRAMURAL PROGRAMS THAT ARE
HAVING IMPACT AT NIH AND AROUND
THE WORLD.
WE HAVE THREE AMAZING SPEAKERS
FOR YOU TODAY AND WE'RE GOING TO
SAVE THE PANEL DISCUSSION UNTIL
THE END SO YOU CAN PUT QUESTIONS
IN THE Q & A AT ANY POINT DURING
THESE THREE TALKS, AND I'LL TRY
TO GET TO AS MANY OF THEM AS WE
CAN DURING THE DISCUSSION.
NEXT I'M GOING TO INTRODUCE OUR
THREE WONDERFUL PANELISTS FOR
THEIR BIOGRAPHIES, PLEASE REFER
TO THE PROGRAM BOOKLET WHICH
WE'RE DROPPING INTO THE CHAT.
DR. LAURA LEWANDOWSKI IS
ASSISTANT CLINICAL INVESTIGATOR
AND HEAD OF THE LUPUS GENOMICS
AND GLOBAL HEALTH DISPARITIES
UNIT AT NIAMS.
HER CURRENT RESEARCH INTERESTS
INCLUDE CLINICAL AND
TRANSLATIONAL RESEARCH IN
PEDIATRIC SYSTEMIC
LEUKOENCEPHALOPATSYSTEMIC LUPUS.
DR. STEVEN HOLLAND IS DIRECTOR
OF THE DIVISION OF INTRAMURAL
RESEARCH, ALSO SERVES AS CHIEF
OF THE IMMUNE PATHOGENESIS
SECTION AND HIS RESEARCH IS
FOCUSED ON PATHOGENESIS AND
MANAGEMENT OF CHRONIC
GRANULOMATOUS DISEASE AS WELL AS
A LARGE NUMBER OF OTHER IMMUNE
DEFICIENCIES OF WHICH SOME HE'S
GOING TO TELL US ABOUT TODAY.
AND THEN FINALLY, DR. ALISON
MOTSINGER-REIF IS THE CHIEF AND
PRINCIPAL INVESTIGATOR IN THE
BIOSTATISTICS AND COMPUTATIONAL
BIOLOGY BRANCH AT NIEHS.
HER WORK FOCUSES ON THE
DEVELOPMENT AND APPLICATION OF
MODERN STATISTICAL APPROACHES
FOR UNDERSTANDING THE ETIOLOGY
OF COMMON YET COMPLEX DISEASES.
WE ARE LOOKING FORWARD TO ALL OF
THE TALKS BUT WITHOUT FURTHER
ADO, I AM GOING TO PASS THE
VIRTUAL MICROPHONE OVER TO
DR. LAURA LEWANDOWSKI TO GET US
STARTED.
LAURA.
>> THANK YOU SO MUCH FOR THAT
LOVELY INTRODUCTION, AND I'M
JUST SO EXCITED AND DELIGHTED TO
BE HERE TODAY AS PART OF THIS
SYMPOSIUM.
I AM GOING TO TALK TODAY ABOUT
UNDERSTANDING GENETIC DRIVERS OF
EARLY ONSET LUPUS AND GLOBAL
POPULATIONS, AND I ALWAYS LIKE
TO PUT MY ACKNOWLEDGMENTS AT THE
BEGINNING OF MY TALK BECAUSE
NONE OF THIS WORK WOULD EVER GET
DONE WITHOUT THESE AMAZING TEAMS
OF PEOPLE IN MY LAB AND MY
MENTOR'S LAB AND WITH MY
COLLABORATORS AROUND THE WORLD,
SO I JUST WANT TO MAKE SURE TO
ACKNOWLEDGE THEIR ROLE AND OF
COURSE THE ROLE OF THE AMAZING
PATIENTS THAT I WORK WITH.
SO LUPUS OR SLE IS A CHRONIC
SYSTEMIC AUTOIMMUNE DISEASE THAT
CURRENTLY HAS NO CURE.
BECAUSE IT IS A SYSTEMIC
AUTOIMMUNE DISEASE, IT CAN
AFFECT ANY ORGAN SYSTEM.
YOU CAN SEE SOME OF THE
MANIFESTATIONS ON THE SLIDE I'VE
PRESENTED HERE, AND IT IS
CURRENTLY ONE OF THE LEADING
CAUSES OF DEATH IN YOUNG WOMEN
IN THE UNITED STATES FROM
CHRONIC DISEASE.
AND MY WORK WITH LUPUS AND
GLOBAL POPULATIONS REALLY BEGAN
DURING MY FELLOWSHIP TRAINING,
WHERE I WORKED AT THE HOSPITAL
THAT YOU CAN SEE PICTURED ON THE
LEFT HERE, RED CROSS CHILDREN'S
HOSPITAL IN CAPETOWN, SOUTH
AFRICA, AND I WORKED WITH MY
COLLABORATOR STUDYING LUPUS
PATIENTS THERE.
NOW I WAS INTERESTED IN
CHILDHOOD ONSET LUPUS BECAUSE
I'M A PEDIATRIC RHEUMATOLOGIST
AND ACTUALLY ONE OUT OF EVERY
FIVE LUPUS CASES IS DIAGNOSED
DURING CHILDHOOD.
AND CHILDREN HAVE A REALLY
SEVERE DISEASE MANIFESTATION, SO
THEY HAVE HIGHER DISEASE
ACTIVITY, THEY NEED MORE
THERAPY, THEY'RE MORE LIKELY TO
HAVE THE SERIOUS MANIFESTATIONS
OF DISEASE LIKE INFLAMMATION IN
THEIR BRAINS OR IN THEIR
KIDNEYS, AND THEY ACTUALLY
ACCRUE MORE ORGAN DAMAGE THAN
ADULTS DESPITE HAVING YOUNGER,
HEALTHIER BODIES.
WE'VE HEARD A LOT TODAY ABOUT
THE FEMALE PREDOMINENCE IN
AUTOIMMUNE DISEASE AND THAT'S
CERTAINLY TRUE IN LUPUS IN
ADULTHOOD, BUT INTERESTINGLY IN
PREPUBERTAL CHILDREN, THE RATIO
IS ABOUT FOUR FEMALES FOR EVERY
ONE MALE, AND THEN AS IT GOES
THROUGH ADOLESCENCE AND
ADULTHOOD, IT GETS CLOSER TO
THAT 9 TO 1 RATIO.
SO STUDYING THIS DISEASE ACROSS
THE LIFESPAN CAN HELP US KIND OF
ELUCIDATE THE ROLE OF GENETICS
AND HORMONES AND SOME OF THE
OTHER FACTORS IN THE FEMALE
PREDISPOSITION TO AUTOIMMUNITY.
AND BECAUSE THEY CAN PRESENT IN
ANY ORGAN SYSTEM, IT IS VERY
HETEROGENEOUS AND THAT MAKES
DEFINING END POINTS FOR
EVERYBODY AND FINDING EFFECTIVE
THERAPIES AND CLINICAL TRIALS
REALLY CHALLENGING BECAUSE
THERE'S SO MANY WAYS THAT LUPUS
CAN PRESENT.
I WAS INTERESTED IN STUDYING
LUPUS IN CHILDREN IN AFRICA
BECAUSE WE KNOW THAT LUPUS IS
MORE SEVERE IN CHILDREN AND MORE
SEVERE IN PEOPLE WHO ARE AFRICAN
AMERICAN IN THE U.S., BUT THERE
WAS VERY LITTLE DATA AT THE TIME
ON CHILDREN IN AFRICA.
WHEN I WENT TO SEE IF THEY WERE
SEVERE AS WELL, THERE WAS JUST
VERY LITTLE INFORMATION, AND SO
THERE'S A LACK OF PEDIATRIC
RHEUMATOLOGY ACCESS IN MANY
PARTS OF THE WORLD SO FIGURE A
HERE IS WHERE MOST OF THE
WORLD'S PEDIATRIC POPULATION IS
CONCENTRATED.
THE DARKER THE COLOR, THE MORE
PEDIATRIC POPULATION.
AND YOU CAN SEE, IND KOOF OF
CONCENTRATED IN LESS RESOURCE
AREAS SO SUB-SAHARAN AFRICA,
SOUTHEAST ASIA, ASIA.
IF YOU LOOK AT WHERE MOST OF THE
WORLD'S PEDIATRIC
RHEUMATOLOGISTS LIVE IN FIGURE
B, IT'S KIND OF AN INVERSE MAP.
SO MOST LIVE IN NORTH AMERICA
AND EUROPE.
SO WE ACTUALLY UNDERSTAND VERY
LITTLE ABOUT THE GLOBAL BURDEN
OF CHILDHOOD ONSET LUPUS.
SO I MOVED TO SOUTH AFRICA TO
STUDY THE LUPUS PATIENTS THERE,
AND ALONG WITH MY COLLEAGUES,
DEVELOPED THE LARGEST REGISTRY
OF CHILDREN WITH LUPUS IN
SUB-SAHARAN AFER KA. WE FOUND
THAT THEY DO HAVE MORE SEVERE
DISEASE THAN THEIR ADULT
COUNTERPARTS LIKE IN THE U.S.,
BUT EVEN WHEN WE COMPARE THEM TO
CHILDREN LIVING IN NORTH
AMERICA, THEY HAVE MORE -- I WAS
CONVINCED THAT STUDYING LUPUS IN
MORE DIVERSE POPULATIONS WAS
CRITICAL TO REALLY UNDERSTANDING
THE DISEASE.
BUT IT WASN'T AN EASY TASK TO
THINK ABOUT BIOLOGIC DRIVERS IN
DIFFERENT POPULATIONS BECAUSE
THERE'S UNEQUAL ACCESS TO
CLINICAL CARE, OF COURSE, BUT
EVEN MORE UNEQUAL ACCESS TO
RESEARCH.
SO UNLIKE SOME TYPES OF
RESEARCH, TRANSLATIONAL RESEARCH
NOT ONLY REQUIRES A CLINICAL
RHEUMATOLOGIST, BUT THERE NEEDS
TO BE THINGS IN PLACE FOR
BIOSAMPLE COLLECTION, STORAGE,
THE ABILITY TO RUN THAT SAMPLE
AND THEN EXPERIMENT THE ABILITY
TO ANALYZE THE RESULTS.
AND THAT REQUIRES SOME REAL
RESEARCH INFRASTRUCTURE AND
SUSTAINED FUNDING, WHICH IS NOT
AVAILABLE IN ALL PLACES IN THE
WORLD.
SO THAT HAS REALLY LED TO GLOBAL
DISPARITIES IN GENETIC RESEARCH.
THIS IS A FIGURE FROM 2019, AND
YOU CAN SEE THIS IS ALL
INDIVIDUALS THAT HAVE BEEN
SEQUENCED IN THE GENOME-WIDE
ASSOCIATION CATALOG, AND 80% OF
THOSE PEOPLE SEQUENCED ARE OF
EUROPEAN ANCESTRY AND THE REST
OF THE WORLD'S POPULATION SHARES
THAT OTHER 20%, SO YOU CAN SEE
WE HAVE A BIG DISPARITY IN WHAT
WE KNOW ABOUT THE GENETICS OF
LUPUS GLOBALLY.
NOW, THERE'S A LOT OF PEOPLE
THAT HAVE RECOGNIZED THAT THIS
IS A HUGE PROBLEM OUTSIDE
RHEUMATOLOGY AND THE GENETICS
FIELD IN GENERAL.
THERE'S MANY EFFORTS SUCH AS
ALL-OF-US AND OTHERS TRYING TO
ADDRESS THESE ISSUES, BUT THE
DISPARITY IS SO BIG, IT'S GOING
TO TAKE US A WHILE TO KIND OF
COVER THE GROUND TO TRULY
ADDRESS THESE DISPARITIES.
WE KNOW LUPUS IS HERITABLE
BECAUSE IN IDENTICAL TWINS,
THERE'S A HIGH CONQU CONCORDANC-
THERE'S BEEN TWO KIND OF AREAS
OF STUDY.
ONE IS COMMON VARIANT STUDIES,
THESE OCCUR COMMONLY IN A
POPULATION, THEY'RE NOT TOO
DAMAGING, THEY'RE KIND OF PASSED
ALONG THROUGH GENERATIONS AND
THEY'RE USUALLY NOT IN THE PART
OF DNA THAT CODES FOR PROTEINS
AND THEY USUALLY HAVE A SMALL
EFFECT SIZE.
SO THEY GIVE YOU 1.2 OR 1.5 THE
RISK OF LUPUS, AND THEN RARE
VARIANTS BY DEFINITION OCCUR
RARELY, THEY'RE USUALLY IN THE
PART OF THE DNA THAT MAKES A
PROTEIN AND THEY CHANGE THE
PROTEINS SO THEY HAVE A BIG
DAMAGING EFFECT, THEY MAKE THE
PROTEIN FUNCTION DIFFERENTLY SO
THEY'RE USUALLY NOT PASSED ON,
BUT THEY HAVE A REALLY BIG
EFFECT ON WHAT'S HAPPENING IN
BIOLOGY.
AND MOST OF THE STUDIES THAT
HAVE BEEN DONE IN LUPUS GENETICS
SO FAR HAS BEEN THESE COMMON
VARIANT STUDIES IN ADULT
POPULATIONS WHO ARE KIND OF LESS
SICK THAN THEIR CHILDHOOD ONSET
COUNTERPARTS.
AS TALKED ABOUT EARLIER, THERE'S
MANY AUTOIMMUNE DISEASES THIS
GENETIC AND ENVIRONMENTAL
INTERPLAY, SO THE THOUGHT IS
THAT THERE'S SOMEBODY WITH A
GENETIC REDISPOSITION EXPOSED
THROUGHOUT THEIR LIFETIME TO
ENVIRONMENTAL EXPOSURES, HAVE
KIND OF DISREGULATED IMMUNITY
AND THAT KIND OF TRUCKS ALONG
UNTIL ALL OF A SUDDEN AN EVENT
KIND OF TIPS YOU OVER INTO LOSS
OF TOLERANCE, YOU START MAKING
AUTOANTIBODIES AGAINST YOUR OWN
CELLS AN.
THE THOUGHT IS THAT IN CHILDREN,
THAT GENETIC PREDISPOSITION IS
MUCH LARGER AND IT PLAYING A
MUCH LARGER ROLE SO YOU DO
HAVE -- YOU HAVE AN
ENVIRONMENTAL EVENT THAT TIPS
YOU OVER BUT IT HAPPENS EARLIER
IN LIFE AND YOUR DISEASE IS MORE
SEVERE.
NOW BECAUSE OF THIS HIGHER
GENETIC LOAD IN PEDIATRICS,
PROBABLY THE IDEAL POPULATION IN
WHICH TO STUDY GENETIC
CONTRIBUTION TO LUPUS AND
THERE'S A THEER RETHAT OLDER
PATIENTS, LATER ADOLESCENT,
PROBABLY HAVE MANY COMMON
VARIANTS BUT NOT MANY OF THOSE
BEING DAMAGING VARIANTS.
EARLY ONSET MIGHT HAVE ONE
DAMAGING VARIANT BUT THEY DON'T
REALLY HAVE -- IT'S EITHER BIG
ADULT COHORTS OR A FEW PATIENTS
THAT HAVE BEEN SEQUENCED REALLY
HASN'T BEEN RIGOROUSLY ANALYZED
IN LARGE COHORTS OF PEDIATRIC
LUPUS PATIENTS.
AND SO OUR LAB AS WORKING
THROUGH COLLABORATION TO REALLY
ADVANCE THE UNDERSTANDING OF THE
GENETIC ARCHITECTURE OF CHILD
ONSET LUPUS.
WE HAVE SOME OTHER
COLLABORATIONS IN PAKISTAN,
MEXICO, CANADA AND THE U.K.
AND OUR FIRST STUDY USED A
METHOD CALLED TRANSMISSION
DISEQUILIBRIUM ANALYSIS.
WE HAD TRIOS, SO AFFECTED
PATIENT AND TWO UNAFFECTED
PARENTS, AND WE HAD THEM FROM
OUR DIVERSE COHORTS THROUGHOUT
THE WORLD.
NOW, WE USED THIS METHOD BECAUSE
WE HAVE CHILDHOOD ONSET
POPULATION SO WE OFTEN HAVE
ACCESS TO PARENT AND WE CAN
COMPARE HOW OFTEN THE PARENTS
TRANSMIT EITHER COMMON OR RARE
VARIANTS TO THEIR OFFSPRING.
IF SOMETHING IS TRANSMITTED MORE
FREQUENTLY IN THE LUPUS PATIE
PATIENTS, THEN TSH AND UNRELATED
FAMILIES, IT KIND OF RAISES OUR
AWARENESS THAT THIS MIGHT BE
INVOLVED IN LUPUS PATHOGENESIS.
THE OTHER NICE THING ABOUT THIS
METHODOLOGY IS YOU USE THE
PARENTS AS THE CONTROL SO
THEY'RE PERFECTLY -- FROM THE
COMMON VARIANT SIDE IT WAS A
SMALL STUDY OF 83 PATIENTS AND
SO WE DID NOT FIND ANYTHING THAT
REACHED STATISTICAL
SIGNIFICANCE, HOWEVER WE DID
FIND THIS WAS A POPULATION
REALLY ENRICHED AND NOVEL RARE
VARIANTS CONTRIBUTING TO LUPUS,
WE FOUND MANY.
WITH SOME REALLY EXCITING
MECHANISMS INCLUDING HNRNPUL2, 1
OF THE MOST TOXIC THINGS THAT
THE CELL SENSES, AND YOU COULD
IMAGINE THAT IT MIGHT TRIGGER
INFLAMMATION, AND IT IS ALSO
PART OF THE FAMILY OF PROTEINS
DESCRIBED IN THE XIST RNP, SO
THAT HAS BEEN AS WE HEARD
EARLIER A REALLY EXCITING
CONTRIBUTOR TO OUR UNDERSTANDING
OF THE FEMALE PR -- IT MIGHT BE
ARE TWO UNROW LATED PATIENTS AND
THEY DON'T HAVE A VARIANT IN THE
EXACT SAME GENE BUT PATIENT A
HAS A VARIANT IN PROTEIN A AND
THIS BIOLOGICAL CASCADE AND
PATIENT B HAS A PROTEIN IN B AND
THEY INTERACT WITH EACH OTHER SO
MOLECULARLY THEY MIGHT LOOK
REALLY SIMILAR EVEN THOUGH THEY
DON'T SHARE THE EXACT GENE SO WE
WANTED TO DEVELOP A METHODOLOGY
TO UNDERSTAND IMPORTANT
MECHANISMS IN LUPUS, SO WE DID A
PATHWAY ANALYSIS TO OUR COHORT.
WE USED ALL 83 PATIENTS AND 109
UNAFFECTED PARENTS.
YOU CAN SEE IN THIS CHART THEY
WERE VERY DIVERSE GENETIC
ANCESTRIES AND GEOGRAPHIC
LOCATIONS, AND SO WE LOOKED FOR
RARE VARIANTS IN THE PROTEIN
CODING REGION OF THE GENE.
WE WERE TRYING TO FIND IMPORTANT
MECHANISTIC DRIVERS, AND TWO
UNRELATED LUPUS PATIENTS, AND
THEN WE ORGANIZED THOSE VARIANTS
AND GENES INTO BIOLOGICAL
PATHWAY IN A PROGRAM CA CALLED
METASCAPE.
WE CREATED A MAP OF THESE
BIOLOGICAL PATHWAYS TO TRY TO
UNDERSTAND WHAT ARE THE
MECHANISMS DRIVING DISEASE USI
USING -- SO THIS IS THE RESULT,
NETWORK OF BIOLOGIC PATHWAYS
ENRICHED FOR VARIANTS FOUND IN
CSLE PATIENTS.
THEY'RE KIND OF CONNECTED BY
LINES AND YOU CAN SEE THAT WE'RE
STARTING SPHO UNDERSTAND THE
MECHANISMS UNDER DRIVING LUPUS
IN THIS COHORT WE HAVE.
SOME OF THEM HAVE BEEN REPORTED
IN OTHER COHORTS THROUGHOUT THE
WORLD LIKE RNA PRO SESSION OR
DNA REPAIR AND OTHERS ARE QUITE
NOVEL.
SO IN CONCLUSION, I HOPE I'VE
COCONVINCED YOU THAT WHILE LUPUS
IS A MIXTURE OF GENETICS AND
ENVIRONMENT, LUPUS PATIENTS ARE
THE IDEAL POPULATION TO REALLY
DEFINE AND WORK OUT GENETIC
CONTRIBUTORS TO SLE, AND
STUDYING LARGE COHORTS OF LUPUS
PATIENTS WILL HELP US TO TAKE US
FROM THIS BROAD CLINICAL
PHENOTYPE TO A MORE PRO SEISE
MOLECULAR PHENOTYPE SO WE CAN
BETTER TARGET THERAPIES AND
IMPROVE OUTCOMES FOR THIS
DEVASTATING DISEASE.
AND WE NEED STUDIES THAT ARE
BROADLY INCLUSIVE SO WE CAN
UNDERSTAND THE BREADTH AND DEPTH
TO UNDERSTAND ALL LUPUS PATIENTS
AROUND THE WORLD.
>> THANK YOU, DR. LEWANDOWSKI.
DR. HOLLAND, I'M NOW GOING TO
PASS THE MICROPHONE OVER TO YOU.
>> ALL RIGHT!
VERY GOOD.
MY SLIDES ARE UP?
>> YOUR SLIDES ARE UP AND YOU
SHOULD BE ABLE TO TAKE CONTROL.
>> ALL RIGHT.
HERE WE GO.
SO THANK YOU VERY MUCH.
IT'S A REAL HONOR TO BE HERE
CELEBRATING THE CAREER OF
DR. PINN AND TO PARTICIPATE WITH
SUCH OUTSTANDING SCIENTISTS AND
PHYSICIANS.
I'M GOING TO TELL YOU A STORY.
IT'S A SINGLE STORY BUT I THINK
YOU'LL SEE WHY IT'S GOT
COMPONENTS THAT ARE RELEVANT TO
MANY OF THE TOPICS OF TODAY.
SO MY STORY STARTS ABOUT A
HUNDRED 40 YEARS AGO.
ROBERT KOCH DECIDES THAT HE'S
GOING TO TELL THE WORLD WHAT
CAUSES TUBERCULOSIS, SO HE
INVITES ALL HIS PALS INTO HIS
HOME TO SHOW THEM M TUBERCULOSIS
UNDER THE MICROSCOPE.
BRAND NEW DISCOVERY, AND IT'S
RIGHT THERE IN HIS KITCHEN,
WHERE HE DOES HIS SCIENCE.
HIS FRIENDS ALL LOOK UNDER THE
MICROSCOPE AND THEY SAY, NO WAY,
THAT CANNOT BE THE CAUSE OF THAT
TERRIBLE DISEASE.
IT'S IT ITTY BITTY AND IT DOESNT
MAKE ANY SENSE.
HOW COULD DO THAT?
THAT'S WHY YOU HAD TO GO ON AND
DEVELOP THESE THINGS CALLED
KOCH'S POSTULATES THAT DETERMINE
HOW WE THINK ABOUT DISEASE.
THE OTHER BIG OUT COME OF THAT
EVENING WAS THAT EVERYBODY SAID
WE ARE NEVER HAVING DINNER AT
BOB'S HOUSE AGAIN.
SO THAT WAS 140 YEARS AGO.
THE DISCOVERY OF M TUBERCULOSIS.
ON THIS CHART, YOU CAN SEE HERE
AT THE TOP, PERHAPS, THAT I'VE
GOT M TUBERCULOSIS AS THE
VERY -- AS THE APEX PREDATOR OF
MYCOBACTERIA.
IT'S VERY VIRULENT.
PEOPLE GET SICK AND DIE FROM IT.
BUT THERE ARE ABOUT 150 OTHER
STRAINS OF MYCOBACTERIA THAT ARE
NOT M TUBERCULOSIS THAT DON'T
CAUSE SUCH SEVERE DISEASE.
AND SO STARTING IN THE 1980s,
WITH THE ADD VENT ADVENT OF THEV
EPIDEMIC, PEOPLE REALIZED THAT
WHEN THE IMMUNE FUNCTION IS
IMPAIRED, MYCOBACTERIA
DISSEMINATE WITHIN THE BODY AND
THAT WAS A MAJOR FEATURE OF
ADVANCED AIDS.
SO WHAT MANY OF US DID GOING
INTO THE 80s AND 90s WAS TO
SAY, OKAY, WE UNDERSTAND HOW HIV
DOES THAT, MAKES FOR
MYCOBACTERIAL DISSEMINATION, BUT
WHAT ABOUT PEOPLE WHO DEVELOP
DISSEMINATED MYCOBACTERIAL
DISEASE WHO DON'T HAVE HIV?
THERE MUST BE SOMETHING ELSE
WRONG WITH THEM.
AND SO OUR LAB AND MANY OTHERS
STARTED TO LOOK AT THESE
NON-TUBERCULOUS MYCOBACTERIA
THAT ARE INVOLVED IN THESE
DISEASES.
SO I'LL REFER TO THESE GLOBALLY
AS NTM OR NON-TUBERCULOUS
MYCOBACTERIA.
THEY ARE IN THE ENVIRONMENT, YOU
ARE EATING THEM, DRINKING THEM,
INHALING THEM ALL THE TIME, AND
THE VAST MAJORITY OF US NEVER
GET SICK FROM THEM.
NOW, IT TURNS OUT THAT THERE ARE
A VARIETY OF WAYS THEY CAN
AFFECT PEOPLE.
SKIN INFECTION IS COMMON, AND
HAPPENS TYPICALLY AFTER
PEDICURES.
SO IF YOU'RE GOING TO HAVE A
PEDICURE, DON'T SHAVE BEFORE THE
PEDICURE, THAT USUALLY WILL GET
RID OF IT, LUNG DISEASE IS VERY
COMMON.
AND IN COUNTRIES THAT HAVE VERY
LOW RATES OF TUBERCULOSIS,
NON-TUBERCULOUS LUNG DISEASE IS
COMMON AND IT'S OVERWHELMINGLY A
DISEASE OF WOMEN.
BUT WHAT I'M GOING TO TALK ABOUT
TODAY IS DISSEMINATED DISEASE.
AND YOU CAN SEE, AS IT'S TRAW
FOR MANY THINGS, WE KNOW ABOUT
THE MOST SEVERE CASES BECAUSE
THAT'S WHERE THE RATIO OF
SYMPTOMS TO DISCOVERY IS THE
BEST.
SO DISSEMINATED DISEASE, AS YOU
SEE IN THIS BOY HERE, IS REALLY
WHAT WE ARE GOING TO TALK ABOUT.
AND WHAT WE KNOW IS THAT
MYCOBACTERIA, SHOWN HERE AS
THESE RED ORGANISMS INSIDE OF
THE MACROPHAGE, THESE RED
ORGANISMS, THE MYCOBACTERIA GET
INGESTED BY MACROPHAGE, AND THAT
LEADS TO THE PRODUCTION OF IL12
AND IL23, THAT THEN WORK ON T
CELLS AND THEN K CELLS TO
UPREGULATE THE PRODUCTION OF
INTERFERON GAMMA.
INTERFERON GAMMA THEN ACTS ON
ITS RECEPTOR ON MACROPHAGES AND
ALL OTHER NUCLEATED CELLS TO
TURN ON A WHOLE SERIES OF
INTRACELLULAR GENES TO LEAD TO
THE KILLING OF MYCOBACTERIA
INSIDE THE CELL.
IT'S A VERY SIMPLE PATHWAY AND
YOU MIGHT SAY, STEVE, IT'S SO
SIMPLE, IT CAN'T POSSIBLY BE
TRUE.
THAT MIGHT BE CORRECT, BUT THERE
ARE REASONS THAT WE THINK IT IS
THE RIGHT PATHWAY TO FOCUS ON
AND THOSE REASONS ARE THAT WE'VE
GOT MENDELIAN MUTATIONS IN ALL
OF THESE GENES SHOWN HERE IN RED
THAT LEAD TO DISSEMINATED
DISEASE.
AND SO THIS HAS TAKEN ON A NAME
CALLED MENDELIAN SUSCEPTIBILITY
TO MYCOB MYCOBACTERIAL DISEASE H
IS A USEFUL WAY TO THINK ABOUT
THE SORT OF GLOBAL
SUSCEPTIBILITY TO DISSEMINATED
DISEASE.
IT HAS NOTHING TO DO WITH LUNG
DISEASE OKAY.
SO THIS PATHWAY THEN IS REALLY
CENTRAL TO WHO GET DISSEMINATED
MYCOBACTERIAL DISEASE.
BUT HERE'S WHERE IT GETS
INTERESTING.
THIS ALMOST ALWAYS OCCURS IN
CHILDHOOD.
AND ALMOST ALWAYS AROUND THE
WORLD OCCURS AFTER PEOPLE ARE
GIVEN BCG VACCINATION,
SUBCUTANEOUS OR INTRADERMAL WITH
LIVE BACTERIA AND THAT LEADS TO
DISSEMINATED DISEASE IN PEOPLE
WHO HAVE THE MUTATIONS SHOWN
HERE.
OKAY.
I'M AN INTERNIST, AND MY PATIENT
IS SHOWN HERE.
SO THIS IS A 60 YEAR OLD WOMAN
FROM VIETNAM, WHO HAD SURVIVED
THE VIETNAM WAR, CAME OUT TO THE
REFUGEE CAMPS, CAME TO THE
UNITED STATES AS A YOUNG WOMAN,
HAD A FAMILY, HAD A JOB, SET UP
HER OWN BUSINESS, AND AT 59, SHE
THEN BEGAN TO LOSE WEIGHT AND
HAVE FEVERS, AND EVENTUALLY WAS
RECOGNIZED TO HAVE THIS DISEASE,
AND YOU SEE HERE THESE SPOTS ON
HER CHEST, AND THEY'RE BECAUSE
SHE HAD INFECTION IN HER BONES
THAT WAS RUPTURING OUT THROUGH
HER SKIN.
AND THESE INFECTIONS WERE DUE TO
MYCOBACTEMYCOBACTERIUM AVIUM COE
OF THE NON-TUBERCULOUS
MYCOBACTERIA.
SO WE'RE NO DUMB S, WE LOOKED AT
THAT AND SAID WAIT A MINUTE,
THIS LOOKS LIKE THE DISSEMINATED
DEEDS WE SEE IN CHILDREN, BUT HE
SH'S NOT A CHILD.
SO IF IT LOOKS LIKE A GENETIC
DISEASE AND IT ACTS LIKE A
GENETIC DISEASE, BUT IT'S COMING
ON LATE IN LIFE AND IN HER CASE,
THE IN VITRO CELLULAR BEHAVIOR
WAS NORMAL, WHAT IN THE WORLD IS
IT?
AND SO THE ANSWER HERE IS THAT
SHE HAS AN AUTO ANTIBODY TO
INTERFERON GAMMA ITSELF.
AND THAT AUTO ANTIBODY IS
COMPLETELY BLOCKING AND GIVES
HER A PHENOTYPE THAT IS A CARBON
COPY OF WHAT HAPPENS IF YOU'RE
MISSING THE RECEPTOR.
WELL, THAT WAS VERY INTERESTING,
AND AS WE STARTED TO LOOK AROUND
A LITTLE BIT AS THIS WAS
HAPPENING, WE NOTICED HERE ARE
THE THREE EARLIEST PAPERS IN
THIS SERIES.
SO THE VERY FIRST PAPER
REPORTING A 25-YEAR-OLD THAI
WOMAN LIVING IN GERMANY WHO HAD
ONE OF THE NON-TUBERCULOUS
MYCOBACTERIUM, SHE GOT SICK AND
DIED.
25-YEAR-OLD WOMAN.
THE NEXT PAPER IS A 57-YEAR-OLD
FILIPINO MAN LIVING IN ENGLAND,
WHO DEVELOPED -- HAD TB AS A
YOUNGER MAN AND THEN
MYCOBACTERIA CHELONAE WITH
AUTOIMMUNITY AND THEN HE DIED.
AND WE HAD SEEN SIX WOMEN, ALL
OF WHOM CAME FROM SOUTHEAST
ASIA, ALL OF WHOM HAD WIDELY
DISSEMINATED DISEASE, ALL OF
WHOM WERE DESPERATELY ILL.
AND THAT GOT US THINKING, WAIT A
MINUTE, THIS SEEMS A LITTLE BIT
TOO MUCH OF A CONNECTION OF
PEOPLE FROM SOUTHEAST ASIA
SHOWING UP WITH THESE PROBLEMS.
SO THE RECURRING STORY,
SOUTHEAST ASIANS OUTSIDE OF ASIA
WHO HAVE AUTOANTIBODIES, IGG
AUTOANTIBODIES TO INTERFERON
GAMMA THAT LEAD TO DISSEMINATED
NON-TUBERCULOUS DISEASE AS WELL
AS SOME OTHER OPPORTUNISTIC
INFECTIONS I'LL TELL YOU ABOUT
IN A MINUTE, AND IT'S BAD, THIS
IS REALLY SEVERE DISEASE.
SO WE STARTED TO THINK, YOU
KNOW, IF THIS IS HAPPENING IN
SOUTHEAST ASIANS OUTSIDE OF
SOUTHEAST ASIA, WHAT IN THE
WORLD IS GOING ON IN SOUTHEAST
ASIA?
BECAUSE ALL OF THESE PEOPLE WERE
DIRECT IMMIGRANTS FROM THOSE
COUNTRY, NOT PEOPLE BORN IN
EUROPE OR THE UNITED STATES.
SO THIS PAPER HERE WAS REALLY
THE SEMINAL PAPER THAT SAID,
OKAY, LOOK, SHE REPORTED ON 59
PEOPLE IN THAILAND WHO DID NOT
HAVE HIV, BUT HAVE WIDESPREAD
OPPORTUNISTIC INFECTIONS IN
ADDITION TO NON-TUBERCULOUS
MYCOBACTERIA.
SO ALL OF THESE INFECTIONS
LISTED HERE ON THE RIGHT SIDE
WERE HAPPENING IN ADDITION TO
NON-TUBERCULOUS MYCOBACTERIA.
AND FOR THOSE OF YOU WHO ARE
REAL NERDS, YOU'LL NOTICE THAT
MOST OF THESE ARE ORGANISMS THAT
LIVE INSIDE THE MACRO FRAJ IN
EMA MACROPHAGE INEXACTLY THE SAE
NON-TUBERCULOUS MYCOBACTERIA DO.
AS WELL AS SOME VIRUSES.
SO WE THEN WORKED WITH PETER
BURBELO, WHO IS AN INVESTIGATOR
AT THAT TIME IN THE DENTAL
INSTITUTE, AND HE DEVELOPED AN
ASSAY CALLED LIPS, WHICH
ASSISTANTS FOR LUCIFERASE
IMMUNOPRECIPITATION SYSTEM.
YOU'LL NOTICE THAT LIPS ARE THE
ONE THING HE'S NOT LETTING US
SEE HERE.
BUT THIS LIPS ASSAY ALLOWS YOU
TO READ OUT ANTIBODIES AS
RELATIVE LIGHT UNITS.
AND I WON'T GO INTO ALL THE
DETAILS OF THE STUDY, EXCEPT TO
SAY THAT WE HAD SEVERAL GROUPS
OF PATIENTS THAT WE COLLECTED IN
THAILAND AND TAIWAN AND YOU SEE
THAT HERE IN THE UPPER PART OF
THE FIGURE ARE PEOPLE THAT HAVE
ANTIBODIES AGAINST INTERFERON
GAMMA.
YOU'LL SEE PATIENTS WITH
DISSEMINATED NON-TUBERCULOUS
MYCOBACTERIAL DISEASE AND THOSE
WITH OTHER OPPORTUNISTIC
INFECTIONS WITH OR WITHOUT
NON-TUBERCULOUS INFECTIONS HAD
HIGH LEVELS OF THESE
AUTOANTIBODIES AGAINST
INTERFATHER ON GAMMA, WHEREAS
THOSE WITH DISSEMINATED
TUBERCULOSIS, PULMONARY
TUBERCULOSIS OR BLOCK BANK
DONORS DID NOT.
THIS IS JUST AN EXAMPLE, YOU SAW
THE WOMAN I MENTIONED AT THE
BEGINNING.
HERE IS A MAN ON THE LEFT WHO
HAS DISSEMINATED TALAROMYCES
MARNEFFEI, THE WOMAN ON THE
RIGHT HAS SALMONELLA LIMB FAD
NIGHTS.
SALMONELLA LY M.P.H.
ADENITIS.
THEY ASKED THIS QUESTION AND
THEY LOOKED AT THEIR PATIENTS
AND SAID, OH, YOU KNOW, MAYBE
THIS IS RELATED TO HLA.
HLA IS A SET OF PROTEINS THAT
RESTRICT HOW WE KILOGRAM
RECOGNIZE ANTIGENS, AND THEY
REALIZED THAT THERE WERE CERTAIN
HLA ALLELES THAT YOU SEE HERE
THAT WERE HIGH LOW
OVERREPRESENTED IN THESE
PATIENTS FROM SOUTHEAST ASIA.
AND HERE DOESN'T MATTER WHAT
THEY ARE, BUT THEY HAVE
INCOMPREHENSIBLE NAMES THAT ARE
HARD TO PRONOUNCE AND REMEMBER,
BUT THEY'RE VERY HIGHLY
OVERREPRESENTED IN THIS PATIENT
GROUP.
WHY SHOULD THAT BE?
WHY WOULD THAT BE INTERESTING?
AND IT TURNS OUT THAT THE
BINDING GROOVE MADE BY THESE
ALLELES IS ABLE TO BIND THE LAST
10 AMINO ACIDS OF THE INTERFERON
GAMMA MOLECULE.
AND YOU CAN SEE HERE IN THE
UNDERLINE IN THE TABLE, THAT IS
THE SEQUENCE OF THE LAST FEW
AMINO ACIDS OF INTERFERON GAMMA.
BUT WE ALL HAVE INTERFERON
GAMMA.
LIFE IS INTRINSICALLY BUILT
AROUND HAVING THAT.
BUT WHAT THEY NOTICED THAT I
THINK WAS REALLY INTERESTING IS
THAT THERE'S AN OVERLAP BETWEEN
THE SEQUENCE IN INTERFERON GAMMA
AND A PEPTIDE IN AS P ASPERGILL.
THEY HAVE AN HLA TYPE THAT
ALLOWS THEM TO RECOGNIZE EITHER
INTERFERON OR AN OVERLAPPING
PEPTIDE IN ASPERGILLUS, SO THE
HYPOTHESIS IS PEOPLE ARE BEING
EXPOSED TO ASPERGILLUS, THOSE
ANTIBODIES NEUTRALIZE AND MAKE
THEM SICK.
IT SHOWS IF YOU BRING OUT THE
RELATIVE EPITOPES, THAT ACTUALLY
CAN MAKE IT GO AWAY.
THAT'S A REALLY NIFTY
RECOGNITION.
AND THAT WOULD SUGGEST, OKAY,
NOW WE'VE GOT ANTIBODIES TO
INTERFERON, WE HAVE AN IDEA WHY
THEY'RE HAPPENING, AND SO ONCE
YOU KNOW WHAT THE PROBLEM IS,
YOU HAVE IDEAS HOW TO TREAT IT.
AND SO WE WANT TO YOU KNOW THAT
IT'S ANTIBODY MEDIATED, ONE OF
THE OBVIOUS THINGS TO DO IS GET
RID OF THE CELLS, MAKING THOSE
ANTIBODIES.
SO THIS IS JUST AN EXAMPLE,
TREATMENT OF THESE PATIENTS WITH
RITUXIMAB WHICH KILLS B CELLS.
YOU CAN SEAT TITERS BEFORE
TREATMENT WERE HIGH, DURING
TREATMENT THEY WERE GOING DOWN
AND AFTER TREATMENT THEY WERE
EVEN LOWER.
IN THE ONE PATIENT HERE WHOSE
PICTURE I SHOWED YOU AT THE
BEGINNING, WHEN WE STOPPED
THERAPY ALONG THE WAY, HER B
CELLS CAME BACK, HER TITERS WENT
UP, VERY SELLED DISEASE AGAIN,
WE TREATED HER AND IT WENT AWAY.
NOW WHY AM I TELLING YOU THIS
STORY HERE?
BECAUSE WHAT'S FASCINATING ABOUT
THIS IS THAT THE DISEASE OCCURS
IN SOUTHEAST ASIA, SOUTHERN
CHINA AND SOUTHEAST ASIA.
IT ALSO OCCURS IN EUROPE, THE
UNITED STATES AND AUSTRALIA.
BUT ALMOST EXCLUSIVELY IN PEOPLE
WHO WERE BORN IN SOUTHEAST ASIA
AND EMIGRATED.
IT IS NOT OCCURRING IN PEOPLE OF
EXACTLY THE SAME ETHNIC AND
GENETIC BACKGROUND WHO WERE BORN
IN THIS COUNTRY.
THE OTHER THING THAT'S REALLY
STAGGERING, LOOK AT THE NUMBERS
HERE, LOOK AT THE RATIO OF MALE
TO FEMALE IN THAILAND ON THE
LEFT.
IT'S ABOUT 6 TO 4.
BUT ONCE YOU GET OUT OF
THAILAND, OR SOUTHEAST ASIA,
IT'S LIKE, YOU KNOW, 9 TO 1.
SO WHAT IS GOING ON THAT ARE
CHANGES, WHY IS IT THAT IT'S
ONLY IN PEOPLE BORN IN SOUTHEAST
ASIA, THAT SUGGESTS THAT THERE'S
A GEOGRAPHIC COMPONENT, BUT
THERE'S ALSO CLEARLY A GENDER
COMPONENT, AND THERE'S A GENETIC
COMPONENT.
SO I'M TELLING YOU THIS STORY
BECAUSE I THINK IT'S A PARADIGM
FOR MANY OF THE THINGS WE'VE
HEARD ABOUT TODAY.
THERE'S GENETICS, THERE'S
CLEARLY AN EXPOSOME COMPONENT,
AS WELL AS A CRITICAL GENDER
COMPONENT.
ALL OF THOSE ARE CONSPIRING TO
GIVE THESE WOMEN PARTICULARLY
BAD DISEASE.
SO I'VE TRIED TO TELL YOU ABOUT
A SYNDROME THAT IS REALLY QUITE
INTERESTING IN TERMS OF
DEVELOPMENT OF AUTOIMMUNITY.
IT'S ASSOCIATED WITH MULTIPLE
OPPORTUNISTIC INFECTIONS.
IT'S GOT AN HLA ASSOCIATION.
IT'S PREDOMINANTLY WOMEN, AND WE
KNOW HOW TO TREAT IT.
AS LONG AS WE CATCH IT IN TIME.
I'LL STOP THERE AND I LOOK
FORWARD TO TAKE ANY QUESTIONS IN
THE QUESTION PERIOD.
THANK YOU.
>> THANK YOU SO MUCH,
DR. HOLLAND.
WE'RE GOING TO MOVE SWIFTLY ON
TO DR. MOTSINGER-REIF AND
QUESTIONS AT THE END.
>> THANK YOU SO MUCH.
I REALLY APPRECIATE THE
OPPORTUNITY TO SPEAK AND THE
SUPPORT FROM YOUR OFFICE.
SO OUR PREVIOUS SPEAKERS HAVE
DISCUSSED THE IMPORTANT ROLE OF
THE ENVIRONMENT AND RISK OF
DISEASES AND THAT'S WHAT I'M
GOING TO FOCUS ON HERE.
I'M TALKING ABOUT SOME WORK A
LITTLE BIT IN THE PRELIMINARY
STAGE BUT REALLY GETTING
ROLLING.
SOME WORK IN THIS SPACE IN A
NORTH CAROLINA BASED COHORT THAT
I'M CO-PI ON CALLED PEGS, THE
PERSONALIZED ENVIRONMENT AND
GENES STUDY.
I SPENT THE LAST ABOUT FIVE
YEARS ASSEMBLING A LARGE AMOUNT
OF DATA AROUND THESE
PARTICIPANTS AND WOULD LIKE TO
SHARE SOME OF THE OUTCOMES OF
OUR ASSOCIATIONS WITH
ENVIRONMENTAL FACTORS.
SO JUST SOME QUICK SNAPSHOTS OF
PEGS.
SO IT'S A NORTH CAROLINA-BASED
COHORT.
IN TOTAL WE HAVE ABOUT -- ALMOST
20,000 PEOPLE ENROLLED, AND WE
HAVE EXTENSIVE HEALTH AND
EXPOSURE DATA ON ALMOST 10,000
OF THOSE 20,000.
HERE'S JUST A SNAPSHOT OF SOME
OF THE DEMOGRAPHICS, OUR AVERAGE
AGE IS JUST UNDER 50, WE'RE A
RELATIVELY DIVERSE COHORT IN
TERMS OF EDUCATION,
SOCIOECONOMIC STATUS, GENDER,
AND RACE/ETHNICITY.
WHICH IS REALLY A WONDERFUL SORT
OF A ASPECT AND POWERFUL ASPECTF
THIS STUDY.
I MIPTIO MENTIONED WE HAVE EXTEE
HEALTH AND EXPOSURE DATA FROM
OUR PARTICIPANTS.
SO WE HAVE EXTENSIVE SURVEY DATA
ON THREE DIFFERENT SURVEYS.
THE FIRST ONE IS WHAT WE CALL
HEALTH AND EXPOSURE, AND I'VE
GOT SOME SNAPSHOTS HERE.
SO HERE WE ASK, HAS A DOCTOR
EVER DIAGNOSED YOU WITH A, B OR
C, AND HAVE YOU EVER BEEN
EXPOSED TO X, Y AND Z IN YOUR
HOME, AT YOUR WORK, ET CETERA?
WHEN I SAY EXTENSIVE
QUESTIONNAIRES, I'M REQUESTING
TO GIVE YOU THE NUMBER OF
QUESTIONS SO IT'S GOING TO TIE
INTO SORT OF THE ANALYSIS
STRATEGY USED DOWNSTREAM.
SO HEALTH AND EXPOSURE SURVEY,
WE HAVE ALMOST 500 QUESTIONS ON,
AGAIN, SELF-REPORTED DISEASES OR
CONDITIONS, LIFESTYLE FACTORS
AND EXPOSURES.
WE HAVE TWO ADDITIONAL SURVEYS
WE CALL OUR EXPOSOME -- HERE
WE'VE GOT OVER 600 QUESTIONS
RELATED TO YOUR EXTERNAL
EXPOSOME.
SO WHAT YOU ARE EXPOSED TO --
OCCUPATIONALLY, WHAT IN YOUR
HOMES, WHAT ARE SOME OF YOUR
HOBBY BASED EXPOSURES, DETAILS
ON YOUR HOUSING AND DISTANCE TO
ENVIRONMENTAL BADS.
AND AGAIN, JUST SOME SNAPSHOTS
HERE, BUT REMEMBER, ALMOST 600
QUESTIONS.
WE ALSO HAVE OUR INTERNAL
EXPOSOME SURVEY WHICH IS OVER
700 QUESTION QES ON S ON THE INL
EXPOSOME.
LIFESTYLE, DIET, PHYSICAL
ACTIVITIES, SLEEP, MEDICATIONS
THAT YOU'RE TAKING, INFECTIOUS
DISEASES YOU'VE BEEN EXPOSED TO
AND CAUGHT.
SO AGAIN, A PRETTY EXTENSIVE
AMOUNT OF EXPOSURE DATA.
AND THIS IS JUST ONE OF THE DATA
DMEENTS WE HAVE IN THIS STUDY.
AND I'M MENTIONING THIS BECAUSE
WHILE WE SPENT A LOT OF TIME
GATHERING THE DATA, AND BECAUSE
WE LOVE TO HAND IT OUT TO PEOPLE
THAT WANT TO ASK AND ANSWER
INTERESTING QUESTIONS.
SO ALREADY MENTIONED WE'VE GOT
EXTENSIVE HEALTH AND EXPOSURE
DATA FROM QUESTIONNAIRES.
WE ALSO HAVE A GROWING NUMBER OF
GEOSPATIAL ESTIMATES OF
EXPOSURE.
WE HAVE ADDRESSES AND ADVERSE
HISTORY FOR ALL OF OUR
PARTICIPANTS, SO WE'VE LINKED
SORT OF OUR PARTICIPANTS TO
ESTIMATES OF AIR POLLUTION, OF
WATER SOURCE CONTAMINATION, OF
SOCIAL DETERMINANTS AND
PLACE-BASED DISPARITIES, GREEN
SPACE, HEALTHCARE ACCESS, ET
CETERA.
AGAIN WE'VE GOT PHENOTYPE DATA
FROM OUR SELF-REPORTED SURVEY
QUESTIONS.
WE'RE IN THE PROCESS NOW OF
LINKING OUR PARTICIPANTS TO
HEALTH RECORDS FROM BOTH UNC AND
CHAPEL HILL, AND THEN WE HAVE A
GROWING NUMBER OF GENOMIC
COMPONENTS THAT WE'RE
COLLECTING.
WE HAVE WHOLE GENOME SEQUENCING
ON A SUBSET OF OUR PARTICIPANTS,
WHICH MEANS YOU CAN GET SINGLE
NUCLEOTIDE VARIANTS, RARE
VARIANTS, STRUCTURAL VARIANTS,
HLA THAT GOT SPOKEN OF EARLIER,
WE'VE ALSO JUST RECENTLY GOTTEN
EPIGENETIC DATA WE'RE WORKING
OUR WAY AND PROCESSING NOW.
SO REALLY MULTI-DIMENSIONAL DATA
SET AND AS A BIOSTATISTICIAN,
STATISTICAL GENETICIST, BIG DATA
PERSON, THIS IS REALLY EXCITING
TO HAVE ALL THESE COMPONENTS.
SO USING THIS RESOURCE, WE'VE
DONE EXPOSOME-WIDE ASSOCIATION
STUDIES OF AUTOIMMUNE DISEASES
IN THE PEGS COHORT.
SO WE TAKE THE SURVEY DATA THAT
I MENTIONED BEFORE SO WE'VE GOT
EXTENSIVE -- ALMOST 1700
QUESTIONS ON EXPOSURES ACROSS
THESE INDIVIDUALS FOR THE
AUTOIMMUNE DISEASES -- FOR
PARTICIPANTS WITH AUTOIMMUNE
DISEASES AND THE DISEASES WE'RE
ABLE TO INCLUDE BECAUSE OF A
REASONABLY HIGH PREVALENCE IS
ALLERGIC RHINITIS, ALLERGIC
RHINITIS, HYPOTHYROIDISM,
HYPERTHYROIDISM AND PSORIASIS.
SO FOR EACH ONE, WSH YOU LOOK
ACROSS THE GENOME, WE'RE GOING
TO LOOK AT THOSE THOUSANDS OF
EXPOSURES IN A SERIES OF
REGRESSION MODELS.
SO VERY SIMPLE STARTING OFF VERY
SIMPLY ASKING EXPOSURE BY
EXPOSURE, WHAT IS ASSOCIATED
WITH THESE DISEASES.
WE DO MULTIPLE -- FALSE POSITIVE
CONTROL, AND THEN CAN LOOK AT
WHAT IS UNIQUE AND SHARED IN
SORT OF ASSOCIATIONS WITH THESE
DISEASE.
WE ALSO ARE INTERESTED IN HOW
THESE EXPOSURES CORRELATE AND WE
DO MULTIVARIABLE MODELING WHERE
WE JOINT LOW LOOK AT THESE
EXPOSURES AND DO SELECTION TO
FIND THE MOST IMPORTANT
EXPOSURES TO FIT WITHIN -- WE
FOLLOW WORKFLOW FOR ALL THESE
AUTOIMMUNE DISEASES.
SO HERE ARE OUR STUDY GOALS TO
INVESTIGATE THE RELATIONSHIP
BETWEEN EXPOSURES AND THESE
COMMON AUTOIMMUNE DISEASES.
SENATE SHOTS, NUMBERS, SAMPLE
SIZES.
SO HERE I'M SHOWING YOU SOME OF
THOSE RESULTS.
I KNOW THIS IS SMALL AND NOT
EASY TO WALK THROUGH.
AND I'M SHOWING THE RESULTS OF
SORT OF THE SIGNIFICANT
ASSOCIATIONS AT AN FDR LEVEL OF
.001, WHICH IS -- VERY, VERY
TIGHT CONTROL.
THE WAY YOU SPHN -- EVERYTHING
I'M CALLING SIGNIFICANT, I ONLY
EXPECT .1% OF THOSE TO .
SO REALLY STRINGENT CONTROL.
WE'RE FINDING THINGS IN
RHEUMATOID ARTHRITIS WITH THE
SMOKING INDOORS TO -- EXPOSED TO
DAILY CONDITIONS, PESTICIDES IN
YOUR WORK, ET CETERA.
WE'RE SHOWING THE TABLES AND
THESE FOREST PLOTS THAT SHOW
EXPOSURES.
WE ALSO FOUND A NUMBER OF
RESULTS FOR VIE CYST.
I KNOW I'M GOING THROUGH THEM
VERY QUICK LE AND YOU CAN'T SEE
THEM BUT I'LL SHOW YOU THE
SUMMARIES.
HYPERTHYROIDISM AND HIGH --
THERE ARE SO MANY SIGNIFICANT
ASSOCIATIONS IT'S ALMOST
UNINTERPRETABLE.
SO I'M GOING TO NARROW IT DOWN
BUT JUST KNOW WE HAVE AN
INCREDIBLE NUMBER OF
ASSOCIATIONS WITH ALLERGIC
RHINITIS.
SO I'M SHOWING YOU A BUNCH OF
RESULTS YOU CAN'T VISUALIZE OR
SUMMARIZE HERE.
SO WHAT I'M SHOWING HERE IS A
MIAMI PLOT SUMMARIZING THE
EXPOSURES THAT WERE SIGNIFICANT
BY GROUPS, LIKE I SAID, WE ASKED
THOUSANDS OF QUESTIONS, SO SHOWN
HERE WHAT CAME UP AS SIGNIFICANT
FOR R.A.
SO SEVERAL QUESTIONS ABOUT YOUR
GENERAL HEALTH, THERE WERE A LOT
OF ASSOCIATIONS WITH
QUESTIONNAIRES RELATED TO YOUR
HOME LIFE AND EXPOSURES THERE.
A NUMBER OF ASSOCIATIONS WITH
MOOD-BASED QUESTIONS.
WHICH ALSO IS RIGHT FOR REVERSE
CAUSALITY, BUT A LOT OF
PSYCHOLOGICAL QUESTIONNAIRES
COMING UP.
EXPOSURES HERE, SORT OF YOUR
CLASSICAL BIG E KINDS OF
EXPOSURES, OCCUPATIONAL
EXPOSURES.
SO A LOT OF ASSOCIATION WITH
FATIGUE AND RELATED VARIABLES,
ANOTHER ASSOCIATION WITH --
STRONG ASSOCIATIONS WITH
OCCUPATION QUESTIONNAIRES AS
WELL.
SIMILAR THINGS WERE FOUND FOR
HYPERTHYROIDISM, SO WE CAN SEE
HERE, SORT OF A LARGE NUMBER OF
ASSOCIATIONS ACROSS THESE
DIFFERENT BROAD CATEGORIES.
HYPOTHYROIDISM LOOKS VERY
SIMILAR, STRONGER ASSOCIATIONS
WITH FATIGUE, AND ACTUALLY SOME
OF THE STRONGEST MAGNITUDE
ASSOCIATIONS WERE SEEN IN
HYPOTHYROIDISM.
QUESTIONS ABOUT GENERAL HEALTH,
MOOD, FATIGUE, AND OCCUPATIONAL
EXPOSURES REALLY HAVING LARGE
EFFECT SIZES.
SIMILAR RESULTS HERE FOR
PSORIASIS.
PSORIASIS HAD STRONGER
ASSOCIATIONS WITH
LIFESTYLE-BASED QUESTIONNAIRES
THAN SOME OF THE OTHERS.
REALLY STRONG ASSOCIATIONS WITH
FATIGUE AND VERY STRONG
ASSOCIATIONS WITH PSYCHOLOGICAL
AND MOOD SORT OF QUESTIONNAIRES.
SO OUR NEXT STEPS ARE TO
CONTINUE DIGESTING THESE
RESULTS.
WE'VE ALSO CONDUCTED STRATIFIED
ANALYSES.
ONE OF THE GOALS OF THIS
WORKSHOP IS FOCUSED OND WOMEN'S
HEALTH, WE FIND DIFFERENT
RESULTS WHEN WE STRATIFY BY MEN
AND WOMEN IN OUR COHORT AND
WE'RE TRYING TO DIGEST THOSE.
WE'RE WORKING ON TRYING TO
INTERPRET AND SYNERGIZE SORT OF
THE RESULTS ACROSS DISEASES AND
ACROSS STRATA, WHICH EXPOSURES
ARE SHARED AMONGST THESE
DISEASES, WHICH ONES ARE UNIQUE
AND THE SAME THING ACROSS
STRATA, WHAT IS SHARED, WHAT IS
UNIQUE.
WHAT ARE OVERALL PATTERNS OF
EXPOSURE AND MORE COMPLEX
MULTIVARIATE MODELING.
WE'VE ALSO -- I MENTIONED WE
HAVE GIS-BASED ESTIMATES OF
EXPOSURE, IN THE MIDDLE OF
CONDUCTING EX-WAS WITH GIS-BASED
ESTIMATES OF EXPOSURE.
WE'RE ALSO WORKING TO LEVERAGE
THE MULTIPLE OMICS THAT WE HAVE
COLLECTED IN PEGS.
SO I'M HIGHLIGHTING OUR EX-WAS
STRATEGY HERE.
WE'RE ALSO RUNNING GWAS TO LOOK
AT GENETIC ASSOCIATIONS THAT WE
SEE IN OUR COHORT.
YOU CAN IMAGINE THE OPPORTUNITY
FOR GENE ENVIRONMENT
INTERACTIONS AS SOMETHING WE ARE
REALLY INTERESTED IN.
FOLKS BROUGHT UP PTPN AS ONE OF
THE CANDIDATE GENES THAT'S
EMERGED IN THIS SPACE.
WE'RE ACTUALLY SEEING VERY
STRONG GENE-ENVIRONMENT
INTERACTIONS WITH PTPN AND THE
DISTANCE TO CAGED ANIMAL FEEDING
OPERATIONS WHERE PARTICIPANTS
LIVE.
SO WE'RE LOOKING AT BOTH
CANDIDATE GENE AND SORT OF BRO
BROADER -- IN THIS DATA AND AS
WE INTEGRATE IT.
THEN WE'RE COMMITTED TO VERY
TRANSPARENT DATA SHARING.
SO IF YOU'RE INTERESTED IN
LOOKING AT BROADLY OUR RESULTS,
WE'VE DONE EX-WAS FOR NOT
AUTOIMMUNE TRAITS BUT A LOT OF
OUR COMMON COMPLEX DISEASES AND
WE'VE DISSEMINATED THOSE ON --
WE SHOW THEM ALL THE RESULTS.
I AM NOT AN EXPERT IN EVERY
DISEASE, NOT AN EXPERT IN EVERY
EXPOSURE BUT WE PUT THE DATA OUT
THERE, MAKE IT SEARCHABLE SO IF
YOU HAVE HYPOTHESES THAT YOU'RE
INTERESTED IN, YOU CAN FIND SORT
OF THE RESULTS FROM PEGS TO HELP
INTERPRET.
SO WE PUT THOSE RESULTS OUT
THERE, BOTH FOR THE COHORT AS A
WHOLE, WITH DIFFERENT STRATA,
YOU CAN CHOOSE DIFFERENT
COVARIATES FOR SENSITIVITY SORT
OF ANALYSIS, AND THEN WE ALSO
SHARE EXPOSOME GLOBES.
WE KNOW EXPOSURES NEVER COME
UNIQUELY.
WE'RE CONSTANTLY EXPOSED TO
MIXTURES IN OUR LIFE AND IN OUR
WORK, SO LET YOU INTERACT WITH
WHAT EXPOSURES HAPPEN TOGETHER.
WHAT IS FURTHER CORRELATION
STRUCTURE ACROSS THE EXPOSOME.
SO I'LL TRY TO GET US BACK ON
TRACK A LITTLE BIT ON TIMING
HERE.
THERE'S SO MANY PEOPLE TO THANK
AND ACKNOWLEDGE.
WHEN I SAY WE, I'M NEVER DOING
ANY OF THAT WORK MYSELF.
SO I HAVE TO THANK MYCOPIJAN
HALL AND LEADERSHIP IN PEGS, A
TEAM THAT WORKS ON THE GIS
MODELING, PARTICULARLY I HAVE TO
HIGHLIGHT GRADUATE STUDENT
DILLON LLOYD THAT'S REALLY BEEN
LEADING THE WORK IN THE EXWAS
WORK WE'RE DOING, HE'S ON THE OE
JOB MARKET.
LOTS OF SUPPORT FOR
BIOINFORMATICS AND DATA
INTEGRATION AND THEN WE PARTNER
WITH A NUMBER OF COLLABORATORS
FOR DOMAIN EXPERTISE INCLUDING
FOLKS THAT HAVE HELPED DEFINE
AND REFINE OUR AUTOIMMUNE
PHENOTYPING AND WILL HELP US
INTERPRET, AND THEN OF COURSE
FIRST AND FOREMOST I HAVE TO
THANK THE PEGS PARTICIPANTS THAT
SHARE THIS EXTENSIVE DATA WITH
US.
THANKS SO MUCH.
I'LL STOP THERE.
>> GREAT.
THANK YOU SO MUCH,
DR. MOTSINGER-REIF.
I'M GOING TO HAVE OUR OTHER
PANELISTS, DR. HOLLAND AND
DR. LEWANDOWSKI JOIN US.
I'M GOING TO ASK THE SAME
QUESTION FROM ALL OF YOU BUT A
VERY QUICK ANSWER FROM EACH OF
YOU.
AND THAT IS WE'VE HEARD A LOT
TODAY ABOUT THE FACT THAT THE
GENETICS DOESN'T EXPLAIN
EVERYTHING, AND WE'VE GOT OTHER
TRIGGERS THAT ARE TRIGGERING THE
IMMUNE SYSTEM.
SO MY QUESTION IS, WHAT NEEDS TO
HAPPEN TO ADVANCE THIS SCIENCE?
CLEARLY WHEN YOU'RE LOOKING AT
THE GENETICS ALONE, YOU NEED
PRETTY LARGE SAMPLE SIZES OF
POPULATIONS IN ORDER TO STUDY,
BUT IF WE'RE THEN LAYERING ON
EXPOSURES, WHAT'S THE ANSWER,
AND HOW CAN WE ADVANCE THAT
SCIENCE?
AND I WILL ASK -- LET'S DO IT
BACKWARDS, DR. MOTSINGER-REIF
FIRST.
>> SO I'LL TRY TO BE BRIEF.
I THINK ONE REALLY EXCITING
EFFORT WHEN WE THINK ABOUT
ADDING ENVIRONMENTAL DATA TO
SOME OF THESE BIG COHORTS IS I
KNOW AND I'VE WORKED WITH
LEADERSHIP AT ALL-OF-US, FOR
EXAMPLE, ON INCORPORATING
ENVIRONMENTAL EXPOSURES INTO
THEIR MEGA BIOBANK, I THINK
WE'RE GOING TO NEED TO ADD
ENVIRONMENTAL DATA TO THESE
ALREADY WELL ESTABLISHED AND
VERY WELL POWERED GENETICS
COHORT.
S.
>> DR. HOLLAND.
>> I THINK YOU'RE SEEING IT
RIGHT HERE.
IT'S EXACTLY THIS KIND OF
INTERACTION WHERE YOU'VE GOT
TERRIFIC INVESTIGATORS PUTTING
ALL OF THE DATA TOGETHER AND
TRYING TO COORDINATE IT.
I DON'T THINK IT'S GOING TO BE
THAT DIFFICULT TO DO.
IT'S LIKE MOST THINGS IN
MEDICINE, YOU HAVE TO ASK THE
QUESTION TO FIND THE ANSWER.
YOU'VE GOT PEOPLE ASKING THE
RIGHT QUESTION, THEY'RE GOING TO
GET THE ANSWERS.
I'M EXCITED.
>> DR. LEWANDOWSKI, YOU'RE GOING
TO TELL ME THE KIDS HAVE THE
ANSWER.
>> OF COURSE, OF COURSE.
CHILDREN ARE OUR FUTURE.
NO, I THINK THAT I'LL JUST ECHO
WHAT EVERYBODY ELSE SAID, I
THINK IT'S GOING TO TAKE A LOT
OF TEAM WORK.
IT'S GOING TO TAKE A LOT OF
SMART PEOPLE GETTING IN THE ROOM
AND COMBINING DIFFERENT
TECHNIQUES AND DIFFERENT
APPROACHES TO THIS QUESTION, AND
THEN IT'S GOING TO TAKE SOME
TIME TO KIND OF PUT THE PIECES
OF THE PUZZLE TOGETHER.
WE'LL WORK OUT THE GENETICS
PIECE, WE'LL LAYER ON THESE
OTHER OMICS AND TOGETHER WE'LL
WORK TO ADVANCE THE FIELD.
>> THAT WAS A WONDERFUL SESSION.
I WANT TO THANK YOU ALL FOR
GIVING US THAT WONDERFUL TOUR OF
YOUR SCIENCE.
I'M GOING TO GIVE OUR AUDIENCE A
VERY BRIEF BREAK.
WE ARE GOING TO BREAK FROM NOW
UNTIL 3:00 P.M.
BUT THEN JOIN US BACK DIRECTLY
AT 3:00 P.M., WE HAVE EXCELLENT
CHAT WITH DR. DAVID FAJGENBAUM,
YOU WON'T WANT TO MISS IT, SO
WE'LL SEE YOU BACK SHORTLY.
>> WELCOME BACK, EVERYONE, AND I
AM NOW REALLY HONORED TO
INTRODUCE OUR NEXT SPEAKER,
DR. DAVID FAJGENBAUM.
MANY OF YOU MAY HAVE HEARD HIS
NAME BEFORE BECAUSE HE'S
SOMEWHAT OF A LEGEND IN THE RARE
DISEASE COMMUNITY.
HE WAS DIAGNOSED WITH CASSELMAN
DISEASE AS A STUDENT AND WENT ON
TO FOUND THE NETWORK AND HAS
DEDICATED HIS LIFE TO
DISCOVERING NEW TREATMENTS AND
POTENTIAL CURES FOR PREVIOUSLY
DEADLY DISORDERS INCLUDING
CASSELMAN'S DISEASE.
IT IS A CONDITION THAT SITS
RIGHT AT THE INTERSECTION OF
AUTOIMMUNITY AND CANCER, AND
IT'S IN THE LIST OF DISEASES
THAT THE OFFICE OF AUTOIMMUNE
DISEASE RESEARCH IS ASKED TO
CONSIDER.
THERE'S ALSO A NOVEL CONNECTION
I WANT TO HIGHLIGHT WITH OUR
AUDIENCE BECAUSE THIS SYMPOSIUM
AS WE'VE SAID, THE EIGHTH ANNUAL
VIVIAN PINN SYMPOSIUM, HONORS
THE FIRST TIME -- DIRECTOR OF
THE OFFICE OF RESEARCH ON
WOMEN'S HELD, DR. VIVIAN PINN.
DR. PINN IS AN ACCOMPLISHED
PATHOLOGIST, SHE WAS THE FIRST
AFRICAN AMERICAN WOMAN TO CHAIR
A PATHOLOGY DEPARTMENT IN THE
UNITED STATES BUT THERE IS A
PIECE OF DR. PINN'S HISTORY THAT
I ONLY FOUND OUT ABOUT QUITE
RECENTLY AFTER WE'D SELECTED THE
SPEAKERS, AND THAT IS THAT
DR. PINN WAS RECRUITED TO
RESIDENCY AND MENTORED BY
DR. CASTLEMAN.
YOU ARE AN ACCOMPLISHED
PHYSICIAN SCIENTIST, YOU'RE A
RECOGNIZED LEADER IN THE FIELD
OF HEALTHCARE, YOU'VE RECEIVED A
NUMBER OF AWARDS AND BEEN
PROFILED IN MANY, MANY
NEWSPAPERS, "THE NEW YORK
TIMES," "THE WALL STREET
JOURNAL," SCIENCE, AND YOU'VE
BEEN ON THE TODAY SHOW IT'S
REALLY A DELIGHT TO HAVE YOU
JOIN US TODAY AND TELL US THE
STORY OF HOW YOU WENT FROM A
COLLEGE FOOTBALL PLAYER TO NIH
FUNDED PHYSICIAN SCIENTIST
SEARCHING FOR CURES FOR RARE
DISEASES.
WELCOME TO THE VIVIAN PINN
SYMPOSIUM.
>> VICKI, THANK YOU SO MUCH FOR
THAT KIND INTRODUCTION.
IT'S REALLY SUCH AN HONOR TO BE
WITH ALL OF YOU AND TO HEAR
ABOUT THE CONNECTION TO
CASTLEMAN DISEASE WITH DR. PINN
IS JUST SO, SO INCREDIBLE.
I APPRECIATE BEING WITH YOU ALL.
>> I WANTED TO START NOT AT THE
BEGINNING OF YOUR STORY BUT
SOMEWHERE IN THE MIDDLE, WHICH
IS THE POINT OF YOUR DIAGNOSIS.
AT THAT POINT I THINK THERE'S A
PICTURE SHOWING ON THE SCREEN,
YOU'D BEEN VERY UNWELL FOR QUITE
SOME TIME, YOU'D HAD MANY
HOSPITALIZATIONS, I THINK AT
THIS POINT IN TIME YOU WERE IN
THE INTENSIVE CARE UNIT AND
ULTIMATELY YOU AS THE KIND OF
ADVOCATE FOR YOUR OWN ILLNESS
SAID YOU NEEDED A LYMPH NODE
BIOPSY BECAUSE TISSUE WAS THE
ISSUE.
DR. PINN WOULD BE VERY PROUD OF
YOU.
I WONDERED IF YOU COULD SHARE
WITH OUR AUDIENCE WHAT HAPPENED
WHEN YOU WERE HANDED THAT
PATHOLOGY REPORT THAT ULTIMATELY
DELIVERED YOUR DIAGNOSIS.
>> WELL, IT WAS SOMETHING WE'D
BEEN SEARCHING FOR FOR 11 WEEKS,
A DIAGNOSIS, WHAT WAS IT THAT
HAD PUT ME IN THE INTENSIVE
CARE, WHAT WAS IT THAT CAUSED
ALL MY ORGANS TO SHUT DOWN, WHAT
WAYS LITERALLY DYING FROM.
FINALLY WE GOT THIS PATHOLOGY
REPORT AND ON IT SAID CONSISTENT
WITH IDIOPATHIC MULTICENTRIC
CASTLEMAN'S DISEASE.
I WAS A THIRD YEAR MED STUDENT
AT THE TIME, I HAVE TO ADMIT I
DIDN'T REMEMBER LEARNING ABOUT
IT, I CERTAINLY DIDN'T KNOW WHAT
IT WAS.
FOR SO MANY PEOPLE WITH
AUTOIMMUNE DISEASES AND THESE
SORT OF EXCEPTIONAL AUTOIMMUNE
SYNDROMES THAT MAYBE AREN'T EVEN
ABLE TO BE CLASSIFIED, WE FIGHT
SO HARD TO GET A DIAGNOSIS BUT
SOMETIMES IT DOESN'T GIVE ALL
THAT MANY ANSWERS.
WE HAD A LOT MORE ANS MORE QUESN
ANSWERS.
>> TELL US KIND OF WHAT HAPPENED
NEXT IN THE STORY.
>> SURE.
SO I WAS A FORMER HEALTHY
COLLEGE QUARTERBACK AND I WAS A
MEDICAL STUDENT.
I WANTED TO BE AN ONCOLOGIST, I
WANTED TO TREAT PATIENTS IN
MEMORY OF MY MOM WHEN OUT OF
NOWHERE I'D GOTTEN SO SICK.
SO WITH THIS DIAGNOSIS OF
CASTLEMAN DISEASE, FORTUNATELY
CAME A LOT OF TREATMENT.
THANKFULLY, I WAS GIVEN FIRST
RITUXIMAB AND THEN IL-6 BLOCK
BLOCKADE, TOCILIZUMAB,
UNFORTUNATELY IL-6 BLOCKADE DID
NOT WORK FOR CASTLEMAN DISEASE
SO I ENDED UP RECEIVING A
COMBINATION OF 17
CHEMOTHERAPIES.
IT WAS THAT COMBINATION OF
CHEMOTHERAPIES THAT JUST
COMPLETELY OWE B OBLITERATED MYE
SYSTEM.
THTHE PA -- CASTLEMAN'S AS YOU
MENTIONED REALLY SITS AT THE
INTERSECTION -- THERE'S CLEARLY
AUTOIMMUNE FEATURES BUT THERE'S
ALSO THIS LYMPHOPROLIFERATIVE
FEATURE TO THE DISEASE AS WELL,
AND THANKFULLY THE CHEMOTHERAPY
SAVED MY LIFE.
YOU CAN SEE SOME PICTURES ON THE
SCREEN OF ME WITH MY DAD.
MY MOM HAD PASSED AWAY FROM
CANCER A FEW YEARS BEFORE, BUT
MY DAD NEVER LEFT MY SIDE.
HE WAS SPENDING THE NIGHT IN THE
HOSPITAL ROOM WITH ME FOR SIX
MONTHS THAT I WAS HOSPITALIZED.
>> AND SO TELL US A BIT MORE
ABOUT KIND OF YOUR JOURNEY
THROUGH THIS PERIOD OF GETTING
TO YOUR DIAGNOSIS AND STARTING
ON TREATMENT.
YOU TALK A LITTLE BIT IN SOME OF
THE STORIES THAT YOU TOLD
ELSEWHERE ABOUT HOPE AND THE
DIFFERENCES BETWEEN HOPE AND
OPTIMISM, AND AT SOME POINT IN
THIS JOURNEY, YOU HAD THIS KIND
OF INFLECTION POINT WHERE YOU
REALIZED THAT HOPE WASN'T THE
WHOLE ANSWER AND THAT YOU NEEDED
SOMETHING ELSE.
CAN YOU TELL US MORE ABOUT THAT
PIECE OF THE STORY?
>> SURE.
YOU KNOW, YOU VICKI, WHEN I WAS
A MEDICAL STUDENT AT PENN, I WAS
HEARING ABOUT ALL THESE BREAK
THROUGHS HAPPENING, FOLLOWING
SCIENCE AND MEDICINE AND SO
HOPEFUL AND OPTIMISTIC THAT, OH,
MY GOSH, THERE ARE EITHER CURES
FOR EVERY DISEASE OUT THERE OR
THERE'S CURES THAT ARE ON THEIR
WAY.
IN HINDSIGHT, IT WAS MAYBE A BIT
NAIVE BUT CERTAINLY I WAS A
REALLY, REALLY HOPEFUL MEDICAL
STUDENT.
ALL OF A SUDDEN WITH A DIAGNOSIS
OF CASTLEMAN DISEASE, I LEARNED
THAT THERE WERE DISEASES LIKE
CASTLEMANs WHERE WE HAVE A
NAME FOR IT.
THANKFULLY BENJAMIN CASTLEMAN
DID IMPORTANT WORK SO WE'VE GOT
A NAME FOR IT BUT WE REALLY KNOW
SO LITTLE ABOUT HOW THE DISEASE
WORKS AND SO LITTLE ABOUT HOW TO
TREAT IT.
SO I REALLY HAD A MAJOR CHANGE
RIGHT AROUND THE TIME THAT I
RELAPSED ON IL-6 BLOCKADE.
SO I MENTIONED IL-6 BLOCKADE
DIDN'T WORK FOR ME IN MY ACUTE
PHASE OF THE DISEASE.
WE THOUGHT THAT MAYBE IL-6
BLOCKADE WITH A DRUG SUL TUCKS
MAN TO KEEP MY DISEASE IN REMIX,
INTERLEUKIN 6, EVERY1 ON THIS
CALL WILL BE VERY FAMILIAR WITH
IL-6, PLAYS AN IMPORTANT ROLE IN
A NUMBER OF AUTOIMMUNE
CONDITIONS.
TOCILUZUMAB WAS FIRST DEVELOPED
FOR CASTLEMAN DISEASE.
THEY DEVELOPED IT FOR
CASTLEMAN'S.
IT'S ACTUALLY A PRETTY
INCREDIBLE STORY.
THEY DISCOVERED I.
WILL 6 WAS IMPORTANT, THEY
DEVELOPED THIS IL-6 RECEPTOR
ANTIBODY.
BEFORE HE GAVE TO THE VERY FIRST
PATIENT WITH CASTLEMAN EA HE
ACTUALLY DECIDED TO TRY IT ON
HIMSELF TO PROVE IT WAS SAFE.
I'M NOT RECOMMENDING THIS FOR
ANYONE THAT YOU SHOULD BE
TESTING NOVEL COMPOUNDS ON
HIMSELF, BUT WHEN HE DIDN'T HAVE
ANY HORRIBLE REACTION TO IT, HE
WENT ON TO STUDY IT IN A PHASE
ONE CLINICAL TRIAL IN JAPAN FOR
CASTLEMAN'S PATIENTS.
IT GOT FIRST APPROVED FOR
CASTLEMAN'S IN JAPAN AND THEN
EVERYONE ON THIS CALL WILL KNOW
THAT IT THEN CAME TO THE UNITED
STATES WHERE WE GOT APPROVAL FOR
ROOM TIERHEUMATOID ARTHRITIS, ME
RECENTLY IN COVID, BUT THIS WAS
A CASTLEMAN'S DRUG THAT WAS
DEVELOPED BECAUSE INTERLEUKIN
6 WAS SO IMPORTANT.
SO IL-6 HAS BEEN SORT OF THE ONE
THING WE'VE KNOWN ABOUT
IDIOPATHIC MULTICENTRIC
CASTLEMAN'S DISEASE ALL THESE --
BUT IT TURNS OUT IT ONLY WORKS
IN ABOUT ONE HALF OF PATIENTS.
SO I LEARNED THAT I FALL INTO
THAT CATEGORY OF PATIENTS, THE
TWO THIRDS OR SO OF PATIENTS
THAT DON'T BENEFIT FROM IL-6
BLOCKADE, AND SO FOR ME,
EMOTIONALLY, THAT WAS SUCH A LOW
POINT, BECAUSE HERE I WAS WITH
THIS DISEASE THAT'S DEADLY BUT,
HEY, AT LEAST WE CAN BLOCK IL-6
AND MAYBE THIS WON'T COME BACK
AGAIN, BUT THEN WE BLOCK THE
HECK OUT OF IL-6, AND IT STILL
CAME BACK AND SO THE PICTURE ON
THE LEFT IS FROM MY FOURTH
RELAPSE OF THE DISEASE, AND
THAT'S WHILE I WAS ON THIS DRUG
SUL TUCKS MAN, AND THAT'S REALLY
SORT OF TO ANSWER YOUR QUESTION,
WHEN MY LIFE CHANGED, WHEN I
WENT FROM SAYING I'M GOING TO
HOPE THAT SOME RESEARCHERS
SOMEWHERE COULD FIGURE OUT
SOMETHING FOR CASTLEMAN'S TO
SAYING IF I'M GOING TO HOPE
THERE COULD BE A TREATMENT FOR
CASTLEMAN EA I NEED TO TURN MY
HOPE INTO ACTION.
AND I WASN'T NAIVE INTO THINKING
I COULD DEVELOP SOME NEW DRUG
FROM SCRATCH.
FRANKLY THERE WEREN'T ANY NOVEL
TARGETS TO GO AFTER ANYWAY BUT I
CERTAINLY DIDN'T HAVE A BILLION
DOLLARS AND 10 YEARS TO CREATE
SOMETHING NEW, SO FROM MAY OF 20
2012, WHEN I HAD THAT FOURTH
DEADLY FLARE OF MY DISEASE, FROM
THAT MOMENT, EXACTLY 12 YEARS
AGO, I MADE THE DECISION THAT I
WOULD DO DEEP IMMUNE PROFILING
OF MY OWN IMMUNE SYSTEM AND
OTHER CASTLEMAN'S PATIENTS'
IMMUNE SYSTEMS AND SEE IF THERE
WERE EXISTING DRUGS THAT COULD
BE REPURPOSE DOLLARS.
ALL OF US IN AUTOIMMUNITY KNOW
DRUGS GET REPURPOSED ALL THE
TIME, THERE WERE NO DRUGS IN
DEVELOPMENT FOR CASTLEMAN'S SO
THE QUESTION WAS COULD I UNCOVER
A MECHANISM, REALLY TO YOUR
QUESTION, IT WAS REALLY BECAUSE
I REALIZED I COULDN'T JUST HOPE
AND WAIT, I WOULD NEED TO TURN
MY HOPE INTO ACTION.
>> I'M GOING TO TAKE IT BACK A
LITTLE BIT AND WE'RE GOING TO
COME BACK TO HOW YOU KIND OF
MOVE THIS FORWARD.
WHEN YOU GOT TREATMENT WITH SELL
TUCKS MAN, IT WAS STILL A DRUG
IN CLINICAL TRIAL FOR
CASTLEMAN'S.
SO YOU WERE TRYING TO ACTUALLY
ENROLL IN A CLINICAL TRIAL AND
THEN YOU HAD A RELAPSE THAT
MEANT YOU WERE SUDDENLY TOO SICK
TO ENROLL IN THE CLINICAL TRIAL.
YOUR DOCTORS HAD TO APPEAL TO
THE FDA TO GET IT APPROVED AS
EXPERIMENTAL THERAPY OUTSIDE OF
A CLINICAL TRIAL CAN YOU TELL US
A LITTLE ABOUT HOW THAT FELT,
WHAT THAT EXPERIENCE WAS LIKE,
AND JUST SHARE WITH US WHAT THAT
FELT LIKE?
>> SURE.
I WAS SO HOPEFUL THIS DRUG WAS
GOING TO KEEP ME IN REMISSION
LONG TERM AND THAT BLOCKING IL-6
WAS GOING TO BE THE SOLUTION.
MAYBE IT COULD HELP TO KEEP ME
IN REMISSION.
WHEN ALL OF A SUDDEN I STARTED
TO RELAPSE JUST BEFORE I COULD
GET STARTED ON THIS -- JOIN THE
TROIL, IT WAS HEARTBREAKING.
SO MANY OF US ON THE CALL THAT
ENROLL PATIENTS IN CLINICAL
TRIALS, YOU ALL KNOW SOMETIMES
CLINICAL TRIALS ARE OUR ONLY
HOPE.
SO IT GO FROM BEING SO EXCITED,
SEEING MY DOCTOR SAYING YOU'RE
GOING TO GET ON THIS DRUG AND IT
WILL HOPEFULLY KEEP YOU IN
REMISSION TO THEN NOT BEING
ELIGIBLE, THAT WAS HEARTBREA
HEARTBREAKING.
THE FLIP SIDE OF IT WAS IT WAS
SO EXCITING FOR MY FAMILY AND I
WHEN WE FOUND OUT THAT THE FDA
HAD GRANTED ME EMERGENCY
COMPASSIONATE USE.
AMAZINGLY WITHIN ABOUT 48 HOURS
OF THE REQUEST GOING IN, WE HAD
AMAZING, AMAZING OFFICIALS
WITHIN THE FDA THAT DEAL WITH
THESE ON SHORT NOTICE, NIGHTS,
WEEKENDS, THEY GRANTED ME
EMERGENCY BE COMPASSIONATE USE,
THE DRUG COMPANY GRANTED --
AGREED TO THE EMERGENCY
COMPASSIONATE USE SO I WAS ABLE
TO GET THAT DRUG.
SO SORT OF FROM THE LOWEST OF --
OR HIGHEST OF HIGH, LOWEST OF
LOWS, BACK TO HIGHEST OF HIGH,
AND AS YOU KNOW, VICKI, THAT
DRUG ENDED UP NOT WORKING, SO
BACK TO THE LOWEST OF LOWS.
>> AND THEN, YOU KNOW, YOU
RECOVERED FROM THAT FLARE WITH
KIND OF FAIRLY BROAD
CHEMOTHERAPY.
I MEAN, THEY TREATED YOU
EXTREMELY AGGRESSIVELY, AND
YOU'D HAD THIS KIND OF SHIFT IN
KIND OF, OH, WE NEED TO LOOK
FURTHER AT RARE DISEASES, WHAT
OTHER DRUGS ARE OUT THERE AND
HOW CAN WE REPURPOSE THEM.
TELL US A LITTLE BIT ABOUT WHAT
YOU DID WITH THE CASTLEMAN
DISEASE COMMUNITY, BECAUSE YOU
WERE STILL A MEDICAL STUDENT.
YOU HAD NOT PUBLISHED PAPERS.
YOU HAD NOT GOT CREDIBILITY IN
THE SCIENTIFIC FIELD, BUT YET
YOU WERE ABLE TO REALLY
GALVANIZE THIS COMMUNITY AND
SORT OF COME OUT WITH A STRATEGY
TO ADVANCE THE SCIENCE.
CAN YOU SHARE WITH US A LITTLE
BIT ABOUT WHAT YOU DID?
>> SURE.
I THINK A COUPLE THINGS
IMMEDIATELY COME TO MIND.
SO FIRST OFF, I WAS A THIRD YEAR
MEDICAL STUDENT, SO I DIDN'T
KNOW ANYTHING ABOUT ANYTHING.
I DIDN'T KNOW ANYTHING ABOUT HOW
DISEASES WORKED, I DIDN'T KNOW
HOW MEDICAL RESEARCH HAPPENED, I
HAD SOME IDEAS, BUT THAT SORT OF
LIKE NOT KNOWING HOW THE SYSTEM
WORKED, I THINK HELPED IN MANY
WAYS BECAUSE I GOT INVOLVED WITH
PENN'S ORPHAN DISEASE CENTER
RIGHT AROUND THAT TIME AND I
STARTED DIGGING DEEPLY INTO HOW
RARE DISEASE RESEARCH WAS
HAPPENING, AND I WAS SO CONFUSED
BECAUSE WHAT I LEARNED WAS THAT
GROUPS WOULD RAISE MONEY AND
THEN THEY WOULD INVITE
RESEARCHERS TO APPLY FOR THE
FUNDS AND THEN YOU SORT OF HOPE
THAT THE RIGHT RESEARCHER
APPLIES FOR THE RIGHT PROJECT AT
THE RIGHT TIME.
AND THAT WORKS REALLY WELL IF
YOU'RE THE NIH AND YOU'RE
GETTING THOUSANDS OF APPLICANTS.
BUT IT WORKS REALLY POORLY IF
YOU'RE A RARE DISEASE WITH TWO
OR THREE APPLICANTS.
WHAT'S THE CHANCE THAT YOUR TWO
OR THREE APPLICANTS ARE GOING TO
HAVE THE RIGHT IDEA FOR WHAT
RESEARCH SHOULD BE DONE AND THE
CAPABILITIES TO PERFORM THAT
RESEARCH.
SO WE JUST ASKED A SIMPLE
QUESTION, WHAT IF INSTEAD OF
RAISING MONEY AND HOPING THE
RIGHT RESEARCHER APPLIES, WHAT
IF WE ACTUALLY ASK PHYSICIANS,
RESEARCHERS AND PATIENT, WHAT
ARE THE IMPORTANT QUESTIONS THAT
SHOULD BE ASKED ABOUT CASTLEMAN
DISEASE IN THE LABORATORY,
CLINICALLY, WHAT ARE THOSE
QUESTIONS, AND THEN ONCE WE
PRIORITIZE WHAT THEY ARE, LET'S
GO FIND THE BEST PERSON IN THE
WORLD TO COME STUDY THOSE
QUESTIONS.
SO WE RECRUIT AMAZING
RESEARCHERS LIKE PJ ETZ TO STUDY
CASTLEMAN DISEASE.
WE RECRUIT THE BEST PROTEOMICS
RESEARCHERS TO STUDY CASTLEMAN
DISEASE.
SO IT'S ABOUT WHAT SHOULD BE
DONE AND BRINGING IN THE RIGHT
PEOPLE TO DO IT, AND IT WAS SUCH
A SIMPLE CONCEPT THAT REQUIRED
NO BRILLIANCE WHATSOEVER, BUT
THAT WAS REALLY TRANS FOIRMTIVE.
SO NOW WE KNEW WHAT WE NEEDED TO
GO AFTER.
WE HAD A PLAN.
AND THE SECOND PIECE WAS THAT
NOW THAT WE HAD PLAN, WE REALLY
NEED TO BUILD A TEAM AROUND US.
THE FIRST WAS REACHING OUT TO
PATIENTS, PHYSICIANS,
RESEARCHERS, REALLY BUILDING
THIS COMMUNITY FIRST VIRTUALLY
CONNECTING AND THEN ALSO
CONNECTING IN PERSON AND THEN
YOU CAN SEE FROM THESE PICTURES,
I WAS A MEDICAL STUDENT AND THEN
I DID BUSINESS SCHOOL HERE AT
PENN RIGHT AFTERWARDS, SO I
REACHED OUT TO ALL MY CLASSMATES
IN MED SCHOOL AND BUSINESS
SCHOOL AND ASKED THEM TO BE A
PART OF OUR TEAM, AND YOU CAN
SEE LITERALLY DOZENS, EVEN
HUNDREDS OF MEDICAL SCHOOL AND
BUSINESS SCHOOL CLASSMATES OF
MINE FROM PENN GOT INVOLVED IN
HELPING TO ORGANIZE CASTLEMAN'S
MEETINGS, ONLINE DISCUSSION
BOARDS, SUPPLEMENTS, RAISING
FUNDS FOR RESEARCH THAT REALLY
WAS SUCH A TEAM EFFORT.
>> IT'S AMAZING TO ME, WHAT YOU
WERE ABLE TO DO, BUT THAT YOU
DID THIS AT FIRST BY NOT TELLING
ANYONE THAT YOU HAD CASTLEMAN'S
DISEASE, YOU JUST TRIED TO SORT
OF GALVANIZE THE FIELD WITHOUT
EXPLAINING THAT YOU ALSO HAD THE
DISEASE.
BUT YOU KIND OF CROWDSOURCED THE
PROBLEM.
YOU BASICALLY WENT TO THE
SCIENTISTS AND THE OTHER
PATIENTS AROUND THE WORLD AND
REALLY BROUGHT THIS COMMUNITY
TOGETHER, MADE YOUR KIND OF LIST
OF LIKE WHAT STEPS NEED TO
HAPPEN IN ORDER TO ADVANCE THIS
FIELD, AND THEN SORT OF ALMOST
UPVOTED THEM TO, LIKE, WHAT
NEEDS TO HAPPEN RIGHT NOW,
WHAT'S THE FIRST NEXT STEP, AND
HOW WOULD WE MAKE THAT HAPPEN.
AND THEN YOU TELL A STORY ALSO
IN SOME OF YOUR BOOKS, YOU TALK
ABOUT THIS SEARCH WHERE YOU
REALIZE THE FIRST NEXT STEP
NEEDED A CERTAIN NUMBER OF LYMPH
NODE BIOPSIES AND THAT PEOPLE --
NO ONE SINGLE CASTLEMAN DISEASE
RESEARCHER WOULD HAVE THAT MANY
SAMPLES.
CAN YOU SHARE THAT STORY WITH
US?
>> SURE, THIS IS AN IMPORTANT
LESSON FOR ALL OF US TO DO RARE
DISEASE RESEARCH, AND THAT'S
THAT NONE OF US AT ANY ONE OF
OUR CENTERS WILL EVER HAVE
ENOUGH SAMPLES OR PATIENTS TO
LEARN ENOUGH ABOUT OUR RARE
DISEASES.
IT REQUIRES COLLABORATION AND SO
YOU'RE EXACTLY RIGHT, SO WE
REALIZED NO INDIVIDUAL CENTER
WOULD HAVE ENOUGH SAMPLES AND
GOSH, WE ALL KNOW HOW DIFFICULT
IT IS TO PUT IT TOGETHER,
MATERIAL TRANSFER AGREEMENTS AND
GET SAMPLES SHARED BETWEEN
PLACES LIKE THE NIH P AND PENN
FOR EXAMPLE.
WHAT IF WE CAN START ENROLLING
PATIENTS DIRECTLY INTO OUR
STUDIES.
SO CREATING ONE CENTRAL IRB
WHERE PATIENTS CAN CONSENT FROM
ANYWHERE IN THE WORLD TO GIVE
BLOOD SAMPLES, TO HAVE EXCESS
TISSUE AT THEIR SITE BUT THEN
SENT TO US BY THE PATIENT
DIRECTLY TO OUR BIOBANK SO WE
CAN PROCESS AND THEN MAKE IT
AVAILABLE TO THE WORLD.
THAT WAS SO IMPORTANT FOR US
BECAUSE WE CAN'T LIVE IN A WORLD
WHERE EVERY ONE OF THE FIVE OR
SIX CENTERS THAT'S INTERESTED IN
CASTLEMAN'S WERE ALL STUDYING A
HANDFUL OF SAMPLES EACH AND
WE'RE PUBLISHING PAPERS ON A
HANDFUL OF PATIENTS.
WE'VE GOT TO PULL SAMPLES
TOGETHER.
BECAUSE IMPORTANTLY THERE'S ALSO
ACTUALLY A LOT OF PATIENTS WITH
THESE RARE DISEASES THAT DON'T
GO TO THOSE HANDFUL OF CENTERS
THAT ARE REALLY THE LEADING
CENTERS, SO NEED TO FIGURE OUT
WAYS TO REACH OUT TO THEM AND
CONNECT WITH THOSE PATIENTS TOO.
>> AND I WANTED TO PULL YOU BACK
TO SORT OF SOME OF THE
EXPERIENCES YOU'VE HAD IN YOUR
LIFE THAT PREPARED YOU FOR
BRINGING THIS COMMUNITY
TOGETHER, AND I GUESS I MISSED A
FEW PARTS OF YOUR STORY BY
STARTING IN THE MIDDLE.
YOU HAD FACED A FEW CHALLENGES
BEFORE YOU FACED THIS CHALLENGE
WITH CASTLEMAN'S DISEASE.
YOU'D OBVIOUSLY BEEN A VERY
COMPETITIVE COLLEGE ATHLETE.
YOU KNEW ABOUT SUCCESS AND
FAILURE.
YOU KNEW ABOUT WHAT WAS NEEDED
TO TRAIN TO A HIGH LEVEL.
BUT YOU ALSO KNEW ABOUT GRIEF,
BECAUSE YOUR MOTHER HAD DIED
WHEN YOU WERE AN UNDERGRADUATE
STUDENT, AND YOU KNEW ABOUT
BRINGING COMMUNITIES TOGETHER
BECAUSE IN HER MEMORY, YOU WOULD
SET UP A FOUNDATION TO HELP
OTHER COLLEGE STUDENTS WORKING
THROUGH GRIEF.
CAN YOU TELL US A LITTLE BIT
ABOUT HOW THOSE PREVIOUS
EXPERIENCES REALLY HELPED YOU?
>> THEY HELPED IN SO MANY WAYS.
SO FIRST OFF MY MOM WAS THE MOST
INCREDIBLE PERSON IN THE WORLD.
SHE WAS JUST -- WAS ALWAYS THE
SUPPORTER FOR EVERYONE ELSE AND
SHE LIVED THIS JUST -- SUCH A
PURPOSE-DRIVEN, MISSION-DRIVEN
LIFE.
SO WITH HER PASSING, THAT WAS SO
DIFFICULT FOR ME, I WAS 19 YEARS
OLD, AND FOR ME IT WAS OKAY, I'M
GOING TO DEDICATE MY LIFE TO
GOING INTO A CAREER IN MEDICINE
AND MEDICAL RESEARCH TO TRY TO
FIND TREATMENTS FOR PATIENTS
LIKE HER.
THAT EXPERIENCE ALSO LED ME AS
YOU MENTIONED TO START THAT
ORGANIZATION CALLED AMF, AMF
STOOD FOR ACTIVELY MOVING
FORWARD, IT STILL STANDS FOR
ACTIVELY MOVE FORWARD BUT ALSO
MY MOM'S INITIAL, ANNE MARIE
FAJGENBAUM, SO AS A WAY TO KEEP
THE LEGACY GOING OF THIS PERSON
WHO WAS ALWAYS THERE FOR
EVERYONE ELSE.
AND SO THROUGH AMF, GEORGETOWN'S
CAMPUS, JUST DOWN THE ROAD FOR A
FEW OF YOU, WHEREAS YOU
MENTIONED I ALSO PLAYED ON THE
FOOTBALL TEAM.
WE LOST MOST OF OUR GAMES AT
GEORGETOWN, THE FOOTBALL TEAM,
SO YOU PROBABLY WEREN'T AWARE
THAT WE HAVE A FOOTBALL TEAM BUT
WE DO HAVE ONE, BUT DURING MY
TIME AT GEORGETOWN, WE GREW A
MANAGEMENT F FROM A GROUP AT
YORNLG TOWN TO A NON-PROFIT THAT
SUPPORTED COLLEGE STUDENTS ALL
OVER THE UNITED STATES.
AT OUR PEAK WE HAD OVER 200
COLLEGE CAMPUSES WITH PEER-LED
SUPPORT GROUPS WHERE STUDENTS
WERE SUPPORTING ONE ANOTHER AND
ALSO GETTING INVOLVED IN
COMMUNITY SERVICE IN MEMORY OF
THEIR LOVED ONES WHO HAD PASSED
AWAY.
AMF STILL CONTINUES, IT DIDN'T
HAVE AS MANY CHAPTERS BUT IT
STILL SUPPORTS STUDENTS AT
CAMPUSES ALL OVER THE COUNTRY.
I HAVEN'T BEEN INVOLVED WITH
MAMF FOR ALMOST 10 YEARS NOW BUT
I STILL LOVE TO HEAR ABOUT THE
GREAT JOB IT'S DOING SUPPORTING
PEOPLE EVEN JUST DOWN THE STREET
AT PENN.
SO THAT EXPERIENCE OF BUILDING
THIS NON-PROFIT AND TAKING ON
WHAT REALLY WAS A SYSTEMIC
CHALLENGE OR ISSUE ON CAMPUSES
AND THAT'S THAT THERE WERE A LOT
OF STUDENTS DEALING WITH GRIEF,
BUT NO ONE WAS TALKING ABOUT IT
SO EVERYONE FELT ALONE AND IT'S
BECAUSE THERE WASN'T A PLACE FOR
GRIEVING COLLEGE STUDENTS TO
COME TOGETHER.
THE EXPERIENCE OF BUILDING THAT
NON-PROFIT, GETTING PEOPLE
TOGETHER TO SOLVE THAT PROBLEM
MEANT THAT WHEN I WAS CONFRONTED
WITH CASTLEMAN'S AND I DECIDED I
WAS GOING TO TAKE IT ON ALONG
WITH MY COLLEAGUE FRITZ VAN RIE,
THAT I COLLEEN ON THAT
EXPCOULD LEAN ON THATEXPERIENCED
CERTAINLY IT HELPED
TREMENDOUSLY.
>> AND I THINK SOMETIMES WE
DON'T ALWAYS REALIZE THAT
HISTORY IS PREPARING US FOR
SOMETHING THAT WE'RE GOING TO
FACE IN THE FUTURE AND IT JUST
REALLY STRUCK ME AS I WAS
READING YOUR STORY THAT THAT WAS
THE CASE IN YOUR CASE.
YOU ALSO HAD GOOD BACKGROUND IN
ACADEMICS AND RESEARCH.
YOU HAD OBVIOUSLY COMPLETED YOUR
UNDERGRAD AT GEORGETOWN, BUT
THEN ALSO HAD A MASTER'S THAT
YOU COMPLETED AT OXFORD
UNIVERSITY, GIVEN YOU SET UP THE
FRAMEWORK FOR ANALYZING AND
ANSWERING THESE COMPLEX
PROBLEMS.
TELL US A LITTLE BIT ABOUT HOW
YOU USED THOSE SKILLS.
DURING THAT TIME WHEN YOU WERE
STILL A MEDICAL STUDENT WHEN YOU
WERE TRYING TO GET THE CASTLEMAN
DISEASE COLLABORATIVE NETWORK TO
KIND OF MOVE THE SCIENCE
FORWARD, HOW DID YOU TAKE THOSE
SKILLS AND DO THAT STILL AS A
MEDICAL STUDENT?
>> YOU KNOW, I THINK ALL OF
THOSE EXPERIENCES HELPED ME SO
MUCH.
I THINK I ALSO -- IT'S VERY
IMPORTANT TO EMPHASIZE THIS
AMAZING TEAM OF PEOPLE.
SO YES I RECEIVED THE TRAINING
AT OXFORD THAT CERTAINLY HELPED
WITH SOME OF THE METHODOLOGIES
THAT I WAS USING, BUT I ALSO HAD
THESE AMAZING CLASSMATES THAT I
TURNED TO, THAT WERE DOING
PH.D.s IN VARIOUS DISCIPLINES
THAT WERE DOING MBAs AND WHO
WOULD HAVE NECESSARILY THOUGHT
THAT AN MBA STUDENT ISNESS
SAIRLY GOING TO BE HELP YOU BE
ABLE TO ADVANCE RESEARCH FOR A
DISEASE?
THE TRUTH IS A LOT OF MEDICAL
RESEARCH IS ABOUT ORGANIZING AND
UTILIZING FINITE RESOURCES AND
BEING EFFICIENT AND BUILDING
STRATEGIES, AND SO IT TURNED OUT
THAT, YES, I WAS CERTAINLY
PREPARED FOR MY TRAINING, BUT
MAYBE THE MOST IMPORTANT THING
WAS THAT I WAS ABLE TO JUST
BUILD AN AMAZING TEAM AND TO QO
NECONNECT WITH PEOPLE SO WE COUD
CREATE REALLY A UNIFIED STRATEGY
THAT THE WORLD OF CASTLEMAN'S
RESEARCHERS AND PHYSICIANS COULD
REALLY GET BEHIND, AND ONCE WE
BUILT THAT CONSENSUS AND WE HAD
A CLEAR PLAN, IT WAS JUST
EXECUTION.
>> YEAH, AND YOU YOURSELF, I
THINK, REALIZED PRETTY EARLY ON
THAT YOU NEEDED TO HAVE THE
SCIENCE BACKGROUND BUT THAT YOU
ALSO NEEDED THE BUSINESS
BACKGROUND, SO AFTER YOU FIN
ESFINISHED MEDICAL SCHOOL, YOU
WENT TO BUSINESS SCHOOL, YOU
WERE PRETTY ACTIVE AT THAT POINT
IN THE RARE DISEASES CENTER AT
PENN.
CAN YOU TELL US ABOUT THAT
DECISION?
WHY DID THE BUSINESS SCHOOL
TRAINING MAKE SENSE AND HOW HAVE
YOU USED TO MOVE THINGS FORWARD?
>> SO THERE WERE A FEW THINGS
THAT SORT OF CAME TOGETHER ALL
AT ONCE THAT LED ME TO DO THAT.
THE FIRST IS THAT AS YOU KNOW, I
WAS CONTINUING TO RELAPSE FROM
MY CASTLEMAN DISEASE, SO EVERY
EIGHT TO 12 MONTHS, I WAS BACK
IN THE ICU FOR A MONTH AT A
TIME, WITH ALL OF MY ORGANS
FAILING, ON DIALYSIS, VERY, VERY
ILL, MULTI-AGENT CHEMOTHERAPY
WOULD SORT OF BRING ME FROM THE
BRINK OF DEATH BUT I'D BE SORT
OF BACK THERE NOT TOO LONG
AFTER.
SO I KIND OF LIMPED THROUGH THE
FINISH LINE OF GRADUATING FROM
MEDICAL SCHOOL.
THE QUESTION IS, YOU KNOW,
DAVID, DO YOU GO DO A RESIDENCY,
DO YOU DO A POSTDOC, AN MBA,
WHAT DO YOU DO HERE?
AND I DECIDED TO DO AN MBA FOR A
FEW REASONS.
ONE IS THAT I KNEW I WOULD HAVE
BANDWIDTH TO BE ABLE TO ACTUALLY
WORK IN THE LAB, SO JUST DOWN
THE STREET, A TRANSLATIONAL
RESEARCH LABORATORY, I HAD SOME
LAB SPACE.
SO I KNEW I HAD SOME BANDWIDTH
TO ACTUALLY WORK IN THE LAB AND
SPECIFICALLY WHY THE MBA IS THAT
AS I WAS DOING MORE AND MORE
WORK IN TRYING TO BRING TOGETHER
PEOPLE, I REALIZED THAT THE
SCIENCE AND THE TECHNOLOGY
ACTUALLY WAS ALREADY THERE.
THE ISSUE WAS JUST GETTING THE
RIGHT RESOURCES AND SORT OF
LEVERAGING THE TOOLS THAT
ALREADY EXISTED.
SO SINGLE CELL RNA SEQUENCING
WAS COMING ON THE XENO.
ON THE SCENE, THETECHNIQUES WER.
IT WASN'T WE HAVE TO CREATE SOME
NEW TECHNIQUE.
IT WAS LIKE HOW DO WE LEVERAGE
THEM, HOW DO WE UTILIZE THEM IN
THE RIGHT WAY WITH THE RIGHT
SAMPLES WITH THE RIGHT FUNDING
AMOUNTS.
SO I THOUGHT THAT AN MBA WOULD
HELP TO BUILD THE SKILLS TO BE
ABLE TO DO THOSE THINGS, AND I'M
SO GLAD THAT I DID, BECAUSE
EVERYONE ON THIS CALL WILL
CERTAINLY APPRECIATE, WHETHER
YOU RUN A LAB, YOU'RE PART OF A
TEAM, YOU'RE PART OF A CENTER,
IT'S ALL ABOUT THE TEAM AND HOW
YOU WORK TOGETHER WITHIN AN
ORGANIZATION, AND I WAS REALLY
HAPPY I DID THE PROGRAM.
>> YEAH, AND IT HAS ALLOWED YOU
TO REALLY TRANSFORM SOME OF HOW
WE DO RESEARCH, WHICH IS
INCREDIBLE.
TELL US A LITTLE BIT ABOUT WHAT
YOU ARE DOING NOW IN TERMS OF
HARNESSING SOME OF THESE LARGE
LANGUAGE MODELS, A.I., TO KIND
OF MINE BIG DATASETS FOR DRUG
REPURPOSING.
>> SURE.
WE WERE FOCUSED ON REPURPOSING
TO TRY TO TAKE ON CASTLEMAN'S,
WE KNEW WE COULDN'T COME UP WITH
A NEW DRUG FROM SCRATCH,
DISCOVERED THERE WAS INCREASED
MTOR ACTIVATION IN MY OWN
LYMPHOTISSUE, MY IMMUNE SYSTEM
HAD HYPERACTIVATION OF THE MTOR
SIGNALING PATHWAY WHICH LED ME
TO TRY TO REPURPOSE CERILIMUS,
I'LL QUICKLY WALK YOU THROUGH
IT, SO THE TOP OF THE SCREEN IS
A REACTIVE LYMPH NODE, JUST ONE
IMAGE OF MTOR ACTIVATION OR
PHOSPHO -- 6 EXPRESSION IN A
TYPICAL LYMPH NODE.
WHAT YOU'LL NOTICE IS THE VAST
MAJORITY OF CELLS ARE BLUE,
THEY'RE COUNTER STAINED SO
THEY'RE NOT EXPRESSING
PHOSPHO -- 6, MTOR IS NOT TURNED
ON IN THE VAST MAJORITY OF
IMMUNE CELLS IN THE LYMPH NODE.
I REPEATED THE SAME EXPERIMENT
ON MY OWN LYMPH NODE TISSUE AND
WAS REALLY -- WHICH IS THE
BOTTOM OF THE SCREEN, AND I WAS
JUST BLOWN AWAY BY THE
TREMENDOUS AMOUNT OF MTOR
ACTIVATION, AND I WAS LED TO
MTOR BASED ON A LARGE SERUM
PROTEOMICS ANALYSIS I DID WITH
SIM LO JIX WHICH GAVE ME A
MINUTE THAT THERE WAS AN MTOR
SIGNATURE WHICH LED US TO
CONFIRM IT IN THE LABORATORY
HERE.
SO THAT LED ME TO THEN ACTUALLY
START TREATING THIS DISEASE WITH
CIRALIMUS, ACTUALLY IT WAS A
COLLEAGUE AT THE NIH, I WALKED
INTO THE NIH CLINICAL CENTER
WITH THESE IMAGES AND I DROPPED
THEM ON THE TABLE IN FRONT OF
THE ABP, WHICH I'M SURE YOU ALL
HAVE SPENT A LOT OF TIME AT AT
THE NIH CLINICAL CENTER, SHOWED
TO MY COLLEAGUE AND WE DISCUSS
WHRAD TO DO AND HE SAID I THINK
WE SHOULD TRY AN MTOR INHIBITOR,
LET'S GO WITH CIROLIMUS SO THAT
WAS THE IMPETUS FOR TRYING THE
DRUG.
THIS PAST JANUARY MARKS 10 YEARS
I'VE BEEN IN REMISSION, SO AFTER
RELAPSING AND NEARLY DYING FIVE
TIMES IN ABOUT FIVE YEARS BEFORE
SERALIMUS, NOW IT'S BEEN OVER 10
YEARS IN REMISSION ON IT.
SO THIS IS A PICTURE OF MY WIFE
AND MY TWO KIDS, BY OF COURSE IT
JUST FEELS LIKE A DREAM THAT I'M
HERE WITH YOU TODAY, TALKING
ABOUT OUR WORK, AND I HAVE THESE
AMAZING KIDS AND SUCH A SPECIAL
FAMILY.
BUT FOR ME, THIS DIDN'T JUST
SAVE MY LIFE.
IT JUST OPENED MY EYES UP TO
SOMETHING THAT EVERYONE ON THIS
CALL ALREADY KNOWS, AND THAT'S
THAT THE DRUGS THAT WE HAVE THAT
ARE FDA-APPROVED HAVE ADDITIONAL
POTENTIAL TO HELP MORE PATIENTS
AND MORE DISEASES THAN THEY
CURRECURRENTLY DO.
AND THE MORE AND MORE I DUG INTO
THIS, THE MORE AND MORE I
LEARNED THAT THERE IS -- THERE
ARE TREMENDOUS AMOUNTS OF DATA
THAT CAN LINK EXISTING DRUGS TO
DISEASES THAT DON'T HAVE ANY
TREATMENTS, BUT THE PROBLEM IS
THAT THERE ARE SYSTEMIC BARRIERS
THAT PREVENT US FROM FULLY
UTILIZING EXISTING MEDICINE.
SO PROBABLY THE MOST IMPORTANT
ONE ARE FINANCIAL BARRIERS, SO
OVER 80% OF FDA-APPROVED DRUGS
ARE ALREADY GENERIC, WHICH MEANS
THAT THERE'S NO INCENTIVE FOR
DRUG COMPANIES TO DO FURTHER R &
D ON 80% OF THE DRUGS THAT ARE
IN OUR CVS, THAT COULD HELP
PEOPLE TOMORROW, WE'RE NOT DOING
R & D ON.
IN ADDITION TO THAT, THERE'S
NEVER BEEN A CENTRALIZED PLACE
FOR DATA SHARING AROUND NEW USES
FOR EXISTING MEDICINES.
WE SORT OF ALL WORK IN OUR
SILOS, YOU KNOW, I REPURPOSE
DRUGS FOR CASTLEMAN'S HERE, WE
COME ACROSS DRUGS THAT MAYBE
THEY COULD BE USED FOR
IDG4 RELATED DISEASE BUT THAT'S
NOT WHAT YOU STUDY SO I SORT OF
KEEP DOWN MY CASTLEMAN'S TRACK.
THEN IMPORTANTLY THERE ACTUALLY
ISN'T A PLAYER IN OUR MEDICAL
SYSTEM THAT IS RESPONSIBLE FOR
MAKING SURE THAT FDA-APPROVED
DRUGS ARE USED FOR ALL THE
DISEASES POSSIBLE.
THAT'S NOT THE FDA'S JOB.
THE FDA'S JOB IS TO SAY, BASED
ON THE INDICATION THAT'S BEEN
SUBMITTED, IS THIS DRUG SAFE AND
EFFECTIVE FOR THAT INDICATION.
IT'S NOT WHAT ARE THE OTHER
INDICATIONS THAT THIS DRUG COULD
BE USEFUL FOR.
NIH DOESN'T HAVE THAT REMIT,
PHARMA DOESN'T HAVE THAT REMIT,
REALLY KNOW ONE HAS A REMIT
SAYING IF IT'S ON THE PHARMACY
SHELF FOR ONE THING, WHAT ARE
THE OTHER THINGS, BUT WES ARE
SORT OF DO IT FOR OUR OWN
FAVORITE DISEASE AT A TIME.
SO IT BECAME VERY CLEAR, THE
MORE DAYS AND MONTHS THAT WENT
BY THAT I WAS IN REMISSION AND
THE MORE PATIENTS WE TREATED
WITH MTOR INHIBITION FOR
CASTLEMAN DISEASE, THE CLEARER
IT WAS THAT THIS WASN'T JUST
SORT OF A ONE-OFF THING.
WE'RE LIKE, OH, CERILIMUS
HAPPENED TO BE WAITING THERE.
THERE'S ACTUALLY A LOT OF OTHER
DRUGS WAITING TO BE USED IN NEW
WAYS.
SO ABOUT TWO YEARS AGO, WE
LAUNCHED A NON-PROFIT
ORGANIZATION CALLED EVERY YEAR,
AND E --CALLED EVERY CURE.
WE BELIEVE NO ONE SHOULD SUFFER
LIKE I DID FOR THREE YEARS WHILE
THERE'S A TREATMENT SITTING ON
THE PHARMACY SHELF WAITING TO BE
UNLOCKED.
THE REASON WE DECIDED TO START A
COUPLE YEARS AGO IS THAT WE
UTILIZED ARTIFICIAL INTELLIGENCE
IN A NUMBER OF MACHINE LEARNING
ALGORITHMS, ACTUALLY SEVERAL OF
WHICH WERE DEVELOPED THANKS TO
FUNDING FROM NCATS, ON DATASETS
AGAIN THAT WERE CONSTRUCTED WITH
FUNDING FROM NCATS.
THIS INCREDIBLE PROGRAM CALLED
THE TRANSLATOR PROGRAM.
SO COME UP WITH PREDICTIVE
SCORES FOR THE LIKELIHOOD OF
EVERY SINGLE DRUG TO TREAT EVERY
DISEASE.
SO IT WAS ABOUT 3,000
FDA-APPROVED DRUGS AND ABOUT
22,000 HUMAN DISEASES, SO
UTILIZING THIS REALLY ROBUST
DATA INFRASTRUCTURE AND A
HANDFUL OF MACHINE LEARNING
ALGORITHMS, WE CAN QUANTIFY THE
STRENGTH OF EVIDENCE FOR EVERY
MATCH AND THEN THAT CAN SERVE AS
A STARTING PLACE FOR THEN US TO
SAY WHAT'S THE TOP HIT OR WHAT'S
THE TOP -- WHAT ARE THE TOP
1,000 HITS FOR DRUGS VERSUS
DISEASES THAT MAYBE DESERVE
FURTHER RESEARCH, WHETHER OR NOT
THEY COULD EVER BE PROFITABLE
FOR A PHARMACEUTICAL COMPANY.
>> MAYBE YOU ALSO NEED TO
PROGRAM IN THE NEED FROM THE
PATIENT END.
>> ABSOLUTELY.
>> SOME OF THESE DISEASES REALLY
HAVE NOTHING AND MAYBE THOSE ARE
THE ONES THAT SHOULD KIND OF
FALL TO THE TOP OF THE LIST.
YOU RECENTLY, OR YOUR
NON-PROFIT, I BELIEVE, RECENTLY
ALSO RECEIVED A HUGE GRANT FROM
ARPA-H FOR PART OF THIS WORK.
CAN YOU TELL US ANY MORE ABOUT
THAT?
>> SURE.
YEAH, SO WE'RE SO THRILLED.
ARPA-H, BRAND NEW FEDERAL AGENCY
MODELED AFTER DARPA, BUT FOCUSED
ON HEALTH.
THEY ARE DOING SOME REALLY
AMAZING THINGS IN THE BIOMEDICAL
RESEARCH SPACE, AND THEY MADE AN
EARLY INVESTMENT INTO THIS
NON-PROFIT, EVERY CURE,
SPECIFICALLY TO BUILD OUT OUR
A.I. PLATFORM.
SO TO TAKE IT FROM WHERE WE ARE
NOW, WE ACTUALLY RAN IT FOR THE
FIRST TIME EVER LAST MARCH, SO
CLOSING IN AROUND 15 MONTHS,
WE'VE CONTINUED TO REFINE IT,
BUT TO GO FROM THIS SORT OF BETA
VERSION OF THE ALGORITHM AND OUR
PLATFORM TO A FULLY BUILT OUT
PLATFORM WHERE THE WORLD'S
BIOMEDICAL KNOWLEDGE IS
HARNESSED TO COME UP WITH A
SCORE FOR EVERY DRUG VERSUS
EVERY DISEASE, AND THE
ALGORITHMS WE USE ARE OPTIMIZED,
RIGHT NOW WE USE FIVE DIFFERENT
A.I. ALGORITHMS.
WE WANT TO WORK TOWARDS ONE THAT
COMBINES THE BEST OF EACH, AND
THEN WE'RE GOING TO SHARE THOSE
RESULTS WITH THE WORLD, ACTUALLY
WITHIN 18 TO 24 MONTHS, THERE
WILL BE A SCORE FOR EVERY DRUG
VERSUS EVERY DISEASE, WHICH FOR
EVERYONE ON THE CALL THAT'S A
CLINICIAN, THAT MIGHT SEEM MAYBE
KIND OF, I DON'T KNOW, SCARY BUT
SORT OF POTENTIALLY CHALLENGING
IN SOME WAYS, BECAUSE YOU CAN
IMAGINE YOUR PATIENT CAN GO
ONLINE AND RHEUMATOID ARTHRITIS,
3,000 DRU AND THERE WILL BE A
SCORE NEXT TO EVERY DRUG FOR
R.A.
SO JUST TO SORT OF -- FOR ANYONE
WHO IS ANXIOUS WHEN THEY HEAR
THAT, WE'RE GOING TO START OUT
WITH WHAT WE PROVIDE BEING FIRST
WHAT ARE THE DRUGS THAT ARE
FDA-APPROVED FOR THAT KRNTION
SECONDLY WHAT ARE THE DRUGS THAT
ARE ALREADY INCLUDED IN THE WELL
ESTABLISHED GUIDELINES.
AND BY THE TIME YOU CLICK THE
THIRD, YOU'RE GOING TO GET THIS
VERY MUCH RESEARCH SCORE GREAT
FROM ZERO TO 1 FOR EVERY OTHER
DRUG AGAINST THAT DISEASE OF
INTEREST, SO WE'LL BE MAKING IT
AVAILABLE TO THE WORLD, SO IT'S
JUST AN INCREDIBLE INVESTMENT TO
BUILD THE TEAM NECESSARY, AND
THEN AT THE SAME TIME, WE'RE
ALSO BUILDING A MEDICAL TEAM SO
THAT WE CAN PICK OUT AMONG THOSE
66 MILLION POSSIBILITIES WHICH
DRUGS FOR WHAT DISEASES LOOK
MOST PROMISING THAT WE WANT TO
DO CLINICAL TRIALS.
SO EVEN IF THERE IS AN INCENTIVE
FOR DRUG COMPANIES TO DO T WE
CAN DO THE TRIAL SO THAT
HOPEFULLY RESULT IN THAT DRUG
BEING UTILIZED IN A DISEASE
AREA.
>> SO I HAVE TO ASK BECAUSE I'LL
GET IN TROUBLE WITH DR. CLAYTON
IF I DON'T ASK THIS.
SO IN YOUR LARGE DATASET, I
ASSUME YOU'RE LOOKING AT MEN AND
WOMEN IN THE DATASET?
GLA?>> ABSOLUTELY.
THANK YOU FOR ASKING.
>> BECAUSE WE DO KNOW THAT
SOMETIMES WOMEN RESPOND TO DRUGS
DIFFERENTLY.
>> ABSOLUTELY.
AND I THINK IT'S AN IMPORTANT
QUESTION YOU BRING UP.
A, BECAUSE IT'S ESSENTIAL BUT B,
BALLS HISTORICALLY, THAT'S NOT
THE WAY THAT RESEARCH HAS BEEN
DONE, AND SO WE ARE ALREADY A
BIT BEHIND THE 8 BALL IN THE
SENSE THAT THERE HAS NOT
HISTORICALLY BEEN ENOUGH
RESEARCH IN WOMEN TO DATE AND
ALSO A NUMBER OF OTHER IMPORTANT
POPULATIONS, WHICH MEANS THAT
THE DATASETS, THE WORLD'S WORLDS
BIOMEDICAL KNOWLEDGE IS MISSING
A LOT OF BIOMEDICAL KNOWLEDGE.
SO WE START BY RELYING ON
PUBLICLY AVAILABLE BIOMEDICAL
KNOWLEDGE, BUT ONE THING WE'RE
DOING THAT'S DIFFERENT FROM
OTHER GROUPS IS WE'RE WORKING
REALLY HARD TO FILL IN THE GAPS,
WE CALL IT THE IGNOROME, ALL THE
SPOTS OF THE KNOWLEDGE IMRAF KNH
THAT DON'T INCLUDE PEOPLE OF
CERTAIN RACE, CERTAIN GENDERS.
THAT'S THE IGNOROME.
SO WE WANT TO USE OUR GAPS TO
FIGURE OUT WHAT IS THE IGNOROME,
THE GAPS IN THE MEDICAL
KNOWLEDGE SO WE CAN PROPERLY
FILL IT.
>> WONDERFUL TO HEAR.
I'M GOING TO TAKE YOU BACK NOW
FULL CIRCLE TO SOME OF THE
THINGS THAT YOU KIND OF BROUGHT
UP EARLIER.
WHAT YOU'RE DOING NOW IS SORT OF
FILLING ME WITH OPTIMISM.
IS IT FILLING YOU WITH OPTIMISM
TOO, AND IS THERE AN OUNCE OF
HOPE STILL?
>> YES, THERE IS.
I AM SO EXCITED.
OBVIOUSLY I SHARED MY OWN
PERSONAL EXPERIENCE BUT MAYBE
I'LL SHARE ANOTHER COUPLE
ANECDOTES, REASONS WHY I'M SUPER
EXCITED.
SO AN EXAMPLE OF A DISEASE THAT
WOULD FALL INTO AS MAYBE YOU
DESCRIBE IT AS LOW HANGING FRUIT
OR SORT OF TOP OF THE LIST IS
ONE THAT MANY ON THIS CALL WILL
BE FAMILIAR WITH, AND THAT'S
DATA 2, DEFICIENCY OF ADA2,
WHICH YOU MAY BE FAMILIAR WITH
THE WONDERFUL WORK THAT'S BEEN
DONE AT NIH AND ELSEWHERE TO
IDENTIFY TNF INHIBITION.
>> YEAH, AND I ACTUALLY HAD A
PATIENT WITH DATA 2 ONCE.
VERY RARE DISEASE.
>> WOW.
DID YOU HAVE THE PATIENT ON A
TNF INHIBITOR AND THE PATIENT
DID WELL?
>> HE DID.
>> AMAZING!
SO FOR THOSE THAT HAVEN'T MAYBE
SEEN THE DATA 2 PATIENT OR ARE
NOT AWARE OF THIS AMAZING STORY,
BUT ABOUT 15 YEARS AGO,
RESEARCHERS BOTH AT THE NIH BUT
ALSO IN A FEW OTHER PARTS OF THE
WORLD WERE REALLY HONING IN ON
WHAT IS THIS SYNDROME,
DEFICIENCY OF ADA2?
CHISH WCHILDREN WERE EXPERIENCIG
DOZENS AND DOZENS OF STROKES,
REALLY DEBILITATING STROKES,
WASN'T CLEAR WHY.
A RESEARCHER DECIDED TO TRY A
TNF I INHIBITOR OFF LABEL, NO
STROKE, ZERO STROKES AFTER THE
FIRST DOSE.
IT TOOK ABOUT 10 YEARS BETWEEN
THAT FIRST PATIENT GETTING -- WE
PARTNER WITH A GROUP CALLED THE
DATA 2 FOUNDATION.
THE FIRST EVER TREATMENT
GUIDELINES PUBLISHED ABOUT A
YEAR AGO.
OVER THE COARSE OF THOSE 10
YEARS, SOME PATIENTS GOT IT,
SOME PATIENTS DIDN'T, I'M SO
GLAD TO HEAR THAT, BUT BECAUSE
GUIDELINES HASN'T BEEN
DEVELOPED, THE WORLD HASN'T COME
TOGETHER TO SAY THIS IS HOW YOU
TREAT DATA TWO, PATIENTS
SUFFERED WHEN THERE WAS
LITERALLY SOMETHING THAT COULD
HAVE BEEN LIFE SAVING FOR THEM.
NOW THERE ARE GUIDELINES AND
WHAT I HEAR FROM CHIP IS THAT
EVERYONE WHO HAS DATA 2 IS
ACCESSING A TNF INHIBITOR
DESPITE THE FACT IT'S NOT -- A
CLINICAL TRIAL HASN'T BEEN DONE
BUT THE NATURAL HISTORY IS SO --
IF YOU DON'T GIVE THESE KIDS TNF
INHIBITION, THEY ARE DEBILITATED
WITH STROKES, IF YOU DO, THEY
LIVE FULL LIVES.
SO THAT, FOR ME, PART OF THE
PROBLEM IS SOMETIMES WE DO
THINGS SOMEWHERE CLINICALLY AND
IT DOESN'T EVER SORT OF RISE TO
THE TOP.
WE WANT TO FIND THOSE
OPPORTUNITIES BUT IT ALSO
PROVIDES ME A LOT OF HOPE AND
EXCITEMENT.
MAYBE I'LL SHARE ONE MORE
EXAMPLE.
AND THAT'S THAT WE RAN ALGORITHM
FOR THE FIRST TIME LAST MARCH
AND YOU END UP GETTING ALL
66 MILLION SCORES, YOU CAN
IMAGINE I'M BIASED SO I LOOKED
AT CASTLEMAN'S.
NORMALIZED ACROSS DISEASES
MEANING A .89 FOR A DRUG FOR
LUPUS IS BETTER THAN A .75 FOR A
DRUG FOR CASTLEMAN'S.
THE SCORE IS NORMALIZED SO THAT
THE TOP HITS FOR ONE TEASE COULD
BE COMPARABLE TO THE TOP HITS
FOR ANOTHER DISEASE.
BUT I ZOOMED IN ON CASTLEMAN'S
OBVIOUSLY, AND WAS REALLY,
REALLY INTERESTED TO SEE THE TOP
HIT BECAUSE JUST A COUPLE WEEKS
BEFORE, WE HAD COMPLETED A LARGE
PROTEOMICS STUDY WHICH LED US TO
ACTUALLY USE A TNF INHIBITOR IN
A CASTLEMAN'S PATIENT, GETTING
READY TO GO INTO HOSPICE CARE.
WE USED THIS TNF INHIBITOR FOR
THE FIRST TIME WE'RE AWARE --
BUT IT ACTUALLY WORKED REALLY
WELL FOR THE PATIENT, IT'S WELL
OVER A YEAR, HE'S IN REMISSION,
WHAT WAS SO COOL TO SEE WAS THE
NUMBER ONE DRUG PREDICTED FOR
CASTLEMAN'S DISEASE AND THE
NUMBER THREE DRUG FOR CASTLEMAN
EAZ WERE BOTH TNF INHIBITORS.
THERE'S A LOT OF REASON TO
BELIEVE FROM THE INTERSECTION
AND SIMILARITIES BETWEEN CASS
MAN AND OTHER AUTOIMMUNE
DISEASES, THAT MAYBE ONE WOULD
PREDICT THAT, BUT IT STILL WAS
REALLY EXCITING FOR US TO SEE.
>> AND I DO THINK THAT'S
EXCITING TO SEE AND HEAR AND THE
REALITY IS WE DO AS
RHEUMATOLOGISTS END UP USING OFF
LABEL TREATMENTS.
>> YES.
>> AND IT WOULD BE GREAT TO HAVE
BETTER EVIDENCE TO GUIDE SOME OF
THAT AND TO DRIVE LIKE DECISIONS
ABOUT WHICH CLINICAL TRIALS
SHOULD BE RUN BECAUSE THAT'S
ANOTHER PROBLEM WE HAVE, AND WE
WOULD DEARLY LIKE YOU TO LET US
KNOW WHAT WE SHOULD BE LOOKING
AT IN LUPUS.
>> YES, LUPUS IS A GREAT
EXAMPLE, RIGHT, AND I THINK
THAT, YOU KNOW, WHAT I WOULD
LOVE IS FOR THIS TO BE REALLY A
TWO-WAY DIALOGUE BETWEEN THE
SYSTEM AND BETWEEN OUR MEDICAL
COMMUNITY, WHERE OBVIOUSLY WE
UTILIZE THESE BIOMEDICAL
KNOWLEDGE GAPS, WE GIVE SCORES
TO THE COMMUNITY SO THE NUMBER
THREE PREDICTED -- BUT WE ALSO
WANT THE MEDICAL COMMUNITY TO
SHARE YOUR FEEDBACK AND YOUR
INSIGHTS WITH US SO THAT WAY WE
CAN REFINE OUR SCORES AND MAYBE
SOMETHING THAT GOT A REALLY
GREAT SCORE, IT'S NONSENSICAL OR
VICE VERSA, YOU KNOW, WE WANT TO
ENGAGE AND WE WANT TO HEAR ABOUT
PATIENTS WHERE YOU'VE TREATED --
USED A DRUG, IT'S WORKED, CAN WE
UTILIZE THAT AS WE THINK ABOUT
WHAT TRIALS TO MOVE FORWARD.
>> AND I THINK THAT'S SOMETHING
THAT YOU'VE DONE SO WELL AND
THESE OTHER DISEASES, KIND OF
BRINGING COMMUNITY OF SCIENTISTS
AND PATIENTS TOGETHER AND BEING
ABLE TO KIND OF SCALE THAT TO
OTHER DISEASES WOULD BE REALLY
WONDERFUL.
WE'VE ONLY GOT A FEW MINUTES
LEFT, SO I WANTED TO GIVE YOU A
CHANCE TO TELL PEOPLE, HOW CAN
THEY LEARN MORE ABOUT YOUR STORY
AND HOW CAN THEY LEARN MORE
ABOUT WHAT YOUR FOUNDATION IS
DOING?
>> SURE.
SO YOU CAN GO TO EVERYCURE.ORG
TO LEARN MORE ABOUT WHAT WE'RE
DOING WITH THIS NON-PROFIT
THAT'S LOOKING -- I WAS GOING TO
SAY FOCUS ON ALL DRUGS AND ALL
DISEASES BUT I DON'T THINK FOCUS
IS THE RIGHT TERM WHEN LITERALLY
EVERY DRUG AND EVERY DISEASE IS
IN SCOPE FOR US.
SO CHECK OUT EVERYCURE.ORG.
I SEE ON THE SCREEN THERE'S A
PHOTO OF THE BOOK THAT I WROTE
ABOUT MY JOURNEY CALLED CHASING
MY CURE, WHICH FOR ME WAS SO
SPECIAL TO BE ABLE TO SHARE THIS
EXPERIENCE, WHAT MY FAMILY, WHAT
I WENT THROUGH GOING FROM BEING
A HEALTHY MEDICAL STUDENT TO A
SICK MEDICAL STUDENT TO A
MEDICAL RESEARCHER AND AN
ADVOCATE, SO A REAL HONOR FOR ME
TO WRITE, BUT I DO THINK THE
TITLE SHOULD ACTUALLY BE
DIFFERENT.
IT SHOULDN'T BE CHASTING MY
CURE, IT SHOULD BE CHASING OUR
CURE BECAUSE I THINK BHA YOU
HEARD ME SAY EARLIER IS IT
CERTAINLY WASN'T ME ON MY OWN
BECAUSE IF IT WAS ME ON MY OWN,
I WOULD NOT BE ALIVE RIGHT NOW.
IT WAS BECAUSE I HAD THIS
AMAZING TEAM, MEDICAL STUDENTS,
COLLEAGUES AT NIH AND BEYOND
THAT WERE PART OF THIS EFFORT.
SO IT SHOULD HAVE BEEN CHAIT CHG
OUR CURES, SO OBVIOUSLY YOU CAN
CHECK OUT THE STORY THERE.
BUT MOST IMPORTANTLY, FEEL FREE
TO -- IF YOU -- THERE ACTUALLY
IS A LOT OF OVERLAP.
IF YOU EVER SEE A CASTLEMAN'S
PATIENT, PLEASE DO EMAIL ME.
VERY EASY TO FIND, PLEASE REACH
OUT TO ME, WE'D LOVE TO GET THAT
PATIENT INTO ONE OF OUR STUDY,
GET SAMPLES, GET THEM INTO OUR
REGISTRY AND ALSO JUST EAGER TO
SHARE WITH OTHERS ABOUT OUR
APPROACH, AND JUST THANKFUL FOR
ALL OF YOU, REALLY SUCH AN HONOR
TO BE A PART OF THIS, AND OF
COURSE AN EVENT NAMED AFTER
DR. PINN.
>> I REALLY WANT TO THANK YOU,
DAVID, FOR JOINING US TODAY, FOR
SHARING YOUR STORY WITH OUR
COMMUNITY.
YOUR BOOK RESONATED WITH ME, THE
THING THAT PROMPTED ME TO INVITE
YOU TODAY, AND THIS WAS JUST
SUCH AN ENJOYABLE EVENT AND I
REALLY THANK YOU AGAIN FOR
TAKING THE TIME TO JOIN US.
I'LL PASS THINGS BACK OVER TO
DR. CLAYTON TO INTRODUCE
DR. KARR.
>> THANK YOU SO MUCH, DR
DR. FAJGENBAUM.
DR. KARR'S CAREER HAS HAD SO
MANY HIGHLIGHTS SO FAR.
CAN YOU READ THE FULL BIO IN THE
PROGRAM BOOKLET THAT'S ONLINE
BUT I WOULD LIKE TO MEX MENTIONA
FEW.
SHE RECEIVED A SPECIAL
RECOGNITION AWARD FOR
CONTRIBUTIONS TO THE STUDIES ON
THE TREATMENT AND PATHOGENESIS
OF SYSTEMIC VASCULITIS.
IN THE D.C. ACADEMIC COMMUNITY.
AND THESE ARE JUST A FEW OF HER
ACCOMPLISHMENTS.
AND IN 2019, DR. KARR KERR WASE
FIRST TO USE THE FIRST
RHEUMATOLOGIST TO RECEIVE THE
JOHNS HAPPEN KINS UNIVERSITY
16TH MYRON BISFELT DISTINGUISHED
VISITING PROFESSORSHIP IN
DIVERSITY.
DR. KERR'S CLINICAL RESEARCH
ACTIVITIES HAVE BEEN BASED ON
CLINICAL AND OBSERVATIONAL -- OF
CHRONIC DISEASE, ALL REFLECTING
REAL WORLD CARE.
AND I'M GOING TO END BY SAYING
SHE IS ALSO THE 2023 RECIPIENT
OF THE AMERICAN COLLEGE OF
PHYSICIANS D.C. CHAPTER
EXCELLENCE IN TEACHING AWARD,
AND NOT MANY PEOPLE ARE
RECEIVING EXCELLENCE IN TEACHING
AND CLINICAL CARE AND IN
RESEARCH.
AND IN 2023, DR. GAIL KERR WAS
ALSO DESIGNATED AS A MASTER OF
THE AMERICAN COLLEGE OF
RHEUMATOLOGY, THE FIRST BLACK
WOMAN TO RECEIVE ITS HIGHEST
HONOR.
AS A FRIEND AND COLLEAGUE,
PLEASE JOIN ME IN WELCOMING
DR. GAIL KERR FOR OUR CAPSTONE
ADDRESS, WHICH SHE HAS ENTITLED
"MAKING A DIFFERENCE."
GAIL?
>> THANK YOU VERY MUCH,
DR. CLAYTON, AND THANKS,
EVERYONE, WHO CONSIDERED ME TO
TAKE PART IN THIS.
IT IS INDEED A PRIVILEGE.
A DISTINCT ONE, BECAUSE DR. PINN
IS ON THE LINE SO THANK YOU VERY
MUCH.
IT'S AN OPPORTUNITY FOR ME FOR
SHARING SOME THOUGHTS, REGARDING
PROVIDING BETTER CARE FOR
PATIENTS.
THANK YOU VERY MUCH FOR BEING
HERE.
IT'S A PRIVILEGE TO PARTICIPATE,
PARTICULARLY WITH DR. PINN ON
THE LINE, TOWARDS TAKING CARE
AND BETTER CARE OF PATIENTS WITH
RHEUMATIC DISEASES.
THESE ARE MY DISCLOSURES.
MY MOTIVATION REALLY TO BECOME A
RHEUMATOLOGIST STARTED MANY
YEARS AGO, WHEN I WAS ASKED TO
SEE A PATIENT, A KAU S CAUCASIAN
WITH MALAISE, ARTHRALGIA, AND
WHAT BROUGHT HER IN WAS THIS
RASH INITIALLY IN THE FEET BUT
THEN LATER WENT ON TO DEVELOP --
TO INVOLVE HER HANDS AND
FINGERS.
AM I BEING ALLOWED TO ADVANCE MY
SLIDES?
SO THIS IS THE RASH SHE HAD ON
HER PALMS AND HANDS AND MOST
SIGNIFICANT WAS ONE ON THE
FINGER, A PAINLESS NODULAR
HEMORRHAGIC LESION.
THAT ALONG WITH MID SYSTOLIC
MURMUR IN THE MITRAL AREA AND
ELEVATED SED RATE LED ME TO MAKE
THE DIAGNOSIS OF EN ENDOCARDITI.
I ORDERED BLOOD CULTURES, ECHO
AND STARTED APPROPRIATE
ANTIBIOTICS.
THIS OCCURRED MANY YEARS AGO,
WHEN I WAS A RESIDENT WHERE I
TRAINED, AT THE UNIVERSITY OF
WEST INDIES IN JAMAICA.
THE NEXT MORNING, MY ATTENDING
ASKED IF I HAD CONSIDERED
HYPERSENSITIVITY VASCULITIS.
THAT INDEED IT WAS, BECAUSE IN
HER MEDICAL HISTORY, SHE IN FACT
HAD TAKEN TRIMETH
TRIMETHOPRIM-SULFAMETHOXAZOLE
THE WEEK BEFORE.
EVERY PAPER I PULLED WAS
ACTUALLY BY THE SAME GENTLEMAN.
ALL THE PAPERS.
IT OCCURRED IN A PLACE I HAD
NEVER HEARD.
THE NATIONAL INSTITUTES OF
HEALTH IN A PLACE OF BETHESDA,
MARYLAND.
AND WHO WOULD HAVE THOUGHT THAT
SOME YEARS LATER, I WOULD
ACTUALLY BE PART OF THAT GROUP
AND WRITING PAPERS ON SYSTEMIC
VASCULITIS IN ITS EARLY DAYS OF
THE VASCULITIS NETWORK.
IT IS THAT EXPOSURE AND
OPPORTUNITY THAT LED TO THE
TRANSITION AND THE ASSOCIATIONS
WITH THE THREE INSTITUTIONS THAT
I NOW REPRESENT, AND THAT HAS
MERGED INTO UNION OF SUPPORT,
AND FOR THE PAST THAT I'VE
SUBSEQUENTLY TAKEN.
SO IF I'M TO TAKE YOU DOWN THOSE
PATH AND SUMMARIZE THEM AS
OBJECTIVES TO MEET MY ASSIGNED
TOPIC THAT IS MAKING A
DIFFERENCE, IT WOULD INVOLVE
THESE THREE THINGS AND NOT
NECESSARILY IN SEQUENTIAL ORDER
AND THEY'RE NOT MUTUALLY
EXCLUSIVE.
AND THAT IS CREATING
COLLABORATIONS,
RECOGNIZING/IDENTIFYING GAPS,
AND SEEING THE BIG PICTURE.
AFTER LEAVING THE NIH, I HAVE
BEEN A MEMBER OF THE VETERANS
HEALTH AFFAIRS AT THE
WASHINGTON, D.C. V.A. MEDICAL
CENTER FOR THE PAST 28 YEARS,
AND NOT UNLIKE THE NIH, IT IS A
VERY LARGE INSTITUTION AND WE
SERVE ABOUT 5 MILLION VETERANS.
IN FACT, A RECENT CDC COHORT
ANALYSIS OF THE BEHAVIORAL RISK
FACTOR SURVEILLANCE SYSTEM DATA
SHOWED THAT A THIRD OF VETERANS
ARE DIAGNOSED WITH ARTHRITIS.
AND THIS OCCURS IN THEIR
PRODUCTIVE YEARS, BETWEEN THE
AGES OF 18 TO 44, THERE ARE
TWICE AS MANY VETERANS WHO HAVE
ARTHRITIS COMPARED TO
NON-VETERANS AND 60% MORE
PREVALENCE IN FEMALES.
SO WE HAVE A LOT OF PATIENT WITH
RHEUMATIC DISEASES TO CARE FOR.
ON MY EYE RIFLE, I WAS
DESIGNATED AS THE CHAIR OF THE
RHEUMATOLOGY FIELD ADVISORY
COMMITTEE, AND I TOOK THAT ROLE
AND TYPE LITERALLY AND MY JOB,
THEREFORE, WAS TO BRING
INFORMATION FROM THE FIELD TO
CENTRAL OFFICE TO INITIATE
DISCOURSE AND THEN GO BACK TO
THE CLINIC TO GIVE BEST CARE TO
THE PATIENTS.
I ALONG WITH MY PROGRAM
ASSISTANT AT THE TIME CALLED ALL
VAs IN THE COUNTRY AND GOT A
FULL LIST OF THE RHEUMATOLOGISTS
THERE, SOME OF WHICH WERE
ACTUALLY UNDER THEIR UNIVERSITY
DESIGNATION EVEN THOUGH THEY'RE
BEING PAID BY THE V.A.
ABOUT THE SAME TIME, THERE WAS A
KNOCK ON MY DOOR, AND THIS WAS
FROM THE HENRY JACKSON
FOUNDATION WHO CAME TO LET ME
KNOW THAT THEY HAD AN
EDUCATIONAL GRANT SPECIFIC FOR
RHEUMATOLOGY.
SO THE STARS WERE ALIGNED.
AND SO I GOT TOGETHER A GROUP OF
RHEUMATOLOGISTS IN 2001 AND WE
FIRST MET IN SANTA MONICA FOR
OUR FIRST MEETING, ABOUT 30 OF
US, AND IT WAS AROUND THE TIME
OF THE TNF INHIBITORS, WHICH
WERE ON THE MARKET SO WE HAD VA
PHARMACY, A ROBUST DISCUSSION.
BUT THAT GATHERING AND THE
COLLEGIALITY HATCHED WHAT WAS
DESIGNATED THEREAFTER AS THE VA
RHEUMATOLOGY CONSORTIUM, VARC.
AND I PULLED THIS SLIDE FROM ONE
OF MY OLD STATE OF THE
CONSORTIUM ADDRESS AT ONE OF OUR
ANNUAL MEETINGS.
AND I CHANGED THE ORDER A BIT.
I'M SORRY, THERE'S A BIG LAG
HERE.
I CHANGED THE ORDER A BIT, AND
REALLY TO EMPHASIZE THAT
WHATEVER WE DO, WHATEVER
INITIATIVE WE HAVE, THAT WHAT
MAKES IT ENDURING, AND YOU'VE
HEARD THIS THEME ACROSS ALL THE
PRESENTERS, THAT COLLABORATION.
THE CAMARADERIE, THE BONHOMIE IN
SOME INSTANCES.
THAT VALIDATED WHAT WAS REQUIRED
OF THE FIELD ADVISORY COMMITTEE.
WE NOT ONLY BROUGHT
RHEUMATOLOGISTS OUT OF THE
SHADOWS, BUT WE'RE NOW ABLE AND
FAMILIAR WITH EVERYBODY BY NAME
AND THEIR LOCATION.
AND THAT TURNED OUT TO BE MUSIC
TO THE EARS OF THE VETERANS WHEN
THEY WERE RELOCATING AND WE
COULD ACTUALLY TELL THEM THE
NAME OF THE PHYSICIAN THEY WERE
GOING TO SEE.
AND THEY WERE COMFORTED AND
REASSURED BY THE FACT THAT THEY
WOULD REMAIN IN THE V.A. ROOM
GROUP PRACTICE.
THE COLLEGIALITY LED TO A NUMBER
OF OTHER ACHIEVEMENTS.
WE WERE ABLE TO PROVIDE
RECOMMENDATIONS ON WORKLOAD AND
PERFORMANCE ISSUES, HAD A
UNIFIED SYSTEM WITHOUT LOSING
OUR INDIVIDUALITY, AND WE WERE
ABLE TO DEVELOP SPECIFIC DISEASE
TEMPLATES FOR OUR ELECTRONIC
HEALTH RECORDS.
BUT WHAT IS MOST NOTABLE WAS THE
COLLABORATION THAT LED TO THE
DEVELOPMENT OF OUR CHRONIC
DISEASE REGISTRIES.
AND THERE ARE THREE OF THEM.
THE FIRST WAS THE VA RHEUMATOID
ARTHRITIS LED BY TED MICHAELS IN
OMAHA, NEBRASKA, AND THEN A
PROGRAM TO UNDERSTAND THE LONG
TERM OUTCOMES OF THE AXSPA
PULSAR, CO-LED IN TEXAS.
AND CRYSTAL, RELOCATED BACK TO
L.A. WHERE IT WAS FIRST STARTED,
NOW IN MICHIGAN, AND NOW ALSO
ALONG WITH JOHN FITZGERALD.
BUT IT'S THE VARA REGISTRY
THAT'S BEEN THE LONGEST TENURE,
AND REALLY HAS SET THE BAR FOR
REGISTRIES NOT ONLY IN THE V.A.,
BUT ALL ACROSS ALL REGISTRIES.
IT'S REALLY MASTERED THE SOURCES
THAT WE HAVE, BECAUSE ALONG WITH
LONGITUDAL OBSERVATIONAL DATA WE
COLLECT IN CLINIC THAT'S
EXTRACTED ON THE BACK END INTO
FIELDS, AND INTEGRATION WITH
LINKAGE TO V.A. CLAIMS DATA AND
NATIONAL V.A. DATA, WE'RE ABLE
TO POSE VARIOUS HYPOTHESES
DRIVEN QUERIES.
WE CAN ALSO LOOK AT ADHERENCE OF
MEDICATION AND DEVELOP
ALGORITHMS TO ASSESS TREATMENT
EFFICACY THAT'S USED IN
REGISTRIES AS WELL.
WITH RHEUMATOID ARTHRITIS,
INTERSTITIAL LUNG DISEASE.
THE GROUP HAS HAD MULTIPLE
FUNDING WITHIN AND OUTSIDE THE
V.A., AND IT ALSO HAS TAKEN ON
MENTORING, AND TO NAME A FEW --
ENGLAND AND JOSH BAKER AND THOSE
THAT FOLLOW.
AND IT'S BEEN VERY PRODUCTIVE IN
PUBLICATIONS, OVER 120 AT LAST
YEAR'S ACR MEETING, WE HAD OVER
23 ABSTRACTS, MANY WERE PLENARY.
AND IT'S A LESSON IN TEAM
SCIENCE AS TED MICHAELS HAS
INDICATED.
AND IT ALLOWS THE GROUP THAT
WHEN WE HAVE QUERIES THAT
REQUIRE SURVEYS, THEY'RE VERY
RESPONSIVE.
TO GIVE YOU AN IDEA, THE
RESPONSE RATE WE GET IS CLOSE TO
7%.
MOST SURVEYS ONLY EXPECT ABOUT
30%.
BUT WHAT WE'RE PROUD OF OTHER
THAN THE SMILES YOU SEE ON
EVERYONE'S FACES HERE WHEN WE
GATHER IS THE DIVERSITY OF THE
GROUP.
THAT IS NOT SOMETHING THAT CAN
BE REPLICATED VERY EASILY IN OUR
FIELD OF MEDICINE.
AND MANY OF YOU ARE ALREADY
FAMILIAR WITH THIS DATA.
THERE IS LACK OF DIVERSITY IN
THE WORKFORCE AND ALSO IN
RHEUMATOLOGY AND THAT'S
NATIONWIDE, AND MANY OF THAT HAS
NOT CHANGED OVER THE PAST
CENTURY.
THIS HAS BEEN DOCUMENTED WITH
BLACK PHYSICIANS IN PARTICULAR,
EITHER AS A GROUP OR CATEGORIZED
BY GENDER AND THERE HAS BEEN AN
OVERALL DECLINE IN MALE
PHYSICIANS.
AND THE PROJECTIONS APPEAR THAT
IT REMAINS STATIC AT LEAST FOR A
NUMBER OF YEARS, AND ANY
INCREASE IN PHYSICIANS AND IN
ETHNIC MINORITY PHYSICIANS, AT
LEAST BY THE YEAR 2060, IS
PRIMARY GOING DOING FILLED BY
HISPANICS AND ASIANS.
AND THE REASON IT'S DUPLICATED
AT THE SOURCE IN MEDICAL
SCHOOLS, MEDICAL DEGREES GRANTED
FROM U.S. SCHOOLS OVER THE PAST
30 YEARS WHEREAS THERE'S BEEN
INCREASE IN FEMALES MAINLY DUE
TO INCREASE IN ASIANS, OVERALL
MEN ARE DECREASED IN MEDICAL
SCHOOLS AND THEY'RE STILL ON THE
REPRESENTATION IN THE ETHNIC
MINORITIES, BLACKS, HISPANICS,
NATIVE AMERICANS, AND FAR BELOW
THEIR RESPECTIVE PERCENTAGES IN
THE U.S. CENSUS.
THIS OCCURS FOR TWO REASONS, TWO
HISTORICAL ACTS.
ONE IS SEGREGATION.
AS EXPECTED, YOU KNOW THAT
BLACKS WERE BANNED IN THE SOUTH
AND DISCOURAGED IN THE NORTH
FROM SEEKING HIGHER EDUCATION,
AND THEREFORE HAD TO DEVELOP
THEIR OWN INSTITUTES OF
LEARNING, HISTORICALLY BLACK
COLLEGES PRIMARILY.
AND THE SECOND ACT, THE SECOND
ACT WAS THE FLEXNER REPORT, AND
IN THAT ONE, IN AN ATTEMPT TO
VALIDATE ALL MEDICAL SCHOOLS OF
WHICH THERE WERE 155, THE BLACK
SCHOOLS WITHOUT THE FUNDING
COULD NOT MAKE THOSE
ADJUSTMENTS, AND THEREFORE MANY
OF THEM WERE CLOSED, AND THIS
WAS SIGNIFICANT NOT FOR TEACHING
STUDENTS, BUT ALSO FOR PATIENT
CARE, BECAUSE IT NOT ONLY
PROVIDED CARE TO BLACK PATIENTS
BUT ALSO POOR RURAL WHITES.
AND THIS IS A SLIDE THAT SHOWS A
HYPOTHETICAL MODEL EXAMINED THE
WHAT IF.
AND THEY PRESUME THAT IF FIVE OF
THOSE 13 BLACK SCHOOLS HAD
REMAINED OPEN AND MET THOSE
CRITERIA OF VALIDATION, WE WOULD
HAVE ABOUT 35,000 MORE GRADUATES
IN 2019.
THAT'S ABOUT A 30% INCREASE IN
AFRICAN AMERICANS.
AND THE NEXT SLIDE WILL TELL US
WHAT HAS HAPPENED AS A RESULT OF
THAT, BECAUSE THAT IS HISTORY
AND THIS IS THE HERE AND NOW.
FROM THAT, WE HAVE TWO THAT WERE
LEFT, HOWARD UNIVERSITY AND M
MEHARY, AND SINCE THEN TWO MORE,
CHARLES R. DREW AND MOREHOUSE
SCHOOL OF MEDICINE IN ATLANTA.
THE NEXT SLIDE TELLS YOU WHAT WE
DID AT HOWARD UNIVERSITY.
AND AROUND 2009, WE WENT IN AND
SAID WE WANT EVERY RESIDENT TO
ROTATE IN OUR SPECIALTY.
WE REQUESTED TWO RESIDENTS AS
THEY DO FOR CARDIOLOGY.
FOR ADDED VALUE.
AND THEY HAD A STRUCTURED
ROTATION WITH FOUR OUTPATIENT
CLINICS, WEEKLY LECTURES AND
CONFERENCES, AND LIKE FIRST YEAR
FELLOW, THEY WERE ON THE CALL
SCHEDULE FOR INPATIENTS AND
OUTPATIENTS.
THESE RESIDENTS WOULD THEN
COMPETE TO PRESENT EF AT OUR
ANNUAL KENNETH AUSTIN
RHEUMATOLOGY SYMPOSIUM FOR THE
BEST PRESENTATION OF A CLINICAL
CASE FROM THE CLINIC.
AND OUR PRESENTER AT OUR
SYMPOSIUM THIS APRIL WAS A
ROTATING DERMATOLOGY RESIDENT.
THE NECTS SLADE SHOWS WHAT
HAPPENS -- WHAT HAPPENED FROM
THAT EFFORT.
AND OVER THE PAST FEW YEARS, WE
HAVE PRODUCED 15 ETHNIC MINORITY
RHEUMATOLOGIES TO THE WORKFORCE,
TAKING INTO MIND OUR
DENOMINATOR, IT'S THE MOST FROM
ANY SINGLE INSTITUTION.
AND THEY HAVE PERFORMED NO LESS
THAN EXPECTED, NOR THAN ANY
OTHER ETHNIC MINORITY CANDIDATE
OVER THE YEARS, AND A THIRD OF
THEM HAVE ENTERED THE ACADEMICS
FAIR.
SO THE QUESTION WAS WHETHER THIS
MODEL OF THIS ONE INSTITUTION
COULD BE TAKEN ELSEWHERE AND
LEAD TO SIMILAR EFFECTS,
INCREASING THE WORKFORCE AND
SPECIFICALLY IN ETHNIC
MINORITIES.
AND THE NEXT SLIDE SHOWS YOU
SUCH AN ENDEAVOR.
I'M PRIVILEGED TO BE INCLUDED AS
A COLLABORATOR ON THIS ARTHRITIS
FOUNDATION SPONSORED GRANT.
IT'S LED IN STELLAR FASHION BY
CANDACE FELDMAN AT THE BRIGHAM,
ALONG WITH A STAR CAST OF
EDUCATORS AND LEADERS, WHO AIM
TO BUILD A WEB-BASED PROGRAM TO
SUPPORT WORKFORCE EXPANSION
AIMED PRIMARILY AT INCREASING
ETHNIC MINORITY RECRUITMENT.
CALLED THE AWARD PROGRAM.
THE GROUP HAS -- THE GOALS ARE
AS LISTED HERE, TO FOSTER
COMMUNITY, TO COORDINATE
NATIONAL EFFORTS, AND CREATE A
DIVERSE RHEUM WORKFORCE, AND
QUANTIFIABLE METRICS OF
ACCOUNTABILITY.
I HAVE BEEN CHARGED WITH
DEVELOPING PILLAR 2, AND THE
GROUP CONSISTS OF A MEDICAL
STUDENT, RESIDENT AND ALLIED
HEALTH PROVIDER AS WELL.
IN MY CHARGE AS A PILLAR
2 LEADER, I HAVE TO DEVELOP
INFORMATIONAL TOOL KITS AND
PIPELINE OF OPPORTUNITIES, WHILE
PILLAR 1 IS LED BY -- AND WITH
WORK TO PILOT ADAPTATIONS IN THE
CURRICULUM TO INCREASE AWARENESS
OF SOCIAL AND RACIAL BARRIERS IN
ACHIEVES EQUITY AND MAKE THEM
DISEASE-SPECIFIC.
AND TO SENSITIZE ALL CANDIDATES
TO AREAS OF LEADERSHIP SO THAT
WHEN THEY ARE IN A POSITION SO
CHOSEN, THEY HAVE THE SKILLS TO
SEEK AND PERFORM THESE ROLES,
AND THIS PILLAR IS LED BY
VALERIE STONE, SO WE'RE VERY
EXCITED ABOUT THIS.
WE MEET WEEKLY.
WE'RE NOW IN THE PHASE ONE
INFRASTRUCTURE DEVELOPMENT AND
LOOK FORWARD TO ITS
DISSEMINATION AND EXPANSION IN
PHASE TWO.
BUT THE NEXT SLIDE SHOWS
SOMETHING ELSE THAT WAS OBVIOUS
FROM THAT GROUP OF RESIDENTS,
AND THAT IS THE NEXT INDICATOR
WAS THAT 50% OF THEM WERE WOMEN.
AND WE ARE EXPERIENCING AS THE
NEXT SLIDE SHOWS A SHIFT IN THE
GENDER DISTRIBUTION IN THE
WORKFORCE IN MEDICINE.
THE SPECIALTIES WITH THE HIGHEST
PERCENTAGE ARE PRIMARILY FOCUSED
ON CHILDREN AND WOMEN.
PEDIATRICS IS UP TO 64%, OB-GYN
59, ENDOCRINE NOLG 52,
DERMATOLOGY AT 50 AS IS FOR
RHEUMATOLOGY AND WAS THE CASE IN
MY RESIDENTS.
AS DR. CLAYTON SHOWED, OF THE
FEMALENESS OF THE DISEASE, SHE
WENT THROUGH THIS QUITE
ELOQUENTLY, THE TRANSITION OF
THE MALE MICE TO WOMEN AS IT
WERE.
AND I'D JUST LIKE TO ADD TO
FURTHER SUPPORT, IS THAT
ANTIBODIES TO THIS COMPLEX WHO
HAVE BEEN FOUND IN PATIENTS WITH
AUTOIMMUNE DISEASE, IT'S ABSENT
IN THOSE WITHOUT.
AND LIKE ALL DISCOVERIES AS
DR. BUCKNER SHOWED, IT SEEMS TO
BE A MULTI-POLICE ILTITY IS
MULTIPLICITY IS GOING TOGIVE USS
CERTAINLY EXPANDS THE POBLGHTS.
BECAUSE IT MAY PROVIDE
BIOMARKERS OR PROVIDE SOME AREAS
OR TARGETS FOR PREVENTION.
BUT WHERE WE HAVE MADE PROGRESS
IS IN FERTILITY AND PREGNANCY ON
THE NEXT SLIDE.
AND WE'VE DONE THIS BECAUSE WE
CAN DIAGNOSE DISEASES EARLIER
AND WE HAVE BETTER THERAPIES IF
WE CAN GET THEM TO THE PATIENT
AND THESE AUTHORS HAVE WORKED TO
PROVIDE THESE DATA.
BUT FIRST WE HAVE TO APPRECIATE
THAT WE PROBABLY ARE NOT DOING A
VERY GOOD JOB AT INCLUDING
DISCUSSIONS IN EDUCATION AND
CHILD BEARING, AND WE WERE USING
A CONTRACEPTIVE HISTORY AS A
SURROGATE OF THAT EFFORT.
I THINK WE'VE FAILED BECAUSE I -
THE TOPIC WE USE TO GET THAT
HISTORY WHEN WE'RE CONCERNED
ABOUT A TERATOGENIC MEDICATION,
AND IT'S EVEN WORSE COLLECTION
OF THIS DATA IN ETHNIC
MINORITIES.
A CREEKY JOINT SURVEY SHOWED 65%
OF WOMEN DID USE SOME FORMT OF
EFFECTIVE CONTRACEPTION BUT WHEN
THERE WAS NO CONTRACEPTION THIS
WAS MOSTLY THE PSORIATIC
ARTHRITIS PATIENTS.
THEREFORE IMPLYING THE
DISCUSSION IS NOT BEING HAD.
BUT WHEN THERE IS PREGNANCY AS
OCCURS IN LUPUS, THERE IS A
DOCUMENTED WORSE OUT COME AND
PARTICULARLY IN ETHNIC
MINORITIES.
PATIENT SAMPLE DATA OVER A
TWO-YEAR PERIOD AND 13,000
DELIVERIES SHOWED THAT THERE WAS
40% MORE CESAREAN SECTIONS
COMPARED TO THE 12 MILLION
WITHOUT LUPUS, AND IN ETHNIC
MINORITY PATIENTS, THE BLACKS
AND HISPANICS HAD TWICE AS MUCH
PRETERM LABOR AND 20% INCREASE
IN PREECLAMPSIA AND GESTATIONAL
HYPERTENSION.
SO IT IS CLEAR WE HAVE TO
EDUCATE PATIENTS ON THE BEST
OUTCOMES AND WE DO IN CLINIC AND
TRY TO TELL THAT THE BEST OUT
COME IS WHEN DISEASE IS
INACTIVE.
BUT WE KNOW THAT DOES NOT WORK
ALL THE TIME.
AND THE WORK OF CLOWSE IN
DEVELOPING THESE HEALTHY
OUTCOMES IN PREGNANCY WITH SLE
THROUGH EDUCATION, AND I'LL SAY
HERE WITH AND OF PROVIDERS, IS
VERY, VERY HELPFUL, AND SHE
DEVELOPED THIS AND PILOTED IT AT
ONE OF THE WOMEN IN RHEUMATOLOGY
MEETINGS.
AND IT HAS PROMOTED THE
EDUCATION OF RHEUMATOLOGISTS TO
UNDERSTAND AND EMBRACE THE
OVERWHELMING REPRODUCTIVE DESIRE
OF MOST OF OUR PATIENTS.
AND IF WE REPLACE DISEASE
REMISSION WITH GOOD PREGNANCY
OUT COME MOTHER AND CHILD AND
SERVE THAT AS A SURROGATE AND
HAVE THOSE DISCUSSIONS
REPEATEDLY AND PLAN ACCORDINGLY,
WE WILL GET BETTER DISEASE
ACTIVITY CONTROL AND BETTER
ADHERENCE OF MEDICATIONS.
WE CAN EDUCATE THEM ON ALL THESE
ASPECTS, AND THE NEXT LINK SHOWS
ACTUALLY HER WEBPAGE THAT'S VERY
USEFUL THAT I KEEP WITH ME IN
THE CLINIC TO FACILITATE THOSE
DISCUSSIONS AND TO TALK ABOUT
THE MEDICATIONS THAT ARE
APPROPRIATE.
BUT THE WORKFORCE IS OF WORRY TO
EVERYONE AND RHEUMATOLOGY IS NO
DIFFERENT AND THE DANGER ON THE
NEXT SLIDE SHOWS THIS.
AN ASSESSMENT OVER A 10-YEAR
PERIOD SHOWS THAT THERE MAY BE
GOOD NEWS, 23% EXPANSION IN
RHEUMATOLOGISTS, AND AN
EXPLOSION ACTUALLY OF THE
ADVANCED PRACTICE PROVIDERS.
BUT THE DEVIL IS IN THE DETAILS
IN THAT THERE IS ONLY ONE
RHEUMATOLOGIST FOR 30,000
PATIENTS, AND IN RURAL COUNTIES,
90% OF THEM HAVE NO
RHEUMATOLOGISTS AND IT'S NOT
THAT MUCH BETTER WITH URBAN
COUNTIES.
HALF OF THEM DON'T HAVE A
RHEUMATOLOGIST.
FURTHER, IT SEEMS THAT PEOPLE
LEAVE AND WHEN YOU LOOK AT THE
ABSOLUTE INCREASE IN NUMBERS
OVER THAT TIME PERIOD STATED,
IT'S ONLY A THOUSAND
RHEUMATOLOGISTS.
THE POPULATION HAS EXPANDED, AND
THAT NUMBER 5600 IF MY MEMORY
SERVES ME RIGHT WAS ABOUT THE
SAME NUMBER IN 2015 WHEN WE WERE
FOREWARNED THAT THERE WAS GOING
TO BE A WORKFORCE SHORTAGE.
SO IT SEEMS AS IF THERE'S AN
ATTRITION IN THE RANKS AND 43%
OF THEM ARE, IN FACT, FEMALES.
THEY LEAVE AT ABOUT AGE 62 YEARS
OF AGE.
AND MOST OF THEM WILL LEAVE IF
THEY'RE IN A BIG HEALTHCARE
SYSTEM.
SOMEHOW THAT DOESN'T WORK WELL.
AND MORE LIKELY TO STAY IN A
SMALLER PRACTICE, ONE TO TWO
INDIVIDUALS, AND IF THEY'RE
LOCATED IN THE SOUTH.
SO MEASURES HAVE TO BE HAD AND
INTERVENTIONS MADE, AND THE NEXT
SLIDE GIVES US A FEW POINTERS.
AND THAT WE HAVE TO LOOK OUT FOR
WORK-LIFE BALANCE, ROSETTA
STONE, THESE ARE SOME OF THE
STRATEGIES LISTED HERE.
THEY HAVE TO BE REAL AND THEY
HAVE TO BE ACTIVE.
AND THE SAME ATTRACTIVENESS OF
RHEUMATOLOGY TO WOMEN IS ALSO
SOME OF THE ATTRITION THAT TAKES
PLACE BECAUSE THEY ARE THE
DECISIONS TO HAVE FAMILY BUT
THEY SHOULDN'T BE PENALIZED FOR
THAT.
WE SHOULD HAVE WAYS OF HAVING
FLEXIBLE WORK OPTIONS, MAKING
ADAP TAI DAITIONS FOR CHILD CAR,
ESPECIALLY FOR SIX CHILDREN SICN
BECAUSE THAT'S WHO ACHES THEM TO
THE PHYSICIAN, AND WE ARE
REQUIRED TO HAVE LACTATION
FACILITIES, BUT WE HAVE TO HAVE
THEM FUNDED TO BE FUNCTIONAL
WITH REFRIGERATORS AND HYGIENE
AS WELL.
SO IT REQUIRES A LOT OF
ADAPTATIONS TO MAKE THIS WORK.
AND THE OTHER FACTOR THAT MIGHT
EFFECT SOME OF THE ATTRITION IS
THEY'RE WORKING HARD AS ANYONE
ELSE, AND THE NEXT SLIDE SHOWS A
RECALCITRANT PROBLEM WE'VE HAD,
AND THAT'S A DIFFERENCE IN
COMPENSATION BY GENDER.
AND THIS APPLIES TO RHEUMATOLOGY
BUT ALSO OTHER SPECIALTIES.
A SURVEY OF 29 -- 13,000
PHYSICIANS OVER A FOUR-YEAR
PERIOD EXCEPT FOR 2019 SHOWS
THERE WAS A PERSISTENT 17%
DIFFERENCE IN PAY, AND THAT'S
BEEN UNCHANGED SINCE THEN, AND
WE WONDER WHETHER THESE ARE EVEN
WORSE FOLLOWING THE COVID ERA.
WHAT HAPPENS OVER THE LIFETIME
OF A PHYSICIAN?
A FEMALE PHYSICIAN?
AND THE NEXT SLIDE SHOWS THAT
WITH WHITE MALES AS A REFERENCE.
AND MANY OF YOU ARE FAMILIAR
WITH THESE DATA, THE EQUAL
PAYDAY.
AND HERE IT SHOWS IF A WHITE
MALE FINISHES OR GETS INCOME AT
THAT TIME, THE AMOUNT OF
ADDITIONAL TIME, VARIOUS ETHNIC
SUBSETS OF FEMALES HAVE TO WORK
TO MEET AND MATCH HIS INCOME,
AND IF THEY'RE MOTHERS AS WELL,
THEY ALSO HAVE AN EXTENDED
PERIOD.
TRANSLATING THIS TO A LIFE OR A
CAREER IN PRACTICE, 40 YEARS, IT
MEANS THAT THEY'RE BEHIND
1.8 MILLION IN THEIR RETIREMENT
FUNDS.
OR THEY'LL HAVE TO WORK AN
ADDITIONAL 8.2 YEARS TO MATCH
THEIR INCOME.
AND IT TRICKLES OVER INTO
ACADEMIA.
AND THE NEXT SLIDE WILL SHOW
SOME OF THESE DATA, WHERE THERE
IS ALSO A DIFFERENCE EVEN AS WE
APPROACH 50/50 IN THE WORKFORCE
IN RHEUMATOLOGY.
AND AT THE HIGHER RANKS, THERE'S
DEFINITELY FEWER WOMEN IN THOSE
POSITIONS, THEY'RE ALSO IN FEWER
ROLES OF LEADERSHIP, SUCH AS --
SIMILARLY WHEN WE DID TO
RESEARCH WHEN WE WANT TO GET
MORE WOMEN IN TO SEEK ANSWERS,
50% OF THEM HAVE LESS
AUTHORSHIP, EITHER SENIOR OR
FIRST AUTHOR, AND ALSO IN
ACHIEVING ANY GRANTS INCLUDING
NIH FUNDING.
SO THE THING IS, JUST LIKE OUR
DISEASES WHERE WE SEEK VARIABLES
TO MAKE DIAGNOSIS AND MEASURE
EFFICACY, WE HAVE TO DO THE SAME
WITH ANY DISPARITY AND GENDER
BIAS.
WE HAVE TO ACKNOWLEDGE IT
EXISTS, SEEK MEASURES -- SEEK
VARIABLES OF MEASUREMENT, AND
ALSO ANALYZE OUR ORGANIZATIONAL
STRUCTURE.
TO IDENTIFY POINTS OF INEQUITY
AND SEE WHERE ANY EVALUATION
PROCESS CAN BE INSTITUTED AND
REVIEW ANY POLICIES THAT NEED TO
BE CHANGED.
BUT WHILE AT HOWARD I DISCOVERED
SOMETHING ELSE AS WELL.
THE NEXT SLIDE TELLS YOU AS I
PONDERED WHAT COULD BE DONE TO
INCLUDE ON THE NEXT SLIDE, THESE
ARE THE ONES EXISTING AT THAT
TIME.
OVERALL, FEW OF THEM --
COREVITAS, PREVIOUSLY
CORONAVIRUS, HAD VERY FEW.
THE CLEAR DATABASE PRIMARILY
DEALT WITH EARLY RA AND WAS
FOCUSED OND GENETICS AND WAS
REGIONAL.
AND THE NATIONAL DATABASE HAD NO
OTHER DATA EXCEPT THOSE ENTERED
BY THE PATIENTS.
SO UNDER THE UMBRELLA OF HOWARD
AND THE NEXT SLIDE IT DEVELOPED
ANOTHER REGISTRY CALLED THE
ETHNIC MINORITY RHEUMATOID
ARTHRITIS CORE SORE SHUM.
THERE WERE EIGHT MEMBERS WHO
STEPPED UP AND THEY SAW
PRIMARILY ETHNIC MINORITY
PATIENTS.
FOUR OF THOSE CENTERS WERE
ACADEMIC, FOUR WERE IN PRIVATE
PRACTICE.
AND WE COLLECTED ONLY CLINICAL
DATA, NO SEROUS SAMPLES, AND WE
AIMED TO HAVE A MINIMUM OF TWO
OUTPATIENT VISITS A YEAR BUT AS
MANY AS POSSIBLE.
AT THE END OF THE DAY, WE HAD
ABOUT -- WITH ALMOST COMPLETE
DATASET, 1500 PATIENTS AND ENDED
UP WITH ABOUT 40% WHITES, 30%
BLACKS, 13% HISPANICS AND 10%
ASIANS, AND THIS IS ONE OF THE
FEW CORE HORTS ACTUALLY FOR
RHEUMATOID ARTHRITIS THAT HAS
SUCH A DIVERSE CLIENTELE.
THE NEXT SLIDE SHOWS SOME OF OUR
FINDINGS OVER THE YEAR, YEAR, E
WERE ABLE TO VALIDATE WHAT WAS
REPORTED BY MANY OTHERS, SUCH AS
THAT BLACKS AND HISPANICS HAVE
ESTABLISHED DISEASE, LESS
EDUCATION, BUT ALSO ENDORSE THE
FACT THAT ACROSS VARIOUS -- THAT
ALL PATIENTS WE SAW IN THE REAL
WORLD RARELY MET A RANDOMIZED
CONTROL TRIAL ENTRY CRITERIA,
LESS THAN 5%.
BUT WE WERE ALSO ABLE TO AT --
BUT LED TO MORE PROGRESSION OF
THAT DISEASE.
AND VULNERABILITY NOT ONLY
DELAYED DIAGNOSIS AND TREATMENT
BUT IT WAS ALSO ARE -- RODOLFO
PEREZ-ALAMINO WAS ABLE TO
DEMONSTRATE THERE WAS SOME --
BETWEEN TOBACCO ABUSE AND ETHNIC
MINORITY STATUS.
ALL WHAT WE CONTINUALLY DESCRIBE
ABOUT DISPARITY, WE USE THIS
INFORMATION TO ACT.
AND WE DID DO THINGS, AND THAT
WAS A WEB-BASED PROGRAM TO ALLOW
EARLIER REFERRAL, FILL IN THE
CRITERIA FOR RHEUMATOID
ARTHRITIS, THE RESULT, WE SAW
THEM WITHIN TWO WEEKS COMPARED
TO FOUR MONTHS.
THAT WAS ROUTINE.
75% OF THE PATIENTS WE SAW GOT
THEIR DMARD AT THE FIRST VISIT,
100% IN THE YEAR, AND BY 12
MONTHS, ONLY 20% OF THEM WERE ON
PREDNISONE.
SOMETHING WE'RE ALL TRYING TO
REDUCE IN OUR PRACTICE.
THE NEXT THING WE DID ON THE
NEXT CLICK WAS TO FOCUS ON
EDUCATING PATIENTS AND THE
IMPORTANCE OF TREE TO TARGET AS
YOU DO FOR DIABETES OR
HYPERTENSION.
BY USING A PATIENT NAVIGATOR, WE
EDUCATED THEM SO THEY COULD
UNDERSTAND THE NEED TO CHANGE
MEDICINE IF THIS WAS NOT
ACHIEVED.
THE RESULT?
WE HAD SIGNIFICANT IMPROVEMENT
IN DISEASE ACTIVITY.
50% CHANGED THEIR MEDICATION TO
ACHIEVE THIS.
BUT WE REALIZED ANOTHER THING,
THAT THIS PATIENT EDUCATION
INTERACTION UNDERSCORED THE
IMPORTANCE OF TRUST BETWEEN
PHYSICIAN AND PATIENT IN
ACHIEVING A GOOD OUTCOME.
THE NEXT SLIDE SHOWS OUR FINAL
MANUSCRIPT ON ALL DATA, AND WE
WANTED TO LOOK AT SOMETHING
DIFFERENT AND USING THE FOUR
ETHNIC SUBSETS.
THIS IS A MANUSCRIPT CURRENTLY
UNDER REVIEW AND WE SPOKE TO HOW
WE MAKE DECISIONS TO TREAT
PATIENTS UNDER DISEASE MEASURES.
AND WE FOUND THAT WHEN WE BUNDLE
DISEASE ACTIVITY MEASURES AND
INCLUDED A LAB VALUE, THAT MORE
PEOPLE WERE IN REMISSION.
IN CONTRAST TO WHAT IS USUALLY
USED IN THE OFFICE, THE
CONVENIENT PATIENT-REPORTED
MEASURE ALONE, AND MAYBE WE NEED
TO REVIEW THAT.
AND ALSO NO MATTER WHAT WE USED,
THE BLACK PARTICIPANTS WERE LESS
FREQUENTLY IN REMISSION ACROSS
ALL STATES, ALL MEASURES, AND
THEY ARE THE ONES ACTUALLY THAT
MET THE RANDOMIZED CONTROL TRIAL
INCLUSIONS.
SO WE SUGGESTED THAT THERE
SHOULD BE SOME STANDARDIZATION
OF R.A. MEASURES IN ETHNIC
MINORITIES BECAUSE IT'S SO
IMPORTANT TO DETERMINE THERAPY
AND ALSO TELLS US THAT THEY CAN
ACTUALLY QUALIFY FOR TRIALS.
ONE OF THE CHALLENGES IN TRYING
TO MAKE INTERVENTIONS IS TO
RECOGNIZE WHAT YOU CAN CHANGE
AND WHAT YOU CAN'T CHANGE, AND
SOME OF THESE DISPARITIES,
HOWEVER, ARE OF OUR OWN
CREATION.
AND THE NEXT SLIDE SHOWS THAT
SOMETIMES IT'S THE SYSTEM AND
THE HEALTH SYSTEM, AND HERE I
WANTED TO SEE WHETHER RACE ALONE
WAS A DETERMINANT OR ASSOCIATED
WITH UTILIZATION OF BIOLOGIC
THERAPY.
AND I CHOSE THE RELATIVELY PRY
VAT SEPRIVATE SECTOR AND VA SYS,
RELATIVELY UNGETTERS CARE
TREATMENTS, ACCESS TO CARE AT
THE TIME, WE DIDN'T HAVE A
PREFERRED BIOLOGIC FORMULARY
THEN AND WE FOLLOWED DISEASE
TREATMENT GUIDELINE.
I WAS SURPRISED TO FIND OUT WE
PARSED INDIVIDUALS ONLY BY THEIR
RACE, THERE WAS ACTUALLY NO
DIFFERENCE.
EQUAL, EITHER PREDNISONE, A
DMARD OR BIOLOGIC THERAPY.
WHEN I PUT THEM BACK INTO THEIR
SYSTEM, HOWEVER, THAT'S WHERE
THE DISPARITIES OCCURRED.
THE NEXT SLIDE SHOWS THAT THERE
WAS DIFFERENCES BETWEEN THEM,
WITHIN THEIR SYSTEMS, BUT
THROUGH THE QUESTION BEING ASKED
ABOUT UTILIZATION OF BIOLOGICS,
IT APPEARED THAT IN THE PRIVATE
SECTOR, THERE'S TWICE AS MUCH
USE IN CAUCASIANS COMPARED TO
CAUCASIANS IN THE V.A., AND
SIMILAR USE, MORE INCREASED USE
IN THE NON-CAUCASIANS BUT WAS
NOT STA T STATISTICALLY SIGNIFI.
THE CLEAR LIMITATION HERE IS
THAT WE DID NOT HAVE
SOCIOECONOMIC STATUS,
COMORBIDITIES AND THIS WAS NOT
ALGORITHMIC TREATMENT IN EITHER
GROUP.
AND WE DIDN'T CALL OUT -- BUT
WHAT IT DID SHOW HOWEVER IN A
SYSTEM THAT DIDN'T HAVE TO GO
THROUGH THE RIGORS OR BA BA BARS
OF ACCESS TO PIE LO JIX THAT
THERE WAS NOT OVER UTILIZATION
OF BIOLOGIC THERAPY.
WHICH BY THE WAY THERE WAS
EQUIVALENT DISEASE ACTIVITY
BETWEEN THESE TWO GROUPS.
SO AT THE END OF DAY I MUST SAY
I WAS SCRATCHING MY HEAD MOST OF
THE TIME TO SEE WHAT I COULD DO
TO MAKE THINGS BETTER, AND THE
NEXT SLIDE SHOWS MY CONCLUSION,
THAT IT'S REALLY COMPLICATED.
ALL OF THESE VARIOUS VARIAB
VARIABLES -- SO I WONDERED IF
THERE WERE OTHERS WHO HAD THE
SAME EXPERIENCES I WAS HAVING,
AND IN DIFFERENT AREAS OF THE
COUNTRY.
SO I SORT OF PULLED OUT, ZOOMED
OUT AND TOOK A DRONE VIEW OF
THINGS, AND THE NEXT SLIDE SHOWS
THAT -- I PULLED ON THE
ASSOCIATION OF WOMEN IN
RHEUMATOLOGY TO SEE THEIR
INTEREST, AND THE ISSUE HERE WAS
TO SEE WHETHER THE PATIENTS I
WAS SEEING, WHETHER THEY WERE
SEEING A SIMILAR PROFILE IN
MEETING THAT TASK WERE ASSIGNED
BY OUR COLLEGE AND THAT WAS
DISEASE REMISSION IN RHEUMATOID
ARTHRITIS, WHERE WE'RE ALL AT
THE SAME STARTING POINT.
HUGE REGISTRY OF 190 SITE ACROSS
THE COUNTRY, ABOUT 180,000
ENTRIES, AND WE DID THE SO
CONCENTRATION OF HIGH DISEASE
ACTIVITY, CRITICAL MORBIDITY AND
VULNERABLE PATIENTS IN THE SOUTH
PRACTICES AND MOST OF THEM ARE
COVERED ACTUALLY BY MEDICARE AND
MEDICAID, AND THEN WE UN -- ON
THE NEXT SLADE, WE FOUND THAT
VERY FEW PRACTICES TO BEGIN WITH
SAW MEDICAID PATIENTS AND THOSE
THAT DID ONLY ABOUT 20 -- TALLLY
10% OF THOSE PRACTICING SITES
CARE FOR MORE THAN 50% OF THOSE
PATIENTS.
SO IN THE NEXT SLIDE, WE CALL
THIS A MISMATCH IN CARE IN RAM
TOYED ARTHRITIS.
RHEUMATOID ARTHRITIS IN THAT
MUCH WAS BEING ASKED OF THE VERY
FEW WHO SAW THESE VULNERABLE,
COMPLICATED CO-MORBID PATIENTS.
AND IT CLEARLY NEEDS AN
EXPANSION OF MEDICAID
REIMBURSEMENT OF MEDICAID, AND
SOME BILLING MODIFICATIONS FOR
THAT INDIVIDUAL PRACTICE, THAT
PRACTITIONER, WHO SEES THOSE
COMPLICATED PATIENTS.
DOES COST SHARING HAVE ANYTHING
TO SOLVE THE PROBLEM?
AND THE NEXT SLIDE WE LOOKED AT
THE RELATIONSHIP OF THIS DISEASE
BURDEN WITH HOW MUCH THEY HAD TO
PAY EITHER AT AN OFFICE VISIT OR
TO GET THE MEDICATIONS THAT WE
PRESCRIBED.
AND ALTHOUGH ACROSS THE BOARD A
SIMPLE CO-PAY OF $10 WAS THE
ORDER OF THE DAY, IN THE SOUTH
AGAIN, WHICH HAD MORE CO-MORBID
DISEASE ON THE Y AXIS, THAT
HIGHER CATEGORIES OF CO-PAY WAS
MORE PREVALENT.
AND THEREFORE, IT IS CLEAR THAT
CHANGES HAVE TO BE MADE.
ON THE NEXT SLIDE, WE SUGGESTED
A MODIFICATION OF COST SHARING,
EVEN AT THE BARGAIN PRICE OF
$10, IN THOSE PATIENTS WHO HAVE
MULTIPLE COMORBIDITIES.
A PATIENT WHO HAS HYPERTENSION,
DIABETES, HYPERLIPIDEMIA, NOT
ONLY HAS TO SEE RHEUMATOLOGY,
HAS TO SEE EITHER A SPECIALIST
FOR THOSE DISEASES OR MULTIPLE
VISIT FOR THEIR PRIMARY CARE AND
THAT $10 BECOMES CUMULATIVE SO
WE HAVE TO THINK OF OTHER WAYS
TO KEEP ADHERENCE TO MEDICATION
AND VISITS FOR THIS VULNERABLE
POPULATION.
SO WHAT DOES THAT MEAN?
I THINK IF WE TRANSLATE THIS TO
WHAT WE'RE BEING ASKED TO DO ON
THE NEXT SLIDE, AS FOR ALL OUR
DISEASES, IS THAT IF WE HAVE
THIS TARGET WE WANT TO ACHIEVE,
IN ANYTHING, THAT THE STARTING
POINT FOR THE PEOPLE WHO WALK
INTO OUR OFFICE ARE NOT ALL THE
SAME.
SOME HAVE UNFETTERED AK SE SOME
HAVE ADMINISTRATIVE HURDLES TO
GO OVER, SOME HAVE A LOT OF
BAGGAGE TO GO AT THE START.
, AND SIMPLY SAYING ON THE NEXT
CLICK THAT THEY HAVE EQUAL
INSURANCE OR THEY HAVE LOW
CO-PAY, IT DOESN'T QUITE GET
THEM THERE.
AND WHAT WE HAVE TO SEEK IS THAT
OF EQUITY ON THE NEXT CLICK.
AND THE CMS DEFINITION OF THIS
IS THE ATTAINMENT OF THE HIGHEST
LEVEL OF HEALTH BY A FAIR AND
JUST OPPORTUNITIES REGARDLESS OF
RACE, SOCIOECONOMIC STATUS, AND
ALL THE OTHER CONFOUNDERS AND
BARRIERS THAT POPULATES OUR
LITERATURE.
BUT I MUST SAY THE THAT ON THE
NEXT SLIDE, I AM ONE VOICE, AND
AS ONE OF MY COLLEAGUES HAS
SAID, A ROOM TOLL JILS FROM A
JOURNAL, SO MANY OF OUR ISSUES
CAN ONLY BE EFFECTIVELY MANAGED,
TREATED OR CURED AT A SOCIETAL
LEVEL.
AND MY VOICE AND MY ASSOCIATIONS
AND BODIES ARE JUST A FINITE
NUMBER, AND WE HAVE TO ADVOCATE
MORE.
BUT THIS IS NOT PART OF OUR
TRAINING CURRICULUM, NONE OF THE
PROGRAMS IN RHEUMATOLOGY AT
LEAST HAVE ADVOCACY AS A PART OF
THIS.
SO I ALONG WITH THREE OF MY
FELLOWS, THE ECR GOVERNMENT
REPRESENTATIVE AT THE TIME, WE
DEVELOPED A TOOL TO SENSITIZE
FELLOWS AT THE EARLY STAGE TO
EMPHASIZE THE IMPORTANCE OF
THIS.
IT'S ABOUT EIGHT CASES, TAKES
ABOUT AN HOUR TO DO.
I INVITE ANYONE TO VISIT THIS ON
THAT WEBSITE UNDER ADVOCACY, AND
WE'VE SENT IT OUT AND HAD A GOOD
RESPONSE FROM OTHER
INSTITUTIONS.
AND WE MAKE CHANGES ACCORDING TO
THE CURRENCY OF LEGISLATION
THAT'S REQUIRES.
WE ALSO TAKE -- GEOGRAPHIC
LOCATION AND WE GO ON THE HILL
EACH SEPTEMBER AND THAT IS A
CALENDAR ITEM ON OUR TREANING
PROGRAM.
SO IT SOMETHING WE HAVE TO
EXPAND AND EMPHASIZE.
SO FINALLY, I THINK OUR TIME OR
MY TIME, THE NEXT SLIDE, IS
FINITE, AND WE'RE CHALLENGED TO
MAKE OUR ACTIONS AND
CONTRIBUTIONS ENDURING, SO WE
SO THE WORLD AROUND US I THINK
IS BECOMING MORE AND MORE CLEAR
THAT WE WHAT WE EAT, DRINK AND
BREATHE IS BECOMING MORE
IMPORTANT, AND WE NEED DATA TO
VALIDATE OUR INTUITIONS BEFORE
WE CAN ACT.
AND NEXT WE HAVE TO ADVANCE AS
WE ADVANCE, WE MUST ALWAYS AND
IN TANDEM SEEK AND REA INSPECT
THE PATIENT'S VIEW BECAUSE WE
MAY KNOW WHAT'S BEST FOR THEM
BUT THEY MAY KNOW BETTER, AND IF
WE WORK WITH THEM, WE CAN
DEVELOP EVEN BETTER BEST
PRACTICES, SO WE HAVE TO -- BOTH
STRUCTURAL AND ADMINISTRATIVE.
AND WE NEED MORE OF US ACROSS
THE BOARD.
MORE SLOTS FOR TRAINING.
MORE SENSITIZATION TO OUR
SPECIALTY AND OTHERS.
SO WE CAN MANAGE AND INVESTIGATE
ALL THAT WE WANT TO.
EVEN THOUGH MY REMARKS ARE
MOSTLY ABOUT RHEUMATOLOGY, WE
TEND TO SPEND SO MUCH TIME IN
SILOS MEAND OF THE PREVIOUS
AND MANY OF THE SPEAKERSHAVE EMO
COLLABORATE, AND WE HAVE TO JOIN
TO DO THIS AND I LOOK FORWARD TO
WHAT THE INSTITUTE HAS TO OFFER
FOR US TO DO JUST THAT.
AND MY LAST SLIDE, THANKS TO ALL
OF THOSE I'VE WORKED WITH WHO
HAVE CONTRIBUTED TREMENDOUSLY TO
ALL THIS WORK.
THANK YOU VERY MUCH.
>> THANK YOU SO MUCH, DR. KERR,
FOR THAT INCREDIBLE PRESENTA
PRESENTATION.
WHAT A WONDERFUL SUMMARY OF SO
MUCH WORK THAT'S BEEN DONE BY SO
MANY INDIVIDUALS.
AND I JUST WANT TO COMMEND YOU
FOR YOUR LEADERSHIP IN THIS
SPACE AND THE VERY THOUGHTFUL,
METHODICAL AND RIGOROUS APPROACH
YOU'VE TAKEN TO THIS WORK THAT'S
SO IMPORTANT.
YOU BROUGHT US BACK TO SOME OF
THE ISSUES THAT ARE STILL FACING
US IN MEDICINE, AND HEALTH
DISPARITIES, HEALTH EQUITY AND
THEN DIVERSITY IN OUR WORKFORCE,
DIVERSITY IN OUR RESEARCH
WORKFORCE, ALL OF THOSE ARE
CRITICAL.
I AM GOING TO ASK YOU ONE
QUESTION, AND DR. SHANMUGAM IS
ON THE SCREEN AS WELL.
I SEE DR. PINN IS THERE.
WE ARE GOOD WITH TIME, RIGHT, I
VICKI?
>> YOU'RE GOOD.
>> SO GAIL, IF YOU KNEW
EVERYTHING YOU KNOW NOW, AND YOU
WERE TALKING TO YOUR YOUNGER
SELF -- I KNOW THIS IS KIND OF A
HOKEY QUESTION, BUT IT REALLY
MAKES YOU THINK ABOUT WHAT
ADVICE WOULD YOU GIVE SOMEONE
ENTERING THE SPACE WHERE THE
CHALLENGES WE HAVE FOR MEDICINE
AND DELIVERING HIGH QUALITY CARE
TO EVERYONE ARE VAST, BUT THE
KNOWLEDGE WE HAVE TO GAIN
THROUGH RESEARCH IS STILL THE
PROMISE FOR DELIVERING THE BEST
CARE TO EVERYONE, WHAT WOULD YOU
SAY TO YOUR YOUNGER SELF
ENTERING, YOU KNOW, RHEUMATOLOGY
FELLOWSHIP, YES, YOU'RE OVER
HERE IN BUILDING 10, YOU'RE
ROUNDING WITH TONY FAUCI, AND SO
THAT'S WHERE YOU ARE, WHAT WOULD
YOU SAY TO YOUR YOUNGER SELF?
>> SO I THINK IT TAKES TIME TO
REALIZE WHAT YOU CAN DO AND
WHAT'S NEEDED.
YOU DON'T WAKE UP AND DECIDE I'M
GOING TO DO RESEARCH OR ASK A
SPECIFIC QUESTION.
AND IF ANYBODY TOLD ME THAT I
WOULD BE DOING RESEARCH AT ANY
KIND OF LEVEL, I WOULD NOT THINK
THEY WERE IN THEIR RIGHT MIND.
AND IT CAME FROM SEEING PATIENTS
PRIMARILY, SEEING THAT I KNEW
WHAT I HAD TO DO AND WHAT NEEDED
TO BE DONE BUT I COULDN'T GET IT
DONE.
AND YOU HAVE TWO CHOICES AT THAT
POINT.
YOU CAN TURN AND WALK AWAY OR
YOU CAN DO SOMETHING.
AND THAT SAYING, THAT FORK IN
THE ROAD THAT YOU AS AN
INDIVIDUAL BECAUSE OF WHO YOU
ARE WILL HAVE TO ANSWER.
I DON'T THINK THAT'S SOMETHING
THAT CAN BE NECESSARILY TAUGHT.
THEY CAN SEE YOU DO IT AND MAYBE
TAKE THAT ADVICE.
HAVING SAID THAT, TRY AND
NURTURE SOME CURIOSITY IN YOUR
TRAINEES.
YOU ASK QUESTIONS AND MOST OF
THE TIMES I DON'T KNOW THE
ANSWER BUT I'M ASKING THE
QUESTIONS.
SO WE ALL LOOK IT UP.
YOU INTERACT WITH THE PATIENT TO
LET THEM KNOW IT'S NOT JUST A
MATTER OF TAKING THOSE ITEMS IN
THE HISTORY, BUT I ALSO ASK THEM
QUESTIONS ABOUT THEIR LIFE AND
YOU GET INTO THE LIFE AND SEE
WHAT'S IMPORTANT TO THEM.
AND THEN AT SOME POINT, MAYBE
THAT WILL COME TOGETHER, AND
SOMETIMES THE MOST UNLIKELY
PEOPLE ARE THE ONES WHO DECIDE
TO STEP INTO THAT RESEARCH
ARENA.
AND MAYBE NOT CALLING IT
RESEARCH IN THE INITIAL STAGES
MIGHT BE MORE ATTRACTIVE.
JUST SAYING, I WONDER WHAT THE
ANSWER IS TO THIS.
START WITH THAT.
AND MAYBE THAT'S A WAY TO GET
THESE PEOPLE IN.
I THINK A KEY THING, THOUGH, FOR
EVERYTHING I HAVE DONE OR
ACHIEVED, IT SAYS IT HAS NOT
BEEN A SOLO EFFORT, A CRAZY
PERSON TRYING TO DO THINGS, BUT
THE INDULGENCE, THE KINDNESS OF
OTHERS AND THE COLLABORATION IS
SO IMPORTANT, OF LIKE-MINDED
PEOPLE BUT ALSO PEOPLE YOU MAY
DISA GREE WITH, BUT YOU COME
TOGETHER AND THAT'S PART OF THE
TRAINING OF LEADERSHIP, SEEING
THINGS DIFFERENTLY.
CREATING THE THE SAME STORY TO
GET THE SAME ANSWER.
SO THAT'S ALSO IMPORTANT.
SO I LIKE OTHERS ON THIS CALL
ARE LOOKING FORWARD TO WORKING
WITH THE INSTITUTE, BECAUSE I
THINK THIS IS THE FIRST OUTREACH
TO OUR COMMUNITY TO HAVE THIS AT
SUCH A HIGH LEVEL, AND I'M
HOPING -- BECAUSE NOT ALL OF US
ARE BASIC SCIENTISTS, BUT WE
WANT THE SAME THING, AND I'M
HOPING THAT WE CAN BE INCLUDED
AT SOME LEVEL, EVERYBODY'S
INTEREST, TO ACHIEVE WHAT'S BEEN
ASSIGNED TO US.
>> THANKS SO MUCH FOR THOSE
COMMENTS.
THE WAY THIS SYMPOSIUM HAS BEEN
ORGANIZED, I WANT TO GIVE
DR. SHANMUGAM A SHOUT OUT ON
THIS, IS REALLY THE WAY WE THINK
ABOUT THESE ISSUES, THAT WE NEED
TO ATTACK THEM AND ADDRESS THEM
FROM MULTIPLE ADVANTAGE TAJ
VANTAGE POINT ANDOUR POWER IS T,
COLLECTIVELY.
WE FEEL VERY PRIVILEGED TO HAVE
BEEN IDENTIFIED TO HAVE THE
OFFICE OF AUTOIMMUNE DISEASE
RESEARCH WITHIN ORWH, AND FEEL
FREE TO COMMENT HERE, THE
CHALLENGE IS VERY CLEAR FOR US
TO DO THINGS IN A COORDINATED,
CONCERTED, INTERDISCIPLINARY WAY
AT NIH.
AND ORWH HAS ALWAYS WORKED IN
PARTNERSHIP, EVERYTHING WE DO IS
IN COLLABORATION AND
PARTNERSHIP, AND SO I THINK THIS
IS A LITTLE BIT OF AN EXPERIMENT
IF YOU THINK ABOUT HOW NIH IS
SET UP, EACH TIME SOMETHING GETS
FORMED, THERE'S A NEW OFFICE, A
NEW INSTITUTE OR NEW
ORGANIZATIONAL UNIT, SO VICKI
MAYBE YOU WANT TO COMMENT ON
YOUR THOUGHTS ON -- ESPECIALLY
IN LIGHT OF GAIL'S COMMENTS
ABOUT HOW WE NEED TO BRANCH THE
LAB AND THE CLINIC AND REAL
WORLD SETTINGS, BECAUSE ALL OF
THAT NEEDS TO COME TOGETHER TO
ADDRESS THE NEEDS THAT OUR
PATIENTS HAVE.
>> I APPRECIATE THAT, BRINGING
OUT THAT POINT AND THANK YOU SO
MUCH, GAIL, FOR THAT WONDERFUL,
WONDERFUL TALK.
IT'S JUST WITH BEEN A PLEASURE O
WATCH.
AS ONE OF YOUR FORMER TRAINEES,
I AM JUST AMAZED BY EVERYTHING
YOU DO.
SO FROM THE POINT OF VIEW OF THE
OFFICE, YES, ABSOLUTELY.
EVERYTHING WE DO, WE DO IN
COLLABORATION WITH BOTH THE
INSTITUTES AND CENTERS IN NIH
AND THEN ACROSS THE COMMUNITIES
THAT WE SERVE, AND I THINK THE
BREADTH AND SCOPE OF WHAT WE'VE
BEEN ASKED TO DO COULD NOT BE
DONE ALONE AND I THINK IT'S ONE
OF THOSE UNIQUE OPPORTUNITIES TO
GO SOMEWHAT UPSTREAM OF ANY ONE
INDIVIDUAL DISEASE TO THINK
ABOUT COMMONALITIES AND
DIFFERENCES, TO THINK ABOUT WHY
DO WOMEN GET MORE AUTOIMMUNE
DISEASE BUT MEN OFTEN GET MORE
SEVERE AUTOIMMUNE DISEASE AND
TRYING TO UNDERSTAND THOSE
DISCORDANT FINDINGS, AND BEING
GIVEN AN OPPORTUNITY TO
RECOGNIZE THE BIOLOGY IS TELLING
US SOMETHING AND WE NEED TO
FIGURE OUT HOW TO HELP THE
SCIENCE TO GO IN THE RIGHT
DIRECTION, AND I THINK THAT'S
ONE OF THE GOALS OF OUR OFFICE
AND THE WORK THAT WE'RE TRYING
TO DO TOGETHER.
>> THANKS SO MUCH, VICKI.
GAIL, I WANT TO GIVE YOU THE
CHANCE TO HAVE THE LAST WORD,
AND I WILL SHARE THAT I REALLY
LIKE WHAT YOU SAID ABOUT NOT
NECESSARILY CALLING IT RESEARCH,
BECAUSE IT IS AS YOU SAID A VERY
INDIVIDUAL DECISION, AND SOME
PEOPLE ARE JUST REALLY INNATELY
CURIOUS.
THEY JUST WANT TO KNOW WHY.
AND THAT'S THE WAY THEIR BRAIN
WORKS.
BUT WE ALSO CAN ASK LOTS OF
DIFFERENT QUESTIONS THAT GET US
LOTS OF DIFFERENT -- THAT WILL
HELP US TO FORM A COMPLETE
PICTURE, AND WE NEED ALL OF
THOSE VOICES AND WE NEED ALL OF
THOSE QUESTIONS.
WOULD YOU LEAVE US WITH A
CHALLENGE, YOU KNOW, A CALL TO
ACTION FOR US?
I'M GIVING YOU A CHANCE, I DON'T
USUALLY DO THAT.
I'LL GIVE YOU THE CHANCE TO GIVE
US A CHALLENGE THIS TIME.
>> I THINK EVERYBODY ON THE CALL
TODAY AND THOSE THAT SIGNED IN,
YOU HAD A VERY GOOD TURNOUT,
THEY HAVE THROWN DOWN THE
GAUNTLET FOR THIS AND THERE'S
HIGH EXPECTATIONS HERE.
AND THE CHALLENGE TO USE IS TO
PICK THE IMPORTANT ONES AND PUT
THEM TOGETHER TO GIVE AN OUTCOME
AND BE REALISTIC ABOUT THE
TIMELINES AND TO GET PEOPLE, IF
THEY COMMIT TO KEEP THAT
COMMITMENT --
>> I THINK THAT'S GOING TO BE
HOW IT WORKS.
>> THANK YOU SO MUCH, DR. KERR,
FOR AN INCREDIBLE PRESENTATION,
A LOVELY DISCUSSION, AND I'M
GOING TO TURN IT BACK OVER TO
YOU, DR. SHANMUGAM.
>> THANK YOU.
SO IT'S MY VERY GREAT PLEASURE
NOW TO INTRODUCE DR. VIVIAN
PINN.
DR. PINN WAS THE INAUGURAL
FULL-TIME DIRECTOR OF THE OFFICE
OF RESEARCH ON WOMEN'S HEALTH
FROM 1991 UNTIL HER RETIREMENT
IN 2011.
DR. PINN WAS ALSO THE NIH'S
ASSOCIATE DIRECTOR FOR RESEARCH
ON WOMEN'S HEALTH, AND UNDER DRE
OFFICE LED THE IMPLEMENTATION OF
NIH INCLUSION POLICIES FOR WOMEN
AND GROUPS IN RESEARCH,
DEVELOPED THE FIRST IN SEVERAL
SUBSEQUENT NATIONAL STRATEGIC
PLANS FOR WOMEN'S HEALTH
RESEARCH AND ESTABLISHED MANY
NEW RESEARCH FUNDING INITIATIVES
AND CAREER DEVELOPMENT PROGRAMS.
DR. PINN AS WE MENTIONED IS AN
ACCOMPLISHED PATHOLOGIST.
SHE'S RECEIVED MORE THAN 300
AWARDS AND HONORS.
WE CAN'T INCLUDE THEM ALL BUT WE
DID INCLUDE HER BIOGRAPHY IF
YOU'D LIKE TO READ MORE ABOUT
DR. PIRN IN PINN IN THE PROGRAM
BOOKLEATHER ONLINE.
IT'S REALLY A DELIGHT, DR. PINN,
THE MICROPHONE IS YOURS.
>> THANK YOU, AND WHAT A
WONDERFUL CONFERENCE THIS HAS
BEEN TODAY.
I WAS THINKING BACK WHEN THE
OFFICE FIRST STARTED, AUTOIMMUNE
DISEASES WERE ALWAYS AT THE TOP
OF OUR LIST OF WHAT SHOULD BE
PRIORITIES FOR OUR OFFICE TO
LOOK INTO, CONSIDERING WHAT'S
IMPORTANT TOPICS FOR WOMEN'S
HEALTH RESEARCH.
SO I WAS ALWAYS THERE AND I WAS
THINKING HOW DIFFERENT IT WAS
BECAUSE I REMEMBER I WOULD START
THOSE CONFERENCES WITH, IT'S
IMPORTANT TO FUND RESEARCH TO
HELP US LEARN WHY MORE WOMEN
THAN MEN ARE AFFECTED BY
AUTOIMMUNE DISEASES.
AND TODAY WE STARTED OFF WITH A
PRESENTATION, IN FACT,
DR. CLAYTON INCLUDED IN HER
PRESENTATION SOME OF THE
RESEARCH TODAY SHOWING THE
GENETIC BASIS OF THAT DISEASE
AND WHAT ARE PROBABLY SOME OF
THE MAJOR CONTRIBUTORS TO THAT
DIFFERENCE, SEX DIFFERENCE IN
THE OCCURRENCE OF THE DISEASES.
SO WE'VE COME A LONG WAY, I
REALLY ENJOYED EVERY
PRESENTATION AND HEARING WHAT
WAS PRESENTED WITH DR. BUCKNER
REALLY GIVING A WONDERFUL
OVERVIEW AND REALLY SETTING US
UP WITH A BASIC UNDERSTANDING OF
THE GENETIC IMPLICATIONS OF
AUTOIMMUNE DISEASES.
AS WE KNOW THEM TODAY.
AND BELIEVE ME, WE'VE COME A
LONG WAY SINCE WE FIRST STARTED.
OBVIOUSLY THIS HAS BEEN
IMPORTANT TO ME PERSONALLY, AND
I RECALL WHEN THE OFFICE WAS
FIRST SET UP THERE WAS A CALL
FOR SETTING UP A SEPARATE OFFICE
OF AUTOIMMUNE DISEASES BY THE
ADVOCACY COMMUNITY.
ACD WE PROTESTED SAYING REALLY
WE WERE FOCUSING ON AUTOIMMUNE
DISEASES WITHIN OUR OFFICE
BECAUSE IT'S PRIMARILY A DISEASE
OF WOMEN AND IN THE FEW
INSTANCES WHEN IT AFFECTED MEN
MORE AS WE LOOKED AT SEX AGENDA
DIFFERENCES, THAT REALLY FELL,
WE THOUGHT, WITHIN OUR SCOPE,
OUR MISSION, SO ACTUALLY I WAS
DELIGHTED WHEN THIS NEW OFFICE
WAS ACTUALLY ESTABLISHED
WITHIN THE OFFICE OF RESEARCH ON
WOMEN'S HEALTH.
I THINK THAT'S A WONDERFUL WAY
TO WORK TOGETHER TO SHOW THE
TEAM WORK AND THE COLLABORATION,
AND VICKI, I'M SURE YOU WILL GET
THE SUPPORT OR ARE GETTING THE
SUPPORT THAT YOU NEED TO TAKE
FORWARD THE AUTOIMMUNE STRATEGIC
IDEAS FOR RESEARCH.
I HEARD SO MUCH WITH THE
INTRAMURAL RESEARCH AND EXAMPLES
OF MAJOR STUDIES WHICH ARE
SHEDDING INFORMATION WE NEED
JUST TO BETTER UNDERSTAND
AUTOIMMUNE DISEASES AND OF
COURSE I LOVE THE CONCEPT OF
TISSUE IS THE ISSUE, HOW WHEN
DR. -- AND THEN I'M GOING TO
BLANK ON HIS NAME -- GAVE SUCH A
WONDERFUL, WONDERFUL FIRESIDE
CHAT, AND OF COURSE I REALLY
RELATED TO THAT BECAUSE I DID
TRAIN UNDER CASTLEMAN, DR. CAST,
DR. CASTLEMAN DID SELECT ME FOR
AN NIH FELLOWSHIP IN -- NOW I'M
BLANKING ON THE WORD --
FELLOWSHIP IN AUTOIMMUNE, THAT'S
NOT THE WORD I WANT ANYWAY, TO
WORK IN AUTOIMMUNE DISEASE IS
WHAT I DID AS AN NIH FELLOW AT
MGH.
AND OF COURSE THAT TIME WE
DIDN'T HAVE ALL THE GENETIC WORK
THAT YOU HAVE NOW PROTESTING, SO
MOST OF THE WORK ON THE BASIS OF
BIOPSIES AND SERUM STUDIES AND
BIOPSIES, AND I MADE SO MANY
PRIMARY DIAGNOSES OF AUTOIMMUNE
DISEASES ON THE BASIS OF A
KIDNEY BIOPSY OR SKIN BIOPSY,
BUT MOST OFTEN THE KIDNEY BIOPSY
TO EITHER FIRST PROPOSE A
DISEASE OF AUTOIMMUNE ORIGIN OR
TO MAKE THE DIAGNOSIS BECAUSE OF
SOME OF THE SPECIFIC TRAITS WE
SEE IN THE KIDNEY.
SO I REALLY WAS ALWAYS ONE WHO
REALLY AGREED WITH GIVE ME A
PIECE OF TISSUE AND I'LL GIVE
YOU A DIAGNOSIS.
BUT I LOVED THE PRESENTATION OF
DR. FAJGENBAUM, PROBABLY
MISPRONOUNCED HIS NAME, AND THE
FACT THAT ALL THE WORK HE HAS
DONE AS A PATIENT WHO WAS
SUBJECTED TO OR WHO HAS BEEN
SUBJECTED TO AND SUFFERING FROM
ASPECTS OF CASTLEMAN DISEASE,
HOW HE WENT AHEAD ON HIS OWN AND
COMPLETED MULTIPLE DEGREES,
BECOMING A PHYSICIAN, AND
LEADING RESEARCH IN THIS AREA.
I KNOW DR. CASTLEMAN WOULD JUST
BE SO DELIGHTED, HE WOULD BE
SMILING AND HE WAS ONE THAT
COULD REALLY -- IF HE WAS
PLEASED, GIVE YOU A WONDERFUL
SMILE.
AND I CAN JUST SEE HIM SMILING
AT THE WORK YOU'RE DOING TO
LEARN MORE ABOUT THIS DISEASE
THAT WAS NAMED FOR HIM, BECAUSE
VERY LITTLE WAS KNOWN OTHER THAN
THE DIAGNOSIS WHEN IT FIRST WAS
YOU BE GIVEGIVEN HIS NAME.
I LOVE THE CONCEPT OF SYNERGY IN
SCIENCE, THAT'S SOMETHING THE
OFFICE HAS REALLY BROUGHT
FORWARD OVER THE YEARS AND THAT
WAS REALLY THE INTENT WE TALKED
ABOUT, TEAM WORK, THAT WAS
REALLY THE INTENT OF THE
INTERDISCIPLINARY PROGRAMS, THE
BIRCH PROGRAM AND THE SCORE
PROGRAM AND THE OTHERS, TO SHOW
THE SYNERGY OF GETTING RESULTS
WHEN YOU BRING THE WISDOM FROM
DIFFERENT AREAS WORKING
TOGETHER, AND I WAS DELIGHTED TO
HEAR OVER AND OVER TODAY THE
CONCEPT OF THE NEED FOR
COLLABORATION AND WORKING
TOGETHER.
AND OF COURSE DR. KERR, YOUR
COMMENTS, ALL THAT YOU DID, IT
WOULD TAKE AN HOUR TO SORT OF
SUMMARIZE, THERE'S SO MANY
THINGS THAT YOU HAVE DONE AND
HAVE ACCOMPLISHED, BUT I LOVE
THE FACT THAT YOU'VE WORKED ON
NOT ONLY THE DISEASE AND
CLINICAL APPLICATION OF WHAT WE
KNOW TO AUTOIMMUNE DISEASES, BUT
ALSO LOOKING AT HOW TO GENERATE
AND VALIDATE COLLABORATIVE
RESEARCH AND THEN DEALING ALSO,
SO YOU DEALT WITH THE CLINICAL
ASPECT, THE RESEARCH -- AND MORE
WITH THE IDEA OF DIVERSITY IN
THE WORKFORCE AND YOU HAVE PUT
FORTH SOME WONDERFUL IDEAS THAT
YOU'VE HELPED TO DEVELOP OR ARE
WORKING WITH, THE DIVERSITY THAT
WE SO NEED.
I HAVE TO ADD ONE MORE THING.
YOU MENTIONED THE KENNETH AUSTIN
SYMPOSIUM, AND I'M NOT SURE
EVERYONE KNOWS, BUT WHEN I WAS
AT HOWARD, THE RHEUMATOLOGIST
THAT I WORKED WITH WAS
DR. KENNETH AUSTIN, WHO WAS A
FABULOUS IMMUNOLOGIST, AND OF
COURSE AGAIN AS YOU POINTED OUT,
DR. KER, HE WAS THE ONLY
RHEUMATOLOGIST THERE, BUT HE
HAPPENS TO BE DR. JANINE AUSTIN
CLAYTON'S FATHER, SO SHE
CERTAINLY HAS BEEN BROUGHT UP IN
A WORLD THAT ACKNOWLEDGES AND
THAT VALUES THE AREA OF
RHEUMATOLOGY BECAUSE SHE WAS
BROUGHT UP THAT WAY.
NOW OTHER THAN MY OLD AGE SAYING
I'VE FORGOTTEN WHAT IT WAS I
TRAINED AS IN PATHOLOGY, LET ME
JUST SAY THAT THIS WAS A
WONDERFUL OCCASION.
I HAVE TO THANK BOTH OF YOU,
VICKI AND JANINE, FOR CARRYING
MY NAME FORWARD.
I SO APPRECIATE THAT.
I ENJOYED MY YEARS IN ORWH, AND
I'M DELIGHTED WITH HOW YOU'RE
TAKING FORWARD AND IMPROVING ON
WHAT WE DID DURING THE TIME I
WAS THERE, AND SEEING SO MANY
NEW PROGRAMS, SO MANY NEW IDEAS,
AND SO MANY NEW RESEARCH
PROJECTS COMING OUT.
SO WITH THAT, I THINK I'VE
TALKED A LOT.
I WANT TO THANK YOU FOR
INCLUDING ME FOR HONORING ME,
AND I WANT TO CONGRATULATE ALL
OF YOU WHO SPOKE TODAY.
WHAT SUPERB PRESENTATIONS.
JANINE, YOU REALLY PICKED A GOOD
CREW AND A GOOD PROGRAM, AND I'M
GOING TO SAY THANK YOU, AND
THANK YOU FOR INCLUDING ME IN
ALL OF THIS.
AND I LEARNED A LOT.
I TOOK NOTES, AND I'M RETIRED
BUT I'M TAKING NOTES FROM WHAT I
HEARD TODAY.
IT WAS JUST WONDERFUL.
THANK YOU.
>> THANK YOU SO MUCH, DR. PINN.
I'M GOING TO TURN TO YOU IN ONE
SECOND, VICKI.
IMMUNOPATHOLOGY, I MEAN, AND
YOUR WORK IN THE RENAL PATHOLOGY
SPACE, IMMUNOLOGY WAS SOMETHING
THAT YOU WORKED ON FROM THE
BEGINNING, AND IN FACT, IT WAS
ACTUALLY THE FIRST COLLEGE
COURSE THAT I TOOK, BECAUSE IT'S
JUST MY FIRST LOVE, FROM A
SCIENCE PERSPECTIVE.
SO JUST WANTED TO PERSONALLY SAY
THANK YOU FOR TAKING YOUR TIME.
YOU DID AN INCREDIBLE WRAP-UP,
AND OVER TO YOU, VICKI, TO CLOSE
US OUT.
>> WONDERFUL.
SO THANK YOU BOTH, AND ON BEHALF
OF THE OFFICE OF RESEARCH ON
WOMEN'S HEALTH AND THE OFFICE OF
AUTOIMMUNE DISEASE RESEARCH,
THANK YOU TO ALL OF OUR
EXCELLENT PRESENTERS TODAY.
WE DEEPLY APPRECIATE YOUR TIME,
YOUR COMMITMENT, YOUR EXPERTISE,
AND YOUR ENERGY ON THE IMPORTANT
TOPIC OF AUTOIMMUNE DISEASE
RESEARCH.
I WANT TO ALSO TAKE A MOMENT TO
SAY A SPECIAL THANK YOU TO ALL
OF THE ORWH AND NIH STAFF WHO
SUPPORTED THIS EVENT.
MANY OF WHOM PROVIDED TECHNICAL
ASSISTANCE AND ALL OF THE
ASSISTANCE GETTING THE
ORGANIZATION OF THIS EVENT
TOGETHER.
THERE WILL BE SOME POST EVENT
MATERIALS INCLUDING THE
RECORDING AND A SUMMARY UP ON
OUR WEBSITE SOON.
AND AGAIN, THANK YOU ALL FOR
ATTENDING, WITH THESE CLOSING
REMARKS, THIS YEAR'S -- IS NOW
ADJOURNED, THANK YOU AGAIN FOR
JOINING US.