Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov THE SPEAKER TODAY IS DR. HANNAH H. VALANTINE AT STANFORD UNIVERSITY IN PALO ALTO, CALIFORNIA. SHE EARNED HER DEGREE FROM LONDON UNIVERSITY IN THE UNITED KINGDOM. SHE COMPLETED POST GRADUATE TRAINING IN HONG KONG BEFORE MOVING TO THE UNITED STATES FOR POST-DOCTORAL FELLOWSHIP TRAINING AND CARDIOLOGY AT STANFORD. SHE ROSE TO FULL PROFESSOR OF MEDICINE IN 2000 AND BECOMING THE FIRST SENIOR ASSOCIATE DEAN FOR THE PROGRAM IN STANFORD IN 2004. AFTER A DISTINGUISHED CAREER AT STANFORD AS A NATIONAL AND INTERNATIONAL LEADER IN THE FIELD OF CARDIAC TRANSPLANTATION, DR. VALANTINE CAME TO NIH IN THE SPRING OF 2014 AS THE FIRST CHIEF OFFICER FOR SCIENTIFIC WORKFORCE DIVERSITY. SHE ALSO WAS APPOINTED AS SENIOR INVESTIGATOR IN THE LABORATORY OF TRANSPLANTATION GENOMICS IN THE INTRAMURAL RESEARCH PROGRAM OF THE NATIONAL HEART, LUNG AND BLOOD INSTITUTE. DR. VALANTINE'S NATIONALLY RECOGNIZED FOR HER TRANSFORMATIVE APPROACHES TO DIVERSITY AND LED NIH'S EFFORTS TO PROMOTE DIVERSITY THROUGH INNOVATION AMONG THE BIOMEDICAL WORKFORCE EMPLOYING A RANGE OF EVIDENCE-BASED APPROACHES. DURING HER SIX YEARS AT THE NIH SHE ESTABLISHED THE DISTINGUISHED SCHOLARS PROGRAM A MODEL FOR ENHANCING DIVERSITY AND INCLUSION OF PRINCIPAL INVESTIGATORS IN THE NIH INTRAMURAL PROGRAM AND NIH EQUITY COMMITTEE WHICH WAS THE RESULT OF THE NIH GENDER AND EQUALITY ACTION TASK FORCE. HER LEADERSHIP HAS A SIGNIFICANT INCREASE IN REPRESENTATION OF WOMEN AS TENURE TRACK AND AFRICAN AMERICAN AND BLACK AND HISPANIC PRINCIPLE INVESTIGATORS IN THE INTRAMURAL PROGRAM. SHE ALSO PLAYED A MAJOR ROLE IN ADDRESSING WORKPLACE HARASSMENT AT THE NIH AND DEVELOPING STRATEGIES TO IMPROVE WORKPLACE DYNAMICS. DR. VALANTINE'S RESEARCH PROGRAM AT THE NATIONAL HEART, LUNG AND BLOOD INSTITUTE WAS HIGHLY PRODUCTIVE. SHE CREATED THE GENOMIC RESEARCH ALAYNCE FOR TRANSPLANT -- ALLIANCE FOR TRANSPLANTATION. A CONSORTIUM OF FIVE HEART AND LUNG TRANSPLANT PROGRAMS IN THE WASHINGTON, D.C. METROPOLITAN AREA AND ACTIVELY FOLLOWING MORE THAN 500 PATIENTS. 40% OF WHOM ARE AFRICAN AMERICAN. WITHIN THE COHORT SHE STUDIED DONOR- DONOR-DERIVED CELLS IN BLOOD TO ELUCIDATE THE MECHANISMS OF REJECTION AND EXPLAIN HOW AND WHY BLACK RECIPIENTS REJECT ORGAN TRANSPLANTS AT A HIGHER RATE THAN WHITE RECIPIENTS. SHE HAS AUTHORED MORE THAN 160 PRIMARY RESEARCH ARTICLES AND REVIEWS AND SERVED ON THE EDITORIAL BOARDS OF THE JOURNALS GRAFT AND ETHNICITY AND DISEASE. SHE IS A RECIPIENT OF THE NIH DIRECTOR'S PATH FINDER AWARD FOR DIVERSITY IN THE SCIENTIFIC WORKFORCE AND WAS ELECTED TO THE NATIONAL ACADEMY OF MEDICINE IN 2020 FOR HER NATIONAL LEADERSHIP IN BOTH SCIENTIFIC WORKFORCE DIVERSITY AND CARDIAC TRANSPLANTATION RESEARCH. UPON HER RETIREMENT FROM THE NIH IN 2020, DR. FRANCIS COLLINS RECOGNIZED DR. VALANTINE'S ACCOMPLISHMENTS OF PROMOTING INCLUSIVENESS AND EQUITY AND HER FOCUS ON EXPANDING RECRUITMENT AND RETENTION OF THE BRIGHTEST MINDS REGARDLESS OF RACE, ETHNICITY, GENDER, DISABILITY AND SOCIO ECONOMIC STATUS OVER A FEW SHORT YEARS. DR. VALANTINE WILL SPEAK TODAY ON INCLUSIVE EXCELLENCE IN BIOMEDICAL RESEARCH, APPLYING GENOMICS TO UNRAVEL HEALTH DISPARITIES IN ORGAN TRANSPLANTATION AND WE'RE PLEASED TO WELCOME HER BACK TO THE CLINICAL CENTER. HANNAH. >> THANK YOU, SO VERY MUCH, FOR THAT WONDERFUL INTRODUCTION. I FEEL SO HONORED TO HAVE BEEN A MEMBER OF THIS WONDERFUL COMMUNITY OF SCIENTISTS HERE AT THE NIH AND I'M HALLE TO BE PRESENTING TODAY AT THE CLINICAL CENTER GRAND ROUNDS. I'LL BE TALKING TODAY ABOUT THE APPLICATION OF GENOMICS TO UNRAVEL HEALTH DISPARITIES IN ORGAN TRANSPLANTATION WHICH IS KEY IN THE BIOMEDICAL RESEARCH ACROSS THE BOARD. AT THE AGE OF 13 MY PARENTS MOVED TO LONDON WHERE I FIRST ENCOUNTERED WHAT FELT LIKE TO BE THE ONLY ONE BECAUSE I FOUND MYSELF IN A HIGH SCHOOL OF 500 STUDENTS AND THE ONLY OF COLOR AND A HAD A SENSE OF NOT BELONGING AND FRANKLY MY ACADEMIC STRUGGLE TO THE EXTENT AT THE AGE OF 18 AT THE END OF HIGH SCHOOL, I HAD ZERO ASPIRATION TO GO TO UNDERSTAND. I WORKED IN THE MICROBIOLOGY LAB AND WAS SET BACK ON MY TRAJECTORY TOWARDS THE ACADEMIC CAREER HE HAS DESCRIBED. AND THIS WAS MY FIRST ENCOUNTER WITH BEING EXCLUDED AND I PUT DOWN THAT LAPSE IN MY CAREER PATH TO THIS EXPERIENCE OF NOT BELONGING. AT LEAST THAT'S MY STORY AND I'M STICKING TO IT. THERE IS THE '60s WITH THE ROLLING STONES AND BEATLES AND THAT WAS AT THE FOREFRONT AS WELL AND I COMPLETED MY TRAINING IN LONDON AND THEN IN '85 MOVED TO THE UNITED STATES AT STANFORD BECAUSE I WAS FASCINATED BY THIS IDEA OF HEART TRANSPLANTATION WHICH WAS JUST COMING INTO ITS OWN. THE IDEA YOU CAN PUT AN ORGAN TRANSPLANT AND TAKE AN ORGAN FROM A DECEASED PERSON AND PUT IT INTO A LIVING PERSON AND IT WORKS QUITE FRANKLY I'M STILL IN AWE OF THE IDEA. MY CAREER DEVELOPED AND AS YOU HEARD DR. COLLINS RECRUITED ME TO COME TO THE NIH TO DO TWO THINGS. ONE IS TO BECOME THE CHIEF OFFICER OF SCIENTIFIC WORKFORCE DIVERSITY AND ALSO AN INVESTIGATOR IN THE NHLBI. WHAT I'LL TALK A LITTLE BIT ABOUT IS BRIEFLY MAKE THE CASE OF WHY WE NEED THIS DIVERSITY IN THE SCIENTIFIC WORKFORCE ON THE BASIS OF THE NEED OF EXCELLENCE IN RESEARCH, PATIENT CARE, INCLUSION AND CLINICAL RESEARCH. ALL OF WHICH SUPPORT THE NIH MISSION. I WILL TALK THEN A LOT ABOUT TO THE WORK THAT I DID WITHIN THE NHLBI WITH A TREMENDOUS OPPORTUNITY OF USING GENOMICS TO UNDERSTAND ORGAN TRANSPLANT REJECTION AND WRAP UP WITH SOME OF THE KEY AREAS I BELIEVE HAVE BEEN -- ARE GOING TO BE PIVOTAL TO ACHIEVE WORKFORCE DIVERSITY ACROSS NIH SPONSORED UNIVERSITIES. I MENTIONED HERE THAT WE NEED SCIENTIFIC WORKFORCE DIVERSITY IN BOTH THE SCIENTIFIC AND MEDICAL WORKFORCE FOR A NUMBER OF REASONS LISTED HERE. WE KNOW UNDER REPRESENTED GROUPS IN MEDICINE, AFRICAN AMERICAN, HISPANIC, ASIAN PACIFIC, NATIVE HAWAIIAN ARE AT LEAST TWO TIMES MORE LIKELY TO WORK IN UNDER SERVED COMMUNITIES REGARDLESS OF THE SPECIALTIES. WE ALSO KNOW THE PATIENTS FROM THESE UNDER REPRESENTED GROUPS ARE MORE LIKELY TO ADHERE TO ALL OF THE RECOMMENDATIONS FROM PHYSICIANS WHEN IT COMES TO KEEPING GOOD HEALTH AND MORE LIKELY TO ADHERE WHEN THE PHYSICIANS ARE FROM SIMILAR RACIAL BACKGROUNDS. WE ALSO KNOW PHYSICIAN SCIENTISTS FROM UNDER REPRESENTED RACIAL GROUPS ARE MORE LIKELY TO BE FOCUSSED ON RESEARCH TOPICS THAT ARE RELATIVE TO THEIR COMMUNITIES AND DISPROPORTIONATELY AFFECT THEIR COMMUNITIES. MY WHOLE TALK TODAY IS BASED ON OBSERVATIONS I PERCEIVED A LONG TIME AGO, 30 YEARS AGO WHEN I WENT INTO CARDIAC TRANSPLANTATION OF THIS DER -- D DERETERIOUS AFFECTS THAT THEY DON'T DO AS AS WELL AND WE KNOW THE CLINICAL RESEARCH INCLUDING CLINICAL TRIALS WHEN THEY HAVE INVESTIGATORS WHO ARE FROM UNDER REPRESENTED GROUPS AND WHEN THEY INCLUDE PATIENTS FROM UNDER REPRESENTED GROUPS, THE QUALITY AND ELIMINATING THE RACIAL DISPARITIES IN A RANGE OF HEALTH ISSUES INCLUDING THAT OF ORGAN TRANSPLANTATION. I'LL START BY A CASE THAT'S STUCK WITH ME THROUGHOUT MY CAREER. THIS IS A PATIENT DIAGNOSED WITH IDIOPATHIC CARDIOMYOPATHY AT A YOUNG AGE OF 20. SHE HAD A TRANSPLANT AND THEN HAD A DAUGHTER AND WE WERE ALL EXTREMELY WORRIED ABOUT HER GETTING PREGNANT BUT SUFFICE TO SAY SHE DID EXTREMELY WELL AND UNFORTUNATELY AFTER A WHILE SHE DEVELOPED THE CHRONIC REJECTION WHICH STEMS FROM REPEATED ACUTE REJECTION EPISODES AND WE WERE ABLE TO OFFER HER A SECOND CHANCE OF LIFE THROUGH RETRANSPLANT. I'M SHOW YOU SOME IMAGES OF HER HEART IN THE ECHO CARD YOG -- CARDIOGRAPHY AND YOU CAN SEE BEFORE PREGNANCY THIS IS THE ECHO CARDIOGRAPHY OF HER HEART WORKING EXTREMELY WELL BUT UNFORTUNATELY AFTER SHE HAS HER CHILD WE SEE A DETERIORATION IN HER CARDIAC FUNCTION. YOU CAN SEE HOW THIS HEART IS NOT REALLY AS WELL AS FUNCTIONING AS THE IMAGE ON THE LEFT-HAND SIDE. ON TOP OF THAT, WHEN WE DID THE CORONARY ANGIOGRAM THE INJECTION OF CONTRAST IN THE LEFT CORONARY ARTERY YOU CAN SEE IT OUTLINING THE LEFT AN TEAR YO DESCENDING ARTERY AND ITS BRANCHES. YOU CAN SEE THIS APPEARANCE WHERE THERE IS DIFFUSE NARROWING OF THE CORONARY ARTERIES AND WHY THE HEART IS NOT FUNCTIONING VERY WELL. TO GIVE YOU A PICTURE OF WHAT THIS LOOKS LIKE HISTOLOGICALLY THIS IS A SECTION ACROSS THE CORONARY ARTERY WITH A CHRONIC WE -- REJECTION AND THERE'S THICKENING OF THE INTERNAL LINING OF THE HEART WITH THE TINIEST BIT OF LUMEN THROUGH WHICH THE BLOOD IS FLOWING AND THE INTENSE INFLAMMATION AROUND IT. SIMILARLY ON THE LEFT-HAND SIDE THERE'S A LUNG SECTION OF A PERSON WHO HAS BEEN SUFFERING FROM WHAT IS OBLITERATIVE BRONCH BRONCHIOLI BRONCHIOLITIS AND THIS PATIENT IS CLEARLY NOT DOING WELL. AND MAY BE DRIVEN BY ANTIBODY MEDIATED REJECTION. LET ME SHOW YOU OUTCOMES. OVERALL PATIENTS DO EXTREMELY WELL I WOULD SAY IN TERMS OF THEIR SURVIVAL RATES. WHAT YOU CAN SEE HERE ON THE LEFT-HAND SIDE IS THE SURVIVAL RATE OF A HEART TRANSPLANTATION ON THE VERTICAL AXIS AND YEARS ON THE HORIZONTAL AXIS. ESSENTIALLY WHAT YOU ARE SEEING IS THAT FOR THE MEDIAN SURVIVAL FOR ADULTS IS 10.8 YEARS AND FOR PEDIATRICS A LITTLE BIT BETTER. THIS CONTRASTS REMARKABLY TO THE LUNG TRANSPLANTS SURVIVING LESS WITH AN AVERAGE MEDIAN OF ABOUT SIX YEARS. SO THE NEED TO RAPIDLY DIAGNOSE REJECTION AND TREATED AND PREVENTED IS IMPORTANT BOTH FOR HEART AND LOUNGE TRANSPLANT AND MORE FOR LUNG TRANSPLANT. THESE ARE SOME OF THE REASONS WHY WE LOSE PATIENTS UNFORTUNATELY AFTER A YEAR. GRAFT FAILURE AND COMPLICATIONS OF THE IMMUNOSUPPRESSIVE DRUGS WE PRESCRIBE THEM ONE OF WHICH IS THE MALIGNANCY. SO THAT'S WHAT WE ARE FACED WITH AND CONTINUALLY ASK HOW CAN WE DO BETTER. THIS IS A STUDY WE BROUGHT INTO BAD GENE EXPRESSION PROFILING AND DEMONSTRATED IN TO THE STUDY NOT ONLY COULD WE RECOGNIZE AND TREAT REJECTION EARLIER BUT COULD DIM UP -- DIMINISH THE HEART BIOPSIES IN THESE PATIENTS AND WHAT STUCK WITH ME IS WHETHER OR NOT IN A COHORT OF PATIENTS EXTREMELY WELL CARED FOR WHETHER WE'D SEE THE DIFFERENCES IN THE OUTCOMES VIS A VIS THE RACE OF THE RECIPIENT. UNFORTUNATELY, THE ANSWER IS YES. EVEN IN THE WELL CARED FOR PATIENTS WE SAW A DIFFERENCE AND I'M SHOWING THE COMPOSITE END POINT OF AS THE PERCENTAGE ON THE VERTICAL AXIS WITH DAY SINCE RANDOMIZATION ON THE LEFT. YOU CAN SEE THE SURVIVAL IN BLEW FOR WHITE PATIENTS WAS MARKEDLY SUPERIOR FOR THE SURVIVAL OF AFRICAN AMERICANS OF PATIENTS OF COLOR INDICATES THAT YES, THERE IS SOMETHING THAT IS HAPPENING HERE THAT NEEDS FURTHER INVESTIGATION. BY THE WAY, THE PATENT OF A POORER OUTCOME FOR AFRICAN AMERICAN PATIENTS IS PRESENT IN ALL ORGAN TRANSPLANT BE IT KIDNEY, LIVER AND THE REST OF IT. WE'VE ASKED THE QUESTION WHAT IS THE ROLE OF GENETIC DISTANCE BETWEEN DONOR AND RECIPIENT AND DOES THAT CONTRIBUTE AND IS THIS IN SOME WAY RELATED TO MITOCHONDRIAL DNA MISMATCH? WE HAVE COLLEAGUES AT UCSF WHO HAVE ELEGANTLY DEMONSTRATED IF YOU TRANSPLANT MISMATCHED MITOCHONDRIA IN THE SETTING OF CELL TRANSPLANTS THE CELLS ARE REJECTED EVEN THOUGH THE GENETICS OF THE NUCLEAR DNA ARE IDENTICAL SO THERE'S SOMETHING ABOUT MITOCHONDRIAL DNA THAT MAKES THE REJECTION MORE LIKELY AND HOLD THE THOUGHT BECAUSE WE'LL GET TO THAT LATER ON. ANOTHER QUESTION THAT IS KEY IS ANY OF THIS PARTIALLY RELATED TO THE SOCIAL DETERMINATES OF HEALTH. AND I WANT TO STEP BACK AND TELL YOU ABOUT THE TECHNOLOGY THAT HAS BEEN ALLOWING US TO CONDUCT THESE STUDIES IN THE LAB. ABOUT 10 YEARS AGO A PREEMINENT SCIENTIST, GENETICISTS AND BIOPHYSICISTS JOINED STANFORD UNIVERSITY AND BEGAN TO DO WORK ON A NEW GENERATION SEQUENCING TECHNOLOGY FOR DIAGNOSIS OF A RANGE OF DISEASES INCLUDING PRE PRE -- PRENATAL DIAGNOSIS AND WHEN I SAW HIS WORK I ASKED ABOUT THE ORGAN TRANSPLANT AND ME SAID IT'S ESSENTIALLY A GENOME TRANSPLANT AND WOULD BE VERY MUCH INCLINED TO BELIEVE THIS TECHNOLOGY WOULD WORK. AND THE CELL DNA IS CIRCULATING IN THE SERUM IN THE PLASMA AND URINE AND SMALL FRAGMENTS AND HAS A SHORT LIFE, HALF LIFE, AND THEREFORE AMENABLE TO BE A BIOMARKER. TO CALL A LONG STORY SHORT OF THE WORK I DID WITH STEVE BEFORE COMING TO NIH WE WERE ABLE TO DO THE PROOF OF CONCEPT EXPERIMENTS AND PUBLISH A RANGE OF ARTICLES INDICATING THAT INDEED THE DONOR DERIVED CELL DNA WAS A MARKER OF GRAFT INJURY AND THEREFORE REJECTION. SOMEWHERE ALONG THE LINE WE IDENTIFIED THE FACT YOU COULD THROUGH SEQUENCING TECHNOLOGIES ACTUALLY PICK UP FRAGMENTS OF NON HUMAN GENOME CIRCULATING IN THE PLASMA AND THAT WOULD HELP US TO MAKE DIAGNOSIS OF INFECTION WHICH IS A HUGE CHALLENGE IN THE PATIENT POPULATION. SO A LITTLE BIT ABOUT THE TECHNOLOGY. YOU TAKE A SAMPLE OF PLASMA, EXTRACT THE DNA AND ON THE YOU PREPARE THE SAMPLE AND SEQUENCE THEM AND YOU CON SEE HERE THE AREAS WHERE THERE IS A DIFFERENCE IN THE BASE PAIRS BETWEEN THE DONOR AND RECIPIENTS AND THROUGH SHOTGUN SEQUENCES, YOU ARE ABLE TO ACTUALLY CALCULATE THE PERCENTAGE DONOR-DERIVED DNA AND FOLLOW A PATIENT THROUGH THE TIME THROUGH THEIR COURSE AND AT SOME POINT WHEN THEY DEVELOP REJECTION, YOU SEE AN ELEVATION OF THE DONOR DERIVED CELL-FREE DNA. THAT'S THE CORNERSTONE OF THE WORK I DID IN THE LABORATORY HERE AT NHLBI THE LABORATORY OF TRANSPLANTATION GENOMICS. AND WE HAD THREE DISTINCT PROJECTS GOING ON. ONE WAS TO CONFIRM THE VALIDITY OF THE CELL FREE DNA AS A BIOMARKER OF REJECTION AND SECONDLY TO SEE WHETHER OR NOT IT WAS PREDICTIVE NOT ONLY OF ACUTE REJECTION BUT CHRONIC REJECTION AND THEN VERY IMPORTANTLY THE THIRD PROJECT WHICH IS ONGOING TO DETERMINE WHETHER OR NOT IT COULD BE USED TO IDENTIFY THE RISK MARKER FOR OUTCOMES IN CERTAIN HIGH RISK POPULATIONS PARTICULARLY BLACK AMERICANS. AND VERY PIVOTAL TO THIS WORK IS A COLLEAGUE OF MINE AND NOW WHO HAS HIS OWN LAB DR. SEAN AGBOUGH AND TOOK THE TECHNOLOGY DEVELOPED AT STANFORD AND REFINED IT IN A WAY WHERE WE'RE ABLE TO GET THE CELL FREE DNA FROM A RANGE OF DIFFERENT CELL TYPES, CONSTRUCT LIBRARIES, DO THE SEQUENCING AND THROUGH INTUITIVE COMPUTING BE ABLE TO DO THIS VERY REPRODUCIBLE CALCULATION TO GIVE THE PERCENT DONOR DERIVED DNA. HE WAS ALSO ABLE TO SHOW IT IS HIGHLY REPRODUCIBLE ACROSS MULTIPLE PLATFORMS, MULTIPLE OPERATORS AND DIFFERENT COHORTS. VERY IMPORTANT GIVEN THE FOCUS OF THE NIH ON REPRODUCABILITY. WE WERE SOMEWHAT -- RE-PRODUCABILITY AND WE WERE CHALLENGED BECAUSE THERE'S NOT ORGAN TRANSPLANTATION GOING ON WITHIN THE NIH INTRAMURAL PROGRAM AND WE LOVE ACRONYMS AND HAD AN APPROPRIATE ACRONYM CALLED GRAFT AND IT IS A COLLABORATION BETWEEN FIVE LOCAL HEART AND LUNG TRANSPLANT CENTERS HERE'S ALONG WITH ORGAN PROCUREMENT CENTERS AROUND AND WE WERE ABLE TO USE THIS WITH A TREASURE TROVE OF INFORMATION TO CONFIRM REPRODUCABILITY AND RELIABILITY AND THE ABILITY TO PREDICT LONG-TERM OUTCOMES. HERE'S JUST A SUMMARY OF WHAT WE'VE BEEN ABLE TO DO. WE'VE DONE THE TECHNOLOGY CONFIRMATIONS AND BY THE WAY WE'RE ABLE TO DO DNA METHYLATION PROFILING TO TELL US THE TISSUE OF ORIGIN. WE HAVE NOW ENROLLED OVER 500 PATIENTS. THIS IS AN OLDER SLIDE HERE. THE DIVERSITY PATIENT COHORT IS HIGHER THAN ANY ORGAN TRANSPLANT COHORT ENRICHED FOR WOMEN AND AFRICAN AMERICAN PATIENTS. EVERY TIME WE SEE THEM WE OBTAIN BLOOD SAMPLES TO STORE IN THE BIO REPOSITORIES THAT INCLUDE PLASMA AND PMCs, WHOLE BLOOD AT MULTIPLE TIME INTERVALS AS WELL AS THE CLINICAL DATA. I'LL SKIP FORWARD TO A RECENT PUBLICATION THAT WE DID ANALYZING THE DATA FOR THE HEART TRANSPLANT COHORT WITHIN THIS STUDY. AND THE SCHEMATIC ON THE RIGHT SHOWS HOW WE GOT TO THE NUMBER OF PATIENTS THAT WERE INCLUDED IN THE STUDY. AND THIS WAS PUBLISHED IN A FAIRLY HIGH-LEVEL JOURNAL CIRCULATION AND THERE'S BEEN A FURRY OF INTEREST -- FURY OF INTEREST, FLOODING OF INTEREST IN THE WORK FROM DIFFERENT FIELDS NOW INDICATING THE TEST IS SENSITIVE AND SPECIFIC AND THAT THERE ARE SPECIFICS AROUND THE CHARACTERISTICS OF THE DONOR-DERIVED CELL FREE DNA MAKING IT LIKELY TO BE ABLE TO USE FOR DISTINGUISHING CELLULAR REJECTION FROM ANTIBODY MEDIATED REJECTION. LET ME TAKE A MOMENT TO SHOW YOU THE DATA. THIS IS LOOKING AT THE CELL-FREE DNA WITH RESPECT TO CARDIAC FUNCTION WHICH WE MEASURED BY EJECTION FRACTION USING THE ECHO CARDIOGRAM I SHOWED YOU ON MY PATIENT EARLIER. WHAT YOU CAN SEE ALONG THE VERTICAL AXIS IS THE PERCENTAGE DONOR-DERIVED DNA AND ON THE HORIZONTAL AXIS THE DECLINE IN LEFT VENTRICULAR REJECTION GREATER THAN 10%. AS YOU CAN SEE AS THE DECLINE IN FUNCTION INCREASES, SO DOES THE DONOR-DERIVED CELL-FREE DNA. HERE IS THE SUMMARY DATA CELL-FR CELL-FREE DNA CELL-FREE DNA WE GET MORE SEVERE REJECTION AND GET MORE PERCENTAGE DONOR DERIVED DNA SHOWING UP IN THE IN THE ASSAY INCLUDING ANTIBODY MEDIATED REJECTION. THE QUESTION AROSE, CAN WE THROUGH THE AMOUNT OF DNA SAY THIS IS MORE LIKELY TO BE CELLULAR REJECTION OR ANTIBODY MEDIATED REJECTION? YOU MAY ASK WHERE WE'RE INTERESTED YOU MAY ASK AND THE QUESTION ABOUT CELL-FREE DNA AND ANTIBODY VERSUS CELLULAR REJECTION IS YES, WE CAN DETECT IT. HERE'S THE DATA FROM HEART TRANSPLANT PATIENTS AND YOU CAN SEE PERCENT OF CELL-FREE DNA IN ANTIBODY MEDIATED REJECTION SHOWN IN ORANGE COMPARED TO CELLULAR REJECTION AND STATISTICALLY SIGNIFICANT AND DIFFERENT AND SAME FOR LUNG TRANSPLANT REJECTION. NOTICE THE DIFFERENCE IN THE SCALE OF THE VERTICAL AXIS BETWEEN LUNG TRANSPLANT DATA AND HEART TRANSPLANT DATA AND THE REASON IS THE SIGNAL IS SO MUCH GREATER IN THE LUNG TRANSPLANT PROBABLY BECAUSE IT'S A GREATER MASS OF TISSUE. NEVERTHELESS THE MESSAGE IS SIMILAR WITH ANTIBODY MEDIATED REJECTION HIGHER LEVELS THAN THE DONOR DERIVED CELL-FREE DNA AND REJECTION. HERE'S THE RECEIVER OPERATOR CHARACTERISTICS WE PLOT THE SENSITIVITY AGAINST 100% MINUS THE SENSITIVITY WHICH GIVES US THE OPERATING CURVE. AND IF IT WAS ABSOLUTELY 100% IT WOULD BE A STRAIGHT LINE BUT WHAT YOU'RE SEEING HERE IS FOR AMR THE AUC IS 0.92 COMPARED TO CELLULAR REJECTION OF 0.82. NOT QUITE AS GOOD AND THE SIMILAR PATTERN FOR LUNG TRANSPLANT. WE CAN SAY WITH CONFIDENCE THAT THIS CELL-FREE DNA IS HIGHLY MEDIAT MEDIATED AND CAN PROBABLY DISTINGUISH THE TWO. THE OTHER FIND FROM THE WORK IS THE DONOR-DERIVED DNA OCCURS EARLIER THAN THE BIOPSY EVIDENCE OF REJECTION. WHAT YOU CAN SEE HERE IS THE MONTHS RELATIVE TO DIAGNOSIS ACROSS THE HORIZONTAL AXIS WITH THE MEDIAN DONOR DERIVED DNA IN THE VERTICAL AXIS. HERE'S WHAT WE SEE WHEN THERE IS NO REJECTION AND WHEN YOU LOOK BACK THERE'S STABLE LOW LEVELS OF DONOR DERIVED DNA. THIS IS IN MARK CONTRAST TO CLINICAL AMR WHERE YOU SEE THAT ACTUALLY DONOR DERIVED CELL-FREE DNA WAS THREE MONTHS BEFORE THE BIOPSY WAS POSITIVE. THIS BECOMES VERY IMPORTANT BECAUSE IT GIVES US AN OPPORTUNITY TO ACT AND TO TREAT THOSE PATIENTS BEFORE THEY PROGRESS TO CHRONIC REJECTION AS I SHOWED YOU IN THOSE PREVIOUS ANGIOGRAMS AND HISTOPATHOLOGY DATA. ANOTHER FINDING FROM THIS STUDY IS THE PHYSICAL CHARACTERISTICS OF CELL-FREE DNA IS DITCH THAN CELLULAR REJECTION AND I'M GOING TO SHOW YOU THIS DATA AS IT PERTAINS TO LUNG TRANSPLANT AND HEART TRANSPLANT. FOR LUNG TRANSPLANT HERE YOU CAN SEE THE PERCENTAGE OF FRAGMENTS THAT ARE OF VARIOUS LENGTHS COMPARED IN THE HORIZONTAL AXIS. YOU CAN SEE WHAT THIS SHOWS IS THAT GENERALLY SPEAKING THE FRAGMENT LENGTHS ARE SHORTER FOR AMR COMPARED TO CELLULAR REJECTION SHOWN IN BLUE. AND SIMILAR PATTERNS ALSO FOR HEARTS. THIS TRANSLATES TO WHAT IS SHOWN IN THE ENSET THE FRAGMENT -- INSET THE FRAGMENT LENGTH OF LESS THAN 120 BASE PAIRS WHICH IS MORE SO IN ANTIBODY MEDIATED REJECTION IN BOTH HEART AND LUNG TRANSPLANT. AND WE'RE ABLE TO CONCLUDE ANTIBODY MEDIATED REJECTION IS CHARACTERIZED BY SHORTER CELL-FREE DNA AND THE FRAGMENTS OF DNA ARE COMING ABOUT NOT IN A RANDOM FASHION BUT AS SOME WAY RELATED TO THE PATHOPHYSIOLOGY OF THE DISEASE. NOW, I MENTIONED WE ARE INTERESTED IN TRACKING THE USE OF THIS HIGHLY SENSITIVE TOOL FOR PREDICTING CHRONIC REJECTION. AND I ALSO POINTED TO THE FACT THAT CHRONIC REJECTION IN THE HEART TRANSPLANT ACTUALLY APPEARS A LOT LATER BUT CHRONIC REJECTION IN THE LUNG TRANSPLANT IS AN RELATIVELY EARLY PHENOMENON THE PULMONOLOGISTS SEE AS EARLY AS TWO YEARS POST TRANSPLANT. SO SEAN AGBAR A PHYSICIAN SCIENTIST OF PULMONARY CRITICAL AREA WAS ABLE TO TAKE THE DATA AND DEMONSTRATE VERY NICELY THAT PATIENTS WITH THE HIGHEST LEVELS OF CELL-FREE DNA WERE MORE LIKELY TO DEVELOP ALOGRAPH FAILURE AS HE FOLLOWED THE PATIENTS OUT AND BROKEN THEM UP INTO TERTILES FOR CELL-FREE DNA AND UPPER TERTILES AND YOU CAN SEE AS I'VE MENTIONED THE PATIENTS WITH THE HIGHEST LEVEL OF CELL-FREE DNA MORE LIKELY TO DEVELOP THIS CHRONIC FAILURE AND MORE LIKELY TO DEVELOP A CLAD. AND WHAT THIS HAS CULMINATED IN OVER THE LAST YEAR IS WE'VE MOVED FROM THIS OBSERVATIONAL WORK TO WIDESPREAD CLINICAL ADOPTION FOR ORGAN TRANSPLANT AND YOU MIGHT ASK WHETHER THIS IS PREMATURE. BUT IN THE CONTEXT OF COVID-19 WHEN PATIENTS WERE UNABLE TO COME TO THE HOSPITALS FOR THE MORE INVASIVE TESTS OF HEART BIOPSIES AND BRONCHOSCOPIES THERE'S A MORE COMMERCIALLY AVAILABLE VERGES OF -- VERSIONS MUCH THE TEST AND THEY'RE DOING WELL WITH THE ILL EFFECTS. LET'S SWITCH GEARS TO THE ISSUE OF CELL-FREE DNA AMONG HIGH RISK POPULATIONS PARTICULARLY AFRICAN AMERICAN PATIENTS. AS I MENTIONED TO YOU, THE GRAFT COHORT IS HIGHLY ENRICHED WITH AFRICAN AMERICAN BEING OVERALL 32% AND IN THE HEART COHORT UP TO 44%. YOU WILL NEVER FIND ANY HEART TRANSPLANT COHORT WITH SUCH A HIGH REPRESENTATION OF AFRICAN AMERICAN PATIENTS. SO WE BEGIN TO ASK THE QUESTION CAN WE USE SELF-IDENTIFIED DATA OF AFRICAN AMERICAN OF RACE AND DOES THAT PREDICT TO THE OUTCOMES IN AS MUCH AS USING GENETIC BASED ANCESTRY DATA. TO DO THAT A HIGHLY WELL TRAINED AND EXPERIENCED BIO INFORMATICIAN IN MY LAB DID THE WHOLE GENOME GENOTYPING IN 171 HEART TRANSPLANT PATIENTS OF WHOM 69 SELF-REPORTED AS AFRICAN AMERICAN. SHE USED THE GENETICS USING THE GENOME AS A REFERENCE AND ABLE TO CATEGORIZE THIS INTO THE AGAP OF GREATER THAN 85% WHICH CATEGORIZED AS AFRICAN AMERICAN AND LESS THAN 15% CATEGORIZED AS NOT AFRICAN AMERICAN. WE WERE ABLE TO LOOK AT THE SERIAL CELL-FREE DNA MEASURES IN THESE GROUPS. THE FIRST THING TO NOTE IS THAT THERE'S A HIGH CONSISTENCY BETWEEN SELF-REPORTED AND THE GENETIC ANCESTRY DATA. NONETHELESS, THE GAP OF GREATER HAN -- THAN 85% OF ANCESTRY SHOWED HIGHER DONOR DERIVED DNA AND WHEREAS THE SELF-REPORTED RACE ANALYSIS THERE WAS A TREND TOWARDS RISK CORRELATION WITH DERIV DONOR DERIVED DNA AND IN ABSTRACT FORM WE CONCLUDED INCREASE GRAFT INJURY IS INDEED ASSOCIATED WITH HIGHER CELL-FREE DNA IN AND AMERICA-- AFRICAN AMERICANS AT THE EXTREMES OF THE ANCESTRY POPULATION AND STARTING TO ASK WHETHER THERE'S AN INTERACTION WITH THE SOCIAL DETERMINATES OF HEALTH. WHEN WE TAKE THE ENTIRE COHORT AND ASK SIMILAR QUESTIONS, UNFORTUNATELY WITH REGARDS TO OUTCOMES WE SEE DIFFERENCES THOUGH THE FOLLOW-UP PERIOD IS ONLY A FEW YEARS. THE LONG DATA, AS I'VE MENTIONED BEFORE SHOWN HERE, WE SEE THIS CLEAR SEPARATION IN REJECTION-FREE SURVIVAL MEANING THE PROBABILITY OF REJECTION WITH AFRICAN AMERICAN PATIENTS HAVING A HIGHER LIKELIHOOD OF REJECTION AND THE DATA IS SIMILARLY SHOWN IN THE HEART TRANSPLANT PATIENTS. IF WE LOOK THEN AT WHAT THE CELL-FREE DNA LOOKS LIKE OVER TIME WHAT WE SEE HERE SHOWN IN RED IS AFRICAN AMERICAN COMPARED TO EUROPEAN AMERICANS AND MEASURED OVER TIME WE SEE THERE'S A DISTINCT SEPARATION WITH AFRICAN AMERICANS HAVING HIGHER LEVELS OF CELL-FREE DNA RIGHT FROM THE GET GO. I COULDN'T EMPHASIZE THIS MORE, AT THE BEGINNING OF TRANSPLANT. THESE SAMPLES ARE DRAWN WITHIN 24 HOURS OF TRANSPLANTATION. THIS IS DESPITE TO THE FACT THAT WHEN WE MEASURED THE BLOOD LEVELS OF THEIR IMMUNOSUPPRESSIVE DRUGS PARTICULARLY THE KEY ONES THAT ARE ANTI-REJECTION WE FIND NO DIFFERENCE AT ALL. SO THIS VIRTUALLY ELIMINATES OR SPEAKS AGAINST THE IDEA THAT THIS IS IN SOME WAY RELATED TO EITHER NON-COMPLIANCE WITH MEDICATIONS OR THAT A DIFFERENT KIND OF METABOLISM OF THE IMMUNOSUPPRESSIVE DRUGS. AND I'M FOCUSSING AGAIN ON THE DAY ONE MEASUREMENT OF THE CELL-FREE DNA YOU SEE HERE IS MARKEDLY HIGHER IN THE AFRICAN AMERICAN PATIENTS POST-TRANSPLANT. SO WE'VE TAKE N THIS FURTHER TO DO PRELIMINARY ANALYSIS IN PATIENTS IN GRAFT WHO HAD ZERO TIME POINT MEASUREMENTS OF CELL-FREE DNA AND WHO HAVE A LARGE PROPORTION OF AFRICAN AMERICAN. AND WHAT WE FIND IS THE SIMILAR PATTERN IN THE MEAN DERIVED PATIENTS IN THE INITIAL FIVE DAYS AFTER TRANSPLANT IN THIS CASE WAS SIGNIFICANTLY HIGHER THAN THOSE OF WHITE PATIENTS WITH A HAZARD RATIO FOR ANTIBODY MEDIATED REJECTION BEING ALSO HIGHER IN THE PATIENT COHORT. NOW WE BEGIN TO SEE THIS GOING HAND IN HAND THE HIGH LEVELS OF CELL-FREE DNA WITH THE INCREASED LIKELIHOOD OF ANTIBODY MEDIATED REJECTION. YOU CAN SEE ON THE RIGHT SIDE OF THE SLIDE THE HIGHER LEVELS OF CELL-FR S CELL-FREE DONOR DNA IS THIS DUE TO GRAFT INJURY OR CAN IT BE EXPLAINED IN PART THAT THE DONOR-DERIVED DNA IS SERVING AS A TRIGGER FOR THE IMMUNE RESPONSE? THIS BECOMES IMPORTANT BECAUSE AS I MENTIONED WE SEE HIGHER LEVELS OF DONOR DERIVED DNA. THIS LED US TO ASK THE QUESTION, WHAT IS THE CIRCULATING CELL-FREE DNA? IS IT OF NUCLEAR ORIGIN OR MITOCHONDRIAL DNA? YOU MIGHT ASK THE QUESTION WHY FOCUS ON MIGTOCHONDRIAL DNA AND THERE'S AN ABUNDANCE OF DATA DEMONSTRATING IT'S EXTREMELY PROINFLAMMATORY AND WORKS THROUGH THE INNATE IMMUNE RESPONSES TRIGGERING THE DAMAGE ASSOCIATION PATHWAYS FOR TISSUE DAMAGE. SO WHAT I'M PLOTTING HERE TO SHOW YOU IN THE SETTING OF REJECTION WE'RE SHOWING THE MITOCHONDRIAL CELL-FREE DNA COPY NUMBERS SHOWN IN BLACK COMPARED TO THE PERCENT OF CELL-FREE DNA IN THIS GROUP OF PATIENTS. YOU CAN SEE AGAIN THAT THE MITOCHONDRIAL DNA IS PRESENT IN AN ABUNDANCE IN THESE SAMPLES. WHEN WE LOOK AT THE CORRELATION OVER TIME OF MITOCHONDRIAL CELL-FREE DNA WITH REJECTION WE SEE THAT IN THE SETTING OF REJECTION A RAPID RISE OF MITOCHONDRIAL CELL-FREE DNA HERE IN THE CONTEXT OF ANTIBODY MEDIATED REJECTION. TAKING THIS EVEN FURTHER ONE OF THE ASSOCIATES IN THE LAB WORKED IN A STUDY CHARACTERIZED THE MITOCHONDRIAL DNA IN THE SINGLE NUCLEOTIDE VARIANT BETWEEN DONOR AND RECIPIENTS PAIRS POST TRANSPLANTATION AND ASSESS THE IMMUNE RESPONSES OF PRESENT IN THESE PATIENTS. AND IN THIS VERY ELEGANT EXPERIMENT FOR WHICH HE WON A PRIZE AT THE INTERNATIONAL SOCIETY OF HEART, LUNG AND TRANSPLANT HE TOOK THE MITOCHONDRIAL DNA MISMATCHES AND DESIGNED PEPTIDES AND THEN SUBSEQUENTLY TOOK PLASMA FROM THE PATIENTS OVER A YEAR POST TRANSPLANT AND DETERMINED WHERE THE RESUP SIP -- RECIPIENTS COULD DERIVE IMMUNITY FROM THE DONOR DERIVED DNA AND OVERALL THERE WAS A HIGHER FREQUENCY OF DONOR RECIPIENT MITOCHONDRIAL D DNA MISMATCHES IN RACE CONCORDANT PAIRS. IMPLYING MITOCHONDRIAL DNA MISMATCH WAS IMPORTANT HERE AND MOREOVER HE WAS ABLE TO DEMONSTRATE THE IMMUNOGENICITY OF THE PEPTIDES GENERATED FROM PATIENTS WITH THESE MISMATCHES. AND THIS IS LEADING US TO BELIEVE IT SUPPORTS OUR HYPOTHESES THAT THESE VARIANTS DO CONTRIBUTE TO ALLOGRAPH IMMUNOGENICITY. CAN WE SHOW THE MITOCHONDRIAL DNA MISMATCHES IN AFRICAN AMERICAN TRANSPLANT PATIENTS AND IF SO, WHAT IS THE CORRELATION OF THE ALLOIMMUNE RESPONSE TO AMR AND TO MAKE IT MORE COMPLICATED IS THIS AN INTERACTION WITH THE KNOWN SOCIAL DETERMINATES IN HEALTH AND EMERGING IN THE LITERATURE IS THE DISCUSSION WHETHER ONE SHOULD OR NOT FOCUS ON THE SOCIAL DETERMINATES WHEN IT COMES TO HEALTH DISPARITIES VERSUS THE GENETIC AND ENVIRONMENTAL CAUSES. AND I WOULD ARGUE WE NEED BOTH TO GET A COMPLETE PICTURE OF WHAT IS GOING ON IN OUR EFFICIENTS AND IN THE -- PATIENTS AND IN THE SETTING OF TRANSPLANTATION AND THE HLA [INDISCERNIBLE] BECOMES IMPORTANT AND ON A -- HLA HAPLOTYPES ARE IMPORTANT AND WHETHER THE CELL-FREE DNA IS SOMETHING TO BE RECKONED WITH WHICH BRINGS US BACK TO WHO WILL BE DOING THE WORK? THAT IS WHERE THE ATTENTION TO THE SCIENTIFIC WORKFORCE AND THE DIVERSITY OF PERSPECTIVES THAT ARE EMBEDDED IN THE SCIENTIFIC WORKFORCE IS CRITICALLY IMPORTANT. BUT UNFORTUNATELY HERE'S THE REALITY. AS WE MOVE ACROSS THE CAREER PATH SHOWN HERE FROM ASSOCIATE DEGREES RIGHT UP TO LEADERSHIP IN ACADEMIC INSTITUTIONS WE SEE A DIMINITION OF THE REPRESENTATION OF ALL GROUPS INCLUDING WOMEN WHO ARE AFRICAN AMERICAN OR HISPANIC OR NATIVE-AMERICAN BACKGROUNDS. AND WE SEE THE DIMINISHMENT OF MEN AS WELL AS FROM THESE GROUPS. OUR WORK IS CUT OUT FOR ALL ACADEMIC INSTITUTIONS TO BE WORKING TOWARDS ACHIEVING EQUITY IN ALL OF THESE DIFFERENT LEVELS. AND FROM MY TIME AT NIH, WHAT I BECAME REALLY AWARE OF IS THAT WHILE WE CAN HAVE INTERVENTIONS AT THE INDIVIDUAL LEVEL WHICH ARE NECESSARY, WE MUST CONTINUE TO BUILD THE PIPELINE BUT WE MUST BEGIN TO THINK ABOUT THIS IN TERMS OF WHAT WE CAN DO AT AN INSTITUTIONAL LEVEL BECAUSE THE INDIVIDUAL LEVEL OF INTERVENTIONS ARE NOT SUFFICIENT. -- TO TAKE US WHERE WE WANT TO GO. AND TO DO THIS WE NEED TO HAVE ACCOUNTABILITY AND TRANSPARENCY. THAT MEANS SYSTEMATIC REVIEW OF ALL OF OUR PROMOTIONS, POLICIES AND OUR DATA AROUND THE DATA AND COLLECTING THE DATA AND AGGREGATED AND DISAGGREGATED FORMS AND TRACK PROGRESS AND PROVIDE TOOLS FOR THE DIVISIONS AND DEPARTMENTS SO THEY CAN DO THEIR RECRUITMENT AND RETENTIONS IN WAYS THAT WILL SUPPORT DIVERSITY WITHIN THEIR WORKFORCE BUT I THINK THE MOST IMPORTANT THING I LEARNED AND MY TIME AT NIH AND IN THE 10 YEARS I'VE BEEN DOING THIS WORK AROUND DIVERSITY IS THAT WE MUST BE LINKING THESE ACTIVITIES TO THE INSTITUTIONAL REWARD SYSTEMS. AND NOTICE I SAY REWARD NOT AWARDS. MANY OF US ARE VERY ACCUSTOMED TO GETTING THE PLAQUE AND THE GIFT CERTIFICATE. THIS IS NOT WHAT WILL LEAD TO CHANGE. IT'S GETTING TO THE CORE OF THE REWARD SYSTEMS. AND THE NIH ACTUALLY HAS A MODEL FOR THIS. DIVERSIFYING THE TALENT POOLS THROUGH SYSTEMATIC UNBIASSED SEARCHS, TRANS INSTITUTIONAL SEARCHS FOR FACULTY POSITIONS, APPROACHES TO IMPLICIT BIAS MITIGATION AND APPROACHES TOWARDS CHANGING THE CULTURE WHICH INCLUDES COHORT HIRING, CREATING A CULTURE OF INCLUSION AND A CULTURE OF MENTORING, ACCOUNTABILITY AND EQUITY FOR TRANSPARENCY TRACKING AND INCENTIVIZING THE BEHAVIORS WE WANT TO SEE AND BEING ATTUNE TO PREVENTING SEXUAL AND RACIAL HARASSMENT THROUGH A RANGE OF ACTIVITIES INCLUDING POLICY TRACKING AND REPORTING. AND THANKS TO THE MEMBERS OF MY LABORATORY OF TRANSPLANTATION GENOMICS WITHOUT WHOM NONE OF THIS WOULD HAVE BEEN POSSIBLE AND I THINK YOU CAN AGREE FROM THE PHOTOGRAPHS HERE I TRIED MYSELF TO HAVE A DIVERSE TEAM DOING THIS WORK THAT ACTUALLY HELPED ME COME UP WITH SO MANY GREAT IDEAS TO SOLVE THIS PROBLEM OF THE POOR OUTCOME FOR AFRICAN AMERICAN PATIENTS USING THESE GENOMIC TOOLS. WE'RE NOW MOVING ON TO A STAGE TO BRING EXPERTS IN THE SOCIAL DETERMINATES OF HEALTH SO WE CAN CREATE THE FULL PICTURE OF WHAT'S GOING ON IN THESE PATIENTS. OF COURSE, FONG OF THIS WOULD HAVE -- NONE OF THIS WOULD HAVE BEEN POSSIBLE WITHOUT THE COLLABORATIVE EFFECT AND TEAM SCIENCE MADE POSSIBLE BY ALL OF OUR COLLABORATORS FROM THE FIVE DIFFERENT SIDES HERE AND HERE ARE THE PHOTOGRAPHS. I'LL LEAVE YOU WITH THE SAYING THAT CONTRARY TO THE USUAL SAYING THAT GREAT MINDS THINK ALIKE. I THINK GREAT MINDS ACTUALLY THINK DIFFERENTLY AND IN THE WORDS OF ALBERT EINSTEIN WE CANNOT SOLVE OUR PROBLEMS WITH THE SAME THINKING WE USED WHEN WE CREATED THEM. I'M SURE YOU WILL AGREE THAT WE ARE NOW THINKING ABOUT TRANSPLANTATION IN A VERY DIFFERENT WAY FROM WHICH WE DID WHEN THE SURGICAL PROCEDURE WAS FIRST MADE POSSIBLE BY MY MENTOR AND SPONSOR. WITH THAT I'LL STOP AND STOP SHARING MY SCREEN AND THANK YOU VERY MUCH FOR YOUR ATTENTION. >> AND WE DO HAVE ONE QUESTION TO START. IT IS AS FOLLOWS. WHAT IS THE PERCENTAGE OF ORGAN DONORS THAT ARE PERSONS OF COLOR? DOES OR WOULD THAT IMPACT THE OUTCOMES OF SUCCESSFUL TRANSPLANTATION FOR PEOPLE OF COLOR? FINALLY, IS THERE RACIAL DISPARITY IN THE SCREENING PROCESS FOR PEOPLE OF COLOR DONATING ORGANS? >> GREAT QUESTION. GREAT TWO-PART QUESTION. THE REPRESENTATION OF AFRICAN AMERICANS IN OPEN DONOR POOL IS LOWER, CONSIDERABLY LOWER THAN THAT OF WHITE POPULATION AND FOR HEART TRANSPLANTATION I BELIEVE IT'S SOMETHING LIKE 25% SO ANY AFRICAN AMERICAN RECIPIENT IS MORE LIKELY TO RECEIVE AN ORGAN FROM A WHITE DONOR. SO THERE'S BEEN A LOT IN THE LITERATURE ESPECIALLY AROUND KIDNEY TRANSPLANT WHERE THE VOLUMES ARE LARGER LOOKING INTO THIS AS TO WHETHER OR NOT AN AFRICAN AMERICAN RECEIVING THE GRAFT FROM A WHITE DONOR WAS MORE LIKELY TO HAVE REJECTION. AND QUITE HONESTLY THE DATA IS NOT AT ALL CONCLUSIVE EITHER WAY AND CERTAINLY NOT STRONG ENOUGH TO EXPLAIN ALL OF THE OBSERVATIONS. AND WHAT IS MORE ESPECIALLY IN THE AREA OF TRANSPLANTATION, IF WE WERE TO WAIT FOR DONOR RECIPIENT CONCORDANCE, THEN A LOT OF PEOPLE WOULD BE DYING ON THE WAITING LIST. IT'S NOT THE RIGHT APPROACH TO LOOK AT IT BUT TO QUICKLY DIG DOWN IN THE MECHANISMS THAT WILL POINT US TO TARGETS TO PREVENT REJECTION LIKE THE MITOCHONDRIAL DNA MISMATCH FOR WHICH BY THE WAY A COLLEGIATE NIH ACTUALLY HAS A COMPOUND OR A SMALL MOLECULE TO ACTUALLY [INDISCERNIBLE] THE OTHER QUESTION AROUND ACCESS AND EVALUATION THE ANSWER IS NO. THERE'S STANDARD PROCEDURES FOR EVALUATING AND TECHNOLOGY THAT GOES ACROSS THE DIAGNOSTIC RATES. >> GREAT. LET'S GO TO THE CHICKEN OR EGG QUESTION ABOUT THE MITOCHONDRIAL DNA. SO THE VERY FACT THAT YOU'RE FINDING MITOCHONDRIAL DNA FLOATING AROUND SUGGESTS SOMEHOW THERE'S MITOCHONDRIAL INJURY. THE QUESTION IS TO WHAT DEGREE AND TO WHAT EXTENT AND HOW DOES THAT HAP VPEN AND IS IT HAPPENING INDEPENDENT OF ANY OTHER CELLULAR INJURY THAT MIGHT RELEASE GENOMIC DNA. >> TERRIFIC QUESTIONS. I DON'T THINK WE KNOW THE ANSWER. HERE'S WHAT WE DO KNOW, IN THE SETTING OF MAJOR TRAUMA WHEN YOU GET THOSE PATIENTS IN THE ICU THERE'S A TREMENDOUS OUTPOURING OF MITOCHONDRIAL DNA CIRCULATING IN THE PLASMA OF THOSE PATIENTS. AND IT HAS BEEN LINKED TO THOSE PATIENTS GOING INTO -- DEMONSTRATING SEPTIC SHOCK OPPOSE TO CARDIOGENIC SHOCK. IMPLYING THAT BY VIRTUE OF ITS PRESENCE THE CIRCULATING MITOCHONDRIAL DNA CAN TRIGGER A LOT OF DOWN STREAM CASCADE OF INFLAMMATORY PROCESSES AND I WOULD SAY HONESTLY, THAT'S WHERE THE FIELD IS. WE'RE UNABLE TO ANSWER THE CHICKEN AND THE EGG QUESTION YET BUT WE'RE HOPING TO DO IT AND ONE PIECE OF DATA I DIDN'T SHOW YOU IS THAT ACTUALLY THE BULK OF THE CIRCULATING DNA IS ACTUALLY COMING FROM HEMATOPOIETIC CELLS AND WE'VE BEEN ABLE TO DO THAT FROM COLLABORATORS IN THE UNIVERSITY OF HONG KONG AND WHICH POINTS TO THE EARLY TIME POINTS. IT SUGGESTS THAT COMING IN IS MITOCHONDRIAL DNA MOST LIKELY FROM HEMATOPOIETIC CELL IN ORIGIN AND GOING IN AND TRIGGERING THE IMMUNE RESPONSE. IF I WAS A BETTING PERSON, WHICH I'M NOT, I WOULD SAY THE MITOCHONDRIAL DNA IS TRIGGERING THE RESPONSE AND IS THE CHICKEN. >> ALL RIGHT. THAT'S VERY HELPFUL. THE FINAL QUESTION RELATES TO THE DISTINCTION BETWEEN ANTIBODY MEDIATED REJECTION AND CELLULAR REJECTION. NOW THAT YOU'RE SEEMINGLY ABLE TO SORT THAT OUT WITH THE CIRCULATING DNA ASSAY, WHAT ARE THE IMPLICATIONS FOR TREATMENT NOWADAYS WITH RESPECT TO TEASING OUT AND FOCUSSING ON ONE VERSUS THE OTHER? >> AGAIN, THIS IS THE EARLY STAGE. WHAT WE REALLY SUSPECT IS REJECTION IS A CONTINUUM. IN THE EARLY DAYS OF TRANSPLANT WE WOULD VIEW IT AS A CLEAR CUT ANTIBODY MEDIATED OR CELLULAR REJECTION BUT IT'S A CONTINUUM. IT'S A T CELL. THE B CELL DRIVEN T CELL RESPONSE, QUITE FRANKLY. AND SO FOR TREATMENT WHEN WE GET TO THAT STAGE, THE CURRENT THERAPIES THAT WE USE ARE PLASMA PHORESIS AND THE OLD GENERATION LIKE RETOXIMAB WERE NOT THAT EFFECTIVE BUT WE USED IT AND THERE ARE NEWER GENERATIONS SPECIFICALLY TARGETED INCLUDING CERTAIN THYROSINE KINASE INHIBITERS AND THERE'S AN OPPORTUNITY FOR TREATING ANTIBODY MEDIATED REJECTION TO MUCH MORE EFFECTIVELY THAN WE EVER HAD. AND A LOT OF THIS IS COMING FROM OTHER FIELDS LIKE TREATMENTS OF MYELOMA THAT HAS B CELL DRIVEN PROCESS THAT HAS REALLY BEEN REVOLUTIONALIZED OVER THE LAST FIVE TO 10 YEARS. I THINK WE CLEARLY HAVE A LOT OF MORE TO DO FOR THE ORGAN TRANSPLANT RECIPIENTS IN THIS SPACE BUT I THINK THE FUTURE IS REALLY VERY BRIGHT IN TERMS OF THE ABILITY TO ABROGATE THE B CELL DRIVEN PROCESSES. >> TERRIFIC. THANK YOU AGAIN, DR. VALANTINE. WE'RE AT THE END OF OUR TIME. IT'S BEEN AN OUTSTANDING PRESENTATION AND QUITE INFORMATIVE. WE WISH YOU AN IN ENJOYABLE AFTERNOON OR IT MAY STILL BE MORNING IN CALIFORNIA. HAVE A PLEASANT MORNING. >> THANK YOU VERY MUCH.