WELCOME, EVERYBODY, TO THE SECOND DAY OF THE OPEN SESSION OF THE NIDCD ADVISORY COUNCIL. WE WILL START TODAY'S PROGRAM BY INVITING DR. LISA CUNNINGHAM TO GIVE US AN UPDATE ON THE INTRAMURAL RESEARCH PROGRAM. DR. CUNNINGHAM IS THE DIRECTOR OF INTRAMURAL RESEARCH FOR NIDCD AND ALSO OUR SCIENTIFIC DIRECTOR. DR. CUNNINGHAM. >> THANK YOU, DR. TUCCI. >> GOOD MORNING, EVERYONE. I'M LISA CUNNINGHAM. AND I HAVE THE OPPORTUNITY TODAY TO PROVIDE YOU WITH AN UPDATE ON ACTIVITIES IN THE DIVISION OF INTRAMURAL RESEARCH. SO THE NEXT SLIDE, PLEASE, GINGER. I WOULD LIKE TO UPDATE THE INTRAMURAL INVESTIGATORS. I HAVE LISTED THEM ON THIS SLIDE. SINCE MY PRESENTATION TO THE COUNCIL LAST YEAR THERE HAVE BEEN THREE NOTABLE CHANGES TO THE GROUP OF INTRAMURAL INVESTIGATORS. FIRST WE HAVE A NEW TENURE TRACK DR. ANGELA BALLESTEROS MORCILLO. I WILL TELL YOU MORE ABOUT HER RESEARCH PROGRAM IN THE NEXT SLIDE. WE WERE ABSOLUTELY DELIGHTED TO RECRUIT DR. BALLESTEROS MORCILLO. WE HAD TO COMPETE WITH SEVERAL TOP INSTITUTIONS SO WE ARE DELIGHTED TO HAVE HER. I'M DELIGHTED TO LET YOU KNOW DR. CLINT ALLEN WAS TENURED SINCE THE LAST TIME I PRESENTED LAST FALL. SO DR. ALLEN IS TENURED. DR. CARTER VAN WAES RETIRED AFTER MANY YEARS OF OUR CLINICAL DIRECTOR. WE WISH DR. VAN WAES A VERY, VERY HAPPY RETIREMENT. SO THE NEXT SLIDE, PLEASE. SO I WANT TO TELL YOU MORE ABOUT DR. BALLESTEROS MORCILLO, THE FIRST STADTMAN INVESTIGATOR. A PROGRAM THAT BRINGS EXCELLENT CANDIDATES TO THE INTRAMURAL PROGRAM. DR. BALLESTEROS MORCILLO IS OUR FIRST STADTMAN PROGRAM. SHE RECEIVED AN MS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY AND TEACHING. AND A PH.D. IN MOLECULAR BIOLOGY IN SPAIN. SHE DID HER FIRST POST DOCTORAL FELLOWSHIP AT THE FOOD AND DRUG ADMINISTRATION. SHE DID ANOTHER ONE AT NIDCD, WHERE SHE WAS CO-MENTORED. SHE DID A THIRD WITH DR. KENTON SWARTZ. SHE STARTED AT NIDCD LAST MONTH AND WE ARE VERY EXCITED ABOUT HER RESEARCH PROGRAM. THE NEXT SLIDE, PLEASE. I INDICATED A MOMENT AGO THAT DR. VAN WAES RETIRED. HE WAS OUR FORMER NIDCD CLINICAL DIRECTOR. HE SERVED IN THIS ROLE FOR 27 YEARS AND HE RETIRED THIS SUMMER. WE WERE ABLE TO HOST A SYMPOSIUM HIGHLIGHTS DR. VAN WAES' WORK AND IMPACT ON THE NIDCD CLINICAL PROGRAM AND IN HIS FIELD, HEAD AND NECK CANCER, WE HELD THE SYMPOSIUM ON MAY 13. JUST AFTER THE RESTRICTIONS WERE LIFTED JUST IN TIME FOR US TO BE ABLE TO HOLD THIS EVENT AS A HYBRID EVENT. IT WAS ONE OF THE FIRST HYBRID EVENTS AT NIH. WE HAD A BIT OF A STEEP LEARNING CURVE, BUT IT WENT REALLY WELL. WE HAD A FULL DAY SCIENTIFIC PROGRAM THAT FEATURED DR. VAN WAES' COLLEAGUES AND FORM ER MENTEES AND TRAINEES FROM THE LAB. IT WAS A LOVELY DAY. YOU SEE THE INDIVIDUALS WHO ATTENDED IN PERSON AND MANY OTHERS ATTENDED VIRTUALLY. I'M HAPPY TO LET YOU KNOW DR. CLINT ALLEN IS CURRENTLY SERVING AS ACTING NIDCD CLINICAL DIRECTOR AND THERE IS A SEARCH UNDER WAY FOR NEW CLINICAL DIRECTOR FOR NIDCD. I HOPE TO SOON BE ABLE TO LET YOU KNOW WHO THAT PERSON WILL BE. NEXT SLIDE, PLIZ. -- NEXT SLIDE, PLEASE. WE HAVE ANOTHER IMPORTANT RETIREMENT COMING THIS FALL THAT IS DR. CARMEN BREWER. IN OCTOBER OF THIS YEAR DR. BREWER WILL RETIRE AFTER 20 YEARS AS THE CHIEF OF OUR NIDCD AUDIOLOGY UNIT. WE WILL ALSO HOST A SYMPOSIUM HONORING DR. BREWER AND HIGHLIGHT HER CONTRIBUTIONS TO THE FIELD OF AUDIOLOGY ON SEPTEMBER 30th. A SEARCH FOR DR. BREWER'S SUCCESSOR IS ALSO CURRENTLY UNDERWAY. WE WILL PROVIDE INFORMATION ABOUT HOW TO ATTEND DR. BREWER'S RETIREMENT SYMPOSIUM VIRTUALLY, IF YOU ARE INTERESTED IN DOING SO. THE NEXT SLIDE, PLEASE. I WOULD LIKE TO PROVIDE AN UPDATE ON THE NIDCD BOARD OF SCIENTIFIC COUNCILORS. YOU SEE THE LIST INCLUDING DR. ELLEN LUMPKIN, WHO HAS NEWLY TAKEN ON THE ROLE OF CHAIR OF OUR BSC. THE OTHER -- WE HAVE ANOTHER NEW MEMBER, DR. MARLAN HANSEN, UNIVERSITY OF IOWA. MEMBERS WHO HAVE BEEN ON THE BOARD ERI HASHINO, DR. JOHNSON, DR. JIAN-DONG LI AND OGHALAI. DR. SEGAL. AND DWYANE SIMMONS FROM BAYLOR UNIVERSITY. NEXT SLIDE, PLEASE. IN 2021, WE COMPLETED THE WORK OF THE NIDCD BLUE RIBBON PANEL. THIS PANEL WAS CONVENED BY DR. TUCCI TO REVIEW THE NIDCD INTRAMURAL PROGRAM AND PROVIDE RECOMMENDATIONS FOR THE PROBLEM. THE KEY RECOMMENDATIONS WERE SUPPORT JOINT HIRES TO OPTIMIZE SPACE AND STRENGTHEN TRANS-NIH TIES. THE NIDCD AUDIOLOGY UNIT SHOULD STRONGLY PURSUE ITS OWN RESEARCH. AND DIR SHOULD CONSIDER MAKING THE AUDIOLOGY UNIT A PI-BASED UNIT. A THIRD RECOMMENDATION IS THE DIVISION OF INTRAMURAL RESEARCH SHOULD TAKE ADVANTAGE OF OPPORTUNITIES TO WORK WITH EXTRAMURAL INVESTIGATORS INCLUDING PROGRAMS LIKE THE U.01. AND DIRs SHOULD WORK TO BUILD DATABASES THAT WOULD BENEFIT THE ENTIRE RESEARCH COMMUNITY, INCLUDING BOTH INTRAMURAL AND EXTRAMURAL INVESTIGATORS. THEY RECK MENDED PRIORITIZING PARTICIPATION IN NIH-WIDE PROGRAMS SUCH AS THE STADTMAN PROGRAM, DISTINGUISHED SCHOLARS. I INDICATED DR. BALLESTEROS MORCILLO IS A MEMBER OF THE STADTMAN PROGRAM AND THE DISTINGUISHED SCHOLARS PROGRAM. WHEN THE NEW CLINICAL DIRECTOR IS NAMED WE WILL TAKE UP THE SPECIFIC RECOMMENDATIONS THAT THE BLUE RIBBON PANEL MADE FOR THE NEW CLINICAL PROGRAM IN COLLABORATION WITH THE NEW CLINICAL DIRECTOR. SO THE NEXT SLIDE, PLEASE. IN RESPONSE TO THE BLUE RIBBON PANEL, RECORDS NIDCD DIR HELD SOME STRATEGIC PLANNING MEETINGS IN THE FALL OF 2021. WE HELD TWO DAYS OF FACILITATED STRATEGIC PLANNING, FOCUSED ON SETTING PRIORITIES BASED ON THE RECOMMENDATIONS OF THE BLUE RIBBON PANEL AND OUR DESIRE TO FOSTER AN INNOVATIVE CULTURE, OPPORTUNITIES FOR TRANS-NIH COLLABORATION AND BUILDING GOOD PATHWAYS TO TRANSLATE BASIC RESEARCH INTO THE CLINIC. THESE DISCUSSIONS WERE GUIDED BY THE REPORT OF THE BLUE RIBBON PANEL IN A SERIES OF STRATEGIC QUESTIONS. THE NEXT SLIDE, PLEASE. THE STRATEGIC PLANNING MEETING RESULTED IN SEVERAL IMPLEMENTATION PRIORITIES FOR DIR AND THOSE INCLUDE FORMING A PROGRAM TO FOSTER INNOVATIVE AND HIGH-RISK, HIGH-REWARD PROJECTS, FORMING STRATEGIC INTERACTIONS AND COLLABORATIONS, RESOURCE BUILDING TO BENEFIT THE ENTIRE COMMUNITY, WHICH AS I INDICATED, WAS ONE OF THE RECOMMENDATIONS OF THE BLUE RIBBON PANEL. MECHANISMS OF TRANSLATING BASIC SCIENCE RESEARCH INTO CLINICAL THERAPIES. ONE OF THE PRIORITIES WAS A FOCUS ON DATA SCIENCE. MACHINE LEARNING, COMPUTATIONAL POWER AND HIGH LEVEL ANALYSIS CAPABILITIES. ANOTHER PRIORITY WAS FORMING AN EFFICIENT PIPELINE TRANSLATING IDEAS INTO THERAPIES AND WE HAD A DISCUSSION ABOUT EQUALITY IN THE SCIENCE AND THE WAYS WE WORK. SO THE NEXT SLIDE, PLEASE. IN RESPONSE TO THE STRATEGIC PLANNING MEETING, WE FORMED WORKING GROUPS TO MAKE SPECIFIC RECOMMENDATIONS FOR IMPLEMENTATION REGARDING STRATEGIES TO ACHIEVE THE OBJECTIVES I MENTIONED IN THE LAST SLIDE. IN RESPONSE TO THE RECOMMENDATIONS OF THOSE WORKING GROUPS AND THE BLUE RIBBON PANEL RECOMMENDATIONS, THE OFFICE OF THE SCIENTIFIC DIRECTOR HAS DEVELOPED AND INNOVATION AWARD PROGRAM WE RECENTLY ANNOUNCED TO INCENTIVIZE HIGH-RISK, HIGH-IMPACT PROJECTS WITHIN DIR AND ACROSS NIH. WE ARE IN TALKS TO DEVELOP A NEUROSCIENCE FOCUS POSTER SESSION IN THE PORTER NEUROSCIENCE RESEARCH CENTER, WHICH IS THE BUILDING OUR DIR LABORATORIES, MOST OF OUR DIR LABORATORIES ARE HOUSED IN. THIS POSTER SESSION, THE GOAL OF THIS IS TO TO FOSTER INCREASED INTERACTIONS BETWEEN DIR LABS AND LABS IN OTHER INSTITUTES AP CENTERS AT NIH. WE ALSO OBTAINED FUNDING FOR AND STARTED WORK ON CLINICAL DATABASE OF HEARING AND BALANCE FUNCTION IN THE AUDIOLOGY UNIVERUNIT. THIS CAME OUT OF THE BLUE RIBBON PANEL RECOMMENDATIONS AND DIR STRATEGIC PLANNING MEETING. THAT WORK IS UNDERWAY AND WE THINK WE WILL HAVE THAT CLINICAL DATABASE AVAILABLE SOMETIME IN 2023. SO THE NEXT SLIDE, PLEASE. I WANTED TO UPDATE YOU A BIT ON OUR NIDCD INTRAMURAL DIVERSITY EFFORTS. WE HAD A PROGRAM BY WHICH A COMMITTEE WAS FORMED TO REVIEW THE APPLICATIONS TO THE NIH POST BACCALAUREATE PROGRAM. AND THAT COMMITTEE IDENTIFIED A DIVERSE POOL OF APPLICANTS TO THAT PROGRAM, HIGHLY QUALIFIED APPLICANTS FOR CONSIDERATION BY THE NIDCD INTRAMURAL LABS. THIS PROGRAM IS VERY POPULAR WITH THE PIs AND SO FAR THREE POST BACCALAUREATE FELLOWS HAVE BEEN SELECTED FROM THE THIS A POOL. THERE WAS A RELOCATION ALLOWANCE. THERE WAS SOME VARIABILITY WHETHER A NEW TRAINEE WOULD RECEIVE A RELOCATION ALLOWANCE. WE STREAMLINED THIS. TO MAKE SURE THAT THE COST OF RELOCATING TO BETHESDA FROM WHEREVER OUR TRAINEES ARE COMING FROM, DOESN'T INHIBIT ANY TRAINEES FROM COMING AND JOINING A DIR LAB. IN ADDITION, THE OFFICE OF THE SCIENTIFIC DIRECTOR SUPPORTED AND FUNDED ALL OF THE SUMMER INTERNS THAT WE HAD IN 2022. THE SUMMER INTERNSHIP PROGRAM IS A GREAT OPPORTUNITY FOR US TO PROVIDE A GOOD FIRST RESEARCH EXPERIENCE IN OUR MISSION AREAS TO YOUNG PEOPLE WHO ARE VERY INTERESTED IN SCIENTIFIC RESEARCH AND PERHAPS HAVE NOT YET SELECTED A SPECIFIC FIELD. SO IT HAS BEEN A FOCUS OF MY OFFICE TO MAKE SURE NIDCD LABS ARE PARTICIPATING IN THE SUMMER INTERNSHIP PROGRAM AND BRINGING THESE STUDENTS TO DIR AND TO OUR MISSIONARIES. IN ADDITION, NIDCD HAS A RECRUITMENT STRATEGIST THAT WAS TRAINED BY THE NIH CHIEF OFFICER FOR SCIENTIFIC WORK FORCE DIVERSITY IN HOW TO BEST ASSIST THE SEARCH COMMITTEES IN MAKING SURE THAT WE HAVE A DIVERSE POOL OF APPLICANTS FOR ALL OF OUR FACULTY POSITIONS AND THE NIDCD RECRUITMENT STRATEGIST WORKS WITH ALL OF OUR SEARCH COMMITTEES AND HELPS US ADVERTISE AND MAKE SURE THAT WE HAVE SPREAD A WIDE A NET AS WE CAN TO MAKE SURE THAT WE HAVE A DIVERSE POOL OF HIGHLY QUALIFIED CANDIDATES. SO THE NEXT SLIDE, PLEASE. WE HAD THIS SUMMER THE NINTH EDITION OF THE E.A.R.SSENTIALS COURSE TAUGHT BY NIDCD FACULTY AND EXTRA MURAL FACULTY. FOCUSED ON CONCEPTS AND TECHNIQUES OF CONTEMPORARY HEARING RESEARCH. THIS COURSE IS FREE. IT IS AVAILABLE TO ANYONE WHO REGISTERS AND THIS YEAR WE HELD IT IN A HYBRID FORMAT. AND WE ADVERTISED THE PROGRAM OUTSIDE THE HEARING FIELD IN ORDER TO TRY TO REACH A DIVERSE POOL OF PARTICIPANTS FOR THIS PROGRAM. I CAN TELL YOU A LITTLE BIT MORE ABOUT THE EARSSENTIALS COURSE IN THE NEXT SLIDE, PLEASE, GINGER. IN 2022 THE EARSSENTIALS COURSE WAS HELD IN A HIGH BRIGGS DISCUSSION. THE PREVIOUS TWO YEARS WE HELD THIS PROGRAM ENTIRELY VIRTUALLY. THIS YEAR THE COURSE WAS REMODELLED. FACULTY PRESENTED A 20-MINUTE MINILECTURE ON EACH OF THE SUBJECTS IN THE COURSE. THAT WAS DONE IN THE MORNING. AND THE PARTICIPANTS HAD AVAILABLE TO THEM ARCHIVED LECTURES LONGER THAN 20 MINUTES AVAILABLE ONLINE FOR NOR-DEPTH LEARNING IN A PARTICIPANT HAD A PARTICULAR AREA THEY WANTED TO HEAR MORE ABOUT OR WANTED MORE IN-DEPTH INFORMATION ABOUT THAT AREA. WE ARE VERY PLEASED THE HYBRID FORMAT ALLOWED US TO HAVE MORE THAN 100 REGISTERED PARTICIPANTS. EVERY DAY OF THE WEEK WE HAD PARTICIPANTS FROM ALL AROUND THE WORLD, FROM INSTITUTIONS AT 11 COUNTRIES, 15 STATES AND PUERTO RICO. I'M REALLY EXCITED ABOUT THIS PROGRAM. IT CONTINUES TO GROW AND IMPROVE AND EVERY YEAR IT ALLOWS US TO REACH A LARGER GROUP OF INTERESTED PARTICIPANTS, MOSTLY TRAINEES OR PEOPLE WHO ARE OUTSIDE OUR FIELD AND INTERESTED IN LEARNING MORE ABOUT INNER EAR RESEARCH. WE ALSO OFFERED A MOUSE GENETICS LAB, AN INTRODUCTION TO THE GENE EXPRESSION AUDITORY RESEARCH PORTAL OPERATED OUT OF THE UNIVERSITY OF MARYLAND AND A ZEBRAFISH LABORATORY. SO I'M REALLY HAPPY ABOUT HOW THE EARSSENTIALS COURSE IS GOING. WE ARE GETTING INTEREST AND PARTICIPATION. I'M HAPPY WE CAN BRING IT FOR FREE TO ANYONE WHO WANTS TO PARTICIPATE AND THE HYBRID FORMAT ALLOWED WORLDWIDE PARTICIPATION. SO THE NEXT SLIDE, PLEASE, GINGER. AND FINALLY, I JUST WANTED TO GIVE YOU A LITTLE BIT MORE INFORMATION ABOUT OUR PARTICIPATION IN THE SUMMER INTERNSHIP PROGRAM THIS SUMMER. AS I INDICATED, IT WAS HELD IN A HYBRID FORMAT. NIDCD HOSTED THREE SUMMER INTERNS IN PERSON AND ONE VIRTUALLY. THE VIRTUAL SUMMER INTERN WAS HOSTED PART OF THE NIH GRADUATE DATA SCIENCE SUMMER PROGRAM. SO THE TRAINEES IN THAT PROGRAM WERE ALL VIRTUAL AND THE OTHER TRAINEES WERE IN WET BENCHES PRESENT ON THE NIH CAMPUS IN BETHESDA. WE SUPPORTED THEM WITH REGULAR MEETINGS WITH TRAINING DIRECTOR AND NIH PROVIDED RESOURCES FOR GUESTS AND HEARING TRAINEES THROUGH THE STRARM TRAINING AND EDUCATION WHICH PROVIDES COMPREHENSIVE RESOURCES AND SERVICES FOR TRAINEES. SO THE NEXT SLIDE, PLEASE. SO THAT'S ALL I HAVE FOR YOU. THANK YOU FOR YOUR SUPPORT OF THE NIDCD INTRAMURAL PROGRAM AND I'M HAPPY TO HAVE ANY DISCUSSION OR TAKE ANY QUESTIONS AND ANY GUIDANCE THE COUNCIL MIGHT HAVE. >> THANK YOU, LISA. DOES ANYBODY HAVE ANY COMMENTS OR QUESTIONS? >> I WAS JUST GOING TO SAY, AMAZING, LISA. AMAZING THE DEPTH AND BREADTH OF ALL THE ACTIVITY ONGOING. I WAS EXHAUSTED BY THE TIME YOU WERE DONE. OH, MY GOD, TOTALLY EXHAUSTED. >> THANK YOU, I APOLOGIZE FOR EXHAUSTING YOU THIS MORNING, ANIL. WE HAVE EXCELLENT GUIDANCE AND LOTS OF ENERGY IN DIR. THANK YOU. WE ARE EXCITED ABOUT DEVELOPING THESE PROGRAMS. RUTH ANNE. >> HELLO, SORRY. LOVELY PRESENTATION, LISA. SO EXCITING TO HEAR ABILITY THE NEW THINGS GOING ON. I HAD A COUPLE OF QUESTIONS. ONE WAS, WELL, I WANTED TO COMMENT THAT IT IS GREAT TO SEE ALL THE MULTILATERAL CONNECTIONS YOU ARE MAKING WITH OTHER PROGRAMS INCLUDING NEUROSCIENCE PROGRAMS. I WONDERED FOR OUTREACH IF NIDCD HAS PLANNED OR INCREASED PRESENCE AT BIG SOCIETY MEETINGS OF OTHER FIELDS? SO I KNOW THEY ARE A BIG PRESENCE AT ARO, I DON'T KNOW ABOUT SOCIETY FOR OTHER MEETINGS. IT MIGHT BE GOOD FOR RECRUITMENT AND GOOD TO PARTNER WITH THOSE SOCIETIES TO INTRODUCE THIS FIELD OF RESEARCH. >> THAT IS A GOOD SUGGESTION, RUTH ANNE. THANK YOU. WE HAVE FOCUSED THIS YEAR ON BUILDING OUR OUTREACH WITH MORE SPECIFIC GROUPS. FOR EXAMPLE, WE FORMED A RELATIONSHIP WITH THE AMERICAN MEDICAL PROFESSIONALS WITH HEARING LOSS. WITH HOWARD UNIVERSITY AND THE BLACK AUDIOLOGY AND SPEECH LANGUAGE PATHOLOGY ORGANIZATIONS. I THINK IT WOULD BE ADVANTAGEOUS TO EXPAND THAT AND I'M WILLING TO TAKE A HARDER LOOK AT HOW WE CAN DO THAT. >> WELL F I CAN BE OF ANY HELP ON NEUROSCIENCE RELATED ONES, JUST LET ME KNOW. THANKS. >> THANK YOU. CYNTHIA, I SEE YOUR HAND UP. >> HI. IT WAS A GREAT PRESENTATION. I'M VERY INTERESTED TO KNOW MORE ABOUT YOUR CLINICAL DATABASE OF HEARING AND BALANCE FUNCTION AND WHETHER JUST AS ONE QUESTION ABOUT IT, DOES IT ALSO INCLUDE GENETIC DATA? >> SO, THE CLINICAL DATABASE WILL BE THE DATA THAT HAS BEEN OBTAINED OVER MANY YEARS IN THE AUDIOLOGY UNIT. AND SO OUR FIRST GOAL IS TO MAKE THIS A CLOUD-BASED SYSTEM THAT IS ACCESSIBLE NOT JUST TO MEMBERS OF NIDCD, BUT TO OTHER SCIENTISTS WHO ARE INTERESTED. THERE IS A LOT OF DATA IN THE AUDIOLOGY UNIT, FOR EXAMPLE, THERE ARE SEVERAL RARE DISEASES FOR WHICH THE AUDIOLOGY UNIT HAS THE LARGEST UNIT DATABASE OF HEARING AND BALANCE DATA ON THOSE DISEASES. WE WANT TO MAKE SURE THOSE DATA ARE AVAILABLE. SOME OF THE INDIVIDUALS WHO HAD THEIR HEARING TESTED AT THE AUDIOLOGY UNIT WILL HAVE GENETIC DATA ASSOCIATED WITH IT THROUGH THE CLINICAL CENTER. I THINK THAT WILL PROBABLY BE A BIT OF A PHASE TWO IN TERMS OF HOW TO MANAGE THAT, SO SOME OF THOSE INDIVIDUALS WILL HAVE DATA, GENETIC DATA ASSOCIATED WITH THEM. HOWEVER, AT THIS POINT, WE AREN'T TO THE POINT WHERE GENETIC DATA IS COLLECTED ON EVERY PATIENT AT THE CLINICAL CENTER. I THINK THERE WILL BE VARIABILITY THERE. >> OKAY, THANKS. >> AND THE NEXT HAND I SEE IS CAROL. >> HI. THANK YOU FOR THE PRESENTATION. I JUST WANTED TO ASK ABOUT THE POST BAC PROGRAM. YOU TALKED ABOUT HAVING DIVERSITY IN TERMS OF THE POOL OF APPLICANTS. HOW DID THAT COMPARE TO WHAT YOU HAVE SEEP IN PREVIOUS YEARS? I KNOW YOU PUT TOGETHER A LOT OF EFFORTS TO REACH MORE PEOPLE. IN PARTICULAR, IF YOU CAN SAY MORE DETAILS ABOUT THE THREE POST BACS THAT CAME FROM THAT DIVERSE POOL IN TERMS OF THEIR DIVERSITY, IN TERMS OF RACE, ETHNICITY, GENDER, DISABILITY, WHATEVER. >> OKAY. SO, WE -- THIS PROGRAM HAS -- I'M REALLY HAPPY ABOUT THIS PROGRAM BECAUSE IT HAS GIVEN US WHAT I BELIEVE IS THE MOST DIVERSE GROUP OF POST BACS WE HAVE HAD AT NIDCD. ALYSSA IS ON THE CALL, BUT I BELIEVE THAT AT LEAST ONE OF THOSE POST BACS IS HEARING IMPAIRED AND TWO OF THOSE POST BACCS ARE FROM GROUPS THAT ARE UNDERREPRESENTED IN SCIENCE AND MEDICINE. >> GREAT. THANK YOU. >> SO THANK YOU FOR THE QUESTION. WE'RE ENTHUSIASTIC ABOUT THIS PROGRAM AND DEFINITELY PLAN TO CONTINUE IT. THE NEXT PERSON THAT I SEE IS NIRUPA. >> YES. THANK YOU. SO I WOULD JUST LIKE TO ECHO RUTH ANNE'S COMMENT AND PERHAPS -- SO I THINK THAT GOING INTO THE SOCIETY FOR NEUROSCIENCE MEETING, I MEAN, APART FROM, OF COURSE, THE BOOTH WHERE THE PROGRAM OFFICERS AND PEOPLE ARE, BUT APART FROM THAT, TO PERHAPS TRY AND USE EITHER YOUR BOARD OF SCIENTIFIC COUNCILORS OR THE COUNCIL AND TEAM UP TO PROPOSE SOME SYMPOSIA FOR THE SFN ANNUAL MEETING AND SHOWCASE SOME OF THE VERY INNOVATIVE AND BROAD-REACHING PROGRAMS THAT YOU HAVE HERE. I THINK THAT WOULD BE VERY IMPACTFUL BECAUSE IT WOULD ALLOW YOU TO A, BE KNOWN, BUT, B, POTENTIALLY RECRUIT -- YOU KNOW, JUST BROADEN YOUR POOL OF PEOPLE FROM WHOM YOU COULD RECRUIT POST BACCS, UNDERGRADS AND POSTER SESSIONS. I THINK A BIGGER PRESENCE AT WOULD BE VERY BENEFICIAL. >> AGAIN, I THINK THAT IS AN EXCELLENT IDEA. ALYSSA AND I WILL WORK ON HOW WE CAN BEST APPROACH THAT AND WE MAY REACH OUT TO YOU AND RUTH ANNE, IF THAT IS OKAY, AS WE HAVE THOSE DISCUSSIONS. THANK YOU. >> THANK YOU, LISA AND THANK YOU ALL FOR YOUR COMMENTS AND SUGGESTIONS. SO WE'LL MOVE ON NOW AND HEAR A LITTLE BIT MORE ABOUT THE INTRAMURAL PROGRAM. SO I'M REALLY HAPPY TO SAY WE HAVE NEXT TO PRESENT US DR. MATT KELLEY. HE IS GOING TO DISCUSS HIS RESEARCH IN A PROGRAM CALLED WALKING THE PATH TO HAIR CELL REGENERATION WITH DEVELOPMENTAL BIOLOGY AS A GUIDE. HIS LAB WORKS ON THE MAMMAL MAMMALIANCOCHLEA. HE WAS AN ASSISTANT PROFESSOR IN CELL BIOLOGY AT GEORGETOWN. SINCE 2004, MATT HAS BEEN THE CHIEF OF THE SECTION ON DEVELOPMENTAL NEUROSCIENCE AT NIDCD. SO WELCOME, MATT, WE LOOK FORWARD TO YOUR TALK. >> THANK YOU, DEB. I HOPE THAT EVERYONE CAN HEAR ME. >> YES. >> I WILL HAVE TO SHARE MY SCREEN HERE. OKAY. IS THAT THE RIGHT VIEW NOW? >> YEP. THAT'S IT. >> OKAY. GOOD. AND YOU CAN SEE MY POINTER AS WELL, I HOPE. YEAH. >> YES. >> OKAY. GREAT. ALL RIGHT, SO THANK YOU VERY MUCH TO DEB AND BECKY FOR THE OPPORTUNITY TO PRESENT TO EVERYBODY TODAY. AS DEB SAID, MY LAB IS INTERESTED IN DEVELOPMENTAL BIOLOGY AND WE THINK THAT DEVELOPMENTAL BIOLOGY IS IMPORTANT TO RESEARCH FOR ITS OWN RIGHT, BUT WHAT I WANT TO DO TODAY IS TO LINK THAT TO EFFORTS TO REGENERATE HEIR CELL WHICH HAS IMPACT TO THE COUNTRY AND HEARING LOSS AND COMMUNICATION DISORDERS. I WILL GIVE BACKGROUND ON THE REGENERATION QUESTION AND THEN TALK ABOUT SOME RESEARCH FROM MY OWN LAB AND OTHER LABS FROM DEVELOPMENTAL BIOLOGY THAT HAS HELPED US TAKE STEPS TOWARDS HAVING A REGENERATIVE SOLUTION HOPEFULLY IN THE NEAR FUTURE. WE ALL KNOW, HEARING LOSS IS THE SIGNIFICANT AND GROWING PROBLEM IN FIRST-WORLD COUNTRIES LIKE THE UNITED STATES. ROUGHLY 30% OF INDIVIDUALS AT THE AGE OF 65 HAVE CLINICALLY RELEVANT HEARING LOSS, GROWS TO 47% AT 75. THE NUMBER OF AMERICANS OVER THE AGE OF 65 IS PROJECTED TO INCREASE FROM 52 MILLION FROM A FEW YEARS AGO TO CLOSE TO 100 MILLION BY 2060. RECENT STUDIES FROM JOHNS HOPKINS HAVE SHOWN A LINK FROM HEARING LOSS TO AN INCREASED RISK OF DEMENTIA. IT RAISES THE NEED TO COME UP WITH SOLUTIONS FOR HEARING LOSS TO DECREASE DEMENTIA AND ALZHEIMER'S WHICH ARE HAVING A HUGE IMPACT ON OUR COUNTRY RIGHT NOW. SO, AS I SAID OR AS WE'LL TALK ABOUT, WHILE THERE ARE SOME OTHER FACTORS THAT CAN CAUSE OR CONTRIBUTE TO AGE-RELATED HEARING LOSS, TYPICALLY THE ULTIMATE PROBLEM THAT MAKES THAT A PERMANENT HEARING LOSS FOR INDIVIDUALS IS THE LOSS OF SENSORY HAIR CELL. MAMMALS ARE UNIQUE IN INABILITY TO REGENERATE HAIR CELL. OTHER ANIMALS ARE ABLE TO. YOU HAVE HEARD OF THE CHICKEN COCHLEA. YOU CAN SEE THE CHICKEN INNER EAR, THE COCHLEA RATHER THAN COILED IT IS SHAPED LIKE A BANANA. IT IS FILLED WITH HAIR CELLS. EVERYONE ONE OF THESE WHITE DOTS IS A HAIR CELL. IN THE LATE 80s, TWO COLLABORATIVE GROUPS, COTANCHE AND CORWIN AND THE SECOND BY RUBEL AND RYALS, THAT YOU CAN RE-CREATE HAIR CELL. THIS IS A BIRD WITH A SIGNIFICANT LEGION. IF YOU LOOK AT THAT SAME COCHLEA A WEEK LATER YOU SEE ALMOST A COMPLETE REPAIR. IN ADDITION TO THE HAIR CELLS COMING BACK, AUDITORY FUNCTION RECOVERS TO ALMOST NORMAL AS WELL. YOU CAN DO THIS OVER AND OVER IN THE SAME BIRDS AND THEY WILL ROBUSTLY REGENERATE HAIR CELLS EVERY TIME. THERE IS A SIGNIFICANT DIFFERENCE BETWEEN MAMMALS AND OTHER ANIMALS TO REGENERATE HAIR CELLS AND RECOVER FUNCTION. FOR A LONG TIME WE THOUGHT HAIR CELL REGENERATION DID NOT HAPPEN AT ALL IN MAMMALS. THAT WAS SHOWN TO NOT BE THE CASE FROM JENNY STONE'S LAB IN 2012. JENNY WAS ABLE TO USE A MOUSE GENETIC APPROACH TO KILL MOST OF THE HAIR CELLS IN THE UTRICAL OF A MOUSE. AND OVER TIME, A LONG TIME WITH THE MOUSE, YOU SEE REGENERATION OF HAIR CELLS. AND THAT IS GRAFT HAIR. IT IS NOT A LOT OF REGENERATION, BUT A SMALL AMOUNT OF REGENERATION OCCURS. THIS DOES NOT LEAD TO ANY REAL MEANINGFUL RECOVERY OF STIM LA FUNCTION. HAIR CELLS ARE COMING BACK, BUT NOT FOR THE SYSTEM TO RECOVER AND WORK AGAIN. THERE IS SMALL POTENTIAL FOR REGENERATION. THAT IS VERY DIFFERENT FROM WHAT WE KNOW ABOUT THE MAMMALIAN AUDITORY ORGAN, WHERE AFTER A BRIEF PERIOD OF TIME WHEN REGENERATION WILL OCCUR, THERE IS ABSOLUTELY NO HAIR CELL REGENERATION GOING ON. SO IT IS A VERY DIFFERENT SITUATION THERE. WE THOUGHT ABOUT WHAT HAS BEEN WORKED ON OVER THE LAST FEW YEARS, MAYBE 20 YEARS SINCE IT BECAME AN OPTION, WAYS TO DEVELOP REGENERATIVE STRATEGIES. THIS IS NOT GOING TO HAPPEN SPONTANEOUSLY. WHAT CAN WE DO TO TRY TO PROMOTE THIS? THERE ARE TWO SEPARATE STRATEGIES THAT EXIST AND ARE LOOKED AT TO SOME DEGREE. THE FIRST SEEKS TO MORE CLOSELY MIMIC WHAT HAPPENS DURING AVIAN REGENERATION AND OTHER VERT BRATS, EXISTING CELLS WITHIN THE ORGAN ACOR ORF CORTI. THEY CAN TRANSDIFFERENTIATION, A SUPPORTING CELL DIRECTLY CONVERTS FROM A PHENOTYPE CELL TYPE TO A HAIR CELL TYPE. I WILL TALK MORE ABOUT THIS. I DID WANT TO MENTION THE OTHER STRATEGY BEING WORKED ON SOMEWHAT THESE DAYS TO POTENTIALLY INTRODUCE NEW HAIR CELLS INTO THE ORGAN OF CORTI. THE GENERAL THINKING IS TO USE STEM CELLS TO FORM AS HAIR CELLS OR HAIR CELL PRECURSORS AND INTRODUCE THOSE INTO THE EAR. THESE STEM CELLS OR HAIR CELLS CAN BE DERIVED FROM EMBRYONIC STEM CELLS OR PLURIPOTENT STEM CELLS WHICH WOULD BE THE PREFERRED APPROACH FOR PATIENT SPECIFIC THERAPY. THIS IS DONE THROUGH ORGANOID TO DRIVE CELLS TO ORGAN FORMATION TO CREATE HAIR CELLS THAT COULD BE TRANSPLANTED. THE CURRENT TECHNOLOGIES HAVE BEEN ONLY ABLE TO GENERATE VESTIBULAR HAIRS. THEY ARE GETTING CLOSE TO MAKING COCHLEA LIKE HAIR CELL. THAT IS PROMISING. ONE OF THE BIGGER CHALLENGES IS EFFORTS TO DELIVER THESE CELLS TO THE COCHLEA. THIS IS LARGELY DUE TO THE FACT THAT HAIR CELLS, WE THINK, HAIR CELLS BETWEEN THE COCHLEA SIT BETWEEN THE BASILAR MEMBRANE AND RETICULAR LAMINA SO THIS IS A CHALLENGE USING STEM CELLS. WE ARE HAVING MORE ENCOURAGING RESULTS FROM THE FIRST ONE. HOW CAN DEVELOPMENTAL BIOLOGY HELP? IF WE INDUCE CELLS TO CHANGE THEIR FATES, WE NEED TO BE ABLE TO UNDERSTAND THE MOLECULAR FACTORS THAT PLAY A ROLE IN HOW THAT ACTUALLY HAPPENS. HOW DOES A CELL TURN ON THE PATHWAY TO LEAD IT TO A HAIR CELL IN THIS PARTICULAR CASE. THREE AREAS I WILL MENTION BRIEFLY DURING THIS TALK. THE FIRST IS WE NEED TO IDENTIFY THE TRANSCRIPTION FACTORS, THE ACTUAL PROTEINS THAT TURN ON OTHER GENES THAT REGULATE HAIR CELL FORMATION. I WILL TOUCH ON TWO ASPECTS HERE. ONE IS PREEXISTING WORK FROM A NUMBER OF LABS INCLUDING MINE, ESSENTIALLY FOCUSED ON THE FIRST STEP THAT MUST OCCUR HERE WHICH IS THE GENERATION OF GENERIC HAIR CELLS. BASICALLY, WE WANT TO LOOK AT THE EARLIEST TIME POINT TO UNDERSTAND HOW WE START MAKING A HAIR CELL. WHAT WE HAVE LEARNED IS IN ORDER TO SUCCESSFULLY REGENERATE A FUNCTIONING AUDITORY ORGAN, WHAT WE NEED TO DO IS UNDERSTAND MORE ABOUT NOT ONLY DO WE MAKE A GENERIC HAIR CELL, BUT DRIVE THAT HAIR CELL TO A PARTICULAR PHENOTYPE AND FOR HEARING FUNCTION, OUTER HAIR CELLS AND INNER HAIR CELLS IN PARTICULAR. THERE IS SOME WORK TO SUGGEST IN ADDITION TO NEEDING TO PROVIDE POSITIVE GENES TO MAKE CELLS BECOME HAIR CELLS, IT MAY BE NECESSARY TO ELIMINATE INHIBITORY CUES THAT PREVENT SUPPORTING CELLS TO BECOME HAIR CELLS. SOMETHING THAT HAS BEEN INTERESTING IN THE LAST FEW YEARS IS WE NEED TO UNDERSTAND MORE ABOUT THE EPIGENETIC MODIFICATIONS WITHIN THE GENOME OF THOSE CELLS THAT WILL PREVENT CELLS FROM MAKING THIS CONVERSE FROM A SUPPORTING CELL TO A HAIR CELL. I WILL TALK ABOUT THAT IN THE NEXT FEW SLIDES. I WANT TO GIVE YOU A LITTLE PRIMER HERE ON HAIR CELL DEVELOPMENT WITHIN THE MOUSE ORGAN OF CORTI. THIS IS A PAINT FILL DONE BY DORIS WU, THE ADULT'S INNER EARER. YOU CAN SEE THE COKE OKLAHOMA SPIRAL. YOU CUT A CROSS SECTION. HERE IS THE INNER HAIR CELL, THREE OUTER HAIR CELLS AND THE VARIOUS TYPES OF PILLAR CELLS. IF WE GO BACK IN TIME WE CAN ASK WHEN DO WE SEE THESE CELLS FORM IN DEVELOPMENT. THIS IS A SERIES OF PAINT FILLS DONE BY DORIS, SHOWING THE MOUSE INNER HERE EMBRYONIC DAYS 11-17. YOU CAN SEE THE OUTGROWTH OF THE COCHLEAR DUCT BEGINNING TO SPIRAL. WE CAN LOOK AT CROSS SECTIONS AND FIND THE CELL AT ORGAN OF CORTI. 13, THERE IS NO SIGN OF HAIR CELLS OR SUPPORTING CELLS. EMBRYONIC DAY 15, THERE IS NO SIGN OF HAIR CELLS, BUT A GROUP OF CELLS HAVE BECOME POST MYTONIC THAT WILL GIVE RISE TO HAIR CELLS AND ARE CALLED PROSENSORY CELLS BECAUSE OF TWOMTAL POTENTIAL. BY EMBRYONIC DAY 17 WE CAN IDENTIFY THE HAIR CELLS WHICH ARE FORMING RIGHT HERE. HERE IS THE INNER HAIR CELL AND OUTER HAIR CELLS AND THE UNDERLYING SUPPORTING CELLS. THIS IS THE WINDOW OF TIME HAIR CELLS BEGIN TO FORM DAY 13 TO 17. I WANT TO TALK TO YOU ABOUT THE GENE MOST INTENSELY FOCUSED IN TERMS OF REGENERATION OVER THE LAST 20 YEARS. THAT IS A GENE CALLED ATOH1. IT IS A BASIC HELIX LOOP TRANSCRIPTION FACTOR. ID BINTS TO DNA AND BINDS TO OTHER TRANSCRIPTION FACTORS. IT WAS INTRIGUING TO LOOK AT FOR MAKING HAIR CELL, BECAUSE THIS CLASS, BHLHs, PLAY IMPORTANT ROLES IN A NUMBER OF DIFFERENT ANIMAL GROUPS INCLUDING DROSOPHILA. THE NAME ATOH1, THIS GENE IS A HOME LOG OF THE DROSOPHILA GENE ATONAL WHICH FLIES USE FOR HEARING AND PHOTORECEPTORS IN THE R8 PHOTORECEPTOR. WHAT MAKES ATOH1 INTERESTING? WE CAN LOOK WHEN IT IS EXPRESSED IN THE DEVELOPING COCHLEA. HERE ARE THE SAME CROSS SECTIONS. HERE AT E15, THE PROSENSORY REGION AND IF WE USE AN ANTIBODY TO DETECTION ATOH1 EXPRESSION, WE SEE IT TURNING ON A SMALL NUMBER OF CELLS IN 15. A FEW DAYS LATER THE ATOH1 IS STRONGLY LOCATED IN THE NUKELY OF THE HAIR CELLS. A FEW DAYS LATER TO P1 IN A MOUSE, THREE DAYS AFTER E17, ATOH1 PROTEIN IS GONE. IT IS EXPRESSED IN A BRIEF PERIOD OF TIME. IT IS ON AND OFF IN A QUICK PERIOD OF TIME. THE TIMING IS VERY CONSISTENT WITH PLAYING A ROLE POTENTIALLY IN THOSE EARLY DECISIONS OF CELLS BECOMING HAIR CELLS. IN FACT, IN RESEARCH THAT WAS DONE BY INITIATELY OVER 20 YEARS AGO AND A FOLLOW UP STUDY BY MY LAB AND OTHERS SINCE THEN ATOH1 IS ESSENTIALLY FOR HAIR CELL FUNCTION. THIS IS A WILD TYPE ANIMAL, SINGLE GROWTH HAIR CELLS HERE, THREE ROWS OF OUTER HAIR CELLS. THIS IS THE ATOH1 MOUSE, NO SIGN OF HAIR CELLS. WITHOUT ATOH1 NO HAIR CELLS FORM, DEMONSTRATING HOW CRUCIAL THIS GENE IS FOR MAKING HAIR CELLS. FOR REGENERATION WE ASK A QUESTION, IS ATOH1 SUFFICIENT TO MAKE A CELL BECOME A HAIR CELL? IT DOESN'T DEMONSTRATE THAT ATOH1 DRIVES THAT DECISION. THAT QUESTION HAS BEEN ASKED AND ADDRESSED BY A NUMBER OF LABS OVER THE LAST 20 YEARS. ONE OF THE NICER STUDIES IS DONE BY MIKE KELLY, WHO IS NOT RELATED TO ME, HE DOESN'T SPELL HIS NAME RIGHT, WHEN HE WAS A GRADUATE STUDENT WITH DR. CHIN AT EMS THERE ORY UNIVERSITY. HE COULD TURN ON EVERY HAIR CELL BY GIVING A COCKTAIL OF DRUGS. WHEN HE DID THIS AT P1 IS HE FOUND THE INDUCTION OF HUNDREDS OF ADDITIONAL HAIR CELLS THAT FORMED WITHIN THE DEVELOPING ORGAN OF CORTI. ATOH1 IS EFFICIENT AT INDUCING CELLS TO BECOME HAIR CELLS. SUGGESTING ATOH1 PLAYS A ROLE IN HAIR CELL REGENERATION. THAT POTENTIAL WAS INITIALLY ADDRESSED IN 2005 WHERE THEY TOOK GUINEA PIGS, TREATED THEM WITH TWO DIFFERENT DRUGS TO KILL MOST OF THE HAIR CELLS WITHIN THE INNER EAR. THEN INTRODUCED A VECTOR GENERATED BY A COMPANY OUTSIDE OF BETHESDA CALLED GENVEC THAT STRONGLY EXPRESSED ATOH1. WHAT THEY FOUND WAS VARIABLE LEVELS OF HAIR CELL PRESENCE IN THE INNER EARS OF THE GUINEA PIGS. THEY WERE DEAFENED, GIVEN THE ATOH1 DRUG AND WERE ABLE TO RECOVER FOR A MONTH. THESE ARE THREE DIFFERENT EXAMPLES, THIS IS THE CONTROL. WHAT YOU SEE ARE VARYING LEVELS OF WHAT LOOK LIKE HAIR CELL LIKE CELLS IN THE EARS OF THE ATOH1 EXPRESSING GUINEA PIGS AND FOUND CROSS SECTIONS VERY ODD LOOKING CELLS SUCH AS THIS ONE THAT HAS A MOR FOLG OF A SUPPORTING CELL. IT ALSO HAS WHAT LOOKED LIKE A VERY SMALL POSSIBLE STEREOCILIA STRUCTURE AT THE TOP. THEY SUGGESTED THESE MIGHT BE CELLS THAT WERE PAR RLGLY CONV CONVERTING. WHAT MADE THIS STUDY COMPELLING WAS THE ABR RESPONSES HERE. THESE ARE ABRs FROM FIVE SEPARATE ANIMALS. THIS IS THE CONTRA LATERAL EAR THAT DID NOT RECEIVE ANY INFECTION AND THE THRESHOLD SHOULD BE DOWN AROUND HERE. THE EAR TREATED STILL SHOWS AFTER 30 DAYS A SIGNIFICANT THRESHOLD. BUT IN THEIR TREATED ANIMALS, MANY SHOWED A RECOVERY OF FUNCTION, YOU CAN SEE HERE COMING DOWN WHAT WOULD BE CLOSE TO THE NORMAL LEVEL OF AUDITORY SENSITIVITY IN THESE EARS. THIS WAS THE FIRST TIME ANYONE HAD DEMONSTRATED RECOVERY OF AUDITORY FUNCTION IN A MAMMALIAN SYSTEM. SUBSEQUENT STUDIES HAVE LED TO SOME CONCERNS ABOUT HOW REPRODUCEABLE THIS RESULT IS. IF YOU TALK TO YOASH, HE THINKS THE MOST LIKELY EXPLANATION IS THE VIRUS WAS GIVEN SOON AFTER THE ANIMALS WERE DEAFENED. IT TURNS OUT ONE OF THE THINGS WE LEARNED ATOH1 CAN ACT AS A SURVIVAL FACTOR FOR HAIR CELLS. RATHER THAN REGENERATION, THE PRESENCE OF ATOH1 HELPED THE HAIR CELLS SURVIVE THE DRUG INSULT GIVEN TO THEM. THERE IS SOMETHING STILL UNCLEAR ABOUT WHAT WAS GOING ON HERE. BASED LARGELY ON THE RESULTS OF THIS STUDY, GENVEC KKTED WITH A CLINICAL TRIAL TO SEE IF ATOH1 CAN REGENERATE. 22 PATIENTS WERE ENROLLED IN THE STUDY. EACH PATIENT RECEIVED CG F166, ATOH1 EXPRESSION. THEY WERE FOLLOWED FOR TWO YEARS TO SEE IF THERE WAS RECOVERY FUNCTION. IT TOOK A LONG TIME FOR THE STUDY TO BE DONE. THE RESULTS WERE PUBLISHED IN MARCH 2021. A LONG TIME AFTER THE STUDY WAS DONE. THEY WEREN'T PUBLISHED. OUT OF 22 PATIENTS, TWO SHOWED SLIGHT INCREASE AND OTHER 20 SHOWED NO CHANGE. NOVARTIS CONCLUDED THIS WAS NOT PURSUING FURTHER AND THEY HAVE NOT ANNOUNCED TO GO FURTHER WITH ANY FURTHER STUDIES. SO IT RAISES A PRETTY INTERESTING QUESTION WHICH IS WHY DIDN'T THE CLINICAL TRIAL WORK? AND ONE OF THE PROBLEMS WITH -- OR ONE OF THE THINGS THAT CAN HAPPEN WITH CLINICAL TRIALS IS AS A CLINICAL TRIAL IS GOING ON, BASIC SCIENTISTS ARE CONTINUING TO DO RESEARCH ON THE SAME QUESTIONS. AT SOME POINT WE IN THE FIELD RESEARCHED A POINT WE WERE CONFIDENT THE CLINICAL TRIAL WOULDN'T WORK BECAUSE OF THE BASIC SCIENCE EXPERIMENTS THAT HAD BEEN DONE. ONE OF THE FIRST THINGS WE LEARNED WAS THE SAME STUDY THAT MIKE KELLY DID. HERE IS THE DATA WHERE MIKE INDUCED EXPRESSION OF ATOH1 ON POST NATAL DAY ONE. IF HE WAITED A WEEK FROM P1 TO P7, HE SAW MUCH LOWER LEVEL OF HAIR CELLS. IF HE WAITED TWO WEEKS TO POST NATAL DAY 14, HE SAW NO EXTRA HAIR CELLS. SUGGESTING THAT SOMETHING SIGNIFICANT WAS CHANGING WITHIN THE EPETHELIUM WITHIN THESE TIME POINTS. AS FAR AS WE COULD TELL, ATOH1 WAS NOT WORKING. THE CELLS WEREN'T LISTENING AND WEREN'T CHANGING INTO HAIR CELLS. ONE CAN ASK A VERY RELEVANT QUESTION, WHICH IS WHY? WHAT HAPPENS WITH THESE CELLS THAT LEADS TO THEM LOSING THE ABILITY TO RESPOND TO ATOH1 SIGNAL? IT PROBABLY HAS TO DO WITH EPIGENETICS. IT REFERS TO CHANGES IN THE STATE OF CHROMOSOMES, THE DNA IN CHROMOSOMES THAT CAN FUNDAMENTALLY ALTER HOW EASY OR HARD FOR TRANSCRIPTION FACTORS TO GAIN ACCESS TO THE GENES WITHIN THAT CHROMOSOME AND TURN THAT GENE ON OR OFF. THERE ARE ESSENTIALLY TWO TYPES OF MODULATIONS WE CAN TALK ABOUT. ONE OR METHYLATION OF CISTENES. THE SECOND THE HISTONE, DNA IS WOUND AROUND HISTONE, WHETHER IT IS TIGHT OR LOOSE IT CAN REDUCE THE TRANSCRIPTION FACTOR TO TURN ON GENES. A FANTASTIC STUDY THAT CAME OUT JUST LAST YEAR SOUGHT TO LOOK AT THIS IN TERMS OF THE CHANGES IN GENE ACCESSIBILITY FOR ATOH1 TARGTSS DURING DEVELOPMENT OF HAIR CELLS AND SUPPORTING CELLS IN THE COCHLEA. I DON'T WANT TO SPEND A TON OF TIME, BUT BASICALLY NEAL USED A CODE FOR THE STATE OF HISTONE H3s, TO TELL IF A REGION OF DNA IS ON, OPEN AND CAN BE BOUND BY TRANSCRIPTION FACTORS. ON A STATE CALLED OFF, BUT POISED. IN THIS STATE THE GENES ARE TURNED OFF, BUT UNDER CERTAIN CIRCUMSTANCES, TRANSCRIPTION FACTORS CAN REVERSE THAT AND OPEN THE DNA BACK UP AND TURN THOSE GENES ON. A FINAL STATE WHICH CONTAINS JUST PARTS OF THE DNA THAT HAVE JUST THIS H3K27ME3. THOSE ARE ESSENTIALLY TURNED OFF. WOUND TIGHT. WHAT NEAL'S LAB DID WAS TO COMPARE THE GENE EXPRESSION IN HAIR CELLS AND SUPPORTING CELLS DURING DEVELOPMENT AND IDENTIFY A LARGE CATALOG OF GENES EXPRESSED IN HAIR CELLS, MOST ARE ATOH1 TARGET GENES, TURNING THEM ON TO MAKE THEM BECOME A HAIR CELL. THEY THEN ASKED IF WE LOOKED AT THE STATE OF THE ENHANCERS AND PROMOTERS. GENE REGULATORY REGIONS FOR THE ATOH1 GENES. COMPARING THEM IN HAIR CELLS AND SUPPORTING CELLS R THEY DIFFERENT? AT THIS EARLY TIME SUPPORTING CELLS CAN TURN INTO HAIR CELLS, BUT NORMALLY DON'T. WHAT NEAL FOUND IS IN NORMALLY DEVELOPING HAIR CELLS, PROMOTE ORS OR ENHANCERS FOR HAIR CELL GENE MOST WERE IN THIS ON STATE, HERE, THIS TYPE OF SITUATION HERE BEING TURNED ON BY ATOH1 AND TURNED INTO HAIR CELLS. IN THE SUPPORTING CELLS HE FOUND THE GENES WERE IN THE OFF BUT POISED SITUATION. IT TONED OUT THEY ARE NOT TURNED ON IN THOSE CELLS BECAUSE THEY ARE NOT -- THOSE SUPPORTING CELLS ARE NOT GOING TO DEVELOP AS HAIR CELLS BUT THEY COULD BE TURNED ON THE ATOH1 IS EXPRESSED IN THE CELLS AS MIKE KELLY DID IN HIS STUDY. THAT IS EXACTLY CONSISTENT WITH WHAT WE WOULD EXPECT. WHAT NEAL'S LAB VERY NICELY SHOWED IS IF YOU LOOK AT THOSE GENES THAT ARE OFF BUT POISED, CRUCIAL TO MAKE A CELL BECOME A HAIR CELL, YOU LOOK AT THEIR STATUS AS THEY DEVELOP AND GET OLDER. IF YOU GO FROM E17 TO P1 TO P6 IN THE SUPPORTING CELLS, THE NUMBER OF GENERALS THAT GO FROM OFF BUT POISED TO OFF SIGNIFICANTLY INCREASES. THIS BASICALLY LOOKING AT THIS MARK HERE, H3K4ME1 WHICH LETS GENES BE IN A POISED SITUATION, THE NUMBER OF PROMOTERS AND ENHANCERS GO DOWN. WHAT NEAL NICELY SHOWED IS IN TERMS OF THE EPI GENOME, ATOH1 NEEDS TO TURN ON ARE BECOMING LESS TO TURNING ON IN THE CELLS. THAT IS KEY TO CHANGING THOSE CELLS TO HAIR CELLS IN RESPONSE THE ATOH1. AND SUGGESTS IF WE USE ATOH1 FOR REGENERATION, WE NEED TO CONSIDER THE STATE OF THE EPI GENOME IN THOSE CELLS. REALLY INTERESTING STUDY THAT SHED A LOT OF LIGHT ON WHAT WE ARE THINKING ABOUT NEXT. I WANT TO MENTION A COUPLE OF OTHER STUDIES LOOKING AT ATOH1 AND HOW IT WORKS. WE LOOK AT THE ATOH1 PROTEIN AND POST TRANSLATION. RATHER THAN LOOKING AT THE GENE, WE ARE LOOKING AT THE PROTEIN. THE FIRST STUDY WAS DONE BY XIE AND SHE IDENTIFIED A HIGHLY CONSERVED SERINE -- THIS IN THE GREEN IS THE BASIC HELIX TO HELIX DOMAIN. SHE IDENTIFIED A -- SHE CREATED A MUTANT. SORRY. NOT THAT, THIS. SHE CREATED A MUTANT IN IT COULD NOT BE PHOSPHORYLATED. THEY ANALYZED THE PHENOTYPE IN THE MICE. THEY OBSERVED IN 193 MUTANT IS WHILE THE HAIR CELLS ARE PRESENT, WHILE HAIR CELLS ARE PRESENT AT BIRTH, THEY THEN START TO DEGENERATE OVER TIME. I'M SHOWING YOU A MILD PHENOTYPE. IF YOU TAKE A MOUSE THAT HAS 193 AND NO SECOND COPY, ALL THE HAIR CELLS ARE ALMOST ALL GONE BY P60. THESE MICE SUFFER FROM AGE-RELATED HEARING LOSS AS YOU WOULD EXPECT AS THEY LOSE HAIR CELLS. THE SIMILAR STUDY DONE BY SHEYKHOLESLAMI ET AL., LOOKED AT THIS CLOSE, NOT PHSPHOALATYED. IT IS SIMILAR PHENOTYPE. MUTATIONS IN THE HELIX DOMAIN LEADS TO NOT COMPLETION LOSS OF FUNCTION OF ATOH1, BUT ASSEMBLY OF HAIR CELLS THAT ARE NOT GOING TO FUNCTION CORRECTLY OR SURVIVE OVER TIME. INSIGHTS INTO POST TRANSLATION TO THE HELIX DOMAIN IN ATOH1 FUNCTION. LASTLY, I WANT TO TALK ABOUT A COLLABORATIVE FUNCTION THAT WENT ON BETWEEN MY LAB AND --'S LAB WHERE WE LOOKED AT A NUMBER OF FAMILY KAREN IDENTIFIED FROM THE MIDDLE EAST THAT HAD NOVEL MUTATIONS LEADING TO DEAFNESS. ONE OF THE ONES KAREN IDENTIFIED IN A FAMILY HAD FIVE GENERATIONS OF NONSYNDROMIC HEARING LOSS AT DELETION AT RESIDUE 1030. THIS IS CLOSE TO THE END OF THE GENE, END OF THE PROTEIN. WHAT HAPPENS IS THE LAST 10 AMINO ACIDS ARE CHANGED AND SIX ADDITIONAL AMINO ACIDS ARE ADDED TO THE PROTEIN. ONE OF THE FIRST QUESTIONS WE ASKED IS DOES THIS MAKE THE PROTEIN INACTIVE. THAT IS NOT THE CASE. IF WE OVEREXPRESSED THIS MUTATED VERSION OF ATOH1 IN SUPPORTING CELLS IN DEVELOPING EAR, IN HAIR CELL FORMATION. IT WAS NOT THE FACT THAT THE PROTEIN WAS INACTIVATED. WE WONDERED IF THIS MUTATION WOULD PLAY A ROLE IN PROTEIN STABILITY. ATOH1 IS TURNED ON FOR A BRIEF TIME DURING NORMAL DEVELOPMENT. WORK FROM TWO OTHER LABS DEMONSTRATED MUTATIONS IN A NUMBER OF SERINES RESULTED IN THE PROTEIN BECOMING MORE STABLE. ATOH1 STUCK AROUND FOR A LONGER PERIOD OF TIME. WE WONDER IF THIS MUTATION IN THIS RHEE ONOF THE PROTEIN INCREASED STABILITY. THAT TURNED OUT TO BE THE CASE. THIS IS A STABILITY ASSAY FOR ATOH1. WE EXPRESS ATOH1 IN CELLS, BLOCK PROTEIN SYNTHESIS AND MONITOR THE ATOH1 IN THOSE CELLS OVER TIME. IT IS FAIRLY RAPIDLY DEGRADED ONCE WE STOP THE CELLS FROM MAKING ATOH1 PROTEINS. THIS BAND IS GETTING SMALLER. IN THE ATOH1C1030DELC MUTANTS, IT IS NOT DEGRADED AND STICKS AROUND ALMOST THE SAME LEVEL THROUGHOUT THE COURSE OF THE EXPERIMENT. WHAT THIS SUGGESTS IS ATOH1 STICKING AROUND FOR TOO LONG IN CELLS MAY, IN FACT, BE BAD FOR THOSE CELLS AND LEAD TO A SITUATION WHERE THE CELLS DON'T SURVIVE APPROPRIATELY LEADING TO PROGRESSIVE DEATH IN SOME OF THOSE PATIENTS. KAREN'S LAB AND MINE ARE WORKING ON THIS. WE DON'T KNOW IF THERE ARE PHOSPHORYLATIONS AND ARE IN THE PROCESS OF MAKING A MOUSE WHERE WE ARE GETTING A BETTER UNDERSTANDING OF WHAT IS GOING ON IN TERMS OF HAIR CELL SURVIVAL. ANOTHER VERY INTERESTING ASPECT WE HAVE LEARNED ABOUT IN TERMS OF ATOH1 FUNCTION, NOT ONLY POST TRANSLATION MODIFIED, BUT IT MAY BE IMPORTANT FOR REGENERATION TO TURN ATOH1 ON AND OFF FOR A BRIEF PERIOD OF TIME. IT SEEMS THE CASE TOO LITTLE ATOH1 IS BAD AND TOO MUCH ATOH1 IS ALSO BAD. SO JUST TO SUMMARIZE WHERE WE ARE WITH ATOH1, THE GENE THAT HAS BEEN MOST INTENSELY LOOKED AT FOR REGENERATION. WE HAVE TO HAVE IT FOR HAIR CELL FORMATION. WE KNOW IT IS SUFFICIENT TO MAKE HAIR CELLS IN VERY YOUNG ANIMALS, BUT THE ABILITY BECOMES MORE LIMITED AS WE MOVE TO MORE MATURE ANIMALS IN TERMS OF THE ORGAN OF CORTI. WORK IN NEAL SEGAL'S LAB THE EPI GENOME IS CHANGING IN A WAY THAT PREVENTS ATOH1 FROM PRODUCING HAIR CELL FORMATION. I MENTIONED WE LEARNED MORE DETAILS ABOUT POST TRANSLATION THAT ARE IMPORTANT. I THINK AT THIS POINT WHERE WE STAND IS I THINK ANY REGENERATIVE EFFORT THAT USES GENE THERAPY IS GOING TO HAVE TO START WITH ATOH1. BUT IT IS NOT GOING TO BE THE CASE THAT ATOH1 IS A MAGIC BULLET THAT BY ITSELF WILL INDUCE REGENERATION. WE WILL HAVE TO INCORPORATE ATOH1 WITH OTHER TYPES OF TREATMENTS TO SUCCESSFULLY INDUCE HAIR CELL REGENERATION. I THINK THAT IS WHERE WE ARE MOVING IN THE FUTURE. OKAY, SO NOW I WOULD LIKE TO SWITCH GEARS AND TALK ABOUT WORK FROM MY OWN LAB. EXCUSE ME. THAT COMES BACK TO THIS QUESTION HERE. I MINGENTIONED WE CAN THINK OF ASPECTS OF HAIR CELL REGENERATION THAT MIGHT BE IMPORTANT. THE FIRST HAS TO DO WITH GENERIC HAIR CELL FORMATION. THE SECOND IS WHILE ATOH1 -- LET ME STEP BACK FOR A SECOND. ONE OF THE OTHER INTERESTING THINGS WE LEARNED ABOUT ATOH1 OR ATOH1 HOME LOG IS EXPRESSED IN EVERY HAIR CELL IN EVERY VERT BRAT WE LOOKED AT. ATOH1 IS VERY GOOD AT GENERATING THE GENETIC HAIR CELL DIFFERENTIATION PROCESS. WE WOULD LIKE TO REGENERATE THE SPECIFIC HAIR CELLS WE NEED, INNER AND OUTER HAIR CELLS FOR HEARING RECOVERY. MY LAB IS TRYING TO BUILD OUT MORE OF THE DEVELOPMENTAL PROCESS AT A MOLECULAR LEVEL TO UNDERSTAND THE TRANSCRIPTION FACTORS TURNED ON AS THE GENE IS BECOMING AN AUDITORY HAIR CELL. WE HAVE BEEN USING SINGLE CELL RNA SEQUENCES TO BUILD THAT PATHWAY. WHICH AM I TALKING ABOUT WITH SINGLE CELL RNA SEQUENCES? BASICALLY WE CAN COLLECT THE RNA AND THE MESSENGER RNAs EXPRESSED FROM SINGLE CELLS. WE WOULD LIKE TO COLLECT HAIR CELLS FROM DIFFERENT TIME PERIODS AND BUILD A TRAJECTORY FOR THOSE CELLS. THROUGH THEIR DEVELOPMENTAL PROCESS. SO SINGLE CELL RNA SEQUENCES REQUIRES TWO DIFFERENT PROCESSES, GETTING THE CELLS YOU ARE INTERESTED IN DOWN TO SINGLE CELLS AND THE SECOND IS COLLECTING RNA FROM THE CELLS. ABOUT SIX, SEVEN YEARS AGO, I HAD SOME GREAT PEOPLE IN MY LAB. THEY REALIZED THIS IS THE WAY WE NEEDED TO GO IN TERMS OF ASKING QUESTIONS ABOUT DEVELOPMENT WITHIN THE INNER EAR. WHAT THEY DID WAS GENERATE A TRIPPED TRANSGENETIC MOUSE WHERE ALL OF THE HAIR CELLS ARE RED AND MOST OF THE SUPPORTING CELLS ARE GREEN AND USED THIS LINE TO DEVELOP AN ASSOCIATION TECHNIQUE TO ISOLATE THE EPETHELIA FROM THE -- WE USED A COMMERCIAL PLATFORM CALLED THE 10X CHROMIUM SYSTEM TO CREATE DROPLETS THAT CONTAIN SINGLE CELLS FROM OUR COCHLEA AND SOMETHING CALLED THE GEM BEAD. THE ONES THAT ARE CRUCIAL ARE THAT IT CONTAINS WITHIN IT IS A PHYSICAL BEAD THAT IS ARRAYED WITH MULTIPLE DNA ALGOS THAT HAVE TWO CRUCIAL PARTS. THE FIRST IS AN ALGO DT, THE SECOND IS THE 10X BAR CODE, WHICH IS A SHORT RUN OF DNA NUKE -- NUCLEOTIDES. THE BAR CODE VARIES FROM EACH ONE. AFTER THE DROPLETS ARE CREATED WITH ONE CELL AND A GEM BEAD, COLLECT THE MRNAs AND DURING THE REPLICATION PROCESS EACH MRNA IS TAGGED WITH THE BAR CODE. WHEN WE GET THE SEQUENCES DATA BACK FROM THE MRNAs, WE NOT ONLY GET DATA ON THE GENE THAT WAS, THAT MRNA CODED FOR, BUT WE ALSO GET A BAR CODE. ALL THE GENES THAT COME BACK WITH THE SAME BAR CODE WE KNOW CAME FROM THE SAME CELL. WE CAN THEN USE THIS REPORT TO LOOK AT THE TRANSCRIPTZOMES. THIS IS A BIRD'S EYE VIEW APPROACH, 150,000 READS PER CELL. THIS DATA ON ABOUT 2,000 GENES. WE ARE GETTING A BIRD'S EYE VIEW OF THE CELL TIMES. IN THIS CASE WE GET DATA FROM THE THREE PRIME END OF EACH TRANSCRIPT. WE CAN REALLY JUST COUNT THE GENES THAT ARE THERE. WE ARE INTERESTED IN TAKING A STEP UP HERE IN THE FUTURE AND BEING ABLE TO ACTUALLY GET FULL-LENGTH READS AND POTENTIAL SPLICE VARIANT RESEARCH WHICH WE ARE WORKING ON WHO RUNS THE SEQUENCES COURT FOR NIDCD. FOR THIS TALK WE USE THREE PRIME READS TO IDENTIFY HAIR CELLS AT DIFFERENT DEVELOPMENTAL TIME POINTS. MANY OF YOU HAVE SEEN A GRAPH LIKE THIS. A T MAP PLOT. EVERY DATA IS FROM A SINGLE CELL. THE CLOSER THE CELLS ARE TO ONE ANOTHER, THE CLOSER THEIR TRANSCRIPTOMES AND WE LEARNED MACHINE LEARNING TO IDENTIFY SIMILAR TRANSCRIPTOMES AND CAN IDENTIFY THE DIFFERENT CELL TYPES WE SEE. THIS IS OUR DATA WE COLLECTED AT P1. WE HAVE ABOUT 10,000 CELLS HERE AND YOU CAN SEE THAT THE HAIR CELLS ARE RIGHT HERE AND RIGHT HERE. FOR THIS TALK, WE WILL FOCUS ON THE OUTER HAIR CELLS BECAUSE WE GET MORE. RATHER THAN BEING IN A TIGHT CIRCLE, THE OUTER HAIR CELLS ARE IN A SMEAR. A NUMBER OF THINGS CAN DRIVE THIS DISTRIBUTION. WHAT IS DRIVING THE DISTRIBUTION IN THIS EXAMPLE IS THESE CELLS ARE SLIGHTLY DIFFERENT STAGES OF DEVELOPMENT. CELLS WITHIN THE ORGAN OF CORTI DEVELOP IN A GRADIENT. THE FIRST HASTINGS GROW AT THE BASE AND EXTEND TOWARD THE APEX OF THE COCHLEA. YOU GET HAIR CELLS AT DIFFERENT STAGES OF DEVELOPMENT. THAT IS USEFUL FOR TRYING TO BUILD A TRAJECTORY. WHAT WE DID FOR THIS STUDY IS COMBINED THESE CELLS FROM P1 TO SIMILAR COLLECTIONS FROM E14, E16, P7. WE TOOK THE DATA FROM EACH CELL, PUT THEM TOGETHER AND USED MACHINE LEARNING TO ACTUALLY GENERATE A DEVELOPMENTAL TRAJECTORY FOR OUTER HAIR CELL FORMATION. EACH DOT IS A CELL. THEY ARE COLOR CODED BASED ON THE DAY THEY WERE COLLECTED. UNBIASED MACHINE LEARNING TO ARRAY THEM FROM THE LEAST MATURE CHELS TO THE MOST MATURE CELLS. THE E13 ARE HYDEN BEHIND. E16, P1 AND P7. WE CAN LOOK AT EXPRESSION OF GENES IN THE CELLS. WE WERE ABLE TO IDENTIFY FOUR PHASES OF GENE EXPRESSION WITHIN THIS DEVELOPMENTAL TRAJECTORY WE CALL PSEUDOTIME. SOME GENES ARE TURNING ON, TWO PULSES AND GENES THAT ARE TURNING ON. SHOW THIS IN GRAPHICAL FORMAT. PHASE ONE GENES TURNING OFF, TWO PULSES OF PHASE TWO AND PHASE THREE AND THESE FAIR FOUR GENES. WE CAN NOW TAKE THIS DATA TO TRY TO IDENTIFY TRANSCRIPTION FACTORS THAT MAY PLAY ROLES IN EACH PHASE OF HAIR CELL DEVELOP. THIS IS WORK I DID WITH CHENG AT NIDCD. THESE BOXES REPRESENT TRANSCRIPT FACTORS THAT ARE INVOLVED IN EACH PHASE. WHILE WE DON'T KNOW THIS FOR SURE, WE BASICALLY THINK WE CAN LOOSELY ASSOCIATE THESE PHASES WITH THESE DIFFERENT PROCESSES WITHIN HAIR CELL FORMATION. DOWN REGULATION OF PRECURSOR GENES. WE THEN SEE A PULSE OF GENERATION OF GENERAL HAIR CELL SPECIFICATION GENES. WE THEN HOPE WE HAVE PHASE THREE SPECIFIC HAIR CELLS AND FINALLY GENES TURNED ON IMPORTANT FOR HAIR CELL FUNCTION. WE SEE GENES INVOLVED WITH TMC. SO IF WE LOOK AT THIS GROUP OF GENES, WE CAN VERY REASSURINGLY SEE WHAT WE WOULD CONSIDER TO WITH THE USUAL SUSPECTS. TRANSCRIPTION FACTORS WE ALREADY KNOW THAT ARE INVOLVED IN HAIR CELL FORMATION. HERE ARE SEVERAL OTHER GENES SHOWN TO IDENTIFY AS A ROLE IN HAIR CELL FORMATION. A NUMBER OF OTHER GENES THAT MIGHT BE PLAYING A ROLE IN HAIR CELL FORMATION THAT WE DON'T KNOW AND WE ARE IN THE PROCESS OF LOOKING AT THE VARIOUS GENES TO UNDERSTAND WHAT THEIR SPECIFIC ROLE MIGHT BE. I WOULD LIKE TO TALK TO YOU ABOUT ONE OF THESE GENES WE IDENTIFIED, THIS IS CASZ1, ZINC FINGER. CA STRKS Z1 IS A DROSOPHILA. IT PLAYS A ROLE IN REGULATING THE TEMPORAL CASCADE THAT ALTERS NEUROBLAST FATE. IT HELPS NEUROBLAST MOVE FROM ONE POSSIBLE CELL FATE TO ANOTHER. WITHIN INVERT BRATS IT HAS BEEN SHOWN TO REGULATE CELL FATE SPECIFICATION COMMITMENT AND DIFFERENTIATION. MUTATIONS LEAD TO NEUROBLASTOMA. REGULATIIING DIFFERENTIATION. IMPLICATED AS A CAUSATIVE GENE IN CHROMOSOME 1P.36 DELETION SYNDROME. WE WORKED WITH BETSY DRIVER TO FULLY CHARACTER CASZ1 IN THE EAR. HERE IS THAT DEVELOPMENTAL TRA GENETICRY I SHOWED YOU BEFORE, WE LOOK AT CASZ1 IT PEAKS HERE IN THIS SORT OF EARLY POST NATAL DAY ONE. WE CONFIRM THAT USING IN SICHO. YOU CAN SEE IT IS EXPRESSED HERE ON ONE OUTER HAIR CELL. IF WE LOOK AT E18, WE CAN SEE WITH A DIFFERENT HAIR CELL MARKER, A STRONG CASZ1 IN THE INNER AND OUTER HAIR CELLS. THIS GENE IS SPECIFIC FOR -- EXPRESSED IN INNERS AND OUTERS. WE CAN GO AND ASK ABOUT -- BECAUSE WE HAVE THIS DATA FROM SINGLE CELL WORK WHETHER CASZ1 TARGETS ARE HERE. THE P1, THE REDDER THE DOT IS THE MORE EXPRESSION OF THE GENE. CASZ1 ONE. STRONGLY EXPRESSED. HERE ARE FOUR CASZ1 TARGTS GENES. THEY ALL TURN ON BASICALLY TO EXTEND IN THE HAIR CELLS HERE, IN A PATTERN THAT SORT OF FOLLOWING BEHIND CASZ1 IN TERMS OF DEVELOPMENT. CONSISTENT WITH THE IDEA WE ARE SEEING MULTIPLE CASZ1 TARGETS. NOW IS ALWAYS THE CASE WITH THESE THINGS THE PROOF IS IN THE PUDDING. IF WE KNOCK OUT CASZ1 TO WE SEE A DEFECT IN HEARING. BECAUSE IT PLAYING A ROLE IN SO MANY ASPECTS OF VERTEBRA DEVELOPMENT, WE DELETED CASZ1 JUST IN THE INNER EAR. WE USED A COCHLEA SPECIFIC GENE CALLED EMS2, TO DRIVE EXPRESSION OF PRERECOMBINATES. THIS IS OUR CONTROL. ONE ALLELE OF CASZ, 1 IS STILL PRESENT. OUR MUTANT OF BOTH ARE PHLOXED SO IT LEADS TO A DELETION. WHAT WE SEE IS NOT A COMPLETE ABSENCE OF HAIR CELLS. HAIR CELLS ARE PRESENT WITHIN THE EARS OF THESE MICE. WE SEE SOME DEVELOPMENTAL DE DEFECTS. THIS IS WHERE THE PILLAR CELLS SHOULD FORM. THEY ARE NOT FORMING NORMALLY, WHICH CAN BE ARN INDICATION THE ENTIRE -- IS NOT FORMING. HAIR CELLS TEND TO GET BIGGER AS THEY DEVELOP. IF WE DO QUANTIFICATION OF THE SURFACE AREA WE SEE SIGNIFICANT DEFICIT IN CASZ1 MUTANTS IN TERMS OF SIZE. THESE MICE ARE VIABLE. WE LOOK IN THE ADULT EAR, ONGOING DEFECTS, SO IN PARTICULAR AS THE ANIMAL GOES FROM P1 TO MATURE, WE SEE THE PILLAR CELL SPACE GETS SMALLER BUT THE OUTER HAIR CELLS ARE MUCH MORE ORGANIZED. WE SEE DEFECTS IN ORGANIZATIONS, THE BUNDLES. MOST IMPORTANTLYs BECAUSE THESE ARE VIABLE, IF WE DO ASSESSMENT OF HEARING, WE SEE DEFECTS IN AUDITORY BRAIN STEM RESPONSE. HERE ARE CONTROLS AND MUTANTS WHICH SHOW ABOUT A 30DB SHIFT IN TERMS OF AUDITORY BRAIN STEM RESPONSE. THIS DATA IS VERY NEW, BUT WE CAN LOOK AT AUTOACOUSTIC EMISSION RESPONSE. IN OUR MUTANTS WE SEE THEM TRACKING WITH THE NOISE. SO WE HAVE A COMPLETE OF OTO ACOUSTIC AND OUTER HAIR CELL FUNCTION IN THESE MICE. VERY EXCITING RESULTS TO GO FROM OUR SINGLE CELL STUDIES TO IDENTIFICATION OF A NOVEL AND HEARING DEAFNESS GENE IN CASZ1. WE ARE WORKING TO UNDERSTAND BETTER. IN PARTICULAR WHAT WE WILL DO IS USING SINGLE CELL APPROACH TO ANALYZE THE TRANSCRIPTION OME IN CASZ1 MUTANT HAIR CELLS TO GET AT THE TARGETS OF CASZ1 LEADING TO HAIR CELL. IN CONCLUSION, I HOPE I CONVINCED YOU DEVELOPMENTAL BIOLOGY IS THE BEST GUIDE TO UNDERSTAND HOW WE INDUCE REGENERATION. I TALKED QUITE A BIT AT ATOH1, A KEY TRANSCRIPTION FACTOR IN HAIR CELL FORMATION AND WILL ALMOST CERTAINLY BE A KEY PLAYER IN ANY HAIR CELL REGENERATION APPROACH. I'M SHOWING YOU COMPELLING DATA THAT EPI GENETICS IS AN IMPORTANT CONSIDERATION AS WELL. IN MY OWN LAB WE ARE USING SINGLE CELL RNA SEQUENCES TO TAP INTO TO ACHIEVE SUCCESSFUL REGENERATION. I TOLD YOU DATA ON ONE GENE, CASZ1 TURNS OUT AH NOVEL GENE FOR HEARING. A FEW ACKNOWLEDGEMENTS. REBECCA HIP AND BETSY DRIVER, TWO FORMER MEMBERS OF THE LAB MIKE KELLY AND LIKHITHA KOLLA THAT WERE INVOLVED IN THE SINGLE CELL DATA. KAREN AVRAHAM WE DID THE ATOH1 WORK WITH. BOTAND BANFI FROM UNIVERSITY OF IOWA AND ANGELS THERE IKA DOETZIHOFER FROM JOHNS HOPKINS WITH THE ATOH1. I WILL STOP SHARING. >> THANK YOU, MATT, THAT WAS A FANTASTIC REALLY EXCITING TALK. DOES ANYBODY HAVE A QUESTION OR A COMMENT? ANDY. >> HEY, ANDY. >> HEY, MATT. THAT WAS A WONDERFUL TALK. THANK YOU SO MUCH. THINKING ABOUT THE CASZ1 STORY AND TRYING TO TIE IT BACK TO WHAT YOU WERE TELLING PEOPLE ABOUT EPI GENETICS EARLIER, SO IN THE RETINA THERE IS EVIDENCE THAT CASZ1 PROMOTTS SORT OF PHOTORECEPTOR FATE BY REPESZING GLIAL CELL FATE. IT RECRUITS SOME OF THESE NEGATIVE EPIGENETIC MODERATORS. THE NERVE COMPLEX AND SO ON. DO YOU -- I KNOW IT IS EARLY STAGES, BUT YOU COULD SEE AN ANALOGY WHERE IT MIGHT BE INVOLVED IN HAIR CELL SUPPORTING CELL DECISION. DO YOU SEE EVIDENCE IN YOUR MUTANTS FOR SUPPORTING CELL GENES STARTING TO COME ON OR DO YOU HAVE TO WAIT FOR THE RNA SEAT TO FIGURE THAT OUT? >> THAT IS A GREAT POINT AND REALLY GOOD IDEA. WE COULD DO THAT WITHOUT WAITING FOR THE RNA SEQUENCE. WE HAVE NOT LOOKED AT THAT YET. WE'VE JUST, I MENTIONED BOTONE AND ANGELIKA, THEY WILL BE DOING THAT. THAT IS A GOOD IDEA. >> MATT, I THINK RUTH ANNE IS NEXT. >> YEAH. >> HI. THANKS, MATT. THAT WAS A LOT OF FUN. IT WON'T SURPRISE YOU THAT I'M GOING TO ASK YOU, BECAUSE I KNOW YOU ARE VERY AWARE OF THE VESTIBULAR EPITHELIA FOR COMPLEMENT MODEL FOR THIS WORK. ON THE ATOH1 MANIPULATION, DID INCREASING EXPRESSION OF ATOH1, DO YOU KNOW IF IT HAD IMPACT ON THE DIFFERENTIAL HAIR CELL TYPES IN THE VESTIBULAR EPITHELIA OR IS THAT UNEXPLORED TERRITORY. >> THE RESEARCH IS DONE WITH ATOH1 SUGGESTED -- ATOH1 IS MUCH BETTER AT MAKING HAIR CELLS IN ADULT EPITHELI THAN IN THE COCHLEA. THOSE ARE TYPE TWO. HAIR CELLS COME FROM ATOH1 INDUCTION ARE TYPE 2s. NO WAY THEY BECOME TYPE 1s. THAT IS A CASE WHERE ADDITIONAL SPECIFICATION FACTORS ARE NEEDED TO MAKE THE TYPE ONE PHENOTYPE. >> I WAS THINKING MORE OF THE FACT THAT TYPE 1 CELLS DON'T EXPRESS ATOH1 AND TYPE 2s DO IN THE ADULT. >> THAT IS TRUE. YEAH. >> YOU MIGHT GET AN EFFECT ON THE NUMBERS OF TYPE 1s IN THOSE ANIMALS. AND ANOTHER SORT OF RELATED QUESTION ON THE CASZ1 MUTANT. THERE IS EMX2 EXPRESSION IN THE ODOLITH, AT LEAST IN UTRICAL IN A SPECIFIC ZONE. HAS ANYBODY LOOKED AT THE IMPACT ON THAT? >> WE HAVE NOT DONE THE DISSECTIONS. THE MICE DO NOT SPIN. >> IT DOESN'T SURPRISE ME AT ALL. >> THEY DON'T HAVE A SIGNIFICANT VESTIBULAR DEFICIT. WE HAVE NOT LOOK T AT THE EPHET EPHETHELIUM TO SEE IF THERE IS A DIFFERENCE IN HAIR CELLS. >> THANKS A LOT. >> THANK YOU. >> GREAT TALK. >> THANK YOU. >> CYNTHIA. >> HI, MATT. THANKS FOR THAT TALK. I THINK ALL OF US APPRECIATE AGE-RELATED HEARING LOSS IS PROBABLY A MORE COMPLEX THING TO UNDERSTAND BECAUSE OF PERHAPS THE NORMAL AGING THAT OCCURS IN ADDITION TO THE ENVIRONMENTAL IMPACT YOU HAVE FROM OTOTOXIC DRUGS AND NOISE, ET CETERA. I'M JUST WONDERING, FROM THE STUDIES THAT HAVE BEEN DONE AND SIX ARE VERY WELL POWERED ACTUALLY NOW, I THINK THERE IS AN EVOLVING SCHOOL OF THOUGHT PART OF THIS IS A STRIAL PROBLEM, METABOLIC PROBLEM, ANOTHER LOSS OF HAIR CELLS. SO IN TERMS OF THE THINK IING BK TO THE NOVARTIS STUDY, HOW WELL WERE THOSE WHO GOT THE ATOH1 DRUG? HOW WAS IT TO SEPARATE THE GROUPS THAT MIGHT NEED TO BE AND IS IT POSSIBLE THAT BASICALLY SOME PEOPLE WOULD NEED SOMETHING THAT IS GOING TO ATTACK A STRIAL PROBLEM, BUT WOULD NEAT THE ATOH1 BOOST AS WELL. >> RIGHT. SO CERTAINLY THE INCLUSION CRITERIA DID NOT MAKE ANY NOTE FOR CONSIDERATION OF THOSE TYPES OF ISSUES. THEY WERE JUST LOOKING FOR PATIENTS WITH HEARING LOSS. THOSE WERE ESSENTIALLY THE CRITERIA, THEY HAD HEARING LOSS. AND SO THERE WAS NO CONSIDERATION MADE OF WHETHER IT WAS SOMETHING THAT POTENTIALLY HAD THEIR LIFE HISTORY AND WHAT MIGHT HAVE CAUSED THE HAIR CELL LOSS. I DON'T THINK, YOU KNOW, THEY DIDN'T TAKE PATIENTS WHO HAD MENIERS OR ANY OBVIOUS CO-FACTORS THAT MIGHT HAVE BEEN REFLECTIVE OF STRIAL DYSFUNCTION. BUT THERE WAS NO SPECIFIC CONSIDERATION OF THOSE TYPE OF NATURAL HISTORY CONSIDERATIONS IN TERMS OF INCLUSION. >> I WAS THINKING IF SOME PATIENTS HAD A NOISE NOTCH IN THEIR AUDIOGRAM, YOU COULD SEPARATE THE GROUPS THAT WAY. >> YEAH. RIGHT. IT WAS A PHASE 1 TRIAL, SO TECHNICALLY, IT WAS A SAFETY TRIAL. THE GOOD NEWS FROM THAT TRIAL IS THAT NOBODY'S HEARING GOT WORSE AND NOBODY HAD ANY SYSTEMIC PROBLEMS, SO IT IS QUITE ENCOURAGING FOR THE DEVELOPMENT OF GENE THERAPY FOR THE INNER EAR IN TERMS OF THE INNER EAR BEING A SAFE PLACE TO CONDUCT GENE THERAPY. BECAUSE IT WAS A FACE 1 TRIAL THE INCLUSION CRITERIA WERE FAIRLY BROAD. THEY WANTED TO BRING IN A GROUP OF PATIENTS TO SEE IF THEY WERE GOING TO HAVE ANY PROBLEMS. AND NIRUPA. >> YES, HI, MATT, THANK YOU. >> HI. >> SO MY QUESTION HAS TO DO WITH THE DEVELOPMENTAL PROGRESSION. YOU, IN YOUR MOUSE STUDY, HOW HAD P7 AS THE OLDEST MICE WITH THE, I IMAGINE, VERY WELL JUSTIFIED, BASIS THAT OFFLINE YOU HAD SEEN THAT THINGS DON'T PROGRESSIVELY GET VERY DIFFERENT TRANSCRIPTIONALLY AFTER THAT. HOW MUCH DO WE KNOW ABOUT THE TRANSCRIPTIONAL DEVELOPMENTAL PROGRESSION IN HUMAN? AND IS IT POSSIBLE THAT THERE ARE ADDITIONAL CASCADES OF TRANSCRIPTIONAL TARGETING SUCH THAT THERE ARE -- THERE'S AN ADDITIONAL STOP POINT WHERE YOU CAN AGAIN. SO YOU FOUND CASZ1 AS A SUBSEQUENT TRANSCRIPTION SORT OF REGULATION, MAJOR REGULATION POINT AND YOUD COULD SEE THAT FROM THE EPIGENETIC CHANGES IN THAT TIME FRAME. I'M WONDERING WHAT YOU KNOW ABOUT THAT? >> SO P7 WAS NOT, IT WAS JUSTIFIED NOT SO MUCH BASED ON FUNCTIONAL DATA AS VERY TECHNICAL ISSUE. >> OH. >> WHICH WAS THAT WE CAN'T, HAIR CELLS BECOME, THE COLLECTION PROCESS TAKES A COUPLE OF HOURS. HAIR CELLS, AS THE EPITHELIAM MATURES. WE TRIED TO GET SOME LATER TIME POINTS THE HAIR CELLS WERE DYING SO QUICKLY THE DATA WAS NOT RELIABLE. WE STOPPED AT P7 BECAUSE WE FELT DIFFERENTIATION OF HAIR CELLS WAS DONE, BUT WITH THE TECHNICAL ABILITY WE HAD RIGHT THEN, TECHNIQUES WE COULD USE, WE COULDN'T GET RELIABLE DATA AT OLDER TIME POINTS. SO IT IS PROBABLY -- WE PROBABLY NEED TO GO ANOTHER THREE, FOUR DAYS IN A MOUSE TO GET TO FULLY FUNCTIONAL HAIR CELLS. >> YES. >> AND THAT IS SOMETHING THAT IS A CHALLENGE BECAUSE HAIR CELLS BECOME SO -- ESPECIALLY OUTER HAIR CELLS BECOME SO FINICKY, THAT APPROACH IS NOT GOING TO WORK. THERE ARE OTHER APPROACHES THAT WE CAN USE, BUT THEN WE WOULD BY TRYING TO WED TWO DIFFERENT BIOINFOMATIC PROCESSES TO BUILD THE SPECTRUM. WE WANT TO DO THAT. WE ARE NOT AT THE END SO WE CAN'T IDENTIFY EVERY TRANSCRIPTION FACTOR FROM THE DATASET WE HAVE RIGHT NOW. WE NEED TO WORK ON BETTER WAYS TO GET THE OLDER HAIR CELLS TO APPROPRIATELY PROFILE THEM TO BUILD A MORE COMPLETE TRAJECTORY. >> YEAH. AND THEN -- I'M SORRY. GO AHEAD, NIRUPA. >> I WAS THINKING, TOO, SEPARATING THE HAIR CELLS FROM THE SUPPORTING CELLS. BUT PERHAPS THAT COULD BE PARSED BIOINFOMATICALLY. >> THERE ARE APPROACHES. -- CLAMPERS ARE GOOD AT GETTING DISASSOCIATION OF ORGAN OF CORTI. THERE HAVE BULLPEN STUDIES WHERE HERE IS THE CELL, YOU CAN SEE IT IS AN OUTER HAIR CELL AND THEY PICK IT UP. IT IS A MUCH LOWER THROUGHPUT WAY OF DOING THING AND WEDDING THAT DATA WITH THE HIGHER THROUGHPUT DATA CAN BE CHALLENGING. THAT IS PROBABLY THE WAY WE ARE MOVING. FOR THE OLDER AGES WE WILL HAVE A LOT MORE TRANSCRIPTIONAL DATA ON A LOT FEWER CELLS. IT WILL BE GOOD DATA, NOT JUST THE SAME DATA FOR THE YOUNGER AGES AND WEDDING THAT TOGETHER WILL BE A CHALLENGE. >> I HATE TO CUT OFF A GREAT CONVERSATION. THIS HAS REALLY BEEN INTERESTING. ANIL, WILL YOU FOLLOW UP WITH MATT SEPARATELY AND WE WILL MOVE TO THE NEXT PRESENTATION. OKAY. THANK YOU SO MUCH, MATT. THAT WAS OBVIOUSLY A GREAT, GREAT TALK. >> THANK YOU. >> SO NEXT WE'LL MOVE ON TO THE ALL OF US RESEARCH PROGRAM PRESENTATION. DR. GEOFF GEOFF IS WITH US TO-- DR. GEOFF GINGS BURST IS THE CHIEF MEDICAL AND SCIENTIFIC OFFICER OF THE ALL OF US PROGRAM AT NIH. HE LEADS THE DIVISION OF MEDICAL AND SCIENTIFIC RESEARCH AND RESPONSIBLE FOR HELPING TO SET THE SCIENTIFIC VISION AND THE STRATEGY FOR THE PROGRAM. HE ALSO OVERSEES THE PROGRAM'S COLLECTION AND CURE RATION OF DATA. THE INTEGRATION OF NEW DATA TYPES TO SUPPORT A WIDE RANGE OF IMPACTFUL SCIENTIFIC DISCOVERIES. PRIOR TO JOINING ALL OF US, I KNEW DR. GINSBURG AT DUKE UNIVERSITY. WE WERE COLLEAGUES THERE. HE WAS THE FOUNDING DIRECTOR FOR THE CENTER FOR APPLIED GENOMICS AND PRECISION MEDICINE. HE PIONEERED THE DEVELOPMENT OF NOVEL DIAGNOSTICS. WE INVITED DR. GINSBURG HERE TO TELL US ABOUT THE ALL OF US PROGRAM IN GENERAL AND ALSO A LITTLE BIT ABOUT THE POTENTIAL FOR PERFORMING STUDIES RELATED TO NIDCD MISSION AREAS. SO THANK YOU, GEOFF, VERY MUCH FOR BEING WITH US. >> AND THANK YOU, DEB, AND IT IS REALLY GREAT TO HAVE YOU LEAD THE WAY, BLAZING A TRAIL FROM DUKE TO NIH THAT I COULD FOLLOW. AND ALSO THANK YOU FOR INVITING ME TO THIS SESSION. IT WAS A REAL PRIVILEGE TO HEAR DR. CUNNINGHAM DESCRIBE THE INTRAMURAL RESEARCH PROGRAM AS WELL AS DR. KELLEY ON DEVELOPMENTAL BIOLOGY RELATED TO HEARING AND HAIR CELLS. WE ARE GOING TO SHIFT GEARS. THIS IS SOMETHING MORE CLINICALLY ORIENTED IN THIS SESSION. I'M GOING TO TELL YOU ABOUT THE ALL OF US RESEARCH PROGRAM TO LEVEL SET WITH COUNCIL AN GUESTS. I WANT TO TELL YOU ABOUT THE KINDS OF DATA WE HAVE BEEN COLLECTING. I ALSO WANT TO HIGHLIGHT THE CONCEPT OF AN ANCILLARY STUDY, A MECHANISM BY WHICH WE WILL ENGAGE WITH OTHER INSTITUTES AND CENTERS AT NIH. OBVIOUSLY, IT IS RELEVANT TO THIS DISCUSSION WITH NIDCD AND I WILL MAYBE SHARE WITH YOU THE LAST SLIDE SOME MUSINGS ABOUT HOW ALL OF US AT NIDCD COULD POTENTIALLY COLLABORATE. YOU ARE THE EXPERTS. I'M JUST SETTING THE STAGE. SO THE ALL OF US RESEARCH PROGRAM, YOU MAY HAVE REMEMBERED IT AS THE PRECISION MEDICINE INITIATIVE STARTED BY PRESIDENT OBAMA AND LAUNCHED IN 2016 AS ALL OF US. OUR VISION IS REALLY TO ACCELERATE HEALTH RESEARCH, MEDICAL BREAK THROUGHS THE AND TO ALSO ENABLE IN THE CLINIC INDIVIDUALIZED PREVENTION, TREATMENT, AND CARE FOR ALL OF US WITH SMALL AO AND U. MEANING TO REPRESENT THE FULL DIVERSITY OF THE UNITED STATES POPULATION. WE BUILT THIS STRATEGY BY FORMING A STRATEGIC PARTNERSHIPS AND PARTICULARLY PARTNERING WITH OUR PARTICIPATING COMMUNITY AND HAVING THEM ENGAGE AND WILLING TO SHARE THEIR DATA. CREATING WHAT WE THINK IS ONE OF THE LARGEST BIOMEDICAL RESEARCH DATABASES ON THE PLANET. TO USE THIS AS A REAL MAGNET TO GALVANIZE COMMUNITIES AND NIH AND EXTRA MURALLY AND INTERNATIONALLY AND COMMERCIALLY EVENTUALLY TO HELP ENABLE US TO ACHIEVE THE VISION AT THE TOP. SO OUR GOALS ARE TO RECRUIT A MILLION OR MORE INDIVIDUALS ACROSS THE UNITED STATES REPRESENTATIVE OF OUR POPULATION. ACTUALLY, WE ARE INTENTIONALLY RECRUITING OVERRECRUITING UND UNDERREPRESENTED MINORITIES IN BIOMEDICAL RESEARCH. TODAY WE CONSENTED OUR 500,000th PARTICIPANT. 372,000 PARTICIPANTS DATA HAS GONE THROUGH OUR CURE RATION PROCESS, WHERE IT IS QUALITY CHECKED TO BE RELEASED IN WHAT WE CALL OUR COMMON DATA REPOSITORY. AS YOU CAN SEE ON THE RIGHT, THERE ARE DATA FROM AMONGST THE 372,000, 80% ARE FROM UNDERREPRESENTED AND PRIOR MEDICAL RESEARCH ACTIVITIES AND 45% IDENTIFY AS RACIAL OR ETHNIC MINORITIES. SO OUR STRATEGY HAS BEEN FOCUSED ON PARTICIPANT ENGAGEMENT IN COMMUNITIES AROUND THE UNITED STATES, PARTICULARLY THOSE THAT HAVE NEVER BEEN INVOLVED IN RESEARCH STUDIES TO ASSEMBLE A LARGE DATASET THAT IS BIOLOGICAL, MOLECULAR AND SOCIAL. I WILL TELL YOU MORE ABOUT THAT IN A MOMENT. TO PROVIDE A VERY FACILE AND NIMBLE OPEN ACCESS PLATFORM I WILL ALSO DESCRIBE. SOME OF THE REAL SECRET SAUCE OF THE RESEARCH PROGRAM IS TO FOLLOW PARTICIPANTS FOR DECADES AND OTHER THEIR LIFE COURSE. WHILE WE INITIALLY STARTED RECRUITING INDIVIDUALS 18 AND ABOVE, NEXT YEAR WE WILL RECRUIT FROM PEDIATRIC POPULATIONS. THIS IS A SNAPSHOT OF THE DIMENSIONALITY OF DATA WE HAVE BEEN ABLE TO ASSEMBLE OVER THE LAST SEVERAL YEARS. IT COMINGS IN SEVERAL FORMS. PARTICIPANT PROVIDED INFORMATION INNER TERMS OF SURVEYS, WHERE WE HAVE 372,000 SURVEY ELEMENTS FROM PARTICIPANTS. I WILL TELL YOU MORE ABOUT THAT AS WELL AS THE DETAILS BEHIND PHYSICAL MEASUREMENTS OVER 300,000 PARTICIPANTS. INDIVIDUALS SHARE PERMISSION FOR US TO ACCESS AND SHARE THEIR ELECTRONIC HEALTH RECORD DATA. WE RECENTLY HAD A GENOMICS RELEASE. IT IS NEARLY 100,000 WHOLE GENOME SEQUENCES LEASED IN MARCH. OUR GOAL IS TO RELEASE 250,000 BY THE END OF THIS YEAR, PAIRED WITH GENO TYPING ARRAYS THAT ALLOW FOR MORE FOCUSED AND TARGETED WORK. AN INTERESTING ATTRIBUTE OF OUR PROGRAM IS THE WEARABLE TECHNOLOGY. WE HAVE BEGIN A WEARABLE TECHNOLOGY PLATFORM. WE HAVE BEGUN TO ASSEMBLE FIT BIT DATA AND APPLE HEALTH KIT. INTERESTINGLY ENOUGH, THIS IS THE DENSEST DATASET AMONGST THE ONES YOU SEE HERE. WE HAVE BIOSPECIMEN COLLECTIONS. I CAN SHARE WITH YOU THE DETAILS OF THE SPECIMENS WE ARE COLLECTED FROM 360,000 PARTICIPANTS, MOST OF WHICH HAVE NOT BEEN USED WHICH WILL BE AN INTERESTING PART OF OUR DISCUSSION LATER IN THE SESSION. THIS IS JUST TO HIGHLIGHT SOMETHING I TOLD YOU ABOUT, THE GENOMICS DATA RELEASED IN MARCH. WHEN WE LOOKED AT THE DATA WE FOUND 600 MILLION UNIQUE VARIANTS THAT HAD NOT BEEN SEEN IN PRIOR PUBLICLY AVAILABLE DATASETS, WHICH IS REALLY, I THINK, A TESTAMENT TO THE FACT THAT UNDERREPRESENTED MINORITIES IN BIOMEDICAL RESEARCH CONSTITUTES A SIGNIFICANT PORTION OF THE GENOME DATA RELEASED HAVE NEVER BEEN SEEN IN GENOMIC DATABASES. ON THE RIGHT-HAND SIDE IS ANOTHER UNIQUE ASPECT, THE ABILITY TO LOOK AT GENOMIC DATA ALONGSIDE OTHER TYPES OF DATASETS, ELECTRONIC HEALTH MEASUREMENTS, SURVEYS, 81,000 PARTICIPANTS ARE SHARED ACROSS THOSE. THE GENOME SEQUENCES, PHYSICAL MEASUREMENTS AND RESPONSES. AT THE BOTTOM YOU CAN SEE A SMALLER, BUT SIGNIFICANT NUMBER UNIQUE IN THE WORLD GENOMIC DATA ASSOCIATED WITH WEARABLE PHE PHENOTYPING INFORMATION. THAT IS ONLY GOING TO GROW OVER THE COURSE OF THE PROGRAM. THIS IS, WE THINK, A SUPER INTERESTING AND IMPORTANT RESOURCE FOR THE COMMUNITY. WE HAVE ALSO MADE A VERY SPECIFIC DIRECTIVE TO REALLY MAKE THE WORK ACCESSIBLE TO AS MANY RESEARCHERS AS POSSIBLE. OUR GOAL FOR THIS YEAR WAS TO HAVE 2,300 RESEARCHERS AK -- ACTIVELY PARTICIPATING IN OUR WORKBENCH. WE EXCEEDED THAT GOAL. WE HAVE 400 INSTITUTIONS, NOT FOR PROFIT, HEALTH CARE ORGANIZATIONS ACROSS THE UNITED STATES. YOU MIGHT SEE AT THE BOTTOM OF THE BAR GRAPH WE HAVE FOSTERED RELATIONSHIPS WITH HISTORICALLY BLACK COLLEGES AND UNIVERSITIES AND HISPANIC SERVING INSTITUTIONS. WE HAVE A PROJECT DIRECTORY WHICH HAS OVER 2400 PROJECTS RIGHT NOW. THE PUBLICATIONS HAVE JUST BEGUN TO COME OUT ON USING ALL OF US DATA AND WE WILL PROBABLY SEE A G GEOMETRIC INCREASE IN PUBLICATIONS. AT LEAST WE HOPE. WE ARE SEEING FINDINGS FROM INDIVIDUALS GOING OUT TO USE THE WORKBENCH ON THEIR OWN. I'M GOING TO TELL YOU NOW A LITTLE BIT ABOUT THAT. GO TO RESEARCHALLOFUS.ORG, ANY OF YOU WILL SEE THIS SPLASH PAGE THAT HIGHLIGHTS THE DIFFERENT DATA TYPES AND THE NUMBERS OF FEATURES THAT EXIST WITHIN THOSE DATA TYPES WITHIN THE WORKBENCH. ONLINE TUTORIALS THAT ARE AVAILABLE TO ANY WORKBENCH USER TO TEACH THEM HOW TO USE IT. WE HAVE DONE FACE-TO-FACE OR VIRTUAL WORKSHOPS WHERE WE BRING INSTRUCTORS IN TO PERHAPS A GROUP OF NIDCD INVESTIGATORS, INTRAMURAL OR EXTRAMURALLY TO WALK THEM THROUGH HOW TO ACCESS THE DATA. THAT IS OUR GOAL TO MAKE THIS AS EASY AS POSSIBLE. THERE ARE THREE TIERS OF ACCESS AT THE WORKBENCH. THE PUBLIC TIER IS AVAILABLE TO EVERYONE AND IS MAINLY AGGREGATE DATA. I WILL SHOW YOU SEARCHS I HAVE DONE RELATIVE TO THIS GROUP FROM THE PUBLIC TIER. AS YOU GET TO THE REGISTERED TIER AND CONTROLLED TIER, THERE IS MORE GRANULARITY OF THE DATA, LESS BLURRING OF THE DATA. IT MIGHT HAVE SPECIFIC DATES OR SURVEY ELEMENTS AT THE INDIVIDUAL LEVEL AND ON THE CONTROL TIER WHICH IS OUR HIGHEST TIER OF PRIVACY IS WHERE THE GENOMIC DATA EXISTS, IS WHERE WE LEAVE MORE DEFINITIVE DATES THAT WE HAVE OBTAINED FROM THE AHRs AND OTHER TYPES OF DATA THAT ARE EATING AWAY AT WHAT WE CALL OUR PRIVACY BUDGET. TO ACCESS THE REGISTERED TIER AND CONTROL TIER REQUIRES RESEARCHERS TO TAKE ONLINE MODULES AND PASS SHORT EXAMS AT THE END OF THOSE. IT IS NOT ONEROUS, BUT IT IS IMPORTANT TO LET OUR RESEARCHER COMMUNITY KNOW THE PRIVILEGE OF ACCESSING INDIVIDUAL DATA AND ALSO WARN THEM ABOUT NEFARIOUS USE OF DATA THAT COULD ELIMINATE PRIVACY FOR OUR PARTICIPANTS. I'M GOING TO BRIEFLY SHARE WITH YOU THE FIVE OR SO DATA TYPES WE HAVE BEEN COLLECTING OVER THE LAST SEVERAL YEARS. ONLINE EHR DATA. MOSTLY STRUCTURED DATA, THE TYPES YOU SEE IN THE BOX. NEXT YEAR WE HOPE TO RELEASE TOOLS THAT ALLOW FOR NATIONAL LANGUAGE PROCESSING OF PHYSICIAN OR NURSES OR OTHER TYPES OF NOTES IN THE DATA, WHICH I THINK WILL BE QUITE IMPORTANT AND EXCITING FOR OUR RESEARCH COMMUNITY. WE HAVE HAD ROUGHLY HALF A DOZEN SURVEYS TAKEN BY OUR PARTICIPANTS. BASIC HEALTH AND DEMOGRAPHIC INFORMATION, LIFESTYLE, HEALTH CARE ACCESS AND UTILIZATION, PERSONAL AND FAMILY HISTORY AND THIS YEAR SOCIAL DETERMINANTS OF HEALTH. DURING THE PANDEMIC WE PIVOTED TO HAVE A COVID EXPERIENCE CALLED COPE. MINUTE SURVEYS TO ASK PARTICIPANTS TO SHARE WITH US WHETHER THEY HAVE HAD COVID-19 OR WHETHER THEY HAVE BEEN APPROPRIATELY IMMUNIZED AND THAT DATA, WHY THEY ARE CLOSED, ARE COMPLETELY AVAILABLE LATER THIS YEAR AND EARLY IN 2023 WE WILL RELEASE A SURVEY ON MENTAL HEALTH. THESE ARE THE TYPES OF OBJECTIVE PHYSICAL MEASUREMENTS WE HAVE OBTAINED ON MOST OF OUR PARTICIPANTS. AS I MENTIONED, WE HAVE A VERY SIGNIFICANT BIOSAMPLE BANK WITH EACH OF THESE SOURCES. PRESERVING MATERIALS, BLOOD AND SALIVA CAN BE USED FOR DNA. WE ARE COLLECTING DATA FROM MOBILE DEVICES SUCH AS FIT BITS AND APPLE WATCH DATA SOMETIME IN THE NEAR FUTURE. SO LET ME JUST SHIFT NOW TO WHERE WE ARE GOING SCIENTIFICALLY, WHICH WAS MY CHARGE IN COMING TO THE PROGRAM. I HAVE -- WE HAVE BEEN WORKING HARD ON SCIENTIFIC PLAN TO UTILIZE THE DATA. THIS GRAPH IS A REPRESENTATION OF THE FEATURES WE ARE AIMING TO DO FOR THE PROGRAM AT A LARGE AND HIGH LEVEL VIEW. THIS IS MEANT TO LOOK LIKE A HOUSE. AND SO THE BOTTOM, THE FOUNDATIONAL ASPECT OF THIS HOUSE IS THE DATA I HAVE JUST TOLD YOU ABOUT, THE WORKBENCH, THE METHODOLOGY AND TOOLS THAT WILL ENABLE RESEARCHERS TO OPTIMIZE THE UTILITY OF THE DATA WE COLLECTED. VERY CLEAR THAT OUR STRATEGY SHOULD HELP BUILD CAPACITY FOR RESEARCHERS AROUND THE COUNTRY, WHETHER THEY ARE TRAINEES, EARLY INVESTIGATORS OR OLDER FOLKINGS LIKE MYSELF TO REALLY UNDERSTAND HOW TO OPTIMALLY INTERACT WITH AND DO THEIR SCIENCE. COMING FROM THE REPORT OF THE ADVISORY COMMITTEE TO THE DIRECTOR OF THE PRECISION PROGRAM, WE ARE EMBRACING THE SCIENCE AROUND DRIVERS OF HEALTH AND DISEASE. ACD REPORT OF LIFESTYLE AND GENETICS WERE THE PILLARS. WE ADDED HEALTH EQUITY AS AN IMPORTANT PILLAR TO UNDERSTAND HOW DISEASE TRANSITIONS OCCUR. IN SURVEYING OUR SCIENTIFIC COMMUNITY WE HAVE IDENTIFIED A NUMBER OF CROSS CUTTING THEMES THAT ARE QUITE BROAD AND TOUCH MANY DISEASE AREAS AND INSTITUTES AT NIH. YOU SEE THEM HERE. THEY ARE NOT EXHAUSTIVE. I WANTED TO GIVE YOU A SNAPSHOT OF THE QUESTIONS WE ARE ASKING ABOUT SOCIAL DETERMINANTS OF HEALTH, MENTAL HEALTH, EARLY DISEASE DETECTION GIVEN THE LONGITUDINAL NATURE OF OUR PROGRAM. OUR ABILITY TO LOOK AT RESILIENCE AND HEALTHY AGING. I THINK THE PROGRAM WILL NAUL SHORT IF WE DO NOT HAVE A STRATEGY TO MOVE OUR DATA TO OUR PARTICIPANTS AND HAVE THECHL USE THAT DATA FOR MAKING DECISIONS ABOUT THEIR HEALTH AND POTENTIALLY SHARING IT WITH THEIR PROVIDERS. THE IMPACT ON HEALTH IS THE OUTCOME OF THE PROGRAM. AT THE TOP OF THE HOUSE WE SEE AREAS THAT ALL OF THESE DATA THAT LIE BENEATH THOSE ROOMS, SO TO SPEAK, WILL CONTRIBUTE TO OUR ABILITY TO ADVANCE OUR ABILITY TO PREDICT RISK WITH MORE PRECISION AND DEVELOP PREVENTIVE STRATEGIES SIMILARLY FOR DIAGNOSIS AND SCREENING, TREATMENT AND OUTCOMES AND CONTINUAL MONITORING AND SURVEILLANCE OF OUR POPULATION. FINALLY THE FOUR PILLARS OF THIS HOUSE ARE THE POPULATIONS THAT ARE CONTRIBUTING TO IT. ADULTINGS MAINLY TODAY, CHILDREN COMING IN 2023. THE DIVERSITY OF OUR POPULATION, ESPECIALLY POPULATIONS THAT WILL EITHER ALREADY EXIST OR THAT WILL COME IN THROUGH THE ANCILLARY STUDIES ROUTE. THIS IS -- SO WE HAVE A PROJECTS DIRECTORY, IF YOU VISITED THE WEBSITE, THE LINK IS AT THE BOTTOM OF THE SLIDE AND ALL OF THESE SLIDES WILL BE SHARED WITH YOU. YOU CAN SEARCH ON JUST ABOUT ANYTHING YOU WANT TO SEE IF SOMEBODY IS ACTUALLY WORKING ON IT. SO I TOOK THE LIBERTY, FIRST OF ALL, OF LOOKING AT THE DATA BROWSER AND ASKING THE QUESTION OF HOW MANY OF OUR PARTICIPANTS HAVE BEEN ANNOTATED AS VERY HEARING LOSS. THIS DATA WOULD BE ASCERTAINED FROM THE ELECTRONIC HEALTH RECORD WE CAPTURED OR FROM, I BELIEVE THERE IS A SURVEY QUESTION ABOUT HEARING THAT I CAN FOLLOW UP WITH YOU ON. BUT REGARDLESS, AS YOU CAN SEE, THERE'S ABOUT 35,000 INDIVIDUALS THAT HAVE BEEN IDENTIFIED WITH HEARING LOSS AND SEVERAL DIFFERENT SUB CATEGORIES OF HEARING LOSS ARE ILLUSTRATED ON THIS SLIDE. THE OTHER THING I WANTED TO DO TODAY WAS JUST HIGHLIGHT THAT IF YOU LOOK ON THE WORKBENCH OF THE 2,400 PROJECTS I MENTIONED, SEVEN ARE MENTIONING HEARING LOSS IN THEIR TITLE. AND THAT IS A SMALL NUMBER MAYBE. BUT I THINK IT IS GROW CERTAINLY WITH YOUR HELP AND THE KINDS OF THINGS THAT I, IF YOU LOOK ON THE WORKBENCH YOU'LL SEE NOT ONLY THERE IS A TITLE, THERE IS AN ABSTRACT OF NAMES OF INVESTIGATORS WORKING ON THE PROJECTS. YOU MAY KNOW SOME FROM YOUR OWN EXTRAMURAL COMMUNITY. THERE ARE AT LEAST TWO PROJECTS THAT I SEE THAT ARE LOOKING AT HEARING LOSS AND COGNITION AND DEMENTIA. USING MAINLY ELECTRONIC HEALTH RECORD DATA THERE IS A PROJECT OF HEARING LOSS AND THE USE OF THE HYPERTENSIVE MEDICATION AND PROBING THAT ASSOCIATION. THERE ARE A NUMBER OF GENETIC STUDIES LOOKING AT THE RELEVANCE OF KNOWN GENETIC MUTATIONS RELATED TO HEARING LOSS IN UNDERREPRESENTED PARTICIPANTS AS WELL AS GENETICS OF CONGENITAL HEARING ABNORMALITIES AND ALSO A PROJECT THAT IS LOOKING AT GENERAL PREDICTORS OF HEARING LOSS, USING ELECTRONIC HEALTH RECORD AND SURVEY DATA. THIS MAY BE A TEASER, BUT I THOUGHT YOU MAY BE INTERESTED IN SEEING WHAT THE RESEARCH COMMUNITY IS WORKING ON TODAY. AND I WOULD LIKE TO NOW JUST TURN TO THE PARTNERSHIP OPPORTUNITIES THAT LIE AHEAD OF US. I MENTIONED THAT WE -- I MENTIONED ANCILLARY STUDIES, BUT I WANTED TO TELL YOU ABOUT SOME ACTIVITIES THAT WE HAVE TAKEN ON THAT ARE AHEAD OF ANCILLARY STUDIES. SO THIS YEAR WE RELEASED IN MAY A NOSI FOR EXISTING GRANTS TO PROMOTE WORK ON THE WORKBENCH EITHER USING DATA THAT EXISTS OR DIVERSITY SUPPLEMENTS AND I WILL COME BACK TO THAT IN A MOMENT. IN 2023, WE ARE GOING TO BE PUTTING FORWARD AN RO3 PROGRAM, AGAIN, TO ENCOURAGE DATA ANALYTICS OF THE WORKBENCH DATA. THIS IS ALL EXISTING DATA AS WELL AS AN R21 PROGRAM FOR RESEARCHERS TO BRING FORWARD NEW METHODOLOGY TO ANALYZE THE DATA. THE NOSI PROGRAM WAS QUITE SUCCESSFUL. OUR PROGRAM, ALL OF US, FUNDED I BELIEVE 15 OF THE -- YOU CAN SEE 15 INSTITUTES AND CENTERS HAD NOSI AWARDS FUNDED. MOST OF US HAVE BEEN FUNDED BY ALL OF US RESEARCH DOLLARS. THE OFFICE OF AIDS RESEARCH DECIDED TO FUND TWO. THE OFFICE OF THE DIRECTOR HAS FUNDED ONE AND THERE HAVE BEEN SOME OTHERS WHERE ICs HAVE INDIVIDUALLY SELECTED AS FUNDING. ON THE RIGHT YOU CAN SEE AN AWARD, I DON'T KNOW IF THE NOTICE OF AWARD HAS GONE OUT, I HOPE IT HAS, TO ONE OF YOUR INVESTIGATORS ON LOOKING AT GENETICS AND DIFFERENT ALGOR ALGORITHMS TO DETERMINE DIFFERENT PHENOTYPES OF HEARING LOSS. THAT PROGRAM IS UNDERWAY. WE WILL COME BACK AND LOOK AT THE NOSI PROGRAM TO DRIVE WORK ON THE WORKBENCH ACROSS THE ICs. I KNOW YOU WANTED TO SEE THAT IS MOVED FORWARD. AND I HOPE NIDCD HAS SIGNED UP FOR THAT. I WILL NOT GO OVER ALL OF OUR GOALS BY 2026, THE THIRD GOAL IS THE LAUNCH ANCILLARY STUDY AS A CORE AND SCALABLE CAPABILITY. THAT IS WHAT I WANT TO TALK ABOUT IN THE NEXT FEW MINUTES. WE DEFINE AN ANCILLARY STUDY AS A PARTNERSHIP THAT EXPANDS OUR DATASET IN ORDER TO ANSWER NEW SCIENTIFIC QUESTIONS. THAT IS AN EXPANSION BEYOND THE DATA I HAVE ALREADY SHOWED YOU. IT CAN BE DONE BY ADDING NEW PARTICIPANTS THAT NORMALLY WOULD NOT BE RECRUITED TO THE PROGRAM OR BY ADDING NEW DATA. WHICH COULD COME FROM PREVIOUSLY COLLECTED BIOSPECIMENS. WE COULD IMPORT DATA TIED TO THE ELECTRONIC MEDICAL RECORD AND GATHER DIRECTLY FROM PARTICIPANTS ON A SMALL SUBSET, ON AS FEW AS A FEW THOUSAND OR ACROSS THE ENTIRE COHORT, DEPENDING ON THE TYPES OF QUESTIONS WE MIGHT ASK. ANCILLARY STUDIES COME IN A NUMBER OF DIFFERENT FLAVORS. BIOSPECIMENS, NEW QUESTIONNAIRES, PARTICIPANT RECONTACT OR THE POSSIBILITY OF DOING RANDOMIZED CONTROLLED CLINICAL TRIALS BY ASCERTAINING MEMBERS OF THE ALL OF US RESEARCH COHORT. THIS IS ANOTHER VIEW IN THIS PYRAMID DIAGRAM. THE BOTTOM IS THE DATA THAT CURRENTLY EXISTS. WE HAD THREE ANCILLARY STUDIES ALREADY LAUNCHED OVER THE LAST COUPLE OF YEARS. ONE WAS OCOVID SEROLOGY STUDY TO ASCERTAIN IF INDIVIDUALS HAD COVID ANTIBODIES THAT MAY OR MAY NOT HAVE KNOWN THEY HAD THAT DIAGNOSIS. WE ARE ALSO ABOUT TO ENROLL OUR FIRST PARTICIPANT IN A MENTAL HEALTH ASSESSMENT STUDY CALLED EXPLORING THE MIND, MAINLY USING SURVEYS AS WELL AS SOME WEARABLE DEVICES. WE LAUNCHED THE NUTRITION FOR PRECISION HEALTH. INTENSE DIETARY ASSESSMENTS AND DIETARY CHALLENGES WITH ASSOCIATED METABALOMIC AND BIOME WORK. THE DATA AND COMPLEXITY OF ANCILLARY STUDIES INCREASES AS YOU GO FROM BIOSPECIMEN TO AN RCT, OF COURSE. WE THINK THE EASIER OPPORTUNITIES IN THE NEAR TERM WILL BE MORE AT THE BOTTOM OF THIS DIAGRAM THAN AT THE TOP, BUT WILLING TO PLAN FORWARD SEVERAL YEARS TO DO SOMETHING MORE COMPLEX AND EXTENSIVE. THIS IS OUR PROJECTED GOALS OF WHERE WE WOULD LIKE TO BE BY 2026. AS I MENTIONED, WE HAVE THREE ANCILLARY STUDIES, ONE COMPLETED AND TWO UNDERWAY. WE ALSO ARE HOPING TO ATTRACT NEW PROPOSALS THROUGH CONVERSATIONS LIKE THIS THIS YEAR AND ONGOING SO WE HAVE 20 STUDIES IN OUR PIPELINE BY 2026. ONE THING I WANT TO MENTION IS WE ARE OFTEN GETTING REQUESTS FROM INDIVIDUAL INVESTIGATORS TO ACCESS SAMPLES, DATA THEY CAN DO ON THEIR OWN, SAMPLES REQUIRE ANOTHER PROCESS WE ARE IN THE PROCESS OF DEVELOPING. OUR GOAL IS TO HAVE THE ANCILLARY STUDIES PRIMARILY WITH NIH INSTITUTES RATHER THAN INDIVIDUAL INVESTIGATORS. THE LAST SLIDE, THESE ARE MORE MY MUSINGS AROUND WHAT NIDCD COULD DO WITH THE ALL OF US RESEARCH PROGRAM AND YOUR STRATEGIC PLAN. REALLY IN THE FIRST AREA IS TO UNDERSTAND WHAT DATA EXISTS ACROSS THE DATA WE ARE COLLECTING, MORE OF A LANDSCAPE ANALYSIS. CERTAINLY THE OPPORTUNITY TO DO THE -- CAPTURE AUDIOGRAMS AND OTHER DATA TYPES FROM THE ELECTRONIC MEDICAL RECORD OR DEVELOP DCD COMPATIBLE COMPATIB PHENOTYPES. THE SECOND PRIORITY IS TO HARNESS THE GENETIC DATA WE ARE DOING, WE ARE GATHERING AND LOOKING ACROSS THE DIFFERENT UNDERREPRESENTED MINORITIES AND ALSO TO ENHANCE ANNOTATION AND CALLS FOR UNDERREPRESENTED GROUPS. BIOMARKERS FOR HEARING AND COMMUNICATION DISORDERS WOULD SEEM LIKE ANOTHER RIPE OPPORTUNITY. IN TERMS OF IMPROVING DIAGNOSIS AND TREATMENT, WE HAVE A LOT OF DATA ON LIFESTYLE AND SOCIAL DETERMINANTS OF HEALTH. WE WILL CAPTURE MORE DATA THIS YEAR AND NEXT YEAR. THE OPPORTUNITY DOES EXIST, AGAIN, TO LOOK AT GENETIC RELATIONSHIPS BETWEEN ENVIRONMENTALLY INDUCED HEARING LOSS AS WELL AS OTHER FACETS OF HEARING LOSS. FINALLY, IN TERMS OF IMPROVING OUTCOMES, WE HEARD ABOUT A CLINICAL TRIAL FROM DR. KELLEY. MAYBE CLINICAL TRIALS CAN BE MARSHALLED USING THE ALL OF US RESEARCH PROGRAM PARTICIPANTS AND THE OPPORTUNITY TO LOOK AT DIGITAL HEALTH TECHNOLOGIES THAT COULD IMPROVE SCREENING OR MANAGEMENT OF HEARING DISORDERS. I WILL STOP THERE. I WANTED TO GIVE YOU THAT OVERVIEW AND HOPEFULLY STIMULATE GREAT CONVERSATION NOW ABOUT WHAT CAN BE DONE BETWEEN ALL OF US AND NIDCD. THANK YOU. >> THANK YOU, JEFF. THAT WAS ABSOLUTELY FANTASTIC. JUST PERFECT. I HAVE ASKED ANIL TO KICK OFF THE DISCUSSION AND MODERATE FROM HERE. >> THANKS, DEB. DR. GINSBURG, THANK YOU FOR A WONDERFUL TALK. ONE OF THE THINGS THAT ALWAYS HAMPERS HEARING AND BALANCE STUDIES IS THAT WE DON'T -- IT IS OFTEN NOT PART OF THE LARGER DATA COLLECTION. WE ARE AN AFTER THOUGHT AND STUFF. DO YOU THINK THERE IS OPPORTUNITIES, FOR EXAMPLE, AS I WAS THINKING THE FITBIT THING. APPLE PHONES COME WITH BEING ABLE TO MEASURE SOUND LEVELS AND BEING ABLE TO CAPTURE SOUND EXPOS EXPOSURE. ONE OF THE STUDIES THAT IS VERY HARD TO DO CLINICALLY IS CORRELATING SOUND EXPOSURE AND SENSITIVITY TO NOISE-INDUCED HEARING LOSS. THIS SEEMS LIKE A PERFECT PLATFORM. YOU HAVE THE GENETIC DATA. WE COULD POSSIBLY CAPTURE THE EXPOSURE DATA. I WONDER IF YOU CAN SPEAK TO HOW EASY OR HOW HARD TO COLLECT DATA ABOUT HEARING AND BALANCE ISSUES OR THE ANCILLARY PROCESS? IS THAT A VERY HARD PROCESS FOR US TO EXPLORE? JUST BROADLY, IF YOU COULD TALK ABOUT THOSE THINGS. >> EVERYTHING YOU MENTIONED IS CERTAINLY ON THE TABLE. I HONESTLY DID NOT KNOW AND IT WOULD BE GREAT IF INDIVIDUALS FROM THIS COMMUNITY COULD LOOK AT WHAT DATA MIGHT BE HIDDEN IN THE EHRs THAT CAN ADDRESS SOME OF THE IDEAS YOU JUST MENTIONED, BUT SPECIFICALLY AROUND USING A PHONE OR OTHER TYPES OF WEARABLE DEVICES, PROVIDED YOU BELIEVE IT IS A VALID TECHNOLOGY TO DO WHAT IT IS MEANT TO DO. IT IS IMPORTANT WE CAPTURE QUALITY DATA THAT IS REPRESENTING SOMETHING THAT IS USEFUL. THAT IS A RELATIVELY EASY LIFT. AND I THINK WE WOULD, IN ANY OF OUR ANCILLARY STUDIES THAT ARE ADDING NEW DATA, IT WOULD BEHOOVE US TO THINK ABOUT A PILOT STUDY SMALLER IN SCALE TO MAKE SURE WE UNDERSTAND THE QUALITY OF THE DATA, THE WORK FLOWS TO GET THE DATA AND YOUR ABILITY TO POTENTIALLY ANALYZE IT BEFORE IT GETS SCALED UP. THE PHONE DEVICES WOULD BE RELATIVELY EASY AS ARE THE SURVEYS. WE ARE PROBABLY DOING A POOR JOB OF CAPTURING SELF-REPORTED INFORMATION YOU DESCRIBED. WE HAVE ALMOST NOW STANDARDIZED THE WAY THAT WE DEVELOP, VALIDATE AND RELEASE AND CAPTURE DATA FROM SURVEYS. SO IN TERMS OF THE -- THAT WOULD BE A FAIRLY STRAIGHT FORWARD ANCILLARY STUDY. BRINGING PEOPLE BACK TO THE RESEARCH LAB TO AUDITORY PHENOTYPING, IT IS A HEAVIER LIFT. THAT IS DOABLE. IT WOULD TAKE MORE TIME AND RESOURCES FOR US TO THINK ABOUT HOW TO MAKE THAT HAPPEN. ONE ADDITIONAL QUESTION AND I SEE DR. MARTIN HAS RAISED HER HAND, TOO. I SEE ALL OF US IS A WONDERFUL MODEL OF CONNECTING GENOMIC DATA WITH CLINICAL DATA. ARE YOU EXPANDING THIS PARTICULAR MODEL TO OTHER LARGER DATABASES WHERE THAT GENETIC PART IS MISSING WHILE THE RICHNESS AND SPECIFICITY OF THE DATA IS PRESENT? ARE YOU TAKING YOUR MODELS TO THE OTHER NATIONAL SURVEYS THAT ARE OUT THERE ALREADY? >> IT IS A GREAT QUESTION. WE HAVE A VERY STRONG CONNECTION TO THE CDC AND TRYING TO WORK WITH THEM. I DON'T ENVISION US IMPOSING OUR MODEL ON ANYBODY, BUT THE OTHER GROUPS WANT TO ADOPT THE ALL OF US MODEL, EVERYTHING I SHOWED YOU TODAY, ALL THE SURVEY INSTRUMENTS AND OTHER WAYS WE COLLECT DATA TYPES IS PUBLICLY AVAILABLE AND WE ARE HOPING THAT OTHER GROUPS EITHER, WHO ARE ONGOING, DOING ONGOING COHORT STUDIES OR DEVELOPING NEW ONES WILL TAKE ADVANTAGE OF THE WORK WE HAVE DONE AND ALLOW US TO HARMONIZE WITH THEM. THE ONE OTHER THING I WILL SAY IS THE WORKBENCH IS HOUSED ON A PLATFORM MAINTAINED BY VERILY, CALLED TERRA. TERRA HOUSES A NUMBER OF LARGE-SCALE DATASETS INCLUDING ALL OF US. WE ARE REALLY AGGRESSIVELY PURSUING THE ABILITY TO PUT COHORTS SIDE BY SIDE AND CREATE DATA LIQUIDITY BETWEEN THEM SO THE RESEARCHERS WHO DISCOVER SOMETHING IN OUR COHORT CAN RAPIDLY VALIDATE IN A SECOND ONE AND VICE VERSA. THAT IS SOMEWHAT RELATED TO THE QUESTION YOU WERE ASKING. MAYBE IF N HAYNES WANTED TO SIDE WITH US, WE WOULD WELCOME IT. >> DR. MARTIN. >> HI, GEOFF, THANKS FOR GIVING US THIS UPDATE. A NUMBER OF YEARS AGO I WAS INVOLVED WITH THE GENOMIC MEDICINE VISERY PROGRAM AT THE VA. I UNDERSTAND THE VA HAS RICH RECORDS WITH RESPECT TO AUDIOLOGY. DID THOSE INDIVIDUALS BECOME INCORPORATED INTO ALL OF US OR DOES MILLION VETERANS PROGRAM STILL EXIST SEPARATELY? >> WE ARE SEPARATE, BUT THERE IS OVERLAP. WE ARE ACTIVELY RECRUITING ALL OF US PARTICIPANTS FROM SOME VAs. IT IS GOOD TO KNOW. I WAS NOT AWARE THE VA AUDIOGRAM AND OTHER DATA IS THAT ACCESSIBLE. WE SHOULD LOOK INTO IT. I DON'T KNOW OFF THE TOP OF MY HEAD WHAT SUBSET OF OUR 500,000 THAT HAVE CONSENTED ARE ACTUALLY VA PARTICIPANTS, BUT IT IS A GREAT CALL AND I WILL FOLLOW UP ON THAT. BUT, YOU KNOW, WHERE WE WANT TO GO AT SOME POINT IS HAVE MVP, THE MILLION VETS PROGRAM AND ALL OF US DO MORE SYNERGISTIC WORK. AS YOU PROBABLY KNOW MVP IS A DIFFERENT MODEL. NOT JUST DIFFERENT DATA MODEL, BUT ALSO DIFFERENT MODEL OF HOW THEY HANDLE THEIR DATA, WHO THEY RELEASE IT TO AND RELEASING RESULTS TO PARTICIPANTS. SO WE HAVE SOME WORK TO DO TO MAKE THAT HAPPEN BUT I'M OPTIMISTIC IT WILL. >> DR. TUCCI. >> YEAH, I HAVE SORT OF A MECHANICISTIC QUESTION. SO IF WE WERE TO DEVELOP AN ANCILLARY STUDY THAT WOULD INVOLVE GETTING AUDIOMETRIC DATA. WHAT IS AVAILABLE FROM THE AHRs. WOULD THAT BE DONE THROUGH ACADEMIC MEDICAL CENTERS OR BY DIRECT SOLICITATION TO PARTICIPANTS? >> I THINK, WELL, BOTH ARE POSSIBLE. I CAN ENVISION A FEW DIFFERENT MODELS. ONE YOU HAVE PROBABLY A NETWORK OF INVESTIGATORS, CLINICAL GORS THAT ARE DOING AUDIOGRAMS AND -- INVESTIGATORS THAT ARE DOING AUDIOGRAMS AND ARE DOING OVERLAP WITH OUR RECRUITMENT SITES AND SITES WHERE THOSE INDIVIDUALS EXIST AND HARMONIZE THE CAPTURE OF DATA ACROSS ALL OF US PARTICIPANTS OR MAYBE BRING INDIVIDUAL PATIENTS WHO WILL GOING TO SEE SPECIALISTS IN YOUR CENTERS TO ENROLL IN ALL OF US. >> MM-HMM. >> THAT WOULD BE ONE WAY TO DO IT. WE'VE ALSO ENVISIONED IN OUR RECRUITMENT SITES IT COULD BE POSSIBLE TO PUT AN AUDIOGRAM STATION SO AS PART OF THEIR ENROLLMENT, WHILE THEY ARE GETTING THEIR BLOOD DRAWN AND BIOMETRICS DONE, THEY HAVE AN AUDIOGRAM AS PART OF THE RECRUITMENT PROCESS. THAT COULD BE DONE. THAT WOULD BE A DIFFERENT WORK FLOW IN THE SITES ENGAGED IN RECRUITING OUR PARTICIPANTS AND ADDITIONAL RESOURCES TO STAND THAT UP. IT IS ALL POSSIBLE. GETTING IT DIRECTLY FROM PARTICIPANTS, I'M NOT SURE HOW THAT -- I CAN IMAGINE ONLY A SUBSET OF PARTICIPANTS HAVE DIRECT ACCESS TO THOSE DATA, BUT I MAY BE WRONG. I THINK THE CLINICAL SITES, ACADEMIC MEDICAL CENTERS WOULD BE THE BEST ROUTE TO TAKE. >> I WAS JUST THINKING, ALSO, WE ARE GETTING TO THE POINT WHERE PATIENTS CAN DO A HEARING TEST ON THEIR PHONES, PROBABLY, AND GET PRETTY ACCURATE DATA AT LEAST FOR CERTAIN KINDS OF HEARING LOSS. >> AGAIN, I'M A STICKLER WHEN IT COMES TO THE MEDICAL GRADE VERSUS NOT MEDICAL GRADE DIGITAL HEALTH TECHNOLOGIES. I WOULD LEAVE IT TO YOUR GROUP TO DECIDE WHICH DEVICES ARE ACTUALLY PROVIDING A HEARING TEST THAT HAVE CLINICAL VALIDITY YOU CAN USE IN THIS TYPE OF THING. ASSUMING THAT IS THE CASE, SURE, IT CAN BE DONE. >> YEAH. >> I HAVE A QUESTION, MORE LIKE THE PRIOR TALK WAS BY MATT KELLEY AND HE WAS INTERESTED IN A GENE CALLED CASZ1. CAN I GO ON ALL OF US AND SEE IF THERE ARE MUTATIONS OF CASZ1 AND LOOK AT THEIR MEDICAL RECORDS TO SEE IF THEY HAVE THAT? CAN I DO THAT NOW? >> YES. AS LONG AS YOU HAVE CONTROL TIER WHERE THE GENOMIC DATA LIVES IN THE WORKBENCH. IF YOU HAVE GONE THROUGH THE TRAINING MODULES, HAVE AT IT. NO. YOU REALLY COULD. >> NO. THAT IS VERY EXCITING. BECAUSE I'M SURE MATT IS INTERESTED IN KNOWING WHETHER THERE ARE HUMANS OUT THERE THAT HAVE HEARING LOSS WITH THIS GENE AND MAYBE EVEN CHARACTERIZED IN THE PHENOTYPE. THAT WOULD BE SO EASY AND YOU WOULDN'T HAVE TO DO A LOT OF WORK AND YOUR DATABASE IS IDEAL FOR THAT. >> I AGREE AND I THINK THE SCALEABILITY OF LOOKING AT EXTREME PHENOTYPES AND UNDERPINNINGS COULD PROVIDE A NICE FEEDBACK LOOP FROM LABS LIKE DR. KELLEY'S AND THE DATASETS WE HAVE. THAT INTERACTION IS CRITICAL. I'M PLEASED YOU POINTED THAT OUT. >> I WAS LISTENING TO YOUR TALK, EVERY TIME I HAVE A QUESTION ABOUT GENE OR HEARING LOSS OR DEMOGRAPHIC QUESTIONS. I'M EXCITED ABOUT THE OPPORTUNITY TO COLLECT DATA BY NOISE EXPOSURE HUMANS HAVE. OTHERWISE WE HAVE NO WAY TO HAVE A DOSAGE FOR NOISE EXPOSURE AND CAN'T DO GENETIC STUDIES ON NOISE EXPOSURE. THIS IS AN OPPORTUNITY TO USE YOUR WONDERFUL PLATFORM TO PURSUE STUDIES LIKE THAT IN OUR FIELD. >> I WOULD SAY OUR DISCUSSIONS FROM THE NATIONAL INSTITUTES AND ENVIRONMENTAL HEALTH SCIENCES ARE ADVANCED TO DEFINE ENVIRONMENTAL EXPOSURES BROADLY AS AN ANCILLARY STUDY DATA TYPE WITH A NUMBER OF QUESTIONS THAT HAVE BEEN TEED UP. DEB, I DON'T KNOW IF ANY OF THE NIDCD PEOPLE WERE AT A WORKSHOP WE HOSTED A MONTH OR TWO AGO ON THIS, BUT I WOULD URGE -- AND I COULD FACILITATE THE INCLUSION OF NOISE AS AN ENVIRONMENTAL DATA TYPE WE CAN CAPTURE. YOU MENTIONED THE TECHNOLOGY THAT CAN BE USED FOR THAT, BUT I ALSO WONDER IF THERE ARE -- IF YOU CAN INFER FROM GEOSPATIAL MAPS, THE KINDS OF NOISES EXPOSURES THAT INDIVIDUALS LIVING IN A PARTICULAR GEOGRAPHY, ZIP CODE OR COMMUNITY COULD HAVE. THAT WOULD BE AN INTERESTING DATA SCIENCE PROJECT AND WOULD TAKE ADVANTAGE OF PUBLICLY AVAILABLE DATA. >> ABSOLUTELY. THAT IS REALLY INTERESTING. YEAH. I THINK NOISE IS A REALLY IMPORTANT ENVIRONMENTAL FACTOR TO BE ABLE TO TRACK. >> IT TIES NICELY ALSO TO SOCIOECONOMIC DETERMINANTS. SOMETIMES THERE IS A DIRECT CORRELATION, AS YOU WERE ALLUDING TO, YOUR NOISE IN YOUR ENVIRONMENT AND ECONOMIC STATUS AND WHERE YOU ARE ABLE TO BUY PROPERTIES AND DENSITY OF LIVING AND SO ON. THERE ARE FOCUS ON THOSE KIND OF ENVIRONMENTAL INTERACTIONS WITH HEALTH DETERMINANTS AND SO ON. SO I THINK IT IS VERY APPROPRIATE. >> GREAT. WELL, THANK YOU, GEOFF. THANK YOU, ANIL, FOR LEADING THE DISCUSSION. THIS IS REALLY, REALLY HELPFUL. WE WILL CONTINUE TO PROMOTE ALL OF US WITH OUR RESEARCH COMMUNITY AND WORK AS CLOSELY AS WE CAN TO FACILITATE THAT. >> THANK YOU. MAY I JUST TAKE ONE MINUTE TO MENTION SOMETHING VERY PRACTICAL THAT WORKS WITH OTHER DISCUSSIONS WITH INSTITUTES IS IDENTIFY A SMALL GROUP OF PEOPLE THAT COULD OWN THIS AND HAVE DISCUSSION DO SOME BRAINSTORMING AND THE POSSIBILITY OF ANCILLARY STUDIES TO MOVE THE CONCEPT ALONG. WHEN WE HAVE SOMETHING THAT IS A LITTLE MORE CONCRETE, WE CAN PRESENT IT BACK TO YOU OR YOU WOULD BE DIRECTLY INVOLVED AS YOU WISH. >> MM-HMM I >> THE WORKSHOP WE DID WITH NIEHS, TO TAKE A DEEP DIVE TO THE OPPORTUNITY SPACE WE HAVE HERE CAN'T BE DONE IN A SERIES OF ZOOM CALLS OR SHORT ONE-HOUR MEETINGS. THE IDEA OF ALL OF US AND NIDCD WORKSHOP, A FEW HOURS A DAY, TWO DAYS, WHATEVER YOU THINK OR WHATEVER WE THINK WILL GET US TO THE POINT WHERE WE CAN SAY SOMETHING OF VALUE ABOUT WHAT AN ANCILLARY STUDY PORTFOLIO MIGHT LOOK AT COULD BE QUITE VALUABLE TO LOOK AT. >> THAT IS A GREAT SUGGESTION. WE WILL DEFINITELY FOLLOW UP ON THAT. >> THANK YOU. AND THANKS FOR HAVING ME TODAY. I REALLY APPRECIATE IT. >> ALL RIGHT, WE ARE A LITTLE BIT OVER, BUT VERY, VERY VALUABLE INFORMATION IN THIS AFTERNOON'S SESSION. SO WE WILL GO AHEAD AND SIGN OFF AND THANK YOU ALL VERY MUCH FOR JOINING AND WE WILL BE IN TOUCH. THANKS AGAIN, GEOFF. BYE-BYE.