>> I'D LIKE TO CONVENE THE 143rd NATIONAL ADVISORY EYE COUNCIL MEETING. WE HAVE AN INTERESTING MORNING LINED UP FOR US AND WE WOULD LIKE TO THANK MONICA IN PARTICULAR FOR THE EXTRA DUTY PRESENTING AND MAKING THE PRESENTATIONS THIS MORNING. WE HAVE A FULL SLATE OF COUNCIL MEMBERS BY THE ADDITION OF FOUR NEW COUNCIL MEMBERS, TOM GLAZIER DENNIS LEVY, AND TOM COMES FROM THE UNIVERSITY OF SCHOOL OF MEDICINE DEPARTMENT OF CELL BIOLOGY AND HUMAN ANATOMY. TOM HAS BEEN WORKING ON DEVELOPMENTAL OCULAR AND RETINAL ISSUES FOR QUITE SOMETIME. TOM, THANK YOU FOR BRINGING THAT EXPERTISE TO THIS GROUP. DENNIS LEVI, PHYSICIAN FOR OPERATING GLOBALLY TOMETRY AND VISION SERVICES, HE WAS THE DEAN THERE AND WHEN HE STEPPED DOWN WE TOOK HIM IMMEDIATELY BECAUSE WE KNEW HE WOULD HAVE A LOT OF EXTRA TIME ON HIS HANDS. HE HAS BEEN WORKING IF ARE A NUMBER OF YEARS IN VISUAL PERCEPTION AND PARTICULARLY AMBIOPIA. DENNIS, THANK YOU FOR JOINING THE GROUP. >> LOU P A SQUALI AS GUESS THE PILOT HAD FAMILY ISSUES OR SOMETHING, MUST BE QUITE A SCENE IN THE COCKPIT. HE IS A PROFESSOR OF SOCIOLOGY AT HARVARD, SPECIALIST IN GLAUCOMA AND HAS BEEN VERY ACTIVE IN THE GENETICS, LOOKING AT THE GENETICS AND ENVIRONMENTAL FACTORS THAT LEAD TO GLAUCOMA AND SYLVIA SMITH PROFESSOR AND CHAIR OF CELL BIOLOGY AND ANATOMY AT AUGUSTA UNIVERSITY GEORGIA PREVIOUSLY KNOWN AS BY WHAT OTHER NAMES, UNIVERSITY? OF MEDICAL COLLEGE OF GEORGIA? OKAY. SHE HAS A DEEP INTEREST IN NEURO PROTECTIVE PROPERTIES OF SOME FACTORS THAT MAY BE IMPORTANT ULTIMATELY IN TREATING DIABETIC RETINOPATHYAT. SYLVIA IS RETURNING HOME IN A SENSE HAVING STARTED AT THE NEI WITH AN INTRAMURAL RESEARCH TRAINING AWARD AND THEN A STAFF FELLOW POSITION HERE AT NEI. SO THANK YOU AGAIN FOR JOINING US, SYLVIA. WE WILL PAUSE LATER TO TAKE A PICTURE OF THE GROUP ASSEMBLES. LET ME GIVE YOU ABOUT A FEW BITS OF INFORMATION ABOUT A VERY BUSY LIFE THAT OCCURS AT NIH AND THE NATIONAL EYE INSTITUTE. OVER THE PAST YEAR AND HALF, TWO YEARS WE HAVE WORKED TO RESTRUCTURE THE THE NEI, DIVISION OF EXTRAMURAL RESEARCH, THE DIVISION THAT HANDLES GRANT APPLICATIONS AND SOME OF THE PEER REVIEW DEVELOPED SCIENCE PROGRAMS. THERE ARE A NUMBER OF DIFFERENT MODELS AMONG THE 27 INSTITUTES AND CENTERS AT NIH AND HOW THOSE ACTIVITIES ARE HANDLED. PREVIOUSLY WE HAD A SINGLENTITY, DIVISION, CALLED THE DISCIPLINARY VISIONS OF EXTRAMURAL RESEARCH THAT HANDLED ALL ASPECTS OF THAT, DEVELOPING THE SCIENCE, REVIEWING THE SCIENCE AND FUNDING THE SCIENCE. LIFE HAS GOTTEN BUSY OVER THE PAST 10 AND 20 YEARS AND PARTS OF THIS JOB ARE BEYOND CAPACITIES FOR SINGLE PEOPLE SO WE HAVE CREATED TWO DIVISIONS. ONE IS EXTRAMURAL SCIENCE PROGRAMS, THAT IS THE FRONT END OF THE OPERATION AND THE DIVISION OF EXTRAMURAL ACTIVITY, D. E. A. D. E. S. P. MEANING SCIENCE PROGRAMS WILL PLAN AND DIRECT THE CONCEPTS, DEVELOP THE SCIENCE PROGRAMS AND HOUSES THE PROGRAM OFFICERS THAT YOU OFTEN INTERACT WITH. MIKE STEINMETZ IS AND WILL LEAD THAT. MIKE IS NO STRAIMPLEGGER TO NEI OR NIH, HE CAME TO NEI A DECADE AGO IN TWO THIS HAPPENED SEVEN FROM JOHNS HOPKINS WHERE HE WAS A TENURED PROFESSOR WITH A LONG HISTORY IN PRODUCTIVE WORK IN VISUAL NEUROSCIENCE AND THEN PREVIOUSLY AT NEI, HE DIRECTED THESE FOR THE VISUAL PROCESSING PROGRAM. LORIANNE, RETIRED FROM HER POSITION AS DIRECTOR OF D. E. R. IN OCTOBER 2014 AND MIKE AS BEEN THE ACTING DIRECTOR OF D. E. R. SINCE THEN. ALSO IN HIS SPARE TIME HE REPRESENTS NEI ON THE NIH BRAIN INITIATIVE WHICH IS A VERY BUSY AGENDA IN ITS OWN RIGHT. AND FOR THE NEW DIVISION OF EXTRAMURAL ACTIVITIES THIS IS HANDLING ASPECTS, SOME OF THE ASPECTS OF PEER REVIEW, MONITORING AND HANDLING THE FUNDING OF APPLICATIONS AND ONE OF THE PRINCIPLE REASONS FOR THIS RESTRUCTURING IS TO CREATE AN APPROPRIATE ADMINISTRATIVE FIRE WALL BETWEEN THE DEVELOPMENT OF SCIENCE PROGRAMS AND THE REVIEW AND FUNDING OF THOSE SCIENCE PROGRAMS. AS I SAID A NUMBER OF NIH INSTITUTES PREFER THE MODEL THAT WE ARE MOVING TO. BALL SHEHEE, PAUL IS THE NEWEST MEMBER OF THE NEI, HE COMES FROM NIGMS WHEREFORE THE PAST SEVERAL YEARS HE WAS THE DEPUTY DIRECTOR FOR NIGMS, AND THEN PRIOR TO THAT, IN THE 10 YEARS FROM 1994-2004 HE WAS SCIENCE REVIEW ADMINISTRATOR IN THE NEUROLOGY INSTITUTE, NINDS. SO PAUL WELCOME AND ACTUALLY BOTH AND MIKE AND PAUL, THANK YOU FOR TAKING ON POSITIONS, JOBS ARE REALLY AT THE CORE OF WHAT THAT INSTITUTE IS ABOUT. THANK YOU. OTHER STAFF CHANGES. MARTHA FLANKEDDERS, DR. FLANKEDDERS HAS JOINED NEI AS A PROGRAM DIRECTOR. AND IS OVERSEEING GRANTS ON CENTRAL VISUAL PROCESSING. SHE CAME FROM THE UNIVERSITY OF MINNESOTA WHERE SHE WAS PROFESSOR IN THE DEPARTMENT OF NEUROSCIENCES. SHE HAS A LONG HISTORY OF FUNDING AT NIH INCLUDING FUNDING THROUGH NINDS. AND AMONG OTHER THINGS WILL BE INVOLVED WITH THE BRAIN--BRAIN INITIATIVE. FOR PRIOR BACKGROUND, A Ph.D. OF SCIENCE AND ZOOLOGY IN MICHIGAN STATE UNIVERSITY. >> [INDISCERNIBLE] >> YOU MAY ASK MARTHA. OH, YEAH, PAUL, A LITTLE LATE IN THE GAME BUT PLEASE, YES. AND THEN WE HAVE A RETIREMENT OF DR. ELLIE SHRAWN, SHE WAS A PROGRAM DIRECTOR IN THE EXTRAMURALKIVITYS OF COLLABORATIVE CLINICAL RESEARCH. SHE HAD BEEN AT NEI SINCE 2009. PRIOR TO THAT AT HEART LUNG AND BLOOD NHLBI WHERE SHE MANAGED CLINICAL TRIALS WHICH WAS PART OF HER--WHICH WAS HER CORE ACTIVITY HERE AT THE EYE INSTITUTE. THE PORTFOLIO FOR TRIALS HAS BEEN DISTRIBUTED AMONGST DAWN EVERETT AND MARY ANN. THOSE ARE THE SIGNIFICANT STAFF CHANGES OF THE PAST FEW MONTHS. THE NEI BUDGET, I KNOW YOU'RE ALLOT EDGE OF YOUR CHAIR TO KNOW WHAT MONEY IS DOING AND KAREN COBERT WILL PRESENT THAT TODAY. KAREN IS THE DIRECTOR OF THE NEI BUDGET OFFICE, CAME TO US RECENTLY. A FEW OTHER PIECES OF INFORMATION, NIH LEADERSHIP MEANING FRANCIS AND THE INSTITUTE DIRECTORS NOTED THAT THE--THAT THERE WAS A MISREADING BY GRANDEES OF THE STATEMENT IN THE NIH RESEARCH GRANT APPLICATIONS CONCERNING PUBLIC HEALTH RELEVANCE INSPECT THAT THE WAY IT WAS WORDED IT EMPHASIZED VERY CLEARLY THE NIEKS H MISSION AND COMMITMENT TO SUPPORTING CLINICAL RELATED ACTIVITIES OR ACTIVITIES THAT PLAYED OUT IN THE CLINICAL ARENA AND IT WAS A MISREADING THAT SEEMED TO SLIGHT THE PURSUIT OF BASIC BIOLOGICAL KNOWLEDGE SO THAT HAS BEEN CLEARED UP AND YOU MAY HAVE NOTED A PIECE BY FRANCIS IN SCIENCE TWO MONTHS AGO IN SCIENCE MARCH 2016. FOR THOSE WHO ARE PUZZLED BY STATEMENT, GOOD, IT MEANS YOU WEREN'T MISREADING THAT. BUT THE EMPHASIZE AT NIH IS ON FULL SPECTRUM RESEARCH WHICH STARTS WITH BASIC KNOWLEDGE AND EXTENDS ALL THE WAY TO TOUCHING HUMAN INDIVIDUALS IN THE FORM OF IMPROVING HEALTH CONCERNS OF THE POPULATION IN THIS COUNTRY AND ABROAD. WE HAD AN INTERESTING MEETING IN HAD APRIL, APRIL 4-20-16, SMALL MEETING ABOUT 30 INVITED SCIENTISTS AND THE TOPIC WAS TO EXPLORE MOUNTING A CHALLENGE TOMITITION FOR 3D OCULAR AND SPECIFICALLY RETINA ORGOID. THIS MEETING CAME ABOUT THROUGH AN INTERESTING CHANNEL AND THAT WAS LANGUAGE WHICH WAS DIRECTED TO NEI, CONGRESSIONAL LANGUAGE TOWARD NEI LAST FALL TALKING ABOUT A CHALLENGE COMPETITION TO SPEED RESEARCH IN RETINAL DISEASES. IT WAS VERY TARGETED LANGUAGE. THAT LANGUAGE IN PART CAME FROM THE INTEREST OF A CONGRESS MAN FROM TEXAS PETE SESSIONS AND IN CONJUNCTION ABOUT HIS IDEAS JEFF GORDON AND STEVE BUCKER HAVE PUT TOGETHER A CONCEPT, A FRAMEWORK FOR A CHALLENGE COMPETITION AND IT WAS THAT TOPIC THAT WAS THE REASON FOR THE MEETING APPROXIMATELY FOUR. WE PLANNED TO LAUNCH THIS CHALLENGE SOMETIME IN THE FALL OF THIS CALENDAR YEAR WHICH PUT IT IN THE FISCAL YEAR 2014 AND THE GOAL OF THE CHALLENGE--17. AND THE GOAL OF THE CHALLENGE WILL BE TO DEVELOP RETINA ORGANOIDS FOR DISEASE MODELING, DRUG SCREENING AND AS A TISSUE SOURCE POSSIBLY FOR THERAPEUTIC TRANSPLANTATION. THERE IS A LITTLE BIT OF MONEY CONNECTED WITH THIS, MOSTLY AT THIS POINT IT IS A CONCEPT PIECE. SO AS THAT UNFOLDS WE WILL BE TALKING WITH THE PERSON, SWITCHING BACK TO A MATTER AT THE NIH LEVEL, SOME OF YOU MAY HAVE NOTED OVER THE PAST MONTH AND THE PAST FEW WEEKS THAT ACTIVITY AND NEWS ABOUT THE NIH CLINICAL CENTER. THE CLINICAL CENTER IS A RESEARCH HOSPITAL, BUDGET OF WHICH IS NOMINALLY $350 MILLION A YEAR, THAT BUDGET COMES THROUGH CAPS THROUGH TAX, THROUGH EACH OF THE INSTITUTES AND IT IS PAID FOR THE FACILITY AND THE MEDICAL OPERATIONS OF THE HOSPITAL CLINICAL RESEARCH CENTER. OPERATING HOSPITAL SYSTEM A NONTRIVIAL TASK AS I KNOW ALL OF YOU KNOW FROM YOUR HOME INSTITUTION AND THE COMPLEXITIES OF THAT HAVE ONLY GROWN, I THOUGHT I WOULD SAY AN EXPONENTIAL CASE AND COST OVER THE PAST 15 YEARS AND IT HAD GOTTEN TO THE POINT THAT THERE WERE SOME CRACKS IN THE EDIFICE. THERE IS AN ADVISORY COUNCIL TO THE NIH DIRECTOR IN THE WAY THAT YOU ARE THE ADVISORY COUNCIL TO THE NEI GROUP, THE OTHER IS THE ADVISORY COUNCIL TO THE DIRECTOR, THE ACD AND FRANCIS COLLINS TOOK THESE CONCERNS TO THE ACD, A HIGH LEVEL TEAM, WORKING GROUP OF THE ACD WAS APPOINTED BUT THE COLLOQUIAL NAME OF THE RED TEAM THAT WAS CHAIRED BY FORM AUGUSTINE, A RETIRED CEO OF LOCKHEED MARTIN AND HAS CONSIDERABLE FAMILIARITY WITH WHAT IS HAPPENING AT NIH. ONE OF THE MEMBERS OF THAT TEAM WAS DON GAGLIANO. DON IS AN OPHTHALMOLOGIST, COUNCIL MEMBER HERE AND HE IS NOW AT WALTER REED BUT BACK ON THE THEME OF THE RED TEAM, THE RED TEAM IDENTIFIED RISK OF BOTH IMMINENT AND POTENTIAL, PUT A REPORT TOGETHER, SOME OF THE CONTENTS OF THAT REPORT WERE OF INTEREST TO THE MAJOR NEWSPAPERS IN THE COUNTRY AND THAT'S WHY YOU MAY HAVE SEEN THIS. THE BOTTOM LINE ON THIS IS THAT THE DIRECTING OF THE CLINICAL CENTER IS BEING TOTALLY REVISED AND THE CURRENT DIRECTOR, THE POSITION OF THE CURRENT DIRECTOR WILL BE REPLACED BY THREE TOP OFFICIALS: A CEO, CHIEF OPERATING OFFICER AND A CHIEF MEDICAL OFFICER. IT WILL BE INTERESTING ON HOW GOVERNMENT BUDGETS ACCOMMODATE INDIVIDUALS WHO COMMAND LARGE SALARIES IN YOUR INSTITUTIONS. SO IF YOU SRO A FAVORITE ADMINISTRATOR [INDISCERNIBLE]. NOW TURNING TO THE NATIONAL EYE INSTITUTE, THE AUDACIOUS GOALS INITIATIVE. I AM PERSONALLY VERY PLEASED WITH WHERE WE STAND ON THAT. THROUGHOUT THE COURSE OF THE AGI, I HAVE REPEATEDLY TOLD THIS GROUP, THE EYE COUNCIL THAT IT ULTIMATELY RESTS IN YOUR HANDS AND YOU BEAR A RESPONSIBILITY FOR HELPING TO DIRECT THIS. THE DAY-TO-DAY OPERATIONS ARE IN GOOD CONTROL AND ACTIVITIES ARE MOVING ALONG. THE MOST RECENT ACTIVITY, WAS A WORKSHOP HELD THE DAY BEFORE OUR VOTE BEGAN, THAT WAS ON SATURDAY APRIL 30, WITH THE TOPIC OF REPLACING RETINAL GANGLION CELLS BY ENDOGENOUS SOURCES. WE NEED TO THANK MONICA VIEDER, AND [INDISCERNIBLE] HITCHCOCK, AND WHO ARE BOTH HERE TODAY AND WILL GIVE US A SUMMARY OF WHAT CAME OUT OF THAT MEETING. AS YOU RECALL, THESE WORKSHOPS ARE BY INVITATION TO ASSEMBLEOT ORDER OF 20-30 EXPERTS IN THE FIELD WHO CAN GIVE ALL OF US A SUMMARY OF WHERE THINGS STAND AND WHAT NEXT STEPS WOULD MOVE THIS ALONG MORE QUICKLY. THE NEXT DAY WE HELD AN AUDACIOUS GOALS INITIATIVE TOWN HALL. THE TOPIC THERE WAS DISEASES AND DISEASE STATES. REGENREATIVE MEDICINE TARGETS DISEASES AND DISEASE STATES, THE NEED FOR THAT MEETING WAS THAT FOR THE PAST TWO YEARS WE HELD A NUMBER OF WORKSHOPS IN ASSESSING THE STATE OF THE SCIENCE, BASIC STATE OF THE SCIENCE, STATE OF THE BASIC SCIENCE, BUT TO INTERFACE THIS WITH MEDICAL OUTCOMES MEANS TO TAKE THIS INTO DISEASES AND TO ENGAGE CLINICIANS. SO THEN AT THAT TOWN HALL MEETING BEN LEVINE WAS THE TOWN HALL MODERATOR, AND IS HERE WITH US AND WE'LL HEAR LETTER FROM YOU, BUT SECOND TO YOU IS THE FIRST BALL HAS BEEN WHAT'S UP THERE, WHERE YOU WILL GET THE CELLS, GANGLION CELLS, PHOTORECEPTORS WHERE WILL WE GET THEM? THERE ARE ONLY TWO KINDS WE KNOW OF IN THE HUMAN, AND HOW DO YOU GET THOSE CONNECTED UP, THOSE ARE INTRIGUE AND BASIC QUESTIONS INCLUDING ENGAGING A DEVELOPMENTAL BIOLOGY TO RECAPITULATE EVENTS OF DEVELOPMENT, BUT TO DO SO, ALL OF THAT MORE OR LESS CONCEPTUALLY STRAIGHT FORWARD. THE NEXT PART OF IT, THE SECOND BALL IS EXACTLY WHAT DISEASES, WHAT STAGES OF DISEASE WOULD ANY OF THIS ACTUALLY BE APPLICABLE IN WHAT WOULD BE. SO THAT'S THE NEED TO MOVE THIS AND TO ENGAGE CLINICIANS IN WORKING WITH THE SCIENTISTS TO ANTICIPATE WHERE THE SCIENCE IS GOING AND GET PREPARED FOR THAT. ON THE NEI CAMPUS, WE HAVE BEGUN TO GET TRACTION WITH NIH AS A WHOLE AND PART OF THAT IS THROUGH A SEMINAR SERIES THAT WE INITIATED IN NEUROREGENERATION. OBVIOUSLY PARKINSON'S AND A NUMBER OF CNS, AND DISEASES WOULD BE INTERESTED IN NEUROREGENERATION. THESE SEMINARS HAVE BEEN WELL ATTENDED, THEY ARE HELD HERE ON THE NIH CAMPUS IN FEBRUARY AND THEN IN APRIL, WE HAD TWO SPEAKERS, THE FIRST DENNIS CLAYING WHO IS AT UC SANTA BARBARA, PRESENTED A TALK ON CELL THERAPIES FOR OCULAR DISEASE AND THEN IN APRIL JOHN FLANIGAN WHO IS AT HARVARD PRESENTED THE VERY INTRIGUING TALK ON MOLECULAR CLUES FOR AXON GUIDANCE AND REGENERATION. THE IN OTHER WORDS IT'S GREAT TO HAVE THE RETINA REPOPULATED BUT HOW DO YOU GET IT CONNECTED INTO THE PERCEPTUAL CENTERS IN THE CNS. LOOKING AHEAD, THE WAY THE AGI WORKSHOPS HAVE PLAYED OUT, THERE HAVE BEEN TWO A YEAR, ONE HELD AT ARVO, AND A SECOND HELD AT THE SOCIETY FOR NEUROSCIENCE. THOSE ARE DIFFERENT AUDIENCES, SOME PEOPLE GO TO BOTH MEETINGS BUT ACTUALLY NOT ENOUGH, SO THE MEETING COMING UP IN NOVEMBER IN SAN DIEGO AT THE SFN MEETING THERE WILL BE ON THE TOPIC OF CREATING A CELLULAR ENVIRONMENT FOR NEUROREGENERATION. AND CO SHARES MARIE BURNS AND BETH STEVENS, MARIE AT UC DAVIS AND BETH STEVENS AT HARVARD. THE NEED FOR THIS IS TO LOOK AT THE ENVIRONMENTAL EXTRA CELLULAR MILLUE IN WHICH ALL OF THESE IDEAS OF CELL REGROWTH OR TRANSPLANTATION WILL PLAY OUT. SOME OF THE IDEAS THAT WILL NEED TO BE ADDRESSED SOON WOULD BE THE ROLL OF GLEA IN THE RETINA AND HOW THE IMMUNE SYSTEM IS GOING TO BE MONITORING WHAT'S HAPPENING AS YOU THINK ABOUT WHAT'S GOING ON WITH AGI AND YOU COULD HAVE A DISCUSHION OF YOUR THOUGHTS ON HOW THIS MIGHT BE DEVELOPED OVER THE NEXT 12 AND 24 MONTHS. TO TURN TO AN ISSUE THAT'S FAR MORE MUNDANE WITH THE POST DOCS AND THAT IS PAY. THE DEPARTMENT OF LABOR ISSUED NEW REQUIREMENTS UNDER THE FAIR LABOR STANDARDS ACT AND THAT IS TO SET A FLOOR OF PAY BELOW WHICH EMPLOYEES ARE ENTITLED TO OVERTIME. THAT FLOOR HAD BEEN SET APPROPRIATELY--WHAT? 30 YEARS AGO AT $23,000. THE DOLLAR ANTICIPATE --AIN'T WHAT IT USED TO BE FOLKS AND THAT HAD NEVER BEEN INCREMENTED SO 23,000 HAS NOW BEEN CONVERTED TO 47,500. AND NIH TOOK NOTE OF THAT IMMEDIATELY BECAUSE THE AVERAGE POST DOC PAY IS BELOW THAT WHICH WOULD MEAN THAT POST DOCS WOULD BE ENTITLED TO OVERTIME. WELL EACH OF YOU CAN IMMEDIATELY IN YOUR CONTEXT UNDERSTAND THE CHAOS THAT THAT WOULD BRING. SO NIH IS INCREASING THE POST DOCTORAL PAY TO THAT NEW MINIMUM OF 47,500 WHAT YOUR INSTITUTIONS DO IS NOT IN OUR JURISDICTION BUT I'M SURE THAT YOU ALREADY ARE ENGAGED, LOCAL INSTITUTIONS ON HOW TO DOLE WITH IT, THE NEW LAW GOES INTO EFFECT BEFORE THE END OF THE YEAR ON DIAGRAM FIRST. AND THEN A VERY IMPORTANT DEVELOPMENT CONCERNS HUMAN SUBJECTS PROTECTION IN MEDICAL RESEARCH THAT COMES UNDER THE NAME OF THE COMMON RULE. THE COMMON RULE IS THE FEDERAL POLICY THAT PROVIDES GUIDANCE FOR PROTECTION OF HUMAN SUBJECTS. THE COMMON RULE NEEDED TO BE UPDATED THAT WAS TAKEN ON BY FRANCIS AND BY HIS DEPUTY CATHY HUDSON, THIS IS SOMETHING LIKE FIVE OR SEVEN OR MORE YEARS IN DEVELOPMENT BUT NOW WILL BE--IT IS--IT HAS BECOME FINAL AND I WILL NOT GO INTO ALL OF THE INTRICACIES AND THE OTHER TO NOTE TWO THINGS--ONE THAT'S A FEDERAL PENALTIES FOR NOT COMPLYING ARE SIGNIFICANT. AND THE PENALTYPPLIES TO THE INVESTIGATORS. WILL THIS IS NOT AT THE INSTUITIONAL LEVEL. THIS IS AT THE LEVEL OF YOUR PEERS AND YOUR INSTITUTIONS WHO ARE DOING HUMAN MEDICAL SUBJECTS RESEARCH. SIGNIFICANT DOLLAR NUMBERS PER DAY, SO IT WOULD BEHOOVE ALL OF US TO PAY ATTENTION TO IT. AND A SECOND PART OF THIS TOO CRYPTIC FOR ME TO GIVE YOU ANYTHING OTHER THAN THE NOTE THAT IT EXISTS AND THAT IS THAT THE PROTOCOLS UNDER WHICH THE WORK IS BEING DONE WILL NEED TO BE SUBMITTED AS PART OF THE COMPLIANCE PROCESS. I DON'T KNOW WHAT THAT MEANS BUT THAT SHOULD BE VERY INTERESTING FOR A LOT OF PEOPLE TO DEAL WITH. AND THIS HAPPENS QUICKLY SO YOUR INSTITUTIONS ARE ALREADY BEING MENTIONED. AND THEN THE TWO OTHER EVENTS THIS MORNING GEORGE MCKEE, DR. MCKEE IN THE EXTRAMURAL PROGRAM WILL BE GIVING US AN OVERVIEW OF THE CORNEA PROGRAM. YOU WILL RECALL THAT IN JANUARY MUMAR MIRAGE GAVE US A OVERVIEW OF THE CATARACT LENS AND WE ARE GOING THROUGH OUR PROGRAM SYSTEMATICALLY TO HAVE THOSE PRESENTED AT THE ADVISORY EYE COUNCIL MEETING SO YOU GET A SENSE OF WHERE THINGS STAND IN THIS PROGRAM AND THEN FINALLY ALONG THE WAY IN THE MORNING MINE STEINMETZ WILL BRING US UP TO DE ON THE BRAIN INITIATIVE. SO WITH THAT LET ME ASK IF THERE ARE ANY COMMENTS RIGHT NOW? JANE'S PUZZLING OVER SOMETHING? ALL RIGHT. LET'S GO TO THE JAN MENUTES. LET ME THANK ANNE SCHAFFNER, FOR HANDLING ALL OF THIS. >> I WANT TO EXTEND A WELCOME TO NIH AND NEI STAFF THAT ARE HERE AND THE SUPPORTERS OF VISION RESEARCH, NAVER AND ARVO, FOR THE PURPOSES OF OPENNESS AND TRANSPARENCY, THIS OPEN SESSION IS BEING VIDEOCAST. SO THERE WERE A COUPLE PEOPLE WORKING BEHIND THE SCENES, I WANTED TO MENTION THEIR NAMES, MICHAEL WRIGHT, MICHAEL PH AN, WHO IS HELPING PEOPLE LOAD THEIR PRESENTATIONS AND HELEN AND JOY. I HAD POSTED THE JANUARY MINUTES ON THE ELECTRONIC COUNCIL PORTAL AND WAS HOPING YOU COULD LOOK THEM OVER QUICKLY AND IF THERE WERE ANY EDITS OR CHANGES OR QUESTIONS? I COULD ATTEND TO THOSE. AND IF THERE ARE NO ONE COULD I GET A MOTION THAT THEY BE ACCEPTED? AND A SECOND? ALL RIGHT, THANK YOU VERY MUCH. SO NEXT ON THE AJEANED IS A BUDGET UPDATE FROM KAREN COLBERT, THE NEI BUDGET OFFICER. >> THANK YOU ANNE. GOOD MORNING AND THANK YOU FOR THE OPPORTUNITY ON TO SHARE THIS BUDGET UPDATE. I WILL GIVE AN OVERVIEW OF THE 2016 AND SHARE WHAT YOU KNOW SO FAR ABOUT 2017. THIS FIRST SLIDE IS THE SLIDE APPROPRIATION HISTORY. THIS IS A COMPARISON TO THE ACTUAL OPERATING FUNDS WE HAVE IN HAND TO MANAGE OUR NEED FOR THE YEAR. AS YOU CAN SEE, THE ENACTED APPROPRIATION AND THE OPERATING LEVEL CAN BE QUITE DIFFERENT. WHEN WE ULTIMATELY RECEIVE AN APPROPRIATION THEY'RE OFTEN DIFFERENT FUNDING LEVELS OUT THERE IN THE COMMUNITY SO I WANT TO PROVIDE SOME CONTEXT FOR WHAT WE ACTUALLY HAVE IN HAND TO DO BUSINESS. WE GENERALLY ARE NOT A FULL APPROPRIATION TO US SO WE BASICALLY GET WHAT'S LEFT OVER AFTER ALL THE TRANSFERS AND REDUCTIONS HAPPEN. AND SO AN EXAMPLE OF AN EXTERNAL ADJUSTMENT WOULD BE AN ACROSS THE BOARD RESCISSION OR SEQUESTRATION IN 2013 OR EVEN THE HHS SECRETARY'S TRANSFER OF AUTHORITY. EXAMPLES OF INTERNAL ADJUSTMENTS WOULD BE THE NIH OFFICE OF AIDS RESEARCH OR THE NIH DIRECTORS. JUST TO LET YOU KNOW, A REDUCTION AND A TRANSFER CAN HAPPEN AT ANY STAGE OF THE FISCAL YEAR, WE'RE ANTICIPATING ONE RIGHT NOW. WE'VE BEEN TOLD THAT THE HHS SECRETARY'S TRANSFER AUTHORITY MAY BE USED THIS FISCAL YEAR TO TRANSFER FUNDS OUT OF NIH TO COVER COSTS ASSOCIATED WITH UNACCOMPANIED MINORS COMING INTO THE COUNTRY AND SO HHS IS REVIEWING THE DATA TO FIGURE OUT IF THE NUMBER OF CHILDREN COMING INTO THE COUNTRY HAS INCREASED SIGNIFICANTLY THIS YEAR AND IF IT HAS, WE WILL LIKELY BE TASKED TO COVER THOSE COSTS BUT WE SHOULD KNOW BY THE END OF JUNE WHETHER OR NOT THE TRANSFER WILL ACTUALLY HAPPEN. OUR FY2016 BUDGET HISTORY. THE PRESIDENT'S BUDGET REQUEST WAS 195.2 MILLION. AND WE RECEIVED THE FUNDS CONFERENCE MARK WE DID BETTER THANAUR 2016 REQUEST. THAT REFLECT HELD POSITIVELY, CONGRESS USED THE MISSION OF NIH. THE GENERAL INCREASE EXCLUDING BRAIN IN 2016 WAS APPROXIMATELY 3.9%. AND LOOKING FORWARD TO FY2017, THE SENATE PROPOSED A BILL THAT WOULD PROVIDE A SIMILAR GENERAL INCREASE. THEY'VE GIVEN NIH AN INCREASE OF TWO BILLION DOLLARS ABOVE THE 2016 ENACTED LEVEL. AND AGAIN THE PROPOSED INCREASE IS HIGHER THAN THE 825 MILLION THAT NIH ACTUALLY REQUESTED SO AGAIN THAT RETECTS A POSITIVE VIEW THAT THE SENATE AND CONGRESS HAVE OF NIH. THAT'S THE GOOD NEWS. THE NOT SO GOOD NEWS IS THAT THERE ARE CAVEATS IN THE BILL THAT MAKE THE SENATE PROPOSAL NOT FEASIBLE IN A FINAL BILL. FOR EXAMPLE, OTHER AGENCIES WOULD LIKELY HAVE TO BE CUT IN ORDER FOR NIH TO RECEIVE SUCH A LARGE INCREASE AND ALSO THE SENATE BILL RELIES ON $300 MILLION COMING FROM THE NONRECURRING EXPENSES FUNDS WHICH IS NOT REALLY A RELIABLE SOURCE OF MONEY. AND WE--THE HEALTH MARK--THE HEALTH MARK UP OF THEIR BILL HAS BEEN POSTPONED AND WE'RE HOPING TO SEE ACTIVITY WITHIN THE NEXT WEEK OR SO AND HOPEFULLY WE WILL KNOW WHETHER OR NOT THE HOUSE IS FEELING GENEROUS TOWARDS NIH AS THE SENATE. FY2016 OPERATING PLAN. THIS PIE CHART REFLECTS THE SHARES OF EXTRAMURAL RESEARCH, INTRAMURAL RESEARCH AND RMS. THIS PIE HAS BEEN PRETTY CONSISTENT. LOOKING FORWARD TO 2017, I WILL SAY THERE'S POTENTIAL FOR THE INTRAMURAL SHARE TO GROW, WITH THE RECENT REVIEW OF THE CLINICAL CENTER AND THE FINDINGS THAT RESULTED NIH'S ICs WILL BE TAPPED INTE BEGIN NOTHING 2016 TO MAKE THE NEEDED CORRECTIONS AND SO IT'S ANTICIPATED THAT THE COST OF THE CLINICAL CENTER ASSESSMENTS TO THE NIH ICs WILL SPIKE CONSIDERABLY IN 2017 AND WE WILL NEED TO PLAN ACCORDINGLY. THIS IS OUR 2016 OPERATING PLAN VERSUS 2017 FUNDING MECHANISM AND YOU CAN SEE THE BOTTOM LINE IS THE SAME, THERE WERE MINIMAL CHANGES BY FUNDING MECHANISM BETWEEN 2016 AND 2017. THE 2017 BUDGET REQUEST ALLOWS FOR AN INCREASE STIPENDS AND TO ESSENTIAL TAPS AND ASSESSMENT AND PRETTY MUCH NOT MUCH ELSE THE FY2017 ADJUSTMENT TO THE CLINICAL CENTER TAPS IS NOT REFLECTED HERE ASA ALL CAME ABOUT AFTER THE 2017 PRESIDENT'S BUDGET WAS ALREADY RELEASED. RESEARCH PROJECT GRANTS. THIS SLIDE LOOKS AT THE NUMBER OF COMPETING AND NONCOMPETING RPGs OVER TIME, IT'S BEEN PRETTY CONSISTENT. THERE HAVE NOT BEEN MAJOR CHANGES OVER TIME. THE COMPETING RPG SUCCESS RATES. THIS IS NEI VERSES NIH, AS CAN YOU SEE, NEI HAS CONSISTENTRY WELL A SUCCESS RATE THAT'S HIGHER THAN NIH'S. NEII COMPETING FUNDED AND UNFUNDED SUCCESS RATE, AS YOU CAN SEE, BEGINNING IN 2015, THE NUMBER OF TOTAL APPLICATIONS [INDISCERNIBLE]. AND THE LAST SLIDE, I AM HAPPY TO ANSWER ANSWER ANY QUESTIONS YOU HAVE ABOUT THE BUDGET, MY CONTACT INFORMATION IS HERE AND THE CONTACT INFORMATION FOR THE NEI BUDGET OFFICE IS HERE. I WILL BE HAPPY TO ANSWER QUESTIONS. >> SO KAREN I NOTED YOU HAD MONEY COMING FROM THE NEI FROM THE IN, IH BRAIN INITIATIVE. CAN YOU EXPLAIN THAT ABOUT GROWING OR WHAT IS YOUR GUESS ABOUT THAT? >> WE'RE NOT SURE WHETHER OR NOT BRAIN WILL GROW BECAUSE OF 2017 BUDGET REQUEST IS FLAT, RIGHT NOW WE ANTICIPATE THE BRAIN WILL BE FLAT BUT THAT REMAINS TO BE SEEN AT THE AS THE HOUSE AND SENATE COME TOGETHER WE'LL KNOW MORE LATER. >> SO I THINK I SAW 4.6 MILLION, IS THAT GIVEN TO THE NEI TO ADMINISTER THOSE NCEREBELLUMS I RELATED GRANTS? >> YEAH, THAT'S INCLUDED IN OUR TOTAL. >> SO THAT'S THE NCEREBELLUMS I PUT MONEY INTO THE BRAIN INITIATIVE? >> YES. >> AS WELL? >> YES. >> SO WHAT IS THE BALANCE TOTAL? WHAT ARE WE RECEIVING OR PUTTING IN. >> WE ARE RECEIVING AND WE PUT IN ABOUT A MILLION DOLLARS. >> SO MAYBE I CAN EXPLAIN AND I'LL SHOW YOU SOME PROJECTED NUMBERS FOR BRAIN INITIATIVE, BUT THE WAY IT'S FINANCED IS THE MONEY THAT COMES FROM CONGRESS AND NEW MONEY DOES NOT GO INTO SOME NIH POT, IT'S DIVIDED UP AND PUT INTO THE APPROPRIATIONS FOR THE 10 INSTITUTES THAT PARTICIPATE IN IT AND IT'S PASS-THROUGH MONEY WHEN THE DIRECTORS DECIDE WHAT GRANTS WILL BE FUNDED REGARDLESS OF WHAT AREAS OF SCIENCE THEY ARE IN, THEY ARE PASSED OUT TO THE INSTITUTES AND THEY PAY THOSE GRANTS AND CONTRACTS UNTIL THE MONEY THAT WAS PUT INTO THEIR BUDGETS HAS BEEN SPENT. SO IT SHOWS UP AS AN INCREASE IN OUR BUDGET BUT IT'S ACTUALLY PASSED THROUGH TO THE BRAIN GRANTS. >> THANK YOU. I HAVE A QUESTION ABOUT THE POST DOC INCREASE, I UNDERSTAND THE TRAINING GRANTS WILL BE SUPPLEMENTED TO,A COUNT FOR THAT, BUT THAT? >> I CAN ANSWER THAT ONE ALSO. STARTING IN DECEMBER THE F32 LEVELS FOR YEARS ZERO, ONE, AND TWO WHICH WILL BE BELOW THAT THRESHOLD WILL ALL BE INCREASED. THERE'S ALSO A 2 PERCENT INCREASE THAT'S ANTICIPATED AND THERE'S SOME DISCUSSION ABOUT MAYBE ALL LEVELS WILL GO UP FOR 2017. BUT NIH HAS DECIDED ON A POLICY--THIS IS GOING TO COST $50 MILLION OR SO FOR THESE INCREASED BUDGETS TO NIH, BUT NIH HAS DECIDED ON A POLICY THAT GRANTS POST DOCS WHO ARE FUNDED ON THOSE GRANTS THAT WILL NOT BE SUPPLEMENTED IF THE UNIVERSITIES DECIDE TO MAKE THE CORRESPONDING INCREASES IN THE POST DOC SALARIES THAT COME FROM GRANTS. >> I HAVE A QUESTION, ALSO ALONG THOSE LINES. ONE OF THE GRAPHS THAT WE DON'T NORMALLY SEE ON THE BUDGET UPDATE SYSTEM THE AVERAGE SIZE OF AN AWARD, I'M THINKING PARTICULARLY OF AN RO-1 WHICH I SUSPECT IS GONE DOWN OVER TIME. IS THAT TRUE? HAS IT GONE DOWN SIGNIFICANTLY? >> SO WE ARE GIVEN TARGETS IN TERMS OF THE NUMBERS OF GRANTS AND THE AVERAGE GRANT AND OUR AVERAGE GRANT AWARD IS FIXED AT $404,000 IN TOTAL COST AND IT HAS BEEN THAT FOR FOUR OR FIVE YEARS? EIGHT YEARS? SO WE'RE OBLIGATED TO HOLD THAT STEADY WHICH IS REASONABLE GIVEN THAT OUR BUDGET HAS BEEN FLAT FOR 10 YEARS AS WELL. BUT THAT'S THE AVERAGE NUMBER FOR ALL RPG GRANTS. >> SO FOR THE RO-1 THOUGH, DO YOU HAVE IT? >> THAT'S THE MAIN PLAN? >> [INDISCERNIBLE]. >> THANK YOU VERY MUCH. >> I JUST WANT TO REMIND COUNCIL MEMBERS THAT I TAKE ALL THE SLIDE PRESENTATIONS AND CREATE PDF FILES AND PUT THEM ON THE ELECTRONIC COUNCIL BOOK UNDER A TAB THAT I'LL CALL PRESENTATIONS, SO YOU DON'T HAVE TO TAKE A LOT OF NOTES HERE, YOU'LL HAVE THE INFORMATION ACCESS. >> LET ME JUST GIVE A BRIEF OVERLAY ON THE BUDGET. AS YOU CAN SEE, THE NEI BUDGET IS FAR MORE COMPLEX THAN A PIE AND HOW MUCH GOES HERE AND THERE AND WHEREVER, THERE ARE A LOT OF INTERACTING COMPONENTS. SO WE GET AN APPROPRIATION NUMBER FROM CONGRESS AND THEN BEFORE WE ACTUALLY GET THAT MONEY, THERE ARE SLICES TAKEN OFF THE TOP, SLICES AT THE LEVEL ABOVE NIH AND THEA THE NIH LEVEL AND THEN NUMBERS FOR SPECIFIC PROGRAMS SUCH AS THE PASS THROUGH FOR ARE THE BRAIN INITIATIVE WHICH IN THIS CASE IS 4.8 MILLION WHICH IS AN ADDITIONAL MILLION THAT THE EYE INSTITUTE IS CONTRIBUTING YEARLY, THAT WAS STARTED LAST YEAR, SO WE'RE PUTTING INTO BRAIN ABOUT 5 MILLION PLUS ONE, ABOUT $6 MILLION. IN ADDITION THE EYE INSTITUTE IS PART OF NIH WHERE ONE OF 27 INSTITUTES AND CENTERS AND THERE IS ACCORD NATION AT THE NIH LEVEL FOR SOME OF OUR ACTIVITIES SUCH AS MIKE STEINMETZ ALREADY SAID, THE AVERAGE FOR THE ANNUAL PORTFOLIO COST, DIRECT AND INDIRECT. IN YEARS PREVIOUS WE WERE TOLD NOT TO LOWER THE COST BUT TO INCREASE THE NUMBERS THAT WE WERE FUNDING. THAT WAS HARD WHEN WE DIDN'T HAVE ANY NEW MONEY, I DON'T KNOW HOW OUR BUDGET DID THAT BUT ANYWAY, THE POINT OF WHAT I'M SAYING IS THAT THIS IS NOT A MATTER OF STRAIGHT FORWARD BUDGET SHEET, SO IN ORDER TO HANDLE THIS INSTITUTE, HAS PLANNING THAT HAPPENS AT MULTIPLE LEVELS WITHIN THE EXTRAMURAL PROGRAM THEREUPON IS A BIG INPUT AT THE LEVEL OF KAREN'S OPERATION, THERE IS A GLOBAL PERSPECTIVE OF ALL MONIES FOR THE--THAT THE INSTITUTE EXPENDS AND MORE THAN ONCE A YEAR SENIOR NEI STAFF, WE SIT TOGETHER TO LOOK AT WHAT IS POSSIBLE AND TO USE OUR BEST JUDGMENT ON HOW TO PROTECT THE NUMBERS OF GRANTEES AND THE DOLLARS. STEVE, MAYBE I'M DETECTING UNDER YOUR QUESTION THAT THE FACT THAT WHILE FROM OUR PERSPECTIVE, THE NUMBER IS THE SAME EVERY YEAR, IT WOULD LOOK SMALLER EVERY YEAR AND THAT'S BECAUSE THERE ARE INFLATIONARY COSTS THAT YOU ARE PAYING OR DENNIS YOU'RE SAYING WHAT ABOUT THESE POST DOCS? WELL, WE DON'T HAVE NEW MONIES IN OUR BUDGET TO INCREASE THE INDIVIDUAL RO-1 GRANTEE YEAR BY YEAR AND AT THE SAME TIME MAINTAIN THE NUMBERS OF GRANTEES. SO IF THERE IS SOME THREAD THAT I CAN PULL TOGETHER OUT OF WHAT I'M SAYING HERE IT IS FOR YOU TO BE AWARE THAT DECISIONS NEED TO BE MADE, PREFERABLY WITH YOUR INPUT ON ONE FUNDAMENTAL QUESTION: AT WHAT POINT ARE THE--IS THE BUDGET OF AN INDIVIDUAL GRANTEE BECOMING SO SMALL THAT THE PROGRAMS REALLY CANNOT BE HANDLED BY A GRANT? GRANT ALLOCATION. AND IN THAT CASE, ONE WOULD BEGIN TO CONSIDER DECREASING THE NUMBERS OF GRANTEES. THERE'S A TRADE OFF. DOLLARS PER GRANT TIMES NUMBER OF GRANTS EQUALS A NUMBER AND AT SOME POINT IF THAT NUMBER DOESN'T GO UP,OU HAVE TO MAKE INTERNAL DECISIONS. >> IF SHOULD IS THE OPPORTUNE TIME TO DISCUSS THIS IT IS MY OPINION, AS CONGRESS HANDLES THE BUDGETARY EXPECTATIONS AND THE COUNCIL'S EXPECTATIONS, WITHIN THE RO-1 YOU SUBJIT A BUDGET AND PERHAP ITS EVOLVES OVER TIME THAT THERE'S THREE FULL AIMS YOU HAVE, MAYBE TWO FULL AIMS THAT ARE ACCOMPLISHED OVER A TIME PERIOD, I WOULD LOBBY FOR THAT TO MAINTAIN THE PERSON WILL STRUCTURE TO LOOK AT THE PORTFOLIO NUMBER AND THE SERIES OF EXPERTISE AND I THINK IT'S IMPORTANT TO MAINTAIN THAT INFRASTRUCTURE FROM A NATIONWIDE PERSPECTIVE AND MAINTAIN THE NUMBER OF INVESTIGATORS AND LABORATORIES BUT PERHAPS THEA A--YOU KNOW THAT THEY'RE NOT ACCOMPLISHING AS MUCH WITH ONE RO-1. THAT WOULD BE MY POSITION AND I WOULD LIKE TO PAUSE IT TO THE GROUP. >> SO THE OTHER SIDE OF THE EQUATION IS TO CAP THE SIZE OF THE GRANT AND THE PARTICULARLY THE GRANTS THAT ARE GIB TO INVESTIGATORS THAT ARE ALREADY WELL FUNDED INSTEAD OF REDUCING THE AMOUNT OF INVESTIGATORS FROM THE BOTTOM, YOU CAN LEVEL OUT THE BUDGET FROM THE TOP. THAT MAY BE MORE FAIR AND WHEN TIMES ARE TIGHT, YOU WOULD BE MORE EMPOWERED TO ASK THE INVESTIGATORS THAT ARE VERY WELL FUNDED TO TIGHTEN THEIR BELT. I THINK ALSO THIS IS AN ISSUE THAT HAS TO TRICKLE DOWN TO THE REVIEWERS BECAUSE SOMETIMES THEY IMPLEMENT COMMENTS ABOUT BUDGET AND WITHOUT THIS KNOWLEDGE, IT MAY BE ACTUALLY SURPRISINGLY A WHILE BEFORE THEY REALIZE WHAT THE DEPARTMENT OF LABOR IS REQUESTING IF WE'RE NOT WITH THEIR INSTITUTIONS, I KNOW IT'S SOMETHING DISCUSSED ACTIVELY WHERE I AM BUT I DON'T KNOW IF IT'S NECESSARILY GETTING TO ALL THE VIEWERS. >> I JUST WANT TO ASK IF YOU'RE ABLE TO FUND MORE BECAUSE YOU'RE REDUCING THE NUMBER OF YEARS THAT YOU'RE-- >> WE HAVE BY LAW, WE HAVE TO AVERAGE FOUR YEARS ON OUR AWARDS. >> THEN MY PERCEPTION THAT THE YEARS HAVE BEEN REDUCED IS NOT CORRECT? >> NO ACTUALLY WE'VE INCREASED. OUR AVERAGE HAS GONE FROM 3.5 TO 3.6, TO 3.99 THIS YEAR. SO THE AVERAGE LENGTH HAS INCREASED BECAUSE THEY HAVE A DIFFERENT WAY OF REACH TAG AVERAGE THAT WE'VE USED IN THE LAST TWO YEARS. >> I WONDER IF DIFFERENT COST STRUCTURE, DIFFERENT TYPES OF RESEARCH MIGHT BE DIFFERENT. FOR EXAMPLE, IF YOU ARE DOING RESEARCH WITH LIVE ANIMALS THAT'S ONE KIND OF COST STRUCTURE IF YOU DO HUMANS WITH CADAVERRIZED AND DO YOU RESEARCH WITH TESTING AND THAT'S ANOTHER COST STRUCTURE AND MAKES ME WONDER IF THE UPPER LIMIT IDEA COULD HAVE FLEXIBILITY TO IT THAT DEPENDING ON THE NATURE OF WHAT YOU'RE PROPOSING TO DO THERE'S A LIMIT ON WHAT IT COULD BE, BUT I DON'T THINK A SINGLE LIMIT IS APPROPRIATE GIVEN THE BREDTH OF RESEARCH THAT GOES ON. >> I KNOW THIS IS CONTROVERSIAL BUT ANOTHER IDEA IS THAT OFTEN INVESTIGATORS HAVE 70%, 80% OF THEIR SALARIES PAID ON [INDISCERNIBLE] THERE'S INSTITUTIONS WITH ALMOST [INDISCERNIBLE]. ONE POSSIBILITY IS TO HAVE IT CAPPED OR SOMETHING LIKE THAT ON HOW MUCH SALARIES [INDISCERNIBLE] >> IN AN EN--STRATEGIES - -INTUITION WHERE THAT WOULD BE PROBLEMATIC AND WHERE WE DON'T REQUIRE OUR RESEARCHERS TO HAVE SALARY ON GRANTS AS MANY PLACES, I DON'T THINK THAT WILL BE PRACTICAL. BECAUSE SOME PLACES ARE REQUIRING RESEARCHERS TO HAVE 90% OF THEIR SALARY ON GRANTS. BASICALLY THERE ISN'T ANY MONEY ANYWHERE. THERE'S THE ISSUE. >> I HAVE TO LOBBY WITH ALL DUE RESPECT AGAINST DR. LEVY'S POSITION BECAUSE IT WOULD HAVE--WELL WHAT I THINK THE OUTCOME OF THAT WOULD BE TO EFFECTIVELY REDUCE THE NUMBER OF INVESTIGATORS BUT INSTEAD OF DOING IT AT THE FEDERAL LEVEL, YOU ARE DOING IT AT THE LOCAL INSTITUTIONAL LEVEL AND I THINK THAT WOULD ACCOMPLISH THE SAME GOAL AS JUST LIMITING THE NUMBER OF APPLICATIONS, SO I WOULD WITH ALL RESPECT DISAGREE WITH THAT. >> I DON'T THINK INSTITUTIONS GENERALLY AREN'T GETTING MORE MONEY AND THEIR COSTS ARE GOING UP TOO, I JUST DON'T THINK THEY WILL BE ABLE TO MAINTAIN THE NUMBER OF INVESTIGATORS. YOU WILL END UP HAVING UNIVERSITIES CAP IT RATHER THAN NIH CAPPING IT AND AS I TOOK MY INITIAL POSITION,--AT LEAST MAINTAINING IF WE CAN'T GROW THE FIELD OF EXPERTISE IN SAY LENS RESEARCH, GLAUCOMA, CORNEA, RETINA SO THAT YOU MAINTAIN THE NATIONAL INFRASTRUCTURE OF SCIENTIFIC EXPERTISE AND I THINK YOUR PROPOSAL WOULD DECREASE IT FROM A DIFFERENT ROUTE. >> OKAY THIS IS A RECURRING THEM SO WE'LL COME BACK AGAIN BUT FOR THE MOMENT LET'S HEAR ABOUT BRAIN. >> GOOD MORNING SO I THOUGHT I WOULDED TAKE A FEW MINUTES TO UPDATE YOU TO WHAT'S HAPPENING AT NIH WITH THE BRAIN INITIATIVE. SO I'M SURE YOU'RE ALL AWARE THIS IS AN EFFORT LAUNCHED QUITE BY SURPRISE IN 202,013, PRESIDENT OBAMA'S STATE OF THE UNION ADDRESS CAUGHT US COMPLETELY OFFGUARD AND THE GOAL OF THE BRAIN INITIATIVE IS TO REVOLUTIONIZE OUR UNDERSTANDING OF THE HUMAN BRAIN BY ACCELERATING THE DEVELOPMENT AND APPLICATION OF INNOVATIVE TECHNOLOGIES AND PROCESS BEGAN WITH AN ADVISORY COMMITTEE TO THE NIH DIRECTOR THAT WAS PUT TOGETHER, THAT WAS CHAIRED BY BILL NEWSOME AND COREY BARDMAN AND THEY SPENT AN INCREDIBLE HALF YEAR INTERVIEWING ALL EXPERTS IN ALL AREA AND TOOK A TRAVELING SHOW AROUND THE COUNTRY AND HAD MEETINGS TO BRING EVERYONE'S VIEWS TOGETHER THAT RESULTED IN REALLY QUITE A REMARKABLE REPORT THAT YOU CAN FIND ON THE NIH BRAIN INITIATIVE WEB SITE CALLED BRAIN 2025 A SCIENTIFIC MISSION. AND THAT DOCUMENT HAS LARGELY BEEN THE BLUEPRINT THAT THE BRAIN INITIATIVE HAS BEEN FOLLOWING. THE BRAIN INITIATIVE IS MUCH BIGGER THAN NIH ALONE, IT HAS PUBLIC-PRIVATE PARTNERSHIP WHICH INCLUDES SEVERAL FEDERAL AGENCIES, THE NIH, NSF, DARPA, AND FDA AND IARPA, WHICH NO ONE HAD HEARD OF IT'S THE RESEARCH DIVISION OF THE INTELLIGENCE COMMUNITY WHO IS ALSO VERY INTERESTED IN BRAIN RESEARCH BUT THERE ARE ALSO SEVERAL FOUNDATIONS AND INSTITUTES, UNIVERSITY AND INDUSTRY THAT ARE ALL CONTRIBUTING TO THIS EFFORT. THE BUDGET BEGAN IN FISCAL YEAR 2014 WITH FORWARDING $6.1 MILLION. SOME OF THIS WAS NEW MONEY THAT CAME FROM CONGRESS AND OTHERS WERE INVESTMENTS THAT CAME, THIS IS THE NIH PART OF THE BUDGET THAT CAME FROM VARIOUS INSTITUTES AND CENTER AND OFFICES ACROSS THE NIH, THE 10 INSTITUTES THAT I HAVE LISTED AT THE BOTTOM OF THE NEI ARE CALL CONTRIBUTING TO THIS EFFORT AS WELL AS DOLLARS THAT WERE CONTRIBUTED BY THE NIH BLUEPRINT CONSORTIUM, THE OFFICE OF BEHAVIOR AND SOCIAL SCIENCE RESEARCH AND MONIES FROM THE OFFICE OF THE DIRECTOR AND FROM THE OFFICE OF RESEARCH ON WOMEN'S HEALTH. THERE WAS--CONGRESS GAVE AN INCREASE TO THE BUDGET IN 2015 TO A TOTAL OF $85 MILLION. THIS YEAR IN 16 THERE WAS AN INCREASE WHERE WE'RE ESTIMATING--DEPENDING ON THE CONTRIBUTIONS FROM THE VARIOUS NIH INSTITUTES--TO BE SOMEWHERE AROUND 150 MILLION THE NUMBERS THAT HAVE COME OUT OF THE PRESIDENT'S BUDGET WOULD INCREASE THIS BY ANOTHER 45 MILLION IN 2017 TO THE LEVEL OF 195 MILLION. JUST A COUPLE OF WEEKS AGO, THE SENATE BUDGET COMMITTEE REPORTED OUT A RESOLUTION THAT TAGGED THIS AT $250 MILLION. SO IT'S POSSIBLE THAT THIS CAN GO UP EVEN LARGER THAN THAT IN FISCAL YEAR 17. OVER ON THE RIGHT, YOU SEE SOME FIGURES THAT THE ADVISORY COMMITTEE REPORTED OUT FOR WHAT THEY THOUGHT IT WOULD TAKE TO FULLY FUND THE INITIATIVE THAT THEY PLANNED IN THE 2025 REPORT AND YOU CAN SEE, WE'RE FALLING A BIT SHORT OF THIS BUT IT'S REALLY GROWING AT A RAPID RATE. SO THIS SLIDE HERE SHOWS THE FUNDING OPPORTUNITY ANNOUNCEMENTS THAT WERE RELEASED IN 2014 AND 2015. THERE WERE 15 INITIATIVES HERE AND ABOUT 125 AWARDS WERE MADE IN THAT TIME AND THE SLIDE BREAKS THEM DOWN BY CATEGORIES. ONE MAJOR EFFORT IS TOCCATA LOG ALL THE CELLS IN THE BRAIN AND THEY ARE SHOWN IN THE DARK RED TO DEVELOP TOOLS FOR UNDERSTANDING CIRCUITS AND HOW THEY FORM AND ACT TOGETHER SHOWN IN ORANGE. NEW TECHNOLOGY FOR MONITORING NEURAL ACTIVITY IN YELLOW AND TOOLS FOR MODULATING NEURAL ACTIVITY AND GREEN THEORY AND ANALYSIS, TOOLS AND LIGHT BLUE HUMAN NEUROSCIENCE, AND DARK BLUE AND INTEGRATIVE APPROACHES WHICH COMBINE ELECTROPHYSIOLOGY, NEUROANATOMY, BEHAVIOR, COMPUTATIONAL APPROACHES REALLY AT UNDERSTANDING BASIC CIRCUITS. AND YOU CAN SEE THAT IN THE FIRST TWO YEARS, THE MAJOR IMP SIS HERE HAS BEEN ON NEW TOOLS TO MONITOR ACTIVITY AND CONTROL ACTIVITY IN CIRCUITS. AND THAT WAS THE EXPECTATION OF THE ADVISORY COMMITTEE THAT THE FIRST FIVE YEARS WOULD BE INVOLVED IN TOOL DEVELOPMENT AND THIS NEXT FIVE YEARS, WE WOULD WOULD START TO MOVE TO THE ACTUAL ANALYSIS OF CIRCUITS. AND THE CURRENT YEAR THERE WERE 14 NEW ANNOUNCEMENTS. THEY'RE BE REVIEWED NOW. THE FUNDING PLANS WILL BE PUT TOGETHER SHORTLY AND THE GRANTS WILL GO OUT BEFORE THE END OF THIS FISCAL YEAR. AND YOU CAN SEE THERE'S STILL A STRONG DEVELOPMENT HERE IN THE YELLOW AND GREEN AT TOOLS TO MONITOR NEURAL ACTIVITY AND CONTROL NEURAL ACTIVITY BUT THE BIG CHANGE HERE IS ADDITION IN THE AREAS OF THEORY AND DATA ANALYSIS TOOLS AND THE LIGHT BLUE AND SEVERAL NEW ANNOUNCEMENTS ON ADVANCING HUMAN NEURAL SCIENCE AND AGAIN A SLIGHT TREND TOWARDS INTEGRATIVE APPROACHES. IF YOU LOOK AT THE WHOLE PORTFOLIO AT HOW IT'S BROKEN OUT BY DOLLARS HERE OVER TIME THROUGH THESE INITIATIVES, YOU WILL SEE THAT THIS PROJECT, THIS INITIAL PROJECT TO REALLY MAKE A CENSUS OF ALL THE TYPES OF CELLS HAS HAD IT SHOWN IN THE DARK ORANGE AT THE BOTTOM HAS BEEN VERY PRODUCTIVE AND LOTS OF ADVANCES IN THESE AREAS, THERE'S AN INCREASING AMOUNT OF MONEY INTO DEVELOPING TOOLS FOR ANALYZING CIRCUITS AND FOR NEURAL RECORDINGS IN THE LIGHT ORANGE AND LIGHT BLUE AND YOU SEE THE BIG STEP HERE AND HUMAN IMAGING AND MODULATING BRAIN ACTIVITY IN THE LIGHT BLUE AND A SLIGHT IPT GREATER CREASE IN UNDERSTANDING OF CIRCUTES AND BEGINNING WITH LAST YEAR AND AGAIN IN THIS YEAR, A SMALL AMOUNT OF MONEY HAS STARTED TO DEVELOP PROGRAMS FOR TRAINING AND DISSEMINATING THE NEW TECHNOLOGY. COMING ABOARD IN FISCAL YEAR 17, THESE ARE STILL PLANS, MANY OF THESE INITIATIVES THAT EXIST INDEED 2016 WILL BE CONTINUED BUT SOME NEW IDEAS THAT ARE ON THE TABLE ARE TO DEVELOP SOME SPECIALIZED PHENOTYPING CENTERS FOR THE CELL CENSUS OPERATION AND ALSO A SPECIFIC PROJECTS FOR CATALOGING--CATALOGING HUMAN AND NONHUMAN PRIMATE CELL TYPES. ALSO THE ESTABLISHMENT OF A CELL CENTER TO INTEGRATE AND COORDINATE ALL THESE VARIOUS TYPES OF INFORMATION THAT ARE COMING OUT ON HOW CELLS ARE CATALOGED. THERE ARE ALSO GOING TO A MOVEMENT TO DEVELOPMENT BRAND NEW TOOLS ARE IMAGING HUMAN BRAIN ACTIVITY. THE PRIOR YEAR THERE WERE PLANNING GRANTS PUT TOGETHER TO DO THIS AND THIS WILL MOVE INTO A SECOND PHASE WHERE NEW TOOLS FOR IMAGING THE BRAIN WILL BE DEVELOPED IN THE COMING YEARS. THERE WILL ALSO BE SOME NEW TRAINING AND CAREER AWARDS, F32S AND K18S ARE IN THE PLANS AND THEN AGAIN TO START TOW MOVE TOWARDS REALLY PROJECTS TO UNDERSTAND CIRCUITS WITH TARGETED INTEGRATIVE APPROACHES AND EXPLORATORY IDEAS WITH REGULAR RO-1S AND R21 GRANTS. MOST OF THE FUNDING THAT HAS BEEN DONE SO FAR HAS BEEN WITH THE U-MECHANISM, THESE ARE COOPERATIVE AGREEMENTS THAT HAVE SUBSTANTIAL NIH OVERSIGHT AND NOW THE THOUGHT OF THE COUNCIL WORKING GROUP IS THAT WE ALSO MOVE TOWARD RO-1 AND R21 MECHANISMS. AND WE ARE ALSO LOOKING AT ADMINISTRATIVE SUPPLEMENTS OF GRANTS AND PEOPLE WHO ARE DEVELOPING TECHNOLOGY IN ORDER TO CREATE MECHANISMS FOR THAT TECHNOLOGY TO BE SHARED BROADLY AND PROPAGATED THROUGHOUT THE COMMUNITY. ALSO THIS YEAR THERE HAS BEEN SOME CONCERN AND THIS WAS PART OF THE ORIGINAL REPORT WITH ALL THIS ABILITY TO MAP HUMAN BRAIN ACTIVITY AND MODULATE HUMAN ACTIVITY IN THE BRAIN THAT THE BRAIN CONSIDERED TO NEED THE ETHICS WORK GROUP HAS BEEN PUT TOGETHER CO CHAIRED BY CHRISTINE GRADY AND HANK GREELY, AND THEY WILL TALK ABOUT WHAT NEED TO BE PRIORITIZED AND ADDRESSED AND THE SECOND MEETING IS PLANNED FOR THIS AUGUST TO CONSIDER HAVING WORKSHOPS THAT WOULD ADDRESS ISSUES OF PRIVACY OF HUMAN DATA, ETHICS AND RESEARCH USING NOVEL TECHNOLOGIES AND THERE'S ALSO AN RFI OUT ON THE STREET TO ASK FOR GUIDANCE AND OPPORTUNITIES IN THIS AREA. IT WAS JUST PUBLISHED IN JUNE AND THERE'S A LINK TO IT HERE ON THE BOTTOM OF THE SLIDE IF YOU WANT TO CONTRIBUTE TO THAT. PART OF THE INITIATIVE OF THE INVESTIGATORS IS TO BRING THEM TOGETHER ANNUALLY AND THE FIRST MEETING WAS REALLY JUST THE GRANTEES VERY EARLY AND THEM TO INTRODUCE THEMSELVES. WE HAD A SECOND ANNUAL MEETING LAST DECEMBER AND IT WAS HELD HERE IN WASHINGTON. THERE WAS 500 PEOPLE THAT ATTENDED. THERE WERE 190 PRESENTATIONS AND SOME KEY NOTE ADDRESSES AND IT REALLY GENERATED SOME CONSIDERABLE EXCITEMENT AMONG THE GRANTEES AND THE NIH STAFF. IT GAVE AN OPPORTUNITY FOR PEOPLE TO SHARE THEIR IDEAS WITH ONE ANOTHER AND A LOT OF COOPERATIVE ARRANGEMENTS CAME OUT, CAME OUT OF THAT MEETING AND IT WAS VERY, VERY PRODUCTIVE. A THIRD MEETING IS BEING PLANNED NOW FOR THIS DECEMBER. IT'S GOING TO BE EXPANDED TO INCLUDE NOT JUST THE GRANTEES BUT TO HAVE OPEN SESSIONS FOR THE PUBLIC, IT WILL ALSO BE HELD HERE IN TOWN. WE'RE ANTICIPATING 700 OR MORE PARTICIPANTS TO ATTEND AND THE REGISTRATION FOR THAT WILL OPEN ON SEPTEMBER FIRST. SO THE SLIDE SET THAT IS BEING SENT AROUND FOR PEOPLE TO GIVE TO COUNCILS INCLUDED EXCITING ADVANCES, INCLUDING FIVE OR SIX OF THEM AND I THOUGHT I WOULD SHARE A COUPLE OF THEM WITH YOU. SO THIS ONE FROM SARAH STANLEY, STAIRA HAS FOUND A WAY TO TAKE IRON MOEITIES, AND FOUND THEM AND INCLUDE THEM AND ATTACH THEM TO THE ACTIVATING PART OF AN ION CHANNEL AND SHE'S DONE IT IN TWO WAYS. ONE USING TEMPERATURE SENSITIVE CHANNELS AND ANOTHER ONE TO CHLORIDE CHANNELS AND THE INTERESTING ASPECT OF THIS IS THAT FROM OUTSIDE THE ANIMAL YOU CAN USE RADIO WAVES THAT EFFECT THESE IRON PARTICLES HERE AND THEN GATE THIS CHANNEL AND BY DOING THIS THEY'RE ABLE TO USE ELECTROMAGNETIC WAVES AND ACTIVATE GLUCOSE SENSING NEURONS IN THE MOUSE HYPE THALAMUS THAT ACTUALLY CHANGED PLASMA GLUCOSE LEVELS AND INSULIN LEVELS AND STIMULATED FEEDING BEHAVIORS IN THE ANIMALS AND BY INCLUDING THE SAME MECHANISM IN THESE CHLORIDE CHANNELS THEY'VE BEEN ABLE TO CREATE ALL THE OPPOSITE EFFECTS LEADING TO DECREASED GLUCOSE, HIGHER INSULIN AND SUPPRESSED FEEDING. SO CAN YOU SUPPRESS YOUR APPETITE BY STANDING CLOSE TO YOUR RADIO HERE IS THE ULTIMATE-- >> [INDISCERNIBLE]. >> --YEAH. [LAUGHTER] EMPLOY SO THIS IS JUST A TYPICAL EXAMPLE OF THE INCREDIBLE INNOVATIONS THAT HAVE COME OUT OF THIS PROGRAM. THE GRANTS THAT ARE BEING WORKED ON ARE PROMISING REALLY STUNNING TECHNOLOGY. ANOTHER ADVANCE THAT EVERYONE IS HIGHLIGHTING IS THIS ONE AT THE BRAIN INSTITUTE, THEY USED RNA SEQUENCING AND STUDIED OVER 1600 NEURONS IN THE PRIMEAR I VISUAL CORTEX AND USING RNA SEQUENCING SHE'S BEEN ABLE TO IDENTIFY 49 UNIQUE CELL TYPES IN THE VISUAL CORTEX, 23 OF THEM ARE ININCREASE IN BODYITORY CELLS, 19 ARE FLUTA MA TERNALLIC AND 17 ARE NONNEURONAL AND BY USING AN WATOMICAL AND ELECTROPHYSIOLOGICAL TECHNIQUE SHE'S BEEN ABLE TO DEMONSTRATE THAT MOST OF THESE UNIQUE TYPES ARE IDENTIFIED BY TRANSCRIPTOMICS ALSO HAVE UNIQUE OR ELECTROPHYSIOLOGICAL OR ANATOMICAL PROPERTIES. SO THERE'S BEEN A LOT OF STEP FORWARD IN UNDERSTANDING THE NEURONS THAT MAKE UP THE VISUAL CORTEX. AND ANOTHER ADVANCE THAT THEY'RE SENDING AROUND IS ONE FROM THOMAS EULERWHO IS USING TWO-PHOTON IMAGINGLY TO OBSERVE RETINAL IMAGING IN THE CELL OF THE MOUSE. SO THIS TECHNIQUE USING 2-PHOTON CALCIUM IMAGING, MEASURED RESPONSES FOR MORE THAN 11,000 RETINAL GANGLION CELLS, WHY THEY'RE BEING STIMULATED WITH VARIOUS KINDS OF STIMULI AND THEN USE AUTOMATED UNSUPER VISED UNBIASED CLUSTERING PROCEDURES TO IDENTIFY HOW MANY TYPES OF THESE CELLS CLUSTER OUT. AND SO FAR BY THEIR COUNT, THEY SEE SOMEWHERE BETWEEN 32 AND 49 DIFFERENT TYPES OF RETINAL GANGLION CELLS WHICH MAY BE TWICE AS MANY AS PREVIOUSLY IDENTIFIED. AND THIS PROJECT IS IN COLLABORATION WITH SEBESTIAN SUNG H, WHO CAME AND PRESENTED THE OTHER SIDE OF THIS A FEW COUNCILS AGO AND THEY ARE USING 3D EM RECONSTRUCTION OF THESE CELLS TO LOOK AT ALL THE ANATOMY AND THE CONNECTIONS BETWEEN THESE CELLS AND EVENTUALLY THE ANATOMY AND THE PHYSIOLOGY WILL BE BROUGHT TOGETHER IN ORDER TO TRY TO IDENTIFY UNIQUE CELLS AND HOW THE PROPERTIES ARE ASSOCIATED WITH THEIR IDENTIFICATION TYPE. AND LASTLY WE JUST LEARNED RECENTLY THAT--SO SO FAR ALL OF THE NEI HAS FOR THE BRAIN INITIATIVE HAS BEEN RUN ON A VOLUNTARY BASIS. THERE ARE NO BRAIN STAFF AT NIH. THERE ARE PROGRAM OFFICERS, THERE ARE SIX PROGRAM OFFICERS IN THIS ROOM WHO PARTICIPATE IN THESE WORK GROPES THAT WRITE THE FOAs, MANAGE COOPERATIVE AGREEMENTS, PULLET TOGETHER FUNDING PLANS AND RUN THE INFRASTRUCTURE OF THE BRAIN INITIATIVE AND IT TAKES THE SUBSTANTIAL PART OF THEIR EFFORT IN ADDITION TO THEIR DAY JOBS. s SO THERE WAS A RECENT FUNDING INITIATIVE TO USE A SMALL FRACTION, MAYBE ONE OR 2 PERCENT OF THE BRAIN ALLOCATION TO SUPPORT RMS FUNCTIONS AND THIS WILL BE TO HELP REIMBURSE INSTITUTES FROM THE COST OF RUNNING REVIEW MEETINGS AND FOR THE CONFERENCES AND TO REIMBURSE INDIVIDUALS LIKE MYSELF WHO HAVE A CONSIDERABLE PERCENTAGE OF THEIR EFFORT FOR THIS. THERE'S ALSO A SEARCH UNDERWAY TO HIRE PROGRAM OFFICERS SOMEWHERE BETWEEN FIVE OR SIX WHO WOULD WORK THE MAJORITY OF THEIR EFFORT WOULD BE ON THE BRAIN WORK GROUPS AND OVERSEEING THESE GROUPS AND IT WOULD BE ABSOLUTELY MANDATORY AS THE NUMBER OF THESE GRANT SYSTEM GROWING RAPIDLY, THE CONCEPT IS THAT THESE PEOPLE WOULD DEVOTE MAYBE 75% OF THEIR EFFORT STRICTLY TO THE BRAIN INITCHIAATIVE, THEY WOULD HAVE A FOOT IN ONE OF THE BRAIN INSTITUTES AND HAVE AN ASSIGNMENT THERE OF MAYBE 25% OF THEIR EFFORT AND THE SALARY WOULD BE SHARED. ALSO THERE IS A SEARCH UNDERWAY TO HIRE AN OVERALL DIRECTOR FOR THE NIH BRAIN INITIATIVE. AND THIS PERSON WHAT WE ARE LOOKING FOR IS AN ACTIVE SCIENTIST, WELL KNOWN AND RESPECTED IN THE COMMUNITY, WHO WOULD COME AND OVERSEE THIS OPERATION AT NIH AND ALSO HAVE THE CRITICAL FUNCTION OF BEING THE LIAISON BETWEEN THE OTHER FEDERAL AND NONFEDERAL PARTNERS AND THE INITIATIVE AND MY PERSPECTIVE IS THAT THIS HAS BEEN AN AREA THAT IS FAIRLY WEAK AT THIS POINT. THE COOPERATION BETWEEN THE OTHER PARTNERS HAS NOT BEEN AS GOOD AS PEOPLE WOULD LIKE AND I THINK HAVING A PERSON IN THIS POSITION--THE FULL-TIME RESPONSIBILITY FOR THIS WILL BE A GREAT ASSET TO THE PROGRAM. THAT'S REALLY ALL I HAD TO UPDATE YOU WITH THE COUNCIL THAT OVERSEES THIS IS A MULTICOUNCIL WORKING GROUP THAT HAS REPRESENTATIVES FROM ALL THE COUNCILS AND RAFA IS OUR REPRESENTATIVE ON THAT COUNCIL. WOULD YOU LIKE TO SAY SOMETHING? >> I THOUGHT YOU DID AN EXCELLENT JOB. MAYBE ONE THING THAT EVERYONE SHOULD KNOW IS THAT THE DEPARTMENT OF ENERGY IS TOYING WITH THE IDEA OF ENTERING THE BRAIN INITIATIVE AND THEY ARE MOVING VERY SLOWLY BUT THEY'RE A MONSTER EN--STRATEGIES TUITION AND AS FAR AS I KNOW--INSTITUTION AND AS FAR AS I KNOW THE MOVE IS IN THE RIGHT DIRECTION SO IT'S POSSIBLE THAT WITHIN A YEAR OR SO THERE WILL BE A GORILLA IN THE ROOM OF THE BRAIN INITIATIVE AND THEY COULD DEVOTE UP TO 11 NATIONAL LABORATORIES TO WORK ON THE DEVELOPMENT OF THESE TYPES OF TECHNOLOGIES AS A MULTIINVESTIGATOR CENTER SITE. >> THANK YOU RAFA. ANY QUESTIONS? >> I'M SURE YOU THOUGHT ABOUT THIS, IS THERE SOME WAY WE COULD LEVERAGE THIS INTO THE AUDACIOUS GOALS INITIATIVE. LIKE FOR EXAMPLE, THAT GANGLION CELLS THING, I KNOW THAT THE IMAGING STRATEGIES YOU CAN USE IN THE EYE WOULDN'T ALL WORK FOR THE BRAIN GENERALLY BUT ONE WAY THEY COULD WORK IS THE IDEA OF DEVELOPING DIFFERENT TYPES OF QUANTUM OR IMAGES PROPERTIES AND YOU COULD WORK OUT THE ANATOMY OF ALL THAT STUFF IN THE EYE SO THAT YOU HAD A SENSE OF WHAT THE SIGNALING LOOKED LIKE WHEN YOU DID MRI IMAGES OF THE BRAIN PARTICLES AND YOU COULD ADDRESS OR INTERROGATE SORT OF GENERIC BIOCHEMICAL PROCESSES LIKE OXIDATIVE DAMAGE AND THOSE SORTS THINGS SO WHEN I HEAR THE DEFENSE DEPARTMENT GETS INVOLVED WITH IT, THAT'S A MASSIVE AMOUNT OF MONITOR THAT'S COULD HELP FUND THE AUDACIOUS GOALS INITIATIVE. SO THE INTERESTING THING IS THAT THE BRAIN INITIATIVE HAS LARGELY STAYED OUT OF THE AREA OF DEVELOPMENTAL PROCESS OR INJURY PROCESS AND THIS REALLY FOCUSED ON ISSUES SO THAT DOVETAILS NICELY WITH THE DOFF TAIL INITIATIVES AND I EXPECT WHAT WILL COME OUT OF THIS, WILL BE A COMPLETE UNDERSTANDING OF THE RETINA. IN FACT THE ADVISORY COMMITTEE REPORT SAYS IN IT THAT THEY EXPECT THE RETINA TO BE THE FIRST BRAIN CIRCUIT THAT IS COMPLETELY UNDERSTOOD. THE FIRST BIG PROJECT IS ACTUALLY THIS ONE TO UNDERSTAND WHAT IT IS LIKE IN THE RETINA, WHAT IT IS LIKE, WHERE IT'S CONNECTED TO, WHERE IT CONNECTS IN THE BRAIN, HOW IT OPERATES AND HOW IT EFFECTS VISUAL PERCEPTION FROM EACH CELL TYPE. SO IT'S A GREAT OPPORTUNITY WITH TECHNOLOGY COMING OUT OF THIS TO HELP THE ORBS DASHES GOALS TO HELP WITH THIS BUT I DON'T EXPECT THE BRAIN INITIATIVE TO GET INVOLVED IN TISSUE REGENERATION AND WE'RE ARE UNIQUE THIS THAT. >> I WAS THINKING THE REVERSE, THAT SOMEHOW WE ACCEPTED PRO POSSESSAL TO THEM AND THEY FUND US. >> SO OUT OF THE FIRST ROUND OF GRANTS THAT WERE FUNDED BY THE BRAIN INITIATIVE, 40% OF THE GRANTS WHO WERE EITHER NEI INVESTIGATORS OR INVESTIGATORS WHO WEREUTESSING THE VISUAL SYSTEM OF THEIR MODEL OR PART OF THEIR MODEL. AND THE SECOND ROUND WAS MORE LIKE 20% OR SO AND OF COURSE WE DON'T KNOW WHAT WILL HAPPEN THIS YEAR. SO I THINK THE VISUAL SYSTEM BECAUSE IT'S SO WELL UNDERSTOOD IN TERMS OF CONNECTIONS AND THE MAPS AND VARIOUS AREAS THERE'S A TERRIFIC MODEL FOR PEOPLE TRYING TO UNDERSTAND CIRCUITS SO THE VISION COMMUNITY HAS ALREADY BEEN A BIG RECIPIENT OF THIS AND WE WILL STAY ON THE COMMITTEES TO MAKE SURE THAT IT DOES. >> SO MAYBE ONE WAY TO LOOK AT IT IS WITH A SUBSET OF GRANTS OR MAYBE WITH THE 500 INVESTIGATORS THAT WILL ATTEND THE MEETING THE ONES IN THE VISUAL SYSTEM AND PUT THEM TOGETHER WITH THE AUDACIOUS GOALS INVESTIGATORS? >> BECAUSE THAT LADY WHO DID PART OF THE ARM, THAT PART OF TECHNOLOGY COULD BE BROUGHT IN RIGHT AWAY AND THAT COULD PRODUCE IMMEDIATE OF FUNCTIONAL AND ANATOMICAL INFORMATION ON LIVING PATIENTS POTENTIALLY. GETTING CREATIVE ABOUT WHAT PARTICLES USE INSTEAD OF DESIGN PARTICLES. >> SO MAYBE BRAINSTORMING, ONE YOU SEE ONE WAY TO DO THIS, IT WOULD BE SINCE WE HAVE THE AUDACIOUS GOALS, WORKSHOPS, WITH RO-1, INVITE TO THOSE, SOME OF THE CRITICAL INVESTIGATORS IN SORT OF A TARGETED FASHION SO MAYBE JUST BRING A FEW [INDISCERNIBLE] >> IT'S ALMOST UNFAIR BECAUSE IT'S LIKE CHERRY PICKING THE BEST PEOPLE FROM OUTSIDE AND BRINGING THEM IN TO SIMPLY REDEPLOY THEIR TECHNOLOGY ESSENTIALLY. >> IT WOULD BE IN EVERYONE'S INTEREST, A LOT OF THESE DEVELOPERS ARE WORKING IN ISOLATION AND FOR THEM TO KNOW THAT PEOPLE CARE ABOUT THEIR METHODS AND [INDISCERNIBLE] >> THE WIN, WIN SITUATION. >> IT MAY BE UNFAIR BUT WE'RE NOT ABOVE THAT. >> [LAUGHTER] >> I FORGOT TO SAY SOMETHING WITH THE BRAIN INITIATIVE, AS YOU KNOW THERE ARE BRAIN INITTIAIVE ITS IN MANY DIFFERENT COMPANIES BESIDES THE EUROPEAN UNION THERE IS ONE IN JAPAN, AUSTRALIA, CANADA, ISRAEL, ONE ABOUT TO START IN CHINA, I'M BLANKING, BUT ANYWAY, SO THERE'S A THE BEGINNING OF MY PROCESS TO LINK ALL THESE BRAIN INITIATIVES IN THE WORLD AND TO MEET IN NEW YORK CITY WITH THE UNIT NATION GENERAL WORLD ASSEMBLY, ONE OF THEM OR BOTH OF THEM WOULD BE SPONSORED BY THE NSF WHO HAS A CONGRESSIONAL MANDATE TO TRY TO COORDINATE GLOBAL BRAIN PROJECTS. SO ONE OF THEM MIGHT HAPPEN TO BE AN ORGANIZER FOCUS ON THE DESIGNS PORTFOLIO, FOR THE DIFFERENT BRAIN PROJECT AND THE OTHER ONE IS ORGANIZED BY THE DEPARTMENT OF STATE. BY THE VICE PRESIDENT'S OFFICE WHO WANTS TO USE THIS AS AN EXAMPLE OF INTERNATIONAL COOPERATION. SO THIS IS AGAIN A HIGH GLOBAL POLITICAL SPIN-OFF OF THE BRAIN INITIATIVE TO MAKE IT--TO DEMONSTRATE TO THE WORLD OR INTERNALLY ALSO THAT THIS THERE IS COUNTRIES AROUND THE WORLD INCORPORATING IN THE SAME SPIRIT AS THE CLIMATE. >> THANK YOU ALL. >> OUR NEXT PRESENTATION WILL BE FROM THE TWO CO SHARES OF THAT EGI WORKSHOP ON REPLACEMENT OF RETINAL GANGLION CELLS BY ENDOGENOUS SOURCES AND THAT WILL BE MONICA VETTER, AND PETER HITCHCOCK, THAT WAS DONE ON APRIL 30th THE DAY BEFORE THE ARVO MEETING. >> THANK YOU VERY MUCH FOR THE OPPORTUNITY TOW GIVE YOU AN UPDATE ON THE WORKSHOP THAT WAS HELD BEFORE ARBO, APRIL 30th IN SEATTLE, WASHINGTON. IT WAS A PLEASURE TO WORK WITH PETER HITCHCOCK ON THIS SO WE WILL GO BACK AND FORTH A LITTLE BIT. AND THE FIRST PART OF THE PRESENTATION WILL--WE TRY TO GIVE CONTEXT, IT'S NOT INTENDED TO BE A COMPREHENSIVE VIEW OF THE FIELD BUT JUST TO SET THE STAGE FOR WHAT WE WENT INTO THE DISCUSSION WITH AND THEN WE'VE REALLY TRIED TO SUMMARIZE THE KEY POINTS THAT CAME OUT OF THE DISCUSSION AND WE'LL END WITH A SERIES OF KEY RECOMMENDATIONS AND SOME MILESTONES THAT WE THINK ARE ACHIEVABLE. AND AND WE WANTED TO FIRST--YOU CAN STAND WITH ME, IT'S FINE. WE WANT TO FIRST THANK THE WORKSHOP PARTICIPANTS, SEVERAL OF THE PEOPLE IN THE ROOM HERE, IT WAS A REALEE DIVERSE GROUP THAT REPRESENTED BOTH Ph.D. RESEARCHERS AS WELL AS PHYSICIAN-SCIENTISTS AND CLINICIANS AS WELL AS A FEW PEOPLE WORKING OUTSIDE OF THE VISUAL SYSTEM AND WE THINK THAT THIS DIVERSITY OF EXPERTISE REALLY HELPED FUEL THE DISCUSSION AND GOT SORT OF A RANGE OF PERSPECTIVES. AND THE CHALLENGE SIMPLY PUT IS THAT HUMANS HAVE A LIMITED ABILITY TO REPAIR OR REPLACE RETINAL GANGLION CELLS BUT OTHER SPECIES CAN DO IT QUITE WELL, THESE WERE COMMENTS THAT CAME OUT OF THE OPENING REMARKS, ANDRY REALLY WANTED TO HAPPENED WHAT CAN WE LEARN FROM THOSE SPECIES, WHAT LOOKS PROMISING AND THE GOAL ULTIMATELY BEING CAN WE TAKE OUR KNOWLEDGE OF BIOLOGY, ADDRESS GAPS IN THAT KNOWLEDGE AND ULTIMATELY DEFINE A PATH TOWARDS RGC REPLACEMENT IN HUMAN DISEASE. AND THE FOCUS OF THE WORKSHOP WAS ON ENDOGENOUS SOURCES. WE DO TOUCH ON THE INTRODUCTORY SOURCES, JUST TO GIVE CONTEXT AND WE ULTIMATELY ALSO TRIED TO STEER CLEAR OF TOPICS THAT HAD BEEN COVERED IN PREVIOUS WORKSHOPS SUCH AS THE SIGNATURES 95 CANT CHALLENGE OF RECONNECTING THESE NEURONS IN THE VISUAL SYSTEM BECAUSE THE CONNECTIVITY HAD BEEN COVERED IN SEVERAL WORKSHOPS. SO I DON'T NEED TO GO OVER THIS IN DETAIL WITH THIS GROUP BUT WE WANTED TO HIGHLIGHT THAT THERE ARE A NUMBER OF DISEASES WITH SIGNIFICANT FEATURE, RETINAL GANGLION CELL LOSS OR PRIMARILY RETINAL CELL LOSS, ONE OF THE MOST PREVALENT IS GLAUCOMA BUT IT'S MULTIPLE OTHER EXAMPLES HERE OF DISEASES FOR TRAUMATIC EVENTS THAT CAN LEAD TO RGC LOSS SO CLEARLY THERE'S A SIGNIFICANT MEDICAL NEED TO BE ABLE TO TRY TO ALLEVIATE THE SIGNIFICANT VISUAL LOSS THAT COMES WITH THESE DISEASES. AND THERE ARE IMPORTANT ASPECTS TO CONSIDER WITH RETINA GANGLION CELL REPLACEMENT. WHAT'S THE BEST SOURCE OF CELLS TO REPLACE THOSE LOST RGCs? HOW DO WE DIRECT THEIR DIFFERENTIATION? HOW DO WE PROMOTE INTEGRATION INTO CIRCUITS WITHIN THE RETINA. HOW CAN WE MONITOR AND MAINTAIN THE LONG-TERM SURVIVAL OF THOSE CELLS? HOW DO WE MONITOR AND ESTABLISH APPROPRIATE CONNECTIVITY? CAN WE GET A HANDLE ON THIS HUGE DIVERSITY OF RETINAL GANGLION CELL SUBTYPES THAT WE JUST HEARD ABOUT AND WHAT KINDS OF NUMBERS WILL WE NEED TO REPLACE TO RESTORE VISUAL FUNCTION AND HOW DO WE BEST ASSESS THE FUNCTION OF THE VISUAL SYSTEM. AND SO I WON'T GO IN DETAIL IN THIS BUT I WANTED--ONE OF THE THINGS WE HEARD ABOUT AND WE KNOW IS AN IMPORTANT CONSIDERATION IS THAT RETINAL GANGLION CELLS ARE DIVERSE, THEY HAVE DIVERSE MORPHOLOGIES AND SIGNIFICANT FUNCTIONAL DIVERSITY IN TERMS OF VISUAL RESPONSES AND CONNECTIVITY AND THEY DISTRIBUTE DIFFERENTLY WITHIN CONNECTIONS WITHIN THE RETINA AND A LOT HAS BEEN LEARNED OVER THE YEARS ABOUT HOW NEURONS ARE GENERATED DURING DEVELOPMENT AND SO THERE'S A GROWING BODY OF KNOWLEDGE ABOUT WHAT ARE THE GENE REGULATORY NETWORKS THAT HELP DRIVE PROGENITORS TOWARDS DIFFERENT RETINAL CELL STATES. THIS REVIEW IS TAKEN FROM VALERIE MILLER AND CAPTURES IT IN WORLD. AND ONE OF THE IDEA SYSTEM TO CAPTURE THIS BREDTH OF KNOWLEDGE THAT'S BEEN CAPITALIZED ON THE DEVELOPMENT AND WE KNOW IN THE CASE OF RETINAL GANGLION CELL THAT THERE ARE COLLECTIONS OF TRANSCRIPTION FACTORS THAT ACT COOPERATIVELY AND SEQUENTIALLY TO ULTIMATELY PROJECT RETINAL PROGENITORS TOWARDS RETINAL CELL STATES SO I DON'T THINK OUR UNDERSTANDING OF THIS IS COMPLETE BUT WE HAVE THE BASIS FOR BEGINNING TO UNDERSTAND THAT PROCESS. AND THIS IS JUST ONE EXAMPLE OF WHAT HAS BEEN LEARNED. THERE ARE MANY LABS THAT CONTRIBUTE TO IT THIS INCLUDING TOM GLAZIER'S LAB WHO JUST JOINED US HERE FOR THIS COUNCIL AND THIS IS A REVIEW FROM BILL KLEIN SHOWING WE'VE LEARNED A LOT ABOUT THE SEQUENCE OF GENE EXPRESSION THAT'S INVOLVED IN DIRECTING OF RETINA PROGENITORS TOWARDS THE GANGLION CELL STATE. THEY ARE AT THE HIGHER OF THE HIERARCHY ARE GENES THAT FUNCTION IN THE PROGENITORS THAT ARE IN THESE DIVIDING CELLS AND THAT THE EXPRESSION OF TRANSCRIPTION FACTOR CANS ULTIMATELY ACTIVATE A CASCADE OF ADDITIONAL TRANSCRIPTION FACTORS THAT WILL ACT IN CONCERT TO DERIVE CELLS TO EXIT THE CELL CYCLE AND EXPRESS TERMINAL DIFFERENTIATION GENES AND HELP CELLS FUNCTION TO BECOME RETINAL GANGLION CELLS AND ASSUME THEIR NORMAL MATURE PROPERTIES. AND RECENTLY IT'S BEEN SHOWN THAT TWO OF THESE MIDLEVEL FACTORS WHEN EXPRESSED TOGETHER CAN REDIRECT NEURONS THAT WOULD NORMALLY BECOME OTHER CELL TYPES SUCH AS AMACRIPS OR BI-POLARS TOWARDS RETINAL GANGLION CELLS SO WE CAN GO DEEPER INTO THIS HIRE ARCH SCHESTART TO DRIVE CELLS DOWN TO DIFFERENTIATION PATHWAY SO THE WHYED IS CAN WE START TO RUES SOME OF THIS KNOWLEDGE TO HELP DIRECT THIS DIFFERENTIATION PROGRAM. SOME OF THE CHALLENGES IS THAT WE STILL KNOW RELATIVELY LITTLE ABOUT HOW THE DIVERSITY OF RETINAL GANGLION CELL SUBTYPES IS ESTABLISHED AND WHAT ARE THE FACTORS WHETHER THERE'S DIFFERENT SIGNALING FACTORS OR INTRINSIC TRANSCRIPTION FACTORS THAT DIRECT THAT PROCESS. SO WE STILL HAVE A LOT OF WORK TO DO TO FLESH THIS OUT AND UNDERSTAND IN DETAIL WHAT'S GOING ON. FIRST I WANT TO NEXT TOUCH ON THE EXOGENOUS SOURCES FOR RETINAL GANGLION CELLS BECAUSE THERE'S BEEN A LOT OF FOCUS ON POTENTIALLY USING STEM CELLS AS A SOURCE FOR CELLS THAT CAN BE USED IN TRANSPLANTATION AND I THINK IN THE LAST FEW YEARS THERE'S BEEN SIGNIFICANT PROGRESS AND FOCUS ON RETINAL GANGLION CELLS IN PARTICULAR AND THE IDEA TAKEN--THEY WE CAN TAKE EITHER EMBRYONIC STEM CELLS OR INDUCED PLURIPOTENT STEM CELLS AND START TO WORK OUT THE CONDITIONS THAT WILL DIRECT THEM TOWARDS THAT RETINAL GANGLION CELL FATE AND PEOPLE ARE NOW STARTING TO REALLY FOCUS ON HUMAN CELLS AS A SOURCE AND TRYING TO UNDERSTAND THE PROPERTIES OF THOSE CELLS THAT ARE GENERATED AND FOCUS ON THE FUNCTIONAL PROPERTIES OF THE CELLS THAT RESULT SO THIS IS A STEP FORWARD IN ENABLING US TO MODEL THE EVENTS THAT WILL BE REQUIRED FOR APPLICATION. AND AS WE HEARD ABOUT EARLIER, THIS IS AN INCREASING INTEREST IN ORGANOID CULTURES AS A WAY TO MODEL HUMAN DISEASE AND I WILL NOT GO INTO DETAIL IN THIS, BUT I THINK BASED ON THE PIONEERING WORK OF DR. FACAI, THERE'S BEEN REMARKABLE PROGRESS IN THE ABILITY TO GENERATE RETINAL ORGANOIDS THAT ARE ABLE TO RECAPITULATE THE GENESIS OF RETINAL CELL TYPES INDLIEWDING RETINAL GANGLION CELLS. AND THE ABILITY TO POTENTIA WILY OPTIMIZE THIS PROCESS AND SCALE IT AND STORE THESE CELLS MIGHT ENABLE US TO CREATE A PIPELINE FOR FIRST MODELING DISEASE AND THEN POTENTIA WILY DERIVING CELLS AS AN EXOGENOUS CELL SOURCE FOR APPLICATION, ONE ALTERNATE STRATEGY AND IS SOMETHING THAT HAS TO BE CONSIDERED IS THIS IDEA OF CELL FUSION MEDIATED FANATIC CELL REPROGRAMMING, IT'S BEEN SHOWN THAT INTRODUCTION OF BONE MARROW DERIVED CELLS INTO THE RETINA, INTO A DAMAGED RETINA RESULTS IN CELL FUSION AND NORMALLY THOSE CELLS WOULD DIE BUT WHEN SIGNATURES NAIL SUGGEST ACTIVATED IT CAN RESULT IN THE STABLE FUSION, THOSE CELLS CAN DIVIDE AND A NUMBER OF THEM CAN DIFFERENTIATE INTO SALES AND GANGLION CELLS THAT ACTUALLY WILL RECONNECT AND HAVE FUNCTIONAL PROPERTIES. THIS IS VERY EARLY WORK AND THERE'S A LOT WE NEED TO UNDERSTAND ABOUT THE NATURE OF THE HYBRID CELLS, BUT THEY--IT WAS SHOWN THAT NOT ONLY BONE MARROW DERIVED CELLS BUT OTHER STEM CELL THAT IS ARE INTRODUCED UNDER GO IN CELL FUSION SO CELL FUSION IS PRETTY PREVALENT EVENT AND SOMETHING THAT NEEDS TO BE KEPT IN MIND AND MONITORED AND UNDERSTOOD. SO EXOGENOUS SOURCES FOR RGC REPLACEMENT, WE PUT TO THE PANEL BEFORE WE STARTED WHAT ARE THE QUESTIONS AND CHALLENGES TO THINK ABOUT FOR THIS AND THIS WAS--AS A WAY TO 55OT TOWARDS ENDOGENOUS CELLS, SOME OF THE ADVANTAGES ARE THAT WE CAN MANIPULATE THESE CELLS INVITRO AND THAT THERE ARE A REAL RANGE AND DIVERSITY OF GENETIC TOOLS IN WHICH WE CAN APPLY TO DO THOSE KINDS OF MAIN EPIGENETICCULATIONS AND A LOT OF THIS TECHNOLOGY HAS REALLY ADVANCED IN THE LAST TWO YEARS SO WE'RE READY TO REALLY TRY OPTIMIZING THE GENESIS OF RGCs AND TRY SOME OF THESE IN ANIMAL MODELS. THERE ARE MANY CHALLENGES STILL. IT'S STILL DIFFICULT TO GET EFFICIENT, RELIABLE AND SCALABLE RETINAL GANGLION CELLS. YOU HAVE TO BE CAREFUL ABOUT WHICH STAGE IN THE RIFFE RENTIATION PROCESS, THOSE CELLS ARE TRANSPLANTED BASED ON WORK THAT'S BEEN DONE IN OTHER BRAIN SYSTEMS SO IF YOU PLANT--TRANSPLANT TOO EARLY OR TOO LATE, THE EFFICIENCY AND EFFICACY IS REDUCED. WHAT IS THE BEST MODE OF DELIVERY AND HOW DO WE PROMOTE INTEGRATION OF THOSE CELLS. I THINK THERE'S A LOT TO LEARN ABOUT THAT, ULTIMATELY HOW DO WE COAX THEM TO ESTABLISH CNS CONNECTIONS. THERE HAS TO BE A WAY TO MONITOR LONG-TERM SURVIVAL AND THERE'S ALWAYS THE CONCERN ABOUT POTENTIAL MUTATIONS IN IPSC DERIVED CELLS. AND ESPECIALLY IN DISEASE STATES WE HAVE TO THINK A LOT ABOUT THE ROLE OF THE HOST ENVIRONMENT AND HOW RECEPTIVE THE TISSUE IS TO THESE TRANSPLANTED CELLS AND THE POSSIBILITY OF IMMUNE REJECTION DEPENDING ON THE SOURCE OF THE CELLS. SO, WITH THAT, THOSE CAVEATS WE WANT TO FOCUS THE BULK OF THE DILINGS CUSHION ON THE WORKSHOP ON INDODGEIOUS THERAPIES AND I WILL TURN THIS NOW TO PETER. THIS, SNRRKS THANK YOU MONICA, MY ROLE WAS TO GO OVER THESE ROLES AND THESE ARE THE ANIMAL MODELS, AND THESE ARE THE MODELS WITH PARA --TO TREATING GANGLION CELLS. SO I WILL BE GIVING BRIEF COMMENTS. WE HAVE TIME FOR DISCUSSION SO IF THERE'S FURTHER QUESTIONS YOU MIGHT WANT TO ASK AROUND THESE, SO THE THREE MODELS HAVE SERVED AS THE SOURCE OF RETINAL SOURCE OF REGENERATION, THESE ARE RETINAL'MA AMPHIBIAN AND THE FISH. I WILL DESCRIBE EACH OF THEIR CAPACITIES. IT'S BEEN KNOWN FOR OVER A CENTURY NOW THAT AMPHIBIANS IS RETINAL REGENERATION. THIS GIVES RISE TO A DENEWTED RETINAL EPITHELLIAL CELLSIAL, THEY RECOURSE THOSE AND THEN THEY RECREATE A TWO LAYERED STRUCTURE HERE OVERLYING RETINAL PIGMENTED EPITHELIUM AND A NEW OVERLYING NEURAL EPITHELIUM AND A NEWLY POPULATED UNDERLYING RETINAL EPITHELIUM AND THEN IN THE PROCESS, IT'S LIKE THE EMBRYONIC DEVELOPMENT OF THE RETINA, THIS OPERATING GLOBALLY THELIUM DIFFERENTIATES INTO THE MULTIPLE LAYERS OF NORMAL RETINA, INCLUDING GANG LIAISONNAL CELLS. NOW THIS MODEL. THIS OBSERVATION LED TO THE STUDIES THAT I'LL DESCRIBE NEXT IN THE CHICK BUT IS ALSO THE HISTORICAL BACKGROUND AROUND STUDIES AND INVESTIGATOR AND IDENTIFY RPE STEM CELLS THAT EXIST IN THE HUMAN EYE AND THESE RPE STEM CELLS CAN BE INDUCED AND DIFFERENTIATED INCLUDING NEURONAL IMAGES. SO RETINA REGENERATION IN CHICKS COME IF TWO FLAVORS, ONE IS EARLY, EMBRYONIC RETINA, WHICH IS ILLUSTRATED HERE SCHEMATICALLY AND AGAIN THE INJURY IS RETINAL LOCATIONINNECTOMY AND WHAT THAT RESULTS IN IS THE RPE OF THE ABSENCE OF THE FACT THAT THE RETINA HAS BEEN REMOVED BUT ONLY IN THE PRESENCE OF EXOGENOUS FACTOR WILL THEY RECAPITULATE WHAT WAS SHOWN FOR THE AMPHIBIANS AND FOR THE CELLS, LOSER PIGMENT PROLIFERATE AND THEN ALL NEURAL CELL TYPES INCLUDING RETINAL GANGLION. THE INTERESTING ASPECT OF THIS IS THAT THERE'S A TEMPORAL [INDISCERNIBLE]. AFTER FOUR OR FIVE DAYS, THE RPECELLs BECOME REFRACTORY, AND ALTHOUGH IT WAS FGF WON'T UNDERGO THIS PROLIFERATIVE DIFFERENTIATION IN THE RETINA. IN A NEWLY POST HATCHED CHICK THE POTENTIAL FOR FOR NEURONS CHANGED FUNDAMENT AND THAT IS TO THE MUTUAL GLEEL CELLSA IN THE RETINA. NOW THERE'S A NARROW ANNULUS IN THE PRIERIVEERAL REGIONS IN WHICH THE CAPAC IT'D IS RETAINED, AND INDUCED EITHER BY NEUROTOXIN WHICH KILLS NETINAL NEURONS AND INDUCES THE GLEA TO UNDERGO CELL DIVISION AND GIVE RISE TO NEUROPROGENITTOR CELLS WHERE THE UTILITY OF THIS CELL IS DOWN A LITTLE BIT IS THERE'S VERY, VERY LITTLE OF THE NEURON. SO EVEN THOUGH IT CAN RESPOND TO THE INJURY AND MAKE PROGENITORS, THOSE PROGENITORS ARE STALLED OR FORMED AND THEY CAN'T MAKE THEM RUN. IMPORTANTLY IT'S ALSO BEEN ESTABLISHED THAT EACH IN THE INJURY, THEY ARE SUFFICIENT TO DRIVE THEM INTO THE CELL PSYCHE AND HE WILL THAT'S SOMETHING I WILL COME BACK TO A LITTLE BIT. AND I SAID THE UTILITY OF THIS MODEL IS LIMITED BY THE FACT THAT THERE'S NOT COMPLETE REGENERATION AND THERE'S BEEN FUNDAMENTAL REGENERATION ON THIS AND THERE'S FUNDAMENTAL OBSERVATION MADE THAT IN FACT INFLAMMATORY MECHANISMS PROMOTIONAL PLAY A ROLE IN GOVERNING THIS INJURY INDUCED PROLIFERATION AMONG THE GLEA AND THAT WAS TAKEN HERE FROM THE PAPER BY ANDIE FISHER. SO HERE'S CENTRAL RETINA AND HERE'S PERIPHERAL RETINA, WHICH I DESCRIBE TO YOU WHICH CAN MORE READILY ENTER THE CELL CYCLE IN RED OR SOX NINE POSITIVE MUTE O GLEEL CELLSA ONE OF THE FIRST THING HAS HAPPENS IS THE NUCLEOTIDES LE I DISPURSE THROUGHOUT THE INNER NUCLEAR LAB AND THAT'S TRUE BOTH IN THE CENTRAL AND PERIPHERAL REGION AND WHAT YOU SEE IS THERE'S MANY MORE BRDU LABELED CELLS AND DOUBLE LABELED AND GLIAL CELLS, HOWEVER IF YOU FIRST DEPLETE THIS RETINA OF MICROGLEEL CELLSA WHICH ARE THE CELL TYPES THAT MEDIATE MEN OF THE INFLAMMATORY MECHANISMS WITHIN THE RETINA, THIS RESPONSE COMPLETELY FAILS AND THIS IS ESSENTIALLY WHAT A NORMAL RETINA LOOKS LIKE, THIS IS THE MONOLAYER OF MICROFLEA, MONOLAYER OF GLEA AND O NO RESPONSE TO CELL INJURY AND DEATH AND THAT'S QUANTIFIED HERE ON THE SIDE. LET ME TURN NOW THEN TO ZEBRAFISH AND THIS IS WHERE PROBABLY THE MOST WORK IS BEING DONE OVER THE RECENT YEARS. AND LET ME DESCRIBE THE FISH IN GENERAL, THEY'RE NORMALLY MITOTIC ACTIVE AND SO THE FISH GROWS FROM THE BEGINNING TO ADULTHOOD, AND THESE ARE ADDED TO THE EXISTING LAWN OF NEURON IT KEEPS TED REDOBSIN SENSITY CONSTANT AND THE ABSOLUTE SENSITIVITY OF THE FISH IRRESPECTIVE OF SIZE AND WE KNOW THAT NEW FLEA ARE IN FACT THE ORIGINS OF THESE NEW PHOTORECEPTORS SO MUTE O GLEA IN A FISH ARE NATURALLY MITOTIC AND NEUROGENIC, HOWEVER IF CELL DEATH OCCURS WITHIN THE RETINA, THIS RARE EVENT IN THE GROWING RETINA ALL BECOMES SYNCHRONIZED WHICH IS ILLUSTRATED HERE VERY NICELY WHERE NEWT O FLEA ARE SHOWN [INDISCERNIBLE] PROTEIN AND PC NA LABELING MITOTICALLY ACTIVE NUCLEI, THIS IS THROWN INTO SYNCHRONY WHEN THERE'S NEARBY CELL DEATH. THIS IS REGIONAL RESPONSE TO REGIONAL CELL DEATH. THERE'S CHARACTERISTIC OF THE IRRESPECTIVE OF THE NATURE OF THE INJURY, ILLUSTRATING FOR PHOTORECEPTOR DEPLETION BUT IT DOESN'T MATTER WHAT IT MIGHT BE. TRANSIC GLOWOSEISIS FOLLOWED BY THE NUCLEAR MIGRATION WHERE THEY MIGRATE TOWARDS THE OUTER PORTIONS, THE MICROGLEEL CELLSA GIVE ONCE, GIVE RISE TO A PROGENITOR CELL, AND RETURNS TO THE INNER NUCLEAR LAYER AND THE NEUROPROGENITTORS ARE THE CELLS THAT RESPOND QUANTITATIVELY TO THE EXTENT OF CELL DEATH AND MIGRATE TO THE AREA WHERE THE CELL DEPLETION IS AND REPLACE THE MISSING RETINA, FOAL O RECEPTOR DEPLETION AND THE NEUROGENIC CLUSTERS, THEY USE THEM AS A SCAFFOLD, MIGRATE TO THE OUTER NUCLEARALATER AND PHOTORECEPTOR LAYER. THERE'S BEEN A LOT OF WORK BY LABS AROUND THE WORLD STUDYING THIS, THERE'S SUMMARY DIAGRAM TAKEN FROM A REVIEW PAPER INDICATING THE CELL INJURY, ESSENTIALLY CELL KEITH AND PLAYED OUT THROUGH MULTIPLE MECHANISMS WHICH INCLUDE STRESS RESPONSE, INFLAMMATION, GLEEL CELLSOSEIS AND CELL MIGRATION AND THEY CONNECTICUT VERGE ON THE MUTE O GLEA AND THE MUTE O GLOWA DERIVED PROGENITOR CELLS. NOW THERE ARE A COUPLE OF NODES, IN THE ABSENCE OF EXPRESSION ASCLONE A, THE SEQUELY THAT ARE THAT HAPPEN REQUEST CELL DEATH TO THE RETINA, MUCH OF THE MECHANISMS PASS THROUGH THE TRANSCRIPTION FACTOR AND THE OTHER IS THIS FORM OF EPIDERMAL GROWTH FACTOR, OF THE GROWTH FACTOR WHICH WHEN INJECTED INTO THE EYE, ABSENCE OF INJURY IS SUFFICIENT TO DRIVE THE MUTE O GLEA IN THE CELL CYCLE SO THESE ARE TWO KEY MOLECULES THAT PLAYED A ROLE IN THESE. NOW THEREYA A RECENT PAPER THAT CAME OUT JUST THIS MONTH WHICH IDENTIFIES ANOTHER TRANSCRIPTION FACTOR THAT PLAYS A VERY KEY ROLE IN REGULATING MITOTIC ACTIVITY OF THE NEWT O GLEA, AND THESE INVESTIGATORS STILL--IT'S IN [INDISCERNIBLE] NOT ZEBRAFISH, CREATED TECHNOLOGY WHERE THEY TARGET THIS TRANSCRIPT FACTOR, AND SO, AS I JUST DESCRIBED, WHEN THERE'S INJURY TO THE RETINA, AND THE NIGHT O GLEA AND YOU HAVE HLSEVEN IS SELECTIVELY DRIVEN AND EXPRESS INDEED THE MUTE O GLEA IN THE ABSENCE OF INJURY, THESE EXPRESSING AGL SEVEN AND QUIESCENT MUTE O FLEA, THERE'S CELL CYCLE, NEUROGENIC CLUSTERS AND THEY WILL MAKE NEW [INDISCERNIBLE]. PARENTHETICALLY IN THIS PAPER, IN THIS DISCUSSION, THE AUTHORS NOTE THAT WHILE 807 DRIVE IT IS THE MUTE O GLEA INTO THE CELL CYCLE AND CAN GENERATE NEURONS THERE'S A BIAS TOWARDS GENERATING RETINAL GANGLION CELLS. SO HERE'S A FUNDAMENTALLY IMPORTANT FACTOR, SINGLE CELLS WHICH WE KNOW HAVE INTRINSIC STEM CELL LIKE PROPERTIES CAN IN FACT BIAS TOWARDS GENERATING RETINAL GANGLION CELLS I WON'T BELABOR THE POINT MUCH BUT THEY THINK IT'S SOMETHING TO ADD TO THIS, AS A--AS A PASSING OBSERVATION. NOW FOLLOWING FROM THE WORK THAT'S BEEN DONE IN FISH, OTHER STUDIES THAT ARE NOW USING MAMMALS AND I THINK THIS IS QUITE TELLING STUDIES, THIS IS TAKEN FROM A STUDY FROM TOM RAY'S LAB WHERE HE IS NOW--EXPRESSED--FORCED THE EXPRESSION OF TRANSGENIC MICE ASCLWOBDERFUL--WONDERFUL IN THE MUTE O GLEA IN THE MOUSE RETINA. TWO NOTABLE OBSERVATIONS WERE MADE FROM THIS, THAT IS IT YOU COULD FORCE THE EXPRESSION OF ASCLONE IN MUTE O GLOWA BUT IN THE ABSENCE OF AN INJURY, IT WOULD BT ENTER THE CELL CYCLE IF THERE'S AN INJURY THAT KILLS MICE IN THE AND GIVES RISE TO PROGENITORS AND THE SECOND IS, THIS IS SOMETHING WE HAVE TO CONSIDER IS SOME TAKEN--THEY CAPACITY OF THE CELL CYCLE IS OBSERVED ONLY IN JUVENILE MICE, ONCE THEY AGE PASSED THREE OR FOUR WEEKS THE CAPACITY OF THE PRESENCE OF THE INJURY, AND THEN THE OTHER IS TAKEN FROM WORK, WHO PARTICIPATED FROM THE AGI, WORKSHOP THAT IS PRIMARY CULTURES OF HUMAN MUTE O GLEA UNCULTURED, THERE ARE A SUBSET OF THOSE CELLS THAT PROLIFERATE AND SHOW STEM CELL LIKE PROPERTIES AND THEY DEVELOPED A CULTURE SYSTEM WHERE THEY CAN DRIVE THESE CELLS INTO GANGLION CELLS AND THEY'VE BEEN VALIDATED BY SEVERAL APPROACHES BUT THEY ARE IN FACT RETINAL GANGLION CELLS AND WHEN TRANSPLANTED BACK INTO THE EYE, SO THERE'S HUMAN MUTE O GHEA THE GANGLION CELLS WHEN TRANSPLANTED BACK INTO THE EYES OF RATS CAN IMPROVE FUNCTION IN ANIMALS WHICH HAVE RETINAL GANGLION CELLS. SO THERE ARE LIMITATIONS TO THESE REGENERATION MODELS AND THERE'S LOTS OF LIMITATIONS MORE GAPS IN OUR KNOWLEDGE AND WHILE WE KNOW THAT THE ANIMAL VS CAPACITY TO COMPLETELY REGENERATE A RETINA, WE DON'T KNOW THE DETAILS AROUND THIS. THERE'S MANY QUESTIONS ABOUT THE WHETHER THE CELLS ARE REGENERATED, ARE THEY CELL SPECIFIC MANNERS? DO THEY RECREATE THE NORMAL CIRCUITS WITH THE IPL AND WE DON'T KNOW THESE NEURONS IN ANY OF THE MODELS WE STUDIED. AND THE GAPS OF THIS KNOWLEDGE IS LARGELY A CONSEQUENCE ALTHOUGH IT'S COMPLETELY TRACKABLE SET OF QUESTIONS WE DON'T HAVE A REGENERATION MODEL WHERE WE CAN SELECTIVE REDEPLETE AND OBSERVE THE REGENERATION. AND THEN IT WAS RAISED IN THE PREVIOUS DISCUSSION OF THE AGI WORKSHOP AT THE SITE FOR NEUROSCIENCE, WE DON'T UNDERSTAND THE DIFFERENCES IN THE DIFFERENCES CAPACITIES BETWEEN WARM BLOODED ANIMALS AND AMPHIBIANS AND PERHAPS WE'RE NARROWING THAT GAP MORE GIVEN WHAT I JUST SHOWED YOU ABOUT THE DATA FROM REGENERATION IN MAMMALIAN MODELS. SO I'D LIKE TO CLOSE WITH INTRODUCING YOU TO A FEW KEY CONCEPTS THAT WE THINK IN MIND. BECAUSE WE THINK ABOUT HOW REGENERATE NEURONS WITH THE ENDOGENOUS SOURCES WITH THE HUMAN RETINA AND THAT IS THE HUMAN BRAIN, ALL MAMMALIAN BRAINS ARE NEUROGENIC, THERE ARE ISSUES WHERE ARE THERE STEM CELLS NEURONS TO INTEGRATING CIRCUITS AND THE MAMMALIAN BRAIN CAN ACCOMMODATE THE INCORPORATION OF NEW NEURONS, WE THAN AND THAT'S AN IMPORTANT CONCEPT. THE SECOND IMPORTANT CONCEPT CAME OUT OF THIS STUDY WE'RE STUDYING INTO THE SEREBIAL CORTEX AND THAT IS THE WHITE MATTER, UNINJURED WIGHT MATTER IS AXONAL GROWTH. SO EMBRYONICT MOTOR NEURONS TRANSPLANTED INTO,A DOLT MOTOR TORE TEX, INTEGRATE IN THE CORTEX BUT STRIKINGLY, THE CORTICAL WHITE MATTER AND TARGET APPROPRIATE THALAMIC AND SPINAL TRACT. SIMILARLY WITH THE EMBRYONIC VISUAL NEURONS OR ESC DERIFED NEURON WHICH IS ADOPT A VISUAL CORCORTEX OF IDENTITY OR TRANSPLANTED, THEY INCORPORATE LOCALLY INTO THE CORTICAL CIRCUITRY AND THEN THEY TOO, SEND THEIR AXONS INTO THE WHITE MATTER FOR THE APPROPRIATE TARGETS. THESE CONVERSION EXPERIMENTS AND TRANSPLANTATIONS THOSE GO TO THE WHITE MATTER SO FROM'S REGIONAL IDENTITY THAT CAN TAKE THE GUIDANCE MOLECULES IN THE CORTICAL WHITE MATTER FOR THE APPROPRIATE SUBCORTICAL TARGET. NOW I WANT TO INTRODUCE WHAT I THINK IS A STRIKING OBSERVATION THAT CAME FROM JEFF GOLBERG'S LABORATORY IN WHICH THEY TRANSPLANTED THE ISOLATED GFP POSITIVE NEURONS, RETINA GANGLION CELLS FROM NEW BORN MICE INTO THE EYES OF ADULT [INDISCERNIBLE]. AND THEY--PUBLISHED THIS IN 2015 AND GAVE RISE TO THESE STRIKING IMAGES SO THESE ARE GFP, INPUTTING MOUSE RETINAL GANGLION CELLS THAT HAVE MIGRATED THROUGH THE INNER LIMIT MEMBRANE, INCORPORATED INTO THE RETINA GANGLION CELL LAYER AND SET THE PROCESS INTO THE PLAYER AND THE AXONS FOR THE OPTIC LAYER AND THE INDIVIDUAL CELL LEVEL, THESE CELLS ARE STRIKINGLY RESEMBLE RETINAL GANG LIAISONNAL CELLS AND THEY THE WHOLE CELLS DEMONSTRATE THAT. THEY WILL RESPOND TO LIGHT. THE CAVEAT HERE IS THESE ARE EXCEEDINGLY RARE EVENTS. SO THEY INJECTED OVER 150 EYES AND LESS THAN 10% DID THEY SEE ANY INTEGRATION OF THE RETINAL GANGLION. NUMBER TWO, OF ALL THE NEURONS THAT DID INTEGRATE THAT WAS ONE% OF THE TOTAL NEURONS THAT WERE INJECTED. SO IT'S CLEAR A LOT HAS TO BE LEARNED IF WE WILL USE ENDOGENOUS AND I ALSO THINK THIS IS A GOOD MODEL FOR HOW A HEALTHY RETINA CAN ACCOMMODATE THE NEURON. THESE GROI TO THE OPTIC NERVE HAD INTO THE NERVE THROUGH THE CHIASM, AND INTO THE THALAMUS DIRECT IN THE AREA OF THE BRAIN. AND MY CONTEXT AROUND THE BIOLOGY OF THE SOURCES AND THE KEY CONCEPTS YOU WANT TO KEEP IN MIND DESCRIBE NOW WHAT WE DID WITH RESPECT TO THE ACTUAL WORKSHOP ITSELF. IT WAS ALSO THE HIGHLY STRUCTURED, I WOULD THINK TO SAY, SO WE--WEET UP SORT OF AN OVERALL QUESTION AND THEN HOLD THE GAP AND THE BARRIERS OF THE SCIENTIFIC PROCESS, AND WE ASKED THE SERIES OF THREE FUNDAMENTAL QUESTIONS AROUND THREE TOPICS. WHAT ARE THE CELLULAR SOURCES FOR GANGLION REGENERATION AND PLACEMENT. THE KEY CONCEPTS AROUND DELIVERING INTEGRATION AND WHAT ARE THE KEY CONCEPTS AROUND ASSESSING OUTCOMINGS OF THE GENERATION SOURCES AND THEN WE FOLLOW IT UP WITH SORT OF A PROSPECTIVE VIEW OF THE FUTURE OF WHERE THIS MIGHT BE. IT ALL TURNS BACK OVER TO MONITORITTICCA AND SHE WILL SUMMARIZE THE DISCUSSION SO SOME OF THE TAKE AWAYS FROM IT. >> THANK YOU PETER SO AS CAN YOU MOWING WE HAD FAIRLY ACTIVE DISCUSSION AND WE TRIED TO DISTILL THE KEY POINTS DOWN FROM EACH OF THESE MAIN SESSIONS. THIS ISN'T COMPREHENSIVE BUT WE TRIED TO HIT ON THE CORE TOPICS. SO THE FIRST SUBJECT OF DISCUSSION IS WHAT ARE THE CELL SOURCES FOR RETINAL GANGLION CELL REGENERATION AND REPLACEMENT AND IF WE WILL THINK ABOUT EXOGENOUS SOURCES WHICH WAS NOT THE MAIN FOCUS OF THE DISCUSSION, WE STILL NEED TO OPTIMIZE THE DIFFERENTIATION OF HUMAN EMBRYONIC STEM CELLS OR IPS CELLS INTO RETINA GANGLION CELLS AND BE ABLE TO UNDERSTAND AND DEAL WITH THE HETEROGENEITY OF CELL TYPES THAT ARE GENERATED. FOCUSING ON ENDOGENOUS SOURCES, SOLES THAT ARE INTRINSIC TO THE RETINA. THE IDEA IS THAT WE NEED TO CONTINUE TO TARGET CELLS THAT CAN TRANSDIFFERENTIATE IN NONMAMMALLIAN MODELS AS PETER JUST DISCUSS TED THE MUTE O GLOWA OR RPE, BUT RPE HAS NOT BEEN SHOWN TO MAKE RGCs IN VIVO SO WE THEY'D TO WORK ON THAT AS A POTENTIAL SOURCE. ANOTHER IDEA WE START TO THINK OUTSIDE OF THE BOX IS COULD THERE BE A POSSIBILITY OF TARGETING AND REPROGRAMMING OTHER CELL TYPES THAT ARE IN PROXIMITY TO THE GANGLION CELL LAYER SO WE OVERCOME THE IDEA THAT CELLS HAVE TO MIGRATE AND INTEGRATE FROM EXISTING LOICATIONS TO THE GANGLION CELL LAYER SO COULD WE REDIRECT ASTROCYTES IN THE NERVE FIBER LAYER O DISPLACED CELLS THAT ARE ALREADY IN THE GANGLION CELL LAYER AND SORT OF HIGH JACK THE EXISTING PROGRAMS AND DIRECT THEM TOWARDS AN RGC FATE. TO BE ABLE TO DO THOSE KINDS OF MANIPULATIONS, WE NEED TO BETTER DEFINE THE TRANSCRIPTION FACTORS AND SIGNALING PATHWAYS THAT PROMOTE REPROGRAMMING OF CELLS AND CAN MORE SELECTIVELY AND EFFICIENT LITE DRIVE RETINAL GANGLION CELL DIFFERENTIATION AND A BIG FOCUS OF THE DISCUSSION IS NEEDING TO REAL LE DEFINE THE CRITERIA FOR SUCCESS AND GET THE FIELD TO AGREE ON THIS. WHAT DEFINES A BONA FIDED RETINAL GANGLION CELL, HOW DO WE KNOW WHEN WE REALLY REFLECTED THESE CELLS AND REPROGRAMMED THEM AND ACHIEVED THAT THAT REPLACEMENT AND I THINK--WE THINK THAT ONE THING WORTH CONSIDERING IS REALLY TRYING TO UNDERSTAND WHAT ARE THE CUES THAT INDICATE THE LOSS OF THE GANGLION CELL AND TRIGGER REGENERATION SO IN THESE NONMAMMALLIAN MODELS, THE MUTE O GLEA CAN SENSE THE LOSS OF NEURONS AND THIS WILL TRIGGER THE REGENERATION RESPONSE AND IF WE CAN UNDERSTAND THOSE MECHANISMS CAN WE ACTUALLY HIJACK THEM IN A MAMMALIAN SYSTEM AND REDIRECT CELLS AND CAN WE UNDERSTAND THE NECKANISMS THAT CONTROL CELL MIRROR IMAGE GRIGS TO THE GANGLION CELL LAYER SO THAT WE CAN INSURE THAT THE CELLS END UP IN THE RIGHT PLACE AND CAN ESTABLISH CONNECTIVITY. THE SECOND TOPIC WAS ON DELIVERY AND INTEGRATION, SO IF WE ARE GOING TO TARGET CELL POPULATIONS WITHIN THE RETINA, WE NEED TO REALLY OPTIMIZE DELIVERY OF THE CUES, EITHER THE MOLECULES OR THE GENES THAT ARE GOING TO TRIGGER THE REPROGRAMMING AND EVENTS AND THERE'S YOU HUMAN RETINA SO HOW CAN WE OPTIMIZE GENE DELIVERY FOR THE SPECIFIC CELL TYPES THAT WE WANT DO TARGET IN THE HUMAN RETINA. AS I MENTIONED IN MY PART OF THE INTRODUCTION, WE NEED TO DISTINGUISH TRUE CELL REPLACEMENT FROM OTHER TYPES OF EFFECTS THAT COULD ACHIEVE SOME RESTORATION OF VISUAL FUNCTION SUCH AS CELL FUSION OR EVEN NEUROTROPIC EFFECTS WHERE THE CELLS WOULD HELP MAINTAIN FIX RETINAL GANG RYAN CELLS BEFORE THEY'RE COMPLETELY LOST. WE THEY'D TO THINK ABOUT HOW TO OPTIMIZE THE SURVIVAL AND SIN APT O GENESIS OF THESE NEW RETINAL GANGLION CELLS. WE DON'T KNOW A LOT ABOUT HOW THAT IS HAPPENING AS THESE CELLS ARE REDIRECTED AND REINTRODUCED INTO THE RETINA AND IN ORDER TO DO THAT WE ACTUALLY HAVE TO BE ABLE TO FOLLOW THE NEW CELLS, WE HAVE TO KNOW WHICH ARE THE NEW CELLS AND ESTABLISH THEM FROM THE PREEXISTING CELLS AND FOLLOW THEM OVERTIME WE CAN TAKE ADVANTAGE OF VARIOUS TOOLS AND TECHNOLOGIES TO DO THAT AND THAT COMBINED WITH THE CUTTING EDGE, IN VIVO IMAGING WAS FELT HAD TREMENDOUS IMAGING FOR THE TOOL TO HAVE PROCESS OF INTEGRATION AND RETINAL CELL GANGLION FUNCTION BUT THE COMMITTEE WORKSHOP PARTIC PAPTS FELT THEY NEEDED TO WORK ON THE COMMON STANDARDS THAT THE FIELD AGREES ON AS SORT OF WHAT ARE THE ACHIEVABLE TARGETS AND READ OUTS THAT WE'LL FOCUS ON. ONE IDEA, ESPECIALLY TO OPTIMIZE THIS FOR HUMAN APPLICATION IS TO TAKE ADVANTAGE OF THESE 3D CULTURE SYSTEMS TO REALLY OPTIMIZE PARAMETERS FOR INTEGRATION, HOW DO WE REDIRECT CELLS AND THEN GET THEM TO GET TO THE RETINAL GANGLION CELL LAYER. AND SINCE ULTIMATELY THIS HAS TO BE APPLIED IN DISEASE SETTINGS WE NEED TO FACTOR IN THE CHANGES WITH THE DISEASE. FOR EXAMPLE, CHANGES IN THE EXTRA CELLULAR MATRIX, CHANGES IN THE ACTIVITY OF THE IMMUNE SYSTEM, WILL A HOSTILE DISEASE ENVIRONMENT BE NONPERMISSIVE. WILL IT KILL NEW CELLS AS THEY'RE GENERATED WILL THEY BE ABLE TO REINTEGRATE AND FUNCTION AND BE MAINTAINED OVER TIME. AND THEN THE LAST CATEGORY WE FOCUSED ON IS OUTCOME ASSESSMENT AND THAT IS CRITICAL FOR DECIDING IF YOU ACHIEVED ANYTHING WITH THE RGC STRATEGY. SO WOO HAVE TO HAVE ASSAYS AND MONITOR CELL RESPONSES AND CONNECTIVITY. WE NEED TO DEVELOP FUNCTIONAL ASSAYS THAT ARE USEFUL AND APPLICABLE IN MODEL SYSTEMS IN THESE AREAS OF ANIMAL MODELS THAT ARE TESTED AS WELL AS IN HUMANS AND THERES A BIG FOCUS ON MAKING SURE THAT WE REALLY KEPT AN EYE ON THOSE FUNCTIONAL READ OUTS AT ALL LEVELS. WE NEED TO DETERMINE IF TREATMENTS WILL LEAD TO IMPROVED VISUAL OUTCOMES BECAUSE WE HAVE TO HAVE A SIGNIFICANT EMPHASIS ON VISUAL FUNCTION TESTING. AND THEN THERE WAS A REAL DEBATE ABOUT HOW--HOW DO WE DECIDE WHEN WE'RE SUCCESSFUL. HOW MANY RETINAL LOCATION NONAPOPTOTIC GANGLION CELLS DO YOU REALLY NEED IN ORDERED TO RESTORE YOUTHFUL VISION AND WHERE DO THEY NEED TO BE DISTRIBUTED ACROSS THE RETINA, CAN WE HAVE A RELATIVELY SMALL NUMBER IN A KEY PART OF THE RETINA THAT WOULD BE SUFFICIENT TO RESTORE A CERTAIN LEVEL OF VISUAL FUNCTION? THAT WOULD DEPEND ON WHETHER THE GOAL IS SIMPLY BEING ABLE TO WALK AROUND THE ROOM AND HAVE AMBULATORY VISION OR REALLY HAVE DISCRIMINATORY VISION. AND IT'S FORMER WE MAY NOT NEED QUITE AS MANY GANGLION CELLS AND WE MAY NOT NEED TO WORRY AS MUCH ABOUT ALL THE DIVERSITY OF RETINAL GANGLION CELL TYPES. WE MAY FOCUS ON A FEW KEY RGC SUBTYPES. THERE WAS DISCUSSION ABOUT WHAT ARE THE BEST HUMAN DECEASES TO TREAT I WILL NOTY DWELL ON THIS BECAUSE DR. LEVIN WILL SPEND TIME TALKING ON THIS AND THE IDEAS THAT CAME OUT OF HIS GROUP'S DISCUSSION AND ONE POINT THAT CAME UP IS WE HAVE TO DECIDE WHAT'S THE BEST POINT OF INTERVENTION: IS IT BET TORE RESCUE THICK RGCs OR REPLACE RGCs AND THAT DEFINES WHAT WE SHOULD TARGET AND THE IDEA IS TO INTERVENE BEFORE THERE ARE SIGNIFICANT REMODELING BOTH WITHIN THE RETINA AND THE TARGET TISSUE THAT WOULD ALTER THE CONNECTIVITY OF THE VISUAL PATHWAYS. SO THESE ARE SORT OF THE MAIN POINT S THAT COIL OUT OF THESE TOPICS AND BASED ON THIS, PETER AND I DISTILLED THIS DOWN TO WHAT WE THINK WERE THE KEY RECOMMENDATIONS THAT CAME OUT OF THIS WORKSHOP THAT THERE SEEM TO BE A LOT OF CONSENSUS FROM THE WORKSHOP PARTICIPANTS. THE FIRST IS TO REALLY FOCUS ON SYSTEMATIC COMPARISON OF ANIMAL MODELS THAT DO AND DO NOT REGENERATE RETINAL GANGLION CELLS AND TO REALLY CONTINUE TO SUPPORT BASIC INVESTIGATION OF MECHANISM AND THESE REAL COMPARATIVE APPROACHES. THE SECOND RECOMMENDATION IS TO REALLY THOROUGHLY AND SYSTEMATICALLY TEST CANTEDIDATE CELL TYPES FOR ENDOGENOUS RETINAL GANGLION CELLS IN MOST MODELS AND TO TEST SOME OF THESE OUT OF THE BOX IDEAS OF REDISTRICTING OTHER NEARBY CELL TYPES OR RDC PROPERTIES. AND IMPORTANT FOR THE FIELD IS TO ESTABLISH STANDARD RITERRIA FOR SUCCESS, HOW DO WE EVALUATE THAT FUNCTION IN ANIMAL MODELS AND IN HUMAN SO THAT WE CAN REALLY LOOK ACROSS ALL THESE DIFFERENT STUDIES AND COMPARE WHAT SUCCESSFUL AND WHAT IS NOT. AND TO REALLY CAPITALIZE ON THE OTHER EFFORTS TO PROMOTE IN VIVO HIGH RESOLUTION IMAGING AND DEPLOY OPTOGENETICS AND CELL INTEGRATION AND LONG-TERM SURVIVAL AND CONNECTIVITY AND THEIR FUNCTION. AND A HUGE RECOMMENDATION WAS TO REALLY FOCUS ON HUMAN DISEASE AND LAY THE FOUNDATION FOR ULTIMATELY TRANSLATING THIS INTO APPLICATIONS IN HUMAN DISEASE. AND REALLY FOCUS ON TRACKABLE MODELS FOR INITIAL STUDIES. AND SOME OF THE PARTING COMMENTS FROM THE WORKSHOP PARTICIPANTS WAS REALLY TO ENCOURAGE AND PROMOTE TEAM BASED COLLABORATIVE APPROACHES THAT SPAN INDUSTRY, GOVERNMENT AND ACADEMIA. WHICH I THINK MANY OF THE AGI MECHANISMS HAVE BEEN DOING VERY SUCCESSFULLY. SO FINALLY WE THINK OUT OF THIS, THERE ARE SOME ACHIEVABLE MILESTONES. WE HAVEN'T PUT TIMELINES ON THIS AND SOME OF THESE ARE SHORTER TERM AND SOME OF THESE ARE CLEARLY LONGER TERM. ONE OF THE SHORTER TERM TARGETS IS TO REALLY FULLY CHARACTERIZE HUMAN RETINA GANGLION CELLS, WE NEED TO UNDERSTAND THE DEVELOPMENT AND THE MOLECULAR PROPERTIES AND THE FUNCTION OF HUMAN RETINAL GANGLION CELLS, AS THOROUGHLY AS POSSIBLE TO APPLY THESE REPLACEMENT STRATEGIES TO HUMAN DISEASE AND SOME OF THE BRAIN INITIATIVES WE'VE HEARD ABOUT ARE GOING TO SIGNIFICANTLY ULTIMATELY ADVANCE THIS. I THINK THE FIELD IS WORKING TOWARDS DEFINING THE BEST ENDOGENOUS CELL POPULATION TO TARGET FOR RGC REGENERATION, IN THE MUTE O FLEA BUT WE REALLY NEED NEED TO SETTLE ON A STRATEGY THAT WILL BE THE MOST EFFECTIVE FOR DIRECTING CELLS DOWN THAT PATHWAY. WE NEED TO OPTIMIZE THE CONDITIONS FOR RGC REGENERATION. SO EVEN THOUGH PEOPLE HAVE HAD SOME SUCCESS AT GETTING CELLS TO DIFFERENTIATE TOWARDS RGCs, IT'S ILRELATIVELY INEFFICIENT, MANY OTHERS ARE GENERATED AND WE NEED A WAY TO KIND OF REALLY REDIRECT THESE CELLS MUCH MORE COMPLETELY TOWARDS THE RGC DIFFERENTIATION PATHWAY AND WE NEED TO CONTINUE TO DEFINE THE MOLECULAR PATHWAYS INVOLVED IN RGC GENESIS AND APPLY THESE TO THE REGENERATION MODELS AND THEN AS I MENTIONED WE NEED TO DEFINE THE CRITERIA FOR SUCCESS. HOW DO WE KNOW WHEN IT'S WORKING? WE NEED STRUCTURAL READ OUTS AND FUNCTIONAL TESTS OF EACH ANIMAL MODELS AND IN HUMANS SO WE CAN KNOW WHEN WE MADE SIGNIFICANT PROGRESS AND COMPARE ACROSS STUDIES AND FINALLY TO REALLY PROMOTE AND ENCOURAGE A PIPELINE FROM ANIMAL STUDIES AND BASELINE AND WHEN TO MOVE ON TO THE NEXT STEP. PETER AND I THINK BOTH PARTICULARLY WANT TO THANK DR. STEVEN BECKER WHO WAS TREMENDOUSLY HELPFUL IN ORGANIZING AND COORDINATING THE WORKSHOP, GETTING A TERRIFIC GROUP OF PARTICIPANTS TOGETHER, GETTING TOM GREEN WELL, AND GUIDED US IN OUR SELECTION OF PARTICIPANTS AND HOW TO PREPARE FOR THIS. WE DIDN'T HAVE THE NAME OF THE PERSON WHO WAS PROBABLY THE MOST IMPORTANT PERSON IN THE ROOM, A PERSON WHO TOOK THE NOTES AND PROVIDED VERY THOROUGH SUMMARY OF THE DISCUSSION WHICH WAS TREMENDOUSLY HELPFUL AFTERWARDS AND WE REALLY WANTED TO THANK THE WORKSHOP. IT WAS VERY DIVERSE AND FUN GROUP TOO HAVE THIS DISCUSSION WITH. I THINK THAT CONCLUDES OUR PRESENTATION. THANK YOU. KD--SALLY APLACES --[ APPLAUSE ] EMPLOY. >> I HAVE A COMMENT. THE IN THE SPINAL CORD INJURY, IT'S BEEN SHOWN THAT IMMEDIATELY VIRTUALLY WITHIN MINUTES AFTER INJURY, THERE ARE CHANGES IN SYNAPTIC ANATOMY AND ACTUALLY [INDISCERNIBLE] IN THE RETINA, WITHIN 10 MINUTES AND MAXIMALLY WITHIN TWO HOURS YOU SEE AFTER RETINAL DETACHMENT REACTION OF THE PHOTORECEPTOR BIPOLAR SYNAPSES SO I'M NOT SURE IF THE ACUTENESS OF THE INJURY DOES CREATE AN OPPORTUNITY IN THE WAY THAT YOU MIGHT HAVE BEEN IMAGINING. THE OTHER POINT I WANT TO MAKE IS CAN YOU MEASURE THE VISUAL ACUITY IN FISH? YOU CAN? DOES IT TURN OUT HOW GOOD YOUR VISUAL ACUITY S&P RELATED TO YOUR ABILITY TO REGEEPERATE YOUR RETINA. >> I HAVE NO IDEA. >> SO THE VISUAL ACUITY IS LOW. >> WHAT I'M THINKING ABOUT IS IF I GAVE MY KID A MATRIX CAN 30 ELEMENTS VERSUS FIVE HELIOS POSITIVE ENTHUSIASMS ME COULD PROBABLY GETET FIVE ELEMENT 15% OF THE TIME AND THE 30 ELEMENT 15% OF THE TIME AND I WONDER IF THAT'S WHAT'S RELATED TO THE ABILITY TO REGENERATE THE RETINA. HOW MUCH COMPLEXITY IS BEING REGENERATED AND THOSE ANIMALS VERSUS [INDISCERNIBLE] >> YEAH, THAT'S' UNKNOWN, THE DEGREE TO WHICH THE REGENERATED RETINA HOW PRISTINE IT IS FOR NORMAL DEVELOPING AND THE CONSEQUENCE OF--THE CONSEQUENCE OF PHOTORECEPTOR REGENERATION IS THAT NEARLY CRYSTALLINE ARRAY OF PHOTORECEPTORS AND ALL THE PHOTORECEPTOR TYPES AND THAT CRYSTAL ARRAY IS DEGRADED. IN FACT IT DOESN'T FORM. SO, THERE ARE DEVELOPMENTAL [INDISCERNIBLE] BABY CELLS TURNED INTO THE ARRAY BUT THAT FAILS TO BE RECREATE BIDE REGENERATION EVEN THOUGH THE PHOTORECEPTORS ARE THERE, THEY DON'T RECREATE THAT PRECISION. SO LET ME ALSO ASK, THE ACUTE AROUND THE RECURRING DISEASES ANDLET GANG RYAN CELLS INTO A RETINA, THAT'S IN A CHRONIC ONGOING DISEASE STATE, HOW DO YOU SEPARATE THE CHRONIC VERSUS ACUTE INJURY WHERE YOU MIGHT HAVE MORE TIME ON YOUR SIDE ALTHOUGH I ABSOLUTELY AGREE WITH YOU THAT CHANGES THAT YOU SEE AND THE CHANGES IN THE ZEBRAFISH FOR EXAMPLE, WITHIN MINUTES OF THE ONSET OF THE INJURY. >> I HAVE TWO ANSWERS FOR YOU FIRST I WOULD STUDY THE CRITICAL PROTOCOL OF SPINAL CORD INJURY, THAT WOULD GIVE YOU A SENSE OF HOW FAST YOU HAVE TO IMPLEMENT THERAPEUTIC STRATEGIES, THE OTHER THING SIGNIFY WOULD TALK TO STEVE FISHER AND JEFF LEWIS BECAUSE THEY SHOWED THAT THERE'S PRINTOUTS OF, YOU KNOW AFTER RETINAL DETACHMENT THREE DAYS LONG, IT'S BY POLAR CELL SPROUTING. YOU'RE RIGHT, TIME IS YOUR ENEMY BUT I THINK IT'S NOT AS MUCH AS YOU THINK. >> THANK YOU VERY MUCH. >> I'D LIKE TO SCHEDULE A SHORT BREAK AT THIS POINT AND COME BACK AND WE WILL HEAR FROM LYNN, BUT I'LL ALSO RECALL IF YOU REMEMBER AT THE JANUARY MEETING, CAROL AND JASON WERE HERE AND THEY GAVE A PRESENTATIONOT AGI WORKSHOP ON RECONNECTING NEURONS IN THE VISUAL SYSTEM AT THE OCTOBER SOCIETY FOR NEUROSCIENCE MEETING. THEY HAVE SINCE FRO DUCED A WHITE PAPER THAT'S GOING TO BE PUBLISHED BY THE JOURNAL OF NEUROSCIENCE AND THEY SENT US THAT PAPER AND THEY SAID THAT THEY WANTED TO MAKE THAT AVAILABLE TO COUNCIL MEMBERS SO I WILL PUT THAT IN THE ECB UNDER THAT PRESENTATIONS TAB. >> AND JUST A NOTE THIS IS A DRAFT OF THE PAPER IT'S NOT YET ACCEPTED FOR PUBLICATION BUT THEY FELT VERY COMFORTABLE CIRCUITING AMONG THE COUNCIL MEMBERS AND. >> AND LET ME ADD MONICA AND PETER THANK YOU FOR MUCH FOR CHAIR TAG SESSION AND FOR THIS REPORT: I THINK IT HAS LEGS. THANK YOU. >> SO LET'S RECONVENE IN ABOUT 15 MINUTES. >> LET ME JUST REMIND OUR COUNCIL MEMBERS THAT THERE'S A FOLDER AT YOUR PLACE THAT HAS TWO CONFLICT OF INTEREST AND CONFIDENTIALITY FORMS THAT NEED TO BE SIGNED BEFORE YOU LEAVE TODAY AND RETURNED TO MISS GAYLE SAUNDERS. SHE'S OVER HERE. TWO FORMS THAT ATTEST TO THE FACT THAT DURING THE CLOSED DISCUSSION THAT YOU DID NOT PARTICIPATE IN ANY DISCUSSION WITH WHICH YOU HAD A CONFLICT. YOU WILL NOT AND THEN YOU DID NOT. SO BOTH NEED TO BE SIGNED AND RETURNED NONAPOPTOTIC GAYLE. THANK YOU. AND THEN AS PAUL MENTIONED EARLIER THIS MORNING IN HIS OPENING REMARKS, IT WAS REALLY IMPORTANT FOR ALL THIS WORK BEING DONE IN THE AGI EFFORT THAT THERE BE ENGAGEMENT WITH THE CLINICAL COMMUNITY TO IDENTIFY DISEASE STAGES AND THOSE DIFFERENT TYPES OF VISUAL DISEASES AND DISORDERS THAT MIGHT BE BEST TARGETED WITH ALL OF THESE STRATEGIES. SO, THERE WAS KIND OF A TOWN HALL, THE FIRST DAY AT THE ARVO MEETING IN SEATTLE AND LEN LEVINE MODERATED THAT TOWN HALL. SO HE WILL PRESENT THE RESULTS OF THAT. >> THANK YOU. I AM GRATEFUL TO THE NEI TO PRESENT THE WHAT CAME FROM THE TOWN HALL, ARVO, MANY OF US UNDERSTAND THE RESEARCH, THE TRANSFORMATION OF BASIC SCIENCE FINDINGS, FINDINGS FROM THE LABORATORY TO THE CLINIC. IT OFTEN WORKS AND BUT IT ALSO OFTEN FAILS. ONE OF THE REASONS WHY IT'S FAIL SYSTEM BECAUSE IT CAN BE VIEWED AS A RELAY RACE WHERE THE BATON IS PASSED FROM THE BASIC SCIENTISTS TO CLINE DALE SCIENTISTS AND EVENTUALLY TO THE USE OF A NEW THERAPY BUT I THINK IT'S MUCH MORE LIKE A SOCCER GAME. ALL OF THE KIDS PLAY SOCCER AND IF YOU WATCH A SOCCER GAME, THE BALL IS PASSED BACK AND FORTH SOMETIMES DEFENSE CAN SCORE, SOMETIMES THE CENTER MOVES FORWARD ALL THE WAY AND SCORES, BUT IT'S BASICALLY A A PROCESS OF INTEGRATIVE PASSING OF THE BALLS WHERE THE TEAM IS INVOLVED AND I THINK WHAT WAS POINTED OUT IN THE PREVIOUS PRESENTATION FOR MONICA AND PETER IT'S IMPORTANT THAT ALL THE PARTIES ARE INVOLVED SO IT'S NOT TOO EARLY TO START TO THINK VERY CAREFULLY ABOUT THE INVOLVEMENT OF THE CLINICAL DEVELOPMENT IN THE AUDACIOUS AND VISIONARY TRANSLATIONAL PROJECT. THE PARTICIPANTS WERE DON ZACH, LOIS SMITH AND MARTY FREED LANDER FROM SCRIPS, AND A ROOM OF HUNDREDS WITH THE VERY STRONG LEVEL OF AUDIENCE ENGAGEMENT THE QUESTIONS AND DISCUSSION. THE OUTLINE THAT I DISCUSSED TO KIND OF MORE OR LESS SEMESTER SUMMARIZE WHAT HAPPENED, FIRST THE BACKGROUND AGI, I WON'T SPEND MUCH TIME ON AT ALL BRIEFLY DISCUSS THE ISSUES WHICH CAME UP WHICH IS RESUSCITATION VERSUS REGENERATION AND GET INTO TARGET DISEASES AND GO INTO THAT DEPTH AND TRANSLATIONAL ISSUES, ASSESSING EFFICACY WHICH WILL BE CRITICAL TO THE CLINICAL SIDE AND THEN SOME OTHER MISCELLANEOUS ISSUES THAT ARE RELL VABT TO THESE TRANSLATIONAL EFFORT, SO THE AUDACIOUS GOALS IS TO RESTORE VISUALS THROUGH A GENERATIONS OF NEURONS AND NEURAL CONNECTIONS IN THIS THE EYE AND VISUAL SYSTEM AND THE GOAL BY 2025 JUST NINE YEARS AWAY IS TO DEMONSTRATE THE USEABLE VISION IN HUMANS. SO WHAT ARE THE BARRIERS TO SUCCESS. ONE IS AS YOU'VE HEARD ALREADY, THERE'S DAMAGED NEURONAL CIRCUITRY IN LATE STAGE REGENERATION, THAT IS IN MOST DISEASES IT IS NOT JUST THE INDIVIDUAL NEURON THAT DIES AND THAT NEEDS IN A SENSE TO BE REPLACED OR REGENERATED BUT ALSO THE CIRCUITRY AND THE CONNECTIONS AMONGST THE NEURONS BOTH THE AFERENCE AND EFERENCE AND THEN OF COURSE THE EFERRENT CONNECTION BECAUSE THE DOUBLE OR TRIPLE AND SO ON WHICH ALSO DEGENERATE IN LATE STAGE DISEASE. THIS LYE ALSO DAMAGE TO LOCAL CELLS AND DISTANT CELLS IN THE NEURONAL PATHWAY WHICH ARE THE FLEA AND THE VASCULAR SYSTEM. SO THIS IDEA OF THINKING ABOUT EVERYTHING THAT OCCURS IS RELEVANT. SO IN GLAUCOMA THERE'S TISSUE CULTURE MEDIA NOT ONLY AT AXONS OF THE NERVE HEAD BUT ALSO LOST OF THE STRUCTURAL SUPPORT. THE DISK BY EXKAFERATION OR CUPPING BECOMES BIOMECHANICALLY DIFFERENT FROM A OPTIC NERVE HEAD WHICH IS MORE SUSCEPTIBLE TO NEURONS SO WITHOUT TAKING THAT INTO ACCOUNT AND WITHOUT LOOKING BEYOND THE NEURON AND LOOKING AT THE OTHER SUPPORTING TISSUES OR NUTRITIONAL TISSUES ONE CAN ACHIEVE REGENERATION BUT NOT ACTUALLY ACHIEVE A LONG-TERM RESULT. SO IN ADDITION BEYOND THAT THERE'S OFTEN REPARAATIVE CHANGE THERE IS OCCUR IN THE PATHOLOGICAL STATE ARE ACTUALLY ANTIREGENRATIVE. SO FOR EXAMPLE, GLEEL CELLSOSEIS, FIBERAL VASCULAR CELLS IS A BARRIER AND THEN OF COURSE THEY CAN DO THE REMODELING OF TISSUES THAT TAKES PLACE IS SOMETIMES MORE THAN JUST A PHYSICAL BARRIER BUT ACTUALLY A CHANGE IN THE WAY THE TISSUE IS FORMED THAT MAKE ITS EXTREMELY DIFFICULT TO REGENERATE SO FOR EXAMPLE, AN OPTIC NERVE FOR WHICH THERE'S BEEN A GREAT DEGREE OF GLEEL CELLSOSEIS AND FIBROSIS MAY SERVE AS AN IMPENETRANTABLE BARRIER AND THE BIGGEST BARRIER TO SUCCESS AND THE ONE WE SPENT THE MOST TIME TALKING ABOUT IS HOW WE ASSESS SUCCESS IN HUMAN PATIENTS WHICH WAS ALLUDED TO IN THE PREVIOUS PRESENTATION AND THE DIFFICULTY WHEN ONE IS DOING REALLY GROUND BREAKING RESEARCH WHERE WE EXPECT AT THE BEGINNING A SMALL AMOUNT OF REGENERATION TO TAKE PLACE IS TO BE ABLE TO TELL THAT THIS HAS HAPPENED SO THAT'S ONE OF THE GREATEST BARRIERS THAT WE NEED TO DEAL WITH. ONE OF THE ISSUES THAT COMES UP IS A CONCEPT OF RESUSCITATION VERSUS REGENERATION. RESUSCITATION WILL BE DEFINED AND WE DISCUSSED, THE PRESERVING OR GROWING OF DAMAGED TISSUE BEFORE THE POINT WHERE NOTHING IS LEFT. THAT IS IN THE SAME SENSE AN ORGANISM, A PERSON WHO MAY BE SICK, VERY SICK BUT YET NOT DEAD, IT MAY BE EASIER TO RESUSCITATE TISSUE CELLS, CIRCUITS THAT HAVE NOT YET BREECHED THAT POINT OF NOW RETURN AND THEN REGENERATION,OT OTHER HAND, EACH THOUGH IT MAY BE EASIER, REGENERATION WORKS BEST WHEN THERE'S COMPLETE LOSS. SO IN THE SITUATION WHERE THEY HAVE BEEN COMPLETE LOSS WHICH COVERS MOST PEOPLE WITH END STAGE BLINDING DISEASE, BECAUSE IT'S GREAT CAUSES OF BLINDNESS, MACULAR DEGENERATION, HERETITARY DEGENERATIONS, BY THE TIME THE PERSON BECOME ESSENTIALLY BLIND, LOST, USEABLE VISION THERE'S PROBABLY VERY LITTLE TISSUE LEFT TO ACHIEVE RESUSCITATION, SO THAT'S THE REGENRATIVE APPROACH, DISCUSSED THE REGENRATIVE APPROACH IS MORE RELEVANT IN THESE CASES AND IT'S MORE RELEVANT TO THE GOALS OF THE AUDACIOUS GOALS INITIATIVE. SO LET'S GET INTO THE TARGET DISEASES AND WHAT WE DISCUSS, AS YOU KNOW THIS APPROACH THAT WE'RE DISCUSSING IS FOCUSED EITHER AS DECEASES OF THE OUTER RETINA, AND PHOTOARE SEPTORSOR RELATED DISEASES OR THE OPTICAL IMAGESSAL NERVE, SO REALLY THERE'S TWO DIFFERENT ISSUES AND ASPECTS WE NEED TO DISCUSS. SO FOR THE PHOTORECEPTORS WHICH IS REALLY THE PHOTORECEPTOR/RPE COMPLEX, THESE ARE EXAMPLES THAT ARE THE HEAVY HITTERS, AGE RELATED MACK RADEGENERATION, HEREDITARY RETINAL DEGENERATION AND DIABETIC RETINOPATHYATHY. THESE ARE ALL RELATIVE TO THE STRATEGY IN TERPS OF CONSIDERING SHOULD ONE OF THESE BE A TARGET DISEASE, IN AGE RELATED MACULAR BEDENEGATION, THERE ARE TWO KINDS OF NEW O VASCULAR ORIE TYPES OF MACULAR DEGENERATION WHERE THERE'S RPE DEGENERATION WITHOUT THE VASCULAR COMPONENT. IT INVOLVES A CENTRAL PART OF VISION. IN DISTINCTION WHICH TYPICALLY ARE MORE CENTRIPITTAL, AND TAKE AWAY VISION OVERA LONG TOWARD OF TIME IN MOST CASES. THOSE HAVE THE REVERSE PATTERN OF GOING FROM THE OUTSIDE IN AS OPPOSE TO MORE OR LESSOT INSIDE, AND SO, PEOPLE--IT'S RARE FOR EXAMPLE, VERY LESS COMMON TO SEE COMPLETE BLINDNESS IN MACULAR REGENERATION, WHERE IN RETINA DEGENERATION, THAT CAN HAPPEN WHERE PATIENTS HAVE DINNER TYPES OF GENETIC DISEASE AND CAN BE DEFERRED. SO THE STRATEGY IN HOW ONE DESIGNS A CLINICAL STUDY TO TEST REGENERATION MAY BE DIFFERENT IN THESE KINDS OF CASES. WHERE DIABETIC RETINOPATHYATHY IS A DIFFERENT KIND WHERE THERE'S MANY TYPES OF LOTIONS FROM RETINOPATHYATHY, INCLUDING ONE SIDE OF THE MACULAR ADEMA IN TISSUE FLUID AND PARTS OF DECREASE VISION BUT NOT TAKING AWAY VISION COMPLETELY. AT THE OTHER END OF THE SPECTRUM SOMEONE WHO HAD SUCH LARGE AMOUNTS OF NEOVASCULARRIZATION, OF NEW BLOOD VESSEL FORMATION, LEADING, FIBROSIS AND TRACTIONAL ATTACHMENTS CHANGING THE STRUCTURE AND TAKING IT OFF ITS SUPPORTS THAT OVER A LONG TOWARD OF TIME MAY RESULT IN COMPLETE LOSS OF VISION BUT AT THE SAME TIME MEAN THAT THE SCAFFOLD ON WHICH ONE WOULD BUILD AND REGENERATE CELLS MAY BE VERY DIFFERENT. SO THE DIFFERENT DECEASES HAVE A BIG IMPLICATION ON HOW ONE WILL TEST THE REGENRATIVE STRATEGY BECAUSE IN THE DIFFERENCES IN WHAT PARTS OF THE RETINA ININVOLVE HOW FAR ALONG IT IS AND IS THERE A SCAFFOLD THERE, ARE DIFFERENT. WITH RETINAL GANG LIAISONNAL CELL DISEASES, THE ISSUES ARE DIFFERENT. IN MOST OF THE CELL DISEASES, THE STRUCTURAL CHANGES ARE VERY SIMILAR EXCEPT FOR THE CASE OF GLAUCOMA, SO AS I MENTIONED BEFORE, WE DISCUSSED HOW THE LOSS OF THE TISSUE, SUPPORTIVE TISSUE IS QUITE DIFFERENT FROM THE GLEEL CELLSOSEIS, INCREASED NUMBER OF GLIAL CELLS AT THE HOSPITALLIC NERVE HAD OCCURRED IN MOST OF THE OTHER OPTIC NERVE DISEASES, SO GLAUCOMA IS THE MOST COMMON OPTIC NERVE DISEASES AND COMMON CAUSE OF BLINDNESS IN THE WORLD, IRREVERSIBLE BLINDNESS BUT ALL HAVE THEIR OWN ADVANTAGES AND DISAD SAPTAGES BEING CONSIDERED AS A TARGET THERAPY ANDA ACTIVITIES AND PROJECTSY FOR THE PROOF OF PRINCIPLE FOR THE INITIATIVE, SO IN THE NEUROPATHY, THERE'S TWO KINDS, IN BOTH CASES THEREAIN INFARCTION, A STROKE OF THE OPTIC NERVE HEAD. THAT HAS A BIG ADVANTAGE THAT AFTER A CERTAIN LENGTH OF TIME GOES BY, IT'S LIKELY TO IMPROVE. MOST PATIENTS WITH AION, MOST OF THOSE PATIENTS DON'T HAVE COMPLETE VISION LOSS ALTHOUGH THERE ARE SOME WITH A CERTAIN TYPE, 10% THAT HAVE IT SO SEVERELY THAT THAT WOULD BE GOOD CANDIDATES. IN LABOR HERETITARY NEUROPTIC NEUROPATHY, THERE AGAIN CAN BE SEVERE LOSS OF VISION, USUALLY IN THE CENTRAL PART, HOWEVER SOME OF THESE PATIENTS PROJECTION NEURONS OR PIONS TANIOUSLY RESOLVE, SO IT CAN RANGE FROM A FIVE-45%, AND SPONTANEOUSLY IMPROVE MONTHS TO YEARS LATER AND SO ONE CAN ARGUE THAT THOSE MIGHT NOT BE A GOOD CANDIDATE FOR STUDYING BECAUSE OF THE SPONTANEOUS RESOLUTION WILL CONFUSE THE QUESTION OF WHETHER THE REGENERATED RIFT STRATEGY HAS BEEN THE CAUSE OR SOMETHING ELSE THAT THE CELLS BROUGHT IN IT A TROPEIC SUPPORT OF SOMETHING ELSE THAT'S IMPROVED. SIMILARLY WITH DOMINANT OPTIC ATROPHY DOES NOT IMPROVE BUT HAS THE SAME PATTERN OF LOSSES, TRAUMATIC OPTIC NEUROPATHY CAME UP IN THE DISCUSSION EARLIER HAS THE SAME ADVANTAGES IN THAT IT'S AN ACUTE INJURY, WHERE AFTER A CERTAIN LENGTH OF TIME IT CAN BE CLEAR THAT ONE IS NOT LIKELY TO HAVE SPONTANEOUS RESOLUTION, THE OTHER PART IS THAT THE DAMAGE OCCURS AT A LOCALIZED AREA FAR AWAY FROM THE EYE, ON THE OPTIC CONNAL, AND IT ENTERS THE SKULL AND SO IN THOSE KINDS OF SITUATIONS THERE'S CONTROL AND UNDERSTANDING OF EXACTLY WHERE THESE ARE, SO 80% HAVE BILATERAL OPTIC NEUROPEN MEETING AT SCHETHEN OTHERS WE DISCUSSED ARE ALL CANDIDATES ALL WITH THEIR ADVANTAGES AND DISADVANTAGES. SO IT MAKES THE WHOLE BATTLEFIELD STRATEGY VERY DIFFERENT DEPENDING ON WHICH TYPE OF DISEASE ONE WANTS TO LOOK AT AND THE SPECIFIC OF THE DISEASE ITSELF. YAWPED THAT IS ANOTHER QUESTION AS ONE LOOK EARLY VERSUS LATE IN THE DISEASE SO THIS WAS A BIG TOPIC OF DISCUSSION AT THE TOWN HALL SO EARLY DISEASE HAS SOME ADVANTAGES AND DISADVANTAGES, THE BIG ADVANTAGE IS THE GUIDANCE STRUCTURES, SCAFFOLD IS OFTEN NOT NOT CHANGED AS MUCH EARLY ON, BUT IT WAS POINTED OUT AND INDEED VERY EARLY CHANGES, ALMOST ALL OF THE SITUATIONS AT THE CELLULAR LEVEL BUT IN TERMS OF THE RESPONSE OF OTHER TISSUES, THE LOSS OF CONNECTIVE CELLS, IT'S USUALLY LESS EARLY ON THAN LATE AND THAT MAKES A BIG DIFFERENCE BECAUSE IF YOU HAVE LESS TISSUE RESPONSE, YOU HAVE MORE OPPORTUNITY TO PUT A CELL IN, HAVE IT REGENERATE OR HAVE IT DIFFERENTIATE INTO THE CELL YOU WANT IF IT'S AN ENDOGENOUS CELL AND THEN EXTEND THE AXON, THE DENDRITE AND MAKE THE CONNECTIVITY. DEALING WITH LESS VARIABLES IN THAT SITUATION. ON THE OTHER HAND LATE DISEASE HAS ITS ADVANTAGES, TOO, AND AS CAN YOU TELL WE'RE NOT GOING TO COME TO AN ANSWER TODAY BUT THESE ARE THE IMPORTANT ISSUES THAT CAME UP AT THE TOWN HALL. THE LATE DISEASE IS THE BIG ADVANTAGE BECAUSE IT'S EASY TO TAKE INTO EFFECT, AND OF COURSE YOU KNOW THAT THE LIKELIHOOD OF IMPROVEMENT IS INFETAL COMPARTMENT TEES MAL. UNLIKE EARLY IN THE DISEASE THERE CAN BE SOME RESPONSE OR REVERSAL AND PROMOTIONAL LESS SAFETY ISSUES WHEN YOU LOOK LATE IN THE DISEASE WHEN SOMEBODY LOST SO MUCH VISION THAT IF THE THERAPY TURNS OUT TO HAVE AN ADVERSE EFFECT AND YOU LOST VISION FROM THE THERAPY, YOU ARE LESS LIKELY, THAT MARGIN OF INJURY, MARGIN OF SAFETY IS--HAVE YOU LESS TO LOSE SO TO SPEAK IN A LATE DISEASE STATE. AND THESE ARE THINGS THAT NEED TO BE WORKED OUT AS THE PROCESS GOES ON FOR THE TRANSLATIONAL PROGRAM. THE LOSS OF AFERENCE AND EVENS WHICH ARE REFERRED TO AN EARLY DISEASE, BY THE TIME YOU GET LATE DISEASE THOSE ARE FAR ADVAUNT VANCEED IN THE CASE OF GLAUCOPE AYOU LOSE THE CONNECTIVITY AND THE LOSS OF ALGERONTOLOGYSTS OR SHRINKAGE OF ALGAE AND NEURONS YOU CAN ALSO SEE THIS AT THE LEVEL OF VISUAL CONCORTEX, SO THESE EFFECTS IN LATE DISEASE ARE RELEVANT. THE THIRD AREA IS THE GENETIC VERSUS ACQUIRED DISEASE AND EACH OF THOSE HAVE ADVANTAGES AND DISADVANTAGES. GENETIC DISEASES ARE OFTEN FAIRLY SYMMETRIC, IT HAS AN ADVANTAGE BECAUSE IT MAY BE MORE PREDICTABLE, MORE OF A CONTROL OR BEDDING OF --UNDERSTANDING OF WAYOU DO IN ONE EYE. THE OTHER ADVANTAGE IN THE DIFFERENT PART OF THE DISEASE IS THAT THE ACQUIRED DISEASE MAY NOT HAVE THE SAME PROBLEM AS THE GENETIC DISEASE IF YOU CAN FOR EXAMPLE, SOMEONE WHO LOST VISION FROM GLAUCOMA LET'S SAY THE INTEROCULAR PRESSURE WAS VERY HIGH. THEY WERE TREATED BUT IT WAS TOO LATE AND THEY LOST VISION. THEY HAD PREVIOUS LOST VISION, THEY STABLINGIZED THE VISION, YOU CAN CONTROL THE PRESSURE AND THEREFORE YOU DO NOT EXPECT VISION--THE DAMAGED VISION TO COME BACK AND A GENETIC DISEASE, INHERENT DEFECT MAY STILL BE THERE AND OF COURSE IT DEPENDS ON THE DISEASE, FOR EXAMPLE, IF SOMEONE HAS A SPECIFIC DAMAGE IN THE RETINAL LOCATIONINOID CYCLE THAT LED TO THE LOSS OF VISION, IF I DO ENDOGENOUS REPLACEMENTS, THE GENETIC DEFECT MAY STILL THERE BE, AND SOMETHING TO KEEP IN MIND THAT THE GENETIC DEFECT MUST HAVE THE DISADVANTAGE AND ANY OTHER CASE THAT'S DUE TO SOME--LET'S CALL IT INHERENT DEFECT, THOSE ARE GOING TO SKEW HOW ONE DOES THE STUDY BECAUSE THE DEFECT MAY BE THERE EVEN AFTER REGENERATION. A FOURTH IS ACUTE IT PRESERVES SOMEBODY LOOKING EARLY AND SOMEBODY CLINICALLY [INDISCERNIBLE] AND MAY ALSO REVERSE, THEY REVERSE BECAUSE SOME CASES ENDOGENOUS RECOVERY AND MANY, MANY DIFFERENT DISEASES FOR EXAMPLE, TRAUMATIC RETINOPATHYATHY MAY HAVE EARLY REVERSE, BY THE NEI DECOMPRESSION TRIAL, THEY SAW 43% OF SUBJECTS IMPROVE VISION BY THREE LINES OR MORE OVER SIX MONTHS. SO ACUTE DISEASES WE KNOW HAPPEN RAPIDLY CAN REVERSE WHEN LOOKING LATER ON. SO THIS IS IMPORTANT UNLESS ONE KNOWS THE NATURAL HISTORY CAREFULLY IN GREAT DETAIL. THE DISADVANTAGES OF THIS CHRONIC DISEASE AS MENTIONED BEFORE, HAPPENING IN LATE DISEASE IS THAT THE LONG-TERM EFFECTS OF THE DISEASE PROCESS MAY LEAD TO VORCE KINDS OF CHANGES THAT ARE IRREVERSIBLE, SIMILARLY THE CHANGES IN THE AFFERENTS AND EFERRENTS. >> UNIVERSAL VERSES BILATERAL, THIS OVERLAPS WITH WHAT I BROUGHT UP WITH GENETICS, ABOUT I LAT RAHAS A FEW LESS SAFETY ISSUES, SOMEONE THAT IS COMPLETELY BLIND, THEY HAVE LESS TO LOSE EARLY ON IN DOING A STUDY. THERE ALSO ISN'T INHER EPT CONTROL BECAUSE THEY HAVE TWO EYES, AND IF YOU DO THE STUDY CAREFULLY HAVE YOU THE OTHER EYE AS INHERENT CONTROL. ONE COULD ARGUE THAT A BILATERAL DISEASE IS MORE EFFECTING QUALITY OF LIFE. SOMEBODY ALREADY LOST VISION BRIEFLY OR TO THE SAME DEGREE IN BOTH EYES, THEY IN A SENSE MAY BENEFIT THE MOST FROM A CERTAIN INCREMENT AND IMPROVE VISION FROM A REGENRATIVE STRATEGY. OT OTHER HAND, ONE CAN ALSO ARGUE THAT A PATIENT WITH A UNILATERAL DISEASE MAY HAVE GREATER MOTIVATION FOR BEING AN EXPERIMENTAL TREATMENT BECAUSE THEY NOW KNOW WHAT THEY'RE MORE CONCERNED RIGHTFULLY SO ABOUT LOSING THE VISION IN THEIR SO CALLED GOOD EYE. SO THESE ARE AREAS WHICH REALLY OVERLAP WITH SOME ETHICAL ISSUES THAT ARE RELEVANT AGAIN TO CHOOSING THE DISEASE AND AT WHAT STAGE ONE DOES THIS. BEYOND THIS WE DISCUSS TRANSLATIONAL ISSUES. WHAT IS ONE OTHER TARGET CELL, I DON'T WANT TO SPEND TOO MUCH TIME THAT OVERLAPS WHAT YOU JUST HEARD FROM THE WONDERFUL RESENTATION FROM PETER AND MONICA, WE HAVE TO DECIDE IN SOME DECS, IT'S MORE IMPORTANT TO TARGET PHOTORECEPTORS AND PHOTORECEPTOR ENDOGENOUS PROBLEMS VERSUS THE RPE, IN SOME CASES BOTH ARE GONE AND HAS TO COME UP WITH THE STRATEGY TO DEAL WITH THAT AND YOU HEARD ABOUT THE VERY MARKET DIVERSITY OF THE CELLS BOTH STRUCTURALLY IN TERMS OF WHERE THEY ARE AND HOW THEY ACCOUNT, FUNCTIONALLY IS MANY OTHER FEATURES AND ONE HAS TO CONSIDER IN MANY DISEASES OF THE OPTIC NERVE THAT THE GLEA ARE ALSO CHANGED. THEY BECOME THE GLEEL CELLSOSEIS AND/OR LOSS OF SUPPORTING TISSUE IN THOSE DISEASES. AND THEN IN THE ESPECIALLY MORE SO IN THE OPTIC NERVE DISEASE, EVEN IN SOME OF THE PHOTORECEPTOR DISEASES ONE HAS TO CONSIDER NOT JUST A CELL ABOUT THE BODY REPLACEMENT BUT OF COURSE THE ACTUAL AXONAL REGENERATION AND OPTIC NERVE DISEASE THIS IS A BIG BARRIER BECAUSE YOU HAVE TO EXTEND AN AXON BUT IT HAS TO CROSS AND MAKE IT THROUGH THE OPTIC NERVE HEAD, THROUGH THE POTENTIALLY INHIBITORY ENVIRONMENT OF THE DAMAGE IN THE OPTIC NERVE, MAKE ITS WAY THROUGH THE CHIASM, AND THEN THROUGH THE APPROPRIATE TARGET AREAS AND ALLOWED [INDISCERNIBLE] FUNCTIONAL VISION IN THE HUMAN. SO SHE'S ARE BIG ISSUES THAT NEED TO BE KEPT IN MIND AND IMPORTANT FOR TRANSLATING FROM THE LABORATORY TO THE CLINICAL VENUE. OTHER TRANSLATIONAL ISSUES THAT CAME UP THEA THE WORKSHOP SORRY WHERE THE CHOICE OF ANIMAL MODELS. THERE ARE VARIOUS ANIMAL MODELS, THEY REALLILY DIFFER. SOME OF THEM ARE FOR EXAMPLE,'RE NO GOOD MODELS FOR THE DISEASE, NONHUMAN PRIMATES BUT IT DIFFERS DEPENDING ON THE DISEASE. THE AND THE DIFFERENCES BETWEEN MODELS IN GENERAL IF YOU LOOK BACK AT PRECLINICAL RESEARCH, TRANSLATED TO THE HUMAN REALM, DIFFERENCE--MORE DIFFERENCES BETWEEN MODELS GET DIFFERENT RESULT WHEN IS ONE LOOKS AT THERAPEUTIC STRATEGIES, THIS CHAOTIC BEHAVIOR IS A REAL PROBLEM AND THE DIFFERENCE IF THERE'S AN ANIMAL MODEL THAT'S RELATIVELY SMALL AND HAS A BIG DEFICIENCY IN RESULTS WHAT HAPPEN WHEN IS YOU TRANSLATE TO HUMAN AND THEY SEE THE RESULTS THAT ARE MORE SEVERE. SO THIS IS AN INITIATIVE THAT NEEDS TO BE KEPT IN MIND AND FINALLY THE QUESTION THAT COMES UP IS HOW RELEVANT IS THE CHOICE OF MODEL FOR SOME OF THE REPLACEMENT THERAPIES. THAT DOES IT MATTER IN THE ANIMAL WHETHER THE RAT OR MOUSE OR LOSS OF VISION FROM TRAUMA OR ESCHEMIA OR INENEMIATION: IF THE GOAL IS TO FIRST--FIRST PROOF OF PRINCIPLE TO BE ABLE TO REPLACE THE GANGLION CELL AND GET IT TO EXTEND IT BACK, SO THIS IS AN OPEN QUESTION, A LOT DEPENDS ON UPON WHAT IS THE--WHAT'S LEFT ON THE BATTLEFIELD AFTER THE PATHOPHYSIOLOGICAL DAMAGE IS TAKING PLACE IN THE ANIMAL MODEL AND HUMAN MODEL. ANOTHER ISSUE RELATED TO TRANSLATION IS THE CHOICE OF A SPECIES. SO WE KNOW WELL, THERE'S A BIG SPECIES DIFFERENCE BETWEEN MICE AND RAT, RATS AND NONHUMAN PRIMATES AND NONHUMAN PRIMATES AND HUMANS. IT'S HUGE. AND WE ALL KNOW, NOT JUST BECAUSE WE HAVE AN EFFICACY TRANSLATION BUT A VAST PROBLEM AND I DON'T WANT TO HAVE TO BRING UP THE HISTORY OF PHASE ONE PRECLINICAL TRIALS WHERE A DRUG THAT WAS VERY SAFE IN A VARIETY OF ANIMALS CAN LEAD TO UNEXPECTED EFFECTS IN HUMANS AND THE SAME THING MAY BE TRUE FOR THE KINDS OF THERAPIES WE'RE DISCUSSING SO AGAIN WE HAVE TO KEEP THAT IN MIND. THE OTHER ISSUE IS ESPECIALLY FOR THINGS RELATED TO PHOTORECEPTORS DISEASES THAT RODENTS DON'T HAVE MACULAR, IT'S THESE--IT'S NOT THAT WE CAN'T DO THESE BUT IT MAKE ITS MORE DIFFICULT SO AGAIN THIS IS RELEVANT TO THE PROGRESS OF IT. THE ASSESSING EFFICACY, THE SAFETY STUDIES AND EFFICACY STUDY, THIS WAS A BIG POINT BROUGHT UP IN THE MEETING, SO SAFETY STUDIES THAT WE'RE NOT GOING TO MAKE SURE WE ARE NOT GOING TO MAKE THINGS BAD, THOSE CAN BE DONE IN END STAGE DISEASE, IDEALLY THE VERY FIRST SAFETY STUDY WILL BE DONE IN PEOPLE WHO ARE COMPLETELY BLIND. I THINK IT'S GENERAL AGREEMENT WITH THAT. EFFICACY IS IT THES DON'T NECESSARILY HAVE TO BE AT THE END STAGE. THEY MAY WELL BENEFIT FROM BEING AT THE END STATE. ANOTHER CAME UP WITH REGENERATION OR SOME OTHER EFFECT OF THE THERAPY AND THE IDEA OF PARACRIP EFFECT OR TROPH IC RESCUE, THEY CAN BE DIFFUSIBLE, CELL DIRECTED AND CAN BE CONFUSING IN THE ANALYSIS OF THE RESULTS. ONE OF THE WAYS TO ATACT THIS IS THE ROLE OF IMAGING AND I WANT TO BRING UP HERE A VERY IMPORTANT PART OF TED AGI WHICH IS THE EMPHASIS ON IMAGING AND IT BRINGS UP A SUBSEQUENT SLIDE, IMAGING IS CRITICAL TO BEING ABLE TO TELL WHAT ACTUALLY HAPPENED. BECAUSE AT LEAST YOU WERE ABLE TO SEE THE SAME WAY THE PRESENTATION OF JEFF GOLDBERG'S STUDY WHERE YOU SEE THE GANGLION CELLS THEMSELVES EXTEND THEIR WAY ALL THE WAY UP TO THE OPTIC NERVE. IF YOU CAN SEE THE SAME THING IN THE HUMAN THAT THE CELLS ARE GONE SOMEWHERE, THAT GIVES YOU MORE CONFIDENCE THERE'S AN EFFECT. THE OTHER ISSUE THAT COMES UP WAS THIS REGENERATION OF SOMETHING ELSE, VARIABILITY, GETTING BACK IT'S SOMETIMES REVERSAL, SOMETIMES WORSENING, DISEASES ARE VARIABLE IN CLINICAL ASSESSMENT OF FUNCTION ARE HIGHLY REVERSIBLE. SO THIS SHOULD BE KEPT IN MIND. SO THE END POINT, STRUCTURAL END POINTS THAT HAVE A WOMBINNATION OF BOTH. SO STRUCTURAL END POINTS. ARE THERE NEW CELLS THERE? AXONS THERE? CONNECTIONS THERE? IT'S POSSIBLY MORE SENSITIVE THAT A STRUCIALURAL VIABLEIDESSATION, BUT IN GENERAL, ONE CAN PICK UP SMALL NUMBERS OF CELLS MORE EASILY THAN LARGE NUMBERS AND SMALL NUMBERS VIEWED IN A FUNCTIONAL SENSE IN A PERSON. IT'S ALSO POSSIBLE BUT NOT ALWAYS LESS VARIABLE THAT AS YOU CAN--YOUR ASSESSMENT OF DO YOU SEE A CELL OR NOT IS MORE OR LESS A BINARY QUESTION, IS THERE FUNCTION IT'S OFTEN OVERLAID ON THE NOISE OF CLINICAL ASSESSMENT. SO ARE THEY NEW CELLS? THIS IS WHERE THE AGI IMAGING COMPONENT COMES IN, THE DIRECT IMAGING OF CELL BODIES, THIS IS MORE APPROPRIATE IN THE RETINA, IS THERE THICKENING NEW AXONS IN THE NEUROFIBER LAYER. CAN YOU LOOK IN THIS THE OPTIC NERVE HEAD AND DTI TO SEE ALL THE NEWAXONS THAT GO DOWN THE OPTIC NERVE AND ONE CAN USE REPORTER PROTEINS IN IS DONE ROUTINELY IN ANIMALS TO TELL US, YES THERE'S A NEW CELL, IT IS THERE, IT IS THE RIGHT KIND OF CELL. HOWEVER IN PEOPLE, THERE MAY BE SOME ETHICAL AND SAFETY ISSUES ABOUT REPORTER PROTEINS. AND FUNCTIONAL IMAGING IS MORE RELEVANT TO THE PATIENT. THE PATIENT DOES CARE THAT THEY GET A NEW CELL, WHAT THEY CARE IS DO THEY SEE BETTER, IT'S PROBABLY MORE VARIABLE BECAUSE MOST FUNCTIONAL ASSESSMENTS ARE MORE VARIABLE. THE NICE THING AND THIS IS AGAIN A COMPONENT OF THE AGI IMAGING INITIATIVE IS IT'S POSSIBLE IMAGE FUNCTION IN CELLS AND AXONS. LOOK AT METABOLIC CHANGES AND THESE ARE EXAMPLES OF HOW THIS CAN BE DONE. ONE CAN LOOK AT CONNECTIVITY TO AFREER ENSEL AND EFER ENSEL, LOOKING AT ACTIVITY DEPENDENT METABOLIC CHANGES, LOOKING AT TARGET FUNCTIONAL CHANGES AND I WON'T GO INTO DETAIL BUT THIS IS A BIG PART OF THE AGI IMAGING AND I THINK IT'S IMPORTANT FOR DISTINGUISHING SO WE JUST HAVE STRUCTURAL RECOVER OR FUNCTIONAL RECOVER. TO FINISH UP. OTHER ISSUES. THERE'S ETHICAL ISSUE IN HOW WE DO THIS, NONAPOPTOTIC THE THAT IT'S A PROBLEM BUT WE NEED TO PAY ATTENTION AND THIS WAS ALREADY ERASED IN THE PREVIOUS PRESENTATION, THE PREVIOUS PRESENTATION, WHO SHOULD BE PARTICIPATING IN THESE EARLY STAGES. WHEN I SAY THE EARLY STAGES OF THE PROGRAM, NOT THE EARLY STAGE OF THE DISEASE. HOW DO YOU PROVIDE HOPE BUT NOT FALSE HOPE TO SOMEONE PARTICIPATING BECAUSE ASTERISKS STD BEGINNING WE DON'T KNOW IF IT WILL BE EFFECTIVE OR NOT AND OF COURSE THERE'S ALWAYS RISKS IN SAFETY STUDIES SO THE SUBJECT WHO IS ARE PARTICIPATING NEED TO UNDERSTAND [INDISCERNIBLE]. THE FINAL ISSUE IS FDA AND THERAPY BECAUSE EVENTUALLY WHEN THIS WORKS. THIS WOULD BE A PART MERSHIP THAT'S NECESSARY BECAUSE THIS WILL BE DEVELOPED HOPEFULLY, ONE OF THESE THERAPIES STARTS TO COME INTO PRACTICE, IT WILL BE A PARTNERSHIP WITHIN INDUSTRY AND WE KNOW THAT HOW THE FDA LOOKS AND APPROVES, NEW THERAPY IS BASED ON MEANINGFULLY KLINEICALLY MEANINGFUL CHANGES TO KEEP NAIN THE BACK OF OUR HEAD SYSTEM WHAT IS GOING TO HAPPEN, WHAT'S MEANINGFUL TO THE PATIENT. IT'S DIFFERENT FROM A PROOF OF PRINCIPLE STUDY WHERE WE WANT TO--AT THE BEGINNING THOUGH, DOES THIS WORK OR NOT. IN SUMMARY, TESTING REGENRATIVE THERAPIES IN THOUGHTFUL AND FEASIBLE CLINICAL TRIALS WILL BE COMPLETELY CLINE CRITICAL TO THE GOALS. ONE PRECLINICAL TACKNIQUES, TRANSLATIONAL DESIGN WHO WE DISCUSSED AT TOWN HALL MAKE UP THE NECESSARY TRIAD FOR ACHIEVING AGI GOALS. THANK YOU. [ APPLAUSE ] >> THE WELL THE IMAGING THING I THINK IS A BIG DEAL BECAUSE IT ALLOWS TO YOU HAVE A BIG PATHWAY. SO OF COURSE THE PATIENTS WANT FUNCTIONAL IMPROVEMENT BUT THAT'S NOT GOING TO HAPPEN WHEREAS YOU CAN SEE INCREMENTAL IMPROVEMENT WITH APPROPRIATE IMAGING TECHNOLOGY AND I ALMOST WOULD SAY IT'S A PREREQUISITE BEFORE PROCEEDING WITH THE TRIAL. ANOTHER THING I THINK IS WORTH THINKING ABOUT, IS I WILL SUGGEST WHO WILL BE SITTING AROUND THE TABLE WHEN WE'RE MAKING GO-NO GO DECISIONS SO THE BILATERAL VERSUS THE UNILATERALLY MIND PERSON, I LEARNED AND THIS IS SURPRISING TO ME BUT I LEARNED THERE ARE TWO KINDS OF BIASES IN CLINICAL TRIALS. THERE'S ALLOCATION BIAS AND THERE'S ASCERTAINMENT BY AS. NOW ASCERTAINMENT BIAS CAN BE HANDLED BY DOUBLE MASKING WHICH IS POSSIBLE IN A SURGEERAL TRIAL, BASICALLY BUT FORTUNATELY THAT ONLY--THE FAILURE TO DOUBLE MASK ONLY LEADS TO AN OVERESTIMATION OF TREATMENT BENEFIT BY A NUMBER THAT'S CLOSE TO 20%. BUT THE ALLOCATION BIAS LEADS TO OVERESTIMATION OF TREATMENT BENEFIT ACCORDING TO THE GUY NAMED SHULTSD WHO STUDIED THIS IS BY 30 OR 40% AND ALLOAMACYICATION BIAS IS USUALLY HANDLED BY CONCEALMENT OF ALLOCATION AT THE SELECTION BIAS. AND SO I'M VERY WORRIED THAT AUNE LAT LATERALLY BLIND PERSON IS THE WRONG CANDIDATE PRECISELY BECAUSE OF THIS. BUT THAT'S SOMETHING THAT IS OW OF OUR AREA OF EXPERTISE BUT IN ADDITION TO EMPHASIS, YOU NEED A PERSON FOR THE RIGHT CLINICAL TRIAL DESIGN BACK GROUPED TO HELP. >> I COMPLETELY AGREE AND YOUR POINT IS--BECAUSE IT WAS RAISED AT THE MEETING ONE PERSON BROUGHT UP THE UNILATERAL VERSES BILATERAL AND WE A PANELISTS WE DISCUSS THAT AND I THINK EVERYBODY WOULD AGREE WITH THAT BUT AGAIN RIGHT NOW WE'RE AT THE VERY, VERY EARLY STAGES AND THE POINT ABOUT HAVING TRIAL, NOT JUST ETHICIST BUT TRIALIST IS VERY CRITICAL. OKAY, THANK YOU. >> LEVINE, THANK YOU FOR MODERATING THAT DISCUSSION AND THIS PRESENTATION, ALSO, THIS IS THE FIRST VENTURE IN THIS AREA AND I'M SURE IT WILL GO ON FOR A WHILE. NAND NOW WE'RE GOING TO HEAR FROM GEORGE Mc KIE, HE'S THE PROGRAM OFFICER FOR CORNEA AND INFLAMMATION AND INFECTION. >> I'D LIKE TO THINK EVERYBODY TODAY FOR LETTING ME PRESENT THE CORN RAPPORT FOLIO AND I WANT TO ECHCISE IT'S NOT JUST THE DUST COVER, DON'T WORRY ABOUT THAT AND I'M SURE OTHER CORNEA RESEARCHERS DO AS WELL WE'RE GOING TO TRY AND CONVINCE YOU, TRY TO CONVINCE YOU TO EMPHASIZE THE IMPORTANCE OF THE CORNEA. SO IF YOU BEAR WITH ME FOR A MINUTE. I JUST WANT EVERYBODY IN THE ROOM FOR THE SAME PAGE WITH THE LOCATION OF THE DESCRIPTION OF THE CORNEA, LET ME TURN MY MOUSE HERE SO I CAN DRIVE RIGHT AND GO IN THE RIGHT DIRECTION. HOLD ON FOR TECHNICAL DIFFICULTIES. THE CORNEA IS ON THE FIRST PART OF THE EYE, IT'S CLEAR FILM SHAPED TISSUE, YOU AND SEE THE IRIS AND PEOPLE THE BLACK HOLE, THE PUPIL, SO THE CORNEA IS THE CLEAR OUTER TISSUE THAT COVERS THE EYE AND HISTOLOGICALLY THERE'S THE EPITHELIUM, ON THE FRONT SURFACE, OF YOUR SKIN, THE BOW MAN'S LAYER THE MAIN THICKNESS OF THE CORNEAL TROLLA AND ON THE POSTERIOR PART IS THE BOWMAN'S MEMBRANE AND THEN THE STROME TROVALLA AND DESCEMET'S MEMBRANE AND ENDOTHELIUM AND YOU GET WHAT YOU'RE BORN WITH AND ONCE A DIE OFF, YOU'RE OUT OF LUCK. SO TO GIVE YOU AN IDEA OF THE RELATIVE SIZE OF THE CORNEA PROGRAM, WE'RE THE THIRD LARGEST PRACTICAL IN THE NEI, SECOND TO RETINAL DISEASES AND APEs, WE ARE 13% OF THE NEIS APPLICATION THAT COME AND FUNDED ARE IN HAD THE CORN RAPROGRAM. THIS SLIDE WILL GIVE YOU AN OVERVIEW OF THE RESEARCH BEING DONE IN THE PORTFOLIO, AND THIS BY ALL MEANS DOES NOT COVER EVERYTHING BECAUSE THERE'S A BROAD DEPTH OF INVESTIGATION IN MANY AREAS OF THE PORTFOLIO SO I JUST KIND OF LISTED THE TOPICS THAT HAVE THE MOST APPLICATIONS IN THESE AREAS BUT AGAIN MANY, MANYIARYS THAT AREN'T LISTED HERE SO THESE ARBITRATE BY ANY MEANS THE FULL DEPTH OF THE PORTFOLIO AND I LISTED THESE INVESTIGATORS ON HERE AND AGAIN THESE ARE INVESTIGATORS I WILL HIGHLIGHT WORK, I'VE DONE IT, JUST TO GIVE YOU AN IDEA AND AGAIN IT'S NOT THE FULL DEPTH OF THE WORK BEING DONE HERE. SO A LARGE MAJORITY OF THE PORTFOLIO DOES INVOLVE TRY EYE AND TEARS WHICH ARE VERY IMPORTANT TO THE MAINTENANCE OF THE CORNEA AND DR. GORDON LAURIE IS HIS RESEARCH WHICH LOOKS AT A COMPONENT OF NORMAL TEARS AND HE'S CLOSE TO STUDYING LACK RATIN REPLACEMENT DROPS, FOR PEOPLE WITH DRY EYE, IT'S ESSENTIAL FOR NORMAL TEARING AND OCULAR SURFACE MAINTENANCE. INFECT YOWS DISEASES OF THE CORNEA IS PROBABLY THE LARGEST COMPONENT OF MY PORTFOLIO AND THERE'S MANY COMPONENTS OF INFECTIOUS DISEASES, VIRAL, BACTERIAL FUNGAL, VIRAL BEING HELP YOUIES AS YOU KNOW SINCE I'M GENERALLY PRESENTING BY O HAZARDS ARE HERPES AND I LISTED THREE INVESTIGATORS AND THESE ARE THREE INDEPENDENT LABS THESE ARE DR. CARR GIAASI, AND MOHAMED, ADENOVIRUS WHICH YOU'RE ALL FAMILIAR WITH, YOUR KIDS GET CONJUNCTIVITIS AND GET TO SPEND A FEW DAYS AT HOME. DR. CHODOSH, IS A RESEARCHER IN THAT IRBIA, BACTERIA AND PSEUDOMONAS AND STAFFY LO CALKOUS; THEN OFTEN TIMES AFTER A FUNGAL INFECTION THE PATIENT IS PUT ON TOPICAL STEROIDS AND THEY GET A REOCCURRING FUNGAL INFECTION, HE IS LOOKING FOR AN ALTERNATIVE TO TREAT THE PATIENTS SO THE IMMUNE SYSTEM IS NOT SUPPRESSED AND THEY DON'T GET REOCCURRING INFECTIONS. STEM CELLS AS YOU CAN IMAGINE IS A BIG AREA IN THE CORNEA, BECAUSE THERE ARE STIMCELLS AND THEY DO REGENERATED AND A LOT OF THE WORK RECENTLY HAS BEEN TAKING THE STEM CELLS AND TRANSPLANTING THISEM FOR WOUND HEALING AND FIBBING OUTS WHERE THEY'RE ACTUALLY LOCATED AND HOW THEY DIFFERENTIATE. THERE'S BEEN SOME RECENT FINDINGS, THINKING THEY'RE NOT ALWAYS LOCATED IN THE LIM BUS OR LOCATED THROUGHOUT THE CORNEA SO THAT'S BEEN INTERESTING, ENDOTHELIAL DISEASE, THE MOST COMMON ENDOTHELIAL DISEASE IS FUCHS ENDOTHELIAL DYSTROPHY, DOCTORS AFSHARI, GOTTSCH, AND MOOTHA, AND I WILL BACK UP, I SKIPPED WOUND HEALING. DR. MURPHY IS LOOKING AT THE MECHANICAL FORCES, AND NEUROEFFECTS, CORNEAL TRANSPLANTS, DR. SHIUY, I WILL SET THEM ASSAYED BECAUSE I WILL INTO MORE DETAIL ABOUT THEIR WORK LATER IN THE PRESENTATION, STRUCTURAL MALFORMATIONS, THAT STLES A TERM I CREATED FOR KERATOCONUS, BECAUSE IT'S BULGING OF THE CORNEA ASK BUT WE'VE HAD A LOT OF WORK DONE WITH DR. RAB RABINOWITZ, AND CHAKATORI, SO I NARROW IT DOWN TO--I LIKE TO NARROW IT DOWN TO THE THREE SUPER POWERS OF THE CORNEA, IT'S A BARRIER PROTECTION, SHIELDS THE EYE FROM THE ENVIRONMENT AND IT'S ALSO THE MOST REFRACTIVE TISSUE IN THE EYE. THE OVER ALL REFRACTION OF THE EYE IS ABOUT 60 DIOPTERS, IT'S ALSO THE MOST INNERIVATED TISSUE IN THE BODY, 300-600 TIMES THE SENSITIVITY OF THE SCENE. THE CORNEA IS REALLY GOOD AT BEING--AT FIGHTING, I'LL GOING TO START WITH THE FIRST SUPER POWER OF THE CORNEA THE CORNEA IS PREALLOTY IMPED AT BEING RESISTANT TO INFECTION AND I'M LEANING ON INFECTIONS AS PART OF A BERNEA DEETIER BECAUSE IT'S THE MOST COMMON RESEARCH BEING DONE IN THE AREA AND YOU CAN SEE HERE THAT IT HAS REALLY GOOD DEFENSES. IF YOU PUT BACTERIA ON AN EYE OVERTIME AT 14 HOURS, ALMOST ALL THE BACTERIA, ZERO--MOST--I SHOULD SAY ALL THE BACTERIA ARE GONE, AND THIS HAS BEEN SHOWN FOR BOTH PSEUDOMOANUS, STAFF LO CAUCUSAURIAS. NOW, DR. SUSY FLESHING WHO IS STUDYING BACTERIAL INFECTIONS OF THE CORNEA AND SHE STUDIES CONTACT LENS RELATED CONINFECTIONS SINCE THAT THE MOST COMMON CAUSE OF BACTERIAL INFECTIONS OF THE CORNEA IS WEARING A CONTACT LENS. THE AND IT'S THE MOST COMMON CAUSE OF BLINDNESS DUE TO CORNEAL DISEASE IS DUE TO BACTERIA. SO HIGH WANTS TO LOOK AT HOW A HEALTHY CORNEA RESISTS BACTERIA VERSUS HOW A SICK CORNEA REACTS TO THIS BACTERIA. SO SHE'S LOOKING AT WHOLE HEALTHY EYES SO THIS IS AN EXAMPLE OF AN IMAGING TECHNOLOGY SHE CREATED AND THIS IS OF A MOUSE CORNEA THAT'S NOT BEEN SECTIONED, NOT BEEN FIXED BUT THE PSEUDOMOANUS AND PUT ON THIS CORNEA AND SHE PICKED PSEUDOMOAN ISOTOPE SINCE THE CONTACT LENS INFECTION AND YOU CAN SEE THAT THIS IS AFTER SIX HOURS SHE PUT ONE BILLION COLONY FORMING UNITS PSEUDOMOAN ISOTOPE ON THE SIDE AND TO GET THIS BACTERIA SHE HAD TO SUPERVISUALLY FRAYED IT WITH TISSUE PLOTTING PAPER OTHERWISE THE BACTERIA FELL OFF AND THE ONLY WAY IT WOULD--AND YOU CAN SEE IT HAS BT PEN FREIGHTED DOWN TO THE STROMA YET. THE ONLY WAY TO GET IT TO PENETRATE THE STROMA IS TO INJURY THE STROMA. SO NOW INVESTIGATORS HAD BEEN STUDYING WHY IS THE CORNEA SO RESISTANT TO BACTERIA AND THREE OF THE REASONS THEY DISCOVERED IS THE TEAR FLUID, IT'S VERY GOOD AT WORKING ON THE MIKE ROPES DIRECTLY ITSELF BUT IT CHANGES GENE EXPRESSION OF THE CORNEAL EPITHELIAL CELLS TO MAKE THEM MORE RESIST APT TO BACTERIAL FIN FECKSES AND THERE'S ALSO BEEN DISCOVERY ABET MICROBIAL PEPTIDES ARE FOUND IN THE CORNEAL EPITHELIAL CELLS AND ANTIMICROBIAL PEPTIDES ARE SMALL PROTEINS WITHIN EPI-BLAST THELLIAL CELLS ACT BEING DIRECTLY ON THE INFECTION, KIND OF LIKE LITTLE NATURAL ANTIBODIES OR ANTIBIOTICS IF YOU THINK ABOUT IT THAT WAY. AND THE CORNEAL EPITHELIAL SETS, SO THEY TRAPPED LYSOSOMES INSIDE, THEY TRAP THAT INSIDE THEIR LYSOSOMES WHERE THEY KILL THEM AND YOU CAN SEE IN THIS MOVIE, LYSOSOMES FILLED WITH BACTERIA HERE. >> NOW UNFORTEDINATELY PSEUDOMOANUS HAD THE NATURAL DEFENSES AND AGAIN DR. FLESHING LAB DISCOVERED THAT PSEUDOMOANUS FOR A VERY LONG TIME IS CONSIDERED TO BE EXTRA CELLULAR DR. FLESHER AS DISCOVERED THERE'S A INTERNATIONAL CLASSIFICATIONIA CELLIAR AND YOU KEY IT'S CIRCLING AROUND IN THIS EPITHELIAL CELL, IT'S REPLICATING IT TAKES IT AND PUSHES THE CYTOPLASM AWAY FROM THE PLASMA MEMBRANE AND CREATES THESE BLEBS WHERE IT CREATES A NICE AND HAPPY HEALTHY HOME THERE. AND IT WILL PRESENT THE CELL FROM COMMITTING SUICIDE SO IT CAN LIVE IN IT'S LITTLE HAPPY HOME. THE OTHER THING THAT PSEUDOMOANUS HAS DONE TO AVOID BEINGITEN BY LYSOSOME IT PLOWS THE CELL UP BEFORE IT'S EATEN OR LET ME SHOW YOU THIS VIDEO HERE, IN THIS BLEB IT CREATES IT GETS INSIDE THE BLEBS AND USED IT TO TRANSPORT A CELLS. AND IN THIS SLIDE THERE'S WITHIN A HUNDRED TIMES THE CONCENTRATION OF THE GENOMICEIN PUT ON THIS EPITHELIUM AND YOU CAN SEE THE PSEUDOMOANUS IS PROTECTED FROM THE ENVIRONMENT INSIDE THE BLEB. NOW TO MAKE MATTERS WORSE, THEY DISCOVERED THAT PSEUDOMOANUS ADAPT TO THE OCULAR SURFACE TO BECOME MORE VIRULENT. SO THIS--TAKEN NORMAL RATS DONE NOTHING TO THEIR EYES WHATSOEVER, NOT ASHES BRAIDED THEM, NOT CATCHED THEM OR ANYTHING AND EFFECTED THEM WITH CONTACT LENSES WITH THEY PUT THEM ON THE RAT AND IN A MEDIAN OF ABOUT SEVEN DAYS ALL THE RATS GET INFEBLGHTIOUS KERRA TITIS. NOW IF THEY TAKE THESE OFF THE RATS AND PUT ON OTHER NORMAL HEALTHY RATS, THE MEDIAN TIME TO INFECTION GOES FROM SEVEN DAYS DOWN TO TWO DAYS SO THESE ARE GETTING INFECTED QUICKER AND THEY NOD THAT ONCE THE PSEUDOMOANUS HAS BEEN ON THE OCULAR SURFACE FOR SOME PERIOD OF TIME, A CHANGE IN GENE EXPRESSION ALLOWS THEM TO INVADE THE CELLS FASTER. >> ALL RIGHT, WELL I WILL LEAVE THE BARRIER ALONE FOR A SECOND AND I WILL GO TO THE SUPER POWER OF THE REFRACTIVE AREA OF THE CORNEA, OR THE REFRACTION OF THE CORNEA, FRACTION OF THE REFRACTIVE AREA, BECAUSE UNFORTUNATELY NOT ALL OF US ARE BORN WITH EYES OF NORMAL REFRACTIVE CAPABILITIES AND SO MANY--SO FAR I VERY LONG TIME MANY INVESTIGATORS HAVE FOUND A WAY TO CORRECT THE CORNEAL REFRACTION TO HELP IMPROVE OUR VISION. THE FIRST EYA GLASS SAYS WERE RECREATED AND IN THE 13th IN ITALY, AND I REALLY TRIED HARD TO GET A COPY OF THE ITALIAN EYE GLASSES, I THOUGHT THEY WOULD BE COOL BUT I COULDN'T FIND IT. THE FIRST CONTACT LENSES, NOT A COPY OF THE ACTUAL GLASSES BUT THE FIRST PICTURE, THE FIRST CONTACT LENSs WERE MADE OUT OF GLASS IN THIS 18ATE, AND IN THE 1970S EXIMER LASER WAS DEVELOPED AND DR. TROKEL, USED IT ON CADAVERRERS AND LIVE RABBIT AND MONKEY CORNEAS, AND IN 1988 A 60 YEAR-OLD WOMAN AGREED TO WITH THE FIRST PHOTOREFRACTIVE KERECTOMY PROCEDURE PERFORMED AND THEN IN THE 90S, TWO YEAR AN DOCTORS DISCOVERED HOW TO CREATE A CORNEAL FLAP INSTEAD OF JUST WORKING ON CORNEAL SURFACE AND IT WAS PRK TURNED INTO NOW LASIK, AND IN 2000, THIS ALLOWED THE CORNEA RESHAPING AND THEN CUT THE FLAP FROM THEY USED A SECOND LAZE TORE CUT THE FLAP INSTEAD OF A BLADE. NOW NOT MANY OF YOU ARE OLD ENOUGH TO UNDERSTAND PRESCRIBING BIOPIA, YET, BUT TRUST ME YOU WILL ALL GET THERE AND I LIKE TO SAY THERE ARE MANY STAGES OF PRESCRIBING BIOPIA, YOU HAVE THE DENIAL PHASE WHERE YOU DO THIS .... OH YEAH, I CAN SEE. THEN YOU HAVE THE ACCEPTANCE PHASE AND YOU SHOP FOR THE PAIR OF GLASSES THAT ARE FASHIONABLE, THE RIGHT COLOR AND SHAPE FOR YOUR PHASE AND THEN YOU YOU GET TO A PHASE WHERE YOU DON'T CARE ANYWHERE YOU HAVE A PAIR IN EVERY ROOM OF YOUR HOUSE, IN YOUR PURSE, YOU ALSO HAVE A PAIR WITH YOU. NO PRESCRIBING BIOPIA CANNOT EFFECT CORNEA DIRECTLY BUT AN ENGINEER AT THE UNIVERSITY OF WISCONSIN DECIDED HE WILL HELP THE CORNEA CORRECTLY REFRACT FOR WHAT THE LENS CAN'T DO ON ITS OWN. AND HE'S 38 YEARS OLD AND HE GOT--AND I--NIH DIRECTOR'S NEW INNOVATOR AWARD AND HE SEES ON 38--AND I WANT TO BE THE FIRST PERSON TO RUES THIS 38 WHEN I'M IN MY 40S BECAUSE I DON'T WANT TO HAVE GLASSES AND HE, BEING AN ENGINEER HAS THREE CHALLENGING ENGINEERING COMPONENT TO THE CONTACT LENS, THE CENTER OF THE LENS IS A TUNEABLE LIQUID LENS SO IT COVERS YOUR PUPIL AND MADE FROM SILICONE WATER INTERFACE, THAT IS A THERMOSENSITIVE HYDROGEL THAT CHANGES SHAPE BASED ON THE THERMOSENSITIVE HYDROGEL, AND PUTTING SENSORS OR CONTROLS ELECTRONICS FOR AUTOFOCUSING LIKE A CAMERA. DR. GINNING REALIZES HE HAS TO HAVE A POWER SOURCE TO SUPPLY THESE, TO SUPPLY POWERS TO THESE SENSORS AND CONTROL ELECTRONICS AND HE KNOWS THAT YOU CAN'T PUT THE SMALLEST BATTERY IN A CONTACT LENS SO HE'S GOING TO HARVEST ENERGY FROM THE ENVIRONMENT SO AROUND THE PERIPHERY OF THE CONTACT LENS SHE'S GOING TO PUT OTHER SMALL ENGINEERING COMPONENTS CONSISTING OF SMALL SILICONE NANO WIRES AND A LOT OF ENGINEERING STUFF I DON'T REALLY UNDERSTAND AND HE'S GOING TO DEVELOP THESE LITTLE COMPONENTS SO THAT IT NOT ONLY HARVESTS ENERGY FROM THE ENVIRONMENTS SO IT STORES THEM SO THIS CONTACT LENS IS FUNCTIONAL FOR A COUPLE HOURS WHEN THE ENVIRONMENTAL SOURCE IS WEAK OR GONE FOR THESE CONTACT LENSES. AND THE THIRD CHALLENGE FOR THIS ENGINEER IS GETTING ALL THESE COMPONENTS MOLDING TO A CONTACT LENS, FLEXIBLE MATERIAL AND HE WANTS TO USE CONTACT LENSES AVAILABLE THAT SO THAT THERE'S PATIENT, SAFETY AND COMFORT THERE AND HE WILL CREATE SPECIAL CONLENS TO PUT THEM IN AND TAKE THEM OUT SO YOU STORE THEM OVERNIGHT WITH THE SYSTEM IS TAKE THEM IN THERE, AND FULLY CHARGED AND READY TO GO. AND HE IN HIS LAST YEAR OF HIS AWARD AND HE HAS CREATED ACCORDING TO A REPORT TO US, HE HAS THE CAM OPPOSITE BEHAVIORIAL PHENOTYPENTS AND ABOUT TO PUT THEM IN THE CONTACT LENS. SO CROSS YOUR FINGERS, WE'LL SEE WHERE THIS GOES. NOW I WILL SWITCH TO THE THIRD SUPER POWER WHICH IS THE CORNEAL NERVE. THESE ARE SUPPLIED BY THE CENTRAL AND TRIGEMINAL NETWORK AND THEY RECEIVE MECHANICAL AND NERVE AND CHEMICAL PAIN RESPONSES SO YOU WOULD DRAW WITH THE STIMULI AND THE THEY ALTS WORK TO PRODUCE TROPH IC FACTORS TO MAINTAIN A CORNEA, AND I FEEL WE HAVE VERY FEW INVESTIGATORS INVOLVING CORNEAL NERVE NEGLIGENCE THE PORTFOLIO AND THE INVESTIGATORS WE HAVE INVOLVING CORNEAL NERVES ARE LOOKING AT ABNORMAL DRY EYE SENSATIONS FOR PEOPLE WHO HAVE DRY EYE THAT'S RESPONDING TO TREATMENT OR MAYBE IT'S RESOLVED AND THEY HAVE THE DRY EYE SENSATIONS IN THESE EYES AND THEY WONDER WHERE THESE NERVES CONTINUOUSLY FIRE WHEN STEMMULATED SO THIS IS AN AREA THAT THE PORTFOLIO THEY THINK WE COULD USE SOME MORE SUPER MOR. YOU COULD USE SOME MORE HELP. NOW I'M GOING TO SWITCH TOPICS TO CORNEAL TRANSPLANT. CAN YOU JUST TRANSPLANT THE CORNEA AND PUT A NEW ONE IN. IN 1905--BUT FORTUNATELY FOR CORNEA RESEARCHERS YES WE CAN TRANSPLANT THE CORNEA BUT THAT'S NOT A HUNDRED PERCENT A SURE THING FOR EVERYBODY YET. IN 1905, THE FIRST SUCCESSFUL HUMAN CORNEAL TRANSPLANT WAS PERFORMED AND YOU CAN SEE ON THE SIDE, IT WAS AFTER MANY DECADES OF TRIAL AND ERROR FROM TRANSPLANTATION TO GASLE TO USING A XENOGRAFT IN A HUMAN AND IT WAS NOT SUCCESSFUL NOT SURPRISINGLY. AND THEY CAME ALONG IN 905 WITH ANT SEPTIC AND ISSUES AND ANESTHESIOLOGY, AND MORE ROUTINE TODAY, DIDN'T OCCUR IN ADVANCEMENTS OF HYPOCORTICO STEROIDS AND ANTIBIOTICS AND ADVANCES IN SURGICAL EQUIPMENT SUCHS THE TREE BYING THE OPTICAL IMAGESERATING MACROSCOPE, FUTURE MATERIAL AND SO FORTH. NOW TAKE A MINUTE AND KIND OF GIVE YOU A BRIEF DIAGRAM,--SOME DOCTORS ARE CRINGING BECAUSE IT MAKE ITS TOO SIMPLE. HERE HAVE YOU AT PATIENT HOPING WITH THE RETRACTOR AND THERE'S A TREE THAT PUNCHES OUT THE CORNEA, COOKER CUTTER, PART OF THE CORNEA YOU WANT TO REMOVE AND THEN YOU TAKE IN AND CUT OUT THE PIECE OF THE CORNEA OR THE PIECE OR SECTION OF THE CORNEA YOU WANT TO REPLACE, YOU PUT THE DONOR IN THIS BECAUSE IT ALWAYS FITS RIGHT IN THERE PERFECTLY LIKE IT WAS MADE TO AND THEN YOU METICULOUSLY SUTURE IT IN AND CAN TELL YOU HAVING TRIED THIS THAT THIS TAKES A LOTS OF PRACTICE GETTING THOSE SUTURES PUT IN THERE, SO TODAY CORNEAL TRANSPLANTS ARE SUCCESSFUL 80 OR 90% OF THE TIME BUT THERE ARE COMPLICATIONS THAT ARE ASSOCIATED WITH THE CORNEAL TRANSPLANTS, EYE INFECTIONS CATARACTS, GLAUCOMA, VISION PROGRAMS, NOT HAVING A NORMAL REFRACTION BECAUSE YOU'RE TAKING IN SOMEONE ELSE'S CORNEA, AND PUTTING IT IN YOUR EYE KLF-TWO REALLY DOESN'T MASK THAT, I SAY THE MOST COMMON COMPLICATION IS REJECTION AND THAT OCCURS 20% OF THE TIME ROUGHLY. AND EVEN THOUGH SOME PATIENT HIS REJECTION, YOU CAN IT CAN BE 10-20 YEARS SO CAN YOU LIVE FOR A LONG TIME WITH THE CORNEAL TRANSPLANT BUT THE CONCERN IS NOW, THE AVAILABLE OF A CORNEA FOR PATIENT WHO IS NEED THEM. SO ONE OF THE TWO REASONS THEY'RE LESS AVAILABLE IS THE AGING POPULATION. NOW IT'S BEEN SHOWN THAT IT DOESN'T MATTER HOW OLD THE CORNEA IS THAT YOU USE, AS LONG AS THE ENDOTHELIAL CELLS THE SINGLE LAYER ON THE BACK PART OF YOUR EYE THEY ARE HIGH ENOUGH IN NUMBER BECAUSE THEY CONTROL THE DELIEDERATION OF THE CORNEA AND KEEP IT CLEAR AND AS YOU AGE, YOU LIEUS YOUR ENDOTHELIAL CELL COUNT SO YOU CATCH THOSE ENDOTHELIAL CELLS AND THE OTHER CONCERN IS MANY PEOPLE ARE HAVING LACIC PROCEDURES OTHER REFRACTIVE SURGERIES NOW WHICH MAKES THAT CORNEA NO LONGER AVAILABLE FOR TRANSPLANTATION. SO DUE TO THIS, THERE ARE ARTIFICIAL CORNEAS ON THE MARKET SO PEOPLE LOOK AT WAYS TO TAKE--NOT USE A HUMAN CORNEA FOR A HUMAN BUT TAKE AND CREATE ARTIFICIAL CORNEA LIKE POLYMETHALKALKATE, BUT THE PROBLEM WITH THE BOSTON KPRO IS THAT YOU'RE REQUIRED TO HAVE A DONOR CORNEA OR A CORNEAL TRANSPLANT, THE SUTURE THE PROSTHETIC INTO AND THEN YOU TAKE THAT AND PUT THAT INTO YOUR HOST CORNEA, SO NOW HAVE YOU ALL THE COMPLICATIONS OF THE CORNEA TRANSPLANT PLUS, ADDITIONAL TRANSPLAINT OF THE ARTIFICIAL CORNEA WHICH INCLUDE INTRUSION AND INFECTION, NOW THE ALPHA CORE IS THE OTHER ON THE MARKET AND IT'S NICE BECAUSE YOU DON'T HAVE TO HAVE A CORNEA TO INSERT IT INTO, CAN YOU INSERT INTO YOUR HOST EYE. IT DOES REQUIRE A POCKET THAT TAKES ABOUT--A METICULOUS THREE HOUR PERIOD OF TIME TO DISSECT THIS POCKET TO PUT THIS PROSTHETIC INTO AND IT AS A DIFFERENT SET OF COMPLICATIONS. FROM'S STILL THE ADDED RISK OF EXTRUSION AND INFECTION, BUT IT TAKESSA ABOUT THREE MONTHS FOR THIS POCKET TO HEAL AND DURING THIS TIME, THE PATIENT IS NOT ABLE TO SEE OUT OF THIS EYE WHILE YOU WAIT THIS POCKET TO HEAL. NOW DR. SHUI, IS WORKING ON WHAT CAUSES THE KERRA CLEAR, IT'S APPROVED USE IN THE AMERICA AND AWAITING TRIALS IN THE UNITED STATES, YOU CAN SEE THE CORNEA ON THE LEFT NEEDS A TRANSPLANT AND THE PICTURE ON THE RIGHT WHERE THE KERRA CLEAR HAS BEEN PLACED IN THE PATIENT AND NICE THING ABOUT THE KERRA CLEAR IS THAT IT'S MADE OF A FLEXIBILITY APPROXIMATELY MERSO YOU INSERT IT, YOU POP INTO THE CORNEA, INTO A PATE THICKNESS WITH THE LASER WITH WITH 33.5-MILLIMETER INCISION SO THIS DECREASE TOGS 15 MINUTES VERSUS SEVERAL HOURS WITH CORNEAL TRANSPLANTS OR OTHER PROSTHETICS AND THE OTHER NICE THING ABOUT THIS PROSTHETIC, CHANCE OF INFECTION AND IMMEDIATE VISUAL RECOVERY AND ACCORDING TO DR. CHUI, YOU CAN CONTROL ASTIGMATISM AND REFRACTIVE AIR WITH THIS POLYMER AS WELL. SO I HOPE THAT I--YOU MAY HAVE BEEN THINKING THROUGH THIS TALK THAT IT'S JUST THE DUST COVER, BUT I HOPE I LEAVE YOU WITH THE IMPRESSION THAT IT IS A DUST COVER BUT IT HAS A LOT OF IMPRESSIVE CAPABILITIES WITH IT. >> THANK YOU ON BEHALF OF A CORNEA CONTIGERRENT. GEORGIAIA, IS ANYBODY LOOKING WITH THE THEME AND REGENERATION AND SO FORTH, IS ANYBODY EXPLORING HOW TO GET THE ENDOTHELIAL CELLS OF THE CORNEA BE ABLE TO DIVIDE? BECAUSE THEY DO IN LOTS OF SPECIES, RIGHT? >> YEAH, CURRENTLY THE WORK I'M SEEING THAT WE'RE FUBBING NOW, I'M NOT SURE THEY LOOKEDDA THE IT PREVIOUSLY AND I'M NOT AWARE, BUT THERE'S AN INVESTIGATOR THAT IS ACTUALLY THINKING THEY DON'T REGENERATE BECAUSE OF THE WAY THEY'RE CONNECTED TO OTHER ENDOTHELIAL CELLS, ENDOTHELIAL--INTERACTION PROHIBITS THEM FROM REGENERATING SO, I'M NOT SURE, TO ANSWER YOUR QUESTION, IF ANYBODY'S LOOKING. >> IN JAPAN THEY'RE USING A ROCK INHIBITOR TOPICAL EYE DROP TO TRY TO DO THIS. STHRKS THANK YOU. >> ALL RIGHT, I'M SURE EVERYBODY'S READY FOR LUNCH. >> SO WE DO HAVE TIME TO OPEN THE FLOOR UP FOR GENERAL COUNCIL DISCUSSION, IF ANY ARE ANY TOPICS PEOPLE WANT TO RAISE, STEVE DO YOU WANT TO SHARE THE TELECONFERENCE YOU SAT IN ON OR? ANY HIGHLIGHTS. >> YEAH, ACTUALLY I DIDN'T REALLY COME WITH THAT IN MIND EMPLOY SO I'M SORT OF AN NEI PERSON ON THIS BD2K WHICH INITIATIVE, VERY, VERY BRIEFLY, COUPLE YEARS AGO WE'RE NOW LIVE IN THIS WORLD OF BIG DATA. NAWAS CLEAR BUT WHAT WAS ALSO CLEAR IS THAT MOST OF US DON'T HAVE THE FAINTEST CLUE HOW TO LIVE IN THAT WORLD, WE DON'T HAVE THE EXPERTISE, OR TOOLS AND THE CLEARLY THIS IS THE WAY OF THE FUTURE, SO, IT WAS THIS INITIATIVE TO TRY AND PROVIDE SOME GUIDANCE IN TERMS OF DEVELOPING TOOLS. WHEN WE THINK ABOUT BIG DATA WE'RE THINKING NOT ONLY ABOUT, SORT OF ELECTRONIC MEDICAL RECORDS, THOSE KINDS OF THINGS BUT GENOMICS, TRANSCRIPTOMICS, ALL KINDS OF AREAS THAT MIGHT FALL UNDER THAL GENERAL UMBRELLA. EMPLOY SO THE WAY THIS IS HAS BEEN DONE IS THIS IS SORT OF A TRANSNIH INITIATIVE, ESSENTIALLY BUILT AROUND, I THINK THERE ARE 13 CENTERS AROUND THE COUNTRY. EACH ONE WITH A DIFFERENT FOCUS, ONE FOR EXAMPLE IS DEVELOPING TECHNOLOGIES TO MONITOR SORT OF MOBILE DEVICES AS A WAY OF FOLLOWING THROUGH HEALTH OR ALL KINDS OF THINGS ON THE ELECTRONIC MEDICAL RECORDS. THERE'S A BIG INITIATIVE FOR EXAMPLE ON PROFILING DRUG INTERACTIONS AND MASSIVE SCREENING OF ENORM NORMOUS MEMBERS OF COMPOUNDS AGAINST CELL TYPES FOR EXAMPLE. THESE CENTERS ARE SORT OF THE CORE OF THE EFFORT SO AND MANY OTHER INITIATIVES ARE NOW LAID ON THESE CENTERS FOR EXAMPLE, DEVELOPING SHALL WE SAY TRAINING PROGRAMS TO BRING PEOPLE UP TO SPEED. SO THESE WOULDED KNOW HOWESED AND LOCATED IN THE VARIOUS CENTERS SO MUCH AS WE HERE SORT OF HAVE A SUPERVISORY ROLE SO THAT NEW INITIATIVES ARE DISCUSSED ONCE PROJECTS HAVE BEEN WITH YOU, YOU KNOW, WE WOULD HAVE TO TAKE A ELECTRIC AT THEM IN THAT SETTING. THIS IS--WE DON'T ACTUALLY PHYSICALLY GATHER. THIS IS ALL DONE THROUGH THE INTERNET. I SHOULD SAY I SHOULD HAVE BROUGHT SOME MORE LITERATURE, IF YOU ACTUALLY ARE INTERESTED, YOU ACCOUNTED IF YOU JUST GO TO THE BD2K WEB SITE, THEY PUBLISH ALL THE MINUTES AND WHAT WAS DISCUSSED LAST TIME. DISCIPLINARY BRING A LITTLE BIT OF PAPERWORK AS WELL IF ANYBODY'S REALLY INTERESTED. FROM OUR POINT OF VIEW I DON'T THINK OF THIS PARTICULAR MEETING THERE WAS INTERESTING VERY PIVOTAL, THERE WAS A LOT OF DISCUSSION OF NEW TRAINING INITIATIVES AND SO FORTH THERE ARE LOTS OF DISCUSSIONS, SOME DRY MATERIAL ABOUT METADATA STANDARDS AND WHEN THESE--WHEN DAT WASETS ARE GENERATED WHO WILL HAVE THEM--DATA SETS ARE GENERATED WHO WILL HAVE THEM, WHO WILL ACCESS THEM, WHERE WILL THEY BE HOUSED? WHAT WILL FILE FORME AT BE SO IT'S NOT SUPER EXCITING STUFF SO IT'S ALL VERY NECESSARY SO A LOT OF THE EFFORT COMES FROM THE NATIONAL LIBRARY OF MEDICINE WHICH COORDINATES THE BIG EFFORT. I DON'T THINK WE HAVE IT IN TERMS OF THREES 13 CENTERS, I DON'T THINK WE REALLY HAVE LIKE AN EYE CENTER, ARE ALTHOUGH I'M SURE THERE ARE--THERE'S PERIPHERAL CONNECTIONS TO THE VISUAL RESEARCH COMMUNICATE COMMUNITY. SO THAT'S THAT. LET. >> SO I WOULD REALLY LIKE TO ENCOURAGE TO YOU GO BACK TO I DIDN'T DEPARTMENTS AND COLLEAGUES IF YOU HAVE PEOPLE THAT ARE INTERESTED IN THIS ISSUE OF BIG DATA IN A WAY THAT IT MIGHT HELP THE VISION COMMUNITY BECAUSE THIS IS A TRANSNIH ACTIVITY AND WE ARE TAPPED TO THE TUNE OF A MILLION DOLLARS PER YEAR TO SUPPORT THIS AND SO FAR WE'VE BEEN VERY DISAPPOINTED THAT NOBODY IN THE VISION COMMUNITY HAS STEPPED UP AND PLAYED ANY KIND OF ROLE OR APPLIED FOR ANY OF THE GRANTS THAT ARE OFFERED UNDER THIS PROGRAM. >> [INDISCERNIBLE]. WILL. >> SO IF YOU HAVE PEOPLE THAT ARE INTERESTED, PLEASE HAVE THEM TALK TO US OR GO TO THE BD2K WEB PAGE AND LOOK AT THE FUNDING ANNOUNCEMENTS AND SEE IF WE CAN'T GET THE VISION COMMUNITY INVOLVED MORE IN THIS. >> AND YEAH, AND TO FOLLOW UP ON THAT, SO, I WOULD BE HAPPY TO BE APPOINTED CONTACT THERE AS WELL BECAUSE I DO SIT THERE AND LISTEN TO ALL OF THIS. SO I HAVE A LITTLE BIT OF A FEEL FOR WHAT SORT OF FLIES AND WHAT DOESN'T SO I WILL BE HAPPY TO DISCUSS THAT WITH ANYBODY TO TALK ABOUT. >> IT SEEMS LIKE THERE ARE SO MANY OF OUR RESEARCHERS THAT ARE INVOLVED IN THE BRAIN INITIATIVE AND THERE'S HUGE AMOUNTS OF DATA THAT ARE GENERATED THROUGH THESE BRAIN INITIATIVE PROJECTS, THE CONNECTOME AND ALL OF THIS WEALTH OF SECONVINCE DATA THAT THERE NEEDS TO BE EFFORT TO INSURE THERE IS THAT PIPELINE TO PROPERLY MANAGE THOSE LARGE AMOUNTS OF DATA SO I'M WONDERING IF IT'S WORTH IT TO GO TO THOSE RESEARCHERS AND ENCOURAGE THEM, YOU KNOW, IS THERE SOME REQUIREMENT FOR THESE MECHANISMS ARE ARCHIVING AND MANAGING THE DATA, CAN WE DEVELOP THE BIG DATA APPROACHES SO THAT IT WILL BE ACCEPTABLE AND USEABLE BY THE COMMUNITY. SO IT'S PROBABLY WHERE WHERE A LOT OF IT, THE HUMAN GENETIC WORK IS WHERE THE BIGGEST IMPACT, AND IMMEDIATE IMPACT MAY BE. >> THERE ARE DISCUSSIONS ABOUT COMPETING POWER BECAUSE THAT BECOMES AN ISSUE IN THINKING ABOUT THE PROJECTS AND THIS SPACE, SO, I'M--YOU KNOW I FEEL IN BIG DATA ALL THE TIME AND YOU KNOW ONE PROJECT COULD BE JUST TO SEE IF WE COULD DO AN AGNOSTIC SEARCH OF LARGE DATABASE, SEE IF THERE ARE DRUGS WE CAN REPURPOSE FOR THE TREATMENT OF GLAUCOMA AND AN APPROACH LIKE THAT WOULD REQUIRE A TREMENDOUS AMOUNT OF COMPUTING POWER AND THAT'S THE RATE LIMITING STEP IN A PROJECT LIKE THAT, IS THERE ANY DISCUSSION ABOUT THAT THIS GROUP? >> THESE MUST BE ISSUES THAT PEOPLE HAVE THOUGHT ABOUT. >> LEVERAGE EXTRAORDINARY AMOUNT OF COMPUTING POWER, SO IT'S DIFFERENT, WE DO THIS--I FEEL WE'RE DISCONNECT FROM EACH OTHER, YOUR POINT IS A GOOD ONE SO MAYBE, YOU KNOW SO WHO SHOULD YOU TALK TO HERE, YOU KNOW? SO THIS IS--THIS IS THE PROBLEM, I THINK, I GUESS THAT'S MY JOB ACTUALLY. >> NOW THAT I THINK ABOUT IT. [LAUGHTER] >> I HAD A QUESTION ABOUT PRECISION MEDICINE WHICH WE DISCUSSED PREVIOUSLY AND I WONDERED IF THERE WERE ANY UPDATES? I READ IN THE BOSTON GLOBE A COUPLE DAYS AGO THAT ROBERT CRAFT THE OWNER OF THE PATRIOTS HAS DONATED $20 MILLION TO PRECISION MEDICINE BUT NONAPOPTOTIC TO A MEDICAL SCHOOL TO THE HARVARD OBJECTS SCHOOL SO I WONDERED IF THERE ARE ANY UPDATES FROM THE MEDICAL GUYS? >> THERE IS NOT MUCH OF AN UPDATE, THERE IS A DIRECTOR FOR THAT APPOINTED. SOMEONE COMING OUT OF I THINK IT'S GOOGLE. WORKING IN THE BIG DATA LIFE SCIENCE, BIG DATA GOOGLE, THE EFFORT AT THIS POINT IS TO GET THINGS UP AND RUNNING. THE FIRST PASS ON SELECTING HEALTHCARE NETWORKS THAT CAN PROVIDE LARGE NUMBERS OF PATIENTS AND APPROPRIATE PATIENT RECORDS, FIRST BASS ON THAT HAS BEEN DONE MORE NOW, PENDING MONEY IS COMING AGAIN THIS YEAR FROM CONGRESS. THE MONEY IS ABOUT FOUR/FIFTHS NIH AND ONE/FIFTH IS NEI, WITH TARGETED CANCER GENOMICS THAT IS UNDERWAY SO THE UPDATE IS THINGS ARE VIGOROUSLY IN-PROCESS BUT THERE'S NOTHING SUBSTANTIALLY DIFFERENT NOW THAN THERE WAS THE LAST TIME. >> HOW ABOUT THE FLATTENED BUDGETS FOR THE, NEI AND IN THE REDUCTION IN THE EFFORTS? SO IS THERE ANY WAY TO THINK ABOUT THIS IN A NOVEL ANGLE. SO JUST TO THROW OUT SOME IDEA--SOME ASPECTS OF OF THE PORTFOLIO ARE RELATED TO COMMERCIAL ACTIVITY. IS IT POSSIBLE TO GET COMPANY ANNIES TO MAYBE INFUSE MONEY INTO THE NEI. >> SO WE HAVE SBIR SMALL BUSINESS INITIATIVE THAT IS A CONGRESSIONAL MANDATE SET ASIDE OUT OF OUR BUDGET IF IT WERE SET ASIDE OUTSIDE FUNDS IT WOULD NOT REMOVE OUR OBLIGATION TO PUT MONEY INTO THAT. IT IS THREE--3.5%. IT WAS UNDER THREE% RECENTLY. CONGRESS HAS A BIG INTEREST IN THIS AND THE NUMBER IS GOING UP SO GOOD QUESTION, GOOD PROPOSAL TO GET OUTSIDE MONIES TO SUPPLEMENT THAT, BUT IT WOULD BE A SUPPLEMENT, IT WOULD NOT BE A REPLACEMENT. >> I SUSPECT THIS IS ALREADY HAPPENING BUT WHEN I THINK ABOUT BIG DATA I DON'T KNOW HOW EXACTLY HOW TO CONNECT THE DOTS ON THIS BUT ALMOST BY DEFINITION, NO EFFICACY TRIAL IS POWERED TO LOOK AT THE INCIDENCE OF SEVERE BUT UNCOMMON SIDE EFFECTS EVEN A 50% INCREASE WILL NOT BE DETECTABLE EVEN BY THE LARGEST CLINICAL TRIALS RUN BY COMPANIES. AND THE PHASE FOUR MARKETING ANALYSIS IS SOMETHING THAT'S HEAVILY BIASED AS CAN YOU IMAGINE AND ONE WAY TO GENERATE THE EQUIVALENT AND EVEN BETTER DATABASE, AND THE VALUE OF DOING THAT, FINANCIAL VALUE OF DOING THAT IS THE GOVERNMENT CAN SAVE MONEY BY LOOKING AT REAL WORLD OUTCOMES FOR DIFFERENT PRODUCTS AND THEN LOOK AT PRICING RETROSPECTIVELY. THE QUESTION I'M ASKING IS WHAT PART OF NIH IS THE PART THAT FITS WITH THIS PROJECT. I MEAN, LIKE I KNOW THERE'S A CLINICAL TRIALS PART OF NEI, I IMAGINE THERE'S A CLINICAL TRIALS PART OF NIH AND DO THEY DO THIS ALREADY OR ARE THEY PLANNING TO DO? , SO YOU'RE RIGHT IN THAT NEI DOESN'T HAVE THAT IN OUR CLINICAL TRIAL PORTFOLIO BUT THEY ARE A HUGE [INDISCERNIBLE] WITH A LOT TO DO AND SOME OF THE PARTS FOR TECHNOLOGY FOR THE INSTITUTES FOR THE NIAID, BUT IN RELATION TO THE BIG DATA COMPONENTS TO EMPHASIZE WHAT STEVE HAS ALREADY INDICATED AT THE NCI RECENTLY LAUNCHED THE NCI DATA COMMONS, BIG SPLASH AT THE MEETING AND PROVIDE THAT IN THE CONTEXT OF THE NCI PRECISION MEDICINE AND MOON SHOT. SO, THAT'S AT THE NCI LEVEL. AT THE NIH LEVEL, THE BD2K CONCEPT OF AN NIH COMMON IS BEING DISCUSSED. THIS WOULD BE--THIS WOULD NOT BE JUST BE A PLACE WHERE FOLKS WILL PUT THE DATA AS A REPOSITORY. THIS WILL PROVIDE THE INFRASTRUCTURE ARE IF YOU TO COMPUTE. TO ANALYZE AND SHARE TOOLS AND FOR THE COMMUNITY TO DEVELOP DATA STANDARDS. AND IT'S GOING TO BE PRESENTED--I THINK IT'S ALREADY PRESENTED TO THE DIRECTOR ADVISORY COUNCIL, THE CONCEPT, IT'S GOING TO HAVE A NICE MORE, FOCUS MORE ON THE BD2K MONEY TO DO THAT. >> SO JUST TWO THINGS BEFORE WE BREAK FOR LUNCH. ONE IS THAT OUR NEI PHOTOGRAPHER DUSTIN HAYES WANTS TO GET A PICTURE OF ALL THE COUNCIL MEMBERS SO WE THOUGHT WE WOULD DO THAT BEFORE YOU HEAD INTO THE CAFE OR OUTSIDE OR WHEREVER YOU'RE GOING FOR LUNCH. THE SO THAT'S JUST ON THE FIRST FLOOR. IT'S RIGHT NEAR WHERE YOU CAME IN THE FRONT DOORS OF THE BUILDING. SO, IF YOU COULD ALL JUST GATHER UP THERE FOR A FEW MINUTES. AND THEN LET'S TAKE ABOUT 45 MINUTES FOR LUNCH AND GATHER BACK HERE SAY BETWEEN ONE AND 1:10 THIS AFTERNOON?