>> I'D LIKE TO WELCOME YOU TO THE 146th MEETING OF THE NATIONAL ADVISORY EYE COUNCIL, I'M PAUL SHEEHY, EXECUTIVE SECRETARY OF THE COUNCIL. BEFORE WE GO ANY FURTHER I WOULD LIKE TO TELL YOU THIS IS BEING WEBCAST, IN OPEN SESSION, SO YOUR CHILDREN MAY BE WATCHING. SO WHY DON'T WE START WITH INTRODUCTIONS STARTING WITH DR. PASQUALE AND WE'LL GO AROUND. >> GOOD MORNING, LOUIS PASQUALE, I'M AT HARVARD, GLAUCOMA SPECIALIST. >> GOOD MORNING, DOUGLAS REE, GLAUCOMA SPECIALIST AT UNIVERSITY HOSPITAL, CASE WESTERN IN CLEVELAND, OHIO. >> GOOD MORNING, MONICA VETTER, UNIVERSITY OF UTAH. >> GOOD MORNING, DENNIS LEVI, UNIVERSITY OF CALIFORNIA AT BERKELEY, SCHOOL OF OP TOM TRI. >> BELINDA SETO. >> PAUL RECEIVING, DIRECTOR OF THE NATIONAL EYE INSTITUTE. >> MICHAEL STIMUS, DIRECTOR OF EXTRAMURAL SCIENCE PROGRAMS. >> I'M CAROL MESA FROM COLUMBIA AND NEUROSCIENCE, ALSO ASSOCIATED WITH OPHTHALMOLOGY. >> JANE GUAZDA, NEW ENGLAND COLLEGE OF OP TOM TRIIN BUSINESS TON. >> STEPHEN McCLOUD, ( INAUDIBLE). >> (INAUDIBLE) CALIFORNIA DAVIS. >> THANK YOU. WE WILL START WITH -- TRY TO GET& SOME BUSINESS DONE, THEN WE'LL HAVE A SERIES OF PRESENTATIONS ON SCIENCE AND NIH OPERATIONS, AND THAT WILL TAKE US MOSTLY THROUGH THE MORNING. THE IMMEDIATE ISSUE OF BUSINESS IS CONSIDERATION OF LAST COUNCIL MEETING'S MINUTES. THERE'S A COPY ON THE ELECTRNIC COUNCIL BOOK. IF YOU HAVEN'T READ IT, I ASSURE YOU IT'S A TERRIFIC AND RIVETTING READ, AND MOSTLY TRUE. SO ANY DISCUSSION? MOTION TO ACCEPT? AYE? >> AYE. >> THANK YOU. SO WITH THAT WE'LL MOVE TO A PRESENTATION FROM BLAIR FELDMAN -- OH. DR. SIEVING WILL REMARK. >> YES, GOOD MORNING. AND WELCOME TO THE 146th NATIONAL EYE ADVISORY COUNCIL. THANK YOU TO THE COUNCIL MEMBERS WHO ARE JOINING US TODAY. ONE MORE IS IN TRANSIT, EDDIE ALPHONSO, FROM MIAMI, FLORIDA, WAS CAUGHT IN PLANE TRAFFIC AND WEATHER IN THE D.C. AIRPORTS LAST NIGHT. WE HOPE THAT HE ARRIVES SAFELY. HIS LUGGAGE MAY PRECEDE HIM, BUT WE HOPE HE WILL BE HERE. LET ME JUST GIVE YOU A BIT OF OVERVIEW OF EVENTS THAT ARE HAPPENING AT THE NATIONAL EYE INSTITUTE, AND THINGS ACROSS THE NIH. FIRST, DR. FRANCIS COLLINS WILL REMAIN OR HAS BEEN REAPPOINTED AS THE NIH DIRECTOR. THAT WAS AN ANNOUNCEMENT BY THE WHITE HOUSE A WEEK AGO. WE ARE CERTAINLY PLEASED AT THAT. FRANCIS HAS TAKEN GOOD CARE OF THE NIH AS A WHOLE, AND HAS HAD SOME SPECIFIC INTEREST IN ACTIVITIES OF THE EYE INSTITUTE, SPECIFICALLY IN REGENERATIVE MEDICINE. AND THAT WORK OF EXPLORING POSSIBILITIES FOR iPSL THERAPIES IN THE FUTURE IS GOING ALONG IN ROBUST FASHION. PLEASED IN MAY 2017 TO DELIVER THE COMMENCEMENT ADDRESS AT THE COLLEGE OF OPTOMETRY, STATE COLLEGE OF NEW YORK, SUNY. THEY HAVE A FINE BUILDING RIGHT IN THE HEART OF THE CITY. THIS WAS AN INVITATION BY PRESIDENT DAVID HEATH, AND IT WAS A FINE OCCASION TO LOOK OUT OVER AN AUDIENCE OF PROUD GRADUATES, MANY OF WHOM ARE GOING INTO DIRECT PATIENT CARE, AND ARE ONE OF THE FRONT LINES OF THE EYE CARE SERVICES HERE IN THE UNITED STATES. AT THE SAME TIME, IT WAS A PLEASURE TO SPEND A DAY WITH A NUMBER OF THE RESEARCH FACULTY AT SUNY OPTOMETRY, MANY OF THESE NAMES BLOOMFIELD, ALONZO, KASEEM AZIDI, THE LAST TWO BROUGHT ME UP TO DATE ON IDEAS AND HOW THEY ARE PROCESSED FROM PHOTORECEPTORS AND MAINTAINED ALL THE WAY INTO CORTICAL CIRCUITS. THAT WAS A FINE, FINE OCCASION. IT IS ALSO GOOD TO NOTE THAT ANDREA FAU, OPTOMETRIST, IS PRESIDENT OF THE AMERICAN OPTOMETRIC ASSOCIATION, FACULTY AT SUNY COLLEGE OF OPTOMETRY. LET ME JUST GIVE A MENTION ON BUDGET, NOT TO PREEMPT KAREN COLBERT, DIRECTOR OF THE NEI BUDGET OFFICE, AND IN A MOMENT YOU'LL BE HEARING FROM BLAIR FELDMAN, WHO IS DEPUTY THERE. SHE WILL BE PROVIDING AN UPDATE ON THE BUDGET. I JUST WANT TO GIVE A WORD ABOUT THE CURRENT BUDGETS. BUDGETS USED TO BE SIMPLE. MONEY CAME IN, MONEY WENT OUT. PRETTY SIMPLE EQUATION. AND YEAR TO YEAR, YOU COULD EQUATE WHAT HAPPENS THIS YEAR TO AN INCREMENT OR DECREMENT FROM THE YEAR PRIOR. THAT HAS REALLY CHANGED AT THIS POINT. AND AS EVERYONE AROUND THE TABLE KNOWS, THERE ARE A NUMBER OF BUDGET NUMBERS THAT ARE IN THE WIND, AND IT'S REALLY COMPARING APPLES AND ORANGES, AS BLAIR WILL MENTION LATER. LET ME TELL YOU SOMETHING ABOUT THE FY 2017 NIH BUDGET. I'M GOING TO GIVE YOU THREE PERCENT NUMBERS. 6.2%, 4.1%, AND 3.4%. 6.2%, THAT IS THE INCREMENT OF THE TOTAL AGGREGATE NIH BUDGET THIS YEAR COMPARED TO LAST YEAR. THEN DROPPING TO 3.4%, THAT IS THE NET NEI INCREASE THIS YEAR COMPARED TO LAST YEAR. HOWEVER, THESE NUMBERS ARE APPLES AND ORANGES. THE 6.2% INCLUDES $630 MILLION, A VERY TARGETED MONIES, MONIES THAT WILL NOT FLOW THROUGH THE EYE INSTITUTE BUT WILL FLOW THROUGH OTHER INSTITUTES. THAT WILL INCLUDE $400 MILLION FOR ALZHEIMER'S RESEARCH, $100 MILLION FOR BRAIN, SOME OF THAT IN FACT DOES FLOW THROUGH THE EYE INSTITUTE. PRECISION MEDICINE, $80 MILLION. ANTIMICROBIAL RESISTANCE $50 MILLION. THAT TOTALS $630 MILLION. SO WHEN ONE THINKS ABOUT THE NIH BUDGET, PERHAPS A BETTER WAY TO THINK ABOUT IT IS THAT THE INCREMENT THIS YEAR COMPARED TO LAST YEAR IS 4.1%, AND THEN THERE ARE OTHER SPECIFIC TARGETED MONIES THAT INCREASE THE TOTAL PORTFOLIO TO 6.2%, NOW AT 4.1% VERSUS 3.4% FOR NEI. THERE'S ALSO AN ACCOUNTING, MAJOR ACCOUNTING CHANGE FOR THE NEI BUDGET, AND THAT IS THAT PREVIOUSLY THERE WAS AIDS MONEY THAT WAS -- IT'S BEING EXPENDED AT NIH, AND PART OF THAT WAS ALLOCATED THROUGH THE NEI BUDGET. THAT IS A $7 MILLION TRANSFER THAT IN YEARS PREVIOUS CAME INTO OUR BASE AND THEN IMMEDIATELY FLOWED OUT. WELL, AT THIS POINT THAT HAS NOW BEEN REMOVED FROM THE BASE, AND THAT TAKES US TO ABOUT THE 3.4% THAT IS ACTUALLY OUR BUDGET. SO IN FACT, LOOKING ACROSS NIH AND THE EYE INSTITUTE, THE EYE INSTITUTE IS FLOATING EQUALLY -- ESSENTIALLY EQUALLY WITH OTHER INSTITUTES, AFTER THE BUDGETING IS ACCOUNTED FOR. SIMILARLY, AS ONE LOOKS FORWARD TO THE 2018 BUDGET, THE ONLY NUMBER THAT IS ON THE TABLE AT THE MOMENT IS THAT OF THE PRESIDENT'S BUDGET, THE PRESIDENT'S PROPOSED NIH BUDGET. AND THERE THE NIH HAS A MAJOR STEP BACKWARDS. IT WILL REMAIN TO BE SEEN HOW THIS ACTUALLY PLAYS OUT IN CONGRESSIONAL BUDGETS. CONGRESS ULTIMATELY DECIDES AND APPROVES THE BUDGET. AND A NUMBER OF FACTORS ARE COMING INTO PLAY THIS YEAR. TWO ARE WORTH SPECIFICALLY MENTION, THAT IS THE SEQUESTRATION COMES BACK INTO PLAY IN 2018. THERE HAVE BEEN -- SEQUESTRATION IS A 10-YEAR EFFORT, IT WENT INTO EFFECT IN MARCH 2013. IT'S A 10-YEAR GOAL OF CUTTING $1.5 TRILLION FROM THE FEDERAL BUDGET. FISCAL YEARS FY16 AND 17 WERE ROLLED TOGETHER INTO A TWO-YEAR RESOLUTION. AND CONSEQUENTLY, WE HAVE NOT HEARD ANYTHING ABOUT SEQUESTRATION IN THE CURRENT YEAR OF FY17, BUT IT WILL COME BACK THIS NEXT YEAR AND HAVE TO BE DEALT WITH. THE SECOND AS I THINK WE'RE AWARE FROM READING NEWSPAPERS IS THAT THERE IS A DEBT CEILING, AND THAT IS GOING TO NEED TO BE DEALT WITH BY CONGRESS OVER THE SUMMER AND FALL MONTHS. SO GOING FORWARD ONE IS GOING TO HEAR A LOT -- A NUMBER OF DIFFERENT BUDGETS AND NUMBERS PROPOSED, AND I WOULD SIMPLY THANK THE NEI BUDGET OFFICE FOR BEING FULLY AWARE OF THE CURRENT STATE OF THINGS AND RESPONDING TO CALLS FOR PROPOSED BUDGETS FROM EACH OF THE INSTITUTES THAT ARE LOOKED AT, UP THE ROAD. SO LET'S NOT BE ALARMED YET. AND SIMPLY WORK THROUGH THE PROCESS OF FUNDING GOOD HIGH QUALITY SCIENCE. IN TERMS OF ADVOCACY FOR NIH, A MAJOR EVENT HAPPENED ON MAY 8th, WHICH WAS A WHITE HOUSE SUMMIT ON FEDERAL RESEARCH FUNDING. THAT WAS A SUBSTANTIAL EVENT THAT CAME ABOUT THROUGH EFFORTS OF BILL FORD, AN INVESTMENT BANKER IN NEW YORK CITY, AND REED CORDISH, WHO IS IN THE WHITE HOUSE, AS THE ASSISTANTS FOR INTRAGOVERNMENTAL AND TECHNOLOGY INITIATIVES. BILL FORD IS ON THE BOARDS OF ROCKEFELLER UNIVERSITY AND MEMORIAL SLOAN-KETTERING. AND BECAME AWARE OF POTENTIAL EFFECTS OF FEDERAL BUDGETS ON BIOMEDICAL FUNDING. SO A MEETING WAS CONVENED, AND YOU CAN GOOGLE THAT EVENT, IF YOU WISH, A FINE PICTURE THERE WITH THE PRESIDENT AND OTHERS IN THE WHITE HOUSE. THE INTENT OF THIS WAS TO LOOK AT THE WHOLE ECOSYSTEM THAT CONSTITUTES BIOMEDICAL FUNDING. AND TO CONSIDER WHAT CAN AND CANNOT BE PICKED UP BY PRIVATE INVESTMENT. THE BASIC UNDERPNNINGS OF UNDERSTANDING BIOLOGY, BASIC RESEARCH, IS SOMETHING THAT THE NIH DOES VERY WELL, AND THE IMPLICATIONS OF BUDGETS UP OR DOWN WAS CONSIDERED AT THAT EVENT, AMONG OTHERS WHO WERE THERE, FRANCIS COLLINS CERTAINLY REPRESENTING NIH, OTHERS RICK LIFTON, WHO IS CURRENTLY PRESIDENT OF ROCKEFELLER UNIVERSITY, CORI BARGMANN WHO HAS JUST MOVED TO THE CHAN ZUCKERBERG INITIATIVE IN PALO ALTO, HELEN HOBBS A KNOWN HEART RESEARCHER FROM UT SOUTHWESTERN AND OFFICIALS FROM THE WHITE HOUSE, INCLUDING IVANKA TRUMP. SO THE CLIMATE FOR BUDGETS FOR NIH IS BEING DULY CONSIDERED, AND I WOULD SIMPLY SAY STAY TUNED ON THAT. ONE OF THE THINGS THAT WE WILL BE HEARING ABOUT LATER IN THE MORNING FROM LARRY TABAK IS FUNDING OF YOUNG SCIENTISTS. LARRY, DR. TABAK, IS THE PRINCIPAL DEPUTY DIRECTOR OF NIH AND IS WORKING WITH ALL OF US AT NIH TO IMPLEMENT IDEAS TO PROTECT YOUNG INVESTIGATORS AS I THINK WE WILL HEAR WHEN LARRY IS HERE. THE NEI IS ACTUALLY DOING EXEMPLARY JOB OF THAT USING TOOLS THAT ARE ALREADY IN PLACE AT NIH. MEANWHILE, THE NIH HAS STRONG BIPARTISAN BICAMERAL SUPPORT IN CONGRESS, AND A NUMBER OF SENATORS AND REPRESENTATIVES ON THE HEALTH COMMITTEE ARE FULLY AWARE OF THE BENEFITS TO THE COUNTRY AND TO KNOWLEDGE OF FUNDING THROUGH NIH. IN TERMS OF YOUNG INVESTIGATORS I'D LIKE TO POINT OUT FOR YOUR INFORMATION THAT NEI FOR A NUMBER OF YEARS HAS PAID PARTICULAR ATTENTION TO THE YOUNG, YOUNG INVESTIGATORS, THOSE WHO ARE NOT YET APPLYING FOR FUNDING BUT WE HOPE WILL IN THE FUTURE. THIS IS A PROGRAM TO HAVE SUMMER INTERNS, YOUNG PEOPLE WHO ARE HIGH SCHOOL STUDENTS, COLLEGE STUDENTS, GRADUATE STUDENTS, MEDICAL STUDENTS, AND THIS PARTICULAR PROGRAM CALLED DIVRO IS FOCUSING ON AFRICAN-AMERICAN, LATINO, NATIVE AMERICAN YOUNG FLEDGLING SCIENTISTS, STANDING FOR DIVERSITY IN VISION RESEARCH AND OPHTHALMOLOGY. THIS WAS INITIATED IN 2011. AND THE POINT OF CONTACT IS DR. CAESAR PEREZ-GONZALEZ IN THE OFFICE OF THE SCIENTIFIC DIRECTOR. I'M MENTIONING THIS TO YOU BECAUSE THE WINDOW OF APPLICATION WILL BE COMING UP IN JUST A FEW MONTHS, STARTING IN NOVEMBER. AND RUNNING THROUGH THE WINTER MONTHS. AND IF YOU KNOW OF YOUNG INDIVIDUALS WHO FIT THE PROFILE, PLEASE CONTACT CAESAR ABOUT THIS. SO FAR, WE HAVE -- THIS PROGRAM HAS MENTORED 47 INTERNS, 8 MEDICAL STUDENTS, 6 GRADUATE STUDENTS, 29 COLLEGE STUDENTS, AND 7 HIGH SCHOOL STUDENTS. AND WE HAVE TAKEN A LOOK AT THE OUTCOMES, THE FUTURE PATHS OF THESE YOUNG FLEDGLING RESEARCH -- VISION RESEARCH SCIENTISTS, AND ARE PLEASED TO SEE THAT A NUMBER OF THEM HAVE GONE INTO PROFESSIONAL SCHOOLS, GRADUATE SCHOOLS AND MEDICAL SCHOOLS. SO, AGAIN, IF YOU KNOW OF SOMEONE WHO IS INTERESTED IN YOUR VICINITY, PLEASE TELL THEM THAT WE ARE LOOKING FOR THEM AND IF YOU'LL POINT THEM OUT WE'LL EVEN FIND THEM. I WOULD LIKE TO MENTION A NEW INITIATIVE THAT THE EYE INSTITUTE HAS LAUNCHED AS OF MAY 1, IT IS 3D ROCK. IT'S NOT A ROCK BAND. COULD BE, COULD BE. BUT THIS IS 3D RETINA ORGANOID CHALLENGE, ROC. THIS CAME ABOUT THROUGH CONGRESSIONAL INTEREST OF PETE SESSIONS AS I THINK YOU HAVE HEARD PREVIOUSLY. AND HAS TAKEN THE FORM OF A FEDERAL PRIZE COMPETITION, TARGETED AT GENERATING MINIATURE EYEBALLS OR AT LEAST RETINOID IN A DISH. SUCH WORK IS NOW ROBUST OVER THE LAST TWO YEARS, BUT IT HAS A WAYS TO GO, AND IT AFFORDS OPPORTUNITIES TO LOOK AT FUNDAMENTAL DEVELOPMENTAL BIOLOGY, BUT ALSO WITH AN EYE TOWARD RECAPITULATING AT LEAST SOME ASPECTS OF DISEASE IN A DISH. I WOULD THINK JEFF MESRIC, JEFF GORDON AND STEVE BECKER FOR WORK ON THIS OVER THE PAST YEAR. THIS IS COMING IN TWO STAGES WITH A TOTAL OF $1.1 MILLION IN PRIZE MONEY. THE TWO STAGES ARE FIRST TO GET IDEAS ON THE TABLE, HENCE CALLED THAT HAS A DEADLINE FOR SUBMISSION OF TWO MONTHS FROM NOW, AUGUST 1. NOT AN INSURMOUNTABLE HURDLE, BUT WE'RE HOPING TO GET A SET OF IDEAS PROPOSED THAT CAN THEN MOVE FORWARD INTO THE SECOND PHASE, WHICH WOULD BE TO DEVELOP THOSE IDEAS, AND SPECIFICALLY TO DEVELOP FUNCTIONAL RETINA ORGANOID PROTOTYPES, THAT WILL LAUNCH IN THE FALL OF THIS YEAR, FALL OF 2017. MULTIPLE WINNERS ARE PROBABLE, I WOULD SAY, BOTH FOR THE INITIAL $100,000 FOR THE IDEATION STAGE AND SUBSEQUENTLY FOR THE $1 MILLION IN PRIZE MONEY. THERE IS A SHORT NOTE ON THIS, FOR THOSE INTERESTED, IN THE ISSUE TODAY OF "NATURE." IT IS A PIECE THAT STEVE BECKER PUT TOGETHER TO INFORM A WIDE AUDIENCE OF THE AVAILABILITY OF THIS. LOOKING AT THE AGENDA THIS MORNING, IT IS A BUSY AGENDA, GRACE SHEN WILL GIVE US AN OVERVIEW OF THAT PROGRAM, WHAT IT STANDS AT THE MOMENT. JODY BLACK IS DEPUTIY DIRECTOR OF NIH OFFICE OF EXTRAMURAL RESEARCH AND WILL BE TALKING ABOUT CLINICAL TRIAL STEWARDSHIP ACTIVITY. AND THE DEFINITIONS OF A CLINICAL TRIAL. LISA NEUHOLD, ALSO NEI BUDGET PROGRAM DIRECTOR, RAN A GOOD COURSE AT ARVO, ORGANIZED THAT COURSE FOR THE SATURDAY BEFORE ARVO, AND WILL HAVE A REPORT ON THAT. STEVE BECKER WILL BRING US UP TO DATE ON THE LATEST EVENTS OF THE AUDACIOUS GOALS INITIATIVE, AND I WOULD REMIND YOU THAT THAT AGI INITIATIVE, WE ARE I BELIEVE TAKING GOOD CARE OF IT, BUT IT DOES REST IN THE HANDS OF COUNCIL. SO WE'RE LOOKING FOR SUGGESTIONS FROM YOU, COMMENTS FROM YOU ON AGI, THE CURRENT STATE OF IT AND WHERE IT CAN BE GOING. AND THEN FINALLY, JIM HANDA, A PHYSICIAN OPHTHALMOLOGIST FROM JOHNS HOPKINS WILL BE HERE, TO PROVIDE AN UPDATE ON THE AMD PATHOBIOLOGY WORKING GROUP, THAT IS A SUBSET OF EYE COUNCIL. IT'S A WORKING GROUP OF THE NAEC. THIS GROUP WAS ORGANIZED TO BRING TOGETHER A FEW PEOPLE, IN THIS CASE NINE, TO THINK ABOUT BIOLOGIC CAUSES OF AMD, AND TO GIVE SPECIFIC THINKING ABOUT HOW TO FORMULATE THE BIOLOGY IN TERMS OF HYPOTHESES THAT COULD BE -- COULD UNDERPIN CLINICAL STUDIES. SO JIM WILL GIVE US THE UPDATE ON THAT. AND THEN THERE ARE A FEW OTHER THINGS HAPPENING. AND THEN FINALLY, WHEN WE BREAK FOR LUNCH, I WOULD ASK THE COUNCIL MEMBERS TO MEET IN THE LOBBY UPSTAIRS AND WE WILL GET A GROUP PHOTOGRAPH. SO WITH THAT, LET ME ASK COUNCIL FOR ANY COMMENTS OR ANY FEEDBACK OR EXTENSION. >> (INAUDIBLE). >> IT'S PART OF THE INTRAMURAL RESEARCH PROGRAM HERE, YES. THE NIH HAS A VERY ACTIVE SUMMER PROGRAM FOR SUMMER STUDENTS, ALL OF THE INSTITUTES PARTICIPATE IN THAT. THE NEI HAS HAD A NUMBER OF INTERNS OVER THE YEARS WHO HAVE GONE ON TO DO INTERESTING WORK IN VISION, OR OTHER AREAS OF SCIENCE. THIS IS PARTICULARLY FOCUSED ON BRINGING IN AFRICAN-AMERICAN AND HISPANIC STUDENTS. >> HAS THERE BEEN ANY -- WILL THERE BE ANY EFFECT WITH NEI, GIVEN THE DISCUSSIONS ABOUT THE SCORING SYSTEM AND THE CAPPING? >> YES. THAT WILL BE ON THE TABLE. DR. TABAK, LARRY TABAK, THAT'S IN HIS PORTFOLIO. AND HE WILL BE TELLING YOU THE LATEST VERSION OF THAT, JUST TO GIVE YOU SOME HEADS-UP ON IT. THE CONCEPT OF SETTING A CAP ON FUNDING FOR INDIVIDUAL INVESTIGATORS HAD THE INTENT OF FREEING UP MONEY THAT IN MAJORITY WE HOPED WOULD BE DIRECTED TOWARD YOUNG INVESTIGATORS. AFTER PUTTING THIS OUT FOR PUBLIC COMMENT, IT HAS NOW BEEN REVISED, AND INSTEAD OF CAPPING INDIVIDUALS, IT WILL BE PROGRAMS SPECIFICALLY TARGETING THE YOUNGER -- SUPPORT FOR YOUNGER INVESTIGATORS SO THE CAPS ARE EFFECTIVELY NOT BEING CONSIDERED AT THIS POINT. BUT DR. TABAK WILL BE LAYING ALL THAT OUT FOR YOU. ALL RIGHT. WITH THAT -- OKAY, GOOD. >> OKAY. SO MY NAME IS BLAIR FELDMAN, VERY NICE TO MEET YOU ALL. I'M DEPUTY BUDGET OFFICER, STEPPING IN FOR KAREN COLBERT WHO WASN'T ABLE TO BE HERE. TWO GOALS, BUILDING OFF WHAT DR. SIEVING STARTED IN HIS INITIAL REMARKS, FIRST I'M GOING TO TALK ABOUT THE DIFFERENT FUNDING LEVELS WE EXPERIENCED DURING A FISCAL YEAR AND NEXT I'M GOING TO TALK TO YOU A LITTLE BIT ABOUT THE PRIORITIES THAT WE HAVE FOR FY17 AND BEYOND. SO FIRST WHAT IS THE BUDGET? THERE ARE A WHOLE LOT OF TERMS THAT GET THROWN OUT THERE. MULTIPLE LEVELS DURING A FISCAL YEAR, THAT HAVE DIFFERENT MEANINGS. SO THE FIRST IS CONTINUING RESOLUTION. WE ALSO HAVE BUDGET AUTHORITY, APPROPRIATION, ACTUAL OBLIGATIONS, THEY ALL MEAN DIFFERENT THINGS. SO THIS TIMELINE IS GOING TO TRY AND EXPLAIN WHAT THOSE DIFFERENT THINGS MEAN. WE HAVE THREE CONTINUING RESOLUTIONS THIS YEAR. THEY LASTED ALMOST 65% OF OUR ENTIRE FISCAL YEAR, WHICH REALLY PUT US IN A VERY WEIRD SITUATION, A SITUATION WE HAVEN'T BEEN IN BEFORE BECAUSE WE HAD A LOT OF -- WE WEREN'T SURE ABOUT WHAT WAS COMING TOWARD US, TOWARD THE END OF THE YEAR, AND WE WERE OPERATING JUST KIND OF PIECEMEAL FOR A WHILE. AND SO IT WAS BETWEEN OCTOBER 1 AND MAY 5 WE WERE UNDER THOSE CONTINUING RESOLUTIONS THAT WE DIDN'T KNOW WHAT OUR BUDGET WAS GOING TO LOOK LIKE FOR THE FULL YEAR. ON MAY 5 THE PRESIDENT SIGNED INTO LAW OMNIBUS APPROPRIATIONS, WITH THAT BILL WE GOT $732 MILLION, JUST OVER THAT. AND SO ONCE WE HAVE AN APPROPRIATION, THAT'S KIND OF OUR ENACTED AMOUNT BY LAW BUT THAT'S NOT NECESSARILY THE AMOUNT WE GET EVERY YEAR. THERE ARE THINGS THAT HAPPEN, A LOT OF POTENTIAL FOR TRANSFERS AND ADJUSTED AUTHORITY, THINGS ENACTED BY LAW LIKE OAR HIV TRANSFER, UP TO 3% ALLOWED TO MOVE IN AND OUT OF THE DIFFERENT ICs AND REAPPORTION SO THEY CAN FOCUS ON AIDS RESEARCH. WE ALSO HAVE THINGS LIKE THE SECRETARY TRANSFER, HHS SECRETARY IS ALLOWED TO TRANSFER UP TO 1% OUT OF THE BUDGET, WE HAVE POTENTIAL FOR RESCISSION AT ANY POINT DURING THE YEAR OR ADDITIONAL EMERGENCY APPROPRIATION. THERE ARE A LOT OF THINGS THAT CAN CHANGE THAT INITIAL NUMBER WE GET FOR THE YEAR. WHAT WE THEN GET IS OUR BUDGET AUTHORITY. ONCE WE HAVE ALL OF THOSE DIFFERENT THINGS SETTLE OUT. THEY CAN HAPPEN AT ANY POINT IN THE YEAR AS WELL. LAST YEAR WE HAD THE FINAL CHANGE TO BUDGET AUTHORITY I THINK JULY 30, SO TWO MONTHS BEFORE THE END OF THE FISCAL YEAR, SO THAT WAS VERY LATE FOR US. MOVING ON, WE GET TO OMB APPROVAL, THAT'S KIND OF THE STATE WE'RE IN RIGHT NOW WHERE YOU HAVE PUT TOGETHER A PLAN, WE'VE SUBMITTED TO OMB AND WE'RE WAITING FOR APPROVAL ON THAT PLAN. SO UNFORTUNATELY BECAUSE WE DON'T HAVE THAT APPROVAL, I REGRET THIS BUT I'M NOT ABLE TO SPEAK IN GREAT SPECIFICITY ABOUT OUR BUDGET, BUT I WILL TRY AND GIVE YOU AS MUCH DETAIL AS I CAN WITHOUT BREAKING THE OMB RULES. AND SO ONCE WE DO GET OMB APPROVAL WE'RE ALLOWED TO RAISE OUR BUDGET AND BUDGET PLAN PUBLICLY, WE GET TO SEPTEMBER 30 WHERE WE CLOSE DOWN THE BUDGET. OUR GOAL IS ALWAYS TO SPEND AS MUCH OF OUR BUDGET AUTHORITY AS POSSIBLE BECAUSE THERE'S SO MUCH GREAT SCIENCE OUT THERE. AND WHAT WE GET TO IS REPORTING PHASE, RECONCILIATION OF DATA, ACTUAL OBLIGATION. APPROPRIATION IS THE FIRST PIECE, BUDGET AUTHORITY IS THE PIECE WE OPERATE UNDER ONCE WE HAVE THE TRANSFERS IN AND OUT, AND THEN WE HAVE OUR ACTUAL OBLIGATIONS, WHAT WE ACTUALLY SPEND AS OF SEPTEMBER 30. SO THAT'S ALL OF THE DIFFERENT NUMBERS YOU HEAR. YOU ALSO HEAR THINGS LIKE THE PRESIDENT'S BUDGET, THAT'S PART OF A DIFFERENT PHASE OF OUR BUDGET, REFERRING TO A DIFFERENT FISCAL YEAR THAN THE ONE WE'RE CURRENTLY OPERATING IN. SO APPLES AND ORANGES, THERE WE GO. SO THIS IS OUR ENACTED APPROPRIATION LAST YEAR. $715 MILLION. THIS YEAR $732, LIKE COMPARING A RED APPLE TO GREEN APPLE, I SAY THAT BECAUSE THIS NUMBER, THE 715,000, HAS -- ISN'T OUR BUDGET AUTHORITY. WE END UP TRANSFERRING MONEY OUT, LAST YEAR WE TRANSFERRED OUT A LARGE SUM FOR AIDS RESEARCH. AND THAT'S HOW WE GOT TO OUR $707 MILLION LEVEL. THIS NUMBER HERE ACTUALLY ALREADY DID THAT IN THE APPROPRIATIONS BILL. SO THE MONEY FOR AIDS HAS ALREADY BEEN TRANSFERRED OUT. WE'RE NOT GOING TO SEE THE BIG TRANSFER HAPPEN AGAIN. SO THAT'S WHY COMPARING THESE TWO NUMBERS IS COMPARING A RED APPLE TO A GREEN APPLE. THEY ARE BOTH ENACTED, BUT THEY DON'T REALLY REFLECT THE DIFFERENCE THAT WE'RE GOING TO HAVE. THE $707 MILLION TO THE $732 MILLION IS LOOKING MORE LIKE JUST OVER 3.5% INCREASE, AND THAT'S KIND OF THE TRUE IMPACT THIS APPROPRIATION LANGUAGE HAD ON OUR BUDGET, ON OUR INCREASE. I SEE A COUPLE CONFUSED FACES. IF ANYBODY WANTS TO INTERRUPT AND ASK QUESTIONS, FEEL FREE TO DO SO. AND OUR ACTUAL LEFT, THIS IS WHAT I SPOKE ABOUT BEFORE. PRIORITIZING OUR GOALS, THE SECOND PART OF MY PRESENTATION. AS ALWAYS, OUR GOALS FOR FUNDING VEERCH, BUILDING INTRAMURAL PROGRAM, TRAINING THE GENERATION OF SCIENCES AND EXPANDING DATA RESOURCES, RESOURCE AVAILABLE TO THE EXTRAMURAL COMMUNITY. IT IS ALWAYS OUR GOAL TO SPEND 80% OF OUR MONEY OUT THE DOOR ON GRANTS. THE REST OF THE 20% IS TO OPERATE HERE AT NEI. THAT'S ON R&D CONTRACTS, INTRAMURAL RESEARCH AND RESEARCH MANAGEMENT AND SUPPORT. OF THAT 80%, 63% GOES TO NON-SBIR RPGs, GENERALLY THE THINGS THAT UNIVERSITIES AND INDEPENDENT RESEARCH INSTITUTIONS ARE GOING TO APPLY FOR. THIS IS A VERY INTERESTING SLIDE AND TELLS A COUPLE INTERESTING STORIES. WHAT WE SEE HERE IS OUR TOTAL GRANT COUNT, ALONG THE BOTTOM, OR ALONG THE SIDE HERE. SO OVER THE LAST 10 FISCAL YEARS, WE SEE A GRANT COUNT RANGING FROM JUST UNDER 1,050 TO JUST OVER 1100 GRANTS. BUT IT'S REALLY IMPORTANT TO REMEMBER THE NUANCE OF THAT. THE GRANT COUNT IS GOING TO FLUCTUATE BECAUSE THE COST OF GRANTS AND MIX OF GRANTS THAT WE'RE DOING CHANGE. SO YOU SEE HERE THESE YELLOW BARS COME INTO PLAY. THESE ARE U01s. SO ONE U01 OVER THE COURSE OF 10 YEARS, THE MEAN OF THE AVERAGE COST OF A U01 IS ABOUT EQUAL TO ALMOST SIX R21s OR THREE RO1s. AS WE THANK THE MIX, THE TOTAL GRANT COUNT ISN'T THE MOST IMPORTANT STATISTIC. REALLY THE MOST IMPORTANT STATISTIC IS LOOKING AT HOW WE'RE SPENDING OUR MONEY AND TOTAL AMOUNT WE'RE SPENDING AS A PROPORTION OF OUR TOTAL BUDGET. WE'VE NORMALLY SPENT THIS LINE HERE, FROM 61 TO 62% OF OUR BUDGET ON NON-SBIR RPGs. THIS LAST FISCAL YEAR IN FY 2016 WE WENT UP TO ALMOST 63%, AND THIS HICCUP RIGHT HERE IS SEQUESTRATION. THAT'S BECAUSE WE HAD TO CUT THINGS THAT WERE NOT GRANTS ON SEQUESTRATION, SO THAT'S OUR NOVEL YEAR. THE REASON I BRING THIS UP IS TALKING AS MUCH ABOUT FY17 AS I CAN, WE ARE FACING KIND OF AN UNKNOWN OF FY 18. WE DON'T KNOW WHERE THE BUDGET IS GOING TO GO. WE HAD TO PROPOSE 23% DECREASE. WE UNDERSTAND THAT TO BE DEAD ON ARRIVAL IN CONGRESS BUT WE DON'T KNOW WHAT WE'RE GOING TO GET, IF WE SHOULD ANTICIPATE A CUT OR WHAT'S REALLY COMING FOR US SO WE HAVE TO ENSURE OUR FINANCIAL STABILITY, AND WE'RE GOING TO TRY AND BRING THAT PERCENTAGE BACK DOWN TOWARDS THE 62% INSTEAD OF 63, SO THAT MAY MEAN A GRANT COUNT GOES DOWN, BUT IT KIND OF DEPENDS ON THE MIX, AND SO WHEN YOU'RE LOOKING AT THE STATISTICS IT'S KIND OF IMPORTANT TO REMEMBER NUANCES AND REMEMBER THE REASON WE MIX IT THE WAY WE DO AND REASON WE PROVIDE THE MONEY FOR IT THAT WE DO IS ALWAYS TO ENSURE FINANCIAL STABILITY IN THE OUT YEARS BECAUSE WE TAKE OUT A MORTGAGE ON THESE GRANTS. WE COMMIT THEM ON AVERAGE FOR FOUR YEARS, FOR AN RO1, SO WE WANT TO MAKE SURE THAT IF WE'RE GOING TO SAY WE'RE PAYING FOR RO1 WE'RE GOING TO BE ABLE TO PAY FOR AN RO1 IN THE FUTURE. BECAUSE WE DON'T KNOW WHAT FY 18 LOOKS LIKE WE'RE TRYING TO MITIGATE ANY KIND OF RISK WE HAVE THERE. AND SO WITH THAT, I WILL BE HAPPY TO TAKE ANY QUESTIONS. IF YOU DON'T HAVE QUESTIONS NOW BUT THINK OF THEM LATER, FEEL FREE TO E-MAIL EITHER MYSELF OR KAREN OR ANYONE IN OUR OFFICE. WE'D BE HAPPY TO GET BACK TO YOU. AND WITH THAT, I WILL OPEN UP THE FLOOR. YES? >> I HAD A QUESTION ABOUT THE DATA ON THE GRANT COUNT. >> SURE. >> AND ONE OF THE TRENDS I NOTICED IS THAT COMPARED TO MAYBE FIVE OR SIX YEARS AGO THE PROPORTION OF R21s TO RO1s HAS ACTUALLY INCREASED, SO THE NUMBER OF RO1s THAT ARE FUNDED IS ACTUALLY -- IT LOOKS LIKE IT'S DOWN. I'M WONDERING WHAT DRIVES MAYBE THIS MORE OF A PROGRAMMATIC DECISION, WHAT DRIVES THE ALLOCATION OF FUNDS TOWARDS R21 VERSUS RO1 FUNDING? >> MICHAEL, DO YOU WANT TO TAKE THAT? >> OF COURSE IT'S DRIVEN BY APPLICATION POOL, WHAT COMES THROUGH THE DOOR, AND SCORES THAT COME OUT OF THE STUDY SECTIONS IN RESPONSE. BUT IF YOU LOOK AT LAST YEAR'S STATISTICS, THERE'S QUITE A DIFFERENCE IN THE SUCCESS RATE. LAST YEAR NEI HAD A 26% OVERALL SUCCESS RATE GRANT. THAT'S GRANTS FUNDED OVER APPLICATIONS RECEIVED, NOT THE STUDY SECTION SCORE. AND THE SUCCESS RATE FOR RO1s WAS 28%, AND THE SUCCESS RATE FOR R21s WAS 19%. SO WE FUND A SMALLER PROPORTION OF THE R21 APPLICATIONS, BUT AS MORE OF THEM COME IN A HIGHER NUMBER GET FUNDED. ALSO, THESE NUMBERS ARE BIASED BY THE BRAIN INITIATIVE BECAUSE THE NEI SPONSORS AN R21 FOA FOR THE BRAIN INITIATIVE. NOW, SO THESE ARE EY GRANTS AND THEY ARE COUNTED HERE AS R21s. BUT IN FACT THE MONEY TO FUND THEM IS COMING OUT OF THE BRAIN MONEY POOL, PART OF WHICH IS IN THE NEI BUDGET, $5.4 MILLION OF THE BRAIN INITIATIVE IS ACTUALLY IN THE NEI BASE, AND WE PAY THESE R21s PLUS SOME OF THOSE U01s THAT ARE ACTUALLY BEING SPONSORED BY OTHER INSTITUTES AND ARE NOT EY GRANTS. SO I DON'T REALLY THINK THERE'S A LARGE SHIFT HERE. IT JUST APPEARS THAT BECAUSE OF BRAIN. >> YES? >> YOU SAID THAT THE 20% CUT IS PROBABLY DEAD ON ARRIVAL, BUT UNFORTUNATELY IT OPENS UP THE CONVERSATION TO HAVE SOME KIND OF A CUT. >> RIGHT. >> SOME OF THE BUZZ THAT PEOPLE ARE -- WE'RE HEARING ON THE STREET IS THIS IS GOING TO AFFECT INDIRECT COSTS SO AS TO MAINTAIN A REASONABLE NUMBER OF GRANTS TO GET FUNDING. CAN YOU SPEAK TO THAT? IS THERE A DISCUSSION ABOUT HOW INDIRECTS ARE GOING TO BE HANDLED? >> SO RIGHT NOW THE PRESIDENT'S BUDGET PROPOSES THAT -- RIGHT NOW THE NIH SPENDS ABOUT 28% OF ITS EXTRAMURAL GRANT BUDGET ON INDIRECT COSTS. THE PRESIDENT'S BUDGET PROPOSES THAT IT CAPS THAT AT 10%, LIKE YOU SAID. RIGHT NOW, AGAIN, BECAUSE, YOU KNOW, WE DON'T KNOW WHAT'S COMING, WE DON'T REALLY KNOW HOW THE ADMINISTRATION OR CONGRESS WILL RECEIVE THAT, THERE'S NOT MUCH I CAN SAY ABOUT IT, EXCEPT WHAT WAS PROPOSED IN THE PRESIDENT'S BUDGET UNFORTUNATELY. I'M SORRY I CAN'T BE A LITTLE BIT MORE ELABORATIVE ON THAT. YES? >> WHAT ABOUT TRAINING GRANTS? WE HAVE T32s COMING OUT OF NEI. >> YES. >> NOT F31s OR F32? >> YES, WE FUND F 30, F3 1. >> AND 32. IS THERE ANALYSIS OF INCREASE, DECREASE OF FUNDS? >> I CAN'T BE TOO SPECIFIC ABOUT FY17, BUT OAR HAS PUT OUT GUIDANCE FOR SLOT INCREASE, WE'VE ACCOMMODATED THAT, I JUST CAN'T SPEAK TO WHAT IT IS. >> SO OUR GOAL IS TO TRY TO HOLD THE NUMBERS CONSTANT, BUT AS BLAIR POINTED OUT, WE DO HAVE TO INCREASE THE BUDGET IN THAT CATEGORY, IN ORDER TO ACCOMMODATE THE SALARY INCREASES THAT WERE MANDATED. >> YES? >> DOES THE SAME APPLY TO K GRANTS, LIKE K12s? >> I'M SORRY, I FEEL LIKE I'M HANDCUFFED HERE. I WISH I COULD SPEAK WITH SPECIFICITY ABOUT HOW WE'RE TREATING GRANTS IN DIFFERENT CATEGORIES OF GRANTS IN FY17, BUT SINCE WE DO HAVE AN OVERALL INCREASE OF OVER 3%, FOR THOSE KIND OF AWARDS YOU CAN EXPECT TO SEE SOMETHING PROPORTIONAL IS PROBABLY AS FAR AS I CAN GO. >> AND WITH OUR STRATEGY, WITH THE K12s, IS WE'RE TRYING TO MOVE MORE TOWARDS THE INDIVIDUAL GRANTS, K23 AND KO8, WE'LL BE FUNDING THE SAME NUMBER BUT FEWER SLOTS ON K12 TO FREE KO8 AND K23 INDIVIDUAL GRANTS. >> ANYBODY ELSE? THANK YOU FOR YOUR TIME. I ENJOYED PRESENTING TO YOU ALL. IF YOU HAVE QUESTIONS PLEASE FEEL FREE TO CONTACT ME. >> WHILE GRACE IS GETTING PREPARED, WHAT WE'VE BEEN DOING OVER THE LAST FEW COUNCIL SESSIONS IS HAVING INDIVIDUAL PROGRAM OFFICERS COME UP AND TELL YOU ABOUT THE KINDS OF THINGS THAT ARE IN THEIR PORTFOLIO. OVER THE PAST SEVERAL MEETINGS WE'VE HAD REALLY NICE PRESENTATIONS ABOUT THE LENS PROGRAM, ABOUT THE CORNEA PROGRAM, AND ABOUT THE LOW VISION PROGRAM. SO TODAY AND FOR THE NEXT TWO MEETINGS WE'RE GOING TO BE TALKING ABOUT THE RETINA PROGRAM, STARTING WITH GRACE, WHO IS THE COORDINATOR OF THAT PROGRAM FOR US, AND THE PROGRAM OFFICER OF THE RETINAL DISEASES SUBPROGRAM. THANK YOU, GRACE. >> OKAY. SO MICHAEL ALREADY INTRODUCED ME. I'M HERE TO TALK ABOUT THE RETINAL DISEASES PROGRAM. TODAY THE PRESENTATION OUTLINE I HAVE IS I'LL GIVE YOU A VERY BRIEF OVERVIEW OF THE PROGRAM, I'M GOING TO COVER SOME TOPICS AND HIGHLIGHT SUCCESS STORIES DURING THE PRESENTATION, I WILL ALSO PROBABLY MENTION THE DIFFERENT NEEDS AND CHALLENGES IN THE AREA, BY NO MEANS IS IT A DISCLAIMER, IT'S NOT COMPREHENSIVE BECAUSE IT'S THE LAST PROGRAM. IF THERE'S TIME WE'LL HAVE SOME FEEDBACK FROM THE COUNCIL MEMBERS. SO FOLLOWING THE BUDGET TALK, MISS FELDMAN GAVE THE OVERVIEW OF HOW MUCH BUDGET WE HAVE. AND YOU CAN SEE FROM THIS KAREN COLBERT PROVIDED FOR ME FOR LAST YEAR'S GRANTS, BECAUSE ALL THE BOOKS ARE CLOSED. RETINAL DISEASES COMPRISES A HUGE PORTION OF THE EXTRAMURAL BUDGET. BUT THE PROGRAM IS ACTUALLY OVERSEEN BY FOUR OF US HERE, THAT WE ALL CARRY GRANTS IN THIS PROGRAM. SO I'M IN CHARGE OF THE RETINAL DISEASES, WHICH COVERS A DIFFERENT RETINOPATHY, AMD, RP, INHERITED EYE DISEASE, A SMALL PORTION OF THE PROGRAM IS ON THE RETINAL DETACHMENT AND VITREOUS, ANGIOGENESIS IS A LARGE AREA WE COVER AND MY OWN GRANTEES HERE TOO AND THEN GENETICS, MONICA, IS GRANTEE IN THAT AREA, SO LISA NEUHOLD OVERSEES FUNDAMENTAL RETINAL PROCESSES, MORE BASIC BIOLOGY OF PHOTORECEPTOR, RPE, AND RETINAL DISEASE THE FOCUS IS LOOKING AT THE BIOLOGY OF AUTORECEPTOR AND RPE, SHE WILL BE OVERSEEING THAT AND I BELIEVE SHE'S GOING TO TALK PROBABLY TWO COUNCILS FROM NOW. AND GEORGE McKIE IS IN CHARGE OF OVERALL IMMUNOLOGY, INFECTION AND INFLAMMATION. THERE'S A LOT OF INFLAMMATION, CHRONIC INFLAMMATION THAT GOES ON IN THE RETINA DISEASES, WHICH IS REALLY (INDISCERNIBLE) SHE WILL BE FOCUSING ON THE CYTOKINES AND COMPLEMENT ACTIVATION SO THESE AREAS SHE WILL BE IN CHARGE OF THAT. AND TOM GREENWELL WILL BE TALKING AT THE NEXT COUNCIL ON RETINAL NEUROSCIENCE, AND HE ALSO HAS A BIT OF THE EARLY RETINA DEVELOPMENT IN HIS PORTFOLIO. SO THE TOPICS I'LL COVER TODAY, I'M BREAKING IT INTO THREE AREAS, AND TO SHOW THAT WE REALLY ARE MORE ON THE BASIC RESEARCH SIDE. SO FOR THE RETINAL DISEASES, CLINICAL RESEARCH THAT GOES INTO CLINICAL NETWORK GROUPS. AND MODEL SYSTEMS WE GO ALL THE WAY FROM RPG, CELL CULTURE, IN VITRO, LOWER ORGANISM COULD BE DROSOPHILA OR ZEBRAFISH. RODENTS IS BY FAR THE BIGGEST PORTFOLIO WE HAVE, PROBABLY OVER 100 GRANTS ON MICE, 100 GRANTS ON RATS. AND THEN THE LARGER ORGANISMS THAT MIGHT KIND OF RESEMBLE MORE OF THE HUMAN SUBJECTS. AND THEN I WILL FOCUS PROBABLY ON THE BENCH AND BEDSIDE ON THE DIFFERENT AREAS HERE, AND WILL BE INCORPORATING SOME OF THE BASIC RESEARCH TOPICS AS I GO ALONG WITH THE DIFFERENT STORIES. SO FOR THE BENCH TO BEDSIDE, REALLY THAT'S THE KEY OF THE GOAL FOR NIH IS REALLY HOW DO WE GO FROM RESEARCH INTO APPLYING IT TO HELPING THE EYE DISEASE RESEARCH SO THAT WE CAN HELP TO FIND A CURE. AND THE TOOL IS A BIG THING, SO GOING TO COVER ON THE NON-INVASIVE IN VIVO IMAGING, FOCUSING ON OCT BECAUSE IT'S JUST A LOT HAS BEEN DONE DURING THE LAST 40 YEARS, ALSO DO THE MOLECULAR THERAPEUTICS IN NEOVASCULARRIZATION, FOCUSING ON DIABETIC RETINOPATHY BECAUSE YOU'RE GOING TO HEAR MORE ABOUT AMD FROM JIM HANDA LATER ON. AND I'LL MENTION THE SUCCESS STORY IN THE GENE THERAPY AND TOUCHING ON THE STEM CELL, BUT AGAIN WITH THE AUDACIOUS GOAL, A LOT BY DAVID GANN, A SEMINAR AT NEI, AND SO BUT THAT IS THE FINAL TOPIC I'M GOING TO COVER. SO FOR THE NON-INVASIVIVE IN VIVO STEVE BECKER WILL TALK& ABOUT THAT LATER BUT SPLITTING DOWN THE EMPHASIS BASED ON WHAT WE'VE HEARD IN THE LAST TWO OR THREE YEARS, REALLY TRYING TO GET THE HISTOLOGICAL QUALITY IMAGES AT THE CELLULAR LEVEL, AND THERE'S SECOND BULLET TO SEE THE VISUAL STIMULI INDUCED RETINAL CHANGES, NOT JUST STRUCTURE, YOU'RE LOOKING AT THE FUNCTION, STRUCTURE-FUNCTION RELATIONSHIP. AND FINALLY REALLY HELPING -- THE TWO HELPING US LONG AT LONGITUDINAL, SO TIME COURSE, IF YOU CAN GO BACK AND IMAGE THE SAME PLACE, AND THEN YOU CAN ASK QUESTIONS TO SAY WHAT HAPPENED TO ALL THESE NEURONS DURING THE DISEASE PROCESS, OR EVEN IF YOU HAVE SOME INTERVENTION IN THE PATIENT, CAN YOU NOW GO BACK AND WITHOUT, YOU KNOW, DOING SAMPLE SPECIMEN OR ONLY LOOKING AT AUTOPSY CAN YOU TEST RESPONSE TO YOUR TREATMENT. SO WHEN I WAS DOING MY RESEARCH GIVING YOU A LOT OF TIME TO THINK ABOUT IT, I WAS PREPARING THE SEMINAR AND THEN I WAS WATCHING JEOPARDY AND THIS QUESTION CAME UP. OH, I KNOW THE ANSWER BECAUSE THAT WAS IN THE PAPER I WAS READING. AND SO THIS IS A MONUMENT HERE, AND THE MAN HAS THE ELBOW RESTING ON THE BOOKS, ONE IS LABEL "OPTICS." ANYBODY WANT TO TAKE A GUESS? I DON'T HAVE A BUZZER. ANYBODY? VERY SHY AUDIENCE HERE. THE ANSWER IS WHO IS SIR ISAAC NEWTON. SO WHAT I WANTED TO SHARE WITH YOU ABOUT THIS QUESTION IS REALLY LIKE TO SAY THAT REALLY SCIENCE EVEN THOUGH WE'RE TALKING ABOUT HEALTH SCIENCE IS REALLY STARTED FROM ALL BASIC SCIENCE. AND THE LOCO HERNS AND WHITE LIGHT ENTERFEROMETRY HAVE TO DO WITH HE DO THE TIME GATING, HE CAN FILTER OUT SCATTERING AND YOU CAN ACTUALLY SEE THE LOGO. ALREADY IN THE 71 PAPER HE MAKES THAT PREDICTION TO SAY THAT YOU CAN HAVE A POSSIBILITY USING THIS GATED PICTURING TO LOOK THROUGH THE HUMAN SKIN AND LOOK AT BIOLOGICAL TISSUE. AND IT TOOK ABOUT 20 YEARS, AND THIS IS WHAT DAVID WONG, M.D./ PH.D. STUDENT, NOW A PROFESSOR AND GRANTEE IN THE CORNEA PROGRAM, AND HE IS THE ONE THAT I JUST PUTTING THE SKIMMER UP THERE, WHICH IS QUITE STRAIGHTFORWARD, SIMPLE, BUT HE USES THE COMBINATION OF THE BELL LAB EXPERIMENTS AND THE LOW-COHERENCE, INTO THE 50-50 COUPLER OUTPUT, SAMPLE AND REFERENCE THEME, RATHER THAN ONE SINGLE LIGHT SOURCE HE'S HAVING THE SPLIT BEAM GO BACK AND CAPTURE. THE IMAGE DOWN THERE IS THE FIRST IMAGE IN EX VIVO BOVINE EYES. I TOOK OUT THE EYES, THAT STILL HAD TO GO THROUGH A LOT OF TISSUE IN ORDER TO SEE A VERY CLEAR RETINAL IMAGE. AND SO THIS SLIDE JUST -- BECAUSE OF THE TIME I'M SPEEDING FORWARD TO SAY WE HAVE SEEN A LOT OF PROGRESS IN OCT, NOT JUST 2D WAY, THERE'S 3D, 4D OCT AND THEY CAN REALLY TAKE IMAGES, SUM THEM UP, SO THERE'S A LOT OF ENGINEERING AS WELL AS COMPUTER, AND THE THING IS I HAVE ALWAYS BEEN VERY FORTUNATE BECAUSE IT'S JUST TRANSPARENCY THAT YOU HAVE TO PHOTOGRAPH, FLUORESCENT, WITH OCT YOU DON'T HAVE TO PUT DYE IN AND THINGS, SO ONE OF THE THINGS YOU CAN ALWAYS COMPARE, WE ALREADY KNOW WHAT IT LOOKS LIKE BUT THEN NOW CAN YOUR IMAGING TECHNOLOGY IMPROVE TO THAT POINT. AND SO THESE ARE JUST SERIAL CAPTURES OF THE LAYERS AND THEY CAN DO THE ON-FACE IMAGING, NOT JUST SIDEWAYS. SINCE I'M GOING TO TALK ABOUT THE NEXT TOPIC ON THE MOLECULAR THERAPEUTICS I'LL SHOW YOU SOME OF THE SLIDE HERE TOO ON DIABETIC RETINOPATHY, AND DOWN THERE IS THE FUNDERS PHOTOGRAPH WHERE YOU CAN SEE THE PATCH THERE AND WITH THE OCT YOU CAN SEE THAT YELLOW BOX, THE AREA BLOWN UP ON THE RIGHT-HAND SIDE, AND SO IF YOU ZOOM IN FURTHER, ON THE PHOTO, YOU CAN SEE LEAKAGE FROM DYE, YOU CAN SEE ALL THE CAPILLARIES LEAKAGES ON THIS SPOT, AND RIGHT-HAND SIDE IS YOUR OCT PICTURE THAT CAN PRETTY MAP OUT THE SAME SPOT. THIS SIDE YOU DON'T HAVE ANY FLUORESCENT DYE, YOU LOOK AT CAPILLARY LOOPS THAT ARE DIFFERENT. STRUCTURAL CHANGES IS SUFFICIENT TO USE THE OCT TO DO THE IMAGING.& SO REMEMBER I WAS TALKING ABOUT THE STRUCTURE PART, BUT THEN THIS IS JUST A SCHEMA TO SHOW HOW MUCH MORE COMPLICATED IT IS NOW COMPARING WITH THE FIRST OCT FROM DAVID WANG, NOW YOU CAN REALLY USE IT TO DO THE STIMULUS, THE YELLOW BOX ON THE SIDE IS JUST PROJECTOR WHERE YOU CAN DO THE LED AND STIMULATE THE EYE THAT IS ON THE BOTTOM, AND YOU CAN HAVE THE SOURCE AND& REFERENCE LIGHT AND WITH THE REFERENCE BEAM THAT YOU CAN ACTUALLY DO THE STIMULATION AND SEE IF THERE'S REFRACTIVE CHANGES, SO THAT'S REALLY THE SCHEMA OF IT. AND THAT HAS BEEN SOMETHING THAT HAS ONLY BEEN IN 2016 ON THIS REPORT, BUT WHEN I WAS PREPARING FOR THIS TALK, JUST AMAZING NUMBER OF PUBLICATIONS THAT COMES OUT ON THE DIFFERENT ASPECTS, DIFFERENT PEOPLE HAVE VERY, VERY DIFFERENT APPROACHES IN DOING THIS TECHNOLOGY. SO THIS IS JUST A LITTLE BIT OF GOING BACK TO THE EXTRAMURAL TO SAY HOW MUCH THE FUNDING IS, AND WE WILL JUST SEE FROM THE 1991 IS WHERE DAVID WANG HAD THAT PHOTOGRAPH, DATA THAT WAS UP TO 2001, WITH THE ZEISS MICROSCOPE COMPANY, 400 UNITS SOLD, THEY WANTED TO GIVE UP AND CLOSE IT DOWN, THE UNIT, BUT WHEN THEY DECIDED TO MOVE FORWARD, FOURTH GENERATION WHEN THE EQUIPMENT GOT GENERATED YOU CAN SEE IT BECOMES VERY SUCCESS WORLDWIDE PROCEDURE, NOT JUST IN THE UNITED STATES, BUT GLOBALLY, A LOT OF OPHTHALMOLOGISTS ARE USING THIS PARTICULAR PROCEDURE. AND SO AS OF 2017, IT'S NOT ONLY USED IN OPHTHALMOLOGY BUT CARDIOLOGY, DERMATOLOGY AND GASTROENTEROLOGISTS ALL START USING THIS IMAGING TECHNOLOGY. THE FINAL SLIDE IS CHALLENGES AHEAD THAT WE -- EVEN THOUGH WE'VE COME A LONG WAY, I CAN SHOW YOU THE PICTURE THAT YOU CAN SEE DOWN TO THE CAPILLARY, BUT THERE'S STILL A LOT OF CELL TYPES THAT WE'RE NOT SEEING VERY WELL. AND I'M NOT SAYING THAT YOU CAN'T SEE IT. SOME OF THE PAPERS MIGHT PUBLISH ABOUT IT. BUT IT JUST IS MORE LIKE IN THE RESEARCH ENVIRONMENT, AND IN THE VERY PARTICULAR SETTING, BUT IT'S NOT READILY DETECTABLE SO THE THEME TO TRY TO SAY CAN WE GET TO A POINT WE CAN REALLY DISTINGUISH ALL THOSE OTHER NEURONS. AND THEN SO THIS CONTINUES LEAD OF DOING HIGH RESOLUTION IMAGING AND AGI RFA GRANTEES, MULTIPLE GROUPS THAT DO THE TWO FULL TERM MICROSCOPY AND THEN I ALSO HAVE GRANTEES ON ADAPTIVE OPTICS, NOT IMAGING TECHNOLOGY ITSELF BUT PLATFORM THAT CAN COMBINE WITH ALL THE OTHER TECHNOLOGIES TO HELP YOU TO DO SOME OF THE CORRECTIONS OF THE EYE MOTION AND ALSO THE FORMATIC ABERRATION. SO LIKE I WAS TALKING TO LIKE ALBERT SUPRA, HE WAS SAYING IT'S EASY TO PUBLISH A PAPER ON A 20-YEAR-OLD EYE WITH WONDERFUL IMAGES, BUT IF YOU HAVE THIS ELDERLY MAN THAT IS HAVING, YOU KNOW, PROBLEMS WITH THE EYE ALREADY, YOU TELL THEM NOT TO MOVE THE EYE AND JUST TRY TO HAVE THEM LOOK AT IT, IT'S JUST OPTICS IS NOT SOMETHING THAT EVERY HOSPITAL COULD DO IT. SO ONE OF THE GRANTS IS ACTUALLY FOCUSING TO SAY HOW CAN WE BUILD THIS PLATFORM FOR MULTIPLE SITES, AND TRY TO SEE WE CAN TEACH THEM AND TRAIN THEM SO THAT THEY CAN ALL GET THE SAME IMAGES, THEN YOU CAN COMPARE YOUR EXPERIMENTAL RESULTS BETWEEN DIFFERENT HOSPITAL GROUPS, OTHERWISE YOU'LL BE COMPARING APPLES AND ORANGES, THAT ONE TECHNICIAN MIGHT BE ABLE TO DO IT BETTER THAN ANOTHER. BUT IF YOU HAVE THE SAME, THAT COULD BE HELPFUL. MOVING FORWARD TO THE SECOND TOPIC, ON THE MOLECULAR THERAPY, AND AGAIN WE HAVE SUCCESS STORY ON THE NEOVASCULARRIZED EYE DISEASES BECAUSE OF THE ANTI-VEGF AND THAT WE CAN SEE OVER 70% OF THE PATIENTS NEEDED TO GET MONTHLY INJECTIONS THAT SEEMS TO IMPROVE OR PREVENT THE FURTHER DETERIORATION OF THE DISEASE. BUT FOR HALF OF THE PROLIFERATION DIABETIC RETINOPATHY THEY CAN ALSO BE TREATED, BY THE ANTI-VEGF DRUGS, BUT THE THING IS WHAT THIS SLIDE IS TELLING US WHAT HAPPENS WITH THE OTHER HALF, WHAT HAPPENS WITH THE OTHER 30%, AND SO IT'S THE CONTINUED LEAD TO FIND SOMETHING OTHER THAN THE VEGF, AND THE NEXT SLIDE IS JUST TO SHOW YOU WITH DIABETIC RETINOPATHY, IF YOU HAVE THE FIRST SLIDE YOU SEE THE NORMAL VISION, YOU HAVE A NICE FOCUS OF THE TWO HAPPY BOYS. FOR THE PATIENT WHO GETS EVENT, DIABETIC RETINOPATHY, YOU ACTUALLY SEE ALL THESE FLOATING SPOTS BECAUSE THEY ARE HEMORRHAGES THAT REQUIRE PROMPT TREATMENT. IN THE PAST YOU THINK OF DIABETIC RETINOPATHY, OH, IT'S THE BLEEDING DISEASE, BUT THAT'S ALREADY END STAGE. A LOT OF PATIENTS DON'T HAVE THE WARNING UNTIL SOMETHING REALLY BAD IS HAPPENING. AND SO WHAT I HAVE HERE IS A VERY BUSY SLIDE PICTURE, BUT THAT JUST HELPS TO KIND OF GIVE YOU A FLAVOR OF ALL THE GRANTS THAT IS IN MY PORTFOLIO OF PEOPLE TRYING TO LOOK AT THE TARGETS. SOMETIMES WHEN I SIT IN STUDY SECTION, LISTEN TO REVIEW, I ACTUALLY EVEN HEAR SOMEBODY SAY, OH, GOOD IS THIS IS NOT A VEGF GRANT, SOMETHING THAT COULD BE ANOTHER TARGET. AND SO JUST TO KIND OF SHOW YOU A LITTLE BIT OF THE PROCESS THAT THE THINKING, THERE'S A LOT OF NEURONS, IT'S KIND OF WITH THE -- ESPECIALLY WITH DIABETIC PATIENTS THAT DON'T HAVE GOOD GLYCEMIC CONTROL, THAT THEY HAVE FOUND THAT IT GIVES SO MUCH STRESS TO THE NEURONS IN THE RETINA THAT THAT COULD BE APOPTOSIS GOING ON, SEEDING OF NEURAL RETINA, THEY HAVE THE THICKENING OF THE BASE MEMBRANE, AND LIKE THE OCT IMAGES YOU SAW, YOU CAN SEE THE MICROANEURYSM, AND THE LEFT-HAND SIDE PARAGRAPH ACTUALLY SHOWS YOU THE DIFFERENT OTHER PROCESSES THAT THE MICROGLIAL GET ACTIVATED AS A RESULT OF INFLAMMATION, AND THEN PARASITE LOSS, AND SO VEGF IS THE SECOND TO THE LAST, THAT'S ONE TARGET, YOU HAVE TNF ALPHA, A LOT OF OTHER TARGET STEPS PEOPLE HAVE BEEN LOOKING AT TO SAY HOW WE CAN SEE IF YOU CAN DO TREATMENTS, HOW THEY PLAY INTO THE DISEASE PROCESS, CAN WE DO THE INTERVENTION BEFORE YOU FINALLY HAVE ALREADY HAD THE ENDOTHELIAL CELL DEATH AND ALL THE VASCULAR CHANGES, CAN WE TAKE CARE OF IT MORE UPSTREAM. AND SO I JUST HAVE THE SLIDE TO SUM UP SOME EMERGENT THERAPIES THAT I SEE THAT'S COMING OUT. microRNA HAS ONLY BEEN SOMETHNG THAT I SEE ONLY IN PUBLICATIONS FOR THE LAST COUPLE OF YEARS, AND ORANGE IS JUST OTHER GRANTEES THAT I KNOW ARE WORKING, HAVE PUBLISHED ON THE DIFFERENT microRNAs, SO THE TARGETING MOLECULE IS LIKE THE TNF ALPHA, AND PPAR AL FALL ALPHA IS JAMES MA IN OKLAHOMA, TO DO TREATMENT IN DIABETIC RETINOPATHY AND JULIE BUSIK, MICHIGAN STATE, LOOKED AT THE METABOLISM. IN THE NORMAL STATE IN NORMAL CELL SHE MIGHT ONLY SEE MAYBE 80 microRNA, BUT IN THE DISEASED STATE A LOT OF TIMES YOU CAN SEE UP TO 120 MOLECULES, THERE'S MANY microRNA PEOPLE TRYING TO UNDERSTAND HOW THEY PLAY IN PATHOGENESIS. CAN WE TARGET TO MAKE THINGS SLOW DOWN, GO UP, AND THOSE ARE THE THINGS THAT A LOT OF THE RESEARCH OF MY PROGRAM IS DOING. AND SECOND THING THAT SEEMS TO BE A LITTLE BIT DIFFERENT IS THE SYSTEMIC TREATMENT WITH INTRAMURAL NEI, EMILY CHU HAS DONE WORK ON THAT, AN ORAL PILL, MORE DESIRABLE THAN HAVING INJECTION ALL THE TIME, PLUS THERE ARE PATIENTS WHO DOESN'T RESPOND TO THE INJECTIONS, SO THAT'S ANOTHER AREA OF RESEARCH, BUT STILL CONTINUES THE STUDY. OTHER POTENTIAL TARGETS, ELEVATED VITREOUS LEVEL IN THE DIABETIC MODELS HE'S LOOKING AT, AND MOST RECENT ONE, WAY LI FROM MIAMI, SELECTED THIS SECRETOGRANIN FAMILY OF MOLECULES, PEPTIDE HORMONE CAN LOOK AT. SO I THINK THIS IS MY FINAL TOPIC HERE, ON THE GENE THERAPY WHICH I WOULD ONLY -- I WOULD ALSO TOUCH ON THIS A LITTLE BIT ON THE CHALLENGES AHEAD. SO THIS IS JUST A SLIDE THAT SHOWS AGAIN ANOTHER GRANTEE, STEPHEN DAIGER, UT HOUSTON, A HUGE DATABASE THAT IF ANYBODY IS INTERESTED IN INHERITED EYE DISEASES HE HAS THAT CATALOG EVERY DISEASE, THE MUTATIONS, AND YOU CAN SEE AT THE TIME WHEN THE GENE THERAPY FIRST STARTED IN 1996 THERE'S ONLY ABOUT 19 GENES BEING REPORTED THERE. BUT AS OF TODAY IT'S ABOUT 256. SO THERE'S A LOT MORE TARGETS THAT PEOPLE CAN LOOK AT WHERE THEY WANT TO DO THE GENE THERAPY TREATMENT. AND THIS IS JUST SOME OF THE KIND OF DATES THAT TALKS ABOUT THE GENE-BASED THERAPY, THAT AGAIN IS FAIRLY RECENT, IF YOU THINK ABOUT IT. 1995 IS WHEN THEY FIRST SAY, OKAY, LET'S TRY TO DO THIS GENE TRANSFER. THAT WASN'T SUCCESSFUL. THEN 1996, JEAN BENNETT, ANOTHER GRANTEE OF MINE, MANAGED TO DO IT IN THE MOUSE MODEL RESCUE, AND THEN IN THE 2001 THAT'S WHEN YOU ACTUALLY IN THE DOG, THEY FIND THE PROTEIN THAT'S MUTATED, AFFECT VISUAL CYCLE, PIGMENT CYCLE. AND SO THEY FIND THAT IF YOU REINTRODUCE THAT GENE THAT COULD HELP THE DOGS TO STAY OR AT LEAST DO THE MOTION TEST. AND THEN 2007 IS THE FIRST TRIAL TARGETING THE LCA MUTATION, THEY HAVE THAT PARTICULAR MUTATION. SO INITIAL PART OF THE GENE-BASED THERAPY IS REALLY TRYING TO INTRODUCE THAT GENE THERE. AND AS OF TODAY, THESE ARE PUBLISHED PAPERS, LIKE 244 IS WHAT I READ, THERE'S PROBABLY A LOT MORE. AND THEN THE GOOD THING FOR THE PAST 10 YEARS IS STILL A FAIRLY GOOD SAFETY RECORD, SOME OF OF YOU MIGHT RECALL ABOUT GENE TRANSFER IT'S NOT IN THE EYE FIELD BUT WHEN YOU HAVE A DEATH RIGHT AWAY EVERYTHING GETS SHUT DOWN, EVERYBODY GETS WORRIED, BUT SEEMS TO BE AT LEAST WITH THE EYE WHEN YOU DO THE RETINA DELIVERY THAT SEEMS TO BE FAIRLY SAFE SO FAR. AND I ALSO WANT TO BRING UP THE 2013, NOW THAT YOU CAN ACTUALLY DO THE CRISPR/CAS9, LIKE THAT'S REALLY THE KIND OF FIRST TIMELINE WHERE YOU CAN USE THAT GENOME EDITING NOW TO CORRECT MUTATION AND YOU CAN DO THE DOUBLE-STRANDED CUT IN THE DNA OF THE HUMAN GENOME, AND THEN REPLACE IT WITH THE GENE SEQUENCES THAT YOU WANT. SO SINCE 2013 YOU CAN DO THAT IN THE EUKARYOTES, I WAS SEARCHING ALL THE PUBLICATION IN THE RETINA, PROBABLY 2016, 2017, A LOT OF PAPERS ARE JUST BEGINNING TO COME OUT. I'M BEGINNING TO SEE A LOT OF THE GRANTS THAT I'M HEARING IN STUDY SECTION. SO THE CHALLENGES AHEAD I THINK THAT'S PROBABLY MY LAST SLIDE HERE. AND SO IN THE GENE THERAPY BECAUSE THEY HAVE BEEN AROUND A LOT LONGER WE HAVE MORE KNOWLEDGE ABOUT WHAT'S GOING ON, AND THERE'S STILL KIND OF THE CHALLENGE TO SAY EVEN THOUGH THERE'S IMPROVEMENT, THEY KIND OF LIKE FOLLOW THE PATIENTS THAT HAVE GENE THERAPY, AND THEY FIND THAT EFFICACY MIGHT NOT BE WHAT THEY INITIALLY THINK IT IS. AND SO THEN THE LOSS OF THE THERAPEUTIC EFFECT AND THEN THEY NOTICE THE PHOTORECEPTOR CONTINUES TO DIE SURROUNDING IN THESE PATIENTS THAT HAVE THE TREATMENT, SO YOU REALLY HAVE TO FIND OUT HOW DO YOU INCREASE THE EFFICACY AND EFFICIENCY OF THE GENES PROLIFERATE, SO I HAVE GRANTS THAT IS ON THE AAV DELIVERY, LENTIVIRAL DELIVERY, SO THE LIPOSOME. THERE'S JUST SO WAYS TO SEE HOW CAN WE DELIVER THE GENE CORRECTLY. AND ESPECIALLY IT'S NOT JUST RPG CELLS, IT'S POST MITOTIC PHOTORECEPTOR, ONCE YOU DELIVER THE GENE THERE IT'S NOT DIVIDING AND HAS DILUTION, BUT ON THE OTHER HAND YOU KIND OF LIKE IF YOU CAN'T GET IN THEN YOU REALLY CANNOT HAVE THAT EFFECT THAT YOU NEED. AND SO ALSO THE OPTIMAL THERAPEUTIC WINDOW, HOW FAR GONE IS TOO FAR GONE? YOU KNOW, LIKE DO YOU -- IF YOU DO IT TOO EARLY, THE PATIENT IS NOT HAVING THE PROBLEM YET, AND IS THAT GOING TO BE SAFETY PROBLEM? BUT IF YOU DO IT TOO LATE, YOU MIGHT NOT SEE ALL THIS NEURONAL DEGENERATION ALREADY HAPPENING AND IT MIGHT BE TOO FAR GONE FOR IT TO RECOVER. SO THOSE ARE THE RESEARCH THAT NEEDS TO GO ON. I MENTIONED A LITTLE BIT ABOUT THE CRISPR/CAS9 IS AGAIN STILL CONTINUES, CONCERN ABOUT OFF-TARGET, NOT JUST THE GENE YOU'RE LOOKING AT, WHAT HAPPENS IF YOU JUST HAPPEN TO MUTATE A LOT OF OTHER GENES THAT MIGHT HAVE ILL EFFECTS, THE SAME THING GOES WITH STEM CELL THERAPY, TO DIFFERENTIATE IT RIGHT, DO YOU MAKE THE RIGHT CONNECTIONS, YOU KNOW, JUST THROWING A WHOLE BUNCH OF WIRES TOGETHER DOESN'T MAKE YOU A RADIO OR TV. YOU REALLY HAVE TO HAVE THAT RIGHT CONNECTION WHICH I THINK MAKES -- WE MIGHT BE ABLE TO TALK MORE ABOUT CONNECTIVITY OF DIFFERENT NEURONS, AND AGAIN I CAME FROM THE CANCER VIEW AND SO YOU STILL WORRY ABOUT STEM CELLS, CAN IT BE TUMORGENIC, HOW DO YOU MAKE SURE IT'S DIFFERENTIATED INTO THE RIGHT CELL TYPE IN THE RIGHT ENVIRONMENT? SO ALL THOSE ARE KIND OF AREAS THAT WE HAVE SOMETHING TO THINK ABOUT. SO I'M JUST WANTING TO HAVE SOME FEEDBACK. >> THANKS FOR A REALLY FASCINATING UPDATE. WHEN YOU THINK EPIDEMIOLOGICALLY ABOUT RETINAL DISEASE, OBVIOUSLY THE ONE THAT VISUAL DISABILITY WOULD BE THE (INDISCERNIBLE) WHAT DO YOU SEE AS PATHWAY, WHERE DOES IT FIT IN THE PROGRAM, THE NEXT STEPS? >> I JUST DON'T HAVE ENOUGH TIME TO COVER, CRYOMD IS A BIG PART OF THE PORTFOLIO, I HOPE JIM HANDA WILL COVER THAT. YEAH, IT'S SUCH A LARGE PERCENTAGE OF THE PEOPLE AND THERE'S A LOT OF PEOPLE STUDYING ABOUT THE OXIDATIVE STRESS, BUT I WOULD SAY EVEN TRYING TO UNDERSTAND THE COMPLEMENT FACTOR, WHAT HAPPENS IN THE WHOLE PATHWAY, SO I DO HAVE A LOT OF BASIC RESEARCH GRANTS IN THAT AREA. [APPLAUSE] >> OUR NEXT TOPIC IS CLINICAL TRIAL STEWARDSHIP REFORMS, SPEAKER IS DR. JODY BLACK. JODY IS DEPUTY DIRECTOR OF THE NIH OFFICE OF EXTRAMURAL RESEARCH THAT IS THE ENTITY THAT SPANS ALL THE INSTITUTES AND CENTERS. SO IN HER ROLE SHE HAS RESPONSIBILITY FOR MANAGING AND DEVELOPING PROGRAMS THAT APPLY TO THE FULL SPAN OF EXTRAMURAL ACTIVITIES GRANTS, GRANTS MANAGEMENT PROGRAM AND REVIEW. AND SHE SPANS THE FULL RANGE OF ACTIVITIES FROM SBIRs TO RESEARCH GRANTS TO, IN THIS CASE, CLINICAL TRIALS. HER CAREER SPANS -- RESEARCH MANAGEMENT HAS BEEN IN CANCER, INFECTIOUS DISEASE AND GENOMICS, AND SHE'S MADE A PARTICULAR INTEREST IN DEVELOPING RELATIONSHIPS BETWEEN ACADEMIC INSTITUTIONS AND COMMERCIAL INSTITUTIONS, AND SO THE IDEA IS TO DEVELOP INNOVATIVE TECHNOLOGIES AND BRING THEM TO IMPROVED HEALTH OF THE NATION. BEFORE JOINING OER, SHE HAD SENIOR LEADERSHIP POSITIONS IN BOTH CANCER INSTITUTE AND HEART LUNG INSTITUTE. WITH THAT I'LL TURN IT OVER TO JODY. >> THANK YOU FOR INVITING ME TO BE HERE TODAY. I HEAR THERE'S ANXIETY ABOUT DEFINITION OF CLINICAL TRIALS AT NIH. I HOPE TO RELIEF THAT AND HAVE AN OPEN DISCUSSION, WE'RE IMPLEMENTING NEW RULES, IT'S BUMPY, LET'S RELIEVE YOUR ANXIETY. FIRST I WANT TO REMIND YOU OF WHY WE'VE MADE SO MANY SIMULTANEOUS CHANGES IN THE WAY WE'RE ACCEPTING AND MANAGING AND MONITORING CLINICAL TRIALS. SO A QUARTER CENTURY AGO IAN CHALMERS PUBLISHED IN JAMA, SUBSTANTIAL ENOUGH OF CLINICAL TRIALS ARE NEVER REPORTED, FAILURE TO PUBLISH LEADS TO INAPPROPRIATE DECISIONS. NIH WORKED WITH COLLABORATORS INCLUDING JOSEPH ROSS, SHE PUBLISHED A STUDY THAT SHOWED THAT ABOUT 50% OF NIH SUPPORTED STUDIES DON'T REPORT THEIR TRIAL RESULTS WITHIN 24 MONTHS. THE PROBLEM CONTINUES HERE. THIS IS PUBLISHED LAST YEAR. THESE FOLKS LOOKED AT LARGE PHASE 3 CANCER TRIALS, AND THEY WERE ABLE TO SHOW THAT WITHIN ABOUT -- IF YOU LOOK AT THE BOTTOM HERE, THIS IS MONTHS, HERE IS PERCENTAGE OF TRIALS THAT PUBLISH RESULTS. LESS THAN 40% PUBLISHED AFTER 24 MONTHS, AND WHEN YOU GOT OUT TO 60 MONTHS, FIVE YEARS, IT WAS ONLY 65% AND NEVER HIT 100%. IT LEVELED OFF. THIS IS A PROBLEM. AND THEN HARLAN KRUMHOLZ LOOKED AT PUBLICATION PROCESSES, REPORTING HABITS OF THE 50 LARGE -- TOP 50 ACADEMIC INSTITUTIONS, TOOK A LOOK AT OVER 4,000 STUDIES TO SEE HOW MANY OF THEM WERE PUBLISHING WITHIN EITHER PUBLICATION OR clinicaltrials.gov. HE FOUND EVEN THE BEST ONE, UNIVERSITY OF MINNESOTA, THE BEST ONE ONLY HAD A 55% OF THEIR STUDIES PUBLISHED. SO I'M GOING TO ASK YOU NOW, I DON'T KNOW IF ANY OF YOU ARE AFFILIATED WITH THESE OTHER INSTITUTIONS BUT WHAT'S GOING ON IN YOUR HOUSE? I HOPE YOU LOOK AT THAT SERIOUSLY. HE PUBLISHED A COMMENTARY A WHILE LATER AND SUGGESTED THAT THERE'S A CULTURE THAT'S BEEN SET UP IN ACADEMIC MEDICAL CENTERS WHERE PUBLISHING AND REPORTING TRIAL OUTCOMES IS DISCRETIONARY RATHER THAN MANDATORY. AND SO HE GAVE ACADEMIC MEDICAL CENTERS AN F IN SHARING RESEARCH RESULTS. THIS IS A PROBLEM FOR ALL RESEARCHERS, NOT JUST FOR CLINICAL TRIALS. AND OF COURSE A LOT OF OUR SHARING POLICIES ARE CHANGING, THERE WILL BE SOME PROCESSES TO RESULT. NOT REPORTING RESULTS YOU'LL AGREE THIS VIOLATES A BASIC PRINCIPLE OF SCIENTIFIC METHOD, HARMS PATIENTS AND SOCIETY AND SCIENCE AND DISHONORS THE PARTICIPANTS WHO GAVE CONSENT AND BORE THE RISK AND INVESTED TIME IN THESE STUDIES. SO THIS IS SOMETHING THAT NIH IS TRYING TO FOCUS ON IN A COMPREHENSIVE WAY TO GET STUDIES WE SUPPORT PUBLISHED, REPORTED IN clinicaltrials.gov IN SOME FORM. SO THAT'S SORT OF THE BACKGROUND FOR WHY A LOT OF THESE CHANGES ARE HAPPENING NOW. SO THIS IS CURRENTLY THE BROADENED NIH DEFINITION OF A CLINICAL TRIAL. IT'S A RESEARCH STUDY IN WHICH ONE OR MORE HUMAN SUBJECTS ARE PROSPECTIVELY ASSIGNED TO EVALUATE EFFECT THOSE INTERVENTIONS HAVE ON HEALTH-RELATED BIOMEDICAL OR BEHAVIORAL OUTCOMES. YOU'LL FIND THIS IS LISTED ON THE OFFICE OF SCIENCE POLICY WEBSITE, IN ADDITION TO OER WEBSITE. DEFINITIONS ARE LISTED ON THE BOTTOM HERE. SO THE BASIC PREMISE THAT NIH WAS THINKING WHEN THEY BROADENED DEFINITION OF CLINICAL TRIAL ALL NIH-FUNDED RESEARCH IS HEALTH RELATED. AND SO BASED ON THAT PREMISE, NIH DECIDED THE DEFINITION OF CLINICAL TRIALS SHOULD BE BROADENED AND TO ENCOMPASS BIOMEDICAL AND BEHAVIORAL OUTCOMES. RECENTLY IN JANUARY THE COMMON RULE WAS PUBLISHED IN THE FEDERAL REGISTER, AND THE COMMON RULE ACCEPTED NOTICE OF PROPOSED RULE MAKING DEFINITION OF CLINICAL TRIALS WHICH IS IDENTICAL TO THE NIH DEFINITION OF CLINICAL TRIALS. THIS WAS PUBLISHED IN THE REGISTER ON JANUARY 12th, AND ON PAGE 7260, DEFINITIONS PAGE, YOU'LL SEE THIS DEFINITION OF CLINICAL TRIALS. THIS ISN'T A PREAMBLE BUT THE DEFINITION IS LISTED ON THIS PAGE. THIS TRIAL, THIS DEFINITION, IS TO BE USED STARTING JANUARY 19, 2018. SO WE CAN'T EVEN DEBATE IT ANYMORE. AND SO THE WAY WE'RE TRYING TO HELP PEOPLE THINK ABOUT WHETHER OR NOT YOU'VE GOT A CLINICAL TRIAL IS BY LOOKING AT THESE FOUR QUESTIONS. SO IF THE ANSWER TO ALL FOUR OF THESE QUESTIONS IS YES, THEN THE STUDY WOULD BE CONSIDERED A CLINICAL TRIAL ACCORDING TO THE NIH DEFINITION AND DEFINITION IN THE COMMON RULE. THE FIRST ONE IS OBVIOUS, DOES THE STUDY INVOLVE HUMAN PARTICIPANTS, ARE THE PARTICIPANTS ASSIGNED, YES, IS THE STUDY DESIGNED TO EVALUATE EFFECT OF THE INTERVENTION ON PARTICIPANTS, AND IS THE EFFECT BEING EVALUATED A HEALTH-RELATED BIOMEDICAL OR BEHAVIORAL OUTCOME. THE CAVEAT, STUDIES USING SURVEYS LOOKING FOR USER PREFERENCE OR CERTAIN KINDS OF INFORMATION RETENTION AND FOCUS GROUPS ARE NOT CONSIDERED CLINICAL TRIALS. AND SO I WANTED TO TELL YOU THAT STARTING WITH APPLICATION ALSO THEN COME IN ON OR AFTER JANUARY 25, 2018, WE'LL BE ACCEPTING CLINICAL TRIALS IN RESPONSE TO DEDICATED FOAs, SO THE PARENT RO1 WILL NO LONGER ACCEPT CLINICAL TRIALS, THERE WILL BE ANOTHER RO1 THAT ALLOWS CLINICAL TRIALS TO COME IN THAT INSTITUTES CAN CHOOSE TO SIGN ONTO. THERE WILL BE OTHER FUNDING OPPORTUNITY ANNOUNCEMENT THAT WILL ACCEPT CLINICAL TRIALS AND THE REASON WE HAD TO DO THIS IS BECAUSE WE'RE ASSOCIATING A SPECIAL FORM WITH THOSE FUNDING OPPORTUNITY ANNOUNCEMENTS THAT CONSOLIDATES AND COLLECTS NEW REQUIRED CLINICAL TRIAL INFORMATION SO THE GOAL WAS TO MAKE IT EASY. HUMAN SUBJECT INFORMATION WAS SCATTERED AROUND A LOT OF DIFFERENT PLACES PREVIOUSLY. WE'VE CONSOLIDATED. YOU CAN PREVIEW IT HERE AT THIS WEBSITE. I UNDERSTAND YOU HAVE ACCESS TO THESE SLIDES. THIS IS A SNAPSHOT OF THE FORM ON THE FIRST PAGE. THESE ARE THE FOUR QUESTIONS, AND IF YOU ANSWER YES TO ALL OF THESE THEN YOU'LL BE PROMPTED TO PUT IN ADDITIONAL INFORMATION ABOUT THE STUDY POPULATION CHARACTERISTICS, ABOUT THE PLANS FOR PROTECTION AND MONITORING, ABOUT THE PROTOCOL SYNOPSIS AND ANY OTHER FOA-SPECIFIC INFORMATION THAT MIGHT BE REQUIRED. LET'S SEE. SO BASICALLY LET'S TAKE A LOOK& AT A COUPLE CASE STUDIES. THIS STUDY IS NOT A CLINICAL TRIAL. SO THIS STUDY IS RECRUITING PATIENTS WITH KNOWN DISEASE X, THEY WANT TO EVALUATE INVESTIGATIONAL IN VITRO DIAGNOSTIC DEVICE. THE STUDY IS DESIGNED TO EVALUATE THE ABILITY OF THE DEVICE TO DETECT ANTIBODIES. SO DOES THE STUDY INVOLVE HUMAN PARTICIPANTS? YES, ARE THEY ASSIGNED TO INTERVENTION, IN THIS CASE THE THINKING WAS THAT THEY ARE BECAUSE THE INTERVENTION IS THE IVD. IS THE STUDY DESIGNED TO EVALUATE EFFECT OF THE INTERVENTION ON THE PARTICIPANT? THE ANSWER IS NO. THE DEVICE ITSELF HAS NO EFFECT ON THE PARTICIPANT. ALL THEY ARE LOOKING FOR IS WHETHER OR NOT THE DEVICE CAN DETECT ANTIBODIES, PROBABLY A VALIDATION STUDY OF THE DEVICE ITSELF. SO THIS IS NOT A CLINICAL TRIAL. DOES THAT MAKE SENSE? OKAY. LET'S LOOK AT THE NEXT ONE. THIS STUDY INVOLVES RECRUITMENT OF CHILDREN AT TWO SCHOOLS TO EVALUATE THEIR PREFERENCES ABOUT GRAPHICS AND COLORS USED IN HEALTHY FOOD ADVERTISEMENTS. CHILDREN WILL BE PRESENTED WITH MULTIPLE DIFFERENT ADVERTISEMENTS THAT HAVE DIFFERENT COLORS AND GRAPHICS ON THEM. AND THEN THEY ARE GOING TO BE ASKED WHICH ONES THEY LIKE BETTER. SO DOES THE STUDY INVOLVE HUMAN PARTICIPANTS, YES, ASSIGNED TO INTERVENTION, YES, SHOWN DIFFERENT ADVERTISEMENTS WITH DIFFERENT COLORS AND DIFFERENT GRAPHICS. IS IT DESIGNED TO EVALUATE EFFECT OF INTERVENTION ON PARTICIPANT? ONE COULD THINK YES, WE WANT TO UNDERSTAND WHICH ONE THEY LIKE BETTER. IS THE EFFECT OF BEING EVALUATED A HEALTH RELATED BIOMEDICAL OR BEHAVIORAL OUTCOME? THE ANSWER IS NO BECAUSE PREFERENCES FOR GRAPHICS AND COLORS ARE NOT HEALTH RELATED. DOES THAT ONE MAKE SENSE? OKAY. SORRY. >> IF YOU'RE OPEN FOR QUESTIONS. >> SURE. >> (INAUDIBLE) OF COLORS FOR INSTANCE IN A TEST WOULD THAT BE A CLINICAL TRIAL? THAT'S THE KIND OF THING THAT MY COLLEAGUES ARE CONCERNED ABOUT. >> YEAH, AND SO THOSE KINDS OF QUESTIONS, THERE'S A LOT OF CONCERN ABOUT HOW WE'RE PARSING THIS, SO WE'RE REALLY LISTENING VERY CAREFULLY TO THE COMMUNITY. WE'VE PUT TOGETHER A LITTLE GROUP INTERNALLY WITH OER AND OSP LEADERSHIP, MYSELF INCLUDED. IF PROGRAM STAFF OR IC STAFF CAN'T HELP RESOLVE WHETHER OR NOT, YOU KNOW, IT'S A TRIAL, WE'RE HAPPY TO HELP. WE'LL WORK THROUGH THESE AND WE'VE DEVELOPED ABOUT 27 DIFFERENT EXAMPLES OF CLINICAL STUDIES THAT ARE AND ARE NOT ANSWERING ALL FOUR OF THESE QUESTIONS, WE'RE GOING TO POST THOSE ON THE OSP WEBSITE VERY SOON SO HOPEFULLY THAT WILL BE HELPFUL. YES? >> IN THIS LAST POINT, IN WHICH THE ANSWER IS NO, SEEMS TO BE AT ODDS WITH THE ORIGINAL PREMISE THAT ALL NIH RESEARCH IS HEALTH RELATED. >> RIGHT, BUT WE PUT THAT CAVEAT IN AT THE BEGINNING. OOPS. WHERE DID I PUT THAT? WE HAVE THIS CAVEAT IN FOR THAT PREMISE. DOES THAT HELP? OKAY. SO IN TRYING TO COLLECT ALL OF THIS AND GIVE YOU A FRAMEWORK, IF YOU'RE DOING A STUDY AND IT DOESN'T INVOLVE SURVEYS OR USER PREFERENCE OR FOCUS GROUPS OR CERTAIN KINDS OF INFORMATION RETENTION AND YOU ANSWER NO, IS THE STUDY DESIGNED TO EVALUATE THE EFFECT OF INTERVENTION ON PARTICIPANTS, NO, IT'S NOT A CLINICAL TRIAL. IF IT'S YES AND NOT ANY OF THE ABOVE AND FUNDED BY THE NIH, THEN IT IS A CLINICA TRIAL. >> SORRY. SO IF THE STUDY LOOKS AT VISUAL ACUITY, IS THAT A CLINICAL TRIAL? >> SO WALK ME THROUGH IT TO MAKE SURE I UNDERSTAND. SO WE HAVE -- YOU'RE BRINGING IN HUMAN SUBJECTS AND YOU'RE GOING TO DO WHAT? >> YOU'RE GOING TO HAVE THEM PRACTICE SOME TOSS, SOME VISUAL TASK. >> INTERVENTION IS VISUAL TASK. >> YES, MAYBE AT TWO DIFFERENT LIGHT LEVELS. >> OKAY. >> AND THEN YOU LOOK AT THE OUTCOME AS A MEASURE OF VISUAL ACUITY. IS THAT -- >> YES, BECAUSE YOU'RE LOOKING AT TASKS AT DIFFERENT LIGHT LEVELS TO SEE HOW IT AFFECTS VISUAL ACUITY SO THERE'S A DIRECT EFFECT OF INTERVENTION ON SOMETHING ABOUT THE PERSON, VISUAL ACUITY. YES, THAT WOULD BE CONSIDERED A CLINICAL TRIAL. >> THAT'S WHAT IS CAUSING A LOT OF HEARTBURN FOR PEOPLE. >> AND THE REASON IS BECAUSE IN THE PAST IT WOULDNT BE CONSIDERED A CLINICAL TRIAL. HEARTBURN IS BECAUSE THERE'S MORE INFORMATION THAT'S GOING TO BE REQUIRED OR THERE'S REPORTING INFORMATION THAT'S GOING TO BE REQUIRED? >> WELL, BECAUSE THERE ARE LOTS OF STUDIES THAT INVOLVE VERY SMALL NUMBERS OF NORMAL HUMAN SUBJECTS THAT ARE ASKING REALLY BASIC MECHANISTIC QUESTIONS USING BEHAVIORAL OUTCOME, SUCH AS VISUAL ACUITY, COLOR DISCRIMINATION, THAT OFTEN RESEARCH IS DONE BY STUDENTS ROTATING IN THE LAB OR IN THE SUMMER. THERE ARE GOING TO BE THOUSANDS OF STUDIES THAT ARE ALL OF A SUDDEN CLINICAL TRIALS WITH A LOT OF -- >> RIGHT, LET ME TELL YOU WHAT THE CURRENT THINKING IS ALONG ONE THING NIH WANTS TO AVOID DESPERATELY, AND I DON'T THINK ANY OF YOUR STUDIES ARE LIKE THIS, BUT WHAT WE'RE CALLING SMALL CRAPPY TRIALS WITH TWO FEW INDIVIDUALS TO REALLY GET A MEANINGFUL OUTCOME FROM. A LOT OF THAT INFORMATION GETS INTO THE LITERATURE OR IT DOESN'T, AND IT DOESN'T ADD ANY VALUE. THAT'S ONE THING WE WANT TO CONTROL. THE SECOND THING WE WANT TO MAKE SURE IF YOU HAVE A STUDENT WHO IS DOING ONE OF THESE STUDIES THAT THEY ARE DOING IT UNDER THE LEADERSHIP AND MENTORING OF A SENIOR PERSON SO IT'S NOT THE STUDENT WHO SHOULD BE RUNNING THE SHOW BUT THE LAB P.I. AND THE MENTOR SHOULD BE VERY HEAVILY INVOLVED, TO MAKE SURE THAT THE STUDIES ARE SUFFICIENTLY POWERED AND OUTCOMES ARE WHAT ONE MIGHT EXPECT, WHAT A REASONABLE PERSON MIGHT EXPECT. SO ACTUALLY THESE NEW REQUIREMENTS ARE DESIGNED TO HELP CONTROL SOME OF THOSE EXAMPLES. YES? >> I HAD A QUESTION ON A DIFFERENT SCENARIO. WHAT IF THE PERSON IS HAVING AN INTERVENTION, AS A RESULT OF THEIR NORMAL MEDICAL CARE. SO BUT THEN WE'RE TAKING MEASUREMENTS OFF OF THAT, MEASUREMENTS THAT HADN'T BEEN STUDIED BEFORE. >> YOU HAVE PEOPLE WITH DISEASE X WHO ARE COMING IN FOR ROUTINE CARE. >> RIGHT. LET'S SAY THEY ARE HAVING CATARACT SURGERY. >> OKAY. >> HAVING CATARACTS. THEY HAVE CHOSEN TO HAVE CATARACT SURGERY AS PART OF THEIR CARE. >> UH-HUH. >> WE WANT TO MAKE WHAT HAPPENS TO THE DEPTH OF ANGLES, LENGTH OF THIS, WHATEVER OF THAT, TAKING A BUNCH OF MEASUREMENTS. IS THAT NOW A CLINICAL TRIAL? >> SO ARE YOU GOING TO USE THOSE MEASUREMENTS TO INFORM PATIENT CARE? >> YES. >> YES. AND THEY WOULD HAVE TO HAVE CONSENTED TO THAT. >> YEAH. >> THAT'S GOING TO BE A TRIAL. >> I HAVE A CONCERN ABOUT THE BUREAUCRATIC BURDEN THAT SMALL INSTITUTIONS WHERE THERE AREN'T SO MANY MUCH US THAT OVERSEE CLINICAL RESEARCH, AND ULTIMATELY THE P.I. IS THE PERSON WHO WILL ANSWER THESE QUESTIONS, AND REGISTER THE SMALL STUDY ON clinicaltrials.gov AND HANDLE EVERYTHING. BUT WE HAVE A LOT OF STUDENT PROJECTS LIKE DENNIS MENTIONED, JUST SMALL SHORT-TERM PROJECTS, AS PART OF OUR T35 TRAINING, AND THERE MAY NOT BE THAT MANY SUBJECTS. BUT THEY USED TO COLLECT PILOT DATA FOR LARGER HOPEFULLY REAL WELL-DEFINED CLINICAL TRIALS, AND NOW ALL THESE SMALL PROJECTS WITH SMALL SUBJECT NUMBERS ARE GOING TO GET REGISTERED ON clinicaltrials.gov, PROSPECTIVE PATIENTSN MY CASE MYOPIC PATIENTS WHO WANT TO KNOW WHAT TO DO ABOUT THEIR CONDITION, ARE GOING TO GO AND THEY ARE GOING TO WANT TO REGISTER IN OUR SMALL STUDENT PROJECTS AND I SEE THIS AS CREATING A LOT OF CONFUSION AND A LOT OF POTENTIALLY UNNECESSARY BUREAUCRATIC OVERSIGHT. >> SO YOU'RE NOT THE FIRST PERSON WHO SAID THAT. UNFORTUNATELY I CAN'T -- WE CAN'T UNDO IT BECAUSE IT IS GOING FORWARD BUT WHAT WE'RE TRYING TO DO IS MAKE IT AS EASY AS POSSIBLE. AND SO IT'S TRUE THAT THE P.I.s ARE GOING TO HAVE TO REGISTER STUDIES IN clinicaltrials.gov BUT THAT'S THE LAW AND ACTUALLY HAS BEEN SINCE 2002 OR 2003. WE DIDN'T IMPLEMENT UNTIL 2007 BUT IT'S BEEN THE LAW FOR QUITE SOME TIME. THE NEW RULE THAT CAME OUT LAST YEAR ACTUALLY GAVE US THE ABILITY TO HAVE A COMPLIANCE ENFORCEMENT PIECE. THE WAY THE REGULATION WAS WRITTEN BEFORE IT WAS INSUFFICIENTLY WORDED TO ALLOW US TO HAVE COMPLIANCE ACTION BUT THAT'S ALL CHANGED. SO THE GOAL HERE IS ACTUALLY TO GET THOSE CLINICAL TRIALS REGISTERED AND WE'RE GOING TO HAVE TO HELP THE COMMUNITIES WHAT THE INFORMATION IN THAT REGISTRY MEANS IN clinicaltrials.gov. YES? >> I WAS GOING TO SUGGEST THAT THERE BE SOME EDUCATIONAL PIECE TO THIS FOR THE COMMUNITY. >> SO WE'RE DOING A LOT OF OUTREACH INTERNALLY NOW. AND I KNOW A LOT OF OUR PROGRAM STAFF AT THE ICs ARE PLANNING OUTREACH AND TRAINING EFFORTS THEMSELVES. SO THAT'S PART OF THE OVERALL IMPLEMENTATION PLAN. >> BUT INCLUDING FOR SUMMER PROJECTS, QUOTE/UNQUOTE? >> I WILL BRING THAT UP SPECIFICALLY WITH KAY LUND WHO OVERSEES OUR DIVISION OF BIOMEDICAL WORK FORCE, VERY EMBEDDED IN THE REQUIREMENTS HERE. >> IF WE WERE TO BE COLLECTING TISSUES OR MATERIALS THAT WOULD NORMALLY BE TAKEN FROM A PATIENT IN A SURGICAL PROCEDURE OR INTERVENTION, AND MEASURING SOMETHING ON THAT TISSUE, TO SEE THE EFFECTS OF CERTAIN THINGS THAT THE PATIENT MAY OR MAY NOT DO, DOES THAT -- >> LET'S BREAK THIS DOWN. IF YOU'RE COLLECTING TISSUES AS PART OF NORMAL COURSE OF SURGERY TO PUT THEM IN A BANK AND INTERROGATE THEM LATER, NO. IF YOU'RE JUST LOOKING FOR BIOMARKERS AND JUST TO LOOK FOR MECHANISTIC ISSUES, NO, THAT'S NOT A CLINICAL TRIAL. IF YOU'RE GOING TO COLLECT THAT SAMPLE DURING SURGERY, MEASURE SOMETHING AND USE THAT TO MAKE A PATIENT DECISION ABOUT CARE, THEN IT IS. >> FOR EXAMPLE, VERY FORWARD, PATIENTS WHO WEAR DIFFERENT TYPES OF CONTACT LENSES, BECAUSE THEY CHOOSE WHAT CONTACT LENS BETTER FITS THEM. >> YES. >> WE TAKE THE CONTACT LENSES AFTER THEY ARE GOING TO BE DISCARDED AND WE MEASURE THE MICROBIOME ON THOSE CONTACT LENSES THAT COULD POTENTIALLY TELL US HOW THOSE CONTACT LENSES MODIFY THE SURFACE MICROBIOME OF THE PATIENT AND THAT MAY IN FACT HAVE AN EFFECT ON THE INCIDENCE OF INFECTION FROM THE PATIENT. >> YES, SO WILL YOU -- ARE YOU COLLECTING GENERALIZABLE INFORMATION TO UNDERSTAND MORE ABOUT THE MICROBIOME THAT BEFORE AND AFTER CONTACT LENS USE OR ARE YOU COLLECTING INFORMATION ABOUT A PATIENT'S MICROBIOME TO MAKE DECISIONS ABOUT TREATMENT OF THAT PATIENT EVEN WITH THE DIFFERENT KIND OF CONTACT LENS? >> SO IF WE DEIDENTIFY AND NOT ASSIGN THAT CONTACT LENS TO A PATIENT, THEN IT'S NOT A CLINICAL TRIAL? >> SO IF THE CONTACT LENS ESSENTIALLY BECOMES A BIOSPECIMEN THAT YOU'RE GOING TO INTERROGATE FOR GENERALIZABLE KNOWLEDGE, NO, IT IS NOT A CLINICAL TRIAL. OKAY? SORRY. >> NO PROBLEM. I JUST WANT TO COMMENT ON THE BACK END OF THIS. BECAUSE I'VE BEEN IN COMPLIANCE WITH THIS OF COURSE EVEN WITH NON-NIH FUNDED WORK AND I HAD SOME TROUBLE WITH THE ACTUAL REPORTING, AND THE FIELDS WERE REALLY CLUNKY AND IT TOOK ABOUT THREE HOURS GOING BACK AND FORTH. >> WAS THAT RECENT? >> NOT A YEAR AGO. >> THE NATIONAL LIBRARY OF MEDICINE HAS BEEN WORKING VERY HARD TO REVAMP THE clinicaltrials.gov WEBSITE TO MAKE IT MORE USER FRIENDLY AND HOPEFULLY IT IS. I CAN'T SPEAK TO THAT, BUT THAT WAS THE INTENTION, AND WE'VE ACTUALLY -- WE'VE MARRIED ALL OF OUR ELEMENTS IN THE FORM AND REQUIRED ELEMENTS IN clinicaltrials.gov SO IT'S ALL HARMONIOUS. SO THAT WAS DONE INTENTIONAL TO MAKE THINGS EASIER. >> I'D LIKE TO RETURN TO THE QUESTION ABOUT SMALL BEHAVIORAL STUDIES ON NORMAL SUBJECTS SO FOR INSTANCE YOU WANT TO ANSWER A THEORETICAL QUESTION THAT IS A CERTAIN VISUAL PROCESS PHOTON LIMITED, THE WAY YOU ANSWER IT IS BY MEASURING VISUAL PERFORMANCE AT SEVERAL DIFFERENT LIGHT LEVELS, AND THIS IS TYPICALLY DONE IN THESE KIND OF BEHAVIORAL STUDIES ON A VERY SMALL NUMBER, MAYBE THREE OR FOUR WELL-TRAINED SUBJECTS, SO YOU CAN ACTUALLY DRAW STRONG CONCLUSIONS. YOU DON'T NEED TO PAIR IT UP WITH 50 PEOPLE, BUT THERE'S AN INTERVENTION, AND THERE'S A BEHAVIORAL OUTCOME MEASURE WHICH -- SO IS THAT A CLINICAL TRIAL? >> TELL ME AGAIN WHAT THE OUTCOME MEASURE IS. >> THE OUTCOME MEASURE COULD BE VISUAL ACUITY, COLOR DISCRIMINATION. >> YOU'RE MEASURING THE ACTUAL CHANGE IN A PERSON'S PHYSIOLOGY OR BEHAVIOR? >> RIGHT. >> WHAT THEY CAN SEE? YES, EVEN THOUGH IT'S SMALL, THAT WOULD BE A TRIAL. CHARACTERISTICS OFG- DISCRIMINATOR. >> THAT WOULD BE A TRIAL. WITH SMALL TRIALS AS LONG AS YOU CAN GET THE KIND OF ANSWER YOU'RE LOOKING FOR, THAT'S FINE. WE WANT TO AVOID THE PROBLEM OF POORLY POWERED STUDIES, NOT AN UNCOMMON PROBLEM. >> BASICALLY EVERYONE WHO IS DOING THIS KIND OF WORK IS GOING TO HAVE -- >> YES, THAT'S WHAT IT COUNTS LIKE. >> IT WOULD BE A CLINICAL TRIAL. >> JODY, TO CLARIFY, THE INTERVENTION IN THIS CASE, DENNIS' EXAMPLE IS NOT TO CHANGE THAT PERSON'S ACUITY OR CHANGE THEIR PERCEPTION OF MOTION, BUT PURELY TO MEASURE CAPACITY OF SOMEONE TO PERCEIVE MOTION OR THEIR ACUITY UNDER THOSE PARTICULAR CONDITIONS. >> RIGHT. YOU'RE GIVING THEM AN INTERVENTION THAT WILL HAVE EFFECT ON THEIR ACUITY. >> NO. IT'S ONLY TO MEASURE THEIR ACUITY. >> OH, NO. IF IT'S MEASURING ACUITY, JUST WITHOUT DOING ANYTHING TO EFFECT THE ACUITY, IS THAT CORRECT? IF YOU'RE NOT DOING ANYTHING TO AFFECT ACUITY, JUST MEASURING, NO, THAT'S NOT A TRIAL. >> OKAY. >> (INAUDIBLE). >> RIGHT. >> A LOT OF THIS -- (INAUDIBLE) -- BUT I THINK WHERE YOU'RE GOING -- (INAUDIBLE). >> WHAT I'M TRYING TO UNDERSTAND IS IF YOU'RE DOING SOMETHING THAT WILL AFFECT -- >> (INAUDIBLE). >> I'LL IGNORE IT. >> SO THE EXAMPLE IS THAT YOU CHANGE THE BRIGHTNESS OF THE SCREEN THAT THEY ARE LOOKING AT AND ASK, BASICALLY, DOES THAT CHANGE THEIR ABILITY TO DISCRIMINATE. >> SO, YES, I THINK THAT WILL BE CONSIDERED A CLINICAL TRIAL. >> YOU'RE INTERVENING ON THE SCREEN, NOT IN THEIR -- >> BUT THEY HAVE TO LOOK AT THE SCREEN, SO THE CHANGE IN LIGHT IS THE INTERVENTION. SO THAT'S -- THAT'S WHAT I'M THINKING. I WILL BRING ALL THESE EXAMPLES BACK SO WE CAN HAVE A DISCUSSION ABOUT THEM BUT THAT'S WHAT I THINK IS GOING TO BE THE DECISION. >> SO JUST LET ME -- I THINK WHAT THE CONCERN IS, IS THAT AT A GIVEN LIGHT LEVEL THERE'S NOTHING TO CHANGE THE ACUITY. >> OKAY. >> IT IS NOT MODULATABLE IN THE INTERVENTION OR -- I MEAN, SO IT MIGHT BE AT THE END OF IT YOU SAY, LIKE, WELL TURN UP THE SCREEN BRIGHTNESS, BUT THAT'S NOT A CLINICAL -- THAT'S WHAT WE'RE SAYING, IS THAT A CLINICAL TRIAL? IF THE INTERVENTION IS JUST A DIFFERENT LEVEL, IT IS NOT INTENDED TO MODULATE THE HEALTH-RELATED OUTCOME. >> IF YOU'RE NOT LOOKING FOR SOMETHING THAT'S MEASURABLE, OKAY, IF WHAT YOU'RE DOING IS NOT LOOK FOR A MEASURABLE CHANGE THEN IT PROBABLY IS NOT A CLINICAL TRIAL IF I'M UNDERSTANDING THIS CORRECTLY. DOES THAT MAKE SENSE? OKAY. >> I THINK WE'LL NEED TO EXPLORE THAT A LOT -- >> PAUL, LET'S TALK ABOUT IT. LET'S ADD EXAMPLES AND WORK WITH OSP TOGETHER. >> OKAY. YES? >> ONE LAST QUESTION, TO CONFIRM WHAT I THOUGHT I HEARD IF IT'S A MECHANISM OF ACTION TO UNDERSTAND THE MECHANISM, THAT'S NOT A CLINICAL TRIAL? >> SO IF YOU'RE NOT GOING TO USE THE INFORMATION TO INFORM PATIENT CARE, IN MOST CASES IT WON'T BE A CLINICAL TRIAL, BUT YOU WILL NEED TO FILL OUT PARTS OF THAT FORM BECAUSE THAT FORM WILL ENCOMPASS ALL HUMAN SUBJECTS RESEARCH. >> THAT WAS THE QUESTION, ASK THE CONFIRMATION OF THE QUESTION PART IS WHEN YOU ASKED ME WILL THOSE MEASUREMENTS BE USED TO INFORM PATIENT CARE, IT WON'T INFORM THAT PATIENT'S CARE BUT WE'RE TRYING TO UNDERSTAND -- >> YES, BUT YOU CAN AGGREGATE DATA AND IF THOSE SAMPLES EXISTED JUST AS EASILY GO TO A BIOBANK AND GET THEM, CORRECT? IF WHAT YOU'RE GOING TO INTERROGATE ALREADY EXISTED YOU CAN GET THEM FROM A BIOBANK -- >> IN THE CLINICAL EXAMPLE I'M SEEING EVERY RESIDENT PROJECT NOW BEING REGISTERED IN clinicaltrials.gov. A LOT OF TIMES THEY ARE TRYING TO UNDERSTAND WHAT'S HAPPENING, WHEN WE DO A SURGICAL PROCEDURE, THEY ARE GOING TO TAKE A BUNCH OF MEASUREMENTS, I'LL SAY IT GENERALLY, IMAGING MEASUREMENTS, BIOMETRIC >> RIGHT. >> IT WON'T DIRECTLY AFFECT THE PATIENT. >> THAT'S CORRECT, THAT WON'T BE A TRIAL BUT WILL REQUIRE INFORMATION TO BE SUBMITTED ON THE HUMAN SUBJECTS COMPONENT OF THAT FORM. THAT FORM WILL HAVE ALL HUMAN SUBJECT INFORMATION OR NOT. TRIAL OR NOT, YOU WILL STILL PUT INFORMATION IN ABOUT THE POPULATION, WE HAVE TO DO AGE NOW, SEX AND GENDER, ALL THAT INFORMATION WILL HAVE TO BE ON THAT. >> BASICALLY IF I'M UNDERSTANDING THIS CORRECTLY, I APOLOGIZE FOR BEING SOMEWHAT IGNORANT, IS THAT ANYTIME WE DO PRETTY MUCH ANYTHING WITH PATIENTS WE'VE GOT TO GO ON THAT FORM, MAYBE IT'S A TRIAL, MAYBE IT'S NOT. >> YES, PUT IN INFORMATION ABOUT YOUR HUMAN SUBJECTS ANYWAY. NOW WE AGGREGATE WHERE YOU PUT THAT INFORMATION INTO ONE PLACE. >> SO IT SOUNDS LIKE WHAT YOU'RE SAYING IS THAT MY STUDY, THE EXAMPLE I GAVE, WHERE YOU TAKE NORMAL SUBJECTS, YOU'RE TRYING TO ANSWER A BASIC QUESTION, IT'S NOT GOING TO INFORM PATIENT CARE, SO WHY IS THAT A A CLINICAL TRIAL? >> IF IT'S NOT GOING TO CHANGE SOMETHING ABOUT THEM IT DOESN'T SOUND LIKE IT BUT I'LL TALK TO PAUL AND MAKE SURE WE WRITE THESE IN GREAT DETAIL SO WE'RE ON THE SAME PAGE. >> IT'S NOT ACTUALLY GOING TO CHANGE ANYTHING ABOUT THEM. >> OKAY. >> IT'S CHANGING THE CIRCUMSTANCES UNDER WHICH YOU'RE MEASURING THEM. >> OKAY. OKAY. THAT'S PROBABLY NOT A TRIAL. I THINK I GOT IT. SO I'M JUST -- TO FINISH UP VERY QUICKLY, THE NEW FORM, ALL THE NEW FOAs WILL BE REQUIRED ON OR AFTER JANUARY 18, 2017, THAT'S WHEN YOU'LL SEE FUNDING OPPORTUNITY ANNOUNCEMENTS WITH THE NEW CLINICAL TRIALS FORMS AND PARENT RO1 WON'T ACCEPT IT ANYMORE. THESE REQUIREMENTS WILL GO INTO PLACE, REGISTER ON clinicaltrials.gov BY 21 DAYS, AND THEN SUBMIT SUMMARY RESULTS BUT I THINK YOU'RE ALL FAMILIAR WITH THAT. AND THEN AS I TOLD YOU EARLIER, WE ARE GOING TO HAVE TO HAVE SOME ENFORCEMENT ACTIONS FOR FOLKS THAT AREN'T IN COMPLIANCE AND THAT ACTION IS GOING TO BE THAT WE'RE GOING TO WITHHOLD FUNDING TO PENDING TRIALS AT AN INSTITUTION IF THERE IS A SINGLE INVESTIGATOR OUT OF COMPLIANCE. SO WE THINK IT WILL ONLY HAPPEN ONCE, BUT THAT'S WHAT THE ENFORCEMENT ACTION IS LOOKING AT. THAT'S HOW IMPORTANT IT IS TO NIH. YOU KNOW THE FDA CAN GO ONE STEP FURTHER AND FINE INSTITUTIONS $10,000 A DAY, SO THAT'S HOW IMPORTANT THIS IS TO GET OUT INTO THE REPORTING WORLD. WE'RE MAKING A LOT OF CHANGES AS YOU KNOW, THEY INCLUDED THINGS LIKE GOOD CLINICAL PRACTICE IS NOW REQUIRED, WE'RE GOING TO HAVE TRAINING ELEMENTS FOR OUR STAFF AND EXTERNAL STAFF, WE'RE MAKING VERY STRATEGIC USE OF clinicaltrials.gov, WE'RE ASKING ALL THE ICs TO HAVE CLINICAL TRIALS MONITORING POLICIES. AND TO MAKE SURE EVERYBODY HAS THEM SO THE STAFF UNDERSTAND HOW THEY WORK AND WE'RE ASKING FOLKS DOING MULTI-SITE STUDIES TO USE A SINGLE IRB, SO LOTS OF CHANGES. IF HAVE YOU QUESTIONS, I'M HAPPY TO ANSWER THEM. IF YOU CAN'T -- IF THE EYE INSTITUTE STAFF HAS QUESTIONS PLEASE FEEL FREE TO CALL US UP. SO THAT'S IT. YES? >> I THINK THIS QUESTION CAME UP AT A PREVIOUS COUNCIL MEETING THAT THE clinicaltrials.gov LISTS ALL CLINICAL TRIALS, NOT JUST NIH OR FDA SPONSORED. >> YES. >> AND IT'S FOR THE UNINITIATED, IT'S A FAIRLY COMPLEX WEBSITE TO NAVIGATE BECAUSE NOT ALL TRIALS ADHERE TO FAIRLY STRINGENT STANDARDS OF, YOU KNOW, -- AND THERE'S A DISCLAIMER ON THE CLINICAL TRIALS WEBSITE BUT THERE'S -- IT'S VERY DIFFICULT TO SORT OUT EXACTLY WHICH TRIALS KIND OF FALL INTO THE MORE STRINGENT CRITERIA. IS THERE ANY DISCUSSION OF HOW TO IDENTIFY THOSE TRIALS THAT SORT OF MEET THESE STANDARDS OF RIGOR AND . >> IF YOU'RE FUNDED BY NIH, THEY MEET THE STANDARDS OF RIGOR. IF YOU'RE NOT FUNDED BY NIH, IT'S MORE -- THE TRIALS ARE WHAT THE FDA REGULATES. SO WE'RE BEYOND -- THE NIH IS LOOKING AT ALL STUDIES BEYOND WHAT THE FDA REGULATES AND FOR THE PRIVATE SECTOR THEIR STUDIES ARE RELEVANT TO WHAT THE FDA REGULATES. >> ON THE WEBSITE IS THERE -- THERE'S NO TAB THAT LISTS JUST NIH TRIALS. >> I DON'T THINK THERE IS. >> SEEMS LIKE IT WOULD BE USEFUL AS A PATIENT RESOURCE TO BE ABLE TO IDENTIFY THOSE TRIALS THAT SORT OF ARE NIH APPROVED BECAUSE EVEN IN THE RETINA FIELD OR EYE FIELD I'VE SEEN HORRIBLE AND DRAMATIC EXAMPLES OF TRIALS GONE BAD AND VERY POOR OUTCOMES FOR PATIENTS. >> (INAUDIBLE). >> IT WILL SAY FDA APPROVED AND YOU CHECK -- IF -- >> (INAUDIBLE). >> I'LL TALK TO THEM ABOUT HAVING SOME SORT OF WAY TO DISCRIMINATE BETWEEN NIH -- I'M NOT SURE THEY WILL SEE THAT BUT I'LL HAVE A CONVERSATION ABOUT THAT. >> SO I'D LIKE TO, A, CONCUR WITH THAT COMMENT. YOU KNOW, NOT ONLY OBVIOUSLY ARE THERE NIH TRIALS AND FDA TRIALS BUT OF COURSE YOU JUST CAN'T PUBLISH ANYTHING, EVEN THE SMALLEST CRAPPIEST TRIAL UNLESS IT'S BEEN REGISTERED, AND SO IT MEANS THAT PRETTY MUCH EVERYTHING SHOWS UP THERE. AND SO INDEED IF THERE WAS SOME WAY TO DISCRIMINATE FEDERALLY FUNDED AND THEN PROBABLY EVEN INDUSTRY FUNDED, AND SORT OF A WAY TO IDENTIFY WHAT IS REALLY THE DETRITUS, AS IT WERE. >> I HEAR THAT. >> THE OTHER THING I WILL SAY IS THAT THE clinicaltrials.gov, WHICH IT IS MUCH BETTER THAN IT WAS, IT STILL IS A VERY LEGALISTIC DOCUMENT AS YOU READ THROUGH IT. >> OKAY. >> I WAS LOOKING AT STEPS FOR REGISTERING CLINICAL STUDY, THE LANGUAGE IS VERY LAWYERLY. SO I THINK IT WOULD BE PROBABLY A GOOD IDEA TO HAVE SOMEONE THINK ABOUT MAKING THE LANGUAGE A LITTLE EASIER. >> I'LL BRING THAT BACK. ANY OTHER QUESTIONS? YES? >> IN YOUR PREVIOUS COMMENTS ABOUT THE REGULATIONS FOR INSTITUTIONS THAT MAY HAVE FOR EXAMPLE A CORE GRANT THAT SUPPORTS A LOT OF TRAINEE RESEARCH THAT MAY BE DOING CLINICAL TRIALS, WILL THE REGULATORY ENVIRONMENT BE THE SAME WHERE IF WE FAIL TO REGISTER APPROPRIATELY OR PROCEED WITH DOCUMENTING RESULTS OF ALL THESE CLINICAL TRIALS, THE PENALTIES ARE GOING TO BE THE SAME? >> YEAH, THAT'S ALL WRITTEN INTO THE REGULATION SO I CAN'T ALTER THAT. >> OKAY. >> YES. >> (INAUDIBLE). >> RIGHT. I JUST WANTED TO MAKE IT CLEAR. >> ARE THESE NEW REGULATIONS GOING TO AFFECT THE REVIEW OF GRANT APPLICATIONS? >> SO THE WAY GRANT APPLICATIONS WILL BE REVIEWED THAT ARE PROPOSED IN CLINICAL TRIALS WILL HAVE ADDITIONAL REVIEW CRITERIA SPECIFIC FOR CLINICAL TRIALS. YES? >> IS THERE A WAY TO COMBINE BASIC SCIENCE AND CLINICAL TRIAL RESEARCH IN A GRANT. >> YES. >> OR ARE THEY COMPLETELY SEPARATE? >> WE'RE DEVELOPING FUNDING OPPORTUNITIES THAT ALLOW YOU TO DO SOME PRE-CLINICAL OR MECHANISTIC WORK AND MAKE A DECISION WHETHER YOU DO A TRIAL, THE FORM WILL ALLOW YOU TO USE COMMONS ACCOUNT FOR DELAYED START TO PUT THE INFORMATION IN LATER. ANYTHING ELSE? THANK YOU SO MUCH FOR YOUR TIME. [APPLAUSE] >> THAT WAS A PRETTY GOOD DISCUSSION, WHY DON'T WE TAKE A SHORT BREAK AND WE WILL BE BACK IN 15 MINUTES. I WANTED TO TELL YOU ABOUT A COURSE THAT I ORGANIZED IN CONJUNCTION WITH ARVO. IT WAS A FULL-DAY COURSE, IT WAS HELD THIS PAST MAY AT THE BALTIMORE CONVENTION CENTER. THE TITLE WAS STEM CELLS AND ORGANOIDS AS MODELS OF DISH DIFFERENTIATION AND EYE DISEASES. THERE WERE 150 PEOPLE REGISTERED FOR THE COURSE, FIVE THAT RECEIVED CME CREDIT, AND THE SURVEY SHOWED IT WAS A HUGE SUCCESS. ON THE NEXT SLIDE I WANT TO MENTION WHAT THE COURSE COVERED. THE COURSE DISCOVERED ALL AREAS OF THE EYE, INCLUDING IT'S ANTERIOR AND POSTERIOR SEGMENTS, AND TAUGHT ABOUT HOW 3D CULTURES DIFFER FROM 2D AND ADVANTAGES AND LIMITATIONS OF BOTH. WE ALSO TALKED ABOUT ORGANOID CULTURE METHODS AND HOW TO GET 3D CULTURES GROWING, VARIOUS SCAFFOLD, DRUG SCREENING AND SOURCE FOR TRANSPLANTATION TISSUE. I WANTED TO SHOW THE AGENDA. THE PLENARY TALK WAS GIVEN BY TOM RAY FROM UNIVERSITY OF WASHINGTON, WHO TALKED ABOUT THE OVERVIEW OF STEM CELLS AND WHAT THE BENEFITS AND DISADVANTAGES ARE OF 3D VERSUS 2D. THE FIRST PART WE TALKED ABOUT, I WANTED PEOPLE TO TALK ABOUT 2D CULTURES, AND WHAT HAS BEEN DONE AND WHAT THE PROBLEMS ARE GOING FORWARD. THE FIRST PART WAS ON THE ANTERIOR SEGMENT, AND CHEFFER TRENG TALKED ABOUT CORNEA AND LIMBAL STEM CELLS, DR. ZHANG TALKED ABOUT ENDOGENOUS STEM CELLS AND JEFF GOLDBERG AT STANFORD TALKED ABOUT RETINAL GANGLION CELLS AND INTEGRATION INTO RETINA. ANAND SWAROOP TALKED ABOUT PHOTORECEPTORS AND JEFF STERN FROM NEW YORK TALKED ABOUT RPE. THEN IN THE AFTERNOON, WE MOSTLY TALKED ABOUT THE DIFFERENCE SCAFFOLDS HOW TO MAKE MODELS FOR LOOKING AT DEVELOPMENT IN DISEASES. AND FIRST DAVID KAPLAN FROM TUFTS UNIVERSITY, HE TALKED ABOUT ENGINEERING 3D CORNEA, AND IN HIS TALK HE PRIMARILY USED THE SCAFFOLDING I'LL TALK ABOUT LATER. REBECCA CARRIER FROM NORTHEASTERN UNIVERSITY TALKED ABOUT DIFFERENT BIOMATERIALS AND HOW IT'S IMPORTANT TO USE MATERIALS FOR CONTROLLING MICROENVIRONMENT. AND VALERIA SOLER FROM JOHNS HOPKINS, AND KAPIL BHARI TALKED ABOUT TAKING ADVANTAGE OF THE 3D CULTURES IN ORDER TO LOOK AT PATIENT-SPECIFIC PROCESSES, OR MECHANISMS, FOR VARIOUS DISEASES LIKE AMD. AND DAN HUH FROM U PENN TALKED ABOUT THE ION CHIP, YOU CAN MAKE MINI EYES WHICH I THOUGHT WAS COOL, IT HAS THE EYELID, LASHES, EVEN HAD LASHES, AND THE CORNEA, SCLERA, NOT VASCULARIZED BUT HE'S WORKING ON THAT. BUT THE MAIN ADVANTAGE OF THIS RIGHT NOW IS HE'S WORKING WITH PHARMACEUTICAL COMPANIES TO SCREEN FOR COSMETICS. SO AFTER LISTENING TO THE TALKS AT THE END OF THE DAY I REALIZED THERE WERE THREE MAIN THEMES THAT FELL OUT, AND THE FIRST ONE WAS ACTUALLY -- IT HAD TO DO WITH PROTEIN TRANSFER, NORMALLY WHEN YOU HAVE STEM CELLS AND YOU PUT THEM INTO THE SUBRETINAL SPACE THEY THOUGHT THEY WERE INTEGRATING FOR A LONG TIME BUT TURNS OUT THERE MIGHT BE PROTEIN TRANSFER RESULTS FROM THESE VESICLES, I'LL SHOW YOU THAT LATER. AND THEN THE USE OF ENDOGENOUS STEM CELLS IN ORDER TO REPLACE THE TISSUE, YOU CAN STIMULATE WHAT'S ALREADY THERE, AND THEN THE SCAFFOLDING AND WHAT THE VARIOUS PROTOCOLS ARE FOR SCAFFOLDING. THIS SLIDE WAS PRESENTED BY TOM REH, ACTUALLY TAKEN FROM ONE OF MIKE DYER'S PAPER, A "NATURE" PAPER, UNIVERSITY OF TEXAS, IT GIVES A VERY NICE DIAGRAM OF THE PROCESS, AND I SAID THAT BEFORE IT WAS THOUGHT THAT THE STEM CELLS ARE PRECURSORS, WHEN YOU INJECT INTO THE SUBRETINAL SPACE THEY THEY WERE THEY WERE INTEGRATING BECAUSE THEY WOULD SCREEN FOR ANTIBODIES THAT MIGHT LOOK FOR HUMAN CELLS AND COME UP POSITIVE, BUT WHAT HE SHOWED IS THAT FROM THE PRECURSORS MICROVESICLES BUD OFF AND FUSE WITH EXISTING PHOTORECEPTORS AND THAT GIVES THE POSITIVE SIGNAL BECAUSE IT'S HUMAN PROTEIN. SO YOU'RE NOT REALLY GETTING INTEGRATION, YOU'RE GETTING TRANSFER OF MATERIAL THROUGH MICROVESICLES, IMPORTANT TO KNOW BECAUSE IT TELLS YOU HOW THINGS ARE WORKING. ON THE NEXT SLIDE WAS ALSO FROM DR. REH'S LAB, HE LOOKED AT AXONS TRANSPLANTED, GROWING IN ECTOPIC LOCATION, TOOK HUMAN EMBRYONIC STEM CELLS AND THEY WERE TRANSFORMED WITH GFP AND THEY PUT THEM INTO THE SUBRETINAL SPACE OF MOUSE AND THEN THEY WERE ABLE TO TRACK WHERE THEY WENT. AND JUST TO ORIENT YOU, THIS LAYER HERE IS THE NERVE FIBER LAYER, THE GANGLION CELL LAYER, INTERPLEXOFORM AND NUCLEAR LAYER. RPE AND PHOTORECEPTORS LAYERS ARE DOWN HERE, HE DIDN'T SHOW THAT IN HIS SLIDE. WHEN HE TOOK THESE AND STAINED IT FOR GFP YOU COULD SEE A LOT WAS IN THE GANGLION CELL LAYER AND NUCLEAR FIBER LAYER, AS YOU CAN SEE HERE, AND AXONS ARE SHOOTING IN ALL DIFFERENT DIRECTIONS, THESE WERE NOTHING INTEGRATED. HE LOOKED FOR HUMAN MARKER IN MOUSE, FC21, YOU CAN SEE AXONS GOING IN WRONG DIRECTIONS IN MANY LAYERS, THEY DID THE DOUBLE STAINING, HE'S SHOWING STEM CELLS WHEN PUT IN ARE NOT MIGRATING TO THE RIGHT PLACE AND AXONS ARE GOING EVERYWHERE. IN THE NEXT SLIDE I WANTED TO TALK ABOUT THE ENDOGENOUS STEM CELLS. THE FIRST SLIDE ON THIS THAT I WANTED TO PRESENT, THESE ARE JUST HIGHLIGHTS, BECAUSE THERE WERE OTHER TALKS AS WELL. I PICKED SOME THAT I THOUGHT WERE REALLY GOOD. HE FOCUSES ON USING ENDOGENOUS STEM CELLS TO REGROW THE LENS. AND MOST OF YOU ALREADY KNOW THAT WHEN YOU HAVE CATARACTS AND THEY CUT ON THE THE CATARACT, THEY ALSO CUT OUT THE LENS CAPSULE, AND THEREFORE THE LENS DOESN'T REGROW BACK AND THEY USE AN ARTIFICIAL LENS TO REPAIR IT. WHAT HE SHOWED THOUGH IS THAT IF YOU -- FIRST OF ALL, IF YOU PUT IN ANTI-BMI 1 RNA VECTOR INHIBITION IS REQUIRED FOR MAINTENANCE AND RENEWAL OF ENDOGENOUS LENS EPITHELIAL STEM CELLS. HE DID THESE EXPERIMENTS WHERE HE TOOK THE MINIMALLY INVASIVE SURGERY BUT THEY REMOVED THE TISSUE, AND THEN YOU HAVE THIS DOUGHNUT SHAPE HERE WHICH IS THE LENS CAPSULE AND IT CONTAINS THE STEM CELLS. AND THEN WHEN YOU PUT IN THE VIRAL VECTOR, THEN YOU START TO GET GROWTH OF THE LENS, THE STEM CELLS, DIFFERENTIATION AND SO IT STARTS TO FILL THIS IN UNTIL YOU HAVE A FULL LENS. AND THIS I SHOW THIS DIAGRAM BECAUSE IN MONKEY HE TOOK THE LENS IN A WILD TYPE JUST FOR COMPARISON BUT WHEN HE EXCISED THE LENS PORTION, THE LENS HERE GREW IN FIVE MONTHS AND THIS SHOWS THE LENS IN THE MONKEY. THIS IS DIRECT ILLUMINATION IN SLIT LAMP. AND NOW HE'S DOING THIS IN PHASE 1 CLINICAL TRIALS IN HUMAN INFANTS. ANOTHER TALK USING ENDOGENOUS STEM CELLS WAS BY JEFF STERN, IN NEW YORK, AND HE WAS LOOKING TO ACTIVATE THE RPE IN ORDER TO REPAIR DAMAGE TO PHOTORECEPTORS. PROBABLY YOU KNOW IF YOU HAVE A HEALTHY RPE, YOU MAY HAVE HEALTHY PHOTORECEPTORS, BUT IF THE RPE IS DAMAGED PHOTORECEPTORS BECOME DAMAGED. SO THIS IS A RAT MODEL OF AMD, AND THIS IS A FUNDUS PHOTOGRAPH, THIS IS THE OPTIC NERVE, BLOOD VESSELS, THIS IS WHERE THE PERUSIN AND SCAR TISSUE IS. BY MAKING THIS SLOW RELEASE MICROBEADS WITH FGF2 THAT STIMULATES ENDOGENOUS STEM CELLS TO REGENERATE RPE. SO IF YOU LOOK AFTER -- I GUESS IT'S A WEEK, YOU START TO SEE GROWTH IN HERE, FOR THE RPE AND THEN AFTER ABOUT FIVE WEEKS YOU SEE SUBSTANTIALLY MORE. SO THIS WAS AN INTERESTING RESULT BECAUSE THAT KIND OF SHOWS HOPE THAT MAYBE WE COULD TRY THAT IN HUMANS SOMEDAY. THEN THE NEXT SLIDE HAS TO DO WITH THE SCAFFOLDING. DAVID KAPLAN FROM TUFTS IS USING THESE SILK-BASED SCAFFOLD TO GENERATE 3D CORNEAL TISSUE, AND THIS IS A BIOSYNTHETIC POLYMER, AND THE WAY THIS IS MADE IS THAT HE MAKES THIS MOLD, SO IT HAS THE RIGHT DIMENSIONS FOR THE CORNEA, AND THEN HE CAPS THE SILK SOLUTION ON IT AND THEN SEEDS WITH HUMAN CORNEAL STROMAL STEM CELLS, AND THIS GROWS AFTER A WHILE, AND TAKES ABOUT TWO DAYS, AND THIS IS JUST A SCHEMATIC DIAGRAM, BUT AFTER TWO DAYS IT STARTS TO GROW. AND THEN THEY DO THE STACKING BY ADDING ANOTHER LAYER OF SILK AND THEN MORE CELLS AND LET THAT GROW UNTIL EVENTUALLY THEY HAVE THE RIGHT DIMENSIONS FOR A 3D CORNEA, ALL DONE IN CELL CULTURE AT THE MOMENT BUT ADVANTAGES ARE PRETTY MUCH THE SAME. YOU CAN LOOK AT SPECIFIC DISEASES IN PATIENTS, YOU HAVE TRANSPLANTATION, A SOURCE OF TISSUE FOR TRANSPLANTATION, AND DRUG SCREENS. ANOTHER TALK THAT I THOUGHT WAS REALLY VERY GOOD WAS THIS BIOPRINTING TO DEVELOP A 3D RPE TISSUE BY BHARTI USING IT TO STUDY AMD. HE HAS THIS BIODEGRADABLE SCAFFOLD, AND ON ONE SIDE HE DOES THE BIOPRINT WHICH IS TO PUT IN THE HYDROGEL CONTAINING THE ENDOTHELIAL CELLS, FIBROBLASTS AND PARASITES, AND THEN YOU FLIP IT OVER, ON THE OTHER SIDE HERE YOU SEED IT WITH iPS CELLS FROM SPECIFIC PATIENTS, SO THEN YOU GROW THE RPE ON THAT SIDE. THEN AFTER ABOUT FIVE WEEKS, THE SCAFFOLD DEGRADES AND THEN YOU HAVE THE 3D RPE COREOID TISSUE. I THOUGHT THAT WAS PRETTY NEED. AND THEN I END WITH QUESTIONS. YES? >> WAS THERE A DISCUSSION OF THE NATURE OF MATERIAL, WHETHER IT'S PROTEIN AS YOU HAVE ON THE SLIDES OR RNA? >> YOU MEAN WITH THE TRANSFER? YEAH, HE DID SAY IT WAS -- I THINK IT WAS MOSTLY PROTEIN MATERIAL BUT IN ONE SENTENCE HE SAID THERE WAS GENETIC MATERIAL AS WELL. >> I'M STEPHEN BECKER, WITH THE PLEASURE TO GIVE YOU AN UPDATE ON THE NEI AUDACIOUS GOALS INITIATIVE, A 10-15 YEAR EFFORT TO CATALYZE INNOVATION IN VISION RESEARCH, WITH EMPHASIZE ON PHOTORECEPTOR CELLS AND RETINAL GANGLION CELLS IN ADDITION TO REGENERATING THE OPTIC NERVE. SO SINCE 2014, THIS IS A TIMELINE OF THINGS WE'VE BEEN DOING. I'VE GONE OVER THIS A COUPLE TIMES SO I WANTED TO SUMMARIZE THAT WE'VE HAD A NUMBER OF WORKSHOPS AND WE'VE ISSUED TWO FUNDING OPPORTUNITY ANNOUNCEMENTS. AND THESE ARE IN MORE DETAIL, JUST WANTED TO HIGHLIGHT THAT THE WHITE PAPERS ARE PUBLISHED, AND WE'VE REALLY SEEN THAT CATALYZE PROPOSALS IN THE RO1 PORTFOLIO. AND IN ADDITION TO WORKSHOPS WE'VE BEEN DOING TOWN HALLS AS YOU KNOW. LAST YEAR'S WAS ON OCULAR DISEASES AND DISEASE STATES, AND IN MARCH THE PANELISTS AND MODERATOR LEN LEVINE PUBLISHED A NICE PERSPECTIVE PIECE IN OPHTHALMOLOGY, TALKING ABOUT THE CONSIDERATIONS FOR CELLULAR THERAPIES, THE LAST ARVO, WE HELD A TOWN HALL, KIND OF ALONG THE SAME THEMES ON ADVANCING CELLULAR THERAPIES IN THE CLINIC AND HAD BRIEF PRESENTATION BUYS FOUR PANELISTS, PETER COFFEY WITH LESSONS LEARNED, DAVID GAMM TALKED ABOUT APPROACHES FOR PHOTORECEPTOR TRANSPLANTATION, JEFF GOLDBERG DISCUSSED SOME OF THE STRATEGIES THAT COULD BE USED FOR RGC REPLACEMENT AND PROGRAM OFFICER NINDS DISCUSSED SOME OF THE STUDIES FOR NEURONAL REPLACEMENT, AND IN PARTICULAR THOSE LESSONS FROM PARKINSON'S AND ALS. AND SO WE HAD A REALLY NICE DISCUSSION, A LOT OF POSITIVE FEEDBACK FROM THAT EVENT, CURRENTLY THOSE PANELISTS ARE WRITING UP THAT DISCUSSION AND IN A SIMILAR PERSPECTIVE PIECE WE HOPE TO HAVE IT PUBLISHED IN A COUPLE MONTHS. THERE WILL BE A PRESENTATION SUMMARIZING THAT WHITE PAPER AT THE NEXT COUNCIL BY MARK BUMENKRANZ. WHAT WE'VE BEEN DOING THE PAST COUPLE MONTHS TO TRYING TO SYNTHESIZE DATA FROM TOWN HALLS AND WORKSHOPS, ENGAGING RESEARCHERS BECAUSE WE THINK ONLY BY COLLABORATION ARE WE GOING TO ADVANCE TOWARDS OUR GOAL. AND SO ONE OF THE THINGS THAT ACTUALLY COUNCIL MENTIONED THAT WE'RE IMPLEMENTING THIS SUMMER IS ENGAGING THE TRAINEES, AND SO AT THE END OF THIS SUMMER THE LAST WEEK OF AUGUST, WE'VE DEVELOPED A COURSE THAT WILL GO INTO THE ACTUAL REGENERATION METHODS FOR THE VISUAL SYSTEM. IT'S IN PARTNERSHIP FOR OUR KIND OF IN-HOUSE EXPERTISE CALLED THE FOUNDATION FOR ADVANCED EDUCATION OF SCIENCE, THEY ARE USED TO HOLDING SHORT COURSES ON TOPICS AND ARE EXCITED TO HELP US PUT TOGETHER SUCH A COURSE. WE'RE LEVERAGING INTRAMURAL EXPERTISE THAT WE HAVE, IN ORDER TO OFFER HANDS-ON DEMONSTRATIONS, SO APPROXIMATELY 50% OF THIS COURSE WILL BE ACTUALLY GOING THROUGH IN HANDS-ON OR DEMONSTRATION OF TECHNIQUES AND OUTSIDE EXPERTISE LOOKING AT THE PORTFOLIO. REGISTRATION OPENING NEXT WEEK, THERE'S LIMITED NUMBER OF STUDENTS, TO TRY TO KEEP IT GOOD ENVIRONMENT FOR LEARNING THESE KIND OF TECHNICAL TECHNIQUES TO ONLY 18 STUDENTS. AND WE ALSO MENTIONED THIS AT ARVO, AND THERE WAS A LOT OF ENTHUSIASM BOTH FROM STUDENTS AND FROM VARIOUS EDUCATORS AND RESEARCHERS. YEAH? >> (INAUDIBLE). >> YES, THERE IS A TUITION COST THAT'S ON THE WEBSITE. WE'RE TRYING TO KEEP IT RELATIVELY AFFORDABLE. IT'S GRADED ACCORDING TO YOUR LEVEL OF EDUCATION, GRADUATE STUDENTS, TRAINEES, IF YOU'RE A STAFF SCIENTIST A LITTLE BIT MORE, IF YOU'RE FROM AN OUTSIDE COMPANY IT'S A LITTLE BIT MORE AS WELL. BUT IT'S A PRETTY GOOD VALUE FOR WHAT YOU'RE GETTING. ARVO COURSE WAS WELL ATTENDED, AND SO WE FEEL LIKE THIS CAN SERVE PERHAPS AS A PILOT FOR IF THERE IS DEMAND FOR OTHER COURSES IN THE FUTURE. SO ANOTHER WAY THAT WE'RE TRYING TO PROMOTE COLLABORATION OBVIOUSLY IS THROUGH THE GRANTEE CONSORTIUMS THAT WE STOOD UP. THE FIRST ONE WAS THE IMAGING CONSORTIUM, AND WE HAD -- WE'RE GOING TO HAVE OUR SECOND FACE-TO-FACE P.I. MEETING THIS SUMMER, SET FOR AUGUST 25, AND SO WE BRING IN AN EXTERNAL OVERSIGHT COMMITTEE, AND THESE ARE INDIVIDUALS THAT HAVE EXPERTISE THAT CAN HELP ALL THE PROJECTS KIND OF MOVE FORWARD AND HELP WITH THE TROUBLESHOOTING. THE GRANTEES HAVE REALLY USED THIS OPPORTUNITY TO EXPRESS THEIR CHALLENGES AND ALSO FIGURE OUT WAYS THAT THEY CAN WORK TOGETHER TO OVERCOME THEM. SO TO REMIND YOU THAT OUR GRANTEES CONSIST OF FIVE PROJECTS, HERE IS A LIST OF KIND OF THE LEAD P.I.s AND THEIR TITLE NAMES. AND THIS IS -- THEY STARTED IN 2015, SO THEY ARE INTO THEIR SECOND YEAR NOW AND PROBABLY SOME OF YOU HAVE HEARD SOME OF THEIR PROGRESS AT ARVO, BUT THIS GROUP JUST DID A LITTLE PUBLICATION SEARCH, ACCORDING TO GRANT NUMBERS, REALLY STARTING TO PRODUCE A NUMBER OF PUBLICATIONS. SO I KNOW I WON'T HAVE TIME TO GO THROUGH ALL OF THESE BUT I WANTED TO HIGHLIGHT, YOU KNOW, WHAT SOME OF THE STUFF IS COMING OUT. SOME OF THE PROJECTS ARE WORKING ON NEW IMAGING TECHNIQUES SUCH AS INTERFERON METRIC OPTOPHYSIOLOGY, A LOT OF THEM ARE TRYING TO NON-INVASIVELY MONITOR ACTIVITY OF INDIVIDUAL NEURONS. YOU HEARD EARLIER TODAY WITH GRACE'S PRESENTATION THAT THAT HAS COME A LONG WAY AND WE THINK THIS CONSORTIUM IS REALLY A PART OF THAT MOVEMENT TO ADVANCE IT TO STUDYING REGENERATION AND DISEASE. A LOT OF THE NEW TECHNOLOGIES COMING OUT ARE IN THE IMAGE PROCESSING END AND ALSO YOU HEARD ABOUT KIND OF THE IMPORTANCE OF EYE TRACKING. THAT'S AL DUPRA'S WORK THERE. AND THERE'S ALSO -- IF YOU'RE FAMILIAR WITH CHRIS PALCZEWSKI'S WORK, TESTING TWO PHOTON MICROSCOPY IN MONKEYS AND ASSESSING SAFETY LEVELS OF LIGHT EXPOSURE THERE. SO WE'RE LOOKING FORWARD TO THE UPDATE WE'LL HAVE THIS SUMMER, IN AUGUST, AND JUST WANTED TO HIGHLIGHT SOME OF THE TAKEAWAYS THAT THEY ARE PRODUCING, A LOT OF PUBLICATIONS ALREADY. THE REASON WE LAUNCHED THIS FIRST IS THAT BECAUSE IT'S GOING TO BE CRITICAL IN ORDER TO EVALUATE THE EVENTUAL REGENERATIVE STRATEGIES THAT PEOPLE ARE TESTING TO MONITOR OVER EXTENDED LONGITUDINAL TIME PERIOD, EFFECTIVENESS OF THESE INTERVENTIONS. AND WE THINK THAT THESE IMAGING TECHNOLOGIES PROVIDE A FOUNDATION TO STUDY A VARIETY OF DISEASES. AND WE'RE REALLY PLEASED THAT A LOT OF THESE GRANTS HAD EMBEDDED ALREADY TRANSLATIONAL ELEMENTS AND WILL BE TESTED SOON, IF NOT ALREADY IN NON-HUMAN PRIMATES. SO THE OTHER CONSORTIUM THAT WE HAVE IS THE REGENERATIVE FACTORS CONSORTIUM, TO IDENTIFY NEW FACTORS THAT ARE UNKNOWN, THAT ARE INVOLVED IN REGENERATION. AGAIN, WE HAVE A SIMILAR SETUP WITH EXTERNAL OVERSIGHT COMMITTEE WITH EXPERTISE NEEDED TO HELP SCREEN FOR THESE MOLECULES, THE CHAIR IS MIKE DYER, AND WE REALLY ARE LEVERAGING A LOT OF THE BROADER NEUROSCIENCE COMMUNITY LOOKING BROADLY AT NEURAL REGENERATIVE FACTORS. HERE IS A LIST OF THOSE PROJECTS. THERE'S SIX PROJECTS, OVER THREE YEARS, SO THEY JUST HAD THEIR FIRST KICKOFF MEETING LAST DECEMBER, SO WE'VE DECIDED THIS DECEMBER WE'LL HEAR AN UPDATE, PERIODIC PHONE CALLS, AND GIVE UPDATES OVER THOSE CALLS. AGAIN, A LOT OF THESE AWARDS ARE TRYING TO DEVELOP HIGH THROUGHPUT STRATEGIES TO DETERMINE BOTH CANDIDATES, TRANSCRIPTOMICALLY, PROTEOMICALLY AND LIPIDOMICS, VARIATIONS THAT ALLOW ONE SYSTEM TO REGENERATE AND NOT THE OTHER AND THERE'S A COUPLE GROUPS LOOKING FOR CUES THAT GUIDE AXON TO APPROPRIATE TARGETS, IMPORTANT IN OPTIC NERVE REGENERATION. WE'VE HEARD DAVID GAMM CAME TO GIVE AN AGI SEMINAR A COUPLE WEEKS AGO, INVOLVED IN BOTH CONSORTIA, GAVE A NICE UPDATE ON THEIR PROGRESS AND, YOU KNOW, THE INITIAL SCREENING PLATFORMS ARE DELIVERING A NUMBER OF HITS AND PEOPLE ARE JUST NOW MEETING TO TRY TO DETERMINE A WAY TO SHARE THESE PRELIMINARY HITS AND PERHAPS CROSS-VALIDATE ON DIFFERENT PLATFORMS AND DIFFERENT SPECIES ANALOGS, SO THE IDEA OF COLLABORATION, WE'RE EXCITED THEY HAVE EMBRACED IT AND ARE CARRYING FORWARD. WE'RE TRYING TO FIGURE OUT HOW TO BRING IN, YOU KNOW, ADDITIONAL PIECES TO MOVE ON OUR ULTIMATE GOAL OF CELLULAR THERAPIES, AND SO WE'VE IDENTIFIED A COUPLE AREAS THAT WE'D LIKE TO BRING IN. SO DEVELOPMENTAL BIOLOGY WE THINK IS CRITICAL BECAUSE WE'RE GOING TO EVENTUALLY NEED TO INTEGRATE THESE CELLS INTO CIRCUITS, AND PROBABLY THE BRAIN INITIATIVE IS ANOTHER PLACE THAT WE CAN LEVERAGE SOME OF THAT RESEARCH GOING ON. THEY HAVE A GREAT CELL CENSUS WHICH HAS BEEN LED BY A TEAM THAT IS IDENTIFIED THE RETINAL CELL TYPES IN THE MOUSE. WE'RE ALSO LOOKING TO GET THE DISEASE BIOLOGY BETTER UNDERSTOOD SO WE KNOW WHAT TIME TO INTERVENE WITH THESE CELLULAR THERAPIES. THE STEM CELL BIOLOGY IS GOING TO BE CRITICAL TO UNDERSTAND HOW TO INTEGRATE THESE CELLS, AND ALSO TO SEE ACTUALLY THE ROLE OF THE UNDERLYING ENVIRONMENT TO NURTURE AND TO CULTIVATE THOSE CELLULAR TRANSPLANTATIONS. AND WE'RE ALSO TRYING TO LEARN FROM THE CLINICAL OBSERVATIONS AND DATA ABOUT HOW DISEASE PROGRESSES AND HOW NATURALLY THERE COULD BE SOME REPAIR MECHANISMS THAT COULD BE ACTIVATED. AND SO JUST WANTED TO SHOW A LITTLE DIAGRAM IN OUR THINKING HERE, WE'RE TRYING TO -- WE THINK WE'RE BUILDING A FOUNDATION HERE WITH OUR FIRST TWO CONSORTIA, TO GET THE TECHNOLOGY TO ASSESS THESE REGENERATIVE STRATEGIES, WE NEED OF COURSE COMPENDIUM OF WHAT REGENERATIVE FACTORS CAN BE TARGETED FOR INTERVENTION TO EXPLORE, AND NOW ALSO THE TOP OF THE PYRAMID TRYING TO WORK, YOU KNOW, UNDERSTANDING THIS DISEASE AND SO THAT'S WHY THE TOWN HALL FOCUS ON THE MORE CLINICAL ASPECTS OF WHAT IS THE CONSIDERATIONS FOR DISEASE IN TERMS OF THE STAGING AND DIFFERENT ATTRIBUTES THAT MIGHT BE TAKEN INTO CONSIDERATION, WHEN TRYING TO COME UP WITH A CLINICAL TRIAL. SO WE'RE IN THIS SPACE WHERE WE KNOW WE'VE GOTTEN A NICE FIRM FOUNDATION, AND WE'RE TRYING TO MOVE FORWARD. SO I'D LIKE TO PROPOSE TO COUNCIL WHAT OUR NEXT FOA CONCEPT IS GOING TO BE ABOUT. SO AS I DISCUSSED, ALL THESE WORKSHOPS WE'VE BEEN HOLDING A COMMON THEME, WE NEED IMPROVED ANIMAL MODEL SYSTEMS TO HELP UNDERSTAND THE ACTUAL BIOLOGY OF THE REGENERATIVE PROCESSES. WE'VE DONE A PORTFOLIO ANALYSIS, AND IDENTIFIED ALL THOSE GRANTS THAT ARE RELEVANT TO AGI, OVER 130 PROJECTS AND OVER 100 P.I.s WORKING IN THIS SPACE BUT WHEN LOOKING AT IT THERE IS SILOS AND WE THINK WE NEED TO AGAIN CONTINUE TO BRING TOGETHER DEVELOPMENTAL BIOLOGY PEOPLE WITH THE RETINAL DISEASES IN ORDER TO GET SOME TRACTION ON ADVANCING IT. SO THE IDEAS ARE THAT AN FOA SHOULD GENERATE MODELS THAT CAPITULATE THE HUMAN DISEASE AND ARE AMENABLE TO REGENERATIVE MEDICINE APPROACHES. THESE MODELS NEED TO RESEMBLE THE HUMAN PHYSIOLOGY ANATOMY. YOU HEARD GRACE THAT A MAJORITY OF OUR MODELS ARE IN MOUSE RIGHT NOW, IN RODENTS, SO WE'D LIKE TO ADVANCE THAT. WE ALSO NEED TO TEST THESE MODELS, AND SEE HOW THE FUNCTION -- YOU KNOW, DEVELOP FUNCTIONAL ASSAYS TO DETERMINE WHETHER IT'S INTEGRATED, WHETHER IT'S PROTEIN TRANSFER OR WHAT NOT WE WANT TO SEE WHAT THE MECHANISM IS, AND COME UP WITH THE KIND OF STANDARD ASSESSMENTS FOR VISUAL IMPROVEMENT, SO EVERYBOY IS WORKING FROM THE SAME PAGE AND WE CAN COMPARE DIFFERENT STRATEGIES. AND SO WE THINK IN THE NEXT FISCAL YEAR WE COULD PUT OUT A SOLICITATION AND SUPPORT UP TO THREE TO FIVE GRANTS, $4 TO $5 MILLION, AND SO INTERESTED IN GETTING FEEDBACK ON THAT AND WANTED TO OPEN IT UP FOR DISCUSSION. THANKS. [APPLAUSE] >> HOW WILL YOU DETERMINE THAT IT MORE CLOSELY MIMICS HUMANS? >> GOOD QUESTION. SO WE KNOW -- SO A LOT OF THE CRITICISM IS THAT ANIMAL MODELS RECAPITULATE AN ASPECT OF HUMAN DISEASE, NOT FULLY REPRESENTATIVE. AND SO I THINK UNDERSTANDING WHAT TRANSLATES AND WHAT COULD TRANSLATE SO IT'S A LOT OF THINGS THAT WORK IN THE MOUSE OBVIOUSLY AREN'T GOING TO TRANSLATE UP, BUT SO ONE PLACE THAT WE THINK WILL GET A BETTER IDEA OF WHAT'S GOING TO WORK IN HUMANS IS GOING TO NON-HUMAN PRIMATES, THE OTHER, YOU KNOW, IDEA IS THERE ARE, YOU KNOW, CLEVER RESEARCHERS THAT ARE HUMANIZING MICE AND TRYING TO BETTER, YOU KNOW, MAKE A MORE CO-INDOMINANT MOUSE, OR SOMETHING LIKE THAT, AND WHETHER THAT'S, YOU KNOW, A GOOD APPROACH OR HAS FEASIBILITY TO GIVE US INSIGHT ON HOW IT'S GOING TO WORK IN THE HUMAN, WE'RE INTERESTED IN AT LEAST EXPLORING THAT BECAUSE WE DO NEED THOSE TOOLS WHEN WE MAKE THE TRANSLATION. >> JUST A COMMENT, COMING FROM THE GLAUCOMA PERSPECTIVE THE BIG CHALLENGE IS GETTING AXONS GOING TO THE RIGHT PLACE, AND I HEARD JEFF GOLDBERG TALK YESTERDAY IN BOSTON, THEY HAVE, YOU KNOW, MODEST SUCCESS GETTING STEM CELLS TO GO TO THE RIGHT PLACE WHEN THE SYSTEM IS INTACT TO BEGIN WITH BUT WHEN THE SYSTEM IS DISEASED, IT'S ZERO. AND SO I THINK SOME EMPHASIS NEEDS TO BE FOCUSED ON GRANTS THAT ARE IN TUNE TO GUIDANCE TOOLS THAT GET AXONS TO THE RIGHT PLACE. >> YES, THANK YOU. OKAY. NOTHING MORE, THANK YOU VERY MUCH. >> SO WE'RE PLANNING ON ISSUING AN FOA THAT WILL HAVE MORE DETAIL IN IT. AND IT WILL COME OUT, THE INTENTION IS THAT IT WILL COME OUT IN THE UPCOMING FISCAL YEAR, AND SO WE'D LIKE TO ASK YOUR APPROVAL FOR ISSUING AN FOA BASED ON THE CONCEPT YOU JUST HEARD. DISCUSSION? ANY MOTION FOR? AGAINST? THANK YOU VERY MUCH. >> PAUL, WHEN EXACTLY WOULD THAT BE, EARLY WINTER? >> (INAUDIBLE). >> OKAY. >> SO NEXT WE'LL HAVE JIM HANDA, PRESENTING AN UPDATE ON THE AMD PATHOBIOLOGY WORKING GROUP. WELCOME, JIM. JIM, AS MANY OF YOU KNOW, IS A PROFESSOR OF OPHTHALMOLOGY AT JOHNS HOPKINS WHERE HE WORKS IN VITRIOL RETINAL DISEASE, ACCOMPLISHED SURGEON, CURRENTLY IMPLANTING SURGEON FOR ARGUS 2 RETINAL IMPLANT. MORE PERTINENT TO TOPIC AT HAND HAS A STREAM OF WORK ON EARLY ASPECTS OF AGE-RELATED MACULAR DEGENERATION, AMD, CURRENTLY HOLDS TWO RO1 AWARDS FROM THE EYE INSTITUTE. JIM IS HERE REPRESENTING THE AMD PATHOBIOLOGY WORKING GROUP, AS I HAD MENTIONED EARLIER THIS IS A WORKING GROUP OF YOU, OF EYE COUNCIL, IN THIS CASE REPRESENTED BY MARCO ZARBIN, EX OFFICIO ON THE EYE COUNCIL. OTHER MEMBERS OF THIS GROUP ALL JUST NAME MIKE GORE, JIM HANDA HERE, ANDREW DICK, KATHY BOWS RICK MAN, LINDSAY FARR, MARIOUS UFING, JOAN MILLER AND CYNTHIA TOTE. SO THE GROUP HAS MET TWICE, ONCE BY PHONE, ONCE IN PERSON, A FEW WEEKS AGO, AND SO LET ME TURN THIS OVER TO JIM WHO CAN RECAPITULATE SOME IDEAS THAT HAVE COME UP FROM THE GROUP. THANK YOU, JIM. >> IT'S A PLEASURE TO BE HERE. AS I SAID LAST TIME, IT'S A REAL HONOR TO REPRESENT THE GROUP. I'M VERY HUMBLED AND IMPRESSED WITH THE COMMENTS THAT EACH AND EVERYBODY HAS BECAUSE THERE'S A WIDE VARIETY AND VARIABILITY OF EXPERTISE, AND IT'S REALLY INTERESTING FOR ME FROM MY PERSPECTIVE TO BE ABLE TO TAKE SOME OF THESE IDEAS AND THINK ABOUT SCIENCE I DO OR PATIENTS WHO I SEE. SO JUST TO PUT EVERYBODY ON THE SAME PAGE, I MIGHT HAVE SHOWN THIS LAST TIME. WE ALL KNOW AMD IS A MAJOR CAUSE OF BLINDNESS, WITH ABOUT TWO MILLION AMERICANS HAVING ADVANCED DISEASE. WE ALL KNOW THAT WE HAVE MADE SIGNIFICANT PROGRESS IN TREATING THE NEOVASCULAR FORM OF THE DISEASE BUT REALLY COMPELLING TREATMENT FOR DRY AMD IS OBVIOUSLY STILL NEEDED. THIS WAS AN ARTICLE THAT GARY AND LISA BROWN PUBLISHED IN 2005 THAT'S BURIED IN LITERATURE BUT I THINK IT'S REALLY INTERESTING THAT THE IMPACT OF AMD IF YOU HAVE MILD AMD THERE'S A 17% REDUCTION IN QUALITY OF LIFE. IF HAVE YOU MODERATE OR INTERMEDIATE DISEASE IT'S 40% REDUCTION, EQUIVALENT TO ANGINA OR HEMODIALYSIS. IF YOU HAVE SEVERE DISEASE, THERE'S A PROFOUND REDUCTION IN QUALITY OF LIFE, WITH SIMILAR TO PEOPLE WHO HAVE METASTATIC PROSTATE CANCER WITH SEVERE PAIN OR BEDRIDDEN PATIENT WITH STROKE. SO THE WORKING GROUP THAT DR. SIEVING PUT TOGETHER IS A THINK TANK AND IT'S A HIGH LEVEL RESOURCE FOR COUNCIL. AND IT'S INPUT ON THE OBVIOUSLY HIGH PRIORITY TOPIC. THE GOALS WE'VE SET IN SHORT TERM TO IDENTIFY BIOLOGICAL CAUSES AND DISEASE MECHANISMS OF AMD, AND LONGER TERM TO DEVELOP HYPOTHESES FOR CLINICAL STUDY INCLUDING CLINICAL TRIALS THAT ARE REALLY BASED ON HIGH IMPACT PRE-CLINICAL EVIDENCE. AND AS PAUL MENTIONED EARLIER THIS IS THE GROUP. I HAPPEN TO BE RIGHT IN THE MIDDLE. I GUESS BECAUSE I'M CLINICIAN AND SCIENTIST, THERE'S A WIDE DIVERSITY, KATHY RICKMAN IS REALLY COMPLEMENT BIOLOGY, ANDREW DICK FROM ENGLAND PROVIDES TREMENDOUS EXPERTISE IN IMMUNOLOGY, LINDSAY FARER AND MIKE GORDON PROVIDE GENOMICS AND GENETICS, JOAN MILLER WITH WISDOM FROM CLINICAL PERSPECTIVE AS WELL A LITTLE EXTRACELLULAR MATRIX, CYNTHIA TOTH IS PROVIDING EXCELLENT IMAGING, INSIGHTS AS WELL AS CLINICAL INSIGHTS, CLINICAL TRIALS. MARIUS UEFFING IS SYSTEMS BIOLOGY, INSIGHT INTO WHAT'S GOING ON AS A TEAM APPROACH THROUGHOUT EUROPE. AND MARCO ZARBIN PROVIDES INSIGHT FROM THE CLINICAL SIDE AS WELL AS EXTRACELLULAR MATRIX APPROACHES. SO HOW DO -- WHAT WE FOCUSED ON WAS LEVERAGING GENETIC ASSOCIATION TO CAUSATIVE MECHANISTIC BIOLOGY-BASED CLINICAL STUDIES. THAT'S A FAIRLY MASSIVE UNDERTAKING AT THIS POINT. AND CLEARLY A WORK IN PROGRESS. SO IF YOU LOOK AT THE GENETICS, CLEARLY GENETICS HAS REALLY REVOLUTIONIZED HOW WE THINK ABOUT THIS DISEASE, IT CAUSED MANY OF US TO SCURRY AND LOOK TO SEE WHAT COMPLEMENT BIOLOGY WAS WHEN IT WAS DISCOVERED TEN YEARS AGO. BUT IF YOU LOOK AT THE PROGRESS WE'VE MADE WE REALLY DON'T KNOW WHAT THE ROLE OF THESE POLYMORPHISMS HAVE, WHAT'S THE IMPACT IT HAS ON DISEASE DEVELOPMENT. SO WE REALLY KIND OF DISCUSSED HOW DO WE LINK THE GENETIC UNDERSTANDING OF AMD TO ITS PATHOBIOLOGY, OR BIOLOGY-BASED CLINICAL STUDIES. AND IF YOU BREAK IT DOWN, YOU CAN SEE MULTIPLE DIFFERENT GENES THAT HAVE BEEN IDENTIFIED WITH GENETIC ABNORMALITIES, WE CAN LOOK AT COMPONENTS, PHOTORECEPTORS, MEMBRANE AND THINKING ABOUT BIOLOGY INVOLVED, TRANSFER, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, DEFECTS AND PHAGOCYTOSIS, PROTEIN DEGRADATION, EXTRACELLULAR MATRIX REMODELING, COMPLEMENT ACTIVATION, INFLAMMASOME, CHRONIC INFLAMMATION, AND THEN SORT OF THE PATHOBIOLOGY OF THE ABNORMAL RPE PIGMENTATION OR LOSS OF RPE CELLS, DRUSEIN DEPOSITS, MICROVASCULAR CHANGES, CHANGES IN BROOKS MEMBRANE, HOW DO THEY LEAD TO GEOGRAPHIC ATROPHY, MORE ADVANCED DISEASES, NEOVASCULAR AMD, AND ARE THERE OVERLAPPING THEMES, WHAT'S THE TEMPORAL SEQUENCE AND PRIORITY? WE PUT TOGETHER HIGHLY RELEVANT TOPICS, SOME A LITTLE BIT MORE CHARACTERIZED, SOME WE THOUGHT WERE MISSING, WE TALKED ABOUT COMPLEMENT, ABOUT INFLAMMASOME, IMMUNE SIGNALING, WHAT DOES THAT MEAN? WE TALKED ABOUT EMERGING IMPORTANCE OF MITOCHONDRIAL DYSFUNCTION, BECAUSE OF THE LONGSTANDING INTEREST PEOPLE HAVE IN OXIDATIVE STRESS, OF COURSE THE EXTRACELLULAR MATRIX WITH DRUSIN DEPOSITS IS A BAFFLING TOPIC FOR MANY PEOPLE, IT'S CHALLENGING TO STUDY, MIX THAT WITH GENETICS, CURRENT STATE OF MOLECULAR IMAGING, BRING IN RADICAL IDEAS SUCH AS PROGRAM CELLULAR SENESCENCE, MIX IN SOME BAD DIET AND CHOLESTEROL LIPID PATHWAYS, AND WE COME UP WITH WE HAD A WIDE RANGE OF DISCUSSIONS AND TRIED TO ASK QUESTIONS AT THE LAST MEETING ABOUT WHAT THE GAPS IN KNOWLEDGE AND BARRIERS PREVENTING US FROM UNDERSTANDING INTERPLAY BETWEEN THE IMPLICATED BIOLOGICAL PATHWAYS WITH GENETIC PREDISPOSITION. WE SPENT A LOT OF TIME ASKING THE QUESTION HOW WOULD UNDERSTANDING EARLIER EVENTS IN AMD HELP US UNDERSTAND THE DISEASE BETTER AND ALTER PATIENT CARE WE CAN PROVIDE. ARE PATHWAYS THAT CAUSE EARLY DISEASE THE SAME AS THOSE THAT INDUCE THE LATE EVENTS? AND ARE THERE DIAGNOSTIC IMAGING STRATEGIES FOR EARLIER DISEASE THAT WOULD WARRANT FURTHER DEVELOPMENT, AND WHAT DO WE WANT AMD DIAGNOSIS AND TREATMENT TO LOOK LIKE IN TEN YEARS, WHAT ARE CANDIDATE BIOMARKERS THAT REALLY WE SHOULD BE EMPHASIZING FOR FURTHER DEVELOPMENT. SO A LIVELY DISCUSSION, AND REALLY WHAT WE FOUND OUT WE THOUGHT WE KNOW A LOT BUT WE REALLY DON'T. AND, YOU KNOW, WE DO THINK THAT UNDERSTANDING EARLY EVENTS WOULD MAKE SOME SENSE, THEY COULD HAVE SOME IMPACT ON PATIENT CARE. BUT WE ALSO HAVE TO UNDERSTAND WHAT ARE PATHWAYS THAT GO WRONG FIRST, TEMPORAL SEQUENCE OF EVENTS, WHAT ARE THE MAJOR EVENTS, EVENTS HAPPENING THAT ARE ACTUALLY IMPORTANT IN THE DISEASE PROCESS? AND WE CAN -- OUR CURRENT APPROACH IS WE'RE CHOOSING OUR SORT OF TRIGGER OF CHOICE SUCH AS INFLAMMATION, LIPID TURNOVER, STRESS PATHWAYS, SHOWING ELEMENTS OF DISEASE BUT LACK UNDERSTANDING AND CONTEXT OF WHERE THAT FITS IN WITH EITHER THE PROGRESSION OF THE DISEASE OR THE ACTUAL IMPORTANCE IN CAUSING THE DISEASE. SO WE NEED BASICALLY A LITTLE BIT MORE INFORMED STRATEGIES, AND ONE OF THE THINGS WE CAME ON WAS EVERYBODY WAS PASSIONATE ABOUT WHAT THEY STUDIED AND THERE WAS NO PREDOMINANT ORDER OF THE PATHOLOGIC EVENTS OR PRIORITY OF WHAT IS IMPORTANT. SO WE DECIDED TO LISTEN TO THE GENETICS PEOPLE AND GENOMICS PEOPLE AND SAID WE NEED TO TAKE A MORE SYSTEMS BIOLOGY APPROACH TO AUGMENT REDUCTION OF THIS APPROACH THAT WE TYPICALLY TAKE WITH OUR STANDARD RO1 AWARDS, SO WHAT THAT MEANS IS WE REALLY NEED LARGE-SCALE UNBIASED APPROACHES THROUGH HIGH THROUGHPUT SCREENS, FOR INSTANCE, OR WHATEVER TO UNCOVER NOVEL EVENTS IN THE DISEASE PROCESS AS WELL. THAT REALLY REQUIRES THE AVAILABILITY OF HIGH QUALITY HUMAN AMD TISSUE TO UNDERSTAND WHAT'S GOING ON WITH THE DISEASE. EUFFING IN GERMANY ARTICULATED HOW SOPHISTICATED EUROPE HAS BECOME, ABLE TO GET HIGH QUALITY GLOBES, DOING A LARGE NUMBER OF HIGH THROUGHPUT SCREENS AND SYSTEMS BIOLOGY APPROACHES FROM RNA-SEQ TO ATAXI TO METABOLOMICS, BLOOD AND URINE SAMPLES TO UNDERSTAND REAL SIGNALS GOING ON IN THE DISEASE ITSELF WITH THE HOPE THAT WILL GUIDE MORE REDUCTIONIST APPROACHES TO UNDERSTAND MECHANISMS AND WE FOUND A LOT OF ENTHUSIASM TO THAT APPROACH BRINGING IN BIOINFORMATICS PEOPLE AND HAVING APPROPRIATE TISSUE TO BEGIN WITH. THAT TRANSITIONED INTO SOME DISCUSSIONS ABOUT THE RELEVANT IN VITRO AND ANIMAL MODEL DATA, HOW CAN WE USE THAT, AND APPLY IT TO HUMAN DISEASE. WE CAME UP WITH THE CONCLUSION SINCE THERE'S NOT ONE GREAT MODEL OUT THERE WE WANT CROSS-VALIDATION ACROSS DIFFERENT SYSTEMS TO SORT OF COVER DIFFERENT WEAKNESSES. WE RECOGNIZE MOST OF THE MODELS WILL FOCUS ON A PARTICULAR ASPECT OF THE AMD PHENOTYPE, AND WE CAN LEARN FROM THAT BUT WE ALSO NEED TO, AGAIN, LOOK AT IRRELEVANT MODELS TO TEST ROBUSTNESS OF THE PARTICULAR PATHWAY THAT WE'RE STUDYING. SO, YOU KNOW, REALLY THE QUESTION IS HOW WELL DO ALL OF THESE MODELS RECAPITULATE AMD PATHOLOGY. EVERYBODY KNOWS THERE IS -- THESE ARE SOMEWHAT DEFICIENT. WE THOUGHT IT WOULD BE APPROPRIATE TO GENERATE A WHITE PAPER TO REALLY PROVIDE PERSPECTIVE ON WHERE THE GAPS ARE IN MECHANISTIC UNDERSTANDING AND CLINICAL TREATMENT OF THE DISEASE AND POINT FOR NEEDED FUTURE DIRECTIONS FOR THE AMD RESEARCH COMMUNITY OR FOR OTHER PEOPLE BECAUSE SOMETIMES NICHEY EFFECT MIGHT BRING IN FRESH IDEAS TO GUIDE US TO INCLUDE A CLINICAL PERSPECTIVE TO UNDERSTANDING CURRENT CONCEPTS, STRATEGIES IN AMD RESEARCH, WHAT A SYSTEMS APPROACH COULD DO TO GAIN A DEEPER UNDERSTANDING OF AMD PATHOBIOLOGY, AND THEN THE IMPORTANCE OF INTERFACING AMD PATHOBIOLOGY WITH CLINICAL UNDERSTANDING OF AMD. WE KIND OF ENDED THERE WITH ALSO UNDERSTANDING THAT THIS IS A VERY DIFFERENT APPROACH THAN MOST OF US USE. THERE IS -- IT'S VERY IMPORTANT THAT WE PUT TOGETHER GROUPS OF PEOPLE WITH THE IDEA THAT ONE PLUS ONE EQUALS TEN, SINCE THIS IS A CHALLENGING APPROACH, BUT WE ALL FEEL VERY STRONGLY THAT THIS IS A GREAT FUTURE DIRECTION TO GO. AND I WILL END THERE AND CERTAINLY HAPPY TO ANSWER ANY QUESTIONS PEOPLE MIGHT HAVE. THANK YOU. [APPLAUSE] >> JIM, ENJOYED YOUR TALK. HOW DO YOU DEAL WITH THE ISSUE OF DOING METABOLOMICS OR BIOMARKERS ON TISSUE WITH AMD THAT LIKELY HAD TREATMENT? >> SO ACTUALLY I THINK THE MORE RELEVANT CONCERN RIGHT NOW WITH METABOLOMICS IS THE VARIABILITY, SO IF SOMEBODY WAS ALMOST HIT BY A CAR CROSSING THE STREET BEFORE THEY GO IN TO SEE THE PATIENT, METABOLIC PROFILE IS PROBABLY GOING TO BE DRAMATICALLY DIFFERENT THAN THE PATIENT THAT GOT A GOOD NIGHT OF SLEEP. THAT'S A HUGE ISSUE AND UNRESOLVED. SOME APPROACHES IS THROUGH BIOINFORMATICS TO WHITTEL DOWN THROUGH SAMPLE SIZE, AND SOME, THE OTHER STRATEGY THAT HAS BEEN DISCUSSED IS USING LABORATORY ANIMALS WHERE YOU CAN CONTROL THE CONDITIONS, IDENTIFY SPECIFIC METABOLOMIC MARKERS OR CUSTOMERS OF MARKERS AND TEST IN REFINED APPROACH. BESIDES AMD TISSUE ONE THING WE'RE DOING AT HOPKINS IS TRYING TO GET A LOT OF AQUEOUS, SO YOU CAN LEARN ABOUT METABOLOMICS, PROTEOMICSU RNA-SEQ, GETTING SAMPLES FROM PATIENTS, EASIER WITH AVASCULAR AMD BECAUSE WE CAN TAKE SAMPLES BEFORE ANTI-VEGF BEFORE INFECTION, MORE CHALLENGING WITH DRY, WE HAVE IRB APPROVAL TO DO THAT. >> MY QUESTION, NICE PRESENTATION, IS THERE MUCH GOING ON IN TERMS OF TRYING TO CREATE A MODEL? THAT WAS ONE THING I MISSED, IN TERMS OF GENERATING A MODEL OF AMD BASED ON ELIMINATION OF EITHER ONE OR MORE PARTICULAR PROTEINS? >> NOT NECESSARILY THAT STRATEGY. ACTUALLY I THINK THIS IS REALLY KATHY BOWS RICKMAN'S PLATFORM, SHE'S A PROPONENT PEOPLE HARSHLY CRITICIZED ANIMAL MODELS WHICH ARE OUT THERE AND I THINK THE STRATEGY SHE'S TAKEN AND MAYBE SHE FITS INTO THE BIOLOGICAL VARIABLES APPROACH THAT WE'RE ALL REQUIRED TO ON GRANTS, BUT AGING IS A FACTOR. AND IF YOU LOOK AT MANY OF THESE MODELS, PEOPLE ARE USING 2-MONTH-OLD ANIMALS, IT'S HARD TO RECAPITULATE AN ELDERLY PERSON. HER STRATEGY HAS -- SHE GETS COMPELLING PHENOTYPES BY AGING THESE MICE AND STARTING THEM AT SORT OF 2 YEARS OLD AND THEN GOING THROUGH THE STRESS TREATMENT THAT SHE DOES, AND THE PHENOTYPE IS CLEARLY MUCH STRONGER. SO I THINK HER MESSAGE IS NOT TO THROW THE BABY OUT WITH THE BATH WATER. SO I THINK THERE ARE SOME GOOD MODELS OUT THERE, I THINK YOU NEED TO UNDERSTAND THE LIMITATIONS. I THINK WE NEED TO SORT OF CROSS-FERTILIZE AND LOOK AT A NUMBER OF DIFFERENT SIMILAR MODELS TO TEST ROBUSTNESS OF THE PATHWAY AND WHAT YOU'RE GETTING AT I THINK OBVIOUSLY FURTHER DEVELOPMENT OF MODELS NEEDS TO GO BUT ON A SYSTEMATIC BASIS OR ORGANIZED BASIS NOBODY'S DOING THAT AT THIS POINT. >> YOU HAD A NICE DISCUSSION ABOUT STRATEGY. DID YOU TALK ABOUT TACTIC? TALKING ABOUT TEAM SCIENCE, GROUP SCIENCE. DID YOU TALK ABOUT HOW TO MAKE THAT HAPPEN? >> WELL, IN GENERALITY, WE REALLY ONLY TALKED GENERALITY. I THINK MY PERSONAL PERSPECTIVE FROM SITTING IN THE ROOM ALSO FROM PARTICIPATING IN THE BECKMAN CONFERENCES IS THERE'S A TREMENDOUS AMOUNT OF SYNERGY THAT YOU GET FROM BRINGING PEOPLE WITH DIVERSE BACKGROUNDS INTO A ROOM, AND THAT I THINK GENERATED A LOT OF EXCITEMENT. I THINK TO MAKE THIS WORK ONE NEEDS TO SORT OF PULL IN PEOPLE WITH A COMMON THEME BUT VARYING EXPERTISES. I THINK THE CORNERSTONE REALLY NEEDS TO BE BIOINFORMATICS, AND PEOPLE TO BE ABLE TO REALLY TEASE OUT HOW TO REALLY UNCOVER WHAT THE IMPORTANT PATHWAYS ARE TO REALLY GET A FRESH PERSPECTIVE OR AT LEAST TAKE AN UNBIASED APPROACH. I ALSO THINK THAT THERE NEEDS -- MY PERSONAL PERSPECTIVE THERE NEEDS TO BE A STRATEGY TO IMPROVE OUR ABILITY TO GET HIGH QUALITY AMD TISSUE. I'M JUST INVOLVED IN SORT OF A SYSTEMS BIOLOGY PAPER LOOKING AT ATAC C, CHROMATIN UNWINDING, SEVEN PAIRS OF GLOBES, EACH COST NEARLY $10,000 SO WE SPENT $60,000 ACCUMULATING GLOBES. THAT'S COST PROHIBITIVE, PARTICULARLY METABOLOMICS WITH SUBTLE DIFFERENCES, YOU CAN IMAGINE SAMPLE SIZE YOU'LL NEED. I DON'T HAVE A SOLUTION BUT THERE NEEDS TO BE SUBSIDY. TO BE ABLE TO GET TISSUE IN A SUITABLE MANNER, IF YOU USE RNA TREATMENT, I KNOW FROM MY OWN EXPERIENCE IF WE GET TISSUE 24 HOURS LATER, IT'S OFTENTIMES MUSH, AND SO IT'S REALLY CHALLENGING TO GET HIGH QUALITY TISSUE FOR RNA-SEQ OR WHATEVER YOU WANT TO DO SO I THINK THAT'S AN AREA WHERE YOU NEED TO HAVE REALLY IMPROVEMENT. HOW THAT'S DONE IN COST EFFECTIVE WAY I HAVE TO LEAVE FOR PEOPLE WHO ARE SMARTER THAN ME ON THAT. BUT THAT'S THE HARSH REALITY OF IT. AND THEN FINALLY I THINK IF THERE WAS A FUNDING MECHANISM THAT WOULD ENABLE PEOPLE TO GET TOGETHER TO PUT THIS, TO STUDY ON A SYSTEMS BIOLOGY APPROACH I THINK THAT WOULD BE A REALLY NICE COMPLEMENT TO THE CURRENT SORT OF RO1 SYSTEM WHICH WE HAVE NOW. AND THEN THE LAST THING I THINK THERE'S SOMETHING ABOUT PARTNERING WITH INDUSTRY AND I THINK THAT CAN BE A VERY VALUABLE APPROACH, AT WILMER WE HAVE A RELATIONSHIP WITH PHARMACEUTICALS WITH COMMON PROJECTS WHERE WE HAVE USED OUR AREA OF EXPERTISE IN DIFFERENT DISEASES AND THEY HAVE 4 MILLION SMALL MOLECULE COMPOUNDS WHERE THEY CAN DO SOME SCREENING SO WE INGRATE BOTH TOGETHER AND THERE CAN BE SOME NICE SYNERGY WHICH CAN DEVELOP FROM THAT STRATEGY AS WELL. >> THANK YOU, JIM. APPRECIATE YOU TAKING TIME TO COME AND FOR BEING PART OF THAT GROUP. WE WILL BE LOOKING OVER THE NEXT YEAR TO PUT THREADS TOGETHER AND HAVE ACTIONABLE ITEMS. >> (INAUDIBLE). >> LET ME TEE OFF THE NEXT TOPIC WAITING FOR LARRY TO SHOW UP. AND THAT IS A GENERAL COUNCIL DISCUSSION OF ANYTHING YOU WANT TO DISCUSS WITH PARTICULAR ATTENTION TO WHERE THE SCIENCE IS HEADED, AND WHAT I THINK THE TOPIC WILL ALSO BE, WHAT KINDS OF PROBLEMS YOU'RE FACING IN INSTITUTIONS AT THIS POINT. I WILL REST MY MIC AND LET YOU OPEN THIS AND THEN WE'LL HAVE LARRY TALK AND THEN RESUME THIS. >> I'LL START. I TALKED TO PAUL AS A SIDEBAR CONVERSATION. I THINK THAT THE DEVELOPMENT OF TELEMEDICINE TOOLS AND A.I. TECHNOLOGY, THERE'S A REALLY OPPORTUNITY THERE TO REDUCE THE COST OF DOING RANDOMIZED CLINICAL TRIALS, AND, YOU KNOW, WE NEED TO SORT OF LEVERAGE THIS CONVERSATION THAT THERE'S A LITTLE BIT OF MONEY AND THERE'S A LOT OF TRIALS TO DO. AND FIGURE OUT HOW TO SOLVE THE PROBLEM. SO A LOT OF RANDOMIZED CLINICAL TRIALS IN OPHTHALMOLOGY REQUIRE A RETINAL IMAGING CENTER, OCT IMAGING CENTER, REQUIRE SOME FUNCTIONAL ASSESSMENT. AND THESE THINGS REQUIRE READING CENTERS AND THOSE ARE EXPENSIVE. ALSO THE ACQUISITION OF DATA IS EXPENSIVE. SO WHAT I'M THINKING ABOUT IS FOR INSTANCE THERE ARE TECHNOLOGIES COMING DOWN THE PIKE THAT FOR INSTANCE WILL TAKE A RETINAL PHOTOGRAPH AND USE A.I. TECHNOLOGY AND BASICALLY READ IT BETTER THAN FIVE PEOPLE SITTING IN A ROOM TRYING TO DECIDE IF THIS OPTIC DISC IS GETTING WORSE OR THIS AMD IS GETTING WORSE. THOSE TECHNOLOGIES ARE PROMISING BUT NEED TO BE VALIDATED, AND SO ONE OF THE THINGS THAT NEI COULD DO IS PUT OUT AN RFA TO VALIDATE THESE TECHNOLOGIES SO AS TO REDUCE THE COST OF DOING RANDOMIZED CLINICAL TRIALS. THE SAME THING CAN HAPPEN IN VISUAL FIELD TESTING. THERE'S POSSIBILITY NOW TO RUN A IPHONE, PUT IT IN A VIRTUALUR- REALITY SETUP, AND THIS IS BEING DONE AT BASKIN PALMER. AND THAT PATIENT CAN DO THE TEST 100 TIMES IF THEY WOULD LIKE, AND IT COULD GET DOWNLOADED INTO A SECURE AREA, YOU TAKE THE TECHNICIAN OUT OF THE EQUATION, YOU RUN SOME SOFTWARE IN THE BACKGROUND THAT BREAKS THE VISUAL FIELD INTO PRINCIPAL COMPONENTS AND DECIDE WHETHER IT'S GETTING WORSE OR NOT. TAKE THE TECHNICIAN OUT OF THE EQUATION AND YOU TAKE THE NEED TO READ THE VISUAL FIELD OUT OF THE EQUATION. OF COURSE, ALL OF THESE THINGS NEED TO BE VALIDATED. AGAIN, THINK THAT'S WHERE NEI SHOULD SPEND SOME EFFORT IN TERMS OF VALIDATING THOSE THINGS BECAUSE ONCE THE COSTS OF THE TRIAL GO DOWN WE CAN START TO DO THE STUDIES. >> THANK YOU FOR STARTING THAT DISCUSSION. WE'LL PICK THAT UP IN A MOMENT. NEXT I'M PLEASED TO HAVE LARRY TABAK HERE, DR. TABAK IS THE PRINCIPAL DEPUTY DIRECTOR OF THE NIH AND THE TOPIC IN A MOMENT WILL BE A NEW NIH INITIATIVE ON NEXT GENERATION RESEARCHERS. AND THAT COUPLES INTO THE TOPIC OF WHICH MANY OF YOU ARE FAMILIAR, GRANT SUPPORT INDEX. JUST FOR A MOMENT FOR LARRY, HE FOR TEN YEARS WAS DIRECTOR OF NIDCR DENTAL AND CRANIOFACIAL RESEARCH. AND SINCE THEN ABOUT 2010 HAS BEEN THE PRINCIPAL DEPUTY DIRECTOR OF NIH. HE ORIGINALLY CAME FROM ROCHESTER, WHERE HE WAS PROFESSOR OF BIOCHEMISTRY AND BIOPHYSICS, ALSO DENTISTRY. AND SERVED AS ASSOCIATE DEAN FOR RESEARCH, ALL OF YOU AT THE TABLE WOULD WISH THAT YOU HAD HAD HIS PREVIOUS STATUS, NIH MERIT RECIPIENT. THAT WOULD BE NICE, WOULDN'T IT? AND HE IS AN ELECTED MEMBER OF NATIONAL ACADEMY OF MEDICINE. LARRY, PLEASE, YOU CAN WALK US THROUGH THE TOPIC. >> THANK YOU, PAUL. GOOD AFTERNOON, EVERYBODY. I THINK ALL PAUL DID WAS VERIFY THAT I'M AN OLD GUY AND IT'S TRUE. SO BUT THE TOPIC THAT I'D LIKE TO SHARE WITH YOU TODAY IS AN IMPORTANT ONE RELATED TO HOW THE AGENCY IS GOING TO ENHANCE ITS STEWARDSHIP IN ASSURING A ROBUST BIOMEDICAL RESEARCH WORKFORCE OF THE FUTURE. SO THE UNDERPINNINGS OF THIS OF COURSE HAVE THE NIH STRATEGIC PLAN WHICH I KNOW I HAD THE OPPORTUNITY TO DISCUSS WITH AT LEAST SOME OF YOU. AND WITHIN THAT STRATEGIC PLAN OF COURSE IS THIS PRINCIPLE OF NEED TO ENHANCE STEWARDSHIP, TO RETAIN AND RECRUIT OUTSTANDING RESEARCH WORK FORCE AND THAT WORKFORCE HAS TO BE DIVERSE IN NATURE. SO MANY PEOPLE IN THE EXTRAMURAL COMMUNITY HAVE MADE A SERIES OF OBSERVATIONS OVER THE LAST SEVERAL YEARS, AND THEY ARE TYPIFIED BY THIS PERSPECTIVE BRUCE ALBERTS AND COLLEAGUES PUBLISHED IN PNAS IN 2014, AND IN IT THEY ARTICULATE THE VIEW THAT THE LONG-HELD BUT ERRONEOUS ASSUMPTION OF NEVER ENDING RAPID GROWTH IN BIOMEDICAL SCIENCE HAS CREATED UNSUSTAINABLE HYPERCOMPETITIVE SYSTEM DISCOURAGING EVEN OUTSTANDING STUDENTS FROM ENTERING THE PROFESSION. AS I'VE GONE COUNCIL TO COUNCIL, I THINK THIS IS 21, THIS IS THE ONE PHRASE THAT RESONATES WITH EVERYBODY BECAUSE ALL FIELDS OF BIOMEDICAL RESEARCH ARE FACING THIS DILEMMA. HOW DO WE ATTRACT PEOPLE IN WHEN THEY SEE HOW DIFFICULT IT IS FOR THE PROFESSORS AND SO FORTH. SO LET ME SHOW YOU VISUALLY WHAT WE MEAN BY HYPERCOMPETITION. THE UPPER TRACING IN BLUE WOULD COME AS NO SURPRISE TO ANYBODY HERE. IT REPRESENTS NUMBER OF APPLICANTS WE'VE HAD FOR NIH SUPPORT FROM 2003 TO 2015, AND NUMBER JUST KEEPS GOING UP. THE LOWER CURVE IN RED DOES SURPRISE SOME PEOPLE. AND THAT DISPLAYS THE NUMBER OF AWARDEES THAT WE'VE HAD DURING THE SAME TIME INTERVAL. AND YOU DON'T NEED HIGHER MATH TO VISUALIZE THE FACT THAT THAT HAS REALLY REMAINED FLAT. IT'S REMAINED CONSTANT. AND SO THE DIFFERENCE BETWEEN THESE TWO CURVES REPRESENTS COMPETITION, MORE COMPETITION, HYPERCOMPETITION. AND THAT IN ESSENCE IS THE PROBLEM THAT WE'RE HAVING. NOW, THIS NEW LEGISLATION THAT PASSED IN A BIPARTISAN WAY WHICH IS SO REMARKABLE, THE 21ST CENTURY CURES ACT, DOES MANY, MANY THINGS FOR NIH. AMONG THE THINGS THAT ARE TUCKED IN THERE IS THE NEXT GENERATION OF RESEARCHERS INITIATIVE, WHICH IS ARTICULATED AS FOLLOWS, THAT THE NIH DIRECTOR HAS TO COORDINATE ALL POLICIES AND PROGRAMS WITHIN THE NIH THAT ARE FOCUSED UPON PROMOTING AND PROVIDING OPPORTUNITIES FOR NEW RESEARCHERS AND EARLY RESEARCH INDEPENDENT, BASICALLY THE ACT SAYS WE HAVE TO DO SOMETHING, JUST DOESN'T TELL YOU WHAT TO DO. THAT'S ACTUALLY A GOOD THING. SO THESE ARE NIH INVESTIGATORS THAT ARE FUNDED. EACH YEAR FROM 1990 THROUGH 2015. AND THEY ARE STRATIFIED BY AGE. SO LET'S START WITH THIS LOWER CURVE FIRST. THOSE WHO ARE IN THE LATER STAGES OF THEIR CAREER, I AM A PROUD LONGTIME MEMBER OF THIS COHORT. SO I WILL TELL YOU HOW EXCITED AND PROUD WE ALL ARE TO SEE HOW MUCH WE HAVE BEEN IMPROVING YEAR BY YEAR. HOORAY FOR US. THAT COMES AT A COST PERHAPS, HOWEVER, BECAUSE -- AND THIS MIDDLE CURVE SHOULD BE NO SURPRISE, EARLY CAREER, 45 OR YOUNGER, EXPERIENCED A PRECIPITOUS DECLINE THROUGH THE MID-2000s. NIH INSTITUTED THE EARLY STAGE INVESTIGATOR POLICY, AND THAT FORTUNATELY STOPPED THE FREE FALL, BUT REALLY ONLY STABILIZED THINGS AND NEVER LED TO THIS COHORT INCREASING IN NUMBER. AND THEN PERHAPS THE MOST CONCERNING CURVE IS THIS UPPER CURVE IN GREEN, WHICH SHOWS MID-CAREER INVESTIGATORS FROM 45 TO 60, AND AS YOU CAN SEE THEY WERE DOING VERY WELL THROUGH THE MID-2000s, AND THEN THEY STARTED TO LEVEL OFF, PRESUMABLY SOME RESOURCES WERE DIVERTED TO EARLY STAGE INVESTIGATORS, BECAUSE, AGAIN, MY COHORT KEPT ON JUST FINE, THANK YOU. BUT NOW WE'RE SEEING A SLOW DECLINE AMONGST THESE MID-CAREER INVESTIGATORS, AND THIS CONCERNS US. NOW, SOME OF YOU ARE THINKING, WELL, THIS IS BABY BOOMER DEMOGRAPHICS. AND THIS IS WHERE I MAKE THE COMMENT WHICH WILL BE OF GREAT INTEREST TO A SUBSET OF THE MEMBERS HERE, AND YOUR STAFF, PAUL. I TELL EVERYBODY DON'T WORRY, THE BABY BOOMERS WILL EVENTUALLY FADE AWAY. OKAY. AND THERE ARE CERTAIN SMILES BACK THERE, PAUL, I WON'T TELL YOU WHICH OF THE PEOPLE SMILED. YOU CAN KIND OF GUESS. AND IT IS TRUE. WE WILL EVENTUALLY DISAPPEAR. I PROMISE. I PROMISE MY KIDS THAT, MY 30-SOMETHING-YEAR-OLDS. BUT THE TRUTH IS THIS IS NOT JUST DUE TO BABY BOOMER DEMOGRAPHICS. RATHER WHAT APPEARS TO BE HAPPENING IS THE MOST ESTABLISHED P.I.s ARE OUTCOMPETING EVERYBODY ELSE. BUT I'M NOT TALK BECOME JUST GETTING HIGHER PRIORITY SCORES. I'M TALKING ABOUT THE SCENARIO WHERE TWO APPLICANTS, ONE AN EXPERIENCED INVESTIGATOR AND ONE AN EARLY CAREER INVESTIGATOR, JUST MISS AN RO1 PAYLINE. THE EARLY CAREER INVESTIGATOR, IF HE OR SHE HAS USED UP THEIR RECRUITMENT PACKAGE FROM THE UNIVERSITY AND IF THEY ARE LIKE TRUE AT MOST INSTITUTIONS THEY MAY NOW BE IN TROUBLE BECAUSE THEY HAVE NO WHEREWITHAL TO PUT IN THE SECOND REVISION OF APPLICATION. THE MORE EXPERIENCED INVESTIGATOR, MORE TYPICALLY, HAS OTHER SUPPORT, FROM NIH OR OTHER PLACES, OR DEPENDING UPON THE INSTITUTION OF COURSE CAN TAP INTO EITHER INSTITUTIONAL AND/OR DEPARTMENTAL OR DIVISION RESOURCES. SO BECAUSE OF THAT OTHER TYPE OF RESOURCES AVAILABLE, WE SAY THE ESTABLISHED P.I.s HAVE AN INCREASED RESILIENCY TO THE SHORTFALLS AND SO TIME AND TIME AGAIN WE THINK THIS IS REALLY WHAT IS HAPPENING, DRIVING THIS CONTINUED SUCCESS OF THE COHORT THAT CONSISTS OF THE MOST EXPERIENCED PEOPLE. SO OF COURSE THEN THE QUESTION IS HOW DO WE REDRESS THIS, INCREASE THE NUMBERS OF THESE EARLY CAREER FUNDED SCIENTISTS? AND IT'S CURRENT TRANS-NIH POLICY WHICH HAS BEEN EFFECTIVE IN THAT IT STOPPED THE FREE-FALL BUT HASN'T YET GOTTEN US UPWARD, PROVIDES A BOOST FOR FIRST-TIME APPLICANTS, SUCH THAT EARLY STAGE INVESTIGATORS SUCCESS RATES ARE MADE SIMILAR TO THOSE OF THE MORE EXPERIENCED INVESTIGATORS, BUT DESPITE DOING THAT AND I'M USING FISCAL YEAR 2016 NUMBERS, THIS IS ILLUSTRATIVE, BUT WE HAVE A FULL DATASET FOR 2016 AS WE'RE IN THE MIDDLE OF 2017. SO IN FISCAL YEAR 16, 100 APPLICATIONS PERCENTILES EQUAL TO OR LESS THAN 25, OR FOR OUR PHASE NO PERCENTILE PRIORITY SCORES EQUAL TO OR LESS THAN 35, THAT WERE NOT FUNDED. NOW, IF YOU THINK FOR A MOMENT, SOME OF YOU CAN DO THIS, THE GOOD OL' DAYS WHERE WE FUNDED ONE OUT OF THREE GRANTS, GRANT APPLICATIONS, VERY FEW PEOPLE WHO HAVE BEEN ON STUDY SECTION IN RECENT YEARS WOULD ARGUE THE POINT THAT WE ARE NOT LEAVING A LOT OF REALLY GOOD SCIENCE UNSUPPORTED. SO THE MOTION THAT WE WOULD REACH DOWN TO THE 25th PERCENTILE, THAT'S FUNDING ONE OUT OF EVERY FOUR, NO ONE IS UNCOMFORTABLE FUNDING ONE OUT OF EVERY FOUR NIH GRANTS, SO THAT'S THE RATIONALE FOR SELECTING THE 25th OR BETTER PERCENTILE. WE NEED TO EXTEND THE PAYLINE FOR THESE FOLKS AND FUND MORE OF THEM IN THIS CATEGORY. HOW DO WE DEAL WITH THIS UPPER CURVE? THESE MID-CAREER FOLKS? THERE ARE TWO TYPES OF MID-CAREER FOLKS I WANT TO DRAW YOUR ATTENTION TO. THE FIRST ARE THOSE MID-CAREER PEOPLE, SO THIS IS TYPICALLY FOLKS WHO ARE WITHIN TEN YEARS OF BEING AN NIH P.I., JUST MISS FUNDING FOR THEIR FIRST COMPETITIVE RENEWAL. AND ALL OF YOU KNOW THAT THIS COMES TYPICALLY AT A VERY CRUCIAL TIME FOR AN INVESTIGATOR, THEY ARE TYPICALLY GETTING READY TO GO UP FOR PROMOTION, AGAIN DEPENDING UPON THE INSTITUTION THAT THE INDIVIDUAL WORKS IN, MAY OR MAY NOT HAVE RESOURCES TO BRIDGE PEOPLE, TO PUT BACK IN A REVISED APPLICATION. IT'S REALLY A CRUCIAL TIME. AND IN FISCAL YEAR 16 THERE WERE 263 RO1s FROM THESE TYPES OF INVESTIGATORS WHO JUST MISSED. SO WE THINK THAT WE NEED TO PRIORITIZE SUPPORT FOR THESE INVESTIGATORS WHO ARE ABOUT TO LOSE ALL NIH SUPPORT AND IN MANY INSTANCES ARE QUITE LIKELY TO LEAVE THE WORKFORCE. THE SECOND CATEGORY OF MID-CAREER INVESTIGATORS THAT I WANT TO DRAW YOUR ATTENTION TO ARE THE SO-CALLED RISING STARS. THEY ARE THE ONES WHO HAVE AN RO1 AND THEY PUT IN THEIR SECOND RO1 APPLICATION AND THEY JUST MISS. AND THE REASON WHY WE THINK THESE ARE IMPORTANT TO PRIORITIZE IS BECAUSE THAT'S WHAT GIVES THEM THE RESILIENCY THAT THE MORE SENIOR INVESTIGATORS ENJOY. SO, AGAIN, FOLKS WHO JUST MISS THAT SECOND RO1, WHO PROGRAM STAFF HAVE IDENTIFIED AS BEING REALLY STRONG, THOSE ARE PEOPLE THAT WE WANT TO IDENTIFY AND SUPPORT, AND THERE WERE 75 SUCH APPLICATIONS IN FISCAL YEAR 2016. JUST TO GIVE YOU A SENSE OF THE ORDER OF MAGNITUDE. SO WE HAVE HAD INTENSE CONVERSATIONS ABOUT THIS WITH INSTITUTE AND CENTER DIRECTORS. I DON'T THINK INTENSE IS TOO STRONG A WORD. AND I THINK AT THE END OF THOSE DISCUSSIONS AND DELIBERATIONS THERE'S CERTAINLY AGREEMENT THAT ALL INSTITUTES AND CENTERS ARE COMMITTED TO ENSURING SUPPORT FOR HIGHLY MERITORIOUS EARLY STAGE AND MID-CAREER SCIENTISTS. SO STARTING IMMEDIATELY, THE OFFICE OF THE DIRECTOR IS CREATING AN INVENTORY OF ALL OF THESE FOLKS THAT IS EARLY STAGE INVESTIGATORS AND MID-CAREER INVESTIGATORS IN THOSE TWO CATEGORIES THAT ARE WITHIN A FUNDABLE RANGE, WILL TRACK IC FUNDING DECISIONS OF THESE INDIVIDUALS, AND THEN THAT WILL HELP US EVALUATE WHETHER OR NOT INSTITUTES AND CENTERS ARE APPLYING SORT OF A UNIFORM STRATEGY IN TRYING TO REACH MORE OF THESE INDIVIDUALS. AND THAT'S NOT TO SAY THAT EVERYBODY ON THIS INVENTORY WILL BE SUPPORTED. THERE'S CERTAINLY LEGITIMATE REASONS WHY AN INSTITUTE MAY NOT WANT TO SUPPORT, A NUMBER MUCH REASONS WHY AS COUNCIL MEMBERS YOU COULD THINK OF WHY IT WOULDN'T BE APPROPRIATE. BUT FOR THE MOST PART WE THINK INSTITUTES AND CENTERS WILL FIND IT APPROPRIATE AND WE WILL BE ABLE TO, YOU KNOW, EVALUATE THAT GOING FORWARD BY TRACKING ALL OF THESE. SO, TO ROLL THIS ALL UP IN THE WAY OF THE NEW PROPOSED PLAN IF WE TAKE ALL THREE GROUPS AND LUMP THEM TOGETHER, AND AGAIN THIS IS BASED ON FISCAL YEAR 2016, SO THESE NUMBERS WILL CHANGE A LITTLE BIT UP OR DOWN, WE ESTIMATE YOU NEED $210 MILLION A YEAR TO FUND THESE ADDITIONAL INVESTIGATORS, IN THE FIRST YEAR. AND WHATEVER THE OUT-YEAR COMMITMENTS ARE YOU NEED THE SAME AMOUNT OUT THREE, FOUR, FIVE YEARS, WHATEVER IT IS. AND SO EVENTUALLY, AGAIN MAKING THE ASSUMPTION THEY ARE ALL FIVE-YEAR AWARDS, WHICH OF COURSE THEY ARE NOT, YOU REACH A STEADY STATE AT A COST OF $1.1 BILLION, AND SO THE BIG QUESTION OF COURSE IS WHERE DOES ALL THAT MONEY COME FROM? YOU ALREADY KNOW THE ANSWER YOU SEE IT EVERY MEETING, IT'S ABOUT PRIORITIZATION. SO THIS MONEY WILL COME FROM AN EXTANT RESOURCES THE INSTITUTE AND CENTER REPRIORITIZES, MAKING IT A HIGHER PRIORITY THAN SOMETHING ELSE. NOW, THERE ARE OTHER APPROACHES THAT SOME INSTITUTES AND CENTERS ARE USING TO SURE UP PEOPLE IN THE CATEGORIES. I WANT TO SHARE THEM. NOT ALL INSTITUTES AND CENTERS DO IT BUT SUBSETS DO. SOME INSTITUTES AND CENTERS MAKE USE OF R56s, AS A WAY OF TIDING OVER PEOPLE WHO NEED AN EXTRA YEAR PRIOR TO RESUBMITTING AN APPLICATION THAT JUST MISSED. OTHER INSTITUTES AND CENTERS ARE BUILDING RESILIENCY TO THE FIRST AWARD THEY ARE GIVING PEOPLE, ADDING IN ADDITIONAL TIME FOR SUPPORT AND ADDITIONAL MONEY FOR SUPPORT, SO FOR EXAMPLE NIGMS AND NIDCR ARE DOING THIS WITH MIRA AND SOAR AWARDS, RESPECTIVELY, AND THEY FEEL THESE THESE INDIVIDUALS WON'T NEED TWO RO1s, THE LARGER AND LONGER WILL BE SUFFICIENT. OTHERS PROVIDING RESOURCES TO PROVIDE RESILIENCY TO MID-CAREER INVESTIGATORS WHO GET THEIR RO1 AND GIVE THEM EXTRA RESOURCES TO BASICALLY BUILD IN RESILIENCY FOR THEM. AGAIN, ALL OF THESE ARE VERY APPROPRIATE AND REASONABLE APPROACHES, IT DEPENDS ON THE INSTITUTES OR CENTER. IN GENERAL WE WANT TO PICK MORE YOUNG PEOPLE UP AND FUND THEIR RO1s BUT CERTAINLY INSTITUTES AND CENTERS WILL CONSIDER A MIX OF OPTIONS AND I'M IGNORANT OF WHICH OF THESE NEI USES BUT THIS IS TO -- ACROSS THE WHOLE AGENCY. NOW LET ME GET TO THE MORE INTERESTING PART OF THIS COMMUNITY DISCUSSION. AND THAT RELATES TO HOW WE DO FUNDING DECISIONS, AND FUNDING DECISIONS ARE WHAT INSTITUTE AND CENTER DIRECTORS DO EVERY SINGLE DAY. IF I HAD TO LIST THE JOB DESCRIPTION OF AN I.C. DIRECTOR, MAKING FUNDING DECISIONS IS PROBABLY NUMBER ONE ON THE LIST, MAYBE NUMBER TWO. BUT IT'S CERTAINLY WAY UP THERE. BUT CERTAINLY MAKING THOSE DECISIONS IS A COMPLEX PROCESS, AND MANY FACTORS HAVE TO GO IN TO MAKING THOSE DECISIONS. NOW, IF WE HAD THE BENEFIT OF TIME, I COULD TELL YOU WITH GREAT PRECISION THE VALUE OF ANY GRANT THAT WE SUPPORT AT NIH. AND SO WE COULD, FOR EXAMPLE, ASCERTAIN WHETHER OR NOT THE WORK DISRUPTED PREVAILING PARADIGMS, WHETHER PATENTS OR LICENSE, NEW TECHNOLOGY, MEDICAL INTERVENTION, CHANGES TO MEDICAL PRACTICE, IMPROVEMENTS TO PUBLIC HEALTH OR MORE YOU COULD COME UP WITH. I DON'T HAVE 10 OR 20 OR 30 OR 40 YEARS TO SEE HOW EVERYTHING COMES OUT. INSTITUTES DIRECTORS HAVE TO MAKE DECISIONS IN REAL TIME. AND SO NIH IS CONSTANTLY LOOKING FOR SURROGATES TO GIVE AN INDICATION ABOUT WHAT THE VALUE OF OUR INVESTMENTS ARE SOONER THAN 10 OR MORE YEARS. SO WE NEED TO FIND A RELIABLE APPROACH TO MEASURE THIS INTERIM INFLUENCE. NOW, THE SHORT-TERM ASSESSMENT, DO THE THOUGHT EXPERIMENT, WHAT WOULD YOU NEED, WHAT TOOLS WOULD YOU NEED TO DO THIS? YOU NEED TWO THINGS. FIRST OF ALL, YOU NEED VALIDATED METRICS FOR OUTPUT, THAT IS PRODUCTIVITY, AND SECOND YOU NEED METRICS FOR AMOUNT OF GRANT SUPPORT THAT AN INDIVIDUAL ENJOYS, BUT JUST CAN'T BE A DOLLAR AMOUNT. THAT WOULDN'T MAKE ANY SENSE BECAUSE, FOR EXAMPLE, CLINICAL WORK TYPICALLY IS MORE EXPENSIVE THAN DROSOPHILA GENETICS. BOTH EQUALLY IMPORTANT, BUT OBVIOUSLY THEY COST DIFFERENT AMOUNTS OF MONEY. SO IN TERMS OF A MEASURE OF OUTPUT, I'M SURE YOU ARE ALL FAMILIAR WITH BIBLIOMETRIC MEASURES PEOPLE HAVE USED IN THE PAST, THEY HAVE POSITIVES AND NEGATIVES. AND NIH SCIENTISTS CREATED THIS RELATIVE CITATION RATIO RCR, THE WORK DESCRIBING THIS IN GREAT DETAIL WAS PUBLISHED IN PLoS BIOLOGY IN 2016 AND I WOULD RECOMMEND THAT YOU TAKE A LOOK AT THIS PUBLICATION, IF YOU'VE NOT HAD THE OPPORTUNITY TO DO SO YET. WHAT'S UNIQUE ABOUT THIS METRIC, WHAT MAKES IT DIFFERENT FROM OTHER METRICS, CAN YOU DO FIELD NORMALIZATION AND THAT IS YOU'RE ABLE TO LOOK AT THE INFLUENCE OF A PARTICULAR PUBLICATION RELATIVE TO OTHER PUBLICATIONS IN THAT FIELD OF SCIENCE. NOT JUST ACROSS THE BOARD SO YOU'RE NOT COMPARING ORANGES TO ELEPHANTS. THEY ARE BOTH ALIVE BUT THEY ARE VERY DIFFERENT. SO THE FIRST PASS AT SAYING, WELL, DOES THIS RCR MEAN ANYTHING WE TOOK THREE PANELS OF SCIENTISTS LIKE YOURSELVES, WE GAVE THEM A STACK OF PUBLICATIONS, FUNDED BY EITHER NIH OR NIH PLUS HHMI, ASKED THEM TO READ ALL THE PAPERS, ASKED THEM TO SCORE THE PAPERS IN TERMS OF THEIR IMPACT, IMPORTANCE, AND SO FORTH. WE DID THIS WITH THREE SEPARATE PANELS OF INDIVIDUALS, THREE SEPARATE SETS OF PUBLICATIONS. AND THEN POST HOC PLOTTED THAT AGAINST THE RCR FOR EACH OF THOSE PUBLICATIONS. AS YOU WILL SEE IF YOU TAKE A LOOK AT THIS ARTICLE, IT WAS A REMARKABLE CORRESPONDENCE. THE CORRELATION WAS QUITE STRONG. SO WE THINK AT THE VERY LEAST THE RCR SCORE CORRELATES WELL TO WHAT SCIENTISTS THINK OF A PAPER. NOW, DOES THAT MEAN HIGH RCR SCORE MEANS THAT PAPER WILL CHANGE PARADIGMS? WILL CHANGE PRACTICE? WILL LEAD TO SOME NEW INTERVENTION? WE'LL FIND OUT BUT WE'RE GOING TO HAVE TO WAIT 10 OR 20 OR MORE YEARS. AND OF COURSE WE'RE GOING TO DO THAT TYPE OF ANALYSIS GOING FORWARD. BUT WE'RE NOT GOING TO WAIT FOR THOSE 20 OR 30 YEARS BEFORE ANYTHING IS DONE. WE THINK THIS IS SOMETHING THAT NEEDS TO BE EXPLORED. SO THE UNDERPINNINGS OF THIS RCR METRIC IS FOUND ON A PUBLIC WEBSITE, THE LINK IS HERE. IT IS BASICALLY A DASHBOARD OF BIBLIOMETRICS, WHICH YOU CAN TYPE IN THE NAME OF ANY INDIVIDUAL, START WITH YOURSELF, AND YOU'LL FIND SOME INTERESTING THINGS, OKAY? FOR EXAMPLE, THIS IS PROBABLY THE BEST TEST, YOU ALL KNOW WHAT YOUR BEST PUBLICATIONS WERE. THE ONES THAT WERE REALLY IMPORTANT. I PREDICT FOR YOU EACH THAT THOSE WILL BE THE ONES THAT HAVE THE HIGHEST RCR VALUE. WE ALL KNOW WE'VE PUBLISHED SOME PAPERS BECAUSE WE HAD A GRADUATE STUDENT WE REALLY HAD TO GET OUT, OR A POSTDOC WHO CAME AND EVERYTHING DIDN'T WORK, SO YOU PUBLISHED SOMETHING BECAUSE, BECAUSE. THOSE WEREN'T NECESSARILY THE BEST THINGS YOU DID IN YOUR CAREER. MY PREDICTION IS THOSE RCRs ARE GOING TO BE LOWER. DO THE TEST FOR YOURSELVES, OKAY? I TELL PEOPLE THAT I DID A DIFFERENT TEST. I TYPED IN FRANCIS COLLINS AND TYPED IN ME. I KNOW NOW WHY HE'S THE BOSS. I'LL JUST LEAVE IT AT THAT. ALL RIGHT. IN ANY EVENT, THIS IS NOT THE END ALL, BE ALL, NOT THE ONLY WAY TO DO THIS. WE'VE GOT TO FIGURE OUT OTHER APPROACHES TO DO THIS TYPE OF THING. SO THE OTHER PART OF THIS, FIGURING OUT HOW MANY GRANTS YOU HAVE, THE SO-CALLED GRANT SUPPORT INDEX, WHICH HAS BECOME THE NEW FOUR-LETTER WORD AT NIH, WE EXPLORED THIS. THERE WAS A TREMENDOUS PUBLIC DISCUSSION ABOUT THIS. AND I THINK THE SUMMARY STATEMENT ABOUT THIS IS THAT MUCH MORE WORK NEEDS TO BE DONE BEFORE WE USE THIS TYPE OF APPROACH. AND THERE WERE A NUMBER OF VALID CONCERNS RAISED, SOME OTHER CONCERNS RAISED THAT FRANKLY DON'T HOLD WATER BUT THAT'S WHAT A PUBLIC DISCUSSION IS ABOUT. AS YOU'LL SEE GOING FORWARD WE HAVE AN APPROACH THAT WE WANT TO USE TO DEAL WITH THIS. O GOING FORWARD, BEGINNING IMMEDIATELY, FISCAL YEAR 2017, WE ENJOYED EXTRAORDINARY BOOST OF FUNDS BECAUSE OF THE OMNIBUS, WE'RE COMMITTED TO REDISTRIBUTING, ESTIMATES BASED ON 2016 NUMBERS, $210 MILLION A YEAR, STEADY STATE OF $1.1 BILLION OVER THE NEXT FIVE YEARS, TO DIRECTLY SUPPORT MORE ESIs AND MID-CAREER SCIENTISTS. SECONDLY ENCOURAGE INDEPENDENT ANALYSES OF METRICS THAT MIGHT BE USED TO ASSETS IMPACT OF -- ASSESS IMPACT OF NIH PORTFOLIO, ENGAGE EXPERTS, A LOT OF THE BEST WORK ARE FOLKS WHO HAVE NOTHING TO DO WITH BIOMEDICAL RESEARCH. THERE'S A WHOLE FIELD OF STATISTICIANS THAT DO THIS SORT OF THING, ECONOMISTS DO THIS SORT OF THING. LOTS OF FOLKS, ENGINEERS, A LOT OF PEOPLE WHO DO THIS TYPE OF THING. WHAT WE WILL DO IS HAVE THESE ANALYSES REVIEWED BY WORKING GROUP OF THE ADVISORY COMMITTEE TO THE NIH DIRECTOR, ACD, AND ULTIMATELY THIS WILL BE FULLY DISCUSSED AS WE JUST DID IN OUR PREVIOUS ACD MEETING ON JUNE 8 AT AN OPEN MEETING OF THE ACD, AND OF COURSE ALL ACTIONS WILL CONTINUE TO BE INFORMED BY STAKEHOLDER. HERE ARE SOME OF THE FOLKS WHO HAVE HELPED WITH THIS. AND THERE ARE MANY OTHERS, AND WE'RE CERTAINLY VERY GRATEFUL TO ALL THE EXTRA EFFORT THEY ALL PUT IN. WE'RE VERY GRATEFUL FOR THE MANY, MANY COMMENTS THAT WE RECEIVED. MY E-MAIL BOX, WELL, ALMOST 4,000 IN A 3 1/2-WEEK PERIOD. AN INTERESTING EXERCISE. PROFESSIONAL SOCIETIES, INSTITUTIONS, AND INDIVIDUAL INVESTIGATORS AND TRAINEES. YOU KNOW, I WAS SO GLAD TO SEE TRAINEES WRITING. THAT'S GREAT. AND YOU KNOW, THEY HAD BOTH VIEWPOINTS. GOOD IDEA, TERRIBLE IDEA. THAT'S ALSO OF COURSE FINE. BUT THE FACT THAT THEY FELT, YOU KNOW, THAT IT WAS IMPORTANT TO WRITE IN AND STATE WHAT THEIR VIEW WAS, THAT WAS REALLY GOOD. SO YOU'RE DOING A GREAT JOB TRAINING THOSE YOUNG PEOPLE. WITHOUT GOOD TRAINING THEY WOULD NEVER DO THAT, OKAY? THAT'S PRETTY WONDERFUL. OBVIOUSLY THE ACD SPENT A LOT OF TIME. IF THERE'S ANY RESIDUAL HATE MAIL ABOUT THIS, PLEASE SEND IT TO ME DIRECTLY, DON'T BOTHER ALL THOSE OTHER PEOPLE. SO WITH THAT I'LL STOP AND, PAUL, IF THERE'S QUESTIONS OR COMMENTS YOUR COUNCIL WOULD LIKE TO MAKE I'M HAPPY TO LISTEN OR ADDRESS. >> THANK YOU. I WILL OPEN THE FLOOR. AS ASK YOU YOUR QUESTION INTRODUCE YOURSELF. >> MONICA VETTER, UNIVERSITY OF UTAH. THANK YOU VERY MUCH. THAT WAS A VERY INTERESTING AND CLEAR PRESENTATION. BY SETTING THIS TARGET OF 25th PERCENTILE THERE'S QUITE A BIT OF VARIABILITY ACROSS THE INSTITUTES IN TERMS OF PAYLINES, IS THERE GOING TO BE AN EFFORT TO CREATE MORE STANDARDIZATION? >> I'VE GIVEN YOU AVERAGES, SO TO TAKE EXTREME CASES, A PARTICULAR INSTITUTE PAYLINE, I'M MAKING NUMBERS UP OBVIOUSLY, 10%, IT DOESN'T SEEM REASONABLE THEY WILL NOW GO TO 25%. CONVERSELY IF SOMEBODY'S ALREADY AT 25% IT DOESN'T SEEM REASONABLE TO SAY WE'RE DONE, YOU EXPECT THEM TO GO A LITTLE FURTHER. WE'LL BE HAVING A MEETING IN THE NEAR TERM WITH ALL INSTITUTE AND CENTER DIRECTORS TO WORK THROUGH SPECIFICS. WHAT I'VE PROVIDES IS A ROLLED UP AGGREGATE BECAUSE EACH I.C. OF COURSE IS -- THE REAL GOAL IS TO GET MORE OF THESE YOUNG PEOPLE WHO HAD MERITORIOUS WORK READY AND, YOU KNOW, ABLE TO SUSTAIN. >> DENNIS LEVI. AT ONE POINT THERE WAS DISCUSSION ABOUT SOMETHING LIKE A AWARD WHERE A SENIOR INVESTIGATOR STEPPING DOWN WOULD HAVE A MENTEE. SO THERE'S A MENTOR-MENTEE RELATIONSHIP, EARLY STAGE INVESTIGATOR, THAT GRANT WOULD BE HANDED OVER ESSENTIALLY. >> SO THAT WAS MET WITH EXTRAORDINARY ANGER, AND RESISTANCE BY THE COMMUNITY. AND ELICITED -- IN SOME INSTANCES VITRIOLIC RESPONSE, AND I WON'T GUESS WHICH COHORT THOSE PEOPLE BELONGED TO. SO, YOU KNOW, BASED UPON, YOU KNOW, VERY, VERY NEGATIVE FEEDBACK, WE DECIDED, YOU KNOW, TO STEP AWAY FROM THAT APPROACH. THERE STILL MIGHT BE MERIT REVISITING THAT IN THE FUTURE BUT WHEN THE LAST TIME WE DID HAVE A PUBLIC DISCUSSION, WHICH IS WHAT YOU NEED TO DO, IT WAS PERCEIVED IN A VERY NEGATIVE WAY. >> THANK YOU VERY MUCH. IT WAS ACTUALLY HELPFUL TO HEAR WHAT YOU SAID. I HAVE A DIFFERENT ANGLE. LOOKING AT TRAINING AND PEOPLE WHO OPT OUT OF THE DOING A POSTDOC, FOR EXAMPLE, BECAUSE THERE'S NOWHERE TO GO, THESE ARE PEOPLE WHO DON'T NECESSARILY WANT TO START THEIR OWN LAB. THEY CAN'T OR WON'T APPLY FOR K9 9, FOR EXAMPLE, SO HAS THERE BEEN DISCUSSION BROADLY, NOT INSTITUTES, ABOUT STAFF SCIENTIST, PHYSICIAN, NCI IS THE ONLY ONE I KNOW OF THAT HAS FUNDING FOR THAT. >> YEAH, THEY ARE THE ONLY ONES. >> IN OTHER WORDS, TO KEEP THE RESEARCH ENTERPRISE, I USED TO THINK THIS WAS IMPORTANT FOR œSENIOR SCIENTISTS, PARTICULARLY, THAT IS TO KEEP THEIR STAFFER SCIENTISTS IN PLAY BUT IT COULD BE ALSO IMPORTANT FOR THE EARLY STAGE INVESTIGATOR. >> SO THERE'S A LOT TO UNPACK IN WHAT YOU JUST ARTICULATED. IT IS CERTAINLY TRUE THAT NOT ALL Ph.D.s WANT A BENCH OR, YOU KNOW, ACADEMIC RESEARCH CAREER. AND LUCKY FOR US, BECAUSE WE NEED THESE INCREDIBLY TALENTED PEOPLE TO DO OTHER SORTS OF THINGS LIKE POLICY AND PROGRAM OVERSIGHT AND REVIEW OVERSIGHT AND SO ON. AND I PERSONALLY AM AN ENORMOUS BENEFICIARY OF, YOU KNOW, VERY WELL-TRAINED VERY HIGHLY TALENTED PEOPLE WHO DO THAT. SO TARA, Ph.D. IN BIOPHYSICS, POSTDOC, GREAT LAB, LUCKY ME, SHE CAME TO NIH A NUMBER OF YEARS AGO THROUGH FELLOWSHIP PROGRAM AND HAS STAYED IN THIS SIDE OF SCIENCE. BUT WE'RE NOT -- SO WE'VE HAD THOSE BROADER CONVERSATIONS, AND SO THE BEST PROGRAM IS ONE, YOU KNOW, APPROACH TO MAKING SURE THAT YOUNG PEOPLE UNDERSTAND THAT THERE ARE OTHER OPTIONS AND THEY ARE NOT ALTERNATIVE CAREERS. RIGHT? THEY ARE NOT LESSER CAREERS. THEY ARE CRUCIALLY IMPORTANT CAREERS THAT WE NEED TO RECRUIT PEOPLE TO, OKAY? BUT THE FOLKS THAT WE'RE SPEAKING ABOUT WITH THIS INITIATIVE ARE THE ONES WHO HAVE MADE THE COMMITMENT TO, YOU KNOW, REMAIN ACTIVE IN SOME SORT OF RESEARCH PROGRAM. AND SO THAT'S WHY WE'RE, YOU KNOW, LAYING OUT THE APPROACHES THAT WE HAVE. THE STAFF SCIENTIST ISSUE IS ALSO COMPLICATED. I THINK THAT THERE IS A MIXED FEELING ABOUT STAFF SCIENTISTS AMONG FACULTY. BY NECESSITY, STAFF SCIENTIST SALARIES ARE CONSIDERABLY HIGHER THAN GRADUATE STUDENTS OR POSTDOCS. AND THEY ARE MEANT TO BE BECAUSE IT IS A TRUE CAREER POSITION. UNIVERSITIES, NOT ALL UNIVERSITIES, BUT MANY UNIVERSITIES AREN'T QUITE SURE WHAT TO DO WITH STAFF SCIENTISTS BECAUSE THEY ARE EMPLOYEES BUT ONLY AS LONG AS THERE'S FUNDING FOR THEM, AND IF THERE ISN'T FUNDING FOR THEM THEIR STATUS BECOMES TENUOUS AT BEST. SO SOMETIMES THE VIEW IS EXPRESSED THAT, NO, NO, WE'RE BETTER OFF WITH POSTDOCS WHO WE KNOW HAVE TO GO ON, OR GRADUATE STUDENTS WHO WE KNOW HAVE TO GO ON. I COULD ARGUE THAT EITHER WAY. I PERSONALLY THINK CREATING A STABLE WORKFORCE OF STAFF SCIENTISTS WOULD BE WONDERFUL, BUT THAT WOULD REQUIRE SOME UNIVERSITY BUY-IN, AND THESE DAYS, I DON'T HAVE TO TELL YOU BECAUSE YOU LIVE THIS EVERY DAY, WITH UNIVERSITIES UNDER INCREASING STRESS FINANCIALLY AND OTHERWISE, THE NOTION OF SOMEHOW TAKING ON YET ANOTHER COHORT FOR WHOM THEY NEED TO BE RESPONSIBLE FOR, I'M NOT SURE HOW THAT WILL WORK, YOU KNOW, AT MOST IF NOT ALL INSTITUTIONS. YOU KNOW, THE NCI IS PILOTING SOMETHING, THEY ARE THE ONLY ONES, ALSO THE ONLY ONES WITH A $5 BILLION BUDGET, WE CAN REVISIT BUT I MUST SAY IT'S HARD TO QUANTIFY BUT I DON'T THINK THERE'S OVERWHELMING SUPPORT AMONGST INVESTIGATORS. I THINK THEY PREFER POSTDOC, GRADUATE STUDENT MODEL. AND THERE ARE DIFFERENT WAYS OF VIEWING THAT. THERE ARE POSITIVE WAYS OF VIEWING THAT AND THERE ARE LESS POSITIVE WAYS OF VIEWING THAT. AND I'M SURE YOU COULD FILL IN THE DETAILS OF EITHER INTERPRETATION. SO, YEAH, BUT IT IS AN IDEA THAT I'M SURE WE WILL, YOU KNOW, REVISIT. PLEASE. >> THANK YOU AGAIN FOR THE VERY CLEAR PRESENTATION. DOUGLAS REESE, CASE WESTERN. WHAT WAS THE NATURE OF THE FEEDBACK THAT RESULTED IN THE CHANGE FROM A CAP OF FUNDING FOR INVESTIGATORS? >> YEAH, SO I THINK THERE WERE TWO MAJOR ELEMENTS. THE FIRST IS THE FRAMEWORK THAT WE LAID OUT FOR THE ORIGINAL GSI WAS NOT SENSITIVE ENOUGH TO TEAM SCIENCE. DESPITE ATTEMPTS TO BUILD IN THE BANDWIDTH, IF YOU WILL, TO CAPTURE THE MANY DIFFERENT TYPES OF TEAM SCIENCE APPROACHES, WE NEVER QUITE CAPTURED IT IN THE RIGHT WAY. AND SO THEN WHAT WE STARTED TO DO WAS WE STARTED TO EXCLUDE CERTAIN TYPES OF MECHANISMS WHERE TEAM SCIENCE IS SORT OF ESSENTIAL FOR WHAT IS BEING DONE. AND AS WE KEPT ITERATING WE FOUND OURSELVES IN A PLACE WHERE IF WE COULD EXCLUDE SO MANY DIFFERENT THINGS, IT WASN'T WORTH DOING ANYMORE, BECAUSE YOU ONCE FREE UP ENOUGH FUNDS TO REALLY MAKE A DIFFERENCE. THAT WAS THE FIRST MAIN ISSUE. SO GOING FORWARD IF WE'RE GOING TO DO THIS WE'RE GOING TO HAVE TO FIGURE OUT A MUCH MORE SOPHISTICATED APPROACH TO ACCOUNTING FOR TEAM SCIENCE. THE SECOND ISSUE THAT WAS RAISED WAS THAT OF THE NEED TO HAVE EACH INDIVIDUAL INVESTIGATOR CONSIDERED ON A CASE-BY-CASE BASIS BECAUSE WHEN YOU'RE LOOKING AT AVERAGE CURVES, YOU ARE LOOKING AT AVERAGE CURVES. AND YOU DON'T NECESSARILY ACCOUNT FOR THE UNIQUE INDIVIDUAL WHO REALLY CAN CONTINUE TO MAKE A VERY EXTRAORDINARY CONTRIBUTION REGARDLESS OF HOW MUCH SUPPORT, YOU KNOW, THEY ENJOY. THE DATA SHOW THAT THERE ARE SOME PEOPLE LIKE THAT, BUT THE CONUNDRUM IS EVERYBODY THINKS THEY ARE ONE OF THOSE PEOPLE. AND IT'S A LITTLE BIT LIKE, YOU KNOW, GETTING THE TROPHY FOR SHOWING UP SYNDROME, RIGHT? NOT EVERYBODY IS EXCEPTIONAL, BUT EVERYBODY IS EXCEPTIONAL IN THEIR OWN VIEWPOINT. AND SO WE PIVOTED TO SOMETHING CALLED DYNAMIC CAP, WHERE THE INSTITUTE OR CENTER WOULD ACTUALLY DO THAT TYPE OF REVIEW, BUT AT THE END I THINK THOSE WHO FELT THAT THIS CASE-BY-CASE REVIEW WAS ESSENTIAL, YOU KNOW, PUT ENOUGH CONCERN IN PEOPLE'S MINDS THAT THEY FELT, YOU KNOW, IT WAS PREMATURE TO LAUNCH SOMETHING OF THIS TYPE SO THOSE ARE THE TWO MAIN THINGS. >> ONE OF THE RATIONALES BEHIND THE CAP WAS AT LEAST IN THE EXPLANATION I SAW, THE ANNOUNCEMENT, NOTED THERE WAS INCREASING CONSOLIDATION OF RESEARCH DOLLARS INTO JUST FEWER NUMBER OF INSTITUTIONS. THIS IS A WONDERFUL PRESENTATION ON HOW TO ADDRESS THE AGE ASPECT. ARE THERE INITIATIVES OR THOUGHT ABOUT HOW TO ADDRESS THAT CONCERN? >> WELL, SO IT'S -- IT'S A BIT OF A -- IT'S A CONUNDRUM. PEOPLE AT RESEARCH INTENSIVE INSTITUTIONS DO HAVE CERTAIN ADVANTAGES, PARTICULARLY FOR CERTAIN TYPES OF SCIENCE, WHERE THE INFRASTRUCTURE IS THERE, AND YOU DON'T HAVE TO TRYING TO FIGURE OUT HOW TO DO SOMETHING. IT'S ALREADY THERE FOR YOU TO TAKE ADVANTAGE OF. THAT SAID THOUGH, THERE IS ENORMOUS TALENT ACROSS THIS COUNTRY, AND OUR JOB AS STEWARDS OF THE RESOURCES IS TO MAKE SURE THAT WE GIVE, YOU KNOW, HIGHLY MERITORIOUS WORK FROM PLACES OTHER THAN, YOU KNOW, THE USUAL PLACES WE ALL KNOW THE OPPORTUNITY TO MAKE THEIR CONTRIBUTION. AND SO IN EITHER OF THESE SCENARIOS, AT LEAST SOME OF THE PEOPLE WHO WILL NOW GET SUPPORT, COME FROM INSTITUTIONS THAT ARE SOMEWHAT LESS RESEARCH INTENSIVE. BUT THERE'S NO SPECIFIC TARGETING FOR THAT. IT'S JUST THE MATH OF THIS. THE PLACES THAT ARE VERY RESEARCH INTENSE, MANY OF THEM, AND I'M GOING TO MAKE A GENERALIZATION NOW WHICH IS JUST THAT, A GENERALIZATION, MANY BUILD LARGE RESEARCH GROUPS AND DON'T NECESSARILY ENCOURAGE OR PERHAPS ATTRACT PEOPLE WHO DON'T WANT TO SEND IN THEIR OWN INDEPENDENT AWARDS. PLACES THAT ARE LESS RESEARCH INTENSE TEND NOT TO HAVE VERY, VERY LARGE GROUPS. SO PEOPLE DO TEND TO SEND IN AWARDS. SO WE HOPE THAT SOME OF THAT REBALANCE OCCURS BUT THERE WILL BE NO SPECIFIC, YOU KNOW, TARGET OR METRIC. WE'RE JUST GOING TO LET THE MERIT SYSTEM WORK OUT WITH THE UNDERSTANDING WE WANT TO FUND MORE YOUNG PEOPLE SO WE THINK THAT THAT ALONE WILL BEGIN TO SHIFT SOME OF WHAT YOU'RE REFERRING TO. >> LARRY, THANK YOU FOR COMING AND TAKING TIME TO EXPLAIN. >> MY PLEASURE. >> WE WILL CONTINUE OUR DISCUSSION AND TARA WILL MAKE SURE EVERYTHING ELSE (INDISCERNIBLE). THANK YOU. [APPLAUSE] >> LET'S PUT IN 15 MINUTES OF GENERAL DISCUSSION AND GO UPSTAIRS FOR A PICTURE AND HAVE LUNCH. THE CAFETERIA IS OPEN UNTIL 1:30. WE'VE GOT SOME TIME. 15 OR 20 MINUTES. AN OBSERVATION CLINICAL TRIALS ARE EXPENSIVE WHEN IT'S DIFFICULT TO AFFORD THEM, OTHER WAYS OF GATHERING DATA, THEY WILL BE THE SAME FACTS GATHERED IN OTHER WAYS. SO THANK YOU FOR THAT COMMENT, AND ANYONE ELSE WHO WOULD LIKE TO BRING UP ANY TOPIC, WHATEVER. OR FEEDBACK ON THIS PRESENTATION. >> I JUST WANT TO MAKE THE COMMENT THAT, YOU KNOW, WITH THE LAST PRESENTATION IT'S ALWAYS REALLY TOUGH WHEN IT'S ZERO SUM GAME AT LEAST ON THE INPUT, AND IT'S HARD FOR ANYONE TO COME UP FEELING LIKE A WINNER. I DO HAVE TO SAY I'M VERY IMPRESSED AT THIS BEING PROBABLY ONE OF THE LEAST BUREAUCRATIC AND MOST PRAGMATIC PRESENTATIONS OF A VERY DIFFICULT AREA THAT I'VE HEARD IN A WHILE. ULTIMATELY, THE CHALLENGE IS GOING TO BE DECIDING ON WHAT REALLY ARE THE OUTPUTS THAT BECOME THE MEASURES THAT HELP TO DRIVE, YOU KNOW, HOW FUNDING DECISIONS ARE MADE, AND REALLY THERE'S A LOT OF MERIT TO LOOKING AT, YOU KNOW, EACH APPLICATION ON ITS OWN MERIT, AND WHAT THE INTRINSIC QUALITIES ARE, BUT THEN TYING THAT TO WHAT THE ULTIMATE GOALS OF THE ORGANIZATION ARE AND HAVING METRICS FOR THAT IS A REALLY, REALLY HARD THING, BUT THAT PROBABLY IS SOME EXPERIMENTATION IN THAT, AT SOME LEVEL, PROBABLY GOING TO BE NECESSARY AT SOME POINT BECAUSE THERE ARE DIMINISHING RESOURCES. BUT, AGAIN, I'M VERY IMPRESSED BY THE THOUGHTFULNESS THAT'S GONE INTO THIS. AND IT'S REALLY THINK IT'S A PITY THAT THE AMERICAN PUBLIC DOESN'T HAVE A BETTER SENSE OF THE THOUGHTFULNESS WITH WHICH THESE VERY IMPORTANT SCHOLARS HAVE SPENT. >> MICHAEL, NOT TO PUT YOU ON THE SPOT BUT WOULD YOU HAVE ANY SUMMARY OF HOW THE EYE INSTITUTE CURRENTLY IS HANDLING THIS AND WHERE WE'VE BEEN? >> SURE, THIS IS A REAL EASY ONE FOR ME BECAUSE THIS IS WHAT WE DO EVERY DAY. SINCE THEY GAVE US THE STANDARD OF MATCHING THE NEW INVESTIGATOR SUCCESS RATE TO THE SENIOR INVESTIGATOR SUCCESS RATE, WE HAVE NEVER MISSED THAT GOAL. AND WE'RE ONE OF FEW INSTITUTES THAT DO THAT. THEREIN LIES THE PROBLEM OF THE AVERAGE CURVE THAT YOU SEE THERE. SO I WOULD BE SHOCKED TO HEAR THAT WE DID NOT FUND NEW INVESTIGATOR WITH A 25th PERCENTILE SCORE. WHEN WE LOOK AT THE DISTRIBUTIONS OF SCORES EVERY ROUND, WHAT WE FIND IS WHEN YOU GET DOWN TO THE POINT WHERE THE LINE IS GOING TO BE DRAWN IN EACH OF THE PORTFOLIOS THE SCORES ARE ALL VIRTUALLY TIED. THAT'S THE WAY STUDY SECTIONS SCORE THINGS. AND SO THERE ARE VERY DIFFICULT DECISIONS THAT NEED TO BE MADE THERE, AND SO THE PROGRAM OFFICERS RESPONSIBLE FOR EACH OF THE PORTFOLIOS SIT DOWN AND DISCUSS EVERY SINGLE GRANT, AND THE REVIEW, AND THE FUNDING THAT THAT INVESTIGATOR HAS, AND THE UNIQUENESS OF THAT PIECE OF RESEARCH TO THE PORTFOLIO BEFORE THEY RANK THEM. SO THE KINDS OF THINGS THAT HE'S TALKING ABOUT ARE THE KINDS OF THINGS THAT NEI HAS ALWAYS DONE AND WILL CONTINUE TO DO. IT'S NOT EASY. I'LL HAVE TO SAY THAT. THERE'S A LOT OF LOUD DISCUSSION. BUT IN THE END, YOU HAVE TO DRAW THE LINE SOMEWHERE. AT THE END OF THE YEAR, THERE'S OFTEN MONEY THAT COMES TO US BY SURPRISE, WHEN THEY ARE SWEEPING THE FLOOR IN THE VAULT AND THERE'S A FEW EXTRA BILLS. AND WE KNOW MONEY MAY NOT BE THERE NEXT YEAR, AND SO WE DON'T LIKE TO MAKE OUT-YEAR COMMITMENTS ON MONEY THAT MIGHT COME IN AT THE END OF THE YEAR, AND SO WE USE THAT MONEY TO BRIDGE FUND THE COMPETING RENEWALS OF PEOPLE THAT HAVE JUST MISSED PAYLINE, AND AGAIN WE LOOK AT DID THEY HAVE OTHER SOURCES OF FUNDING, IS THIS THE ONLY GRANT THAT WILL CLOSE -- IT WILL CLOSE THEIR LAB DOWN, AND LAST YEAR I KNOW THAT WE REACHED ALL THE WAY TO THE 40th PERCENTILE TO FUND COMPETITIVE RENEWALS THAT WERE A-1s OF PEOPLE WHO HAD NO OTHER SOURCE OF FUNDING IN THEIR GRANT, IN THEIR LABORATORIES. SO I THINK WE'RE IN PRETTY GOOD SHAPE HERE. WE'LL KEEP AN EYE ON IT. >> I'M NOT SURE TO WHAT EXTENT THIS IS POSSIBLE BUT THE GROWTH IN LATE STAGE INVESTIGATORS WAS PARTICULARLY STRIKING, AND, YOU KNOW, I AGREE THAT RESILIENCY IS ONE CONTRIBUTING FACTOR, BUT TO WHAT EXTENT WAS THERE SORT OF ASSESSMENT OF OTHER CONTRIBUTING FACTORS, SO THE THINGS LIKE POTENTIAL INFLUENCE ON REVIEW PANELS, THESE ARE PEOPLE WELL KNOWN IN THEIR FIELD AND, YOU KNOW, ARE CONNECTED AND HAVE COLLEAGUES THAT ARE, YOU KNOW, WHOSE GRANTS ARE -- WHO ARE SERVING ON PANELS OR THE AVAILABILITY OF NON-NIH SUPPORT,& PROBABLY NOT APPROPRIATE TO FACTOR THAT, BUT CLEARLY THERE ARE INVESTIGATORS WHO BENEFIT FROM SUBSTANTIAL NON-NIH SUPPORT AND IT'S SIGNIFICANTLY ENHANCING THEIR COMPETITIVENESS WHEN THEY DO COME IN FOR NIH FUNDING BECAUSE THEY HAVE, YOU KNOW, SIGNIFICANT PRELIMINARY DATA AND, YOU KNOW, ACCESS TO TOP DRAWER TOOLS AND EQUIPMENT, SO TO WHAT EXTENT WAS THERE A DEEPER ANALYSIS OF THOSE CURVES? IT WAS QUITE DRAMATIC. >> I CAN SEND OUT THE LINK TO THE PUBLICATION, IT SHOWS -- FOR INSTANCE THE PRIORITY SCORE DISTRIBUTION OF THE THREE COHORTS LINE UP RIGHT ON TOP OF EACH OTHER, WE DON'T HAVE ACCESS TO OTHER SUPPORT ON THAT SORT OF SCALE OF INVESTIGATORS, BUT IF WE DO A SIMPLE POLL OF, YOU KNOW, HOW MANY PEOPLE THINK NEW INVESTIGATORS HAVE ENDOWED CHAIRS, HOW MANY PEOPLE THINK THAT THEY HAVE -- I MEAN, SO ALL THE NON-NIH FACTORS THAT WE CAN IDENTIFY ARE PRETTY MUCH ON THE RESILIENCY SIDE, SO THE ONE THING THAT PEOPLE DO THINK ABOUT IS IT'S VERY PRODUCTIVE MID-CAREER INVESTIGATORS, MOVING INTO THE OLDER INVESTIGATORS. SO THAT ANALYSIS HAS ONLY BEEN DONE FOR ONE INSTITUTE, BUT OVER THAT 10-YEAR PERIOD THEIR NUMBER OF RO1s DECLINED BY 155, AND 153 OF THOSE WERE MID-CAREER INVESTIGATORS. AND SO WHAT HAPPENED WAS THAT THE -- AND THE NUMBER OF EARLY STAGE INVESTIGATORS ARE -- IT'S CONSTANT, SO AS WE LOOK AT PERCENTAGES OF THE POPULATION, THE OLDER INVESTIGATORS INCREASED, BUT THE NUMBER OF OLDER INVESTIGATORS ACTUALLY STAYED CONSTANT, SO THE OLDER INVESTIGATORS ACTUALLY ARE RETIRING AND LEAVING, INFLUX AND OUTFLUX IS THE SAME, ONLY FOR THIS ONE INSTITUTE ATTRIBUTABLE TO DECREASE IN THAT SINGLE COMPARTMENT. YOU KNOW, YEAH. >> ONE MORE COMMENT ON THE STAFF INVESTIGATOR AND BRIDGE FUNDING, AS TO MAYBE STRATEGIC AREAS THAT I THINK WE MAY NEED TO MOVE INTO, AND I CAN SPEAK ON BEHALF OF MY PERSONAL EXPERIENCE, NUMBER ONE TENURE LINE POSITIONS ARE PROBABLY A DINOSAUR AT MOST UNIVERSITIES, THEY DON'T EXIST ANYMORE BECAUSE OUTSIDE AUDITORS SAY THE MORE TENURE YOU HAVE, POSITIONS YOU HAVE, THE MORE LIABILITY YOU HAVE, SO UNLESS YOU GET PHILANTHROPY TO SUPPORT THEM, SO I CAN'T HIRE A FACULTY MEMBER IN A TENURE LINE POSITION LEST THEY GET AN RO1, WHICH CREATES A CONUNDRUM. SO THAT'S THE MID-CAREER INVESTIGATOR, THAT CAN'T GET INTO THAT SCENARIO, SO THE ABILITY OF SUPPORT FOR THOSE PEOPLE IS TO MOVE THEM OUT OF THE FACULTY TRACK AND PUT THEM INTO A STAFF SCIENTIST TRACK. OTHERWISE THEY HAVE TO GO INTO REAL ESTATE SALES BECAUSE THEY CAN'T CONTINUE TO BE SCIENTISTS. SO IT'S A REAL CONUNDRUM. THE SECOND CONUNDRUM IS BRIDGE OR GAP FUNDING, AND, AGAIN, THIS IS FULLY SUPPORTED INSTITUTIONALLY, BY PHILANTHROPY, BECAUSE WE CAN'T SET ASIDE MONIES ON A YEAR TO YEAR BUDGET SO THERE'S NO ROLLOVER FUNDS I CAN KEEP FOR A RAINY DAY SO UNLESS I GET YEARLY PHILANTHROPY I CAN'T GAP BRIDGE OR BRIDGE GAP AN INVESTIGATOR. AND THIS IS BECOMING MORE AND MORE REALITY FOR A LOT OF US SO I THINK WE NEED TO THINK OF A WAY TO REALLY STRATEGICALLY USE& THOSE FUNDS THAT MAY ONLY BE THERE WHEN THEY ARE THERE, BUT PERHAPS SET ASIDE SOME MONIES FOR THESE TALENTED INVESTIGATORS THAT DON'T SEE A WAY TO GET OUT OF THAT. >> LET ME SAY A COUPLE WORDS ABOUT THE PILOT THAT LARRY REFERRED TO. THE STAFF SCIENTIST, THE PILOT, SO THERE'S TWO APPROACHES THAT ARE BEING TESTED. ONE IS TO AWARD INSTEAD OF INSTITUTIONAL GRANTS, US A KNOW ALL YOUR GRANTS ARE TWO-YEAR INSTITUTION, TO AWARD A STAFF SCIENTIST AWARD TO AN INDIVIDUALS FOR PERIOD OF TIME THAT WOULD HAVE SALARY AND SOME TRAVEL MONEY AND THEY WOULD COMPETE FOR IT BASED ON THEIR SKILLS AND COULD MOVE ANYWHERE, IF YOU HAD PARTICULARLY GIFTED AND ANALYSIS OF MRI IMAGE AND THE TEAM WAS NO LONGER IN LOVE WITH THEM THEY COULD MOVE THE GRANT TO ANOTHER INSTITUTION OR TO ANOTHER LABORATORY TO MAKE A FLEXIBLE WORKFORCE WHERE THE INDIVIDUAL WOULD HAVE SOME CONTROL OVER THEIR CAREER AND WHO THEY ARE WORKING WITH AND WHERE THEY ARE WORKING, AND THE OTHER OPTION THAT'S BEING TRIED IS TO HAVE SIMILAR SORT OF POSITION, BUT GIVE IT TO THE INSTITUTION INSTEAD OF TO THE INDIVIDUAL TO ALLOW THEM TO CREATE A POSITION THAT WOULD ALWAYS BE THERE THAT MIGHT NOT BE ASSOCIATED WITH PARTICULAR GRANT, OR PARTICULAR INVESTIGATOR, BUT WOULD BE LIKE AN INSTITUTIONAL POSITION THAT THEY COULD HIRE SOMEONE IN TO KEEP A PARTICULAR POSITION, THESE ARE JUST STARTED A YEAR AGO I BELIEVE, SO IT WILL TAKE SOME TIME TO SEE HOW THEY TURN OUT BUT THEY ARE VERY INTERESTING IDEAS THAT I THINK WE NEED TO LOOK AT. >> MIKE, IS THIS UNDER NEI'S -- >> NO, NCI IS RUNNING THE FIRST PILOT. >> NCI PILOT, OKAY, YEAH. >> AN INTERESTING PHENOMENON, ACADEMIC INSTITUTIONS JUST KIND OF HAVE A SMALL STROKE OVER, THAT'S WHEN YOU SUPPORTED AN INVESTIGATOR, JUNIOR INVESTIGATOR FOR A NUMBER OF YEARS, GIVEN THEM THE START THEY NEED, MENTORING AND SO FORTH, THEY GET THE FIRST RO1 AND LEAVE BECAUSE NOW THEY ARE SO RECRUITABLE, AND SO YOU JUST MENTIONED, MIKE, THE GRANT IS GIVEN, AWARDED TO THE INSTITUTION, NOT TO THE PERSON, YET THE PERSON HAS THE EXPERTISE, IT BECOMES DIFFICULT, SO INSTITUTIONS ARE FORCED INTO A MEGA RETENTION PACKAGE, IF THEY CAN AFFORD IT. IF THEY CAN'T, SOMEONE CAN DO SOMETHING MORE TANTALIZING. >> COULD WE CHANGE THE CONVERSATION NOW OR MOVE ON TO TOPICS OF SCIENCE? YOU'VE HAD A MORNING RICH IN THE SET OF IDEAS, ACROSS THE SPECTRUM, AND I WOULD LIKE TO KNOW WHETHER YOU SEE AREAS OF SCIENCE, RESEARCH OR BASIC, OR TRANSLATIONAL THAT WE SHOULD BE CONSIDERING IN THE PORTFOLIO, OBVIOUSLY SUCH CHANGES DON'T HAPPEN OVERNIGHT BUT IS THERE SOMETHING THAT YOU'RE PERCEIVING THAT IS WORTH US THINKING ABOUT MORE DEEPLY? >> I THINK WITH RESPECT TO THE AGR, THE FOA BEING CONSIDERED, IT WOULD BE GOOD TO NAIL DOWN THE MECHANISM OF MATERIAL TRANSFER, THAT'S GOING ON THAT IS RELEVANT TO STEM CELL WORK AND TRANSPLANTATION WORK, TO MAYBE THERE WAS A SUBLINE IN THE FOA THAT SAID PROJECTS THAT INVESTIGATE THE NATURE OF THE TRANSFER, HOW IT WORKS AND TO WHAT EXTENT IT EXPLAINS PHENOMENA THAT'S OBSERVED WOULD BE IMPORTANT. MORE LIKELY TO BE RNA. IT'S AN OPEN QUESTION. AND IT MAY UNDERLIE A LOT OF PHENOMENA THAT'S OBSERVED. IT'S VERY IMPORTANT, WE'RE PUTTING IN A LOT OF RESOURCES TO LOOK AT THE TRANSLATIONAL SIDE OF THIS, AND I THINK IT'S VERY IMPORTANT TO HAVE A CLEAR UNDERSTANDING OF THE BASIC MECHANISM. >> (INAUDIBLE). >> THIS IS RECOGNIZED ACROSS NIH AND IN FACT THERE'S TWO INITIATIVES ON THE DRAWING BOARD, ONE THROUGH THE COMMON FUND AND ONE THROUGH THE NEUROSCIENCE BLUEPRINT THAT TIES US TOGETHER TO TRY TO UNDERSTAND THESE EXOSOMES MUCH BETTER THAN THEY ARE NOW TO TRY TO IDENTIFY NOT ONLY HOW THEY ARE CONTROLLED BUT WHAT CONTENT IS AND HOW IT TRANSFERS FROM ONE CELL TO ANOTHER. SO WE'RE SIGNED ON TO THOSE AND PAYING ATTENTION AND WE'LL DEFINITELY BE INVOLVED. >> I WOULD JUST SECOND, WITH RESPECT TO RETINAL APPROACHES, THE FOCUS HAS BEEN ON PHOTORECEPTORS BUT I THINK WE CAN'T RULE OUT THIS MAY APPLY TO OTHER CELL TYPES, SUCH AS RGC EXPERIMENT SO I THINK THAT NEEDS TO BE LOOKED AT. >> ONE OF OUR AGI PROJECTS IS IN FACT LOOKING AT THAT IN RETINA. >> I HAD A QUESTION ABOUT THERE'S, YOU KNOW, MANY OF THE WORKSHOPS AND TODAY'S PRESENTATION SORT OF A FOCUS ON EXPANDING THE USE OF ANIMAL MODELS AND REALLY DEVELOPING THOSE THAT MAY BE PARTICULARLY RELEVANT TO HUMAN STUDIES, AND I WONDER IF THERE'S GOING TO BE A PLAN FOR ANY KIND OF TARGETED MECHANISMS LIKE POTENTIALLY SORT OF R21 TYPE, SHORTER FUNDING PERIOD, MAYBE FAIRLY FOCUSED JUST ON MODELS, DEVELOPMENT AND SORT OF TESTING THAT WOULDN'T NECESSARILY HAVE TO BE QUITE AS HYPOTHESIS DRIVEN AS OTHERS BUT WOULD SORT OF TAKE POTENTIAL MODELS AND PUT THEM THROUGH PACES AND ASSESS WHETHER THEY ARE GOOD FEASIBLE MODELS, AND WHETHER THAT WOULD BE A CONTRIBUTION IN SOME KEY AREAS TO CREATE SORT OF ACCEPTABLE PLATFORMS AND MODELS THAT PEOPLE CAN TURN TO AND A LOT OF THAT GROUND WORK WILL HAVE BEEN SPECIFICALLY SUPPORTED. >> DO YOU MEAN OTHER SPECIES OR OTHER, FOR EXAMPLE, RETINA IN A DISH, NAILING DOWN WHAT IT TAKES? >> THAT COULD BE UP FOR DISCUSSION. I HAD ASSUMED SOME OF THIS WAS SORT OF IN VIVO WHOLE ANIMAL WORK BUT I THINK THAT NEEDS TO BE DEFINED, WHAT IS IT THAT PEOPLE, YOU KNOW, WHAT IS THE NEED IN THE FIELD AND WHETHER JUST SOME EMPHASIS IN THESE INITIAL STAGES ON SORT OF DEFINING WHAT THESE MODELS NEED, HOW DO THEY NEED TO LOOK IN ORDER TO BE USEFUL. >> AND PLAY OUT. >> YEAH. >> EVERYONE'S HAPPY? HAPPY AND HUNGRY. OKAY, LET'S TAKE A PAUSE, UPSTAIRS FOR OUR PICTURE AND THEN SOME LUNCH AND BE BACK 2:00