I WANT TO WELCOME ALL OF YOU TO THIS JOINT MEETING OF THE NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES ADVISORY COUNCIL. IT'S THE 18th MEETING. 17th OR 18th? WHICHEVER IT IS, AND CURRENT MEETING OF THE CURES ACCELERATION NETWORK REVIEW BOARD. 22nd MEETING OF THAT. AND IS OUR WANT, WE CO-GAVEL THIS MEETING INTO ORDER BECAUSE WE HAVE TWO DIFFERENT GROUPS. I'M THE HEAD OF THE COUNCIL AND LYNN MARKS IS THE HEAD OF THE CAN BOARD OF THE WE WILL GAVEL THIS INTO ORDER SIMULTANEOUSLY. SO 1, 2, 3. PRETTY GOOD! SO WE'RE IN ORDER NOW. AND I HOPE ALL OF YOU WHO WERE ABLE TO PARTICIPATE IN THE CAN BOARD VIRTUAL MEETING LAST MONTH, WERE ABLE TO APPRECIATE THE DIFFERENCES PERHAPS MORE THAN YOU HAD BEFORE BETWEEN THE COUNCIL AND THE CAN BOARD. AND I MIGHT ASK LYNNE WHEN THE TIME COMES TO JUST REITERATE THAT, BECAUSE IT'S VERY IMPORTANT. SO, WE HAVE A LOT OF NEW MEMBERS WHO ARE OFFICIAL TODAY. THESE ARE FACES WE HAVE SEEN BEFORE, BUT HAVE BEEN AD-HOC MEMBERS BEFORE. I WANT TO SAY A FEW WORDS ABOUT THEM LATER. THE FULL MEMBERS WHO HAVE BEEN FULL MEMBERS FOR A WHILE ARE DAN HARTMAN, ALAN, HARRY, AND ANNA. STILL AD-HOC ARE RON BARTEK, WHO IS RIGHT THERE, JEFF LING, WHO I DON'T SEE YET, MIKE WHO I DON'T SEE YET AND PAUL WHO HOPEFULLY WILL BE ON THE PHONE. TERRY AND FRANK, WE EXPECT A LITTLE LATER AS WELL. AND WE EXPECT DAVID ATKINS ON BEHALF OF ROCHELLE FROM THE VA. THE PEOPLE WHO ARE NOT GOING TO BE WITH US TODAY ARE MEAGAN, TODD, RICK AND ERIC. THEY SEND THEIR REGRETS. SO WE HAVE TWO INVITED SPEAKERS. ARE THEY HERE YET? THERE THEY ARE. YOU WILL HEAR FROM ON THE TISSUE CHIP SECTION PROGRAM. SO, IF WE COULD JUST TAKE A LOOK AT OUR AGENDA BRIEFLY, JUST TO SEE WHERE WE ARE GOING TODAY, WE HAVE THE USUAL BUSINESS THAT WE HAVE TO DO THIS MORNING, AND THEN I WILL -- WE WILL GO THROUGH INTRODUCTION OF NEW STAFF. WE HAVE BEEN BLESSED WITH A NUMBER OF NEW FANTASTIC STAFF I WANT YOU TO MEET, OR AT LEAST RECOGNIZE AND THEN I'LL HAVE MY DIRECTOR'S REPORT AFTER THAT. WE'LL HAVE AN UPDATE FROM LYNNE AND RON ON THE CURES ACCELERATION NETWORK REVIEW BOARD. OF COURSE WE LAST MET LESS THAN A MONTH AGO. AND THEY WERE VERY BUSY OVER THE HOLIDAYS. BUT I'M NOT SURE HOW MUCH WILL HAVE HAPPENED IN THE LAST THREE WEEKS. BUT WE'LL HEAR FROM THEM AND THEN AFTER THE BREAK, WE HAVE ONE CONCEPT THAT WE NEED YOU TO HEAR ABOUT AND WE HOPE AGREE WITH AND CLEAR. AND THEN WE HAVE A DISCUSSION OF THE TISSUE CHIP VALIDATION CENTERS, BOTH CONCEPTUALLY AND OPERATIONALLY AND DAN WILL BE LEADING THAT. THEN AFTER LUNCH, WE ARE GOING TO SPEND THE ENTIRE OPEN SESSION AFTER LUNCH ON THE DIVISION OF PRE-CLINICAL INNOVATION. YOU'VE HEARD A FAIR AMOUNT FROM ME, AND MOST OF MY DIRECTOR'S UPDATES, ABOUT INDIVIDUAL PROJECTS GOING ON AT DPI THROUGH LITTLE SNIPITS OR ANECDOTES. BUT IT OCCURRED TO US AFTER THE LAST COUNCIL, THAT SOMEHOW WE HAVE GOTTEN FIVE YEARS INTO MY DIRECTORSHIP WITHOUT THE COUNCIL AND CAN BOARD EVER HAVING A FULL PRESENTATION ON THIS DIVISION OF NCATS, WHICH IS REALLY INTERESTING. SO WE REALLY HAVE SOME GROUND TO CATCH YOU UP ON. SO WE ARE GOING TO SPEND TWO HOURS ON THAT. ANTON, WHO IS OUR SCIENTIFIC DIRECTOR, HEAD OF DPI, WILL NOT BE TALKING AT YOU FOR THAT AMOUNT OF TIME. WE ARE AIMING FOR THE USUAL SPLIT OF 1/3 PRESENTATION, TWO-THIRDS DISCUSSIONS. SO HE'S AIMING FOR 40 MINUTES OR SO OF PRESENTATION. WE HOPE THAT YOU WILL ASK LOTS OF QUESTIONS AND WE'LL HAVE SOME ROBUST DISCUSSION, WE HOPE, IN THAT SECTION. AND THEN WE'LL ADJOURN THE OPEN SESSION DO OUR CLOSED SESSION. OKAY. SO NOW I'D LIKE TO BRIEFLY TURN IT OVER TO ANNA WHO WILL GO THROUGH SOME LOGISTICS FOR US. >> ANNA: THANK YOU, CHRIS. THE MINUTES FROM THE SEPTEMBER 2017 MEETING ARE AT YOUR SEATS AND ALSO POSTED IN ECB. I WOULD ACTUALLY LIKE TO HAVE A MOTION TO APPROVE THE MINUTES FROM A MEMBER. SECOND? ALL IN FAVOR? ANY OPPOSED? AND ANY ABSTENTIONS? THE MINUTES ARE APPROVED. THE 2018 COUNCIL PROCEDURES ARE ALSO IN THE ELECTRONIC COUNCIL BOOK AND IN YOUR FOLDERS. WE HAVE A MOTION TO APPROVE THE 2018 COUNCIL OPERATING PROCEDURES? SECOND? ALL IN FAVOR? ANY OPPOSED? ANY ABSTENTIONS? THE 2018 COUNCIL OPERATING PROCEDURES ARE APPROVED. THE FUTURE MEETINGS OF THE GROUP WOULD BE IN 2018 ON MAY 10 AND SEPTEMBER 27. 2019 THE DATES ARE JANUARY 10, MAY 16 AND SEPTEMBER 19. THE CANNERY VIEW BOARD ONLY VIRTUAL MEETINGS WILL BE HELD IN 2018 ON DECEMBER 14 AND IN 2019 ON DECEMBER 13. Y SEEING THAS SOON AS THE 2020 DATES ARE AVAILABLE WE WILL SHARE THAT INFORMATION. IT'S TIME TO START OUR STAFF INTRODUCTIONS. >> BEFORE I DO THAT, I WANT TO REMIND ALL OF YOU THAT THIS IS VIDEO CAST. SO PLEASE DO USE YOUR MICROPHONES SO THAT PEOPLE WHO ARE WATCHING FROM THEIR OFFICES OR FROM HOME, CAN HEAR THE DISCUSSIONS. VERY IMPORTANT FOR US AS AN OPEN SESSION PUBLIC MEETING. SO WE WANT EVERYONE TO BE ABLE TO BENEFIT FROM ALL THE DISCUSSION THAT HAPPENS TODAY. SO BE AWARE OF THAT IT'S LIVE VIDEO CAST AND IT'S ARCHIVED AS WELL FOR FUTURE USE. SO, WHAT I'M GOING TO DO NOW IS ASK ONE PERSON TO TALK A BIT ABOUT HIMSELF AND THEN HAVE HIM GO THROUGH A CASCADE OF PEOPLE WHO WILL INTRODUCE OTHERS BRIEFLY, NEW STAFF. SO, THE PERSON THAT I WANT TO INTRODUCE AND WANT TO YOU HEAR FROM IS MIKE WHO IS SITTING TO DAN'S LEFT. MIKE, WE WERE REALLY DELIGHTED TO BE ABLE TO RECRUIT TO NCATS IN DECEMBER, TO TAKE OVER THE DIVISION OF CLINICAL INNOVATION. A LOT OF YOU PROBABLY REMEMBR THAT PETRA KAUFMAN, WHO HAD TWO JOBS FOR THE LAST THREE YEARS, I THINK, SHE WAS HEAD OF DCI AND HEAD OF THE OFFICE OF RARE DISEASES RESEARCH. WE WERE ABLE TO HAVE HER BE ABLE TO TRANSITION TO ONLY ONE JOB FOR THE FIRST TIME. SO SHE IS REMAINING AS HEAD OF THE OFFICE OF RARE DISEASES RESEARCH. AND WE WERE ABLE TO -- REALLY DELIGHTED TO BE ABLE TO RECRUIT MIKE TO TAKE OVER DCI. SO MIKE HAS A REALLY DISTINGUISHED BACKGROUND. HE HAS HIS BACHELOR'S FROM CALL TECH AND M.D., PH.D. FROM DUKE AND THEN POSTDOCTORAL FELLOWSHIP AT HARVARD. HE AND I WERE THERE AT THE SAME TIME ALTHOUGH WE DIDN'T KNOW EACH OTHER THEN, I DON'T THINK, ALTHOUGH WE WORKED IN THE SAME BUILDING, AMAZINGLY. AND THEN HE WENT FROM THERE TO THE PHARMACEUTICAL INDUSTRY AND WORKED AT DuPONT PHARMA AND THEN WYAF FOR A NUMBER OF YEARS AND THEN MOVED TO NIAID IN 2003. AND HAS MOVED UP THE CHAIN OF COMMAND AT THE NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES FOR THE LAST SEVERAL YEARS SERVING AS THE DIRECTOR OF THE OFFICE OF BIODEFENSE RESOURCES AND TRANSLATIONAL RESEARCH. HIS PARTICULAR AREA OF RESPONSIBILITY WAS IN BIODEFENSE AFTER 9/11; BUT IS HAS A ENORMOUS WEALTH AND BREATH OF EXPERIENCE IN THE WHOLE SPECTRUM OF WHAT NCATS DOES EVERYTHING FROM TARGET VALIDATION ON THE LEFT SIDE TO CLINICAL TRIALS IN THE MIDDLE TO PUBLIC ENGAGEMENT AND COMMUNITY ENGAGEMENT AND IMPLEMENTATION ON THE RIGHT SIDE. SO, WE ARE REALLY DELIGHTED TO HAVE MIKE WITH US. SO, I WAS JUST GOING TO ASK MIKE TO SAY A FEW WORDS. YOU WILL BE GETTING TO KNOW MIKE QUITE WELL OVER THE NEXT FEW YEARS. AND SO I WANTED HIM TO SAY A FEW WORDS ABOUT HIS CAREER AND HIS THOUGHTS ABOUT BEING HERE. SO WELCOME, MIKE. >> MIKE: THANK YOU, CHRIS. IT IS A PLEASURE, AND I FEEL PRIVILEGED WITH THE OPPORTUNITY. I CAN HONESTLY SAY I'M STILL DRINKING FROM THE FIRE HOSE. THERE IS STILL QUITE A BIT TO TAKE ON. IN MANY WAYS, WHAT I DID FOR ALMOST 15 YEARS AT NIAID IN TERMS OF DEVELOPING MECHANISMS FOR TRANSLATIONAL EFFORTS TO INFECTIOUS DISEASES IS A LITTLE BIT OF A MIKE COMP OF WHAT ESSENTIALLY WHAT NCATS DOES. MICROCOSM. SO I SPAN A LARGE RANGE OF PREVENTIVE INTERVENTIONAL DIAGNOSTIC AND RESPONSE CAPABILITIES AS WELL AS THE FOCUS ON ENSURING THAT THE APPROPRIATE RESOURCES ARE AVAILABLE IN WHICH TO DO WORK, PARTICULARLY IN INFECTIOUS DISEASES BIOCONTAINMENT LABORATORIES AND SKILLED WORKFORCE EMERGENCY RESPONSE CAPABILITIES IS A CRITICAL COMPONENT ON BEING ABLE TO ADDRESS WHAT CONTINUES TO BE, UNFORTUNATELY, IN SPITE OF THE FACT THAT THE 20TH CENTURY WITNESSED UNPRECEDENTED PROGRESS IN TERMS OF ADDRESSING INFECTIOUS DISEASES, THERE IS STILL AN ENORMOUS AMOUNT OF ISSUES AND CONCERNS GLOBALLY THAT PRESENT PROBLEMS AND PROBABLY EVERY OTHER YEAR THERE IS YET ANOTHER THING ARISING. SOMEWHAT AS A RESULT, I WOULD EXPLAIN TO PEOPLE THAT IT IS REALLY OUR TECHNOLOGIES THAT HAVE BEEN DEVELOPED THAT ALLOWS US TO RECOGNIZE WHAT IS GOING ON. AND SO NOW THAT WE CAN'T JUST WATCH SOMETHING COME AND GO AND THEN NEVER REALIZE WHAT IT IS, SO THE ABILITY TO RESPOND APPROPRIATELY AS EXPEDITIOUSLY AND EFFICIENTLY AS POSSIBLE, IS BASICALLY SOMETHING WE OWN NOW AND MUST CONTINUE TO ADDRESS. SO I LOOK FORWARD TO APPLYING MANY OF THE CONCEPTS IN THE BROADER CONTEXT ACROSS ALL OF MEDICINE IN TERMS OF TAKING ADVANTAGE OF A LOT OF THE SCIENTIFIC DISCOVERIES AND BREAKTHROUGHS THAT NIH IS FUNDING IN ORDER TO ENABLE THEM TO BE EVENTUALLY REDUCED TO COMMON PRACTICE AND CONSIDERED AS SIMPLE TODAY AS ASPIRIN AND PENICILLIN ARE. SO, WITH THAT -- SHOULD I CONTINUE WITH THE INTRODUCTIONS THAT THE POINT? >> CHRIS: SO WHY DON'T YOU GO TO DAN AND THEN JANE. WE'LL WORK DOWN THE -- BEFORE YOU DO THAT, VALERIE HAD A QUESTION. >> VALERIE: I DO HAVE A QUESTION, BECAUSE YOU TOUCHED ON SOMETHING THAT I HAVE BEEN THINKING ABOUT WITH ALL OF THE INNOVATION THAT IS OCCURRING AND THE ABILITY OF US TO BE AS INCLUSIVE AS POSSIBLE IN ALL OF OUR WORKFORCE BEING ABLE TO PARTICIPATE, MANY OF THE INSTITUTIONS ARE LIMITED BY THEIR CAPACITY TO PARTICIPATE, PARTICULARLY WHEN YOU'RE TALKING ABOUT NEEDING BSL3 AND 4 AND SOME OF THE BIOSAFETY NEEDS. AND YOU DON'T HAVE TO ANSWER THIS NOW BUT I'D LIKE US TO THINK ABOUT, PARTICULARLY IN THE FACE OF INNOVATION, BECAUSE I THINK IT WILL REQUIRE SOME INNOVATIVE COLLABORATION FOR US TO ENSURE THAT WE ARE NOT CREATING TOO MUCH DUEPLICITY, BUT ALSO ARE NOT LIMITING THE OPPORTUNITIES FOR MORE INCLUSIVE WORKFORCE BECAUSE OF LIMITATIONS THAT ARE PLACED BECAUSE OF WHERE ALL OF THESE FACILITIES ARE. AND I THINK AS WE THINK ABOUT THESE INNOVATION OR GRANTS THAT ARE COMING THROUGH AND WE ARE LOOKING FOR INNOVATION, WE COULD GET SILOED INTO THOSE OPPORTUNITIES ONLY BEING AT A CERTAIN TYPE OF INSTITUTION BECAUSE THEY ARE THE ONLY ONES THAT HAVE THAT HIGH-LEVEL LABORATORIES OR FACILITIES WHERE THAT RESEARCH CAN BE DONE. SO I'D LIKE FOR US TO THINK ABOUT THAT AND WHEN WE THINK ABOUT INNOVATION. >> AS CHRIS MENTIONED, I DID MY MEDICAL WORK AT DUKE AND I DON'T KNOW HOW BROADLY THIS IS, BUT THERE ALWAYS USED TO BE, THE MANTRA WAS SEE ONE, DO ONE, TEACH ONE. SO I HAVE SEEN CHRIS INTRODUCE ME SO I WILL BOTH DO AND TEACH JANE BY INTRODUCING HER. SO LET ME INTRODUCE DR. JANE ATKINSON. SHE ARRIVED AT THE SAME TIME I DID AT NCATS AND SHE IS THE DIRECTOR NOW OF OUR TRIALS INNOVATION NETWORK THAT IS WITHIN THE DIVISION OF CLINICAL INNOVATION. I THINK MOST PEOPLE ARE AWARE OR FAMILIAR WITH THE TRIALS INNOVATION NETWORK SO I'LL TALK MORE ABOUT JANE'S BACKGROUND. SHE COMES TO US BY WAY OF THE NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH AT NIDCR, AND SHE BEGAN AS A CLINICAL RESEARCH FELLOW THERE IN THE INTRAMURAL PROGRAM EVENTUALLY MOVING ON TO BECOMING A PRINCIPAL INVESTIGATOR FOR A NUMBER OF STUDIES INVOLVING SALIVARY GLAND DYSFUNCTIONS AND ORAL MUCOSAL DISEASES. AND THEN SHE STILL RETAINS THE POSITION OF STAFF DENTIST AT THE NIH CLINICAL CENTER. SO IF THERE ARE ANY DENTAL EMERGENCIES AT THE MOMENT, YOU'RE VERY WELL TAKEN CARE OF HERE. [ LAUGHS ] SHE IS ALSO ON FACULTY AT THE UNIVERSITY OF MARYLAND IN THEIR COLLEGE OF DENTAL SURGERY AND THEN SHE RETURNED TO NIDCR AS THE INTRAMURAL PROGRAM AS THE DEPUTY CLINICAL DIRECTOR AND THEN MOVED MOST RECENTLY FOR ABOUT THE LAST DECADE, HAS BEEN THE DIRECTOR OF CLINICAL RESEARCH FOR ALL OF THE EXTRAMURAL RESEARCH FUNDED BY NIDCR. SO WE WELCOME HER AS A CONSIDERABLE ASSET IN OVERSEEING THE TRIAL INNOVATION NETWORK, WHICH IS BOTH THE TRIAL INNOVATIONS AND RECRUITMENT INNOVATIONS ENTITIES. JANE? >> JANE: THANK YOU. IT GIVES ME GREAT PLEASURE TO INTRODUCE DR. VALERY GORDON, OUR NEW SENIOR ADVISOR FOR HUMAN SUBJECTS PROTECTION FOR THE TRIAL INNOVATION NETWORK. PRIOR TO JOINING NCATS, DR. GORDON WAS THE DIRECTOR OF THE CLINICAL RESEARCH POLICY PROGRAM IN THE OFFICE OF SCIENCE POLICY IN THE OFFICE OF DIRECTOR AT NIH AND IN THAT POSITION, SHE WORKED ON TRANS-NIH INITIATIVES, PRIORITY PROJECTS FOR NIH RELATING TO CLINICAL RESEARCH INCLUDING THE NEW POLICIES RELATED TO CLINICAL TRIALS, AND ENSURING AND ENHANCING PROTECTIONS FOR HUMAN RESEARCH PARTICIPANTS. DR. GORDON HAS BEEN AT NIH SINCE 1992, PREVIOUSLY SHE WORKED IN THE INTRAMURAL PROGRAM. SHE HAD A LABORATORY IN THE NATIONAL INSTITUTE OF DENTAL RESEARCH, THEN THE OFFICE OF EXTRAMURAL RESEARCH AND THE NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING. DR. GORDON RECEIVED HER PH.D. IN PHARMACOLOGY FROM THE UNIVERSITY OF VIRGINIA AND A MASTERS IN PUBLIC HEALTH FOCUSING ON ETHICS AND HEALTH POLICY FROM THE JOHNS HOPKINS UNIVERSITY SCHOOL OF PUBLIC HEALTH. THANK YOU. >> I HOPE YOU WILL SEE, WE HAVE SOME -- WHAT I'M TALKING ABOUT WHEN I SAY THE ALL-STARS WHO HAVE JOINED US. REALLY EXTRAORDINARY PEOPLE. CONTINUING ON THAT WHERE IS MARY? SO MARY, DO YOU WANT TO INTRODUCE PABLO AND ALENA? MARY SILENT HEAD OF THE HUBS PROGRAM FOR THE -- IS THE HEAD OF THE HUBS PROGRAM FOR CTS PROGRAM AND ONE OF OUR FEW PUBLIC HEALTH SERVICE PROGRAM. THE ONLY ONE? I THINK WE HAVE ONE OTHER ONE WHO IS JUST JOINING US AT DPI. >> MARY: GOOD MORNING. IT GIVES ME GREAT PLEASURE TO INTRODUCE DR. PABLO. AND PABLO HAS BEEN WITH US SINCE NOVEMBER OF LAST YEAR AND COMES TO US FROM NHLBI WHERE HE WAS PROGRAM DIRECTOR FOR TWO YEARS AND MANAGED A PORTFOLIO OF NON-CLINICAL AND CLINICAL PROJECTS INCLUDING MULTICYCLIN TRIALS. PRIOR TO THAT, HE WAS WITH THE CHILDREN'S NATIONAL MEDICAL CENTER, SPECIFICALLY WITH THE CT IS. A PROGRAM THERE WHERE HE WAS THE DIRECTOR OF THE CLINICAL RESEARCH UNIT AND ALSO INDEPENDENT FUNDED PRINCIPAL INVESTIGATOR. PABLO IS CURRENTLY BEEN ASSIGNED TWO NEW CTSA HUBS AND ALSO WILL BE WORKING ON THE COORDINATING CENTER. I THINK THAT IS PRETTY GOOD CONSIDERING HE HAS ONLY BEEN HERE A COUPLE OF MONTHS. WELCOME, PABLO. I'D ALSO LIKE TO INTRODUCE OUR PRESIDENTIAL MANAGEMENT FELLOW WHO IS ALENA. SHE COMES TO US FROM JOHNS HOPKINS UNIVERSITY AND SHE JOINED US LAST SEPTEMBER. SHE HAS A NUMBER OF YEARS OF EXPERIENCE AS A SENIOR RESEARCH TECHNOLOGIST AND IS ALSO SIMULTANEOUSLY ENROLLED IN THE MBA PROGRAM AT JOHNS HOPKINS IN THE CARRY SCHOOL OF BUSINESS. SHE HAS A CERTIFICATE IN BUSINESS MANAGEMENT OF HEALTH CARE SYSTEMS. IS THAT RIGHT? AND SHE IS ON TRACK FOR GETTING HER MBA, I BELIEVE, IN MAY. YOU ALREADY GOT IT? STRONG WORK! [ LAUGHS ] AND ALENA IS WORKING ON A VARIETY OF PROJECTS RELATED TO THE CTSA PROGRAM INCLUDING METRICS AND A NUMBER OF OTHER THINGS THAT ARE BEING ASSIGNED TO HER. SO SHE IS LEARNING AND ALSO HITTING THE GROUND RUNNING HERE SO WE ARE DELIGHTED TO HAVE HER. AND THEN ONE OTHER PROGRAM OFFICER, RAJ, PROBABLY YOU HAVE ALREADY KNO KNOW HER. SHE HAS BEEN WITH THE RARE DISEASE RESEARCH PROGRAM, OFFICE OF RARE DISEASE RESEARCH FOR A NUMBER OF YEARS AND WE WERE LUCKY ENOUGH TO RECRUIT HER OVER TO THE CTSA HUB PROGRAM. PRIOR TO BEING WITH THE RARE DISEASE PROGRAM, SHE WAS WITH NCI AND HAS HAD VERY LONG AND DISTINGUISHED CAREER WITH NIH AND HAS STARTED WITH NCATS IN THE MIDDLE OF EARLY NOVEMBER AND AT THIS POINT, SHE IS MANAGING FOUR CTSA HUBS AND IS ALSO TAKING THE LEAD OF THE LIFESPAN DOMAIN TASK FORCE. SO WELCOME. >> CHRIS: THANK YOU. AND PETRA OR ANN -- >> PETRA: TOGETHER WITH MY PARTNER ANN, WE ARE WELCOME TO OFFICE OF RARE DISEASES RESEARCH, ALICE CHEN WHO IS RIGHT THERE. ALICE JOINED US IN NOVEMBER AFTER MORE THAN 3 YEARS AT THE FDA. SHE RECEIVED HER MD FROM THE UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE AND WORKED AT THE FDA IN THE OFFICE OF TRANSLATIONAL SCIENCES AND KNOWLEDGE MANAGEMENT AND REGULATORY SCIENCE INITIATIVES AND SHE DID SOME COOL THINGS THERE TO DO WITH DATA. SHE WORKED ON DEMOGRAPHIC SUBGROUP PARTICIPATION AND CLINICAL COLLABORATIONS AND ALSO ON MAKING SURE THAT THE DATA GATHERED DURING INTERNAL FDA REVIEWS THAT THIS WEALTH OF DATA COULD BE USED BETTER TO CONNECT THE DIFFERENT GROUPS AT THE FDA AND REALLY TO PIONEER NEW WAYS TO UNLOCK THIS WEALTH OF INFORMATION SUCH BENEFIT PROGRESS FOR PATIENT. AND AT THE OFFICE OF RARE DISEASES RESEARCH, ALICE HAS JUMPED RIGHT IN AND HAVE DONE GREAT WORK IN PARTICULAR WORKING ON THE TOOLKIT, RARE DISEASES REGISTRY PROGRAM RADAR YOU WILL HEAR MORE FROM DR. AUSTIN WHICH HAS ALSO TO DO WITH DATA AND THE SMARTER USE OF INFORMATION AND KNOWLEDGE. AS WELL AS ON THE RARE DISEASES CLINICAL RESEARCH NETWORK. SO WE ARE DELIGHTED TO HAVE YOU, ALICE AND ALSO ON BEHALF OF ANN AND MYSELF WILL INTRODUCE DR. ERIC WHO IS HERE. HE IS THE PRESIDENTIAL MANAGEMENT FELLOW WHO JOINED US IN SEPTEMBER. AND RECEIVED HIS MD AND MASTERS IN HEALTH ADMINISTRATION FROM THE UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE AND SCHOOL OF PUBLIC HEALTH. PRIOR TO BECOMING A FELLOW WITH US, HE SERVED AS BOARD MEMBER FOR THE WASHINGTON ACADEMY OF FAMILY PHYSICIANS FOUNDATION AND WAS AWARDED FIRST PLACE IN THE NATIONAL TEAM COMPETITION FOR THE INSTITUTE OF HEALTH CARE IMPROVEMENT. HIS INTERESTS ARE IN POPULATION HEALTH AND HEALTH MANAGEMENT AND ADDRESSING HEALTH DISPARITIES THROUGH INNOVATION IN THE OFFICE OF RARE DISEASES RESEARCH. ERIC HAS ALSO HIT THE GROUND RUNNING AND IS WORKING ON OUR REGISTRY PROGRAM TOOLKIT AND ALSO OUR GUARD THE GENETICS AND RARE DISEASES INFORMATION CENTER. SO, PLEASE JOIN US IN WELCOMING ERIC AND HAND IT OVER TO ANN. >> ANN: I'D ALSO LIKE TO INTRODUCE DR. TINA. I THINK MANY OF YOU KNOW TINA FROM THE DCI PROGRAM. SHE HAS BEEN AT NCATS. TINA, CAN YOU STAND UP? Y SHE WAS AT THE DCI FOR THE PAST FEW YEARS WORKING ON THE CTSA PROGRAM AND SHE IS RECENTLY JOINED US AND SHE IS A NEW PROGRAM DIRECTOR FOR THE RARE DISEASES CLINICAL RESEARCH NETWORK. TINA HAS A WEALTH OF NIH EXPERIENCE. SHE SPENT ABOUT 10 YEARS AT CHILD HEALTH WORKING ON THE NEWBORN SCREENING PROGRAM AND SHE IS REALLY WITH HER WEALTH OF EXPERIENCE, HER SCIENCE BACKGROUND AND HER PASSION ESPECIALLY FOR HELPING CHILDREN, SHE IS ALREADY MADE A TREMENDOUS DIFFERENCE TO THE RARE DISEASES PROGRAM AND WE ARE DELIGHTED TO HAVE HER. >> CHRIS: OKAY. SO THANK YOU FOR ALL OF THOSE INTRODUCTIONS AND WE ARE GOING TO GO ON TO THE DIRECTOR'S UPDATE NOW SO I'M GOING TO RUN THROUGH. I WANT TO BE CLEAR ABOUT WHY WE SPEND TIME INTRODUCING PEOPLE. NCATS IS AN UNUSUAL ORGANIZATION AND WE TRY TO KEEP IT THAT WAY. AND ONE OF THE THINGS THAT IS UNUSUAL ABOUT IT IS THAT WE TAKE EACH OTHER'S OPINIONS AND POINTS OF VIEW VERY SERIOUSLY BECAUSE WE ARE -- WE FEEL VERY STRONGLY THAT IS HOW THE BEST SCIENCE IS DONE. PARTICULARLY IN THE TRANSLATIONAL SPACE. AND WE FIND THAT IT IS REALLY DIFFICULT FOR PEOPLE TO WORK WITH EACH OTHER IF THEY DON'T KNOW WHO EACH OTHER IS. SO RATHER THAN HAVING A BUNCH OF PEOPLE WHO JUST COME AND SIT AROUND A TABLE AND HAVE NO IDEA WHO IS SITTING NEXT TO YOU, WE GO TO SOME EFFORT TO PROVIDE SOME CONTEXT FOR ALL OF YOU SO WE CAN WORK TOGETHER AS A TEAM MORE OPTIMALLY AND WE DO THAT INTERNALLY, AND YOU JUST HEARD THAT. I'M GOING TO DO THAT A BIT NOW BY INTRODUCING SOME OF YOUR NEW COUNCIL COLLEAGUES. SO, YOU HEARD ABOUT MIKE ALREADY, AND HE STARTED ABOUT I GUESS EXACTLY A MONTH AGO TODAY. HAS SURVIVED THIS LONG, SO THAT IS A GOOD SIGN. [ LAUGHS ] SO WELCOME. THERE ARE A NUMBER OF YOU WHO, PARTIALLY BECAUSE OF THE TIME IT TAKES TO GO THROUGH THE APPROVAL PROCESS, BUT REALLY BECAUSE OF THE FREEZE, HIRING FREEZE, FEDERAL HIRING FREEZE WHICH STARTED LAST JANUARY, THAT EFFECTED ALL SPECIAL GOVERNMENT EMPLOYEES WHICH MEANS COUNCIL MEMBERS AS WELL, THAT WAS REALLY RESPONSIBLE FOR A VERY LONG DELAY. BUT I'M GOING TO INTRODUCE THE FOLKS WHO ARE AS WE LIKE TO SAY, NOW REAL AND CATHY -- WHERE IS CATHY? THERE SHE IS. SO CATHY, SITTING NEXT TO DAN HARTMAN, SHE IS FOR A LITTLE WHILE LONGER, I THINK I CAN SAY THAT, PUBLICLY, EXECUTIVE DIRECTOR FIST STANFORD OFFICE OF TECHNOLOGY LICENSING BECAUSE SHE WILL BE RETIRING AFTER A REALLY DISTINGUISHED FOUR DECADE-CAREER THERE. RESPONSIBLE FOR LICENSING OF A VARIETY OF TECHNOLOGIES, MANY OF WHICH YOU KNOW THAT HAVE COME OUT OF STANFORD IN THE LAST 30, 40 YEARS. SHE HAS A BS IN CHEMICAL ENGINEERING FROM CORNELL AND MS IN CHEMICAL ENGINEERING FROM WASH U AND WORKED IN THE PRIVATE SECTOR FOR A WHILE AND HAS BEEN AT REALLY A LEADER IN ESTABLISHING AND RUNNING ONE OF THE UNIVERSITY'S LEADING TECH TRANSFER AND PARTNERING OFFICES. SO WE ARE REALLY DELIGHTED TO HAVE CATHY JOIN US. AS YOU ALL KNOW, AS AN ADAPTER OR A BRIDGE FROM THE PUBLIC SECTOR TO THE PRIVATE SECTOR, THAT IS A LOT OF WHAT NCATS DOES. THIS IS A PARTICULARLY IMPORTANT EXPERTISE FOR US SO WE ARE REALLY GLAD TO HAVE CATHY WITH US AND MORE DELIGHTED EVEN WHEN SHE RETIRES SHE WILL BE ABLE TO STAY WITH US AS I TOLD HER, I'M REALLY INTERESTED IN HER BRAIN, NOT A REPRESENTATIVE OF STANFORD, AS MUCH AS I LIKE STANFORD, WE ARE REALLY INTERESTED IN CATHY. SO WELCOME. THE SECOND PERSON I WANT TO HAVE YOU GET TO KNOW IS BRAD WHO IS SITTING RIGHT THERE. HE HAD A NUMBER OF POSITIONS AS WELL BUT HE CURRENTLY CO-FOUNDER AND CHIEF EXECUTIVE OFFICER AND WORKS ON DISCOVERY PLATFORMS AND THERAPEUTICS FOR BRAIN DISEASES. BEFORE THAT HE WAS CO-FOUNDER AND FOUNDER OF PEARLA JEN, WHICH A NUMBER OF YOU KNOW ABOUT IT, DEVELOPED A MASSIVELY PARALLEL DNA ANALYSIS TECHNOLOGY. THIS WAS ONE OF THE EARLY COMPANIES THAT DID THE GRAPHIC, USED THE PHOTOGRAPHIC TECHNOLOGY FOR SYNTHESIZINGAL GO MICROARRAYS. AL GOES ON MICROARAISE. SO ALSO A CO-FOUNDER OF ENVOYS THERAPEUTICS WORKING ON BRAIN DISEASES. HAS DISTINGUISHED ACADEMIC CAREER INCLUDING MBA FROM HARVARD. THE REASON I ASKED HIM TO BE ON THE COUNCIL WAS NOT ONLY HIS EXPERIENCE IN BIOTECH, BUT ALSO BECAUSE OF HIS EXPERIENCE AS A DAD. HE HAS TWO CHILDREN AND HAS BEEN A FOUNDER AND VOLUNTEER PRESIDENT OF THE 18 CHILDREN'S PROJECT FOR THE LAST MANY YEARS. SO HE KNOWS THIS BUSINESS AND THE PROBLEMS WE WORK ON FIRSTHAND FROM BOTH A BUSINESS PERSPECTIVE AND A PERSONAL PERSPECTIVE. SO HE REALLY BRINGS A UNIQUE PERSPECTIVE TO US. SO WELCOME, BRAD. CALL PENNA MERCHANT FILLS A BIT OF A HOLE IN OUR COUNCIL EXPERTISE. HER EXPERTISE IS IN THE DIVISION OF PRE-CLINICAL INNOVATION SPACE THAT YOU WILL BE HEARING FROM THIS AFTERNOON. SHE IS A TRANSLATIONAL SCIENCE PERSON, DISCOVERY PERSON, WORKING PARTICULARLY IN NEUROSCIENCE METABOLIC DISORDERS AND ONCOLOGY. HER EXPERTISE IS PARTICULARLY SCHIZOPHRENIA AND PSYCHIATRIC AND NEURODEGENERATIVE DISORDERS. SHE IS PREVIOUSLY TRANSLATIONAL SCIENCE HEAD AT LILI AS WELL AS TAILOR THERAPEUTICS. SHE HAS BEEN AN ADVISOR TO THE MICHAEL J. FOX FOUNDATION, WHICH IS RUN BY ANOTHER COUNCIL MEMBER WHO COULDN'T BE WITH US TODAY. AND CONTRIBUTES TO A NUMBER OF OTHER ACADEMIC AND NIH INITIATIVES INCLUDING AT NORTHWESTERN AND AAAS. SO BRINGS AN EXPERTISE IN PRE-CLINICAL DRUG DEVELOPMENT, WHICH WILL BE REALLY HELPFUL FOR US. SO WELCOME TO KALPANA. VALERIE YOU JUST HEARD FROM A MINUTE AGO. VALERIE IS PRESIDENT OF THE MOREHOUSE SCHOOL OF MEDICINE. SHE JOINED MORE HOUSE IN 2011 WHERE SHE WAS DEAN AND SENIOR VICE PRESIDENT. SHE GRADUATED FROM HARVARD A YEAR AFTER I DID. SO SHE IS A YOUNGSTER BUT WE WELCOME HER ANYWAY. DID HER INTERSHIP AND RESIDENCY IN OBGYN AT EMORY AND A CLINICAL FELLOWSHIP IN ENDOCRINOLOGY IN DETROIT. SO HER EXPERTISE IS IN REPRODUCTIVE MEDICINE IN CANCER AND MENOPAUSE AND EXTENSIVELY PUBLISHED AND REALLY A LEADER IN OBGYN AND IN THE ACADEMIC DEAN COMMUNITY WHICH IS HOW WE GOT TO KNOW EACH OTHER. VALERIE AND I. AND ALSO BECAUSE THE MOREHOUSE SCHOOL OF MEDICINE IS A PARTNER IN THE ATLANTA CTSA ALONG WITH GEORGIA TECH AND EMORY. SHE IS AMONG OTHER THINGS, RECOGNIZED FOR HER SUPPORT AS YOU JUST HEARD FOR THE CAREERS OF WOMEN AND UNREPRESENTED MINORITIES AND AS YOU'LL HEAR LATER IN MY PRESENTATION, THIS IS SOMETHING THAT WE ARE REALLY ARE WORKING ON VERY HARD AT NCATS AS A VERY IMPORTANT TRANSLATIONAL PROBLEM THAT IS HOW TO INCREASE REPRESENTATION IN OUR CLINICAL STUDIES. SO WE ARE JUST DELIGHTOD TO HAVE VALERIE HERE. SHE ALSO IS, I THINK IS IT FAIR TO SAY LIKE ALL OF YOU ON THE COUNCIL, SHE IS A THINK DIFFERENT KIND OF PERSON. WE ACTUALLY - EYE REMEMBER THIS MEETING WE HAD, A DISCUSSION WE HAD AT A COUNCIL OF DEANS MEETING, AND WE BOTH FOUND OURSELVES SAYING, YOU KNOW, THIS REALLY NEEDS TO CHANGE-UP A LITTLE BIT, HOW THINGS ARE CURRENTLY DONE. THERE IS SOME THINGS WE COULD BE DOING A LITTLE BETTER. AND BUT WE HAD LOTS OF DISCUSSIONS ABOUT THAT. AND LOOK FORWARD TO HER INPUT ON ALL OF THOSE THINGS. I WANTED TO MENTION HE HAS BEEN ON THE COUNCIL BEFORE JOINING THE CAN BOARD AS WELL AS THE COUNCIL WHICH IS WHY I PUT HIM J. FOX FOUNDATION. STEVE SPIELBERG FILLS AN IMPORTANT AREA IN OUR COUNCIL EXPERTISE. WE DIDN'T HAVE ANY LITTLE PEOPLE EXPERTISE. WE DIDN'T HAVE ANY PEDIATRICS EXPERTISE. AND SO THIS IS NOT ONLY A REALLY IMPORTANT AREA FOR US GIVEN OUR INTEREST IN RARE DISEASES, 60% OF WHICH APPROXIMATELY, HAVE ONSET IN THE PEDIATRIC AGE GROUP, BUT ALSO BECAUSE THEY PRESENT KIDS PRESENT OF COURSE UNIQUE TRANSLATIONAL CHALLENGES, CLINICAL TRIAL CHALLENGES, RECRUITMENT CHALLENGES, ETHICAL CHALLENGES, CONSENT CHALLENGES, ALL KINDS OF THINGS. STEVE RECEIVED HIS TRAINING IN PHARMACOLOGY AND PEDIATRICS AT THE UNIVERSITY OF CHICAGO. HE IS A MEMBER OF THIS ALMOST EXTINCT TRIBE KNOWN AS CLINICAL PHARMACOLOGISTS. SO SOME REALLY IMPORTANT FIELD WHICH WE RUN INTO ALL THE TIME BECAUSE LACK OF KNOWLEDGE OF CLINICAL PHARMACOLOGY IS RESPONSIBLE FOR VERY FREQUENT DRUG DEVELOPMENT FAILURE. SO STEVE BRINGS EXPERTISE IN THERE THAT AREA TO US. DID HIS INTERNSHIP AND RESIDENCY AT CHILDREN'S AND HARVARD. AND THEN WAS ASSOCIATE HERE IN PEDIATRICS AT NICHD, THEN IN TORONTO AT SICK KIDS FOR A NUMBER OF YEARS. AMONG THE INCREDIBLE THINGS THAT STEVE HAS DONE, HE HAS BEEN DEAN OF THE MEDICAL SCHOOL AT DARTMOUTH, WAS VICE PRESIDENT FOR PEDIATRIC DRUG DEVELOPMENT AT JOHNSON & JOHNSON. SO HE HAS DONE DRUG DEVELOPMENT IN THE PHARMA WORLD AND TO ROUND OUT THE TRIFECTA, HE WAS THEN DEPUTY COMMISSIONER FOR MEDICAL PRODUCTS AND TOBACCO AT THE FDA BEFORE TRYING TO RETIRE AND BECOMING AN EDITOR OF A NUMBER OF JOURNALS AND CONSULTANT. SO I HAVE KNOWN STEVE FOR MANY YEARS, BOTH THROUGH THE PHARMA WORLD OF CLINICAL PHARMACOLOGY WORLD, THE CLINICAL WORLD, AND THE F NIH, WHOSE BOARD HE SERVED ON FOR A NUMBER OF YEARS. ARE YOU STILL ON THAT BOARD? NO. SO REALLY DELIGHTED TO HAVE STEVE WITH US. SHARON WHO IS RIGHT THERE ALSO HAS A REALLY INTERESTING BACKGROUND. YOU HEARD THAT WE HAVE A DENTIST IN OUR MIDST WHO CAN TAKE CARE OF YOUR DENTAL PROBLEMS. WE ALSO HAVE A CHAPLIN IN OUR MIDST. SO IF YOU WANT TO DO SOME PRAYING BEFORE YOU GET YOUR TEETH EXTRACTED, SHARON CAN HELP YOU. [ LAUGHS ] BUT HER STORY IS COMMON AMONG PARENTS WHO -- SHARON WILL ELOQUENTLY TELL YOU, NEVER WANTED TO BE DOING WHAT SHE IS CURRENTLY DOING. SHE HAD A VERY NICE LIFE AND LIFE PLANNED, AND THEN HAD TWO BEAUTIFUL NOW ADULT CHILDREN, WHO BOTH OF WHOM I KNOW, DIAGNOSED WITH A RARE DISEASE. AND THAT LED HER ON A NOW 30 OR SO-YEAR JOURNEY. SHE AND HER HUSBAND, WHO WAS WORKING IN CONSTRUCTION AT THE TIME, SO NOT A TYPICAL SCIENTIFIC BACKGROUND, A CHAPLIN AND A CONSTRUCTION WORKER WALK INTO A LAB AND THEY CLONED THE GENE FOR THEIR OWN DISEASE. AND I DON'T THINK I HAVE HEARD A STORY LIKE THAT ANYWHERE ELSE. AND IT SHOWS ONE OF THE THINGS THAT WE RUN INTO ALL THE TIME, THAT IS THE ABILITY OF A MOTIVATED HUMAN BRAIN TO DO REMARKABLE THINGS. AND SO WE ARE VERY RESPECTFUL AROUND HERE OF CREDENTIALS AND WE HAVE LOTS OF PEOPLE WITH CREDENTIALS AND THAT'S GREAT. BUT WE ARE ALSO VERY RESPECTFUL AND SOMETIMES IN AWE, OF PEOPLE WHO ARE ABLE TO DO THINGS BY SHEAR DINT OF WILL AND LEARNING AND SHARON HAS CERTAINLY DONE THAT. AFTER WORKING ON THIS FOR A NUMBER OF YEARS WHICH SHE STILL WORKS ON AND FOUNDED PIX INTERNATIONAL AND REALIZED AS MANY OF US DO NOW AND NCATS REALLY I THINK SO ABOUT, THE PROBLEMS WHICH CONFRONTED PXE WERE THE SAME ONES THAT CONFRONT AT, OR ANY DISEASE, REALLY, AND SO AS A RESULT OF THAT, IT WAS ABOUT 20 YEARS AGO TOOK OVER THE GENETIC LINE, WHICH IS AN ALLIANCE OF ABOUT 900 ORGANIZATIONS, I THINK? 2000 ORGANIZATIONS, SORRY. OFF BY AN ORDER OF MAGNITUDE. ORGANIZATIONS WORKING ON THE KINDS OF THINGS THAT NCATS IS INTERESTED IN. HOW DO WE BUILD GENERALLY USEFUL TOOLS TO ALLOW PEOPLE TO DO THE THINGS THAT THEY NEED TO DO TO ADVANCE TRANSLATIONAL RESEARCH FOR DISEASES THEMSELVES? AND SO HAS BEEN A REALLY CLOSE COLLEAGUE OF MINE AND IN A BE IN OF ORGANIZATIONS FOR A NUMBER OF YEARS. SO WELCOME. SHARON IS AMONG OTHER THINGS NOW, SHE IS JUST RECENTLY BECOME THE HEAD OR EXECUTIVE SOMETHING OR OTHER OF THE PEOPLE POWERED RESEARCH NETWORK, WHICH IS THE -- PEOPLE-CENTERED RESEARCH FOUNDATION, WHICH IS THE SUCCESSOR TO PCORI AND ONE OF THINGS WE ARE INTERESTED IN DOING THROUGH THE TRIAL INNOVATION NETWORK AND OTHER THINGS IN RDCRN IS TO FIGURE OUT HOW TO WORK BETTER WITH PCORI. WE HAD A GREAT RELATIONSHIP WITH THEM AND WE HAVE LOTS OF THINGS IN COMMON BUT I DON'T THINK WE HAVE ACTUALLY MANAGED TO DO ANYTHING DIRECTLY TOGETHER. SO WE LOOK FORWARD TO DOING THAT. SO, WELCOME ALL OF YOU. AND I LOOK FORWARD TO WELCOMING THE REMAINING AD-HOC PEOPLE AT THE NEXT COUNCIL BECAUSE I'M SURE YOU WILL BE OFFICIAL BY THEN. SO REAL QUICKLY, SOME POLICY AND LEGISLATIVE UPDATES. A LOT OF THIS HAS BEEN AROUND FOR A WHILE BUT I WANTED TO REMIND YOU OF THE FISCAL WORLD IN WHICH WE LIVE BECAUSE THIS IS YOUR RESPONSIBILITY IN PART AS A COUNCIL TO HELP US AND PROVIDE OVERSIGHT AND ADVICE HERE. YOU REMEMBER THAT BACK IN MAY, THE FY18 PRESIDENT'S BUDGET REQUEST WAS ABOUT A 20% REDUCTION FOR THE NIH. THAT REQUEST WAS NOT TAKEN UP BY EITHER THE HOUSE OR THE SENATE. SUBCOMMITTEES WHO WORK ON THE NIH BILLS AND EACH OF THE HOUSE AND SENATE APPROPRIATIONS COMMITTEES PASSED A BILL FOR THE NIH BUT NEITHER BILL WAS VOTED ON BY A FULL CHAMBER. BUT IMPORTANTLY, THE AMOUNTS THAT WERE CONSIDERED IN EACH CASE WERE A SMALL INCREASE IN THE NIH BUDGET. NOT TAKING UP THE PRESIDENT'S SUGGESTION. FY18 BEGAN OCTOBER 1. AND AS THE CASE FOR THE LAST SEVERAL DECADES, WE DID NOT HAVE A BUDGET, EVEN THOUGH THE FISCAL YEAR STARTED. SO WE HAVE BEEN AS WE VERY OFTEN HAVE BEEN OPERATING UNDER A CONTINUING RESOLUTION. THIS MEANS A RESOLUTION -- NOT QUITE A BILL BUT SOMETHING LIKE IT, PASSED BY THE CONGRESS WHICH CONTINUES THE FUNDING AND PROGRAMS OF THE PREVIOUS YEAR. SO ESSENTIALLY TIME HAS STOOD STILL. WE ARE FOR FUNDING AND POLICY PURPOSES STILL IN FY17 AND SO WE CAN START NO NEW PROGRAMS AND OUR BUDGET LEVEL IS THE SAME AS IT WAS LAST YEAR. SO, GENERALLY WHAT HAPPENS IS THERE ARE A NUMBER OF CONTINUING RESOLUTIONS UNTIL THE CONGRESS CAN AGREE ON A REAL BUDGET OR SOMETIMES A FULL YEAR CONTINUING RESOLUTION SO WE HAD A FIRST CR THAT RAN THROUGH DECEMBER 8. AND THEN WE HAD A SECOND ONE THAT RAN FOR ABOUT TWO WEEKS AFTER THAT UNTIL RIGHT BEFORE CHRISTMAS AND THEN RIGHT BEFORE CHRISTMAS, THEY PASSED ANOTHER -- THE CONGRESS PASSED ANOTHER AND THE PRESIDENT SIGNED A THIRD CR THAT RUNS THROUGH NEXT FRIDAY. WE GOT RUMORS YESTERDAY THAT MAYBE ANOTHER CR, WHICH RUNS UNTIL THE MIDDLE OF FIFE, AND THE HOPE IS BY THAT TIME, THE CONGRESS WILL BE ABLE TO AGREE ON A FULL-YEAR BUDGET, WE HOPE. SO THIS CREATES ALL SORTS OF PROBLEMS FOR US. WE MANAGED THIS AS BEST WE CAN. HOWEVER, REALIZE PARTICULARLY THOSE OF YOU WHO RUN A LAB OR RUN A COMPANY, IMAGINE YOU ARE HALFWAY THROUGH THE FISCAL YEAR AND YOU HAVE NO REAL IDEA OF WHAT YOUR SPENDING CAPACITY WILL BE AT THE END OF THE YEAR? AND IT REMAINS POSSIBLE YOU HAVE ALREADY SPENT MORE THAN YOUR ENTIRE BUDGET WILL BE AT THE END OF THE YEAR. IT'S A FORMAL POSSIBILITY. AND YET, WE HAVE MANY GRANTEES AND STAFF RELYING ON US. SO WE HAVE BALANCED THOSE IMMEDIATE NEEDS AND OUR RESPONSIBILITIES WITH THE FACT THAT WE HAVE NO IDEA WHAT OUR EVENTUAL BUDGET WILL BE, PARTICULARLY IN THE AREA OF A PRESIDENT'S BUDGET WHICH IS NOT AS FRIENDLY AS IT HAS BEEN IN PAST YEARS. SO THAT MEANS THE OUTYEAR OBLIGATIONS FOR GRANTS PER NIH POLICY ARE ALWAYS FUNDED AT 90% OF THE APPROVED LEVEL. SO 10% BELOW WHAT WAS AGREED TO, HOPEFULLY WE'LL GO BACK UP TO 100% AND GET A REAL BUDGET. AND WE HAVE TO BE VERY CAREFUL ABOUT NEW OBLIGATIONS AND NEW GRANTS. BECAUSE WE DON'T KNOW WHETHER WE WILL HAVE MONEY TO ACTUALLY FUND THEM. HOWEVER, WE ARE MOVING FORWARD WITH JUDICIOUSLY WITH BOTH OF THOSE. SO-CALLED TYPE I NEW GRANTS AND OUTYEAR OBLIGATIONS. BUT I WANTED TO GIVE YOU A SENSE OF JUST HOW MUCH WORK THIS IS FOR THE PROGRAM STAFF AND THE GRANTS MANAGEMENT STAFF AND THE PROGRAM STAFF AND HOW MUCH WORK THIS IS FOR A GRANTEE TO HAVE TO DEAL WITH THIS. WE ARE HOPING THAT CONGRESS WILL PASS A BILL VERY SOON. WE HAD A WONDERFUL VISIT FROM THE CHAIR OF THE SUBCOMMITTEE OF THE SENATE APPROPRIATIONS COMMITTEE LAST MONTH AND SENATOR BLUNT HAS BEEN AN ENORMOUS BOOSTER FRIEND TO NIH AND BIOMEDICAL RESEARCH. HE AND TOM FROM OKLAHOMA ON THE HOUSE SIDE HAVE AMONG OTHERS BEEN RESPONSIBLE FOR THE INCREASES IN THE ENOUGH BUDGET YOU HAVE SEEN IN THE LAST TWO YEARS AND WE HOPE WE WILL SEE THIS YEAR AS WELL. DESPITE A VERY UNFAVORABLE ENVIRONMENT IN OTHER WAYS, THEY HAVE REALLY GONE TO BAT FOR NIH BECAUSE THEY REALLY BELIEVE IN HEALTH RESEARCH. AND THE UNIQUE RESPONSIBILITY AND OBLIGATION THE FEDERAL RESOURCES HAVE TO SUPPORT BIOMEDICAL RESEARCH WHICH OTHERWISE WOULDN'T BE SUPPORTED. SENATOR BLUNT KNOWS A LOT ABOUT THE CLINICAL SIDES OF WHAT WE DO, PARTICULARLY THE CTSA PROGRAM. I VISITED THE WASH U CTSA WITH PAMELA McGINNIS LAST YEAR AND WITH SENATOR BLUNT. BUTTED THAT PIQUED HIS INTEREST IN WHAT NCATS DOES. WHAT IS TRANSLATIONAL SCIENCE ANYWAY? AND WHAT ELSE DO YOU ALL DO? AND SO HE CAME UP AND SPENT AN ENTIRE MORNING WITH US AT THE LAB AND WE TAUGHT HIM ABOUT ASSAYS AND SCREENING AND TISSUE CHIPS AND PHARMACOLOGY AND ADD ME AND MEDICINAL CHEMISTRY AND CHEMICAL INFORMATICS AND ALL KINDS OF THINGS. SO HE IS A VERY QUICK STUDY. WE INVITED HIM BACK AND THAT URGE REOCCURRED AND IT WAS A WONDERFUL VISIT FOR US. AND I THINK WE HAVE EVEN GREATER ADVOCATE THAN WE DID BEFORE. WHAT I'M GOING TO DO NOW IS GO THROUGH THE YEAR IN REVIEW. I WANT TO GIVE YOU A SENSE OF WHAT LAST YEAR HAS BEEN THE LAST FISCAL YEAR, REMEMBER THE FISCAL YEAR-ENDED SEPTEMBER 30 LAST YEAR. BUT WE HAVEN'T HAD A COUNCIL MEETING. WE HAD A CAN BOARD MEETING IN DECEMBER BUT NOT A REGULAR MEETING SINCE THE FISCAL YEAR-ENDED TO GIVE YOU A SENSE OF THE ACCOMPLISHMENTS OF LAST YEAR. SO, TO REMIND YOU, THIS IS WHERE OUR BUDGET IS RELATIVE TO THE OTHER INSTITUTES. THERE ARE 27ICSITUTES AND CENTERS AND WE ARE -- 27 INSTITUTES AND CENTERS. WE LIKE TO THINK OF OURSELVES AS GOLDILOCKS. NOT TOO BIG AND NOT TOO SMALL. WE ARE RIGHT IN THE MIDDLE. OF COURSE WE WOULD LOVE TO BE BIGGER BUT WE ARE A GOOD SIZE. AND 706 MILLION WAS OUR APPROPRIATION FOR LAST YEAR. I'LL DRAW YOUR ATTENTION TO THE FACT THOUGH IT IS A RESPECTAL BUDGET, IF YOU LOOK AT THE NATIONAL EYE INSTITUTE, WHICH I'M AN EYE PERSON, I USED TO WORK IN THE EYE INSTITUTE. MY FIRST GRANTS WERE FROM THE EYE INSTITUTE. THEIR BUDGET IS BIGGER THAN OURS IS, WHICH IS INTERESTING AND WE CAN TALK ABOUT WHY THAT IS IF YOU'RE INTERESTED. JUST AS AN EXAMPLE. SO THIS IS WHAT OUR BUDGET LOOKS LIKE. IT'S A VERY STRANGE BUDGET FROM THE STANDPOINT OF ANY OTHER INSTITUTE THAT ONE WOULD SEE. ABOUT 70% OF THE BUDGET IS ONE PROGRAM. DCI, DIVISION OF CLINICAL INNOVATION, THIS IS THE CTSA PROGRAM RIGHT HERE. AND THEN THERE IS A RAINBOW OF OTHER PROGRAMS HERE. THE LARGEST OF THE NON-DCI ONES IS EPI, PRE-CLINICAL INNOVATION. YOU'LL HEAR ABOUT THAT THIS AFTERNOON AND THEN WE HAD THE CURES ACCELERATION NETWORK AND THE OFFICE OF RARE DISEASES AND THE SBIR PROGRAM AND A VARIETY OF OTHER SMALLER MISCELLANEOUS PROGRAMS IN HERE. AS MUCH AS WE KNOW AND LOVE CLINICAL RESEARCH IN THE CTSA PROGRAM, IT DOES CREATE PROBLEMS FOR MANAGING THE BUDGET, AS YOU MIGHT PLAQUE IN. IF YOU JUST THINK ABOUT ANY BUDGET -- MIGHT IMAGINE -- IT JUST MAKES IT A LITTLE DIFFICULT TO MANAGE AT TIMES. BUT THIS IS THE BUDGET CONFIGURATION. THE TRENDS IN THE BUDGET REALLY MIRRORS THE REST OF NIH. WE HAD REALLY SMALL INCREASES SINCE WE WERE FOUNDED BUT NOTHING REALLY SUBSTANTIAL. IF YOU FOLLOW THE INCREASES IN THE NIH BUDGET. WHAT HAPPENED OVER THE LAST SEVERAL YEARS IS QUITE INTERESTING THAT CONGRESS SAID WE ARE VERY ENTHUSIASTIC ABOUT BIOMEDICAL RESEARCH BUT WE WANT TO UNDERSTAND WHAT WE ARE GOING TO GET OUT OF THIS IN A VERY TANGIBLE WAY. SO, VAST MAJORITY OF INCREASES HAVE GONE TO SPECIFIC DISEASES THAT HAVE BEEN FAVORED. SO ALZHEIMER'S DISEASE, THE BUDGET FOR ALZHEIMER'S DISEASE, IS TRIPLED IN 400 MILLION TO 1.2 BILLION IN THE LAST THREE YEARS. THE CANCER MOONSHOT AND BRAIN INITIATIVE AND PRECISION MEDICINE INITIATIVE, ALL HAULED OUT WITH SPECIFIC INCREASES AND THOSE OF US WHO DO NOT HAVE ONE OF THESE GET LESS. AND I THINK ONE OF OUR CHALLENGES WHICH I HOPE WE'LL HAVE TIME, WE TALKED ABOUT IT YESTERDAY, LAST NIGHT OVER DINNER, BUT A LARGE NUMBER OF PEOPLE HAVE TRANSLATIONAL DISEASE. THEY SUFFER FROM A FAILURE OF TRANSLATION AND THEY ARE SICK AND CAN'T GET DIAGNOSED AND SICK OR DIE BECAUSE TRANSLATION DOESN'T WORK. I CHALLENGE YOU TO DEFINE ANYBODY WHO HAS TRANSLATION DISEASE. THEY HAVE ALZHEIMER'S OR THIS OR THAT. SO THEY WORK VERY HARD ON THAT PARTICULAR AREA WITH INADEQUATE TECHNOLOGIES AND APPROACHES THAT NOBODY LIKES, RATHER THAN REALIZING THIS IS A TRANSLATIONAL DISEASE. AND IF WE APPROACH IT THAT WAY, OUR OPINION AND OUR DATA SUGGESTS THAT WE WILL DO BETTER, ALL BOATS WILL BE LIFTED IN ALZHEIMER'S AND CANCER AND EVERYTHING ELSE WILL BE BETTER. AND OUR CHALLENGES IN HOW TO DEFINE THAT, AND HOW TO HAVE OUR POLICYMAKERS UNDERSTAND THAT. AND ALL OF OUR GRANTEES WHETHER TISSUE CHIP PEOPLE OR CTSA, WE ALL HAVE THIS PROBLEM. WE LIVE IN SUCH A HIGHLY SPECIALIZED WORLD WHERE I'M SURE IT'S JUST PICKING ON HARRY. HE IS A CARDIOLOGIST AS WELL AS CTSA HEAD AND I WOULD WAGER TO SAY THAT EVERYONE WHO WORKS WITH HARRY KNOWS WHAT A CARDIOLOGIST IS AND WHAT HE DOES. BUT ISN'T QUITE SO SURE OF THIS OTHER PIECE EVEN THOUGH I WOULD ARGUE THE OTHER PIECE, WHICH IS REALLY CALLED THE OTHER PIECE, HAS MORE IMPACT, ORDERS OF MAGNITUDE MORE IMPACT, THAN HIS CARDIOLOGIST, DESPITE THE FACT HE IS A GREAT CARDIOLOGIST. THAT IS OUR CHALLENGE. SO SOME HIGHLIGHTS FROM -- I WON'T SAY ANYTHING ABOUT DPI BECAUSE YOU WILL HEAR ABOUT THAT THIS AFTERNOON. SINCE THE LAST COUNCIL MEETING, HAD A GREAT FALL PROGRAM MEETING. WE HAD A WONDERFUL MEETING WITH THE STEERING COMMITTEE, WHICH I'LL TELL YOU ABOUT IN A SECOND AND THEN A LARGE MEETING ATTENDED BY 500 PEOPLE, DISCUSSIONS ON A NUMBER OF THINGS, NEW INFORMATICS PROGRAM THAT THE C. THIS SA PROGRAM IS DOING, A NUMBER OF HUB UPDATES, COLLABORATION AWARD UPDATES AND WORK ON THE OPIOID CRISIS I WILL MENTION AND THEN WE HAD A WHOLE DAY MEETING ON THE TRIAL INNOVATION NETWORK ABOUT HOW THAT INITIATIVE IS GOING. IT'S ABOUT A YEAR IN NOW. SO THEY ARE JUST BEGINNING TO GET GOING AND THEN SOME IMPORTANT STRATEGIC SHIFTS IN THAT PROGRAM, WHICH HAPPENED IF A MEETING, WHICH I'M VERY EXCITED ABOUT AND I THINK THE WHOLE GROUP IS. A COUPLE OF THINGS I WANTED TO MENTION TO YOU WERE SOME THINGS THAT -- SOME EXAMPLES WHAT THE PROGRAM DOES AND CAN DO AND WHAT THE POTENTIAL IS HERE. THESE ARE COLLABORATIVE INNOVATION AWARD PROJECTS. PROJECTS THAT WERE PRESENTED AT THE PROGRAM MEETING WHICH IS WHY I PULLED THEM OUT. THESE ARE PROGRAMS YOU PROBABLY REMEMBER WITH OUR -- WHICH ARE PERFORMED BY TWO OR MORE CTSA HUBS AND THEY EITHER ARE WORKING TO DISSEMINATE INNOVATION, GENERALIZE INNOVATION FOR A PARTICULAR TRANSLATIONAL SCIENCE ROAD BLOCK THAT HAS BEEN SOLVED AT A LOCAL INSTITUTION TO DISSEMINATE IT AT OTHER INSTITUTIONS AND OFTEN YOU HAVE TO MAKE MODIFICATIONS TO MAKE IT WORK IN OTHER PLACES AS A PATHWAY TO DISSEMINATING THEM ACROSS THE NETWORK. SO THAT IS ONE KIND. ANOTHER KIND IS SOMETHING THAT HAS -- A PROBLEM THAT IS INTRACTABLE FOR ANYONE INSTITUTE OR CTSA HUB. SO THEY APPLY TOGETHER. LET'S BAND TOGETHER AND SEE IF WE CAN SOLVE THIS PROBLEM TOGETHER. SO, I'M JUST GOING TO MENTION BRIEFLY, THIS ONE ON IPS CELLS, THE WORK OF THE BU, HARVARD, PENN AND CHICAGO CTSA HUBS. AND THEN THIS ONE, STRIDE, WHICH IS UMASS, UAB, UNIVERSITY OF ALABAMA AT BIRMINGHAM AND VANDERBILT. SO THESE ARE THE COLLABORATIVE INNOVATION AWARDS. THE ONLY ONES I WILL TELL YOU ABOUT ARE THESE TWO BUT THERE IS REALLY A REMARKABLE BREATH OF THESE PROGRAMS AND EACH ONE OF THEM FOCUSES ON A REALLY IMPORTANT GENERALIZE TRANSLATIONAL PROBLEM AND DEVELOPING CATALYST TO MAKE THIS PROBLEM GET BETTER. VALERIE? >> VALERIE: HOW DO THEY BUBBLE UP? DOES IT BUBBLE UP FROM SOMETHING INTERNALLY OR IS THERE AN RFP OR RF. THAT COMES OUT? BOTH? >> CHRIS: IT'S A SEPARATE SOLICITATION. SO IT IS LIKE IN MOST OF THESE WHEREAS EXAMPLES, SO-AND-SO AND SO. BUT THE ONLY REQUIREMENT IS THAT THEY IDENTIFY A CRITICAL ROAD BLOCK, GENERALIZE ROAD BLOCK WHICH IF SOLVED, WILL MAKE THE TRANSLATIONAL PROCESS MORE EFFICIENT AND EFFECTIVE GENERALLY. AND IT HAS TO BE THREE CTSAs OR MORE. SOME OF THEM ARE -- IT RANGES FROM IPS CELL NETWORKS TO THIS IS GENE THERAPY FOR RARE PEDIATRIC DISEASES. THIS HAS TO DO WITH PRESYMPTOMATIC CLINICAL TRIALS IN NEWBORNS. THIS IS A REGISTRY RESOURCE REPORTED OUTCOMES. THIS IS DIVERSE POPULATION ENROLLMENT STUDY. SO THERE IS A VARIETY ACROSS. SOME INFORMATICS ONES. THEY REALLY GO ACROSS THE SPECTRUM. A LOT OF REALLY EXCITING SCIENCE. SO THIS IS -- AND I'LL JUST TELL YOU TWO OF THESE TO GIVE YOU A FLAVOR OF HOW THIS WORKS. SO, THE ISSUE HERE IS THAT INDUCED PLURIPOTENT STEM CELLS HAVE BECOME A VERY EXCITING TECHNOLOGY WHICH HAS REALLY BEEN DISSEMINATED ITSELF BUT AS A TECHNIQUE, BUT WE HAVE A TYPICAL SITUATION WHERE THERE ARE MANY, MANY LABS, EACH MAKING INDUCED PLURIPOTENT STEM CELL LINES FROM DIFFERENT DISEASES REPEATING THE SAME THING OVER AND OVER AND OVER AGAIN AND NOT SHARING. WHEREAS WOULDN'T IT MAKE SENSE TO HAVE A CENTRAL REPOSITORY WHERE THESE THINGS ARE MADE, THEY ARE INDUCED PLURIPOTENT STEM CELLS WHICH MEANS BY DEFINITION, THEY GROW FOREVER T SHOULD BE ENTIRELY POSSIBLE TO DISTRIBUTE THESE THINGS BUT THERE WAS NOBODY HAD EVER HAD THE RESPONSIBILITY TO DO THIS. THIS IS A CLASSIC NCATS PROBLEM. AND THERE ARE INDIVIDUAL EFFORTS GOING ON IN INDIVIDUAL INSTITUTES FOR INDIVIDUAL DISEASES, BUT IPS CELLS ARE P, PLURIPOTENT, THAT MEANS THEY CAN BECOME ANYTHING. SO WHOSE INSTITUTE, WHOSE JOB IS IT TO DO THIS? THAT'S WHY NCATS TOOK THIS ON. THE CTSA NETWORK ESTABLISHED A NETWORK OF REPOSITORIES TO ENABLE SHARING OF OVER 1000 NORMAL AND DISEASE-SPECIFIC LINES. A LOT OF THESE HAVE BEEN GENOTYPED EXTENSIVELY. THIS IS MAINTAINING AN OPEN-SOURCE GENE EDITING TOOLBOX TO EDIT THESE IPS CELL LINES TO INDUCE DISEASE MUTATIONS WHEN THOSE DON'T EXIST. AND THEN DEVELOPING INFRASTRUCTURE TO FACILITATE A MODELING OF DISEASES WITH THESE IPS CELLS, DIFFERENTIATED IPS CELLS ACROSS THE ENTIRE CTSA NETWORK. THIS IS JUST A SHOCK AND AWE SLIDE TO SHOW YOU. THESE ARE SOME PAGES OUT OF THE REPOSITORY. THESE INCLUDE FOR INSTANCE HUNDREDS OF LINES FROM THE FRAMINGHAM HEART STUDY DOWN HERE ON WHICH THERE IS OF COURSE DECADES, MULTIGENERATIONAL DECADES OF DATA ON THESE ON PATIENTS FROM WHOM THESE IPS CELLS CAME AND THESE ARE VARIOUS OTHER DISEASE-SPECIFIC IPS CELLS. GENE EDITING HAS BECOME A REALLY REMARKABLE TOOL THAT CONTINUES TO EVOLVE AT A RATHER REMARKABLE RATE. LIKE ANY FIELD LIKE THIS WITH MANY PEOPLE GETTING INTO THIS FOR THE FIRST TIME, YOU DON'T WANT PEOPLE TO HAVE TO RE-CREATE THE WHEEL. YOU DON'T WANT THE GRADUATE STUDENT TO HAVE TO SPEND A YEAR OF THEIR TIME OR POSTDOC, RE-CREATING A GENE EDITING TOOL OR LEARNING HOW TO DO IT. WHAT YOU NEED TO HAVE IS A SERIES OF PROTOCOLS AND TOOLS THAT CAN BE ACCESSED BECAUSE THAT IS NOT THE INTERESTING STUFF. THE INTERESTING STUFF IS WHAT YOU DO WITH THE TOOLS. AND SO THAT HAS BEEN PUT TOGETHER AS PART OF THIS INITIATIVE AS WELL. AND OF COURSE YOU CAN'T JUST HAND PEOPLE THESE THINGS AND TELL THEM TO HAVE A NICE DAY. YOU REALLY NEED A JULIA CHILD ASPECT OF THIS. YOU CAN'T WRITE THE COOKBOOK. YOU HAVE TO HAVE THEM DO COOKING CLASSES. THIS IS WHERE PEOPLE COME IN AND LEARN HOW TO DO IPSC. AND HOW THEY DO GENE EDITING AND DIFFERENTIATION. THIS IS RUN BY THE SAME CCIA AWARD. AND THIS IS JUST ONE EXAMPLE AS A WORKSHOP BEING RUN AT PENN ON MAINTENANCE DIFFERENTIATION AND CHRIS PER CAS9 GENE EDITING AS AN EXAMPLE. SO THIS IS A CLASSIC EXAMPLE OF THE POWER OF THIS PROGRAM AND THIS CONSORTIUM THAT PUTTING TOGETHER ENORMOUSLY POWERFUL INSTITUTIONS ON THEIR OWN, HARVARD, PENN, ET CETERA. WHEN THEY TIE TOGETHER, THIS IS ABSOLUTELY UNSTOPPABLE. WITH THE GOAL GOAL TO DISSEMINATE, NO THE TO KEEP IT INTERNALLY BUT DISSEMINATE AND ENABLE EVERYONE ELSE. AND THAT JUST IS -- THIS IS THE KIND OF THING THAT THIS PROGRAM CAN DO. OKAY, ANOTHER ONE THAT FITS THIS SAME PRINCIPLE BUT PERHAPS AT THE OTHER END OF THE TRANSLATIONAL SPECTRUM IS STRIDE. SO THE GOAL OF STRIDE, REMEMBER& THIS IS A COLLABORATION BETWEEN UMASS, UAB AND VANDERBILT, TO IMPROVE RACIAL AND ETHNIC MINORITY RECRUITMENT AND CLINICAL TRIALS BY CREATING CULTURALLY-RELEVANT TOOLS AND INTERVENTIONS. SO, THIS IS AS I MENTIONED, UMASS, VANDERBILT, AND UA. AND THEY EACH HAVE THEIR OWN APPROACHES TO THESE AND THEY ARE COMPLEMENTARY AND THEY STARTED SHARING THESE. GOSH, WE MADE A LITTLE HEADWAY WITH SIMULATION AND STORY TELLING. VANDERBILT HAS COMMUNITY STUDIOS AND WE HAVE SOME PILOTS HERE INTEGRATING BUT WHAT IF WE PUT THEM ALL TOGETHER? THEN THIS WOULD BE A TEAM TO MAKE A DIFFERENCE. BASICALLY THE WAY I THINK ABOUT THIS IS LIKE PRESCRIBING COMBINATION DRUGS. SOMETIMES ONE DRUG IS ENOUGH, SOMETIMES YOU NEED A COMBINATION. AND THIS IS A COMBINATION TREATMENT FOR THE RECRUITMENT PROBLEM. SO, A NUMBER OF YOU KNOW THIS BUT I WANT TO REITERATE WHY THIS IS SO IMPORTANT. IN GENERAL, 30% OF CLINICAL TRIALS HAVE TROUBLE REACHING ENROLLMENT GOALS AND THAT IS IN MY EXPERIENCE AT LEAST, AN UNDER ESTIMATE. 20% DON'T EVEN ENROLL A SINGLE PATIENT! AND BY THE WAY, SOMEBODY IS PAYING FOR THIS. MAINLY NIH, YOU, TAXPAYERS ARE PAYING FOR THIS. THEY DON'T ENROLL A SINGLE PATIENT. 90% DON'T MEET PROPOSED TIME LINES BECAUSE OF THE DIFFICULTY OF RECRUITING. THAT'S WHY THIS WOULD BE HIGHER IF YOU ASKED HOW MANY REACH THEIR ENROLLMENT GOALS ON TIME AND ON BUDGET. THAT NUMBER WOULD BE VERY LOW. IE LESS THAN 10%. NOW, IN AN ERA OF FACEBOOK, AND ELECTRONIC COMMUNICATION, THIS IS NOT A TECHNICAL PROBLEM. SO WHY ISN'T THIS SOLVED? THE BIGGEST SINGLE CONTRIBUTOR TO INCREASED COSTS. THIS IS WHY WE CREATED THE TRIAL INNOVATION NETWORK AND WHY THESE NETWORKS EXIST. ET CETERA. BUT WHAT IS EVEN MORE STRIKING IF YOU LOOK AT THE DEMOGRAPHICS HERE, MINORITY REPRESENTATION, YOU LOOK AT THE PERCENT OF THE POPULATION VERSUS REPRESENTATION OF CLINICAL TRIALS, YOU LOOK AT AFRICAN-AMERICANS, LATINOS AND WHITES HERE. SO THIS IS THE BLUE IS PERCENT OF THE POPULATION AND ORANGE HERE IS REPRESENTATION IN CLINICAL TRIALS. FOR BLACKS IT'S ABOUT 1/3 OF THE REPRESENTATION. FOR LATINOS IT'S ALMOST UNMEASURABLE. >> CHRIS, ARE THOSE DATA FROM JUST NIH-FUNDED? >> CHRIS: I DON'T THINK SO. >> OR FOR ALL CLINICAL TRIALS? >> CHRIS: I THINK IT'S FOR ALL TRIALS. SO JUST ANOTHER WAY TO LOOK AT THIS IF YOU LOOK AT THE -- THIS IS U.S. POPULATION IN A CENSUS. THIS IS PERCENTAGE BY RACE AND HISPANIC ORIGIN. JUST BRING YOUR ATTENTION TO THE TOP. THE RED HERE IS BLACK INCLUDING MIXED RACE. I WANT TO COMPARE WITH THIS. THIS IS FOUR REAL TRIALS. SO THE COLORS ARE DIFFERENT HERE. THE BLACK AFRICAN-AMERICAN POPULATION IS RED IN THE PREVIOUS ONE IT IS BLUE HERE. SO THIS IS BLUE. THIS IS BLUE. THIS IS BLUE. THIS IS BLUE. AND IF YOU SQUINT, YOU CAN SEE, THERE ARE BARS THERE. BUT -- NOW THIS IS A HUGE -- LOOK AT THESE DISEASES. TYPE II DIABETES. BLADDER CANCER, ASTHMA, OVARIAN CANCER. THEY ARE OVER REPRESENTED IN THE POPULATION THAT IS UNDER REPRESENTED IN THE CLINICAL TRIAL. SO WE HAVE A SEVERE PROBLEM HERE. SO THE BOTTOM LINE, AFRICAN-AMERICANS MADE UP 7% OF CLINICAL TRIAL PARTICIPANTS. SO, WHY IS THIS? VALERIE AND OTHERS HAVE DONE A LOT OF WORK IN THIS AREA. BUT LIKE VALERIE WAS SAYING, MY OWN IMPRESSION OF THIS IS THAT THIS PROBLEM HAS BEEN ASSIGNED TO PEOPLE WHOSE JOB IT WAS TO SOLVE THAT PROBLEM. AND THEN THERE WAS THE MAINSTREAM THAT JUST WENT ON DOING WHAT THEY WERE DOING. AND NOT SURPRISINGLY, WE HAVEN'T SOLVED THE PROBLEM. AND SO, WHAT WE ARE DOING HERE IS TO SAY THIS IS A CRITICAL LIMITING STEP TO ROAD BLOCK, TO TRANSLATIONAL EFFICIENCY, EFFECTIVENESS, RELEVANCE. SO WE WILL TAKE THIS THING ON. SO WHAT DOES STRIDE DO? AND I SHOULD SAY THAT RECRUITMENT INNOVATION CENTER IS DOING A LOT OF WORK IN ITS OWN RIGHT AND I'M NOT GOING TO TALK ABOUT THIS TODAY. THIS IS ANOTHER OF THE PROGRAMS IN THIS AREA. BUT STRIDE IS ANOTHER. SO THE AIM HERE IS TO EXPAND OR DISSEMINATE IN OUR TERMINOLOGY, THREE INTERVENTIONS THAT HAD BEEN DEVELOPED AND SEEM TO BE USEFUL IN INDIVIDUAL PLACES. IF WE SUBSTANTIATED THESE AT OTHER PLACES WOULD THEY BE USEFUL? THIS IS STORY TELLING TO PROMOTE RESEARCH LITERACY. SO THE IDEA HERE IS THAT INSTEAD OF GOING UP TO PERSON X AND GIVING AND READING THE CONSENT FORM, WHICH ALWAYS LEADS TO ADVANCED UNDERSTANDING AND ENTHUSIASM ABOUT THE RESEARCH PROCESS. I'M BEING FACETIOUS HERE. YOU DO WHAT HUMANS DO. HUMANS LEARN BY TELLING EACH OTHER STORIES. SO YOU TELL A STORY ABOUT A PERSON WHO IS SICK AND WHAT HAPPENED IN A CLINICAL TRIAL. AND THEN PEOPLE SAY, I WANT TO DO THAT TOO. I WANT SOME OF THAT. A SIMULATION-BASED TRAINING. SO THIS IS WHERE WE PUT TRAINEES OR CLINICAL TRIALISTS IN AN ENVIRONMENT WHERE THEY ARE SIMULATING A CULTURE AND APPROPRIATE RECRUITMENT AND INFORMED CONSENT, TESTING EFFECTIVENESS OF THESE THREE AND THEN AN E-CONSENT PROCESS. WE ARE TESTING THIS EFFECTIVENESS OF THIS MULTIMODAL INTERVENTION PUTTING THIS TOGETHER TO IMPROVE PARTICIPATION OF AFRICAN-AMERICANS AND LATINOS IN ONGOING CLINICAL TRIALS AT EACH OF THE THREE HUBS. AND THEN IF THESE ARE EFFECTIVE, SO THIS IS THE THREE Ds, DEVELOP, DEMONSTRATE, DISSEMINATE. AND SO IF THE DEMONSTRATION PROJECT WORKS, THE WHOLE IDEA IS, THIS WILL BE PROMOTED TO WIDESPREAD DISSEMINATION TO ALL THE OTHER CTSA HUBS AS WELL AS NON CTSA HUBS. SO COMMUNITY ORGANIZATIONS AND RESEARCH INSTITUTIONS THAT ARE NOT PART OF THE CTSA PROGRAM. I'M REALLY EXCITED ABOUT THIS. THE PRESENTATION AT THE PROGRAM MEETING WAS REALLY EXCITING AND WHO KNOWS. IT IS EARLY. NOT GOING TO DECLARE VICTORY BUT THIS IS AN APPROACH WHICH HAS GREAT PROMISE. SO, YOU CAN SAY RESEARCH ASSISTANT TRAINING AND STORY TELLING FOCUSING ON CLINICAL CHALLENGE OF THESE THREE INNOVATIONS AND PLANNED DISSEMINATION AND WE HOPE HELP TO ADDRESS AND REVERSE THIS UNDER REPRESENTED MINORITY PARTICIPATION AND RESEARCH. >> CHRIS CAN I MAKE A COMMENT? I AM EXCITED AND BELIEVE THAT -- I'M FAMILIAR WITH EACH OF THESE THREE INSTITUTIONS AND APPROACHES THEY ARE TAKING. AND I AM EXCITED THAT THEY HAVE COME TOGETHER TO LEARN FROM ONE ANOTHER AND THEN TO HOPEFULLY BE ABLE TO MONITOR, MEASURE AND DISSEMINATE THIS. HOWEVER, AND I THINK I TOUCHED ON THIS AT OUR LAST COUNCIL MEETING; I BELIEVE THERE NEEDS TO BE ADDITIONAL COLLABORATORS IN THIS SPACE. AND THE INSURERS WHO HAVE DIRECT ACCESS TO THE PATIENTS THAT WE WANT TO ENGAGE AND MEETING THEM WHERE THEY ARE, BECAUSE EVERY INSURER CAN PREDICT WHEN THAT NEXT PATIENT ENCOUNTER WILL BE. AND IF WE PARTNERED WITH THE PROVIDERS WHO ARE CONTINUING TO BE THE MOST TRUSTED INDIVIDUAL FOR THAT PATIENT, WE WOULD REMOVE MANY OF THE BARRIERS. AND YES, WE NEED TO BE TECHNOLOGICALLY SAVVY IN HOW WE GET THIS INFORMATION AND APPROPRIATELY HOW WE GET THIS INFORMATION. BUT THE PARTNERSHIP THERE WITH THOSE INSURERS, WHETHER CMS, MEDICAID OR MEDICARE, WHETHER IT IS INSURERS, I JUST THINK THAT WE ARE STILL JUST GOING TO BE CHIPPING AT THE ICEBERG HERE, WHEN WE COULD BECAUSE OF THE DATA -- THESE MAJOR INSURANCE COMPANIES HAVE DATA ON 140 MILLION LIVES. AND THEY KNOW WHEN THAT NEXT VISIT IS GOING TO BE. SO I WOULD HOPE THAT WE ARE UNDERSTANDING THE POWER OF THAT PARTNERSHIP. AND I THINK THAT THEY WILL BE RECEPTIVE TO COMING IN, IN THIS TYPE OF INNOVATION HUB AND CAN LEND SOME ANALYTICS THAT WILL MAKE A BIG DIFFERENCE. >> CHRIS: GREAT POINT. THANK YOU. >> I'M LOOKING AT THIS AND CURIOUS ABOUT COMMUNITY ENGAGEMENT AS WELL AS THE PEOPLE WHO ARE RECRUITING FOR CLINICAL TRIALS. WHAT DO THEY LOOK LIKE AND DO WE KNOW THEIR BACKGROUNDS? >> CHRIS: THIS IS PERHAPS A LARGER TOPIC, BUT YES, THIS IS ONE OF THE MAJOR ISSUES THAT THESE GROUPS ARE DEALING WITH. AND THAT IS WHY I MEAN CULTURALLY-APPROPRIATE. THESE ARE FOLKS WHO ARE GOING TO BE TRUSTED IN THE COMMUNITY. AND IN GENERAL, YOU LOOK LIKE ME, TALK LIKE ME, COME FROM MY COMMUNITY AND HAVE MY SAME BACKGROUND. THERE IS A LEVEL OF TRUST THERE. AND IT'S NOT VERY COMPLICATED IN SOME CASES. IT'S SOMETHING THAT GATES DEALS WITH ALL THE TIME, I'M SURE. >> TO THE POINT YOU MADE THAT ONLY ABOUT 10% OF THESE TRIALS ARE RECRUITING ON TIME. MY GUESS WOULD BE THAT A GOOD NUMBER OF THAT 10% IS CONDUCTED WITH PATIENT ADVOCACY ORGANIZATIONS DIRECTLY INVOLVED. AND I'M SURPRISED NOT TO SEE THAT PART OF THE COMMUNITY INVOLVEMENT HIGHLIGHTED BECAUSE THAT IS WHERE A LOT OF THE RUBBER HITS THE ROAD. AND PATIENT ADVOCACY ORGANIZATIONS ARE RECRUITING TRIALS IN A MATTER OF HOURS NOT YEARS. >> CHRIS: AND THOSE ARE -- THAT IS THE STANDARD TO WHICH WE HOLD OURSELVES, ACTUALLY THIS IS PJ BROOKS. THE PROGRAM OFFICER. >> TO ADDRESS BOTH THOSE COMMENTS. THERE IS ACTUALLY A VERY STRONG COMMUNITY ENGAGEMENT COMPONENT. THERE ARE COMMUNITY LEADERS THAT ARE DIRECTLY INVOLVED AND FUNDED AS PART OF THESE PROGRAMS TO ENSURE AND ADDRESS THOSE COMMENTS THAT BOTH OF YOU MADE. >> CHRIS: LET'S KEEP GOING BECAUSE I DON'T WANT TO GET TOO FAR BEHIND TIME AND THIS IS A REALLY GREAT DISCUSSION. I WANT TO SHOW YOU WHO THE STEERING COMMITTEE IS NOW. THIS IS A REALLY STRONG GROUP. THE CO-CHAIRS ARE MYSELF AND KATHLEEN BRADY FROM MEDICAL UNIVERSITY OF SOUTH CAROLINA. BUT REALLY A WONDERFUL GROUP OF PEOPLE. VERY, VERY ENGAGED ON THE PHONE CALLS NOW. AND THIS INCLUDES THE HEAD OF THE CT2H PROGRAM, MELISSA, THE CENTER OF THE NEW COORDINATING CENTER, MARTIN AT ROCHESTER. REPRESENTING THE TRIAL INNOVATION NETWORK, DAN FORD FROM HOPKINS. REPRESENTING THE KL2 TRAINING IS JOEL FROM UT SAN ANTONIO AND THE TL1 PROGRAM IS SUSAN FROM UNIVERSITY OF KENTUCKY. A NUMBER OF OTHER UL1 HEADS. SO, REALLY A FANTASTIC GROUP THAT IS REALLY HELPING MOVE THIS PROGRAM FORWARD IN A VERY, VERY ACTIVE WAY. I AND MY COLLEAGUES HAVE MADE THREE VISITS TO CTSA PROGRAMS, ONE TO DAVIS, ONE TO UA ABOUT. AND ONE TO WASH U SINCE WE LAST MET. WE ALSO RE-ISSUED THE FUNDING OPPORTUNITY AND WANTED TO LET YOU KNOW ABOUT THIS AND WE RE-ISSUED THE PROGRAM ANNOUNCEMENT. THIS WAS REALLY A TECHNICAL REISSUE THAT IS TO INCLUDE A NUMBER OF UPDATED FORMS FROM THE NIH, STREAMLINING A LITTLE BIT ABOUT THE KL2 PROGRAM IT IS REALLY IMPORTANT THIS GOT OUT BECAUSE THE LAST WAS ABOUT TO EXPIRE. BRIEFLY A COUPLE OF THINGS ABOUT OPIOIDS. SO THE CTSA PROGRAM I FEEL VERY STRONGLY AND A NUMBER OF THE PIs DO AND PARTICULARLY Mrs. SHAKER WHO IS HERE WITH US, HAVE BOTH THE OPPORTUNITY AND THE OBLIGATION, I THINK, TO HELP ADDRESS THIS NATIONAL NEED. THE NUMBERS CONTINUE TO BE ABSOLUTELY ASTOUNDING. THOUGH THE MILLIGRAM EQUIVALENCE OF PRESCRIBED CONTINUE TO DECREASE, THE NUMBER OF OPIOID DEATHS CONTINUES TO INCREASE BECAUSE OF COURSE OF THE REPLACEMENT IN THE COMMUNITIES OF PRESCRIPTION OPIOIDS WITH SYNTHETIC AND NON-SYNTHETIC, ILLEGAL SUBSTANCES. THIS IS THE 2016 NUMBERS. 64,000 IS ABOUT A 25% INCREASE IN OVERDOSE DEATHS FROM THE PREVIOUS YEAR. THE OVERDOSE DEATHS AND GET READY FOR THIS, LOOK AT THIS GRAPH. I WANT TO DRAW YOUR ATTENTION TO THE BLUE ONE HERE. THIS SLOPE APPROACHES INFINITY. THIS IS FENTANYL AND FENTANYL DERIVATIVES. YOU JUST HAVE TO LOOK THAT THE FOR A SECOND AND REALIZE THE PROBLEM. AND THE SLOPE OF THIS. AND I DON'T THINK -- THE SLOPE CONTINUES TO INCREASE. IT LOOKS LIKE THE SPACE SHUTTLE. SO, AT THE CTSA CONSORTIUM MEETING, WE HAD REALLY GREAT DISCUSSION ABOUT THIS. THE NIH SPENT A LOT OF TIME AND I AND OTHER STAFF SPENT A LOT OF TIME ON AN NIH APPROACH TO THIS GENERALLY AND I'M NOT GOING TO SPEND ANY TIME ON THIS, BUT JUST A BETTER PAIN MANAGEMENT DATA, BETTER ADDICTION TREATMENT AND OVERDOSE REVERSAL. THE THREE PILLARS OF THIS, AND THIS IS AN ONGOING PROGRAM WE ARE WORKING CLOSELY WITH NIDA AND NI FDA IS THIS. THE CHALLENGES YOU KNOW ABOUT. -- NINDS ON THIS. THE CTS PROGRAM HAS A POTENTIAL TO HELP ADDRESS THIS FOR A VARIETY OF REASONS. ONE, I THINK WE ALL FEEL THAT THERE IS AN ENORMOUS OBLIGATION. THESE CENTERS ARE VERY LARGE AND FRANKLY VERY WEALTHY. AND I THINK WE ALL FEEL THAT THERE IS A SOCIAL OBLIGATION TO DO SOMETHING, PARTICULARLY BECAUSE THESE -- THIS IS WHERE THE RESEARCH BRAIN TRUST IS. AND THEY HAVE NOT ONLY THE TRANSLATIONAL EXPERTISE BUT THE COMMUNITY ENGAGEMENT EXPERTISE AND RECRUITMENT EXPERTISE TO HELP HERE. SO, RESEARCH IS NEEDED IN ALL AREAS OF TRANSLATION. AND IF WE CAN SOLVE PROBLEMS IN THE OPIOID SPACE, WE WILL UNDERSTAND OR DEVELOP A SOLUTION WHICH WILL BE GENERALIZABLE, NEW THERAPY DEVELOPMENT, CLINICAL TRIALS, RECRUITMENT AND PARTICIPANTS. THESE ARE NOT PARTICIPANTS COMING BACK FOR THEIR REGULAR VISITS. THESE ARE PEOPLE WHO ARE NOT IN THE HEALTH SYSTEM. YOU HAVE TO RECRUIT THEM AND HIGHWAY UNDERPASSES. LITERALLY. AND SO, TALK ABOUT A RECRUITMENT PROBLEM. THIS IS REALLY AN EXTREME ONE. HOW DO YOU DEPLOY EXISTING PROGRAMS? COMMUNITY ENGAGEMNT, MODELS OF CARE. ALL THINGS THE CTSA PROGRAM KNOWS A LOT ABOUT. SO UNIQUELY SUITED TO CONDUCT THESE. SO WE HAVE BEEN SPENDING A LOT OF TIME ON WHAT THESE EFFORTS MAYBE IT'S A CLOSE COLLABORATION WITH NIDA. RHONDA CHANDLER, THE DEPUTY DIRECTOR FOR A NUMBERS OF NUMBER OF YEARS ASKED BY THE HEAD OF NIDA TO COME BACK TO NIDA. TO BE HER PERSON ON THIS CRISIS AND ONE OF THE THINGS THAT NORA WANTED AND I WAS GLAD TO HEAR, SHE IS GOING TO BE OUR BRIDGE TO NIDA. WE ESTABLISHED A WORKING GROUP WITH THE CTSA PROGRAM COMMITTEE. A NUMBER OF EXAMPLES WHICH ARE BEING DEVELOPED, PHENOTYPING PATIENTS IN THE ER, BEST PRACTICES FOR TRAINING SURGE OBVIOUS ON OPTIMAL PRESCRIBING OF OPIOIDS MOST-OP, COMMUNITY-BASED APPROACHES FOR TAKING BACK UNUSED OPIOIDS AND RESEARCH EFFECTIVE MODELS OF CARE TO ADDRESS OPIOID USE DISORDERS. WE ALSO ARE ABOUT TO RELEASE A SOLICITATION FOR THE CCIA, WHICH YOU JUST HEARD ABOUT FOCUSED ON OPIOIDS. SO STAY TUNED HERE. THERE IS A LOT GOING ON. YES? >> SO, THIS IS MORE EXTREME THAN THE AIDS CRISIS AND WITH HIV/AIDS WE HAD ACTIVISTS WHO WERE WELL POSITIONED TO DO THIS SORT OF THING AND WE KNOW WE DON'T HAVE THEM HERE. SO I THINK THE LEADERSHIP WILL HAVE TO COME FROM SOMETHING LIKE THE CTSA PROGRAM AND TO DO SOMETHING EXTREMELY BOLD IN AN EMERGENCY SITUATION AND SAY THAT ALL DATA FROM ALL OF THESE PLACES IS GOING TO BE SHARED BLANKET. NOBODY GOATS MAKE ANY DECISIONS LOCALLY. EVERYBODY HAS TO SHARE. AND THIS WOULD BE AN EXTREME EXAMPLE AND ONE THAT YOU COULD REALLY INVOKE THIS EMERGENCY STATUS AND THEN AS YOU SAID, THIS ACTUALLY COULD APPLY TO OTHER THINGS LIKE I KEEP ARGUING IN RARE DISEASES AS WELL. FOR THIS, THERE IS NO REASON WHY THE DETOX CENTERS, THE CLINICAL CENTERS, AREN'T ALL SHARING THESE DATA. >> AND THAT IS DEFINITELY THE IDEA. >> SO I DON'T MEAN TO BE RUDE BUT I'M GOING TO BE RUDE. SO, WHAT IS NEW? I HAVE TO TELL YOU CHRIS, I LOOK AT THIS. I RECOGNIZE THIS. I UNDERSTAND THE PAIN. I THINK THAT THE POINTS BEING MADE IS THAT THIS IS AN OPPORTUNITY FOR THE CENTER TO MAKE AN IMPACT. BECAUSE I GOT MY PH.D. BACK IN 19 -- [ LAUGHS ] IN OPIOID RESEARCH. SERIOUSLY, I CAME OUT OF -- THIS IS BACK BEFORE YOU WERE BORN AND I GOT MY PH.D. ON METHADONE. AND ALL THE STUFF I'M LOOKING AT, WHAT IS NEW? SO WE ARE GOING TO DO THE SAME OLE' CHURN AND THROW MORE MONEY INTO THE CALLED RUN AND KEEP STIRRING THE POT AND CONVINCE OURSELVES WE ARE DOING GOOD SCIENCE. IF THAT IS THE ULTIMATE GOAL HERE, WE ARE NOT GOING TO MOVE THE NEEDLE. SO I'M ASKING YOU AGAIN, I THINK THAT FOR SOMETHING LIKE THIS, WHAT WOULD BE BEST TO HIGHLIGHT IS NOT THE EFFORT. THE EFFORT WE GET. IS WHAT IS DIFFERENT? AND THAT IS WHAT THIS -- YOUR CENTER IS SUPPOSED TO BE. NIDA HAS BEEN WORKING ON THIS -- MY FIRST GRANT WAS FROM NIDA. THAT'S ABSURD AND IT WAS ON OPIOIDS AND WE SAW THE SAME THING. PAIN RESEARCH, THREE PILLARS, ALL THIS JAZZ. SO AT THE END OF THE DAY, THIS IS WHERE LEADERSHIP FROM THIS INSTITUTE CAN TAKE US, WHAT IS NEW? I DIDN'T SEE ANYTHING NEW. I'M SORRY TO BE RUDE BUT I DIDN'T SEE A DAMN THING NEW. SO, FOR THOSE WHO STILL PRACTICE MEDICINE, INCLUDING ME, WE STILL GIVE MORPHINE, WHICH WAS USED IN THE CIVIL WAR. SO COME ON! >> CHRIS: IT IS A GREAT QUESTION. >> THERE ARE A FEW THINGS NEW, I HAVE TO SAY. >> PLEASE. >> PARTICULARLY THE FDA NOW IS RESPONSIBLE FOR HOW IT IS PRESCRIBED. THAT'S NEW. BUT TO THAT EXTENT, I THINK WE NEED TO COLLABORATE ON IT AND LOOK AT THE DATA AND GET ACCESS TO ALL THE DATA, TREATMENT CENTERS, DETOX CENTERS, THE STATE, THE LOCAL CENTERS AS WELL AS THE NATIONAL CENTERS. AND THAT IS ONE OF THE ONGOING EFFORTS. >> THERE WAS A HEROIN CRISIS IN 1970, WHICH IS COMING -- [ OFF MICROPHONE ] >> CHRIS: YOU WILL BE INTERESTED TO KNOW, THAT PARENTHETICALLY, AND THEN I'LL ANSWER YOUR QUESTION. THIS INTERESTING TIDBIT, THE DRUG THAT IS CAUSING THE BIGGEST PROBLEM, CAR NET NIN WAS SYNTHESIZED BY PAULIAN SEN IN THE 50s. IT'S 10,000 TIMES AS POTENT AS FET UNTIL. IT IS VERY EASY TO SYNTHESIZE. I COULD PROBABLY SYNTHESIZE IT MYSELF WHICH IS REALLY SAYING SOMETHING BUT IT WAS NEVER MARKETED BECAUSE IT HAS NO USE. YOU WOULD KILL PEOPLE WITH IT. BUT THAT IS ONE OF THE PROBLEMS THAT IS OUT THERE NOW. SO, IT'S A LONG ANSWER. WE ARE AS IS OUR WANT, CONSTANTLY ASKING THE QUESTION THAT YOU JUST ASKED. THE REASON TENTATIVELY OPTIMISTIC IS THAT NIDA HAS COME TO US, COME TO ME, SPECIFICALLY, AND SAID WE CAN'T DO THIS. WE HAVE BEEN BANGING AWAY THAT THE FOR YEARS. WE NEED NCATS. CAN YOU PLEASE PARTNER WITH US ON THIS? THE LIMITATION I MUST SAY AMONG OTHER THINGS THAT THE POINT, I HATE TO SAY THIS BUT IT IS A REALITY, IS MONEY. THAT IS LIKE ANY ORGANIZATION, THE KIND OF MONEY THAT WOULD BE REQUIRED TO REALLY MAKE A DENT IN DOING THE KIND OF CLINICAL RESEARCH AND OUTCOMES RESEARCH THAT WOULD BE REQUIRED HERE IS QUITE A LOT. AND THERE HAS BEEN NO -- WE DON'T EVEN HAVE A BUDGET FOR OUR CURRENT YEAR MUCH LESS ANYTHING ELSE. SO WHAT WE ARE DOING IS DOING -- WHAT WE DID WITH THE CAN PROGRAM. REMEMBER WITH THE CAN PROGRAM? WE DIDN'T HAVE MONEY FOR THAT PROGRAM EITHER BUT WE DID A LOT OF DUE DILIGENCE ON WHAT WE WOULD DO, THE KINDS OF REALLY OUT THERE PROGRAMS WE WOULD DO AND THEN WHEN THE MONEY CAME, WE WERE ABLE TO PUSH THE RED BUTTON AND LAUNCH IT. THAT'S WHAT WE ARE DOING. I LOOK FORWARD TO GIVING YOU MORE UPDATES AND THEN HOLD US TO THAT. BECAUSE WE ARE NOT BIG ON SAME OLD SAME OLD AROUND HERE. SO REAL QUICKLY, OR DR HIGHLIGHTS. SO REALLY INTERESTING -- [ SIRENS ] WHY DON'T WE TAKE OUR BREAK NOW. >> A GOOD TIME FOR A BREAK, EVERYBODY. >> WE WILL HAVE TO HAVE A WORKING LUNCH. NEW PARADIGMS. THIS IS A NEW PARADIGM I WOULD HAVE LIKED TO HAVE AVOIDED. IT WAS POINTED OUT THAT THE FIRE ALARM WENT OFF RIGHT AFTER A SAID THE WORDS, GENE EDITING. I JUST SAID IT AGAIN AND IT DIDN'T GO OFF. THAT'S A GOOD SIGN. SO QUICKLY, I WANT TO FINISH UP AND THEN WE'LL JUST GO -- ANNA WILL TELL US WHAT TO DO BUT MY SENSE IS WE'LL GO TO THE CAN UPDATE AND THEN SKIP OUR BREAK BECAUSE WE JUST HAD IT, AND GO RIGHT INTO THE NEXT SECTION. WHAT I WANT TO TELL YOU ABOUT WAS A VERY EXCITING DEVELOPMENT IN THE RDCRN. THIS IS THE LYSOSOMAL DISEASE NETWORK RUN BY THIS GUY, CHET WHITLEY. HE HAS BEEN SUPPORTED AT NIH INCLUDING BY THE RDCRN FOR MANY YEARS. IT IS A CENTER THAT IS CO-FUNDED BY NINDS AND NIDDK. AMONG OTHER DISEASES, THEY WORK ON TWO DISORDERS WHICH ARE MUCO POLYSACCHARIDEOSEIS 1 AND 2, MPS1 AND 2 CAUSED BY DEFICIENCIES AND ENZYME NEEDED TO BREAKDOWN SUGARS IN CELLS AND THEY ARE MULTI-SYSTEM DISORDERS. OVER THE LAST COUPLE OF DECADES, ENORMOUS HEADWAY HAS BEEN MADE AS IS THE CASE IN MANY RARE DISEASES MOUSE MODELS AND NATURAL HISTORY AND GENE THERAPIES. SO, THE LDN, CHET HIMSELF STARTED A COLLABORATION WITH SANGA MOET NUMBER OF YEARS AGO AND AND THE FIRST GENE EDITING CLINICAL TRIAL FOR THIS DISORDER USING ZINC FINGER NUCLEASES STARTED A COUPLE OF MONTHS AGO IN NOVEMBER. ZINC FINGERS HAVE BEEN AROUND FOR A LOT OF YEARS. THEY CAME IN AFTER ANTISENSE BEFORE RNAI, AROUND THE SAME TIME AS RIBOSOMES IF YOU REMEMBER THAT WHOLE THING. SO ZINC FINGER NUCLEASES ARE USE TO MODIFY DNA IN EXPERIMENTAL SYSTEMS AND THEN ALWAYS HAS BEEN HOPED THAT THIS COULD WORK IN PEOPLE AS WELL. SO, CHET WHITLEY AND HIS LDN COLLEAGUES HAVE BEEN WORKING WITH SANGA MOW ON GENE EDITING CLINICAL TRIAL FOR EVENTUALLY MPS1 AND 2. AND THIS TRIAL OR THE FIRST PATIENT GOT A LOT OF PRESS BACK IN NOVEMBER. THIS PERSON, WHO IS A 44-YEAR-OLD WITH MPS2, OTHERWISE KNOWN AS HUNTER SYNDROME, WAS THE FIRST TO RECEIVE THIS. AND LIKE A LOT OF GENE EDITING AND GENE THERAPY TREATMENTS, THE HOPE IS THAT THIS WILL BE A ONE-TIME TREATMENT. WE DON'T KNOW BECAUSE LIKE WHEN YOU FIRST GIVE A VACCINE, YOU DON'T KNOW HOW LONG THE TITERS, PROTECTION WILL LAST. WE DON'T KNOW HOW LONG THIS WILL LAST EITHER. BUT THE HOPE IS THAT THIS WOULD PREVENT BRIAN FROM HAVING TO GET INFUSIONS OF THE ENZYME FROM HERE ON OUT. SO, REALLY A VERY EXCITING DEVELOPMENT. THIS ONE GOING ON IN THE RDCRN. THE LAST TIME I TALKED TO YOU ABOUT TRIAL GOING ON VIA DPI AND THE TREND PROGRAM ON AROMATIC AMINO ACID DECAR BOX LAYS DEFICIENCY, DELIVERY OF A NORMAL GENE, REMEMBER I SHOWED YOU, AND IS THERE A NUMBER OF OTHER THINGS GOING ON AND I'LL BE CONTINUING TO TELL YOU THESE AS THEY HAPPEN. AND AS THE PROCESS ACCELERATES. WHAT IS EXCITING ABOUT THIS FROM OUR POINT OF VIEW IS THAT WHEN WE APPROACH A PROBLEM LIKE THIS, WE ALWAYS APPROACH IT IN THE TYPICAL NCATS WAY. WE ARE INTERESTED IN DEVELOPING TREATMENTS FOR THESE DISEASE. OF COURSE WE ARE. BUT WHAT WE ARE EVEN MORE INTERESTED IN IS THE PLATFORM THAT CAN BE APPLIED TO MANY, MANY RARE DISEASES. AND THAT IS THE OTHER REASON THIS IS SO EXCITING TO US. SO TO MOVE THIS FORWARD, AND I'M REALLY AS AGGRESSIVE WAY AS POSSIBLE, PETRA KAUFMAN AND PARIS AND THEIR COLLEAGUES IN ORDR, ARE PLANNING A JOINT WORKSHOP ON THE GROWING PROMISE OF GENE THERAPY APPROACHES BY GENE THERAPY WE MEAN NOT JUST CONVENTIONAL GENE THERAPY. EX-VIVO OR IN-VIVO, BUT WITH THE GENE TRANSFER EITHER INTO THE BODY OR LIKE CAR T-CELLS, CELLS ARE TAKEN OUT AND THEN MODIFIED AND THEN PUT BACK IN THE PATIENT. BUT GENE DISRUPTIONS, GENE MODIFICATIONS, GENE EDITING, ET CETERA. AND THERE IS ALL KINDS OF ISSUES RELATED TO NOT ONLY THE TECHNOLOGY BUT THE SAFETY AND THE SCALABILITY, HOW TO DEAL WITH ALL THE DIFFERENT MUTATIONS THAT EXIST IN MOST RARE DISEASES. A LOT OF THESE ARE PRIVATE MUTATIONS OR RARE -- A LOT OF GENETIC HETEROGENEITY IN THESE DISORDERS. SO, STAY TUNED FOR THAT. WE DON'T HAVE A FINAL DATE ON THIS YET BUT WE'LL LET YOU KNOW AS SOON AS THAT HAPPENS. LAST THING I WANT TO TELL YOU ABOUT IS WHAT IS GOING ON WITH THE REGISTRY PROGRAM. THE SO A PATIENT REGISTRY IN NATURAL HISTORY ARE CRITICAL TO DEVELOPMENT OF TREATMENTS. NOT ONLY FOR RARE DISEASES, FOR ALL DISEASES, FOR UNDERSTANDING THESE DISORDERS FOR DEVELOPING BIOMARKERS, PREPARING FOR CLINICAL STUDIES. THE ORDR REALIZING THAT THIS WAS A MAJOR, MAJOR ISSUE IN RARE DISEASE RESEARCH, STARTED A PILOT PROGRAM IN 2010 CALLED THE GLOBAL RARE DISEASE REPOSITORY PROGRAM, GRDR. YOU HEARD ABOUT THIS BEFORE. AND THIS WAS ITS PURPOSE WAS TO DEVELOP A WEB-BASED RESOURCE THAT AGGREGATE,Y IS USE AND STORES DE-IDENTIFIED PATIENT INFORMATION, IMPLEMENT COMMON DATA ELEMENTS, GENERAL INTEREST IN THIS FROM THE RARE DISEASE COMMUNITY. AND THIS WAS DONE AS A DEMONSTRATION PROJECT. THERE WERE 12 PATIENT ADVOCACY GROUP REGISTRIES THAT WERE INCLUDED. THIS IS A PILOT PROGRAM. THIS WAS THE COMBINATION OF THE FIRST TWO Ds IF YOU WANT TO THINK OF IT THAT WAY, DEVELOPING AN APPROACH TO THIS, AND DEMONSTRATING IN A SMALL NUMBER OF DISEASES USING COMMON DATA ELEMENTS, COLLECTION POOLING OF DATA AND THE WHOLE IDEA IS THAT EVENTUALLY THIS WOULD BE POOLABLE ACROSS DISEASES TO BE ABLE TO GENERATE INSIGHTS ACROSS DISEASES NOT JUST INDIVIDUAL ONES. AND IT WAS SO FAR AS IT WENT, SUCCESSFUL. MAYBE THERE WERE ESTABLISHMENT OF 12 REGISTRIES, REGISTRY OF THESE THAT USE COMMON DATA ELEMENTS TO ONE DEGREE OR ANOTHER. INFORMED CONSENT AND ALL OF THAT WAS SUCCESSFUL. BUT WHAT WERE THE LESSONS? THE LESSONS WERE SEVERAL AND I'LL GET TO THOSE IN A SECOND. WE CONCLUDED THE FIRST PROGRAM, FIRST PHASE OF THE PROGRAM IN 2013, AND THE ISSUE HERE WAS IT WAS CLEAR THAT GIVEN ENOUGH RESOURCES, WE COULD DEVELOP REGISTRIES BUT IT WAS CLEAR WE WERE GOING TO HAVE TROUBLE WITH ALREADY WAS TO BE ABLE TO MAP THESE DATA POST-HOC TO EACH OTHER AND TO AVAILABLE STANDARDS AS THOSE THINGS DEVELOPED. SO THERE WAS A GRANT AWARDED TO A GROUP AT HARVARD TO TAKE THESE 12 PATIENT REGISTRIES AND POST-HOC INTEGRATE THEM INTO A COMMON DATA MODEL AND THEN FACILITATE DISCOVERY BY LOOKING AT DATA ACROSS THESE DISORDERS. AND IT DID, THOUGH IT WAS A BIT PAINFUL, IT WAS POSSIBLE TO GENERATE A UNIFIED DATABASE OF THESE MULTIPLE REGISTRIES AND ONTOLOGIES AND THOSE DATA COULD THEN BE TRANSFERRED BACK TO THE PATIENT GROUPS SO THEY COULD USE THEM FOR WHATEVER USE THEY WERE GOING TO HAVE, HOPEFULLY DEVELOP DEVELOPING EITHER BEHAVIORAL INTERVENTIONS OR THERAPEUTIC, PHARMACOLOGICAL INTERVENTIONS FOR THEIR DISORDERS. BUT IT WAS VERY CLEAR THAT THIS APPROACH SIMPLY WOULD NOT SCALE. SO, WE COULD PAT OURSELVES ON THE BACK THAT WE DID 12, BUT THAT LEAVES 6,988 TO GO. SO THIS WAS JUST NOT GOING TO SCALE. AND SECONDLY, AS HAS BEEN THE CASE IN SOME OTHER PROGRAMS THAT WE HAVE DONE HERE AT NCATS, AND OTHER ASPECTS OF THE ORGANIZATION, THE HOPE THAT IT WOULD BE POSSIBLE TO TAKE DATASETS THAT WERE NOT -- WHERE THE DATA WERE NOT GATHERED IN A SYSTEMATIC WAY AND POST-HOC, ASSIST TIES IT, WAS SUB OPTIMAL AT BEST, VERY EXPENSIVE, AND ALSO JUST DID NOT SCALE. AND IN SOME CASES SIMPLY IMPOSSIBLE. YOU COULDN'T SOMETIMES TELL WHAT WAS MEANT BY A TERM IN ONE CASE OR ANOTHER AND ONE HAS TO GO BACK TO FIND THE PERSON WHO WROTE THE NOTE AND SAY, WHAT DID YOU ACTUALLY MEAN WHEN YOU SAID THIS? IT JUST COMPLETELY IMPRACTICAL. SO THEN WE THOUGHT, GOSH, THERE HAS TO BE A BETTER WAY TO DO THIS BECAUSE THIS IS SOMETHING THAT IF WE ARE GOING TO DEVELOP SOMETHING, AND WE CAN DEMONSTRATE THE UTILITY, IT WON'T BE VERY USEFUL UNLESS WE CAN DISSEMINATE IT TO THE COMMUNITY AND ACROSS RARE DISEASES. THE GENERALIZE SOLUTION. AND THIS WAS NOT A GENERALIZE SOLUTION. SO WE DECIDED WE WOULD WORK QUITE HARD ON THE COMMON DATA ELEMENT ISSUE BECAUSE THAT WOULD HELP US TO BE OR TO DEVELOP A FRAMEWORK INTO WHICH THESE OBSERVATIONS COULD GO. AND THAT THE SPECIFIC DISEASES SHOULD INSTITUTION LIES THESE STANDARDS IN ORDER TO ENSURE THAT IT WILL BE POSSIBLE TO MIX THE DATA AND COMPARE THE DATA GOING FORWARD. SO, WE JUST A FEW MONTHS AGO TRANSITIONED TO A NEW PHASE, WHICH WE CALLED VERY SIMPLY, RADAR. RADAR SIMPLY MEANS RARE DISEASE REGISTRY. SO YOU'LL HAVE TO FORGIVE THE THINGS THAT COMES UP AGAIN, THE TORTURED ACRONYM. IT'S A TORTURED ACRONYM BUT WE LIKE THE VISUAL OF WHAT IT IS SUPPOSED TO DO. SO, SOME THINGS ARE AVAILABLE ON THE WEBSITE ALREADY, THE GUID, INFORMED CONSENT TEMPLATES, ET CETERA. WE LEARNED A LOT OF THINGS LIKE ALL EXPERIMENTS. SOME EXPERIMENTS WORK GREAT SOME WORK A LITTLE, SOME DON'T WORK AT ALL. AND I WOULD SAY THIS WORKED REASONABLY WELL BUT CLEARL IT WAS NOT GOING TO BE ABLE TO GO TO THE NEXT LEVEL. SO WE DID WHAT YOU ALWAYS DO. YOU GO BACK AND LEARN AS MUCH AS YOU CAN AND TRY A NEW APPROACH AND THAT IS WHAT WE ARE DOING. THE OTHER THING TO REALIZE IS A LOT HAPPENED SINCE 2010 IN THE INFORMATICS FIELD. AND SO WE WANTED TO BE ABLE TO TAKE ADVANTAGE OF THOSE DEVELOPMENTS AS WELL. I WANTED TO REMIND YOU THAT THE TOOLKIT, WHICH CAME OUT LAST SEPTEMBER, WHICH YOU HEARD ABOUT BEFORE, HAS AS ITS LARGEST SECTION, IN THE TOOLKIT ON PATIENT REGISTRY. SO TOOLS FOR FOLKS TO USE TO DEVELOP PATIENT REGISTRIES. I'M NOW GOING TO EMBARRASS PETRA KAUFMAN BY SHOWING YOU A REALLY GREAT VIDEO THAT WE JUST PUT OUT EXPLAINING NCATS PROGRAMS. >> AT THE NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES OR NCATS, WE HAVE A NUMBER OF PROGRAMS THAT ARE FOCUSED ON MAKING A DIFFERENCE FOR RARE DISEASES. THEY ARE ABOUT 7000 RARE DISEASES. WE HAVE A TREATMENT FOR LESS THAN 5%. MOST OF THEM EFFECT CHILDREN. THE INVESTMENT THAT HAS BEEN MADE INTO RARE DISEASES RESEARCH IS NOT REALLY SUFFICIENT TO BRING MORE TREATMENTS TO MORE PATIENTS. THE GENETIC AND RARE DISEASES INFORMATION CENTER IS A ON LINE PLATFORM THAT PROVIDES ONE-STOP, HIGH-QUALITY INFORMATION TO THE PUBLIC, TO PATIENTS TO, RESEARCHERS. IT HAS IN-DEPTH INFORMATION BUT ALSO LINKS TO OTHER ORGANIZATIONS AND FURTHER RESOURCES. THE TOOLKIT FOR PATIENT-FOCUSED THERAPY DEVELOPMENT WAS BORNE OUT OF MANY INTERACTIONS WITH PATIENT GROUPS WHO WANTED TO EXCHANGE KNOWLEDGE, EXCHANGE BEST PRACTICES, SHARE KNOW HOW SO IT WOULD BE EASIER FOR PATIENT GROUPS AT DIFFERENT STAGES IN THE PROCESS TO ENGAGE WITH A THERAPY DEVELOPMENT PROCESS. WE DIVIDED THE PROCESS UP INTO FOUR PHASES. ONE IS DISCOVERY RESEARCH, ONE GETTING READY FOR CLINICAL TRIALS, IMPLEMENTING CLINICAL TRIALS AND WHAT HAPPENS ONCE THE TRIAL IS DONE AND PEOPLE TOLD US THAT THEY FOUND IT VERY USEFUL IN THEIR QUEST TO FIGURE OUT HOW TO BEST ADVANCE RARE DISEASES RESEARCH IN THEIR DISEASE. WE HAVE A PROGRAM THAT IS CALLED, THE RARE DISEASES CLINICAL RESEARCH NETWORK OR RDCRN. THIS IS A GROUP OF CONSORTIA, EACH OF THEM WORKS ON AT LEAST TWO OR THREE RARE DISEASES AND THEY FOLLOW THE SAME PROTOCOLS, THE SAME METHODOLOGY, THE SAME DATA MANAGEMENT FRAMEWORK BY ALL COLLABORATING WITH ONE DITA MANAGEMENT CENTER THAT WE FUND. WE HAVE IN FACT AT LEAST ONE PATIENT GROUP BE PART OF EACH OF OUR NETWORKS AND ALL THE PATIENT GROUPS TOGETHER IN TURN, FORM A COALITION OF PATIENT GROUPS AND EXCHANGE KNOW HOW, EXCHANGE BEST PRACTICES. THE RDCN HAS STUDIED 200 RARE DISEASES, TRAINED OVER 200 RARE DISEASES RESEARCHERS, AND HAS ENROLLED OVER 40,000 PATIENTS. THE THERAPEUTICS FOR RARE AND NEGLECTED DISEASES PROGRAM AT NCATS HAS WORKED WITH MANY PATIENT GROUPS WITH MANY INDUSTRY PARTNERS, WITH MANY ACADEMIC RESEARCHERS, AND REALLY ADVANCED PROGRAMS TO HELP THEM WITH METHODS, INFRASTRUCTURE, RESOURCES, THAT CAN BRIDGE A GRAP THAT HAS OCCURRED THAT CAN GET THEM ACROSS A BOTTLENECK IN THEIR PRE-CLINICAL DEVELOPMENT SO THAT IN PARTNERSHIP, THEY CAN MOVE THIS THERAPY DEVELOPMENT INITIATIVE FORWARD AND THEY CAN GET IT INTO THE CLINICAL PHASE AND DERISK IT SUFFICIENTLY SO THAT IT CAN BE TAKEN UP BY OTHERS. THE NCATS BRINGS THE INFRASTRUCTURE, THE RESEARCH RESOURCES, THE METHODS, THE KNOW HOW ACROSS-THE-BOARD FOR ANY INDICATION, AND THE PARTNERS BRING THE KNOWLEDGE OF THE PARTICULAR DISEASE, BRING THE QUESTION, BRING THE UNMET NEED TO THE PROGRAM. THE RARE DISEASES REGISTRY PROGRAM OR RADAR, IS MEANT TO HELP RARE DISEASES COMMUNITIES WITH ESTABLISHING REGISTRIES. REGISTRIES ARE VERY IMPORTANT. THEY HELP US UNDERSTAND WHERE PATIENTS ARE, HOW MANY PATIENTS THERE ARE TO SOME DEGREE AND THEN ALSO WHAT SYMPTOMS THEY HAVE AND HOW THEIR DISEASE PROGRESSES. THERE IS GREAT OPPORTUNITY RIGHT NOW TO MAKE A DIFFERENCE FOR RARE DISEASES. WE UNDERSTAND IN MANY CASES WHAT CAUSES THEM AND WE KNOW ENOUGH ABOUT THE BIOLOGY TO MAKE A DIFFERENCE. >> CHRIS: SO YES, PETRA! [ APPLAUSE ] SO LASTLY, ON THE EDUCATION SIDE, THIS IS A REALLY INTERESTING DEVELOPMENT THAT I'M HOPING THAT A LOT OF YOU WILL FIND HELPFUL IN YOUR OWN WORK. SO, AS YOU ALL KNOW, MANY PERHAPS MOST STAKEHOLDERS ARE UNAWARE OF HOW COMPLEX MAKING A NEW THERAPEUTIC INTERVENTION IS, A DRUG, DEVICE, ET CETERA. AND WE HAVE BEEN BEE DEVILED BY THE CHEVRON DIAGRAM WHICH I USE AND LOTS OF OTHER PEOPLE USE, TO EXPLAIN THIS, BECAUSE WE REALIZE REALIZED THAT THOUGH WE TEND TO THINK OF IT AS A CONVENIENT SHORTCUT, PEOPLE TAKE IT LITERALLY. AND THE WORD, PIPELINE, CANOTES A NORMAL PERSON, THAT MATERIAL GOES IN ONE END, COMES OUT THE OTHER END UNCHANGED AT A RATE WHICH IS DEPENDENT ONLY ON THE LENGTH OF THE PIPE AND THE CAGE; WHICH IS COMPLETELY INACCURATE DESCRIPTION OF HOW DRUG DEVELOPMENT ACTUALLY WORKS. BUT WE FIND IT, THE MORE WE TALK TO PEOPLE, THE MORE WE REALIZE THAT POLICYMAKERS AND SCIENTISTS AND PHYSICIANS ACT ON THAT TERMINOLOGY THAT WE HAVE TAUGHT THEM. SO, WE DECIDED WE NEED TO TRY TO DO SOMETHING ABOUT THIS. AND THIS PARTICULAR EFFORT HAPPENED THROUGH AN ACTION COLLABORATIVE OF THE NATIONAL ACADEMY OF SCIENCE ENGINEERING AND MEDICINE, THIS USED TO BE THE IOM. IT'S NOW THE NASEM FORUM ON DRUG DISCOVERY, DEVELOPMENT AND TRANSLATION, THAT I, SHARON TERRY, I GUESS JEFF YOU WERE PART OF IT AT ONE POINT. I DON'T KNOW IF ANYBODY ELSE ON THE COUNCIL IS CURRENTLY ON THIS FORUM. IT'S AN INCREDIBLY GROUP OF PEOPLE ACROSS INDUSTRY, NON PROFITS, PHARMA, ET CETERA. AND YOU CAN READ HOW THIS HAPPENED IN THE PAPER, BUT ESSENTIALLY WHAT WE DID WAS, WE STARTED OUT WITH A MAP THAT SHARON TERRY AND HER GROUP HAD DEVELOPED AT GENETIC ALLIANCE BACK IN 2011, I THINK. SOMETHING LIKE THAT. AND SAID, CAN WE BUILD ON THAT VERSION 1.0 MODEL? AND THEN BEGIN TO DO WHAT HAS HAPPENED IN GOOGLE MAPS, THAT IS THE ORIGINAL MAP AND ORIGINAL PAPER MAP IS VERY USEFUL. IT TELLS YOU HOW TO GET FROM POINT A TO POINT B. BUT EVEN MORE USEFUL IF YOU COULD HAVE A GPS FUNCTION TO TELL YOU WHERE YOU ARE ON THE MAP AND IF THERE IS TRAFFIC. SO IT CAN TELL YOU WHAT STEPS ARE PRETTY EASY. WHAT STEPS ARE PRED PRETTY HARD AND WHAT STEPS ARE REALLY HARD. SO GREEN, YELLOW, RED. SO THAT IS WHAT WE DID. WE CREATED A MAP AND THEN CROWD SOURCED THROUGH THE INPUT OF ABOUT 40 PEOPLE WHO WE BROUGHT INTO THIS, ALL THE PEOPLE ON THE FORUM THAT A BUNCH OF PEOPLE WHO WERE NOT ON THE FORUM, THREW THE AUSPICES OF THE IOM, TO BEGIN TO DEVELOP NOT ONLY A MORE DEVELOPED MAP BUT A MAP FOR SMALL MOLECULES, ONE FOR BIOLOGICS AND TO OVERLAY THE PARTICULAR STEPS THAT ARE PARTICULARLY PROBLEMATIC IN TIME, RISK OR FAILURE OR COST. AND THESE ARE NOW PUBLISHED -- TWO PAPERS, ONE IN NATURE'S REVIEW DRUG DISCOVERY AND ONE IN CLINICAL TRANSLATIONAL SCIENCE JUST LAST MONTH RIGHT BEFORE CHRISTMAS. AND THIS IS WHAT THE MAP LOOKS LIKE. THERE ARE TWO THINGS I WANT YOU TO TAKE FROM THIS. THIS IS THE SMALL MOLECULE MAP. I WANT YOU TO TAKE FROM THIS, FIRST OF ALL, FROM A STANDPOINT FROM THE BACK OF THE ROOM, AND YOU CAN'T READ THIS, THIS IS ON PURPOSE. THIS IS NOT A SIMPLE PROCESS. THAT ALONE, THAT'S THE POINT. THIS IS NOT A CHEVRON. NOW EACH OF THESE COLORS ARE DIFFERENT NEIGHBORHOODS WHICH CORRESPOND IN A DIFFERENT DIAGRAM IN THE PAPER TO THE CHEVRONS. SO THE CHEVRON HAS THESE COLORS AND THEN EACH OF THESE NEIGHBORHOODS HAVE THE SAME COLORS BUT SHOWS YOU HOW IT WORKS AND THEN I DON'T HAVE IT HERE BUT THERE IS A TRAFFIC MAP VERSION OF THIS. SO, WE DID TWO THINGS WITH THIS. ONE IS THAT WE MADE IT OR PUBLISHED UNDER A CREATIVE COMMONS LICENSE SO THE WHOLE IDEA SHEAR THAT PEOPLE WOULD BE ABLE TO DOWNLOAD THIS THING AND SUBSTANCE IT ON THEIR OWN WEBSITES, MODIFY IT, USE IT, WHATEVER THEY WANT, AND DIFFERENT ORGANIZATIONS WILL USE IT IN DIFFERENT WAY AND GENETIC ALLIANCE HAVE ALREADY DONE THIS. WE HAVE DONE THIS ON OUR WEBSITE AND EYE NUMBER OF OTHER PLACES HAVE DONE THIS ALREADY. AND THE SECOND THING WE ARE BEGINNING TO DO, IS TO PUT ON THIS WHAT IS DIFFICULT BUT TO GET A SENSE OF TIME AND COST. NOTICE THE PROBLEM HERE IS THE ARROWS ARE ALL EQUIVALENT LENGTH. SO WHETHER IT TAKES YOU A PROJECT ONE YEAR OR A WEEK, THE ARROWS LOOK THE SAME. AND NO WAY TO LOCATE YOURSELF WITH AN NCATS PROGRAM. SO WE WANT TO HAVE A BRIEF SURVEY. WE WANT TO BE ABLE TO GO TO THIS THING AND FILL OUT A BRIEFING AND IT WILL TAKE YOU LIKE A GPS. YOU ARE HERE. WHAT YOU NEED TO DO IS THIS AND THIS AND THIS AND HERE IS AN NCATS PROGRAM THAT YOU CAN APPLY TO TO MAKE THAT HAPPEN. AND WE THINK THIS IS GOING TO BE EXTREMELY USEFUL FOR EDUCATIONAL PURPOSES, FOR PEOPLE TO NAVIGATE WHAT NCATS DOES. AND IMPORTANTLY FOR DECIDING WHAT WE ARE GOING TO WORK ON. BECAUSE THE AREAS THAT ARE RED ON THE TRAFFIC MAP ARE THE AREAS THAT WE HAVE TO WORK ON. THE GREEN AREAS WE WANT TO WORK ON. THEY ARE NOT RATE LIMITING STEPS IN THE PROCESS. SO VERY EXCITING DEVELOPMENT. IT WAS TWO YEARS IN COMING. SO, WE DON'T HAVE TIME FOR DISCUSSION BUT I'LL TAKE ONE QUESTION, MAYBE A FEW QUESTIONS AND THEN WE HAVE TO GET ON TO THE CAN DISCUSSION. GO AHEAD. >> IT'S NOT A QUESTION. IT'S A GREAT COMMENDATION FOR THE MAP. IT'S EXCEPTIONALLY USEFUL AND WE ARE FINDING IT AS A GREAT ROADMAP FOR OUR INVESTMENTS. SO THANK YOU FOR DOING THAT. I THINK THERE IS LOTS MORE THAT WE CAN DO IN TERMS OF DETAILS LIKE GOOGLE MAP AND FOR DEVICES AND OTHER THINGS AS WELL. >> CHRIS: AND I WANT TO COME BACK TO WHERE I STARTED. IF YOU LOOK AT THE AUTHORS OF THIS THING, IT REALLY IS AN EXCELLENT PART OF HOW NCATS THINGS. JOHN WAGNER AT TEKAEDA, ANDY WHO IS AT LILI, LYNNE HUDSON AT CRITICAL PATH, SHARON TERRY WHO IS AT GENETIC ALLIANCE. RUSS AT MAB AT STANFORD, TERRY WHO IS AT NCATS EUCHARIST WHO USED TO BE AT THE IOM AND MYSELF. SO THIS IS A VERY DIVERSE GROUP OF PEOPLE. THAT IS WHY THIS WORKS. THE OTHER THING I SHOULD SAY IS ONE OF THE THINGS WE DISCOVERED HERE IS THAT UNLIKE IN A NORMAL TRAFFIC MAP, AREAS OF RED CAN DIFFER DEPENDING ON THE SECTOR YOU'RE IN. SO PREINDGLP TOX IS A GREAT EXAMPLE F YOU'RE IN A COMPANY THAT IS TRIVIAL. THAT'S GREEN. IF YOU'RE IN ACADEMIA, THAT IS BRIGHT, DARK RED. SO ANOTHER THING WE WILL DO IS DEVELOP SECTOR-SPECIFIC AREAS. >> CAN I MAKE A COMMENT? I THINK USEFUL AND EXCITING EXERCISE TO GO THROUGH AND PUTS THEM ON REALITY. WHAT THE REAL EXPERIENCE IS VERSUS THE MASS ACTION BELIEF OF THE DEVELOPMENT AND WHAT NOT, WHICH I THINK IS VERY CRITICAL. I DO THINK THAT, AND HAVING GONE THROUGH THE DETAILS OF THE PAPER, BUT DISTINGUISH DIFFERENT PATHS THAT MAY BE AVAILABLE IN DIFFERENT DISEASE SETTINGS. IT'S NOT ALWAYS A ONE-SIZE-FITS-ALL AND I DON'T KNOW TO THE EXTENT THAT THAT HAS BEEN DONE THERE. BECAUSE IT COULD SHOW UP COMPARE AND CONTRAST WHERE THERE COULD BE CROSS-LEARNING AS THINGS BECOME MORE PLATFORM-BASED FOR ADDRESSING ISSUES THAT ARE COMMON TO ONE DISEASE AND COULD BE APPLIED TO OTHERS. BUT THE OTHER THING TOO THOUGH, IS MANY PEOPLE IN DIFFERENT COMPANIES, DIFFERENT SETTINGS ARE TRYING TO BLOW THAT UP AND ACTUALLY REINVENT IT. AND BASED ON ALL THE LEARNING. AND I THINK THAT'S THE TREMENDOUS OPPORTUNITY FOR WORK GOING ON HERE AT NCATS BECAUSE AS I LOOK AT THAT, A LOT OF THAT COMPLEXITY IS BUILT AROUND NOT HAVING INNOVATIVE SOLUTIONS TO THINGS THAT REQUIRE A LOT OF UNKNOWN TRANSLATIONAL PREDICTIVE ABILITY. THE LACK OF DEPLOYING COMPUTATIONAL AND INFORMATION-BASED APPROACHES, LACK OF TOOLS SUCH AS TISSUE CHIP PROGRAM WHICH THAT COULD DO TO REALLY SYNC UP AND ELIMINATE A LOT OF THE ITERATIVE PROCESS THAT IS CONSUMING IN TERMS OF OPERATIONAL COMPLEXITY AND COST AND TIME. SO I THINK THERE IS A TREMENDOUS OPPORTUNITY TO USE THAT AS A BASELINE FOR THE TRANSFORMATION STRATEGY THAT COULD BE REALIZED THROUGH MANY OF THE GREAT THINGS THAT YOU AND YOUR TEAM ARE WORKING ON. >> AND I KNOW WE ARE RUNNING OUT OF TIME, PERHAPS, BUT JUST BUILDING ON WHAT ALAN WAS SAYING. YOU DON'T WANT ANOTHER FIGURE TO TAKE PLACE AT THE CHEVRON DIAGRAM AND BECOME A FIXED ENTITY. SO, PEPPERING THIS WITH REAL-LIFE EXAMPLES WHERE YOU HAVE GONE OUTSIDE OF THE BOX AND STILL MADE THE MEDICINE AND DELIVERED IT MIGHT BE USEFUL AND A SECOND SUGGESTION WOULD BE YOU SAID, FOR ACADEMIC SCIENTISTS IF THEY ARE IN THE TOX SPACE, IT IS FULLY RED. WHY NOT PUT A LIST OF CROs? BECAUSE THESE ARE REALLY THE -- MOST DRUG COMPANIES WORK WITH CROs THEY DON'T DO THIS WORK INTERNALLY ANYWAY WAY. >> IT'S A RESOURCE ISSUE IS WHAT IT IS. >> IT'S A GREAT START. >> IN ORDER TO KEEP OUR SPEAKERS ON TIME, THEY HAVE FLIGHTS TO CATCH, WE WILL HAVE TO CHANGE THE AGENDA SO THAT INSTEAD OF MOVING TO THE CAN UPDATE, WE WILL MOVE TO THE TISSUE SHIP VALIDATION CENTERS UPDATE WITH DAN AND OUR TWO SPEAKERS. >> GOOD MORNING, EVERYONE. SO FROM THE CANNERY VIEW BOARD BOARD MEETING IN DECEMBER WE WERE ASKED TO GIVE AN UPDATE AT THIS COUNCIL MEETING ON THE TISSUE CHIP VALIDATION CENTERS. AND SO WE HAVE THE PRIVILEGE OF HAVING TWO OF OUR PRINCIPAL INVESTIGATORS TO COME AND JOIN US FOR THIS PRESENTATION. SO JUST TO GIVE YOU A BRIEF BACKGROUND IN WHAT THE TISSUE CHIP DRUG SCREENING PROGRAM IS ABOUT, THIS CAME ABOUT BACK IN 2012 ACTUALLY THE FIRST PROGRAM THAT IS FUNDED AND SUPPORTED THROUGH THE CURES ACCELERATION NETWORK. IT CAME ABOUT AS MANY OF YOU ARE AWARE OF THE DIRE NEED TO ADDRESS THE ISSUE OF DRUG DEVELOMENT AND CERTAINLY IN TERMS OF ATTRITION. SO THE FAILURE TO PREDICT EFFICACY AND SAFETY DURING DRUG DEVELOPMENT ACCOUNTS FOR ABOUT 90% OF DRUG FAILURES. AND SO WHAT OUR GOAL IS IN THE TISSUE CHIP PROGRAM IS TO DEVELOP IN-VITRO PLATFORMS THAT USES HUMAN CELLS AND TISSUES THAT SHOULD BE MORE REPRESENTATIVE OF HUMAN RESPONSE TO DRUGS. SO IN SOME WAYS BEING ABLE TO PREDICT BOTH THE SAFETY AND EFFICACY OF PROMISING THERAPIES. OVER THE COURSE OF THE FIVE YEARS THE PROGRAM RAN IN 2012, THE INVESTIGATORS WERE ABLE TO COME UP WITH VARIOUS ORGAN SYSTEMS ON CHIPS LISTED HERE, AND ESSENTIALLY OUR GOAL IN THIS PROGRAM IS OF COURSE TO MAKE THIS RELEVANT TO REPRESENT GENETIC DIVERSITY AND OF COURSE TO HAVE MEANINGFUL PATHOLOGICAL READ OUTS AS WELL. IT'S MODULAR AND IT RECONFIGURABLE SO COMBINE MULTIPLE ORGAN CHIPS TOGETHER TO FORM MULTIORGAN SYSTEMS. THE VIABILITY OF 28 DAYS AND AT THE END WE WANT THIS TO BE AVAILABLE COMMUNITY-WIDE ACCESS AND USE AND THIS IS WHERE THE TISSUE CHIP VALIDATION CENTERS COME IN. SO OUR PROGRAM ESSENTIALLY HAVE BEEN RUNNING FOR FIVE YEARS AT LEAST THE NIH SIDE OF THINGS. THE FIRST TWO YEARS OF THE PROGRAM WERE DEDICATED FOR PLATFORM DEVELOPMENT SO THERE IS A MULTIDISCIPLINARY GROUP OF INVESTIGATORS CONSISTING OF BIOENGINEERED, STEM CELL BIOLOGISTS, PATHOLOGISTS, TOXICOLOGISTS, AND SO THE PLATFORM AND THE CELLULAR RESOURCES WERE GENERATED DURING THE FIRST TWO YEARS AND THEN INDIVIDUAL ORGANS ON CHIPS WERE MADE AND THEN THE LAST THREE YEARS OF THE PROGRAM WAS DEVOTED TO FUNCTIONAL VALIDATION, THAT IS TO DO THE ORGANS AND CHIPS, DO MIMIC PHYSIOLOGICAL RESPONSE AS WELL AS REACTION OR RESPONSE TO TRAININGS OR COMPOUNDS TO SHOW THEY COULD BE USEFUL FOR DRUG DEVELOPMENT. AND THEN ALSO IN MULTI-ORGAN INTEGRATION. FOR THE TRAININGS COMPOUNDS, NCATS PARTNERED WITH ASTRAZENECA AND PFIZER TO PROVIDE ABOUT 120-SOMETHING COMPOUNDS THAT THE INVESTIGATORS HAD ACCESS TO AND USED THEM FOR VALIDATION WITHIN THEIR OWN INDIVIDUAL LABORATORIES. THIS IS ALSO A PARTNERSHIP WITH OTHER AGENCIES, ESPECIALLY WITH DARPA. SO THE NIH, THROUGH CAN, THE CURES ACCELERATION NETWORK AND THE COMMON FUND AND PARTNERSHIPS WITH OTHER INSTITUTES AND CENTERS AT THE NIH, NIBIB, NIEHS, THE OFFICE OF WOMEN'S RESEARCH AND NCI, PITCHED IN TO INVESTMENT OF OVER 75 MILLION DOLLARS OVER FIVE YEARS. DARPA PUT IN ABOUT 75 MILLION DOLLARS OVER FIVE YEARS. THEIR FOCUS WAS PRIMARILY ON THE END GOAL OF GETTING THIS 10-ORGAN PLATFORM LINKED TOGETHER. SO MORE ON THE BIOENGINEERING ASPECTS AND THE NIH SIDE WAS MORE ON THE BIOLOGY SIDE OF THINGS AND THE FDA RECOGNIZING THE KEY PLAYER IN THIS FIELD, WE ENGAGED THEM RIGHT FROM THE BEGINNING THE PROGRAM TO PROVIDE INSIGHT AND EXPERTISE THROUGHOUT THE PROGRAM EVEN THOUGH THEY WERE NOT FUNDING PARTNERS, THEY WERE VERY CRITICAL PARTNERS INTO THIS PROGRAM. IT IS A MILESTONE-DRIVEN PROGRAM SO THERE HAVE BEEN ATTRITION. IF THEY FAIL TO MEET MILESTONES, AND IT HAS BEEN CERTAINLY LARGELY PRODUCTIVE IN PRODUCING A NUMBER OF ORGAN CHIPS AND A NUMBER OF PUBLICATIONS. AS OF OCTOBER 2017, RIGHT AT THE END OF THE PROGRAM, ABOUT OVER 500 PUBLICATIONS THAT HAVE COME OUT, TOP 10 PUBLICATIONS THAT HAS BEEN CITED HAVE COME OUT OUT OF NATURE, MEDICINE, NATURE COMMUNICATIONS, NATURE MATERIALS, AND SCIENCE TRANSLATIONAL MEDICINE. JUST TO GIVE YOU A SENSE WHAT HAVE THIS ORGANS ON CHIPS OR TISSUE CHIPS LOOKS LIKE, THESE ARE NOT JUST REGULAR 3D CELLS IN CULTURE. THEY ARE NOT ORGANOIDS. WHAT MAKES THEM DIFFERENT IS THAT THEY ALSO HAVE THEIR ABILITY TO REPRESENT BIOMECHANICAL PROPERTIES ON THE TISSUE. SO AN EXAMPLE OF THAT IS IN THIS ALPHO LIE ON A CHIP WHERE YOU THE AIR SACKS EXPANDING AND CONTRACTING AS AN INDIVIDUAL TAKES IN AIR. SO IN RECONSTRUCTED TISSUE ON A CHIP, THE LUNG ON A CHIP, THIS IS WHAT THAT LOOKS LIKE WHERE YOU HAVE CYCLIC VACUUMING AND STRETCHING OF THE LUNG EPITHELIAL CELLS IN THIS SCENARIO. ANOTHER DISTINCTIVE OF THE ORGANS ON CHIPS WOULD BE MICROVASCULATURE EITHER DONE THROUGH AN ACTUAL -- I GUESS IT'S NOT PLAYING. BUT THIS IS MICROVASCULATURE ON A CHIP WITH THE ONE MICRON BEADS COURSING THROUGH IT AND FLOWING. AND THEN THE OTHER ASPECTS ABILITY TO INNOVATE SOME OF THESE ORGANS. SO SO FAR, THE SKIN AND IN THIS CASE, THE GUT, HAS BEEN AGGRAVATED WHICH WOULD UNDERGO PAIR STALL SIS. ANOTHER UNIQUE FEATURE IS THE ABILITY TO DO ON LINE REALTIME BIO-SENSING CAPABILITIES. SO WHAT IS SHOWN IS HEPATOCYTES GOING FROM RED TO GREEN INDICATING FOR EXAMPLE APOPTOSIS AS A CONSEQUENCE OF COMPROMISED MITOCHONDRIAL MEMBRANE PERMEABILITY RESULTING FROM INCREASE IN RADICAL OXYGEN SPECIES GENERATION. THERE HAS BEEN A NUMBER OF PLATFORMS THAT HAVE BEEN DEVELOPED UNDER THIS PROGRAM SO THIS IS THE LUNG ON A CHIP IS THIS. THIS WILL BE THE MICROVASCULATURE, THIS BON, THERE IS ALSO THE KIDNEY ON A CHIP AND AS SHOWN HERE, TWO EXAMPLES OF INTEGRATED ORGAN SYSTEMS. THIS IS THE FEMALE REPRODUCTIVE SYSTEM WITH THE FALLOPIAN TUBE, OVARY, UTERUS, CERVIX AND ALSO LINK WITH THE LIVER. AND THIS IS ALSO LIVER, SKIN, MUSCLE, MICROVASCULATURE AND HEART. AND SO YOU CAN SEE THAT THERE IS A QUITE DIVERSITY OF BIOENGINEERED PLATFORMS IN SOME WAYS COMPLEX ENGINEERED PLATFORMS AND SO IN SOME WAYS IT IS QUITE A TALL ORDER FOR THE VALIDATION CENTERS TO TRANSFER TECHNOLOGY TOW THEIR SITE SO THAT IS ONE OF THE HURDLES THAT NEEDS TO BE TAKEN AND SO ONE OF THE CAVEATS IN THIS VALIDATION IS THAT THEY -- WE HAVE TO TAKE A SNAPSHOT OR STATIC POINT BY WHICH THIS TISSUE CHIP PLATFORMS WILL BE EVALUATED SINCE THE PLATFORMS CONTINUE TO EVOLVE AND RAPIDLY DEVELOP. WE HAVE AS I HAVE SAID, ENGAGED WITH THE FDA AND SO THIS IS FROM PAUL BROWN IN TERMS OF WHAT WE ARE FOLLOWING IN TERMS OF PRINCIPLES FOR VALIDATION. THIS IS FROM THE OECD GUIDANCE DOCUMENT AND VALIDATION AND INTERNATIONAL ACCEPTANCE AND INCLUDES ANYTHING FROM ASSAY, DETAILED PROTOCOLS, TEST METHODS BEING DEMONSTRATED, AND A NUMBER OF DIFFERENT THINGS THAT NEEDS TO BE ADHERED TO TO REALLY GET THEM VALIDATED. SO WHAT WE CAME UP WITH IS ESSENTIALLY TISSUE CHIP VALIDATION FRAMEWORK WHICH WILL BE AT THREE LEVELS. THE FIRST ONE WAS DONE AND CONDUCTED BY THE TISSUE CHIP DEVELOPERS AS SHOWN HERE. THIS IS THE PHYSIOLOGICAL VALIDATION, MEANING LOOKING AT THE ORGAN FUNCTION AND STRUCTURE AND DO THEY REALLY MIMIC THE ORGAN SYSTEM OR TISSUE SYSTEM THAT THEY ARE DEPICTING OR MIMICKING? AND ALSO TRAINING A SET OF COMPOUNDS WHETHER THEY WOULD ACTUALLY PROVIDE THE RIGHT OR APPROPRIATE RESPONSE TO THE SET OF COMPOUNDS. THE SECOND STAGE IS THE ANALYTICAL VALIDATION AND WE AIM THIS TO BE INDEPENDENT SO THAT MEANS WHATEVER THE TISSUE CHIP DEVELOPERS HAVE DONE WILL BE TO TRANSFER THE TECHNOLOGY TO THE ANALYTICAL VALIDATION SITES AND IT'S INDEPENDENT TO DEMONSTRATE ROBUSTNESS, REPRODUCIBILITY AND RIGOR. AND THIS IS DONE WITH A VALIDATION SET OF COMPOUNDS AND GENERALLY DONE THROUGH A TESTING CENTER WHICH NCATS SET UP. THE LAST STAGE OF VALIDATION IS WHAT WE CONSIDER THE INDUSTRIAL VALIDATION. IT IS ULTIMATE STABLING WHERE INDUSTRY AND HOPEFULLY A REGULATORY AGENCY WILL BE ABLE TO EMBRACE TECHNOLOGY AND THEN START USING THEM INTO THE DRUG DEVELOPMENT PIPELINE IN A SET OF COMPOUNDS AND COULD BE DONE IN A CRO-TYPE ENVIRONMENT. THIS IS CERTAINLY IN LINE WITH OUR EVENTUAL GOAL OF DISSEMINATING THIS TECHNOLOGY EITHER THROUGH ADOPTION BY THE SCIENTIFIC COMMUNITY OR COMMERCIALIZATION. AND CERTAINLY FALLS THE PRINCIPLES OF 3Ds BY NCATS TO DEVELOP THE TECHNOLOGY TO DEMONSTRATE ITS UTILITY AND THEN EVENTUALLY TO DISSEMINATE. SO IN TERMS OF THE VALIDATION SET OF COMPOUNDS, WE HAVE CONTINUED OUR PARTNERSHIP WITH THE FDA AND ALSO ESTABLISHED A PARTNERSHIP WITH THE IQ CONSORTIUM MADE UP OF SEVERAL PHARMACEUTICAL COMPANIES AND THE IQ AND THE FDA CAME UP WITH A SET OF PROPOSED BIOMARKERS, ASSAYS, AS WELL AS VALIDATION COMPOUNDS FOR EACH OF THE ORGAN SYSTEMS BEING TESTED. THIS IS THEN LED TO THE FORMATION OF THE TISSUE CHIP TESTING CENTERS, WHICH ARE RESOURCE CENTERS THAT WAS ESTABLISHED AND AWARDED JUST IN SEPTEMBER OF 2016. SO THE TESTING CENTERS ARE IN OPERATION FOR A LITTLE OVER A YEAR NOW AND AS I MENTIONED BEFORE, THEY HAVE THE GOAL OF PROVIDING INDEPENDENT, ANALYTICAL VALIDATION AND TISSUE CHIP PLATFORMS. AND I ALREADY MENTIONED THAT THE FDA AND IQ ARE CRITICAL MEMBERS IN TERMS OF PROVIDING GUIDANCE ON THE VALIDATION SET OF COMPOUNDS ASSAYS AND BIOMARKERS. THE TESTING CENTERS AND AGAIN, QUITE THE GREAT OPPORTUNITY TO HAVE AND WELCOME MURAT, FROM MIT, ONE OF THE PIs FROM ONE OF THE TESTING CENTERS AND THEN WHAT WE DON'T HAVE AT THIS STAGE IS THE DATABASE THAT WILL BE A PUBLIC DATABASE BUT THAT WILL BE SOMETHING THAT WE WILL BE ONCE IT IS MORE POPULATED, CERTAINLY WE WOULD WELCOME THE OPPORTUNITY TO HAVE MORE JOIN US AND PRESENT COUNCIL AND CANNERY VIEW BOARD WITH AN UPDATE. THESE ARE THE CURRENT PLATFORMS BEING TESTED RIGHT NOW. EITHER HAVE BEEN TESTED OR CURRENTLY BEING TESTED AND I'M SURE YOU WOULD WANT TO HEAR MORE ABOUT HOW THIS IS GOING AND SO WE'LL HAVE MURAT COME AND JOIN US AND GIVE HIS UPDATE. JUST BEFORE I DO THAT, BACK IN SEPTEMBER, 2017 COUNCIL, WE PROVIDED CONCEPT CLEARANCE TO RENEW FUNDING OF THIS TESTING CENTER FOR ANOTHER TWO YEARS WITH A GOAL OF MAKING THEM SELF SUSTAINING AFTER N CAT SUPPORT. AND SO, THE RFA HAS BEEN OUT AND APPLICATION RECEIVED DATE IS MARCH 21. WE HOPEFULLY WILL BE BRINGING BACK TO YOU YOUR CONCURRENCE FOR A RECOMMENDATION TO FUND THE APPLICATIONS THAT HAVE BEEN SCIENTIFICALLY MERITORIOUSLY REVIEWED PROBABLY IN SEPTEMBER 2018 COUNCIL. SO WITH THAT, I'LL INVITE MURAT TO GIVE THE UPDATE. >> THANK YOU FOR THE INVITATION. SO I'M GOING TO TALK ABOUT THE APPLICATION OF THE TISSUE CHIP TECHNOLOGY AND SYSTEMS FOR DIFFERENT APPLICATIONS FROM TOXCOLOGY TOW PHARMACOKINETICS. SO JUST BRIEFLY, YOU CAN FOCUS ON TOXICOLOGY APPLICATIONS WITH HEALTHY CHIPS. WITH THE MOVEMENT TOWARDS MORE DISEASE MODELING, YOU CAN GO TO PHARMACODYNAMICS AND ULTIMATE GOAL OF TECHNOLOGIES IS INTRODUCING A PERSONALIZED MEDICINE AND GOING BETTER APPROACHES TO IDENTIFY THE RIGHT TREATMENT FOR RIGHT PATIENTS. AND SO FAR A LOT OF STUDY HAS BEEN DONE WITH THE SMALL MOLECULES BUT THESE TECHNOLOGIES ARE NOT LIMITED WITH SMALL MOLECULES. WE CAN EXPAND TO THERAPEUTICS. A LOT OF OPPORTUNITY IN THIS PHARMACOLOGY FIELD WITH THIS TECHNOLOGIES. JUST LOOKING AT THE DRUG DISCOVERY PIPELINE. THERE ARE DIFFERENT NEEDS AT DIFFERENT STAGES OF DRUG DISCOVERY. IF YOU'RE AT EARLIER STAGES, TARGET OF VALIDATION, THERE ARE THOUSANDS OF COMPOUNDS THAT NEEDS TO BE SCREENED THROUGH AND THERE IS SUBSET OF COMPOUNDS WILL MOVE THROUGH THE PRE-CLINICAL PIPELINE AND EVENTUALLY ONE COMPOUND WILL GO TO DEVELOPMENT PIPELINE. AND THERE ARE DIFFERENT NEEDS FOR THE THROUGH PUT NEEDS OR HIGH CONTENT INFORMATION NEEDS. CLOSER TO THE CLINICAL TRIALS YOU NEED TO UNDERSTAND THE MECHANISM OF ACTIONS BETTER WITH THESE TECHNOLOGIES AND EARLIER STAGES, THE THROUGH PUT IS MORE IMPORTANT BUT THE HIGH CONTENT FORMATION IS LESS CRITICAL. AND THEREFORE THERE IS NOT ONE SIZE FITS TYPE OF APPROACH FOR THESE SYSTEMS. DIVERSITY WILL BE REALLY IMPORTANT. A LITTLE BIT ABOUT OUR VISION AND APPROACH. BEING ON THE COMPUTATIONAL BIOLOGY BACKGROUND, WE USE THIS TYPE OF WORK FLOWS TO REALLY COMBINE THE QUANTITATIVE EXPERIMENTAL APPROACHES WITH THE COMPUTATIONAL PARADIGMS TO REALLY PREDICT CLINICAL OUTCOMES. SO WE CAN CREATE INFORMATION, GENERATE INFORMATION FROM THE TISSUE CHIPS, COMBINED WITH THE IN-VIVO INFORMATION, USE THE COMPUTATIONAL TOOLS, SOME LIKE PHYSIOLOGICALLY BASED, TO INCLUDE MISSING ORGANS OR COMPLEXITY AND ALSO THE HUMOR POPULATION VARIABILITY TO CLINICAL OUTCOMES AND I WILL SHOW COME EXAMPLES OF DIFFERENT CHIPS HOW WE BUILD THIS TYPE OF COMPUTATIONAL TOOLS ALONG WITH THE QUANTITATIVE APPROACHES WITH THE TISSUE CHIPS. SO OUR TESTING OR VALIDATION STRATEGY IS TWO TIERS. THE FIRST IS THE TECHNOLOGY TRANSFER. WE GET THIS FROM THE DEVELOPER LAB AND THEN WE LOOK AT SOME TESTING OF THE PLATFORM TESTING, WHETHER THE PLATFORMS ARE OPERATING PROPERLY AND WE LOOK AT ALSO WHETHER THEY ARE PROPER FOR PHARMACOLOGICAL TESTING. SPECIFIC BINDING IS REALLY IMPORTANT FRONT. WE NEED TO IDENTIFY AND QUANTIFY EVERYTHING WITH THESE SYSTEMS AND IMPORTANT PART IS THE IMMEDIATE COMPOSITION MOVING INTO OUR SERUM-FREE MEDIA ALL DEFINED MEDIA COMPOSITIONS. REALLY ESSENTIAL TO UNDERSTAND THE UNBOUND DIRECT FRACTIONS SO WE CAN TRANSLATE THE INFORMATION FROM IN-VITRO TO IN-VIVO. AND OF COURSE THE BIOLOGY -- A LOT OF ASSAY DEVELOPMENT GOES INTO THAT AND WE ARE FOCUSING MAINLY CLINICAL MARKERS IF POSSIBLE FOR GIVEN ORGAN SYSTEM. ONCE WE SHOW THE REPRODUCIBILITY, WE SHARE THIS RESULTS WITH THE TISSUE CHIP DEVELOPERS AND NIH AND NCATS AND IQ CONSORTIUM AND ALSO IVAN. ONCE WE GET THE REPRODUCIBILITY WE MOVE TO TIER 2, DRUG TESTING. AND IT DEPENDS ON THE TYPE OF ORGAN WE CAN DO FARM KINETIC TESTING AND OTHER TESTING. AND THESE ARE ALL BEING COMBINED IN OUR PIPELINE. WE FINISHED FIRST THREE SYSTEMS. RIGHT NOW WE ARE IN MIDDLE OF FINALIZING THE WORK WITH THE BRAIN FROM JOHNS HOPKINS UNIVERSITY AND GUT AND CARDIAC AND WE ARE ONBOARD IN THREE MORE MPSs, TUMOR AND SKIN AND LIVER LIVER. SO SOME SNAPSHOTS FROM TESTING. DATA GENERATED FROM THESE TECHNOLOGIES AND BECAUSE OF THE TIME LIMITATION, I WILL FOCUS ON ONE TYPE OF DATA. SO A LITTLE BIT TALKING ABOUT WHAT GOES INTO TESTING. SO FIRST STEP IS THE CHARACTERIZATION AND IDENTIFICATION OF THE CELL SOURCES. IT'S REALLY IMPORTANT HOW THE ISOLATION PROCESS IS OF THESE CELLS EFFECT IN THE TISSUE CONSTRUCT FORMATION. SO WE SPEND A LOT OF TIME TO IDENTIFY THE BEST CELL SOURCES. AND THEN ASSAY DEVELOPMENT. œLOOK AT THE CLINICALLY RELEVANT METRICS N THIS CASE, KIDNEY INJURY MARKER ONE IS THE CLINICAL MAKER AND WE ALSO GET MULTIPLE METRICS SO WE CAN HAVE CORRELATIONS OF UNDERSTANDING MECHANISM OF ACTION AND CORRELATION OF DIFFERENT TECHNOLOGIES. AND WE CONDUCT TOXICOLOGY TESTING USUALLY 4-5 DRUGS. YOU LOOK AT 3-4 DOSES AND WE TRY TO DO LONGER EXPOSURE TIMES TO UNDERSTAND BOTH ACUTE AND CHRONIC TOXICITY PROFILES AND ALL OF OUR CULTURES ARE UP TO 4-WEEK CULTURE PERIODS AND IN THIS PARTICULAR KIDNEY MPS TECHNOLOGY TRANSFER, WE HAD 10 STUDIES AND WE HAD GENERATING 1500 SAMPLES AND ANALYZED ALL THE SAMPLES. IN THE TIER 1 AND TIER 2 WE LOOK AT THE 4 DRUGS AND 4 DOSES AS I DESCRIBED. SO WE WERE SUCCESSFUL WITH THIS TECHNOLOGY TRANSFER ON THE LEFT-HAND SIDE I'M SHOWING THE UNIVERSITY OF WASHINGTON PUBLICATION AND THE RESULTS FROM USING THE CHIP TECHNOLOGY ON AND YOU CAN SEE THE PROXIMAL TUBAL FORMATION AND THESE ARE THE RESULTS GENERATED IN MY LAB. AND YOU CAN SEE THE NICE TUBULAR FORMATION REALLY ROBUST SYSTEM. AND THE NEXT STEP ALSO WOULD LIKE TO UNDERSTAND IS THIS TECHNOLOGY REALLY BETTER THAN THE EXISTING 2D? WHAT IF WE TAKE THE CELLS AND THROW ON REGULAR 2D PLATES? WHAT HAPPENS? YOU JUST A SIMPLE DEMONSTRATION HERE YOU CAN SEE THE CULTURE TIME INCREASING. THAT SHOWS THAT THE CELLS ARE NOT HAPPY IN THE 2D ENVIRONMENT. THEN WE PUT THE SAME CELLS ON THE 3D ENVIRONMENT WITH THE SHEAR FLOW AND TUBULAR FORMATION, WE GET A HEALTHY TUBE FORMATION. AND FOR THE DRUG STUDY FOR THIS CASE, CADMIUM RESULTS FOR THIS, YOU CAN SEE THAT HIGHER DOSES AT EARLIER STAGES, YOU CAN DETECT HUGE RELEASE, EARLY TIME POINTS AND THIS IS IN DEVELOPMENT WITH THE CLINICAL FINDINGS. AND NOW WE ARE WORKING WITH THE TRANSLATION OF THIS INFORMATION TO WHAT WILL BE THE -- IF WE REALLY GET THIS DATA AND TAKE THE PARAMETERS AND COMBINE WITH THE PBPK MODELS. AND ANOTHER EXAMPLE IS THE BRAIN MPS. THIS IS COLLABORATION WITH UNIVERSITY OF WISCONSIN GROUP. SO WE WORK WITH MULTIPLE CELL SOURCES BUT MAINLY PROGENITOR CELLS IN THIS SYSTEM. BIOMATERIALS ARE REALLY IMPORTANT. THESE ARE THE FUNCTIONAL MATERIALS GENERATED BY BILL MURPHY'S GROUP AT UNIVERSITY OF WISCONSINED AND COMMERCIALIZED BY STEM PHARMA. SO WE USE MORE STANDARDIZED TOOLS AND BIOMATERIALS TO REDUCE THE VARIABILITY, BENCH TO BENCH VARIABILITY. WE USE INFRASTRUCTURE CMBS BIO18 PLATFORM GIVES FLOW TO THE SYSTEM AND AS A DEVELOPMENT WE LOOK AT CLINICAL METRICS, DJ1, AND MORE GENERIC METRICS AS WELL LIKE LDH. AND THEN FINISH THE STUDY WITH 5 DRUGS AND 5 DOSES WITH 14 DAYS OF EXPOSURE AND TOTAL CULTURE TIME WAS 28 DAYS. WE ALSO COMPARED WHY WE NEED A MORE COMPLEX SYSTEM. WHY WE NEED THE CELL POPULATION VERSUS A SINGLE CELL TYPE. IN THIS CASE WE USED A CDI CELL NEURON AS CONTROL GROUP AND IT IS NEARLY PURE NEURONAL POPULATION. THEN WE LOOK AT THE DEFERENCEIATED NEUROPROGENITOR CELLS. WE CAN SEE THE NEURONS AND PSCs IN THE SYSTEM AND ALL OF OUR STUDIES ARE SIDE-BY-SIDE TO SHOW WHY WE NEED THESE SYSTEMS TO GET A BETTER ANSWER. SO HERE WE HAVE SET OF DRUGS HIGHLIGHTED ON THE TUBE. ONE IS DOCETAXEL AND THE OTHER IS TAMOXIFEN. IF YOU STUDY THESE TWO COMPOUNDS IN THE 2D CULTURE, YOU DON'T SEE ANY DIFFERENCES WITH THE DJ1 RELEASE. NO TOXICITY. BUT WHEN YOU CONSTRUCT TISSUE IN THE MICROPHYSIOLOGICAL ENVIRONMENT, YOU START GETTING THE DIFFERENCES, THE PIQUE ON A HIGH DJ1 RELEASE WITH HIGH DOSES OF THE NEUROTOXIC DRUGS WHEREAS WITH THE NON-NEUROTOXIC DRUGS WE DIDN'T OBSERVE THE DJ1 RELEASE IN THE SYSTEM. ANOTHER STUDY AS I EXPLAINED, THESE ARE EARLIER STUDIES UNDER TESTING CENTER BUILDING COMPUTATIONAL TOOLS TO TRANSLATE THAT INFORMATION. AND THIS IS A WORK EARLIER DONE UNDER THE DARPA PROJECT BUT I WANT TO HIGHLIGHT WHAT WE DID WITH THE COMPUTATIONAL TOOLS. SO, WE CAN GENERATE OR LOOK AT THE DONOR-DONOR VARIABILITY IN TISSUE CHIPS. SO GET THE HEPATOCYTES FROM MULTIPLE DONORS AND STUDY THE MULTIPLE -- DIFFERENT DRUGS, PHARMA KINETICS AND GET A RESULT INCLUDING THE VARIABILITY, DONOR VARIABILITY AND RESIDUAL& VARIABILITY AND REQUIRES COMPUTATIONAL TOOLS TO UNDERSTAND THIS COMPLEX INFORMATION. SO WE USE THE NON-LINEAR MIX EFFECT MODELING TO REDUCE DIMENSIONS OF THE DATA AND THEN COMBINE WITH THE POPULATION PPBK AND WE WERE ABLE TO ACTUALLY PREDICT CLINICAL VARIABILITY IN PHASE I TRIALS. AND AS DAN MENTIONED, SYSTEM INTERVENTION IS ALSO REALLY IMPORTANT AND BEING A PART OF THE EARLIER DARPA PROGRAM INTEGRATING UP TO 10 DIFFERENT ORGANS, WE STARTED REALIZING INTEGRATION IS REALLY IMPORTANT BECAUSE THE ORGANS WHILE THEY ARE INTERACTIVE, THEY EFFECT THE SCIENTIFIC BEHAVIOR. IN THIS CASE, WHEN WE COMBINE GUT WITH LIVER, IN A PHYSIOLOGIC REPRESENTATION OF THE FLOWS, WE REALIZE THERE IS A DIFFERENTIAL CHANGE IN THE METABOLISM ACTIVITY. FOR EXAMPLE, IN THIS CASE, 1A2 AND 2D6 WERE CHANGED WITH THE INTEGRATION BUT IF YOU LOOK AT THE 3A4, IT'S BEEN DECREASED AND 2C9 BEING INCREASED AND WE VALIDATE THIS FINDING WITH THE ANOTHER STUDY, RUNNING THE PHARMACOKINETIC STUDY ON INTEGRATED SYSTEM SO WE WERE ABLE TO GET FROM THE MIXING CHAMBER WHICH IS SIMILAR TO BLOOD COMPARTMENT, WE CAN OPERATE THE SYSTEM UNDER THE PHARMACOLOGICAL CONCENTRATIONS SO NOT HIGH CONCENTRATIONS BUT REALLY WHAT HUMAN BODY SEES IN THESE DRUGS. SO, WE HAVE ALSO GETTING ALL THIS COLLECTIVE DATA GOES TO OUR INTERNAL DATABASE AT MIT. WE HAVE MULTIPLE DATABASES INTEGRATED ON THE SAME FRAMEWORK. SO WE HAVE THE SAMPLE MANAGEMENT DATABASE, ELECTRONIC LAB NOTEBOOKS TO DOCUMENT EVERYTHING THROUGHOUT THE TESTING. AND THEN THESE ALL GOES TO OUR LAB KIT DATABASE WITH EXPERIMENTAL DESIGN QUANTITATIVE DATA AND IMAGELESS. THEN WE ARE WORKING WITH UNIVERSITY OF PITTSBURGH DATABASE AND TRANSFER OUR RESULTS FROM OUR DATABASE TO UNIVERSITY OF PITHBURG TO GIVE THE COLLABORATOR AND THE PUBLIC ACCESS. SO FAR THESE ARE ALL GREAT EXAMPLES BUT THERE IS A LOT TO ACCOMPLISH IN THIS SYSTEM. THERE ARE A LOT OF CHALLENGES BUT THAT GIVES ALSO OPPORTUNITIES. ONE OF THE BIG CHALLENGES FOR PHARMA ADOPTION IS THE BROAD BIOLOGY AND PHYSIOLOGY EXPERTISE EXPERTISE. SO MULTIPLE KNOWLEDGE AROUND TISSUE ENGINEERS AND BIOLOGISTS AND ENGINEERS NEED TO COME TOGETHER TO BUILD THIS MULTI-INFRASTRUCTURE AND THAT DOESN'T EXIST IN PHARMA YET. AND THE OTHER ISSUE IS THE CELL SOURCING. THERE ARE CELLS AVAILABLE OUT THERE BUT THEY ARE NOT ALL RELIABLE. BENCH TO BENCH DIFFERENCES CAUSING A LOT OF DIFFERENCES FROM THE TESTING FOR THE BIOLOGY REPLICATES. TISSUE CULTURE MEDIUM IS REALLY IMPORTANT. RIGHT NOW YOU'RE FACING SOME ISSUES WITH BACK ORDERS WITH THE TISSUE CULTURE MEDIUM. MOST OF TISSUE CULTURE BEING MANUFACTURED IN PUERTO RICO AND RIGHT NOW WE CANNOT GET IPSC MEDIUM YET. IT'S BACK ORDER UNTIL JUNE. ASSAY DEVELOPMENT, CLINICAL ASSAY DEVELOPMENT IS REALLY IMPORTANT USING THIS TECHNOLOGIES MORE TOWARDS CLINICAL RESEARCH. PLATFORM MATERIAL WILL BE ESSENTIAL TO DO DRUG STUDIES THROUGH PUT AND AUTOMATION BECAUSE THERE IS ALWAYS A NEED FOR LOOKING FOR MORE DRUGS OR MORE CONDITIONS. AND ALSO IN BETWEEN TRANSLATION USING COMPUTATIONAL FRAMEWORKS. WITH THAT, I WILL LIKE TO THANK MY TEAM, NIH, NCATS, LUCY AND DAN, GREAT PROGRAM MANAGERS FOR US. THANK YOU. [ APPLAUSE ] >> CHRIS: DAN, DO YOU WANT TO HAVE IVAN TALK AND THEN TAKE QUESTIONS AT THE END? WHAT DO YOU WANT TO DO? >> SO I'M IVAN A PROFESSOR AT TEXAS A&M UNIVERSITY AND I'M A TOXICOLOGIST AND FELLOW SPECIAL GOVERNMENT EMPLOYEE. I THINK IT'S VERY IMPORTANT TO DEAL WITH ALL THE CONFLICTS OF INTEREST. SO ONE DAN ALREADY DISCLOSED. I'M A GRANTEE SO THAT IS A VERY IMPORTANT CONFLICT. THE SECOND IS MORE CONCEPTUAL. I'M A TOXICOLOGIST, NOT A POTENTIAL CHIP DEVELOPER AND ABOUT A YEAR AGO OR SO, I WAS INTERVIEWED BY NATURE MEDICINE. AND ALTHOUGH I DON'T HAVE TO ISSUE ANY RETRACTIONS, I DID GET QUOTED ON THE LITTLE THINGS I WAS HOPING THE REPORTER WOULD OVERLOOK. BUT IT'S IN PRINT. I'M NOT ASHAMED OF IT. BUT THIS WAS WHERE I WAS WHEN WE WERE JUST GETTING FUNDED FOR THIS PARTICULAR PROGRAM. SO, AGAIN AS A TOXICOLOGIST, I DON'T WANT TO ASSUME THAT SOMETHING MORE COMPLICATED IS BETTER AND I ALSO WAS QUOTED AS SAYING I'M A HEALTHY SKEPTIC. I THINK IT'S A GOOD BALANCE TO BE A TISSUE CHIP DEVELOPER, TO COME 234 FROM A PERSPECTIVE OF IN-VITRO AND IN-VIVO TOXICOLOGIST UNDERSTANDING THE NEEDS, WHAT THE REALITIES ARE, AND TO ALSO NOT BE AWED BY PRESENTATIONS BUT TO ACTUALLY TRY TO TAKE THESE SYSTEMS, BRING THEM INTO THE LAB AND SEE HOW THEY WORK. SO, THE VALIDATION, AND THIS IS THE EXACT TITLE OF THE RFA OUT ON THE STREET RIGHT NOW AND I UNDERLINE VALIDATING BECAUSE WHERE I COME FROM, VALIDATION IS A DIRTY WORD IT'S NOT USED OFTEN. PEOPLE KNOW WHAT VALIDATION MEANS. TRY TO AVOID IT. SO OUR -- I'M GLAD CHRIS PUT HIS MICROPHONE DOWN. PEOPLE IN MY WORLD CALL IT TESTING. FOR A SPECIFIC REASON. VALIDATION IS ALMOST A LEGAL TERM AND I PUT HERE ON THE LEFT INFORMATION FROM FDA, BIOMARKERS QUALIFICATION PROGRAM, QUESTION AND ANSWER ON THEIR WEBSITE AND THEY TALK ABOUT CONTEXT OF USE AND THEY ARE TALKING ABOUT QUALIFICATION RATHER THAN VALIDATION. AND EVEN THOUGH MOST FREQUENTLY USED IN TERMS OF BIOMARKERS, THE DEVICES ARE ALSO BEING QUALIFIED AND TISSUE CHIPS ARE DEVISES AND COMMODITY FOR RESEARCH. SO, THERE IS IN MY OPINION, NO COMPETITIVE ADVANTAGE FOR USERS TO BE THE SOLE USER OF A PARTICULAR TECHNOLOGY BECAUSE THE TECHNOLOGY NEEDS TO BE APPROVED BY SOME REGULATOR AND THE REGULATOR WANTS TO HAVE CONFIDENCE THAT IS SOMETHING THAT ANYONE OR MOST PEOPLE CAN DO. AND IN MORE TOXICOLOGY AND ENVIRONMENTAL TOXICOLOGY AND CHEMICAL TOXICOLOGY WORLD, VALIDATION ALSO IS VERY SPECIFICALLY PRESCRIBED BY THIS ORGANIZATION OF ECONOMIC CORPORATION AND DEVELOPMENT GUIDELINES. IT'S DEFINED IN TERMS OF BOTH WHAT A VALIDATION IS AND THEN EVERY WORD IN THAT DEFINITION IS DEFINED SEPARATELY. SO, I THINK IT IS VERY IMPORTANT TO REALIZE THAT THIS RELIABILITY WHEREAS CAN WE ACTUALLY REPRODUCE THIS SOMEWHERE ELSE VERSUS RELEVANCE, WHICH IS THE MEANINGFUL FOR PARTICULAR PURPOSE AND PHYSIOLOGICAL RELEVANCE OF THAT PARTICULAR DEVICE TO THE DISEASE OR ORGAN OF INTEREST; ARE REALLY NOT THE SAME OF THE SO I APPLAUD NCATS FOR BEING ABLE TO PUT BOTH OF THOSE THINGS INTO THE SAME RFS AND TO ASK APPLICANTS LIKE OURSELVES TO TRY TO ADDRESS BOTH EVEN THOUGH THE PHYSIOLOGICAL RELEVANCE IS MORE ON THE DEVELOPER SIDE THAN ON THE TESTER SIDE. AND FINALY, THE REAL LOOK AT THE REALITY OF WHAT VALIDATION IS IN THE WORLD OF RAPID ACCELERATION OF TOOLS DEVELOPMENT AND THE NEED TO TEST, NOT JUST HUNDREDS OR 10S OR SINGLE DRUGS, BUT TENS OF THOUSANDS OF ENVIRONMENTAL COMPOUNDS WAS ADDRESSED BY NATIONAL ACADEMY COMMITTEE THAT ISSUED A REPORT A YEAR AGO AND I WAS VERY HAPPY TO SEE NCATS WAS ONE OF THE SPONSORS. ONE CHAPTER IN THAT REPORT WAS ON VALIDATION AND TRYING TO FIND THE BRIDGE BETWEEN THE OECD34 GUIDELINE, WHICH IS INCREDIBLY RIGID, AND THE REALITY WHICH IS ALL THE TOOLS HAVE NEW ASSAYS PROBABLY HAVE 6-12 MONTHS USEFUL TIME BEFORE A BETTER VERSION IS DEVELOPED AND HOW DO YOU VALIDATE SOMETHING WHICH IS ALREADY NO LONGER THERE? AND DO WE NEED TO VALIDATE BUT YOU OBVIOUSLY NEED FOR REGULATORS TO LOOK AT SOMETHING THAT IS -- THEY CAN TRUST. AND THE KEY THEMES THERE WERE IT HAS TO BE FIT PURPOSE AND HAS TO BE CLEARLY DEFINED, HOW YOU GO INTO RESOLVE THE POSITIVE AND NEGATIVE, TRYING NOT TO CREATE SOMETHING THAT IS PERFECT BECAUSE THAT IS THE ENEMY OF THE GOOD, AND THEN PERFORMANCE STANDARDS, WHAT IS GOOD ENOUGH? AND THAT IS WHERE WHEN WE WERE WRITING THE PROPOSAL, WE WERE TRYING TO HIT. SO, OUR DELIVERABLES ARE GOING TO BE COMPARISONS BETWEEN 3D AND 2D BECAUSE MOST OF THE DEVELOPERS ARE 3D PEOPLE. BIOENGINEERS AND LIVE IN THE WORLD OF COMPLICATED SYSTEMS AND THEY NOT OFTEN HAVE A COMPARATOR WHICH IS THE TRADITIONAL SYSTEM. WHAT IS THE BEST COMPARATOR? LIKE A CLINICAL TRIAL. WHAT IS THE STANDARD OF CARE? AND THE STANDARD OF CARE IS REALLY NOT A PRACTICE IN BIOENGINEERING FIELD. THE DETAILED TECHNOLOGY TRANSFER AND EXPERIMENTAL PROTOCOLS: IT GOES WITHOUT SAYING THAT THE PROTOCOL THAT THE DEVELOPER GIVES YOU IS NOT THE PROTOCOL YOU CAN RUN IN YOUR OWN LAB. SO WE ARE AIMING TO HELP DEVELOPERS DEVELOP BETTER PROTOCOLS AND NOT JUST FOR US AND THEN BUT FOR OTHER USERS. THEN, PHENOTYPIC ENDPOINT DESCRIPTIONS AND GUIDANCE FOR INTERPRETATION, EACH LAB AND COMPANY WILL HAVE A SLIGHTLY DIFFERENT SET OF INSTRUMENTS SO WE ARE TRYING TO TRY DIFFERENT THINGS AND TRYING TO DOCUMENT THAT AND THERE IS THE WHOLE CONCEPTUAL ISSUE, DO YOU USE SYRINGE PUMPS OR BUY SOMETHING VERY EXPENSIVE THAT ONLY FOR THAT THING HAS BEEN DEVELOPED ESSENTIALLY DO YOU NEED A BOX OR CAN YOU RETRO FIT THIS IN YOUR OWN LAB? AND THEN LAST BUT NOT LEAST, PER SAMPLE COST. QUICKLY EXCEEDS THE COST OF MULTIPLE ANIMALS. AND I'M A TOXICOLOGIST. I KNOW ANIMALS ARE NOT EXPENSIVE. BUT SOME OF THESE DEVICES ARE MANY MULTIPLES OF WHAT THE ANIMAL WOULD COST AND IT'S A COMPLETE SYSTEM. IT'S NOT A HUMAN BUT A COMPLETE SYSTEM. SO WHEN WE DESIGNED THE PROPOSAL, WE HAD IN MIND THREE BASIC PRINCIPLES. WE WANTED TO EMULATE, NOT TO PLAN ON THE COMPANY THAT IS IN THIS SPACE, THE REAL WORLD. AND THE REAL WORLD TO US IS THE COLLEAGUES IN PHARMA. SO AGAIN AS A TOXICOLOGIST, MY STUDENTS, MY TRAINEES GO TO PHARMA AND SO I THINK I HAVE A PRETTY GOOD UNDERSTANDING HOW IT WORKS. SO USUALLY A BIG COMPANY HAS A LOT OF EXPERTISES IN DIFFERENT PARTS BUT YOU HAVE EXPERTISE. AND THEN YOU HAVE TO HAVE ALTERNATIVE METHODS EXPERIENCE AND HOW ALTERNATIVE METHODS ARE BEING USED, NOT JUST SAYING ANIMALS HAVE FAILED US THERE THEREFORE LET'S DO SOMETHING ELSE. ALTERNATIVES ARE USEFUL TO A LIMITED EXTENT AND UD NEED TO UNDERSTAND THAT. AND WE DECIDED THAT IT WOULD BE GOOD TO HAVE A TESTING SITE THAT IS ACTUALLY NOT BEEN FUNDED BY DEVELOPER SITES. SO YES WE NEED TO HAVE BIOENGINEERS BUT WE WANT TO BE DIVORCED FROM THE TISSUE CHIP 1.0 AND WHEN YOU LOOK AT THE PUZZLE BOARD, THAT'S WHAT OUR CENTER IS. WE HAVE TOXICOLOGY EXPERTISE, MOLECULAR PHENOTYPING AND LOCAL CHEMISTRY AND PHARMACOKINETIC MODELING, REGULATORY SUBMISSIONS, AND QAQC. SO ALL OF THOSE THINGS, ANY PHARMA COMPANY OR CHEMICAL COMPANY OR GOVERNMENT ORGANIZATION SHOULD BE ABLE TO REPLICATE IN-HOUSE. IT LOOKS COMPLICATED BUT WE BASICALLY HAVE TWO SITES. ONE THAT I COORDINATE IN COLLEGE STATION. WE HAVE A BEAUTIFUL FACILITY IN HOUSTON AT TEXAS MEDICAL CENTER AN HOUR-AND-A-HALF AWAY FROM COLLEGE STATION WHERE THERE IS A HEW THROUGH PUT TESTING FACILITY AND A BEAUTIFUL IMAGING FACILITY AS WELL. WE WORK VERY CLOSELY. WE TEST SOME TISSUE CHIPS IN HOUSTON. MOST IN COLLEGE STATION. OUR GOAL IS TO DO SOMETHING ON THE TISSUE CHIP WITHIN A 6-9 MONTH PERIOD BECAUSE IF WE CAN GET IT TO WORK, MANAGEMENT STRUCTURE IN PHARMA WILL PROBABLY FAIL THAT IMMEDIATELY. AND THEN OUR TISSUE CHIP DEVELOPERS ARE LISTED HERE. IQ CONSORTIUM, UNIVERSITY OF PITTSBURGH AND MIT ARE GREAT PARTNERS. SO THIS IS ONE BIG SYSTEM. OUR TIMELINES ARE AS FOLLOWS. WE STARTED OCTOBER 2016 AND HAVE TO FINISH IN SEPTEMBER. THE WE ARE ABOUT 2018. THE CHIPS IN BLUE ARE TESTED IN HOUSTON AND THE CHIPS IN MAROON ARE TESTED IN COLLEGE STATION. AND I'LL TAKE YOU THROUGH SOME OF THESE BUT WE ARE STICKING TO THIS SCHEDULE PRETTY CLOSELY, OBVIOUSLY SLIPPING A LITTLE BIT BUT I'M VERY CONFIDENT THAT BY SEPTEMBER WE WILL BE DONE WITH 11 MODELS. OUR STRATEGY IS PRESENTATIONS ON TIERS MADE US THINK ABOUT WHAT OUR TIERS ARE AND REAL USERS WILL HAVE TWENTY FOUR TIERS. TIER MINUS 1 IS CAN WE DO BUSINESS WITH YOU? WE WERE NOT ABLE TO DO BUSINESS WITH A COUPLE OF TISSUE CHIP DEVELOPERS. IT TOOK TOO DARN LONG TO ESTABLISH ALL THE TRANSFER AGREEMENTS AND OTHER PAPERWORK. TIER 0 IS UNDERSTANDING WHAT IS IN THE PAPER OR ANOTHER PRESENTATION WHEN YOU GET IT IN THE BOX, ARRIVING TO YOU, HOW DOES THAT COMPARE TO WHAT YOU HAVE SEEN IN THE PRESENTATION? ALWAYS ONE-TO-ONE. AND YOU TRY TO OBTAIN IT, PLUG IT IN AND HOPE IT WORKS. TIER 1 REALLY IS TRYING TO REPEAT WHAT THE FOLKS HAVE DONE IN TISSUE CHIP 1 .0 HIT MILESTONES AND HIT THE SAME MILESTONES AND TIER 2, CAN WE DO MORE? THEY ARE YAPPING IN OUR EAR ONCE A MONTH AND SAY DO MORE AND MORE. AND FASTER SO WE ARE TRYING TO DO IT. I WOULDN'T CALL THIS UGLY BUT THE LEAST SUCCESSFUL MODEL. BLOOD BRAIN BEAR GER A BIG NEED IN THE FIELD AND -- BARRIER -- AND ONE MODEL THAT WAS AVAILABLE TO US WAS FROM THE UNIVERSITY OF VANDERBILT IT'S TWO SEPARATE CHAMBERS. FOUR DIFFERENT CELL TYPES. IT'S ABOUT 28 DAYS TO ESTABLISH THAT MODEL. IT IS 21 DAYS TO ESTABLIS IT AND THEN MAY HAVE 5-7 DAYS OF USEFUL LIFE OF THE CELLS TO DO THE TESTING. IT'S THE LARGEST INCUBATOR YOU CAN BUY ON THE MARKET AND IT TAKES THREE WEEKS FOR BARRIER TO ESTABLISH. DOESN'T COME THE SAME IN EVERY CHIP. SO THERE IS VARIABILITY. BY THE END OF THE 21 DAY, ALL CHIPS DEVELOP BARRIER AND THEY ARE FOUR CHIPS ON THE LEFT. IT'S NOT THAT WE ONLY TRIED 9, WE TRIED OVER 40 CHIPS. 9 WERE DEEMED SUCCESSFUL TO AT LEAST SURVIVE OVER WEEKS. 4 WERE DEEMED SUCCESSFUL TO DO TESTING. ONE WAS CONTROL 3 WERE ONE DRUG AND ONE COMBINATION OF THE DRUGS AND WE DID REPLICATE TESTING. COMPARISON OF PERFORMANCE IS DIFFICULT BECAUSE THERE IS NO REPLICATION TO SPEAK OF. SO WE STRUGGLED WITH THIS FOR 7-8 MONTHS. WE HAD MULTIPLE VISIT AND COUNTER VISITS. IT'S INCREDIBLY DIFFICULT SYSTEM. INCREDIBLY GOOD SYSTEM WHEN IT WORKS. BUT IT'S PROBABLY SOMETHING THAT CAN ONLY BE DONE AT THE DEVELOPER SITE RATHER THAN YOU CAN NOT PROBABLY ONBOARD THIS VERY SUCCESSFULLY IN EVERY LABORATORY. THE UNIVERSITY OF WASHINGTON PROXIMAL KIDNEY TUBULAR MODULE IS PORTAL. IT'S A CHIP. IT'S A CHANNEL IT'S A LUMEN. 5000 CELL IN IT THEY LINE UP AND YOU CAN FLOW MEDIA THROUGH IT AND DO A LOT OF PHYSIOLOGY WITH IT. SO ON THE TOP RIGHT YOU CAN SEE YOU PUT LOWER P. AND START SEEING AMMONIA PRODUCED, YOU TINKER WITH VITAMIN D METABOLISM AND CHANGE THE METABOLITES BEING FORMED AND INDUCE CYTOCHROME 24P21 SO THIS WAS BEAUTIFUL PHYSIOLOGICAL RELEVANCE. WE REPLICATED MOST OF THESE ENDPOINTS AS SAID. WE COULD CULTURE CELLS FOR 28 DAYS IN TWENTY FOUR D AND THREE D. WE CAN SEE A DIFFERENCE BETWEEN DIFFERENT -- IN 2D AND 3D. AND WE COULD NOT REPRODUCE -- SHARED ALL THE INFORMATION WITH THE DEVELOPERS AND HAVE BEEN VERY OPEN WITH THEM. THEY LOOKED AT OUR DATA AND AGREED THIS IS PROBABLY AN ENDPOINT THAT IS CHALLENGING TO REPLICATE. THE THROUGH PUT, REPLICATION OF WHAT THE UNIVERSITY OF WASHINGTON DID WAS 10 CHIPS. TESTING OF COMPOUNDS, SIMILAR ONES WAS 24 CHIPS. AGAIN ABOUT A 6-8 MONTH PERIOD. YOU CAN SEE 34 CHIPS IS BETTER THAN 4. BUT AGAIN, EVERY CHIP IS A LONG PROCESS AND YOU NEED TO NURSE THEM FOR QUITE A BIT OF TIME. BONE TUMOR MODEL FROM COLUMBIA UNIVERSITY IS SOMETHING WE ARE FINISHING UP RIGHT NOW. THIS IS A TISSUE CONSTRUCT. THIS IS A BOVINE TRABECULAR BONE. HUMAN OSTEOBLAST ON IT AND SARCOMA CELLS ON IT. SO ESSENTIALLY YOU HAVE A MODEL THAT YOU CAN LOOK UNDER THE MICROSCOPE IN 3D WHERE YOU HAVE ALL OF THIS TOGETHER, IT'S A ONE-MONTH, IN OUR HANDS. IT TAKES ABOUT 2-3 WEEKS FOR COLUMBIA TO MAKE THEM. SO IT'S NOT A VERY FAST MODEL BUT YOU CAN PUT A LOT OF THEM INTO THE SAME DEVICE. ON THE 2D, SARCOMA, WE HAVE DONE ESSENTIALLY DRUG COMBINATIONS OR CLINICALLY RELEVANT REGIMENS OF TREATMENTS AND AS YOU CAN SEE HERE, DAYS 1-7 NO TREATMENT AND DAYS 8-24, DIFFERENT TREATMENTS AND DAYS 25-38 TO FOLLOW-UP TO SEE WHAT GREW UP AND THIS WAS IDENTICAL BETWEEN 2D AND 3D AND NOT TO BORE YOU WITH THE DOSE RESPONSE, 3 DOES. BEAUTIFUL DOSE RESPONSES AND ALSO HAS OSTEOBLAST SO DEXAMETHASONE KILLS OSTEOBLAST BUT DOESN'T KILL EWING SARCOMA CELLS IN 2D. SO WE CAN MONITOR THAT AND IT'S INTERESTING SYSTEM TO WORK WITH. IT'S HIGHER THROUGH PUT. NO FLOW SO IT IS JUST A DEVICE IN THE MEDIA YOU HAVE TO CHANGE MEDIA BUT THE THROUGH PUT WAS LIMITED BY WHAT COLUMBIA COULD GIVE US. WE COULD HAVE DONE MORE. IT'S JUST VERY DIFFICULT TO MAKE IT. SO THE THROUGH PUT CHALLENGE IS ON THE DEVELOPER RATHER THAN THE TESTER. THE GUT MODEL FROM JOHNS HOPKINS BAYLOR COLLEGE OF MEDICINE IS THE ONE VERSION THAT WE TESTED IS ACTUALLY IN THE MULTI-WELL PLATE. THESE ARE ESTABLISHED FROM THE HUMAN STEM CELLS. THEY FORM BARRIER AS YOU CAN SEE ON THE TOP. YOU CAN ACTUALLY THEN KILL THEM WITH OTHER GI DRUGS AND WE WERE LARGELY ABLE TO REPRODUCE ALL OF THIS. WE ARE DOING CELLS IN PARALLEL AND BECAUSE IT'S A HIGHER THROUGH PUT SYSTEM WE ARE VERY INTERESTED IN NOW THIS IS THE TESTING ONGOING. WE ARE TESTING A VERY LARGE NUMBER OF COMPOUNDS THAT HAVE DATA ON KCO2 CELLS AND HUMAN DATA ON GUT PERMEABILITY AND AS YOU CAN SEE, 36 WELLS, 144 WELLS AND OVER 300 WELLS. THIS IS REALLY GETTING TO BE MEDIUM THROUGH PUT TECHNOLOGY AND REALLY INTERESTING. AND THEN FINALLY, CARDIAC CHIP MODEL. WE WORK A LOT WITH 2DIPS CARDIOMYOSITES IN MY LAB SO IT WAS INTERESTING TO GET A CHIP. THIS CHIP IS ABOUT 50,000 CELLS. THEY BEAT IN THE CHIP AND IT'S A NATURAL GRAPHITY FLOW SO BASICALLY PUT MEDIA INTO THESE TIPS AND THEN IT JUST FLOWS THROUGH THE CHIP. SO YOU DON'T HAVE TO HAVE COMPLICATED BUMPS IN IT. IT'S STILL NOT A VERY FAST SYSTEM. SO IT TAKES TWO WEEKS TO PURIFY CELLS B TWO WEEKS TO MAKE THEM BEAT AND THEN YOU CAN DO YOUR TESTING. WE CAN MAKE THEM BEAT. WE CAN LOOK AT CALCIUM FLOW. THE PANEL ALONG THE BOTTOM IS FROM THE DEVELOPERS WHERE THEY ADDED AND SHOWN THE CELLS WILL SPEED UP AND THEN WILL CRASH AND I WILL NOT RUN THE VIDEO BUT BASICALLY WE CAN SEE THE SAME THING IN THE CONTROL. THEY BEAT WITH ABOUT 26 BEATS PER MINUTE AND ADD LOWER CONCENTRATIONS OF ARAPPA MILL AND SPEED UP TO TWICE THAT AND THEN LATER THEY CRASH. SO WE ARE IN PROGRESS RIGHT NOW. WE TESTED 24 CHIPS WITH CONTROL AND THREE DRUGS. TIER 2 IS IN PLANNING. WE ARE WAITING FOR UNIVERSITY OF BERKELEY TO IMPROVE THEIR TISSUE CHIP MAKING BUT IT IS SOMETHING THAT IS AGAIN REASONABLY HIGH-THROUGHPUT. SO THIS IS A TABLE OF WHERE WE ARE. WE HAVE 11 SYSTEMS. WE HAVE COMPLETED PAPERWORK WITH EVERYBODY. WE HAVE SEEN EVERY CHIP. WE HAVE PROTOCOLS FOR EVERYONE WE VISITED. ALL EXCEPT FOR TWO CENTERS. THOSE VISITS ARE NEXT WEEK AND IN THREE WEEKS, SO AGAIN WE ARE ON TASK TO OR ON TRACK TO FINISH WITH THIS IN SEPTEMBER. SO LET ME JUST PART WITH A COUPLE OF THOUGHTS TO STIMULATE THE DISCUSSION, PERHAPS. SO AGAIN, JUST TOY REMIND EVERYONE, I'M NOT A DEVELOPER. I'M A CUSTOMER. I WANT TO USE THESE. I WANT THEM TO BE USEFUL AND RELEVANT AND ALSO DON'T WANT THEM TO BE INCREDIBLY COMPLICATED AND COSTLY UNLESS YOU ABSOLUTELY HAVE TO HAVE IT. BECAUSE FOR IT TO REPLACE SOMETHING ELSE, YOU NEED TO UNDERSTAND WHAT ARE YOU REPLACING. SO I AM COMPLETELY IN SUPPORT OF THIS TECHNOLOGY BUT I THINK THE DEVELOPERS NEED TO REALIZE THAT THE BRIDGE TO USE IS THERE AND THAT BRIDGE IS NOT TO THE REGULATOR. THE BRIDGE IS TO THE USER. BECAUSE THE REGULATORS ARE OVER ANOTHER CANYON ON THE OTHER SIDE. SO AS A TOXICOLOGIST AGAIN, I THINK MY JOB SECURITY IS PRETTY GOOD. I DON'T THINK THAT THESE DEVICES WILL REPLACE ANIMAL TESTING IN MY LIFETIME OR AT LEAST USEFUL LIFETIME. HOWEVER, THIS IS NOT TO MEAN THAT THEY SHOULD NOT BE DEVELOPED. THEY SHOULD BE. AND I THINK WHAT DEVELOPERS REALLY DON'T APPRECIATE BUT WHAT THIS PROGRAM HAS MADE THEM APPRECIATE, IS THAT THE COST AND EASE OF USE IS SOMETHING THAT THEY REALLY NEED TO PAY ATTENTION TO. AND I THINK WHAT NCATS IS DOING IS TRYING TO DRAW THAT BRIDGE AND THAT BRICK TO THE END USERS. AND THE WORKFORCE EXPERTISE AND VERSATILITY OF EQUIPMENT AND INSTRUMENTATION IS SOMETHING THAT IS DIFFICULT TO ASCERTAIN BECAUSE PROBABLY ALL THE COMPONENTS OUR CENTER HAS ARE THERE BUT NOT REALLY WORKING TOGETHER YET. AND BY SHOWING HOW OUR CENTER DID THIS, WE CAN TEACH OTHER USERS HOW TO DO IT. AND THEN FINALLY REGULATORS ARE ONLY AT THE STAGE OF LOOKING AT THE SEMINARS RIGHT NOW AND READING SOMETHING IN THE NEWSPAPERS AND THINKING THIS IS REALLY COOL. BUT FDA STARTED ON-BOARDING SOME OF THESE CHIPS NOW AND I THINK THEIR INITIAL REACTION IS MIXED. SO, VALIDATION. VALIDATION, TRUE VALIDATION MEANS THIS. 37 LABORATORIES IN EUROPE COMPRISE A EUROPEAN NETWORK FOR TESTING UNDER OECD GUIDELINES. VALIDATION IS MANY THINGS. IT'S NOT TWO THINGS. IT'S NOT CHEAP AND THE IT'S NOT QUICK. IF YOU WANT TO DO IT UNDER OECD34. AND IF NCATS WANTS TO DO THAT THEY CAN BUT PROBABLY NOT WITH THE CURRENT BUDGET AND NOT WITH THE CURRENT STRUCTURE. BUT THAT IS WHAT REAL VALIDATION IS. WHAT WE ARE DOING RIGHT NOW I THINK, IS ORGANIC VALIDATION. SOMEBODY IS BUILDING IT AND HOMER SIMPSON IS ME, SO PLEASE DO NOT GET INSULTED. THERE IS A LOT OF STUFF, TUBES, BLINKING LIGHTS, AND OTHER THINGS AND THE REALITY IS THAT ON-BOARDING IS A CHALLENGE BECAUSE YOU ALWAYS ONCE YOU BRING THIS IN, YOU ALWAYS ASK NEW QUESTIONS AND NEW QUESTIONS MEANS THE TECHNOLOGY CHANGES. WHAT ARE WE VALIDATED IN THE 1st PLACE? WHAT WE ARE TRYING TO DO BEFORE THE DEAD LINES OF THE MARCH WHATEVER THAT IS, IS TRYING TO DETERMINE IF WE CAN THINK OF SOME SORT OF A SAFE HARBOR CONSORTIUM. BECAUSE THE USERS HAVE TO COME OR MAKE A STEP TOWARDS US AS WELL. AND I AM NOT CONVINCED THAT IS GOING TO HAPPEN. I THINK THE USERS WANT TO SIT ON THIS SIDE AND NCATS IS FUNDING VALIDATION AND PARTICIPATING IN TELECONFERENCES. THIS IS VERY LOW COST, LOW ENERGY FOR THEM, TYPE OF VALIDATION. THE REALITY HAS TO BE THE USERS HAVE TO DRIVE THE NEED AND THEY HAVE TO TELL THE VALIDATION CONSORTIUM WHAT MODELS THEY NEED TO BE VALIDATED. WHAT MODELS ARE GOOD FOR MANY COMPANIES RATHER THAN FOR ONE COMPANY. WHAT MODELS ARE FORWARD-LOOKING RATHER THAN OH, MY GOD, I HAVE A PROBLEM NOW THEY NEED TO FIX IT AT ANY COST POSSIBLE. AND WHAT WE ARE TRYING TO SEE IF ACADEMIC INDUSTRY GOVERNMENT, CONSORTIUM IS POSSIBLE AND IF WE ARE ABLE TO BUILD THAT, WE'LL GLADLY SUBMIT AN APPLICATION. BECAUSE THAT IS THE FUTURE. AND I DON'T THINK THE COMPANIES WILL NEED TO ONBOARD EVERYTHING BECAUSE IT IS EXPENSIVE IT'S PUTTING ALL EGGS INTO ONE BASKET. I DON'T THINK A CRO CAN SURVIVE BECAUSE THIS IS A VERY, VERY DIFFICULT BUSINESS TO BE IN. I THINK A CONSORTIUM WHERE PEOPLE CAN COME AROUND THE TABLE AND TALK FREELY ABOUT THE COMMODITY OF A TISSUE CHIP AND THEN HAVE SOMEONE WITH EXPERTISE OF DIFFERENT SYSTEMS DO THAT, IS A PATH FORWARD BUT THIS IS UP FOR DISCUSSION. SO THANK YOU VERY MUCH. [ APPLAUSE ] >> CHRIS: QUESTIONS? COMMENTS? MORE HEALTHY SKEPTICISM? UNHEALTHY SKEPTICISM? RON? >> I HAVE A QUICK QUESTION. AND IT'S ABOUT THE BRAIN CHIP. IT MAY APPLY TO THE OTHER TISSUES AS WELL. WONDERING WHEN WE SAY BRAIN CHIP, HOW MUCH OF THE BRAIN ARE WE TALKING ABOUT? GIVEN THE FACT THAT SO MANY DIFFERENT KINDS OF CELLS, DIFFERENT KINDS OF NEURONS AND THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM, HOW MUCH OF THAT NERVOUS SYSTEM ARE WE TRYING TO MODEL? AND COULD IT BE ADAPTABLE IF PARTICULAR USER WANTED TO USE A CHIP FOR A DIFFERENT KIND OF NEURON? >> THAT PARTICULAR EXAMPLE I SHOWED WAS FROM THE EMBRYONIC STEM CELLS SO THE BRAIN INSIDE THE DEVELOPING BRAIN EXAMPLE, SO IT'S NOT A FULL BRAIN, IT IS THE SUB POPULATION OF THE NEUROPROGENITOR CELLS AND NEUROGLEIA ALSO SOME ASTROCYTES AND ABOUT OTHER QUESTION IT IS MORE LIKE DEVELOPING TYPE OF QUESTION. I CANNOT REALLY COMMENT ON THAT. BUT WHERE IT GOES IN THAT FIELD BUT THERE ARE A LOT OF DEVELOPMENT IN THE BRAIN FIELD AT THE MOMENT. >> AGAIN, AS A USER, I CRINGED WHEN I READ MANY BRINGS IN A DISH OR SOMETHING OF THAT NATURE OR KIDNEY ON A CHIP WHICH IS THE PROXIMAL TUBIAL RATHER THAN THE WHOLE KIDNEY. I UNDERSTAND THE NEED FOR DEVELOPERS TO EMBELLISH A LITTLE BIT TO ADVANCE THE SCIENCES AND IT'S A NEW SCIENCE. IT'S A DIFFICULT SPACE TO BE IN. BUT YOU RAISE A GOOD POINTED, WHICH IS THE TERMINOLOGY IS IMPORTANT. AND THE TERMINOLOGY IS IMPORTANT FOR SUSTAINABILITY OF THIS BECAUSE IT IS REALLY EASY TO EXCITE BUT THAT EXCITATORY PHASE QUICKLY FALLS DOWN AND I LIVED THROUGH BUSTS OF GENOMICS AND OTHER THINGS BEFORE, AND SO IN MY CONVERSATION WITH DEVELOPERS, I TRY TO BRING THEM TO BE SPECIFIC ABOUT WHAT THEY ARE TRYING TO MODEL AND NOT TO EMBELLISH TOO MUCH BUT THAT SAY DEVELOPING RELATIONSHIP, I THINK. >> SO I TOO WANT TO ASK A MORE SIMPLE QUESTION FROM A HIGH LEVEL. IT'S GREAT TO THE HAVE BOTH OF YOUR PERSPECTIVES AND I THINK I HAVE COME TO APPRECIATE THIS FROM THIS PRESENTATION HOW BROAD THE EFFORTS HAVE BEEN AND HOW MANY DIFFERENT AREAS ALL THESE CHECK LIST OF VALIDATION STEPS TO SATISFY REGULATORY PEOPLE TO MAKE SURE IT IS REPRODUCIBLE AND ALL THAT. BUT IN THE END, THE REASON THIS IS A GREAT POSTER CHILD FOR NCATS IS BECAUSE IT IS SUPPOSED TO GET US SOMETHING THAT HAPPENED FASTER AND SO, I DIDN'T GET A FEEL FOR, ALTHOUGH YOU TALKED ABOUT SOME CLINICAL VALIDATION HERE AND THERE AND CITED STUDIES AND STUFF. I DIDN'T GET A FEEL FOR WHEN IN THE FUTURE THIS YEAR OR 10 YEARS, I DON'T KNOW. WHEN WILL IT COME A POINT WHERE ONE OF THESE THINGS WILL BE ADOPTED BY A GLOBAL PHARMA USING INSTEAD OF WHAT THEY DO NOW, SO THEY CAN MOVE MORE QUICKLY AND THEY WILL BE SO CONFIDENT IN USING IT IF IT GETS NEGATIVE RESULTS THEY'LL KILL THE DRUG. IF THEY ARE NOT THAT CONFIDENT, IT'S A COOL THING TO PLAY WITH. BUT IT'S NOT GOING TO DO WHAT WE REALLY WANT TO DO AT NCATS. AND I'M A SKEPTIC TOO. I HAVE BEEN CONSIDERED CERTAINLY ON NEURONAL STUFF, WE HAVE TO UNDERSTAND HOW THESE THINGS ARE ARTIFICIAL BUT IN MANY CASES THEY ARE MUCH BETTER THAN WHAT WE HAVE IN ANIMALS, BECAUSE WE DON'T HAVE ANYTHING IN ANIMALS SOMETIMES. SO IT'S VERY, VERY EXCITING BUT WHAT I COULDN'T GET FROM THE PRESENTATIONS, MAYBE DAN YOU WANT TO WEIGH IN TOO, LIKE ARE WE REALLY, REALLY DAYS AND NOT GOING TO LIKE LAUNCH UPON OUR ROCKET SHIP TO THE MOON FOR ANOTHER 10 YEARS OR ARE WE GETTING REALLY CLOSE AND THERE ARE HINTS ALREADY THAT SOME OF THIS STUFF IS REALLY TRANSLATABLE SO YOU COULD USE IT AND PREDICT. CAN YOU PREDICT HUMAN DOSING FOR A DRUG BETTER THAN YOU CAN BY TESTING IN RATS BY USING TISSUE CHIPS OR CAN YOU -- AND I KNOW -- SOME OF THE ASSAYS SOUND LIKE THEY ARE ALREADY DONE ON ANIMALS AND SO A LOT OF THINGS ARE WORKED OUT. AND YOU ALREADY BELIEVE THE BIOLOGY. SO MAYBE THOSE YOU BELIEVE MORE READILY WITH TISSUE CHIPS THAN OTHER ONES WHERE IT'S NEW. CAN YOU JUST AND KEEP IT ATIZE LEVEL. ARE WE CLOSE? FAR? WHEN IS SOMEONE GOING TO USE THIS INSTEAD SO WE CAN GET THINGS TO PROGRESS MORE QUICKLY AND ADD VIOLENCE MORE QUICK LEOR THE ALTERNATIVE -- ADVANCE -- BECAUSE WE WILL BE CONFIDENT ENOUGH USING THESE TO KILL PROGRAMS? >> SO THAT'S A GOOD POINT, BRAD. SO FROM MY KNOWLEDGE OF THE FIELD, IN TERMS OF PHARMA UPTAKE, AND CERTAINLY FROM THE FDA AS WELL, THEY HAVE BEEN CERTAINLY BEEN WORKING WITH THE TECHNOLOGY. SOME OF THEM HAVE PORTED THE TECHNOLOGY INTO THEIR OWN LABORATORIES, R&D LAP LABS, FDA AND PHARMA. SOME PHARMA COMPANIES HAVE STOOD UP THEIR OWN DIVISIONS ON MPS OR MICROPHYSIOLOGICAL SYSTEMS. ONE OF OUR PROGRAM MANAGER WENT TO ONE TO LEAD ONE OF THOSE DIVISIONS THERE. AND SO I THINK THE ACTUAL, WHEN DO WE SEE AN IND COMING OUT OF CHIP DATA, LEAVES TO BE DETERMINED ALTHOUGH I KNOW THAT THERE IS SEEMS TO BE AN UNSPOKEN RACE AMONG PHARMA COMPANIES IN TERMS OF WHO COMES OUT WITH THE FIRST CHIP DATA TO GO FOR APPROVAL AT THE FDA. HAVING INTERACTED WITH THE FDA, HOWEVER, AND WITH PHARMA, I THINK FDA WOULD SAY WE WILL LOOK AT YOUR CHIP DATA BUT IN COMPARISON TO THE CONVENTIONAL WAY. AT LEAST UNTIL THEY BUILD CONFIDENCE INTO THE CHIP DATA. SO I THINK THAT COULD COME MAYBE TWO YEARS, 3 YEARS DOWN THE ROAD. WE DON'T KNOW. IT REALLY DEPENDS ON THE COMPOUND AND AS WAS SAID, IT IS ESSENTIALLY THE CONTEXT OF USE. WHAT INDICATION ARE YOU GOING TO BE USING THE DRUG AND WHAT ARE YOU TESTING FOR AND WHICH ORGAN SYSTEM? SO IT WILL BE VERY SPECIFIC. IT'S NOT GOING TO BE A CATCH-ALL AT THIS POINT. >> SO, JUST TO ADD TO THAT, I THINK THE FORK IN THE ROAD IS NOW AND WE CAN PARAPHRASE, YOU WILL GET THERE AND TAKE IT. BUT, THE REALITY IS IF THE DEVELOPMENT OF TISSUE CHAMPIONSHIPS CONTINUES TO GROW ORGANICALLY, WHICH IT PROBABLY SHOULD IN ACADEMIA, IT WILL NOT TRANSLATE INTO QUICK SOLUTIONS. THIS IS WHERE CONSORTIUM WHERE PHARMA REALLY NEEDS TO BE AT THE TABLE AND NOT JUST LISTENING TO ALL THAT IS BEING DONE BUT DRIVING THE DISCUSSION. THEY SHOULD BE THE ONES SAYING, FOR US, REALLY THIS IS THE NUMBER 1, NUMBER 2, NUMBER 3 CHALLENGE AND WE THINK WE HAVE SEEN IN SOME PRESENTATION OR SO-AND-SO PUBLISHED A PAPER, THAT IS THE CHIP, THAT POTENTIALLY COULD HELP US. SO LET'S BUNDLE RESOURCES AND ALL TOGETHER SEE IF WE CAN ACTUALLY BRING THAT CHIP AND LEARN FROM IT. SO UNLESS THEY ARE AT THE TABLE DRIVING THE DISCUSSION, THERE WILL BE NO PROGRESS IN THIS. ORGANIC GROWTH WILL GO INTO WHAT IS INTERESTING TO ACADEMICS, NOT WHAT IS PRACTICALLY RELEVANT. AND I THINK THOSE TWO CAN BE TOGETHER BUT ONLY THROUGH WHAT NCATS IS TRYING TO DRIVE AT AND THAT IS WHY I'M IN COMPLETE SUPPORT OF THE PLAN. >> SO I SUGGEST THAT AS WELL. SO WE FOSTERED THIS COLLABORATIVE ATMOSPHERE WITH THE DEVELOPERS WITH PHARMA, FDA, REGULATORY AGENCIES AND OTHER STAKEHOLDERS AND IN THE PRESENTATIONS TODAY, THE TECHNICAL DIFFICULTIES OF ESSENTIALLY LOOKING AT THIS AS A TECHNOLOGY THAT HAS BEEN COOKING ONLY FOR FIVE YEARS. SO IT'S STILL RAPIDLY EVOLVING AND CAN STILL HAVE A LOT OF IMPROVEMENT. BOTH IN TERMS OF MINIATURIZATION AND MAKING THIS A TURNKEY TECHNOLOGY. I PRESENTED THIS IN COUNCIL PROBABLY NOT TO ALL OF YOU BECAUSE WE HAVE A NUMBER OF NEW MEMBERS. THAT'S ONE OF THE REASONS THAT NCATS HAS PARTNERED WITH NASA AND THE CENTER FOR ADVANCEMENT OF SCIENCE AND SPACE. WE VALUE THE INPUT OF THE SPACE ENGINEERSES WHO CAN TRANSFORM EARTH-BASED INSTRUMENTS INTO SOMETHING THAT IS USEFUL AND HIGHLY MINIATURIZED, VERY PORTABLE TECHNOLOGY THAT CAN BE DONE IN A PAYLOAD AND ASTRONAUT CAN PUSH A BUTTON AND MAKE IT WORK. SO THAT'S WHERE OUR GOAL IS WITH OUR PARTNERS WITH NASA. I'M HOPING AT OUR NEXT MEETING IN MARCH WHERE WE BRING TOGETHER ALL OUR INVESTIGATORS FOR THE DISEASE MODELS AND TESTING CENTER AND AS WELL AS THE INVESTIGATORS WORKING WITH TISSUE CHIPS IN SPACE. THERE IS TRANSFER OF THAT TECHNOLOGY SUCH THAT THE TECHNOLOGY INVOLVING WILL RAPIDLY EVOLVE FASTER AND HYPERACCELERATED WITH THE PARTNERSHIPS WITH THE PAYLOAD DEVELOPERS AND SPACE ENGINEERS. MORE TO COME. >> I WANTED TO THANK YOU GUYS. FOR GREAT PRESENTATIONS. AND I WANTED TO INJECT A BIT OF MAYBE UNHEALING HEALTHY IF NOT RATIONAL OPTIMISM IN THAT WE NEED YOU TO GO FASTER. MY WORRY IS THAT WE CLING TO THE OLD SYSTEMS WE HAVE COMPLAINED ABOUT SINCE I WAS IN SCHOOL IN TERMS OF LACK OF REPRODUCIBILITY, LACK OF PREDICTABILITY AND WE REJECT NEW MEDICINES BECAUSE THEY FAILED IN SOME ANIMAL MODEL THAT WE CAN TRY TO GIVE US INFORMATION, WHICH MAY OR MAY NOT HAVE BEEN TRULY VALIDATED AND THE OPPORTUNITY TO MOVE FORWARD IN THIS SPACE SEEMS TO ME TO BE A RATE LIMITING STEPS TO OUR ABILITY TO TRULY ACCELERATE CURES AND I WORRY ALSO THAT JUST BECAUSE WE DON'T HAVE PERFECTION IN NEURONAL SYSTEM, THAT THAT WILL SOMEHOW NEGATIVELY IMPACT ON PROGRESS IN A RENAL SYSTEM OR SOMETHING ELSE WE CAN USE BECAUSE THESE ARE OTHER KEY AREAS FOR THE PROGRESS. SO FROM MY TWO CENTS WORTH, I'M A CHOMP YON AND ADVOCATE. I HAVE NO CLUE WHAT YOU'RE DOING BUT I'M EXCITED ABOUT IT -- CHAMPION. >> I THINK THERE IS A LOT OF INTERESTING CONCEPTS HERE. AND I TOO WOULD LIKE TO THINK THERE IS MORE OPTIMISM BUT AT THE SAME TIME I ALSO FEEL LIKE, IS TOXICOLOGY AND TOXICITY THE RIGHT TARGET FOR THIS TECHNOLOGY? WHAT I WORRY IS THAT TOXICOLOGY -- DRUG TOXICITY, THERE IS A WHOLE PROCESS FOR FDA APPROVAL. BUT REALLY IN THE CLINICAL SERVICES, THE DRUG TOXICITY ULTIMATELY SHOWS UP TWO YEARS AFTER MARKETING. WHEN THOUSANDS OF PATIENTS ARE EXPOSED TO THE DRUG AND THAT IS WHEN YOU REALLY FIGURE OUT THAT THERE IS SOMETHING THAT YOU COULDN'T PREDICT WITH ANY OF THESE MODELS. SO, WOULDN'T IT BE BETTER THAN TO GO FOR UNIQUE EFFICACY MODELS FOR DISEASES THAT WE DON'T HAVE GOOD MODELS FOR OR FROM CELLS THAT ACTUALLY ARE TAKEN FROM PATIENTS WITH DISEASES. BECAUSE IN PROOF-OF-CONCEPT OF EFFICACY, WE HAVE VERY POOR REPRODUCIBILITY. WE HAVE NO GOOD MODELS. AND THERE YOU CAN ACTUALLY TEST THE PROOF OF CONSENT AND REJECT A DRUG EARLY. AND WE KNOW MOST DRUGS FAIL FOR EFFICACY, NOT FOR TOXICITY. NOW WE HAVE THE TOXICITY PART WELL ORGANIZED AND PEOPLE KNOW WHEN NOT TO TAKE A DRUG FORWARD BECAUSE OF TOXICITY. I WONDER IF WE ARE DRIVING THIS TECHNOLOGY FOR THE WRONG END OR THE WRONG RESULTS? IT'S WORTH THINKING ABOUT. >> TO ADDRESS YOUR POINT, SO THE TISSUE CHIP 2.0 THAT WAS ESSENTIALLY A RENEWAL OF THE PROGRAM THAT STARTED IN SEPTEMBER LAST YEAR, IS AN ATTEMPT TO ADDRESS THE EFFICACY ISSUE. SO IN THAT PROGRAM, THE TISSUE CHIP 2.0 IN EFFICACY TESTING IS INTENDED SO WE HAVE ABOUT 13 FUNDED INVESTIGATORS WORKING IN VARIOUS DISEASES AND SOME ARE INTRACTABLE WITH NO DISEASE MODELS AT ALL. AND THE GOAL OF THE NEW PROGRAM IS TO DEVELOP CHIPS FOR THE FIRST TWO YEARS AND VALIDATE DISEASE MODELS AND LAST THREE YEARS OF FUNDING DEVOTED FOR TESTING PROPRIETARY COMPOUNDS TO HOPEFULLY ADDRESS ALSO BRAD'S POINT AND GO INTO THE CLINICS IN A FASTER WAY AND WILL REMAIN IN THE CLINIC AND BE USED BECAUSE WE HAVE MORE ROBUST DATA SUPPORTING THEM. OF COURSE THAT NEEDS TO BE DETERMINED. WE JUST STARTED A FEW MONTHS AGO. >> JUST FOLLOWING UP ON YOUR COMMENTS, I THINK THE ISSUE IS WHAT PROBLEM OR WHAT IMPEDIMENT WE NOW HAVE IN DEVELOPMENT COULD BE ADDRESSED BY THIS. THE ISSUE OF HUMIDIO SINK SEE AND HUMAN HETEROGENEITY, THE THINGS THAT WE PICK UP IN THE ONE AND 1000 PATIENTS, ONE IN 10,000 PATIENTS, THIS DOESN'T SEEM LIKE A USER FRIENDLY MODEL. WE DON'T HAVE ANY USER-FRIENDLY MODEL UNFORTUNATELY TO PICK UP ON THOSE IDIOSYNCRASIES UNLESS YOU CAN BAKE IN AN IDIOSYNCRATIC CHIP BASED ON THE SPECIFIC MECHANISM, BUT I DON'T THINK WE ARE THERE YET. THE ISSUE OF TRYING TO LOOK FOR GENERALIZE TOXICITY, I MEAN WE KNOW RATS DON'T PREDICT, GUINEA PIGS DON'T PREDICT, MONKEYS DON'T PREDICT, BUNNIES, WHETHER IT IS ISSUES OF TEARTOLOGY OR ISSUES OF GENERALIZE TOXICOLOGY.& THIS HAS THE ADVANTAGE OF BEING GENERALLY HUMAN. BUT YOU ALWAYS ASK WHAT HUMOR WHO IS HUMAN. THOSE CELLS ARE ORIGINALLY DERIVED FROM AND HOW MUCH THAT SAYS WITH RESPECT TO SUBPOPULATION RISK. I THINK WE PROBABLY NEED A LITTLE BIT MORE GRANULARITY AROUND THE QUESTIONS OF WHAT QUESTIONS ARE WE REALLY TRYING TO ADDRESS? AND NOT PUT OUT HOPES OF ADDRESSING THINGS THAT A MODEL LIKE THIS CAN'T ADDRESS AND PUTTING OUR EFFORTS INTO MODELS& THAT CAN BE ADDRESSED. >> I TOTALLY AGREE. BUT THAT DOESN'T NEGATE THE NEED TO THEN ACTUALLY INDEPENDENTLY THIRD PARTY TEST WHATEVER THE CONCLUSIONS OR CLAIMS HAVE BEEN MADE BY THE DEVELOPER. AND THE USERS AND THE REGULATORS WILL BENEFIT FROM A THIRD PARTY VALIDATION. AND THE QUESTION HERE IS HOW TO ORGANIZE THAT THIRD PARTY VALIDATION BECAUSE IF IT GOES INTO TRIALS AND TAKES 5 YEARS, THEN IT IS REALLY IMPRACTICAL. AND I THINK WHAT NCATS IS TRYING TO DO IS THE MOST SENSIBLE PATH FORWARD BUT AT THE SAME TIME, THE OTHER PART OF THE COMMUNITY, THE USERS, THE PHARMA, REALLY NEED TO DRIVE THE AGENDA FOR WHICH MODELSY TO DEVELOP. BECAUSE THE TESTING IS EASY ONCE THE RIGHT MODELS ARE DEVELOPED. >> I THOUGHT THIS WAS A VERY BALANCED PRESENTATION AND I APPRECIATE THAT. ANY TIME YOU'RE BRANCHING OUT INTO SOMETHING NEW LIKE THIS, IT IS EASY TO HYPE AND HARD TO CHALLENGE. AND I THINK YOU DID A GREAT JOB OF PROBABLY A LITTLE BIT OF BOTH. AND I THINK REALLY THINKING ABOUT THE PROBLEM WE ARE SOLVING IS THE QUESTION QUICKLY FOLLOWED BY HOW MUCH IS IT WORTH? SO HOW MUCH ARE WE WILLING TO SPEND ON THIS AND WHAT TYPE OF PROGRESS DO WE NEED TO SEE A DIFFERENT POINTS AND JUST RELATING IT TO PRODUCT DEVELOPMENT. WHAT IS THE TARGET PRODUCT PROFILE FOR TISSUES ON A CHIP IN FROM A COST PERSPECTIVE, TIME PERSPECTIVE, ALL OF THOSE TYPES OF THINGS. I THINK AS YOU GO FORWARD, TRYING TO THINK ABOUT THOSE THINGS, WHICH I'M SURE YOU ARE AND I HEARD PARTS OF IT, WILL BE REALLY VALUABLE BUT I APPRECIATED THE VALIDATION COMPONENT OF IT AND HOW YOU'RE THINKING ABOUT IT. >> STEVE? >> AND I THINK BASED EXACTLY ON THAT KIND OF THINKING, I HOPE AT THE END OF THE DAY WHAT WE DON'T END UP IS WITH A RAT, WHICH DOESN'T PREDICT EFFICACY AND DOESN'T PREDICT TOXICOLOGY VERY MUCH. AND AGAIN, IT IS THINKING VERY MUCH FROM A STRATEGIC POINT OF VIEW OF WHAT QUESTIONS IN HUMAN BIOLOGY CAN WE GET AT WITH THIS TECHNOLOGY IN REALTIME THAT CAN ASSIST -- I'M NOT SO WORRIED ABOUT FDA DOWN THE LINE. VALIDATION IS CRITICAL BUT THE ISSUE IS, CAN A COMPANY USE THIS TO AMONG A SERIES OF MOLECULES, PICK A CANDIDATE TO GO FORWARD WITH AND REJECT OTHER CANDIDATES ON THE EFFICACY SIDE? MORE RAPIDLY THAN OUR CURRENT MODELS ALLOW US TO DO. HOW DOES IT FIT WITH PRECISION MEDICINE AND TARGETED THERAPY WHERE REALLY OUR SCREENING NOW IS AGAINST DOING HIGH-THROUGHPUT SCREENING LOOKING FOR IT FOR A PARTICULAR TARGET, PUTTING THOSE TWO TOGETHER COULD THIS MOVE THAT THROUGH FASTER? SO I THINK WE SHOULD REALLY BE -- THE TECHNOLOGY AND THE WHOLE CONCEPT BEHIND IT IS ABSOLUTELY DELICIOUS. I MEAN, IT IS UNBELIEVABLE. IF YOU ASKED ME 20 YEARS AGO WOULD WE BE EVEN CONCEIVING OF THESE KINDS OF THINGS, I WOULD ASK WHAT YOU WERE SMOKING. NOW HERE WE ARE ACTUALLY DOING IT. BUT I THINK WE DO NEED TO STEP BACK A LITTLE BIT AND THINK MORE STRATEGICALLY ABOUT THE QUESTIONS THAT WE CAN ASK AND REALLY PUT OUR EFFORTS INTO VALIDATING THOSE PATHWAYS THAT ARE GOING TO BE MOST USER-FRIENDLY FOR THE USERS, MOST USER-FRIENDLY FOR THE AGENCY ULTIMATELY THAT WILL HAVE TO LOOK AT THE DATA. BUT ULTIMATELY MOVE FASTER IN FINDING MOLECULES THAT ARE MORE EFFECTIVE AND MOLECULES THAT ARE LESS TOXIC. >> A COUPLE MORE QUESTIONS AND THEN WE'LL BREAK FOR A HALF HOUR LUNCH. >> FIRST OF ALL THE PRESENTATIONS WERE FANTASTIC AND I THINK IT WAS GREAT TO SEE THE ACCUMULATIVE PROGRESS FROM THE BEGINNING TO WHERE WE ARE TODAY AND I THINK THE HEALTHY SKEPTICISM ABOUT WHERE WE ARE TODAY JUST REFLECTION OF RESPONDING TO THE TECHNOLOGY AND ADVANCEMENTS THAT HAVE BEEN MADE AND THEN DEFINING WHAT THE GAPS ARE FOR MOVING FORWARD. I THINK IT IS REALLY POSITIVE. AND I WANT TO REINFORCE THE POINT THAT WAS MADE ABOUT GETTING INDUSTRY INPUT. I REALLY THINK THAT TIME -- MANY OF THE PEOPLE THAT HAVE BEEN INVOLVED FROM INDUSTRY HAVE BEEN TOXICOLOGISTS BECAUSE THEY SEE THAT AS MAYBE THE MORE PROXIMAL APPLICATION OR THE MOST DIRECT. -- RUN THROUGH PRE-CLINICAL MODEL AND THEN FIND AN ISSUE IN PHASE I. HOW CAN I I RAPIDLY ISOLATE WHAT THAT MIGHT BE AND THEN HAVE AN ASSAY SYSTEM THAT CAN GO BACK AND FIND ADDITIONAL COMPOUNDS ORITERATE THROUGH THE PROBLEM THROUGH MOLECULAR MODIFICATION. THAT IS WHAT YOU REALLY WANT. AND I THINK BRINGING TOGETHER SOME PRACTITIONERS THAT REPRESENT MORE DIVERSE DRUG HUNTERS THAN JUST TOXICOLOGY COMMUNITY, REALLY DEFINED THE USE CASES AND PUT THIS INTO SOME VERY ACTIVE EFFORTS THAT YOU CAN GET THAT FIRSTHAND INFORMATION. SO I THINK THAT WOULD BE A REALLY GOOD FOLLOW-UP TO BRING SOME OF THESE EXPERTS TOGETHER AND PUT THIS IN FRONT OF THEM AND SAY HOW WOULD YOU USE THIS? HOW CAN IT BE APPLIED? I THINK THAT WOULD BRING A LITTLE BIT MORE DIRECTION AND FULLER THOUGHT. THE THE THING ABOUT INDUSTRY IS REALLY IMPORTANT IS WHILE A LOT OF THE TISSUE CHIPS ARE FOCUSED ON HUMAN TISSUE, THE TRADITION PATH THROUGH INDUSTRY IS THROUGH ANIMALS. THERE IS MUCH MORE DATA IN ANIMALS AND COMPOUNDS THAN THERE ARE IN HUMANS WHERE WE RUN INTO HUMAN ISSUES. -- ESPECIALLY WITH THINGS YOU MAY PICK UP IN MORE ACUTE SHORT-TERM TOX STUDIES THAN IF YOU HAD THE SYSTEM YOU COULD USE IN LIEU OF SOME OF THE ANIMAL STUDIES THAT CAN BE TIME CONSUMING AND CONSUME A LOT OF COMPOUND. THIS HAS COMPOUND SPARINGS. MANY THINGS YOU CAN THINK ABOUT THAT WOULD MAKE IT MORE TRACTABLE AND APPROACHABLE FROM THE CONSUMER END. THE OTHER THING I WANTED TO AMPLIFY AT THIS POINT ABOUT ANIMAL MODEL PREDICTABILITY. AGAIN, THIS HAS BEEN A MAJOR MAJOR CHALLENGE FOR THE INDUSTRY AND WE TALKED EARLIER ABOUT THE OPIOID CRISIS. THERE HAS BEEN BILLIONS OF DOLLARS SPENT IN PHARMA TRYING TO FIND ALTERNATIVE PAIN MEDICATIONS. BUT ONE OF THE KEY CHALLENGES HAS BEEN THE POOR LACK OF -- VIRTUALLY NO PREDICTABILITY OF PAIN MODELS. MANY HAVE BEEN ARMS THROWN UP IN CAPAC PIRRATION. AND I THINK PAIN MAY BE A DIFFICULT ONE IN THIS CONTEXT BUT THINKING ABOUT THAT PROBLEM COULD BE A BREAKTHROUGH FOR TRANSLATIONAL SCIENCE WHERE TOOLS LIKE THIS COULD REALLY BEGIN TO RECAPITULATE THE HUMAN SETTING. IF YOU CAN DO THAT WITHOUT HAVING TO GO THROUGH HUMANS DIRECTLY AND HELP NARROW IN YOUR FOCUS ON POTENTIAL TARGETS AS WELL AS UNDERSTANDING MORE DETAILS AROUND PHYSIOLOGY THAT CAN BE CAPTURED IN THE SYSTEMS, I THINK IT COULD BE A TREMENDOUS ADVANCEMENT. I WOULDN'T MISS THAT OPPORTUNITY IN TERMS OF SOME OF THE FUTURE PLANNING. >> THAT'S JUST REALLY VERY USEFUL POINTS. WE HAVE BEEN WORKING WITH IQ FOR A WHILE AND THEY DO HAVE A TOX PERSPECTIVE. THAT'S WHAT THEY DO. IS THERE A GROUP, THE EFFICACY PEOPLE? IF YOU WERE GOING TO GO, SHORT OF GOING TO BILL CHEN OR NOW RICK, IS THERE A PHARMA GROUP OF -- IQ IS GREAT BECAUSE THEY ARE GEEKS AND THAT'S WHAT WE WANT. THAT IS REAL SCIENTISTS NOT THE HIGH-LEVEL PEOPLE. SO IS THERE A GROUP LIKE THAT? >> I DON'T KNOW OF A PARTICULAR GROUP THAT I COULD POINT TO. I THINK THE OPPORTUNITY TO BRING TOGETHER SOME PEOPLE BUT I WOULD GO FOR THE DRUG HUNTERS. THE MEDICINAL CHEMISTS, COMPUTATIONAL SCIENTISTS. >> [ OFF MICROPHONE ] >> NOT THAT I'M AWARE OF. IT ISN'T ORGANIZED LIKE THAT BECAUSE THE PROBLEM WITH PHARMA IS A LOT OF THE COMMUNITIES THEY KIND OF LIKE AGGREGATE IN THEIR OWN DISCIPLINE. THEY DON'T COME TOGETHER AS AN INTEGRATED FORUM. >> I'LL SOUND LIKE A BROKEN RECORD BUT THE CTS SAMPLE A GOOD PLACE FOR THOSE PEOPLE WHO -- CTSA -- WHO LOOK AT EFFICACY, NOT SPECIFICALLY CLINICAL TRIALISTS BUT A LOT OF DISCOVERY SCIENTISTS WHO ARE WORKING ON HUNDREDS OF DISEASES. SO I THINK WE SHOULD THINK ABOUT A VARIETY OF RARE DISEASE COMMUNITIES IS ANOTHER ONE WHERE WE CAN CREATE IN SILICO MODELS OR -- >> CHRIS: THANK YOU FOR THAT DISCUSSION. THANK YOU FOR THE PRESENTATIONS. [ APPLAUSE ] AND THANK YOU TO THE COUNCIL FOR -- A LOT OF REALLY GOOD POINTS THAT WE TOOK DOWN AND WE WILL TAKE TO HEART. SO, WE ARE GOING TO GO TO A BRIEF LUNCH NOW DUE TO OUR FIRE DRILL. WE WILL NEED TO COME BACK EARLIER BECAUSE I REALLY WANT TO HAVE TIME TO DO THE CONCEPT CLEARANCE, TO DO THE CAN UPDATE AND HAVE ENOUGH TIME TO DO THE DPI UPDATE. SO CAN WE COME BACK AT QUART OF? AND IF YOU WANT TO CHEW DURING THE PRESENTATION, WE WON'T OBJECT. >> I WANT TODAY TO LET EVERYBODY KNOW THAT THOSE WHO NEED BADGES CAN GO DOWN STAIRS NOW. STAFF WILL WALK YOU DOWN THERE. THEY ARE WAITING FOR US. NOT A LOT OF TIME. LYNN MARKS IS GOING TO GIVE AN JILL AND RON BARTEK. WELCOME BACK. WE'RE GOING TO DO CAN WORD, ONE CONCEPT CLEARANCE FROM PETRA AND START WITH DPI. SO LYNN, TAKE IT AWAY. >> THE LIGHTS CERTAINLY HELP. THANKS, CHRIS. WELCOME BACK, EVERYBODY. RON AND I ARE GOING TO DO A DOUBLE TEAM IN TERMS OF THE CAN REVIEW BOARD, AND OUR MEETING WAS JUST IN THE MIDDLE OF DECEMBER SO NOT A LOT OF TIME ELAPSED FROM THAT. THE FIRST THING I WANTED TO DO IN TERMS OF ON BEHALF OF THE ADVISORY COUNCIL AND CAN REVIEW BOARD, I BELIEVE I'M SPEAKING FOR ALL MY COLLEAGUES, AS TO WHAT EXCITEMENT THERE IS FOR NEW STAFF MEMBERS THAT WERE INTRODUCED EARLIER. TREMENDOUS SPECTRUM OF TALENT, LOOKING FORWARD TO WORKING WITH YOU, I'M SURE I'M SPEAKING ON BEHALF OF LYNN, SO A ROUND OF APPLAUSE FOR ALL. [APPLAUSE] AND ALSO NEW ADVISORY COUNCIL CAN REVIEW BOARD MEMBERS, SOME GOT OUR BADGES TODAY AFTER A BIT OF A WAIT SO WE'RE OFF TO AN ENORMOUS POSITIVE START. THE AGENDA OF THE MEETING WE HELD CARRIED ACROSS A FEW THINGS. ONE WAS THE PART THAT CHRIS TALKED ABOUT EARLIER, THE BUDGET IMPACT AND CONTINUING RESOLUTION ASPECT OF THAT. I HAVE REALLY NEVER PAID MUCH ATTENTION TO THAT, AS 25 YEARS IN INDUSTRY AND 5 YEARS IN ACADEMIC MEDICINE, CONTINUING RESOLUTION, YOU STILL GOT A BUDGET, WHAT ARE YOU WHINING ABOUT? NOW THAT I'M A CONTRACTOR FOCUSING ON BARDA WORK AND ASPR, YOU SEE WHAT HAPPENS TO THE FEDERAL GOVERNMENT WHEN THERE'S LACK OF CLARITY AROUND BUDGETARY ISSUES. WE TALKED ABOUT THE OPIOID CRISIS AND INABILITY FOR THE GOVERNMENT TO REALLY GET NEW PROGRAMS READY TO GO AND FUNDED, AND THEN EVERY TIME YOU RUN UP TO A GOVERNMENT SHUTDOWN, YOU BEGIN TO DIVERT THE ENERGY OF THE GOVERNMENT AND ALL THE STAFF TOWARDS PREPARING FOR A SHUTDOWN. YOU ACTUALLY HAVE TO HAVE MEETINGS TO HAVE AN ORDERLY SHUTDOWN, AND SO FAR YOU'VE ORDERLY PREPARED TO SHUT DOWN THREE TIMES, WITH POTENTIAL FOR AN ORDERLY PREPAREDNESS TO SHUT DOWN FOUR TIMES. THAT IS AN ENORMOUS WASTE OF THE EFFORT, SO I'M HOPING ALL OF OUR CONGRESSIONAL COLLEAGUES AND FRIENDS WILL UNDERSTAND THAT IN THE LONG TERM BECAUSE THIS IS NOT A GOOD WAY TO MANAGE ANY KIND OF ORGANIZATION OR BUSINESS. I THINK EVERY KEY PIECE ON THE OTHER PREVIOUS SLIDE, THE FACT WE HAD A BRAINSTORMING SESSION, AND THE WHOLE PHILOSOPHY AND RATIONAL FOR WHY THE CAN REVIEW BOARD IS IN PLACE WAS PART OF THAT BIG FOCUS. FOR US TO ACTUALLY BECOME MUCH MORE PRO-ACTIVE IN GETTING FEEDBACK TO CHRIS AND THE NCATS TEAM IN TERMS OF WHAT WE NEED, WHAT WE THINK GAPS ARE AND BARRIERS TO ACCELERATING CURES ACROSS A RANGE OF DISEASE AREAS. THE OTHER PIECE IN THAT I WANT TO THE MENTION IN THE 21ST CENTURY CURES ACT THE CLINICAL TRIALS CAN NOW SPREAD OUT EVEN FURTHER, THAT MAY SEEM LIKE A SMALL THING BUT THESE ARE CRITICALLY IMPORTANT CHANGES IN DRUG DEVELOPMENT, ONE COULD ARGUE THEY NEED TO EXPAND FURTHER TO NOT RESTRICT FREEDOM TO OPERATE IN THIS SPACE BUT WE'LL TAKE PROGRESS WHEN WE CAN BEGIN TO FIND SOME PROGRESS ALONG THE WAY. I DO WANT TO TURN OVER TO RON TO CHAT ABOUT THE CAN PROGRAM. >> AND JUST A SUMMARY OF THE ORIGINS OF THE CAN REVIEW BOARD, IT'S IMPORTANT TO NOTE ENOUGH ABOUT THE ORIGINS TO RECOGNIZE IT'S NOT BY ACCIDENT THE CAN REVIEW BOARD AND NCATS ADVISORY COUNCIL ARE SIDE BY SIDE. GO BACK TO INCEPTION INCEPTION WHICH WAS A PROPOSAL MADED BY THEN-SENATOR JOE LIEBERMAN, HE PROPOSED A NETWORK OF $150 BILLION WITH A B OVER A 10-YEAR PERIOD WITH A MISSION SIMILAR TO THE NCATS MISSION, ACCELERATING FROM BENCH TO BEDSIDE TO GET TREATMENT TO PATIENTS FASTER, PRETTY MUCH THE CURES ACCELERATION NETWORK MISSION. HE PROPOSED THAT 15 YEARS AGO, IT HAD A COUPLE FALSE STARTS, LEGISLATIVE PROPOSALS THAT DIDN'T MAKE IT. THEN THE TORCH WAS PICKED UP AGAIN IN 2009 BY THEN-SENATOR ARLON SPECTOR, PROPOSED -- FIRST THE JOE LIEBERMAN PROPOSAL WAS IT NOT BE LOCATED AT THE NIH BUT INDEPENDENTLY SEPARATE FROM NIH. SPECTRUM MADE THE PROPOSAL IN 2009, DAMPENED DOWN TO $1 BILLION FOR THE FIRST YEAR SHALL, AND TO BE AT THE NIH. THAT WAS LEGISLATIVE PROPOSAL, IT WAS REDUCED TO WHEN IT WAS SIGNED INTO LAW, ALONG WITH THE AFFORDABLE CARE ACT IN 2010, WAS WHEN CAN WAS LEGISLATED, OR ENACTED. IT WAS REDUCED TO -- AUTHORIZED $500 MILLION FOR THE FIRST YEAR, SO ENACTED IN 2010, FIRST YEAR WOULD HAVE BEEN FY 2011, AUTHORIZED $500 MILLION, APPROPRIATED ZERO. THAT STARTED CAN, THEN AT THAT TIME NIH OFFICE OF THE DIRECTOR SUBSEQUENT YEARS APPROPRIATED $10 MILLION, FOR ABOUT THREE YEARS, THEN BOUNCED TO $25 MILLION, THE BUDGET FOR THE CAN REVIEW BOARD OVER THE LAST THREE OR FOUR YEARS AND THE PROPOSAL FOR FY2018 AND AND THIS FISCAL YEAR. IT WAS MOVED FROM OFFICE OF DIRECTOR TO NCATS UPON INCEPTIONED, ESTABLISHMENT OF NCATS. WE ALSO AT THE CAN REVIEW BOARD MEETING WENT THROUGH THE STATUS OF THE CURRENT CAN PROGRAMS THAT YOU SEE LISTED THERE. THEN WE WENT TO CLEARANCE OF CONCEPTS, TWO OF THEM, ONE WAS THE NEXT STEPS FOR THE BIOMEDICAL DATA TRANSLATOR, THE SECOND WAS VERY INTERESTING COLLABORATIVE APPROACH PRESENTED BY PJ BROOKS ON PLATFORM VECTOR GENE THERAPY PROGRAM. CONCEPT CLEARANCE YOU FIND ABOUT THREE DISEASES THAT ARE ALREADY BEING INVESTIGATED IN THE RARE DISEASE CLINICAL RESEARCH NETWORK, AND THAT WOULD BE ABLE TO USE -- SIGNAL THE SAME VECTOR, CONDUCTING PLATFORM TRIAL, HOW FAMILIAR DOES THAT SOUND FOR THE NCATS MISSION, RIGHT? DEVELOP A PLATFORM APPLICABLE TO THREE DISEASES IN, IF YOU CAN'T FIND THREE CUSTOM-MADE FOR USING THE SAME VECTOR TO CONDUCT GENE THERAPY AGAINST SIMILAR TARGETS, YOU CAN GO OUTSIDE THE RDCRN TO FIND A PERFECT PATCH, AND CONDUCT A PILOT CLINICAL TRIAL USING THAT ONE VECTOR AGAINST ALL THREE DISEASES IN THE CLINICS THAT WE HAVE ALREADY ESTABLISHED. SO WE APPROVED UNANIMOUSLY BOTH OF THOSE CONCEPTS. THIS IS JUST REALLY A GRAPHIC ILLUSTRATION OF THOSE SAME CONCEPTS, WHERE THEY ARE ON THE TIMELINE. THEN WE GOT TO BRAINSTORMING SESSION THAT LYNN HAS HIGHLIGHTED. IT WAS REALLY A FINE DISCUSSION, AND WE'VE SEPARATED THE DISCUSSION POINTS. WHAT WE DID IS WE ASKED THE GROUP, AND THIS WAS PRETTY WIDELY GROUPED ON THE PHONE AND IN PERSON HERE, IN DISEASE, AND WE ASKED THEM TO SHARE WITH US WHAT THEY THOUGHT WERE THE MOST IMPORTANT BARRIERS, BIGGEST OBSTACLES TO CLINICAL PROGRESS IN THEIR FIELD. AND PEOPLE RAPIDLY IDENTIFIED THE FOLLOWING FOUR OR FIVE KEY BARRIERS. THE FIRST WAS YOU'VE HEARD A LOT ABOUT BIOMARKERS, EVERYBODY NEEDS THEM, NOBODY'S GOT THEM. SECOND WAS WE HAD A GOOD NUMBER OF PEOPLE ON THE CALL IN THE MEETING THAT SAID WE'VE GOT OUR TARGETS SELECTED. WE JUST NEAT BETTER DRUGS. WE NEED COMPOUNDS THAT WILL INGEST THESE TARGETS. SECOND SET OF PEOPLE SET WE'VE GOT COMPOUNDS, MOSTLY PHARMA PARTNERS, WE'VE GOT COMPOUNDS, WE JUST NEED A BETTER SYSTEM FOR PICKING THE RIGHT DISEASE GROUP, RIGHT MECHANISM OF ACTION, RIGHT MECHANISM OF DAMAGE, RIGHT TARGETS WITHIN THOSE DISEASE GROUPS AND WE'LL START POUNDING THOSE TARGETS WITH OUR COMPOUNDS AND SEE WHICH ONE WORKS. A VERY IMPORTANT OBSTACLE, WE NEED BETTER OUTCOME MEASURES, AND, YOU KNOW, WE HEAR THAT A LOT, YOU HEAR WE NEED BETTER BIOMARKERS, NEED BETTER CLINICAL OUTCOME MEASURES. BUT THIS REALLY GOT DOWN IN DIFFERENT GRANULAR LEVEL, BECAUSE WE NOT ONLY NEED BETTER CLINICAL ENDPOINTS OF THE CLASSIC VARIETY, YOU KNOW, WE NEED BETTERWEIGHTING SCALES FOR NEUROLOGICAL CONDITIONS, BUT ALSO GOT INTO A DISCUSSION OF THINGS WE'VE BEEN HEARING FROM OUR DEAR COLLEAGUES AT THE FDA. WE'RE NOT TALKING YOU ABOUT PRIMARY OR NECESSARILY SECONDARY END POINTS. WE'RE TALKING ABOUT WAYS TO METRICS TO COLLECT ADDITIONAL EVIDENCE THAT THE PATIENT IS FEELING AND FUNCTIONING BETTER ESPECIALLY IN AN ENVIRONMENT WHICH IS ALMOST ALWAYS OUR CASE UNFORTUNATELY THAT WE'RE NOT TALKING ABOUT A CURATIVE OR PROFOUND BIBENEFICIAL COMPOUND, YOU'RE TALKING ABOUT MAYBE INCREMENTAL IMPROVEMENTS IN OUR CONDITIONS; THOSE OF US THAT HAVE NO DRUGS APPROVED WILL WELCOME THAT FIRST OPPORTUNITY. THAT ENVIRONMENT CLASSIC ENDPOINTS, SCALES YOU'RE USING, MIGHT NOT BE SUFFICIENTLY SENSITIVE TO MEASURE INCREMENTAL IMPROVEMENTS AND SO YOU NEED ADDITIONAL EVIDENCE THAT EVEN IF YOU HAVE A SLIGHT SIGNAL OF IMPROVEMENT, YOU KNOW, THE FDA DOESN'T CALLS TRUST THE CLASSIC ENDPOINT DOES THAT REFLECT IMPROVEMENT IN ACTIVITIES OF DAILY LIVING AND QUALITY OF LIFE, NOT SO SURE, BUT IF YOU HAVE THE MILD SIGNAL IN THE END POINT, COLLECT ADDITIONAL EVIDENCE THE PATIENT IS AT LEAST FEELING AND FUNCTIONING BETTER TO THE EXTENT REFLECTED IN THAT INCREMENTAL SIGNAL, AND WE ASKED THEM IMMEDIATELY WHEN THEY TOLD US THAT, DOES IT HAVE TO BE AGAINST A VALIDATED OUTCOME MEASURE, DO WE HAVE TO COLLECT THAT EVIDENCE, GOD BLESS 'EM, NO, IT DOES NOT HAVE TO BE AGAINST A VALIDATED OUTCOME MEASURE, CAN BE COMPLETELY EXPLORER TO. THEY ARE SAYING CONDUCTING A CLINICAL TRIAL, YOU COME FOR APPROVAL ON THE BASIS OF CLINICAL OUTCOME MEASURES, MILD SIGNAL, POTENTIAL MILD IMPROVEMENT, GIVE US ANOTHER REASON TO SAY YES. THIS IS VERY IMPORTANT AND THIS IS A BEAUTIFUL SEGUE TO THE NEXT POINT, AND THIS IS THE LAST ONE AS I RECALL. YES, IT IS. CRITICALLY IMPORTANCE OF HIGH QUALITY NATURAL HISTORY DATA. STEVE RAISED THAT FIRST ON THE CALL THAT, YOU KNOW, IT'S ALMOST -- IF YOU ASK ANY PATIENT ADVOCATE IN THIS ROOM OR ANY OTHER ROOM, WHAT THE MOST IMPORTANT THING THAT THEY CAN DO AS A PATIENT ADVOCACY ORGANIZATION, AND WHAT THE FDA AND NIH THINK MOST IMPORTANT THEY WILL SAY NATURAL HISTORY STUDIES, COLLECTING POPULATION, CLINICAL OUTCOME MEASURES AND BIOMARKERS AND SO FORTH. THOSE WERE THE BARRIERS THAT WERE IDENTIFIED AND SO WONDERFUL SEGUE TO THE NEXT PRESENTATION FROM PETRA BECAUSE THE NEW CONCEPT CLEARANCE SHE WILL BE AFTER WILL ADDRESS MOST OF THOSE BARRIERS. SO -- >> THANKS, RON. >> YEAH. >> I WAS JUST GOING TO CLOSE BY SAYING I THINK THE CHALLENGE FOR THE CAN REVIEW BOARD IS TO NOT ONLY SHOULD WE ADVOCATE FOR ADDITIONAL FUNDING BECAUSE I THINK THAT IS REALLY IMPORTANT FOR OUR MISSION, BUT WE CAN'T BE PARALYZED WAITING ON THAT BUCKET OF RESOURCES TO SHOW UP ON OUR DOORSTEP. HOW CAN WE MORE ACTIVELY INTEGRATE OURSELVES, BEING A CATALYST IN OTHER AREAS, LINKING WITH OPIOID GROUP, FOCUSING ON THINGS LIKE THE WEARABLE DEVICES, HAND-HELD DEVICES IN TERMS OF BUILDING BETTER PATIENT OUTCOMES, HOW CAN WE BE A CATALYST FOR THAT, WITHOUT REQUIRES TONS OF MONEY BUT LEVERAGING RESOURCES FROM OTHER INSTITUTES AND OTHER GROUPS. AND ACTUALLY I THOUGHT IT WAS A VERY EXCITING MEETING, AND HOPEFULLY PORTENDS A SHIFT IN THE CAN REVIEW BOARD MOVING FORWARD. >> I WANT TO ON BEHALF OF NCATS THANK LYNN AND RON FOR THEIR LEADERSHIP HERE. ALL OF US WERE SO VERY IMPRESSED BY THE WAIT WAY YOU RAN THAT MEETING IN DECEMBER, YOU WERE EXCITED ABOUT NEW DIRECTIONS YOU'RE TAKING US IN, SO THANK YOU. WHAT QUESTIONS DO WE HAVE, IF ANY, FOR RON AND LYNN? >> NOTHING. >> SO IN THAT CASE I THINK WE WILL -- AS RON SAID, THIS IS A NICE SEGUE INTO THE CONCEPT CLEARANCE THAT PETRA'S GOING TO DO NOW. AND I THINK WE HAVE SOME DISCUSSANTS, RIGHT? >> THANK YOU SO MUCH, LYNN AND RON, FOR SETTING THE STAIN FOR THIS. I APOLOGIZE FOR MY VOICE. HOPE YOU CAN HEAR ME. I'M LOOKING TO CREATE A CONCEPT FOR CLINICAL TRIAL READINESS FOR RARE DISEASES, AND I'M PRESENTING ON BEHALF OF THE ENTIRE TEAM AND STAKEHOLDERS WHO HAVE DISCUSSED THIS IMPORTANT TOPIC WITH US. THERE ARE OVER 7,000 RARE DISEASES, ACTUALLY THE NUMBER KEEPS INCREASING IT SEEMS RAPIDLY, LESS THAN 5% HAVE EFFECTIVE TREATMENT. ON THE OTHER HAND, WE HAVE UNPRECEDENTED OPPORTUNITIES IN PART AS A RESULT OF NIH INVESTMENTS NOW TO HAVE AN UNDERSTANDING OF WHAT CAUSES DISEASES AND HOW WE CAN ACTUALLY WITH SOME OF THE BREAKTHROUGH TECHNOLOGIES NOW MAKE A TRANSFORMATIVE DIFFERENCE. WE OFTEN KNOW THAT IT'S DIFFICULT TO FIND THE BUSINESS MODEL FOR THERAPY DEVELOPMENT IN RARE DISEASE, SO TO THE EXTENT WE CAN HELP DE-RISK PRIVATE SECTOR INVESTMENT AND WE'VE LEARNED OF COURSE WHAT THE PRIVATE SECTOR IS LOOKING FOR IS HAVING HIGH-QUALITY OUTCOME MEASURES, TO THAT EXTENT WE WANT TO DO SO, HELP RARE DISEASE INDICATIONS NOT ABLE TO GET MUCH ATTENTION. WE ALSO KNOW ON A DAILY BASIS IN THE OFFICE OF RARE DISEASES RESEARCH THAT OUR PATIENT GROUPS ARE ACTIVELY SEEKING TO CONTRIBUTE TO TRIAL READINESS IN THEIR FIELD FOR THEIR DISEASE, BY COLLECTING NATURAL HISTORY STUDIES. WE PARTNERED WITH THE FDA IN RECENT YEARS ON THE NATURAL HISTORY INITIATIVE, AND WE BELIEVE THAT AS BACKGROUND AND SUMMARY IT'S CRITICAL THAT IN A GIVEN DISEASE INDICATION THERE BE HIGH QUALITY NATURAL HISTORY DATASETS SO WE CAN UNDERSTAND THE PRESENTATION IN THE DISEASE, HAVE INFORMATION ABOUT APPROPRIATE SAMPLE FOR A GIVEN STUDY, AND ALSO WE CAN LEARN MORE ABOUT OUTCOME MEASURES, HOW SENSITIVE, RELIABLE, VALID RESPONSIVE AND MEANINGFUL ARE THEY. AND THESE SLIDES BRIEFLY REGARDING THE GOALS, SO ONE GOAL IS THAT WE HAVE THE RIGHT SCOPE, SO WE HAVE VERY LIMITED BUDGET AND UNCERTAINTY ABOUT THE BUDGET, BUT ON THE OTHER HAND OF COURSE THERE'S OVER 7,000 DISEASES, WE COULD IMAGINE THERE COULD BE A VERY VAST NUMBER OF GROUPS, UNDERSTANDABLY AND JUSTIFIABLY SO, SEEKING OUR ASSISTANCE. WE HAD TO HONE IN ON SOMETHING WHERE OUR INVESTMENT WOULD MAKE THE BIGGEST DIFFERENCE, WE DO NOT HAVE UNLIMITED BUDGET, ADDRESSING STUDIES TO OBSTACLES OF UPCOMING TRIALS, NOT AN ENTIRE HISTORY, THAT WOULD BE GREAT, BUT THE TRIAL THAT IS SETTING THE STAGE FOR SUCCESSFUL TRIALS. THE TIMES OF DESIGNS COULD BE CROSS-SECTIONAL, RETROSPECTIVE, PROSPECTIVE BUT GIVE HIGHER PRIORITY TO DISEASES THAT HAVE CANDIDATES AWAITING CLINICAL TRIAL AND GIVE HIGHER PRIORITY TO DISEASES WHERE PARTNERSHIPS ARE LEVERAGES, IN FIND OR FUNDED, IF THERE'S A COMPANY INTERESTED IN DOING A TRIAL OR PATIENT GROUP, AND WE WOULD ALSO WANT TO MAKE SURE THAT THE FDA REMAINS INVOLVED AS A PARTNER, FOR EXAMPLE, THROUGH CRITICAL PATH MEETINGS, AND THROUGH THE CONSIDERATION OF RELEVANT GUIDANCE IN THESE APPLICATIONS. THE STUDIES COULD BE STAND-ALONE BUT CERTAINLY COULD ANCILLARY TO ONGOING STUDIES OR NETWORKS BECAUSE WE ANTICIPATE BUDGETARY LIMITATIONS, THAT WOULD BE A GOOD JOB, BUT OPTIONAL. AND IT COULD ALSO CERTAINLY HELP US IN PROMOTING HARMONIZATION AND ALSO FOSTERING INNOVATION POTENTIALLY FROM THINGS THAT CAME UP IN THE CAN BOARD PRESENTATION OR USING EHR MORE USING, FOR EXAMPLE, APPROACHES AND ANTICIPATE THAT SUCH STUDIES WOULD BE CARRIED OUT AT MULTIPLE SITES. LOWER LIKELIHOOD IN THE AREAS OF CANDIDATE THERAPEUTICS HAVE LESSER PRIORITY, ALSO INDICATIONS THAT HAVE ALREADY A NUMBER OF ONGOING OR COMPLETED TRIALS BECAUSE THEN THE READINESS WOULD KIND OF ALREADY BE TESTED. IT IS NOT INTENDED TO SUPPORT I.T. PLATFORMS, AND ALSO NOT INTENDED TO HELP BIOMARKER DISCOVERY, CHARACTERIZATION OR CORD CHARACTERIZATION, THAT WOULD BE MAYBE OTHER MECHANISMS FOR THAT. OUTCOME WOULD BE NCATS IN PARTNERSHIP WITH OTHER NIH INSTITUTES AND CENTERS, BUT ALSO PATIENT GROUPS AND PRIVATE SECTOR STAKEHOLDERS, SOLICIT THESE APPLICATIONS AND MAKE POTENTIAL IMPACT IF EVIDENT UNDER THE MISSION OF OFFICE OF RARE DISEASES RESEARCH TO ACCELERATE RARE DISEASE TO BENEFIT PATIENTS AND UNDER NCATS MISSION TO BRING MORE TREATMENTS TO PATIENTS AND ACCELERATE THE PROCESS AND HOPE TO ADDRESS THEIR CRITICAL GAPS IN AREAS WHERE THIS INVESTMENT WOULD HOPEFULLY LEAD TO RETURN IN FUTURE, THEN PRESENTING THESE CONCEPTS WE'RE ALWAYS ASKED TO SHARE WITH YOU WHAT WE WOULD CONSIDER CRITERIA FOR EVALUATING SUCCESS. I THINK SUCCESS WOULD BE IF SOME OF THE PRODUCTS OF THE INITIATIVES WERE TO BE USED IN CLINICAL TRIALS, NATURAL HISTORY DATASET WORKED, USE FOR PLANNING A TRIAL OR IF A BIOMARKER OUTCOME MEASURE STUDIED UNDER THIS INITIATIVE COULD BE HELPFUL FOR PLANNING, AND A SUCCESS IF IN A GIVEN INDICATION WE SEE TRIALS BEING LAUNCHED. OBSTACLES ARE OF COURSE BUDGETARY UNCERTAINTY, AND ASKED TO GIVE AN OVERVIEW OF THE LANDSCAPE IN TERMS OF OTHER INITIATIVES IN THIS SPACE. ONE THAT WE WERE PARTICULARLY INTERESTED IN THE EFFECT COLLABORATING WITH NINDS CLINICAL TRIAL READINESS, RARE NEUROLOGICAL AND NEUROMUSCULAR DISEASES ANNOUNCEMENT. THAT HAS BEEN IN PLACE FOR A NUMBER OF YEARS. ALSO AN INITIATIVE BY NICHD, ORPHAN PRODUCTS, NATURAL HISTORY PROGRAM, AND THEN WITHIN NCATS RELEVANT TO THE RARE DISEASES CLINICAL RESEARCH NETWORKS WHICH ARE IN THE SAME SPACE BUT DIFFERENT BECAUSE THEY HAVE A LARGER NETWORK THAT SORT OF DOES A NUMBER OF STUDIES AND ALSO INTO THE TRIAL NETWORK THAT CAN PROVIDE SOME PLATFORMS AND SOME OF THE TREATMENT INFRASTRUCTURE THAT IS SO CRITICAL IN PARTICULAR FOR RARE DISEASES I'M THINKING OF THINGS LIKE SINGLE IRB, FOR EXAMPLE. SO WITH THIS, AGAIN, I WANT TO POINT OUT THAT I'M PRESENTING ON BEHALF OF THE ORDR TEAM, IN PARTICULAR (INDISCERNIBLE) WHO HELPED IN HER SHORT TENURE, AND I'LL BE HAPPY TO ANSWER QUESTIONS. >> WE HAVE TWO DISCUSSANTS. >> YES, RON AND STEPHEN. >> RON AND STEPHEN. >> OKAY, I'LL BE GLAD TO GO FIRST. FIRST, I'M VERY ENTHUSIASTIC ABOUT THIS CONCEPT. I THINK IT'S WONDERFULLY DESIGNED, AND FOR SOME OF THE REASONS LYNN AND I STATED, YOU KNOW, IT REALLY ADDRESSES SOME KEY OBSTACLES AND MIGHT PRESENT A PLATFORM FOR A LOT OF DISEASE GROUPS TO MOVE FORWARD MORE RAPIDLY. REALLY CRAZY ABOUT THE AMOUNT OF COLLABORATIVE ENERGY THAT WE'VE EXPRESSED. I MEAN, COLLABORATING WITH NINDS AND CLINICAL TRIAL READINESS PROGRAM HAS BEEN UNDERWAY FOR A COUPLE YEARS, AND THE FDA'S NATURAL HISTORY STUDY GRANT PROGRAM REALLY VERY IMPRESSED WITH THE PROGRESS THEY ARE MAKING. AND THE NICHD PROGRAM. AND COLLABORATION, YOU'RE PRIORITIZING WITHIN INDUSTRY AND PATIENT ADVOCACY GROUPS, JUST SEEMS LIKE, YOU KNOW, YOU'VE REALLY PUT SOME SOLID THOUGHT BEHIND THE COLLABORATIONS YOU WANT TO INSTILL. AND ALSO REALLY IMPRESSED WITH YOUR USE, IN MY EXPERIENCE, IN THE FEW TIMES WE'VE GONE TO A CTSA PROGRAM ASSET LIKE THE TRIAL INNOVATION NETWORK AND APPLIED TO THE RARE DISEASE COMMUNITY, I THINK IT'S A WONDERFUL OPPORTUNITY TO BRING THOSE TWO POWERFUL NCATS ASSETS TO PLAY FOR RARE DISEASES THAT NEED IT SO BADLY. AND ALSO REALLY FASCINATED BY YOUR REFERENCE TO THE TECHNOLOGIES NEEDED TO BE ADVANCED IN TERMS OF CLINICAL OUTCOME MEASURES. AS I JUST SORT OF EMOTIONALLY EXPRESSED, WE'RE REALLY EXCITED ABOUT THE FDA'S INTEREST IN OUR ABILITY TO COLLECT ADDITIONAL EVIDENCE AGAINST NON-VALIDATED EXPLORATORY ENDPOINTS. WHAT BETTER OPPORTUNITY TO LOOK AT THINGS LIKE WEARABLES AND CARRYABLE TECHNOLOGIES TO REPORT ON HOW THE PATIENT IS FEELING AND FUNCTIONING ON A DAILY BASIS IN THEIR OWN ENVIRONMENT, NOT EVERY THREE MONTHS WHEN THEY COME TO THE CLINIC AFTER AN ALL-NIGHT FLIGHT FROM CALIFORNIA AND SO FORTH. SO I THINK THOSE ARE WONDERFUL ASPECTS OF WHAT YOU'RE WANTING TO GET DONE. I'LL STOP THERE. I DO HAVE ONE QUESTION MAYBE. IT IS WITH ALL THAT COLLABORATIVE ENERGY, YOU'RE READY TO EXERT, IF YOU'RE LOOKING AT OTHER GRANT PROGRAMS, FOR EXAMPLE, NINDS AND NICHD AND FDA, WHAT WOULD BE THE INTERFACE, THE ACTUAL INTERFACE? HOW WILL YOUR PROGRAM -- LET'S SAY IT FINDS THAT DISEASE GROUP THAT REALLY NEEDS YOUR HELP WITH NATURAL HISTORY OR CLINICAL OUTCOME MEASURES AND SO FORTH, BIOMARKERS, WHATEVER, HAS A GRANT FROM NICHD, OR NINDS, OR THE FDA. SO WILL THAT INCREASE OR DIMINISH THE CHANCES OF GETTING SUPPORT? AND HOW WILL THE TWO GRANTS WORK TOGETHER? HOW DO YOU ENVISION THAT KIND OF INTERFACE? >> SO THE NEED IS OF COURSE VERY GREAT IN THE RARE DISEASES SPACE. SO THAT I THINK, YOU KNOW, WE'RE NOT TOO CONCERNED THAT THERE'S ANOTHER OPPORTUNITY COMING UP FOR GETTING THIS KIND OF DATA FOR RARE DISEASES, GIVEN THE LARGE NUMBER OF RARE DISEASES THAT I THINK NOW HAVE REALLY TREMENDOUS OPPORTUNITIES THERE IN TERMS OF THE SCIENTIFIC FOUNDATION FOR DEVELOPING EFFECTIVE TREATMENTS. AND LIKE WITH EVERY NIH GRANT, SHOULD I THINK -- IT'S DIFFICULT TO ANSWER OUTSIDE SO IT DEPENDS REALLY ON MAKING THE CASE. SO IT COULD BE SYNERGY. SOMEBODY COULD AS I MENTIONED FOR EXAMPLE DESCRIBE HOW RELATIVELY SMALL ADDITIONAL INVESTMENT, YOU KNOW, ADDED PERHAPS AN ANCILLARY STUDY TO AN EXISTING PROGRAM COULD REALLY GIVE THAT PIECE OF -- THAT TOOL OR PIECE OF NATURAL HISTORY INFORMATION THAT IS CRITICAL TO BE READY FOR TRIAL. IT COULD ALSO BE THAT PEER REVIEWERS REVIEWERS WILL HELP US VALIDATE AS ALWAYS. IN ANOTHER PROJECT SAY THERE'S ALREADY SOMETHING VERY SIMILAR AND OF COURSE WE ALWAYS FROM STEWARDSHIP PROGRAM PERSPECTIVE OF COURSE LOOK FOR OVERLAP WITH OTHER NIH INSTITUTES, FOR EXAMPLE, WORK CLOSELY WITH NIH COLLEAGUES ALREADY IN MANY INITIATIVES SUCH AS RARE DISEASES CLINICAL RESEARCH NETWORKS THAT ARE OF COURSE RELATED TO THIS NEW CONCEPT PROPOSAL AND ALSO WORK WITH COLLEAGUES AT THE FDA, CERTAINLY INDIVIDUAL CASE-BY-CASE BASIS ADDRESS THESE KINDS OF ISSUES. >> MY LAST QUESTION WAS WHAT KIND OF RESOURCES DO YOU ENVISION? >> YES. EXCELLENT QUESTION. THE NEED IS CERTAINLY GREAT. WE HAVE NO CERTAINTY REGARDING RESOURCES, SO AS YOU HEARD EARLIER HOPEFULLY IT WILL BE ENOUGH TO MEET SOME OF THE NEED. >> THANKS. I REALLY CONCUR WITH WHAT RON HAS SAID AND WITH YOUR PRESENTATION, PETRA. IT'S VERY CLEAR THAT A LARGE NUMBER OF CLINICAL TRIALS, NOT BECAUSE THE COMPOUNDS DON'T WORK BUT BECAUSE WE DON'T UNDERSTAND NATURAL HISTORY OF DISEASE AND THEREFORE DESIGN STUDIES AND STUDIES FAIL, NOT THE DRUGS OR INTERVENTION. SO THIS IS REALLY TIMELY, AND AS RON INDICATED, I THINK THERE'S GREAT SYNERGY POTENTIAL ASSUMING WE CAN BRING ALL THESE THINGS TOGETHER. THERE ARE A COUPLE OTHER THOUGHTS. I MEAN, WHEN I WAS IN MEDICAL SCHOOL, IF YOU'LL EXCUSE THE EXPRESSION, IN THE 1960s, I WAS TAUGHT THAT UNDERSTANDING RARE GENETIC DISEASES PROVIDES ENORMOUS INSIGHT INTO THE REST OF HUMAN BIOLOGY. AND I THINK THERE IS EVEN MORE OF AN OPPORTUNITY OF AN INITIATIVE LIKE THIS FOCUSED ON RARE DISEASE TO GENERALIZE IN CLINICAL TRIALS IN GENERAL AND DISEASE STATES IN GENERAL. A COUPLE THOUGHTS IN THAT REGARD. EVEN FOR COMMON CONDITIONS, WE DON'T OFTEN DESCRIBE THE DISEASES ADEQUATELY. WE DON'T HAVE RICHNESS OF CLINICAL INFORMATION. WE DON'T HAVE THE RICHNESS OF PATIENT INPUT. AND WE DON'T HAVE THE RICHNESS OF ONE GROUP THAT WAS LEFT OUT OF THIS, I WANT TO SPEND A COUPLE SECONDS ON THAT, PHYSICIANS WHO TAKE CARE OF THE PATIENTS. EHRs ARE USELESS UNLESS DOCS ARE COLLECTING THE CORRECT INFORMATION. AND THERE IS AN OPPORTUNITY HERE, BOTH IN THE RARE SPACE, BECAUSE THE NUMBER OF PHYSICIANS FOCUSED ON PATIENTS ARE RARE DISEASES OFTEN KNOW THOSE PATIENTS IN DETAIL. BUT ALSO DON'T COLLECT DATA IN A WAY THAT BECOMES USER FRIENDLY FOR CLINICAL TRIALS SUBSEQUENTLY. CYSTIC FIBROSIS DOCS ARE GOOD AT THIS, ONE OF THE REASONS CF MOVED FORWARD AS WELL. I WOULD ARGUE WE SHOULD BE TALKING BOTH TO THE DOCS AS WELL AS PATIENTS, AND MAYBE PROVIDING SOME WAYS AND PATHWAYS FOR PATIENTS AND DOCS TO INTERACT MORE EFFECTIVELY IN WHAT THEY DO IN EXPRESSING WHAT THE ISSUES ARE, EXPRESSING THE NATURAL HISTORY OF THE DISEASES, AND PUTTING THAT TOGETHER IN STANDARD FORMAT SO THAT THE EHRs CAN BECOME MORE THAN BILLING DOCUMENTS. THEY CAN BECOME EFFECTIVE RESEARCH TOOLS. THE SECOND ISSUE I HAVE TO PUT ON MY PEDIATRIC HAT AGAIN AND I'M GLAD YOU'RE TALKING TO THE FOLKS AT NICHD, BUT ALSO REGULATORY ISSUES IN FDA AND PEDIATRIC VERSUS ADULT STUDIES IN ALL DISEASES. RARE DISEASE MAY BE EASIER IN A WAY BUT NATURAL HISTORY AND PROGRESS OF RARE DISEASE IN A 2-YEAR-OLD TO A 5-YEAR-OLD IS VERY DIFFERENT THAN IT IS IN A 40-YEAR-OLD VERSUS A 45-YEAR-OLD. OKAY? AND THE FDA STRUGGLES ALL THE TIME BOTH IN COMMON AND RARE DISEASES TO, QUOTE, EXTRAPOLATE EFFICACY OF A DRUG FROM ITS BENEFIT IN THE ADULT POPULATION TO THE PROBABLE BENEFIT FROM BENEFIT IN THE PEDIATRIC POPULATION. TRIALS DON'T OF OFTEN DON'T INCORPORATE DIFFERENCES BETWEEN THE WAY THE CHILD DISEASE PROGRESSES VERSUS ADULT DISEASE NOR OUTCOME VARIABLES A 5-YEAR-OLD CAN DO VERSUS A TEENAGER, VERSUS AN ADULT. THIS APPLIES BOTH TO RARE DISEASES AND TO COMMON DISEASES, AND IS ONE OF THE REASONS WE'RE NOW SEEING MAJOR PROBLEMS IN FDA'S ABILITY TO SCIENTIFICALLY IMPLEMENT LEGISLATION AND TO USE KNOWLEDGE FROM ADULTS INTO THE PEDIATRIC POPULATION. SO, IN A WAY, AGAIN, GOING BACK TO WHAT I WAS TAUGHT IN MEDICAL SCHOOL, LOOKING AT THE RARE DISEASE POPULATION, WE SHOULD BE ABLE TO GAIN A LOT OF INSIGHT IN WHAT TO DO ON THE NON-RARE DISEASE POPULATIONS. BUT I THINK WE SHOULD BE THINKING ABOUT THAT SORT OF UP FRONT. WHAT ARE THE LESSONS, IF YOU WILL, THE PLATFORM THAT WE USE FOR RARE DISEASE, HOW CAN THAT BE APPLIED TO SAVING CLINICAL TRIALS IN GENERAL, WHICH CONTINUE TO FAIL IN EVERYTHING FROM DIABETES UP AND DOWN THE LINE. COMMON THINGS AND RARE THINGS. IT COULD UNITE US FOR VERY RICH DIALOGUE, AND THE ONE THING I WOULD AT LEAST PUT ON THE SLIDE, DON'T OMIT THE DOCS. GUYS IN PRACTICE ARE FEELING A LITTLE BIT LEFT TO THE SIDE AND IF THEY CAN BE BROUGHT INTO THE PROCESS USING CTSAs AS EXAMPLE OF HOW DOING CLINICAL MEDICINE IS DOING SCIENCE SIMULTANEOUSLY, IF WE ASK THE RIGHT QUESTION, PARTNER WITH YOUR PATIENTS AND PUT THAT INFORMATION IN A COHERENT FORM IN AN EHR THAT NIH CAN USE, FDA CAN USE, THAT PHARMACEUTICAL SPONSOR CAN USE. >> THANK YOU FOR THE EXCELLENT POINT. I THINK YOUR POINT REGARDING EXTRAPOLATING OR LEARNING FROM RARE DISEASES FOR COMMON DISEASES IN PARTICULAR NOW TIMELY THAT WE'RE LOOKING AT PRECISION MEDICINE IN LUNG CANCER DEVELOPMENT RECENTLY YOU COULD SAY SOME RARE DISEASES AND METHODOLOGIES ARE THE OTHER SIDE OF THE COIN, PERSONALIZED, INDIVIDUALIZED, THANK YOU. >> YEAH, THIS SOUNDS WONDERFUL. AND A COUPLE COMMENTS, JUST SO WE KEEP MOVING OUTSIDE THE BOX THAT WE CURRENTLY TRAVEL IN MOST EASILY. ONE IS YOU SAID THESE WERE PROBABLY MULTIPLE SITES. I JUST WOULD OFFER IF IT'S, FOR EXAMPLE, AN ADVOCACY ORGANIZATION APPLICANT LOOKING AT PROs COLLECTED THROUGH SMARTPHONE, THAT THE FIGHT WON'T MAKE ANY DIFFERENCE OTHER HAVE SENSIBILITY AND LOTS OF US DON'T WORK IN FIGHTS, WE WORK BASED ON INDIVIDUALS, ONE COMMENT. THE OTHER IS A LOT OF US, MOST OF US, ARE NOT CONNECTED TO ANY OF THE EXAMPLES YOU GAVE IN TERMS OF NETWORKS, FDA AND NINDS AND OTHERS BECAUSE WE HAVEN'T BEEN ABLE TO BREAK INTO THOSE AREAS. PRECISELY FOR THE REASONS THAT YOU'RE TRYING TO ADDRESS. AND SO I HOPE THAT IN THE REVIEW WE WON'T HAVE THE SCENARIO THOSE OF US NOT ALREADY PART OF SOMETHING LIKE RARE DISEASE CLINICAL RESEARCH NETWORK OR OTHER THINGS ARE DINGED ESSENTIALLY FOR THAT. >> GOOD POINT. >> OKAY. >> I KEEP SOUNDING LIKE A BROKEN RECORD BUT I'M GOING TO CONTINUE TO PLAY IT AGAIN. MOST PEOPLE WITH RARE DISEASES HAVE SOME TYPE OF INSURANCE OR SOMETHING THAT IS SUPPORTING THEIR CARE. SO DO NOT ELIMINATE OR DON'T LIMIT OURSELVES WITH THE OPPORTUNITY TO PARTNER WITH BOTH HEALTH CARE PROFESSIONALS, BECAUSE AGAIN THOSE PEOPLE WITH RARE DISEASES, THEIR NEXT VISIT IS EVEN MORE PREDICTABLE, AND A LOT OF TIMES THAT'S WHEN YOU CAN REALLY GET PEOPLE TO BEGIN TO GIVE YOU THEIR NATURAL HISTORY AND GET THAT NATURAL HISTORY JUST FROM THE INSURER'S RECORD OR ELECTRONIC HEALTH RECORD, SO LET'S NOT LEAVE THEM OUT AS PARTNERS. >> THANK YOU. >> GOOD. DO YOU WANT TO DO THE VOTE? [APPLAUSE] >> HEARING NO MORE DISCUSSION, AND A ROUND OF APPLAUSE, I'M GOING TO ASK FOR A MOTION TO APPROVE THE CONCEPT. >> SO MOVED. >> SECOND? >> YES. >> ANY OPPOSED? ALL IN FAVOR? >> AYE. >> ANY OPPOSED? ANY ABSTENTIONS? CONCEPT IS APPROVED UNANIMOUSLY. THANK YOU. >> SO THANKS, EVERYBODY. ONE THING I SHOULD HAVE SAID BEFORE, FOR THE NEW FOLKS, IF YOU SEE SOMETHING IN FRONT OF YOU, A GREEN THUMB DRIVE THAT SAYS ACTIVITY SUMMARY ON IT, WHAT THAT IS IS JUST WHAT IT SAYS. IT'S AN ACTIVITY -- IT'S A SUMMARY, BRIEF SUMMARY, OF WHAT WE THINK ARE THE COGENT ACTIVITIES THAT HAVE HAPPENED AT NCATS, DISCOVERIES, ACTIVITIES, ET CETERA, SINCE THE LAST COUNCIL MEETING. IT'S RELATIVELY SHORT AND WITH IT THERE ARE LINKS TO MORE INFORMATION. IT CAN'T COVER ANYTHING IN THE DIRECTOR'S UPDATE SO WE WANT YOU TO HAVE THESE. WE USED TO HAND IT OUT AS PAPER BUT WE'RE TRYING TO SAVE TREES. SO THAT'S WHAT THIS IS. SO PLEASE HAVE A LOOK AT IT ON YOUR PLANE ON THE WAY BACK. HMM? >> (INAUDIBLE). >> OH MY HEAVENS. OH, MAN. WE SHOULD MAKE THEM PURPLE, SO THEY ARE NCATS COLORS. IF YOU HAVE YOUR LAPTOP AND WANT TO DOWNLOAD ON YOUR COMPUTER AND GIVE IT BACK TO ANNA WE'LL RECYCLE THEM AND USE THEM FOR NEXT TIME. OKAY. I'M GOING TO GIVE YOU AN ORIENTATION TO WHAT DPI IS AND WHERE IT FITS WITH THE NEW ORGANIZATION AND HAND OFF. BACK TO THE NCATS MISSION, YOU ALL KNOW GENERATION OF INNOVATIVE METHODS AND TECHNOLOGIES, IN THE PRE-CLINICAL SPACE, FROM TARGET VALIDATION THROUGH TO FIRST-IN-HUMAN, ALL IN THAT SPACE. THIS IS THE SPECTRUM YOU'VE SEEN BEFORE, JUST TO REMIND YOU WE DON'T USE THE T1 THROUGH T4 TERMINOLOGY. WE USE WORDS WHICH WE HOPE ARE UNDERSTANDABLE, SO INSTEAD OF T 0 BEING BASIC, WE USE CLINICAL RESEARCH, AND PUBLIC HEALTH, REMEMBER BASIC RESEARCH IS IN PURPLE, NOT BECAUSE WE THINK IT'S IMPORTANT, WE DO, MANY OF US STARTED AS BASIC RESEARCHERS, BUT WE ALL DO IT, RELY ON COLLEAGUES IN THE BASIC RESEARCH WORLD TO SUPPLY THAT INFORMATION AND WE DO THE TRANSLATION. SO WHAT YOU'RE GOING TO HEAR ABOUT IS THIS. DIVISION OF PRE-CLINICAL INNOVATION. YOU'VE BEEN HEARING ABOUT CLINICAL RESEARCH, CLINICAL IMPLEMENTATION, PUBLIC HEALTH, PATIENT INVOLVEMENT, BUT THIS IS WHAT YOU'LL HEAR ABOUT NOW. IT'S NOT ALL OF THE AREAS OF PRE-CLINICAL INNOVATION AT NCATS ARE IN DPI, TISSUE CHIP PROGRAM IS A PRE-CLINICAL PROGRAM. BUT THIS IS THE LARGEST PART OF IT. OKAY. YOU I THINK HAD SEEN THIS. I HOPE YOU'VE SEEN IT BEFORE. THIS IS THE LIST THAT WE USE AROUND HERE OF THE TRANSLATIONAL PATIENTS PROBLEM LIST, IF YOU THINK ABOUT THE TRANSLATIONAL PROBLEM AS A PATIENT, THIS IS THE PROBLEM LIST THE PATIENT HAS. THESE ARE ALL THE REASONS THAT ARE INDEPENDENT OF ANY DISEASE THAT BEDEVIL EVERY TRANSLATIONAL PROJECT NO NATURALLER -- MATTER THE DISEASE. THE ONES YOU'RE HEAR ABOUT FOR DPI ARE THESE, PREDICT I CAN TOXICOLOGY, -- PREDICTIVE TOXICOLOGY. UNDRUGED MEANS THERE IS A PROTEIN OR A GENE WHICH HAS BEEN IDENTIFIED IN HUMANS AS POTENTIALLY BEING INTERVENTION POINT IN A DISEASE BUT THERE HAS BEEN NO SMALL MOLECULE OR ANTIBODY, NO EXOGENOUS AGENT DEVELOPED TO MODULATE IT, TO TURN IT BACK ON, IF A DISEASE TURNS IT OFF, OR TURN IT OFF IF A DISEASE HAS TURNED IT ON. THAT'S WHAT WE'RE ALWAYS TRYING TO DO. THOSE ARE THE THREE THINGS YOU'LL HEAR IN LARGE PART FROM ANTON. WE ALSO HAVE THIS LIST OF CULTURAL ORGANIZATIONAL PROBLEMS THAT WE WORK ON AS INNOVATION 2. AND ONES THAT DPI WORKS ON ALL OF THESE. SO DATA TRANSPARENCY, EPIGENETIC, PROJECT MANAGEMENT, CREDIT FOR TEAM SCIENCE, EDUCATION, COLLABORATIVE STRUCTURES, THEY WORK VIA THE 3D PARADIGM, YOU'RE HEAR ABOUT INDIVIDUAL PROJECTS, A STRUCTURE WHICH ANTON WILL TELL YOU ABOUT. THESE ARE THE DEMONSTRATION PROJECTS. WHAT DPI IS DOING IS DEVELOPING NEW WAYS OF DOING SOME ASPECT OF PRE-CLINICAL TRANSLATION, BETTER FASTER CHEAPER, MORE EFFICIENTLY, AND REACH OUT TO THE ENTIRE RESEARCH COMMUNITY FOR TARGET EXPERTS, DISEASE EXPERTS TO COLLABORATE WITH US, WE CAN'T HAVE EXPERTISE IN 7,000 DISEASES AND BRING IN DEMONSTRATION PROJECTS VIA COLLABORATION AND THEN IF THOSE WORK OF COURSE WE WORK ON DISSEMINATING THEM. ANOTHER WAY TO THINK ABOUT THIS IF YOU'RE AN AFAIR AN AFICIONADO OF THE VALLEY OF DEATH WHICH ALL OF US ARE IN A STRANGE KIND OF WAY IS THIS. I ADAPTED THIS SLIDE FROM SCOTT WEIR, UNIVERSITY OF KANSAS, THERE'S A FAIR AMOUNT OF FUNDING FROM THE GOVERNMENT AND PHILANTHROPY, IDENTIFYING CAUSES DISEASES, THESE ARE TARGETS, SOMETIMES TARGETS FOR INTERVENTION THEY ARE CALLED, AND THAT'S ACTUALLY QUITE WELL FUNDED. OVER HERE THE PRIVATE SECTOR, DEVELOPMENT OF INTERVENTIONS FOR PROVEN TARGETS, DE-RISKED TARGETS, THERE'S QUITE A BIT OF MONEY FOR THAT TOO. BUT IN THE MIDDLE THERE HAS ALWAYS BEEN A SPACE WHICH IS TOO APPLIED FOR NIH, TOO RISKY FOR INDUSTRY. ACTUALLY THE MAJORITY OF TARGETS, MAJORITY OF DISEASES, FIT IN THIS CATEGORY. SO THE CURRENT NUMBER IS 90% OF TARGETS ENCODED BY HUMAN GENOME HAVE NEVER BEEN STUDIED. 90%. 95% OF DISEASES HAVE NO TREATMENT, OF THOSE 95% NOBODY IS WORKING ON, ENORMOUS SPACE TO WORK ON. IT MAKES PERFECT SENSE. THIS IS THE VALLEY OF DEATH. NCATS LIVES IN THE VALLEY OF DEATH ON PURPOSE. AND OUR GOALS AS I SAID LAST NIGHT, TO TURN THE VALLEY OF DEATH INTO THE OASIS OF LIFE. [LAUGHTER] I COULD WRITE A BOOK ABOUT THAT OR SOMETHING. THAT'S WHAT WE'RE TRYING TO DO. HERE IS THE MODEL. SO HAVE FUNDING WHICH GOES ALL THE WAY ACROSS, WHERE THE INNOVATIONS TURN POTENTIAL, THAT'S WHAT THE DISCOVERY IS, THE DISCOVERY SAYS, GOSH, I THINK THIS TAR TARGET COULD BE GREAT FOR THIS DISEASE. THEY PUBLISH A PAPER, A DRUG IN 3 TO 5 YEARS BECAUSE POTENTIAL IS SO GREAT. POTENTIAL IS NOT THE SAME THING AS REALITY, RIGHT? WE'LL TALKED ABOUT THAT WITH THE TISSUE CHIPS. IT'S CERTAINLY TRUE FROM A BUSINESS PERSPECTIVE. BUSINESS PEOPLE DO NOT FUND BY AND LARGE POTENTIAL WAY DOWN HERE. POTENTIAL DE-RISKED TO SOME DEGREE, SURE, BUT YOU CAN'T MEET YOUR FIDUCIARY RESPONSIBILITY TO SHAREHOLDERS TAKING TOO MUCH RISK. THAT'S A BAD THING. THAT'S WHAT WE DO IN THE MIDDLE, TURN POTENTIAL INTO PROOF-OF-CONCEPT. ONCE THAT'S DONE, DE-RISK AND GO TO THE NEXT ONE AND THEN THE PRIVATE SECTOR, OTHER ORGANIZATIONS, ET CETERA, CAN TAKE IT ON. SO THE GOAL HERE IS TO TURN THE DEAD STEER INTO A HAPPY STEER, REMEMBER IN THE VALLEY OF DEATH THAT'S WHAT IT LOOKS LIKE. THEY ALWAYS SHOW THE DEAD STEER. WE WANT A LARGE NUMBER OF HAPPY STEERS. THAT'S THE IDEA. OKAY. SO WHAT ANTON IS GOING TO USE FOR THOSE NOT FAMILIAR WITH THIS TERMINOLOGY, I WANTED TO INTRODUCE YOU TO THIS, BECAUSE ANTON MAY USE A LOT OF VERNACULAR THAT IF YOU DON'T LIVE IN THIS WORLD IT MAY BE FOREIGN. I'LL INTRODUCE CONCEPTS. DOWN HERE IS DISEASE MECHANISM, RIGHT? THIS IS NCATS DOESN'T DO A BASIC RESEARCH, AS TYPICALLY ENVISIONED. SO WE START HERE, AND THIS IS ESSENTIALLY DRUG DEVELOPMENT IN SIX EASY STEPS. THIS IS CLINICAL TRANSLATIONAL PROCESS, USING SMALL MOLECULE DRUGS HERE AS EXAMPLE, DIFFERENT FOR ANTIBODIES, DEVICES, BEHAVIORAL INTERVENTIONS BUT THE CONCEPT IS BASICALLY THE SAME. ONE HAS TO IDENTIFY A TESTING SYSTEM KNOWN IN THE BUSINESS AS AN ASSAY, JUST MEANS TRY IN FRENCH, ASSAY DEVELOPMENT. ONE HAS TO TRY LOTS OF POTENTIAL OUTCOMES BECAUSE WE DON'T UNDERSTAND WHAT THE GENERAL PRINCIPLES ARE, UNDERLYING THESE STAGES OF THE TRANSLATIONAL PROCESS, WE HAVE TO GUESS. AND WE HAVE NO IDEA WHAT WE'RE LOOKING FOR, SO WE TEST HUNDREDS OF THOUSANDS OF POTENTIAL COMPOUNDS, MILLIONS OF POTENTIAL COMPOUNDS, BECAUSE -- AND OVER TIME WHAT WE'RE TRYING TO DO IS DEFINE THE RULES BUT RIGHT NOW WE CAN'T SO WE TEST LOTS OF COMPOUNDS. AS YOU KNOW HERE ONCE YOU GET OUT OF THESE THINGS, IT'S NEVER A DRUG, NEVER CLOSE. YOU HAVE TO DO A LOT OF CHEMISTRY IN THE MIDDLE, TEST IN ANIMALS AND HOPEFULLY TISSUE CHIPS BEFORE LONG AND TEST IN HUMANS. WHAT PART OF THIS DOES DPI DO? THIS PART. IT WORKS ON MECHANISMS THAT WERE DISCOVERED IN THE RESEARCH COMMUNITY, AS DEMONSTRATION PROJECTS. BUT THIS IS WHAT IT WORKS ON, PRE-CLINICAL DEVELOPMENT, TINY BIT CLINICAL BASE SOMETIMES, THE REASON WE DO THAT IS IT REALLY DEPENDS ON HOW MUCH THE PROJECT HAS BEEN DE-RISKED IN ORDER TO HAVE A COMPANY BE ABLE TO PICK IT UP. AND WE HAVE TO CARRY IT DOWN THIS PIPELINE, IF I'M GOING TO USE THAT TERM, DOWN THIS PROCESS, TO A DEGREE THAT IS INVERSELY PROPORTIONAL TO THE TARGET AND PREVALENCE OF THE DISEASE. SO THE LESS PRECEDENTED THE TAR TARGET IS AND LOWER THE PREVALENCE THE FARTHER WE HAVE TO TAKE THIS DOWN THE PROCESS BEFORE A PRIVATE SECTOR COMPANY CAN MAKE A BUSINESS CASE TO ADOPT IT. SO YOU ARE HERE, ONE CASE, IN PARTNERSHIP AGAIN BECAUSE EVERYTHING IS IN PARTNERSHIP, IN ONE CASE WE PARTNER WITH A COMPANY, RDCRN AND CTSAs, DUAL HAND OFF TO SUCCESSFULLY GET ANYTIME IT IN THIS SPACE. THAT'S IT. TAKE IT AWAY, ANTON. >> THANK YOU, CHRIS. IT'S GREAT TO BE HERE AND ACTUALLY LIFT THE HOOD ON THE DPI AND SHOW YOU WHAT'S IN THERE. GIVEN THE RIGHT POWER, I PROMISE TO NOT ASK YOU TO LEARN ANYMORE ACRONYMS, JUST DPI -- GIVEN THE LATE HOUR. I FOUND MY WAY OUT OF THE VALLEY OF DEATH. [LAUGHTER] SO DPI IT IS. SO AS CHRIS MENTIONED, WHAT WE'RE TRYING TO DO HERE IS ADDRESS SHORTCOMINGS OF THE PROCESS, BASIC RESEARCH, DISCOVERIES, THROUGH TO FIRST-IN-HUMAN TESTING. IN OTHER WORDS, WHY ARE THERE SO MANY PAPERS IN "SCIENCE," "NATURE," AND OTHER SIMILAR JOURNALS DESCRIBING REALLY GREAT NEW CONCEPTS, AND WHY ARE THERE SO DRUGS COMING OUT THE OTHER END, WHAT HAPPENS IN THE MIDDLE, SO SOME CHARACTERISTICS OF THE SHOP, PART OF NCATS, WE REALLY HAVE UNIQUE COMBINATION OF STAFF MEMBERS WITH VERY VARIOUS BACKGROUND. A NUMBER OF DIFFERENT DISCIPLINES AND SUBDISCIPLINES INVOLVED, THE NUMBER IS PRETTY LARGE, SOME SUBDISCIPLINES WE HAVE SOMETIMES JUST SINGLE PERSONS RESPONSIBLE FOR THAT SECTOR, BUT WE HAVE ENGINEERS WORKING TOGETHER WITH BIOLOGISTS, WITH CHEMISTS, WITH INFORMATICIANS, ALL UNDER ONE ROOF. THIS IS WHAT MAKES THE PLACE UNIQUE AND POSSIBLE TO ACTUALLY LEVERAGE THESE DIFFERENT RESOURCES, AND DIFFERENT GREAT BRAINS TO A TREMENDOUS DEGREE AND TO ACTUALLY SCALE THINGS UP LIKE NEVER BEFORE. THE OTHER THING WE DO NOT HAVE IS TENURE-TRACK SYSTEM. WE'RE HIGHLY DIFFERENT FROM THE REST OF NIH WHERE THERE IS TRADITIONAL TENURE SYSTEM. THIS ALLOWS PEOPLE TO REALLY FOLLOW THE PROBLEMS IN TRANSLATION AND TO ACTUALLY SWITCH GEARS PRETTY RAPIDLY, DEPENDING ON WHAT THE COMMUNITY NEEDS. SUFFICE IT TO SAY, REWARD SYSTEM ASSOCIATED WITH TRADITIONAL TENURE IS POORLY ALIGNED WITH WHAT NEEDS TO BE DONE WITHIN TRANSLATIONAL SPACE WHERE YOU HAVE MULTI-DISCIPLINARY TEAMS, YOU HAVE DELIVERABLES, THAT ARE NOT REALLY PUBLICATIONS, WITH SENIOR AUTHORSHIP AND SO ON. SO WE'VE ACTUALLY KEPT THIS MODEL FOR THE PAST DECADE OR SO OF NOT HAVING TENURE/TENURE TRACK. IT SERVED US WELL. IF IT ENDS UP FAILING DOWN THE ROAD, LIKE OTHER EXPERIMENTS WITH NCATS, WE'LL TAKE A LOOK AND CHANGE IT. SO WE NEED PEOPLE WHO ARE JACK-OF-ALL-TRADES, MASTER OF AT LEAST TWO. RECOGNIZING THAT IN THE TRANSLATIONAL FIELD, ONE NEEDS TO BE MULTI-LINGUAL. IF WE HAVE ISSUES TO UNDERSTAND PATHWAYS AND BIOLOGY, TO A CERTAIN DEGREE TO UNDERSTAND HOW TO BEST ANALYZE DATA, CHEMISTS NEED TO UNDERSTAND BIOLOGY, BIOLOGISTS NEED TO RECOGNIZE COMPLEXITY OF CHEMISTRY, LIABILITIES OF CERTAIN SMALL MOLECULES AND OTHER CANDIDATES. SO REALLY PEOPLE WHO ARE PART OF DPI HAVE TRAVERSED THIS PATH OF HAVING DONE MULTIPLE THINGS IN THEIR LIVES, AND ACTUALLY SPEAKING AT LEAST TWO LANGUAGES OR HAVING BASIC UNDERSTANDING IN THE SECOND ONE. AS AN INTRAMURAL LAB WE'RE PRETTY FLEXIBLE AND HAVE ACTUALLY BEEN ABLE AND ASKED TO RESPOND TO PUBLIC HEALTH CRISES, WORK ON THINGS LIKE ZIKA, EBOLA, AND I'LL GIVE YOU SOME EXAMPLES TO THIS EFFECT LATER. COLLABORATIVE PROBLEMS IN TRANSLATION DO NOT GET INVENTED BY US INTERNALLY. SO THEY ACTUALLY COME FROM THE OUTSIDE. WE TAKE CUES FROM THE COMMUNITY AND WORK WITH OUTSIDE EXPERTS IN SPECIFIC DISEASES, PATHWAYS, TECHNOLOGIES, TO ACTUALLY DEVELOP THESE IMPROVEMENTS AND SO ON. WE KNOW THIS IS KEY TO CARRYING THINGS ACROSS OR TRANSLATING. WE'RE WORKING VERY CLOSELY WITH THE REST OF NCATS. THIS IS FAIRLY DIFFERENT FROM THE OTHER NIH INSTITUTES AND CENTERS WHERE THINGS ARE PRETTY MUCH PI-DRIVEN, HYPOTHESIS DRIVEN AND YOU DON'T NEED TO INTERACT WITH THE REST OF YOUR INSTITUTE TO CARRY OUT YOUR RESEARCH. WE'RE WORKING VERY CLOSELY WITH THE OFFICE OF STRATEGIC ALLIANCES BECAUSE OF ALL THESE HANDOFF POINTS CHRIS MENTIONED EARLIER, AS WELL AS WITH OTHER OFFICES IN NCATS, INCLUDING DCI, CPSI AND SO ON. OUTSIDE NCATS WE HAVE A NUMBER OF COLLABORATIONS WITH OTHER PARTS OF HHS, WITH OTHER NIH INSTITUTES AND CENTERS, AND THE REST OF FEDERAL GOVERNMENT. VARIOUS GOVERNMENT LABS, THE ENVIRONMENTAL PROTECTION AGENCY AND SO ON. AGAIN, RECOGNIZING TRANSLATION REQUIRES MULTIPLE PLAYERS WITHIN THIS ECOSYSTEM. ULTIMATELY WE'RE TRYING TO USE INNOVATION TO INCREASE THE QUALITY AND EFFICIENCY OF DISCOVERY AND TO ACCELERATE EVENTUALLY. SO WHAT'S WITHIN DPI? WE HAVE HISTORICALLY CREATED THROUGH VARIOUS ACQUISITIONS, MERGERS, INITIALLY PART OF THE HUMAN GENOME RESEARCH INSTITUTE WITH RELATIVELY NARROW MANDATE THE FIRST SEVERAL YEARS, DIFFERENT PROGRAMS WERE ADDED TO THE SHOP. I'M NOT GOING TO GO OVER DIFFERENT NAMES AND ACRONYMS, I PROMISED THAT. BUT THE POINT IS WE'RE TRYING TO MATCH OURSELVES AGAINST THIS NAIVE CHEVRON DIAGRAM. BY DOING SO WE'RE TRYING TO CONVEY THE MESSAGE HERE, THAT WE'RE ACTUALLY TACKLING DIFFERENT TRANSLATIONAL PROBLEMS SPECIFIC TO SEGMENTS OR CHEVRON DIAGRAM, STARTING FROM THINGS THAT ARE VERY CLOSE TO BASIC RESEARCH, LIKE TARGET VALIDATION, VERY OF VERIFYING BY GENOMICS MEANS, SMALL INTERFERING RNA, siRNA EXPERIMENTS THAT TARGET MAY ACTUALLY HAVE VALID ROLE IN PARTICULAR DISEASE PROCESS, ALL THE WAY TO ENABLING CLINICAL TRIALS THROUGH MANUFACTURING, FORMULATION DEVELOPMENT, CLINICAL SUPPLY, TOXICOLOGY AND SO ON. IN ORDER TO TACKLE DIFFERENT PROBLEMS IN THIS SPACE THE EXEMPLAR PROJECTS ENTER THROUGH VARIOUS POINTS, AND THEN THEY CAN EXIT IN VARIOUS STAGES OR POINTS. WE DON'T NECESSARILY TAKE A PROJECT AND CARRY IT THROUGH FROM A-Z. THAT'S NOT THE GOAL OF THIS PLACE. WE'RE NOT REALLY HERE TO ARE ESSENTIALLY REPEAT OR DUPLICATE WHAT OTHERS ARE DOING. SO REALLY THE PROJECTS CAN BE A SPECIFIC PURPOSE, WHETHER TO PROVE A POINT OF DEVELOPMENT OF BLOOD FORM APPROACH OR SOLVE OTHER PROBLEM IN THE SPACE, AND, AGAIN, THIS IS ALL DONE IN TERMS OF ORGANIZATIONAL STRUCTURE TO PROMOTE TEAM SCIENCE, SO WE'RE REALLY OPERATING BASED ON MULTI-DISCIPLINARY TEAMS. AGAINST AS I MENTIONED, WE'RE NOT TENURE/TENURE TRACK. I HAVE TO MENTION THE STRONG ROLE PROJECT MANAGEMENT PLAYS IN OUR ORGANIZATION, ESPECIALLY IN THE LATE STAGE PROJECTS THAT ARE APPROACHING IND AND REGULATORY ENVIRONMENT. AGAIN, FAIRLY DIFFERENT FROM OTHER NON-PROFIT ENVIRONMENTS LIKE UNIVERSITIES AND OTHER NIH LABS, WHERE PROJECT MANAGEMENT IS ALMOST UNHEARD OF. WE HAVE A NUMBER OF DELIVERABLES. AGAIN THE GOAL OF THIS SHOP IS NOT TO DO ENDLESS BASIC RESEARCH. THIS IS SOMETHING THAT OTHERS ARE DOING. ACTUALLY TO PRODUCE SOMETHING THAT OTHERS WILL USE, INCLUDING OTHERS THAT ARE NOT PART OF THESE COLLABORATIONS PARTS OF THESE EXEMPLAR PROJECTS. SO THESE DELIVERABLES INCLUDE PHYSICAL STUFF, SUCH AS SMALL MOLECULE TOOLS, DRUG CANDIDATES, THINGS THAT PEOPLE CAN TAKE AND USE IN THEIR OWN LAB, RESEARCH OR DEVELOP FURTHER. DATABASES, VARIOUS TYPES OF DATA THAT OTHERS CAN MINE AND BUILD PREDICTIVE MODELS, GENOME DATABASES FROM siRNA, SCREEN MOLECULES AND PROFILES, PROFILES FOR UNWANTED EFFECTS, SMALL MOLECULES, TOXICS EFFECTS AND SO ON. SO REALLY THE END GOAL IS TO ENABLE OTHERS TO CONDUCT TRANSLATION MORE EFFICIENTLY. AND, AGAIN, I'LL BE GIVING EXAMPLES OF ALL THIS LATER ON. SO CHRIS MENTIONED THESE ITEMS, I'LL BE GIVING YOU EXAMPLES OF HOW WE ADDRESS SOME OF THEM, STARTING WITH PREDICTIVE TOXICOLOGY. WHY IS THIS IMPORTANT? APPROXIMATELY 30% OF DRUG CANDIDATES STILL FAIL DUE TO ADVERSE EVENTS, OR TOXICITY THAT ARE GOING UNNOTICED DURING EARLY STAGE DEVELOPMENT, ONLY REVEAL THEMSELVES LATER. SO AS ONE SUCH EFFORT WITH ACTUALLY IS MARKING ITS TENTH ANNIVERSARY THIS YEAR IS THIS TOX21 COLLABORATIVE, WHICH WE INITIATED IN PARTNERSHIP WITH SEVERAL GOVERNMENT AGENCIES, OTHER NIH INSTITUTES, SPECIFICALLY NATIONAL TOXICOLOGY PROGRAM, NATIONAL INSTITUTES OF ENVIRONMENTAL HEALTH SCIENCES, AND THE EPA'S NATIONAL CENTER FOR TOXICOLOGY DOWN IN NORTH CAROLINA. SO THIS WAS THE FIRST MEMORANDUM OF UNDERSTANDING, BACK IN 2007, 2008, LATER FDA JOINED THIS PARTNERSHIP. REALLY THE GOAL THERE IS TO DEVELOP PREDICTIVE MODELING FOR BIOLOGIC RESPONSE TO NEW CHEMICALS IN HUMANS AND TO REDUCE THE USE OF ANIMALS. NOW BIOCHEMICALS MEANS BOTH DRUG CANDIDATE CHEMICALS AS WELL AS ENVIRONMENTAL CHEMICALS BECAUSE PREDICTIVE TOXICOLOGY OR TOXICITIES EFFORTS HAVE A BEARING ON THESE TWO TOPICS, OR DISCIPLINES, IF YOU WILL, TOXICOLOGY RELATES TO DRUG DISCOVERY AND DEVELOPMENT, AND TOXICITY EFFECTS OF CHEMICALS IN THE ENVIRONMENT ON HUMANS. THERE ARE 80,000 CHEMICALS IN COMMERCE, BY SOME ESTIMATES, AND HUMANS ARE EXPOSED TO A LOT OF THESE IN THEIR DAILY LIVES. AND THERE'S ANIMAL TOX DATA ON ONLY A FEW THOUSAND OF THESE. SO LESS THAN 1/10 ARE BEING CHARACTERIZED. WE'RE TRYING TO ADOPT SYSTEMS BIOLOGY APPROACH, TRYING TO IDENTIFY PATTERNS OF CHEMICALLY INDUCED BIOLOGICAL RESPONSE TO BEGIN TO UNDERSTAND ADVERSE EVENTS, CAN WE DEVELOP PANEL ALSO OF IN VITRO ASSAYS THAT ARE CHEAPER, MORE EASILY SCALABLE ACROSS MULTIPLE CHEMICALS TO PREDICT WHAT ABOUT HAPPEN IN VIVO OR AT THE VERY LEAST PRIORITIZE CHEMICALS FOR MORE EXTENSIVE TOXICOLOGICAL EVALUATION AND GUIDE OPTIMIZATION, WHETHER THEY ARE GOING TO BE USED AS DRUG CANDIDATES IN DEVELOPMENT OR BY THE CHEMICAL INDUSTRY FOR SOME NEW NEED. SO THE PROJECT REALLY ENTAILS BUILDING THIS COLLECTION OF DIVERSE CHEMICALS, WHICH WE CALL THE 10K CHEMICAL COLLECTION, APPROXIMATELY 10,000 CHEMICALS, NOMINATED, PROCURED JOINT BY EPA AND NCATS, FAILED CRUCIAL, APPROVED DRUGS, PESTICIDES, INDUSTRIAL CHEMICALS. THIS UNDERWENT CONTROL. FOR THOSE FAMILIAR WITH CHEMICAL QC, ONLY A THIRD ARE DRUGS OR DRUG-LIKE MOLECULES. THIS IS A DIFFERENT BEAST. THEY IONIZE IN MASS SPEC, PRESENTED HUGE PROBLEMS, WE HAD TO DEVELOP ANALYTICAL TECHNIQUES TO FOLLOW THEM. ALL THAT DATA ON THE LIBRARY QC IS BEING MADE PUBLISH FOR OTHERS TO RELATE IF WE'RE GENERATING ON THIS COLLECTION TO PURITY AND STABILITY OF THESE MOLECULES, AS THEY ARE TESTED. ONE ALSO NEEDS IN VITRO TEST METHODS, SCREENING PLATFORMS, TO GENERATE THIS HIGH QUALITY BIOACTIVITY. WE'VE RUN OVER 50 SCREENING CAMPAIGNS TO DATE. AND THEN FEED THIS DATA TO BUILD PREDICTIVE MODELS, AND I'LL MENTION HOW WE DO THIS AND HOW WE'VE DONE IT THROUGH COMMUNITY INVOLVEMENT. SO REALLY OVER THE PAST SEVERAL YEARS WE'VE BEEN ABLE TO SET UP THIS INFRASTRUCTURE TO ENABLE HIGH THROUGHPUT FULLY AUTOMATED TESTING OF THESE CHEMICALS. REALLY THE LARGEST SCALE OF SUCH EFFORT TO REALLY KICK START IN VITRO PREDICTIVE TOXICOLOGY WITH MULTIPLE QUALITY CONTROL MEASURES IN PLACE. I DON'T HAVE TIME TO DESCRIBE ALL THE OTHER QC MEASURES BESIDES JUST CHEMICAL ANALYSIS ON THE LIBRARY BUT ALSO INFORMATICS PROCESSES, ASSAY QUALIFICATIONS AND SO ON. ALL OF THEIR DATA FROM THIS EFFORT GOES IN THE PUBLIC DOMAIN PURVIEW WITH MINIMUM DELAY TO ENABLE INITIAL MANUSCRIPT BUILDUP, SIX TO EIGHT MONTHS, ALMOST 100 MILLION DATA POINTS HAVE BEEN DELIVERED INTO THE PUBLIC DOMAIN. SO BUILDING MODELS OUT OF THESE, WE'VE DONE SOME WORK OURSELVES AND WE'VE PUBLISHED IT, AGAIN I DON'T HAVE TIME TO DESCRIBE ALL THESE EFFORTS, BUT TO KNOW EVERYTHING, RETURN TO THE WORLD-WIDE AUDIENCE TO HELP US BUILD THESE MODELS THROUGH CROWD-SOURCING EFFORTS, THROUGH DIFFERENT CHALLENGE COMPETITIONS, SOMETIMES WITH MONETARY PRIZES, SOMETIMES WITHOUT, AND THE RESULTS HAVE BEEN PRETTY FASCINATING. SOME PREDICTIVE MODELS WERE ABLE TO PREDICT THE BIOACTIVITY OF A NEW CHEMICAL, FEEDING SIMPLY STRUCTURE AND USING YOUR STRUCTURE AND ACTIVITY DATA FROM THE 10K SET, WITH UP TO 90% ACCURACY. A LOT OF THESE WINNING MODELS FROM THESE COMPETITIONS CAME FROM SMALL COUNTRIES AND SMALL UNIVERSITIES WORLDWIDE, SPEAKING TO THE POWER OF USING THE LARGE COMMUNITY AND GIVE YOUR DATA TO THAT COMMUNITY SO THEY CAN DO BETTER THINGS WITH IT THAN YOU COULD, BECAUSE REALLY THERE'S A LOT OF GREAT BRAINS OUT THERE. A LOT OF THIS IN VITRO DATA IN ADDITION TO BEING USED TO BUILD INITIAL MODELS IS BEING USED BY THE EPA NOW, BEGINNING TO BE USED BY THE EPA FOR REGULATORY PURPOSES STARTING WITH THE ESTROGEN RECEPTOR ASSAYS. AND ALSO THERE'S BEEN UPTAKE BY OTHERS, IMI, OVER THE EUROPEAN UNION, ACADEMIC GROUPS TO BEGIN TO USE THESE IN VITRO DATA TO RANK COMPOUNDS FOR VARIOUS PRIORITIZATION PURPOSES. I MENTIONED RAPID RESPONSE, INTRAMURAL LAB, 2010, ALMOST EIGHT YEARS AGO, THE DP HORIZON GULF OIL SPILL HAPPENED, REALLY BIG DISASTER IN THE GULF OF MEXICO BP WAS READY TO DUMP HUGE AMOUNTS OF DISPERSANTS IN THE OCEAN TO DISPERSE THE OIL SLICK AND CONTROL THE DISASTER BUT DIDN'T HAVE DATA ON THE MOLECULES. THE EPA DIDN'T HAVE DATA EITHER. AND SO GIVEN THE CLOCK WAS TICKING IN UNITS OF HOURS, DAYS, NOT IN UNITS OF MONTHS/YEARS, WE WERE ASKED TO STEP IN LITERALLY OVER THE MEMORIAL DAY HOLIDAY, RECEIVED THIS PERSON'S MICRO TITER PLATES, REVIVE ANDROGEN ESTROGEN RECEPTOR ASSAYS, CONDUCT TESTS, DELIVER RESULTS TO EPA IN LITERALLY A FEW DAYS AND WRITE THE REPORTS. AND EVERYTHING -- THIS DISPERSANT WHICH ULTIMATELY WAS USED, INCLUDING THE SPILL, WAS ACTUALLY NEGATIVE IN THESE TESTS, AND THIS WAS REALLY THE ONLY THING EPA COULD DO, GIVEN THE VERY LIMITED AMOUNT OF TIME TO GENERATE SOME SORT OF DATA ON MOLECULE, CHEMICAL BP HAD TO DUMP IN THE OCEAN, PRETTY MUCH, RECOGNIZED BY AWARD FROM THE EPA FOR TOX21 TEAM, BACK THEN. WE'RE ALSO ENGAGING INDUSTRY IN THIS EFFORT, ACTUALLY HEAVILY INTERACTING WITH THE IQ CONSORTIUM, IN THE AREA OF DRUG METABOLISM. THIS IS AN AREA OF GREAT IMPORTANCE TO PHARMACEUTICAL COMPANIES, TO BUILD PREDICTIVE MODELS ON WHETHER A NEW DRUG CANDIDATE WILL BE FAST OR SLOW METABOLIZER, THIS IS IMPORTANT, NOT JUST BECAUSE IT WILL TELL YOU HOW LONG IT WILL LIVE IN CIRCULATION BUT ALSO WHETHER IT WILL HAVE CROSS-REACTIVITY WITH OTHER TREATMENTS. IT'S BEEN VERY HARD TO BUILD THESE DATABASES AND IMPROVE PREDICTIVE MODELS BECAUSE THIS IS CONSIDERED COMPETITIVE SPACE, PEOPLE DON'T HAVE ANY WAY OF SHARING COMPOUND STRUCTURAL INFORMATION, WHATTER IN WORKING ON. WHAT WE'RE DOING IN ANY THIS SPACE IS GENERATING EXPERIMENTAL PROFILES, STARTING WITH CYTOCHROME P450 ISOSOMES AND MOVING ON, PUTTING THAT DAILY IN THE PUBLIC DOMAIN, GIVING IT CAREFUL TO PROTOTYPE PROTOCOLS AND PORTAL FOR COLLABORATIVE IMPROVEMENT TO PREDICTIVE MODELS WHERE WE'RE SEEDING WITH OUR OWN DATA AND ALLOWING PHARMACEUTICAL PARTNERS TO PLAY WITH THEM AND USE MACHINING LEARNING AND ALGORITHMS WITH APPROPRIATE FIRE WALL HOPING TO USE EVERYBODY'S DATA TO IMPROVE THE MODEL WITHOUT ACTUALLY REVEALING THE STRUCTURES THAT ARE USED IN FEEDING THIS MODEL. SO REALLY AN INTERESTING PARTNERSHIP AND SOME OF YOU WILL RECOGNIZE THE NAMES, SCOTT OBACH, ACTUALLY PROVIDING DIRECT ADVICE AND INPUT INTO HOW THIS IS DONE. MOVING TO PREDICTIVE EFFICACY, THIS IS ANOTHER AREA WHERE DRUGS FAIL, RIGHT? YOUR DRUG CANDIDATE WORKS GREAT, CELL ASSAY TYPE SYSTEM, MICRO TITER PLATE, GREAT RESULTS, THEN IT MOVES TO HUMANS AND DOES NOTHING, OR DOES VERY LITTLE. AND WE KNOW OF MANY SUCH EXAMPLES. FOR DUCHENNE MUSCULAR DYSTROPHY IS ONE, WORKS GREAT IN CELL-BASED ASSAYS AND KEEPS FAILING IN CLINICAL TRIALS. SO WHAT CAN WE DO AT THE EARLY STAGE OF DISCOVERY TO IMPROVE THESE EFFICIENCIES? WELL, WE ACTUALLY STARTED USING WHEN WE WERE SETTING UP OUR OPERATIONS WITH LOOKING AT THE BASIC PROCESS TO DO EARLY DISCOVERY, WHICH IS THE SCREENING PROCESS. AND WE HAVE TO RECOGNIZE THIS PROCESS IMPROVED TREMENDOUSLY OVER THE PAST DECADE OR TWO. REALLY TWO DECADES BACK THERE WAS NO SUCH THING AS HIGH-THROUGHPUT SCREENING. THINGS WERE DONE IN PETRI DISHES, ONE TEST AT A TIME, SLOWLY, MANUALLY, WITH INCREDIBLE AMOUNT OF NOISE AND VARIABILITY. NOWADAYS, EVERYTHING CAN BE DONE IN AUTOMATED FASHION WITH ROBOTIC ARMS MOVING MICROTITER PLATES, WE HAVE THAT SYSTEM UP AT OUR PLACE, EIGHT MILES FROM HERE IN ROCKVILLE. YET PROBLEMS IN THIS PROCESS REMAIN. THERE ARE MULTIPLE ISSUES ASSOCIATED WITH HIGH-THROUGHPUT SCREENING, BUT STILL PREVENT ITS WIDE USE AND REALLY LIMIT ITS ROBUSTNESS. SO WE WORKED VERY HARD, AIDED BY ALL THESE ADVANCES IN EXTREME MINIATURIZATION, AUTOMATION, AND INFORMATICS DATA PROCESSING, TO DEVELOP A WAY TO TEST THESE DRUG CANDIDATES AT MULTIPLE DOSES. THIS IS ONE OF THE LIMITING FACTORS IN SCREENING, WHERE PEOPLE WOULD JUST TAKE THE CANDIDATES, RUN THEM AT SAY 10 MICROMOLAR CONCENTRATION, APPLY STATISTICAL CUTOFFS, AND DEAL WITH ALL THAT NOISE AND LACK OF REPRODUCIBILITY. SO, WOULDN'T IT BE NICE TO INSTEAD OF PAYING THOSE RESPONSE CURVES, WE MADE IT FASHION ACROSS, SAY, HALF A MILLION OR A MILLION MOLECULES, SO WE DEVELOPED THESE PROCESSES AND AS A RESULT WE ACTUALLY GET THESE PHARMACOLOGICAL DATASETS, TO SHOW THE DEPENDENCE ON THOSE. AND THIS REALLY IMPROVED RELIABILITY OF THE DATA GENERATED IN THIS EARLY STAGE, REDUCED FALSE POSITIVE AND FALSE NEGATIVES, ALLOWED US TO RECOUP SOME COSTS THAT GO INTO SCREENING MORE SAMPLE AT MULTIPLE DOSES. MILLIONS OF DATA POINTS HAVE BEEN DEPOSITED IN THE PUBLIC DOMAIN FROM EFFICACY TYPE SCREENS. I MENTIONED THE TOXICOLOGY SCREENS EARLIER, WE'RE ALSO MAKING DATA PUBLIC, ALSO MAKING DISCOVERIES USING DISEASE SCREEN MODELS, AND WE'RE ALSO ABLE TO USE THIS PARADIGM OF QUANTITATIVE SCREENING TO PROFILE THE LIBRARIES FOR UNWANTED PROPERTIES, SUCH AS AGGREGATION, REACTIVITY, FLUORESCENCE, THINGS THAT OBSCURE SCREENING ASSAYS AND MAKE DATA INTERPRETATION DIFFICULT. WE'RE ENUMERATING NEGATIVE PROPERTIES, PUTTING THAT INFORMATION IN THE PUBLIC DOMAIN AND ACTUALLY COMING UP WITH SPECIFIC RECOMMENDATIONS TO THOSE WHO RUN SUCH SCREENS OUT THERE, AS TO HOW TO ADJUST THEIR ASSAY CONDITIONS, ASSAY DESIGNS, TO MINIMIZE THE EFFECT OF THESE BIOPHYSICAL PROPERTIES, SMALL MOLECULES HAVE, THEY ARE ACTUALLY PLAGUING THIS PROCESS. WE'RE ALSO CONTINUING TO IMPROVE ROBUSTNESS OF SCREENING BY INNOVATING IN THE DESIGN OF ASSAYS, DESIGNING BETTER REPORTER SYSTEMS, AND ALSO BETTER NEGATIVE CONTROLS FOR GENOMIC SCREENS AND SO ON. AND PUTTING ALL THIS IN THE PUBLIC DOMAIN PRETTY RAPIDLY, WHATEVER THAT PRODUCT IS, WHETHER IT'S SOURCE CODE, VECTOR, SO THAT OTHERS CAN PICK IT UP AND UTILIZE IT IN THEIR OWN SHOPS, AS RAPIDLY AS POSSIBLE. ANOTHER AREA OF IMPROVEMENT IN THIS SPACE OF PREDICTIVE EFFICACY AGAIN A LOT OF EARLY TESTS RELY ON EASY TO GROW CELLS, TWO DIMENSIONAL CULTURES, AND THEN DON'T REPRODUCE WHEN YOU MOVE EVEN INTO ANIMALS, AND OF COURSE THEY DON'T REPRODUCE WHEN YOU MOVE INTO HUMANS. SO CAN WE INCREASE SOPHISTICATION OF THESE SCREENING TESTS WITHOUT COMPROMISING THE THROUGHPUT OF THESE TESTS TOO MUCH, TO IMPROVE PREDICTABILITY. SO ONE AREA OF WORK THAT WE STARTED RELATIVELY RECENTLY IN PARTNERSHIP WITH DAN TAGLE'S TEAM, FUNDED BY CURES ACCELERATION NETWORK, USING 3D PRINTING TO ACTUALLY MAKE ARRAYS OF TISSUES, WHICH WE CALL BIOPRINTING, SHOWN HERE IN THIS SORT OF NAIVE CARTOON WHERE YOU SUSPEND CELLS, MULTIPLE CELL TYPES, INTO VARIOUS HYDROGELS, FILL SYRINGES WITH THOSE CELLS SUSPENDED IN HYDROGEL AND USE THE 3D PRINTER WITH XYZ CONTROL TO LAYER COMPONENTS OF THIS TISSUE IN VARIOUS TYPES OF CONTAINERS, WHETHER IT'S MICROTITER PLATE OR LARGER DISH, ALSO WORKING ON DEVELOPING VARIOUS WAYS TO ARRAY THESE. AND THEN AFTER INCUBATION SOME MAY DEGRADE, ALLOWING CELLS TO REORGANIZE AND FORM NEW TISSUE. THEY ARE WORKING ON SEVERAL PILOT PROJECTS FOR DIFFERENT TISSUES, BLOOD VESSEL WALL, SKIN, AND THE SKIN WAS ACTUALLY THE FIRST ONE TO BE GRADUATED FOR COMMUNITY USE, THIS IS ACTUALLY FROM THE INTERNET. NATIVE SKIN, STAINED, THIS IS ACTUALLY 3D BIOPRINTED SKIN PRODUCED IN LABS AT DPI. SO ONCE WE LEARNED HOW TO MAKE A PARTICULAR TISSUE, THE MODEL HERE IS TO OPEN IT UP FOR COLLABORATIVE DEVELOPMENT, FOR PEOPLE WHO ARE EXPERTS IN DISEASES RELATED TO THIS PARTICULAR TISSUE, SAY MELANOMA, IN THE CASE OF SKIN, TO COME TO US WITH THEIR DISEASE MODEL AND TO WORK JOINTLY ON ESSENTIALLY REALIZING THAT DISEASE MODEL AND RUNNING DRUG SCREENS ON LIBRARIES OF APPROVED DRUGS TO FIND THERAPEUTIC CANDIDATES. AND, AGAIN, THIS IS FUNDED THROUGH CAN AND WE JUST STARTED ONBOARDING THE FIRST TWO PROJECTS, AS WAS DISCUSSED LAST TIME AT COUNCIL. HOW DO YOU FILL DEVICES, BIOPRINTERS AND ALSO TISSUE CHIPS MENTIONED EARLIER WITH CELLS? HOW DO YOU USE THEM FOR PERSONALIZED MEDICINE. YOU CANNOT DO THAT BY BUYING POOLED MATERIAL FROM CURRENT SUPPLIERS. THESE ARE POOLED PRIMARY CELLS, ACTUALLY VERY BATCH-TO-BATCH SPECIFIC. WOULDN'T IT BE NICE TO USE POWER EFFECT INDUCED PURE PLEURIPOTENT STEM CELLS TO PRODUCE LARGE QUANTITIES OF CELLS TO USE IN DRUG SCREENING AND ALSO FOR REGENERATIVE MEDICINE PURPOSES? INDEED OVER AND OVER AGAIN, REPRODUCIBLY, SCALABLE, CHEAPLY, AND BE ABLE TO TRANSFER THESE METHODS. THE FIELD IS NOT THERE RIGHT NOW. THE PRESENT METHODS FOR PRODUCTION OF CELLS FOR DRUG SCREENING AND REGENERATIVE MEDICINE, THEY ARE NOT CHEAP, THEY ARE NOT STANDARDIZED, THEY ARE NOT SCALABLE. TO BE CLEAR WE'RE TALKING INDUCED PLEURIPOTENT STEM CELLS, NOT EMBRYONIC. WITH iPSCs YOU DERIVE FROM AN INDIVIDUAL FROM EVERY SINGLE PERSON IN THIS ROOM USING BLOOD CELLS OR FIBROBLASTS, ESTABLISH AN iPS LINE, AND THEN HOPEFULLY DRAW IT UP IN THE REACTOR TO PRODUCE A LOT OF CELLS AND DEVICE REPPINGSATE THEM TO -- DIFFERENTIATE TO LINEAGE, TO EMBED DISEASE MODELS OR USE FOR REGENERATIVE MEDICINE PURPOSES. TO THIS END, TO TACKLE THIS INFLATIONAL PROBLEM OF STANDARDIZING THE FIELD OF STEM CELL TECHNOLOGIES, AND IMPROVING PROTOCOLS, WE CREATED WITH HELP FROM THE NIH COMMON FUND A STEM CELL TRANSLATIONAL LAB WITH DPI, IT USES REALLY CUTTING EDGE TECHNOLOGY, SINGLE CELL PROTEOMICS AND OTHERS TO DERIVE AND DISSEMINATE QUALITY CONTROL STANDARDS IN THIS FIELD. HOW DO YOU DEFINE A MATURE CARDIOMYOCYTE? DO YOU NEED TO STAIN FOR JUST TWO MARKERS? OR 35 MARKERS? OR ONE MARKER? THE FIELD IS ALL OVER THE PLACE BECAUSE THERE HAS BEEN VERY POOR CONNECTIVITY MADE BETWEEN FULLY FUNCTIONAL MATURE CELL TYPE AND SEMI FUNCTIONAL CELL TYPE IS GUIDED BY A COUPLE OF MARKERS. SO WE INTEND TO ACTUALLY STUDY THESE PROCESSES AND DERIVE GENERAL STANDARDS FOR THIS FIELD. SECONDLY HERE RELATES TO METHOD IMPROVEMENT, HOW DO WE HELP ALL BOATS RISE? WE'RE PLANNING TO DISSECT THESE METHODS FOR iPS CELL GROWTH, AND DIFFERENTIATION, AND DERIVE SMALL MOLECULES, CHEAPER MOLECULES, TO HELP WITH THESE PROCESSES AND MAKE THESE METHODS A LOT CHEAPER. THEY NEED TO GO DOWN IN COST, AT LEAST PROBABLY THOUSAND-FOLD IF WE'RE GOING TO BE SCALING THEM AND USING THEM FOR VARIOUS THERAPEUTIC AND DISCOVERY APPLICATIONS. AND THIS IS REALLY THE DELIVERABLE, IF WE'RE GOING TO PROVIDE TO THE COMMUNITY IMPROVED METHODS, DEMONSTRATION OF TRANSFERABILITY AND SCALABILITY. THE LAB OPENED ITS DOORS MID-SUMMER. WE USE AUTOMATION TO ACTUALLY BEGIN TO BUILD THESE METHODS WITH DIFFERENTIATION. THIS IS EXAMPLE OF PREPARING THE DRUG SCREENING READY, LIVER CELLS, HEPATOCYTES IN 380 WELL PLATES, MAINTAIN STERILEITY, WORKING TO DEVICE BETTER WAYS OF GROWING iPS CULTURES, TO ACTUALLY PROMOTE STRESS-FREE SCALEUP. CURRENT CULTURING METHODS LEAD TO STRESS, PUT CELLS IN OVERDRIVE, SO WHAT WE FOUND THROUGH MONITORING CELLS 24/7, IS THAT THIS STRESS LEADS TO CELL DEATH AND CLONAL SECTION, EVENTUALLY ENDING UP WITH MORE CELLS THAN YOU STARTED, HAPPY CAMPER, SCALE UP iPS CELLS, BUT AT THE COST OF AN ACTUAL DRIFT. SO THERE ARE TWO VIDEOS HERE, GREEN MEANS BAD, SO IN THE LEFT SIDE YOU'LL SEE QUITE A BIT OF THESE ARE DEAD CELLS. SO THAT MEANS THE CELLS THAT SURVIVE ARE ACTUALLY SPECIFIC CLONES, NOT REPRESENTATIVE OF THE INITIAL POPULATION. ON THE RIGHT SIDE YOU SEE VERY LITTLE GREEN. THIS IS A NEW TWO-SMALL MOLECULE COMBINATION, COCKTAIL OF TWO SMALL MOLECULES WE DISCOVERED RECENTLY PROMOTING STRESS-FREE EXPANSION OF iPS CELLS, SO WE'RE HOPING TO DISSEMINATE THIS, PUBLISH IT AND PROVIDE IT TO THE COMMUNITY WITHIN PROBABLY A MONTH OR TWO. WE'RE ALMOST THERE IN CHARACTERIZING THIS SYSTEM. SO THIS IS REALLY THE FIRST TANGIBLE PRODUCT, IF YOU WILL, FROM THE STEM CELL LAB THAT WE'RE GOING TO BE PROVIDING TO THE COMMUNITY. MOVING ON TO THE OTHER SCIENTIFIC PROBLEM, UNDRUGGABLE TARGETS, UNTREATABLE DISEASES, AGAIN THIS IS A VERY LARGE TOPIC OF PRODUCTS OF GENES OUT THERE THAT HAVE NEVER BEEN MODULATED BY SMALL MOLECULES, AND ALSO TREATABLE DISEASES WHERE THERE'S BEEN NO MODEL FOR HOW TO TACKLE THE RARE DISEASES. >> A QUICK QUESTION BEFORE YOU MOVE TO THE NEXT PART, ON THE STEM CELL SCREENING WHEN YOU'RE DOING PHENOTYPIC SCREENS ARE YOU DOING ANYTHING TO IMPROVE HOW PEOPLE CAN DECONVOLUTE RESULTS AND FIGURE OUT WHAT TARGETS THEY HIT SO THEY CAN OPTIMIZE COMPOUNDS? EVERYBODY AND THEIR MOTHER IS DOING PHENOTYPIC SCREENS ON THE WORLD RIGHT NOW. FOUNDATIONALITY GRANT PROPOSAL, NINE OUT OF TEN, MAKE iPSC OUT OF YOUR KIDS AND DO SCREENS, OFTEN CHEMISTRY AFTERWARDS, UNLESS IT PERFECTLY CORRECTS ANYTHING, THE COMPOUND, I HEAR A LOT OF COMPLAINTS. ARE YOU ADDRESSING THAT? >> I WILL TOUCH ON THIS LATER. FOR A LOT OF THESE RARE DISEASE SCREENS WE USE THE DRUG LIBRARIES BECAUSE DRUG REPURPOSING IS REALLY THE ONLY HOPE, OR THE FIRST STOP FOR DISEASE FOUNDATIONS WHERE THEY SIMPLY DON'T HAVE THE FUNDING AND TIME AVAILABLE TO TRAVERSE THE LONG JOURNEY. WE DO HAVE SPECIFIC EXAMPLES, WHERE ONCE WE HAVE A MOLECULE THAT AFFECTS PHENOTYPE, WE HAVE EMBARKED ON COLLABORATIVE JOURNEYS TO IDENTIFY THE CAR GET. WE DON'T DO IT OURSELVES. WE HAVE A COLLABORATE WITH THE RIGHT ANCILLARY ASSAYS TO HELP WITH THAT DECONVOLUTION WHICH LEADS ME TO THE NEXT SLIDE, WHICH IS THE HUGE ROLE OF MEDICINAL CHEMISTRY, FULLY INTEGRATED INTO THE PROCESS OF DISCOVERY AND IMPROVEMENT OF MOLECULES THAT COME OUT OF THE HIGH THROUGHPUT SCREENS, AND ONE OF THE THINGS THAT CAN BE DONE THROUGH MET CAM, ATTACH A HANDLE ON YOUR MOLECULE ACTIVE IN SCIENTIFIC SCREENING AND USE IT TO FISH OUT POTENTIAL TARGETS, AND WE'VE DONE THAT. REALLY FOR US, AGAIN FOR THOSE IN THE AUDIENCE WHO PRACTICED MET CAM, AND FOR MANY, MANY YEARS, THIS IS A FAMILIAR STATEMENT THAT WE IN MEDICINAL CHEMISTRY AT OUR PLACE DOES NOT EXIST IN ISOLATION. WE HAVE ON-SITE METABOLISM GROUP, MOLECULES OPTIMIZED, NOT JUST FOR POTENCY AGAINST SPECIFIC TARGET OR PHENOTYPIC OUTPUT BUT ALSO FOR PROPERTIES THAT PREPARE FOR IN VIVO TESTING. TODAY WE'VE GENERATED 200 HIGH QUALITY PROBES. WE USE PROBES AND TOOLS INTERCHANGEABLY, TOOLS THAT SELECTIVELY HIT A PARTICULAR PROTEIN TARGET, OR PATHWAY, AND ARE ACTUALLY USEFUL IN STUDYING SPECIFIC DISEASE BIOLOGY. SOME OF THESE END UP GRADUATING TO BECOME DRUG CANDIDATES, BUT NOT ALL OF THEM DO. ALL THESE MOLECULES COULD BE MADE PUBLICLY AVAILABLE AND USED BY MANY LABS TO ADVANCE BIOLOGY, OVER THE YEARS. JUST ONE EXAMPLE IN THIS SPACE, DEVELOPING PROBES TO STUDY CANCER METABOLISM, IT'S WELL RECOGNIZED NOW, THE TUMOR NUTRITIONAL REQUIREMENTS. PEOPLE TALK ABOUT THE WARBURG EFFECT, OXIDATIVE STRESS THAT CANCER CELLS ARE UNIQUELY SUBJECT TO. SO WE ACTUALLY SCREEN HUMAN PYRUVATE KINASE, TWO YEARS BACK, ALL OF THAT, TO DEVELOP THE FIRST IN CLASS PROBE THAT ACTIVATES THIS ENZYME BY ALLOSTERIC MECHANISM, SO THE TWO MOLECULES HAVE BEEN SHARED WITH DOZENS AND DOZENS OF LABS. THIS IS AN EXAMPLE OF WORK DONE JOINTLY WITH LOU CANTLEY TO ELUCIDATE CANCER BIOLOGY AS RELATES TO CANCER METABOLISM, FAIRLY YOUNG IN THE FIELD A COUPLE YEARS AGO BY OUR PROSPECTIVE WORK ON PREVIOUSLY UNDRUGGED TARGETS WE WERE ABLE TO ESSENTIALLY OPEN THIS FIELD, PROVIDING THESE TWO MOLECULES, TO OTHERS WHO STUDY BIOLOGY. SO I MENTIONED DRUG REPURPOSING EARLIER. THIS IS IMPORTANT FOR US, ESPECIALLY IN THE CONTEXT OF RARE AND NEGLECTED DISEASES, NOT EVERYBODY CAN BUILD A BUSINESS CASE FOR FOLLOWING THIS ROAD, THIS CHEVRON DIAGRAM TAKING WELL OVER 10 YEARS, SCREENING MANY COMPOUNDS, DOING MET CAM AND INVESTING HUGE AMOUNTS OF MONEY, ESPECIALLY WHEN YOU ACCOUNT FOR FAILURE RATE, SO THIS CONCEPT OF TAKING SOMETHING ALREADY APPROVED BY THE FDA AND TESTING IN SOME RAPID FASHION AGAINST NEW DISEASE MODEL TO FIND NEW USE OF EXISTING DRUG IS PRETTY APPEALING AND OBVIOUSLY THE RATIONALE IS ACCELERATE DISCOVERY AND DEVELOPMENT, HOPEFULLY MAINTAIN, REDUCE DEVELOPMENT COSTS, ALSO DERIVE NEW THERAPEUTIC HYPOTHESIS BECAUSE A LOT OF THESE EXISTING DRUGS HAVE NO TARGET, NO MECHANISM OF ACTION, EVEN IF THEY DON'T GET REPURPOSED FOR THAT INDICATION THEY WILL LEAD TO NEW HYPOTHESIS AS FAR AS MECHANISM OF INTERVENTION. SO HOW DO YOU IMPLEMENT THIS IN THE CONTEXT OF HIGH THROUGHPUT TESTING, AUTOMATED TESTING? FIRST, YOU NEED A COMPREHENSIVE COLLECTION OF SUCH APPROVED DRUGS AND AGENTS IN DEVELOPMENT. YOU DON'T ACTUALLY SNAP YOUR FINGERS AND CUT A CHECK AND BUY SUCH A COLLECTION. INFORMATICS TEAM NEEDED SEVERAL YEARS TO ACTUALLY SEARCH WORLDWIDE DATABASES, TO DEAL WITH MISSPELLED NAMES OF THE SAME DRUG, TO RECONCILE CHEMICAL STRUCTURES, STEREO ISOMERS TO BUILD A DATABASE OF ALL DRUGS APPROVED FOR HUMAN USE, AND THOSE IN DEVELOPMENT. THERE WAS NO SUCH DATABASE BEFORE, SO WE DID THIS YEARS AGO, PUBLISHED IT, PEOPLE CAN ACTUALLY SEE WHAT THESE DRUGS ARE, NOT JUST FDA BUT WORLDWIDE. AND THEN EMBARKED ON A JOURNEY OF BUILDING THE PHYSICAL COLLECTION WHICH WE'RE STILL DOING, WE'RE ACTUALLY SYNTHESIZING SOME OF THESE MOLECULES IN HOUSE. ONLY THE FIRST THOUSAND OUT OF THESE THREE OR FOUR THOUSAND DRUGS ARE AVAILABLE. THE REST HAVE TO BE PROCURED SEPARATELY, ONE BY ONE, CUSTOM SYNTHESIZED. WE HAVE THIS COLLECTION ON SITE, AND WE'VE BEEN USING IT TO SCREEN PATIENT-DERIVED CELLS IN VARIOUS MODELS, OR PATHOGEN CELLS. AND HAVE ALSO USED IT IN RAPID RESPONSES TO PUBLIC HEALTH EMERGENCIES AS I MENTIONED EARLIER. IN THE CASE OF ZIKA LAST YEAR, THERE WERE REALLY NO GOOD MODELS WHEN THE EPIDEMIC HIT AND HIT THE NEWS WIRES AND EVERYTHING ELSE, SO WE HAD TO SCRAMBLE TO DERIVE ASTROCYTES OUT OF iPS LINES TO BUILD THE FIRST SCREENING METHODS. AND IN JUST A FEW MONTHS, THE TEAM THAT'S PART OF THE RARE DISEASES GROUP WAS ABLE TO NOT JUST SET UP THE SCREENS, RUN THEM AGAINST APPROVED DRUGS, BUT DO SOME VALIDATION ON HITS, AND PUBLISH IN A TIME SPAN OF 3 1/2 MONTHS. SO WE PREFERRED TO PUT THAT DATA IN THE PUBLIC DOMAIN AS RAPIDLY AS POSSIBLE, IN CASE OF SUCH EMERGENCIES, BECAUSE, AGAIN, THERE IS NOT ENOUGH TIME TO BUILD AN INTERNAL TEAM TO WORK ON ALL THESE HITS, SO WE'D RATHER GIVE THEM TO THE COMMUNITY AND IMMEDIATELY, SO THEY CAN ACTUALLY TAKE THOSE ON AND VALIDATE THEM FURTHER. ANOTHER TRANSLATIONAL PROBLEM IN THIS SPACE OF TREATABLE DISEASES RELATES TO RAPID DISCOVERY OF DRUG COMBINATIONS. THIS IS OBVIOUSLY NOTHING NEW, DRUG COMBINATIONS ARE VERY RELEVANT IN MANY GENE, HIV, ALSO CALLED DRUG COCKTAILS. HOW DO YOU GO ABOUT RAPIDLY DISCOVERING NOVEL COMBINATION OF DRUGS? SO YOU NEED THE RIGHT LIBRARIES. I MENTIONED THOSE. APPROVED DRUGS, CANDIDATES IN DEVELOPMENT. YOU NEED APPROPRIATE TECHNOLOGIES TO ALLOW YOU TO STAMP THESE CUSTOM DOSES OF DRUG A AND DRUG B WITHOUT BREAKING THE BANK AND UTILIZE CUTTING-EDGE TECHNOLOGY OF ACOUSTIC DISPENSE, DELIVER THESE CUSTOM DOSES OF EACH DRUG VERY RAPIDLY AND TEST DRUG A AGAINST REMAINING WITHIN A COUPLE OF HOURS ACTUALLY, DEVELOPED INFORMATICS PROCESSES TO ACTUALLY CALCULATE THESE INDICES OF SYNERGISM AND IDENTIFY ACTIVE PAIRS IN PRETTY OF AUTOMATED FASHION. THIS WAS FIRST DEMONSTRATED AND DISSEMINATED THROUGH THIS PAPER USING ONCOLOGY EXAMPLE. AS I MENTIONED EARLIER, VERY MUCH DELIVERABLES ORIENTED SO WE DIDN'T JUST PUBLISH THE PNAS PAPER TO BE FAMOUS OR WHATEVER. WE ACTUALLY PROVIDED SOURCE CODE FOR THE SELF TOUR, TEACHING OTHERS HOW TO PROGRAM THESE MACHINES SO THAT OTHERS CAN ACTUALLY REPLICATE THIS PROCESS. P WE FOLLOWED MORE RECENTLY USING COMBINATION SCREENING PROCESS TO COMBAT RESISTANCE TO ANTI-INFECTIVES. AGAIN, ONCOLOGY AND INFECTIOUS DISEASES ARE SOMEWHAT RELATED IN THIS SPACE. RESISTANCE IS IMPORTANT IN BOTH. CANCER CELLS DEVELOP RESISTANCE, AND THERE'S PRESENT OF DRUG RESISTANCE IN THE PATHOGEN WORLD, SO WE ACTUALLY COLLABORATED WITH SCIENTISTS HERE ON CAMPUS AT THE NIH CLINICAL CENTER TO TEST DRUG RESISTANT CLINICAL ISOLATES IN A COUPLE THOUSAND, SINGLE AGENT, TWO AGENT, THREE-AGENT COMBINATIONS. GREEN MEANS TWO-AGENT COMBINATIONS, THIS IS SYNERGISM. A COUPLE EXAMPLES. DOWN BELOW IS HEAT MAP, AND SEVERAL THREE-DRUG COCKTAILS. THE TOP THREE YOU CAN SEE MORE RED MEANS BETTER EFFECT, MORE EFFICACIOUS COMBO. TOP IS EFFECTIVE AGAINST ALL TEN ISOLATES. SO THIS HOPEFULLY BRINGS US ONE STEP CLOSER TO THIS PERSONALIZED TESTING, WHERE ONE DAY WE HOPE THAT WE CAN HAVE THE SMART MACHINE OR PROCESS EASILY DEPLOYED IN CLINICAL SETTING TO GUIDE THE CLINICIAN AS TO WHAT ANTIBIOTIC, ANTIMICROBIAL TO GIVE TO A PARTICULAR PATIENT BASED ON WHAT THIS RAPID SCREENING WILL PROVIDE. WE'RE NOT THERE YET BUT HOPING TO FURTHER DEVELOP THIS TECHNOLOGY TO ALLOW SUCH RAPID ON THE SPOT TESTING. MOVING TO PROBLEMS IN THE LATER STAGE DEVELOPMENT, CHRIS MENTIONED VALLEY OF DEATH. A LOT OF PROJECTS GET STUCK REALLY AT THE LATE STAGE, LEADING TO IND AND FIRST-IN-HUMAN TESTING. FOR THAT SPACE WE ACTUALLY HAVE -- THERAPEUTICS FOR RARE AND NEGLECTED DISEASES PROGRAM AND BRIDGING INTERVENTIONAL DEVELOPMENT GAPS PROGRAMS THAT WERE ESTABLISHED BEFORE NCATS WAS CREATED, TO TACKLE THESE PROBLEMS IN THE LATE-STAGE DEVELOPMENT SPACE. SO THE MODEL HERE IS, AGAIN, COLLABORATIVE IN-KIND SUPPORT, WITH THE ULTIMATE GOAL TO MOVE THESE PROJECTS CLOSER TO FIRST-IN-HUMAN TESTING. TO DE-RISK ENOUGH TO BECOME ATTRACTIVE TO PRIVATE INVESTMENT, WHETHER IT'S ONE PROBLEM THAT WE NEED TO SOLVE TOGETHER OR MULTIPLE PROBLEMS. WE HAVE OBVIOUSLY THE SCIENTIFIC EXPERTISE IN-HOUSE, SOME OF THE WORK WE DO IN-HOUSE. THE REST OF THE WORK WE DO THROUGH GOVERNMENT CONTRACTS. AND, AGAIN, THESE ARE JOINT MILESTONE-DRIVEN PROJECT TEAMS, WITH, AGAIN, VERY STRONG ROLE OF PROJECT MANAGEMENT. SO TRND, RARE DISEASES PROGRAM, IS RESTRICT TOLLED RARE AND NEGLECTED DISEASE, BRIDGs WORKS ON END DISEASE AND TARGETS UNMET NEEDS IN PRE-IND SPACE, TOX PACKS DEVELOPMENT, YOU NAME IT. CAPABILITIES ARE REALLY ALL OF THE ABOVE, THAT RELATE TO THE LATE-STAGE DEVELOPMENT SPACE. A LOT GOES ON HERE. PROCESS R&D AND MANUFACTURE, THIS IS NOT GLAMOROUS THING. YOU DON'T PUBLISH SCIENCE PAPERS WHEN YOU SOLVE FORMULATION PROBLEM OR SCALE-UP PROBLEM. THIS IS REALLY WHERE A LOT OF THESE PROJECTS GET STUCK, AND THEY FAIL TO RAISE ADDITIONAL INVESTMENTS, OR THE COMPANY IS TOO SMALL AND DENTE HAVE ENOUGH EXPERTISE -- DOESN'T HAVE ENOUGH EXPERTISE TO SOLVE THE PROBLEM. THEY COME TO US. WE DE-RISK ASSETS, SOMETIMES DOING ONE THING, NOT THE REMAINING ELEMENTS OF THE WORK. AND AGAIN WE HAVE THE IN-HOUSE TEAMS TO DO ADME/PK, WORK ON MANUFACTURING SCALEUP AND TO ALSO MANAGE CONTRACTS ON THE SCIENTIFIC SIDE WITH CRLs. WE'RE PARTNERING MORE AND MORE WITH THE CPSAs AND A -- CTSA AND FDA IN NATURAL HISTORY STUDY. RARE DISEASES, THIS IS CRUCIAL. WE DON'T WANT SOMEONE COMING WITH A CANDIDATE THERAPY AND THEN WE WORK ON THE PROJECT AND WE END UP NOT KNOWING HOW TO STRUCTURE THE CLINICAL STUDY DOWN THE ROAD, WHAT TO FOLLOW IN SAY DISEASE THAT PROGRESSES VERY SLOWLY SO WE'RE WORKING ON DEVELOPING COMPUTATIONAL METHODS TO PREDICT DISEASE PROGRESSION BASED ON NATURAL HISTORY STUDIES. SO, JUST SOME NUMBERS HERE, THERE'S BEEN A LOT OF INTEREST IN THESE PROGRAMS OVER THE PAST 7, 8 YEARS OF THEIR EXISTENCE WITHIN NCATS AND BEFORE. SO THIS IS REALLY CUMULATIVE OUTPUT. A LOT OF THESE PROJECTS STARTED WELL BEFORE ENTERING NCATS, SO IT'S HARD TO COMPARE THESE METRICS. BUT REALLY THERE'S BEEN PRETTY GOOD GRADUATION RATE, BOTH IN TERMS OF INDS CLINICAL TRIALS AS WELL AS LICENSING, ACQUISITIONS, COMPANIES RAISING ADDITIONAL FUNDING, AND START-UPS GETTING FORMED. AGAIN, I DON'T HAVE TIME TO GO OVER TOO MANY DETAILS. BUT JUST ONE EXAMPLE IN THE SPACE, THIS IS REALLY AN INTERESTING ONE, BECAUSE AS YOU WILL SEE IN A MOMENT, INVOLVES PRETTY LARGE PARTNERSHIP NETWORK THAT WE HAD TO ESSENTIALLY ESTABLISH, PULMONARY LDL WORK, WITH BRUCE TRAPNELL AT CINCINNATI H OSPITAL, MAIN COLLABORATOR. REALLY THE GORY DETAILS HERE, IF YOU REALLY WANT TO WATCH HOW THIS IS DONE, THERE'S A LINK TO WHOLE LUNG LAVAGE, INVASIVE, GENERAL ANESTHESIA, INVOLVES SEDATING THE PATIENT, FILLING UP THE LUNGS, SHAKING THEM, EITHER MANUALLY, TAPPING ON THEIR CHEST OR THROUGH VARIOUS MACHINES BEING DEVELOPED, EMPTYING THE LUNGS, FILLING THEM AGAIN, RUNNING THESE OVER SEVERAL CYCLES UNTIL YOU BEGIN TO DERIVE CLEAR FLUID. AND YOU DO THIS AGAIN A COUPLE OF YEARS LATER, AND SO IT'S ACTUALLY PRETTY INVASIVE PROCEDURE. SO, IN OUR CASE, THE PROJECT ENDED UP BEING A REPURPOSING PROJECT. GM-CSF, GRANULOCYTE MACROPHAGE COLONY FACTOR, A TYPE OF CYTOKINE, THERE'S APPROVED IN IV FORM, COMES FROM GENSINE, SO THESE SURFACTANTS ARE ACTUALLY CLEARED THROUGH THE ACTION OF MACROPHAGES, AND GMCFS CONTROLS MATURATION AND DEVELOPMENT OF MACROPHAGES, IN THE CASE OF AUTOIMMUNE PULMONARY ALVEOLAR PROTEINOSIS, ANTIBODIES IN THE PATIENTS INTERFERE WITH GM-CSF AND PREVENT IT GOING FROM THE ALVEOLI, CONTROLLING MACROPHAGE MATURATION, CLEARANCE OF THESE SURFACTANTS. SO THE GOAL OF THIS PROJECT, TO REPURPOSE SOMETHING APPROVED IN IV FORM TO DELIVERY THROUGH INHALATION ROUTE. SO REALLY THE ROLE OF THE TRND PROGRAM WAS TO WORK ON NON-GLP AND GLP TOX THROUGH NEW ROUTE OFFED A PLRGS. - - OF ADMINISTRATION. CONDUCTED AND MOVED TO PARTNER WITH DCI TO ENABLE TO CLINICAL TRIAL. THIS IS REALLY THE UNIVERSE THAT ENDED UP GRADUALLY GETTING BUILT BECAUSE IT'S NOT JUST ABOUT THE TRND PROGRAM CONDUCTING GLP TOX STUDY. IT'S ABOUT EVERYTHING ELSE, DE-RISKING IS NOT JUST DOING ONE THING, YOU REALLY NEED THE UNIVERSE OF PARTNERS, RDCRN, THE COLLABORATOR WHO CAME TO US WITH THE PROJECT, AND THEN DCI COLLEAGUES TO ENABLE THE FUNDING OF THE CLINICAL TRIAL TO CTSA SUPPLEMENT, STARTED LAST YEAR, IT'S PROGRESSING RIGHT NOW. SO REALLY NICE EXAMPLE OF HOW WE WORK ACROSS ORGANIZATIONAL UNITS TO DE-RISK A PROJECT REALLY BIGGER THAN JUST ONE ORGANIZATIONAL UNIT WITHIN NCATS. SPEAKING OF PATIENTS, WE VIEW THEM AS PARTNERS, NOT JUST TOWARDS THE END WHEN TREATMENT IS READY AND IS ABOUT TO BE DEPLOYED. BUT ALSO IN EARLY STAGES OF SETTING UP SCREENINGS AND ASSAYS, WE'VE BEEN WORKING AT DPI WITH DISEASE FOUNDATIONS FOR A WHILE NOW, ESPECIALLY TAPPING EXPERTISE GRANTEES HAVE WITH PARTICULAR DISEASE. BECAUSE THIS IS THE ONLY WAY FOR US TO JOINTLY WORK ON DEVELOPING A RELEVANT SCREENING METHOD FOR RARE DISEASE. THOSE SCREENING ASSAYS DON'T EXIST AND THEY ARE VERY DIFFICULT TO BUILD FROM SCRATCH, SPECIFIC CELL LINES, PLACING THE REPORTER IN PARTICULAR EPIGENETIC CONTEXT. SO -- AND OF COURSE WE MEET WITH THE PATIENTS. THEY LIKE TO COME AND GET TOURS, AND IT ACTUALLY WORKS BOTH WAYS. OUR OWN SCIENTISTS LEARN MORE ABOUT THE DISEASE, AND GET TREMENDOUSLY MOTIVATED BY MEETING THESE PATIENTS. OTHERWISE, YOU END UP WORKING IN ISOLATION AND REALLY YOU DON'T KNOW WHAT YOU'RE DOING IN THE END. BUT THEY ARE REALLY MAINTAINING THESE PARTNERSHIPS, AND UTILIZING RESOURCES THE FOUNDATIONS HAVE IN TERMS OF KNOWLEDGE OF THE PARTICULAR DISEASE. AND THEN OF COURSE WE HAVE KNOWLEDGE AND TECHNOLOGIES AND EARLY DISCOVERIES, SO THAT'S HOW WE MEET IN THE MIDDLE. SPEAKING OF DISSEMINATION, THIS IS AN AREA WHERE WE'RE PAYING INCREASING ATTENTION TO, NOT JUST DEVELOPING IMPROVEMENTS AND MAYBE DISSEMINATING THROUGH ONE PUBLICATION, BUT REALLY PROVIDING MORE COMPREHENSIVE PORTALS OR MECHANISMS TO SHARE THE KNOW-HOW. IN THIS CASE, NOT INTERNAL JUST TO NCATS, BUT TO OTHERS IN THIS ECOSYSTEM. ASSAY GUIDANCE MANUAL STARTED AS AN INTERNAL MANUAL FOR ASSAY DEVELOPMENT AND SCREENING AT ELI LILLY, AND ABOUT 12 YEARS AGO WE PARTNERED WITH ELI LILLY AND CHRIS AND OTHERS WERE ABLE TO CONVINCE LILLY'S LEGAL TEAM TO RELEASE THEIR INTERNAL MANUAL TO THE PUBLIC DOMAIN. THIS STARTED THIS DECADE-LONG JOURNEY TO DEVELOP THIS NOW INTO A PRETTY COMPREHENSIVE BOOK RIGHT NOW, E-BOOK ON THE NATIONAL LIBRARY OF MEDICINE BOOKSHELF, TO TEACH OTHERS HOW TO SET UP SCREENING ASSAYS, HOW TO ANALYZE DATA, HOW TO PAY ATTENTION TO ARTIFACTS. ONLINE ACCESS TO THE WEB PAGE HAVE BEEN GROWING. THIS PLOT, WAY DOWN HERE, WE'RE ACTUALLY DISSEMINATING THROUGH VARIOUS CHANNELS, AND I MENTIONED EVERYBODY'S INVOLVED, DIFFERENT PLAYERS IN THIS ECOSYSTEM, AND THIS IS REALLY WITNESSED THROUGH THE DIVERSE EDITORIAL BOARD MEMBERSHIP, FROM BOTH NON-PROFIT UNIVERSITIES, STAND-ALONE INSTITUTES AS WELL AS COMPANIES AND NCATS. IN ADDITION TO EDITORIAL BOARD MEMBERSHIP, WE SOLICIT NEW CHAPTERS AND NEW CONTENT FROM THE ENTIRE SCIENTIFIC COMMUNITY. BECAUSE THIS IS AN E-BOOK, IT'S A LIVING DOCUMENT, WE DON'T HAVE TO WAIT A COUPLE YEARS FOR NEW EDITION. WE CAN CONSTANTLY UPDATE THE CONTENT, ADDING NEW TOPICS LIKE STEM CELL-BASED SCREENING, PRE-CLINICAL DEVELOPMENT AND SO ON. AND MOST RECENTLY, WE'VE ACTUALLY BEGUN TO DISSEMINATE THIS EVEN MORE DIRECTLY TO THE END USERS BY CONDUCTING THESE LECTURES AND WORKSHOPS THAT HAVE BEEN ATTENDED BY REALLY DIVERSE AUDIENCE. MEMBERS OF INDUSTRY, LOCAL INSTITUTIONS, UNIVERSITIES AND SO ON. AND WE HOPE TO CONTINUE THIS AND BUILD ON THE MOMENTUM TO REALLY MEET THE NEEDS OF OUR EDUCATIONAL MISSION HERE, NCATS. SO IN CONCLUSION, WHAT WE'RE ALSO DOING IS WE'VE RECENTLY STARTED STRATEGIC PLANNING PROCESS, THIS FALLS IN THE FOOT STEPS OF LARGER NCATS PLAN RELEASED IN 2016. WE STARTED WITH OUR OWN DRAFT PLAN PRESENTED TO THE INTERNAL DPI LEADERSHIP, OFF-SITE RETREAT, CREATED INTERNAL WORKING GROUPS TO DEVELOP STRATEGIC PLANS, WITH MORE DETAIL AROUND IMPLEMENTATION. WE HAVE MONTHLY FOLLOW-UP MEETINGS. AND THEN WE INTEND TO BRIEF NCATS LEADERSHIP WHEN WE FINISH THIS INITIAL PLANNING, AND YOU ALL SOON THEREAFTER. WE ALSO RECENTLY IMPLEMENTED WHAT WE CALL AD HOC SCIENTIFIC REVIEWS OF THE VARIOUS UNITS THAT ARE PART OF DPI. AND THESE ARE, AGAIN, REVIEWS BY EXTERNAL NON-EXPERTS, SO RESULTS FROM AD HOC REVIEWS WILL FORM IMPLEMENTATION PLANS. SO TO FINISH, I'D LIKE TO JUST BRING UP A COUPLE POINTS. I HOPE I CONVINCED YOU WE'VE BUILT INFRASTRUCTURE THAT ENABLES US TO EMBARK ON THIS JOURNEY OF TACKLING PROBLEMS IN TRANSLATION. AGAIN, THIS WAS NOT THE CASE SEVERAL YEARS AGO. SO WE HAD TO BUILD THE SHOP FROM SCRATCH. WE'VE DEVELOPED, DEMONSTRATED, DISSEMINATED PROCESS IMPROVEMENTS, BROWSING PLATFORMS TO THE COMMUNITY, WE'VE PUT OUT THERE A LOT OF NOVEL ASSAYS, METHODOLOGIES, PARADIGMS, AND ACTUAL HIGH-QUALITY SMALL MOLECULES TO STUDY DISEASE BIOLOGY. AND WE'VE ACTUALLY DE-RISKED A NUMBER OF CLINICAL PROJECTS, HELPING OTHERS, INCLUDING COMPANIES, ACADEMIC COLLABORATORS, DISEASE FOUNDATIONS, TO CROSS THIS VALLEY OF DEATH BY DE-RISKING THEIR ASSETS. WE'RE ALSO HEAVILY ENGAGED IN A LOT OF CROSS-NCATS PARTNERSHIPS AND PARTNERSHIPS, 3D BIOPRINTING, TRANSLATOR, WE'RE PART OF THAT, MEMBERS FROM INFORMATICS TEAM, AND WE'VE REALLY BEGUN TO DEMONSTRATE LEADERSHIP IN SOME OF THESE FIELDS OF TRANSLATIONAL SCIENCE EDUCATION, TEAM SCIENCE MODEL, AND MORE TECHNICALLY SMALL MOLECULE LIBRARY CONSTRUCTION AND DRUG REPURPOSING. WITH THIS I WILL STOP, THANKING ALL COLLEAGUES, COLLABORATORS AND OTHER PARTNERS, AND YOU FOR YOUR ATTENTION TODAY. [APPLAUSE] >> THANKS, ANTON. WE HAVE A GOOD 20-SOMETHING MINUTES FOR QUESTIONS, AND SEE WHO WANTS TO START. HELEN? >> THANKS SO MUCH FOR A COMPREHENSIVE PRESENTATION HERE, VERY EXCITING IN TERMS OF SOME OF THE TOOLS YOU GENERATED, THE LIBRARY GENERATION, ET CETERA. I'M PARTICULARLY INTERESTED IN YOUR PREDICTIVE EFFICACY MODEL YOU DESCRIBED, MAYBE BECAUSE OF LACK OF TIME YOU HAD TO WALK PRETTY FAST. HOW ARE YOU BUILDING IN THE PREDICTIVE VALIDITY OF MODEL SYSTEMS, ASSAY SYSTEMS, ONLY PICKING CERTAIN AREAS, DISEASE INDICATIONS, WHERE YOU HAVE GREATER CONFIDENCE IN THE MODEL SYSTEMS, PICKING PHENOTYPES YOU WANT TO STUDY, I'M ASSUMING PHENOTYPIC ASSAYS BASED ON THE QUESTION EVEN BRAD WAS ASKING BUT IF YOU CAN EXPAND A BIT MORE, WHY DO YOU THINK THESE ASSAYS ARE MORE PREDICTIVE, HOW ARE YOU BUILDING THOSE? >> FOR A LOT OF GENETIC DISEASES, SINGLE MUTATION IS IMPLICATES IN THOSE, WE CAN ACTUALLY DEVELOP ASSAYS, REPORT ON THAT MUTATION, WHETHER IT'S (INDISCERNIBLE) COMPENSATION TYPE DISEASE OR SOMETHING ELSE. THESE DON'T HAVE TO BE PHENOTYPIC SCREENS. DPI LABS HAVE ACTUALLY WORKED PRETTY HARD IN THE PAST SEVERAL YEARS TO DEVELOP BETTER REPORTER SYSTEMS. AGAIN, I DIDN'T HAVE TIME TO DISCUSS THESE, BUT ONE EXAMPLE IS THE COINCIDENCE REPORTER THAT WAS DEVELOPED A COUPLE YEARS AGO, WHERE INSTEAD OF HAVING, FOR EXAMPLE, JUST LUCIFERASE REPORTER IN SYNC WITH YOUR PROMOTER AND WHAT NOT WE KNOW LUCIFERASE IS ACTUALLY SUBJECT TO FALSE POSITIVE SIGNALS BY THE SMALL MOLECULES IN THE LIBRARY THAT INHIBIT AS REPORTER. INSTEAD OF HAVING ONE REPORTER, WE HAVE TWO IN TANDEM, INTERRUPTED BY WHAT'S CALLED SELF CLEAVING P 2A SO YOU PRODUCE TWO REPORTERS IN INK, CONTROLLED CONSTANT MOLAR RATIO, AND ONLY IF YOU SEE POSITIVE SIGNALS FROM BOTH REPORTERS, SO COINCIDENCE TERM, ONLY THEN YOU BELIEVE THAT HIT THAT YOU'RE GETTING FROM YOUR TEST, IF ONLY ONE REPORTER LIGHTS UP, THE OTHER ONE DOESN'T, IT MUST BE A REPORTER-SPECIFIC INTERFERENCE, AND YOU DO NOT PROGRESS THESE HITS ANY FURTHER. SO THIS IS AN EXAMPLE OF VERY DELIBERATE ASSAY DEVELOPMENT TO IMPROVE THESE REPORTING SYSTEMS THAT ARE SUBJECT TO A LOT OF FALSE POSITIVES THAT WAY. YOU CAN COMBINE LUCIFERASE AND GPF, TWO TYPES OF LUCIFERASE. >> HOW ABOUT THE SYSTEM YOU PICK UP FOR ASSAYS, HOW ARE THOSE INFORMED? >> SO OF COURSE WE STARTED WITH LOW-HANGING FRUIT, FOR A LOT OF THE EARLY SCREENS WE USED EASY TO CULTURE CELLS BUT NOW WE'RE INCREASING IN SOPHISTICATION, ESPECIALLY WITH iPS TECHNOLOGIES. ZIKA SCREENING I MENTIONED EARLIER WAS RUN ON ASTROCYTES PRODUCED FROM iPS CELLS. YOU CAN RUN ZIKA SCREEN USING VIRO CELLS, WE'VE DONE THAT CELLS, THEY ARE MONKEY KIDNEY CELLS, EASY TO HANDLE BUT NOT REALLY HUMAN AND NOT REPRESENTATIVE OF NEURONAL IMAGE, WHERE ZIKA IS KNOWN TO BE ACTIVE PRIMARILY AS FAR AS MICROCEPHALY. WE'RE TRYING TO SET UP MOST RELEVANT SCREENS DEPENDING ON DISEASE CONTEXT. >> JUST ONE MORE REAL SLIGHT PUSHBACK ON THAT. PUBLISHED SEVERAL YEARS A PAPER COMPARED A SCREEN WITH KIDNEY CELLS, SAME HITS, SIMILAR POTENCY. I THINK REALLY THAT'S WHAT I WAS DRIVING AT. WHEN DO YOU DETERMINE THAT YOU NEED A CADILLAC VERSUS YOU CAN RIDE A BIKE, AS WE WERE DISCUSSING THIS MORNING, STILL GET THE SAME RESULTS, OR ARE THERE ASSUMPTIONS HERE THAT BECAUSE YOU'RE USING HUMAN DERIVED VCSs THEY ARE MORE PREDICTIVE OR ARE YOU BUILDING IN PREDICTIVE ALGORITHMS TO SAYING WE'RE MAKING IT MORE PREDICTIVE? >> I DON'T THINK WE HAVE AN ANSWER YET BUT WE'RE DOING WITH BIOPRINTING, WHICH WE VIEW AS A BRIDGE BETWEEN TWO CELL CULTURES, EASY TO EXECUTE SCREENS AND TISSUE CHIP, WHERE IT'S CLEARLY MORE SOPHISTICATED, BUT ALSO CLEARLY YOU'RE NOT GOING TO BE ABLE TO RUN HALF A MILLION COMPOUND SCREEN ON TISSUE CHIP SYSTEMS, AT LEAST NOT THE WAY THEY ARE CONFIGURED NOW, WE VIEW THIS AS A CONTINUUM, AND WE HAVE TO ACTUALLY BUILD THE TECHNOLOGIES AND RUN THE EXPERIMENTS BEFORE WE CAN ANSWER THIS QUESTION. SO, THAT'S WHY WE'RE TRYING TO FILL THIS GAP BETWEEN TISSUE CHIP AND 1536-WELL 2B CULTURE TYPE PLATE EXPERIMENT WITH BIOPRINTING. BIOPRINTING WILL NOT ALLOW US TO RUN AT THE SAME THROUGHPUT AND SPEED AS 1536 WELL PLATES HANDLEED BY ROBOTIC ARMS, DEFINITELY HIGHER THROUGHPUT AND TISSUE CHIP, SO AT SOME POINT WE HOPE TO ACTUALLY HAVE DEMONSTRATION STUDIES, ALONG THE LINES OF WHAT YOU DESCRIBED, 2D SCREEN, 3D SCREEN, DOUBLE BLIND, CAN WE PREDICT SOMETHING AT HIGHER ACCURACY BY USING THESE MORE SOPHISTICATED MODELS OR ARE WE JUST WASTING OUR TIME. >> THANK YOU, ANTON. A COUPLE COMMENTS, I APOLOGIZE IN ADVANCE IF THEY ARE A LITTLE BIT -- A COUPLE QUESTIONS FOR YOU TO CONSIDER. YOU KNOW, I REALLY LIKE A NUMBER OF THE KEY TECHNICAL ACHIEVEMENTS YOU'VE MADE WITH A LOT OF THINGS THAT THE GROUP DECIDED TO WORK ON, AND I THINK THEY ARE VERY NICE EXAMPLES OF NICE COLLABORATIVE SCIENCE, SOLVING KEY PROBLEMS ON TOOLS AND TECHNOLOGIES. I GUESS WHAT I'M THINKING ABOUT IS IF YOU THINK ABOUT WHAT THE OVERALL MISSION IS TO REALLY BRIDGE THIS GAP, ARE YOU JUST FILLING IN THE VALLEY WITH STUFF OR ARE YOU REALLY RAISING THE FLOOR? I THINK THAT'S KIND OF WHAT THE POINT OF THE WAY THIS IS HEADED, I THINK A LOT OF SOLUTIONS ARE NICE BUT HOW DOES IT FIT TOGETHER TO REALLY CREATE TRANSFORMATIVE PARADIGMS ADOPTED AND MIMICKED IN THE COMMUNITY? IT HAS TO TAKE THE NEXT STEP. COUPLED TO THAT, VARIOUS PIECES, THERE'S BEEN TREMENDOUS ADVANCES IN BIOPHYSICAL SCIENCES, YOU KNOW, CERTAINLY WITH ADDITIONAL TOOLS HELPING TO BETTER DEFINE DRUGGABLE SURFACES AND UNDERSTAND HOW YOU CAN TAKE A PARTICULAR PROTEIN AND THINK ABOUT WAYS TO EITHER BUILD COMPUTATIONAL METHODS OR EVEN, YOU KNOW, STRUCTURE GUIDED APPROACH, RAPID ADVANCE IN CRYO-EM AND OTHER TECHNOLOGIES ARE SUPPLANTING MORE TRADITIONAL SCREENING PARADIGMS WHICH I THINK PEOPLE FOUND HAVE A DIMINISHING RETURN, BUT CAN BE USED MORE IN TANDEM OR PART OF EXTENDED PROCESS. IF THE STATEMENT IS THERE'S A GAP BETWEEN BASIC RESEARCH AND WHAT INDUSTRY IS DOING OR WILL ADOPT, YOU KNOW, HOW ARE YOU BRIDGING THAT WITH THE BEST POSSIBLE TOOLS THAT CAN BE PARADIGM CHANGING, VERSUS WHAT I'VE SEEN, AND I DON'T MEAN TO BE OVERLY CRITICAL, JUST ASSEMBLING A NUMBER OF NICE TOOLS AND PROJECTS, BUT HOW DO THEY LINK TOGETHER AND REALLY CREATE A TRANSFORMATIVE LINK TO NEW FRONTIER IS MY CHALLENGE. >> LET ME TRY TO WORK BACKWARDS WITH THE PRE-CLINICAL WORK, LATE-STAGE WORK WE'VE DONE. AGAIN, I DIDN'T HAVE TIME TO DISCUSS THIS. TAKE THE EXAMPLE OF ( INDISCERNIBLE) AND CYCLODEXTRINE IN PHASE 3, NOW THE FIRST CANDIDATE GRADUATING TO ADVANCED TESTING BUT BEGINNING OF A PARADIGM BUILDING. WE LOOK FOR COMMONALITIES ACROSS SEVERAL DISEASES, MULTIPLE DISEASES, THAT SHARE THE SAME MOLECULAR MECHANISM AND TRY TO USE ONE OF THEM OR TWO OF THEM AS EXEMPLARS TO BUILD THIS PLATFORM. SO WE HAVE COLLABORATIVE RESEARCH AND DEVELOPMENT AGREEMENT, CRADA WITH THE TEST, TO ACTUALLY CONTINUE JOINT WORK TO EVALUATE PSYCHODETXRTNE FOR OTHER CHOLESTEROL MISTRACKING DISORDERS. WE'RE TAKING THIS PLATFORM VIEW, WHEN WE LOOK OR WORK ON ONE PARTICULAR PROJECT. IN THE AREA OF BIOPHYSICS, WE'RE ACTUALLY DEVELOPING A LOT OF METHODS RELATED TO DISCOVERY OF NON-INHIBITOR CHEMICAL CHAPERONES. THIS IS ALSO THE NEW FRONTIER, HOW DO YOU DISCOVER SOMETHING THAT IS NOT INHIBITORY? YOU CANNOT USE ENZYME INHIBITION ASSAY. THIS IS IMPORTANT IN GOSHAY'S DISEASE AND ALL RELATED DISEASES WHERE A PROTEIN IS MISFOLDED. FINDING ALLOSTERIC SMALL MOLECULES THAT WILL HELP REFOLD THIS NEW PROTEIN WILL HELP MANY BOATS RISE. PROBABLY SEVERAL DOZEN SUCH DISEASES. SO WE'RE WORKING ON BIOPHYSICAL DISCOVERIES, THE MORE RECENT ADVANCES IN CELLULAR THERMAL SHIFT, WE'RE ACTUALLY WORKING ON HIGH THROUGHPUT CELLULAR THERMAL SHIFT PLATFORM, WHICH WE HOPE TO MAKE PUBLICLY AVAILABLE SOON TO ALLOW THIS UNBIASED DISCOVERY OF SMALL MOLECULE MODULATORS FOR TRADITIONALLY ENZYMATIC OR OTHER ASSAY WILL NOT WORK, SO WE'RE DOING THAT. >> YEAH, I GUESS MAYBE IN FUTURE ASSAYS IT WOULD BE NICE TO SEE A LITTLE BIT OF THAT MORE KIND OF FOREIGN-LOOKING REPRESENTATION STRATEGY, HOW COMPONENTS CAN SIT TOGETHER TO REALLY TACKLE SOME OF THESE ACTIVITIES IN A MORE -- IN A WAY VIEWED AS TRANSFORMATIVE, THAT WOULD BE HELPFUL FOR THE COMMITTEE. >> THANKS, ANTON. THIS IS GREAT. ONE QUESTION, ASKING A COMPLETELY DIFFERENT TYPE OF QUESTION. TECHNICALLY THIS IS WONDERFUL. IS THERE A WAY YOU CAN ALSO TRACK COST? BECAUSE THE COST OF DRUG DEVELOPMENT IS GETTING COMPLETELY ASTRONOMICAL. ARE THERE WAYS THAT THESE KINDS OF NEW PROCESSES CAN SHORT-CIRCUIT THE COST OF DRUG DISCOVERY AND COMING TO A LEAD COMPOUND? OR TO REACH ANY GIVEN TARGET FOR DISEASE? >> FOR THE VERY EARLY STAGE OF HIGH-THROUGHPUT SCREENING, THE METHOD WE DEVELOPED AND ARE PRACTICING, WHICH IS TO TEST THE LIBRARY MEMBERS AT MULTIPLE CONCENTRATIONS, I DON'T HAVE HARD NUMBERS RIGHT NOW, BUT WE KNOW WE'RE ACTUALLY SAVING MONEY BECAUSE EVEN THOUGH WE'RE TESTING MORE SAMPLES INITIALLY, TO DERIVE THESE DOSE-RESPONSE CURVES FOR EVERY MOLECULE IN THE LIBRARY, WE ACTUALLY GET DATA OF SUCH HIGHER QUALITY THAT WE'RE SO MUCH BETTER INFORMED IN HIGH-THROUGHPUT SCREENING HITS WE DON'T EXPERIENCE SO MUCH LOSS OF HITS UPON CONFIRMATION. SO THERE'S TREMENDOUS COST RECOVERY AND ACTUAL SAVINGS, BECAUSE YOU CAN DERIVE PRELIMINARY STRUCTURE ACTIVITY RELATIONSHIPS RIGHT OUT OF THE PRIMARY SCREEN, AND WE'RE BEGINNING TO TEST DIFFERENT MACHINE LEARNING METHODS TO LOOK AT THE SCREENING DATA, AND USE THEM TO BUILD MACHINE LEARNING MODELS, TO PREDICT NOVEL MOLECULES THAT ARE NOT PART OF THE LIBRARY, WITHOUT HAVING CRYSTAL STRUCTURED TARGET OR ANY OTHER KNOWLEDGE. BECAUSE OF THE HIGH QUALITY OF THESE SCREENING PROCESSES THAT ARE IN PLACE, WE'RE ABLE TO ASK THESE QUESTIONS AND TO BUILD THESE NEW MODELS. >> I'LL ALSO EXPAND ON THAT ANTON IS SAYING, AS EVERYONE KNOWS, THERE ARE TWO THINGS THAT LEAD -- TWO ASPECTS THAT LEAD TO COST. ONE IS THE UNIT COST, AND THE OTHER IS THE FAILURE RATE. AND WE'RE CERTAINLY WORKING ON BOTH. BUT TO US, WHERE THE REAL MONEY IS IS IN THE FAILURE RATE. THAT'S A MULTIPLIER. SO WE LOOK AT WHERE A LOT OF THIS COMES FROM. IT'S FROM -- IT'S THE OLD -- IT'S HOPE OVER EXPERIENCE, RIGHT? YOU THINK YOU KNOW SOMETHING WHEN YOU TURN OUT TO NOT KNOW IT. SO WE'RE BIG ADVOCATES OF DEVELOPING METHODS THAT ARE A LOT MORE ROBUST AND RELIABLE, SO THAT YOU DECREASE THE RATE AT WHICH YOU LATER FIND OUT, BUT WHAT YOU FOUND WAS ACTIVE BUT IRRELEVANT. AND SORT OF LIKE WE HAVE THIS ADAGE THAT WE USE UP THERE THAT EVERY FINDING IS AN ARTIFACT UNTIL PROVEN OTHERWISE. THAT'S TURNED OUT TO BE VERY USEFUL BECAUSE IT'S TRUE. IT'S MUCH EASIER TO FIND AN ARTIFACT, BUT WE ALL KNOW THE DATA IN DRUG DEVELOPMENT ABOUT CONFIRMATION BIAS AND SO WE VERY ACTIVELY DESIGN OUR SYSTEMS TO ASSUME THAT WILL HAPPEN, AND PREVENT IT FROM HAPPENING IN THE FIRST PLACE. AND ANOTHER WAY TO THINK ABOUT IT, WE DO HAVE SOME DATA, THAT'S A BIT OLD NOW, BUT IT ACTUALLY COMES FROM ANALYSIS THAT WE DID A FEW YEARS AGO, LOOKING AT THE COST OF DEVELOPING A PROBE. THIS IS THROUGH TO THE PROBE STAGE. AND THE COMPAREATIVE NUMBER SENT FROM FOLKS AT A PHARMACEUTICAL COMPANY WHICH WILL GO UNNAMED BUT THERE ARE PEOPLE IN THIS ROOM WHO HAVE BEEN AT THIS COMPANY AND THE COST THAT WE EXPERIENCED WAS 1/6 OF THAT COST. AND SO A LOT OF INTERESTING QUESTIONS WHY THAT IS BUT I THINK FOR THE MOST PART, IT WAS THIS FAILURE ISSUE. AND YOUR OTHER THING WE HAVE DONE THAT ANTON DIDN'T HAVE TIME TO TALK ABOUT, WE DID AN ANALYSIS A FEW YEARS AGO OF THE RARE DISEASE PORTFOLIO THAT ANTON MENTIONED, TOGETHER WITH A FINANCE PROFESSOR AT M.I.T. AND ASKED HIM TO LOOK AT COST AND FAILURE RATE. BOTTOM LINE OF THIS, A SMALL RETROSPECTIVE STUDY, TAKE THAT WITH A GRAIN OF SALT, BUT WHAT WAS FOUND BY HIM, NOT BY US, USING OUR DATA, WAS THAT THE SUCCESS RATE OF THE PROGRAM WAS TWICE THE INDUSTRY AVERAGE AND COST WAS HALF THE INDUSTRY AVERAGE. AND SO THE SITUATION WE'RE IN NOW, WE HAVE PHENOTYPIC OBSERVATIONS, SO THE FIRST QUESTION, WHAT'S THE MECHANISM, WHY IS THAT? AND WE'RE STILL TRYING TO FIGURE THAT OUT, I THINK, BUT LITERALLY DATA POINT. >> YEAH, I THINK WHAT YOU AND ANTON UNDERSELL THAT, THAT'S A VALUE ADDED, BEYOND TECHNOLOGY AND NEW DISCOVERIES, BECAUSE AS YOU KNOW AS ANYBODY WILL TELL YOU, SMALL MOLECULE, MOST INVESTORS SAY, OKAY, FINE, YOU'RE NOT MY TYPE AT ALL BECAUSE I'M GOING TO SPEND $150,000, A MILLION DOLLARS TO DEVELOP A NEW DRUG, SO EXPENSIVE IT'S UNAFFORDABLE, SO ESPECIALLY FOR SMALL MARKETS AND RARE DISEASES, TO MAKE DRUG DISCOVERY AND DRUG DEVELOPMENT AFFORDABLE, THIS BECOMES A BIG ISSUE. >> IT GOES BACK TO ONE OF OUR CORE VALUES OF COLLABORATION. YOU SAW IT IN THE PAP EXAMPLE. IF WE HAD BEEN IN A CONVENTIONAL PLACE, WE WOULD HAVE TRIED TO DO ALL THAT OURSELVES. AND WE VERY QUICKLY -- WE DO THIS IN EVERYTHING WE DO, TRUE WITH ALL OUR PROGRAMS, WE ASSUME -- WE LOOK FOR OTHER PEOPLE TO HELP RATHER THAN TRY TO DO SOMETHING OURSELVES. AND SO THE REASON WE DO THAT, WE DON'T CARE WHO GETS THE CREDIT BECAUSE, THESE FOLKS, THEY DON'T HAVE TENURE, TENURE TRACK, DON'T HAVE TO WORRY ABOUT IT. AND WE'RE NOT A COMPANY. WE CAN BE COMPLETELY OPEN. WE HAVE TROUBLE WITH PAP, VERY QUICKLY WENT TO THE RDCRN, TO THE CTSAs, BRINGING IN A HUGE GROUP OF PEOPLE, WHICH WE'VE BEEN -- WE DIDN'T HAVE TO DO -- -- YOU KNOW, ALL THE AGREEMENTS AND LEGAL STUFF AND ALL THAT STUFF THAT WE WOULD HAVE HAD TO DEAL WITH, WE JUST DIDN'T. AND THERE IS AN AMAZING OPPORTUNITY COST OF ALL OF THAT WORK, YOU KNOW, VERY HIGHLY PAID PEOPLE, WHO JUST -- WHO ADD TO THIS COST OF DRUG DEVELOPMENT. SO I THINK THAT'S ANOTHER REASON WHY IT'S MORE EFFICIENT. THE QUESTION FOR US IS -- WE DEAL WITH THIS ALL THE TIME, HOW DO WE DISSEMINATE THAT? WE'VE CREATED THIS ENVIRONMENT IN A SPECIAL PLACE, COLLABORATE ALL OVER THE PLACE, BUT AS WE TALKED ABOUT LAST NIGHT, ACADEMIC CENTERS AND COMPANIES HAVE DIFFERENT PRESSURES ON THEM MAKING IT DIFFICULT TO AS ACT WE DO EVEN IF WE'VE SHOWN IT'S A BETTER WAY TO WORK. THAT'S THE NEXT CHALLENGE. >> PART OF DEVELOPING NEW TYPES OF REWARD SYSTEMS WITHIN OUR ACADEMIC EXPERIENCE, WHICH I MEAN WE WOULD ALL TREASURE THE OPPORTUNITY TO NOT HAVE TO WORRY ABOUT COMPOSITION, RDUs ACROSS OUR MISSION, BUT THAT'S NOT THE REALITY. AND SO, YOU KNOW, PERHAPS WE CAN CONTINUE TO DO AS YOU ALL ARE DOING, AND BROADENING THE COMMUNICATION, GETTING MORE PEOPLE AROUND THE TABLE, WILL AT LEAST GET THE OPPORTUNITY FOR PEOPLE TO TAKE THE MODELS BACK TO THEIR INSTITUTION. THEY ARE NOT BEING SO REDUNDANT IN DOING THINGS IN THEIR INSTITUTION THAT REALLY CAN BE DONE MUCH MORE EFFICIENTLY AND EFFECTIVE IN A CORE TYPE OF SITUATION. >> YOU KNOW, WE DON'T HAVE MUCH MORE TIME FOR THIS DISCUSSION NOW, BUT THIS IS EXACTLY WHAT I WOULD LIKE THE COUNCIL TO SPEND TIME THINKING ABOUT WITH REGARD TO DPI. IT'S NOT ONLY -- TWO QUESTIONS THAT WERE ASKED, TWO POINTS, VALERIE'S POINT, AND THEN ALAN'S POINT, THOSE ARE THE THINGS WE THINK ABOUT A LOT. AND LIKE ANYTHING, WE'VE DONE SOME THINGS PRETTY WELL, I THINK IN THIS SPACE, OTHER THINGS WE WANT TO DO BETTER. AND SO YOUR GUIDANCE ON WHAT THOSE WOULD BE IS REALLY WHAT WE NEED FROM YOU. NOT TODAY. BECAUSE WE HAVE TO GO TO CLOSED SESSION. I WANT TO THANK ANTON FOR A MASTERFUL PERFORMANCE. THANK YOU. [APPLAUSE] YEAH, WHERE IS HIS PRESENTATION GOING TO BE? WHERE DO THE SLIDES GO? DO THEY -- >> WE CAN SEND THEM OUT, POSTING THEM ON THE WEB IS ANOTHER MATTER. >> OKAY. ALL RIGHT. BECAUSE OF 508. GOVERNMENT RULE ABOUT ABILITY OF PEOPLE WITH DISABILITIES, VISUAL AND HEARING DISABILITIES, TO INTERPRET THE SLIDES, AND SO IT'S MUCH EASIER FOR US TO JUST SEND THEM TO YOU, YEAH. WELCOME TO ANOTHER GOVERNMENT THING WE HAVE TO DEAL WITH. SAID WITH A SMILE. OKAY. AND YOU WILL HEAR -- WE'RE GOING TO REGULARLY BE BRING -- ANTON IS REGULARLY GOING TO BRING RESULTS OF PROGRAM REVIEWS TO TELL YOU -- EXTERNAL PEOPLE REVIEWED TOX21 SIX MONTHS AGO OR SO, SO WHAT DID THEY FIND? AND ALSO STRATEGIC PLAN, YOU'LL HEAR ABOUT THAT TOO. OKAY. SO THIS BRINGS OUR OPEN SESSION TO A CLOSE, SO DR. MARKS AND I WILL -- ONE, TWO, THREE.