GOOD MORNING EVERYONE I'M LARRY MARNETT THE CHAIR OF THE FNLAC ADVISORY COMMITTEE. I'D LIKE TO WELCOME OUR COMMITTEE MEMBERS AND OUR STAFF AND OUR GUESTS TO THIS MORNING'S MEETING. AS COMMITTEE MEMBERS, I WANT TO REMIND YOU YOU MUST ABSENT YOURSELF DURING SPECIFIC DISCUSSIONS WHENEVER YOU'RE PARTICIPATION AND DELIBERATIONS OF A PARTICULAR PRODUCT, PROGRAM OR OTHER SPECIFIC MATTER WOULD CONSTITUTE A CONFLICT OF INTEREST OR CREATE THE APPEARANCE OF ONE. IT IS INCUMBENT UPON YOU TO SO ADVISE THE EXECUTIVE SECRETARY, DR. KARIN LIME AN, AND ABSTAIN FROM ANY PARTICIPATION IN THE DISCUSSION OR ACTION REGARDING THAT MATTER. IN KEEPING WITH CURRENT POLICIES GOVERNING CONFLICT OF INTEREST BASED ON FINANCIAL HOLDINGS OF SPECIAL GOVERNMENT EMPLOYEES, WHICH CATEGORY INCLUDES ALL MEMBERS OF THIS COMMITTEE, WE MUST DEPEND ON YOU TO VOLUNTARILY ABSENT YOURSELF DURING ALL DISCUSSIONS OF MATTERS THAT COULD CONCEIVABLY IMPACT THE STATUS OF THOSE HOLDINGS. WE TRUST YOUR JUDGMENT IN THESE INSTANCES. MEMBERS OF THE PUBLIC WHO MAY WISH TO EXPRESS VIEWS REGARDING ANY ITEMS DISCUSSED DURING TODAY'S MEETING, MAY DO SO BY WRITING TO DR. LIME AN, EXECUTIVE SECRETARY OF THE COMMITTEE, WITHIN 10 DAYS AFTER THE MEETING. ANY WRITTEN STATEMENTS BY MEMBERS OF THE PUBLIC WILL RECEIVE CAREFUL CONSIDERATION. BY LAW, A QUORUM OF COMMITTEE MEMBERS IS REQUIRED FOR EACH INSTANCE IN WHICH A VOTE OCCURS. DURING TODAY'S MEETING, A MINIMUM OF 7 APPOINTED MEMBERS MUST BE PRESENT TO VOICE THEIR VOTES. SINCE WE CANNOT PREDICT THE TIME OR OCCURRENCE OF ANY MOTION, YOUR PRESENCE IS A MUST FOR ALL SEGMENTS OF THE MEETING. KARIN, DO WE HAVE A QUORUM? >> YES, SIR, WE DO. >> OKAY. FIRST I'D LIKE TO ASK IF THERE ARE ANY AMENDMENTS HORRIDITS TO THE MINUTES THAT WERE CIRCULATED FROM THE OCTOBER MEETING? HEARING NONE, I'D LIKE TO ASK FOR A MOTION TO APPROVE THE MINUTES. SECOND? ALL RIGHT. MOVED AND SECONDED. ALL IN FAVOR? SO THE MINUTES HAVE BEEN APPROVED. FOR FUTURE MEETING DATES, THE JULY 20th, 2018 MEETING HAS BEEN CANCELED. OUR NEXT MEETING WILL BE OCTOBER 29-30, 2018. SO PLEASE MARK YOUR CALENDARS ACCORDINGLY. AND TO BETTER SPREAD OUT THE MEETINGS, THROUGHOUT THE YEAR, BEGINNING IN 2019, THE PRANKS ARE TO SCHEDULE MEETINGS IN FEBRUARY -- PLANS -- JUNE AND OCTOBER WITH THE FEBRUARY MEETING BEING HELD VISUALLY. SO THE JUNE AND OCTOBER MEETINGS WILL BE IN-PERSON. IF ANYONE HAS ANY THOUGHTS ABOUT THIS AT THIS POINT, LISA? >> LISA: -- >> PLEASE USE YOUR MICROPHONE. >> THE SHEET LIST MAY, JULY AND NOVEMBER 2019. >> THOSE WILL BE CHANGED. >> ALL RIGHT. >> OTHER COMMENTS ABOUT THE CHANGE IN MEETING SCHEDULE? TO ENSURE THE PROPOSED CHANGES OCCUR, WE NEED TO HAVE A VOTE. SO MAY I HAVE A MOTION TO CHANGE THE MEETING SCHEDULE AS INDICATED? THANK YOU, ANGELA. MOVED AND SECONDED. KEVIN. ALL IN FAVOR? OPPOSED? ALL RIGHT. SO ONCE WE HAVE SECURED ROOMS, MEETING DATES WILL BE SENT TO YOU FOR A CONFIRMATION VOTE AND THAT INCLUDES THE FEBRUARY VIRTUAL MEETING IN 2019. THE FIRST ITEM ON TODAY'S AGENDA IS THE DIRECTOR'S REPORT FROM THE NCI. AND DR. NED SHARPLESS WILL GIVE IT. GOOD MORNING, EVERYONE. THANK YOU FOR COMING. AND HELPING TO PROVIDE GUIDANCE ON FREDRICK NATIONAL LAB. I WILL TRY AND MAKE MY REMARKS BRIEF SO WE HAVE TIME FOR Q&A. I DON'T WANT TO USE THE WHOLE TIME SHOWING SLIDES BUT THERE ARE A FEW THINGS. I WOULD LIKE TO SAY A WORD ABOUT APPROPRIATIONS. FY18 WAS ENACTED IN MID-MARCH AND WE ARE STILL -- THERE IS A LOT GOING ON RELATED TO FQ18. IN TERMS OF FY19 SOME VIGOROUS DISCUSSION HAS ALREADY STARTED ABOUT PLANNING FOR THE 19 BUDGET. THE HOUSE AND SENATE COMMITTEES HAVE BOTH BEEN WORKING ON A VARIETY OF MEASURES AND THIS WILL GO ON THROUGH THE SUMMER. WE HAVE HEARD THAT THERE IS A INTEREST IN MAYBE GETTING A BUDGET DONE EARLIER THIS YEAR FOR A VARIETY OF REASONS THAN IN THE LAST FEW YEARS. WE'LL SEE IF THAT COMES TO PASS. TO RECAP THE LAST FEW YEARS, THE BUDGET HAS BEEN GOOD. FOUR YEARS IN A ROW OF INCREASES. THIS IS WONDERFUL NEWS FOR THE NIH AND NATIONAL CANCER INSTITUTE. SHOWN HERE IS 2014 THROUGH ENACTED 2018. IT'S IMPORTANT TO NOTE THAT THE ORANGE IS THE MOONSHOT 21ST CENTURY CURES FUNDING ON TOP OF THE GENERAL APPROPRIATION TO THE NCI, NOT IN ADDITION TO. SO -- I MEANT TO SAY IN ADDITION TO FOR BOTH LAST YEAR AND THIS YEAR. SO THAT IS 300 MILLION IN ADDITION TO 275 MILLION DOLLAR INCREASE IN THE APPROPRIATION OF THE NCI THIS YEAR, WHICH IS FRANKLY MORE THAN WE EXPECTED. WE WERE THINKING THE SENATE NUMBER WAS GOING TO BE 160 MILLION MORE. THIS WAS A WELCOMED SURPRISE. WE LEARNED OF THIS ORANGEY A FEW WEEKS BEFORE THE BUDGET WAS ENACTED. THIS IS THE 2019 BUDGET THAT IS BEING DISCUSSED NOW. SO WE WILL DO THAT, THAT IS INVESTMENT IN INVESTIGATOR INITIATED EXTERNAL SCIENCE BUT -- AND THIS IS THE LAST YEAR FOR SUCH A BIG INCREASE, BY THE WAY. BUT THAT MONEY DOESN'T RAISE PAY LINES FOR NEW AWARDS. SO I THINK THAT IS PART OF THE REASON. AND YOU CAN SEE THE TOTAL CONTRIBUTION TO THE POOL HAS BEEN GOING STEADILY UP AND WE'LL WILL BE CLOSE TO 2.2 BILLION DOLLARS NEXT YEAR. SO A VERY LARGE INCREASE IN THE RPG POOL. SO, A FEW THINGS ABOUT INTERGOVERNMENTAL AFFAIRS THAT MIGHT BE OF Z A LOT OF INTERESTING THINGS GOING ON WITH THE FDA AND CMS. BOTH AGENCIES HAVE A DATA SHARING PROPOSAL THAT HAVE A LOT OF DATA THEY WOULD LIKE TO TRY AND SHARE IN A VARIETY OF WAYS AND WE ARE HAVING ACTIVE DISCUSSIONS WITH BOTH AGENCIES ABOUT HOW TO DO THAT BETTER. WE HAVE A JOINT SHARE PROGRAM THAT IS INTERESTING. ONCOLOGY REGULATION WILL BE PUT IN ONE BRANCH OF THE AGENCY SO INSTEAD OF HAVING DEVICES, DIAGNOSTICS AND DRUGS IN DIFFERENT PLACES, EVERYONING CANCER NOW HAS SOME ASPECTS OF THAT ON IN THE ONCOLOGY CENTER FOR EXCELLENCE AND THAT IS NOW FULLY FUNDED WITH THE 2018 OMNIBUS BILL. AND THEY ARE ADVISING US, IN SEVERAL WAYS WE ARE REGULATED BY THE FDA. WE WILL TALK ABOUT THE CELL MANUFACTURING FACILITY WE ARE TRYING TO GET UP IN FREDRICK AND SINCE WE WANT THAT FACILITY TO INCLUDE NOVEL MANUFACTURE TECHNOLOGIES, WE ARE GETTING GUIDE ABS FROM THE FDA HOW TO DO THAT. I'M GIVING GRAND ROUNDS NEXT WEEK TO DISCUSS THIS TOPIC, AMONG OTHERS. A LOT OF INTERESTING COLLABORATIONS WITH THE DOD AND V.A. THE ONES AT THE DOD ARE A BIT MORE FLUSHED OUT. THIS IS THE APOLLO RETREAT. COLONEL SCHRIVER IS ONE OF THE MAJOR LEADERS. FOR THOSE WHO DON'T KNOW, HE HAS TO BE THE -- I DON'T THINK THERE IS ANY COLONEL WITH MORE CELL PAPERS THAN CRAIG. HE IS A VERY HIGHLY PUBLISHED, FULL-FLEDGED GENOMICS RESEARCHER AND ONCOLOGIST COMMITTED TO CANCER RESEARCH AND A GREAT PARTNER FOR THE NCI AND TRYING TO FIGURE OUT HOW TO GET THE APOLLO PROJECT, A LARGE PROSPECTIVE SERIES OF ACTIVE DUTY AND SOME V.A. PATIENTS FULLY SEQUENCED IN TERMS OF RNA AND DNA AND THEN PROTEOMICS CHARACTERIZATION AND THEN ALSO REALLY SOPHISTICATED MINING OF THE EHR AND THE DOD HAS ONE E HAD. R. AND THIS IS A GREAT REALLY EXCITING PROJECT AND IT'S A REAL PLEASURE TO WORK WITH HIM. HE HAS BEEN ONE OF THE MAJOR NCI LEADS FOR THIS. LET'S SEE IF THE MOVIE WORKS. THING PROJECT IS PROBABLY WELL-KNOWN TO THIS GROUP BUT WE& HAVE SEVERAL ACTIVE COLLABORATIONS WITH THE DEPARTMENT OF ENERGY. THIS ONE MODEL RAS IN THE MEMBRANE HAS BECOME QUITE INTERESTING. AND I THINK THAT THE PROJECTORY ACQUIRES EVERY SORT OF BIT OF COMPUTING POWER. MODELS EVERY ATOM IN EVERY MOLECULE OF WATER AND LIPID AND RAS PROTEIN, AND THE INTERACTIONS OF THOSE GROUPS IS STARTING TO LEAD TO INTERESTING FINDINGS. AND I THINK WE WILL BE HEARING MORE ABOUT IT. AND THEN ANOTHER INTERESTING DEPARTMENT OF ENERGY COLLABORATION IS ON EHR MINING WITH SEER. A MAJOR FOCUS HAS BEEN ON THE ISSUE OF PATHOLOGY REPORTS. SO SEER GETS 400,000 PATHOLOGY REPORTS A YEAR. IT'S DIFFICULT TO -- PATHOLOGISTS WRITE FLOATERS DIFFERENT BASE USE DIFFERENT LANGUAGES TO DESCRIBE CANCERS AND SO BEING ABLE TO TRAIN NATURAL LANGUAGE PROCESSING TO MINE THOSE AND GET THOSE INTO SEER IN A RAPID WAY IS VERY, VERY IMPORTANT. THAT'S NOT THE ONLY EHR MINING PROJECT GOING ON BUT THAT SEEMS MOST ADVANCED TO ME WHERE WE ARE SEEING REAL OUTPUT AND THE CLASSIFICATION RATES THAT ARE EXCEEDING HUMAN ABSTRACTORS, FOR EXAMPLE. AND THEN THE CANCER PANEL, THE PRESIDENT'S CANCER PANEL IS SOMETHING THAT IS INDEPENDENT OF THE NATIONAL CANCER INSTITUTE AND MANAGED BY THE NCI. AND THE PCP THAT INCLUDED BARBARA RHYMER TOOK ON A NUMBER OF INTERESTING REPORTS. COMPOSED REPORTS OF CHOOSING AND DECIDED TO FOR EXAMPLE TAKE ON THE ISSUE OF CONNECTIVITY IN RULE POPULATIONS AND THEN THE HPV REPORT, WHICH HAS BEEN ONE OF THE MOST SUCCESSFUL PCP REPORTS OF ALL-TIME IN TERMS OF PICKUP AND IMPACT ON THE FIELD. AND THE MOST REPORT IS ON DRUG PRICING COMING OUT AT THE SAME TIME AS REPORTS ON DRUG PRICING FROM NATIONAL ACADEMY OF MEDICINE AND THEN ALSO FROM THE COUNCIL OF ECONOMIC ADVISORS. THOSE REPORTS HAVE SOME CONCLUSIONS THAT ARE DIFFERENT AND SOME THAT ARE SIMILAR. ONE REOCCURRING THEME IN THOSE THREE REPORTS IS THE ISSUE OF VALUE-BASED PRICING, SOMETHING WE ARE DISCUSSING, VALUE-BASED CONTRACTS. WE ARE DISCUSSING THAT CONTACT WITH CMS PROVIDING ADVICE ON THE TOPIC. THIS REPORT WAS A GREAT INTEREST TO THE WHITE HOUSE AND SO BARBARA WAS INVITED DOWN TO PRESENT THIS TO ANDREW BLOOMBERG, DIRECTOR OF THE DOMESTIC POLICY COUNCIL AND I WENT WITH HER AND THAT'S A SELFIE WE TOOK WITH THE WEST I THINK IN THE BACKGROUND WHICH I THOUGHT WAS COOL. SO I CAN TELL YOU THAT THIS TOPIC IS OF GREAT INTEREST TO THE PRESENT ADMINISTRATION AND I WAS VERY IMPRESSED BY HOW KNOWLEDGEABLE BLOOMBERG IS ON THIS TOPIC. AND HE ASKED A LOT OF GOOD QUESTIONS AND HAD A LOT OF THOUGHTS AS THOSE OF YOU FOLLOWING THE NEWS KNOW THIS IS NOW A TOP ISSUE FOR THE PRESIDENT AND SECRETARY. THESE WORKING GROUPS ARE NOW UP AND RUNNING. SO IN ONE MET, THAT IS ABOUT TO MEET. THE ROSTERS ARE FILLED OUT. THESE WILL ADVISE US ON THESE TOPICS WHERE I THINK WE NEED SOME GUIDANCE AND SO FAR THE QUESTIONS AND THE ENTHUSIASM HAS BEEN REALLY EXCITING AND I'M GLAD PEOPLE ARE AGREEING TO SERVE AND PUTTING A LOT OF TIME. A LOT GOING ON WITH THE MOONSHOT. THIS IS THE PROCESS SUMMARY SLIDE THROUGH LAST FALL. AND SHOWED THE FIRST BATCH OF FOAs RELEASED SINCE THEN MORE FOAs ARE FUNDING ANNOUNCEMENTS THAT ARE CONTINUOUSLY COMING OUT OUT. I THINK THE MOONSHOT IS GOING WELL FROM THIS POINT OF VIEW, GETTING THIS FUNDING OUT WITHOUT INCREASING A LARGE NUMBER OF FTEs TO MANAGE IT IS TESTIMONY TO DEANA'S LEADERSHIP OF THE SHE HAS DONE A GREAT JOB OF MANAGING THIS PROGRAM WHICH HAS INTENSE FOCUS AND INTEREST NATIONALLY. AND THE VISION OF THE 10 TOPICS AND THEN THE VARIOUS INTEREST AREAS WITHIN THE 10 IS REALLY COMING TO LIFE. AND SO WE ARE SEEING GREAT SCIENCE NOW BEING APPLIED FOR AND IT'S EXCITING. AND THERE ARE NEW FOAs COMING OUT ALL THE TIME AND NOW WE HAVE FOAs IN ALL 10 AREAS AND SOME INCLUDE EXTRAMURAL SCIENCE AND MANY THROUGH THE UMECHANISM GRANTS AND I THINK THIS TONSE CREATE A LOT OF ENTHUSIASM. THE MOONSHOT PROVIDES CHALLENGES AS WELL. THE BUDGET GOES 300 MILLION FOR A WHILE AND THEN 400 MILLION AND THEN DOWN TO 200 MILLION AND THEN OFF. SO THERE IS TWO, 200 MILLION DOLLAR CUTS IN THERE IN THE NEAR FUTURE PLANNED FOR THE NCI SO WE HAVE TO THINK ABOUT HOW TO MANAGE THAT FROM A FINANCIAL PERSPECTIVE CONSIDERING THE CROFTS OF THE PROPOSALS BUT IT'S A GOOD PROBLEM TO HAVE IT. A BILLION DOLLARS OF EXTRA FUNDING. SO VERY EXCITING. AND I MENTIONED A FEW ITEMS FOR THE MOONSHOT, TWO MIGHT BE INTERESTING TO THIS GROUP ARE RECOMMENDATION D. A LOT IS GOING ON THE IN THE NATIONAL CANCER DATA ECOSYSTEM. TONY IS HERE AND CAN TELL YOU MORE ABOUT THAT AND THEN THIS IS THE ANNOTATION EFFORTS TO GET -- MOSTLY OUR PROBLEM WITH BIG DATA IN PATIENT SAMPLES IS THAT WE HAVE THESE SAMPLES THAT ARE CHARACTERIZED WITH NO CLINICAL INFORMATION. BUT THIS ACTUALLY RECOMMENDATION IS TO GET AT THE OTHER PROBLEM WHERE WE HAVE NCT TRIALS WHERE WE KNOW A LOT ABOUT WHAT HAPPENED TO PATIENTS BUT NOT MUCH GENOME CHARACTERIZATION SO WE WILL BE SELECTING TRIALS FOR FURTHER GENOMIC CHARACTERIZATION IN THE NEAR FUTURE AS PART OF THE MOONSHOT FOR THAT. THIS IS A WHEELS OF LIFE THAT SHOWS THE QUITE ELABORATE ISSUES RELATED TO THE CANCER ECOSYSTEM. AND THE VARIOUS OUTSIDE COLLABORATORS. THIS IS AN AREA WE TALKED ABOUT BEFORE AT THIS MEETING AND TONEY IS HERE TO ANSWER QUESTIONS IF THERE ARE OTHERS. PACT IS FULLY-FLEDGED OFF THE GROUND. THIS IS A MORE VISIBLE MOONSHOT INITIATIVE. WE CREATED THESE FOUR CANCER MONITORING ANALYSIS CENTERS AT THESE PLACES AS WELL AS THE DATA COORDINATION AT DANA FARBER AND THEN PHARMA CAME IN, 12 PHARMACEUTICAL COMPANIES WITH AN INTEREST IN IMMUNO-ONCOLOGY AND CONCONTRIBUTED 5 MILLION DOLLARS EACH, SO 60 MILLION DOLLARS FROM INDUSTRY AND PACT HAD A FEW MEETINGS, INCLUDING A STEERING MEETING AT AACR AND THEM THE FIRST MEETING OF EXECUTIVE COMMITTEE TWO WEEKS AFTER THAT. AND I THINK THERE IS A LOT OF WEEDY ISSUES OF CONTRACTUAL AGREEMENTS BETWEEN THE CENTERS SO THEY CAN EXCHANGE SAMPLES AND DATA. AND THEN OF COURSE THE PHARMACEUTICAL SPONSORS ARE INTERESTED IN WHAT PROJECTS GET PUT INTO THE QUEUE IN WHAT PHASE. BUT OVERALL, THE PROCESS IS REALLY GOING WELL AND IT'S EXCITING. THE IDEA OF PACT IS TO BE PRE-EXIT EF TO STANDARD MARKSER& FOR RESPONSIVE ONCOLOGY. SO WE HAVE TWO DIFFERENT PD-1 ANTIBODIES ARE TESTED IN THE SIMILAR DISEASES, LUNG CANCER, AND WITH OTHER AGENTS AND ONE APPEARS TO WORK AND ONE DOESN'T. THE QUESTION IS ARE THE AGENTS DIFFERENT OR THE BIOMARKER TO ALLOCATE PATIENTS TO THERAPY DONE DIFFERENTLY BETWEEN THE TWO PHARMACEUTICAL COMPANIES? IN MANY INSTANCES WE BELIEVE THAT'S THE CASE. THE PD-L1 STAINING OR HOW THEY WERE 58 INDICATED THERAPY MAY DIFFER. SO AN IDEA IS TO COMPARE THESE TRIALS AND STANDARDIZE THESE BIOMARKERS USED TO PREDICT RESPONSE IN THESE TRIALS AND SO, THE TIER 1, TIER TWO, TIER 3 BIOMARKERS. TIER 1 IS EVERYTHING YOU WOULD WANT IN IMMUNO-ONCOLOGY, IT'S EXTRA SEQUENCING, PROTEOMICS, SOME PROTEIN CHARACTERIZATION MULTIPLEX IHC AND INCLUDES ANALYSIS ON SINGLE-CELL ANALYSIS WITHIN THE CELLS WITHIN A TUMOR AND I THINK THAT REAL FOCUS IS TO GET THESE THINGS STANDARDIZED AND REPRODUCIBLE SO THAT THEY CAN THEN BE DONE ON LOTS OF RETROSPECTIVE SAMPLES AND PROSPECTIVE SAMPLES INITIALLY. THE INITIAL TRIALS ARE MOSTLY NCTN, NCI-SPONSORED TRIALS BUT THE HOPE AND EXPECT NATION IS WE WILL START TO SEE PHARMACEUTICAL SPONSORS INVOLVED AND ALSO PROVIDE SAMPLES FOR CHARACTERIZATION WITH CLINICAL ANNOTATION AND EXPERTISE. SO, THIS IS UP AND RUNNING NOW AND I THINK IT IS A REALLY IMPORTANT MOONSHOT INITIATIVE. TWO NEW IMMUNOTHERAPY CENTERS WILL BE AWARDING SOON. THESE ARE PRE-CLINICAL CENTERS IN ADULT AND PEDIATRIC CANCER AND FUNDED BY THE MOONSHOT. SO A LOT OF IMMUNOTHERAPY AS YOU CAN SEE. AND THEN A NEW PROJECT HERE OR AT FREDRICK WILL BE THAT IS JUST STARTING TO GET UP IS TO USE SOME OF THE GMP SPACE FOR THE MANUFACTURE OF CELLS FOR T-CELLS, ENGINEERED T-CELLS AND CAR T-CELLS. SO THERE IS AN INTENSE CRUNCH IN MANUFACTURING CAPABILITIES AND WHILE THERE ARE A NUMBER OF FACILITIES IN THE WORKS TO SUPPORT BUILDING 10, SOME OF THEM WILL TAKE A WHILE. SOME OF THEM ARE GOING TO BE SMALLER THAN WE WOULD NEED. AND OF COURSE THEY HAVE TO SERVE THE ENTIRE NIH NOT JUST THE NCI AND THERE ARE ISSUES, HEART, LUNG AND BLOOD WANTS TO MAKE CELLS FOR OTHER REASONS. WE FEEL THERE IS A PRESSING NEED FOR CELL PRODUCTION CAPACITY AND COMMITTED TO DO THIS SO THE MACHINES ARE BOUGHT AND WE ARE STARTING TO GET THE SPACE UP AND RUNNING. I THINK IT WOULD BE IMPORTANT OR AN OPPORTUNITY FOR THIS FACILITY IS TO TRY AND PUSH THE ENVELOPE WITH REGARD TO MANUFACTURING, TOW USE NOVEL MANUFACTURING TECHNIQUES THAT WOULD BE OF BENEFIT TO THE ENTIRE COMMUNITY. I SUSPECT SHOULD WE EVER HAVE SOME DAY IN THE FUTURE WHERE WE HAVE ACCESS CAPACITY FOR CELL PRODUCTION IN BUILDING 10, THIS FACILITY COULD ALSO SERVE THE EXTRAMURAL COMMUNITY. THAT WOULD BE A GOOD PROBLEM TO HAVE. I DON'T EXPECT US TO HAVE THAT PROBLEM ANY TIME SOON. BUT THE INTENT, THIS ISIBLE GOING TO BE ONE PIECE OF A LARGER CELLULAR IMMUNOTHERAPY STRATEGY THE NCI IS BEGINNING TO TALK ABOUT, HOW TO STANDARDIZE SOP ACROSS THESE MANY FACILITIES TO ALLOW US TO DO MULTIINSTITUTIONAL TRIALS RATHER THAN ONE OFFS AT EACH PLACE EACH WITH A DIFFERENT CONSTRUCT. THE OTHER THING THIS IS MADE READILY ABUNDANT WE ARE JUST DIGGING INTO. WHILE CELL THERAPY MANUFACTURER IS LIMITED CAPACITY NATIONALLY, THE VECTOR PRODUCTION IS ALSO A LIMITING CAPACITY AND IT REALLY COMES DOWN TO A FEW COURSE NATIONALLY THAT ARE USED BY ALMOST ALL OF THE GOP FACILITIES THAT MAKE CERTAIN KINDS OF CAR T-CELLS FOR EXAMPLE. SO, THE NCI IS WONDERING IF THIS IS A VECTOR PRODUCTION SOMETHING WE SHOULD TAKE ON TO SERVE THE COMMUNITY IN THIS TOPIC AS WELL. I THINK THIS IS IMPORTANT BECAUSE WHILE WE SEE THERE IS A LOT OF MOVEMENT IN INDUSTRY, WE HAVE ALSO SEEN THAT INDUSTRY IS LIMITED IN THE KINDS OF PROJECTS AND NEW PROJECTS THEY TAKE ON SINCE THEY HAVE TO COMMIT TO THE CLINICAL DEVELOPMENT OF SPECIFIC REAGENTS SO I THINK IT'S A GOOD TOPIC OF FOCUS FOR FREDRICK NATIONAL LABS. I ANNOUNCED THESE KEY FOCUS AREAS BASED ON THIS 6 MONTH LEARNING AND LISTENING TOUR THAT IS NOW CONCLUDED, ALTHOUGH I WILL CONTINUE TO LEARN AND LISTEN MY ENTIRE CAREER, I HOPE, BUT THESE WERE THINGS THAT THE NCI WAS ALREADY DOING TO BE SURE. BUT AREAS WHERE I THOUGHT A NEW FOCUS OR NEW RECOMMITMENT WAS USEFUL, THIS IS BASED ON CONVERSATIONS WITH LITERALLY HUNDREDS OF STAKEHOLDERS, INCLUDING PATIENTS -- SO THEY ARE HIGHLY RELATED. I WILL NOT GO THROUGH IN GREAT DETAIL. THESE ARE THINGS WELL-KNOWN TO THIS GROUP. I WILL MAKE A FEW HIGHLIGHTINGS. ONE IN THE AREA OF WORKFORCE TRAINING AND DEVELOPMENT. THIS INVOLVES A NUMBER OF STEPS, TWO THAT ARE WORTH MENTIONING ARE THESE BOTTOM TWO HERE. SO, THE ESI PROBLEM IS SOMETHING I HEARD A LOT ABOUT AS I TRAVEL NATIONALLY. ALMOST 100% OF THE ACADEMIC INSTITUTIONS I GO TO, SOMEONE WILL COMPLAIN AND OFTEN IT IS SOMEONE QUITE ESTABLISHED AT THE INSTITUTION, COMPLAIN ABOUT THE ACTIVITY THE YOUNG PEOPLE HAVE AT THEIR INSTITUTION GETTING THEIR FIRST GRANT. SIMILARLY, THE 21ST CENTURY CURES BILL INCLUDED LANGUAGE THAT FROM CONGRESS DIRECTING THE NIH TO DO SOMETHING ABOUT THE POLITE OF THE EARLY-STAGE INVESTIGATOR. SO WE THOUGHT A LOT ABOUT WHAT WE CAN DO AT THE NCI AND A LOT OF IT IS VERY HIGHLY DATA DRIVEN. SO MICHELLE AND DOUG AND DEANA AND OTHERS HAVE REALLY DUG INTO THIS QUESTION. AND WE HIT UPON A FEW THINGS. SOME ARE EASIER THAN OTHERS. ONE IS AN ADDITIONAL SET ASIDE FOR RO1 FUNDING THIS YEAR TO INCREASE THE BENEFIT. SO AS KNOW, IF IT'S SUCCESS RATE FOR ESTABLISHED INVESTIGATORS IS 12% AND TRADITIONALLY THE NCI HAS BEEN THE SUCCESS RATE WILL BE MORE LIKE 15 OR 16% RATE. SO WE EXPECT TO INCREASE THAT BUMP WITH A SET ASIDE FUNDING. WE THINK WE HAVE ENOUGH FUNDING SET ASIDE TO INCREASE THE TOTAL NUMBER OF ESI RO1s BY 25%. SO GOING FROM 90 AWARDS TO 120 AWARDS. SO A SUBSTANTIAL BOOST. YOUR CHANCES IS GREAT. THE R37 IS LIVE. IT'S OFFICIALLY ENACTED. AND IT IS -- THE WAY IT WORKS, IT WAS PARTLY BASED ON THE SUCCESS OF THE OUTSTANDING INVESTIGATOR AWARD WHICH IS A REALLY POPULAR PROGRAM IN THE COMMUNITY. AND FOR THOSE WHO DON'T KNOW HOW THAT WORKS, AN OUTSIDE INVESTIGATOR HAS TO GIVE UP RL1s TO GET A SIMILAR AMOUNT OF FUNDING FROM THE R35 MECHANISM THAT LASTS FOR SEVEN YEARS. SO IT'S A SEVEN YEAR AWARD AND THE SCIENTISTS WHO HAVE GOTTEN THIS AWARD TOLD ME REPRODUCEIBLY IT ALLOWS THEM TO STOP THINKING ABOUT WRITING GRANTS ALL THE TIME AND FOCUS ON SCIENCE AND RECOMMIT TO THE LAB TO NOVEL INNOVATIVE STUFF. AND IF THAT IS RELEASED FROM THE GRANT FUNDING CYCLE PRESSURE IS GOOD FOR ESTABLISHED INVESTIGATORS, WE ARE INTERESTED IN EXPERIMENT WHETHER IT IS ALSO GOOD FOR EARLY-STAGE INVESTIGATORS, PARTICULARLY FACULTY. AND SO THE IDEA THE R37 IS, IF AN ESI APPLIES FOR AN RO1, AND GETS IT, GETS A SCORE WITHIN THE PAY LINE, THEN INSTEAD OF GETTING AN RO1, THEY WILL GET AN R37, WHICH IS LIKE WHAT THEY APPLIED FOR, EXCEPT AT THE END OF FIVE YEARS, THEY WILL HAVE THE OPTION TO APPLY FOR TWO ADDITIONAL YEARS OF FUNDING. SO POTENTIALLY A SEVEN-YEAR AWARD. WE THOUGHT INITIALLY WE WOULD GIVE THEM 7 YEAR AWARDS. BUT THAT'S NOT LEGAL. THEY HAVE TO WRITE AN ADDITIONAL BUDGET FOR THE EXTRA YEARS OF FUNDING. BUT WE ENVISION THIS AS BEING LESS PAPERWORK THAN A COMPETING RENEWAL, FOR EXAMPLE. AND THEREFORE FREE UP TIME FOR THESE EARLY-STAGE INVESTIGATORS TO FOCUS MORE ON SCIENCE AND PROVIDE THEM WITH MORE CONTINUOUS LEVEL OF SUPPORT AT A PARTICULARLY PRECARIOUS TIME IN THEIR CAREER. AND THAT IS HAPPENING NOW. BY THE WAY, IT'S ALSO IMPORTANT THE PEOPLE WHO GET THE RO1 ARE NOT WITHIN THE PAY LINE SO THEY ARE FUNDED BY SELECT PAY. THOSE PEOPLE JUST GET AN RO1. SO THE CONTROL GROUP FOR THE EXPERIMENT. SO WE, IN 10 YEARS WE WILL HAVE DATA AS TO WHETHER OR NOT 7 YEARS VERSUS 5 YEARS OF FUNDING MATTERS IN TERMS OF FUTURE SUCCESS. SO THOSE ARE UP AND RUNNING AND I THINK THERE ARE OTHER THINGS WE'D LIKE TO DO FOR WORKFORCE TRAINING AND EARLY STAGE INVESTIGATORS. PARTICULARLY RELATED TO TOPICS IN WHICH PEOPLE WORK. SO WE WANT TO FOCUS AND MAKE SURE NEW INVESTIGATORS HAVE THE RIGHT SKILL SET FOR THE FUTURE. BUT SOME OF THOSE INITIATIVES WILL TAKE LONGER AND WE WILL TALK ABOUT THEM IN THE FUTURE. AND THEN A LOT GOING ON IN BIG DITA. I THINK WE ARE NOW LOOKING AT A NUMBER OF WAYS TO BETTER LINK EXISTING DATASETS. SO FOR EXAMPLE, OR TO ANNOTATE EXISTING DATASETS. SO WE HAVE THESE VARIOUS DATA THE SETS ABOUT CANCERS IN THE SAME PATIENTS WHO MAY HAVE SOME IMAGING DATA AND CLINICAL DATA AND SOME GENOMIC DATA BUT THEY ARE NOT INTEROPERABLE IN A WAY THAT IS SUESFUL. OR WE HAVE ONE PIECE OF THAT AND WE NEED TO COLLECT THE OTHER PIECES AND THEN BY FURTHER ANNOTATION. SO WE HAVE A VARIETY OF PROJECTS TO DO THAT. I THINK THAT IT IS PROBABLY FAIR TO SAY THAT THE NATIONAL CANCER INSTITUTE DOESN'T KNOW HOW TO DO THIS. THAT RATHER THAN TRY TO FIGURE THIS OUT AND BUILD A SKYNET LIKE MASSIVE DATA BASE, WE ARE MORE INTERESTED IN FUNDING THIS SORT OF PROJECTS THAT ARE A BIT SMALLER AND USE DIFFERENT APPROACHES TO SEE WHAT THE IDEAL SOLUTION FOR THIS PROBLEM S I MENTIONED THE DATA ECOSYSTEM IS FUNDED BY THE MOONSHOT, WHICH IS A LOT OF PIPES AND PLUMBING AND VERY IMPORTANT THINGS TO ALLOW DATA SHARING AND DATA INTEROPERABILITY. IT TURNS OUT TO BE A LOT OF œTHINGS THAT ARE QUITE COMP CALLED FOR NON-DATA SCIENTISTS LIKE DATA ONATOLOGIY AND SOURCES AND VARIOUS KINDS OF HARDWARE AND CLOUD USAGE. BUT IMPORTANT. AND MAYBE BENEATH THE RADAR TO BIOMEDICAL RESEARCHERS WHO WANT THE DATA AVAILABLE TO THEM AND WILL ENABLE THE FIELD CREATING COMMON DATA STANDARDS AND SHARING AGGREGATION THROUGH OUR POLICIES. AND BRIEFLY I'LL JUST -- HERE IS THE OVERVIEW OF TODAY'S AGENDA. THESE ARE THE THINGS WE ARE SORT OF PLANNING TO TALK ABOUT. I WON'T SAY MORE ABOUT THEM TODAY. AND I'D BE HAPPY TO MAKE ONE OTHER POINT. A LOT OF DISCUSSION IS GOING ON AT THE NATIONAL CANCER INSTITUT NOW ABOUT HOW TO USE THE FREDRICK NATIONAL LAB. I HAD THE OPPORTUNITY TO DO TWO DAYS OF MYC BIOLOGY AND AT DINNER, AT THE MYC BIOLOGY MEETING, THEY WERE ASKING THE NCI DIRECTOR WHEN WE WERE GOING TO HAVE THE MYC INITIATIVE AT FREDRICK NATIONAL LAB AND SIMILARLY, I HAD PEOPLE ASK ME ABOUT THE p53 INITIATIVE. WHEN IS THAT GOING TO START? AND THOSE WATCHING THE CELL IMMUNOTHERAPY WORLD HAVE SEEN THE NEW FACILITY AND WONDERED IS THIS THE START OF THE CELL IMMUNOTHERAPY AT FREDRICK? SO I THINK IT IS PROBABLY ACCURATE TO SAY FREDRICK HAS SOME CAPACITY AND IN BOTH TERMS IN RESOURCES AND DESIRE TO TAKE ON NEW THINGS AND I THINK WE'LL HEAR A LOT ABOUT THAT FROM ETHAN AS WELL. BUT THAT IS REALLY IN LARGE PART THIS AWARD. WE ARE INTERESTED IN YOUR THOUGHTS ABOUT WHAT FREDRICK CAN DO THAT IS INNOVATIVE AND NEW AS PROSPECTS ALLOW. SO I WOULD BE HAPPY TO TAKE QUESTIONS IN THE TIME REMAINING WHICH IS ABOUT 10 OR 15 MINUTES. >> WE ARE OPEN FOR QUESTIONS. LET ME BEGIN. SO YOU DREW THE PARALLEL TO THE OUTSTANDING INVESTIGATOR AWARD WITH THE R37. BUT DO INDIVIDUALS WHO ARE AWARDED R37S HAVE THE OPTION TO APPLY FOR ADDITIONAL RO1s? >> YES. IT'S JUST LIKE AN RO1. SO NO PENALTY OR DOWNSIDE TO GETTING IT OTHER THAN 5 YEARS IN, YOU CAN WRITE FOR TWO MORE YEARS. AT YEAR FOREYOU WILL WRITE FOR YOUR 6th AND 7th YEAR OF FUNDING. I SUSPECT THESE NUMBER CHANGES -- I'M CERTAIN THESE NUMBER CHANGES ARE GOING TO CAUSE SOME CONFUSION IN THE COMMUNITY BECAUSE I KNOW FROM BEING A NATURAL SCIENTIST THEY ALWAYS CAUSE -- AND THIS IS ONE OF THE REASONS WE ARE TALKING ABOUT IT BECAUSE I THINK THOSE WILL BE GETTING LETTERS SAYING THEY ARE GETTING SOMETHING THEY DIDN'T APPLY FOR AND THEY WILL BE CONFUSED BY THAT. AND YOU HAVE TO EXPLAIN TO THEM IT IS GOOD NEWS. >> WHEN THEY COME IN FOR THE ADDITIONAL TWO YEARS, WHAT IS DIFFERENT THERE THAN JUST APPLYING FOR A NEW RO1? IS IT AN EASIER HOAR DIFFERENT REVIEW PROCESS? -- EASIER OR DIFFERENT REVIEW PROCESS? >> WE'LL FIGURE THIS OUT IN 4 YEARS. THE FIRST SORTS OF AWARDS ARE STARTING NOW. SO NO ONE HAS REAPPLIED FOR THE SUBSEQUENT FUNDING BUT OUR VISION IS THAT THE NON-COMPETING RENEWAL FOR YEAR 6 AND 7 WILL LOOK MORE LIKE A NON-COMPETING RUE NEUL OF AN RO1 NOW. THERE WILL BE SOME PAPERWORK WE WILL HAVE TO DO. IT WILL INCLUDE A BUDGET, SUMMARY OF PROGRESSED AND THE SPECIFIC AIMS AND THE PERSONAL THE SAME, BUT WE ENVISION IT BEING LIKE A NON-COMPETING RENEWAL THAN LIKE A NEW RO1. >> NON-COMPETING IS KEY THERE. >> RIGHT. AND DAMON HAS A PROJECT LIKE THIS, AND I WAS ON THEIR BOARD FOR A WHILE. AND IT WAS REALLY NICE. 3 YEARS AND THEN TWO MORERS. >>> OF FUNDING AND PEOPLE HAD TO DESCRIBE WHAT THEY WERE DOING AND I THINK THAT IT IS A GOOD FOR THE FUNDER BECAUSE YOU HAVE ALREADY INVESTED IN THESE PEOPLE AND YOU BELIEVE IN THEM SO THEY ARE A WINNING PROSPECT. I THINK IT'S PARTICULARLY GOOD FOR -- POTENTIALLY QUITE GOOD FOR THE FUNDEE BECAUSE THIS IS A DIFFICULT -- WE ALL SEEN THESE REALLY GREAT JUNIOR SCIENTISTS WHO GET DERAILED FOR A YEAR OR TWO FOR WHATEVER REASON. AND THAT CAN BE VERY DISRUPTIVE. SO I THINK WE BELIEVE THIS IS A GOOD IDEA. BUT IT INCLUDES A CONTROL GROUP. WE ARE GOING TO TRY AND ACTUALLY REALLY MAKE SURE -- IT REALLY HELPS PEOPLE AND DOESN'T -- YOU COULD SAY MAYBE THIS WILL COMPROMISE THEIR INITIATIVE AND WON'T WORK AS HARD BECAUSE THEY -- SO WE ARE OPEN TO THE POSSIBILITY THIS WON'T BE AS BENEFICIAL AS WE THINK. ONE OF THE OTHER THINGS WE TALKED ABOUT WITH THE R37, WHICH IS ANECDOTALLY WE HEARD STORIES ABOUT HOW THIS PARTICULARLY DIFFICULT TIME FOR YOUNG WOMEN FACULTY AND CERTAINLY THE -- MANY INSTITUTIONS DO A GOOD JOB OF HIRING WOMEN AT THE ASSISTANT PROFESSOR LEVEL, BUT THE PIPELINE APPEARS TO BE SLOWER THAN WE WOULD LIKE AND THIS IS ONE OF THE THINGS THAT WE CAN DO THAT WAS RELATIVELY SIMPLE TO TRY AND ADDRESS THAT PROBLEM. I DON'T BELIEVE THIS IS BY ITSELF IS ENOUGH. I THINK THERE ARE OTHER ISSUES THE NCI SHOULD CONSIDER BUT WE CAN THINK THIS MIGHT BE ONE STEP IN THE RIGHT DIRECTION. >> NED, CAN YOU HELP US UNDERSTAND THE SHORT-TERM AND LONG TERM THINKING ABOUT THE STATUS OF THE MANAGEMENT CONTRACT FOR FREDRICK? >> THERE ARE DEVELOPMENTS THERE. THE BRIDGE AWARD -- >> DOUG: THE BRIDGE AWARD IS IN PROCESS WITH NIH AND THE OFFICE OF GENERAL COUNSEL. AND WE ARE HOPING THAT IT WILL BE RELEASED AND BE ABLE TO IMPLEMENT IN THE VERY NEAR FUTURE. THE RECOMPTITION -- I WANT TO FOR SOME PEOPLE WHO VIOLENT BEEN ON THE BOARD THAT LONG. THE RECOMPETITION WAS HELD UP OR ESSENTIALLY STOPPED BECAUSE FIRST THE FNLAC FELT IT HAD NOT HAD AN ADEQUATE OPPORTUNITY TO WEIGH IN ON WHAT THE RECOMPETITION, WHAT THE GOALS MIGHT BE FOR THE FREDRICK NATIONAL LAB. AND THE SECOND REASON WAS THAT WHEN RECOMPETITION WAS STARTED, IT WAS BEFORE THE MOONSHOT HAD AND IT LOOKED AS THOUGH IT WAS GOING TO BE IMPORTANT FOR THE FREDRICK NATIONAL LAB TO FOCUS ATTENTION ON THE MOONSHOT ACTIVITIES THAT WERE BEING CONDUCTED AT THE FREDRICK NATIONAL LAB. SO THOSE ARE THE -- SO THAT THEN MADE IT NECESSARY TO PENDING ESSENTIALLY TO EXTEND THE CONTRACT. THE EXPECTATION IS THAT AFTER THE BRIDGE AWARD IS COMPLETED -- IS COMPLETED, AND IN EFFECT THAT THERE WILL BE AN OPPORTUNITY FOR FNLAC TO WEIGH IN BECAUSE THAT IS VERY IMPORTANT, AND THEN AT SOME POINT AFTER THAT, FOR THE RECOMPETITION TO RESUME. >> IT'S TAKING LONGER THAN WE WOULD HAVE HOPED BUT I'M LEARN BEING FEDERAL CONTRACTING. [ LAUGHS ] >> YOU TALKED ABOUT INTERFACING WITH THE FDA ABOUT CELL THERAPIES AND COMPLIANCE AND YOU ALSO MENTIONED AT THE NATIONAL LAB THERE WILL BE A DEVELOPMENT OF A NEW CELL THERAPY FACILITY. DOES IT RUN IN PARALLEL OR IS THIS SOMETHING THAT THE FDA AND YOU GUYS ARE GOING TO TALK ABOUT ABOUT? >> DR. SHARPLESS: AS MANY OF THE ACTIVITIES IN BUILDING 10 ARE REGULATESSED BY THE FDA AND WE HOLD A REMARKABLE NUMBER OF INDs FOR EXAMPLE, AND THIS FACILITY SIMILAR HE WILL BE AS ARE ALL IN THE COUNTRY, COMPLYING WITH GUIDELINES AND THE PRODUCTION OF REAGENTS FOR HUMAN USE. SO THIS IS A LONG HISTORY OF BOTH WORKING AS PARTNERS AND FEDERAL AGENCIES AND ALSO BEING TO SOME EXTENT REGULATED BY THEM. I BELIEVE THAT WE CAN DO THIS IN A WAY THAT IS SAFE FOR PATIENTS BUT ALSO ALLOWS FOR SOME INNOVATION THAT WOULD BE HARDER FOR SAY AN INDUSTRY PARTNER TO DO, AND WE HAVE ALREADY BEGUN TO SPEAK WITH THE FDA, PARTICULARLY ABOUT THE ISSUE OF THE TOPIC OF CELLULAR MANUFACTURER. AS YOU KNOW THIS, PROCESS IS QUITE EXPENSIVE AT PRESENT AND THE IT MAY BE THAT THERE ARE SOME MODIFICATIONS TO MANUFACTURER SCHEMES FOR MORE RAPID TURN AROUND AND LOWER-COST PRODUCTION OF ENGINEERING T-CELLS AND SO THAT IS PART OF THE ASPIRATION OF THE FACILITY. NOT ONLY TOW ADDRESS THE NEED THAT EXISTS IN BUILDING 10 AND LATER ON TO THE EXTRAMURAL COMMUNITY BUT ALSO TO ALLOW FOR THE CONSIDERATION OF NOVEL MANUFACTURE. FOR EXAMPLE, WHEN I BUILT A CAR T FACILITY AT THE UNIVERSITY OF CALL LINEA. IT REQUIRED ONE PATIENT PER ROOM -- CAROLINA. WE HAD 5 ROOMS AND 5 PATIENTS AT A TIME WHICH LIMITED OUR CAPACITY EXTENSIVELY. NOW WE HAVE CLOSED SYSTEMS, AND THE FDA ALSO AGREES THAT WE CAN DO MULTIPLE PATIENTS IN ROOMS AND THAT WOULD ALLOW THE USE OF SPACE MUCH MORE EFFICIENTLY FOR EXAMPLE AT FREDRICK NATIONAL LAB SO, I THINK THERE IS IT A WILLINGNESS TO SHARE DATA THAT MAY -- AT THE TOP, THAT MAYBE A BIT OF A CHANGE FOR THOSE ORGANIZATIONS. THE CMS DATA IS REALLY -- A LOT OF IT IS PROBABLY BEST SUITED FOR SEER. SO BETTER TO USE CLAIMS DATA TO EXTEND APPROXIMATE THE SEAR MEDICARE EFFORTS THAT EXIST BUT CMS HAS A LOT OF VERY INTERESTING CLAIMS THAT ARE BEING INCREDIBLY USEFUL FOR THE NC TONIGHT HAVE AND STARTING TO GET A LOT OF MEDICATE DADE A SO STATE-LEVEL DATA TO TALK ABOUT POPULATIONS LESS THAN THE AGE OF 65 FOR EXAMPLE THEY BELIEVE THEY WILL BE ABLE TO SHARE. SO THAT I THINK IS MORE LIMITED BY OPERATIONS. SO THEY HAVE YEARS TO DO IT AND THERE ARE CONCERNS ABOUT PRIVACY. BUT WE HAVE ALREADY DONE SOME DATE SHARING BUT IT IS EXACTLY HOW YOU DO IT AND SORT OF OPERATIONAL. THE FDA ISSUE, THEY HOLD A LOT OF TOX DATA FROM PHARMACEUTICAL SPONSORS AND THEY HAVE THE ABILITY TO SHARE SOME OF THAT DATA ALREADY WITH FOR EXAMPLE THE EMA IN EUROPE BUT NOT CANCER RESEARCHERS. AND THEY HAD HAVE EXPRESSED AN INTEREST IN DOING THAT. THAT WOULD BE NEW. IT'S A NEW INITIATIVE THAT RIGHT NOW DOESN'T EXIST. SO, THERE ARE SOME LEGITIMATE CONCERNS AMONG THE SPONSORS ABOUT THE SHARING OF DATA. BUT WE ARE BEGINNING TO HAVE DISCUSSIONS ABOUT HOW TO DO THAT. I CAN TELL YOU THAT THE BRIGHT SPOT THERE IS THE PHARMACEUTICAL COMPANIES HAVE HEARD VERY LUCIFEROUSLY FROM THE COMMUNITY THEY NEED TO DO A BETTER JOB ABOUT SHARING DATA SO THEY ARE ALREADY SELF ORGANIZING INITIATIVES TO MORE OF THEIR DATA OUT INTO THE COMMUNITY SO I THINK THAT THEY WOULD BE WILLING PARTICIPANTS TO THE EXTENT THAT -- THEY ARE AFRAID OF THE FDA TO SHARE DATA THAT WOULD ALLOW SOMEBODY TO DO A REANALYSIS FOR A DRUG AND CHANGE A DECISION. THAT IS A LEGITIMATE CONCERN FOR SOMEONE WHO HAS ASSETS. SO HOW CAN WE GET THE BIOMEDICAL RESEARCH COMMUNITY ACCESS TO THESE VERY NOVEL AND IMPORTANT FDA DATA IN A WAY THAT DOESN'T JEOPARDIZE THE ASSETS OF THE PHARMACEUTICAL COMPANY PARTNERS. SO THEY ARE GOING TO TAKE A WHILE. BUD I THINK THEY ARE EXCITING BUT THEY WILL BE SLOW. >> ANY OTHER QUESTIONS? WE ARE RIGHT ON TIME. >> THANK YOU VERY MUCH. >> NEXT PRESENTATION IS ETHAN. IT'S HIS FIRST PRESENTATION TO THE COMMITTEE. HE IS THE PRESIDENT OF THE LIEDO FREDRICK NATIONAL LABORATORY. THIS IS A REPORT ON CURRENT OPERATIONS AND FUTURE PLANS. ETHAN? >> DR. DMITROVSKY: I WANTED TO BEGIN BY THANKING ALL THE PANEL MEMBERS FOR YOUR SERVICE. WE RESPECT AND APPRECIATE YOUR GUIDANCE. THROUGHOUT MY CAREER I HAVE CONTINUOUSLY SERVED ON NIH REVIEW PANELS AND SO I WANT YOU TO KNOW HOW MUCH I TRULY RESPECT AND APPRECIATE YOUR TIME AND ALSO LIKE TO THANK EVERYONE IN THE AUDIENCE, THE MEMBERS OF FREDRICK NATIONAL LABORATORY, OUR COLLEAGUES AT THE NATIONAL CANCER INSTITUTE, MANY AT THE TABLE, AND IN THE AUDIENCE. OTHER INSTITUTES, FOR ATTENDING TODAY AND TAKING TIME FROM YOUR HECTIC SCHEDULES. SO I'M GOING TO TALK ABOUT CURRENT OPERATIONS AND FUTURE PLANS OF THE FREDRICK NATIONAL LABORATORY. MY OBJECTIVES TODAY ARE 3 FOLD. FIRST I'M GOING TO REVIEW THE HISTORY AND ACHIEVEMENTS AND HARD WORK AND OPERATIONS OF THE LABORATORY. AND THE PERSPECTIVE I'M GOING TO BRING TO THIS CONVERSATION IS TO EMPHASIZE OUR COLLECTIVE RECORD& OF SERVICE, SERVICE TO THE NCI, NIH AS A WHOLE AND THE EXTRAMURAL SCIENTIFIC COMMUNITY AND I'LL DISCUSS A FUTURE PLANS AND CERTAINLY LEAVE AMPLE TIME TO ADDRESS YOUR QUESTIONS. FREDRICK NATIONAL LABORATORY HAS A NOTABLE HISTORY. IN 1972, PRESIDENT NIXON, IN A REMARKABLE MOVE, THAT CAN ONLY BE DESCRIBED AS BEATING SWORDS INTO PLOW SHEERS, DECOMMISSIONED NEARLY 70 ACRES OF BIOWARFARE FACILITIES ON THE FORT DIETRICH SITE, TO BECOME WHAT IS NOW TODAY THE FREDRICK NATIONAL LABORATORY SPONSORED BY THE NCI AT FORT DIETRICH. IN 1972, TO TODAY, WE ENJOY AN INCREDIBLE RECORD OF GROWTH BEGINNING WITH ONLY 300 EMPLOYEES UNTIL NOW, 2200. SEMINOLE EVENTS IN OUR HISTORY ARE SHOWN IN THIS TIMELINE BUT I'D LIKE TO POINT OUT IT WAS ONLY IN 2012 THAT HOW VERY MUSAND DOUG LOWY AND THEIR COLLEAGUES DESIGNATED OUR FACILITY AS A NATIONAL LABORATORY. IN 2016, TO MY MIND FAR-REACHING PRUDENT DECISION WAS MADE TO REFURBISH THESE NEARLY 70 ACRES OF FACILITIES AND THROUGHOUT, THE COMMUNITY THAT I SERVE DEEPLY HAS A SENSE OF PUBLIC RESPONSIBILITY TO SERVE THE PUBLIC'S HEALTH. FREDRICK NATIONAL LABORATORY SERVES THE PUBLIC INTEREST AND OUR GOAL IS TO BE A NATIONAL RESOURCE THAT COMBATS CANCER, AIDS, AND INFECTIOUS DISEASES AND EMERGING CHALLENGES TO THE PUBLIC'S HEALTH. THIS IS DONE PROUDLY IN CONCERT WITH OUR COLLEAGUES AT THE NCI, NIGH ADD AND MANY OTHER INSTITUTES. I WANTED TO POINT OUT THAT THIS MISSION -- NIAID -- THIS MISSION IS LARGER THAN ANY ONE OF US. THERE ARE FIVE TYPES OF REACH UNDERWAY AT THE FREDRICK NATIONAL LABORATORY AND THROUGH MY PRESENTATION, WILL YOU HEAR ME TOUCH ON EACH OF THESE IN TURN. FOR INSTANCE THE DISCOVERY AND TRANSLATIONAL SCIENCE, THE NEXT IS ADVANCED CORE FACILITIES. THESE ARE VIEWED AS SOPHISTICATED AS SCIENTIFIC PLATFORMS OF DISCOVERY THAT ENGAGE INTERDISCIPLINARY COLLEAGUES, COLLABORATIONS BOTH AT THE NCI AND OTHER INSTITUTES AND FREDRICK NATIONAL LABORATORY LABORATORY. NEXT AS NED DESCRIBED, AN EXAMPLE OF TEAM SCIENCE AND THE RAS INITIATIVE IS AN EXAMPLE OF THAT. COLLABORATIVE SCIENCE I'LL TALK ABOUT, IN CONCERT ESPECIALLY WITH NCI AND NIAID, AND FINALLY ADVANCED TECHNOLOGY SUPPORT TO THE EXTRAMURAL COMMUNITY. SO THIS WILL BE THE THEME OF MY PRESENTATION. WHAT THE IS FREDRICK NATIONAL LABORATORY DOING NOT ONLY TOW SUPPORT OUR COLLEAGUES AT THE NCI AND OTHER INSTITUTES, BUT NATIONALLY? SOME RECENT MAJOR ACHIEVEMENTS TO CALIBRATE WHERE WE ARE IS THE RAS INITIATIVE I WILL TOUCH ON IN SUMMARY. ELUCIDATING THE BASIC BIOLOGY THAT WILL ENABLE US TO DISCOVER NEW AGENTS TO COMBAT WHAT HAS BEEN A LUCID PROBLEM. I'LL TOUCH ON THE INITIATIVE WE SPOKE ABOUT QUITE A BIT THE LAST TIME WE CONVENED TOGETHER. THIS INITIATIVE TO ACCELERATE THERAPEUTICS AND OPPORTUNITIES OF MEDICINE, THE CONSORTIUM BETWEEN FOUR FOUNDING INSTITUTIONS, LABORATORY AT LAWRENCE LIVER MORE, AND THE GOAL IS TO APPROACH THE PRE-CLINICAL DOMAIN OF A DRUG DISCOVERY AND DEVELOPMENT TO DECREASE THAT LAG FROM 6 OR MORE YEARS DOWN TO ONE YEAR. YES IT'S AN AMBITIOUS AGENDA AND GOAL BUT IT IS A WORTHY ONE. TO SUPPORT A GLOBAL VACCINE EFFORTS IN ZIKA, EBOWL AHPV AND OTHER VACCINATION EFFORTS I'LL TOUCH ON -- EBOLA. AND THE ELECTRON MICROSCOPY INITIATIVE. AND WE WILL HAVE A SPEAKER AFTER ME AND HE WILL TELL YOU MORE ABOUT THIS EXCITING WORK. JUST TO SAY WHERE WE HAVE BEEN. SOME MAJOR PARTIAL LIST OF ACHIEVEMENTS IN SUPPORT OF EXTRAMURAL COMMUNITY INCLUDE IMMUNOTOXINS FOR REMISSION AND LEUKEMIA. MONOCLONAL ANTIBODY AGAINST GD-2. WE PROUDLY SUPPORT THE GOOD WORK OF DOROSHOW AND OTHERS THROUGH THE MATCH TRIAL SUPPORT AND NECKS TRIAL SUPPORT YOU'LL HEAR MORE ABOUT THAT FROM DR. DOROSHOW AND DR. PATCH MEANT. AND WE ARE SO PLEASED TO WORK WITH DR. SINGER ON MOONSHOT EFFORTS. THE GLIOBLASTOMA TRIAL THAT WAS CONDUCTED AT DUKE, IT WAS PRODUCED AT FREDRICK AND WE CONTRIBUTED TO THE HIV KIT, THE DEVELOPMENT OF THAT KIT THAT SECURED THE NATION'S BLOOD SUPPLY AGAINST THE TERRIBLE FEAR OF HIV INFECTION. WE ARE DEVELOPING AND TESTING VACCINES THAT I'LL TALK ABOUT AGAINST ZIKA, EBOLA, AND I'D LIKE TO LEAVE YOU WITH THIS NOTION THAT THIS WORK IS DONE IN CONCERT WITH THE NCI AND OTHER INSTITUTES AND ESPECIALLY WITH THE EXTRAMURAL COMMUNITY. LET'S GIVE YOU TWO EXAMPLES OF DISCOVERY AND TRANSLATIONAL SCIENCE. THE FIRST COMES FROM THE WORK OF MARY WHO PUBLISHED THIS ABOUT A MONTH OR TWO AGO IN SCIENCE. AND WHAT MARY HAS FOUND IS THAT IMMUNORESPONSE GENOTYPES DETERMINE IF INNATE IMMUNE CELLS WILL KILL OR LET SURVIVE HIV-INFECTED CELLS. I THINK THIS IS A TRAILBLAZING DISCOVERY THAT HAS BROAD IMPLICATIONS NOT ONLY FOR HIV BIOLOGY BUT A WAY FOR US TO GET AN INSIGHT INTO THE BIOLOGY OF MANY CANCER PROBLEMS. I'D ALSO LIKE TO JUST MENTION IN PASSING THAT I WILL BE BRINGING MY LAB FROM MD ANDERSON HERE AND I'LL TELL BUT ONE PROJECT THAT WILL BE DEVELOPING HERE. THIS IS A PROJECT THAT IS DEVOTED TO ERADICATING A HALLMARK OF CANCER, WHICH AS YOU KNOW CAUSES SO MANY HISTOLOGIES. A NUMBER OF YEARS AGO MY LABORATORY UNCOVERED A PATHWAY THAT WE CALLED ANAPHASE CATASTROPHE. THIS IS A CYCLIN-DEPENDENT CTK2 DEPENDENT PATHWAY. WE HAVE UNCOVERED THE MOLECULAR MECHANISMS FOR THIS PATHWAY AND INVOLVES PHOSPHORYLATION OF A SENT ROW ZOME PROTEIN CALLED CP110. QUITE INTRIGUINGLY, WE DISCOVERED THROUGH SCREENS THAT RAS-DRIVEN CANCERS ARE PARTICULARLY SENSITIVE TO THIS PROGRAM. WHY? BECAUSE IT DOWN REGULATES CP110. THIS OCCURS LIKE INHIBITION OF CENTROSOMES. THIS IS WHY ANPLOYED CELLS DIE AND WHY THEY SPARE NORMAL CELLS. SO I'LL SHOW YOU A QUICK VIDEO OF THIS PROGRAM. THIS IS A TRI-POLAR CELL EVENT. YOU SEE THE FATES OF TWO CELLS, ONE CELL IS OUT OF THE PLANE. AFTER CDK2 INHIBITION, ITS KEY POINT HERE IS NOT DURING MITOSIS BUT IT'S THE PROGENY CELLS THAT DIE. AND YOU CAN SEE COALESCING THE TWO DAUGHTER CELLS THAT ARE BEGINNING TO BECOME HYPNOTIC AND ULTIMATELY HERE IS THE FIRST CELL DYING AND NOW THE SECOND CELL DIES. BUT I PUBLISHED A SERIES OF PAPERS AND I WAS CONTACTED BY TACK WHO PUBLISHED A PAPER IN CANCER CELL WITH IDENTICAL LOOKING CELLS AND HE SAID PERHAPS THIS IS A PROGRAM THAT IS ALSO ACTIVATED BY WHAT HE WAS STUDYING, A POLAR-LIKE KINASE 4 INHIBITOR. SO HE AND I JUST PUBLISHED A PAPER IN PNAS THAT SHOWS IT IS A DIFFERENT DEATH PROGRAM. NOT SEPTEMBER ROW ZOME CLUSTERING BEING INHIBITED -- SENT ROW ZOME BUT RATHER OVER DUPLICATION OF CENTROSOME. WELL SO WHAT WE UNCOVERED IS A NEW WAY TO KILL ANPLOYED CELLS PREFERENTIALLY IN RAS-DRIVEN TUMORS AND IT'S TARGETING SENT ROW ZOME DUPLICATION. ANOTHER EXAMPLE OF THE WORK AT FREDRICK NATIONAL LAB IS ADVANCED CORE FACILITIES. THESE ARE THE SOPHISTICATED INTERACTIVE PLATFORMS THAT I DISCUSSED. TWO-WAY STREET, BI-DIRECTIONAL PARTNERSHIP, A GOOD EXAMPLE OF THAT IS THE LASP PROGRAM OR ANIMAL SCIENCES PROGRAM. BY STEVE JONES. I WANTED TO SAY THIS IS A RESOURCE OF GREAT SERVICE TO THE NCI. BUT ALSO HAS POTENTIAL TO CONTRIBUTE TO THE EXTRAMURAL COMMUNITY A GOOD EXAMPLE TO SITE IS THE PROGRAM THAT STEVE HAS IN PLACE AS WELL AS INSIGHTS FROM THE SMALL IMAGING ANIMAL IMAGING PROGRAM AND THE GENOME MODIFICATION PROGRAM. YET ANOTHER EXAMPLE OF SERVICE TO THE EXTRAMURAL COMMUNITY IS THE NANOTECHNOLOGY CHARACTERIZATION LABORATORY. THIS IS TRULY A RESOURCE FOR THE EXTERNAL COMMUNITY. HERE YOU CAN SEE BOTH THE PARTNERSHIPS FOR THE DIFFERENT ASPECTS THIS LABORATORY SERVES. PARTNERSHIPS WITH PHARMACEUTICAL COLLEAGUES IN TERMS OF NANOMATERIAL DEVELOPMENT, NEW METHODS, BASIC RESEARCH THAT IS PUBLISHED, REGULATORY AGENCIES THAT WE HELP PROVIDE INFORMATION FOR AND INDEED THIS HAS LED TO TRANSNATIONAL COLLABORATIONS. SO, THE MESSAGE TO GIVE IS HERE IS AN EXAMPLE OF FREDRICK NATIONAL LABORATORY SERVING NOT ONLY THE EXTRAMURAL COMMUNITY BUT THE COMMUNITY, THE SCIENTIFIC COMMUNITY AT LARGE, INCLUDING THE BIOTECHNOLOGY COMMUNITY. TEAM SCIENCE EXAMPLE THAT NED MENTIONED IS ONE THAT WE ARE VERY PROUD TO SPEAK ABOUT. WITH A CONCEPT OF THIS BEING A HUB AND SPOKE MODEL, WHERE WE ENGAGE INTRAMURAL LABORATORIES, TARGET KRAS AND AS HAS BEEN MENTIONED, TO UNDERSTAND THE BIOLOGY OF KRAS. NOVEL CLASSES OF COMPOUNDS ARE BEING DEVELOPED TO TARGET KRAS AND CONVENIENCE ARE UNDERWAY. I'D LIKE TO POINT OUT THIS NOTION OF PARTNERSHIP UNDER THE JDACS4C WITH THE DEPARTMENT OF ENERGY TO BRICK USING COMPUTING CAPABILITY TO BRIDGE GAPS IN KNOWLEDGE. THIS PARTNERSHIP IS WITH THE ACADEMY, BIOTECHNOLOGY, THE NIH AS A WHOLE, AND OUR COLLECTIVE GOAL IS TO DEVELOP LEADS AND PUSH THOSE LEADS TUSSER A CLINIC TO HELP PATIENTS. HERE IS YET ANOTHER EXAMPLE OF THE COMPUTATIONAL INSIGHTS THAT ARE BEING DEVELOPED. THIS THE IS HOW THE KRAS 4B PROTEIN SITS IN THE MEMBRANE AND IN CONCERT WITH THE WORK OF DWIGHT AND COLLEAGUES AT THE DEPARTMENT OF ENERGY, YOU CAN SEE YOU CAN MODEL HOW THE RAS PROTEIN OVER TIME FORMS THESE SUPER STRUCTURES WHETHER THESE SUPER STRUCTURES ARE THEMSELVES TARGETS FOR ANTI-NEOPLASTIC APPROACHES TO COMBAT RAS DEREGULATED GROWTH WILL BE INVESTIGATED, BUT IT'S AN EXAMPLE OF HOW WE ARE ENGAGING THE NATIONAL LABORATORY COMMUNITY AS A WHOLE. THE ATOM CONSORTIUM, YOU'LL MORE MORE DETAIL LATER, IS OUR MISSION TO ACCELERATE THE DEVELOPMENT OF MORE EFFECTIVE THERAPIES FOR CANCER PATIENTS. THE VISION IS A NEW STARTING POINT RATHER THAN HAVE A LINEAR PROCESSING. BUT TO HAVE THE PARALLEL PROCESSING WHERE WE WILL AT THE SAME TIME USE IN SILICO MODELING BOTH OF ANIMAL MODELS AND ALSO OF CELLULAR RESPONSE TO GIVE US INSIGHTS INTO TOXICITY AND EFFECTIVE SIGNALING WITH PHARMACODYNAMIC APPROACHES. THIS HAS BEEN A EXHILARATING PROGRAM TO BE PART OF AND I WANTED TO SAY THAT THIS IS A PROGRAM THAT ALL ARE WELCOME TO PARTICIPATE. WE HAD A ROLL OUT OF THE AT OM INITIATIVE AT AACR, A LITTLE MORE THAN A WEEK AGO I PRESENTED AT THE CANCER CENTER DIRECTOR'S MEETING THAT NED SHARPLESS HOSTED, AND WE HAD A TREMENDOUS RESPONSE TO THESE OUTREACH EFFORTS. AND THEY ARE SHOWN ON THIS SLIDE. I'M NOT GOING TO SPEAK ABOUT THEM IN DETAIL BUT SIMPLY TO SAY IT'S THE FIRST TIME IN MY CAREER I HAVE BEEN PART OF A TWITTER EXERCISE. I'M REALLY PROUD THAT WE HAD MANY VIEWS AND MANY RESPONSES AND ALTHOUGH IT'S A NEW WORLD FOR ME, I'M PROUD TO BE PART OF THAT NEW WORLD. BUT SINCE THE MEETING, I HAVE BEEN APPROACHED BY MANY DIRECTORS. THEY WILL BE VISITING FREDRICK NATIONAL LABORATORY AND SPECIFICALLY WILL BE DISCUSSING HOW THE EXTRAMURAL COMMUNITY CAN BE PART OF THIS INITIATIVE. AN EXAMPLE OF COLLABORATIVE SCIENCE IN CONCERT WITH THE NCI AND NIAID AND OTHER INSTITUTES. WHAT I'D LIKE TO TOUCH ON NOW, WE PROVIDE GLOBAL SUPPORT FOR VACCINE TRIALS THAT PLAYS A KEY ROLE IN THE CONVECT OF THESE TRIALS. THEY INCLUDE NOT ONLY EBOLA BUT ZIKA. EARLY PHASE I-3 TRIALS IS AN INCREDIBLE EFFORT TO CONDUCT THESE TRIALS WITH UNDERSTANDING THE CULTURE OF OTHER COUNTRIES BUT THIS IS AN EXAMPLE OF THE SPACE THE FREDRICK NATIONAL LABORATORY OCCUPIES THAT WOULD NOT READILY BE OCCUPIED BY THE ACADEMIC COMMUNITY. OR PERHAPS EVEN THE BIOTECHNOLOGY COMMUNITY. SO IT SERVINGS A SPECIFIC NICHE. AN EXAMPLE IS THE WORK THAT IS CONDUCT WOULD AT THE NCI AND IS ENABLED BY A GRANT FROM THE BILL AND MELINDA GATES FOUNDATION. THIS IS A TRIAL IN A WAY YOU HEARD ABOUT IN COSTA RICA TO ASK THE QUESTION AFTER THE SEMINOLE WORK OF JOHN CHILLER AND DOUG LOWY, FOR THE DISCOVERY OF THE HPV VACCINE, VACCINATIONS BE EQUAL TO TWO OR EQUAL TO ONE. AND WHEN YOU ENVISION THE DEMOCRATIZATION OF THIS DISCOVERY, IF IT WERE TO POSSIBLE HAVE HAVE ONE AND NOT 3, JUST THINK OF ALL THE OTHER COUNTRIES BEYOND OUR BORDERS WHO COULD NOW AFFORD THIS VACCINATION. THE STUDY, YOU CAN SEE THE PARTICIPANTS. I'D LIKE TO RECOGNIZE DR. PINN TOW AND MANY OTHER INVOLVED IN THIS, IS AN EFFORT TO MAKE THIS INFORMATION AVAILABLE TO THE CANCER SCIENCE COMMUNITY. BUT WHAT I WANTED TO EMPHASIZE IN THIS IS THIS SENSE OF SERVING THE PUBLIC INTEREST. AND WE ARE REALLY SO PRIVILEGED TO TAKE A -- WHO HAVE DONE THEIR PART IN THIS WORK. THE VACCINE RESEARCH CENTER MAY BE SOMETHING YOU'RE FAMILIAR WITH OR PERHAPS YOU'RE NOT. I'M GOING TO TAKE A MOMENT TO GIVE YOU A SENSE OF SOMETHING THAT WE ARE VERY PROUD OF, THIS ROLE THAT WE PLAY IN A LARGER EFFORT LED BY NIAID, THAT INCLUDES BASIC RESEARCH GMP-GRADE PRODUCTION, THAT IS IT DONE BOTH AT THE BETHESDA SITE AND AT FREDRICK. AND I LIKE TO CALL OUT DAVID LINDSEY FOR HIS LEADERSHIP IN THIS AREA. THIS WORK HAS GARNERED A LOT OF VISIBILITY FOR THEIR TEAM. HERE YOU CAN SEE ON THE COVER OF SCIENCE WAS THE DNA VACCINE FOR ZIKA. THE ZIKA VIRUS. THIS IS A STUDY THAT IS NOW BEING CONDUCTED WORLDWIDE. BUT WHAT YOU SHOULD ALSO BE AWARE OF, THERE ARE A NUMBER OF PROJECTS, DIVERSE PROJECTS IN THIS SPACE, RELATED TO VACCINE DEVELOPMENT AND MANUFACTURING UNDERWAY. JEFF'S WONDERFUL TEAM IS WORKING ON WAYS TO HOPEFULLY ONE DAY CURE HIV AND THIS INVOLVES BOTH ANTIBODY AND VACCINE APPROACHES. EFFORTS ARE UNDERWAY FOR THE RESPIRATORY TOW TACKLE THE RESPIRATORY VIRUS BROADLY ACTIVE INFLUENZA VACCINE. AND MANY OTHER DAUNTING PROBLEMS WORLDWIDE THAT ARE ALSO SHOWN IN THIS FIGURE. SO THIS IS A WORK OF SERVICE TO MANY PEOPLE SUFFERING FROM DEADLY DISEASES. WE ARE JUST SO DELIGHTED TO WORK WITH JIM DOROSHOW. JIM, I WANTED TO -- MY NEXT FEW SLIDES I WANTED TO JUST SEGUE AND THANK YOU PUBLICLY FOR WHAT YOU'RE DOING FOR THE EXTRAMURAL COMMUNITY UNTIL JUST ABOUT FIVE MONTHS AGO, I WAS A MEMBER OF YOUR COMMUNITY AND JIM HAS DONE SO MUCH TO MAKE AVAILABLE SOME REMARKABLE RESOURCES. I'M JUST GOING TO TOUCH ON A FEW. YOU WILL HEAR MORE ABOUT THERE FROM JIM AND ALSO FROM RALPH PATCHMENT. THE NEXT PROGRAM WHICH IS AWAY FOR THE ACADEMIC COMMUNITY TOW DEVELOP DRUGS AND IND-ENABLED TO USE THIS INCREDIBLE CONSORTIUM OF SCIENTIFIC EXPERTISE TO HOPEFULLY DEVELOP DRUGS THAT WOULD NOT BE DEVELOPED IN A PHARMACEUTICAL INDUSTRY. A BIT OF HISTORY SO YOU HAVE A DEEPER SENSE OF THE MOMENTUM OF THIS PROGRAM. THE CHEMICAL BIOLOGY CONSORTIUM BEGAN IN 2008, AND OF COURSE ALL OF THIS WORK IS OVER SEEN BY THE NCI SENIOR ADVISORY COMMITTEE. THIS CONSORTIUM WAS RECOMPETED SUCCESSFULLY IN 2015 AND I'D LIKE TO UNDERSCORE THAT THERE ARE SEVEN DEDICATED CENTERS THAT INCLUDE UNIVERSITIES, INSTITUTES, COMPANIES AND 15 SPECIALIZED CENTERS THAT ALSO INCLUDE THE SPECTRUM OF THE BIOMEDICAL COMMUNITY. AND IN THE BIOMEDICAL RESEARCH, IT HAS ALSO BEEN INVOLVED IN ISSUING SUBCONTRACTS OF A SIZEABLE AMOUNT SHOWN HERE. THIS IS AN EXAMPLE OF A SUPER TEAM. HERE ARE THE COLLABORATING SITES THROUGHOUT THE NATION. AND IS IT A TESTAMENT TO THE INCREDIBLE EFFORTS TO MAKE THIS A RESOURCE FOR THE EXTRAMURAL COMMUNITY. I WANTED TO THANK DEANA SINGER FOR THE OPPORTUNITY TO CONTRIBUTE TO THIS WONDERFUL VISION ABOUT THE MOONSHOT PROGRAM. I'D LIKE TO TOUCH ON ONE AREA THAT WE ARE INVOLVED IN AND THIS IS WITH JIM DOROSHOW. AND NICKY WILLIAM AND RALPH PAY A KEY ROLLED AMONG OTHERS IN PARTNERSHIP WITH JIM AND HIS TEAM TO ESTABLISH A NATIONAL BIOBANK, REPOSITORY, CONTAINING LONGITUDINALLY-ACCRUED BIOSPECIMENS OF NEWLY-DIAGNOSED PATIENTS. THIS IS A BOLD INITIATIVE. IT WILL GIVE US INSIGHTS INTO RESISTANCE AND SENSITIVITY TO THE NEW THINGS WE ALL TALK ABOUT. BUT ALSO GIVE US INSIGHT INTO THOSE WHO HOPEFULLY RESPOND IMMUNOTHERAPY, THOSE WHO ARE UNFORTUNATELY RESISTANT TO THIS LINE OF THERAPY, BUT ALSO GIVE US A WAY TO UNDERSTAND TOXICITY, WHICH FROM THE CLINICIANS AND MYSELF INCLUDED, IS SOMETIMES ONE OF THE MOST DAUNTING ASPECTS OF CARRY FIGURE PATIENTS WITH IMMUNOTHERAPY. THE TOXICITIES CAN BE DELAYED. THEY CAN BE LIFE-THREATENING AND WE REALLY OWE IT TO OUR PATIENTS TO USE SCIENCE TO COMBAT THESE PROBLEMS. THERE ARE BOTH CHALLENGES AND OPPORTUNITIES IN THIS BOLD INITIATIVE. ONE WOULD BE OBVIOUSLY PATIENT AND PHYSICIAN ENGAGEMENT. BUT THE FOCUS AND ENROLLMENT OF MINORITIES AND THOSE WHO ARE UNDERSERVED FROM UNDERREPRESENTED POPULATIONS, IS A KEY ASPECT OF THIS LONGITUDINAL ACCRUAL PROGRAM. OF COURSE WE MUST ACCRUE THE HIGHEST QUALITY REAGENTS FOR STUDIES FOR THE SCIENTIFIC COMMUNITY AND WE MUST ALSO HAVE SUFFICIENT CLINICAL DATA TO INTERPRET WHAT THE FINDINGS WILL TELL US. SO WE HAVE BEFORE US A CHALLENGE TO DEVELOP INTERACTIVE DATABASES THAT CAN BE USED BY THE COMMUNITY AND OF COURSE, BECAUSE THIS IS AN INTERDISCIPLINARY EFFORT OF LARGE COMPLEXITY, WE HAVE ISSUES RELATING TO SUBCONTRACTING. LET ME -- MY GOAL WAS TO LEAVE AMPLE TIME FOR QUESTIONS. I'M GOING TO END WITH THE FIFTH EXAMPLE. THIS IS HOW FREDRICK NATIONAL LABORATORY IS ADVANCED TECHNOLOGY TO SUPPORT THE EXTRAMURAL COMMUNITY. AND I'D LIKE TO CALL OUT -- FOR WHAT YOU HAVE DONE. YOU AND YOUR TEAM TO MAKE AVAILABLE THE NATIONAL FACILITY. THIS IS LAUNCHED ABOUT A YEAR AGO AND OVER THE COURSE OF JUST ONER. >>> , 20 UNIVERSITIES AND 78 CANCER PROJECTS HAVE BEEN UNDERTAKEN OR COMPLETED. THE FIRST PUBLICATION WAS IN NATURE COMMUNICATION. HERE ON THIS FIGURE ARE THE SO FAR COLLABORATING INSTITUTIONS. YOU'LL HEAR MORE ABOUT THIS LATER. AND I'M JUST GOING TO GIVE YOU ONE EXAMPLE OF THESE STUNNING TECHNOLOGIES. THIS EXAMPLE IS FOCUSED ON SCANNING. THIS IS AN EFFORT UNDERWAY AT NCI. WE ARE -- OUR ROLE IS TO SUPPORT THE NATIONAL CANCER INSTITUTE AND CCR SPECIFICALLY. THIS IS THE TECHNOLOGY CALLED FIB SCANNING ELECTRON MICROSCOPY. LET ME STOP FOR A MOMENT AND GIVE YOU A PERSPECTIVE. THESE ARE NOT NEW TECHNOLOGIES. THEY COME FROM THE MATERIAL SCIENCE COMMUNITY BUT WHAT IS NEW, IS THAT THESE TECHNOLOGIES THAT HAVE BEEN HONED IN THE MATERIAL SCIENCE COMMUNITY, ARE NOW BEING APPLIED TO BIOMEDICAL RESEARCH. WHILE CRYO-EM GIVES US INSIGHTS AT THE MOLECULAR ATOMIC LEVEL, THIS GIVES US INSIGHTS IN A LARGER SIZE FRAME. HUNDREDS OF NANOMETERS. SO THAT LEAVES OPEN THE POSSIBILITY FOR US TO LOOK AT ORGANELLES. LET US MOVE TO THE NEXT SLIDE, WHICH IS A WONDERFUL VIDEO THAT OUR COLLEAGUES PRODUCED. THIS IS THE FIB CEM TECHNOLOGY. THIS IS THE MACHINE IN CARTOON. IT'S POSSIBLE TO IMAGE THESE CELLS FLUORESCENTLY. AND THEN TO EMBED INDIVIDUAL CELLS IN RESINS. THE RESINS PROTECT THE CELL OF INTEREST AND ALSO ALLOW US TO SCORE AFTER A SUITABLE PROCESSING SO WE KNOW EXACTLY WHERE THEY REGISTER WITHIN THE EMBEDDED RESIN. BY PLACING BOTH PLATINUM PAD AND THEN SUBSEQUENTLY CARBON PAD, YOU CAN REGISTER THE SURFACE THAT WILL ENABLE THE INVESTIGATOR TO DETERMINE WHERE A STRUCTURE EXISTS IN THE CELL FOR A MILLING PROCESS, TRENCHES ARE PREPARED. THE CELL THEN IS EXPOSED AND SCANNED AND IMAGED AND BECAUSE OF THE REGISTERING, YOU CAN THEN IN A SENSE, GET A THREE-DIMENSIONAL VIEW OF THE CELL. THE THREE-DIMENSIONAL VIEW CAN, THROUGH AN EXTRAORDINARY EFFORT OF COMPUTATIONAL SCIENCE, TO REGISTER THESE IMAGES, ALLOWS THE INVESTIGATOR TO DETERMINE EXACTLY WHERE A STRUCTURE EXISTS WITHIN A CELL. AND THESE PAPERS ARE PUBLISHED IN THE HIGHEST TIERED JOURNALS. YOU WILL HEAR FROM OTHERS. ONE IS THE FIRST EXAMPLE I JUST SHOWN YOU, THE HIV SYNAPSE THAT WAS PUBLISHED IN PNAS. THIS IS A NEW AGE OF IMAGING AND SCIENCE OF IMAGING. AND WE ARE PROUD TO PLAY A ROLE IN THIS. HERE SAY PARTIAL LIST OF THE INITIATIVES THAT MY COLLEAGUES AND I HAVE UNDERTAKEN. I HAVE LAUNCHED LISTENING AND LEARNING TOUR. WE HAVE 2200 EMPLOYEES. MY GOAL IS TO BE ABLE TO HAVE SAID THAT I HAVE MET WITH EACH AND EVERY ONE OF THE EMPLOYEES, THE STAFF NEITHER SMALL GROUPS OR ONE-ON-ONE MEETINGS. I HAVE ALSO REACHED OUT EXTENSIVELY TO THE NCI AND NIH LEADERSHIP FOR ONE-ON-ONE MEETINGS. I'M WELL ON THE WAY TO COMPLETING THIS GOAL. WE HELD A LEADERSHIP RETREAT WHERE WE ARE BRINGING OUR COMMUNITY TOGETHER TO DEFINE OUR COAL VALUES AND IN LIGHT OF WHAT NED HAD SPOKEN ABOUT, I WANTED TO SAY THAT I SHARE HIS COMMITMENT TO TRAINING THE NEXT GENERATION. AND WE ARE LOOKING FOR INNOVATIVE WAYS FOR US TO TRAIN THE NEXT GENERATION. WE HAVE FINALIZED COLLABORATION MOU WITH GEORGETOWN UNIVERSITY. WE HAVE DONE THE SAME WITH HOOD COLLEGE, HOPE TO DO THE SAME WITH ST.MARY UNIVERSITY, AND WE ARE WORKING WITH THE UNIVERSITY OF MARYLAND SCHOOL OF ENGINEERING. JUST YESTERDAY, DR. SPRINGFIELD AND I MET WITH PROVOST OF HOWARD UNIVERSITY TO DISCUSS HOW FREDRICK CAN SUPPORT HER INITIATIVE IN THE ICARE PROGRAM. THIS IS A WAY OF BRINGING UNDER REPRESENTED STUDENTS, BOTH UNDERGRADUATES AND GRADUATE STUDENTS TO THE NATIONAL CANCER INSTITUTE BEHIND THE INITIATIVE AND HER GOAL WE SUPPORT IN EVERY WAY POSSIBLE. I'D LIKE TO TOUCH ON THE KINDS OF RELATIONSHIPS WE ARE TRYING TO BUILD THAT ARE NOT ONE-SIZE-FITS-ALL. WHAT I'D LIKE TO GIVE YOU AS AN EXAMPLE IS THE HOOD COLLEGE INITIATIVE. MANY OF YOU OVER A CERTAIN AGE THAT YOU MAY HAVE EVEN ATTENDED THE FAMOUS HOOD COLLEGE NCI ONCOGENE SCIENCE MEETINGS. I DID WHEN I WAS A POSTDOCTORAL FELLOW -- SHOWING MY AGE. THOSE MEETINGS WERE DISCONTINUED ABOUT 12-15 YEARS AGO. SO I APPROACHED THE PRESIDENT OF HOOD COLLEGE AND WE HAVE AGREED TO RE-LAUNCH, RE-CREATE THE FAMOUS MEETINGS. AND IN CONCERT WITH ANDREW QUAN AND OTHERS, WE ARE GOING TO HOLD THE FIRST MEETING NEXT YEAR. AND THE TITLE OF THE MEETING IS, IMAGING SCIENCE MEETS CANCER BIOLOGY. WE HAVE AS A GOAL, TO DEVELOP RELATIONSHIPS THAT DON'T ADD EXPENSE TO THE NATIONAL CANCER INSTITUTE. SO THIS WILL BE CONDUCTED EXCLUSIVELY THROUGH THE -- WILL BE LED THROUGH HOOD COLLEGE. LET ME GIVE YOU ONE EXAMPLE THAT OCCURRED ON FRIDAY AFTER I PREPARED THESE SLIDES. WE SIGNED A MEMORANDUM OF UNDERSTANDING WITH MYI MEXICO AND THEY WILL BE 1 FULLY FUNDING TRAINEES TO COME TO THE FREDRICK NATIONAL LABORATORY AND I'D LIKE TO SAY IF WE DON'T HAVE THE RIGHT LAB FOR THE TRAINEES, THEY WILL BE AT NCI AS A WHOLE, THESE TRAINEES WILL BE THEIR BEST AND BRIGHTEST SO TO SPEAK. WHY? BECAUSE THEY HAVE BEEN PRE-VETTED TO BE OFFERED A FACULTY POSITION WHEN THEY GO FOR POSTDOCTORAL TRAINING. AND THEY WILL BE WELCOMED BACK ON THE FACULTY NCI MEXICO. SO HERE IS A MODEL WHERE WE ASSIST FREDRICK NATIONAL LABORATORY AND WE ASSIST OUR PARTNERS. AND IT'S VERY COST EFFECTIVE APPROACH IF SOMEONE ELSE PAYS THE STIPEND. WE DO MOST SINCERELY WANT TO DEVELOP DEEPER PARTNERSHIPS THROUGHOUT THE NCI, NIAID AND OTHER INSTITUTES AND ESPECIALLY THE NATIONAL LABORATORIES AND THE EXTRAMURAL COMMUNITY. THAT IS OUR RESPONSIBILITY. AS WE LOOK TOWARDS OUR FUTURE, OF BECOMING A NATIONAL LABORATORY, IT'S A SOURCE OF PRIDE AND PURPOSE. AND WE ARE COMING TOGETHER AS A COMMUNITY TO MAKE THIS DESIGNATION OUR UNIFYING PRINCIPLE. THIS WILL ONLY HAPPEN THROUGH OUR SCHOLARSHIP PARTNERSHIPS AND SERVING PUBLIC INTERESTS. AND AS I CONCLUDE, AS I PROMISED LEAVING AMPLE TIME FOR QUESTIONS, I'D LIKE YOU TO TAKE AWAY FROM MY PRESENTATION THAT FREDRICK NATIONAL LABORATORY IS A NATIONAL RESOURCE FOCUSED PRIMARILY ON BIOMEDICAL RESEARCH, UNLIKE THE OTHER NASH LABORATORIES. ITS REASON FOR BEING IS SERVING THE PUBLIC'S HEALTH. WE WORK WITH NCI AND OTHER INSTITUTES ON PROX THAT ARE DIFFERENT, PERHAPS DISTINCT, FROM THE ACADEMIC COMMUNITY, FROM INDUSTRY AND OTHER NATIONAL LABORATORIES. BUT WE DO SO IN PARTNERSHIP WITH THESE OTHER ENTITIES. WE ARE PROUD OF THIS PARTNERSHIP AND THE WORK WE DO WITH AND FOR NCI, NIH AND THE EXTRAMURAL COMMUNITY AND SERVE THE PUBLIC'S HEALTH. SO AS I END, IN ANOTHER HUB AND SPOKE METAPHOR, WHERE I HAVE GRATUITOUSLY PLACED FREDRICK NATIONAL LABORATORY IN THE CENTER, MY APOLOGIES. I WANTED TO UNDERSCORE SOMETHING I HAVE LEARNED IN MY SHORT TENURE. ONE IS THAT WE HAVE EXPENSIVE COLLABORATIONS IN THE ACADEMIC COMMUNITY AND HERE AS OF ABOUT A WEEK AGO, ARE THE CURRENT ONES AND PAST ONES. BIOTECHNOLOGY COMMUNITY SHOWN HERE. AND WITH THE CANCER CENTER COMMUNITY. AND OBVIOUSLY WITH THE NATIONAL LABORATORIES. THERE ARE 17 NATIONAL LABORATORIES. THEY WORK ON PROBLEMS THAT INVOLVE NATIONAL SECURITY. THEY INVOLVE KEEPING OUR NUCLEAR STOCKPILE SAFE, MAKING SURE THAT OUR -- THAT THERE ARE SAFEGUARDS FOR SO MANY OF THE NATIONAL ENDEAVORS. BUT IN RECENT YEARS, THEY HAVE BEGUN TO FOCUS UPON HOW THEY CAN USE THE REMARKABLE -- AS AN EXAMPLE, COMPUTING CAPABILITY, TO TACKLE BIOMEDICAL PROBLEMS. AND WE ARE JUST DELIGHTED TO BE PART OF THAT ENDEAVOR. SO, I END WITH AMPLE TIME FOR QUESTIONS. AND I WANTED TO SAY THANK YOU VERY MUCH FOR SERVING TODAY. THANK YOU EVERYONE FOR BEING HERE TODAY. AND I'LL ANSWER ANY QUESTION YOU MIGHT HAVE. >> OKAY. THANK YOU, ETHAN. WE HAVE ADEQUATE TIME FOR QUESTIONS. >> THIS IS SORT OF MAYBE NOT THE BEST TO START WITH BUT I'LL THROW OUT A QUESTION FOR YOU. MAYBE NEW THIS BOARD, WHAT I NOTICE SAID THERE IS A BIG COLLECTION OF AMAZING PROJECTS THAT YOU HAVE THERE. BUT YOU ARE A SEPARATE ENTITY. YOU'RE OUT HERE IN A DIFFERENT PLACE. A NATIONAL LABORATORY, WHAT IS THE PURPOSE AND HOW CAN WE TAKE ADVANTAGE OF THE FACT THAT YOU'RE NOT JUST ADDITIONAL SPACE, SAY, FOR THE NCI? IS THERE SYNERGY OUT THERE OR A REASON TO HAVE A SEPARATE ENTITY AND MAYBE WE CAN DO THAT ON PURPOSE SOMEHOW? >> WHAT A GREAT QUESTION TO BEGIN THE CONVERSATION. THERE ARE MANY WAYS THAT I CAN APPROACH YOUR QUESTION WHICH I APPRECIATE. I WASN'T AWARE OF THE OAF - AS YOU SAID, THE REMARKABLE CAPABILITIES OF THE FREDRICK NATIONAL LABORATORY. AND PART OF MY GOAL IS TO BE A SPOKESPERSON AS I'M DOING NOW, TO EDUCATE STAKEHOLDERS TO SEE WHAT IS HOBBLE. I CITED SOME OF THE WORK -- POSSIBLE -- DANE SINGER AND HER MOONSHOT TEAM HAVE ENABLED. I SHOWED YOU AN EXAMPLE OF WHAT WE ARE DOING WITH JIM DOROSHOW. I DON'T THINK IT IS FULLY APPRECIATED, AT LEAST I DIDN'T FULLY APPRECIATE IT UNTIL COMING TO FREDRICK NATIONAL LAB, HOW MUCH OF OUR ACTIVITY SERVICE THE EXTRAMURAL COMMUNITY -- SERVES. I SHOWED YOU AN EXAMPLE OF THE TECHNOLOGY LABORATORY. REALLY 90sY% OF THE WORK, ROUGHLY, IS OF EXTRAMURAL FOCUS. I THINK ONE OF THE BEST EXAMPLES IS WHAT NED SHARP LESS POINTED TO -- SHARPLESS. REPURPOSEING THE AVAILABLE GMP FACILITIES FOR NODDIFIED T-CELL PRODUCTION. -- MODIFIED -- SO WE CAN EXTEND THE REACH OF FREDRICK NATIONAL LABORATORY BACK TO THE NCI AND HOPEFULLY IN THE FUTURE, TO THE EXTRAMURAL COMMUNITY. WHEN ITCHES AT MD ANDERSON -- I WAS -- WE HAD TRIALS IN THIS SPACE AND I ACUTELY KNOW HOW LIMITING HAVING A GMP FACILITY IS FOR A CENTER. AND YOU NEED TO HAVE WAYS TO EXPAND. THIS RESOURCE IS ONE THAT WE HAVE TO LEARN FROM HOW WE CAN MUCH MORE EFFECTIVELY PRODUCE THE MODIFIED CELLS. I THINK THERE IS A QUIET REVOLUTION GOING ON. NED REFERRED TO IT ABOUT PROCESSING TABLE TOP CLOSED SYSTEMS WHERE INSTEAD OF TAKING WEEKS TO MONTHS TO PRODUCE CELLS, WE CAN DO SO IN A FEW DAYS. SO I THINK THAT WOULD BE A GREAT SERVICE AS WE DEVELOP INNOVATIVE WAYS TO EXPAND ENGINEERED T-CELLS. I GUESS I WASN'T JUST FAMILIAR AS I SHOULD HAVE BEEN HONESTLY WITH THE VACCINE PROGRAM. I CHAIR THE BOARD OF SCIENTIFIC COUNCILORS AT THE NCI WHEN THE COSTA RICA TRIAL WAS REALLY BEGINNING. I JUST SO IMPRESSED WITH WHAT IT HAS DONE AND THINK OF THE REACH. I THINK THOSE ARE A FEW EXAMPLES. THE OTHER IS THAT I WOULD INVITE YOU AND ANY MEMBER OF THE EXTRAMURAL COMMUNITY WANTS TO LEARN MORE, THAT WE WOULD BE GLAD TO PROVIDE YOU MORE DETAILED INFORMATION. INCOME LINE WITH ALL THE RULES AND REGULATIONS ASSOCIATED WITH YOU BEING ON THIS PANEL. WE WOULD WELCOME THE OPPORTUNITY TO EDUCATE. I DON'T KNOW IF THAT ADDRESSES YOUR QUESTION BUT IT WAS A GOOD FAITH EFFORT. >> WHAT YOU LISTED AGAIN, THE EXTRAORDINARY WORK YOU'RE DOING. AND MY QUESTION WAS HOW CAN WE BUILD SYNERGY AS A SEPARATE LOCATION -- >> SO WE USE THE WORD SYNERGY, I'D LIKED YOU TO CALIBRATE SYNERGY BETWEEN WHICH PARTNERS? NCI? >> EXTRAMURAL SUPPORT. SO MAYBE YOUR UNIQUE ROLE IS TO BUILD LAW MIGHT CALL SUPER COAL FACILITY. SO EXTRAMURAL IMMANENTY. I DON'T KNOW IF WE NEED A THEME OR IF WE SHOULD TREAT THE LABORATORY AS A COLLECTION OF EXCELLENT THINGS THAT ALMOST HELPS TO HAVE DEVELOPED THERE. >> LET ME TRY -- SO I ALSO HAD BEEN CONFUSED BY FREDRICK. I DIDN'T REALIZE THE SCALE AND SCOPE. AND WHEN YOU LOOK AT NCI FUNDING YOU ALWAYS SEE THAT SUBCONTRACT AS THE FIRST THING AND IT'S A LARGE NUMBER. SO I WAS CURIOUS AND I ASKED EVERY FORMER LIVING NCI DIRECTOR ABOUT FREDRICK NATIONAL LAB. AND I COME TO THINK ABOUT IT IN A SUBSTANTIALLY DIFFERENT MANNER FROM BEFORE STARTED. FREDRICK IS A REMARKABLE CAPABILITY GRANTED TO THE NCI BY THE CANCER ACT. AND IF WE DIDN'T HAVE IT, WE WOULD DESPERATELY WANT IT. IT ALLOWS US TO DO THINGS THAT ARE VERY IMPORTANT FOR THE CANCERSHIP ENTERPRISE. NAMELY SPECIFIC ADVANTAGES TO THE SPEED WITH WHICH WE CAN DO NEW STUFF. SO IT IS A CAPABILITY THAT IS VERY, VERY VALUABLE TO THE NCI. AND BUT BY DEFINITION, IT'S ALSO SORT OF TAKE ON NEW THINGS WHERE SPEED IS AN ISSUE. SO IT HAS TO HAVE A LITTLE BIT OF EXTRA CAPACITY BECAUSE WE HAVE TO BE ABLE TO TAKE ON SOMETHING NEW LIKE CELLULAR MANUFACTURER OR HIV SEROLOGY OR WHATEVER -- AND BY DEFINITION IT WILL TAKE ON DISPIRIT THINGS. THERE WILL BE NO UNITING THINGS ACROSS ALL FREDRICK ACTIVITIES. I THINK IT WAS DR. VARMUS WHO ALSO STARTED WITH SOME SKEPTICISM ABOUT FREDRICK AND AS HE LEARNED MORE ABOUT IT, HE DECIDED IT WAS VERY, VERY IMPORTANT. SO WE WILL HAVE FREDRICK AND IT HAS TO BE AWESOME. AND THAT WAS A DECISION THAT TO STEREO GET THE RAS INITIATIVE AND TO GET REALLY GREAT SCIENCE, AND WE THINK ABOUT HOW IT INTERACT WITH ACADEMIA AND TO CONSIDER A NUMBER OF NOVEL IDEAS. SO THE TRAJECTORY IS QUITE GOOD BUT WE NEED TO CONTINUE THAT. WE NEED TO THINK ABOUT HOW TO USE IT AND HOW TO BALANCE THESE SPECIAL CAPABILITIES THAT ARE VERY IMPORTANT TO THE NCI WITH EXCITING SCIENCE AND KEEPING IT A CUTTING-EDGE MODERN FACILITY THAT IS A VALUE TO THE EXTRAMURAL COMMUNITY AND NOT JUSTANCH INTRAMURAL PROGRAM. SO THAT IS WHY YOU'RE HERE. WE NEED HELP WITH THAT. WE NEED EXTRAMURAL PERSPECTIVE. >> I'M A FAN. DON'T GET ME WRONG. BUT THAT LAST SENTENCE EXPLAINED IT. SO SPEED AND ALSO FACILITIES THAT ARE USED BY THE EXTRAMURAL COMMUNITY. AND THAT IS SOMETHING TO TRY TO UNDERSTAND FOR US. >> THE OTHER THING YOU SAID IS THAT IS WHY WE ARE HERE. THAT'S PART OF THE ROLE OF THIS COMMITTEE. >> THANK YOU VERY MUCH FOR THE OVERVIEW AND CONGRATULATIONS ON TAKING THIS ON. BUT ONE OF THE ASPECTS OF FREDRICK THAT I DIDN'T SEE MENTIONED WAS REALLY THE VAST RESOURCE OF THE MOUSE MODELING OR THE MOUSE STRAIN REPOSITORY. AND I'D LIKE TO KNOW WHAT THE STATUS OF THAT IS AND HOW, WITHIN YOUR PER VIEW AND COLLABORATION, PERHAPS WITH NCI, YOU CAN 11 THAT RESOURCE BETTER FOR THE EXTRAMURAL COMMUNITY. TING IS REALLY AN UNDERUTILIZED RESOURCE. >> DO YOU WANT TO MENTION ANYTHING ABOUT THAT? BECAUSE WE HAD A LOT OF CONVERSATIONS ABOUT THIS. >> SO, THE MOUSE REPOSITORY THAT YOU'RE REFERRING TO WAS ESTABLISHED ABOUT 15-20 YEARS AGO THROUGH THE MOUSE MODELS OF HUMAN CANCER CONSORTIUM AND TAKES IN A NUMBER OF LARGE NUMBER OF MOUSE MODELED STRAINS THAT ARE NOT AVAILABLE THROUGH OTHER SOURCES AND MAKES THEM AVAILABLE TO THE COMMUNITY. WE HAVE CONTINUED TO GROW THAT RESOURCE TO TAKE IN MODELS THAT ARE GOING TO BE OF INTEREST TO THE GENERAL COMMUNITY AND THEN SEND THEM OUT AS CRYOPRESERVED NOW PROBABLY MOSTLY CRYOPRESERVED PERSONNEL AT NO COST TO THE COMMUNITY. -- AND WE CONTINUE TO WORK WITH STEVE JONES ON THE REPOSITORY TO MAKE IT MORE USEABLE AND MORE INTERESTING RESOURCE AND THERE ARE AREAS THAT YOU THINK THAT WE CAN IMPROVE, WE WOULD LIKE TO HEAR ABOUT IT. >> I WOULD ADD TO WHAT YOU JUST SAID AND ALSO SAY WAYS WE CAN IMPROVE THE COMMUNICATION ABOUT THE RESOURCES. A LOT OF EFFORTS. THIS IS WHAT DEANA SINGER AND I HAVE BEEN WORKING ON TO COMMUNICATE. BUT IT'S NOT BEEN PICKED UP TO THE EXTENT THAT WE WOULD HAVE THOUGHT. I DON'T KNOW IF WE USED TWITTER YET BUT WE HAVE USED SOCIAL MEDIA AND OTHER MECHANISMS BUT THERE IS REALLY AN EDUCATION NEED. CAN I JUST TAKE A MOMENT AND CIRCLE BACK TO THE LAST CONVERSATION? I WANTED TO ADD ONE MORE POINT THAT IS SOMETHING I LEARNED SINCE MY ARRIVAL AT FREDRICK. AND WE HAVE MANY PROJECTS UNDERWAY AND WHAT YOU MIGHT NOT BE AWARE OF, AND I CERTAINLY WASN'T, IS I SPEND TYPICALLY HOURS A DAY ON CONFERENCE CALLS WHICH ARE MONTHLY READ OUT OF HOW WE ARE DOING. AND SO WE ARE HELD TO AN INCREDIBLE TIMELINE. THIS IS WHAT NED WAS REFERRING TO. AND IF WE GET OFF THE TIMELINE, I CAN ASSURE YOU WE HEAR ABOUT IT AND WE HAVE TO HAVE PLANS. AND REMEMBER OUR WORKFORCE DOESN'T HAVE TENURE SO WE HAVE A FLEXIBILITY THAT DOESN'T ALWAYS EXIST IN THE ACADEMIC COMMUNITY. THE INSIGHT THAT I'M TRYING TO GIVE YOU AS A NEW MEMBER LOOKING AT THIS, WHAT IS DIFFERENT FROM HOW WE CONDUCT BUSINESS AND THE EXTRAMURAL COMMUNITY, IT IS A TIMELINE OF PROJECTS THAT ARE PRE-SET METRICS. WE HAVE TO COMPLY WITH THOSE AND THERE IS AN INCREDIBLE COMMITMENT TO STAY ON THE TIMELINE. PROJECTS THAT BECOME RED FLAGGED ARE PROJECTS THAT I HEAR ABOUT THE MOMENT IT OCCURS AND WE DEVELOP MEDICATION PLANS IMMEDIATELY. SO, I HOPE YOU DON'T TAKE THE CONVERSATION IN RESPONSE TO YOUR QUESTION, THAT IT WAS JUST A CATALOG. IT IS NOT MEANT TO BE THAT. IT WAS JUST NO, I DON'T GIVE A SENSE OF THE SCOPE BUT THERE IS SCIENCE WE PARTNER WITH OTHERS TO MAKE THAT HAPPEN. >> WE HAVE REALLY BEEN TRYING TO UNDERSTAND YOUR UNIQUE ROLE AND PART IS WHAT THE CONTRACTS THAT HAPPENS INTRAMURALLY. AND THAT IS INTERESTING. AND YOU PROVIDE FLEXIBILITY AND THE ABILITY TO EXPLORE NEW AREAS AND CHANGE THEM QUICKLY. I'M BEGINNING TO UNDERSTAND IT IS IMPORTANT FOR US TO ASK QUESTIONS. >> I WELCOME THE QUESTIONS. >> ANIMAL FACILITIES AND STRAIN REPOSITORY QUESTION. ONE OF THE VERY FIRST MEETINGS OF THIS COMMITTEE BACK IN 2011, THERE WAS A DISCUSSION ABOUT WHETHER THERE SHOULD BE SOME CONSIDERATION OF THE BEST ANIMAL MODELS FOR SCREENING. INDUSTRY WAS PARTICULARLY INTERESTED IN THIS AND THERE WAS A THOUGHT OF WHETHER IT WOULD BE POSSIBLE FOR ACADEMA TO IDENTIFY A SET OF ANIMAL MODELS THAT COULD BE USED IN TESTING COMPOUNDS. AND THAT MAY BE UNREALISTIC GIVEN THE BREATH OF CANCERS WE KNOW THERE ARE BUT WITH THE REQUIREMENTS THAT -- NOT REQUIREMENTS, BUT DESIRE FOR ANIMALS TO HAVE INTACT IMMUNE SYSTEMS TODAY, MAYBE IT IS WORTH REVISITING THAT DISCUSSION AND MAYBE LEVERAGING THE FACILITY BETTER THAN IT HAS BEEN. >> I THINK THAT IS A FABULOUS IDEA. I CHAIRED FOR ABOUT 10 YEARS THE NCI PREVENT CANCER PANEL, AND THAT WAS A PANEL THAT OVERSAW LATE PRE-CLINICAL DEVELOPMENT ANIMAL MODELS FOR PREVENTION. AND UNDER BARRY KRAMER'S LEADERSHIP, WE UNDERTOOK A SEVERAL-YEAR EFFORT TO HONE ALL THE MODELS DOWN THAT WERE BEAUTIFUL BIOLOGICAL MODELS BUT THEY WERE NOT ALWAYS PREDICTIVE OF CLINICAL ACTIVITY AND PREVENTION AGENTS. THAT WHITTLING DOWN WAS AN INCREDIBLY PRODUCTIVE EXERCISE. AND NOW THE MODELS THAT THEY HAVE IN THEIR REPOSITORY ARE QUITE PREDICTIVE OF HUMAN RESPONSE. SO I TAKE TO HEART YOUR SUGGESTION AND MAYBE DR. AND SINGER AND I CAN TALK ABOUT THAT OFF LINE. THAT'S A GREAT QUESTION. >> DID YOU HAVE A QUESTION? >> NATIONAL LABS HAVE A SPECIAL RODE -- A SPECIAL ROLL AND DECIDE WHAT NOT TO DO. SO HAVE YOU IN YOUR -- SOMETIMES IT'S REALLY IMPORTANT WHAT THEY DON'T DO BECAUSE SOME THINGS COULD BE DONE BY THE EXTRAMURAL COMMUNITY. HAVE YOU GOTTEN A SENSE JUST NOT ON THE NIAID SIDE BUT PURELY ON THE NCI SIDE, IF A PROJECT COMES TO YOU, HAVE YOU DEVELOPED A RULE OF THUMB OF WHEN YOU SHOULD NOT DO IT? WHEN IT IS BENEFITS DONE BY SOMEONE ELSE? >> LET ME JUMP IN. THE OFFICE OF SCIENTIFIC OPERATIONS THAT KRISTEN IS DEEPLY INVOLVED WITH ACTUALLY MAKES A DECISION FOR EVERY REQUEST THAT WOULD GO TO THE NATIONAL LABORATORY AND NOT IN FREQUENTLY DETERMINE THAT IT IS NOT MOST SUITABLE. WHAT OSO TRIES TO DO IS NOT JUST TO SAY WE ARE NOT YOUR WAITER, BUT IN ADDITION TO TRYING TO PROVIDE SOLUTIONS FOR WHATEVER THE SCIENTIFIC ISSUE THAT IS TRYING TO BE ADDRESSED. >> KRISTEN? >> SO WE GOT THE CONTRACTING OFFICER OVER THERE SO I HAVE TO MAKE SURE I'M TALKING CORRECTLY ABOUT THE FAR. BUT THE FEDERAL ACQUISITION REGULATION STATES SPECIFICALLY THAT FFRDC CAN'T COMPETE WITH COMMERCIAL SECTOR AND SO OUR MAIN MANTRA IS THAT IF IT CAN BE DONE AS EFFECTIVELY BY ANOTHER GOVERNMENT MECHANISM, GRANTS, INTRAMURAL RESEARCH, OTHER CONTRACT MECHANISMS AND THAT KIND OF THING, IT SHOULDN'T BE DONE AT THE FFRDC. SO WE USE THAT AS OUR CENTRAL FOCUS. >> EVEN AFTER SOMETHING IS DEEMED TO BE APPROPRIATE TO BE DONE, WE TRIED TO MAKE IT WORK BUT NOT EVERYTHING IS AS SUCCESSFUL AS EVERYTHING ELSE. AND THERE ARE PROJECTS THAT NEED TO BE CHANGED SUBSTANTIALLY. >> TO UNDERSCORE, YOU GOT A SENSE OF HOW THE FILTERING PROCESS GOES ON IN TERMS OF PROJECTS THAT MOVE FORWARD. I CAN TELL YOU THAT THE SCIENTIFIC QUESTIONS THAT ARE BEING ASKED PROVIDE READY OPPORTUNITY FOR INPUT BY MYSELF AND A NUMBER OF OTHER PEOPLE AND I'M INVOLVED IN SO MANY PROJECTS TO MAKE SURE THAT WE GET THE MOST EFFECTIVE WAY FORWARD. AND YOU WILL HEAR SOME EXAMPLES OF THAT PERHAPS IN JIM'S PRESENTATION OR RALPH'S. SO THIS IS ANNOTATIVE PROCESS. IT'S NOT ONE THAT IS CHISELED IN STONE WHEN IT COMES TO US AND WE HAVE READY OPPORTUNITY TO HELP THE SCIENCE BECOME AS IMPACTFUL AS POSSIBLE. I HAD AN ADDITIONAL QUESTION. THE SLIDES YOU SHOWED NEAR THE END DESCRIBING WHAT ONE MIGHT CONSIDER NEW EDUCATIONAL INITIATIVES, AN OUTREACH AND ALSO MORE TRAINING AND PARTNERSHIPS WITH GEORGETOWN COLLEGE. IT SEEMS TO BE RELATIVELY NEW, MAYBE ON YOUR WATCH, IN FACT. SO I'M VERY INTERESTED IN THAT. THERE HAD BEEN DISCUSSION AT THIS BOARD OR COMMITTEE YEARS AGO ABOUT VISITING SCHOLAR PROGRAMS, POSTDOCTORAL PROGRAMS, ARE WE SEEING WHAT YOU MAY BE THINK OF AS THE LEADING EDGE OF GREATER EDUCATIONAL PROGRAMS AT FREDRICK? >> WELL SAID. YOU CAN SEE THE MODEL I'M USING TO BRING NEW POSTDOCTORAL TRAINING TO HAVE A SPONSORING INSTITUTION TO SUPPORT. THAT IS THE MODEL WE ARE USING AND WILL PROBABLY HAVE OUT ANOTHER COLLABORATION SOON. THE VISITING SCHOLARS PROGRAM IS A FASCINATING IDEA THAT I FIND IT REALLY INTRIGUING WAY TO MOVE FORWARD IN A SENSE. ROOK AT WHAT FRANK HAS DONE AS AN EXAMPLE OF A VISITING SCHOLAR WHO BRINGS NEW INSIGHTS TO HELP THE NATIONAL LABORATORY TO ACHIEVE ITS REACH. I EMBRACE THAT IDEA AND WHAT I'M TRYING TO -- WHAT I'M REFLECTING ON IS HOW THAT COULD BE DONE IN A COST EFFECTIVE WAY. WE SEE THE VALUE OF BRINGING IN SOMEONE FROM THE EXTRAMURAL COMMUNITY. WE'LL HAVE THOSE DIFFERENT INSIGHTS THAT WILL BE PERHAPS HOW WE MIGHT DO SCIENCE IN A DIFFERENT WAY. AND NED AND I COME FROM THE EXTRAMURAL COMMUNITY. SPENDING YOUR WHOLE CAREER WORKING HARD TO BE RL1 FUNDED GIVES YOU INSIGHT INTO WHAT IS PRACTICAL AND WHAT IS DOABLE AND THE NCI HAS A GOAL TO ASK QUESTIONS THAT ARE HIGH-RISK, HIGH-GAIN. AND EXTRAMURAL INVESTIGATOR CAN BRING THAT PERSPECTIVE IN WHAT WOULD BE OF THE HIGH RISK, HIGH GAIN, WHAT WOULD BE THE MOST LIKELY TO MOVE FORWARD? I HAVE BEEN THINKING A GREAT DEAL ABOUT THE SCHOLARS PROGRAM. WE HAVE IDEAS ABOUT WHO WOULD BE APPROPRIATE BUT WHAT WE WANT TO DO IS NOT DO TOO MUCH. WE WANT EVERYTHING WE ARE LAUNCHING TO BE ACHIEVED AND I'M THINKING ABOUT THAT PROGRAM MORE IN THE NEXT YEAR AND IT WOULD BE A WAY TO BEGIN THE CONVERSATION TO BENEFIT FROM FREDRICK NATIONAL LABORATORY. YOU COULD ENVISION ALL SORTS OF CREATIVE WAYS THAT COULD HAPPEN. THERE MIGHT BE PROJECTS THAT MIGHT BE JOINTLY RUN. IT MIGHT BE EXCLUSIVELY RUN. MAYBE AT CCR OR NCI. AND WE WOULD SUPPORT AND A LOT OF FLEXIBILITY IN THAT MODEL. IT IS A DISTINCT MODEL THAT HAS VALUE. >> I HAVE A QUESTION. IF YOU LOOK AT MANY OF THE NATIONAL LABS THAT ARE INVOLVED IN SCIENCE, THEY ARE DIFFERENT FROM THE -- LAB BECAUSE THEY HAVE A VERY DEFINITIVE MISSION. MANY OF THE INITIATIVES THAT THOSE LABS PROPOSE, THEY CONSIDER THE NEEDS OF THE AGENCY AND THE NEED OF SCIENCE BUT THEY DRIVE THE INITIATIVES INTERNALLY AND INVENT NEW PROJECTS AND I DON'T HAVE A GOOD SENSE OF HOW MUCH OF YOUR PROGRAM IS INVENTED AT YOUR LAB AS OPPOSED TO GIVING TO YOU AS A JOB. BECAUSE THERE IS A NEED IN THE COMMUNITY. AND PERHAPS YOU COULD TELL US A LITTLE BIT ABOUT THAT BECAUSE I THINK TO THE EXTENT YOU DO MORE AND MORE SCIENCE, YOU HAVE ALSO, BECAUSE YOU HAVE ALSO THE CAPABILITIES INTERNALLY TO INVENT THE NEW THINGS THAT ARE NEEDED. FOR EXAMPLE, IF YOU LOOK AT ELECTROMICROSCOPY, RIGHT NOW, YOU ARE TAKING COMMERCIAL MICROSCOPES AND SETTING UP A PROGRAM WHERE THE COMMUNITY CAN USE IT THERE IS A WHOLE SET OF STUDIES OUTSIDE OF YOUR ORGANIZATION THAT LOOKS AT THE LIMITS OF WHAT YOU CAN ACTUALLY CRYOELECTROMICROSCOPY WHICH SEEMS TO BE A BIT BEYOND WHAT THE STATE-OF-THE-ART IS. AND CRYOELECTROMICROSCOPY FOR YOUR MOLECULAR SYSTEMS IS SO IMPORTANT THAT YOU COULD START FOR EXAMPLE AN INITIATIVE WITH OTHERS TO TAKE THE NEXT STEP IN CREATING THOSE MICROSCOPES. THAT WOULD BE A ROLE FOR A NATIONAL LAB WHERE THE LAB LOOKS AT THE GENERAL PICTURE AND INVENTS A NEW PROGRAM. SO I'D LIKE TO UNDERSTAND THE BALANCE OF THAT BECAUSE I THINK IN TIME, THE HOPE THAT I UNDERSTOOD FROM HAROLD VAR VARMUS IS YOU BECOME MORE LIKE THE OTHER LABS INITIATING NEW IDEAS AND NEW PROGRAMS. AND I DON'T GET A GOOD SENSE OF WHAT THAT BALANCE IS. >> SO LET ME ADDRESS THE LAST ASPECT FIRST. IF YOU'RE PATIENT FOR A FEW MOMENTS, YOU WILL HEAR FROM DR. DR. SUBRAMANIAM ABOUT HIS IDEAS HOW TO TAKE ADVANTAGE OF THE NEW IMAGING SCIENCE. THE NATIONAL LABORATORY COMMUNITY IS ONE THAT I WAS NOT AS FAMILIAR WITH AS I AM NOW. THERE IS 17 NATIONAL LABS AND I AGREE WITH YOU THAT THEY ARE ENGINES OF DISCOVERY. THEY HAVE INTERESTING SOCIOLOGY ENERGY WILL LAUNCH COMPETING PROJECTS TO SEE THE BEST IDEA WENT OUT. WHAT YOU CAPTURED IS THE MOMENT OF WHERE WE ARE IN THE EVOLUTION OF BECOMING A NATIONAL LABORATORY. WE ARE IN TRANSITION. WE ARE NOT YET AT THE LEVEL OF OAKRIDGE OR LIVER MORE, ET CETERA. WHAT I HAVE BEEN DOING TO TRY TO UNDERSTAND HOW SCIENCE IS CONDUCTED IN THAT SPACE IS I HAVE BEEN MEETING WITH OTHER LABORATORY DIRECTORS. MET WITH THE OAKRIDGE DIRECTOR AND I WILL BE VISITING LIVER MORE SOON AND PLAN TO MEET WITH A NUMBER OF THE LABORATORY DIRECTORS. IT WAS DIFFERENT THAN AT OTHER NATIONAL LABORATORIES BECAUSE THIS INSTITUTION HAS COME ABOUT AS I SHOWED THE TIMELINE. IN A SENSE, BEING OF SERVICE TO THE NCI LARGELY AND THEN ULTIMATELY NIAID. WE HAVE A WAYS TO GO AS AN HONEST STATEMENT AND ASSESSMENT. I TRIED TO GIVE YOU A SENSE OF HOW WE ARE TRYING TO BRING IN NEW DISCOVERY AND TRANSLATIONAL SCIENCE WHICH IS WHY I JUST TOUCHED ON WHAT MY LAB WILL BE WORKING ON. IT ISN'T AN AREA THAT IS OVERLAPPING WITH WORK GOING ON RIGHT NOW AT CCR AS FAR AS I CAN TELL. AND PART OF MY RESPONSIBILITY IS TO ARTICULATE A CRISP 0 TO THAT QUESTION OVER THE NEXT TIMES THAT WE MEET TOGETHER. I EMBRACE THAT CHALLENGE. AND IT'S AN APPROPRIATE QUESTION. >> WE ARE RIGHT ON THANK YOU FOR LEAVING ADEQUATE TIME FOR DISCUSSION. WE WILL COME BACK AT 11:00. THE COLLECTIVE SENSE WAS THAT CRYO WAS A TECHNOLOGY THAT WAS GROWING RAPIDLY IN TERMS OF CAPABILITIES AND APPLICATIONS AND THIS WOULD BE AN IMPORTANT THING TO TAKE ON THEA THE NATIONAL LAB AND EVENTUALLY IT WAS APPROVED BY THE FNLAC AND AFTER A YEAR OF SET OF TIMES, WE GET THE ROOM SET UP, MICROSCOPES, THE PEOPLE, WE PROUDLY LAUNCHED THIS A YEAR AGO AND THERE'S A WEBSITE, THERE'S A LOST INFORMATION ON THERE. SO, WHAT I WANT TO DO TODAY IS TO TOUCH ON 3 TOPICS. FIRSTLY, JUST TO PROVIDE A GENERAL INTRODUCTION TO THE VERY RAPID GROWTH IN THIS FIELD. I ALSO SHARED WITH YOU IN THE CONTEXT OF THE EARLIER DISCUSSION, SOME EXAMPLES OF RECENT WORK IN MY LAB IN THE NCI IN THE INTRAMURAL PROGRAM AND THE IDEA OF THE LAB REALLY WAS MY PARTICIPATION WAS TO FIND A WAY TO TRANSITION THINGS SO WE WERE DOING TO BE ABLE TO SUPPORT THE WORK NATIONALLY I HAVE AT NATIONAL LAB. I WANT TO BRIEFLY TOUCH ON PERFORMANCE AND HAVE YOU, VALENTINEDUATE HOW WE'RE DOING OVER THE LAST YEAR, SHARE METRICS WITH YOU AND ALSO OPEN THE FLOOR FOR DISCUSSION AND IDEAS FROM YOU ON WHAT YOU THINK WE MIGHT BE DOING IN FUTURE YEARS AND HOW IT MIGHT SERVE ITS MISSION BETTER. HERE'S A PART FROM THE E. M. DATA BANK WITH THE CRYO STRUCTURES WORLD WIDE AND IT TALKED ABOUT HOW THE FIELD HADZ BEEN GROWING RAPIDLY AND FOR THE LAST SEVERAL YEARS OVER A DECADE OR SO, BUT IF YOU LOOK AT THE REAL EXCITEMENT, THE RIGHT EDGE OF THIS PLOT FOR THE STUDIES SO PREVIOUSLY I ENDED UP WITH THE CRYSTALLOGRAPHY AND NOW WE CAN GET THIS INFORMATION WHICH HAS A PROFOUND IMPLICATION THIS WAS AWARDED TO THE APPROXIMATE PIONEERS THAT LED TO THIS REVOLUTION TODAY. THERE'S ANOTHER SORT OF INTERESTING ASPECT TO THE GROWTH OF THIS FIELD WHICH IS THAT HISTORICALLY IN THE EARLY DAYS OF KRIST O-EM, MOST OF THE WORK WAS FOCUSED ON LARGE SYMMETRIC OBJECTS OR PERHAPS LARGE ASYMMETRIC OBJECTS BUT THE ACCOUNT FACT THAT THEY'RE LARGE WAS IMPORTANT BECAUSE IT WAS EASY TO ALIGN THE IMAGES AND THIS LED TO WORK ON I HAVE RAWSS VIRUSES RIBOSTUDIES OF MULTIPLE ENDOCRINES AND THE LIKE. PROTEIN COMPLEXIO STUDIES OF MULTIPLE STUDIES OF MULTIPLE ENDOCRINES BUT 1 OF THE IMPORTANT THINGS THAT HAS CHANGED WHICH IS RELEVANT TO OUR MISSION IS THAT NOW THERE'S A MUCH LARGER SPECTRUM OF TARGETS IF YOU WILL, PROTEIN COMPLEXES THAT CAN BE ANALYZED BY KRIST O-EM BUT THERE'S USEFUL INFORMATION THAT GUIDES STUDIES THINGS SUCH AS DRUG DESIGN AND IT REALLY NOW OPENS IT UP TO THE LARGER BIOLOGICAL COMMUNITY AND OUR IDEA WAS THAT THIS WOULD BE VERY IMPORTANT FOR THE CANCER RESEARCH OPPORTUNITY TO TAKE ADVANTAGE OF GIVEN THE RAPID PACE OF THESE DEVELOPMENTS.I'D LIKE TO QUI CKLY GO THROUGH THIS TO HIGHLIGHT THAT IN EACH OF THESE 4 CASES IF YOU ME ORIGINAL--OR ANYONE ELSE, COULD YOU DO THIS WITH CRYO, VERY DIFFICULT. BUT NOW TWHA WE CAN DO THEM, DIFFERENT RES CAN BE TAKEN ON. THE FIRST 1 WAS ON IDH1, AND MUTATIONS OF IDH1, A SINGLE POINT MUTANTS OF 32, LEAD TO A CHANGE IN METABOLISM INSEDENTARY OF GETTING THE GLIEWTERATE, THE ENZYME PRODUCES 2 HYDROXY GLIEWTERATE AND THE METABOLITE, I BECAME INTRODUCED THROUGH THIS WORK THROUGH PEOPLE AT NCATS AND THIS LED TO A PAPER A COUPLE OF YEARS AGO WHERE WE DEMONSTRATE THAD--DEMONSTRATED THAT THESE COULD BE TACKLED BY CRYOEM AND A COUPLE RLGT WAS REALLY THE FIRST FOR THE CONFIRMATIONAL IN THESE PROTEINS BUT IMPORTANTLY 1 THAT WE WERE INTERESTED IN WAS TO DEMONSTRATE THAT 1 COULD LOCALIZE DRUGS IN SMALL AND DYNAMIC PROSEENS SUCH AS AND THIS LED TO NEW INSIGHTS INTO WHAT HAPPENS WHEN THESE DRUG MOLECULES BIND THAT ARE SHOWN HERE IN RED AND TO THE VERY INTERESTING AND POTENTIALLY IMPORTANT CONFIRMATIONAL CHANGES THAT IS A RESULT OF WHAT HAPPENS WHEN THE DRUGS BIND. IT ALSO LETS US COMPARE THE BINDING SITES OF THIS MOLECULE, THE 1 WE DID WAS DEVELOPED AT THE NCATS, ML309 AND COMPARE THESE WITH THE OTHER REPORTER STRUCTURES. --SECOND EXAMPLE WAS WORK THAT WE DID IN COLLABORATION WITH THE NEXT CONSORTIUM WHICH WAS ALREADY MENTIONED THIS MORNING AND THIS WAS WORK DONE THROUGH THE CHEMICAL BIOLOGY CONSORTIUM WHERE THEY HAD A LOT OF INTEREST IN P97 AND FINDING MOLECULES THAT INHIBIT IT AND PARTNERSHIP WITH THEM, WE WERE ABLE TO ADVANCE STRUCTURAL STUDIES OF P97 AND DYNAMIC ENZYME AND DEMONSTRATE INTERESTING COMPOSITIONS BUT THIS COULD DO SOMETHING THAT PREVIOUSLY HAD NOT BEEN DONE IN THE CRYO-EM, THE BINDING SITE OF A SMALL MOLECULE THAT WAS BOUND TO THIS ENZYME. THIRD EXAMPLE WAS TO TAKE ON AWLINGS ANOTHER CLASS OF--ALSO ANOTHER CLASS OF PROBLEMS WHICH WAS VERY DIFFICULT TO DO BY KRIST O EM, THIS IS THE STRUCTURE OF THE CRSPR, AS TYPE 1 F, WHICH WE DID IN COLLABORATION WITH THE MEMORIAL SLOAN KETTERRING INSTITUTE AND ALSO HOW IT DETERS FROM THE INHIBITORS SO THERE WERE A NUMBER OF STRUCTURES WE REPORTED HERE AND WHAT WAS INTRIGUING WAS THAT FOR THE FIRST TIME WE COULD VISUALIZE THESE TYPES OF COMPLEX STRUCTURES WHERE THERE'S NO SYMMETRY, RELATIVELY SMALL AND TO BE ABLE TO DESCRIBE MECHANISTIC ASPECTS TO FIGURE OUT WHAT HAPPEN WHEN IS THESE INTERACT WITH THE DNA AND FINDINGS DISCOVERIES WAS THE CHANGE--DRAMATIC REDUCTION THETIC CHANGE IN PITCH OF THE GUIDE RNA AS A RESULT OF DNA BINDING. THE LAST EXAMPLE, ALSO RELEVANT TO CANCER IS WORK WE PUBLISHED RECENTLY AND THIS WAS AN INTRAMURAL COLLABORATION AT THE CENTER FOR CANCER RESEARCH WHERE WE TOOK ON A PROBLEM WHERE WE ARE LOOKING AT UNDERSTANDING STRUCTURAL ASPECTS OF CHROMOSOME SEGREGATION, WHEREAS YOU KNOW CHROMOSOME SEGREGATION REQUIRES ASSEMBLY OF CO-PROTEINS OF THE SENT ROW MERE WHICH IS EPIGENETICALLY MARKED BY NUCLEOSOMES CONTAINING THE HISTONE H3 VARIANTS AND WHAT WE SHOW SIDE THAT IT CONFINES BENDING SPECIFICITY THROUGH THE INTERACTION AT THE L1 GROUP, STABILIZED BY ELECTROSTATIC WITH THE NEW CLE O STUDIES OF MULTIPLE ENDOCRINAL DNA. THESE ARE CHALLENGING PROJECTS THESE STRUCTURES BOUND TO LARGE ENTITY LIKE THE NUCLEOSOME IS VERY, VERY EXCITING. SO THE IDEA FOR THE FACILITY WAS THAT PROBLEMS LIKE THIS WHICH ARE OBVIOUSLY IMPORTANT HAVE A NUMBER OF INVESTIGATORS WHO COULD BE USING THIS COULD BE DISSEMINATED VIA THE AH AH--AUSPICES OF THE THESE, THIS IS THE HEAD OF THE NIF NLCR, THIS OVERSEES THE PEOPLE WHO WORK AT THE NATIONAL KRIST O FACILITY WITH THE MICROSCOPY WHO OVERSEES A SMALL TEAM OF TOM EDWARDS, HELEN AND MATT HUTCHISON WHO WORK TOGETHER TO MAKE THIS--MAKE THIS HAPPEN AND ESSENTIALLY PROVIDE VERY POWERFUL RESOURCE FOR THE EXTRA MURAL RESEARCH COMMUNITY. IF YOU LOOK AT THE PERFORMANCE, ETHAN PRESENTED SOME OF IT. THIS IS A SLIGHTLY MORE UPDATED VERSION. WE'VE DONE OVER 90 PROJECTS IN THE LAST YEAR, FROM 20 DIFFERENT INSTITUTIONS, THEY'RE FROM ALL OVER THE U.S., SOME OF THEM HAVE SEVERAL ADVANCED FACILITIES OF HEIR OWN. THEY STILL SEE SOME VALUE IN COMING TO US. MANY OF THESE INSTITUTIONS DON'T HAVE ACCESS TO THESE HIGH END MICROSCOPES AND THAT WAS 1 OF THE ORIGINAL GOALS TO BRING THESE TECHNOLOGIES TO THEM AND IT HAS BEEN BY THIS MEASURE VERY SATISFYING EXPERIENCE TO BE ABLE TO PROVIDE THE FACILITIES WHERE WE LOWERED AMONG THE MANY THINGS WE COULD DO. ONE OF THE PRINCIPLE BARRIERS AT THAT TIME WAS THE MERE FACT TO ACCESS TO THESE VERY EXPENSIVE MULTIIN ILLEGALSION DOLLAR MACHINES THAT PEOPLE DIDN'T HAVE TO FIRST GO OUT AND BUY THEM AND EVEN IF YOU BOUGHT THEM TO RUN THEM AND HAVE THEM WORK ROUTINELY THESE ARE VERY CHALLENGING THINGS SO THE LOWERING OF THE BARRIER TO COLLECT DATA, WORTH WHILE DATA THAT WAS PROCESSED WAS IMPORTANT AND THIS IS WHAT WE'VE DONE AT THE END OF YEAR 1. USE THE PUBLICATIONS HAVE STARTED TO COME OUT, WE'RE VERY PLEASED TO SEE THIS AS ALL OF YOU KNOW, IT TAKES A LONG TIME BETWEEN ACTUALLY HAVING RESULTS AND HAVING THINGS PUBLISHED, IT TAKES 8 MONTHS OR SO AND WE ARE SEEING RESULTS OF DATA COLLECTED AT THE NATIONAL LAB, BEING REPORTED AND THIS IS REALLY 1 OF THE MISSIONS WAS TO FIND WAYS TO CATALYZE THIS AND SO, I THINK WE WILL SEE MORE IN THE YEARS TO COME. AT THE PREVIOUS PRESENTATION, I SAID THAT WE WERE BUILDING THIS FACILITY AT THE ATRF TO ACCOMMODATE MORE THAN 1 MICRO SCOPE, IT COULD TAKE UP TO4. THE PRESENT MICROSCOPE IS LOCATED IN THE FACILITY IN GATHERS BERG, WE ARE ON TRACK TO HAVE THIS COMPLETED BY JUNE. THAT'S THE HUGE OBJECT BEING LIFTED ACROSS THE--YOU CAN SEE THE SKYSCRAPER. FREDERICK IS SORT OF HIGHLIGHTED BY THIS AND IT'S NOW ESSENTIALLY VERY MUCH IN THE FINAL STAGES OF COMPLETION, WE EXPECT--EXPECT IT WILL BE DONE SOON. WE'VE HAD VERY POSITIVE FEEDBACK, FROM THE COMMUNITY AT THE END OF YEAR 1. UNIFORMLY PEOPLE HAVE BEEN HAPPY WITH WHAT THEY'VE HAD AND IT'S IN LARGE MEASURE BECAUSE OF THE COMPETENCY AND PROFESSIONALISM OF THE PEOPLE WHO WORK IN THE FACILITY WITH A SMALL TEAM BUT THEY ARE--COMMUNICATE EFFECTIVELY WITH THE PEOPLE THAT COME THERE, AND YOU KNOW ESSENTIALLY THE RESOLUTIONS WE ACHIEVE HERE AND THE THROUGH PUT IS COMPARABLE TO--COMPARABLE IF NOT BETTER TO WHAT IS ACHIEVED ANYWHERE ELSE IN THE WORLD. SO I WANTED TO KEEP MY PRESENTATION SHORT BECAUSE WE WOULD VERY MUCH YOUR THOUGHTS ON WHAT MIGHT WE DO? WE VIEWED THIS AS A LONG-TERM PROJECT WHERE WE THEED TO GET OFF THE GROUND BY SIMPLY DEMONSTRATING WE CAN PROVIDE THIS CAPABILITY AND I THINK WE WOULD VERY MUCH INTERESTED IN YOUR THOUGHTS ON HOW WE MIGHT INCREASE THE IMPACT OF THE NATIONAL--THE FACILITY WITH EXPANSION AND SCOPE OF ACTIVITIES AND TO PRIME THIS, I WANTED TO ADDRESS A QUESTION THAT CAME UP EARLIER IN TERMS OF TECHNOLOGY DEVELOPMENT. IN MY OWN LAB AT THE INTRAMURAL PROGRAM I'VE BEEN HERE ABOUT 17 YEARS. OVER A DECADE AGO, 12, 13 YEARS AGO, THE PROGRAM THAT I LAUNCHED WAS VERY MUCH IN THAT--SORT OF WITH THAT IN MIND. WHICH IS AT THAT TIME IF YOU GO BACK TO THE EARLY 2000S, IF YOU LOOKED AT THE OBJECT OF INTEREST IN BIOLOGY, THE PROTEINS, VIRUSES, LIKE HIV, BACTERIAL CELLS, OLD TISSUE, WE REALLY DID NOT HAVE VERY GOOD METHODS TO STUDY THEM IN 3D. AND THE PROGRAM THAT I LAWRCHED HERE AND--LAUNCHED HERE AND OTHER LABS WORLD WIDE WAS WITH THE VISION THAT THEY WOULD COME BUT ELECTRON MICROSCOPY COULD GET TO THE ATOMIC RESOLUTION WITH THE PROTEINS AND THIS WAS ALMOST AN IMPOSSIBLE DREAM FOR MANY OF US, BUT THERE WERE A FEW BELIEVERS INCLUDING ME. THIS IS WHAT WE WORKED TRS. SIMILAR WITH HIV, WE PUBLISHED THE FIRST STRUCTURES OF GLYCO PROTEINS ON INFECTIOUS VIRUSES, THE IDEA YOU COULD DO TOMOGRAPHY TO GET THESE STRUCTURES ALSO WAS VERY FAR FETCHED BUT THE TOPOGRAPHIC METHODS WERE BEING JUST IN INFANCY AT THIS TIME AND MUCH MORE POWERFUL. SIMILARLY LOOKING AT WHOLESALE AND SIGNALING ARRAYS AND INTACT SELLS, THAT'S ALSO SOMETHING WE DEVELOP AND ETHAN MENTIONED THE TECHNOLOGIES WE DEVELOP ON FOCUS ON NEW IMAGING, IN SOME SENSE, ALL OF THESE, THEY DON'T NECESSARILY HAVE TO BE DEVELOPED DIRECTLY IN 1 OF THE OTHER LABS BUT I THINK THERE'S AN OPPORTUNITY TO WORK WITH THE NEXT PHASE OF THESE TECHNOLOGIES AT THE NATIONAL LAB AND MAYBE THAT'S--MAYBE THAT'S WHAT YOU'RE REFERRING TO. THE FINAL SLIDE I WANT TO SHARE WITH YOU IS WHEN WE LAUNCH THE NATIONAL CRYO-EM FACILITY. THIS IS PART OF THE PRESENTATION I HAD 2 YEARS AGO. HIDEFINEED THE SETS OF THE USER COMMENTS THAT MIGHT BENEFIT FROM THIS AND DIVIDED THOSE IN 3 GROUPS. THE FIRST OF THESE WERE THE 1S WE WANTED TO TAKE ON AT FIRST. AND THIS WAS AT THAT TIME A RELATIVELY SMALL COMMUNITY AND IT HAS GROWN SIGNIFICANTLY IN THE LAST COUPLE OF YEARS AND THESE ARE PEOPLE WHO EITHER YOUNG INVESTIGATORS WHO ESTABLISHED THESE, AND PEOPLE ARE WORKING ON THIS CRYO-EM, AND THE TECHNOLOGY, AND SOME ACCESS TO LOCAL MICROSCOPES BUT UNIFORMLY DID NOT HAVE CERTAINLY 2 YEARS AGO, DID NOT HAVE ACCESS TO HIGH END INSTRUMENTATION BUT THEY--WE FELT WOULD BE THE KEY DRIVERS OF GROWTH OF THIS FIELD IN THE U.S. AND THOSE ARE THE 1S WE TOOK ON IN THE FIRST PHASE AND FROM THE--NEARLY A HUNDRED PROJECTS WE'VE DONE, WE SLEEP APNEA AND OBESITY THAT'S EXACTLY WHAT HAPPENED. OUR VISION WAS THAT IN STEP 2, WE WOULD--WE WOULD SEE A SECOND GROUP, PEOPLE ARE STRUCTURAL BIOLOGIST AND ADJACENT SPECIMENS, SPECT ORDER OF MICRONSETRY, AND UNDERSTANDING THIS STRUCTURES IN GBL AND THEY DON'T HAVE DIRECT EXPERIENCE IN CRYOAND SPECIMEN PREPARATION, DATA COLLECTION AND ESPECIALLY HANDLING THE RELATIVELY LARGE AMOUNTS OF DATA THAT COME UP, WE ARE TALKING TERRA BYTES THAT COME OUT OF SINGLE DATA COLLECTION SESSIONS. SO, OUR VIEW WAS THIS WOULD BE THE LOGICAL NEXT COMMUNITY, AND PHOTOCOPY WE LOOK AT THE GROWTH GROWTH--EVEN WITHIN THE LAST YEAR, WE ALREADY BEGAN TO TRANSITION, EARLIER THAN I WOULD EXPECTED INTO THIS COMMUNITY, A LOT OF CRYSTALLOGRAPHERS SCR PUBLICLY STATED THIS HAS TAKEN ON MORE OF A--MORE IMPORTANT IN THEIR OWN LABS THAN THEIR METHODS SO THEY'VE BEEN USING BEFORE SO THIS IS ALREADY HAPPENING. SO IT'S WORTH EVALUATING HOW BEST TO ADDRESS THIS PROBLEM. THIS COMMUNITY IS TRYING TO BE THE FIRST COMMUNITY IN GROUP 1 BUT GROUP 3 WHICH IS REALLY PROBABLY THE BY FAR THE LARGEST COMMUNITY BY ORDERS OF MAGNITUDE, A BIOLOGISTS AND RESEARCHERS ACROSS THE COUNTRY WHO WORKING ON BIOMEDICAL, BUT NOT STRUCTURALLY YOUAL BIOLOGIST BY TRAINING BUT AND THEY WOULD NEED HELP AT MULTIPLE LEVELINGS AND REALLY COLLABORATIONS THAT DRIVES THE SCIENCE, BASIC OR CLINICAL, I THINK THIS IS HOW WE THOUGHT THE--THE SEVERAL YEARS IN THE NATIONAL LEVEL WOULD PLAY OUT AND I THINK AT THE END OF YEAR 1, I THINK IF YOU TRANSITION FROM GROUP 1 OR TRANSITIONING FROM GROUP 1 TO GROUP 2, WE'RE I JUST WANTED STOP THERE AND I WOULD BE HAPPY TO--TO TAKE ANY OPEN THE DISCUSSION TO YOUR SUGGESTIONS, QUESTIONS. >> WE ARE OPEN FOR QUESTIONS. IS THERE ANY CHARGE FOR USE OF THE FACILITY AT THIS POINT. >> WE DO NOT CHARGE ANYTHING. >> AND IT'S GREAT TO SEE PUBLICATIONS WITH STRUCTURES COMING OUT, ARE THEY CITING THIS FACILITY. >> WE KEEP A CLOSE WATCH ALL THE 1S. >> THESE ARE CORE FACILITIES. >> HELEN KEEPS CLOSE WATCH AND ENCOURAGINGLYS THEM TO MAKE--PRESSURES THEM TO MAKE SURE THEY ACKNOWLEDGE US. >> OKAY. YES, CLAUS. >> DO YOU ENVISION A WAY THAT YOU CAN DEVELOP NEW CAPABILITIES HERE? HOW WOULD THAT HAPPEN? COULD YOU EXTEND THE FIELD ITSELF OR THE TECHNOLOGY? >> YEAH, IT'S A VERY GOOD QUESTION AND I KNOW THIS CAME UP EARLIER AS WELL. I THINK THE--WE VIEW THIS AS A LONG-TERM PROJECT AND TO PROVE OURSELVES, WE HAD TO GET OFF THE GROUND WITH THIS FIRST PHASE. BUT I THINK DEVELOPING THE NEXT GENERATION IS--COULD BE A VERY IMPORTANT MISSION AND MAYBE DOUG CAN SPEAK TO THIS IN TERMS OF WHAT HIS TALK IS ABOUT. >> THIS IS AN AREA THAT CERTAINLY IS UNDER ACTIVE DISCUSSION. AT THIS POINT THE RATE LIMITING STEP IS NOT COLLECTING DATA. IT'S ANALYSIS OF THE DATA ANDPLEASE CORRECT ME IF I'M WRONG THAT-- >> YEAH, IT'S A GOOD POINT. MAYBE I CAN PROVIDE A BIT MORE CONTEXT TO THAT. SO 2 YEARS AGO, THE--IF YOU LOOK AT LANDSCAPE IN THE U.S., YOU KNOW, THERE WERE MAYBE HALF A DOZEN INSTITUTIONS TO THESE HIGH END INSTRUMENTS MAYBE 6 TO 10 AT BEST AND THE PERCEPTION WAS THAT ALL YOU NEEDED WAS A LARGE AMOUNT OF DATA AND EVERYTHING WILL WORK OUT AT THAT POINT SO THERE WAS THIS HUGE BOTTLENECK OF HIGH QUALITY DATA COLLECTION, AS THE FIELDS PROGRESSED AND THE NUMBER OF INSTRUMENTS EXPANDED AND YOU SEE ACROSS THE WORLD, YOU SEE THIS, ALL OF A SUDDEN COLLECTING RELATIVELY LARGE AMOUNTS OF DATA HAS BECOME EASIER. BUT NOT--NOT EVERYONE EXERCISES QUALITY CONTROL IN WHAT THEY COLLECT THE DATA ON. SO IT IS INTERESTING TO SEE THIS TOO, WHICH IS ONCE THE SPEED OF DATA, THEY COLLECT LOTS OF DATA BUT IS IT ANY GOOD OR NOT. ONE THING WE DO AT THE NATIONAL LAB IS TO EXERCISE THAT KIND OF QUALITY CONTROL TO MAKE SURE THE DATA THAT'S COLLECTED IS GOOD. THAT'S RELATED TO YOUR QUESTION, BECAUSE IF YOU HAVE GOOD DAT ATHE EASE OF THE NEXT STEP IF YOU THINK WHAT TO DO WITH IT BUT WE ARE ALREADY SEEING THE FRACTION OF PEOPLE THAT ARE COMING AND WE HAVE GOOD BIOCHEMISTRY, THEY CAN MAKE THE SPECIMENS WE CAN GIVE THEM THE BEST DATA OBTAINED SO THEN IT TAKES TIME. SO THE PUBLICATIONS WE SEE ARE PEOPLE THAT KNOW WHAT TO DO WITH THE DATA, AND THEN THERE'S--I WOULD SAY THAT THAT'S A FAIR POINT THAT AT THE END OF YEAR 1, THAT'S 1 GAP THAT EMERGED THAT PERHAPS THERE'S A REAL NEED TO ACCELERATE CONVERSION OF DATA AND TO RESULTS THAT CAN THEN BE USED. >> IT JUST SEEMS TO ME THAT WITH THE INITIATIVES YOU ARE UNDERTAKING WITH THE D. O. E. LABS WHICH HAVE MASSIVE COMPUTATIONAL POWER AS WELL AS PROGRAMMING CAPABILITIES THAT THAT OUGHT TO BE 1 THING YOU EXPLORE IS WHETHER A PARTNERSHIP BETWEEN FREDERICK AND ECOSYSTEMS RIDGE WHICH IS GETTING ANOTHER GARGANTUATHERAPIST COMPUTER THIS YEAR COULD ACTUALLY HELP WITH DATA ANALYSIS. >> I WILL CERTAINLY--IT WOULD CERTAINLY CONTINUE DISCUSSIONS ON THIS POINT. I THINK THERE'S 2 PIECES TO THIS. ONE IS TO THE CAPACITY TO PROCESS LARGE AMOUNTS OF DATA. BUT WHAT COMES BEFORE THAT IS THE KNOW HOW OF WHAT TO DO TO GET IT IN. SO I THINK THE--TODAY, THE RATE LIMITING STEP IS NOT SO MUCH THE CAPACITY BUT IT WILL BE AS WE GO--THE NEXT 2 OR 3 YEARS, I THINK IT WILL BE BUT I THINK--MY ASSESSMENT IS THAT THE LIMITING FACTOR NOW IS JUST THE SHEER KNOW HOW. THE FIELD HAS GROWN SO RAPIDLY THAT A LOT OF PEOPLE END UP WITH HARD DRIVES OF TERRA BYTES OF DATA AND NOT MANY PEOPLE WHO KNOW WHAT TO DO WITH THIS SO THAT KNOW HOW IS PROBABLY THE FIRST STEP WHICH WOULD LEAD TO ACCESS HIGH END COMPUTING. AND YOU ALOUDED TO THIS A BIT ALREADY, 1 OF THE LIMITING RATE ASPECT SYSTEM ACTUALLY HAVING MATERIALS THAT ARE AMENABLE TO DATA COLLECT ONCE YOU HAVE RELEASED THE DATA COLLECTION IS NOT THE LIMITING STEP ANYMORE. HOW DO YOU ENVISAGE GETTING OVER THAT HURDLE, AND OBVIOUSLY CRYSTALLOGRAPHERS KNEW HOW TO PREPARE THE MATERIALS AND THAT'S WHY PEOPLE LIKE THAT CAN COLLECT CRYO-EM DATA VERY WELL. SO HOW WOULD THE NATIONAL LAB ADDRESS THE PROBLEM OF REALLY HAVING MATERIALS THAT ARE AMENABLE TO GOOD DATA COLLECTION. YEAH, IF YOU LOCK AT THIS PROBLEM, OVERALL, WHAT HASN'T CHANGED IS THERE'S 3 PIECES TO THIS ENTIRE PIPELINE. THERE'S WHAT DO YOU LOOK AT? HOW DO YOU GO FROM SAY A GENE TO SOMETHING THAT'S WORTH GOING INTO A MICROSCOPE, HOW DO YOU COLLECT THE DATA. HOW DO YOU PROCESS IT. SO IF IN THE FIRST PHASE WE DECIDED WE WOULD LOWER THE BARRIER TO GETTING THE DAILY BASIS AT FOR THOSE THAT ACTUALLY HAD SAMPLES. AT LEAST WE EASE THE PIPELINE THERE. IT SEEMS TO ME THE WAY TO ADDRESS, YOU KNOW BOTH THESE ISSUES WHICH IS HOW DO YOU--HOW DO YOU HANDLE PEOPLE THAT DON'T HAVE THE EXPERTISE, BUT HAVE A TEAM THAT ACTUALLY HELPS THAT PROCESSING, I THINK THE NATIONAL LAB COULD POTENTIALLY IF THIS IS WHAT YOU ADVISE, EXPAND IN THOSE DIRECTIONS BUT MAYBE DOUG HAS SOMETHING ON THAT ALSO? >> AND 1 POSSIBILITY COULD BE THAT TO TAKE ADVANTAGE OF THE EXPERTISE THAT HAS BEEN DEMONSTRATED IN THE RAS INITIATIVE IN ADVANCES WITH THE INSTITUTE HAVE BEEN ENABLES BECAUSE OF PURIFICATION AND ANALOGOUS TECHNOLOGY YOU COULD BE BROUGHT TO BEAR BUT I THINK AT THE SAME TIME I WANT TO THINK ABOUT THE POSSIBLE ROLE OF EXTRA MURAL INVESTIGATIONS IN ADDITION TO THE CAPABILITY SPECIFICALLY AT THE LAB. >> NOW WHEN YOU REACH CAPACITY AND I THINK YOU WILL SOON EVEN WITH THE ADDITION OF [INDISCERNIBLE] FOR PRIORITIZING PROJECTS HOW WILL THAT BE MANAGED? >> THATYA A GOOD QUESTION AND WE ARE VERY MUCH AWARE OF THAT, I WANT TO SHARE WITH THE PREVIOUS GROUP THAT ASKED ABOUT WHAT IS THE QUEUE FOR EXAMPLE, HOW DOES IT PROGRESS THROUGH EACH? WE HAVE SOME FOR EXAMPLE, HERE'S WHAT IT LOOKS LIKE RIGHT NOW NOW--YOU GET THIS ON THE SCREEN? SO WE WATCH THIS CLOSELY AND 1 DECISION WE MADE WAS THAT WE WOULD NOT MAKE A JUDGMENT ON WHETHER A PROJECT WAS WOR WORTHY OF BEING STUDIED OR NOT. PEOPLE STUDYING THE PROJECTS, THE SCIENCE IS DETERMINED BY THEIR OWN FUNDING STREAMS AND MECHANISMS, ALL THAT WE ASK FOR S&P THIS SOMETHING THAT COULD BE--DATA COULD BE COLLECTED ON USEFULLY SO WE ASK THEM TO SUBMIT 1 IMAGE THAT IS A SPECIMEN AND THE PEOPLE ARE VERY, VERY GOOD AT FEASING OUT INFORMATION BECAUSE MOST PEOPLE ARE REASONABLY GOOD YOU GO A GOOD FRACTION WILL SEND THE BEST IMAGE AND THE WHOLE SPECIMEN LOOKS LIKE THIS BECAUSE IT'S CERTAINLY NOT TRUE. BUT IT HAS BEEN READ, ALMOST EVERYBODY IS GOOD DATA AND PART BECAUSE OF THIS SKILL SET OF THE--AND WE SEE THIS DEVELOP AND STILL DON'T WANT TO BE REVIEWING PROPOSALS. THE REASON WE ARE NIMBLE IS WE ARE NOT IN THE BUSINESS OF REVIEWING PROPOSALS TO SAY THIS IS A GOOD PROPOSAL OR NOT, A GOOD SAMPLE WE WANT TO GO AHEAD AND THOSE TO DIE, AND PRODUCE A GOOD SAMPLE. I THINK SO FAR AT LEAST YOU SEE OTHERWISE OUR FEELING IS AND IT TAKES AWAY A LOT OF THE OVERHEAD OF REVIEWING THE PROPOSALS BUT THAT WAS CERTAINLY THE VIEW THAT WAS DISCUSSED WITH THE FNLAC BEFORE BUT I'M OPEN TO HEARING OTHER THOUGHTS ON HOW WE MIGHT DO THIS. >> I IF I UNDERSTAND, YOU DON'T FAR PII SYSTEMSITATE IN SAMPLE EXCEPT IN PRODUCTION-- >> THIS IS YEAR 1, THIS IS HOW WE CHOSE TO GET OFF THE GROUND. BECAUSE THE ASSESSMENT IS THAT WE MADE THIS NEED AND IT TURNS OUT TO BE RIGHT THAT CAN MAKE SPECIMENS QUICKLY AND THIS' ALSO A LARGE SUBSET OF THOSE THAT HAVE GRIDS THAT I CAN SCREEN LOCALLY THAT LOOK REASONABLY GOOD AND AND SITTING ON IT, STORING IT, WE CONVERT THAT TO DATA THAT CAN BE PROCESSED AND SO THAT WAS THE IDEA AND IF THERE IS CAPABILITY OR CERTAINLY EXPERTISE AT THE NATIONZAL LAB, 1 COULD TAKE THIS ON BUT RIGHT NOW WE ADVISE THEM ON GOOD PRACTICES AND I THINK THEY UNIFORMLY FIND IT HELPFUL. >> SORT OF AN ACTIVATION BARRIER TO SEE IF THEY TAKE IT SERIOUSLY BUT FOR YOUR NEXT GROUP, GROUP 2, HOW DO YOU INTEND TO HELP PEOPLE LEARN HOW TO DO THAT? THAT WILL BE HARDER FOR SURE BUT REALLY VALUABLE? >> I THINK IT WILL NEED AGAIN A THEY HAVE 1 THING TO MAKE SURE THAT SAMPLES COME IN WITH TD DATA YOU GET FROM THE MICROSCOPES. WE HAVE TO DEFINE THE PROBLEM AND PUT A TEAM TOGETHER AND SOLVE IT AS IF YOU HAD GOOD DATA. WHAT DO YOU GET OUT OF IT? AND LIKEWISE, IF YOU HAVE GOOD PROTEIN--YOU KNOW HAVING BEEN IN THE FIELD FOR ALL THESE YEARS, FROM EXPERIENCE, THE SUCCESS RATE IS SOMETIMES UNPREDICTABLE, WE HAVE A NUMBER OF PROJECTS THAT WE WORK ON AND WE HAVE NO IDEA WHY IT'S NOT WORKING. >> I AM ALWAYS INTERESTED IN DATA STRATEGY. THERE'S 2 TYPES OF DATA IN THE WORLD. TYPE 1 DATA YOU PROCESS IT AND YOU THROW IT AWAY BECAUSE, YOU KNOW THE STRUCTURE, WHATEVER YOU GET OUT OF IT IS ALL YOU NEED, THE OTHER TYPE OF DATA, TYPE 2 DATA, ALGORITHMS IMPROVE, QC IMPROVES AND THERE'S AN INTEREST IN GOING BACK AND SEEING WHAT MORE IS IN THE DATA WHEN YOU HAVE BETTER UNDERSTANDING OF EVERYTHING. WHAT IS CRYO-EM, ANYWAY? DO YOU THROW IT OUT AND GET RID OF IT OR IS IT WORTH GOING BACK TO. >> SADLY IT'S ALL TYPE 2. SO, I CAN TELL YOU FROM MY OWN EXPERIENCE, WE PUBLISHED THAT TIME THE VERY FIRST 2-ANGSTROM STRUCTURE BY THE IMPERIAL ACTIVATION, IT WAS VERY EXCITING WE SEE WATER MOLECULES IN A PAPER THAT'S JUST ABOUT TO COME OUT NEXT WEEK, WE REFINED THIS AND DEPOSITED THE DATA PUBLICLY AND IT'S BEEN OUT THERE FOR 2 YEARS OR MORE, WE PROCESSED IT WITH BETTER ALGORITHMS IN THE LAB, I WILL HAVE A DENSITY LAB THAT WILL LOOK LIKE THE 1.5 ANGSTROM, SO WE DON'T THROWN--EQUALLY OUT THE RAW DATA-- >> TREMENDOUS INTEREST THEN? >> TREMENDOUS INTEREST, YES. , SOME ABILITY TO REPROCESS, YES, YES,. >> NOT JUST INVESTIGATOR. >> YEAH, SO THE DATA WE COLLECT, THE DATA WE COLLECT FROM THE HUNDRED OR SO WE DON'T WANT TO LE LITE ANY PRIVACY ISSUES SO THE DAY-TO-DAY WE COLLECTLY THERE IS A DEFINED NEED FOR THE NATIONAL LAB TO PROVIDE EITHER SUPPORT TO SPEED UP THE PROCESSING OR PROVIDE AN OBJECT IVE THERE ARE MANY CONTROVERSYYS IN THE FIELD ANGELA KNOWS THE HISTORY OF NMR, I KNOW THE HISTORY OF CRYO-EM, AND PEOPLE PUBLISH PAPERS AND SOMETIMES THERE NEEDS TO BE A NEUTRAL PARTY THAT CAN SAY THIS IS THE RIGHT STRUCTURE AND THIS IS THE WRONG STRUCTURE SO THERE MAY BE TREMENDOUS VALUE IN A NATIONAL LAB TAKING ON THIS NEUTRAL ROLE OF CONVERTING STRUCTURES AND THAT IS SOMETHING THAT COULD BE DONE. >> COULD YOU SEE A ROLE FOR THE NATIONAL LAB TO HAVE DATA SETS IN THE DEPOSITORY THAT ARE NOW USED BY THE DEVELOPERS FOR NEW ALGORITHM DEVELOPMENT FOR SPECIFICALLY CRYO-EM ASSIGNMENTS AND COULD THE NATIONAL LAB PLACENTA I A MAJOR ROLE IN THAT. >> YEAH, I THINK THE ANSWER IS A RESOUNDING YES. IS THE NATIONAL LAB GOING TO BE A DRIVER OF TECHNOLOGIES AND MLGTS IN THE FIELD, WHAT IS THE ROLE? CLOSER TO THESE THE WAY OTHER NATIONAL LABS IN THE U.S. WORK. VERSUS WHERE, WELL, WE'VE JUST STARTED, SO WE'VE DEMONSTRATED WE CAN DO THE FIRST PHASE BUT YES, BECAUSE ALL THE DAT COLLECTED HERE, EXCEPT FOR, YOU KNOW THE TECHNOLOGY DEVELOPMENT PROJECTS WE DO A BIT TO CHECK THE DETECTORS AND SO ON, ALL OF THIS DATA BELONGS TO THE USER SO YOU KNOW WE DON'T TOUCH IT. BUT THERE COULD BE A MIGDZ WITH THE INCREASING--MISSION WITH THE INCREASING CAPABILITY, AND WE COULD SAY IT'S TO DO EXACTLY THAT WHICH IS TO PROVIDE ACCESS TO DATA AND MAYBE INFORMATION THAT CAN BE PROCESSED BY PEOPLE ACROSS THE WORLD, YES. COULD YOU REVIEW FOR US THE CURRENT PLANS OF THE EXPANSION OF THE NEW FACILITY WITH THE NEW INSTRUMENTS OVER THE NEXT YEAR OR SO AND THEN WHETHER THERE WILL BE ADDITIONAL STAFF HIRED TO SUPPORT THIS? >> YES, THE--WE STARTED WITH 1 INSTRUMENTED WHICH IS IN GAITHERSBURG WHICH IS NOW FULLY OPERATIONAL. THE SECOND 1 ARRIVES NEXT MONTH WHICH WILL INSTALL AND AS SOON AS IT'S UP AND RUNNER WHICH WE EXPECT WILL BE IN FALL AND WE WILL MOVE THE SECOND 1 INTO THE FACILITY SO BY THE END OF THIS YEAR, WE EXPECT TO HAVE 2 FULL INSTRUMENTS RUNNING AND WE HAVE FUNDING TO BUY A THIRD 1 THAT I PROJECT WILL HAPPEN IN 2019 WHICH WILL CONTINUE TO INCREASE IN CAPACITY AND THIS--WHICH IS WHY I THINK THE TIME IS RIGHT TO THINK ABOUT A WAY TO EXPAND THIS IN A WAY THAT HAS A MUCH BIGGER IMPACT AND USING THIS FACILITY BECAUSE WHAT'S HAPPENED NOW IN THE LAST FEW YEARS THROUGH NIH, THE TIME WE LAUNCHED THIS I HAD WRITTEN A WHITE PAPER AND DOUG IS ALSO ININVOLVED IN DISCUSSIONS AND HOW NIH MIGHT DISSEMINATE THIS AND THAT'S HPPENING NOW, ASK WHAT'S EXCITING IS THAT THERE WILL BE 3 NATIONAL CENTERS THAT PROVIDE ACCESS TO MANY PEER PEOPLE SO THERE'S 3 INSTRUMENTS SO WE HAVE AN OPPORTUNITY TO DO SOMETHING THAT GOES BEYOND SIMPLY ROUGH ATOM VIEDING ACCESS WHICH IS IMPORTANT TO DO FOR THE LAST YEAR BUT WHAT YOU SAY COULD WELL BE THE NEXT PHASE. SO WE HAVE--WE HAVE AN ADD OUT FOR A MICROSCOPIST TO HELP RUN THE NEW MICROSCOPE BUT WE DON'T NEED TO DOUBLE OUR STAFF. WE WILL ADD A FEW PEOPLE AND GROW THE USER FACILITY PIECE IF WE HAD 3 HIKE ROUGH ATOM SCOPES WE COULD PROBABLY DO A VERY GOOD JOB WITH 2 OR 3 ADDITIONAL STAFF BUT IF WE HAVE OTHER CAPABILITIES OR OTHER MISSIONS LIKE WHAT WE'VE BEEN DISCUSSING THAT WOULD TAKE SIGNIFICANT ECPANGZ. >> YEAH, YOU SAID THE RATE LIMITING STEP IS THE KNOW-HOW IN CRUNCHING THE DATA, SO ARE YOU--DO YOU HAVE ANY INITIATIVES, OUT OR ARE YOU TAKING A LEAD ROLE IN EDUCATION IN THE COMMUNITY FOR EXACTLY ACCOMPLISHING THEM. >> SO 2 ASPECTS TO YOUR QUESTION, 1 IS TO PROVIDE THE KNOW-HOW FOR SPECIFIC RESEARCH PROJECTS, WHERE PEOPLE BRING THINGS IN AND THE SECOND IS THE BROADER EDUCATIONAL GOAL WHICH IS TO EDUCATE PEOPLE SPECIAL SO THE SECOND IS NOW, SORT OF AN ACTIVE GOAL WITH A NUMBER OF INSTITUTIONS, UNIVERSITIES, INSTITUTEDS LOTS OF INFORMATION ON THE WEB AND I'M JUST AMAZED, ALMOST EVERY WEEK, THERE'S A LOT OF INFORMATION, LOTS OF WORKSHOPS SO THAT'S HAPPENING ALREADY. THE FIRST PART THERE'S QUITE A SIGNIFICANT GAP WHICH IS PEOPLE SAY, WELL, IT'S ALL GREAT, I'VE READ THESE AND LOOKED AT THE ARTICLES AND SEEN THE COURSES AND SEEN THE VIDEOS BUT I'M HAVING TROUBLE PROCESSING MY DATA. MAYBE THAT'S WHERE THE DIFFERENTIAL IS FOR THE NATIONAL LAB, IS YOU WANT SOMEBODY TO TREAT YOU WITH YOUR PROBLEM. AND WHILE OF COURSE KNOWING THERE'S LOTS OF SOURCES TO GET GENERAL EDUCATION, SO I THINK THE--MY PERSONAL OPINION IS THAT THE LIKELIHOOD OF THE NATIONAL LAB CAN HAVE AN IMPACT IN THIS FIRST PIECE WHERE THE SPECIFIC TARGETED COLLABORATION AND WHILE PEOPLE ACROSS THE WORLD ARE DOING A GREAT JOB IN SICK SEMESTERINATING THIS. >> SO ARE YOU DOING ANYTHING PROACTIVELY TO ADDRESS THAT? >> ONE THING IS THAT WE WANT TO DO WITH THE DISCUSSION IF YOU HAVE THAT IN YEAR 1 TO YEAR 2 IS EXACTLY WHAT WE WOULD DO. >> BOB, YOU HAD A-- >> JUST A QUICK COMMENT. I WANT TO GO BACK TO THE COMMENT THAT THE DATA IS THE INVESTIGATOR'S DATA. THAT'S TRUE IN 1 SENSE BUT ONCE IT'S PROCESSED BY A NATIONAL FACILITY YOU COULD ARGUE THAT IT'S SHARED DATA AND AFTER AN EXCLUSIVITY PERIOD OR EMBARGO PERIOD OF A YEAR OR 2 YEARS, YOU KNOW YOU ALSO HAVE SOME RIGHTS TO IT BECAUSE YOU PROCESS IT. >> WE ARE EXERCISING THIS SO THE EM DATA BANK ENCOURAGES PEOPLE TO DEPOSIT NOT JUST THE FINAL STRUCTURES BUT DATA AND WE'VE BEEN DOING THIS FOR SOMETIME IN MY LAB, IN FACT, THE DATA SET, THESE WERE DEPOSITED AS BENCHMARKS FOR THE HIGH RESOLUTION DATA BUT IF THE NATIONAL LAB TAKES ON THIS ROLE TO ACCELERATE, AFTER A PERIOD OF TIME WE COULD RELEASE THIS AND THIS COULD BE AN A VERY IMPORTANT ROLE FOR THE COMMUNITY. >> WELL I THINK WE PROBABLY ALL REALLY LIKE THE IDEA OF STRATEGIC THINKING AROUND THIS FACILITY AND I IDENTIFYING THINGS YOU CAN REALISTICALLY DO AND NOT FORGETTING THAT YOU'RE NOT CHARGING FOR ACCESS AND IT'S NOT UNUSUAL FOR CHARGES TO FOR A THOUSAND TO $2000 A DAY FOR INVESTIGATORS TO GET CRYO-EM DATA COLLECTION AND TYPICALLY MULTIPLE DAYS ARE REQUIRED SO THAT I THINK WILL ASSURE YOU A STEADY STREAM OF CUSTOMERS AND THE ABILITY TO HELP MOVE THE FRONTIER IS SOMETHING AGAIN THAT'S SORT OF UNIQUELY NCI, UNIQUELY FREDERICK, HAVE YOU THIS. YOU DON'T HAVE TO WORRY ABOUT RO1S, YOU HAVE THE TIME AND THE ABILITY TO DO IT AND I THINK THE FACILITY OFF TO A GREAT START AND JUST THINKING ANOTHER YEAR OR 2 AHEAD AND WHAT CAN YOU DO THAT WILL BE REALLY SPECIAL, I THINK COULD BE AWESOME. >> THANK YOU VERY MUCH. >> I HATE TO SHUT OFF THIS DISCUSSION WITH A COMMENT BUT WE HAVE 5 MINUTES FOR QUESTION FIST ANYBODY HAS ANYMORE. >> THANK YOU VERY MUCH. TERRIFIC PRESENTATION. >> OKAY WE HAD A PRESENTATION AT THE LAST MEETING ON THE NEXT PROGRAM AND WE WILL BE DELVING MORE DEEPLY INTO NEXT WITH 3 PRESENTATIONS, THE NEXT OF WHICH IS BY JIM DOROSHOW, THIS WILL TAKE US UP TO LUNCH AND THEN WE'LL HAVE 2 PRESENTATIONS AFTER LUNCH. JIM? >> GREAT. THANK YOU AND VERY MUCH APPRECIATE THE CHANCE TO UPDATE YOU WITH THE ACTIVITIES. THIS WILL BE A 3-PART PRESENTATION. I WILL TALK ABOUT DRUG DISCOVERY AND THEN ALSO SOME OF OUR LATE STAGE PROJECTS, RALPH WILL TALK ABOUT THE INTERMEDIATE ACTIVITIES IN FARM CO DYNAMICS THAT ARE REALLY A BRIDGE NOT ONLY BETWEEN DORPHY AND CLINICAL ACTIVITIES AND JEFF MOSCOW WHO IS THE CHIEF OF THE INVESTIGATIONAL DRUG BRANCH IS GOING TO TALK ABOUT HOW OUR EARLY PHASE CLINICAL STUDIES UTILIZE THE RESOURCES AT FREDERICK TO DO PRETTY MUCH STATE-OF-THE-ART DYNAMIC STUDIES IN SUPPORT OF EARLY PHASE CLINICAL TRIALS. SOPHISTICATED TO REMIND YOU IS THE NEXT PROGRAM IS THE THERAPEUTIC DRUG DISCOVERY ACTIVITIES, THEY SUPPORT FROM EARLY STAGE ACTIVITIES, HIGH THROUGH PUT SCREENS, ET CETERA ALL THE WAY THROUGH PHASE 1 TO INVESTIGATIONS. AND WE PROVOID A RANGE OF SERVICES TO INDIVIDUALS PRIMARILY IN THE AREA OF EARLY DISCOVERY AND DEVELOPMENT AND THOSE INDIVIDUALS WHO WORK IN EARLY BIOTECH AND SMALL BIOTECH BUT WHEN WE MOVE INTO THE LATE PHASE 1, PHASE 1, PHASE 2 ARENA WE HAVE SIGNIFICANT INTERACTIONS WITH THE WIDE RANGE OF PHARMA PARTNERS AND JEFF WILL TELL YOU ABOUT HOW WE INTERACT WITH THEM, WHAT KINDS OF STUDIES WE DO AND HOW WE PROVIDE ACCESS TO RESOURCES AND IMPROVE THE KINDS OF TRIALS WHY CAN DO ESPECIALLY INVESTIGATIONAL COMBINATION, SO AS I SAID, I WILL TALK ABOUT CBC AND DRUG DISCOVERY AND ALSO SOME ADVANCED CLINICAL PROJECTS AND RALPH WILL TALK ABOUT THE INTERMEDIATE PIECE IN FARM CO DYNAMICS AND HOW IT RELATES TO BOTH DISCOVERY AND CLINICAL TRIALS AND JEFF WILL TALK ABOUT THE EARLY CLINICAL TRIALS PROCESS. WHAT I DON'T HAVE TIME FOR--THE PROGRAM HAS A LANGUAGE SUCCESSFUL TRACK RECORD OF ASSISTING THE ACADEMIC COMMUNITY IN BIOLOGICS AND VACCINES THIS IS AN IMPORTANT THING WE DO IN GENERAL AND THOSE ARE ACTIVITIES THAT ARE RIGHT SMACK DAB IN THE MIDDLE OF THE PIPELINE. THAT IS SOMETHING THAT IS COMING WITH PRELIMINARY DEVELOPED. MANUFACTURE OR DO TOXICOLOGY, MAKE CLINICAL GRADE MATERIAL FOR A TRIAL AND WE DO THAT ASK HELP THEM LAWRCH THE CLINICAL TRIAL WITH REGULATORY ACTIVITIES SO ANTHONY WELCH WILL PRECEPT TO YOU AT THE NEXT MEETING ABOUT THOSE ACTIVITIES THAT ARE PART OF THIS ENTIRE PIPELINE. SO LET ME REMIND YOU, I TALKED ABOUT THIS BEFORE BUT HOW DO THESE PROJECTS BECAUSE THESE ARE SERVICES FOR THE EXTRA MURAL COMMUNITY AND HOW DO WE GO ABOUT TRYING TO PRIORITIZE THE USE OF RESOURCES SO 3 TIMES A YEAR WE ACCEPT APPLICATIONS TO THE NEXT PROGRAM. THOSE CAN BE APPLICATIONS THAT AGAIN ARE WIDE RANGING AND THEY CAN BE REQUEST FOR ACCESS TO MEDICINAL CHEMISTRY. AND RESOURCES THEY COULD BE REQUESTED FOR US TO CONDUCT A PHASE 1 PROGRAM FOR SOMEONE AND THEY CAN BE EVERYTHING IN THE MIDDLE IN TERMS OF DEVELOPING ASSAYS THAT WILL HELP THEM MOVE THEIR PROGRAM AHEAD IN SMALL MOLECULES AND IT'S BIOLOGICS AND ALSO AGAIN NOT SOMETHING WE WILL HAVE TO PRESENT TO YOU SPECIFICALLY IN TIMES, I THINK WE'VE HAD GOOD OUTCOMES IN TERMS OF SUBSTANTIAL INFORMATION, THEY WILL BE USEFUL AND IMAGING AGENTS AND PRODUCING THE QUALITY MATERIAL AND HELPING WITH REGULATORY AND LAUNCHING CLINICAL CLINICAL TRIALS OF IMAGING AGENTS. I WON'T TOUCH ON THAT TODAY BUT I THINK IT'S IMPORTANT. WE HAVE A SPECIAL PANEL ABOUT EXPERTS HALF ACADEMICS AND HALF FROM INDUSTRY, MANY WITH BIOLOGIC EXPERTISE AND INDIVIDUALS WITH EXPERTISE WHO REVIEW THESE APPLICATIONS AND PRIORITIZE THOSE, WE GET ROUGHLY A HUNDRED APPLICATIONS A YEAR AND WHY REALLY ONLY MOVE AHEAD WITH THE TOP 10-15% OF THOSE PROJECTS THAT ARE HIGHLY RANKED AND THE FIRST THING WE DO WHERE IT'S APPROPRIATE IS TO DO A TRUST BUT VERIFY SET OF EXPERIMENTS BECAUSE OF THAT 15% OF PROJECTS ABOUT A THIRD TURN OUT TO FAIL. IF WE TRY TO REPRODUCE SOMETHING, SO WE HAVE A PRETTY HIGH BAR FROM MOVING SOMETHING AHEAD, IT HAS TO--WE HAVE TO BE ABLE TO TAKE THE MODEL AND GET THE--GET THE REAGENT WHETHER IT'S BIOLOGIC OR SMALL MOLECULE AND REPRODUCE WHAT THE APPLICANT HAS PUT FORWARD THERE IN THEIR APPLICATION AND ASSUMING THOSE THINGS OCCUR, THEN EITHER IF IT'S SMALL MOLECULE OR BIOLOGIC, IT GOES TO OUR STEERING COMMITTEE OF CBC SITES AND ETHAN SHOWED YOU THAT THAT WE HAVE 20 OR SO CUTCHES WITH BROAD EXPERTISE TO,A CYST US AND THEY ARE PART OF THIS STEERING COMMITTEE AND WHAT WE DO AFTER WE VERIFY A PROJECT IS WE BASICALLY GET THE INPUT FROM OUR INVESTIGATORS, NOT THE INVESTIGATORS FOR THE PROJECTS BUT THE COMPONENTS, THE BUT IS THE CHEMISTRY REASONABLE TO DO AND HOW MIGHT 1 DO THAT AND THEN WE FORM A PLANNING GROUP AND TRY TO SELECT THE APPROPRIATE SITES THAT WOULD BE USEFUL WHEN A WORK PLAN IS PRODUCED. FOR THE THINGS THAT COME IN FROM PHARMA EITHER BIOTECH OR BIG PHARMA FOR EARLY PHASE TRIALS, THOSE ARE PRIORITIZED BASED ON NEEDS FOR OUR PORTFOLIO, WE AN EXTRA MURAL GROUP THAT HELPS US TRY TO MOVE FORWARD IN TERMS OF WHAT KIND OF DRUG DEVELOPMENT PLANS ARE APPROPRIATE. HOW DO WE COMBINE AGENTS WITHIN OUR PORTFOLIO TO DO INVESTIGATIONAL COMBINATIONS THAT ARE NOT EASY TO DO. OTHERWISE, THOSE--THE CLINICAL TRIALS THAT DR. MOSCOW ARE CONDUCTED UNDER A GRANTS PROGRAM BUT ALL OF THE SUPPORTING CORRELATIVE RELEVANT ASSAYS ARE DONE IN A BIOPHARMA DYNAMICS GROUP AT LIDOS. THIS IS JUFULT A BROADER VIEW OF SOME OF THE MAJOR PROJECTS WE HAVE, PROJECTS IN THE DISCOVERY REALM, PROJECTS THAT ARE MORE PRECLINICAL AND CLINICAL TRIALS I WILL TELL YOU ABOUT, A COUPLE OF THOSE INHIBITOR AND ANOTHER AGENT, I WILL TELL YOU ABOUT PROGECS THAT HAVE MOVED VERY NICELY THROUGH THIS PIPELINE AND GIVE YOU SOME UPDATES ON THOSE BUT WE HAVE A--WE HAVE A FAIRLY ROBUST IDEA OF WHAT THE PROGRAM OUGHT TO BE CONSIST OF AND WHAT WE CAN SUPPORT. SO THAT WE REALLY ARE THE--THE BAR IS PRETTY HIGH TO GET INTO THE PROGRAM, BUT EVEN WITH THAT HIGH BAR, WE FAIL A FAIR NUMBER OF AGENTS THAT COME THROUGH, WE ARE PREPARING FOR OUR YEARLY PRIORITIZATION REVIEW THAT WILL OCCUR IN EARLY AUGUST WHERE WE HAVE A PRETTY STRONG RECORD OF KILLING PROJECTS THAT HAVE NOT MADE APPROPRIATE PROGRESS WITH THE INVESTMENT OF THE SUBSTANTIAL RESOURCES AND IN PREPARATION FOR DOING THAT JUST TO GIVE YOU AN IDEA OF WHERE THE PORTFOLIO STANDS ACROSS THE EARLY PROJECTS WE'VE TRIED TO LOOK AT THE PROJECTS WE DO HAVE AND TRY TO UNDERSTAND THEM IN TERMS OF RISK. SO YOU SEE THERE ARE A FAIR NUMBER OF PROJECTS IN RED, AND IT'S HIGH RISK AND THAT DEPEBDS ON HOW, WHAT THE STATE OF THE SCIENCE IS IN TERMS OF TARGET VALIDATION AND THE TARGET THAT WE'RE GOING AFTER. WE HAVE MEDIUM RISK PROGECS AND P97, THEY TALKED ABOUT THAT A BIT AND WE HAVE PROGECS THAT MAY BE EARLY IN STAGE, WITH THE SHIP 2 INHIBITOR WHERE THE TARGET IS WELL ESTABLISHED SO THAT WE KNOW IF WE'RE SUCCESSFUL IT'S VERY, VERY LIKELY THAT IT'S GOING TO LEAD TO AN AGENT THAT WILL BE VERY USEFUL IN A VARIETY OF DIFFERENT MALIGNANCIES. SO LAST TIME YOU HEARD A DISCUSSION FROM STEVE VESSICK, FROM MCLWOBDERFUL--WONDERFUL AND ANTIAPOPTOTIC PROTEIN AND PROGRESS HAD BEEN MADE IN THAT PROJECT AND HE DID SHOW YOU THIS SLIDE WHERE WE STARTED OUT WITH A MOLECULE THAT WAS NOT VERY POTENT, OVER A HUNDRED MICROMOLAR POTENCY AND WITH SUPPORT FROM THE CBC, GRANTS AND THE RESOURCES TO VANDERBILT AND MOVED THAT TO A SUBNANO MOLAR COMPOUND THROUGH INNOVATIVE FRAGMENT BASED DESIGN, AND THOSE MOLECULES HAD SIGNIFICANT INVIVO AND PROOF OF MECHANISM STUDIES PERFORMED, I THINK HE SHARED THOSE WITH YOU AND THE REASON THIS SLIDE IS UP IS SINCE THAT PRESENTATION WE'RE HAPPY TO REPORT TO YOU THAT THIS PROJECT AND THE MOLECULES ASSOCIATE WIDE IT HAVE BEEN OUTLICENSED TO BERNEA DEET I--BERRINGER, AND IN A YEAR OR YEAR AND HALF THEY WILL BE IN THE CLINIC WITH THE MOLECULES ESTABLISHED THROUGH THE NEXT PROGRAM. I'M NOT SURE WHETHER IN THE RECENT PAST WE HAVE PRESENTED THIS PROJECT TO THE GROUP, IT ORIGINATED AT UNIVERSITY OF NORTH CAROLINA AND CAME INTO PROGRAM AND WITH COLLABORATION VERY STRONG COLLABORATION, WITH THE NCATS LABORATORIES, THE NGCC LABORATORY MOLECULES WERE IMPROVED AND IMPROVED OVER A 5 YEAR PERIOD WITH HIGH SELECTIVITY WITH PKPD PROPERTIES. AND THIS IMPORTANT--I'M NOT SURE I--CAN PROBABLY SCREW THIS UP. GREAT. THE LATEST MOLECULE SO CALLED OO6 MOLECULE HAS IF YOU WILL SEE ON THERE, TO YOUR RIGHT, THE COMPARISON OF THE NCGC MOLECULE WITH THE CLINICAL COMPOUND, THE AGIOS COMPOUND HAS MUCH BETTER PROPERTIES, INVIVO PROLONGED INHIBITION OF THE TARGET AND THIS MOLECULE HAS JUST BEEN OUTLICENSED TO FORTRESS BIOTECH ABOUT--IT'S PROBABLY LESS THAN 2 WEEKS AGO. SO I WILL BRING YOU UP TO DATE ON A VERY EXCITING SERIES OF PROJECTS RELATING TO THE TARGETING P97 AND A VERY IMPORTANT PROTEIN THAT MODS MODS--MODULATES PROTEINS IN A VERY PARTICULAR WAY NOT ONLY IN THE ENDORETIC CUE LUMBUT IN THE AUTOPHAGEY FOR THE PROCESSING OF THE PROTEIN COMPLEXIO STUDIES OF MULTIPLE ENDOCRINE SO THIS PROJECT BEGAN SOME TIME AGO AND THE LEAD EN--STRATEGIES TUITION WAS UNIVERSITY OF PITTSBURGH AND DONNA HERN AND HER COLLEAGUES AND AS YOU CAN SEE, THEY STARTED WITH THE COMPOUND THAT WAS REALLY NOT VERY POTENT BIOCHEMICALLY AND DIDN'T HAVE A SUBSTANTIAL AMOUNT OF CELLULAR THERAPEUTIC ACTIVITY, BUT OVER A PERIOD OF A COUPLE YEARS THIS ALOESTERRIC INHIBITOR THAT THEY DEVELOPED REALLY HAS MADE MAJOR PROGRESS AND NOW HAS ACTIVITY THAT IS EQUIVALENT AT A BIOCHEMICAL AND TARGET LEVEL TO THE ONLY OTHER COMPETITOR IN THE FIELD WHICH IS A SET OF SMALL MOLECULES THAT WERE DEVELOPED BY CLEAVE-BY O SCIENCES A SMALL BIOTECH COMPANY THAT WILL DEVELOP A NONALOESTERRIC AND SPECIFIC SITE SPECIFIC INHIBITOR AND SO WE MADE A LOT OF PROGRESS IN THIS AREA AND THIS WILL REMAIN AN ACTIVE AREA OF INVESTIGATION BUT WHAT I'M GOING TO DESCRIBE TO YOU IS REALLY 1 OF THE THINGS THAT I THINK IS UNIQUE ABOUT THE CBC NEXT PROGRAM AND THAT IS THAT WE'RE ABLE TO MAKE DECISIONS ABOUT--IN A PARTICULAR AREA IF WE DEVELOPED EXPERTISE THAT I THINK CAN HELP MOVE MOLECULES FORWARD VERY QUICKLY AND SO AFTER OUR LAST MEETING AS OF LATE LAST FALL. AS WE WERE MOVING AHEAD WITH THIS ALOESTERRIC INHIBITOR OF P97, DEVELOPED CELLULAR DATA IN TERMS OF POTENCY, WE WERE CONTACTED BY BIOSCIENCES, SMALL BIOTECH. THEY HAD SEVERAL BACK UP MOLECULES THEY WERE HOPING TO DEVELOP BECAUSE THEIR MOLECULE I SHOWED ON THE LAST SLIDE FAILED IN FIRST HUMAN STUDY. IT DIDN'T FAIL BECAUSE OF POTENTIAL LACK OF POTENCY IT FAILED BECAUSE OF UNANTICIPATEDAUR-TARGETING SYSTEM THE INHIBITION OF PROOF THE O GLANDIN E6 ENZYMATIC ACTIVITY THAT LEADS TO I HAVE AG RALIKE TEMPORARY LOSS OF VISION IN THE CLINIC SO THEY SHUT DOWN THEIR PROGRAM. THEY DID NOT HAVE SIGNIFICANT RESOURCES TO MOVE THEIR SECOND LINE COMPOUND FORWARD AFTER DISCUSSION WITH THE CBC AND OUR REVIEW COMMITTEES, WE DECIDED TO TAKE IN THEIR SECOND GENERATION COMPOUND 5339 WHICH HAS MANY PROPERTIES THAT ARE ADVANTAGEOUS AND IT'S CLEARLY MUCH LESS POTENT IN TERMS OF INHIBITING THE PROOF THE O GRANDIN E6 AND LIKELY NOT TO CAUSE THE PROBLEMS THAT THE INIT MOLECULE PRESENTED AND WILL GIVE US AN OPPORTUNITY SINCE THEY'VE DONE AN EXPENSIVE AMOUNT OF WORK ON THIS MOLECULE ALREADY TO MOVE THIS QUICKLY WE HOPE INTO THE CLINIC. THIS IS OUR TIMELINE AND WE'RE ACTIVELY ENGAGED IN NUMBER WOB TRYING TO MAKE SURE THAT THAT--THIS USING OF CANINE MODELS AND KININE TOXICOLOGY MODELS FOR WHICH THE PRODUCT THEY HAVE CAN BE EMPLOYED AND TO DETERMINE WHETHER OR NOT THERE'S VISUAL LOSS OR NOT, BUT THEN BECAUSE WE KNOW THEY'VE DONE ALL THIS CELLULAR AND MOUSE EXTEN SO GRAPH WORK WHICH WE DON'T NEED TO REPEAT AND WE WILL MOVE THIS QUICKLY IN THE SUMMER AND THE SPONTANEOUS WHICH IS LIKELY TO BE A TARGET DISEASE FOR THESE KINDS OF PROTEIN MODIFIERS AND THAT REALLY IS GOING TO SERVE AS OUR GO-NO GO FOR THIS MOLECULE AND BY THE TIME, PERHAPS IF NOT THE NEXT MEETING THEN SOON THEREAFTER, THIS GROUP WILL KNOW WHETHER OR NOT WE WILL HAVE MATERIAL THAT WE CAN DEVELOP AN IND AROUND AND MOVE INTO THE CLINIC, I THINK PROBABLY BY--OR EARLY NEXT YEAR, I HOPE. LET ME THEN TURN IF I CAN TO--I SAID I WAS GOING TO DO BRACKETING OF OUR PURCHASE. SO THESE ARE NEW MOLECULES, NOT BEEN IN PATIENTS BEFORE, NOW LET ME TELL YOU A BIT ABOUT THE PRODUCTS OF THE NEXT PIPELINE THAT HAVE ACTUALLY GOTTEN INTO PHASE 1 AND ACTUALLY EVEN PHASE 2 STUDY BECAUSE YOU OFTEN DON'T HEAR ABOUT THOSE MOLECULES BUT THEY'RE PART OF THIS EXACT SAME PROCESS. SO SOUTHERN RESEARCH CAME TO US WITH MOLECULES BOTH 1 IS APHASE O DEOX DINE, THESE WERE DISCOVERED, DEVELOPED AND SYNTHESIZED AS PUBLISHED ON AS ANTIMETABOLITES MORE THAN 20 YEARS AGO. THERE'S ACTUALLY NO INTELLECTUAL PROPERTY SURROUNDING THESE MOLECULES AT ALL. THEY'RE WAY TOO LONG BUT FOR REASONS AFTER SERL YEARS I HAVEN'T BEEN ABLE TO DISCERN, INVESTIGATORS AT SOUTHERN DECIDED THESE MOLECULES MIGHT HAVE ACTIVITY AS EPIGENIC MODULATORS AND THEY CONDUCT EXPERIMENTS WHICH DEMONSTRATED VERY CLEARLY BOTH OF THESE MOLECULES INHIBITED DM D1 ACTIVITY. AND HAD THERAPY THERAPEUTIC ACTIVITY AND DIDN'T HAVE THE MECHANISMS TO CARRY FORWARD MORE STUDIES OR TO TAKE THESE INTO THE CLINIC. THE THING THAT WAS VERY INTERESTING TO OUR SPECIAL EMPHASIS PANEL ON THESE COMPOUNDS CAME IN IS WHAT THE SOUTHERN RESEARCHERS HAD SHOWN CLEARLY IS THAT THESE WERE ORLALLY BIOACKIVE COMPOUNDS ON THE OTHER COMMERCIALLY AVAILABLE D& M INHIBITORS SO THAT WILL BE A BREAK THROUGH FOR THE FIELD IF WE CAN DEVELOP A ORAL-ORAL MOLECULE SO THIS WAS TAKEN IN AND SERIES OF STUDIES HAVE BEEN DONE BOTH AS YOU WILL SEE, TO BET BETTER INFORMATION ABOUT PRECLINICAL MECHANISM TO DEVELOP BIOMARKERS FOR THESE COMPOUNDS AND ACTUALLY FOR 1 OF THEM, TO HAVE TAKEN IT INTO--INTO PHASE 1 TRIAL ALREADY AND THE OTHER IS READY TO INITIATE PATIENT ENTRY VERY SOON. THINK I CAN POINT IT OUT IS THAT THESE COMPOUNDS VERY SIMILAR BUT THEY'RE NOT. AND WE FOUND THE MORE WE STUDY, WE FIND OUT THAT 1 COMPOUND, MAY BE ACTIVE AND 1 SET OF EXTEN O GRAPHS, THE OTHER MAY BE POTENT IN ANOTHER SET OF XENOGRAFTS OR THEY MAY BE POTENT IN A THIRD PDX MODEL SO THEY'RE REALLY NOT AT ALL CLEAR SIMILAR FROM A NECKANISTIC PERSPECTIVE EXCEPT THAT THEY BOTH INHIBIT DMD1 AND NOT DMD3. WE KNOW THAT BOTH MOLECULES WILL HIT A VARIETY OF TARGETS THAT OTHER EPIGENIC MODULATORS WILL HIT IN BOTH CELL CULTURE AND IN EXTEN O GRAPHS, SO THE DECISION WAS MADE BY THE PROJECT TEAM DEVELOPING THESE FOR THE CBC THAT WAS APPROPRIATE TO CONTINUE THE STUDIES OF MECHANISM OF ACTION BUT ALSO TO BRING AT LEAST BOTH OF THESE ACTUALLY INTO THE CLINIC. LET ME GIVE YOU MORE MECHANISTIC INFORMATION THAT HAS COME TO LIGHT OVER THE LAST YEAR AND HALF AS WE MOVE FORWARD WITH THESE COMPOUNDS WITH A COLLABORATOR WHO IS PART OF THE PROJECT TEAM AT VCU, STEVE GRANT WHO IS AN EXPERT IN EPIGENETICS, HE'S SHOWN--HE'S SHOWN THAT IF YOU CRSPR OUT DMDB1, AND THE ACTIVITY OF THE PHYTODEOX DINE, IN THE UNCRSPRED CELL LINES WE BLUNT THEM SIGNIFICANTLY AND THE TARGET IS GONE. WE HAVE COLLABORATED EXTENSIVELY WITH THE INTRAMURAL INVESTIGATOR, DR. PETER APLAN, WHO IS AN EXPERT IN THE AREA WE WOULD EXPECT THESE COMPOUNDS MIGHT BE USEFUL FOR AND USING HIS MODELS HAVE SHOWN THAT I HOPE YOU CAN SEE THAT IN THE ANIMALS TREATED WITH THE DEOXYCYTODINE IN ORANGE, THE DEVELOPMENT OF LEUKEMIA HAS BEEN VERY SIGNIFICANTLY REDUCED, THESE ARE WHITE COUNTS AND EACH OF THESE YELLOWISH SORT OF ORANGE REDDISH LINES ARE INDIVIDUAL MIETION AND THEIR BLOOD COUNTS. IN BLACK THESE ARE NON--BASICALLY VEHICLE TREATED ANIMALS WHO BASICALLY BLAST OFF IN THIS MODEL DEVELOP LEUKEMIA AND WHEREAS THERE'S BEEN A SIGNIFICANT DIMINUTION IN THE NUMBER OF ANIMALS TREATED WITH PHYTODEOX DINE WITH MINIMAL TOXICITY AND THIS SHOWS THERE'S A SURVAIFAL ADVANTAGE WHEN WE TREAT THESE ANIMALS. SO WE'RE ENCOURAGED FROM MECHANISTIC PERSPECTIVE AND HERE I CAN SHOW YOU THE FIRST 20 PATIENTS THAT HAVE RECEIVED THIS MOLECULE INVIVO SINCE THIS IS THE FIRST HAD HUMANNINGS STUDY, WE STARTED AT A LOW DOSE AND SINGLE PATIENT ESCALATION WHERE WE DOUBLE THE DOSE WITH EACH NEW PATIENT WHO IS ENTERED. AND NUMBER 1 THERE'S GOOD ORO-BIOAVAILABILITY, MINIMAL TOXICITY TO DATE. WE HAVE PATIENT WHO IS HAVE BEEN ON TRIAL FOR PROLONGED PERIODS OF TIME. I DON'T HAVE YET HAVE DATA TO SHOW YOU THAT THERE ARE ANY ANY OBJECTIVE PARTIAL REMISSIONS IN THESE SOLID TUMOR PATIENTS BUT 18 CYCLES, 11 CYCLES, 8 CYCLES A LOT OF STABLE DISEASE SO IT'S LIKELY WE ARE DOING SOMETHING WITH THESE FOLKS, PERHAPS THIS IS GIVEN ORALLY ON A SCHEDULE WHERE THESE PATIENTS GET DAILY DOSING FOR 5 DAYS, GET THE WEEKEND OFF, GET 5 DAYS IN A ROW AND THEN A WEEK OFF. SO 5 DAYS ON, 2 DAYS OFF, 5 DAYS OFF AND THEN A WEEK. TWO WEEKS OUT OF 3 AND VERY WELL TOLERATED AND WHAT'S EXCITING TO US IS THAT MOST OF THESE PATIENT FIST NOT ALL HAVE CIRCULATING EPITHELIAL TUMOR CELLS IN THE CASE OF THE SARCOMA CIRCULATING MYZENCHEMALL CELLS, IN ALL CASES AFTER A COUPLE TREATMENTS THESE GO FROM NO EXPRESSION OF P16 TO EASILY MEASURABLE PERCENTS OF INCREASED PERCENTAGES OF P16 EXPRESSION IN THEIR TOMBER CELLS THAT CIRCULATE SUGGESTING WE'RE HAVE SOMETHING BIOLOGICAL EFFECT OF THESE MOLECULES. LET ME THEN CLOSE BY GIVING YOU AN IDEA OF A PROJECT THAT IS ALSO SOMETHING THAT THE NCI CAN DO LIKE THE PREVIOUS EXAMPLE WHERE THERE'S--ANYTHING NEW MODKIEWL BUT NO INTELLECTUAL PROPERTY THAT ESSENTIALLY NO PHARMA WOULD DO AND THIS IS THE STORY OF INDOCKS FIN. THIS COMES FROM A PROJECT THAT WAS FUNDED BY AN NCI SUPPORT GRANT, AND THEY ARE INTERESTED IN THE METABOLISM OF TAMOXIFEN WHICH HAS BEEN WELL KNOWN FOR A LONG TIME BUT--WE'RE ACTUALLY MOST INTERESTED IN THE FACT THAT THE ACTIVE METABOLITE OF TAMOXIFEN, ENDOCKS FENNISTERATION IS MORE ACTIVE INVITRO THAN THE PARENT MOLECULE AND ALSO ALSO AS A SERIES OF BIOLOGICAL ACTIVITIES THAT IS UNLIKE THE PARENT MOLECULE INHIBITS E. R. ALPHA ACTIVITY AND IT CAN OVERCOME RESISTANCE TO THE ENHANCERS ENVIF O. SO THEY THEN TOOK ON FARM CO GENETIC EXPERIMENTS BASED ON THEIR UNDERSTANDING OF THE METABOLISM OF TACK OX FENNISTERATION AND SHOWED--SHOWED THAT IN FACIENTS TREATED WITH TAMOXIFEN, LARGE NUMBERS ENTERED UNDER TRIAL AT THE MAYO CLINIC THERE WERE SUBSTANTIAL DRVESS IN THE PHARMA CO KINETICS OF THE ENDOXIFEN, AND THE METABOLITE BASE ON THE PRESENCE OR ABSENCE OF VARIANT OF SUBDUTY 6, THAT ACTIVATES TAMOXIFEN TO ENDOXIFEN, SO THEY THOUGHT THAT PERHAPS THERE'S A PERCENTAGE OF WOMEN WITH BREAST CANCER, MAYBE 15-20% WHO WHEN THEY GET TAMOXIFEN DON'T METABOLIZE IT SO THEREFORE IT'S INACTIVE AND THE OTHER THING THAT CAME TO INTO FOCUS ABOUT 5 OR 6 YEARS AGO WAS THAT MANY PATIENTS WITH BREAST CANCER ARE--LIKE MANY CANCER PATIENTS ARE SIMULTANEOUSLY ARE TAKING ANTIDEPRESS ABTS ALL OF WHICH ARE METABOLIZED BY [INDISCERNIBLE] AND INTERFERE WITH THE ACTIVATION OF TAMOXIFEN AND IF YOU DEVELOP THE END PRODUCT MOLECULE AND THEN GIVE THAT DIRECTLY, IT DIDN'T REQUIRE METABOLISM THAT MIGHT BE A USEFUL APPROACH TO MAISHT WHO IS HAD PROGRESSIVE DISEASE AFTER AROMA TAIS INHIBITOR WHO WOULD BE CANTIDATES FOR OTHERWISE TAMOXIFEN THERAPY TO BEGIN WITH SO BASICALLY WE THOUGHT THAT--MISTAKENLY--THAT BECAUSE THIS METABOLITE HAD BEEN IN THE BODIES OF MILLIONS OF WOMEN WHO HAD ALREADY GOTTEN TAMOXIFEN THAT THE FDA WOULD NOT REQUIRE A FULL TOXICITY PACKAGE, WRONG. THIS WAS A NEW MOLECULE SO THE NCI MADE GMP QUALITY ENDOX IFEN, AND STARTED 2 CLINICAL TRIALS IN HUMAN, IN ESSENCE STRANGE TO SAY THAT A METABOLITE THAT'S BEEN IN MILLIONS OF HAD YOU MANS BUT DIRECTLY ADMIN IFORTERRED 1 OF THE MAYO CLINIC IN PATIENT WHO IS HAD AROMA TAIS INHIBITOR RESIST ABT BREAST CANCER AND 1 AT THE CLINICAL CENTER, THIS STUDY IN WHICH PATIENTS ANY PATIENT WITH ESTROUGH ATOM GEN RECEPTOR POSITIVE DISEASE, BREAST CANCER OVARIANCE CANCER OTHER DISEASES THAT HAD CLEAR IMMUNE O HISTOCHEMISTRY WERE INTERESTED, AND WE'VE JUST RECENTLY COMPLETED THIS TRIAL AND SOME VERY NICE THINGS HAVE COME TO FORE. NUMBER 1, YOU CAN SEE IN THE BOX THAT THE PHARMACOKINETICS IS DRAMATICALLY DIFFERENT. ONE CAN DELIVER SAFELY MUCH, MUCH HIGHER CONCENTRATION OF THE ACTIVE METABOLITE BY ITSELF THAN YOU CAN WITH TAMOXIFEN. THERE HAVE BEEN MODEST TOXICITY. WE'VE UNEQUIVOCALLY HAD OBJECTIVE REMISSIONS OF EVIDENCE IN PATIENTS BEING RESISTANT TO AROMA TAIS INHIBITOR INHIBITOR WHICH IS IS NICE AND PROBABLY THE MOST IMPORTANT THING IS THAT WE'VE BEEN ABLE TO DEVELOP WITH THE HELP OF OUR MODEL CITIZEN LEAKULAR IMAGING COLLEAGUES IN THE CLINICAL CENTER TO USE FLUORO18 FLUOROESTROUGH ATOM DIAL PET SCANNING TO DEMONSTRATE A PATIENT WITH A BONE METASTASIS PRETREATMENT WHO GOT 5 DAYS OF TAMOXIFEN AND BASICALLY WE BLOCKED THE MOST LIKELY BLOCKED THE E. R. RECEPTOR AT THE SITE SO CHEMON STRAIGHTING PROOF OF MECH MECHANISM. NOW NOT CLEARLY EVERYONE WHO IS BLOCKED WILL RESPOND TO TREATMENT FOR A VARIETY OF OTHER REASONS BUT WE HAVE ABOUT A HALF DOZEN PATIENT WHO IS HAVE UNDERGONE THIS IMAGING TO DEMONSTRATE WE ACTUALLY HAVE DONE WHAT WE HOPED TO DO. AND LASTLY, BASED ON THESE RESULTS AND THE POSITIVE RESULTS FROM THE MAYO CLINIC TRIAL A PUBLISHED A KOWPY MONTHS AGO IN THE JOURNAL OF CLINICAL ONCOLOGY, A RANDOMIZED PHASE 2 TRIAL, AND AROMA TAIS INHIBITOR INHIBITOR INHIBITION POST MENOPAUSAL PATIENT WHEN IS IT LAWRVED BY THE COPRAATIVE GROAP AND WE EAGERLY AWAIT THE OUTCOME OF THAT STUDY. SO I WOULD LIKE TO CLOSE AND THANK MANY PEOPLE WHO HAVE BEEN INVOLVED IN THESE ACTIVITIES FROM A VERY, VERY EARLY STAGE TO OUR EARLY STAGE CLINICAL TRIALS AND HAPPY TO TAKE QUESTIONS. >> THANK YOU JIM. WE'RE OPEN FOR QUESTIONS. COULD YOU SAY MORE ABOUT THE KAN--KANAINE POPULATION YOU HAVE FOR ADVANCED PRECLINICAL TESTING. SO THIS IS A WONDERFUL RESOURCE AND THEE HAD A REAL NEED TO DEVELOP MODELS FOR OFTIO GENIC SARCOMA WHICH IS THE FOCUS OF HIS RESEARCH AND THOSE OCCUR COMMONLY IN KAN--KANAINE PATIENTS BUT TO DO THAT THEY HAD TO SET UP A GROUP OF CENTERS AROUND THE COUNTRY. THERE ARE 20 + INSTITUTIONS AND CENTERS. UC DAVIS, MANY, MANY EN--STRATEGIES TUITIONS AND HAVE ORGANIZED THAT OPERATION REALLY LIKE A COOPERATIVE GROUP THAT ARE UNDER [INDISCERNIBLE] IN ECDTD AND THEY CARRY OUT STUDIES AND YOU WILL SEE DATA IN RALPH'S PRESENTATION. FOR THE FIRST WEEK, WE CONDUCTED A SERIES OF NOVEL STRUBLGHTURES WITH THE ISOQUINNA LINES, WE DID A RANDOMIZED PHASE 1 TRIAL OF 3 COMPOUNDS BECAUSE FROM THE ANIMAL--FROM THE MOUSE DATA WE COULD NOT DECIDE WHAT WAS THE BEST THING TO MOVE FORWARD THAT WASN'T ENOUGH DATA AND I DON'T THINK RALPH WILL PRESENT ALL THAT INFORMATION BUT IT WAS INCREDIBLY USEFUL NUMBER 1. WHAT COULD WE USE, WE COULD ACCRUE FASTER IN THE KACCT TIEN ONCOLOGY PROGRAM THAN IN OUR COOPERATIVE KAN--KANAINE TRIALS. WE COULD GET BIOPSY SPECIMENS FOR RELATIVE STUDIES ON A TIME SCALE. NOT ONLY DID THEY COME IN QUICKLY BUT THEY COULD BE DONE AT TIME POINTS THAT YOU COULD NEVER DO IN A HUMAN AND WE COULD GET--THE VETERINARY ONCONSTS WHO RUN THESE TRIALS ARE QUITE EXPERT CLINICAL TRIALISTS SO WE COULD GET EXPERT DATA ON EFFICACY OF THE COMPOUNDS WE WERE STUDYING. SO BASED ON THAT EXPERIENCE WHERE WE FOUND 1 OF THOSE 3 AN LOGS TO BE SUBSTANTIALLY BETTER WITH THE RESPONSE RATE WAS 80% VERSES 30%. WE HAD TAKEN THAT COMPOUND, I HAVEN'T TALKED ABOUT IT HERE BUT IT'S IN PHASE 1 TRIAL IN THE CLINICAL CENTER. THAT WE PRODUCED THAT TRIAL AND THE OPPORTUNITY IS SIGNIFICANT IN TERMS OF TAKING MOLECULES AND THERE ARE SOME MAJOR FORM SUITICAL COMPANIES IN THIS APPROACH. SOME ARE LESS INTERESTED BUT FROM MY PERSPECTIVE, THE ABILITY TO DO FORM CO DYNAMIC STUDIES PROOF OF MECHANISM STUDIES AND THE TISSUE AND THE TIME POINT SYSTEM UNPARALLELED. SO WE ACTUALLY HAVE A WHOLE PROGRAM NOW WITH THE COMPARATIVE ONCOLOGY GROUP SO THAT BASICALLY EVERYTHING WE THINK IS LIKELY TO GO INTO THE CLINIC THAT HAS NOT ALREADY BEEN STUDIED IN THIS WAY IS NOT OUTLICENSED WHERE THE PHARMACEUTICAL COMPANY TAKES OVER THE RESPONSIBILITY WILL GO THROUGH THIS PROGRAM TO DEVELOP REALLY DEFINITIVE DYNAMIC INFORMATION THAT WILL ALLOW US TO USE ASSAYS IN PATIENTS WITH A BETTER UNDERSTANDING. WHAT'S THE TIME POINT, WHEN SHOULDLET BIOPSY BE TAKE EXPEN I THINK IT'S A WONDERFUL OPPORTUNITY. THAT'S A TREMENDOUS RESOURCE, THATIA A NATURALLY OCCURRING TUMOR SO FROM AN IMAGING POINT OF VIEW THEY'RE FAR SUPERIOR AND I SHOULD SAY THAT OUR COLLEAGUES IN THE CCR WHO RUNS THIS PROGRAM ACTUALLY WORKS IN THE IMAGING GROUP IN THE CCR, SO THESE DOGS ACTUALLY HAVE BEEN IMAGED AND EVEN SOME VERY SOPHISTICATED IMAGING, PROACHS HAVE BEEN APPROACHED AND BEEN UTILIZED, THE THING I DIDN'T REALIZE AT ALL IS THAT THERE ARE MANY MORE--SOMETHING LIKE--MY UNDERSTANDING IS THERE'S SOMETHING LIKE 57,000 NONHODGE KINS LYMPHOMA KAN--KANAINE PATIENTS PER YEAR IN THE UNITED STATES, FAR MORE OF THEM THAN HUMANS FOR LYMPHOMA SO IT'S A REMARKABLE OPPORTUNITY. >> OTHER QUESTIONS? EDDIE? I THINK YOU WOWED THEM. OKAY. >> LET ME THEN INTRODUCE--IF WE'RE GOING--WE'RE GOING TO LUNCH. >> CAN I JUST SAY 2 WORDS ABOUT AFTER LUNCH SO I WILL START WRITING. --SO, RIGHT AFTER LUNCH YOU WILL HEAR FROM RALPH P A RCHMENT WHO HAS BEEN MY VERY, VERY CLOSE AND STRONG COLLEAGUE FOR A DECADE WHO REALLY HELPED US DEVELOP A FARM CO DYNAMIC CAPACITY IN FREDERICK, I THINK THAT YOU WILL SEE A SMALL FRACTION OF THE TECHNOLOGY TRANSFERS THAT HE'S BEEN ABLE TO DO THAT REALLY HAVE BEEN INCREDIBLY USEFUL TO ALL THE DRUG DEVELOPMENT ACTIVITIES THAT WE'VE UNDERTAKEN AND JEFF MOSCOW WHO OVERSEES OUR EARLY PHASE CLINICAL TRIALS PROGRAM THAT HAS MORE AND MORE UTILIZED THESE ASSAYS. I WILL TRY TO DIRECT WHAT WE DO IN THE CLINIC. SO THANK THANK YOU >> THANKS, JIM. WE WILL HAVE A LUNCH BREAK AND THEN WE WILL HAVE A CLOSED ADMINISTRATIVE SESSION AT LUNCH AND WE WILL BE BACK FOR THE OPEN SESSION AT 1:15. >> WELCOME BACK. WE ARE ABOUT TO BEGIN THE AFTERNOON SESSION WITH A CONTINUATION OF THE DISCUSSION FROM THE NEXT PROGRAM AND SO THIS IS ON THE ROLE OF MOLECULAR FARM CODYNAMMICS AND BOTH DRUG DISCOVERY AND DEVELOPMENT. RALPH P A RCHMENT. RALPH? >> THANK YOU, LARRY. IT'S A PLEASURE TO BE HERE. MY NAME IS RALPH P A RCHMENT, I AM THE DIRECTOR OF THE FARM CO DYNAMIC LAB. IT'S BEEN 7 OR 8 YEARS SINCE PRESENTING TO YOU LAST TIME AND MADE SIGNIFICANT PROGRESS IN THE FIELD OF FARM CO DYNAMICS AND THE APPLICATION TO THE NEXT PROJECT TEAMS. INTENTIONAL CONNECTIONS TO THE WIDER RESEARCH COMMUNITY AND THE TRANSFER OF THE PD KNOWLEDGE OUTSIDE OF FREDERICK. SO I'M SURE AS YOU KNOW, PHARMACODYNAMICS IS LOOSELY TERNED BY WHAT THE A DRUG DOES TO BODY, WHICH IS PHARMA CO DYNAMICS WHICH IS WHAT THE BODY DOES TOLET DRUG. AT THE MOLECULAR LEVEL, PHARMACODYNAMICS FOCUSES ON TRARGET, STRUCTURE AND FUNCTION AS WELL AS DOWN STREAM AT THE BIOCHEMICAL AND CELLULAR LEVEL. AND IF THOSE CHANGES WITH BE REPRODUCIBLY MEASURES THEY CAN BE CANDIDATE BIOMARKERS TO ASSESS AND QUANTIFY DRUG EFFECT AND THERE'S WO0 IMPORTANT PRINCIPLES IN PHARMACODYNAMICS THAT SORT OF PROVIDE A FRAMEWORK FOR THINKING ABOUT AN APPROACH IN THE DRUG AND THE ASSESSMENT. THE 50 IS PROOF OF MECHANISM OF ACTION, WHAT THAT MEANS IS CONFIRMING THAT THE DRUG ACTS AS IT'S DESIGNED TO DO ON ITS INTENDED TARGET, THIS IS ESPECIALLY IMPORTANT WHEN JUMPS FROM THE LAB TO ANIMAL MODELS AND ALSO TRANSLATIONALLY JUMPING FROM ANIMAL MODELS AND FIRST IN HUMAN STUDIES. THAT MECHANISTIC INFORMATION OFTEN DRIVES THE CLINICAL DEVELOPMENT PLAN AND DOES SCHEDULING ON A NUMBER OF FACTORS AND IT'S IMPORTANT TO CONFIRM THAT THE MECHANISM IS THE SAME AS INTENDED COMING OUT OF THE DISCOVERY SPACE. THE SECOND IMPORTANT PRINCIPLE IS PROOF OF CONCEPT. THIS IS REALLY RELATING DRUGS, MECHANISM OF ACTION ON TARGET TO ITS EFFICACY. IN OUR RECENT WORK IN THE TIEN ACE INHIBITORS ILLUSTRATES THIS, SO IN THE CENTER, WE SEE THE RESULTS OF MECHANISM STUDY WHERE 3 INHIBITORS WERE ADMINISTERED A SINGLE DOSE. THEY ARE SHOWN HERE TO MICE HARBORS UCFXENO GRAPH TUMORS, IT'S CONTROLLED BY PHOSPHORYLATION OF A SPECIFIC TYROSEEN RESIDUE, AND A CANDIDATE BIOMARKER IS MEASURING THE PROPORTION OF MET MOLECULES IN THE TUMOR THAT ARE FOSTER NURSED FARALATED AT THAT--PHOSPHORALATED AT THAT SITE. SO THIS MEASURES THAT PROPORTION OR RATIO. WHAT'S SHOWN HERE IS THE RESPONSE OF THAT BIOMARKER OVERTIME TO INCREASING DOSES OF THESE 3 INHIBITORS. SO WHAT YOU CAN SEE IS THAT THE INHIBITORS CAUSE DOSE DEPENDENT AND TIME DEPENDENT DURATION DEPENDENT INHIBITION OF THAT BIOMARKER BUT WHAT YOU WILL ALSO NOTE, I THINK IS THAT THE DURATION OF CONTROL OF THE MOLECULAR TARGET DIFFERS ACROSS THE 3 AGENTS. SO WHAT THIS MEANS IMPORTANTLY IS THAT THE SAME DOSAGE REGIMEN OR SAME DOSE AND DOSE SCHEDULES CAN'T BE USED FOR ALL 3 COMPOUNDS TO ACHIEVE EQUAL DEGREE OF MOLECULAR TARGET CONTROL. THEY HAVE TO BE CUSTOMIZED AROUND THE PHARMACODYNAMIC RESPONSE. SO BY DESIGNING THOSE DOSAGE COMPOUNDS FOR EFFICACY AT THESE DOSE LEELS AND THESE SCHEDULES, WHICH SHARE IN COMMON THE ABILITY TO MAINTAIN TK SUPPRESSION OF MET AT LEVELS OF 90% OR GREATER THROUGHOUT THIS ENTIRE DOSING PERIOD, SHOW THAT CONCEPTUALLY THAT ACHIEVES THE SAME DEGREE OF TUMOR CONTROL INDEPENDENT OF THE STRUCTURE OF THE COMPOUND. SO THAT PD GUIDANCE, THAT'S A PROOF OF CONCEPT THAT EQUAL LEVELS OF MOLECULAR TARGET CONTROL YIELD DEGREES OF EFFICACY. NOW DURING THIS WORK, WE FOUND THAT MANY OF THE AVAILABLE ANTIBODIES THAT RECOGNIZE TYROSEEN 1235 IN THE PHOSPHORALATED IN MET HAVE DUBIOUS SPECIFICITY. IN FACT, 1 OF THE COMMONLY USED CLONES CALLED D26 THAT'S USED IN MANY STUDIES THAT HAVE BEEN PUBLISHED, WE FOUND WOULD RECOGNIZE MET EVEN WHEN TYROSEEN 35 WAS REPLACED BY ASPARTIC ACID. IMPOSSIBLE TO BE PHOSPHORALATED. SOPHISTICATEDY WE CREATE A NEW MONOCLONAL ANTIBODY AND IT'S PHOSPHORALATED FORM AND IT RECOGNIZES THAT RESIDUE SPECIFICALLY AND INDEPENDENTLY OF THE PHOSPHORYLATION STATUS OF THE ADJACENT AMINO ACID TYROSEEN 34, THIS IS A HIGHLY SPECIFIC ANTIBODY AND WE DEPOSITED THIS ANTIBODY AT THE UNIVERSITY OF IOWA DEVELOPMENTAL STUDIES BANK SO THE COMMUNITY CAN ACCESS IT. THEY'RE CONVERTING IT TO RECOMBIN ANT FORM SO IT CAN BE REDUCED AT MILLIGRAM LEVELS.--A NUMBER OF COMPOUNDS DEVELOPED IN THE CLINIC, THIS DEVELOPMENT EFFORT WAS RECENTLY REVIEWED A COUPLE MONTHS AGO BY HUGHS HUGHS AND SEMEN, AND IN THIS REVIEW, A INCLUDE A 157 CLINICAL TRIALS AND FOUND THAT 0 OF THOSE 157 TRIALS USED PD GUIDANCE CONFIRM MECHANISM ACTION OR TO SET DOSE SCHEDULES. AND IN FACT ONLY 14 OF THOSE 157 TRIALS USE ANY BIOMARKER AT ALL THAT HAD ANY RELATIONSHIP TO THE 1235 SITE IN THE ACTIVATION OF MET TYROSINE KINASE ACTIVITY. SO WHAT THEY CONCLUDED WAS THAT MET TK DEVELOPMENT REALLY HAS NOT STARTED YET. THERE'S JUST BEEN A BUNCH OF TRIALS AND WHAT THEY CALLED FOR AND THIS IS A BIT SELF-SERVING BUT I THINK IT'S IMPORTANT--OOPS IS THAT THERE'S AN ASSAY AVAILABLE, THIS IS THE ASSAY I DESCRIBED TO YOU AND THAT THIS ASSAY SHOULD BE INTEGRATED INTO THE FUTURE DEVELOPMENT PLANS FOR MET INHIBITORS [INDISCERNIBLE]. SO FOSTER NURSED FOCUSED ON SITES OF PROTEINS ARE USUALLY INVOLVED IN RAPID MOLECULAR RESPONSES, THAT ALSO MAKES THEM HIGHLY LABILE DURING THE HANDLING AND PROCESSING DOWN STREAM. AND MET'S NO EXCEPTION TO THIS. SO PART OF THIS SUCCESSFUL STUDY OF MET PHARMACODYNAMICS WAS FINDING OUT THAT THE FOSTER NURSED FOCUSED ON SITES IN MET ARE EXTREMELY LABEL EVEN UNDER CONDITIONS OF COLD ECSCHEMIA, THAT MEANS AMBIENT RHEUM TEMPERATURE LIKE YOU MIGHT FIND IN A CLINICAL PROCEDURE ROOM, LIKE A BIOPSY SUITE. WHAT YOU CAN SEE HERE IS THAT FOSTER NURSED FOCUSED ON MET RESIDUE IS NEARLY COMPLETELY LOST WITHIN 4 MINUTES OF REMOVING THE TISSUE FROM THE SAMPLE FROM THE TUMOR AND IN ORDINANCE NUMBER TORE SUCK SEDENTARY WE HAD TO DEVELOP AN SOP WHICH INVOLVED RAPID SNAP FREEZING OF THE BIOPSY AT POINT OF COLLECTION, SO CLINICALLY THIS MEANS IN THE RADIOLOGY SUITE, PRECLINICALLY IT MEANS WHERE THE MICE ARE HANDLED AND SAMPLED. STORING THAT IN THE SNAP FROZEN CONDITION, AND THAT'S BEEN ABLE TO SOLVE THIS PROBLEM AND MADE THE ANALYSIS OF FOSTER NURSED FOCUSED ON MET POSSIBLE. DISP WE SHARE THESE THROUGH THE BIOMARKER RESEARCH AND RESOURCES AND TAKEN--THEY'S THE WEBSITE. SO WE FOUND THAT OUR SOP FOR PRESERVING THOSE BIOSPECIMENS ALSO RESOLVES AN ISSUE WITH THE MOST NOTORIOUSLY LABELED BIOMARKERS KNOWN TO HUMAN KIND WHICH IS PHOSPHORALATED AKT. THIS ISSUE WAS RAISED YEARS AGO BY THE GARTH LAB, SHOWING THAT FOSTER NURSED FOCUSED ON AKT FTION RAPIDLY DEGRADED AND THERE WAS NO METHODOLOGY TO STABILIZE IT AT THE TIME AND THAT MEANT THERE WAS A HIGH VARIABILITY IN FOSTER NURSED FOE KT MEASUREMENTS BETWEEN PRENATAL COORDINATED BIOPSY AND A COMPLETE LOSS IN SURGICAL SAMPLES. SO YOU CAN IMAGINE IF YOU ARE TRYING TO QUANTIFY A FORS% CHANGE IN FOSTER NURSED FOCUSED ON AKT THAT THIS VARIABILITY WON'T ALLOW IT. BUT THAT'S TECHNICAL VARIABILITY AND NOT BIOLOGICAL VARIABILITY. SO WE FOUND THAT OUR SOP WILL PRESERVE THE FOSTER NURSED FOE AKF AND USING THAT NEWLY DEVELOPED ASSAY TO MEASURE KEY FOSTER PHOSPHO SITES IN AN AKT ISOLINED SPECIFIC MANNER THAT WE CAN ATIEN REPRODUCIBLE MEASUREMENTS IN AKT IN PRECLINICAL MODELS AND THAT THE BIOLOGICAL VARIABILITY IS SUFFICIENTLY SMALL THAT WE CAN DEMONSTRATE A DRUG EFFECT BY TREATING THOSE TEAM MEMBERS WITH PI3 INHIBITORS. THIS WORKS NICELY NO MATTER IF THE SPECIMEN GUESS TO EXTRACTION AND ASSAY OR CUTS SECTIONS BUT THE IMPORTANT POINT TO MAKE THIS SUCCESSFUL IS THE HANDLING OF THE BIOPSY SPECIMEN ONCE IT,A RIEFS IN THE ANALYSIS LAB. WE FOUND THE ONLY WAY TO STABILIZE THE FOSTER NURSED FOCUSED ON MARKERS IN EITHER SITUATION IS TO THAT YOU OUT THE SPECIMEN UNDER EXTRACTION BUFFER WITH PROTEASE AND FOSTER NURSED FOCUSED ON TASE INHIBITORS OR THAT YOU OUT--THAW OUT THE SPECIMEN. OTHER WAYS OF DROPPING THE ROOM TEMPERATURE IN PRESERVING ISN'T SUFFICIENT NOR IS ALIGNING THE SNAP BIOPSY TO THAW AND THEN ADDING PRESERVATION MEDIA, IT HAS TO BE DONE THIS WAY OR YOU'LL LOSE THE PHOSPHO SIGNAL. SO BEING ABLE TO USE THESE MARKERS REDUCES DAMAGE AS WELL. THIS IS OUR PORTFOLIO AND YOU WILL SEE THAT MANY OF THEM ARE PHOSPHORALATED, HERE, HERE, HERE, HERE, HERE. AND THOSE PHOSPHORYLATION EVENTS ARE RESPONSES, MOLECULAR RESPONSES TO DNA DAMAGE SO WE WOULD LIKE TO ASEPS THEM AND WE FOUND THE SOP, THE FUNDAMENTAL SOP FOR PRESERVING PROTEINS PRESERVES AS NUCLEAR MARKERS AS WELL. AND WE'VE APPLIED A NEWLY DEVELOPED IFA THAT MEASURES 3 NEW NUCLEAR MARKERS FOR DAMAGE RESPONSE, RAD 51 FOCUSED FOCI, AND 149 AND IN A SERIES MUCH COLON RECTAL CANCER BIOPSIES FROM THE DEVELOPMENT OF THERAPEUTICS CLINIC IN BETH ESTIMATE THAD KACCT,--BETHESDA, WE FOUND THE BASE LINE NATURALS OCCURRING VALUES OF THESE BIOMARKERS BUT IT ALSO STRESSES THAT THE THESE 3 BIOMARKERS PROVIDE INDEPENDENT ASSESSMENT OF DNA DAMAGE THAT'S VERY IMPORTANT BECAUSE NLT EARLY CLINICAL TRIAL, THERE'S USUALLY AN OPPORTUNITY TO GET 1, MAYBE 2 SAMPLING TIME POINTS BY BIOPSY. SO HAVING A MULTIPLEX ASSAY WITH INDEPENDENT MARKERS IMPROVES THE ODDS OF FINDING A DDR SIGNAL AT THAT SINGLE TIME POINT. NOW IF YOU AGGREGATE THAT CLINICAL DATA, SHOWN BELOW, YOU CAN SEE THAT YOU START TO SEE AN UPPER LIMIT ON THE NATURAL BASE LINE RANGE OF THESE VALUES. AND THIS IS REALLY IMPORTANT TO ESTABLISH BECAUSE A DRUG EFFECT, IN ORDER TO CONCLUDE THERE'S BEEN A FARM CO DRUG EFFECT THESE WOULD HAVE TO RISE ABOVE THAT NORMAL RANGE TO REACH STATISTICAL SIGNATURES NOVEMBER CANC. SO WE'RE CONFIRMING THESE DATA IN THE LARGER SERIES OF COLORECTAL PATIENTS AND WE HOPE TO SOON SUBMIT THESE CUT OFF VALUES THAT ALLOW THESE PEOPLE TO FINALLY INTERPRET THESE BIOMARKER LEVELS AT LEAST FOR 33 BY O MARKERS NOW THE OTHER INDEPENDENCE THAT YOU SEE IS IN TUMOR HETEROGENEITY. SO HERE YOU SEE A EXTEN O GRAPH MODEL TREATED WITH TOP O TICAN, AND IT'S AFTER WORD, AND IT'S STAIN WITH THE MULTIPLEX SARKS A, RAD 51, FOCI IS GREEN, PHOSPHORYLATIONED SYRIAN 343 IS GOLD COLOR AND 139 IS THE PINK, PINKISH RED, BLUE IS NUCLEAR MASKING. AND I THINK WHAT YOU ALL WILL AGREE, YOU SEE IS TREMENDOUS BIOMARKER RESPONSE TO JUST A SINGLE DOSE OF TOPOTICAN AT A SINGLE TIME POINT. SOPHISTICATEDY WE DEVELOP IMAGE ANALYSIS PIPELINES TO ANALYZE THIS TYPE OF SITUATION AND ASK HOW MANY CELLS ARE POSITIVE FOR 1 MARKER, 2 MARKERS, 3 MARKERS, IS IT RELATED TO CELL CYCLE, STAUS OR NOT. HOW TO INTERPRET THAT BIOMARKER RESPONSE. ONE PARTICULARLY DIFFICULT BIOMARKER TO INTERPRET IS THE GAMMA H2 AX MARKER, THAT MARKS DOUBLE STRAND BREAKS AND AS YOU KNOW CHEMO THERAPEUTICS INDUCE DOUBLE STRAND BREAKS BUT THE ENDONUCLEACE WITH APOPTOSIS ALSO CLEAVES BY INTRODUCING DOUBLE STRAND BREAKS. SO IT'S POSSIBLE THE GAMA H2 X INDICATES BOTH OF THOSE PROCESSES AND THEREFORE THE INTERPRETATION TO BE ABLE TO INTERPRET GAMMA H 2 X RESPONSE AND WE HAVE TO DISTINGUISH THOSE 2 OUTCOMES. IT TURNS OUT THAT DURING STRUCTURES THAT FORM IN THE CYTOPLASM WHICH HAVE BEEN CALLED PUNCTA, THEY FORM AROUND CYTOKERRA KERATINS AND THEY HAVE 3 KASP A R PACE 3 POSITIVE. SO WE THOUGHT WE SHOULD ADD THAT MEASUREMENT OF CASP A S SPACE TO THE NUCLEAR GAMMA H2A X TO GET A SPECIFIC MEASUREMENT OF APOPTOSIS. AND THAT TURNED OUT NICELY HERE, THERE'S IMAGES WHERE YOU CAN SEE GAMMA HTWORKS X SCREEN AND CLEAVE CASP A S 3, PUNKTA RED, THE MDA 231 MODEL IS RESPONSIVE TO VERINO PATH IN A DOSE RESPONSIVE MATTERED BUT THE OTHER MODELS ARE COMPLETELY RESISTANT AND WE USE THAT TO VALENTINED DAID THE BIOMARKERS AND HERE IT SHOWS THE DATA. THE PRESENT POSITIVE CELLS IN GAMMA H2 X IN GREEN AND THE SUBSET THAT ARE ALSO POSITIVE FOR CLEAVED CASP A CE, AND ADDING THAT SECOND BIOMARKER MAKES FOR A DRAMATIC INCREASE IN THE SPEC SPECIFICITY AND THE ABILITY TO INTERPRET THE GAMMA TWOKS 2 X CIRCLE AND THE MODEL DID NOT SHOW A RANGE IN EITHER. NOW THE CONVERSE HAPPENS IN THE PLATINUM RESISTANT MODEL. SO IN THIS MODEL A2780 XENOGRAPHS WERE TREATED AT INCREASING DOSES. YOU CAN SEE THE TUMOR DOESN'T RESPOND WELL AT ALL, TO SIS PLATIN BUT THERE'S A GAMMA H2 X RESPONSE AFTER THE DOSE. HOWEVER, NOTE THAT THAT GAMMA H2 X RESPONSE IS ROBUST IS NOT ASSOCIATED WITH THE APPEARANCE OF THE CLEAVE CASP A CE, GLOVES SO THE INTERPRETATION OF THIS GAMMA H2 X SIGNAL IS GAMMA INDUCED DOUBLE STRAND BREAKS THAT ARE REPAIRED AND DON'T LEAD TO APOPTOSIS. WE'VE TESTED THIS ASSAY IN SPONTANEOUS NONHODGE KINS LYMPHOMA MODEL, DOGS. THESE DOGS WERE ON A VETERINARY CLINICAL TRIAL, TREATED WITH INVESTIGATIONAL TOPO 1 INHIBITORS FROM THE INDIN O ISOQUINN LAN CLASS COMING FROM THE NCI DEVELOPMENT PROGRAM. THESE IMAGES SHOW THE PD BIOMARKER RESPONSE AND BIOPSIES 2 AND 6 HOURS AFTER DOSING OF THE PARTICULAR INDIN O ISOQUINN LAN, BOTH OF THOSE DOGS ARE RESPONDERS SO GREATER THAN 60% SHRINKAGE OF TUMOR. AND WHAT SHOULD BE APPARENT IS THE H2 X POSITIVE CELLS ARE ALSO POSITIVE FOR THE CLEAVE CASP A CE 3 PUNKTA IN THE CYTOPLASM. THEY DIFFER IN THE TIME COURSE AND YOU CAN IMAGINE THAT MAYBE THE PEEK TIME FOR SAMPLING IS SOMEWHERE IN BETWEEN. BUT CLEARLY BOTH OF THEM SHOW THAT APOPEITOSEIS SPECIFIC PROFILE. IT ALSO SUGGESTED THAT THERE MAY BE 2 END POINTS WE COULD USE CLINICALLY TO MEASURE APOPTOSIS OR QUANTIFY APOPTOSIS AND 1 OF THOSE IS THE MAX PERSET CELLS IN APOPTOSIS WHICH IS INDICATED BY THESE ORANGE BARS OR THE MAXIMUM PERCENT OF H2 X POSITIVE CELLS THAT ARE ALSO POSITIVE FOR CLEAVE CASP A CE 3, AND YOU CAN SEE THE VALUES OF THOSE END POINTS IN THE T-RESPONDERS VERSUS THE NONRESPONDING PATIENTS. AND JUST TO POINT OUT THE IMPORTANCE OF HIGH THROUGH PUT MICROSCOPY IN IMAGE ANALYSIS, IS THAT THESE DATA ARE BASED ON THE EVALUATION OF 15,000 CELLS PERBIOPSY WHICH IS NOT POSSIBLE THROUGH MANUEL COUNTING AND THE PIPELINE HAS BEEN SO IMPORTANT, SO APOPTOSIS IS IMPORTANT PROCESS, OBVIOUSLY CANCER DRUG DEVELOPMENT AND TREATMENT. SO WE'VE ALSO DEVELOPED A FIT FOR PURPOSE ASSAY THAT MEASURES 15 AN LIGHTS INVOLVED IN INTRINSIC APOPTOSIS INCLUDING THOSE AN LIGHTS SHOWN IN BLUE, WHICH ARE HETEROGENEOUS ROW DIMERS THAT ARE IMPORTANT CONTROL POINTS IN MEDIATION OF APOPTOSIS, THIS WAS MADE POSSIBLE BY TECHNOLOGY. Q.THE PROTEIN EXPRESSION LAB AT FREDERICK, DON'S LAB, HE WAS ABLE TO ENGINEER THESE INHIBITORS SO WE HAD CALIBRATOR CONTROLS TO SHOW OUR TISSUE PROCESSING SOP COULD STABILIZE THOSE DIMERS AND THAT WE COULD FIND THEM, MEASURE THEM IN THE ASSAY. CLEAR . IT ALSO INVOLVES THE BIOPSY IN A CYTOPLASMIC AND MEMBRANE FRACTION MONITORED BY THESE MARKERS BECAUSE THE ASSAY SO THAT WE COULD OBTAIN ADDITIONAL INFORMATION ABOUT THESE BIOMARKERS NOT JUST THEIR LEVEL BUT THEIR MOVEMENT BETWEEN THE CYTOSWROAL AND THE MIGHT O CONDRIAL FRACTIONS BECAUSE THAT'S PART OF THEIR CONTROL OF APOPEITOSEIS. SO USING THE SAME MODEL YOU'VE RESPONSIVE AND NONRESPONSIVE, TREATMENT WITH THE KASP A R PACE SIGNATINAL, AND YOU SEE THAT HERE IS AND IT WAS CORROBORATED IN CYTOSOLIC LEVELS OF NUCLEAR LAMIN B, INCREASES RESULT FROM THE PROTEIN COMPLEXIOL SIS OF LAMIN B AND RELEASED INTO THE CYTOSOL. THERE WAS NO BIOMARKER RESPONSE IN THE NONRESPONSIVE BOTTLE. THIS THE REFERRED TO EARLIER IN THE PROJECT TEAM IN THE BIOLOGIC CONSORTIUM. THEY USE AN APOPTOSIS ASSAY TO INFORM THEIR LEAD IDENTIFICATION AND OPTIMIZATION AND THIS JUST SHOWS TYPICAL DATA, THIS IS SINGLE DOSE DATA OF ALL THESE DIFFERENT AN LOGS, THE END POINT OF THE ASSAY, THE TEAM FELT WAS MOST INFORMATIVE WAS HETEROGENEOUS ROW DIMER LEVELS IN THE MITOCHONDRIAL FRACTION. SO MECHANISTICALLY, THAT'S BECAUSE MCL 1 INHIBITOR, RELEASED THIS BACK, ALSO, ALLOWS BIM TO MOVE BACKS AND COMPLEX WITH BACK IN THE OUTER MITOCHONDRIAL MEMBRANE. SO THIS WAS A DIRECT MEASUREMENT OF THE INTENDED MECHANISM OF ACTION OF THE MCL INHIBITORS. AND THAT PLAYED OUT AT PROOF OF CONCEPT BASED ON THIS END POINT TURNED OUT TO BE EFFECTIVE TUMOR CONTROL AS WELL IN XEIN, OGRAPH MODELS. SO THERE'S BEEN A LOT OF FOCUS ON THIS IN THE FARM AENTITIES AND THE ORIGINAL PANEL WAS MODZIFIED SLIGHTLY AND COMMERCIALIZED BY BIOFOR PURCHASE FOR OUR ROLE AT FREDERICK IS TO PROVIDE LABORATORY TRAINING OF PEOPLE WHO WANT TO RUN THE ASSAY IN THE HANDLING AND PROCESSING OF BIOPSIES AND THE FRACTION OF THE MEMBRANE FRACTIONS, THAT'S THE --ASSAY. AGAIN, THEY KNOW ABOUT THAT PROGRAM ON THE BIOMARKER WEBSITE AS WELL AS JUST THROUGH COMMUNICATION AT THE TEAM LEVEL. AMPERSAND BIOSCIENCES PICKED UP THE ASSAY. THEY OFFER FEE FOR SERVICE MODEL, GOOD LABORATORY PRACTICE BUT NOT CLA. IF IT NEEDS A DIAGNOSTIC CLEA USE, RBMMYRIAD PROVIDES THE CONTRACT TO THE COMMUNITY. SO JUST TO CONCLUDE THEN, I WANTED TO LIST THE NUMBER OF WAYS THAT THE PD PROGRAM SUPPORTS CBC DISCOVERY TEAMS AND ETCTN DEVELOPMENT TEAMS, WE BELIEVE IN PHARMACODYNAMICS OBVIOUSLY AND WE ROUGH TRY TO PROVIEDMAN A NUMBER OF AVENUES FOR THE TEAM TO ACCESS THE PD TECHNOLOGY SO IT RANGES FROM ESPECIALLY GENERATING NEW MONOCLONAL ANTIBODIES. WHAT OFTEN HAPPENS IS THE TEAM DESIGNS A DRUG WITH THE SPECIFIC INTENDED MECHANISM OF ACTION. THERE'S NO ANTIBODY AVAILABLE TO MEASURE THAT MECHANISM SO WHAT WE DO IS, WITH APPROVAL IS LAUNCH A PROGRAM TO CREATE AN ANTIBODY, SPECIFICALLY RECOGNIZES THE CHANGE CAUSED BY THOSE DRUGS. BUT THERE'S A NUMBER OF OTHER WAYS INCLUDING DISTRIBUTING ASSAY KITS. WE ALSO HAVE A FREDERICK PROGRAM WHERE USERS CAN COME AND TRAIN IN THE USE OF THE ASSAY, AND THEN WE TRANSFER KEY REAGENTS, PROFICIENCY PANELS, TEST SPECIMENS TO THEIR LAB RATOORY SITE--LABORATORY SITE WHEN THEY RETURN BACK AND DO A FORMAL TRANSFER UNDER THE SOP AND TEACH THEM HOW TO DO THE ASSAY AND THEREBY CREATE A NATIONAL NETWORK OF USERS OF THE ASSAY AND WE MONITOR THAT FOR TRENDING AND FOR ASSAY PERFORMANCE AND WE CAN ACTUALLY COMMUNICATE AS A NETWORK OF ASSAY LABORATORIES. AND MORE RECENTLY WE'VE BEEN CONTRIBUTING TO THE SCIENCE OF TUMOR SAMPLING. IT'S A LITTLE BIT DIFFERENT FOR BIOSPECIMEN SCIENCE. THIS IS ACTUALLY PREANALYT CALVARIABLE CONTROL. --PREANALYTICAL VARIABLE CONTROL. WE FOUND THIS IS IMPORTANT THAT MIEWNICATION BETWEEN THE LABORATORY OTHER PATHOLOGY, ONCOLOGIST RUNNING THE TRIAL AND FEEDING BACK WHAT THE RADIOLOGIST SEES AND BIOPSY, RESULTS FROM THE IMAGE AND IMPROVE THE SAMPLING UPFRONT AND WHAT WE'VE BEEN ABLE TO DO IS RAISE YOUR SUCCESS RATE IN ANALYZING PAIRED BIOPSIES FOR ABOUT 60% TO OVER 80% IN THE LAST YEAR JUST THROUGH TAKING THIS COURSE OF ACTION. AND IT ALSO STIMULATED A CONFERENCE LAST SPRING BETWEEN PATHOLOGIES AND RADIOLOGYSTS OF RETHINKING BIOPSIES FOR CORRELATIVE STUDIES. THESE ARE NOT DIAGNOSTIC APPLICATIONS, CORRELATIVE APPLICATIONS. COMPLETELY DIFFERENT. TRYING TO THINK ABOUT THESE THINGS FOR CLINICAL TRIALS AT LEAST DIFFERENTLY. SO FINALLY WHAT'S AHEAD. I THOUGHT I SHOULD JUST COMPILE A LIST OF THE PD BIOMARKERS THAT ARE OF INTEREST TO THE NEXT PROGRAM. I'VE ORGANIZED IT SO THAT THE BLUE TARGETS SHOW YOU PROJECT TEAMS ON THE CBC THAT WE'RE INTERACTING WITH AND THE YELLOW CODED TARGETS SHOW YOU TARGETS IN EARLY CLINICAL TRIALS OF THE ETCTN THAT YOU WILL HEAR MORE ABOUT FROM JEFF, BUT JUST TO SHOW THAT WE'RE ACTIVE IN THE PROJECT TEAMS BOTH IN DISCOVERY SPACE AND DEVELOPMENT AND I WOULD JUST LIKE TO THANK THE NCI FOR THEIR CLOSE COLLABORATION WHICH MAKES ALL THIS POSSIBLE, THE PARTNERSHIPS FANTASTIC AND, THE TEAM AND THE PD LAB, AS WELL AS OTHER GROUPS AT FED RICK THAT WE NEVER DO THIS--FREDERICK THAT WE NEVER DO THIS WITHOUT AND ESPECIALLY THE PATIENTS ON TRIAL WHO ARE WILLING TO UNDERGO BIOPSIES. THANK YOU AND WILL DO SOME QUESTIONS. >> WE HAVE TIME FOR A COUPLE OF QUESTIONS. . CLAUS? >> COULD YOU GIVE US A BIT OF A FEELING FOR HOW MANY RESOURCES YOU HAVE THERE TO DO THIS WORK? AND IN TERMS OF THE IMPACT YOU HAVE CITATIONS OR SOME MORE OBJECTIVE MEASURE? IT CERTAINLY LOOKED INTERESTING, AND I'M NOT IN THE FIELD BUT I'M TRYING TO GAUGE THE BIGGER PICTURE. >> SO MAYBE WORK BACKWARDS THROUGH THAT. SO IMPACT, THE IMPACT IS IN SEVERAL MEASURABLE IN SEVERAL WAYS SO I TRIED TO PUT THE PUBLICATION RESPHRENS FERENCES BELOW EACH OF THE SLIDES AS WE'VE BEEN PUBLISHING THIS WORK AND DOLLAR'S ALSO THE IMPACT BY POSTING THE SOPs AND THE KNOWLEDGE SO TO SPEAK ON THE BIOMARKER WEBSITE AND INCORPORATING THAT INTO WHAT'S CALLED THE BI ONY MARKER REVIEW COMMITTEE. WHICH REVIEWS ALL THE BIOMARKER PROPOSALS FROM ETCTN TRIALS AND THAT'S WHERE OUR EXPERTISE CAN DOVETAIL WITH THE CLINICAL DEVELOPMENT PLAN AND WE CAN USE BEST PRACTICES SO TO SPEAK TO IMPACT HOW THOSE ARE HANDLE AND WHAT THOSE BIOMARKERS MAY BE AND THE TIMING OF THE BIOPSY SO THAT'S HARD TO MEASURE BUT IT'S DEFINITELY A TANGIBLE IMPACT. RESOURCES--RESOURCES OF FREDERICK FOR VERY IMPORTANT SO THERE'S PDX MODELING, XENOGRAPH MODELING, DCD OPERATES. MOST OF THESE TEST COMPOUNDS WERE SYNTHESIZED BY THE EDCTD FOR INTURNOVERRAL--INTERNAL USE. WE CAN WORK ON COMPOUNDS MATERIALS THROUGH CREATEUS IF WE HAVE A COOPERATIVE DEVELOPMENT AGREEMENT BUT THAT COMES WITH RESTRICTIONS AND THE NCI HAS BEEN CLEAR THAT WE'RE DOING THIS FOR THE PUBLIC GOOD. WE DON'T WANT RESTRICTIONS ON PUBLICATIONS SO USING COMPOUNDS MADE INTERNALLY FOR SCHOLARLY WORK IS THE SOURCE OF MOST OF THE THESE COMPOWPPEDS AND JIM, I DON'T KNOW IF YOU WANT TO SAY ANYTHING ABOUT THAT? BUT OKAY. AND THEN JUST THE ANIMAL--YOU KNOW TREMENDOUS INFRASTRUCTURE AT FREDERICK THAT MAKE THIS IS POSSIBLE. >> SO IF I UNDERSTAND, YOU ORGANIZE THE EFFORTS OF A LOT OF THE OTHER GROUPS AT FREDERICK TO MAKE THIS PURPOSE-- >> COORDINATE. >> COORDINATE. WE DON'T HEAR TOO MUCH ABOUT THE USE OF ORGANIC CHEMISTRY. WHEN I VISITED THERE, IT WAS A HUGE ELEMENT OF THE ACTUAL WORK BEING DONE, YOU KNOW? WHERE ELSE DOES IT COME INTO PLAY THROUGHOUT THE WHOLE ENTERPRISE THERE? >> YEAH. >> SO MY UNDERSTANDING, I DON'T ACTUALLY REMEMBER IT, KEVIN DOES BUT A LONG TIME AGO, WE HAD HUNDREDS OF MEDICINAL CHEMISTS AND ORGANIC CHEMISTS IN BETHESDA AND FREDERICK, MOST OF THAT HAS GONE AWAY WITH TIME. WE HAVE A VERY SMALL CHEMISTRY EFFORT RELATED TO THE NEXT PROCESS THAT'S IN FREDERICK, RIGHT? THERE A WHOLE INTRAMURAL CLINICAL CENTER FOR CANCER RESEARCH, CHEMICAL BIOLOGY EFFORT THAT IS AN ACADEMIC CHEMICAL BIOLOGY EFFORT, THE VAST MAJORITY OF THE CHEMISTRY RESOURCES THAT WE UTILIZE ARE ALL EXTRA MURAL SCIENCE. >> SO HOW COME WE DON'T HEAR ABOUT THE ACADEMIC CHEMICAL BIOLOGY EFFORT. IT STRUCK ME AS EXCITING AND INTERESTING AND USUALLY ISN'T PRESENTED HERE. IS IT A REASON OR INCORPORATED IN OTHER THINGS? >> SO WHEN WE HAD STEVE ESSICK PRECEPT, THAT'S A PARDIME OF A LARGE ACADEMIC CHEMICAL BIOLOGY GROUP THAT'S INVOLVED IN THIS PROCESS. WE HAVE SEVERAL OTHER--WE IS A GROUP AT SANFORD BERNUM, WE HAVE A LARGE ORGANIZATION, SEVERAL OTHERS ECSF IS--I DIDN'T PRESENT PROJECTS BY EACH OF THOSE GROUPS. >> SO CLAUS, YOU WERE NOT REFERRING TO THE GROUP AT CENTER FOR CANCER RESEARCH, WERE YOU? >> WHERE IT WAS EXACTLY BUT-- >> THIS IS AN INTRAMURAL IN THE CCR, THERE'S CHEMICAL BIOLOGY GROUP. >> NO, I WAS REFERRING TO SOMETHING THAT WAS AT THE NATIONAL LABORATORY ITSELF AND I MET A LOT OF GROUPS THERE AND THEY SHOWED ME SOME VERY EXCITING CHEMICAL PROBES AND MAYBE IT'S AN ASIDE, IT'S NOT RELEVANT TO THIS PRESENTATION BUT WE DON'T HEAR MUCH ABOUT IT AND I THINK THERE'S POTENTIAL THERE AS WELL THAT WE COULD BE TALKING ABOUT. >> IT'S REALLY IMPORTANT FOR THE COMPARATIVE FIRM FARMATOLOGYST BECAUSE WE'RE TRYING TO LEARN ABOUT THE CLASS AND HAVE IT IMPACT THE WHOLE DEVELOPMENT PROGRAM FOR THAT CLASS. YEAH. AND I THINK JEFF OF SHOW EXAMPLES OF P A RP INHIBITORS, SO-- >> ANY OTHER QUESTIONS? >> OKAY, THANKS RALPH. >> THANKS. >> THE NEXT PRESENTATION IS NCI'S EARLY THERAPEUTIC TRIALS NETWORK MOVING NEW AGENTS INTO THE CLINIC. JEFF MOSCOW WILL GIVE THAT PRESENTATION. >> MODEL, HUH? WELL IT'S A PRIVILEGE TO BE ABLE TO TALK TO YOU TODAY ABOUT THE RELATIONSHIP BETWEEN THE PD PROGRAM AND THE EXPERIMENTAL THERAPEUTICS CLINICAL TRIALS NETWORK AND IT'S ESPECIALLY EASY AFTER FOLLOWING RALPH'S PRESENTATION BECAUSE AS HE SHOWED, IN EARLY CLINICAL TRIALS THE USUAL END POINTS ARE RESPONSE AND TOXICITY AND OCCASIONALLY WE CAN RELATE A PRECLINNAL OR PRETHERAPY VARIABLE TO RESPOND. BUT WHAT WE TRY TO ACTUALLY DETERMINE IN A CLINICAL TRIAL WHETHER THE DRUG ENGAGED THE TARGET AND WHETHER THE RESPONSE TO THE TARGET RELATED TO THE CLINICAL RESPONSE, THAT'S A WHOLE OTHER LAYER OF COMPLEXITY AND IT'S--BUT IF WE DON'T DO THAT, THEN WE'RE NOT REALLY TAKING ADVANTAGE OF EVERY PATIENT EXPERIENCE AND AND WE'RE REALLY NOT LEARNING WHAT WE COULD LEARN FROM EVERY CLINICAL TRIAL. SO WE ENDEAVOR TO DO THAT IN THIS NETWORK. TO TAKE A STEP BACK, AS JIM MENTIONED IN HIS TALK, THE NEXT SPECIAL EMPHASIS PANEL SELECTS AGENTS FOR A CLINICAL DEVELOPMENT AS WELL AS FOR PRECLINICAL DEVELOPMENT ASSISTANCE. AND THE AGENTS THAT ARE SELECTED FOR CLINICAL DEVELOPMENT IN OTHER WORDS PHASE 1, PHASE 2, STUDIES ARE ASSIGNED TO THE INVESTIGATIONAL DRUG BRANCH FOR CLINICAL DEVELOPMENT IN THE EXPERIMENTAL THERAPEUTICS CLINICAL TRIALS NETWORK. SO WHY DO PHARMA COMPANIES COME TO NCI AND ASK FOR DEVELOPMENT? THERE ARE REALLY 4 MAJOR REASONS. FIRST, WE HAVE ACCESS TO NOVEL AGENTS FROM COMPETITORS. MANY PHARMA CUTCHES HAVE ONLY A COUPLE AGENTS IN THE PIPELINE. THEY HAVE THEORETICAL REASONS WHY COMBINING THEIR AGENT WITH ANOTHER AGENT WILL BE BENEFICIAL. THEY DON'T HAVE THE CONTEXT OR MECHANISM TO ALLOW A COLLABORATION BETWEEN THEIR COMPANY AND ANOTHER COMPANY, AND WE PROVIDE A SAFE HARBOR FOR THOSE COMPANIES TO COME IN WHERE WE HAVE AGENTS IN OUR PORTFOLIO AND WE MAKE IT EASY TO COMBINE AGENTS ACROSS DIFFERENT PHARMA COLLABORATORS. SECOND IS THEY RECOGNIZE THERE ARE POTENTIAL THERAPEUTIC IBD KAIGDZS THAT SIMPLY DON'T COMPETE FOR THEIR LIMITED CORPORATE RESOURCES AND USUALLY THIS INVOLVES RARE PATIENT POPULATIONS. COMPANIES WITH THEIR FIDUCIARY RESPONSIBILITIES WILL GO FOR THE INDICATIONS THAT ARE MOST LIKELY TO RESULT IN AN FDA INDICATION AND A LARGE MARKET BUT THEY RECOGNIZE THAT THERE MAY BE OTHER INDICATIONS BUT THEY JUST AREN'T GOING TO INVEST IN THEM BECAUSE FOR FINANCIAL REASONS. THEY KNOW THAT WE HAVE A NETWORK OF EXPERIENCED EARLY PHASE CLINICAL TRIALISTS WHO CAN CONDUCT THE STUDIES SO THEY HAVE CONTIARAS DENSE THAT WE CAN PERFORM HIGH QUALITY CLINICAL STUDIES AND THEY KNOW THAT WE WILL INVEST IN CORRELATIVE SCIENCE STUDIES THAT EXPAND THE KNOWLEDGE OF THE AGENT: AND THAT'S WHERE THE RELATIONSHIP OF OUR PROGRAM AND THE PD PROGRAM COME INTO PLAY BECAUSE WE DEPEND ON THE FREDERICK PD PROGRAM TO HELP US GUIDE THE CORRELATIVE SCIENCE ASPECT OF OUR TRIALS. SO THEN WHY, YOU MIGHT ASK WHY DO WE SPEND PUBLIC MONEY TO HELP DRUG COMPANIES DEVELOP TRADITIONALLY--THEIR DRUGS? AND THE FIRST IS THERE IS A SIGNIFICANT PUBLIC INTEREST FOR NEW ONCOLOGY DRUGS BEYOND THOSE THAT MAY BE THE MOST PROFITABLE AND SECOND, WE KNOW THAT WE CAN ADVANCE THE UNDERSTANDING OF CANCER BIOLOGY AND TREATMENT THROUGH CAREFULLY DESIGNED CLINICAL TRIALS AND THROUGH THE CORRELATIVE BIOMARKER STUDIES THAT ARE 'EM BEDDED WITHIN THOSE TRIALS. SO THE NETWORK I WILL TALK TO YOU ABOUT FOR A MINUTE AGAIN TO SET THE CONTEXT FOR THE REST OF THE TALK IS THE ETCTN AND THE MISSION OF THE ETCTN IS SOLELY TO PROVIDE--PERFORM PHASE 1 AND PHASE 2 STUDIES OF AGENTS THAT ARE APPROVED THROUGH THE NEXT PROGRM. SO FOR NEXT SELECTED AGENTS, NCI WILL NEGOTIATE CRETAs WITH THE CLIENT. SO WE BECOME THE IND HOLDER FOR THOSE TRIALS. WE SPONSOR THE CLINICAL TRIALS THROUGH COOPERATIVE GRANTS TO THE ECTCN CLINICAL TRIAL SITES WE WORK WITH OUR INVESTIGATORS COLLABORATIVEY LOAMACY WITH THE PHARMA PARTNERS TO FORMULATE THE CLINICAL AND PHARMA FOR THAT AGENT AND AS WE REFERRED TO EARLIER, WHEN A NEW AGENT COMES INTO OUR PROGRAM AND WE EXPECT MORE THAN 1 OR 2 TRIALS WITH IT, WE WILL FORM A DRUG PROJECT TEAM THAT'S COMPOSE OF EXTRA MURAL INVESTIGATORS AS WELL AS INTRAMURAL STAFF AND TOGETHER OVER A PERIOD OF 8-12 WEEKS WHILE WE'RE NEGOTIATING THE CRETA, WE WILL FORM AN INITIAL DRUG DEVELOPMENT PLAN THAT PRIORITIZES TRIALS IN ORDER OF PRIORITY THAT WE THINK WOULD BEST SERVE THE PUBLIC INTEREST AND KNOWLEDGE OF THE BIOLOGY OF THE AGENT. AND THEN, AFTER THE TRIAL IS GOING INTO EFFECT, THE INVESTIGATIONAL DRUG BRANCH PHYSICIANS STAFF MONITOR THE TRIALS FOR SAFETY SINCE WE ARE THE OFFICIAL SPONSOR OF THE IND HOLDER. AND ALTHOUGH THE EXTERNAL--THE SET PANEL IS THE EXTERNAL PANEL THAT HELPS--THAT DOES SELECT THE AGENTS THAT COME INTO THE PROGRAM. ONCE THEY'RE IN THE CLINICAL PROGRAM, THE ECCTN ACTIVITIES ARE OVERSEEN BY A SEPARATE EXTERNAL ADVISORY CALLED THE INVESTIGATIONAL DRUG STEERING COMMITTEE. SO JUST TO GIVE YOU AN EXAMPLE, AN IDEA OF THE SIZE AND SCOPE, WE HAVE 41 TRIAL SITES, WE HAVE 75 AGENTS CURRENTLY YOU SHOULD CRETA, WE HAVE CURRENTLY SEIVET ACTIVE PHASE 1 AND PHASE 2 STUDIES SO AS YOU CAN SEE SOME OF THE AGENTS ARE NOT ACTIVE RIGHT NOW, SOME OF THEM ARE VERY ACTIVE IT JUST DEPENDS ON THE AGENT, WE EXPECT TO ACCRUE A THOUSAND PATIENTS THIS YEAR IN OUR VARIOUS CLINICAL TRIALS AND WE HAVE AN EXTENSIVE CENTRALIZED CLINICAL TRIAL SUPPORT SYSTEM FOR NETWORK FUNCTIONALITY SO ALL THESE 41 TRIAL SITES CAN FUNCTION TOGETHER AS A NETWORK AND EVERYBODY CAN ENROLL PATIENTS IN EVERYBODY ELSE'S TRIAL. WE HAVE A DEDICATED EARLY THERAPEUTICS CIRB. AND WE HAVE A NUMBER OF RESOURCES WE USE TO RUN THE NETWORK INCLUDING IDENTITY AND ACCESS MANAGEMENT, REGULATORY SUPPORT SERVICES, DOCUMENT MANAGEMENT, SERVICES, DATA COLLECTION AND ADVERSE--ADVERSE EVENT REPORTING SYSTEMS. SO WHEN--SO WHEN A CLINICAL TRIAL PROPOSAL OR LOI COMES INTO US, IT GOES THROUGH 2 LEVELS OF REVIEW, IT GOES THROUGH A PROTOCOL REVIEW COMMITTEE WHICH EVALUATES THE PROPOSAL FOR STUDY CONCEPT AND DESIGN BUT ALSO NOW IT GOES THROUGH A BIOMARKER REVIEW COMMITTEE FOR BIOMARKER ASSAY QUALIFICATION. SO THIS IS SOMETHING WE INSTITUTED IN THE LAST FEW YEARS IN BIG PART RESPONDING TO WHAT WE'VE LEARNED FROM THE PD PROGRAM TO IMPROVE THE REPRODUCIBILITY OF THE ASSAYS THAT ARE INCORPORATED INTO OUR TRIALS AND TO LEARN MORE FROM THE PATIENT EXPERIENCES ON OUR TRIALS. JUST TO LET YOU KNOW THAT THIS PROGRAM WHICH IS AN EARLY BASED PROGRAM BUT IT LEADS TO LATER BASED STUDIES THAT HAVE LED TO FDA INDICATIONS IN A NUMBER OF AGENTS AND I JUST WANTED TO POINT OUT DYNACTUXA MAB WHICH WAS MENTIONED BEFORE THIS WAS A AN AGENT FOR PEDIATRIC NEUROBLASTOMA THAT THE AGENT WAS MADE BY NCI AS WELL AS THE INITIAL CLINICAL TRIALS WERE PERFORMED IN AN EARLY THERAPEUTICS PROGRAM, THE PIVOTAL TRIAL WAS PERFORMED BY THE CHILDREN'S ONCOLOGY GROUP AND THEN IT WAS LICENSED OUT FOR COMMERCIAL PURPOSES TO THE UNITED THERAPEUTICS AND HASN'T HAD A SIGNIFICANT IMPACT IN THE OVERALL SURVIVAL OF CHILDHOOD NEUROBLASTOMA. SO WE ALWAYS TRY TO INCORPORATE BIOPSIES CAN CORRELATIVE STUDIES TO DETERMINE THE RELATIONSHIP OF TUMOR BIOLOGY AND TARGET ENGAGEMENT WITH CLINICAL RESPONSE BUT AS RALPH POINTED OUT, THERE ARE NUMEROUS FACTORS THAT EFFECT RELIABILITY AND REPRODUCIBILITY AND WE'VE BECOME MUCH MORE COGNIZANT OF THAT AND TRIED VERY--MADE A NUMBER OF INITIATIVES TO TRY TO IMPROVE ALL OF THESE ISSUES AND THE ASSAYS THEMSELVES SO WE COULD HAVE MORE CONFIDENCE THAT THE ASSAYS THAT WE PERFORM IN OUR STUDIES LEAD TO RESULTS THAT ARE VALID AND REPRODUCIBLE AND THE PD BIOMARKER STAFF HAS BEEN IMPORTANT BECAUSE THEY HAVEON STRAIGHTED THE NEED FOR BIOMARKER ASSAY DEVELOP AM AS YOU HEARD FROM RALPH'S TALK IN TERMS OF THE WAY THAT, PROACH ASSAY DEVELOPMENT AND THE VALIDATION OF THOSE ASSAYS. AND THEY'VE ALSO PROVIDED THE LABORATORY SCIENCE OF EXPERTISE FOR INCORPORATING A NEW LEVEL OF RIGOR INTO HOW WE ACQUIRE SPECIMENS AS WELL AS HOW WE ANALYZE THEM. SO AS RALPH ALLUDED TO, 1 OF THE CONSEQUENCES OF PROGRAMMATIC QUONSQUENCES OF SEEING A REHABILITATION REHABILITATION LABILE, AND ALSO LEARNING THAT WHEN THEY HAVE TAKEN IN SAMPLES WE'VE SEEN THAT MANY OF THE BIOPSY SPECIMENS, SPECIALLY WITH WE GET PAIRED BIOPSY SPECIMENS 1 PART OF THE PAIR IS NOT ADEQUATE AND THEN THAT TAKES AWAY THE WHOLE POINT OF THAT PATIENT'S EXPERIENCE IS TO--TO MAKE A CONCERTED EFFORT TO START FROM THE VERY BEGINNING OF THE PROCESS, INVOLVE INTERVENTIONAL RADIOLOGISTS IN THE--IN THE RESEARCH PROCESS INSTEAD OF JUST TREATING THEM AS, YOU KNOW THAT HAPPENS BEFORE THE SCIENCE BEGINS, THAT'S ACTUALLY PART OF WHAT THE SCIENCE IS. AND SO WE--WE DID HAVE THIS CONFERENCE THAT RALPH DESCRIBED AND SUBSEQUENT THAT THAT CONFERENCE WE NOW FUND AN INTERVENTIONAL RADIOLOGYST AT EACH OF OUR LEAD ACADEMIC ORGANIZATIONS HAVE ASKED THEM NOT ONLY TO IMPROVE THE QUALITY OF BIOPSIES AT THEIR SITE, BUT ALSO TO, WOTOGETHER TO DEVELOP SOPs THAT ALL OF OUR SITES CAN SHARE SO THAT OVERALL WE CAN IMPROVE THE QUALITY OF BIOPSIES THAT OUR PATIENTS ARE SUBJECTED TOO. THEY'VE ALSO PROVIDED EXPERTISE FOR THE SCIENTIFIC REVIEW OF BIOMARKER ASSAYS THAT ARE INCORPORATED INTO THE ETCTN STUDIES. THE BRC UTILIZES EXPERTISE IS 1 OF THE THINGS THAT WE'VE DONE WHEN WE CELT UP THE BRC IS OUR GRANTEES COMPLAINED WE GAVE THEM AN UNFUNDED MAN DAYLIGHT THAT THEY HAD TO ANALYTICALLY VALIDATE THAT AT A DIDN'T HAVE TO ANALYTICALLY VALIDATE BEFORE. THEY HAD TO PROVE WRA THEY WERE FIT FOR PURPOSE WHERE THEY DEPARTMENT HAVE TO FIT THAT THEY WERE FOR PURPOSE BEFORE AND WE RESPONDED BY THEY COULD APPLY FOR ADMINISTRATIVE SUPPLEMENT TO DEVELOP ASSAYS TO SATISFY THE REQUIREMENTS WE PLACED ON THEM. AND THE STAFF AT FREDERICK AS BEEN GREAT AT WORKING WITH THEM AND HELPING THEM DEVELOP THEIR WORK--THEIR PROJECTS SO THAT THEY CAN SUCCESSFULLY COMPLETE THEM AND GET BRC APPROVAL FOR THEIR ASSAYS. IN MORE AND MORE THOUGH, WE'VE RELIEDOT PD BIOMARKER PROGRAM TO PERFORM THE ASSAYS BECAUSE AS YOU SAW THEY'RE BEAUTIFUL ASSAYS AND WE WANT MORE AND MORE TO INCORPORATE THEM INTO OUR STUDIES. THIS IS A GRAPHIC THAT SHOWS THE AGENTS WE HAVE UNDER DEVELOPMENT. WE HAVE MANY IMMUNOTHERAPY AGENTS. I WILL TALK TODAY ABOUT P A RP INHIBITORS, DIN, APK, WE HAVE A NUMBER OF AGENTS THAT EFFECT DNA REPLICATION AND REPAIR. QUICKLY SPEAK ABOUT THE WI1 KINASE, WE HAVE A NUMBER OF RTK INHIBITORS INCLUDING C-MET AND MET OTHER AGENTS AS WELL. AND RECENTLY WE'VE--THESE ARE THE AGENTS THAT HAVE COME IN THIS THE LAST YEAR INCLUDING ATRI, DNA PK INHIBITOR, WHICH I WILL MENTION AT THE END, ALSO WANT TO HIGHLIGHT BECAUSE WE'RE NO GOING INTO RAD RADIO PHARMACEUTICALS AS A NEW CLASS OF AGENTS THAT WILL BE DEVELOPING IN THE ECTCN, AND THIS IS JUST A LIST OF SOME OF THE STUDIES THAT FOR WHICH WE--FREDERICK IS INVOLVED IN MEASURING AN END POINT OF THE STUDY. AND THERE HAVE BEEN A FEW--I GUESS UNEXPECTED BENEFITS OF THE CLOSE COLLABORATION WE'VE HAD WITH FREDERICK. SO, RALPH MENTIONED THE--THE ASSAY FOR FOSTER NURSED FOCUSED ON MET WHICH WAS CRITICAL IN BEING ABLE TO DEMONSTRATE PROOF OF MECHANISM AT MET TKs AND 1 OF THE AGENTS THAT WE HAD IN OUR PORTFOLIO THAT WAS ACCEPTED INTO OUR PORTFOLIO AS A MET INHIBITOR, WAS AN RQ--ARQ 197 COMPOUND. AND THE PD GROUP PERFORMED THESE ASSAYS LOOKING AT THE MET INHIBITORY ACTIVITY, A NUMBER OF MET INHIBITORS AND AS YOU CAN SEE, IN MANY OF THESE, THE ACTIVITY GOES DOWN, IT GOES DOWN, IT GOES DOWN BUT THIS 1 IT DIDN'T. AND SO, WE LEARNED THAT WE HAD IN OUR PORTFOLIO AND WERE CONDUCTING CLINICAL TRIALS OF A MET INHIBITOR THAT DIDN'T INHIBIT MET AND THAT HELP US LEAD TO THE DISCONTINUATION OF THAT PROGRAM. WE WOULDN'T HAVE KNOWN THAT IF IT HADN'T BEEN FOR THE PD PROGRAM HAVING THIS ASSAY THAT WE KNEW WAS VALID AND THAT COULD GIVE US THE VITAL INFORMATION THAT HELPED US MAKE DECISIONS ABOUT OUR CLINICAL TRIALS PORTFOLIO. AND THIS IS ANOTHER 1. YOU KNOW, THE FED RICK GROUP HAD A P A RP INHIBITORY PROGRAM AND WE HAD INCLUDED--WE HAD, ABOUT TO 'EM BARK ON A TRIAL BSI 210 AND AS ANOTHER AGENT WHERE THEY DEVELOPED AN ASSAY FOR P A RP INHIBITION AND HERE--HERE ARE ACTIVE COMPOUNDS AND HERE'S THE 1 THAT WASN'T. AND SO AGAIN YOU WOULD THINK THAT BY THE TIME A DRUG WOULD GET TO US, THAT THE MECHANISM OF ACTION WOULD BE KNOWN BUT THAT'S NOT ALWAYS THE CASE AND THAT HELPED LEAD US TO DISCONTINUATION AND/OR FAILURE--AT LEAST WE DIDN'T GO FORWARD WITH A CLINICAL TRIAL THAT WE OTHERWISE WOULD HAVE GONE FORWARD WITH IF WE HAD NOT KNOWN THIS INFORMATION. ANOTHER--ANOTHER EXAMPLE IN THE P A RP WORLD OF THE IMPACT OF THE PD PROGRAM HAS BEEN THAT THEY WERE ABLE TO SHOW THROUGH LACKING THE PHARMACODYNAMIC EFFECT THAT THE VALIPRIB A P A RP INHIBITOR WHICH HAD BEEN GIVEN ON A DAILY SCHEDULE DOES DID NOT HAVE TARGET ENGAGEMENT FOR 24 HOURS. AND THATIA SHOWN HERE THAT THE-OF BY THE TIME YOU GET TO 24 HOURS, THERE'S NOT MUCH COMPARED TO THE 2 HOUR LEVEL. AND SO, THAT LED TO A CLINICAL TRIAL--THE 50 CLINICAL TRIAL THAT AND THIS WAS BY THE WAY, A PHASE TRIAL. SO THIS WAS A TRIAL THAT WAS DONE IN PATIENT SPECIFICALLY TO LOOK AT THE PHARMACODYNAMICS OF A P A RP INHIBITION AND THAT LED TO BID DOSING MODEL PHASE 1 TRIAL OF VELIP A RIB AND AML AND IT POINTED OUT A COUPLE THINGS ABOUT THIS AND 1 IS THAT THERE WAS SOME ACTIVITY IN PATIENTS IN THE COMBINATION AND NOW WE HAD A RELABLE P A RP ASSAY THAT COULD DEMONSTRATE TARGET ENGAGEMENT WITH--WITH SIGNIFICANT DOWN REGULATION OF P A RP ACTIVITY AND EVEN THOUGH WE WERE ABLE TO SHOW THAT P A RP THERE WAS TARGET ENGAGEMENT, THERE WAS NO CLEAR DIFFERENCE BETWEEN THE RESPONDERS AND NONRESPONDERS. SO THAT TOLD US THAT TARGET ENGAGEMENT IS IMPORTANT BAH IT'S NOT THE WHOLE STORY AND WE WOULDN'T HAVE KNOWN THAT IF WE HADN'T ACTUALLY LOOKED TO SEE WHETHER OR NOT THE TRUG WAS INTERACTING WITH THE TARGET. AND THEN THAT HELPS US KNOW THAT THERE'S MORE TO THE STORY IT WE'RE GOING TO UNDERSTAND WHO'S A RESPONDER AND WHO'S NOT GOING TO BE A RESPONDER IN THE FUTURE SO THAT HELPS US LEAD TO THE NEXT STUDY. >> I THINK RALPH SHOWED THIS SLIDE. THIS SHOWS A NUMBER OF DNA DAMAGE REPAIR ASSAYS THAT HIS GROUP HAS DEVELOPED THAT WE WILL BE INCORPORATING INTO CLINICAL TRIALS. YOU KNOW I WANT TO POINTED OUT 1 OF THE--A COUPLE OF THEM, THIS IS THE IMMUNE O FLUORESCENCE DDR, PANEL, AS YOU CAN SEE, THE RAD 51 FOZ FOCUSED ON MBS AND GAMMA H2 X AND THEY CAN DO THIS AS A MULTIPLEX, IMMUNE O FLUORESCENCE ASSAY AND THIS IS THE APPLICATION OF TAKEN--THEY PANEL. AT LEAST A FEW THAT SHOW FIRST OF ALL, LOOKING AT SINGLE AGENT WI1 INHIBITOR ACD1775 THAT WERE PATIENTS THAT RESPONDED AND YOU CAN SEE FROM THE PATIENT WHO RESPONDED HERE'S PREDOSED GAMMA H2 X WHICH IS NOT EXPRESSED IN FOZ FOCUSED ON, THE CDK WHICH IS HI, YOU CAN SEE THE TARGET, DOWN STREAM OF TARGET IS ENGAGED AND GAMMA H2 X IS UPREGULATED SO IT SHOWS BOTH TARGET ENGAMEMENT AND THE DOWN STREAM EFFECT, THE PHARMA CO DYNAMIC EFFECT OF THE AGENT. SO THIS SHOWED THAT WE WERE GETTING THE DRUG TO WHERE IT NEEDED TO BE AND IT WORKED SO THAT GIVES US--IT JUST SHOWS HOW WE PLAN TO USE THIS IN THE FUTURE. WE BROUGHT IN M3814. WHICH IS THE DNA MPK INHIBITOR INTO THE PROJECT TEAM FORMED WITH A NUMBER OF EXTERNAL PARTICIPANTS, EXTRA MURAL PARTICIPANTS. THEY ARRIVED AT 6 STUDIES THAT THEY FELT HAD HIGH PRIORITY FOR DEVELOPMENT AND THESE STUDIES WERE APPROVED BY THE COMMITTEE SO THEY WILL GO FORWARD AS ETCTN STUDIES AND --I JUST WANTED TO POINT OUT THAT IN ALL THE STUDIES BUT I ONLY HAD ROOM ON THE SLIDE FOR 2, THAT WE PLAN TO INCORPORATE THE P A DDUS IMMUNE O FLUORESCENT PANEL INTO THE END POINTS OF THE STUDIES WHERE BIOPSIES WILL BE OBTAINED PREAND POST DOSING AND WE WILL LOOK TO DETERMINE PHARMACODYNAMIC EFFECTS IN EACH OF THESE STUDIES. SO THE FUTURE THAT I HOPE TO SEE WITH OUR INTERACTION WITH THE PD PROGRAM IS AS I MENTIONED WE HAVE SUPPLEMENTAL FUNDING PROGRAM AND FRANKLY IT'S JUST BEEN HARD TO--THEY HAVEN'T ALL BEEN SUCCESS EMPLOY. THERE'S A BIG GULF BETWEEN LABORATORY SCIENCE DISCIPLINE THAT RALPH PRESENTED TODAY AND THE MIND SET THAT GOES INTO IT AND THE APPROACH OF BASIC SCIENTIST AND CLINICAL SAMPLE ANALYSIS. SOMETIMES WE'RE ABLE TO GET THE ASSAYS UP TO WHERE WE THINK THEY SHOULD BE TO JUSTIFY A BIOPSY IN A PATIENT AND THE RISK THAT'S ENTAILED BY THAT. AND SOMETIMES WE DON'T. AND SO, WE WANT TO INCREASINGLY RELY ON THE PD BIOMARKER PROGRAM FOR THE DEVELOPMENT OF PD ASSAYS AND USE IN OUR CLINICAL TRIAL. AND WE ALSO WANT TO INCREASINGLY BE ABLE TO USE THEIR STAFF TO--AT THE EARLIER STAGE IN PROTOCOL DEVELOPMENT WHEN WE'RE THINKING ABOUT WHEN THE TIMES AND WHEN THE BI APSEYS WILL BE--BIOPSIES WILL BE PERFORMED AND IS IT RATIONAL AND DOES IT MAKE SENSE GIVEN ABOUT THE PHARMACOKINETICS OF THE AGENT AND THE PHARMACODYNAMICS OF THE INTERACTION WITH THE TARGET. WE RIGHT NOW, IT'S FRANKLY A LOT OF THE PROPOSALS ARE JUST YOU KNOW NOT BASED ON SCIENCE. AND SO I THINK WE HAVE A REPERTOIRE OF KNOWLEDGE ABOUT THESE TARGETS THAT WE NEED TO TAP INTO TO MAKE SURE THAT OUR WHOLE BIOPSY PLAN IS RATIONAL AND LIKELY TO PRODUCE OPTIMAL RESULTS. AND WE HOPE TO USE THESE PANELS IN A NUMBER OF ETCTN STUDIES BUT WE'RE FOCUSED ON THE MISMATCH REPAIR ASSAYS AND EMT ASSAYS. SO WITH THAT I'M--I'D LIKE TO BE ABLE TO JUST ANSWER ANY QUESTIONS. >> OKAY THANK YOU VERY MUCH, JEFF, OPEN FOR QUESTIONS. >> NOT EXACTLY A FREDERICK ISSUE BUT CAN YOU TALK MORE ABOUT THE CENTRAL IRB AND HOW THAT WORKS. WHERE THE INSTITUTION IS EAGER TO ADOPT THAT ISSUES WAS A THAT A STRUGGLE AND IS IT FUNCTIONING THE WAY YOU WOULD LIKE NOW I THINK THIS A PROBLEM FOR CLINICAL TRIALS NETWORKS AT LARGE AND I WONDER HOW IT WORKS FOR YOU GUYS? >> SO IT--IT--[SIGHS ]--SO OF COURSE ANYTHING NEW HAS ITS GROWING PAINS AND THERE ARE 2 ASPECTS TO IT. THE FIRST IS INSTITUTIONS ACCEPTING THE CIRB, AND THE SECOND IS THE CIRB KIND OF UNDERSTANDING ITS ROLE AND GETTING COMFORTABLE WITH IT. AND I WOULD SAY, IN THE FIRST PART BECAUSE THERE'S ALREADY BEEN A LOT OF EXPERIENCE WITH CIRBs, I DON'T--IT REALLY WASN'T THAT MUCH OF A LIFT TO GET OUR INSTITUTION TO ACCEPT IT. AND THE WORK LOAD FOR THEIR LOCAL STAFFS ONCE THEY DO IT IS--IS--SO NOTICEABLE THAT THEY--THEY QUICKLY COME AROUND IF THEY HAVEN'T COME AROUND IMMEDIATELY. IT'S BEEN--THE SECOND PART OF IT HAS BEEN MORE PROBLEMATIC. EVERYBODY HAS THEIR OWN INTERPRETATION OF WHAT A CIRB SHOULD DO AND THE CIRB IS INDEPENDENT SO WE CAN'T TELL IT WHAT TO DO. SO,--SO THERE HAVE BEEN A LOT--THERE HAVE BEEN A LOT OF BACK AND FORTH BETWEEN US AND THE CIRB AND OUR INVESTIGATORS IN TERMS OF WHAT THE ROLE SHOULD BE AND HOW MUCH THEY SHOULD BE IMPOSING ON INVESTIGATORS. SO, MY UNDERSTANDING IS THAT THE LATER PHASE CIRB WENT THROUGH THE SAME PROCESS AND IT TOOK ABOUT A YEAR AND HALF TO WORK ITSELF OUT AND I THINK WE'RE STILL IN THE PROCESS OF IT WORKING ITSELF OUT. >> BOB? >> JUSTICE A QUESTION ABOUT THE GAP YOU NOTED BETWEEN THE LABORATORY SCIENCE TRAINING THAT PEOPLE HAD AND WHATTAY REQUIRED TO GET SOMETHING [INDISCERNIBLE]--HAVE YOU THOUGHT ABOUT PROVIDING ANY TRAINING OR ANYTHING LIKE THAT TO SORT OF CLOSE THAT GAP A BIT? >> WELL, WE--IT'S NOT SO MUCH A MATTER OF TRAINING, YOU KNOW IT'S A MATTER OF, YOU KNOW WE WERE PRETTY SPECIFIC ABOUT WHAT THEY NEED TO DO, JUST--YOU KNOW WHAT IS FIT FOR PURPOSE MEANS? IT MEANS THAT JUST BECAUSE YOU'VE DONE THIS ASSAY ON LEUKEMIA CELLS DOESN'T MEAN IT WORKS ON OFTIO SARCOMA, OKAY? SO YOU HAVE TO GO--WELL, THEY MAY NOT WANT TO DO THAT OR THEY DON'T HAVE THE SPECIMENS TO DO THAT OR THEY DON'T THINK THEY SHOULD HAVE TO DO THAT, WHY ARE WE ASKING THEM TO DO THAT? SO WE GET A LOT OF THOSE KINDS OF ISSUES WHERE THERE'S JUST NOT AN ACCEPTANCE OR ANOTHER EXAMPLE FOR PHARMA CO DYNAMIC IS, SAY THEY WANT TO PROVE THAT THEY'RE GOING TO REDUCE A LEVEL OF A FOSTER NURSED FOCUSED ON PROTEIN FROM A 40% TO 20%. OR 60% TO 20%, WE WILL SAY THAT SO WE WILL SAY, OKAY, PROVE THAT CAN YOU DO THAT. PROOF THAT YOU CAN ACCURATELY MEASURE SOMETHING THAT'S 60% ABOVE RELIABLY AND 20% ARE LOWER SO YOU HAVE ACCURACY AMONG THE CUT OFFS. AND THEY SAY WELL WE HAVE THE WESTERN BLOT CAN IT SHOWS IT VERY CLEARLY. AND WE SAY NO, NO, NO, THAT'S NOT WHAT WE'RE TALKING ABOUT. SO THE IDEA OF BUILDING CALIBRATORS INTO YOUR EXPERIMENT SO YOU ALWAYS HAVE AN INTERNAL CONTROL AND YOU AWLTS KNOW YOUR--SO THOSE THINGS WHERE WE SAY, WELL, IF WE ARE GOING TO--IF A SECONDARY OBJECTIVE OF THE STUDY IS TO SHOW THAT THIS DRUG HAS THIS EFFECT, THEN OUR SAYING IS PROVE IT. PROVE THAT YOU CAN MEASURE IT. AND THAT--YOU WOULD BE SURPRISED AT HOW MUCH RESISTANCE WE GET TO WHAT IT TAKES TO--WE JUST DEFINE WHAT YOU NEED TO DO TO ACCURATELY SHOW THAT, AND THEN THERE'S A LOT OF PUSH BACK. >> SO THE 3 PRESENTATIONS WE'VE HEARDOT NEXT PROGRAM, CLINICAL TRIALS PROGRAM AND JIM I WONDER IF YOU COULD COMMENT ON THEIR INTERRELATIONSHIP, HOW THEY'RE ORGANIZED, ARE THEY ORGANIZED AS A UNIT? PART OF SEPARATE THINGS THAT INTERRELATE TO EACH OTHER? QUESTION 1? >> YES, SO BASICALLY EACH OF THE COMPONENT ABSOLUTELY DEPENDS ON THE OTHER COMPONENTS, RIGHT? SO WE MEET TOGETHER. WE HAVE JOINT LAB MEETINGS, ACTUALLY WEEKLY WHERE THE EARLY PHASE CLINICAL TRIALISTS AND THE DESCRUG DISCOVERIES AND THE PD GROUP ALL MEDE TOGETHER TO DISCUSS TO WHAT SHOULD WE PLAN FOR, DEVELOPMENT, WHAT IS IN THE PIPELINE? WHAT DO WE HAVE TO PLAN FOR? I THINK THERE IS--THERE'S JUST A LOT OF INTEREST IN PROVIDING--ACTUALLY RAISING THE BAR OF WHAT WE REQUIRE BEFORE SOMETHING ACTUALLY GETS TO A PATIENT AND THEN WHEN WE PUT IT IN THE PATIENT WHAT KIND OF INFORMATION WE CAN ELUCIDATE FROM EACH AND EVERY PATIENT AND THAT REQUIRES EVERYBODY TO BE INVOLVED IN 1 WAY OR ANOTHER IN THIS PROCESS. >> SO LET'S--LET'S JUST CONSIDER A COMPOUND THAT COMES THROUGH ORIGINALLY IN THE CHEMICAL BIOLOGY CONSORTIUM AND IT MOVES ALONG IN THE NEXT DEVELOPMENT PATHWAY. SO, ALL OF THIS IS AVAILABLE TO SUCH COMPOUNDS? >> SO IN FACT, THE YOU TEAMS, LET'S SAY FOR EVERY COMPOUND THAT COMES IN TO THE DISCOVERY PHASE, THERE WILL BE A TEAM. THEY THINK THEY ARE COMPOSED OF CLINICIAN, A PD PERSON AS WELL AS THE APPROPRIATE CHEMISTRY AND MOLECULAR PHARMACOLOGY EXPERTISE. SO THEY'RE PLANNING. I MEAN IN SOMETHING FAILS VERY EARLY, OKAY, PERHAPS WE DON'T NEED THE PD ASSAY OR SOMETHING BUT AS SOON AS WE HAVE A COMPOUND THAT LOOKS LIKE THE REASONABLE SHOT THAT IT MIGHT MAKE IT TO A LEAD, WE NEED TO BE THINK HAPPENING IN ADVANCE BECAUSE IT TAKES--EVEN THE SIMPLEST OF THESE ASSAYS WE DEVELOP, YOU KNOW IT TAKES 6 MONTHS OR LONGER. SO WE NEED TO BE PROJECTING IN ADVANCE, IT LOOKS LIKE THE P97 INHIBITOR WILL WORK HOW CAN WE DEVELOP THE ASSAYS WE HAVE TO FACILITATE THE DISCOVERY OF THE APPROPRIATE COMPOUNDS TO BRING INTO THE CLINIC? >> OKAY, SO COMPOUNDS COULD GO THROUGH THE PIPELINE, MAY MIGHT GET LICENSED AT SOME POINT IN THEIR DEVELOPMENT AS WE SAW EXAMPLES OF TODAY BUT SOMETHING THAT LOOKS PROMISING CAN CONTINUE ON AND WILL EPPED UP IN PATIENTS--END UP IN PATIENTS SUPPORTED BY THAT'S KINDS OF ACTIVITIES. >> ABSOLUTELY. YES. >> OTHER QUESTIONS? OKAY. THANK YOU JEFF. SO AT OUR LAST MEETING WE HEARD FOR THE FIRST TIME ABOUT THE THE ATOM PROJECT, ACCEL BRATEING THERAPEUTICS FOR OPPORTUNITIES IN MEDICINE. ERIC STAHLBEARE, G WILL PRESENT. >> I GET TO PRESENT ON ATOM. THANKS FOR THE MEY KREBS CYCLE BEING TURNED ON. THE OTHER THING I WOULD LIKE TO THANK IS WHOEVER PUT THE AGENDA TOGETHER. BECAUSE THE AGENDA THAT'S BEEN LAID OUT WHERE WE'VE LOOKEDDA THE THESE LAST 3 PROGRAMS AND ENDING WITH ATOM SHOWS A WONDERFUL PROGRESSION FROM THE ALL-IMPORTANT PHYSICAL ASK ANIMAL MODELs AS WE LOOK FORWARD INTO THE FUTURE WHERE WE START LOOKING AT COMPUTATIONAL MODELS. >> YEAH, I'LL TAKE CREDIT FOR ALL OF THAT. >> VERY GOOD. AND THE OTHER THINK THIS I THAT I ACTUALLY HAVE TO MAKE SURE I SAY THANK YOU TO IS THE WHOLE ATOM TEAM. MANY OF YOU ARE INVOLVED DIRECTLY, MANY OF YOU ARE INVOLVED INDIRECTLY BUT MANY OF HAVE A ROLE IN SHAPING WHAT WE ARE PRESENTING TODAY. SO AS WE GO THROUGH THE PRESENTATION, THERE ARE 3 KEY THOATS I WANT YOU TO KEEP IN MIND. ONE IS A NATIONAL RESOURCE, WE HEARD ABOUT THAT ALREADY TODAY, FREDERICK NATIONAL LAB, NATIONAL RESOURCES SO KEEP THAT IN MIND AS WE LOOK AT THE UPDATE FOR ATOM. THE SECOND 1 I WANT YOU TO KEEP IN MIND IS TEAM WORK AND TEAM SCIENCE. ATOM WILL BE ESSENTIALLY AN 'EM BODIMENT OF WHAT TEAM SCIENCE CAN DO AND THE THIRD 1 I WOULD LIKE YOU TO KEEP IN MIND IS INNOVATION AND WHAT'S THE ROLE OF THE NATIONAL LABS TO DEVELOP INNOVATIVE NEW APPROACHES AT THE INTERFACES OF DIFFERENT TECHNOLOGIES SO AS WE GO THROUGH THE PRESENTATION, JUST KEEP THOSE THINGS IN MIND AND THEN WE WILL COME BACK TO THEM AT THE END. SO THE PRESENTATION, THE QUICK UPDATE IS LET'S DEFINE ATOM. ATOM WAS KNEW IT WAS NEW, NEW CONCEPT AND HADN'T MATERIALIZED AND A LOT HAS HAPPENED TO BRING THAT TO FRUITION AND DEFINE THAT SO WE WILL GIVE YOU AN UPDATE IN THAT CONTEXT. ATOM IS A CONCERTIUM HAS THAT BEEN ESTABLISHED, THERE'S LOTS OF ACTIT URPD WAY BUILDING MOMENTUM SO WE'LL GIVE YOU AN UPDATE ON THAT AND FINALLY 1 WITH LOOKING AHEAD. WHAT DO WE SEE GOING FORWARD FOR ATOM? AND THE INVOLVEMENT OF EVERYON TO MAKE IT A SUCCESS. SO IN DEFINING ATOM, IT'S KEY TO UNDERSTAND THAT IT'S AN OPEN PUBLIC PRIVATE CONSORTIUM, LAUNCH WIDE A CRETA AND THAT CRETA IS TO BUILDING A RESOURCE TO ACCELERATE DRUG DISCOVERY. YES THIS WILL BE INSILL COAPPROACHES BUT IT'S DEPENDENT UPON THE MODELS, PHYSICAL MODELS AND CELL LINES AND ALL THESE WONDERFUL TECHNOLOGY WE'VE HEARD ABOUT ALREADY. THAT'S WHERE THE REALITY IS THAT ATOM WILL WORK TO VIRTUALIZE SO WE CAN ACCELERATE THE DRUG DISCOVERY. SO IF WE LOOK AT IT, WHAT'S THE CHALLENGE AND THIS IS THE MOTIVATION FOR ATOM. THIS IS CLEARLY AN INDUSTRY CHALLENGE, DPLAKS O SMITH GUIDELINE OF HAD-GLAKS O SMITH KLEIN AND U. K. BERKELEY AT SAN FRANCISCO HAVE COME AROUND THIS PARTICULAR CHALLENGE. IT TAKES 5 AND HALF TO 6 YEARS TO DEVELOP A DRUG IN THE PRECLINICAL CONTEXT. MANY OF THEM FAIL. SO WHAT IS IT WE CAN DO TO MAKE THIS MORE EFFICIENT AND MORE RAPID SO THAT WE CAN ACTUALLY DEVELOP MORE TREATMENTS MORE RAPIDLY AND MORE EFFECTIVELY. TO DO THAT, AS WAS ALREADY MENTIONED WE ARE TRANSITIONING FROM WHAT IS ESSENTIALLY A SERIAL APPROACH, WHERE WE ARE EMILY LIMITING AND OPTIMIZING OUR COST AND WE CAN GO CONCURRENT, SO THAT WAY THROUGH THE MODEL WE WILL DEVELOP IN THE ATOM PROJECT WE CAN BRING THESE ALTOGETHER THROUGH THE HIGH PERFORMANCE COMPUTING AND THROUGH THE DIVERSE BIOLOGICAL DATA WHICH IS EVER CRITICAL TO THE SUCCESS OF WAATOM WILL DO, AND EMERGING BIOTECH CAPABILITIES THAT WILL PROVIDE INSIGHT AND NEW DATA THAT WE DON'T NECESSARILY HAVE TODAY, DEVELOP THESE MODELS AND BY DOING THESE TOGETHER CONCUR OBJECTLY WE CAN LOOK AT ISSUES OF TOXICITY, WE CAN LOOK AT PK, WE CAN LOOK AT EFFICACY, ALL OF THESE THINGS CONCURRENTLY, EVEN LOOKING AT THE SYNTHESIZABILITY OF THE MANUFACTURABILITY OF THE MOLECULES THEMSELVES. SO THAT'S THE GOAL, IS TO TAKE THE 5 AND HALF TO 6 YEAR AVERAGE AND REDUCE IT DOWN TO 12 MONTHS. IT'S A PRETTY AUDACIOUS GOAL FOR ATOM SET OUT TO DO. AND IT'S A PRETTY AUDACIOUS TEAM PUTTING TOGETHER. SO THE CONSORTIUM AND OPEN CONSORTIUM WAS FOUNDED WITH 4 KEY PARTNERS. TWO NATIONAL LABS, 1 WITH A STRONG EMPHASIS IN CANCER WHICH IS FREDERICK, LAWRENCE LIVER MOORE WITH THE STRONG EMPHASIS ON COMPUTATIONAL MODELS AND SCIENCE, INDUSTRY, GLAXO-SMITH KLEIN BECAUSE THERE'S MORE DATA THERE AND FINALLY THE ACADEMIC DOMAIN WHICH BRINGS IN UCSF, IT'S AN INTERESTING CONSORTIUM IT'S UNIQUE IN COMP STIGZ IN THE FACT THAT IT HAS A LABS, ACADEMICS AND INDUSTRY AND SOME OF THOSE INDUSTRIES ARE INTERNATIONAL SO AS A CONSORTIUM IT'S REPRESENTING MANY OF THE COMMUNITIES THAT NEED TO COME TOGETHER TO MAKE ATOM SUCCESSFUL. SO ATOM, IT'S A CONSORTIUM AND A CR EDO, THAT'S WHAT BRINGS THE ORGANIZATIONS TOGETHER AND IT WILL BRING EVERYONE TOGETHER IN THE PUBLIC INTEREST, OPEN TO NEW MEMBERS AND IT ALINED WITH THE SHARED AIMS OF THE NCI COLLABORATION SO THE CONSORTIUM IS WHAT 'EM BODIES ATOM. THAT'S WHAT WE'RE DEVELOPING FOR THE KREDDA SO WE A KREDDA TO PURSUE AND DRIVEN BY SCIENCE WILL CREATE THIS PARTICULAR CAPABILITY. LAUNCH WIDE A MULTICAREER CREDA, SUPPORTING ACTIVE LEARNING WE'LL EXPLAIN A BIT LATER BUT ALSO INCORPORATES THE EXPERIMENT AND DATA PULLING DATA FROM PUBLIC SOURCES, PARTNERS AND SO FORTH AND THE OTHER THING ABOUT THE CREDA IS THAT WILL CHALLENGE CONTINUES TO INVOLVE. WE'RE PILOTING NEW THINGS THAT WE DON'T KNOW HOW THEY WILL END UP ABOUT YOU WE KNOW THE DIRECTION THEY GALLON AND HOW WE MAKE IMPROVEMENTS AS WE GO FORWARD. SO THE ORGANIZATIONAL STRUCTURE. KEY TO ATOM IS THE INTEGRATED WORKFORCE. THOSE ORGANIZATION WE BROUGHT TOGETHER ARE ALL WORKING TOGETHER AT A SITE IN SAN FRANCISCO. COLLABORATION WILL BE KEY FOR THE FUTURE. THE ORGANIZATIONS WILL BE REPRESENTATIVE IN MANY DIFFERENT DOMAINS AND THE INDIVIDUALS THAT HAVE AN OPPORTUNITY TO WORK IN ATOM, WILL HAVE THAT EXPERIENCE OF WHAT IT IS TO COLLAB 8 WITH OTHER ORGANIZATIONS. THROUGH THE COURSE OF MOO I CAREER, HIAN OPPORTUNITY TO WORK IN SEVERAL DIFFERENT TYPES OF ORGANIZATIONS AND I FOUND HOW ESENATIAL THAT IS WHEN YOU'RE BUILDING PARTNERSHIPS IS TO UNDERSTAND THE CONTEXT FOR THE PEOPLE THAT YOU WANT TO WORK WITH. THAT GIVES YOU A TREMENDOUS AMOUNT OF OPPORTUNITY TO DEFINE THAT VALUE PROPOSITION THAT EVERYBODY WILL FIND SUCCESS IN. LEADING THAT WORKFORCE ARE OPERATIONAL COMMENNENT BUT JOINT RESEARCH COMMITTEE AND [INDISCERNIBLE] JOINT RESEARCH COMMITTEE MEMBER AND THAT JOINT RESEARCH COMMITTEE HAS REPRESENTATIVES FROM THE CONSORTIUM MEMBERS. THEY FRAME AND GUIDE THE WORK THAT ATOM WILL DO TO FULFILL THAT CREDA, ON TOP OF THAT IS THE ATOM HEAD. SO BRINGING ALL THIS TOGETHER IS AN INDIVIDUAL, IT'S INTERIM LEADERSHIP REPRESENTATIVE FROM THE MEMBERS OF THE CONSORTIUM PROVIDING GUIDANCE ACROSS THESE WHOLE ENTERPRISE. THE ATOM HEAD INTERFACES WITH THE ATOM GOVERNING BOARD FROM THE ORGANIZATIONS, ADDITIONALLY THERE'S A SCIENTIFIC ADVISORY BOARD THATY BEEN CONCEIVED AND THAT'S DEVELOPING AT THIS PARTICULAR TIME. SO AS WE LOOK AT THAT IN SUMMARY WE HAVE THE GOVERNING BOARD WHICH IS REPRESENTATIVE OF ALL THE ORGANIZATIONS. THEY HAVE INSIGHT AND PROVIDE THE GUIDANCE. THEY BRING THEIR LEADERSHIP THAT THEY HAVE IN THEIR ORGANIZATIONS TO THE CHALLENGE THAT ATOM IS ENDEAVORING TO OVERCOME AND THE PROGRESS THAT ITS WORKING TO REALIZE FOR EVERYONE. IF HAS A SCIENTIFIC ADVISORY BOARD, A JOINT HEAD, BRINGING TOGETHER THE RESOURCES TO ADDRESS THE CHALLENGES AND THE SCIENTIFIC AREA FOR ATOM. AND ULTIMATELY THE OPERATIONAL PART THAT MAKES IT ALL WORK. ALL RIGHT. SO WHERE'S ATOM IS NCI? SO FREDERICK NATIONAL LAB IS THE SIGNATTORY TO THE CONSORTIUM FOR ATOM AND IN THAT ETHAN AND MYSELF ARE ON THE GOVERNING BOARD MUCH AS WE MENTIONED DWIGHT AND SOPHISTICATED THE WERE COMMITTEE AND OUR OPERATIONS DEBHOPE IS PROVIDING LEADERSHIP THERE. IN ADDITION WE HAVE MANY OTHER PEOPLE FROM FREDERICK NATIONAL LAB WHAT ARE MENTIONED HERE WHO ARE INVOLVED IN DIFFERENT ASPECTS INCLUDING COMMUNITY ENGAGEMENT, OUTREACH AND DEVELOPING INVOLVEMENT WITH THE BROADER COMMUNITY, COMMERCIAL AND ACADEMIC AND OTHER LABS. THE NCI SUPPORT AND LEADERSHIP IS PROVIDED BY THE LEAD OF EMILY C-SPAN AND INFORMATICS AND ZUMI HENSON WHO WAS A AAA FELLOW WHO WAS SUPPORTING OUTREACH EFFORTS FOR ATOM. SO WHAT IS IT THAT ATOM IS DOING AND HOW DOES IT EXTEBD WHAT WE'VE ALREADY HEARD TODAY? ON THE RIGHT HAND SIDE OF THE PRESENTATION, YOU WILL SEE A TRADITIONAL IMPERICAL APPROACH FOR DOING DIRECT DISCOVERY. THAT PARTICULAR APPROACH IS IMPORTANT AND CENTRAL TO WHAT ATOM NEEDS TO DO. ON THE LEFT-HAND SIDE THERE'S INSILL COFRAMEWORK. AND THE ACTIVE LEARNING CONCEPT IS TAKE THE MODELS THAT ARE DEVELOPED TO INFORM ON WHAT NEW INSIGHTS ARE NEEDED IN ORDER TO MAKE PROGRESS TOWARDS THE GOAL. IN THIS CASE, FOR ATOM IT'S FINDING A DRUG THAT WILL SUCCESSFULLY TREAT A PARTICULAR IDENTIFIED TARGET. SO THOSE COMPUTATIONAL MODELS ARE INFORMING THE SCIENCE THAT NEEDS TO BE DONE IN THE LABORATORY. THE LABORATORY PICKS UP ON THOSE CHALLENGES AND TAKES THOSE AND FINDS THAT INFORMATION DEVELOPS THAT INSIGHT THAT CAN THEN FEEDBACK IN THE DATA IN ORDER FOR THAT ANALYSIS TO BE DONE. IT'S VERY SIMILAR TO THE TYPES OF THINGS WE'VE DONE IN SCIENCE ALL ALONG. THE ANALYSIS THAT WE DO AFTER THE DATA COLLECTION AND MOST OF OUR EXPERIMENTS IS SOMETHING THAT'S VERY COMFORTABLE AND COMMON TO US. WHAT WE'RE DOING IN THE CONTEXT OF ATOM IS ENDEAVORING TO ENCLUED A MUCH MORE COMPUTATIONAL COMPONENT WITH THE MODELS THAT ARE AVAILABLE TO PROVOID A GREATER LEVEL OF INSIGHT. A COUPLE OF OTHER IMPORTANT THINGS FOR CONTEXT ON THIS, ON THE COMPLETE LEFT-HAND SIDE, YOU WILL SEE THE PATIENT SPECIFIC SO ATOM WHILE IT'S GENERATING A CAPABILITY AND THE SEVERAL MODELS, IS INTENDED TO ACTUALLY SUPPORT THE PRECISION MEDICINE ASPECT. WHAT'S THE PROFILE OF AN INDIVIDUAL PATIENT AND HOW DO WE DEVELOP AND IDENTIFY SPECIFIC TREATMENTS FOR THEM. ON THE RIGHT HAND SIDE, YOU WILL SEE THE MODELS THAT COME OUT. SO THIS IS WHERE THE NATIONAL RESOURCE COMES IN AND GETS 'EM BEDDED. CONCEPTUALLY ATOM IS A NATIONAL RESOURCE. IT'S GOING TO HELP DEVELOP NOT JUST THE PHYSICAL TECHNOLOGIES THAT ARE--NEED TO BE DEVELOPED IN THE CONTEXT OF THE IMPERICAL, BUT ALSO THE COMPUTATIONAL MODELS THAT WILL BE PART OF THAT RESOURCE. IT WILL ALSO GIVE YOU THE FRAMEWORK WITHIN WHICH TO USE THOSE MODELS AND IN IS ALL DEVELOPED COLLECTIVELY THROUGH THE CONSORTIUM. SO ATOM IS AN EMERGING RESOURCE HAS SEVERAL CHALLENGES IT NEEDS TO OVERCOME, THE COMPUTATIONAL PREDICTION AT THE PROTEIN CELL TUMOR TISSUE ORGAN ORGANISM LEVEL, WE NEED MULTISALES OF DATA, MANY OF THOSE WE HEARD REFERENCED TODAY COMING TOGETHER. WE NEED RAPID IMPERICAL TESTING, WAYS WE CAN ACTUALLY SPEED UP, HOW DO WE GET THE INSIDE OF WHAT THE OUTCOME OF A PARTICULAR ASSAY WILL BE? AND USE THAT EEIVELGT IEVERLY SO THAT WE CAN ACCELERATE THE TIME AND THE DECISION THAT WE NEED TO MAKE TO DEWHETHER A PARTICULAR DRUG WILL BE VIABLE. WE NEED INSILL COAND COMPLEX MODELS TO BE DEVELOPED. THE ACTIVE LEARNING PART, PUTTING THOSE TOGETHER SO WE CAN REDUCE THE RELIANCE ON HUMAN MODELS. IT'S NOT ELIMINATING IT, IT'S EXTENDING IT INTO AN INSILL COSPACE, WHERE THE COMPUTATION CAN BE BROUGHT AT THE SCALE AND FINALLY FOR ATOM TO BE SUCCESSFUL WE HAVE TO FOCUS ON THE REGULATORY REQUIREMENTS. WITH WHATEVER WE DO IN THE CONTEXT OF ATOM, IF THE FDA IS NOT EVOLVE FORWARD IN AND BEGIN TO ADOPT INSILL COMODELs AS A VIABLE APPROACH FOR PREDICTION, ATOM WILL ONLY BE ABLE TO IMPROVE SO MUCH BUT BY WORKING WITH THE FDA, WE SEE OPPORTUNITIES TO ACTUALLY IMPROVE AND SHORTEN THE OVERALL CYCLE. SO WHAT IS THE NATIONAL RESOURCE THAT WE HAVE IN ATOM? YOU SEE A SCHEMATIC HERE ON THE LEFT-HAND SIDE, THE DATA COMES IN FROM MANY DIFFERENT PLACES IT GETS AGGREGATED AND LAWRENCE LIVER MORE IS SERVINGA AS THAT PARTY FOR THIS CONTEXT FOR ATOM WHERE ALL THE DATA COMES ITTH BUT IT IS SECURE. IT'S AVAILABLE FOR DEVELOPING MODELS THAT REMAINS IN ISOLATION FROM THE DIFFERENT PARTIES. SO THAT IT CAN ACTUALLY BE USED EFFECTIVELY TO DEVELOP THOSE MODELS. THE COMPUTATION YOU SEE ON THE RIGHT HAND SIDE IS LIVER MORE IS PUT NOTHING A LARGE AMOUNT OF COMPUTE, IT DEVELOPS AND MODELS AND SUPPORTS SIMULATIONS, WE HEARD REFERENCE TO THE RAS SIMULATIONS, THAT'S THE TYPE OF COMPUTING LAWRENCE LIVER MORE CAN BRING FORWARD FOR THE ATOM RESOURCE. THAT DERIVED DATA FEEDS BACK IN, INTO THAT DISCOVERY CYCLE. AND ULTIMATELY WHAT WE SEE IS THE ATOM DELIVERING OUT PRECOMPETITIVE PLATFORM THAT DELIVERS THE MODEL, SOFTWARE AND THE DERIVED DATA THAT'S AVAILABLE FOR EVERYONE TO USE. SEE HERE'S THE PROGRESS UPDATES. SINCE ATOM WAS FOUNDED IN OCTOBER 2017, THAT'S WHEN THE CREDA WAS SIGNED BY ALL PARTIES. THERE WAS A AN AWFUL LOT OF THE PARTIES AND TIME TOGETHER TO GET THOSE PARTS TOGETHER. IF YOU CAN IMAGINE THE LEGAL CHALLENGES THAT GO THROUGH THAT, AND THE LAWYERS THAT ARE INVOLVED, IT WAS NOT A SIMPLE TASK. BUT THAT'S 1 OF THE VALUES OF ATOM AS WELL. THE FRAMEWORK WAS IN EXISTENCE FOR ALL THESE ORGANIZATION TO COME TOGETHER. DATA, THE GLAXO-SMITH KLEIN CONTRIBUTED A SIGNIFICANT AMOUNT OF DATA. PUBLIC DATA IS INGESTED AND PUBLIC POLICIES ABOUT HOW THE DATA IS ACCESSED. IN PK THEY'VE DEVELOPED NEW MODELS USING THE DATA THAT WAS BROUGHT IN. SAFETY IN THE SAME WAY. AND MECHANISTIC MODELS LAWRENCE HAS A LOT OF CAPABILITIES TO DO SIMULATIONS THOSE ARE PROVIDING ADDITIONAL DATA AND THOSE ARE ALL IN PLACE AT THE MOMENT. SO WHAT'S DIFFERENT ABOUT ATOM'S APPROACH? ONE THING THAT'S DIFFERENT IS EPITHELIALIGRATION. CAN YOU SEE THAT IN A SLIDE THAT IMPOSSIBLE TO BUILDIGRATION IS A COMMON THEME. IT'S INTEGRATING THE DIFFERENT TYPES OF DATA, IT'S INTEGRATING THE TYPES OF EXPERTISE WE HAVE, COMPUTATIONAL AND EXPERIMENTAL. INTEGRATING TECHNOLOGY, INTEGRATING THE WORKFORCE, INTEGRATING PARTNERS AND INTEGRATING ALL OF THESE INTO AN ASSAY, NATIONAL RESOURCE WE CAN ALL TAP INTO TO DEVELOP THESE MODELS. WHAT'S REALLY EXCITING FOR ATOM IS THE FACT THAT IT WILL CREATE THESE MODELS WE CAN ALL USE AS REFERENCES AND TUNE UP FOR OUR OWN SPECIFIC PURPOSES. SO THE R&D PLAN, THIS IS A BASIC STRUCTURE FOR IT. IT EPITOMIZES THE INTEGRATION YOU FIND IN ATOM. CROSS CUTTING CAPABILITIES YOU SEE LISTED ON THE LEFT-HAND SIDE, COMPUTATIONAL INFRASTRUCTURE, DATA, MODELS MECHANISTIC MODELS, DATA-DRIIVE MODELS CHEMICAL AND BIOLOGICAL DIVERSITY AND ALL THOSE DIFFERENT ASPECTS, THEY'RE INTEGRATED IN THE TEAMS LOOKING AT THE PK CHALLENGE, EFFICACY CHALLENGE AND ULTIMATELY IDENTIFYING EFFECTIVE MOLECULES THAT CAN BE BUILT COST EFFECTIVELY AND DELIVERED. ACROSS THE TOP OF THAT IT'S ALL INTEGRATED WITH AN OVERALL PROJECT TEAM THAT WORKS TO BRING ALL OF THOSE TEAM TOGETHER. SO YOU CAN SEE THAT ATOM IS A VERY INTEGRATED RESOURCE. SO AS THE WORKFORCE WE MENTIONED DEB HOPE IS THE OPERATIONAL LEAD. BUT WE ALSO HAVE ADAM FELLOWS. WE HEARD COMMENTS TODAY ABOUT WORKFORCE AND EDUCATION APPROXIMATE SO FORTH, SO CBID IS SUPPORTING ATOM FELLOWS TO WORK IN THE ATOM ENVIROMENT. AND THE FIRST ATOM FELLOW IS ON BOARD AND THE SECOND IS ARRIVING IN JULY. SO THESE ARE YOUNG SCIENTISTS WHO HAVE THE OPPORTUNITY TO WORK IN THIS ENVIRONMENT AND GAIN THAT EXPERIENCE. WE ARE IN THE PROCESS OF PURSUING AN ATOM DATA SCIENTIST FOR FREDERICK SO THAT WE HAVE AN INDIVIDUAL ONSITE SPECIFICALLY FOCUSING ON FREDERICK INTERESTS. AND THEY WILL BECOME PART OF THE 28 INTEGRATED PERSONNEL ALREADY WORKING ON THE ATOM EFFORTS. A LITTLE BIT OF AN IDEA OF THE DATA IS A PROFILE FROM GSK'S PROPRIETARY DATA. ONE OF THOSE IS THE 2 MILLION ORDER OF MICRONS POUNDS THAT GSK PROVIDED. WHAT'S THE DATA? THE COMPOUNDS AND THE DATA. THESE ARE COMPOUNDS THAT WERE FAILED. FROM A COMMERCIAL PERSPECTIVE, FROM A VIABILITY PERSPECTIVE, 1 REASON OR ANOTHER THESE COMPOUNDS DIDN'T MOVE FORWARD. BUT THE IMPORTANT THING IS THAT THAT DARK DATA ACTUALLY HAS BIOLOGICAL INSIGHT. SO THAT'S PART OF WHAT ATOM IS DOING AS WELL IS USING THAT BIOLOGICAL INSIGHT FOUND IN THESE PARTICULAR DATA THAT AM CANS FROM INDUSTRY AND USING THAT TO DEVELOP THESE MODELS FOR WHAT EITHER CAN BE SUCCESSFUL, OR WHAT NEEDS TO BE SCREENED OUT AS AN INVIABLE CANDIDATE. THE IMPORTANT THING IS THAT IT'S A LARGE AMOUNT OF DATA. AS WE LOOK AT THAT DATA CUSTOMER PROTECTION THE OTHER THING THAT'S IMPORTANT IS THAT PARTICULAR DATA S&P NOT NECESSARILY IDEBTICAL TO WHAT'S OUT THERE PUBLICLY. THE GRAPH ON THE TOP, YOU SEE A LITTLE BIT OF A CIRCLE WHERE IT SAYS ATOM DATA AND WHAT YOU SEE THERE IS THE FACT THAT THE PREDICTIVE MODELS THAT ARE COMMON PLACE IN INDUSTRY WHICH ARE BUILT ON PUB LIKELY AVAILABLE DATA, DON'T NECESSARILY APPLY WHEN ACTUALLY TESTED AGAINST THE SPECIFIC DATA THAT GSK HAS. THE IMPORTANT POINT HERE IS THAT THE BETTER MODELS ARE BUILT WHEN YOU COMBINE THE DATA BECAUSE YOU HAVE A REPRESENTITATION OF THE SPACE OF INVESTIGATION THAT YOU'RE WORKING IN TO BRING THESE& ALTOGETHER. THE BOTTOM SLIDES ARE SHOWING THE DIVERSITY OF CHEM ALCOHOL SPACE IN THE PUBLIC DOMAIN AND GSK DOMAIN AND RECOGNIZING THOSE AREN'T OVERLAPPING THEY'RE COMPLIMENTARY. YES, THERE'S SOME MODEST AMOUNT OF A BUTTON AND OVERLAP IN IT BUT THEY ARE DISTINCT SPACES. SO GOING FORWARD, AN IMPORTANT ASPECT IS OUTREACH EFFORTS, THAT DIVERSITY AND SPACE YOU SAW THERE, THE NEED FOR THE BROAD AMOUNTS OF DATA IS CRITICAL TO ATOM AND ATOM TO BE SUCCESSFUL SO THE OUTREACH IS ESSENTIAL. AND AS ETHAN MENTIONED EARLY ON, THERE WAS AN ATOM MEETING AT THE AACR MEETING AT THE END OF APRIL AND THAT WAS A VERY SIGNIFICANT OUTREACH EFFORT TO ENGAGE THE EXTRA MURAL COMMUNITY AND THE CANCER CENTER DIRECTORS YOU CAN CAN SEE THE NUMBERS THERE, THE MEMBER OF CONTEXT THAT REMAIN, INVITATIONS THAT WERE EXTENDED TO LET PEOPLE KNOW THAT ATOM IS OPEN, IT'S AVAILABLE FOR PEOPLE TO JOIN AND FIND WAYS TO JOIN THE COLLABORATION AND JOIN IN THE CONSORTIUM. SO AS WE START LOOKING AT MOVING AHEAD, THE FIRST STAGE OF RESEARCH IS UNDERWAY WITHIN THE--USING THE AVAILABLE DATA. STAFF ARE ONSITE. THERE'S AN INTEGRATED TEAM WORKING TOGETHER ON THESE CHALLENGES. THERE'S INITIAL RERESEARCH PLAN AND THE AVAILABLE DATA IS ALREADY LEADING TO INSIGHTS THAT NEED TO BE ADDRESSED. EXPANDING INVOLVEMENT IS KEY TO SUCCESS FOR ATOM, SO THE OUTREACH TO NEW MEMBERS IS ALREADY UNDERWAY. SO AS WE LOOK AHEAD, WHAT IS IT THAT WE SEE. SO AS WE LOOK AT THE ATOM ROADMAP, YOU SEE IT EMBODIED HERE. ON THE TOP YOU LOOK AT THE CURRENT STATE. CURRENT STATE FOR DRUG DISCOVERY, DRUG DEVELOPMENT, AND YOU SEE THAT LEAD DISCOVERY TIMELINE, THAT LEAD OPTIMIZATION TIMELINE. BEING DONE SEQUENTIALLY AND THAT TAKES THE 5 AND HALF YEARS. WHAT WE'RE LOOKING IN THE FIRST COUPLE OF YEARS OF ATOM IN WHAT'S IDENTIFIED AS STAGE 1 AND 2 IN THE CHART IT TO REDUCE THAT LEAD DISCOVERY TIME. REDUCE THE LEAD OPTIMIZATION TIME AND PRECLINICAL TIME NOT NECESSARILY ADDRESSED YET. PART OF THAT IS BECAUSE THAT'S WHERE THE INFORMATION IS, WHERE WE HAVE THE FOCUS. BUT AS WE ANY INTO STAGE 3 AND THE PROOF OF CONCEPT. WE'RE ACTUALLY GOING TO COMBINE THESE AND BEGIN TO REDUCE BOTH BY USING ACTIVE LEARNING. WE'RE NOT GOING TO ELIMINATE NECESSITY FOR DOING THE ANIMAL STUDIES BUT BE MORE EFFICIENT AND OPTICAL OPTIMAL IN THE STUDIES THAT NEED TO BE DONE. FOR THE REGULATORY CONSIDERATIONS WE CONTINUE THAT FORWARD AND RECOGNIZE THAT THAT IS AN UNKNOWN, ATOM DOES NOT HAVE THE OPPORTUNITY TO INFLUENCE DIRECTLY AND CONTROL THE TIMELINE FOR HOW FDA AND REGULATORY RESPONSE MIGHT TAKE ADVANTAGE OF THE NEW CAPABILITIES BEING DEVELOPED. SO THAT'S A LITTLE BIT OF AN UNKNOWN THAT LEADS US TO THAT FUTURE STATE WHICH IS THE BIG GOAL FOR ATOM TO BE ABLE TO DO ALL OF THIS WITHIN THE SPAN OF 1 YEAR. YES, THE 4 MIRACLES WE IDENTIFY EARLY ON HAVE TO HAPPEN BUT THAT'S THE TIMELINE AND THE PROGRESSION AND THE VISION FOR ATOM GOING FORWARD. SO THAT'S WHY THERE'S KNOW A CONSORTIUM. NOT SOMETHING A SMALL GROUP OF PEOPLE CAN DO,A LONE. IT WILL TAKE EVERYONE CONTRIBUTING, DAT, EXPERTISE ACCIDENT INSIGHTS, KNOWLEDGE ABOUT SPECIFIC CANCER CHALLENGES BECAUSE IN THE END, IT'S AN PREMELY COMPLEX DISEASE WHERE EVERYTHING HAS TO COME TOGETHER. ATOM SUCCEEDS WITH THE COMMUNITY. UP THERE YOU CAN SEE THE E-MAIL. IF ANYONE'S INTERESTED IN JOINING ATOM, THAT'S THE E-MAIL TO SEND TO OR CAN YOU TALK TO ANY PEOPLE THAT ARE PART OF ATOM TEAM AND WHEN YOU SEE THAT TEAM, IT'S GOING TO BE VERY LARGE. SO WHAT'S AHEAD FOR FREDERICK NATIONAL LAB AND ATOM? IT'S GROWING THE COMMUNITY. EXPANDING DATA RESOURCES AND BRINGING FORWARD ADDITIONAL EXPERTISE. IT'S REALLY ABOUT DEVELOPING THE NEW OPPORTUNITIES AND DELIVERING ATOM AS A RESOURCE. WITH THE ACKNOWLEDGMENTS YOU CAN SEE THAT THERE'S A LOT OF PEOPLE THAT PUT TIME AND EFFORT INTO BUILDING THIS ATOM TO BRING IT TO WHERE IT IS TODAY. ANY OF THESE PEOPLE THAT YOU SEE ON THE LIST COULD BE PEOPLE THAT YOU COULD REACH OUT TO AND ASK ABOUT BEING PART OF ATOM AND SO WITH THAT I THINK WE KIND OF HIT OUR POINTS, HOPEFULLY WE EMPHASIZE THAT ATOM INVOLVES TEAM SCIENCE, ATOM IS BUILDING INNOVATIONS, AND ATOM IS REALLY FOCUSING ON DEVELOPING NEW CAPABILITIES. AND SO WITH THAT I'M OPEN FOR QUESTIONS. OR IF THERE ARE NO QUESTIONS, THE BREAK CAN COME EARLY. THANK YOU. >> I THINK WE MIGHT HAVE A QUESTION OR 2. BOB, YOU WANT TO START? >> I DO HAVE A BUNCH OF QUESTIONS ABOUT THIS. IT LOOKS LIKE SOMETHING THAT HAS I LOT OF POTENTIAL AND YOU'RE BRINGING TOGETHER PEOPLE. SO IF I UNDERSTOOD YOU THERE ARE 3 AREAS BRINGING TOGETHER, PROVIDED ACIS ESES TO PROPERLY CURATED DATA,. >> CORRECT. >> THE SECOND THING IS YOU NEED TO TESTING, SO AS YOU GET INTO THE COMPUTATION, YOU NEED A WAY TO EVALUATE YOUR PREDICTIONS AND IN THATOR OF THE THING, I THINK REALLY, DATA IS IMPORTANT, IT'S AT THE HEART BUT IN A SENSE THE EASIEST, THE COMPUTATION PART IS WHERE THE NOVELTY COMES, RIGHT? >> I THINK--YEAH, THE SHOVE ELTY IS CERTAINLY IN THE COMPUTATION AND THE NOVELTY WILL COME FROM THE NOW INNOVATIONS ARE NEEDED. SO YOU KNOW IT WOULD BE VERY HELPFUL FOR US OVER TIME TO EVALUATE THIS TO MORE SPECIFICS. I THINK YOU'VE SHOWN A REALLY BEAUTIFUL ORGANIZATIONAL PLAN, LIKE IT WOULD WORK AND YOU ARE JUST STARTING SO I WAS BT HERE AT THE BEGINNING OF THE RAS THING, I IMAGINE IT STARTED THE SAME WAY. LET'S BRING A LOT OF PEOPLE TOGETHER AND SEE WHAT NEW THINGS THEY CAN DO BECAUSE THEY'RE TOGETHER AND I GUESS THAT'S WHERE WE ARE HERE? >> YEAH, THEY ARE THERE. THEY ARE ACTUALLY 1 OF THE SYSTEMS THEY'RE USING AT LIVER MORE AND THEY'VE ESTABLISHED THE DATABASES AND DATA LINKS AND THE SCIENTISTS ARE PULLS THE DATA AND DEVELOPING THE MODELS AND SO FORTH BUT IT IS AS YOU SAID VERY EARLY BUT EVEN IN THE EARLY STAGES WHAT THEY ARE WORKING WITH NOW IS PROVIDING INSIGHT TO WHAT THEY NEED. >> SO AS WE GO FORWARD, I JUST WANT TO SAY IT WOULD BE VERY HELPFUL TO SEE SPECIFICS AND I ASSUME YUL GET INTO THAT? AND THEN I DON'T WANT TO TAKE THE WHOLE TIME BUT I HAD A FEW SPECIFIC QUESTIONS RIGHT NOW. OKAY, SO, YOU SHOWED THE DATA THAT HADN'T WORKED FROM ATTEMPTED DRUG DISCOVERY. AND I GUESS AT SEVERAL POINTS ALONG THE PATH TO A COMPLETED DRUG IT HAD WORKED TO GET NICE POSITIVE OUTCOMES THAT WE COULD USE TO EVALUATE MODELS. ISN'T THAT WHAT YOU NEED AND DO YOU HAVE MORE OF THAT WHERE YOU HAVE TEST DATA THAT WORK? >> SURE, SURE. AND THAT'S 1 OF THE THINGS THAT'S NOT LISTED ON THERE IS THAT THE PUBLIC DATA IS NOT NECESSARILY ALL PUBLIC FAILED DATA. THERE'S PUBLIC SUCCESS DATA AND GSK HAS INVESTED TIME TO PUT THAT INFORMATION IN THERE FOR THOSE DRUGS THAT ARE SUCCESSFUL BECAUSE YOU DO NEED THE BALANCE IN THE DATA SETS NOT ONLY INFORMATION FROM FAILED EXPERIMENTS BUT THOSE THAT ARE SUCCESSFUL. >> THE LAST 1 IS TRIVIAL BUT I OBJECTEDN'T HELP BUT WONDER, YOU TALK ABOUT THE TOXICOLOGY AT END, BINDINGA THE BEGINNING BUT WHEN YOU SUCCEED WOULD YOU REALLY TAKE A DRUG THAT WAS DOING VERY WELL IN ALL THESE EARLY STAGES AND JUST 96 IT BECAUSE YOU PREDICTED--NIX IT BECAUSE YOU PREDICTED AT THE END IT WOULD NOT WORK. >> ME PERSONALLY, NO I WOULD TRY TO ADOPT IT AND UNDERSTAND WHAT WAS IN THE MODELS THAT WAS BT QUITE RIGHT. AND THAT'S WHERE SOME OF THAT INNOVATION THAT WE WERE TALKING ABOUT A MOMENT AGO COMES IN. IS THAT WHEN SOMETHING FAILS, UNDERSTANDING WHY LEADS TO SCIENTIFIC QUESTION AND THEN THE TECHNOLOGY THAT BEGINS TO ADDRESS THAT, AND TO IMPROVE IT IS, YOU KNOW THE CAPABILITY THAT EVERYONE CAN BENEFIT FROM. >> THE LAST QUESTION IS A DEVIL'S ADVOCATE COMMUNITY. I SEE AM IN THIS COMMUNITY AND I SEE PEOPLE TRYING TO DO THIS, THEY GIVE TALKS AND COMPUTATIONAL PEOPLE DOING THIS, AND THEY TALK ABOUT THEIR RATHER LIMITED DATA SET. SO WHAT CAN YOU DO HERE THAT'S DIFFERENT THAN THE INDIVIDUAL GROUPS? IS IT BECAUSE OF THE CURATED DAILY BASIS AT? IMMEDIATE TESTING AND COMPARE TO OTHER GROUPS TRYING IT THE SAME DATA SET? WHAT IS IT THAT MAKES THIS SUM GREATER THAN THESE USUAL? >> ONE OF THE KEY THINGS THAT HOPEFULLY WAS COMING ACROSS IS THAT IT'S BRINGING THE DATA TOGETHER. THIS IS WHAT MAKES IT REALLY CLICK AND THE OPPORTUNITY TO FILL IN GAPS IN THE DATA WITH THE COMPUTATIONAL APPROACHES AT THE SCALE THAT LIVER MORE THAT IS AVAILABLE. THOSE ARE TYPES OF THINGS THAT ARE NOT NECESSARILY BEING TRY INDEED ALL CASES. THERE'S ANY NUMBER OF SITUATIONS WHERE PEOPLE ARE ADDRESSING A PIECE OR PART OF THE CHALLENGE BUT NOT LOOK BEING AT IT COLLECTIVELY AS A WHOLE AND HOW WE CAN LEVERAGE EACH OF THE PIECES THAT WE'RE INVESTING. SO THAT REALLY IS WHAT MAKES ATOM DIFFERENT. THE FACT THAT IT INTEGRATES EVERYTHING AND BRING ITS ALTOGETHER. HOW IT HAPPENS? , JUST A FOLLOW UP TO 1 OF CLAUS'S COMMENTS, IT WOULD HAVE BEEN HELPFUL HERE TO HAVE AN EXAMPLE OF A COMPOUND OR TARGET, SOMETHING THAT YOU'RE WORKING ON, EACH IF IT'S A EARLY STAGE TO SEE WHAT--WHAT'S THINKING THAT'S GOING INTO THIS? WHO'S DRIVING THE BUS? YOU DIDN'T FILL IN ANY NAMES, OF THE INDIVIDUALS IF IN ANY OF THOSE POSITIONS THAT YOU LISTED. I PRESUME FROM A FUNDING POINT OF VIEW, SINCE THIS IS A BOOT STRAP EFFORT THAT THERE'S NOT LOTS OF FUND FREE RADICALS GENERATED ANY OF THE INSTITUTIONS IT'S MORE AN IN-KIND MATCH OR EFFORT? OR AM I WRONG? IS SOMEBODY PUTTING UP A BIG PILE OF CASH TO MOVE THIS FORWARD? >> I THINK YOUR FIRST PERCEPTION IS RIGHT. PEOPLE ARE PUT NOTHING A LOT OF TIME AND EFFORT TO MAKE THIS HAPPEN. IS THERE A LARGE AMOUNT OF CARB THAT'S BEEN CONTRIBUTED INTO THAT? I GUESS THAT DEPENDS ON WHO YOU ARE TALKING TO ASK WHAT THEY CONSIDER LARGE. SO FROM THAT PERSPECTIVE, THERE'S--THERE'S FINANCIAL ASSETS THAT ARE BEING CONTRIBUTED SO THAT THE INFORMATION CAN BE GENERATED AND THE INDIVIDUALS CAN ACTUALLY OBVIOUS REWORK TOGETHER AND SO FORTH. >> YEAH AND I WOULD LIKE TO SAY THAT THAT I THINK IT'S A GOOD THING TO SET AN AUDACIOUS IMPOSSIBLE GOAL. >> GOOD. >> ONE OUGHT TO DO THAT FOR ONESELF- EVERY ONCE IN A WHILE BECAUSE EVEN IF YOU DON'T MAKE IT THERE MIGHT BE SIGNIFICANT LEARNING, IF YOU SHAVE A YEAR OFF THAT PROCESS THAT WOULD MEAN A LOT TO A LOT OF PEOPLE BUT FOR US TO EVALUATE WHAT YOU ARE DOING, WE WILL HAVE TO SEE-- >> A LOT MORE SPRVEGS. >> --A LOT MORE DETAIL. >> YEAH. >> BOB? >> THAT WAS A GREAT TALK. I THINK YOU GAVE US A LOT OF INFORMATION THAT WAS MISSED WHEN IT WAS MENTIONED AT THE LAST MEETING. I HAD 2 QUICK QUESTIONS 1 IS WHEN YOU SPEND SO MUCH MONEY DEVELOPING DRUGS AND OVER SO MUCH TIME, IF THERE IS AN EDGE YOU CAN GET FROM ANY TECHNOLOGY THAT PEOPLE INVESTING A BILLION DOLLARS ARE LIKELY TO DO THAT AND COMPUTATION IS 1 OF THEM. SO IN THIS CONTEXT IN WHICH LIVER MORE IS PROVIDING COMPUTATIONAL, WHAT SORT OF IN YOUR OPINION DIFFERENT ABOUT THIS? IT COULD BE JUST MORE CYCLES SO THAT THERE JUST WEREN'T ENOUGH CYCLES BEFORE? IS IT BETTER ALGORITHMS? IS IT JUST BETTER PEOPLE AND THEY KNOW HOW TO DO THIS? SO IN TERMS OF THE COMPUTATION GONE IN THE PAST HOW DO YOU SEE THE EDGE HERE OR IT JUST A DATA. I WAS JUST TRYING TO SEE-- >> IT'S ACTUALLY THE COMPLEMENT OF THAT, THE CLEARLY THE DATA AND HAVING THE COMPLIMENTARY DATA IS CRITICAL FOR ATOM, BUT THOSE CAPABILITIES SUCH AS WHAT LAWRENCE LIVER MORE HAS IN DOING THOSE MOLECULAR SIMULATIONS PROVIDE THAT INSIGHT WHERE WE DON'T NECESSARILY HAVE EXPERIMENTAL DATA AVAILABLE AND IT'S REALLY THAT INTEGRATION THAT BRING ITS TOGETHER BECAUSE YOU'RE RIGHT. IN THE VARIOUS INDUSTRIES THERE'S BEEN COMPUTATIONAL CHEMISTRY AND MANY DIFFERENT CONTEXTS IN THE PAST BUT FOR THE MOST PART THEY HAVE NOT REALLY BROUGHT EVERYTHING TOGETHER IN THAT CONTEXT AND THAT'S WHAT ATOM'S DOING NOT ONLY TO BRING THESE TECHNOLOGIES AND THE DATA TOGETHER BUT BRINGING THE EXPERTISE OF THE COMMUNITY TOGETHER AS WE GO FORWARD. >> JUST A FOLLOW UP QUESTION. I DON'T KNOW IF IT'S--IF OOTH BEEN DECIDED YET BUT I HEARD IN A MEETING TALKING ABOUT ATOM AND I WAS TRYING TO UNDERSTAND IF SOMEONE WANTS TO JOIN AND GET ACCESS TO SOME OF OF THIS DATA WHAT IS THE MODEL FOR THAT. SOME OF THE CONVERSATIONS I HEARD, IT WAS QUITE EXPENSIVE SO HOW WERE THEY THINKING THROUGH THIS. >> SO 1 THING'S IMPORTANT TO KNOW IS THAT ATOM IS NEW, IT'S EVOLVING AND ADAPTING SO THE BEST THING TO DO IS JUST START THE CONVERSATION. BECAUSE WE'VE HAD THE OPPORTUNITY TO INTERACT WITH THE COMMUNITY, IT'S FINDING THAT MUTUAL VALUE PROPOSITION THAT BENEFITS BOTH THAT WILL MAKE IT SUCCESSFUL. >> I HAD TO MAKE 1 MORE COMMENT AND THEN IF ANYBODY ELSE WANTS TO ASK, THAT'S FINE BUT I WANT TO GO BACK TO THE OPENING STATEMENT YOU SAID WHICH WAS YOU WANTED TO COMPLEMENT WHOEVER ARRANGED THE-- >> YEAH, THAT AGENDA WAS FANTASTIC,. >> I GRATUITOUSLY TOOK CREDIT FOR THAT WHICH I DID NOT DO BUT I THOUGHT IT WAS VERY INTERESTING BECAUSE YOU'RE TRYING TO IDENTIFY SAVINGS THAT COULD BE HAD BY AGGREGATING DATA AND THEN WE JUST HEARD FROM JEFF AND RALPH HOW HARD IT IS TO GET PEOPLE TO DO GOOD EXPERIMENTS THAT PROVIDE THOSE DATA SO IT LOOKS LIKE THERE OUGHT TO BE AN ARM OF THIS PROJECT THAT LOOKS OUT INTO THE REAL WORLD AND SAYS, WE HAVE TO HAVE GOOD DATA TO MOVE THIS STUFF FORWARD AND WE'RE NOT GETTING IT FROM A LOT OF PEOPLE. >> THAT IS ACTUALLY 1 OF THE PERSPECTIVES THAT GSK HAS BROUGHT IS THAT THE INDUSTRIAL SCALE OF THE DATA THAT THEY CAN DO FOR CONSISTENCY, BUT ALSO THE EMPSETION ON ATOM TO LOOK AT WHAT ARE--WHAT THE POSSIBLE TECHNOLOGIES ARE WHERE YOU CAN GET THAT RELIABLE INFORMATION AND WHAT INSIGHT CAN YOU GET FROM THEM SO THAT'S CERTAINLY IN THE SCOPE OF ATOM. >> ANYONE ELSE. OKAY. LET'S TACK A BREAK. MAKE WE CAN COME BACK ABOUT 5 AFTER 3, IS THAT OKAY? ALL RIGHT. THANK YOU. >> WE DON'T TOTALLY COVER ALL THOSE SUBJECTS BUT WE CAN GIVE YOU A BROAD VIEW ESPECIALLY FROM TD COMMITTEE'S VERY STRONG AND BIOLOGICAL UNDERSTANDING OF WHAT THIS MIGHT DO. I THINK WE'RE LESS EXPERT WHEN IT AM CANS--WHEN IT COMES TO DEEP LEARNING TECHNOLOGIES JUDGING THE PART THAT THE D. O. E. IS DOING AND THERE WILL BE RECOMMENDATIONS ON THAT FRONT. THE COMMITTEE IS SET UP TO REPORT TO THIS COMMITTEE. AND IS BEYOND BY PAY GRADE TO KNOW ARE WHY THAT HAS TO BE STRUCTURED THAT WAY BUT I AM TOLD THAT IS THE WAY IT HAS TO BE STRUCTURE SO I WON'T GO INTO THAT. NOW THE COLLABORATION GOT STARTED WHEN ERNIE TALKED ABOUT THIS IS HOW TO BRING TOGETHER THE ENORM AUSPOWER OF--E ENORMOUS POWER, AND NATIONAL STRAY JECTORY TOOJIC COMPRIEWTING INITIATIVE AND BRING TAKEN--THEY TO THE ENORMOUS AMOUNT OF DATA AND THE COMPLEXITY OF UNDERSTANDING THAT DATA BY USING TECHNIQUES THAT ARE POSSIBLE WITH THE NEXT LEVEL OF COMPUTING. NOW THERE HAS ALWAYS BEEN COMPUTATION IN THE BIOLOGICAL AREA AT THE HIGH PERFORMANCE LEVEL BUT NOW WE'RE TALKING ABOUT PUSHING THAT TO THE EXOSCALE. IN THE EXOSCALE IS DESIGNED TO EXTEND TO THE 18th FLOATING POINT OPERATIONS PER SECOND WHICH IS A STAGGERING NUMBER. DISP THE TECHNOLOGY HAS BEEN IMPROVING VERY FAST, THE IPHONE 6 HAS 6 GIGA FLOPS AND SO, IF YOU LINE UP 200 MILLION IPHONE 6s, YOU HAVE THE EXOSCALE. IN GOING TO THE EXOSCALE THE ARCHITECTURE IS VERY IMPORTANT IN PART BECAUSE THE POWER TO RUN THE STANDARD CPUs IS ENORMOUS SO HAVE YOU THESE ENORMOUS FACILITIES THAT SUCK UP MEGAWALTS AND THINGS LIKE THAT AND 1 ADVANCE HAS BEEN TO USE GRAPHIC GPUs, GRAPHIC PROCESSING UNITS. THE PLAY STATION 4, I THINK HAS GOT 1800 GIGA FLOPS. SO YOU ONLY HAVE TO PUT HALF A MILLION PLAY STATION 4S TO GET TO THE EXOSCALE. BUT THAT GIVES YOU A SENSE OF WHAT THE PROBLEM OF SCALE HERE IS. BECAUSE FELT EXOSCALE INITIATIVE, IT HAS A RESPONSIBILITY TO MAKE THAT TECHNOLOGY USEFUL FOR THE NATION AND IN THE D. O. E. SYSTEM, A LOT OF THE TECHNOLOGIES HAVE BEEN PREDICTIVE AND MECHANSTIC WHEN WE HAVE MODELS OF WEAPONS OR PARTICLE PHYSICS AND SO ON. THE NEW ELEMENT IS THAT THERE ARE TECHNOLOGIES FOR DEEP LEARNING THAT USE DEEP NEURAL NETWORKS TO TRY TO UNDERSTAND PATTERNS IN NATURE OR IN DATA THAT SIMPLER APPROACHES MIGHT NOT BE ABLE TO DO. THE D. O. E. IS INTERESTED IN PROMOTING THIS, NOT ONLY FOR CANCER RESEARCH, BUT THEIR OWN USES. SO IN THE COLLABORATION, WHILE THE NCI IS TRYING TO UNDERSTAND HOW TO APPLY THIS TO CANCER IN ORDER TO HAVE BETTER TRAJECTORYS FOR PATIENTS AND SO ON, THAT NCI, DOE IS TRYING TO USE THIS FRAMEWORK TO TRY TO UNDERSTAND ITSELF HOW DO WEIGH DEAL WITH THE COMPLEXITY OF ISSUES LIKE THAT THAT WE HAVEN'T DEALT WITH BEFORE WHEN WE SPECIFY THE NEXT GENERATION OF COMPUTING. SO IN FACT, THEY HAVE ALREADY USED SOME OF THINGS THAT HAVE BEEN DEVELOPED IN ORDER TO WRITE THE SPECIFICATION FOR THE NEXT PROCUREMENT OF THE EXOSCALE COMPUTING SO IT'S QUITE USEFUL FOR THE DEPARTMENT AND OF COURSE THE HOPE IS THAT THIS APPROACH WILL BE VERY USEFUL FOR THE NCI. UNDER THE DOE AND NCI COLLABORATION, WE DON'T REALLY KNOW WHERE THIS WILL END UP AND HOW USEFUL IT WILL BE BUT IT SEEMS VERY IMPORTANT TO EXPERIMENT AND TO TEST THIS AND I THINK THE PROGRAM HAS BEEN STRUCTURED CORRECTLY TO HAVE PILOT PROGRAM SO THIS IS A PILOT AT THE CELLULAR LEVEL THAT LOOKS AT PREDICTIVE MODELS FOR PRECLINICAL SCREENING. THERE IS A MOLECULAR LEVEL PILOT THAT HAS TO DO WITH THE BEHAVIOR OF RAS ON MEMBRANES AND THERE IS A THIRD PILOT THAT IS THE POPULATION INFORMATION INTEGRATION INFORMATION ANALYSIS THAT IS TRYING TO USE NATURAL LANGUAGE THROUGH ITS TECHNIQUES WHICH ARE AGAIN DEEP LEARNING TECHNIQUES TO EXTRACT DATA FROM THE SEER DATABASE WHICH SOMEDAY WILL INCLUDE ALL THE PATHOLOGY AND PICTURES AND EVERYTHING ELSE THAT YOU COULD TRY TO INCORPORATE. SO, THESE 3 THINGS AT THE CELLULAR, MOLECULAR AND POPULATION LEVEL ARE SORT OF THE RIGHT 3 PILOTS IT SEEMS FOR THIS PROJECT. NOW WHEN YOU USE THIS TECHNIQUES THERE IS ALWAYS THE ISSUE OF UNCERTAINTY QUANTIFICATION. AND THAT'S A VERY COMPLEX SUBJECT AND WELL IS A CROSS CUT THAT IS TRYING TO INCLUDE UNCERTAINTY QUANTIFICATION AND THESE 3 PILOTS AND FINALLY, SOMETHING THAT IS VERY EXCITE SUGGEST THAT ALREADY THE CANDLE PROJECT WHICH IS THE CANCER DISTRIBUTED LEARNING ENVIRONMENT IS MAKING VERY GOOD PROGRESS IN MAKING THE TOOLS THAT ARE DEVELOPED IN THIS PILOTS AVAILABLE TO A BROADER COMMUNITY. AND IN FACT, THIS CANDLE ENVIRONMENT THAT WILL USE ALL OF THE TECHNOLOGY THAT THE PILOTS DEVELOP WOULD BECOME AVAILABLE AND FOR EXAMPLE WOULD MAKE ATOM MUCH MORE USEFUL IN THAT THERE WOULD ALREADY BE A--SITES WHERE YOU COULD HAVE LEARNING DATABASES, YOU COULD HAVE DIFFERENT PROGRAMS AND STRUCTURES IN YOUR DEEP LEARNING TECHNOLOGY AND SO ON AND SO FORTH. SO THE 3 PILOTS ARE LEADING TO VERY IMPORTANT PROGRAMS OF UNCERTAINTY QUANTIFICATION AND THEN SCAN MAKING ALL THOSE TOOLS AVAILABLE TO A BROADER COMMUNITY INCLUDING ATOM. SO THIS PILOT IS TO GO INTO MORE DETAIL. THE PILOT 1, THE CELLULAR LEVEL, DEVELOPED RELIABLE MACHINE LEARNING BASED ON PREDICTIVE MODELS OF DRUG RESPONSE. IT WILL INTEGRATE UNCERTAINTY QUANTIFICATION AND EVENTUALLY THE HOPE IS THAT NOT ONLY 1 WILL LEARN THE PATTERNS ON THE DATA BUT AS 1 STARTS PUTTING MODELS OR PIECES OF MODELS INTO THE DEEP LEARNING STRUCTURE, THIS HIBRIT PREDICTIVE MODELS WILL LEAD US TO MORE MECHANISTIC UNDERSTANDING. I DID ASK THE QUESTION OF 1 OF THE PRINCIPLES BEING A PARTICLE PHYSICIST IF IN THE EARLY 60S, I DUMPED ALL THE DATA WITH THE DEEP LEARNING HIGH PERFORMANCE COMPUTING WOULD THE COMPUTER HAVE TOLD ME, OH WELL IT'S OBVIOUS IT'S 3 QUARKs AND 3 LEPTONS AND ALL THAT, NO IT WOULDN'T HAPPEN THAT WAY UNLESS I PUT THE MODEL OR SOMETHING AKIN TO A SERIES OF MODELS INTO THE DEEP LEARNING STRUCTURE AND THEN I COULD GET SOMETHING LIKE THAT. SO, YOU NEED TO BE CAREFUL WITH THAT. THE RAS BIOLOGY IN MEMBRANES AGAIN IS THIS MULTICASE MODELING OF MOLECULAR ASSISTANCE WHICH ARE HUGE BY NORMAL STANDARDS WHEN THEY SIMULATE 1 MICRON BY 1 MICRON OFF THE MEMBRANE THAT CONTAINS AN ENORMOUS AMOUNT OF MOLECULES AND SO ON AND THEY'RE ALL DYNAMIC AND MOVING AND SO, IT'S IN PARTICULAR A PROGRAM THAT TIES THE STRUCTURAL ELEMENTS TO THIS MUCH LARGER PARAMETER SPACE WHICH IS THE MEMBRANE AND 1 WANTS TO UNDERSTAND HOW RAS BEHAVES, HOW RAF INTERACTIONS IN THE LIP I EDUCATIONAL BI-LAYER ACTIVATE OR DEACTIVATE RAS. IN SOMETHING THAT IS ALSO COMPLICATED TO UNDERSTAND BUT THERE ARE SO MANY CONFIGURURATIONS THAT ARE DEVELOPED IN THIS SIMULATIONS, THAT THEY WANT TO INCLUDE DEEP LEARNING TECHNIQUES TO TRY TO UNDERSTAND THE VARIOUS CONFIGURURATIONS THAT OCCUR IN THE SIMULATIONS IN ORDER TO GIED THE SIMULATIONS. AND THE LAST 1 IS THE INFORMATION CAPTURE OF STRUCTURE CLINICAL TESTS USING NATURAL LANGUAGE AND TRY TO UNDERSTAND AND MAKE SOMETHING LIKE THE SEER DATABASE VERY, VERY USEFUL ACROSS THE BOARD AND IN PARTICULAR IN ALL OF THESE THINGS YOU COULD IMAGINE WE COULD LEARN WHAT THE BEST TRAJECTORIES ARE FOR PATIENTS ACCORDING TO WHAT THE DATA SHOWS US, POTENTIALLY VERY COMPLEX PATTERNS. SO THIS IS THE OVERALL PICTURE, I THINK I I'VE GONE THROUGH ALL OF THOSE THINGS AND THEN ATOM SITS AT THE BOTTOM OF THIS AS 1 WAY TO INTEGRATE ALL THE STUFF THAT WOULD BE DEVELOPED UNDER THE PILOTS. SO LET ME GO A LITTLE BIT MORE INTO THE PILOTS, THE PILOT 1 IS THE PREDICTIVE MODEL FOR PRECLINICAL SCREENING. IT DOES HAVE SOME VERY GENERIC BUT SEVERAL NEURAL NETWORK ARCHITECTURES THAT ARE TRIED AGAINST THE DATA AND THERE IS TRAINING DATA THAT COMES FROM THE CELL LINES AND THE--RNA SEQUENCING AND ALL THE DATA THAT YOU CAN GATHER REGARDING CELL LINES. THE STRUCTURE IS BUILT SO THAT YOU CAN TAKE PDX AND ORGANLES AND EVENTUALLY TUMORS FROM PATIENTS AT LEAST THROUGH INTERESTING BIOLOGY OR PIECES OF LARGE UNCERTAINTY, IT THEN RECOMMENDS THROUGH THIS SET OF EXPERIMENTS THAT GENERATE POTENTIALLY ADDITIONAL TRAINING DATA AND WHAT ARE THEY TRYING TO LEARN? THE FIRST TEST WAS TO TRY TO UNDERSTAND THE CASES IN WHICH YOU USE 2 DRUGS AND WHETHER THEY'RE SINNER GESTIC OR WHETHER THEY'RE NOT. --SYNERGISTIC OR WHETHER THEY'RE NOT AND WHETHER YOU CAN PREDICT THE SIN--SYNERGY ON THE PATTERN GIVEN THE DATA THIS YOU KNOW. --THAT YOU KNOW. THE PROGRAM HAS--I DON'T GO INTO THE DETAILS ABOUT YOU ALL OF THIS DEEP LEARNING TECHNIQUES MORE STRAIGHT FORWARD THING IS TO PREDICT AGAINST A SET OF TRAINING DATA AND THEN YOU ADJUST THE PARAMETERS OF THE MODEL BUT THERE IS ALSO UNSUPER VISED DEEP LEARNING IN WHICH YOU JUST LET OUT THISNEURONS TO TRY TO FIGURE OUT WHAT THE GENERAL PATTERNS ARE AND THAT IS ALSO USEFUL AND BOTH OF THOSE THINGS HAVE BEEN TRIED. THIS IS AN EXAMPLE AND I WON'T GO INTO THE DETAILS BUT IT WAS VERY IMPRESSIVE BECAUSE IN A TABLE LIKE THIS, IT WAS ROLLED OUT AND IT WENT FROM 1 SIDE OF THE TABLE TO THE OTHER. AND WHAT IT IS, IS A MAP OF CELL LINES WHICH ARE INVISIBLE HERE AGAINST COMPOUNDS, AND THE RED LINES INDICATE PREDICTIVE SYNERGYS WITH HIGH OR MEDIUM CONFIDENCE. THE WHITE IS NOT INTERESTING AT THIS POINT AND THE BLUE IS LOW MODEL CONFIDENCE. SO YOU CAN--FOR THE FIRST TIME THAT YOU HAVE A LANDSCAPE PICTURE AND YOU CAN GO INTO CERTAIN PARTS OF THE LANDSCAPE AND START TO ASK QUESTIONS. IN SUMMARY IT'S A WELL DEFINED PROJECT WITH LANDSCAPE RESULTS. THERE ARE CANCER CELL LINES IN 2 WAYS, DOSE DEPENTINE REGIMENNENT AND NOT DOSE DEPENDENT. IT INCLUDES QUANTIFICATION AND THEY'RE STARTING TO MAKE ALREADY INTERESTING BIOLOGICAL OBSERVATIONS. FOR EXAMPLE, THEY FIGURE THEY PAIR DRUG FRACTION OF SYNERGISTIC INTERACTIONS APPEARS TO BE FROM DRUG FEATURES AND THE INTERDICTION IN BREAST CANCER IS SIGNIFICANTLY BETTER THAN FOR OTHER TISSUE TYPES. SO THEY'RE STARTING TO LEARN SOME OF THIS--STARTING TO DERIVE AT THE VERY BEGINNINGS, VERY INTERESTING INSIGHT INTO THE DATA. THERE'S A WHOLE BUNCH OF PROPOSED NEXT STEPS THAT WE SUGGEST. OUR COMMITTEE BECAUSE OF THE WAY IT IS STRUCTURES WE CANNOT MAKE RECOMMENDATIONS, SO, SINCE WE MEET IN PRIVATE, NOT IN THE PUBLIC EYE, WE CAN'T MAKE RECOMMENDATIONS ABOUT YOU WE CAN IMAGINE WHAT PROPOSED NEXT STEPS MIGHT BE. THERE IS AN ISSUE GIVEN THIS LANDSCAPE OF SPEEDING UP THE DATA FLOW AND QUICKEN THE EXPERIMENTAL FEEDBACK LOOP. TO DEVELOP POTENTIAL MECHANISMS TO ENGAGE FROM THE INTRAMURAL COMMUNITY TO GENERATE COLLABORATIONS BUT IN PARTICULAR TO DEVELOP POTENTIAL MECHANISMS WAS THAT COMMUNITY TO GATHER DATA AND FOCUS ON HUMAN SAMPLES AND PDX MODELS AS OPPOSE TO CELL LINES. THE CELL LINES I'M FINDING OUT ARE NOT THE MOST USEFUL THING WHEN IT COMES TO TRYING TO UNDERSTAND CANCER ALTHOUGH THEY'RE CLEARLY VERY USEFUL IN MANY OTHER CONTEXTS. FOR FUTURE STUDY TO CONSIDER PRIMARILY GOING NOW TO HUMAN TISSUE DERIVED DATA, THAT MIGHT BE AVAILABLE FROM DEVELOPING FROM PATIENTS AND ENTERING EARLY AND LATE PHASE CLINICAL TRIALS, WHICH WOULD BE HIGHLY ANNOTATED AND THE RESPONSE AND RESISTANT TO SPECIFIC AGENTS IS KNOWN. THE WORKING GROUP WILL CONSIDER WORKING WITH THE LAB TO IDENTIFY AN EXPERT TO PROVOID ADDITIONAL OVERSIGHT. I WILL COME BACK TO THAT POINT AND DOWN THE LINE AS I MENTIONED IN THE BEGINNING, OUR COMMITTEE SHOULD RECOMMEND OR SHOULD CONSIDER CONVENING AN AD HOC GROUP SPECIFICALLY FOR PILOT 1 AND 3. WITH DEEP EXPERTISE ON THIS ARTIFICIAL INTELLIGENCE DEEP LEARNING TECHNIQUE BECAUSE WE CAN--I THINK THE COMMITTEE MOSTLY COMPOSED OF BIOLOGISTS CAN JUDGE THE IMPACT THAT MIGHT HAVE ON THE BIOLOGICAL SAMPLE BUT IF THERE ARE THINGS AS A TECHNICAL COMMITTEE THAT WE HAVE TO SAY, WERE HANDICAPPED TAKEN--THEY WE DON'T HAVE EXPERTISE ON ARTIFICIAL INTELLIGENCE AND THE METHODS OF DEEP LEARNING, THAT IS SOMETHING FOR THE COMMITTEE DIFFICULT TO ACTUALLY ENGAGE IN. SO I THINK IT WOULD BE VERY USEFUL. AT SOME POINT IT HAS TO GIVE SPACE TO THIS INITTATIVE TO GO FORWARD TO HAVE A REVIEW ON THE ACTUAL TECHNICAL ISSUES THAT ARE BEING APPLIED IN THIS SYSTEMS. THE OTHER ASPECT IS THE LINK BETWEEN THE DOE AND THE NCI WE FELT NEEDED TO BE STRENGTHENED. AND IN PARTICULAR THE FOLKS IN THE DOE LABS ARE NOT NECESSARILY--KNOWLEDGEABLE ABOUT THE ENORMOUS NUMBER OF RESOURCES THAT NCI HAS THAT COULD BE BROUGHT INTO THE PICTURE. AND SO, WE THOUGHT THAT STRENGTHENING SCIENTIFIC STAFF OR A GROUP AT THE LAB THAT COULD ACTUALLY HAVE THE MISSION TO IMPROVE THE COUPLING BETWEEN THE DOE AND NCI BROADLY BY BEING VERY KNOWLEDGEABLE ABOUT WHAT GOES ON IN THE NCI, AND EVENTUALLY ALSO DEVELOPING THE CAPABILITIES TO UNDERSTAND EXOSCALE OR HIGH PERFORMANCE COMPUTING THAT STRENGTHENING THAT GROUP AT THE LAB WOULD ACTUALLY MAKE THIS WHOLE THING GO PROBABLY IN A STRONGER WAY. THE RAS PILOT IS VERY INTERESTING AND AS I SAID BEFORE, IT MODELS ANATOMIC RESOLUTION GOING ALL THE WAY TO SOMETHING THAT IN THE SCALE OF ATOMIC RESOLUTION IS HUGE, 1 MIRROR MICRON BY 1 MICRON IN THE MEMBRANE AND I THINK EARLIER WE SAW A PICTURE OF RAS ACCIDENT MOVING AROUND AND MAKING COMPLEXES AND SO ON. THIS IS THE COMPLEX WITH OTHER ELEMENTSOT SURFACE AND THE ENVIRONMENT WITH THE AND REALLY UNDERSTAND THIS POWER IN THE WORLD UNLESS YOU DO SOME OPOXMATIONS, IT'S NOT A QUANTUM MECHANIC IT'S SEMICLASSICAL AND DOESN'T MEAN IT'S WRONG, IT REALLY MEANS THAT YOU HAVE TO TEST EXPERIMENTALLY WHAT YOU ARE SEEING THAT'S 1 OF THE POWERS OF THIS PILOT PROJECT LET IS THAT IT'S SIMULATING THINGS CAN YOU GO AND TAKE A LIQUID BI-LAYER AND NANO DISK AND MEASURE THINGS THAT THE PROPROGRAM DOES PREDICT SO THERE IS A PREDICTIVE ON THE 1 SIDE THAT ARE IN THE LAB AND ALL THE PREDICTIONS THAT GO ON THIS SIDE BUT AS I MENTIONED BEFORE THERE'S ANOTHER SIDE BUT YOU HAVE THE MECHANISTIC PREDICTIONS IN ORDER TO GUIDE THAT THAT'S ADAPTIVE SAMPLING THAT ALLOW YOU TO IN SUCH A WAY THAT IS SUFFICIENT, AND THEN THERE IS MACHINE LEARNING VALIDATION IN WHICH YOU PUT A SET OF NEURAL NETWORKS TO UNDERSTAND WAOUR CONFIGURURATIONS--WHAT OUR CONFIGURURATIONS ARE HAPPENING ON THE MEMBRANE AND WHAT IS RELEVANT AND WHAT IS NOT. SO I WILL STOP HERE AND MELISSA CAN TAKE OVER. OH, I AM EARLY, SORRY. SO THERE IS SOME COMPUTATIONS THAT IT'S 'EM BEDDED IN THE LARGER INITIATIVE SO IT HAS RELEVANCE TO WHAT THEY'RE DOING IN THAT INITIATIVE. AND THE DYNAMICS FROM THE MACROMENTIONED THAT SIMULATIONS ARE VALIDATED, MULTIPLE EXPERIMENTS, AND CHANGE IN THE DYNAMICS OF KRASE MODEL AND--BUT ISOLATEED AND THE PROPOSED NEXT STEPS TO DETERMINE THE VISIBILITY OF ENGAGING THE PRIVATE SECTOR FOR THE DATA ACQUISITION, ACCELERATION AND COLLABORATION, AND IDENTIFY POTENTIAL MECHANISMS TO ACCELERATE ADDITIONAL DATA SETS DOWN THE LINE IS NOT THE SAME COMMITTEE AS WE PROPOSE FOR POETIC LOT 1 AND 3 WHERE DEEP LEARNING IS THE KEY ISSUE. HERE IS REALLY THE MOLECULAR DYNAMIC SIMULATION AND HOW REALISTIC CAN WE EXPECT TO DETAILS ON MOLECULES ATTACHING AND DEACTIVATING OR ACTIVATING RAS. THERE IS A WHOLE FIELD OF MOLECULAR DYNAMICS IT HAS BT BEEN TACKLEDDA THE THIS SCALE BUT EXPERTS IN THAT AREA COULD BRINGINSIGHTS AS TO WHETHER WE'RE DOING THE RYE THINGS IN--RIGHT THINGS IN THERE TECHNICALLY. SO THERE IS THE ISSUE OF ARE WE USING THE BEST CAPABILITIES OF EACH INTO THE COLLABORATION. THE MANAGEMENT GROUP, JOINT MANAGEMENT GROUP OF DOE AND NCI PROVIDES SOME OF THIS. BUT IT--SO THERE IS A QUESTION OF HOW TO MAKE SURE THAT YOU ARE BRINGING TO THIS PROJECT WHICH I THINK IS QUITE IMPORTANT THE BEST EXPERTISE FROM BOTH SIDES AND I THINK THAT'S WHERE WE HAD PLANNED, YEAH. TO SWITCH ON PILOT 3. >> SO THANK YOU. SO AS WAS MENTIONED PILOT 3 IS LOOKING AT THE POPULATION LEVEL AND IT WAS BROUGHT UP EARLIER THIS MORNING WITH THE SEER DATABASE AND PATHOLOGY REPORTS THAT THERE ARE MANY DIFFERENT METHODS AND WAYS IN WHICH THE DATA IS REPORTED. SO TO BE ABLE TO EFFECTIVELY AGGREGATE THAT DATA ACROSS THE POPULATION AND LEARN FROM THAT DATA IS KIND OF THE MOTIVATING APPROACH FOR PILOT 3. SO SOME OF THE GOALS THAT ARE SET FORTH FOR PILOT 3 IS THE USE OF NATURAL LANGUAGE PROCESSING AND DEEP NEURAL NETWORKS FOR THAT INFORMATION CAPTURE. SO USING THESE ADVANCED MACHINE LEARNING TECHNIQUES TO TAKE THAT PATIENT INFORMATION, CAPTURE IT FROM THE UNSTRUCTURED CLINICAL REPORTS, SO AS TO THE SEMIAUTOMATE THAT COLLECTION OF DATA IN THE SEER PROGRAM. AND THEN FROM THAT, NOVEL DATA ANALYTIC TECHNIQUES FOR PATIENT INFORMATION INTEGRATION. SO USING SCALABLE GRAFS AND VISUAL ANALYTICS TO BE ABLE TO UNDERSTAND THE ASSOCIATION BETWEEN PATIENT TRAJECTORIES AND PATIENT OUTCOMES SO WE CAN LEARN FROM THOSE PRACTICES AND IMPLY THE BEST TECHNIQUES THAT ARE AVAILABLE. AND THEN LASTLY, THE DATA DRIVEN INTEGRATED MODELING AND SIMULATION FOR PREDITION ONCOLOGY. SO PRECISION MODELING OF THOSE PATIENT TRAJECTORIES AS WELL AS INSILLY COCLINICAL TRIALS. SO IN SUMMARY FOR THIS PILOT, THEY HAVE SHOWN VERY GOOD PROGRESS AND INTERACTIONS WITH THE COMMUNITY THUS FAR. THERE WAS NOTED A RELATIVELY SLOW START ON ACCESSING THE REGISTRIES DUE TO PUTTING TOGETHER THE AGREEMENTS AND ACCESSING THAT DATA. BUT THEY'VE DEVELOPED, DEPLOYED AND REFINED THAT PIPELINE AND THEY'RE PARTNERING WITH INFORMATION MANAGEMENT SERVICE, TESTED NATURAL LANGUAGE PROCESSING TOOLS AND DELIVERING THOSE VIA APPLICATION PROGRAM AND INTERFACES. THEY'VE DEVELOPED, DEPLOYED AND TESTED THESE NATURAL LANGUAGE PROCESSING TOOLS FOR AUTOMATED IDENTIFICATION OF THE FOLLOWING, THE PRIMARY SITE, THE LATERALLYITY, HISTOLOGY, GRADE, AND BEHAVIOR. THEY'VE ALSO DEVELOPED BREAST CANCER SCHEMA FOR BIOMARKERS AND RECURRENCE DATA ELEMENTS AND DEVELOPED AND BENCHMARKED 4 SUPERVISED DEEP LEARNING ARCHITECTURES SO IN THE DEEP PROCESS OF THE WORK THEY'RE DOING, THEY'RE DIDN'T TAKE A SINGULARITY APPROACH AND LOOKED AT DIFFERENT METHODS WITHIN THE DEEP LEARNING TECHNIQUES THAT THEY COULD APPLY TO THIS DATA. THEY'VE ALSO PACKAGED THE DEEP LEARNING MODEL INTO THE SOFTWARE PRODUCT TO RETURN TO THE CANCER COMMUNITY WITH CANDLE. AND THEY'VE DEVELOPED AND BENCHMARKED 2 U-CUBED STRATEGIES WHICH I WILL TALK ABOUT IN A MOMENT. SO AS PROPOSED NEXT STEPS THE COMMITTEE WOULD DETERMINE THE FEASIBILITY OF INCORPORATING DIFFERENT TYPES OF PATIENT REPORTS INCLUDING SUCH THINGS AS WHOLE SLIDES AND RADIOLOGY REPORTS AND DETERMINE HOW THE SEER DATA CAN BE MORE RELEVANT TO PRECISION MEDICINE AND CONSIDERED STATED PROJECT GOALS. WHILE RETROSPECTIVE ANALYSIS OF THE SEER DATA SETS THAT CAPTURED MORE COMPREHENSIVE MEVERGZ WOULD BE HIGHLY DEIRABLE AND MAY WELL GENERATE NOVEL NATURAL LANGUAGE PROCESSING APPROACHES AND METHODS, IT'S NOT CLEAR HOW THE CURRENT PROJECT IS RELEVANT TO REALTIME CLINICAL DECISION MAKING AND SO THAT'S KIND OF AN IMPORTANT ASPECT GOING FORWARD. HOW DO WE BRIDGE THAT GAP. DOWN THE LINE AS PIERRE SUGGESTED EARLIER, CONVENING THAT AD HOC WORKING GROUP THAT WOULD BRING IN THE EXPERTISE AND DEEP LEARNING APPLICATIONS THAT ARE BOTH IMPORTANT FOR PILOT 1 AND PILOT 3. AND SIMILARLY DETERMINE IF THERE'S SOME NEED FOR NCI, POTENTIALLY DOE TO PROVIDE MANAGEMENT OVERSIGHT AND ASSISTANCE EVEN TO INSURE THAT THE BEST CAPABILITIES OF EACH AGENCY IS BROUGHT TO THIS COLLABORATION. LASTLY THEY'RE ENGAGING THE COMMUNITY TO INSURE THAT EACH OF THE AGENCIES ARE BROUGHT TO PRACTICES VIED MORE DATA FOR DEEP LEARNING AS IT IT'S APPLIED TO NATURAL LANGUAGE PROCESSING AND THE OTHER NOT YET ADDRESSED GOALS OF THIS IMPORTANT PILOT. SO CANDLE WHICH STANDS FOR THE CANCER ADVANCED RESEARCH LEARNING ENVIRONMENT IS AN IMPORTANT PIECE OF THIS EFFORT, THIS CAN BE A FUNDAMENTAL FOUNDATION FOR ATOM AS WE MOVE FORWARD. AND SO, THE CANDLE ASPECT IS IN SUPPORT OF ALL 3 OF THESE PILOTS AND IN SUPPORTING THEM IN THE VERY SPECIFIC NEEDS THAT EACH 1 REQUIRE. WITH RESPECT TO MACHINE LEARNING AND DEEP LEARNING. SO THE GOALS INCLUDE DEEP LEARNING TO HELP OTHERS INCREASE PRODUCTIVITY AND WE CAN ENVISION THIS NOT BEING LIMITED TO THE PROJECTS BUT TO THE BROADER COMMUNITY. AND SUPPORTING AND ESTABLISHING DEEP LEARNING FRAMEWORKS THAT ARE PROVIDED BY OTHER ENTITIES SUCH AS GOOGLE AND SITUATING THEM SO THAT THEY CAN RUNOT D. O. E. SUPER COMPUTERS EFFICIENTLY AND CAN BE USED BY THE COMMUNITY. AND THEN LASTLY THEY ARE MANAGING THE CANDLE TRAINING DAT THAT'S USED WITHIN THESE PROJECTS. SO CANDLE WILL ENLARGE THE COMMUNITY THAT WILL USE THE EXOSCAL COMPUTING TO ANSWER SCIENTIFIC QUESTIONS BY MAKING THESE PROJECTS AND TRAINING DATA READILY AVAILABLE. AND THE CONTRIBUTION SPECIFICALLY TO THE DIFFERENT PILOT PROJECTS FOR PILOT 1 PROVIDED THE FIRST VERSION OF COMBO AND CANDLE. FOR PILOT 2, CREATED A PROTOTYPE DEEP NEURAL NETWORK THAT PERFORMS THE UNSUPER VISED FEATURE LEARNING NECESSARY FOR YOU KNOW INTERFACING BETWEEN WHAT IS HAPPENING IN THE SIMULATION AND WHAT IT HAPPENING EXPERIMENTALLY. AND THEN FOR PILOT 3, CREATING THAT PROTOTYPE DEEP LEARNING NETWORK FOR INFORMATION EXTRACTION IN THOSE CLINICAL REPORTS SPECIFICALLY THE NATURAL LANGUAGE PROCESSING. AND IT IS NOTED THAT CANDLE ALSO HAS CLEARLY DEFINED FUTURE MILESTONES. I WILL TALK ABOUT EACH OF THESE CROSS CUTTING EFFORTS AND THEN BRING TOGETHER THE PROPOSED NEXT STEPS FOR THEM AS 1. SO THE NEXT CROSS CUTTING ACTIVITY IS THE UNCERTAINTY QUANTIFICATION. SO THE THEORY OF THE UNCERTAINTY QUANTIFICATION IS CENTRAL TO ALL THE SCIENTIFIC RESULTS AND ALL THE PILOTS. SO IN THE USE OF MACHINE LEARNING AND DEEP LEARNING IT'S IMPERATIVE THAT WE UNDERSTAND WHAT WE'RE ABLE TO PREDICT AND MAYBE MORE IMPORTANTLY WAWE'RE ABLE TO PREDICT. SO THERE'S MANY TECHNIQUE OUTED THERE IN TERMS OF E. Q. AND WE AS A COMMITTEE REALIZE THIS IS A HIGHLY TECHNICAL SUBJECT. ONE WE DO NOT OR DID NOT HAVE THE EXPERTISE TO COMPLETELY UNDERSTAND AND SO IT IS AS WE MENTIONED BEFORE, IT IS REALLY IMPORTANT THAT WE MAYBE REACH OUT TO THE COMMUNITY AND BRING IN MORE EXPERTISE TO HELP US THAT THESE DIRECTIONS ARE WELL UNDERSTOOD. BUT AS I SAID THE U. Q. CUTS ACROSS ALL COLLABORATIONS AND MAKES--UNCERTAINTY AND UNDERSTANDING WHAT THAT MEANS IN THEIR CONTEXT. SO THE TASK RELATED TO U. Q. ARE COMMON AND IMPLEMENTED IN CANDLE AND INCLUDING THOSE THAT ARE LIST SAID HERE. --LISTED HERE. LASTLY IN TERPS OF CROSS CUTTING ACTIVITIES AS ATOM I WON'T SPEND A LOT OF TIME ON THIS BECAUSE ERIC HAS ALREADY WELL VERSED YOU ON THE ACTIVITIES THAT ARE ONGOING WITH ATOM, BUT HIGHLIGHTS ARE THE STRONG PUBLIC PRIVATE PARTNERSHIP THAT IS DEVELOPING AND THAT IS BUILDING ON BOTH WHAT NCI AND DOE BRAINING TO THE TABLE IN TERMS OF THEIR STRENGTHS AND AGAIN I WILL SKIP THIS SINCE WE'VE ALREADY GONE OVER THAT TODAY. SO THAT LEADS US TO THE PROPOSED NEXT STEPS FOR THESE THREEZ CROSS CUTTING ACTIVITIES IN TERMS OF CANDLE. CONSIDER IMPROVING THE APPLICATION OF CANDLE BY PARTNERING WITH THE NYI ITR PROGRAM IN TERMS OF UQ, DETERMINING FEASIBILITY OF SPECIFYING SOURCES OF UNCERTAINTY AND THE FEASIBILITY OF ADDRESSING VALIDATION AND RELATION TO U. Q. AND THEN FOR ATOM CONSIDERING THE FEASIBILITY OF ESTABLISHING A NONPROFIT ENTITY AND EXPANDING PARTNERSHIP TO GAIN MORE RELEVANT DATA SETS. SEE IN CONCLUSION, WITH RESPECT TO THE 3 PILOTS THEY ARE MOVING WELL, MOVING FORWARD VERY WELL, FORTUNATELY AND THEY'RE INDEPENDENT DOMAINS. THE CROSS CUTTING ELEMENTS THAT ARE SUPPORTING THESE PILOTS IN TERMS OF CANDLE AND UNCERTAINTY QUALIFICATION ARE A CENTRAL COMPONENT AND I THINK THEY ARE 1 OF THE PRIME REASONS THAT THE PILOTS HAVE BEEN SO SUCCESSFUL THUS FAR. THROUGH CANDLE THERE EXISTS THE FOWBDATION FOR STRONG PARTICIPATION AND ENGAGING THE WIDER RESEARCH COMMUNITY AND ENABLING THEM TO TAKE ADVANTAGE OF ALL OF THE INTELLECTUAL ASPECTS THAT THESE PILOTS HAVE PRODUCED THUS FAR. AND THEN LASTLY ATOM POSSIBLY ORGANIZES NOT FOR PROFIT ORGANIZATION COULD ACHIEVE MAJOR ACCOMPLISHMENTS AND IMPROVEMENTS IN THE TIME TO DEVELOP NEW THERAPEUTICS. SO TO WRAP THINGS UP OVERALL CONSIDERING--CONSIDER STRENGTHENING THE HUB AT THE LAB TO CONNECT THE D. O. E. EFFORTS TO THE LARGE NUMBER OF NCI SUPPORTED PROGRAMS THAT COULD SUPPORT AND/OR PROFIT FROM THE COLLABORATION. I THINK PIERRE MENTIONED THAT EARLIER. WHILE THE WORKING GROUP THAT WE--THAT WAS CONVENED CAN PROVIDE A BROAD EVALUATION OF THE PILOTS, AND THOSE CROSS CUTTING EFFORTS, WE LACK SOME OF THE EXPERTISE. AND SO IN MANY OF THE PROJECTS, SUCH AS THE UNCERTAINTY QUANTIFICATION AS I MENTIONED, OR THE MULTISCALE MOLECULAR DYNAMICS AS WAS MENTIONED EARLY EARLIER, THESE WERE HIGHLY SPECIALIZED SO LOOKING AT MAYBE SOMETIME IN THE FUTURE CONSIDERING ORGANIZING AN AD HOC WORKING GROUP THAT WOULD HAVE A SPECIAL IN THESE SUBJEKS AND THEN LASTLY START TO PLAN FOR PROPOSAL DRIVEN SPECIFIC RESEARCH USING THE TOLL-LIKE TOOLS AND RESOURCES THAT WERE DEVOTED TO IT PROGRAM. FOR EXAMPLE, CONSIDER AN ADDITIONAL PILOTS OR PROJECTS TO ANSWER SPECIFIC QUESTIONS USING ALL OF THE INFRASTRUCTURE AND MECHANISMS THAT WERE DEVELOPED IN THIS COLLABORATION CONCURRENTLY. THAT'S IT. IF THERE ARE ANY QUESTIONS? >> WE'RE OPEN FOR QUESTIONS. YEAH, KEVIN? >> FOR THE SEER PILOT, NOW OR IN THE FUTURE IS THERE A CONSIDERATION FOR INCLUDING GENOMIC DATA IN THE DAT THAT'S BEING COLLECTED? >> THAT WAS NOT MENTIONED SPECIFICALLY BUT THAT IS SOMETHING THAT THEY WILL CONSIDER. AND BEYOND WHAT WAS MENTIONED IN TERMS OF THE HISTOLOGY AND PRIMARY SITE, ET CETERA, I THINK THAT IS SOMETHING THAT THEY SHOULD POTENTIALLY INCLUDE. THEY DIDN'T MENTION THAT SPECIFICALLY. >> OR PATIENTS ARE MORE [INDISCERNIBLE]. >> EXACTLY. >> OKAY, 1 OF THE QUESTIONS I HAVE IS, PIERRE MENTIONED THAT WITH REGARD TO PILOT 2 THAT'S AN ATTRACTIVE 1 BECAUSE YOU CAN MAKE PREDICTIONS TAKEN--THEY CAN BE TESTED EXPERIMENTALLY. SO, COULD YOU PERHAPS COMMENT ON WHAT THE OUTCOME ANALYSIS WILL BE FOR PILOTS 1 AND 3? WILL THERE BE TESTABLE HYPOTHESIS OR SOME DATA SET YOU CAN COMPARE YOUR MODELS TOO? >> YOU WANT TO ANSWER THAT? I THINK FOR PILOT 1 THERE ALREADY IS A CYCLE THROUGH PRIVATE INDUSTRY TO TEST ON CELL LINES. I THINK WE ALSO HEARD THERE ARE WAYS IN WHICH NCI WILL SPEED UP PDXs AND SO ON AND SO FORTH. SO YOU CAN ALWAYS TAKE A SET, TRAIN ON THAT SET AND PREDICT WHAT WOULD HAPPEN ON A SET THAT YOU HAVEN'T YET TRAINED. SO THERE IS DEFINITELY A WAY OF EXPERIMENT, OF DOING EXPERIMENTS SO THAT YOU ACTUALLY TEST WITH THE DEEP LEARNING MODEL HAS LEARNED ANYTHING OR NOT. SO I THINK THE STABILITY IN PILOT 1 IS PRETTY CLEAR. IN PILOT 3, I THINK, YOU KNOW, THEY LOOKED AT SOME CHARACTERISTICS LIKE LATERALITY AND THINGS LIKE THAT IN TRYING TO EXTRACT FROM NATURAL LANGUAGE PROCESSING, THE CHARACTERISTICS, YOU CAN ALSO TEST THAT BECAUSE YOU CAN SEND PEOPLE TO LOOK AT HOW THIS FEATURES FROM THE DATA HAVE BEEN EXTRACTED BY THE DEEP LEARNING VERSUS WHAT A HUMAN WOULD ACTUALLY DO. SO YOU CAN ALSO KEEP TESTING THAT BY--TRAINING ON THE SUBSET AND LOOKING HOW YOU PREDICT WITH ANOTHER SUBSET AND MEASURING THAT. SO YOU CAN SCORE THAT, YOU KNOW 90% EFFECTIVE, 95% EFFECTIVE AND YOU TRY TO IMPROVE THAT. THEY'RE NOT REALLY SCIENTIFIC EXPERIMENTS. THEY'RE TESTS OF ENGINEERING THAT YOU HAVE PUT IN PLACE. ACTUALLY, LEADS TO A RELIABLE ANSWER AND WHEN IT DOESN'T, YOU ARE IN TROUBLE. BUT THAT'S WHY THE UNCERTAINTY QUANTIFICATION IS SO IMPORTANT BECAUSE ASSOCIATED WITH EVERYONE OF THESE TESTS, YOU ALSO PREDICT AN ERROR AND YOU ARE GOING TO SEE WHETHER YOU FALL WITHIN THE ERROR BOUNDS SO WHETHER YOU'RE OUT IN LEFT FIELD SOME PLACE. I DON'T KNOW IF YOU WANT TO ADD ANYTHING TO THAT. >> NO, I'M GOOD. >> BOB DID YOU HAVE A COMMENT? >> IS THERE A THREAT IN ANY OF THESE PROJECTS TO--LET ME BACK UP. I NOTICED THERE ARE A COUPLE DIFFERENT PLATFORMS IN A COUPLE DIAGRAMS USED TO COMPUTE FROM THE DIFFERENT LABS, IS THERE A THREAT TO COMPARE THE SPEEDING COSTS OF WHAT'S BEING DONE FOR THESE 3 PROJECTS WITH THE ARCHITECTURES THEY'RE USING TO SORT OF LIKE JUST TAKING A COMMODITY CLUSTER OF [INDISCERNIBLE] OR SOMETHING LIKE THAT WHICH IS SORT OF CLUSTERS OR FLOWS OR SOMETHING LIKE THAT SINCE SO MUCH EFFORT IS GOING INTO HERE SO WE CAN UNDERSTAND THE BROADER CONTEXT IN WHICH THESE THINGS CAN BE DONE MORE GENERALLY. >> I DON'T HAVE THE ANSWER TO THAT 1. >> I WOULD JUST SAY FROM MY UNDERSTANDING WITH THE CANDLE ENVIRONMENT AND THE DEEP LEARNING NETWORKS THEY'RE USING THEY ARE LEVERAGING WHAT'S IN THE COMMUNITY ALREADY. IT'S JUST THE ACTIVITY OF BEING ABLE TO RUN THOSE ON THE D. O. E. MACHINES. I DON'T KNOW IF THAT ANSWERS YOUR QUESTION THOUGH ON THE COMPARISON? >> I DON'T THINK--I IT'S A VERY GOOD QUESTION. I'LL REPHRASE IT. INSTEAD OF HAVING THIS HIGHLY PARALLEL WITH THIS VERY FANCY CROSS SWITCH FOR ALL THE CPUs AND GPUs AND ALL OF THAT, WHAT HAPPEN FIST INSTEAD OF AIAN FARM, A FORM OF VARIOUS MACHINES AND VIDEOS IN ALL OF THAT. I DON'T KNOW THE ANSWER TO THAT. I SUSPECT THAT YOU STILL FLEED TO HAVE THAT SWITCH IN THE PROCUREMENT--THEY ARE EXPLORING THAT. AND THE GPUs ARE FAR MORE FRIENDLY TOWARDS DEEP LEARNING BECAUSE BECAUSE DEVELOPED FOR GAMES THEY WERE APPLYING MATRIXES FOR OBJECTS AND WARRIORS SO ON AND SO FORTH, THAT TURNED OUT TO BE FOR SOME OF THESE APPLICATIONS THE BEST WAY TO GO. >> COMMENTS FROM ANYONE? ALL RIGHT. THANK YOU VERY MUCH. SO THIS IS THE PART OF THE MEETING WHERE WE'RE OPEN FOR DISCUSSION. >> OH, OH, OH I'M SORRY, I FORGOT. WE NEED TO HAVE A VOTE. >> WE DON'T HAVE A QUORUM. >> OH, OKAY. WE NEED TO HAVE A VOTE TO ACCEPT THE WORKING GROUP'S REPORT WHICH WE JUST HEARD HIGHLIGHTS OF. SO BOB MOVES THAT YES, WE HAVE A SECOND AND THANKS CLAUS, OKAY. [LAUGHTER] ALL IN FAVOR? >> AYE, ALL RIGHT. >> SO THAT WAS--APPROVED. THANK YOU. SO WE'RE OPEN FOR DISCUSSION OF ANYTHING THAT WE HEARD TODAY, ANY ONGOING ISSUES, PARTICULARLY WE HAD A CHANCE TO TALK A LITTLE BIT ABOUT SOME OF THE FUTURE PROSFECTS FOR SOME OF THESE PROJECTS THAT ARE CURRENTLY GOING ALONG VERY NICELY. IMLN WANT TO SPEAK UP. --ANYONE WANT TO SPEAK UP? YES PIERRE? >> IT SEEMS TO ME, I'VE BEEN ON THE COMMITTEE 2 AND HALF YEARS, SOMETHING LIKE THAT, AND THERE DEFINITELY SEEMS TO ME THESE MEETINGS ARE MORE EXCITING THAN THE FIRST MEETINGS AND PARTICULARLY BECAUSE THERE ARE--THESE INITTIAIVE ITS WHAT YOU HEARD ABOUT THERAPEUTICS IN THE LAB, I THOUGHT WAS EXCITING, ALL THESE TESTS, TECHNOLOGY THAT DEVELOPMENT AND AND VERY IMPORTANT AND MAY NOT BE ON PRIOR ELECTRON MICROSCOPY, IT MIGHT COME LATER BUT IT IS A BROAD RANGE OF ACTIVITIES WHERE THE LAB IS REALLY PUSHING THE FRONTIER AND I THINK IN THIS ISSUE OF--AS I AT 1 POINT MENTIONED, TRY TO BUILD SOME STRENGTH IN THE LAB TO BE THIS NEXUS BETWEEN THE SITE PERFORMANCE COMPUTING EXOSCALE AND SO ON WITH THE REST OF THE COMMUNITY. IT IS IMPORTANT THERE SHOULD BE A CENTER SOME PLACE. THE LAB IS A NATURAL PLACE. I DON'T UNDERSTAND EXACTLY HOW NCI'S ORGANIZED. MAYBE YOU WANT TO PUT IT SOME PLACE ELSE BUT HAVING THE LAB I THINK IS AN ASSET. THEY ARE CERTAINLY INVOLVED IN THIS WHOLE ASPECT SO I THINK THAT'S VERY USEFUL BUT I THOUGHT THE PRESENTATIONS BECAUSE THEY WERE VERY EXCELLENT. >> WELL I AGREE WITH THAT, ACTUALLY I WANTED TO THANK THE PRESENTERS FOR THE VERY HIGH QUALITY PRESENTATIONS WE HEARD TODAY. THERE WAS TERRIFIC BASIC SCIENCE, SOME VERY NICE CLINICAL TRANSLATION AND AS WELL SOME REALLY FUTURISTIC AND ALMOST ASPIRATIONAL PRESENTATIONS. AND I THINK IT DOES JUST TO FOLLOW UP ON PIERRE, IT DOES SORT OF POSITION FREDERICK TO BE MORE OF A NATIONAL LAB TO BE DEFINING FRONTIERS RATHER THAN JUST A KIEWMULATION OF CORE FACILITIES AND I DON'T THINK IT'S THAT WAY AT ALL. ANYWAY, I JUST SAID IT BUT I THINK THE TRUTH IS THERE'S A LOT OF REALLY GOOD SCIENCE GOING ON AND THE INTEGRATION AND THE SYNERG EPI-BLAST AMONG COMPLIMENTARY GROUP SYSTEM REALLY PALPABLE AND IMPRESSIVE. I THINK THE NEXT PRESENTATIONS WERE TUCKLY EFFECTIVE IN THAT REGARD IN THESE COMPUTATIONAL COLLABORATIONS WITH D. O. E. OR POISED TO BE VERY SIMILAR TO THAT. SO IF ANY OF YOU HAVE ANY THOUGHTS ABOUT THE MEETING AFTER TODAY, PLEASE FEEL FREE TO SHARE THEM WITH DR. KAREN LINEMEN, HERE AND JUST A REMINDER THAT OUR NEXT MEETING WILL BE OCTOBER 29th AND 30th. SO THE 30th WILL BE THE DAY OF THE MEETING. AND THAT WILL BE HERE AT SHADY GROVE. SO MARK DOWN YOUR CALENDARS AND THEN WITH THE NEW SCHEDULE OF MEETINGS, WE'LL BE DISTRIBUTING SOME TIMES AND PLACES OVER THE NEXT FEW MONTHS. THANK YOU ALL VERY MUCH FOR YOUR TIME, THANK EVERYBODY FROM THE NCI. AND EVERYBODY WHO'S TRAVELED HERE FOR THE MEETING TODAY.