>> OKAY. WELL, LET'S CONVENE TODAY'S MEETING. THANKS FOR JOINING US. WELCOME, EVERYBODY. I THINK I HAVE TO READ THE OBLIGATORY STATEMENT HERE TO KICK US OFF, SO MEMBERS OF THE PUBLIC WHO WISH TO EXPRESS VIEWS INVOLVING ANY ITEMS DISCUSSED AT THIS MEETING MAY DO SO IN WRITING TO THE EXECUTIVE SECRETARY WITHIN TEN DAYS FOLLOWING THE MEETING. WRITTEN STATEMENTS WILL RECEIVE CAREFUL CONSIDERATIONS. TO THE COMMITTEE, ALL MEMBERS OF THE COMMITTEE SERVE AS SPECIAL GOVERNMENT EMPLOYEES AND CERTAIN CONFLICT OF INTEREST RULES APPLY. YOU MUST ABSENT YOURSELF WHEN YOUR PARTICIPATION, DELIBERATIONS ON A PARTICULAR PRODUCT, PROGRAM OR OTHER SPECIFIC MATTER WOULD CONSTITUTE A CONFLICT OF INTEREST OR WOULD CREATE THE APPEARANCE OF ONE. IT IS YOUR OBLIGATION TO ADVISE THE EXECUTIVE SECRETARY AND ABSTAIN FROM ANY PARTICIPATION OR DISCUSSION OR ACTION REGARDING THE MATTER. IF YOU HAVE ANY QUESTIONS ABOUT A SITUATION, POTENTIAL FOR CONFLICT CONFIRM WITH TOM VOLLBERG. YOU'RE TO OBSERVE CURRENT POLICY BASED ON FINANCIAL HOLDS, MUST VOLUNTARILY ABSENT YOURSELF DURING ANY AND ALL DISCUSSION OF MATTERS THAT WOULD IMPACT THE STATUS OF THOSE HOLDINGS. WE TRUST YOUR JUDGMENT IN THESE INSTANCES. ADDITIONALLY A RECUSAL LIST WAS GENERATED FROM INFORMATION THAT YOU REPORTED AND IS IN THE PURPLE FOLDER. TAKE A MOMENT TO EXAMINE THIS FOLDER. BY LAW YOU ARE PROHIBITED FROM PARTICIPATING IN COMMITTEE DISCUSSION OR ACTIONS RELATING TO SPECIFIC PARTY, MATTER OTHER PROGRAM THAT INVOLVES OR AFFECTS ANY OF THE LISTED ENTITIES. YOU MAY PARTICIPATE IN DISCUSSION OF GENERAL MATTERS THAT COULD APPLY TO THESE LIST ENTITIES SO LONG AS DISCUSSIONS REMAIN GENERAL. A QUORUM IS REQUIRED FOR EACH INSTANCE. A MINIMUM OF SEVEN MEMBERS MUST BE PRESENT TO VOICE THEIR VOTES. SINCE WE CAN'T PREDICT THE TIME OH OR OCCURRENCE OF MOTION YOUR PRESENCE IN THE ROOM FOR ALL SEGMENTS IS MUST. PLEASE USE THE MICROPHONE TO ALLOW VIEWERS TO HEAR YOU AND ALLOW VERBATIM REPORTER WITH HER WORK. >> IT IS BEING WEBCAST? >> THAT'S WHAT IT SAYS. >> AND RECORDED. >> AND RECORDED. >> SO PLEASE CONFINE YOUR LANGUAGE TO -- [ LAUGHTER ] I JUST WANTED TO SEE WHETHER PEOPLE WERE READING IN THE LOOP. LET ME SAY A COUPLE THINGS AT THE BEGINNING. FOR REASONS I'LL EXPLAIN IN A MOMENT, THIS IS A PIVOTAL MEETING OF THIS GROUP IN MY VIEW. WE'RE IN A VERY BIG ROOM. THAT HAS NOTHING TO DO WITH THE PIVOTAL NATURE OF THE MEETING BUT A SOME WHAT SMALLER PRESENTATION OF THE COMMITTEE, A FEW ABSENTEES, BUT ALSO SOME NEW MEMBERS. ONE OF THE THINGS WE LIKE ABOUT THIS COMMITTEE WHICH WAS ESTABLISHED IN RESPONSE TO CONCERNS BY THE NATIONAL CANCER ADVISORY BOARD MOST PEOPLE DIDN'T UNDERSTAND WHAT WAS GOING ON UP IN FREDERICK, AND IT WAS TIME TO PROVIDE MORE COORDINATED OVERSIGHT BY A HIGHLY INTERDISCIPLINARY GROUP, AND WE ESTABLISHED THIS ABOUT THREE YEARS AGO, INITIALLY LED BY ZAK HALL, NOW ABLY BY JOE GRAY, ZAK WAS ABLE ALSO BUT JOE IS HERE TODAY. I THINK IT MIGHT BE WORTHWHILE GIVEN THE FACT THAT THE PROGRAM TODAY IS NOT DENSELY PACKED, SOME OF YOU ARE NEW TO THE COMMITTEE AND TO EACH OTHER, IT MIGHT BE WORTHWHILE TO GO AROUND WHERE YOU'RE FROM AND YOUR MAJOR INTEREST IN SCIENTIFIC LIFE. >> I'M GAIL BISHOP, FROM THE CANCER CENTER AT THE UNIVERSITY OF IOWA, AND MY CANCER RELATED RESEARCH IS IN THE AREA OF MOLECULAR PATHOGENESIS OF B-CELL MALIGNANCY WITH NEWER PROJECT THAT WE'RE EXCITED ABOUT, USING B-CELLS IN CELLULAR VACCINES FOR CANCER. >> WHILE WE ARE THE NATIONAL CANCER INSTITUTE AND WE HAVE RESPONSIBILITY FOR THE FREDERICK NATIONAL LAB, THAT THE NATIONAL LAB CONDUCTS RESEARCH THAT'S NOT CANCER RELATE AND WE DO RESEARCH FOR MANY AGENCIES AND INSTITUTES HAD HE NIH, SO ONE DOESN'T NEED TO WEAR THE CANCER BADGE TO BE VERY WELCOME HERE. >> I REALLY LOVE TRASC MOLECULES. >> AND KEN PIENTA FROM HOPKINS. >> I'M JILL MESIROV. PLY CANCER FOCUS FOR 15 YEARS HAS BEEN ON MEDULO BLASTOMA, I'VE ALSO WORKED ON OTHER PARTICULAR TUMOR TYPES, AND I ALSO AM VERY ACTIVE IN TAKING THE ALGORITHMS WE DEVELOP, WRAPPING THEM IN USER FRIENDLY SOFTWARE, AND SHARING THEM WITH RESEARCH COMMUNITY AT LARGE. >> I'M STEVE ROSEN, THE PROVOST CANCER CENTER DIRECTOR AND NOW DIRECTOR OF THE BECKMAN RESEARCH INSTITUTE AT CITY OF HOPE AND MY BACKGROUND IS MEDICAL ONCOLOGY AND EXPERIMENTAL THERAPEUTICS, >> I'M BOB GROSSMAN, THE DIRECTOR OF THE CENTER FOR DATA INTENSIVE SCIENCE, UNIVERSITY OF CHICAGO, AND I'M IN THE INSTITUTE FOR GENOMICS AND SYSTEMS BIOLOGY THERE. MY SCIENTIFIC AREA IS DATA INTENSIVE SCIENCE, FORMERLY KNOWN AS BIG DATA, AND I'M LY INTERESTED IN APPLICATIONS TO CANCER GENOMICS. >> LEVI GARRAWAY FROM DANA-FARBER, ALSO THE BROAD INSTITUTE, WE DO CANCER GENOMICS. >> LARRY MARNETT, VANDERBILT SCHOOL OF MEDICINE, I'M INTERESTED IN CHEMICAL BIOLOGY OF INFLAMMATION IN CANCER. >> I'M DAVID BOTSTEIN, LATE OF PRINCETON AND NOW CHIEF SCIENTIFIC OFFICER OF KELLICO, A NEW ENTITY IN CALIFORNIA, INTERESTED IN THE BASIC SCIENCE OF AGING. MY TECHNICAL EXPERTISE IS GENETICS AND GENOMICS AND WITH RESPECT TO CANCER, THE BIG THING WAS GENE EXPRESSION PATTERNS TO IDENTIFY SUBTYPES OF ORIGINALLY BREAST CANCER AND THEN VARIOUS OTHER CANCER AND GOT INTO THE BIOINFORMATICS REALM. >> BOB WILLTREAD, A CANCER IMMUNOLOGIST WITH A PARTICULAR INTEREST IN INNATE IMMUNE TONSES. >> DONNA SIEGLE, TO NCI. >> DOROSHOW. >> I DO RESEARCH ON PAPILLOMA VIRUSES. >> BEFORE WE GET UNDERWAY WITH THE REPORT FROM DAVE HEIMBROOK, LET ME SAY WHY THIS IS OCCURRING AT A SIGNIFICANT TIME IN THE HISTORY OF WHAT DOUG JUST REFERRED TO AS FREDERICK. AND THE REASON I EMPHASIZE DOUG'S ABBREVIATION, ONE OF THE THINGS WE'VE ACCOMPLISHED IS REVEALING THE CONTOURS OF A COMPLEX LANDSCAPE WE HAVE AT FREDERICK. FREDERICK IS A CIVIL WAR CITY THAT HAS A LOT OF FEDERAL INSTALLATIONS, IT'S HAD MANY COMPONENTS OF THE NCI, THROUGH THE AGENCY OF THIS COMMITTEE AND ATTENTION HAS BEEN PAID TO THE FREDERICK CAMPUS, MOST PEOPLE, FAR FROM ALL, NOW FAIRLY CLEAR UNDERSTANDING WE HAVE A THIRD OF OUR INTRAMURAL PROGRAM, MOSTLY CCR BULY, CENTER FOR CANCER RESEARCH, ON THE FREDERICK CAMPUS. WE HAVE A FEDERAL FUNDED RESEARCH AND DEVELOPMENT CENTER, THE ONLY SUCH PROGRAM DEVOTED TO MEDICAL RESEARCH IN THE GOVERNMENT. THE ONLY ONE DEVOTED TO THAT TOPIC OBVIOUSLY WITHIN THE DEPARTMENT WHICH HAS ONLY ONE OTHER VERY SMALL FRDC. THE PEOPLE NOW UNDERSTAND THE FFRDC DOES AT LEAST TWO MAIN THINGS. CONTRACT SERVICES FOR THE EXTRAMURAL COMMUNITY FOR MANY MAJOR PROJECTS, SUCH AS THE CANCER GENOME ATLAS, BUT IT ALSO RUNS A LABORATORY, SET OF LABORATORY ACTIVITIES WE CALL -- NOW CALL THE FREDERICK NATIONAL LAB FOR CANCER RESEARCH. WE GAVE IT THAT NAME, THIS COMMITTEE DID, A COUPLE OF YEARS AGO, TO CLARIFY THIS A NATIONAL LAB, IT HAS SOME OF THE POTENTIAL THAT'S INHERENT IN THE MANY OTHER NATIONAL LABS THAT ARE RUN BY THE DEPARTMENT OF DEFENSE, ESPECIALLY THE DEFENSE OF ENERGY. IINK SIMPLY BY VISITING AND LEARNING LESSONS FROM THOSE FOR FAMOUS AND LONGER ESTABLISHED NATIONAL LABS WE'VE BEGUN TO CHANGE THE LANDSCAPE OF WHAT WE DO, THAT'S BEEN VERY IMPORTANT. IN ADDITION TO PROVIDING MANY IMPORTANT LABORATORY SERVICES TO OTHER INSTITUTES, EXTRAMURAL INVESTIGATORS, EXTRAMURAL INVESTIGATORS, THE NATIONAL LAB ALSO IS TAKING ON BIG PROJECTS, PROJECTS THAT WE BELIEVE, I MEAN THIS COMMITTEE AND SOME OF THE LEADERS OF THE NCI, A FEW OF WHOM ARE AT THE TABLE, OTHERS AS WELL THAT VIEW AS AMBITIOUS, PARTICULARLY IMPORTANT, DIFFICULT TO ACHIEVE WITHOUT CONCERTED EFFORTS CARRIED OUT BY THE PROGRAM WE ASSEMBLE WITH INHERENT FLEXIBILITY ON THE FREDERICK CAMPUS AND BY EXTENSION MANY IN THE SCIENTIFIC COMMUNITY. WE'VE BEEN HELPED BY A CHANGE IN LEADERSHIP AT WHAT IS NOW CALLED LIDOS, BIOMEDICAL RESEARCHING, DAVE HEIMBROOK WAS RECRUITED BY SAIC, NOW LIDOS, JUST AFTER I ARRIVED, AND PARTNERSHIP WITH HIM HAS BEEN IMPORTANT BUT WE ALSO RECOGNIZE IT'S A CONTRACT. IT GETS RECOMPETED AND WE LEARNED IT'S POSSIBLE WE WOULD INCLUDE IN THE RECOMPETITION NEXT TIME COMPETITORS WHO REPRESENT ACADEMIC INSTITUTIONS OR OTHER FORMS OF CONTRACT ORGANIZATIONS AND THAT I THINK HAS LENT SOME DEGREE OF SPICE TO THE WHOLE PROCEEDING BECAUSE PEOPLE ARE SEEING THAT WE ARE SERIOUS ABOUT TRYING TO DO THINGS IN A MORE TARGETED AND INTENSE WAY AT THIS LAB, NOT SIMPLY PROVIDING THE GOOD SERVICES THAT WERE AFFORDED BEFORE BUT TAKING ON MAJOR PROBLEMS IN BIOMEDICAL RESEARCH MORE BROADLY BUT CANCER RESEARCH SPECIFICALLY. I THINK ONE OF THE GREAT ACCOMPLISHMENTS OF THE FIRST FEW YEARS OF THIS ACTIVITY, PARTICULARLY THIS COMMITTEE'S ACTIVITY, HAS BEEN THE IDENTIFICATION OF THE -- WE CALL IT THE RAS PROBLEM, THE BASIS FOR A MAJOR NEW INITIATIVE. WE'VE BEEN FORTUNATE IN RECRUITING NEW LEADERS OF THAT PROGRAM, HAVING DAVE WORK WITH US TO REORIENT MANY OF THE RESOURCES OUT THERE, BOTH MONEY AND PEOPLE, TO BUILD A PROGRAM THAT HAS INTERNATIONAL ACCLAIM, TO JUDGE ITS ULTIMATE PRODUCTIVITY WILL BE MEASURED WHEN WE KNOW NOW HAVE ABOUT HOW RAS GENES WORK TO HAVE NEW KINDS OF THERAPEUTIC AND PREVENTIVE STRATEGY. WE FELT THE NEED TO HAVE SPECIFIC OVERSIGHT OF THAT PROGRAM AND LEVI GARRAWAY HAS TAKEN ON THE CHAIRMANSHIP. WE'LL HEAR FROM HIM AND FRANK McCORMICK WHO RUNS THE PROGRAM AND ED ABOUT THE CONNECTIONS THAT HAVE BEEN MADE FROM WHAT WE CALL THE HUB ACTIVITY AT THE FREDERICK LAB TO EXTRAMURAL ACTIVITY IN THE RAS INITIATIVE BUT WE ALL AGREE THAT HAVING ONE SIGNATURE PROGRAM IS NOT ENOUGH TO TRULY TRANSFORM THE WAY THE FREDERICK NATIONAL LAB DOES ITS BUSINESS, AND WE HAVE BEEN LOOKING AT HOW OTHER NATIONAL LABS, ESPECIALLY DOE LABS TRY TO WORK TOWARD IDENTIFICATION OF PROJECTS TO BE PARTICULARLY APPROACH IT. JOE HAS BEEN HELPFUL IN BRINGING LEADERS OF SOME LABS, TAKING US TO THE BERKELEY-LAWRENCE LAB AND LEARN HOW THEY WORK WITH ACADEMIC INSTITUTIONS, WITH INVESTIGATORS AROUND THE COUNTRY, TO INCUBATE NEW IDEAS, SEE WHAT MIGHT BE AN APPROPRIATE TOPIC THAT FITS THE CHARACTERISTICS THAT I THINK ALL OF US FEEL ARE ESSENTIAL IF WE'RE GOING TO MAKE GOOD USE OF THIS LAB AND NOT BE APPROPRIATELY ACCUSED BY OUR EXTRAMURAL COLLEAGUES OF SQUANDERING GOOD GRANT ONEY ON A CONTRACT PROGRAM. SO THIS HAS GOT TO FIT THE BILL. WE HEARD AT THE LAST TIME WE MET FROM SEVERAL PEOPLE WHO HAD INTERESTING IDEAS ABOUT WHAT WE MIGHT DO FOR THE NEXT ACT, I DIDN'T HEAR UNIVERSAL ENTHUSIASM FOR ANY OF THOSE PROJECTS. THEY ALL HAVE VIRTUES. THIS AFTERNOON WE'RE GOING TO HEAR IN MUCH MORE DETAIL THAN WE HAVE BEFORE ABOUT A POTENTIAL NEW PROJECT IN STRUCTURAL BIOLOGY, BASED LARGELY ON CRYO-EM AND GIVE THAT QUITE AN EXTENSIVE AIRING BECAUSE THIS HAD PRELIMINARY VETTING FROM JOE AND OTHERS, AND IT WILL BE UP TO US OR UP TO YOU TO ADVISE THE NCI ABOUT WHETHER THIS IS AN APPROPRIATE ACTIVITY FOR THE NATIONAL LAB, BECAUSE I PERSONALLY FEEL WE NEED TO IDENTIFY ADDITIONAL PROJECTS AND BEGIN TO MAKE THIS MORE THAN A ONE-TRICK PONY. SO THOSE ARE MY HISTORICAL REFLECTIONS ON WHERE WE ARE, AND THE EXPLANATION FOR WHY I THINK TODAY'S MEETING IS SO CRITICAL, AND WHY I'M SORRY THAT MANY OF OUR MEMBERS ARE UNFORTUNATELY NOT WITH US TODAY. BUT WE WELCOME THE NEW ONES, AND HOPE TO MAKE GOOD USE OF YOU AND THE OTHERS WHO HAVE BEEN ABLE TO GET HERE TODAY. ANY QUESTIONS? I REALIZE I HAVEN'T DONE THE TRADITIONAL NCI DIRECTOR'S COMMENTS ABOUT BUDGET AND SO FORTH BUT I DON'T THINK THAT'S PARTICULARLY PERTINENT. YOU GUYS KNOW WHAT'S GOING ON. WE'RE AT STALEMATE, NOT VERY INTERESTING BUT THE QUESTION OF HOW WE MAKE USE OF THE FREDERICK NATIONAL LAB IS SOMETHING THAT WITH YOUR ADVICE AND FROM NCAIB AND HELP FROM LIDOS WE'VE RESHAPED IN A WAY THAT IS PRETTY IMPRESSIVE AND WE'VE GOT AN OPPORTUNITY WITH MOMENTUM FROM THE RAS PROJECT TO DO THINGS WITH SIMILAR HIGH POTENTIAL AND I'D LIKE TO MAKE RESOURCES WHEN RESOURCES ARE PRETTY DAMN LIMITED. SORRY, I MADE A CURSE , THE D WORD. COMMENTS, QUESTIONS? IF NOT, BACK TO YOU, MR. CHAIRMAN. WE'LL LAUNCH INTO THE DAY'S >> I THINK THE OPENING EVENT HERE IS FROM DAVID, IT'S GOING TO GIVE US THE UPDATE ON THE NATIONAL LABORATORY AND I THINK ONE OF THE THINGS THAT IS REALLY IMPORTANT ABOUT THIS PRESENTATION IS THAT AS WE THINK ABOUT EVOLVING THE NATIONAL LABORATORY IT'S IMPORTANT TO UNDERSTAND IN DETAIL HOW IT WORKS AND SO I THINK THIS IS TAKING US IN THE DIRECTION OF THAT UNDERSTANDING. DAVID? >> THANKS VERY MUCH. I APPRECIATE YOUR COMMENTS VERY MUCH, HAROLD, ABOUT HOW MUCH PROGRESS WE'VE MADE AND HOW MUCH MORE THERE IS TO DO TO REACH THE ASPIRATION WE'RE SPEAKING TO ACHIEVE WITH FREDERICK LABS. I'D LIKE TO COVER FOUR SUBTOPICS IN TERMS OF DISCUSSING PROGRESS ON A NUMBER OF CRITICAL PROGRAMS, ESPECIALLY IN TERMS OF PARTNERING. FIRST, HOWEVER, I WANTED TO SHARE WITH YOU SOME OF OUR EFFORTS SUPPORTING THE NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASE, IN THEIR BATTLE AGAINST THE EMERGING CRISIS FOR EBOLA AND THEN THE CONTRACTOR CREATOR MECHANISMS, AND TALK ABOUT TWO PROGRAMS, THEY ARE POISED TO MEET INCREASING DEMAND FOR THEIR SERVICES AND FOR THEIR SCIENTIFIC CONTENT. AND SO THEN WE'LL HAVE PLENTY OF TIME THEN FOR DISCUSSION. SO THE EBOLA CRISIS CONTINUES TO EXPAND IN SIGNIFICANT WAYS GLOBALLY, WE'RE SUPPORTING THE NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASE THROUGH VCMP. THIS WAS PRESENTED TWO YEARS AGO, I THOUGHT IT WOULD BE APPROPRIATE TO HAVE BACKGROUND MATERIAL TO PROVIDE THE CONTEXT FOR THE WORK WE'RE DOING. SO THE VACCINE RESEARCH CENTER, WHICH IS PART OF NIAID, WAS CREATED BY EXECUTIVE ORDER -- >> IT WAS PART OF NCI AS WELL. >> OKAY, SO THERE'S A CERTAIN SYNERGY HERE THEN AS WE CLOSE THE LOOP. [ LAUGHTER ] SO THE FOUNDING STATEMENT BEHIND IT IN TERMS OF WHY IT'S CREATED IS PROVIDED IN THIS QUOTE FROM DR. FAUCI. AND THE KEY IS THAT IT'S TO HELP TRANSLATE FINDINGS AND HAVE RAPID RESPONSE CAPABILITY TO MANUFACTURE CANDIDATE VACCINES AND EVALUATE THEM IN EARLY CLINICAL STUDIES. IT WAS RECOGNIZED IN 1999, AND THIS WAS THEN ACCELERATED WITH THE 9/11 CRISIS AND THE ANTHRAX ELEMENTS THERE WAS A NEED FOR A PILOT PLANT TO HELP SUPPORT THIS MISSION. THE IDEA WAS TO PROVIDE AGAIN A VERY RAPID AND DEDICATED RESPONSE CAPABILITY TO MEET NIAID'S AND VRC'S PRIORITIES, APPROVED IN 2003 AND COMMENCED GMP MANUFACTURING OPERATIONS IN 2006, A FAIRLY RAPID TURNAROUND TIME. I BELIEVE THIS FIRST -- THE FIRST PRODUCED PRODUCT THERE WAS I BELIEVE TO ADDRESS AVIAN FLU. FREDERICK NATIONAL LAB OPERATES THE VACCINE PILOT PLAN ON BEHALF OF THE NIAID, THE DEPARTMENT IN OUR AREA WHICH OPERATES IT IS THE VACCINE CLINICAL MATERIALS PROGRAM. THEY ALSO DO OTHER THINGS BUT THEIR KEY OBJECTIVE AND KEY GOAL IS OPERATING THE VPP. THE CORE IS THE VACCINE PILOT PLAN FACILITY LOCATED ABOUT 7 MILES OFF OF FORT DETRICK POST. THE CORE IS 50,000 SQUARE FEET OF MANUFACTURING AND FORMULATION FILLING CAPABILITY, THERE ARE FOUR PARALLEL TRAINS WITHIN THE MANUFACTURCE THAT CAN FUNCTION INDEPENDENTLY, SORT OF THE LARGEST OF THEM CONTAINS THIS 2000-LITER BIOREACTOR AND THEN OF COURSE THE PRODUCT EMERGES THROUGH THE FORMULATION FILLING. THERE'S A VARIETY OF SUPPORT AREAS ON THE FAR RIGHT, YOU CAN SEE THE TECHNOLOGY, DEVELOPMENT AND ASSAY TRANSFER LABS TO TAKE THE PROCESSES DEVELOPED BY THE VRC ON THE EARLY STAGE AND ADAPT THEM TO GMP MANUFACTURING CAPABILITIES. AS IS INDICATED. IT'S A NICE MODERN STATE OF THE ART FACILITY. THE INITIAL ELEMENTS THAT WERE EXECUTED WITHIN THE VPP, IT STARTED TO BE VERY FOCUSED ON DNA-TYPE VACCINES, SO THESE INCLUDE DNA PLASMID, ADENOOVIRUS. YOU CAN MOVE THEM FORWARD RAPIDLY, IS A CENTERPIECE AND CONTINUES TO BE A CENTERPIECE OF THE TYPE OF WORK SUPPORTED THERE. MORE RECENTLY, THEY MOVED INTO MORE PRO TENACIOUS MATERIALS INCLUDING VIRUS-LIKE PARTICLES, TO HELP SUPPORT A VARIETY OF ALPHA VIRUS DISEASE STUDIES FOR NIAID, INCLUDING MOST RECENTLY THE CHIKUNGUNYA VIRUS VACCINE PRODUCED AND RELEASED FOR STUDY RECENTLY PROFILED IN THE "LANCET" A MONTH AGO. WE MADE USE OF THE 2000-LITER BIOFACILITY TO PRODUCE MONOCLONAL ANTIBODIES, VROC 1 AND THEN MULTIPLE BATCHES TO GENERATE BATCHES AS AN ANTI- HIV VACCINE CANDIDATE. OUR SUPPORT FOR EBOLA PRECEDED THE CURRENT CRISIS AS IT DID FOR PHARMA AND MANY OTHER RESEARCH ORGANIZATIONS. THE PROGRAM WAS REALLY INITIATED BY NIAID IN 2011, AND IT WAS FAIRLY BROADLY DEFINED STATEMENT OF WORK THAT WE WOULD HELP SUPPORT GMP VACCINE MANUFACTURING, FILLING AND FINISH AND REGULATORY APPROVAL. THIS INCLUDES OUR ABILITY TO DO CONTRACTS FAIRLY RAPIDLY AS WELL AS OUR ABILITY TO SUPPORT IT WITH WET LAB ACTIVITIES. AND SO WE CAN BE VERY ADAPTABLE FOR THAT. THAT'S REALLY COME TO THE FORE IN THE CURRENT WORK WITH THE INVESTIGATIONAL CHIMPANZEE ADENOVIRUS VECTOR VACCINE WITH OKAIROS, ACQUIRED BY GLAXOSMITHKLINE, THIS WOULD SHOW PROMISE IN PRIMATE MODELS, AND THERE'S A PUBLICATION IN "NATURE." DURING THE SUBCONTRACTING FOR THE MANUFACTURER OF THE VACCINE, HELPING TO PROVIDE QA AND QC OVER THAT MANUFACTURING CAPABILITY AND BRINGING IT OVER TO THE VPP WHERE WE CONDUCT FORMULATION, FILL AND FINISH OF THE DRUG PRODUCT. WE'VE ALSO HELPED SUPPORT THE FILING OF THE IND OF THIS FIRST CHIMP ADENOVACCINE, YOU CAN SEE A PICTURE OF THE VIAL WHICH APPEARED IN THE "WALL STREET JOURNAL" A MONTH, AND YOU MIGHT BE ABLE TO MAKE OUT THE LIDOS BIOMED IN THE BOTTOM RIGHT CORNER. THAT'S WHAT CONSTITUTES ADVERTISING, I GUESS. WE SUPPORTED THE IND AND THE IMPORTANCE OF THIS PROGRAM IS REFLECTED BY THE FACT THAT IT WAS SUBMITTED, THE IND, WAS SUBMITTED ON A FRIDAY,15, AND WE RECEIVED THE SAFE TO PROCEED ON THE FOLLOWING TUESDAY, THE 19th, THE FIRST PATIENT IN THE NIH CLINICAL TRIAL WAS SEPTEMBER 2. THIS IS OBVIOUSLY A RAPIDLY MOVING AREA, BECOMES A TOP PRIORITY AND WE'RE PLEASED TO HELP DO THAT. THIS IS AN ONGOING EFFORT. HOWEVER, IT'S NOT A ONE AND DONE. THERE'S MUCH SCALEUP TO BE DONE WITH THIS CHIMP ADENOVIRUS VECTOR AND WE'RE IN DISCUSSIONS TO DO THAT. IT'S RECEIVED A LOT OF PRESS BECAUSE I THINK IT'S A VERY IMPORTANT STRATEGIC EFFORT AND A VERY INTERESTING CANDIDATE TO HELP RESPONSE. SOME OF THE EFFORTS WE'RE GOING TO CONTINUE ARE APPROVED OR IN DISCUSSION INCLUDING WORKING COMPANION BOOSTER VACCINE, WHICH IS SHOWN INTERESTING IN PRE-CLINICAL ACTIVITY, WE'LL SUPPORT THAT IN TERMS OF MANUFACTURE OR FORMULATION AND FINISH. SCALEUP OF THE ADENOVIRUS VACCINE IN THE UK AND AFRICA, AND ACTUALLY RELYING ON ANOTHER PART OF LIDOS BIOMED OR FREDERICK NATIONAL LABS TO SUPPORT EBOLA TRIALS IN AFRICA THROUGH SUBCONTRACTING OR PROVIDING TRAINING CAPABILITIES. THESE ARE UNDER DISCUSSION AND WE'RE OBVIOUSLY HOPING THAT ADDITIONAL CANDIDATES ABOUT FLOW THROUGH AND WE'LL BE ABLE TO HELP SUPPORT NIAID'S VERY IMPORTANT EFFORTS TO ACHIEVE THIS. AGAIN RESPONDING TO URGENT BIOMEDICAL CRISES. NEXT THING I WOULD LIKE TO TALK ABOUT, PROVIDE AN UPDATE ON PARTNERING EFFORTS THAT WE'VE DONE. AS YOU RECALL WE RECEIVED APPROVAL TWO YEARS AGO TO INITIATE CONTRACTORS AUTHORITIES TO DO THESE COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENTS DIRECTLY WITH OUTSIDE COMPANIES OR RESEARCHERS. THIS WAS A FAIRLY BIG MILESTONE, OPENING UP A LOT OF OPPORTUNITIES AND WANTED TO TELL YOU WHAT WE'RE DOING TO MAKE THE MOST OF THIS OPPORTUNITY FOR THE BENEFIT OF THE EXTERNAL BIOMEDICAL COMMUNITY. THE IDEA BEHIND THIS CONTRACTOR CCRADA INVOLVES INTELLECTUAL CONTRIBUTIONS, IT'S A CONTRACTOR CCRADA, FOCUSED ON FREDERICK NATIONAL LAB SCIENTISTS AND EXTERNAL PARTNERS DOING THE WORK, THERE'S NO DIRECT PARTICIPATION BY GOVERNMENT PERSONNEL, THERE IS APPROVAL AND OVERSIGHT OF THE EXECUTION OF THE CCRADA ACCORDING TO NORMAL REVIEW PROCESS, USEFUL FOR PROJECTS OF LONG SCOPE AND DURATION, ALLOWS US TO ESTABLISH RELATIONSHIPS IN TRANSLATIONAL RESEARCH, THE KEY IS IT PROVIDES SPECIAL PROTECTIONS FOR JOINT IP THAT MIGHT EMERGE, AND THAT OF COURSE IS THE CONCEPT BEHIND THE CCRADA, INCLUDING CO-LOCATION OF SCIENTISTS, CAN INCLUDE PARTNER PROVIDING FUNDS TO HELP OFFSET THE COST OF THE WORK THAT WE'RE EXECUTING, WITHIN FREDERICK NATIONAL LABS, AND ALSO COME-EYE USED BY DOE FFRDCs TO FOSTER STRATEGIC RELATIONSHIPS THEY WANT TO MOVE FORWARD. THEY WERE APPROVED IN AUGUST OF 2012, SINCE THAT TIME WE'VE HAD SIX CONTRACTOR CCRADAs, THE FINAL APPROVAL OCCURRED WITHIN REALISTICALLY THE LAST 13 MONTHS OR SO BECAUSE IT TOOK TIME TO SET UP AND NORMALIZE THE PROCESS TO MAKE THESE HAPPEN. MEDIAN TIME FROM CONCEPT APPROVAL, THE FIRST REVIEW STEP WE HAVE WITHIN THE OVERALL PROCESS, THE FINAL SIGNATURE, IS ABOUT FIVE MONTHS, LONGER FOR THE FIRST ONE, SHORTER FOR THE ONES THAT WE'RE DOING AND WE'RE CONTINUING TO TRY TO MOVE TOWARD THAT GOAL OF GETTING IT IN THE THREE TO FOUR MONTH RANGE AS WE ORIGINALLY PROPOSED WOULD BE OUR GOAL BACK WHEN ALL OF THIS WAS APPROVED. YOU CAN SEE THAT SOME OF THESE ARE RELATED TO THE AIDS AND CANCER VIRUS PROGRAM, LED BY JEFF LISSEN, WHO IS IN THE AUDIENCE TODAY. THOSE ARE THE LARGER ONES AND LONGER TERMS ONES. WE'VE GOT ONES THAT USE OUR STANDARD TECHNOLOGY WITHIN THE CANCER RESEARCH AND TECHNOLOGY PROGRAM, WITH BIOJENIDA TO K AT WAYS TO USE OUR TECHNOLOGY WE'VE DEVELOPED TO DO PROTEIN SCALEUP, IMMUNOLOGY FOR THE HUMAN PAPILLOMA VIRUS ANTIBODY, PATIENTS, SUPPORTED BY ALICIA PINTO'S LABORATORY AND OTHERS, ONE RELATED TO RAS, ANOTHER RELATED TO NEXT GEN SEQUENCING. THESE HAVE BEEN EXECUTED, INCLUDING PHARMA AND ACADEMIC COLLABORATIONS. WE HAVE SIX MORE IN PROCESS. SO, AGAIN, SOME OF THESE ARE -- ONE AT LEAST AT THE TOP THERE IS RELATED TO RAS TO HELP US FACILITATE TRANSFER OF REAGENTS BACK AND FORTH. THEN WE HAVE ONES WITH PHARMA AS ELL AS ANOTHER RESEARCH UNIVERSITY. I DID WANT TO NOTE HERE THAT THE AIDS AND CANCER VIRUS PROGRAM SHOWS UP AS BEING ONE OF THE MORE PROMINENT USERS OF THIS. >> DAVID, COULD YOU JUST SAY A LITTLE BIT ABOUT WHO IS INITIATING THE CCRADAs? >> PART IS GENERATED BY US, WE WORK WITH PEOPLE AND DETERMINE THE CCRADA WOK WOULD BE A GOOD WAY TO DO IT. THEY ARE EXAMPLES OF BOTH, WHERE WE FIND THE PARTNER AND THE PARTNER COMES TO US. THE AIDS AND CANCER VIRUS PROGRAM AND NANOTECHNOLOGY CHARACTERIZATION LAB, NCO, LED BY DR. SCOTT MCNEIL IN FREDERICK, ALSO HERE IN THE AUDIENCE, ARE AT THE FOREFRONT OF UTILIZING PARTNERING OPPORTUNITIES BECAUSE THEY HAVE ORGANIZATIONS IN THEIR SCIENCE MOST AMENABLE TO HAVING A MAJOR IMPACT WITH PARTNERS ON THE OUTSIDE. I'M SORRY? [OFF [OFF MIC] BECAUSE THESE DEALS HAVE NOT BEEN FINALIZED YET. OTHER ELEMENTS BESIDES STANDARD AND FULL BLOWN CONTRACTOR CRADA IS THE MATERIALS CRADA, ALLOWS US TO BRING MATERIALS IN, THEY HELP SUPPORT BROADER CONTRACTOR CCADAs, RELATED TO JEFF'S LAB TO GET WHAT THEY NEED FOR THEIR PRIMATE MODELS FOR HIV, TWO EXECUTED, TWO IN PROGRESS. WE HAVE COLLABORATION AGREEMENTS WE'VE REINFORCED OUR EFFORTS TO GO FORWARD WITH, FIVE HAVE BEEN EXECUTED IN THE LAST YEAR OR SO. AGAIN, HAVE FAIRLY BROAD RANGE OF EXPERTISE AND REASONS BEHIND DOING THEM AND TIMES OF SCIENCE THAT WE'RE UTILIZING. IN THE CENTER, THE PAC BIO, WE'RE USING OUR SORT OF CENTRAL EXPERTISE TO HELP PUSH THE ENVELOPE OF EXPLOITING THESE, IN COLLABORATION WITH THE COMPANY SOMETIMES, OTHER TIMES THERE ARE OTHER PARTNERS INVOLVED AS WELL. IN ADDITIWE HAVE A COLLABORATION FOR RAS WE SET UP TO LOOK AT RAS GAP CO-STRUCTURES, YOU'LL PROBABLY HEAR MORE ABOUT FRANK McCORMICK. AND THE TECHNICAL SERVICES AGREEMENT IS MORE STREAMLINED, PART OF THE CONTRACTOR CRADA, SOMETHING WE OFFER THAT'S WELL PRE-DEFINED, YOU CAN GO FORTH, THE TIMING AND APPROVAL, TO MAKE IT HAPPEN. IT'S MORE STREAMLINED. THE THINGS THAT WE HAVE THAT ARE ESPECIALLY COMMONLY USED ON THE OUTSIDE AND WHERE THERE'S NO ISSUE WITH JOINT IP EMERGING CAN BE DONE THROUGH A TECHNICAL SERVICE AGREEMENT. THEY ARE LISTED ON THE WEBSITE BELOW AROUND BEGIN GETTING OFFERED AROUND THE SAME TIME AS THE CRADA, THE INITIAL CONTRACTOR CRADA. IN FY 13, $250,000, AND THIS YEAR MORE HAS BEEN COMMITTED. THE KEY PROVIDERS FOR WHICH THERE'S BEEN THE MOST DEMAND ARE AIDS AND CANCER VIRUS PROGRAM UNDER JEFF LISSEN, WITH EIGHT SERVICES AND LABORATORY ANIMAL SERVICES PROGRAM, THE ONES WHICH ACCOUNT FOR MOST OF THE ACTIVITY. WE'RE CONTINUING TO ADD NEW TECHNICAL SERVICES AS PEOPLE INDICATE THAT THEY WOULD LIKE TO HAVE THEM AVAILABLE AND GET ACCESS TO SOME OF THE THINGS THAT WE OFFER, RIGHT NOW IT'S 20 AND COUNTING, YOU CAN SEE IT AT THE WEBSITE. WITH THE ADVENT OF WHAT WE'RE DOING WITH PARTNERING, IT'S CLEAR THAT ESPECIALLY WITHIN THE AIDS AND CANCER VIRUS PROGRAM, AS WELL AS SOME OF THE OTHER NANOTECHNOLOGY CHARACTERIZATION LABORATORY, THERE ARE SOME IMPORTANT ELEMENTS BEING RECOGNIZED ON THE OUTSIDE HAVING A MAJOR IMPACT TO HELP ENABLE SCIENCE ON THE SO I'D LIKE TO TAKE A STEP BACK AND SAY WHAT EXACTLY DO WE CHARACTERIZE AS A NATIONAL PROGRAM? I THINK WE HAVE ALL TALKED ABOUT AND ALL ARE AWARE OF THE RAS PROGRAM BUT I THINK WE CAN DEFINE IT IN TERMS, I'LL TAKE A SHOT HERE, PEOPLE MAY AGREE OR CAN MODIFY IT AS THEY SEE, BUT FIRST OF ALL THE FREDERICK NATIONAL PROGRAM IS DIRECTED TOWARD A COHERENT OBJECTIVE, AS HAROLD INDICATED BEFORE MUCH OF WHAT WE DO SUPPORTS SCIENCE THAT'S GOING ON WITHIN NCI. I THINK WE WOULD AGREE A NATIONAL PROGRAM IS ONE THAT IS REALLY FOCUSED ON EXPLORING AND ENABLING SCIENCE ON THE OUTSIDE. SO A HEAVY EXTERNAL FOCUS. IT HAS SCIENTIFIC CONTENT WHICH IS FUNDAMENTALLY DRIVEN BY TEAMS OF FREDERICK NATIONAL LAB SCIENTISTS AS OPPOSED TO GOVERNMENT SCIENTISTS. AND ALSO THAT IT'S HIGHLY VISIBLE AND IMPACTFUL TO THE EXTERNAL SCIENTIFIC COMMUNITY. O I THINK WITH THOSE TYPES OF CHARACTERIZATIONS FOR THIS, WE COULD SAY BASED ON THIS DEFINITION THERE ARE AT LEAST TWO PROGRAMS WITHIN FREDERICK NATIONAL LABS THAT CAN BE CHARACTERIZED AS NATIONAL. THE FIRST IS AIDS, I TALK ABOUT DR. LIFSON'S AREA AND USING THE CRADA MECHANISM, THE SPONSOR IS DIAGNOSE CRAIG REYNOLDS. WE HAVE THE NANOTECHNOLOGY CHARACTERIZATION LAB. WITH THE SUPPORT OF THEIR SPONSORS, WE'VE RECOGNIZED WITH ALL OF THE DEMAND FOR THE SERVICES THAT ARE GOING ON, THERE'S AN OPPORTUNITY FOR STRATEGIC EXPANSION, WITHIN THESE PROGRAMS TO DO EVEN A LITTLE BIT MORE FOR THEM. SO WE'VE HAD DISCUSSIONS WITH THE NCI SPONSORS AND I'D LIKE TO OPPORTUNITIES ACTUALLY ARE. SO FIRST A LITTLE BIT OF REVIEW ON THE TWO PROGRAMS, BOTH HAVE BEEN PRESENTED TO THE MFAC IN THE PAST, FOR THE AIDS AND CANCER PROGRAM THE GOAL IS TO CONDUCT RESEARCH, AND TO DEVELOP NOVEL RESEAR THOUGHTS, ANALYTICAL TECHNIQUES AND REAGENTS TO MAKE THESE AVAILABLE TO THE BROADER RESEARCH COMMUNITY. AGAIN, SIMILAR TO WHAT WE'RE GOING ON SOME OTHER AREAS, THE IDEA IS TO ENABLE THE EXTERNAL COMMUNITY BEHIND US AND THE GROUP HAS BEEN DOING A GOOD JOB. SOME DISTINGUISHING FEATURE ALSO OF THE ACD PROGRAM IS THAT THERE'S SMALL A PRINCIPAL INVESTIGATORS, AND SUPPORT CORES, WHICH ARISE FROM THE -- QUESTION? >> YEAH, COULD YOU JUST TELL ME HOW -- WHERE AN NCI SPONSOR COMES FROM? I DON'T UNDERSTAND THE RELATIONSHIP. >> CERTAINLY. SO EVERYTHING THAT WE DO WITHIN FREDERICK NATIONAL LABORATORIES HAS AN NCI OR NIH SPONSOR. SO THE WAY THE WORK COMES INTO FREDERICK NATIONAL LABS IS THAT ONE OF THE DIVISIONS OFFICES AND CENTER SCIENTISTS SEE THE OPPORTUNITY TO DO WORK MORE EFFECTIVELY THROUGH THE CONTRACT THAN OTHER MECHANISMS AND SO THEY WORK WITH US TO ESSENTIALLY SAID UP A LABORATORY, A SERVICE, OR SET UP SOME SUBCONTRACTS. IT ORIGINATES WITH THE SPONSOR. >> HOW IS THAT VETTED? >> VIRTUALLY ALL OF THE NCI SCIENTISTS, THE PRINCIPAL INVESTIGATORS AND OTHERS, ARE REVIEW CYCLES, AND THIS WORK AND THE ACCOMPLISHMENTS OF THE WORK GOING ON IS PART OF THE NORMAL REVIEW CYCLE OF THE PRINCIPAL INVESTIGATORS. YES? >> [ INAUDIBLE ] >> MICROPHONE. >> I'M SORRY. COULD YOU DEFINE SMALL. >> I'M SORRY? >> SMALL P.I.-HEADED RESEARCH SECTIONS. SINCE I'M NOT A DENIZEN -- I DON'T LIVE INSIDE THE BELTWAY, I WONDER WHAT DO YOU MEAN BY "SMALL." >> SMALL I P. >> YES. WITH THAT AMBIGUITIY I WANT TO HIGHLIGHT, YES. >> THREE TO FIVE PEOPLE PER SECTION. >> THAT MEANS THE P.I. IN IN A LAB OF FOUR? >> TWO TO FOR. >> GOTCHA. THAT'S SMALL. THAT'S NICE. >> OKAY. SO THESE RESEARCH CORES ARISE FROM NEED FROM DEMAND, IT'S COMING FROM THE OUTSIDE, AND MANY OF THEM OFFER UNIQUE REAGENTS OR UNIQUE SERVICES. AND FINALLY EXTENSIVE INTERACTIONS AND SUPPORT WITHIN THE NCI AND P.I.s AND CORES, HIGH DYNAMIC BACK AND FORTH INTERACTION IS THE CORE OF THE SUCCESS OF THE ORGANIZATION, THE DYNAMIC AND INTERACTION WITH THE EXTERNAL COMMUNITY THAT MAKES IT SPECIAL AND KEEPS THE SCIENTISTS INTERESTED WITHIN THE AVCP AND WHAT THEY ARE DOING. I THINK BASED ON THIS, WE SEE THE ACVP AS A NATIONAL RESOURCE FOR ENABLING HIV WORK. MOST OF THE WORK IS HIGHLY COLLABORATIVE LEADING TO PROMINENT AND RECENT PUBLICATIONS, SOME KEY WORK HELPS IDENTIFY CAPABILITY ALSO OF ACVP ARE UNIQUE PRIMATE MODELS, BRINGING THEM AND VIRUSES TO THE FLOOR AND USE THEM FOR TESTING TO DO THE QUANTITATIVE ANALYSIS OF VIRUS LEVELS WITHIN THE ANIMALS. THESE ARE THE TIMES OF THINGS THAT ARE I THINK MOST VALUED AND ARE NOT AVAILABLE ANYWHERE ELSE IN THE RESEARCH COMMUNITY. AS WAS WAITED, ACVP BECAUSE OF THIS CAPABILITY EXECUTED MOST OF THE TECHNICAL SERVICE AGREEMENTS THAT HAVE BEEN DONE TO DATE. THE COMMITTED PARTNER CONTRIBUTIONS UP TO THIS POINT EXCEED $1.9 MILLION FOR FY 14. THAT OF COURSE OFFSETS THE COST OF PRODUCING THE REAGENTS THAT PEOPLE ARE UTILIZING AS PART OF THE T.S.A.s. IT'S CLEAR THERE'S MORE TO BE DONE HERE, HOWEVER. EVERYBODY IS RECOGNIZING THE LIMITATIONS AND COMBINATION ANTIRETROVIRAL THERAPY, CONTROL THING AS A CURE OR ELIMINATION. AND SO THERE IS STILL A SIGNIFICANT AMOUNT OF WORK TO BE DONE TO DEVELOP MORE DEFINITIVE TREATMENT. EXAMPLE IS WHAT THE PICTURE IS SHOWING, THE BERLIN PATIENT WHO OF COURSE THROUGH FAIRLY SIGNIFICANT AND HEROIC MEASURES DOES APPEAR TO ACTUALLY HAVE VIRAL ERADICATION OR CURE. AND THERE'S A BIG COMMITMENT FROM NIH FROM INDUSTRY, FROM THE GATES FOUNDATION, AND OTHER CHARITABLE ORGANITO TRY AND MOVE HIV THERAPY TO THE NEXT LEVEL MAKING IT DEPENDENT ON NONPRIMATE MODELS, TO FIND THE VIRAL RESERVOIRS AND WHAT YOU DO TO TREAT THEM. IT'S A CORE EXPERTISE WITHIN THE ACVP, REFLECTED IN RECENT PUBLICATIONS IN TERMS OF HOW YOU CAN ACTUALLY DO THIS. RIGHT NOW OUR ABILITY TO DELIVER AND FULFILL THE DEMAND IS LIMITED BY THE AMOUNT MUCH SPACE CURRENTLY AVAILABLE IN THE BETHESDA CAMPUS. WORKING WITH OUR NCI SPONSOR, WE'VE IDENTIFIED A FACILITY, OFF-SITE FACILITY TO ALLOW US TO DO AN EXPANSION OF THESE CAPABILITIES, IT WILL CREATE THE COLLABORATIVE DEMAND AND ACTUALLY FULFILL THE PENT-UP DEMAND THAT ALREADY ACTUALLY EXISTS. WE HAD THE OPPORTUNITY TO DO THIS BY JUST GOING OFF AND LEASING THIS OFF-SITE CAPABILITY, AND AGAIN IT WILL ALLOW US TO MEET THE NEEDS, EXPANSION OF THE CRADA CAPABILITIES. THE COLLABORATIONS AND CRADAs WILL BECOME SELF FULFILLING OR SELF SUSTAINING TO BRING IN ENOUGH COLLABORATION TO PROVIDE RESOURCES PEOPLE ARE LOOKING FOR ON THE OUTSIDE AND LONG-TERM IT WILL BE ALMOST -- IF EVERYTHING GOES WELL, BE COST NEUTRAL. IF IT DOESN'T WORK, OF COURSE, THEN WE'LL BACK OUT OF IT BUT AT THIS POINT WE'RE SEEING MORE THAN ENOUGH PENT-UP DEMAND TO MAKE THAT HAPPEN. THAT'S OUR OPPORTUNITY THAT EXISTS WITHIN THE AIDS AND CANCER VIRUS PROGRAM. >> SO JUST IN TERMS OF HOW YOU'RE THINKING ABOUT THIS, WHAT SORT OF COST BENEFIT ANALYSIS DO YOU GO THROUGH AS YOU START THINKING ABOUT THESE KINDS OF EXPANSION PROJECTS? >> SO, WELL, IT'S MOSTLY DRIVEN DRY THE FACT INTERACTIONS AND COLLABORATIONS THAT WE'VE GOTTEN ALREADY IN TERMS OF WHERE THE PHARMAS, MERCK GILEAD AND ACADEMICS INDICATED STUDDIZE WE COULD LIKE TO DO. WE JUST CAN'T DO THEM. WE CAN ESTIMATE AND COST THEM OUT AND WE JUST PROPOSE GOING OUT THAT THIS IS -- CAN PROJECT OUT THE CRADA WORK STREAMS. >> SO DO THESE -- DOES THIS EXPANSION HAVE AN IMPACT ON OTHER PROJECTS THAT YOU MIGHT BE DOING? >> NO, IT'S JUST AN EXPANSION OF OUR ACTUAL PRIMATE FACILITIES. WE'LL HAVE TO BRING IN ADDITIONAL -- WE'LL CONTINUE TO SUPPORT PRIMATE WORK GOING ON WITHIN CCR ON CAMPUS, WE'LL HAVE TO BRING IN SOME OTHER PEOPLE TO OBVIOUSLY DO THE ANIMAL HANDLING HERE, BUT THAT'S A PART OF THE CRADA COST WE ENVISIN DOING AFTER THE FIT-OUT. ANY OTHER QUESTIONS? >> I DIDN'T GET TO ASK THIS DURING THE INITIAL PART ABOUT THE EBOLA VACCINE WHICH IS OBVIOUSLY VERY IMPORTANT AND INTERESTING. I WAS CURIOUS, IN THE LARGER CONTEXT, IS THE NCI EFFORT THE SOLE EFFORT OR ARE PARALLEL EBOLA EFFORTS GOING ON? HOW DOES THAT FIT VIS-A-VIS AWAY WHAT IS A WORLDWIDE RESPONSE. >> CERTAINLY. WE'RE CONTRIBUTING ONE PART OF EVEN JUST NIAID'S VACCINE EFFORTS WITH NUMEROUS OTHER COMPANIES WITH THERAPEUTIC ANTIBODIES AND VACCINE EFFORTS GOING ON. NO, WE'RE NOT -- THE WORK I DESCRIBED HERE IS CERTAINLY NOT THE ONLY EFFORT THAT'S GOING ON, EITHER DRIVEN BY NIH OR WITHIN THE BROADER COMMUNITY. >> TO BE CLEAR, THE FREDERICK NATIONAL LAB SERVING NIAID, NOT NCI-SPONSORED ACTIVITY. >> I'M TRYING TO UNDERSTAND IN THE CONTEXT, IT'S AN IMPORTANT EFFORT BUT HOW DOES ONE THINK ABOUT IT IN THE OVERALL -- IF IT'S ONE OF 600 EFFORTS, THEN IT DOESN'T MEAN IT'S NOT CRUCIALLY IMPORTANT. I WAS JUST CURIOUS IN TERMS OF WHERE IT FALLS IN THE LANDSCAPE OF RESPONSES TO THE LATEST OUTBREAK IN TERMS OF VACCINE EFFORTS. >> YEAH, I'M CERTAINLY NOT AN EXPERT IN THAT AREA. I KNOW WHAT I SEE IN THE POPULAR PRESS AND HEARD ON NPR DRIVING IN THIS MORNING AS THEY WERE TALKING ABOUT A VARIETY OF DIFFERENT THERAPIES THAT ARE GOING ON. >> THERE ARE ONLY TWO VACCINES THAT ARE BEING CONTEMPLATED FOR TRIALS, ONE OF THEM IS THIS VACCINE THAT'S BEEN DEVELOPED WITH GFK WITH GARY NABO, WORKING ON EBOLA SINCE THE LATE '90s, IT'S BEEN IN DEVELOPMENT THROUGH THE VACCINE RESEARCH CENTER, THE FIRST DECADE OF THE CENTURY. >> YES, IT'S OUT FRONT. >> THE PSEUDOTYPE IS PROBABLY DIFFERENT IN CHARACTER. >> OKAY. ANY ADDITIONAL QUESTIONS? IF NOT THEN I'LL CARRY ON. WE'D LIKE TO TALK ABOUT ONE ADDITIONAL OPPORTUNITY THAT WE HAVE, WHICH IS THE NANOTECHNOLOGY CHARACTERIZATION LABORATORY. SO THIS IS DRIVEN WITH A SIMILAR TYPE OF PHENOTYPE AS THE ONE I JUST DESCRIBED. THE NCL IS FOCUSED ON ENABLING WORK ON THE OUTSIDE TO ENABLE EXTERNAL PARTNERS TO BE ABLE TO MOVE NANOMATERIALS THROUGH THE CLINICAL DEVELOPMENT PROCESS, BY PROVIDING A REPOSITORY OF INFORMATION, EXPERTISE AND ANALYTICAL CAPABILITY TO ALLOW COMPANIES THAT DON'T HAVE ACCESS TO THIS SPECIALIZED TECHNOLOGY OR ACADEMICS WHO DON'T HAVE ACCESS TO MOVE FORWARD. A LITTLE BACKGROUND, THE PROGRAM STARTED IN 2004, JUST CELEBRATED ITS TENTH ANNIVERSARY, CREATED AN ASSAY WORK FLOW WHICH INCLUDES BOTH PHYSICAL, CHEMICAL IN VITRO AND IN VIVO ASSAYS, TO HELP MOVE COMPOUNDS THROUGH FROM THE EARLIEST STAGES ALL THE WAY INTO TOXICOLOGY STUDIES. IT'S A COLLABORATION BETWEEN FREDERICK NATIONAL LABS/NCI, MIST AND THE FOOD AND DRUG ADMINISTRATION. OUT OF THIS BY LOOKING AT MANY COMPOUNDS WE CAN DEVELOP GENERALIZED CAPABILITIES, AND SO AFTER TEN YEARS, THE AMOUNT OF INFORMATION AND DATA THAT'S BEEN ACCUMULATED WITHIN THE ASSAY CASCADE HAS GIVEN THEM AN EXPERTISE THAT'S UNIQUE. THEY HAVE CHARACTERIZED MORE THAN 300 DIFFERENT NANOMATERIALS, DURING THAT TEN-YEAR PERIOD, AND A TOTAL OF TEN COLLABORATIONS HAVE MOVED PRODUCTS INTO CLINICAL TRIALS AS WELL AS GENERATED OVER 100 PUBLICATIONS, PRIMARY RESEARCH PAPERS HIGHLIGHTING SOME OF THE WORK THAT'S BEEN DONE ON A PARTICULAR COMPOUND TO MORETLY THE MORE GE NERALIZED CAPABILITIES OF WHAT YOU SHOULD LOOK FOR IN TERMS OF HOW TO DEVELOP A NANOMATERIAL FOR A BIOMEDICAL TREATMENT. THIS IS INCLUDING -- WE ACTUALLY EVEN WROTE THE BOOK ON IT. THERE'S A HANDBOOK THAT WAS PUBLISHED A COUPLE YEARS AGO GENERATED BY THE NCL TO HELP ILLUMINATE THAT FOR PEOPLE WHO MIGHT BE INTERESTED IN MOVING COMPOUNDS FORWARD. ON AN AVERAGE, WE HAVE 15 DIFFERENT ACTIVE COLLABORATIONS AT ANY GIVEN TIME, 75 SAMPLES A YEAR. THE KEY FOR NANOTECHNOLOGY DRIVEN PHENOTYPES, METALS, DEN DRIMEERS, ANYTHING PEOPLE CAN ATTACH A DRUG TO MOVE IT FORWARD. DISCERNING THE GENERAL PROPERTIES AND STEERING PEOPLE INTO THE RIGHT TYPES OF FORMULATION TO HELP THEM MEET GOALS HAS BEEN A CORE ELEMENT OF WHAT NCL TRIES TO ACCOMPLISH, THEY ARE THE ONLY LAB EVALUATING THIS BREADTH OF MATERIALS, IN THE NANOMEDICINE FIELD. YES? >>> I HAVE A QUESTION. THERE'S A HUGE AMOUNT OF ENTHUSIASM. HOW FREQUENTLY DOES AAPPROACH OF NANOTHING ACTUALLY WORK? >> WELL, THERE ARE SEVERAL EXAMPLES OF, QUOTE, NANOMEDICINES, ONE OR TWO, OF APPROVED DRUGS THAT HAVE CARRIED FORWARD. LIPOSOMAL DRUG DLIVERY, IT'S TOO EARLY TO SAY. JUST OF HOW THE TECHNOLOGY HAS MOVED FORWARD, THE RABBIT MOVING THROUGH THE PYTHON, IF YOU WILL, NOT TOO VISUAL AN ANALOGY, COMPOUNDS ARE MOVING INTO CLINICAL TRIAL NOW. IT'S TOO EARLY TO SAY. >> WHEN DO YOU THINK YOU WOULD GET SOME IDEA ABOUT THAT? >> WELL, WE'VE HELPED SUPPORT -- >> I UNDERSTAND THERE'S A LOT OF ENTHUSIASM. >> TEN COMPOUNDS IN CLINICAL TRIALS, ULTIMATELY YOU'LL KNOW WHEN THEY MOVE INTO PHASE 2 AND PHASE 3 STUDIES. SOME ARE MOVING INTO THAT NOW. I WOULD EXPECT IN A COUPLE YEARS. BUT THE KEY IS IT WILL BE VERY -- IT'S NANOTECHNOLOGY -- IT'S LIKE CANCER. IT'S NOT A SINGLE THING. THERE ARE MANY DIFFERENT TIMES OF FORMULATIONS, VERY MANY DIFFERENT TYPES OF UG DELIVERY VEHICLES, EACH ONE MAY BE DIFFERENT. I DON'T THINK A SUCCESS OR FAILURE IN ANY INDIVIDUAL WILL VALIDATE THE FIELD. >> THE QUESTION IS HOW BIG A FACILITY DO YOU NEED, MAY IN FACT BE DRIVEN, NOT BY ENTHUSIASM UP FRONT. >> SURE. >> WE LEARNED THAT WITH GENE THERAPY. >> YES, YES. >> SO BUT RATHER THE ENTHUSIASM A LITTLE BIT FURTHER DOWN. >> YES. >> AND SO THE QUESTION IS WHEN DO YOU INVEST TO EXPAND? >> YES, YES. SO, WELL, OF COURSE WHAT WE'RE TRYING TO DO IS ENABLE THE COMPOUNDS TO MOVE FORWARD INTO THAT STAGE. WE'RE NOT RUNNING THE CLINICAL TRIALS. WE'RE TRYING TO ENABLE THEM TO GET THAT ANSWER AS RAPIDLY AS POSSIBLE. AND I THINK THAT AS YOU POINT OUT THE ENTHUSIASM IN THE OPPORTUNITY SPACE CONTINUES TO EXPAND BUT THERE'S ALSO BEEN AN EVOLUTION IN THE TYPE OF REQUEST THAT WE'RE DOING, SO IT'S NOT JUST MORE, BUT IT'S DIFFERENT IN TERMS OF THE TIMES OF THINGS AS THE FIELD HAS PROGRESSED. I THINK ALIGNED WITH THE POINT YOU JUST MADE. RELATIVELY EARLY ON AT INCEPTION OF THE PROGRAM ALL OF THE REQUESTS WERE FOCUSED ON PHYSICAL, CHEMICAL, ANALYTICAL CHARACTERIZATION OF THE MATERIALS. WHAT INSTRUMENTATION SHOULD WE USE? HOW DO YOU EVALUATE BATCH TO BATCH CONSISTENCY? CAN WE HELP EVALUATE BATCH TO CATCH CONSISTENCY AND WHAT TYPE OF ASSAY SHOULD WE DEVELOP? YOU CAN SEE NOW THERE'S CMOs AND CROs DEVELOPED TO HELP ANSWER OR ADDRESS THOSE AND WE'RE HELPING THEM IN TERMS OF SETUP. AFTER THE TIMES OF COMPOUNDS AND BEGIN UNDERSTANDING WHAT IT IS WE'RE DOSING THE NEXT SERIES OF QUESTIONS, WHAT ABOUT THE BIOLOGY OF THIS? THIS IS THE AREA WHERE I THINK THE INTEGRATED ASSAY CASCADE IS PROVIDING VALUE. WE HAVE THE IN VITRO STUDIES TO HELP EVALUATE WHAT THE UNIQUE TOXICOLOGY OF THESE NANOMATERIALS MIGHT BE, HOW THEY MIGHT BE AVOIDED IN TERMS OF GETTING THEM INTO THE RETICULAR ENDOTHELIUM SYSTEMS, AND THEN HOW YOU WOULD ACTUALLY MEASURE THEM GOING FORWARD. THE NEXT WAVE IS INTEGRATING THEM INTO MULTI-DISCIPLINARY APPROACHES, REFORMULATION OF APIs TO FIX THINGS THAT AREN'T ACTUALLY WORKING, BEING ABLE TO EXPAND INTO NONONCOLOGY BASED NANOMEDICINE, SO THE LOW-HANGING FRUIT HAS BEEN IN ONCOLOGY BUT WE EXPANSION INTO THAT AREA. THEN ALSO HOW TO ESSENTIALLY BEGIN ESTABLISHING GNP MANUFACTURING CAPABILITY SO YOU HAVE THE REPRODUCIBILITY THAT YOU NEED TO ACTUALLY PRODUCE A MATERIAL CAPABLE OF GOING INTO HUMANS. THEN ON A REGULATORY STANDPOINT, ONE VERY BIG QUESTION IS NANOSIMILARS. IF YOU HAVE A NANODRUG, MORE W DO YOU ENVISION WHAT THAT NANOSIMILAR MIGHT LOOK LIKE? IS IT MORE LIKE AN ANTIBODY HAVE YOU HAVE TO LOOK AT A BIOSIMILAR OR A SMALL MOLECULE WHERE YOU'RE LOOKING AT IDENTITY? THEIR INTERACTION COLLABORATIONS WITH THE FDA BECOME AN IMPORTANT PART OF IT. ONE THING EMERGING IN THE E.U., THE NANOTECHNOLOGY WAVE IS EXPANDING OVERSEAS AS WELL, SO THE E.U. IS PLANNING ON MAKING A SIGNIFICANT INVESTMENT THROUGH THEIR HORIZON PROGRAM AND THEY ARE UTILIZING THE LABORATORY THAT'S BEEN ESTABLISHED HERE AS A REFERENCE FOR HOW TO ACTUALLY DO IT PROPERLY AND WE'RE HOPING THAT WE'LL BE ACTIVE PARTICIPANTS IN THOSE EFFORTS AS WELL. YES? >> DAVE, COULD YOU COMMENT, LET'S SAY AN ACADEMIC INVESTIGATOR HAS COMPOUNDS THAT LOOK PROMISING THAT WOULD BENEFIT FROM POTENTIALLY NANOFORMULATION. >> YES. >> HOW DO THEY APPROACH THE NCO, HOW IS A DECISION MADE OF WHETHER OR NOT TO GO FORWARD WITH IT, AS A JOINT PROJECT, AND HOW IS THAT PAID FOR? >> CERTAINLY. SO CURRENTLY THAT'S ALL DONE THROUGH -- THERE'S A PROCESS FOR COMPOUNDS TO BE COMING THROUGH THERE, REVIEWED BY AN NCI SUBCOMMITTEE TO HELP DETERMINE THE PRIORITIZATION, AND THEN THEY COME INTO THE NCO FOR ANALYSIS BASED ON THAT SELECTION IN TERMS OF THEIR IMPACT, LIKELIHOOD OF SUCCESS, WHETHER OR NOT WE THINK WE CAN REALLY ACTUALLY HELP. THE NCI IS COVERING THE COST OFAT, THERE'S NO DIRECT CHARGE BACK. HAVE I GOT THAT RIGHT, SCOTT? >> YES. >> HE SAID IF WE REFORMULATE THE PARTNER PAYS FOR THAT COST. >> AT WHAT STAGE DO YOU ADVISE COMPANIES OR ACADEMIC INVESTIGATORS TO APPROACH YOU WITH PROMISING NANOPARTICLE FORMULATIONS BECAUSE THESE ARE SO WIDESPREAD, THERE'S SO MUCH ENTHUSIASM THE END OF PROMISING PRE-CLINICAL STUDIES OR FURTHER ALONG? >> WE HELPED AT ALL STAGES. DURING THE EARLY PART OF THIS , THE COMPANIES, THERE WERE SMALL BIOTECHS OR ENGINEERING COMPANIES THAT DIDN'T UNDERSTAND HOW THEY WERE DOING IT, REPRODUCIBILITY. AS WE INDICATED IN THE CONTRACT CRADA LIST THERE ARE NOW MAJOR PLAYERS INTERESTED IN WORKING WITH US SETTING UP CONTRACTOR CRADAs. THAT'S A MORE ADVANCED STAGE. CONTINUING ON, I GUESS THE CRUX OF THIS, NANOMEDICINE MATURES, THE COLLABORATORS ARE ASKING FOR NEW AND CHANGING -- ASKING FOR HELP IN NEW AND CHANGING AREAS. THERE'S SOME WORK GOING ON AT THE EARLIER STAGES BUT YOU CAN SEE THERE'S BEEN A BIT OF A SHIFT IN THE TIMES OF -- TYPES DEMAND AND WE WOULD LIKE DEVELOP THAT TO FACILITATE THIS FIELD MOVING FORWARD ON A REGULAR BASIS, TO CONTINUE PROVIDING ASSAY CASCADE BUT THE BREADTH OF OPPORTUNITY IS SHOWING ON THE VARIETY OF OTHER AREAS, IN ADDITION TO THAT. IT WAS INDICATED THE REFORMULATION GMP, COLLABORATION WITH FORMULA, HAVE IN NANOMEDICINE, CARDIOVASCULAR, THE RISK BENEFIT BEGINS EVOLVING. YOU CAN MOVE IT INTO SOME NONLIFE-THREATENING DISEASES AS WELL. WE HAVE WORKING WITH SOME OF THE COMPANIES TO DEVELOP THE ABILITY TO ANALYZE THESE IN A SPECIALIZED FASHION. MANY ONE OF THESE NANOPARTICLES WILL BECOME DOMINANT AND SHOW A SUCCESS STORY AND THAT WOULD BE AN IMPORTANT ELEMENT. WE HAVE IMPORTANT BASIC RESEARCH CHALLENGES THAT NEED TO BE DONE, INCLUDING THE GENERATION OF IMMUNOTOXICITY FROM ADMINISTERING THESE PARTICLES AND ACTIVELY TARGET THEM. ONE AREA THAT IS VERY IMPORTANT FOR US AND REPRESNTS OUR UNIQUE CAPABILITIES IS HONEST BROKER WITHIN THIS FIELD, AN FFRDC, OUR INTERACTION WITH THE FDA, EQUIVALENCE TESTING FOR NANOSIMILARS, AN AREA THAT BECOME IMPORTANT RELATIVELY SOON BECAUSE THERE ARE REGISTERED DRUGS OUT THERE CLASSIFIED AS NANOMATERIALS, ADDRESSING SCIENTIFIC QUESTIONS, DEVELOPING ASSAYS THAT THE FDA AGREES ARE APPROPRIATE FOR ANALYZING THIS. AND THEN NBCZs, NONBIOLOGYIC COMPLEX DRUGS, A DESCRIPTION THAT HIGHLIGHTS THE FACT THAT THIS IS A VERY DIFFERENT TYPE OF BEAST. AND THEN AS I INDICATED, THE TRANSNATIONAL COLLABORATION, WITH THE E.U., SOMETHING WHICH IS EMERGING AS A KEY AREA. IF WE'RE ABLE TO ACTUALLY DO THIS, AGAIN WE'RE JUST IN DISCUSSION WITH OUR SPONSORS TO HOW WE CAN MAKE THIS HAPPEN. THIS IS CONCEPTUAL. WE WANT TO REINFORCE WHAT IS ALREADY OCCURRING, WHAT WE'VE DONE IS CONTRIBUTE I THINK ENORMOUS VALUE TO THE FIELD, AND WE WANT TO BE ABLE TO CONTINUE TO MOVE THAT FORWARD. WE HAVE TO ADAPT TO THE FACT THAT THE FIELD HAS CHANGED SINCE 2004. INITIAL ASSAYS WILL HAVE INCREASINGLY LESS VALUE AS THE FIELD GOES FORWARD AND WE NEED TO HELP MEET THE CORE MISSION OF ADVANCING NANOMEDICINES FORWARD. WE APPRECIATE THE SUPPORT OF THE NCI FREDERICK ADVISORY COMMITTEE. YOU SEE WHAT WE DO. HELPING GET THE MESSAGE OUT, BRINGING MOLECULES FORWARD IS SOMETHING THAT WE WOULD APPRECIATE AND WHY I'M DOING THIS PRESENTATION. THERE'S A POSSIBILITY OF DIFFERENT OPERATING MODELS FROM WHAT WE CURRENTLY HAVE. RIGHT NOW IT'S ALL FUNDED THROUGH THE NCI, B WE SEE OPPORTUNITIES TO GET ADDITIONAL FUNDING THROUGH OTHER GOVERNMENT AGENCIES, THROUGH CCRADASs, FOUNDATIONS AND GRANTS. AFTER WE GET IT STARTED AND BEGIN MOVING IN, MOST OF THE COST CAN BE OFFSET BY INCOME THAT'S COMING IN BY COST REIMBURSEMENT THAT'S COMING IN FROM OUTSIDE PARTNERS. YES? >> DO YOU HAVE A SENSE IN THE TRIAGE PROCESS WHAT PERCENT OF PEOPLE WHO APPLY GET TURNED DOWN? >> I DON'T. SCOTT, CAN YOU ILLUMINATE THAT? >> ABOUT 60%. >> ABOUT 60% IS THE ACCEPTANCE RATE CURRENTLY. YES? >> JUST IN TERMS OF GROWTH, I THINK A LOT OF FFRDCs ARE UNDER CAPS, HOW YOU EXPAND IS DIFFERENT CLOSER YOU ARE TO CAP. ADDRESS IF YOU ARE UNDER CAP AND HOW CLOSE YOU ARE AND IF THAT'S DETERMINING SOME OF YOUR STRATEGIC CHOICES? >> YEAH, THERE IS A CAP IN FLOOR ASSOCIATED, WE'RE NOWHERE NEAR THE CAP. I THINK ALL OF THE WORK WE'RE DOING, AS WE TALKED ABOUT IT, THE MONEY THAT COMES IN IS DETERMINED BY OUR SPONSORS. EACH ONE INDIVIDUALLY DECIDING HOW MUCH WE WANT TO COLLECTIVELY -- HOW MUCH THEY INDIVIDUALLY WANT TO SPEND ON THE WORK GOING ON HERE RATHER THAN A HIGH LEVEL WE'RE GOING TO GIVE OF YOU $250 MILLION AND DO WHAT YOU THINK IS BEST OR SOMETHING ALONG THOSE LINES. JEFF? >> SO IN THE NCL, HOW MANY DIFFERENT FUNDING STREAMS CONTRIBUTE TO THE SUPPORT OF THAT? IS IT JUST ONE? >> RIGHT NOW IT'S JUST ONE THROUGH THE SPONSOR. WE THINK THERE'S HUGE OPPORTUNITY TO DO MUCH MORE. >> OKAY. BUT I MEAN WITHIN THE NCI THERE'S ONE TASK? >> CORRECT. WE DON'T HAVE CONTRACTOR CRADA SET UP EITHER. >> YOU TOOK A STAB AT CHARACTERISTICS AND HAVE THE AIDS AND CANCER VIRUS AND NANOTECHNOLOGY AS EXAMPLES OF THAT, BUT I SUPPOSE -- OF COURSE YOU COULD ALSO INCLUDE THE GENERAL KIND OF VACCINE DEVELOPMENT, EBOLA VIRUS AS AN EXAMPLE AS WELL, BECAUSE THAT'S HAROLD ANSWERED THE QUESTION THAT I HAD, WHICH IS -- IT'S RIGHT OUT IN THE FRONT LINES OF WHAT'S ACTUALLY GOING TO THE CLINIC, WHICH IS TO ME A HUGELY IMPORTANT ADVANCE AND CAPABILITY. WHAT I'M GETTING AT, ONE OF THE ISSUES HAS COME UP SEVERAL TIMES IN THIS COMMITTEE IS NOT EVEN SO MUCH WHAT THE CONTENT IS BUT HOW DO YOU MESSAGE IT TO A COMMUNITY THAT EITHER DOESN'T KNOW OR IS THINKING -- >> YEAH. >> BUT IT SEEMS LIKE THAT -- THERE'S SUBSTRATE NOW, I THINK SORT OF CASTING THE RAS PROJECT THEY DIDN'T HAVE THE CONSOLIDATED IDENTITY BEFORE BUT THERE'S ACTUALLY A SERIES OF EFFORTS AND COMING UP -- WHAT I'M GETTING AT, HOW DOES FNLCR THINK ABOUT THE MESSAGING AND BRANDING IN A CONSOLIDATED WAY? MY SENSE IS THERE'S GENERALLY THE RAS PROJECT HAS HELPED IN TERMS OF GAINING VISIBILITY IN THE CANCER COMMUNITY ABOUT A NEW INITIATIVE, BUT CERTAINLY THERE'S PROBABLY STILL SOME LACK OF CLARITY OF WHAT IT IS, AND JUST MORE GENERALLY HOW THAT FITS INTO WHAT FNLC OFFERS. >> IT'S A GREAT POINT. FOR THE WORK WITH EBOLA, THAT'S PART OF THE REASON I'M DISCUSSING IT. THIS IS THE FIRST DISCLOSURE OR FIRST DISCUSSION THAT HOW THE FREDERICK NATIONAL LABS IS CONTRIBUTING TO THE EFFORT. IT'S BEEN MOVING RAPIDLY. I WAS DELIGHTED EVERYBODY AT NIAID AGREES IT'S IMPORTANT TO GET THIS MESSAGE ACROSS. >> WE PROVIDED SERVICES TO NIAID, $90 MILLION WORTH OF BUSINESS ALMOST EVERY YEAR, MAKING VARIOUS THINGS FOR THEM, ANTIBODIES, VACCINES AND SO FORTH. AND THEY ARE NOT -- THEY ARE ONE ON A LONG LIST. >> THAT WAS WHY WE CAME UP WITH THIS CONCEPT OF A NATIONAL MISSION INITIALLY FOR RAS AND THESE NATIONAL PROGRAMS BECAUSE I THINK IT CONVEYS WHAT WE'RE TRYING TO ACCOMPLISH HERE IN A WAY THAT WE'RE ALL SCIENTISTS BY TRAINING BUT IT'S MESSAGING IS IMPORTANT. THAT'S ESSENTIALLY WHY WE'RE PUTTING THOSE TWO IN. THERE ARE OTHER PROGRAMS AS WELL, THAT I THINK COULD BE CLASSIFIED IN A SIMILAR WAY, WE COULD TALK ABOUT MUCH MORE ACTIVELY ABOUT ON THE OUTSIDE BUT THOSE WERE THE TWO THAT WERE THE MOST LOW-HANGING FRUIT. IN TERMS OF CORE MESSAGING ELEMENT OR PUBLIC RELATIONS GROUP WE HAVE A COMMUNICATIONS GROUP, AN INDIVIDUAL WITHIN FREDERICK NATIONAL LABORATORIES, AND BUT TO BE HONEST MOST OF THAT FOCUSES ON WHAT WE'RE DOING WITH THE COMMUNITY, I THINK THERE'S AN OPPORTUNITY THERE. ANY OTHER QUESTIONS? I JUST HAVE -- I'M SORRY, NOW I HAVE TO GO ALL THE WAY THROUGH MY ADDITIONAL SLIDES AS I BACKED UP. THE CONCLUSIONS, SUPPORT FOR THE NIAID EBOLA VACCINE EFFORTS, MERGING AS A PROMINENT CONTRIBUTION TO ADDRESSING THIS CHALLENGE. I THINK WE'RE DOING A LOT OF WORK USING THE CONTRACTOR CRADA AUTHORITIES GRANTED TO US TWO YEARS AGO TO BOOST THE IMPACT THAT WE HAVE ON SCIENCE ON THE OUTSIDE, AND IN ADDITION WE HAVE THE AIDS AND CANCER VIRUS PROGRAM AND THE NATIONAL -- THE NANOTECHNOLOGY CHARACTERIZATION LABS ARE PROGRAMS WE SEE AS BEING NATIONAL POISED FOR EXPANSION, WE'RE LOOKING FORWARD TO WORKING WITH APPROPRIATE SPONSORS TO MAKE THAT HAPPEN. WITH THAT, I'LL TAKE ANY FINAL QUESTIONS. YEAH? >> DAVID, DO YOU HAVE EXAMPLES OF PRODUCTS THAT HAVE BEEN COMMERCIALIZED AS A RESULT OF THESE EFFORTS? >> FOR THE NANOTECHNOLOGY, NOT DIRECTLY, BUT CERTAINLY FOR THE -- ONE EXAMPLE IS THE SUPPORT FOR JIM DOROSHOW'S AREA, D.C.TD. WE HAVE OUR BIOPHARMACEUTICAL DEVELOPMENT PROGRAM, ONE ANTIBODY WE PRODUCED, THIS WAS DRIVEN THROUGH THE -- INITIALLY THROUGH JIM'S PROGRAM, CAME TO US, WE MANUFACTURED THE MATERIAL THAT HELPED ENABLE CLINICAL TRIALS IN PEDIATRIC NEUROBLASTOMA THAT WERE SUCCESSFUL, NOW THE PROCESS HAS BEEN SUCCESSFULLY TRANSFERRED TO A COMPANY ON THE OUTSIDE THAT HAS FILED FOR REGULATORY APPROVAL FOR THAT. SO THAT WILL CERTAINLY -- PRESUMABLY THAT WILL BECOME A SUCCESSFUL COMMERCIAL PRODUCT. THAT'S THE ONE THAT POPS TO THE TOP OF MY MIND. >> I JUST WANT TO UNDERSCORE WHAT LEVI SAID. IF YOU LOOK AT THE OTHER NATIONAL LABS, PEOPLE IN THOSE SCIENTIFIC COMMUNITIES THAT THE LABS ADDRESS, THE HIGH ENERGY PHYSICS, OR FLUID DYNAMICS COMMUNITIES, THEY ALL KNOW WHAT THE NATIONAL LABS ARE, WHAT THEY OFFER TO THEM IN THEIR SCIENTIFIC ENDEAVORS AND SO ON. I THINK MOST PEOPLE, EVEN IN THE CANCER RESEARCH COMMUNITY, ARE JUST NOT AWARE OF FREDERICK NATIONAL LAB, OR HOW THEY MIGHT ENGAGE IT. I DON'T KNOW WHAT THE ANSWER IS. I THINK THE INSTITUTES AT NIH MAY BE MUCH MORE AWARE OF WHAT'S OFFERED, AND WHAT THEY CAN TAKE ADVANTAGE OF. BUT I THINK IT WOULD WELL SERVE THE LAB AND THE COMMUNITY TO MAKE THAT BETTER KNOWN. >> WE'VE KNOWN THIS FOR A -- >> I KNOW, I KNOW, I KNOW. WE TALK ABOUT IT EVERY TIME. >> WE HAVE THE COMMITTEE, ALMOST EVERY TALK I GIVE HAS SOMETHING ABOUT THE FREDERICK NATIONAL LAB. YOU TELL ME WHAT MORE TO DO. PEOPLE TO UNDERSTAND THERE'S A CONDUIT, MANY WAYS TO GET INVOLVED. WE'RE NOT KEEPING ANYTHING UNDER A BUSHEL. >> I WISH I KNEW THE SECRET SAUCE, HAROLD. >> I'M NOT SURE A WEBSITE -- >> WELL -- >> THIS OBVIOUSLY IS NOT THE ANSWER. >> YEAH. >> ONE VEHICLE MAY BE TO HAVE RFAs WHERE YOU HAVE TO USE THE NATIONAL LABORATORY IN ORDER TO GET THE MONEY. I MEAN, THAT'S WHAT -- THAT'S AN EXAMPLE. [OFF MIC] >> UNLIKE THE DEPARTMENT OF ENERGY WHICH USED THE NATIONAL LABS AROUND THE COUNTRY, THE DOMAIN OF ENERGY SCIENCE, THE PHYSICS AND OTHER FIELDS, THERE'S GOING TO BE A PROCESS OF MAKING WHAT I THINK WAS RATHER SECRET AND NOT INTENTIONALLY SECRET BUT BECAME HARD TO UNDERSTAND, AS I EXPLAINED EARLIER, AND MAKE IT PLAINER. >> GO AHEAD, DAVID. >> I GUESS THERE IS A SECRET SAUCE. THE SECRET SAUCE IS SUCCESS. SECRET SERVICE IS ACCOMPLISH SOMETHING THAT ACTUALLY GOES SOMEWHERE. THE ARGUMENT FOR RAS, AS I REMEMBER IT, WAS THAT RAS WAS AN UNDERSERVED AREA THAT LOTS OF PEOPLE KNEW ABOUT IT, AND I THINK THAT VISIBILITY OF THE RAS PROGRAM HAS BEEN EXEMPLARY BECAUSE IT'S ACTUALLY DOING SOMETHING FOR LOTS OF PEOPLE OUT I THINK THAT'S THE WAY FORWARD. THAT'S WHY I THINK THE RATIONALE FOR EXPANSION OF THESE THINGS IS WHEN THERE'S SOME MOMENTUM. OKAY. AND AS LONG AS WE'RE IN THIS SITUATION OF, WELL, SO THE EBOLA THING WILL GET YOU MORE BUSINESS, THAT'S GOOD, AND THE RAS THING IS GOING TO GET YOU MORE VISIBILITY FOR, YOU KNOW, GETTING TOGETHER PEOPLE AROUND AN OBVIOUS BUT NEGLECTED ISSUE, MORE PROPAGANDA, MORE WEBSITES, MORE TWEETS IS GOING TO DO ANYTHING BECAUSE SERIOUS PEOPLE DON'T DO THINGS THAT WAY. THEY LOOK AT THE SUCCESS, RIGHT? >> HERE IS AN IRONY, DAVID. I AGREE WITH MANY OF THE THINGS YOU SAID, BUT THE NANOTECHNOLOGY CHARACTERIZATION LAB IS A SUCCESS FROM MANY POINTS OF VIEW. IF YOU LOOK AT, SPEAKING NOW AS A FORMER CHAIR AT PCAS, IT DOES ITS ANNUAL REPORT ON NANOTECHNOLOGY, NCL FIGURES IN A LARGE WAY BUT PEOPLE DON'T RECOGNIZE IT AS PART OF A NATIONAL LAB IN PART BECAUSE WE HADN'T DEFINED THE FREDERICK OPERATION AS A NATIONAL LAB. >> THAT'S A MATTER OF MAKING THE CONNECTION. >> IT'S NOT THAT THERE HASN'T BEEN SUCCESS. >> NO, IT'S POSSIBO HIDE SUCCESS. >> THE SUCCESS, AIDS TEST KIT WAS DEVELOPED AT FREDERICK BUT THE CONTEXT -- >> HAROLD, THERE'S A BIGGER PROBLEM WITH NANOTECHNOLOGY, WHICH I TRY TO LEAD INTO, FROM WHERE I SIT, A BIGGER CHEMICAL ISN'T NECESSARILY A BETTER CHEMICAL. THAT NEEDS TO BE -- THE ARGUMENT FOR LIPISOMOSE IS WELL: INSTRUCTED, AND ANCIENT. THERE WAS LIPISOMES WHEN I WAS A GRADUATE STUDENT, THAT WAS A LONG TIME AGO. I THINK THE NANOTECHNOLOGY IS A WONDERFUL THING FOR THE CENTER, WHATEVER IT'S CALLED, I'M TOO OLD TO REMEMBER ABBREVIATIONS. IT'S A WONDERFUL THING FOR EVERYBODY TO BE DOING, BUT THE QUESTION OF WHEN YOU WANT TO EXPAND IT AND MAKE IT FAMOUS MAY BE AFTER SOMETHING GOOD HAPPENS, WHICH COULD BE SOON. THAT'S WHY I ASKED THE QUESTION. IT COULD BE TWO YEARS FROM NOW. >> YOU WANT PEOPLE IN OUR SCIENTIFIC CONSTITUENCIES -- >> I MEANT FAMOUS IN THAT SENSE. >> BUT WE SHOULD PURSUE THAT NOW. >> RIGHT, BUT IT'S NOT GOING TO WORK BY -- >> RECOGNIZED LIKE NASA. >> I DO THINK SOME GENTLE PUSH MECHANISMS TO RAISE AWARENESS OF SOME OF THESE SUCCESSES THAT HAVE HAPPENED ARE NOT INAPPROPRIATE BECAUSE WHETHER WE LIKE IT OR NOT, THAT IS INCREASINGLY HOW THE WORLD RECEIVES INFORMATION, AND I'M NOT SAYING THAT THERE NEEDS TO BE 15 TWITTER FEEDS A DAY, WHAT HAVE YOU, BUT I THINK THAT ENGAGING THE VARIOUS MEDIA VENUES THAT ARE ENGAGE NOW TO RAISE AWARENESS OF WHAT'S HAPPENING, EITHER WE'RE IN THAT OR WE'RE NOT. I DON'T KNOW THAT -- YOU CAN BE AS SUCCESSFUL AS YOU WANT BUT IF YOU DON'T HAVE A SAVVY WAY OF COMMUNICATING IN THE 21st CENTURY IT'S GOING TO BE AN UPHILL BATTLE. >> I'M OLDER THAN EVERYONE, NOT EVERYONE, BUT LET ME MAKE THE FOLLOWING POINT. MAKING PROPAGANDA WHEN YOU HAVE ACTUALLY SOMETHING TANGIBLE TO SELL, OKAY, THAT'S ONE THING. I'M FOR THAT. I THINK YOU SHOULD DO THAT. BUT I WORRY THAT IF YOU GET OUT THE TRUMPETS BEFORE YOU ACTUALLY HAVE SOMETHING SUBSTANTIVE TO SELL, IT'S A PROBLEM, BECAUSE YOU KNOW, THE LITTLE BOY WHO CRIED WOLF. WHAT YOU WANT IS YOU WANT TO TWEET AND, YOU KNOW, GET THE PRESS IN AND SO FORTH AND SO ON WHEN THERE'S SOMETHING TO SEE. THE EBOLA THING, ABSOLUTELY, I'M THERE. >> IF I CAN OFFER ONE ADDITIONAL COMMENT, DAVID, WITH RESPECT TO THE NCL, THIS IS A DEMAND-DRIVEN PROCESS. WE'RE NOT OUT TOUTING NANOTECHNOLOGY IS GOING TO BE THE CURE FOR CANCER OR CURE FOR A CANCER. WHAT WE'RE SAYING IS WE HAVE THE TECHNOLOGIES FOR THOSE INTERESTED WITH PARTICLES, WE HAVE THE TECHNOLOGY THAT CAN HELP YOU ANSWER THE QUESTION THAT YOU RAISE. IS THERE SUBSTANCE HERE? THAT'S WHERE THE OPPORTUNITY LIES, IN HELPING ENABLE THE ANSWER TO THE QUESTION, RATHER THAN TRY AND JUMP ON AFTER THAT SHIP HAS SAILED. >> IS THERE REALLY ANYBODY IN THE NANOTECHNOLOGY BUSINESS WHO DOESN'T KNOW ABOUT YOU? >> I THINK THERE IS WITHIN PHARMA. I THINK THERE ARE OPPORTUNITIES THAT STILL DON'T EXIST, BUT EVEN NOW WE'VE GOT THE DEMAND BASE AND AS WE SAID IT'S JUST BEGINNING TO SPIN UP OVER IN EUROPE, WHICH IS OBVIOUSLY DRIVING A LOT OF WHAT'S GOING ON IN THE BIOMEDICAL FIELD. >> I JUST WANT TO MAKE A COMMENT ABOUT -- I WAS LOOKING AGAIN AT YOUR CRITERIA, IF YOU LOOK AT HOW THEY THINK OF THE NATIONAL PROGRAM THIS IS PROGRAM IMPLICIT, IT WASN'T ON THE LIST, A UNIQUE INSTRUMENT OR DEVICE OR FACILITY THAT CAN'T BE DONE ELSEWHERE BECAUSE OF THE SCALE REQUIRED, RESOURCES, LONG-TERM COMMITMENT, THAT PUT THAT IN THERE AND THAT GIVES A SIMPLE WAY TO INTERACT TO OTHER SCIENTISTS IN TERMS OF WHY IS ANY NOT TAKING, NOT A BASIS FOR COLLABORATION, AND IT WAS IMPLICIT IN WHAT YOU DID BUT WASN'T EXPLICIT. NO OTHER FACILITY CAN DO IT. NO OTHER ORGANIZATIONAL CONSTRUCT CAN DO IT. >> AGREED. WE DON'T HAVE A USER FACILITY SHINY LIGHT THING LIKE MOST OF THE DOE FRDCS. YOU'LL HEAR A PROPOSAL TODAY, I THINK IT CREATES QUITE AN OPPORTUNITY FOR US. >> WE NEED TO BRING THIS TO CONCLUSION. THIS IS THE FIRST TIME YOU'VE BEGUN TO COALESCE CHUNKINGS OF WHAT EXIST IN FREDERICK IN WAYS YOU'RE BEGINNING TO TAKE INTELLECTUAL OWNERSHIP ON. IN TERMS OF THE CONCEPT OF DEVELOPING A REAL NATIONAL LABORATORY, IT'S AN IMPORTANT CHARACTERISTIC TO PURSUE. I THINK YOU'RE TO BE CONGRATULATED FOR IDENTIFYING AND BEGINNING TO ORGANIZE YOURSELF IN WAYS THAT WILL ALLOW YOU TO THINK, OKAY, WHAT IS THE LARGER PROGRAM, WHAT ARE THE MEASURABLE DELIVERABLES AND SO ON. IT'S A STEP IN THE RIGHT DIRECTION. WE NEED TO BRING THIS TO A CONCLUSION RIGHT NOW, AND TURN THE FLOOR OVER TO HAROLD. >> WE ALWAYS HAVE A MOMENT OF RECOGNITION OF EFFORTS, AND A MOMENT OF GRATITUDE FOR MEMBERS WHO ARE RETIRING, DR. STOVE ROSEN WILL BE LEAVING OUR COMMITTEE, WE'RE GRATEFUL FOR HIS SERVICE. AND FOR HIS USESFUL CONTRIBUTIONS TO OUR DISCUSSION. THANK YOU VERY MUCH, STEVE. AND WE HAVE A PLAQUE FOR YOU BUT NO PHOTOGRAPHER. [ LAUGHTER ] >> A FINE PLAQUE. >> RIGHT. SOMEONE TAKE A SELFY. [ LAUGHTER ] >> OKAY. WE HAVE A BREAK UNTIL 10:40. >> ALL RIGHT. I'M FRANK McCORMICK, I'M GOING TO GIVE YOU A BRIEF OVERVIEW OF THE RAS NATIONAL PROGRAM. LEVI HAS A DETAILED DOWNLOAD FROM THE SUBCOMMITTEE IN JULY GOING OVER IT'S PROGRESS IN THE LAST YEAR. WE HAVEN'T GOT TIME TO GO THROUGH THOSE DATA ALL OVER AGAIN BUT I WILL GIVE YOU A FEW HIGHLIGHTS FROM WHAT HAS BEEN ACHIEVED IN THE LAST YEAR, LEVI WILL GO THROUGH THE DETAILED ANALYSIS AND HOPEFULLY JOE WANTS TIME AT THE END TO DISCUSS WHAT WE LEARNED AND HOW CAN IT APPLIED TO THIS AND OTHER PROGRAMS. SO VERY BRIEFLY I APOLOGIZE TO THE PEOPLE WHOSE WORK I HAVEN'T GOT TIME TO SHOW BECAUSE THIS GROUP HAS DONE A TREATMENT AMOUNT OF FANTAS WORK IN THE ONE YEAR THAT THIS PROGRAM HAS BEEN FULLY OPERATIONAL. I'M EXTREMELY PROUD OF WHAT THE TEAM HAS DONE AND IT WON'T DO THEM JUSTICE TODAY. I HAVE TO REMIND YOU WHY THIS PROGRAM IS SO IMPORTANT AND WHY WE HAVE TO FIND WAYS TO TREAT RAS CANCER, A MILLION PEOPLE DIE A YEAR FROM CANCER DRIVEN BY RAS. WE CAN'T TREAT THEM AND DON'T HAVE A WAY OF TARGETING RAS PROTEINS EFFECTIVELY, NO DRUGS IN CLINICAL TESTING THAT REALLY ATTACK RAS PROTEINS DIRECTLY. THIS IS A MAJOR PLAYER IN CANCER, K RAS IS A MAJOR PLAYER, THAT'S THE FOCUS OF THE PROGRAM OF THE FREDERICK NATIONAL LAB. LOOK AT A SLICE OF LUNG ADENOCARCINOMA, SHOWING 32% OF THESE CANCERS HAVE MUTATIONS IN KRAS, BUT ALL OF THESE MUTATIONS HERE AFFECT THE RAS PATHWAY IN ONE WAY OR ANOTHER. THROUGH UPSTREAM ACTIVATION OF RTKs THE THAT WORK THROUGH RAS OR LOSS OF REGULATORS SUCH AS THE NF 1 GENE. 75% OF LUNG CANCERS INVOLVE DRIVERS IN THE RAS RTK PATHWAY. THIS SLICE OF THE PIE HAS BEEN CHIPPED AWAY RECENTLY THERE ARE ACTIVE MUTATIONS IN ANOTHER WAY OF ACTIVATING ROST, AND A NEGATIVE REGULATOR. THIS PIE IS BEING CHIPPED AWAY, MAYBE IT WILL PLATEAU AT A HIGH NUMBER, MAYBE ALL OF THESE TIMES OF CANCERS ARE DRIVEN BY GENES THAT REGULATE RAS YET TO BE DETERMINED BUT 75% OF LUNG CANCERS ALONE ARE DRIVEN BY ACTIVATED RAS PATHWAY. SO WHEN WE PUT THIS PROGRAM TOGETHER WE LOOKED AT CHALLENGES THAT FACE TARGETING RAS. THIS PROTEIN IS BEING DEEMED UNDRUGGABLE, BUT MANY ATTEMPTS TO DRUG RAS WERE CARRIED OUT 20 OR 30 YEARS AGO, OFTEN FOCUSED ON HRAS, THE GENE MOST PEOPLE ARE INTERESTED IN, A LOT OF STUFF WAS NEVER SOLVED, THINGS WHICH HAVE TO BE SOLVED IF YOU WANT TO TAKE RAS OR KRAS SERIOUSLY AS A DRUG TARGET. THERE'S NO STRUCTURE OF ONCOGENIC MUTANT, WE DON'T KNOW HOW THEY LOOK WITH PROTEINS THAT THEY DRIVE OR DRIVE THEM. THERE'S NO STRUCTURE FULL LENGTH KRAS, WE DON'T KNOW HOW IT ACTIVATES -- ONE MAJOR EFFECT IS RAS KINASE, ACTIVATED IN THE PLASMA MEMBRANE WHICH I'LL GET BACK TO. THIS IS A HUGE KNOWLEDGE GAP RIGHT HERE. THERE'S NO STRUCTURES OF RAS-BOUND. WE DON'T HAVE ANY STRUCTURES AND DON'T KNOW HOW THEY WORK. EVEN UNCLEAR WHICH KRAS MUTANT CANCERS DEPEND ON KRAS IN VIVO AND UNCLEAR WHICH AFFECTED PATHWAYS DOWNSTREAM ARE CRITICAL IN VIVO FOR MAINTENANCE OF TUMORS. WE DON'T KRAS CANCERS SHOW THE SAME RESPONSE RATES MORE OR LESS FOR RAS-DRIVEN, THE SAME RESPONSE RATES TO CHECKPOINT INHIBITORS, THEY DON'T SEEM TO BE DIFFERENT IN THAT RESPECT BUT THERE MAY BE OPPORTUNITIES FOR TARGETING KRAS CANCERS BY IDENTIFYING PROTEINS ON THE SURFACE THAT CAN BE USED FOR ATTACK WITH, SAY, THERAPEUTIC ANTIBODIES FOR EXAMPLE. WE LOOK AT THIS LIST, WE SEE A HUGE NUMBER OF OPPORTUNITIES, AND OUR GOAL IS TO SOLVE SOME OF THESE KNOWLEDGE GAPS AND PROVIDE THE RESEARCH COMMUNITY WITH INFORMATION TOOLS, TECHNOLOGY, WHICH WILL HELP RESEARCH COMMUNITY ATTACK THIS PROBLEM AND SOLVE IT ONCE AND FOR ALL. THAT'S OUR I MAJOR MISSION. DRILL DOWN ON THE PROTEINS THEMSELVES, THESE ARE THE PARAMETERS THAT AFFECT THE ACTIVITY OF MUTANT KRAS WHICH CAN EXIST IN GTP STATE. HYDROLYSIS DOESN'T WORK ON RAS PROTEINS. THIS RATE IS SLOW BUT IT'S MEASURABLE AND IT'S IMPORTANT. TO GO BACK TO THE ACTIVE STATE, RAS HAS TO DUMP GDP AND BIND GBT. NOW WE LEARNING RAS PROTEINS EXIST IN DIFFERENT RATIOS OF GDP AND GPT IN THE CELL. IF THE RATES WERE EQUAL WE WOULD HAVE 50-50 RAS BUT THE PRECISE RATIO IN THE ACTIVE STATE HAS NOT BEEN ACCURATELY DETERMINED BUT WE NEED TO FIGURE THAT OUT. ONCE IN THE ACTIVE STATE, ONE OF A NUMBER OF EFFECTORS, HOW THEY COMPETE, COMBINE TO RAS, WE DON'T KNOW. AND HOW THESE ENGAGE, WE DON'T KNOW. THERE'S A LOT OF IMAGINE GAPS, A LOT OF THIS COMES DOWN TO HARD CORE BIOCHEMISTRY. STRUCTURAL PROTEIN IS ONE OF OUR MAJOR PRIORITIES, MUCH MORE DETAIL FROM LEVI IN JUST A MOMENT, BUT THE GROUP AT FREDERICK IS FANTASTICALLY EFFICIENT AND ANALYTIC PROTEIN AND ANALYZING THEM IN EXQUISITE DETAIL. THEY HAVE MADE ALL THESE DIFFERENT MUTANT PROTEINS, AND THESE ARE THE ONES WHICH PLAYED A MAJOR ROLE IN HUMAN CANCER. WE'RE FOCUSING ON ALLELES KNOWN TO PLAY A MAJOR ROLE IN HUMAN CANCER, AND WE SHOULD ALSO SAY THE CANCER IS DRIVEN BY EACH OF THESE DIFFERENT MUTANTS ARE DIFFERENT IN THEIR RESPONSES TO THERAPY AND SIGNALING, A BIG NEED TO UNDERSTAND HOW EACH OF THESE MUTANT PROTEINS BEHAVE, COMING DOWN TO BIOCHEMISTRY AND STRUCTURES, ON THEIR OWN AND IN THE FULLY PROCESS STATE AND COMPLEXED WITH EFFECTORS. THIS IS ONE OF OUR SHORT-TERM PRIORITIES TO GET THESE STRUCTURES, GET THEM OUT TO THE COMMUNITIES SO THE PEOPLE CAN START LOOKING AT THEM AND TRYING TO IMAGINE WAYS IN WHICH MORE MOLECULES OR OTHER APPROACHES COULD BE USED TO INHIBIT RAS ACTIVITY. AGAIN, THE GROUP AT FREDERICK IS GOOD ALSO AT BIOCHEMICAL MUTANT PROTEINS, DETERMINING HOW MUCH RAS IS IN THE GDT OR GTP STATE. THIS SCALE IS REMARKABLE, THE DEGREE TO WHICH THESE VARY. THESE HAVE DIFFERENT INTRINSIC RATES, A HUNDRED-FOLD LESS THAN WILDTYPE. SOME ARE COMPARABLE TO WILDTYPE. DIFFERENCES HAVE MAJOR IMPLICATIONS IN SIGNALING. WE THINK WHEN MUTANT RAS BINDS TO RAS, EACH OF THESE PROTEINS WILL HAVE A DIFFERENT ABILITY TO FULLY ACTIVATE RAS KINASE. WE UNDERSTANDING THE BIOLOGY OF THE PROTEINS AND AS A POTENTIAL THERAPEUTIC APPROACH BECAUSE THE SMALL INCREASE IN INTRINSIC TTPI WOULD INACTIVATE THE PROTEINS IF THE MODELS ARE CORRECT. THIS IS SOMETHING WHICH WE'RE LOOKING AT CAREFULLY, INITIALLY WITH RECOMBINANT PROTEINS, WE'RE MOVING TOWARD FULLY PROSED, WHERE THE ACTION IS IN IN RAS. WE CAN MAKE CRYSTALS AND WE'RE WORKING TO GET CRYSTAL STRUCTURES OF THE MAJOR MUTANTS ON THEIR OWN AND LATER WITH COMPLEX WITH OTHER PROTEINS. WE RECOGNIZE EARLY ON WE CAN E PROTEINS AND SHIP THEM OUT TO OTHERS TO HELP SOLVE THE CRYSTAL STRUCTURES, WE DON'T HAVE AN IN-HOUSE EXPERT ON THE TEAM, AN EXPERT IN CRYSTALLOGRAPHY SO WE HIRED DR. SIMANSHU, HAROLD MAY KNOW HIM, A CANDIDATE FOR ANY FACULTY POSITION, VERY PRODUCTIVE AND HE'S JOINING US IN OCTOBER AS OUR IN-HOUSE EXPERT IN STRUCTURAL BIOLOGY. I SHOULD ALSO SAY THAT WE'VE MADE A NUMBER OF REALLY KEY RECRUITS SINCE WE STARTED, MATT HOLDERFIELD WAS THE FIRST, NOW IN CHARGE OF THE ASSAY GROUP THAT I'M SHOWING HERE, WE'VE RECRUITED A LARGE NUMBER OF TALENTED INDIVIDUALS TO SUPPORT THE PROJECTS. THE TEAM HAS COME TOGETHER REALLY WELL. SO PROJECT NUMBER ONE ESSENTIALLY IS TO FIND STRUCTURES THAT MIGHT YIELD NEW WAYS OF TARGETING PROTEINS AND COMPLEXES. WE'RE ALSO DEVELOPING SCREENS, BIOCHEMICAL OR PHENOTYPIC, SOME ARE CLOSE TO PROSECUTION ALREADY AND WE HOPE TO GET SOME OF THESE SCREENS UP AND RUNNING BEFORE THE YEAR, USING THE FACILITIES AT NFAC AND OTHER GROUPS, DAVE COULD MENTION THIS LATER ON IN THIS DISCUSSION. THIS SHOWS WE CAN SET UP ALPHA SCREENS, A RAF BINDING TO RAF, AND SCREENS THAT CAN BE DISCUSSED LATER AND HAVE BEEN DISCUSSED IN PREVIOUS PRESENTATIONS. MOST OF THE RAF ACTION IS IN THE PLASMA MEMBRANE. AND THERE'S REASON TO BELIEVE THERE ARE SPECIFIC INTERACTIONS BETWEEN THE MEMBRANE AND RESIDUE ON THE RAF PROTEIN THAT AFFECT INTERACTION ON THIS SIDE OF THE PROTEIN THROUGH NETWORKS. SO AS I SAID BEFORE, RAS COMBINED RAF IN THE TEST TUBE DOESN'T ACTIVATE IT. THE BIOCHEMISTRY IN THE MEMBRANE IS LIKELY TO BE DIFFERENT THAN IN SOLUTION. THIS MAY SOUND TRIVIAL BUT IT'S NOT. PROCESSING REACTIONS ARE COMPLICATED. THERE ARE THREE OF THEM, AND TO PRODUCE PROTEINS FULLY PROCESSED HAS BEEN A TECHNICAL CHALLENGE, THE GROUP HAS MADE SIGNIFICANT AMOUNTINGS OF FULLY PROCESSED KRAS PROCESSED BY ENZYMES WHICH HAD TO BE ENGINEERED INTO THE BACILO VIRUS. J. GROVES FROM UC-BERKLEY GAVE A FANTASTIC SEMINAR AND TALKED ABOUT HIS WORK ON RAS D IMERIZATION IN MEMBRANES, ESTABLISHING RAS CAN DIMERIZE IN MEMBRANES. HE'S WORKING WITH US TO PRODUCE THE SAME EXPERIMENTS USING FULLY PROCESSED KRAS AND WE HAVE POTENTIALLY EXTREMELY INTERESTING COLLABORATION WITH JAY TO FOLLOW UP HIS INITIAL EXPERIMENTS AND POTENTIAL COLLABORATIONS WITH NANOTECHNOLOGY AND BIOPHYSICAL AND BIOCHEMICAL. THIS IS SOMETHING WHICH HASN'T BEEN DONE BEFORE. IT'S A BIG NEED AND WE THINK WE'RE ABLE TO ADDRESS THIS MAJOR NEED. KRAS PROTEINS DO EXIST. THIS IS WORK WITH STEVE CHEW AND OTHERS, INTERACTION BETWEEN RAS PROTEINS COULD BE TARGETED WITH SMALL MOLECULES TO DISRUPT THIS AND WE'RE EVALUATING SEVERAL WAYS OF SETTING UP ASSAYS TO LOOK AT AT DISRUPTING RAS DIMERS, LOOKING PROMISING AND HOPEFULLY CAN PROSECUTE SOME OF THOSE IN THE RELATIVELY NEAR FUTURE ALSO. WE HAVE DEVELOPED A CELL SYSTEM WHICH WE THINK IS EXTREMELY POWERFUL, AND THAT IS SYSTEM BASED ON WORK FROM MARIO BARBACID WHERE WE CAN MAKE CELLS WITH NO RAS PROTEIN, THEY CAN BE RESCUED WITH INDIVIDUAL RAS PROTEIN, MUTANT OR WILD LINE, LOOKING AT SIGNALING TYPES WITHOUT THE COMPLEXITY OF WILDTYPE PROTEINS AND OTHER COMPLEXES, AND WE'RE ALREADY HAVE VERY INTERESTING DATA TO SUGGEST THESE PROTEINS ARE DIFFERENT, AS I SAID EARLIER. WE'RE GOING TO USE THIS AS A PRIMARY SCREEN FOR COMPOUNDS HITTING KRAS G12V. WE'RE ALSO -- WE'VE HAD INTEREST FROM FARMER USING THIS PANEL OF CELLS TO IDENTIFY SPECIFICITY OF RAS DRUGS, GROWING IN THE ABSENCE OF RAS, RESCUED BY RAS OR MERCK. MEC. SO THIS PANEL WE THINK ISLY HELPFUL IN HEL PING PEOPLE VALIDATE POTENTIAL RAS COMPOUNDS AS WELL AS PRIMARY SCREENS FOR TARGETING RAS. THE SCREEN WE LIKE BEST IS TO MAKE CELLS THAT ARE GREEN OR RED AND EXPRESS HRAS OR KRAS-4B, WE MIX THEM AND LOOK FOR A CHANGE IN GREEN-RED RATIO, MORE DIFFICULT THAN WE EXPECTED. WE'RE EVALUATING THIS AND STRAIGHT FORWARD PROLIFERATION ASSAYS, AND THIS LOOKS REALLY INTERESTING AND GOOD. FOR EXAMPLE, THIS PAIR HERE, THE SAME RATE, SENSITIVE TO CHEMO DRUGS TO THE SAME DEGREE, BUT GRATIFYINGLY TO DAVE ONLY THE HRAS ARE SENSITIVE TO INHIBITORS, A GREAT SYSTEM. THE SIGNALS DOWNSTREAM OF KRAS COMPLICATED, WE DON'T KNOW WHICH ONES ARE MOST IMPORTANT. WE ARE INTERROGATING THIS IN COLLABORATION WITH MASS GENERAL AND NIH AND TINA YUAN IN MY LAB, WE ASSEMBLED 135 CELL LINES FROM COLON, LUNG AND PANCREATIC CANCER INCLUDING EVERY KRAS CELL LINE ON THE PLANET, ENTER GATING THE DEPENDENCE OF CELL LINES FOR THESE INDIVIDUAL WHAT WE CALL SIGNALING MODES. SO THESE ARE THE DIFFERENT DOWNSTREAM PATHWAYS, A NODE WOULD BE A COLLECTION OF, SAY, ALL THE ROWS OR ALL THE RACKS, BECAUSE WE KNOW IF YOU KNOCK DOWN ONE OF THESE IT REALLY DOESN'T DO MUCH. YOU HAVE TO KNOCK DOWN THE WHOLE MODE. WE HAVE 40 MODES DEFINED, MODEM KNOCK EACH DOWN FROM THE COLLABORATION WITH SCOTT LOWE AND WE CAN KNOCK THESE DOWN THREE AT A TIME AND SEE HOW RESPOND TO KNOCKDOWN, AND THE ASSAYS INVOLVE GROWTH, PROLIFERATION RATES, APOPTOSIS CELL SIZE. EACH OF THESE CELL LINES IS BEING TRANSFUSED WITH GFP, WE TRANSDUES IN SRNA AGAINST THENODE AND SRNA, YOU HAVE A KNOCKDOWN ON A POPULATION, YOU GET A DOSE RESPONSE INCLUDING THOUSANDS OF KNOCKDOWNS, YOU RUN THE WHOLE THING AND ON THE SINGLE CELL BASIS YOU CAN MAKE ALL THESE PARAMETERS THAT TRACK WITH KNOCKDOWN OF A TARGET, LIKE DOING A MASSIVE AMOUNT OF DATA IN ONE EXPERIMENT, BUT THE INFORMATION IS EXTREMELY RICH, AND WE ARE WORKING WITH THIS GROUP TO GO THROUGH A WHOLE PANEL OF CELLS AND WE'LL HAVE THIS DONE BY PROBABLY NOVEMBER DECEMBER. WHEN WE PRESENTED THIS TO LEVI'S GROUP, THERE WAS SOME CONCERN HOW TO PRESENT THE DATA SO WE HAVE A FOLLOW-UP MEETING PLANNED WITH THIS GROUP, PLUS MIKE WHITE FROM THE GROUP WHO IS GOING TO COME UP OFF TELEPHONE TO GIVE US GUIDANCE ON HOW TO ANALYZE THESE DATA, MOST EFFECTIVELY PLANNED IN OCTOBER. WE WANT TO FIND NEW PROTEINS, MAPPING THE SURFACE OF KRAS CELLS. WE HAD A NICE WORKSHOP WHICH ED AND SARAH ORGANIZED, FOR MAPPING THE SURFACE. THE FOLLOW-UP FROM THE WORKSHOP WAS TO PUT TOGETHER A VIRTUAL PROJECT IN WHICH WE BRING IN INFORMATION FROM ALL THOSE DIFFERENT TECHNOLOGIES AND OTHER CREWS WORKING ON THE SAME PROBLEM TO FOCUS TECHNOLOGY ON KRAS CANCERS, STILL A WORK IN PROGRESS. THAT WE ARE EXTREMELY INTERESTED IN INFORMATICS AND DATA FROM SOURCES RELEVANT TO KRAS. THIS IS ONE EXAMPLE OF AN IN-HOUSE QUESTION, DEBATE WHETHER KRAS, 4A AND 4B HAVE DIFFERENT BIOLOGIL PROPERTIES. SO BOB STEVENS HAS GONE THROUGH DATA TO LOOK FOR CELLS WHICH THE RATIO OF 4A TO 4B IS EXCEPTIONAL HIGH AND ASK GENES OF INTEREST TO TRACK WITH HIGH 4A OR LOWA, THERE ARE GENES OF INTEREST WHICH CREATE HYPOTHESES TO TEST. WE DECLARED WE WOULD LIKE TO DO A RAS-CENTRIC ANALYSIS OF DATA ACROSS THE DIFFERENT TISSUE SITES, AND LEVI SUGGESTED WE SHOULD CONTACT, BRING IN THE WHOLE COMMUNITY, NOT INTERNALLY, AND CONTACT GABBY GOETZ TO GET HELP, SO WE'RE PLANNING A RAS-CENTRIC ARTICLE ON CTDA DATA WHICH GABBY WILL LEAD TO MINE ALL INFORMATION ABOUT RAF PATHWAY FROM TUMOR SETS. AND E-MAIL WILL GO OUT NEXT WEEK TO DEFINE THE RAS PATHWAY AND WE'LL LAUNCH AN EFFORT TO EXTRACT INFORMATION RELEVANT TO RAS AND TCGA DATASETS. I WANT TO MENTION WE DO HAVE WEBSITES UP AND RUNNING WHERE WE CAN DOWNLOD INFORMATION RELEVANT TO RAS, COMMENTS FROM GET FEEDBACK, THE FIRST TO SOLICIT FROM THE COMMUNITY TO PUT ON THIS WEBSITE, SOMETHING WHICH DAVID SUGGESTED IN FRAN USING DATA AS LOW HANGING FRUIT. SKIMMING THROUGH THE THINGS GOING ON, AND NOW LEVI WILL DIG IN DEEP ON HIS ANALYSIS FROM THE SUBCOMMITTEE MEETING. THANK YOU. >> FRANK, CAN I ASK A TECHNICAL QUESTION? THAT ANALYSIS THAT YOU SHOWED, I'M TRYING TO UNDERSTAND WHAT EXACTLY YOU DID HERE. >> DON'T ASK ME. >> OH. ALL RIGHT. >> I'LL SHOW YOU THE GUY THAT DID IT. >> IT LOOKS LIKE SOMEWHAT NONTRADITIONAL APPROACH, I'M JUST TRYING TO UNDERSTAND WHETHER YOU USED MANUALLY CURATED SETS, SINGLE CELL ANALYSIS. >> WE'LL FOLLOW UP. >> GREAT, THANKS. >> SO THIS IS -- IF ANYBODY WHO HAS GONE TO ASCO, THIS IS LIKE FRANK GAVE THE OUTSTANDING PLENARY TALK AND NOW I HAVE TO BE THE DISCUSSANT WITHOUT THE BEAUTIFUL SLIDES AND DATA. MY SLIDES ARE BULLET POINTS AND TITLES, SO I WAS THINKING AS FRANK WAS SPEAKING THE IDEAL WAY TO DO THIS WOULD BE TWO PROJECTORS, ONE WITH MINE AND ONE WITH FRANK'S. OTHER FIRST MEETING AT THE RAS GROUP TO BE AN ADVISORY GROUP TO FRANK WAS ALMOST EXACTLY TWO MONTHS AGO TODAY AND I THINK THE CONSENSUS OF THAT GROUP, I FELT IT WAS A RICH SCIENTIFIC -- RICH ENGAGING SCIENTIFIC DISCUSSION WITH SUGGESTIONINGS FROM THE GROUP AND IT'S BEEN GRATIFYING TO SEE EVEN IN THE SHORT PERIOD OF TIME SINCE THAT MEETING HOW SEVERAL OF THOSE SUGGESTIONS HAVE BEEN INCORPORATED AND THERE'S SORT OF FOLLOW-UP FROM THAT. IN GENERAL, THE SPIRIT AND ENTHUSIASM AROUND THIS PROJECT FROM THE WORKING GROUP WAS VERY HIGH OVERALL. I'LL LEAD WITH THAT. OUR MISSION AS YOU KNOW IS TO HOPEFULLY PROVIDE THE HIGHEST QUALITY OVERSIGHT TO TECHNICAL AND SCIENTIFIC ASPECTS OF WHAT FRANK'S PROGRAM IS DOING AND PROVIDE FEEDBACK. A COMPONENT OF WHAT'S BEING EVALUATED ARE THE SCIENTIFIC GOALS AND PRIORITIES, ET CETERA, THAT FRANK HAS AND HOW THEY MAY CHANGE OVER TIME, BUT ALSO THE ASSESSMENT OF HOW THE EXTRAMURAL COMMUNITY IS ENGAGED, THIS IS AN AVENUE TO BRING THAT ENGAGEMENT NOT JUST IN THE RAS PROGRAM BUT JUST IN GENERAL OF EMBLEM ATTIC OF WHAT FNLCA WANTS TO BE. OUR MISSION ON THATIN LATE JULY WAS TO REVIEW MAJOR COMPONENTS, PROVIDE FEEDBACK, PROVIDE AN ASSESSMENT OF WHAT'S GOING WELL. A COUPLE KEY POINTS THAT WERE EMPHASIZED BY FRANK, IS THIS GROUP MAY REALIZE THIS, THIS WAS A PIVOT AS HAS BEEN DESCRIBED BY DAVID AND OTHERS, SO IT'S A SUBSTANTIAL COMMITMENT BY NCI, $10 MILLION ANNUALLY, IT DOESN'T COMPRISE NEW MONEY. I FIND IN MY ONE ON ONE DISCUSSIONS, SOMETIMES THERE'S AN ASSUMPTION THERE'S SOMEHOW NEW MONEY THAT THE BUDGET GREW FREDERICK TO MAKE THIS HAPPEN, AND THEY ARE LESS LIKELY TO BE FUNDED, BUT THIS IS A -- WHAT'S THAT? ESPECIALLY THEIRS. BUT THE FACT THAT THERE WAS NO NEW MONEY HERE WAS AN IMPORTANT POINT TO REMEMBER. I THINK THE OTHER INTERESTING COMPONENT IS THIS IDEA OF HUB AND SPOKE THAT FNLCR WILL BE A HUB IN TERMS OF THE KINDS OF RESEARCH THE COMMUNITY IS DOING BUT WILL HAVE SEVERAL WAYS IN WHICH THERE WITH BE CONNECTIVITY, AND IT WAS MENTIONED THIS MORNING THERE'S NOW A UO1 MECHANISM ANNOUNCED IN AUGUST AROUND THE NEXT GENERATION OF SYNTHETIC LETHAL SCREENS PARTICULARLY AROUND THE KRAS -- IF KRAS? KRAS MUTANT CONTEXT. AND THERE'S GOING TO BE A POSTDOCTORAL FELLOWS PROGRAM AT FNLCR AROUND THE RAS PROGRAM. THE IDEA OF BEING ABLE TO BRING IN TRAINEES AT VARIOUS -- TRAINEES AND FACULTY AT VARIOUS STAGES OF DEVELOPMENT IN COLLABORATION WITH MAYBE HAVING A MENTOR HERE AND CONNECTIVITY ELSEWHERE IS AN INTERESTING ONE THAT WE'LL BE INTERESTED IN FOLLOWING. FRANK'S PROGRAM HAS FIVE PROJECTS, THESE HAVE BEEN OUTLINED PREVIOUSLY. AT THE CORE IS STRUCTURAL AND BIOCHEMICAL ASPECTS OF RAS, MUTANT RAS PROTEINS AND WHAT MUTANTS THEY INTERACT WITH. THE SECOND IS CELL-BASE AND PHENOACTIVIC ASSAYS. THE THIRD IS WITH IMAGING AND SCREENING FOR PARTICULAR R EADOUTS OF WAS BIOLOGY, THE FOURTH IS MAPPING THE SURFACE OF K RAS COMMUTE ANTICANCER CELLS, HOPING TO FIND SELECTIVE MEMBRANE TARGETED BY IMMUNOTHERAPY, AND THE FIFTH IS NEXT GEN K RAS SYNTHETIC. THERE WAS A LOT OF EXCITEMENT BECAUSE THIS WAS FELT THAT THIS ACTIVITY SYNERGIZES WITH CAPABILITIES OF FNLCA, GENERATING REAGENTS, DETERMINING STRUCTURES, IT WAS STRIKING I THINK TO US IN THE WORKING GROUP HOW IT'S INTUITIVELY OBVIOUS K RAS IS DRIVING CANCER AND THERE ARE NO STRUCTURES SOLVED WITH THEIR INTERACTING PARTNERS SEEMS LIKE AN OMISSION BUT THE ACTIVITIES SCALING UP PURIFIED PROTEINS AND STRUCTURAL DETERMINATIONS SEEMED TO FIT IN THE SWEET SPOT OF WHAT FNLCR DOES. THERE'S THE BIOPHYSICAL PARAMETERS, HEARKENS BACK TO NANOTECHNOLOGY LABORATORIES, PARALLEL TECHNOLOGY, AND PRODUCING PROCESS KRAS, ET CETERA. THIS SET OF ACTIVITIES THERE WAS ENTHUSIASM AROUND THE PRIORITIZATION FRANK HAS BECAUSE IT WAS FELT LIKE THIS IS -- FNLCR IS IDEALLY SUITED AND THERE MAY NOT BE MANY PLACES WHERE THIS COULD BE DONE SYSTEMATICALLY BUT THESE ARE BADLY NEEDED AGENTS IN RAS BIOLOGY. WHAT WAS CLEAR FROM FRANK'S GROUP, THIS IS NOT GOING TO BE EASY. IN SOME WAYS IT REINFORCES 9 MISSION AROUND DOING THAT HERE, WHETHER YOU CAN HAVE MULTIPLE FULL-TIME EQUIVALENT DEDICATING EFFORTS HERE, BUT ALREADY, FOR EXAMPLE, WHEN ONE TRIES TO CRYSTALLIZE RAS IT TURNS OUT THAT THERE ARE CONDITIONS AROUND CRYSTALLIZATION THAT AFFECT THE CONFIRMATION THAT RAS TAKES, AND SO THIS SECOND BULLET POINT WAS TRUE THAT THERE IS NO RAS STRUCTURAL BIOLOGY, BUT NOW FRANK HAS FIXED THAT PROBLEM BY THIS NEW RECRUIT. THAT OBVIOUSLY IS A HUGE BOON IN TERMS OF HAVING ON-SITE EXPERTISE, BUT THERE'S ALSO CONTRACT RESEARCH ORGANIZATIONS INVOLVED IN TERMS OF SCALING UP THE CRYSTALLIZATION AND STRUCTURAL ASPECTS. THESE ARE SOME CHALLENGES THAT ARE ALREADY IN THE MIDST OF BEING ADDRESSED. THE OTHER CHALLENGE WHICH MAYBE IS MORE NONLINEAR IS THE IDEA OF UNDERSTANDING RAS COMPLEX TO THE GAP PROTEINS WHICH NORMALLY NEGATIVELY REGULATE, UNDERSTANDING HOW THAT NEGATIVE REGULATION OCCURS AND COMPOUNDS THAT COULD STABILIZE THAT, SOMETHING THAT'S EXCITING BUT THIS WILL TAKE TIME, PROBABLY NONLINEAR SINCE THIS IS CHALLENGING TO DO. SIMILARLY THE EFFECTOR. IN GENERAL, THE RAS STRUCTURAL BIOLOGY IS EXCITING BECAUSE THERE ARE CHALLENGING COMPONENTS THAT MADE IT HARD TO DO BUT MANY FNLCR SEEMS WELL SUITED, DIVIDED AROUND BRUTE FORCE COMPONENTS THAT ARE NONLINEAR BECAUSE THAT ARE MORE COMPLEX IN TERMS OF THE FACTORS AND PURIFICATION THAT'S REQUIRED. SO RECOMMENDATIONS, AGAIN, ENDORSING THE HIGH PROFILE NATURE, THIS COULD BE LOW HANGING FRUIT FOR CHARACTERIZATION AND DELIVERABLE TO THE COMMUNITY, ONE CAN IMAGINE WHEN THIS IS DONE HAVING THE STRUCTURES GO OUT AND MAKING IT KNOWN AND HAVING THE PURIFIED PROTEINS AS REAGENTS THAT COULD BE MADE AVAILABLE TO INVESTIGATORS COULD BE AN EXCITING OBVIOUS EARLY DELIVERABLE OF SHOWING THE RAS PROGRAM IS DOING TANGIBLE -- MAKING TANGIBLE PROCESS TO ENABLE THE ENTIRE COMMUNITY. IT WAS SUGGESTED PERHAPS, AGAIN, RECOGNIZING THAT SOME OF THESE EFFORTS MAY HAVE HAPPENED ALREADY, SO FOR EXAMPLE HAVE THERE BEEN PHARMACEUTICAL EFFORTS SHELVED OVER THE YEARS BECAUSE THEY WERE LINKED TO TRANSFERASE INHIBITORS, COULD THERE BE CONNECTIVITY AND ENGAGING DAVID HEIMBROOK, COULD THIS BE SOMETHING, ANOTHER AVENUE, THAT COULD BE LEVERAGED. A POINT MADE BY DAVID, THERE ARE NOW -- THE ABILITY OF CULTURING RAS MUTANT CANCER CELLS EX VIVO MIGHT PROVIDE ANOTHER REAGENT, A PARALLEL REAGENT OF PATIENT-DERIVED MATERIALS WHERE ONE CAN PURIFY RAS FROM THERE IN ADDITION TO FROM KIND OF THE HIGH THROUGHPUT SYSTEMS FOR APPROACHING EXPRESSION, THAT COULD BE A COMPLEMENT. AND THEN THE OTHER POINT WAS THAT IF ONE IS GOING TO DELVE DEEPLY INTO, FOR EXAMPLE, FOR THE GAP RAS COMPLEX WITH YOU SHOULD DO THAT MORE THAN ONCE. IS EVERY GAP ITS HONEYBEES OR IT'S OWN BEAST? JUST HAVING CLEAR MILESTONES, INCLUDING GO/NO-GO DECISIONS, HOW APPROACHING PURIFICATIONS WORK AND HAVING THAT LAID OUT IN TERMS OF GANT SO IT CAN BE REFERRED BACK TO FOR OUR GROUP AND OTHERS. >> DO YOU HAVE A COMPUTATIONAL CHEMIST ON YOUR COMMITTEE? SOMEBODY LIKE XAO MING WANG? >> WE DO NOT. ONCE THE SCREENING GETS LINKED, THAT WOULD BE AN INTERESTING ADDITION. THAT'S A GOOD POINT. >> SOMEBODY LIKE THAT COULD HAVE, EVEN AT THIS POINT, INTERESTING INPUT SINCE THEY USE THIS KIND OF INFORMATION TO DESIGN DRUGS, SOME OF THEM VERY SUCCESSFULLY. >> A GREAT SUGGESTION. SARAH, WHO BY THE WAY IS THE NCI, YOU KNOW, CO-CHAIR, IF YOU WILL, OF OUR WORKING GROUP, WE COULD TOUCH BASE OFFLINE AND ALSO WITH FRANK ABOUT ADDING SOMEONE LIKE THAT, AND HOPEFULLY SOONER RATHER THAN LATER. OKAY. SO THE OTHER INITIAL KIND OF RAS BIOCHEMISTRY PROJECT FRANK ALLUDED IT TO WHICH THERE WAS ENTHUSIASM AROUND WAS THE IDEA OF MAKING REAGENT AVAILABLE NOT SOLELY AT THE PURIFIED PROTEIN LEVEL BUT RAS IN THE CONTEXT OF MEMBRANE AND HOW IT ASSOCIATES WITH MEMBRANE, THE RAS THAT DOES ITS BUSINESS IN THE CELL. THOSE REAGENTSES ARE NOT AVAILABLE TO THE COMMUNITY ESSENTIALLY AND HAVING THEM AVAILABLE COULD BE HIGHLY ENABLE FOR BIOLOGY. THERE ARE OTHER ENZYMATIC EFFECTINGS THAT ARE ALL REQUIRED TO INSERT RAS INTO THE MEMBRANE. THERE'S AN EFFORT ONGOING IN FRANK'S GROUP TO GENERATE WASINS USING BAC KLOWVIRUS TECHNOLOGY IN THE CONTEXT OF MEMBRANES, LIPOSOMES, ET CETERA. THERE'S A NEW WAVE OF STUDIES OF BONA FIDE WAS. YES, DAVID? >> OR FRANK, IN FRANK'S PRESENTATION THERE WAS AN EXPERIMENT WHICH PURPORTED TO SHOW THAT TRANSFERRATION INHIBITORS INHIBIT CELLS WITH NRAS OR H RAS BUT NOT KRAS. I TRY TO UNDERSTAND THIS SLIDE BECAUSE PARENYLATION IS REQUIRED. THE KRAS WOULDN'TING PARENYLATED EITHER. [OFF MIC] THIS MAY BE MY IGNORANCE. >> NORMALLY K RAS IS, BUT WHEN IT'S NOT, IT REACTIVATES. >> THE TRANSFERASE DRUGS WORK WELL ON HRAS BUT NOT NRAS OR KRAS FOR THAT REGION. >> HAS THAT BEEN TARGETED? >> IT'S BEING DISCUSSED. THE THOUGHT HAS BEEN TARGETING THAT WOULD BE TOO TOXIC, ALTHOUGH MAYBE DAVE -- PEOPLE HAVE BEEN RETHINKING, BUT YOU HAVE TO TARGET BOTH. >> IT SOUNDS LIKE LET THE JURY DECIDE, LET'S DO AN EXPERIMENT. >> THERE BEEN DRUGS IN THE CLINIC WHICH DID AFFECT PARENYLATION. DAVE WAS THERE. HE KNOWS BETTER THAN I. WE HAVE A WORKSHOP TO DISCUSS THOSE ISSUES WHICH MAYBE PEOPLE GAVE UP ON TOO EARLY. >> THAT'S WHAT I WAS THINKING. >> YOU'RE OPENING A WOUND THAT'S 20 YEARS OLD, SO THANK YOU FOR THAT. >> IT HURTS ME MORE THAN YOU. >> AS FRANK SAID, THERE'S IS CROSS PARENYLATION. ONE COMPONENT OF THE ENZYMES IN SHARED. IT WAS TOXIC, THERE'S SO MANY PROTEINS THAT USE THE GENERAL-GENERAL TRANSFERASE. THERE'S NOT THAT MANY PROTEINS, BUT LOTS ARE GENERAL-GENERAL, WE CURRENT FIND A WINDOW TO HIT KRAS, WHERE IT WAS NOT SIGNIFICANTLY TOXIC. >> DAVE, IS THERE ANY EVIDENCE FOR PALMETTO E LATION FOR KRAS, NO. >> WHEN YOU SAY PARENYLATED, WHICH ONE ARE YOU MAKING? OR BOTH? >> MOST RAS PROTEINS ARE GENERAL-GENERAL LATED. WE NEED TO ADD HUMAN TRANSFERASE, THAT'S WHAT WE'RE DOING. WE'RE MAKING HUMAN K RAS, WHICH WE PUT INTO THE CELLS. >> IS THAT WHAT YOU WANT TO DO? >> YEAH. >> IS GENERAL-GENERALATEDK RAS TOXIC? I MEAN DOES IT CAUSE CANCER, RIGHT. >> YEAH, GENERAL-GENERAL TAKES OVER, THAT'S SUFFICIENT TO KEEP TUMORS GOING. >> WHY AROUND YOU MAKING GENERAL-GENERALATET RAS? IT'S ONLY RELEVANT WITH TRANSFERASE. >> IF YOU'RE INTERESTED IN HOW RAS DOES ITS BUSINESS, EITHER ONE WOULD GIVE YOU INFORMATION. >> YEAH, NO REASON WE COULDN'T MAKE GENERAL-GENERAL TRANSFERASE AS WELL. >> YOU DON'T KNOW THERE'S A LOW BND OF GENERAL-GENERATED, DO YOU, IN YOUR AVERAGE PANCREATIC CANCER? >> IT COULD BE 1 OR 2%. IT'S ALWAYS ASSUMED -- >> YOU GUYS ARE IN THE BUSINESS OF LOOKING DEEPLY, I WAS SUGGESTING THAT YOU WORRY ABOUT THIS. >> YEAH, THAT'S A -- A LOT OF THESE DATA WERE DERIVED 20 YEARS AGO, NO OFFENSE, DAVE. >> I UNDERSTAND. >> IT MAY BE WORTH REVISITING BUT I DON'T THINK IT'S BEEN LOOKED AT MORE RECENTLY. GOOD POINT. >> BUT THE FEELING, IN OUR WORKING GROUP REVIEWING THIS COMPONENT, THE SENSE WAS THAT IRREGARDLESS OF HOW THE THAT YOU COULD STUDY, IT'S SOMETHING THAT'S BEEN MISSING, AND HAVING IT W OULD BE A GREAT THING. IF THE CHARACTERISTICS WERE DIFFERENT THAT COULD BE IMPORTANT FOR SCREENING FOR COMPOUNDS THAT WORK IN DIFFERENT WAYS, AND PERHAPS ONE COULD HOPE HAVE A DIFFERENT THERAPEUTIC WINDOW THAN THE GENERAL-GEN XEI MOIDES. IT'S GREAT AT MAKING PROTEIN BUT ONE HAS TO ENGINEER IT TO HAVE RAS GET TRANSLATED, POST TRANSLATION MODIFIED IN THE PROPER WAY AND THAT HAS TO DO WITH ADDING HUMAN NGI AND METHYL TRANSFERASE PROTEIN, SO THESE -- THERE'S TECHNICAL STUFF ONGOING TO MAKE A MODIFIED BACK LOW VIRUS SYSTEM SO MOST IS PROCESSED, SO WE'RE WE'LL BE EXCITED TO SEE THE RESULTS OF THOSE EXPERIMENTS. THIS IS AN EXAMPLE OF A DELIVERABLE OF GREAT BENEFIT, THE KIND OF THING NOT HAPPENING WIDESPREAD AND WOULD BE IN HIGH DEMAND FROM BOTH ACADEMIA AND POTENTIALLY PHARMACEUTICAL INDUSTRIES, THE RECOMMENDATION WAS IN ADDITION TO CHELATING, HOW WILL IT INCORPORATE, ROBUSTTRICS ONCE THIS IS WORKING TO EXPAND THE PRODUCTION AND BE ABLE TO SHARE THESE REAGENTS WITH THE COMMUNITY IN SUCH A WAY THAT ANYBODY WHO MIGHT WANT IT COULD GET THAT. THAT'S BEEN OBVIOUSLY -- WE ALL KNOW A BENEFIT OF FNLCR IN THE PAST. THEN THE CONVERSATION TURNED FROM THESE VERY BIOCHEMICAL REAGENT-DRIVEN CONVERSATIONS TO SOME OF THE LARGER ASSAYS BEING DONE. YOU YOU'VE HEARD ABOUT SOME OF THESE, FOR EXAMPLE, THERE ARE CELL-BASED SCREENS THAT I WENT GO THROUGH IN GREAT DETAIL BUT THE IDEA HERE IS READ OUT ASPECTS OF RAS BIOLOGY, ABILITY TO DIMERIZE AND LOCALIZE IN THE C AND VARIOUS WAYS OF DOING THAT. I'M NOT DIGGING INTO THE WEEDS BUT SOME ARE RATHER SOPHISTICATED AND COMPLICATED, ONE WOULD IMAGINE IF ONE WAS GOING TO USE THEM FOR SCREENS THEY MIGHT BE SECONDARY SCREENS RATHER THAN PRIMARY SCREENS, SO THE AGGREGATE SUMMARY OUR GROUP HAD FOR FRANK WAS TO BE MINDFUL OF THE VAGARIES THAT COULD CREATE IN VITRO ARTIFACTS THAT MAY NOT BE RELEVANT IN VIVO. IN CELLS, THE CONCENTRATIONS OF KRAS AND C-RAF, THERE WAS DISCUSSION ABOUT THE KINDS OF HITS THAT MIGHT COME OUT ONCE THE ASSAYS ARE USED, HITS THAT STABILIZE AS WELL AS DESTABILIZE THESE INTERACTIONS COULD BE INTERESTING. THE GENERAL PRINCIPLE, THESE COULD BE POTENTIALLY CHALLENGING ASSAYS, ONE WOULD WANT TO MAKE SURE NOT TO LET THEM GET TOO ELABORATE AND COMPLICATED, SO RARIFIED THEY MAY NOT BE GENERALIZABLE. WHEN THEY ARE RENDERED SCREEN READY, MAKE SURE THEY ARE MADE AVAILABLE TO AS MANY SCREENING LIBRARIES AS POSSIBLE SO ONE IDEA HAS BEEN TO LEVERAGE THE NCAST LIBRARY BUT THERE MAY BE OTHER LIBRARIES WHERE SCREENS CAN BE USEFUL IN IDENTIFYING LEAD COMPOUNDS. YOU HEARD ABOUT THE RAS-LESS ISOFORM, HIGH-THROUGHPUT SCREENING COULD BE DONE. THERE COULD BE FALSE POSITIVE AND FALSE NEGATIVE. IF I RECALL THIS CORRECTLY, FRANK, CORRECT ME IF I'M WRONG, P53 KNOCKOUT COULD RESCUE PROLIFERATION IN THESE SETTINGS. THERE CAN BE EFFECTS IN SIGNALING NETWORKS THAT ARE NOT LINKED TO RAS THAT COULD CAUSE RESCUE OR NOT. UNDERSTANDING HOW TO DESIGN EACH OF THESE SCREENS SO THAT THEY ARE PROBABLY CONTROLLED COULDED A LEAST MITIGATE THE POSSIBILITY OF THOSE THINGS COMING THROUGH, WHAT THE -- WHAT ONE COMPARES THESE TO AND READS OUT A COMPARISON BETWEEN A KRAS AND NRAS, FOR EXAMPLE. THINKING CAREFULLY ABOUT SOURCES OF FALSE POSITIVES AND NEGATIVES, THERE WAS ENTHUSIASM AROUND THIS REAGENT THAT COULD BE A NICE CLEAN CELL BASED READOUT OF SOME SMALL MOLECULES THAT SCORE IN THE BIOCHEMICAL SCREENS THAT WERE DESCRIBED EARLIER. THEN WE GET INTO THE AREA THAT FRANK MENTIONED AT THE END, PROTEOMICS BASED APPROACH TO LOOK AT CELL SURFACE COMPONENTS, THE OTHER WAS THE NODES. THERE'S EARLY DATA PRESENTED WHERE THE IDEA IS TO INTERROGATE WILDTYPE -- CELLS WILDTYPE FOR KRAS AND CELLS KRAS DRIVEN, AND READOUT CELL SURFACE PROTEINS ON THE MEMBRANE THAT MIGHT DIFFER BETWEEN THE TWO AND THERE WAS PRELIMINARY DATA SHOWN AROUND 666, IT SEEMS LIKE A DIABOLIC NUMBER, COMPARED TO NONKRAS DRIVEN CELLS, AND EIGHT WERE IDENED BY ORTHOGONAL APPROACHES. POTENTIALLY AN INTERESTING EXPERIMENTAL LINE BUT THE EFFORTS WERE FELT TO BE PRELIMINARY. SO ONE OF THE BIG I GUESS HIGH LEVEL VIEWS ON THIS WAS ONE OF THE CHALLENGES OF PROTEOMIC STUDIES HISTORICALLY HAVE BEEN THE COST AND THROUGHPUT, THE LABOR CAN BE SO CONSIDERABLE THAT OFTEN THE NUMBERS OF COMPARATORS IS SMALL. HERE IT WAS A SINGLE STUDY OF A KRAS DRIVEN LINE AND A WILDTYPE LINE, THERE ARE OBVIOUSLY CONFOUNDERS AROUND HOW BIG SHOULD THE STUDY BE, WHAT IS YOUR ACTUAL WILDTYPE COMPAREATOR, SO THE STRONG ENCOURAGEMENT TO FRANK WAS TO EARLY ON BRING IN THOUGHTS ON THE DESIGN. ONE IS THE PROTEOMICS PEOPLE OUT THERE DOING THE STATE OF THE ART LIKE STEVE GIGY, PUSHING THE ENVELOPE MAKING SURE THE PROTEOMIC IS WHERE IT NEEDS TO BE, HOW MANY KRAS MUTANT, DO YOU WANT TO FOCUS ON KRAS CODE 12 VERSUS -- AND HOW BIG, AND DESIGN THE IDEAL EXPERIMENT TO ALLOW ONE TO DISCOVER MEANINGFUL GENERALIZABLE DIFFERENCES. HAVING SAID THAT, THAT WAS KIND OF A SERIES OF RECOMMENDATIONS, SOME OTHERS THAT I WON'T GO INTO DEEPLY. HAVING SAID THAT IF ONE COULD GENERATE SUCH A RESOURCE OF MEMBRANE COMPONENTS THAT ARE RELATIVELY SELECTIVE TO KRAS, MAYBE KRAS MUTANT DRIVEN CONTEXT THAT COULD BE A VERY INTERESTING RESOURCE FOR THE COMMUNITY, BUT NOW IS THE TIME TO REALLY BRING IN THE EXPERTISE AND MAKE SURE THOSE EXPERIMENTS ARE DESIGNED SO THAT THE CONFOUNDERS THAT ARE OFTEN EMBEDDED IN SMALL SAMPLE SIZES AND LINEAGE DISTINCTIONS DON'T KIND OF GET IN THE WAY. YES? >> MAYBE AN OBVIOUS POINT BUT USING CRISPR TO CORRECT KRAS MUTATIONS IN HUMAN CELL LINES WOULD GIVE YOU A USEFUL COLLECTION OF CELL LINES WITH THE IMPORTANCE IN THE COMMUNITY. >> WOUND COULD EASILY IMAGINE, THERE ARE -- EVEN IN TERMS OF EXISTING CELL LINES, BEFORE WE GET INTO ORGANOIDS, IF YOU CRISPR THEM CORRECTLY ARE THEY GOING TO STOP PROLIFERATING. IF THAT WERE POSSIBLE FOR A SUBSET OF CASES THAT WOULD BE A VERY NICE COUNTERPOINT. [OFF MIC] RIGHT. >> I ASSUME THAT YOUR GROUP WAS ALARMED BY THIS COMPARISON OF B-CELLS TO EPITHELIAL BREAST CELLS, RIGHT? >> SINCE THIS IS A PUBLIC MEETING I DIDN'T EXPRESS DETAILS OF THE ALARM, YES, THIS WAS ADDRESSED. >> A CALLING FOR EXPERTISE WHEN COMMON SENSE IS REQUIRED IS A FAILURE MODE. YOU DON'T WANT MORE EXPERTS. YOU WANT CLEANER EXPERIMENTAL DESIGN. AND I THINK THE CRISPR IS A WAY TO GO. THERE HAS TO BE A BETTER WAY TO DO THAT EXPERIMENT. THE GOAL OF THE EXPERIMENT, I GET IT. OKAY. BUT B-CELLS, I MEAN, YOU KNOW -- [OFF MIC] >> YOU'RE RIGHT. IF IT WAS PART OF THE EXECUTION, SO SOME, YOU KNOW, SOME GUY AT AGILAN DESIGNED THIS. MASS SPECTOMETRY, NOT A LOT OF COMMON SENSE. >> ONE GROUP WHICH WAS MOBILIZED IS THE CP-TACK GROUP WHICH SPEND ENORMOUS AMOUNTS OF TIME AND EFFORT FOCUSING ON THE TECHNOLOGY TO IDENTIFY DIFFERENCES IN PROTEINS BETWEEN VARIOUS TYPES OF COLON CANCER, JUST HAD A BIG PAPER IN "NATURE" A FEW WEEKS AGO AND THEY HAVE ALSO VERY STRONG BIOINFORMATIC COMPONENT OF THAT. YOU'VE GOT THEM AT YOUR DISPOSAL. >> I MEAN, JUST TO ADDRESS BOTH OF THOSE POINTS, THE CONVERSATION OF THE WORKING GROUP AROUND THIS PROJECT WAS THAT IT WAS CERTAINLY -- IT WAS VIEWED THIS IS AN INITIAL EXPERIMENT TO KIND OF GET THE TECHNOLOGY ESTABLISHED BUT WE PUSHED BACK ON GETTING ANY OF THE 666 AND 8 OVERLAPPING STEERED AWAY FROM THE CONVERSATION ABOUT WHAT PROTEINS WERE BECAUSE THE EXPERIMENT HAD TO BE DESIGNED PROPERLY BEFORE ONE COULD INTERPRET ANY OF THE DATA. THAT'S HOW IT WAS RECEIVED. OR THAT WAS THE MESSAGE WE CONVEYED. >> THIS MIGHT BE A NAIVE SUGGESTION, BUT IF WHAT YOU'RE LOOKING AT HERE IS THE SURFACE ANTIGENS AND NOT WHAT'S REQUIRED FOR KRAS MUTANT CELL LINE TO PROLIFERATE, COULDN'T YOU PUT KRAS INTO A KRAS-NEGATIVE BREAST EPITHELIAL LINE AND CREATE A POSITIVE IF YOU'RE SCREENING FOR PROLIFERATION HERE? >> RIGHT. ONE MINOR QUIBBLE, IS BREAST CANCER THE BEST PLACE TO DO THIS BECAUSE YOU DON'T EVER GET KRAS, BUT YOUR POINT IS WELL TAKEN. THE IDEA IS OBVIOUSLY ONE WANTS TO SIMPLIFY THE VARIABLES. OTHERWISE ISOGENIC LINE, THE COMPAREATOR IS NULLIFIED, MAYBE WILDTYPE VERSUS MUTANT, OR AS HAROLD SAID MAYBE A COMPANION WHERE YOU CRISPR IT OUT, MAYBE THE EXPERIMENT HAS COMPONENTS OF EACH, FOCUSED IN A PARTICULAR LINEAGE LIKE AGE LIKE PANCREAS OR SOMETHING LIKE THAT. THE FOCUS IS NOT ON I DIMENSIONALITY OF A FUTURE TYPE EXPERIMENT. IT MAY BE COMMON SENSE TO US WHO THOUGHT ABOUT FUTURE SELECTION AND GENETIC DIVERSITY, IT'S BRINGING IN PEOPLE WHO HAVE ADVISE THAT GROUP ABOUT HOW TO THINK ABOUT WHAT IS A FUTURE SELECN TYPE OF EXPERIMENT. >> WE TOOK YOUR ADVICE, WE WANTED TO PULL TOGETHER PEOPLE FROM THE COMMUNITY AND GET AN INTERNAL EXPERT BUT I WANT TO DEFEND POINT TWO. THAT'S NOT HOW THE WHOLE EXPERIMENT WAS DESIGNED. PANEL WAS TRANSFE RRED BY 20 ONGENES, STRANGE FOR PHAGE, THE SYSTEM STARTED BEFORE THE RAS PROJECT AT FREDERICK. WE THOUGHT IT WOULD BE USEFUL TO SEE WHAT WE DETECT MATCHES WHAT HE FOUND TRANSFORMED BY KRAS, AS A PRACTICAL MATTER. SO IT WASN'T AN EXPERIMENT DESIGNED TO SHOW KRAS IN BREAST CANCER B-CELL COMPARISON, WE HAPPENED TO HAVE A LUNG CANCER CELL LINE AND B-CELLS DERIVED FROM THE SAME PATIENT AS A CONTROL FOR SOME OF THE PROTEINS AS BREAST. >> WE'RE ON THE SAME PAGE, THESE WERE MORE TECHNICAL PROOF-OF-CONCEPT EXPERIMENTS THAN THE EXPERIMENT TO FIND THE -- FIRST EXPERIMENT TO FIND THE ANTIGEN. THAT WAS -- I THINK WE'RE CAPTURING HERE, THIS IS CLEARLY ONE OF THE MORE SPIRITED DISCUSSIONS, BUT I THINK HOPEFULLY IT SEEMS LIKE THE MESSAGE GOT THROUGH. SO THEN IT'S OTHER COMPONENT WHICH FRANK ALLUDED TO, THE IDEA OF SYSTEMATICALLY PERTURBING RAS SIBLING NODES, YOU SAW THE DIAGRAM OF VARIOUS EFFECTORS, THERE ARE AGENTS ONE CAN INTRODUCE AND SORT FOR LEVEL OF KNOCKDOWN AND DO FOR EXAMPLE GENE EXPRESSION READOUTS OF CHANGES THAT ARE LINKED TO THE PERTURBOGENS. THAT'S ONE GOAL HERE. AND THERE'S A VARIETY OF WAYS IN WHICH FRANK WOULD LIKE TO DO THAT. SO I'M GOING THROUGH, GLOSSING THROUGH THE PARTICULARS, TO GET TO OUR RECOMMENDATIONS BECAUSE THIS AREA WAS ALSO -- THERE WAS WAS RECOGNIZED THERE'S A LOT OF RABBIT HOLES IN THIS APPROACH, AND THEY RANGE FROM -- SO THE VISUAON COMPONENT, MAKING SURE ONE CAN UNDERSTAND AVA VARIABILITIES, DOING IT IN ONE PLACE VERSUS ANOTHER. SOME OTHER CONFOUNDERS THAT COULD AFFECT DATA INTERPRETATION, FOR EXAMPLE, GFP READOUT AND MORE GENERALLY WE'RE PRIVY -- THERE WAS A , SYNTHETIC LETHAL MEETING IN JANUARY. AGAIN, AS WITH THE PROTEOMICS, THE APPROACH WAS EXCITING BUT THE DATA AT PRESENT WAS FELT TO BE PRELIMINARY AND THERE'S AN AMBITIOUS EFFORT IN GENERAL. THE IDEA OF HAVING CLEAR METRICS AND DELIVERABLES AND INTERFACING WITH PEOPLE IN THE COMMUNITY DOING THESE ANALYSES FOR A LIVING AND STNG OVER THE CHALLENGES AND GETTING THAT IN PLACE EARLIER RATHER THAN LATER WAS FOUND TO BE IMPORTANT. ANY OTHER -- FRANK, DO YOU WANT TO PUSH BACK? >> NOT REALLY. WE TOOK YOUR ADVICE TO HEART, AGAIN ANALYZING THE DATA WILL BE DONE IN A COLLECTIVE BRAIN DUMP INCLUDING PEOPLE FROM YOUR COMMITTEE VERY SOON. WE FEEL PRETTY GOOD ABOUT THE REAGENTS. WE MEASURED OFF-TARGET EFFECTS IN CELLS WITH NO KRAS, WE'VE GOT SOME CONTROL AND SOME FEELING THE QUALITY OF THE SRNAS IS HIGH BUT WE RECOGNIZE POTENTIAL PITFALLS. WE'LL HAVE A PRELIMINARY DATA SET THIS YEAR AND HOPEFULLY YOU CAN COME IN AND KICK OUR BUTTS. >> OKAY, GREAT. YES? >> SO A COMMENT AND QUESTION. THE COMMENT IS THAT IN TERMS OF THE PERTURBOGEN PROJECT, THE NIH ROAD MAP LINKS PROJECT IS DOING THAT FOR OTHER CELL LINES, THERE MIGHT BE A USEFUL COLLABORATION THERE SINCE THEY ARE DEVELOPING THE EXPERIMENTAL AND COMPUTATIONAL INFRASTRUCTURE TO PERTURB SYSTEMS BROADLY, THAT MIGHT BE WORTH AT LEAST THINKING ABOUT PLUGGING INTO. THE QUESTION IS THE -- SO I THINK ONE OF THE INTERESTING THINGS THAT'S COME OUT OF THIS IS THE IDENTIFICATION OF THE NUMBER OF KNOWLEDGE GAPS YOU'RE PARTLY FILLING AT FREDERICK BUT IT WOULD SEEM THAT WOULD ALSO THE COMMUNITY IS PAYING ATTENTION, ARE PEOPLE ACTUALLY TAKING THE QUESTIONS THAT YOU'RE ASKING AND USING THOSE TO FOCUS RO-1 RESEARCH ON? >> FRANK, DO YOU WANT TO TAKE THAT FIRST? >> I DON'T KNOW IF THAT'S TRUE SPECIFICALLY. IT'S TRUE TO SAY THAT THE RAS COMMUNITY IS NOW RETHINKING A LOT OF THE ISSUES FROM THE PAST ABOUT, FOR EXAMPLE, DIFFERENT ALLELES HAVING DIFFERENT BIOLOGICAL FUNCTIONS, THINGS WE BROUGHT TO PEOPLE'S ATTENTION. WE'VE HAD AN IMPACT ON THE WHOLE GENERAL FIELD IN A SORT OF SOFT WAY BUT I COULDN'T TELL YOU THAT THE RO-1 APPLICATIONS HAVE BEEN AFFECTED BY ANYTHING WE'VE DONE YET. WE HAVE LOTS OF COLLABORATORS PROCEEDING PROTEINS TO LEVERAGE THEIR GRANTS. MAYBE ED WILL TOUCH ON THAT. >> JUST TO THE EXTENT THAT IT'S POSSIBLE TO EASILY GET THE INFORMATION, KEEPING TRACK OF HOW THAT IMPACTS THE RO-1 COMMUNITY WOULD BE A MEASURABLE AND POSITIVE OUTCOME OF THE PROGRAM. >> GREAT THOUGHT. >> WHAT'S REALLY GREAT ABOUT THIS, I THINK, IS YOU HAVE A CHANCE TO LOOK BACK AT FUNDAMENTALS, WHAT MAYBE 20 OR 30 YEARS AGO THE COMMUNITY MISSED. OKAY. I THINK I SEE THAT ORIENTATION, I THINK IT'S FABULOUS. BUT THERE IS ONE BECAUSE HAROLD JUST BROUGHT UP CRISPR, AND I HAD COME PREPARED WITH THE FOLLOWING THOUGHT. WE ARE VERY, VERY FOND OF SAYING FOR A PARTICULAR EVEN CELL LINE THAT IT'S RAS DRIVEN, BUT VERY FREQUENTLY THIS IS WITH, HOW SHALL I SAY, EVIDENCE FAR FROM THE ACTUALITY. IT'S PROBABLY TRUE, BUT IT SEEMS TO ME THAT YOU'RE NOW IN A POSITION HAVING MADE ALL THESE LINES THAT WITH ONE CRISPR CONSTRUCT YOU COULD TEST THIS FOR ANY, YOU KNOW, SMALL EXPERIMENT, REALLY, AT THAT POINT. >> YOU'RE TALKING ABOUT ZERO? >> WE'RE AWARE OF THAT. WE'RE DEVELOPING CRISPR AGENTS, 4A VERSUS 4B TO ASK THAT QUESTION, BUT THIS PROJECT STARTED BEFORE CRISPR BECAME MAINSTREAM. >> I TOTALLY GET IT. >> THE POINT IS WHEN A TOOL LIKE CRISPR COMES ALONG, AT LEAST MY INTUITION, OH, GOODNESS, THERE'S A BETTER WAY TO GET WHERE I'M GOING BY THIS PATH, AND FOR THIS PARTICULAR ISSUE, ALL OF THESE CELL LINES HAVE A MUTANT RAS, THANKS TO THE SEQUENCING, YOU KNOW WHICH ONE IS DEFECTIVE, OKAY? SO THE QUESTION IS, OR ACTIVATOR, WHATEVER YOU WANT TO CALL IT, MUTANT, OKAY? SO THE THING TO DO, I THINK, IS OUT, THE PARTICULAR ONE, AND KNOCK OUT IS EASY BECAUSE IT'S THE SAME REAGENT OVER AND OVER AGAIN. AND IT WOULD BE VERY INTERESTING TO BE ABLE TO TAKE YOUR -- ALL THE CELLS YOU CHARACTERIZED AND FINDING THOSE THAT DON'T GROW, IF YOU DO THAT. >> PROJECT ZERO, THE QUESTION THAT WAS RAISED AT THE BEGINNING, FRANK WAS ALREADY ON YOUR WAVELENGTH, IT'S IMPORTANT TO KNOW A CELL LINE WITH A RAS MUTATION IS ACTUALLY RAS DRIVEN. >> THE TOOL IS AT HADN'T. >> ANOTHER ASPECT, THERE ARE CELL LINES THAT ARE RAS DEPENDENT IN 3D BUT NOT 2D. SO WE'VE ALSO DISCUSSED -- >> WE CAN DO THAT TOO. >> WE HAVE THAT. >> NOT TO MINIMIZE CRISPR BUT YOU COULD ARGUE THAT A KNOCKDOWN WITH S RNA MORE CLOSELY IS WHAT A DRUG MIGHT DO. >> WITH ALL DUE RESPECT, I'M A GENETICIST. THE RISE OF CRISPR REALLY MADE ME SLEEP BETTER, OKAY? >> WHY USE AN IMMUNOLOGIST AT CITY OF HOPE, SHE CAN IDENTIFY ANTIBODIES THAT ALLOWS THEM TO PENETRATE CELLS, IN VITRO AND ANIMAL MODELS, YOU MIGHT WANT TO TALK TO HER ABOUT TARGETING RAS. >> VERY INTERESTING. >> IF THE CELLS ARE K RAS DRIVEN YOU WON'T RECOVER CRISPR CLONES, IT WOULD HAVE UNDERGONE REARRANGEMENT. TO DO THAT EXPERIMENT, A GREAT EXPERIMENT, ONE MIGHT HAVE HAVE TO FIRST ENGINEER FOR EXAMPLE MUTANT KRAS AND ENDOGENOUS LOCUS. >> THIS WAS TRUE FOR MAKING ALL THE LETHAL MUTANTS IN THESE TOO. I KNEW THAT. >> OKAY. >> PART OF THE DESIGN. >> OKAY. SO THEN THE LAST COUPLE OF COMPONENTS BEFORE I GIVE SUMMARY RECOMMENDATIONS WERE AROUND THE BIOINFORMATICS, IT WAS CLEAR THERE NEEDS TO BE NOT ONLY DATA REPOSITORIES BUT ANALYTICAL MECHANISMS TO INTEGRATE DATA THAT'S GENERATED AS PART OF THE PROGRAM WITH EXISTING DATABASES QUESTIONS SO FOR EXAMPLE FRANK ALREADY SHOWED THE INTERESTING QUESTION OF THE RATIO OF KRAS 4A AND 4B WHICH WAS DOABLE WITH TCGA DATA, THAT WAS AN OBVIOUS. IN ADDITION TO THE STRUCTURES OF MUTANT KRAS, FOR EXAMPLE, HAVING AN INITIAL AN ANALYSIS OF RAS-OLOGY, IF WE LOOK AT 4A AND 4B, MUTANT VERSUS WILDTYPE, THERE'S A SERIES SERIES OF QUESTIONS. THERE WILL BE INTEREST IN THE FIELD OF ANALYTICAL READOUT OF RAS BIOLOGY THAT DRAWS FROM THE TCGA DATA. THEN THERE WAS SOME DISCUSSION AGAIN, SO MOST OF THE MEETING WAS ABOUT THE SCIENTIFIC CONTENT BUT THERE WAS A FAIR BIT OF DISCUSSION AS WELL ABOUT THE INITIAL EFFORTS AROUND CONNECTION WITH THE EXTERNAL COMMUNITY AND SO THERE'S A RESOURCE CALLED RAS CENTRAL TO FACILITATE AND ENCOURAGE COLLABORATIONS, VARIOUS COMPONENTS THAT ARE HAPPENING OR ABOUT TO START, AND THEN THERE WAS AN INTERESTING SUGGESTION, FOR EXAMPLE CONCERNING THE PROGRAM COMMITTEE AT AACR, SINCE FRANK WAS PRESIDENT AND MAY HAVE CLOUT, MAYBE A MINI SYMPOSIUM. SO IN TERMS OF ONE WAY OF HAVING VISIBILITY OF WHAT THE RAS PROGRAM IS DOING AND THE ENTIRE BASIC CANCER REACH SEARCH COMMUNITY COMING TOGETHER EVERY YEAR, PERHAPS MAYBE NOT THIS YEAR BUT NEXT YEAR WHEN THERE'S REAL MEAT TO SHOW THAT COULD BE ONE SORT OF NICE INTERFACE WHERE SCHOLARSHIP COULD BE FEATURED BUT ALSO IT'S A WAY OF RAISING AWARENESS AND BROADENING THE POSSIBILITIES FOR A COLLABORATION, ET CETERA. >> LEVI? >> YES. >> SO AROUND THE BIOINFORMATICS CHALLENGES THAT YOU WERE TALKING ABOUT, IT JUST OCCURRED TO ME IF ONE COULD DEVELOP A SORT OF WELL-DEFINED PROBLEM CHALLENGE, DOING SOMETHING LIKE DREAM CHALLENGE, IT DOESN'T HAVE TO BE DREAM CHALLENGE, IT COULD BE ANOTHER KIND OF CHALLENGE, BUT HAVING A CALL FOR THAT KIND OF CHALLENGE, WHICH PEOPLE WOULD PARTICIPATE IN, WOULD GET YOU A VERY, VERY BROUGHT -- I MEAN, IT'S AMAZING WHAT THINGSME IN FROM THE CHALLENGES, FROM PEOPLE YOU WOULD NEVER EXPECT, THAT ARE NOT PART OF THE TRADITIONAL CANCER INFORMATICS OR CANCER COMPUTATIONAL BIOLOGY COMMUNITY. AND SO IT'S A WAY OF REACHING A REALLY BROAD AUDIENCE, BUT THE CHALLENGE OF COURSE HAS TO BE SCIENTIFICALLY WELL-DEFINED AND THE DATA HAS TO BE MADE AVAILABLE, OBVIOUSLY. BUT IT'S JUST AN IDEA. >> AN I'LL APPROACH THE THEME THAT JOE RAISED EARLIER, AS ONE GOES THROUGH PROJECTS AND REVIEWS THEM, ONE SEES WHERE THERE ARE SPECIFIC PERSONNEL NEEDS OR GAPS OR WHAT HAVE YOU, EVEN THIS WHOLE ACTIVITY, FOR EXAMPLE RUNNING A CHALLENGE SUCH AS THAT, THERE WOULD NEED TO BE SOMEBODY WHO IS GOING TO CHAMPION THAT AND MAYBE DIFFERENT THAN THE STRUCTURAL BIOLOGIST GENERATING DATA, SO ONE THINKS SHOULD SUCH A PERSON LIVE AT FREDERICK OR IS THERE ANOTHER PLACE IN WHICH THAT ACTIVITY HAPPENS WITH A COLLABORATION. COMING UP WITH WAYS IN WHICH THE COMMUNITY NOW SAYS HERE IS A DATA SET AROUND THAT TOUCHES RAS IN SOME IMPORTANT WAY, THERE'S A QUESTION, SEVERAL GROUPS COMPETE AND IF THEY GET CLOSEST TO AN ANSWER OR NEW IDEA OR NEW ALGORITHM THERE'S SOME REWARD. THAT'S OBVIOUSLY CREATED EXCITEMENT IN OTHER AREAS. >> THE ADMINISTRATION IS FOND OF PRIZES, AND WE'RE THINKING ABOUT PRIZE COMPETITIONS OF VARIOUS KINDS. >> YES. >> IN ADDITION TO GETTING PUBLISHED. >> RIGHT, EXACTLY. KEN? >> GIVEN THAT WE'RE SIX MONTHS AWAY, THE RATE AT WHICH DATA IS BEING GENERATED, HAVING A MEETING THIS COMING ACR IS A GOOD IDEA, ESPECIALLY TALKING ABOUT ADVERTISEMENT, I WOULD THINK THERE WOULD BE ENOUGH DATA TO HAVE A MEETING, AND NOT WAIT 18 MONTHS. >> ONE OF THE QUESTIONS SO OFTEN, EVEN BY LATE JULY, WHEN THIS WAS HAPPENING, THE ACR, THE PROGRAM IS LARGELY FORMED. SO THERE WAS A QUESTION ABOUT WHETHER OR NOT THE TEMPO OF THAT PARTICULAR MEETING WAS GOING TO LEND ITSELF TO 2015. I DON'T KNOW IF YOU LOOKED INTO THIS, FRANK. >> YEAH, THIS MAY BE TOUGH TO ET ON THE AGENDA IN A FORMAL WAY. ANYBODY WITH AN ABSTRACT OF THE MEETING WITH THE RECORD RAS IN IT, AND HAVE AN ORGANIZED DISCUSSION AROUND TOPICS RELEVANT TO RAS. WE'VE DONE THAT, THIS HAS BEEN ORGANIZED BY STEVE AND HIS GROUP, HAVING INTERESTING AND INTERACTIVE. WE'LL DO THAT AGAIN AT THE NEXT ANNUAL MEETING, IT'S SORT OF A TRADITION. THAT'S A GOOD VENUE TO PUT OUT LINKS AND INFORMATION ABOUT THE PROGRAM. >> THE OTHER WAY, MY UNDERSTANDING IS THAT NCI HAS ALWAYS A SESSION, AN NCI-SPONSORED SESSION AT ACR WITH INTERNAL VETTING OF WHAT NCI IS GOING TO DO AT THAT SESSION. IF NOT THIS YEAR, AT SOME POINT THAT COULD BE ANOTHER AVENUE TO RAISE VISIBILITY FOR THIS PROJECT POTENTIALLY. >> OKAY. SO THEN WE JUST REITERATED WHAT WE'VE ALREADY MENTIONED IN SEVERAL FORMS HERE BUT JUST THE ROLE OF FNLCR TO GENERATE AND MAKE AVAILABILITY HIGH QUALITY VECTORS AND CELL LINES, COMPONENTS THAT ENABLE ALL OF THAT, AND HOW WILL IN THE FUTURE AS THOSE -- ASSUMING SUCCESS IN SOME AREAS, HOW ABOUT THE REAGENT REQUEST BE VETTED AND DISTRIBUTED. ANTICIPATING THIS NOW SO THERE ARE NO WEBSITE DEBACLES WHEN THE DEMAND RISES FROM THE COMMUNITY, THAT THAT CAN BE MET READILY. EVEN HAVING SOME GUIDANCE FROM THE COMMUNITY ABOUT WHERE DO WE THINK THE DEMANDS WILL BE GREATEST AND WHEN, WHAT NEEDS TO BE IN PLACE MORE OR LESS AS SOON AS THE PURIFIED PROTEINS OR WHAT HAVE YOU BECOME AVAILABLE TO SCALE THEM UP, AND MAKE THEM -- QC THEM AND MAKE IT SO THE ENTIRE COMMUNITY CAN HAVE THEM. BRIEFLY, DAVE HEIMBROOK POINTED OUT A FACE-TO-FACE MEETING BETWEEN FNLCR AND PHARMA COMPANIES AROUND THE RAS PROGRAM, AND I GUESS WAS THERE A FOLLOW-UP MEETING IN AUGUST? THAT WAS PLANNED. I GUESS IT HAPPENED. I HAVEN'T HEARD. >> A TELECONFERENCE, NOT FACE TO FACE. >> GREAT. AND THE IDEA WAS TO CONSIDER A CONSORTIA BETWEEN FNLCA AND PHARMA IN THE GENERAL OR PARTICULAR, AND ACTUALLY I HAVEN'T MENTIONED THIS EXPRESSLY YET THERE ARE PLANS TO LAUNCH A POST DOCTORAL FELLOW PROGRAM IN FNLCR AND THAT COULD BE ONE WAY IN WHICH THAT CONSORTIUM COMES TO LIFE, THE GLUE FOR SOMETHING LIKE THAT. IT WAS POINTED OUT THAT THERE ARE FROM TIME TO TIME REGULATIONS IN THE GOVERNMENT AND BOUNDARIES THAT CAN PROVIDE -- PRESENT OBSTACLES. IT SEEMS THE CONTRACTOR CRADA MECHANISM COULD HELP ALLEVIATE THOSE BUT IT WILL BE NECESSARY TO ANTICIPATE THOSE KINDS OF CONSTRAINTS AND ARE THERE, YOU KNOW, NCI CONSORTIA ACADEMIA ASPECTS, MAKING THE PROGRAM MORE BROADLY AVAILABLE, NOT ONLY INCREASE KNOWLEDGE BUT ANOTHER WAY OF SHOWING HOW FNLCR IS DOING THINGS NEEDED IN THE COMMUNITY BUT ONLY A NATIONAL LABORATORY COULD HANDLE. SO I'M NOW DOWN TO I THINK THREE MORE SLIDES, AND SO IN THE END, THERE'S A WORKING GROUP RECOMMENDATION, WE'RE ESSENTIALLY ENDORSING SEVERAL AROUND THE OUTREACH FRANK ALREADY PRESENTED, THE FNLCR INDUSTRY CONSORTIUM, POSTDOCTORAL FELLOW PROGRAM WHICH IS UNDERWAY, I HAVE E-MAILS IN MY IN-BOX. AM I RUNNING IT OR SOMETHING? IT'S COMING MY WAY, SOMETHING I HAVE TO REVIEW SOMEHOW. DEVELOPING THE RAS CENTRAL COMMUNITY, ROLLING RAS SCIENTIFIC CONFERENCES AT FREDERICK AND EXISTING MEETINGS, AND SOME VERY EXCITING IDEAS AROUND WORKSHP ON IMMUNOTHERAPY, HOW CAN ONE SEEK AND CAPTURE WAYS TO LEVERAGE NEW IMMUNOTHERAPEUTIC AS EXPECTS AROUND RAS-DRIVEN CANCERS. JUST, AGAIN, THIS IS WHY WE HAVE SUMMARIZED EVERYTHING I SAID, IN TERMS OF IMMEDIATE NEAR-TERM OBJECTIVES THE COMMUNITY COULD ACHIEVE AND PUT OUT THERE, EARLY SIGNS OF SUCCESS, CRYSTAL STRUCTURES OF THE CANCER-ASSOCIATED WAS MUTANTS AND A MEANS TO HAVE REAGENTS AVAILABLE WOULD BE A GREAT EARLY SUCCESS, KIND MUCH A PERFECT FREDERICK-LIKE ACTIVITY. AND AS WE MENTIONED, THE RAS-CENTRIC ANALYSIS, COMPLETED IN THE NEXT YEAR OR SO, GIVE OR POTENTIAL DELIVERABLES IN A CERTAIN AMOUNT OF TIME. IF THOSE WERE OUT THERE, THERE WOULD BE A SENSE THE PRS ARE GENERATING USEFUL REAGENTSES, AGENTS, IT'S OFF TO A GREAT START. THE POST DOCTORAL PROGRAM WILL BE LAUNCHED. AND OTHER THINGS THAT ARE PRELIMINARY, INTENSIVE EFFORTS AROUND THE PROTEOMIC STUDIES TO MAKE SURE RESOURCE IS USEFUL AND RAS IMMUNOTHERAPY WAS BROUGHT UP BY A COMMITTEE MEMBER, WHETHER THEY COULD BE ACTIVATED TO KILL RAS TUMOR CELLS, THAT COULD BE A NICE NOVEL. IT HASN'T STARTED BUT THAT WAS A SUGGESTION, AND THE WORKSHOP, THIS MAY GET TACKLED THERE. THE FINAL POINT, BRINGING ADDITIONAL INTELLECTUAL LEADERSHIP TO FNLCR IN THE AREAS IDENTIFIED, THE STRUCTURAL BIOLOGIST COMPONENT, A BIG STEP HAS BEEN TAKEN IN THAT DIRECTION. IN TERMS OF PROTEOMICS AND SIGNALING AND THE PERTURBOGE NEXT, N, THERE'S A LOT GOING ON. SOME COMES PERIODALLY TO FREDERICK, MAKING SURE, AND HAVING POSTDOCS WHO SPEND PART OF THEIR TIME HERE AND PART OF THEIR TIME WITH A MENTOR OR RECRUITING THE ACTUAL EXPERTS THEMSELVES, AND A PART-TIME MODEL SUCH AS WHAT FRANK IS DOING, I DON'T KNOW IF THAT COULD BE AS EXTENSIVE WITH AN APARTMENT. AND THEN IN GENERAL, HAVING SORT OF THE GANT CHART TO SEE WHERE THINGS ARE AND FINALLY PLANS FOR THE FUTURE WORKING GROUP MEETINGS, A CONFERENCE CALL THAT'S NOW BEEN SET UP, IT'S HAPPENING OCTOBER 31, THE WORKING GROUP ITSELF WILL MEET DURING ACR IN APRIL. THAT'S BASICALLY WHERE WE ARE. IN SUMMARY THERE WAS A LOT PRESENTED, A LOT GOING ON. OF COURSE MANY COMPONENTS ARE STILL VERY EARLY, AND IT'S BEEN JUST REALIZING WHAT THE CHALLENGES ARE AND GETTING THINGS TO WORK BUT THERE'S A LOT OF ENTHUSIASM ABOUT THE EFFORTS THAT ARE GOING, THE SCIENCE. FRANK HAD GREAT LEADERSHIP AROUND VERY EXCITING SCIENTIFIC OBJECTIVES, SO I THINK THERE IS THE SPIRITS THAT WERE HIGH AMONG THE WORKING GROUP FROM THIS INITIAL MEETING OVERALL. YES? >> LEVI, IT LOOKS LIKE THE WORKING GROUP GAVE FRANK A LOT OF GOOD ADVICE. WHO IS ON THE WORKING GROUP? HOW BIG? >> I SHOULD HAVE MADE A SLIDE. SARAH, DO YOU HAVE -- GIDEON BOL,A, TUBE SON, SCHREIBER, JAFFEE, MIKE WHITE, NOLAN. >> HE'S ON THE COMMITTEE, HE WASN'T THERE. [OFF MIC] >> OKAY. >> THAT'S GOOD. MAYBE YOU CAN SEND THAT TO US AT SOME POINT. >> SURE. ARE THERE ANY AREAS IN THE WORKING GROUP OR AREAS OF RESEARCH THAT YOU WOULD LIKE TO ADD SOME STRENGTH ON? >> I THOUGHT CHEMICAL INFORMATICS WAS A GOOD SUGGESTION. >> I'M NOT VOLUNTEERING, BY THE WAY. >> POTENTIALLY SO IN AS MUCH AS ONCE THE CLARITY HAPPENS AROUND WHAT IS GOING TO HAPPEN WITH PROTEOMICS AND SIBLING -- WE HAD HAD MIKE WHITE AND THAT'S GREAT BUT MAYBE THERE SHOULD BE A PROTEOMICS PERSON THAT COULD ADVISE IF THERE ARE OTHER TECHNOLOGIES AROUND PROTEIN MEMBRANE, A RELATIVELY RARIFIED AREA IN TERMS OF GETTING ENOUGH CELLS TO KNOW THAT YOU'RE GOING DEEP INTO A MEMBRANE COMPONENT, MAYBE THAT'S ONE TO CONSIDER BUT WE MAY GIVE OURSELVES A CHANCE TO BREATHE AND SEE HOW SOME OF THE PROJECTS TAKE SHAPE AND THEN ADD APPROPRIATE EXPERTISE AS NEEDED. [OFF MIC] >> OH, MATT, THAT'S RIGHT, YES. >> SO YOU GUYS HAVE BEEN TALKING ABOUT THE AACR ANNUAL MEETING, AS A PLACE TO PUSH THIS, BUT THE AACR RUNS THESE TOPICAL MEETINGS, AND YOU'VE CONVINCED ME TODAY THAT THERE'S ENOUGH MEAT ALREADY OUT THERE FOR TWO OR THREE-DAY MEETING ON THIS TOPIC THAT WOULD BE SCIENTIFICALLY INTERESTING AND PROBABLY BRING IN NEW P OSTDOCS AND SO ON TO THE FIELD. I WOULD WANT TO PUT SOMETHING LIKE THAT ON THE QUEUE PRETTY QUICK. >> A GOOD POINT. GETTING THAT CONVERSATION STARTED MAY NOT HAPPEN FOR A COUPLE YEARS. THAT WOULD BE PERFECT. BY THAT TIME THERE'S A LOT OF RESULTS FROM THE RAS PROGRAM HERE AND THE COMMUNITY -- YOU KNOW WHO YOUR AUDIENCE IS GOING TO BE. >> OR THE RAS MEETING RUN BY THE ACR IN ORLANDO, WAS IT THIS YEAR? YEAH, THAT WAS ONE OF THE BETTER -- WELL-ATTENDED MEETINGS. WE COULD TRY TO GET THAT REPRODUCED. >> MORE REGULAR. YEAH. >> GREAT. >> I WANTED TO, YOU KNOW, PUT A LITTLE BIT OF EMPHASIS ON THE IDEA OF GETTING BIOINFORMATICS FOCUSED ON RAS, EXTRACTING DATA FROM OTHER PLACES. THAT'S A REALLY GOOD IDEA, BUT YOU WANT TO DO IT IN A WAY WHICH OTHER PEOPLE CAN UNDERSTAND. AND SO I THINK THAT'S A TASK FOR WHICH YOU COULD PROBABLY RECRUIT SOMEONE SOONER RATHER THAN LATER. IF YOU DO IT WELL, PEOPLE WILL COME TO THERE, LOOKING FOR INFORMATION, WHICH IS WHAT YOU WANT. >> HAVE YOU -- HAS GADDY SIGNED UP? >> GADDY WAS THE ORIGINAL POINT OF CONTACT. IF THERE NEEDS TO BE AN INTERFACING AND INTERFACE AND DO IT THEMSELVES, THAT MAY BE A DIFFERENT SKILL SET THAN THE ALGORITHMS THEMSELVES THAT GADDY WOULD RUN. >> LIKE YOU DECIDED AN IN-HOUSE CRYSTALLOGRAPHER, WHICH I COMPLETELY AGREE, I THINK FOR THIS THE SAME THING IS TRUE. THAT A YOUNG PERSON, STARTING OUT IN HIS CAREER, TO GET ON THERE, TO THINK ABOUT THIS, SOMEWHAT SOPHISTICATED ENOUGH TO KNOW WHICH METHODS, HE OR SHE COULD BE A DATA ANALYST FOR YOU. I THINK THAT WOULD BE REALLY GOOD, BECAUSE THERE'S A HUGE AMOUNT OF CONFUSION, WHICH YOU'RE GOING TO CLEAR UP, AND SO, YOU KNOW, YOU'LL HAVE, I HOPE, GOLD STANDARD COMPARISONS, YOU KNOW, WHICH ARE MORE OR LESS ISOGENIC ABOUT WHAT YOU'RE GOING TO GENERATE A LOT OF INFORMATION, BUT CONNECTING THAT TO THE INFORMATION THAT ALREADY EXISTS IS GOING TO BE IMPORTANT AND I THINK IT WOULD MAKE SENSE TO START SOONER RATHER THAN LATER WITH THAT. >> I WASN'T GOING TO SAY ANYTHING, BUT IT'S A TIME OF RAPID CHANGE IN BIOINFORMATICS, THERE MAY BE OPPORTUNITY HERE. WHAT YOU MIGHT CONSIDER DOING IS HAVING DAVE'S SYMPOSIUM OR SOMETHING LIKE THIS PRELIMINARY TO SOMETHING, YOU KNOW, IT MAY LEAD TO SOMETHING LIKE JILL SAID WHERE YOU BRING SORT OF WHAT'S GOING ON IN BIOINFORMATICS, BRING THE PEOPLE WHO HAVE THE PROBLEMS AND SEE SOMETHING INTERESTING ARISE, IN CONJUNCTION TO WHAT YOU WERE SAYING. >> THAT'S A VERY GOOD SUGGESTION. EARLY ON IN THE TCGA, THEY WOULD HAVE WHAT THEY CALLED ANALYSIS JAMBOREES, YOU WOULD BRING THE PEOPLE WHO WOULD BE DOING THE WORK, SO THE DATA WAS JUST STARTING TO COME OUT, PEOPLE WOULD GET A LINE, DATA ARCHITECTURE, SO WHEN THE ANALYSIS HAPPENED IT WAS SORT OF STREAMLINED AND NORMALIZED ACROSS ALL THE GROUPS. >> RIGHT. AS PART OF THAT, YOU KNOW, THERE'S MORE OF A WAY THE DATA, WHEN YOU CREATE RESOURCES THESE DAYS, YOU MAKE THEM AVAILABLE FOR OTHER MACHINE TO MACHINE INTERACTION SO PEOPLE DON'T HAVE TO GO TO DOWNLOAD THE DATA, HAVING A ONE-DAY WORKSHOP MIGHT CREATE A FRAMEWORK FOR PEOPLE TO START THINKING ABOUT THINGS LIKE THAT. >> I THINK OBVIOUSLY I AGREE, BUT I THINK WHAT'S REALLY IMPORTANT HERE IS TO MAKE THE OUTREACH IN THAT AREA AS BROAD AS POSSIBLE, NOT JUST FOCUSED ON THE PEOPLE WHO HAVE BEEN DOING ANALYSIS FOR TCGA. AGAIN, THERE ARE ALL THESE POCKETS OF VERY, VERY TALENTED PEOPLE WHO JUST NEED TO BE CHALLENGED IN THE RIGHT WAY, AND SO IT PAYS TO TRY AND MAKE THIS -- THAT'S THE ADVANTAGE OF SOMETHING LIKE A COMPETITION, BECAUSE PEOPLE COME OUT OF THE WOOD WORK, LIKE THEY DID WITH DREAM AND I THINK THE WORKSHOP IS A GOOD IDEA. BOB IS RIGHT, THINKING ABOUT HOW YOU'RE GOING TO USES THE DATA BEFORE YOU ORGANIZE THE DATA, SO IT'S ACTUALLY DONE IN A WAY THAT IS FUNCTIONAL. >> YOU NEED TO HAVE SOMEBODY HERE WHO IS GOING TO BE RESPONSIBLE FOR IT. >> YEAH, YEAH, YEAH. >> I AGREE WITH ALL THAT. >> WE DON'T DISAGREE. THE COMPETITION, YOU KNOW, IF ONE WANTED, ONE COULD RUN THAT THROUGH STEPHEN AGAIN. I MEAN, HE HAS THIS WHOLE THING ALREADY THAT HE DOES, BUT ONE COULD ALSO HAVE IT MANAGED RIGHT OUT OF FREDERICK. MAYBE THAT'S THE RIGHT WAIT TO DO IT, I DON'T KNOW, ESPECIALLY IF YOU CAN -- I THINK THE ADVANTAGE IS IF YOU CAN PROVIDE BOTH THE DATA AND THE COMPUTATIONAL RESOURCE TO ANALYZE THE DATA HERE AT COMING IN AND ALL THEIR PIPELINES ARE RUNNING IN THE SAME PLACE, THEY ARE USING THE SAM DATA STORE, PIPELINES ARE SAVED IN A REASONABLE WAY, THAT'S POWERFUL IN TERMS OF SHARING. >> ONE WAY IN WHICH IN THE INITIAL MEETING WE DIDN'T VIEW THE PRESENTATION WAS SORT OF THROUGH THE LENS OF WHAT KIND OF PERSONNEL NEEDS -- WHAT PRIORITIZATIONS OF PERSONNEL DO WE NEED TO BRING IN SO EACH OF THESE THINGS HAPPEN. IF THE RAS STRUCTURE MUTANTS AND COMPUTATIONAL BIOLOGY, RAS PROJECTS WITH THE FIRST THING, WHAT DOES THAT MEAN ABOUT PERSONNEL NOT HERE. COMING OUT OF THIS CONVERSATION, AN EARLY RECRUIT WITH THE RIGHT PHENOTYPE, WE COULD ENABLE THAT AND UNDERSTAND HOW IT NEEDS TO LOOK EXTERNALALLY AND HAVING SOMEONE LIKE THAT HERE MIGHT BE SOONER RATHER THAN LATER KIND OF HIGHER, AND WE HADN'T DRILLED DOWN ON THAT BUT IT'S A GOOD SUGGESTION. >> ONE LAST COMMENT BEFORE LUNCH, KEN? >> THIS MAY SOUND LIKE A SILLY YES, GIVEN THE STRUCTURE OF THE WAY FREDERICK IS ADMINISTERED, DOES THIS PROJECT NEED AN NCI SPONSOR OR IS THAT DR. VARMUS? ON PAPER ARE YOU THE OFFICIAL SPONSOR? >> WE'VE BEEN -- SEVERAL HAVE BEEN GOING UP ONCE EVERY COUPLE MONTHS, UP TO FREDERICK AND HEARING FROM FRANK AND HEARING ABOUT VARIOUS PROJECTS. THE SPONSOR NOTION IS FABRICATED. >> THE OTHER QUESTION, DO YOU FEEL THAT THE FREDERICK -- THIS PROJECT, THE RAS PROJECT, IS WELL INTEGRATED INTO THE REST OF THE INTRAMURAL PROGRAM OF THE NCI? IS THERE AN OFFICIAL WAY THAT YOU'RE DOING THAT OR NOT TRYING TO DO THAT? >> WE'RE NOT TRYING TO DO THAT. WE WOULD LIKE IT TO BE, YOU HE NO, A CENTRAL FEATURE OF THE FREDERICK CAMPUS, PEOPLE INTERACTING AS THEY DO ACROSS THE -- YOU KNOW, WHATEVER LIMITED DIVIDE OCCURS BETWEEN THE FFRDC AND INTRAMURAL PROGRAM. IT HAS A CENTRALITY WHEN YOU GO UP THERE, THE TERM "RAS" IS ALL OVER THE PLACE, NOT JUST AS PART OF RASCAL BUT ON IT'S OWN AND IT'S CLEAR THIS IS THE CENTER OF THE PROGRAM, BUT DAVE COULD COMMENT ON THAT.>> I MEANT THE NEXT TO THE LAST >> OKAY, THANK YOU. FIRST OF ALL, I WANT TO THANK LEVI AND COLLEAGUES FOR DOING AN EXEMPLARY JOB. ONE OTHER TOPIC THAT JUST OCCURRED TO ME, AS I WAS THINKING THROUGH WHAT THE FACE OF THIS PROJECT WILL BE LIKE TO THE EXTERNAL COMMUNITY, THE PROPOSAL YOU MADE, FRANK, TO DO THERAPEUTIC CLINICAL TRIAL ON BLADDER CANCER BUT HRAS MUTATIONS. HAS THAT GONE AWAY? >> WELL, ACTUALLY JIM FAGAN, FORMER COLLEAGUE AT SLOAN-KETTERING. >> FRIEND. >> I GET CONFUSED ALL THE TIME. HRAS, BUT IT MIGHT BE SWEPT IN -- MIGHT THE SWEEP IN BLADDER CANCER AND OTHER HRAS BUT I WANTS TO DO THYROID, PRE-SELECTED HRAS MUTATIONS, WORKING WITH I THINK JANSON IS THE ONLY COMPANY THAT STILL HAS A TRANSFERASE COMPOUND IN THE CLINIC, AND THEY SEEM WILLING TO GIVE HIM -- TO LET HIM DO THE TRIALS. I'M NOT SURE IT'S LOCKED DOWN BUT HE PRESENTED ONLINE, OUR WEBSITE, HIS DESIGN FOR A TRIAL AROUND HRAS CANCER. >> ARE THERE ENOUGH PATIENTS? >> I DON'T KNOW. IT'S AT LEAST 5%. >> IT'S STILL ON THE TABLE? >> IT'S ON THE TABLE, HE'S ACTIVELY PUSHING IT. YEAH. >> OKAY. SO LET'S BREAK FOR LUNCH. GRAB YOUR -- I'M SORRY? OH, YEAH. SO GIVEN THAT WE'RE GOING TO LOSE OUR QUORUM AROUND 4:00, ONE OF THE THINGS WE'RE GOING TO TRY TO DO IS ACCELERATE THE AFTERNOON'S AGENDA A BIT, AND TRY TO BRING IT TO A CONCLUSION AT FOUR. WE'RE GOING TO HAVE SOME OFFLINE DISCUSSIONS DURING LINE, IF YOU WOULD GRAB LUNCH AND COME. OH, I'M SUPPOSED TO READ THIS. OKAY. DURING LUNCH TOM VOLLBERG REQUESTED AN ADMINISTRATIVE SESSION IN THE ROOM. FOR ALL OTHERS WE ASK YOU LEAVE. PLEASE ENJOY YOUR LUNCH. THE MEETING WILL RESUME AT 1:10. ENGAGING THE SCIENTIFIC COMMUNITY AND DISCUSSING OTHER POSSIBLE NATIONAL LABORATORY PRO JETHS. BUT ED. >> THANK YOU. SO TWO WAYS TO THINK ABOUT INTERACTING WITH THE COMMUNITY. THE RESEARCH COMMUNITY, FROM THE PERSPECTIVE OF THIS GROUP. ONE IS HOW THE -- HOW WE THINK ABOUT THE NEXT INITIATIVES. I RECOGNIZE THE TRANSITION PIECE BETWEEN MORNING AND AFTERNOON, SO THAT JUXTAPOSITION IS NOT QUITE SURPRISING. FIRST SLIDE HERE EASILY BEGINS -- OUTLINES MANY OF THE THINGS YOU'VE HEARD. I TRIED TO COMPILE IN ONE SLIDE -- YOU CAN LEAVE THE LIGHTS ON. ALL THE SLIDES WILL BE EASY. I HOPE. ALL THE EXAMPLES HOW THE RAS PROGRAM HAS BEEN INTERACTING WITH THE COMMUNITY AND SAY WHAT MIGHT HAPPEN IN THE NEXT LITTLE BIT. YOU HEARD ABOUT THE OBSERVATION THAT THE RAS HAS BEEN GENERATING REAGENTS, THOSE ARE NOW BEING MADE AVAILABLE. THERE IS A NUMBER OF DNA CLONES FROM RAS PATHWAY PROTEINS THAT ARE ALREADY AVAILABLE TO THE COMMUNITY IN A COMPLETELY ORGANIZED SET PUT TOGETHER IN EXACT HEY THE SAME WAY. THERE IS A WHOLE SET OF PROTEINS AND OTHER KINDS OF REAGENTS THAT ARE BEING PLANNED THAT WILL MOVE INTO ACCESS. THIS IS AN INTERACTION THAT TAKES PHYSICAL PROPERTIES, PHYSICAL EVENTS AND MOVES THEM FROM THE RAS PROJECT TO THE COMMUNITY. THERE IS A WEBSITE FOR THE RAS PROGRAM. IT'S NOW GETTING RATHER MORE FILLED OUT. IDENTIFIES ACCESS TO THE REAGENTS, HAS BLOGS FROM EXPERTS. DISCUSSION FORUMS FOR NEW HOT TOPICS. THEY'RE NICE VIDEOS FROM RECENT RAS RESEARCH TALKS. WIDE RANGE OF TALKS ALL UP ON THE WEBSITE. HIGHLIGHTS OF RECENT HOT PAPERS IN THE FIELD. IT'S AVAILABLE FOR SHARING OF DATASETS AND WHOLE SERIES OF OTHER RESOURCES PULLED UP FOR THE RAS COMMUNITY. THE MAJOR PART IS CALLED RAS CENTRAL. THERE IS A LOT MORE PLANNED. THIS IS AN ACTIVE SITE. THIS IS A TEST, THE FIRST TIME THE COMMUNITY HAS COME TOGETHER ON ONE SITE TO TRY TO WORK ON THIS. WE'LL SEE HOW IT WORKS. A GOOD INITIATIVE, GOOD ONES WORKING THROUGH. ONE THING WE HAVE DONE IS HAD A SERIES OF RAS WORKSHOPS. THEY HAVE BEEN TIED TO GOALS OF THE RESEARCH PROGRAM. THEY COME EXACTLY -- THE GROUP HAS BEEN THINKING ABOUT OR WHERE THEY'RE HAVING PROBLEMS. REFERENCE TO THOSE HAVE BEEN TALKED ABOUT A LITTLE BIT. THERE IS A DISCUSSION ABOUT SYNTHETIC LETHAL SCREENS, NEED FOR NEXT GENERATION SCREENS THAT MIGHT TOUCH CASPER OR USE OTHER ASSAY SYSTEMS OTHER THAN 2D TISSUE CULTURE CELLS. THERE IS A PAR ON THE STREET, OPEN RIDE NOW, FOR -- OPEN RIGHT NOW FOR THE COMMUNITY TO RESPOND. THAT WILL TIE DIRECTLY INTO THE ACTIVITIES OF THE RAS PROGRAM. ANOTHER WORKSHOP WAS ON MEASURING AND MODELING THE PATHWAY AND HOW A FULL DAY'S DISCUSSION HOW ONE COULD DO THAT. WHAT NEEDED TO HAPPEN. I THINK WHAT CAME FROM THAT, IT WAS A VERY INTERESTINGxD PROJECT. IT MIGHT NOT BE CRITICAL PATH FOR THE RAS PROJECT SO WE SORT OF PASS ALONG THE INFORMATION FROM THAT DISCUSSION TRYING TO MOVE IT TO OTHERS WHO MIGHT WANT TO SPONSOR CERTAIN PARTS OF IT. THERE MAY BE PARTS THAT THE RAS INITIATIVE WILL WANT TO DO BUT MOST WAS IN AN OPERATION THAT WAS AT A ARM'S LENGTH FROM THE RAMS. YOU HEARD PEOPLE -- RAS PROJECT. YOU HEARD PEOPLE TALKING ABOUT TUMOR CELLS, THIS HAPPENED BEFORE THE AD HOC COMMITTEE MEETING, PRE-OUTLINED A LOT OF PROBLEMS INVOLVED AND A WHOLE SERIES OF TO DO STEPS THAT HAVE FOLLOWED FROM THAT. MANY OF WHICH HAVE STARTED, OTHERS THAT YOU HEARD REFERENCE TO. SO ONE PAR ON THE STREET, NEW COLLABORATIONS WITH RESEARCHERS FROM THE COMMUNITY, SOMETHING THAT HAPPENED IN THE CELL SURFACE ANALYSIS. ALSO REFOCUSING OF THE INITIATIVE WORK, IN SOME CASES RESHAPED OR DIRECTED. THIS IS A SERIES OF COLLABORATIONS AND CRADAS WITH EXPERTS IN THE RAS COMMUNITY THAT HAVE BEEN PUT IN PLACE. MORE INFORMAL -- SOME VERY FORMAL, DEPENDING ON WHAT THE INFORMATION IS LIKE. THAT'S BEEN A RELATIVELY AGGRESSIVE COMMON EVENT. PART OF THIS GOES TO FRANK'S SETTING IN THE FIELD. EVERYBODY WANTS TO BE A FRIEND OFF FRANK. THERE IS ABEASY OPERATION TO SET UP THOSE THINGS TOGETHER. FREDERICK IS DOING WHAT THEY CALL ROCK STAR VISITS WHICH IS GETTING MAJOR PLAYERS TO COME AND TALK AT FREDERICK, PICKING THOSE UP AND FIGURING OUT WHAT KIND OF INTERACTIONS CAN OCCUR. THAT HAS BEEN A VERY COMMON EVENT, LOTS OF GOOD EXCHANGE OF INFORMATION AND SETTING UP RESEARCH COLLABORATIONS. YOU'VE HEARD ABOUT POSTDOC PROGRAMS. VERY INTERESTING. THREE SEPARATE OPERATIONS. ONE ALREADY ON THE STREET. TWO OTHERS IN LATE STAGES OF PLANNING. IT WILL PUT NEW POSTDOCS THINKING ABOUT RAS RELATED PROBLEMS RELATED TO THIS INITIATIVE. THIS WILL GENERATE A COHORT OF INDIVIDUALS THAT WILL BE ENGAGED IN THE SAME KIND OF PROBLEMS, INTERESTING IDEAS ABOUT THEM COMING TOGETHER ONCE A YEAR FOR MEETINGS THAT THEY SHOULD SPEND A MONTH OR SO IN THE FIRST PART OF THEIR OPERATION TO BE AT FREDIC SO THEY -- THE RAS PROJECT GUYS CAN INTERACT AND KNOW EVERYBODY. TRYING TO MAKE THE NEW PEOPLE IN THE FIELD FAMILIAR WITH WHAT'S GOING ON. GROWING INTEREST IN A PHARMOBIO TECH CONSORTIUM. NOT CLEAR WHETHER THIS IS ABSOLUTELY GOING TO HAPPEN BUT THERE IS CLEAR INTEREST. A LOT OF MAJOR PHARMA WANTED TO GET INVOLVED. THEY HAVE BEEN IN HIRING SPECIFIC SERVICES. I PUT ONE BULLET POINT AT THE BOTTOM. HAVING WATCHED THIS CLOSELY, THERE IS ONE MAJOR PART OF THE PROGRAM WHICH IS VERY HARD TO MANAGE. I PUT IT OUT THERE, I DON'T HAVE A SLUGS FOR HOW -- SOLUTION FOR HOW THIS MIGHT HAPPEN. IN SOME WAYS WE'RE ASKING THE RAS INITIATIVE TO BE FAST ON THEIR FEET. MOVE IN SOME WAYS LIKE A BIO TECH OR PHARMA MIGHT BE ABLE TO MOVE. BUT WE DON'T HAVE ALL THE TOOLS THEY NEED TO BE ABLE TO DO THAT. THERE ARE CERTAIN PARTS OF INTERACTING WITH THE COMMUNITY THAT YOU CAN'T DO WITHOUT HAVING A COMPETITION, WHICH YOU CAN'T GO THROUGH A LONGER PROCESS THAT NEEDS TO BE DONE. SO I MENTION THAT TO SAY THAT THERE ARE A LOT OF PLACES THAT THE RAS INITIATIVE HAS INTERACTED WELL WITH THE COMMUNITY. WHEN YOU'RE THINKING ABOUT DOING AN OPERATION WITH PEOPLE OUTSIDE OF THE RAS INITIATIVE ITSELF IN WHICH THERE IS A TRANSFER OF FUNDS TO THAT GROUP NEEDED TO MAKE IT HAPPEN, IT DOESN'T HAPPEN EASY. IT'S SLOW. LIKE SLOW IN THE TERM OF A YEAR TO MAKE IT HAPPEN. SO IT DOESN'T MAKE THEM BE ABLE TO WORK MUCH LIKE A BIO TECH. THEY HAVE THAT PART OF THEIR WORLD BLOCKED. MAYBE THAT'S APPROPRIATE, THE WAY IT SHOULD GO BUT IT MEANS IT'S MORE DIFFICULT TO DEAL WITH. SO JUST A SUMMARY OF HOW THE RAS PROGRAM IS INTERACTING. HAPPY TO TAKE QUESTIONS ON THAT NOW OR LATER. I HAVE A FEW SLICE THINKING ABOUT HOW YOU FIND NEW IDEAS AND THESE, MANY OF THEM YOU WILL KNOW ABOUT. I TRIED TO START BY PICKING UP AND PUTTING MY INTERPRETATION OF WHAT I THOUGHT A NATIONAL INITIATIVE MIGHT LOOK LIKE. SO WE HEARD ABOUT THAT BEFORE. IN ONE OF DAVE'S SLIDES. I GRABBED IT FROM MY VIEWPOINT. THIS IS MOSTLY APPLYING TO THE RAS PROGRAM. YOU CAN THINK IF I HAVE IT ABOUT RIGHT OR NOT. I CAN THAT IT REALLY NEEDS TO BE A PROBLEM OF NOTE, HOW I DESCRIBED IT HERE. YOU CAN THINK ABOUT, THAT PROBLEMS IN TWO FLARES. I PERMANENTLY LIKE THE IDEAS -- PERSONALLY LIKE THE IDEA IT'S A SCIENTIFIC PROBLEM WE WANT TO SOLVE. IT COULD BE TECHNICAL, AS WELL. SO IT FITS IN BOTH OPERATIONS. HAS TO BE ONE THAT PEOPLE RECOGNIZE IMMEDIATELY AND SAY I WANT TO SOLVE THAT. I HOPE NCI CAN MAKE THAT HAPPEN SO IT HAS TO HAVE THAT FLAVOR. IT HAS TO BE THE RIGHT SIDE. IT CAN'T BE TOO SMALL, OR TOO LARGE. THERE IS A INDEPENDENT WITHO HE -- THERE IS A WINDOW, FAIRLY BROAD BUT HAS TO BE THE RIGHT KIND OF SIZE. YOU CAN'T ANSWER THIS BY USING OTHER MECHANISMS. SO YOU COULD LINK PO1s, OR U54s OR SOMETHING TO PUT THEM TOGETHER, TO ANSWER THE PROBLEM. IT DOESN'T -- IT WON'T BE SOMETHING THAT WILL WORK WELL AS A NEW NATIONAL INITIATIVE. IT HAS TO HAVE A SETTING WHERE WE KNOW ENOUGH THAT IT MIGHT WORK, SO IT CAN'T BE AN IDEA THAT EXISTS OUT, THERE JUST AS A CONCEPT BUT WITHOUT ANY FLAVOR, IN MY VIEW, ANYWAY. THERE HAS TO BE SOMETHING WHERE THIS IS NOT OWE ROT OF WORK ALREADY GOING ON. WE'RE NOT TRYING TO COMPETE WITH THE RESEARCH COMMUNITY AS A WHOLE. WE'RE LOOKING TO AUGMENT AND DRIVE NEW PROBLEMS THROUGH. SUCCESS SHOULD PROVIDE A MAJOR ADVANCE. THE SORT OF THING, IF WE WERE SUCCESSFUL, IT WOULD WORK WITH. THERE NEEDS TO BE SOME TANGIBLE OUTPUT TO MEASURE SUCCESS. AT LEAST IN MY OWN CONCEPT OF WHAT THIS MIGHT BE. I LIKE THE IDEA IT MIGHT NEED INTERACTIONS WITH THE COMMUNITY FOR SUCCESS. THAT ISN'T REQUIRED. HELPFUL BUT NOT REQUIRED. LASTLY, ANOTHER FEATURE I LIKE ABOUT THE RAS PROGRAM, RAS INITIATIVE, IT'S DIFFICULT ENOUGH THAT IT MAY NOT GUARANTEE IMMEDIATE SUCCESS. IT NEEDS THE ATTENTION THAT A CONCERTED NCI ACTIVITY MIGHT BE INVOLVED IN. AND MIGHT BE OTHER ONES THAT YOU WOULD ADD, THAT WOULD BE MY BRIEF LIST OF THE SORT OF THINGS THAT I WOULD EXPECT WHEN THINKING ABOUT ONE BEGINS TO BUILD THIS. WHERE WOULD YOU GO TO LOOK FOR INITIATIVE IDEAS? OBVIOUSLY, NCI WILL HAVE A SET OF NEEDS OF ITS OWN. WE HEARD SOME OF THOSE. I DON'T KNOW WHETHER WE EXHAUSTED THE LIST. MY SENSE IS THERE IS INTEREST IN A LOT OF THEM BUT THEY HAVE NOT GATHERED ENOUGH TRACTION THAT IT'S MOVING FORWARD. YOU CAN IMAGINE TALKING TO GROUPS LIKE THIS, OTHER ADVISORY GROUPS THAT MIGHT HAVE IDEAS. I THINK AN INTERESTING GROUP THAT MIGHT HAVE THE -- AT LEAST SOME OF THE PEOPLE THAT WERE DIRECTORS OF CANCER CENTERS MIGHT HAVE VIEWS ABOUT WHAT THEY MIGHT THINK WOULD FALL INTO THIS CATEGORY. REAL EXPERIENCE OF WHAT'S WORKING AND NOT. MIGHT BE INTERESTING. COULD PUT TOGETHER A SPECIAL PANEL. EXPERTS WOULD HAVE A LIST OF INDIVIDUALS WHO MIGHT BE ABLE TO CONTRIBUTE. HE WOULD SAY A LITTLE BIT ABOUT PROVOCATIVE QUESTIONS, TO SAY THAT PROCESS IS WORKING RELATIVELY WELL IN A WORKSHOP WHERE WE GO TO THE COMMUNITY AND WE SAY TELL US WHAT YOUR BEST IDEA IS AND HAVE A DISCUSSION OVER WHAT QUESTIONS ARE. AT LEAST THAT METHOD OF INTERACTING OF THE COMMUNITY HAS SOME VALUE. SO THESE ARE FOUR OF THE MAJOR OPPORTUNITIES THAT I SEE THAT COME FROM WORKSHOP EXPERIENCE. SOMETHING THE COMMUNITY CAN SEE. THAT IS CREDIBILITY TO THE PROCESS, ASKING THE COMMUNITY TO HELP BUILD SO IT'S NOT A TOP DOWN, BUT HAS CREDIBILITY, MORE CREDIBILITY, I THINK. IT BUBBLES UP. THE PREPARATION OF PEOPLE WHO COME TO THE WORKSHOP INVOLVES SOME CHALLENGES FOR THEM. THEY HAVE TO THINK WHAT WOULD I SAY AMONG MY COLLEAGUES WOULD BE THE MOST EXCITING THING I WOULD SUGGEST. SELF-CORRECTING. YOU CAN'T BE TOO EGOCENTRIC, YOU CAN'T DRIVE THINGS TOO RELATED TO WHAT YOUR BACKGROUND IS. AND THEN THIS IDEA THAT -- THE DISCUSSIONS THEMSELVES ALWAYS LEAD TO THIS AHA MOMENT. THAT HASN'T HAPPENED IN EVERY WORKSHOP. ALMOST EVERY SINGLE ONE. MOMENTS WHERE SOMEONE HAS SAID LET'S DO IT THIS WAY, AND BOB IN THE AUDIENCE SAYS DID YOU MEAN THIS OR DID YOU MEAN THIS. OH, YES. THIS IS A BUILD THAT COMES IN, YOU GET TO NEW GROUND THAT NEITHER OF YOU HAVE SEEN. SO THIS IS A REAL VALUE IN THAT KIND OF INTERACTION. AS AN EXAMPLE OF THE KIND OF THINGS THAT HAPPEN WE DID A SERIES OF WORKSHOPS, PQ WORKSHOPS IN BOSTON THE WEEK BEFORE LAST. AND WE HAD NORMAL PQs SUGGESTS. GENERATED A LOT OF INTERESTING NEW IDEAS. WE ALSO HAD MOMENTS IN THE DISCUSSION WHERE PEOPLE TALKED ABOUT GRAIN SIZES THAT WERE BIGGER THAN A NORMAL PQ. AND THIS IS JUST A LIST OF THEM THAT I PUT UP THIS. I PUT ALL OF THEM THAT I REMEMBER FROM THOSE DISCUSSIONS, SO THIS IS NOT EDITED IN ANY WAY. BUT INTERESTINGLY TWICE IN OUR DISCUSSIONS, ONCE BY BOB WINEBURG IN A RATHER ELOQUENT DESCRIPTION WHY SOMEONE WHO CARES ABOUT THE MECHANICS OF HOW CELLS MOVE FROM BEING A NORMAL CELL TO A CANCER CELL, ON TO METASTASES. MAYBE A POWERFUL ARGUMENT, WE NEED TO REVISIT PREVENTION. AS A FIELD WE NEED TO THINK ABOUT PREVENTION. IN HIS VIEW, AND THE VIEW OF THE OTHER WORKSHOP, THE COMICS OF THE SITUATION -- ECONOMICS OF THE SITUATION DEMAND IT. AS WE CHASE SMALL MOLECULARS AND OTHER THERAPEUTIC -- WHERE COSTS ARE GOING UP BUT WE'RE NOT MAKING A REMARKABLE DIFFERENCE AND WE'RE CHASING THIS, GETTING MORE AND MORE RESISTANT COLONIES. TUMORS, RATHER. IT'S A VERY POWERFUL ARGUMENT ABOUT UNDERSTANDING WHAT YOU WANT TO GO AFTER. THEY BOTH CAME TO THE CONCLUSION THAT WE NEED TO RETHINK REVENTION. -- PREVENTION. ANOTHER WORKSHOP, SOMEBODY ELSE BROUGHT UP THIS PROBLEM WE HEARD MULTIPLE TIMES OVER THE LAST COUPLE YEARS WE HAVE BEEN TALKING ABOUT PQs. THAT THE LENGTH BETWEEN EPIDEMIC ALLY IDENTIFIED EVENTS AND FIRST STEPS OF A TUMOR OUTLINES A SERIES OF INSULTS AND CHANGES THAT GENERATE A TUMOR. IF WE COULD LINKER THOSE IN A FORMAL CAUSATIVE WAY, THAT WOULD BE NORMSLY POWERFUL. -- ENORMOUSLY POWERFUL. THOSE WOULD BE STEPPED YOU CAN IMAGINE SOME SORT OF PREVENTION THAT WOULD BE ENGAGED. WE HAVE ALWAYS MADE PREVENTION WORK IN SOME AREAS. NOW SIMPLE UV LIGHT AND SUN SCREEN, TOBACCO AND REMOVING THE CARCINOGENIC INSULT. IN MANY CASES WE DON'T REALLY UNDERSTAND HOW THOSE THINGS ARE HOOKED TOGETHER IN THOSE -- SO THERE IS AN OPPORTUNITY TO THINK ABOUT HOW THAT GOES. I THINK ABOUT THIS AS A FRAMEWORK FOR PREVENTION. HAVING THOSE STEPPED IDENTIFIED, CHEMO PREVENTION OR OTHER STEPS. SEVERAL PEOPLE WERE THINKING ABOUT THIS PROBLEM THAT KEEPS COMING BACK ALL THE TIME THAT WE REALLY AREN'T VERY GOOD AT EVEN THINKING ABOUT HOW ONE SHOULD DRUG TRANSCRIPTION FACTORS. WE WORKED HARD, NCI FUNDS GROUPS THAT ARE INVOLVED IN THIS PROBLEM. WE STILL DON'T REALLY UNDERSTAND HOW TO DO THIS. THIS MIGHT BE VERY VALUABLE. A VERY SPECIFIC EXAMPLE WITHIN THIS CLASS OF GOING AFTER MYC, COUNTER TO THE RAS PROBLEM. I CAN SEE SOME SYNERGIES THAT MIGHT BE ACCOMPLISHED BETWEEN THOSE OPPORTUNITIES BUT JUST THE IDEA THAT YOU COULD BEGIN TO THINK ABOUT PICKING ONE GENE IN THAT SETTING. I'M NOT SURE MYC WOULD BE MY GUY. I WOULDN'T GO FOR P53, BUT MAYBE PICKING ANOTHER TARGET VERY DIFFICULT TO THINK ABOUT. I HAVE DOUBTS HOW WELL THIS WOULD WORK. I THINK WE'RE DOING A FAIR AMOUNT OF WORK IN THAT AREA. WHETHER THERE IS ENOUGH OF AN ANGLE BUT AT LEAST AN IDEA. WHEN YOU BRING SMART PEOPLE TOGETHER THEY OFTEN GENERATE SOMETHING THAT GIVES YOU THAT FRAMEWORK TO THINK ABOUT. THOSE ARE -- WHOOPS. I JUST LOST MY LAST SLIDE. A REPEAT OF THE SLIDE BEFORE TO START THINKING ABOUT -- START THE DISCUSSION ABOUT, AMONG YOU, WHAT SORT OF WAYS DO YOU THINK THAT WE OUGHT TO CONSIDER IN TRYING TO GATHER A LIST, MAYBE FOR THIS ROUND OF NEW RAS ACTIVITY OR MAYBE FOR A ROUND OF OTHER ISSUES THAT WOULD COME DOWN THE LINE. SO I'LL STOP THERE, TRY NOT TO TAKE TOO MUCH TIME. LEFT EVERYBODY HAS A CHANCE TO BEGIN TO THINK ABOUT A DISCUSSION YOU MIGHT WANT TO HAVE. BACK TO JOE. >> BEFORE WE LAUNCH INTO THE DISCUSSION, ONE OF THE REASONS I WANTED ED TO BRING THIS UP IS BECAUSE WE'VE HAD SEVERAL ATTEMPTS AND ELICITING IDEAS FOR THE NEXT RAS PROJECT. AND GOTTEN GOOD ONES BUT SO FAR, PERHAPS LATER TODAY WE'LL GET THE EXCEPTION. SO FAR WE HAVEN'T CONVERGED ON THE NEXT RAS. SO I THINK THAT IT WOULD BE GOOD IN THE NEAR TERM TO THINK ABOUT WHAT ACTIVITIES WE REALLY OUGHT TO MORE FULLY NIGERIA IN TO TRY TO STIMULATE THAT PROCESS. SO THE LIST THAT ED HAS ON THE BOARD HERE ARE SOME CREDIBLE IDEAS. IT WOULD BE NICE TO WALK OUT OF THIS ROOM WITH SOME CONCEPT ABOUT WHAT IT IS WE'RE GOING TO DO NEXT. SO WITH THAT, JOE. >> YEAH. I JUST MAD A QUICK -- HAD A QUICK QUESTION. WHEN BOB FOCUSED ON PREVENTION, WAS HE INCLUDING IN THAT EARLY DETECTION? DID HE REALLY MEAN -- PREVENTION. >> HE MEANT PREVENTION. BUT I MIGHT SAY THAT EARLY, EARLY, EARLY STRATEGY DETECTION -- STAGE, DETECTION MIGHT FIT IN AS WELL. BUT I DON'T THINK WE NECESSARILY HAVE TO FOLLOW THE DEFINITION BUT HE WAS STRUGGLING AS SOMEBODY WHO THINKS ABOUT THE INFORMATION FLOW THAT COMES FROM WORK LIKE HIS. HAS BEEN TRANSLATED ANY REAL DRUG DOCTORS THAT ARE HAVING AN IMPACT BUT NOT HAVING THE REMARKABLE IMPACT HE'D LIKE TO SEE. HOW ARE WE GOING TO DO ABOUT THAT. THAT WOULD BE THE ONLY PLACE -- >> THE OTHER THING, THIS PQ EXERCISE THAT YOU HAVE BEEN DOING, WHAT I LIKE ABOUT THAT IS THAT, AGAIN, ENLARGES THE UNIVERSE OF PEOPLE THAT YOU ARE TRYING TO QUESTION OR PROVOKE OR HAVE THEM PROVOKE US, RATHER THAN SPECIAL PANELS OF NATIONAL EXPERTS WHO ALREADY HAVE THEIR OWN VERY FOCUSED RESEARCH AGENDA WHICH MAYBE EXCELLENT BUT THIS IS A WAY OF DEMOCK RATIZING AND BROKENING THAT UNIVERSITY. >> THERE IS A REALLY VALUE IN THAT AS IT GOES ON. IT TAKES A WHILE AT A FORMULATE. IT'S NOT AN END-ALL. >> JUST FOR THE INITIAL -- >> AND ENGENERAL THEY HAVE WORKED QUITE WELL. PEOPLE ENJOY DOING THIS. THEY COME IN WITH THEIR OWN IDEA THAT FITS IN THEIR WORLD, BUT AFTER A SHORT WHILE ARE FORCED TO SAY OKAY, THAT'S TOO NEAR TERM. I HAVE TO THINK BIGGER IN DIFFERENT WAYS. THAT LEARNING PROCESS, PARTICULARLY AROUND CREDIBLE COLLEAGUES WHO CAN SAY DIDN'T WORK FOR ME, THAT'S REALLY NOT GOOD ENOUGH. BEGINS TO REFORMULATE AND MAKE IT GO. >> STEVE, THEN DAVID. >> I DON'T HAVE A PROVOCATIVE QUESTION BUT HAVE A PROVOCATIVE OPPORTUNITY. THERE IS A SURGEON IN SOUTHERN CALIFORNIA WHO IS INVOLVED WITH A SIGNIFICANT INITIATIVE TO ESSENTIALLY CONQUER CANCER, PANCREATIC CANCER IS HIS FOCUS. HE PURCHASED 10- ACRES OF LAND, TAKEN FACTORIES, GUTTED THEM AND FILLED THEM WITH MACHINERY FOR SEQUENCEING. ALSO HAS BROUGHT TOGETHER INCREDIBLE INFORMATICS TEAM. HE'S LOOKING FOR PARTNERSHIPS. HE'S WORTH 12 TO 14 -- >> I'M GOING TO BE IN THE -- DROP THE F. BOMB AGAIN. [LAUGHTER] >> BUT THE AMOUNT OF RESOURCES HE HAS AVAILABLE TO DO SIGNIFICANT THINGS, AND HE'S LOOKING FOR PARTNERS. AND THAT'S WHY -- >> YOU SHOULD JOIN UP WITH HIM. >> BUT IN ALL HONESTY, WITH THE MATTER OF CAPITAL HE HAS AVAILABLE TO DO SIGNIFICANT THINGS, I THINK IT'S WORTH AT LEAST A DIALOGUE. FRANK, HAVE YOU HAD ANY CONVERSATIONS WITH HIM? >> NO. >> SO IT'S -- PANCREATIC CANCER IS HIS FOCUS. SO -- >> WELL, SEND OUR ALLEGIANCE OF SMART PEOPLE TO TALK WITH HIM. >> I HAVE TWO REACTIONS. ONE IS I COMPLETELY AGREE WITH THE PROVOCATIVE QUESTION THING. I HAVE TO A LIMITED NUMBER OF THESE. MOST OF THEM WERE NOT IN MY AREA OF EXPERTISE AT ALL. I HAD LIMITED UNDERSTANDING WHY I WAS THERE. BUT THEY WERE A LOT OF FUN FOR EVERYBODY. AND THINGS COME OUT. JUST AS YOU SAY. SO IT IS WAY, WAY BETTER THAN THE OTHER PROCESSES -- NO QUESTION ABOUT THAT. ON THE ISSUE OF PREVENTION I'M STRONGLY INCLUDE TO GREEN WITH BOB, NOT YOU'LL THAT COMMON ON THESE ISSUES, THAT WE'RE MISSING SOMETHING THERE. AND THE PART THAT STRIKES ME AS BEING WHAT KIND OF EPIDEMIOLOGICAL EVENTS ARE ASSOCIATED. I'M WITH YOU ON THAT. WHAT KEEPS COMING BACK ALL THE TIME IS INFLAMMATION. THE CONNECTION BETWEEN INFLAMMATION AND CANCER, ABOUT WHICH WE KNOW MUCH, MECHANISTICALLY ZILCH OR CLOSE TO ZILCH. AND THAT CONNECT IMMEDIATELY TO A PROBLEM WHICH IS NOT COMPLETELY TRACKABLE AT THE MOMENT, SORT OF LIKE RAS, WHICH IS THE MICROBIOME. SO IT'S VERY CLEAR THERE ARE FEW CANCERS, GASTRIC CANCER BEING THE NUMBER ONE, IN WHICH WE ACTUALLY KNOW THE BUG THAT DOES IT. WE DON'T KNOW WHAT IT ABOUT THE BUG DO THAT HE IS IT -- BUG THAT DOES IT. THAT SEEMS TO HAVE BEEN DROPPED. IF YOU THINK ABOUT CANCER MORE GENERALLY, AND YOU THINK ABOUT THE MICROBIOME, AND YOU LOOK AT THE -- WHAT IS BEING DONE IN THE TECHNOLOGY THEY'RE LOOKING AT 16SRNA. YOU COULD HAVE DONE THAT -- THEY'RE TELLING YOU THE CLAVES OF BACTERIA PRESENT. WE'RE NOT INTERESTED IN THAT. WE'RE INTERESTED IN WHAT IS THE PROTEIN OR THE ACTIVITY OR THE METABOLISM OF THE BUG THAT IS RELEVANT. AND THAT BRINGS ME TO THE LAST POINT THAT ALSO IN THAT WHOLE BUCKET OUGHT TO GO METABOLIC THINGS. METASTASES IS COMING BACK, TECHNOLOGY IS COMING BACK. THERE ARE CANCERS THAT ARE DRIVEN BY AN OFF METABOLITE -- REALLY, SO IS THAT AN ISOLATED INCIDENT? I DON'T THINK SO. WHAT I WOULD ARGUE IS THAT SOMEWHERE IRON THERE, WITH THE GOAL OF TRYING TO FIND PRECANCER INITIATING EVENTS, NOT JUST OBESITY BUT MECHANISTICALLY. WE WANT TO DO THIS AS REAL BIOLOGY. WE DON'T WANT TO DO THIS AS EPIDEMIOLOGY, GOD FORBID. >> I WAS GOING TO SAY, HOW MANY EPOLOGISTS ARE IN THE ROOM? >> NO, WE HAVE TO DO WHAT WE'RE GOOD AT HERE. THIS ISN'T THE PLACE TO DO EPIDEMIOLOGY. SO I'M VERY VERY MUCH IN FAVOR OF THINKING ABOUT SOMETHING IN THAT ARENA. I DON'T KNOW EXACTLY WHAT IT WOULD BE. BUT I SORT OF LEAN TOWARD THE INFLAMMATION ONE. BUT THAT COULD CONNECT ALL THE OTHERS. HAS TO BE FOCUSED ENOUGH SO THERE IS SOMETHING TO DO. A FRANK McCORMICK TO BE RECRUITED. IT CAN'T BE ALL OVER THE MAP. HOW MANY TIMES HAVE WE HEARD THE CONNECTION OF INFLAMMATION TO CANCER AND WHAT DO WE KNOW ABOUT IT? >> IT'S NOT AN EMPTY AREA. THERE IS A FAIR AMOUNT OF WORK IN INFLAMMATION. NOT MY FIELD, SO I CAN'T TELL YOU THE ACT ISSUES. AT LEAST PEOPLE HAVE IT IN SIGHT AND TRYING TO WORK ON IT. WHETHER IT'S THE RIGHT FOCUS, I CAN'T TELL YOU THAT. >> LIKE RAS IN THAT REGARD. >> IN THE SPIRIT OF GETTING FINISHED BY 2:00 WE HAVE TO CUT THIS OFF QUICKLY. ONE OF THE REASONS THAT I WANTED TO -- THAT I WAS PUSHING YOU ON MONEY EARLIER WAS THAT ONE OF THE APPEALING THINGS ABOUT THE PROVOCATIVE QUESTION INITIATIVE IS THAT PEOPLE THAT ACTUALLY ENGAGE IN THAT DIALOGUE HAVE THE EXPECTATION THIS IS GOING TO BE AN ACTUAL INITIATIVE IS THAT RESULTS OUT OF IT. AND I THINK THAT ONE OF THE THINGS WE WOULD ACTUALLY LAKE TO DO IS ENCOURAGE ONE OR MORE OF THESE MECHANISMS. I DON'T REALLY WANT TO DO THAT UNTIL WE'RE CONVINCED THAT THERE IS AT LEAST THE GLIMMER OF HOPE THAT IT WILL MATERIALIZE. I THINK WE'LL BE ASKING OUR COLLEAGUES TO DO A LOT OF WORK HERE. AND WE NEED TO MAKE SURE THAT -- SO MAYBE OFF LINE, WE COULD TALK ABOUT HOW IT IS THAT WE CAN THINK ABOUT THIS. BUT JUST GO AHEAD. >> I WAS THINKING BACK TO A COMMENT DAVID MADE IN PASSING. I CAN'T REMEMBER IF IT WAS ON THE FIRST SLIDE, AND I AGREE WITH EVERYTHING YOU HAD, BUT THERE SHOULD BE SOMETHING THAT FREDERICK CAN DO. DOESN'T NEED TO BE TECHNOLOGY THAT ISN'T EXISTENT AT ALL. THAT MADE ME THINK, WHEN YOU WERE TALKING ABOUT INFLAMMATION WHICH IS NOT EXACTLY THE SAME. BUT IF YOU TALK TO THE IMMUNOLOGISTS, THEY WILL TELL YOU THERE ARE THREE AREAS OF IMMUNOTHERAPY THAT ARE RELEVANT. ONE IS THE CHECK OPPONENT, BLOCKADE, ANOTHER IS THE T. CELL, EITHER ADOPTED TRANSFER OR CHIMERIC. THE THIRD IS NOW SORT OF OUT OF FAVOR BUT MANY PEOPLE BELIEVE IN IT, VACCINES. THE VACCINE THING IS ONE THING THAT FREDERICK DOES DO HERE. IT MAY NOT BE -- THE VACCINES HAVE BEEN FLAILING A BIT OF LATE. MOST IMMUNOTHERAPY FLARED FOR A FEW DECADES. IF THERE WERE SOMETHING TO DO IN THAT AREA, THAT WOULD BE AT LEAST SOMETHING WHERE CLEARLY, THERE IS LEADERSHIP HERE. THERE IS HUGE CAPABILITY. AND MAYBE THERE WOULD BE SOMETHING TO C I DON'T KNOW. >> MAY REMEMBER THIS OR NOT. AT THE SAN FRANCISCO RAS MEETING THERE WAS A SUGGESTION ABOUT VACCINES THAT WAS -- I'M GOING TO GET IT A LITTLE BIT WRONG. IT CAME FROM DISCUSSION OF USING THE SITEEN AND MUSTTANT IN THE RAS POCKET AS A COVALENT INTERSITE T QUESTION WAS WHETHER YOU COULD USE THAT TO INTRODUCE A NEW EPITOPE THAT YOU COULD HAVE PREIMMUNIZED FOR IN THAT SETTING. YOU COULD IMAGINE IF THIS WERE A SET, YOU COULD SAY THIS IS A PLACE TO MAKE VACCINES VERY QUICKLY. ANOTHER THING ABOUT THAT, A STORY, I DON'T KNOW IF IT'S TRUE, A LOT OF THE HDAC INHIBITORS MAY BE WORKING BY REPROGRAMMING HLA, ALLOWING THE IMMUNE RESPONSE TO COME BACK ON. SO THE REASON THEY MAY BE WORKING AS PART OF A THING ISxD ACTUALLY TURK ON THE IMMUNE RESPONSE SELECTED EARLY ON. I PASS MID TIME ON THAT ONE. >> THANKS, ED. I'D LIKE TO GET US TO THE POINT WHERE MAYBE WE HAD SOME QUICK CONSENSUS AS TO WHICH, IF ANY OF THESE ACTION WE REALLY OUGHT TO TRY TO INITIATE BEFORE THE NEXT IMPACT MEETING. I CERTAINLY LIKE THE IDEA OF USING THE PROVOCATIVE QUESTIONS FORUM THAT YOU ALREADY HAVE GOT AND ADD THIS TO THE LIST OF THINGS TO BE DISCUSSED. IN THE SPUR OF THE DOING -- SPIRIT OF DOING THINGS THAT FREDERICK CAN DO, ONE OF THE THINGS THAT WOULD BE HELPFUL WOULD BE TO HAVE THE INTRODUCTORY TWO OR THREE SLIDE DECK THAT HIGHLIGHT WHAT FREDERICK IS CURRENTLY CAPABLE OF, IF YOU WILL. WHAT ABOUT ENGAGING THE CANCER CENTER DIRECTORS, OR A SPECIAL PANEL OF NATIONAL EXPERTS? >> I WOULD DEFINITELY WANT TO INCLUDE THE DIRECTORS IN THE DIALOGUE. I FEEL THEY CAN TELL YOU WHAT THEIR NEEDS ARE. THEY CAN DISCUSS WHAT MAY BE BENEFICIAL WITH THE STRENGTH THAT EXISTS HERE AT FREDERICK AND HOW THEY CAN CONTRIBUTE FROM THEIR OWN INSTITUTIONS. >> WELL, MAYBE THOSE TWO THINGS ARE PROBABLY ENOUGH TO TRY TO BITE OFF BEFORE THE NEST MEET. WHEN IS THE CENTER DIRECTOR'S MEETING. >> USUALLY THE END OF FEBRUARY, EARLY MARCH. >> COULD WE GET ON THE AGENDA? >> SURE. >> THIS IS THE ACI MEETING WHICH IS IN 3 OR 4 WEEKS IN CHICAGO. >> I'LL TRY TO WORK WITH ED TO GET THOSE TWO THINGS TO HAPPEN BEFORE THE NEXT MEETING. THANKS, ED. OKAY. WE'RE GOING TO SHIFT GEARS NOW AND TALK ABOUT THE NATIONAL MOLECULAR MICROCY LABORATORY. DR. SUBRAMANIAM IS AN EXPERT, AND THIS IS AN AREA OF TECHNOLOGY THAT HAS SEEN AMAZING ADVANCES LITERALLY IN THE LAST YEAR. I THINK THAT IT'S SOMETHING THAT WE HAVE BEEN TALKING ABOUT TECHNICALLY ORIENTED PROJECTS FOR THE NATIONAL LABORATORY. AND SO I THINK MYSELF, THIS IS A PRIME CANDIDATE FOR SOMETHING THAT WE SHOULD THINK ABOUT. >> THANK YOU, JOE. THANK YOU FOR THE INVITATION TO SPEAK TO THIS COMMUNITY. I'M A SCIENTIST IN THE INTRAMURAL PROGRAM. I HAVE BEEN FOR 14 YEARS. BEFORE THAT I WAS IN CAMBRIDGE WHICH IS WHERE I LEARNED STRUCTURAL BIOLOGY AND CRIO EM FROM THE PEOPLE THAT PIONEERED THE FIELD STARTING FROM THE 60s. THE LAST 15 YEARS HE HAVE BEEN WORKING BOTH TO DEVELOP NEW METHODS IN THIS FIELD WITH THE GOAL OF ACHIEVING ATOMIC RESOLUTION BUT ALSO TO LOOK AT PROTEIN COMPLEXES AND THINGS THAT ARE DIFFICULT TO LOOK AT. I'LL TOUCH OPTHAT IN MY PRESENTATION. THE PRESENTATION ITSELF, THIS IS THE ROUGH OUTLINE OF MY PRESENTATION. I WOULD LIKE TO BEGIN WITH A TEN MEN SUMMARY AT THE BEGINNING WHERE I'D LIKE TO ESSENTIALLY DISSTILL THE ESSENCE OF WHAT -- WHERE THE FEELERS -- WHERE THE EXCITEMENT IS, AND THE POSSIBLE OPPORTUNITIES FOR PERHAPS A NATIONAL MISSION AT FREDERICK T FREDERICK NATIONAL LAG. I HAVE AN EXTENDED SEGMENT ON WHY NOW, MEANING MORE INDEPTH LOOK AT THE ASSORTMENT OF THINGS THAT ARE BEING DONE IN THE FIELD AND MORE BROADLY [INAUDIBLE], NOT JUST ABOUT ISOLATED MOLECULARS. GREAT POTENTIAL TO LOOK AT PROTEIN COMPLEXES IN THE CONTEXT OF CELLS AND VIRUSES. THESE ARE VERY, VERY IMPORTANT AREAS. A LOT OF GROWTH. I ALSO HAVE A COLLECTION OF SINGLE SLIDES MAINLY ON SOME OF THESE MORE PRACTICAL ASPECTS SUCH AS WHAT ARE THE UNIQUE ASPECTS OF THE LAB THAT YOU MIGHT CONSIDER THIS AS A SUITABLE PLACE FOR IT TO CONDUCT THIS TYPE OF WORK. SOME ATTRIBUTES TO THE TYPE OF LEADERSHIP THAT COULD BE PRIDED TO DRIVE -- PROVIDED TO DRIVE THIS FORWARD. AND FOR PEOPLE NOT TAKING ADVANTAGE OF THESE TECHNOLOGIES. A LITTLE BIT ABOUT THE SCOPE OF THE KINDS OF THINGS THAT COULD BE DONE ON A NATIONAL SCALE EFFORT. A FEW WORDS ABOUT WORK FLOW. REALLY WHAT IT BRINGS, TECHNOLOGIES LIKE THIS. TO BUYOLOGISTS THAT MAY NOT BE STEEPED IN THE METHODS AS THEY'RE BEING DEVELOPED, BUT COULD BEGIN TO USE IT ONCE YOU WHAT YOU HAVE TO DO. I'LL TOUCH BRIEFLY ON OPPORTUNITIES FOR INNOVATION FOR US TO BE AT THE FOREFRONT OF THIS FIELD THAT IS GROWING RAPIDLY, AND ESTABLISH THINGS THAT LOOK OUT AHEAD NEXT 5-10 YEARS. ALSO SOME ASPECTS ON TRAINING AND PARTNERSHIPS WITH BOTH NEARBY AND INSTITUTIONS FURTHER AWAY. FINALLY, SOME SPECIFIC MILESTONES. WHAT MIGHT YOU EXPECT. AND IF THIS WERE TO BE A NATIONAL MISSION, SOME THOUGHTS ON WHAT MIGHT COME OUT OF IT. I'D LIKE TO BEGIN BY POINTING OUT THAT WE RECOGNIZE THAT SOMETIMES, THIS GOES BACK TO A REVIEW I WROTE TEN YEARS AGO. WE RECOGNIZE LOOKING ACROSS THE IMAGING SPECTRUM IT'S VERY CLEAR THAT THERE IS A MAJOR GAP IN AN UNDERSTANDING OF STRICT RECALL ASPECTS OF THINGS -- STRUCTURAL ASPECTS OF PROTEIN COMPLEXES, VIRUSES, AND ENTITIES IN THIS RANGE FALL IN A GAP BETWEENTICATION THAT WE ARE USED TO LOOKING AT, CRYSTALLOGRAPHIES, ISOLATED PROTEINS THAT CAN BE CRYSTALIZED. AND THINGS THAT ARE IN THE REALM OF CELL BIOLOGY. WE NEED CHEMICAL MECHANISMS BUT THERE WASN'T REALLY A WAY TO GET AT IT. WE WORK INTENSIVELY TO FOCUS ON THE METHODS AND APPLYING THEM TO SPECIFIC PROBLEMS. ONE OF THE, I THINK, CENTRAL THEMES OF THE WORK THAT WE DID WHICH CAPTURED IN THIS SLIDE, THE IDEA OF DOING THIS IN AND INTEGRATED WAY. TO LOOK NOT JUST AT PREPARES AN ISOLATED FORM BUT LOOK AT THEM IN LOOKING AT VIRUSES, WHOLE CELLS, BACTERIAL CELLS, MEMALLIAN CELLS. TO ME, THESE CAPTURED DIFFERENT FACETS OF THE TOOLS WE NEEDED TO DEVELOP TO GET INTO QUESTIONS OF INTEREST. IN WHOLE CELL IMAGING, WE WERE REALLY FOCUSED ON DEVELOPING TOOLS TO IMAGE BOTH THE NEEDLE AND HAY STAKE, TO LOCALIZE INDIVIDUAL MOLECULES. IN THE CONTEXT OF A VERY LARGE CELL. WE WORKED IN DEVELOPING METHODS TO VISUALIZE IN MOLECULAR DETAIL, SIGNALING MACHINERY -- WE CHOOSE BACTERIA FOR A NUMBER OF TECHNICAL ROBE REASONS. THIS IS TEN TIMES SMALLER THAN MAMELIAN CELLS. WE ALSO [INDISCERNIBLE] WHERE THERE IS NO SYMMETRY. YES, THERE IS GREAT INTEREST UNDERSTANDING HOW THESE STRUCTURES ARE INVOLVED IN INFECTION. AND ALSO THE IDEA THAT ONE COULD GET STRUCTURES OF PROTEINS WITHOUT CRYSTALIZING THEM, BUT LOOKING AT ATOMIC RESOLUTION. YOU SEE THIS SIGNIFICANT PROGRESS IN ALL THESE FEELING. I WANT TO SET THE CONTEXT FOR WHY IT IS THAT DEVELOPMENTS ARE PARTICULARLY EXCITING OVER THE LAST YEAR. IN WHOLE CELL IMAGING GOING BACK MANY YEARS AGO WE DEVELOPED FOCUSED AT SCANNING ELECTRON MISCOPY. I KNEW THESE WERE USED IN THE SCIENCE WORLD AND SEMI CONDUCTORS. WE TEAMED UP WITH THE COMPANIES THAT MADE THESE, APPLIED THEM SHOWING AT FIRST IT COULD BE DONE IN YEAST CELLS. THIS IS NOW ROUTINELY APPLIED, AND WE LEARNED A GREAT DEAL BOW THE ARCHITECTURE HOW VERY ORGANELLES ARE ARRANGED IN CELLS. COMBINING THIS WE ARE AT THE THRESHOLD WE CAN BEGIN TO LOCALIZE MOLECULES IN THE CONTEXT OF A LARGE CELL. ANOTHER AREA THAT WE INVESTED A LOT OF TIME AND EFFORT, WAS TO DEVELOP THE TOOLS USING ELECTRONIC TOMOWINGGARY, TO VISUAL WHOLE BACTERIAL CELLS AND THE PROTEINS THAT MADE UP THIS SIGNALING ARRAYS. PUBLISHED THE FIRST STRUCTURES, BACTERIAL CELLS, AND CONNECTED THIS TO FUNCTION. WE SHOWED THAT THESE RECEPTORS COULD BE IN DIFFERENT STATES. WE COULD DRIVE THEM FORWARD OWNED BACKWARDS USING LIGAND AND METHODS TO METHYLATE THAT LED TO ADAPTATION. THE IDEA WAS THE NOTION OF DEVELOPING TOOLS TO LOOK AT MOLECULARS, AND USE THAT AS A PREDICTIVE TOOL. WE WENT ON TO PUBLISH PAPERS WHERE WE COULD BEGIN TO USE THIS INFORMATION TO PREDICT WHAT THESE BACTERIA DID. AS YOU CHANGE THE CONDITIONS AND THE GROWTH¨— MEDIUM. ANOTHER FACET OF THE TECHNOLOGY DEVELOPED IS -- WE APPLY TO HIV. THIS SHOWS HOW THIS WORKED. TAKE A SOLUTION OF VIRUSES CAPABLE OF IDENTIFYING CELL -- ENTERING CELLS. ONCE IT GOES INTO THE MICROSCOPE WE CAN ROTATE THE SAMPLES RELATIVE TO THE BECAME. BUT FROM THIS, THE UNIT OF INFORMATION THAT EMERGES IS 3D. IN 2008, WE BEGAN TO DEVELOP THESE METHODS, APPLY THEM TO HIV. BECAUSE EACH OF THESE INDIVIDUAL IMAGES OF VIRUSES ARE AT VERY LOW RESOLUTION, WE DEVELOPED TOOLS TO AVERAGE A LOT OF THESE MAPS TOGETHER FOR INDIVIDUAL SPIKES SPOKEN HERE IN THIS ANIMATION. WE DEVELOPED TOOLS THAT -- ALMOST COMPLETELY AUTOMATED NOW WE GET MOST OF THE INFORMATION FROM, IN THIS CASE, PROTEIN SPIKES TO DETERMINE STRUCTURES AT LOW RESOLUTION WHICH COMBINE WITH X-RAY INFORMATION ON THE INDIVIDUAL PROTEINMERS THAT CAME FROM PETER'S WORK, YOU COULD THEN BEGIN TO BUILD MODELS FOR THESE LARGE ENTITIES, WHICH WE HAD STUDIED AT LOW RESOLUTIONS BUT COULD COMBINE THE INFORMATION AT CRYSTALLOGRAPHY. THE LAST AREA WE WORKED ON WAS REALLY THIS DREAM OF DETERMINING STRUCTURES WITHOUT CRYSTALLOGRAPHY. THIS ANIMATION I HAVE BEEN MAKING EVER SINCE 2001 WHEN I CAME TO THE NIH, OUR VISION WAS ONE DAY THERE WOULD BE A MACHINE YOU COULD INJECT SAMPLES AND SOMETHING WOULD HAPPEN AND STRUCTURES WOULD COME OUT. AND IT REALLY WAS NEVER FAR FETCHED IN MY MIND. WE KNEW THAT ALL THE INDIVIDUAL STEPS COULD BE OTMATED IN 2001. WE SHOWED THE COMPANY THAT MADE THE MICROSCOPES. THIS IS THE AREA WHERE THERE IS TREMEXCITE -- TREMENDOUS EXCITEMENT. TO GIVE YOU A SENSE OF WHAT HAS HAPPENED, HERE IS A SCHEMATIC. CAPTURED THE IDEA. IF YOU LOOK BACK AT THE LAST 20c YEARS IN THE FIELD OVER THE LAST TWO DECADES THIS WERE MANY STRUCTURES DONE AT RESOLUTION, OCCASIONALLY GOING TOxD HIGH RESOLUTION. BUT IF YOU LOOK AT THE CHALLENGE LEVEL ON THE Y AXIS AND RESOLUTION, THERE WAS THE PERCEPTION AND REALITY THAT WE COULD GET TO HIGHER RESOLUTION WITH EASIER THINGS. AS YOU GO TO THE HARDER THINGS, DYNAMIC PROTEIN COMPLEXES, THINGS THAT WERE INVOLVED IN SIGNALING, VARIOUS OTHER THINGS, WE ONLY KNEW THEM AT THE LEVEL OF BLOBS. WE COULD DRAW BLOBS OF A WITH B AND THAT WAS IT. THERE WERE SUCCESSES LOOKING AT SECONDARY STRUCTURES BUT THIS IS WHERE THE FIELD LAY FOR 2 DECADES. THE ONES THAT HAVE NOW CREATED THE MOST INTEREST ARE THE ONES, HIGH RESOLUTION. AND I WANTED TO LOOK AT THAT MORE CLOSELY, BECAUSE IT TELLS US A LOT ABOUT WHERE THE FIELD IS TODAY AND WHERE IT'S LIKELY TO BE HEADED. IF YOU LOOK, THIS IS CURRENT SCORE CARD OF THINGS THAT HAVE BEEN DONE. IF YOU LOOK AT PROTEIN COMPLEXES BEING DOWN NOW IN THE LAST COUPLE OF YEARS BY THIS METHOD OF SINGLE PARTICLE CRIO-EM, THERE IS ABOUT 11 ENTRIES HERE. WE'VE CONTRIBUTED A TO. MANY OTHERS HAVE CONTRIBUTED -- THE WORK IN GERMANY, BAYLOR HOUSTON, AS WELL AS UCSF. THERE ARE SEVERAL TRENDS. ALL THESE PLACES THAT HAVE -- LIKE OUR OWN LAB, BEING IN THIS FIELD FOR A COUPLE DECADES. SECOND, AS THE EARLIER ONES, THERE WAS A NOTION THAT LARGER THINGS WERE EASIER TO GET AT THAN SMALL IRRELEVANT THINGS. -- SMALLER THINGS. THERE WAS A LOT OF WORK FOR SEVERAL DECADES, AND EVENTUAL LEE WORK IN CAMBRIDGE LED TO NEAR -- THESE ARE LARGER THINGS. AS THE SIZE GETS SMALLER IT'S HARDER TO GET THE ATOOTHIC RESOLUTION. I WOULD TOUCH ON THIS LATER IN THE TALK. WHAT DOES THE FUTURE HOLD? SOMETHING I TRIED TO CAPTURE IN THIS VIRUS WHICH IS IF YOU LOOK AHEAD AT THE STRATEGIC VISION FOR HOW ONE CAN RIDE THIS WAVE, I SEE TWO PIECES TO IT. ONE IS THIS JUMP FROM WHERE WE ARE TODAY, TO IN A FEW YEARS, TO BEGIN TO EXPAND THIS LANDSCAPE. AS I SAID BEFORE, THE SUCCESSES HAVE COME FROM PROTEINS THAT -- BOTH FROM LABS DOING THIS FOR A LONG TIME AND ALSO RELATIVELY WELL DEFINED SYSTEMS IN PROTEIN COMPLEXES, IF YOU WILL. I THINK THERE IS GREAT NEED TO EXTEND THIS ENVELOPE TO OTHERS WHO ARE NOT IN THE CRIO EM FIELD. CHRISGRAPHERS BIO ECONOMISTS, TO WHERE ONE CAN BEGIN TO BRING THESE ADVANCES, TO GET THE RESOLUTION PERHAPS LOWER SO ONE CAN TAKE VAC OF THESE DEVELOPMENTS. THE SECOND ASPECT, REALLY THE OTHER FACET OF WHAT A NATIONAL LAB MIGHT DO, IS DRIVE THE TECHNICAL FORWARD. THIS GREAT NEED FOR ADVANCES TO BE MADE BOTH IN HIGHER RESOLUTION. I SHOW HERE AS -- 2 AS THE DESIRED TARGET. 2, YOU KNOW WHAT YOU NEED TO KNOW IN TERMS OF HYDROGEN BONDS, PARTICULAR INTERACTIONS. AND THAT'S -- IT'S ENTIRELY POSSIBLE THAT TECHNOLOGIES COULD BE DRIVEN WITH ENOUGH SORT OF FORCE AT A NATIONAL LAB TO GET US THERE. BUT IT'S NOT GOING TO BE JUST ABOUT RESOLUTION. IF YOU LOOK AT THIS PAGE, THIS SHAPE UNDER-REPRESENTED THE LANDSCAPE OF PROBLEMS WE NEED TO SOLVE. MOST, IF NOT THE VAST MAJORITY, OF INTERESTING PROTEIN COMPLEXES ARE GOING TO BE HERE. THEY'RE GOING TO BE DIFFICULT, DYNAMIC, SHOW LOTS OF DIFFERENT -- IT MAY NOT ALWAYS BE POSSIBLE TO GET ATOMIC RESOLUTION BUT THE BIOLOGY ALREADY LIES -- WE'VE SEEN EXAMPLES ENTHE LAST COUPLE YEARS WHERE INFORMATION COMES OUT AT THESE LOWER RESOLUTIONS. THAT'S WHAT I SEE AS GREAT POTENTIAL. DIFFICULT TO DO WITHOUT THAT KIND OF BROAD SCOPE. AND ANYWAY, THAT WAS THE LAST OFF MY INITIAL SET OF SLIDES. I CAN PAUSE AND TAKE A FEW QUESTIONS AT THIS POINT. >> SO YOU'RE GOING TO TELL US WHAT YOU'RE GOING TO PROPOSE; RIGHT? >> IN TERMS -- I COULD GO TO THE DETAILS. SO I -- I SEE TWO PIECES TO A NATIONAL MISSION OF THIS KIND. ONE IS AN INFRASTRUCTURE FOR EQUIPMENT, WHERE THE LATEST MICROSCOPES ARE OPERATED BY PEOPLE THAT KNOW WHAT TO DO WITH THEM. BEGIN TO PROVIDE A BASE OF USER TO COME IN FROM ACROSS THE U.S., AROUND ALSO WHERE PEOPLE CAN GET TRAINED TO COLLECT THE DATA THAT THEY CAN, THEN, GET ANSWERS TO QUESTIONS. THAT'S A MODEL THAT EXISTS ON A SMALL SCALE IN MANY LABS ACROSS THE U.S. AND ALSO ACROSS THE WORLD. ONE MODEL THAT HAS BROUGHT THIS FURTHER TO SOMETHING LIKE WHAT WE COULD TO HERE IS IN THE UNITED KINGDOM. A COUPLE OF MICROSCOPES HAVE BEEN INSTALLED. AND LOTS OF USERS COME IN TO COLLECT DATA AND THERE IS STAFF THAT CAN EDUCATE THEM ON WHAT TO DO. THE SECOND PIECE, I THINK, HAS TO LOOK A LOT CLOSER TO SOME OF THE DOE LABS WHERE THIS IS TECHNOLOGY DEVELOPMENT. NEW TOOLS CAN BE PARTNERED WITH COMPANIES, FOR EXAMPLE, AS YOU KNOW JOE, WE HAVE A VERY STRONG PARTNERSHIP WITH SEI THAT MANUFACTURES THESE MICROSCOPES. I THINK THOSE TWO PIECES WILL BE THE CORE. THEY'RE TWO SEPARATE FACTORS AND I FEEL THEY'RE EQUALLY IMPORTANT. I HAVE A FEW SLIDES IN THE END WHICH I COULD GO INTO. ONE OF THE -- COME BACK TO THIS LATER ON. ONE OF THE SPECIFIC THINGS, I THINK, A LAB LIKE THIS COULD DEVELOP WORK FLOWS WHICH REALLY TRANSLATEST THESE TECHNOLOGIES TO PEOPLE THAT CAN USE THEM IN SPECIFIC -- ADDRESS SPECIFIC BIOLOGICAL PROBLEMS. IN PARTICULAR HERE ARE SOME BULLET POINTS THAT I THINK A LAB LIKE THIS CAN DO, DEVELOP REPRODUCIBLE WORK FLOWS THAT ACTUALLY ALLOW PEOPLE TO USE IT. MOST -- THE VAST MAJORITY OF QUESTIONS WHERE RAS IS A GOOD EXAMPLE, IT SITS IN DIFFICULT -- TOP PORTION. EXACTLY WHAT ONE SHOULD DO TO BEGIN TO GET STRUCTURAL INFORMATION IS SOMETHING THAT THE LACK COULD ENABLE. DIFFERENT -- I THINK HAVING AN INFORMED AND TECHNICAL STATUTE THAT CAN TEASE IS OUT IS SOMETHING A NATIONAL LAB CAN DO. THE THIRD ASPECT THAT THE LAB COULD DO IS EXTEND THIS FAR BEYOND. IMAGING VIRUSES, BACTERIAL MAMMALIAN CELLS, THOSE ARE ALL EXTREMELY IMPORTANT PROBLEMS AND WILL LEAD THEIR OWN WORK NOS, DRIVEN BY PEOPLE THAT CAN HELP MAKE THIS HAPPEN. FINALLY WE NEED DO WORK CLOSELY WITH THOSE THAT MAKE THESE INSTRUMENTS. THEY HAVE VERY LITTLE BIOLOGICAL BACKGROUND AND PROVIDE TECHNICAL -- THEY HAVE6z TECHNICAL INTEREST BUT I THINK IF WE'RE ABLE TO FOCUS THESE DEVELOPMENTS TO PROBLEMS, IT WILL BE, I CAN, EXTREMELY PRODUCTIVE. IN A WAY THAT WOULD BE DIFFICULT TO DO IN A SMALL SCALE. >> I THINK IT WOULD HELP US TO UNDERSTAND IF YOU COULD GIVE US AN EXAMPLE OF AN EXPERIMENT THAT SOMEBODY WOULD WANT TO DO, AND WHAT THEY WOULD HAVE TO DO AT HOME IN THEIR OWN LAB, AND WHAT THEY BRING TO THIS FACILITY, AND WHAT THEY TAKE AWAY FROM THIS FACILITY. WHAT THEY TAKE AWAY FROM THIS FACILITY IS A HARD DRIVE WITH ELECTRONICS ON IT, I GOT THAT. BUT THE QUESTION IS WHAT DO THEY DO TO DO THE EXPERIMENT? I'VE DONE A FAIR AMOUNT OF ELECTRONIC MICROPY, WAY BACK IN THE DAY. THAT USED TO BE A EXTENSIVE PROCESS. IT WAS NOT STRAIGHT FORWARD BY ANY MEANS. YOU HAD TO MANAGE THE BIOLOGY AND THEN YOU HAD TO TAKE THE SAMPLES IN SUCH A WAY THAT YOU -- SO COULD YOU GIVE AN EXAMPLE OF SUCH A THING? >> I PREPARED A FEW EXAMPLES SO MAYBE I CAN BEGIN WITH THIS. LET ME GO BACK HERE. SO HERE ARE TWO EXAMPLES OF SOMETHING THAT -- PAPERS THAT WERE RECENTLY DONE THAT GIVE AN IDEA OF THIS. HERE IS A BLUE MATE RECEPTOR AS A -- GLUTAMATE RECEPTOR THAT COULD BE PURIFIED IN A LAB. VERY OFTEN, THE PURIFICATION OF THESE PROTEINS THAT WE NEED FOR CREO EM IS SIMILAR DO THE STANDARDS OF CRYSTALLOGRAPHY, NEEDS TO BE VERY GOOD AND STABLE. THERE IS A BIG GAP BETWEEN GETTING INFORMATION HIKE THIS, WHICH IS THE INTEREST -- ONE OF THE DISCOVERIES THAT WE MADE RECENTLY IN GLUTAMATE RECEPTORS -- THIS COMES OUT OF DATA TO. COLLECT THE DATA IN THE MICROSCOPE IS SOMETHING THAT THE FREDERICK NATIONAL LACK COULD ACCELERATE. -- LAB. THE GREATEST GAP I SEE IN THE FIELD IS A KNOWLEDGE OF WHAT IT IS THAT NEEDS TO BE DONE TO PROTEINS ONCE PURIFIED, TO GET INTO THE MICROSCOPE AND ONCE THEY LEAVE THE MICROSCOPE, THEY CAN TAKE BACK DATA BUT THE BELIEVING OF WHAT TO DO WITH IT IS WHERE WE COULD MAKE A BIG DIFFERENCE. I HAVE A SECOND EXAMPLE, I WANT TO GO THROUGH THIS. YOU MENTIONED EARLYIER ABOUT METABOLISM. HERE IS A STRUCTURE OF GLUTAMATE, IMPORTANT METABOLIC ENZYME, IMPORTANT IN CANCER. WHAT'S EXCITING IS NOW FOR A PROTEIN LEAK THIS, THIS IS 360 -- WE HAVE RESOLUTIONS THAT WE CAN GET STRUCTURES LIKE THIS FROM IMAGING ABOUT 20,000 MOLECULES, WHERE WE CAN SEE THE SIDE CHAINS, AND LOCALIZE LIGANDS. FOR US RIGHT NOW, IT TAKES JUST A COUPLE DAYS TO GET THESE STRUCTURES, THIS KIND OF RESOLUTION. >> FOR THIS EXPERIMENT, SOMEBODY BROUGHT YOU PURIFIED PROTEIN OR YOU MADE PURIFIED PROTEIN, AND THEN YOU -- WHERE DID THE LIGAND COME FROM? THERE WAS AN EXPERIMENT ASSOCIATED WITH THAT? THE LIGAND WAS IN THERE? >> SO WE PURIFIED IT IN THE LAB. IT'S DONE -- WE ADDED -- >> GUTTED. >> CORRECT, THEN WE ADDED THE LIGAND, ADP. A NUMBER OF OTHER LIGANDS, WE ADDED IT. A MINUTE LATER IT'S FROZEN IN THE LAB, A TOOL WIDELY AVAILABLE, THEN IT GOES INTO A MICROSCOPE. IT STAYS AT LIQUID NIGHTTRO GEN. THE PROCESS OF COLLECTING THE DATA IS A COUPLE DAYS. >> SO YOU'RE COLLABORATORS CAN COME WITH ALREADY FROZEN STUFF? >> CORRECT. >> THEY COME WITH WITH LIQUID NITROGEN AND YOU FISH IT OUT THERE. >> OR THEY COULD MAKE THE SAMPLES ON SIGHT. >> SO I CAN CLEARLY -- AT LEAST I THINK I SEE HAVE IS A TECHNOLOGY THAT IS RESINHIBIT AT FREDERICK, THAT IS RARE, AT LEAST OTHER PLACES. I THINK WHAT DAVID IS GETTING AT IS IN ORDER FOR THE PROPOSAL TO RISE TO THE LEVEL OF A RAS-LIKE PROJECT, THERE WOULD NEED TO BE EITHER A LONG LINE OF COMPLEXES THAT ARE NOT SOLVED, WHERE SOLVING THEM WOULD BE REALLY IMPORTANT, AND SORT OF -- YOU KNOW THAT THAT DEMAND IS THERE, AND THAT LOGISTIC IS THERE, OR A FOCUS ON SOME EXTREMELY HARD, BUT IF WE JUST KNEW IT, TRANSFORMATIVE SMALLER SETxD OF COMPLEX OR SOMETHING LIKE THAT. I GUESS WHICH OF THOSE DO YOU ENVISION? IF IT'S THE FORMER, IT SEEMS LIKE MAYBE THERE IS ANOTHER KIND OF MECHANISM, RFAs, WE NEED TO MODEL THE SWITCH COMPLEX. IT'S BIGGER THAN ONE PROTEIN. MAYBE IT FITS THAT AREA WHERE YOU COULD WITH THESE NEW TECHNICALS YOU COULD MODEL IT. IT WOULD BE FASCINATING. ONE COULD LEARN. I DON'T KNOW. I'M TRYING TO SORT OF PLUG IN THE SWEET SPOT, THE REST OF ED'S CRITERIA THAT HE LAID OUT THERE IN TERMS OF THE CHARACTERISTICS OF A NATIONAL LABORATORY PROPOSAL, LIKE THE RAS -- I THINK IT'S EXCITING. I CAN CLEARLY SEE MECHANISMS WHERE ONE WOULD LIKE TO ACCELERATE USE OF THIS IN THE COMMUNITY. I'M TRYING TO UNDERSTAND HOW IT FITS THAT LARGER -- >> YEAH. I THINK THE -- WITHOUT DOUBT, IT HAS TO BE THE FORMER. IT'S GOING TO BE BROADLY APPLICABLE TO LOTS OF DIFFICULT THINGS. I THINK THE FIELD RIGHT NOW HAS FOCUSED AND CERTAINLY THE INTEREST IN MY OWN LAB, MEMBRANE PROTEIN COMPLEXES AND THE LIKE. AND I THINK THE WAY I ENVISION IS, IT'S AN ENABLING TOOL FOR PEOPLE TO GET THERE. IT'S ACROSS, DIFFERENT INSTITUTES, DIFFERENT KINDS OF BIOLOGICAL PROBLEMS. IT COULD HAVE GREAT GENERAL IMPACT. AND I CAN THE WAY THAT MAY BE ANSWERING DAVID'S QUESTION AS WELL, I THINK THE WAY FOR INTERACTION HERE WOULD BE FOR -- AS SPECIFIC EXAMPLES AND SUCCESSES COME OUT, I THINK PEOPLE WILL SEE WHAT CAN BE DONE. I THINK THE WORK WE'VE DONE AND OTHERS HAVE DONE, IN MEMBRANE PROTEINS. [INDISCERNIBLE] ALMOST 2 DECADES AGO. WE'RE GETTING TO THIS -- THE FACT YOU CAN GET THIS INFORMATION WITHOUT SUNSHINE IS EXCITING. THE OTHER ASPECT BROAD SPECTRUM, THE ABILITY TO LOOK AT DIFFERENT CONFIRMATIONS. STRUCTURAL BIOLOGY, IF YOU LOOK AT THE LAST FIVE DECADES, THE NEED TO CRYSTALLIZE HAS BEEN A CORNERSTONE TO GET TO THESE INFORMATION. INFORMATION AT THIS RESOLUTION. IF ONE CAN BEGIN TO DESCRIBE THIS LANDSCAPE WITHOUT HAVING TO CRYSTALIZE IT, IT'S VERY PROFOUND. >> SO WHAT YOU'RE KIND OF DESCRIBING REALLY, IS A MASSIVE CORE FACILITY IN A SENSE. ANALOGOUS TO THE SINK ATRON SYSTEM, NOW THAT YOU CAN PROVIDE TO INVESTIGATORS DETAILED INSTRUCTIONS FOR HOW TO PREPARE THEIR PROTEIN, FREEZE IT DOWN AND SHIP IT HERE JUST THE WAY WE SHIP CRYSTALS OFF TO ARGON. SO THERE IS A LOT OF CREO EM THAT GOES ON AROUND THE COUNTRY AS YOU KNOW. SO THE JUSTIFICATION FOR HAVING THIS WOULD BE THAT IN THE EXTRAMURAL COMMUNITY, KEEPING YOUR EQUIPMENT AT THE FRONT EAR. THERE IS -- FRONT ANOTHER. THERE -- FRONTIER. SO PEOPLE WOULD ALWAYS HAVE ACCESS TO THE LATEST. WHAT I DON'T SEE IS -- WHICH IS MORE TYPICAL, MAYBE OF A NATIONAL LAB, IS THE DEVELOPMENT OF THAT NEXT TECHNOLOGY. I THINK YOU SAID SOMETHING SENSIBLE EARLY. [TECHNICAL DIFFICULTIES] TO CAPITOL TO DO THE WORK HE'S DONE SO WELL. ONE OF THE REASONS I WAS ENTHUSIASTIC ABOUT THEM SHARE THIS WITH YOU, HE HAS A LONG HISTORY OF BEING ABLE TO DRIVE TECHNOLOGIES ENPARTNERSHIP WITH -- TECHNOLOGY IN PARTNERSHIP WITH INDUSTRY. FUNDING THIS GUY'S LAB OVER TEN YEARS HAS REALLY BEEN A BIT OF A CHALLENGE BUT IT'S BEEN MITIGATED TO SOME EXTENT. HE'S BE EXTREMELY ENTREPRENEURIAL IN GETTING SEVERAL OF THE BIG MICROSCOPE COMPANIES ON BOARD WITH ACTUALLY SEEING THE VALUE OF BEING ABLE TO APPLY THEIR TECHNOLOGY TO BIOLOGY. SO I THINK THAT THAT DRIVING OF THE TECHNOLOGY IS REALLY IMPORTANT. I THINK HE'S DEMONSTRATED HE CAN DO THAT. I DO SHARE YOUR CONCERN ABOUT, AT SOME POINT, IT'S BECOMING A SERVICE FUNCTION WHERE IF WE DIDN'T CONTINUE TO DRIVE THE TECHNOLOGY, WE'D EVENTUALLY BECOME OBSOLETE. >> MAYBE I COULD JUST MENTION, THIS IS ONE EXAMPLE OF THE GREATER PARTNERSHIP WE HAVE WITH THE COUNTRY THAT MAKES THESE MICROSCOPES. THREE YEARS AGO WE SET UP A CRADA, THEY CONTRIBUTED GENEROUSLY TO -- THE GOAL WAS THE KIND OF THING WE JUST TALKED ABOUT. TO DEVELOP ROUTINE WORK FLOWS. WHAT THIS MEANS IS THIS IS WHAT WE WERE INTERESTED IN TO BREAK THIS BARRIER. NOW WE'VE GONE TO 3 ANG TROMS. WE HOPE TO GO TO 2. BUT THE TECHNOLOGY DEVELOPMENT IS CRITICAL. I WANT TO SEE THE iPHONE VERSION OF THE MICROSCOPES. THAT'S WHAT WE DON'T HAVE. >> WHEN I WAS AT NORTHWESTERN, NOW AT CITY OF HOPE, PROBABLY ONE OF THE MOST REWARDING EXCHANGES IS WITH THE ENGINEERS. WE HAD ENGINEERING SABBATICALS. AT THE CITY OF HOPE WE'RE WORKING WITH ACCURATELY TECH. -- CAL TECH. WE PRESENTED CLINICAL PROBLEMS. THE ENGINEERS SAID THIS IS TRIVIAL. WE WILL SOLVE THIS IN A MOMENT. WHETHER IT'S DEVICES, NEW IMAGING, MONITORING, I THINK TO WORK AROUND THAT CONCEPT WOULD BE VERY EXCITING, PERSONALLY. THERE WAS WORK RECENTLY WHERE YOU PREDICT BILL BE-- THERE IS GREAT POTENTIAL THERE. >> SO IT WOULD SEEM LIKE -- THIS TECHNOLOGY SOUNDS GREAT, BUT BOTH CAN SEE THAT I HAVE NO STRUCTURAL BIOLOGY EXPERTISE.E> VERY MUCH SO. MAYBE JOE CAN SPEAK TO THIS. >> WELL, I MEAN SO THIS IS AN AREA THAT WE'RE BEGINNING TO BRING UP AS WELL. AND I THINK THAT ONE OF THE -- THERE ARE SEVERAL THINGS THAT ARE RATE HIMING IN THIS BUSINESS. ONE OF THEM IS THAT -- RATE LIMITING. ONE OF THEM, PROBABLY -- MADE IT SEEM TOO EASY. IN TERMS OF THE SAMPLE PREPARATION PART OF THIS. YEAH, IT TAKES A COUPLING OF DAYS TO PREPARE THE SAMPLE -- TO IMAGE THE SAMPLE. IT MAY TAKE YOU A COUPLE OF MONTHS OR 6 MONTHS TO ACTUALLY GET ONE THAT'S OF THE QUALITY THAT ONE IMAGES. AND SO ONE OF THE THINGS THAT'S LACKING IN THE FIELD RIGHT NOW IS THAT BODY OF EXPERT TEETHES THAT ALLOWS PEOPLE TO LOVE INTO THE EM DOMAIN. THERE IS A LOT OF PEOPLE IN THE FIELD OF CRYSTALLOGRAPHY THAT NOW GET IT. OKAY, YES, THAT'S HAPPENING IN OUR PLACE. BUT PART OF THE PROBLEM HERE IS HAVING THE EXPERTISE TO ACTUALLY ALLOW YOU TO PREPARE IMAGINABLE QUALITY PROTEINS. SO I THINK THAT'S ONE OF THE THINGS THAT IS RATE LIMITING, ONE OF THE THINGS THAT I THINK THAT THE NATIONAL LABORATORY COULD PROVIDE, SORT OF THE -- THE SERVICE TO THE COUNTRY. AND TO INTEGRATE -- LOTS OF PEOPLE ARE INNOVATING THIS AREA. LIKE THE RAS PROGRAM, INTEGRATING DIFFERENT ASPECTS OF RAS BIOLOGY. I CAN IMAGINE THIS PROGRAM WOULD INTEGRATE DIFFERENT ASPECTS OF SAMPLE PREPARATION, NOT JUST INDIVIDUAL PROTEINS. BUT PROTEINS IN CELLS, ET CETERA, ET CETERA, SO I SEE THAT HAPPENING. THE OTHER THING THAT'S INTERESTING IS THAT YOU CAN DO A LOT OF SCREENING AT HOME ON RELATIVELY CHEAP INSTRUMENTS. WHAT YOU REALLY WANT IN THE END OF THE DAYf‡ IS TO HAVE THE STATE OF THE ART INSTRUMENT WITH THE BEST DETECTOR. WE DON'T ALL NEED TO BUY THAT ONE. THAT ONE COULD BE HERE. I THINK THAT HAVING A PLACE WHERE ONE CAN GO AND GET BEAM TIME WOULD BE REALLY A SERVICE TO THE COMMUNITY. >> THIS IS NOT MY FIELD, BUT THERE SEEMS TO BE THIS DISTINCTION BETWEEN HOW MUCH OF THIS IS AN ABSOLUTELY NECESSARY NATIONAL CORE SERVICE VERSES HOW MUCH IS A UNIQUE NATIONAL RESOURCES. YOU THINK IN TERMS OF THE CREATION WE HEARD EARLIER ABOUT A NATIONAL LAB. I WANT TO THROW THE QUESTION TO YOU, AGAIN, THOUGHT AS AN EXPERT. IF THEIR WERE ONE OR TWO THINGS YOU COULD DO TO SORT OF FURTHER THE STATE THAT YOU THINK YOU COULD DO, BROADEN CONCEPT, TO FURTHER THE STATE OF THE ART TO CREATE A UNIQUE NATIONAL RESOURCE LIKE THIS, WHEW WOULD THOSE THINGS -- WHAT WOULD THOSE THINGS BE TO PUSH THE STATE OF THE ART IN THE INSTRUMENTATION. >> IT WOULD NEED TO BE REAL SUCCESSES IN SOLVING PROBLEMS THAT ARE REALLY HARD, FOR EXAMPLE, PROTEIN RECEPTORS BOUND TO LIGANDS. IF YOU COULD DO IT QUICKLY WITHOUT CRYSTALLIZING THAT WOULD BE A GREAT SUCCESS. IN ORDER FOR THAT TO HAPPEN IN A WAY THAT IS USEABLE, TECHNOLOGY NEEDS TO BE FASTER, COST THESE TO GO DOWN. THE TECHNICAL IS IN AN EARLY PHASE. I WOULD LIKE TO SEE THIS MORE AUTO MATED. THERE IS A LOT TO BE DONE TO GET THESE WORK FLOWS, TO GET SAMPLES IN BUT THE OTHER THING THAT I DIDN'T REALLY FOCUS ON, WHICH IS WHERE WE SPEND THE BULK OF OUR TIME, IS COMPUTING. WE PUMP OUT FROM EACH OF THESE MICROSCOPES, 1-2 TERABYTES A DAY. IT'S GOING TO BE MENETRIERA BYTES IN THE NEXT YEAR OR TWO. SO NOT MANY PLACES HAVE THE ABILITY TO HANDLE THIS VOLUME OF DATA AND TO REDUCE IT TO SOMETHING MEANINGFUL. SO I THINK THE -- WHAT ALL THESE OTHER THINGS EXTREMELY IMPORTANT, HANDLING DATA AND COMPUTING IS GOING TO BE A HUGE BOTTLENECK BEFORE LONG. THESE ARE AREAS WHERE NATIONAL EFFORT WOULD BE OF GREAT VALUE. >> SOMETIMES IT'S EASIER IF YOU BROADEN IT AND BECOME MORE AMBITIOUS. THAT MAY MAKE IT MORE UNIQUE IN SOME WAY. >> SO I THINK THE THING THAT YOU SAID THAT RESONATED WITH ME, YOU WANT TO MAKE AN iPHONE OUT OF THIS. I WAS THINKING YOU WERE GOING TO MAKE THIS PRINCEN FUSION REACTOR, HUNG, AND THERE IS -- HUGE AND THERE IS ONE OF THEM IN THE COUNTRY. IF YOU'RE WORKING WITH A COUNTRY. IT'S TO MOVE THE FIELD TO -- THE COMBINATION OF INTERACTIONS WITH COMPANIES, AND HIGH QUALITY COMPUTING, WHICH YOU'VE GOT IN FREDERICK, RIGHT? YOU'RE IN A UNIQUE POSITION TO REALLY MOVE THE FIELD AND GENERATE THE KIND OF TECHNOLOGY THAT WILL HAVE A BIG IMPACT GOING OUT FROM THE COMPANIES RATHER THAN YOU RUNNING THE SAMPLES HERE. >> I COULDN'T AGREE MORE. I THINK THE ADVANTAGE OF HAVING MAYBE SOME BANDWIDTH FOR PEOPLE TO USE IT, I THINK IT WILL BRING INTERESTING AND IMPORTANT BIOLOGICAL PROBLEMS TO THE PLACE, SO THE TECHNOLOGY ACTUALLY SOLVES THOSE KIND OF PROBLEMS. TO THE EXTENT [INAUDIBLE] SO THERE IS VALUE. BUT NOT TO MAKE IT A PLACE WHERE THERE IS -- THAT IS FLOODED BY SAMPLES COMING IN. THE TEXTBOOK PICTURE THAT THE LIGAPPED COMES IN. YOU'RE SITTING IN THE MEMBRANE. THINGS ARE CHANGING. YOU HAVE TO MAKE ALL THAT HAPPEN IN VITRO. IN ORDER TO USE YOUR GADGET, RIGHT? SO THAT MEANS I HAVE TO HAVE ALL THE SUBUNITS OF THE RECEPTORS, I HAVE TO HAVE THE DOWN-STREAM SECOND MESSENGERS, ALL THAT STUFF, AROUND. AND THAT SOUNDS LIKE A VERY, VERY HARD BUY CHEMISTRY EXPERIMENT. QUITE APART WHERE YOU'RE THE CENSOR, WHETHER SOMETHING HAS HAPPENED OR HASN'T HAPPENED. BUT THAT -- THE BIO CHEMISTRY FOR CRYSTALLOGRAPHY IS RELATIVERY STRAIGHT FORWARD. YOU HAVE TO BE VERY PURE AND IT HAS TO CRYSTALLIZE. IF YOU WANT TO DO ANY DYNAMICS, THEN YOU HAVE THIS -- YOUR DUMPING THIS STUFF EVERY 200 MILLION SECONDS OR LESS, THAT SOUNDS LIKE A VERY DIFFICULT BUY CHEMISTRY STRETCHES. >> THE REAL APPEAL, THE INTENT IS PREADVISORY TO TRAP AND FREEZE INTERMEDIATE CONTRACTS. FOR EXAMPLE THE WORK WITH THE GLUTAMINE RECEPTOR. THERE ARE SEVERAL -- GLUTAMATE, WE HAVE A DOZEN COMBINATIONS. A COUPLE HAVE BEEN CRYSTALLIZED. WHAT OF THE ONES THAT DON'T? >> I GET THAT. TO GET IT INTO YOUR MACHINE, AND I HATE TO TELL YOU THIS, BUT OUT IN THE ACADEMIC WORLD, THE NUMBER OF REALLY GOOD BIOECONOMISTS IS -- BIO CHEMMISTS IS NOT VERY MANY ANYMORE. THERE USED TO BE TONS OF THEM. >> I WAS ABOUT TO TOUCH ON THAT. I THINK THAT -- JOE MENTIONED THIS, TOO. DOING THE BIO CHEMISTRY PROPERLY IS VERY IMPORTANT. IF YOU LOOK FIVE YEARS AHEAD, WHERE WE'RE HEADED, THE KIND OF WORK WE'RE DOING IN WHOLE BACTERIA, TO IMAGINExD MOLECULES IN CELLS, ESPECIALLY SIGNALING COMPLEX. THERE /Ö WAS A DISCUSSION THIS MORNING ON RAS. WE NEED TO UNDERSTAND HOW IT WORKS. SO MANY OF THE TOOLS WE DEVELOP ARE APPLICABLE TO THOSE SYSTEMS THAT MAY BE PARTIALLY PURIFIED, PERHAPS IN TACT CELLS. ALL THE WORK WITH HIV WAS DONE WITH IN TACT VIRUSES. IF I LOOK AHEAD THAT'S WHERE WE'VE DONE THINGS IN LOWER RESOLUTION. IN FIVE YEARS MUST THAT WILL BE EXPLOSIVE SO I'M VERY MUCH IN LINE WITH WHAT YOU'RE SAYING. >> BUT JUST FROM OWE TECHNOLOGY DRIVER POINT OF VIEW, ONE OF THE THINGS THAT IS REMARKABLE TO ME IS THAT THE TECHNOLOGY TURN IN THIS BUSINESS RIGHT NOW IS ABOUT 12 MONTHS. SO SORT OF THE -- THE NEXT ADVANCE IN EITHER COMPURIFIED PROTEINTATIONAL OR ANALYTICAL TECHNOLOGY OCCURS ABOUT ONCE A YEAR. MAYBE FASTER THAN THAT. SO THE GENERAL SCIENTIFIC COMMUNITY THAT WANTS TO BE CONSUMERS OF THIS TECHNOLOGY IS GOING TO HAVE A HARD TIME KEEPING UP WITH THAT, AT LEAST UNTIL IT SLOWS DOWN A BIT. SO JUST HAVING AT LEAST A FEW LABORATORIES IN THE WORLD THAT PROVIDE THAT CAPABILITY WHERE YOU BRING YOUR SAMPLE, YOU SOLVE THE CHEMISTRY PROBLEM, TO THE START OF THE ART PLACE, WOULD BE A BIG SERVICE FOR A WHILE. >> MENTIONED 3 POSSIBLE PUTES TO IMPROVING WHAT'S THE USE OF THIS TECHNOLOGY. ONE IS TECHNOLOGY IMPROVEMENT, ONE IS DOING THINGS FOR OTHER PEOPLE ON SITE. THE THIRD IS TRAINING PEOPLE SO THEY CAN DO IT IN THEIR OWN PLACE. THE OTHER DIMENSION THAT WAS BROUGHT UP, SAMPLE PREPARATION. WHAT ISN'T CLEAR TO ME IS WHETHER THE 6 MONTHS IT TAKES TO GET A GOOD SAMPLE IS STO CASSIC THAT YOU CAN'T RECENTLY REPRODUCE, OR YOU CAN DO IT AGAIN EVERY TIME. YOU HAVE ONE SAMPLE THAT CARRY TO FREDERICK AND ANALYZE. SO BE USEFUL TO ME TO HEAR HOW NOT ONLY HOW YOU WOULD ALLOCATE AMONG THOSE VARIOUS WAYS OF DOING THINGS, BUT ALSO WHAT KINDS OF RESOURCES ARE EXPECTED? YOU SAY YOU'RE GOING TO GET TO RESOURCES AND DOLLARS. I DON'T MEAN TO PIN YOU DOWN BUT SOME ORDER OF MAGANY DUDE ESTIMATE WOULD BE QUITE USEFUL. WE NEED TO THINK ABOUT THE IT, WE CAN TAKE THE WHO LATER ON. I HEAR BOB CONCERNED WITH HIS OWN PERSONNEL. THERE ARE WAYS TO DO THINGS THAT INVOLVE REVISION RATHER -- >> NO, EXACTLY. I WATCHED THIS DONE IN A NIM OF DIFFERENT PROJECTS SO I KNOW HE'S PERSONALLY CAPABLE OF HELPING TO DRIVE SOMETHING BUT I CERTAINLY WOULDN'T WANT HIM TO BE RESPONSIBLE -- >> [INAUDIBLE] >> YEAH. YEAH. NO, THE QUESTIONS YOU RACED, THIS IS WHAT I THINK ABOUT ALL THE TIME. WHERE ARE THE -- HOW DO DIFFERENT PROJECTS ADVANCE? IF I TAKE INDIVIDUAL EXAMPLES ONE AT THAT TIME, IT'S TAKEN A LOT OF HARD WORK. WHERE WE WORK COLLABORATIVELY WITH BIO CHEMMISTS, PEOPLE THAT KNOW WHAT THEY'RE DOING. THE PROBLEM IS DIFFERENT IN EACH CASE. WORK WITH HIV, THEY'RE WORLD EXPERTS IN THE STUFF. SO THE SUCCESSES IN EACH CASE, AND IF YOU LOOK WORLDWIDE WHERE THE SUCCESSES ARE, IT'S TAKEN ALL THE ABOVE. GOOD BIO CHEM INDUSTRY, MICROPY AND COMPURIFIED PROTEINTATION. [TECHNICAL DIFFICULTIES]. I CAN THE FOCUS NEED TO BE HEAVILY ON THE TWO SIDES BEFORE AND AFTER. BECAUSE MICROSCOPY CAN BE PURCHASED AND OPERATED. BUT HAVING QUALIFIED PEOPLE, OWNED EXPERTS IN COMPURIFIED PROTEINTATION, THOSE ARE AT THIS AREAS THAT NEED -- IN COMPUTATION, THOSE ARE TWO AREAS THAT ARE NEEDED. >> WE ARE TALKING ABOUT THIS AS A PROJECT THAT THE FRIDAY NIWOULD SUBPOENA -- NCI WOULD SUPPORT THROUGH OUR NATIONAL LAB BUT WHAT YOU'RE TALKING ABOUT HERE IS BROADRY APPLICABLE TO VIRTUALLY ALL FIELDS OF SCIENCE. SHOULD THIS BE SOMETHING THAT NIH HELPS TO PAY FOR THROUGH OTHER FUNDING MECHANISM, COMMON FUNDS AND DECIDED AT THE NATIONAL LAB. I THINK ONE OF THE THINGS WE HAVE TO TALK ABOUT AS A GROUP IS WHAT OTHER KINDS OF EVALUATION OF THE GENERAL PROPOSAL THAT YOU'RE MAKING SHOULD BE CARRIED OUT. SHOULD WE -- I THINK WE ALL KNOW THAT THIS ARE POCKETS, YOU MENTIONED POCKETS OF HIGH QUALITY CREO EM BEING DONE AROUND THE COUNTRY AND IN EUROPE. SHOULD WE BRING IN A BUNCH OF FOLKS TO THINK ABOUT WHETHER THERE IS VALUE IN HAVING SOME CENTRALIZED EFFORT? OR IS THERE SOME PART OF THE WHOA PROCESS THAT COULD BE EMPHASIZED IN A NATIONAL LAB AND DISSEMINATED TO OTHER PARTS OF THE COUNTRY? SO THERE ARE LOTS OF MODELS NOT BEING AN EXPERT MYSELF, ONLY TALKING TO EXPERTS, I'M NOT TOTALLY SURE WHAT THE BEST WAY IS TO MOVE FORWARD. BUT MY CONVERSATIONS WITH A LOT OF KNOWLEDGEABLE PEOPLE IS NO DOUBT THIS IS AN IMPORTANT COMING TECHNOLOGY THAT NEEDS TO BE MADE ACCESSIBLE TO PEOPLE WHO -- WORKING ON CANCER OR CARDIOVASCULAR OR METABOLIC DISEASE, OF GREATER ACCESS TO THESE TECHNOLOGIES. MAYBE WE SHOULD OPEN THIS DISCUSSION DO A WORKSHOP WE SUPPORT, OR BRING IN THE WELL-KNOWN EXPERTS THAT WE'VE DISCUSSED. OWNED -- WIDELY KNOWN. AND SEE HOW THEY WOULD RESPOND TO A SUGGESTION THAT WE SITE SOME COMPONENT OF TECHNOLOGY DEVELOPMENT AND TECHNOLOGY USED A FREDERICK. HOW WOULD THAT BE VIEWED AS AN OPPORTUNITY BY VARIOUS PEOPLE? >> YEAH, I WAS GOING TO MAKE THAT SUGGESTION THAT THIS SOUNDS LIKE A PERFECT WORKSHOP TOPIC WHERE PEOPLE -- THE STRUCTURAL BUYOLOGISTS AND CELL BIOLOGIST WHOSE ARE LINKED TO HIGH RESOLUTION ANALYSIS COME TOGETHER AND FROM THAT, ONE WOULD LIKE TWO THINGS. ONE IS CONSENSUS ENTHUSIASM. THINKING BACK TO THE RAS PROJECT, THIS WASN'T A LOT OF ELABORATE REVIEW. THERE WAS SOME. BUT IT'S KIND OF -- [INAUDIBLE] >> THE WORKSHOP IN SAN FRANCISCO, BEFORE WE GOT IT AWAY WAS HIGH HEY CRITICAL. PEOPLE SAID YES IT WOULD BE GREAT TO DO THIS. >> SO THERE WAS -- I RECALL A MEETING IN THIS GROUP WHERE MAYBE EVEN YOU PROPOSED A PERSPECTIVE, THERE WAS A CONSENSUS IN ENTHUSIASM THAT -- RITUAL CENSUS, THIS WOULD BE A GREAT THING. THEN A WORKSHOP IN SAN FRANCISCO -- WHAT'S THAT? [INAUDIBLE] >> IT WAS YOUR IDEA. [LAUGHTER] BUT IT WAS -- THE ENTHUSIASM PORTION WAS HIGH AT MULTIPLE LEVELS. THERE WAS A NO BRAINER ACROSS THE COMMUNITY, THERE WAS A SENSE THIS IS A BIG CHALLENGE. THERE WASN'T ANY SINGLE THING LIKE IT ELSE WHERE. ENTHUSIASM WAS ONE. FOR THIS, IN PARTICULAR, THERE NEEDS TO BE A SET OF USERS. WHAT ARE THE FIRST TEN OR 12, WHATEVER THE RIGHT NUMBER OF BIG THINGS THAT GET SOLVED USING THIS TECHNOLOGY, AND IF THAT'S NOT THERE, THEN EVEN IF THE FIRST WAS THERE, SOUNDS GREAT BUT THERE ARE NO -- YES, I'LL PUT TREE POSTDOCS AND THEY'LL SPEND 6 MONTHS WORKING OUT CONDITIONS TO GET MY PROCESS MEASURED. THAT WOULD BE THE OTHER KEY COMPONENT. >> SO JUST RESPONDING TO LEVI, AND I DON'T REMEMBER IF IT WAS DAVID OR LARRY, THAT MENTIONED WHAT ULTIMATELY WOULD BE A DEMONSTRATION PROJECT. ONE OF THE THINGS INTRIGUING TO ME WAS LISTENING TO FRANK THIS MORNING TALK ABOUT -- HE HAS A NUMBER OF STRUCTURES HE WOULD LIKE TO SOLVE. SOME SEEM AMENABLE TO CRYSTALLOGRAPHY. SOME ARE NOT. AND ONE OF THE SIDE BENEFITS TO SOMETHING LIKE THIS, AGAIN, IF IT'S APPROPRIATELY VETTED AND THERE IS 245-0678, COULD BE REAL SYNERGY AT THE NATIONAL LAB TO MAKE PROGRESS ON TWO FRONTS OF THE ONE ON THIS, THE OTHER REHATED TO SOLVING DIFFICULT -- RELATED TO SOLVING DIFFICULT PROBLEMS THAT FRANK HAS. MAYBE THAT'S MINIMAL, MAYBE SUBSTANTIVE. I DON'T KNOW. IT OCCURRED TO ME AS I WAS LISTENING TO FRANK THIS MORNING. >> I WAS THINKING THE SAME THING IN A DIFFERENT WAY. SOMEHOW, IF THIS THING HAD COME TO US WITH A PROPOSAL THAT YOU COULD TELL THE CONFIRMATIONS OF ALL THE DIFFERENT RAS CONSTRUCTS THAT FRANK IS GOING TO MAKE IN THIS RAS MINUS CELL, RIGHT, AND THAT YOU COULD TELL THEM APART WITH THIS GADGET, WELL, THAT WOULD BE A GOOD THING. IN A CELL, RIGHT? THIS IS YOUR MEDIUM RESOLUTION. THERE IS A DEPRESSING TENDENCY FOR CRYSTAL GRAPHERS AND OUR GUYS TO GO TO THE HIGHEST END OF RESOLUTION, WHEN THERE IS MUCH TO BE LEARNED AT LOWER RESOLUTION. YOU DIDN'T DO THAT, BUT IT IS AN ISSUE. BUT -- SOME KIND OF A PROPOSAL TO DO THAT COULD JUSTIFY, IN MY MIND A FAIR AMOUNT OF INVESTMENT IN A RELATIVELY SHORT TIME. I DON'T KNOW WHEN THESE THINGS ARE GOING TO BE READY. SOMETIMES NOT SO DISTANT FUTURE. >> WE HAVE SPOKEN SEVERAL TIMES ABOUT THIS, FRANK. >> THIS WOULD BE A TREMENDOUS BENEFIT TO ALL PROGRAM FOR THE ROPES YOU SUGGESTED, AS WELL AS LOOKING AT THE DIFFERENT MUTANT PROTEINS, THE SIGNALING COMPLEXES WHICH RAS RECRUITS, INCLUDE IN THE CASE OF RAS, PROBABLY A DOZEN PROTEINS ARE ASSEMBLED IN -- ALL THIS STUFF. IN WAYS THAT BIO CHYLEMISTS HAVING HAVEN'T BEEN ABLE TO FIGURE OUT AT ALL, AND IT ALL HAPPENS AT THE MEMBRANE. SEEING THE COMPLEXES AND WHAT'S IN THEM, THIS KIND OF RESOLUTION, WOULD BE A FANTASTIC BREAK THROUGH FOR THE RAS FIELD. BIOLOGY AND BIO CHEMISTRY FUTURE IS IN THE MEMBRANE IN THESE COMPLEX SYSTEMS. >> I COULD ADD, ALTHOUGH I DIDN'T DWELL ON THIS, THE PLACE WE MADE THE BIGGEST DENT, THIS IS HIV AND VIRUSES. WE'VE DONE 70 OR 80 STRUCTURES OF LIKO PROTEINS, LIGANDS, ANTIBODIES, ET CETERA. IT DOESN'T NEED -- HAS NOT NEEDED TO GO TO HIGH RESOLUTION. THE BIOGRAPHY HAS COME OUT IN TERMS OF WHAT THE FUNCTIONAL MEANING OF THE BINDING OF THESE ANTIBODIES ARE. AND I THINK THE SAME THING WITH RAS. WE HAD NUMEROUS DISCUSSIONS HOW TO PROCEED. >> WHAT FRANK SAYS RESONATES WITH ME PROVIDED YOU CAN IDENTIFY ALL THE DIFFERENT PROTEINS WHEN YOU'RE LOOKING AT THEM. THEY CAN ALL LOOK LIKE BLOBS. YOU HAVE TO FIGURE OUT WHICH BLOB IS WHICH. IN THIS CASE IT'S SIMPLE BUT IN THESE OTHER CASES -- BUT I'M NOT PUT OFF BY THAT. WHAT I WAS LOOKING FOR WAS A FOCUS FOR THIS TECHNOLOGY THAT WE COULD UNDERSTAND THAT IT WAS GOING TO BE A GIANT STEP. BECAUSE I UNDERSTAND THAT IT'S TECHNICALCALLY A GIANT STEP, BUT BUT -- WE WANT TO WORK ON SOMETHING. >> THE ONE THING THAT KIND OF GETS ME EXCITED IS THIS SLIDE THAT YOU SHOWED EARLY WHERE THE HIGHEST RESOLUTION STRUCTURES WERE THE BIGGEST COMPLEXES. RIGHT? TWO MEGADALTONS, YOU GET THREE ANGSTROM RESOLUTIONS. >> WE'VE DONE IT WITH SMALLER ONES. >> YOU CAN LOOK AT BIG COMPLEX THINGS, LIKE TRANSCRIPTION COMPLEXES. WE ARE TALKING ABOUT DRUGGING TRANSPORTATION EXCEPTION FACTORS EARLIER TODAY. AND THE WORKSHOP, WE TALKED ABOUT BRANDING THE NATIONAL LAB. SO THIS, I THINK, WOULD INCREASE VISIBILITY AND CREATE EXCITEMENT IN A COMMUNITY THAT DOESN'T THINK ABOUT A NATIONAL LAB. HAVING THEM HERE, TALKING ABOUT THIS POSSIBILITY I THINK WOULD BE GOOD FOR THE LAB. REGARDLESS. >> I WANTED TO MENTION A COUPLE OF THINGS. ONE IS THE ISSUE OF RESOLUTION ITSELF. WHILE THE TECHNOLOGIES WILL GET THERE SOONER THAN LATER, I THINK NOT ALL THE -- NOT ONLY WILL MANY OF THE PROBLEMS NEED HIGH RESOLUTION. THEY NEVER GET THERE BECAUSE PROTEINS ARE FLEXIBLE. MUCH OF THE WORK WE DO IS FOCUSED ON TEASING OUT TO UNDERSTAND WHAT THIS MEANS. IN TERMS OF PROBLEMS, THOUGH, THE PROBLEM SPACE, STILL VERY EARLY. THIS IS LESS THAN A DOZEN OF THESE ENTITIES THAT GET CLOSE TO [INDISCERNIBLE] BUT IF YOU LOOK AT THE DISTRIBUTION IN TERMS OF WHAT THEY REPRESENT THAT'S WHERE THE EXCITEMENT IS. HERE ARE LARGE PROTEIN COMPLEXES, INDIME COMPLEXES -- ENZYME COMPLEXES. METABOLIC, I THINK IT'S JUST STARTING. ONE OF THE THINGS I SEE LOOKING AHEAD IS AT PROBLEMS SUPPORTED BY THE RESEARCH, SUPPORTED BY EVERY INSTITUTE. IMMUNOLOGY OR CELL BIOLOGY. I THINK THEY WILL ALL BE USEFUL. AS WE GO FORWARD, THE ONE SET WILL TEACH US WHICH THINGS CAN BE TACKLED AND WHERE THE WORK NEEDS TO BE TO WORK ON THE DIVIDEND THINGS. RAS IS ONE OF THE MORE DIFFICULT ONES. SO IT'S WELL WORTH INVESTIGATING EFFORTS TO UNDERSTAND HOW TO CRACK IT USING THESE METHODS. >> I'M VERY ENTHUSIASTIC BUT PEOPLE ON THE RAS TEAM HAVE BEEN DO VISIT YOUR LAB AND DISCUSS THE DETAILS. VERY ENTHUSIASTIC ABOUT THE OPPORTUNITY TO SOLVE THESE BIG PROBLEMS USING THIS TECHNOLOGY. >> WE HAD MANY OF THE RAS TEAM HAD COME OVER AND WE HAD MANY DISCUSSIONS ON HOW WE WOULD TEAM UP WITH THEM. >> WE'RE SCHEDULED FOR A BRIDGE LET ME SUGGEST, LET'S TAKE THE BREAK. BUT WHEN WE COME BACK IN ABOUT 15 MINUTES, COULD YOU GIVE US WHAT THIS WILL LOOK LIKE IN TWO YEARS? WHAT SPECIFICALLY ARE YOU GOING TO PROPOSE TO THIS WORKSHOP THAT I THINK WE'RE TALKING ABOUT CONVENING? WHAT IS THE MAGNITUDE OF THE PROJECT THAT YOU'RE TALKING ABOUT? AND WHAT ARE YOU ACTUAL HEY GOING TO DELIVER WITHIN TWO YEARS? >> OKAY. >> I THINK THAT'S A GOOD IDEA. I ALSO THINK THIS IS ANOTHER WAY TO APPROACH THE WORKSHOP, THAT IS TO SAY HERE WE HAVE AN EMERGING TECHNOLOGY. MORE AND MORE WIDELY USED. IT HAS OBVIOUS ADVANTAGES OVER CRYSTALLOGRAPHY. IT'S GOT -- OFFERS POTENTIAL FOR LOOKING AT MUCH LARGER STRUCTURES, AND MORE CONVENIENT WAYS, AND MEMBRANE PROTEINS. HOW SHOULD THE SCIENTIFIC COMMUNITY GO ABOUT FOSTERING THE GROWTH AND APPLICATION OF THOSE TECHNOLOGIES? AS ANOTHER WAY TO -- RATHER THAN SAY HERE IS THE PROPOSAL UP OR DOWN. I THINK THERE MAY BE SOME BENEFIT TO SAYING LET'S THINK ABOUT THE WAY WE GET -- DO THIS MOST EFFECTIVELY. TH ARE THOSE ELEMENTS THAT I MENTIONED BEFORE, TRAINING A LOT OF PEOPLE. HAVING A SERVICE CENTER, HAVING -- FOSTERING DEVELOPMENT OF TECHNOLOGY AT ONE PLACE OR MULTIPLE PLACES. WHEN YOU BRING IN PEOPLE FROM DIFFERENT CENTERS YOU'VE GET A VARIETY OF VIEWS HOW THESE THINGS CAN BEST BE DONE. HOPEFULLY SOME PEOPLE WILL BE HONEST AND SAY WE WANT TO SERVE OURSELVES, NOT HUNDREDS OF PEOPLE THAT MAY COME TO SEE US. OTHER PEOPLE PLAY SAY TECHNOLOGY DEVELOPMENT WILL GO ON EVERYWHERE, AND SHOULDN'T BE CENTRALIZED. I THINK WE'D HAVE AN INTERESTING UNITED NATIONS OF VIEWS. >> I HAVE A DIFFERENT TAKE ON IT. I THINK THAT THIS IS LOOK LIKE -- THEY CAME AND SAID WE CAN CLONE THIS STUFF. WE CAN EXPRESSION THIS STUFF. WE CAN MAKE PROTEINS. IN HUGE AMOUNTS. IFER THERE WAS A TECHNOLOGY THAT APPLIED TO EVERYTHING, THERE IT WAS. OKAY? BUT HOW DID IT ACTUALLY GET ESTABLISHED? SOMEBODY HAD THE IDEA WE'RE GOING TO MAKE HUMAN INSULIN. THAT BECAME THE DEMONSTRATION PROJECT. DIDN'T MATTER HOW MANY OTHER -- ALL THE TECHNOLOGY GOT DIFFUSED BUT THE DRIVER WAS THIS VERY DIFFICULT PROJECT THAT WASN'T -- WE DIDN'T INTEND TO REPLACE BIOCHEMISTRY. EVERY KNEW THAT ONCE YOU -- I DON'T THINK YOU WANT TO REPLACE CRYSTALLOGRAPHY. >> NO, NOT AT ALL. >> LET'S DO RAS. >> TO BE SLIGHTLY ARGUMENTATIVE THERE IS A WRIST OF THINGS THAT HAVE ALREADY BEEN ACCOMPLISHED. IT'S NOT A QUESTION OF WHAT TO DO WITH RECOMBINANT DEW POINT. >> BUT EVEN AT THAT POINT, WHAT REALLY MADE THE IMPACT BOTH ON THE SCIENTIFIC COMMUNITY AND EVERYBODY ELSE, WAS SOMETHING THAT ACTUALLY WAS USEFUL THAT COULDN'T HAVE BEEN ACCOMPLISHED ANY OTHER WAY. >> YEAH, BUT I THINK YOU MIGHT SAY THE SAME THING ABOUT VIRAL RECEPTOR INTERACTIONS. >> YOU COULD. YOU COULD. BUT I THINK RAS ACTUALLY ATTRACTIVE FOR THE REASON YOU CAN'T DO IT BY CRYSTALLOGRAPHY. THAT'S THE WHOLE POINT. IT'S IN VIVO. >> WE CAN COME BACK TO THIS BUT THERE IS GREAT MERIT IN DEFINING A FEW VERY DIFFICULT THINGS. MY INTENTION WAS TO PAINT THE VISION. IT HAS TO BE TRANSLATED INTO SPECIFIC THINGS. RAS, DESCRIPTION OF THE VARRIOUS, SUFFICIENT DETAIL, THAT WOULD BE A GREAT GOAL. COULD BE THE THING THAT ONE COULD GO AFTER. >> THERE ARE OTHER KINDS OF STORIES YOU MAY WANT TO HEAR. MCKINNON SOLVED A BIG MEMBRANE PROBLEM WITH CHRISALGRAPHY BUT NOW HIS LAB IS DOING CRIO EM SO WE'D LEAK TO HEAR MORE ABOUT THAT. >> I THINK IF WE'RE GOING TO HAVE THIS KIND OF WORKSHOP WE OUGHT TO PUT ON THE TABLE THERE IS A -- >> I'M NOT CONTESTING THAT. THAT'S NOT THE ONLY THING. >> HE WHY YES. >> LET'S TAKE A 15 MINUTE BREAK. GIVE US SOME -- TODAY'S VERSION OF THE SPECIFICS WHEN WE COME BACK >> ALL I ASKED HIM TO DO IS PREPARE COMPLETE DETL AND PROPOSALS IN 15 MINUTES. BUT I THINK WHAT WE WOULD LIKE TO DO IS TO RESUMMARRIZE SORT OF THE GENERAL BONES OF WHAT YOU'RE PROPOSING AND THEN TO SPEND A COUPLE OF MINUTES TALKING ABOUT WHAT A WORKSHOP MIGHT LOOK LIKE THAT WOULD SERVE TO EXPAND AND EXPLORE THE GENERAL CONCEPTS THAT YOU'RE PROPOSING HERE. MAYBE YOU COULD INTRODUCE THAT. DIFFERENT US SOME SENSE OF WHAT THE SCALE IS THAT YOU'RE TALKING ABOUT AND THEN LET'S TALK A LITTLE BIT ABOUT THE WORKSHOP. >> THANK YOU. >> I'M TRYING TO DO JUSTICE TO THE SCOPE WHAT YOU'RE ASKING FOR. LET ME BEGIN BY SAYING THAT I THINK THAT THREE MAJOR THESIS THAT A NATIONAL LAB LIKE THIS HAS. THE ONE IS THE TIME FRAME, THERE NEEDS TO BE A PLACE WHERE PEOPLE -- CAN ACTUALLY COME TO AND TAKE AWAY SOMETHING TANGIBLE. THAT'S A VERY CLEAR CUT PIECE. THAT WILL LEAD PEOPLE -- I THINK PEOPLE WHO KNOW HOW TO USE THE INSTRUMENTS, KNOW HOW TO MAKE -- WHAT TO DO WITH THE DATA. I THINK THAT PART PROBABLY HAS TO BE THE FIRST ELEMENT WHICH BEGINS TO DISSEMINATE THE TECHNOLOGY TO USE THAT AREN'T -- FROM AFAR. IT'S A GOOD EXAMPLE AND I'VE HAD MANY DISCUSSIONS WITH FRANK AND MANY OTHERS. IT'S A DIFFICULT PROBLEM. BUT THESE A SYSTEMATIC WAY TO GO AFTER THAT, THE THINGS THAT COULD BE DONE, THINGS TO BE AVOIDED. I THINK WE COULD PICK A FEW OF THOSE BUT I THINK THERE'S NO DOUBT THAT IN THE FIRST CASE, THERE HAS TO BE A WELL DEFINED PLAN WITH PEOPLE AND INSTRUMENTS AND PEOPLE WHO OPERATE IT TO ACTUALLY GET UP. PEOPLE WHO DON'T DO IT YOU MENTIONED -- THEY ARE PERHAPS THE MOST INTERESTING COMMUNITY RIGHT NOW WHO ARE RIGHT NEXT -- WHO CAN SEE THE POTENTIAL OF COMBINING WHAT THEY DO AT THIS LEVEL. WHAT THEY DO. IT'S NOT ABOUT REPLACING IT AT ALL. I THINK -- ESSENTIALLY PART AND PARCEL OF THE WHOLE PROCESS. YOU WANT TO USE IT AS BEST AS POSSIBLE AND DO THE THINGS WE CANNOT DOING AS EASILY. IF YOU LOOK, IT IS SHORT OF THE COMPLEXITY OF THE RESOLUTION. THE THINGS THAT -- CONTINUES TO DO ARE HARDER THINGS. BUT IF YOU LOOK AT THE UPPER END THE THINGS THAT FRANK SPOKE B IT WOULD BE NEARLY IMPOSSIBLE TO GET AT -- BUT WE WANT TO WORK WITH -- THAT'S THE, TO ME THAT'S THE FIRST PIECE THAT CAN -- SPECIFIC SUCCESSES. THESE LECTURES ARE ENFORCED I THINK FOR AN ESTABLISHMENT LIKE THIS SHOULD BE BEYOND THE PLACE -- WE CAN TAKE DATA BACK. I THINK WE NEED TO ENGAGE WITH THE COMMUNITY -- I WANT TO BUILD THAT MACHINE. ACTUALLY IT'S BUILT IN A WAY THAT WAS USEFUL TO BIOLOGISTS. I THINK THAT CAN HAPPEN AND IT WILL TAKE SOMETIME BUT WE NEED TO BEGIN TO ENGAGE WITH THE -- ARE IN LINE FOR THE TYPES OF PROBLEMS THAT NEED TO BE SOLVED. I THINK OTHERWISE, THEY CAN EASILY BE A DISCONNECT BETWEEN TECHNOLOGIES THAT DO THE GREATEST THING BUT SAMPLES THAT ARE ACTUALLY RELEVANT WITH WHAT ONE NEEDS TO WORK WITH. THERE NEEDS TO BE VERY LARGE -- OF PEOPLE THAT CAN SPEAK THIS LANGUAGE, USE IT, KNOW WHAT TO DO SO THAT INSTITUTIONS, ONLY OF THE CONVERSATIONS I'VE HAD WITH INSTITUTIONS SEEKING TO BUILD THIS CAPABILITY. WITHOUT EXCEPTION, THEY ALL STUDY WITH THIS -- SHOULD THEY JUST GET A COUPLE OF NEW FACULTY MEMBERS AND THEN BUY ONE INSTRUMENTAL THAT'S AT A LOWER RATE. WHAT DO THEY DO THE NEXT ONE, DO THEY GO TO THE NEXT ONE OR MAKE A VERY LARGE INVESTMENT. I HOPE IT WORKS OUT. A PLACE LIKE THIS THAT COULD LOWER THE VALUE FOR INSTITUTIONS TO INVEST BUT PROVIDE THE TRAINING THAT LETS THEM ACTUALLY BEGIN TO USE THEM AT A SMALLER SYNDICATION WITH INSTITUTIONS, LOCAL INSTITUTIONS. THOSE ARE TO ME IN TERMS, I DON'T KNOW IF THAT'S AS SPECIFIC AS YOU'RE LOOKING FOR. I THINK IT'S THE KEY ELEMENT FOR WHAT I THINK IT WILL TAKE FOR THIS TO BE SUCCESSFUL. >> THANKS. AND SO JUST ROUGH ORDER OF MAGNITUDE SCALE, WHAT ARE YOU THINKING ABOUT? >> SO, THE STUDY -- THESE HIGHER MICROSCOPES BETWEEN FOUR AND $5 MILLION A PIECE. IT MIGHT TAKE A MICROSCOPE TO GET -- THERE WILL BE PEOPLE, 10 OR 20 PEOPLE EARLY ON. I THINK IT NEEDS TO GROW ORGANICALLY. I THINK THE PEOPLE INVESTMENT WILL HAVE TO BE PEOPLE THAT CAN WORK IN THE BIOCHEMICAL END AND THE MICROSCOPY END AND PEOPLE -- GET MORE AND MORE EXPENSIVE. IN THE EARLY DAYS IT DIDN'T USED TO BE SO EXPENSIVE BUT NOW -- ARE LARGE. I THINK THE INVESTMENTS AND COMPUTING ALONE WOULD NOT BEGIN TO BE A SIGNIFICANT PIECE OF THE COST. I THINK THEY'RE TALKING IN THE 10 PLUS MILLION, 10 TO $20 MILLION RANGE. >> SO YOU'VE BEEN SUCCESSFUL IN YEARS PAST WITH, AS I INDICATED EARLIER, WITH GETTING PARTNERSHIPS WITH MICROSCOPE COMPANIES. DO WE THINK THERE WOULD BE PERHAPS EVEN A GREATER OPPORTUNITY TO GET BUY-IN TERMS OF THE HIGH COST ASSOCIATED WITH THE EQUIPMENT FROM SOME OF THESE FOLKS THAT WOULD MITIGATE THE AT LEAST THE START UP COSTS. I REALIZE IT'S A DIFFICULT QUESTION, BUT A CACHE OF SORT OF BEING ASSOCIATED WITH A NATIONAL LABORATORY MIGHT IN FACT BE EVEN GREATER OF THE CACHE ASSOCIATED WITH YOUR LAB, I DON'T KNOW. >> I THINK THERE ARE TWO PIECES FOR WHAT YOU ASK FOR. ONE IS THE INCENTIVE FOR MICROSCOPE MANUFACTURERS TO WORK WITH US. I THINK IT'S VERY HIGH. ALL THE DISCUSSIONS I'VE HAD BECAUSE THEY SEE THIS AS A PORTAL TO GO TO PHARMA BECAUSE THE MOMENT FOR EXAMPLE I MENTIONED, I SHOWED THE -- THE FACT THAT STRUCTURES CAN COME OUT RELATIVELY QUICKLY, I THINK SOME OF THE SYSTEMS WHERE YOU CAN LOCALIZE BOUND LIGANDS IS VERY INTERESTING. I HAVE HAD SEVERAL CONVERSATIONS WITH PHARMACEUTICAL COMPANIES WHO FEEL THIS IS SOMETHING OF GREAT VALUE TO THEM. THE OTHER PIECE OF IT IS INTERESTS FROM OTHER INSTITUTES ON THE CAMPUS. I'VE HAD DISCUSSIONS WITH MANY INSTITUTES, AND YOU KNOW, INSTEAD THEY THEMSELVES DOING IT ON THEIR OWN, THEY MAY BE VERY POSITIVELY INCLINED TO WORK WITH US IF THEY TAKE LEADERSHIP AND JOIN FORCES. BOTH OF THOSE I SEE THE POTENTIAL. >> YOU HAVE TO REMAIN COMPETITIVE FOR FIVE TO SEVEN YEARS. WHAT'S THE REFRESH RATE FOR THE INSTRUMENT? >> IT IS AN INTERESTING NUMBER -- IT IS ABOUT 12 MONTHS. THE INSTRUMENT ITSELF CONTINUES TO EVOLVE. BUT I THINK HOW WE USE IT IS WHERE I'VE SEEN THE BIGGEST CHANGES. THAT'S WHERE THE GREATER GROWTH WILL PROBABLY BE MAYBE NOT SO MUCH IN THE MICROSCOPE ITSELF AT THE END OF THE DAY IT'S AN ELECTRON BEAM OR SOMETHING WHERE YOU COUNT THE ELECTRONS. BUT IN PREPARATION IS AN AREA THAT'S STILL PRETTY MUCH DONE THE WAY IT WAS DONE 20 TO 30 YEARS AGO. COMPUTING WILL BE GREAT ADVANCES. SO THE SPEED AT WHICH THESE THREE PIECES -- PREPARING SPECIMENS OR CONVERTING, I SHOULD SAY, CONVERTING INTERESTING BIOLOGICAL -- ALL SIGNALING COMPLEXES INTO A PATHWAY THAT CAN BE LOOKED INTO. THAT'S ONE AREA. THE MICROSCOPY ITSELF -- WHAT YOU DO WITH THE DATA THAT COMES OUT. I THINK IF WE HAVE A FACILITY THAT HAS A HIGH ENOUGH VISIBILITY LIKE THIS, I WOULD IMAGINE CHANGES ON A YEARLY BASIS. AND THAT WILL BE ALMOST IMPOSSIBLE. >> BUT YOU'RE NOT TALKING ABOUT CHANGING OUT A FIVE, $10 MILLION MICROSCOPE. ESSENTIALLY WHAT YOU'RE ADDING A CAMERA HERE, A FACE PLATE THERE, A NEW CRYO-- HERE, ETCETERA. SO SORT OF INCREMENTAL ADVANCES IN THE TECHNOLOGY SUITE I THINK IS WHAT YOU'RE TALKING ABOUT. >> YES. IF YOU LOOK AT FOR EXAMPLE I CAN SPEAK LITTLE BIT ABOUT THIS MICROSCOPE, THE ONE THAT MANY PEOPLE IN THE FIELD -- WE TOOK DELIVERY OF THE VERY FIRST COMMERCIAL INSTRUMENT IN EARLY 2009. IT TOOK A COUPLE YEARS, WE WORKED WITH IT, I SPEPTD A LOT OF TIME DEBUGGING THIS AND THAT. TWO YEARS LATER IT WAS THE NEXT GENERATION. PERHAPS IMPROVEMENTS ON IT IN A YEARLY BASIS BUT IT'S NOT NEEDED TO BE REPLACING THE ENTIRE MICROSCOPE. WE ADDED THE SECTORS LIKE YOU SAID, WE'VE CHANGED BITS AND PIECES. BUT THERE'S A HUGE GAP FOR EXAMPLE IS ALL OF THE STUFF THAT COMES BEFORE THE MICROSCOPY. THERE'S SOME ROBOTICS THERE. BUT THERE IS YOU IMAGINE IS A VERY VERY STEEP RATE OF CHANGE. NOT AS EXPENSIVE AS THE MICROSCOPE ITSELF -- SIX MONTHS TO 12 MONTHS BASIS. >> I JUST WANT TO EMPHASIZE THAT A HUGE NEED HERE IS THIS IDEA OF SCALABLE PROCESSING SOFTWARE FOR IMAGING. EVEN AT THE LEVEL OF LIGHT MICROSCOPY. THE PROGRAM ARE SO POOR FOR AUTOMATED IMAGING FOR FINDING THIS SPOT REPRODUCIBLY TRYING TO FIND THE CTC ON A SLIDE AND ANYTHING WE DO IN THIS ARENA SHOULD BE SCALABLE. AND YES, SO THAT'S A HUGE PART OF IT. >> ALL RIGHT. SO MAYBE WE COULD TALK A LITTLE BIT ABOUT THE NEXT STEPS WHICH WOULD BE I THINK TO CONVENE THIS WORKSHOP TO GO THROUGH THIS A LITTLE BIT MORE DETAIL AND GET THIS PERSPECTIVE OF THE LARGER TECHNICALLY SOPHISTICATED AND USER GROUPS. I'M NOT QUITE SURE HOW TO GET THAT WORKSHOP TO HAPPEN, BUT MAYBE YOU AND FRANK AND DAVID COULD TAKE THE LEAD IN PUTTING SOMETHING LIKE THAT TOGETHER, PERHAPS VETTING THE INVITEES THROUGH THIS COMMITTEE. SO THAT BUT TRY TO DO THIS IN RELATIVELY SHORT ORDER, SHORT BEING AS SOON AS YOU CAN GET IT TO HAPPEN AND GET THE RIGHT PEOPLE THERE. BUT I THINK THAT WOULD BE THE NEXT STEP. AND YOU KNOW, THEN IF WE COULD GET THAT TO HAPPEN BEFORE THE NEXT MEETING OF THIS COMMITTEE, WHATEVER IT'S CALLED, THEN I THINK WE COULD HAVE A MORE DEFINITIVE DISCUSSION ABOUT THE NEXT STEP. >> THAT'S A GREAT IDEA. I THINK THAT INCLUDING PEOPLE THAT MIGHT BE, WANT TO BE USERS, I THINK THAT'S WHERE I THINK THE GREATEST IMPACT. I THINK HEARING FROM THEM, AND ALSO MAYBE HEARING A SPECTRUM OF IDEAS ON WHAT THE TECHNOLOGY MIGHT DO THAT IT DOES NOT DO TODAY. I THINK THOSE ARE THINGS THAT COULD BE SHARPENED. >> WHAT WOULD PEOPLE THINK ABOUT ACTUALLY INVITING SOME OF THE TECHNOLOGY PROVIDERS TO THAT MEETING? >> MANUFACTURERS. >> YES. >> SURE. >> THE COMPANIES. >> WHY NOT? >> WE COULD DO THAT. >> THE ONLY THING, IF THERE ARE THREE OR FOUR, YOU WANT REPS FROM ALL THREE OR FOUR. >> YES. >> YOU MIGHT GET A PERSPECTIVE ON WHAT THE PACE OF DEVELOPMENT'S GOING TO BE. MAYBE NOT JUST THE MACHINES, MAYBE THE -- >> THE COMPUTERS, ALGORITHMS. >> FACE VALUE AND LOOKING AT IT AS A PROBLEM AS A WHOLE INCLUDING ALL THE THINGS THAT HAPPEN AS DAVID SAYS MAYBE THERE'S NOT SO MANY PEOPLE IN BIOCHEMISTRY. I THINK COUPLING THE BIOCHEMISTRY TO THE MICROSCOPIES -- THOSE ARE REALLY CRITICAL THINGS AND THAT'S WHERE THE GAPS LIE AT THIS TIME. >> OKAY? NEXT STEP. >> MAY I ASK A QUICK QUESTION. IS THERE, IS THERE IMAGE ANALYSIS EXPERTISE, STRONG GROUP HERE AT FREDERICK? >> THERE'S SOME. I THINK IT COULD BE BUILT ON. THE COMPUTING AND IMAGING ANALYSIS IS AN AREA THAT COULD BE SOME EXPERTISE AND IT CERTAINLY COULD BE EXPANDED IN THIS AREA. I WANT TO POINT OUT IN THIS BOOK -- TO PUT THIS BOOK TOGETHER, SOME DETAIL, A FEW PAGES IN THE FRONT THAT SPEAK TO WHAT IT MIGHT BE. SORRY I DIDN'T GET TO YOU EARLY ENOUGH BUT THERE'S A DESCRIPTION IN THE EARLY PAGE ON THE SHAPE OF WHAT THINGS. >> DAVID, JOE AND I DISCUSSED THIS OFF LINE A LITTLE BIT. I THINK IT WOULD BE USEFUL SOMETIME SOONISH TO ACTUALLY HAVE A MORE DETAILED ASSESSMENT OF WHAT'S ACTUALLY AT FREDERICK IN COMPUTATIONAL BIOLOGY. MAYBE AT THE NEXT MEETING YOU COULD GIVE US A LITTLE SORT OF SUMMARY OVERVIEW OF THAT? >> OKAY. THANK YOU VERY MUCH. >> THANK YOU. >> GOOD START. >> OKAY. WE HAVE SEVERAL OTHER AGENDA ITEMS HERE THAT WE NEED TO GET THROUGH. HAROLD SUGGESTED OR WE DISCUSSED THE CONCEPT OF CHANGING THE NAME OF THIS COMMITTEE TO THE FREDERICK NATIONAL LABORATORY ADVISORY COMMITTEE. IF WE'RE GOING TO MOVE FORWARD ON THAT, WE NEED A MOTION TO THAT EFFECT. ALL IN FAVOR. THERE WE GO. OKAY. OKAY. I GUESS ONE OF THE OTHER ACTION -- >> [INDISCERNIBLE]. [LAUGHTER] >> MOVING RIGHT ALONG. [LAUGHTER] >> OKAY. ONE OF THE OTHER THINGS HAT WE DISCUSSED WAS THE IDEA OF HAVING SORT OF A REVIEW OF REVIEWS FOR THE VARIOUS MAJOR THEMES THAT THE NATIONAL LABORATORY. DAVID, MAYBE IT WOULD BE USEFUL AT THE NEXT MEETING FOR YOU TO DEFINE WHAT THOSE MAJOR THEMES ARE IN SOME FORMAL WAY. AND THEN TALK ABOUT HOW IT IS THAT THEY GET REVIEWED AND SORT OF A SCHEDULE AND HOW WE MIGHT HEAR FROM THE REVIEWERS. >> WE MIGHT BRING TO THE MEETING ONE OR TWO AREAS OF THE REVIEW COMMITTEE. >> AGAIN, AS WAS MENTIONED MOST OF THE WORK [INDISCERNIBLE] >> CAN YOU USE THE MICROPHONE. >> I'M SORRY. SO THE WAY IT OPERATES IS THAT MOST OF WHAT WE DO SUPPORTS OF COURSE VARIOUS NIAID PROGRAMS -- PART OF THE BROADER REVIEW. THE ACTUAL WORK WE DO IS REVIEWED ON A BI-ANNUAL BASIS TWICE A YEAR BY A COMMITTEE CALLED THE -- BOARD WHERE THEY COLLECT EVERYTHING AND THAT GENERATES BIG REPORTS THAT WE GO OVER IN GREAT DETAIL. THAT'S HOW OUR PERFORMANCE OVERALL IS ASSESSED IN AN INTEGRATED FASHION. NOW THERE ARE PROGRAMS SUCH AS -- CANCER VIRUS PROGRAM -- WHICH ARE REVIEWED BY EXTERNAL SAME AS ALL PRINCIPAL INVESTIGATORS ARE. THOSE ARE THE EXCEPTIONS RATHER THAN THE RULE. >> LET ME MAKE A SUGGESTION RATHER THAN WAIT UNTIL THE NEXT MEETING WE MIGHT PUT TOGETHER A ONE-PAGER WHAT YOU THINK ARE THE IDENTIFIABLE SUBPARTS THAT ARE DIFFERENT FROM RAS. AND WHAT THE REVIEW MECHANISM IS, WHETHER IT'S THROUGH ACTD PROGRAM OR WHETHER IT'S GENERIC TO THE FREDERICK NATIONAL LAB AND WHEN YOU THINK OR WHAT YOU THINK MIGHT BE APPROPRIATE TO BRING HERE. JOE AND I WILL WORK WITH YOU ON HELPING THE AGENDA ITEM. >> THAT SOUNDS FINE. WE CAN PUT THAT TOGETHER IN THE NEXT COUPLE MONTHS. YES, YES. >> PRESENT SOMETHING NEXT TIME. >> OKAY, GOOD. >> I GUESS THE OTHER THING THAT WE WALKED ABOUT WAS THIS IDEA ABOUT HOW IT IS THAT WE'RE GOING TO GET THE COMMUNITY INPUT ON OTHER BIG IDEAS. AND WE TALKED ABOUT SEVERAL THINGS BUT I THINK WHERE WE LEFT IT WAS WE WERE GOING TO TURN AT LOOSE ON THE PROVOCATIVE QUESTIONS COMMUNITY AND ARM HIM WITH A FEW OVERVIEW SLIDES WHAT THE COMPETENCIES THE CURRENT COMPETENCIES IN THE FREDERICK NATIONAL LABORATORY ARE AND SEE WHAT EMERGES FROM ALL OF THAT. AND THEN I GUESS THE OTHER ACTION ITEM WAS TO TRY TO PUT THIS ON THE AGENDA FOR AN UPCOMING CANCER CENTER DIRECTOR'S MEETING. AND AGAIN SORT OF PRIME THEM WITH THE QUESTION AND SEE WHAT IDEAS ON THAT FRONT SHOW UP. >> I THINK THE LATTER IS REALLY EASY. THEIRST WILL REQUIRE A LITTLE MORE PLANNING. THERE'S REALLY A BIG DIFFERENCE IN MY OWN VIEW BETWEEN WHAT WE'RE TRYING TO DO HERE WHEN WE THINK ABOUT INITIATIVES FOR THE PUBLIC NATIONAL LAB AND THE PROVOCATIVE QUESTIONS ARE ABOUT BUT I THINK THERE'S A POTENTIAL FOR ED TO DEAL WITH THE MANY CAPTIVE AUDIENCES EVERY TIME HE HAS A PQ WORKSHOP. AND NARROW THE WORKSHOP TO SAY THERE'S SOMETHING OUT THERE THAT'S A WAY TO STIMULATE NEW IDEAS. MAYBE A ONE TIME DISCUSSION, TAKE A BREAK FROM QUESTIONS AND TALK ABOUT -- >> MAYBE YOU TRY IT ON A COUPLE OF THEM AND IF IT DOESN'T WORK THEN YOU PUNT. >> LET PEOPLE KNOW ONCEY ACCEPTED AN INVITATION YOU'LL SPEND AN HOUR A DAY TO TALK ABOUT THIS, PUT THEM ON THE WEBSITE AND THINK ABOUT RAS AND WHAT ELSE MIGHT BE APPROPRIATE. HERE'S A CHANCE FOR YOU TO GIVE INPUT WHERE THE NCI OVERSEES THINGS SO IT WOULD BE USEFUL. >> WOULD YOU CONSIDER GETTING TOGETHER AN ALL STAR TEAM TO THE PEOPLE THAT CONTRIBUTED FROM THE ONES YOU'VE DONE AND HAVE A PQ SESSION DEVOTED EXCLUSIVELY TO THIS TOPIC? >> THERE ARE A LOT OF STARS, THOUGH, DON'T YOU THINK? AND YOU DON'T KNOW WHO IS GOING TO BE GOOD AT THAT. >> PROVOCATIVE INITIATIVES. >> YOU DON'T WANT TO BE TOO POSITIVE. >> [INDISCERNIBLE]. >> ONE OR TWO WOULD BE INFORMATIVE. >> THE NEXT ONE -- MAYBE MAKE USE OF THAT. I THINK IT'S PROBABLY CONFUSING. >> LET'S NOT DO THIS. >> YES, RIGHT. [LAUGHTER] >> WELL, SORT OF ON THAT POINT GAIL BROUGHT UP AT THE BREAK THE FACT THAT WE'VE ALREADY HAD IN THIS GROUP ONE ROUND OF PRESENTATIONS OF IDEAS THAT MANY OF US THOUGHT WERE PROPER FOR THESE KINDS OF INITIATIVES. WE SORT OF PRESENTED THEM, AND THEM NOTHING HAPPENED. I MEAN, SO NOTHING WAS SO STUNNING TO EVERYBODY THAT YOU KNOW THERE WAS THIS CLAMOR OF ENTHUSIASM TO GO FORWARD. BUT I THOUGHT IN THOSE DISCUSSIONS THERE WERE SEVERAL REFINEMENTS THAT COULD HAVE BEEN MADE TO ACTUALLY COME UP WITH A BETTER PROPOSAL THAT MIGHT HAVE BEEN BETTER SUITED. GAIL MAYBE YOU CAN COMMENT ON THIS BUT WE SHOULD HAVE AS YOU WERE SUGGESTING SOME MECHANISM ON FOLLOW THROUGH HERE. >> WELL WHEN I WAS TALKING ABOUT THIS I WAS TALKING ABOUT ENTHUSIASM COMING UP WITH NEW IDEAS OUT OF THE COMFORT ZONE TO CONSIDER BRINGING HOME TO THEIR COLLEAGUES THE NEW IDEAS THEY WANT TO SEE WHATEVER HAPPENED TO THAT AND SO WE HAVE TO HAVE I THINK EVEN IF THE ANSWER IS GOOD-BYE, I THINK PEOPLE OUGHT TO HAVE THAT FEEDBACK, WANT TO FIND OUT WHAT HAPPENED. >> THAT'S INDIRECT FEEDBACK BECAUSE THE PRODUCTIVE QUESTIONS WEBSITE LISTS LOTS OF QUESTIONS AND ALSO THE QUESTIONS THAT ARE SELECTED AS PART OF THE -- >> AT A WORKSHOP, SPECIFICALLY DIRECT -- >> THEY ALL KNOW ABOUT THE WEBSITE. MAYBE THIS IS AN INTERESTING QUESTION FOR INCREASING OUR COMMUNITY CONTACT. WHAT DO YOU DO ABOUT FOLLOW UP WITH WORKSHOP PARTICIPANTS. [INDISCERNIBLE]. >> SCIENTIFICALLY THE WORKSHOP WE GET, THE NOTES FROM THE MEETING WHICH LISTS ALL THE QUESTIONS. AND THEN IT DOES GO INTO A BLACK BOX. THE NEXT THING PUBLIC THAT COMES OUT ARE THE FINAL QUESTIONS. SO I MEAN THERE IS A DOCUMENT NOW THAT KIND OF DESCRIBES THE STEPS THAT GO ON DEPENDING ON WHEN YOUR WORKSHOP WAS. YOU MAY OR MAY NOT HAVE SEEN THAT DOCUMENT BUT THERE'S A CAREFUL KIND OF FOLLOWING OF EACH QUESTION HOW IT'S BEEN MODIFIED AND WHICH ONES INFLUENCE THE FINAL QUESTIONS. THERE'S A WAY TO DO THAT WITHOUT BEING ENORMOUSLY COMPLICATED TO KIND OF FOLLOW THE GENERATION OF A QUESTION. BUT WE CERTAINLY COULD EASILY, WHEN THE QUESTIONS COME OUT, DO AN E MALE -- E-MAIL LIST OF ALL THE PEOPLE THAT CONTRIBUTED AND HERE'S WE'VE GOT. THAT'S KIND OF AN EASY FIX TO DIRECT PEOPLE TO THAT. ONE OF THE THINGS THAT'S INTERESTING WHICH IS PART OF THE DYNAMICS OF THIS WHOLE PROCESS IS THAT EVEN THOUGH THE PEOPLE WHO GET EXCITED ABOUT BUILDING THE QUESTIONS, KIND OF GET THIS INVOLVEMENT, VERY FEW OF THEM ACTUALLY APPLY TO THE ACTUAL QUESTIONS THEMSELVES FOR GRANTS. SOME OF THEM BUT MOST DON'T. SO MAYBE THAT'S A BREAK DOWN IN THE SETTING. I THINK YOUR IDEA ABOUT DOING A NOTE THAT THIS IS THE FINAL PRODUCTMENT TYPICALLY EACH WORKSHOP GENERATES ONE OR TWO QUESTIONS OR THE GENESIS OF ONE OR TWO QUESTIONS COME FROM WORK SHOPS. SO IT'S SOMETHING LIKE THAT. >> WITH RESPECT TO THE QUESTION THAT GAIL ASKED, THE MINUTES WHICH WE NEVER APPROVED. >> WE DID IT BY E-MAIL. >> OKAY, ALL RIGHT. SORRY I MISSED THAT. BUT THERE IS AN EXTENSIVE DISCUSSION IN THE MINUTES OF EACH OF PROPOSALS. IT'S INTERESTING TO LOOK BACK AT WHAT WAS SAID BECAUSE IN MANY CASES WE SAID WE SHOULD HAVE WORK SHOPS TO TRY TO FURTHER DISCUSS SOME OF THE THING THIS PARTICULARLY PROMISING. THERE'S LANGUAGE HERE THAT'S NOT SO DIFFERENT FROM WHAT WE'VE EXPRESSED WITH RESPECT TO -- BUT THERE WAS LESS ENTHUSIASM, THE MAGNITUDE AND APPROPRIATENESS, MANY OF THE THING WE HEARD ABOUT AND THINGS THAT ARE ONGOING IN LOTS OF PLACES, WE MAY NOT NEED THE ENVIRONMENT OF THE PUBLIC NATIONAL LAB. >> TO THE POINT OF GENERATING FORWARD MOTION HERE, ONE OF THE THING WE'RE SORT OF LACKING IS THE MECHANISM TO TAKE ANY ONE OF THESE THINGS FORWARD. >> A COUPLE OF PEOPLE TO LOOK AT -- SOME OF THESE THINGS SHOULD BE BROUGHT BACK TO THE TABLE. >> RIGHT. MAYBE I SHOULD DO THAT. >> WASN'T THERE A FOLLOW UP TO THAT WHERE YOU ASKED EACH OF THE PRESENTERS TO THEN SAY WHAT WOULD YOU LIKE TO DO TO GO FORWARD WITH THIS. >> WE SORT OF DID THAT A LITTLE BIT INFORMALLY BUT THIS WAS NO WHAT I GUESS I WOULD CALL SUPPORT MECHANISM AT THAT TIME ALLOWED THAT TO HAPPEN. SO IT SEEMS TO ME THAT MAYBE WE SHOULD GET EVERYBODY TO READ THE MINUTES. >> NOT JUST TO APPROVE THEM. >> BUT TO ACTUALLY READ THEM. >> OR TO RECIRCULATE THE PROPOSALS OR THE SUMMARIES OF THE PROPOSALS. >> [INDISCERNIBLE] >> BUT THE POINT IS I THINK WE SHOULD TAKE IT UPON OURSELVES THAT IF ONE OF US FEELS PASSIONATE ABOUT ONE OF THESE THINGS, THEN THEY'LL WAIT FOR SOMEBODY TO COME HOLD YOUR HAND, GO AHEAD AND TAKE THE LEAD ON IT AND PUSH IT. I THINK ONE OF THE LESSONS THAT I LEARNED IN WATCHING AGAIN THE DOE LABS BUILD THESE PROJECTS. THOSE AREN'T BUILT FROM A ONE-DAY MEETINGS, THOSE ARE BUILT OVER A PERIOD OF A NUMBER OF MONTHS OR YEARS AS PEOPLE GENERATE THE CONSENSUS AND REFINE THE IDEAS AND SO ON. SO MANY OF THEM STARTED OFF AS QUITE DIFFERENT THAN WHAT ULTIMATELY EMERGED. SO I THINK THAT WE SHOULDN'T TAKE A SOFT YES AS A LICENSE TO GO AWAY. >> ONE THING TO TAKE AWAY FROM THE COMMENTS YOU'VE MADE BEFORE ABOUT HOW THE DOE LAB BUILDS PROJECTS IS THAT THE LABS THEMSELVES HAVE COMMITTEES THAT NURTURE THESE THINGS AND MOVE THEM ALONG. ONE ADVANTAGE I BELIEVE THAT SOME OF THOSE LABS HAVE IS THEY HAVE IN THE CONTRACTING ROLE, ACADEMIC PARTNERS. IT'S NO SECRET ANYMORE, AT LEAST IF THEREFORE WAS A SECRET THAT THEY AND I HAVE BEEN CONVERSATIONS IN SOME OF THE UNIVERSITIES IN MARYLAND TO INTEREST THEM, YOUR UNIVERSITY'S COMING TO VISIT US, VERY VERY SOON, NEXT COUPLE WEEKS. ONE OF THE THING TO HAVE ON THE TABLE ABOUT THOSE DISCUSSIONS IS HOW THEY GET ENGAGED THROUGH THEIR FACULTY WITH A FUNCTION THE NATIONAL LAB MIGHT TAKE YOU. NOW WHETHER ACADEMIC INSTITUTIONS WHICH MIGHT NOT BE CONTRACTORS BUT WHAT AN ENGAGEMENT MIGHT BE INTERESTED IN RECOGNIZING THE IMPORTANCE OF -- >> I DIDN'T MENTION IT IN THE TALK BUT HE'S BEEN COMMUNICATING WITH THOSE SAME UNIVERSITIES AS LOCAL INTEREST IN WHAT HE'S TALKING ABOUT. SO YES. SO WE'LL HAVE A LONGER DISCUSSION ON THAT, I GUESS, AT A FUTURE MEETING. >> GOOD. >> OKAY. THAT SORT OF BRINGS ME TO THE END OF THE THINGS THAT HAROLD WAS SUPPOSED TO TALK ABOUT. >> [INDISCERNIBLE]. >> ARE THERE OTHER THINGS THAT WE WANT TO BRING UP FOR DISCUSSION IN THE REMAINING 30 MINUTES? NEW BUSINESS? NEW IDEAS? GOING ONCE, GOING TWICE. ALL RIGHT, WE'VE BEEN VERY EFFICIENT. THANK YOU ALL, GREAT DISCUSSIONS. AND WE'LL SEE YOU AT THE NEXT MEETING.