>> THANK YOU SO MUCH FOR COMING TODAY TO THIS SECOND WORKSHOP OF THE ADVISORY COMMITTEE TO THE NIH DIRECTOR B.R.A.I.N INITIATIVE WORKING WE ARE THANKFUL TO EVERYONE WHO IS HERE IN PERSON AND WE ARE ALSO GRATEFUL TO EVERYONE WHO IS WATCHING AT HOME ONLINE VIA THE VIDEOCAST THAT IS ALSO GOING TO BE ARCHIVED, SO IN THE EVENT THERE'S ANY SESSION THAT YOU AFTER THE FACT BY GOING TO THE N IH VIDEOCAST WEBSITE. FIRST UP WE ARE GOING TO HAVE DR. JOSHUA GOURD GORDON, DIRECTOR OF THE NATIONAL INSTITUTE OF MENTAL HEALTH, THEN WE'LL GET THE SESSION STARTED. >> Dr. Gordon: THANK YOU EVERYONE JOINING US IN THE ROOM OR ONLINE, I KNOW THERE'S LOTS OF YOU OUT THERE AND WE REALLY APPRECIATE IT. AS MOST OF YOU KNOW BY NOW, THE BRAIN INITIATIVE IS A REALLY GOVERNMENT-WIDE INITIATIVE TO SUPPORT THE DEVELOPMENT OF NOVEL TECHNOLOGIES AIMED AT UNDERSTANDING HOW BRAIN CIRCUITS PRODUCES BEHAVIOR AND APPLYING THATS TO DEVELOP NEW TOOLS FOR NEUROSCIENCE AND EVENTUALLY FOR HUMAN CLINICAL BENEFIT. THE BRAIN INITIATIVE AS IT APPROACHES ITS HALFWAY POINT IS LOOKING TO REVIETZ THE STRATEGIC PLAN THAT WAS DRAFTED BY THE INITIAL WORKING GROUP OF THE ADVISORY COMMITTEE TO THE DREK TO HER OF THE N -- TO THE DIRECTOR OF THE NIH. THAT DOCUMENT BRAIN 2025 SETS OUT PRIORITY AREAS FOR TOOL DEVELOPMENT AND RESEARCH, AND WE FELT IT WAS IMPORTANT WE HAVE AT NIH FELT IT WAS IMPORTANT THAT WE LOOK AT THE PROGRESS THAT'S BEEN MADE IN THE FIRST HALF OF THE BRAIN INITIATIVE, LOOK FOR OPPORTUNITIES TO TWEAK THAT PLAN TO ENSURE WE CONTINUE TO STAY AT THE CUTTING EDGE AND WE MAKE THE MOST OF THE OPPORTUNITIES WE'VE BEEN GIVEN. FOR THOSE OF YOU WHO DON'T KNOW, THE OPPORTUNITY IS CONSIDERABLE. CONGRESS HAS AUTHORIZED AND CONTINUES TO APPROPRIATE FUNDS FOR THE BRAIN INITIATIVE THROUGH 2025. THE CURRENT FUNDING LEVELS ARE APPROXIMATELY AT THE RECOMMENDATIONS OF THE INITIAL WORKING GROUP. IF THE BUDGET PASSES NEXT WEEK, THE FY19 BUDGET WILL BE SOMEWHERE AROUND $420 MILLION FOR THE BRAIN INITIATIVE. I WANT TO POINT OUT TWO FACTS. ONE FACT BEING THAT THIS COMMITMENT IS CONSIDERABLE AND WILL MEAN OUTOF LAYS OF SOMETHING CLOSE TO $4 BILLION FOR THE BRAIN INITIATIVE, AND THE SECOND FACT THAT THIS IS A DROP IN THE BUCKET COMPARED TO THE COMMITMENT OF THE NIH NEUROSCIENCE RESEARCH GENERALLY, IT'S LESS THAN 10 PERCENT OF THE NIH NEUROSCIENCE BUDGET, SO THE BRAIN INITIATIVE IS SQUARELY FOCUSED ON ITS MISSION OF DEVELOPING TOOLS AND TECHNOLOGIES AND KNOWLEDGE AROUND HOW BRAIN CIRCUITS PRODUCE BEHAVIOR. WE ARE DOING THESE WORKSHOPS OUT IN COMMUNITIES LIKE THE UNIVERSITY OF CHICAGO AND THE CHICAGO COMMUNITY AND THE GREATER MIDWEST FOR THE BETTER OF IT TO TRY TO HEAR FROM SCIENTISTS AROUND THE COUNTRY ABOUT PRIORITIES IN DIFFERENT AREAS. THE FIRST WORKSHOP TOOK PLACE EARLIER THIS MONTH IN BOSTON, AND THE FOCUS OF THAT WORKSHOP WAS ON HUMAN NEUROSCIENCE. WE ARE HAVING THIS WORKSHOP TODAY, AND THE NEXT WORKSHOP AND I THINK THE FINAL ONE, IS THAT RIGHT, WILL BE ON OCTOBER 4TH IN HOUSTON, AND THE FOCUS OF THAT ONE WILL BE TWOFOLD, FIRST ON THEORY TO EXPERIMENT AND BACK, IN OTHER WORDS, INCORPORATING THEORETICAL AND COMPUTATIONAL APPROACHES INTO THE BRAIN INITIATIVE, AS WELL AS AN EXAMINATION OF THE ISSUES AROUND BIG SCIENCE AND BIG PROJECTS AS I WOULD SAY COMPLEMENTED BY SMALL SCIENCE OR INDIVIDUAL INVESTIGATOR LABS, SO THERE'S SORT OF A DUAL ROLE FOR THAT WORKSHOP. SO WE LOOK FORWARD TO YOUR PARTICIPATION TODAY AT THAT WORKSHOP, AND WE LOOK FORWARD TO HEARING THE ADVISORY COMMITTEE'S FINAL REPORTS BY NEXT JUNE SO THAT WE CAN AT NIH BEGIN PLANNING THE SECOND HALF OF IMPLEMENTATION OF THE STRATEGIC PLAN. WITH THAT, I WILL BRING JOHN MAUNSELL TO THE PODIUM TO TELL US ABOUT TODAY. >> Dr. Maunsell: THANK YOU, JOSH THANK YOU. SO I WOULD LIKE TO WELCOME THOSE OF YOU WHO HAVE COME TO CHICAGO AND ALSO THOSE OF YOU VUPG ON THE VIDEO STREAM. I WOULD LIKE TO JUST TAKE A -- VIEWING ON THE VIDEO STREAM. I WOULD LIKE TO TAKE JUST A FEW MINIMUM TOITS TO EXPLAIN WHAT OUR GOALS ARE AT THIS AND THE OTHER WORKSHOPS WE'VE BEEN WORKING ON. AS JOSH MENTIONED, WE ARE CONDUCTING SORT OF EVALUATION/ REVIEW OF WHAT'S BEEN GOING ON WITH THE BRAIN INITIATIVE. OUR CHARGE HAS BEEN TO EXAMINE THE SORTS OF PROGRAMS THAT HAVE BEEN SUPPORTED, THE RESULTS THAT HAVE COME FROM THOSE PROGRAMS AND TO ASSESS WHETHER THE LANDSCAPE HAS CHANGED SINCE THE FIRST DOCUMENT WAS PREPARED BY THE FIRST WORKING GROUP FIVE YEARS AGO AND WHETHER THERE ARE NEW OPPORTUNITIES THAT COULD BE TAKEN ADVANTAGE OF AT THIS POINT OR NEW WAYS OF TRAINING INDIVIDUALS OR GETTING TECHNOLOGIES DISSEMINATED OUT TO VARIOUS LABS ACROSS THE COUNTRY AND AROUND THE WORLD. OUR WORKING GROUP CONSISTS OF 16 SCIENTISTS WITH A BROAD RANGE OF EXPERTISE RELEVANT TO THE CHARGE THAT WE'VE BEEN GIVEN. MOST OF THEM ARE HERE TODAY. SOME ARE JOINING BY VIDEO. WE ALSO HAVE EX-OFFICIO MEMBERS ON THE WORKING GROUP WHO REPRESENT THE NIH AND THE VARIOUS PARTNER INSTITUTIONS THAT ARE INVOLVED WITH NIH IN BRINGING THE BRAIN INITIATIVE TO FRUITION. I'LL MENTION ALSO THAT WE HAVE A SORT OF SISTER COMMITTEE THAT IS FOCUSING ON NEUROETHICS. NEUROETHICS ARE WRAPPED UP IN ALL ASPECTS OF THE BRAIN INITIATIVE AND ARE A SUBSTANTIAL ENOUGH COMPONENT ABOUT THAT THAT WE HAVE A SUBGROUP THAT IS FOCUSING ON THAT, AND WE ARE COORDINATING CLOSELY WITH THAT SUBGROUP AND SOME OF THOSE MEMBERS ARE HERE TODAY JOINING US AS WELL. IN TERMS OF OUR WORKING GROUP, IT'S BEEN A HARD WORKING GROUP. WE FIRST MET IN APRIL OF THIS YEAR AND SINCE THEN WE HAD A SERIES OF VIDEO CONFERENCES IN WHICH WE WERE REVIEWING AND EVALUATING THE VARIOUS PROGRAMS THAT NIH HAS PUT FORTH FOR THE BRAIN INITIATIVE. AS JOSH MENTIONED, WE'RE THOWMP IN THE MIDDLE OF A SERIES OF WORKSHOPS, THIS ONE BEING THE SECOND, WHERE WE'VE ASKED EXPERTS IN PARTICULAR FIELDS TO COME AND SPEAK TO US ABOUT THEIR RESEARCH AND THEIR FIELD AND WHERE THE OPPORTUNITIES LIE IN THOSE AREAS, SO WE'RE HOPING THAT THAT'S WHAT WE'LL LEARN AT THIS WORKSHOP TODAY. THE FORMAT IS THAT WE'VE ASKED 13 SPEAKERS TO COME AND GIVE US THEIR OVERVIEW ON WHERE THE OPPORTUNITIES LIE. EACH OF THEM WILL HAVE 15 MINUTES IN WHICH TO GIVE THEIR PRESENTATION AND ANSWER QUESTIONS. AT THE END OF EACH SESSION, I WILL ASK THE SPEAKERS TO COME TO THE FRONT OF THE ROOM, WHERE WE'LL HAVE AN EXTEND 25D-MINUTE PANEL DISCUSSION TO TAKE -- 25- MINUTE PANEL DISCUSSION TO TAKE UP IN MORE DEPTH SOME OF THE TOPICS THAT CAME UP DURING THE COURSE OF THOSE TALKS. ONCE WE HAVE COMPLETED THE WORKSHOPS AND THE TOWN HALL, WE'LL BE PREPARING A REPORT THROUGH THE WINTER AND SPRING. WE'LL ALSO BE GETTING COMINTS FROM THE -- COMMENTS FROM THE BROADER SCIENTIFIC COMMUNITY AND THE PUBLIC AT THAT TIME AS THE DRAFT REPORT IS PREPARED. AS JOSH MENTIONED, THERE IS AN UPCOMING WORKSHOP IN EARLY OCTOBER. THERE'S A LINK HERE, YOU CAN SEE , WHERE YOU CAN GET MORE INFORMATION ABOUT THE DETAILS OF THAT WORKSHOP AND REGISTER TO ATTEND. THERE WILL ALSO BE A TOWN HALL MEETING AT THE SOCIETY FOR NEUROSCIENCE'S ANNUAL MEETING IN SAN DIEGO IN NOVEMBER. WITH THAT, I'LL JUST CLOSE BY SAYING THAT WE HAVE THESE LINKS THAT WILL BE OPEN AND AN E-MAIL ADDRESS WHERE YOU CAN PROVIDE FEEDBACK TO THE COMMITTEE AT ANY TIME IF YOU'RE INTERESTED. AT THIS POINT I WOULD LIKE TO TURN THE SESSION OVER TO TIM DENISON, OUR WORKING GROUP MEMBER WHO IS GOING TO CHAIR THE FIRST SESSION. >> Dr. Denison: GOOD MORNING, EVERYONE. THE FIRST TOPIC OF THIS WORKSHOP IS THINKING ABOUT DISSEMINATION OF TOOLS, THE IMAGE THAT YOU SEE IN FRONT OF YOU IS ACTUAL AROUND ASTROLAB WHICH IS A COMMON TOOL HUNDREDS OF YEARS AGO, AND I PUT THIS UP BECAUSE I WAS WORKING THROUGH THE MUSEUM OF THE HISTORY OF SCIENCE IN OXFORD WHICH YOU SHOULD VISIT IF YOU'RE EVER IN TOWN, AND YOU REALIZE THAT THIS VERY FUNCTIONAL TOOL REALLY PROPAGATED ACROSS THE WORLD HUNDREDS OF YEARS AGO. AND IF YOU STEP BACK AND WE THINK ABOUT SOME OF THE GOALS OF THE BRAIN INITIATIVE AND CREATING USEFUL TOOLS BUT ALSO IMPORTANTLY DISSEMINATING THOSE TOOLS FOR USE, YOU CAN REFLECT ON SOME OF THE PROPERTIES OF AN ASTROLAB AND THE TOPICS WE'RE GOING TO TALK ABOUT THIS MORNING FIRST, OBVIOUSLY, THE TOOLS NEED TO HAVE UTILITY AND IN THE CASE OF THE ASTROLAB, A NICE MODEL OF THE CELESTIAL UNIVERSE MAPPED INTO TWO DIMENSIONS. WE DO A LOT OF WORK IN THE BRAIN INITIATIVE TALKING ABOUT UTILITY OF TOOLS AND COMING UP WITH MODELS, BUT THERE ARE OTHER THINGS WE'RE GOING TO TALK ABOUT IN THIS FIRST SESSION THAT ARE ALSO IMPORTANT TO DISSEMINATION OF TOOLS AND TO THE ECOSYSTEM, THINGS LIKE PRICE POINTS. SO THIS IS A BEAUTIFUL EXAMPLE, THEY ACTUALLY HAVE ELIZABETH THE FIRST ASTROLAB WHICH IS QUITE EXCEPTIONAL AS YOU CAN IMAGINE, THERE ARE ALSO WOODEN ASTROLABS, YOU CAN MAKE THEM OUT OF PAPER, MEETING THE NEEDS OF THE COMMUNITY IT WAS IMPORTANT FOR THIS, ALSO LOOKING AT THE HISTORY BOOKS, THEY WOULD TEACH CHILDREN HOW TO USE ASTROLABS, TRAINING, SUPPORT, ALL THESE ELEMENTS CRUCIAL IN TERMS OF GETS IT OUT OF ONE SPECIFIC MAKER'S LAB AND MAKING IT AVAILABLE TO THE BROADER COMMUNITY. SO WE TRY TO SET UP A PRETTY USEFUL DISCUSSION CAPTURING SEVERAL MEMBERS OF THE COMMUNITY , THE GOVERNMENT, FOUNDATIONS, AS WELL AS ENTREPRENEURS, GIVE YOU A SNAPSHOT OF SOME OF THE CHALLENGES THEY'RE DEALING WITH AND TO SHARE SOME OF THEIR IDEAS FOR WHAT WE CAN DO BETTER IN BRAIN 2.0 TO PROPAGATE TOOLS AND CREATE AN ECOSYSTEM. WE'LL START WITH ELIZABETH. SHE'LL BRING THE PERSPECTIVE OF NIST AND METROLOGY TOOLS, KIND OF THE WORLD'S EXPERTS IN TERMS OF STANDARDS AND GETTING THESE OUT TO THE COMMUNITY AS WELL AS BRINGING A PERSPECTIVE OF WORKING AT DARPA AND THINKING ABOUT INSTRUMENTATION FOR THE BRAIN INITIATIVE. WE'LL THEN HEAR FROM A FOUNDATION, TWO SPEAKERS THAT HAVE COMPLEMENTARY TOOL SETS THEY'RE PUTTING OUT INTO THE COMMUNITY IS SHARE WHAT THEY SEE FROM A FOUNDATION PERSPECTIVE WE MIGHT DO AS A BETTER JOB, THEN FINALLY WE'LL HEAR FROM AN ENTREPRENEUR, FLORIAN SOLZBACHER AND HIS WORK WITH BLACK ROCK OVER THE PAST SEVERAL DECADES TRYING TO SUPPORT THE ECOSYSTEM AS WELL. WITH THAT, I WOULD LIKE TO INVITE ELIZABETH UP WHO WILL PROVIDE OUR FIRST OVERVIEW TALK. WELCOME, ELIZABETH. [APPLAUSE] YOU. >> Dr. Strychalski: GOOD MORNING. WHO IS READY FOR SOME MEASUREMENT SCIENCE AND STANDARDS? [LAUGHTER] IF THAT DOESN'T QUICKEN YOUR PULSE, I'M HERE TO SUGGEST TO YOU THAT YOU CONSIDER SHIFTING YOUR PERSPECTIVE BECAUSE AS WE ALL KNOW, THE IRCHES DID BETWEEN OKAY SCIENCE AND GREAT SCIENCE CAN BE HOW GOOD YOUR MEASUREMENT IS AND THE DIFFERENCE BETWEEN YOUR TECHNOLOGY LANGUISHING IN YOUR LABORATORY AND SUCCESSFULLY MOVING TO MARKET WITH YOUR START-UP CAN BE HAVING THE RIGHT MEASUREMENTS FOR EXAMPLE TO GET IT THROUGH REGULATORY APPROVAL. SO I'VE HAD THE PRIVILEGE OF SERVE EPG IN THE FEDERAL GOVERNMENT IN TWO DIFFERENT DEPARTMENTS, IN AGENCIES WITH COMPLEMENTARY MISSIONS. NIST IS THE NATIONAL INSTITUTE OF STANDARDS AND TECHNOLOGY. IT'S A MEASUREMENT STANDARDS LABORATORY AND IT'S ONE OF THE MANY NATIONAL METROLOGICAL INSTITUTES IN THE WORLD. THE KEY HERE IS THAT IT'S NON REGULATORY, WE REALLY ARE HERE TO HELP YOU AT ANY STAGE IN YOUR TECHNOLOGY DEVELOPMENT, AND IN THE BIOSCIENCES, NIST IS WORKING TO HELP THE BIOTECHNOLOGY ENTERPRISE TRANSITION TO THE WIDESPREAD USE OF QUANTITATIVE MEASUREMENTS, AND WHAT THIS OFTEN INVOLVES IS HELPING INDUSTRY DEVELOP THE MEASUREMENT TOOLS AND STANDARDS THAT THEY NEED TO MANUFACTURE EFFICIENTLY, RELIABLY, AND THESE ARE OFTEN TOOLS THAT CAN'T OR WON'T DEVELOP ON THEIR OWN. NOW, NIST SCIENTIST, TRANSITION ED TO CHEMISTRY AND EVENTUALLY A COUPLE YEARS AGO I FOUND MYSELF DEVELOPING NIST PROGRAM IN ENGINEERING SYNTHETIC BIOLOGY WITH SOME OF MY COLLEAGUES AND WHAT OUR FOCUS IS NOW IN THAT SPACE IS TO WORK TO MEASURE THE EFFECT OF ENVIRONMENTAL CONTEXT AND EVOLUTIONARY DYNAMICS ON BIOLOGICAL SYSTEMS AS THE KEY CHALLENGES THAT WE SEE TO MOVING TOWARDS PREDICTIVE ENGINEERING. NIST TAUGHT ME THAT METROLOGY IS DEEPLY CONSEQUENTIAL, IT SEPARATES US FROM THE ANIMALS, IT'S THE STUFF OF CIVILIZATION AND TRADE, BUT MORE IMMEDIATELY, IT CAN MEAN THE DIFFERENCE BETWEEN KNOWING IF YOUR OBSERVATION IN A LABORATORY IS REAL OR AN ARTIFACT OF YOUR MEASUREMENT APPROACH. IT CAN MEAN THE DIFFERENCE BETWEEN GETTING REGULATORY APPROVAL OR NOT GETTING REGULATORY APPROVAL, MORE PRACTICALLY. NOW, DARPA, AS YOU KNOW, INVESTS IN BREAK THROUGH TECHNOLOGIES FOR NATIONAL SECURITY. AT DARPA I MANAGED ABOUT $120 MILLION PORTFOLIO AIMED AT BUILDING A RIGOROUS CONTROL ENGINEERING FOR BIOLOGICAL SYSTEMS, AND I ALSO WORKED ON THE NEURAL ENGINEERING SYSTEMS DESIGN PROGRAM FOR ADVANCING NEURAL ENTER FAILSES TO PROVIDE HIGH -- INTERFACES TO PROVIDE HIGH RESOLUTION SPEED AND DATA TRANSFER BETWEEN THE BRAIN AND ELECTRONICS. DARPA TAUGHT ME THAT ENABLING HIGH QUALITY MEASUREMENTS AND TECHNOLOGY TRANSFER ARE REALLY WORTH BUILDING INTO YOUR RESEARCH WORK FLOWS UPFRONT AND THAT THSE MAKE REALLY GOOD SENSE FOR RETURN ON INVESTMENT. SO THE ORGANIZERS OF THE WORKSHOP MADE ME THROW OUT MY NORMAL SLIDE DECK. IT IS AVAILABLE TO YOU AS A BRIEF, AND IT IS A PRACTICAL GUIDE FOR HOW TO ENGAGE NIST WITH EXAMPLES TO MEET YOUR MEASUREMENT NEEDS ESPECIALLY AS THEY PERTAIN TO TECHNOLOGY TRANSFER. BECAUSE REMEMBER, THIS IS NIST'S CORE MISSION, WE'RE YOUR METROLO GISTS ON CALL. IN INSTEAD I GIVE YOU HERE THE QUESTIONS THAT THE ORGANIZERS GAVE TO THE PRESENTERS IN THIS SESSION, AND I'VE GOT THOUGHTS ON ALL OF THESE BUT I WANT TO REALLY FOCUS ON NUMBER 3 AND THEN MAKE A FEW SHORT STATEMENTS ON NUMBER 6. SO WITH REGARD TO QUESTION 3, I CAN OFFER YOU TWO IDEAS. BASED ON MY EXPERIENCE, BOTH AS A FUNDER AT DARPA AND AS A METRO LOGIST AT NIST AND I'M HESITANT TO TELL NIH HOW TO DO THEIR JOB, BUT THEY DID ASK. THE FIRST IDEA IS TO WRITE TECHNOLOGY TRANSFER AND RELATED ACTIVITIES DIRECTLY INTO THE DEFINITION OF SUCCESS FOR GRANTEES, FOR PROGRAM OFFICERS, FOR THE INITIATIVE AS A WHOLE, AND THEN, AND HERE IS THE REALLY IMPORTANT PART, ALLOCATE FUNDING AND RESOURCES TO BACK THAT UP. SO AT THE PROGRAM ACT LEVEL, I MIGHT ASK QUESTIONS LIKE WHERE CAN THE STRUCTURE AND ADMINISTRATIVE PROCESSES OF BRAIN BE APPROVED TO BETTER SUPPORT AND INCENTIVIZE TECHNOLOGY TRANSFER? ARE THE EVALUATION CRITERIA FOR FUNDING SELECTION ADEQUATELY AND REALISTICALLY TAKING INTO ACCOUNT THE GRANTEE'S INTEREST, APTITUDE AND RESOURCES AROUND TECHNOLOGY TRANSFER? ARE THE PROGRAM OFFICERS INFORMED AND AUTHORIZED TO ACTIVELY HELP RESEARCHERS CONNECT ACROSS THE GOVERNMENT FOR FOLLOW-ON FUNDING AND TO NAVIGATE THE REGULATORY PROCESS? SO FOR EXAMPLE, ARE GRANTEES ENCOURAGED TO BUILD RELATIONSHIPS WITH PROGRAMS FOR ENTREPRENEURS AND TECH INCUBATOR S, LIKE THE FEDERAL LABORATORY CONSORTIUM, THERE ARE SO MANY OF THESE, AND EVEN IF YOUR GRANTEES FEEL LIKE THEY CAN PARTICIPATE, THIS OFTEN INVOLVES NIGHTS AND WEEKENDS, IS THERE SUPPORT FOR CHILD CARE, DISPLAMPLE YOU MIGHT ALSO ASK WHAT PARTNERSHIPS WITH OTHER AGENCIES AND FEDERAL RESEARCH LABORATORIES COULD BE A WIN-WIN FOR FURTHER TECHNOLOGY BEYOND ACADEMIC USE, BEYOND THE END OF THEIR BRAIN FUNDING? AS YOU KNOW, CONNECTING ACROSS THE FEDERAL GOVERNMENT CAN BE DIFFICULT EVEN FOR FEDS, AND THIS CAN BE AN INCREDIBLY DAUNT ING TASK, ESPECIALLY FOR YOUNG RESEARCHERS, SO HOW DO WE SUPPORT THAT? OFTENTIMES, AND I KNOW THIS THROUGH MY EXPERIENCE WITH DARPA AND AS SOMEBODY WHO GOES AFTER FUNDING THEMSELVES FOR THEIR OWN RESEARCH, IT'S NOT ALWAYS OBVIOUS WHO TO TALK TO. IT CAN BE QUITE CONFUSING, AND REALLY DEMORALIZING. SO THAT'S AT THE SORT OF PROGRAM ACT LEVEL. AT THE PORTFOLIO LEVEL I WOULD ASK NOT JUST IS MY PORTFOLIO BALANCED BUT IS MY PORTFOLIO BALANCED WITH REGARD TO TECHNOLOGY TRANSFER? NOW, EVERYONE IS VERY MUCH PUSHING, THOAPT SEE PRODUCTS THAT GO -- THEY WANT TO SEE PRODUCTS THAT GO TO MARKET, GREAT, BUT NO ONE WANTS TO MISS OUT ON FUNDING THAT FUNDAMENTAL BREAKTHROUGH, THAT'S REALLY TRULY GAME CHANGING. SO, YOU KNOW, YOU WANT TO FUND INVESTMENTS THAT HELP BUILD IN THE NEAR TERM A VIBRANT TECHNICAL FIELD AND ROBUST USER BASE SO THAT WHEN THAT BREAK THROUGH TECHNOLOGY THAT YOU FUNDED, THAT YOU DIDN'T EXPECT TO GO TO MARKET RIGHT AWAY, IS READY, THAT THERE'S SOMEBODY WHO CAN USE IT. THEN AT THE INDIVIDUAL GRANT LEVEL, I WOULD ASK, IS THIS PI AND LABORATORY EMPOWERED TO PLAN FOR, INITIATE AND FOLLOW THROUGH ON TECH TRANSFER? NOT EVERYBODY NEEDS TO BE. AND IF THEY'RE NOT, WHO CAN I CONNECT THEM WITH WHO CAN FACILITATE THAT PROCESS OR MAYBE EVEN JUST RUN WITH IT ON THEIR OWN AND TAKE THE LEAD? SO ONCE TECHNOLOGY TRANSFER IS ABSOLUTELY BAKED INTO THE STRUCTURE, AND THIS IS IMPORTANT TOO, CULTURE OF THE BRAIN INITIATIVE, MY SECOND RECOMMENDATION IS TO BUILD MEASUREMENT SCIENCE INTO TECHNICAL WORK PLANS EXPLICITLY AND UPFRONT. THIS CAN ONLY RESULT IN BETTER TECHNICAL RESULTS AND BETTER POTENTIAL PRODUCTS. YOU KNOW, THE LAST THING THAT UPTS YOUR START-UP TO HAVE TO DO IS TO WASTE ALL THAT PRECIOUS TIME AND MONEY REDOING ALL THE BASIC SCIENCE BEHIND THEIR PRODUCT, MAYBE EVEN TO FIND OUT THAT IT'S WRONG. THIS HAPPENS. HOW DO WE AVOID THAT? YOU MIGHT CONSIDER FUNDING ORTHOGONAL MEASUREMENTS. SO I KNOW THIS COULD BE ESPECIALLY CHALLENGING FOR BIOLOGICAL SYSTEMS, BUT THE GOOD NEWS IS THAT YOU HAVE A WHOLE FEDERAL LABORATORY TO HELP YOU, AND WE SIT AROUND ALL DAY THINKING ABOUT THIS. SO YOU MIGHT ASK, INSTEAD OF FLOW SIGH TROM TRI MEASUREMENTS -- CYTROMETRY AND STOPPING THERE, CAN YOU FUND SOME MASS SPEC TO MAKE SURE THAT THING YOU'RE MEASURING IS REAL? YOU MIGHT ALSO CONSIDER FUNDING REPRODUCIBILITY STUDIES. THIS IS SO IMPORTANT IN THE BIOSCIENCES. THIS COULD EVEN BE A JOINT EFFORT WITH BACKING FROM NIST. I WOULD ALSO WANT TO KNOW, ARE MY GRANTEES WORKING TO SOLVE SOME COMMON MEASUREMENT CHALLENGE? THIS IS WHERE IT'S REALLY ADVANTAGEOUS TO BRING IN NIST, YOU COULD EITHER PARTNER ONE ON ONE WITH A NIST, OR AS A WORKSHOP, PEOPLE CAN COME TOGETHER AND FEEL IT'S A SAFE SPACE. WE COULD PART CONSORTIA. WE'VE GOT A GREAT GENE EDITING CONSORTIUM THAT'S STARTED UP THAT MAY BE RELEVANT TO SOME OF WHAT THE BRAIN COMMUNITY IS DOING. THERE ARE SO MANY OPTIONS WE HAVE HERE, BUT UNTIL WE HAVE A CONVERSATION, WE CAN'T KNOW WHAT YOUR MEASUREMENTS NEEDS ARE, QUEANT WORK TO SERVE THOSE AND REALLY TAYLOR A SOLUTION THAT -- AND REALLY TAILOR A SOLUTION THAT WILL WORK BEST FOR THIS COMMUNITY. NIST REALLY IS FULL OF METROLOGI STS ON CALL FOR YOU, MANY OF US ARE CAREER STAFF SCIENTISTS WHICH IS A GOODS THING BECAUSE AS FAR AS I CAN TELL, NO ONE LEARNS TO BE A METR OLOGIST OVERNIGHT. FOR FURTHER RT DETAILS I REFER YOU AGAIN TO THE SLIDES THAT GOT TOSSED OUT. NOW, WITH REGARD TO QUESTION 6, I WANT TO SPEAK AS A CONSUMER AND AS AN AMERICAN. THAT'S A LITTLE DRAMATIC. [LAUGHTER] YOU KNOW, I WORRY ABOUT THE SAFETY AND SECURITY. I WORRY THAT IF BRAIN DOESN'T FUND RESEARCH IN THIS SPACE YOU AND RESEARCH DOESN'T HAPPEN IN THE UNITED STATES, THAT WE ARE AT A REAL -- WE RUN A REAL RISK OF LUFSING A COMPETITIVE ADVANTAGE, THEN INNOVATION AND TECHNOLOGY TRANSFER ARE LIKELY TO SWITCH TO OTHER PLACES, AND IF THESE TECHNOLOGIES ARE DEVELOPED ELSEWHERE, THEY'RE PROBABLY BEING DEVELOPED ACCORDING TO SOMEBODY ELSE'S RULES, SOMEONE ELSE'S DEFINITION S OF SAFETY AND EFFICACY, THAT MAY NOT BE SUITABLE FOR THE U.S. MARKET AND MAY NOT ADHERE TO WHAT WE WOULD CONSIDER MORAL AND ETHICAL. THIS COULD LEAVE CUSTOMERS WITH UNSAFE PRODUCTS THAT ARE VULNERABLE TO ATTACK, IT COULD EVEN GIVE OUR ADVERSARIES A STRATEGIC ADVANTAGE. SO WITH THAT, I WILL LEAVE YOU WITH, I HOPE MY BACKUP SLIDES ARE HERE, A SLIDE ONTOLOGY TRANSFER AND NIST -- ON TECHNOLOGY TRANSFER AND NIST TO PONDER WITH SOME EXAMPLES OF WAYS IN WHICH YOU MIGHT CONSIDER ENGAGING NIST ALONG THE PATH FROM TECHNOLOGY DISCOVERY TO HAVING A PRODUCT OUT TO MARKET. SO THANK YOU SO MUCH FOR YOUR ATTENTION AND I'M HAPPY TO TAKE ANY QUESTIONS. [APPLAUSE] >> Dr. Denison: ANY QUESTIONS TO START FROM THE WORKING GROUP? ONE THING I'M CURIOUS ABOUT -- IS THAT A HAND GOING UP? OKAY. SO WE'LL GRAB THE MICROPHONE. OF WE'LL GO OVER THERE FIRST. >> COULD YOU ELABORATE ON THE ORTHOGONAL STUDIES YOU MENTIONED IN COLLABORATION WITH NIST THAT THE SCIENTISTS CONDUCT TO MAKE SURE THEIR OBSERVATIONS CAN BE VALIDATED BY MULTIPLE MEANS? >> Dr. Strychalski: ABSOLUTELY. THIS IS SO IMPORTANT HE IS SPECIAL IN THE BIOSINCE -- BIOSCIENCES, IF YOU'RE LOOKING FOR AN EFFECT, YOU WANT TO MAKE SURE IT'S NOT BECAUSE OF SOME MEASUREMENT OR EXPERIMENTAL DESIGN, IF IT'S REAL, HOPEFULLY THERE'S ANOTHER WAY YOU CAN MEASURE IT, SO FOR EXAMPLE, IF I WERE MAKING A MEASUREMENT THAT DEPENDED ON DETECTING A FLUORESCENT MOLECULE, I WOULD THEN WANT TO MAKE AN ORTHOGONAL MEASUREMENT THAT HAD NOTHING TO DO WITH THAT FLUORESCENT LABEL THAT I WAS USING OR THE FLUORESCENT PROPERTIES. MAYBE I COULD DETECT SOMETHING IN A MASS SPECTROMETER OR MAYBE THERE'S SOME OTHER FUNCTIONAL ASSAY SAY I COULD DO THAT DOESN'T INVOLVE OPTICAL MICROSCOPY AND LITTLE BY LITTLE MEASUREMENT BY MEASUREMENT YOU BUILD UP A STRONGER BODY OF EVIDENCE THAT THE EFFECT YOU THINK YOU'RE MEASURING IS ACTUALLY REAL. >> DO YOU HAVE SOME PROGRAMS THAT YOU ARE COLLABORATING WITH THE SCIENTISTS TO DO THESE STUDIES? >> Dr. Strychalski: SURE. THE SHORT ANSWER IS THAT ALL OF NIST IS THERE TO HELP YOU DO THIS. THE LONGER ANSWER IS THAT WITH REGARD TO THE TECHNOLOGIES USED IN THE BRAIN INITIATIVE, NIST DOES NOT HAVE, TO THE BEST OF MY KNOWLEDGE, IT'S A BIG PLACE, A PROGRAM DEDICATED TO NEUROSCIENCE OR THE KINDS OF IMPLANTABLE DEVICES THAT GET USED A LOT BY THIS COMMUNITY. THIS IS SOMETHING WE WOULD BE HAPPY TO LEARN MORE ABOUT. NIST IS ALWAYS MOVING INTO NEW SPACES. BUT AGAIN, WE DON'T KNOW THAT YOU HAVE A NEED FOR, FOR EXAMPLE , ORTHOGONAL MEASUREMENTS IF YOU DON'T COME TALK TO US BECAUSE ALTHOUGH WE ARE A BIG PLACE, THERE ARE A LOT OF MEASUREMENT NEEDS OUT THERE, AND WE WANT TO MAKE SURE THAT WE'RE SERVING INDUSTRIES IN THE U.S. MARKET IN A WAY THAT HELPS THEM THRIVE, IMPROVES THE QUALITY OF LIFE FOR AMERICANS. THIS IS OUR CORE MISSION. >> Dr. Denison: ANY QUESTIONS FROM THE BROADER AUDIENCE? >> ELIZABETH, I'M GOING TO MENTION IT MYSELF, BUT THE DIFFICULTY I THINK WE HAVE IN THE ENTIRE COMMUNITY WITH THIS IS THAT THE ACADEMICS ARE REALLY GOOD AT DISCOVERY AND HAVE NO EXPERIENCE WHATEVER IN PRODUCT DEVELOPMENT. THERE'S A BIG GAP THERE. AND I DON'T THINK THE NATIONAL LABS ARE PARTICULARLY BETTER AT IT OR AT LEAST EXPERIENCED AT IT , SO I THINK WHAT I WANT TO KNOW IS, HOW DO YOU SEE BRIDGING THE GAP IN A NONCOMMERCIAL WAY? BECAUSE I WILL MAINTAIN MOST OF THESE NEW TOOLS ARE SPECTACULAR RESEARCH DEVICES AND PRETTY CRUMMY BUSINESSES. >> Dr. Strychalski: THANK YOU FOR MAKING THAT POINT. ONE OF THE THINGS THAT NIST CAN UNIQUELY BRING IS THAT WE CAN -- BRING NOT JUST ACADEMICS TO THE TABLE BUT ALSO START-UPS, MORE ESTABLISHED COMPANIES, TO HAVE A CONVERSATION ABOUT EXACTLY THIS ISSUE OR ANY OTHER ISSUES THAT YOU MAY WANT TO HAVE. WE ALSO PARTNER CLOSELY WITH FDA , FOR EXAMPLE TO UNDERSTAND THEIR MEASUREMENT NEEDS AROUND BRINGING PRODUCTS TO MARKET. SO I WOULD SAY THAT THE BIGGEST ASSET IN THIS REGARD THAT NIST PRESENTS TO YOU IS THE CONVENING POWER. >> Dr. Denison: THANK YOU, ELIZABETH. WE'LL ACTUALLY PICK THAT UP IN THE PANEL AS WELL. I'LL DO SOME FOLLOW-UP. LET'S THANK ELIZABETH. >> Dr. Strychalski: THANK YOU. [APPLAUSE] >> Dr. Denison: TIM? TIM IS UP NEXT. SO TIM HARRIS IS COMING FROM JAN ELIA RESEARCH CAMPUS TO TALK ABOUT SOME WORK ON SENSING STIMULATION TECHNOLOGY. SO LET'S WELCOME TIM HAS -- TIM AS HE GETS SET UP. [APPLAUSE] >> SO TIM, I DON'T KNOW HOW TO USE A A MASTER LACTATE. >> Dr. Denison: I'LL DO SOME LESSONS OVER LUNCH. SO HE'S GOOD WITH THE MIC NOW. >> Dr. Harris: OKAY. I'M NOT ADVERTISING WHAT -- MAN, THIS IS HARD TO POINT -- WHAT I DID, BUT I WANTED TO GIVE PEOPLE THE CONTEXT OF MY THOUGHTS. SO OVER THE LAST FIVE YEARS OF THIS GROUP OF NONPROFIT CHARITIES HAVE SPENT AROUND $10 MILLION MAKING THIS DEVICE HERE, WHICH IS CALLED NEURO PIXELS, IT'S A NOMINALLY THOUSAND SITE 380 CHANNEL ELECTROPHYSIOLOGY DEVICE, AND THE REASON THEY'RE EXPENSIVE IS BECAUSE THEY REQUIRE STATE OF THE ART MICROELECTRONICS FABRICATION, VASTLY BEYOND WHAT'S AVAILABLE AT A UNIVERSITY YOU REALLY NEED TO GO TO PEOPLE WHO MAKE COMPUTER CHIPS FOR A LIVING, AND THE PROBLEM WITH THEM IS THAT UNLESS YOU'RE GOING TO MAKE LITERALLY A MILLION A WEEK, THEY'RE NOT INTERESTED. SO THE FACT THAT ANYONE WOULD MAKE THIS IS REALLY A TERRIFIC ADVANCE. SO ANYWAY, THIS DEVICE PLUGS INTO AN ANIMAL, SO FAR NOT HUMANS BECAUSE WE LACK COURAGE EVEN THOUGH THE NEUROSURGEONS DON'T SEEM TO, AND YOU CAN RECORD HUNDREDS OF NEURONS ON YOUR FIRST ATTEMPT IN YOUR FIRST HALF HOUR. THIS IS THE SORT OF VISCERAL RESPONSE WE GET FROM THE COMMUNITY. HOW DO I GO -- DO I PAGE DOWN? THERE WE GO. THAT'S ON ITS WAY OUT AND ITS DEPLOYMENT IS MY CONTEXT, BUT THERE'S FOLLOW-UP. SO ANOTHER GROUP -- THIS IS THE PROBLEM NOT BEING ABLE TO EDIT YOUR SLIDES IN THE LAST 48 HOURS , IS THAT ANOTHER GROUP, LET ME GO BACK, SO THESE CHARITIES PAID FOR THE FIRST ROUND, AND THIS ROUND IS BEING PAID FOR BY JANELIA, CHOMPALONOD E AND NERF WHICH IS A BLEM-ISH ORGANIZATION, AND WELCOME, AND WHAT YOU WANT TO BE ABLE TO DO IS PUT 8 SHANKS, WHICH MEANS SOMETHING LIKE 800 TO 2400 CHANNELS IN A MOUSE OR A RAT AND SOMETHING LIKE THIS ON A MARCH MOW SET, SO -- ON A MARMOS ET, SO THIS IS ALREADY UNDERWAY. THE QUESTION IS FOR THESE TWO COMMUNITIES, PRIMATE AND RODENT AND EVENTUALLY HUMAN, HOW DO WE GET THERE? SO THE REASON THAT I PUT THIS UP IS BECAUSE I HAVE THE VERY GOOD FORTUNE TO BE WORKING WITH AN ORGANIZATION THAT CAN MAKE A PRODUCT-READY DEVICE. IT DOESN'T HAVE SUPPORT, YOU CAN'T CALL ANYBODY, BUT IT IS IN FACT, FINISHED, FINISHED, READY TO GO. THAT IS A NONACADEMIC EXERCISE, IN MY OPINION. SO I DON'T HAVE TO BILITYD THAT BRIDGE BUT I THINK MOSTLY WE DO HAVE TO BUILD THAT BRIDGE AND THERE'S BEEN A CONVERSATION GOING ON AT JANELIA FOR THE LAST TWO YEARS ABOUT WHAT ORGANIZATION CAN WE INVENT THAT CAN BUILD THE BRIDGES OF ORPHAN ED RESEARCH TOOLS THAT CAN'T GET OUT? WE HAVEN'T DONE IT YET, SO CLEARLY THE SOLUTION IS -- JUST SO THOSE WHO ARE WRITING CHECKS, AND I WILL FREELY ADMIT I AM NOW AN INTERESTED PARTY BECAUSE I'M A PART-TIME RESEARCH PROFESS SORP AT JOHNS HOPKINS BIOMEDICAL JERGS, I FIRMLY BELIEVE THAT THIS IS FIRMLY POSSIBLE THAT YOU CAN PUT 20 TO 50,000 SIMULTANEOUS CHAMS, FOR THOSE OF WHO YOU DON'T DO THIS, DEPENDING ON YOUR FILTER, THAT'S EQUAL TO THE NUMBER OF NEURONS, SORT OF HALF THAT MANY NEURONS THAT YOU'RE RECORDING SIMULTANEOUSLY IN NON-HUMAN PRIMATES SOMETHING LIKE 100 OR 200,000 NEURONS SIMULTANEOUSLY, THAT'S A LOT, IT'S STILL A VERY SMALL FRACTION OF WHAT'S THERE, BUT ON THE OTHER HAND, NOW THIS -- SO THE DEVICE IS DONE AND THE QUESTION IS -- SO THIS IS TENS OF GIGA BITES A SECOND OF DATA TRANSFER REQUIRED TO GET THE DATA OFF OF THE ANIMAL AND OVER TO YOUR -- SO FORTUNATELY THE WORLD IS REALLY GOOD AT HIGH SPEED DATA COMMUNICATIONS SO WE DON'T HAVE TO INVENT THIS BUT WE DO HAVE TO TRANSCEND WHAT WE'VE BEEN DOING, SO WE THINK THIS IS PERFECTLY FEASIBLE AND I HOPE THE BRAIN INITIATIVE DOES TOO, BUT THIS IS MY MESSAGE. SO THERE'S A DEVELOPMENT CHALLENGE, I THINK IT WOULD HAVE BEEN -- NEURO PIXELS WOULD HAVE BEEN A TOUGH CELL IN THE NIH FUNDED COMMUNITY FIVE YEARS AGO WHEN WE STARTED TO ASK FOR FIVE AND A HALF MILLION DOLLARS DIRECTLY TO THE VENDOR AND ANOTHER TWO OR THREE FOR US TO DO OUR PART OF THE PROBLEM TO DEVELOP A SINGLE STICK. THAT'S A BIG ASK. I THINK THE COMMUNITY IS WILDLY ENTHUSIASTIC, REALLY THE SMARTEST INVESTMENT EVER AFTER WE'RE FINISHED, SO I FEEL REALLY FORTUNATE THAT THESE CHARITIES SORT OF STUCK THEIR NEXT OUT. SO NOW THAT WE'VE DONE THAT, WE HOPE WE CAN USE THAT AS AN EXAMPLE. SO THE DEVELOPMENT OF PRODUCT READY IS SORT OF 10 MILLION BUCKS, BUT THE MODEL I WANT TO FOLLOW UP ON IS THAT IT'S SELF- SUSTAINING, YOU CAN MAKE THESE THINGS FOR SORT OF 1100, $1,200 EACH, AND THE COMMUNITY CAN AFFORD THAT, THEY'RE NO MORE EXPENSIVE THAN WHAT WE HAVE NOW THAT ARE 10X LESS INTERESTING SO THE QUOTE IS HOW DO WE DEPLOY SOMETHING THAT IS PRODUCT READY, THAT CA BE SELF-SUSTAINING, BUT THERE'S NO PHONE NUMBER ON THE BOX, YOU CAN'T CALL ANYBODY, HOW DO YOU DO THAT? YOU GO LOOKING FOR EXAMPLES. THIS IS WHAT I WANT THE DISCUSSION TO BE. THERE'S NOBODY TO CALL FOR SUPPORT IF YOU'RE DOING PATCH PHYSIOLOGY. SOMEBODY THAT YOU KNOW HAS TO TEACH YOU HOW TO DO THAT. SO I'M HOPING THAT WE CAN FOLLOW THAT MODEL. SO THE DISTRIBUTION MODEL WE'RE FOLLOWING, BECAUSE WE GOT WAY A LOT OF PUSHBACK FOR JUST LICENSING, WAS, OKAY, SO THE OVERHEAD, YOU'VE GOT TO HAVE ORGANIZATION X, YOU'VE GOT TO PUT THINGS IN BOXES AND SEND THEM OUT, THAT REQUIRES SOME OVERHEAD, MAYBE 10 OR 15%, SO SHALL WE JUST GET SOMEBODY ELSE TO PAY FOR THAT OR SHALL WE MARK UP THE DEVICE? THEN THERE'S SUPPORT. WE'RE GOING TO HAVE -- ARE WE GOING TO HAVE PAID SUPPORT OR ARE WE JUST GOING TO HAVE A LIST OF PEOPLE, HERE YOU GO, CALL THEM FAIR ENOUGH NEED HELP OR GO VISIT THEM? ONE OF THE MAJOR ISSUES IS THAT IT LOOKS LIKE WE'RE GOING TO SPEND SOMETHING LIKE 500 -- WE'RE GOING TO VEND SOMETHING LIKE 500 OF THESE A MONTH. THAT'S A HALF A MILLION DOLLARS WORTH OF STUFF. I'M SORRY TO SAY FOR YOU GUYS, UNIVERSITIES DO NOT PAY THEIR BILLS, SO THE AVERAGE FLOAT IS SOMETHING LIKE THREE MONTHS. YOU NEED A MILLION DLARPZ IN THE BANK JUST TO GET STARTED. THE QUESTION IS -- ARE YOU GOING TO GET SOMEBODY TO LOAN YOU A MILLION BUCKS? HOW ARE YOU GOING TO GET A MILLION DOLLARS? THEN TRAINING. HOW DO WE TEACH PEOPLE TO USE THESE? THEY'RE NOT SIMPLE. DO WE HAVE SUMMER SCHOOL? SURE. WHAT I'VE BEEN DOING IS TEACHING PEOPLE AT JANELIA AND THEN MAKING THEM PROMISE AND WE'LL TEACH SOMEBODY ELSE IF YOU TEACH US NOW. WE'LL SEE WHETHER OR NOT THEY COME THROUGH, BUT THAT'S THE CURRENT MODEL. SO ANYWAY, THE QUESTION IS, YOU KNOW, HOW DO WE BRIDGE THIS, FROM PUBLICATION READY, WHICH IS 95 PERCENT PLUS OF WHAT WE DEVELOP, TO PRODUCT READY, WHICH IS A BIG JUMP. I USED TO DO ONLY THIS. I'VE DONE BOTH NOW. SO YOU NEED MONEY, BUT IN ANSWER TO ELIZABETH WHO IS THE BIG QUESTION BECAUSE YOU CAN FIND MONEY IF YOU'VE GOT A COMPETENT WHO, I THINK. SO THE QUESTION IS WHERE DO WE GET A COMPETENT WHO? I THINK THE PROBLEM IS THERE'S NO HOT THE PROFILE PUBLICATION OUT OF THAT TRANSITION, YOU CAN'T GO GET AN ACADEMIC JOB BY MAKING SAYING -- BY MAKING A PRODUCT OUT OF A RESEARCH ARE TOOL, I THINK RPS THE PROFESSIONAL LABS, AND THE OTHER PROBLEM, FLORIAN WILL TELL US, THESE ARE NOT GET-RICH BUSINESSES THAT IN FACT SOMETIMES THEY'RE NOT EVEN BREAK -EVEN BUSINESSES. BUT THEY'RE STILL FANTASTICALLY VALUABLE TOOLS. SO THE QUESTION IS HOW DO WE TAKE A LITTLE BIT OF PUBLIC MONEY AND GET THIS STUFF OVER THE HUMP SO THE USERS CAN SORT OF PAY THE RUNNING COSTS? SO THERE'S A SMALL BUSINESS PATH , THERE'S SBIR, YOU HAVE TO GO STRAIGHT TO PHASE II TO GET ANYTHING DONE, PHASE I ISN'T ENOUGH TO GET ANYWHERE NEAR THIS SORT OF THING. THE BIGGER THE MARKUP, NORMAL COMMERCIAL ENTITIES WANT 3X, 5X, 10X MARKUPS, YOUR PENETRATION IS JUST PLUMMETING. SO THERE'S THE NONPROFIT PATH, SO YOU NEED FUNDING FOR ENGINEERING, FUNDING FOR SUPPORT IF YOU'RE GOING TO OFFER IT, YOU NEED FUNDING FOR TRAINING, SO THEN EVEN HARDER THAN THAT IS THAT ALL OF THIS IS FOR RATS. WHAT HAPPENS IF YOU WANT TO DO THIS IN PEOPLE? FIRST OF ALL, I'M HERE TO TELL YOU I DON'T KNOW HOW TO DO THAT. I FIND THAT REALLY WORRISOME. I FIND IT EVEN MORE WORRISOME THAT I GET REGULAR CALLS FROM NEUROSURGEONS SAYING, CAN WE HAVE SOME? I'M THINKING, NO, NOT YET. [LAUGHTER] YOU KNOW, MY EMPLOYER THE HOURS HUGHES MEDICAL INSTITUTE IS NOT INTERESTED IN THAT ISSUE, NEITHER IS PAUL ALLEN SPENDING HIS FORTUNE THAT NO ONE WILL GET SUED WHVMENT WE RUN WORKSHOPS, RECENTLY, WE INVITED NEUROSURGEONS, I GUESS I SHOULD CALL YOU OUT, AS OPPOSED TO NON PRIMATE NEUROSURGEONS, THEY'RE ALL IN, THINKING GREAT, WE HAVE 19TH CENTURY TOOLS, WE'RE READY TO GO. SO THERE'S THE ISSUE OF FOR THE BRAIN PROJECT, HOW DO HE WITH TAKE WHAT I THINK HAS BEEN FANTASTIC PROGRESS IN THE SORT OF MODEL ANIMAL BUSINESS AND TURN IT INTO SOMETHING FOR HUMANS? BECAUSE AFTER ALL, THE TAXPAYERS ARE NOT ALL THAT INTERESTED IN MOUSE BRAINS AS WE ARE. SO I'M HAPPY TO TAKE ANY QUESTIONS. BUT THAT'S A DISCUSSION I WOULD LIKE TO HAVE. [APPLAUSE] >> Dr. Denison: ANY QUESTIONS FROM THE WORKING GROUP? >> I'M INTERESTED WHEN YOU SAID THE POINT ABOUT HOW YOU CAN'T ADD A MARKUP TO THE COST OF THE DEVICE BECAUSE YOU'LL LIMIT THE PENETRATION FOR THAT DEVICE BEING BOUGHT BY PEOPLE AND USED BY PEOPLE, BUT YOU'RE ACKNOWLEDGING THAT THERE IS A DEVELOPMENT COST THAT NEEDS TO GET COVERED AT SOME POINT, RIGHT SO WHAT YOU SORT OF POEMSED IS THAT WE USE -- POSED IS THAT WE USE MONEY AVAILABLE TO PAY FOR THE DEVELOPMENTS SO THAT THE PRODUCT COSTS CAN BE LOW. BUT, YOU KNOW, RESEARCHERS ARE USED TO HAVING TO PAY FOR THEIR STUFF, THEY PAY FOR IT WITH NIH GRANTS, THEY PUT IT INTO THEIR BUDGET AND THEY BUY IT. I'M JUST INTERESTED IF YOU REALLY THINK THAT IT'S NECESSARY FOR THIS THING TO COST $1,000 FOR THE RESEARCHERS OR WHETHER THE RESEARCHERS WHO NEED IT, IF IT WAS SHIFTED A LITTLE BIT, WOULD BE WILLING TO TAKE ON SOME MORE OF THE COST OF THE PURCHASE PRICE. >> Dr. Harris: THERE'S NO ONE YOU ALWAYS DO THAT OR YOU NEVER DO THAT ANSWER I THINK. THE DIFFICULTY IS IF YOU THINK ABOUT WHO WOULD HAVE WRITTEN A CHECK FOR SOMETHING APPROACHING 10 MILLION DLARPZ ON THE BET YOU COULD MAKE A PROFIT SELLING NEURO PIXELS, THAT'S A REALLY SHORT LIST, SO RECOVERING THE DEVELOPMENT COSTS I THINK YOU'RE RIGHT IS THAT THAT'S WHERE PUBLIC FUNDING AND CHARITABLE FUNDING HAS BEEN NECESSARY. BUT I WOULD ARGUE THAT THE ENTHUSIASM FOR THESE DEVICES WOULD BE SUBSTANTIALLY DIFFERENT AT $4,000 APIECE THAN $1,100 APIECE. NOW, WHAT THAT MEANS IS SLOWER ADOPTION. I MEAN, YOU'VE GOT SOME PEOPLE WHO ARE RICH AND THEY'RE GOING TO BUY THEM RIGHT AWAY, AND THEN SOME PEOPLE THINK, MAN, $50,000, I DON'T HAVE THAT IN MY GRANT, WHERE AM I GOING TO GET IT? THE ANSWER IS YOU PUT IT IN NEXT YEAR. I REALLY FIRMLY BELIEVE THAT THE PEOPLE WHO PAID FOR MY PROJECT HAVE A REALLY STRONG ETHIC AS THE WIDEST POSSIBLE USE AT THE LOWEST POSSIBLE COST. SO I'M LOOKING FOR A PATHWAY THAT FULFILLS THAT RECIPE, AND THAING A 3X -- AND THAING A 3X MARKUP IN ORDER TO MAKE A SORT OF STABLE COMMERCIAL ENTITY LIMITS THAT IN A REALLY SIGNIFICANT WAY. >> ONE THING I'M CURIOUS ON THAT , TIM, THINKING ABOUT MY OWN DEPLOYMENT EXPERIENCES, DO YOU SEE AN OPPORTUNITY TO STAGE THE DEPLOYMENT, LIKE MAYBE YOU WOULD START OUT -- SOMETIMES A LITTLE BIT OF A BARRIER INITIALLY TO ENTRY WILL ENSURE YOU GET THE HIGHEST QUALITY RESEARCHER TO ENGAGE FIRST, SO AS OPPOSED TO -- I AGREE IT'S A GREAT VISION, BUT WHAT'S YOUR THOUGHT ON THE SEQUENCING OF THE STEPS TO GO FROM INTERNAL TO JANELIA TO THEN AVAILABLE TO THE WORLD? >> Dr. Harris: I THINK I CAN LIVE THIS EXAMPLE, TIM, BECAUSE NOW PEOPLE KNOW MY NAME, AND IF WE HAD ENOUGH OF THESE DEVICES TO SUPPLY 1,000 LABS IN THE NEXT SIX MONTHS, I WOULD HAVE TO GO INTO HIDING. SO FORTUNATELY, MY STRATEGY IS WE DON'T HAVE THAT MANY, AND WE'RE GOING TO MAKE THE INITIAL ORDERS FAIRLY HIGH NUMBER SO WE'RE NOT GOING TO LET YOU BUY EXPWUN SEE IF IT GOES, WE'RE GOING TO MAKE YOU BUY A SIGNIFICANT NUMBER SO THAT YOU ACTUALLY HAVE TO COMMIT TO THESE DEVICES. IN MY ONE EXAMPLE, WE'RE GOING TO LIMIT THE GROWTH BY SIMPLY REQUIRING PEOPLE WHO ARE SERIOUS ABOUT IT TO GET GOING. BUT ON THE OTHER HAND, I DON'T KNOW THAT THAT'S THE BEST EXAMPLE ACROSS THE BOARD. BUT ON THE OTHER HAND, IF YOU HAVE A RESEARCH TOOL THAT MY CURRENT CUSTOMERS ARGUE THIS CHANGES EVERYTHING, THE LAST THING YOU WANT TO DO IS SLOW DOWN ITS INTRODUCTION. SO THERE'S SORT OF A DILEMMA HERE. >> Dr. Denison: WE'LL PICK THAT ONE UP AT THE PANEL. QUESTIONS FROM THE BACK, WE'VE GOT TWO. >> Dr. Harris: BOBBY. >> Dr. Denison: I WANT TO MAKE SURE PEOPLE ONLINE CAN HEAR US. >> IS THERE A STRATEGY FOR THE DEPLOYMENT OF THE DATA AND THE ANALYTICS, GIGABYTES PER SECONDS SOUNDS LIKE A LOT, AND DO YOU THINK THAT THE SUCCESS OF ADOPTION DEPENDS ON THE SUCCESS OF DEALING WITH THE DATA? >> Dr. Harris: SO I THINK THAT FORTUNATELY THE COMPUTATIONAL PEOPLE IN MY FIELD GOT OFF OF THEIR LAZY BACK SIDES WHEN THE PROSPECT OF THESE DEVICES CAME ALONG AND IMPROVED THE SPEED OF THE ANALYSIS BY 1,000X IN ONE STEP. WHAT ANGERRERS ME IS WHY DIDN'T DO YOU THAT BEFORE, WHY DID IT TAKE ME THREE AND A HALF DAYS YOU TO ANALYZE A TRIVIAL AMOUNT OF DAYS WHEN I CAN ANALYZE A MOUNTAIN IN AN HOUR. SO I DON'T THINK THIS MY POINT, IN MY 250,000 NEURONS AT A TIME, I THINK WE'RE IN TROUBLE, BUT WE'RE NOT THERE YET. SO I THINK THAT WE'RE OKAY THAT THE SECOND QUESTION THAT I HEARD FROM YOU WAS DATA SHARING ISSUES , AND, YOU KNOW, I GUESS I WOULD JUST ASK THE PEOPLE WHO MAKE IMAGES OUT OF FAST CAMERAS, WHAT DO YOU GUYS THINK? BECAUSE WE'RE SORT OF A FACTOR OF 5 BEHIND THEM, SO WE DON'T HAVE TO INVENT THAT. I'M A DATA SHARING SKEPTIC. I CAN BARELY ANALYZE MY OWN DATA , LET ALONE ANYONE ELSE'S, SO I'M NOT SURE THAT'S A MAJOR BARRIER TO SCIENCE. GLORIA -- FLORIAN, DO YOU HAVE -- >> I'M WATCHING OUR TIME CLOCK. SAVE YOURS FOR THE PANEL, FLORIAN, I'LL LET YOU ASK YOURS AT THE PANEL. THANK YOU, TIM, FOR GETTING US GOING. [APPLAUSE] SO THE NEUROSCIENCE TOOLS. NOW WE'LL HAVE LUKE COME ON UP AND JOIN US. LUKE LAVIS IS ALSO FROM JANELIA BUT HE'LL TALK ABOUT SOME OF THE MOLECULAR TOOLS AND IMAGING AS A COMPLEMENT TO WHAT TIM WAS TALKING ABOUT. SO LET'S WELCOME LUKE. [APPLAUSE] >> Dr. Lavis: IT'S A PLEASURE TO BE HERE TO REPRESENT ORGANIC CHEMISTRY AND CHEMICAL BIOLOGY AND THE MAIN POINT I WANT TO MAKE TODAY IS THAT THERE ARE SOME EMERGING MOLECULAR TOOLS THAT INCORPORATE SMALL MOLECULES , BUT IF WE WANT THEM TO HAVE MAXIMUM IMPACT, WE HAVE TO SOLVE THIS DISTRIBUTION PROBLEM, AS I'LL MENTION THROUGHOUT THE TALK, THAT COMPETITION IS LITERALLY FREE, SO WE NEED TO FIGURE OUT HOW TO GET THESE COMPOUNDS INTO BIOLOGIST'S HANDS. I'VE BEEN DOING THIS CHEMICAL TOOL BUILDING THING FOR A WHILE, STARTING ALMOST 20 YEARS AGO WHEN I WAS A LOCALLY RESEARCH TECHNICIAN AT MOLECULAR PROBES, SO MAYBE YOU GUYS REMEMBER THE 90s WHEN CHEMICAL TOOLS MORE OR LESS RULED. SO IF YOU WANTED TO LABEL SOMETHING, YOU WOULD BUY ONE OF THE AT THE TIME ALEXO FLUORODYES OR ONE OF THESE STAINS TO LIGHT UP AN ORGANELLE, IF YOU WANTED TO SENSE SOMETHING, YOU WOULD USE FLOW 3 OR BCEC CF FOR THAT COMPOUND FROM ROGER CHEN, YOU WOULD USE PHARMACOLOGICAL AGENT OR DRUG, IF YOU WANTED TO ACTIVATE THE SOMETHING WITH LIGHT, YOU WOULD USE A NEUROTRANSMITTER, THEN BASICALLY EVERYTHING CHANGED AND CHEMISTS GOT CUT OUT, SO NOW IF YOU WANT TO LABEL SOMETHING, YOU USE A FLUORESCENT PROTEIN AND ALL THE RID ONES AND THEN THEY TURNED THEM INTO SENSORS AND THEN PEOPLE SAID A, WE CAN JUST KNOCK OUT PROTEINS INSTEAD OF USING SOME DRUG AND THEN OF COURSE THE REVOLUTION WITH EPIGENETICS WHERE YOU DIDN'T HAVE TO BUY CASE GLUTAMATE AND DO THAT WHOLE THING. SO THE REASON THESE WERE TRANSFORMATIVE IS YOU COULD EXPRESS THEM IN SPECIFIC CELLS, THEY WORKED IN VIVO SO IT OPENED UP MANY MORE SYSTEMS FOR INQUIRY , BUT I THINK MOST IMPORTANTLY THESE THINGS ARE CHEAP. SO IF YOU DO MODERN CALCIUM IMAGING IN A MOUSE, MOUSE IS LITERALLY TAKING THE FOOD, CHOW, AND TURNING IT INTO THIS AMAZING TOOL PRESSING IT IN SPECIFIC CELLS SO YOU CAN ACTIVATE THOSE NEURONS WITH LIGHT. SO THIS IS WHERE WE'RE AT, AND WE'VE BEEN DOING NOW THIS GENETICALLY ENCODED TOOL THING FOR MAYBE 15, 20 YEARS, AND WE'RE STARTING TO HIT SOME CEILINGS, FLUORESCENT PROTEINS ARE SOMEWHAT DIM, THEY HAVE POOR PHOTOSTABILITY AND THERE'S LIMITED OPTIONS IN THE FARRAD, THAT MAKES SENSING WITH PHOTON INTENSIVE EXPERIMENTS LIKE VOLTAGE DIFFICULT, KNOCKOUTS ARE EXPENSIVE STILL, BUT HAVEN'T FULLY GONE AWAY, AND UPPER GENETICS ARE -- AND OP TOE GENETICS ARE GREAT -- OPTO GENETICS ARE GREAT, THERE ARE NOW EMERGING HYBRID STRATEGIES YOU THAT COME OUT WHERE WE COMBINE THE BENEFITS OF GENETICALLY ENCODED TOOLS AND SMALL MOLECULE TOOLS. SO THESE SELF-LABELING TAGS LIKE SNAP TAGS FROM PROMEGA, JOHNSON, WE'VE BEEN WORKING ON SMALL ARE ARE MOLECULE TOOLS IN SMALL ANIMALS AND WE'VE BEEN INCORPORATING THESE DYES INTO HYBRID SENSOR SYSTEMS TO MAKE VERY PHOTO STABLE THINGS FOR VOLTAGE OR FARRAD CALCIUM INDICATORS, THERE ARE THESE INTERESTING CELL TYPES, PRO DRUG STRATEGIES, SIMPLY TETHERED DRUGS, AND THEN PHOTO PHARMACOLOGY FROM DERK TROW NER, THESE FAR-RED CAGES AT NCI, SO ALL THESE ARE COOL, THEY HAVE ADDED BENEFITS OVER EXISTING GENETICALLY ENCODED TOOLS, BUT THEY ALL HAVE SMALL MOLECULES. SO THESE ARE THE CHALLENGES OF SMALL MOLECULES, IT REQUIRES EXPERT HUMAN HANDS TO ACTUALLY MAKE THEM, YOU CAN'T JUST DO AN ENZYME REACTION WITH FOUR BUILDING BLOCKS AND AMPLIFY A PLASMID. SO THEY'RE VERY EXPENSIVE, YOU RUN OUT OF THEM AND THEY HAVE A SHELF LIFE. IN A TYPICAL ACADEMIC LAB, MADE UP OF GRADUATE STUDENTS OR POST-DOCS, IT'S KIND OF A WASTE OF THEIR TIME TO HAVE A TRAINEE MAKE A MOLECULE THAT'S ALREADY BEEN MADE, AND BECAUSE WE'RE PUTTING EFFORT INTO THIS, CHEMISTS UNDERSTANDABLY REQUIRE AUTHORSHIP. AGAIN, THE MARKET ON THESE THINGS IS SMALL, AND THE COMPETITION IS LITERALLY FREE. YOU JUST SPEND $50 AT AD GENE SP YOU'RE OFF TO THE RACES SO YOU CAN'T RUN A HIGH VOLUME BUSINESS AND YOU CAN'T RUN A HIGH MARGIN BUSINESS. THE I IP SPACE IS MESSY, PEOPLE INVENT A NEW CAGE OR SOMETHING, THE UNIVERSITY THE THINKS THEY'RE GOING TO GET RICH, THEY'RE NOT GOING TO GET RICH. [LAUGHTER] IF YOU WANT TO GET RICH, DEVELOP A DRUG, DON'T DO TOOLS ON. [LAUGHTER] AND THEN FOR A COMPANY TO TAKE A RISK ON A NEW PRODUCT, IT'S A BIG INVESTMENT, I WAS IN THAT SPACE, IT'S A PROBLEM TO GO IN IF YOU DON'T HAVE EXCLUSIVE LICENSE, IT'S TRICKY AND THAT'S SOMETHING THAT ACADEMICS TYPICALLY DON'T THINK ABOUT. AND OF COURSE THE THEME FOR THIS WHOLE PANEL THING IS IT'S VERY DIFFICULT TO TAKE A CHEMICAL TOOL FROM VERSION 1.0 TO SOMETHING THAT'S TURNKEY, THAT'S BECAUSE GRANTING AGENCIES VALUE INNOVATION, SO THERE'S STILL ODDLY AN INNOVATION SCORE EVEN ON THESE DISSEMINATION GRANTS, CHEMISTRY DEPARTMENTS COUNT PAPERS, ACTUALLY GET CHILDED BY COLLEAGUES SAYING -- CHIDED BY COLLEAGUES, SAYING I HAVE TOO MUCH DATA IN MY PAPER, SHOULD SLIESTLES THE SA LA MY THIN -- THE SALAMI THINNER, AND CHEMISTRY JOURNALS VALUE NOVELTY OVER UTILITY, SO THERE'S A PRESSURE IN OUR FIELD TO DO SOMETHING THAT'S NEW VERSUS SOMETHING THAT'S USEFUL. WHAT ARE WE TRYING TOLD AT JANELIA? SO IN ORDER TO SOLVE THE EXPENSE PROBLEM, WE INVEST NOT ONLY IN BUILDING NEW MOLECULES BUT IN BUILDING THE METHODS THAT WE USE TO BUILD MOLECULES, SO BY INVESTING IN THE CHEMICAL SYNTHESIS, WE'RE ABLE TO MAKE MOLECULES MORE EFFICIENTLY AND THAT DRIVES DOWN THE COST. TO DEAL WITH THIS TRAINEE ISSUE, WE JUST HIRE CAREER SCIENTISTS, TECHNICIAN SENIOR SCIENTIST WHO IS ARE NOT TRYING TO GO OUT AND GET A JOB IN THE NEXT TWO YEARS. THEN THIS AUTHORSHIP DEAL, WE JUST FOR ME, I DON'T ASK FOR AUTHORSHIP BECAUSE I THINK IT'S DUMB, WE NEED TO EXPECT AUTHOR SHIP IF ALL I DID WAS PUT A BIO IN A BAG AND SEND IT TO SOMEONE. SO TO DEAL WITH THIS ISSUE OF FREE COMPETITION, WE BASICALLY JUST GIVE AWAY EVERYTHING WE MAKE FOR FREE AND YOU MIGHT THINK HOW CAN WE DO THAT? SO THE BIOS THAT WE TYPICALLY SEND OUT IT WOULD HAVE MARKET VALUE OF $5,000, COST US 72 CRENTSZ TO MAKE, 12 CENTS OF THAT IS THE VIAL, SO -- [LAUGHTER] SO WE GIVE OUT A FEW THOUSAND VIALS A YEAR, IT'S LIKE $1,500, CAN HANDLE THAT. IN TERMS OF THIS IP SPACE, THE DREAM THAT I'M THINKING ABOUT IS TO HAVE AN AD CHEM AS IT A A COMPLEMENT TO AD GENE WHERE THIS BECOMES A CLEARINGHOUSE FOR CHEMICAL TOOLS, THERE'S SOME SET ROYALTY THAT IP HOLDERS CAN GET AND JUST HAVE THE CLOUT, HAVE A BLANKET BOILERPLATE IP AGREEMENT , AND THEN MAYBE MAKE THAT AN INCUBATOR SO NEW CHEMICAL TOOLS IF THEY TAKE OFF, TECHNOLOGY -- OR COMPANIES CAN PICK THEM UP AND MAKE THEM BETTER. AND THEN IN TERMS OF JUST FUNDING AND SUPPORTING TOOL BUILDING, WE SHOULD SCORE GRANTS ON THE USE OF TOOLS, CHEMISTRY DEPARTMENTS NEED TO CHANGE AWARD COLLABORATION AND FRANKLY WE SHOULD JUST WEIGH CHEMISTRY JOURNAL PAPERS LESSESES THINKING ABOUT CHEMICAL TOOLS BECAUSE IT'S IN A CHEMISTRY JOURNAL, IT PROBABLY DOESN'T WORK. THE SO THAT'S MY SPIEL, I'M HAPPY TO TAKE ANY QUESTIONS. THANK YOU VERY MUCH. >> Dr. Denison: QUESTIONS FROM THE WORKING GROUP TO GET STARTED >> TWO QUESTIONS. SO ONE IN TERMS OF THE COST OF DISTRIBUTING THE CHEMICAL YOU MENTIONED, HOW MUCH WOULD THAT BE IF YOU ADDED ON MANPOWER? SO THAT'S ONE THING. SO SECOND THING -- >> Dr. Lavis: 72 CENTS IS OUR COST FOR LABOR AND SYNTHESIS, IT DOESN'T COUNT MY COST FOR COMING IN SUNDAY NIGHT AND PUTTING VIAL INSIDE A BAG WHICH I DO EVERY WEEK, AND IT DOESN'T COVER THE SHIPPING. WE HAVE THAT INFRASTRUCTURE AT JANELIA. I DON'T THINK IT'S -- I'M PRETTY SURE THE BIGGEST COST IS THE FEDEX, THE SECOND BIGGEST COST IS THE BOX, WE BUY THESE REALLY NICE BOXES. [LAUGHTER] SO 5 BUCKS. SO, YOU KNOW, THEN THE LABOR TO DO THIS. BUT IT'S NOT HARD. I THINK WE COULD EASILY, YOU KNOW, IF YOU WERE GOING TO GO ON AN ADD GENE MODEL, YOU COULD DO IT FOR 50 OR $100 AND IT WOULD COVER COSTS. >> THAT'S MY SECOND QUESTION, I DON'T KNOW WHAT THE ADD GENE MODEL IS, SO IF YOU COULD JUST CLARIFY. >> Dr. Lavis: I'M SORRY. THE ADD GENE MODEL IS THIS IS A GENETICALLY ENCODED TOOL REPOSITORY, YOU SUBMIT SOMETHING , THEY BASICALLY GIVE YOU SMALL AMOUNTS FOR A NOMINAL FEE. SO THEY BASICALLY ARE A CENTRAL CLEARINGHOUSE FOR THESE GENETIC ALLY ENCODED REAGENTS, BUT BECAUSE IT'S DNA BASED, WE CAN EASILY REAMPLIFY IT, THEY DON'T HAVE TO SEND VERY MUCH, ONE LITTLE PIECE OF PAPER WITH SOME DNA ON IT IS GOOD, THAT'S VERY DIFFERENT THAN CHEMICAL TOOLS WHICH RUN OUT. >> SO THE IDEA THERE, YOUR PROPOSAL S THAT THIS WOULD JUST RUN AT COST, THERE WOULDN'T BE A PROFIT MOTIVE, BUT THE TOOL WOULD GET OUT THERE BY JUST BEING SELF-SUSTAINING? >> Dr. Lavis: WE WOULD HAVE A NONPROFIT, ADD GENE IS A NONPROFIT INSTITUTION, SO WE WOULD WANT TO HAVE A NONPROFIT, I THINK AGAIN, 20 YEARS AGO, YOU DIDN'T HAVE ANY COMPETITION, BUT NOW THE COMPETITION IS FREE, SO IF SOMEONE IS FACED WITH SPENDING $5,000 ON SOME CHEMICAL REAGENT OR THEY CAN GET A GENETICALLY ENCODED REAGENT FOR $50 FOREVER, ESSENTIALLY FREE, THEN, YOU KNOW, ONLY A SMALL HANDFUL OF LABS WILL USE THIS VERY EXPENSIVE TOOL IS BETTER. >> SORRY. WHEN YOU MENTIONED COSTS, COULD YOU HELP EXPLAIN WHAT YOU MEAN BY THAT? WHAT DID YOU ACCOUNT FOR IN YOUR COST CONSIDERATION? DOES IT INCLUDE THE BUILDUP OF KNOWLEDGE BASE, EQUIPMENT, INFRASTRUCTURE, OVERHEAD TO KEEP THINGS RUNNING, DEPRECIATION, ALL THESE THINGS, YOU KNOW, IF SOMEBODY SELLS SOMETHING FOR $4,000 AND YOU'RE OFFERING IT FOR CENTS, THEY USUALLY WON'T HAVE A $3,999 PROFIT MARGIN ON THIS THING. SO I WOULD BE VERY INTERESTED IN WHAT THE ASPECTS ARE, JUST LIKE IN A UNIVERSITY WHEN WE DO THINGS AND WE DO THEM AT COST BUT EVERYBODY FORGETS THAT WE HAVE $150 MILLION NANOFAB BEHIND THAT SOMEBODY GAVE THAT WE DON'T HAVE TO ACCOUNT FOR. >> Dr. Lavis: SO THIS COST, THE WAY WE USUALLY DO IT NOWADAYS, IS WE HAVE EVERYTHING BUT THE LAST STEP OUTSOURCED, OUR CHEMISTRY IS GOOD ENOUGH TO WHERE WE CAN NEGOTIATE WITH OUTSIDE COMPANIES TO GIVE US ESSENTIALLY AN ULTIMATE COMPOUND , YOU DO ONE STEP, DO THIS IN OUR SPARE TIME. I THINK THAT THE ISSUE HERE IS MY JOB IS TO MAKE MOLECULES, RIGHT? SO I DON'T CONSIDER THAT PART OF THE COST BECAUSE I ALREADY HAVE THAT EQUIPMENT. THAT'S MY DAY JOB. WE MAKE MOLECULES THE LAST 15 MINUTES OF THE DAY OR SOMETHING FOR THIS, SO, YOU KNOW, WE DON'T HAVE TO -- IT'S NOT A VERY DIFFICULT THING BECAUSE IT'S JUST ONE STEP. WE'RE NOT ACCOUNTING THE EQUIPMENT COST BECAUSE WE ALREADY HAVE IT. SO THAT'S ONE ISSUE. I THINK THE OTHER THING, THE WAY I THINK ABOUT IT, IS JANELIA AND ALSO THE BRAIN INITIATIVE, WE'RE NOW PAYING FOR THE DEVELOPMENT NOT JUST OF INITIAL TOOLS, VERSION 1.0 TOOLS, BUT WE'RE ALSO PAYING FOR THESE OPTIMIZED TOOLS THAT -- SO IT FEELS WEIRD TO PAY FOR THAT DEVELOPMENT, GET SOMETHING THAT'S ALMOST COMMERCIALLY VIABLE AND THEN EXPECT, YOU KNOW, SOME COMPANY TO MARK IT UP BY 1,000 PERCENT. SO I THINK WE SHOULD, GIVEN THE CHANGE THAT WE'RE DOING IN TERMS OF FUNDING, DEVELOPMENT, SHOULD BE MORE GENEROUS. >> Dr. Denison: ALL RIGHT. WE'RE ACTUALLY AT A GOOD TIME. THANK YOU AGAIN. [APPLAUSE] SO TO WRAP UP THE FORMAL PRESENTATIONS, IT'S MY PLEASURE TO BRING FLORIAN SOLZBACHER IN. FLORIAN HAS A DUAL ROLE BOTH IN THE ACADEMIC SETTING AT THE UNIVERSITY OF UTAH BUT ALSO HERE TODAY REALLY SHARING HIS EXPERIENCES RUNNING BLACKROCK AND LESSONS LEARNED FROM THAT ENTERPRISE OF TRYING TO RUN A COMPANY TO SUPPORT RESEARCH TOOLS. SO LET'S ALL WELCOME FLORIAN. [APPLAUSE] >> Dr. Solzbacher: THANK YOU VERY MUCH, AND TIM, THANK YOU FOR THE INTRODUCTION, FOR HAVING ME HERE, AND YES, IT'S ALL A REPEATING THEME YOU'VE ALREADY HEARD. IT'S NOT EASY. SO HOW ALL OF THIS CAME ABOUT IS THAT BEFORE I DID ONE OF MY FIRST BUSINESSES AS A GRADUATE STUDENT, EXITED THAT AND THEN WENT BACK INTO ACADEMIA AND STARTED FOCUSING ON THIS FIELD AND WAS AFTER A FEW YEARS IN A SITUATION WHERE I HAD TO THINK ABOUT HOW DO I TRANSLATE THESE TECHNOLOGIES, AND IF I'M REALLY INTERESTED IN HELPING HUMAN SUBJECTS AND PATIENTS IN OUR TRADITIONAL WISDOM WAS YOU PICK A SPECIFIC APPLICATION, THEN YOU FIND VENTURE CAPITAL OR PRIVATE EQUITY MONIES AND YOU SORT OF LASER FOCUS ON ONE APPLICATION AND GO DOWN THAT PATH, AND THERE'S BEEN SOME CASES, IF YOU LOOK AT BOB GREENBERG'S EFFORTS, PROBABLY EXCEEDED A HALF BILLION OR SO INVESTED INTO THIS, AND IT'S OFTEN VERY, VERY HARD TO DEFINE WHAT YOU REALLY NEED, YOU KNOW, WHEN YOU TALK TO A LOT OF THE CLINICIANS AND USERS, THEY ALL P HAVE AN OPINION AS TO WHAT THEY WANT, BUT IT'S VERY HARD TO IDENTIFY WHAT YOU REALLY NEED AND TAKE SOME TIME. SO A MODEL WE TRIED OUT IS TO GO OUT AND SAY, WELL, WE'RE IGNORING THE FACT THAT THERE IS A NICHE, VERY SMALL, BUT EXISTING RESEARCH MARKET, RESEARCHERS THAT STUDY NEUROLOGICAL DISORDERS, THAT HAVE THE SAME VISION AND MISSION IN WANTING TO HELP PATIENTS, FOR EXAMPLE, WITH NEURO PROSTHETIC DEVICES, AND EVERYBODY IS BUILDING THEIR OWN TOOLS TO A LARGE EXTENT. SO IF WE CAN GO OUT AND BUILD TOOLS THAT ARE SORT OF STANDARDIZED TO BECOME A STANDARD FOR PEOPLE TO USE WITH THE RIGHT LEVEL OF SUPPORT, THEN THE HOPE IS THAT THAT WILL CARRY YOU INTO THE RIGHT APPLICATIONS. IN ADDITION, IN THE CONTEXT OF THIS RESEARCH MARKET, YOU CAN LEARN, INSTEAD OF BEING IN A SITUATION WHERE YOU SORT OF MOVE FORWARD IN ONE SPECIFIC APPLICATION VERY LATE IN THE GAME, YOU'VE GOT TO LEARN A LOT OF THE CHALLENGES, YOU CAN GO OUT THERE AND DIVERSIFY YOUR RISKS BECAUSE THERE'S A FEW THOUSAND LABS OUT THERE THAT DO WORK IN THIS SPACE, AND SO SO FAR, SO GOOD, THAT CONCEPT WORKED REMARKABLY WELL, BUT THE TRANSITION INTO THE CLINICAL MARKET IS NOT TRIVIAL FOR A NUMBER OF REASONS. ON THE UP SIDE, OF COURSE, YOU CAN FAIRLY QUICKLY GENERATE A BUSINESS THAT GENERATES SOME REVENUE AND THAT CAN SUPPORT CERTAIN TOOLS, BUT WHAT YOU CAN'T UNDERESTIMATE IS THE AMOUNT OF EFFORT THAT GOES INTO CONTINUOUSLY DEVELOPING THOSE TOOLS. THE FACT THAT YOUR CUSTOMERS ALMOST ALWAYS -- YOUR CUSTOMERS ARE APPLES ALWAYS A COMPETITOR AS WELL, THEY'RE ALL VERY BRIGHT PEOPLE, THEY KEEP DRIVING TECHNOLOGY, THEY ALWAYS HAVE A WAY OF, HEY, I CAN DO THIS A LOT BETTER. AND OF COURSE THERE'S ALSO A LACK OF APPRECIATION OF THE FULL COST AND THEIR OWN OPPORTUNITY COST, AND I'VE MADE THE MISTAKE MYSELF IN MY OWN LAB OF SOME OF THE EQUIPMENT WE USE TO BUILD THINGS, SAY I'VE GOT A GRADUATE STUDENT, WE CAN BUILD THAT STUFF MYSELF, THREE YEARS LATER YES YOU SPENT A QUARTER OF WHAT IT COST TO BUY THE REACTOR, BUT I'M NOT FOCUSES USING ON WHAT I WANT TO ACTUALLY ACCOMPLISH. THESE ARE REAL CHALLENGES, SO EVERY TIME THERE'S AN INITIATIVE LIKE OPEN EPHIS OR OTHER THINGS WITH EVEN -- THINGS FREE OR WITH A SIGNIFICANT DISCOUNT, EVERYBODY RUNS FOR THAT BECAUSE WE'RE RESOURCE CONSTRAINED AND YOU WANT TO MAKE USE FOR THAT. THE PART YOU'RE FOR GETTING ON THAT IS WHAT IS YOUR PATH TOWARDS LONG-TERM SUSTAINABILITY BECAUSE ONCE THAT FUNDING RUNS OUT OR, YOU KNOW, IF A CHARITABLE ORGANIZATION SUPPORT ED SOMETHING, ONE OF THE BIG CHALLENGES IS, YOU KNOW, HOW DO YOU THEN DISSEMINATE AND DISTRIBUTE IT? HOW DO YOU PROVIDE THE SUPPORT? ONCE THIS THING GOES OUT THE DOOR, YOUR EFFORT FOR ENGINEERING AND SUPPORT GOES UP. YOU'RE NOT DONE. IT'S THE MISCONCEPTION. YOU'VE GOT YOUR GRANT, YOU'VE BUILT SOMETHING, IT WORKS GREAT, YOU'VE GOT A FEW AMAZING PAPERS, EVERYBODY CALLS YOU BECAUSE THEY WANT IT. NOW YOU NEED A STAFF OF PEOPLE THAT HAVE Ph.D.'S IN ENGINEERING, NEUROSCIENCE BACKGROUND, THEY COULD TECHNICALLY BE THEIR OWN ACADEMIC RESEARCHER THAT NEED TO SUPPORT PEOPLE OUT THERE SO THAT THE PRODUCT WORKS AND IS SUCCESSFUL AND SO THAT YOU KEEP LEARNING. THAT IS WHERE THE COST IS, NOT THE PARTS. AND THEN OF COURSE YOU NEED TO HAVE, YOU KNOW, OVERALL OVERHEAD AND BUSINESS INFRASTRUCTURE TO DO SO. AND THEN THE TRANSLATION INTO CLINICAL PRODUCTS CAN TAKE VERY, VERY, VERY LONG. AFTER TEN YEARS, IT'S BEEN PROBABLY 25 YEARS AGO THAT THE ELECTRODE ARRAY WAS INVENTED, 15 YEARS AGO CAME ON BOARD HELPED WITH SOME OF THE TRANSLATION, TEN YEARS AGO THAT WE STARTED AND NOW WE'RE AT THE POINT WHERE THERE'S A HANDFUL OF CLINICAL APPLICATIONS THAT MAY OR MAY NOT START TAKING OFF, AND I'M GOING TO LOOK AT ANOTHER TEN YEARS TO HAVE THOSE GO INTO VOLUME. BUT THE IT IS A MODEL THAT ALLOWS YOU TO IMPROVE SYSTEMATIC INTEGRATION, TO IMPROVE TECHNOLOGICAL READINESS LEVEL, AND IF YOU DO IT RIGHT AND PEOPLE WORK WITH YOU AND NOT AGAINST YOU, YOU'LL HAVE A PLATFORM OF PARTS THAT YOU CAN THEN PUT TOGETHER AS YOU START ADDRESSING NEW APPLICATIONS. IN THE RELATIONSHIP BETWEEN ACADEMIA AND INDUSTRY, YOU KNOW, ONE OF THE QUESTIONS OFTEN PEOPLE COME UP WITH NOVEL IDEAS FOR NEW PRODUCTS THAT THEY'RE INTERESTED IN, AND WHAT IS A GOOD PATH TO ADDRESS THOSE ORPHAN PRODUCTS OREGON FAN PUBLICATIONS? ONE OF THE LEARNINGS FROM THE LAST TEN YEARS IS THAT IT IS REALLY, REALLY ADVISABLE TO TRY AND PARTNER UP, IF YOU CAN, AND USE AS MANY EXISTING COMPONENTS AS POSSIBLE. THE IF YOU'RE SERIOUSLY INTERESTED IN NOT JUST STOPPING AT THE PAPER LEVEL BUT TRANSITIONING, AS TIM AND LUKE HAVE ALSO SAID, INTO UTILITY LEVEL, DOES IT REALLY WORK, IS IT USEFUL OUT THERE, HAVING SOMETHING LIKE NIH REGIONAL CENTERS COULD BE USEFUL. I KNOW THAT IN MOUSE PHENOTYPING , VANDERBILT FOR MANY YEARS HAD A CENTER, AND INSTEAD OF EVERYBODY HAVING THEIR OWN PHENOTYPING LAB, YOU COULD GET SUBSIDIZED SERVICES THERE, I THINK THERE'S A REAL ADVANTAGE IN HAVING THAT, PROVIDED YOU'RE NOT DIRECTLY COMPETING WITH INDUSTRY OUT THERE. OBVIOUSLY I'VE GOT A CONFLICT OF INTEREST THERE, WHICH TIM ALREADY MENTIONED, MENTION AT& THE OUTSET, THROUGH MY DUAL ROLE , SO I HAVE A BIT OF A TAINT ED VIEW THERE POSSIBLY, BUT I STILL BELIEVE THAT UNLESS YOU HAVE EITHER THE A COMMITMENT FOR THE NEXT 30 YEARS PLUS FROM A DOLE NOR OR AN ORGANIZATION TO SUPPORT SOMETHING, I THINK YOU'RE BETTER ADVISED IN HAVING YOUR INVESTOR BE THE ENTIRE MARKET, AND THAT MEANS YOU HAVE TO HAVE A MODEL TOWARD SUSTAINABILITY, WHICH MEANS THAT PRICING NEEDS TO ALLOW FOR THAT. OPEN SOURCE VERSUS PRIVATE AND HYPER-DISSEMINATION WAS ANOTHER TOPIC THAT CAME UP IN THE QUESTIONS TO PANEL MEMBERS. OBVIOUSLY IF YOU HAVE SOMETHING THAT IS OPEN SOURCE OR FREE, THAT REALLY LOWERS THE BARRIER TO ENTRANCE FOR PEOPLE TO TRY AND ADOPT IT. A WORD OF CAUTION, WHENEVER SOMETHING IS FREE, THERE'S ALSO A CHALLENGE IN GETTING PEOPLE TO REALLY INVEST TIME INTO THEN DEVELOPING IT FURTHER AND SUPPORTING IT. I'VE SEEN MANY CASES WHERE WE SHIP SAMPLES TO PEOPLE FREE, STILL IN THE DOOR, IF YOU CHARGED THEM $50,000, THAT IS URGENT, THAT'S NOT JUST NICE TO HAVE, THAT IS A NEED TO HAVE AND YOU HAVE AN OBLIGATION TO SHOW YOU SPEND SO MUCH MONEY ON THIS, WHAT ARE YOU FREAKING GOING TO DO WITH IT? SO THERE'S A COMPONENT THAT YOU DON'T WANT TO FORGET IN THAT. I THINK YOU NEED TO LOOK AT IT ON A CASE-BY-CASE BASIS, AND ONE THING THAT WE'VE SEEN WORK QUITE WELL IS WHERE PEOPLE HAVE COME BACK AND SAID, WELL, YOU KNOW, YOU CAN WORK TOGETHER. YOU CAN LICENSE TECHNOLOGIES THROUGH A BUSINESS IF IT MAKES SENSE, YOU CAN MAYBE JOINTLY BUILD THINGS WHERE SOMETHING IS DONE IN A UNIVERSITY LAB OR IN ANOTHER ORGANIZATION AND THEN YOU HAVE CERTAIN COMMERCIAL COMPONENTS THAT ARE USED TOGETHER TO LOWER THE COST AND ABILITY TO ENTER THE MARKET. I THINK IT IS REALLY, REALLY IMPORTANT TO HAVE MECHANISMS IN PLACE THAT FORCE PEOPLE TO PLAY TOGETHER. YOU KNOW, AGAIN, AS TIM ALREADY SAID, THE MARKET IS NOT BIG ENOUGH, THIS IS NOT A WAY TO GET RICH, AND IT'S ALSO TOO COMPLEX OF A TOPIC THAT ANY SINGLE TEAM OR GROUP CAN SOLVE ALL THE PROBLEMS. SO IT'S REALLY AN OPPORTUNITY FOR PEOPLE TO COLLABORATE, AND IT IS VERY HARD BECAUSE ACADEMICS, WE COMPETE WET EACH OTHER, AND EVERYBODY WANTS TO BE A LITTLE -- WE COMPETE WITH EACH OTHER AND EVERYBODY WANTS TO BE A LITTLE BIT BRIGHTER, AND REALIZE THAT AS INDIVIDUAL PRODUCT EFFORTS, PEOPLE MAY HAVE SPEND UPWARDS OF A BILLIO DOLLARS TO GET SOMETHING OUT THERE. WE CAN POOL, ARING IF YOU'RE REALLY COMMITTED, WE SHOULD GET TOGETHER AND SAY, YOU KNOW, DO IT LIKE SRC AND THE SEMI CONDUCT ARE TORS, CREATE THESE USER GROUPS WHERE YOU REALLY SHARE AND EVERYBODY CONTRIBUTES THOSE COMPONENTS WHERE THEY HAVE THE MOST VALUE YOU CAN CONTRIBUTE TOWARDS THE TOTAL SOLUTION, AND IF YOU HAVE PROGRAMS THAT INCENTIVIZE, THAT I THINK WE'LL SEE PROGRESS AND LESS TRAKS PARALLEL DEVELOPMENTS -- AND LESSES PARALLEL DEVELOPMENT THAT ARE RESEARCH INTENSIVE AND ARE OFTEN DOOMED BECAUSE THERE'S NO FOLLOW-UP. VERY IMPORTANT ALSO NOT TO BE IGNORED IS THE USER BASE, INCLUDING THE SURGICAL TRAININGS , ET CETERA, WHEN YOU LOOK AT COCHLEAR IMPLANTS, IT TOOK THEM ABOUT 30 YEARS TO REALLY GROW THE NUMBER OF HOSPITALS, SURGEONS, PEOPLE THAT KNEW HOW TO USE IT, PEOPLE TO MAKE IT WORK. THE INITIAL CONCEPTS WERE EASY. SAME SITUATION HERE. EFFORTS LIKE BRAINGATE AND OTHERS HAVE HELPED DISSEMINATE SOME OF THAT AND THERE'S A GROWING NUMBER OF SITES OUT THERE, BUT FOR EVERY SINGLE TOOL THAT YOU ARE CONCEIVING, YOU'LL HAVE THE SAME UPHILL BATTLE THAT PEOPLE WILL NEED TO FIGURE OUT HOW TO USE IT, WHAT WORKS, WHAT DOESN'T WORK, AND SOME OF THAT CAN NOT BE ACCELERATED. THAT MAY TAKE A DECADE OR TWO TO LEARN ALL THOSE THINGS. HOW ARE WE GOING TO GO SUSTAIN THAT? AND IN PARTICULAR AS AN ACADEMIC , WHERE THE INCENTIVE ZA I GUESS IS NOVELTY, NEW KNOWLEDGE, YOU KNOW, AND INNOVATION, THAT IS VERY HARD, AND I'VE SEEN IT IN MY OWN EFFORTS, WHENEVER I'VE TRIED, IT'S NOW WORKING A LITTLE BIT BETTER AFTER 15 YEARS BACK IN THAT BUSINESS, IT'S STILL HARD, AS WE'VE SAID, SOME GRANTS SHOULD REALLY BE UTILITY BASE, THERE IS AN INNOVATION SCORE IN IT, AND THE SORT OF SQUIRREL EFFECT LOOKS SOMETHING NEW, ALMOST ALWAYS BEATS THE OH, YEAH , WE'VE SEEN THE ARRAY SINCE NORMAN STARTED IT, THIS IS BORING, THIS IS THE 50TH VERSION OF AN ENCAPSULATION QUESTION YOU'RE TRYING TO ADDRESS, BUT THAMS THE REALITY. IF YOU'RE SERIOUS ABOUT NOT JUST YOURSELF AND THE KNOWLEDGE GAME BUT IF YOU'RE SERIOUS ABOUT WE WANT TO MAKE THAT WORK, IT'S A DIFFERENT TASK, AND BRIDGING THAT IS QUITE CHALLENGING. STANDARDIZATION IS SOMETHING THAT I THINK IN PRACTICE I'VE ALWAYS SEEN IT HAPPEN OVER TIME. I THINK WE'RE STILL A LITTLE BIT EARLY. IT'S IMPORTANT TO THINK AND TALK ABOUT THAT, BUT IN THE PAST USUALLY WHAT HAPPENS IS THAT CERTAIN SOLUTIONS JUST WORK WELL THEY WORK WELL FOR YOU, FOR YOUR COLLEAGUES, FOR OTHERS, MORE PEOPLE ADAPT THEM, AND THEN YOU HAVE A BASIS TO DISCUSS HOW TO TURN IT INTO SOMETHING THAT CREATES SYNERGY. SO A LITTLE BIT OF AN EYE TEST. I WORKED ON A FEW ITEMS HERE THAT, YOU KNOW, YOU CAN GET ACCESS TO THE SLIDES AND THEN READ IN YOUR OWN TIME. I THINK THE SINGLE-MOST IMPORTANT MESSAGE THAT I PERSONALLY WOULD LIKE TO BRING ACROSS HERE IS LISTEN TO THE PATIENT. WE'RE ALL IN THAT USUALLY BECAUSE WE WANT TO HELP PEOPLE, BUT THEN YOU GET LOST ON THE WAY BECAUSE OF THE COMPETITION AMONGST ACADEMICS, BECAUSE OF THE NEED TO DEMONSTRATE KNOWLEDGE, AND SOMETIMES WE PUT OURSELVES ONTO A PEDESTAL WHERE WE SAY ETHICALLY WE SHOULDN'T DO IT YET UNLESS ALL THESE THINGS ARE SOLD, NMS THE IMPLANT WORKS TEN YEARS, 20 YEARS, AND IT'S FULLY WIRELESS. WHEN YOU TALK TO NATHAN COPELAND AND IANBURKLAND, WHAT HAVE YOU, THEY TELL YOU ARE YOU NOT LISTENING? FOR A FEW YEARS, I'VE TOLD YOU, I WANT TO BRING IT HOME, I DON'T EVEN CARE THAT THERE'S A PLUG SHES YOU'VE GOT A PROBLEM WITH IT, I DON'T, IT'S A CONVERSATION STARTER FOR ME EVEN. SO FOCUS ON SOME OF THOSE THINGS , AND, YOU KNOW, I THINK THERE'S A CASE TO BE MADE TO SAY WE'VE GOT USABLE THINGS OUT THERE RIGHT NOW. GETTING THOSE IN ORPHAN POPULATIONS OUT INTO THE CLINIC INTO USE CASES WILL REALLY HELP ALL OF US BECAUSE WE'LL LEARN THINGS, WE'LL UNDERSTAND NEW PROBLEMS WE'RE NOT EVEN SEEING BECAUSE IN THE PAST 30 YEARS WE'VE DABBLED INTO HERE IS A THU THING, GET IT INTO A RODENT, MAYBE INTO A PRIMATE, OUT OF THOSE, ONE OR TWO MAYBE EVENTUAL LY HAVE MADE IT INTO A HUMAN SUBJECT AND THEN WE GO BACK AND SAY, WELL, THIS DOESN'T WORK SO WELL. SO I WOULD LIKE TO ENCOURAGE EVERYBODY TO KEEP THAT IN MIND WHEN PLANNING, AND I HOPE THAT IN THE NEXT PHASE OF THE BRAIN INITIATIVE, AT LEAST A SIGNIFICANT PORTION OF RESOURCES CAN FOCUS ON MAKING THESE DEVICES USEFUL AND ALLOWING PEOPLE TO TAKE THEM HOME AND THEN ADDRESSING THOSE SPECIFIC PROBLEMS THAT COME WITH NO, YOU CAN'T HAVE FOUR Ph.D.'S IN THE ROOM THAT HELP YOU START IT UP AND SPEND THE FIRST TWO HOURS GETTING GOING. THIS NEEDS TO BE SWITCHING ON YOUR PHONE OR WHATEVER AND CLICKING A FEW BUTTONS. THANK YOU VERY MUCH FOR YOUR TIME. [APPLAUSE] >> SO I COULD TAKE ONE SPECIFIC -- COME ON UP. >> FLORIAN, CAN YOU ADDRESS THE ISSUE THAT ON SOME LEVEL ALL ACADEMICS ARE UNIQUE, SO PARTICULARLY IN THE WORLD THAT BLACKROCK LIVES IN WITH BEHAVIORAL NEUROSCIENCE, THE CUSTOMERS TEND TO HAVE VERY DIFFERENT NEEDS TO USE, AND SO HOW DO YOU ADDRESS THE ISSUE OF THAT OFTENTIMES YOU HAVE TO MODIFY THESE AND THE FACT THE THAT THEY WORK OUT OF THE BOX IN THE ONE CASE WHERE THEY WERE TESTED DOESN'T NECESSARILY MEAN THEY WORK OUT OF THE BOX IN THE VERY SPECIFIC CASE THAT THE ACADEMIC IS THEN USING THEM? DOES THAT MAKE SENSE? >> Dr. Solzbacher: ABSOLUTELY. THAT IS ONE OF THOSE ASPECTS THAT MAKES UP FOR THE COMPARABLY HIGH COST FOR BUYING THAT, ON OBVIOUSLY THERE'S A LEARNING CURVE. WHAT YOU CAN TRY TO DO AND WHICH IS WHAT WE'VE DONE IS THAT OVER TIME YOU DEVELOP ON THE ONE HAND A MODULAR OR PLATFORM CONCEPT WHERE YOU HAVE A LOT OF COMPONENTS THAT ARE AS VERSATILE AS POSSIBLE AND ROBUST IN CERTAIN SETTINGS, AND THEN YOU'VE GOT WHAT I WOULD CALL ADAPTERS AND A KNOWLEDGE BASE THAT YOU'RE BUILDING. SO THAT REALLY IS AN INVESTMENT INTO THE HUMAN RESOURCE SIDE. SO WE START PEOPLE OFF, FOR EXAMPLE, IN IN-HOUSE SUPPORT, MOVE FROM IN-HOUSE TO FIELD SUPPORT, FROM THERE TO SALES. BY THE TIME THEY GO BACK INTO R & D, THEY WILL HAVE SEEN 300, 500, 800 LABS, PROBABLY MORE SURGERIES THAN YOU AND I WILL HAVE SEEN IN EXPERIMENTS, AND THEY GATHER THAT EXPERIENCE, AND THAT IS ALSO WHY AFTER TEN YEARS WE ARE MUCH, MUCH BETTER THAN WE WERE FIVE YEARS AGO, TWO YEARS AGO, AND IT'S A MUTUAL LEARNING CURVE THAT THEN FEEDS BACK INTO A CONSTANT REINVESTMENT INTO THE EQUIPMENT. TO SOME EXTENT, IT LOOKS LIKE SOME OF THE BOXES AND THINGS LOOK THE SAME THEY HAVE, BUT THEY'RE ACTUALLY NOT, THERE'S A LOT OF WORK THAT GOES INTO THIS ONE. AND AGAIN, THAT MAKES A DIFFERENCE BETWEEN THE COST THAT IS SOMETIMES SEEN, HEY, I CAN BUILD THIS FOR A FEW HUNDRED DOLLARS, AND THE COST THAT YOU TO MAINTAIN, YOU KNOW, 50, 60 PEOPLE THAT DO THAT. AND YES, SOMETIMES YOU FAIL. THAT'S ANOTHER THING, YOU KNOW, YOU GO INTO A NEW APPLICATION, RESEARCHERS CONSTANTLY PUSH THE BOUNDARIES, AND YOU NEED TO RESPOND TO THAT AND YOU NEED TO HAVE A TEAM THAT WORKS WO THEM, AND AS LONG AS THAT COMMUNICATION IS THERE, USUALLY BOTH SIDES END UP HAPPY AND YOU KEEP IMPROVING THE PRODUCT. THANK YOU FOR THAT QUESTION. >> Dr. Denison: ANY BURNING QUESTIONS? >> THANKS. I HAVE A QUESTION ABOUT SOMETHING THAT ALSO CAME UP AT THE LAST WORKSHOP AND HAS COME UP A COUPLE OF TIMES AMONG YOU AS WELL, WHICH IS THAT THE NEUROSURGEONS SEEM TO BE OUT AHEAD, LET'S SAY, OF THE DEVICE DEVELOPERS IN THINKING ABOUT HOW TO DEPLOY TOOLS IN HUMANS AND THAT THE QUESTIONS THERE ARE NEURO ETHICAL. I WONDER IF YOU COULD SPEAK TO HOW WE DEAL WITH THAT, HOW WE GENERATE THE RULES OR THE GUIDELINES BY WHICH WE CAN REDUCE THAT GAP. >> YOU'RE THE HUMAN DEPLOYMENT PERSON. >> THOUGHTS ON THAT? >> WELL,ING SO I HAVE BEEN SHOCKED AT WHAT SEEMS TO ME TO BE A FAIRLY CAVALIER RISK ASSESSMENT FROM THE NEUROSURGEONS THAT I'VE TALKED TO AND HAVING NEVER DEPLOYED ANYTHING TO HUMANS BEYOND A WRISTWATCH, I THINK THE FIRST ORDER QUESTION IS THEIR LOCAL IR B'S. THEY HAVE TO GET PERMISSION TO DO SOMETHING FROM PEOPLE WHO ARE BOTH LOCAL AND SUPPOSEDLY LITERATE. THE ADVANTAGE THAT MY TOOLS SO FAR HAVE IS THAT THEY'RE TEMPORARY, INTERVENTIONAL, NOBODY IS TRYING TO IMPLANT ANYTHING FOREVER, YOU KNOW, EITHER DURING AN OPERATION OR WHILE THE PATIENT IS IN-HOUSE SORT OF INTRAOPERATIVE IDEAS, AND SHOCKINGLY ENOUGH AGAIN TO ME, YOU TALK TO THESE SURGEONS AND THEY SAY, WELL, WE'RE DOING EPILEPSY SURGERY WHERE WE'RE GOING TO WHACK OUT A PRETTY GOOD -SIZED PART OF CORTEX, HOW MUCH HARM CAN IT DO? SO THE FIRST THING IS YOU WANT TO BE REALLY GLAD YOU DON'T HAVE EPILEPSY, BUT YEAH, I THINK THAT I DON'T HAVE A VERY GOOD PERSPECTIVE ON THAT BECAUSE IT ALL SEEMS VERY FOREIGN TO ME. PEOPLE ARE PRETTY CAVALIER ABOUT RODENTS, THEY DON'T HAVE MUCH OF A LOBBY. I THINK MAYBE WE CAN LEARN SOMETHING FROM HOW FAR THE PRIMATE PEOPLE TREAT THEIR ANIMALS JUST BECAUSE THEY ARE SORE VALUABLE NOT ONLY FROM AN ETHICAL PERSPECTIVE BUT FROM A TRAINING PERSPECTIVE. YOU PUT 18 MONTHS OR TWO YEARS INTO TRAINING A MONKEY, AND THE LAST THING YOU WANT IS SOMETHING TO GO WRONG. AND SO, YOU KNOW, I DON'T THINK THE TOOLS THAT I SEE MADE ARE VERY INSIGHTFUL IN THAT PRETTY IMPORTANT QUESTION. >> [AWAY FROM MIC] >> IS THE MICROPHONE ON? >> [AWAY FROM MIC] >> HOW DO YOU THINK ABOUT DEVELOPING CHEMICAL TOOLS FOR HUMANS? >> I DON'T. [LAUGHTER] I MEAN, I THINK WE THINK ABOUT PHARMACOLOGICAL AGENTS, BUT WE ARE REALLY FOCUSED ON BASIC RESEARCH TOOLS SIMPLY BECAUSE IF YOU'RE GOING TO ADD THE RISK OF A GENETICALLY ENCODED THING PLUS A CHEMICAL, NOT EVEN A NEUROSURGEON IS THAT CAVALIER, I GUESS. >> SO THIS POINT ACTUAL DID COME UP IN THE NEUROETHICS DISCUSSIONS THAT WE WERE HAVING, WHICH IS YOU SAY, WELL, TO ONE IS GOING TO DO GENETIC MODIFICATION IN HUMANS, SO IT DOESN'T MATTER, RIGHT? BUT THE FACT IS IF IT'S POSSIBLE AND IT DOESN'T MATTER IF IT'S NOW OR FIVE YEARS FROM NOW OR DOWN THE LINE, ANY ONE OF THESE THINGS, IF IT'S TECHNICALLY POSSIBLE, THE POTENTIAL IS THERE FOR SOMEONE TO DO IT, AND THE ACTUAL -- THE WAY THAT NOW WE'RE SHARING, WHICH IS GREAT, IT'S GREAT TO SHARE AND MAKE SURE THESE THINGS GET OUT THERE TO PEOPLE WHO WANT THEM, YOU HAVE NO WAY OF PREVENTING SOMEONE FROM TAKING WHAT YOU'VE DEVELOPED AND ACTUALLY LIMITING THEM FROM DOING THAT. AND THAT WAS AN INTERESTING POINT THAT CAME UP IS ON WHOSE SHOULDERS IS IT TO REGULATE OR TRY TO SORT OF KEEP IN THE BAG SOME OF THIS POTENTIAL FOR, SAY, NEFARIOUS USES OR OTHER USES OF THE TECHNOLOGIES THAT WE'RE DEVELOPING IN GOOD FAITH FOR RESEARCH PURPOSES. >> Dr. Strychalski: AS YOU MAY OR MAY NOT KNOW, OTHER FIELDS ARE DEALING WITH THIS, FOR EXAMPLE, SYNTHETIC BIOLOGY AND FOR GENE FITTING, AND IF THE FIELD THINKS THAT THE REVIEW PROCESSES THAT ARE IN PLACE ARE INADEQUATE AND AREN'T CAPTURING THE FULL SCOPE OF CONCERNS AND THE FULL SCOPE OF THE CONVERSATION, THEN WIDEN THE CONVERSATION. IS THERE A MORE PUBLIC WORKSHOP THAT NEEDS TO BE HELD? IS THERE A DOCUMENT THAT NEEDS TO BE CIRCULATED? BECAUSE YES, IT'S IMPORTANT FOR TOOL MAKERS AND RESEARCHERS ARE AND THE SCIENTISTS TO AGROO HE ON WHAT SHOULD AND SHOULDN'T BE DONE, HOW TOOLS COULD OR COULDN'T BE USED, BUT AT THE END OF THE DAY HERE, IT'S THE TAXPAYER WHO IS PAYING, AND IT COULD BE REALLY BAD FOR SCIENCE IF THERE IS A BACKLASH AGAINST THESE TOOLS. AND AGAIN, THAT COULD PUSH INNOVATION ELSE WRA, AND I THINK THAT'S NOT WHAT WE WANT TO THE SEE HERE. >> ELIZABETH, YOU KNOW, IT SEEMS TO ME THAT, FIRST OF ALL, IT'S A VERY GOOD POINT, WHAT ROLE DO WE APPEARS THE ORIGINATORS, I THINK GIVEN MY LEVEL OF LITERACY, YOU KNOW, MOSTLY JUST MAKE SURE THAT WE UNDERSTAND THE RISKS THAT I UNDERSTAND. OKAY, SO HERE IS A DEVICE, I WANT TO TEACH YOU ALL OF THE SORT OF WHAT I KNOW ABOUT HOW THINGS MIGHT GO WRONG, BUT AGAIN , THEY'RE SO FAR DIFFERENT FROM MY SPACE, I DON'T HAVE GREAT CONFIDENCE, BUT AT LEAST I CAN MAKE SURE THEY UNDERSTAND WHAT I KNOW. BUT AGAIN, WHEN I THINK ABOUT THE TRANSITION TO THE CLINIC, I'M GOING TO LEAN REALLY HARD ON THE NON-HUMAN PRIMATE COMMUNITY BECAUSE THESE SAME SURGEONS THAT WANT PROBES TO PUT IN HUMANS ARE IN SOME CASES ALSO DOING SURGERY FOR NON-HUMAN PRIMATE RESEARCH ERS. SO THEY GET TO SEE A FAILURE POSSIBILITY IN A SOMEWHAT LESS RISKY ENVIRONMENT, YOU KNOW, THAT AS I SAID, THAT THESE ANIMALS ARE TRULY VALUABLE TO THE PEOPLE WHO OWN THEM, BUT AGAIN, I HAVE SO LITTLE EXPERIENCE IN THIS, I'M ASKING THEM, OKAY, SO TELL ME WHAT YOU WANT TO DO, I'LL TELL YOU EVERYTHING I CAN THINK OF YOU SHOULD THINK ABOUT, AND THEN I'M OUT OF LITERACY TO HELP. >> Dr. Solzbacher: ACTUALLY TYING SOME OF THOSE THINGS TOGETHER, FIRST OF ALL, I DO BELIEVE THERE ARE QUITE A FEW SAFEGUARDS IN PLACE, THE IRB'S USUALLY AS WELL AS, USUALLY THEY REQUIRE YOU TO HAVE AN IN PLACE. AT THAT POINT FAR MORE CAREFUL AND CONSERVATIVE MECHANISM GETS ROLLING, AND I'VE BEEN IN THESE CALLS WHERE YOU HAVE THE MORE CAVALIER NEUROSURGEON FROM THE RESEARCH GROUP WHO WANTS TO PUSH FORWARD AND YOU HAVE AN FDA NEUROSURGEON WHO HAS THE SAME BACKGROUND AND THAT IS AN INTERESTING DISCUSSION THAT THEN HAPPENS, YOU NEED TO DE-ESCALATE THAT, BUT I THINK THERE ARE MECHANISMS IN PLACE. UNLIKE WHEN I TALKED TO WHO CREATED MEDDLE, THE -- MED-EL, THE COCHLEAR IMPLANT COMPANY, THEY SAID WE STARTED PUTTING STUFF INTO PATIENTS AND WE BUILT MORE AND IT TOOK MANY YEARS, THOSE HURDLES ARE VERY, VERY HIGH. YOU HAVE TO ABILITIES TO GET INTO THE MARKET, ONE OF THEM A LITTLE MORE SHORT-TERM THAT IS BY LEVERAGING EXISTING ACCESS PATHS, AND EPILEPSY IS ONE OF THEM THAT'S BEEN A REAL GODSEND FOR A LOT OF THE RESEARCH IN THIS SPACE BECAUSE THE SURGICAL PROCEDURES ARE UNDERSTOOD, THE RISKS ARE FAIRLY WELL UNDERSTOOD , MOAFTD TISSUE IS RESECTED, ET CETERA, THE OTHER ONE, THAT TAKES ENDURANCE THAT IS BUILDING SORT OF AN INSTALL BASE, AND IT HAS WORKED FOR EXAMPLE BRAINGATE AND OTHER INITIATIVES HAVE STARTED DOING WHERE AGAIN YOU NEED A PARTNERSHIP WHERE YOU WORK TOGETHER WHERE OVER THE COURSE OF TEN, FIFTEEN, TWENTY YEARS YOU BUILD UP A GROWING NUMBER OF CLINICAL CENTERS THAT CAN DO THE PROCEDURE AND UNDERSTAND THE RISKS. SO I THINK THERE ARE COMPONENTS IN THERE. OTHER ETHICAL QUESTIONS THAT ARE VERY INTERESTING IS AS THERE ARE NEW GROUPS THAT COME INTO THE SPACE THAT THINK ABOUT HUMAN ENHANCEMENT WITH THOSE TECHNOLOGIES, THAT OF COURSE IS SOMETHING WHERE, YOU KNOW, INSPIRED BY SCIENCE FICTION BOOKS, I DON'T QUITE KNOW HOW TO HANDLE THAT. AND AT ONE POINT, THAT CAN EITHER LEAD TO A SPLIT OF SOCIETY OR THEY GO ROGUE OR WHATEVER, BECAUSE ONCE THE CAPABILITIES ARE THERE AND THEY HAVE BEEN CLEARED, THESE BECOME PLATFORMS JUST LIKE YOUR PHONE WHERE YOU CAN RUN APPS ON AND DO NEW THINGS, WHICH IS WONDERFUL IN TERMS OF CREATING FUNCTION, BUT AT THAT POINT THEN IT CAN GO VIRAL AND THEN YOU HAVE ALL THE QUESTION OF WHETHER YOU CAN CONTAIN IT AND HOW YOU CAN CONTAIN IT. I THINK AT THE EARLIEST STATE RIGHT NOW, I THINK WE'RE FAIRLY WELL PROTECTED BECAUSE A HOSPITAL DOESN'T WANT TO TAKE THE RISK OF PUTTING SOMETHING IN WITHOUT THE PROPER CLEARANCES. >> SO JUST REAL QUICK, WE'LL TAKE YOUR QUESTION HERE IN A MOMENT, JUST FOR THE WORKING GROUP MEMBERS ONLINE, I WANT TO GIVE YOU THE OPPORTUNITY ASK A QUESTION IF YOU HAVE ONE, BUT PLEASE REMEMBER TO UNMUTE YOURSELF. OKAY. WE'LL TAKE THE QUESTION FROM THE AUDIENCE. >> THANK YOU. THIS IS A QUESTION FOR ELIZABETH AND BOTH TIMESES -- AND BOTH TIM 'S AND I GUESS THE REST OF THE COMMITTEE AS WELL. A LOT OF ACADEMICS WENT INTO ACADEMIA BECAUSE THEY DIDN'T WANT TO GO INTO INDUSTRY, AND A LOT OF ACADEMICS ACTUALLY DON'T WANT TO DO PRODUCT DEVELOPMENT BUT ACTUALLY MAKE LOTS OF DISCOVERIES THAT HAVE PRODUCT CONSEQUENCES, AND I WANTED TO KNOW IF YOU COULD TALK ABOUT MECHANISMLESS THAT DON'T ASSUME THAT AN ACADEMIC WHOSE GOAL IS TO MAKE SOME SCIENTIFIC DISCOVERY IS ACTUALLY GOING TO THEN START THAT WHOLE PRODUCT DEVELOPMENT CYCLE WHICH, YOU KNOW, AS I SAID, MANY ACADEMICS ACTUALLY DON'T WANT TO DO. >> Dr. Denison: I'M ACTUALLY GOING TO PIVOT, BECAUSE YOU'RE HINTING AT THE QUESTION I WAS GOING TO ASK THE PANEL. WHAT I HEAR THROUGHOUT A LOT OF THE MORNING'S DISCUSSION IS WHAT I PUT DOWN AS MISSION MIS ALIGNMENT, AND I'M ALWAYS BIG ON SETTING UP A STRATEGY OF MISSION ALIGNMENT AMONG ALL THE CONSTITUENT PARTIES. SO WITH THAT CONTEXT, AND IT'S A GREAT QUESTION, I'M GOING TO ACTUALLY TAKE IT UP TO 20,000 FEET, WHAT DO YOU SEE APPEARS THE AREAS FOR IMPROVING MISSION ALIGNMENT WHILE BEING REALISTIC ABOUT THE DIFFERENT STAKES AT EACH -- THAT EACH OF THE MEMBERS HAVE THAT ARE PART OF THIS ECOSYSTEM? I WANT TO HEAR FROM ALL FOUR OF YOU. >> I WILL JUST SAIS IN ANSWER TO THAT QUESTION, ONE OF THE THINGS WE DO AT JANELIA ARE THESE PROJECT TEAMS AND THE IDEA IS BASICALLY SMALL START-UP COMPANIES WHOSE GOAL IS TO LOSE A MILLION AND A HALF DOLLARS A YEAR, IN DEVELOPING A PRODUCT, AND THE IDEA IS THERE'S A DISCOVERY MADE IN A JANELIA LAB, LET'S SAY, LIKE SOME OF THE EARLY G CAMP THAT IS STARTED WORK ON G CAMP 3, THAT'S GREAT FOR THE POST-DOC, BUT THEN WHO WANTS TO MAKE G CAMP 4 AND 5, YOU KNOW WHAT I MEAN, THERE'S DIMINISHING RETURNS THERE. SO THEN WE CREATED THIS TEAM, A SMALL START-UP COMPANY AND THE G CAMP 6'S AND 7'S COMING OUT THAT EVERYONE USES FOR FUNCTIONAL IMAGING CAME OUT OF THIS LARGE HIGH THROUGHPUT SCREENING THING, SO THAT IS ONE MECHANISM. WE HAVE SEVERAL OF THEM SORT OF BIGGER SCIENCE, MORE INDUSTRY- TYPE MANAGEMENT AND DELIVERABLES, ET CETERA. SO THAT'S SOMETHING WE'RE DOING AT JANELIA. >> YEAH, I THINK IN TERMS OF MISSION ALIGNMENT, WHAT HELPS IS EVENTS LIKE THESE ONES HERE WHERE YOU HAVE COMMUNICATION, YOU FIGURE OUT WHAT EACH AND EVERY PARTICIPANT'S GOALS R I THINK WE ALL HAVE A RESPONSIBILITY TO TRY AND HELP EACH OTHER. IN PRACTICE, WE ALREADY HAVE, WE HAVE PEOPLE THAT DO THE DISCOVERY, THE INITIAL INNOVATION, THERE ARE PEOPLE THAT LOOK AT TRANSLATIONAL DEVELOPMENT, IT'S NOT QUITE AS WELL ORGANIZED YET, AND THEN YOU HAVE THE PRODUCT COMMUNITY AND YOU NEED TO UNDERSTAND THAT. OF COURSE ONE OF THE CHALLENGES IS THEN IF FUNDING SHIFTS, THE MORE TRANSLATIONAL YOU GO, THE MORE YOU GO TOWARDS PRODUCT, THE LARGER THE FUNDING. I'VE OBSERVED THERE ARE QUITE A FEW COLLEAGUES THAT ARE BASIC SCIENTISTS, THEY REALLY DON'T WANT TO HAVE ANYTHING TO DO WITH PRODUCTS, BUT SUDDENLY THEY APPLY FOR PRODUCT TYPES OR TRANSLATION OF GRANTS RG BECAUSE THERE'S A LOT MORE MONEY, IT SEEMS MORE EXCITING, ET CETERA, THEN YOU HAVE THOSE CHALLENGES THERE, SO IF YOU CAN TURN THAT INTO SOMETHING WHERE YOU HAVE PARTNERSHIPS WHERE YOU SAY YES, LET'S DO THIS TOGETHER, AND WE NEED AN END USER LIKE MEDTRONIC OR BOSTON SCIENTIFIC OR SOMETHING, WE NEED A COMMUNITY OF MS. SIZED START-UPS OR INSTITUTIONS THAT AS CRO'S AND NONPROFITS HELP WITH THAT TRANSLATION MATURING TECHNOLOGIES AND THEN THE BASIC PEOPLE AND ALLOW THAT TO HAPPEN TOGETHER, THAT WAY ALL SIDES LEARN ALSO AN AWFUL LOT BECAUSE YOU LEARN A LOT OF THINGS FROM THE INNOVATION SIDE BUT ALSO AS A BASIC RESEARCHER, HAVING THE USE CASE IN THE ENTIRE VALUE CHAIN TEACHES YOU THINGS, YOU SAY OH, WOW, THAT IS ACTUALLY A REAL IMPORTANT SCIENTIFIC PROBLEM THAT YOU DO NOT SEE IF YOU SAY I'LL THROW IT OVER THE FENCE AND THEN INDUSTRY IS GOING TO DO SOMETHING, AND THEY WON'T BECAUSE IT'S PREMATURE. >> Dr. Strychalski: I WOULD LIKE TO ECHO SOME OF WHAT FLORIAN SAID BUT FIRST AS AN EX-PROGRAM MANAGER, I WOULD SAY THE ACADEMIC THAT YOU MENTIONED WHO ISN'T INTERESTED AT ALL IN TECHNOLOGY TRANSFER, THAT THEY MIGHT CONSIDER GETTING FUNDING ELSEWHERE IF THEY'RE GOING AFTER MONEY WHERE IT'S VERY CLEAR THAT PART OF THE MISSION IS TECHNOLOGY TRANSFER. THE NOW, THAT SAID, IT MAY BE TO THAT RESEARCHER'S BENEFIT TO SAY , WELL, I AM GOING TO GO AFTER THAT MONEY, BUT INSTID OF -- INSTEAD OF TAKING MY TECHNOLOGY TO MARKET MYSELF, I'M GOING TO SET UP US JUST THE SAME WAY YOU HAVE A DATA MANAGEMENT PLAN OR YOU HAVE VARIOUS REVIEWS THAT HAPPEN BEFORE YOU EVEN START YOUR RESEARCH, YOU WOULD THEN HAVE A TECHNOLOGY TRANSFER PLAN. IT'S SOMETHING WE TALKED A LOT ABOUT AT DARPA, IT'S SOMETHING WE TALK A LOT ABOUT FOR RESEARCH THAT WE DO AT NIST AS WELL BECAUSE WE WANT TO MAKE SURE THAT WE'RE REALLY TIED INTO THE MARKETPLACE AND HOW WE CAN BRING JOBS AND WEALTH AND QUALITY OF LIFE TO THE AMERICAN PEOPLE. THERE ARE SO MANY RESOURCES THAT ARE AVAILABLE. THE MORE I LOOK, THE MORE I FIND IT DOES TAKE TIME AND ENERGY TO DO. I WOULD LOVE TO SEE THAT BRAIN INTEGRATES MORE OR MAYBE CENTRALIZES OR SOMEHOW GETS OUT TO GRANTEES THAT, LOOK, HERE ARE SOME RESOURCES YOU CAN START HUNTING DOWN, IF YOU'RE THE KIND OF PERSON WHO IS GOING TO DO AMAZING SCIENCE, AMAZING DISCOVERY UNDER BRAIN BUT MAYBE WANTS SOME HELP OR GUIDANCE OR DIRECTION TO MOVE TOWARDS TECH TRANSFER. >> I WANT TO EXPRESS TWO LEVELS OF SKEPTICISM TO START. REGARDLESS OF THE INTERESTS OF YOUR HYPOTHETICAL PROFESSOR, THE VAST MAJORITY OF THEM ARE SIMPLY NOT CAPABLE OF PRODUCT DEVELOPMENT. [LAUGHTER] THEY'VE NEVER DONE IT. IT'S REALLY HARD. THERE ARE A BUNCH OF PLACES TO GET IT WRONG. IF YOU LOOK AT THE RATE OF SUCCESS OF PRODUCT DEVELOPMENT IN PEOPLE WHO GET UP IN THE MORNING TO DO THAT AND THAT ALONE, YOU SHOULD BE PRETTY DISCOURAGED ABOUT UNIVERSITIES JUMPING INTO THAT. SO THAT'S THE FIRST THING. THE SECOND THING IS THAT REGARDLESS OF THE ENTHUSIASM OF THE INVENTER OF THIS, THERE ARE LOTS OF THINGS THAT JUST AREN'T WORTH TURNING INTO PRODUCTS, AND THE LEAST QUALIFIED PERSON TO MAKE THAT CHOICE IS THE PERSON WHO IS INVESTED IN IT. SO WHAT WE'VE BEEN TALKING ABOUT , WHAT I THINK THAT I WOULD JUST SUGGEST OUT RIGHT TO THE NI H BRAIN INITIATIVE IS TO INVENT A STEERING GROUP THAT YOU DON'T HAVE TO PAY THEM ANYTHING, THEIR JOB IS TO MEET ONCE A QUARTER ON ZOOM SO YOU DON'T EVEN HAVE TO BUY AN AIRPLANE TICKET, AND JUST RUN THROUGH A LIST OF VOLUNTARILY SUGGESTED PUBLISHED THINGS THAT ARE GENUINELY WORTH MOVING INTO A BETTER ENGINEERED SPACE. SO NOW WE HAVE A LIST, AND IT'S GOING TO BE 5 PERCENT OR SOMETHING OF THINGS THAT ARE REALLY WISELY USABLE THAT WE'RE SPENDING ENOUGH MONEY TO GO FROM PUBLICATION TO PRODUCT. AND THEN YOU'VE GOT TO DO THE HARD PART, WHICH IS, YOU KNOW, ONE OF THE THINGS THAT I WONDER WHETHER OR NOT THAT NATIONAL LABS CAN HELP WITH, ARE YOU GOING TO HIRE SOME ENGINEERS AND HAVE A TEAM THAT ACCEPTS SOME FLOW OF THESE THINGS TO TURN INTO PRODUCTS AND WILL BE VENDED BY EITHER LICENSING OR, YOU KNOW , PROFIT, IT DEPENDS. THE THING THAT MAKE US ALL JEALOUS WHO DON'T MAKE RS GENETICALLY DEVELOPED TOOLS IS ADD GENE BECAUSE YOU JUST SEND THEM A PIECE OF FILTER PAPER AND YOU ARE GET UNIVERSAL PENETRATION, IT'S JUST AWESOME. SO THE ADD CHEM OR ADD GENE FOR TECHNOLOGY IS A REALLY TEMPTING SPACE TO BE, IT CAN BE SELF- SUPPORTING IN TERMS OF REVENUE, BUT GETTING OVER THAT HUMP OF MAKING -- AND ALMOST ALL MANUFACTURING, ESPECIALLY IN ELECTRONICS TECHNOLOGY IS RELIABLY OUTSOURCABLE. YOU CAN GET PEOPLE TO MAKE CIRCUIT BOARDS AND CABLES AND ALL KINDS OF THINGS THAT YOU DON'T HAVE TO HAVE A MANUFACTURING CAPABILITY. YOU HAVE TO HAVE A GET IT TO PRODUCT CAPABILITY THE AND A FIGURE OUT HOW TO SELL IT CAPABILITY, AND SO I THINK THAT IS A DIFFERENT PLACE THAN A UNIVERSITY, AND IT'S NOT MOST THINGS. >> ONE BRIEF COMMENT ACTUALLY JUST AS AN IDEAS CAME YOU TO MIND IS WE HAVE THESE PUBLIC/ PRIVATE PARTNERSHIP AGREEMENTS WITH COMPANIES IN THE CONTEXT OF THE BRAIN INITIATIVE WHERE COMPANIES PROVIDE TOOLS TO RESEARCHERS. WHAT WE STARTED DOING ON THE BUSINESS SIDE AND WHICH YOU COULD POSSIBLY THEN ADD TO THIS EXISTING MODEL IS THAT WE HAVE NOW A GROWING NUMBER OF GROUPS THAT COME TO US TO TRY AND LICENSE AND TRANSLATE TECHNOLOGIES, AND ONE OF THE FIRST THINGS WE DO IS AS PART OF THE DESIGN CONTROL PROCESS IS ESSENTIALLY THE MARKET ANALYSIS AND MARKETING BRIEF AND FIGURING OUT IS THERE A MARKET FOR THAT.& I THINK THAT IS SOMETHING THAT, FOR EXAMPLE, WE WOULD BE VERY WILLING TO HELP AND PROVIDE, YOU CAN'T DO THAT WAY TOO OFTEN BECAUSE IT IS TIME AND COST- INTENSIVE, SO SOME SUBSIDY FOR THAT WOULD HELP, BUT THIS IS A PROCESS THAT WILL RUN THINK WHERE BETWEEN A MONTH AND MAYBE SIX MONTHS WHERE YOU GO OUT TO YOUR USER BASE, AND WHEN SOMEBODY SAYS I HAVE THIS REALLY BRILLIANT IDEA OF THIS PAPER, IT RAISES THE TENSION, DOES IT MAKE SENSE TO TRANSLATE, IS THE MARKET THERE, AND THAT INCLUDES -- -- THAT INCLUDES THAT COMPONENT AND ALSO THE COST IN MATURING IT AND THE COST IN MANUFACTURING, ASK THAT WAY YOU CAN DOWN-SELECT THEM AND WE PROBABLY HAVE SORT OF A 10 PERCENT SUCCESS RATE AND STUFF THAT COMES TO US AND SAY YEAH, WE'RE LOOKING ACHT A LOT OF THINGS WE'RE SHOOTING DOWN, BUT WHEN THE WE DO SO, WE LET PEOPLE DOWN GENTLY, WE SAY WELL HERE IS AN OPTION, MAYBE WE'LL HELP YOU WITH AN SPR GRANT OR SOMETHING, BUT I THINK IT WOULD BE, I DON'T KNOW, JUST AS AN IDEA TO SAY GOING FORWARD IN THESE PARTNERSHIPS, COMPANIES CAN PROVIDE THAT ACCESS BECAUSE WE HAVE A MUCH BROADER CUSTOMER AND USER BASE AND WE CAN PROVIDE SOME OF THAT INPUT THAT HELPS YOU THEN EVALUATE IS THERE SOMETHING THAT WAS A WONDERFUL ACCOMPLISHMENT, YOU'LL GET A PLAQUE FOR, AND IT WON'T BECOME A PRODUCT OR SOMETHING THAT WILL BECOME A TOOL. >> Dr. Strychalski: I WANTED TO ECHO A LOT OF THESE POINTS. IT'S NO COINCIDENCE WE HAVE TWO PEOPLE FROM JANELIA FROM THIS PANEL BECAUSE IT'S EXACTLY TRUE, LIKE THE ACADEMIC MODEL DOES NOT MESH WITH THIS ABILITY TO ROLL THESE OUT AND THE FACT THAT YOU GUYS HAVE HAD ENORMOUS IMPACT WITH G CAMP AND THEN YOUR TECHNOLOGIES IS BECAUSE YOU'VE BEEN ABLE TO DO IT IN THIS WAY. SO I THINK WE HAVE TO RECOGNIZE THAT, THAT IT NEEDS THESE HUBS, ACTUALLY I LOVED YOUR IDEA OF THE NATIONAL LABS IN PARAGRAPHS FORMING THESE HUBS, BUT IT'S ABSOLUTELY ESSENTIAL THAT WE HAVE THIS COALESCENCE OF EXPERTISE, THIS GUIDANCE, THIS ABILITY TO SORT OF, YOU KNOW, HELP THAT POOR CLUELESS ACADEMIC GIVE THEM PINT OF REFERENCE TO HELP THEM TO MAKE THESE DECISIONSES TO MOVE FORWARD. SO THAT'S FORMING SOME SORT OF PICTURE THING IN MY MIND OF LIKE WE NEED THESE HUBS, WE NEED TO HELP PEOPLE WHEN THEY CAN'T HELP THEMSELVES, RIGHT? BUT THE OTHER COUNTER POINT I WANT TO BRING UP, WE MAKE THIS POINT OVER AND OVER AGAIN, NOT EVERY BRILLIANT IDEA IN A LAB IS A COMMERCIAL SUCCESS, IS GOING TO BE A COMMERCIAL SUCCESS, AND I WOULD ARGUE MANY OF THESE TECHNOLOGIES DEVELOPED BY BRAIN FOR NEUROSCIENCE RESEARCHERS NEVER, EVER, EVER TURN A PROFIT, EVER, BY ANY STANDARDS THAT ANY INVESTOR WOULD LOOK AT THIS AND SAY TO WAY, RIGHT? LIKE NEGATIVE POSSIBILITY OF MAKING MONEY. BUT THAT DOESN'T MEAN THEY'RE ABSOLUTELY VITAL FOR MAKING ANOTHER VITAL, RIGHT, THAT THERE'S FIVE RESEARCHERS THAT NEED THIS DESPERATELY, RIGHT? SO I THINK WE HAVE TO TAKE THAT ON, NOT AS TO SAY WELL, THERE'S NO POINT IN DEVELOPING THIS PRODUCT, RIGHT? YOU DON'T CALL IT A PRODUCT. ALL WE NEED IS TO HELP THAT PERSON SCALE IT UP, AND MAYBE THAT CAN BE DONE BY KEEPING ON THAT POST-DOC AND DOING IT IN THE RIGHT WAY. SO WE CAN CALL THOSE ORPHAN PRODUCTS, WE CAN CALL THEM WHATEVER, I THINK WE HAVE TO RECOGNIZE THAT, WE HAVE TO GUIDE THEM, LIKE MAYBE IT'S A REALLY STUPID IDEA, RIGHT? BUT IF IT'S NOT A STUPID IDEA BUT FIVE PEOPLE NEED IT, WE HAVE TO COME UP WITH A BUSINESS MODEL AND IT'S NOT SBR AND IT'S NOT COMMERCIAL, MAYBE IT'S GETTING THE COMPANIES JUST THROWING THE COMPANY SOME MONEY AND BEING JUST LIKE PLEASE JUST USE YOUR EXPERTISE TO DEVELOP THIS THING, MAKE FIVE OF THEM, DON'T WORRY ABOUT EVER TURNING A PROFIT, KEEP THE IP, BUT WE JUST NEED YOUR HELP TO MAKE THIS INTO SOMETHING THAT THESE FIVE, TEN, 50 PEOPLE CAN USE. WE HAVE TO ACCEPT AND ACKNOWLEDGE THIS, OTHERWISE WE'RE JUST -- >> Dr. Strychalski: I WOULD LIKE TO OFFER TWO QUICK COMMENTS IN RESPONSE. ONE IS THAT I WANT TO GET RID THIS MISCONCEPTION AS NATIONAL LABORATORIES BEING A PLACE WHERE YOU CAN LEAVE YOUR TECHNOLOGICAL BABY AND WE'LL RAISE IT FOR YOU, CERTAINLY WE CAN BE A HUB AND PARTNER WITH YOU TO DEVELOP YOUR TECHNOLOGY. THE OTHER THING I WOULD LIKE TO SAY IS THAT MAYBE IT WOULD BE WORTH NIH AND THE BRAIN INITIATIVE BEING ABSOLUTELY CRYSTAL-CLEAR ON WHAT THEY MEAN BY TECHNOLOGY TRANSFER BECAUSE MAYBE IT DOESN'T MEAN A COMMERCIAL PRODUCT THAT TURNS A PROFIT. MAYBE SUCCESS IN TECHNOLOGY TRANSFER MEANS WHAT TIM IS ALREADY DOING, FOR EXAMPLE, AND MAKING SOMETHING THAT THEY THEN SHARE WITH ANOTHER LABORATORY AND GET THEM UP AND RUNNING WELL ENOUGH. >> [AWAY FROM MIC] IT'S NOT NECESSARILY OUTSIDE THE SCOPE OF AN ACADEMIC, BUT WITH SOME SUPPORT FOR THAT PURPOSE. YOU CAN'T JUST DO IT WITHOUT THAT SUPPORT. BUT IT DOESN'T TAKE THAT MUCH EXTRA MONEY, CHEMISTRY CAN BE SHARED IN SMALLER KIND OF GROUPS , YOU KNOW, THE KIND OF CHEMISTRY THAT DOES HAVE COMMERCIAL POTENTIAL. >> YEAH, I MEAN, I THINK IT'S MORE OF A CULTURAL PROBLEM, ASK CHEMISTRY, AS I TRIED TO ALLUDE TO, RIGHT, CHEMISTS WANT TO OWN EVERYTHING, THEY WANT TO BE ON EVERY PAPER, AND THEN SO AMAZ INGLY, OUR EXPERIMENT WAS HEY, LET'S PUT A CHEMIST WHERE THERE ARE NO OTHER CHEMISTS WITH A BUNCH OF NEUROSCIENTISTS AND SEE WHAT HAPPENS, AND SO MY PARENTS WERE HIPPIES, I JUST LIKE TO GIVE STUFF AWAY, FROM OREGON, THAT'S WHAT HAPPENED. BUT YEAH, I AGREE, IT'S NOT A HUGE COST. I MEAN, THE OTHER THING IS, YOU KNOW, THIS IS WHAT I DO, RIGHT? I HAVE TO MAKE 10 MILLIGRAMS OF EVERY COMPOUND I MIKE JUST TO CHARACTERIZE IT, SO THEN THAT STUFF JUST SITS THERE. THAT'S 1,000 VIALS IN SOME CASES OF STUFF. SO, YOU KNOW, IF THERE WAS A WAY TO DO IT, ONE IDEA FOR THIS ADD CHEM IDEA, THIS CONCEPT IS WHAT IF A RESEARCHER SAYS OH, YOU KNOW, I'M GETTING A LOT OF REQUESTS FOR THIS THING I MADE, THEN YOU MAKE THEM PROVIDE THE FIRST THOUGHT, THEY HAVE SKIN IN THE GAME, NIH THROWS IN SOME MONEY TO HELP THAT AND THEN IF IF THIS ADD CHEM SAYS OH YEAH THAT FIRST INITIAL LOT THAT SOLD WELL OR A LOFT PEOPLE WANTED IT, THEN THEY TAKE IT ON, BUT YOU HAVE THAT INITIAL TRIAGE RATHER THAN EVERY SINGLE CHEMIST IN THE WORLD SAYING YEAH, YEAH, MAKE MY THING TOO. SO THEIR IDEA IS TO SORT OF MAKE THIS WORK. AND IT ISN'T THAT HARD. I MEAN, RE REALLY DON'T EVEN HAVE TO HIRE ANYONE, IT'S LIKE I'M THE ONE PUTTING THE THINGS IN THE BAG. IT'S NOT A BIG DEAL. YEAH. YEAH. >> [AWAY FROM MIC] >> YEAH, YEAH. >> I JUST WANTED TO MAKE A COMMENT, WHICH IT'S VERY CLEAR THAT THERE'S A VERY BIG DIVIDE BETWEEN THE KIND OF ENTREPRENEURIAL COMMUNITY AND ACADEMIA. SO SEVERAL OF US ARE TRYING KIND OF A BOLD NEW EXPERIMENT IT'S CALLED THE BRAIN MIND ECOSYSTEM, WE'VE SET IT UP, REED HOFFMAN, A GENTLEMAN NAMED MICHAEL McCULL LA WHO IS AN INVESTOR, ONE IN RI CAS AND LAURA RONLT SON AS CHAIR AT STANFORD, WE'RE WORKING TOGETHER TO BRING THIS ECOSYSTEM WHO BRINGS ENTS PRE NEUROS, HIGH WORTH INDIVIDUALS, WHO ARE DEEPLY COMMITTED TO SOCIAL IMPACT INVESTING AND TRYING TO CREATE A STRUCTURE WHERE YOU PUT SCIENTISTS WITH THESE ENTREPRENEURS FOR DAYS ON END AND SEE WHAT COMES OF IT. SO IT'S NOT TRYING TO CHANGE ACADEMIA, YOU KNOW, WE'RE NOT GOING TO BE DIFFERENT, WE'RE GOING TO BE INVENTERS, DISCOVER ERS, INNOVATORS, BUT BRINGING THE ENTREPRENEURIAL COMMUNITY CLOSER AND HAVING THEM KIND OF GRAB HOLD OF AN IDEA THAT POTENTIALLY COULD BE ACTION ABLE. SO IT'S A REALLY DIFFERENT MODEL , AND IT TRIES TO DEMONSTRATE RESPECT THAT THE EXISTING STRUCTURES ARE REALLY NOT SUFFICIENT, THEY'RE TOO SMALL, THEY DON'T SCALE, THERE ISN'T ENOUGH COMMUNICATION ACROSS THE CULTURES, AND WE'LL SEE WHAT THIS EXPERIMENT LEADS TO. BUT THINGS LIKE THIS I THINK COULD CHANGE THE GAME. YOU KNOW, JUST RELYING ON THE EXISTING STRUCTURES. WE CAN BE PARTNER, BUT I'M NOT SURE IT'S GOING TO CHANGE THE GAME. >> Dr. Denison: ONE FIEBL QUESTION, THEN WE'LL HEAD TO BREAK. >> MORE OF A COMMENT, I WANT TO FOLLOW UP ON FLORIAN'S POINTS OF VIEW, JUST AN ANALOGY MAYBE FROM THE SOFTWARE INDUSTRY, RIGHT? IF YOU ARE MAKING AN APP, THE LAST THING YOU WANT TO DO ACTUALLY IS HAVE TO BRING IT TO MARKET AS A SUSTAINABLE THING, AND THE IDEAL OUTCOME IS THAT YOU GET ACQUIRED BY GOOGLE OR MICROSOFT, THEY WOULD PUT YOUR THING INTO THE PRODUCT THAT THEN HAS A BILLION -- AND I THINK THAT REALLY THAT'S GREAT POE POTENTIALLY FOR ADVANCES ON THE TECH SIDE TO PARTNER WITH BIGGER ESTABLISHED COMPANY, WE HAVE ECOSYSTEM OUT THERE OF A VARIETY OF DIFFERENT COMPANIES, RIGHT, THAT RS FOR THOSE ADVANCES. I THINK THAT'S THE STANDARD WAY OF DOING THINGS THAT WE ALREADY HAVE OUT THERE AND MAYBE DON'T THINK ENOUGH ABOUT. >> SO KEEPING AN EYE ON THE CLOCK, SO WE'LL STOP HERE. WE'LL BE AVAILABLE OVER BREAK. ONE THING I WOULD ASK IS CONTINUING THIS CONVERSATION BECAUSE COMING UP WITH MODELS ARE IMPORTANT. I THINK CAPSTONE IS HUNTER PECUM WHO IS A REAL INNOVATOR IN THE NEURO TECH FIELD AND IS ONE OF THE FEW PEOPLE WHO IN AN ACADEMIC COMMUNITY DID TRANSLATE INTO HUMANS, I ALWAYS LIKE TO SAY, WE HAVE TO INNOVATE HOW WE INNOVATE, AND I THINK THAT'S ONE WAY I WOULD KIND OF LIKE TO LEAVE THIS SESSION IS THINKING ABOUT INNOVATING IN THE WAY WE INNOVATE, BUT MY ONE REQUEST AND IT'S ACTUALLY BACK TO THE QUESTION YOU ASKED TO ME, YOU SAID BOTH TIM'S, AND I'LL GET AROUND TO ANSWERING IT, IS TO ALSO BE VERY INTENTIONAL AND RESPECTFUL OF HOW EACH PERSON, THE ROLE THAT THEY PLAY WITHIN THIS ECOSYSTEM. EVEN IN THE WORDS TODAY, SAYING THE CLUELESS RESEARCHERS OR THIS , IN REALITY, EVERYONE -- I DIDN'T SAY THAT, BUT IN REALITY, I SEE IT MORE AS BUILDING A BAND SO I'M ONLY SIX WEEKS INTO ACADEMIA, SO I'M NOT GOING TO SPEAK AS AN ACADEMIC. [LAUGHTER] SO IN INDUSTRY, EVEN WITHIN MY COMPANY, I WORKED IN R & T, BUT THEN I WOULD HAND IT TO A DEVELOPMENT PARTNER. CREATED AND HE WOULD SPEND THREE YEARS ON IT, AND THEN THE OPERATIONS TEAM WOULD TAKE WHAT KEVIN DEVELOPED AND THEY WOULD SEE THE FULL LIFE CYCLE. AND THE REASON THAT IT WORKED IS BECAUSE WE EACH RESPECTED EACH OTHER. SO THEY WOULD SAY, YOU KNOW, CLUELESS TIM OR THIS AND ALL THOSE OPS PEOPLE, WE REALIZE THAT EACH OF US HAD A CRITICAL ROLE TO PLAY, AND I ALWAYS THINK OF THE GEARS OF A TRANSMISSION, YOU CAN HAVE THE BEST ENGINE, APOLOGIES TO ELECTRIC CARS RIGHT NOW, I'LL MODIFY THIS THIS FUTURE, BUT IF YOU DON'T HAVE A FULL TRANSMISSION TO THE WHEEL, IT DOESN'T DO YOU ANY GOOD. SO REALLY AS OPPOSED TO STEPPING BACK ASK SAYING, YOU KNOW -- AND SAYING, YOU KNOW, EACH OF THESE ROLES AND TRYING TO CHANGE EACH OTHER, WE ACTUALLY INSTEAD SAY HOW DO WE TAKE THESE DIFFERENT -- ACTUALLY WHAT'S GREAT ABOUT HUMANITY, THESE HODGEPODGES OF DIFFERENT INTERESTS AND ACTUALLY LOOK TO ALIGN THEM TO SOLVE INTERESTING PROBLEMS. SO THAT'S HOW I WOULD LIKE TO CLOSE OUT THIS SESSION. AND AS YOU DO HAVE YOUR IDEAS, WE'RE OPEN FOR THEM, CREATING A MECHANISM, COMMUNICATE WITH US AS YOU SAW IN THE TIMELINE, WE HAVE PLENTY OF TIME TO CONSIDER THOSE AND WORK THOSE INTO THE REPORT. THANK YOU FOR YOUR ACTIVE PARTICIPATION IN THIS COMMUNITY SESSION. [APPLAUSE] >> Dr. Monteggia: WE'RE GOING TO GET STARTED ON THE SECOND SECTION THAT'S FOCUSED ON CELLS AND CIRCUITS AND AS EACH OF THE DISCUSSION LEADERS WERE REALLY FOCUSING ON WHAT WAS THE THEEMG, WHAT WE'RE GOING TO REALLY HONE IN ON, WORKSHOP 2 TODAY IS REALLY VERY ECLECTIC TO SAY THE LEAST. WE'RE GOING TO BE JUMPING ALL OVER THE PLACE A LITTLE BIT. THE COMMON THEME IS REALLY LEADERS IN THE FIELD THAT ARE APPROACHING CELLS AND CIRCUITRY IN DIFFERENT WAITZ. WE'RE GOING TO TALK ABOUT PROTEINS FIRST WITH JOHN BEING OUR FIRST SPEAKER TODAY, REALLY HONING IN ON HIS WORK, WE'RE GOING TO GO TO GUL WHO IS GOING TO ACTUALLY TALK ABOUT A LOT OF HER WORK ON CIRCUITRY, SOCIAL BEHAVIOR. I THINK SHE'S GOING TO REALLY BROADEN IT A LITTLE BIT CONSIDERING I SAW THIS MORNING THAT IF YOU JUST GOOGLE IN TOP NEWS STORIES OF THE DAY, IT'S SCIENTISTS GAVE OCTOPUS ECTASY AND HERE IS WHAT HAPPENED. SO THERE WILL PROBABLY BE A LITTLE BIT OF AN INTERFACE WITH CURRENT NEWS STORIES. CAGLA IS GOING TO PRESENT SOME OF OUR BEAUTIFUL WORK ABOUT REALLY GLIA INTEGRATION INTO SICIALGHT TRI ASK WE'LL END THIS SESSION WITH NAT HEINTZ TALKING ABOUT GENETIC KNOCK-OUT APPROACHES MOVING FORWARD. WITH THAT, WE'LL START WITH JOHN , AND PROCEED. >> Dr. Yates: OKAY. THANKS FOR THE INVITATION TO COME. I'M ON MY WAY BACK FROM NIA- SPONSORED WORKSHOP ON HEEZ, SO I'M -- ON ALZHEIMER'S DISEASE , AND I'M CALLING THIS BRAIN WEEK, WHAT A BETTER WAY TO END BRAIN WEEK, THAT FUNDHIS, JOKE ABOUT UNIVERSITY OF CHICAGO MY JOB HERE IS TO GET YOU GUYS EXCITED ABOUT PROTEINS AND I'M NOT TALKING ABOUT MY OWN WORK BECAUSE I WAS TOLD NOT TO, BUT I'M GOING TO TALK ABOUT WHAT'S GOING IN PROTEOMICS FIELD, AND THIS IS AN OUTLINE OF THE TOPICS THAT I'LL TOUCH ON AND TRY TO TELL YOU, I'M GOING TO TALK MORE TECHNOLOGICALLY ABOUT PROTEOMICS AND METHODS THAT HAVE BEEN DEVELOPED AND SORT OF EXPERIMENTS AND THIS IS CERTAINLY, THIS IS JUST RATHER MUNDANE PROTEOMICS, LARGE SCALE IDENTIFICATION QUANTIFICATION OF PROTEINS AND MODIFICATIONS. IF YOU SCRATCH THE SURFACE ON ALMOST ANY STUDY THAT IS BASED ON PROTEINS, YOU'LL USUALLY FIND THESE MASS SPECTROMETRY PROTEOMICS TECHNIQUES UNDERNEATH THEM, THEY'RE REALLY DRIVING A LOT OF MOLECULAR AND CELLULAR BIOLOGY THESE DAYS, A LOT OF TIMES IT'S A BACK STORY AND IT'S NOT REALLY THE FRONT PART. OCCASIONALLY YOU SEE THESE LARGE SCALE STUDIES BEING PUBLISHED YOU AND I'LL SHOW YOU A COUPLE AT THE END, BUT THESE ARE VERY IMPORTANT TOOLS THAT ALLOW US TO REALLY LOOK AT WHAT PROTEINS ARE DOING AT THE CELLULAR AND TISSUE LEVEL. ONE OF THE WAYS ONE CAN QUANTITY TAILLIGHT IS BY USING STABILIZED TOPE LABELS, MY LAB HAS PUT THEM INTO ANIMALS, SO YOU CAN DO VERY INTERESTING SORTS OF EXPERIMENTS , YOU CAN DO THIS AS A WAY TO JUST QUANTITATE PROTEIN EXPRESSION CHANGES BETWEEN A CONTROL AND SOME PROTUBATION, YOU CAN USE THIS IS TO LOOK AT PROTEIN TURNOVER, LONGEVITY OF PROTEINS, HOW LONG PROTEINS EXIST IN SYSTEMS. IF WE WERE TO DO THESE EXPERIMENTS AGAIN, WE WOULD PROBABLY USE A MULTIPLEXING STRATEGY USING TANDEM MASK TAGS ALTHOUGH YOU CAN'T DO THINGS LIKE TURNOVER AND THINGS LIKE THIS USING THIS, THIS IS A STRATEGY THAT ALLOWS YOU TO MULTIPLEX AND COMPARE UP TO ELEVEN DIFFERENT STATES, THESE ARE ISOBARIC TAGS, I DON'T WANT TO GET TOO MUCH INTO THE CHEMISTRY OF THIS, AND THEY'RE ACTUALLY BEING USED QUITE READILY TO DO A LOT OF LARGE SCALE STUDIES AS MASS SPECTROMETERS HAVE MORE FEATURES HAVE BEEN ADDED TO MASS TO FIX SOME OF THE PROBLEMS ASSOCIATED WITH THESE TANDEM MASS TAGS. ONE OF THE THINGS THAT I KNOW THERE'S A HUGE AMOUNT OF INTEREST IN SINGLE CELL ANALYSIS , SINGLE CELL ATLAS AND SO FORTH AND PEOPLE HAVE DABBLED IN THAT AREA WITH MASS SPECTROMETERS FOR A LONG TIME, ARE MEASURING PROTEIN IN MAMMALIAN CELLS, AWARDS METHODS FOR PEOPLE TO DO PROTEOMICS. SLAVICH, DEGRADATION, THOSE WHO REMEMBER THAT TECHNIQUE, DOING IT AT THE SINGLE CELL LEVEL, SINGLE PROTEIN LEVEL, REALLY INTERESTING METHODS, THIS IS JUST THE METHOD THAT SLAVOV AND BUDNIKS HAVE DEVELOPED, IT TOOK THEM A WHILE TO GET A PAPER PUBLISHED, THEY NOW HAVE A PAPER IN PRESS GENOME BIOLOGY WHERE THEY'VE USED THIS METHOD AND THEY'VE REALLY ADVANCED BEYOND WHAT THEY WERE TRYING TO GET ORIGINALLY GET PUBLISHED. THEY HAVE A PAPER ON BIOARCHIVE FOR ABOUT TWO YEARS, THERE'S BEEN AN ELEMENT OF UNBELIEVER ABILITY TO THEIR WORK AND REVIEW ERS HAVE PUSHED BACK ON IT , BUT THEY'RE USING THIS TMT REAGENT AS A WAY TO DO SIFNG HE WILL CELL REANALYSIS, THEY PUT IN 200 CELLS AS A CARRIER TO GET MSMS SPECTRA TO IDENTIFY PROTEINS, MULTIPLEX FOR SINGLE CELLS, QUANTIFY 1,000 PROTEINS PER CELL, I IMAGINE THIS WILL IMPROVE AS THEY IMPROVE THEIR WORK FLOWS AND HE CLAIMS THEY'RE DOING AUTOMATED ANALYSIS OF MORE THAN 1,000 CELLS PER WEEK PER INSTRUMENT, SO THIS IS SOMETHING THAT THIS IS OTHER PEOPLE ARE STARTING TO ADOPT THIS SORT OF STRATEGY SO I EXPECT THAT IT WILL IMPROVE OVER TIME. BIOORTHOGONAL CHEMISTRY HAS CERTAINLY BEEN AROUND FOR ABOUT TWO DECADES OR SO BUT THERE'S BEEN AN INCREASING AMOUNT OF METHODS TO INSERT MOLECULES INTO BIOLOGICAL SYSTEMS, GLYCAN ANALYSIS AND THINGS OF THAT NATURE. CERTAINLY ONE OF THE AREAS THAT'S BEEN BIG IN THE NEURAL BIOLOGY FIELD IS BECAUSE OF SHOE COUNCILMAN DAVE TERREL IS THE USE OF BONCAT, MY LAB HAS DONE SOME OF THIS WITH HOLLI KLEIN, USING A METHIONINE AN ANALOG WHICH CAN BE DIRECTLY INSERTED INTO PROTEIN SO YOU CAN USE THAT AS A WAY TO ENRICH FOR THOSE PROTEINS. WE'VE HAD MADE A STABILIZED VERSION OF AHA SO NOW WE CAN DO DIRECT QUANTITATION USING THIS STRATEGY TO LOOK AT PROTEIN EXPRESSION. PROBABLY YOU CAN ALSO USE THIS AS A WAY, WE'VE ALSO PERFECTED STRATEGIES TO INTRODUCE AHA INTO ANIMALS BY FEEDING THEM, THERE ARE PROBABLY OTHER WAYS YOU CAN INTRODUCE THEM AS WELL THROUGH INJECTION, HOLLI'S LAB HAS DONE INJECTION INTO THE RETINA THAT AS A WAY TO LABEL THE OPTIC NERVE BUT THERE ARE WAYS YOU CAN USE THIS TO LOOK AT CONTROL VERSUS PROTUBATION STATES. SHOEMAN'S LAB HAS ALSOS PUBLISHED A REALLY EXCITING PAPER USING CELL TYPES LABELING OF PROTOYOAMS IN VIVO WHERE THEY'VE USED AN ASODO NOROLUCENE , SYN THINK SAIS AS A WAY TO INSERT SPECIFIC CELL TYPES APRIL REAGENT YOU CAN USE AS A WAY TO EITHER LABEL WITH FLUOROPHORES OR USE THAT AS A WAY TO PULL OUT PROTEINS FROM VERY SPECIFIC TYPES OF CELLS. I THINK THIS IS REALLY EXCITING AND PROBABLY SOMETHING THAT WILL BE REALLY INTERESTING IN THE NEUROBIOLOGY FIELD ALWAYS WAY WAY TO LABEL VERY SPECIFIC NEURONS, VERY SPECIFIC CELL TYPES AND GET PROTEIN EXPRESSION INFORMATION DIRECT FROM THAT. IT KIND OF GETS AROUND SOME OF THE ISSUES ASSOCIATED WITH SINGLE CELL ANALYSIS BY DOING SINGLE CELL TYPES. THE OTHER AREA THAT'S EMERGING QUITE RAPIDLY IS THIS IDEA OF GLOBAL IN VIVO PROTEIN COMPUTATION ANALYSIS, A NUMBER OF TECHNOLOGIES -- CONFORMATION ANALYSIS, THERE ARE A NUMBER OF METHODS LOOKING AT PROTEIN IN VIVO ON A LARGE SCALE, THIS WILL BE INTERESTING PARTICULARLY IN THE NEURAL FIELD THERE ARE A LOT OF NEURAL OH DEGENERATIVE DISEASES BASED ON PROTEIN UNFOLD ING SO THIS WILL POTENTIALLY GIVE US A WAY TO START LOOKING AT HOW PROTEINS ARE FOLDING IN VIVO AND HOW THAT MIGHT CHANGE OVER TIME OR MIGHT CHANGE AS A FUNCTION OF TREATMENTS OR CONDITIONS OR SOMETHING OF THAT NATURE. THE OTHER AREA IN MASS SPECTROMETRY, IN PROTEOMICS THAT'S BEEN GOOD IS PROTEIN- PROTEIN INTERACTION ANALYSIS, YOU CAN ASSEMBLE PROTEIN COMPLEXES AND PATHWAYS OF PHYSIOLOGICAL PROCESSES, STEVE GIDGES LAB HAS PUBLISHED A FEW PAPERS, WILL GET THE HUMAN ENTIRE INTERACTIM DONE IN THE NEXT FEW YEARS, THE FUNDAMENTAL BIOLOGICAL PROCESSES THE COMPLEXES ARE PROBABLY GOING TO BE THE SAME, ONE OF THE THINGS WE NEED IS FASTER AND MORE GLOBAL METHODS TO EMERGE AND THERE ARE SOME CANDIDATE THE METHODS COMING ALONG THAT MIGHT BE BETTER WAYS TO LOOK AT PROTEIN-PROTEIN INTERACTIONS SO YOU CAN LOOK AT THE DYNAMICS OF INTERACTIONS AS A FUNCTION OF DISEASES OR PROCEED TU BASES OR SOMETHING OF THAT NATION BECAUSE IT WILL TAKE STEVE ABOUT A DECADE TO GET THIS HUMAN INTERAC TDOME DONE AND YOU CERTAINLY CAN'T DO THAT FOR EACH KIND OF PROTUBAT I ON YOU WANT TO DO. ONE OF THE THINGS WE DID IS USED HE CAN CRK IT CAN O FC INTERACTION SCREEN TO IDENTIFY L IGANS FOR RECEPTOR PAIRS, WE TOOK RECEPTOR PROTEINS FROM THE SYNAPSE AND MAPPED THEM ON A CELL, ON BEADS, AND THEN TOOK RAT BRAINS AND HOME OJ NIEPTZED THEM AND PASSED THEM THROUGH TO -- HOMOGENIZED THEM AND PASS ED THEM THROUGH TO FIND THINGS WHICH BOUND TO RECEPTORS, RECEPTORS DONE WITHOUT LIGANDS, DONE OVER AT OCSD A WHILE AGO AND WERE ABLE TO FIND LIGANDS GANS THAT BOUND TO CERTAIN RECEPTORS. THIS IS A STRATEGY YOU HAVE TO SCALE DOWN, THE WAY THEY WERE DOING IT TOOK TOO MUCH MATERIAL AND TOOK TOO LONG TO DO BUT IF YOU COULD SCALE THIS DOWN AND REALLY REDUCE IT IN SIZE, YOU COULD VERY REALISTICALLY DO A LARGE SCALE SCREEN TO TRY TO FIGURE OUT RECEPTOR LIGAND PAIRS FOR EVERYTHING YOU CAN FIND IN THE SYNAPSE. SPATIAL PROTEOMICS HAS ALSO EMERGED BASED ON SOME METHODS, BIOID AND APEX, THESE ARE WAITZ TO TAG PROTEINS IN THE VICINITY OF A BAIT BREEN, SO THIS IS SOMEWHAT DIFFERENT THAN WHAT YOU ARE MIGHT THE DO A PROTEIN- PROTEIN INTERACTION STUDY, SO THESE METHODS HAVE THE ABILITY TO TAG AND PICK UP THINGS WHICH MIGHT BE NOT HIGH INFINITY ENTER ACTORS OF ANOTHER DAIRK INTERACTORS OF A PROTEIN, THIS HAS TAKEN THE PROTEIN- PROTEIN INTERACTION AREA BY STORM, BASED ON THE BIO ID METHOD AS WELL AS THE APEX METHOD OF AL ALICE TING AND THE DIRECTOR OF NIH ACTUALLY JUMPED IN ON THIS AND HE CAME UP WITH A REALLY INTERESTING STRATEGY FOR DOING THIS WHICH IS BASED ON EW ING AN ANTIBODY -- USING AN ANTIBODY, ANOTHER ANTIBODY TO THAT ANTIBODY LABELED WITH HRP AS A WI TO ADD THE BIOTIN TAGS ONTO PROTEINS, I THOUGHT THIS WAS APRIL VERY CLEVER STRATEGY BECAUSE IT ALLOWS YOU TO USE EXISTING ANTIBODIES AGAINST THINGS RATHER THAN HAVING TO GO IN AND EPITOPE TAG PROTEINS, SO YOU CAN LOOK AT ENDOGENOUS SYSTEMS RATHER THAN LOOK AT SYSTEMS WHICH IS YOU'VE UTURPED, YOU CAN ALSO DO CELL AND TISSUE IMAGING BY MASS SPECTROMETRY TRI, CYTOFF HAS BEEN IN THE NEWS, THE DOWNSIDE IS IT REQUIRES ANTIBODIES AS A WAY TO LABEL THINGS BUT YOU CAN DO ABOUT 100 OR SO CHANNELS PER EXPERIMENT, ALSO MULTIPLE IMAGINING METH TO DO SO, A METHOD CALLED MALDESI IMAGING, GROUPS DOING HIGH IMB IMAGING, THIS DOESN'T WORK THAT WELL FOR PROTEINS, LIMITATIONS OF THESE METHODS ARE OFTEN ASSOCIATED WITH STHALZ WITH MOLECULAR IDENTITY AS WELL AS RESOLUTION FOR SOME OF THE METHODS, THEY CERTAINLY DON'T HAVE THE SUPER- RESOLUTION CAPABILITY OF SOME OF THE IMAGING METHODS NOWADAYS, THIS IS JUST AN EXAMPLE OF A MALDESI IMAGE I GOT FROM DAVE BUDDYMAN'S LAB IMAGING DOPAMINE AS WELL AS GABA IN TISSUE SLICES. JUST THOUGHT I WOULD BE REMISS IF I DIDN'T MENTION METABOLOMICS , SO THERE ARE INCREASINGLY IMPROVING METHODS FOR GENERAL PROFILEING METABOLITES, SOME LABS HAVE BEEN WORKING ON SINGLE CELL METABOLITES, SINGLE CELL ANALYSIS OR MORE GLOBAL ANALYSIS , LIPIDOMICS HAS BEEN A HUGE GROWTH YAIRP IN THE METABOLOMIC FIELD. SO WE'RE TOLD TO MENTION, COME UP SOME MOONSHOT IDEA SO ONE OF THE THINGS I'VE BEEN THINKING ABOUT DOING IS LARGE SCALE PROTEIN-PROTEIN INTERACTIONS IN CELLS OF THE BRAIN EITHER DIRECT AND SPATIAL, HELP DEFINE FUNCTIONS OF PROTEINS IN THE NEURON, WILL A PROTEIN HAVE THE SAME SORT OF INTERACTIONS IN THE NEURON THAT IT MIGHT HAVE IN HEC 2 93 CELLS IN THE GIDGI CONSTITUTED DILD AND POTENTIAL IDENTIFY A LIGAND AT THE RECEPTOR FOR THE SYNAPSE, ONE COULD THINK OF DOING THIS AS A FUNCTION OF DIFFERENT KINDS OF NEURONS IN THE BRAIN. THAT'S IT. [APPLAUSE] >> COULD YOU ELABORATE A LITTLE BIT MORE ABOUT THE CHALLENGES OF DOING MANY OF THESE APPROACHES IN SITU? BECAUSE PEOPLE ARE LOOKING AT A GENE EXPRESSION AND PROFILING OF SINGLE CELL, ET CETERA, AND BEING ABLE TO DO ALL OF THESE IN SITU IS REALLY ONE OF THE GOLDEN GOAMS RIGHT NOW. IS IT -- GOALS RIGHT NOW. IS IT CON RECEIVERRABLE TO DO SOMETHING LIKE THIS WITH PROTEINS? >> Dr. Yates: PROBABLY THE IMAGING METHODS WOULD BE ONE OF THE WAYS TO LOOK AT THINGS IN SITU. , OTHERWISE FOR SOME OF THE SINGLE CELL PROTEOMIC STRATEGIES , SORTING THE NEURONS, FLOW SORTING, THINGS OF THAT NATURE. >> LARGE SCALE PROTEIN-PROTEIN INTERACTION IN TERMS OF THE BRAIN DIRECT AND SPATIAL, YOU DON'T MEAN IN THE ACTUAL TISSUE? >> Dr. Yates: FROM TISSUE, YES. >> FROM TISSUE, BUT NOT WITHIN. >> Dr. Yates: NO. SO YOU CAN CONFIRM PROTEIN- WITH IMAGING METHODS THAT YOU IDENTIFY IN THE MORE UNBIASED STRATEGY, AND YOU COULD THINK ABOUT USING SOME OF THE BIO ORTHOGONAL LABELING METHODS AS A WAY TO INSERT SPECIFIC MOLECULES THAT WOULD ALLOW YOU TO PULL OUT PROTEIN COMPLEXES. THERE ARE SOME STRATEGIES EMERGING THAT WILL BE -- WON'T REQUIRE TAGGING INDIVIDUAL PROTEINS WITH BAITS, WITH EPITOPE TAGS. >> IN SITU IN IMAGING, ONE NEEDS THE CORRESPONDING ANTIBODIES, AND IS THAT THE IDEA THAT THE IMAGING WOULD REQUIRE ANTIBODIES >> Dr. Yates: NO. WELL, CYTOF DOES, BUT SOME OF THE OTHER IMAGING TECHNIQUES DO NOT. THE ORIGINAL GARY NOLAN CYTOF METHOD IS BASED ON A SORT OF FLOW SORTER IN FRONT OF THE MASS SPECTROMETER BUT ANOTHER METHOD IS BEING DEVELOPED IN SWITZERLAND, FORMER NOLAN POST-DOC THEY'RE USING A HIGH ENERGY BEAM TO DISRUPT OUT OF THE TISSUE INTO THE MASS SPECTROMETER AND THEN MEASURING THE LABELS WITH THE ICP MASS SPECTROMETER. >> LAST QUESTION S HOW MUCH ARE ALL THESE STUDIES BEING DONE AT THE PROTEIN LEVEL VERSUS PROTEIN VARIANT LEVEL? SPLICING ISOFORS. >> Dr. Yates: A LOT OF THE METHODS I TALKED ABOUT ARE WHAT WE CALL IN THE FIELD BOTTOM-UP METHOD, WE'RE TAKING INTACT PROTEINS, DIGESTING THEM DOWN THE PEPTIDES AND ANALYZING THE PEPTIDES, THAT'S PROBABLY THE FASTEST, LARGEST SCALE, MOST SENSITIVE STRATEGY. THERE ARE COMPETING METHODOLOGIES BEING DEVELOPED TO DO WHAT'S CALLED TOP-DOWN, LOOK AT INTACT PROTEINS, PUT THEM IN THE MASS SPECTROMETER AND THEN TRY TO FIGURE OUT WHO THEY ARE. SOME OF THE ADVANTAGES TO THAT ARE THAT YOU CAN GET WHAT WE CALL PROTEOFORMS, SO IT'S A COMBINATION OF THAT'S A TERM THAT'S A COMBINATION OF ISOFORMS VERSUS MODIFIED FORMS OF PROTEINS. SO THE INFORMATION THAT YOU GET BY TOP-DOWN IS MORE DIRECTED RELATED TO THE PROTEOFORM OF THE PROTEIN, BUT IT'S HARD TO GET. THESE METHODS ARE NOT AS ROBUST AND AS MATURE AS THE BOTTOM-UP STRATEGIES, BUT THEY ARE MOVING ALONG AT A FAST CLIP. >>> DR. DOLEN: ALL RIGHT, EVERYBODY, THANK YOU FOR COMING AND LISTENING. I'M A LITTLE BIT DIFFERENT FROM SOME OF THE SPEAKERS THAT WE'VE HEARD UP UNTIL NOW IN THAT I'M REALLY NOT A TOOL MAKER, I'M MUCH MORE OF A TOOL TAKER, SO WHAT I REALLY WANTED TO SHOW TODAY IS SOME OF THE NEW AMAZING ANALYSIS AND HYPOTHESIS IRCH DR. QUESTIONS WE CAN ASK USING SOME OF THESE TOOLS AND THIS FIELD HAS EXPLODED SO THERE'S BEEN A LOT OF WORK DONE THAT I DON'T HAVE TIME TO SHOW. I JUST WANTED TO GIVE YOU A REALLY QUICK SURVEY OF IT USING SOME EXAMPLES THAT ARE RELEVANT TO DISEASE. AND THEN IN THE SORT OF SECOND HALF I'LL TELL BU WHAT MY MOON SHOT IS -- TELL YOU ABOUT WHAT MY MOONSTHOT IS AND HOPEFULLY I CAN STIR UP A DISCUSSION. SO I THINK EVERYBODY HERE KNOWS, BUT MAYBE FOR THE WIDER AUDIENCE , THIS TECHNOLOGY OF OPT OGENETICS HAS REALLY TRANSFORMED NEUROSCIENCE, SO THE REASON FOR WHY THIS IS SO TRANSFORMATIVE IS THAT IN THE BRAIN, NEURONS ARE ORGANIZED IN SUCH A WAY THAT CELL TYPES ARE INTERMIXED WITH EACH OTHER. SO IF YOU JUST PUT IN A METAL ELECTRODE AND TRIED AND STIMULATE A BRAIN REGION, CHANCES ARE YOU'RE GOING TO BE STIMULATING A REALLY WIDE VARIETY OF CELLS WHO ARE SENDING PROJECTIONS TO A REALLY WIDE ARRAY OF BRAIN REGIONS, AND YOU'RE REALLY GOING TO HAVE A HARD TIME FIGURING OUT WHICH FUNCTION BELONGS TO WHICH CELL AND WHICH CELL BELONGS TO WHICH CIRCUIT AND WHAT ARE ARE THESE -- AND WHAT DO THESE CIRCUITS DO. WHAT THIS TECHNOLOGY DOES IS ALLOW YOU TO MOLECULARLY SPECIFY NEURONAL SUBTYPES TO ENCODE A LIGHT-SENSITIVE PROTEIN, IN MOST PEOPLE THESE CHANNEL RHODOPSIN OR A VARIANT OF THAT, THIS IDEA OF USING MOLECULAR SPECIFICATION TO DRIVE DIFFERENT TYPES OF PROTEINS IS NOT JUST FOR STIMULATING OR INHIBITING NEURONS, WE CAN ALSO USE IT TO IMAGE NEURONS OF DIFFERENT CLASSES. SO THE OTHER TECHNOLOGY THAT'S REALLY BEEN CRITICAL TO MAKING THIS SO UNIVERSALLY USEFUL FOR NEUROSCIENTISTS IS VIRAL- MEDIATED DREAM TRANSFER. SO IN THE EARLY DAYS, WHEN I STARTED IN NEUROSCIENCE, PEOPLE WERE DELIVERING GENES WITH SIMBI S VIRUS, WHICH IS EXTREMELY NEUROTOXIC, SO WITHIN HOURS THE CELLS ARE DYING, AND THEN, YOU KNOW, AND PEOPLE HAVE ALSO USED LENTI-VIRUS AND THESE ARE GREAT BECAUSE THEY ALLOW YOU TO LABEL A SPARSE POPULATION OF CELLS, SO IF YOU WANT TO RECORD FROM A CELL THAT'S BEEN GENETICALLY MODIFIED AND ALSO RECORD FROM A CELL RIGHT NEXT TO IT THAT IS NOT GENETICALLY MODIFIED, THIS IS A GREAT PROTEIN. AND THE ADVANTAGE OF THIS IS THAT LENTI VIRUSES ARE SORT OF EASY TO MAKE, YOU CAN DO A LOT OF MANIPULATIONS IN A LAB WITHOUT BEING TERRIBLY SOPHISTICATED ABOUT MAKING VIRUS ES. THE NEGATIVES OF THIS IS THAT AS I SAID, YOU KNOW, IT'S SORT OF SPARSELY -- IT SORT OF SPARSELY GETS AT NEURONS, SO IF YOU'RE TRYING TO DO BEHAVIORAL EFFECTS, THESE CAN BE VERY DIFFICULT. THEN THERE'S A VERY, VERY SMALL CHANCE THAT WHEN YOU LOAD UP A BRAIN REGION WITH THIS VIRUS, THAT YOU'RE GOING TO GET POSITIONAL EFFECTS OF INTEGRATION. RABIES VIRUS HAS BEEN EXTREMELY USEFUL BECAUSE IT IS A VIRUS THAT IS TRANSPORTED RETROGRADELY , SO THIS IS REALLY GREAT FOR BEING ABLE TO FIGURE OUT WHERE -- IF YOU'RE IN A SPECIFIC BRAIN REGION, WHAT OTHER BRAIN REGIONS ARE SENDING AXONS TO THAT BRAIN REGION. BUT THIS VIRUS IS PRETTY TOXIC, SO WITHIN 7-10 DAYS YOU REALLY START TO SEE NEURONS BEING UN HEALTHY. HERPES IS SIMILAR, IT'S BIG, SO YOU CAN PACK NG A LOT OF DNA -- PACK IN A LOT OF DNA, BUT IT'S ALSO PRETTY TOXIC. I THINK SORT OF THE STAR IS REALLY AAV, THIS WAS A VIRUS THAT WAS DISCOVERED ACCIDENTALLY , THEY ALWAYS FOUND IT SORT OF NEXT TO ADENO VIRUS, SO ITS NAME IS ADENO ASSOCIATED VIRUS, IT'S GREAT BECAUSE IT HAS NO KNOWN PATD GENICITY, AND PEOPLE HAVE SPENT A LOT OF TIME JERPG THE CAPSID OF THIS VIRUS SO -- ENGINEERING THE CAPSID OF THIS VIRUS SO YOU CAN CAPTURE DIFFERENT FEATURES SUCH AS TROPISM FOR NEURONS OR THE ABILITY TO MAKE IT GO RETROGRADE AND ALSO I THINK THE MOST EXCITING OF THIS IS SOME OF THE WORK COMING OUT OF VIVIANA GRADI NARA'S LAB THAT IS ENGINEERING VERSIONS OF THIS THAT ARE BLOOD-BRAIN BARRIER PERMEABLE, AND I THINK IN COMBINATION WITH MAGNET OH GENETIC APPROACHES, I THINK THIS IS THE KIND OF THING THAT COULD IN 50 YEARS ARE PUT NEUROSURGERY OUT OF BUSINESS BECAUSE YOU CAN IMAGINE TH AT YOU GIVE SOMEBODY A PILL THAT HAS A VIRUS AND THEN YOU SHINE A MAGNET OVER THEIR HEAD AND YOU'RE ABLE TO STIMULATE WHATEVER NEURON THAT YOU WANT. SOY REALLY THINK THERE'S A LOT OF POTENTIAL IN THIS KIND OF DELIVERY. I'M NOT GOING TO GO THROUGH ALL THE DIFFERENT STRATEGIES THAT PEOPLE HAVE USED TO COMBINE DIFFERENT CREE LINES AND DIFFERENT MOUSE VIRAL MEDIATED GENE TRANSFER TO ACCOMPLISH LOTS OF DIFFERENT THINGS, BUT THERE IS A REVIEW OUT IF YOU WANT THE TO READ MORE ABOUT THE VARIOUS COMMENT EDITORIALS WE CAN DO. I THINK THE MOST IMPORTANT REASON THIS HAS HAD A BIG IMPACT ON THE FIELD IS IN THE EARLY DAYS OF THE FIELD WHEN WE WANTED TO DO CIRCUIT ANALYSIS, WE WERE PRETTY MUCH LIMITED TO SENSORY SYSTEMS LIKE THE VISUAL CORTEX WHERE WE DISCOVERED A LOT OF THE ORGANIZATIONAL PRINCIPLES OF THE BRAIN, SO FOR EXAMPLE, THIS ONE IS PARALLEL PROCESSING WHERE WE HAVE TWO STREAMS OF VISUAL INFORMATION THAT ENCODE DIFFERENT FEATURES OF THE VISUAL IMAGE, AND WE WERE ABLE TO DO THIS BECAUSE WE COULD MANIPULATE THE SO-CALLED RECEPTIVE FIELD. SO WHAT THE VISUAL SYSTEM IS SEEING, AND THEN MEASURE WHAT'S HAPPENING IN THE BRAIN. BUT IN OTHER CIRCUITS LIKE THE BUY ZALY GANGLIA, THIS RECEPTIVE FIELD -- THE BASAL GANGLIA, THE RECEPTIVE FIELD HE IS AN INTERNAL STATE, IT'S BEEN MUCH MORE DIFFICULT TO USE THOSE KINDS OF EARLIER TECHNOLOGIES TO MAP THESE BRAIN REGIONS. BUT OPTOGENETICS AND THE SORT OF MOLECULAR SPECIFICATION REVOLUTION HAS REALLY CHANGED THAT. SO I'LL JUST GIVE YOU AN EXAMPLE , YOU KNOW, FROM THE BASA L GANGLIA WE KNOW FROM EARLY WORK THAT THERE'S A DIRECT PATHWAY AND AN INDIRECT PATHWAY, I WON'T GO THROUGH ALL THE SPECIFICS, BUT I THINK THE OLD VIEW OF THIS WAS THAT ESSENTIALLY THE DIRECT PATHWAY IS THE GO MOVEMENT PATHWAY AND THE INDIRECT PATHWAY IS THE DON'T GO MOVEMENT PATHWAY. THESE HAD BEEN VARIOUSLY IMPLICATED IN HUNTINGTON'S DISEASE WHERE THERE'S A CHORIO FORM ACTIVITY SO THAT THE PATIENTS HAVE MOVEMENTS THEY CAN'T CONTROL, VERSUS PARKINSON'S DISEASE WHERE YOU SEE A GENERAL DECLINE IN THE ABILITY TO MOVE, BUT THEN ALSO HAVING TREM MORPZ. SO WHAT I THINK THE OPTOGENETICS AND CALCIUM IMAGING TECHNIQUES HAVE REALLY OFFERED IS THAT WHEN WE STARTED TO TEST THESES HYPOTHESES DIRECTLY WITH THESE TECHNOLOGIES, WE FIGURED OUT THAT THIS OLD MODEL OF GO, NO GO , IS PROBABLY SORT OF RIGHT BUT IS ACTUALLY A LITTLE BIT MORE COMPLICATED THAN THAT. SO I THINK THAT THIS IS REALLY OFFERING SOME BIG INSIGHTS INTO NEUROPSYCHIATRIC DISEASE. SO I WILL JUST QUICKLY TELL YOU ABOUT A WAY THAT WE'RE USING IT. SO WE IN MY LAB STUDY OXYTOCIN SIGNALLING AND WE KNOW THAT THERE ARE OXYTOCIN CELLS THAT ARE BIG CALLED MAGNOCELLULAR AND PARVOCELLULAR, WE'VE HYPOTHESIZED THAT THEY ENCODE DIFFERENT BEHAVIORS, AND WHAT'S MORE IS THAT WE SYMPATHY -- IS THAT WE THINK THAT SOME OF THESE BEHAVIORS ARE GOING TO BE REALLY RELEVANT TO DISEASES LIKE AUTISM BUT OTHERS ARE NOT GOING TO BE SO MUCH RELEVANT TO AUTISM SO WE'RE TESTING THE HYPOTHESIS USING OPTOGENETICS AND THESE MOLECULAR SPECIFICATION TOOLS SO USING A COMMONATORIAL APPROACH WHERE WE HAVE ONE LINE OF MICES THAT SPECIFIES MAGNO CELLULAR, ONE USES OXYTOCIN, WE COMBINE THEM AND CAN USE THIS STRATEGY TO ACTIVATE ONE OR THE OTHER. THIS IS IMPORTANT BECAUSE GOING BACK TO THIS MODEL CURRENTLY ALL OF THE DRUGS IN CLINICAL TRIALS FOR OXYTOCIN AND AUTISM ARE REALLY TARGETING THIS PATHWAY WHICH IS DISTORT OF OPPOSITE OF OUR HYPOTHESIS THAT THIS IS THE PATHWAY THAT MIGHT BE MORE RELEVANT TO AUTISM DISEASE PATHOGENESIS. OKAY. SO IN THE LAST FEW ANYONE -- LAST FEW MINUTES, I WANT TO SWITCH DIRECTIONS AND TELL YOU MY MOONSHOT IDEA. I KNOW THIS IS GOING TO BE CONTROVERSIAL, BUT I REALLY JUST WANT TO PUT IT OUT THERE AND OPEN UP THE DISCUSSION. SO I REALLY THINK THAT IN THE 1960S AND '70S, NEUROSCIENTISTS WERE EXTREMELY INTERESTED IN OCTOPUSES, AND BECAUSE OF THE MOLECULAR GENETIC REVOLUTION, I THINK THESE ANIMALS KIND OF FELL BY THE WAYSIDE. BUT I THINK THAT WITH SOME OF THE NEUROADVANCES, MODERN MOLECULAR GENETICS, MAYBE IT'S TIME TO COME BACK TO THIS MODEL. SO WHY DO WE CARE ABOUT OCTOPUS ES, WHAT DO WE WANT TO STUDY WITH THEM? OCTOPUSES ARE REALLY INTERESTING , AND THEY DO A LOT OF DIFFERENT THINGS THAT WE CAN'T DO. SO PEOPLE HAVE BEEN EXPLOITING THESE ABILITIES TO DESIGN NEW ROBOTS, SO THEY HAVE A MUSCULAR HYDROSTAT, SO NEW ROBOTICS APPLICATIONS ARE BEING DESIGNED BASED ON THAT WAY OF MOVING, AND THIS KIND OF WORK IS REALLY FUND ED A LITTLE BIT BY DARPA, I BELIEVE. THEY ALSO HAVE VERY UNUSUAL TISSUES THAT HAVE BEEN USED FOR TISSUE BIOENGINEERING. FAIR ENOUGH CUT OFF AN ARM, THEY'RE ABLE TO REGENERATE, SO THAT HAS REALLY BIG POTENTIAL FOR TRYING TO DISCOVER NEW WAYS OF TREATING SPINAL CORD INJURIES THEY HAVE A UNIQUE VISUAL SYSTEM , SO EVEN THOUGH THEY HAVE ONLY ONE -- PROTEIN, THEY'RE ABLE TO SEE AND USE COLOR USING A DIFFERENT STRATEGY, SO WE CAN POTENTIALLY LEARN HOW TO MAKE NEW KINDS OF VISUAL SYSTEMS DIFFERENT FROM THE ONES THAT WE KNOW AND LOVE. AND THEN, YOU KNOW, I THINK THERE'S A REALLY BIG OPPORTUNITY TO STUDY AGING IN THESE ANIMALS BECAUSE IN SOME SPECIES, THESE ANIMALS GO IMMEDIATELY INTO SINE SENS AFTER THEY MATE AND ANOTHER SPECIES THEY DON'T DO THAT AT ALL, SO WE COULD POTENTIALLY DISCOVER REGULATORY MECHANISMS FOR IN AND OUT OF SIN ESENSE BY COMPARING ACROSS THESE SPECIES. FOR MYSELF I'M REALLY INTERESTED IN THESE ANIMALS BECAUSE THEY ACTUALLY HAVE REALLY ADVANCED COGNITIVE ABILITIES. SO ONE OF THE HALLMARK FEATURES OF AUTISM IS AN IMPAIRMENT IN THEORY OF MIND BEHAVIORS, AND THIS BEHAVIOR IS SOMETHING THAT WE SEE IN HUMANS STARTING AROUND AGE 4, BUT, YOU KNOW, MOST ANIMALS, INCLUDING MICE, WE CANNOT, WE HAVE TRIED, BUT WE'VE HAD A REALLY HARD TIME DEMONSTRATING A THEORY OF MIND LIKE BEHAVIOR IN THESE ANIMALS, SO IT'S BEEN REALLY HARD TO TEST WHETHER OR NOT OUR INTERVENTIONS ARE WORKING AND BE ABLE TO TRANSLATE THAT BACK TO HUMANS. BUT OCTOBERING PUTS, THIS PARTICULAR SPECIES OF OCTOPUS IS A SOCIAL OCTOPUS AND IT DOES THIS BEHAVIOR WHICH I'M HAPPY TO PANTOMIE FOR YOU LATER THAT REALLY SUGGESTS THAT THEY MIGHT HAVE SOMETHING LIKE THEORY OF MIND OR SOCIAL COGNITION. SO I THINK THAT'S A REAL OPPORTUNITY, ESPECIALLY BECAUSE ARE THE GENOME OF THIS OCTOPUS HAS BEEN SEQUENCED AND FOR ALL OF THE AUTISM GENES THAT HAVE BEEN IDENTIFIED THAT WE'VE LOOKED AT, WEAVER SEEN HOMOLOGS IN THIS OCTOPUS. SO THAT'S VERY ENCOURAGING. AND I THINK THE REASON THAT IT'S TIME TO COME BACK TO IT IS BECAUSE CRISPR CAS GENE EVIDENCE ITING REALLY OPENS THE DOORS TO BE ABLE TO DO THESE MOLECULAR GENETIC MANIPULATIONS OF PRETTY MUCH ANY ANIMAL, INCLUDING OCTOPUSES, WE STARTED TO PILOT OUT SOME OF THIS STUFF, HERE ARE SOME NEURONS IN THE VERTICAL LOBE OF THE OCTOPUS BRAIN THAT HAVE BEEN TRANCE SPECULATED WITH GFP AND ARE EXPRESSING GFP PROTEIN AND WE'RE ABLE TO RECORD FROM THEM AND DETECT GLUT MA TER JIK SYNAPSIS. I'M ALMOST DONE. I LEFT THIS, THE TITLE OF THIS SLIDE AS REALLY PROVOCATIVE BECAUSE OBVIOUSLY I STUDY CIRCUITS AND TO ASK THE QUESTION OF WHETHER OR NOT CIRCUITS MATTER AT ALL. I KNOW IT'S GOING ON STIR UP SOME ANGER, BUT, YOU KNOW, THIS STUDY THAT WE RECENTLY PUBLISHED THAT LISA MENTIONED REALLY HAS GOT ME THINKING BECAUSE WHAT WE FOUND IN THIS STUDY IS THAT THE OCTOPUS HAS A HOMOLOG OF THE SEROTONIN TRANSPORTER GENE THAT IS NOT THAT SIMILAR FOR THE WHOLE GENE COMPARED TO HUMAN CER T, BUT IN THE SEROTONIN BINDING POCKET AND THE BINDING POCKET THAT OVERLAPS WITH NDMA'S BINDING POCKET, THERE'S A HIGH DEGREE OF OVERLAP AND WHAT'S MORE IS THAT IT WE GIVE MDMA TO AN OCTOPUS, THEIR BEHAVIORAL RESPONSE IS VERY, VERY SIMILAR TO A HUMAN SO THE REASON THAT THIS CHALLENGES I THINK THE VIEW OF THE BRAIN IS THAT THESE ARE ANIMALS THAT DO NOT HAVE A CORTEX, THEY DON'T HAVE A BASAL GANGLIA, THEIR BRAIN IS ORGANIZED TOTALLY DIFFERENT FROM MAMMALS, AND YET THEY'RE ABLE TO DO, YOU KNOW, RESPOND TO THESE DRUGS IN A VERY SIMILAR WAY. SO IT BEGS THE QUESTION, YOU KNOW, IF ALL YOU REALLY NEED TO HAVE A COMPLEX BEHAVIOR IS SEROTONIN TRANSPORTER, ARE WE REALLY GAINING AS MUCH VALUABLE INFORMATION AS WE THINK FROM DOING ALL OF THIS CIRCUIT ANALYSIS? AND THIS IS A REAL CHALLENGE AND I THINK WE NEED TO THINK ABOUT THIS HARD AND I'M HAPPY TO DISCUSS IDEAS AND THOUGHTS I HAVE ABOUT THIS. OKAY. SO JUST IN WRAPPING THINGS UP, I REALLY THINK THAT THE BRAIN INITIATIVE IS A GOOD PLACE TO FUND THIS KIND OF TRANSFORMATIVE NEW SPECIES WORK BECAUSE, YOU KNOW, WE ALL AS SCIENTISTS APPRECIATE THAT SOME OF OUR BEST IDEAS V ABSOLUTELY NO GOAL WHEN WE DO THEM, SO I THINK OUR MOST FAMOUS EXAMPLE IS THE NSF FUNDED SOME SCIENTISTS TO GO AND LOOK AT THESE REALLY WEERDZ BACTERIA WHO WERE LIVING AT EXTREMELY HIGH TEMPERATURES IN THERMAL VENTS IN YELLOWSTONE NATIONAL PARK AND I WOULD ARGUE THAT THE DISCOVERY OF THE ENZYME THAT MADE THIS POSSIBLE TACT POLYMERASE IS PROBABLY THE MOST REVOLUTIONARY DISCOVERY OF THE 20TH CENTURY AND HAS TRANSFORMED ALL OF BIOLOGY, ALL OF MEDICINE AND ALSO FORENSIC SCIENCE, BUT THIS WAS NOT FUNDED WITH A SPECIFIC GOAL IN MIND, AND THE REASON THAT I THINK THAT IT'S THE BRAIN INITIATIVE'S JOB TO FUND SOMETHING LIKE THIS IS BECAUSE SOME OF THE OTHER ALTERNATIVES REALLY DON'T HAVE THE LONG VIEW TO MAKE THIS KIND OF FUNDING POSSIBLE. SO BIG PHARMA IS NOTORIOUSLY INTERESTED IN THINGS THAT CAN BE TRANSLATED WITHIN ONE OR TWO YEARS. MANY OF THE PRIVATE FOUNDATIONS, YOU KNOW, HAVE NAMES LIKE CURE AUTISM NOW, WHICH IS A GREAT FOUNDATION, BUT IT HAS A GOAL. SO THEY'RE NOT GOING TO BE LIKELY TO FUND THIS COOL BACTERIA LIVING IN THE THERMAL VENTS. I THINK THE NEW DIRECTORS, NEW INNOVATOR AWARD IS A STEP IN THE RIGHT DIRECTION, BUT AS THE NAME IMPLIES, THIS IS FOR YOUNG EARLY STAGE INVESTIGATORS AND I THINK SOMETHING LIKE THIS, IF IT WERE EXPANDED AND INCLUDED EVERYBODY, THEN WE COULD START TO DO MORE OF THESE KINDS OF IDEAS. AND THEN I'LL JUST END WITH, YOU KNOW, I THINK THAT THE BRAIN INITIATIVE COULD BE THE LEADER IN CHANGE OUR GRANT REVIEW SYSTEM TO BE BLINDED BECAUSE DESPITE THE BEST EFFORTS OF OUR PROGRAM OFFICERS TO LIMIT THE EFFECTS OF EXPLICIT BIAS, STUDY AFTER STUDY TELLS US THAT THERE IS IMPLICIT BIAS, AND IMPLICIT BIAS TRAINING DOES NOT WORK. THE ONLY WAY TO OVERCOME IMPLICIT BIAS IS TO BLIND THE REVIEW PROCESS. AND I REALLY THINK THAT NIH COULD -- AND THE BRAIN INITIATIVE COULD BE A LEADER IN CHANGING THE WAY WE DO THIS. OKAY. SO THAT'S IT. [APPLAUSE] >> I LIKE THE QUESTION ON DO IRKTS IS MATTER. I'M JUST -- DO CIRCUITS MATTER. I'M JUST CURIOUS ABOUT IT, DO YOU SEE IT MORE ABOUT SAYING WHAT ABOUT CIRCUITS MATTER IN TERMS OF -- SO I COME FROM SEMICONDUCTOR CIRCUITS, SO I CAN HAVE TWO COMPLETELY DIFFERENT CIRCUITS THAT DO THE SAME OPERATION, AND WHAT THAT DOES IS TELL ME ACTUALLY MORE ABOUT FUNDAMENTALLY PROCESSING THAN ANALYZING, GETTING OVERLY DONE ABOUT ONE SPECIFIC IMPLEMENTATION. SO IF YOU CAN JUST TEASE THAT ARE OUT A LITTLE BIT MORE, I WOULD BE INTERESTED IN WHERE YOU WOULD GO WITH IT. >> Dr. Dolen: ACTUALLY THIS IDEA IS NOT REALLY MY OWN. JZ YOUNG WHO WAS A JOINT IN THE NEUROSCIENCE FIELD ACTUALLY PROPOSED THIS IDEA IN THE 1960S IN A BOOK CALLED A MODEL OF THE BRAIN, AND WHAT HE ARGUED IS THAT YOU WANT TO STUDY A SPECIES LIKE OCTOPUS BECAUSE IT'S VERY, VERY DIFFERENT ANATOMICALLY THAN A HUMAN BRAIN. SO IF YOU CAN FIND -- AND THEY ARE ABLE TO DO COMPLEX FUNCTIONS SO HAVING THIS COMPARATOR THAT IS SO DIFFERENT THAT MIGHT HAVE SOLVED THE PROBLEM IN A TOTALLY DIFFERENT WAY EXACTLY ALLOWS YOU TO DETERMINE WHAT ARE THE RULES FOR BUILDING A COMPLEX FUNCTION. RIGHT? SO I THINK THAT THIS IS A GREAT IDEA AND WE SHOULD BE DOING THIS SO THAT WE GET A BETTER SENSE OF WHAT MATTERS BECAUSE IN CORRECTING DISEASE, SOME OF THESE DISEASES, WE'RE NOT GOING TO BE ABLE TO JUST RESTORE THE BRAIN TO NORMAL. THE WE MIGHT WANT TO CORRECT THE PROBLEM BY IMPLEMENTING AN ALTERNATIVE SOLUTION, AND WE MIGHT COME UP WITH THOSE ALTERNATIVE SOLUTIONS IF WE HAVE A BETTER SENSE OF WHAT THE RULES ARE. >> [AWAY YOU FROM MIC] >> WE'RE GOING TO TALK ABOUT NOT ONLY OUR FOCUS WHICH IS HAS BEEN ON NEURONS BUT NOW OTHER CELL TYPES INCLUDING GLIA. >> Dr. Eroglu: THANK YOU VERY MUCH FOR INVITING ME TO BE HERE TODAY, IT'S A GREAT PLEASURE, AND I HAVE THE RESPONSIBILITY TO PRESENT THE HALF OF THE BRAIN THAT WE HAVE NOT TALKED ABOUT YET, WHICH IS THE NONNEURONAL CELL, THE GLIAL CELLS AND HOW THEY RELATE TO THE FUNCTIONS OF SYNAPTIC CIRCUITS. SO AS MANY OF YOU, MY PRINCIPAL INTEREST IS TO UNDERSTAND HOW THE BRAIN SYNAPSES ARE FORMED DURING DEVELOPMENT, REMODELS, BY EXPERIENCES THROUGHOUT LIFE, AND THEN HOW THEY CAN BE DYSFUNCTION AND DISEASE. HOWEVER, ONE OF THE THINGSING THAT WE'VE COME TO APPRECIATE IS THAT THIS IS NOT ONLY HAPPENING DUE TO THE COMMUNICATION BETWEEN NEURONS, BUT THERE IS A BI DIRECTIONAL AAND EXTREMELY ACTIVE COMMUNICATION BETWEEN NEURONS AND OTHER COMPONENTS OF THE NERVOUS SYSTEM. THEREFORE, WHAT ARE THE ROLES OF THESE NONNEURONAL CELLS? IN A NUTSHELL, WE CAN CALL THEM THE GLIAL AND VASCULAR CELLS IN BRAIN FUNCTION. I'M APOLOGIZING BECAUSE I WILL NOT MENTION TOO MUCH ABOUT THE VASCULAR CELLS BECAUSE OF MY PRINCIPAL INTEREST IN GLIAL CELLS, BUT I WANT TO REPRESENT THE GLIAL CELLS THERE AND JUST TO TELL YOU THAT THE NAME GLIA IS ALREADY MISLEADING BECAUSE IT ACTUALLY LITERALLY MEANS GLUE FROM GREEK, AND MAYBE DIMINISHES A LITTLE BIT FROM THE GET-GO THE IMPORTANCE OF THESE CELLS FOR BRAIN FUNCTION BECAUSE THE ORIGINAL UNDERSTANDING WAS THAT THESE WERE THE CONNECTIVE TISSUE BETWEEN NEURONS, JUST PULLED EVERYTHING TOGETHER. HOWEVER, IT WAS LIKE THE CEMENT BETWEEN THE STONES IN A BUILDING , IT DID NOT NECESSARILY HAVE ANY ACTIVE ROLE IN SHAPING THE STRUCTURE. THE GLIAL STRUCTURES WERE NOTICED BY MANY EARLIER LEADERS IN THE FIELD, INCLUDING IROMINIC CAHALL AND HE DID MAKE A STATEMENT WHICH UNFORTUNATELY WAS TRUE FOR A VERY LONG TIME AND JUST TO READ IT, WHAT'S THE FUNCTION OF GLIAL CELLS IN NEURAL SNERNTS THE ANSWER IS NOT KNOWN AND THE PROBLEM IS EVEN MORE SERIOUS BECAUSE IT MAY REMAIN UNSOLVED FOR MANY YEARS TO COME UNTIL THE PHYSIOLOGISTS FIND DIRECT METHODS TO ATTACK IT , AND I THINK THIS PART IS THE PART THAT IS VERY CRITICAL. WE NEED DIRECT METHODS TO ATTACK THAT WE BEING ADDRESS THE PROPER FUNCTIONS OF GLIAL CELLS AND I WOULD SAY THANKS TO MANY MOLECULAR AND GENETIC ADVANCES AND ALSO THANKS IN GREAT PART TO THE TOOLS DEVELOPED BY BRAIN INITIATIVE AND OTHER SUCH INITIATIVES, WE NOW HAVE A MUCH, MUCH BETTER UNDERSTANDING OF THE ROLES OF GLIAL CELLS. SO THE MACRO AND MICROGLIA IN THE BRAIN, JUST TO NAME A FEW, WOULD CONSTITUTE, FOR EXAMPLE, CELLS LIKE ASTRO SITES AND -- CY TES AND OLIGONENDRACYTES SAME PART OF THE BRAIN. ASTROCYTES INTERACT WITH AND WITH THE BLOOD VESSELS AND HAVE REALLY FUNDAMENTAL ROLES WITH SUSTAINING FUNCTIONAL TIP IN THE BRAIN. MIGHT CROW GLIA IS APPRECIATED AND PLAYING IMPORTANT ROLES BOTH DURING THE REMODELING OF BRAIN IN DEVELOPMENT AS WELL AS UNDER DISEASE CONDITIONS. EVEN THOUGH IT'S REALLY EXTREMELY HELPFUL DOES NOT REALLY FULLY REVEAL THE COMPLEXITY OF THESE CELLS AND I WANT TO SHARE WITH YOU JUST TWO IMAGES FROM MEMBERS OF MY LAB, HERE IS A YOU DYE-FILLED ASTROCY TE FROM MOUSE BRAIN, AS YOU CAN SEE, IT ACTUALLY INFILTRATES INTO THE NERVE AND CONTACTS EVERY POSSIBLE NEURAL COMPONENT INCLUDING SYNAPSES AND THIS IS NOT JUST FUNCTIONAL, NOW WE KNOW THERE'S A FUNCTIONAL INTERACTION BETWEEN THE ASTROCYT E AND HAS ABILITY TO INTERACT WITH THIS SYNAPTIC BRAIN IN ITS NEIGHBORHOOD AND LISTEN TO THE SYNAPSE. CALCIUM INDICATORS, G CAMP AND SUCH AND VIRAL TOOLS TO TARGET THEM TO ASTROCYTES, WE NOW KNOW THAT ASTROCYTES IN RESPONSE TO LOCAL NEURONAL ACTIVITY CAN UNDERGO LOCAL AND GLOBAL CALCIUM TRANSIENTS. WE'RE STILL TRYING TO DECIPHER WHAT DOES THAT MEAN AND HOW IMPORTANT IT IS FOR THE COMPUTATIONAL POWER OF THE BRAIN ANOTHER ONE,S MICROGLIA HERE, AS YOU CAN SEE, IT'S NOT LOOKING LIKE A FRIED EGG, IT'S ACTUALLY WELL, AND IF YOU WATCH THESE CELLS THIS REALTIME, YOU'LL SEE THAT THEY ARE ACTIVELY SURVEILLING THEIR NEIGHBORHOOD AND THROUGH THAT SURVEILLANCE THEY ARE TOUCHING NEARBY SYNAPTIC STRUCTURES AND IF YOU STAIN THEM AND LOOK IN IN RELATIONSHIP TO AXONAL TERMINALS DURING CERTAIN CRITICAL PERIODS OF DEVELOPMENT, YOU CAN SEE THAT THEY ARE CONTAIN BEING AXONAL TERMINALS INTO THEIR BODY BECAUSE THEY WENT AHEAD AND TRIM MED AND PRUNED UNWANTED CONNECTIONS BETWEEN NEURONS, REVEALING HOW IMPORTANT THESE CELLS COULD BE AND THEIR FUNCTION COULD BE IN TERMS OF REMODELING TISSUES. BRAIN TISSUE. AND JUST IN THIS SLIDE, I WANT TO -- I DON'T WANT YOU TO REALLY FOCUS ON EACH AND EVERY DETAIL, BUT THIS IS JUST TO SHOW YOU AN OVERVIEW OF WHAT WE HAVE LEARNED SO FAR. WE KNOW THAT BOTH ASTROCYTES AND MICROGLIA ARE SECRETING FACTORS IN SYNAPSES AND NEW SYNAPSE FORMATION, THEY ALSO SECRETE SMALL MOLECULES AND IONS AS WELL AS PROTEINS TO CONTROL SYNAPSE A AND CIRCUIT PLASTICITY AND THEY BOTH HAVE DIFFERENT MOLECULAR MECHANISMS THROUGH WHICH THEY GO INTO PHAGOCYTOSIS AND ELIMINATE UNWANTED SYNAPSES. WE HAVE COME A LONG WAY, WE NOW UNDERSTAND HOW ASTROCYTE AND IS MICROGLIA ARE DIRECTLY AFFECTING SYNAPTIC CIRCUITS AT THE MOLECULAR LEVEL. THAT SAID, THIS IS PROBABLY JUST A DROP IN A VERY, VE LARGE POOL OF KNOWLEDGE THAT IS STILL COMPLETELY INACCESSIBLE TO US, AND ONE OF THE REASONS AGAIN BRINGING BACK TO RAMON CAJAL'S POINTED OF NOT HAVING ENOUGH PHYSIOLOGICAL TOOLS TO REALLY UNDERSTAND THE FULL FUNCTIONS OF GLIAL CELLS. SO I THINK IT'S NICE THAT I JUST TALKED AFTER DR. YATES AND DOLEN BECAUSE THAT WAY THEY HAVE GONE THROUGH SOME OF THE REALLY COOL TECHNIQUES THAT ARE AVAILABLE RIGHT NOWT FOR MANY RESEARCHERS SUCH AS MYSELF TO NOT ONLY TARGET NEURONS AND NEURONAL CIRCUITS, BUT UNDERSTAND THE FUNCTIONS OF GLIAL CELLS IN RELATION TO NEURONS. WE HAVE HAD AMAZING INSIGHT INTO THE GENE EXPRESSION PROFILES OF NOT JUST DIFFERENT NEURON TYPES BUT ALSO DIFFERENT GLIAL CELL TYPES, BOTH IN GENETIC MODELS AND IN HUMANS, AND THIS LED TO THE DEVELOPMENT OF REALLY IMPORTANT GENETIC TOOLS TO CHARACTERIZE AND TARGET NON NEURONAL CELLS. AND EE LEWIS ADDITION OF MOLECULAR HETEROGENEITY IN GLIAL CELLS WHICH IS SOMETHING THAT HAS BEEN NEGLECTED UNTIL RECENT LY THINKING GLIA IS ALL THE SAME OR EVEN AN ASTROCYTE IS THE SAME AS THE NEXT ASTROCYTE, WE'RE TRYING TO REALIZE THAT THIS IS MAYBE NOT TRUE. IMPORTANTLY, APPLICABLES BRAIN INITIATIVE TOOLS TO TARGET THE SYNAPTIC CIRCUITS LED TO US TO UNDERSTAND THAT GLIAL CELLS ARE REGULATING SYNAPTIC CONNECTIVITY IN AN ACTIVITY-DEPENDENT MECHANISM, AND THE IMAGING TOOLS THAT ARE BEING DEVELOPED TO IMAGE NEURONS ARE OF COURSE ALSO VERY VALUABLE TO IMAGE GLIAL CELLS SUCH AS ASTROCYTES, MICRO GLIA, AS WELL AS THE VASCULAR COMPONENTS OF THE BRAIN , SO ALL THESE ARE LEADING TO REALLY IMPORTANT DISCOVERIES IN THE FIELD. HOWEVER, WE STILL HAVE MISSING TOOLS AND MISSING GAPS IN OUR KNOWLEDGE. ONE OF THEM IS HOW CAN WE NOW TAKE WHAT WE LEARNED WITH THE TRANSCRIPTIONALLY BASED CLASSIFICATIONS OF GLIAL CELLS AND TAKE THEM TO A PROTEIN LEVEL ANALYSIS. THAT IS SOMETHING THAT WOULD BE IMPORTANT TOCHED IN THE NEXT FIVE YOU TO TEN -- IMPORTANT TO DO IN THE NEXT FIVE TO TEN YEARS AND HOW CAN WE STUDY THE FUNCTIONAL HEAD ROTE -- OF VASK GLIAL CELLS, MICROGLIA, AND DETERMINE THEIR DISTINCT FUNCTIONS IN CONTROLLING CIRCUITS AND ARE WE ACTUALLY ABLE TO CAPTURE ARE GLIAL FUNCTION? BECAUSE AS I MENTIONED, ONE OF THE TOOLS WE USE IS G CAMP TO SEE THE CHANGES IN CALCIUM TRANSIENTS IN FOR EXAMPLE ASTROCYTES BUT MAYBE CALCIUM IS NOT THE MOST IMPORTANT SECONDARY MESSENGER IN AN ASTROCYTE. WE ACTUALLY NEED MORE PROBES, MORE SENSORS FOR OTHER SECONDARY MESSENGERS TO SEE MAYBE THERE IS A MUCH MORE DYNAMIC CHLORIDE OR PH VARIATION IN THESE CELLS AND THE TOOLS FOR THOSE ARE NOT UP TO THE SAME LEVEL AS CALCIUM, SO WE SHOULD REALLY INVEST IN FINDING NEW TOOLS AND SENSORS THAT MAY REVOLUTIONIZE THE WAY WE SEE GLIAL CELLS. ALSO CAN WE TAKE OUR UNDERSTANDING OF GLIAL CELLS FROM MOLECULAR CELLULAR LEVEL ALL THE WAY TO THE SYSTEMS LEVEL , CAN WE HAVE THESE STUDIES YOU TO HIGHER IMAGING AND OTHER MECHANISMS. SO CAN A ALSO DEVELOP BETTER WAYS TO TARGET NONNEURONAL CELLS FOR RESEARCH AND FOR THERAPEUTIC PURPOSES BECAUSE THESE CELLS, EACH AND EVERY ONE OF THESE CRESMS AND THE MOLECULAR MECHANISMS THAT I JUST GLANCED OVER ARE LINKED TO DISEASES CHANGING FROM AUTISM, ALZHEIMER'S DISEASE AND EPILEPSY SO TARGETING GLIA ITSELF MAY BE ACTUALLY A VERY PROMISING WAY TO CURE NEUROLOGICAL DISORDERS. SO FARP THE BRAIN INITIATIVE FUNDED RESEARCH THAT REALLY HELPED THE GLIAL FIELD BUT IN A MORE INDIRECT WAY AND I'M HOPING THAT IN THE NEXT FIVE YEARS, THERE WILL BE MORE INITIATIVES WITHIN THE INITIATIVE TO TARGET GLIAL CELLS AND I'M HAPPY TO SAY THAT THE BRAIN INITIATIVE THIS YEAR STARTED A PROGRAM TOOLS TO TARGET, IDENTIFY AND CORRECT NON NEURONAL CRESMS IN THE BRAIN, AND I THINK THIS IS FANTASTIC AND I HOPE THIS WILL BE SOMETHING THAT THEY WILL CONTINUE IN DIFFERENT ROUNDS TO FUND, AND I'M ALSO VERY EXCITED BECAUSE A GRANT FROM ILAB AND MY COLLABORATOR SCUT SUDDERSINGLY'S LAB WAS AWARDED ACTUALLY YESTERDAY, SO VERY FRESH, AND WE ARE AIMING TO USE SOME OF THE VERY CUTTING-EDGE PROTEOMIC TECHNIQUES THAT DR. YATES MENTIONED ABOUT TO REALLY HONE IN ON THE CONNECTIONS THAT THE ASTROCYTES MAKE DIRECTLY WITH THE DIFFERENT ELEMENTS OF THE SYNAPSE AND HOW THAT GOES BACK AND USES GENOME EDITING STRATEGIES TO TEST THEIR FUNCTIONAL SEQUENCES OS SYNAPTIC CIRCUITS. AND WITH THAT, I WOULD LIKE TO THANK YOU ALL, AND IF I HAVE ANY TIME LEFT, ISLAND BE HAPPY TO TAKE QUESTIONS. THANK YOU. [APPLAUSE] >> FOR THE SAKE OF TIME, WE'LL COME BACK TO THE QUESTIONS AT THE END. OUR LAST SPEAKER BY NO MEANS THE LEAST IS NAT HEINTZ WHO WILL TALK ABOUT SOME OF HIS WORK. HEINTZ WELL, I THINK I. >> DR. HEINTZ: WELL, I THINK I MIGHT BE THE ONLY ONE TO CRITICIZE A LITTLE BIT WHAT'S HAPPENED, BUT VERY GENTLY. I'VE BEEN STUFFED DID IING CELL TYPES IN THE CNS FOR ABOUT 20 YEARS, BEEN VERY FASCINATED WITH THEM, AND IT'S BEEN POSSIBLE FOR QUITE SOME TIME TO STUDY THEM IN A LOT OF DETAIL BOTH BILL COMMON ATORIAL AND KNOCK-OUT TECHNIQUES, SOME BEAUTIFUL DISCOVERIES HAVE BEEN MADE. I WOULD SAY THE BRAIN INITIATIVE FOR GENETIC TARGETING HAS BEEN INCREDIBLY IMPORTANT. YOU KNOW, THE DEVELOPMENT OF SORT OF NEW CAPABILITIES, LESS EXPENSIVE AND FASTER TECHNIQUES FOR ACTUALLY GENETICALLY TARGET ING CELLS, AND THEN VIRAL METHODS THAT ARE REALLY ONLY IN THEIR INFANCY, THERE'S ONLY A FEW CASES WHERE CELL-SPECIFIC VIRUSES HAVE BEEN ACTUALLY GENERATED, BUT THERE'S A LOT OF INTEREST IN THAT BECAUSE WE WOULD LIKE TO GO TO OTHER ANIMAL SPECIES. THERE ARE ALSO MANY TOOLS FOR CHARACTERIZING ACTUALLY WHAT CELLS EXPRESS, WHICH CAN TELL YOU A GREAT DEAL ABOUT HOW THEY FUNCTION. THE FIRST ONES CAME OUT, GAVE US COMPREHENSIVE LOOKS AT THE PROFILES OF CELLS. SO WE KNOW, FOR EXAMPLE, FROM CHARACTERIZING SPECIFIC CELL TYPES THAT EACH CELL EXPRESSES BETWEEN 10 AND 12,000 GENES. THE THEY ARE VERY FINE-TUNED, THE GENES THAT ARE SPECIFICALLY EXPRESSED IN A CELL TYPE CAN BE OF ANY NATURE. SO IT'S NOT JUST ION CHANNELS AND TRANSCRIPTION FACTORS. MORE RECENTLY, SINGLE CELL METHODS HAVE COME OUT. THESE ARE REALLY VERY NICE IN THAT THEY'RE UNBIASED, THEY'RE VERY HIGH THROUGHPUT, THEY'RE PRETTY CHEAP, THEY'RE VERY POPULAR, THEY GIVE YOU SEQUENCE THAT I WOULD CONSIDER MORE OF A SURVEY THAN AN IN DEPTH CHARACTERIZATION OF A CELL. THE DATA ARE SHALLOW AND NOT COMPREHENSIVE, BUT THEY'RE EXTREMELY IMPORTANT FOR DISCOVERY-BASED CERT REASONS, FOR EXAMPLE, TRYING TO CHARACTERIZE ALL CELL TYPES IN A TISSUE. THE THERE ARE BOTH BULK POPULATION METHODS AND SINGLE CELL METHODS FOR EPIGENETIC PROFILING, SO CHIP STUDIES, METHYLATION STUDIES, HMC STUDIES I WOULD SAY IN THIS CASE, THE POPULATION-BASED METHODOLOGY IS VERY WELL DEVELOPED, JEREMY NATH ANS HAS PUBLISHED BEAUTIFUL PAPERS ON THIS. THE SINGLE CELL METHODS ARE MUCH LESS WELL DEVELOPED THAN THEY ARE FOR TRANSCRIPTIONAL PROFILING. SO IF YOU'RE REALLY INTERESTED IN THE DETAILS OF WHAT HAPPENS TO A PARTICULAR GENE AT A PARTICULAR TIME IN A PARTICULAR ANIMAL, THE SINGLE CELL EPIGENETIC METHODS ARE DIFFICULT YOU, SOME OF THEM ARE VERY ACCURATE, ATAC TENDS TO BE VERY GOOD, BUT THE METHYLATION-BASED ANALYSIS I PERSONALLY DON'T THINK IS UP TO SNUFF YET. NOW, WHAT I SAID ABOUT COMPREHENSIVE PROFILING IS IMPORTANT BECAUSE I'M INTERESTED IN EVERY SMALL DETAIL OF HOW NEURONS FUNCTION, AND WHEN YOU DO POPULATION BASE BY SORTING OR HOWEVER YOU'RE GOING TO DO IT, YOU CAN SEE ALL 10,000 GENES EXPRESSED IN A PARTICULAR CELL TYPE. SINGLE CELL METHODS GIVE YOU ABOUT 5,000 OR SO IF YOU'RE LUCKY. SO WHAT YOU SEE IS ACTUALLY A LOT OF VERY INTERESTING THINGS, IMPORTANT DISCOVERIES ARE MADE, BUT YOU DON'T SEE THE ENTIRE PHENOTYPE OF THE CELL IN ANNAL TERRED CONDITION. -- IN AN ALTERED CONDITION. WHAT I WOULD SAY THE BOTTOM LINES ARE IS THAT THIS IS A VERY RAPIDLY MOVING FIELD. BRAIN HAS HAD A REALLY IMPORTANT IMPACT ON IT. AND I THINK THAT THERE'S NO QUESTION THAT WE WILL GET AN INTEGRATED VIEW OF WHAT CELLS LOOK LIKE AND HOW THEY ACT IN DIFFERENT CONDITIONS IN THE NEXT FEW YEARS IN GENETICALLY ACCESSIBLE ANIMALS OR IN EXPERIMENTAL ANIMALS. WHAT ARE THE CHALLENGES? DATA QUALITY IS A BIG CHALLENGE. SO THESE PAPERS ARE E TREEMLY DIFFICULT TO -- EXTREMELY DIFFICULT TO REVIEW. DOWNLOADING ALL THE DATA IN A PRIMARY MANUSCRIPT IS ALMOST IMPOSSIBLE IN THE TIME YOU'RE GIVEN, AND MISTAKES ARE MADE. SO I THINK THIS IS AN IMPORTANT ISSUE. DATA ANALYSIS IS ALSO IMPORTANT. THE INFORMATICS PROGRAMS RUN ON THE SAME BASIC PRINCIPLES, SOME OF US DON'T THINK THAT THEY ARE ACTUALLY DESIGNED PERFECTLY, SO THAT COULD TAKE SOME WORK. AND THEN BIOLOGICAL INTERPRETATION, I THINK WE'RE MISSING THE OPPORTUNITY TO HAR NEMS THE BIOLOGICAL KNOWLEDGE OF OUR ENTIRE COMMUNITY BECAUSE THESE DATA ARE DIFFICULT TO ACCESS. SO WHAT I MEAN IS ANYBODY IN THIS ROOM SHOULD BE ABLE TO GO INTO ANY OF THESE DATASETS AND WITH AN ALREADY ESTABLISHED WEBSITE WITH ANALYTICAL TOOLS GO IN AND COMPARE TWO SETS OF DATA. I DON'T SEE ANY IMPEDIMENT TO THAT, BUT IT'S ALMOST IMPOSSIBLE TO DO UNLESS YOU'RE VERY WELL VERSED IN INFORMATICS RIGHT NOW. WHAT ARE THE CONCEPTUAL? WELL, WE DON'T KNOW WHAT I ACELL TYPE IS, NO ONE AGREES, MY OPINION IS QUITE DIFFERENT THAN MOST. THE STATUS STATUS QUO IS NOT GOOD ENOUGH, AS FAR AS I CAN TELL. IF WE JUST KEEP GOING WITH THE SAME METHODOLOGIES AND KEEP APPLYING THEM AT LARGER, LARGER SCALE, WE'LL MISS A LOT OF DETAIL THAT'S VERY IMPORTANT, AND I DON'T THINK THE HUMAN BRAIN PROBLEM IS JUST A PROBLEM OF SCALE. I'M WORKING ON IT ACTIVELY. IF YOU WANT TO STUDY CELL TYPES IN THE HUMAN BRAIN, IT'S A DIFFICULT ISSUE, AND I THINK IT CAN BE DONE, BUT IT'S GOING TO TAKE SOME MORE DEVELOPMENT. AND THEN THE LAST THING I WOULD LIKE TO TALK ABOUT IS THERAPEUTIC DEVELOPMENT BECAUSE I HAVEN'T HEARD IT DISCUSSED, I'M VERY INTERESTED IN IT, I DECIDED TO SPEND THE LASTS, YOU KNOW, EPIC OF MY LIFE TRYING TO TRANSLATE OUR KNOWLEDGE INTO THERAPIES, WHAT I MEAN BY THIS IS CAN WE DEVELOP CIRCUIT THERAPIES AND CAN WE DESIGN DISEASE MODIFYING THERAPIES, I'VE FOUND TWOD COMPANIES FOR THIS, I'LL GIVE YOU ONE EXAMPLE FROM ONE OF THEM THAT I THINK IS ILLUSTRATIVE. OKAY. IN MY THINKING, CIRCUITS ARE PERFECT FOR THERAPEUTIC DEVELOPMENT BECAUSE THEY ARE COMPLEX AND THEY CAN BE MODULATED. THERE ARE MANY NODES FOR MODULATION, SO IF WE KNEW HOW TO TAKE ADVANTAGE OF THAT WITH SOME KIND OF INTERVENTION, WE COULD DO SOMETHING THAT'S BENEFICIAL FOR PARENTS -- FOR PATIENTS. NOW, PROOF OF CONCEPT IS THERE ALREADY WITH DEEP BRAIN STIMULATION, WHICH HAS A VERY IMPORTANT THERAPEUTIC ROLE ALREADY. THESE ELECTRODES ARE THREADED IN WE DON'T ACTUALLY KNOW WHAT THEY DO, BUT THEY DO HAVE A STRONG CLINICAL IMPACT. SO I'M GOING TO TELL YOU ONE STORY THAT WE STARTED A LONG TIME AGO THAT'S IN THE CLINIC NOW. IT'S ABOUT IMPROVING THERAPY FOR PARKINSON'S DISEASE. SO WHAT'S KNOWN FROM EXPERIMENTAL ANIMALS IS THAT WHEN THE SUWSTANTION NIAGRA DIES AND YOU GIVE PATIENTS L DOUGH PA IT WORKS VERY BEAUTIFULLY FOR THE FIRST FOUR OR FIVE YEARS AND THEN YOU GET LDOPA INDUPSED TOXICITY AND DYSKINESIA, THAT'S THOUGHT TO ARISE IN EXPERIMENTAL ANIMALS FROM THE INDIRECT PATHWAY DOPAMINE NEURONS AND THE THERAPY IS PRIMARILY DUE TO THE DIRECT PATHWAY NERVES, SO WHAT WE DID, AND THIS WAS QUITE SOME TIME AGO, IS PROFILE THESE TWO CELL TYPES AND LOOK FOR DRUG TARGETS L TARGETS THAT WOULD BE SPECIFIC AND WE WERE VERY LUCKY, WE FOUND ONE THAT WAS VERY SPECIFIC FOR THE THERAPEUTIC ARM OF THE PATHWAY, IT'S THE ONLY PLACE THAT'S EXPRESSED IN THE WHOLE BRAIN, AND THIS HAS BEEN DRUTIOND, THE FIRST PATIENTS ARE RECEIVING THIS -- DRUGGED, AND THE FIRST PATIENTS ARE RECEIVING THIS THING NOW. I THINK IT'S IMPORTANT BECAUSE IT SAYS YOU CAN GENERATE INTEREST FROM PHARMA FOR DOING NOVEL THERAPIES IF YOU HAVE A GOOD ENOUGH THERAPEUTIC HYPOTHESIS, AND THIS DRUG WORKS VERY NICELY IN EXPERIMENTAL ANIMALS IN MONKEYS. I HAVE NO IDEA WHETHER IT WILL WORK IN HUMANS, BUT IF IT DOES, IT WOULD BE A RATIONALLY DESIGNED CIRCUIT THERAPY THAT'S IMPORTANT. SO WHAT I THINK IS WE'VE BROUGHT THE FIELD THROUGH ALL THESE NEW METHODS TO THE POINT WHERE WE CAN DESIGN INTERVENTIONS, ANTI-S ENSOLIGOS DRUGS OR VIRUSES THAT COULD BE USEFUL AND MY PROBLEM THEN WAS OKAY, WHAT'S MISSING, IT WE CAN DO THAT, WHAT IS REALLY MISSING? AND I JUST WANT TO FINISH WITH A FEW SLIDES ON HUMAN BRAIN BECAUSE I THINK IT'S REALLY INSTRUCTIVE. SO WE STUDY MOUSE BRAIN UNTIL ABOUT THREE OR FOUR YEARS AGO, BUT OBVIOUSLY MOUSE BRAIN IS MOUSE BRAIN. I WANTED TO START TO STUDY LATE ONSET PRODROMAL PHASES OF HUMAN DISEASE. THAT'S NOT EASY BECAUSE GETTING THE TISSUE ACTUALLY IS DIFFICULT , BUT ALSO THE MOLECULAR TECHNIQUES WERE NOT UP TO SNUFF, SO WHAT SHUD DID IS MODIFY WHAT PEOPLE HAVE USED FOR YEARS, WHICH IS FACT SORTING, BUT ADD A FEATURE WHERE WE COULD FACT SORT FOR SPECIFIC CELL TYPES FROM POSTMORTEM BRAIN AND WHAT THEY DEMONSTRATED WAS THAT WE CAN GET ABSOLUTELY BEAUTIFUL CELL SPECIFIC PROFILES FROM ANY CELL TYPE THAT WE SORT THE AND THEY ARE EXTREMELY REPRODUCIBLE BETWEEN BRAINS. SO THESE THREE CELL TYPES, 16 PEOPLE FOR EACH CELL TYPE, THE DATA LOOK ALMOST EXACTLY THE SAME, IT'S ALSO VERY DEEP PROFILE SO YOU GET 15,000 GENES OR 12,000 GENES FROM EACH CELL TYPE. SO THIS IS IMPORTANT BECAUSE POSTMORTEM HUMAN BRAIN IS AVAILABLE AND DPT CAT IS IT GOOD , BECAUSE THESE ARE NUCLEAR RNA, THE DATA IS VERY NICE, YOU CAN ASK QUESTIONS LIKE HOW DIFFERENT ARE CELL TYPES BETWEEN HUMAN AND MOUSE, AND THE ANSWER IS YOU WOULD RECOGNIZE A HUMAN CELL TYPE FROM A MOUSE PROFILE BUT THEY ARE NOT IDENTICAL, SO THERE ARE ABOUT 1550 GENES THAT ARE COMPLETELY ON IN HUMAN CELL TYPES OF ANY SORT THAT ARE NOT ON IN MOUSE, AND THIS IS TRUE FOR ALL THE CELL TYPES THAT WE'VE CHARACTERIZED. WHAT DOES THAT MEAN? THAT MEANS THAT THE CELLS FUNCTION ALMOST THE SAME BUT NOT EXACTLY THE SAME. AND IF YOU'RE TRYING TO DEVELOP THERAPIES, THIS IS IMPORTANT. THE SECOND THING WE FOUND IS THAT IN NORMAL CONTROL BRAINS, SO HERE IS DATA FROM A BUNCH OF GENES FROM ONE CELL TYPE, 16 PEOPLE, THREE OF THEM HAD THIS MOLECULAR SIGNATURE THAT WAS JUST VERY STRANGE, IT'S CLEARLY AN INDUCED PATHWAY, AND WE DON'T KNOW WHAT IT IS BECAUSE IT EITHER HAPPENED DURING THE DEATH OF THESE PEOPLE OR THEY HAD IT BUT THERE'S NOTHING IN THEIR CLINICAL CHARTS. THE POINT I'M TRYING TO MAKE IS WE HAVE TO CHARACTERIZE A VARIETY OF DIFFERENT NORMAL CONTROLS BEFORE WE START TO LEARN ANYTHING ABOUT DISEASE. SO WHAT I LEAVE YOU WITH IS THAT , YOU KNOW, I THINK IT'S ESSENTIAL TO HAVE VERY HIGH QUAWMENT REPRODUCIBLE DATA. -- QUALITY REPRODUCIBLE DATA, IT'S POSSIBLE TO GET IT, AND THEN I THINK THE BRAIN INITIATIVE SHOULD THINK ABOUT PUBLIC/PRIVATE PARTNERSHIPS WHERE DEVELOPMENT OF NEW THERAPIES BECOMES PART OF THE PROGRAM BECAUSE ACTUALLY RAISING THE MONEY TO DO THIS IS NOT EASY , IT TAKES A LOT OF EFFORT, BUT IF IT COULD BE TAKEN TO ONE STEP FURTHER THAN WE'RE ABLE TO BEFORE WE RAISE THE MONEY, I THINK IT WOULD BE VERY PRODUCTIVE. SO I'M GOING TO END THERE, AND I'M HEACH TO TAIL YOUR QUESTIONS -- AND I' M HAPPY TO TAKE YOUR QUESTIONS. [APPLAUSE] >> JUST QUICKLY, YOU MENTIONED TRA EXTENDING TO HUMANS IS MORE THAN JUST AN ISSUE OF SCALE. CAN YOU KIND OF BRIEFLY ELABORATE ON THAT? >> DR. HEINTZ: SO THE HUMAN BRAIN IS SO LARGE THAT IT'S BOTH A DIFFICULTY AND AN OPPORTUNITY. THE OPPORTUNITY IS THAT THERE ARE SO MANY CELLS IN EACH REGION THAT IF YOU WANT TO DO POPULATION-BASED PROFILING OF A SPECIFIC CELL TYPE, IT'S PRETTY SIMPLE. THE DIFFICULTY IS THAT IF YOU WANTED TO, FOR EXAMPLE, CHARACTERIZE A RARE CELL TYPE ACROSS THE HUMAN CORTEX, BY SINGLE CELL, FOR EXAMPLE, YOU WOULD BE COLLECTING HUGE, HUGE AMOUNTS OF DATA THAT YOU'RE NOT INTERESTED IN TO GET TO THAT ONE CELL TYPE. SO I THINK THERE'S A ROLE FOR SINGLE CELL ANALYSIS FOR CHARACTERIZATION OF SORT OF THE COMPLEXITY OF THE HUMAN BRAIN, BUT IT WON'T SOLVE THE PROBLEM OF ANALYZING IN DETAIL WHAT HAPPENS TO A CELL TYPE IN ANY STRUCTURE, AT LEAST I DON'T THINK, IN A DISEASE STATE. >> [AWAY FROM MIC] >> Dr. Monteggia: SOLT WE'VE HEARD A VERY DYNAMIC GROUP OF SPEAKERS ON A RANGE OF TOPICS, VERY COMPLEMENTARY IN MANY WAYS BUT ALSO ARE WITH VERY DIFFERENT PERSPECTIVES, WHICH IS REALLY COMING IN FROM DIFFERENT ANGLES AND I THINK PROVIDING A NUMBER OF DIFFERENT IMPORTANT THE POINTS TO CONSIDER. I REALLY WANT TO COME BACK TO SEVERAL POINTS, BUT I WANT TO START WITH THIS IDEA OF CELL SPECIFICITY, WHAT NATE MENTIONED , AND REALLY THIS IDEA WHICH I REALLY GRAPPLED WITH WITH HOW DO WE THINK ABOUT CELL SPECIFICITY AS YOU MENTIONED BETWEEN SPECIES BUT WITH DISEASE STATES, TO ME I HAVE A HARD TIME , IT'S DIFFICULT TO THINK, A CELL ISN'T GOING TO GO LIVE IN ISOLATION, AND IF THERE'S MANY THINGS GOING ON AROUND IT, NEURODEGENERATIVE DISORDERS OR PERHAPS AN INDIVIDUAL WITH A DEBILITATING PSYCHIATRIC ASPECT, IT'S REALLY TO KNOW WHEN THAT TIME COURSE COMES ON. HOW DO WE REALLY START TO THE DECIPHER THIS INFORMATION? HOW DO WE START TO THINK ABOUT IT? BECAUSE IT'S VERY FUNDAMENTAL FOR STARTING TO THEN GO TO QUESTIONS MAYBE OF CIRCUITRY AND HOW ARE WE GOING TO INTERVENE, WHICH I DO WANT TO GET INTO THE QUESTIONS OF CIRCUITRY, WHICH GUL MENTIONED AND THEN ALSO CAGL A OF NONNEURONAL CELLS AND ALSO HOW PROTEINS FIT INTO THIS. >> I WOULD SAY THAT WE UNDER ESTIMATE, I UNDERESTIMATED ORIGINALLY THE CLINICAL COMMUNITY HOW DEDICATED THEY ARE TO FINDING THE VERY EARLIEST CUE S TO THESE DISEASES HAS ARE PRODROMAL FOR THE CLIN -- BUT THE CLINICAL PROBLEM IS NOT YET FULLY SHOWN AND ALSO THE COMMITMENT OF GRADE BANKS TO EVEN GET DONORS, EVEN IF THEY DIE EARLY, SO MATERIAL IS DIFFICULT TO GET, BUT THE IF IT'S WELL CHARACTERIZED BY THE PEOPLE STUDYING THE DISEASE, I THINK YOU CAN GET THAT, AND THEN YOU CAN ASK, TO ONE KNOWS, BUT ARE THERE MOLECULAR CHANGES THAT OCCUR IN PRODROMAL DISEASE THAT ARE INSTRUCTIVE. I THINK THERE WILL BE BECAUSE IN ANY ANIMAL MODEL ANYONE HAS EVER LOOKED AT, THE ANSWER IS THAT IS TRUE. >> Dr. Monteggia: AND HOW DO YOU THINK YOU'RE GOING TO GET A QUESTION THAT IS INSTRUCTIVE? >> Dr. Heintz: SO WHAT'S CAUSATIVE VERSUS WHAT'S A RESPONSE? MONT MOPT YES. >> Dr. Heintz: SO THIS IS THE AGE OLD QUESTION, AND I THINK IF YOU ASKED 40 PEOPLE TOO LOOK AT A LIST OF RESPONDING GENES, YOU WOULD PROBABLY GET 40 DIFFERENT ANSWERS ABOUT WHAT TO DO. MY OWN VIEW IS I DON'T KNOW WHAT WOULD BE INSTRUCTIVE, BUT IF WE GET THE RIGHT PEOPLE IN A ROOM WITH LOTS OF DIFFERENT POINTS OF VIEW TO VIEW THESE DATA AND THEN HASH THROUGH THEM VERY SERIOUSLY BOTH CLINICAL PEOPLE, PHARMA PEOPLE, AND EDUCATED NEUROSCIENTISTS, WE'RE IN A MUCH BETTER POSITION THAN WE ARE WITHOUT HAVING THIS INFORMATION. SO SINCE NO ONE HAS EVER SUCCEEDED, I CAN'T TELL YOU THAT I THINK I'LL SUCCEED, BUT I THINK PEOPLE TOGETHER CAN SUCCEED WITH THIS ADDITIONAL INFORMATION. >> IF WE THINK ABOUT MENTAL DISORDERS AS A YOU CYCLIC DISEASE, YOU MENTION MED THE FOR EXAMPLE OF PARKINSON'S, BUT PARKINSON'S WE HAVE SOME HINTS OF WHAT TO LOOK AT. IT'S NOT CLEAR WE KNOW WHAT TO LOOK AT IN SCHIZOPHRENIA OR DEPRESSION AND OTHER ILLNESSES, SO HOW DO WE GO FROM THE APPROACH YOU'RE PROPOSING OF LOOKING AT INDIVIDUAL CELLS AND HOW THEY DIFFER? WHERE DO YOU LOOK? >> Dr. Heintz: SO THIS IS WHAT OUR FIELD IS DOING RIGHT NOW. ALL OF OPTOGENETICS AND IN- CIRCUIT MAPPING GIVES US INSIGHTS INTO SPECIFIC CIRCUITS AND SPECIFIC BEHAVIORS. DEEP BRAIN STIMULATION UNLESS OTHER INTERVENTIONS IN HUMAN BRAINS ALSO PROVIDE A LARGE AMOUNT OF INFORMATION. SO MY OWN VIEW IS INSTEAD OF WAITING UNTIL WE KNOW HOW THE, QUOTE, UNQUOTE, BRAIN WORKS, LET'S START TO STUDY THINGS THAT ARE WRONG WITH IT IN THE CONTEXT OF THIS EXPLODING KNOWLEDGE OF CIRCUITRY AND SEE IT WE CAN MAKE SOME ADVANCES. AND I DON'T THINK IT'S GOING TO BE ONLY PHARMA AND, YOU KNOW, CONVENTIONAL SMALL MOLECULE DRUGS, BIOLOGICS, VIRUSES, ANTI- SENSE INTERVENTIONS ARE ALL GOING TO BE IMPORTANT. BUT I DON'T SEE A REASON WHY IT SHOULDN'T BE STARTED ON THE CIRCUITS WE KNOW SOMETHING ABOUT ALREADY. >> JUST SORT OF AS A SIDE NOTE, I AGREE WITH YOU THIS THEORY. I THINK ONE ISSUE THAT COMES INTO IT IS APPROACHING IT FROM A VERY DIFFERENT WAY, FOR EXAMPLE, FROM BEHAVIOR, HOW DO WE LOOK AT AN ANIMAL AND KNOW IF IT'S DEPRESSED OR SCHIZOPHRENIC OR WHATEVER? OBVIOUSLY PEOPLE HAVE GRAPPLED WITH THIS, THERE'S A LOT OF QUESTIONS. EVERY TIME I READ GRAINT ON DEPRESSION, I ALWAYS GET ASKED, ARE YOU DEVELOPING BETTER ANIMAL MODEL OS DERETION? WOULDN'T WE ALL LIKE THAT. YOU CAN DEVELOP PARADIGMS, IT'S THE SAME APPROACHES, USE OF TECHNOLOGY, ASKING A SLIGHTLY DIFFERENT QUESTION, IT REALLY KIND OF COMES INTO THE QUESTION, THOUGH, OF IF THE BEHAVIOR WE'RE QUESTIONING IN TERMS OF WHAT IT'S REPRESENTING SHES IT'S HARD TO KNOW WHAT THE CIRCUITRY IS TELLING US, BUT AGAIN, THAT DOESN'T NECESSARILY REFLECT WHAT'S HOT OR HOW THE FIELD MAY BE MOVING FORWARD IN DIFFERENT WAYS. >> Dr. Heintz: I GUESS I WOULD RESPOND BY SAYING NO ONE KNOWS THE ANSWER YET, AND YOU NEED A LOT OF VOICES IN THE ROOM IN ORDER TO APPROACH THESE THINGS. AND THE DIFFICULTY IS RAISING MONEY TO DO THIS HAS BEEN, IN MY EXPERIENCE, NOT POSSIBLE YET FROM NIH, ALTHOUGH I THINK IT'S GOING TO HAPPEN, AND FOR ME IT WAS EASIER TO GO AND RAISE THE MONEY SOMEWHERE ELSE. I DON'T THINK THAT THAT'S THE RIGHT MODEL. I THINK THE RIGHT MODEL IS TO HAVE A CONSORTIA OF PEOPLE THAT ARE VERY CLOSELY INTERESTED AND ALSO CARE ABOUT DATA QUALITY, REALLY DEEPLY CARE ABOUT IT, THAN HAVE LOTS OF OTHER PEOPLE VIEW THE DATA. >> SO I HAVE A QUESTION THAT RELATES TO WHAT JOHN AND CAGLA TALKED ABOUT. IT'S CLEAR THAT THE FIELD OF NEUROSCIENCE IS STARTING TO ADOPT GEOMIC TECHNOLOGIES FOR A LOT OF REASONS, AND I'M WONDERING WHERE THE FIELD OF PROTEOMICS STANDARDS NOW IN TERMS OF STANDARDIZING SOME OF THE APPROACHES BOTH ON THE DATA ACQUISITION SIDE, DATA DEPENDENT ACQUISITION, DATA INDEPENDENT ACQUISITION, THERE'S SUCH A VARIETY OF METHODS AND NEW METHODS ARE COMING ONLINE AS WE SPEAK, SO HOW DO WE TRY TO STANDARDIZE BOTH DATA ACQUISITION AND ANALYTICS IN ORDER TO MAKE PROTEOMICS AM DO BELIEVE A LOT OF NEUROSCIENCE QUESTIONS. >> Dr. Yates: SO YOU WANT TO KILL INNOVATION S TWHAPS YOU'RE SAYING? >> I DIDN'T SAY THAT. I WANT TO HEAR YOUR VOICE. >> Dr. Yates: STANDARD ZA I GUESS IS USUALLY ABOUT STOPPING INNOVATION. >> BUT IS THERE A SENSE OF SORT OF WHICH ARE THE RIGHT APPROACHES FOR THE RIGHT KIND OF QUESTIONS? >> Dr. Yates: NO. THE APPROACHES ARE VERY FIT FOR PURPOSE. IT THE DEPENDS ON WHAT YOU WANT TO DO. DIA, FOR EXAMPLE, DATA INDEPENDENT ACQUISITION HAS BECOME VERY POPULAR FOR BIO MARKER TYPES OF STRATEGIES BECAUSE THEY CLAIM THAT THE DATA IS MORE REPRODUCIBLE, FEWER MISSING VALUES. AND THAT REALLY HAS TO DO WITH HOW THEY DID THE DATA ANALYSIS, NOT REALM THE DATA ACQUISITION STRATEGY. SO ONE OF THE GREAT THINGS ABOUT PROTOTHE YOA MIX IS THAT IT'S A RAPIDLY EVOLVING FIELD. ONE OF THE BAD THINGS ABOUT PROTEOMICS IS THAT IT'S A RAPIDLY EVOLVING FIELD. SO IT'S TOUGH TO KEEP UP. WE HAVE TO GET VERY EXPENSIVE INSTRUMENTS IN ORDER TO KEEP UP, SO IRS THAT NEW INSTRUMENTS THAT ARE COMING OUT EVERY TWO YEARS, AND THAT HAS A TENDENCY TO YOU CHANGE THE QUALITY OF THE DATA, THE TYPE OF DATA YOU'RE GETTING AND SO IT'S VERY DIFFICULT TO STANDARDIZE, AND THERE ARE A WIDE RANGE OF STRATEGIES FOR DOING DATA ANALYSIS. THE CP TACK PROGRAM HAS FIVE DATA GENERATION CENTERS AND FIVE DATA ANALYSIS CENTERS. I THINK THERE'S GOING TO BE CHAOS THERE, BUT THAT'S WHAT THEY DECIDED TO DO. SO THE BEST THING TO DO IF YOU WANT TO DO PROTEOMICS IS WORK WITH AN EXPERT, HIRE AN EXPERT, DO SOMETHING LIKE THAT, AND SETTLE ON A STRATEGY AND GO FORWARD. >> JUST TO ADD TO THAT, AND I AGREE, I THINK, I MEAN, I'M NOT AN EXPERT IN PROTEOMICS, BUT I AM WORKING WITH EXPERTS IN PROTEOMICS, AND WHAT I FEEL LIKE , WE HAVE TO HAVE TEAMS WHERE PROTEOMICS IS TEAMED WITH SCIENTISTS WHO CAN GO BACK AND VALIDATE OR DISCARD WHAT HAS BEEN PULLED OUT AS HITS AND VERIFY THEIR FUNCTIONAL RELEVANCE BECAUSE I THINK THE PROTEOMICS METHODS ARE GOING TO REALLY DETECT AS MANY MOLECULES AS POSSIBLE, BUT THAT WOULD ALSO BRING UP A LOT OF NOISE. SO WE NEED SOME POST SCREENS WHERE WE CAN GO AFTER THE TOP CANDIDATES, AND VALIDATE THEM OR DISCARD THEM FROM A FUNCTIONAL POINT OF VIEW. >> JOHN, YOU MENTIONED TWO MOON SHOTS, AND CATHERINE POKED YOU A LITTLE BIT AT THE FIRST ONE AND I WAS JUST GOING TO POKE YOU AT THE SECOND ONE, THIS IDENTIFY EVERY LOG-IN FOR EVERY RECEPTOR. AS A MOONSHOT, WHERE DO WE STAND DO YOU FEEL LIKE WE HAVE THE METHODS AND THAT WE'RE READY TO LIKE TURN THE CRANK, OR, YOU KNOW, DO WE NEED TO DEVELOP A NEW CLASS OF METHODS BUT YOU CAN CONCEIVE THAT WHAT THOSE WOULD LOOK LIKE? IS THERE A MOONSHOT OR A MARS SHOT OR -- >> I THINK IT'S PROBABLY JUST MOON, BECAUSE DOING PROTEIN- PROTEIN INTERACTIONS ARE WELL ESTABLISHED METHODS, THERE'S ANOTHER EMERGING STRATEGY, THERE WAS A PAPER IN CELL, A PAPER IN NATURE DOING THIS FROM ED MARCOT'S LAB AND EMILY'S LAB USING PCP, PROTEIN CORRELATION PROFILING METHOD, THAT'S A WAY TO TRY TO GET AT PROTEIN COMPLEX INSPECTS A VERY FAST MANNER. SO THAT OPENS UP THE OPPORTUNITY LOOK AT THE DYNAMICS OF PROTEIN- PROTEIN INTERACTIONS. IT'S NOT IN SITU, BUT IT GETS YOU THAT INFORMATION. AND THEN YOU CAN FOLLOW THAT UP WITH FOLLOW-UP-SPECIFIC THINGS WITH IMAGING METHODS TO ESTABLISH THEM IN SITU. THE OTHER THING THAT ED IS DOING THAT'S REALLY CLEVER IS HE'S TAKING FRACTIONS FROM THAT, CLAIG THEM OUT AND DOING QUIOME ON PROTEIN COMPLEXES, TRYING TO COMBINE THE COMPONENTS OF COMPLEXES AS WELL AS STRUCTURE. THE SECOND STRATEGY, THE LIGAND STRATEGY I THINK REALLY IS JUST THE METHOD IS THERE, WE USED THAT METHOD WITH GOSHA'S LAB AND I THINK WE GOT LIKE TWO OR THREE , MAYBE THREE NEURON PAPERS OUTS OF IT, GOT THE COVER FOR ONE OF THEM. AND IT'S JUST A QUESTION OF SCALING THAT DOWN BECAUSE RIGHT NOW THE WAY THEY'RE DOING IT, THE WAY WE DID IT IS JUST TOO LARGE SCALE. I THINK THERE ARE REALLY GREAT OPPORTUNITIES TO SCALE THAT DOWN SO THAT YOU CAN THINK ABOUT DOING IT ON A LARGE SCALE. >> I'M SORRY. ALL RIGHT. SO I WANTED TO RETURN TO THIS ISSUE WITH FACE VALIDITY, SO GUL RAIMSED A REALLY INTERESTING POINT, WE CAN'T MODEL A MIND DEFICIT IN A ANIMAL THAT NEVER IT DEVELOPED ONE, SO IF THE CONTROL MODELS DON'T EXHIBIT THE PHENE TIP WITH DIRECT RELEVANCE TO THE HUMAN CONDITION, I THINK THE PROVOCATIVE QUESTION, YOU CAN USE ALL THE FANCY TOYS WITH CELL BUSTING AND CIRCUITING PROFILING BUT WHAT'S THING TRANSLATIONAL UTILITY IF WE'RE NOT NECESSARILY MODELING THINGS RIGHT OR DON'T HAVE REFINED ANIMAL MODELS? >> I MEAN, IT'S A HARD PROBLEM, AND, YOU KNOW, I'VE DEFINITELY WRITTEN SOME CRAZY GRANTS ASKING FOUNDATIONS TO FUND OUR EFFORTS TO COME UP WITH A THEORY OF MIND -LIKE TASKS IN MICE, AND I ACTUALLY MAKE THE GRADUATE STUDENTS DESIGN ONE EVERY YEAR FOR THEIR FINAL EXAM, AND THEY COME UP WITH SOME REALLY CREATIVE STUFF, BUT MOST OF IT WE'VE TRIED ASK WE JUST CAN'T DEMONSTRATE IT IN A MOUSE. BUT ON THE OTHER HAND, IF I THINK ABOUT THEORY OF MIND IN PARTICULAR, THERE ARE OTHER IDEAS THAT THE DEFICIT THAT WE SEE IS THAT THEORY OF MIND DEFICIT IN AUTISM IS ACTUALLY SECONDARY TO A MORE PRIMARY PROBLEM WITH SOCIAL REWARD, SO THAT CIRCUIT WE THINK IS CONSERVED IN MICE. SO WE MAY HAVE TO DO IT IN BABY STEPS, BUT I DO ALSO THINK YOU THAT THERE'S UTILITY IN LOOKING AT THE DIVERSITY OF THE ANIMAL KINGDOM AND REALLY REALIZING -- I MEAN, I THINK THE BEST HISTORICAL EXAMPLE OF HOW POWERFUL THAT CAN BE IN TERMS OF SOCIAL NEUROSCIENCE IS THE PRAIRIE MOUNTAIN BULL MOUSE STORY. -- VOL. PRAIRIE VOL DO MICE BONDING BEHAVIOR. MICE DON'T. PRAIRIE VOLS DON'T DO COMMUNAL GROUP LIVING, MICE DO COMMUNAL GROUP LIVING. HUMANS DO BOTH AND WE CAN START TO LEARN ABOUT PIECES OF THAT CIRCUITRY FROM THOSE DIFFERENT ANIMALS WHO DO COMPONENTS OF OUR VOL HUMAN REPERTOIRE SO ICHG THAT'S KIND OF A BETTER APPROACH THAN JUST SO I THINK THAT'S KIND OF A BETTER APPROACH THAN JUST FOCUSING ON ONE SPECIES. MODERN TECHNOLOGIES, LIKE CRISPR , IT'S A MYSTERY TO ME OR SOMEBODY WHO WORKS THIS A MOUSE LAB AND YOU'RE NOT GOING OUT AND THINKING ABOUT ANOTHER SPECIES THAT CAN DO SOMETHING COOL THAT YOU HAVEN'T BEEN ABLE TO STUDY AND WHY YOU'RE NOT GOING OUT AND TRYING TO LOOK AT THAT. >> I WANT TO ASK JOHN WHETHER THE MOONSHOTS HE HAS IN MIND MAY BE AN AREA THAT WOULD BE SUITABLE FOR SOMETHING LIKE A BRAIN OBSERVATORY OR A LARGE SCALE EFFORT, GENERALLY WHAT DO PEOPLE THINK ABOUT THOSE UNDER THE BRAIN INITIATIVE? >> Dr. Yates: I DIDN'T GET -- UNDER WHAT? >> THE BRAIN OBSERVATORY, THE STYLE APPROACH TO THE MOONSHOT. THE [AWAY FROM MIC] >> Dr. Yates: I PROPOSED DOING A MUCH SCALED DOWN VERSION OF THIS , JUST LOOK AT 25 PROTEINS ASSOCIATED WITH ALZHEIMER'S DISEASE, GO DO MOUSE MODELS AND HUMAN MODELS AND THE STUDY SECTION THOUGHT THE DATA WAS GOING TO BE A LOT LIKE EPIDEMIO LOGICAL DATA WHERE IT DIDN'T MEAN ANYTHING. SO THERE'S NOT A LOT OF -- THERE'S NOT GENERAL BUY-IN ON THIS KIND OF STRATEGY FOR THINGS I HAVE FOUND THROUGH MY 25 YEARS OF DOING THIS, DOING PROTEOMICS, THAT PROTEIN-PROTEIN INTERACTION DATA IS THE MOST ACTIONABLE DATA THERE ARE HYPOTHESES THAT ARE GENERATED, THERE IS FOLLOW-UP THAT YOU CAN THINK ABOUT. WHEN I DO PROTEIN EXPRESSION ANALYSIS, SOMETIMES YOU'RE JUST TOSSING UP YOUR HANDS, WHAT DO I FOLLOW UP ON? BECAUSE THERE'S TOO MANY THINGS THAT ARE CHANGING. AND PEOPLE KNOW THAT FROM AN RNA EXPRESSION. YOU GET 5,000 THINGS CHANGING SHES YOU KNOW, MCP PLUS MINUS, AND WHAT DO YOU FOLLOW UP ON? >> IS THERE ANYONE ONLINE YOU WHO HAS ANY QUESTION? IF SO, YOU CAN UNMUTE YOURSELVES . >> ARE THERE ANYONE ONLINE WHO WOULD LIKE TOKING SCB A QUESTION PLEASE UNMUTE YOURSELF AND ASK THE QUESTION. >> HUNA IS ONLINE AND SHE HAS UN MUTED HERSELF, BUT I DON'T KNOW IF WE CAN HEAR HER. >> SO THERE ARE LOTS OF WAYS YOU COULD THINK ABOUT DOING PROTEIN- PROTEIN INTERACTIONS. WE'RE DOING IT OUT OF BRAIN TISSUE RIGHT NOW, AND WE'RE DOING IT QUANTITATIVELY AND IT'S WORKING. >> I GUESS MY QUESTION IS MORE, -- [AWAY FROM MIC] >> Dr. Yates: YEAH, I THINK YOU PROBABLY WANT TO DO SOMETHING LIKE THAT, BECAUSE IT'S TAKEN STEVE GIDGY'S LAB TWO YEARS TO DO THE TECH 293. >> SO I HAVE A SORT OF SIMILAR QUESTION BUT RELATED THE TOP GLI AWE. -- RELATED TOP GLIA. IT SEEMS LIKE OVER THE LAST TEN YEARS OR SO, REALLY PEOPLE STUDY ING GLIA HAVE BROUGHT I'VE REVOLUTION ON HOW WE THINK THE INTERACTION BETWEEN GLIA AND NEURON AND THE FUNCTION OF THE& BRAIN THANKS TO GLIA. TO SOME EXTENT AT SOME POINT THERE WILL BE A NEED FOR PEOPLE NOT TO BE JUST GLIA NEUROSCIENTISTS BUT PEOPLE TO INTEGRATE BOTH TYPE OF CELL TYPES IN THEIR CIRCUIT STUDY. WHAT DO YOU THINK THE BEST WAY WOULD BE TO DO THAT? >> Dr. Eroglu: UP BROUGHT AN EXCELLENT POINT, THIS IS ANOTHER PART OF BRAIN INITIATIVE'S ROLE WOULD BE TO BRING PEOPLE FROM OUTSIDE THE GLIA FIELD INTO STUDYING THE GLI YOU A, SO BRINGING IN PEOPLE -- THE GRI A -- THE GLIA, BRINGING IN PEOPLE, LIKE IT HAPPENED FOR NEUROSCIENCE, BRINGING PEOPLE WHO ARE CHEMISTS, OR ENGINEERS, WHO ARE COMPUTATIONAL BIOLOGISTS TO STUDY AND EXPAND THE UNDERSTANDING OF GLIA. AND AT THE SAME TIME ALSO, YOU KNOW, ENCOURAGE CLASSICAL NEUROBIOLOGISTS TO KEEP AN EYE ON GLIAL CELLS AND HOW THEY MAY INFLUENCE THE CIRCUITS AND/OR THE PHENOMENONS THAT THEY ARE STUDYING. SO ONE OF THE WAYS OF COURSE TO HAVE THE FUNDING OPPORTUNITIES WHERE THIS WILL REQUIRE MULTIPLE LABS TO GET TOGETHER AND BRIDGE THE GAP BETWEEN BOTH THOSE SIDES , AND I ENCOURAGE EVERYONE HERE WHO HAS NOT WORKED, TALKED ABOUT GLIAL CELLS, TO GO BACK AND THINK ABOUT THEM BECAUSE IT'S A REALLY BURGEONING AND YOUNG FIELD AND A VERY FRIENDLY AND ENCOURAGING FIELD, AND WE REALLY NEED PEOPLE WHO ARE THINKING IN A DIFFERENT WAY THAN US SO THAT WE CAN START TO DECIPHER SOME OF THE THINGS THAT HAVE BEEN CHALLENGING TO DECIPHER. BUT ON THE OTHER HAND, WE ALSO NIED TO REALIZE THAT -- NEED TO REALIZE THAT GLIAL CELLS ARE NOT LIKE NEURONS, THEY ARE DIFFERENT CELLS, AND WE NEED TO COME UP WITH STRATEGIES THAT WILL TARGET SPECIFIC BIOLOGY OF THESE CELLS, AND THAT'S ANOTHER THING THAT WE SHOULD NOT FORGET TO GO AFTER AND I THINK THAT WOULD BE ALSO, THAT SHOULD BE WITHIN THE BRAIN INITIATIVE'S GOALS BECAUSE PART OF THE BRAIN IS MADE UP OF GLIA. >> I WANTED TO SEE, SO IF YOU UN MUTE YOURSELF, WE SHOULD BE ABLE TO HEAR YOU IN THE ROOM NOW . ONE SECOND. ARE THERE OTHER QUESTIONS? >> WHILE SHE'S TYPING A QUESTION , I'LL ASK ANOTHER QUICK ONE. SO WE STARTED TO THINK A LOT COMPARATIVELY ABOUT CLASSIFYING NEURONS ACROSS DIFFERENT MODEL ORGANISMS AND THINKING CAREFULLY ABOUT HOW SIMILAR MOUSE NEURONS TO HUMAN NEURONS AS WE JUST HEARD FROM NAT HEINTZ. HOW MUCH OF THAT HAS THAT BEEN THOUGHT ABOUT FOR NONNEURONAL CELL TYPES? DO WE THINK THAT MOUSE GLIA, FOR EXAMPLE, ARE SIMILAR TO NEURON GLIA AND HOW MUCH OF THAT HAS BEEN DONE SO FAR? >> Dr. Eroglu: THERE ARE SOME REALLY EXCITING STUDIES PUBLISHED IN THE PAST COUPLE YEARS FROM BARROWS LAB AND ELLEN INSTITUTE HAS SOME STUDIES WHERE THEY'VE COMPARED HUMAN, FOR EXAMPLE, ASTROCYTES TO MOUSE ASTROCYTES, AND THERE ARE ALSO CLASSICAL STUDIES COMPARATIVE BIOLOGY STUDIES THAT SHOW THAT ASTROCYTES IN HUMAN BRAIN ARE -- THEY ARE FAR MORE ELABORATE, THEY INTERACT WITH 10 TO 20 FOLD MORE SYNAPSES AT ONCE. SOMETIMES THEY CAN PROJECT LONGER PROCESSES, NOT JUST STAY LOCAL, BUT LONGER PROCESSES WITHIN THE CORTEX TO OTHER LAYERS OF THE CORTEX. WHY ARE THEY DOING THIS, WE DON'T KNOW, BUT IT'S REALLY EXCITING AND INTERESTING TO CONSIDER THAT HUMAN ASTROCYTES MAY HAVE EVOLVED TO GAIN ADDITIONAL FUNCTIONS, AND THE POINTS THAT WERE RAISED BY NATE ALSO SHOWS THAT THERE COULD BE ALL THOSE GENES IN ASTROCYTES THAT ARE SPECIFIC TO HUMAN ASTROCYTES WHICH ARE MEDIATING SOME OF THESE FUNCTIONS. SO I THINK THIS IS GOING TO BE ANOTHER VERY EXCITING FIELD OF GLIAL BIOLOGY. >> SO WE HAVE LOTS OF COMPARISON S ALREADY, AND GLIA ARE SUPER-INTERESTING. THE BOTH MICROGLIA AND ASTROCYTE S AND OLIGOS AT LEAST WITH RESPECT TO EXPRESSION VARY BETWEEN HUMANS AND MICE THE SAME WAY NEURONS DO, AND THEY VARY A LOT MORE BETWEEN REGIONS. SO IT'S VERY HARD TO DETERMINE WHAT'S A STATE-DEPENDENT CHANGE VERSUS WHAT'S AN ACTUAL LINEAGE- DEPENDENT CHANGE, AND IT WILL TAKE SOME TIME, I THINK, I'M NOT AN EXPERT TO FIGURE THAT OUT. >> THEY WERE NOT ABLE TO GET HUH DA'S QUESTION, SO HOPEFULLY WE'LL HAVE IT AFTER THE SESSION. I WANT TO FOR THE SAKE OF TIME CLOAFS THE SESSION. I FEEL LIKE THERE'S SO MANY UN ANSWERED QUESTIONS THAT REALLY WERE BROUGHT UP IN THIS REALLY EXCITING AND WONDERFUL WORKSHOP BY THE SPEAKERS, EVERYTHING FROM HOW DO WE INTEGRATE SPECIFIC PROTEINS, WHICH I THINK ARE IMPORTANT, AND POPULATION TO SPECIFIC PROTEINS, NONNEURONAL CELLS INTO IRKTS IS, HOW ARE WE THINKING ABOUT PARTICULAR CELL TYPES AND THEIR INTEGRATION, AND ULTIMATELY WHAT IS A CIRCUIT, HOW IMPORTANT IS THIS IN TERMS OF PERHAPS IN TERMS OF TREATMENT APPROACHES. WE DID TOUCH A LITTLE BIT ON TREATMENT IN THE END, BUT I THINK THE IMPLICATIONS ARE QUITE BROAD. SO WE'LL TAKE UP THIS A LITTLE LATER. HAVING SAID THAT, WE ACTUALLY DO HAVE A QUESTION NOW. >> YES, WE DO HAVE THE QUESTION NOW, SO THIS IS FROM HUDA. QUESTION TO JOHN, I AGREE PROTEIN INTERACTION DATA WHEN RELIABLE. HOW ARE WE TO VALIDATE THE MASSIVE DATA AND PINPOINT RELIABLE ONES? ALSO, WE NEED TOOLS TO INTERROGATE ENDOGENOUS PROTEINS AT PHYSIOLOGIC LEVELS IN THE CORRECT CELL TYPE. CAN YOU THINK OF A STRATEGY TO DO THIS RELIABLY? THE COMMUNITY WASTES MILLIONS OF DOLLARS ON BAD ANTIBODIES. WHAT DO YOU RECOMMEND TO BRING IN TO CONSIDER TO SOLVE THIS PROBLEM? >> AND YOU HAVE TWO MINUTES. [LAUGHTER] >> Dr. Yates: YATES YOU MIGHT HAVE TO STEP THROUGH THOSE QUESTIONS FOR ME. SO TO THE VALIDATION OF THE PROTEIN-PROTEIN INTERACTION, SO THERE ARE BETTER INFORMATIC TECHNIQUES THAT HAVE BEEN DEVELOPED TO DO THAT SO PEOPLE GET ANSWER WHICH IS HAVE MORE STATISTICAL CONFIDENCE. MY THIS MY EXPERIENCE, ONE OF THE BEST WAYS TO MAKE SURE YOU'VE GOT GOOD PROTEIN-PROTEIN INTERACTION DATA IS TO DO REPLICATES AND MAKE SURE YOU'VE GOT GOOD CONTROLS BECAUSE A PULL -DOWN CAN VARY AS A FUNCTION OF YOU LET IT SIT FOR AN EXTRA FIVE OR TEN MINUTES BEFORE YOU PULL IT DOWN SO MAKING SURE DO YOU REPLICATES, GOT GOOD CONTROLS AND USE INFORMATIC TOOLS TO ANALYZE THE DATA AND FILTER OUT SIGNAL FROM NOISE BECAUSE ONE PERSON'S NOISE IS ANOTHER PERSON'S LOW AFFINITY BINDING KINASE. [LAUGHTER] SO OFTENTIMES IT DOES REQUIRE VALIDATION. NEXT QUESTION? I CAN'T READ HE THAT BE. I NEED GLALSZ DISWROO WE NEEDED TO INTERROGATE ENDOGENOUS PROTEINS AT PHYSIOLOGIC LEVELS. CAN YOU THINK OF A STRAT GITE TO DO THIS RELIABLY? >> Dr. Yates: YES. SO I'VE BEEN TRYING TO GET A PAPER PUBLISHED WHERE WE USE CRISPR CAS TO INSERT AN EPITOPE TAG INTO AN AN ENDOGENOUS GENE AND BOY WE SENT IT TO NATURE METHODS AND IT WAS LIKE WE POKED A BEAR WITH A STICK BECAUSE WE DID A COMPARISON BETWEEN OVER EXPRESSION VERSUS ENDOGENOUS EXPRESSION LEVELS AND BOY, PEOPLE WERE NOT HAPPY. SO WE'RE STILL TRYING TO GET THAT PAPER PUBLISHED, BUT THAT'S A GOOD WAY TO INSERT AN EPITOPE TAG INTO AN ENDOGENOUSLY EXPRESSED GENE, PEOPLE HAVE DONE THAT FOR YEARS IN YEAST ASK THERE WAS A CLASSIC STUDY IN 2002, ONE LAB DID OVEREXPRESSION IN YEAST AND ANOTHER LAB DID ENDOGENOUS EXPRESSION USING A TAP TAG SYSTEM AND THE DIFFERENCES IN PROTEIN-PROTEIN INTERACTION IS LIKE NIGHT AND DAY, THE ENDOGENOUS EXPRESSION SYSTEM WAS MUCH BETTER. AGAIN, SOME PEOPLE ARGUE THAT USING THE OVEREXPRESSION SYSTEMS YOU CAN PICK UP LOW AFFINITY ENTER ACTORS, KINASES AND THINGS LIKE THAT. THIRD QUESTION, ANTIBODIES, WHY ARE THEY BAD? [LAUGHTER] >> WASTE MILLIONS OF DOLLARS ON BAD ANTIBODIES, WHAT DO YOU RECOMMEND BRAIN CAN DO TO SOLVE THIS PROBLEM? >> Dr. Yates: NTI HAS A BIG PROGRAM TO GENERATE ANTIBODIES. WHAT I DON'T KNOW ABOUT THE COMMERCIAL ANTIBODY FIELD IS WHAT THEY DO TO VALIDATE THE ANTIBODIES. DO THEY USE MASS SPECTROMETRY AS A WAY TO SEE WHAT IT'S ACTUALLY BINDING TO? SO I DON'T KNOW. I KNOW SOME OF THE BAD ANTIBODIES ARE COMING FROM OUTSIDE THE U.S. WHERE I'VE HEARD THERE'S A LOT OF SUSPICION ABOUT THEM, BUT WE ALWAYS VALIDATE OUR ANTIBODIES BY MAKING SURE WE UNDERSTAND WHAT THEY BIND TO BY MASS SPECTROMETRY. >> GREAT. I THINK WITH THAT, WE'RE GOING TO GO ON A BREAK NOW. SO WE WANT TO THANK THE SPEAKERS FOR THE SESSION. AND WE'LL RETURN AT 11:50. THANK YOU. [APPLAUSE] WE'LL START OUR THIRD ARE SESSION OF THE SECOND WORKSHOP OF THE ADVISORY COMMITTEE TO THE DIRECTOR BRAIN INITIATIVE 2.0, AND I'LL GET THE RIGHT SLIDES UP. >> Dr. Dzirasa: IT'S STILL MORNING, GOOD AFTERNOON TO ALL OF YOU, IN NORTH CAROLINA. I'M EXCITED ABOUT THIS SESSION, MY NAME IS KAFUI DZIRASA, WE STARTED REVIEWING THE INITIAL OUTLINE FOR THE BRAIN 2025 INITIATIVE, THERE WAS AN EMPHASIS FOCUSING ON CIRCUITS SO THE SESSION BEFORE WE TALKED ABOUT LINKING MOLECULES UP TO CIRCUITS AND THIS ONE WE'LL TALK ABOUT CONNECTING CIRCUITS TO BEHAVIOR. WE HAVE FIVE REALLY EXCITING SPEAKERS THAT WILL OUTLINE SOME OF THE QUESTIONS THAT WE AS A COMMITTEE HAVE REALLY BEEN WRESTLING ABOUT, BOTH HOW TO QUANTIFY BEHAVIOR, THINKING ABOUT USING BEHAVIOR TO MODIFY IRKTS IS, HAVE WE THOUGHT ABOUT HOW CIRCUITS ARE INTEGRATED INTO MORE GLOBAL BRAIN STATES AND IN THE IDEA OF LINKING CIRCUITS TO BEHAVIOR, DO WE NEED TO GIVE MORE BROAD THOUGHT TO THE ANIMALS ABOUT HOW THIS INTEGRATION OCCURS, WE HAVE FIVE SPEAKERS TO COVER THESE TOPICS, FOCUS IN ONE AREA AND ALSO SPRING SPRINKLE INTO THE OTHERS. WE'LL START OFF WITH MACKENZIE MATHIS WHO SS AT HARVARD. >> Dr. Mathis: THANK YOU FOR HAVING ME BE HERE, IT'S A PRF TO TALK TO YOU ALL TODAY. AS WE SEE IN THIS MORNING'S SESSIONS, MODERN TECHNIQUES HAVE REALLY REVOLUTION ALIZED THE WAY WE CAN PROBE AND MANIPULATE NEURAL CIRCUITS BUT I WOULD ARGUE THAT TO UNDERSTAND NEURAL CIRCUITS IS THAT YOU REALLY HAVE TO UNDERSTAND BEHAVIOR BECAUSE BEHAVIOR PROVIDES UNDERSTANDING, AND TO DO THAT, WE NEED TO BE ABLE TO BETTER ARE MEASURE BEHAVIORAL OUTPUTS. SO AS TIM BURG LAMENT BD IN THE '60S IS THAT BEHAVIORAL DESCRIPTIONS AND QUANTIFICATIONS WERE CRUCIAL BUT IN THE WAY OF MODERN PUBLISHING EVEN AT THAT TIME DESCRIPTIONS WERE GOING BY THE WAYSIDE AND ACTUALLY TO DO THIS WE NEED TO HAVE LIBRARIES AND ARCHIVES AND VIDEOS IN ORDER TO ACTUALLY CAPTURE BEHAVIOR. BUT IN TODAY'S MODERN WORLD, THE HARD DRIVE NOW CAN SERVE APPEARS THAT LIBRARY AND WE CAN HARNESS COMPUTER VISION TO START TO MINE THIS DATA AND PRO PROVIDE NEW INSIGHTS -- TO PROVIDE NEW INSIGHTS TO START TO REALLY UNDERSTAND HOW THE BRAIN AND CIRCUITS ACTUALLY DRIVE BEHAVIOR SO WHAT I WOULD LIKE TO TELL YOU ABOUT TODAY IS POSE ESTIMATION AND HOW WE CAN USE THIS IN THE LABORATORY AND TO EXPLAIN THIS WHAT I WILL DO IS DESCRIBE SOME OF THE METHODS PREVIOUSLY USED TO DO THIS. POSE IS SICIALLY THE ACTION OF ANALOGY ANIMAL TO MEASUREMENT ITS MOVEMENT AND THERE'S BEEN MANY WAYS THAT YOU PROBABLY ARE FAMILIAR WITH OR MAYBE EVEN CURRENTLY DO IN YOUR LAB NOW, I'LL JUST RUN THROUGH SOME OF THESE. THE WAY I'LL ORGANIZE THIS IS FROM THE DETAILED POSE AND ON THE OTHER AXIS LI TALK ABOUT THE TIME COMMITMENT AND IN FLEXIBILITY OF THESE TRACKING SYSTEMS THAT ARE BEING USED RIGHT NOW. SO OF COURSE WE CAN TRACK THE CENTER OF MASS OF AN ANIMAL, MOVING IN AN ARENA, WE CAN USE DEPTH CAMERAS TO GET AN OUTLINE OF THE ANIMAL, WE CAN USE MARKERS OR TATTOOS TO MARK INDIVIDUAL FEATURES OR LABELS, SOME CAN BE LABORIOUS, IN JOHN'S LAB, IT TOOK THREE MONTHS TO TRACK THE MONKEY TO DO ABLE TO DO 3D RECONSTRUCTION. YOU CAN MAKE BODY MARKERS OF THE ANIMALS, ELLIPSIS ON THE FLY OF A WING OR WORMS, WE CAN USE ARMY OF UNDERGRADUATES WAY OFF THE CHARTS IN TERMS OF LABOR, MOTION CAPTURE SYSTEMS HAVE BEEN GREAT WITH WILLING PARTICIPANT YOU CAN ASK A HUMAN TO PUT ON ONE OF THESE SUITS AND PRETTY ACCURATELY TRACK THEM, THERE'S BEEN NEW FEATURE DETECTORS IN ORDER TO TRACK ANIMALS AS WELL BUT I WOULD ARGUE ABOUT WHAT WE REALLY WANT TO BE IS UP HERE, WE WANT A REALLY DETAILED POSE OF THE ANIMAL, DO THIS WITH VERY LITTLE TIME COMMITMENT ANDMENT IT TO BE HIGHLY FLEXIBLE AND I'LL ARGUE THE COMPUTER VISION HAS ALREADY SOLVED THIS. HERE IS A VIDEO USING A DEEP NEURAL NETWORK OF A GROUP OF HUMANS, IT DOESN'T KNOW HOW MANY HUMANS IT NEEDS TO FIND, THE BACKGROUND, VARIABILITY CHANGES WILDLY AND YOU CAN SEE THIS IS A PRETTY -- THIS DOES A PRETTY REMARKABLY GOOD JOB, THIS IS A FRAME BY FRAME PREDICTION. WHAT'S THE CATCH, RIGHT? SO ALL OF THESE NETWORKS, DEEP POSE, DEEPER CUT, OPEN POSE AND MANY OTHERS RELY ON THIS NOTION OF A DEEP NEURAL NETWORK AND THEY ALL EFFECTIVELY WORK SOMETHING LIKE THIS. YOU TAKE AN IMAGE, YOU TRAIN A PREDICTOR AND YOU GET A POSE OUT THE CATCH IS THAT WHEN YOU TRAIN THIS, YOU NEED A LOT OF LABELED DATA SO THE IF YOU HAVE A MILLION PARAMETERS THIS YOUR MODEL, YOU NEED 10 TO THE 6 OR MORE ACTUAL DATA POINTS IN ORDER TO TRAIN THIS, SO THAT'S A PROBLEM. SO AS ANDREW NICK NICELY DESCRIBED TO US, THE PERFORMANCE OF DEEP LEARNING HAS BEEN PHENOMENAL AND MUCH OUTSURPASSES OTHER TRACKING ALGORITHMS BUT THE AMOUNT OF DATA WE NEED TO DO THIS IS VERY, VERY HIGH. SO IN THIS DATA HUNGRY WORLD WITH THESE ALGORITHMS HOW CAN WE ACTUALLY USE THIS IN A LABORATORY SETTING AND THE LEVEL OF A SINGLE LAB OR EVEN A SINGLE BEHAVIORAL EXPERIMENT? SO THIS NOTION IS CALLED TRANSFER LEARNING. WHAT WE CAN DO IS TAKE A TRAINED NEURAL NETWORK AND ASK IT TO LEARN A NEW TASK MUCH LIKE WE ASK A CHILD OR A PERSON TO LEARN A NEW BEHAVIOR. SO I CAN EDIT HIS GRAPH IF YOU'LL ALLOW AND WE CAN SAY NOW WITH THE ADVENT OF TRANSFER LEARNING PLUS DEEP LEARNING WE CAN NO LONGER JUST NEED A LOT OF TASK DATA, WE CAN GET TASK- RELATED DATA AND REALLY LOWER THE BURDEN OF THE AMOUNT OF DATA THAT WE NEED TO GET REALLY HIGH PERFORMANCE. SO EFFECTIVELY NOW WE CAN TAKE THIS AND USE ONLY A FEW EXAMPLES , AND THIS IDEA IS THAT YOU CAN TAKE A NETWORK, SAY LIKE A RESIDUAL NEURAL NETWORK, THE AFICIONADOS AND PRETRAIN IT ON ANOTHER DATASET, IE IMAGE NET, THIS DATASET CONTAINS 1.2 MILLION IMAGES OVER 1,000 CLASS OF DIFFERENT OBJECTS AND WHAT THIS DOES IS ELM INTOS THIS NEURAL ARCHITECTURE WITH EFFECTIVELY GOOD SCENE STATISTICS SO IT HAS SOME VISUAL REPRESENTATIONS ALREADY SO WHEN YOU GIVE IT ONLY A FEW EXAMPLES OF THE BEHAVIOR YOU CARE ABOUT APPEARS THE EXPERIMENTER NOW YOU CAN END T O END TRAIN THESE AND GET A REALLY ROBUST OUT OF IT. ALREADY BEING EMPLOYED IN LABS, ON THE LEFT IS AN EXAMPLE OF A RAT REACHING FOR A PELLET TASK TRAWK AND YOU CAN SEE THIS IS REALLY CHALLENGING EVEN IF YOU WANTED TO USE HEURISTIC, HOW WOULD YOU SEGMENT OUT THIS HAND, ATTRACT ALL THE THE PELLETS, ALL THE DIGITS IN THE KNUCKLES. IN THE MIDDLE SATELL LAB AT COLUMBIA UNIVERSITY, THEY HAVE A MOUSE RUNNING ON A TREAD TRED MILL AND THEY HAVE A MIRROR PLACED AT THE BOTTOM AND YOU CAN GET TWO VIEWS AND DO 3D RECONSTRUCTION AND THIS IS ONE NEURAL NETWORK THAT DOES THIS. THE RAT ON THE LEFT IS TRAINED WITH 150 LABELED IMAGES, MEANING IN ONE AFTERNOON YOU CAN SIT DOWN, LABEL YOUR DATA, TRAIN A NETWORK FOR 16 TO 24 HOURS AND USE THIS AND GENERALIZED ACROSS OTHER ANIMALS AND EVEN SLIGHTLY DIFFERENT CAMERA ANGLES, DIFFERENT RESOLUTIONS, I'M HAPPY TO TALK ABOUT THAT AT THE END, ON THE FAR RIGHT ANIMALS DOIPT MOVE THIS ONE PLANE, HERE IS AN EXAMPLE OF A DROSOPHILA FRUIT FLY LIVING IF A 3D CHAMBER LAYING EGGS, BACKGROUND STATISTICS CHANGE, THIS ANIMAL IS MOVING ALL AROUND AND MAYBE I'M A BIT BIASED, BUT I THINK THIS IS PRETTY INCREDIBLE TRACKING OF AN ANIMAL IN THE 3D WORLD, THESE ARE JUST SORT OF COMMON ANIMALS BUT THIS HAS ALREADY BEEN EXTENDED TO OTHER SPECIES, INSECTS, LEECHES, BACTERIA, CHEETAHS,. >> HE VERTEBRAS, IN THE WILD, HUMANS, BABIES, WHATEVER YOU WANT TO TRACK -- Z, EBRAS, IN THE WILD, WHATEVER YOU WANT TO TRACK, YOU CAN TRACK IT IN DEEP LEARNING. AI HAS POAMPSED REVOLUTIONALIZED OTHER FIELDS. A BEAUTIFUL EXAMPLE FROM A LAB WHERE THEY USE MACHINE LEARNING APPROACHES TO CHARACTERIZE BEHAVIORS OF DROSOPHILA AND MAP THESE ONTO ANATOMICAL SUBSTRATES FOR DIFFERENT COMPLEX BEHAVIORS. I ALSO WANT TO POINT OUT THAT IN THE FUTURE WE CAN ALSO DO THIS USING EVEN DEEPER ARCHITECTURES, SO AT THE TOP YOU'LL SEE A DIAGRAM OF HUMAN ACTION SETS, SO PEOPLE ARE MINING THESE DATASETS AND GIVING THEM ACTION LABELS AND THE BOTTOM IS JUST A DETAILED EXAMPLE OF A NETWORK ARCHITECTURE, BUT THE PUNCHLINE IS THIS. SO YOU CAN TAKE AND TRAIN A PRE NETWORK USING THIS NOTION OF TRANSFER LEARNING AGAIN AND YOU CAN SAY IS THIS PERSON KICKING A BALL, SO NOW YOU CAN TAKE A 2D DENSE NET WHICH IS VERY SIMILAR TO RESIDUAL NEURAL NETWORK BUT NOW DO IT IN X-Y TIME, MAKE IT 3 D AND GET AN ACTION LABEL. NOT ONLY ARE WE ABLE TO NOW TRACK ANIMALS WITH UNPRECEDENTED DETAILS AND ROBUSTNESS, WE'RE POSED TO TRACKING ANIMALS AND THEIR ACTIONS, SO I MIGHT BE A BIT BIASED BECAUSE I REALLY LOVE BEHAVIOR BUT I THINK THIS IS AN AREA THAT THE BRAIN INITIATIVE IN PARTICULAR COULD REALLY SUPPORT THESE TOOLS. NEXT I JUST WANTED TO SAY THAT OF COURSE ALL THESE TOOLS, I HOPE THAT IT OPENS NEW AVENUES FOR US AND WHAT WE CAN ACTUALLY STUDY AND THINGS THAT WE CAN RE VISIT AS I ALLUDED TO. SO NOW WE CAN GO BACK AND POTENTIALLY LOOK AT EVEN SIMPLE AND ROBUST SINGLE TRIAL PARADIGM S LIKE CLASSICAL CONDITIONING THAT MEASURE MORE THAN LICKING OR EYE PUPILOMETRY, MEASURE THE WHOLE ANIMAL, EXPERIMENTER KNOWS BEST, YOU PICK WHAT YOU WANT TO LABEL, GO BACK ASK WE CAN DO THIS. LABS ARE GOING BACK TO SOME OF THE OLD VIDEO DATA THEY HAD AND COLLECTED WITH NEURAL DATA TO RE ANALYZE YOU THIS IN THE LIGHT OF THESE TYPE OF METHODS WHICH I FIND INCREDIBLY EXCITING AND SOMETHING THAT SHOULD DEFINITELY BE FUNDED. WE CAN ALSO THINK OF MORE COMPLEX AND MORE VARIABLE DATASETS, EVEN MULTIDIRECTIONAL REACHING IN 3D WHICH THERE'S ALSO A HUGE AI REVOLUTIONING THAT I DON'T HAVE TIME TO TALK ABOUT AND UNDERSTANDING THE NEURAL CIRCUITS INVOLVED IN THAT , AND WE CAN OF COURSE LOOK AT OTHER MORE ETHOLOGICALLY RELEVANT BEHAVIORS, AN EXAMPLES BEHAVIOR AT CAL TECH WITH A LOOM ING STIMULUS, THIS MOUSE FREEZE WHZ IT SEES THIS, BUT YOU COULD NOW MEASURE THIS WITH HIGHER DETAIL POTENTIAL AM BUT WE WANT TO BE ON THIS CHART OF NATURAL BEHAVIORS THAT ARE COMPLEX THAT HAVE LESS TRIAL STRUCTURE AND THEY CAN BE IN MORE NATURAL HABITATS SO HERE YOU HAVE AN EXAMPL OF A FEMALE MOUSE WITH HER PUPS POTENTIALLY EVEN IN A WILD-LOOKING DEN, CHEETAHS IN THE WILD, THIS LAB AT COLUMBIA STUDIES AGGRESSION IN BETA FISH WHICH IS ALSO VERY HARD TO TRACK BECAUSE THE SHAPE OF THE ANIMAL CHANGES A LOT. HERE SENIOR A DEER MOUSE FROM MY BACKYARD DOING THIS INCREDIBLE CLIMBING BEHAVIOR AND WE CAN USE MULTIPLE MICE AND THINGS LIKE THAT EVEN IN THE LABORATORY. SO JUST TO RECAP, I WOULD LIKE TO SAY, YOU KNOW, THESE TOOLS, THIS ROBUST TRACKING AND BEHAVIORAL PHENOTYPING CAN REALLY OPEN IDEAS FOR NEWLY PARADIGMS SO I THINK DAVID HE HAD-ISH IS GOING TO EX--- RED -ISH IS GOING TO EXPAND UPON IN THE NEXT TYPE. KEY CHALLENGES FOR THE FIELD AND HOW WE DISSEMINATE TECHNOLOGY. ONE IS A LOFT US RELY ON YOU GPU COMPETING RESOURCES, LABS NEED ACCESS TO THESE GRAPHICAL PROCESSING EXPUNTS COMPANIES ARE MAKING THESE BETTER AND BETTER SO THIS IS SOMETHING WE NEED TO BE MINDFUL OF. WE NEED NEW LARGE DATASETS. ONE SORT OF MOON SHOOT IDEA IS SAY WE WANT TO MAKE A MOUSE NETWORK THAT CAN TRACK A MOUSE IN AN OPEN FIELD, CLASSIC PARADIGM USE THIS HAD MANY LABS, IT COULD WORK ACROSS ALL LABS, SO ALL OF YOU SEND ME FIVE SLIDES OF YOUR FAVORITE PARADIGM AND LET'S MAKE A SUPERNET, LET'S SHARE IT, MAKE IT OPEN HE TO THE MUNLT -- TO THE COMMUNITY. WE NEED GOOD DATA, IT HAS TO BE RELIABLE FOR THAT. VOG REAF MEANS WE NEED NEW TOOLS , NEW COME PRESENTATION ALGORITHM, EFFICIENT STORAGE MECHANISMS, RS DEEP NEURAL NETWORKS, WE WANT THEM FASTER, WE WANT TO DO REALTIME AND REALTIME CAN VARY BASED ON YOUR EXPERIMENT SO EVEN UP TO 1,000 FRAMES PER SECOND COULD BE USEFUL, WE WANT TO DO 3D, WE WANT TO USE VIDEO INFORMATION BECAUSE A LOT OF THESE ARE FRAME BY FRAME PREDICTIONS BUT THEY'RE QUITE GOOD. I WOULD ARGUE WE WANT TO MAKE THIS OPEN SOURCE AND REALLY ACCESSIBLE, SO THIS IS SORT OF TWO FRONTS, ONE OPEN SOURCE REALLY ALLOWS THE COMMUNITY TO GET INVOLVED AND TO MAKE BETTER CODE DATABASES, BUT ALSO ACCESSIBILITY, THAT MEANS WE NEED TO TRAIN GRADUATE STUDENTS AND POST-DOCS AND PEOPLE IN OUR LABZ DIFFERENTLY SO THEY CAN USE THESE TOOLS, ASK WE NEED TO WRITE THEM SO THEY'RE VERY ACCESSIBLE. I LIKE THIS NOTION OF BENCHMARK ING, SO THIS HAS BEEN DONE A LOT IN COMPUTER VISION, WHERE YOU HAVE LARGE DATASETS AND PEOPLE SUBMIT THEIR ALGORITHMS AND ESSENTIALLY HAVE COMPETITION, I THINK THIS COULD BE WELL SUPPORTED UNDER THESE TYPES OF FUNDING MODELS. AND THESE MAKE THINGS MUCH MORROW WUS AND RELIABLE. -- MORE ROBUST AND RELIABLE. I THINK A BIG QUESTION I COULD TALK A LOT MORE ABOUT IS WHAT DO WE ACTUALLY MEASURE, SO DECIDING WHERE AND WHAT TO TRACK AND WHAT TO DO WITH THAT DATA, I THINK WE CAN ALL THINK ABOUT THAT AND COLLECTIVELY THINK ABOUT HOW WE WANT TO USE THESE TOOLS IN EVEN OUR MOLECULAR AND PROTEOMUS EXPERIMENTS IF YOU WANT TO UNDERSTAND HOW A MOUSE'S LIFE HAS CHANGED OVER TIME AND YOU WHAT'S HAPPENED IN THE GLIA CIRCUITS, THINGS YOU WANT TO UNDERSTAND IN THE LIGHT OF BEHAVIOR AND LASTLY TAKING THESE TOOLS FROM THE LAB TO THE CLINIC , I REALLY ENVISION A FUTURE WHERE WE HAVE SOMETHING LIKE A CLINICIAN WITH THEIR i PHONE CAN TAKE A VIDEO OF A PATIENT WITH PARKINSON'S DISEASE AND DO TRACKING TO GET MUCH MORE BEHAVIORAL READOUTS IT IS THAT ARE NOT -- THAT ARE NOT JUST THESE SIMPLE TASKS OR FALLING OVER OR THINGS LIKE THIS, THERE'S REAL POTENTIAL BUT IT OF COURSE TAKES MONEY AND PEOPLE WITH TIME AND TALENT. WITH THAT I WOULD LIKE TO GO THE THINGS THAT I THINK AREOF- REALLY CHANGING THE WAY WE COULD APPROACH BEHAVIOR. ONE, THESE NEW ARTIFICIAL NEURO NETWORKS HAVE ALLOWED FOR ROBUST TRACKING, THOUSAND WE CAN GO FROM LABORIOUS AND TIME-CONSUMING ARE METHODS TO TRACK FLIES IN ARGUABLY MORE NATURAL ENVIRONMENTS, THIS NOTION OF TRANSFER LEARNING, TAKING AND TRAIN NETWORK AND APPLYING IT TO A NEW PROBLEM CAN BE REALLY HELPFUL ESPECIALLY WITH HIGHER DATA COSTS, SO JUST TO HIGHLIGHT A FUN EXAMPLE, THIS IS A NETWORK-TRAINED ON THIS HORSE ON THE LEFT AND THIS WAS USED ONLY ABOUT 100 IMAGES TO TRACK THIS HORSE, IT ACTUALLY WORKS ACROSS HORSES ARE, AND THEN WE USED ONLY ELEVEN FRAMES TO TRAIN ON THE HORSE ON THE RIGHT, THIS IS VERY DIFFERENT BACKGROUND STATISTICS, AND THESE THINGS ARE WORKING QUITE WELL. AS I BRIEF HIGHLIGHTED, I MEAN, WE NEED NEW TOOLS, WE REALLY WANT TO PUSH THIS TO THE CLINIC CAN WE WANT TO STUDY MORE COMPLEX BEHAVIORS. SO FOR EXAMPLE, IN MEDIA LAB, THEY'RE STARTING TO USE ONE OF THESE DEEP NEURAL ARCHITECTURES THAT I DISCUSSED TODAY TO LOOK AT CHILDREN THAT HAVE AUTISM AND TRACK THEIR FACIAL MOVEMENTS AND BODY TO SEE HOW THEY INTERACT WITH ROBOTS AND I THINK THIS CAN BE DONE ON AN EVEN BROADER SCALE ON THE RIGHT SYNC A REALLY BEAUTIFUL SET OF EXPERIMENTS FROM LEAH KUBICR'S GROUP AT UC DAVIS, LAB REARED RATS VERSUS RATS RAISE IN A VERY LARGE PEN AND YOU CAN SEE EVEN THE SOMATOSENSORY MAPS ARE WILDLY DIFFERENT SO I THINK THE MORE COMPLEX YOU CAN GET WITH THESE BEHAVIORS, OF COURSE IF YOU CAN TRACK THE LIFE LIFETIME OF THIS ANIMAL, I WOULD BE VERY EXCITED, I THINK THIS REALLY OPENS UP THE AVENUE FOR NEW TOOL DEVELOPMENT. WITH THAT, I WOULD BE DELIGHTED IT TAKE YOUR QUESTIONS. PLAZ. [APPLAUSE] >> Dr. Dzirasa: WE'VE GOT ABOUT A MINUTE AND A HALF, TWO MINUTES FOR QUESTIONS. DO WE WANT TO START WITH ANYBODY ON THE WORKING GROUP? >> I HAVE A QUESTION. CAN YOU GUYS HEAR ME? THIS IS AN CHURCHLAND. >> I APPRECIATE THE ENTHUSIASM. NOW I'M KIND OF CURIOUS, HOW COULD IT GO WRONG? ESPECIALLY I'M CURIOUS IN THE TRANSFER NETWORKS, SO IF I'VE STUDIED SOMETHING, DOES IT BRING A BIAS THEN THAT MIGHT HAVE TO BE CONSIDERED AS YOU DO TRANSFER INTO ANOTHER AREA? IN THAT ONE MINUTE, WHERE CAN THIS GO WRONG ON US AND WHAT DO WE HAVE TO LOOK OUT FOR? >> Dr. Mathis: GREAT QUESTION. THERE'S A HUGE AMOUNT OF QUESTION ON LOTS OF WAYS THAT ARTIFICIAL NEURAL NETWORKS CAN BE TRICKED, THEY CAN BE VEZ EASILY FOOLED. -- VERY EASILY FOOLED. ON THE BROADER SCALE, ADD VER SAIROUS EXAMPLES AND THINGS LIKE THAT, THINGS AT THAT NEED TO BE SOLVED, BUT INDEPENDENT OF THAT, IN THE LAB I THINK WE CAN POTENTIALLY BE FOOLED BY NOT PICKING THE RIGHT LABELS OR THINGS LIKE THAT, OR WITH TRANSFER LEARNING, IT'S PRETTY ROBUST, THAT MEANS I'VE ALREADY PREDEFINED MY POIBTS THIS ONE NETWORK AND USING IT MORE DIRECTLY TO ANOTHER. THE LARGER NOTION OF TRANSFER LEARNING, I.E., TRAINING IT FOR RECOGNITION TASK AND THEN PORT ING THIS OVER TO DO FEATURE DETEXTS, IP DIBILITY GET INTO THE DWOA TAILS, WE USE DEACON VOLUTIONAL LAYERS TO DO THIS, THAT'S MUCH MORE FLEX INL, SO THE NETWORK WE PROVIDED CAN BE USED FOR ALL THESE APPLICATIONS. THERE ARE LIMITATIONS. >> WE HAVE A QUESTION FROM ANNE CHURCHLAND. IN YOUR EXPERIENCE OF SHOWING THE TOOL SO FAR, WHAT FRACTION OF INVESTIGATORS HAVE ACCESS TOP COMPUTING POWER GPU'S SUFFICIENT TO ANALYZE THEIR BEHAVIORAL DATA AND FOR THOSE THAT DO ARE DO ARE THEY MOSTLY INSTITUTION SUPPORTED RESOURCES OR LOCAL WITHIN THE LAB? >> Dr. Mathis: S FABULOUS QUESTION. MY OWN EXPERIMENT, WE RECENTLY PUT A PAPER ON THE ARCHIVE IN APRIL AND WE'VE BEEN REALLY FORTUNATE TO HAVE AROUND 200 LABS ADOPTING THIS TECHNOLOGY ALREADY. SO THIS DOES ACTUALLY ROWN A CPU , IT'S ABOUT 100 TIMES OR TEN TIMES TO 100 TIMES SLOWER DEPENDING ON THE PIXEL SIZE YOU SCALING, IT'S SOMETHING WE'VE TRIED TO ENABLE. ONE THING WE DID SLSZ WE HAVE RESOURCES IN-HOUSE AND WE'VE TRIED TO HELP LABS LIKE GIVE US YOUR DATA, IT TAKES US A FEW HOURS TO TRAIN THIS FOR YOU, THAT'S NOT EXACTLY SCALABLE FOR A LAB OF FOUR PEOPLE, BUT WE ARE TRYING TO ENABLE THAT. COMPANIES ARE ACTUALLY QUITE GENEROUS, SO VIDIA GIVES A LOT OF GPU GRANTS AWAY, WE'VE ALSO SUPPORTED APPLICATIONS FOR THOSE TYPES OF THINGS. I THINK THE INSTITUTIONS ARE GETTING MORE INVOLVED IN SUPPORTING THIS, AND THE PRICE IS GOING DOWN, SO RIGHT NOW A GP U THAT COULD RUN THIS, YOU KNOW, 30 TO 90 FRAMES PER SECOND IS ABOUT $550 RIGHT NOW, IT'S BECOMING MUCH MORE ACCESSIBLE RIGHT NOW I THINK. >> THANKS SO MUCH. THANKS SO MUCH, MACKENZIE. OUR NEXT SPEAKER IS DAVID REDISH FROM THE UNIVERSITY OF MINNESOTA >> Dr. Redish: THANKS. THE THERE WE GO. SO I WANT TO ALSO THANK THE ORGANIZERS FOR GIVING ME AN OPPORTUNITY TO TALK TO YOU TODAY AND I WANT TO THANK MACKENZIE FOR SETTING EVERYTHING UP SO PERFECTLY. WHAT I WANT TO DO TODAY S THIS WORKING? NO. HOW DO WE -- I SEE. THERE WE GO. SO I WANT TO REMIND EVERYBODY OF THIS GRAPH, THIS FIGURE THAT WE'VE ALL SEEN 1,000 TIMES, WHICH IS OF COURSE THE VARIOUS ABILITIES AND VARIOUS TECHNOLOGIES THAT ARE WAYS OF DETECTING NEUROPHYSIOLOGY AT BOTH TIME AND SPACE, AND I HAVE A PROBLEM WITH THIS FIGURE BECAUSE IT'S MISSING WHAT I THINK IS THE MOST IMPORTANT WAY OF MEASURING NEUROPHYSIOLOGY, WHICH IS BEHAVIOR. SO A LOT OF WHAT WE'RE TALKING ABOUT AND A LOT OF I GUESS THE TAKE-HOME MESSAGE FROM AT LEAST THESE FIRST FEW TALKS IS THAT WE'RE TRYING TO UNDERSTAND HOW BEHAVIOR ARISES FROM NEUROPHYSIOLOGY, BUT BEHAVIOR OF COURSE CHANGES CIRCUITRY WHICH CHANGES NEUROPHYSIOLOGY, AND THE KEY HERE IS THAT I WANT TO ARG YOU'LL WE HAVE TO DEFINE THE BEHAVIOR CAREFULLY, AND BY CAREFULLY, I MEAN SOMETHING VERY DIFFERENT FROM WHAT I THINK YOU ARE GOING TO EXPECT I MEAN, WHICH IS THAT WE NEED TO TAKE COMPUTATIONAL THEORIES TO CONNECT THOSE LEVELS AND GET THE BEHAVIOR RIGHT. AND I WANT TO START OFF WITH KIND OF SOME OLD SCHOOL POINTS ABOUT BEHAVIOR, ONE OF WHICH IS THE PROBLEM OF EQUIIF I FINALITY WHICH IS THAT IF YOU TAKE SOME SAMPLE BEHAVIOR, WE HAVE A RAT TRAINED TO RUN FROM THE SOUTH ARM TO THE WEST ARM OF A T MAZE AND THERE ARE TWO ACTUAL ALGORITHMS THAT THIS RAT COULD BE USING, ONE OF WHICH IS TO SAY I KNOW WHERE I AM, I'M ON THE SOUTH ARM, I KNOW WHERE I WANT TO BE, I WANT TO BE ON THE WEST ARM, HOW DO I GET FROM ONE TO THE OTHER, I HAVE TO TURN LEFT. THE OTHER IS THE RAT COULD SIMPLY LEARN WHEN I'M PUT ON THE MAZE, I TURN LEFT. BOTH OF THOSE ARE VALID SOLUTION S TO THIS PROBLEM, AND IF YOU SIMPLY RUN YOUR BEHAVIOR, AND THIS IS ALL YOU LOOK AT, YOU DON'T KNOW THE ANSWER TO WHAT THE ANIMAL HAS BEEN DOING. THIS HAS BEEN KNOWN FOR DECADES NOW. AND OF COURSE THE ANSWER IS THAT IF WE WERE TO TRAIN THE RAT ON A PLUS MAZE SO THE RAT KNOWS THAT WHOLE SPACE, WE CAN DIFFERENTIATE THOSE TWO ALGORITHMS BY PURGT THE RAT ON THE NORTH ARM AND NOW WE GET I KNOW I'M ON THE NORTH ARM, I WANT TO BE ON THE WEST ARM, WHAT DO I HAVE TO DO? I TAKE A DIFFERENT ACTION TO GET TO THE SAME LOCATION, OR I'M ON THE MAZE, I TURN LEFT, AND NOW I I UNDERSTAND UP AT A DIFFERENT PLACE. I WANT TO POINT OUT IT'S NOT THAT EITHER OF THESE ARE RIGHT OR EITHER OF THESE ARE WRONG. THESE ARE PROBES INTO WHAT THE ANIMAL IS ACTUALLY DOING, AND OF COURSE WE KNOW FROM MANY, MANY YEARS OF WORK THAT THE FIRST ONE IS A SYSTEM THAT TENDS TO INVOLVE A AWE HIPPOCAMPAL CIRCUIT ASK THE ONE ON THE RIGHT THE RESPONSE STRATEGY TENDS TO INVOLVE A DORSILATERAL CIRCUIT. WHEN WE LOOK AT COMPUTATION OF THESE, WE ACTUALLY KNOW A LOT ABOUT THE MECHANISMS AND COMPUTATIONS THAT THESE DIFFERENT CIRCUITS ARE ACCOMPLISHING, AND BY LOOKING AT THAT, WE CAN GO IN AND START LOOKING FOR THE NEUROPHYSIOLOGY OF THOSE COMPUTATIONS, AND I'M NOT GOING TO GO INTO THAT TOO MUCH TODAY, BUT I WANT TO POINT OUT THAT'S THE KEY LINK, THAT WE'RE LINKING FROM THE BEHAVIOR DLU THE COMP -- THROUGH THE COMPUTATION TO THE UNDERLYING CIRCUITS. ONE OF THE ISSUES, OF COURSING, NOW IS THEN TRANSLATION, HOW DO YOU TRANSLATE ACROSS CIRCUITS? IF WE LOOK AT THE DELIBERATION CIRCUITING WHERE WE SAY THE ANIMAL IS DOING AN ACTUAL SEARCH PROCESS, THIEF REFT CLI WE SHOULD BE ABLE TO GO IN AND LOOK FOR THAT SEARCH PROCESS, WE'VE BEEN ABLE TO DO THAT IN THE RAT, WELL, WE CAN RECORD FROM LARGE ENSEMBLES OF NEURONS, OF COURSE, AND WHAT WE FIND IS THAT AT CERTAIN MOMENTS WE'LL SEE SEQUENCES RUNNING IN THE HIPPOCAMPUS FORWARD BACK AND FORTH TO THE VARIOUS GOALS. NOW, IT TURNS OUT THAT WHEN HUMANS ARE DOING PLANNING, THEY ALSO USE THE SAME STRUCTURES, SO WE CAN ACTUALLY MAKE THESE CIRCUIT ANALOGIES BETWEEN THE COMPUTATIONS OF A RAT PLANNING TO GO TO A SPATIAL GOAL AND A HUMAN DECIDING WHERE TO GO FOR VACATION, WHETHER TO GO SKIING OR TO GO TO STONEHENGE AND THE POINT HERE IS WE'RE COMPARING THE CIRCUITS REQUIRES COMPARING THE COMPUTATIONS UNDERLYING THAT BEHAVIOR. I ALSO WANT TO POINT OUT THAT WHEN WE'RE TALKING ABOUT THIS, WE'VE GOT TO GET THE ATHOLOGY RIGHT, I WANT TO SPEND A COUPLE SLIDES TALKING ABOUT THIS. I WANT TO GO BACK TO ONE OF MY FAVORITE OLD CLASSIC HUMAN DATA, THIS IS THE LASON AND JOHNSON 972 PAPER WHICH IS THAT THEY GAVE SUBJECTS FOUR CARDS AND TOLD THEM A VOWEL ON ONE SIDE IMPLIES AN ODD NUMBER ON THE OTHER, YOU HAVE FOUR CARDS, A, B, 7 AND 2, WHICH CARDS DO YOU HAVE TO FLIP OVER TOLL PROVE THAT THIS IS CORRECT, TO CHECK THAT THIS STATEMENT IS CORRECT? EVERYBODY FLIPS OVER A BECAUSE OF COURSE YOU HAVE TO SEE IS THERE AN ODD NUMBER ON THE OTHER SIDE, MOST PEOPLE CANNOT SOLVE THIS, MOST PEOPLE FLIP OVER 7, THE CORRECT ANSWER ANSWER IS OF COURSE TO FLIP OVER 2 AND MAKE SURE THERE'S NO VOWEL ON THE OTHER SIDE. IF YOU REPHRASE THIS AS EUROPE A WAITER AT A BAR AND THERE ARE FOUR PEOPLE, ADULT, CHILD, THIRDS PERSON TORDED A WHISKEY, FOURTH PERSON OMPEDDED A SODA, WHOTION DO I HAVE TO CHECK TO MAKE SURE NOBODY IS DRINKING ILLEGALLY,ING EVERY SINGLE AMERICAN GETS THIS RIGHT. YOU'VE GOT TO GET THE ETHOLOGY, AMERICANS ARE NOT USED TO DEALING WITH CARDS AND NUMBERS AND LOGIC, THEY'RE VERY COMFORTABLE DEALING WITH DPLINGS A BAR. THIS WORKS IN OTHER SPECIES TOO. FOR EXAMPLE THERE'S A CLASSIC TASK FOR RATS AND MICE, IT ACTUALLY WORKS FOR RATS, THERE'S ISSUES IT HAS NOT BEEN SUCCESSFUL TRANSLATED TO MY KNOWLEDGE TO MICE, INTERESTING STATEMENT. FOR RATS THERE'S A CLASSIC TASK CALLED THE M HA ZZER ADJUSTING DELAY TASK, WHERE YOU HAVE A CHOICE, ON ONE LEVER YOU'LL HAVE A SMALLER REWARD, SAY ONE PELLET DELIVERED OR TWO PELLETS DELIVERED AFTER ONE SECOND BEING AND ON THE OTHER SIDE YOU'LL HAVE A LARGE HE WERE LATER REWARD SAY SIX PELLETS DELIVERED AFTER A DELAY AND THEN THE DELAY IS TIE TRAIPTED BASED ON THE CHOICE AND THEORETICALLY THE ANIMAL SHOULD FIGURE OUT WHICH SIDE IS LATER, CHOOSE ONE SIDE UNTIL IT'S BALANCED AND THEN ALTERNATE. IT TURNS OUT THAT RATS DON'T DO THAT, IN FACT, THERE'S A BEAUTIFUL PAPER BY RUDOLPH CARDI NOL WHEN HE WAS WITH TREF TREVOR ROBBINS AND FOUND THAT YES ON AVERAGE IN THE LONG TERM THESE TASKS DO DEMONSTRATE IMPULSIVITY AND ABLE TO MEASURE IMPULSIVITY. THE FACT BEING IS AT ANY MOMENT THEY CAN'T DIFFERENTIATE THE RAT 'S BEETZ HAIF YOR FROM RANDOM WE TRANSLATED THIS TASK TO SPHAIS AND SAID WE'LL TAKE THESE TWO THINGS, IT'S NOT LEVERS, IT'S SPATIAL LOCATIONS, NOW RATS BEHAVIOR PERFECTLY ANATOMICALLY AND WE COULD STUDY THIS AT A NEURAL CIRCUIT LEVEL. RATS UNDERSTAND SPACE, THEY DON'T REALLY UNDERSTAND LEVERS VERY WELL. I WANT TO TALK AND THEN THE THIRD KIND OF MAJOR POINT I WANT TO MAKE TODAY, I'LL MAKE FOUR POINTS, THE THIRD POINT I WANT TO MAKE TODAY IS THAT COMPLEX BEHAVIORS ARE ACTUALLY BETTER. IF YOU'RE SIMPLY COUNTING, THIS IS EXACTLY WHAT MACKENZIE WAS JUST TELLING YOU, IF YOU'RE SIMPLY COUNTING THE NUMBER OF LEVER PRESSES, YOU'RE MISSING A LOFT INFORMATION. AND THAT BY -- A LOT OF INFORMATION. AND THAT BY GOING TO THESE MORE COMPLEX TASKS, YOU ACTUAL HAVE COMPLEX SUBTLETIES THAT YOU CAN ACCESS AND YOU CAN LOOK FOR AND IT WILL TELL YOU WHAT CIRCUIT IS HAPPENING. ONE OF THE THINGS WE FOUND, FOR EXAMPLE, IS THAT WHEN RATS ARE MAKING CHOICES BASED ON THIS KIND OF PLANNING SYSTEM, THEY TEND TO SHOW THIS BEHAVIOR CALLED VICARIOUS TRIAL AND ERROR AND WE CAN ACTUALLY BY LOOKING AT THE PHYSICAL PATH OF THE ANIMAL THROUGH THESE BEHAVIORS, WE CAN SEE THESE DIFFERENCES AND EVIDENCE FOR WHICH CIRCUITS ARE BEING DRIVEN. I WANT TO TAKE A LITTLE BIT OF TIME AND TALK SPECIFICALLY ABOUT TRANSLATION AND ABOUT THE COMPLEX BEHAVIOR TRANSLATION. THIS IS A TASK WE'VE BEEN USING IN MY LAB FOR NOW A NUMBER OF YEARS WHERE YOU HAVE A RAT, IT'S RUNNING AROUND A CIRCULAR MAITZ, THERE'S FOUR -- MAZE, THERE'S FOUR WHAT WE CALL RESTAURANTS, EACH OF WHICH PROVIDES A DIFFERENT DPLAIFER OF FOOD, AND ARMTZ THE ANIMAL PASSES BY A RESTAURANT, IT HEARS A TONE AND THE PITCH OF THE TONE INDICATES THE DELAY IT WILL HAVE TO SPEND TO GET FOOD. IT IS A LIMITED TIME BUDGET, SO NOW TIME IS AN ECONOMIC VARIABLE SO WHAT THE ANIMAL BASICALLY HAS TO SAY IS WHEN I HEAR A 20- SECOND TIME FOR CHERRY, IS IT WORTH 20 SECONDS OF MY ONE-HOUR LIMITED TIME BUDGET TO SPEND WAITING FOR THE CHERRY OR DO I WANT TO THE SAVE THAT AND SPEND IT AT THE BANANA RESTAURANT NEXT-DOOR? WE FOUND THAT RATS DO THIS VERY NICELY, BUT WE WANTED TO TRANSLATE THIS TO HUMANS, AND WHEN WE STARTED TO LOOK FOR IT, WE HAD TO FIGURE OUT WHAT DO HUMANS FORAGE FOR ETHOLOGICALLY, AND I LOVE THIS, I WANT TO GIVE CREDIT TO GRAHAM ABRAM, A GRAD STUDENT IN ANY LAB, HUMANS FORAGE FOR IS VIDEOS ON THE INTERNET, SO WE CREATED THE A VIDEO VERSION OF THIS WHERE NOW YOU HAVE A DOWNLOAD BAR AND THE QUESTION IS IS IT WORTH 7 SECONDS TO WAIT FOR MY KITTEN VIDEO OR DO I WANT TO SKIP IT AND TRY MY LUCK AT THE LANDSCAPE RESTAURANT NEXT-DOOR? NOW MICE, RATS AND HUMANS LOOK BEHAVIORALLY IDENTICAL TO THREE OR FOUR ORDERS OF MAGNITUDE. WE'VE DONE THE NEUROPHYSIOLOGY TO CONNECTING IT UP AND WE CAN DO ALL THIS BUT I WANT TO POINT OUT SOMETHING ABOUT THIS, WHICH IS THIS IS NOT EASY, THIS TOOK THREE DIFFERENT LABORATORIES, MY LAB THAT WORKS IN RATS, ANGUS MCDONALD'S LAB THAT WORKS ON HUMANS AND MARK THOMAS' LAB THAT WORKS ON MICE AND THE FIRST RESTAURANT ROW TASK WAS 2012 AND OVER THE COURSE OF FIVE YEARS TORE GET TO THIS POINT WE WENT BACK AND FORTH MODULATING TASKS, HOW AM I DOING, IS THAT A TIME THING? OKAY. 8 MINUTES, I'M FINE. THAT IT TOOK GOING BACK AND FORTH AND MODIFYING EACH OF THESE TASKS SAYING OKAY, THE RATS DON'T DO IT QUITE THIS WAY, OKAY, THAT MEANS WE HAVE TO GO BACK AND DO THE MICE DIFFERENTLY OR DO THE HUMANS DIFFERENTLY, ASK WE CYCLED THROUGH THIS TO FINALLY GET TO THE POINT WHERE WE COULD RUN THESE LAST THREE COHORTS IDENTICALLY AND WE COULD MATCH THE BEHAVIORS, I THINK THIS IS A VERY IMPORTANT THING THAT CRITICALLY FROM A FUNDING PERSPECTIVE RESPECT FOR BEHAVIORAL COMPLEXITY IS IMPORTANT. SO WE ACTUALLY, AS I SAID, HAVE A VERY COMPLEX VERSION OF THIS TASK AND THE KEY IS THAT IT HAS SUBTLETIES WITHIN IT THAT WE'RE ABLE TO ACTUALLY UTILIZE, IN PARTICULAR, IT HAS SEPARATE DECISION ZONES, AND I'M NOT SAYING THAT THIS TASK IS KIND OF THE ONLY ONE TO USE, I'M USING THIS AS AN EXAMPLE, THAT BY HAVING A MORE COMPLEX TASK, WE'RE ABLE TO ACCESS WHAT THE CIRCUITS ARE DOING WITHIN THE SAME TASK, AND WE'VE BEEN ABLE, FOR EXAMPLE, TO SEE THAT WE SEE DIFFERENT DECISION PROCESSES IN DIFFERENT COMPONENTS, AND THAT ALLOWS US TO MEASURE DIFFERENT EFFECTS OF PHARMACOLOGY. FOR EXAMPLE, COCAINE AND MORPHINE TREATMENT HAVE DIFFERENT EFFECTS ON THESE DIFFERENT DECISION ZONES, AND THAT ACTUALLY TRANSLATES INTO DIFFERENT CIRCUIT COMPONENTS THAT WE'VE BEEN ABLE TO DO AND WE CAN ACTUALLY MODIFY THESE DIFFERENT CIRCUITS AND AFFECT ONE WHILE LEAVING THE OTHER INTACT, AND THAT GIVERS US DOUBLE AND TRIPLE ASSOCIATIONS WITHIN A SINGLE TASK. AND I THINK THAT'S REALLY IMPORTANT THAT YOU'RE GOING INTO THAT DEPTH IN THE COMPLEX TASK, GETS YOU PAST THAT EQUIFINALITY PROBLEM. I ALSO QUICKLY WANT TO POINT OUT WHM WE'RE TALKING ABOUT MODULATING CIRCUITS, I THINK IT'S IMPORTANT THAT WE'RE DIFFERENTIATING BETWEEN MODULAT ING THE ACTIVITY OF A CIRCUIT AT A MOMENT AND MODULATING THE ANATOMY, WHETHER THROUGH CONNECTIVITY, FOR EXAMPLE, IN THIS THIRD PAPER WE MODULATED THE CONNECTIVITY BETWEEN THE INFRALIMBIC CORTEX AND THE ACULP BENT SHELL AND EXAMINED THE CONSEQUENCES OF THAT MODULATION, NOT MOPPED LAT ING THE ACTIVITY, THE ACTIVITY IN THE THE INFRALIMBIC CORTEX IS INTACT, WE MODULATED THE ANATOMY, THE CONNECTION STRENGTHS. YOU CAN OF COURSE MODULATE CONNECTIVITY AND THE TRICK IS THESE ARE ALL USE INFORMAL DIFFERENT PLACES. LAST POINT O I WANT TO TALK ABOUT THE NEW USE OF THIS IN COMPUTATIONAL PSYCHIATRY AND THE REAL PUSH PEOPLE ARE TRYING TO MAKE FROM A TREATMENT PERSPECTIVE OF USING THESE COMPLEX TASKS AS BIOMARKERS. THIS IS THE CLASSIC PAPER BY CLAIRE GILLIN WHERE SHE AND HER TEAM WERE ABLE TO TAKE WHAT WE COMMONLY CALL THE DAW2 TASK, WHICH IS NOT FAIR BECAUSE OTHER PEOPLE WERE ON THE PAPER, NATHANIEL WAS THE FIRST PERSON ON THE PAPER YOU THAT DESCRIBED THIS, A TASK THAT SEPARATES OUT SUBLGHTS TIES OF BEHAVIOR BETWEEN PLANNING AND REACTIONARY AND KIND OF PROSPECTIVE AND RETROSPECTIVE BEHAVIORAL DECISION PROCESSES. AND THEY USED MTURK TO COME IN AND THEN DID A SET OF QUESTIONNAIRES, DID A FACTOR ANALYSIS, AND THEY FOUND THAT PARTICULAR ASPECTS OF THIS TASK WERE HIGHLY INDICATE YOUTIVE OF A PARTICULAR -- INDICATIVE A PARTICULAR FACTOR RELATED TO COMPULSIVE BEHAVIOR AND INTRUSIVE THOUGHT ON THESE SURVEY QUESTIONNAIRES, AND THE KEY HERE IS THAT THE HOPE IS THAT THESE KINDS OF TASKS CAN BE USED AS ONE OF MY COLLEAGUES SAID, ARRANGES THE BLOOD TEST FOR PSYCHIATRY. THE PROBLEM HERE, THIS IS REALLY KIND OF A FUNDING POINT I WANT TO KIND OF PUT FORWARD FOR BRAIN AND REALLY NEEDS TO START HAPPENING IS WE NEED TO KNOW THE TEST/RETEST RELIABILITY OF THESE HIGHLY COMPLEX BEHAVIORS. WE NEED TO FURTHER REDUCE THE BURDEN OF THESE TESTS AND THOSE BOTH COME BECAUSE THESE TESTS WERE DESIGNED FOR RESEARCH, THEY WERE DESIGNED SO WE COULD GO IN WITH NEUROPHYSIOLOGY AND EXAMINE THE MOMENT BY MOMENT BEHAVIOR OF ANIMAL, HUMAN AND NON-HUMAN ANIMALS, BUT IT THE WE'RE GOING TO MAKE THEM INTO CLINICAL TESTS , WE NEED TO ACTUALLY KNOW THAT THEY ARE RELIABLE, WE NEED TO KNOW THAT THOSE PARAMETERS COME OUT REGULARLY, WE NEED TO MAKE IT SO THAT A PATIENT DOESN'T SPEND AN HOUR PLAYING THIS VIDEO GAME, AND WE NEED TO FURTHER PARAMETERIZE THESE TESTS TO DETERMINE WHICH OF THESE COMPLEX FACTORS THESE KINDS OF POSE MEASURES FOR EXAMPLE THAT MACKENZIE WAS TALKING ABOUT THAT WE CAN GO IN AND PULL OUT, RIGHT THERE ARE THESE VERY, VERY SUBTLE EFFECTS THAT CAN ACTUALLY PROVIDE A LOT OF INFORMATION FOR US. AND FINALLY, AS I MENTIONED, WE NEED TO REMEMBER THAT BEHAVIOR IS EQUIFINAL, IT COMES FROM MULTIPLE SOURCES, SO WE NEED TO GET THAT PHYSIOLOGY TO LOOK AT HOW THOSE COMPLEX BEHAVIORS ARE BEING REALIZED, BUT AGAIN MY POINT IS BY GOING TO THE COMPLEX BEHAVIORS YOU HAVE BETTER ACCESS TO THOSE UNDERLYING CIRCUITS. SO IN SUMMARY, I WANT TO GIVE FOUR TAKE-HOME MESSAGES. ONE IS TO REMIND EVERYBODY THAT BEHAVIOR DOES ARISE FROM MULTIPLE CIRCUITS, BUT IF WE THINK OF IT FROM A COMPUTATION PERSPECTIVE, IT REALIZES THE DIFFERENT COMPUTATIONS REALIZE THESE DIFFERENT COMPLEX BEHAVIOR S SUBTLY DIFFERENTLY AND THAT SUBTLETY IS REALLY IMPORTANT, AND THEREFORE COME PLEEKS BEHAVIORS ARE OFTEN BETTER THAN THE SIMPLE TASKS BECAUSE THEY HAVE EXACTLY THAT, MORE SUBTLETIES TO ACCESS. WHEN TRANSLATING ACROSS SPECIES, IT'S CRITICAL TO GET THE ETHOLOG Y RIGHT. IF YOU TAKE A RAT AND TRY TO SHOW IT VIDEOS, IT DOESN'T WORK SO WELL. IF YOU HAVE A HUMAN AND ACTUALLY HAVE THEM WALK AROUND, WE TRIED THIS, IT'S REALLY HARD TO GET THEM TO RUN RELIABLY. [LAUGHTER] AND USING BEHAVIOR AS BIOMARKERS WILL REQUIRE A LOT OF WORK, REALLY GETTING WHAT THE PARAMETERS ARE OF THESE NEW AND COMPLEX TASKS AND DETERMINING WHAT THEY ACTUALLY MEAN AND HOW WE GET DL. -- AND HOW WE HAVE GET THERE. HOW AM I DOING ON TIME? >> ALL RIGHT. THANKS. [APPLAUSE] >> WE'VE GOT ONE OR TWO MINUTES FOR SOME QUESTIONS. >> THANK YOU. THAT WAS A GREAT TALK, AND I REALLY APPRECIATE THE APPROACH OF USING GREATER COMPLEXITY TO REVEAL DIFFERENT COMPUTATIONS, BUT I THINK YOU WOULD PROBABLY AGREE THAT YOU HAVEN'T REACHED AN ENDPOINT ON COMPLEXING TI, BUT YOU'VE PROBABLY THOUGHT ABOUT THIS MORE THAN ALMOST ANYONE ELSE. IS THERE A WAY OF KNOWING WHEN YOU'VE GOT ENOUGH COMPLEXITY FOR A GIVEN SITUATION? >> Dr. Redish: THAT'S A GREAT QUESTION. I DON'T KNOW THAT ONE CAN KNOW WHETHER -- I MEAN, THERE'S A TRADE-OFF BETWEEN COMPLEXITY AND YOU SIMPLICITY, RIGHT? OF THAT AS UP GET MORE AND MORE COMPLEX, YOU IN SOME SENSE NEED MORE AND MORE EXAMPLES TO ACTUALLY SEE THE DIFFERENCES AND AT SOME LEVEL FAIR ENOUGH GET MORE AND MORE SIMPLE, THINGS GET HIDDEN, SO THERE'S KIND OF AN OPTIMUM THAT SHIFTS DEPENDING ON THE QUESTION HE, AND I DO THINK IT REALLY DEPENDS ON THE QUESTION. I DON'T WANT TO THE SAY THAT THESE -- SOME OF THOSE SIMPLE BEHAVIORS, LIKE THAT TEESM MATES TASK IS AN ELEGANT SIMPLE BEHAVIOR THAT TOAPPED UP APRIL FUNDAMENTAL QUESTION ABOUT THE DIFFERENT DECISION SYSTEMS IN RODENTS AND THAT WAS A BIG PART OF THE PROCESS. I THINK THAT THE KEY IS THAT IT DEPENDS ON THE QUESTION AT HAND AND THERE'S A CONTINUUM OF USEFULNESS, AND ONE THING THAT IS TRUE IS THAT THE BETTER TOOLS HAS WE'RE HAVING FOR BEHAVIORAL ANALYSIS ACTUALLY IS IMPROVING AND MAKING IT EASIER AND EASIER TO USE MORE AND MORE COMPLEX BEHAVIORS. >> Dr. Dzirasa: MAYBE ONE MORE. >> DAVID, HOW DO YOU DEAL WITH THE FACT THAT THE MORE THE COMPLEX THE BEHAVIOR THEY GET, THE HARDER IT IS TO DEFINE THEY DID THAT BEHAVIOR RATHER THAN SOMETHING NOT QUITE LIKING THAT BEHAVIOR AND I DON'T KNOW WHETHER THE DIFFERENCE MATTERS? >> Dr. Redish: I WOULD ACTUALLY ARGUE THAT THAT PROBLEM ARISES MORE WITH THE SIMPLE BEHAVIOR, SO BECAUSE EVERY RAT ACTUALLY DOES PRESS A LEVER SLIGHTLY DIFFERENTLY, AND THE QUESTION IS IF YOU SAID I'M GOING TO ONLY COUNT PRESSING THE LEVER AS MY BEHAVIOR, HOW DO YOU KNOW THAT THE FACT THAT WE HAD ONE RAT THAT ACTUALLY DECIDED TO PRESS THE LEVER WITH ITS BACK SIDE IN AN EARLY EXPERIMENT, AND DID THAT MATTER? ACTUALLY THE NUMBERS LOOK THE SAME AT THE MOTIVATION MEASURES WE WERE MEASURING. SO, YOU KNOW, THE QUESTION COMES , I THINK THAT'S TRUE OF ANY BEHAVIOR, AND I WOULD ANSWER THAT THE MORE DATA ANALYSIS, COMING BACK TO WHAT MACKENZIE WAS SAYING, THE MORE DATA YOU HAVE AVAILABLE FROM THE ANIMAL IN THESE BEHAVIORS, THE EASIER IT IS TO DETERMINE WHAT PARTS MATTER AND WHICH DON'T. >> THANK YOU. >> WE CAN CLAP. [APPLAUSE] >> Dr. Dzirasa: OUR NEXT SPEAKER IS KARIN PARKER FROM STANFORD. >> Dr. Parker: I WANT TO BEGIN BY THANKING THE ORGANIZER FOR HAVING ME AND DAVID FOR PERFECTLY SETTING UP MIYATAKE. JUST TO FRAME ME FROM WHERE I'M COMING FROM, I RUN A TRANSLATIONAL SOCIAL SCIENCE LAB AT STANFORD AND WE STUDY VARIOUS BRAIN DISORDERS IN PATIENTS PARTICULARLY AUTISM AND THEN WE'RE IN THE PROCESS OF DEVELOPING REFINED ANIMAL MODELS WHERE WE CAN DEVELOP BIOMARKERS AND THEY ARE ARE PUT I CAN INTERVENTIONS, SO THE GOAL HERE IS -- THERAPEUTIC INTERVENTIONS, SO THE GOAL HERE IS TO OPTIMIZE TRANSLATION. IN TERMS OF KEY POINTS IN THE TALK, I'M GOING TO NOT NECESSARILY IN THIS ORDER ARE, BUT I'M GOING TO BE ADDRESSING SOME ISSUES WITH ANIMAL MODELS, WHAT WE NEED TO CONSIDR SORT OF PIGGYBACKING ONTO WHAT DAVID TALKED ABOUT IN HIS LAST TALK, HOW DO WE SELECT THEM, THE IMPORTANCE OF PRIMATE MODELS IN STUDYING BRAIN DISORDERS, THE NEED FOR INCREASED INVESTMENT IN PRIMATE RESOURCES WHICH HASN'T BEEN COVERED, AND THEN A LITTLE BUILT ABOUT THINKING ABOUT MARMOSETS, WHICH ARE A NEW EMERGING MODEL. AT LEAST IN TERMS OF THINKING ABOUT TOOL USE. AND THEN ALSO APRIL BIT ABOUT HOW DO WE THINK REALLY CAREFULLY ABOUT THE BEHAVIORAL ASSAY THAT IS WE DEVELOP AND THEN A LITTLE BIT ABOUT BRAIN STATES, MY LAB FOCUSES ON NEUROPEPTIDES PARTICULARLY OXYTOCIN AND VASOPRESSIN SO I'LL TALK A LITTLE BIT ABOUT THAT AND THEN SOME EMERGI NG AND NEEDED TECHNOLOGIES. SO EVERYBODY HAS THEIR FAVORITE ANIMAL, AND I THINK IN TERMS OF MODELS, EVERY ANIMAL MODEL HAS VALUE, AND WE JUST HAVE TO LEVERAGE IT APPROPRIATELY. BUT THERE'S A REASON WHY WE SPEND BETWEEN 1.7 AND 2.4 BILL YOU YON DOLLARS TO BRING A DRUG TO MARKET, AND WHAT I SUBMIT TO YOU IS THIS IS PARTLY DUE TO THE FACT THAT THE MAJORITY OF DRUGS FAIL IN CLINICAL TRIALS FOR DRUGS THAT WERE EFFICACIOUS IN ANIMALS. SO WHAT I THINK WE REALLY NEED TO DO IS THINK ABOUT DEVELOPING MORE REFINED ANIMAL MODELS, AND THESE ARE THE THINGS WE NEED TO BE THINKING ABOUT, AND I DON'T THINK WE'RE THINKING CAREFULLY ENOUGH ABOUT THIS. IF WE'RE MODELING THIS IN AN ANIMAL AND WE CARE ABOUT AUTISM, IT HAS TO BE NEURODEVELOPMENTAL. IF WE'RE THINKING ABOUT DEMENTIA , WE NEED TO BE STUDYING THIS IN ADULTS. IS THE PREVALENCE SEX BUYS AD -- BIASED, IS DO WE SEE THIS MORE PREVALENTLY IN THE MALES VERSUS SIMILARLY DEPRESSION, MANY OF OWRM NEUROPSYCHIATRIC DISEASES ARE SEX BIASED, ARE WE MODELING HOMOLOGOUS OR ENDOPHENOTYPIC FEATURES OF OUR DISEASE? SOME DISEASES ARE SHARED BETWEEN ANIMALS AND PEOPLE, LIKE DIABETES, ANIMALS GET DIABETES, BUT FOR SOME OF THE MORE COMPLEX FEATURES OF NEUROPSYCHIATRIC DISORDERS, MAYBE WE'RE ONLY MODELING A PIECE OF THEM, RIGHT? FACE VALIDITY, A REALLY, REALLY CRITICAL ISSUE. IS THERE OUTWARD SIMILARITY IN APPEARANCE BETWEEN THE BEHAVIOR EXHIBITED BY THE ANIMAL AND THE SPECIFIC SYMPTOMS OF THE HUMAN CONDITION? AND I'LL GET A LITTLE BIT MORE INTO THAT LATER. CRUCT VALIDITY. THE SIMILARITY TO THE UNDERLYING CAUSES OF THE DISEASE, RIGHT? SO GENES FIRST APPROACHES TO MANY OF THE DISORLDZ WE'VE BEEN STUFFED DID IING AND ALSO PREDICTIVE VALIDITY. IS THE MODEL'S ABILITY TO IDENTIFY AND TEST DRUGS WITH THERAPEUTIC VALUE FOR PATIENTS?& SOME OF THE SINS I THINK WE'VE COMMITTED AS A FIELD. IGNORING CONSTRUCT VALIDITY. SO FMENT -- SO FS WE'RE THINKING ABOUT AUTISM, FOR DECADES WE DID RESEARCH ON PEER-REARING MONDAY CITZ, REMOVE THEM FROM 30 DAYS FROM MOMS, THEY LOOK MORE LIKE ROMANIAN ORPHANS, NOT AUTISTIC, HUGE LESIONS, NO CONSTRUCT VALIDITY IN TERMS, BUT WE NEED TO LOOK AT SPONTANEOUSLY OCCURRING SOCIAL DEFICITS OR GENES FIRST MODELS, IGNORING FACE VALIDITY, FOR ME WITH AUTISM, IT'S A COMPLEX SOCIAL COGNITION DISORDER ARE IN A SPECIES THAT USES VISION AS ITS PRIMARY SENSORY MODALITY, WE NEED TO THINK CAREFULLY ABOUT THIS. AGAIN, PIGGYBACKING ONTO WHAT DAVID SAID, WE NEED TO USE ECOLOGICALLY INFORMED BEHAVIORAL READOUTS, RIGHT? TESTING RATS DURING THE LIGHT PHASE OF THEIR CYCLE WHEN THEY'RE NOCTURNAL IS PROBABLY NOT A GOOD IDEA. ALSOS CANNED AND HIGHLY AUTOMATED TESTS ARE NOT NECESSARILY OUR FRIENDS. I CAN'T TELL YOU HOW OFTEN PEOPLE GET EXCITED ABOUT OH, THIS IS AUTOMATED, I DON'T EVEN HAVE TO LOOK, SOMETIMES YOU IN SOCIAL PREFERENCE TESTS, AND THE ANIMAL IS BREAK EGG THE BEAM AND GOING OVER INTO THE OTHER ANIMAL 'S CAGE, I'M LIKE, WHAT ARE THEY DOING? ARE THEY FIGHTING? YOU DON'T KNOW BECAUSE YOU'RE NOT LOOKING AT THE BEHAVIORS. ANOTHER PET PEEVE OF MINE, SO THERE'S BEEN ALL KINDS OF MEDIA ATTENTION ABOUT GIVING OXYTOCIN VERY EARLY IN LIFE TO ANIMALS AND THERE WAS A FEW YEARS AGO GOD, OXYTOCIN IS TERRIBLE, WE SHOULDN'T GIVE IT TO AUTISTIC KIDS, BUT THE ANIMALS THAT WERE TREATED WERE NEUROTYPICAL ANIMALS, THEY DIDN'T HAVE SOCIAL DEFICITS, SO IN SUBSEQUENT FOLLOW-UP WORK WHEN DAN GESHWIN DID WORK WRG CAT KNAPP 2 MOUSE ASK THERE'S BEEN SOME MICE WE KNOW THEY HAVE OXYTOCIN SIGNALLING DEFICITS AND IF YOU TREAT THEM EARLY IN LIFE YOU RESTORE SOCIAL FUNCTIONING AND YOU ACTUALLY RESTORE THE NUMBER OF OXYTOCIN-PRODUCING NEURONS TO WILD-TYPE, RIGHT? SO YOU DRAW VERY DIFFERENT CONCLUSIONS BASED ON HOW YOU THINK ABOUT YOUR ANIMAL MODEL. ANOTHER THING IS IGNORING THE IMPORTANCE OF HOUSING AND WELFARE ON EXPERIMENTS. TWHEAN THIS IS ONE OF THE LEADING REASONS WHY -- WE KNOW THIS IS ONE OF THE LEADING REASONS WHY WE FAIL YOU TO REPLICATE BUT THERE ISN'T MUCH OF AN EFFORT ACROSS LABS TO STANDARDIZE AND THINK ABOUT THESE VERY SIMPLE CONSIDERATIONS SO WHEN WE STARTED DOING MODELING AUTISM, THIS IS A MAP THAT I ACTUALLY MADE, SO IT'S THINKING ABOUT WHAT ARE THE PROS AND CONS TO DEVELOPING A RODENT MODEL VERSUS A PRIMATE MODEL? AND DEPENDING ON WHAT YOU'RE TRYING TO GET OUT OF IT, YOU WILL PICK A DIFFERENT MODEL, RIGHT? SO FOR US WE WERE REALLY INTERESTED IN MOVING INTO TESTING THINGS IN THE DRUG SPACE SO WE KNOW THAT PRIMATES, WE KNOW THAT RODENTS ARE REFRACTORY TO THE NEUROTOXIC EFFECTS OF MTP T AND THAT THERE WAS AN INTERNATIONAL TRAGEDY BECAUSE WE RURBLED TO THE MARKET TO GIVE THALIDOMIDE AND WE KNOW THAT IT WAS TERATOGENIC IN PRIMATES BUT IT WASN'T IN RODENTS SO WE NEED TO THINK CAREFUL ABOUT WHAT FEATURES OF MODELS WE CARE ABOUT AND AGAIN ALL MODELS HAVE VALUE BUT THEY'RE NOT CREATED EQUALLY DEPENDING ON YOUR QUESTION. SO ANOTHER THING TO GO THINK ABOUT IS ACTUALLY THINKING DEEPLY ABOUT THE DISEASE, SO I STUDY AUTISM AND WE KNOW THAT AUTISM ARISES FROM DISTINCT GENETIC AND PHYSIOLOGICAL ABNORMALITIES THE AND THAT THERE'S TWO KEY DIAGNOSTIC THING CRITERIA, AND WHAT WE WANT TO DO IS THINK DEEPLY ABOUT HOW DO WE MODEL THESE BEHAVIORALLY AND PHYSIOLOGICALLY AND WHAT ARE THE POINTS OF ENTRY. SO MY LAB HAS SORT OF DONE THIS IN THREE DIFFERENT WAYS. WE HAVE A BEHAVIOR FIRST APPROACH WHERE WE'VE GONE INTO, THERE'S GOOD EVIDENCE THAT THE MAJORITY OF GENETIC BURDEN IN AUTISM IS POLYGENIC, AND THAT INDIVIDUAL DIFFERENCES IN SOCIAL FUNCTIONING HAVE UNDERLYING POLYGENIC TRAITS, SO WE'VE GONE INTO A LARGE MONKEY POPULATION OF 5500 ANIMALS, CREATED A STATISTICAL CLASSIFICATION ALGORITHM TO IDENTIFY THE ANIMALS AT THE EXTREMES AND THEN GENES FIRST APPROACHES WHERE WHEN YOU ACTUALLY KNOW THE CANDIDATE SIGNALLING PATHWAYS THAT'S ANOTHER GOOD WAY TO ESTABLISH CONSTRUCT VALIDITY. BUT WHEN WE DID IN AND SAY WHAT ARE THE BEHAVIORAL ASSAYS, HOW DO WE DEVELOP THEM, THE FIRST QUESTION IS WHAT ARE THE CORE SYMPTOMS THAT THE PATIENTS EXHIBIT? SOME OF US ARE CLINICIAN SCIENTISTS, SOME OF US ARE BASIC SCIENTISTS, WALK DOWN THE STREET AND TALK TO THE CLINICIANS. WHEN WE STARTED DEVELOPING OUR MONKEY MODEL, I SAT DOWN WITH 15 CLINICIANS AND SAID WHAT DO YOU WANT TO SEE IN MY MODEL SO YOU'LL BELIEVE THAT I HAVE A MODEL OF AUTISM, RIGHT SNT THAT HE IS REALLY IMPORTANT, IT TOOK A LOT OF TIME, BUT I THINK IT WAS WORTH IT IN THE END. CAN WE MODEL THESE FEATURES IN OUR SPECIES? IT WE CAN'T, GO BACK TO THE DRAWING BOARD. I THINK THAT IT MIGHT BE HARD AND DID I FEEL BUT NOT DOING IT RIGHT DOESN'T GET US ANYWHERE. AND THEN IN TERMS OF I'M GOING TO TALK A LITTLE BIT ABOUT ONE OF THE MODELS THAT WE DEVELOP.& WE DEVELOPED THE FIRST PRIMATE BEHAVIOR SOCIAL TEST BATTERY AND WE ASKED QUESTIONS AS WE WERE VETTING THE TEST TO PUT INTO THIS BATTERY. THE FIRST ONE WAS, ARE THERE RELEVANCE TO KEY SOCIAL DEFICITS OBSERVED IN THESE PATIENTS? SO WHAT CAN I MODEL IT A PATIENT -- SORRY, WHAT CAN I MODEL IT A MONKEY YOU THAT LOOKS LIKE THE PATIENTS? THEN AGAIN, THE ECOLOGICAL RELEVANCE TO AND PRIOR SUCCESSFUL IMPLEMENTATION IN MEC ASKA RELATED SPECIES, ARE THE TESTS DESIGNED OPTIMALLY SO THAT THE MONKEYS WILL PERFORM THEM, ARE THESE INTERESTING, WILL THE MONKEYS DO THESE THINGS NATURALLY IN THE WILD? IF WE'RE GOING TO BE PLAYING SOUND PLAYBACKS USING AND EXPLOITING THEIR NATURAL VOCALIZATIONS AS A WAY TOY START -- WAY TO START THINKING ABOUT POROSITY, BUT GIVING VOCAL ZA ITIONZ THAT A HUMAN MIGHT HEAR MAYBE NOT SO MUCH, THEN WAYS TO EVALUATE PERFORMANCE. SO THEN WE EXPLOITED EYE TRACKING BECAUSE ONE OF THE HALLMARK FEATURES TOURS IN AUTISM IS DEFICITS IN EYEGAZE, WE WERE ABLE TO DO THAT IN PRIMATES, THAT'S A SENSORY MODALITY BETWEEN HUMAN AND NON-HUMAN HUMAN PRIMATES, WE CATHYED A TEST BATTERY WHERE WE CAN PROBE THE ANIMALS ON FACE RECOGNITION VERSUS OBJECT RECOGNITION, WE HAVE VIDEOS WE SHOW THEM WITH SOCIAL CUES -- I DIDN'T SEE THE TIME. PERFECT. AND SO WE ASKED THEM IF WE SHOW YOU A VIDEO OF A MONKEY YOU LIP SMACKING, WHICH IS AN AFILLLY YA TIVE GESTURE IN PRIMATES, HOW DO YOU REACT TO THAT? TO DAVID'S POINTED ABOUT LOOKING AT REALLY COMPLEX BEHAVIOR, WE'RE RECORDING EYEGAZE AND ALL THESE DIFFERENT RESPONSES. IT WE SEE, THIS IS AN AGGRESSIVE GUY, HE SCAIRPZ ME, WE SHOW THEM AGGRESSIVE VIDEO, DO YOU GAZE OVER IT? SOMEBODY APPROACHES YOU AND THEY'RE BEING REALLY AGGRESSIVE, THIS ANY PRIMATE SPECIES, THEY'RE GOING TO BEAT YOU UP, THEY GAZE AVERT. OF SO OF THE JOY ATTENTION, THIS IS EASY TO MODEL, PRIMATES, THIS GUY LOOKING OVER HERE, THIS IS SOMETHING IN AUTISM, WE CAN DO ALL KINDS OF MANIPULATIONS. WE HAVE A SOCIAL INTERACTION WITH PEERS TEST WHERE WE HAVE FOUR GO PRO CAMERAS BEING ABLE TO MAP THE ENTIRE SPACE OF THE TESTING ARENA. WE'RE GIVING THEM VOCAL CUES, WE HAVE A SOCIAL MOTIVATION TEST BASED ON SOMETHING THAT MICHAEL PLAT DEVELOPED WITH PAIN WITH JUICE TO BASICALLY GET ACCESS TO SOCIAL INFORMATION, AND THEN WE HAVE A COUPLE TESTS TO START ARE PROBING INTELLECTUAL DISABILITY WHICH CAN BE A FEATURE OF AUTISM . SHIFTING GEARS, THE ROAD DENT WORK IS REALLY ELEGANT AND CAN PROVIDE MECHANISTIC INSIGHTS BUT THESE DON'T READILY TRANSLATE TO PRIMATES AND HUMANS AND I THINK ONE POINT THAT'S PARTICULARLY INTERESTING IS THE ISSUE OF PRAIRIE VOLS, ONE OF MY FAVORITE CREATURES FOR MANY YEARS I STUDIED, LARRY YOUNG'S GROUP HAS PROVIDED LOVELY DATA SHOWING THAT OXYTOCIN RECEPTOR SPREPTION IN THE NUCLEUS ACCUMBENS REALLY IS A DRIEMP OF PAIR BONDING AND ALL KINDS OF OTHER SOCIAL BEHAVIORS AND THAT THIS IS NATURAL VARIATION WITHIN A PRAIRIE VOL POPULATION WITHIN THE SAME LAB SO THIS HAS ALL KINDS OF REALLY INTERESTING IMPLICATIONS FOR SOCIAL REWARD DEFICIT DISORDERS IN HUMANS BUT HOW DO WE MEASURE THIS? WE DON'T HAVE ANY GOOD LIGANDS, WE CAN'T DO PET IMAGING, SO HOW DO WE TRANSLATE THESE SORTS OF FINDINGS IN A LIVING HUMAN BRAIN , RIGHT? WE DON'T HAVE THE TECHNOLOGY. SO I THINK WE NEED TO DEVELOP THESE TOOLS, PET LIGANDS, SPECTROSCOPY, TO BE ABLE TO TAKE& THESE SORT OF REVOLUTIONARY FINDINGS IN RODENTS AND MOVE THEM INTO PRIMATES AND PEOPLE. OKAY. THEN IN TERMS OF HUMANS, VERY GROSS MEASUREMENTS, SO PEOPLE ARE LOOKING AT PLASMA, SALIVA, URINE MEASURE OF OX TOE EXPIN VASOPRESSIN, WE DON'T HAVE ANY IDEA WHAT THIS MEANS IN TERMS OF BRAIN FUNCTION BUT HUNDREDS OF LABS A ACROSS THE WORLD ARE DOING THIS WORK, LOW ABUNDANCE PROTEINS AND PEPTIDES, WE HAVE SPENT MORE MONEY THAN I CARE TO TELL YOU IN TRYING TO DEVELOP TOOLS BUT THEY DON'T WORK WELL, LUMIX DOESN'T WORK, MASS SPEC DOESN'T WORK, WE'RE SORT OF LEFT WITH THESE GUYS BUT I'M NOT SUPER HAPPY WITH THOSE, THEN THE PHARMACOLOGICAL MANIPULATIONS WE'RE DOING IN PEOPLE ARE GIVING PUFFS IN THE NOSE OF A DOSE THAT NOBODY UNDERSTANDS WHY, WE DON'T KNOW WHAT THE TARGET ENGAGEENT IS, MOST OF IT RUNS DOWN THE BACK OF YOUR THROAT, SO IT'S REALLY CRITICAL I THINK TO MOVE FORWARD BUT WE DON'T HAVE FUNDING INITIATIVES FOR IT AND IT'S DIFFICULT TO GET MONEY LIKE SOMEBODY HAD MENTIONED IN AN EARLIER SESSION TO DO THIS SORT OF FUNDAMENTAL WORK, RIGHT? OKAY. SO IN TERMS OF IMPACTFUL AND EMERGING TECHNOLOGIES, SO WHOLE GENOME SEQUENCING, THE COSTS ARE BEING DRIVEN DOWN, I THINK THERE'S A REALLY WONDERFUL OPPORTUNITY TO ESTABLISH HOMOLOGY WITH MUM DISEASES, HE IS -- HUMAN DISEASES, ESPECIALLY FOR POLYGENIC FEATURES, BUT THIS WILL REQUIRE SELECTIVE BREEDING AND CENTRALIZED DNA BANKS PROBABLY AT THE NATIONAL PRIMATE CENTERS. WE NEED REALTIME NEURO CHEMICAL SENSORS IN TERMS OF SPECIFIC RESOLUTION IN THE BRAIN, SO WE'VE BEEN WORKING A LITTLE BIT ON AN INITIATIVE AT STANFORD ON THIS. WE NEED BETTER NEURO IMAGING TECHNIQUES TO NONINVASIVELY AND LONGITUDINALLY PROBE THE HUMAN BRAIN, THAT WILL PROBABLY REQUIRE INVESTMENT ESPECIALLY AT THE PRIMATE INSTITUTIONS, AND RS GENOME ENGINEERING CONSTRUCTING FOR PRIMATE ANIMALS CIRCUIT BUST ING, THIS IS EXPENSIVE TORQUES WE CENTRALIZE THIS OR NOT? MOVING INTO THAT, BOTH JAPAN AND CHINA HAVE MADE HUGE NATIONAL INVESTMENTS IN TRANSGENIC MONKEYS AND THEY'VE MADE A BET BECAUSE THERE ARE FEATURES OF THE BRAIN THAT I WOULD SUBMIT WE CAN ONLY ARGUE SORT OF MEASURE IN PRIMATES AND SO THESE ARE BIG NATIONAL INVESTMENTS BUT WE HAVEN'T DONE MUCH IN THE U.S. ON THIS, SO WE HAVE 7 NATIONAL PRIMATE RESEARCH CENTERS THAT ARE SORT OF SCATTERED AROUND THE COUNTRY, AND WE HAVE SOME ISSUES SO THEIR UNDERFUNDED, P51 BASE GRANTS WHICH ARE THE NIH GRANTS THAT UNDERWRITE THIS FUNDING, THEY HAVE BEEN STATIC FOR 10-15 YEARS, WHICH BASICALLY RESULTS IN A 20 PERCENT REDUCTION IN FUNDS IF WE ACCOUNT FOR INFLATION. SOME OF THESE FACILITIES HAVE NOT BEEN UPDATED SINCE THE '60S OR '70S ERA, SO WE CAN'T ADD THESE EMERGING TECHNOLOGIES LIKE GENOME EDITING WITHOUT SIGNIFICANT CASH INFUSIONS. AND MANY OF THE PRIMATE, I WAS JUST AT THE PRIMATE MEETING AT N IH, I'M ON THE ORGANIZERRING COMMITTEE FOR THE TRANSGENIC NATIONAL ACADEMY OF SCIENCE IN D C IN TWO WEEKS, BUT ONE OF THE BIGGEST ISSUES WE CAN'T EXPAND TO MEET USER DEMAND FOR MARMOSETS, THESE ARE JOWTD DATED FACILITIES COMPLETELY UNDER FUNDED. WHAT WAS THE FINANCIAL MODEL? DO WE DO THIS AT THE INDIVIDUAL UNIVERSITY LEVEL, CENTRALIZE THIS? WE HAVEN'T FIGURED THIS OUT YET. I DON'T HAVE ANY ANSWERS THERE. IT'S PROBABLY ABOVE MY PAY GRADE BUT THESE ARE REALLY IMPORTANT QUESTIONS TO THINK ABOUT. OKAY. SO MARMOSETS ARE THIS EMERGING GENETIC MODEL, I WAS ASKED TO TALK BRIEFLY BECAUSE I'M A PRIMATE PERSON HERE ON MARMOSETS WE HAVE A LITTLE BIT ABOUT MOVING INTO THIS SPACE AND DONE A LITTLE BIT OF WORK IN IT. MARMOSETS ARE ATTRACTIVE FOR SEVERAL REASONS, VERY SOCIAL, COMPLEX COGNITION, SIMILAR PHYSIOLOGICAL PROFILES, RE PRODUCTIVE TECHNOLOGIES ARE WELL ESTABLISHED, THEY WERE THE FIRST PRIMATE TO HAVE GERMLINE TRANSMISSION OF A TRANSGENE, THEY'RE SMALLER AND MORE TRACK ABLE THAN MATAX WHICH RESULTS IN LESS FEEDING POSES, YEAR AROUND OVARIAN CYCLES, RESULTS IN HIGHER REPRODUCTIVE OUTPUT, NOT AS AGGRESSIVE, FREE OF ZONOTIC DISEASES, DON'T HAVE MONKEY Z VIRUS, CAN BE FATAL TO HUMENTZ, THERE ARE WEAKNESSES, THEY'RE MORE COSTLY TO MAINTAIN THAN RODENTS, THEY REQUIRE A NON , IF YOU'RE NOT AT AN NPRC, YOU NEED A FINANCIAL BACKSTOP, IT'S NOT CLEAR TO ME IF THE UNIVERSITIES ARE WILLING TO MAKE THIS THE BACKSTOP IS MILLIONS OF DOLLARS POTENTIALLY, THEY REQUIRE SPECIALIZED HOUSING, BREEDING AND VETS, THERE'S A THRARNLG PHYLOGENETIC SEPARATION OF ABOUT 10 MILLION YEARS OF A COMMON ANCESTOR BETWEEN OLD WORLD MONKEYS AND HUMENTZ AND MARMOSETS, CEPHALIC BRAIN TOO DIFFERENT, MALES DIE ACHROMATIC, HUMANS ARE TRI CHROMATIC, TWINS EXCHANGE CELLS IN UTERO, THEY ALSO VS A MUTATED FORM OF OXYTOCIN, WHICH IS WHY I NO LONGER STUDY NEW WORLD MONKEYS, AND THERE'S A WORLDWIDE SHORTAGE CURRENTLY. A FEW DISPUNTS SOLUTIONS. I THINK WE NEED TO WALK THE TALK . SO WE NEED TO CREATE FUNDING MECHANISMS FOR DIRECT TRANSLATION. ALMOST EVERYBODY I KNOW WHO DOES ANIMAL AND HUMAN WORK HAS BEEN DENIED GRANTS WHEN THEY TRIEF TO PUT THE TWO PIECES OF THE WORK TOGETHER, SO I PUBLISH PAPERS WITH THE TWO OF THEM TOGETHER BUT I'VE NEVER SUCCESSFULLY WRITTEN A GRANT WHERE I CAN PUT MY MONKEY AND HUMAN WORK TOGETHER. HAVING GREATER THAN 500K DIRECT COSTS FOR NON-HUMAN PRIMATE GRANTS, BECAUSE WE HAVE SUCH AN EMPHASIS ON REPRODUCIBILITY WHICH I THINK IS GOOD BUT WE'RE NOW BEING TOLD WE HAVE TO CLUE FEMALES AND WE HAVE TO REPLICATE OUR FINDINGS, MONKEYS ARE REALLY EXPENSIVE HABIT, SNRIET SO THE 500K IN DIRECT COSTS IS JUST SIMPLY NOT ENOUGH AND PARTICULARLY BECAUSE NON-HUMAN PRIMATE COSTS HAVE SKYROCKETED. WE ALSO NEED TO KEEP VALUABLE ANIMALS ON PER DIEM WHETHER OR NOT THEY'RE ON STUDY AND BECAUSE THE BASE GRANTS ARE UNDERFUND UNDERSTAND THAT'S REALLY DIFFICULT SO WE -- UNDERFUNDED THAT'S REALLY DIFFICULT SO WE LOSE VALUABLE ANIMALS WHEN THEY GO OFF PER DIEM. ALSO IT WE WANT TO TAKE RISKS AND DEVELOP MONKEY MODELS, AND ESPECIALLY IF WE'RE THINKING ABOUT TRANSGENICS, WE NEED TO GET PRELIMINARY DATA BUT AN R21 FOUR FOR A MONKEY WITH 275K IS NOT ENOUGH MONEY, MAYBE FOR RODENTS AND EVEN PROBABLY THE RODENT PEOPLE TELL ME IT'S NOT ENOUGH MONEY BUT IT'S REALLY TRICKY TO MOVE THE NEEDLE WITH MONKEY STUDIES WITH AN R21. AND THEN I THINK WE NEED TO ALSO THINK ABOUT UNIVERSITIES THAT ARE TRYING TO DEVELOP THESE PRIMATE CENTERS THAT ARE NOT IN THE NPRC'S, DO WE OPEN UP THE BASE GRANTS FOR COMPETITIVE FUNDING, THESE ARE QUESTIONS WE NEED ANSWERS TO. QUICKLY BECAUSE I'M PROBABLY OUT OF TIME, SOME CONCLUSIONS. I THINK WE NEED TO DEVELOP MORE REFINED ANIMAL MODELS WITH DIRECT RELEVANCE TO HUMAN DISEASE, THAT'S THE ONLY WAY WE'LL BE ABLE TO TRANSLATE WITH ANY SORT OF EFFICIENCY, WE NEED TO MAKE A NATIONAL INVESTMENT JUST LIKE CHINA AND JAPAN HAVE IN SUPPORTING AND ADVANCING NON-HUMAN PRIMATE MODELS OF COMPLEX BRAIN DISORDERS ARE IN A BIG WAY OR WE'LL BE LEFT BEHIND AND ONE OF THE EARLIER SPEAKERS TALKED ABOUT THIS, WHICH IS WE CAN LOSE OUR COMPETITIVE ADVANTAGE BUT THEN WE ALSO DON'T CONTROL THE SPACE, RIGHT? THE DRUGS THAT ARE BEING MADE, THERAPY NOT BEING MADE IN THE U.S., THEY'RE BEING MADE OTHER PLACES. WE NEED TO SCALE EXISTING TECHNOLOGIES LIKE WHOLE GENOME SEQUENCING FOR LARGE COLONIES AND INVEST IN NEW TECHNOLOGIES FOR THESE LONGITUDINAL STUDIES AND THAT'S IT. OKAY. I'LL TAKE QUIZ. [LAUGHTER] [APPLAUSE] S. >> Dr. Dzirasa: WE HAVE TIME FOR ONE QUESTION. >> [AWAY FROM YOU MIC] >> SO IT'S SOMETHING WE'RE ACTIVELY DISCUSSING, WE RECOGNIZE IN TICKING MANY OF THE ISSUES THAT WERE RAISED ARE IMPORTANT ISSUES, PARTICULARLY THOSE AROUND THE DEVELOPMENT OF TRANSGENIC MODELS, AND THE SUPPORT FOR AND THE CHALLENGES REGARDING TO EXPANDING MARMOSETS , SO THESE ARE THINGS WHICH WE'VE BEEN ACTIVELY DISCUSSIG BOTH AT THE BRAIN INITIATIVE AND AT INDIVIDUAL INSTITUTES. >> Dr. Dzirasa: THANK YOU. OUR NEXT SPEAKER IS YEVGENIA KOZ OROVITSKIY FROM NORTHWESTERN. >> Dr. Kozorovitskiy: THANK YOU VERY MUCH, I AM SPEAKING SO CLOSE TO LUNCH THAT MANY OF MIYATAKEING POINTS HAVE ALREADY BEEN MENTIONED, BUT STILL THEY WILL BEAR REPEATING AT LEAST SOME OF THEM AND SOME OF THE NEW IMAGING TOOLS WORK IS PROBABLY GOING TO BE RELATIVELY UNIQUE IN OUR GROUP TODAY. I'M GOING TO TALK TO YOU A LITTLE BIT ABOUT THE VALUE OF MODEL ORGANISM DIVERSITY NEUROSCIENCE RESEARCH THAT HAS BEEN TOUCHED UPON BY A NUMBER OF US ALREADY HERE. SOME OF THE OPENING OF UNDERSTANDING SUBCORTICAL SYSTEMS AND PARTICULAR PARTICULARLY NEUROMODULATION WHERE I THINK A LOTS OF THE CON CON OK CAL LABORATORY RODENTS STILL HAVE A TREMENDOUS AMOUNT OF UTILITY AND LEVERAGE TO GIVE TO THE PARTICULAR UNIQUE SYNTHETIC SYNTHESIS OF EXPERIMENT THEY ENABLE AND ALSO MENTION A LITTLE BIT SOME OF THE NEW IMAGING TOOLS THAT REALLY RANGE NEAR THE SPACE OF ADDRESSABLE QUESTIONS IN NEUROSCIENCE AND THERE I WON'T REALLY PROVIDE ANSWERS SO MUCH AS RAISE SOME CONSIDERATIONS OF THINKING ABOUT FREELY MOVING ANIMALS, WIRELESS CONTROL, HEAD FIX PREPARATIONS AND SOME OF THE LIMITATIONS THAT INEVITABLY EACH OF THOSE APPROACHES ENTAILS. FIRST I AM LIELD TO START WR THE PRINCIPAL IN NEUROSCIENCE AND BIOLOGY AND SOMETHING WE TEACH OUR GRADUATE STUDENTS. IN 1929, AUGUST CROACS SAID THAT FOR A LARGE NUMBER OF PROBLEMS THERE WILL BE A FEW SUCH ANIMALS ON WHICH IT WILL BE MOST CONVENIENTLY STUDIED AND I THINK THIS PRINCIPLE CAN BE USED AS A LITTLE BIT OF AN INSPIRATION FOR THINKING ABOUT WHATTED TO DO NEXT FOR THE BRAIN INITIATIVE AND I WANT TO ELM HE FA SIZE IT'S BEEN VERY, VERY NICELY IMPLEMENTED THIS A LOT OF METHODOLOGICAL DEVELOPMENTS WE HAVE THIS NEUROSCIENCE. WE TURN ON GENES FROM JELLYFISH FOR FLUORESCENT LABELING, TARGET ING CELL TYPE IN WHICH BRAIN, ALGAE FOR OPTICAL CONTROL OF NEURAL ACTIVITY, VIRAL GENES FOR DELIVERING VALUABLE CARGO OWES TO, CRISPR FOR GENOME EDIT ING, MANY, MANY, MANY, MANY OTHER EXAMPLES, SO WE LOOKING TO THE WHOLE TREE OF LIFE FOR THE METHODS AND YET WE AREN'T REALLY LOOK TO GO THAT MANY MODEL ORGANISMS FOR THE ACTUAL SCIENCE THAT WE DO. IT WE HAVE TIME LATER, I HAVE SOME SLIDES FROM NDS PROVIDED THEIR NONRESPONSIVE OF BRAIN INITIATIVE FUNDING T WE GET TO THAT LATER. HERE AN EXAMPLE OF A SPARSE TREE OF LIFE HIGHLIGHTING SOME OF THE KEY PLAYERS IN MODERN LABORATORY NEUROSCIENCE STUDIES AND WHAT'S REALLY IMPORTANT IS TO REMEMBER HOW DIFFERENT IN SIGNS AND SCALE THOSE ARE, THIS ONE PIXEL OF THE FLY, I STUCK IN THE C. ELEGANS AS WELL, AND THE POINT I WOULD LIKE TO EMPHASIZE IS THAT THESE DISTINCT BRAINS AND THE DISTINCT PATTERNS OF BEHAVIOR THAT ACCOMPANY THEM ALL HAVE SOMETHING TO TEACH US ABOUT THE WAY THAT THE HUMAN BRAIN MAY OPERATE, MAY SOLVE CERTAIN PROBLEMS, BUT ESPECIALLY WHAT WE WANT TO DO IS FIX PROBLEMS WITH THE HUMAN BRAIN. SO I WILL GIVE YOU ONE EXAMPLE OF THAT THAT WAS RECENTLY PUBLISHED FROM A COUPLE OF LABILITIES AT NORTH WESTERN UNIVERSITY -- LABORATORIES AT NORTHWESTERN UNIVERSITIES. THEY REALLY LEVERAGE THE KIND OF POWER OF COMPARATIVE APPROACHES TO LOOK AT SOME FUNDAMENTAL FEATURES OF CHANNELS THAT ARE VERY, VERY HIGHLY CONSERVED, THIS IS A STORY OF NOCICEPTION BY TRIP A1. FIRST THE AUTHORS THE USE THE PL ENARIA FANTASTIC FOR STUDYING REGENERATION MORD TO DISCOVER THAT YOU IF PREVENT THE FUNCTION OF THIS CHANNEL, THE PLENARIA AVOID THE VERY UNPLEFNLT TOO HOT REGIONS OF THE PLATE IN VERY, VERY SIMPLE BEHAVIORAL ASSAYS, THIS IS THE RNA KNOCKDOWN. IT TURNS OUT THAT THE SAME TRP A 1 FUNCTION IN FLIES, SAME, SENSING NOXIOUS HEAT THE AND WHAT'S CRITICAL IS THAT EITHER PUTTING BACK INTO FLY THE MISSING TRP A11 OF THE OF THE HUMAN, RESCUES BEHAVIOR, THESE GENE SWAPPING TECHNIQUES ARE NOT REALLY FEASIBLE TO DO IN PRIMATES, NOT SO EASY TO DO IN LABORATORY THE RODENTS EITHER, SO INVERTEBRATES HAVE A LOT TO TEACH US THERE AND YOU CAN THEN DELVE DEEPER MECHANISTICALLY AND YOU FIGURE OUT THAT IN FACT THESE TRP A1'S ARE ACTIVATED BY HYDROGEN PEROXIDE, GIVING US INSIGHT INTUTS RESPONSES OF COMPLEX SYSTEMS THAT ARE CONSERVED OVER 500 MILLION YEARS OF EVOLUTION, THAT'S ONE EXTREME EXAMPLE OF REMEMBERING THE FACT THAT INVERTEBRATES HAVE A LOT OF USEFUL THINGS TO CONTRIBUTE THE TO SOME OF THE QUESTIONS THAT THE BRAIN INITIATIVES WOULD LIKE TO ADDRESS THANKFULLY KARIN HAS IRCH GO US AN EXCELLENT -- KAREN HAS IRCH GO US AN EXCELLENT REVIEW OF THE SPRENGTS OF MARMOSET MODELS, SINCE I DID A LITTLE WORK AS A GRADUATE STUDENT, I WANT TO MENTION A COUPLE STRINGT SAYS, THEY'RE HIGHLY SOCIAL, JUVENILES ARE ENGAGED IN OFFSPRING CARE, TWINS ALTHOUGH THEY ARE CHIMERIC SERVE AS A KIND OF MARVELOUS BUILT IN CONTROL GROUP TEAR COMPARISON FOR A LOT OF ASSAYS INVOLVING BEHAVIOR. MARMOSETS ARE GOOD AT RECOGNIZING AND TRACKING INDIVIDUALS, THEIR GAZE FOLLOWING HAS BEEN STUDIED A LOT AND WE KNOW QUIEFLT A BIT ABOUT THEIR FACE PROCESSING SYSTEM, FOR EXAMPLE, MANY OTHER LABS HAVE NOW MAPPED FEATURES OF THE CORTICAL DISTRIBUTION OF DIFFERENT SYSTEMS IN MARMOSETS. AND OF COURSE ONE COULD ARGUE ON ONE HAND THAT THE CEPHALIC CORTEX IS IN SOME WAYS POTENTIALLY QUITE DIFFERENT FROM THE HUMAN VERY CONVOLUTED CORTEX BUT ON THE OTHER HAND IT DOES MAKE IT RATHER ACCESSIBLE FOR A LOT OF IMAGING APPLICATIONS, SO THIS IS WHERE YOU HAVE TO KIND OF REALLY BALANCE THE COMPLEX TIFF AND THE SIMILARITY OF THE SYSTEM AGAINST THE SORTS OF EXPERIMENTS THAT YOU COULD SO I THINK THERE ARE MANY EXPERIMENTS THAT ARE NOT FEASIBLE IN HUMANS, THAT ARE NOT FEASIBLE IN MACATS THAT ARE ACTUALLY FEASIBLE IN MARMOSETS. LABORATORY MICE THOUGH, IT'S DEFINITELY EASY TO KIND OF COMPLAIN ABOUT A LOT OF THE WAYS IN WHICH THEY FAIL TO MODEL HUMAN DISEASE. THEY STAND AT A PRETTY VALUABLE NEXUS, AT THE CONVERGENCE OF BEING COMPLEX ENOUGH WITH A TON OF REGIONAL HOMOLOGY TO THE HUMAN BRAIN AND BEING HIGHLY, HIGHLY TRACKABLE IN PART DUE TO A LOT OF DEVELOPMENTS WE'VE SEEN OVER THE COURSE OF THE BRAIN INITIATIVE AND REALLY EVEN BEFORE, SO SOME OF THE SPECIFIC AREAS YOU THAT HAVE BECOME INCREASINGLY TRACTABLE ARE THE THINGS THAT LIE BELOW THE CORTEX , THE THINGS WHERE WE CANNOT RELY ON THE ORDERLY STRUCTURE OF THE CORTEX TO TELL US WHICH CELL TYPES WE'RE REALLY LOOKING AT. THE THINGS THAT RELATES TO NEUROMODULATION HERE ILLUSTRATED BY THIS TRANSITION OF SPIKING FOR A NEUROTON A VERY DIFFERENT KIND OF PATTERN, IT DOESN'T TAKE A COMPUTATIONAL NEUROSCIENTIST TO INFER THAT A CIRCUIT TRANSITIONING FROM THIS KIND OF ACTIVITY TO THIS KIND OF ACTIVITY IS DOING SOMETHING DIFFERENT AND IN FACT IT MAPS ONTO FUNCTION. SO WHAT I THINK HAS BEEN REALLY FANTASTIC OVER THE LAST DECADE AND ESPECIALLY SINCE THE ONSET OF THE INITIATIVE IS THAT MANY SUBCORTICAL SYSTEMS, SYSTEMS THAT STAND AT THE BRAIN BODY INTERFACE, ARE NOW TRACTABLE, THESE ARE THE THINGS THAT DON'T GET MUCH CREDIT FOR THINKING BECAUSE WE'VE INCREASINGLY COME TO RECOGNIZE THE EXTENT TO WHICH CORTICAL REGIONS ARE CONSTANTLY INTERACTING WITH MIDBRAIN AND HIGH BRAIN REGIONS, THINGS THAT GO TAKE CARE OF HOME YOAP STATIC NEEDS, BREATHING, CIRCADIAN VARIATION AND SO ON, SO IN PARTICULAR WE'RE EXTREMELY INTERESTED IN INDIVIDUAL NEURO MODULAR SYSTEMS AND THE FACT THE THAT THEY'RE SO TRACTABLE IN MICE NOW, AS WELL AS STARTING TO THINK A LITTLE BIT MORE ABOUT HOW THEY INTERACT BECAUSE OF COURSE TO MAKE ALREADY HIGHLY DISTRIBUTED PROJECTION SYSTEMS WITH COMPLEX SIGNALLINGING MOTIF TO MAKE THE MATTER EVEN WORSE, THEY ALSO INTERACT. SO THAK THANKFULLY I DON'T NEED TO SPEND TCH TIME INTRODUCING THE BASAL GANGLIA SINCE IT HAS COME UP ALREADY A FEW TIMES, BUT I WANT TO GIVE A STRONG SHOUT OUT TO NAT AND THE PROJECT WHICH HE REALLY STARTED AND TOGETHER WITH CHIP THEY WERE THE FIRST PEOPLE THAT HAVE BASICALLY OPENED UP THE MOUSE, THE THINGS THAT ARE BELOW THE MOUSE CORTEX, AND LONG BEFORE INITIATIVES WERE EVEN A THING, ESSENTIALLY HAVE STARTED AN INITIATIVE THAT HAS IRCH GO US UNBELIEVABLE TRACTION OVER THE IRKTS IS OF THE BASAL GANGLIA AND THAT'S REALLY IMPORTANT BECAUSE NEURONS THAT ARE INTERMINGLED WITHIN THESE SORT OF LESS ORDERED, LESS CLASSICALLY ORDERED STRUCTURES SEND DIFFERENT PROJECTIONS, THEY USE VERY DIFFERENT KIND OF NEURO MODULATORY SIGNALLING AND THEY HAVE DISINGT IS IT RELEVANCE THAT IS STILL BEING TO SOME EXTENT ELUCIDATED FOR MOTOR FUNCTION. HE IS SPECIAL THE ALSO REALLY NICELY FOR ME I VALUE THE FACT THAT IN MICE WE CAN IMAGE THESE TYPES OF NEURONS IN VIVO THANKS TO THE TOOLS THAT HAVE BEEN CREATED BUT THEN WE CAN ALSO& FOLLOW THIS UP WITH EX-VIVO INTERROGATION AND ASK VERY PRECISE QUESTIONS, FOR CELL TYPE TARGETED NEURONS, WHAT IS THE STRENGTH OF INDIVIDUAL SYNAPSIS? THIS IS JID SINGLE SNAPS ON CAG ING INVOKED RESPONSES FOR WHICH WE'RE USING AS WE LEARNED THROUGH THE 1990S TYPE OF TECHNOLOGY LIKE MNI GLUTAMATE WHICH WE CAN USE TO STIMULATE INDIVIDUAL POSTSYNAPTIC SITES, WE CAN EVEN DO MORE, IF INSTEAD OF PATCHING THE NEURON WE USE GENETICALLY ENCODED FLOOR OH FOR S WE CAN USE STIMULATION PATTERNS IN ORDER TO PRODUCE CAUSALLYALLY NEW DENDRITIC SPINES THAT HOUSE PROTOSYNAPSES FROM THESE CELLS AND THAT GIVES US TRACTION IN ORDER TO ASK INCREDIBLY FINE SCALE QUESTIONS ABOUT WHAT ARE THE NECESSARY AND SUFFICIENT FEATURES AND WHAT ASPECTS OF NEURAL OH MODULATION -- NEUROMODULATION CONTROL THESE SORTS OF ACTIVITY DEPENDENT PROCESSES IN THE BRAIN IN MICE WE CAN DO THAT REALLY LITERALLY IN THE SAME ANIMAL AND MORE AND ALSO VERY NICELY MULTIPLEX SUCH THAT LET'S SEE IF I COULD MANAGE TO GET THIS VIDEO TO WORK, I HAVE A FEW VIDEOS. THIS IS JUST AN EXAMPLE OF ONE OF THESE SPINY STRIATAL PROJECTION IMAGES, ALONG WITH DOPAMINERGIC AXON TERMINALS THROUGH THE SAME PART OF THE REALLY GOOD. YES, IT'S MUCH BETTER OVER THERE HERE. THE POINT IS THAT WE CAN COMBINE MANY QUESTIONS AND FOLLOW UP POST BEHAVIORAL ASSAYS IN MICE IN A WAY THAT WE CANNOT CURRENTLY DO IN ANY OTHER CONTEXT. ANOTHER AREA THAT AGAIN HAS BEEN INTRODUCED IS THAT SOME OF THIS GENETIC TRACTION IS REALLY CHANGING HOW WE THINK ABOUT PEPTIDES AND PEPTOGERCIC CIRCUITS IN THE BRAIN, INCLUDING OXYTOCIN WHICH IS CRITICAL FOR SOCIAL BEHAVIOR AND MOTHER-OFF SPRING INTERACTIONS EXPTIONZ SO ON AND IN THIS CONTEXT I THINK IT'S IMPORTANT TO REMEMBER THAT MANY OF THE BEHAVIORS THAT WE THINK OF AS BEING IN SOME WAY DEFINITIONAL TO OUR HUMANITY ARE REALLY, REALLY FUNDAMENTALLY HORMONAL MEDIATED AND THEY ARE MEDIATED BIT HORMONES THAT ARE ALTHOUGH IN SOME DIFFERENT WAYS IMPLEMENT ED ACROSS SPECIES ARE REALLY PRETTY SIGNIFICANTLY CONSERVED ACROSS A WIDE NUMBER OF ANIMALS, SO IN PARTICULAR THINGS LIKE OXYTOCIN AND VASOPRESSIN ARE INTERESTING IN THIS REGARD BECAUSE THEY ALSO STAND AT THE KEY POINT IN THE BRAIN-BODY AXIS WHICH OF COURSE POSES A LOT OF COMPLEXITY TIZ FOR DESIGN OF STUDY, INTERPRETATION, FIGURING OUT IF YOUR PERIPHERAL VALUESES OF OXYTOCIN HAVE ANYTHING TOLD WITH CENTRAL VALUES, IT'S REALLY HARD , BUT AT THE SAME TIME I FEEL LIKE NEUROSCIENCE HAS MATURED ENOUGH THAT TODAY WE'RE READY TO PUT THE BRAIN IN THE CONTEXT OF THE BODY IN A WAY THAT INVOLVES BOTH THINKING ABOUT BEHAVIOR AND ALSO THINKING ABOUT HOW EXPERIENCE COMMUNICATES THROUGH THESE PERIPHERAL SYSTEM AND FEEDBACK SYSTEMS BACK TO THE BRAIN IN ORDER TO MODULATE FUTURE BEHAVIOR. SO THEN THERE ARE MANY LABS INCLUDING A NUMBER THAT ARE ACTUALLY REPRESENTED HERE IN THE AUDIENCE THAT HAVE LEVERAGED SOME OF THESE NEW TOOLS IN ORDER TO REALLY GAIN NEW INSIGHTS INTO THINGS RANGING FROM SOCIOSEXUAL BEHAVIOR TO PAIN PROCESSING AND SO ON, JUST TO GIVE DID YOU A TINY VIGNETTE THE FROM MY LAB, WE WERE THINKING A LOT ABOUT THE POSSIBILITY THAT OXYTOCIN INTERACTS WITH MIDBRAIN DOPAMINERGIC SYSTEMS THAT FACILITATE REWARD GLOBALLY THROUGH MORE PLACES THAN JUST NUCLEUS ACCUMBENS SO WE'VE USED THAT PANEL OF FUNCTION EXPAL ANATOMICAL TECHNIQUES IN ORDER TO FIGURE OUT THAT TOXOTOE SYN NEURONS DO IN FACT DIRECTLY TARGET MIDBRAIN DOPAMINE REGIONS WHERE INTRIGUINGLY THEY STEAM TO CAWRPZ THE SEIZING OF THE GENETICS DOPAMINE RELEASE, OPPOSITE MODULATION IN THE ACTIVITY OF DOPAMINE NEURONS THAT ARE MORE LINKED TO REWARD PROCESSING COMPARED TO DOPE MY IN HER JIRK NEURONS IN THE -- THESE ARE THE TWHAWNS DIE IN PARKINSON'S DISEASE, THAT WAS VERY SURPRISING AND WE CAN EXPLAIN THE CIRCUIT LEVEL FEATURES THAT LEAD TO THIS OPPOSING MODULATION. MORE RECENT WORK, WE'VE ALSO LOOKED TO SEE FOR THE DOPAMINE, WE'VE DISCOVERED THERE'S NOT ONLY -- OF CELLS THEMSELVES, BUTS ALSO WHAT THEY'RE LISTENING TO, PRESYNAPTIC INPUTS, THAT TURNED OUT TO INVOLVE AN ENDOCAN BOYD MEDIATED MECHANISM AND FURTHER BE PATHWAY SPECIFIC. OXYTOCIN PRIMES DPA DOPAMINE SYSTEMS FOR ACTION BUT FILTERS WHICH INPUTS THEIR LISTENING TO AND I THINK THAT'S REALLY INTERESTING BECAUSE THIS CIEBD OF WORK IS TYPICAL CIRCUIT ANALYSIS WORK IN PRIMATES AND I WANT TO EMPHASIZE THAT IT GIVES A LOT OF POTENTIAL INSIGHTS THAT COULD BE RELEVANT TO THE CLINIC. IT SUGGESTS THAT MAYBE OXYTOCIN COULD BE NEURO PROTECTIVE IN SOME CONTEXTS IN PARKINSON'S, IT MAKES US THINK ABOUT CAN WE LEVERAGE SOMETHING ABOUT OXYTOCIN AND THE CANNABINOID INTERACTION IN ORDER TO START THINKING ABOUT AUTISTIC CHILDREN IT MAKES VERY CLEAR-CUT PREDICTIONS FOR SOME OF THE BEHAVIORAL ASSAYS WE'RE CURRENTLY RUNNING INCLUDING USING MACKENZIE'S APPROACHES THAT SUGGEST THAT SINCE THE SYSTEM APPEARS TO BE SEX IN VARIANT, MAYBE IT'S IMPORTANT FOR EARLY LIFE BEHAVIOR. THESE EFFECTS ARE REALLY FAST, THESE SEEM TO LAST MUCH LONGER. HOW DO WE THINK ABOUT THIS AT THE COMPUTATIONAL LEVEL? I POMPTZ IT THAT THERE'S STILL TREMENDOUS VALUE OF FINE-SCALE SYNTHETIC COMBINING MULTIPLE APPROACHES TYPE ANALYSIS IN MICE , PARTICULARLY FOR NEURO MOD TO HER SYSTEMS THAT FOR SO LONG HAVE BEEN HARD TO TRACK BECAUSE STUDYING NEUROMODULATION IS JUST HARDER THAN STUDYING FAST NEUROTRANSMISSION WHERE YOU CAN MEASURE AN EP CR OR AN IPC. ANOTHER THING THAT'S REALLY NOORNT WE THINK ABOUT A LOT OF COURSE IS COMBINING THOSE TYPES OF MECHANISTIC STUDIES WITH IMAGING IN THE CONTEXT OF BEHAV ING ANIMALS, AND HERE I THINK IT'S VALUABLE TO COMPARE AND CONTRAST APPROACHES THAT ALLOW FREELY MOVING ANIMALS COMPARED TO HEAD RESTRAINT SYSTEMS WHERE WE CAN GET MUCH HIGHER RESOLUTION AT SOME COST. SO ON ONE END, YOU HAVE THESE APPROACHES WHERE YOU CAN USE FOR EXAMLE FIBERS IN ORDER TO RECORD THE ACTIVITY OF GENETIC ALLY ENCODED INDICATORS AND SOME OF THESE HAVE BEEN RECENTLY MINIATURIZED IN REALLY POWERFUL WAYS WHERE YOU CAN EVEN USE MIE CROW AND GET READOUT OF THIS ACTIVITY IN A WIRELESS MANNER. ON THE OTHER END OF THE SPECTRUM , WE HAVE SINGLE PHOTON ENDOSCOPIC TECHNIQUES WHICH WHILE SUFFERING A LOT OF ABERRATIONAL RESOLUTION LIMITATIONS HAVE BEEN NOW SIGNIFICANTLY IMPROVED BY THE ADVANCEMENT IN COMPUTATIONAL APPROACHES THAT ALLOW US TO PULL OUT SIGNALS FROM THESE NEURONS. I THINK I'M PROBABLY GOING TO SKIP MAYBE THIS SLIDE, BUT I WANTED TO INTRODUCE A LITTLE BIT ABOUT SOME OF THE CONTROL ABILITIES THAT VIRTUAL REALITY PAIR DIEMENTZ OFFER TO US AND I'M GOING TO END REALLY WITH A KIND OF A DREAM EXPERIMENT THE WHICH WE'RE SLOWLY MAKING APPROACHES TOWARDS THROUGH A VARIETY OF IMAGING TECHNIQUES THAT ARE STILL ONLY UNFORTUNATELY CURRENTLY POSSIBLE IN HEAD RESTRAIGHT SYSTEM, AND THAT INCLUDES FIRST FER ALL REALLY INCREASING OUR ABILITY TO IMAGE NEURONS QUICKLY. MANY LABS ARE WORKING TOWARDS THAT, I JUST WANTED TO INTRODUCE SOME OF THE WORK OUR LAB HAS DONE THAT'S VERY MUCH INSPIRED BY OPM APPROACHES IN ELIZABETH HILLMAN'S TECHNIQUES, LIGHT TECHNIQUES TO SHAPE LIGHT FOR FASTER IMAGING. OTHER GROUPS, STARTED BIT VALENT INA, A WHOLE BUNCH OF LABS , ARE IN ORDER TO STIMULATE ARBITRARY PATTERNS NEURONS ACROSS THE BRAIN THIS LARGE 3D SPACES, THAT CAN BE COMBINED WITH LIGHT FIELD TECHNOLOGIES IN ORDER TO IMAGE THE ACTIVITY EXTRACT THE INFORMATION ABOUT FIRING FROM NEURONS IN 3D AND THAT ALL THESE KINDS OF APPROACHES ARE BUILDING FOR AN EXPERIMENT THAT I THINK IS REALLY IMPORTANT AND REALLY COMPLEX WHERE WE CAN HAVE A BEHAVING ANIMAL AND WE CAN RECORD THE ACTIVITY OF MANY NEURONS AND WE CAN PLAY BACK IN ARBITRARY PATTERNS FOR A KIND OF DYNAMIC CLAMP AT THE SYSTEMS LEVEL ON A WHOLE POPULATION OF NEURONS AND PRETTY MUCH MANY PARTS OF BRAIN. SO WITH THAT, I WANT TO EMPHASIZE THE IMPORTANCE OF MODEL SYSTEM DIVERSITIES, CORTICAL SYSTEM EXPNGD CONTINUED GROWTH IN OPTICAL TOOLS THAT'S NECESSARY TO BRING IT ALL TOGETHER. AND THANKS TO ALL THE PEOPLE THAT I TALKED TO IN THE PROCESS OF THINKING ABOUT THIS. [APPLAUSE] >> Dr. Dzirasa: THANKS. WE'LL HOLD QUESTIONS FOR THE PANEL AT THE END. OUR NEXT SPEAKER IS CONOR LISTON . >> Dr. Liston: ALL RIGHT. THANKS KAFUI AND THANKS TO THE WORKING GROUP TO BRING ME HERE. I'M THRILLED TO BE HERE. HOW MANY MINUTES DO WE HAVE? >> Dr. Dzirasa: TEN. >> Dr. Liston: TEN. ALMOST EVERYTHING I HAVE TO STAY HAS ALREADY BEEN SAID BY AT LEAST ONE PERSON HERE TODAY AND I US ALSO KNOW THAT I'M THE ONLY THING STANDING IN THE WAY OF EVERYONE IN THIS ROOM AND LUNCH SO I'LL TREAT THIS AS A BRIEF -- >> [AWAY FROM MIC] >> Dr. Liston: THE SECOND THING BETWEEN YOU GUYS AND LUNCH. I'LL TREAT THIS AS A RECAP, I'LL RUN QUICKLY. ASK QUESTIONS AT THE END IF I GLOSS OVER ONE THING. I THINK ONE OF THE MOST EXCITING AREAS IN EFFORTS TO UNDERSTAND HOW BRAIN STATES GIVE RISE TO BEHAVIOR INVOLVES SHIFTING OUR FOCUS TOWARDS UNDERSTANDING HOW NEURO ANATOMICALLY DISTRIBUTED BRAIN STRUCTURES INTERACT. I THINK HISTORICALLY FOR VERY GOOD SENSIBLE REASONS, MANY STUDIES HAVE FOLK IT UPSED ON JUST ONE OR TWO BRAIN REGIONS, BUT INCREASINGLY WE'RE BEGINNING TO APPRECIATE THAT IT'S IMPORTANT TO UNDERSTAND HOW MULTIPLE BRAIN REGIONS ARE INTERACTING IF WE'RE GOING TO GET A GOOD HANDLE ON THIS QUESTION, AND THOSE STUDIES ARE BEING ENABLED BY NEW TECHNOLOGIES THAT ARE MAKING IT EASIER AND EASIER TO RECORD FROM LARGE SWATHS OF THE BRAIN, THIS EXAMPLE FROM HILLMAN'S LAB IS ONE BEAUTIFUL EXAMPLE OF CALCIUM IMAGING NEARLY CORTEX WIDE, MULTISCALE IMAGING IS ANOTHER EXAMPLE WHERE WE CAN IMAGE AT VARIOUS -- WHERE WE CAN IMAGE AT VARIOUS IMAGES OF. >> AM TO UNDERSTAND HOW THESE REGIONS ARE INTERACTING, WE'VE ALSO INCREASINGLY ARE BEGINNING TO SEE EFFORTS TO RECORD ELECTRICALLY FROM MULTIPLE BRAIN REGIONS, MULTIELECTRODE STUDIES. THIS IS ONE EXAMPLE I'LL RETURN TO. AND WE ALSO ARE INCREASINGLY ABLE TO INTEGRATE THESE APPROACHES, THIS NEW TECHNOLOGY FROM CAVA'S LAB IS ONE EXAMPLE OF HOW THIS MIGHT WORK, THESE FLEXIBLE PROBES THAT CAN BE USED TO RECORD ELECTRICALLY AND YOU CAN IMAGINE HOW THEY COULD BE EASILY INTEGRATED WITH OPTICAL IMAGING METHODS, IT'S ALSO DESIGNED TORE ALLOW YOU TO DELIVER LIGHT FOR OPTOGENETIC CONTROL AND TO DELIVER DRUGSING IF THAT'S OF INTEREST. SO YOU CAN IMAGINE HOW THESE APPROACHES CAN BE INTEGRATED TO BOTH RECORD FROM LARGE SWATHS OF THE BRAIN AT RELATIVELY HIGH SPEEDS AND MANIPULATE THE ACTIVITY OF THOSE BRAIN REGIONS EXPERIMENTSALLY TO GET A BETTER HANDLE ON CAUSAL RELATIONSHIPS. I'M GOING TO HIGHLIGHT WHAT I SEE AS KIND OF SIX PRIORITIES FOR RESEARCH IN THIS AREA, AND I'LL DO SO BRIEFLY FOR EACH OF THEM. ONE I THINK IS CLEARLY DATA ANALYSIS METHODS, SO THESE APPROACHES ARE GENERATING ENORMOUS QUANTITIES OF DATA, SOMETIMES TERABYTES OF DATA IN JUST MINUTES OF RECORDING, SO WE NEED NEW METHODS FOR ANALYZING THIS KIND OF DATA. I LOVE THIS EXAMPLE FROM COFF'S LAB IN WHICH HE BASICALLY ASSEMBLED A TEAM OF STATISTICIAN S, ENGINEERS, NEUROSCIENTISTS, PSYCHIATRISTS, PUT THEIR HEAD TOGETHER, CAME UP WITH THIS APPROACH USING MACHINE LEARNING TO ANALYZE SIGNALS DERIVED FROM MANY DIFFERENT AREAS SIMULTANEOUSLY AND IN A DATA DRIVEN WAY IDENTIFY TO HIPPOCAMPALLY DIRECTED SPATIO- TEMPORAL DYNAMIC THAT SEEMS TO BE IMPORTANT IN DETERMINING RESILIENCE VERSUS SUSCEPTIBILITY TO STRESS AND I THINK INCREASINGLY WE NEED EFFORTS TO KIND OF OPTIMIZE AND STANDARDIZE METHODS FOR ANALYZING THIS KIND OF DATA AND KIND OF DEVELOP BEST PRACTICES. WE'VE ALREADY TALKED A LOT ABOUT UNDERSTANDING CELL TYPE INTERACTIONS, I THINK IN THE INTEREST OF TIME I'LL JUST SKIP THAT, WE CAN DISCUSS IT FURTHER IN THE PANEL IF WE LIKE. A THIRD AREA THAT I THINK IS REALLY EXCITING IS ENABLED BY NEW TOOLS FOR NOT JUST STUDYING NEURAL ACTIVITY SPIKING, BUTS STUDYING THE INTRACELLULAR SIGNALLING MECHANISMS THAT ARE DRIVING THAT ACTIVITY. THE BOTTOM EXAMPLE FROM THE DYSE ROTH LAB ALMOST TEN YEARS AGO, HYDROIN HER JIK SIGNALLING AND PROBES FOR VISUALIZING MET AN BOW GLUTAMATE SIGNALLING,ING FOR IDENTIFYING NEW THERAPEUTIC TARGETS. A FOURTH KEY AREA I BELIEVE IS CONNECTIVITY MAPPING, UNDERSTANDING HOW THE BRAIN'S WIRING DIAGRAM CONSTRAINS BRAIN STATES AND THE RELATIONSHIP TO BEHAVIOR, TISSUE CLEARING METHODS ARE ENABLING LONG RANGE -- EXCUSE ME, ARE ENABLING& LONG RANGE CONNECTIVITY MAPPING IN INTACT TISSUE. I LOVE THIS EXAMPLE FROM HERU KA SAI'S LAB AS WELL IN WHICH THEY DEVELOPED A NEW OPTICAL PROBE FOR EXPERIMENTING MITCH LATING THE SURVIVAL OF SYNAPSES IN ORDER TO ESTABLISH CAUSAL RELATIONSHIP NOT JUST CORRELATIONS BETWEEN SYNAPSE ORGANIZATION AND CIRCUIT FUNCTION. WE NEED, WE WOULD DEFINITELY BENEFIT FROM MORE TOOLS LIKE THIS, AS WELL AS NEW SOFTWARE APPROACHES TO ANALYZING DATA IN CLEARED TISSUE. A FIFTH AREA THAT I THINK HAS GOTTEN A LITTLE BIT LESS ATTENTION BUT I DO THINK IS REALLY IMPORTANT IS LONGITUDINAL STUDIES, UNDERSTANDING HOW BRAIN STATE BEHAVIOR RELATIONSHIPS, THE EXTENT ON WHICH THEY'RE STABLE OVER TIME AND CHARACTER IZING HOW THEY EVOLVE OVER TIME AND UNDERSTANDING WHY AND WHAT ARE THE FACTORS THAT DETERMINE THAT, THAT I THINK WILL BE INCREASINGLY IMPORTANT GOING FORWARD AND THEN FINALLY, AND WE'VE TALKED A LITTLE BIT ABOUT THIS IN MULTIPLE SESSIONS ALREADY TODAY, THE IMPACT OF OTHER BIOLOGICAL VARIABLES, LIKE SEX, STRESS, NEURO MODULATORS, WE JUST DISCUSSED AROUSAL STATES , ALL OF THESE THINGS PRESUMABLY HAVE POWERFUL EFFECTS ON BRAIN STATES AND THEIR RELATION TO BEHAVIOR, THIS EXAMPLE FROM THE NSR LAB IS ONE STRIKING ONE I THINK WRG THEY SHOWED THAT -- WHERE THEY SHOWED THAT THERE ARE THESE AMAZINGLY SEX-SPECIFIC TRANSCRIPTIONAL SIGNATURES ASSOCIATED WITH DEPRESSION AND THE RESPONSE TO STRESS IN RODENTS WS VERY LITTLE OVERLAP. SHIFTING GEARS A LITTLE BIT FOR THE LAST COUPLE MINUTES, I'LL TALK A LITTLE BIT ABOUT HOW WE MIGHT USE METHODS IN HEALTHY HUMAN POPULATIONS AND CLINICAL POPULATIONS TO TACKLE RELATED QUESTIONS. MANY LABS ARE USING EEG, ECOG, THE SUBNETS PROGRAM FOR KIND OF CLOSED-LOOP RECORDING AND STIMULATION TO INTERROGATE THESE QUESTIONS. I'M NOT GOING TO TALK AS MANY ABOUT THAT AS I WILL ABOUT HUMAN NEURO IMAGING BECAUSE IT HAPPENS TO BE AN AREA THAT I KNOW MORE ABOUT, BUT I THINK THIS IS A GREAT EXAMPLE OF A FIELD THAT IS REALLY RAPIDLY MATURING. THERE ARE TOOLS FOR LIKE TASK- BASED FMRI FOR UNDERSTANDING THE CORRELATIONS BETWEEN BEHAVIOR AND BRAIN STATES, RESTING STATE FMRI FOR UNDERSTANDING THE BRAIN NETWORKS IN THE HUMAN BRAIN, DIFFUSION WEIGHTED MRI FOR CHARACTER IERS ING THE ARCHITECTURE OF WHITE MATTER IN THE BRAIN AND REALLY IMPORTANTLY AND I THINK AN AREA OF INCREASING INTEREST GOING FORWARD ARE EFFORTS TO SIMULTANEOUSLY MANIPULATE BRAIN ACTIVITY THROUGH TMS OR OTHER INTERVENTIONS AND RECORD THE EFFECT USING FMRI OR OTHER MODALITIES. THESE WILL ENABLE US TO MOVE BEYOND CORRELATIONS AND TRY TO ESTABLISH CAUSAL LINKS. WHAT ABOUT PRIORITIES RT IN THIS -- PRIORI TIES IN THIS AREA? SO I THINK ONE OF THE MOST IMPORTANT ONES, AND WE'VE ALREADY TALKED ABOUT IT A LITTLE BIT, I THINK IT APPLIES ESPECIALLY IN HUMAN NEURO IMAGING, IS A GREATER CONCERN WITH DATA QUALITY. THAT'S ACTUALLY GOTTEN INCREASING ATTENTION OVER THE PAST FIVE OR TEN YEARS, THE REALLY PROFOUND EFFECTS THAT GO HEAD MOTION AND OTHER PHYSIOLOGICAL VARIABLES THAT INDUCE GLOBAL SIGNAL ARTIFACTS IN THESE NEUROIMAGING MODALITIES , THE IMPACT IT CAN HAVE ON THE DATA YOU GET, SO THERE'S A REALLY GREAT NEED FOR VERY CAREFUL THINKING ABOUT WHAT CONSTITUTES GOOD DATA AND WHAT CONSTITUTES NOT GOOD DATA THAT JUST CAN'T BE ANALYZED. THE HUMAN CONNECTOME PROJECT HAS BEEN REALLY HELPFUL AND WILL CONTINUE TO BE PRESUMABLY IN DEVELOPING MORE STANDARDIZATION IN THE WAY THESE DATA ARE COLLECTED PREPROCESSED AND ANALYZED, AND REPRODUCIBILITY OBVIOUSLY IS ANOTHER REALLY IMPORTANT FACTOR HERE, DESIGNING STUDIES IN A WAY THAT THEY CAN BE EASILY REPRODUCED BY OTHERS AND OTHERS TAKING UP THE CHALLENGE OF ACTUALLY GOING AND DOING THAT. HERE TOO I THINK LONGITUDINAL STUDIES ARE REALLY IMPORTANT AND GETTING MORE ATTENTION, TRYING TO UNDERSTAND THE DEGREE TO WHICH RESTING STATE FMRI, FOR EXAMPLE, THE DEGREE TO WHICH RESTING STATE FMRI MEASURES OF NETWORK ORGANIZATION ARE STABLE IN A PERSON'S BRAIN OVER TIME, WHAT KIND OF FACTORS INFLUENCE THE STABILITY OF THOSE MEASURES AND THIS SEEMS OBVIOUSLY ESPECIALLY IMPORTANT FOR DISORDERS THAT ARE FUND MEANT ALLY EPISODIC -- FUNDAMENTALLY EPISODIC LIKE DEPRESSION IN WHICH UNDERSTANDING THE MECHANISMS THAT DRIVE CHANGES OVER TIME IS REALM CRITICAL, AND TO ACCOMPLISH THIS I THINK WE NEED MORE FOCUS ON MULTS DISCIPLINARY TEAMS LIKE WE'VE TALKED ABOUT MULTIPLE TIMES ALREADY TODAY COMBINING THE STERT EXPERTISE OF STATISTICIANS , ENGINEERS, MR PHYSICIAN TIS CYSTS WHO KNOW WHAT THEY'RE DOING -- META PHYSICISTS WHO KNOW WHAT THEY'RE DOING IN TERMS OF DATA COLLECTION, MAKING SURE WE HAVE GOOD DATA QUALITY, REPRODUCIBLE RESULTS AND WE ARE ACTUALLY MEASURING WHAT WE THINK WE'RE MEASURING. FINALLY, I THINK THESE APPROACHES HOLD PROMISE FOR INFORMING IN SOME TIME IN THE FUTURE THE WAY WE GO ABOUT DIAGNOSING MENTAL ILLNESS AND SELECTING TREATMENTS, THAT'S ONE THING WE'VE BEEN INTERESTED IN OF IN MY LAB, IN TRYING TO UNDERSTAND WHETHER WE CAN IDENTIFY DIFFERENT PATTERNS OF ALTERATION TION IN THE BRAIN THAT MIGHT BE CHARACTERISTIC OF DIFFERENT SUBGROUPS OF PATIENTS WITH THESE ILLNESSES WHICH ARE FUNDAMENTALLY WE KNOW THEY'RE HETEROGENEOUS DIAGNOSTIC CATEGORIES, THEY DON'T CORRESPOND TO UNITARY DISEASE ENTITIES, SO FMRI, EEG, OTHER METHODS HOLD SOME PROCESS FOR THINKING ABOUT DIAGNOSTIC HETEROGENEITY STRATIFICATION AND HOPEFULLY ULTIMATELY CHOOSING THE RIGHT TREATMENTS FOR THE RIGHT INDIVIDUAL PATIENTS. TO CLOSE, I JUST WANT TO TOUCH BRIEFLY ON SOMETHING I SPECIFICALLY WAS ASKED TO DISCUSS, AND THAT'S THINKING ABOUT HOW TO GO ABOUT QUANTIFYING CLINICAL SYMPTOMS AND RELATED BEHAVIORS IN OUR HUMAN SUBJECT STUDIES. I THINK TOO OFTEN WE DON'T PAY CLOSE ENOUGH ATTENTION TO THE TOOLS WE'RE USING TO MEASURE SOME CONSTRUCT IN A PERSON, SELF -REPORT ASSESSMENTS OF ANHED ONIA ARE NOT THE SAME AS A CLINICIAN REPORTING OF ANHEDONIA AND NOT THE SAME, AND UNDERSTANDING HOW THESE THINGS RELATE, WHAT THEY'RE MEASURING, HOW THEY CONVERGE AND WHEN THEY DIVERGE AND WHY WILL BE REALLY IMPORTANT. I THINK LIKEWISE, WE'VE HEARD ABOUT THIS FROM KAREN, FROM DAVID EARLIER,S BEHAVIORAL ASSESSMENTS THAT CAN BE APPLIED ACROSS SPECIES ALSO HOLD GREAT PROMISE IN KIND OF CONSTRAINING OUR INTERPRETATION OF THE DATA THAT WE ACQUIRE IN OUR HUMAN NEUROIMAGING STUDIES, THESE ARE JUST A FEW EXAMPLES THAT I REALLY ADMIRE OF BEHAVIORS THAT CAN BE READILY APPLIED HE ACROSS SPECIES, THIS EFFORT VALUATION TASK THAT YOU RECEIVE AT RIGHT IS ONE EXAMPLE OF A BEHAVIORAL TASK IN HUMANS THAT HAS ALSO BEEN APPLIED YOU IN SOME KIND OF ANALOGOUS FORM IN RODENTS AND THAT STEAMS TO CORRELATE WITH AN HI DOAN YA -- ANHEDONIA, AND LASTLY I WANT TO THE REEMPHASIZE SOMETHING THAT'S BEEN SAID MULTIPLE TIMES, WHILE THESE APPROACHES FOR ACQUIRING BEHAVIORAL ASSESSMENTS ACROSS SPECIES ARE REALLY POWERFUL, IT'S ALSO REALLY IMPORTANT TO BE MINDFUL AND ACTIVELY KIND OF QUESTION AND VALIDATE ASSUMPTION S ABOUT CROSS-SPECIES BEHAVIORAL ANALOGIES AND WILL NEUROANATOMICAL A ANALOGIES AS WELL, CHT WAY A HUMAN GOES ABOUT SOLVE I AN PROBLEM MAY NOT BE THE SAME AS THE WAY A RAT GOES ABOUT SOLVING IT EVEN THOUGH IF SUPERFICIALLY THEY ACHIEVE THE SAME OUTCOME AT THE END AND I THINK PART OF THE REASON THAT KAREN'S WORK AND DAVID'S WORK ASK THESE EXAMPLES HAVE BEEN SO SUCCESSFUL IS THAT THEY'RE THOUGHTFUL ABOUT THOSE LIMITATIONS, AND I WILL STOP WITH THAT. I THANK THE PANEL. >> Dr. Dzirasa: LET'S HAVE ALL THE SPEAKERS COME TO THE FRONT, PLEASE. SO I WILL ASK THE FIRST QUESTION , THEN I WILL SORT OF BOOKEND OUR TWO SPEAKERS. I'M REALLY INTERESTED IN THIS IDEA OF HAVING AUTOMATED WAYS OF QUANTIFYING BEHAVIOR AND I'M ALSO THINKING A LOT ABOUT BRAIN STATES. I'M WONDERING HOW WE POOL BOTH OF THESE THINGS TOGETHER, PARTICULARLY WITH REGARDS TO TIME SCALE. SO SHUFFLED WE BE THINKING ABOUT PUTTING GO PROS ON THE FAMILY MEMBERS OF ALL OF OUR PATIENTS? SHOULD WE BE VIDEOTAPING IN THE CLINIC? WHAT TIME OF TIME SCALE SHOULD WE BE THINKING ABOUT WHEN IT COMES TO FEELINGS VERSUS THINGS LIKE MOVEMENTS, HOW DO WE STITCH THESE TWO THINGS TOGETHER? >> I'LL JUST START. I THINK OTHERS ON THIS PANEL ARE BETTER EQUIPPED TO ANSWER SOME PARTS OF THAT QUESTION, BUT I THINK THAT NATURALISTIC ASSESSMENTS ON THE PATIENT'S SIDE OUTSIDE THE LAB ARE GOING TO BE REALLY IMPORTANT IF THEY'RE DONE THOUGHTFULLY AND, YOU KNOW, WE RELY ON -- WE RELY TOO MUCH ON PATIENT'S SELF- REPORT FOR LACK OF BETTER INFORMATION, I THINK, BUT TAKE INSOMNIA, FOR EXAMPLE, IF YOU ASK ME HOW I SLEPT LAST NIGHT, I'LL PROBABLY GIVE YOU A REASONABLE EVALUATION OF THAT. BUT IF YOU ASK ME ABOUT LAST WEEK, I DON'T THINK I'LL BE VERY RELIABLE, AND WHILE I'M NOT IN DISTRESS, SO HAVING NATURAL STICK OF BEHAVIOR IS REALLY IMPORTANT TO ME. >> I WOULD JUST SECOND THAT GO AS WELL. I THINK MORE NATURALISTIC BEHAVIORS AND ESPECIALLY BEING ABLE TO MEASURE PATIENTS IN THEIR HOME SETTING BECAUSE AT THE END OF THE DAY I THINK ONE OF THE OTHER SPEAKERS MENTIONED THIS, LIKE WE'RE NOT LISTENING TO THE PATIENTS ENOUGH, LIKE THEY WANT TO GO HOME WITH DEVICES, THEPTS TO BE ABLE TO HOLD THE HAND OF THEIR LOVED ONE , THEY WANT TO BE ABLE TO BRUSH THEIR OWN TEETH, THINGS LIKE THAT IN DISEASES, SO I THINK BEHAVIORAL MONITORING IN SOME WAY THAT'S NOT TOO CREEPY COULD BE RELATIVELY USEFUL FOR THESE TYPES OF THINGS, AND I THINK ON THE NOTION OF GETTING DATASETS, HOW WOULD YOU EVEN TRAIN THIS, SO THERE IS SOME EFFORT TO TAKE LIKE LABELED SEGMENTS OF ACTIONS OR LIKE THE KITCHEN TASK WHERE THERE'S LOTS OF LABELED DATA WITH PEOPLE DOING EVERYDAY BEHAVIORS SO I THINK THIS IS POTENTIALLY BECOMING A REALITY QUITE SOON. >> CAN I ADD TWO QUICK THINGS TO THAT. ONE IS A NOTE OF CAUTION, WHICH IS THAT WHEN WE'RE TALKING ABOUT GOING CROSS-SPECIES, I THINK IT'S VERY, VERY IMPORTANT TO BE AWARE OF THE TIME COURSES OF EACH OF THE DIFFERENT TECHNOLOG IES THAT WE HAVE. FOR EXAMPLE, FMRI IS NOT EASILY TRANSLATABLE TO MULTIELECTRODE RECORDING, AND EVEN CALCIUM IMAGINGING, WHICH OFTEN IS THEN TRYING TO TRANSLATE ITSELF TO MULTIELECTRODE RECORDING, I DON'T REALLY UNDERSTAND WHY BECAUSE IT'S ITS OWN SIGNAL AND CARRIES OTHER INFORMATION, BUT WE NEED TO BE VERY CAREFUL NOT TO TRY TOP TRANSLATE IT INTO SOME UNIFIED LANGUAGE BUT, RATHER, TO RELATE THEM TO EACH OTHER THROUGH KNOWN MECHANISM AND IS COMPUTATION, SO THAT'S ONE. THE OTHER IS I WAS GOING TO POINT OUT THAT THERE'S A LOT OF TECHNOLOGY THAT WE ARE IN FACT ALREADY GATHERING EXPERIMENTALLY , AND FOR EXAMPLE, YOU KNOW, I MEAN, THIS IS AN OLD STYLE WATCH, BUT FROM FIT BITS AND THINGS LIKE THAT AND THE FACT OF WHAT YOU CAN SCRAPE OFF A PHONE IS KIND OF AMAZING THESE DAYS LEGALLY OR ILLEGALLY, APPARENTLY. BUT ALSO JUST FROM THE SLEEP THING, I MEAN, MY UNDERSTANDING IS THAT THERE'S A LOT OF DATA OF HOW WELL YOU CLAIM YOU SLEPT AND HOW WELL YOU ACTUALLY SETTLEMENT OFTEN ARE NOT AS WELL RELATED AS EVERYBODY WOULD LIKE TO THINK. >> I'M SO THE SENIOR ETHICS SUBCOMMITTEE AND ACTUALLY THIS HAS ALREADY COME UP IN EVERYTHING EVERYONE HAS SAID IS THE ISSUE OF CONSENT AND WHAT KINDS OF INFORMATION WE'RE ABLE TO SCRAPE USING AI TOOLS FROM BEHAVIORAL MONITORING AS WE'RE ABLE TO UNDERSTAND AND MANIPULATE BRAIN STATES, WHAT CONTROLS DO WE HAVE OVER WHAT WE'RE ALLOWED TO DO. SO I WOULD LOVE TO KNOW HOW YOU GUYS ARE THINKING ABOUT THAT, WHETHER YOU GUYS ARE THINKING ABOUT THAT, AND IF NOT, HOW CAN NIH HELP YOU WITH THAT. >> WE ARE STARTING TO DO WORK AT MINNESOTA IN CLINICS WITH A LOT OF THESE KINDS OF PULLING IN DATA FROM, YOU KNOW, THESE KIND OF THINGS, AND ESSENTIALLY IT COMES DOWN TO BEING VERY CLEAR ARE TO THE PATIENT, I MEAN, AN IRB THING, RIGHT? I MEAN, WE HAVE TO BE VERY, VERY STRICT ABOUT PATIENT PRIVACY, WE HAVE TO BE VERY STRICT ABOUT PATIENT CONSENT, AND AS A NON-HUMAN ANIMAL, I ALWAYS LIKE TO POINT OUT HUMANS ARE ANIMALS TOO, AS A NON-HUMAN ANIMAL RESEARCHER GETTING INVOLVED IN THE HUMAN ANIMAL WORLD, I'VE BEEN VERY SHOCKED AT THE DIFFERENCE BETWEEN WHAT ICOOC WILL LET YOU DO AND WHAT IRB WILL AT THE TIME YOU DO, IN TERMS OF RANGES, NOT PERMISSION, ICOOC IS VERY INTERESTED IN IS THIS RANGE OKAY AND GO IRB IS VERY STRICT ABOUT YOU MUST DO THIS TASK. I THINK IRB'S ARE COVERING THAT, THAT'S BEEN MY EXPERIENCE, IN THIS KIND OF THING. >> [AWAY FROM MIC] CONSENT WAS NOT PROVIDED FOR. >> NETWORKS I THINK YOU RAISE A REALLY EXCELLENT POINT. THERE'S A LOT OF THINGS THAT PEOPLE INADVERTENTLY DO THAT THEY'RE NOT EXPLICITLY CONSENT ING TO AND I THINK THAT IS SOMETHING WE SHOULD TAKE SERIOUSLY. IF YOU'RE MINING YOUTUBE VIDEOS, NOT EVERYONE REALLY UNDERSTANDS THAT THAT DATA CAN BE USED FOR SOMETHING. SO I THINK AS A RESEARCHER WE HAVE A REAL RESPONSIBILITY TO MAKE SURE WE ETHICALLY USE THIS DATA, SO I FULLY SUPPORT THAT. >> I WOULD LIKE TO ASK A QUESTION IN THE SENSE OF I VERY MUCH RESONATED WITH MUCH OF WHAT EVERYBODY SAID. ONE THING I FOUND THAT WAS MISSING WHICH I THINK IS IMPORTANT IS CONSIDERING INDIVIDUAL VARIATION IN BEHAVIOR , AND THIS WAS SORT OF TOUCHED UPON BY A FEW OF THE QUESTIONS AND A DPU OF THE COMMENTS BUT NOT REALLY EMPHASIZED, AND IT'S OF COURSE OF FUNDAMENTAL BIOLOGICAL IMPORTANCE AND IF YOU WANT TO UNDERSTAND HOW CIRCUITS WORK, IT SEEMS UNDERSTANDING TREATING INDIVIDUAL VARIATION NOT AS THE VARIANCE AROUND A MEAN BUT AS A RICH SOURCE OF DATA ITSELF IS IMPORTANT, I WOULD BE CURIOUS TO HEAR SOME COMMENTS ABOUT THAT. >> WHAT'S INTERESTING IS I THINK PEOPLE THINK OF INDIVIDUAL VARIATION AS A NUISANCE VARIABLE , A LOT OF THE TIMES IN DESIGNING STUDIES BUT I THINK AS WE THINK ABOUT A PRECISION MEDICINE APPROACH ESPECIALLY IN THINKING ABOUT TREATMENT IT'S REALLY CRITICAL. OUR WORK HAS DONE WORK WHERE THERE'S BEEN A LOT OF INTEREST IN TREATING PATIENTS WITH AUTISM AND A VARIETY OF OTHER BRAIN DISORDERS WITH OXYTOCIN AND THERE WAS A LOT OF EARLY HYPE TO THINK THAT THIS COULD BE BENEFICIAL IN THESE SINGLE DOSE STUDIES AND A LOT OF THE TRIALS HAVEN'T WORKED VERY WELL, SO I THINK IN TAKING A PAGE FROM THINKING ABOUT THE ANIMAL STUDIES WHERE YOU CAN DEMONSTRATE SIGNALLING DEFICITS OF WHERE THE PEPTIDE IS MADE, WE PUBLISH A STUDY SHOWING THAT THE DRUG ACTUALLY WORKED IN KIDS WITH AUTISM AND IT WORKED THE MOST WHEN WE COULD CONCENTRATE THE SIGNALS SO THE LOWER YOUR BASELINE OXYTOCIN LEVELS, THE MORE BENEFICIAL THE DRUG WAS, RIGHT? SO I THINK THAT THAT YOU CAN EMBED THIS IN CLINICAL TRIALS AND YOU CAN BED IT IN STUDIES. I THINK OBVIOUSLY WHEN YOU'RE LOOKING AT INDIVIDUAL DIFFERENCE S, IT REQUIRES MORE MONEY TO GET THE STUDY DONE BECAUSE YOU OFTEN NEED LARGER SAMPLE SIZES, BUTS I THINK IF YOU'RE SMART ABOUT THE WAY YOU DESIGN YOUR TRIALS AND YOU DESIGN YOUR STUDIES, YOU CAN GET INDIVIDUAL IRCHES DIDS AND I THINK THAT'S THE KEY TONESS VA ING HUMAN HEALTH. -- KEY TO ADVANCING HUMAN HELTS. >> IN CONTEXT WE MEASURED IT IN BLOOD, WE'VE MEASURED IT IN C TH S TOO, ASK WE PUBLISHED PAPERS SHOWING THAT BLOOD IS RELATED TO CNS IN THE SAME PATIENTS THE AND WE CAN VALIDATE IT WITH A BEHAVIORAL MEASURE, THERE'S SOME HAND WAVING BUT YOU'RE NOT GOING TO GET PEOPLE TO TAP THEIR KID TO ENROLL IN A CLINICAL TRIAL, IT'S NOT GOING TO HAPPEN, WHEN YOU WORK WITH, THIS IS ONE OF THE LIMITATIONS WHEN YOU DEAL WITH HUMANS, THERAPY NOT AS TRACTABLE FOR SOME OF THE QUESTIONS SCIENTIFICALLY YOU MIGHT WANT TO ASK. >> JUST AS A QUICK ANSWER ON THE INDIVIDUAL DIFFERENCES POINT, THERE ARE A LOT OF CASES IN THE NON-HUMAN ANIMAL LITERATURE WHERE PEOPLE BIFF GOING INTO THE INDIVIDUAL DIFFERENCES HAVE ACTUALLY MADE NEW DISCOVERIES ABOUT CIRCUITS AND IRCHES DIDS AND THAT'S BEEN -- AND IRCHES DIDS AND THAT'S BEEN A BIG EXAMPLE. I ALSO WANT TO POINT OUT THAT I THINK THE BIGGER ISSUE IS THAT IT'S NOT SO MUCH, ALTHOUGH I THINK IT'S ALWAYS GREAT TO HAVE LARGER STUDIES AND ET CETERA, IF YOU HAVE THE RIGHT DATA ANALYSIS , A LARGE PART OF THE PROBLEM IS ACTUALLY THE WAY THAT DATA IS ANALYZED IN THESE KIND OF VERY OLD SCHOOL STATISTICAL WORLDS THAT DON'T TAKE INTO ACCOUNT MODERN COMPUTER TECHNOLOGIES THAT WE CAN ACTUALLY MEASURE RELATIONSHIPS AND PARAMETERIZATIONS AND WE DON'T NEED TO DO THINGS LIKE DIVIDE EVERYTHING INTO TWO GROUPS AND WE CAN HAVE MUCH MORE SOPHISTICATED ANALYSES, CONFINE THOSE INDIVIDUAL DIFFERENCES EVEN IN RELATIVELY SMALL POPULATIONS. SO I JUST THINK THAT'S AN IMPORTANT POINT. >> I THINK THAT THERE'S ALSO SORT OF TWO OTHER ASPECTS IN WHICH INDIVIDUAL IRCHES DIDS HAVE BEEN MENTIONED -- DIFFERENCES HAVE BEEN MENTIONED OR AT LEAST ARE RELEVANT IN THE CONTEXT OF WHAT WE DISCUSSED TODAY, THAT INCLUDES SOME OF THE EMERGENCE OF STRESS RESILIENCE, THIS WAS STILL A LITTLE A LITTLE BIT OF A TWO-GROUP COMPARISON, BUT WE KNOW THERE ARE A LOT OF INDIVIDUAL IRCHES DIDS IN ANIMALS AND HUMAN RESPONSES TO STRESS SO THAT'S A VERY ACTIVE AREA OF RESEARCH WHICH VERY CAREFULLY TAKES INTO ACCOUNT INDIVIDUAL VARIATION IN BEHAVIOR ANOTHER AREA IN PARTICULAR WITH THE HEAD FIXED IMAGING IN REAL WORLD OR VIRTUAL WORLD PREPARATIONS, A LOT OF PEOPLE INCLUDING JOHN M MAUNSELL'S LAB HERE AND MANY OTHERS ARE DOING INCREDIBLY FINE SCALE PSYCHOMETRIC CURVES WHERE THEY CAN MEASURE BEHAVIOR EXTREMELY PRECISELY EVEN BEFORE THE ADVENT OF REALLY COOL AI TECHNOLOGIES THAT CAN DO THAT NOW IN MANY MORE DIFFERENT CONTEXTS SO WE COULDED DO THOSE THINGS AND RELATE IT IN A VERY FINE WAY TO CORRELATED ACTIVITY PATTERNS OR INDUCED PER TOUR BASES THAT YOU COULD RELATE TO VERY SUBTLE CHANGES IN BEHAVIOR SO A LOT OF THE FIELD IS TAKING THAT ASPECT VERY SERIOUSLY. >> SO IF YOU'VE HEARD MIKE SNYDER OR ERIC TOPAL TALK RECENTLY, YOU KNOW SOME OF THESE GUYS ARE WEARING EIGHT TO TEN SENSORS ALL THE TIME AND IT SEEMS LIKE THERE SHOULD BE -- THEY'RE LOOKING PRIMARILY AT PHYSIOLOGICAL DATA, BUT THERE SHOULD BE BEHAVIORAL DATA YOU CAN EXTRACT OUT OF THAT. YOU COULD MONITOR, LOOK AT ERIC 'S PHYSIOLOGICAL RESPONSES AS HE TWEETS DURING THE DAY, TWEETS OUT ALL THESE PAPERS AND READS THESE PAPERS. BUT IT SEEMS LIKE THE NEURO FIELD REALLY SHOULD BE GETTING ON BOARD THE SENSOR ISSUE BECAUSE THEY'RE COMING. >> YES. I FULLY AGREE. THE CAVEAT BEING THAT YOU HAVE TO EFFECTIVELY HAVE A WILLING PARTICIPANT IN ORDER TONT DISRUPT NATURAL WOULD HE HAIF YORES, SO -- NATURAL BEHAVIORS, SO IT'S DIFFICULT TO PUT MARK ERPZ ON A FRUIT FLY I FLY OR EVEN A MOUSE, THEY'RE NOT GOING TO BE ABLE TO HANDLE MARKERS AND A LOT OF EXTRA WIRES AND I THINK AT THE END OF THE DAY WE DON'T WANT TO NECESSARILY STUDY THEM IN THAT CONTEXT ANYWAY, BUT TO YOUR POINT I THINK YOU'RE RIGHT THERE IS A LOT OF REALLY GOOD DATA THAT CAN BE MINED AND I THINK PEOPLE ARE DOING THAT OR THEY SHOULD BE DOING IT IF THEY'RE NOT. >> I'LL POINT OUT THAT THE PHONE DATA IS ACTUALLY PROVIDING HUGE, WAY MORE THAN WE KNOW WHAT TO DO WITH ANYWAY. THERE IS IN ADDITION TO ALL THESE PHYSIOLOGY THINGS, THE DATA EXISTS, LIKE ADRIAN WAS BRINGING UP, THERE'S AN ETHICAL ISSUE OF HOW FAR DUF PUZZLE OUT THE CONSENT WHEN, YOU KNOW, SOMEBODY SAYS YES YOU CAN TAKE EVERY KEY STROKE OG MY PHONE. I MEAN, THERE'S DATA NOW THAT THE TYPING, THE WAY YOU TYPE ON YOUR PHONE IS INDICATIVE OF SOME OF THESE KINDS OF ISSUES THAT PEOPLE HAVE. >> SO I HAVE A COST-EFFECTIVE THAT'S KIND OF FROM MUCH HIGHER UP. I THINK PART OF PROBABLY WHY YOU GUYS ARE ALL HERE IS YOU'RE VERY KIND OF POLYMATH, RIGHT? YOU SEEM LIKE YOU SPAN LOTS AND LOTS OF DIFFERENT AREAS AND YOU'RE TALKING ABOUT WANTING TO GET NEW TECHNOLOGIES AND USE MODERN ANALYSIS METHODS AND THEN INTEGRATE THEM WITH NEUROSCIENCE CONCEPTS AND STUFF. HOW COULD THE BRAIN INITIATIVE DO A BETTER JOB OF PULLING TOGETHER ALL OF THOSE PIECES AND MAKE YOUR ABILITY THE TO ADOPT THESE NEW TECHNOLOGIES, THESE NEW METHOD BETTER? DO YOU SEE WAYS IN WHICH THAT COULD BE DOFN DONE BETTER AND MORE EFFICIENTLY THAN IT IS NOW? >> TRAINING GRANTS. I MEAN, IN FACT, WE JUST DEPOSIT A TRAINING GRANT AT MINNESOTA WHICH WAS BASED IN LARGE PART ON TEACHING PEOPLE COMPUTATIONAL ANALYSES AND BRINGING OUR NEUROSCIENCE UNDERGRADS -- SORRY , NEUROSCIENCE GRADUATE STUDENTS AND POST-DOCS WITHOUT THAT KIND OF TRAINING TO GIVE THAT KIND OF COMPLEX TRAINING, AND THERE ARE TRAINING GRANTS AROUND FOR THAT. ONE OF THE THINGS THAT'S BEEN FASCINATING TO ME COMING ORIGINALLY FROM THE COMPUTER WORLD, I WON'T SAY, MORE THAN 20 YEARS AGO, IS WHEN WE FIRST CAME IN AND THE IDEA OF YOU SHOULD HAVE A COMPUTATIONAL CORE CLASS IN NEUROSCIENCE, IN FACT, EVEN WHEN I WAS A JUNIOR FACULTY, I SAID THIS IS PROBABLY SOMETHING, AND TO SAY IT WAS SHURT DOWN WOULD BE POLITE. -- SHUT DOWN WOULD BE POLITE. IN FACT, IT IS NOW PART OF OUR CORE AND IN FACT IT WAS THE OTHER FACULTY WHO DEMANDED IT. SO IN FACT ALL OF OUR STUDENTS ENDED UP TAKING, IT'S OFFICIALLY CALLED QUALITATIVE NEUROSCIENCE, IT INCLUDES RIGOROUS -- EXPERIMENTAL DESIGN, COMPUTATIONAL DESIGN, ONE OF THE THINGSING EVERYBODY DEMANDED WAS MATH LAB, I WAS SURPRISED, ALL OF THE OTHER FACULTY, INCLUDING THE OLD SCHEDULE NEUROSCIENCE FACULTY SAID NO MY STUDENTS NOW NEED TO KNOW HOW TO BE ABLE TO DO THIS IN ORDER TO MOVE FORWARD , SO TRAINING. >> THANK YOU. >> SO SOMEBODY ELSE MENTIONED EARLIER MISSION ALIGNMENT AND I THINK THAT PUTTING THE MONEY BEHIND THE MISSION ALIGNMENT IS IMPORTANT ARE. SO IF WE'RE THINKING ABOUT TRANSLATIONAL UTILITY, WE NEED TO FUND STUDIES THAT ARE ACTUALLY GEARED TOWARD TRANSLATION, RIGHT? I MENTIONED THIS DURING MIYATAKE IB TONS OF PEOPLE WHO DO -- I KNOW TONS OF PEOPLE WHO DO WORK IN ANIMALS AND DO WORK IN PEOPLE HE AND THEY HAVE NEVER SUCCESSFULLY GOTTEN A GRANT FUN NED AT ALL THE FANCY SCHOOLS THAT EVERYBODY IS AT AND WE ALL GET AN RO1 FOR OUR ANIMALS AND AN RO1 FOR OUR PEOPLE AND WE STITCH IT TOGETHER AND IT WOULD BE FAR SIMPLER TO BE ABLE TO, YOU KNOW, EVEN HAVE GO, NO GO, RIGHT, I GET IT THE IF YOU'RE DOING IT IN AN ANIMAL AND THE MODEL FAILS YOU SHOULDN'T GET THE MONEY FOR THE PEOPLE BUT HAVING SOME SORT OF ABILITY TO PIVOT AND BE ABLE TO IN THE SAME FUNDING MECHANISM BE ABLE TO DO THAT TRANSLATION WOULD REALLY STREAMLINE OUR ABILITY TO BE EFFICIENT AND CREATE ADVANCES IN HUMAN HEALTH. >> BUILDING A LITTLE BIT ON WHAT DAVID SAID, IN ADDITION TO TRAINING GRANTS IN PARTICULAR, KIND AFTER INTERDISCIPLINARY TRAINING GRANTS, WHICH SOME T32 'S ALREADY ARE AND I'VE SEEN THAT WORK EXTREMELY WELL IN SOME CASES, I THINK IT WOULD ALSO BE FANTASTIC TO HAVE SOME MORE BRAIN INITIATIVE FUNDING FOR STAFF SCIENTIST TYPE POSITIONS BECAUSE SOME OF US BUILD SOME NEW TOOL BUT WE'RE NOT REALLY READY TO DO AN SBIR TYPE THING, BUT IT WOULD BE SPECTACULAR AND REALLY IMPORTANT FOR CONSISTENT TRAINING IN THESE NOW INCREASINGLY MULTIDISCIPLINARY FLAVORED NEUROSCIENCE LABS TO HAVE A BIT MORE STAFF CONTINUE TO THAT COMES FROM HAVING HIGHLY TRAINED PEOPLE IN POSITIONS THAT ARE GOOD FOR THEM, THAT CAN BE KIND OF A LIFETIME VERY SOPHISTICATED POSITION. I FEEL LIKE THAT COULD BE A BIT OF GAME CHANGER FOR AT LEAST THE SUBSET OF NEUROSCIENCE CURRENTLY DONE. >> SO YOU'RE SAYING STAFF SCIENTIST POSITIONS SPECIFICALLY FOR TOOL DEVELOPMENT AND DISSEMINATION, OR IN GENERAL? >> WELL, I THINK HAVING ACTUALLY BOTH STAFF SCIENTIST POSITION, THAT OPTIMIZED TOOLS FOR DISSEMINATION, AS WELL AS SIMPLY JUST MORE NIH FUNDED BRAIN INITIATIVE AND OTHERWISE STAFF SCIENTISTS THAT HELP TRANS DISCIPLINARY RESEARCH WOULD BE FANTASTIC. >> ONE THING THAT WOULD BE VERY USEFUL ALSO BUILDING ON THAT WOULD BE STAFF SCIENTISTS FOR WITHIN UNIVERSITIES AND WITHIN, YOU KNOW, SO THAT THERE'S A LOCAL EXPERT TO DO THIS AND THAT CAN HELP PEOPLE. THAT CLEARLY MAKES A BIG DIFFERENCE. SO THAT KIND OF STAFF SCIENCE CONTROL. SOME UNIVERSITIES ARE DOING THAT , AND THERE ARE CORES THAT CAN DO THAT, BUT THAT KIND OF A PROCESS. >> I THINK TO PIGGYBACK ON THAT, I THINK ONE OF THE BIGGEST BOTTLENECKS THAT WE SEE IN SCIENCE ESPECIALLY WITH BIG DATA AND I THINK CONOR ALLUDED TO THIS IN HIS TALK, IS TO HAVE THE QUANTITATIVE EXPERTISE TO BE ABLE TO HELP THOSE OF US WHO HAVE REASONABLE QUANTITATIVE SKILLS BUT WE'RE NOT -- YOU KNOW , BUT THAT'S NOT WHAT THE WE DO FOR A LIVING, YOU KNOW, TO HAVE THEM AVAILABLE, YOU KNOW. THERE'S A LOT OF QUANTITATIVE STUFF AT MY UNIVERSITY BUT THE FANCY STATISTICIANS HAVE THEIR OWN RESEARCH PROGRAMS, RIGHT? AND UNDERSTANDABLY. BUT HAVING PEOPLE THERE THAT COULD REALLY HELP US RATHER THAN JUST CONSULTING WITH US HERE AND THERE I THINK WOULD BE A GAME CHANGER. SO ALONG MAYBE HAVING A STAFF SCIENTIST POG FOR THAT. >> -- POSITION FOR THAT. >> THAT SPEAKS TO THE MISSION ALIGNMENT THING BECAUSE YOU CAN FIND AN EXPERT IN T BUT THERE'S NOT A PERSON WHO WILL DO IT AND WHO WILL CONTINUE TO DO IT, AND WE END UP HAVING TO HAVE A GRAD STUDENT OR POST-DOCS AND WE HAVE A VERY SHORT LIFETIME FOR THEN TO DEVELOP SOME AWESOME ALGORITHM AND THEN LEAVE, AND IT'S NOT AN EFFICIENT WAY FOR US TO BE WORKING AT THE VERY HIGHEST LEVEL FOR THE SCIENCE NOW. >> I WANT TO -- >> [AWAY FROM MIC] >> TO REPEAT, ARE THERE ANY OF THE WORKING GROUP NEBZ ONLINE WHO HAVE -- MEMBERS ONLINE WHO HAVE ANY QUESTIONS BEFORE WE CLOSE? IF NOT, I WOULD LIKE TO BRING THIS SESSION TO AN END. I WANT TO THANK ALL THE SPEAKERS IN ALL THREE SESSIONS FOR REALLY EXCELLENT TALKS THAT WERE REALLY HELPFUL, I THINK, FOR THE WORKING GROUP. SO THANK YOU ALL AGAIN. [APPLAUSE]