WELCOME TO NIGMS LECTURE EARLY STAGE INVESTIGATOR GIVE A TALK ABOUT HIS OR HER RESEARCH, 30 MINUTES. GEARED TOWARD AN UNDER GRADUATE AUDIENCE. ALTHOUGH HOPEFULLY IT WILL BE ACCESSIBLE TO ANYONE. AFTER THAT WE'RE GOING TO HAVE A 30 MINUTE QUESTION AND ANSWER SESSION BETWEEN ME AND THE SPEAKER TO TALK ABOUT THE SPEAKER'S CAREER PATH AND OTHER AREAS OF SCIENTIFIC INTEREST. MANY QUESTIONS WILL COME FROM UNDER-GRADUATES AROUND THE COUNTRY THAT CONTRIBUTED IN ADVANCE OR WILL HOPEFULLY CONTRIBUTE VIA E-MAIL OR TWITTER. BECAUSE WE'RE DOING A DISCUSSION OF THE SPEAKER'S CAREER PATH AT THE END OF THE TALK I'M NOT GOING TO SPEND MUCH TIME INTRODUCING, BUT I WANT TO START BY THANKING THE PEOPLE THAT MADE THIS HAPPEN, JULIE [INDISCERNIBLE], JUDITH GREENBERG, DEPUTY DIRECTER OF THE INSTITUTE AND BEV, AND A NUMBER OF PEOPLE WORKED VERY HARD TO MAKE THIS FIRST EVER LECTURE HAPPEN. BLAKE WIEDENHEFT IS AS ASSISTANT PROFESSOR IN THE DEPARTMENT OF IMMUNOLOGY AT MEDAL OF -- A PROMISING AND AT THIS POINT VERY PROMINENT SCIENTIST. HAS ALREADY AUTHORED NEARLY 40 RESEARCH PAPERS, JUST TO PUT THAT IN PERSPECTIVE. THAT REALLY IS TRULY IMPRESSIVE AT THIS STAGE OF SOMEONE'S CAREER. CONSISTENT WITH THAT, JUST LAST YEAR, HE WON 2 DIFFERENT AWARDS FOR HIS WORK AND MENTORING IN TEACHING. THE FIRST IS THE 2015 AMJEN YOUNG INVESTIGATOR AWARD A V PRESTIGIOUS NATIONAL AWARD. HE WAS THE WINNER OF A STUDENT NOMINATED AWASHED FOR EXCELLENCE FROM THE MONTANA STATE UNIVERSITY ALUMNI ASSOCIATION. EVEN WITH ALL THE PRESTIGIOUS NATIONAL AND INTERNATIONAL AWARDS GETTING AN AWARD FROM STUDENTS IS THE HIGHEST HONOR YOU CAN ACHIEVE BECAUSE THEY ARE REALLY THE SHARPEST AND MOST PERCEPTIVE CRITICS, I THINK. HIS RESEARCH HAS BEEN SUPPORTED CURRENTLY BY AN NIGMS, OUR INSTITUTE RESEARCH GRANT, RO1. HE HAS BEEN A MEMBER OF THE MONTANA STATE CENTER OF BIOMEDICAL RESEARCH EXCELLENCE WHICH IS AWARD FROM NIGMS'S IDEA PROGRAM THAT SPORTS RESEARCH AND MENTORING OF JUNIOR INVESTIGATORS IN 23 STATES AND PAT RILEY. THE TITLE OF THE TALK -- PUERTO RICO. THE TITLE IS BACTERIA, VIRUSES AND LET'S HEAR IT. >> THANK YOU VERY MUCH. GOOD AFTERNOON. THANK YOU FOR THE KIND INTRODUCTION AND REALLY FOR THE OPPORTUNITY TO SHARE WITH YOU SOME OF THE WORK THAT WE HAVE BEEN DOING MICROBIAL IMMUNE SYSTEMS. I WANT TO TALK ABOUT BACTERIA AND THIS PERPETUAL STRUGGLE THAT WITH THE VIRUSES THAT INFECT THEM, AND TO TRY TO EXPLAIN HOW INSIGHTS INTO UNDERSTANDING HOW BACTERIA DEFENDANT THEMSELVES FROM VIRAL INFECTIONS HAS LED TO A TRANSFORMATIVE NEW TECHNOLOGY USED IN MOLECULAR BIOLOGY LABS AROUND THE WORLD, AND HOW THIS TECHNOLOGY IS NOW USED TO PERFORM GENOME SURGERY ON VIRTUALLY ANY CELL TYPE. THIS EXTENDS TO HUMAN CELLS, OF COURSE, AND THE POTENTIAL APPLICATION OF THIS IS, OF COURSE, THAT IT CAN BE USED TO SURGICALLY ALTer OR MODIFY GENES THAT RESULT OR FIX GENETIC MUTATIONS THAT CAUSE DISEASE BEFORE I GET TO THAT I WANT TO REMIND YOU THAT BACTERIA GETS SICK. THIS HAPPEN A LOT. VIRUSES THAT INFECT BACTERIA ARE THE MOST DIVERSE BIOLOGICAL AS ON THE PRANAB THE. THERE IS AN -- PLANET. THERE IS 10 TO 31 VIRUS PARTICLES ON EARTH THAT CAUSE AN INFECTION EVERY SECOND. I THINK THOSE NUMBERS ARE HARD TO CONCEPTUALIZE. TO PUT IT IN A MORE, MAYBE MORENO BID TERM -- MORBID TERM, DEATH FROM VIRAL INFECTION, FROM BACTERIA, IS RESPONSIBLE FOR TURNING OVER 20-30% OF THE BIO MASS IN THE OPEN OCEAN EVERY DAY. THESE INFECTIONS ARE NOT RESTRICTED TO MARINE HABITATS. THIS IS HAPPENING ALL AROUND US. ONE OF THE CHALLENGINGSES FOR THE COMING DECADE OF MODERN MEDICINE WILL BE TO TRY TO UNDERSTAND HOW CERTAIN VIRAL INFECTIONS THAT INFECT THE COMMUNITY SO IMPORTANT TO OUR OWN HUMAN HEALTH SOMETIMES CAN PURCHASE TURBTHIS ECO -- PERTURB THIS HE CANEE SYSTEM THAT PREDISPOSES US TO DISEASE. THAT'S AN AREA OF INTEREST IN MY LAB BUT OVER 3.5 YEARS WE HAVE BEEN LESS FOCUSED ON THE COMMUNITY STRUCTURE AND MORE FOCUSED ON THE FUNCTION OF MACRO MOLECULAR MACHINES INSIDE THESE CELLS THAT ARE RESPONSIBLE FOR PROTECTING THIM FROM VIRAL SALTS. SO, OF COURSE, THE IMMUNE SYSTEM OR MECHANISM THAT I'M REFERRING TO IS THE SO-CALLED CYSTER SYSTEM -- CRISPR. IT'S AN ACRONYM, STANDS FOR CLUSTER OF REGULARLY INTERSPACED SHORT PALIN DREAMIC REPEATS. IT GIVE AN ACCURATE DESCRIPTION OF THE ARCHITECT SHOWN HERE. EACH CRISPR IS FOLLOWED BY A UNIQUE SPACER SEQUENCE OF ABOUT THIS LENGTH, REPEAT SPACER, REPEAT, SO ON. THIS ARRANGEMENT IS CAN EXTEND FOR SEVERAL KB. IT'S NOT UNUSUAL FOR MULTIPLE LOCI TO BE PRESENT IN A SINGLE CHROMOSOME. SO ALTHOUGH WE HAVE KNOWN ABOUT THE PREVALENCE OF CRISPR LOCI IN BACTERIAL GENOMES FOR SEVERAL DECADES, GOING ON 80 YEARS NOW, THE BIOLOGICAL SIGNIFICANCE OF THESE REPETITIVE ELEMENTS REMAIN OBSCURE UNTIL IT WAS REALIZE THAT HAD THESE SPACER SEQUENCES ARE NOT UNIQUE AT ALL. THEY'RE OFTEN TIMES IDENTICAL TO KNOWN VIRAL AND PLASMA SEQUENCES. TIST REALLY THIS BIOINFORMATIC OBSERVATION THAT LED TOTH HONEST THAT CRISPRS WERE SIMPLE COMPONENTS OF AN ACID IMMUNE SYSTEM. SO I'M GOING TO GIVE YOU A 60 SECOND OVERVIEW, HOW WE THINK THIS IMMUNE SYSTEM WORKS. THEN I'LL SPEND THE REST OF THE TIME TELLING YOU ABOUT SOME OF MY LAB'S CONTRIBUTIONS TO THE DEVELOPMENT OF THIS MODEL. SO THE CRISPR SYSTEM ISN'T ANY DIFFERENT THAN ANY OTHER IMMUNE SYSTEM. IT HAS TO BE ABLE TO DISTINGUISH SELF-FROM NON CELL. ALTHOUGH THE MOLECULAR DETERMINANTS THAT DISTINGUISH THE BACTERIAL CHROMOSOME FROM THIS FOREIGN DNA REMAIN LARGELY UNKNOWN. WHAT WE DO KNOW IS THAT FRAGMENTS OF FOREIGN DNA ARE SINGLY INTEGRATED INTO THE CRISPR. YOU CAN THINK OF CRISPRS AS MOLECULAR VACCINE NATE NATION CARDS. SINCE THEY GROW IN A POLARIZED FASHION, THEY MAINTAIN A CHRONOLOGICAL RECORD OF ALL PREVIOUS ENCOUNTERS WITH FOREIGN GENETIC ELEMENTS. THE CRISPR LOWCUS IS MOLECULAR MEMORY. IT HAS TO BE TRANSCRIBED, AND THIS LONG PRECRISPR TRANSCRIPT IS PROCESSED INTO A LIBRARY OF MAUL RNAS THAT EACH HAVE A UNIQUE SEQUENCE THAT WAS DERIVED FROM, AND THEN BY DEFINITION, COMPLEMENTARY TO A PREVIOUSLY ENDOCUMENTERED FOREIGN NUCELAIC ACID. THESE ARE BOUND BY A LARGE NUMBER OF CRISPR ASSOCIATED PROTEINS, AND THESE PREPARE COMPLEXES PATROL THE INTRACELLULAR ENVIRONMENT AND FIND AND FORM NUCELAIC ACIDS AND FLAG THEM FOR DESTRUCTION. IT'STH PART OF THE IMMUNE SYSTEM THAT I'LL FOCUS MOST OF MY TALK ON. BUT THERE IS ANOTHER ASPECT TO THIS IMMUNE SYSTEM THAT MANY OF YOU HAVE PROBABLY ALREADY REALIZED. IS THAT THIS SEQUENCE IS IDENTICAL TO THIS SEQUENCE. THIS MACHINE HAS TO BE ABLE TO DISTINGUISH THIS SEQUENCE FROM THIS ONE IN ORDER TO AVOID AN AUTOIMMUNE REACTION, AND THE DESTRUCTION OF THE BACTERIA OWN CHROMOSOME. SO IN ORDER FOR THAT TO HAPPEN, THIS MACHINE RECOGNIZES A SEQUENCE UNIQUE TO THIS FOREIGN DNA. THIS SEQUENCE AS I'VE DISCUSSED IS CALLED THE SPACER. THE ORIGIN OF THE SPACER IS CALLED THE PROTO SPACER. AND ADJACENT TO THE PROTO SPACER, THERE IS A SHORT DIE, SOMETIMES [INDISCERNIBLE] MOTIF CALLED THE PROTO SPACER ADJACENT MOTIF OR PAM. THIS DISTINGUISHES SELF-FROM NON SELF. I'LL TELL YOU AT ATOMIC RESOLUTION HOW THAT IS DONE. SO THESE 3 STAGES OF ADAPTIVE IMMUNITY, ACQUISITION, BIOGENESIS AND INTERFERENCE, THESE ARE CONSERVED I THINK ALL CRISPR SYSTEMS BUT THE CRISPR SYSTEMS THEMSELVES ARE REMARKABLY DIVERSE. WORK DOWN HERE AT THE NIH BY AND UNIQUE'S LAB HAS SHOWN THAT THERE IS AT LEAST 16 TYPES OF THIS IMMUNE SYSTEM. THINK OF THIS AS A FAMILY TREE. ALL THESE DIFFERENT IMMUNE SYSTEMS ARE RELATED TO EACH OTHER, BUT THEY'RE GENETICALLY DISTINCT. WE THINK THIS DISTINCTION HAS FUNCTIONAL SIGNIFICANCE. THAT'S PART OF WHAT WE'RE TRYING TO UNDERSTAND. SO OUT OF ALL THESE DIFFERENT IMMUNE SYSTEMS YOU'RE ALMOST -- MOST CERTAINLY FAMILIAR WITH THE CAST 9 BASED SYSTEMS, THE TYPE 2 IMMUNE SYSTEMS. THIS HAS BEEN POPULARIZED BECAUSE CAST 9s, [INDISCERNIBLE] CREATIVELY REPURPOSED FOR TARGETED GENOME ENGINEERING. I'M NOT GOING TO GET INTO DETAILS BUT THE WAY THIS WORKS, THIS NUCLEASE CAN BE PROGRAMMED TO TARGET ANY SEQUENCE USING SIMPLE BASED PAIRING RULES. THE 5 PRIME END OF THIS PIECE OF RNA CAN BE CHANGED TO BOW COMPLIMENTARY TO ANY SEQUENCE YOU WANT TO TARGET. CAST 9 BINDS TO THIS DNA TARGET AND WHEN IT DOES IT CLEAVES BOTH STRANDS OF THE DNA. AT THIS POINT, THE CELLULAR DNA REPAIR MACHINERY DOES THE REST OF THE WORK. MEANING THAT THIS DNA LESION HAS TO BE REPAIRED AND WHEN IT'S REPAIRED IT'S OFTEN DONE IN AN IMPERFECT WAY, WHICH ALTERS THE CODING REGION OF THIS GENE AND CHANGES THE FUNCTION. THE OTHER THING YOU'LL NOTICE IS THAT THIS BACTERIAL ENZYME HAS BEEN APPENDED WITH A NUCLEAR LOCALIZATION SIGNAL. THAT'S PROBABLY THERE FOR OBVIOUS REASONS. BACTERIA, THEY DON'T HAVE A NUCLEUS, OF COURSE, SO TO GET THIS EPISOME THAT HAS TO ACCESS THE DNA YOU HAVE TO TRANSPORT IT INTO THE NUCLEUS. THIS IS A MAUL PEPTIDE INVOLVED IN THAT TRANSPORT. THIS HAS REALLY BECOME TECHNICAL SENSATION AS I SAID BEFORE THAT'S REVOLUTIONIZING HOW MOLECULAR BIOLOGY IS DOPE. AND MY LAB DOES A LITTLE BIT OF WORK ON CAST 9. FOR THE REST OF THIS LECT, INSTEAD I'LL TELL YOU ABOUT SOME IMMUNE SYSTEMS THAT IN SOME RESPECTS, I THINK, ARE EVEN MORE INTERESTING. THEY'RE MORE INTERESTING IN THAT THEY'RE MORE COMPLICATED. WE WANT TO UNDERSTAND HOW THESE BIG MACHINES FUNCTION, SO TODAY I'M GOING TO TELL YOU ONE STORY ABOUT A TYPE ONE E SYSTEM IN E. COLI. THE OTHER SYSTEM IS TYPE ONE F SYSTEM FROM [INDISCERNIBLE]. ORIGINAL WORK ON THIS TYPE 1E SYSTEM WAS DONE BY STAN [INDISCERNIBLE], WHILE HE WAS A POST-DOC IN THE NETHERLANDS. WHAT THEY SURMISED, THEY HAD IDENTIFIED A CRISPR LOCUST IN THE E. COLI GENOME, AND THEY HYPOTHESIZED THAT THE GENOMES AI CAN'T SAYTANT THIS REPENTIVE ELEMENT WOULD BE INVOLVED IN THE IMMUNE SYSTEM. TO TEST THAT, THEY TAGGED EACH ONE OF THESE CAST GENES AND PERFORMED PULL DOWNS. AND WHEN THEY PULLED DOWN ON ANYONE OFF THESE CAST GENES, THEY PULLED DOWN ALL OF THESE COLORED CAST GENES TOGETHER TO THIS BIG COMPLEX THAT WAS ASSOCIATED WITH A 61 NUCELOTIDE CRISPR DERIVED RNA. THAT WAS A BIG DISCOVERY, THE FIRST DIRECT EVIDENCE OF A SMALL RNA BEING AN IMPORTANT COMPONENT OF THIS IMMUNE SYSTEM. SO THEY CALLED THIS COMPLEX THE CRISPR ASSOCIATED COMPLEX FOR ANTIVIRAL DEFENSE WHICH AGAIN IS A BIT OF A MOUTHFUL, SO THEY ABRIEFULATED THIS TO CASCADE. THE QUESTION WAS WHAT'S THE ROLE OF CASCADE IN ADAPTIVE IMMUNITY? SO TO ASK OADDRESS THAT QUESTION THEY TOOK ADVANTAGE OF AN IMMUNOCOMPROMISED STRAIN OF E. COLI, THE BL21 STRAIN. IT DOESN'T CONTAIN THE CAST GENES, THAT'S IMPORTANT. IF IT WORKED THE WAY I JUST EXPLAINED IT WOULD FRUSTRATE OUR ATTEMPTS TO: DNAS ON PLASMA OR OVEREXPRESSED GENES ON EXPRESSION FACTORS, SO ON. SO THEY TOOK ADVANTAGE OF THIS COMPROMISED STRAIN OF E. COLI AND ASKED COULD THEY VACCINATE THIS? AND THEY DID, THAT OVEREXPRESSED THE COMPETES OF THIS CASCADE COMPLEX. ALONG WITH A CRISPR THAT CONTAINED SPACERS THAT WERE COMPLEMENTARY TO ESSENTIAL GENES AND WHAT THEY FOUND, THIS PROVIDED NO PROTECTION. THEY WENT BANGED USED ANOTHER -- BACK AND USED ANOTHER EXPERIMENT CALLED CAS3. WHEN THEY OVEREXPRESSED THIS, THEY GET NO PRODUCTS AGAIN. BUT WHEN THEY COMBINE ALONG WITH THE COMPLAINTS AND CRISPR THAT TARGETS [INDISCERNIBLE] NOW THEY GET MORE THAN 7 LOGS, KNOCK DOWN IN PHAGE TIGHTS. SO THE EVOLVING MODEL, CASCADE WAS THIS RNA GUIDED SWABS -- IT CHANGED THE FUNCTION FROM MOLECULAR SWANKS TO THE SORT OF -- SURVEILLANCE TO THE BEACON THAT WOULD RECRUIT THIS CAS3 THAT WOULD COME IN AND DEGRADE THE TARGET. SO THIS IS WHERE I GOT INVOLVED IN THE PROJECT. I WANTED TO UNDERSTAND HOW THESE MACHINES WORKED AT A RESOLUTION BEYOND WHAT WAS AFFORDED BY KNEES CARTOONS. SO WHILE I WAS A POST-DOC I TEAMED UP WITH GABE, WHO AT THE TIME WAS A POST-DOC, AND TOGETHER, GABE AND I DETERMINED THE STRUCTURE OF CASCADE. USING CRIO ELECTRONIC MICROSCOPY. THE PONCE OF THIS STRUCTURE IS THAT IT SHOWED US WHERE THE DIFFERENT PARTS OF THIS MACHINE FIT TOGETHER AND HOW THEY FIT TOGETHER TO MAKE THIS RNA GUIDED SURVEILLANCE COMPLEX. WE THOUGHT THIS LOOKED LIKE A SEA HORSE WHERE YOU HAD A PROMINENT PEAK FEATURE AND THE HELPED WAS CONNECTED TO THE TAIL THREW THIS TWISTED BACK BONE LIKE STRUCTURE. I THINK WE LEARNED MORE ABOUT THIS STRUCTURE THAN IT LOOKED LIKE A SEA HORSE. I WON'T GET INTO THE DETAILS, BECAUSE WHEN I STARTED MY OWN LAB I REALLY WANTED TO GO AFTER A HIGHER RESOLUTION STRUCTURE OF THIS COMPLEX. AND THE REASON FOR DOING THAT IS THAT WE WANTED TO GET A MOLECULAR BLUE PRINT OF THIS MACHINE, SO I LIKE TO LOOK LIKEN THESE STRUCTURES TO A MOLECULAR BLUE PRINT OF ANY SORT, AN ENGINEER'S BLUE PRINT. THIS BLUE PRINT EXPLAINS HOW ALL THE DIFFERENT PARTS OFTH MACHINE FIT TOGETHER IN A WAY THAT COMPLETES SOME FUNCTION. THIS MACHINE IS MADE FOR FLYING. THIS MACHINE IS MADE FOR RNA GUIDED DETECTION OF INVADING NUCLEARIAC ACIDS. AND THIS MACHINE IS COMPOSED OF 11 PARTS AND SINGLE 61 NUCLEOTIDE RNA, FOR A TOTAL MOLECULAR WEIGHT OF ABOUT 105 KILADALTONS. BEYOND JUST A TECHNICAL ACCOMPLISHMENT, I THINK LIKE I SAID, THIS STRUCTURE EXPLAINS HOW THIS MACHINE WORKS. TO SHARE WITH YOU SOME OF THE MORE SALIENT FEATURES OF THE STRUCTURE I WANT TO SHOW YOU A MOVIE MADE BY AN UNDERGRADUATE STUDENT IN MY LAB, JOSH CART, WORKED WITH RYAN JACKSON, A POST-DOC IN THE LAB TO DETERMINE THE STRUCTURE OF CASCADE. SO WHAT I TOLD YOU IN THE BEGINNING, THE CRISPR RNA IS SPRAINS DESCRIBED AS THIS LONG PRECRISPR TRANSCRIPT, PROCESSED OR DICED INTO A LIBRARY OF SMALL RNAS. THAT'S DONE BY THIS ENZYME, CAS6. HERE YOU CAN SEE IT BOUND TO THE CRISPR RNA. BINDS TO THE STEM LOOP OF THE CRISPR RNA USING SEQUENCE AND NON SEQUENCE INTERACTIONS. IT STICKS TO THIS BETA HAIRPIN INTO THE MAJOR GROVE OF THE CRISPR RNA. WHEN IT DOES THAT, IT POSITIONS THE CLEAVAGE SITE OR C CELL PHOSPHATE INTO THE ACTIVE SITE FOR CLEAVAGE CREATING THE MATURE CRISPR RNA SPECIES. THERE IS A FRAGMENT OF THE REPEAT SEQUENCE OB ONE END, FOLLOWED BY A VIRAL DERIVED SEQUENCE T REMAINING REPEAT SEQUENCE ON THE OTHER END. THE CAS6 PROTEIN REMAINS TIGHTLY ASSOCIATED TO THIS 3 PRIME END TO THE RAP. THERE IS A SERIES OF THESE CAS7 PROTEINS THAT BIND TO THE RNA. EACH OF THESE PROTEINS ARE LIKENED TO A RIGHT-HAND WHERE -- I GOT BEHIND HERE. THE FINGERS, PALM, IN THIS CASE, THE THUMB REACHES BEHIND THE HEAD AND INSERTS THIS [INDISCERNIBLE] INTO THE GROVE ON THE BACK SIDE OF THE HEAD. AS I WAS SIGHING, THANKTH -- SAYING,TH PROTEIN -- THERE IS 6 OF THESE CAS7 PROTEINS THAT ARE ALONG THE ENTIRE LENGTH OF THE RNA. EACH OF THESE LOOK LIKE A RIGHT-HAND. HERE IS THE FINGERS, PALM AND THUMB. [TECHNICAL DIFFICULTIES]. SLOTS INTO THIS GROVE AN THE ADJACENT MOL MOLECULE. THIS PROCESS CONTINUES ALL THE WAY TO THE FIVE PRIME END. RECENTLY WE HAVE SHOWN THAT WE UNDERSTAND THIS COMPLEX WELL ENOUGH FROM THE STRUCTURE THAT WE CAN PROGRAM IT TO TAKE ON DIFFERENT STATES. WE CAN LENGTHEN THE LENGTH OF THE RNA, AND START ADDING MORE SUBUNITS OR SHORTEN IT AND GO THE OTHER WAY. SO THIS SEQUENCE ON THE END, REPEAT DERIVED. THIS IS ASSOCIATED WITH ALL CRISPR RNAS. THIS SEQUENCE IS ALSO RECOGNIZED PIE A PROTEIN IN THIS CASE CALLED CAS5. IT HAS A THUMP THAT FOLDS OVER THE TOP. RNA. WHEN CAS5 BINDS, IT CREATES A PORE THAT SERVES AS A DOCKING MODULE FOR A SHORT [INDISCERNIBLE] THAT REACHES THROUGH THE POOR AND INTERACTS WITH NUCLEOTIDES. THAT PRONE THAT JUST LOADED IS THE SO-CALLED SCE1 PROTEIN. THIS PART OF THE MACHINE IS ABSOLUTELY REQUIRED FOR DOUBLE STRANDED DNA BINDING, SOMETHING I'LL TALK MORE ABOUT LATER ON. THESE LAST TWO SUBUNITS YOU SEE LEADING HERE ARE THE SO-CALLED BELLY SUBUNITS, THEY CONNECT THE TAIL TO THE HEAD. AND I KNOW MOST OF YOU ARE AWARE, BUT THIS PAT CIRCUIT RENDITION OF THIS CONTRAST IS AN ELECTRIC STATUS CIRCUIT REPRESENTATION OF THIS MACHINE. THERE IS IMPORTANT -- THIS IS AN RNA GUIDED DETAIL BINDING PROGRAM. CHARGE PRAYS AN IMPORTANT ROLE -- PLAYS AN IMPORTANT ROLE IN ASSOCIATING WITH THE SUBSTRATES. ONE OF THE THINGS WE WERE MOST INTERESTED IN, WHAT'S THE ROLE. PROTEIN IN POSITIONING THE RNA? AND WHAT YOU CAN SEE HERE IS THAT THESE THUMBS BOOK END SEGMENTS OF THE RNA. AS A CONSEQUENCE, THEY PREORDER SEGMENTS. . RNA INTO A PSEUDO A FORM CONFIGURATION, INTO A HELICAL CONFIGURATION THAT LOOKS LIKE DNA OR RNA WHEN IT'S DUPLEXED. THAT EXPLAINS HOW THIS THING HAS AN ADVANTAGE, THERMODYNAMIC ADVANTAGE FOR RECOGNIZING A TARGET. SO IN ADDITION TO LOOKING AT THIS IN TERMS OF A SURFACE REPRESENTATION, JOSH WAS ALSO INTERESTED IN UNDERSTANDING WHICH PARTS OF THIS MACHINE ARE MOST IMPORTANT FOR ITS FUNCTION. AND TO DO THAT HE PERFORMED A PRETTY COMPREHENSIVE GENETIC ANALYSIS, THEN MAPPED THE HIGHLY CONSERVED RESIDUES ON TO THIS 3 DIMENSIONAL STRUCTURE. THESE ARE SHOWN IN THE RUSTY ORANGE COLOR. YOU CAN SEE IMMEDIATELY, THESE ARE NOT EQUALLY DISTRIBUTED. THE HIGHLY CONSERVED POSITIONS ARE LOCALIZED OR CONCENTRATED ON THE PALM AND THUMB. I THINK THAT THE ASSEMBLY OF THIS SPICICATED MACHINE EXPLAINED WHY THOSE POSITIONS WOULD BE SO IMPORTANT TO THE FUNCTION OF THIS MACHINE. MANY OF YOU ARE AWARE THAT THE CRISPR FIELD IS PRETTY LOT. WE'RE NOT THE ONLY ONES WORKING ON THESE QUESTIONS. AROUND THE SAME TIME THERE WERE SEVERAL STRUCTURES THAT WERE SIMILAR TO THE ONES THAT WE WERE WORKING ON, THOUGH I WOULD ARGUE THEY'RE PRETTY COMPLEMENTARY. I'LL TRY TO EXPLAIN WHAT THE COLLECTION OF THESE STRUCTURES HAVE TAUGHT US. SO WE DETERMINED THE STRUCTURE OF THE SURVEILLANCE COMPLEX CASCADE WITHOUT ANY TARGET BOUND TIGHT. IT JUST HAS THE GUIDE RAP. SCOTT'S LAB, A FRIEND OF MY AT JOHNS HOPKINS DETERMINED THE STRUCTURE OF CASCADE BOUND TO A SINGLE STRANDED DNA TARGET. AROUND THAT SAME TIME, JENNIFER, MY OLD MENTOR, DETERMINED THE STRUCTURE OF CASCADE BOUND TO A DOUBLE STRANDED DNA TARGET. OF COURSE THIS IS AN IMPORTANT STRUCTURE BECAUSE THIS IS THIFIESLOGICALLY RELEVANT TARGET OF CASCADE. BUT THIS IS A CRIO EM STRUCTURE. THIS DIDN'T HAVE THE RESOLUTION TO ADDRESS THE QUESTIONS THAT WE WERE MOST INTERESTED IN. AND ONE OF THE QUESTIONS WAS IN THE CONTEXT OF A DOUBLE STRANDED TARGET, THIS MACHINE IS CAPABLE OF DISTINGUISHING SELF-FROM NON SELF. THAT'S NOT TRUE IN SINGLE STRANDED CONTEXT. SO WE THOUGHT THAT IT WOULD BE IMPORTANT TO DETERMINE THE STRUCTURE OF CASCADE BOUND TO A PHYSICIANLOGICALLY RELEVANT TARGET THAT EXPLAINED THE MECHANISM OF ANTIGEN RECOGNITION. AND WE WERE FORTUNATE ENOUGH TO TEAM UP WITH [INDISCERNIBLE] LAB AT CORNELL UNIVERSITY, AND DETERMINED OR PARTICIPATED IN THE DETERMINATION OF THE STRUCTURE OF CASCADE BOUND TO A PARTIALLY DOUBLE STRANDED DNA. IT'S PARTIALLY DOUBLE STRANDED IN THE REGION THAT'S RESPONSIBLE FOR DISTINGUISHING SELF- FROM NON SELF. SO I'M GOING TO SHOW YOU ANOTHER MOVIE. THIS TIME I'M GOING TO COMPARE THE UNBOUND STRUCTURE FROM THE NEW STRUCTURE THAT INCLUDES THE DOUBLE STRANDED DNA TARGET AND SHOW YOU WHAT WE'VE LEARNED ABOUT CAPTURING THIS COMPLEX IN TWO DIFFERENT CONFIRMATIONAL STATES. THE ARCHITECT IS VERY SIMILAR. IF YOU SUPER IMPOSE THE STRUCTURES USING THE COMMON BACK BONE OR THIS BACK BONE STRUCTURE AS A COMMON ARCHITECTURAL FEATURE, THEY SUPER IMPOSE, NEARLY IDENTICAL. WHAT YOU CAN ALSO SEE, THERE IS A CONFIRMATIONAL CHANGE IN THIS COMPLEX AS A CONSEQUENCE OF TARGET BINDING. THE PELLEY SUBUNITS MOVE DOWN THE BACK BONE AND IT COCKS THE HAMMER ON THIS 4 HELIX BUNDLE, PROBABLY A VERY IMPORTANT MOLECULAR SIGNAL. REMEMBER IN THE BEGINNING WHEN I WAS SHOWING YOU THESE CARTOONS, CASCADE IS JUST A PROGRAMABLE DNA BINDING PROGRAM. IT DOESN'T ELIMINATE THE DNA ON ITS OWN. IT HAS TO BIND THE DNA AND GIVES A SIGNAL TO THIS TRANSACTING NUCLEASE, CALLED CAS, 3 RESPONSIBLE FOR ELIMINATING THE INVADING DNA. SO ONE OF THE THINGS I WANTED TO POINT OUT HERE IS THAT BY HAVING THIS MOLECULAR BLUE PRINT, WE COULD IDENTIFY COMPONENTS OF THIS MACHINE THAT WE THOUGHT MIGHT BE CRITICAL TO ITS FUNCTION. WHAT WE NOTICED IS THAT IN THIS RIGHT-HANDED MORPHOLOGY OF THIS BACK BONE OF THE VERTEBRAE THAT FORMED THE BACK BONE OF THIS COMPLEX, ON THE PINKY SIDE OF THIS RIGHT-HAND, THERE IS A CHARGED ALTHAT HELIX, LYSINE RICH. WE THOUGHT THROUGH MIGHT BE IMPORTANT. WE NOTICED THIS HELIX POINTS TOWARD THE TAIL OF THE COMPLEX AS IT LIG MERIZES FOR ALL THE SUBUNITS, ESPECIALLY THE FINAL FINGER WHICH WHAT YOU'LL SEE IS THAT THE ENTIRE FINGER DOMAIN ROTATES 180 DEGREES AT THE TAIL OF THIS COMPLEX. THAT'S IMPORTANT BECAUSE WHAT HAPPENS IS IT FORMS A LYSINE RICH VICE THATCIPED THE DOUBLING STRANDED DNA. BY HAVING THE STRUCTURE WE CAN TEST THAT IDEA THROUGH USING MOLECULAR TECHNIQUES AND SHOW THAT THAT LYSINE RICH VICE IS CRITICAL TO BINDING DNA. ALL RIGHT. SO NOW WHAT WE'RE GOING TO DO IS ZOOM IN ON THIS SEQUENCE CALLED THE PAM. THIS IS THE ANTIGENIC SIGNATURE. WHAT WE FOUND IS THAT THERE IS A TRITON MECHANISM. THERE IS 3 POINTS OF CONTACT, ALL INSERTING INTO THE MINOR GROOVE OF THE DNA MAKING BOTH SEQUENCE SPECIFIC AND SHAPE BASED SPECIFIC RECOGNITION OF THIS ANTIGENIC SEQUENCE MOTIF. PART OF WHAT HAPPENS HERE IS ALSO THAT THIS IS THE SPLIT BETWEEN DOUBLE STRANDED AND SINGLE STRANDED, AND SO YOU HAVE TO ANCHOR THE DNA IN SEVERAL LOCATIONS IN ORDER TO APPLY FORCES THAT WILL UNWIND THE DNA. AND HERE WE'RE JUST SHOWING SOME ATOMIC LEVEL RESOLUTION EXPLAN NASE FOR HOW THOSE FORCES ARE APPLIED TO THIS DNA TARGET. I JUST TO WANT FINISH BY SAYING THAT THE STRUCTURES THAT WE'VE DETERMINED SO FAR ARE JUST REALLY STATIC SNAPSHOTS THAT CAPTURE CASCADE IN DIFFERENT POSES. IT'S A MACHINE THAT DOES A JOB. WE CAPTURED IT IN ONE POSE, AND ANOTHER POSE, AND SURMISED WHAT HAPPENS IN BETWEEN. BUT NOW WHAT WE'RE DOING IN COLLABORATION WITH BRIAN'S LAB AT MONTEGGIA STATE UNIVERSITY IS USING -- MONTEGGIA STATE -- MONTANA STATE UNIVERSITY, MONITORING THE AT THIS DIS OF THIS MACHINES. ALL THE MACHINES HAVE MOTION, THIS ONE IS NO EXCEPTION. WE'RE LOOKING AT DIFFERENCES IN THE MACHINE AS IT GOES THROUGH THIS CONFIRMATIONAL CHANGE. WHAT'S SHOWN IN RED ARE POSITIONS THAT GET PROTECTED OR NO LONGER CONFIRMALLY AVAILABLE ONCE YOU BIND DNA. SO WE'RE TRYING TO UNDERSTAND WHAT THE DYNAMICS TELL US ABOUT THE FUNCTION OF THIS MACHINE. SOME OF THESE PLACES, WE HAVE NO IDEA WHAT'S HAPPENING. OTHER PLACES WE HAVE POSITIVE CONTROLS, LIKE THE PAM WE KNOW SHOULD TURN BRIGHT RED. SHOULD NO LONGER BE ACCESSIBLE TO EXCHANGE ONCE YOU BIND TO A TARGET. THAT'S WHAT WE SEE DOWN HERE. ALL RIGHT. SO SO FAR I'VE TOLD YOU THAT THERE IS ALL THESE IMMUNE SYSTEMS THAT ARE INCREDIBLY NICICATED. AND THEY'VE EVOLVED TO PROTECT BACTERIA PER PHAGE CHALLENGE. FROM PHAGE CHALLENGE. A QUESTION YOU MIGHT HAVE IS WELL, IF THEY'RE SO EFFECTIVE, THEN WHY HAVEN'T ALL THE VIRUSES GONE ESTATING? I THINK THAT THAT'S AN EXCITING QUESTION. YOU MIGHT EXPECT THAT. THIS IS A PERPETUAL MOLECULAR ARMS RACE, BACK AND FORTH BETWEEN EACH OTHER. AND ONE OF THE THINGS I THINK I'M BECOMING MOST INTERESTED IN IS TO TRY TO UNDERSTAND HOW VIRUSES SUBVERT THESE IMMUNE SYSTEMS. WHAT ARE THEY DOING TO COUNTER OR SUPPRESS THESE SYSTEMS TO CONTINUE TO REPLICATE. AND YOU MIGHT IMAGINE THAT ANYONE OF THESE STEPS IN THE IMMUNE SYSTEM, WHETHER IT'S BLOCKING THE ACQUISITION OF THE FOREIGN DNA, STOPPING THE PROCESSING OF THE CRISPR TRANSCRIPTS OR INTERCEPTING THESE SURVEILLANCE COMPLEXES, PREVENTING THEM FROM BINDING TO A DNA TARGET WOULD ALL BE POSSIBLE WAYS THAT THE VIRUS MIGHT SUBVERT THESE IMMUNE SYSTEMS. I SUSPECT THAT ALL OF THEM ARE IN PLAY. AND IN COLLABORATION WITH GABE LANDER AND ALLEN DAVISON'S LAB, WE'RE GOING AFTER STRUCTURES THAT SHOW US PRECISELY HOW THESE THINGS ARE IN CONFLICT, AN ATOMIC RESOLUTION MAY BE HOW SOME OF THE CONFLICTS ARE RESOLVED. WITH THAT I'LL FINISH UP BY THANKING SOME OF THE PEOPLE IN THE LAB WHO HAVE TON THE WORK. RYAN JACKSON IS A POST-DOC IN MY LAB, RESPONSIBLE FOR DETERMINING THE STRUCTURE OF CASCADE. HE WAS HELPED BY SARAH GOLDEN, RESEARCH TECHNICIAN AND JOSH CARTER WHO I MENTIONED MADE MANY OF THE MOVIES THAT I JUST SHOWED YOU. HE ALSO WAS INVOLVED IN COLLECTING SOME OF THE DATA. AND HIS RESEARCH EXPERIENCE IN THE LAB WAS SUPPORTED BY AN HHMI GRANT FOR UNDER-GRADUATE RESEARCH. WE'VE BEEN FORTUNATE TO HAVE SUPPORT FROM THE NATIONAL INSTITUTES OF HEALTH AND AS WAS MENTIONED I WAS FORTUNATE TO WIN SUPPORT FROM AMGENFOR JUNK INVESTIGATOR AWARD -- YOUNG INVESTIGATOR AWARD T NATIONAL SCIENCE FOUNDATION, SOME OF THE INSTRUMENTATION WE'VE PURCHASED SINCE I GOT TO MSU WAS PURCHASED USING MURDOCH -- SUPPORT FROM THE MURDOCH FOUNDATION. WE HAVE A PROJECT SUPPORTED BY BILL AND MELINDA GATES TO TRY TO DEVELOP NEW WAYS TO LOOK AT HOW THE HUMAN MICROBIOME MIGHT BE IMPACTED BY VIRAL CHALLENGE. AND OF COURSE NONE OF THIS WORK WOULD HAVE BEEN POSSIBLE WITHOUT GENEROUS SUPPORT FROM ALL THESE PEOPLE. I'D LIKE TO SAY THAT WE LIVE AND WORK IN A SMALL ALPINE VILLAGE HERE IN MONTANA THAT LOOKS PERFECT TO ME. BUT WE'RE FORTUNATE TO BE ABLE TO INTERACT WITH SCIENTISTS FROM ALL OVER THE WORLD. AND RANDY REED, AT CAMBRIDGE AND TOM AT [INDISCERNIBLE] NATIONAL LAB WERE ABSOLUTELY CRITICAL IN DETERMINING THE STRUCTURE OF CASCADE. I'VE WORKED WITH JOHN FROM THE NETHERLANDS SINCE I WAS A GRADUATE STUDENT, WE WERE WALKING AROUND YELLOW STONE NATIONAL PARK COLLECTING SAMPLES FROM HYPER THERMAL ENVIRONMENTS. [INDISCERNIBLE] A FORMER POST-DOC, WE RECENTLY COLLABORATED ON THE STRUCTURE OF CASCADE BOUND TO A DOUBLE STRANDED DEW POINT TARGET. I ALLUDED TO A NEW COLLABORATION BETWEEN MY OLD FRIEND, GABE, AND NOW AN ASSISTANT PROFESSOR AT SCRIPTS, AND ALLEN DAVIDSON, TO TRY TO UNDERSTAND THAT ATOMIC RESOLUTION, HOW THE VIRAL SUPPRESSER PROTEINS ARE INTERCEPTING THIS MACHINERY AND PREVENTING IT FROM WORKING IN TERMS OF PHAGE RESPONSE. SO WITH, THAT THAT'S ALL I HAVE. MAYBE I COULD ANSWER A FEW QUESTIONS. [APPLAUSE] >> THANK YOU SO MUCH. CAN YOU HEAR ME? SOUNDS LOOK LIKE IT'S ON, IT'S NOT VERY LOUD. >> WE COULD PASS THIS BACK AND FORTH IF IT'S EASIER. >> IT IS OWN. OKAY. CAN YOU HEAR ME NOW WITH THE CAMERA. THANK YOU VERY MUCH. SORRY FOR THAT. I'M GOING TO OPEN MY COMPUTER SO I CAN SEE IF THERE ARE TWITTER OR E-MAIL QUESTIONS. WE'LL START WITH [INDISCERNIBLE]. TELL ME ABOUT YOUR CHILDHOOD. [LAUGHTER] >> WHERE DID YOU GROW UP? >> THIS COULD BE A LONG AFTERNOON. IVES -- I WAS JOKING EARLIER, I TRUE UP IN WEST DAKOTA. WHAT I MEAN, I GREW UP IN THE MIDDLE OF NOWHERE MONTANA, LIVING 60-MILES FROM THE NEAREST PAVED ROAD. THE ROAD FROM NORTHEAST MONTANA TO THE NIH IS ONE THAT'S NOT OFTEN TAKEN, BUT IT HAS BEEN AN ADVANTAGE. >> WE HAVE QUITE A NUMBER OF QUESTIONS FROM STUDENTS. WHICH IS TERRIFIC. SO WE'LL START WITH SOME OF THOSE. THERE WERE SEVERAL OF THEM ABOUT YOUR CAREER PATH. MAYBE WE CAN BEGIN WITH THAT. HOW DID YOU FIND OUT WHAT [INDISCERNIBLE] YOU WANTED TO WORK IN AND HOW DID YOU GET EXPERIENCE IN THAT FIELD? >> THAT'S A VERY IMPORTANT PART OF MY JOB. I WOULD SAY I WAS A LATE BLOOMER BY ANYBODY'S METRICS, REALLY. MY EXPERIENCE IN THE LAB CAME THROUGH MEETING AN INSPIRATIONAL SCIENTIST. I THINK THAT PROBABLY HAPPENS TO A LOT OF PEOPLE. NOT SO UNUSUAL. I MET DR. MARK YOUNG, MY Ph.D. MENTOR, AT THE END OF MY UNDER-GRADUATE CAREER. AND HE, TOGETHER WITH TREAVOR DOUGLAS WERE DOING SOMETHING THAT WAS PRETTY INNOVATIVE. EVEN BY TODAY'S STANDARDS. THEY WERE REPURPOSING VIRAL PARTICLES FOR -- AS CONSTRAINED REACTION VESSELS FOR MATERIAL SYNTHESIS. WHAT I MEAN BY THAT IS USING A VIRUS PARTICLE, TAKING OUT THE NUCLEARIAC ACIDS, USING THEM TO MAKE NANOMAGNETS, OR FILL THEM WITH CHEMOTHERAPY DRUGS FOR TARGETED DRUG DELIVERY. ALL SORTED OF CREATIVE PIPES. THAT -- APPLICATIONS. THAT LEFT QUITE AN IMPRESSION. THE EXPERIENCE YOU OFTEN GET AS A GRADUATE STUDENT IS THE SMARTEST STUDENTS ARE THE ONES THAT ARE BEST AT MEMIZING AS MUCH MATERIAL AS FAST AS YOU CAN. I WASN'T BAD AT THAT. I WAS PRETTY -- I WAS OKAY AT DOING THAT. BUT I THINK WHAT REALLY LIT ME UP WAS THIS IDEA THAT YOU COULD COMBINE THOSE ANALYTICAL SKILLS WITH CREATIVITY, AND I THINK THAT'S REALLY WHERE THE FUN IN SCIENCE IS. >> IS THERE ANYTHING IN GRADUATE SCHOOL THAT SETS APART WHERE YOU WERE FROM SOMEPLACE ELSE YOU MIGHT HAVE BEEN, SAY IN YOUR PAST. >> SO I MEAN THAT WAS AS AN UNDER-GRADUATE. AS A GRADUATE STUDENT, I WASN'T READY FOR GRADUATE SCHOOL RIGHT AWAY. I WAS MORE INTERESTED IN EXPLORATION AND CURIOUS -- I WAS FROM NORTHEAST MONTANA. MY WORLD VIEW WAS FIRELY NARROW. BUT I RECOGNIZED THAT, AND I WANTED TO TRAVEL AND SO I SPENT A FEW YEARS DOING JUST THAT. I WORKED IN ATLANTIC AS A FISHERY -- ALASKA AS A FISHERIES BIOLOGIST. I TRAVELED TO WEST AFRICA IN THE SUMMERS, TAUGHT SCHOOLS. I THINK LIKE I SAID, I WAS NOT ON THE FAST TRACK. IT TOOK A LOT OF DIFFERENT LIFE EXPERIENCES IN ORDER FOR ME TO REALLY COME TO TERMS AND UNDERSTAND THAT MY REAL PASSION WAS IN SCIENCE. >> GRADUATE SCHOOL. >> AS A GRADUATE, STUDENT, I WAS INSPIRED BY MARK YOUNG. AT THE TIME MARK WAS JUST STARTING SOMETHING CALLED THE THERMAL BIOLOGY INSTITUTE. WHERE THE MISSION WAS TO UNDERSTAND LIFE IN HIGH TEMPERATURES. AND SO MY PROJECT AS A GRADUATE STUDENT WAS TO GO TO YELLOW STONE NATIONAL PARK. THIS SOUNDED -- STILL SOUNDS LIKE A DREAM JOB TO ME. AND FIND THE MOST INHOSPITABLE ENVIRONMENTS THAT YOU COULD. AND THOSE WERE OFTEN TIMES -- SOMETIMES MORE THAN 100 DEGREES CELSIUS. I COULD TELL YOU CRAZY STORIES. I'LL KEEP IT NARROW. GO TO YELLOW STONE NATIONAL PARK, TAKE SAMPLES, BRING THEM BACK TO THE LAB AND GROW THEM UP I THINK ARTIFICIAL HOT SPRINGS, OUR BEST ATTEMPT TO MIMMICK THE NATURAL SETTING OF THESE MICROORGANISMS THAT WERE GROWING IN THESE HIGH TEMPERATURE ACIDIC ENVIRONMENTS. I WAS REALLY INTERESTED IN THE VIRUSES THAT INFECT THOSE MICROORGANISMS. >> AT SOME LEVEL BEING IN MONTANA REGION ALLOWED YOU TO HAVE ACCESS TO PARTICULAR NATURAL PHENOMENON. >> YEAH, I THINK MARK WAS CLEVER TO HAVE REALLY APPRECIATED WHAT IS THE THING THAT WE HAVE IN MONTANA. WHAT IS THE RESOURCES THAT WE HAVE THAT SETS US APART? I THINK YELLOW STONE OF COURSE IS ONE OF THOSE NATURAL WONDERS THAT YOU DON'T FIND MANY OTHER PLACES IN THE WORLD. SO I MATURED AS A SCIENTIST AND PERSON A LOT UNDER HIS MENTORSHIP. >> AND THEN GOING FURTHER, ANOTHER ONE OF THESE QUESTIONS, WHAT ADVICE WOULD YOU TELL YOURSELF, GOING BACK TO WHERE YOU WERE, AS AN UNDER-GRADUATE, HOW TO BE SUCCESSFUL IN YOUR CAREER BASED ON WHAT YOU KNOW NOW? >> WELL, I THINK SOME OF THAT I JUST SAID. FOR ME, IT WAS -- I DIDN'T GET INVOLVED IN SCIENCE EARLY ENOUGH. AND SOMETHING I RECOGNIZED A LOT. AND PART OF MY EFFORT IS NOW TO RECRUIT STUDENTS AS EARLY AS I CAN. SO I WORK WITH HIGH SCHOOL STUDENTS, BY RUNNING A PROGRAM CALLED THE MONTANA VIRUS HUNT, A 3 DAY WORKSHOP THAT WE HOLD AT THE MSU CAMPUS. WE BRING STUDENTS IN AND TAKE THEM TO THE WASTE WATER TREATMENT PLANT. THESE ARE HIGH SCHOOL STUDENTS. AND WE TOUR THE WASTE WATER TREATMENT FACILITY. ISOLATING VIRUSES, AND -- I CHEESE THE WASTE WATER TREATMENT PLANTED AS COMPARED TO MAYBE YELLOW STONE WHERE WE COULD HAVE WENT AS WELL. I THINK -- >> [INAUDIBLE]. >> WELL, THEY BOTH STINK, ACTUALLY. BUT THE WASTE WATER TREATMENT PLANT IS LOCAL SO THERE IS NO BUS RIDE INVOLVED. IT'S A LITTLE BIT SAFER. AND IT HAS AN OO FACTOR THAT GETS KIDS EXCITED IN A WEIRD WAY THAT I CAN RELATE TO. [LAUGHTER] I WOULDN'T NECESSARILY -- NOT MORE THAN THE HOT SPRINGS. BUT -- >> RIGHT. TERRIFIC. SO A FEW SCIENTIFIC QUESTIONS THAT CAME IN. IN YOUR PREVIOUS WORK, YOU TALKED ABOUT THIS DURING YOUR BEAUTIFUL LECTURE, YOU TALKED ABOUT HOW VIRUSES ARE ABLE TO [INDISCERNIBLE] WHAT ARE SOME OF THE PARTICULAR WAYS THAT VIRUSES HAVE EVOLVED [INDISCERNIBLE] >> 24 IS REALLY AT THE CUTTING EDGE OF CRISPR BIOLOGY, I THINK. IN MY OPINION, THIS IS THE NEXT FRONT EAR OF WHERE THE FIELD WILL GO. AND MY OWN LIMITED CONTRIBUTIONS TO THIS FIELD HAVE SO FAR BEEN EXCLUSIVELY IN COLLABORATION WITH ALLEN DAVIDSON'S LAB. WE FOUND SUPPRESSERS THAT -- IN VIRUSES THAT INFECT [INDISCERNIBLE] TOO SHUT DOWN 24 IMMUNE SYSTEM. THEY'RE EXCLUSIVE TO THE IMTUNE SYSTEM IN SUED MOANIS. THEY DON'T WORK IN GENOMIC. THAT'S NOT TO SAY -- GENOMICS. WHEN I SAY THE IMMUNE SYSTEM IN SUED MOANIS, THESE THINGS ARE BEING SHUFFLED LIKE A DECK OF CARDS ALL THE TIME. BUT THE SUPPRESSERS APPEAR TO BE BEING SHUFFLED TOO. SO WE FIND A SUPPRESSER THAT WORKS ON ONE PARTICULAR IMMUNE SYSTEM. THE ONLY IMMUNE SYSTEM WE FOUND SUPERVISE PRESERS ARE ON THE TYPE ONE F SYSTEMS WHICH I DIDN'T TALK MUCH WITHOUT TODAY. THEY DON'T WORK IN THE TYPE ONE E SYSTEM, APPARENTLY THE LEAST CLOSELY RELATED. THEY DON'T WORK AT ALL. ONE OF THE SUPPRESSERS THAT WE KNOW OF -- WELL, WE KNOW OF TWO DIFFERENT SUPPRESSERS THAT BIND TO THE COMPLEX, A SURVEILLANCE COMPLEX, ANALOGOUS TO CASCADE. ONCE THEY BIND THEY PREVENT TARGET BINDING. SO WE TOTHAT THEY BIND AND NOW WE'RE GOING AFTER HIGH RESOLUTION STRUCTURES OF THOSE COMPLEXES TO UNDERSTAND EXACTLY HOW THEY BIND, HOW THEY BLOCK THE MECHANISM. WHAT WE EXPECT IS THAT THE INTERFACE BETWEEN THE VIER THE PROTEIN AND SURVEILLANCE COMPLEXES, THOSE POSITIONS WILL BE UNDER HIGH SELECTIVE PRESSURE. WE EXPECT THEY'RE EVOLVING AT ACCELERATED RATES TO KEEP PACE ON THIS EVOLUTIONARY ARMS RACE. THERE IS SIGNATURES IN THE SEQUENCE THAT YOU CAN USE TO LOOK FOR THOSE KINDS OF POSITIVE SELECTIONS. >> SO RELATED TO THAT, GIVEN THAT YOU KNOW ABOUT THESE IMMUNE SYSTEMS AND YOU'RE GOING TO BE LEARNING MORE, WHEN YOU SAY IT'S CUTTING EDGE IN YOUR PARTICULAR INTEREST, IS THERE A POSSIBILITY OF USING THAT INFORMATION TO ACTUALLY FIND BETTER WAYS OF TREATING BACTERIAL INFECTIONS? >> YEAH. THAT'S A HARD QUESTION. I THINK I WANT THAT PERSON IN MY LAB. >> OKAY! WE'LL START THAT UP. >> YEAH. I THINK THERE IS WAYS TO USE THEM. I MEAN YOU USE VIRUSES IN A WAY AS A MOLECULAR WINDOW TO LOOK AT MORE COMPLEX EVENTS THAT ARE HAPPENING IN THE CELL. THEY MIMMICK THE CELLULAR ENVIRONMENT. THE OPPOSITE IS ALSO TRUE. I DON'T KNOW IF IT'S OPPOSITE, BUT NOW THAT YOU HAVE THIS ADDITIONAL LAYER OF THESE VIERALLY ENCODED SUPPRESSERS, THEY'LL TEACH US MORE ABOUT HOW THE IMMUNE SYSTEM WORK. HOW THEY CAN BE USED USED USED FROM A BIOTECHNICAL ASPECT I'M NOT SURE. IF YOU WANT TO TURN THESE ON AND OFF, THESE MAY BE RHEOSTATSER FOR THAT KIND OF THING. THAT'S WHERE THE FUN OF SCIENCE AND CREATIVITY COMES IN. >> CRISPR IS A HOT TOPIC, OBVIOUSLY, AS YOU MENTIONED. HOW IMPORTANT, THIS IS ONE OF THE QUESTIONS. HOW IMPORTANT IS IT THAT THE GEM PUBLIC UNDERSTANDS THE SORT OF THINGS THAT YOU'RE TALKING ABOUT, AND MORE APPLICATIONS OF CRISPR AND WHAT IS THE BEST WAY TO EDUCATE THEM IS? >> WELL, ONE WAY TO EDUCATE THEM IS THINGS LIKE WHAT WE'RE DOING RIGHT NOW. OF COURSE AS I'VE EXPLAINED WE HAVE A FAIR BIT OF OUTREACH. I TRY TO INTERACT WITH STUDENTS EARLY, HIGH SCHOOL, COMMUNITY COLLEGES, SO ON. VARIOUS DIFFERENT CAPACITIES. WHAT WAS THE FIRST PART OF THE QUESTION? >> SO HOW IMPORTANT DO YOU THINK IT IS THAT THE PUBLIC KNOW ABOUT CRISPR? >> I THINK I'VE A PROFESSIONAL RESPONSIBILITY TO SHARE WHAT I'M DOING AND TRY TO EXPLAIN WHY IT'S IMPORTANT. AFTER ALL, I'M ASKING THE TAXPAYER FOR A SIGNIFICANT CONTRIBUTION TO DISTRIBUTE TO MY RESEARCH EFFORTS. I DON'T TAKE THAT LIGHTLY. SO THE RETURN ON THE INVESTMENT IS ALL OVER. >> A GREAT QUESTION. SO A LOT OF THE STUDENTS ARE VERY INTERESTED IN THE APPLICATION OF CRISPR. YOU BEAUTIFULLY DESCRIBED THE BASIC SCIENCE YOU'RE DOING AND THE IMPORTANCE OF BASIC SCIENCE MAKING THESE SORTS OF TECHNOLOGIES AND [INAUDIBLE]. WHAT KINDS OF APPLICATIONS ARE THERE FOR CRISPR RIGHT NOW? DO YOU HAVE ANY SENSE OF WHERE IT MIGHT HIT? >> THE TEAMED HAS PROGRESSED SO QUICKLY. THE APPLICATIONS NOW ARE TO KNOCK JEEPS OUT, TO -- GENES OUT, TO KNOCK IN NEW GENES, TO CORRECT GENTIC DEFECTS, TO IMAGE DNA IN THE CELL AT HIGHER RESOLUTION. TO KNOCK NOT JUST SINGLE GENES OUT BUT I THINK THAT THIS IS A PROFOUND ADVANCE, WORK BY [INDISCERNIBLE] AT M.I.T. HAS SHOWN YOU CAN NOT JUST KNOCK OUT A GENE, BUT YOU CAN -- WE DO THIS IN MY LAB, REKNOCK OUT EVERY GENE IN THE HUMANE GENOME, 6 DIFFERENT WAYS. ONE EXPERIMENT. WE DO THAT IN A WEEK. >> [INAUDIBLE] >> CULTURED CELLS. SORRY. >> BE CLEAR. [LAUGHTER] >> DIRECTED EVOLUTION. NO. YEAH, OF COURSE, IT'S IN TEST TUBES AND IN CULTURED CELLS. I SHOULD HAVE MADE THAT CLEAR. WHERE IS IT GOING? IT'S GOING INTO THE CLINIC. I THINK THAT IT'S INCREDIBLY ENCOURAGING, THE PROGRESS THAT HAS BEEN MADE. AND I THINK IT WON'T BE LONG BEFORE THERE ARE REAL THERAPEUTICS THAT ARE DERIVED FROM THESE BACTERIAL IMMUNE SYSTEMS, AND THEY WILL BE CURING SOME PRETTY DEVASTATING DISEASES. >> GOING ALONG THE SAME LINES, A LOT OF THE STUDENTS ARE INTERESTED IN THE ETHICAL IMPLIICATIONS. YOU'RE A BASIC SCIENTIST WORKING ON BASIC MECHANISMS OF CRISPR. WHAT ARE YOUR THOUGHTS AT THAT LEVEL ABOUT RISKS AND ETHICS OF CRISPR, SOMETHING VERY MUCH IN THE NEWS. >> I THINK YOUR EMPHASIS IN THE EARLY PART OF THIS QUESTION THAT I'M A BASIC RESEARCH SCIENTIST IS SOMETHING THAT'S REALLY IMPORTANT. I DON'T CLAIM TO BE A BIOETHICIST. I'M NOT TRAINED TO DO THAT KIND OF THING. I HAVE MY OWN OPINIONS, OF COURSE, AND I THINK THAT TO BE ABLE TO USE TECHNOLOGY LIKE THIS TO CURE SOME DEVASTATING GENETIC DISEASES, I THINK WE HAVE A MORAL OBLIGATION TO DO THAT, IF POSSIBLE. TO WHAT EXTENT, HOW FAR THAT SHOULD GO IN TERMS OF IN THE NEWS, THERE IS LOTS OF QUESTIONS ABOUT ENHANCEMENTS. GERM LIKE MODIFICATIONS, ALL THOSE THINGS. I THINK -- I REALLY APPLAUD THE EFFORTS OF PEOPLE LIKE MY FORMER ADVISOR, JENNIFER [INDISCERNIBLE] AND MANY OTHER LEADERS IN THE FIELD FOR THEIR RESPONSIBLE APPROACH TO THIS, TO INVOLVE THE GENERAL PUBLIC. TO ASK WHERE DO WE -- HOW DO WE FEEL ABOUT THIS? AND WHAT ARE WE GOING TO BE COMFORTABLE WITH? HOW DO WE EDUCATE THE POPULATION THAT BRINGS THE TAXPAYER, THE GENERAL PUBLIC, INTO THE DISCUSSION? AND WE FOUND A COMMON GROUND. I THINK WHAT I BELIEVE IN MIGHT NOT BE THE SAME AS WHAT PETER IS COMFORTABLE WITH. IN A DISCUSSION WE'LL FIGURE OUT WHERE WE ALL STAND AND NOT EVERYBODY IS GOING TO BE HAPPY WITH THE SAME THINGS, BUT I THINK THERE IS A COMMON GROUND TO BE FOUND THERE. >> A VERY GOOD ANSWER. ANOTHER QUESTION ALONG THE DISEASE LINES IS -- CANCER CELL IS REFERRED TO AS IMMORTALIZED. THEY CONTINUE TO GROW BASICALLY INDEFINITELY. THE QUESTION S VERY INTERESTING, IS IT POSSIBLE TO USE CRISPR TO REMOTERALIZE THE CANCER CELL LINE, MAKE IT NOT IMMORTAL ANYMORE? AND CURE A CANCER IN SOME WAY. >> THAT'S AN IDEA I HAVE NOT HEARD OF. THAT'S AN EXAMPLE OF THE CREATIVE POSSIBILITIES OF CRISPRS, I SUPPOSE. THERE ARE EXAMPLES OF USING CRISPRS TO TAKE CHROMOSOMES THAT WERE INAPPROPRIATELY CONNECTED AND SEPARATE THEM. BUT I THINK -- IN A LOT OF CANCERS -- I SHOULD -- THIS IS PROBABLY OBVIOUS, I'M NOT A CANCER BIOLOGIST, BUT DURING CANCER, THEY PROGRESS -- THEY ACCUMULATE LOTS OF DIFFERENT MUTATIONS. AND CHROMOSOMAL ABNORALITIES. SO IT'S NOT JUST THAT YOU GO INTO A CELL AND MAKE A SURGICAL ALTERATION THAT THEN FIXES IT. I GUESS IT'S CONCEIVABLY POSSIBLE. I DON'T KNOW IF IT'S PRACTICAL. IT'S A GOOD IDEA. I LIKE THAT CREATIVITY. >> ANOTHER PERSON TO JOIN YOUR LAB. >> YES, REALLY. >> VERY GOOD. SO GOING BACK TO THE IDEA OF STUDENTS FROM DIFFERENT PARTS OF THE COUNTRY, BEING INTERESTED IN SCIENCE, WHAT ADVICE DO YOU GIVE TO A STUDENT TO IS GROWING UP IN A RURAL PART OF THE COUNTRY, OR MAYBE IN THENER CITY, IN TERMS OF GETTING INVOLVED IN DOING SCIENCE? EARLY ON. HIGH SCHOOL OR IN COLLEGE? >> YEAH, I THINK I'M NOT UNUSUAL IN THAT REGARD. I THINK LOTS OF PROFESSORS ARE HAPPY TO AND EXCITED TO WORK WITH STUDENTS. OF COURSE THERE IS A LIMIT TO EVERYBODY'S ABILITY TO -- THERE IS SOME LIMIT TO YOUR BANDWIDTH. BUT I HAVE A REALLY HARD TIME SAYING NO TO STUDENTS. AND I THINK IF THERE IS A CHANCE TO PARTICIPATE, THEN I WANT TO GIVE IT A TRY. SEE IF IT GETS YOU EXCRETED. FOR ME, IT WAS -- EXCITED. FOR ME IT WAS MEETING THAT PERSON. THAT WAS MORE IMPORTANT THAN THE SCIENCE. MARK YOUNG WAS SO EXCITED ABOUT SCIENCE HE COULDN'T CONTAIN HIMSELF. THAT -- I DON'T KNOW IF IT'S LITERALLY INFECTIOUS, BUT I WAS INFECTED. [LAUGHTER] AND I GUESS I TRY TO SHARE MY PASSION SINCE HE -- WHATEVER CAREER STAGE THEY'RE IN, AND IT'S ONE OF THE MOST REWARDING ASPECTS OF MY JOB, TO SEE THOSE STUDENTS THAT HAVE MORE TALENT THAT I COULD EVER HOPE FOR, JUST GET LIT UP. >> YOU'D ENCOURAGE THEM TO REACH OUT TO FACULTY IN THEIR AREA AND MAKE CONTACT. >> YEAH. >> AS SOON AS POSSIBLE. >> MAYBE THERE ARE OTHER WAYS. I THINK YOU JUST HAVE TO SEEK OPPORTUNITIES. BUT ESSENTIAL BEING INVOLVED IN SOME SORT OF RESEARCH PROGRAM AT THE UNIVERSITY LEVEL, I THINK, IS ESSENTIAL FOR ANY SORT OF TRAINING OPPORTUNITY OR FOR TRAINING STUDENTS, RATHER. BUT EVEN AT THE HIGH SCHOOL LEVEL, I THINK THIS ARE OPPORTUNITIES AND MY LAB CERTAINLY PARTICIPATES IN SOME OF THOSE. >> GREAT. ALL RIGHT. WE'RE GETTING SHORT ON TIME SO I'M GOING TO ASK YOU A BIG QUESTION TO CLOSE THIS OUT. DO YOU THINK THAT THE STRUGGLE BETWEEN PHAGE AND BACTERIA WHICH YOU DESCRIBED DURING YOUR TALK, HAS TAUGHT US EVERYTHING THERE IS TO KNOW ABOUT THAT PARTICULAR SERIES OF -- THAT PARTICULAR ARMS RACE AS YOU SAID, OR IS THERE MORE AMAZING DISCOVERIES POSSIBLY LURKING THERE. >> I THINK THAT BY DEFINITION, THIS AVENUELUTIONRY ARMS RACE CONTINUED ADINFA NIGHTEM. THINK ABOUT THE EXAMPLE OF E. COLI. PEOPLE THOUGHT THERE WAS EVERYTHING THERE IS TO KNOW. TO DISCOVER THIS ADAPTIVE IMMUNE SYSTEM NOW SEEMS LIKE WHERE WAS I SO LONG AGO? YEAH, I THINK THERE IS PLENTY TO LEARN EVEN IN E. COLI. >> WE HAVEN'T LEARNED IT ALL. THERE IS A LOT MORE TO LEARN. THANK YOU FOR A FANTASTIC TALK. KEEP UP THE GREAT WORK. THANKS VERY MUCH. [APPLAUSE] >> GOOD AFTERNOON. WELCOME TO CLINICAL CENTER GRAND ROUNDS FOR THE GREAT TEACHER'S PRESENTATION. IT IS MY GREAT PLEASURE TO INTRODUCE DR. JIMMY >> GOOD AFTERNOON. WELCOME TO CLINICAL CENTER GRAND ROUNDS FOR THE GREAT TEACHER'S PRESENTATION. IT IS MY GREAT PLEASURE TO INTRODUCE DR. JIMMY HOLLAND, RECOGNIZED INTERNATIONALLY AS THE FOUNDER OF THE SUBSPECIALTY OF PSYCHO ONCOLOGY, A SUCSPECIALTY ON ONCOLOGY. HOLDS THE FIRST CHAIR IN PSYCHIATRIC ONCOLOGY, THE WAYNE CHAPMAN CHAIR AT MEMORIAL SLOAN-KETTERING, AND PROFESSOR OF PSYCHIATRY. DR. HOLLAND WAS BORN IN TEXAS, ATTENDED BAYLOR UNIVERSITY, ALSO OBTAINED HER MEDICAL DEGREE AT THE BAYLOR SCHOOL OF MEDICINES IN 1952. DID HER INTERNSHIP AT ST. LOUIS HOSPITAL IN WASHINGTON UNIVERSITY IN ST. LOUIS. THEN WENT TO MASSACHUSETTS GENERAL HOSPITAL IN CAMBRIDGE, SERVED AS CHIEF RESIDENT IN THE CONSULTATION LIAISON PSYCHIATRY SERVICE. THEN MOVED TO EJ MEYER MEMORIAL HOSPITAL IN BUFFALO, NEW YORK, DIRECTED THE PSYCHIATRY CONSULTATION LIAISON SERVICE AND BECAME THE CLINICAL DIRECTOR. IN 1972, DR. HOLLAND WENT ON A U.S. MEDICAL DIP PLOMCY MISSION IN MOSS COULD YOU, USSR AS IT WAS REFERRED TO THEN, SERVED AN A CONSULTANT WITH THE RUSSIANS. ON RETURN IN 1973, SHE BECAME THE DIRECTOR OF THE PSYCHIATRY DEPARTMENT AT ALBERTINETINE SCHOOL OF MEDICINE IN THE BRONX. THEN IN 197 77, SHE BEGAN THE FIRST TIME PSYCH PSYCHIATRIC SERVICE IN A CANCER HOSPITAL MEMORIAL SLOAN KETTERING CANCER CENTER. IN 1996, BECAME THE FIRST WOMAN CHAIR OF A CLINICAL DEPARTMENT AT MEMORIAL, AND SERVED UNTIL 2003. THE DEPARTMENT OF PSYCHIATRY AND BEHAVIORAL SCIENCES HAS TRAINED OVER 300 PSYCHIATRISTS, PSYCHOLOGISTS, CLINICIANS AND MANY OTHER DISCIPLINES INCLINICAL RESEARCH AREAS INCLUDING THE NCI JULYI ROADS AND LORI WEINER. DR. HOLLAND WAS PRINCIPLE INVESTIGATOR OF THE FIRST RESEARCH TRAINING GRANT IN PSYCHO ONCOLOGY, CONTINUED UNINTERPRETED FOR 34 YEARS. SHE HAS SERVED AS VICE CHAIR OF THE PSYCHIATRY DEPARTMENT AT WILD CORNELL MEDICINE FROM 94 TO 2003. DR. HOLLAND HAS WON NUMEROUS AWARDS AND VISITING FELLOWSHIPS AROUND THE WORLD, INCLUDING TO NAME A FEW, THE AMERICAN CANCER SOCIETY MEDAL OF HONOR OR CLINICAL RESEARCH IN 94, THE ACADEMY OF PSYCHO SOMATIC MEDICINE, MEMORIAL AWARD IN 94. THE AMERICAN PSYCHIATRIC ASSOCIATION PRESIDENTIAL COMMONIDATION IN 200 AND ADOLF MIRE AWARD IN 2005, THE AMERICAN ASSOCIATION FOR CANCER RESEARCH, 2005. 2006, GUILDA STAR AWARD FROM GUILDA'S CLUB WORLDWIDE. IN THE FIRST FELLOW CLASS OF THE AACR ACADEMY IN 2013. AND MOST RECENTLY, THE MARGARET AWARD FOR WOMEN AND SCIENCE FROM MD AROUND CANCER CENTER IN 2015. SHE HAS 2 AWARDS NAMED IN HER HONOR, THE HOLLAND DISTINGUISHEDSHIP AWARD FROM THE AMERICAN PSYCHO SOCIAL ONCOLOGY SOCIETY, AND JAMES AND JIMMY HOLLAND FOR RESEARCH IN AFRICA, ESTABLISHED IN 2015. SHE STUDIED THE PREVRANCE AND NATURE OF THE PSYCHOLOGICAL PROBLEMS IN PATIENTS WITH CANCER IN THE 70s, ESTABLISHED THE FIRST COMMITTEE STUDYING PSYCHOLOGICAL AND QUALITY OF LIFE ISSUES AND COOPERATIVE GROUP. THE CANS LEUKEMIA GROUP B. IN THE 80s SHE BECAME THE FOUNDING PRESIDENT OF THE INTERNATIONAL PSYCHO ONCOLOGY SOCIETY, AND AMERICAN PSYCHO SOCIAL ONCOLOGY SOCIETY. DR. HOLLAND CHAIRED THE NATIONAL COMPREHENSIVE CANCER NETWORKS PANEL ON MANAGEMENT OF DISTRESS SINCE THE BEGINNING IN 1997, PROVIDING THE FIRST CLINICAL PRACTICE GUIDELINES FOR PSYCHO SOCIAL CARE AND MANAGEMENT OF DISTRESS. ELECTED TO THE INSTITUTE OF MEDICINE IN 1995, AND SERVED ON A PANEL THAT ESTABLISHED A NEW QUALITY OF CANCER CARE WHICH DEMANDS PSYCHO SOCIAL DOMAIN BE INTEGRATED INTO ROUTINE CANCER CARE. SHE DOESN'T WANT ME TO TAKE ALL HER TIME. I'M ALMOST FINISHED. DOCUMENTED IN THE 2015PBS SERIES CANCER, THE IMMIRROR OF ALL MALADIES WHICH THEY ARE BOTH FEATURED. DR. HOLLAND PUBLISHED MORE THAN 250 PEER REVIEW PAPERS, 100 BOOK CHAPTERS, SENIOR EDITOR OF THE TEXTBOOKS IN PSYCHO ONCOLOGY, INCLUDING THE FIRSTHAND BOOK WHICH THE THIRD ADDITION CAME OUT IN 2015. SHE CONTINUES AS COEDITOR. SHE AND SHELDON LEWIS COAUTHORED A BOOK TO HELP PATIENTS AND FAMILIES COPE WITH CANCER CALLED HUMAN SIDE OF PATIENT. SHE HAS BEEN DIRECTING A RESEARCH GROUP EXPLORING PSYCHOLOGICAL ISSUES OF OLDER PEOPLE. OFF SHOOT IS THE VINTAGE READERS BOOK CLUB, STIMULATING ELDERS TO READ CLASSICAL LITERATURE. WITH MINDY GREEN TYPE, SHE BROUGHT NEW RESEARCH ON AGING TO THE PUBLIC AWARENESS TO REDUCE FEEDS AND NEGATIVE ATTITUDES ABOUT AGING AND HER BOOK, LIGHTER AS WE WORKS PUBLISHED IN 2014. BRINGS -- LIGHTER AS WE GOVERNMENT BRINGS TOGETHER CONCEPTS OF AGING IN A POSITIVE LIGHT. LASTLY, BUT NOT LEAST, DR. JIMMY HOLLAND IS THE MOTHER OF 6 CHILDREN, INCLUDING NIH'S VERY OWN STEVEN M. HOLLAND. SHE HAS TEN GRANDCHILDREN. BEEN A VERY KIND INSPIRATIONAL MOTHER-IN-LAW TO ME FOR ALMOST 30 YEARS. I PROUDLY PRESENT THE EXTRAORDINARY DR. HOLLAND. [APPLAUSE] >> MY GOODNESS. SEE HOW NICE IT IS TO BE A MOTHER-IN-LAW TO SOMEBODY LIKE THAT? ISN'T THAT LOVERY? [APPLAUSE] VERY SWEET. A LITTLE LONGER THAN I WOULD HAVE ANTICIPATED, BUT THAT WAS VERY SWEET. I THANK YOU. IN DEED, MY HUSBAND WOULD SAY IF HE WERE STANDING HERE, SOUNDED A LITTLE BIT TOO MUCH LIKE AN OBITUARY. WE DON'T LIKE THAT KIND OF THING AT OUR AIM. WE LIKE TO MAKE IT SOUND MORE CHEERFUL, RATHER THAN ALL THE LIFE ACCOMPLISHMENTS THAT ARE ROLLED OUT WITH THE CORPS. ANYWAY, I COULDN'T BE MORE DERIGHTED AND HONORED TO BE ABLE TOTATION THIS PODIUM, AND TO TALK WITH YOU ABOUT AGING BECAUSE IT'S A SUBJECT DEAR TO MY HEART. I HOPE I CAN GIVE YOU DIFFERENT ATTITUDES AS WE CHAT FOR THIS COMING HOUR. SO FIRST OF ALL, I HAVE TO TELL YOU FINANCIAL DISCLOSURES. TO TELL YOU THE TRUTH, THIS BOOK SO FAR HAS BEEN NONPROFITABLE. SO YOU DON'T HAVE TO WORRY ABOUT PROFITS. THE SECOND THING IS I CAN SEE WHISPERING, HOW OLD IS SHE INOH, MY GOD. IS THAT HER REAL HAIR, DIED HAIR. FOR FULL DISCLOSURE, I HAD MY 88th BIRTHDAY ON SATURDAY, A PARTY LAST NIGHT AND I'M STILL HERE. MY HAIR IS MU OWN! IT'S GETTING A LITTLE GRAY IF YOU LOOK. [APPLAUSE] AND THE LAST DISCLOSURE, I'M AN ADVOCATE FOR OLDER PEOPLE. I THINK THEY NEED IT. SO I HAVE TO TELL YOU WHAT WE'RE GOING TO TALK ABOUT BUT I ALREADY TOLD THAT. I WANT TO SHOW YOU THIS PICTURE OF THE GREAT WAVE WHEN THE JAPANESE FIRST ALLOWED PEOPLE COMING IN IN THE EARLY 1900S, THIS WAS A WOOD COCK APPARENTLY. AND THIS GOT TO BE THE PICTURE OF JAPAN THAT PEOPLE SAW IN OUR BEGGAR WORLD. YOU CAN SEE THE BOATS ARE BEING TOSSED AROUND THERE. INTERESTING HOWEVER, IN THE BACKGROUND, MOUNT FUGI. APPARENTLY, THE JAPANESE ARTIST THOUGHT THAT IT WAS TERRIBLE, SHOULDN'T BE OUT THERE. BUT THIS IS HOW JAPAN IS KNOWN AND THERE ARE MILLIONS OF PRINTS OF THIS AROUND. IT IS IMPRESSIVE. IT'S GOTTEN A BIT MORE INVOLVED BECAUSE PEOPLE HAVE TALKED ABOUT THE SILVER TSUNAMIS, THE GREAT OF OUR COUNTRY. IF YOU WANT TO GET THE FACTS ABOUT THAT, IN POINT OF FACT, LET ME GET MY HANDS DOWN HERE. POINT OF FACT, YOU CAN SEE THAT WE ARE ABOUT TO DOUBLE OUR POPULATION, OVER 65 MARINE AND THE GLOBAL SITUATION IS NOT PARDON BEHIND. BY 2050. YOU HAVE A CHANCE, US LOOK ON THAT -- YOU CAN LOOK ON THAT AS GOOD NEWS BACK NEWS. LINDA FREED WOULD LIKE TO SAY OLD PEOPLER ARE THE ONLY INCREASING NATURAL RESOURCE IN THE WORLD. I WOULD SAY THAT'S GOOD NEWS. SO THE WORLD ECONOMIC FORUM IS VERY -- HAS BEEN VERY INVOLVED IN THIS. THE LAST TWO YEARS THEY HAVE HAD A COALITION ON AGING, AND I'VE HAD THE PRIVILEGE TO BE INVOLVED IN THE NEW YORK GROUP WHERE NEW YORK HAS BEEN VERY ACTIVE, WITH NEW YORK AGING FRIENDLY. VERY GOOD THING. BUT THEY ARE LOOKING AT IT FROM ALL ASPECTS. AND FIRST PART IS LOOK AT THE NEW MARKET. APPARENTLY IN THE U.S., MOST MONEY LIES IN THE HANDS OF OLDER PEOPLE LIKE $25 TRILLION, IS THE ESTIMATE. THINK OF WHAT YOU COULD DO WITH CONSUMERISM HERE. IT'S AN UNTAPPED ECONOMIC DRIVER, THEY FEEL. BUT IF WE'RE GOING TO MAKE THIS THING WORK AT ALL, MAKE INDEED AGING A RESOURCE, THEN WE'RE GOING TO HAVE TO KEEP PEOPLE HEALTHY. SO THE TWO YEAR -- PROGRAM IS UP SHORTLY AND WE'RE GETTING INTERESTING REPORTS FROM ALL OVER THE WORLD. WHEN I SAY IT'S GLOBAL, YOU CAN SEE HERE, ADVOCACY, BUSINESS, ACADEMIA, GOVERNMENT, THESE ARE BIG, BIG PLAYERS. AND THEY ARE LOOKING AT IT FROM ALL ASPECTS. SO I CAN THAT WE'VE GOT REASON TO THINK THAT SOME GOOD THINGS WILL COME OUT OF THIS LOOKING AT IT. BUT WHAT'S THE BAD NEWS? THAT'S WHAT -- PART OF WHAT WE'LL BE TALKING ABOUT. 2008, THE -- DUE TO MEDICINE, DID THIS RETOOLING FOR AN AGING AMERICA. DO YOU THINK WE DID ANYTHING ABOUT IT? NO. NOT CHANGED ONE'S OATA. BUT, THEN, WELL, THEY GOT WORRIED AGAIN. THEY CAME OUT AGAIN. 2013. DELIVERING HIGH QUALITY CANCER CARE BECAUSE ONLY, AGING IS GOING TO HIT CANCER IN A BEG WAY. SO THEY HAVE -- BIG WAY. SO THEY HAVE THE SECOND WARNING. BUT THE TSUNAMI IS NOT JUST ABOUT CANCER. IF YOU THINK ABOUT IT FOR A MINUTE, HERE IS OBESITY, DIET, EXERCISE, ALL, BY THE WAY, BEHAVIORALLY CONTROLLED. WE CAN DO IT OR NOT TO IT TO GET TO THESE PROBLEMS. BUT THERE IS FACTORS FOR DIABETES, CARDIOVASCULAR, CANCER, PROBLEMS WITH FALLING IN THE OLDER COMMUNITY SO THAT THESE ARE RISKS FOR CHRONIC ILLNESS, THE TSUNAMI IS GOING TO HIT THERE. THIS IS A PRETTY AMAZING SLIDE THAT SHOWS THE U.S. LITERALLY OFF THE CHART IN TERMS OF 2010. AND OBESITY. AS COMPARED TO WEST AND EVEN TO KOREA WAY DOWN HERE. BUT THIS IS INDEED A WORRISOME SOCIETAL PROBLEM THAT WE NEED TO GET SOME HANDLE ON. AND WE'RE NOT SO FAR. BUT WHAT ABOUT HOW IT RELATES TO CANCER? IN DEED, OUR POPULATION IS AGING. WE'VE TALKED ABOUT THAT. CANCER IS INCREASING, I'LL SHOW YOU THE SURVIVOR DATA IN A MINUTE. BUT THE COST OF CANCER IS ASTRONOMICAL. PART OF -- TOO MUCH OF THE GDP AND IT'S MORE COMPLEX, AS WE GET TO SO-CALLED PRECISION MEDICINE. CHOOSING THE RIGHT CHEMICALS -- RIGHT THERAPIES. IMMUNOTHERAPIES FOR TREATING THE MUTATION ITSELF. SO THINGS HAVE CHANGED. BURDEN ON HOME CAREGIVERS. I'M ASTOUNDED AT HOW WE, TODAY, SEND PEOPLE HOME SICKER AND QUICKER AS WE SAY. WITH A FAMILY TO TAKE CARE OF THEM. WE WOULD NEVER HAVE ASKED TO ASK THE FAMILY IN THE PAST. THE BURDEN ON HOME CARE AND PEOPLE WHO MUST CONTINUE TO WORK, VERY BIG. THE WORKFORCE HASN'T CHANGED, YET IT'S INADEQUATE ALREADY. ALL THESE WARNINGS ARE YOU BETTER START PREPARING FOR THE INFLUX OF -- AND THE COST OF OLDER PEOPLE. NOTHING HAS HAPPENED. NO REAL FINANCIAL INCENTIVES. I THINK WE HAVE BEEN LAUGHING TODAY ABOUT WHO IS AT THE BOTTOM OF THE PECKING ORDER IN MEDICINE. MEDICINE, SURGERIES UP HERE. AND YOU START GOING TOWN AND THEN YOU GET TO THE BOTTOM AND WE'RE FIGHTING BETWEEN PSYCHIATRY AND PALLIATIVE CARE AND JER ATTICS, PEOPLE ARE NOT JUMPLING FOR PEOPLE TO GO INTO JER ATTICS, BUT HO WILL WE HAVE MORE EXPERTS IN THIS AREA? IT'S A BURNING QUESTION. THESE ARE CANCER SURVIVES. IN THE COUNTRY. 14 MILLION. YOU THINK OF CANCER SURVIVORS AS BEING KIND OF YOUNG, HEALTHY LOOKING KIDS, YOUNG ADULTS. NOT SO. IT'S 59% ARE OVER 65. SO THIS IS A BIG POPULATION. THEIR NEEDS WILL BE GREAT. HOW ABOUT THE TSUNAMI OF UNMET PSYCHOLOGICAL NEEDS OF OLDER PATIENTS WHO ARE ILL? IF YOU THINK FOR A MINUTE, THERE ARE A NUMBER OF PROBLEMS THAT DO BECOME APPARENT. I'M NOT A POLY ANNA. THERE ARE PLENTY OF PROBLEMS WITH GETTING OLDER. MAYBE WE LOOK AT THEM DIFFERENTLY. BUT PHYSICAL, WE CAN'T MOVE AROUND QUITE AS WELL AS WE DID. OUR BONES CREEK A LITTLE MORE. AND THEN THERE IS LOSSES. PEOPLE TELL ME I LOST MY GOOD FRIEND, IT'S SO FEIGNFUL. I SAY I KNOW. -- PAINFUL. WE'RE STIGMATIZED, WE'RE COLD, YOU DON'T BELONG HERE. WORK, I THINK WE ALL IDENTIFY OF WHO WE ARE BY THE WORK WE'VE DONE. AND LOSING THAT IS A BIG LOSS OF IDEAY, A PURPOSE AND MEANING. WHAT DO YOU FIND SOMETHING TO SUBSTITUTE. BIG ISSUES FOR MY HUSBAND, ME, AND FOR OUR THINKING ABOUT IT ALL. AND THEN YOU GET THE WHOLE ISSUE, JUST OLD AGE. DOCTORS SAY YOU'RE JUST GETTING OLD, DON'T WORRY ABOUT IT. YOU SAY, WELL, I GUESS THAT'S JUST OLD AGE THAT MY BACK HURTS, SO ON. SO WHAT TO DO ABOUT THE PSYCHOLOGICAL SIDE. YOU HEARD THAT'S MY GENERAL AREA OF DEALING WITH PSYCHOLOGICAL PIECES OF PEOPLE WHEN THEY'RE LARGELY ILL. THIS IS A STUDY WE DID BACK, REPORTED IN 2006 IN THE CLINICAL TRIALS GROUP THAT I WAS ABLE TO SERVE AS CHAIR OF OURS, QUALITY OF LIFE COMMITTEE. MY HUSBAND WAS THE CHAIR. AND I LIKE TO SAY THAT IT WAS A LITTLE BENIGN NEPOTISM, THAT I WAS ABLE TO GET THAT COMMITTEE. I'M NOT SURE IT WOULD HAVE HAPPENED IN NORMAL TIMES. BUT WE TOOK ELDERLY PEOPLE, MEN AND WOMEN, RECEIVING CHEMOTHERAPY AND WE RANDOMIZED THEM TO A BOOKLET ABOUT COPING VERSES A SIMPLE PHONE CALL TO ASK THEM QUESTIONS ABOUT THEIR MENTAL STATE. THIS IS THE QUESTIONS ON THE HOSPITAL ANXIETY DEPRESSION SCALE. VERY SIMPLE, ABOUT TEN QUESTIONS. AND WE DID THAT FOR 6 MONTHS. INTERESTING, LOOK AT THIS DATA. THE TELEPHONE MONITORING GROUP IN RED, 6 MONTHS, BOTH ANXIETY AND DEPRESSION WERE DOWN AS COMPARED TO THE TELEPHONE MONITORING. I SAID WHAT'S GOING ON? WE DIDN'T EVEN DO ANYTHING THERAPEUTIC. AND PEOPLE SAID -- WE ASKED THIS QUESTION, WHAT WAS USEFUL, AND SOMEBODY CARED WITHOUT ME. THAT'S NOT EXACTLY ROCKET SCIENCE TO FIGURE THAT OUT. BUT I THOUGHT GEE, IF JUST ASKING PEOPLE ABOUT MENTAL HEALTH CAN DO THAT WHAT WOULD HAPPEN IF WE DID AN INTERVENTION. SO WE PUT TOGETHER A TELEPHONE CARE INTERVENTION. WE HAVE TAKEN 60 PATIENTS OVER 70 WHO WERE DISTRESSED. AND RANDOMIZED THEM TO OUR INTERVENTION WHICH IS GIVEN BY THE TELEPHONE. HARD FOR OLDER PEOPLE TO GET IN, WHO ARE ON CHEMOTHERAPY. AND WE DID FIVE PHONE SESSIONS. ASKED ABOUT THEIR ILLNESS, LONELINESS, PROBLEM SOLVING. NOW ARE YOU COPES, BASICALLY. AND WE USED PEOPLE OVER 70, OUR EXPERT PANELISTS. SAID HOW DO WE DO THIS? ONE OF THE FIRST THINGS WE DID IS SET UP BIG NOTEBOOKS THAT WEIGHED A TON. WE COULDN'T CARRY THEM AROUND, SO WE PUT THIS TOGETHER AND USED WILL RUTTER WE THOUGHT WAS HELPFUL. THIS IS AN EXAMPLE ON THE LEFT THERE LOOKING AT THE HERE AND NOW. WHAT CAN YOU DO NOW, TRYING TO USE INTERVENTIONS OR GETTING THEM THINKING ABOUT THINGS THAT WOULD REMOVE SOME OF THE THOUGHTS ABOUT ILLNESS. ONE OF THE BIG THINGS WE FOUND IS HUMOR. HUMOR IS TERRIBLY IMPORTANT. WHEN YOU CAN'T CHANGE SOMETHING, YOU CAN ALWAYS LAS VEGAS ABOUT IT. WHAT DID FEE WIPED -- WE FIND? THE STRESS SHOWED GAIN. DEPRESSION DIDN'T DO TOO WELL. WE MIGHT BE A BOOSTER SHOT, THERE BUT ANXIETY CAME DOWN. THE LONELINESS REALLY CAME DOWN. AND COPING, BEING ABLE TO PLAN AHEAD, AGAIN, DID WELL. AND MEANING WENT WAY UP. THIS ISSUE OF PURPOSE AND HAVING SOME REASON FOR WE GO THE TERRIBLY IMPORTANT. MY FRIEND MINDY AND I GOT MORE INTERESTED IN AGING, AND WHAT'S BEHIND ALL. THIS I KEPT THINKING IT'S NOT PEOPLE'S PSYCHOPATHOLOGY THAT WE WORK WITH, THEN THEY'RE ILL, WE WORK WITH WHAT ARE THEIR STRENGTHS? WHAT HAVE THEY THEY GOT THAT AND WHAT IS IT THAT SUSTAINS PEOPLE TO LONG AND LENGTHY LIFE? BUT ALSO IT MUST HAVE SOMETHING TO DO WITH SURVIVAL OF SOCIETY AS WELL. SO THE [INDISCERNIBLE] WITH A GROUP, PETERSON BUT OTHERS, SPENT A COUPLE OF YEARS LOOK TRYING THE GREAT RELIGIONS, CULTURES, THE KORAN, JUDEA CHRISTIAN. WROTE DOWN ALL OF THE POSITIVE CHARACTERISTICS THAT SEEMED TO BE IMPORTANT IN -- THAT REPRESENTED STRENGTHS IN PEOPLE. WHEN YOU SORT OF SYNTHESIZED THOSE AND STEW THEM DOWN TO A FEW PIECES, IT REALLY WAS OLD GREEK VIRTUES, WHICH I FOUND VERY INTERESTING. IT SAYS SOMETHING THAT HUMAN NATURE DOESN'T CHANGE MUCH. HUMAN THINKING DOESN'T CHANGE. EMOTIONS DON'T CHANGE. THE SAME AS THEY HAVE ALWAYS BEEN. AND WHAT ARE THOSE? IT'S WISDOM. I THINK SOME WISDOM COMES FROM LIVING, FROM BEING A LITTLE BIT MORE EXPERIENCED. HUMANITY, CARE FOR YOUR FELLOW MAN. TEMPRANCE, BEING ABLE TO MODULATE YOUR APPETITES FOR FOOD, SEX, WHATEVER. TEMPRANCE, COURAGE, HAVE TO HAVE THAT. JUSTICE, FAIRNESS. [INDISCERNIBLE] -- ANYWAY, A PIECE OF THAT IS BEING ABLE TO BE SOMETHING BIGGER THAN YOURSELF. THAT I'M A PART OF A CAUSE. I'M A POLITICIAN, I'M X, WHATEVER X IS. BUT THAT WE HAVE SOMETHING THAT'S BIGGER THAN US, OURSELVES, THAT COULD BE A RELIGION, VALUES, BUT I THINK THAT'S IMPORTANT. PART OF THAT IS BEING ABLE TO TAKE ISSUES AND MAKE HUMOR OF THEM. IF THERE IS ANYTHING THAT WE'VE LEARNED IN THE COURSE OF THIS, HOW IMPORTANT THAT PIECE IS. I JUST WANTED TO SHOW, THIS IS MY 99-YEAR OLD TEACHER FROM FIFTH GRADE. SHE IS GOING STRONG. HONORARY DIRECTOR IN HER ASSISTED LIVING. IF YOU SEE HER FACE THERE, SHE'S WALKING, SHE'S HELPING WITH THE AMERICAN CANCER SOCIETY MOVE AND SHE IS QUITE SOMETHING. MY ROLE MODEL. THAT'S THE KIND OF THING THAT SAYS SOMETHING ABOUT WHO DOES WELL WITH AGING. SO WHAT OPERATIONALLY, HOW DO THESE CHARACTER STRENGTHS WORK. I THINK BEING ACTIVELY ENGAGED IN SOMETHING. DOESN'T MATTER WHAT IT IS, SO MUCH, AS IT'S MENTALLY STIMULATING. INTEREST IN OTHER PEOPLE. FINDING A PURPOSE. I OFTEN SAY WHAT MAKES YOU GET UP IN THE MORNING? WHY DO YOU GET UP? THESE PEOPLE SAY WELL, I HAVE TO GET TO X. I CAN'T LET THAT WORK GO AREA SIDE. THAT'S GOOD TO KNOW. USE HUMOR TO KEEP PERSPECTIVE. INTERESTING DATA, THESE ARE FROM BIOLOGICAL AND HER COLLEAGUES WHO HAVE LOOKED AT PEOPLE WHO HAVE A SENSE OF PURPOSE IN THEIR LIFE AND PEOPLE WHO DON'T. AND IF YOU LOOK ON THE LEFT THERE, YOU SEE THAT PEOPLE WITH A HIGHER PURPOSE HAVE A SLOWER DECLINE THAN DO OTHER PEOPLE WHO HAVE LOW PURPOSE. AND HERE ON THE RIGHT, LOWER PURPOSES, ALSO, MORE DISABILITY. SO THIS IS -- THESE ARE GOOD DATA THAT SUGGEST -- AND THIS IS VERY HELPFUL TO BE ACTIVE IN THE OLDER YEARS. NOW I'M GOING TO TELL YOU ABOUT MY GRAND DARE, MADELEINE, WHO IS THE MIDDLE CHILD OF STEVEN -- THIS IS HER ON MY -- MY GRANDMOTHER NECKLACE. SO SHE -- I LEARNED FROM HER, BY THE WAY, ALWAYS LEARN FROM YOUR GRANDCHILDREN. SHE TOOK A GAP YEAR AFTER HIGH SCHOOL AND SHE SAID I DON'T WANT ANYBODY TO TELL ME WHAT TO READ. I'M GOING TO READ THE HARVARD FIVE FOOT CLASSICS. SHE STARTED IN THE SUMMER. BY ADD I CAME TO VISIT AND SHE SAID -- BY DECEMBER, SHE SAID I DON'T THINK I CAN DO IT, IT'S TOO MUCH. SO I SAID WHY DON'T WOE START AN E-MAIL BOOK CLUB? WE DID, TO READ THE HARVARD CLASSICS. WE STARTED WITH SOME GREAT THINGS LIKE, YOU KNOW, CONFUSIONISM, THE BIBLE, BUT WHEN SHE WENT BACK TO SCHOOL SHE DIDN'T WHY DON'T YOU GET YOUR GROUP TO READ THE CRASS? I WAS -- CLASSICS? I DON'T KNOW IT WILL WORK, I SAID, BUT I'LL TRY IT. I BEGAN SENDING OUT EVERY MONTH IN BIG FONT, THE READING FOR THE MONTH. AND THEY LOVED IT. SO WE MEET MONTHLY, WE EAT LUNCH. VERY IMPORTANT TO SERVE FOOD FOR THESE THINGS. THEY CAN COME IN OR CALL, EITHER WAY. AS A MATTER OF FACT, I SEND NOW STILL, 3 YEARS, READINGS EVERY MONTH AND MY MENTOR FROM MASS GENERAL IS 102. HE SAID PLEASE DON'T STOP SENDING THEM, THEY'RE WONDERFUL. SO IT'S BEEN G THESE ARE JUST SOME OF THE BOOKS WE HAVE READ. BEN FRANKLIN AUTO BOEING IS A HOOT. IF YOU HAVEN'T HEAD THAT IT'S A MUST. AND THESE FABLES ARE PRETTY INTERESTING TOO. PEOPLE WERE ENGAGED. ATTENDANCE DOUBLED. THERE WAS ANIMATED DISCUSSION ABOUT THE HUMAN CONDITION. WHAT WAS IT BEFORE, WHAT IT'S LIKE NOW. I THINK THEY SAW THEMSELVES NOT AS A A BUNDLE OF SYMPTOMS AND SELF-INVOLVED, BUT THAT THEY LOOKED AT THEMSELVES IN A BROADER SENSE, WITH A LOT OF HUMOR. ONE OF THE QUOTES WAS WE DON'T WANT ANY ORGAN RECITALS. DON'T TELL US ABOUT YOUR BOWELS OR BREATHING OR ANYTHING ELSE. NO ORGAN RECITALS HERE. SO WE TALK ABOUT OTHER THINGS.