WELCOME. TO THE 26th ANNUAL NIH RESEARCH FESTIVAL. THOSE OF YOU WHO ARE COUNTING, I THINK THIS SHOULD BE THE 27th BUT WE SKIPPED 1987 BECAUSE NIH WAS CELEBRATING ITS CENTENNIAL THAT YEAR. THAT MEAN THIS MUST BE THE 125 ANNIVERSARY OF NIH AND THAT IS SECRET OTHERWISE KNOWN AS THE QUASQUICENTENNIAL. NIH HAD ITS ORIGINS IN 1887 IN THE LABORATORY OF HYGIENE ON STAT TON ISLAND WITH A SINGLE EMPLOYEE, DR. JOSEPH KINYOUN WITHIN THE MARINE HOSPITAL SERVICE. REMARKABLY, DR. KINYOUN HAS AGREED TO APPEAR AT THIS, THIS MORNING WHICH IS QUITE A FEAT SINCE HE DIED 93 YEARS AGO. NIBIB, TEN YEARS. NICHD AND NIGMA BOTH HITTING 50 YEAR MARK AND NCI CELEBRATING 75th. [LOW AUDIO]. WHAT'S OUR THEME? THEME HERE IS THE NIH AT 125: TODAY'S DISCOVERIES AND'S CURES. I HOPE YOU'VE NOTICED THE FESTIVAL ARTWORK WHICH ADORN THE POSTERS. [LOW AUDIO]. WHAT IS THIS, YOU MIGHT ASK? THIS IS A [LOW AUDIO] -- BURSTING OUT OF A N NUETRAPHIL. THIS WAS CHOSEN BECAUSE OF OUR 125th ANNIVERSARY BECAUSE OF THE CONNECTION TO JOSEPH KINYOUN AND THE HIGH GENERALIC LABORATORY TO REMIND US OF PAST BATTLES THAT HAVE LARGELY BEEN WON FOR DISEASES LIKE CHOLERA, YELLOW FEVER, SMALLPOX AND PLAGUE, [LOW AUDIO]. SO THIS PARTICULAR YEAR WE'RE TRYING SOMETHING LITTLE DIFFERENT AND IN TERMS OF THE WAY IN WHICH THE FESTIVAL HAS BEEN ARRANGED. THIS MORNING HERE IN MA SUR WE'RE GOING TO HAVE THREE DYNAMIC BIG-PICK TALKS FROM GARY GIBBONS, JENNIFER LIPPINCOTT-SCHWARTZ, AND RON GERMAIN. WE'LL ALSO HAVE A PANEL TALKING ABOUT THE CURRENT STATE OF THE INTRAMURAL PROGRAM AND ALL OF THE PROMISE WE SEE IN FRONT OF US. THEN I WOULD LIKE TO ENCOURAGE ALL OF YOU WHEN THAT COMES TO A CLOSE THIS MORNING AT ABOUT 12:10 TO MAKE SURE WAY QUICKLY ACROSS CAMPUS TO THE NATCHER BUILDING BECAUSE THAT'S WHERE THE REST OF THIS RESEARCH FESTIVAL WILL BE GOING ON AND IT WILL BE GETTING UNDERWAY QUITE QUICKLY AT 12:30 WITH A CONVERSATION WITH REPRESENTATIVE ANDY HARRIS OF THE FIRST DISTRICT OF MARYLAND WHO IS BOTH A REPRESENTATIVE [LOW AUDIO] TO THE U.S. CONGRESS, HE IS ALSO AN M.D. AND PRIOR NIH GRANTEE AND ON THE FACULTY OF JOHNS HOP KINS IN THE FIELD OF ANESTHESIOLOGIST. HE IS THE ONLY MEMBER OF THE U.S. CONGRESS WHO'S BEEN A PREVIOUS NIH GRANTEE SO HE WILL NO DOUBT HAVE SOME WORDS FOR US ABOUT WHAT THIS LOOKS LIKE FROM HIS PERSPECTIVE. [LOW AUDIO]. I ENCOURAGE TO YOU MAKE YOUR WAY OVER THERE. THIS WILL BE IN THE E 1 AND E 2 CONFERENCE ROOM ON THE BOTTOM FLOOR OF NATCHER AND THERE WILL BE REFRESHMENTS -- WHICH RARELY HAPPENS AROUND HERE ANYMORE BUT SOMEHOW WE HAVE COME UP WITH A WAY TO SUPPORT REFRESHMENTS AT THAT MOMENT. SO IN TERMS OF NIH RESEARCH FESTIVAL, THIS IS CERTAINLY BEEN A REMARKABLE EXPERIENCE IN TERMS OF THE WAY IN WHICH THIS HAS BROUGHT US ALL TOGETHER YEAR AFTER YEAR. I DON'T KNOW IF [LOW AUDIO] HOPKINS HAPPENS TO BE HERE -- [LOW AUDIO] -- DESERVES A LOT OF CREDIT TO BE THE PERSON WHO INITIALLY ENCOURAGED THIS IDEA [LOW AUDIO] AND HAS GOTTEN BIGGER AND BETTER EVERY YEAR. THIS YEAR, THE BIGGEST EVER. THERE WILL BE POSTERS, THERE WILL BE PRESENTATIONS. AGAIN, I WANT TO ENCOURAGE ALL OF YOU, USE THIS AS AN OPPORTUNITY TO FIND OUT WHAT'S GOING ON IN THIS REMARKABLE COMMUNITY CALLED NIH. OBVIOUSLY FOR GRADUATE STUDENTS, POST DOCS, FACULTY OR WO HEESHG, WE ALL HAVE OUR OWN CIRCUMSTANCE THAT WILL WE MIX AND MINGLE WITH IN TERMS OF OUR RESEARCH, BUT HERE'S A CHANCE TO ENLARGE YOUR CIRCUMSTANCE UNTIL A BROADER WAY TO RUB SHOULDERS WITH PEOPLE WHO ARE DOING RESEARCH YOU MAY NOT HAVE BEEN AWARE OF. I CAN TELL YOU MANY STORIES OF HOW THIS RESEARCH FESTIVAL HAS TRIGGERED COLLABORATION BECAUSE OF THAT KIND OF INTERACTION. I SUSPECT THIS YEAR WILL HAVE THAT SAME OPPORTUNITY FOR SOME OF YOU SITTING HERE THIS MORNING. THIS IS A CHANCE TO EXPAND YOUR HORIZONS. PARTICULARLY WANTED TO RECOGNIZE SPECIAL GROUP OF PARTICIPANTS IN THE CONFERENCE. THESE ARE FOLKS WHO ARE PART OF THE NATIONAL GRADUATE STUDENT RESEARCH CONFERENCE WHO ARE HERE AT NIH, MOST OF THEM NEARING THE END OF THEIR OWN GRADUATE PROGRAM AND LOOKING FOR POST DOCTORAL IDEAS AND OPPORTUNITIES AND SO MAYBE I COULD ASK THOSE INDIVIDUALS WHO ARE PART OF THAT PROGRAM TO STAND UP SO WE COULD ALL SEE WHO YOU ARE. ALL RIGHT. [APPLAUSE] THANK YOU. SO ALL OF US WHO ARE LOOKING FOR NEW POST DOCS SHOULD HAVE NOW IDENTIFIED YOU AND WILL HAVE A CHANCE TO LOOK AT YOUR POSTERS THIS AFTERNOON AND MIX AND MINGLE. THIS IS A GREAT PLACE TO DO DOCTORAL TRAINING. AT LEAST ONE OF YOU IS INTERVIEWING WITH ME THIS AFTERNOON AND I'M LOOKING FORWARD TO THAT. BEFORE I SIT DOWN, I PARTICULARLY WANT TO THANK THOSE WHO HAVE WORKED SO HARD TO MAKE THIS HAPPEN. THIS IS A ENORMOUS UNDERTAKING TO PUT TOGETHER A CONFERENCE OF THIS SORT AND I WANT TO THANK ANTONELLO BONCI AND CONSTANTINE STRATAKIS, THE SCIENTIFIC DIRECTORS FOR NIDA AND NICHD WHO YOU WILL BE HEARING FROM THROUGHOUT THE COURSE OF THE EVENT BECAUSE THEY'VE DONE A GREAT DEAL OF WORK TO MAKE IT HAPPEN. I WANT TO THANK THE FAIR COMMITTEE AND THE MEMBERS OF THE NIH RESEARCH FESTIVAL COORDINATING COMMITTEE FOR THE WORK THEY'VE DONE. WITHOUT FURTHER ADO IT'S TIME FOR ME TO GET OUT OF THE WAY AND ENCOURAGE YOU TO ENJOY WHAT'S GOING TO BE A REMARKABLE SEVERAL DAYS, EXCELLENCE SCIENCE STARTING RIGHT OFF WITH THESE PRESENTATIONS. HAVE A GREAT TIME, EVERYBODY. IT'S GREAT TO BE HERE WITH YOU. IT'S AN HONOR FOR ME TO BE SERVING AS YOUR NIH DIRECTOR AT MOMENTS LIKE THIS WHERE WE GET TOGETHER TO CELEBRATE REMARKABLE SCIENCE GOING ON HERE AT [LOW AUDIO]. THANK YOU VERY MUCH. [APPLAUSE] >> GOOD MORNING I'M ALLEN [INDISCERNIBLE] THE DIRECTOR OF THE [LOW AUDIO] HERE AT NIH. [LOW AUDIO]. CONSTANTTINE APPROACHED ME -- [LOW AUDIO]. IT'S A REAL PERSONAL PLEASURE TO INTRODUCE DR. GIBBONS WHO CAME THIS SUMMER. SHE WAS FAMILIAR WITH NHLBI BECAUSE HE ALREADY SERVED ON ADVISORY COUNSEL AS WELL AS EXTRAMURAL BOARD AND BEEN A SUPPORTED RESEARCHER FOR A NUMBER OF YEARS. HE GOT HIS UNDERGRADUATE DEGREE FROM PRINCETON, WENT TO HARVARD GRADUATE SCHOOL WHERE HE GRADUATED MAGNUM QUME LOU DI. GARY HELPED PROVE US DIRECTLY GOING ON TO DO A MEDICINE RESIDENCY CARDIOLOGY FELLOWSHIP IN BOSTON THEN WENT TO JOIN THE FACULTY FIRST AT STANFORD AND THEN HARVARD BEFORE MOVING TO MOOREHOUSE COLLEGE OF MEDICINE WHERE HE WAS PROFESSOR OF MEDICINE AND PHYSIOLOGY AND HEAD OF THE GARMENT OF PHYSIOLOGY AND THE FOUNDING DIRECTOR OF THE CARDIOVASCULAR HEALTH RESEARCH INSTITUTE. -- DEPARTMENT. H HE HAS LED NIH-FUNDED RESEARCH IN A NUMBER OF AREAAREAS.H HE'S SOMEONE WHO IS ADMIRED FOR THE BREADTH OF HIS INTEREST AND RESEARCH AND ALSO FOR THE QUALITY OF HIS TEACHING AND HIS QUALITY AS A CLINICIAN, DIRECT DELIVERER OF CARE AND IS SOMEONE WHO LEADING THE NHLBI, I THINK IS A WONDERFUL LEADER FOR IT BECAUSE OF HIS INTEREST IN THIS BROAD RANGE OF RESEARCH BOTH FROM FUNDAMENTAL DISCOVERY TO APPLICATION IN WAYS THAT IMPROVES PEOPLE'S HEALTH AND LIVES. BASED ON THAT INTEREST, HE EASE CHOSEN TO SPEAK TODAY ABOUT THE SOCIAL SIGNIFICANCE OF SCIENCE. IT'S WITH GREAT PLEASURE I INTRODUCE TO YOU DR. GARY GIBBONS. [APPLAUSE] >> GOOD MORNING. THANK YOU FOR THAT KIND INTRODUCTION. FORTUNATELY, ALLEN DIDN'T DISCLOSE ALL THE THINGS WE DID IN MEDICAL SCHOOL TOOL, JUST THE SCHOLARLY PARTS. IN THE SPIRIT OF THIS BEING A HISTORICAL SORT OF DAY AND IN HONOR OF THE SPIRIT OF JOSEPH KINYOUN WHO'S SOMEWHERE IN THE BUILDING, I THOUGHT I'D START OFF THE TALK [LOW AUDIO] CASE STUDY. ONE THAT NOTES A PARTICULAR TIME HISTORY. MANY OF YOU WILL NOTICE THAT THIS IS FRANKLIN ROOSEVELT AND IT'S A PICTURE SHOWING HIM WHEN HE DEDICATED ACTUALLY THIS CAMPUS -- IT'S BUILDING 1 THAT HE'S IN FRONT OF AS HE ENVISIONED THIS CAMPUS. THOUGHT IT WAS NOTE WORTHY THAT WE START WITH FDR. ONE OF THE THINGS THAT CHARACTERIZED FDR IS THAT HE HAD HIGH BLOOD PRESSURE OR HYPER TENSION. NOW, BACK IN THOSE DAYS IN THE 40s, IT WAS THOUGHT THAT THAT WAS SORT OF A BENIGN CONDITION OF AGING THAT AS YOU GOT OLDER YOUR BLOOD PRESSURE WOULD GO UP, BUT ACTUALLY FDR'S PAINFULLY RECOGNIZED AS SOMEONE WHO SUFFERED FROM THE MALIGNANT NATURE OFHYPER TENSION. THIS IS FDR WITH STALIN AND CHURCHHILL DECIDING WHAT THE FACE OF THE WORLD WOULD LOOK LIKE AFTER WORLD WAR II. AT THIS POINT HE WAS GRAVELY ILL AS A RESULT OF HYPER TENSION. IT WAS AFFECTING HIS COGNITION AND PROMOTING STROKES AND HE DIED A COUPLE MONTHS LATER. THIS CONTINUES TO BE ONE OF THE MOST COMMON CAUSES OF MORBIDITY AND MORTALITY TODAY. INDEED, HE HAD BLOOD PRESSURES THAT WERE EXTRAORDINARY THAT WOULD HAVE BEEN CALLED FOR MEDIATE HOSPITALIZATION TODAY. AND SO IT'S WITH THAT FACTOR OUT OF HISTORY THAT WE LOOK AT WHERE WE'VE COME FROM IT. I SUMMARIZE DATA HERE ABOUT STROKE MORTALITY SINCE THE TIME OF ROOSEVELT. WITH THE ADVANCES OF RESEARCH AND CLINICAL INVESTIGATION AND CLIN CALINICAL MEDICINE -- WHAT'S NOTE WORTHY HERE ARE THE BLUE AND RED BARS THAT DO NOTE AFRICAN AMERICAN MEN AND WOMEN AND THE GAP IN HEALTH INEQUITIES THAT PERSIST IN STROKE MORTALITY [LOW AUDIO] COMPARED TO THEIR CAUCASIAN U.S. COUNTER PARTS. ALTHOUGH WE'VE MADE TREMENDOUS PROGRESS, THAT GAP PERSISTS TODAY. ANOTHER EFFECT OF HYPER TENSION IS THAT IT INCREASES KIDNEY FAILURE. THERE'S BEEN A TREND SO THAT IT'S BEEN INCREASED PARTICULARLY IN AFRICAN AMERICANS AS COMPARED TO CAUCASIANS IN THIS COUNTRY. IT'S REALLY IN THIS CONTEXT THAT I HAVE A PARTICULAR INTEREST IN UNDERSTANDING THESE HEALTH INEQUITIES. FOR ME THIS IS SOMETHING PERSONAL P THAT FOR SO MANY PEOPLE WHO ARE IN MY FAMILY WHO HAVE HYPER TENSION. INDEED, MY MOTHER DIED AWAY IN THE SAME WAY THAT FDR DID, HYPER TENSION. I HAVE HYPER TENSION, MY SISTER AND MY BROTHER HAS HYPER TENSION AND WE KNOW COUNTLESS FAMILIES ATTENDED BY THIS DISORDER. MY FAVORITE R AND B SINGER, LUTHER VANDROSS HAS PASSED AWAY BECAUSE OF THIS DISORDER. ALONZO MORNING DEVELOPED DID KIDNEY FAILER EVEN WHILE HE WAS PLAYING BASKETBALL. THIS IS WHAT HAS DRIVEN BEME TO PURSUE THIS AS A SCIENTIFIC QUESTION AND PROBLEM THAT I WANT TO ADDRESS. REFLECTED ON THIS, MARTIN LUTHER KING SUMMARIZED THIS VERY WELL BACK IN THE 50s AND 60s. WE RECOGNIZED THIS INTERRELATIONSHIP BETWEEN SOCIAL INEQUALITY AND HEALTH EQUITY. CAN READ HIS QUOTE HERE BUT HE WAS SAYING THAT AFRICAN AMERICANS HAVE HALF OF THE GOOD THINGS IN LIFE AND DOUBLE THE BAD THINGS IN LIFE, AND OF ALL THE FORMS OF INEQUITY, INJUSTICE IN HEALTH CARE IS THE MOST SHOCKING AND INHUMANE. THERE'S THIS INTERRELATIONSHIP BETWEEN BEING A CITIZEN ADDRESSING SOCIAL PROBLEMS BUT ALSO APPRECIATING THEIR HEALTH IMPLICATIONS AND THAT'S ACTUALLY GUIDED ME THROUGHOUT MY CAREER. NOW, TO ADDRESS SOMETHING AS COMPLEX AS THESE INEQUITIES IN HEALTH THAT ARE INFLUENCED BY RACE AND CLASS, YOU HAVE TO APPRECIATE THAT THIS IS A COMPLEX MULTILEVEL SYSTEMS PROBLEM, AT LEAST THAT'S HOW I FOCUS IN ON IT. INDEED, YOU CAN UNDERSTAND IT AT VARIOUS LEVELS OF SCALE AND COMPLEXITY. INDEED, IT CAN BE ADDRESSED AT THE FINEST MOLECULAR LEVEL OF THE GENOME AND THE E P EPI GENOME. [LOW AUDIO] IT'S INFLUENCE ON DISEASE PHENOTYPES AND EVEN UNDERSTAND IT AT THE LEVEL OF COMMUNITIES AND SOCIAL SYSTEMS AND HEALTH SYSTEMS. INDEED, WE RECOGNIZE THAT THESE RACIAL DISPARITIES OFTEN REFLECT THAT THE INDIVIDUAL IN A BROADER EC ECHO ECOSYSTEM IF YOU WILL -- ONLY IN UNDERSTANDING THESE DYNAMIC I BELIEVE WE'RE GOING TO MAKE OUR GREATEST PROGRESS IN ADDRESSING THE MULTIPLE LAYERS AND MULTIPLE LEVELS OF THIS PROCESS. INDEED, NEW SYSTEMS APPROACHES ARE BEING APPLIED AND WE THINK THAT THOSE ARE OPPORTUNITIES FOR ADVANCEMENT. THIS IS WORK [INDISCERNIBLE] DONE BY WILL RECOLLECT AZO [INDISCERNIBLE] IN WHICH HE TOOK MEDICARE CLAIMS DATA OF ELDERLY AND LOOKED FOR THE INTERRELATIONSHIP OF DIAGNOSIS IN HIS DAYTABASES. ONE OF THE THINGS HE DID WAS COMPARED BLACK MALES IN BLUE, WITH WHITE MALES SHADED IN PINK AND LOOKED AT THE DISEASE PHENOTYPES AND THE INTERRELATIONSHIPS THAT CAME OUT IN UNBIAS WAY IN THIS COMPUTATIONAL EXERCISE. WHAT HE NOTED IS THAT HE COULD SEE HERE THE SEN NODE FOR THE AFRICAN AMERICAN MALE RELATED TO THE DIAGNOSIS OF HYPER TENSION AND CLEARLY RELATED TO IT FOR SEVERAL OTHER DIAGNOSIS THAT RELATED TO BRAIN, THROAT, HEMORRHAGE AND KIDNEY DISEASE. IN THE WHITE MALE OF THE CENTRAL NODE WAS RELATED TO A [INDISCERNIBLE] DISEASE AND THEIR INFLUENCES. THAT REAL [LOW AUDIO] -- THAT THERE IS THIS DIFFERENTIAL CLUSTERING OF DISORDERS AND TRYING TO UNDERSTAND WHY THAT IS. IN THAT REGARD, WE'VE HAD THIS WORKING MODEL OF THE IDEOLOGIES THAT TRY TO LOOK AT THE VAIFRT LEVELS OF THIS PHENOMENON -- VARIOUS LEVELS. AS WE TRY TO ON THIS PROBLEM OF RACIAL DISPARITIES OF STROKE AND KIDNEY FAILURE, THAT ANALYSIS [INDISCERNIBLE] RECOGNIZED THE DRIVING FORCES OF HIGHLY PREVALENT CONDITIONS LIKE OBESITY, DIABETES, AND HYPER TENSION. YOU CAN ALSO APPRECIATE FROM MARTIN LUTHER KING'S ANALYSIS THAT MANY OF THESE [INDISCERNIBLE] ARE RELATED TO THE SOCIAL CONTEXT IN WHICH AFRICAN AMERICANS FIND THEMSELVES. PART OF OUR SCIENTIFIC CHALLENGE IS THAT INTERFACE AND PATHWAYS THAT GO AND MEDIATE IN-BETWEEN THOSE TWO PHENOMENONS. THE HOPE IS THAT F WE CAN E LOUIS DAD THOSE MECHANISMS -- ELUCIDATE -- ONE OF THE THINGS I'LL EMPHASIZE TODAY IS THE NOTION OF A BIOSOCIAL INTERFACE. AGAIN THE NOTION THAT THIS INDIVIDUAL [LOW AUDIO] SYSTEMS OF BIOLOGICAL MECHANISMS INSIDE IS INTERACTIONS TO SOCIAL ENVIRONMENTAL MILIEU AND THERE ARE SERIES OF INTERFACES THAT OCCUR, THAT STRADDLE THIS BIOLOGICAL AND SOCIAL DOMAIN WHETHER IT'S THE MICROBIOME [LOW AUDIO] OR THE EPI GENOME. I'LL WALK YOU THROUGH A COUPLE OF EXAMPLE WHERE IS THAT MIGHT PLAY A ROLE IN HEALTH INE QUESTION ETIES -- INEQUITIES. FIRST WE DID A TELEPHONE SURVEY OF BIRACIAL SAMPLE IN AT LAN THAT TA IN WHICH WE COMPARED AFRICAN AMERICANS AND WHITES. -- ATLANTA. WE SAW CLUSTERING OF CERTAIN DRIVERS. AFRICAN AMERICAN HAD A LARGER BODY MAZ INDEX CONSIST WITH GREATER OBESITY -- MASS -- HIGHER PREVALENCE OF DIABETES. THIS CLUSTERING CORRESPONDS TO ANOTHER NETWORK ANALYSIS BY DAN LEVY HEART STUDY INTERNAL INVESTIGATOR WHO'S NOTED THE SAME PATTERN IN WHICH OBESITY APPEARS TO BE A KEY DRIVER OF THE INTERCONNECTION OF PROMOTING RISK FACTOR FOR CARDIOVASCULAR DISEASE. IN TRYING TO UNDERSTAND WHAT ARE THE DRIVERS OF OBESITY, CLEARLY IN OUR SURVEY WE GOT A SENSE THAT AFRICAN AMERICANS HAD LOWER PHYSICAL ACTIVITY AND LOWER FRUIT AND VEGETABLE INTAKE AN THAT THAT MAY INDEED BE CONTRIBUTING TO THAT HIGHER PREVALENCE. WERE THE DETERMINANTS OF THOSE LIFESTYLES? WELL, AGAIN, WE WERE TESTING HIGH POST'S THE THAT IT COULD EITHER BE -- HYPOTHESIS THAT IT COULD EITHER THE B THE PEOPLE OR THE PLACE. WHERE YOU LIVE, WORK, AND PLAY HAS AN IMPACT ON YOUR HEALTH AND SO WE ASKED THE QUESTION: BY NEIGHBORHOOD OFFERS MANY OPPORTUNITIES TO BE PHYSICALLY ACTIVE AND WE ASKED WHETHER THEY AGREE OR DISAGREED. OF NOTE THE AFRICAN AMERICANS SIGNIFICANTLY WERE PONDERING THOSE WHO DISAGREED WITH THE STATEMENT. IRREGARDLESS OF THEIR INCOME LEVEL COMPARED TO THE WHITES IN OUR CAMPSAMPLE. SUGGESTING THAT THE NEIGHBORHOODS WERE IN FOOD DESERTS WHERE THEY HAD EXPOSURE JUST TO FAST FOOD RESTAURANTS, VERY FEW SUPERMARKETS AND ISSUES WITH CRIME AND THAT THAT WAS SHAPING THEIR WHOLE MENU OF LIFESTYLE CHOICES AND RESTRICTING IT. SO THE PLACE WHERE PEOPLE PLAY, WORK, AND LIVE MATTERS. NOW, ONE OF THE OTHER ELEMENTS OF THIS SOCIAL CONTEXT WAS SUGGESTED BY THIS VERY PROVOCATIVE HYPOTHESIS THAT INVOLVED THE NOTION OF NETWORKS AND SOCIAL [INDISCERNIBLE] AND THAT IS WELL ILLUSTRATE BID THE WORK OF NICHOLAS [INDISCERNIBLE] IN LOOKING AT THE FRAMING HAM DATA SET. HE APPLIED A NETWORK ANALYSIS LOOKING AT OBESITY IN THE FRAMING HAM STUDY. HAD 3 # YEARS OF LONGITUDINAL DATA. YOU'RE ALL -- 32 YEARS -- YOU'RE ALL FAMILIAR WITH THE CONCEPT OF [INDISCERNIBLE] IN WHICH WE ALL SORT OF CONJUGAGRES CONGREGATE TOGETHER, BIRDS OF A FEATHER, FLOCK TOGETHER. IF ROBERT DEVELOPS OBESITY AS MY CLOSE FRIEND, THIS ANALYSIS SUGGESTED THAT I'M ALSO LIKELY TO BECOME OBESE. INDEED, THAT RELATIONSHIP HAD A DECAY IN WHICH THE FURTHER AWAY THE FRIEND WAS IN TERMS OF OUR RELATIONSHIP, THE LESS EFFECT THAT FRIEND HAD ON MY PHENOTYPE MY PROPENSITY TO DEVELOP OBESITY. INDICATIVE OF THE NOTION THAT THERE MIGHT BE A BEHAVIOR MIGHTUATE THROUGH A SOCIAL NETWORK OR A PHENOMENON MIGHT PERMEATE THROUGH A SOCIALPUATE THROUGH A S OCIAL NETWORK OR A PHENOMENON MIGHT PERMEATE THROUGH A SOCIEUATE THROUGH A SOCIAL NETWO RK OR A PHENOMENON MIGHT PERMEATE THROUGA CATTHUGA CI NWO OR PNONOMIT RMTE HRGH STEHRGH SIA NEOROR PNONMIT TWK AHEMEN GHTOU AOCL PEEA OU AOCAUTEHRGH SIA EOROR PNONOMIT WO OA ENEN MHTHUGA CI ERATTHUGA CIATTHUGA CI WO OA ENEN MHT ERATTHUA CITEHRGH SIA NEOROR PNONOMIT RMTEHRGH SIA TOU AOCL TWK AHEMENGH PEEA TOU AOCL ROH SOAL ETRKR PHOMONI MEE ROH SOAL ETRK NEANMANEH ICAI ACETICROS ATHA SOA NETWORK BECOMES CIRCUMSTANCE SCRIBED IN A WAY THAT MAY REINFORCE CERTAIN UNHEALTHY LIFESTYLES THAT AGAIN MIGHT DRIVE [LOW AUDIO]. THIS IS INTRIGUING SOCIAL SCIENCE ABOUT NETWORKS, BUT IT ALSO RAISED THE QUESTION OF WHAT THE BIO SOCIAL INTERFACES, WHAT COULD BE THE MECHANISM THAT MIGHT MOVE SOCIAL CON DAY YEN. FRANCIS ILLUSTRATED ONE OF THE ELEMENTS OF THE HISTORY IN WHICH THE LABORATORY WAS ABOUT HYGIENE AND THE NOTION OF MICROBES AND GERMS THAT WOULD SPREAD DISEASE. WE TEND NOT TO THINK OF THAW RELATED TO OBESITY AND CARDIO VASULAR DISEASE BUT RECENT WORK HAVE STARTED TO TALK ABOUT THE NOTION OF HOW THAT THE [LOW AUDIO] IN OUR DIE YES, SIRTIVE TRACK MIGHT INFLUENCE HOW WE RESPOND TO DIET, AND INDEED THE DEVELOPMENT OF ATHEROSCLEROSIS. YOU'RE AWARE OF THE RELATIONSHIP BETWEEN DIET AND VASCULAR DISEASE -- STAN DID AN INTERESTING EXPERIMENT IN WHICH HE FOUND THE METABOLITES IN THE DIET THAT APPEARED TO ACTIVATE THE IMMUNE SYSTEM AND PROMOTE @ ROE GENESIS, ONE OF THOSE WAS KOE LEAN. IF H HE FED A MOUSE COLLEEN, IT EXACERBATED THE DEVELOPMENT OF ATHEROSCLEROSIS. THIS SAME METABOLITE UNDERSTOOD WENT SEVERAL METABOLIC STEPS THAT WAS DPEBT ON THE [LOW AUDIO] OF THE GUT FLOOR IN THESE MICE AND ACTUALLY IS SHOWN HERE IF HE TREATS THE MICE WITH ANTIBIOTICS TO ELIMINATE THE GUT FLOOR, HE ALSO ATTENUATED THE ATHEROSCLEROSIS. HE COULD HAVE THE MICE COHABITATE THE GERM-FREE MICE AND THAT PROPENSITY OF DIET-INDUCED @ ROE GENESIS COULD BE TRANSFERRED TO THE GERM-FREE MICE AS WELL SUGGESTING AN INTERACTION WITHIN A SOCIALA@ ROE GENESIS COULD BE TRANSFERRED TO THE GERM-FREE MICE AS WELL SUGGESTING AN INTERACTION WITHIN A SOCIT@ ROE GENESIS COULD BE TRANSFERRED TO THE M-EEIASE T E SENGN TECTN TH A CIROROGESI O BTRSFRETOHE U TRSFRETOHE SOALOEENISWII ERF ME WL MREMI AWE OCGESI COD TNSRR TH GE-FE CES LL UGSTG ERTI WHI SINES EIANNTAOITN WO -TH H -BERE OULLO T PCRTI T RENTHOERIS CLIC ALH YET TO REPRODUCE THIS KIND OF OBSERVATION. -- THAT THEY INTERACT WITH OUR IMMUNE SYSTEM IN A WAY THAT IS [INDISCERNIBLE] AND IS CONSISTENT WITH THIS NOTION THAT THERE MAY BE ELEMENTS OF THE SOCIAL CONTEXT THAT ARE MEDIATED THROUGH THIS BIOSOCIAL INTERFACE WITH SYSTEMS SUCH AS THE IMMUNE SYSTEM AND PREDISPOSED TO THE RISK FACTORS THAT CAUSE HYPER TENSION, DISEASE. SIMILAR SORT OF INTERACTION AND TRANSDUCTION OCCURS RELATED TO THE BLOOD VESSEL, AND AS WE'RE TRYING TO UNDERSTAND THE TARGET OR THE DAMAGE OF HYPER TENSION SUCH AS STROKE AND THE RELATIONSHIP WITH THE RISK FACTORS THAT EPIDEMIOLOGISTS HAVE TAUGHT US ABOUT, WE'VE COME TO APPRECIATE THAT THE BLOOD PRESSURES THEMSELVES ARE SENSORS AND TRANSDUCERS AND MEDIATORS OF THIS PATHOGENIC PROCESS. INDEED, WE CAN RECOGNIZE THAT EARLY CHANGES IN VASCULAR FUNCTION REALLY FORERUNNERS IN PRESSAGE IN PREDISPOSITION TO THESE COMPLICATIONS. IN THIS COMMUNITY-BASED SAMPLE WE COMPARED WHITES AND BLACKS OF OTHERWISE HEALTHY FOLKS IN ATLANTA, WE COULD LOOK FOR A MEASURE OF AN ABNORMALITY IN THE VASCULAR PHYSIOLOGIST AS TO WHETHER THEIR BLOOD VESSELS WERE GETTING STIFF OR NOT. AS YOU GET OLDER A LOT OF PARTS OF OUR BODIES GET STIFF AND THE BLOOD VESSELS ARE NOT DIFFERENT, THEY GET LESS RESILL YEBT WITH TIME AND THIS IS A PROCESS -- RESILIENT -- WHAT'S NOTABLE IS WHEN WE COMPARED BLACK AND WHITE FEMALES, AGAIN THE AFRICAN AMERICANS HAD STIFFER MORE DISEASED VESSELS COMPARED TO THEIR CAUCASIAN COUNTER PARTS TRUE FOR FEMALES AND MALES. RACIAL DIFFERENCES, REALLY CAN'T BE EXPLAINED BY THE STANDARD RISK FACTORS SUGGESTING THAT, AGAIN, CHANGES IN THEIR VASCULAR BIOLOGY HAD ALREADY ENSUED. WHAT ARE THE UP STREAM MEDIATORS OF THIS DYSFUNCTION? AGAIN, WHAT ARE THE MEDIATOR PATHWAYS THAT BRINGS THIS? ONE OF THE WORKING HYPOTHESES, AGAIN, RELATED TO THEIR SOCIAL CONTEXT. WHEN WE SURVEYED THESE PATIENTS -- THESE PARTICIPANTS -- AFRICAN AMERICANS WERE MORE LIKELY TO REPORT THEY HAD SLEEP DEPRAVATION, HIGHER LEVELS OP STRESS, HIGHER LEVELS OF -- THERE WERE FACTORS THAT MIGHT BE PREDISPOSING THEM TO THIS HIGH RISK STATUS AGAIN AND MAY BE ALTERING OF THEIR VASCULAR BIOLOGY. WHAT COULD BE THE MEDIATORS OF THIS PROCESS? WE'RE INTRIGUED BY THE WORK OF DAVID HARRISON WHO WAS ALSO A COLLEAGUE OF OUR IN ATLANTA IN WHICH HE WAS LOOKING AT T CELLS IN HYPER TENSION. THERE'S A MODEL OF STRESS-INDUCED HYPER TENSION BASICALLY INVOLVED A SORT OF PSYCHOSOCIAL STRESS WHERE YOU PUT ONE MALE MOUSE IN THE CAGE WITH OTHER MALE WHICH COULD BE A LITTLE STRESSFUL PARTICULARLY IF HE THINKS THAT OTHER MALE IS GOING TO ATTACK HIM AND EVENTUALLY YOU KEEP DOING THAT AND THEY DEVELOP HYPER TENSION. WHAT WAS NOTE WORTHY IS WHEN DAVID DID THIS SAME STRESSFUL STIMULUS TO IMMUNODEFICIENT MICE, THEY APPEARED TO BE RESISTANT TO THIS STRESS-INDUCED HYPER TENSION. WHEN HE DID ADOPTED TRANSFER AND GAVE THEM BACK THEIR THE T CELLS THEY WERE ABLE TO BE LIKE WILD TYPE AND DEVELOP HYPER TENSION IN RESPONSE TO PSYCHOLOGICAL STRESS. NOTE WORTHY THAT BOTH ANIMAL TYPES HAD A NORMAL SORT OF FIGHT AND FLIGHT RESPONSE OF INCREASE CORTICOSTEROID RELEASE IN SUGGEST THAT THERE MIGHT BE ACTIVE STRESS ACTIVATING THE T CELLS AND PROMOTING VASCULAR DYSFUNCTION TO HYPER TENSION IN THIS CONTEXT. THOSE ARE JUST MICE, BUT WE'RE SEEING THIS RELATIONSHIP BETWEEN AFRICAN AMERICANS REPORT SO MUCH MORE STRESS WITH OTHER BIOMARKERS OF ACTIVATION AND INFLAMMATION, AND INDEED, WE SAW ASSOCIATIONS BETWEEN THESE PSYCHOSOCIAL REPORTS AND BIOMARKERS OF INFLAMMATION, PARTICULARLY IN THIS CASE, C REACTIVE PROTEIN AMONGST THE AFRICAN AMERICANS IN RED COMPARES TO THEIR CAUCASIAN COUNTER PARTS. THEIR DEFENSE SYSTEM OF ANTIOXIDANTS THAT PROTECTS THE BLOOD VESSELS INFLAMMATORY CYTOKINES WAS DIMINISHED INDICATIVE OF THE NOTION THAT NAY BE SUSCEPTIBLE TO PROINFLAMMATORY STATE, PROOX DEBIT STATE WHICH WOULD CAUSE VASCULAR DISEASE AND DAMAGE. CARRY THIS ONE STEP FURTHER, BY FOCUSING IN ON COMPARISON AMONGST OBESE AFRICAN AMERICAN WOMEN COMPARED TO THOSE WHO ARE LIEN AND -- LEAN -- THIS SHOWS AN ANALYSIS. YOU COULD SEE FROM THE BACK THAT THESE ARE THE LEAN AFRICAN AMERICANS WOMEN AND THESE ARE THE OBESE ONES. THERE'S STRIKING DIFFERENCE IN THEIR GENE EXPRESSION PROFILE AND MANY OF THESE GENES RELATE TO INFLAMMATORY PATHWAYS RELATED TO OBESITY. NOT ONLY IS THIS TRUE WITH THE PERIPHERAL MONO CITES, BUT THE IT WAS ABLE TO TAKE A MONO CITE AND PUT IT IN A DISH, PROMOTE MICROPHAGE -- EX VIVO AND STUDY THESE MICROPHAGES NOW. DESPITE THE FACT IT'D BEEN 10-14 DAYS THE OBESE MACROPHAGES EXHIBITED A PHENOTYPE SUGGESTING THEY HAD A MEMORY OF THAT MILIEU. INDEED, TEAR ELECTROPHYSIOLOGICAL TRACES WERE DIFFERENT SUGGESTING THAT THESE MILIEU HAD CHANGED THINGS DRAMATICALLY SINCE THERE WAS A CELLAR MEMORY OF THE METABOLIC MILIEU THAT WAS PERSISTENT. AS CONSISTENT WITH THIS MODEL IN WHICH THIS EFFECT OF OBESITY WAS MODULATED [LOW AUDIO] IN A WAY THAT'S PROINFLAMMATORY AND INDEED WAS PRECIPITATING AND REDISPOSING TO VASULCULAR DISEASE. THESE ARE PART OF THESE BIOSOCIAL INTERFACE IN WHICH SOME OF THESE CRY -- PSYCHOSOCIAL FACTORS --. THE E EPI GENOME IS ANOTHER TRANSDUCER OF THIS INTERFACE OF HOW THE ENVIRONMENT MODULATE SYSTEMS IN A WAY THAT INDUCES CELLAR MEMORY THAT CAN SUSTAIN AND PROMOTE CHRONIC DISEASES. WE'RE INTRIGUED BY THIS HYPOTHESIS THAT THE EXPRESSION, FEE KNOWTY PICK EXPRESSION OF THE GEE KNOW TIME CAN BE MODULATED BY CHEMICAL EXPRESSIONS OF THE CODE. THIS MAY TAKE THE FORM OF CHANGES THAT INFLUENCE, FOR EXAMPLE, THE PROMOTER OF THE GENE AND MODULATE TRANSCRIPTIONAL ACTIVITY OR OTHER FACTORS SUCH AS GENERATION OF MIE RNAs. EITHER WAY THESE CHANGES CAN INDUCE CHANGES IN GENE EXPRESSION AND AFFECT CELL PHENOTYPE AND WHAT'S INTRIGUING IS THE STUDY LOOKING GENOME WIDE AT PATTERNS OF CPG, DNA METHYLATION WITH PATIENTS WITH TYPE I DIABETES WHO HAD ALREADY DEVELOPED THE KIDNEY DISEASE COMPARED TO TYPE I DIABETIC WHO IS HAD NOT. EVEN IN THEIR CIRCULATING IMMUNE CELLS, A PATTERNS OF DIFFERENCES IN DNA METHYLATION COULD BE DISCERNED BETWEEN THOSE TWO. AND THE LOCI WHERE THOSE DNA PATTERNS CORRESPONDED IN A FEW CASES CORRESPOND TO GENES THAT HAVE BEEN ASSOCIATED WITH THE DEVELOPMENT OF DIABETIC [INDISCERNIBLE] SUGGESTING AGAIN THAT THERE MAY BE MEDIATOR PATHWAYS THAT ARE SENSITIVE TO THE [INDISCERNIBLE] OF THE EPI GENOME MAY CHANGE IN THE PATHOGENESIS OF DISEASE AND THIS IS AN ACTIVE AREA OF INVESTIGATION, AND IT'S CONSISTENT WITH HYPOTHESIS WE'VE BEEN TESTING IN WHICH WE'VE BEEN STUDYING THAT THE PATHOGENESIS OF HYPERTENSION -- WE'VE OBSERVED MODIFIED DNA METHYLATION GLOBALLY AND IN SITE-SPECIFIC MANNER. THE KEY MEDIATOR APPEARS TO BE N-DNA METHYL TRANSFERASE ONE. IF WE BLOCK A BASIL ACTIVE FACTOR, IT CAN BE REDUCE. -- GENES THAT KEEP THE BLOOD PRESSURE DOWN, PROTECT THE VESSEL FROM DEVELOPING [LOW AUDIO]. THIS SET UP THE POSSIBILITY OF THE THAT THIS COULD BE MANIPULATED IN A THEY ARE PEW THE TICK STRATEGY IF WE UNDERSTAND THE ENZYMES AND TARGETS THAT AFFECT THE EPI GENOME PARTICULARLY IF THEY COULD BE SELECTIVE, WE THOUGHT WE MIGHT BE ABLE THE TO MODIFY THE COURSE [LOW AUDIO], IN ESSENCE SHAS WHAT THIS INDICATES [LOW AUDIO] -- IF WE BLOCK DMT 1 AND DNA METHYLATION WE CAN [INDISCERNIBLE]. WE'VE TRIED TO SHOW YOU AS AN EXAMPLE OF THE [INDISCERNIBLE] THAT MAY OCCUR IN THE EPI GENOME IN CONTEXT OF THE -- OR EVEN DIET AND THIS HAS IMPLICATIONS BECAUSE THERE CAN BE AN INTERACTION BETWEEN THE EPI GENOME AND THE GENOME ITSELF MIGHT PLAY A ROLE IN RACIAL INEQUITIES AND DISEASE. OUR GENOME IS IN ESSENCE GIVES US AN ARCHITECTURE OF OUR POPULATION HISTORY, THE FINGERPRINTS ARE THERE, AND IT'S INFLUENCED BY OTHER ELEMENTS OF A POPULATION HISTORY WHETHER IT'S COMING OUT OF AFRICA OR BE A MIXTURE THAT HAPPENED WITH AFRICAN AMERICANS THAT CAME TO THIS COUNTRY SUCH THAT IN [INDISCERNIBLE]'S WORK HE'S DOCUMENTED THIS MOSAIC NATURE OF THE GENOME IN AFRICAN AMERICANS WHERE THERE'S THESE VARIOUS ELEMENTS THAT ARE EITHER EUROPEAN, RED, OR AFRICAN IN BLUE, AND EACH LOCUS ALONG THE GENOME AT VARIOUS CHROMES THERE'S AN INTERPLAY AND A MOSAIC THAT'S VERY DYNAMIC ACROSS THE POPULATION SUCH THAT EVEN THOUGH BOTH HOLLY AND ALONG SOW ARE AFRICAN AMERICANS IT'S VERY LIKELY THAT THEY'RE PATTERN IS VERY DIFFERENT. THIS GROUP WE TALKED ABOUT IN TERMS OF SKIN COLOR MIGHT BE QUITE HETERO GENIUS WHEN WE -- THIS IS, I THINK, ILLUSTRATED BY THIS VERY PROVOCATIVE FINDING AND BY [INDISCERNIBLE] AND INCLUDED AN INTRAMURAL INVESTIGATOR, DR. JEFFREY [INDISCERNIBLE] TO FIND THIS ASSOCIATION BETWEEN [LOW AUDIO] VARIANT AND KIDNEY DISEASE IN AFRICAN AMERICANS WHICH HAVING THIS RISK VARIANT CONFERRED A FIVE TO TENFOLD INCREASE IN DEVELOPING KIDNEY DISEASE. THIS IS PROBABLY AN ANCIENT SYSTEM THAT WAS INVOLVED IN HOW YOU RESPONSE TO YOUR ENVIRONMENT, CASE OF PARASITE INFESTATION THAT WOULD PROTECT YOU IN AFRICA. NOW IN THE CON TECH OF AMERICA, IT WAS MALL ADAPTED AND MAYBE PROMOTING AND REALING AN INFLAMMATORY RESPONSE THAT PREDISPOSED TO ORGAN DAMAGE. JUST TO END HERE ON A PROVOCATIVE NOTE, THIS RAISES THE POSSIBILITY THAT WE MIGHT BE ON THE THRESHOLD OF CONTEMPLATING STUDIES IN WHICH WE ACTUALLY COULD TAKE A VARIANT THAT HAS BEEN DISCOVERED, PARTICULARLY IN AFRICAN AMERICANS, AND START TO DESIGN GENOMIC MEDICINE, THERAPEUTIC STRATEGY THAT'S ORIENTED AROUND THAT VARIANT TO REDUCE THESE RACIAL INEQUITIES IN CHRONIC KIDNEY DISEASE. THIS COULD TAKE THE FORM OF PREDICTING WHO'SED A RISK LONG BEFORE THEY DEVELOP CLINICAL MANIFESTATIONS OF KIDNEY FAILURE AND WE MAY EVEN BE PREEMPTED IN SAYING MAYBE WE SHOULD TREAT THEIR BLOOD PRESSURE TO A LOWER TARGET BECAUSE THEY ARE SO PREDISPOSED. THERE MAY BE A PHARMACOGENOMIC STRATEGY AND WE TAKE THE -- AND [LOW AUDIO] MAY BE A CANDIDATE IN THAT REGARD, AND SIMILARLY THERE'S NEW THERAPIES AGAIN IN THE SPIRIT OF THE CONFERENCE AS WE UNDERSTAND WHAT IS ADDITIONAL TO [INDISCERNIBLE] AND HOW IT INTERACTS WITH THE BLOOD PRESSURE, KIDNEY WE MAY IDENTIFY THOSE PATHWAYS THAT LINK THIS KINETIC VARIANT. WHAT I TRIED TO DO AS QUICKLY AS I COULD WAS TOED A DLESZ COMPLEX PROBLEM THAT HAS THESE VARIOUS DIMENSIONS OF THE ECOSYSTEM IN WHICH AFRICAN AMERICANS FIND THEMSELVES AS WELL AS THEIR POPULATION HISTORY AND GENOMIC VARIATION THAT'S DISTINCT AND HOW THAT MAY PLAY A ROLE IN THE DRIVING FORCE DEVELOPING [INDISCERNIBLE] AND TO HOPEFULLY END WITH THE NOTION THAT PART OF MY INSPIRATION, PART OF MY PASSION RELATES TO THAT PERSONAL ASPECT OF HOW THIS IS AFFECTING FAMILIES AND NEIGHBORHOODS AND COMMUNITIES AND REALLY THAT'S WHAT'S DRIVEN ME TO COME TO NIH. I HOPE WILL EXCITE SOME OF THE STUDENTS HERE TO PURSUE THESE QUESTIONS THAT HAVE SUCH IMPORTANT CLINICAL AND PUBLIC HEALTH IMPACT AS NOT ONLY SCIENCE THETIST INTERESTED IN INTELLECTUAL PUZZLES BUT SCIENTISTS WHO ARE TRYING TO MAKE A DIFFERENCE AND AFFECT PATIENTS AND THEIR LIVES. WITH THAT I'LL CONCLUDE WITH THIS QUOTE FROM [INDISCERNIBLE]. A LOT OF PEOPLE ARE WAITING FOR MARTIN LUTHER KING TO COME BACK BUT THEY'RE GONE. WE'RE IT. IT'S UP TO US, THE IT'S UP TO YOU. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> THANK YOU FOR A GREAT PRESENTATION. SO I'M PLEASED TO PRESENT TO YOU OUR NEXT SPEAKER, JENNIFER LIPPINCOTT-SCHWARTZ WHO LEADS SECTION OF ORGAN BIOLOGY [INDISCERNIBLE] AT THE EUNICE CAN DISSTRIVER [INDISCERNIBLE]. THE INSTITUTE THAT I'M PRIVILEGED TO LEAD AS A SCIENTIFIC DIRECTOR. DR. SCHWARTZ WAS BORN IN KANSAS WHERE HER FATHER WAS PROFESSOR OF CHEMISTRY AND SHE GREW UP WITH A PERIODIC TABLE IN HER KITCHEN. SHE WAS REALLY EK POSED TO SCIENCE EARLY AND DECIDED TO PURSUE SCIENCE AT THIS YOUNG AGE. HOWEVER, SHE DID FIRST MAJOR IN PSYCHOLOGY AND PHILOSOPHY AND FOR A WHILE SHE WAS TEACHING IN KENYA WHERE SHE TAUGHT SCIENCE TO TEENAGE GIRLS. SHE THEN CAME BACK AND TAUGHT BIOLOGY TO TEENAGE BOYS IN WEALTHY PALO ALTO OFFERING HER WHAT SHE DESCRIBES IS A PHENOMENAL PERSPECTIVE OF DISPARITIES OF TEACHING AND LEARNING OF SCIENCE. AFTER A MASTERS PROGRAM AT STANFORD, JENNIFER COMPLETED HER Ph.D. IN BIOCHEMISTRY IN HOPKINS. HERE, SHE REALLY WAS INTRODUCED TO THE [INDISCERNIBLE] TECHNIQUES THAT SEND HER ON TO CELL BIOLOGY. THE REST IS HISTORY. AFTER GRADUATING FROM HOPKINS, JENNIFER CAME TO THE NIH WHERE SHE WAS A FOSTERED WITH RICK [INDISCERNIBLE] HERE AT NICHD AND STAYED EVER SINCE. THROUGH THE 1990s, SHE HELPED TO CHANGE THE PERCEPTION OF HOW MOLECULES ARE OBTAINED WITHIN THE ER, [INDISCERNIBLE] AND PLASMA MEMBRANE AND REALLY BECAME A CELL BIOLOGY FOR [INDISCERNIBLE], BUT THEN STHE REALIZED THE MOLECULES SHE WAS LOOKING AT ARE NOT STATIC, THEY MOVE AND THEY MOVE FAST, AND JENNIFER WAS DETERMINED TO CAPTURE THEM IN IMAGES. IN 2002 ALONG WITH YOUR POST DOCTORAL FELLOW, GEORGE [INDISCERNIBLE] NOW WITH HIS OWN LAB AT [INDISCERNIBLE], SHE DEVELOPED THE PHOTO ACTIVATABLE GREEN FLORENCE PRODUCT, GFB WHICH CHANGED THE WAY WE DO CELL BIOLOGY AND SCIENCE TODAY. THIS ADVANCE LED TO THE BREAKTHROUGH IMAGING TECHNIQUE THAT NOW IS CALLED PALM. IT WAS THIS TYPES OF ACHIEVEMENTS BOTH IN BASIC BIOLOGY AND IMAGING TECHNOLOGY THAT MADE JENNIFER LAST YEAR OR ACTUALLY IN 2008, TO BE ELECTED TO THE NATIONAL ACADEMY OF SCIENCES. PALM WAS JUST THE BEGINNING. JENNIFER HAS DEVELOPED MANY OTHER TECHNIQUES SINCE AND TODAY IS GOING TO GIVE US A PRESENTATION ON NAVIGATING THE CELLAR LANDSCAPE WITH NEW OPTICAL PRONE PROBES, IMAGING STRATEGIES AND TECHNICAL INNOVATIONS. JENNIFER. [APPLAUSE] >> THANK YOU FOR THAT KIND INTRODUCTION. UM, SO I THINK ONE OF THE THINGS THAT IS REALLY IMPORTANT TO REALIZE AS RESEARCHERS IS HOW IMPORTANT TECHNOLOGY IS AND TECHNOLOGY DEVELOPMENT IN ORDER FOR US TO CONTINUALLY MOVE FORWARD IN OUR DISCOVERED ABOUT BASIC SCIENTIFIC PROCESSES AS WELL AS BIOMEDICAL DISEASES. ONE PARTICULAR AREA OF TECHNOLOGICAL DEVELOPMENT THAT HAS BEEN UNDERGOING REALLY TREMENDOUS ADVANCES OVER THE LAST 15 YEARS IS FLORENCE IMAGING. NOW WHAT THAT ALLOWS US TO DO IS TO ACTUALLY GO IN AND VISUALIZE HOW MOLECULES ARE COMMUNICATING WITH EACH OTHER WITHIN CELLS. IT ALLOWS US TO TAG ORGANELLES AND DEPARTMENTS WITHIN CELLS AND THEN WATCH VISCERALLY HOW THESE PROCESSES COMMUNICATION ON ARCHER SKRA ARCHER SCALES TO ENABLE ORGANISMS TO MOVE AND SET UPGRA UPGRADE -- SET UP, GRADIENTS. IT'S BUILDING ON THE ACTIVITIES OF MANY DIFFERENT DISPRCIPLINES IN SCIENCE. THE PROBE DEVELOPMENT WHICH LED TO GREEN FLORENCE, REALLY PROMOTED BIOLOGIES TO DEVELOP TECHNIQUES FOR USING THOSE PROBES INSTIGATED PROVIDED A BACKDROP FOR PHYSICISTS TO DEVELOP MORE ADVANCED MICROSCOPY APPROACHES AND THEN BECAUSE FOR THE FIRST TIME WITH THESE FLOR FLUORESCE FLUORESCE FLUORESCENT PROBES, IT'S ENABLED MATHEMATICIANS TO COME IN AND BUILD PREDICTIVE MODELS FOR HOW BASIC PROCESSES ARE OCCURRING WITHIN CELLS. NOW WHAT I WANT TO TALK ABOUT TODAY IS A PARTICULAR PROBE, THE PHOTO ACTIVATABLE FLUORESCENT PROTEIN THAT HAS BEEN DRIVING THIS SYNERGY AMONG DIFFERENT FIELDS OF SCIENCE FOR ULTIMATE BIOMEDICAL BENEFIT. THE PHOTO ACTIVATABLE FLUORESCENT PROTEIN IS ONE WHERE AT THE IMAGING WAVELENGTH, ONE DOESN'T SEE ANYTHING UNTIL YOU ACTIVATE YOUR FIELD OF VIEW WITH A PULSE, A UV LIGHT PULSE. WHAT THAT DOES IS CHANGE THE ABSORPTION SPECTRUM THAT'S BEING EXPRESSED IN THIS CELL HERE SO THAT NOW IT'S VISIBLE, GIVING OFF LIGHT. THIS ALLOWS TO YOU SWITCH ON MOLECULES OF INTEREST AS ILLUSTRATED IN THIS MOVIE SEQUENCE HERE WHERE WE'RE LOOKING AT A [INDISCERNIBLE] PROTEIN MOVE THROUGH THE SEEKTORY PATHWAY. IN THIS SEQUENCE WE'VE SWITCHED ON SELECTIVELY THE VIRAL MOLECULES IN THE GOAL CHI APPARATUS LOCALIZED IN THIS LOCATION HERE AND BECAUSE IT'S ONLY THIS POPULATION OF MOLECULES THAT HAS BEEN SWITCHED ON, WE NOW HAVE THE ABILITY TO FOLLOW THIS SPECIFIC PATHWAY THAT THEY FOLLOW FROM THE GOAL CHI APPARATUS ON TO THE PLASMA MEMBRANE WHERE THEY FUNCTION TO BUD OUT FROM THE CELL. NOW THE PHOTO ACTIVATABLE FLUORESCENCE PROTEIN ALSO ENABLE ONE TO QUALIFY VISUALLY FOR THE FIRST TIME PROTEIN TURNOVER WITHIN CELLS. IN THIS PARTICULAR EXAMPLE WE'RE MON NORRING THE TURNOVER -- MONITORING -- OF CELL THAT HAS BEEN EXPRESSED IN THE N CELLS. WHAT HAS BEEN KNOWN FOR MANY YEARS IS THIS MOLECULE'S FAIRLY UNSTABLE WHEN IT'S EXPRESSED AS AN OR FAN SUB UNIT AND BY HIGH LIGHTING THE POOL OF THE MOLECULES IN CELLS USING THIS PHOTO ACTIVATING FLUORESCENT PROTEIN ONE CAN VISUALLY MONITOR THE TURNOVER RATE OF THESE MOLECULES WHICH OCCURS BY A PROCESS WHERE THEY'RE DISLOCATED FROM THE MEMBRANES OF THE [INDISCERNIBLE]. WITH THIS APPROACH, YOU CAN MONITOR THE TURNOVER RATE IN INDIVIDUAL CELLS, YOU GET THOUSANDS OF DATA POINTS, AND YOU CAN COMBINE THIS WITH PHARMACEUTICAL MANIPULATION OF THE SYSTEM TO UNDERSTAND AT WHAT RATE-LIMITING STEPS THOSE DRUGS OR OTHER PER TER BINS CAN INTERFERE WITH THIS PROCESS, AND CORRELATE IT WITH A DISEASE SITUATION. NOW ONE CAN ALSO LOOK AT THE TURNOVER OF WHOLE ORGANELLES. IN THIS CASE WE'RE LOOKING AT THE TURNOVER OF AN ORGANELLE CALLED THE [INDISCERNIBLE] WHICH PLAYS AN IMPORTANT ROLE IN SEQUESTERING DAMAGED ORGANELLES AND DELIVERING THEM TO LYSOSOMES FOR DESTRUCTION. P WHAT YOU CAN SEE IN THIS MOVIE SEQUENCE HERE WHERE WE'VE SWITCHED ON ALL OF THE AUTO [INDISCERNIBLE] IS THE TURNOVER RATE OF THESE ORGANELLED WHICH REFLECTS THE SPEED WITH WHICH THEY FUSE AND DLI THEIR CONTENTS TO LIE E SEW SOEMS. LYSOSOMES. WITH THE PROTEINS THAT HAVE BEEN TAGGED TO PARTICULAR ORGANELLES OF INTEREST, ONE NOW HAS THE WAY, THE ABILITY, TO MONITOR WITHIN THE SINGLE CELL LEVEL THE HALF LIFE OF COMPARTMENTS WHETHER THEY'RE TURNED OVER OR STABLE WITHIN CELL WHICH IS IS EXTREMELY IMPORTANT FOR PUTTING TOGETHER A MORE GLOBAL TRAFFICKING COMPARTMENTAL UNDERSTANDING OF CELLAR METABOLISM. NOW HERE'S JUST ONE OTHER EXAMPLE THAT DOESN'T INVOLVE USING THE PHOTO ACTIVATABLE PROTEINS FOR TURNOVER BUT RATHER TO GET INSIGHT INTO THE SPATIAL TEMPORAL DYNAMICS OF MOLECULES WITHIN CELLS. WHAT YOU'RE LOOKING AT HERE IS THE LEADING EDGE OF A CRAWLING CELL WHICH IS HIGHLY DYNAMIC UNDERGOING THESE OSCILLATORY PROTRUSION AND RETRACTION CYCLES. WHAT YOU'RE VISUALIZING HERE IS AN ACTIN WHICH IS UNDERGOING ASSEMBLY, DISASSEMBLY, AND FORMATION INTO THE USE OF STRUCTURAL BUNDLES AT THE REAR OF THIS LEADING EDGE WHERE ADHESIONS ARE LAID DOWN AND OTHER IMPORTANT FUNCTIONS IN ORDER TO ALLOW THE CELLS TO CRAWL FORWARD. WHAT WE CAN DO WITH THE PHOTO ACTIVATABLE FLUORESCENT PROTEINS IS GAIN INSIGHT INTO WHAT'S THE SPATIAL TEMPORAL RELATIONSHIP IN THE MeSH WORK THAT'S BEING BUILT IN THIS LEADING EDGE OF THE CRAWLING CELL WITH THE ACTIN WE SEE IN THE REAR HERE THAT APPEARS AS THE ARK-LIKE BUNDLES. HERE'S THE EXPERIMENT WITH A PHOTO CONVERTIBLE FLUORESCENT PROTEIN. BEFORE ACTIVATION ALL OF THE MULE MOLECULES ARE GREEN. WE CAN SELECTIVELY PHOTO CONVERT THE GREEN MOLECULES TO RED USING UV LIGHT PULSE WHERE WE SELECTIVELY SWITCH ON THAT POOL OF MOLECULES AND THEN WE CAN MONITOR WITH TIME THE FATE OF THOSE MOLECULES AND THE ABSENCE OF ANY OTHER MOLECULES THAT ARE BEING CONVERTED IN ORDER TO TRACK THEM IN THESE CELLS. WHAT YOU CAN SEE FROM THIS EXPERIMENT IS THAT THOSE MOLECULES THAT HAVE BEEN SWITCHED ON IN THIS VERY LEADING EDGE ACTUALLY MOVE BACK TO CREATE THE ACTIVE ARKS FOUND IN THE REAR OF THIS EDGE ZONE. WHAT THAT'S ALLOWED US TO DO IS TO FORMULATE A BIOPHYSICAL MODEL IF YOU WILL FOR THE BEHAVIOR OF THE ACTIN DRIVING THESE LEADING EDGE MOLECULE MOTIONS AND WHICH FORM THE FOUNDATION OF THE FOCAL ADHESION SUB STRAIGHT OF THIS CELL WITH ITS CRAWLING SURFACE. THIS IS JUST A DIAGRAM ILLUSTRATING THAT WHERE THESE DYNAMIC PROTRUSION AND RETRACTION ACTIVITIES WHICH IS REFLECTIVE OF THE ASSEMBLY OF AN ACTIN MeSH WORK AT THE LEADING EDGE IS ESSENTIALLY DRAWN BACK DOWN INTO THESE ARK-LIKE SHAPED THROUGH RECRUITMENT OF MOTOR MOLECULES THAT ARE ABLE TO CONVERT THIS MeSH WORK ACTIN INTO THIS DYNAMIC BUNDLED FORM THAT CAN TRACK THAT REAR EDGE BRINGING IT BACK INTO [INDISCERNIBLE] MOTION. FLUSH FLSH THOSE ARE EXAMPLES OF JUSTING FLORENCE IN LIVE CELL IMAGING, BUT REESSENTIALLY WE'VE DISCOVERED -- RECENTLY WE'VE DISCOVERED THEY CAN BE USED FOR SUPER RESOLUTION IMAGING. IF ONE USING CONVENTUAL LIGHT MICROSCOPE, AN IMAGE [INDISCERNIBLE] ALL YOU WOULD SEE IF YOU PEER THROUGH YOUR LENS IS A BLURRY BLOB AND THE REASON IS THAT CONVENTIONAL MICROSCOPES ONLY HAVE A RESOLUTION IN THE XY OF ABOUT 250 NANO METERS. WITH THESE SUPER RESOLUTION IMAGING TECHNIQUES INCLUDING PALM -- WHICH I'LL TALK ABOUT IN A SECOND -- YOU GET RESOLUTION DOWN TO 20 NANOMETERS IN XY AND THAT ENABLES YOU TO BE ABLE TO DECIPHER EACH OF THE 15 NANOMETER BEADS IN THIS AGGREGATE. THE WAY THAT PALM WORKS IS BASED ON POINTS LOCALIZATION. WE HAVE PHOTO ACTIVATABLE FLUORESCENT PROTEINS THAT WE CAN SWITCH ON AND IN THIS APPROACH, WE SWITCH ON SMALL SUBSETS OF THESE FLUORESCENT MOLECULES AND BECAUSE THE FLORENCE THAT'S GIVEN OFF BY INDIVIDUAL MOLECULES WHICH IS DEFRACTION LIMITED AND APPEARS AS A BLURRY SPOT, WE CAN SET THE SHAPE TO DEFINE WHERE THE MOLECULE MUST BE LOCALIZED IN THE LIMITED SPOT THAT APPEARS WITH JUST A CONVENTION LIGHT MICROSCOPE. IT'S BECAUSE WE CAN ISOLATE THESE MOLECULES TEMPORALLY THAT WE HAVE THE ABILITY TO [INDISCERNIBLE] WITH VERY HIGH ACCURACY THEIR EMPLOYEE LOCALIZATION. IN THIS TECHNIQUE CALLED PHOTO ACTIVATED MICROSCOPY, WHAT ONE CAN DO IS ESSENTIALLY REPEATEDLY OVER THOUSANDS OF FRAMES ACTIVATE SUBSETS OF MOLECULES THAT POP LATE -- POPULATE A VERY DENSE SAMPLE. AT THE END OF THE EXPERIMENT YOU THEN SUM UP THE POSITION PROBABILITIES OF ALL OF THESE SEN TROIT-FITTED BLURRY SPOTS THAT YOU'VE ACQUIRED FROM DEFRACTION LIMITED IMAGING AND U GET YOUR SUPER RESOLUTION IMAGE. THIS IS JUST SHOWING YOU HOW THIS TECHNIQUE OPERATES LIVE. HERE'S YOUR RAW IMAGE THAT YOU ACQUIRING. THESE ARE A SERIES OF FRAMES THAT WERE SHOWING HOW INDIVIDUAL MOLECULES HAD BEEN ACTIVATED OVER THE COURSE OF BUILDING THIS SUPER RESOLUTION IMAGE. OVER TO THE RIGHT HERE IS THE PALM P IMAGE THAT'S DEVELOPED BY FITTING ALL OF THESE INDIVIDUAL DEFRACTION LIMITED SPOTS THAT APPEAR ON THE REPETITIVE PHOTO ACTIVATION. WHAT THIS TECHNIQUE IS REALLY ALL ABOUT IS [INDISCERNIBLE]. MANY OF YOU ARE AWARE OF THE ART MOW NAY AND OTHERS USE POTILLAS IS AND WE'RE ESSENTIALLY CREATING AT SHARP SUPER RESOLUTION IMAGE BY ESSENTIALLY POSITIONING WITH VERY HIGH ACCURACY THE LOCALIZATION OF INDIVIDUAL MOLECULES THAT COMPRISE THAT IMAGE. OVER THE LAST SEVEN YEARS THERE'S BEEN SINCE PALM AND STORM WHICH IS NOW AT ITS TECHNIQUE USING PHOTO [INDISCERNIBLE] THERE'S BEEN A WHOLE ASSORTMENT OF SIMILAR-BASED TECHNIQUES FOR IMPROVING YOUR RESOLUTION DRAMATICALLY THROUGH POINT LOCALIZATION APPROACHES. HERE'S JUST ONE EXAMPLE WHERE RECENTLY COLLABORATION WITH A POST DOC IN MY LAB, THE TWO OF THEM USES BREACHING OF JUST CONVENTIONAL DYES TO CREATE A SUPER RESOLUTION IMAGE. SO HERE'S A -- THESE ARE MICROTUBULES THAT ARE LABELLED WITH FLUORESCENT DIES AND IF YOU IMAGE OVER TIME THE INDIVIDUAL MOLECULES BLEACH. AS THEY BLEACH, THAT PROCESS IS [INDISCERNIBLE] AND SO IF WE SUBTRACT INDIVIDUAL FRAMES DURING OUR COLLECTION SEQUENCE FROM EACH OTHER, YOU CAN ACTUALLY VISUALIZE THE MOLECULES UNDERGOING BLEACHING AND YOU CAN FIT THE BLEACHED SPOT THAT APPEARS TO ITS SEN TROID TO CREATE A SUPER RESOLUTION IMAGE. HERE'S A DEFRACTION LIMITED IMAGE OF A MICROTUBULE. YOU CAN SEE THE VERY SORT OF SPREAD-OUT RESOLUTION THAT YOU HAVE, AND HERE'S THE FITTED BALM MOLECULE OF THE TUBELINS WE'VE BEEN LABELING. FOR COMPARISON, HERE'S AN I MU KNOW EM OF THE CRY CROW TUBE WALL WHERE WE'VE LABELED THEM WITH GOLD TUBE WALLS AND VISUALIZED BY ELECTRO --. NOW WHAT'S NEAT ABOUT THIS BLEACHING STRATEGY FOR CREATING SUPER RESOLUTION IMAGES IS THAT YOU CAN MULTI PLEX. YOU CAN ESSENTIALLY USE MANY DIFFERENT COLORS OF FLUORESCENT DYES TO ADDRESS THIS. NOW, THIS STRATEGY OF SUPER RESOLUTION IMAGING BUILDING UP POINT LOCALIZATIONS HAS LED TO MANY P DIFFERENT DIRECTIONS THAT THIS FIELD HAS MOVED INTO. ONE IS STRUCTURAL ANALYSIS, THAT IS JUST GO INTO GREATER DETAIL INTO DEFINING HOW PARTICULAR MOLECULES LOCALIZE IN A STRUCTURE OF INTEREST. SO HERE'S AN EXAMPLE WHERE WE RECENTLY LOOKED AT MOLECULES THAT COMPRISE THE HIV [INDISCERNIBLE] WHICH YOU SEE BUDDING OFF THE SURFACE OF THIS CELL. WHAT WE CAN NOW DO WITH THIS TECHNIQUE IS LOCALIZE SPECIFIC MOLECULES THAT ESSENTIALLY BUILT THIS STRUCTURE. WE'RE LOOKING AT A PLASMA MEMBRANE MARKER IN RED DWOEG WITH ESCORT THREE WHICH IS A MOLECULE THAT PLAYS AN IMPORTANT ROLE IN THE MACHINERY THAT SEVERS OFF THAT VARYON TO ALLOW IT TO BE RELEASED. THERE'S A LOT OF INTEREST IN UNDERSTANDING HOW THAT MACHINERY ACTUALLY FUNCTIONS TO SERVE THE VARY ON AND THIS STRUCTURAL ANALYSIS IS KEY FOR UNDERSTANDING WHAT TYPE OF MECHANISM IS THE APPROPRIATE ONES FOR EXPLAINING IT. IT TURNS OUT THIS THESE SUPER RESOLUTION IMAGING APPROACHING CAN ALSO BE USED IN LIVE CELLS TO LOOK AT MOLECULAR MOTION. SO HERE WHAT YOU'RE LOOKING AT IS THE SURFACE OF THE CELL THAT'S EXPRESSING THE [INDISCERNIBLE] PROTEIN, EACH ONE OF THOSE SPOTS REPRESENTS A DIFFERENT MOLECULE ON THE PLASMA MEMBRANE THAT'S DEFUSING. BECAUSE THESE SPOTS ARE ISOLATED WITH EACH OTHER AND GET VERY ACCURATE INFORMATION ON THE TRAJECTORY THAT THE MOLECULE HAS, BASED ON THAT, WE CAN CREATE DEFUSION MAP FOR HOW MOLECULES MOVE ON THE CELL SURFACE OR IN OTHER PLACES WITHIN THE CELL. AND HERE'S JUST TWO EXAMPLES OF VERY DIFFERENT MOLECULES, VERY DIFFERENT MOLECULAR BEHAVIOR BY THE [INDISCERNIBLE] PROTEIN WHICH AS YOU CAN SEE IS DISP PURSED ALL OVER THE PLASMA MEMBRANE AND HAS ESSENTIALLY TRAJECTORYs AT MANY DIFFERENT DIFFUSION SCALES COMPARED TO THE HIV GAG PROTEIN WHICH VERY QUICKLY UPON BEING INSERTED ON THE PLASMA MEMBRANE MOVES INTO VIRAL BUDDING STRUCTURES AND WE CAN VISUALIZE THAT AND ESSENTIALLY MAP OUT THE PROCESS BY WHICH THESE MOLECULES ENTER THESE VARYONES, HOW QUICK THAT OCCURS AND THE TIME SCALE USING THIS TYPE OF LIVE CELL SUPER RESOLUTION IMAGING. FINALLY, THESE TECHNIQUES BECAUSE THEY ARE SINGLE MOLECULE-BASED, ALLOW US TO BEGIN TO INTERROGATE ASPECTS OF PROTEIN ORGANIZATION AND STOKE YOM INDUSTRY. IN THIS LAST EXAMPLE HERE, WHAT WE'RE LOOKING AT IS THE QUESTION OF HOW DIFFERENT PLASMA MEMBRANE MOLECULES WHICH HAVE VERY DIFFERENT PROPERTIES IN TERMS OF THEIR ABILITY TO BE EXTRAKTSED BY DIFFERENT DETERGENTS, THEIR PARTITIONING INTO DIFFERENT LIPID ENVIRONMENTS, HOW EACH ONE OF THOSE MOLECULES ARE ORGANIZED AT THE NANO SCALE. USING A CORRELATION ALGORITHM THAT ALLOWS US TO CORRELATE INDIVIDUAL MOLECULES WITH OTHER MOLECULES OF THE SAME KIND IN DIFFERENT ENVIRONMENTS WITHIN THE CELL LIKE THE PLASMA MEMBRANE, WHAT WE'VE BEEN ABLE TO DO IS TO GET INSIGHT INTO HOW THESE MOLECULES ARE CLUSTERS, THE SIZES, THE NUMBER IN THE CLUSTERS AND FROM THAT GAIN INSIGHT INTO OU THESE DIFFERENT MOLECULES ARE ORGANIZED FOR SIGNALING AS WELL AS OTHER IMPORTANT FUNCTIONS THAT THEY TAKE PART OF ON THE MRAZ MEMBRANE. BASED ON THIS PARACORRELATION ANALYSIS, THE STEADY STATE DISTRIBUTION OF THESE FOUR DIFFERENT PROTEINS INCLUDING LIN AND LAT WHICH ARE SIGNALING MOLECULES THAT WE BEEN ABLE TO SURMISE BASED ON THIS PARACORRELATION APPROACH. WITH THAT I WANT TO END AND SORT OF EMPHASIZE HOW EXCITING THIS WHOLE FIELD OF IMAGING IS. I WANT TO ALZ EMPHASIZE HOW IMPORTANT THIS SORT OF BASIC BIOLOGICAL INVESTIGATION IS FOR US TO BE ABLE TO MAKE BROADER DISCOVERIES AT THE THERAPEUTIC CLINICAL LEVEL. IN OUR RESEARCH WE COLLABORATE HEAVILY WITH PEOPLE NOT ONLY AT NIH BUT AT OTHER INSTITUTES INCLUDING [INDISCERNIBLE] WHERE PHYSICISTS ARE CLOSE COLLEAGUES. NIH AS I MENTIONED ARE CLOSE CRAB RAY TOR AND THESE ARE PEOPLE IN MY LIFE THAT HAVE PARTICIPATED IN WORK THAT I'VE TALKED ABOUT. THANK YOU VERY MUCH. [APPLAUSE] THANK YOU JENNIFER, AMAZING TALK. IT'S MY REAL PLEASURE TO INTRODUCE OUR NEXT SPEAKER, RON GERMAIN. HE'S ACTUALLY CHIEF OF THE NIAID FOR [INDISCERNIBLE] -- HE BEGAN TO BE A SCIENTIST IN HIS TEENAGER YEARS WHEN HE EXPERIMENTS ON TABLE WITH MICE. HE ALSO COVERED [INDISCERNIBLE] HE DID UNDERGRADUATE STUDIES IN MASTERS DEGREE AT BROWN UNIVERSITY BEFORE MOVING TO HARVARD TO GET HIS MD AND THEN HIS Ph.D. AND BECOME A [INDISCERNIBLE] AT HARVARD. NIH WAS LUCKY ENOUGH IN 1981 TO HAVE HIM AS A GUEST SCIENTIST HERE AND THEN SINCE 1987, HE BECAME SENIOR INVESTIGATOR AND THEN CHIEF OF THE LYMPHO CITE BIOLOGY SECTION [INDISCERNIBLE] LYMPHOCYTE. HE HAS A LOT OF MAJOR SCIENTIFIC ACCOMPLISHMENT. HE'S A WORLD-CLASS IMMUNOLOGY. HE'S A BIG-PICTURE, FUNDAMENTAL QUESTIONS SCIENTIST -- WHICH IS THE BEST I THINK -- AND HIS WORK [INDISCERNIBLE] IS FOCUSED ON T CELL RECEPTOR SIGNALING, PARTICULAR RESPONSE TO PEPTIDES TO THE MHC COMPLEX AND [INDISCERNIBLE]. HE'S ALSO BEEN CITING A LOT THE BASIC FUNDAMENTAL MECHANISM THAT CONTROL THE DYNAMIC PROPERTIES OF THE IMMUNE CELLS IN VIVO. HE HAS WON NUMEROUS AWARDS INCLUDING BEING ELECTED AS [INDISCERNIBLE]. HE IS ALSO A PERFECT EXAMPLE OF WHAT WE DO AT NIH BEST. WE COLLABORATE WITH EACH OTHER. HE IS THE CENTER -- HE RUNS, ACTUALLY -- THE CENTER FOR HUMAN IMMUNOLOGY WHICH HE HELPED WITH CREATE WITH OTHERS AT NIH AND THIS CENTER BRINGS TOGETHER INVESTIGATORS FROM SEVEN DIFFERENT NIH INSTITUTES, AND THIS GROUP RIGHT IS BASICALLY [INDISCERNIBLE] AND HOW THE SYSTEM GETS PERTURBED BY VACCINES, INFECTIONS OR THERAPIES. SO HE SAYS THAT HE DESCRIBES HIS TENURE HERE AT NIH AS AN INTELLECTUAL JOURNEY AND HE WILL SHARE PART OF THE JOURNEY WITH US TODAY IN A LECTURE WHICH HAS VOYAGE OF [INDISCERNIBLE] INTO THE DYNAMIC LIFE OF THE IMMUNE SYSTEM. PLEASE WELCOME RON. [APPLAUSE] >> THANK YOU MUCH FOR THAT INTRODUCTION. I'VE BEEN TOLD THAT I SHOULD WANDER AROUND MAKE THIS MORE DYNAMIC. WE'RE TALKING ABOUT WHAT JOSEPH KINYOUN THOUGHT WHAT BECAME OF THE NIH AND SO LET'S TALK ABOUT THE DANGEROUS WORLD WE LIVE IN. WE HAVE BACTERIA THERE ARE VIRUSES, FUN GUY, PARA SITES ALL OF WHICH THINK WE'RE A GREAT MEAL, A WONDERFUL ENVIRONMENT TO LIVE IN AND WE'RE PROTECT BID THE CELLS AND THE STRUCTURES OF THE IMMUNE SYSTEM. THEY COMPRISE THESE MYELOID DERIVED CELLS THAT ARE IMPORTANT FOR INNATE COMMUNITY -- AND I'LL COME BACK TO WHAT THAT MEANS IN A MOMENT AND THESE LYMPHOCYTES THAT GIVE US THIS -- AND THOSE CELLS ARE GENERATED PRIMARIFULLY THE BONE MARROW AND GO INTO THE SECONDARY [LOW AUDIO] [INDISCERNIBLE] THEY HAVE A PROBLEM. THEY HAVE TO DEFEND US AT THE BRAIN -- [LOW AUDIO] -- LUNGS, LIVER, DIGESTIVE TRACK, ALL SORTS OF DIFFERENT PRAISES WITH SKIN ALL OVER THE SURFACE OF THE BODY. THERE IS A LOCATION ISSUE HERE. SO ONE OF THE PROBLEMS IS THAT EXCEPT DURING A PROCESS LIKE THIS IN WHICH THESE FEW CELLS THAT ARE GOING TO FORM THE IE CLUB ACTUALLY FORM A PARTICULAR STRUCTURE, MOST OF THE CELLS IN THE ADULT BODY ARE RELATIVELY [INDISCERNIBLE] -- THE IMMUNE SYSTEM NEEDS TO BE DYNAMIC. IT HAS TO BE LIKE THESE AIRCRAFT GOING IN TO [INDISCERNIBLE] THEY HAVE TO KNOW WHERE THAT HUB S THEY HAVE TO FLY IN, BE ON TIME, HOPEFULLY, AND LEAVE AND GO TO THEIR OTHER DESTINATIONS. TODAY WHAT WE'RE GOING TO DO IS TAKE THIS FANTASTIC VOYAGE. WE'RE NOT GOING TO DO IT IN A SMALL LITTLE INJECTED VEHICLE THAT GOES AROUND IN YOUR BLOOD STREAM. WE'RE GOING TO TALK ABOUT THE ADVANCES IN MICROSCOPY AND USE A PROCESS CALLED MULTIFOE TOM MULTIPHOTON IMAGING. THERE'S A LITTLE BIT OF SURGERY INVOLVED, WE TAKE A POWERFUL LASER THAT'S PULSED AND GO ACROSS ON THE X/Y DIMENSION, CREATE A PLANE. WE FOCUS UP AND DOWN AND COLLECT THE WHOLE SET OF THESE IMAGES IN A STACK. THAT GIVES US A VOLUME OF INFORMATION, THEN WE REPEAT THAT OVER TIME AND THEN WE CAN PLAY THAT BACK AS IF IT WERE A FLIP BOOK WHERE WE'VE COMPRESSED EVERYTHING DOWN. WE SEE THESE CELLS. THESE ARE NAIVE LYMPHOCYTES LIVING INSIDE A LIVING ANIMAL. I WANT TO POINT OUT WE'RE PLAYING THIS BACK ABOUT THREE HUNDRED TIMES REAL SPEED AND I'M NOT SHOWING YOU EVERYTHING ELSE THAT THOSE CELLS ARE LIVING AMUNGS. WHEN YOU SEE THESE COLORED PICTURES, THERE'S A LOT MORE GOING ON THAN YOU CAN ACTUALLY SEE. WE'RE WALK THROUGH THE DIFFERENT COMPONENTS OF THE -- LET'S START WITH THE SKIN. HERE'S A VECTOR OF THE DISEASE, SAND FLY BITING THE SKIN AND TRANSMITTING ORGANISMS. WHAT HAPPENS ONCE THIS BEGINS TO PROBE AND DAMAGES INTO YOUR SKIN? HERE WE'RE GOING LOOK INSIDE THE SKIN OF A LIVING ANIMAL. GREEN IS THE NEUTROPHILS, THIS AREA HERE IS WHERE THE DAMAGE WAS ACTUALLY CAUSED. THERE'S A BLOOD VESSEL THAT'S RUNNING ALONG OVER HERE. WHEN WE GO AND LOOK AT THIS, WHAT WE SEE IS THAT THESE NEUTROPHILS KNOW EXACTLY WHERE TO GO. THEY LEAVE A BLOOD PRESSURE ONLY APPROPRIATE SIDE WHERE THE DAMAGE IS LOCATED AND THEY RAPIDLY CONJUGATE CONGRESS GRA GAIT IN THIS REGION. GONG CONGRE-- THEY'RE ACTUALLY FILLING THE GAP IN THE HOLE PRODUCED BY THE SAND FLY BITE TO PREVENT OTHER PATHOGENS FROM GETTING ACCESS INTO THE DAMAGED AREA OF THE TISSUES. THE COLUMNS FILLING UP THOSE GAPS AND SEALING OFF THE ENVIRONMENT TO MAINTAIN BARRIER FUNCTION. THIS THEN RAISED AN INTERESTING QUESTION. HOW DO THEY E DO THAT? HOW DO THEY KNOW WHERE TO COME O OUT, WHERE TO GO? WHAT HAPPENS WHEN THEY GET INTO THIS TISSUE AND THE DERMIS WITH THE KCOLLAGEN VESSELS -- [LOW AUDIO]. POST DOC IN THE LAB HAS BEEN STUDYING THIS FOR THE LAST SEVERAL YEARS. HE CREATES VERY PRECISE TISSUE DAMAGE WITH THE LASER. THE NEUTROPHILS WILL BE IN RED HERE. WHEN YOU WATCH WHAT'S HAPPENING, YOU BEGIN TO SEE SEVERAL THINGS. THERE WERE SOME SCOUT CELLS THEN SWARM BEHAVIOR AND THEN AT THE END IT SEEMS TO SORT OF REST. IF WE LOOK OVER HERE, WE'RE ACTUALLY LOOKING AT THE COLLAGEN THAT'S VERY ENRICHED IN YOUR DERMIS AND THAT DISPLACES ALL THE COLLAGEN FIBERS AND CREATES A MATRIX-FREE AREA. THAT'S GOING BECOME VERY IMPORTANT IN UNDERSTANDING HOW THIS WORKS. WE HAVE SCOUTING AND AMPLIFICATION OF [INDISCERNIBLE] WHAT ARE THE SKIGALES? HOW DO THESE CELLS KNOW THERE'S DAMAGE TR TO COME INTO THAT REGION? LET'S LOOK AT THAT AGAIN HERE'S WHAT I JUST SHOWN YOU. GREEN FOR NEUTROPHILS BUT WE'RE ABLE TO ADD A DIE THAT LABELED DNA WHEN IT ES KATES FROM A DYING CELL. WE'RE SEEING A FRACTION OF THOSE NEUTROPHILS UNDERGOING CELL DELL DEATH AND DISLOCATION. THIS IS A NEW WAY OF PRESENTING DIMENSIONS FOUR SETS OF INFORMATION -- [INDISCERNIBLE] DISTANCE FROM THE LESION AS WELL AS LOOKING AT THE PARAMETER OF TIME. WE SEE PRECISELY WHEN THE NEUTROPHILS START DYING THEY BECOME HIGHLY DIRECTIONAL AND VERY RAPID MOVING PRECISELY TO THE SITE OF THE WOUND. SO WE CAN NOW DISSECT THAT IN A MOLECULAR WAY BY TAKING OF THE ADVANTAGE OF THE FACT WE HAVE K TRANSFER NEUTROPHILS THAT ARE NORMAL IN ONE COLOR AND DEFICIENTLY -- LOOK IN THE SAME SITE WITH THE SAME DAMAGE AT THE PROCESS AT HOW THEY BEHAVED. WE'RE TRACKING THOSE CELL, AND IF WE LOOK AT THE WILD TYPE CELLS DAMAGE. WHAT WAS SHOWN IN A LAB [INDISCERNIBLE] AND TIM AND ASSOCIATED FOUND NEUTROPHILS CAN PRODUCE SECRETION -- BY USING AN ANIMAL WHO'S NEUTROPHILS ARE DEFICIENT IN THE RECEPTOR OF LTB 4. THEY'RE NOT REALLY REORIENT AND SUDDENLY GO HERE. THEY EVENTUALLY SORT OF FIND IT, BUT IT'S VERY SLOW AND IF WE LOOK IN THE ACTUAL FORMING SWARM, NOW YOU FIND THAT THE DEFICIENT CELLS WIND UP ON THE PERIPHERY BUT NOT IN THIS CENTER AS COMPARED TO THE WILD TYPE NEUTROPHILS. WHAT'S HAPPENING IN THAT CENTER? THERE'S NO COLLAGEN, NO MATRIX. HOW ARE THE CELLS HANGING OUT? VERY TIGHTLY AGGREGATING UNDER THESE CONDITIONS AND THAT MIGHT SUGGEST SOMETHING CALLED INTEGRANT WHICH IS CELL ADHESION MOLECULES MIGHT BE PLAYING [INDISCERNIBLE] AND THESE ARE QUITE IMPORTANT FOR [INDISCERNIBLE] CELLS TO MIGRATE IN VARIOUS CONDITIONS AND THEY'RE IMPORTANT FOR NEUTROPHILS TO COME OUT OF -- WE CAN ASK SO WHAT DO THESE DO HERE? THE MUTANT INT GRANT LIST CELLS ARE GREEN, WILD TYPE IS RED AND IT'S CLEAR THAT THOSE CELLS WITHOUT THE INT GRANTS ARE EXCLUDED FROM THE CENTRAL SWARM. AS WE SHOW YOU THE COLLAGEN, WHAT YOU SEE IS THAT THEY ARE LIMITED ONLY TO THE AREA WHERE THE COLLAGEN PERSIST BUS THEY DON'T MAKE IT INTO THE CENTRAL AT ALL. THEY CAN MIGRATE PERFECTLY WELL THROUGH THE SPACE, BUT IN CONTRAST TO THE NORMAL MODELS IN WHICH CELL MIGRATION REQUIRES, THESE -- WE CAN DO THIS IN A CARTOON FORM. YOU HAVE WOUNDS PRODUCED THINGS CALLED [INDISCERNIBLE] [LOW AUDIO] NEUTROPHILS COMING ALONG, FEW OF THEM DIE, INDUCE THESE CELLS TO CREATE [LOW AUDIO] SIGNAL RELATE EACH OF THESE CELLS TELLING THE NEXT ONE TO E REORIENT THEM TO GET THAT RAPID SWARMING BEHAVIOR. -- ENABLES ISOLATION OF THE PATHOGEN OR THE RESOLUTION OF THE TISSUE DAMAGE. IF THAT PROCESS WORKS PERFECTLY, YOU'RE GREAT. IT ISN'T USUALLY ABSOLUTELY PERFECT. WHAT KEEPS THOSE ORGANISMS THAT HAVE MADE IT INTO THE SKIN -- THERE ARE TWO TYPES OF VESSELS. BLOOD VESSELS AND LYMPHATIC SYSTEM. IT'S MAINE MAIN PURPOSE IS TO COLLECT FLUID THAT LEEK LEAKS OUT OF YOUR BLOOD VESSELS AND RETURN IT. IF THERE WAS NOTHING IMPEDING THE RETURN OF THE LIMP LYMPH -- WE'VE EVOLVED LYMPH NODES THAT MONITOR. THERE'S A PROBLEM. INNATE IMMUNITY WE THINK ABOUT BEING GENERATED IN THE LYMPH NODE TAKE SEVERAL DAYS TO DEVELOP. WHAT ACTUALLY KEEPS THEM FROM SPREADING IN THE LYMPH WHILE YOU'RE WAITING FOR [LOW AUDIO] TO KICK IN? THIS IS SOMETHING THAT WOLF GANG AND [INDISCERNIBLE] STUDIED IN THE LABORATORY. IF YOU KNOW ABOUT IT I CAN TELL YOU WHAT A LYMPH NODE LOOKS LIKE. IN THIS IS A MOUSE LYMPH NODE. SURROUNDED BY THESE PRIMARY [INDISCERNIBLE] [LOW AUDIO]. HERE ARE THE LIMB CH FA TICKS ARE ARE THE REGION TO WHICH THAT LYMPH DRAINED. THESE ARE A TYPE OF MACROPHAGE [INDISCERNIBLE] CELL AND THEY LINE ALL THE REGIONS THAT THE LIMP [LOW AUDIO] IS DELIVERED TOO INTO. THEY'RE THE FIRST THINGS THAT WILL CONTACT ANYTHING COMING IN BY THAT ROUT. WHAT HAPPENS IF WE GIVE A BACTERIUM THAT CAN GO THROUGH THE LIMB CH. LYMPH. THEY MOVE DOWN THROUGH THE LYMPH IN THIS MANNER AND IN GREEN WHAT YOU SEE IS IN A NORMAL LYMPH NODE IT'S LARGELY CONCENTRATED HERE RIGHT NEAR THESE [INDISCERNIBLE]. WE CAN USE THE LIPOSOME DRUG AND KILL THOSE MACROPHAGES UNDER THOSE CONDITIONS AND ASK WHAT HAPPENED AND NOW WHAT YOU SEE IS THE BACTERIA CAN GO DEEP INTO THE LYMPH NODE. IF WE LOOK IN THE BLOOD YOU SEE A HUNDRED FOLD INOF CIRCULATING BACTERIAL COUNT AND IN THE SPLEEN. THOSE ARE IMPORTANT. THE QUESTION, DO THEY ACT JUST LIKE FLY PAPER? JUST CAPTURING THE PARTICLES AS THEY'RE MOVING THROUGH? REMEMBER THESE ARE PHAGOSITES, TEND TO TAKE PARTICLES IN. TWO HOURS WE SEE THEY'RE BEGINNING TO MAKE OR GAB INFLAMMATORY MEDIATORS -- ORGAN -- NATURAL KILLER CELLS, NATURAL KELLER T CELLS AND SUBSET OF PREVIOUSLY ACTIVATED EDAT CELLS. THAT RESPONSE IS VERY DEPENDENT ON THOSE MACROPHAGES. IF WE LOSE THEM WE LOSE 90% OF THAT RESPONSE. THERE'S A COMMUNICATION BETWEEN THESE. WHERE IS THAT INTERFERON BEING MADE? FEW DOTS IF YOU'RE VERY GOOD AT LOOKING AT IT HERE IT'S EASIER TO SEE OVER HERE THAT THE INTERFERON IS LOCALIZED HERE TO WHERE THESE MACROPHAGES AND VESSELS ARE. WHERE ARE THESE LYMPHOCYTES? THEY COULD BE MOVING AROUND EVERYWHERE AND OCCASIONALLY COMING TO THIS PERIPHERAL SITE AND RESPONDING, BUT PERHAPS A BETTER STRATEGY WOULD BE TO RESIDE ONLY IN THE PERIPHERAL REGION MIGRATING LOCALLY WAITING FOR -- IF UH YOU LOOK AT WHERE THOSE CELL R YOU SEE THE [INDISCERNIBLE] CELLS THE NK CELLS, AND THE GAMMA DELTA CELLS AL LIVE IN THOSE PERIPHERAL SITES AND IN THOSE THEY'RE ACTIVELY MIGRATING AROUND BUT NOT RUNNING THROUGH THE ENTIRE [LOW AUDIO]. THEY HAVE A VERY SELECTIVE REGIONALLIZATION SO THEY'RE PREDISPOSED TO RECEIVE THESE SIGNALS QUICKLY FROM THE SENSORY MACROPHAGES. WE CAN PUT THIS TOGETHER IN A CARTOON. WE CAN HAVE BACTERIA OR VIRUSES COME IN THROUGH THE LYMPH, MULL FLY -- MULTIPLY AND GO OUT. WE HAVE THESE LYMPHOCYTES THAT LIVE IN CLOSE PROXIMITY. ONCE THERE'S MACROPHAGES SENSED, THE PRESENCE OF A PATHOGEN, THEY ACTUALLY ACTIVATE SOMETHING CALLED INFLAMMASOME AND [LOW AUDIO] ACTS BACK ON THE MACROPHAGES TO MAKE THEM MORE ANTIMICROBIAL [LOW AUDIO] AND AT THE SAME TIME ANOTHER PROCYTOKINE IS CONVERTED TO ITS ACTIVE FORM AND THAT CONTRIBUTES TO THE RECRUITMENT OF NEW RA FILLS WHICH [INDISCERNIBLE] SO YOU HAVE A WHOLISTIC TYPE OF DEUNDER THESE CONDITIONS. LIKE CASTLES, ROAD COMES IN, INVADERS COMING, INITIAL SITING TROOPS UP ON THE WALLS, LIGHTING FIRES TO SIGNAL SOLDIERS RECRUITED AND THE IDEA IS TO KEEP EVERYTHING FROM GETTING TO THE CASTLE OR TO THE TOWN. SO I WANT TO MOVE NOW FROM THE INNATE RESPONSE TO LOOKING AT THE LYMPH NODE SITE OF [LOW AUDIO] AND GIVE YOU BACKGROUND. WE HAVE THIS NAIVE NON-ACTIVATED SITES THAT INTO ENTER THROUGH THESE SPECIALIZED CELLS --. IN THE T CELL ZONE THERE'S ANOTHER POPULATION AND THEY SPECIAL FLIEZ PRESENTING LITTLE PIECES OF PATHOGENS AS PEPTIDES ASSOCIATED WITH PROTEIN MOLECULES TO -- THERE ARE VERY RARE LYMPHOCYTES IN THE TOTAL POOL THAT ARE SPECIFIC TO SAY A PIECE OF MUMPS OR FLU AND THERE ARE A FEW OF THESE DENDRITIC CELLS THAT MANAGE THE CAPTURE THAT INFORMATION AND DISPLAY IT. YOU HAVE THIS PROCESS, IF SUCCESSFUL CAN AK VAT T CELLS THAT CAN UNDER GO PROLIFERATION AND THEN THOSE CELLS CAN MOVE BACK INTO THE TISSUE WHERE IS THEY MOVE AROUND LIKE THOSE NEW NEW TROE FAJS I TOLD YOU. LET'S CONCENTRATE ON WHAT GOES ON IN THAT LYMPH NODE. THIS T CELL IS NOT JUST AN EMPTY SPACE, THE IT'S COMPOSED AND SUPPORTED BY THE VERY ELABORATE FIBROBLASTIC STRUCTURE. IF THEY'RE MOVING AROUND THEY HAVE TO AT LEAST BUMP INTO THESE STRUCTURES AS THEY'RE DOING THAT. IF WE CAPTURE AN IMAGE [LOW AUDIO] [* MUSIC PLAYING ] IF WE LOOK AT A STATIC IMAGE, WE CAN FIND OCCASIONALLY LYMPHOCYTES THAT ARE HIGHLY POLARIZED ALONG THESE FIBERS. IS THIS ACTUALLY A WAY OF OPTIMIZING RESPONSE? [* MUSIC PLAYING ] WE LOOK WHERE WE VISUALIZE THOSE FIBERS AND WHAT WE SEE IF THEY'RE GOING ALONG THE FIBER TRACK. WHY IS THAT INTERESTING? WE SAID THEY'RE LOOKING FOR DENDRITIC CELLS AND IF YOU LOOK AT WHERE THEY LIVE, THEY LIVE ON THE SAME FIBERS. SO WE'VE CREATED THIS CONCENTRATED ENVIRONMENT THAT LOOKS AT THE LYMPHOCYTES MOVING ON THE SAME PATH THAT BRING THEM TO THE CELL THAT THEY NEED TO INTERACT WITH IN ORDER TO GENERATE USEFUL ADAPTIVE IMMUNORESPONSE. WHEN THE CELLS ARE MOVING ON THE FIBERS THEY NEED TO MAKE A DECISION WHEN THEY COME TO AN INTERSECTION AND NORMALLY IT LOOKS LIKE THEY'RE MAKING A RANDOM CHOICE. WHAT WE DISCOVERED THAT S THAT ACTIVATED DENDRITIC CELLS ENGAGED WITH OTHER T CELL MAKE THESE [INDISCERNIBLE], DECORATE THE FIBERS AN THESE CELLS ACQUIRE THE RIGHT RECEPTORS IN THAT INFLAMED LYMPH NODE TO FOLLOW THIS TRAIL AND SO THEY TURN AND SPEED UP HITTING THESE CELLS MORE FREQUENTLY. THAT TURNS OUT TO MAKE ALL THE DIFFERENCE IN THE WORLD. THE TWO TYPES OF LYMPHOCYTES -- THIS SEARCH PAT CERTAIN CRITICAL. WE CAN P PUT THIS TOGETHER WHERE WE CONCENTRATED CELLS OF INTEREST AND ANTIGEN IN THE LYMPH NODE BUT THERE'S THIS FRC NETWORK THAT THESE MOVE ON AND THEY FIND THEIR CELLS OF INTEREST THERE AND THEY BIAS THEIR [INDISCERNIBLE] [LOW AUDIO]. IT'S NOT LIKE A PINBALL MACHINE. THIS IS A VERY ORGANIZED STRUCTURE WHERE THERE ARE BOTH STRUCTURAL FEATURES AND CHEMICAL GUIDES THAT OPTIMIZE THESE [INDISCERNIBLE] TO GIVE YOU [LOW AUDIO]. THIS IS GOING TO APPLY NOT ONLY IN THE LYMPH NODE BUT ALSO LOOKING AT SIMPLING OF THE MICRO FLOOR BY DENDRITIC CELLS LOOKING AT THE KIDNEY AND GRAPH RESECTION OR [INDISCERNIBLE] WE CAN LOOK AT N THE SPLEEN. WE'VE LOOKED IN INFECTED LIVERS TO DISCOVER THAT THERE'S VERY LITTLE EFFECTIVE ANTIGEN LIMITATION. WE CAN LOOK IN THE LUNG AND FLU. I'VE SHOWN YOU THIS IMAGE FROM THE EAR SKIN AND T CELLS IN THE SKIN AND STUDIES TO LOOK AT CELLS THAT CAUSE [INDISCERNIBLE] IN THE BONE MARROW. I WANT TO TAKE THE LAST MINUTE OR SO TO LOOK INTO THE FUTURE. WHAT ELSE CAN WE SEE AND AS JENNIFER POINTED OUT MORE COLORS IS GOOD. WE'RE NEXT INTERESTED IN NEXT LEVEL OF MORE CELLS AND MOLECULES. THE IMAGING WE'VE DONE IN THE LYMPH NODE IS RESTRICTED AND WE'D LIKE TO LOOK AT MUCH LARGER AREAS. THAT'S VERY DIFFICULT TO DO BEFORE YOU REALLY UNDERSTAND WHAT CELLS YOU'RE LOOKING AT. MIKE UNTIL THE LABORATORY THE LAST FEW YEARS BUILDING ON WORK NINA HAD DONE PREVIOUSLY DEVELOPED THIS WHOLE PIPELINE THAT I ZONT TIME TO GO THROUGH IN DETAIL TODAY BUT INVOLVED STAINING WITH EIGHT OR NINE DIFFERENT COLORS, IMPROVING RESOLUTION IN A WAY RELATED TO WHAT JENNIFER TALKED ABOUT, SEPARATING ALL THE COLORS, CREATING GATES, AND THEN TURNING THAT INTO A QUANTITATIVE BIBUT SPECIALLY RESOLVED ANALYSIS OF ALL THE INDIVIDUAL CELLS. IF YOU USE SEVEN COLORS AND PUT THEM ALL TOGETHER IT DOESN'T LOOK LIKE BUT QUESTION BEGIN TO SELECT THESE COLORS BY EXCLUDING THESE OVERLAPPING CELL TYPES MARKED BY THESE OTHER MARKERS. WE CAN ADD ADDITIONAL PARAMETERS TO LOOK AT INDIVIDUAL DENDRITIC CELL TYPES AND WHAT MICHAEL HAS DONE IS MAP OUT THE LOCATION ALL THE DIFFERENT DENDRITIC CELL LOCATIONS AND THEN NOT RANDOMLY DISTRIBUTED BUT THEY HAVE THEIR OWN ZONES OF INTEREST AND THAT HAS A MAJOR ROLE TO PLAY IN FUNCTION, BUT HERE'S ONE OF THOSE POPULATIONS THAT HE SAW WAS VERY CLOSE TO THE LYMPHATIC VESSELS AND THEY ACTUALLY REACH INTO THOSE VESSELS WITH THE DENDRITES AND BACTERIUM COMES ALONG THEY'LL GRAB IT, SARM IT, BRING IT INTO THE CELL BODY AND ACTIVATE THE APPROPRIATE T CELL TO RESPOND TO THAT INCOMING ORGAN. WE CAN LOOK AT SIGNALING NOW, FOR EXAMPLE, CALCIUM FLUX [INDISCERNIBLE] DENDRITIC CELL. WE LIKE TO LOOK NOT JUST AT CELL, CELL INTERACTION BUT ALSO SOLUBLE SIGNALING. WE'RE BEGINNING TO USE RELOCALIZATION TO LOOK AT STATS PET BETTER TRIGGERED BY CYTOSCIENCE CYTOKINE. WE CAN TRACK THE LIVING CELLS IN A LIVING ANIMAL THAT COME OUT OF THIS AND GO ON TO FIBER NETWORKS AND IN THE END WE WANT TO COMBINE THESE WITH MOLECULAR STUDY THAT ARE BEGINNING TO BE ABLE TO DO AND THEN JENNIFER POINTED OUT GO ON TO MODELS -- WORK BY MARK [INDISCERNIBLE] -- THAT HAVE THE ABILITY TO ACTUALLY MOVE LIKE REAL CELLS BUT NOT BECAUSE YOU MADE THE CARTOON DO IT BECAUSE THE THESE SIGNAL PATHWAYS GUIDING HOW THEY BEHAVE IN VIVO. WE GET TO WHAT WE CALL PREDICTIVE IMMUNOLOGY. THANK YOU VERY MUCH. [APPLAUSE] >> MY NAME IS MICHAEL GODSMAN AND AT THIS MOMENT I'M PROUD DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH. AFTER THOSE PRESENTATIONS, YOU WOULD APPRECIATE THAT IT'S EVEN MORE AMAZING THAT WE CHOSE THEM RANDOMLY FROM OVER A THOUSAND PIs AT THE NIH. SO THIS IS JUST A TYPICAL KIND OF ACTIVITY THAT WE CARRY ON IN THE INTRAMURAL PROGRAM. NOW IT IS MY GREAT PLEASURE -- WHAT YOU'VE ALL BEEN WAITING FOR -- TO INTRODUCE OUR NEXT SPEAKER, DR. JOSEPH JAMES KINYOUN. THE FOUNDER AND FIRST DIRECTOR OF THE MARINE HOSPITAL SERVICES LABORATORY OF HYGIENE. DR. KINYOUN RECEIVED HIS PRIMARY MEDICAL EDUCATION AT THE SAINT LIEU WE COLLEGE OF PHYSICIANS AND SURGEONS AND SUBS KWEBTLY GRADUATED FROM BELL VIEW HOSPITAL MEDICAL COLLEGE IN NEW YORK IN 1882. HE CONDUCTED POST DOCTORAL STUDIES IN PATHOLOGY AND BACK TIER YOKE AT THE CARNEGIE LABORATORY IN NEW YORK AND LATER IN EUROPE IN PART UNDER GERMAN SCIENTIST ROCKER CLOCK. HE WAS AWARDED Ph.D. FROM GEORGETOWN UNIVERSITY IN 1896. AS DIRECTOR OF THE LA LABORATORY OF HYGIENE AND FOR ITS INITIAL YEAR'S ONLY EMPLOYEE, DR. KINYOUN SUPPORTED QUARANTINE ACTIVITIES AGAINST FOUR EPIDEMIC DISEASES; CHOLERA, YELLOW FEVER, SMALLPOX AND PLAGUE. WITH HIS TIRELESS CAMPAIGN TO ALLEVIATE HUMAN SUFFERING FROM IBFECTION DISEASE, HE USED METICULOUS SCIENTIFIC APPROACH TO IDENTIFY AND ISOLATE CONTAGION AND DR. KINYOUN TODAY IS CONSIDERED TO BE AMONG THE FATHERS OF MODERN U.S. BACK TIER YOKE. DR. KINYOUN DIED IN 1919 AT AGE 58 FROM COMPLICATIONS OF LYMPHO SARCOMA. EARLIER THIS YEAR, HOWEVER, DR. KINYOUN E-MAILED ME FROM BEYOND THE GRAVE -- PRETTY AMAZING CONSIDERING THE NIH SECURITY EFFORT. [LAUGHTER] FORTUNATELY, HIS MESSAGE REACHED ME. DR. KINYOUN EXPLAINED TO ME THAT THERE ARE THREE THINGS THAT CONTINUE TO BOTHER HIM. HENCE THE TITLE OF HIS TALK TODAY IS UNEASY DEATH; THREE THINGS THAT HAUNT ME 93 YEARS AFTER MY DEATH. PLEASE WELCOME DR. KINYOUN TO THE STAGE. [LAUGHTER] [APPLAUSE] >> LADIES AND GENTLEMEN, THANK YOU VERY MUCH [LOW AUDIO] -- PODIUM THERE IT AMPLIFIES YOUR VOICE THROUGH THE AUDITORIUM. >> FASCINATING, AMAZING. YOU KNOW, I SAW A COMPACT DEVICE LIKE THIS ONCE IN BERLIN BUT WHO WOULD HAVE TAUGHT BETHESDA WOULD HAVE ONE LIKE THIS. THANK YOU SO MUCH FOR THIS OPPORTUNITY TO SPEAK AND THANK YOU, DR. [INDISCERNIBLE] FOR THAT KIND AND SUS TIJTS INTRODUCTION. I DIED IN 1919, BUT I HAVE BEEN RESTING UNEASY WITH THREE BURDENS. I MADE SOME NOTES SO THAT I DON'T FORGET WHAT I HAVE TO SAY. MY BRAIN AT 151 ISN'T QUITE WHAT IT IS WITH SOME OF YOU YOUNG WHIPPER SNAPPERS, BUT TO THE POINT, I HAVE THREE CONCERNS THAT I HOPE TO RELAY TO YOU THIS MORNING AND I BESEECH THEE TO TAKE MY CONCERNS TO YOUR HEART AND MOVE FOR THE PACE OF SCIENTIFIC DISCOVERY. MY FIRST CONCERN IS DIPHTHERIA, THE DISEASE THAT TOOK MY YOUNG DAUGHTER, BETTY, AT AGE THREE, AS WELL AS A HOST OF OTHER CHILDHOOD DISEASES WHO'S IDEOLOGYIN IDEOLOGYINGS ARE COMMUNICATED BY VIRUSES. BEFORE MY DEATH, I WITNESSED SOME INTERESTING IMMUNOTHERAPY AND ALSO A VACCINE AGAINST DIPHTHERIA. HOWEVER, EVEN TODAY WE HAVE NO SATISFACTORY TREATMENT FOR THOSE CHILDREN WHO ARE NOT IMMUNIZED. NO TREATMENT IN THIS DAY AND AGE? AND THEN THERE'S SMALLPOX, SCAR LET FEVER, TYPHUS, TYPHOID FEVER, TUBERCULOSIS. WE MUST FIND A WAY TO END THESE SCOURGES THAT HAVE PLAGUED MANKIND SINCE TIME AND MEMORIAL. GIVEN THE TOOLS OF THEIR IDEOLOGY, WE MUST NOT FOCUS ON MERELY QUARANTINE THESE CHILDREN BUT FINDING MEDICINES TO BREAK THE PSYCH OL OF THEIR TRANSITION. >> EXCUSE ME, I DON'T MEAN TO INTERRUPT. >> ONCE YOU TOLD ME I HAD FIVE MINUTES AND I JUST STARTED. YOU LET RON GERMAIN GO ON FOR 20 MINUTES. >> IT'S JUST THAT WE HAVE E ERADICATE SMALLPOX, GREATLY REDUCED THE TRANSMISSION OF THOSE OTHER DISEASES YOU MENTIONED. WORK MUST CONTINUE BEFORE IT REACHES THE WORLD, BUT NEVERTHELESS THIS IS PART OF YOUR LEGACY. >> REALLY? SMALLPOX HAS BEEN ERADICATED? >> THERE ISN'T BEEN A NATURALLY OCCURRING CASE OF SMALLPOX IN NEARLY 40 YEARS. THE VIRUS IS NEARLY EXTENT. TUBERCULOSIS IS HAVING A RESUR GENT SO WE DO REMAIN DILIGENT TO BOTH OLD AND NEW THREATS. AGAIN, THIS IS PART OF YOUR LEGACY. >> WELL THEN I AM TRULY HUMBLED WITH GREAT RELIEF I CAN PUT TO REST ONE OF THESE BURDENS. ALLOW ME THEN IF TIME PERMITS TO PROCEED TO MY NEXT CONCERN WHICH IS ORGAN TRANSPLANTS FROM DECEASED DONORS. SOME PEOPLE THOUGHT I WAS DOCTOR FRANK INSTIEN WHEN I PROSED THIS. I EXPLAINED TO THEM HOW THE ETHICAL CONCERNS COULD BE TAKEN CARE OF IF ONE OBTAINED PERMISSION FROM THE DONOR IN ADVANCE. AS FOR THE TECHNOLOGIES THAT WOULD BE NEEDED TO DO THIS, I DIDN'T HAVE ANY IDEAS, BUT I POSTULATED THAT FUTURE ADVANCES IN THE SURGICAL SCIENCES WOULD ALLOW FOR THE TRANSFER OF ORGANS TO EXTEND LIVES, PARTICULARLY THE LIVES OF INNOCENT CHILDREN BORN WITH DEFORMED AND FAILING ORGANISMS. I CANNOT REST COMFORTABLY UNTIL I KNOW THAT YOU SERIOUS MEN AND WOMEN OF SCIENCE TAKE SERIOUSLY MY IDEA. >> THIS TOO HAS BEEN ACCOMPLISHED. IN THIS REGARD YOU WERE A VISIONARY. TODAY WE CAN TRANSPLANT THE HEART, HEART VALVES, KIDNEY, LIVER, LUNG, PANCREAS, TES TIN, SKIN, AND VAIN. I PROBABLY MISSING A FEW TOO. ANYWAY, YOU ARE AMONG THE FIRST SCIENTIST TO FULLY APPRECIATE INTIMA INTIMATE RELATIONSHIP BETWEEN MICROBIOLOGY AND IMMU BOLG. THAT IN THIS VERY BUILDING NIH SCIENTISTS WERE AMONG THE FIRST TO DEVELOP IMMUNOSUPPRESSANT DRUGS THAT WOULD ALLOW UH THE HOST BODY -- NOT FAR FROM WHERE YOU STAND MORE THAN 45 YEARS AGO ARK YOUNG BOY RECEIVED TWO ARTIFICIAL HEART VALVES THAT REQUIRED NO IMMUNE SUPPRESSION. WE PIONEERED SEVERAL TECHNIQUE AND THE FEDERAL GOVERNMENT HAS ENABLED A NATIONAL PROGRAM OF ORGAN DONORS. >> ONCE AGAIN, I AM TRULY HUMBLED. NOW I CAN LAY TO REST TWO CONCERNS WHICH HAVE BEEN HEAVY ON MY HEART. I CEASE MY BLABBERING UP HERE EXCEPT FOR MY ONE LAST CONCERN AND THAT WOULD BE A SIGNIFICANT FEDERAL INVESTMENT IN A RESEARCH INSTITUTE THAT WOULD RIVAL THE FAMOUS INSTITUTIONS IN EUROPE PIP CALL FAR LABORATORY-SUPPORTED NATIONAL RESEARCH ENTERPRISE TO DELVE INTO THE NATURE, ORIGIN, A AND PREVENTION OF CONTAGIOUS EPIDEMICS AND OTHER HUMAN DISEASES. THIS ENTERPRISE SHOULD ALSO MAKE INQUIRIES INTO MATTERS RELATING TO PUBLIC HEALTH. WHILE MY NAME HAS BEEN FORGOTTEN BY MY SCIENTIFIC PEERS, I DON'T WANT THE SAME FATE FOR THE HYGIENIC LAB WHICH I HELPED ESTABLISH. >> DR. KINYOUN, WE HAVE THE FRUIT OF YOUR LABOR. YOUR LABORATORY OF HYGIENE AS YOU KNOW BECAME THE HYGIENIC LABORATORY IN 1891. 1930 CONGRESS RENAMED YOUR LABORATORY NATIONAL INSTITUTE OF HEALTH. TODAY THE NATIONAL INSTITUTES OF HEALTH IS THE WORLD'S PREMIER BIOMEDICAL RESEARCH ORGANIZATION CONTAINING NOT JUST YOUR CORE LAB NOW CALLED THE NATIONAL OF ALLERGY AND INFECTION DISEASES, BUT ALSO 26 OTHER INSTITUTES AND CENTERS THAT CARRY OUT YOUR VISION OF WORKING GLOBALLY WITH THE BEST SCIENTISTS OF THE NATION AND WORLD TO VIRTUALLY ALL HUMAN DISEASES. AND YOU ARE NOT FORGOTTEN. AT THIS YEAR'S WEEK-LONG NIH RESEARCH FESTIVAL, WE CELEBRATE 125th ANNIVERSARY OF THE FOUNDING OF THE LABORATORY OF HYGIENE, 1887. I SHOULD ADD THAT AN OIL PORT TRAIT OF YOU HANGS IN THE MAIN BUILDING, BUILDING 1, AND OH YES, YOU CAN DOWNLOAD A BOOKLET ABOUT YOUR LEG SI WRITTEN BY DOCTORS. -- FROM THE FESTIVAL WEB SITE. >> THANK YOU DOCTOR AND THANK YOU GOOD SIN ZENS OF THE NATIONAL INSTITUTE OS OF HALE. YOU'VE MADE THIS 151 YEAR OLD MAN EXTREMELY HAPPY AND NOW I CAN REST EASILY KNOWING THAT MY WORK TO ALLEVIATE HUMAN SUFFERING IS BEING CONTINUED IN EARNEST BY YOU INTELLIGENT MEN AND WOMEN OF SCIENCE. THANK YOU. >> NO. THANK YOU. [APPLAUSE] >> AND THANK YOU TO OUR REENVISIONING OF DR. KINYOUN, DR. DAVID ROBIN' SON SCIENTIFIC DIRECTOR OF NIDCD AND THANKS TO CHRIS WHO BROUGHT TO LIFE, REANIMATED, DR. KINYOUN. THANK YOU VERY MUCH. [APPLAUSE] OKAY, SO WE'RE RUNNING A LITTLE BIT LATE AN I THINK THE LAST SESSION WILL BE A LITTLE SHORTER THAN WE HAD INTENDED BUT THAT'LL GIVE US AN OPPORTUNITY TO GET OVER TO NATCHER FOR ANDREW HARRIS' PRESENTATION. SO WHAT I'D LIKE TO DO IS REMIND YOU THAT THERE'S A LOT MORE TO COME AT THE NIH AFTER THIS MORNING. WE'RE KIND OF FOCUSING ON HISTORY THIS MORNING AND IN A FEW MINUTES I'LL HAVE A CONVERSATION CHARLIE ROSE WITH THREE VERY DISTINGUISHED SCIENTISTS BUT THERE'S A LOT MORE GOING ON IN THE RESEARCH FESTIVAL, LOT OF MEN NAR TALKS, LOTS OF POSTERS, AND I PARTICULARLY WANT TO INVITE THE GRADUATE STUDENTS WHO ARE HERE TO PARTICIPATE IN OUR ACTIVITIES. THEY, THEMSELVES WILL G GIVING POSTERS AND WE WILL GREET THEM ENTHUSIASTICALLY AND GET TO KNOW THEM BETTER. SOME OF THEM MAY BE INTERESTED IN BECOMING POST DOCS AT THE NIH IN ONE OF THESE WONDERFUL LABBING THAT THEY'LL BE HEARING ABOUT. I HAVE THREE PEOPLE WHO WILL JOIN ME ON THE STAGE. DR. STEPHEN KATZ WELL KNOWN AS THE DIRECTOR OF NIAMS. HE CAME TO THE NIH IN 74 AS A SENIOR INVESTIGATOR IN DERMATOLOGY BRANCH BECOMING CHIEF IN 1977 AND -- I'M SORRY, ACTING CHIEF IN '77 AND CHIEF IN 1980. STEVE STUDIES LANGER HAND CELLS, CYTOKINES AND HAS REALLY DONE MORE THAN ANYONE ELSE PROBABLY TO POINT OUT HOW IMPORTANT THE SKIN IS AS AN IMMUNE MEDIATING ORGAN. OUR SECOND -- STEVE, WHY DON'T YOU SIT DOWN? OUR SECOND PARTICIPANT IN THIS DISCUSSION IS DR. BILL PAUL. WILLIAM PAUL HAS BEEN CHIEF OF NIAID'S LABORATORY FOR 41 YEARS. HE JOINED NIADI IN 1968. BILL AND HIS COLLEAGUES P PERFORMED KEY EXPERIMENTS THAT LED TO DISCOVERY AND CHARACTERIZATION OF SELF-SIGNALING MOLECULE INTRALIEU KIN FORM, DEMONSTRATED IL 4 IS CRITICAL FOR B CELL. AS LAB CHIEF BILL HAS TRAINED AND MENTORED MORE THAN 80 POST DOCTORAL FELLOWS. ONE OF HIS TRAINEES YOU HEARD FROM TODAY, RON GERMAIN. FROM 94-97 HE SERVED AS DIRECTOR OF NIH OFFICE OF AIDS RESEARCH WHERE HE INVIGORATED HIV VACCINE RESEARCH AND PLAYED A KEY ROLE IN CREATION OF NIAID RESEARCH CENTER. FINALLY JUDY RAPAPORT CHIEF OF PSYCHIATRY BRANCH IN NIMH. EARLY DIAGNOSIS, CHILDHOOD HYPERACTIVITY, OBSESSIVE COMPULSIVE DISORDER AND HAD A BEST-SELLING BOOK CALLED THE BOY WHO COULDN'T STOP WASHING HIS HANDS. I REMEMBER HER ON THE BOOK LECTURE CIRCUIT A FEW YEARS BACK TALK ABOUT THAT. THROW IMAGING JUDY AND HER COLLEAGUES WERE FIRST TO OBSERVE CHANGES IN CHILDREN'S BRAIN RELATED TO MENTAL DISORDERS PROVIDING NEW UNDERSTANDING AND NEW PATHWAYS FOR TREATMENT. ALL OF THESE THREE RESEARCHERS WHO AGAIN REPRESENT SOME OF THE SENIOR MEMBERS OF THE NIH AND ARE A REAL TREASURE NOT ONLY IN TERMS OF THAT THEY HAVE DONE AND CONTINUE DO BUT ALSO BECAUSE THEY GIVES INSIGHTS INTO MAYBE WAYS IN WHICH THE NIH CAN MOVE FORWARD. SO, WHAT I THOUGHT I WOULD DO TO START AND THIS WILL BE AN INFORMAL DISCUSSION AND IT IS NOT SCRIPTED AS DR. KINYOUN'S WAS, IS ASK EACH OF THEM TO TALK FOR A FEW MINUTES ABOUT HOW THEY CAME TO NIH AND WHAT HAS KEPT THEM NIH. BEGINNING WITH BILL PAUL. >> THANK YOU, MICHAEL. FIRSTLY I SHOULD SAY SEEING THAT THE GOOD FORTUNE OF THIS AUDIENCE OR NIH SCIENTISTS THAT I'M PROBABLY PREACHING TO THE CHOIR ABOUT THE WONDERFUL ASPECTS OF THIS FAST FANTASTIC INSTITUTION. FIRST CAME HERE AS A MEDICAL STUDENT. I WOULDN'T WISH TO SAY WHEN BUT I GUESS I'M FORCED TO, IN THE SUMMER OF 1959 DURING MY THIRD YEAR AS A SUMMER OF MY THIRD YEAR WHERE I WORKED IN THE WHAT WAS THEN THE NATIONAL INSTITUTE OF NEW LOGICAL DISEASES AND STROKE, I THINK IT WAS THEN CALLED. I WENT BACK FINISHED MEDICAL SCHOOL, DID AN INTERNSHIP IN RESIDENCY, CAME AS A CLINICAL ASSOCIATE IN THE NATIONAL CANCER INSTITUTE WHERE I HAD THE WONDERFUL OPPORTUNITY TO WORK IN THE RESEARCH BRANCH THAT WAS THE FIRST TO DEVELOP CHEMO THERAPEUTIC CURES FOR METASTATIC DISEASE. MOST PEOPLE DON'T REALIZE THAT THAT FIRST OCCURS AT NIH UNDER ROY HURTS WITH THE TREATMENT OF CARCINOMA. EVERY WOMAN IN THE UNITED STATES VIRTUALLY HAD THIS DISEASE WHICH WAS LARGELY FATAL, CAME TO NIH, MOST OF THEM WITH METASTASES IN THE LUNG THE SIZE OF GRAPEFRUITS AND 77 OF THESE WOMEN WENT HOME CURED AND I DON'T MEAN IN REMISSION, I MEAN CURED. WONDERFUL ACCOMPLISHMENT. AT THE SAME TIME MY COLLEAGUES IN THE MEDICINE BRANCH WERE WORKING DILIGENTLY AND EVENTUALLY EFFECTIVELY TO THE CURE TO DEVELOPMENT OF CURATIVE TREATMENTS FOR LEUKEMIAS, [INDISCERNIBLE] DOING ABSOLUTELY PIONEERING WORK. NIH DOESN'T TAKE ENOUGH CREDIT TO THESE REMARKABLE DISCOVERIES. THEN LEFT AGAIN AND RETURNED IN 1968 AT THE INFECTION DISEASES WITH [INDISCERNIBLE]. HE LEFT TO GO TO HARVARD AND BY GOOD FORTUNE I INHERITED HIS JOB JULY #st 1970. TO 42 YEARS LATER I'M SITTING IN THE SAME PLACE. I DON'T WANT TO GO ON EXCEPT TO SAY WHY DO I STAY. 1st. MANY TIMES IN THE COURSE OF THE YEARS, I LIKE VIRTUALLY EVERYONE IN THIS AUDIENCE HAS BEEN OFFERED A JOB HERE AND I USED TO GO TO THESE PLACES, LOOK REALLY HARD AND COME BACK AND SAY, YOU KNOW, FI REALLY WORK HARD IN FIVE YEARS I MIGHT APPROACH WHAT I HAVE TODAY, WONDERFUL SET OF COLLEAGUES, TERRIFIC OPPORTUNITIES TO DO RESEARCH IN AN ENVIRONMENT WHERE I MUST SAY THE OVERWHELMING CONCEPT IS KWOP RATIVITY. SOME OF THE GREAT INSTITUTIONS IN THIS COUNTRY UNFORTUNATELY DON'T FEATURE THAT WITH LOTS OF, LET'S SAY, INTERACTIONS OF NOT THE MOST PLEASANT NATURE AMONGST COLLEAGUES. MY EXPERIENCE AT NIH HAS BEEN ONE INVARIABLIBLY IN WHICH I CAN COUNT ON MY COLLEAGUES TO WANT MY WORK TO SUCCEED AND DO EVERYTHING THEY CAN DO TO HELP IT AND I MUST SAY I FEEL THE SAME WAY. WITH A VERY SMALL STATEMENT I'M HONORED TO HAVE HAD THE OPPORTUNITY TO WORK IN THIS FANTASTIC INSTITUTION WITH LEADERSHIP LIKE MICHAEL'S AND HIS PREDECESSORS AND MICHAEL IS A OF A VERY DISTINGUISHED LINEAGE OF INDIVIDUALS HOLDING THIS POSITIONS. LET ME SAY THIS IS A FANTASTIC PLACE TO BE. I PROBABLY USED UP MORE OF MY TIME THAN I OUGHT THE TO HAVE. >> I'M SUPPOSED TO BE CHANNELLING CHARLIE ROSE. IN ORDER TO DO THAT -- I DISCOVERED THAT HE'S A FEW YEARS OLDER THAN I AM, ABOUT A FOOT TALLER THAN I AM, ALWAYS SITTING DOWN, AND BUT HE STARTED HIS SHOW ON PBS SAME YEAR THAT I STARTED BEING DEPUTY DIRECTOR OF INTRAMURAL RESEARCH. WE BOTH SHOULD BE EQUALLY INDEPARTMENT AT OUR JOBS [LOW AUDIO]. ADEPT. YOU MENTIONED THE FACT THAT IT'S SO EASY TO COLLABORATE WITH PEOPLE [LOW AUDIO]. DO YOU HAVE ANY SENSE OF WHY THAT IS? WHY IT'S DIFFERENT THAN MIGHT BE AT THE UNIVERSITY SETTING? >> WELL, FIRSTLY I DON'T THINK WE LIVE IN THE ZERO SUM GAME. WE ALL FEEL A SENSE, I THINK, OF NON-COMPETITIVENESS OF THAT THOUGHT. THE OTHER THING IS WHEN I CAME HERE, IMMUNOLOGY WAS STILL A MODEST DISCIPLINE AT NIH WHICH MIGHT SURPRISE MANY OF YOU CONSIDERING THE FACT THAT IMMUNOLOGY INTEREST GROUP IS THE LARGEST INTEREST GROUP AND THERE ARE A GROUP OF US WHO WERE STARTING OUR CAREERS AND WE SORT OF GREW UP TOGETHER. THERE WAS NOT THIS FEELING OF DOMINANT [INDISCERNIBLE] WHO WOULD DETERMINE WHAT HAPPENED AND IF YOU DIDN'T FALL IN LINE WITH HIS VISION YOU WEREN'T ANYWHERE. IT WAS A VERY DIE NAH IDEA WITH PEOPLE INTERACTING WITH ONE ANOTHER AND CHEEDING EXCEEDINGLY POSITIVE WAY. I SUSPECT THAT CHARACTERIZES MOST OF THE DISCIPLINES HERE. >> SO JUDY, TELL US A LITTLE BIT OF HOW YOU GOT HERE AND WHY YOU'RE STILL HERE. >> [LOW AUDIO] I ENDED UP IN WASHINGTON BECAUSE MY HUSBAND WAS ABLE TO JOIN THE PUBLIC HEALTH SERVICE AND THEREFORE THE DRAFT INDIVIDUALLY AND ACTUALLY HAD A GREAT DEAL TO DO WITH SOME PERIOD OF THE SUCCESS OF INTRAMURAL PROGRAM, BUT I PERSONALLY CAME HERE BECAUSE I HAD AN EXTRAMURAL GRANT AT GEORGETOWN COLLABORATING WITH INTRAMURAL INVESTIGATORS AND AFTER A FAU YEARS OF BRINGING SAMPLES BACK AND FORTH IT JUST SEEMED SILLY WHEN A POSITION AROSE I WAS DELIGHTED TO COME AND BE ONE OF THE FIRST TO START CHILD PSYCHIATRY RESEARCH. FOR MOST OF THE YEARS I'VE WORKED HERE I STILL PINCH MYSELF COMING TO WORK AND SAYING THEY'RE PAYING KNOW DO WHAT? WHAT WHICH IS REALLY TO READ AND WRITE AND STUDY WHAT I THINK IS IMPORTANT. PEOPLE I KNOW RETIRE [LOW AUDIO] AND THIS HAS ACTUALLY BEEN THE SAME JOB. I THINK THE THINGS THAT WERE MOST HELPFUL TO ME WHEN I FIRST CAME HERE WAS THE FLEXIBILITY AND VISION FOR EXAMPLE OF AN INSTITUTIONAL IRB THAT LET ME BE THE ONLY PERSON [LOW AUDIO] JUST ONE DOSE TO HEALTHY CHILDREN, THEREBY SHOWING THE MYTH THAT IF A CHILD CALMS DOWN ON STIMULUS -- WHICH IS WHAT PEDIATRICIANS WERE TELLING THEIR PATIENTS ANY TIME THAT THEY BENEFITTED, WE WERE ABLE TO SHOW HERE THAT IT WAS A NON-SPECIFIC EFFECT WITH RESPECT TO DIAGNOSIS AND EVEN OF AGE [LOW AUDIO]. [LOW AUDIO] -- IS THE ABILITY TO STUDY RARE DISORDERS. WE'RE CURRENTLY STUDYING CHILDHOOD SCHIZOPHRENIKITS FRIN SCHIZOPHRENIA. [LOW AUDIO]. WE'RE ABLE TO SHOW MUCH MORE STRIKING GENETIC IDEA IE DELOGIC FACTORS [LOW AUDIO]. WE STARTED OUT THINKING THAT OBSESSIVE COMPULSIVE DISORDER WAS RARE AND THEN LUCKILY WE WERE ON NOT CHARLIE ROSE 20 SLR 20 AND THE PHONES WERE JAMMED FOR SEVERAL DAYS BECAUSE PEOPLE WERE IN FACT FORTUNATELY HIDING AND NOT COMING FOR TREATMENT BECAUSE UNTIL TREATMENTS DEVELOPED THEY DIDN'T HAVE EFFECTIVE TREATMENTS IT TURNS OUT [LOW AUDIO]. THE FLEXIBILITY OF THIS PLACE WAS REMARKABLE BECAUSE HAVING SHOWN CHILDREN WITH OBSESSIVE COMPULSIVE DISORDERS -- [LOW AUDIO]. ASTONISHINGLY I CURE MID VEXED BOG WITH THE SAME MEDICATION BECAUSE LAB DOERS GET K-9 [LOW AUDIO] WHICH TURNS OUT TO BE THE BEST ANIMAL MODEL FOR OBSESSIVE COMPULSIVE DISORDER. ALTHOUGH THE CLINICAL CENTER DID NOT COOPERATE BUT AS AN OUT PATIENT STUDY WE DID SHOW VERY E EFFECTIVE [LOW AUDIO] AND THE FLEXIBILITY I'D LIKE TO GO BACK OF THE ADMINISTRATION FOR NOT GETTING ME TANGLED UP IN ANIMAL RESEARCH LOGISTICS WHEN THESE WERE MY PATIENTS WAS REALLY REMARKABLE. OVER AND OVER IN STUDIES THAT HAVE HAD STRONG CLINICAL IMPLICATIONS AS WELL AS VERY INTERESTING THEORETICAL IMPLICATIONS AND I COULD KEEP ON WITH OTHER EXAMPLES, BUT YOU HAVE THE IDEA. OVER AND OVER IT'S BEEN THE SENSE OF AN IMAGINATIVE FLEXIBLE AND VERY [INDISCERNIBLE] AT MINUTE STRAGS TOGETHER WITH OTHER THINGS [INDISCERNIBLE] THAT HAS MADE IT VERY HARD TO CONSIDER MOVING ANYWHERE ELSE. >> ONE OF THE THINGS THAT I FREQUENTLY TALK ABOUT IS THE THREE Ts THAT ARE INVOLVED. TALENT, TECHNOLOGY, AND TOLERANCE. I THINK BOTH BILL AND JUDY HAVE POINTED OUT THAT IN ORDER FOR THE PROGRAM TO WORK WE HAVE TO BE OPEN MINDED ABOUT THE KIND OF RESEARCH WE DO AND THE WAYS WE APPROACH THAT RESEARCH P OPINION I THINK JUDY WAS REFERRING TO THE FACT THAT THINGS USED TO BE A LOT EASIER TO DO HERE THAN THEY CURRENTLY ARE, BUT WE SURELY APPRECIATE THAT. WE MAKE EVERY EFFORT LEADERSHIP OF NIH TO MAKE SURE PEOPLE HAVE THE WHEREWITHAL TO FOLLOW THEIR DREAMS IN TERMS OF RESEARCH. SO STEVE, TELL US HOW YOU GOT HERE. >> SO FIRST I WANT TO ADD A T. THE T IS TRAINING. I THINK THAT WE HAVE A LONG HISTORY OF TRAINING AND LONG COMMITMENT TO TRAINING NOT ONLY TO GREAT SCIENCE BUT ALSO TO TRAINING THE NEXT GENERATION. SO I GREW UP IN BETHESDA AND I NEVER HEARD OF THE NIH UNTIL 1964 WHEN I FATHER BECAME A PATIENT OF DR. MO RSHG ROW, E HE HAD A BAD HEART. I WAS IN MEDICAL SCHOOL AT THE TIME AND AFTER WARDS I DID A DERMATOLOGY RESIDENCY AND AS ALL MALE PHYSICIANS HAD TO DO, THEY EITHER HAD TO COME TO NIH OR THEY WENT INTO THE ARMY. I WAS IN THE ARMY FOR TWO YEARS BUT I WAS AT WALTER REEDS AND PART OF MY JOB WAS DOING RESEARCH THERE AND I HAD THE GREAT FORTUNE OF INTERACTING WITH TWO VERY GOOD SCIENTISTS HERE, WARN REN AND IRA GREEN. AFTER MY ARMY TIME I WENT TO LONDON TO DO POST GRADUATE WORK AND THEN I GOT A LETTER FROM THE CHIEF OF DERMATOLOGY HERE ASKING ME TO CONSIDER COMING HERE FOR A POSITION AS A SENIOR INVESTIGATOR. NOW, THE OFFER, THE AMOUNT OF MONEY OFFERED IN THE LETTER WOULDN'T HAVE ALLOWED ME TO EVEN HAVE A ONE-BEDROOM APARTMENT WITH MY WIFE AND THREE CHILDREN, SO DESPITE THE FACT THAT I WANTED TO MOVE HERE, I DIDN'T REALIZE THAT I COULD ACTUALLY NEGOTIATE A SALARY WITH THE GOVERNMENT AND I DID AND I CAME HERE IN 1974 IN THE DETERMINE KNOWLEDGE BRANCH FIGURING I'D COME HERE FOR TWO OR THREE YEARS. IF I LIKED IT I'D GO TO A MEDICAL SCHOOL F I DIDN'T, I'D GO INTO PRACTICE WITH MY BROTHER. BILL SAID THAT EVERYBODY'S BEEN OFFERED A JOB. I HAVEN'T BEEN OFFERED A JOB, THAT'S WHY I'M STILL HERE. [LAUGHTER] ACTUALLY, I HAVEN'T REALLY LOOKED AT JOBS BECAUSE I THINK THAT SINCE I CAME HERE IN 1974; I WOULD JUST AGREE WITH WHAT BILL AND JUDY HAVE SAID THAT THIS IS A GREAT PLACE TO WORK AND LET ME THE TELL YOU THE GREATNESS FROM MY STANDPOINT. IT HAS BEEN FOR MANY YEARS BE ABLE TO JOIN CLINICAL DERMATOLOGY WITH BASIC SCIENCE. TO BE ABLE TO LOOK AT CERTAIN SKIN DISEASES, FOR EXAMPLE, AT THEIR MOST FUNDAMENTAL LEVEL. ONE EXAMPLE I'LL GIVE IS DERMATITIS WHICH AND [INDISCERNIBLE] WHICH IS SKIN DISEASE [INDISCERNIBLE] AND VERY RECENTLY WE ONE OF MY STUDENTS AND I WROTE A PAPER P AS A 38-YEAR FOLLOW-UP TO PATIENTS WITH DERMATITIS [INDISCERNIBLE] PATIENTS WHO WERE THOUGHT ALL OVER THE WORLD TO BE HAVING DISEASE LIFE-LONG DISEASE BUT ACTUALLY ABOUT 10-15% OF THEM NO LONGER HAVE A DISEASE AFTER LONG PERIODS OF TIME. VERY INTERESTING DISEASE. SO THAT AND OTHER DISEASES LIKE [INDISCERNIBLE] THAT ARE LIFE-THREATENING DISEASES, WE WERE ABLE TO STUDY THOSE DISEASES HERE TO BE ABLE TO DEFINE THE ANTIGENS THAT WERE TARGETS FOR AUTO ANTIBODIES AND IT REALLY MARRIED THE BASIC AND CLINICAL RESEARCH AND THAT'S REALLY WHAT I LOVE ABOUT THIS PLACE. >> OKAY. WELL, STEVE, THANK YOU. UNFORTUNATELY BECAUSE OUR TIME IS LIMITED, WE'RE NOT GOING TO BE ABLE TO DISCUSS SOME OF THE INTERESTING THINGS -- IN ORDER TO PREPARE FOR THIS SITE WE STARTED CHATTING ABOUT OUR OWN EXPERIENCE AT NIH AND IT'S AMAZING TO ME AND PROBABLY THE MAIN REASON THAT I LIKE BEING AT NIH IS BECAUSE OF MY COLLEAGUES AT THE NIH AND HAVING A CHANCE TO SPEAK TO THESE THREE LUMINARIES HAS REALLY BEEN INFORMATIVE TO ME. MAYBE WE SHOULD RECORD THESE THINGS AND PLAY THEM BACK. >> MICHAEL, 15, IT'S TIME. WOULDN'T YOU ALL AGREE? WE HAVE TIME HERE AND I THINK TIME WHEN YOU GO TO AN ACADEMIC MEDICAL CENTER AROUND THE COUNTRY PEOPLE ARE ALWAYS TALKING ABOUT THE NEED FOR TIME. THEY'RE ON A TIME -- THEY'RE ALWAYS WITHOUT TIME, AND I THINK WE DO HAVE TIME. WE HAVE TIME FOR PATIENTS, WE HAVE TIME FOR RESEARCH, WE HAVE TIME FOR THE COLLABORATION THAT BILL IS TALKING ABOUT. >> THANK YOU ALL FOR GIVING ME YOUR TIME AND SHARING IT WITH THE AUDIENCE. WHAT I WOULD LIKE TO DO IS ENCOURAGE EVERYBODY TO GO TO CONGRESSMAN ANDREW HARRIS' DISCUSSION AT 12:30 NATCHER, E 1 AND E 2. SOME OF YOU ARE PROBABLY BEGINNING TO FEEL PRETTY HUNGRY AT THIS POINT. THERE'LL BE THE RARE OCCURRENCE OF SOME REFRESHMENTS AFTER HIS COMMENTS. SO I URGE YOU TO GET UP TO NATCHER. THAT WILL BE AT 12:30 SO IF UH YOU START NOW YOU SHOULD BE ABLE TO MAKE IT IN TIME AND GET SOME EXERCISE AS WELL. THANK YOU ALL FOR JOINING US THIS MORNING. [APPLAUSE]