>> I'M JOHN GALLIN DIRECTOR NIH CLINICAL CENTER I HAVE THE DISTINCT PLEASURE OF WELCOMING ALL OF YOU TO THE BEGINNING OF OUR 60th ANNIVERSARY CELEBRATION. MEETING ON JULY 6th, 1953 THE FIRST PATIENT WAS ADMITTED TO THE NIH. AND WE HAVE A VERY SPECIAL PROGRAM TODAY. I'M GOING TO TRY TO GIVE YOU A LITTLE BIT OF A SNAPSHOT, TELLING YOU ABOUT OUR PAST AND THEN WE HAVE WHAT I BELIEVE IS THE VERY FIRST EXAMPLE OF A FATHER, SON, PAIR OF SPEAKERS AT GRAND ROUNDS IN THE HISTORY OF THE NIH WITH JIM AND STEVE HOLLAND AND I'LL TELL YOU MORE ABOUT THAT IN A MOMENT. I ALSO WANT TO TAKE A MOMENT NOW TO JUST THANK THE FOUNDATION FOR THE ADVANCED EDUCATION AND THE SCIENCES, OR FAES, WHO AFTER THIS EVENT ARE PROVIDING A LITTLE BIT OF REFRESHMENTS IN THE SOUTH LOBBY AND YOU'RE ALL INVITED. I TOLD THE NEW, THE 88 NEW FELLOWS WHO CAME YESTERDAY FOR THEIR ARRIVAL AT THE NIH, NOT TO MISS THE OPPORTUNITY OF A FREE LUNCH. IT DOESN'T HAPPEN OFTEN. SO AS I BEGAN TO THINK ABOUT WHAT I MIGHT SAY, ON THIS DAY, I BEGIN TO THINK, WELL, WHAT DOES NIH MEAN TO DIFFERENT PEOPLE AND IT REALLY MEANS DIFFERENT THINGS, TO SOME IT'S THE BUILDINGS AND THE GROUNDS. TO MANY IT'S IT IS--THE SCIENCE. TO THE PATIENTS, IT'S THE CARE. BUT I THINK TO EVERYONE, IT'S THE PEOPLE, THE AMAZING GROUP OF PEOPLE WHO WORK HERE WHO WE GET TO INTERACT WITH EVERY DAY AND WHO HAVE BEEN HERE BEFORE US. YESTERDAY WHEN I DID THE INTRODUCTIONS TO THE FELLOWS, I SHOWED A FEW MOVIE CLIPS, WHICH I DECIDED TO SHOW YOU, SETTING THE TONE FOR WHEN THE CLINICAL CENTER OPENED BACK IN 1953 AND THE YEARS JUST BEFORE THAT, SO IF I COULD GET OUR PROJECTIONIST TO START THIS PRESENTATION, WE WOULD LIKE TO SHOW A SPEECH THAT FRANKLIN ROOSEVELT GAVE HERE. >> --6 HOURS AGO THE PRESIDENTIAL SPECIAL TRAIN ROLLED INTO THE WASHINGTON'S UNION STATION BRINGING THE PRESIDENT BACK FROM HIS 1-DAY NEW ENGLAND TOUR WHICH ENDED IN BOSTON LAST NIGHT AND NOW THE PRESIDENT HAS COME BY AUTOMOBILE TO THE NATIONAL HEALTH INSTITUTE IN METHESTIMATE THAD DAILY BASIS, MARYLAND ON THE OUTSKIRTS OF WASHINGTON HERO A PLEASANT INDIAN SUMMER AFTERNOON, A MODERATE AWE AUDIENCE GATHERED BEFORE THE ADMINISTRATION BUILDING SET IN THE GREEN BUILDING HILLS AND SURROUNDED BY RED AND YELLOW AUTUMN LEAVES. >> LADIES AND GENTLEMEN, THE PRESIDENT OF THE UNITED STATES. >> [ APPLAUSE ] >> MR. KOY, DR. THOMPSON, THE GOVERNOR OF MARYLAND, GOVERNOR O'CONNOR, LADIES AND GENTLEMEN, NOWHERE IN THE WORLD EXCEPT IN THE AMERICAS IS IT POSSIBLE FOR ANY NATION TO DEVOTE A GREAT SECTOR OF ITS EFFORT TO LIGHT CONSERVATION RATHER THAN LIGHT DESTRUCTION. ALL OF US ARE GRATEFUL THAT WE IN THE UNITED STATES CAN STILL TURN OUR THOUGHTS AND OUR ATTENTION TO THOSE INSTITUTIONS OF OUR COUNTRY THAT SYMBOLIZE PEACE, INSTITUTION WHOSE PURPOSE IT IS TO SAVE LIFE AND NOT TO DESTROY IT. IT IS WITH THE DEDICATION OF THESE NOBLE BUILDINGS TO THE SERVICE OF MAN THAT WE ARE ASSEMBLED HERE TODAY. THE NATIONAL INSTITUTE OF HEALTH SPEAKS THE UNIVERSAL LANGUAGE OF HUMANITARIANISM. IT HAS BEEN DEVOTED LUTE ITS LONG AND DISTINGUISHED HISTORY TO FURTHERING THE HEALTH OF ALL MANKIND IN WHICH SERVICE IT HAS RECOGNIZED NONAPOPTOTIC LIMITATIONS, IMPOSED BY INTERNATIONAL BOUNDARIES AND RECOGNIZED NO DISTINCTIONS OF RACE OR CREED OR OF COLOR. THE TOTAL DEFENSE THAT WE HAVE HEARD SO MUCH ABOUT OF LATE, THAT TOTAL DEFENSE WHICH THIS NATION SEEKS INVOLVES A GREAT DEAL MORE THAN BUILDING AIRPLANES AND SHIPS AND GUNS AND BOMBS BUT WE CANNOT BE A STRONG NATION UNLESS WE ARE A HEALTHY NATION. >> OKAY, THANK YOU. >> THIS CLIP IS AVAILABLE IN THE LIBRARY OF MEDICINE, AND IS AVAILABLE AND IF YOU ARE INTERESTED WE CAN MAKE IT AVAILABLE IN TOTAL. BUT IT EMPHASIZES BACK IN 1940 BEFORE THE CLINICAL CENTER HAD BECOME ANYTHING, NOT EVEN A TWINK KNEEL AN EYE, PEOPLE WERE TALKING ABOUT THE IMPORTANCE OF THE HEALTH OF THE NATION. AND THE NIH CLINICAL CENTER WAS FIRST AUTHORIZED IN JULY 1 OF 1944 IN THE PUBLIC HEALTH LAW AT THE TIME. IT WAS APPROPRIATED 3 YEARS LATER IN 1947 AND THE CORNERSTONE FOR THE NEW BUILDING WAS LAID BY HARRY TRUMAN IN 1951. AND WHEN TRUMAN CAME HERE, IF WE COULD HAVE THE CLIP, THE NEXT MOVIE CLIP? >> THIS CLINICAL RESEARCH CENTER WILL ADVANCE THE WORK DONE BY ALL OF US TO ACLEAVE BETTER HEALTH. CHRONIC ILLNESSES TAKE A TREMENDOUS HUMAN TOLE--TOLL, MODERN MEDICINE MUST FIND WAYS OF DETECTING THESE DISEASES IN THEIR EARLY STAGES AND OF STOPPING THEIR DESTRUCTIVE FORCE. THAT WILL BE THE MAJOR WORK OF THIS CLINICAL RESEARCH CENTER. >> HE THEN ALSO WENT ON TO SAY, THE GREATEST GROUPS OF SCIENTISTS EVER GATHERED FOR BASIC AND APPLIED MEDICAL RESEARCH TO SERVE FOR MANY GENERATIONS AS A MONUMENT TO OR DESIRE FOR HUMAN HEALTH AND HAPPINESS IN A WORLD OF PEACE WILL BE HERE. AND HOW RIGHT HE WAS. SO I SHOW THIS PICTURE OF WHAT THE CLINICAL CENTER LOOKED LIKE RIGHT AFTER IT OPENED AND I TOLD ALL THE FELLOWS, WE PLAY GOLF. THE CENTER AS YOU CAN SEE WAS IN THE CENTER OF A GOLF COURSE. WHICH SADLY HAD TO BE REMOVED WITH PROGRESS. SO OPEN HAPPENING DAY AS I MENTIONED EARLIER WAS ON JULY 6th 1953 AND THE VERY FIRST PATIENT ADMITTED BY THAT DAY WAS CHARLES MERIDETH, A MARYLAND FARMER WITH PROSTATE CANCER, ALONG WITH 17 OTHER PATIENTS WHO HAD THE DISEASES OF CANCER, HEART DISEASE AND ARTHRITIS. THE COST OF THE NEW CLINICAL CENTER WAS 850 MILLION DOLLARS OR 64 MILLION DOLLARS OR 850 MILLION IN TODAY'S DOLLARS. SO IT WAS ACTUALLY MORE EXPENSIVE THAN THE MARCO HATFIELD CLINICAL RESEARCH CENTER WHICH WAS ABOUT 600 MILLION DOLLARS BUT OF COURSE IT WAS A LITTLE BIGGER. I POINT OUT THE LAST LINE ON THIS SLIDE THAT THE OPENING WAS ACTUALLY DELAYED FOR A YEAR BECAUSE THE BUDGET BURRO'S REFUSAL TO PRO--BUREAU'S CONCERN, IT WAS TOLD IT WAS CONCERNED ABOUT THE OPERATING COST OF THIS CLINICAL CENTER. SO DOESN'T SOUND LIKE TIME VS CHANGED VERY MUCH OVER THE 60 YEARS. THIS IS A CHART DEPICTING WHAT WENT TO PRESIDENT TRUMAN IN 1954, THE PRESIDENT'S BUDGET SHOWING THE BED DISTRIBUTION AND NURSING UNITS FOR THE DIFFERENT INSTITUTES AT THAT TIME WHO WERE HERE. CANCER MENTAL HEALTH, HEART, ARTHRITIS, MICRO, AND NEUROLOGY AND YOU CAN SEE THAT THE LARGEST NUMBER OF BED 35 WAS FOR CANCER, SECOND TO MENTAL AND HEART AND ARTHRITIS AND MICRO AND LAST TO NEUROLOGY, SO 150 BEDS ON OPENING DAY AT 8 NURSING UNITS AND AS OF A YEAR LATER IT WAS TO EXPAND TO 300 AS DISTRIBUTED HERE. SO THE LEGACY OF DISTRIBUTION OF BEDS WHICH WAS SO IMPORTANT IN THE FIRST, OH ABOUT 50 YEARS AT THE CLINICAL CENTER, ARE THOAN HERE WHERE THEY ARE--SHOWN HERE WHERE THEY WERE ASSIGNED PATIENT CARE UNITS TO EACH INSTITUTE. THAT OF COURSE CHANGED WHEN WE MOVE INTO THE MARCO HATFIELD CLINICAL RESEARCH CENTER WHERE WE INSTITUTED A NEW POLICY, CALLED SHARING AND THAT HAD ITS OWN CHALLENGES. SO LOTS HAVE HAPPENED. AS A MATTER OF FACT AS I WAS THINKING ABOUT WHAT TO SAY AND I ASKED ALL THE CLINICAL DIRECTORS TO GIVE ME A LIST OF THEIR ACCOMPLISHMENTS, THE LIST WAS SO ENORMOUS AND SO LARGE THAT I RAPIDLY HAD TO GIVE UP TRYING TO DISPLAY IT HERE. SO I'VE JUST LISTED A FEW TO OVERWHELM YOU TO GIVE YOU A SENSE OF WHAT HAPPENED IN THE FIRST 50 YEARS AND THEN I'LL SHOW YOU A LITTLE BIT WHAT HAPPENED IN THE LAST DECADE. BUT THEY INCLUDED AT THE VERY FIRST MEETING OF THE MEDICAL BOARD IN 1953, RECOGNITION OF A NEED FOR FORMAL REVIEW OF CLINICAL PROTOCOL AND THOSE MINUTES WHICH ARE AVAILABLE IF ANYBODY WANTS TO SEE THEM ARTICUMENT INFORMED CONSENT AND THE WHOLE REVIEW PROCESS AND LATER WERE ADOPTED BY THE SURGEON GENERAL OF THE UNITED STATES TO BECOME THE IRB PROCESS FOR THE UNITED STATES. ALSO WITH THE OPENING OF THE CLINICAL CENTER, VERY EARLY WAS THE CREATION OF A NORMAL VOLUNTEER PROGRAM WHICH SO MANY OF US IN THIS ROOM HAVE TAKEN ADVANTAGE OF IN TERMS OF ENRICHING THE CLINICAL RESEARCH OPPORTUNITIES. THE SPECIFIC EXAMPLES OF ACCOMPLISHMENT ARE LUMPED INTO THE SOME OF THE FOLLOWING BULLETS. CHEMO THERAPY FOR CANCER, FOR CARCINOMA, CHILDHOOD LEUKEMIA, AND HODGE KIN DISEASE, THE CARDIOVASCULAR DISEASE, THE USE OF LEPTIN TO TREAT LINEUPEE DYSTROPHY, THE USE OF NITRO GLYCERIN FOR HEART ATTACKS, THE USE OF ENZYME REPLACEMENT THERAPY FOR GAUCHER'S DISEASE LEADING TO THE FOUNDING OF GEN-ZYME CORPORATION THE FIRST MIGHT ROW HEART VALVE, THE USE OF IMMUNO SUPPRESSIVE THERAPY FOR NONMAL8 HOURSINANT DISEASES, IT WAS AN INFECT YOWS DISEASE, THE FIRST ELECTRONIC MEDICAL INFORMATION SIZE WHICH WE CALLED MIS, THE FIRST TREATMENT FOR AIDS, FIRST BLOOD TESTING FOR AIDS AND HEPATITIS LEADING TO PROVIDING A SAFE BLOOD SUPPLY FOR THE UNITED STATES, THE ASICK LO IS VIRFOR GENITAL HE WERE WERE--HERPES. COMPULSIVE DISORDER, CHILDHOOD SCHIZOPHRENIA, SEVERE MOOD DISREGULATION AND THE PEDIATRIC AUTOIMMUNE NEURODISORDER ASSOCIATE WIDE STRENGTH O COCKAL INFECTION, ALL THIS STARTED HERE, THE STANDARD OF CARE IN THE UNITED STATES, WHICH WE TAKE FOR GRANTED ORIGINATED IN THIS BUILDING. SO WHY DID EVERYBODY SUCCEED? I THOUGHT ABOUT THAT AND LAST FALL, LYNN LOREAL WHAT WAS A CLINICAL LEADER IN THE CHILD HEALTH INSTITUTE, HAD A SLIDE I MODIFIED. FIRST OF ALL THERE ARE LOTS OF SMART AND CREATIVE PEOPLE AND THE INVESTIGATORS WHO WERE HERE LITERALLY HAD THE PICK OF THE LITTER OF THE YOUNG INVESTIGATORS FROM MEDICAL SCHOOLS WHEN IT CAME TO THEIR TRAINEES AND FELLOWS. THEY HAD SEE CURE SALARIES AND FAILURE WAS AN ACKNOWLEDGED PART OF THE SCIENTIFIC PROCESS. SO YOU DIDN'T WORRY IF YOUR STUDIES FAILED, YOU WOULD LOSE A GRANT. INVESTIGATORS WERE IN THE LAB AND ON THE WARD EVERY DAY. IT WAS 1 WE ALTS TRY TO STRUG AND HE WILL PRESERVE AND ENRICH AND RESEARCH QUESTIONS WERE GUIDED BY THE HUMAN CONDITION. EXPERIMENTS OF NATURE, RARE DISEASES, BEDSIDE TO BENCH AND BACK SO WHAT HAPPENS IN THE LAST DECADE? WELL WHAT ABOUT THE NONSCIENTIFIC ACCOMPLISHMENTS, WE MOVE INTO THE CLINICAL RESEARCH CENTER, WE OPEN THE EDMOND J. SOFTWARE FAMILY LODGE. WE BROUGHT IN A MODERN INFORMATICS SYSTEM, CRISP, WE BUILT A NEW BIOMEDICAL TRANSLATIONAL RESEARCH INFORMATION SYSTEM TO MERGE THE BASIC AND CLINICAL SCIENCE TOGETHER. WE OPENED A PACK SIZE FOR ALL OUR IMAGING PICTURES WE COMPUTERIZE THE INTENSIVE CARE UNIT WHO MANY OF THOSE WORKED ON THAT UNIT AND SAW THOSE HUGE SPREADSHEETS WHICH WERE DONE BY A. N. D., THEY'RE GONE NOW AND HIRPLE AND HIS TEAM CREATED A NEW ELECTRONIC DATA TRANSFORMATION SYSTEM. WE HAVE A NEW DATA INITIATIVE COMPLETED WHICH GIVES US THE ABILITY TO TRACK DATA WITH GREAT SOPHISTICATION. WE HAVE ALL KINDS OF PROGRAMS, INCLUDING A TRAINING SUMMER PROGRAM FOR Ph.D. STUDENTS INTRODUCING THEM TO CLINICAL RESEARCH AND RESEARCH MANAGEMENT. WE INITIATED PRODUCT SEARCH FOR HANDICAPPED YOUNG PEOPLE TO COME HERE AND BECOME INTERNS, CHILDREN WITH AUTISM AND DOWNS SYNDROME AND ABOUT 75 TO 80% OF THOSE HAVE NOW BECOME EMPLOYEES, IN OUR CAMPUS. OUR NURSING DEPARTMENT INTRODUCING THE WHOLE NEW FIELD BASICALLY OF INTERNATIONAL CLINICAL RESEARCH NURSING, WITH CLAIR HASTINGS, WE OPENED OUR DOOR TO THE EXTRAMURAL COMMUNITY AND THE FIRST GRANT FOR THIS UNDER REVIEW FOR TODAY. AND TODAY WE OPEN THE PATIENT PORTAL, SO PATIENTS HAVE ACCESS TO THEIR OWN ELECTRONIC MEDICAL RECORD AND IN RECOGNITION OF ALL THE WONDERFUL THINGS THAT YOU ALL HAVE DONE IN 2011, WE WON THE ALASKA BLOOMBERG PUBLIC HEALTH SERVICE AWARD. CLEARLY A WONDERFUL RECOGNITION. SCIENTIFICALLY LET ME SHOW YOU A FEW THINGS THAT HAPPENED IN THE LAST DECADE. IMMUNO SUPPRESSIVE THERAPY FOR APLASTIC ANEMIA, DEVELOPED BY NEAL YOUNG AND HIS TEAM AND NOW THE STANDARD FOR THIS DISEASE. BEN CASTER DISCOVERED THE AUTOINFLAMMATORY DISEASES THE DEAFNESS INSTITUTE IDENTIFIED GENES FOR STUTTERING. THE CANCER INSTITUTE STUDIED MELANOMA WHICH HAS BECOME A MODEL FOR CELL THERAPY FOR CANCER, HAIRY CELL LEUKEMIA, IDENTIFICATION OF THE GENETIC BASIS OF KIDNEY CANCERS WITH NOVEL THERAPEUTIC. NEW OPROACHS TO THE DIAGNOSIS AND MANAGEMENT OF PROSTATE CANCER AND THE APPLICATION OF MICROBIAL WHOLE GENOME SEQUENCING AND AND EPIDEMIOLOGY. THESE ARE ALL AFEW OF THE THINGS THAT HAVE HAPPENED THIS YEAR. WE ALL SHOULD BE PROUD OF THIS AND OF COURSE IT WOULDN'T HAPPEN WITHOUTEUR ON OUR PATIENTS AND OUR PAIBTS--WITHOUT OUR PATIENTS AND OUR PATIENTS HAVE BEEN OUR PARTNERS FOR OVER 60 YEARS AND THEY'RE REALLY AMAZING. LAST WEEK FRANCIS COLLINS SHARED WITH ME A LETTER THAT 1 OF OUR GRATEFUL PATIENTS SENT TO HIM ABOUT HIS EXPERIENCE AT THE NIH COMING FROM A SMALL MIDWESTERN CITY AND I WANTED TO READ THESE WORDS TO YOU, EXTRACT FRIDAY A VERY LONG LETTER, I FEEL THE CALLING THIS EXPERIENCE HUMBLING LIFE CHANGING OR INSPIRATION WOULD SOMEWHAT CHEAPEN OR NOT DEFINE THE MEANING. WHAT HAPPENED TO ME, AT NIH IS LIFE, EVERYONE SHOULD EXPERIENCE LIFE IN SUCH A PLACE. THIS PATIENT IS STILL BEING FOLLOWED HERE AND I THOUGHT HIS WORDS CAPTURED SO MUCH OF WHAT OUR PATIENT SAYS--PATIENTS FEEL ABOUT THIS PLACE, THE THIS ENVIRONMENT THAT ALL OF YOU CREATE. SO I WANTED TO GIVE YOU THIS BRIEF INTRODUCTION TO HIGHLIGHT A FEW OF THE THINGS THAT HAVE GONE ON AROUND HERE AND JUST TO REMIND YOU ABOUT WHAT'S GOING ON AT THE CLINICAL CENTER, NOW, AND WHAT'S HAPPENED IN THE PAST AND AT THIS POINT, I'M GOING TO INTRODUCE THE IMPORTANT SPEAKERS TODAY, DR. JAMES AND DR. STEVEN HOLLAND AND LET ME START WITH DR. JAMES HOLLAND. JAMES F. HOLDING COMPANY SHORTHAND A MEDICAL ONCOLOGIST AND DISTINGUISHED PROFESSOR OFNY O PLASTIC DISEASES IN THE DEPARTMENT OF MEDICINE AND CANCER INSTITUTE AT THE IKAHN SCHOOL OF MEDICINE AT MOUNT SINAI, IN NEW YORK. HE ATTENDED PRINCETON AND GRADUATED COLUMBIA UNIVERSITY COLLEGE OF PHYSICIANS AND SURGEONS IN 1947. HE COMPLETED A RESIDENCY IN INTERNAL MEDICINE AT COLUMBIA IN 1949 AND AFTER A TOUR IN THE ARMORY, HE COMPLETED HIS FELLOWSHIP IN ONCOLOGY AT THE FRANCIS DELLA FIELD HOSPITAL IN 1953. HE ARRIVED ON OPENING DAY OF THE CLINICAL CENTER IN JULY 1953 AND WORKED IN THE NCI, UNTIL NOVEMBER 1954 BEFORE JOINING ROSWELL PARK CANCER INSTITUTE WHERE HE ULTIMATELY BECAME CHIEF OF MEDICINE AND DIRECTOR OF THE CANCER RESEARCH CENTER BEFORE BECOMING DIRECTOR AT THE HAIR OLD H. RESEARCH CANCER CENTER AT MOUNT SINAI IN 1963. FROM 1963-1981 HE RECEIVED AS CHAIRMAN OF THE ACUTE LEUKEMIA GROUP B, LATER NAMED CANCER AND LEUKEMIA GROUP B, AN INTERNATIONAL COOPERATIVE GROUP OF PHYSICIANS AND SCIENTISTS WHO DEVELOPED MULTIMODALITY TREATMENT TRIALS IN ONCOLOGY. UNDER DR. HOLLAND'S OUTSTANDING LEADERSHIP, THE GROUP'S INVESTIGATORS RESULTED IN CURES FOR CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA, THE INTRODUCTION OF SIS PLATNIN AS A THERAPY FOR TESTICULAR CANCER, AND OF DOCKSY RUBE SIN FOR HOSTIO SARCOMA. IN 1972, DR. HOLLAND WAS AWARDED THE ALBERT ALASKA MEDICAL RESEARCH AWARD FOR HIS OUTSTANDING CONTRIBUTIONS TO THE CONCEPT AND APPLICATION OF COMBINATION THERAPY IN THE TREATMENT OF ACUTE LEUKEMIA IN CHILDREN. IN 1997 HE WAS AWARDED AN HONORARY DOCTOR OF SCIENCE DEGREE BY THE STATE UNIVERSITY OF NEW YORK AT SUNI IN BUFFALO FOR HIS SCIENTIFIC CONTRIBUTIONS. HE IS CURRENTLY AN EDITOR OF THE HOLLAND-FRY CANCER MEDICINE, THE FIRST TEXT AND MEDICAL ONCOLOGY WHICH IS NOW IN ITS EIGHTH EDITION. HE IS A EXPERT ADVISE FOR ON CANCER FOR THE WORLD HEALTH ORGANIZATION AND A CONFOUNDER FOR AFRICAN RESEARCH AND TRAINING IN AFRICA KNOWN AS AORTIC. DR. HOLLAND'S MANY HONORS AND AWARDS INCLUDE THE GOLD MEDAL OF DISTINGUISHED ACHIEVEMENTS IN MEDICINE FROM THE ALUMNI ASSOCIATION OF THE COLLEGE OF PHYSICIANS AND SURGEONS AT COLUMBIA 1963. NATIONAL CANCER SOCIETY, THE AMERICAN CANCER SOCIETY OF NATIONAL AWARD IN 1981, THE DISTINGUISHED SCIENTIFIC AWARD OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY IN 93, AND THE T. J. MARITAL FOUNDATION LIFETIME AWARD INDEED 2008. HE'S ALSO ELECTED TO THE INAGERAL CLASS OF THE FELLOWS OF THE AMERICAN ASSOCIATION OF CANCER RESEARCH ACADEMY OF APRIL 2013, BASED ON HIS OUTSTANDING SCIENTIFIC ACHIEVEMENTS AND CANCER RESEARCH. OVER A SPAN OF MANY DECADES USING MOLECULAR METHODS, DR. HOLLAND AND HIS TEAM HAVE RECENTLY DISCOVERED AND INVESTIGATORRED THE HUMAN MAMMARY TUMOR VIRUS IN BREAST CANCER. THEY'RE STUDYING ITS POSSIBLE ETIOLOGIC ROLE FOR BREAST CANCER AS WELL AS POTENTIAL THERAPEUT AND I CAN PREVENTIVE IMPLICATIONS AND TODAY HE'S GOING TO PRESENT THE HUMAN MAMMARY TUMOR VIRUS AND NOW HOW LUCKY WE ARE TO HAVE 1 OF OUR FIRST PEOPLE AT THE CLINICAL CENTER PRESENT HIS CURRENT WORK. [ APPLAUSE ] >> THANK YOU DR. GAILLAN, IT SOUNDED LIKE A PREMATURE OBIT WARE AND I WAS VERY UNHAPPY--OBITUARY AND VERY UNHAPPY TO THERE'S A LEVEL PLACED THERE FOR AN AUTOPSIES. I DID ARRIVE ON OPENING DAY OF THE CLINICAL CENTER AND THE ACTIVITY OF TREMENDOUS INTEREST WAS LYSERGIC ACID DISCIPLINARY AT LA MIDWHICH HAD BEEN USED AT THE NAVY IN SOME VOLUNTEERED SAILORS WHO WERE VOLUNTEERS, OPEN TO QUESTION, AND IT WAS OF GREAT IMPORTANCE BECAUSE IT WAS A TREATMENT THAT WAS DONE AT MICRO GRAM LEVELS. B12 HAD JUST BEEN RECOGNIZED AND IT WAS ACTIVE AT MICRO GRAM LEVELS WRASSE OTHER THING HIS BEEN USED AT GRAM AND MILLIGRAM LEVELS SO THESE WERE IMPRESSIVE ACTIVITIES, THE PAINTINGS MADE BY SAILORS WERE EQUIVALENT TO SAILOR'S ART AND GAVE US CONSIDERABLY INTEREST. PUTTING CONTEXT, THIS WAS 3 MONTHS AFTER WATSON AND CRICK HAD DEFINED THE STRUCTURE OF DNA AND BEFORE THERE WAS ANY INFORMATION ABOUT MESSAGE OR DOWN STREAM PROTEIN SYNTHESIS, AND RETROSPECTIVELY, YOU COULD SAY WE WERE PRETTY PRIMITIVE. OT OTHER HAND, WHEN I GOT HERE, I WAS INTERESTED IN LEUKEMIA, HAD BEEN INTERESTED AS A MEDICAL STUDENT AND COULD I HAVE THE FIRST SLIDE, PLEASE? WAS INTRODUCED TO LLOYD LAW WHO WAS A SENIOR SCIENTIST HERE WHO SHOWED, YOU KNOW WONDERFUL SET OF EXPERIMENTS, SEEN ON THE LEFT. BUT LEUKEMIA WITH SURVIVAL ON THE ORDINANT IN THE YELLOW IN DBA 2 MICE AND IN HYBRID MICE IN RED, THE SURVIVAL OF HAD LEUKEMIA WHICH HE HAD INDUCED WITH DIAST ROSETTA EARLIER ON, LEUKEMIA L1210 WAS VERY SHORT AND WHEN HE GAVE 2 DRUGS THAT WERE KNOWN TO BE ACTIVE IN ANIMAL LEUKEMIA, MEXA TREKSATE, THE SUCCESSOR NAME FOR A-MYTHORINE, WHICH WAS THE SUCCESSOR COMPOUND TO AMIN OPTICAL IMAGES RIN, THE FIRST DRUG SUCCESSFUL IN CHILDHOOD LEUKEMIA AND THEN GAVE IT FIRST, AND THEN ASOGAUNINE, AFTERWARDS THERE WAS SURVIVAL EXTENSION BECAUSE OF THE COMBINATION OF THESE 2 DRUGS. ON THE OTHER HAND, WHEN HE GAVE THEM IN COMBINATION, YOU CAN SEE, ON THE RIGHT, A SIGNIFICANT INCREASE IN SURVIVAL, PARTICULARLY IN THE HYBRID MICE AND THAT WAS THE BEGINNING OF COMBINATION CHEMO THERAPY. I PUT THAT TOGETHER, USING METHOTREKSATE AND 6 MERCAPPIVE PURINE IN GUIDANCE IN PATIENTS AND WE START THAD TRIAL HERE AT THE NIH. ABOUT A MONTH BEFORE I LEFT THE NATIONAL INSTITUTES OF HEALTH WHERE I'VE BEEN VERY HAPPY AT $7200 A YEAR AND GOT AN OFFER OF $11,400 A YEAR AT ROSWELL PARK AND MONEY TALKED IN THOSE DAYS, EVEN THOUGH IT DOESN'T SEEM LIKE AN AWFUL LOT OF MONEY BY COMPARISON. IT'S JUST AN EXAMPLE OF HOW THE DOLLAR HAS LOST ITS VALUE. GEL R JUST BEFORE I LEFT GORED AN ZUBROV ARRIVED AND BECAME THE CLINICAL DIRECTOR. AND HE GRACIOUSLY SAID TO ME, A SENIOR MAN, MY CHIEF, I DON'T HAVE A PROGRAM IN ACUTE LEUKEMIA, WOULD YOU MIND IF I CONTINUED YOURS? AND THAT WAS THE BEGINNING OF INTERINSTITUTIONAL COLLABORATION. I WENT TO ROSWELL PARK, HE RECRUITED TOM FRY. WE BECAME CLOSE FRIENDS FOR THE REST OF HIS LIFE WHICH UNHAPPILY TERMINATED A FEW WEEKS AGO AND THE AND WAS THE FIRST PAPER IN COMBINATION CHEMO THERAPY IN THE TREATMENT OF CANCER WHICH WAS PUBLISHED IN BLOOD AND AND GORDON CAN PERSUADED ME, BUT IN FACT, AND TOM, A SINGLE ARM TREATMENT WASN'T VERY USEFUL BECAUSE YOU COULDN'T HAVE ANYTHING TO COMPARE IT AGAINST. SO WE SHOULD COMPARE 2 ARMS OF TREATMENT AND BY THAT TIME, ABRAHAM GOLDEN ALSO A SCIENTIFIC AT NIH HAD SHOWN THAT THIS--THESE GRAPHS, AMETHOPTICAL IMAGES RIN WHICH WAS THE EARLIER NAME FOR MEX O TREKSATE, IT MADE A DIFFERENCE HOW I GAVE IT, NOT JUST DAILY AS SYDNEY FAR BERNEA DEET HAD DONE BUT IF YOU GAVE IT TO MICE, DAILY OR HIGHER DOSE EVERY FOURTH DAY, AND IT DEPENDED UPON THE AGE OF THE TUMOR ON THE LEFT EARLY TUMOR ON THE RIGHT ADVANCED TUMOR THROUGH MANY VARIATIONS NACOULD LEAD TO A CHANGE IN THE OUTCOME OF CHEMO THERAPY. SO WE PUT TOGETHER A STUDY OF COMBINATION CHEMO THERAPY WHERE METHOTREKSATE EXISTED, THE MEDIAN SURVIVOR WAS 4 MONTHS UNTREATED AND HERE THEN THE MEDIAN SURVIVAL HAD INCREASED TO ALMOST A YEAR AND SUCCESSFULLY IN THE COLLABORATIVE GROUP AND THE CANCER CHEMO THERAPY NATIONAL SERVICE CENTER WAS ESTABLISHED UNDER THE URGING OF MRS. LASKER AND GORDON ZUBROV SUGGESTED WE COPY THE METHODOLOGY THAT HAD BEEN USED IN THE BRITISH MEDICAL COUNCIL FOR THE TREATMENT OF TUBERCULOSIS, A COLLABORATIVE MULTIINSTITUTIONAL SET OF INVESTIGATORS AND SO MANY COOPERATIVE GROUPS WERE ESTABLISHED IN THE UNITED STATES, THE CANCER AND LEUKEMIA GROUP B, IS THE OLDEST CONTINUOUS 1 OF THAT, BUT IT HAS SINCE BEEN BLENDED IN WITH OTHER GROUPS AND IS NOW KNOWN AS THE ALLIANCE FOR CLINE--CLINICAL TRIALS IN CANCER. AND HERE IS A LISTING, BY MAY OF 1969 OF SUCCESSFUL PROTOCOLS NOT REALLY RELATED TO NEW DRUGS BUT MOSTLY RELATED TO HOW THE DRUGS WERE GIVEN. AND HERE THE SAME DATA IN 1994. THESE ARE THE PROGRAMS OF CHEMO THERAPY, CHILDHOOD ACUTE LEUKEMIA DURING THE TIME I WAS THE CHAIRMAN OF THE CANCER LEUKEMIA GROUP B AND YOU CAN SEE BY THE TIME WE STOPPED, 60% OF THE CHILDREN WERE ALIVE WITHOUT EVIDENCE OF DISEASE AT 10 YEARS. SUBSEQUENTLY, THIS HAS BECOME NEARLY A UNIVERSALLY CURABLE DISEASE WITH THE PROPOSITION THAT GETTING CLOSE TO 80% SURVIVAL NOW. WELL, WHEN I LEFT ROSWELL PARK AND WENT TO MOUNT SINAI. I BECAME INTERESTED NOT ONLY IN THESE KINDS OF CHEMO THERAPY THINGS BUT IN THE PROPOSITION, OF WHAT CAUSES CANCER. BUT BEFORE THAT HAPPENED IN 1972, MR. LASKER, WHOSE HERE AND HER SISTER ALICE FOREDICE, WHOSE HERE, FLANKING DR. SYDNEY PARBERNEA DEET WHO WAS THE FIRST REPORTER, SENIOR AUTHOR OF THE PAPER DEMONSTRATING TREATMENT TEMPORARY REMISSIONS IN CHILDHOOD LUNG LEUKEMIA AND THESE ARE THE LASKER PRIZE WINNERS IN 1972. THERE ARE 16 WINNERS THAT YEAR, ORDINARILY IT'S 1 OR 2 BUT THE LASKER FOUNDATION THOUGHT THAT THE CANCER CHEMO THERAPY WAS SO IMPORTANT WE OUGHT TO FIND MOST OF THE THINGS. HERE IS GORDON ZUBROV WHO WAS THE CREATOR AND MASTER OF THE CONCEPT OF MULTIINSTITUTIONAL COLLABORATIVE GROUPS. THIS IS MC LEE AND ROY HERTZ WHO FIRST CURED CORIO CARCINOMA WITH CHEMO THERAPY AND ANNIE. THIS IS BURKEET, OF BIRKET'S LYMPHOMA, BUT ESSENTIALLY EVERYBODY ELSE HERE IS A MEMBER OR AN ALUMANIST OF THE NATIONAL CANCER INSTITUTE, THERE WERE 16 AWARDEES, 10 WERE MEMBERS OR ALUMNI OF THE NATIONAL CANCER INSTITUTE, 6 WERE FROM OTHER INSTITUTIONS. THAT'S ABOUT A GOOD RATIO FOR THE NIH. WHEN I GOT TO MOUNT SINAI, I BECAME INTERESTED IN WHY THE KIDS GET LEUKEMIA AND WHY DO OTHER CANCERS START? AND MOST CANCERS ARISE FROM SPECIFIC CAUSES, THE PROBLEM IS WE JUST DON'T KNOW WHAT THE SPECIFIC CAUSES ARE MOST OF THE TIME. SO, I WAS FASCINATED WITH THE OBSERVATIONS MADE BY JOHN BITTENER IN 1936. 1936 HE RECOGNIZED THAT IF HE TOOK A STRAIN OF MICE THAT HAD BEEN INBRED, BROTHER SISTER MEETINGS AND HAD BREAST CANCER AS 1 OF ITS CHARACTERISTICS, BREAST CANCER HERE IN 1 OF THE GRANDDAUGHTERS WAS EVERY INDIVIDUAL DEVELOPED BREAST CANCER AND HE FOSTER NURSED SOME OF THESE OFFSPRING MILK FROM MICE WHO WERE NOT GIVEN TO HAVING BREAST CANCER AS A FAMILIESIAL EVENT AND HERE 5 OUT OF 6 DID NOT GET BREAST CANCER AND HE REPORTED THAT THERE WAS A MILK FACTOR THAT LED TO CARCINOMA OF THE BREAST IN MICE. OVER THE YEARS THAT MILK FACTOR WAS IDENTIFIED AS THE MOUSE MAMMARY TUMOR VIRUS AND IT IS THE CAUSE OF BREAST CANCER IN MICE AND EVEN A MOUSE THAT DOESN'T HERSELF HAVE BREAST CANCER HAS A CHARACTERISTIC CAN CARRY THE VIRUS AND GIVE IT TO HER OFFSPRING BUT WHEN THE--WHEN A MOUSE WHOSE OFFSPRING ARE FOSTER NURSED, THE INCIDENCE OF BREAST CANCER GOES DOWN TREMENDOUSLY. AND SO IT WAS RECOGNIZED, THE VIRUS PASSED IN THE MATERNAL MILK OF THE MOUSE AND INFECTED LYMPHOCYTES IN THE UPPER GASTROINTESTINAL TRACT AND THE LYMPHOCYTES MIGRATED TO THE BREAST AND INFECTED BREAST CELLS AND THEY GOT BREAST CANCER. SOMETIMES THEY ALSO GOT LYMPHOMAS. WHO DISCOVERED TED FRIEND LEUKEMIA AND WHEN SHE DIED UNFORTUNATELY, PETRIS POGO, HER COLLAB IDENTITIOR CAME WITH ME TO WORK AT THE CANCER CENTER AND SAID SHE DIDN'T WANT TO WORK WITH MICE ANYMORE, BUT I SHE WAS A CLINICIAN AND SAID I WOULD LIKE TO WORK ON HUMANS. AND I SAID IF BREAST CANCER IN HUMANS IS DUE TO A VIRUS, IT'S GOING TO BE A KISSING COUSIN OF THE MOUSE MAMMARY TUMOR VIRUS. AND WE FOUND A SEQUENCE IN THE ENVELOPE GENE OF THE MOUSE MAMMARY TUMOR VIRUS AND IT'S SHOWN IN ENLARGEMENT HERE ON BASE 975 FOCUSED ON 1640 THAT WAS ABSOLUTELY UNIQUE. IT DIDN'T OCCUR IN ANY OF THE I VIRUS AND IT DIDN'T OCCUR IN THE HUMAN GENOME SO FINDING IT, WE KNEW THAT WE WOULD HAVE A FOOT PRINT OF THE VIRUS AND WE MADE PRIMERS AND DID THE PC R, POLYMERASE CHAIN REACTION AND THE AMP LIAISON CONCOULD BE SEEN IN A DNA SOUTHERN PLOT, THESE ARE DNA EXTRACTS FROM THE MOUSE TUMORS, FROM THE HUMAN TUMORS. THIS IS FROM A MOUSE TUMOR, YOU CAN SEE WE FOUND IN THE VIRUS, BY VISUAL INSPECTION IN A BREAST CANCER, BUT EVERY TIME WE HAVE ALWAYS DONE INTERNAL HYBRIDIZATION WITH THE REACTIVE PROBE AND ALTHOUGH YOU CAN'T SEE IT IN 3, IT'S ALSO A POSITIVE BREAST CANCER. AND WE--THOSE ARE FRESH TISSUES THESE ARE ORCHIVAL TISSUES WITH--ARCHIVAL TISSUES WITH A SMALLER DNA SEGMENT, BUT AGAIN INTERNALLY PROBED AND NUMBER 1 IS NEGATIVE AND 2 THROUGH 5 ARE POSITIVE AND THIS IS THE AUTHENTIC ENVELOPE GENE FROM THE MOUSE WHICH SMEARS BECAUSE IT WAS SO POWERFUL. SO WE THEN EXTENDEDLET PC R REACTION--EXTENDED THE PC R REACTION OUT FURTHER IN THE ENVELOPE GENE AND HERE IS A 2.9 KILOBASE PIECE SHOWN IN THE CHROMOSOMES OF A HUMAN BREAST CANCER NOTICE THAT IT'S ALL ON 1--IN 1 STRAND, DOESN'T GO TO BOTH STRANDS IN--AS IS TRUE FOR MMTV, INDISCRIP NATEINANTLY IN SEVERAL DIFFERENT CHROMOSOMES. WELL AT THAT TIME THE CONSER INSTITUTE WAS DEEPLY INVOLVED, WE GOT CANCER TISSUES FROM THE CANCER REGISTRY WHICH INCLUDE THE TUMOR FROM THE BREAST AND NORMAL TISSUE FROM THE SAME BREAST AND NORMAL TISSUE FROM THE SAME BREAST DID NOT CONTAIN MMTV LIKE SEQUENCES. THIS 1 WAS POSITIVE IN THE NORMAL TISSUE AND NEGATIVE IN THE TUMOR AND WE THINK THAT'S A LABELING PROBLEM. BUT YOU SEE, EVEN IF IT WERE TRUE 1% OF THE NORMAL TISSUE AND 30% OF THE TUMOR TISSUES WHICH EXCLUDES GENETIC INHERITANCE. SO WOMEN ACQUIRE THIS VIRUS. AND FINALLY WE INCREASED OUR POLYMERASE CHAIN REACTIONS UNTIL WE GOT THE ENTIRE VIRUS WHICH IS 9.9 KILOBASES LONG. 95% HOMOLOGOUS TO THE MOUSE MAMMARY TUMOR VIRUS, ALL THE GENES ARE REPRESENTED, ONLY A SHORT AREA PARTIALLY HOMOLOGOUS TO THE ENDOGENOUS RETROVIRUS, K10, WHICH IS VERY SIMILAR TO MMTV AND WE THINK THAT EONS AGO SOME WOMAN GOT INFECTED WITH THIS AND IT'S COME UP THROUGH HUMAN DNA AND WE WERE SEEKING HOW DO WOMEN GET INFECT WIDE THIS, WHICH IS INDEED VERY CLOSE TO THE MOUSE MAMMARY TUMOR VIRUS. AND BECAUSE IT CAME FROM HUMAN TISSUE, WE CALLED IT THE HUMAN MAMMARY TUMOR I HAVEEROUS AND HERE ON THE TOP, YOU CAN--TUMOR VIRUS AND HERE ON THE TOP, YOU CAN SEE THE MOUSE MAMMARY TUMOR VIRUS SEQUENCE AND HERE SEVERAL DIFFERENT HUMAN MAMMARY TUMOR VIRUSES, AND NOTICE IN THE LONG-TERMINAL REPEAT, THERE ARE SYSTEMATIC CHANGES IN THE SEQUENCE WHICH MAY REPRESENT EITHER AN UNUSUAL VIRUS FROM THE MOUSE THAT GOD INTO THE WOMAN OR REGRESSION THROUGH CERTAIN KINDS OF HUMAN RESISTANCE TO THE MOUSE MAMMARY TUMOR VIRUS THAT LEADS TO THESE KINDS OF CHANGES IN HUMAN TISSUE. AND THEN THIS IS THE VIRUS. IT LOOKS JUST LIKE THE MOUSE MAMMARY TUMOR VIRUS AND THIS WAS SHOWN BY DANIEL MOORE 15 OR 20 YEARS BEFORE US THAT THERE ARE VIRUSES IN HUMAN BREAST CANCER THAT LOOK LIKE MOUSE TUMOR VIRUSES. THE MOUSE MAMMARY VIRUSES ARE RNA VIRUSES THAT TRANSCRIBE INTO THE DNA AND EVERYTHING I'VE SHOWN YOU IT DNA. BUT NOW THESE ARE THE RNA SEQUENCES THAT ARE CODED FROM THAT DNA OF THE HUMAN VIRUS AND YOU CAN SEE THEY'RE ALL AUTHENTIC SHOWING THAT THE VIRUS--PICTURE I JUST SHOWED YOU IS INDEED HUMAN MAMMARY TUMOR VIRUS, AND NOT SOME OTHER VIRUS THAT'S BEEN LIBERATED. AND WE HAVE INSERTION SITES IN HALF A DOZEN TUMORS. IN THIS PARTICULAR 1 BECAUSE THE MOUSE MAMMARY TUMOR VIRUS AND THE HUMAN MAMMARY TUMOR VIRUS DO NOT CONTAIN ONCA GENES OF THEIR OWN, THEY GET RANDOMLY INSERTED AND THEY MAY IMPACT ON NEARBY VIRUS, THE NEARBY GENES THAT ARE EITHER KNOWN TO BE ONCA GENES OR TUMOR SUPPRESSOR GENES, THESE 2 HAVE SOME ASSOCIATION WITH CANCER IN THIS PARTICULAR INSERTION SITE IN CHROMOSOME 5. AND THIS TURNS OUT TO BE A SIGNIFICANT FACTOR. 40% OF WOMEN WITH BREAST CANCERS HAVE THE VIRAL SEQUENCE IN THEM. IF THE PROBAND HAS A SISTER OR A MOTHER OR AN AUNT WITH BREAST CANCER HISTORY, 63% ARE POSITIVE. IF BREAST CANCER ARISES DURING PREGNANCY OR LACTATION, IT'S ALSO MORE THAN BACKGROUND AND IT IS KNOWN THAT THERE HORMONALLY RESPONSIVE ELEMENTS IN THE LONG-TERMINAL REPEAT OF BOTH MOUSE MAMMARY TUMOR VIRUS AND HUMAN MAMMARY TUMOR VIRUS WHICH MAY ACCOUNT FOR THE FREQUENCY IN WOMEN AS DISTINCT FROM MEN. AND INFLAMMATORY BREAST CANCER IN COLLABORATION WITH PAUL LEVELS INCREASINE WITH WASHINGTON WHO'S AN ALUMANIST WITH NCI, SEIVET%. WELL, WHEN WE REPORTED THIS IN OUR FIRST PAPER, AND I MISS THE FACT THAT THERE ARE NORMAL BREASTS IN WOMEN WHO'S EVERBIOPSIED ARE ALMOST ALWAYS NOT REALLY BIOPSIED BUT HAD REDUCTION MEDICARE AND MEDICAID O PLASTYS FOR BREASTS THAT ARE UNGAINLY OR DIFFICULT, ALMOST 0 BECAUSE THERE ARE ANATIONAL LIBRARY OF MEDICINE MOUSE SPECIMENS WE DON'T KNOW WHAT WOULD HAPPEN TO THESE 2 WOMEN WHICH WE WOULD CERTAINLY LIKE TO KNOW IN PATIENT WHO IS HAVE ENVELOPE POSITIVE BREAST CANCER BUT HAVE A BIOPSY OF THEIR OPPOSITE BREASTS, 2 WERE POSITIVE, PERIPHERAL BLOOD MONONUCLAL CELLS IN WOMEN DON'T HAVE THE VIRAL SEQUENCE, BUT IF FACT, THEY HAVE ENVELOPE POSITIVE BREAST CANCER, THEN ABOUT 1 IN 4, WE DON'T KNOW WHETHER THOSE ARE CIRCULATING BREAST CANCER CELLS OR MONONUCLEOCELLS WHICH IS PART OF THE LIFE CYCLE IN THE MOUSE. WHEN WE PUBLISHED OUR FIRST PAPER TOM STEWART FROM OTTOWA SAID THAT ANSWERED THE PROBLEM FOR HIM. AND I DIDN'T KNOW WHAT HIS PROBLEM WAS BUT HIS PROBLEM WAS WITH THE BREAST CANCER FREQUENCY IN CASES PER HUNDRED THOUSAND PER YEAR IN EASTERN EUROPE HAD ALWAYS BEEN MUCH LOWER THAN THE BREAST CANCER FREQUENCY IN WESTERN EUROPE. AND HE WAS AWARE BUT I WASN'T OF THE WORK OF RUSSELL SAGE WHO HAD PUBLISHED THIS IN 1993 WITH THE DISTRIBUTION OF MICE IN EUROPE AND IN ALL THE COLONIES WITH EUROPE COLONIZED. EAST OF THIS LINE FROM DENMARK ARE MOOSE MUSKULOUS WITH VERY LITTLE MMTV IN THE GENOME AND VERY LOW BREAST CANCER FREQUENCY AND WEST OF IT IS WEST MUSET DOMESTICUS, THE COMMON HOUSE MOUSE WHICH IS PRESENT IN WESTERN EUROPE AND ALL OF ITS COLONIES THAT HAS A LOT OF MMTV IN ITS GENOME AND GETS SPONTANEOUS BREAST CANCER AND THAT PUT AN ONEROUS AROUND US TO GO AROUND THE WORLD AND FIND OUT WHETHER OR NOT THIS WAS OF IMPORTANCE. STEWART POINTED OUT THAT IN THE COUNTRIES THAT HAVE THE HOUSE MOUSE, THE COMMON HOUSE MOUSE, 66 CASES PER HUNDRED THOUSAND PER YEAR AND THEY'RE IN THE WESTERN WORLD AND IN THE EASTERN WORLD 21 CASES PER HUNDRED THOUSAND PER YEAR. AND JUST TO POINT OUT THE HIGH DIFFERENCE IN THE LAND OF MUSETTA DOMESTICUS, AND EVERYBODY KNEW THAT IN ASIA, JAPAN AND CHINA, BREAST CANCER SERS LESS PREWENT THAN IN THE WESTERN WORLD AND ASCRIBED IT TO GENETICS, DIET, ETHNICITY AND WE WENT AROUND THE WORLD AND LOOKED FOR THE BREAST CANCERS AND FREQUENCY OF THE HUMAN MAMMARY TUMOR VIRUS IN THE BREAST CANCERS AND HERE IN THE UNITED STATES, MEXICO, BRAZIL, ARGENTINA, ALSO AUSTRALIA, ANOTHER COLONY OF WESTERN EUROPE, 38 IN THIS PARTICULAR THING OF FRESH VERSES ARCHIVAL BREAST CANCERS. BUT HIGH FREQUENCY, WITH HIGH FREQUENCY OR BREAST CANCERS AND IN JAPAN, 3 POSITIVE--OH MY SLIDE SEEMS TO HAVE CHANGED--12% POSITIVE. IN VIETNAM 0% POSITIVE, 1 OUT OF 120 AND IN CHINA, 7% POSITIVE AND IN IRAN, 0. SO IN THE EASTERN WORLD LESS BREAST CANCER AND LESS MAMMARY VIRUS IN THE BREAST CANCERS IN THE WESTERN WORLD A LOT OF BREAST CANCER AND A HIGH FREQUENCY OF VIRUS. IN AFRICA, WHEN YOU SAW THE AFRICAN HAD HIGH FREQUENCY OF THE DOMESTIC MOUSE IN NORTH AND WEST AFRICA, WE'VE FOUND HIGH LEVELS AND IN TONIESIA WHERE WE HAVE THE MOST SPECIMENS, VERY HIGH FREQUENCY OF THE HUMAN MAMMARY TUMOR VIRUS AND WE WERE ASTOUNDED TO SEE THAT WHERE WE HAD THE MOST AFRICAN SPECIMENS WHOSE 8%, ONLY 1 OUT OF 12 AND THEN I FOUND MATT PARKINS WORK, MATT PARKIN IS A WONDERFUL EPIDEMIOLOGIST WHO WORKS WITH THE CANCER AGENCY FOR RESEARCH, AND HERE IN WEST AFRICA, RED IS BREAST CANCER AND BLUE IS CANCER OF THE CERVIX. THERE ARE NO GOOD CANCER REGISTRIES IN AFRICA, UNFORTUNATELY, BUT CANCER OF THE CERVIX IS VERY COMMON AND EXCEPT IN TUNESTIMATE THADIA WHERE--TUNESIA, EXCEPT FOR CULTURE IT SAYS GIRLS SHOULD BE PALE AND PLUMP TO GET MARRIED AND THEREFORE THEY KEEP THEM IN THE HOUSE AND THERE ARE STRICT LAWS AGAINST PREMARITAL SEX, THERE'S VERY LITTLE CERVICAL CANCER BUT THERE'S HIGH BREAST CANCER FREQUENCIES IN NORTH AND WEST AFRICA, COMPARED TO CERVICAL CANCER WHICH IS ABOUT THE CONSTANT HERE IS UNCOMMON IN EAST AND SOUTH AFRICA, AND THAT'S BECAUSE THEY TRADED WITH ARABIA AND CHINA AND INDIA WHEREAS THE WEST TRADED WITH NORTH AND WEST AFRICA. SO I PRESUME THERE ARE DIFFERENT SPECIES OF MICE IN AFRICA. WE HAD TO SHOW THAT THE VIRUS WAS INFECTIOUS AND INDEED IT IS. THIS IS THE CO-CULTURE ACTIVITIES MOUNT SINAI SCHOOL OF MEDICINE MSSM CELLS ARE BREAST CANCER CELLS WE KNOW ARE PC R POSITIVE AND THERE WERE NONE IN THIS CONTAINER SO ANY POSITIVE IN THE RECIPIENT CELLS WOULD REPRESENT LABORATORY CONTAMEINATION. AND HERE, THERE WERE NO RECIPIENT CELLS, SO ANY POSITIVE HERE THROUGH A 4/10thS MICRON FILTER, WOULD REPRESENT A FELTER CARE AND WE DID COCULTURE EXPERIMENTS USING MOUSE MAMMARY, USING MOUNT SINAI BREAST CANCER CELLS AND RECIPIENT CELLS OF DIFFERENT KINDS. SHE'S ARE THE B-CELLS AND THEY WERE INFECTED, T-CELLS 100%, PERIPHERY BLOOD MONONUCLAL CELLS, 75% AND HUMAN MAMMARY EPITHELIAL CELLS WHICH ARE FROM NORMAL BREAST COMMERCIALLY ACQUIRED, HALF OF THEM WERE INFECTED BY THE VIRUS IN CO-CULTURE EXPERIMENTS. AND INFECTION WAS DEFINED THIS WAY: HERE THE RECIPIENT CELLS PRECULTURE, NO EVIDENCE OF THE ENVELOPE GENE, AFTER THE CULTURE THERE'S THE ENVELOPE GENE THE DNA AMP LIAISON CONAND HERE THE PROTEIN IT IS ACTIVE IN THE CELL BECAUSE USING MONOCLONAL ANTIBODIES WHICH WE'VE DEVELOPED IN THE PRE--THERE'S NO EVIDENCE OF THE PROTEIN, BUT AFTERWARDS, ENVELOPE PROTEIN APPEARS. AND WHEN--BUT WHEN 1 TAKES THE CELLS, THESE ARE--THESE ARE HUMAN MAMMARY EPITHELIAL CELLS TO SHOW THAT THERE'S NO VIMENTORSHIP SKILLIN IN THE--VIMENTIN IN THE PRECULTURE EXPERIMENTS. AND HERE ARE MOUNT SINAI CANCER CELLS SHOWING THAT THEY DO INDEED HAVE VIMETNTIN, WAS A CHARACTERISTIC OF EPITHELIAL MAN VAN THOMMAL CHARACTERISTIC TRANSITION OF CANCER. HERE MICHIGAN CANCER FOUNDATION 10 F CELLS PRECULTURE D AFTER CO-CULTURE THEY HAVE PICKED UP THE EVIDENCE OF VIMENTIN, SUGGESTING THAT THESE MICHIGAN CANCER FOUNDATION, PUTATIVELY NORMAL CELLS IN CULTURE INDEED HAVE ACQUIRED CANCER CHARACTERISTICS BY ACCEPTING THE HUMAN MAMMARY TUMOR I HAVE HAVE--VIRUS. --BUT A WOMAN SHOW FIST SHE HAS AN ENVELOPE OPEN HUMAN MAMMARY VIRUS CANCER, GET THE MUSCLE AND WHICH THEY DO, HALF OF THEM HAVE THE HUMAN MAMMARY TUMOR VIRUS IN THE LYMPHOMA, EXACTLY LIKE THE MOUSE. THE MOUSE GETS LYMPHOMAS, NOT AS FREQUENTLY AS THE BREAST CANCER, BUT THEY DO GET LYMPHOMAS, AND THE ENDOMETRIAL CARCINOMA WE LOOKED AT BECAUSE IT'S ANOTHER TISSUE HIGHLY STIMULATED BY ESTROGEN AND I'LL SHOW YOU THAT IN A MOMENT AND OTHER WORKSER SAW OUR PRIMERS, THEY WERE LOOKING FOR THE CAUSE OF BILLIARY CIRRHOSIS WHICH NOBODY KNOWS, SO THEY GIVE IT A FLING, RUN THE TESTS AND IT WAS POSITIVE IN BILLIARY CIRRHOSIS, ALSO. WITHOUT CANCER WE LOOKED AT 28, NONE HAD THE RIEROUS, AND THEN WE LOOK AT THE CARC NOME AQUART EVER THEM WERE POSSIBLE, THIS IS NORMAL ENDOMETRIUM AND HERE WITH IMMUNO PEROXIDASE, WELL DIFFERENTIATED ENDOCARCINOMA AND HERE UNDIFFERENTIATED ENDOCARCINOMA SHOWING ENVELOPE PROTEIN FROM THE MMTV, THE HMTV AND HOW DO WOMEN GET THIS VIRUS. THERE IS A CASE REPORT OF A TECH DEALING WITH MOUSE BREAST CANCERS WHO HAD NORMAL ANTIBODY TIGHTERS, 3 TIMES IN A ROW AND THEN TURN POSITIVE 9 MONTHS LATER AND DEVELOP BREAST CANCER, A MONTH AFTER THAT MASS IN HERAXILLA WHICH WAS BIOPSIED AND THEN THEN PERHAPS DIRECT CONTACT WITH A MOUSE. AND THE MICE OF THIS WORLD CONTAMINATE OUR FOOD CHAIN UP AND DOWN THE FOOD CHAIN. I HAD A WONDERFUL COLLABORATION WITH THE FOOD AND DRUG ADMINISTRATION WHICH INSPECTED THE WHOLESALE GROCERY WAREHOUSES WHERE MICE AND RATS FREQUENTLY VISIT. THEY COULD TELL OUR VISITATION HAD BEEN PRESENT BECAUSE BY ULTRA ULTRAVIOLET LIGHT, THAT CAN STAN FOR URINE CONTAMINATION BUT THE FDA THEN HAD TO CHANGE AND HAS BEGUN LOOKING FOR POISONS, COMING IN IN IMPORTED FOODS AND DIDN'T HAVE TIME TO DISCUSS MOUSE VIRAL ACTIVITIES. TOO BAD. BUT WE FOUND, AS IN THE MOUSE, NORMAL WOMEN SHED HUMAN MAMMARY TUMOR RIHAVE YOU SEEN IN THE CELLS IN THEIR MILK. EIGHT% OF NORMAL WOMEN AND THEIR 4 MILLION BIRTHS A YEAR IN THE UNITED STATES, 2 MILLION PETRESSABLE MALE BIRTHS, 8% OF 2 MILLION IS ENOUGH TO ACCOUNT FOR THE 40% OF 230, 240,000 BREAST CANCERS EVERY YEAR. IF THIS WERE THE ONLY MEANS OF TRANSMISSION. SO WE THINK THAT THIS IS LIKELY TO A MECHANISM BY WHICH IT GETS TRANSMITTED. IF A WOMAN HAS HAD A BIOPSY OF HER BREAST FOR WHATEVER REASON WHICH REALLY MEANS SOMEBODY THOUGHT THEY MIGHT HAVE BREAST CANCER, 20% ARE POSITIVE SUGGESTING THAT THERE IS A KIND OF MASTITEIS DUE TO HMTV. THE VIRUS HAS BEEN FOUND BY A RUSSIAN SCIENTIST IN PIERS PATCHES--PYRES, PATCHES. IF A WOMAN OR MALE OFFSPRING, BECAUSE THEY ALSO NURSE, GETS VIRUS INTO THEIR CELLS, GOES TO THEIR BREAST, THE MALE MAY NOT GET BREAST CANCER BECAUSE IN FACT, HE DOESN'T HAVE THE CO FACTOR OF ESTRAGEN, BUT THIS IS A LOGICAL MECHANISM AND WE'RE TRYING TO PROVE THAT THAT IS INDEED TRUE. WE HAVEN'T PROVED HMTV CAUSES HUMAN BREAST CANCER YET, BUT OF COURSE WE'RE FOLLOWING THAT. BRINGS ME TO THIS PARABABBLE FROM THE LATE FRANK SHAKELE WHO IS A MOUSE DOCTOR, GOOD FRIEND OF MINE WHO POINTED OUT HUMANS WALK ON 2 LEGS, NOT 4, DRINK WHEN THEY'RE NOT THIRSTY, HAVE A MEATING SEASON THAT'S 365 DAYS LONG BUT OTHERWISE, THEY'RE LIKE ALL THE OTHER ANIMALS. AND I THINK HUMANS ARE LIKE ALL THE OTHER ANIMALS. I THINK THEY'RE LIKE THE MOUSE IN THE THAT THERE'S A VIRUS THAT CAUSES BREAST CANCER IN THE MOUSE AND THAT GETS TRANSMITTED BY THE SAME ROOT, HAS THE SAME PATHOLOGICAL END POINTS AND IN FACT CONSITUTES, I THINK EVIDENCE THAT ZOLANOCIES, ARE MUCH MORE COMMON THAN WE RECOGNIZE AND WE ALL RECOGNIZE THAT RESPIRATORY VIRUSES FROM CHICKENS AND FROM SWINE CAN INFECT HUMANS AND WE SHOULDN'T BE RELUCTANT TO THINK THAT SIMILAR VIRUSES CANNOT. AND TO PROVE THAT, THE NEXT SPEAKER IN HIS METAFOREVER SIS WHEN HE WAS--METAFOREVER O SIS WHEN HE WAS LIKE A YOUNG LIAISON AN LOOKED LIKE AN ANIMAL BUT HE GREW OUT OF IT. AND SO ... I'M VERY HAPPY TO SAY THAT HE'S HERE AND SPECIALIZING IN INFECTIOUS DISEASES AND IF I CAN'T PROVE THAT THE VIRUS CAUSES BREAST CANCER MAYBE HE AND HIS COLLEAGUES CAN. THANK YOU. [ APPLAUSE ] >> WELL I'VE KNOWN A LOT ABOUT STEVE, BUT YOU LEARN SOMETHING EVERY DAY. THAT WAS TERRIFIC, THANK YOU SO MUCH. HE COMES FROM A REMARKABLE FAMILY, NOT ONLY IS HIS DAD A DISTINGUISHED CLINICIAN AND INVESTIGATOR, BUT SO IS HIS MOTHER JIMMY HOLLAND WHO'S ALSO HERE TODAY AND WELCOME TO THE NIH AGAIN. SO NOW LET ME TELL YOU ABOUT OUR NEXT SPEAKER. STEVE HOLLAND WHO RECEIVED HIS MEDICAL DEGREE FROM JOHNS HOPKINS IN 1983 AND CONTINUED ON AS A RESIDENT IN INTERNAL MEDICINE, ASSISTANT CHIEF OF SURFACE AS WELL AS FELLOW AND INFECT YOWS DISEASES, HE CAME TO THE NIH IN 1989 AS A NATIONAL RESEARCH COUNCIL FELLOW IN MAL MARTIN'S LABORATORY OF MICRO BIOLOGY IN NIAID, AND WORKING ON TRANSCRIPTIONAL REGULATION OF HIV. IN 1991 I HAD THE GOOD FORTUNE, AS HE JOINED MY LAB, LABORATORY OF HOST DEFENSES AT NIAID, SHIFTING HIS RESEARCH TO THE HOST SIDE WITH THE FOCUS ON PHAGOCYTE DEFECTS AND THEIR ASSOCIATED INFECTIONS. HIS WORK CENTERED ON THE PATHOGENESIS AND MANAGEMENT OF CHRONIC GRANULA DISEASE AND SYNDROME AND OTHER CONGENITAL IMMUNE DEFECTS INCLUDING PHAGOCYTES AND THOSE PREDISPOSING TO MICROBACTERIAL DISEASES. IN 2004, HE BECAME CHIEF OF THE LABORATORY OF CLINICAL AND INFECT YOWS DECEASES AT NIAID AND IN 2011 HE WAS SELECTED TO SERVE AS THE NIH DEPUTY DIRECTOR FOR INTRAMURAL CLINICAL RESEARCH WORKING VERY CLOSELY WITH MICHAEL GOTTESMAN. AMONG DR. HOLLAND'S AWARDS IS THE 2002, NIH DISTINGUISHED CLINICAL TEACHER AWARD, THE HIGHEST HONOR BESTOWED ON THE NIMH, INVESTIGATOR BY THE NIH CLINICAL FELLOW, IN 2011 HE WAS NAMED AT NIH DISTINGUISHED INVESTIGATOR AND RUN THE BROILS SCIENTIFIC ACHIEVEMENT AWARD OF THE IMMUNE DEFICIENCY FOUNDATION. HE RECEIVED THE AMERICAN COLLEGE OF PHYSICIANS AWARD FOR SCIENCE IN 2012 AND HE'S THE PAST PRESIDENT OF THE INTERNATIONAL IMMUNO COMPROMISED HOST SOCIETY AND THE CLINICAL IMMUNOLOGY SITE AND A FELLOW OF THE AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE. HE'S ALSO AN ELECTED MEMBER OF THE AMERICAN SOCIETY OF CLINICAL INVESTIGATION. HE RECEIVED SEVERAL NIH DIRECTORS AWARDS FOR CLAYRATIVE AND SCIENTIFIC WORK INCLUDING THE DISCOVERY OF THE NEW MICROORGANISM, GRANUE LOW BACTERIA IN 2006 AND DISCOVERY OF THE CAUSE OF JOB'S SYNDROME IN 2008 AND THE DISCOVERY OF DOC 8 DEFICIENCY IN 2010. HE'S AN ACTIVE EDITOR AND REVIEWER AND SERVES AT THE EDITORIAL BOARD AT UMPIRESUNOLOGY AND CONSULTING EDITOR AT THE JCI. AND TODAY HE'S GOING TO TELL US ABOUT LOCATION, LOCATION LOCATION, THE MICROBACTERIAL SUSEPTIBILITY STORY, WELCOME STEVE. [ APPLAUSE ] >> I KNOW THERE'S NO PRESSURE HERE TODAY. SO THANK YOU VERY MUCH, JOHN, IT'S AN EXTRAORDINARY PLEASURE TO BE HERE TODAY, NOT ONLY WITH MY DAD--WHAT A GREAT--I'M JUST A LUCKY GUY BUT ALSO TO HAVE A CHANCE TO TALK TO BUT SOMETHING I'VE BEEN WORKING ON FOR A WHILE AND TO TRY AND EXPLAIN TO YOU WHY WE'VE BEEN DOING IT AND TO SHOW YOU WHERE WE'VE BEEN SUCCESSFUL AND ALSO WHERE WE'VE BEEN LESS SUCCESSFUL. SO I HAVE TO JUST GIVE YOU MY DISCLOSURES. I REALLY DO THINK THESE PRETTY GOOD. [LAUGHTER] AND I'M GOING TO DISCUSS OFFLABEL USES AND YOU'LL HAVE TO WAIT TILL THE END TO FIND OUT ABOUT THE INTERESTING 1S SO THERE ARE OBJECTIVES THAT YOU'LL ACQUIRE AS YOU GO THROUGH O I'M NOT GOING TO REITERATE THOSE NOW. SO WE HEARD ABOUT THE GUY WHO CAME HERE ON THE FIRST DAY OF PATIENT ADMISSION TO THE NIH CLINICAL CENTER AND I WANT TO SHOW YOU HERE, THESE WERE THE LAST IN-PATIENT ROUNDS PERFORMED IN THIS BUILDING, THE MAG ESTIMATE THADON CLINICAL CENTER IN 2005 AND YOU'LL RECOGNIZE SOME OF THESE CHARACTERS, THIS 1 HERE, YOU RECOGNIZE THE THIGH, THIS 1 HERE BEFORE HE HAD THE HAND TRANSPLANT, THAT'S REALLY QUITE ATTRACTIVE JOHN AND YOU RECOGNIZE OTHER PEOPLE THAT WERE INVOLVED IN THE CARE OF PATIENTS HERE AT THE CLINICAL CENTER AND WHAT I WANT TO DO IN THE NEXT 2, 2 AND HALF HOUR SYSTEM WALK YOU THROUGH SOME OF THAT STUFF. SO NOW REMEMBER, THE FIRST HYPOCRITIC AFORRISM, I'M ONLY GOING TO READ IT IN 1 LANGUAGE BUT HE POINTS OUT THAT LIFE IS SHORT, THE ART IS LONG. OPPORTUNITY FLEETING, EXPERIENCE MISLEADING AND JUDGMENT DIFFICULT AND TO THAT I CAN ALL SAY, AMEN. SO WHEN I CAME FROM THE BASIC SCIENCE LABORATORY TO THE CLINICAL LABORATORY, I HAD THE GREAT GOOD FORTUNE TO WORK WITH AN INSPIRED MENTOR AND SCIENTIST JOHN GO AN AND HE SAID, HAY THIS IS JUST EASY. DON'T YOU WORRY ABOUT IT, FIRST FIGURE OUT HOW TO TAKE CARE OF THOSE PATIENTS WE KNOW ABOUT WHO HAVE SOME PRETTY STRANGE DISEASES, THAT'S OKAY, YOU JUST GO FIND YOUR OWN MPLET I THOUGHT WHAT DO YOU MEAN? FIND YOUR OWN? BUT HE WAS OBLIGATIONS ABSOLUTELY RIGHT. IT'S ALL ABOUT YOUR NICHE, YOUR INSIGHT, YOUR RELATIONSHIP TO THE CLINICAL DISEASE. AND THE DISEASES I WANT TO TALK TO BUT TODAY ARE THOSE CAUSED BY THE NONTUBERCULOSIS MICROBACTERIA, SO WE KNOW A LOT ABOUT MICROTUBERCULOSIS DISCOVERED IN A KITCH THENNINE 82 BUT THEN THERE ARE THESE OTHER MICROBACTERIA AND MY LAB AND OTHERS HELP FOCUS ON THE NONTUBERCULOSIS ORGANISMSOT PREMISE THAT IF YOU FIND PEOPLE WHO HAVE INFECTIONS WITH THOSE ORGANISMS, THEY MUST HAVE A PROBLEM. THEY'RE TOO COMMON, THEY'RE ENVIRONMENTAL, SO IF SOMEBODY'S GOT A BAD PROBLEM THERE MUST BE A REASON AND OUR JOB IS TO FIGURE IT OUT. SO I'M GOING TO WALK YOU THROUGH WHY LOCATION MATTERS? BECAUSE IT TURNINGS OUT AND I DIDN'T GET THIS AT FIRST THAT IT'S ALL ABOUT WHAT'S THE INFECTION? WHERE IS IT? AND THAT WILL GUIDE YOU TO WHAT THE PROBLEM IS? SO THERE ARE 3 REAL DISTINCT TYPES HERE IN DISSEMINATED LUNG. THE SKIN DISEASE IS ALL ABOUT CONTACT AND IN THIS ELEGANT SET OF EXPERIMENTS, THIS ELEGANT PAPER DONE BY KEVIN WINTHROM, YOU SEE WHAT SKIN DISEASE LOOKS LIKE IN PEEL WHO HAVE BEEN GOING TO NAIL SALONS TO GET PEDICURES AND THERE WAS A TERRIFIC OUTBREAK IN CALIFORNIA AND YOU SEE HERE THAT THE NUMBER OF CASES WAS GOING UP AND UP AND UP AND UP AND THEN SHARP PEOPLE LIKE KEVIN WINTHROP, GOT INVOLVED AND KREBS WITH THE CDC AND THEY IDENTIFY AID NAIL SALON THAT WAS DOING PEDICURES, THEY CLOSED THE SALON AND THE CASESUENTS AWAY. NOW THERE IS NO FREE LUNCH AND YOU CLOSE DOWN THE PED CARE SALON, THERE ARE CONSEQUENCES TO THEM. BUT THE IMPORTANT TAKE HOME HERE AND I WANT TO GIVE YOU PRACTICAL INFORMATION, THIS IS USUALLY SOMETHING THAT HAPPENS IN HEALTHY PEOPLE. THE INOCULATION IS PERCUTANEOUS, VERY SELF-LIMITED BUT IF YOU AREN'T COMFORTABLE, IT CAN BE TREATED SPECIALLY AND ONLY CERTAIN EXPOSURES LIKE PEDICURE, THE CRITICAL ELEMENT, DON'T SHAVE BEFORE THE PEDICURE, IF YOU TAKE OUT THE SHAVING THE PEDICURES ARE AREN'T THAT BIG OF A DEAL. SO THAT'S 1 OF THOSE OBJECTIVES YOU HAVE TO KNOW. BUT DISSEMINATED DISEASE IS REALLY WHERE WE KNOW THE MOST. THIS IS THE RAREST FORM BUT IT'S 1 ABOUT WHICH WE KNOW A LOT AND THESE ARE A BIG PROBLEM. SO MY EXPERIENCE WITH THESE ORGANISMS AND THESE INFECTIONS BEGAN ENTIRELY AS AN ACCIDENT. I TOOK A PHONE CALL WHEN HIJUST COME INTO JOHN'S LAB FROM A DOCTOR IN FLORIDA WHO SAID, BOY, I GOT THIS CHILD HE'S GOT DISSEMINATED MICROBACTERIAL AI HAVE UMKC COMPLEX, ALL THESE ORGANS HE'S ON PARENTAL NUTRITION, ALL THE IF I'M AND HE'S GOT 2 MATERNAL UNCLE WHO IS HAVE THE SAME PROBLEM. DO YOU THEN COULD BE CHRONIC GRANULA DISEASE. WELL I HAD BEEN IN JOHN'S LAB FOR A WHILE AND I KNEW IT WASN'T LIKELY TO BE THAT DISEASE, THEY DON'T GET THAT INFECTION, BUT I THOUGHT, BOY WITH THE 3 MEMBERS AND 1 FAMILY WHO ALL HAVE DISSEMINATED DISEASE, IT'S LIKELY TO BE GENETIC, LIKELY TO BEOT X-CHROMOSOME BECAUSE BEING TRANSMIT INDEED A SEX-LINKED WAY AND THAT MEANS IT MUST BE DISCOVERABLE AND IT MUST BE IMPORTANT. SO THE LOGICAL THING TO SAY, IS, I DON'T KNOW WHAT THIS IS, BUT BOY YOU OUGHT TO COME TO THE NIH. AND THEY DID. AND WHEN THEY CAME HERE, WE HAD JUST BEEN--JOHN'S LAB HAD BEEN STUDYING INTERFERON-GAMMA ON THE DISEASE, THERE WAS A LOT OF INFORMATION ABOUT HOW TO USE INTERFERON IN THE TREATMENT OF INTRACELLULAR INFECTIONS AND WE DID IT IN THESE PATIENTS AND TO SUMMARIZE WHAT HAPPENED, HERE'S THIS LITTLE BOY, HE HADN'T GROWN IN 2 YEARS WITH THE INITIATION OF INTERFERON, HE GREW AND HIS NUTRITION IMPROVED. HE CAME OFF TPN, HE WAS CURED OF HIS INFECTION. THIS MAN HERE IN HIS 40S HAD 6 LITTERS OF ACIDDINGS BEING BRAINED FROM HIS STOMACH EVERY WE'RE AND WITH THE INITIATION OF INTERFERON, THAT WENT AWAY AND HE WAS CURED OF HIS MICROBACTERIAL DISEASE. WELL YOU KNOW THAT WAS PRETTY EXCITING AND I THOUGHT WOW THIS, IS SOMETHING WE OUGHT TO PAY ATTENTION TO SO I--I CHANGED MY FOCUS AND STARTED LOOKING AT MICROBACTERIAL DISEASE AND WE BEGONE TO TRY AND ILLICIT AND UNDERSTAND THIS PATHWAY IN WHICH THE MICROBACTERIAL MACRO PHAGES THEY LEAD TO PRODUCTION ON INTERLEUKIN 12 AND K-CELLS TO MAKE INTERFERON-GAMMA THAT WORKS ON THE RECEPTOR ON ALL NUCLEATED CELLS UPREGULATING TUMOR NEB NECKROSIS FACTOR AND THEN DRIVING THE KILLING OF MICROBACTERIA THROUGH A PATHWAY THAT IS STILL UNDEFINED. AND OVER THE YEARS OF STUDYING THIS, WE'VE NOW BEEN ABLE TO PUT NOW GENES INTO THIS PATHWAY, AND THEN ABLE TO IDENTIFY NEW MUTATIONS IN IN PATHWAY THAT ARE CLEARLY ETIOLOGIC IN THE CAUSE OF SIS TEMINATED MICROBACTERIAL INFECTION EMPLOY SOME OF THESE GENE VS BEEN IDENTIFIED HERE, MANY OF THESE HAVE BEEN IDENTIFIED ELSEWHERE BUT WE'VE SEEN ALL THESE PATIENTS AND WE'VE TRIED TO USE EACH PATIENT TO UNDERSTAND WHAT'S THE MECHANISM, WHAT'S THE PATHWAY, WHAT SHOULD WE KNOW. IN ADDITION IT FINDING THINGS THAT ARE GENETIC AND GERM LINE WE'VE BEEN ABLE TO IDENTIFY MUTATIONS, THE ACQUISITION OF AUTOANTIBODIES TO INTERFERON-GAMMA AND IL12 AS RECENTLY REPORTED BY SARAH BROWN FROM OUR GROUP CLEARLY IDENTIFY TAG THIS IS THE CRITICAL PATHWAY THAT CONTROLS DISSEMINATED DISEASE, WHETHER YOU HAVE IT IN YOUR GERM LINE OR LATER IN LIFE, THIS IS THE WAY IT HAPPENS. AND THAT IS TRUE FOR DISTEMINATED DISEASE. SO HOUR MANTRA NOW IS THAT IT'S DISTEMINATED MICROBACTERIAL INFECTION, PEOPLE ARE JUST NOT NORMAL, THERE'S A PROBLEM AND IF THEY HAVE A PROBLEM WE CAN FIND IT. IT'S USUALLY IN THE INTERFORGONE GAMMA PATH PAY AND THE EXPOSE SURUSUALLY ENVIRONMENTAL AND THE GEEZ, IF IT'S DISSEMINATED IS USUALLY SEVERE AND PROGRESSIVE AND UNTREATED IT IS FATAL. IT'S NOT EASY TO TREAT AND THEY GET ALL KINDS OF MICROBACTERIAL INFECTIONS. SO WE'RE VERY CONFIDENT NOW THAT IT'S IMMUNE DEFECT THAT CAUSE THESE DISSEMINATED INFECTIONS, NOW THIS IS WHERE WE GO BACK FOR THE FIRST HIP CATTIC AFORRISM THAT JUDGMENT IS DIFFICULT. BECAUSE NOW IF WE STEP OVER AND SAY, WAIT A MINUTE, IF SKIN DISEASE IS SORT OF STRAIGHT FORWARD AND DISSEMINATED DISEASE IS SORT OF IMMUNE HOW DO WE UNDERSTAND THE MOST COMMON SET OF DISEASES AND THOSE ARE DISEASES OF THE LUNG AND THESE REALLY ARE TROUBLESOME. NOT ONLY ARE THEY TROUBLESOME, THEY'RE EXTREMELY IMPORTANT. THESE INFECTIONS SO HERE YOU SEE CURVES LOOKING AT THE RATE OF NONTUBERCULOSIS ISOLATED LUNG DISEASE, NONTUBERCULOSE LUNG DISEASE IN WOMEN AND IN MEN OVER TIME. 1997-2007 AND YOU SEE THE RATE IS GOING UP. YOU ALSO SEE THAT THE RATES ARE DIFFERENT BETWEEN WHITES, BLACKS, ASIANS AND HISPANICS. THAT IS, THERE ARE BOTH AGE AND ETHNICITY INFLUENCES HERE THAT SUGGEST THAT THIS IS GOING TO BE A COMPLEX INTERACTION, IN ADDITION, LOCATION IS CRITICALLY IMPORTANT AND THOSE STATES IN BLACK HAVE VERY HIGH RATES. YOU SEE THESE ARE MOSTLY COASTAL STATES ALTHOUGH STILL LOOKING FOR THE COAST FOR THIS 1. AND THESE ARE RATES THAT ARE VERY HIGH AS OPPOSE TO OTHER STATE WHICH IS HAVE RATES THAT ARE SOMEWHAT LOWER. BUT TO PUT IT IN CONTEXT FOR YOU, THE NONTUBERCULOSE LUNG DISEASE, PULMONARY HIKE ROUGH ATOM TUBERCULOSE LUNGE DISEASE THERE ARE ABOUT 40,000 CASES IN IN COUNTRY. IN CONTRAST, KEEP THAT THE RATE OF TUBERCULOSIS THERE WERE 10,000 CASES IN 2011 AND THAT WAS DOWN 5% FROM THE YEAR BEFORE AND THERE'S NO REASON TO THINK THAT RATE WILL NOTE CONTINUE TO DECLINE SO THESE ARE CLIMBING, THESE ARE FALLING, THESE ARE 10 TIMES MORE THAN THIS. HOW MUCH EFFORT DO WE SPEND TRYING TO UNDERSTAND THIS PROBLEM. SO WE THOUGHT, BOY, LET'S TAKE WHAT WE LEARNED ABOUT IMMUNE DYSFUNCTION AND TRANSFER IT NOW TO LUNG DISEASE AND AFTER YEARS OF WORK, WHAT I CAN TELL YOU IS NO. THERE DO NOT SEEM TO BE ANY REPRODUCIBLE DEFECTS IN PULMONARY MICROTUBERCULOSIS DISEASE, WHEN WE INTERROGATE THIS PATHWAY, IT'S JUST FINE. SO WE THOUGHT, WELL, THIS IS COMFUSING AND WE WENT BACK AND STARTED LOOKING AT OUR PATIENT'S TO ASK ARE THERE OTHER THINGS THAT WE MISSED IF IT'S NOT IMMUNE BASED WHAT ELSE COULD IT BE? WELL, THERE WERE INTERESTING THINGS HERE, SO AS HAD BEEN NOTICED MANY YEARS BEFORE WHY WENT BACK TO TRY AND CONFIRM, IS IT TRUE THAT PATIENTS ARE TALLER AND THINNER AND THE ANSWER IS, YEAH, PATIENTS WITH LUNG DISEASE, HERE WE HAD 60 PATIENTS WITH LUNG DISEASE COMPARED TO A VERY LARGE SAMPLE OF NORMALS FROM THE ANN HANES DATABASE AND OUR PATIENTS WERE CLEARLY TALLER, 1 SQUIFF CENTIMETERS VERSES 161 AND MUCH LEANER, BMIs OF 21, VERSES BMIs OF 28. NOW COULD ARGUE THAT PEOPLE GET THIN BECAUSE THEY GET SICK, BUT CAN'T ARGUE THAT PEOPLE GET TALL BECAUSE THEY GET SICK, RIGHT? THERE WOULD BE A BIG MARKET FOR THIS IN THE BASKETBALL GROUP. [LAUGHTER] SO SOMETHING MUST BE GOING ON AND IT MUST HAVE LONG PRECEDED THE DEVELOPMENT OF DISEASE BECAUSE THIS IS A DISEASE THAT COMES ON TYPICALLY IN WOMEN IN THEIR 60S. IN ADDITION TO THE FACT THAT THEY WERE TALLER AND THINNER, THEY HAD OTHER ABNORMALITIES, SCOLIOSIS WAS FOUND IN OVER HALF, MIGHT ROUGH ATOM VALVE PROLAPSE IN 10% AND PECKIS EXCRAVOTAUM, SUGGEST THANKSGIVING WERE MORE IMPORTANT IN THIS CONDITION. IN ADDITION MUTATIONS IN THE CYSTIC FIBROSIS MEMBRANE CONDUCTANCE REGULATOR WHICH ARE INVOLVED IN CREATION OF THE DISEASE OF CYSTIC FIBROSIS, THESE WERE PRESENT USUALLY AS HETEROGENEOUS ROW ZYGOUS MUTATIONS IN A LARGE NUMBER, BUT DID NOT CAUSE CYSTIC FIBROSIS IN THIS THESE PATIENTS BUT WERE PRESENT. WELL, THEN WORKING WITH KEN OLIVIA AND RON COLUMBOW, WE'RE ABLE TO LOOK AT OUR GROUP OF PARENTS AND SAY, WELL WAIT A MINUTE, AND SAY ALL THESE THINGS HAPPENING AND THINK OF THEM ARE BEFORE DISEASE ONSET AND SOME OF THEM MAY BE DEVELOPMENTAL SO MAYBE THEY'RE GERM LINE SO ARE THERE FAMILIESIAL ASSOCIATIONS. SO THAT WOULD POINT US IN THE DIRECTOR OF GENETICS AS OPPOSE TO ENVIRONMENT. AND SURE ENOUGH THERE WERE FAMILY TREES THAT SUGGESTED AM DOMINANCE AND SOME WITH RECESSIVE INHERITANCE. SO NOW WE HAVE A FUNNY PROBLEM, SO WE RULED OUT IMMUNE DYSFUNCTION AND WE IS A DISEASE THAT IS ENVIRONMENTAL, GENDER BASED ASSOCIATIONS WITH SOMATIC FEATURES, LOOKS LIKE IT'S GENETIC, LIKELY TO BE A SINGLE GENE, AT LEAST IN SOME FAMILIES, CHRONIC AND PROGRESSIVE, DIFFICULT TO TREAT AND AFTER ALL THAT WORK, WHAT WE COULD SAY WITH GREAT CERTAINTY WAS THAT PULMONARY DISEASE IS NOT DISSEMINATED DISEASE. SO THAT MAY SOUND TRIVIAL BUT THAT WAS NOT OBVIOUS WHEN WE STARTED. IT SEEMS LAKE THEY OUTTO BE LINKED. SO IN ORDER TO UNDERSTAND THAT BETTER, CAN OLIVIA AND HIS COWORKERS WENT BACK AND SAID LET'S LOOK AT THE AUTOPSIES PATHOLOGY ON THOSE PEOPLE WHO HAVE LUNG DISEASE THAT HAVE ISOLATED LUNG DISEASE AND DISTEMINATED DISEASE WITH LUNG INVOLVEMENT AND SURE ENOUGH THE REMARKABLE THING IS THAT IF YOU HAD DISSEMINATED DISEASE WITH LUNG INVOLVEMENT, THE INFLAMMATORY RESPONSE WAS QUITE POOR, WELL IF YOU HAD PULMONARY DISEASE WITH PULMONARY INVOLVEMENT, IT WAS QUITE ROBUST. IF YOU LOOK AT THESE, THESE ARE DISSEMINATED BY NATURE, RIGHT? THEY ARE ALL OVER THE BODY BUT THESE PATIENTS THAT HAVE PULMONARY DISEASE, THEY NEVER GET DISEASE OUTSIDE THE LUNG SO NOW WE'RE STUCK SAYING WAIT A MINUTE. IT'S DISEASE THAT'S NOT ASSOCIATE WIDE THE LUNG AND NOT WITH IMMUNE DEFICIENCY, HOW CAN WE UNDERSTAND THAT. SO AS IS OFTEN THE CASE, YOU NEED TO LOOK OUT TO A PARADIGM. WHERE ARE THE PARADIGMS WHY USE TO UNDERSTAND WHAT'S GOING ON. AND THE MOST IMPORTANT PARADIGM, THE MOST WELL STUDIED PARADIGM THAT KEN HAS REALLY BROUGHT TO THE FOREHERE IS CYSTIC FIBROSIS AND THE REALLY IMPRESSIVE THING IS THAT IF YOU LOOK AT THE RATE OF PULMONARY MICROBACTERIAL INFECTION IN CYSTIC FIBROSIS, YOU SEE THAT AS PATIENTS GET OLDER, THE RATE GOES UP INTO ALMOST 50%. SO THIS IS FUNNY, WE HAVE A DISEASE THAT HAS THE ONSET LATE IN LIFE, CYSTIC FIB FIBROSIS IS A DISEASE WITH ONSET LATE IN LIFE, HOW MIGHT WE PUT THOSE 2 THINGS TOGETHER. AND SO NOW, WE HAVE TO GO BACK AND SAY LUNGS, LUNGS ARE COMPLICATED, IT'S NOT JUST AIR IN, AIR OUT, THERE ARE OTHER THINGS THEY HAVE TO DO, THEY ACTUALLY HAVE TO CLEAR OUT ALL SORTS OF DEBRISS AND LET ME SEE IF I CAN MAKE THIS WORK HERE. OH THIS IS EXCITING, SO WHAT IS IT THAT YOU CAN THINK ABOUT IN THE LUNG, IT'S REALLY THAT CILIA HAVE TO BEAT AND I DON'T HAVE MUSIC TO GO WITH THIS, I'M SORRY, TAYLOR SWIFT DOESN'T HAVE A CILIA SONG THOUGH I'M WORKING ON IT, BUT WHAT YOU SEE IS THAT CILIA ARE VERY CAREFUL, VERY RHYTHMIC, VERY SMOOGHT, THEY KNOW WHAT THEY'RE DOING TO GET THINGS WHERE THEY HAVE TO GO AND SO THAT GOT US TO THINK, WAIT A MINUTE, CILIA'REY FUNCTION IS CLEAN AND WE KNOW THAT PATIENTS WITH SILLIAR DEFECT AND CYSTIC FIBROSIS AND ALL THE SECRETION ARE ABNORMAL AND THE SILLIARY FUNCTION IS DIMINISHED. SO MAYBE IF CILIA ARE IMPORTANT AND PEOPLE WITH SILLIARY DEFECTS ARE IN TROUBLE WITH THE MICROBACTERIAL INFECTIONS MAYBE WE BETTER GO LOOK IN OUR PATIENTS WITH NONTUBERCULOSIS BACTERIAL INFECTIONS SO SEE IF THEY HAVE SILLIARY DEFECTS. SO CEDAR FOULER A STUDENT IN THE OXFORD CAME BRIDGE PROGRAM CAME IN AND HELPED US REAMLY BEGIN TO STUDY HOW MIGHT THIS WORK. SO, THE TRUTH IS, THAT YOU KNOW ALTHOUGH THE LUNGS ARE DOWN HERE AND SORT OF DIFFICULT TO GET AT, THERE ARE EASY WAYS TO GET AT THE SAME SORT OF CELLS, AND THOSE ARE ON THE INFERIOR NAISAL TURBINATE, IF YOU DON'T THINK YOUR TURBINATES HAVE THAT, WE CAN HELP YOU OUT BY PROVING IT UNDER THE MICROSCOPE AND CAN YOU SCAPE THOSE INFERIOR TURBINATE AND TAKE THOSE CELLS OUT AND CULTURE THEM OR CAN YOU TAKE THEM OUT ASK LOOK AT THEM UNDER THE MICROSCOPE AND LOOK AT THEIR SILLIARY FUNCTION TO SHOW THEY ARE NORMAL AND IN FACT, CAN YOU COUNT THE BEAT OF THE CILIA, AND DEVELOP SOMETHING CALLED THE CVUP WHICH IS THE FREQUENCY AND IMPORTANT IN HOW YOU CLEAR THINGS. AND SHOVE ENOUGH WHEN WE LOOK AT PATIENTS WHEN WE LOOK AT MICROBACTERIAL INFECTIONS VERSES OTHER GROUPS WHAT YOU SEE HERE, NOLLAL HAVE A RBF IN OUR HAND OF ABOUT 10 BUT THE PULMONARY PATIENT HIS A CBS OF 8. PATIENTS THAT HAVE INTRINSIC AND SEVERE DEFECTS IN THE CILIA KNOWN AS PRIMARY SILLIARY DISKEENIESIA HAVE LATES THAT ARE LOWER AROUND 5 TO 6. SO THAT GOT US VERY INTERESTED IN HOW MIGHT THAT BE IMPORTANT. IS THIS AN ACQUIRED PROBLEM. THAT IS DO THEY LOSE THE FREQUENCY WITH AGE AND SO WE WENT BACK TO LOOK AT WHAT HAPPENS TO CBF OVER AGE, CAN YOU SEE HERE, YOU THIS IS THE CBF, AND YOU CAN SEE CBFs OF POST DOCS AND CBFs OF SENIOR STAFFS BUT YOU ALSO THEN SEE THAT THE RATE OF SILLIARY B-FREQUENCY WITH THE PATIENTS WITH PULMONARY NONTUBERCULOSIS DISEASE IS RELATIVELY STABLE OVER A LONG SPECTRUM OF LIFE, SUGGEST THANKSGIVING IS NOT JUST AN AGE RELATED PHENOMENA AND IN FACT IT'S NOT CAUSED BY INFECTION WHICH WOULD BE ANOTHER THING THAT YOU WOULD THINK ABOUT BECAUSE WHEN WE ADD MICROBACTERIA TO THE CULTURE OF THE CELLS, THE FREQUENCY GOES UP, DOESN'T GO DOWN AND IF WE TAKE CONDITIONS MEDIA FROM THESE PATIENTS AND WE PUT IT ON TO NORMAL CELLS IT DOES NOT ALTER THE SILLIARY B-FREQUENCY SO WE DON'T BEING THIS IS A TRANSMISSIBLE INHIBITORY EFFECT. IN FACT, WE THINK IT'S INTRINSIC AND SO FINALLY TO UNDERSTAND THAT, WE WERE STUDYING HOW THESE CELLS RESPOND TO EXTERNAL STIMULI AND FOR A VARIETY OF REASONS THAT HAVE TO DO WITH OUR STUDIES OF NAIS AT NITRICOXIDE PRODUCTION, WE USED A NITRIC OXIDE DONOR WITH THE S. N. A. P. AND WHEN YOU PUT IT ON TO THINGS IT LIBERATES NITRICOXIDE THAT CAN BE USED BY THE CELL TO PERFORM ITS ACTIVITY AND SURE ENOUGH WHEN WE TAKE OUR PATIENTS WITH PULMONARY NONTUBERCULOSE DISEASE AND ADD NITRIC OXIDE TO THEM, THE SILLIARY B-FREQUENCY NORMALIZED. WELL S. N. A. P. IS NOT AN APPROVED MEDICATION FOR THE TREATMENT OF HUGH MANS, HOWEVER CELL DENNA FILL IS, AND THAT ALSO INHIBITS FOSTER NURSED TO DISCIPLINARY AFT RACE 5 AND LEADS TO THE INCREASE IN THE LEVELS OF INTRACELLULAR NITRICOXICIDE AND SURE ENOUGH SILL DENNA FILL INCREASES THE B-FREQUENCY IN PATIENTS WITH PULMONARY NONTUBERCULOSE DISEASE RIGHT UP TO THE NORMAL LEVEL. AND THAT'S ALL INVITRO AND IF OUR HYPOTHESIS CORRECT THAT SILLULARY DYSFUNCTION IN THE LUNG IS INVOLVED IN PULMONARY MICROBACTERIAL DISEASE AND WE CAN UPREGULATE THE SILLULARY B-FREQUENCY INVITRO WITH I HAVE AG RA, WHAT CAN WE DO THEN IN HUMANS IN VIVO. AND THIS IS PRELIMINARY DATA AND I'M SHOWING IT IN THIS SHELTERED ENVIRONMENT BECAUSE I KNOW THERE'S A FENCE AROUND THE NIH AND WE'RE SAFE LEER, THESE ARE PRELIMINARY DATA BUT PROVOKAATIVE PRELIMINARY DATA AND HERE YOU SEE WHAT UPONS AFTER THE FIRST DOSE OF SILL DEN O FILL, THIS IS 30 MINUTES AFTER THE FIRST DOSE, SO PREE AND POST IN PATIENT WHO IS HAVE PULMONARY MICRO BACTERIAL DISEASE, THIS IS AT DAY 0, THEY'RE STILL RESPONDING, AT DAY 7 AND STILL RESPONDING 8 DAY 30. NOW WHETHER THIS TRANSLATES INTO CLINICAL IMPROVEMENT, THAT'S WHAT CLINICAL TRIALS ARE FOR. THAT'S WHAT THE NEXT PHASE IS ALL ABOUT. BUT SO FAR WE'VE GOT A LOGICAL HYPOTHESIS, WE'VE GOT COMPATIBLE FINDINGS, WE'VE GOT IN VIVO RESPONSES THAT ARE COMPELLING ENOUGH TO MAKE US BELIEVE THAT WE SHOULD BE GOING FORWARD TO LEARN MORE ABOUT THIS. SO PULMONARY INFECTIONS, IT'S A RESPERATTORY DISEASE, IT LOOKS LIKE IT'S GENETIC AND WE'VE NOW GOT DATA WE ARE MINING TO TRY AND FIND OUT WHAT THESE GENES ARE. REMEMBER THAT IN THE CASE OF MULL MONITORARY, PRIMARY SILLIARY DISKINNIESIA, THERE ARE DOZENS OF GENES INVOLVED IN PC D AND SO IT MAY WELL BE THE CASE THAT THERE ARE GOING TO BE MULTIPLE GENES INVOLVED IN IT. IT'S NOT GOING TO BE A SOLO PROBLEM BECAUSE THERE ARE OBVIOUSLY COMPLEX FEATURES TO THIS DISEASE SUCH AS HEIGHT AND MORPH O TIGHT. BUT IT REALLY IS NOT AN IMMUNE DEFECT WHICH MAKES SENSE BECAUSE THIS DISEASE NEVER DISSEMINATES. THERE ARE INTRINSIC SILLIARY ABNORMALITIES THAT CAN BE ALTERED, THAT IS THEY ARE DRUGGABLE. SO THE TAKE HOME MESSAGE SO NOW OVER 20 YEARS OF STUDYING THIS THAT I HAVE FINALLY COME TO IS THAT IN FACT, LUNG DISEASE IS LUNG DISEASE. AND PULMONARY NONTUBERCULOSE MICROBACTERIAL DISEASE IS AN AIR WAY DISEASE WHICH HELPS TO PUT IT IN THE CONTEXT OF ALL THOSE OTHER WAY WAY DISEASES--AIR WAY DISEASES THAT LET US US UNDERSTAND HOW WOULD WE GO ABOUT ALTERING AIR WAY FUNCTION AND DEFENSE. SO I'VE TRIED TO GIVE YOU A SENSE OF HOW LOCATION REALLY MATTERS IN THIS. IN DISSEMINATED LUNG AND IT TURNS OUT THAT WHERE YOUR PROBLEM IS, HAS A LOT TO DO WITH WHAT YOUR PROBLEM IS, SO THE FIRST QUESTION TO ASK IS NOT WHAT'S THE ORGANISM INVOLVED BUT WHERE IS THE ORGANISM INVOLVED AND TRY TO GO BACK TO WHAT THE PATIENT HAS AND THE PATIENT EXPERIENCE AND NOT TRY TO CRAM IT AS I DID FOR THE FIRST 20 YEARS I STUDIED THIS INTO THE MODEL THAT YOU UNDERSTAND THE BEST. SO I WANT TO FINISH BY TALKING ABOUT THAT IS RIGHT KIND OF PC R, PATIENT-CENTERED RESEARCH, IT STARTS WITH PATIENTS. IT'S COMPLICATED AND CONFUSING. IT'S GOT LOTS OF TWISTS AND TURNS BUT MY GOD IT IS THE MOST EXCITING THING OUT THERE AND IT REALLY IS WHAT THE CLINICAL CENTER IS ALL ABOUT. AND IF YOU DIDN'T KNOW THAT FOR SURE, HERE YOU HAVE THE GUY HERE ON DAY 1 TALKING ABOUT PATIENT CENTERED RESEARCH AND HERE WE ARE TODAY, DOING THE SAME DAMN THING, THAT IS REALLY WHAT 60 YEARS OF THIS SEEMS TO BE ABOUT AND I THINK WE'VE GOT EVERY REASON TO BE EXCITED ABOUT THE NEXT 60 YEARS. I'LL JUST ACKNOWLEDGE THE PEOPLE THAT HAVE DONE ALL THE WORK I'VE SHOWN AND I WAS--I'M JUST THE VEHICLE. IT'S AN EXTRAORDINARY TEAM, IT'S AN EXTRAORDINARY PLACE, THE OPPORTUNITY TO COLLABORATE AND WORK WITH SMART PEOPLE WHO DO THESE THINGS IS JUST AMAZING. IN PARTICULAR, IN THE MULL MONITORARY DISEASE, I WANT TO ACKNOWLEDGE SEEDER FOWLER AND KEN OLIVIA, AND DORIS WHOOP AND THE ANTIBODY AND SUSCEPTIBILITY DATA, SARAH BROWN, ELIZABETH AND CRISTA AND IN OUR OTHER WORK THAT'S LEADING ALL UP TO THIS OVER MANY YEARS ALEXANDER FREEDOM AN AND GILBERT AND OUR EXTRAORDINARY TEAM OF STUDY COORDINATORS, NURSES IN THE CLINIC, AND OUR COORDINATORS WHO HAVE DONE SO MUCH TO GET US THROUGH THIS. FINALLY, YOU KNOW NOBODY DOES THESE THINGS WITHOUT A MENTOR, NOBODY DOES THESE THINGS WITHOUT A FAMILY AND FOR ME, IT IS MY ENORMOUS GRATITUDE TO THANK NOT ONLY MY MENTOR JOHN GOWAN, BUT MY PARENTS WHO HELPED TO SHOW ME WHY THIS WAS EXCITING AND HOW TO GET IT DONE. THANK YOU VERY MUCH. [ APPLAUSE ] >> I JUST WANT TO THANK BOTH OF OUR SPEAKERS FOR WHAT I FEEL WAS AN INCREDIBLE START OF A SERIES OF GRAND ROUNDS ALLUDING TO 60 YEARS OF PATIENT CENTERED RESEARCH HERE AND IN INVITE ALL OF YOU TO JOIN US FOR A RECEPTION JUST BEYOND THESE WALLS BEHIND US IN THE SOUTH LOBBY. SO, WE'LL HAVE INFORMAL DISCUSSION THERE. [ APPLAUSE ]