>> GOOD MORNING. IT'S MY DISTINCT PLEASURE TO WELCOME YOU TO THE PHILLIP CHEN LECTURE ON TECHNOLOGY TRANSFER. BEFORE I INTRODUCE TODAY'S SPEAKER WHO FOR MANY OF YOU WILL NOT NEED MUCH INTRODUCTION, I WANT TO TELL YOU ABOUT PHIL. I WAS LOOKING AT THE AUDIENCE AND I REALIZE THAT PHIL RETIRED 11 YEARS AGO AFTER 41 YEARS OF SERVICE WITH A CAPITAL S TO THE NIH AND SOME OF YOU MAY NOT KNOW HIM. WHEN WE STARTED THIS LECTURE SERIES, EVERYBY KNEW HIM. BUT, OTHER THAN THIS ACTIVITY AND THE LEGACY THAT HE LEFT AT NIH HE MAY NOT BE THAT WELL KNOWN TO YOU. LET ME TELL YOU ABOUT HIM. THE LECTURE WAS ESTABLISHED TO HONOR PHIL'S DIVERSE AND CREATIVE CONTRIBUTIONS TO THE NIH BOTH AS A SCIENTIST IN ITS INTRA MURAL RESEARCH PROGRAM AND AS AN ADMINISTRATOR OF MANY IMPORTANT INNOVATOR PROGRAMS. SOME OF YOU MAY KNOW THE NAME CHEN BECAUSE HE IS THE AUTHOR OF 1 OF THE MOST HIGHLY CITED PAPERS IN THE BIOMEDICAL LITERATURE, WHICH ESTABLISHES THE CHEN ANALYSIS FOR PHOSPHATE. SO WE USE THIS IN MY LAB ALL THE TIME. I SUSPECT MANY OF YOU ALSO USE THE CHEN FOSTER NURSED FOE AMMONIUM LIPIDATE TO MEASURE PHOSPHATE. AFTER HIS SCIENTIFIC CAREER ENDED--I SHOULDN'T SAY ENDED, HE GRADUALLY EVOLVED INTO A MORE ADMINISTRATIVE BASIS, THOSE OF US WHO ON DO THIS KNOW HOW THIS HAPPENS. HE EVENTUALLY CAME INTO A TOTAL OF 8 DIFFERENT DIRECTORS, FROM 1956-79 AND THEN FROM 1996-SNIFF, AND MOST OF HIS CAREER WAS IN THE OFFICE OF THE DIRECTOR AND A LOT OF IT WAS THE DIRECTOR OF THE EPITHELIAL RAMURAL RESEARCH. HE WAS KNOWN FOR INNOVATION AND SENSITIVITY THAT EFFECTED SCIENTISTS AT THE NIH AND I WOULD SAY HIS OFFICE WAS CONSTANTLY FULL OF PEOPLE WHO WERE COMING TO EXPRESS CONCERN ABOUT 1 OR ANOTHER SYSTEMS THAT WEREN'T SERVING THEM WELL AND PHIL WAS A VERY ACTIVE PARTICIPANT IN MAKING SURE THAT THE SYSTEMS AT THE NE --NIH WORKED WELL HERE. HE CHAMPIONED NEW PAY AND PAY SERVICES FOR RESEARCHERS, PROGRAMS FOR FOREIGN SCIENTISTS AT THE NIH AND A NOVEL OF ENDEAVORS ON ARCTIC RESEARCH IN THE DEPARTMENT OF HEALTH AND HUMAN SERVICES. MOST RELEVANT TO THIS LECTURE, PHIL ESTABLISHED IN 1968 THE OFFICE OF TECHNOLOGY TRANSFER AT THE NIH AND IN RESPONSE TO THE NEW FEDERAL TECHNOLOGY TRANSFER ACT. HE FORMULATED ALL THE GUIDING PRINCIPLES THAT LEAD TO TECHNOLOGY TRANSFER HERE AT NIH AND HE INVENTED THE COOPERATIVE RESEARCH AND DEVELOPMENT OR CRDA, AND ALL OF THOSE ARE WITH US UNTIL TODAY AND HAVE SERVICED US EXTREMELY WELL. HIS COUNSEL TO ME AND I THINK TO ALMOST EVERYONE WHO CAME TO SEE HIM WAS ALWAYS WISE AND COMPASSIONATE AND HE EARNED THE GRATITUDE OF ALL OF THE SCIENTIFIC ADMINISTRATORS AT THE NE H. PHIL HAS ATTENDED EVERY 1 OF THESE SESSIONS AND HE'S BROUGHT WITH HIM, HIS WIFE AND MUCH OF HIS FAMILY AND I WONDER IF YOU WOULD BE WILLING TO STAND UP SO PEOPLE COULD RECOGNIZE YOU? [APPLAUSE ] SO THANK YOU ALL FOR THE 41 YEARS YOU SPENT AT THE NIH. SOME WERE NOT HERE BEFORE HE RETIRED AND WE APPRECIATE THAT. SO LET ME JUST END BY SAYING THAT WE REALLY APPRECIATE PHIL NOT ONLY FOR ALL THAT HE'S DONE FOR NIH BUT BECAUSE WE HAD THE OPPORTUNITY TO ESTABLISH THIS LECTURE SERIES WHICH RECOGNIZES A DISSINK FEATURE OF THE INTRA MURAL PROGRAM WHICH IS THE ABILITY TO TRANSLATE MOST OF OUR MOST IMPORTANT DISCOVERIES INTO TREATMENTS FOR HUMAN DISEASES AND NO 1 BETTER EPITOMIZES THE SUCCESSFUL TRANSLATION OF THIS KIND OF RESEARCH BETTER THAN JOHN O'SHEA, HE IS THE DIRECTOR OF THE NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL SCIENCES, HE GOT HIS MEDICAL DEGREE FROM THE UNIVERSITY OF CINCINNATI AND CAME TO NIH IN 1981 WHERE HE DID SOME SPECIALTY TRAINING IN ALLERGY AND IMMUNOLOGY AND NIAID AND STARTED HIS OWN LAB AT NCI IN 1989 AND MOVED TO AMS IN 1994. AS CHIEF OF THE LYMPHOCYTE CELL BIOLOGY SECTION, CHIEF OF IMMUNOLOGY AND INFLAMMATION BRANCH IN 2002, AND BECAME NMS SCIENTIFIC DIRECTOR IN 2005. AS A SCIENTIFIC DIRECTOR HE HAS BEEN REALLY EXEMPLARY, HAVING ALWAYS A TRANSNIH VIEW OF WHAT HE DOES AND AS A RESULT, FORTUNATELY FOR HIM, HE'S ON VIRTUALLY EVERY COMMITTEE THAT WE HAVE THAT OVERSEES TRANSNIH ACTIVITIES AND I'M VERY GRATEFUL FOR HIM TO DO THAT. IN ADDITION, HE HAS CONTINUED TO RUN AN INCREDIBLY PRODUCTIVE LAB AND DURING THIS PERIOD OF DEVELOPMENT AND OF THE SCIENTIFIC PROGRAM AMONG OTHER THINGS HE DISCOVERED THE JACK 3 KINE ACE AND SHOWED THAT GEN THETIC DEFECTS IN THAT KINE ACE CAUSE SEVERE IMMUNE O DEFICIENCY, CLONED GENE FOR THE HUMAN VERSION OF THE PROTEIN. HIS WORK LED TO THE CREATION OF DRUGS THAT SPECIFICALLY TARGET JACK KINE ACES. ONE SUCH DRUG TOFASIT--AND I WAS WATCHING TELEVISION AND THERE WAS A BIGAD FOR [INDISCERNIBLE] AND AFTER THEY GOT OVER THE LONG LIST OF HORRIBLE THINGS THAT HAPPEN TO YOU WHEN YOU TAKE IT, IT BECAME CLEAR THAT THIS IS A BLOCKBUSTER DRUG, AND I SUSPECT DRUG WILL TELL US ABOUT THE DEVELOPMENT OF THE DRUG. HE HAS PATENTS RELATED TO THE WORK. HIS LAB CONTINUES TO REVEAL STARTLING INSIGHTS INTO THE STUDY OF CYTOKINES, T-CELLS, HOST DEFENSE AND AUTOIMMUNE DISEASES AND TO ADD TO THAT INCREDIBLE LIST, HE'S RECENTLY BEEN COLLABORATING WITH DR. FRANCIS COLLIN'S' LAB TO BED HOW T-CELL SUPER ENHANCERS EFFECT THE FUNCTION OF THE IMMUNE SYSTEM. HE WAS ELECTED TO THE NATIONAL ACADEMY OF MEDICINE IN 2004. ONE OF THE CONFOUNDERS OF THE NIH OXFORD CAM BRAG PROGRAM AND A MEMBER OF THE NIH UNIVERSITY OF PENNSYLVANIA IMMUNOLOGY PROGRAM AND HOWARD HUGHES MEDICAL STUDENT ADVISOR TO MANY MEDICAL STUDENTS. HE AS A LOT OF AWARDS, THEY'RE COMING FAST AND FURIOUS, IT'S 1'RE HARD TO KEEP UP WITH THEM, 1 OF THEM WAS THE ROSS PRIZE OF MOLECULAR MEDICINE IN 2014 AND THE CITATION THERE READ HIS WORK HAD DEMONSTRATABLE WORK ON THE HUMAN DISEASE PATHOGENESIS. HIS TALK TODAY IS TITLED IMMUNE DISEASE AND DRUGS. THANK YOU FOR TALKING TODAY. [ APPLAUSE ] >> THANKS VERY MUCH FOR THAT MICHAEL IT'S A LITTLE EMBARRASSING BUT NICE TO HEAR THOSE THING. SO I LIKE TO START BY THANKING EVERYBODY HERE AT THE NIH. I'VE BEEN HERE FOR 35 YEARS AND THE EXTENT TO WHICH I'VE BEEN SUCCESSFUL. I MUST SAY, IT'S REALLY, THANKS TO--I HOPE YOU CAN SEE YOUR NAMES HERE, READ THE NAMES, IF YOUR NAME--IF YOU GOAPT SEE YOUR NAME, LET ME KNOW, I TRIED TO AT SOME POINT GET EVERYBODY'S NAME IN HERE BUT I'M SURE I DIDN'T. REALLY IT'S A REMARKABLE PLACE TO WORK AND I'M REALLY VERY THANKFUL FOR THAT AND I WILL TRY TO GIVE YOU EXAMPLES AS I GO ALONG HERE. SO JUST TO GO BACK TO THE BEGINNING, WHEN I WAS A MEDICAL STUDENT, I WAS ON THE INFECTIOUS DISEASE SERVICE AND WE SAW A PATIENT LIKE THIS AND THE ATTENDING TOLD ME SOMETHING THAT REALLY STUCK WITH ME AS YOU'LL SEE ABOUT THIS PATIENT, THE PATIENT HAD AN INFECTION THAT CLEARED BUT THEY WERE IN DISTRESS BECAUSE OF THEIR HOSTED RESPONSE. SO WHAT HE WORKED ON AT THE TIME THIS, IS 1 OF HIS EARLIER PAPERS, JOHN BORNSTEIN, AND HE WAS WORKING ON LEUCOCYTIC PYROGEN, THEY KNEW IT MADE STUFF THAT GAVE YOU FEVERS BUT REMARKABLY IT TOOK A LONG TIME BEFORE WE FIGURED OUT EXACTLY WHAT THAT WAS. ULTIMATELY LIKE CHARLES [INDISCERNIBLE] AND [INDISCERNIBLE], THE A LUM FIGURED OUT IT WAS CALLED INTERLUKEIN 1 BUT AT THE TIME, THE ASSAY FOR THIS WAS TAKING RABBITS AND INJECTS RABBITS WITH THE COLUMN FRACTIONS TO SEE WHERE THIS PYROGEN WAS BEING PURIFIED. AND REMARKABLY, I WAS IN BORSTEIN'S LAB AND EVEN IN 77 THIS IS WHAT THE ASSAY LOOKED LIKE. SO IT WAS FAIRLY CRUDE BUT AT THE SAME TIME I WAS TREMENDOUSLY EXCITED ABOUT THIS AND THEN I WENT ON TO DO MY RESIDENCY AND 1 OF THE PATIENTS I ADMITTED WAS THIS NURSE, VIETNAM NURSE WHO CAME IN--WE DIDN'T HAVE THIS ALLOT THE TIME, THIS IS GREYSON'S WORK WAS TAKING UP THE MATH AND LOOKING AT DISEASE VASC LIGHTIS, DOING BEAUTIFUL WORK USING PET IMAGING OF VASCULITEIS, BACK IN THE 70 THIS IS IS MORE HOW WE DID IT, BUT THE PATIENT HAD IT AND THE ATTENDING DIDN'T KNOW WHAT TO DO WITH THIS DISEASE SO I RAN TO THE LIBRARY AND XEROXED. WE HAD XEROX MACHINES BACK THEN AND 1 OF THE PAPERS THAT EVERYBODY XEROXED AT THAT TIME WAS THIS PAPER AND EVERYBODY WAS LISTENING TO THE WORDS OF TONY FAUCI, AND READING ABOUT TREATING TREATING VASCULITEIS. I WAS CALLING DOWN TO TONY'S LAB AND SAY WHAT DO I DO WITH PATIENT, ET CETERA, ET CETERA. AND THAT WAS MY FIRST REAL AWARENESS OF LIFE AT THE NIH. SO I CAME IT WORKED WITH TONY ON VASCULITIS PATIENTS. SO THE OTHER THING IS THE BIOLOGY OF REVOLUTION, IT LOOKED LIKE VERY LITTLE PROGRESS HAS BEEN MADE BETWEEN 1962 AND THE LATE 80S WHEN THE LAB I WAS WORKING IN WAS TRYING TO FIGURE OUT WHAT [INDISCERNIBLE] BECAUSE [INDISCERNIBLE] WAS. IN THE MEAN TIME, WE HAD MOLECULAR BIOLOGY REVOLUTION, WE'RE SUDDENLY LOTS OF PEOPLE WERE CLONING LOTS OF CYTOKINES AND PEOPLE LIKE WARREN LEONARD AND TOM WELD MAN'S LAB WORKING WITH TOM ULTIMATELY CLONE THE ALPHA CHAIN OF THE IL2 RECEPTOR AND THEN MANY OTHER CYTOKINES AND CYTOKINE RECEPTOR CLONES. BUT--AND OTHER RECEPTORS ARE BEING CLONED AS WELL AND I REMEMBER A MEETING I WENT TO IN THE EARLY DAYS OF THE RECEPTOR, BIOLOGY MEETING WHERE WHEN THE INSULIN RECEPTOR WAS CLONED IT WAS EXCITING BECAUSE WE KNEW TAKEN--THEY INSULIN TYRO SEEN PHOSPHORALATES, AND THE QUESTION WAS HOW DID IT OCCUR? BUT IT WAS EDIFYING IN THE WAY THAT THE RECEPTORS HAD THE ACKIVITY, AND THEY HAD DIFFERENT KINE ACES, THAT WAS THE MYSTERY SOLVED THERE BUT AT THE SAME TIME IT WAS PUTTING CYTOKINES CELLS AND THEY TOO INDUCINGED TYROSEEN PHOSPHORALATION, SO THE RACE WAS ON TO FIGURE OUT THE PATH WAY AND THE KINE ACE PATH WAY. SO AS MICHAEL SAID WE WERE FORTUNATE ENOUGH TO BE INVOLVED IN THIS WITH JIM DARNEL AND GEORGE STARK AND SANDRA PELLIGRINI, AND OUR LAB AND OTHERS FOUND THAT FOR THIS CLASS OF RECEPTORS INSTEAD OF HAVING A RECEPTOR BEING A TYROSEEN KINE ACE, THEY HAD A TYROSEEN KINE ACE THAT WAS ASSOCIATED WITH THE CYTOPLAYSIC DOMAIN OF THE RECEPTOR AND NOW WE KNOW THAT THIS A PATH WAY THAT'S USED BY MORE THAN 60 CYTOKINES AND GROWTH FACTORS AND IT'S EVOLUTIONARARLY CONCERNED THAT APPLIES TO MAN MEDICARE AND MEDICAIDS AND CHUCK'S OFFICE HERE WHO'S RESPONSIBILITY FOR DISCOVERIES RELATED TO THE FLY JACK WHICH ACTUALLY ANTICIPATED ANOTHER DISEASE THAT I'LL TELL YOU ELL YOU LL YOU ABOUT IN A MOMENT. --BUT REALLY WAS THIS REALLY RELEVANT INVIVO. WAS IT REALLY THE CASE THAT FOR A SIGHT ON KINE, THAT ALL OF THE ACTION OF THE CYTOKINE DEPENDS ON THIS PROXIMAL STEP? SO AGAIN, AT THE TIME IT WAS FORTUNATE ENOUGH TO KNOW WARREN, WARREN HAD CLONED AS A MENTION, AN IL2 RECEPTOR BUT THEN FIGURED OUT THAT THE DISEASE SEVERE COMBINED IMMUNE O DEFICIENCIES, BUBBLE BOY SYNDROME, WHICH DUE TO A MUTATION THE COMMON GAMMA CHAIN AND WHEN WE CLONE JACK 3, WORKING WITH WARREN WE SHOWED THAT IN FACT JACK 3 ASSOCIATES WITH A COMMON GAMMA CHAIN AND NOT OTHER CYTOKINE RECEPTORS SO WE MADE THE PREDICTION THAT IT COULD BE THAT CHILDREN WHO HAD A DISEASE THAT LOOKED LIKE BUBBLE DO I SYNDROME MUTATIONS OF THE GAMMA CHAIN MIGHT HAVE MUTATIONS AND IT WOULD NOT BE BOY, IT WOULD BE BOYS AND GIRLS. SO ANOTHER NIH ALUM, IF YOU'RE GETTING THE THEME, THE NIH IS A GREAT PLACE TO WORK, RIGHT? SO EITHER YOU'RE HERE AT 1 POINT IN YOUR CAREER OR YOU COME BACK. T. G. WAS HERE AND WENT BA TO ITALY AND NOW COME BACK AGAIN. G. G. WAS SEEING THESE PATIENTS AND IN FACT SORT OF MADE THAT CONNECTION AS WELL. AND SO, IDENTIFIED PATIENTS WITH JACK 3 MUTATIONS OR HAD A DISEASE THAT LOOKED A LOT LIKE XSKID. SO AS LUCK WOULD HAVE IT, FABIO HAD WORKED WITH G. G. BUT WAS IN MY LAB AT THIS TIME SO COLLABORATING WITH WARREN AND G. G. AND REBECCA BUCKLEY, WE RAPIDLY IDENTIFIED PATIENT WHO IS HAD JACK 3 GENES TO LOOK LIKE MUTATIONS OF THE COMMON GAMMA GENE. SO THE OTHER THING THAT WAS HAPPENING IN TERMS OF INNOVATION WAS THAT AS ALL OF THESE CYTOKINE AND CYTOKINE RECEPTORS WERE DISCOVERED PEOPLE WERE MAKING MONOCLONAL ANTIBODIES AND IN OUR BUSINESS, IN RHEUMATOLOGY, THIS REALLY CHANGED THE LANDSCAPE OF HOW WE TREAT PATIENTS WITH ALL OF THESE DRUGS WE NOW HAVE FOR A VARIETY OF INDICATIONS. BUT THE QUESTION FOR US WAS, CAN YOU TARGET CYTOKINES INTRA CELLULARLY BASED ON WHAT WE LEARN AND I WILL TALK ABOUT THIS CLASS OF RECEPTORS, THE SO CALLED TYPE 1, TYPE 2 CYTOKINE RECEPTORS THAT USE JACKS. SO WE MADE THE BOLD STATEMENT IN THIS PAR, BACK IN 1995 THAT IF YOU TARGETED JAK, HAVE YOU A NEW CLASS OF IMMUNE O MODUE LATTERY DRUGS. NOW WE ALL KNOW THE DIRTY LITTLE SECRET, THAT IF YOU PREDICT SOMETHING IT'S BECAUSE YOU ALREADY KNOW THE ANSWER AND IN 1993 I HAD BEEN TO A MEETING SO THIS WAS A SCIENTIFIC MEETING AND I THINK I WASN'T EVEN SPEAKING AT THIS MEETING, I WAS GIVING A POSTER OF SOMETHING AND I WAS ALLOWED TO GO TO THE MEETINGS, IT WAS VERY EXCITING, YOU KNOW? SO, YOU KNOW I WANT TO SAY PUBLICLY SCIENTIFIC MEETINGS ARE A GOOD THING FOR SCIENTISTS, YOU KNOW IT'S A BOLD STATEMENT, BUT--SO I SHOWED UP AT THIS MEETING AND I--AGAIN, SERENDIPITY THAT HERE'S THIS GUY, AND WE RAN INTO PAUL AND PAUL AND I ACTUALLY HAD WORKED ON SIMILAR AREAS FOR BEFORE I STARTED WORKING ON CYTOKINE SIGNALING AND I SAID PAUL, WHAT ARE YOU DOING HERE, I SAID LYMPHOCYTES AND ANTIBODIES MEETING AND I THOUGHT YOU WORKED ON COMPLEMENT, HE SAID NO, I LEFT THAT, I LEFT HARVARD AND I WORK FOR PFIZER AND WHAT PFIZER WANTS TO DO IS IDENTIFY IDENTIFY KINEAISES THAT WILL BE GOOD FOR TREATING AUTOIMMUNE DISEASE, ET CETERA. SO I SAID HAVE I GOT THE KINE KINASE FOR YOU? AND SO THEY TALK ABOUT THE FAMOUS WALK IN THE WOODS IF YOU HAVE EVER BEEN TO SAXON RIVERS, VERMONT, THERE'S PLENTY TO WALK AROUND. WE TALK ABOUT THE RELATIVITY AND KINASES AND I SAID NO, NO, THE FUTURE OF PFIZER IS IN JAKs. SO THIS BRINGS ME TO THE PART THAT SID STILL IS THE GUY WHO STARTED CRDA, WE HAVE A PATTERN AGAINST JAKs, RIEL TELL --I'LL TELL YOU ABOUT THAT IN A MOMENT BUT WE DEVELOPED THIS BOARD WITH PFIZER THAT WE STILL HAVE. AND IT'S--THANKS FOR THAT--IT'S AN AMAZING INNOVATION, IT'S BEEN A LOT OF FUN FOR ME FOR YEARS TO INTERACT WITH PFIZER SCIENTISTS, YOU KNOW, THE WAY WE DO THINGS, THE WAY INDUSTRY DISS THINGS DIFFERENT AND THEY HAVE A LEVEL OF RIGOR THAT IS REALLY NECESSARY TO GET A DRUG FROM SORT OF A--YOU KNOW A CACAMIMI IDEA TO PAUL IN THE WOODS TO THAT I PITCH PITCHED TO A DRUG THAT WAS GIVEN TO THOUSANDS AND THOUSANDS OF PEOPLE. ON TOP OF THIS WE HAVE THIS PATTEN AND SO ME AND THE NIH HAVE GOTTEN WEALTHY WITH THIS SO I'VE LITERALLY MADE HUNDREDS OF DOLLARS OVER THE YEARS FOR THIS DRUG AND I GUESS THE NIH MAKES MORE THAN THAT. SO SLIGHTLY MORE THAN THAT. BUT EVERYONE IN MY LAB IS ALSO--I'M LOOKING AT YOU, VERY EXCITING EACH YEAR WHEN I GET MY ROYALTY PAYMENT, WE GO DOWN TO THE OLD [INDISCERNIBLE] AND WE CELEBRATE OR THEY CAN HAVE LARGE COFFEES. [LAUGHTER] SO PFIZER DID TAKE THIS PROBLEM ON. AND CAME UP WITH THIS DRUG SHOWN HERE AND I'LL HAVE MORE TO SAY ABOUT THIS, BELIEVE IT OR NOT AT THE TIME, I MEAN THIS IS THE MID90S AND THE IDEA OF TRYING TO TARGET KINASES WITH DRUGS, YOU COULD MAKE THE ARGUMENT, WHAT ARE YOU TRYING TO DO? YOU'RE TRYING TO MIMIC ATP. THAT'S JUST NOT GOING TO WORK. THERE WAS A FAIR PART OF THE COMMUNITY THAT SAID, YOU KNOW THAT'S JUST--YOU CAN'T GET THE SPECIFICITY THAT YOU NEED BUT IN FACT, YOU COULD SEE THE STRUCTURE, THIS MOLECULE AND YOU KNOW FROM MANY OTHER EXAMPLES THAT IN FACT, YOU CAN BUT IT WAS--BELIEVE IT OR NOT, IT WAS CONTROVERSIAL AT THE TIME. SO WE HAVE A MULTIPLE FDA APPROVED JAK, AND IT WAS THE FIRST 1 APPROVED, THIS IS FOR THE DISEASE, [INDISCERNIBLE], ASSOCIATED WITH GAIN OF FUNCTION MUTATIONS OF JAK 2 AND THAT'S WHERE CHUCK'S WORK COMES IN, HE E DENTIFY TED SIMILAR MUTATIONS IN THE SLIDE, CAUSED LEUKEMIA JUST LIKE YOU SAW IN THIS DISEASE IN HUMANS AND HENS THIS AN INDICATION OF TOFFA SIT NIB, AND IT'S JAK 1, AND 3, GREATER THAN 2, APPROVED FOR R. A. AND INFLAMMA FORY BOWEL DISEASE AND SIR EYA SIS, AND WHAT'S EXCITING ABOUT THIS DRUG IT'S SUPERIOR TO MEXA TREKSATE. SO MEXA TREKSATE AGAINST, SOME OF THE FIRST STUDIES USING THIS IN ARTHRITIS WERE DONE HERE. ACTUALLY IN NIAMS, AND THEN IT WAS NIDDK, BUT EVEN SUPERIOR TO THE ANTITMF DRUGS, THESE ARE THE GOLD STANDARDS FOR RHEUMATOID ARTHRITIS SO VERY EXCITING IN THE FIELD. SO I WANT TO TELL YOU ABOUT ANOTHER NIH PATIENT, THIS IS LEO, HE BELONGS TO [INDISCERNIBLE] IN NHGRI. AND AS YOU CAN SEE, LEO IS A VERY UNHAPPY DOG. LEO HAS A SKIN DISEASE HERE, CAN YOU SEE IT'S HARD TO SEE HERE BUT IT'S RED, AND HE'S SCRATCHING ALL THE TIME AND EBONA ACTUALLY HEARD 1 OF MY TALKS, MAX [INDISCERNIBLE] WHO WAS GIVING THE TALK AND EBONA SAID, WHAT DO YOU KNOW ABOUT DRUGS FOR POOR LEO. AND THE ANSWER IS THERE IS A DOGGIE JAK INHIBITOR AND LEO IS STARTED ON THAT AND THIS IS LEO 3 WEEKS AFTER HE WAS STARTEDOT CAININE JAK INHIBITOR, SO IT'S JAK 1, 2, 3, SO IT'S NOT JUST USED FOR OUR SPECIES BUT OTHER SPECIES AS WELL. AND AS I'LL GET TO IN THE NEXT SLIDE, THE SUCCESS OF THESE DRUGS IN DERM TAKEN--THEY LOGICAL CONDITIONS IN DOGS MADE IT OBVIOUS TO SEE IF THE DRUGS WOULD BE USEFUL IN PEOPLE. SO HERE'S AN EXAMPLE, THIS IS A DISEASE CALLED ALOPECIA AREATA, AND THIS IS AN AUTOIMMUNE ATTACK OF HAIR FOLLICLES AND YOU CAN SEE THAT THE JAK INHIBITION RAPIDLY REVERSES THE LOSS OF HAIR IN THESE PATIENTS AND ALSO IT'S INTERESTING SO A LOT OF EXCITEMENT ON THIS, BUT ACTUALLY JAK INHIBITION PROMOTES HAIR GROWTH AND AS YOU CAN IMAGINE I'M VERY EXCITED ABOUT THIS. [LAUGHTER] , THIS MAY BE MY MOST IMPORTANT CONTRIBUTION TO MANKIND, I THINK. BUT IN ADDITION TO THIS DISEASE THERE'S A NUMBER OF OTHER DERM TAKEN--THEY LOGICAL CONDITIONS, INTHAT CAN BE USED INCLUDING VITILIGO, NOW THAT WE ENCOURAGED MARY CAP LANTO TACKER ANOTHER DISEASE THAT THE NIH HAS BEEN WORKING ON AND THIS IS LUPUS, AND AGAIN IN MICE AND WHAT YOU CAN SEE HERE, WITH ESCO AND MAX HAVE DONE HERE S&P TAKE MICE, CONTROL MICE AND THEN MICE HAVE LUPUS, AND THEN THIS --THIS LUPUS MODEL, YOU CAN SEE THE KIDNEYS IN THE MICE. SO AS MIKE WAS SAYING, THAT MAKE ITS EASY TO TRANSLATE WHAT WE'VE DONE TO MICE AND SEE IF THIS IS USEFUL IN HUMANS SO WE STARTED A PHASE 1 B-TRIAL AND SARFARAZI HASNI, AND MARRIANA ARE SPEAR HEADING THAT. SO TO SUMMARIZE WHAT WE'RE THINKING, SO WAY BACK IN VERMONT WHAT I WAS PITCHING TO PAUL WAS IF YOU TARGETED JAK 3, BASED ON WHAT WE SAW WITH THE PATIENT, THAT WOULD GIVE YOU A NEW IMMUNE O MODULATORY DRUG, SO AT THE TIME WE WERE THINK BEING ADAPTIVE IMMUNITY. AND THAT'S BECAUSE ACTUALLY NOBODY WAS REALLY EVEN USING THE TERM IN8 IMMUNITY BACK THEN. EVERYBODY WAS FOCUSING MORE ON T-CELLS AND B-CELLS AND THAT SORT OF THING AND CHARLIE WAS POPULARIZING THIS CONCEPT BUT I'LL COME TO THIS IN A MOMENT. THE OTHER THING OF COURSE IS THAT THE, YOU KNOW WE DIDN'T HAVE THE HUMAN GENOME YET SO WE DON'T KNOW HOW MANY KINASES THERE WERE. IT WOULD BE A FAIR QUESTION TO SAY, OKAY, THIS IS THE QUESTION I RAISED BEFORE, THIS IS SORT OF AN ATP LIKE DRUG, WHAT KINASES ARE YOU INHIBITING. NOW THAT CAN BE DONE ROUTINELY NOW, THAT'S THE SIMPLE ASSAY BUT WE DIDN'T KNOW HOW MANY THERE WERE AT THE TIME. AND ALSO, WE DIDN'T KNOW MUCH ABOUT ALL THE DIFFERENT CYTOKINES, THEY HADN'T DONE ANY YET. SO OF COURSE, NOW WE KNOW THAT THESE DRUGS ACTUALLY INHIBIT JACK 3, JACK 1, JAK TABOO, BUT THE BOTTOM LINE IS THAT YOU'RE INHIBITING CYTOKINES AND AS I WILL GET TO IN A MOMENT, I THINK IF I HAD GONE TO PFIZER IN THOSE EARLY DAYS AND SAID, OH IT'S FINE IF YOU HAVE THIS DRUG THAT BLOCKS 3 OUT OF THE 4 JAK; IT'LL BE FINE BUT IT IS ACTUALLY A LEGITIMATE QUESTION NOW WHEN YOU THINK ABOUT THE EFFICACY OF A DRUG LIKE TOKAFIT NIB. SO FIRST GENERATION, ALL OF THE FIRST GENERATION JAKs THAT I MENTIONED TARGET MULTIPLE CYTOKININGS. NOW AS LUCK WOULD HAVE IT, BEYOND JAKs, THE PRESENT JAK ACTUALLY HAVE PRETTY GOOD KINE OHM SELECTIVITY. THEY DON'T INHIBIT KINASES OTHER THAN THOSE JACKS BUT THEY DO HAVE ADAPTIVE AND INNATE IMMUNE RESPONSES AND THAT'S THE QUESTION, IS THIS PART OF THE EFFICACY AND THE SIDE EFFECTS THAT MICHAEL MENTIONED EARLIER. BUT IF YOU THINK OF A DISEASE LIKE RHEUMATOID ARTHRITIS AND YOU GET THE BUSY SLIDE AND THE POINT ACTUALLY IS JUST THAT, IT'S BUSY THAT THERE'S LOTS OF CYTOKINES THAT CONTRIBUTE TO THE DISEASE LIKE RHEUMATOID ARTHRITIS AND OTHER AUTOIMMUNE DISEASES SO THE 1S THAT ARE LABELEDINK ARE THE 1S THAT ACTUALLY USE JAKs, BY THIS SIGNALING. SO IN FACT, A LOT OF THE CYTOKINES THAT TRIBUTE TO DISEASE IN RHEUMATOID ARTHRITIS ACTUALLY ARE SENSITIVE TO JAK INHIBITION. NOW THE FLIP SIDE OF COURSE, WHAT ABOUT SIDE EFFECTS AND THE BIG THING OF COURSE IS WHERE DID YOU GET THIS IDEA WHEN THEY PITCHED THIS IDEA IN 95, SO THOSE ARE PATIENTS WITH INFECTIONS SO YOU MIGHT ARGUE, YOU INHIBIT JAKs BUT SURPRISINGLY IN A WAY, IS ASSOCIATED WITH SERIOUS INFECTIONS, BUT IT'S REALLY IN THE ON SO DIFFERENT THAN ALL OF THE OTHER DRUGS WE PRESENTLY USE FOR BIOLOGICS, THE INHIBITORS IL6, BLOCKERS, ET CETERA, ET CETERA, SO AGAIN HOW DO YOU SPLINE THAT? PROBABLY IT'S RELATED TO DOSE AND IT'S ALSO THE FACT THAT TOPOSIT NIB IN PARTICULAR HAS A RELATIVELY SHORT FLIGHT, NOT NECESSARILY TRUE OF SOME OF THE OTHER JACK ININCREASE IN BODYS, BUT AGAIN IT PROBABLY IS DOSE RELATED AND THAT YOU'RE NOT ENTIRELY SHUTTING OFF SIGNALING VIA ALL THESE CYTOKINES ALL OF THE TIME. SO WHAT'S IN THE FUTURE, SO FOR NEXT GENERATION, THEY WERE IN THAT PHASE, FIRST GENERATION JAKS, ARE TARGETED AND MULTIPLE CYTOKINES ARE SELECTIVE AND THEY'RE GENERATED AND JAK INHIBITORS THAT JUST INHIBIT JACK 1 AND 2, AND IT REMAINS TO BE SEEN, TELL BE AS EFFICACIOUS AND HAVE FEWER SIDE EFFECTS SO THAT'S ONGOING BUT LAST I CHECKED THERE ARE MANY MORE THAN JAKHELP INITS THAN ARE TESTED. SO MAYBE JUST TO REFLECT ON THE LESSONS LEARNED ON WITH THIS CLASS OF DRUGS, WARREN AND I CERTAINLY PREDICTED THE EFFICACY OF THESE DRUGS BUT WHAT WE DIDN'T KNOW OF COURSE WAS THE SAFETY. SO THAT OBVIOUSLY WE DO KNOW AND AGAIN, MAYBE IT'S A SURPRISE THERE. I THINK THAT NO 1 WOULD HAVE PREDICTED THAT A DEGREE OF SELECTITY THIS WEEKEND WOULD BE ESSENTIAL, IF YOU SAID WELL THESE DRUGS INHIBIT MULTIPLE JACKS AND KINASES MOST PEOPLE WOULD SAY THAT'S JUST NOT TENABLE. IN FACT IT'S A BIG ARGUMENT IN THE FIELD WHETHER SELECTIVITY WOULD BE ACHIEVABLE AND KNOW WHAT'S HAPPENED IN THE INTERIM IS THAT THEY'VE DONE AMAZING THINGS BUT WE'RE NOW DOWN TO THE FACT THAT WE CAN TAKE MOLECULES THAT LOOK LIKE ATP AND YOU CAN MAKE HIGHLY SELECTIVE DRUGS. I DON'T THINK ANYONE WOULD HAVE PRODICKED IF A JAK INHIBITOR WOULD BE A GOOD CANDIDATE WAY BACK IN THE 90S. JAK 1 KNOCK OUTS ARE PERIINATEALLY LETHAL, JAK 2 ARE LETHAL BECAUSE YOU CAN'T MAKE DEFINITIVE HEMEAT O POETICESIS AND FOR THAT REASON MOST PEOPLE IN TIME WOULD SAY IF YOU'RE CHEMIST MADE A JAK INHIBITOR AND IT MADE JAK 1 OR 2 IT WOULD DISQUALIFY THESE CANDIGATES GOING FORWARD. THAT'S NOT THE CASE. WE PREDICTED THESE DRUGS WERE USEFUL FOR PREDOMINANTLY BY ADAPTIVE IMMUNITY T& B CELLS BUT WE DIDN'T KNOW ABOUT INNATE IMMUNITY AND THEY START A BROAD SPECTRUM OF CYTOKINES. WE PREDICTED THEY WOULD BE ASSOCIATE WIDE INFECTION KNOWING THAT JAK 2 WAS SO IMPORTANT FOR HEME AT O POE ICESIS AND, THIS IS INTERESTING, NO 1 PREDIBLGHTED THIS BUT IT REALLY IS UNCLEAR--PREDICTED THIS BUT IT IS UNCLEAR WHETHER THAT'S ASSOCIATE WIDE CARDIOVASCULAR RISKER AND THAT'S 1 OF THINGS THAT MARRIANA CAP LANIS INTERESTED IN AND WE'RE INTERESTED IN THESE LUPUS PATIENTS AT THE CLINICAL TRIAL HERE. SO NOW WE'RE IN PHASE 2, AS TO WHETHER JACK IS ADVAUNT TAJIOUS OR NOT, AND WE'RE NOT SURE. SO OTHER LESSONS, 1 THING NIH DOES WELL IS TO STUDY RARE PATIENTS AND WHAT RARE PATIENTS CAN TEACH YOU ABOUT WHAT COMMON PROBLEMS AND IN THIS CASE, THAT'S CERTAINLY THE ISSUE, THE CASE. KNOCK OUT MICE ARE CERTAINLY INFORMATIVE, THEY HELP YOU THINK ABOUT WHAT PATHWAYS DO AND WHAT--WHAT THEY'RE NONREDUNDANT AND REDUNDANT PATHWAYS, WHAT'S REALLY INTERESTING FROM THIS IS THAT THEY DON'T NECESSARILY PREDICT RIK IN HUMANS. THE OTHER THING THAT I LEARNED FROM THIS CERTAINLY IS THAT DEVELOPING NEW THERAPIES TAKES YEARS, SO ALONG THE LINES OF 20 YEARS, COUPLE OF DECADES FROM THE WALK IN THE WOODS TO TO FDA APPROVAL. AND THE OTHER THING IS THAT IN THAT 20 YEARS, SCIENCE CERTAINLY DOESN'T STAND STILL. OUR NOTING OF BIOLOGY CHANGES DRAMATICALLY AND SO, YOU KNOW, I WOULD HAVE THOUGHT, PEOPLE HAVE THOUGHT ABOUT THIS BEFORE ME, BUT THAT HUMILITY IS SORT OF A STRATEGIC NECESSITY THAT WHEN YOU GO INTO A PROJECT, YOU SHOULD BE THINKING WELL, WHEN PEOPLE ARE ACTUALLY GETTING THIS DRUG, WE WON'T REALLY THINK ABOUT THIS DRUG IN THE WAY WE'RE THINK BEING IT. YOU KNOW? AND SO, I THINK REALLY WE NEED TO EMBRACE OUR IGNORANCE MORE AS WE SET OUT ON SOME OF THESE PROJECTS AND 1 OF THE THINGS I WAS THINKING ABOUT IS NOW THAT WE HAVE THE FDA APPROVED DRUGS, WE ARE THINKING ABOUT USING THEM IN OTHER DISEASES, DERM TO LOGICAL DISEASES, ET CETERA, ET CETERA AND SO, WE'RE GOING TO KEEP LEARNING FROM HUMANS AND ALSO FROM LEO AND OTHER DOGS ABOUT JACK ININCREASE IN BODYITORS AND WHAT THEY CAN DO AND HOW YOU USE THEM AND WE WILL FEBRUARY SOMETIME AND IT MADE ME THINK THAT THE OTHER THING, THAT THE ARTICLE FROM TONY THAT EVERY MEDICAL RESIDENT WOULD HAVE STUCK IN THEIR POCKET OF THEIR WHITE COAT WAS TONY'S ARTICLE ON STEROIDS AND HOW TO USE STEROIDS. TONY WAS WAS INTERESTED IN UNDERSTANDING HOW STEROIDS WORK. NOW STEROIDS OF COURSE, WERE DISCOVERED IN THE 40S AND IN THE 80S WHEN I CAME HERE, TONY HAD INNOVATIVE IDEAS ABOUT HOW TO USE STEROIDS AND TO THIS DAY, PEOPLE ARE THINKING ABOUT THAT PROBLEM, HOW TO USE STEROIDS. AND IN RHEUMATOLOGY, THE ARGUMENT BACK AND FORTH GIVEN THE RISK OF THE PATIENTS IS BECAUSE WE'RE GIVING THEM STEROIDS OR NOT GIVING THEM ENOUGH STEROIDS AND SHOULD WE GIVE THEM--SO I--YOU KNOW, 40 YEARS FROM NOW, LET'S SEE, IT WAS 40 YEARS FROM 1940S TO 80 AND SO, IN THE 2050S, MAYBE, I GUESS PEOPLE WILL BE THINKING ABOUT HOW TO USE JACKINIBs, AND HOW TO USE THEM CORRECTLY. I HOPE THE LEARNING CURVE IS STEEPER OR FASTER THAN IT WAS FROM THE 40S TO THE 80S. BUT IN ANY CASE, THINK THIS GIVES LOTS OF STUDENT FOR RECONSIDERED MECHANISMS OF ACTION SO SORT OF GRAPHICALLY IN OUR BUSINESS IN RHEUMATOLOGY AND THE BIOLOGICAL YOU CAN THINK OF A LIGHT SWITCH. TOO MUCH TNF AND ANTIBODY AND SHUT THAT OFF, THIS IS A BACK TOTE FUTURE SITUATION WHERE NOW, WITH SMALL MOLECULES, IT'S LIKE YOU GO TO HOME DEPOT AND HAVE YOU A DIMMER SWITCH. YOU CAN TURN IT UP, TURN IT DOWN, TRY TO GET IT JUST RIGHT. BUT THE 1 THING THAT I'M STRUCK WITH IS THAT WE REALLY DON'T ALWAYS MEASURE ALL THE THINGS WE SHOULD BE MEASURING TO UNDERSTAND EFFICACY AND SAFETY IN ANY GIVEN PATIENT. AND I'LL COME BACK TO THAT WHEN I'M AT THE END IF I DON'T RUN OVER HERE. SO THE OTHER THING THAT HAPPENED SORT OF FROM THE 80S TO THE 90S IS CERTAINLY IN THE 80S WHEN I CAME TO THE NIH WORKING WITH TONY, WE LEARNED ABOUT THE IMPORTANCE OF CD14 CELLS FROM HIV AND NEW HOW CRITICAL THESE CELLS WERE FOR HOST DEFENSE. BUT WE LEARNED IN THE INTERIM FROM PEOPLE LIKE ALAN SHEER AND CARRY AND OTHERS THAT YOU HAD MULTIPLE FATES FOR T-CELLS DRIVEN BY THE CYTOKINES AND WHAT WE IN THE FIELD LEARN WITH SUCCESS WERE CRITICAL ELEMENTS IN THAT TO GET THE DIFFERENT STATES OF T-CELLS WHICH WERE SO IMPORTANT FOR TARGETING DIFFERENT OR HOST DEFENSE AGAINST DIFFEREN DISEASES. SO WE RECOGNIZE THIS INTERPLAY BETWEEN SIGNAL DEPENDENT TRANSCRIPTION FACTORS, TRANSCRIPTION FACTORS THAT PERCEIVE THE ENVIRONMENT AND LINEAGE DEFINING TRANSCRIPTION FACTORS THAT STABILIZE CELL FATE. NOW AN EXCITING THING HAPPENED IN THE MID2000 WHICH IS IS WE GOT THESE MACHINES TO DO MASSIVE PARALLEL SEQUENCING, WHERE SUDDENLY WE DO AN EXPERIMENT THAT I NEVER EVEN CONCEIVED THAT WOULD BE ABLE TO DO WHICH IS IF YOU WANTED TO KNOW WHERE IN THE HUMAN GENOME, WHERE IN THE HUMAN GENOME, STATS WERE GOING AND OTHER MOLECULES IN RESPONSE TO CYTOKINES IT WAS PRETTY SIMPLE TO DO THAT AND AGAIN WE WERE FORTUNATE TO [INDISCERNIBLE] WHO WAS PIONEER IN THIS AREA AND COLLABORATION WITH THE [INDISCERNIBLE] AND BILL PAUL THAT RIGHT AWAY, WE WERE ABLE TO SAY, OKAY, YOU KNOW, TH17 CELLS, THEY MAKE IL17 AND WHAT'S STAT 3'S ROLE IN IT, PRETTY STRAIGHT FORWARD, STAT 3 THE PROMOTER OF IL17, IL17 F, BINDS TO THE MASTER REGULATOR OF TH17 AND RO1 GAMMA, THAT'S ASSOCIATED WITH CHANGES IN HISTONES IN THIS CASE, IN THIS CASE HISTONE 3 ACETYLATION AND THEN YOU SEE THE OTHER MARKS AS WELL. BUT WE FOUND OVERALL THAT YOU HAVE 3000 OR SO TARGET GENES THAT ARE BOUND BY STATINS AND ALL YOUR FAVORITE MOLECULES THAT RELATE TO THE FUNCTION OF TH17 CELLS, CYTOKINE, CYTOKINE RECEPTORS, ET CETERA WERE BOUND BY STAT. BUT THERE'S MANY OTHER BINDING SITES IN THE HUMAN GENOME AND THE QUESTIONS THEN ARE WHAT'S THAT ALL ABOUT? SO, AT THIS POINT, WE HAD THE COMPLETION OF THE HUMAN GENOME AND THE DISTURBING PART ABOUT THE HUMAN GENOME IS THAT THE HUMAN GENOME OR THE GENOME IS NOT MOSTLY GENES, IT'S MOSTLY NOT GENES, ONLY 3% OF THE GENOME IS GENE. SO IT WAS EXCITING OF COURSE TO UNDERSTAND HOW CYTOKINES REGULATE THE GENES BUT THEN WHAT'S UP WITH ALL OF THIS. IS IT JUST JUNK OR DOES IT MEAN SOMETHING. SO WE WERE VERY INTERESTED IN THE IDEA ABOUT HOW JUNKS MIGHT RELATE TO THE ACTUAL CYTOKINE. SO IT GOES BACK TO THIS GUY WANTING TO IN THE 50S HAD THIS IDEA THAT YOU KNOW THAT SELLS, CELL FATE IS MAINTAINED BY THESE, AND SORT'VE LOOKS LIKE GEOLOGICAL FORCES EPIGENETIC ROLES. BUT OF COURSE WE THINK OF GENETICS, WE REFER TO AS EPIGENOME, RATHER DIFFERENTLY NOW, I MEAN WADDING TON DIDN'T EVEN REALLY KNOW OF WHAT THE PHYSICAL NATURE OF THE GENE WAS, LET ALONE WHAT THE SORT OF BIOCHEMICAL REALITY OF EPIGENOMICS IS, BUT AGAIN, IN THE SORT OF LATE 2000, A FIRST DECADE OF THE 2000 WE CAME TO REALIZE THAT YOU COULD IDENTIFY ENHANCERS IN THE GENOME BY SEVERAL WAYS. ONE WAS LOOKING AT MARKS FOR MONOMETHALATION, THAT WAS THE MARK OF A POISED ENHANCER, WHEN THE ENHANCER BECAME ACTIVATED YOU COULD MEASURE THIS BY--AND AGAIN IT WAS ALL BY CHIP SEQ, AND LICENSING ACETYLATION AND SO THE ANTIBODIES THAT RECOGNIZE THIS MODIFICATION, YOU COULD SEE WERE WITH THE POISED ENHANCER BECAME ACTIVE AND YOU COULD SEE THE ENHANCER WHICH IS THE ENHANCERS OF THE HISTONE MODIFICATION AND YOU COULD MEASURE ERNA AND ENHANCER RNA COMING OFF THESE--THESE ENHANCERS ARE TRANSCRIBED. SO WE WERE QUITE INTRIGUED BY THAT AND WITH HELP FROM COLLEAGUES, WE TACKLED THIS PROBLEM THINKING ABOUT HOW OUR TH1 AND 2 CELLS, AND CELLS FOR INTERFERON GAMMA OR CELLS THAT DRIVE THE ALLERGIC DISEASE OR IL4, HOW ARE THEY SIMILAR TO EACH OTHER AND HOW ARE THEY RELATED TO OTHER CELL PRESIDENCY IN FACT IN A STRIKING EXPERIMENT, WE FOUND THAT IF WE TOOK NAIVE CELLS AND CULTURED THEM FOR JUST A FEW DAYS THAT YOU END HAPPENED UP WITH 20,000 IN ACTIVE ENHANCERS, 20,000 SWITCHES THAT YOU COULD IDENTIFY IN THESE CELLS AND JUST LOOKING AT TH1 AND TH2, EVEN THOUGH THEY'RE BOTH T-CELLS. THEY ONLY HAVE 50% SIMILARITY. SO ABOUT 10,000 SWITCHES SHARED BETWEEN TH1 AND 2. 10,000 SWITCHES UNIQUE FOR TH1 AND 2, AND BASICALLY NO 1 THAT ARE SHATTED BETWEEN T-CELLS AND MACROPHAGE AND EMBRYONIC T-CELLS. NOW ON 1 LEVEL I WAS TREMENDOUSLY EXCITED. WE'VE ALL BEEN THERE, SO YOU GET LIKE AN AMAZING EXCITING RESULT. AND THE FIRST THING YOU THINK IS WOW, THAT'S REALLY EXCITING AND THE SECOND THING YOU THINK IS IT'S GOT TO BE WRONG, GOT TO BE A FACT, IT'S TOO EXSEATING BUT THESE CELLS THEY DO A LOT OF THE SAME THINGS. THEY METABOLIZE GLUCOSE, REPLICATE DNA, THIS HAS TO BE WRONG AND EVERYBODY IN THE LAB, SAYING GOMEZ, GOMEZ, IT JUST MAKES NO SENSE. CAN'T BE TRUE. I'LL EXPLAIN THAT IN A MOMENT. WHAT WE FOUND THAT WAS EXCITING WAS THAT A LOT OF THESE CHANGES REALLY WERE DUE TO STAT MOLECULES. ACTUALLY LINEAGE DEFINING TRANSCRIPTION FACTORS HAD A MORE MODEST EFFECT IT WAS PEOPLE WERE THINKING, THEY WERE THINKING THE IDEA WAS THAT LINEAGE DEFINING TRANSCRIPTION FACTORS SUPER VISED THE EPIGENOME AND THAT'S NOT THE CASE. IN THIS CASE, IT'S REALLY MORE ENVIRONMENTAL SIGNALS, AND OF COURSE, THAT'S VERY EXCITING WHEN YOU THINK OF HOW ENVIRONMENT AND GENETICS INTERACT. SO HERE'S SORT OF THE ANSWER TO WHY YOU HAVE SO MANY SWITCHES AND THEY'RE SO UNIQUE, IS BECAUSE AS YOU HEARD A FEW WEEKS AGO FROM FRANCIS, THAT WE HAVE PARTS OF THE GENOME THAT HAVE SUPER ENHANCER ARCHITECTURE AND THEN, REST OF THE GENOME REALLY HAS SORT OF THIS ARCHITECTURE, SO AGAIN THE WAY THE METAPHOR I USED WAS IS THIS IS MANAT AN SO MANHATTAN HAS ALL THE SKYSCRAPERS AND I'M FROM THE BRONCH, WE DIDN'T HAVE THE SKYSCRAPER AND HERE'S THE BORROWS, SO HAVE YOU--IN THIS CASE, THE GEOGRAPHY WHERE THE DECISION HAS BEEN MADE TO INVEST HEAV ILLEGALS SCHEHAVE LOTS OF DEVELOPMENT IN CERTAIN AREAS BECAUSE IT'S PERCEIVED AS IMPORTANT. THAT'S I THINK HOW THE GENOME WORKS AS WELL, AND IN ANY GIVEN CELL THERE'S PARTS OF THE DENATIONAL LIBRARY OF MEDICINE THAT ARE IMPORTANT SO YOU BUILD SKYSCRAPERS THERE AND OTHER PARTS, YOU KNOW YOU'RE NOT SO INTERESTED THERE. YOU KNOW FOR COMMUTERS OR SOMETHING, I DON'T KNOW. SO THAT'S WHAT RICK YOUNG AND FRANCIS POINTED OUT IS THE NOTION OF SUPER ENHANCERS OR STRETCH ENHANCERS. WE'RE INTERESTED ON COLLABORATING WITH FRANCIS ON THE CELLS AND SO WE'RE THINKING OF THE NONBIASED WAY OF IS CYTOKINE SIGNALING, LETTING THE SELL TELL YOU WHAT'S THE MOST IMPORTANT PART OF THE GENOME BE IT GENES OR NOT GENES OR WHATEVER. AND ALSO LOOKING FOR LINKS TO HUMAN DISEASE. I'M GOING TO JUST SUMMARIZE THE HIGH POINTS HERE AND JUST SHOW THIS PART WHICH IS THAT IF YOU LOOK AT AUTOIMMUNE DISEASES YOU CAN SEE THERE'S A VERY SIGNIFICANT ENRICHMENT OF SUPER ENHANCER ARCHITECTURE FOR DISEASE ASSOCIATED VARIANTS. SO SNPs THAT ARE SHOWN TO BE ASSOCIATE WIDE IBD, ARTHRITIS AND TYPE 1 DIABETES AND MULTIPLE SCLEROSIS, THEY SAY THEY'RE LIKELY TO HAVE SUPER ENHANCER ARCHITECTURE OR TYPICAL ENHANCER ARCHITECTURE AND THE ENRICHMENT FOR SUPERENHANCER ARCHITECTURE AND THE CONTROL HERE IS TYPE 1 DIABETES WHICH IS IMMUNEOLOGICALLY MEDIATED AND TYPE 2 DIABETES, YOU SEE THIS VERY--THIS REALLY STRIKING DIFFERENT IN TERMINGS OF ENRICHMENT OF SUPER ENHANCERS IN T-CELLS NOW FRANCIS TOLD YOU LAST WEEK, OR LAST MONTH, ABOUT A SUPER ENHANCER OR OTHER CELLS FOR TYPE 2 DIABETES. SO IT'S CELL SPECIFIC. SO THE OTHER QUESTION IS WE HAVE DRUGS THAT ARE EFFICACIOUS IN RHEUMATOID ANOTHERERATEIS, WHAT'S THE EFFECT, DO THEY EFFECT THE ENHANCERS, EQUALLY. OR DO THEY PREDOMINANTLY WORK ON SUPER ENHANCERS, AND IT'S THE LATTER, YOU CAN SEE THAT TOFACITINIB, HAs A MUCH GREATER EFFECT ON THE PLOTS ON GENE EXPRESSION, GENES THAT HAVE SUPER ENHANCER ARCHITECTURE VERSUS GENES THAT HAVE TYPICAL ARCHITECTURE. SO NOW I HAVE TO TAKE A SHORT DETOUR AND I HOPE I DON'T CONFUSE YOU BUT I WANT TO TELL YOU ABOUT A NEW DISEASE THAT WE'VE IDENTIFIED RECENTLY COLLABORATION WITH AARON LAWRENCE WHO HAS GONE BACK TO THE U. K. AND MIKE LEONARD O'S GROUP AND BEN AND MICHAEL. AND SO THIS IS A 19 YEAR-OLD FEMALE WHO WE LEARNED ABOUT WHO HAD COLITIS SINCE INFANCY, PULL MONITORARY INFECTIONS AND THEN ACUTELY PRESENTED WITH FEVER, SPLENOMEG MEGALY PAN O CYTOPENIA, HYPOGLAMMA GLOBUE LYNNEMIA, B-CELL ABNORMALITIES, T-CELL ABNORMALITIES AND THE INVESTIGATIONS AT HAMMER SMITH COLLEGE CALLED US UP AND SAID, WE HAD THIS INTERESTING PATIENT, WE SEQUENCED HER AND SHE HAS A MUTATION OF BACH 2, AND IT WAS OF INTEREST TO BECAUSE WE JUST PUBLISHED THE PAPER, SO WE WERE INTRIGUED BY THAT BUT WITH MIKE AND WOR REASON, WE LOOKED TO SEE DO WE HAVE ANY OTHER NIH PATIENTS WITH SIMILAR MUTATIONS AND IN FACT, WE DID. WE HAD FAMILY HERE. THIS LONDON PATIENT, THE NIH PATIENTS SHOWN HERE WITH THIS PATIENTS THE C-TERMINUS, BUT HERE'S THE RUB: PATIENT IT IS ONLY HAD 1 MUTANT ALLELE. WHEN YOU SEQUENCE ALL OF US, WE'RE WAY MORE IMPERFECT THAN WE WOULD HAVE ENVISIONED A FEW YEARS AGO, SO HOW DO YOU MAKE THIS CONNECTION BETWEEN 1 MUTANT ALLELE AND THE DISEASE I JUST TOLD YOU ABOUT FOR THE BACH 2 ALLELE. SO WE HAD BEEN THINKING ABOUT BACH 2 AND IF YOU ASK WHO HAS THE SUPERREST SUPER ENHANCER, AS I ALLUDED TO BEFORE IN DIFFERENT T-CELLS, DIFFERENT CYTOKINES AND DIFFERENT CYTOKINE RECEPTORS AND OTHER GENES HAVE SUPER ENHANCER ARCHITECTURE SO IN TH1 CELLS, THEY MAKE INTERFERON GAMMA THAT'S WHAT THEY'RE KNOWN FOR, INTERFERON GAMMA HAS A SUPER ENHANCER ARCHITECTURE, TH2 CELLS MAKE IL4, IL4 HAS SUPER ENHANCER ARCHITECTURES, TH17 CELLS MAKE IL17, THEY HAVE SUPER ENHANCER ARCHITECTURE. BUT WHAT'S CONSISTENT ACROSS ALL OF THEM IS BBACH 2 IS THE SUPER, SUPER ENHANCER FOR ALL OF THESE. SO WITH NICK WE HAD SHOWN THAT BACH 2 IS CRITICAL, IF YOU DON'T HAVE BACK 2 YOU HAVE WIDE SPREAD AUTOIMMUNITY IN MICE. AND THAT'S BECAUSE WE RECOGNIZED THAT BACH 2 IS A DCELL DEFECTIVE DIFFERENTIATION AND STABILIZER OF REGULATORY CELLS. IT ACTS AND HAS SUPER ENHANCER APPLICATIONS TECT AND YOU ARE ACTS ON MANY LOCI THAT THEY HAVE SUPER ENHANCER ARCHITECT AND YOU ARE HAVE CRITICAL FUNCTIONS IN T-CELLS AND B-CELLS. AND IMPORTANTLY WHAT BEN HAS GONE BACK AND STUDIED CAREFULLY IS THAT MICE THAT ARE HETEROGENEOUS ROW ZYGOUS HAVE 1 MUTANT ALLELE OF BACH 2, THEY HAVE DETECT FIST T-CELLS AND B-CELLS AND BEN HAS DONE THIS WITH THE PATIENT CELLS. BUT BEN GOT TO THINKING AND HE SAID, GHEE, I WONDER IF THERE'S--IF THIS IS SOME BROADER SORT OF LESSON HERE AND WHAT BEN SAID WAS IS IT TRUE THAT GENES IN GENERAL THAT ARE ASSOCIATE WIDE HAPPEN LO INSUFFICIENCY ARE THEY MORE LIKELY TO HAVE SUPER ENHANCER ARCHITECT AND YOU ARE THAT'S THE CASE THAT'S SHOWN HERE SO YOU COMPARE OTHER LOCI, THEY'RE LESS LIKELY TO HAVE SUPER ENHANCER ARCHITECTURES. BUT GENE VS BEEN SHOWN TO HAVE HAPPEN LO INSUFFICIENCY AS THEIR MODE OF INHERITANCE ARE MORE LIKELY TO HAVE SUPER ENHANCER ARCHITECTURE, MEANING IT REALLY MATTERS HOW MUCH OF THIS MOLECULE THAT YOU'RE MAKING. SO AGAIN, I THINK I TORTURED BEN OVER THIS FIGURE FOR A LONG TIME, IT'S A PRETTY BOLD CLAIM AND WE WENT BACK AND FORTH, FRED DAVIS HAD AN IDEA WHICH IS SHOWN ON THIS SLIDE HERE. AND SO, WHAT FRED DID WAS TAKE A VERY DIFFERENT APPROACH AND TOOK THE EXACT DATABASE WHERE WE HAVE LOTS OF SEQUENCE DATA, AND LOTS OF INDIVIDUALS AND WHAT HE WAS ABLE TO SHOW IS THAT SUPER ENHANCER ARCHITECTURE, IS ASSOCIATED WITH INTOLERANCE FOR A MUTATION. SO LOCI THAT HAVE THE LARGEST SUPER ENHANCERS ARE VERY INTOLERANT OF ANY MUTATION THAT ALTERED FUNCTION. AND AGAIN SHOWING THE DATA ANOTHER WAY, IF YOU LOOK AT HAPLOW INSUFFICIENCY AGAIN, VERY INTENSATIVE TO--VERY SENSITIVE TO LOSS OF FUNCTION MUTATIONS. SO OKAY, SO TO SUMMARIZE THIS PART AND I THINK I WILL HAVE ENOUGH TIME TO FINISH HERE, DYNAMIC TISSUE EXPRESSION GENE EXPRESSION SUPER EN--STRATEGIES HAINSER ARCHITECTURE AND CYTOKINE AND CYTOKINE RECEPTORS, LONG NONCODING RNAs ARE ENRICHED FOR ARCHITECTURE IN T-CELLS. RHEUMATOID ARTHRITIS ASSOCIATED GENES WITH SUPER ENHANCER ARCHITECTURE ARE PREFERENTIALLY AFFECTED BY JAKINIB, AS OPPOSE TO ARCHITECTURE, BACH 2 IS THE SUPER-SUPER ENHANCER LOCUS IN THELIOS POSITIVES. POLYMORPHISMS LIKE BACH 2 ARE ASSOCIATE WIDE MANY AUTOIMMUNE DISEASES AND I DIDN'T SHOW IT BUT HIV LIKES TO INTEGRATE INTO THE BACH 2 AS WELL, BUT WHAT BEN AND [INDISCERNIBLE] THERE, HAVE SHOWN, IS THAT MUTATIONS OF BACH 2 IS ASSOCIATED WITH VARIABLE IMMUNE O DEFICIENCIES OR CAUSE OF CRDA, BUT MORE IMPORTANTLY THE ASINGLE ALLELE IF IT HAS A SUPER ENHANCER ARCHITECTURE STRUCTURE, IS PROBABLY NOT CONSEQUENTIAL. SO YOU ARE TRYING TO SORT ALL THIS OUT, YOU MIGHT LOOK TO SEE WHETHER THIS GENE IS ASSOCIATE WIDE SUPER ENHANCER ARCHITECTURE IN THE CELL, IT'S RELEVANT TO THE PATHOGENESIS OF THAT DISEASE. AND AGAIN THIS IS THE COLLABORATION WITH ALL PEOPLE I MENTIONED ALL OF THEM ALONG THE WAY AND DID I SAY WHAT A GREAT PLACE THE NIH IS? SO AGAIN, GREAT PLACE. PEOPLE--ALL SORTS OF DIFFERENT EXPERTISE AND VERY ACTUALLY WILLING TO WORK TOGETHER, BOLD CONCEPT. WORKING TOGETHER, THAT IS. IN ANY CASE, I NOW WANT TO TURN TO THE FINAL PART OF MY TALK IN THE NEXT 7 MINUTES AND RETURN TO THIS ISSUE ABOUT CELL IDENTITY AND HOW YOU THINK ABOUT CELL FATE AND HERE ARE 3 THE 3 VERSIONS OF THE HELPER T-CELLS THAT I REFERRED TO BEFORE. TH1, 2, AND TH17 CELLS. TH1 CELLS MAKING INTERFERON GAMMA, TH2 CELLS MAKING IL4, TH17 MAKING IL17. BUT 1 OF THE OTHER THINGS THAT HAPPENED RECENTLY IS THIS IDEA OF SELECTIVE CYTOKINE PRODUCTION, THAT WAS A MONOPOLY OF T-CELLS AND THAT'S NOT THE CASE THAT THERE ARE INNATE LYMPHOCYTES PATHWAY GIVESAR LENS LENS LENS LENS THE SELECTIVE CYTOKINE PRODUCTION. SO THE QUESTION, AROSE WHEN YOU THINK ABOUT THE RELATIONSHIPS BETWEEN THE CELLS, THE NAMES WOULD IMPLY THAT TH1 CELLS, AND ILC-1 CELLS, PROBABLY SHOULD BE SIMILAR, THAT THEY MAKE THE SAME PRODUCT THEN, SO YOU WOULD EXPECT THAT WITH WHEN WE LOOK GENOME WIDE THEY WOULD HAVE A LOT OF SIMILARITIES. BUT YOU COULD ALSO IMAGINE EQUALLY THAT INNATE CELLS ARE MORE LIKE INNATE CELLS AND T-CELLS ARE MORE LIKE T-CELLS SO WE'RE INTRIGUED BY THIS PROBLEM AND [INDISCERNIBLE] CAME UP WITH AN APPROACH TO THIS. AND SHE WANTED AGAIN TO AN UNBIASED GENOMIC APPROACH IS THIS CLASSIFICATION APT? CAN YOU SPLIT THESE? ONE, 2, ET CETERA? ARE THE RELATIONSHIPS AS IMPLIED HERE? SO WHAT HANU DID WAS TO USE A NEW TECHNIQUE USE AATAC SEQ. AND SO AND TALK ABOUT ATAC SEQ. AND HANUE WAS VERY EXCITED ABOUT THIS AND WHAT YOU CAN DO IS ATAC, SEQ, IT'S VERY SENSITIVE TO HYPER SENSITIVITY. DNA HYPER SENSITIVITY BUT USE A DIFFERENT ENZYME, TRANSPOSEAISE AND SEQUENCE THE DNA AFTER YOU CLEAVE IT AND THEN MAP IT SO YOU CAN SEE WHEREVER YOU HAVE HETEROGENEOUS ROW CHROMATIN, OF COURSE YOU DON'T HAVE PRODUCTS, AND YOU DON'T SEEQUENCE THEM, BUT WHEN HAVE YOU REGIONS IN THE GENOME THAT ARE OPEN, YOU YOU CAN SEQUENCE THESE PRODUCTS AND VISUALIZE THAT BY THESE PEAKS WHEN YOU ALIGN THEM TO THE GENOME. SO YOU SEE THESE, GENES THAT ARE OPEN OF COURSE, GENE BODY, AND--BUT YOU ALSO SEE ENHANCERS WITH THIS TECHNIQUE AS WELL. AND AGAIN IT'S--WHAT WE LIKE ABOUT IT IS UNBIASED, BUT MORE IMPORTANTLY, YOU CAN USE THIS ON SMALL NUMBERS OF CELLS, YOU CAN TAKE CELLS RIGHT OW THE OF ANIMAL OR OUT OF PEOPLE AND AGAIN, HOWARD CHEN TALKED A LOT ABOUT THIS. SO HANUE AND YOHA TALKED THIS PROJECT TO THINK ABOUT HOW ILC1 AND 2, AND 3S WERE SIMILAR OR NOT. AND JUST LIKE THE FINDINGS THAT WE GOT WITH TH1 AND TH2 CELLS, THAT THESE CELLS THAT REALLY INTO THE MICROSCOPE WOULD BE PRETTY IDENTICAL AND REALLY THE ONLY WAY YOU CAN TELL THEM A PART IS BY THE FAIRLY RESTRICTIVE PRODUCTS, ARE ACTUALLY REMARKABLY DIFFERENT IF YOU LOOK AT THEIR EPIGENOMIC LANDSCAPE OR REGULUM, THEY ONLY HAVE 24% SIMILARITY AND THEY'RE DIFFERENT. BUT THE WAY THEY'RE DIFFERENT IS USEFUL BECAUSE THE NKCELLS AND ILC 1 CELLS, THEY HAVE SIMILARITY OF ILC3S, SIMILARITIES AMONGST NKCELLS AND ILC-1S YOU CAN SEE DIFFERENCES WITH GISEPPE, SHOWED SOMETIME AGO THAT THE 2 DIFFERENT TYPES OF ILC3S, 1 HAS THE MASTER TBET, AND 1 DIDN'T. YOU CAN SEE THE DIFFERENT HERE SO IT'S A SENSITIVE WAY OF DISCERNING DIFFERENCES AMONG THE CELL TYPES. SO PAPER IS PUBLISHED EARLY IN THE STRING AND I'M JUST GOING TO HIT A COUPLE OF THE HIGHLIGHTS. ONE OF THE THINGS THAT GISEP, E AND WERE THINKING ABOUT IS--WHAT'S DIFFERENT BETWEEN INNATE IMP O SIGHTS AND T-CELLS, IS INNATE LYMPHOCYTES RAPIDLY RESPOND TO SIGNALS IN THIS CASE, IN THIS CASE, CYTOKINES TO MAKE CYTOKINES LIKE INTERFERON GAMMA SO IT'S A RAPID FORM OF HOST DEFENSE AND YOU CAN SEE THAT THEY MAKE LITTLE BIT OF THESE CYTOKINES BUT YOU SEE THIS MASSIVE INDUCTION, SO THIS IS RNA SEQ. BUT SO WHAT HANU AND GIVING--YOU ACCEPTY WANTS TO KNOW IS WHAT HAPPENS IN THE GENOME IN THE CIRCUMSTANCE THE. AND THE ANSWER IS NOT MUCH. YOU CAN SEE USING ATAC, THAT EVEN BEFORE YOU ACTIVATE THE CELL, THE LOCUST AROUND INTERFERON GAMMA GENE IS OPEN AND AVAILABLE FOR TRANSCRIPTION FACTOR BINDING. AND THEN, WHEN YOU STIMULATE THE CELLS, IT DOESN'T CHANGE MUCH BUT YOU HAVE THIS DRAMATIC INCREASE IN TRANSCRIPTION. SO WHEN DID THIS HAPPEN? WHEN DID THIS HAPPEN TO THE CELLS? SO WE KNOW A FAIR AMOUNT ABOUT HOW HEMATOPOIETIC CELLS ARE GENERATED AND HOW THEY TERMINALLY DIFFERENTIATE INTO THE CELLS. SO "Y IS WHEN DID THIS LAND CAPE APPEAR? AND IT--LANDSCAPE APPEAR? AND IT DOESN'T APPEAR IN THE EARLY STAGES BUT PRIOR TO CELLS BECOMES TERMINALLY DIFFERENTIATED YOU CAN SEE THE REGULUMS, OR THESE SWITCHES THAT ARE READY TO GO ALONG BEFORE THE CELL ACTUALLY MIGRATES TO WHERE IT'S SUPPOSED TO BE AND IS READY TO RECEIVE SIGNALS. SO THAT WAS REALLY INTERESTING. AND THEN THE HANU, CAME UP WITH ANOTHER IDEA AND IT WAS TOTALLY NOT MY IDEA. IT WAS TOTALLY HER IDEA AND SHE SAID, WELL, SINCE WE HAVE IT TECHNIQUE WHERE WE CAN TAKE CELLS RIGHT OUT OF THE LUNG, WHAT WE CAN DO IS TAKE T-CELLS OUT AND INNATE CELLS OUT AND WE CAN COMPARE THEM FOR AN INFECTION. SO HE INFECTED MICE WITH A PATHOGEN THAT INDUCES A STRONG TH2 RESPONSE AND YOU CAN SEE THAT JUST LIKE I SHOWED YOU BEFORE, IN THE INNATE CELLS YOU GOT IN THE LUNG, THE LANDSCAPES ARE OPEN IN THIS KEY LOCUS, THIS IS THE TH2 LOCUST WITH THE CYTOKINE 4 AND IL13 AND 5, CAN THERE ARE MARKS INDICATING THAT THE WHOLE LOCUS IS OPEN, BUT NAIVE T-CELLS THE LOCUST IS CLOSED AND THESE CELLS, THE LOCI ARE OPEN BUT IT'S REALLY VERY INTERESTING, THEY OPEN IN VERY MUCH THE SAME WAY AS THE ILC2. SO, HANU, DESCRIBED IN THIS CARTOON, WHERE FOR INNATE LYMPHOCYTES YOU HAVE THIS DEVELOPMENTAL PROGRESSION WHERE YOU ALTER THE EPIGENOME AND IN T-CELLS, WHEN THEY COME OUT, FROM THYMUS, THEY'RE STILL PRETTY MUCH CLOSED. THEY'RE EPIGENOMES ARE CLOSED AND WHAT HAPPENS TO THEM IS THEY RECEIVE MULTIPLE SIGNALS THROUGH MULTIPLE RECEPTORS, BUT WHEN THEY GET THESE ACUTE SIGNALS, LANDICATE CAPE EMERGES IS LIMEULAR TO WHAT YOU SEE IN THE LANDSCAPE THAT'S DEVELOPED AND DEVELOPMENTALLY IN INNATE LYMPHOID CELLS. OKAY, TO SUMMARIZE THIS, AND I'M 37 SECONDS OVER, I APOLOGIZE. EACH ILCPROCESSES UNIQUE CHROMATIN LANDSCAPE, REGULOMES, ARE MORE IDENTIFIED BY SUBSETS THAN TRANSCRIPT OHMS. I DIDN'T SHOW YOU THAT BUT THAT'S THE CASE. CYTOKINES LOCI, IS PRIMED BY INNATE LYMPHOCYTES PRIOR TO STIMULATION, CONTRAST WITH T-CELLS AND WHEN THEY CONVERGE AT THE END AND THEN ALL ROADS LEAD TO ROME SOLUTION, 1 THING MICHAEL DIDN'T MENTION AND I'M SURPRISED AND HEARD IN A WAY YOU DIDN'T MENTION OUR BAND WITH FRANCIS COLLYNNS THAT I'VE BEEN PLAYING WITH FRANCIS FOR THE LAST 20 YEARS OR SO, AND THIS IS OUR GIG AT THE MUSEUM MUSEUM AND 1 THING I WANT TO POINT OUT IS NOT WHAT'S ON STAGE BUT WHAT'S OFF STAGE SO THEREY A GUY WORKING A THEN CALLED THE MIXER, SO THIS ROBERT WALKER'S MIXER BUT HIS MIXER WAS WAY COOLER THAN OURS. AND I WAS JUST THINKING DARRELL'S IN THE BACK AND HE HAS A MIXER AND DARRELL, I WAS THINKING CAN YOU MAKE ME SOUND MORE--I DON'T KNOW PUT MORE BASS AND MORE REVERB, ARE WE THERE YET? NO, MORE BASS, MORE BASS. UGH, I DON'T KNOW. IT'S NOT WORKING. IT WOULD HAVE BEEN FUNNY, BUT IN ANY CASE, I'VE BEEN THINKING NOW ABOUT, YOU KNOW I TOLD YOU THE METAPHOR OF THE DIMMER SWITCH, THINKING ABOUT THE JAK INHIBITORS--OH NOW, NOW HE'S PUT MORE MIDDLE IN, YOU CAN HEAR THAT. I LIKE IT MORE WITH THE BASS. BUT IF WE THINK OF OURSELVES AS PEOPLE--AS SOUND TECH FOR A ROCK BAND, YOU THINK MORE ABOUT MIXING THERAPIES, RIGHT? SO THERE WE GO. YOU KNOW, I SHOWED YOU ALL THESE SWITCHES AND IF WE REALLY MADE AN EFFORT TO IDENTIFY ALL THE SWITCHES AND WE UNDERSTOOD HOW THEY REGULATED THESE KEY GENES AND WHAT PATHWAYS WERE INVOLVED AND FOR ANY GIVEN PATIENT WE KNOW ABOUT ALL THE DIVERSITY, THE SNPs REVEALED DIVERSITY IF WE KNEW WHICH SWITCH WAS MOST IMPORTANT FOR WHICH PATIENT IN A GIVEN DISEASE, THEN I THINK WE COULD MORE BALANCE OUR IMMUNE O SUPPRESSION SO THAT WE WOULD HAVE A MIXING APPROACH TO OUR THERAPIES THAT YOU COULD HAVE, YOU KNOW SORT OF JUST THE RIGHT DOSE OF JAKINIB, AND ANOTHER PATHWAY, ANOTHER SWITCH WOULD BE INDICATIVE OF ANOTHER PATHWAY THAT WE COULD TARGET. SO AGAIN, I WOULD THINK--BE THINKING ABOUT THERAPIES IN THE FUTURE THE WAY YOU THINK ABOUT A MIXER HERE. OKAY, SO I THINK I MENTIONED PEOPLE'S NAMES ALONG THE WAY SO I WON'T GO THROUGH IT AGAIN BUT AGAIN, THANKS TO PHIL FOR HELPING US SET UP A CRDA WITH PFIZER WHICH WE BENEFITED FROM OVER THE PAST 20 SOMETHING YEARS AND I LISTED COLLABORATORS AS WELL. THANKS VERY MUCH, I'LL STOP RIGHT THERE. [APPLAUSE ] >> SO I'M SURE JOHN WOULD LIKE TO TAKE QUESTIONS. NO 1'S COMING IN HERE FOR THE MOMENT SO WE HAVE SOME TIME. LET ME START, BEFORE YOUR LAST SLIDE, I WAS THINKING ABOUT JAK ININCREASE IN BODYITORS, EACH OF THEM PROBABLY VISIT 4 DIFFERENT JAKs, THERE ARE DISEASE STATES IN WHICH THAT COULD MAKE A DIFFERENCE? YEAH, THAT'S EXACTLY RIGHT AND I ACTUALLY SPENT A FAIR AMOUNT OF TIME TALKING TO VARIOUS COMPANIES ABOUT JUST THAT, IN ANY GIVEN DISEASE. IS IT PRIMARILY TIK 2 DRIVEN. AND WHAT A TIK 2 INHIBITOR OR THE JACK 2 INHIBITOR, SO THAT WOULD BE EXCITING ABOUT GOING FORWARD IS I SUSPECT THAT IS THE CASE AND ALSO YOU SORT OF THINK THAT NOT JUST ANY GIVEN DISEASE, BUT IN A PHASE OF ANY GIVEN DISEASE SO YOU MIGHT IMAGINE THAT YOU USE A BROAD JAKINIB, WHEN A PATIENT IS ACUTELY ILL AND THEN YOU GIVE THEM A SUBMISSION FOR A LOWER DOSE OR SOMETHING LIKE THAT. >> I HAVE A TALK ABOUT THE ENHANCERS SO I KNOW THAT WHEN YOU TREAT THE T-CELLS WITH THE JAK INHIBITOR, NOT EVERY SUPER ENHANCER FOR THE GENE IS A RESPONSE TO A SIMILAR, SO CAN YOU COMMENTOT POTENTIAL MECHANISM AND IS IT ALSO ASSOCIATE WIDE THE SIZE OF THE SUPER ENHANCER? >> SO WHAT YOU SAID WAS THAT NOT ALL SUPER ENHANCERS WERE-- >> RESPONSE LEVEL TO-- >> THAT'S WHAT I WAS GETTING AT, AT THE END, THERE WERE GENES AND SWITCHES ON THOSE GENES THAT ARE HIGHLY RESPONSIVE TO JAK INHIBITIONS AND OTHER SWIGSS THAT ARE NOT. AS MUCH AS I LOVE THE JAK PATHED WAY, THERE'S A LESSER KNOWN PATHWAY, NFCAPPA B. AND IF YOU THINK ABOUT THAT AND INDICATING ALL THOSE DIFFERENT SIGNALS AND DOING THAT IN A LOGICAL WAY NOT JUST IMPERRIC WAY, BUT UNDERSTANDING THE NATURE OF THOSE SWITCHES, YEAH, YOU COULD TARGET SUPER ENHANCERS MORE EFFECTIVELY. DID THAT ANSWER YOUR QUESTION. >> YEAH. >> SORT OF. >> IT WAS SO CLEAR THERE NOW. >> WE WILL HAVE A RECEPTION. NOW BEFORE WE FINISH, YOU MAY HAVE NOTICED IN YOUR PROGRAM THAT THERE'S AN INSERT WHICH INCLUDES A LOT OF NAMES AND THESE ARE NOT JUST JOHN'S COLLABORATORS. BUT THESE ARE PEOPLE WHO GOT PATENTS ISSUED AT THE NIH AND IT'S QUITE AN EXTRAORDINARIES LIST AND IT SHOWS YOU THAT PHIL THE ONGOING TECHNOLOGY TRANSFER THAT YOU ESTABLISH AT THE NIH IS ALIVE AND WELL. AND WE ALSO WANT TO CONGRATULATE THOSE PEOPLE WHO GOT THE PATENTS ISSUED THIS YEAR. SO LET'S GIVE JOHN OTHER ROUND OF APPLAUSE. [ APPLAUSE ] AND THANK PHIL AND HIS LOVELY FAMILY FOR COMING AND FOR MAKING ALL OF THIS POSSIBLE, THANK YOU PHIL. SO THERE--THERE'S A RECEPTION IN THE LIBRARY. [APPLAUSE ]