GOOD AFTERNOON, LADIES AND GENTLEMEN. ON BEHALF OF THE ORGANIZING COMMITTEE -- AND BY NOW YOU SHOULD KNOW OUR NAMES IF YOU'VE RECEIVED ONE OF THESE SEVERAL DOZEN EMAILS THAT GERARDO HAS SENT OUT TO EVERYONE. IT IS MY GREAT PLEASURE TO WELCOME YOU TO THIS SYMPOSIUM IN HONOR OF OUR GREAT FRIEND AND COLLEAGUE, DR. STEVE FEINSTONE, UPON HIS RETIREMENT FROM CBER. UNBELIEVABLY TO ME, AND PROBABLY TO STEVE, AS WELL, IT HAS BEEN 41 YEARS SINCE HE FIRST CAME TO WORK IN THE LABORATORY OF INFECTIOUS DISEASES AT NIH IN 1971. I FIRST MET STEVE OVER LUNCH DURING MY OWN FIRST YEAR AT NIH. I THINK IT WAS SPRING, 1972 AS BEST WE COULD FIGURE. I HAD BEEN INVITED BY BRIAN MURPHY TO JOIN A GROUP OF FOUR OR FIVE GUYS FROM THE LABORATORY OF INFECTIOUS DISEASES WHO REGULARLY ATE TOGETHER IN THE CAFETERIA IN BUILDING 10. I WAS A BIT OF AN OUTSIDER MYSELF AT THAT POINT, A MEMBER OF ANOTHER LAB. HOWEVER, I IMMEDIATELY FELT COMFORTABLE WITH THE LID GROUP. WE WERE UNITED BY OUR LIBERAL POLITICS, OUR ANTIPATHY FOR RICHARD NIXON, AND OUR ANTI-VIETNAM WAR SENTIMENTS. THAT WAS A DAILY LUNCHTIME AGENDA. ON THIS PARTICULAR DAY, A GUY I DID NOT KNOW BY NAME, A SKINNY GUY WITH A FRIZZY BEARD AND A MUSTACHE, BERATED ME FROM THE FAR END OF THE TABLE -- I COULD HARDLY SEE WHERE HE WAS -- FOR SOMETHING I SAID ABOUT EITHER NIXON, ONE OF HIS HENCHMEN, WATERGATE, OR THE WAR THAT WAS NOT SUFFICIENTLY VIRULENT. LATER THAT DAY, I RECALL THINKING, "WHAT'S UP WITH THAT GUY?" OR SOMETHING TO THAT EFFECT. HE HAD AROUSED MY CURIOSITY, AND OF COURSE HE TURNED OUT TO BE STEVE FEINSTONE. OBVIOUSLY, I WAS NOT TERRIBLY PUT OUT BY STEVE'S OUTBURST BECAUSE I ESTIMATE THAT HE AND I HAVE EATEN LUNCH TOGETHER ABOUT 10,000 TIMES IN THE 40 YEARS SINCE THEN, AND WE'VE HAD AT LEAST ONE GOOD LAUGH EVERY SINGLE DAY, AND I WILL MISS HIS COMPANY AFTER SEPTEMBER. SOMETIME DURING THAT -- THE FIRST YEAR OF THE FRIENDSHIP THAT FOLLOWED THAT INCIDENT IN THE CAFETERIA, STEVE ASKED ME TO ACCOMPANY HIM TO WALTER REED TO PICK UP SOME PATIENT SAMPLES. I SAT IN THE CAR WHILE STEVE DISAPPEARED INTO ONE OF THE WORLD WAR II-ERA BUILDINGS AT WALTER REED. HE EVENTUALLY EMERGED WITH A LARGE, STAINLESS STEEL CANISTER THAT I LEARNED THEN WAS FULL OF FRESH STOOL SAMPLES. I VIVIDLY RECALL THAT HE ASKED ME TO HOLD IT IN MY LAP ON THE WAY BACK TO THE NIH CAMPUS. [LAUGHTER] HOLDING A CONTAINER FULL OF HUMAN FECES IS A MEMORABLE EXPERIENCE. THAT'S WHY I'M SURE OF IT. IT IS MY FIRM CONVICTION THAT THOSE VERY STOOL SAMPLES WERE USED TO PROVE THE DISCOVERY OF HEPATITIS A VIRUS BY IMMUNOELECTRON MICROSCOPY IN DR. PURCELL'S AND DR. KAPIKIAN'S AND STEVE'S LAB. IN SOME QUARTERS, THIS WOULD ENTITLE ME TO CO-AUTHORSHIP. CONSIDER THE HISTORICAL IMPLICATIONS IF I HAD NOT BEEN THERE TO PREVENT THE CANISTER FROM TIPPING OVER AND SPILLING ITS CONTENTS ON THE SEAT OF A GOVERNMENT-OWNED VEHICLE. AND, SADLY, MY CONTRIBUTION TO THE WORK HAS NEVER BEEN CREDITED. HOWEVER, I DO NOW HAVE THE HONOR TO INTRODUCE STEVE'S LONGTIME MENTOR AT LID AND AN ACTUAL COAUTHOR, ALONG WITH STEVE AND AL KAPIKIAN, OF THE SEMINAL PAPER DESCRIBING THE IDENTIFICATION OF HEPATITIS A VIRUS IN STOOL OF PATIENTS WITH HEPATITIS A DISEASE. OUR FIRST SPEAKER, DR. ROBERT PURCELL. DR. PURCELL IS CHIEF OF THE HEPATITIS VIRUSES SECTION IN THE LABORATORY OF INFECTIOUS DISEASES. HIS IMMENSE SCIENTIFIC CONTRIBUTIONS THAT FACILITATE DIFFERENTIATION AMONG AND AN IN-DEPTH UNDERSTANDING OF THE ALPHABET SOUP OF VIRUSES THAT CAUSE HEPATITIS SHOULD BE FAMILIAR TO ANYONE AND EVERYONE HERE. DR. PURCELL. ROBERT PURCELL: FAMOUS BUT COMPUTER-CHALLENGED. SO, WE'RE HERE TO CELEBRATE THE CAREER OF STEVE FEINSTONE. I EVEN PUT ON A TIE FOR IT TODAY. STEVE'S GOLDEN YEARS PRETTY MUCH MATCHED THE GOLDEN YEARS OF HEPATITIS RESEARCH, AND I'D LIKE TO SHOW HOW THE TWO PARALLELED EACH OTHER, EACH ENRICHING THE OTHER AT A TIME WHEN IT WAS GREAT TO BE A SCIENTIST AT NIH. THE GOLDEN AGE OF HEPATITIS RESEARCH BEGAN AT THE NIH IN 1964 WITH THE DISCOVERY OF AUSTRALIA ANTIGEN BY BARRY BLUMBERG AND HARVEY ALTER. THAT LED IN RELATIVELY SHORT ORDER TO THE ASSOCIATION WITH HEPATITIS B, THEN CALLED SERUM HEPATITIS, AND THE ASSOCIATION OF HEPATITIS B WITH BLOOD. A GROWING RECOGNITION THAT INCREASING USE OF BLOOD OR BLOOD PRODUCTS WAS ASSOCIATED WITH AN INCREASING INCIDENCE OF HEPATITIS SPAWNED A NUMBER OF MAJOR PROSPECTIVE INSTITUTIONAL STUDIES OF TRANSFUSION-ASSOCIATED HEPATITIS, AND ONE OF THE FIRST WAS THE HEART SURGERY PATIENTS AT THE NATIONAL INSTITUTES OF HEALTH. THE STUDY HAS BECOME SYNONYMOUS WITH HARVEY ALTER. HARVEY HAS BEEN KNOWN FOR HIS DECADES-LONG STUDY OF TRANSFUSION-ASSOCIATED HEPATITIS, BUT HE PICKED UP THE MANAGEMENT OF THE STUDY WHEN HE RETURNED TO THE NIH AFTER HAVING COMPLETED HIS RESIDENCY IN HEMATOLOGY. DURING THAT TIME, COMMERCIAL BLOOD WAS EXCLUDED FROM THE NIH BLOOD BANK AND SECOND GENERATIONS TESTS FOR AUSTRALIA ANTIGEN HAD BEEN DEVELOPED TO EXCLUDE THAT MARKER OF HBV INFECTION FROM THE REMAINING VOLUNTEER POOL. JOHN WALSH HAD SHOWN IN A PREVIOUS STUDY OF THE HEART SURGERY PATIENTS, BEFORE TESTS FOR AUSTRALIA ANTIGEN WERE AVAILABLE, THAT THE ONLY DEMONSTRABLE RISK FACTOR FOR ACQUIRING HEPATITIS WAS RECEIVING COMMERCIAL BLOOD. WHAT HARVEY SHOWED WAS THAT TESTING FOR AUSTRALIA ANTIGEN AND GETTING RID OF COMMERCIAL BLOOD DIMINISHED THE HEPATITIS INCIDENCE IN THESE RECIPIENTS OF APPROXIMATELY 20 UNITS OF BLOOD FROM THE PREVIOUSLY-ESTABLISHED LEVEL OF OVER 30 PERCENT TO ABOUT 7 PERCENT. AND FURTHERMORE, THAT ONLY ABOUT A THIRD OF THAT HEPATITIS WAS CAUSED BY HEPATITIS B VIRUS. IT WAS ASSUMED THAT THE NON-B HEPATITIS WAS CAUSED BY HEPATITIS A VIRUS, THE ONLY OTHER HEPATITIS VIRUS RECOGNIZED AT THE TIME, BUT THE INCUBATION PERIOD OF THE NON-B HEPATITIS FELL BETWEEN THAT OF HEPATITIS A AND THAT OF HEPATITIS B. THIS WAS AN EXCITING TIME FOR HEPATITIS RESEARCHERS. IN THE SAME YEAR AS HARVEY'S PAPER ON HEPATITIS B AND TRANSFUSION IN 1972, WE COLLABORATED WITH JIM MAYNARD'S LAB AT THE CDC TO ESTABLISH THE CHIMPANZEE AS THE FIRST AND STILL ONLY ANIMAL MODEL FOR HEPATITIS B, OPENING THE WAY FOR JOHN GERIN TO MAKE AND TEST THE FIRST PRACTICAL HEPATITIS B VACCINE. STEVE HAD JOINED THE LABORATORY OF INFECTIOUS DISEASES ONLY A YEAR EARLIER IN 1971. WITH A HANDLE ON HEPATITIS B AND THE DEVELOPMENT OF DIAGNOSTIC TESTS FOR THAT VIRUS, WE TURNED TO HEPATITIS A. HERE IS THAT ICONIC PICTURE THAT YOU'VE SEEN. STEVE TEAMED UP WITH AL KAPIKIAN TO LOOK FOR THE ELUSIVE HEPATITIS A VIRUS BY ELECTRON MICROSCOPY BECAUSE AL HAD JUST DISCOVERED IN 1972 THE FIRST GASTROENTERITIS VIRUS, THE NORWALK VIRUS, BY IMMUNE ELECTRON MICROSCOPY. WITH JUST A SMALL NUMBER OF PATIENTS VERY CAREFULLY STUDIED, AL COULD UNEQUIVOCALLY RELATE ANTIBODY TO THE VIRUS PARTICLES AND TO RECENT GASTROENTERITIS CASES. FINDING THE HEPATITIS A VIRUS BY ELECTRON MICROSCOPY PROVED NOT SO EASY, BUT AFTER MANY LATE NIGHTS AT THE MICROSCOPE STEVE DID DISCOVER THE REAL THING. AND AGAIN, WITH JUST A SMALL NUMBER OF CAREFULLY-STUDIED PATIENTS, STEVE WAS ABLE TO SHOW UNEQUIVOCALLY THAT ANTIBODY TO THE PARTICLES WAS DIAGNOSTIC TO HEPATITIS A. THUS, HE WAS ABLE TO DETECT THE VIRAL ANTIGEN IN ACUTE CASES AND THE ANTIBODY DURING CONVALESCENCE. AND THESE WERE THE FIRST DIAGNOSTIC TESTS FOR HEPATITIS A. THUS, JUST TWO YEARS AFTER COMING TO THE NIH, HIS SECOND PAPER IN THE LABORATORY OF INFECTIOUS DISEASES, PUBLISHED IN SCIENCE, WAS A BLOCKBUSTER IN THE ANNALS OF HEPATITIS RESEARCH. WITH TESTS FOR HEPATITIS A AND HEPATITIS B NOW AVAILABLE, STEVE RETURNED TO THE HEART SURGERY STUDIES AND THE CASES OF NON-B HEPATITIS. AGAIN, WITH JUST A FEW PATIENTS, HE SHOWED THAT NOT A SINGLE ONE OF THE NON-B HEPATITIS CASES WAS HEPATITIS A, AND THUS WAS BORN NON-A, NON-B HEPATITIS. THE RESULTS WERE PUBLISHED IN THE NEW ENGLAND JOURNAL OF MEDICINE IN 1975. IT WAS ANOTHER BLOCKBUSTER AND STEVE'S EIGHTH PAPER IN THE LID. FOR THOSE OF YOU WITH AN INTEREST IN THE HISTORY OF MEDICINE, MAKE A PILGRIMAGE TO THE LOBBY OF BUILDING 50. THE ELECTRON MICROSCOPE I SHOWED YOU A FEW MINUTES AGO, WHICH FORMERLY WAS IN THE SUB-BASEMENT OF BUILDING 7, IS NOW ENSHRINED AS A RELIC OF THE EXCITING PATHOGEN DISCOVERIES I JUST DESCRIBED. ACTUALLY, STEVE AND I'LL -- AND AL AND I ARE ALSO RELICS OF THE GLORY DAYS OF VIRUS RESEARCH. THE IDENTIFICATION OF THE HEPATITIS A VIRUS OPENED THE DISCIPLINE OF VIROLOGY TO THIS VIRUS, BUT MAURICE HILLEMAN'S LAB AT MERCK, SHARP & DOHME HAD ALSO BEEN WORKING ON HEPATITIS A AND HAD ESTABLISHED A COLONY OF TAMARINS, WHICH FRITZ DEINHARDT HAD SHOWN PREVIOUSLY WERE SUSCEPTIBLE TO HEPATITIS A VIRUS INFECTION. HILLEMAN WAS CLEARLY INTERESTING IN DEVELOPING A HEPATITIS A VACCINE AND TESTING IT IN TAMARINS. HILLEMAN'S GROUP WAS THE FIRST TO ISOLATE HAV IN CELL CULTURE. THAT BREAKTHROUGH ENCOURAGED US TO GIVE IT A TRY, ALSO. AT ABOUT THAT TIME, IAN GUST HAD TAKEN A SABBATICAL FROM HIS INFECTIOUS DISEASES POSITION IN MELBOURNE TO JOIN STEVE AND HIS HEPATITIS A RESEARCH. AS IAN WILL TELL YOU DURING THIS SYMPOSIUM, HE CAME AT JUST THE RIGHT TIME AND HE BROUGHT WITH HIM GOLD IN THE FORM OF FECES FROM AN OUTBREAK OF HEPATITIS A IN MELBOURNE. [LAUGHTER] WE HAD ALSO ESTABLISHED A COLONY OF TAMARINS FOR THE STUDY OF HEPATITIS A, AND THE MELBOURNE VIRUS WAS PASSAGED IN TAMARINS ALONG WITH OTHER STRAINS AVAILABLE TO US. DICK DAEMER, ONE OF OUR STAFF, WAS CHARGED WITH TRYING TO ISOLATE HAV IN CELL CULTURE. AND OF THE MANY FECAL SAMPLES HE STUDIED, ONLY THE SAMPLES FROM IAN'S MELBOURNE OUTBREAK GREW WELL IN VITRO, AS SEEN IN THIS IMMUNE FLUORESCENCE MICROGRAPH OF INFECTED PRIMARY MONKEY KIDNEY CELLS. NOW, THIS PROVIDED AN OPPORTUNITY TO BIOLOGICALLY AMPLIFY THE VIRUS FOR ATTEMPTS AT MOLECULAR CLONING. AND JOHN TICEHURST, A POST DOC IN THE LAB AT THE TIME, COLLABORATED WITH VINCE RACANIELLO IN DAVID BALTIMORE'S LABORATORY TO PROVIDE THE FIRST MOLECULAR CLONES OF HAV. THEY CLONED THE VIRUS FROM TAMARIN LIVER AND CONFIRMED ITS AUTHENTICITY WITH THE TISSUE CULTURE-GROWN VIRUS. JEFF COHEN, THEN A POST DOC IN THE LAB AND NOW MY LAB CHIEF IN THE LID, WORKING WITH STEVE OBTAINED THE FIRST COMPLETE SEQUENCE OF HAV, WHICH HAD BECOME ATTENUATED BY ADAPTATION TO GROWTH IN CELL CULTURE, AND COMPARED ITS SEQUENCE WITH THAT OF WILD-TYPE VIRUS. JEFF AND STEVE ALSO GENERATED THE FIRST INFECTIOUS CDNA CLONE OF HAV FROM THE ATTENUATED AND CELL CULTURE-ADAPTED VIRUS, BUT WERE UNABLE TO DEMONSTRATE INFECTIVITY OF THE WILD TYPE CLONE. SUE EMERSON FOUND A SINGLE MUTATION IN THE WILD-TYPE CLONE. AFTER CORRECTING IT, SHE WAS ABLE TO DEMONSTRATE ITS INFECTIVITY BY IN VIVO TRANSFECTION DIRECTLY INTO THE LIVER OF A TAMARIN. WORKING WITH THE ATTENUATED AND WILD-TYPE SEQUENCES, STEVE AND SUE AND A NUMBER OF YOUNG PEOPLE IN THE LABORATORY INCLUDING JEFF COHEN -- [BEEPING SOUND] THIS ISN'T A TRUTH TEST, IS IT? [LAUGHTER] JEFF COHEN, JOHN TICEHURST, BAHIGE BAROUDY, RUTH KAREN, ANN FUNKHOUSER, AND GOPA RAYCHAUDURI MAPPED THE MUTATIONS THAT ACCOUNTED FOR ATTENUATION VERSUS VIRULENCE AND THOSE THAT WERE RESPONSIBLE FOR ADAPTATION OF THE VIRUS TO GROWTH IN CELL CULTURE. SUE ALSO SHOWED THAT MUTATIONS THAT ATTENUATED THE VIRUS WERE UNSTABLE AND REVERTED TO VIRULENCE IN ANIMAL MODELS. THUS OUR ORIGINAL PLAN TO MAKE A LIVE, ATTENUATED VACCINE WERE DASHED AND THE VACCINE THAT EMERGED FROM OUR COLLABORATIONS WITH SMITHKLINE BEECHAM, NOW GLAXOSMITHKLINE, WAS AN INACTIVATED WHOLE-VIRUS VACCINE, THE FIRST LICENSED HEPATITIS A VACCINE. I BELIEVE LENNY BINN MAY BE IN THE OFFICE HERE -- IN THE AUDIENCE TODAY, AND I WANT TO ACKNOWLEDGE THE ROLE THAT WALTER REED ALSO HAD IN THE DEVELOPMENT OF THAT VACCINE. NOW, ANOTHER FACET OF STEVE'S CAREER, NOT AS WELL KNOWN AS OTHERS, WAS HIS GROUNDBREAKING WORK WITH POLYMERASE CHAIN REACTION. ONE OF THE FIRST DEFINITIVE PAPERS ON PCR WAS A 1987 REPORT IN SCIENCE FROM THE CETUS CORPORATION. KARY MULLIS, WHO HAD INVENTED PCR ONLY A YEAR OR TWO EARLIER, WAS THE CO-AUTHOR. JUST TWO WEEKS EARLIER, ANOTHER PAPER ON THE DIRECT APPLICATION OF PCR ALSO FROM CETUS IN COLLABORATION WITH CDC WAS PUBLISHED IN SCIENCE. JOHN SNINSKY WAS A COAUTHOR OF THAT PAPER. STEVE HAD ESTABLISHED A COLLABORATION ON PCR WITH JOHN AND PROCEEDED TO SET UP THE EQUIPMENT. THIS WAS ALL PRIOR TO THE DEVELOPMENT OF PCR MACHINES. TO REPRODUCE THE CYCLING AT TEMPERATURES NECESSARY FOR THE PROCEDURE, STEVE RIGGED AN OLD WATER BATH ON SPINDLY LEGS WITH AN IMMERSION HEATER. THIS CYCLING CONSISTED OF PLUNGING THE SAMPLE TO BE AMPLIFIED INTO THE HOT WATER, CAREFULLY TIMING IT, AND THEN WHISKING IT OUT AGAIN. THIS WAS DONE REPEATEDLY. TO KEEP THE WATER IN THE WATER BATH FROM RAPIDLY EVAPORATING, STEVE COVERED ITS SURFACE WITH PING PONG BALLS. [LAUGHTER] THIS WAS A VERY STRANGE MACHINE, BUT IT ALLOWED STEVE WITH SHUICHI KANEKO, A POST DOC IN THE LAB, TO DEVELOP A USEFUL PCR PROCEDURE WITH WHICH THEY COULD DETECT HEPATITIS B VIRUS DNA WITH A HIGH DEGREE OF SENSITIVITY IN CLINICAL SAMPLES. THE PAPER WAS PUBLISHED IN PNAS AND IT LAUNCHED SUICHI ON HIS CAREER IN MOLECULAR HEPATOLOGY. STEVE'S WORK ALSO LED INDIRECTLY TO THE DISCOVERY OF HEPATITIS E. IN THE WINTER OF 1955/1956, A HUGE EPIDEMIC OF HEPATITIS STRUCK DELHI, INDIA. AT THE TIME, IT WAS THE LARGEST SUCH EPIDEMIC EVER RECORDED. SOME LEADING VIROLOGISTS THOUGHT IT WAS CAUSED BY HAV. TWO UNUSUAL ASPECTS OF THE EPIDEMIC WERE ITS PEAK CLINICAL ATTACK RATE AMONG OLDER CHILDREN AND YOUNG ADULTS, AND A HIGH MORTALITY AMONG PREGNANT WOMEN. JULES DIENSTAG, AS A NEW POST DOC IN THE LABORATORY, PICKED UP ON STEVE'S WORK ON HAV AS STEVE WAS LEAVING THE LAB TO COMPLETE HIS RESIDENCY TRAINING. JULES HAD DEVELOPED ADDITIONAL SENSITIVE SEROLOGIC TESTS FOR HAV AND ITS ANTIBODY, AND IN COLLABORATION WITH OTHERS SHOWED THAT VIRTUALLY EVERYONE IN DEVELOPING COUNTRIES HAD ANTIBODY TO HAV BY AGE FIVE YEARS, THUS IT WAS SURPRISING THAT THE DISEASE WAS OCCURRING IN A PRESUMABLY HIGHLY-IMMUNE POPULATION. AND JULES POSTULATED THAT THIS EPIDEMIC MIGHT ACTUALLY BE CAUSED BY A PREVIOUSLY UNRECOGNIZED VIRUS. HOWEVER, TRY AS HE MIGHT, HE COULD NOT OBTAIN PAIRED SERA FROM THE DELHI EPIDEMIC. AFTER JULES LEFT THE LABORATORY, WE WERE ABLE TO OBTAIN PAIRED SERA FROM 14 CASES OF HEPATITIS FROM THE DELHI EPIDEMIC AS WELL AS FROM OTHER WATER-BORN EPIDEMICS IN HEPATITIS IN INDIA. USING SENSITIVE ASSAYS FOR ANTIBODY TO HAV, WE COULD SHOW THAT NONE OF THE PATIENTS HAD SEROLOGIC EVIDENCE OF RECENT HAV INFECTION, AND ALL HAD EVIDENCE OF PAST INFECTION. AT ABOUT THE SAME TIME, MOHAMMED SULTAN KHUROO, A GASTROENTEROLOGIST FROM THE KASHMIR REGION OF INDIA, REPORTED A SIMILAR DISEASE AND EPIDEMIC NON-A, NON-B HEPATITIS WAS BORN. THREE YEARS LATER, MIKHAIL BALAYAN REPORTED ON AN EPIDEMIC OF HEPATITIS IN CENTRAL ASIA. HE HEROICALLY INFECTED HIMSELF WITH THE VIRUS AND FOR THE FIRST TIME VISUALIZED THE EPIDEMIC NON-A, NON-B VIRUS IN HIS OWN FECES AND DOCUMENTED HIS SEROCONVERSION TO THE VIRUS. HE ALSO SUCCESSFULLY TRANSMITTED THE VIRUS TO CYNOMOLGUS MONKEYS, THUS ESTABLISHING THE FIRST ANIMAL MODEL. AND THIS VIRUS EVENTUALLY BECAME HEPATITIS E VIRUS. ALTHOUGH THE EPIDEMIC WAS REPORTED TO HAVE BEEN IN UZBEKISTAN, IT WAS ACTUALLY AMONG RUSSIAN TROOPS IN AFGHANISTAN, BUT THE INFORMATION WAS CENSORED BY THE RUSSIAN AUTHORITIES. HERE ARE THOSE RUSSIAN TROOPS AS THE MUJAHIDEEN, THE FORERUNNERS OF THE TALIBAN, SAW THEM IN 1981. NOW THE TALIBAN ARE LOOKING AT US TROOPS. NOW, AFTER COMPLETION OF HIS RESIDENCY, STEVE RETURNED TO THE LID WHERE HE CONTINUED TO BE HIGHLY PRODUCTIVE. IN 1989 HE BECAME CHIEF OF THE LABORATORY OF HEPATITIS VIRUSES IN THE DIVISION OF VIRAL PRODUCTS, CBER, FDA WHERE HE CONTINUED HIS STELLAR RESEARCH CAREER. HOWEVER, I'VE NOT EXHAUSTED THE LIST OF STEVE'S MAJOR ACCOMPLISHMENTS WHILE AT THE LID. ONE SUCH ACCOMPLISHMENT WAS THE DETERMINATION OF THE INFECTIVITY TITER OF HEPATITIS C VIRUS. NO SIMPLE FEAT, BECAUSE VIRTUALLY NOTHING WAS KNOWN ABOUT THE VIRUS. IT DID NOT GROW IN CELL CULTURE AND THE CHIMPANZEE WAS THE ONLY ANIMAL MODEL. THE VIRUS WAS THE STRAIN OBTAINED FROM MR. HUTCHINSON, A LEGEND IN HCV VIROLOGY. MR. HUTCHINSON WAS ONE OF THE HEART SURGERY PATIENTS FOLLOWED AT THE NIH WHO DEVELOPED CHRONIC HCV INFECTION. THE HUTCH STRAIN, AS IT'S COME TO BE KNOWN, WAS USED FOR A NUMBER OF EXPERIMENTS, FROM BIOCHEMICAL AND BIOPHYSICAL CHARACTERIZATION TO VACCINE DEVELOPMENT. AS CHARLIE RICE WILL TELL YOU LATER, THE FIRST INFECTIOUS CDNA CLONE OF HEPATITIS C VIRUS WAS DERIVED BY STEVE AND CHARLIE FROM MR. HUTCHINSON'S VIRUS. MR. HUTCHINSON NEVER TURNED DOWN A REQUEST FOR A CLINICAL SAMPLE, RIGHT UP TO HIS DEATH TWO OR THREE YEARS AGO. ALTHOUGH A CARRIER OF HCV FOR 30 YEARS, HE DID NOT DIE OF HEPATITIS-RELATED DISEASE BECAUSE HE CONTROLLED HIS INFECTION VERY WELL, BUT RATHER HE DIED OF HEART-RELATED DISEASE. HERE IS ONE OF THE LAST PICTURES OF MR. HUTCHINSON ON THE OCCASION OF HIS 30TH BIRTHDAY PARTY. NOT ACTUALLY HIS BIRTHDAY PARTY, BUT MR. HUTCHINSON'S VIRUS'S BIRTHDAY PARTY. MR. HUTCHINSON WAS ACCOMPANIED BY HIS WIFE AND THE USUAL SUSPECTS. ANOTHER PERSON WHO DETERMINED THE INFECTIVITY TITER OF THE -- OF AN HCV STRAIN WAS DAN BRADLEY OF THE CDC. DAN'S WELL-CHARACTERIZED HCV STRAIN, HCV-1, WAS THE SOURCE OF MATERIAL FOR THE FIRST CLONING AND SEQUENCING OF HCV BY MICHAEL HOUGHTON AND THE GROUP AT CHIRON. DAN AND STEVE COMPETED IN CHARACTERIZING HCV. IN THIS INSTANCE, BY SHOWING THAT THE VIRUS HAD A LIPID-CONTAINING ENVELOPE BY DEMONSTRATING ITS INACTIVATION WITH CHLOROFORM. THE TWO STUDIES WERE PUBLISHED IN THE SAME MONTH IN 1983. HOWEVER, THERE WAS ONE BIG DIFFERENCE IN THE TWO STUDIES. WE PATENTED INACTIVATION OF THE VIRUS BY CHLOROFORM AS A NEW USE FOR MAKING BLOOD PRODUCTS SAFE. WE HAD WORKED WITH THE REVLON CORPORATION WHO OWNED ARMOUR, A MAJOR MANUFACTURER OF HEMOPHILIC CLOTTING FACTOR. WE HAD SHOWED THAT THEIR MANUFACTURING PROCESS, WHICH INCLUDED HEATING THE DRIED CLOTTING FACTOR FOR SEVERAL HOURS, DID NOT INACTIVATE HEPATITIS VIRUSES AND THEY WERE EAGER TO FIND A PROCEDURE THAT DID. STEVE HAD SHOWN THAT AQUEOUS SOLUTIONS OF BOTH HBV AND NON-A, NON-B HEPATITIS VIRUS WERE INACTIVATED BY EXPOSURE TO CHLOROFORM AND THAT SHAM-EXPOSED VIRUSES WERE STILL FULLY INFECTIOUS. WE REPEATED THE EXPERIMENT WITH A DRIED HEMOPHILIC CLOTTING FACTOR AND SHOWED THAT BOTH VIRUSES WERE AGAIN INACTIVATED. FURTHERMORE, IT WAS EASY TO REMOVE THE CHLOROFORM BY SIMPLE EVAPORATION FROM THE CLOTTING FACTOR POWDER. STEVE AND I HAD OBTAINED PERMISSION FROM THE GOVERNMENT TO INDEPENDENTLY PATENT THE FOREIGN RIGHTS TO THIS INACTIVATION PROCEDURE, AND WE INITIATED THE EXPENSIVE PATENTING PROCEDURE AS WE PREPARED TO LICENSE OUT THE TECHNOLOGY TO REVLON. IN THE MEANTIME, REVLON WANTED TO PERFORM THEIR OWN CONFIRMATORY INACTIVATION EXPERIMENTS, SEPARATE FROM OUR STUDIES. WE WERE SHOCKED WHEN THEY TOLD US THAT HBV WAS NOT INACTIVATED UNDER THESE CONDITIONS. MUCH ADDITIONAL SOUL-SEARCHING AND EXPERIMENTAL STUDIES TOOK PLACE BEFORE WE REALIZED THAT INACTIVATION WITH CHLOROFORM REQUIRED THAT IT BE SATURATED WITH WATER. THE AMOUNT OF WATER THAT CAN DISSOLVE IN CHLOROFORM IS MINISCULE, BUT THAT IS ENOUGH FOR INACTIVATION. REVLON HAD TAKEN A NEW AND UNOPENED BOTTLE OF ANHYDROUS CHLOROFORM FOR THEIR INACTIVATION STUDY. ALTHOUGH WE HAD CAREFULLY RECORDED THE MANUFACTURING INFORMATION AND LOT NUMBER OF OUR CHLOROFORM, WE HAD ACTUALLY USED A BOTTLE THAT HAD BEEN OPEN AND ON THE SHELF FOR GOD KNOWS HOW LONG. THE WATER IT HAD ABSORBED OVER TIME APPEARED TO BE ENOUGH TO INACTIVATE THE VIRUS. NOW, BY THE TIME WE FIGURED THIS OUT, FRED PRINCE AND COLLEAGUES HAD DEVELOPED THE SOLVENT-DETERGENT TREATMENT METHOD FOR BLOOD PRODUCTS AND HAD LICENSED IT OUT TO MOST OF THE BLOOD PRODUCT MANUFACTURERS WORLDWIDE. ALTHOUGH A MORE CUMBERSOME PROCEDURE, IT WORKED AND IT WAS TOO LATE FOR US TO MAKE CHLOROFORM ATTRACTIVE. HAD IT NOT BEEN FOR FATE, WE WOULD HAVE BEEN AS RICH AS CROESUS. WELL, MAYBE AT LEAST AS RICH AS FRED PRINCE. AND STEVE AND I WERE LEFT WITH LOTS OF ISSUED PATENTS, WORLDWIDE, PATENTS THAT TURNED OUT TO BE NOT WORTH THE PAPER THEY WERE PRINTED ON. [LAUGHTER] IN CLOSING, I WANT TO POINT OUT THAT STEVE IS NOT LIKELY TO BE BORED IN HIS RETIREMENT. HE'S BEEN AN AVID SAILOR FOR MOST OF HIS LIFE, ALTHOUGH I DON'T THINK MIMI SHARES THAT PASSION WITH HIM. HERE IS STEVE ON ONE OF HIS SAILBOATS WITH ONE OF OUR EX-POST DOCS, BENGT HANSSON FROM SWEDEN. HERE IS STEVE WITH ANOTHER OF OUR POST DOCS, JANOS SLUSORGIC FROM POLAND. THESE ARE VERY OLD PICTURES THAT I SALVAGED FROM DETRITUS IN THE LABORATORY. THE ADAGE FOR THE FINAL PICTURES IS, "IF YOU DRIVE, DON'T DRINK. IF YOU DRINK" -- [LAUGHTER] "IF YOU DRINK, DON'T DRIVE." I WILL, HOWEVER, DRINK A TOAST TO STEVE ON THE OCCASION OF HIS RETIREMENT AND WISH HIM THE VERY BEST OF WHAT WE HOPE WILL CONTINUE TO BE HIS GOLDEN YEARS. I JUST CAN'T BELIEVE THAT I LET MY FAMOUS EX-POST DOC RETIRE BEFORE ME. OBVIOUSLY, HE'S SMARTER THAN I AM. [LAUGHTER] THANKS. [APPLAUSE] GERARDO KAPLAN: DO WE HAVE ANY QUESTIONS FOR DR. PURCELL? ROBERT PURCELL: THE -- I CAN TELL YOU BEFOREHAND THE QUESTIONS ARE, "YES, NO, I DON'T KNOW," AND, "MAYBE." [LAUGHTER] GERARDO KAPLAN: SO, I HAVE ONE. WHO IS THE ONE THAT'S DRIVING THE BOAT? WHO IS THE PERSON? ROBERT PURCELL: THAT'S BENGT HANSSON, AGAIN. HE'S ONE OF OUR POST DOCS FROM SWEDEN. I THINK BENGT IS RETIRED NOW, I THINK, ALSO. ISN'T HE, STEVE? STEPHEN FEINSTONE: I THINK HE RECENTLY RETIRED. [INAUDIBLE] BIG PLAYER IN SWEDEN [INAUDIBLE]. ROBERT PURCELL: IT'S TIME. ANY OTHER QUESTIONS? WHEN AM I RETIRING? DECEMBER 31ST. [LAUGHTER] GERARDO KAPLAN: OKAY, THANK YOU VERY MUCH. OKAY, SO IT'S A GREAT HONOR FOR ME TO INTRODUCE A NEW -- THE NEXT SPEAKER, DR. JAY HOOFNAGLE. HE'S THE DIRECTOR OF THE LIVER DISEASE RESEARCH BRANCH DIVISION OF DIGESTIVE AND DISEASES AND NUTRITION, NIDDK, AT NIH. AND JAY DOESN'T NEED ANY MORE INTRODUCTION. JAY HOOFNAGLE: WE'LL, IT'S A PLEASURE TO BE HERE BUT IT'S A BITTER PLEASURE BECAUSE WE'RE SAYING GOODBYE TO STEVE, AT LEAST GOODBYE PROFESSIONALLY. MY TALK IS ENTITLED "STEVE FEINSTONE AND ME" AND IT'S ABOUT BOTH OF US. IT'S NOT JUST ABOUT STEVE BECAUSE, IN A WAY -- [LAUGHTER] -- WE HAD PARALLEL CAREERS, NOT QUITE PARALLEL LIVES. SO, I'LL TALK ABOUT HEPATITIS RESEARCH IN THE LAST 30 OR 40 YEARS, WITH ITS HIGHS AND LOWS, THE WONDER YEARS, THE GROWING PAINS, AND THEN A NEW ERA FOLLOWED BY MATURE YEARS. IT'S HARD TO COMMUNICATE THE EXCITEMENT THAT WAS SURROUNDING HEPATITIS WHEN STEVE AND I ENTERED THE FIELD, STEVE IN 1971 AND I FOLLOWED IN 1972. WE BOTH CAME TO THE NIH, HE TO THE HEPATITIS VIRUSES SECTION, NIAD WITH BOB PURCELL. AND I ACTUALLY JOINED THE NIH BUT GOT KICKED OUT THE NIH THE FIRST DAY I ARRIVED AND MADE PART OF THE FDA AND I WORKED WITH LOU BARKER. THE FIELD OF VIRAL HEPATITIS HAD JUST EXPLODED AND IT EXPLODED BECAUSE THE IDENTIFICATION OF THE AUSTRALIA ANTIGEN AND THEN ITS LINK TO HEPATITIS B, WHICH BY 1971-72 WAS VERY CLEAR THAT IT WAS. TESTS FOR HEPATITIS B HAD BEEN DEVELOPED, FOR ANTIGEN AND FOR ANTIBODY, AN ANIMAL MODEL HAD BEEN DEVELOPED, AND BLOOD DONATIONS WERE BEGINNING TO BE SCREENED. THIS WAS THE TIME THAT WE ENTERED THE LAB. IT WAS ALSO AN EXCITING TIME TO BE IN WASHINGTON BECAUSE A MONTH BEFORE I CAME THERE WAS A BREAK IN AT THE DEMOCRATIC CONVENTION -- THE DEMOCRATIC OFFICES IN THE WATERGATE. IT MADE WASHINGTON A VERY EXCITING TIME AND QUITE A CHANGE FROM THE 1960S. THE DISMAL 1960S HAD SEEN SO MUCH PROBLEM IN THE UNITED STATES. SUDDENLY, THINGS STARTED LOOKING UP AND THEY WERE LOOKING UP IN THE LAB, AS WELL. THE CHALLENGES WERE IMMENSE. THERE WERE JUST SO MANY THINGS TO STUDY. WE WERE ONLY LIMITED BY THE TOOLS THAT WE HAD. NOW, THE TOOLS THAT WE HAD, I -- MY LAB WASN'T QUITE AS SOPHISTICATED AS BOB PURCELL'S LAB. WE DEALT WITH OUCHTERLONY IMMUNODIFFUSION AND WITH FLUORESCENCE ANTIBODY TESTS, WITH GEL FILTRATION, MAYBE WITH TRANSMISSION EM, WHEREAS STEVE, HE WAS WORKING WITH RADIOIMMUNOPRECIPITATION AND WITH IMMUNE ELECTRON MICROSCOPY. I, TOO, REMEMBER THE LUNCHES WE HAD IN THE CLINICAL CENTER WITH STEVE. IT'S VERY INTERESTING, STEVE WAS NOT EXACTLY A HAPPY PERSON. I'M A KIND OF A CHEERY PERSON, BUT STEVE AS YOU KNOW IS NOT ALWAYS VERY HAPPY. [LAUGHTER] AND OUR LUNCHES WERE FREQUENTLY SPENT TRYING TO CHEER HIM UP. HE WAS DEPRESSED. HE WAS WORKING IN THE BASEMENT OF BUILDING 7 IN THE DARK AND HIS RESEARCH WAS GOING -- WASN'T GOING WELL. AND HIS CAR WAS BROKEN DOWN, AND HIS -- [LAUGHTER] HE DIDN'T HAVE ENOUGH TIME TO GO SAILING AND SO FORTH. HE EVENTUALLY DID CHEER UP, WITH THIS: A LANDMARK DISCOVERY OF HEPATITIS A. NOVEMBER 1ST, 1973. LOOK AT THAT. IT'S QUITE A NICE PAPER TO BE YOUR FIRST FIRST-AUTHOR PAPER AND BEING A SECOND-YEAR FELLOW AT THE NIH. BOB PURCELL HAS TOLD YOU ABOUT THIS, BUT IT REALLY BROKE OPEN THE FIELD IN HEPATITIS A AND SUDDENLY WE NOT ONLY HAD TESTS FOR HEPATITIS B BUT ALSO FOR HEPATITIS A. WELL, MEANWHILE, I WAS PLUGGING AWAY. NOT -- LESS OF A LANDMARK, PERHAPS, BUT LOOK AT THIS. MY FIRST AUTHOR -- MY FIRST FIRST-AUTHOR PAPER WAS ON OCTOBER 20TH. LIKE, I BEAT STEVE BY TWO WEEKS IN OUR LAB. [LAUGHTER] BUT THESE TWO PAPERS WERE GREAT. WE WERE JUST FELLOWS, BUT SUDDENLY WE WERE INTERNATIONALLY-KNOWN SCIENTISTS AND WE GOT INVITED ALL OVER THE WORLD. I WAS CALLED "PROFESSOR." PEOPLE WOULD BE SHOCKED WHEN THEY SAW ME. I DIDN'T LOOK LIKE A PROFESSOR. BUT IT WAS TERRIFIC AND THERE WAS NO END TO THE THINGS THAT WE COULD DO WITH THESE TOOLS THAT HAD BEEN DEVELOPED. I WORKED WITH STEVE. WE COLLABORATED NOT JUST AT LUNCH, KVETCHING ABOUT THINGS, BUT ALSO IN THE LAB. HERE IS A STUDY OF -- THE EXPERIMENTAL DESCRIPTION OF HEPATITIS A VIRUS IN CHIMPANZEES. IT WAS A COLLABORATIVE EFFORT BETWEEN STEVE'S LAB, BOB'S LAB, AND LOU BARKER'S LAB. AND ON THE PAPER, TOO, THERE IS ONE OF MY BIG MENTORS, HANS POPPER. SO, THAT WAS PRETTY EXCITING. BUT THE FOLLOWING YEAR, ANOTHER THING HAPPENED. I GOT A CALL IN THE LAB. I WAS SITTING THERE. STEVE SAID TO ME, "JAY, I'VE GOT REALLY INTERESTING DATA WITH THIS HEPATITIS A TEST." AND I SAID, "OH YEAH? WHAT IS IT?" HE SAID, "WELL, YOU KNOW POSTTRANSFUSION HEPATITIS THAT ISN'T HEPATITIS B?" I SAID, "YEAH." HE SAID, "IT ISN'T HEPATITIS A, EITHER." WELL, IT SEEMS SILLY NOW, BUT THAT WAS A REVOLUTION. IT WAS AN EPIPHANY. AND ACTUALLY, AS SOON AS HE SAID IT, I SAID, "OF COURSE." WHY DIDN'T I KNOW THIS? WHY DIDN'T EVERYBODY KNOW THIS, THAT THIS WASN'T HEPATITIS A? WHY DID WE THINK THAT IT WAS HEPATITIS A? WELL, HERE'S A LITTLE BIT OF THE EVIDENCE. THESE ARE THE INCUBATION PERIOD OF THE 22 CASES THEY TESTED. AND, YOU KNOW, SOME OF THEM ARE VERY MUCH IN THE INCUBATION PERIOD OF HEPATITIS A. OTHERS ARE TOO LONG, IT'S MORE LIKE HEPATITIS B. AND ONE OF THE THINGS THAT WE THOUGHT -- THAT THIS NON-B POSTTRANSFUSION HEPATITIS WAS ACTUALLY HEPATITIS B AND OUR TESTS JUST WEREN'T GOOD ENOUGH YET. WELL, THAT WASN'T TRUE. NOT ONLY WAS SOME OF IT NON-A, NON-B, BUT ALL OF IT. 100 PERCENT WAS NOT A. ALSO IN THIS FIRST PAPER, THEY REALLY -- IF YOU LOOK AT THIS FIRST PAPER, IT DEFINES WHAT WE CAME TO KNOW AS NON-A, NON-B HEPATITIS. HAS A LOW RATE OF JAUNDICE. MOST CASES ARE SUBCLINICAL. ENZYMES AREN'T THAT HIGH, NOT AS HIGH AS IN A OR B. AND LOOK AT THIS, THE CHRONICITY RATE IS QUITE DISTINCTIVE. AND THESE ARE THE FEATURES THAT MARK HEPATITIS C. WELL, I JOINED IN WITH STEVE AND WE COLLABORATED TOGETHER ON THIS WORK FROM OUR GROUP WHERE WE HAD STORED SPECIMENS FROM PRISONERS IN FEDERAL PRISONS FROM THE 1950S WHO HAD BEEN INOCULATED WITH SUSPECTED INFECTIOUS MATERIAL, BELIEVE IT OR NOT. AND THEY HAD SEVERAL INOCULA THAT WERE FROM BLOOD DONORS WHO HAD BEEN IMPLICATED IN POSTTRANSFUSION HEPATITIS. TWO OF THE INOCULA WERE HEPATITIS B, BUT THE OTHER THREE I COULDN'T SORT OUT. AND IN THIS PAPER, WE SHOW THAT IT WAS ALSO NOT A. AND THE INCUBATION PERIODS WERE THE SAME. IT WAS THE SAME THING: SOME SHORT, SOME LONG. WELL, THAT WAS THE EARLY WONDER YEARS WHEN THINGS HAPPENED SO QUICKLY AND WE WERE PUBLISHING LIKE CRAZY. THEN WE HAD AN INTERLUDE, BOTH STEVE AND I LEFT THE NIH FOR A WHILE. WE FINISHED OUR FELLOWSHIPS AND WE HAD A VA INTERLUDE. STEPHEN STARTED IN '74, I STARTED IN '75. FOR STEVE, IT WAS NOT A VERY PLEASANT INTERLUDE. FOR ME, IT WAS OKAY. I ENJOYED IT. I GOT TRAINING IN LIVER DISEASE. BUT AFTER THREE YEARS, WE WERE VERY HAPPY TO RETURN TO THE NIH AS SENIOR INVESTIGATORS, STEVE IN NIAD AT BOB'S LAB. AND I JOINED NIDDK AT THAT POINT, A CLINICAL LAB -- CLINICAL GROUP. BUT WHAT WAS HAPPENING, THOUGH, IS WE WERE ENTERING THE PAINFUL, DIFFICULT YEARS, AT LEAST FOR NON-A, NON-B HEPATITIS. THERE WERE MAJOR ADVANCES BEING MADE IN HEPATITIS A AND B AND DELTA, HEPATITIS E, AS BOB HAS OUTLINED. BUT THE AGENT FOR NON-A, NON-B HEPATITIS REMAINED ELUSIVE. AND IT WASN'T THAT WE WEREN'T TRYING. IN FACT, I THINK A MAJORITY OF STEVE'S TIME WAS SPENT TRYING, AND A LOT OF MY TIME WAS SPENT, AS WELL. NOW, YOU'LL BE SURPRISED BECAUSE WE DIDN'T WRITE ANY PAPERS ABOUT IT DURING THIS PERIOD. AND THE REASON WHY WE DIDN'T WRITE ANY PAPERS IS ALL OF OUR RESULTS WERE NEGATIVE. BUT MEANWHILE, INNUMERABLE REPORTS WAS APPEARING IN THE LITERATURE DESCRIBING ANTIGENS AND ANTIBODIES THAT WERE SPECIFIC TO NON-A, NON-B OR VIRUS PARTICLES OR REVERSE TRANSCRIPTASE ACTIVITY. I'M -- LOST IT HERE. AND THEY WERE IN GOOD JOURNALS. THEY WERE IN SCIENCE, THEY WERE IN THE NEW ENGLAND JOURNAL OF MEDICIN AND LANCET. AND STEVE AND I WOULD HAVE LUNCH TOGETHER A LOT, AGAIN, AND AGAIN THE KVETCHING WOULD START. YOU KNOW, ALL THESE THINGS ARE BEING PUBLISHED AND THEY'RE RIDICULOUS. THESE PEOPLE ARE BEING INVITED TO MEETINGS AND WE WEREN'T? WHAT'S THE PROBLEM? SO, WE DECIDED, WELL, WE WERE GOING TO WRITE A PAPER. AND SO WE WROTE THIS PAPER IN THE NEW ENGLAND JOURNAL OF MEDICINE. IT WAS A -- NOT AN ORIGINAL ARTICLE. IT WAS CALLED, "SOUNDING BOARD," [LAUGHS]. WE SOUNDED OFF AND WE BASICALLY WENT THROUGH THE 30 PAPERS IN THE LITERATURE DESCRIBING AGENTS AND TRIED TO PICK THEM APART. IT WAS -- SOME PEOPLE WELCOMED THIS ARTICLE, THEY THOUGHT IT WAS GREAT, BUT OTHERS DIDN'T LIKE IT VERY MUCH. IN FACT, THOSE PEOPLE STILL FROWN AT ME WHEN I SEE THEM IN THE HALLWAYS AND ALL. [LAUGHTER] IT WAS A DIFFICULT TIME, THOUGH, AND THE AGENT WAS NOT BECOMING CLEAR. NOW, HERE'S THE LIVER UNIT IN 1985 THAT I WORKED IN NIDDK. AND FIRST THING YOU RECOGNIZE, IT'S VERY SMALL. THERE'S ONLY A COUPLE PEOPLE IN THE PICTURE. THESE ARE MY -- THESE ARE TWO OF MY FELLOWS. THIS IS CHRIS PAPPAS AND GARY DAVIS. HERE I AM, YOUNG GUY. JAMES DOOLEY FROM THE ROYAL FREE WAS VISITING FOR TWO YEARS. TONY JONES WAS HEAD OF THE UNIT. THIS IS A MEDICAL STUDENT. AND IN THE MIDDLE, HERE, IS HANS POPPER. HANS WOULD COME DOWN ONCE A MONTH AND SPEND THE DAY WITH US AND TALK ABOUT SCIENCE AND THINGS. HE CAME DOWN AND AFTER OUR PAPER CAME OUT ABOUT NON-A, NON-B HEPATITIS -- WE CALLED IT "NON-A, MAYBE-B." AND HE SAID TO ME, "THAT'S THE STUPIDEST PAPER I'VE EVER READ." [LAUGHTER] AND I SAID, "BUT, HAN'S, WE SEE ALL THESE PAPERS AND THEY'RE NOT REAL. PEOPLE MIGHT BELIEVE IT." HE SAYS, "OH, YOU KNOW, WHY BOTHER WITH THIS? YOU KNOW, SCIENCE IS SELF CORRECTING AND IN FIVE AND 10 YEARS NOBODY WILL THINK ABOUT THESE PEOPLE AGAIN OR READ THEIR PAPERS." WELL, I SAID, "OKAY, OKAY, OKAY. ALL RIGHT." ANYWAYS, THAT WAS 1985. IT'S ALMOST 20 YEARS LATER OR MORE, NOW. HANS IS DEAD. BUT, YOU KNOW, HE WAS RIGHT, NOBODY REMEMBERS. YOU PROBABLY DON'T REMEMBER THOSE OR KNOW ANY OF THOSE PAPERS AT ALL, NOW. AND STEVE, I HAVE TO APOLOGIZE, THAT WAS THE STUPIDEST PAPER WE EVER WROTE TOGETHER. [LAUGHTER] YOU KNOW, JUST WORK ON THINGS ON YOUR OWN AND DON'T WORRY WHAT OTHER PEOPLE ARE DOING. AND THEN, OF COURSE, WE GOT FRUSTRATED WITH NOT BEING ABLE TO FIND THE VIRUS. AND IN OUR GROUP, WE STARTED TRYING THINGS TO TREAT IT WITH. AND I ACTUALLY TRIED SEVERAL THINGS, AND ALL THOSE PAPERS ARE FORGOTTEN ABOUT. BUT THE ONE THING THAT DID WORK IS REMEMBERED, WHEN WE TRIED ALPHA INTERFERON AND SHOWED THAT IT HAD AN EFFECT ON THE LIVER ENZYMES AND THE HISTOLOGY IN A LARGE NUMBER OF PATIENTS AND HALF OF PEOPLE. AND IN SOME, THE EFFECT LASTED. AFTER WE STOPPED THERAPY THEY REMAINED IN REMISSION. WELL, THE IMPORTANT BREAKTHROUGH, THE THIRD BIG LANDMARK DISCOVERY, WAS THE DISCOVERY OF THE HEPATITIS C VIRUS. IT WAS ISOLATED BY -- OH, CDNA FROM THE VIRUSES ISOLATED BY MICHAEL HOUGHTON AND HIS GROUP AT CHIRON, AND THIS OF COURSE CAUSED THE FIELD TO EXPLODE AGAIN. AND IT WAS IN NEED OF AN EXPLOSION BECAUSE PEOPLE WERE DROPPING OUT OF VIRAL HEPATITIS RESEARCH. THEY WERE GOING INTO STUDYING AIDS AND THAT TYPE OF THING. THIS BROUGHT THEM BACK. SUDDENLY, WE HAD SOMETHING TO STUDY AGAIN. AND INDEED, WITH STEVE FEINSTONE WE LOOKED AT THESE PATIENTS WITH HEPATITIS C THAT SEEMED TO IMPROVE ON INTERFERON THERAPY, WHAT WAS HAPPENING WITH THE VIRUS -- AND AS YOU MIGHT IMAGINE, THE VIRUS WAS GOING DOWN DURING TREATMENT. WELL, HERE'S DURING A PLACEBO PERIOD. IT DOESN'T CHANGE. WITH TREATMENT, IT GOES AWAY. AND IN THOSE PATIENTS WHO HAVE A SUSTAINED REMISSION, THE VIRUS REMAINS NEGATIVE. THIS WAS WORK THAT WAS ACTUALLY DONE BY A POST DOC THAT WAS WORKING WITH US, MICHIKO SHINDO, WHO REALLY WORKED VERY CLOSELY WITH STEVE TO DEVELOP THIS PCR ASSAY. IT TOOK MUCH LONGER THAN IT DID FOR HEPATITIS A TO DEVELOP A PCR BECAUSE CHIRON HADN'T RELEASED THE SEQUENCE. [LAUGHS] AND IT WASN'T UNTIL THE JAPANESE SEQUENCED THE FIVE PRIME NONCODING REGION AND FAXED THE SEQUENCE TO EVERY LAB -- I WAS SITTING IN THE LAB, AND ALL THE FAX MACHINE COMES OFF AT CCTA, YOU KNOW. [LAUGHTER] IT WAS THE SEQUENCE THAT WE NEEDED. I DON'T THINK WE COULD HAVE DONE THIS WITHOUT STEVE, AND SOMEONE WOULD HAVE DONE THIS. THIS WAS AN IMPORTANT DISCOVERY. AGAIN, LOOK AT THE DATE. NOVEMBER, 1991. IN THAT FALL, THE FDA HAD AN APPLICATION FOR LICENSURE OF ALPHA INTERFERON FOR TREATMENT OF HEPATITIS C. IT'S BASED ON HISTOLOGICAL IMPROVEMENT AND ALT IMPROVEMENT AND A LOT OF THIS AND A LOT OF THAT. THEY ASKED ME TO SPEAK DURING THE MEETING, THE ADVISORY MEETING, AND I SHOWED THEM MICHIKO AND STEVE'S DATA, AND I THINK IT WON THE DAY. THE FACT THAT THE TREATMENT NOT ONLY IMPROVED ENZYMES BUT ALSO MADE THE VIRUS GO AWAY WAS CONVINCING EVIDENCE. AND INTERFERON WAS LICENSED IN 1991. SO, STEVE HAS BEEN A STALWART WITH ME, AND OF GREAT HELP. SO, THEN THE YEARS OF STUDY PROGRESSED, 1990 TO 2002, AND ALL OF THE AGENTS HAD BEEN -- EVENTUALLY WERE CHARACTERIZED, FULLY CHARACTERIZED, MANY OF THEM GROWN IN CELL CULTURE. DIAGNOSTIC ASSAYS WERE AVAILABLE FOR ALL OF THEM, DEVELOPED. WE HAD THERAPIES FOR SEVERAL FORMS OF HEPATITIS. THEY WERE BETTER IN SOME FORMS THAN OTHERS. AND RATES OF VIRAL HEPATITIS FELL TO HISTORIC LOWS. THIS IS REALLY VERY IMPORTANT. IN 1971 WHEN WE JOINED THIS FIELD, WE HAD NO TEST FOR THESE VIRUSES. THERE WAS NO WAY TO PREVENT THEM, NO WAY TO CONTROL THOSE DISEASES. NOW, THIS IS HEPATITIS A CASES THAT FELL FROM THE 15-16,000 RATE, NOW TO -- ACTUALLY, THIS YEAR IT WILL PROBABLY BE LESS THAN 1,000 REPORTED CASES IN THE UNITED STATES. IT'S -- BE LESS COMMON THAN EHRLICHIOSIS. WHY DID THIS HAPPEN? I THINK STEVE FEINSTONE WAS UP FRONT THERE IN HELPING THIS TO HAPPEN. HEPATITIS B ALSO DECREASED. I THINK THIS YEAR THERE WILL BE LESS THAN 2,000 REPORTED CASES. HISTORIC LOWS FOR THIS DISEASE. HEPATITIS C HAS FALLEN GREATLY. IT'S FALLEN BY 90 PERCENT FROM WHAT IT WAS IN THE '80S, BUT IT'S HANGING ON THERE BECAUSE OF THE FRUSTRATION OF NO VACCINE OR WAYS TO PREVENT IT IN HIGH-RISK POPULATIONS ALWAYS. SO, LET ME SAY SOMETHING ABOUT STEVE AND HIS CHARACTER. DEFINING TERMINOLOGY. FIRST OF ALL, THE RIGOR OF A SCIENCE. SECOND OF ALL, HIS QUESTIONING INTELLECT. AND THIRD OF ALL, HIS GENEROUS NATURE. I HAVE TO SAY SOMETHING VERY SPECIAL ABOUT THAT, BECAUSE IN THE EARLY 1990S I RAN INTO A BIG PROBLEM. THE LIVER SECTION LOST ITS SENIOR INVESTIGATORS. WE HAD THREE, AND WE FELL TO TWO, AND THEN WE FELL TO ONE, AND THEN WE FELL TO ZERO. THERE WAS NOBODY IN THE CLINICAL CENTER WHO WAS A HEPATOLOGIST TO TAKE CARE OF THE PATIENTS AND THE CONSULTS AND MANAGE THE LAB. I WAS AN ADMINISTRATOR. I WAS IN ANOTHER BUILDING, BUT I WAS CALLED UPON TO DO ALL THIS. AND I COULDN'T DO IT. I COULDN'T BE THERE IN THE LAB EVERY DAY WITH THE FELLOWS. AND I APPEALED TO STEVE AND HE MET WITH US REGULARLY AND HE ALSO TOOK A COUPLE OF THEM INTO HIS LABS, AND I'M VERY APPRECIATIVE. AND THOSE PEOPLE ARE APPRECIATIVE, TOO, STILL TODAY. ONE OF THEM WAS SKIP HAYASHI, WHO TOLD ME THAT HE'D NEVER MET ANYBODY QUITE SO RIGOROUS WITH STUDIES. HE'D HAD POSITIVE RESULTS, HE'D RUN IT [INAUDIBLE] AND STEPHEN SAYS, "THAT'S GREAT. REPEAT THEM." [LAUGHTER] YOU KNOW? STEVE WAS ALSO RIGOROUSLY HONEST IN HIS WORK. AND I THINK IF YOU LOOK AT STEVE'S PAPERS, EXCEPT FOR THAT SILLY THING WE WROTE TOGETHER, MOST OF THEM HAVE STOOD THE TEST OF TIME, THAT THEY WERE ACCURATE. HE'S ALSO SELF-EFFACING. I'M SURE HE'S VERY EMBARRASSED BY ALL THESE TALKS ABOUT HIM. HE'S A BIT MELANCHOLIC, TOO, I THINK. BUT IT'S NOT AN INFECTIOUS MELANCHOLY, IT'S JUST KIND OF HIS OWN THING. IT'S NOT A PROBLEM. HERE'S STEVE. THIS IS IN 1983. SEE, I DON'T KNOW THAT THERE'S A SMILE THERE. THE MUSTACHE KIND OF HOLDS IT THERE. [LAUGHTER] THIS IS MIMI. THEY'RE IN THE BACK -- OUR BACK PORCH. I THINK THIS IS A GOING AWAY PARTY FOR DAN SCHAFER. SOMETIMES STEVE SMILED. IN FACT, HE TOLD ME THERE WAS TWO HAPPY DAYS IN HIS LIFE. ONE DAY, WHEN HE DISCOVERED THE HEPATITIS A VIRUS. AND THE SECOND DAY, WHEN HIS SON, NOAH, WAS BORN. HERE'S STEVE WITH NOAH. LITTLE KID. STEVE'S CARRYING HIM. 1980. [LAUGHS] HE'S GOT A SMILE -- LOOK -- ACTUALLY. [LAUGHTER] AND WHAT HAPPENED? 20 YEARS LATER, HERE'S NOAH, BUT STEVE'S NO LONGER CARRYING HIM UNDER HIS ARMS. [LAUGHTER] A BIT BIGGER, NOW. I BELIEVE NOAH IS HERE TODAY, TOO. SO WE CAN HAVE A FOLLOW UP ANOTHER 10 YEARS LATER. AND HE'S STILL SMILING, HOW ABOUT THAT? HERE'S STEVE WITH MARIAN MAJOR, HIS MAJOR COLLABORATOR AND TERRIFIC SCIENTIST THAT HE'S WORKED WITH FOR THE LAST 10 OR SO YEARS. THIS IS AT A HEPATITIS C MEETING IN SAN DIEGO, I THINK. AND HERE IS ANOTHER GROUP OF PEOPLE. THIS IS WHEN FRANK CHISARI GAVE A TALK. AND I SHOW FRANK BECAUSE HE WAS ACTUALLY A FELLOW AT THE SAME TIME WE WERE THERE. HE STARTED TWO YEARS BEFORE ME, A YEAR BEFORE STEVE, AND HE WAS IN THE LAB THAT I WAS IN. AND HE WENT OUT AND BECAME A FAMOUS IMMUNOLOGIST IN SAN DIEGO -- CAME TO GIVE A TALK. AND HERE'S BOB AND JENS BUKH FROM BOB'S LAB. HERE IS JAKE LIANG, WHO I EVENTUALLY HIRED, AND HE SOLVED ALL MY PROBLEMS AS FAR AS NOT HAVING SUPERVISION IN THE LIVER UNIT. IT'S GOT A BIG GROUP, NOW. IT COULDN'T FIT IN THAT LITTLE PICTURE THAT I SHOWED YOU. THIS IS BARBARA REHERMANN WHO WORKS WITH JAKE IN THE LIVER DISEASES SECTION -- STEVE, AND OVER HERE ARE ME AND LEONARD SEEFF. WE ARE IN THE LIVER DISEASE RESEARCH BRANCH, WHICH IS AN EXTRAMURAL BRANCH OF -- AND HERE ARE SOME FACES AND OTHER PEOPLE IN THE HEPATITIS FIELD. AND ONE OF THE EXCITING AND WONDERFUL THINGS ABOUT THIS FIELD WAS THE WONDERFUL PEOPLE THAT YOU GOT TO WORK WITH AND KNOW. THE INCOMPARABLE -- I DON'T KNOW IF ANYBODY CAN RECOGNIZE THESE PEOPLE. I HOPE BOB CAN. THE INCOMPARABLE WOLF SZMUNESS, WHO WAS INSTRUMENTAL IN GETTING A HEPATITIS B VIRUS LICENSED. TERRIFIC SCIENTIST AND EPIDEMIOLOGIST. THIS IS SAUL KRUGMAN, WHO REALLY STARTED THIS FIELD OF VIRAL HEPATITIS AND CAME ALONG WITH IT IN THE FIRST COUPLE YEARS, DEVELOPED AN EXPERIMENTAL HEPATITIS B VACCINE QUITE EARLY. THAT'S HIS WIFE, SYLVIA. AND THIS IS THE -- OF COURSE, BOB PURCELL SURROUNDED BY THE DELTA CONNECTION, TERRIFIC GROUP OF YOUNG SCIENTISTS WHO CAME FROM TURIN IN ITALY. BEHIND HIM THERE IS MARIO RIZZETTO. THIS IS FERRUCCIO BONINO, ANTONINA SMEDILE, AND PATRIZIA FARCI, WHO IS HERE TODAY AND ACTUALLY IS NOW AN INVESTIGATOR IN BOB'S LAB, AS WELL. SO, SHE'S STUCK WITH US. HERE IS A PICTURE. I THINK ALL OF YOU CAN RECOGNIZE THESE TWO GUYS. MICHAEL HOUGHTON AND HARVEY ALTER, TWO IMPORTANT FIGURES IN HEPATITIS C RESEARCH WHO RECEIVED THE LASKER AWARD FOR THEIR CONTRIBUTION. WELL-DESERVED. I DON'T KNOW THAT ANYBODY CAN RECOGNIZE THIS GUY EXCEPT SOME OF YOU IN THE FRONT ROW. THIS IS LACY OVERBY, WHO REALLY WAS A HERO IN HEPATITIS. HE'S THE ONE WHO DEVELOPED THE COMMERCIAL RADIOIMMUNOASSAY FOR HEPATITIS B THAT WAS USED FOR DECADES. DEVELOPED ASSAYS FOR ANTIBODY TO HEPATITIS B, RADIOIMMUNOASSAY, COMMERCIAL TEST FOR ANTI-CORE, AND FOR ANTI-E, AND E. HE'S QUITE A MAGICIAN. HE RETIRED FROM ABBOTT, THEN WENT TO WORK FOR CHRION, AND HE WAS KIND OF THE PUSH BEHIND THEIR EFFORTS IN HEPATITIS C, AN IMPORTANT PERSON BEHIND THE SCENES -- WITH OSCAR FAY, FROM AUSTRALIA. THEN THESE ARE PEOPLE FROM MY GROUP. THIS IS MICHIKO SHINDO, WHO WENT FROM OUR LAB, WHICH -- SHE WAS VERY SUCCESSFUL, WROTE A DOZEN OR MORE PAPERS AND BECAME A PROFESSOR AT KOBE UNIVERSITY. THIS IS ADRIAN DI BISCEGLIE WHO WAS IN THE AUDIENCE, AS WELL, AND WORKED WITH STEVE FOR MANY YEARS AND RAN THE HEPATITIS INTRAMURAL SECTION OF NIDDK FOR MANY YEARS. AND THIS IS -- THESE ARE MY TWO FELLOWS THAT STEVE TOOK INTO THE LAB WITH HIM FOR SEVERAL YEARS, DARYL LAU AND SKIP HAYASHI, WHO SEND THEIR REGARDS TO YOU. SKIP TELLS ME HIS FAVORITE STEVE FEINSTONE-ISM WAS THAT WHEN YOU HAVE A POSITIVE RESULT, LOOK AT THE NEGATIVE CONTROLS, AND WHEN YOU HAVE A NEGATIVE RESULT, LOOK AT THE POSITIVE CONTROLS. AND THAT'S VERY VALUABLE INFORMATION EVEN FOR CLINICAL RESEARCH. VERY VALUABLE. SO, STEVE, "BLISS WAS IT IN THAT DAWN TO ALIVE, BUT TO BE YOUNG WAS VERY HEAVEN." THANK YOU VERY MUCH. [APPLAUSE] MARIAN MAJOR: WELL, THANKS, JAY. WONDERFUL. DO YOU HAVE ANY OTHER QUESTIONS? NO? JAY HOOFNAGLE: WHEN DID HE CUT HIS BEARD? GERARDO KAPLAN: I HAVE A QUESTION FOR YOU. SO, FROM ALL THESE YEARS OF FRIENDSHIP, WHAT ABOUT COINFECTIONS? DID YOU TRY HEPATITIS A AND HEPATITIS C, OR HEPATITIS C AND HEPATITIS B? JAY HOOFNAGLE: COINFECTIONS? GERARDIO KAPLAN: COINFECTIONS. JAY HOOFNAGLE: YOU MEAN, WITH US COINFECTED? [LAUGHTER] GERARDO KAPLAN: NO, NO, NO. IN PATIENTS OR ANIMALS. SO WHAT HAPPENED WITH COINFECTIONS OF HEPATITIS A AND B, FOR INSTANCE? JAY HOOFNAGLE: WELL, YOU KNOW, WHEN YOU HAVE INFECTION WITH ONE HEPATITIS VIRUS IT USUALLY SUPPRESSES THE OTHER. THIS IS ONE OF THE SECRETS TO DELTA HEPATITIS. WHEN YOU GET DELTA ON TOP OF B, IT GENERALLY SUPPRESSES THE B SO THE LEVEL OF HBV DNA ARE VERY LOW. SIMILARLY, IF YOU HAVE CHRONIC HEPATITIS B AND YOU GET ACUTE HEPATITIS A ON TOP OF IT, THE HEPATITIS B VIRUS LEVELS GO DOWN. SO THEY USUALLY PUSH EACH OTHER OUT. IT'S ACTUALLY AN -- OUTSIDE OF IMMUNOSUPPRESSED PATIENTS, IT'S NOT VERY COMMON TO SEE COINFECTION WITH C AND B WHERE BOTH VIRUSES ARE ACTIVE. USUALLY THEY'LL HAVE HEPATITIS B IN DNA, BUT THEY'LL HAVE ANTIBODY TO HEPATITIS C BUT NO VIRUS, OR VICE VERSA. SO THEY SOMEHOW COMPETE FOR THE ACTION. MARIAN MAJOR: OKAY. THANK YOU. OKAY, SO OUR NEXT SPEAKER IS JOHN GERIN, WHO'S PROFESSOR -- [INAUDIBLE] PROFESSOR AND IMMUNOLOGY AT GEORGETOWN UNIVERSITY. AND HE'S GOING TO TALK ABOUT THE CONTRIBUTION OF THE ROCKVILLE LAB TO NIAID'S VIRAL HEPATITIS PROGRAM. JOHN GERIN: THANK YOU, [INAUDIBLE]. YOU KNOW, IT SEEMS IMPOSSIBLE BUT IT'S ALMOST 45 YEARS SINCE I WALKED ONTO THIS CAMPUS AND UP TO BUILDING 7. AND BOB CHANOCK WELCOMED ME AND SHOWED ME MY LABORATORY. HE WAS GOING TO BE MY HOST FOR A COUPLE OF YEARS. AND IT HAPPENED TO BE A BROOM CLOSET ON THE THIRD FLOOR. [LAUGHTER] BUT IT HAD THE ADVANTAGE THAT IT WAS AROUND THE CORNER FROM BOB PURCELL'S LOB WHERE BOB AND DORIS WERE WORKING ON MYCOPLASMA PROJECTS. AND THAT INTERACTION CERTAINLY HELPED WHEN AUSTRALIA ANTIGEN HIT THE NEWS AND BOB DECIDED TO GET INTO THAT BUSINESS, AND I WAS THERE TO ASSIST HIM. I ACTUALLY CAME TO THE NIH TO ESTABLISH A LABORATORY, A RATHER AMBITIOUS PROJECT UNDER AN INTERAGENCY AGREEMENT BETWEEN THE ATOMIC ENERGY COMMISSION AND THE NATIONAL INSTITUTE OF HEALTH TO BRING CERTAIN TECHNOLOGICAL DEVELOPMENTS AT OAK RIDGE MOLECULAR ANATOMY PROGRAM TO THE PROGRAMS -- TO THE INTEREST -- THE PROGRAMS OF INTEREST WITH THE NIAID, WHICH WERE MANY. IT WAS AMBITIOUS. I LATER FOUND OUT THAT I WAS THE THIRD PERSON TO BE OFFERED THE JOB. THE OTHER TWO BEING SMARTER THAN I WAS, OR LESS NÁVE THAN I WAS TO THINK THAT YOU COULD PULL SOMETHING LIKE THIS OFF. BUT IN FACT WE DID IT. TOOK A COUPLE OF YEARS. TOOK THREE YEARS, ACTUALLY, TO BUILD THIS LABORATORY. BUT WE DID, IN ROCKVILLE, AND WE CALLED IT -- AND WE OPERATED THEN THAT PROGRAM FROM ABOUT 1969 THROUGH '78 AS PART OF THE OAK RIDGE NATIONAL LABORATORY JOINT PROGRAM WITH NIH. IT MAY BE A COINCIDENCE, BUT ABOUT THE TIME I WENT DOWN TO OAK RIDGE AND INFORMED THE COMPANY THAT RAN OAK RIDGE NATIONAL LABORATORY, UNION CARBIDE CORPORATION NUCLEAR DIVISION -- I INFORMED THAT WE WERE GOING INTO HUMAN CLINICAL TRIALS WITH AN NIH VACCINE THAT I HAD MADE AND WERE STARTING THOSE STUDIES AT A TRAPPIST MONASTERY NEAR ATLANTA -- SUDDENLY, WITHIN A MONTH OR TWO, WE RECEIVED NOTICE THE ENTIRE LABORATORY WAS DISMISSED AND FIRED ON THE SPOT. TOO MUCH LIABILITY, I THINK. COULDN'T ACCEPT -- NOT WORRYING ABOUT NUCLEAR ENERGY, BUT WORRYING ABOUT THE LIABILITIES OF HUMAN EXPERIMENTATION. SO -- BUT OTHERS TELL ME THAT THEY JUST DECIDED TO GET OUT OF THAT BIOLOGICAL AREA. SO, IN ANY CASE, AT THAT TIME WITH THE SUPPORT OF THE NIH WE SHIFTED THE LABORATORY'S AFFILIATION TO GEORGETOWN UNIVERSITY MEDICAL CENTER, RENAMED THE LAB THE DIVISION OF MOLECULAR VIROLOGY AND IMMUNOLOGY, AND IT OPERATED THERE UNTIL IT CLOSED ABOUT THE TIME I RETIRED. IN THE EARLY YEARS, WE HAD DIVERSE PROJECTS. I JUST WANT TO MENTION THIS. WE WORKED ON INFLUENZA WITH RUDY CASTLE, BOB COUCH, AND ED KILBURN; PARAINFLUENZA WITH BRIAN MURPHY AND BOB CHANOCK; RESPIRATORY SYNCYTIAL WITH BOB CHANOCK, NONBACTERIAL GASTROENTERITIS, NORWALK, AND ROTAVIRUS WITH AL KAPIKIAN, TOM THORNHILL; WORKED ON PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY WITH DAVE HOGAN AND JOHN SEBER; SCRAPIE WITH PAUL BROWN, JOE GIBBS, AND GAJDUSEK; MOUSE HEPATITIS VIRUS WITH LARRY STURMAN AND KEN TAKEMOTO; HIV AIDS WITH WAYNE CLOUGH AND CLIFF LANE; AND VARIOUS CELL BIOLOGY PROGRAMS WITH JOHN GALLEN, MIKE CALENDAR, AND MIKE FRANK. THAT'S A LOT OF DIFFERENT PROJECTS, BUT I TOOK SERIOUSLY THE CONCEPT THAT WE SHOULD BE WORKING BROADLY ACROSS THE INSTITUTE. AS YOU SEE, WE ACTUALLY WORKED ACROSS INSTITUTES. AS I SAY, I WAS POLITICALLY NÁVE IN THOSE DAYS AND IT WASN'T ALWAYS THE RIGHT THING TO DO. BUT THE MAJOR PROJECTS CLEARLY FOCUSED ON VIRAL HEPATITIS. WE WORKED WITH HAV WITH STEVE AND BOB, A LITTLE BIT WITH HCV AND HEV WITH BOB PURCELL. BUT MAINLY WE WORKED -- OUR MAIN FOCUS WAS ON HEPATITIS B VIRUS, HEPATITIS DELTA VIRUS, AND WITH THE -- SUBSEQUENT WITH THE WOODCHUCK HEPATITIS VIRUS, A MODEL OF HEPATITIS B VIRUS INFECTION [INAUDIBLE] WITH BUD TENNANT MAINLY AT CORNELL UNIVERSITY. IN HEPATITIS B VIRUS, WE DID BASIC STUDIES ON THE MOLECULAR BIOLOGY OF THE VIRUS, ESTABLISHED A SIZE-INTENSITY STRUCTURE POLYPEPTIDES OF THE DNA GENOME AND THE DIGEST DNA POLYMERASE. WE SPENT A LOT OF TIME DEVELOPING REAGENTS AND ASSAYS. WE MADE HYPERIMMUNE ANIMAL ANTISERA, WHICH BECAME WHO INTERNATIONAL STANDARDS REFERENCE ANTISERA AND THE BUREAU OF BIOLOGICS REFERENCE ANTISERA. WE MADE -- WORKED ON SECOND- AND THIRD-GENERATION ASSAYS FOR SURFACE ANTIGEN AND ANTI-SURFACE ASSAYS FOR ANTI-HPC, AND THE FIRST TO ESTABLISH MURINE MONOCLONAL ANTIBODIES. JIM SHIH DID THAT IN OUR LABORATORY BEFORE HE JOINED HARVEY ALTER AT THE BLOOD BANK. WE ALSO WORKED WITH BOB PURCELL ON STUDYING THE NATURAL HISTORY OF HEPATITIS B VIRUS INFECTION IN CHIMPANZEES. DID A LOT OF EMPHASIS ON PREVENTION. WE WORKED WITH HARVEY AND LEONARD SEEFF ON THE EFFICACY OF HBIG AND HBV TRANSMISSION AFTER NEEDLESTICK EXPOSURE, ESTABLISHED THE SAFETY AND EFFICACY OF AN HBSAG SUBUNIT VACCINE, IT'S A CHIMPANZEE MODEL, WITH BOB PURCELL. SUBSEQUENTLY WENT ON TO DEVELOP A -- TO SHOW THE SAFETY AND EFFICACY OF THIS VACCINE IN HUMAN TRIALS, INCLUDING -- CULMINATING IN, ACTUALLY, A STUDY IN NEWBORNS OF HPV-POSITIVE MOTHERS IN SHANGHAI. THE AUTHOR OF THAT STUDY ACTUALLY, AT THE INTERNATIONAL MEETING IN ROME, CAME UP TO ME LATE ONE EVENING AND JUST THANKED US FOR THAT CONTRIBUTION. HE SAID THE RESULTS OF THAT STUDY WAS HIGHLY EFFICACIOUS IN THIS STUDY, CONVINCED THE CHINESE GOVERNMENT THAT THEY SHOULD MOUNT A NATIONAL PROGRAM OF IMMUNIZATION, AND HE WAS VERY THANKFUL TO US FOR OUR CONTRIBUTIONS TO THAT. WE SHOWED THE -- WE ESTABLISHED THE EFFICACY OF RECOMBINANT DNA VACCINES AND SYNTHETIC PEPTIDES IN THE CHIMPANZEE MODEL. I WORKED WITH BOB AND RICH LERNER AND OTHERS. WE ALSO WORKED SOMEWHAT ON THERAPY. WE WORKED WITH ESTABLISHING INTERFERON, INTERFERON INDUCERS, WITH BOB, TOM MERIGAN, BILL ROBINSON, HILDEN LEVY. WE ESTABLISHED IN VITRO AND IN VIVO MODELS, PRECLINICAL EVALUATION OF POTENTIAL THERAPIES. AND HEPATITIS DELTA VIRUS WAS ONE OF THE MAIN THRUSTS OF THE LABORATORY. AGAIN, WE WORKED ON THE MOLECULAR VIROLOGY OF THIS UNIQUE AGENT, ESTABLISHING THE SIZE, DENSITY, STRUCTURAL PROTEINS, THE RNA GENOME AND GENOTYPES, AND EFFECT ON PATHOGENICITY. TRANSMISSION OF THIS DELTA AGENT INTO CHIMPANZEE, MAKING -- WORKING WITH BOB AND OF COURSE THE MAIN ACTOR, MARIO RIZZETTO. DEVELOPED ASSAYS AND REAGENTS FOR HEPATITIS DELTA ANTIGEN. TESTS FOR ANTI HEPATITIS DELTA, IGM ANTI DELTA, HYBRIDIZATION BASED ASSAYS FOR HDV RNA IN CLINICAL SAMPLES AND WORKED WITH JAY AND HIS COLLEAGUES ON INTERFERON THERAPY FOR DELTA HEPATITIS. LASTLY, MAJOR PROGRAM -- THE LAST MAJOR PROGRAM WAS THIS LITTLE ANIMAL. IT'S A WOODCHUCK. IT'S NATURALLY INFECTED WITH THE VIRUS CALLED WOODCHUCK HEPATITIS VIRUS, WHICH SHARES MANY FEATURES WITH ITS MORE WELL-KNOWN RELATIVE, THE PATENTED VIRUS WAS HEPATITIS B VIRUS. IT'S ACTUALLY SHARE A SEQUENCE HOMOLOGY AND ANTIGENS WITH HEPATITIS B VIRUS. IT WAS SHOWN BY JESSE SOMMERS AND THE PEOPLE AT FOX CHASE TO BE -- TO INFECT THIS ANIMAL IN NATURE AND TO BE RELATED TO CANCER. SORRY. WORKING WITH BOB TENNANT AT CORNELL UNIVERSITY, AND OF COURSE WITH BOB, AND FRANK TYERYAR, AND THE EXTRAMURAL PROGRAM, WE ESTABLISHED CHRONICITY AS AN OUTCOME OF EXPERIMENTAL INFECTION TO BE THAT SIMILAR TO WHAT OCCURS IN HUMANS. AND THAT IS, IF YOU GIVE A HIGH DOSE OF A PARTICULAR STRAIN OF VIRUS EARLY -- ONE DAY, THREE DAYS, SEVEN DAYS OF INFECTION -- YOU GET A HIGH RATE OF CHRONICITY. AND THAT FALLS OFF WITH AGE OF THE ANIMAL, WHICH -- MUCH AS WHAT YOU SEE IN MAN. THIS WAS HIGHLY PREDICTABLE AND REPRODUCIBLE YEAR AFTER YEAR. I COULD SHOW YOU 10 YEARS OF WORK INFECTING NEWBORN ANIMALS WITH WOODCHUCK HEPATITIS VIRUS. 72 PERCENT DEVELOPED CHRONIC INFECTION WITH A 100 PERCENT RISK OF CANCER, OF LIVER CANCER, HEPATOCELLULAR CARCINOMA AS AN END-STAGE DISEASE. AGAIN, THIS IS 0 PERCENT OF UNINFECTED ANIMALS. THIS IS A LITTLE BUSY. I'M SORRY FOR THAT SLIDE. BUT IF WE LOOK AT THE OUTCOME OF EXPERIMENTAL INFECTION IN THE ADULT ANIMALS, THEY GO THROUGH AN ACUTE COURSE. BUT GENERALLY ONLY 5 PERCENT OF THE ANIMALS OR SO WILL DEVELOP CHRONIC INFECTION. BUT THOSE THAT DO DEVELOP, THEY HAVE A 100 PERCENT RISK OF LIVER CANCER. 95 PERCENT OF THESE ANIMALS RECOVER, BUT STILL THERE'S A RESIDUAL RISK TO LIVER CANCER. AND I'VE ALWAYS PRESSED PALMER BEASLEY [SPELLED PHONETICALLY] ABOUT WHETHER HIS DATA IN TAIWAN WOULD EVER INDICATE THAT THIS HAD THIS RESIDUAL RISK TO HEPATOCELLULAR CARCINOMA FROM RECOVERY, WHICH HE NEVER COULD QUITE AGREE WITH. BUT WE HAD LONG DISCUSSIONS ABOUT IT. IN THE NEWBORN, HOWEVER, THERE'S A SLIGHTLY LONGER INCUBATION PERIOD. BUT IF YOU -- BUT IN THAT CASE, 75 PERCENT, 72 PERCENT AS I'VE SHOWED YOU, DEVELOP CHRONIC INFECTIONS WITH 100 PERCENT CANCER RISK, VERSUS A 25 -- A ROUGHLY 25 RECOVERY, AGAIN WITH THAT RESIDUAL 15 TO 20 PERCENT RISK OF CANCER. IF WE -- THIS SLIDE IS SUPPOSED TO SHOW -- IT DOES SHOW -- DOESN'T SHOW -- DIDN'T SHOW UP. IF WE IMMUNIZE ANIMALS AS NEWBORNS AND AT ONE MONTH WITH A VACCINE COMPARABLE TO THE NIH HEPATITIS B VIRUS VACCINE, THAT IS: PURIFIED SUBUNITS FROM SERUM OF INFECTED WOODCHUCKS HOMOLOGOUS TO THE CHALLENGE VIRUS. WE IMMUNIZE THOSE ANIMALS. IT CONVERTED THE NEWBORN PATTERN TO THAT OF THE ADULT. THAT IS, THAT THE -- THAT IF YOU -- THOSE -- I'M SORRY, THOSE PATTERNS DIDN'T SHOW UP. JUST CAME UP IN A DIFFERENT SLIDE. BUT IT SHIFTED THE PATTERN FROM THE 75 PERCENT CARRIER RATE TO A 25 PERCENT CARRIER RATE. SO THE VACCINE WAS HIGHLY EFFECTIVE IN PREVENTING CHRONICITY AS AN OUTCOME OF INFECTION, AND OF COURSE WITH A CONSEQUENT LOWER RISK TO HEPATOCELLULAR CARCINOMA, VERIFYING -- WE THINK PREDICTING WHAT WE'RE PROBABLY SEEING IN MAN, THAT NEWBORN IMMUNIZATION WILL BE EFFECTIVE AGAINST END-STAGE CANCERS AND END-STAGE LIVER DISEASE. LIKEWISE, WE'VE WORKED ON THERAPY FOR VIRAL HEPATITIS. WITH THE HEPATITIS B VIRUS, THIS IS JUST A SHOWING OF AN OUTCOME DATED WITH -- THERAPY WITH LAMIVUDINE 3TC. THAT IT -- THIS KAPLAN-MEIER PLOT SHOWS IT DELAYS THE ONSET OF CELLULAR CARCINOMA IN CHRONIC CARRYING WOODCHUCKS. HIGHLY SIGNIFICANT CANCER-FREE SURVIVAL. WE FOUND THAT THE WOODCHUCKS LIKED LIVER CANCER. IT WAS GOOD FOR THEIR LIVER. SO, WE LOOKED AT SOME ISSUES RELATED TO TREATMENT AND WE ASKED -- OF COURSE WE HAD ASKED THE QUESTION, COULD PROLONGED SUPPRESSION OF REPLICATION LEAD TO IMPROVEMENTS IN THE COURSE OF DISEASE? AND WE ANSWERED YES, FROM THE PREVIOUS DATA AND MANY, MANY OTHER COMPOUNDS THAT -- OF A SIMILAR NATURE. WE ASKED THE QUESTION, IS IT POSSIBLE -- IS IT NECESSARY TO HAVE LIFELONG TREATMENT OF ANTIVIRALS? BUT WAS IT POSSIBLE THAT WE COULD STIMULATE HUMORAL OR CELLULAR RESPONSES TO THIS VIRUS IN CHRONIC CARRIERS BY IMMUNOTHERAPY AND THEREFORE ELUCIDATE A CURE. WE DID SUCH A COMPLICATED STUDY BY TREATING FIRST WITH AN ANTIVIRAL AGENT, STRONG ANTIVIRAL AGENT, FOLLOWED BY A COURSE OF IMMUNIZATION. FOUR INOCULATIONS IN THE ANIMALS. WITH THE OUTCOME, PRETTY REMARKABLE THAT -- A MARKED IMPROVEMENT OF LONG-TERM SURVIVAL, OF CANCER-FREE SURVIVAL IN THE DOUBLE-TREATED GROUP COMPARED TO THE CONTROLS, IN GREEN, WITH THE MONO THERAPIES FALLING IN BETWEEN. SO OUR THOUGHT WAS THAT THE CONCEPT FOR TREATMENT OF HEPATITIS B VIRUS INFECTION WAS TO SUPPRESS THE VIRAL LOAD, FOLLOWED BY STIMULATION OF THE IMMUNE RESPONSE BY IMMUNOMODULATION BY ANY MEANS TO AFFORD A BETTER OUTCOME OF LOWERED CHRONICITY AND LOWERED CANCER RISK. SO OUR PREDICTIONS WERE THAT THE WORLD-WIDE STRATEGIES OF UNIVERSAL VACCINATION AGAINST HEPATITIS B WILL PREVENT HUMAN END-STAGE DISEASE, INCLUDING THE HEPATOCELLULAR CARCINOMA; THAT THE TREATMENT STRATEGIES WILL DECREASE THE VIRAL LOAD AND SIGNIFICANTLY DELAY OR PREVENT END-STAGE LIVER DISEASE, INCLUDING LIVER CANCER; AND THAT FOCUSED PUBLIC HEALTH PROGRAMS COULD LEAD TO TOTAL ERADICATION OF TYPE B WITHIN A FEW GENERATIONS. NOW TAKE A CUE FROM BOB PURCELL, WHO ALWAYS SAID, "IT'S TIME TO DECLARE VICTORY AND GET OUT." AND ABOUT THIS TIME, I RETIRED. THE LABORATORY WAS DISASSEMBLED, PARTS JOINED THE NIAID, PARTS THAT WENT DOWN TO THE UNIVERSITY CAMPUS WHERE IT STILL OPERATES. I'D LIKE TO MENTION THAT WE HAD A NUMBER OF RESEARCH FELLOWS IN THE LAB OVER THESE YEARS FROM MANY, MANY COUNTRIES. I'D PARTICULARLY LIKE TO POINT OUT ITALY BECAUSE OF THE HIGH -- BIG INFLUENCE THAT MARIO RIZZETTO HAD ON THE DELTA PROGRAM AND THE SUBSEQUENT FOLLOW-UP OF MANY PEOPLE FROM HIS LABORATORY, INCLUDING FERRUCCIO BONINO, ANTONINA SMEDILI, ANTONIO PONZETTO, FRANCESCO NEGRO [SPELLED PHONETICALLY], AND OF COURSE I SHOULD MENTION -- WELL, THOUGH PATRIZIA FARCI WASN'T PART OF OUR LABORATORY, SHE WAS PART OF THAT GROUP. SHOULD WOULD IDENTIFY WITH THAT GROUP, OF COURSE. THIS IS A PICTURE OF MARIO I TOOK A COUPLE YEARS AGO IN SARDINIA ON HOLIDAY. AND LASTLY, I WOULD LIKE TO REMEMBER PEOPLE THAT WERE INFLUENTIAL TO ME AND OUR CONDUCT OF OUR OPERATION. MOST RECENTLY, OF COURSE, THE DEATH OF PALMER BEASLEY. BOB BYRNE AND FRANK TYERYAR WERE PROJECT MANAGERS OF MINE. BOB CHANOCK, OF COURSE, WHO FIRST WELCOMED ME INTO THE NIH. AND OF COURSE WE'VE ALREADY HEARD ABOUT SAUL KRUGMAN, HANS POPPER, AND WOLF SZMUNESS. THEY WERE LEADERS AND HELPED US SO MUCH IN THE EARLY PHASES OF THE HEPATITIS B PROGRAM. SO I'D LIKE TO THINK YOU FOR ATTENTION AND, STEVE, BEST OF LUCK IN YOUR RETIREMENT. THANK YOU. [APPLAUSE] MARIAN MAJOR: DOES ANYONE HAVE ANY QUESTIONS FOR JOHN? NO? OKAY, SO NOW WE'RE GOING TO CHANGE ALPHABETS AND WE'RE GOING TO MOVE TO CHARLIE RICE. IT'S A REAL PLEASURE TO HAVE CHARLIE HERE TODAY. HE'S CURRENTLY A PROFESSOR AND A SCIENTIFIC AND EXECUTIVE DIRECTOR AT THE CENTER FOR THE STUDY OF HEPATITIS C AT ROCKEFELLER UNIVERSITY, AND HE'S GOING TO TALK TO US, AND THE TITLE OF HIS TALK IS "YELLOW FEVER MEETS HEPATITIS C: HOW A PHONE CALL FROM STEVE CHANGED MY LIFE." I THINK MANY OF US COULD TALK ABOUT THAT. CHARLES RICE: ALL RIGHT, LET'S SEE IF WE CAN FIND THE TALK. YEAH, THAT'S IT. WELL, IT'S A GREAT PLEASURE TO BE HERE TO HONOR STEVE, AND I GUESS I'LL BE SORT OF PICKING UP THE STORY A LITTLE BIT, YOU KNOW, LATER IN STEVE'S CAREER. AND JUST TO SORT OF BACK TRACK AND TELL YOU A LITTLE BIT ABOUT SORT OF WHAT I WAS -- SO IT WAS 1989. I'D BEEN AN ASSISTANT PROFESSOR AT WASHINGTON UNIVERSITY THEN FOR ABOUT THREE YEARS. AND WE WERE WORKING ON A FAMILY OF VIRUSES CALLED THE FLAVIVIRIDAE, WORKING ON THE PROTOTYPE VIRUS, THE 17D VACCINE STRAIN, WHICH, AS MANY OF YOU KNOW, IS ONE OF THE MOST SUCCESSFUL LIVE ATTENUATED HUMAN VACCINES THAT HAS EVER BEEN DERIVED. WE'D SEQUENCED THAT, DETERMINED THE GENOME STRUCTURE. WE'D ALSO SEQUENCED THE PARENTAL CB STRAIN, WHICH IS, YOU KNOW, VIRULENT IN MONKEYS, WHEREAS A 17D IS ATTENUATED, AND ESTABLISHED AN INFECTIOUS CLONE FOR 17D SO THAT WE COULD DO -- BEGIN TO DO REVERSE GENETICS ON THIS VIRUS, AND BEGAN TO STUDY, YOU KNOW, HOW THE POLYPROTEIN WAS PROCESSED AND THE PROTEASES THAT WERE INVOLVED, AND THIS PAPER THAT'S SHOWN HERE IS ACTUALLY AN EXAMPLE OF A STATE WHERE I WAS FAIRLY IRATE. WE HAD SENT THIS PAPER TO SCIENCE ON SORT OF THE FIRST INFECTIOUS CLONE FOR A FLAVIVIRUS, AND THEY SORT OF LIKED IT, AND WE SENT IT BACK AFTER REVISION, AND THEN THEY SAID, "WELL, WE JUST DON'T THINK THIS HAS REALLY A, YOU KNOW, HIGH ENOUGH SORT OF PRIORITY TO WARRANT PUBLICATION." SO, AT THE TIME, THERE WAS THIS NEW JOURNAL THAT HAD BEEN CREATED CALLED THE NEW BIOLOGIST, AND, YOU KNOW, THEY HAD SORT OF SAID, "WELL, YOU KNOW, WE'RE INTERESTED IN THIS PAPER. WHY DON'T YOU SEND IT TO US?" SO WE SENT IT TO THE NEW BIOLOGIST, AND THE PAPER GOT PUBLISHED THERE. ACTUALLY, STEVE SAW THIS PAPER, AND, OF COURSE, THIS JOURNAL WENT EXTINCT IN ABOUT A YEAR. AND IT'S KIND OF INTERESTING BECAUSE I THINK ONE OF THE FEW PAPERS THAT WE STILL GET LOTS OF REPRINT REQUESTS FOR, BECAUSE NOBODY CAN REALLY FIND IT. SO ALSO THAT YEAR IN 1989, AS WE'VE HEARD ALREADY, MIKE HOUGHTON AND HIS GROUP REPORTED THE FIRST SEQUENCES OF NON-A, NON-B HEPATITIS, WHICH THEY CALLED HEPATITIS C VIRUS, AND IT TURNED OUT THAT THIS WAS, YOU KNOW, A VIRUS THAT WAS CLOSELY RELATED TO MEMBERS OF THE CLASSICAL FLAVIVIRUSES, ALTHOUGH SOMEWHAT DIFFERENT. AND, YOU KNOW, I WAS BUSILY SORT OF WORKING AWAY IN THE LAB ONE DAY. I THINK IT WAS ACTUALLY IN MY OFFICE, WHICH WAS REALLY JUST A CONVERTED BATHROOM WITH NO WINDOWS AT WASHINGTON UNIVERSITY AT THE TIME. AND I GET THIS CALL FROM SOMEBODY THAT I HAD NEVER MET, STEVEN FEINSTONE, WHO WAS THEN, I THINK, AT THE FDA, AND STEVE HAD SEEN OUR PAPER ON 17D, AND BEING A LID SORT OF VACCINE TRAINEE, HE SAID, "WELL, YOU KNOW, WE CAN JUST GO AHEAD, AND, YOU KNOW, MAKE A CHIMERIC VIRUS WITH, YOU KNOW, HCV ANTIGENS AND 17D, AND, VOILA, YOU KNOW, WE'LL HAVE SOMETHING THAT IS GOING TO WORK AS A VACCINE. AND I WON'T SAY THAT IT WAS -- YOU KNOW, I WAS UNAWARE OF NON-A, NON-B HEPATITIS AND HCV, BUT THIS WAS OBVIOUSLY SUCH AN IMPORTANT BUT VERY CHALLENGING TOPIC FROM SORT OF A MOLECULAR VIROLOGY STANDPOINT THAT WE WEREN'T WORKING ON IT. BUT IT WAS REALLY THIS PHONE CALL FROM STEVE, WHICH I REMEMBER; HE DIDN'T EVEN CALL ON MY OFFICE PHONE, HE CALLED ON THE LAB PHONE, AND I WAS SORT OF OUT THERE IN THE OFFICE. CAME BACK, AND WE REALLY -- THAT WAS SORT OF THE BEGINNING OF OUR INTEREST IN HEPATITIS C. NOW, AT THE TIME, THERE WAS A TECHNICIAN IN THE LAB WHO MANY OF YOU MAY KNOW, ARASH GRAKOUI. AND ARASH HAD HAD SORT OF THE DIFFICULT SORT OF SITUATION WITH ANOTHER VIRUS THAT WE WORKED ON, THE ALPHA VIRUS, THE SINDBIS VIRUS, WHERE THERE WAS KIND OF AN AGGRESSIVE POST-DOC NEXT DOOR THAT WAS REALLY KEEN ON TAKING OVER THE PROJECT THAT ARASH HAD SET UP. AND WE WERE SORT OF AT A TRANSITION POINT IN DECIDING, YOU KNOW, SHOULD WE, YOU KNOW, SORT OF GO TO BAT AND TRY AND CONTINUE THIS PROJECT, OR DO SOMETHING DIFFERENT, RISKY, LIKE START WORKING ON HEPATITIS C. AND ARASH SAID, "AH, WELL, LET'S JUST GO FOR IT," AND THAT WAS REALLY THE BEGINNING OF THIS. BUT IN TERMS OF THINKING ABOUT MAKING CHIMERIC VIRUS, WE WERE JUST CONFRONTED WITH A NUCLEOTIDE SEQUENCE AND A PREDICTED ENCODED POLYPROTEIN, AND WE REALLY DIDN'T EVEN KNOW WHERE THE HCV PROTEINS STARTED AND STOPPED, AND SO THAT WAS REALLY THE BEGINNING OF OUR WORK ON THIS, YOU KNOW, MAKING ANTIBODIES TO DIFFERENT REGIONS OF THE POLYPROTEIN SO THAT WE COULD IDENTIFY THE CLEAVAGE PRODUCTS, AND MAKING EXPRESSION CONSTRUCTS. WE KEPT GETTING THESE TUBES, THE PCR-AMPLIFIED DNA FROM CZESLAW WYCHOWSKI AND STEVE IN THE MAIL, TO SORT OF MAKE THESE FUSION PROTEINS THAT WE USED TO IMMUNIZE RABBITS AS WELL AS EXPRESSION CONSTRUCTS, AND REALLY TRY AND SORT OF FIGURE OUT WHAT THE PROCESSING SCHEME OF THIS VIRUS WAS. SO THIS WAS REALLY THE BEGINNING OF, YOU KNOW, FOR ME, AND MY LAB, AND MANY OF OUR TRAINEES, AN AMAZING SORT OF ERA. THE FIRST PAPER THAT WE PUBLISHED WITH STEVE, ACTUALLY A SERIES OF THREE PAPERS IN 1993, SORT OF MAPPING OUT THE HCV CLEAVAGE PRODUCTS, WITH ARASH AS THE FIRST AUTHOR, LOOKING AT THE CLEAVAGE SITES AND DEFINING, YOU KNOW, WHAT THE SERINE PROTEASE WAS RESPONSIBLE FOR CLEAVING, AND THEN THIS SORT OF UNEXPECTED DISCOVERY THAT HEPATITIS C ACTUALLY ENCODED AT A SECOND PROTEASE, WHICH WAS -- IS DIFFERENT FROM THE CLASSICAL FLAVIVIRUSES LIKE YELLOW FEVER. NOW, THERE'S SORT OF A LONG GAP BETWEEN THAT AND A COUPLE OF PAPERS THAT WE PUBLISHED IN 1995 AND '7, THAT HAD TO DO WITH WHAT BOB PURCELL MENTIONED: MAKING AN INFECTIOUS CLONE FOR HEPATITIS C. AND THIS WAS ACTUALLY A VERY SORT OF FRUSTRATING TIME IN OUR HCV RESEARCH BECAUSE WE WERE ACTUALLY TRYING TO MAKE CDNA CLONES, AND WE TESTED A LOT OF THESE THINGS THAT WE THOUGHT WERE FULL LENGTH BY DIRECT INTRAHEPATIC INJECTION INTO CHIMPANZEE LIVER, AND REALLY CAME UP EMPTY. AND THIS WAS ALL DONE AND MADE POSSIBLE BY OUR COLLABORATION WITH STEVE AND HIS GROUP. AND ALSO USING THE FAMOUS HUTCHINSON ISOLATE, IN THE LAB, ACTUALLY, THEN WAS ABLE TO DETERMINE THAT THERE WAS A CHUNK OF THE HCV THAT -- AT THE 3' END THAT CHRION HAD MISSED. AND THIS WAS THE MOST HIGHLY-CONSERVED RNA ELEMENT IN THAT GENOME, AND THEN WHEN WE MADE A CONSENSUS HCV CLONE WITH THAT SEQUENCE AND INJECTED THAT INTO THE LIVER OF TWO CHIMPANZEES, WE FINALLY WERE ABLE TO SORT OF INITIATE REPLICATION AND COME UP WITH A SYSTEM WHERE WE COULD BEGIN TO MANIPULATE THE GENOME, AND WE KNEW THAT WE HAD A FUNCTIONAL CLONE. AND THIS BEGAN A LONG SERIES OF EXPERIMENTS IN THE CHIMPANZEE MODEL. THIS ONE IS SHOWN HERE; AGAIN, YOU CAN SEE THE ENTRANCE OF MARIAN MAJOR HERE, LOOKING AT A LONG-TERM FOLLOW UP. AND THEN IN 2000, I HAD THE OPPORTUNITY TO MOVE TO ROCKEFELLER. I WASN'T REALLY LOOKING TO GO ANYWHERE, BUT WE CONTINUED OUR WORK WITH STEVE, AND SHOWED, USING THE CHIMPANZEE MODEL, THAT THE SORT OF -- THE ENZYMATIC FUNCTIONS IN THE VIRUS AND THESE CONSERVED ELEMENTS WERE INDEED REQUIRED FOR REPLICATION, SORT OF I THINK VALIDATING THEM AS ANTIVIRAL TARGETS FOR HCV DRUG DISCOVERY. AND STEVE'S LAB, ALSO LINKING UP WITH SOME WORK WITH BARBARA RHEREMANN, BEGAN TO LOOK AT T-CELL RESPONSES, VACCINE STRATEGIES, AND ANTIBODY RESPONSES IN THE CHIMPANZEE MODEL. WE ALSO, TOGETHER WITH JANE MCKEATING, BEGAN TO LOOK AT THE EVOLUTION OF NEUTRALIZING ANTIBODIES IN ESCAPE, USING SERIAL SAMPLES FROM PATIENT H, AND THEN WITH THE ADVENT OF THE JFH INFECTIOUS CLONE SYSTEM, WE WERE ALSO ABLE, AGAIN WITH STEVE'S HELP, TO REALLY DEMONSTRATE THAT THIS JFH, THIS JAPANESE FULMINATE HEPATITIS ISOLATE, WHICH WE COULD GROW IN CELL CULTURE, WAS INFECTIOUS IN CHIMPANZEES AND THAT YOU COULD TAKE SERUM FROM THOSE CHIMPANZEES WITH INFECTIOUS VIRUS AND SHOW THAT IT WAS STILL INFECTIOUS IN OUR FAVORITE CELL CULTURE SYSTEM: HUMAN HEPATOMA CELLS. SO, THE SORT OF NUMBER OF PAPERS AND I THINK ENABLING EXPERIMENTS THAT WE WERE ABLE TO DO WERE REALLY LARGELY DEPENDENT UPON STEVE'S PARTICIPATION AND HIS GENEROSITY. AND I WANT TO JUST HAVE SORT OF A BRIEF SORT OF SCIENCE INTERLUDE, BECAUSE I THINK THE SORT OF FIELD OF HEPATITIS VIRUS RESEARCH, AS YOU HEARD, IS MATURING AND IS CHANGING, AND AS I THINK AS YOU'VE HEARD ALREADY, THE CHIMPANZEE MODEL HAS BEEN EXTREMELY VALUABLE IN VIRTUALLY EVERY ASPECT OF HEPATITIS VIRUS RESEARCH. SOME OF THOSE ARE LISTED HERE ON THE LEFT IN TERMS OF, YOU KNOW, ISOLATION OF THESE VIRUSES AND CHARACTERIZATION OF THEM. I'VE HEARD BOB PURCELL GIVE A TALK THAT BASICALLY SORT OF SUMMARIZED, YOU KNOW, THE KIND OF UNDERSTANDING THAT WE HAVE ABOUT THIS VIRUS BASED ON SORT OF THE VERY EARLY CHIMPANZEE STUDIES, AND REALLY, THAT ENCOMPASSES A LOT OF WHAT WE KNOW ABOUT THE BASICS OF NON-A, NON-B HEPATITIS, HEPATITIS C, TODAY. THE DISADVANTAGES HAS ALWAYS BEEN THAT THESE ANIMALS ARE EXPENSIVE, THEY'RE ONLY -- YOU CAN ONLY USE THEM IN LIMITED NUMBERS, AND, YOU KNOW, WE ACTUALLY RAN INTO A PROBLEM IN SORT OF THE MID-2000S WHERE IT WAS JUST VERY DIFFICULT TO GET EXTRAMURAL GRANTS FUNDED TO CONTINUE TO DO CHIMPANZEE RESEARCH, AND OF COURSE, AS YOU KNOW, WITH THE INSTITUTE OF MEDICINE RECOMMENDATIONS AND BEING ADOPTED BY THE NIH, IT'S GOING TO BE VERY, VERY DIFFICULT TO DO ANY KIND OF EXPERIMENTS IN THE CHIMPANZEE MODEL LIKE THOSE THAT WERE CONDUCTED IN THE PAST. SO, A LITTLE BIT OF AN INTERLUDE. WE'VE BEEN SPENDING A LOT OF TIME TRYING TO SORT OF COME UP WITH PRIMARY HEPATOCYTE SYSTEMS TO MOVE AWAY FROM THIS HUH7 HEPATOMA CELL LINE THAT WE USED A LOT, AND ALSO TO DEVELOP SMALL ANIMAL MODELS, AND I JUST WANTED TO SHOW YOU A FEW SLIDES ON WHERE WE ARE ON THAT SORT OF ANIMAL MODEL SIDE OF THINGS. SO, IN TERMS OF THINKING ABOUT TRYING TO MAKE A MOUSE MODEL FOR HEPATITIS C, YOU KNOW, WHY DOESN'T HEPATITIS C, IN FACT, REPLICATE IN MICE? WELL, AS YOU CAN SEE FROM THIS SLIDE, AND THIS SUMMARIZES A LOT OF WORK THAT I WON'T GO INTO, WE KNEW THAT HEPATITIS C RNA COULD AMPLIFY IN SOME MOUSE CELL LINES. WE KNEW THAT VIRUS ASSEMBLY COULD OCCUR AND RELEASE COULD OCCUR, BUT ENTRY COULDN'T OCCUR, AND THIS LED TO BASICALLY A PROGRAM THAT WE STARTED SOME YEARS AGO TO REALLY TRY AND IDENTIFY THE ENTRY FACTORS THAT ARE INVOLVED IN HCV ENTRY, AND THIS IS A GROWING CAST OF CHARACTERS THAT GOES FROM GLUCOSAMINE AND GLYCANS IN THE LDL RECEPTOR TO E2 BINDING PROTEINS SCAVENGER RECEPTOR CD81 TO TWO PROTEINS THAT WE IDENTIFIED AT THE TIGHT JUNCTIONS OCCLUDIN 1 AND THEN CLAUDIN, AND THEN A NUMBER OF OTHER MOLECULES THAT HAVE BEEN IDENTIFIED IN RECENT YEARS, LIKE THE EPIDERMAL GROWTH FACTOR RECEPTOR, AMONG OTHERS. SO THE CURRENT MODEL FOR ENTRY IS SHOWN IN THIS CARTOON HERE, AT LEAST FOR A CELL-FREE VIRUS. WE'VE GOT THE VIRUS COMING IN AND GOING THROUGH THE SPACE OF DISC, FINDING A HEPATOCYTE, INTERACTING WITH THESE MOLECULES, PERHAPS TRIGGERING MOVEMENT TO THE TIGHT JUNCTION WHERE THE VIRUS GETS TAKEN UP. NOW, A NUMBER OF EXPERIMENTS HAVE SHOWN US THAT REALLY THERE ARE ONLY TWO OF THESE ENTRY FACTORS THAT NEED TO BE HUMAN IN ORDER FOR THE HCV GLYCOPROTEINS TO GET INTO MICE. CD81 AND OCCLUDIN. AND IF YOU TAKE A MOUSE AND YOU INTRODUCE THESE HUMAN ENTRY FACTORS WITH ADENOVIRUS, WHICH IS A VERY GOOD WAY OF EXPRESSING THEM IN THE LIVER, AND YOU HAVE A MOUSE THAT HAS A TRANSCRIPTIONAL STOP CASSETTE UPSTREAM FROM FIREFLY LUCIFERASE SO IT'S OFF, UNLESS YOU EXPRESS A CRE RECOMBINATION, WE MADE SOME HCV DERIVATIVES THAT EXPRESSED THAT ENZYME, YOU CAN ACTUALLY SHOW THAT THESE MICE ARE ACTUALLY NON-PERMISSIVE FOR ENTRY OF THIS RECOMBINANT VIRUS UNLESS YOU EXPRESS HUMAN CD81 AND OCCLUDIN AND -- OR YOU CAN EXPRESS ALL FOUR OF THESE HUMAN ENTRY FACTORS. IN THIS MODEL, ONE CAN USE TO LOOK AT THE ABILITY OF ANTIBODIES THAT FOR INSTANCE BLOCK THE RECEPTOR, LIKE ANTI-CD81 ANTIBODIES SHOWN HERE THAT WILL BLOCK HCV ENTRY, AND YOU CAN ALSO USE THIS IN A VACCINATION STRATEGIES TO TRY OUT SORT OF CANDIDATE VACCINES. AND THIS SHOWS YOU AN EXPERIMENT WHERE MICE ARE IMMUNIZED WITH A VACCINIA RECOMBINANT THAT EXPRESSES THE STRUCTURAL REGION OF GENOTYPE 1A HCV. YOU COME IN WITH THE ENTRY FACTORS AND THEN CHALLENGE THEM WITH HCV, AND WE CAN SHOW THAT THERE'S ANTIBODIES THAT ARE MOUNTED TO THIS VACCINE AND THAT THEY ACTUALLY BLOCK HCV ENTRY. NOW, THIS IS KIND OF A CUMBERSOME MODEL, AND SO WE'VE ALSO MADE TRANSGENIC ANIMALS THAT EXPRESS THESE HUMAN ENTRY FACTORS IN VARIOUS COMBINATIONS, AND AGAIN, THESE HAVE BEEN CROSSED WITH THIS INDICATOR MOUSE THAT GIVES US A SENSITIVE ASSAY FOR ENTRY. AND AGAIN, WE CAN SHOW THAT IN THESE TRANSGENIC ANIMALS ALL YOU NEED TO DO IS EXPRESS HUMAN CD81 AND HUMAN OCCLUDIN, AND THEY BECOME PERMISSIVE FOR HCV ENTRY. THAT'S THE GOOD NEWS, BUT HCV IS NOT WELL-ADAPTED THE MOUSE HEPATOCYTE ENVIRONMENT IN TERMS OF REPLICATION, AND IF YOU ASK WHETHER OR NOT THE VIRUS THAT GETS INTO THESE ANIMALS CAN ACTUALLY REPLICATE AND PRODUCE VIRUS, AS YOU CAN SEE ON THE RIGHT-HAND SLIDE HERE -- SIDE HERE, IT JUST DECAYS AWAY. SO THERE ARE A NUMBER OF EXPERIMENTS WHICH INDICATE THAT THERE'S REALLY A RESTRICTION FOR SOME VIRUS -- RESTRICTIVE VIRAL TROPISM, AND IT'S NOT ALWAYS JUST DUE TO THE RECEPTORS IN TERMS OF GETTING THE VIRUS IN, BUT IT'S OFTEN DUE TO SORT OF THE COMPATIBILITY OF THE VIRUS WITH THE INTERCELLULAR MACHINERY THAT'S SENSING AN INCOMING VIRAL PATHOGEN AND TURNING ON INTERFERON AND OTHER THINGS TO ELIMINATE IT. AND THIS IS JUST AN EXPERIMENT EVEN SHOWING IN ADULT HEPATOCYTES. IF YOU ANTAGONIZE TYPE I INTERFERON BY EXPRESSING PARAMYXOVIRUS B PROTEINS THAT BLOCK THAT SIGNALING PATHWAY, YOU CAN ACTUALLY GREATLY ENHANCE THE ABILITY OF HCV TO REPLICATE. AND THIS CAN ALSO BE DONE WITH CHEMICAL INHIBITORS. SO IN THE CASE OF THE MOUSE MODEL, IF YOU TAKE THESE ENTRY FACTOR TRANSGENIC ANIMALS AND YOU CROSS THEM TO VARIOUS IMMUNODEFICIENT BACKGROUNDS, AND I'M GOING TO JUST SHOW YOU A COUPLE OF EXAMPLES HERE -- IF YOU CROSS THEM TO A STAT1 KNOCKOUT ANIMAL, YOU CAN ACTUALLY SEE THAT YOU GET THIS INCREASED SIGNAL OF LUCIFERASE. IT ACTUALLY PERSISTS OVER A MONTH AND THEN YOU GET THE SORT OF BURST OF LUCIFERASE ACTIVITY AT THE SORT OF ONE- TO TWO-MONTH INTERVAL, AND THEN WE BELIEVE THAT THESE ANIMALS, BECAUSE THEY'RE STILL IMMUNE COMPETENT, ARE ABLE TO ELIMINATE THE VIRUS. AND THIS IS ALSO TRUE, BUT TO A LESSER EXTENT IN THE CASE OF THE INTERFERON REGULATORY FACTOR 1 KNOCKOUT ANIMALS. YOU CAN ACTUALLY TAKE SERUM FROM THESE MICE AND SHOW THAT THERE'S INFECTIOUS HCV, AS SHOWN HERE ON THE LEFT. SO THIS IS SERUM FROM MICE TAKEN SORT OF AT THE -- SORT OF PEAK OF THE LUCIFERASE SIGNAL, AND WE CAN ACTUALLY RECOVER CELL CULTURE-PRODUCED VIRUS. SO THIS IS REALLY, YOU KNOW, SORT OF A DEPARTURE FROM THE SORT OF CLASSICAL STUDIES THAT HAVE BEEN DONE, BUT I THINK IT'S ACTUALLY QUITE INTERESTING AND SORT OF WITH THESE APPROACHES WE'VE ACTUALLY BEEN ABLE TO RECONSTITUTE THE ENTIRE HCV LIFE CYCLE IN A MURINE HOST. SO THERE'S WORK IN PROGRESS TO TRY AND ADAPT THE VIRUS TO THIS AND SEE IF WE CAN GET A MORE ROBUST REPLICATING VIRAL SYSTEM AND MAYBE USE THAT VIRUS THEN TO SEE IF IN A MOUSE MODEL, IF WE CAN GET, YOU KNOW, THINGS THAT MORE MIMIC HUMAN DISEASE, FIBROSIS, AND OTHER KINDS OF PROGRESSION. SO THERE HAVE ALSO BEEN SOME OTHER SURPRISES, I THINK, ON THE ANIMAL MODEL FRONT, AND THAT IS WITH THE DEEP SEQUENCING TECHNOLOGIES, AND THIS IS WORK THAT WAS DONE BY AMIT KAPOOR IN PART IN COLLABORATION WITH A GROUP HERE AT NIH, HAS DISCOVERED SOME NEW CLOSE RELATIVES OF HEPATITIS C, AND THIS WAS IDENTIFIED IN RESPIRATORY SAMPLES IN DOGS, QUITE UNEXPECTEDLY. I THINK MOST OF US THOUGHT THAT OUR CLOSEST RELATIVES TO HEPATITIS C MIGHT BE FOUND IN NON-HUMAN PRIMATES, PERHAPS GREAT APES, BUT THIS VIRUS THAT'S BEEN FOUND IN DOGS IS THE CLOSEST KNOWN HOMOLOGUE TO HCV. AND INTERESTINGLY ENOUGH, A SEROSURVEY UNCOVERED THE FACT THAT THIS ACTUALLY ISN'T ALL THAT PREVALENT IN DOGS, BUT IT'S ACTUALLY QUITE PREVALENT IN HORSES. AND IF YOU JUST LOOK AT HORSE SERA, ABOUT 35 PERCENT OF THE ONES THAT EMIT, AND THE BURBELO LAB HERE AT NIH SCREENED HAD ANTIBODIES THROUGH THIS, AND 22 PERCENT OF THOSE IMMUNOREACTIVE SAMPLES WERE POSITIVE, AND ACTUALLY THE SORT OF EQUINE ISOLATES, THERE HAVE BEEN EIGHT GENOME SEQUENCES DETERMINED, ONE OF THESE IS VIRTUALLY IDENTICAL TO THE CANINE VIRUS. SO IT REALLY PROVIDES SOME EVIDENCE THAT THERE HAS BEEN CROSS-SPECIES TRANSMISSION, EITHER FROM HORSES TO DOG OR POTENTIALLY VICE VERSA. SO WITH THE NEW KINDS OF TECHNOLOGIES, WE'RE BEGINNING TO FIND ALL KINDS OF CLOSE RELATIVES TO HEPATITIS C. SO THAT'S THE SCIENCE. THE SORT OF PERSON THAT REALLY HAS DRIVEN THE ANIMAL MODEL DEVELOPMENT IN MY LAB IS ALEXANDER PLOSS, AN INCREDIBLY TALENTED YOUNG INVESTIGATOR. WE'VE HAD A LOT OF HELP FROM OTHERS, AND ACTUALLY ALL OF THE SORT OF HCV STUDIES THAT MY LAB HAS DONE HAS BENEFITED NOT ONLY FROM OUR INTERACTIONS WITH STEVE, BUT ALSO INTERACTIONS WITH ALL OF THE OTHER SORT OF HEPATITIS INTEREST GROUPS AT NIH. NOW, I WANT TO CLOSE WITH JUST A FEW THOUGHTS ABOUT STEVE, AND, YOU KNOW, TALK ABOUT HIS IMPACT ON MY CAREER. SO I DID A FEW STATISTICS ON THIS. WE CO-AUTHORED 22 PUBLICATIONS, I SHOWED YOU SOME OF THOSE EARLIER. THOSE HAVE BEEN CITED APPROXIMATELY 5,000 TIMES. THAT'S PROBABLY -- THAT'S PRETTY GOOD FOR US. YOU KNOW, MAYBE THAT JUST IS, LIKE, ONE PAPER FOR BOB PURCELL. [LAUGHTER] AVERAGE 200 CITATIONS PER PUBLICATION. OUR VERY FIRST PAPER, WHICH WE PUBLISHED IN JV, GOT 800 CITATIONS. SORT OF BEFORE STEVE, I HAD SIX PUBLICATIONS IN THESE SO-CALLED HIGH-PROFILE, YOU KNOW, SORT OF BASIC SCIENCE JOURNALS. AFTER STEVE, 38 PUBLICATIONS, SO HE'S A GOOD GUY TO KNOW. AND THEN THE NUMBER OF POSH MEETINGS THAT I'D ATTENDED WAS ZERO BEFORE I KNEW STEVE -- [LAUGHTER] -- AND NOW I CAN'T EVEN KEEP COUNT OF THEM. SO THANKS FOR THAT, STEVE. SO I WANT TO JUST -- A FEW MORE CONCLUDING REMARKS. SO STEVE HAD A SHITTY START TO HIS CAREER. WE'VE HEARD A LOT ABOUT THAT. GIVEN HIS ARDUOUS WORK IN ISOLATING HEPATITIS A VIRUS FROM STOOL SAMPLES, PERHAPS THE FDA SHOULD BE RENAMED FEINSTONE'S DIARRHEA ADVENTURE. [LAUGHTER] STEVE'S SENSE OF HUMOR TAKES A LITTLE GETTING USED TO. I THINK, YOU KNOW, SOMETIMES I REALLY COULDN'T TELL WHEN HE WAS, YOU KNOW, SORT OF SERIOUS OR JOKING. IT'S ALWAYS SORT OF A MIXTURE OF THOSE TWO PROPERTIES. AND THEN EVER SINCE I MET STEVE, HE ALWAYS WANTED TO RETIRE. IN FACT, I WAS UNDER THE IMPRESSION ALL THESE YEARS THAT HE WAS ALREADY RETIRED BUT JUST ENJOYED -- [LAUGHTER] -- GOING TO MEETINGS IN TROPICAL PLACES LIKE BARBADOS. AND JUST AS EVIDENCE OF THAT, HERE'S A PICTURE FROM ONE OF OUR MIDWINTER SYMPOSIA THAT WAS ORGANIZED BY THE LATE FRED PRINCE, AND YOU'LL SEE STEVE OVER THERE ON THE RIGHT. HERE, YOU THINK THERE'LL BE A JOB OPENING AT THE FDA SOON, THAT'S ARASH TALKING. "SURE ARASH, I'M GOING TO RETIRE ANY DAY NOW," SAYS STEVE. SO I'D LIKE TO FINISH WITH JUST SORT OF A STATEMENT. YOU KNOW, A SHITTY BEGINNING BUT A KING MIDAS CAREER WITH A GOLDEN TOUCH. I THINK THAT EPITOMIZES STEVE. EVERYBODY THAT HE'S INTERACTED WITH HAS REALLY SORT OF BENEFITED FROM THAT IN BIG WAYS, AND I THINK THE MARK OF A GREAT SCIENTIST IS SOMEBODY WHO'S REALLY INFLUENCED SCIENCE IN A GREAT WAY FOR OTHER PEOPLE. AND SO THANKS, STEVE, HAPPY RETIREMENT, BUT I DON'T THINK YOU SHOULD REALLY RETIRE BECAUSE I THINK SOMEBODY WITH STEVE'S BACKGROUND, SORT OF PASSION FOR VACCINES, UNDERSTANDING OF REGULATORY ISSUES, AND ALL THOSE THINGS HAS A LOT TO CONTRIBUTE TO VACCINE DEVELOPMENT IN THE FUTURE. THANKS. [APPLAUSE] GERARDO KAPLAN: ANY QUESTIONS FOR DR. RICE? GERARDO KAPLAN: OKAY. SO, YEAH. SO WE'RE HAVING THE LAST TALK, AND IT'S A PLEASURE TO INTRODUCE DR. IAN GUST. UNFORTUNATELY HE COULDN'T BE WITH US TODAY, BUT HE SENT US A PRE-RECORD, AND HERE IT IS. [CLIP PLAYING] IAN GUST: GOOD AFTERNOON. WHEN GERARDO APPROACHED ME ABOUT TODAY'S FUNCTION, HE SAID THAT HE WAS SCOURING THE WORLD TO FIND THE VERY BEST SPEAKERS AVAILABLE, MEN AND WOMEN OF IMPECCABLE SCIENTIFIC CREDENTIALS AND INCREDIBLE FACILITY WITH WORDS. UNFORTUNATELY, NONE OF THEM WERE AVAILABLE. I TRUST HE FOUND DR. PURCELL AND HIS COLLEAGUES SUITABLE REPLACEMENTS. BEING ASKED TO SAY A FEW WORDS ABOUT STEVE AT THE END OF LONG SESSION IS A BIT LIKE BEING ZSA ZSA GABOR'S FIFTH HUSBAND ON YOUR WEDDING NIGHT. I KNOW WHAT'S EXPECTED OF ME, BUT I'M NOT SURE THAT I'LL BE ABLE TO RETAIN YOUR INTEREST. BY NOW, NO DOUBT YOU'LL HAVE HEARD ALL ABOUT STEVE'S PLACID NATURE, HIS GLACIAL CALM BEHIND THE WHEEL, AND HIS ZEN-LIKE ABILITY TO OVERLOOK SLIGHTS. DON'T BELIEVE ANY OF IT. I'VE KNOWN STEVE FOR VIRTUALLY MY ENTIRE PROFESSIONAL LIFE AND WHAT IMPRESSED ME ABOUT HIM FROM THE BEGINNING WAS NOT JUST THE QUALITY OF HIS SCIENCE, WHICH IS OF THE HIGHEST ORDER, OR HIS INTELLIGENCE, WHICH AFTER ALL IS NOT UNCOMMON ON THE NIH-CAMPUS, BUT HIS BRUTAL HONESTY AND HIS OPENNESS TO NEW IDEAS. STEVE HAS BEEN AN EXCELLENT SCIENTIST AND A TREMENDOUS MENTOR OF YOUNG SCIENTISTS, BOTH IN HIS TIME AT NIAID AND LATERALLY AT THE FDA. WITH THE HELP OF MIMI AND NOAH, GENERATIONS OF POST DOCS AND VISITING SCIENTISTS HAVE BEEN ADMITTED TO THE FEINSTONE FAMILY AS COLLEAGUES AND FRIENDS, AND HIS SCIENTIFIC OFFSPRING CAN BE NOW FOUND IN EVERY CONTINENT. OUR PATHS FIRST CROSSED IN THE EARLY 1970S, WHEN WE WERE BOTH TRYING TO IDENTIFY THE ETIOLOGIC AGENT OF HEPATITIS A. MYSELF AS A TRAINING PATHOLOGIST AT THE NOW-DEFUNCT FAIRFIELD HOSPITAL IN MELBOURNE, STEVE IN BOB'S LAB AT NIAID, AND WE WERE BOTH EMPLOYING IMMUNOELECTRON MICROSCOPY, WHICH JUNE ALMEIDA AND AL KAPIKIAN HAD USED SO SUCCESSFULLY FOR THE IDENTIFICATION OF A RANGE OF ENTERIC PATHOGENS, AND WE WERE BOTH EXAMINING FECAL EXTRACTS FROM INDIVIDUALS WITH PEDIGREED HEPATITIS A. IN STEVE'S CASE, THE SUBJECTS WERE VOLUNTEERS FROM THE JOLIET STATE PRISON IN CHICAGO WHO'D BEEN EXPERIMENTALLY INFECTED WITH SAUL KRUGMAN'S MS1 STRAIN OF THE VIRUS AND FOR WHOM BOTH PRE-INFECTION, POST-INFECTION SERA AND FECAL EXTRACTS WERE AVAILABLE. IN MELBOURNE, OUR SUBJECTS WERE PATIENTS WITH NATURALLY-ACQUIRED HEPATITIS A WHO HAD BEEN ADMITTED TO HOSPITAL EARLY IN THE COURSE OF THEIR DISEASE, USUALLY WITHIN A WEEK OF THE ONSET OF DARK URINE. THE MAJOR DIFFERENCE IN THE STUDIES WAS THAT BECAUSE WE THOUGHT IT WAS LIKELY THAT, ON ADMISSION, OUR PATIENTS WOULD ALREADY HAVE DETECTABLE HEPATITIS A ANTIBODIES, OUR DETECTOR SERUM WOULD ARRIVE FROM RABBITS, WHICH HAD BEEN IMMUNIZED WITH FECAL EXTRACTS OF HEPATITIS A. IT WAS WITH ENORMOUS EXCITEMENT AND, I ADMIT, SOME DISAPPOINTMENT THAT WE READ THE FAMOUS 1973 SCIENCE PAPER, BUT WITHIN A FEW MONTHS WE WERE ABLE TO CONFIRM THE FINDINGS IN PATIENTS WITH NATURALLY-ACQUIRED DISEASE, AS DID JIM MAYNARD AND HIS COLLEAGUES AT CDC IN COLLEGE STUDENTS WHO'D BEEN INVOLVED IN A WATER-BORNE OUTBREAK. AN EXCHANGE OF REAGENTS BETWEEN THE LABORATORIES INDICATED THAT WE WERE ALL DEALING WITH THE SAME ENTITY. THE NEXT TWO YEARS WERE ENORMOUSLY EXCITING, WITH 700 OR 800 PATIENTS WITH ACUTE HEPATITIS A ADMITTED EACH YEAR AND WITH ACCESS TO ASSAYS, TO HEPATITS A ANTIGEN, AND TOTAL AND CLASS-SPECIFIC ANTIBODIES WE WERE ABLE TO DEFINE MANY OF THE FEATURES OF THE NATURAL HISTORY, AN EPIDEMIOLOGY OF THE DISEASE, IN AUSTRALIA, SOUTHEAST ASIA, AND THE WESTERN PACIFIC REGION. AND ALTHOUGH WE KEPT IN CONTACT AND BOB HAD VISITED AUSTRALIA IN 1974, STEVE AND I DIDN'T ACTUALLY MEET UP UNTIL MARCH 1975, BY WHICH TIME HE'D LEFT NIH AND WAS BEGINNING TO TRAIN AS AN INFECTIOUS DISEASES FELLOW. THE OCCASION WAS A CONFERENCE AT THE NATIONAL ACADEMY OF SCIENCES IN WASHINGTON ORGANIZED BY A COMMITTEE INCLUDING SAUL KRUGMAN, FRITZ DEINHARDT, BOB MCCOLLUM, JOE MELNICK AND ATTENDED BY ALL THE MAJOR FIGURES OF THE TIME: JIM ROBINSON, PAUL HOLLAND, JIM MOSELEY, GEORGE BOUVIER, ALLAN REDEKER, AS WELL AS BOB, JOHN, AND JAY. I STILL HAVE THE PROCEEDINGS: TWO VOLUMES OF THE AMERICAN JOURNAL OF MEDICAL SCIENCE IN THEIR CANARY YELLOW COVERS ON MY OFFICE WALL. STEVE AND I WERE AMONG THE YOUNGEST PEOPLE THERE AND WE WERE BOTH A BIT RETICENT. WE SAT TOGETHER TOWARDS THE BACK OF THE THEATER AND WE SIMPLY HIT IT OFF. IT WAS, AS THEY SAY IN THE MOVIES, THE BEGINNING OF A BEAUTIFUL FRIENDSHIP. VIRAL HEPATITIS HAD BECOME A TOPIC OF GREAT INTEREST IN AUSTRALIA AND THE FAIRFIELD GROUP WERE ACCEPTED AS LEADERS IN THE FIELD. DURING A SUBSEQUENT VISIT WITH BOB, I MENTIONED AN INTEREST IN DOING A SABBATICAL IN THE UNITED STATES AND HE INVITED ME TO JOIN THE LAB AS A FOGARTY FELLOW. BOB'S LAB WAS THE ENVY OF THE GLOBAL HEPATITIS COMMUNITY. IT WAS BRILLIANTLY LED, WELL-FUNDED, WITH ACCESS TO BOTH MARMOSETS AND CHIMPANZEES. IT HAD BECOME A MAGNET FOR THE BEST AND BRIGHTEST FROM THROUGHOUT THE WORLD AND LED THE WORLD ON VERY MANY FRONTS. SO IN 1978, WITH DI AND FOUR CHILDREN UNDER THE AGE OF EIGHT, WE FLEW TO WASHINGTON FOR WHAT WAS TO BE THE FIRST OF TWO MEMORABLE VISITS, AND STEVE COULDN'T HAVE BEEN MORE HELPFUL. HE ORGANIZED A HOUSE FOR US TO RENT WITHIN WALKING DISTANCE OF THE CAMPUS, BORROWED A COUPLE OF NIH VANS TO TRANSPORT US FROM THE AIRPORT, AND FILLED THE HOUSE WITH FOOD, SOMETHING THAT I'VE SEEN HIM DO TIME AND TIME AGAIN OVER THE YEARS. THROUGH STEVE I BECAME FRIENDS WITH BRIAN, LOU, HARRY, HARVEY, AND LATER ANDY, FRIENDSHIPS WHICH HAVE ENDURED AND BEEN A SOURCE OF GREAT JOY. PRIOR TO ARRIVAL, WE DISCOVERED POSSIBLE TOPICS TO WORK ON AND DECIDED TO LOOK FOR BIOLOGICAL DIFFERENCES BETWEEN AMERICAN AND AUSTRALIAN STRAINS OF HEPATITIS A, BECAUSE THERE WAS SOME EVIDENCE THAT AUSTRALIAN STRAINS WERE SHED FOR A LONGER PERIOD OF TIME IN THE FECES. ONCE I'D SETTLED IN MY COLLEAGUE, NOREEN LEHMANN, FORWARDED FECAL SAMPLES FROM A FATHER, MOTHER, AND THEIR CHILDREN WHO'D ACQUIRED HEPATITIS A DURING AN OUTBREAK OF THE DISEASE IN A SMALL, UN-SEWAGED OUTER MELBOURNE SUBURB OF KANGAROO GROUND. AS LUCK WOULD HAVE IT, THE PARCEL CONTAINING THE SAMPLES WAS OFFLOADED ON BOTH THE WEST COAST AND THE EAST COAST AND ARRIVED AT NIH SEVERAL DAYS LATER, BY WHICH TIME ALL THE DRY ICE IN THE PARCEL HAD EVAPORATED. SO WE THOUGHT IT WAS QUITE LIKELY THAT THE VIRUS HAD PERISHED AND I STARTED WORK ON ANOTHER TOPIC, INVESTIGATING WHETHER PIERRE AKLELBERG'S [SPELLED PHONETICALLY] DOUBLE-STRANDED DNA ASSAY WAS A SURROGATE MARKER OF THE PRESENCE OF THE HEPATITIS C VIRUS, WHICH, AS ACKELBERG WAS BASED IN NEW ORLEANS, WAS NO REAL HARDSHIP. SOMETIME LATER, STEVE AND I WERE ALERTED TO THE AVAILABILITY OF FOUR MARMOSETS WHO WERE NEAR THE END OF THEIR LIFE AND WHICH COULD BE USED IN A SIMPLE YES-NO EXPERIMENT, SO WE DECIDED TO TEST THE VIABILITY OF THE SAMPLES THAT WE'D RECEIVED, SELECTED THE LARGEST, WHICH CAME FROM THE FATHER, PREPARED AN EXTRACT WHICH WAS THEN INOCULATED INTRAVENOUSLY INTO EACH ANIMAL. THE SAMPLE HAD THE CODE NAME OF HM175. H FOR HEPATITIS, M FOR MAGIBS MAGOLA [SPELLED PHONETICALLY], THE ELECTRON MICROSCOPIST WHO FIRST STUDIED IT. 175 BECAUSE IT WAS THE 175TH IN THAT PARTICULAR SERIES. WHAT HAPPENED THEN WAS A GREAT EXAMPLE OF SERENDIPITY IN SCIENCE. WE WERE JUST LUCKY. THE SAMPLE WAS LOADED WITH VIRUS, PRODUCED AN UNUSUAL BIPHASIC ILLNESS IN THE ANIMALS, AND WHEN FECAL EXTRACTS OR INFECTED MARMOSET LIVER WERE INOCULATED INTO PRIMARY AFRICAN GREEN MONKEY KIDNEY CELLS, THE VIRUS REPLICATED AND COULD BE READILY DETECTED BY IMMUNOFLUORESCENCE. STEVE, BOB, DICK, AND JOHN TICEHURST CONTINUED TO WORK ON THE STRAIN, ATTENUATING IT BY PASSAGE, CHARACTERIZING THE GENETIC CHANGES, AND DEMONSTRATING THAT BOTH FORMAL AND INACTIVATED AND LIVE ATTENUATED HM175-BASED VACCINES WOULD PROTECT MARMOSETS AGAINST CHALLENGE WITH WILD-TYPE VIRUS. IN 1985, FOLLOWING SOME DISCUSSION WITH STAN HUYGLEN, WHO WAS THEN IN CHARGE OF VACCINE DEVELOPMENT AT RIT IN BELGIUM, WHICH IS NOW GSK, NIH LICENSED THE TECHNOLOGY AND THE COMPANY UNDERTOOK A CRASH PROGRAM TO DEVELOP AND LICENSE THE VACCINE. THE RESULTING PRODUCT, HAVRIX, WAS LICENSED IN EUROPE IN 1991 AND WAS FOR SOME YEARS THE WORLD'S ONLY HEPATITIS A VACCINE. IT CONTINUES TO BE THE LARGEST SELLER, EITHER ALONE OR IN COMBINATION WITH GSK'S HEPATITIS B VACCINE, ENGERIX-B. STEVE AND I HAVE BEEN FRIENDS EVER SINCE. WE'VE TRAVELED TO MANY COUNTRIES, WE'VE SHARED MANY PLATFORMS, WE'VE CAMPED IN THE GRAND CANYON, WE'VE PLAYED SPORT TOGETHER, WE'VE FORDED RIVERS, WE'VE SPENT A LOT OF TIME AT EACH OTHER'S HOMES IN MELBOURNE AND WASHINGTON, WE'VE BEEN TO THE FOOTBALL, TO THE MAJOR LEAGUE BASEBALL, AND TO THE NBA. WE'VE WRITTEN A BOOK TOGETHER AND MORE CHAPTERS ON HEPATITIS THAN I CARE TO REMEMBER. AND SEEN OUR CAREERS EVOLVE AND OUR CHILDREN GROW INTO SPLENDID ADULTS. IT'S BEEN A MOST REWARDING JOURNEY. STEVE HAS BEEN A WONDERFUL COLLEAGUE, FRIEND, AND MUSE, A SOURCE OF BOTH INSPIRATION AND SUPPORT. BECOMING FAMOUS AT A YOUNG AGE CREATES ITS OWN PRESSURES. WHILE MEMORABLE AND THRILLING, HITTING A GRAND SLAM ON YOUR FIRST AT BAT IS NOT AS LASTING AS A LIFETIME BATTING AVERAGE OF 300. STEVE IS ONE OF THE FEW SCIENTISTS THAT I KNOW WHO'S DONE IT BOTH. A GOOD FRIEND OF OURS, THE LEGENDARY NEWSPAPER MAN CREIGHTON BURNS, ONCE SAID, "HAPPINESS IS THE RESPECT OF PEOPLE OF GOOD WILL AND THE LOVE OF A GOOD WOMAN." AGAIN, STEVE HAS HAD BOTH. ALTHOUGH HE IS TOO DISCREET TO SAY SO, TO SAY THREE GOOD WOMEN, CREIGHTON WOULD HAVE UNDOUBTEDLY APPLAUDED. STEVE, I WISH YOU AND MIMI GOOD HEALTH AND A LONG AND PRODUCTIVE RETIREMENT, TO PURSUE YOUR INTERESTS AND ENJOY YOUR FAMILY AND FRIENDS, AND ON BEHALF OF DI AND OUR FAMILY, THANK YOU BOTH FOR ENRICHING OUR LIVES. [END OF CLIP] [APPLAUSE] STEPHEN FEINSTONE: WELL, IT'S MY TURN NOW, AND IT'S SOMEWHAT OF A DIFFICULT TIME. WHEN GERARDO KAPLAN AND MARIAN MAJOR TOLD ME THEY WANTED TO ORGANIZE THIS SYMPOSIUM AFTER I HAD INFORMED THEM THAT I WAS PLANNING TO RETIRE, I WAS VERY MUCH TOUCHED BY IT. OF COURSE, MY FIRST INSTINCT WAS ACTUALLY JUST TO SAY NO, BUT I HAVE BEEN WORKING ON BEING MORE GRACIOUS AND SO I DECIDED TO OVERCOME MY EMBARRASSMENT AND WITH A FEW CHANGES I ACCEPTED. I HOPE THAT THEY, AS WELL AS LEW MARKOFF AND KOSTYA CHUMAKOV, THE ORGANIZERS, UNDERSTAND HOW APPRECIATIVE I AM FOR THEIR THOUGHTFULNESS AND THEIR HARD WORK. I ALSO WANT TO THANK BOB, JOHN, JAY, CHARLIE, AND IAN FOR THE WONDERFUL TALKS THAT THEY'VE GIVEN TODAY. IT'S -- THERE WASN'T -- THEY WEREN'T ENTIRELY TRUTHFUL. I CERTAINLY CAME OFF MUCH BETTER THAN I'D THOUGHT I DID, BUT IT WAS VERY NICE. BUT WHEN MARIAN AND GERARDO TOLD ME THEIR PLANS, WHAT I FIRST SAID TO THEM WAS -- BESIDES NO, I SAID NO ONE WOULD SHOW UP. SO I HAVE TO ADMIT I'M VERY GRATEFUL FOR ALL OF YOU FOR COMING AND IT REALLY MEANS A LOT TO ME. SO I FEEL LIKE TODAY I'M HERE PRIMARILY BECAUSE I'VE SIMPLY BEEN AN EXTREMELY LUCKY PERSON. I'VE BEEN LUCKY, BOTH IN MY PERSONAL LIFE AND IN MY PROFESSIONAL LIFE, IN MY ENTIRE CAREER. YOU KNOW, SCIENCE BEGINS WITH MENTORS. I THINK WE ALL KNOW AND WE ALL LOOK BACK TO OUR MENTORS. AND IN MY CASE I WAS EXTREMELY FORTUNATE TO WORK WITH A MAN IN MEDICAL SCHOOL NAMED MIKE RYTEL, WHO WAS CHIEF OF INFECTIOUS DISEASES AT THE UNIVERSITY OF TENNESSEE SCHOOL OF MEDICINE. MIKE, ALONG WITH THE CHIEF OF MEDICINE, GENE STOLLERMAN, GAVE ME MY FIRST OPPORTUNITY IN THE LAB AND THEY EVEN PUT ME ON THEIR TRAINING GRANT AT $300 A MONTH, WHICH I SHOULD ADD WAS TAX-FREE, MR. ROMNEY. SO, WHEN WORKING IN MIKE'S LAB, MIKE FOUND OUT THAT I WAS GETTING MARRIED. I HADN'T REALLY TOLD ANYONE. AND I WAS GETTING MARRIED ACTUALLY ON THE NEXT WEEKEND. HE WAS SOMEWHAT SURPRISED BY THAT AND ASSUMED THAT I WOULD NEED SOME TIME OFF. WHEN I TOLD HIM THAT, "NO, I'D BE BACK TO WORK ON MONDAY, BUT I PROBABLY WOULDN'T BE ABLE TO GET INTO THE LAB ON SUNDAY TO CHANGE THE CELLS," HIS EYES JUST WIDENED AND I COULD SEE IMMEDIATELY HE THOUGHT HE HAD FINALLY FOUND THE GUY HE WAS LOOKING FOR. [LAUGHTER] WELL, I WROTE TWO PAPERS DURING MEDICAL SCHOOL WITH MIKE AND I'M SURE IT WAS THOSE TWO PAPERS THAT CONVINCED BOB CHANOCK TO ACCEPT ME IN THE LABORATORY OF INFECTIOUS DISEASES. IT WAS EXTREMELY COMPETITIVE BACK IN THE VIETNAM ERA AND I WAS EXTREMELY FORTUNATE TO BE ACCEPTED. BUT WHEN I CAME TO NIH, MY MAIN MENTOR, I THINK YOU ALL UNDERSTAND, WAS BOB PURCELL. WELL, I WORKED ON MANY PROJECTS WITH BOB. MY ENTIRE CAREER IS REALLY BASED ON THE INITIAL IDENTIFICATION OF THE HEPATITIS A VIRUS, AS YOU'VE HEARD. A STORY THAT FEW PEOPLE KNOW IS THAT AFTER WE HAD WRITTEN UP THE FIRST PAPER FOR SUBMISSION TO SCIENCE, THERE WAS SOME PRESSURE FROM THE NIAID SCIENTIFIC DIRECTOR TO MOVE MY NAME FROM THE FIRST AUTHOR POSITION AND PUT EITHER BOB OR AL KAPIKIAN AS THE FIRST AUTHOR, AND BOB JUST SAID, "WELL THAT'S RIDICULOUS," AND HE JUST IGNORED THE PRESSURE. AND, HONESTLY, MY CAREER WAS BASED ON THAT ONE ACT AND I'M ETERNALLY GRATEFUL. NOW, BOB SAID -- I DIDN'T KNOW I HAD THAT GOOD A CAREER, HONESTLY. HE MADE IT LOOK AWFULLY, AWFULLY GOOD. I DO WANT TO SAY ONE THING ABOUT BOB, WHOSE ACHIEVEMENTS ARE JUST SO IMMENSE. HE'S CONTRIBUTED TO EVERY SINGLE AREA OF VIRAL HEPATITIS, BUT IN ONE AREA THAT I DID WORK CLOSELY WITH HIM WAS IN THE FIRST DESCRIPTION OF NON-A, NON-B HEPATITIS. AND JAY MENTIONED, YOU KNOW, WHY DIDN'T -- OBVIOUSLY IT WASN'T HEPATITIS A, BUT NOBODY KNEW THAT, AND -- EXCEPT FOR ONE PERSON. BOB ALWAYS KNEW IT WASN'T HEPATITIS A AND HE WAS JUST LOOKING FOR A WAY TO PROVE IT. AND WHEN WE DID THE HEPATITIS A WORK AND WE FINALLY HAD A TEST, THE VERY FIRST THING THAT HE WANTED TO DO WAS GO AFTER POST-TRANSFUSION HEPATITIS AND TAKE A LOOK AT THAT. HE WAS NOT IN ANY WAY CONFUSED ABOUT THE FACT THAT THAT MIGHT BE DUE TO HEPATITIS A. SO ANOTHER GREAT MENTOR THAT I HAD IN LID WAS AL KAPIKIAN. AL WAS -- I'VE SPENT MANY HOURS WITH AL SITTING DOWN IN THE BUILDING 7 SUBBASEMENT PEERING THROUGH THE MICROSCOPE, AND DURING THOSE HOURS WITH AL I LEARNED PROBABLY TOO MUCH YANKEES BASEBALL LORE, BUT I ALSO LEARNED A LOT OF SCIENCE FROM AL, AND I ESPECIALLY LEARNED ABOUT SCIENTIFIC INTEGRITY AND I HAVE TRIED TO CARRY THOSE LESSONS WITH ME ALL THESE YEARS AND I VERY MUCH APPRECIATE IT. I'M ALSO VERY PROUD TO THINK OF JOHN GERIN AS A MENTOR. JOHN WAS ONE OF THE FIRST TO APPLY BASIC VIROLOGIC TECHNOLOGY TO THE STUDY OF HEPATITIS VIRUSES. YOU REMEMBER, NONE OF THESE VIRUSES WERE CULTIVATABLE AND VERY FEW RESPECTABLE VIROLOGISTS WHO WANTED TO WORK ON THEM, BUT JOHN DID, AND IT WAS THROUGH THE APPLICATION OF THIS KIND OF TECHNOLOGY THAT HE WAS ABLE TO CONSTRUCT THE FIRST HEPATITIS B VACCINE AND PROVE THAT IT WORKED WITH -- HE AND BOB PROVED THAT IT COULD WORK. AND, IN REALITY, IF YOU ACTUALLY GO BACK AND LOOK AT THEIR DATA, THAT WAS PROBABLY THE BEST HEPATITIS B VACCINE THAT'S EVER BEEN PRODUCED AND IT'S A SHAME THAT IT DIDN'T ACTUALLY GET INTO COMMERCIAL PRODUCTION. AS YOU'VE HEARD, BOB'S LAB AND JOHN'S LAB HAD A SPECIAL AND VERY PRODUCTIVE RELATIONSHIP WITH HEPATITIS B, HEPATITIS A, AND ESPECIALLY DELTA AND WOODCHUCK. AND I THINK THOSE -- THAT RELATIONSHIP WAS UNIQUE AT NIH. I ALSO CONSIDER JOHN TO BE ONE OF THE GREAT GENTLEMEN IN THIS FIELD, AND I SAID THAT AND WHEN I -- WHEN -- JOHN AND I HAD SOME EMAILS BACK AND FORTH ABOUT WHAT HE WAS GOING TO TALK ABOUT AT THIS SYMPOSIUM, AND HE MENTIONED SOMETHING ABOUT PAYING SOME OLD DEBTS. SO I WAS SUDDENLY CONFUSED BECAUSE I HAD NEVER PREVIOUSLY HEARD HIM SAY A NEGATIVE WORD ABOUT ANY INDIVIDUAL. WELL, CHANOCK'S LAB WAS REALLY AN EXCITING AND INSPIRING PLACE. EVERYONE IN THE LAB WANTED TO DO GREAT THINGS, AND MANY OF THEM DID, BUT SO MUCH OF THE ENERGY FOR DOING SCIENCE COMES FROM INTERACTION WITH OUR COLLEAGUES AND MY TIME IN CHANOCK'S LAB WAS SUCH A FANTASTIC EXPERIENCE FOR ME AND I WAS VERY FORTUNATE TO MAKE LIFELONG FRIENDS IN THOSE EARLY YEARS WITH SOME TERRIFIC YOUNG SCIENTISTS, INCLUDING BRIAN MURPHY, HARRY GREENBERG, DOUG RICHMAN, IAN GUST, LEW MARKOV, ANDY LEWIS, AND LATER JEFF COHEN AND SU EMERSON, ALL OF WHOM HAD A TREMENDOUS INFLUENCE ON MY CAREER AND HELPED ME SO MUCH IN THE WORK I WAS DOING IN THE LAB. JAY HOOFNAGLE CAME TO NIH, AS HE MENTIONED, AT ABOUT THE SAME TIME I DID, AND I THINK HE UNDERPLAYED A LITTLE BIT HIS CONTRIBUTION WITH THE DEVELOPMENT OF THE ASSAY FOR ANTI-CORE FOR HEPATITIS B ANTI-CORE ASSAY, AND THIS FUNDAMENTALLY CHANGED OUR VIEW OF HEPATITIS B AND -- BOTH CLINICALLY AND EPIDEMIOLOGICALLY. IT WAS INCREDIBLY IMPORTANT AND IT HELPED LAUNCH JAY ON A TERRIFIC CAREER. I THINK EVERYONE KNOWS JAY IS ONE OF THE MOST RESPECTED HEPATOLOGISTS IN THE WORLD AND I'M VERY PROUD OF THE RELATIONSHIPS THAT OUR LABS HAVE HAD OVER THE YEARS. NOW, SCIENCE TODAY IS OFTEN VERY COMPLEX AND ALL OF US BENEFIT FROM COLLABORATIONS. WE ALMOST CAN'T DO ANYTHING ANYMORE WITHOUT THE BENEFIT OF COLLABORATING. SO I WAS ALSO VERY FORTUNATE IN MY CAREER TO HAVE HAD -- TO HAVE WORKED WITH SOME TERRIFIC PEOPLE. CERTAINLY CHARLIE RICE WAS CENTRAL TO OUR WORK AT THE LAB AT CBER. IT'S BEEN AN AMAZING EXPERIENCE TO WORK WITH CHARLIE AND ALSO A GREAT PLEASURE, AS WELL AS WITH SEVERAL OF THE GUYS IN HIS LAB, PARTICULARLY ARASH GRAKOUI AND SASCHA KOLYKHALOV. AMONG INTRAMURAL INVESTIGATORS WITH WHOM I'VE WORKED, AND THIS IS NOT A COMPLETE LIST, WERE JAY BERZOFSKY, KURT HARRIS, JAY HOOFNAGEL AGAIN, ADRIAN DI BISCEGLIE, JAKE LIANG, BARBARA REHERMANN, GARY NABEL, AND PEI ZHANG. I HOPE EACH OF THEM, AND EVERYONE ELSE WITH WHOM I'VE WORKED KNOWS HOW MUCH I VALUED AND BENEFITED FROM THOSE COLLABORATIONS. ALL OF US UNDERSTAND THAT WE'RE TOTALLY DEPENDENT ON THE YOUNG SCIENTISTS WHO COME AND WORK AND TRAIN IN OUR LABS, AND AGAIN I'VE BEEN PARTICULARLY FORTUNATE. THERE ARE TOO MANY OF THEM TO MENTION BY NAME, BUT THEY ARE THE REAL HEART OF ANY LAB AND CERTAINLY WERE IN MINE. I'M VERY GRATEFUL TO ALL OF THEM. I WANT TO MENTION TOSHITAKA AKATSUKA, WHO'S COME HERE TODAY ALL THE WAY FROM JAPAN, AND HE ARRIVED IN MY LAB BEFORE I ACTUALLY HAD A LABORATORY. WE DIDN'T HAVE A PHYSICAL LABORATORY SET UP, AND TOSHI WAS INSTRUMENTAL IN GETTING US OFF THE GROUND. AND EVERYTHING HE DID, HE STAYED WITH US FOR ABOUT SEVEN OR EIGHT YEARS, AND IT WAS TERRIFIC TO HAVE HIM IN THE LAB. I WANT TO MENTION PARTICULARLY GERARDO KAPLAN AND MARIAN MAJOR FOR -- BECAUSE THEY BOTH ACHIEVED TENURE WHILE IN MY LABORATORY AND HAVE GONE ON TO BECOME OUTSTANDING INDEPENDENT INVESTIGATORS ON THEIR OWN, AS WELL AS INFLUENTIAL AND RESPECTED REVIEWERS AT CBER. I'M VERY PROUD OF THEM AND THEIR ACHIEVEMENTS. GERARDO LATER STARTED HIS OWN LAB AND MARIAN WILL SOON. I THINK PROBABLY ON MONDAY. [LAUGHTER] I MUST ALSO MENTION ONE PERSON WHO PROVIDED TREMENDOUS SUPPORT FOR ME ALL THESE YEARS, KATHY MIHALIK. KATHY STARTED WORKING WITH ME BACK IN BOB'S LAB IN 1980. I'LL DO THE MATH FOR YOU: THAT'S 32 YEARS. KATHY AND I OFTEN CHARACTERIZED IT AS IT'S BEING LIKE AN OLD MARRIAGE. YOU KNOW, AS H.L. MENCKEN ONCE SAID, "MARRIAGE. IT'S NOT A WORD, IT'S A SENTENCE." SO KATHY HAS DONE HER TIME AND KATHY RECENTLY RETIRED, AS WELL. FINALLY, EVERYONE GIVING THESE TYPES OF SPEECHES MENTIONS THEIR FAMILY. MY SISTER LINDA IS HERE TODAY. LINDA IS THE KINDEST, THE MOST GENEROUS SISTER ANYONE COULD HAVE. SHE'S THE GLUE THAT KEEPS THE FEINSTONE FAMILY TOGETHER. BUT I CAN TELL YOU THE NIGHT EXACTLY 50 YEARS AGO WHEN I MET MIMI WANG, A 17-YEAR-OLD COLLEGE FRESHMEN AT GOUCHER. IT WAS THE LUCKIEST NIGHT OF MY LIFE. NOW, I DON'T ACTUALLY MEAN I GOT LUCKY THAT NIGHT, BUT -- [LAUGHTER] -- IF THERE IS ANYTHING TOLERABLE ABOUT BEING AROUND ME, YOU CAN ATTRIBUTE IT TO MIMI. AND THEN, OF COURSE, OUR SON NOAH ARRIVED IN 1980 AND THAT COMPLETELY CHANGED THE FOCUS OF OUR LIVES. MIMI AND I ARE THRILLED TO SAY THAT IN JUST TWO WEEKS, NOAH WILL MARRY LAURIE EZELL AND WE'LL HAVE THE DAUGHTER THAT WE ALWAYS WANTED. WE'RE SO LOOKING FORWARD TO THAT. SO IT'S BEEN A WONDERFUL TRIP AND, LIKE I SAID, IT'S BEEN A VERY LUCKY TRIP. BUT PERHAPS THE SINGLE LUCKIEST ASPECT OF MY CAREER WAS THE OPPORTUNITY TO WORK IN TWO OF THE MOST IMPORTANT PUBLIC HEALTH INSTITUTIONS IN THE WORLD, THE NIH AND THE FDA. SO, IN THE END, HAVE YOU EVER SPENT TWO YEARS MAKING A RASH DECISION? I'VE REALLY OFTEN AWAKENED IN THE MORNING AND QUESTIONED THIS DECISION THAT I'VE MADE TO RETIRE, ESPECIALLY WHEN I HEAR THE TALKS TODAY, ESPECIALLY FROM CHARLIE AND I SAY, "MY GOSH THERE'S A LOT OF GOOD STUFF TO WORK ON." BUT IN THE END, I'VE HAD A WONDERFUL CAREER AND I DON'T REGRET ANYTHING. MY WISH IS THAT ALL OF YOU CAN HAVE AS GREAT AN EXPERIENCE IN YOUR CAREERS AS I'VE HAD IN MINE. I WANT YOU TO KNOW HOW APPRECIATIVE I AM THAT YOU'VE COME AND HOW IMPORTANT TO ME IT HAS BEEN TO HAVE KNOWN ALL OF YOU. AND I DON'T -- I THINK I WILL STILL BE HANGING AROUND THE FIELD A BIT, AND I PLAN TO RUN INTO MANY OF YOU AGAIN. THANK YOU VERY MUCH. [APPLAUSE] ANY QUESTIONS? MARIAN MAJOR: HEY, YOU DON'T GET TO GO JUST YET. WE HAVE A FEW GIFTS FOR YOU. THIS IS SOMETHING FOR YOU, WHICH I HOPE WILL -- WHEN YOU LOOK AT IT YOU'LL REMEMBER -- YOUR HEART WILL BEAT A LITTLE BIT FASTER. YOU'LL REMEMBER THE TRAUMA WE'VE PUT YOU THROUGH TODAY TO MAKE YOU COME TO THIS SYMPOSIUM AND REMEMBER ALL OF OUR THOUGHTS AND GOOD WISHES FOR RETIREMENT. STEPHEN FEINSTONE: THANK YOU VERY MUCH. GERARDO KAPLAN: ALSO, ON BEHALF OF THE FDA AND NIH COMMUNITY, WE WOULD LIKE TO OFFER YOU THIS POSTER AND ASK EVERYBODY TO SIGN IT, PLEASE. IT WILL BE OUTSIDE AGAIN. AND SO YOU CAN REMEMBER THIS EVENT. AND SO THIS IS THE END. [LAUGHTER] THIS IS THE END OF THE EVENT AND WE WOULD LIKE TO INVITE EVERYBODY TO REFRESHMENTS AT THE ENTRY HALL, AND THE ORGANIZING COMMITTEE WOULD ALSO LIKE TO THANK VERY MUCH THE SPEAKERS. IT WAS AN INCREDIBLE -- INCREDIBLE PRESENTATIONS AND I THINK EVERYBODY ENJOYED IT VERY, VERY MUCH. THANK YOU, EVERYBODY, FOR COMING. [APPLAUSE]