>> GOOD AFTERNOON. WELCOME TO CLINICAL CENTER GRAND ROUNDS GREAT TEACHER SERIES, I'M DELIGHTED AND HONORED TO INTRODUCE CRYSTAL MACKALL, CHIEF OF THE PEDIATRIC ONCOLOGY BRANCH, NATIONAL CANCER INSTITUTE AS WELL AS THE HEAD OF THE IMMUNOLOGY SECTION IN THE SAME. SHE'S ALSO RETIRED CAPTAIN FROM THE UNITED STATES PUBLIC HEALTH SERVICE. THAT'S RIGHT. ALL CREDIT WHERE CREDIT IS DO. SO DOCTOR MACKALL WAS BORN RAISED AND EDUCATED IN OHIO, GRADUATED SUMMA CUM LAUDE WITH A COMBINED BACHELOR OF SCIENCE AND DOCTOR OF MEDICINE DEGREE FROM THE COMBINED UNDERGRADUATE PEOPLE SCHOOL PROGRAM AT THE COLLEGE OF MEDICINE, UNIVERSITY OF AKRON. SHE, THEN, WENT ON TO COMBINED RESIDENCY TRAINING, PEDIATRICS AND INTERNAL MEDICINE, ACCHRONGENERAL MEDICAL CENTER, ALSO CONCERNED AS CHIEF RESIDENT IN INTERNAL MEDICINE. CAME TO NIH IN 1989 WHERE SHE HAS REMAINED SINCE. QUITE PROLIFIC AND PRODUCTIVE IN EVERY SENSE OF THE WORD. SHE JOINED AS A FELLOW IN PEDIATRIC HEMATOLOGY IN 1989. HER TRAINING WAS IN THE LABORATORY OF DR. JOHN GRESS, THE IMMUNOLOGY BRANCH AT THE NCI. APPOINTED AS A PRINCIPAL INVESTIGATOR SINCE 2003. SHE HAS REMAINED -- SHE HAS BEEN TENURED AS A PI AND HEADING THE IMMUNOLOGY SECTION IN THE PEDIATRIC BRANCH. FROM 2005 TO 8:00 SHE WAS THE ACTING BRANCH CHIEF FOR THE PEDIATRIC BRANCH AND THEN IN 2008 AFTER AN INTERNATIONAL SEARCH, AND THREE GREAT YEARS ACTING I MIGHT ADD, SHE WAS APPOINTED AS CHIEF OF THE BRANCH. SHE IS BOARD CERTIFIED, INTERNAL MEDICINE, PEDIATRIC AND PEDIATRIC HEMATOLOGY, PROUD TO MAINTAIN CERTIFICATION TO THE FELLOW TRAINEES IN THIS AUDIENCE. I WATCH HER WORK VERY HARD EVERY X NUMBER OF YEARS, WE TAKES IT VERY SERIOUSLY. SHE'S BEEN THE RECIPIENT OF NUMEROUS HONORS INCLUDING PREVIOUS NIH TEACHING AWARDS LIKE TODAY'S, NIH AND NCI DIRECTOR'S AWARDS, BEEN ELECTED INTO MULTIPLE SCIENTIFIC INSTITUTIONS, FOR EXAMPLE, THE AMERICAN SOCIETY OF CLINICAL INVESTIGATION. SHE'S ALSO A MEMBER OF NUMEROUS EDITORIAL BOARDS INCLUDING CURRENTLY AS ASSOCIATE EDITOR OF BLOOD AND EDITOR IN CHIEF FOR FRONTIERS AND PEDIATRIC ONCOLOGY. THIS ROOM IS POPULATED BY MANY TRANNIES, A DEDICATED MENTOR THROUGHOUT HER CAREER. MANY ARE INDEPENDENT SUCCESSFUL SCIENTISTS. HER RESEARCH EFFORT HAS BEEN QUITE FOCUSED FROM THE ONSET OF HER TIME IN THE GRASS LAB. SHE READS TRANSLATIONAL RESEARCH PROGRAMS THAT SPANS BASIC T. CELL BIOLOGY STUDIES THROUGH DISEASE MODELING IN THE FIELD OF TUMOR IMMUNOLOGY AND CONDUCTS CLINICAL TRIALS, FOR CANCER. SHE'S CONDUCTED SEMINAL STUDIES AND IS ONE OF THE, IF NOT THE LEADER IN THE INTERNATIONAL COMMUNITY WORKING TIRELESSLY TO BRING IMMUNOTHERAPY TO THE TREATMENT OF CANCERS OF CHILDHOOD. NEEDLESS TO SAY, SHE'S BEEN PROLIFIC, PUBLISHED MORE THAN 100 PEER REVIEWED MANUSCRIPTS, MORE THAN 50 INVITED REVIEWS AND CHAPTERS, AGAIN, ALL IN HER AREA OF FOCUS. NOW, I LOVED READING THROUGH HER CV IN PREPARATION. HER FIRST PAPER, SHE WAS SENIOR AUTHOR. SI GOT TO HEAR MORE ABOUT THIS. I FEEL SORRY FOR THE RABBIT. BUT THAT WAS FOLD BY HER SECOND AND THIRD PAPERS. FIRST AUTHOR ON PAPERS IN BLOOD ON T.C. REGENERATION AND LYNCH NODE DEPLETION AFTER BONE MARROW TRANSPLANTATION AND INTENSIVE CHEMOTHERAPY. THAT WAS FOLLOWED BY HER FIFTH AUTHOR IN THE JOURNAL OF MEDICINE. THAT BEGAN HER CAREER THAT HAS REALLY CONTINUED IN THIS IMPORTANT AREA. FINALLY I HAVE TO END ON A PERSONAL NOTE. SHE IS A TRULY PROUD AND LOVING MOTHER OF TWO WONDERFUL SONS, I'M PRIVILEGED TO HAVE HER NOT ONLY AS MY BOSS BUT ALSO AS A NEIGHBOR AND FRIEND. SO PLEASE JOIN ME IN WELCOMING DR. MACKALL, A GREAT SCIENTIST, A GREAT INVESTIGATOR, INNOVATIVER, LEADER, AND A TRULY GREAT TEACHER. WITH THAT -- >> THANKS. IF YOU EVER WANT TO THROAT YOUR ON THE GROUNDEN, HAVE ALLEN WAYNE INTRODUCE YOU, A TRUE MASTER. THANK YOU VERY MUCH. VALUED COLLEAGUE. SHAH SO MUCH FOR INVITING HE TO SPEAK HERE. THIS IS A REALLY HONOR AND I TOOK IT SERIOUSLY WHEN I GOT THE INVITATION. I REALLY STEPPED BACK AND SAID I CAN TALK ABOUT MY WORK. I'VE BEEN HERE LONG ENOUGH, MOST OF YOU HAVE HEARD ABOUT MY WORK AT SOME POINT OR ANOTHER. SO I DECIDED TO DO SOMETHING COMPLETELY DIFFERENT. TO STEP BACK AND THINK ABOUT WHAT WE'RE ALL DOING HERE, AIMING TO DO IN THE HATFIELD CLINICAL RESEARCH CENTER. MOVING THE TREATMENT OF MEDICINE FORWARD AND IN OUR CASE, REALLY TRYING TO DEVELOP NEW THERAPIES. AND WHAT I DECIDED TO DO WAS TO STEP BACK AND THINK ABOUT EXACTLY HOW PROGRESS IS MADE IN THIS AREA. WHAT THE CHALLENGES ARE. AND MAYBE BEGIN TO UNDERSTAND SOME PATTERNS OF THE WAY THESE THINGS ACTUALLY GO DOWN. THEY ASKED ME TO PUT IN THIS SUBJECTIVE SLIDE. IT'S GOOD, AGAIN, THIS IS A FREE WHEELING TALK. SO IT WILL TRY TO REIGN IT IN A LITTLE BIT. WHAT I HOPE WE DO TODAY IS REVIEW PATTERNS OF SCIENTIFIC PROGRESS WITH A FOCUS ON THE FACTORS THAT DISTINGUISH BASIC FACTORS FROM TRANSLATIONAL RESEARCH. THE KEY WORD, PATTERNS, NOT SO MUCH THE CONTENT OF WHAT I WANT TO TALK ABOUT BUT TO STEP BACK AND LOOK AT THE PROCESS OF THE WAY THESE THINGS OCCUR. I WANT PEOPLE TO GET SOME UNDERSTANDING OF THE FACTORS THAT THREATEN THE DEVELOPMENT OF SUCCESSFUL NEW THERAPIES. AND BY THE WAY, WHILE WE'RE DOING THIS, I WANT TO HAVE SOME FUN. I WANT TO SHARE WITH YOU WHAT I THINK ARE SOME OF THE MOST EXCITING DEVELOPMENTS IN TRANSLATIONAL BIOMEDICAL RESEARCH THAT HAVE HAPPENED OVER THE PAST 50 YEARS, FOCUSING IN THE AREAS OF CANCER AND IMMUNOLOGY. THIS IS A FIELD THAT I KNOW. BUT I HOPE THAT SOME OF THE PRINCIPLES THAT WE TALK ABOUT MIGHT HAVE RELEVANCE TO YOUR OWN INDIVIDUAL FIELDS. SO THIS IS GOING TO BE PART QUIZ SHOW. PART HISTORY LESSEN. PART SCIENTIFIC SEMINAR. OKAY? SO FIRST QUESTION FOR THE QUIZ SHOW. WHO DISCOVERED ONCOGENES? ANYBODY CAN SAY. COME ON, CAROL. CINDY? >> [INAUDIBLE] >> OKAY. MAYBE. OKAY. I'M GOING TO SAY HAROLD VIETNAM VETERANIS AND BIKE MICHIGAN OP. ONE COULD TAKE ISSUE. BUT CERTAINLY, THEY DID SEMINAL WORK THAT IMPROVED OUR UNDERSTANDING OF ONCOGENES. THEY STUDIED SIR COMA VIRUS, A VIRUS KNOWN TO INDUCE CANCER IN NORMAL CELLS. AND THE -- THEY WERE ABLE TO SHOW THAT THEY REALIZED THEY WANTED TO FIND OUT THE VIRUSES, THE GENES THAT WERE CAUSING CANCER. THESE VIRUSES, SINCE THEY DON'T HAVE 20,000 OR 100,000 GENES WHICH PEOPLE THOUGHT AT THE TIME, THEY ONLY HAD A FEW GENES. SO IDENTIFYING THOSE ONCOGENES WOULD PERHAPS BE EASIER, IF YOU STARTED WITH A VIRAL GENOME. IN THIS CASE, THE VIRUS WAS CALLED VSARC. THEIR VOTEABLE DISCOVERY, VERY-SRC, A VIRAL ENCODED GENE, ORIGINATED IN THE HUMAN GENOME. IT WAS ACQUIRED BY THE VIRUS DURING A REPLICATION OF LONG AGO. ARGO, THE CONCLUSION WAS DROWN, THAT V-SRC, IS A PROTO ONCOGENE THAT EXISTS IN OUR OWN DNA AND CONTRIBUTES TO TUMOR DEVELOPMENT. THIS WORK OCCURRED BETWEEN 19 # 0, 1976 AND THEY GOT THE NOBLE IN 1989. INCIDENTALLY, DESPITE SUBSTANTIAL INVESTMENT. SRC INHIBITORS HAVE NOT BEEN DEMONSTRATED AGAINST HUMAN CANCER. I FOCUS ON THE NOBLE PRIZE. WHO WON THIS YEAR FOR PHYSIOLOGY OR MEDICINE? ANYBODY KNOW? SO GIRDIN? AND YOMINACHA. THIS IS FOR THEIR WORK IN STEM CELLS. HE WAS THE FIRST TO SHOW THAT YOU COULD TAKE THE NUCLEARULOUS, PUT IT IN A GERM CELL. THAT COULD DIFFERENTIATE AMONG MULTIPLE LINEAGES. THAT MAY NOT SURPRISE US TODAY. YOU CAN IMAGINE IN 1960, THIS WAS EARTH SHATTERING, IMPLIED THAT IN THE DNA OF ALL OUR CELLS, THERE ARE ALL THE GENES TO ENCODE FOR THE ENTIRE ORGANISM. IT WAS REALLY THE BASIS FOR CLONING. THEN SUBSEQUENTLY, YAMANAKA WAS ABLE TO IDENTIFY THE RECIPE IT TOOK TO MOVE ONE OF THESE DIFFERENTIATED CELLS ALL THE WAY BACK. THAT'S FOUR YEARS OF TIME THAT THIS WORK OCCURRED OVER. SOME OF THE ONES THAT I PARTICULARLY LIKE, THAT I THINK ARE REALLY COOL, SOME OF THE NOTABLE DISCOVERIES AND PHYSIOLOGY IN MEDICINE. I LOVE THE WORK ABOUT PROJECTION, IT'S NOVEL, UNDERSTANDING HOW TILAMERE MAINTENANCE IS PREVENTING SIN NECESSARY THINGS IN CELLS. NEW COOLS WE HAVE FOR UNDERSTANDING IMPORTANT JEANS IN CELLS, BUT ALSO WAYS GENES ARE REGULATED. CRAIG AND ANDREW INFORMATION A FOUR YEAR PERIOD OF TIME. RESTRICTION, ANYBODY WHO IS A SERIOUS IMMUNOLOGIST KNOWS THAT THE SIRIOUS FIELD OF T. CELL BIOLOGY STARTED WHEN THEY FIGURED OUT WHY THE RESPONSES TO A CERTAIN VIRUS IN A GIVEN MOUSE WAS RESTRICTED AND COULDN'T BE TRANSFERRED TO OTHER MICE, BECAUSE THEY WEREN'T RECOGNIZING ELEMENTS OF THE VIRUS, THEY WERE RECOGNIZING IT IN THE CONTEXT OF -- INCREDIBLE WORK DEMONSTRATING WITH ONLY, ABOUT 25,000 GENES IN THE GENOME, WE GET MILLIONS OF DIFFERENT ANTIBODY SEQUENCES BECAUSE YOU CAN REARRANGE THE ORDER IN WHICH THESE GENES ARE ENCODED. ABOUT 7 YEARS TIME. SO WHY GO THROUGH ALL THIS? BESIDES IT BEING FUN TO LOOK AT SOME OF THE MOST AMAZING DISCOVERIES IN THE LAST 50 YEARS? I WANT TO LOOK FOR PATTERNS. THESE ARE, I THINK, AMONG THE SEMINAL DISCOVERIES IN BASIC SCIENCE. WHAT YOU OFTEN SEE, AND WHEN YOU READ ABOUT PEOPLE TALKING ABOUT THEIR WORK, THERE IS AN INCREDITAL EUREKA EFFECT. THE INVESTIGATOR KNEW THERE WAS A NAGGING QUESTION. IT KEPT THEM UP AT NIGHT. ALL OF A SUDDEN, THEY FIGURED IT OUT. IT HAPPENED RELATIVELY QUICKLY OVER A PERIOD OF TIME THAT ONE COULD ARGUE, COULD BE QUITE SHORT. NOW, CLEARLY THEY WERE ENABLING INSIGHTS THAT PROVIDED ESSENTIAL ELEMENTS TO MAKE THESE SCOFFRIES POSSIBLE. WHEN YOU LOOK AT IT, THE DISCOVERY PHASE OCCURRED OVER A RELATIVELY SHORT PERIOD OF TIME. IT WAS ALSO CONDUCTED GENERALLY WITHIN RELATIVELY SMALL GROUPS. IT'S ALWAYS REAL COOL, I THINK, THAT THE ENTHUSIASM THAT THESE DISCOVERIES GENERATE WITHIN THE SCIENTIFIC COMMUNITY TENDS NOT TO DIMINISH WITH TIME. YOU KNOW THAT THIS INSIGHT THAT THEY MADE WAS SEMINAL, IT WAS CRITICAL FOR FURTHER UNDERSTANDING OF EVERYTHING ELSE THAT CAME AFTER. SO CLEAR LINK TO MEDICAL PROGRESS IS NOT A MAJOR FACTOR IN DETERMINING THE IMPORTANCE. SO THIS IS HOW, I THINK, YOU COULD LAY OUT A TYPICAL PATTERN OF DISCOVERY IN BASIC SCIENCE. YOU GOT ACTION THAT HAPPENS OVER A RELATIVELY SHORT PERIOD OF TIME. AND THERE IS THIS EUREKA EFFECT THAT IS FIRST CLEAR TO THE SCIENTIST, BUT ULTIMATELY BECOMES CLEAR TO THE COMMUNITY. THE ENTHUSIASM FOR THE WORK JUST SHOOTS UP. EVERYBODY REALIZES ONCE THEY SEE IT, THIS IS REALLY IMPORTANT. OVER TIME, THERE MIGHT BE SOME WAXING AND WANING. IN GENERAL, PEOPLE LOOK BACK AND THEY CONTINUE TO BELIEVE THAT THEY WERE ABSOLUTELY SEMINAL. ALL RIGHT, SO NOW LET'S MOVE ON TO SOME DIFFERENT TYPES OF PROGRESS. AND BACK TO THE QUIZ SHOW. WHO INVENTED THE LIGHT BULB? EDISON! I GOT MY STRAIGHT MEN IN THERE FOR THE PEOPLE THAT DON'T FOLLOW DEVELOPMENT OF SUCH THINGS. BUT WHEN YOU GO BACK AND LOOK AT WHO INVENTED THE LIGHT BULB, IT'S MUCH MORE COMPLICATED THAN THAT. THE FIRST ELECTRIC LIGHT CAN BE ATTRIBUTED TO A GUY NAMED HUMPHREY DAVIE. CALLED AN ARK LAMB, A WELDING TORCH. YOU HAD A BIG FLAME. IT REQUIRED CONTINUAL POWER AT VERY HIGH LEVELS. THERE WAS ALWAYS THE RISK OF FLAMMABILITY. BUT IT WAS AN ELECTRIC LIGHT. YOU COULD SAY IT WAS THE FIRST ELECTRIC LIGHT. BUT IT REALLY WASN'T PRACTICAL. 40 YEARS LATER, SO AGAIN WE GOT 40 YEARS TIME, THIS GUY, FREDERICK FIGURED OUT THAT IF YOU ENCASED THE BULB IN OXYGEN, IT WAS LESS LIKELY TO CATCH FIRE. SO YOU COULD GET THE LIGHT BUT NOT THE FIRE. AND IT TURNED OUT THAT OXYGEN WAS PART OF IT. IF YOU HAD A VACUUM, IT WORKED BETTER. 1845, J.W., THEN THIS JOSEPH SWAN IN 1878 CAME UP WITH A BETTER FILAMENT. THE PROBLEM WITH HIS, IT GAVE OFF SOOT. THAT WASN'T REALLY WORKING. THEN CAME THOMAS EDISON, 1879. WHAT HE REALLY DID WAS HE MADE A LITTLE BIT OF A BETTER FILAMENT. CARBONIZED BAMBOO BURNERS. HE POPULARIZED THE WORD FILAMENT ALSO AND HAD A BETTER VACUUM. THERE WERE INCREMENTAL ADVANCES HERE. SUBSEQUENT PATENTS WERE GIVEN OUT TO MORE IMPROVED CARBON FILAMENTS, AND OUR CURRENT SORT OF FILAMENTS CLOSER TO WHAT WE USE NOW REALLY WEREN'T DEVELOPED UNTIL 1913. AND SO IT'S NOT AN EASY ANSWER TO SAY WHO INVENTED THE LIGHT BULB. A LOT OF PEOPLE DID. IT WAS A SERIES OF INCREMENTAL ADVANCES. WHAT WE'RE TALKING ABOUT HERE IS THE DIFFERENCE BETWEEN DISCOVERY AND INVENTION. JUST TO -- I THINK WE ALL HAVE A GENERAL FEELING FOR THIS. TO REFER TO THE DICTIONARY. TO DISCOVER IS TO BE THE FIRST OR FIRST OF ONE'S GROUP TO FIND, LEARN, OR OBSERVE, TO GAIN KNOWLEDGE OR AWARENESS OF SOMETHING NOT KNOWN BEFORE, REVEAL OR EXPOSE. THE WHOLE EUREKA IDEA. TO INVENT IS TO PRODUCE OR CONTRIVE. SOMETHING PREVIOUSLY UNKNOWN. BY THE USE OF INGENUITY OR IMAGINATION. AND WHEN I FIRST READ THIS, I WAS KIND OF SURPRISED SAYING ENGINEOUTTY OR IMAGINATION, BUT WHEN YOU HAVE AN PATENT TORE AN INVENTION, PART OF IT IS BASED ON THE IDEA TO ENVISION THIS INVENTION WORKING DOWN THE ROAD. SO, INDEED, THIS INGENUITY OR ABILITY TO IMAGINE IS A CRITICAL PART OF THE PROCESS. I WILL ARGUE THAT DISCOVERY IS FOR THE MOST PART CHARACTERIZED WORK IN BASIC SCIENCE. INVENTION IS REALLY WHAT THOSE OF HUGHES ARE TRANSLATIONAL SCIENTISTS ARE ABOUT. WE'RE TRYING TO INVENT THINGS THAT WORK. AND AGAIN, SOME OF THIS THAT I'M TALKING ABOUT, THERE ARE INVENTIONS FOR DIAGNOSIS AND INVENTIONS FOR PREVENTION. THAT IS NOT THE AREA THAT WE WORK IN. WHAT -- THE AREA I'M TALKING ABOUT IS TRYING TO INVENT NEW THERAPIES. SOME OF THIS MIGHT OR MIGHT NOT BE RELEVANT SO MUCH TO THESE OTHER ARENAS. WHEN YOU'RE TALKING ABOUT SLAVING AWAY, TRYING TO FIGURE OUT A NEW WAY TO TREAT CANCER, OR TO CURE A DISEASE, YOU'RE TRYING TOO INVENT SOMETHING. YOU'RE GOING TO USE DISCOVERIES. THE PROCESS LOOK LIKE THE PROCESS OF INVENTION MORE THAN DISCOVERY. WHO CURED ALL? WALEED. RIGHT. WHO MIGHT BE CREDITED AS THE FATHER OF MODERN ALL THERAPY? SIDNEY FARBER. ALL THE CURE, IT'S NOT COMPLETELY CURED. WE HAVE ABOUT AN 85% SURVIVAL RATE. BUT I THINK ANYBODY WOULD ACCEPT THAT IT'S ONE OF THE MODERN SUCCESS STORIES. A SUCCESS STORY OF MODERN MEDICINE. WHEN DID IT START? WHAT DID IT TAKE TO GET THERE? IT STARTED IN 1947 WHEN THIS PATHOLOGIST AT HARVARD DEMONSTRATED THAT METABOLITES COULD INDUCE TEMPORARY REMISSIONS IN CHILDREN WITH ALL. THAT WAS REALLY EXCITING. 1947. 1950, THERE WAS A COUPLE WHO -- SCIENTIST WHOSE IDENTIFIED ANTI-METABOLITES THAT COULD MIMMICK DNA AND INTERFERE WITH CELL GROWTH. THEY DESIGNED THESE THINGS FOR THAT PURPOSE, CREDITED AS BEING THE FIRST DESIGNER DRUGS. THIS JOHN KID PUBLISHED IN 1953 THAT YOU COULD INDUCE REMISSIONS IN GUINEA PIGS USING -- YOU COULD INDUCE REMISSIONS OF LYMPHOMA USING GUINEA BIG SERUM. THIS OCCURRED NOT BE NECESSARILY KILLING THE CELLS DIRECTLY BUT BY STARVING THEM, BREAKING DOWN AN ESSENTIAL AMINO ACID FOR THE TUMOR. 1960s, THIS GUY, J. ARMSTRONG WAS LOOKING FOR A NEW DRUG FOR COWS AND STUMBLED UPON -- THIS ISN'T WHAT HE WAS LOOKING FOR BUT IT LED TO TESTING IN LEUKEMIA. HERE WE ARE, 1947, ALL THE WAY TO THE 60s BEFORE WE EVEN HAVE OUR DRUGS IN PLACE TO BEGIN TO APPROACH THIS DISEASE. AND WHAT YOU SEE HERE IS THAT A.L.L. WAS CURED BY MANY PEOPLE. LOOKS LIKE THE INVENTION OF THE LIGHT BULB THAN THE DISCOVERY OF ONCOGENES. YOU HAVE A SERIES OF INCREMENTAL ADVANCES OCCURRING OVER THE 1960s TO EVEN NOW IN THE MID 2000s. NOW, THERE WERE SEMINAL ADVANCES. FOR ME, WE HAD THE NOTION YOU HAD THE PROXLAXIS OR THIS ALL OCCURRED IN THE BRAIN BUT STILL, WHEN YOU LOOK AT IT, YOU CAN'T POINT TO ONE THING OR ANOTHER AND SAY THIS IS IN AND OF ITSELF WHAT KILLED A.L.L. THIS WAS A SERIES OF INCREMENTAL ADVANCES. TWO WROTE AN EDITORIAL, A NICE REVIEW ARTICLE IN 2006 IF YOU WANT TO READ ABOUT THE CURRENT STATUS OF A.L.L. THERAPY AND HOW THIS DISEASE WAS CURED. YOU READ THIS AND YOU THINK YOU'LL FIND SOMETHING THAT IS REALLY INTENSE SCIENCE. BUT WHAT YOU FIND IS A BUNCH OF LITTLE THINGS. THAT ADDED U TO A BIG THING. IDENTIFY THE ACTIVE DRUGS, RISK STRATIFY, YOU HAD TO AVOID PHARMACOKINETIC INTERACTIONS, LONG THERAPY, SHORT THERAPY,. YOU HAD TO INTENSIFY THERAPY. IF YOU DID IT TOO MUCH, PATIENTS DIED OF TOXICITY. PROLONGED MAINTENANCE THERAPY. SOME THINGS ARE MUNDANE. DO BETTER WHEN YOU TAKE THE JUGS IN THE EVENING, NOT WITH MILK. THERE ARE PRETTY EXCITING SCIENTIFICALLY ELEGANT THINGS SUCH AS INCLUDING AMAT ANYBODY FOR THE HI RISK AND BONE MARROW TRANSPLANT PLAYED A ROLE. THERE IS A LOT OF INCREMENTAL PROGRESS. LET'S LOOK AT THE NATURE OF PROGRESS WHEN IT COMES TO BASIC SCIENCE VERSES TRANSLATIONAL. WE HAVE CONCEPTUAL HERE VERSES INCREMENTAL ADVANCES. THINGS THAT HAPPEN OVER A RELATIVELY SHORT PERIOD OF TIME IN BASIC SCIENCE, AND LONG SLOGS IN TRANSLATIONAL SCIENCE. OFTEN THESE DISCOVERIES ARE MADE BY SMALL GROUPS, HIGHLY FOCUSED. BUT IN TRANSLATIONAL SCIENCE YOU HAVE MANY DIFFERENT PEOPLE, MULTIPLE DISCIPLINARY TO COME TOGETHER. YOU KNOW HOW THE TRICK OF THE QUESTION IS WHO INVENTED SOMETHING, USUALLY IT'S NOT ONE PERSON. AND USUALLY IT'S NOT TWO PEOPLE OR THREE PEOPLE. BUT LET'S SAY IF YOU HAD TO ATTRIBUTE SOMETHING TO BONE MARROW TRANSPLANTATION, WHO WOULD YOU ATTRIBUTE IT TO? THOMAS WAS GIVEN THE CREDIT, WON THE NOBLE PRIZE IN 1990. AND I THINK IT'S INSTRUCTIVE TO GO BACK AND LOOK AT THE HISTORY OF THE DEVELOPMENT OF THIS THERAPY. HE WENT TO MEDICAL SCHOOL AT HARVARD IN THE 40s. AT THAT POINT HE BECAMENISTED IN LEUKEMIA. NOW, HE WAS FOLLOWING MOUSE STUDIES. NOTED THAT INVESTIGATORS IN THE MOUSE HAD SHOWN THAT YOU COULD EITHER SHIELD THE SPLEEN, WHEN YOU RADIATE A MOUSE AND IT COULD RECOVER, OR GIVE AN INFUSION OF MARROW. EITHER ONE WOULD ALLOW THE MOUSE TO RECOVER. AT FIRST, THERE WAS SOME QUESTION AS TO WHETHER THIS IS DUE TO GROWTH FACTORS. SOME RELEASE OF GROWTH FACTORS OR PROTECTIVE FACTORS. THERE WAS SOME SEMINAL STUDIES IN 1959 THAT SHOWED THAT THE MICE IS THAT WERE PROTECTED BY MARROW INFUSION WOULD ACCEPT SKIN GRAFTS FROM THE SAME STRAIN OF DONORS, WHICH MEANT TO DON THOMAS AND COLLEAGUES THAT IT HAD TO BE CELLS, IT COULDN'T BE A RESTORATIVE FACTOR THAT RENDERED THESE ANIMALS ABLE TO ACCEPT THE SKIN GRAFT. IN 1955 HE MOVED TO COOPERSTOWN AND BEGAN TO PURSUE TRANSPLANTS IN HUMANS AND DOGS, OUTBRED ANIMALS. IN 1957, HE PUBLISHED THE MANUSCRIPT THAT ACCORDING TO HIS WORDS GOT EVERYTHING STARTED. I THOUGHT IT'S INSTRUCTIVE TO LOOK AT THIS MANUSCRIPT. I WAS ABLE TO GET IT FROM -- I DON'T KNOW IF I COULD GET THIS ONLINE. SOME I HAD TO GET FROM THE LIBRARY. THE NEW ENGLAND JOURNAL HAS A CONTEST RIGHT NOW FOR THE MOST INFLUENTIAL, MOST IMPORTANT MANUSCRIPTS IN THE LAST 20th CENTURY, 50 YEARS, THIS IS ONE OF THE FINALISTS. IF YOU THINK THIS IS THE MOST IMPORTANT MANUSCRIPT, GO IN AND VOTE FOR THIS. THERE IS 18 DAYS LEFT OR SOMETHING TO VOTE. LOOK AT THIS MANUSCRIPT. IT'S FASCINATING. SO THIS IS THE SUMMARY AND CONCLUSION, NEW ENGLAND JOURNAL PAPER. OBSERVATIONS FROM YEARS EXPERIENCE IN COLLECTING, STORING, USING HUMAN BONE MARROW ARE RECOUNTED. THE EFFECTS IN A SMALL SERIES OF PATIENTS OF IV INFUSION OF CELLULAR SUSPENSIONS OF MARROW ARE REVIEWED. IT MAY BE OBTAINED FROM FETAL, ADULT CADAVERS, PRESERVED IN APOLOGISTERAL, MINUS 80. AND ADMINISTERED TO PATIENTS WITH SAFETY. THE INDICATIONS, CONTRAINDICATIONS IN GENERAL POTENTIAL FIELD OF USEFULNESS OF MARROW TRANSPLANTATION ARE DISCUSSED. SO LET'S LOOK AT THE DATA. THESE WERE THE PATIENTS THAT WERE REPORTED. THERE WERE 6 PATIENTS. THE EFFICIENCY HAD CML. END STAGE. GOT 30-RADS. T.B.I., MARROW FROM ADULT CAD DARFURS. DIDN'T ENGRAFT, DIED WITHIN 24 HOURS. SOMEHOW CONCLUDED TO BE SAFE. [LAUGHTER] >> SECOND PATIENT HAD A CEREBRAL HEMORRHAGE. NO PREPARE RAIVE REGIMENT. RECEIVED MARROW FROM A LINE DONOR, THIS PATIENT DIDN'T NEED MARROW. NO ENGRAFTMENT, DEATH, 3 WEEKS. MULTI MIGHT LOMMA. GOT 600-RADS OF T.B.I. THIS IS WHAT HE SAW, THE TRANSIENT INCREASE IN BLOOD COUNTS. DEATH IN ONE MONTH. DOUBLE PATIENTS WITH METASTATIC CANCER. THE ONLY TWO THAT SHOWED ANY A GLIMMER GOT MORE T.B.I., NOT EXPECTED. WE -- I COULDN'T FIND WHAT HAPPENED TO THIS PATIENT. I PRESUME HE DIED, I DON'T KNOW. THE OTHER THING, AGAIN, IN THE INTEREST OF HAVING FUN HERE TODAY, IN THE CONCLUSIONS -- THIS IS THE FINAL PARAGRAPH, OF HISTORICAL SIGNIFICANCE BUT ALSO INTERESTING BECAUSE ONE OF THE THINGS THAT DROVE THE DEVELOPMENT OF THIS FIELD WAS THE FEAR OF RADIATION. THAT WAS THE BACK DROP UNDER WHICH ALL OF THIS WAS BEING TAKEN. HERE IS THE FINAL PARAGRAPH [READ SLIDE [ >> [INAUDIBLE] >> SO THIS IS 1957. THE NEXT REAL ADVANCE IN THIS FIELD, 1968. 11 YEARS LATER. THERE ARE TWO PAPERS IN LANCET. THIS -- BOTH WERE PROPOSING TO HAVE DONE A SUCCESSFUL BONE MARROW TRANSPLANT. THIS WAS A 22 MONTH OLD BOY WITH WITH -- HAD GRAPH FAILURE, A SECOND INFUSION. TURNED OUT HE DIDN'T ENGRAFT. WE DIDN'T KNOW THAT UNTIL LATER. HE WAS NOT REALLY CREDITED FOR THE FIRST. THE FIRST SUCCESSFUL BONE MARROW TRANSPLANT IS CREDITED TO BOB GOOD'S GROUP. THIS 5 MONTH OLD BOY WITH ESSENTIALLY -- GOT APLASIA, ANOTHER INFUSION, AND THE REPORTING WAS DONE AT TWO YEARS, GOOD LONG FOLLOW UP, IN GOOD CONDITION. THIS IS PROBABLY THE FIRST REAL SUCCESS. THEY STARTED THIS IN 15955. THIS IS 1968. OKAY? BEFORE YOU HAVE EVEN ANY GLIMMER OF SUCCESS. SO THERE CLEARLY WAS A PERIOD OF DARK DAYS. THERE WAS A REOWE WRITTEN IN 1970, ALL REPORTED HUMAN BONE MARROW TRAN PLANTS, 203 CASES, 152 DIED. ONLY 11 SHOWED ANY EVIDENT OF TAKE AND THREE SURVIVES OF THOSE. ANYBODY LOOKING HAS TO THINK MY GOODNESS, HAS THIS GOT ANY PROMISE WHATSOEVER? AND THERE WAS A LOT OF, I THINK, DISSATISFACTION IN THE MEDICAL COMMUNITY. THERE WAS A LOT OF PUSH BACK. THIS WASN'T SOMETHING THAT WAS BEING FUNDED GLEEFULLY. THIS IS AFTER I ARRIVED AT THE NIH, ONE OF OUR MENTORS, WAS ANTI-BONE MARROW TRANSPLANT. REMOTE THIS, BONE MARROW FOR LEUKEMIA, LAME STOCKING HORSE. WHAT IS THE FUTURE? EVEN IF WE ACCEPT THE INFLATED SURVIVAL RATES WHICH ARISE FROM PATIENT COLLECTION, THE SUCCESS IS LIMITED. MAINLY BECAUSE THE PREPARE RAIVE REGIMENTS, STILL FREQUENTLY FAILED OR ERADICATE LEUKEMIA. IF YOU PICK UP THIS NICE REVIEW IN 11. HISTORY OF BONE MARROW TRANSPLANT, YOU GET A LITTLE BIT OF THE FEELING. I COULDN'T FIND A LOT OF PRIMARY DATA. THERE WAS MUCH SCEPTICISM DURING THAT TIME AND A LOT OF PEOPLE THAT DIDN'T BELIEVE IN BONE MARROW TRANSPLANT. IT'S A MIRACLE THAT THE FIELD DIDN'T DIE. I WAS LUCKY ENOUGH TO HAVE LUNCH WITH DON THOMAS ONCE. MAYBE SOME KNEW HIM. MELINDA EVIDENTLY WENT FISHING WITH HIM. I WASABLING TO ASK, HOW DID YOU KEEP GOING WHEN EVERYBODY WAS TELLING YOU THAT WHAT YOU WERE DOING WAS AT BEST HOPELESS, AND AT WORST, UNETHICAL? WEREN'T YOU -- DIDN'T YOU START TO SELF-EXAMINE, WORKING YOU WERE BARKING UP THE WRONG TREE? HE SAID NO, I REALLY ALWAYS THOUGHT I HAD ANOTHER QUESTION THAT NEEDED TO BE ANSWERED. I HAD SOLUTIONS IN MY OWN MIND THAT FOR EACH OF THE PROBLEMS WE WERE FACING, POTENTIAL SOLUTIONS. SO THE SUCCESSES OF BONE MARROW TRANSPLANT DID OCCUR EVENTUALLY, AND A SERIES OF ADVANCES OVER THE COURSE OF 50 SOME YEARS. ACCURATE TECHNOLOGIES, EFFECTIVE TREATMENT OF FEVER, TRANSFUSION SUPPORT, OPPORTUNITY -- YOU HAD TO ENROLL THE RIGHT PATIENTS, ACCURATELY INMUMERATE STEM CELLS, ON AND ON. BUT THE POINT IS THAT UNLIKE THE PATTERN FOR SCIENTIFIC DISCOVERY WHERE YOU THREAT THE EUREKA MOMENT, EVERY ONE SAYS THIS IS REALLY COOL AND IT STAYS COOL, THERE IS A DIFFERENT PATTERN FOR THE DEVELOPMENT OF NEW THERAPIES. YOU HAVE THE EUREKA MOMENT WHERE YOU SEE A PROMISING EFFECT. ONE OR SEVERAL GROUPS ENVISION WHAT THE FUTURE CAN BRING. I WOULD ARGUE INHERENT TO THE DEVELOPMENT OF THESE THERAPIES, ESPECIALLY IF THE EUREKA MOMENT IS VERY EXCITING, YOU'VE GOT THE SECOND STAGE AND THAT'S DISAPPOINTMENT. THE PROMISE OF THE THERAPY DOESN'T LIVE UP TO EXPECTATIONS, THE SERIES OF DISAPPOINTMENT IS FOLLOWED BY THE LONG SLOG, IT TAKES MANY DECADES. AND THE SHAPE OF THIS CURVE CAN VARY. THE HEIGHT OF THE ENTHUSIASM, THE STEEPNESS OF THE DECLINE. WHAT I'M GOING TO ARGUE IS THAT THIS PATTERN OF INCREDIBLE PROMISE FOLLOWED BY INCREDIBLE DISAPPOINTMENT AND THE LONG SLOG IS WHAT WE SEE FOR MOST OF THE NEW THERAPIES THAT COME DOWN THE PIKE. AND ONE OF THE THINGS I JUST WANT TO SAY ON THIS, I GUESS WE GO PREVIOUS, ONE OF THE INTERESTING THINGS, ONCE YOU GET THIS KIND OF INCREMENTAL ADVANCE GOING, IT TAKES ON A LIFE OF ITS OWN. IT BECOMES A REAL ADVANCE. SOMETIMES MISLEADING BECAUSE IT'S OFTEN BASED ON SMALL PATIENTS SERIES, AND SHORT FOLLOW-UP. BUT THIS KIND OF PROGRESS IS REAL PROGRESS. IT'S -- ONCE YOU GET BACK TO WHERE YOUR BASELINED, THE THING HAS TELEPHONED A MOMENTUM OF -- DEVELOPED A MOMENTUM OF ITS OWN. THERE WERE STILL CONTROVERSY IN THE FIELD IN 1990. BUT IT'S CLEARLY ACCEPTED AS A VERY IMPORTANT MODALITY FOR TREATMENT TODAY, YET WE CONTINUE TO IMPROVE UPON BONE MARROW TRANSPLANT. THE MORTALITY IN THE LAST DECADE HAS CONTINUED TO DECLINE SIGNIFICANTLY. AND WHAT ONCE WAS NOW A VERY HIGHLY TOXIC THERAPY IS SOMETIMES ADMINISTERED AS OUTPATIENT. PROGRESS BEGETS PROGRESS. BACK TO ADD THE FACT THAT THE FOURTH ELEMENT HERE, THAT AGAIN, FOR BASIC SCIENCE, ENTHUSIASM USUALLY PERSISTS REGARDLESS OF PRACTICAL APPLICATION. FOR TRANSACTIONAL SCIENCE, THE ENTHUSIASM CAN VARY GREATLY AND HEAVILY IMPACTED BY EXPECTATIONS. NOW TO MOVE ON TO ANTIBODY THERAPY. PAUL, WHEN HE SAW THE WORK BEING DONE IN 1890 -- WHO WON THE FIRST NOBLE PRIZE FOR NOTING YOU COULD PROTECT RODENTS FROM DIPHTHERIA FROM TRANSFUGS OF BLOOD. HE REALIZED THERE WAS SOMETHING IN THE BLOOD THAT COULD -- HE TARGETED THE TERM. IT WASN'T UNTIL THE 60s THAT WE FIGURED OUT WHAT THE NATURE OF THE HUMORAL PROTECTANT MOLECULE IS, THE ANTIBODY, AND THE ANTIBODY STRUCTURE WAS DECIPHERED. THEN, OF COURSE, THE MAJOR LEAGUE BREAK THROUGH COMING IN 1975 BY KOHLER AND MILLSTEIN. AND IT'S AN INTERESTING STORY. THEY DID THEIR WORK BECAUSE THEY WANTED TO UNDERSTAND THE FINTY MATURE ASIAN. OVER THE COURSE OF RESPONSE, ANTIBODIES START OUT GOOD BINDERS AND BECOME BETTER AS THE RESPONSE GOES ON. THIS IS CALLED AFFINITY MATURE RATION. PEOPLE DIDN'T UNDERSTAND WHAT IT WAS ALL ABOUT. KOHLER MILLSTEIN WANTED TO THEIR THEIR HANDS ON A SIGNIFICANT AMOUNT OF AN ANTIBODY DIRECTED AGAINST THE PARTICULAR ANTIGEN TO FIGURE OUT HOW THIS HAPPENS. SO THEY GENERATED FUSIONS FROM A ANTIBODY PRODUCER, A CELL THAT THEY GOT FROM MIKE POTTER. HE HAD BEEN COLLECTING CELLS FROM PATIENTS HERE, MYELOMA PATIENTS. THEY FUSED IT WITH A HEALTHY B CELL. EITHER FROM AN IMMUNE NICED MOUSE OR NOT. THEY NOTICED YOU COULD CREATE UNLIMITED SUPPLIES OF A PARTICULAR ANTIBODY. UNFORTUNATELY, STILL DIDN'T AFFINITY MATURE. THEY DIDN'T GET THEIR QUESTION ANSWERS. BUT ... BOTH KOHLER, MILLIONSTEIN AND THE COMMUNITY RECOGNIZED QUICKLY THIS COULD HAVE IMPORTANT IMPLICATIONS. THEY GOT THEIR NOBLE PRIZE THREE YEARS AFTER THEIR FIRST WORK. FOR YOUNG PEOPLE THAT DON'T REALLY UNDERSTAND HOW THIS IS DONE I'M SHOWING THIS PICTURE AGAIN. IT'S COOL BECAUSE IT'S TRULY SYNTHETIC BIOLOGY. THIS DOESN'T OCCUR IN NATURE. THIS IS SOMETHING COMPLETELY CONTRIVED IN THE MIND OF A SCIENTIST. SO THEY IMMUNIZE A MOUSE TO STIMULATE ANTI-PRODUCTION. B CELLS ARE MAKING ANTIBODY OF A GIVEN SPECIFICITY BUT THEY'RE NOT IMMORTALIZED. THEY FUSE THE B CELLS WITH THESE CELLS, AND THEY GET A WHOLE ARRAY OF THEM. AND THEN THEY CLONE THEM OUT. ISOLATE THEM, SO WE KNOW ONLY ONE CELL EVER PRODUCES ONE ANTIBODY AT A TIME. SOME OF THE CELLS ARE PRODUCING ANTIBODIES OF INTEREST. THAT IS HOW ANTIBODIES WERE MADE. ANYBODY LOOKING AT THIS COULD SAY MAGIC BULLETS, THIS WAS A RU EEKA MOMENT. ENTHUSIASM. THIS IS GOING TO WORK! I DON'T KNOW IF YOU KNOW LEE NADLER, VERY BRIGHT. SPENT A LOT OF HIS CAREER AT HARVARD, STU, VERY EXCITED TO GET THIS FIRST CLINICAL TRIAL DONE IN A PATIENT WITH LYMPHOMA. PUBLISHED IN CANCER RESEARCH. SOMETHING DIDN'T GO AS WELL AS EXPECTED. IT WAS A NICE PAPER BUT IT WASN'T A LANDMARK PAPER. RESULTS BELOW DEMONSTRATE THAT PATIENT NB TOLERATED INFUSION OF THE ANTIBODY WITHOUT ANY SIDE EFFECTS. TUMOR CELLS WERE CLEARED. MORE SIGNIFICANT RESPONSE WAS PROBABLY PREVENTED BY CIRCULATING ANTIGEN. LACK OF CLINICAL TOXICITY, BLAH, PLAY, BLAH. SO WHAT YOU HAVE, THEN, WAS FROM THE PERIOD OF ABOUT 1978-79 TO 1998, YOU HAVE THE DARK DAYS FOR MONOCLONAL ANTIBODIES. I WILL TELL YOU, I REMEMBER WHEN I CAME HERE TO NIH, I THOUGHT MONOCLONAL ANTIBODIES HAD PROMISE. YOU TRIED TO TALK TO PEOPLE NOT IN THE FIELD ABOUT MONOCLONAL ANTIBODIES? ALL YOU HEARD IS THESE DON'T WORK. WE TRIED THAT. THIS IS SOME DATA TO KIND OF CONFIRM THAT. THIS IS FROM 1998. [READ SLIDE] 20 YEARS IT TOOK, REALLY, FROM GOING FROM THIS INCREDIBLY POINT OF EXCITEMENT TO NOT HAVING ANYTHING TOO MUCH TO BRAG ABOUT. WE NOW KNEW COMING INTO THE LATE 90s, THE GENERAL FAILURE WAS DUE TO TWO MAJOR PRONES, IMMUNOGENICITY AND THE FACT THEY PRODUCED WEAK ACC. THIS WAS THE BEGINNING OF THE NEW PHASE. THAT WAS THE ACTIVITY, PUBLISHED IN 1997. IT WAS SPECIFICALLY SELECTED FOR ITS ABILITY TO ENGAGE FC RECEPTORS TO REDUCE VIGOROUS ADCC. PHASE 2 TRIALS IN PANTS WITH LOW GRADE LYMPHOMA SHOWED MILD EFFECTS. 46%, VERY EXCITING RESPONSE RATES. 1998, THE FIRST REPORTS WITH HERCEPTIN, SIMILAR, WITH A HUMANIZED MONOCLONAL. IMPROVED AFFINITY. THEIR ACTIVITY RATE WASN'T SO GOOD AS A SINGLE AGENT BUT SAID LET'S COMBINE IT WITH CHEMOTHERAPY CHEMOTHERAPY. AND THEY GAVE IT RECRYPTEN, HAD A 24% RESPONSE RATE, MUCH BETTER THAN THE 10% RATE WITHOUT IT. SO THIS WAS THE BEGINNING OF A REALLY EXCITING TIME. SO THERAPEUTIC AND DISCUSSION FROM THIS TRIAL, THERAPEUTIC ANTI-TUMOR ANTIBODIES LONG PROPOSED AS AN ACT TRACTIVE APPROACH. THIS HAS NOT GAINED WIDE USE FOR A VARIETY OF REASONS. AGAIN, ALL THOSE THAT WE TALKED ABOUT. SO YOU SEE A VERY SIMILAR SHAPE OF THE CURVE. YOU HAD THE ANTIBODIES DISCOVERED IN '75 OR INVENTED. THE EUREKA MOMENT. FOLLOWED BY THE PERIOD OF DISAPPOINTMENT. AND THEN YOU HAVE THE LONG SLOG. I CAN TELL YOU THAT DURING THIS TIME MANY PEOPLE ABANDONED THE NOTION ALL TOGETHER. IT WASN'T EASY TO GET FUNDED FOR YOUR WORK IN MONOCLONAL ANTIBODIES. GENE THERAPY, THIS IS NEAR AND DEAR TO THE HEARTS HERITATE NIH. THE VERY FIRST WORK IN 1990. CONDUCTED FOR A GIRL WITH ADA DEFICIENCY. THE GENE WAS INSERTED, EARLY RESULTS OF THE RADICAL THERAPY LOOKED EXTREMELY PROMISEING. RESEARCHERS WERE OPTIMISTIC. WE'LL SHOW YOUNEW YORK TIMES BECAUSE IN THE MODERN AGE, MUCH OF THIS PLAYS OUT IN THE PUBLIC PRESS. THAT'S SOMETHING VERY DIFFERENT THAN WHAT HAPPENED 30 YEARS AGO. SO I THINK WE ALL KNOW THAT IN THE EARLY 90s, THERE WAS A LOT OF REASON TO THINK THAT GENE THERAPY WOULD TAKE THE FIELD BY STORM. AND THEN WE HAD 9 YEARS LATER, NOT ONLY HAD WE HAD A DECADE WHERE THE EFFICACY HAD NOT BEEN CLEARED BUT WE HAD SIGNIFICANT ADVERSE EFFECTS. FOR THOSE OF YOU WHO DIDN'T FOLLOW THIS FIELD, THE BIOTECH DEATH OF JESSE WAS ACTUALLY A CRITICAL BLOW TO THROUGH FIELD. JUST TO READ HERE FROM THE TIMES. [READ SLIDE] SO THE INTERIMOLOGY, IT'S NO LONGER THERAPY, IT'S AN EXPERIMENT CONDUCTED IN HUMANS. AS FAR AS GOVERNMENT OFFICIALS KNOW, JESSE'S DEATH WAS THE FIRST DIRECTLY RELATED TO GENE THERAPY, IMPLYING MAYBE THERE WERE MORE. EVERY REALM OF MEDICINE HAS A DEFINING MOMENT. POLIO, IN VITRO FERTILIZATION, THE WORLD'S FIRST TEST TUBE MAYBE. THIS IS A STAKE IN THE HEART OF GENE THERAPY. JESSE WAS AN 18-YEAR OLD STUDENT AT PENN WHO DID NOT HAVE A LIFE THREATENING DISEASE. HE HAD A TERRIBLE DISEASE, BUT IT WAS A DISEASE. SO IT COULD BE CONTROLLED, AT LEAST FOR MANY YEARS WITH SOME APPROPRIATE DIET. HE COULDN'T LEAD A NORMAL LIFE. HE CHOSE TO ENROLL AS AN ADULT, VERY YOUNG, ON A GENE THERAPY TRIAL OF AN ADENOVIRAL VECTOR TO REPLACE THE GENE. UNTIL JESSE DIED, THE GENE THERAPY WAS PROMISING, ESSENTIALLY, HIS BODY DEVELOPED AN IMMUNE RESPONSE TO THE GENES IN THE VECTOR AND DEVELOPED HEPATIC FAILURE AND DIED. FOUR YEARS AGO, THE ARE THEY GAVE GENE TRANSDUCED STEM CELLS TO KIDS WITH THE GAMMA C IMMUNODEFICIENCY. AND THEY FELT THAT THEY WERE ABLE TO CORRECT THIS. IN FOUR OR FIVE OF THE PATIENTS. CORRECTION OF THE IMMUNODEFICIENCY, ERADICATED INFECTIONS AND ALLOWED THE PATIENTS TO LIVE A NORMAL LIFE, 2002, APRIL. OCTOBER, 2003. A SCIENCE PAPER. LMO2 COLONIAL PROLIFERATION. THESE PATIENTS, SEVERAL, FOUR OF THE NINE WHO HAD HAD TAKE OF THE GENE THERAPY DEVELOPED LEUKEMIA THAT WAS DIRECTLY RELATED TO THE INSERTION OF THE VECTOR. SO YOU CAN IMAGINE THAT THE FIELD REALLY WAS IN A COMPLETE TAIL SPIN. AND SOMEBODY WHO WAS A RATIONAL PERSON LOOKING AT THIS COULD ARGUE THAT WE SHOULD WALK AWAY. IT'S NOT GOING TO WORK. BUT THERE WERE SEVERAL INVESTIGATORS THAT DID NOT DO THAT. THAT COMMITTED INVESTIGATORS, TRUE BELIEVERS PUSHED ON. AND HERE WE ARE, 2009, WITH SOME MORE EXCITING -- I'VE SELECTED ONE OF SEVERAL. BUT THIS HEMATOPOETIC STEM CELL THERAPY FOR A BAD DISORDER, A NEUROLOGICAL DISORDER. THERE WAS EVIDENCE THIS IS AN UNTREATED PATIENT WITH DEMYELINATION OVER THE COURSE OF 18 MONTHS, A TREATED PATIENT WHO HAD TAKE OF HIS VECTOR AND HIS GENE WAS EXPRESSED. AND APPEARED TO IMPROVE. SO HERE WE ARE BACK IN THE LAY PRESS. DECADES OF DASHED HOPES, MANY HAD ALL BUT GIVEN UP THIS IDEA. SO WHERE ARE WE NOW? IN THE PHASE OF GENE THERAPY? BECAUSE IT'S NOT DEAD AT ALL. I'M GOING TO DROP BACK QUICKLY TO THE SYNTHETIC BIOLOGY. IN '89 AND INVESTIGATOR HAD USED SOME INGENUITY AND IMAGINATION TO SEE HE COULD MAKE A BETTER T CELL RECEPTOR, COULD BIND LIKE AN ANTIBODY. THEREFORE COULD BE USED TO TARGET ANY CELL SURFACE RECEPTOR. I WANTED TO GIVE CREDIT TO [INDISCERNIBLE] WHO DID THIS WORK ON SABBATICAL IN STEVE ROSENBURG'S GROUP. THAT WAS 1989 HE DID THIS. TEN YEARS LATER, KARL JUNE AND OTHERS IN THE HIV FIELD TRANSDUCED T. CELLS WITH THESE CHIMERIC RECEPTORS. DIDN'T HAVE THE SECOND MALIGNANCIES. THIS WAS A PAPER FROM 2011 THAT USING RETROVIRAL VECTORS IN MATURE T. CELLS ACTUALLY COULD BE SAFE AND EFFECTIVE. THESE ARE THREE DIFFERENT TRIALS, EACH OF THESE LINES REFLECTED DIFFERENT PATIENTS THAT WAS GIVEN A RECEPTOR, FOR CD4. WHAT THEY'RE LOOKING AT IS THE PERSISTENT OF THE VECTOR OVER TIME. AND THE GOOD NEWS IS THAT THEY PERSISTED. AND THEY DIDN'T GO DOWN WITH TIME SUGGESTING THAT THEY WERE SILENCED OR THEY WERE RADICATED. AND THEY DIDN'T FO UP WITH TIME. SUGGESTING THAT THEY WERE BECOMING LEUKEMIA. SO THIS ABOUT AS GOOD AS YOU CAN HOME FOR A GENE THERAPY EXPERIMENT. THEN IN THE LAST COUPLE YEARS GENE THERAPY HAS HAD REALLY EXCITING EFFECTS AGAINST CANCER. AGAIN I'M SHOWING YOU THE LAY PRESS. A LOT OF THIS IS DRIVEN BY THE LAY PRESS, THE EXCITEMENT FACTOR AT LEAST. THERE IS EVIDENCE THAT YOU CAN TRANSDUCE T. CELLS WITH THESE CHIME MERIC RECEPTORS. YOU CAN ERADICATE LEUKEMIA. AT LEAST FOR A SHORT PERIOD OF TIME. THIS IS A NEW ENGLAND JOURNAL PAPER FROM 2011. BUT STEVE ROSENBERG'S GROUP HAS LED THE WAY ON THIS. USING ANTICD19 TARGETED CHIMERIC ANTIGEN RECEPTORS. WE, OURSELVES, THE ONLY DATA FROM OUR BRANCH, HAVE JUMPED ON TO THIS NOTION THAT GENE THERAPY MAY BE USED SAFELY TO TREAT CANCER. THIS IS A TRIAL LED BY ALLEN WAYNE. OF CD19 RECEPTORS FOR PEDIATRIC LEUKEMIA. OUR FIRST PATIENT TREATED A FIRST MONTHS AGO, 13-YEAR OLD WITH MULTIPLE RELAPSED LEUKEMIA. THIS IS STILL A BIG KILLER OF CHILDHOOD CANCER. TRAPSDUCEING MATURE T. CELLS, NOT STEM CELLS. A RETROVIRUS. I DON'T THINK ANYBODY IS USING RETROVIRUSES THESE DAYS BECAUSE OF THE EXPERIENCE WITH THE GAMMA C. BUT AGAIN, THESE KIND OF INCREMENTAL ADVANCES. WE'RE USING THIS SYNTHETIC T. CELL RECEPTOR, WHICH, AGAIN, CAN TARGET THE ANTIGENS ON THE LEUKEMIA AND RESTRICTED FASHION. AND WE'VE GOT EVIDENCE FOR CLINICAL ACTIVITY. THIS CHILD HAD 12% MARROW BLASTS, BEFORE TREATMENT, .6%. AFTER THE TREATMENT ON DAY 28. HE RECURRED AROUND DAY ONE HUNDRED. A SECOND PATIENT IS VERY INTERESTING TO US. THIS PATIENT GOT A MILLION CELLS PER KILOGRAM. A BIG SLUG. THE SECOND PATIENT, THE TEMPERATURE CELLS DIDN'T GROW. WE GAVE HER CELLS COMPASSIONATELY ASSUMING THEY WEREN'T ENOUGH TO AMOUNT TO ANYTHING. THEY WERE HERS, RATHER THAN TOSS THEM IN THE TRASH LET'S GIVE THEM TO HER. SHE WENT INTO REMISSION AT LEAST ON DAY 14, IN REMISSION, IT'S EARLY. BUT 15% OF THE T. CELLS ARE CAR POSITIVE. WITH A VERY, VERY SMALL DOZE OF THESE GENETICALLY ENGINEERED T. CELLS. SO I THINK JEAN THERAPY, THE SHAPE OF THE CURVE MIGHT VARY A LITTLE BIT. THERE WAS A LONGER PERIOD BEFORE THE ENTHUSIASM HAPPENED, THERE WAS SOME PATIENTS UNTIL THERE WERE EXCESSIVE TOXICITIES, WHICH NEARLY ECLIPSED THE ENTIRE FIELD. THEY NEARLY SHUT THE FIELD DOWN. THE FIELD HAD A VERY, VERY LOW PERIOD. AGAIN, YOU HAD THESE COMMITTED INVESTIGATORS, PEOPLE LIKE CINDY, OTHERS THAT STILL HAD QUESTIONS TO ASK, WAYS TO MAKE THIS THERAPY SAFER. AND SLOWLY BUT SURELY, THE LONG SLOG IS PAYING OFF. I BELIEVE THAT EVENTUALLY GENE THERAPY WILL FIND A ROLE IN MODERN MEDICINE. AND THAT IT'S SIMPLY WE CAN'T GO INTO THINGS NAIVELY, THAT WE HAVE TO PAY THE PRICE ALMOST OF THIS LONG SLOG TO UNDERSTAND THE THERAPY. I'M GOING TO TALK ABOUT A COUPLE THERAPIES THAT HAVEN'T YET BEEN, I THINK, ACTUALIZED. AND BECAUSE OF THE REAL ISSUE HERE, IT'S EASY WHEN YOU LOOK BACK. YOU SAY OH, WASN'T THAT GREAT, DON THOMAS KNEW TO FORGE AHEAD. THE GENE THERAPY PEOPLE, THEY FORGED AHEAD. NOW YOU HAVE NEW EXCITEMENT. IT'S EASY TO JUMP ON THE BAND WAGON NOW. WHEN YOU'RE IN THE DEPTHS, THE DOLE DROPS, AM I HOOKING MY WAGON TO SOMETHING THAT WILL GO FORWARD? OR IS THIS SOMETHING THAT WILL NEVER SEE THE LIGHT OF DAY? ONE OF THESE IS MOLECULARCALLY INFORMED THERAPY FOR CANCER. CANCER IS A GENETIC DISEASE. WE ALL KNOW THAT. IT'S ACCEPTED. THAT WAS PART OF THE WHOLE EUREKA EFFECT OF UNDERSTANDING PROTO ONCOGENES. I THINK WE ALSO HAD THE ENTHUSIASM BROUGHT ABOUT BY THE FACT THAT YOU CAN TARGET GENES AND KILL CANCER CELLS, AT LEAST IN THE POSTER CHILD DISEASE, CHRONIC MY LODGEINOUS LEUKEMIA WITH IMATINIB. WE KNOW TUMORS CAN BY DRIVEN BY DIFFERENT ONCOGENES. BY THE WAY IT LOOKS YOU CAN'T TELL WHAT'S DRIVING IT. THE CONVERSE IS TRUE. EVEN TUMORS THAT LOOK DIFFERENT MIGHT HAVE SIMILAR ONCOGENE DRIVERS. SO NEW TECHNOLOGIES ARE PROVIDING THE OPPORTUNITY TO IDENTIFY NEW ONCOJEEPS IN INDIVIDUAL TUMORS. YOU CAN IMAGINE, IMAGINATION IS RUNNING WILD. PEOPLE ARE REALLY EXCITED ABOUT THIS. AGAIN, MOST OF THIS PLAYS OUT IN THE LAY PRESS. MY NIECE ASKED ME, SHE'S IN A BOILING CLASS. SHE HAS TO HAVE NEWSPAPER ARTICLES ABOUT SCIENCE. AND COULD YOU HELP ME FIND THESE? I SAID CAN I HELP YOU FIND THESE? THIS IS LIKE EVERY SUNDAY I SIT DOWN TO READ THE LATEST MEDICAL ADVANCE IN THENEW YORK TIMES. OF COURSE THIS IS ALL OVER THE LAY PRESS. THIS IS AN EXAMPLE FROM JULY OF THIS YEAR. MORE THAN 200 VERSIONS, [READ SLIDE] PAY ATENSIONS TO THESE WORDS THEY USE. THEY PLAY TO THE ISSUE OF ENTHUSIASM. HYPE. SO THE PUBLISH STUDIED IS THE FIRST PART OF A SWEEPING EFFORT EXPECTED TO PRODUCE A FLOOD OF DISCOVERIES FOR A WIDE RANGE OF CANCERS. THERE ARE SO MANY DIFFERENT WAYS TO ATTACK THIS TUMOR TYPE, THE PRINCIPLE INVESTIGATOR SAID. WE HAVE AN OPPORTUNITY TO COMPLETELY CHANGE THE LANDSCAPE. THEN THERE IS THIS. RESEARCHERS CAUTION THAT ALTHOUGH MUCH IS KNOWN ABOUT THE GENETIC CHANGES, TREATMENT IS HAS NOT CAUGHT UP. IT WILL TAKE TIME. I DON'T WANT TO MINIMIZE THE SINGULAR IMPORTANCE OF THIS PAPER. IT IS TRANSFORMATIVE. WHAT DO YOU THINK THE PERSON READING THAT THINKS, IT WILL TAKE TIME? 3 OR 4 YEARS, 20 YEARS? A BIG DIFFERENCE. THIS WAS SORT OF ONE OF THE CLINICIANS, I THINK, THAT THEY INTERVIEWED FOR THIS PAPER. THOSE DRUGS HAVE YET TO BE DEVELOPED. BUT THE WORK CONFIRMS WHERE SOME OF THE DRUG DEVELOPMENT SHOULD BE GOING. THE NATURE PAPER EXPLAINS IT WILL NOT BE SIMPLE. IT CAN LEAD TO CLINICAL BENEFITS. HERE IS ANOTHER ONE. IT GETS MORE TO THE PERSONAL. THIS IS THE SORT OF SEQUENCING MAPS THAT YOU SEE, VERY HIGH TECH WORK IDENTIFYING GENOMIC ABERRATIONS IN TUMORS, EACH BEING A CHROMOSOME LINED UP. YOU CAN SEE THE INTERACTIONS BETWEEN THE PARTS OF THE GENOME, YOU CAN INTERROGATE DOWN TO INDIVIDUAL GENES AND PATIENT CELLS. HOLY COW, BETH, DR. JOHN GOLDMAN EXPLAINED. HER LIMP NODES SHRUNK TO A NORMAL SIDE, SKIN WAS NOT BRIGHT RED, THE ITCHINESS HAD SUBSIDED. BUT IT ONLY LASTED WEEKS. SEPTEMBER, THE CANCER WAS BACK. FOR NOW, THERE ARE NOT MANY DRUGS THAT CAN TARGET SPECIFIC GENE MUTATIONS IN THE CANCER CELLS. THE HOPE IS WHEN MORE DRUGS ARE DEVELOPED DOCTORS WILL TREAT CANCERS BY BLOCKING. SO WHAT I SEE IS THIS IS AN ERA WHERE WE'RE AT THE SORT OF HEIGHT OF THE ENTHUSIASM PHASE. THERE IS A LOT OF REASONS TO THINK IT WILL WORK. BUT WHEN YOU REALLY LOOK AT IT, AND YOU SAY HOW MANY DRUGS DO WE HAVE THAT HAVE SUCCESSFULLY TARGETED THESE ONCOGENES, THE ANSWER IS VERY FEW. I THINK WE HAVE TO BE CAREFUL AS THIS SORT OF ENTHUSIASM PHASE IS AT ITS PEEK THAT WE DON'T PLAY INTO IT. AND THAT WE SET UP MORE REALISTIC EXPECTATIONS, ALTHOUGH I'M NOT SURE IT'S ALL WITHIN OUR HANDS. I'M GOING TO END WITH THE AID VACCINE. THIS IS AN AREA WHERE ONE CAN ARGUE WE'RE SORT OF IN A LOW POINT AT THIS POINT. FOR THOSE THAT HAVEN'T FOLLOWED THIS, AGAIN, MOSTLY FROM THE LAY PRESS, IT FOLLOWS THE SCIENTIFIC LITERATURE CLOSELY. [READ SLIDE] 1984. OKAY. SO THEN IN 2008, A MUCH AWAITED TRIAL OF MERCK VACCINES FOR HIV COMES OUT. AND IT DIDN'T WORK. A ONCE PROMISING STUDY DEVELOPED BY THE U.S. WILL BE SCALED BACK AND MAYBE SCRUBBED, WILL SET BACK RESEARCH FOR YEARS. ONE OF THE PROBLEMS WAS IT DIDN'T NOT JUST WORK. THERE WAS A QUESTION OF WHETHER THE PEOPLE THAT WERE VACCINATED HAD INCREASED SUSCEPTIBILITY. IT WAS LIKE THE GENE THERAPY. WHERE IT WASN'T SO MUCH THAT IT DIDN'T WORK, WHICH CAUSES ENOUGH LACK OF ENTHUSIASM, BUT IT BECOMES THIS SORT OF ADVERSITY THAT YOU ENTER INTO. THIS IS REFLECTED IN ONE OF THESE STATEMENTS. THE AIDS HEALTHCARE FOUNDATION, LOS ANGELES BASED PROVIDER OF CARE, FOR 65,000 PATIENTS AND 20 COUNTRIES CALLED FOR A MORATORIUM ON HIV VACCINE RESEARCH. UNFORTUNATE THAT IT TOOK AN AIDS VACCINE TRIAL THAT MADE MORE PEOPLE BECOME INFECTED TO MAKE PEOPLE PAY ATTENTION AND STOP THIS RUN AWAY TRAIN. THERE IS KNOW VALIDITY TO THE IDEA THAT THERE WILL BE AN AIDS VACCINE. NOW ON THE OTHER HAND, IN 2009, THERE IS AN INTERESTING PAPER. IN THE NEW ENGLAND JOURNAL. SUGGESTING THAT IT'S THE TIVACCINE, THAT THERE MIGHT BE EFFICACY. SO IT'S THE BEGINNING OF THE MAYBE, THE FIELD IS FINGTO TURN THE CORN -- BEGINNING TO TURN THE CORNER. I'LL END THERE AND GO THROUGH SOME CONCLUSIONS. AND HOPEFULLY I PROVIDED YOU WITH SOME BASIS WITH WHICH TO LOOK AT WHATEVER FIELD YOU'RE WORKING ON IN TERMS OF DEVELOPING A NEW THERAPY AND REFLECT A BIT ABOUT WHERE YOUR THERAPY FITS IN THIS PATTERN. THE TAKE HOME POINTS I WANT TO MAKE. NUMBER ONE, IT DOESN'T HAVE TO BE SEXY TO BE IMPORTANT. AS A JOURNAL EDITOR I'M OFTEN FACED WITH THE ISSUE OF INCREMENTAL. AND I THINK WE ALL KNOW THAT INCREMENTAL IS OFTEN CONSIDERED A DIRTY WORD IN SCIENCE. IF YOU'RE INCREMENTAL YOU'RE NOT DOING ANYTHING ALL THAT IMPORTANT. BUT A SERIES OF ADVANCES CAN AND OFTEN DO ADD UP TO MAJOR ADVANCES. WE HAVE TO BE HONEST, EVERYTHING CAN'T BE CONCEPTUAL BREAK THROUGH. THEY HAVE TO BE FOLLOWED BY ADVANCES BEFORE SOMETHING THEORETICAL BECOMES PRACTICAL. NEW THERAPIES RESULT FROM THE WORK OF CRITICAL MASS OF COMMITTED INVESTIGATORS WITH SUPPORT OF SEVERAL DECADES, FOR THE PEOPLE WHO DECIDE THE FUNDING. I WILL TELL YOU THAT IT'S NOT EASY, WHEN THE HEAD OF THE NIH SAYS THAT YOU GUYS HAVE OVERSOLD THE FIELD OF GENE THERAPY. YOU RISK LOSING YOUR FUNDING ALL TOGETHER. AND I THINK IT'S REALLY IMPORTANT THAT THOSE OF US COMMITTED TO THERAPIES, BECAUSE WE BELIEVE THEY'LL WORK, THAT WE BE HONEST WITH OURSELVES AND BE HONEST WITH OUR BEN FACTORS, BE THEY GOVERNMENT, PRIVATE FOUNDATION FUNDING, OR COMPANIES. AND SET UP REALISTIC EXPECTATIONS, BECAUSE A LOT OF THIS IS ABOUT MANAGING EXPECTATIONS. WHEN YOU LOOK AT THE FIELDS THAT HAVE GONE THROUGH THIS TURMOIL, THERE ARE ONE OR SELF LEADERS WHO ARE IMPORTANT TO KEEPING THE FIELD ALIVE. YOU NEED PEOPLE THAT CAN ENCAPSULATE, CONVEY THE VISION. BUT IT'S A LARGE ROUP OF PEOPLE THAT MAKE THIS PROGRESS HAPPEN. BEWARE OF THE HYPE. OVERSELLING THE PROMISE OR UNDERESTIMATING THE TIMELINE NEEDED TO MAKE THE THERAPY SUCCESSFUL CAN BE A FATAL MISTAKE. NOW, EVEN WITH YOUR BEST OF INTENTIONS, IT IS SOMETIMES IMPOSSIBLE TO MANAGE EXPECTATIONS, ESPECIALLY IN THIS AGE OF INFORMATION SUPER HIGHWAYS. AS RESPONSIBILITY SCIENTISTS AND TRANSLATIONAL SCIENCES WE HAVE TO MAKE EVERY EFFORT TO DO THAT. EVEN VERY PROMISING NEW THERAPIES CAN BE LOST IF TOXICITY IS SEVERE OR EXPECTED. IT SHOULD BE AVOIDED AT ALL TOST. AND THE $1 MILLION QUESTION, KNOWING WHEN TRY GIVE UP OR NOT TO GIVE UP ON A THERAPY. EVERY ONE OF THESE DOESN'T PAN OUT. I PICK THE WINNERS TO TALK ABOUT. BUT THAT'S HIDE SIGHT AND 20/20. THIS ARE THERAPIES TODAY THAT HAVE NOT PANNED OUT AND NEVER WILL. BUT THERE ARE OTHERS WHERE IT JUST TAKES MORE TIME. AND IT TAKES A COMMITTED WORK OF A GROUP OF INVESTIGATORS TO ULTIMATELY MAKE IT HAPPEN. I'LL STOP THERE. TAKE QUESTIONS.