Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov I THINK EVERY ETHICS GRAND ROUNDS IS INTERESTING AND VALUABLE, SOME MORE INTERESTING AND VALUABLE THAN OTHERS. THIS IS HOPEFULLY GOING TO BE ONE OF THOSE. THIS IS ABOUT INNOVATIVE THERAPY AND ETHICS OF INNOVATIVE THERAPY. IT STARTS IN 1974 WHEN CHARLES FRIED (INAUDIBLE) AT THE SAME TIME THE SPINE STARTS TO BE REPLACED FROM RED TO YELLOW MARROW, AND WE BEGIN TO SEE A DOMINANT MARROW IN THE VERTEBRAL COLUMN. THIS CHANGES FROM YESTERDAY ON YELLOW MEASURED BY MRI IN THE AGED INDIVIDUAL, 10% SO THIS IS NOT INCONSEQUENTIAL. THE IMPLICATIONS TO THE SKELETON AND NORMAL HOMEOSTASIS. IN MANY SITUATIONS OF THE ELDERLY IN HUMANS, TO SOME EXTENT IN MICE AS WELL, THE INCREASE IN MARROWED A POSITIVITY IS ASSOCIATED WITH LOWER BONE MARROW DENSITY ARE, THIS HAS BEEN SHOWN IN COHORTS IN THE AEGIS COHORT SUPPORTED BY NIA WHERE WE HAVE NUMEROUS INDICATIONS OF DIFFERENCE BETWEEN MARROW FAT AND BONE STRUCTURE AND BONE DENSITY. SO LED US TO TRY TO UNDERSTAND WHAT THE MECHANISM IS. IN MICE WE SEE DATA FROM A COLLABORATOR WHICH WE DEVELOPED IN OUR LABORATORY. YOU CAN SEE AS THE MOUSE AGES, YOU GET THIS INCREASE IN WHAT WE CALL REGULATED MARROW FAT. THE FAT EXTENDS FROM THE DISTAL TIBIA ALL THE WAY UP THE SHAFT. IN SOME CASES 36 MONTHS REPLACED TOTALLY. WE CAN USE THE AGING MOUSE MODEL AS INDICATOR, THE SAMED A POSITIVITY IN HUMANS. BUT THERE ARE A NUMBER OF OTHER CONDITIONS THAT ARE BONE MARROW ADIPOSITY RESEMBLING HUMAN,% (INAUDIBLE) WITH INCREASE IN MARROW FAT, THAT MAY RECAPITULATE (INAUDIBLE) HERE YOU CAN SEE AN IMAGE FROM B6 MOUSE THAT'S OVARYECTOMIZED. THE DISTAL FEMUR AND TIBIA IN THIS CASE THE TIBIA IS RAPIDLY REPLACED WITH MARROW FAT. AND WE HAVE SOME DATA IN HUMANS THIS BEGINS TO OCCUR WITHIN TWO WEEKS OF ESTROGEN DEPRIVATION, THE GROUP AT AMSTERDAM, ONE COMING TO OUR LAB IN MAY ON A FUNDED SCHOLARSHIP FROM ECTS, HAS REPORTED THAT WITHIN TWO WEEKS OF ESTROGEN DEPRIVATION IN POST MENOPAUSAL WOMAN YOU GET INCREASE IN VERTEBRAL MARROW FAT THAT REPLICATE WHAT WE SEE IN THE MOUSE. ON THE OTHER HAND, YOU ALSO SEE MARROW ADIPOSITY THAT OCCURS QUICKLY, WITH JUST TWO WEEKS OF HIGH FAT FEEDING ONE AGAIN THIS FAT. UNTIL CONTRAST, WE ALSO SEE MARROW ADIPOSITY IN RESPONSE TO CALORIE DEPRIVATION. AND HERE INDEPENDENT OF ALL THESE MINUS DEPOT THERE'S NO FAT. YOU SEE THIS MARKED INCREASE IN MARROW FAT. THIS HAS STRUCK US AS BEING PARADOXICAL. YOU HAVE LOTS OF SUBSTRATE AND UNDERSTAND WHERE FAT COULD BE STORED IN THE MARROW, BUT ON THE OTHER HAND HERE IS A VERY STRESSED INDIVIDUAL IN WHICH YOU SEE MARROW ADIPOSITY, LOW BONE MASS, INCREASED SKELETAL FRAGILITY, NOT UNLIKE AGE-RELATED OSTEOPOROSIS WHERE MARROWED A POSITIVITY IS VERY COMMON. WE CAN REPLICATE IN THE MOUSE, THIS CAME IN TWO DAYS AGO. THIS IS FOUR WEEKS OF CALORIE œWHAT YOU SEE IS THISUSE. PREPONDERANCE OF MARROW FAT WHICH IS RAPID IN OCCURRENCE WITH 30% CALORIE RESTRICTION. THIS IS AN 8-WEEK OLD MOUSE THAT IS RESTRICTED FOR FOUR WEEKS AT 30% WITH THE OTHER CONTROL MICE, AND WHAT YOU CAN ALSO SEE IS THE THIN CORTICES, THEY ARE GAINING MARROW FAT AND LOSINGS BONE. PARADOXICALLY WE'VE DONE THE SAME EXPERIMENT AND PUBLISHED IT WHEN DO YOU IT IN 12-MONTH-OLD MICE YOU SEE THE SAME MARROW FAT CHANGES BUT DO NOT LOSE BONE. SO THE CALORIE RESTRICTION -- THE ENDOTHELIUM UNTIL THEY GET A MESSAGE THAT SAYS PIZZA IS HERE AND THEN THEY GO OUT INTO THE TISSUE. LET ME TELL YOU SCHEMATICALLY HOW THEY DO THAT. THIS IS THE WHITE BLOOD CELL, ROLLING ALONG THE ENDOTHELIUM, THIS IS THE ENDOTHELIUM, AND IT'S GOT A SPECIFIC RECEPTOR ON THE SURFACE CALLED CD15S THAT BINDS TO A RECEPTOR ON THE ENDOTHELIUM, AND THAT MAKES FOR A LOW LEVEL ADHESION THAT ALLOWS IT TO ROLL ALONG SORT OF LIKE A LOOSE VELCRO. AND THEN IT GETS THE MESSAGE HERE THAT SAYS PIZZA HAS ARRIVED, AND AT THAT POINT, THE NEUTROPHIL DISPLAYS A SECOND SET OF RECEPTORS CALLED INTEGRINS, AND THESE BIND TO A DIFFERENT SET AND IT ALLOWS THE NEUTROPHIL TO STICK TIGHT AND SPREAD OUT AND BECOME FLATTENED AND THEN GOES THROUGH A PROCESS THAT YOU'LL REMEMBER CALLED DIAPEDESIS THROUGH WHICH IT WINDS ITS WAY BETWEEN THE ENDOTHELIAL CELLS AND GOES OUT IN THE TISSUE WHERE IT GOES TO DO WHATEVER IT IS IT'S SUPPOSED TO DO. THERE ARE LOTS OF WAYS TO SCREW IT UP. AND SO THE ONE WE'RE TALKING ABOUT TODAY IS MUTATION IN THIS ONE MOLECULE CALLED CD18. THE IMPORTANT POINT HERE IS CD18 IS ONE MOLECULE THAT PARTNERS WITH AT LEAST THREE OTHERS. AND SO WHEN YOU HAVE A MUTATION IN CD18, YOU LOSE BOTH CD18 AND ITS PARTNER MOLECULE, CD11A, HERE IS CD11B AND CD11C AND THESE ARE THE CRITICAL RECEPTORS INVOLVED IN BINDING TO EPITHELIUM AND MANY OTHER MOLECULES THAT HELP MEDIATE THE ABILITY TO BOTH GET OUT INTO THE TISSUE AS WELL AS RESPOND TO SOME BACTERIA DIRECTLY. THIS IS CALLED LEUKOCYTE ADHESION DEFICIENCY TYPE 1 BECAUSE OTHER TYPES HAVE BEEN IDENTIFIED AND THIS IS DUE TO MUTATIONS IN THIS GENE CALLED CD18. SO ONE GENE, THREE MOLECULES, DEFECTIVE. AND IT'S A VERY INTERESTING DISEASE BECAUSE IT IS RARE. IT'S AUTOSOMAL RECEPTIVE AND PATIENTS GET INFECTIONS THAT CAN BE CHRONIC AND REFRACTORY AND TYPICALLY ORAL ULCERS THAT CAN BE SEVERE AND DISABLES, AND ALMOST EVERY PATIENT WITH THIS DISEASE LOSES ALL OF HIS OR HER TEETH BY THE TIME THEY GET INTO ADOLESCENCE. AND RIGHT NOW, THE ONLY TREATMENTS THAT ARE AVAILABLE ARE SYMPTOMATIC, ANTIBIOTICS AND SO ON, EXTRACTION OF TEETH AND BONE MARROW TRANSPLANTATION, QUITE EFFECTIVE THOUGH COMPLICATED IN THIS DISEASE. LET ME GIVE YOU SOME EXAMPLES OF WHAT IS GOING ON HERE. IF YOU TAKE NORMAL NEUTROPHILS AND PUT THEM ON A GLASS SLIDE, AND THEN STIMULATE THEM WITH A CHEMICAL THAT ACTIVATES THEM, THEY SPREAD OUT JUST LIKE A FRIED EGG. AND VERY TYPICAL SORT OF APPEARANCE WHERE THE NEUTROPHIL IS SPREADING OUT IN ORDER TO ATTACH TO THE GLASS. BUT WHAT YOU SEE HERE IS THAT A PATIENT CANNOT DO THAT AT ALL. AT A MORE FUNCTIONAL LEVEL YOU SEE WHAT'S SHOWN HERE, A RECTAL BIOPSY IN A YOUNG MAN WHO HAD LOTS OF INFLAMMATION IN THE COLON, BUT WHAT YOU SEE HERE, THIS IS A TYPICAL RECTAL GLAND WHERE MUCIN IS MADE, THIS IS A BLOOD VESSEL. HERE THE BLOOD VESSEL IS CHOCK FULL OF NEUTROPHILS BUT NOT ONE CAN GET IN THE TISSUE, TISSUE NEUTROPENIA, THEY ARE IN CIRCULATION BUT NOT WHERE WE THINK THE BUSINESS REALLY SHOULD BE. AND THAT REALLY HAS CONSEQUENCES. ONE OF THE CONSEQUENCES IS THAT THEY GET WOUNDS THAT DON'T HEAL. THIS HAD BEEN ON THIS BOY'S CALF FOR SEVERAL MONTHS NOT GETTING BETTER UNTIL WE SURGICALLY REMOVED IT. THEN WHEN YOU HEAL THESE WOUNDS BECAUSE HEALING IS ALL ABOUT HOW NEUTROPHILS GO IN AND CLEAN UP ALL THE SORT OF DEBRIS, WHEN THEY HEAL THESE WOUNDS IT'S A CHARACTERISTIC APPEARANCE REFERRED TO AS CIGARETTE PAPER SCARRING, THAT'S ONLY SOMETHING THAT PEOPLE WHO GREW UP IN THE '60s AND '70s CAN IDENTIFY WITH. BUT IT'S A TYPICAL APPEARANCE THAT SPEAKS TO THE PROBLEMS OF HOW NEUTROPHILS CORRECT TISSUE DAMAGE. THIS IS WHAT THE TEETH LOOK LIKE. THIS YOUNG WOMAN WAS 18, GUMS RECEDED VERY FAR, HER GUMS SHOULD HAVE BEEN AROUND HERE. AND THE BONE WHICH SHOULD BE AROUND HERE HAS RECEDED ALL THE WAY BACK. SO THESE TEETH ARE REALLY LOOSE. SHE CAN'T CHEW ANYMORE. AND SHE HAD TO HAVE THEM REMOVED BECAUSE OTHERWISE SHE WAS REALLY UNCOMFORTABLE, EVERY TIME SHE TRIED TO EAT. OKAY. SO THAT'S THE BACKGROUND. NOW LET ME TAKE YOU TO OUR PATIENT. I HOPE I'VE GIVEN YOU A SMALL FLAVOR FOR THE DISEASE. THIS PATIENT IS A YOUNG ITALIAN MAN WHO ACTUALLY ACCOSTED ME AS A MEETING IN MILAN. AND HE HAD BEEN DIAGNOSED AT AGE 4, HE HAD FREQUENT SKIN INFECTION, PNEUMONIAS, SIGNIFICANT RECURRENT ORAL ULCERS AND PERIODONTITIS. HE DIDN'T WANT HIS TEETH OUT. HE HAD THIS WOUND I'LL SHOW YOU IN A MINUTE THAT HAD GOTTEN WORSE DESPITE LOTS OF PERFECTLY APPROPRIATE THINGS. HE IN PARTICULAR HAD BEEN CONNECTED TO A SURGEON AND I MEAN AS NO OFFENSE TO MY SURGICAL COLLEAGUES BUT WHEN THE FIRST SURGERY DOESN'T WORK THE ANSWER IS LET'S DO ANOTHER. HE HAD SEVERAL OF THESE APPROACHES, NONE OF WHICH HAD MADE HIM BETTER. AND HE HAD BEEN ON A LOT OF STEROIDS TRYING TO CONTROL THE INFLAMMATION SEVERE ENOUGH TO GIVE HIM ADRENAL INSUFFICIENCY. THIS IS A PICTURE OF HIS MOUTH. WHAT YOU SEE HERE ARE HIS TEETH. HE STILL HAS HIS TEETH AT AGE 20 WHICH TELLS YOU HE'S GOT A MILD BUT SIGNIFICANT FORM OF THE DISEASE. AND WHAT YOU SEE HERE IN BLUE IS WHERE HIS BONE OUGHT TO BE. AND IN WHITE YOU SEE WHERE HIS JAW BONE, ALVEOLAR RIDGE, ACTUALLY IS. YOU CAN SEE EXAMPLES IN BITE WINGS. YOU CAN SEE HIS TOOTH ROOT IS COMPLETELY BEING HELD IN JUST BY GUM BECAUSE THE BONE HAS RESORBED COMPLETELY AROUND IT. SAME THING DOWN HERE. THIS IS WHAT YOU GETS WITH BAD ALVEOLAR RIDGE DISEASE IN LAD1. HE CAME FROM ITALY TO VISIT US BECAUSE WE THOUGHT WE HAD SOME IDEAS ABOUT WHAT MIGHT WORK. AND WHEN HE CAME IN HERE, WE LOOKED AT HIS TEETH. THIS IS WHAT HIS TEETH LOOKED LIKE ON HIS FIRST VISIT. YOU CAN SEE HIS GUMS ARE RED AND INFLAMED. THERE'S LOTS OF PLAQUE AND GUM RECESSION. WHAT HE FAILED TO TELL US BEFORE HE WALKED IN THE DOOR WAS ABOUT THIS WOUND, AND I MEAN IN ALL SINCERITY, WE FOUND IT ON THE PHYSICAL EXAM BECAUSE WE STILL DO THAT IN MY INSTITUTE, AND IT WAS NOT VERY SUBTLE. AND HE AND HIS PARENTS WERE DRESSING THIS EVERY DAY. AND TAKING IT DOWN, PUTTING ON BANDAGES AND REMOVING THEM. SO NOW YOU HAVE TO STOP AND SAY, WELL, WHAT'S REALLY GOING ON? SO HE'S GOT A LOT OF INFLAMMATION IN THE TEETH AND HE'S GOT A LOT OF INFLAMMATION IN THE BACK SIDE, WHAT'S REALLY HAPPENING? FOR 40 YEARS FROM THE TIME THIS DISEASE WAS DESCRIBED AND IT WAS AMONG THE VERY FIRST DESCRIPTIONS WAS FROM HERE AT THE NIH BY JOHN GALLIN IN 1979, AND FROM THE TIME IT WAS DESCRIBED EVERYBODY ASSUMED THAT THE SYMPTOMS WERE BECAUSE OF INFECTIONS THAT WERE BECAUSE OF TISSUE NEUTROPENIA, CELLS IN CIRCULATION BUT NOT IN TISSUE LIKED I SHOWED YOU AND THEY CAN'T GET IN TISSUE AND FIGHT INFECTION AND THINGS GET BAD. MAN, THAT MAKES SO MUCH SENSE AND LIKE SO MANY THINGS THAT MAKE SENSE MAYBE IT WAS TOO SIMPLE. BUT THE WORK I'M GOING TO SHOW YOU IN JUST A SECOND IS THAT IN FACT IT'S BECAUSE OF THE HYPERINFLAMMATORY RESPONSE BECAUSE OF THIS THING CALLED IL-17, WHERE IT'S CRITICAL TO WORK AT AN INSTITUTION WHERE YOU'VE GOT SMART PEOPLE ALL OVER THE PLACE. IN PARTICULAR WHAT'S IMPORTANT ARE SMART PEOPLE WHO TELL WHAT YOU YOU'RE DOING WRONG. THOSE COME IN REALLY HANDY. THAT MIGHT EVEN BE USEFUL IN GOVERNMENT. [LAUGHTER] BUT DR. MOUSTOPILIS SAID THIS DIDN'T MAKE SENSE AND LOOKED AT WHAT'S GOING ON IN THE GUM SO WE COULD IDENTIFY WHAT ARE THE MEDIATORS THAT ARE LEADING TO THE INFLAMMATION THERE. AND I WON'T TAKE YOU THROUGH THE DATA BUT I'M GOING TO SCHEMATIZE IN A COUPLE SLIDES BRIEFLY. THE BIG PICTURE NEUTROPHILS ARE IN THE BLOOD VESSEL, IN THE CIRCULATION. MACRO MACROPHAGES ARE IN THE TISSUE. MACROPHAGES, WHEN NOT BEING FED, MACROPHAGES PRODUCE A CYTOKINE CALLED INTERLEUKIN 23, THAT STIMULATES CD4 CELLS TO PRODUCE IL-17 PRODUCING GCSF WHICH LEADS TO MORE NEUTROPHILS AND BONE RESORPTION AND IT'S A VERY POTENT MEDIATOR OF INFLAMMATION. THOSE IN DERMATOLOGY ARE FAMILIAR WITH THIS BECAUSE OF ITS ROLE IN PSORIASIS, INFLAMMATORY BOWEL DISEASE KNOWS ABOUT IT THERE. G-CSF -- WHEN IT INGESTS NEUTROPHILS, IT'S THE FAVORITE FOOD, REDUCING PRODUCTION OF G-CSF AND BONE LOSS AND INFLAMMATION. PATHOLOGICALLY IN LAD1 THEY GOT PLENTY OF NEUTROPHILS BUT CAN'T GET OUT INTO THE TISSUE AND THEREFORE THE MACROPHAGE STARVE AND TURNS OUT MORE IL-23, MORE IL-17 INCREASING BONE LOSS AND INFLAMMATION. IT'S DISSECTING OUT THE REAL MECHANISM THAT LED US TO SAY, WELL, IF THAT'S REALLY THE MECHANISM IT'S NOT ABOUT NOT HAVING NEUTROPHILS IN THE TISSUE BECAUSE OF INFECTION BUT NOT HAVING NEUTROPHILS BECAUSE IT TURNS OFF INFLAMMATION. IN WORK IN MICE THAT'S TRUE, NOT ABOUT GETTING THEM OUT FOR INFECTION BUT FOR THE INFLAMMATION. AND BECAUSE OF THAT, WE REASONED THAT BLOCKING IL-23 WITH THIS ANTIBODY USTEKINUMAB MIGHT BE USEFUL, IF YOU BLOCK IL-23, THE SAME P 40 IN BOTH IL-23 AND IL-12 BUT IF YOU BLOCK THAT YOU BLOCK THE PRODUCTION OF IL-17, WHICH THEN BLOCKS THE INFLAMMATION. AND SO THIS DRUG IS COMMERCIALLY AVAILABLE, AND WE WENT AND READ ABOUT IT BECAUSE IT DOES EXACTLY WHAT WE WERE LOOKING FOR. IT INHIBITS IL-23 SIGNALING WHICH WILL DROP DOWN IL-17 PRODUCTION, IN THE TREATMENT OF PSORIASIS IT WAS QUITE EFFECTIVE WITH A VERY, VERY MODEST INFECTION PROFILE, THAT'S A BIG DEAL IN TREATING PEOPLE WITH AN UNDERLYING IMMUNODEFICIENCY, BUT OF COURSE THIS HAS NEVER BEEN TRIED IN LAD-1 AND NOT MUCH IN THE WAY OF NOVEL THERAPY IN RARE DISEASE, PROSPECTIVELY BECAUSE IT'S HARD TO ACCUMULATE PATIENTS TO DO THAT. OUR PROPOSAL WAS TREAT OFF LABEL USING DOSING REGIMEN FOR PSORIASIS, SAFE AND TOLERABLE IN THAT DISEASE, DIDN'T KNOW ANYTHING ABOUT WHAT IT WOULD DO IN OUR DISEASE. SO THEN THE QUESTIONS THAT ARE BEING POSED HERE BY DR. SUGARMAN WHEN IS THAT ACCEPTABLE, DOES THIS TAKE ADVANTAGE OF A DESPERATE PATIENT, IS INNOVATIVE THERAPY CONSISTENT WITH EVIDENCE-BASED MEDICINE, CAN CLINICIANS OFFER ANYTHING THAT MIGHT HELP, SHOULD INPUT AND REVIEW AND AGREEMENT BY OTHER CLINICIANS OR BODIES BE REQUIRED, AND THEN IS IT ACCEPTABLE TO MANDATE THAT PATIENTS ENROLL IN A CLINICAL TRIAL IN ORDER TO ACCESS INNOVATIVE THERAPIES. AND I WILL STOP THERE FOR DR. SUGARMAN. UNLESS YOU WANT QUESTIONS AT THIS POINT. >> NO. FABULOUS. THANK YOU, STEVE. SO -- [APPLAUSE] A WONDERFUL CASE. SO ONE OF THE THINGS I TEND TO DO, THIS IS CHARACTEROLOGICAL, I'M A BIG FAN OF SHORT INTRODUCTIONS, I'LL CONTINUE WITH THE THEME. IF I TELL YOU EVERYBODY STEVE HAS DONE WE WOULD BE DONE, OR JEREMY WE WOULD NEVER GET THROUGH THE DAY. JEREMY SUGARMAN IS ONE OF THE LEADING PEOPLE IN BIOETHICS IN THE UNITED STATES, HE'S AN ENDOWED CHAIR OF BIOETHICS AND MEDICINE AT JOHNS HOPKINS UNIVERSITY, AND HE'S A GUY WHO TRIES TO GET AWAY WITHOUT ANSWERING THE HARD QUESTIONS, I GOT SIX UP THERE AND HE'S GOING TO TELL US THE ANSWERS TO ALL OF THEM. WELCOME, JEREMY. >> THANKS. [APPLAUSE] THANK YOU VERY MUCH. THAT WAS A GREAT TALK. I CAN'T WAIT TO HEAR WHAT HAPPENED, LIKE MOST OF YOU. LET ME START WITH THE DISCLAIMERS. I AM A MEMBER OF MERCK KGA BIOETHICS ADVISORY PANEL AND STEM CELL RESEARCH, DIFFERENT THAN REGULAR AMERICA, AND A MEMBER OF QUINTILE, I CAN GET PAID BECAUSE I'M NOT A FEDERAL EMPLOYEE. OBJECTIVES TO ETHICAL ISSUES, DISCUSS POSITIVE AND NEGATIVE ASPECTS AND RECOGNIZE NEED FOR ETHICS OVERSIGHT. I SAW THE SLIDES STEVE SHOWED BEFORE BUT WITHOUT THE NARRATION. I HAD TO MAKE UP MY OWN STORIES ABOUT WHAT WAS GOING ON. TRY THAT SOMETIME WITH A SCIENCE SLIDE OF YOUR COMPETITOR. I HAD A DIFFERENT NARRATIVE ABOUT WHAT HAPPENED THERE. [LAUGHTER] SO WE TEND TO THINK THERE'S SEVERAL DIFFERENT PATHWAYS TO TRANSLATION, RIGHT? SO WE'RE BIG FANS, ESPECIALLY IN PLACES LIKE THIS OF TRANSLATIONAL RESEARCH WHERE WE TAKE THINGS FROM THE BENCH, TRY THEM IN ANIMAL MODELS, MOVE TO BEDSIDE AND THEN TEST THEM IN CLINICAL TRIALS, RIGHT? WHEN THOSE THINGS WORK, WHEN THAT TRANSLATIONAL CASCADE WORKS, WE HERALD THOSE AT OUR MEETINGS. WE LEARN ABOUT THEM IN MEDICAL SCHOOL, GRADUATE SCHOOL, WE LOVE WHEN THAT REALLY WORKS. IT DOESN'T ALWAYS WORK THAT WAY. AND MEDICINE HASN'T WORKED THAT WAY. AND BUT WHEN IT WORKS THAT WAY IT'S EXCITING. THERE'S CLINICAL CARE, ESTABLISHED CARE FOR THINGS WE THINK WE'RE DOING RIGHT. WE'RE SOMETIMES RIGHT ABOUT THAT BEFORE WE SUBJECT THEM TO CLINICAL TRIALS. THERE'S MEDICAL INNOVATION OR SURGICAL INNOVATION WHICH WE HAVE HERE AND CLEARLY ALSO INAPPROPRIATE USES OF MEDICAL AND AVAILABLE THERAPIES. IT'S IMPORTANT TO KEEP IN MIND WHEN WE THINK THROUGH THESE QUESTIONS ABOUT WHAT'S THE OVERLAP OF THESE AREAS BETWEEN TRANSLATIONAL RESEARCH AND CLINICAL CARE OR INNOVATION AND CLINICAL CARE, BECAUSE IN EACH OF THESE DIFFERENT AREAS, I DON'T HAVE TIME TO GO INTO THIS TODAY WE HAVE SEPARATE ETHICS IN THE CLINICAL SETTINGS AND WHAT GOES ON IN THE RESEARCH SETTING AND THERE'S A HYBRID AREA THAT GETS US SCREWED UP BECAUSE WE DON'T KNOW WHICH ROLE WE'RE NECESSARILY PLAYING. THIS LITTLE BOY, A PICTURE FROM THE 1980s, THIS YOUNG BOY HAD FANCONI ANEMIA, AND HE WENT INTO DUKE HOSPITAL AND HE NEEDED A TRANSPLANT FOR HIS DISEASE. STANDARD TREATMENT, BONE MARROW TRANSPLANT AT THE TIME. WENT IN, THERE HE WAS. UNFORTUNATELY THERE WASN'T A MATCH ANYWHERE IN THE WORLD FOR THIS YOUNG BOY. HE WAS SEEN BY A WOMAN, JOANNE CURSTBERG PLAYING WITH SOME MICE AND FOUND YOU COULD TAKE CORD BLOOD FROM MICE AND DO TRANSPLANTS AND SHE LOOKED AT THE KID'S MOM AND NOTICED SHE WAS PREGNANT, DIDN'T NEED TO DO A TEST, IT WAS ONE OF THOSE OBVIOUS TIMES WHERE THE LARGEST ABDOMINAL -- THE MOST COMMON MASS IN WOMEN TENDS TO BE PREGNANCY. AND SO SHE SAID I'VE GOT THIS IDEA, WOULD IT BE POSSIBLE AFTER THE BABY IS DELIVERED, COLLECT THE CORD BLOOD FROM YOU, WE'VE NEVER EVER IN THE HISTORY OF THE WORLD DONE A TRANSPLANT OF CORD BLOOD INTO PEOPLE, WE'VE BEEN DOING IT IN MICE. I DON'T EVEN KNOW IF YOUR BABY IS GOING TO BE A MATCH FOR YOUR SON. BUT WE CAN TALK ABOUT THAT LATER. BUT IN THE MEANTIME WE'RE GOING TO KEEP LOOKING FOR A MATCH. WELL, THEY KEPT LOOKING FOR A MATCH. THE KID WAS BORN. PERFECT MATCH, IT TURNS OUT. AND THERE WAS NO OTHER MATCH FOR BONE MARROW TRANSPLANT IN THE WORLD. AND SO THEY OFFERED THE OPPORTUNITY TO DO THIS INNOVATIVE THERAPY OF TRYING THE FIRST CORD BLOOD TRANSPLANT. SO THEY DID THE TRANSPLANT, THEY FLEW TO PARIS, I THINK LUNCH IS BETTER IN PARIS THAN IN DURHAM. WELL, DURHAM IS A PRETTY GOOD LUNC NOW BUT NOT SO MUCH IN THE '80s. THEY DID IT BECAUSE THEY HAD ELIAN GLUCKMAN TO DO THE TRANSPLANT, DID THE MOST IN THE WORLD. HERE HE IS YEARS LATER, DOING EXTRAORDINARILY WELL, WITH THAT TRANSPLANT. THEY PUBLISHED IN THE SMALL REGIONAL MEDICAL JOURNAL PUBLISHED OUT OF BOSTON, THE NEW ENGLAND JOURNAL OF MEDICINE. AND A FIELD WAS SORT OF BORN. I HAVE ANOTHER -- I SAW ANOTHER PICTURE OF HIM RECENTLY. HE'S A FATHER OF HIS OWN. HE'S NOT SO CUTE AND SO WE DON'T SHOW PICTURES OF HIM NOW. [LAUGHTER] HERE IS THE FIRST SET OF KIDS WHO WERE TRANSPLANTED, THE FIRST CORD BLOOD TRANSPLANTS DONE IN KIDS. THIS IS PABLO RUBINSTEIN AND JOANNE CURSTBERG, SOME LEADERS IN THE FIELD. CORD BLOOD IS USED TO TREAT MALIGNANT AND NON-CLINICAL CONDITIONS. THE REASON I SHOW THIS, THE FIRST 200 OR SO CORD BLOOD TRANSPLANTS IN THE WORLD WERE NOT DONE WITH IRB-APPROVED PROTOCOLS, THEY WERE CONSIDERED INNOVATION, CHANGING HEMATOPOIETIC STEM CELLS FROM CORD BLOOD TO MARROW, NO ONE THOUGHT IT WAS IMPORTANT TO OBTAIN IRB APPROVAL BECAUSE IT WAS INNOVATION. HOW INNOVATIVE, IT WASN'T CLEAR. NOW, ONCE IT BECAME CLEAR THERE WERE QUESTIONS TO ASK, IS IT BETTER TO DO BONE MARROW VERSUS CORD BLOOD, THINGS BEGAN TO CHANGE. THE FIRST -- THIS IS ONE OF THE SUCCESS STORIES. HERE IS THE COUNTER NARRATIVE. THOUSANDS, LITERALLY THOUSANDS OF WOMEN RECEIVED HIGH DOSE CHEMOTHERAPY AND AUTOLOGOUS BONE MARROW TRANSPLANT, MANY AT DUKE, I GOT THE OPPORTUNITY TO WORK ON THESE UNITS AND SEE WHAT WAS HAPPENING. THOUSANDS OF PEOPLE RECEIVED IT AND ULTIMATELY NO BENEFIT. OKAY. SO HERE WE WERE THINKING WE'RE DOING A GOOD JOB, SAME THING, INNOVATION. NOT DONE INITIALLY AS RESEARCH, NOT SUBJECTED TO THE SAME KIND SCRUTINY, YET WE'RE IN A SITUATION SHOWN NOT TO BE EFFECTIVE. THE MOST RECENT ONE IS IN THE APTLY NAMED "LANCET," A DESCRIPTION OF A TRACHEAL TRANSPLANT TO BE USED TO CREATE SUPER COOL SCIENCE, NOT AS COOL AS STEVE'S SCIENCE MIND YOU BUT TAKING A SCAFFOLDING AND A PATIENT'S STEM CELLS, PUTTING THEM ON THE SCAFFOLDING, IMPLANTING THAT TRACHEA. GREAT, GROUND BREAKING, WORLD TURNS AROUND, NO TREATMENT FOR THIS DESPERATE CONDITION, AND THERE'S A LOT OF EXCITEMENT OVER IT. SOON LATER, A YOUNG GIRL IN THE UNITED STATES, PARENTS CAN'T AFFORD THIS GROUND-BREAKING INVATTIVE THERAPY, A CROWD SOURCES CAMPAIGN RAISES IT'S $50,000 OR WHAT WAS NEEDED FOR HER CARE, SHE RECEIVES THIS INNOVATIVE THERAPY AND DIE AS FEW DAYS LATER. NOW, THE CHARACTER BEHIND THIS WORK IS SHOWN HERE. HIS NAME IS MACARINI, HE PUBLISHED THIS ONE NOT IN THE NEW ENGLAND JOURNAL BUT VANITY FAIR, WHERE THIS COMES FROM. I THOUGHT IT WAS MACHIAVELLI OR MACARINI, I CAN'T GET IT STRAIGHT, HE'S KISSING THE PRODUCER OF THE NEWS SHOW ENCHANTED BY HIS ABILITY TO SELL SNAKE OIL. THIS GETS WORSE BECAUSE IT'S INVOKED AS YOU MAY HAVE FOLLOWED THIS CASE, IMPLICATED PEOPLE ON THE NOBEL COMMITTEES, A LOT OF QUESTIONS OF FRAUD, READ THE VANITY FAIR THING, TRUE LIFE IS BETTER THAN FICTION. I MEAN, THIS IS AMAZING WHAT'S BEEN DONE. WELL, SOME OF THE WORK I'VE BEEN DOING HAS BEEN WORKING ON THE TASK FORCE FOR THE INTERNATIONAL SOCIETY FOR STEM CELL RESEARCH TO COME UP WITH ETHICS GUIDELINES FOR STEM CELL RESEARCH, BEGUN FOR A VARIETY OF REASONS, FIRST SET OF GUIDELINES DONE ABOUT A YEAR FOLLOWING THE NATIONAL ACADEMY OF SCIENCE GUIDELINE ON HUMAN EMBRYONIC STEM CELL RESEARCH. THE SECOND SET OF GUIDELINES RELEASED IN 2008 AND DEALT WITH CLINICAL TRANSLATION AND WE LOOKED RECENTLY AND COMBINED AND UPDATED WITH ALL THE PROGRESS IN THE FIELD AND THEY WERE JUST RELEASED IN MAY. THE REASON WHY I BRING THESE GUIDELINES TO YOU IS THEY ARE THE CLOSEST CONNECTION OF AN ARTICULATION OF ETHICS GUIDELINES FOR INNOVATIVE CARE. SURGEONS HAVE SOME GUIDELINES ON INNOVATIVE CARE, AND THE STEM CELL COMMUNITY, BUT OTHERWISE IT'S HARD TO FIND GUIDELINES FOR INNOVATIVE CARE, ETHICS GUIDELINES. THE SENT OF ICCSR TO MAKE SURE BASIC STEM CELL RESEARCH IS RESPONSIBLY TRANSLATED INTO APPROPRIATE CLINICAL APPLICATIONS FOR TREATING PATIENTS. WHAT WAS RECOGNIZED IS THAT IN ORDER TO DO THIS THERE ARE SOME FUNDAMENTAL ETHICAL PRINCIPLES YOU NEED TO CONSIDER. THERE'S SOME CONSIDERATIONS, LAB-BASED RESEARCH AS YOU MAY BE AWARE, THERE ARE DEBATES ABOUT THE MORAL STATUS OF HUMAN EMBRYONIC STEM CELL RESEARCH BUT IT GOES WELL BEYOND THAT. WHAT ARE ETHICAL ISSUES ASSOCIATED WITH ORGANOIDS, ASSOCIATED WITH A VARIETY OF GENE EDITING TECHNOLOGIES AND THE LIKE, ALL COMING AT THE SAME TIME. THERE'S CLINICAL TRANSLATION OF STEM CELLS COMMUNICATION AND STANDARD FOR STEM CELL RESEARCH. UNDER THE CLINICAL TRANSLATION OF STEM CELLS RESEARCH REMEMBER THE VENN DIAGRAM I SHOWED AT THE BEGINNING, IT'S CRITICAL TO HAVE CELL PROCESS AND AND MAGNIFYING DOWN, IF YOU HAVE A PLURIPOTENT STEM CELL, YOU WANT TO MAKE SURE IT BECOMES THE CELL YOU WANT IT TO BECOME, HOW CAN YOU MAKE SURE THIS LIVING THING IS ACTUALLY GOING TO DO WHAT YOU WANT IT TO DO AND NOT MAKE TOO MUCH OF IT? AND MAKE SURE IT DOES IT PURELY. HUGELY DIFFICULT STEP. WHAT ARE THE PRE-CLINICAL MODELS AND HOW ACCURATE ARE THEY PREDICTING MOST IMPORTANTLY SAFETY AND EFFICACY IN PEOPLE. CLINICAL RESEARCH AND HOW DO WE CONDUCT THAT CHANGING THE STANDARDS OF CLINICAL RESEARCH. WHAT I WANT TO FOCUS ON GIVEN THE TOPIC IS STEM CELL-BASED MEDICAL INNOVATION. SO UNDER HERE, THERE'S A PROVISION AND THIS WAS AN INITIAL SET OF CLINICAL TRANSLATION GUIDELINES RECOGNIZING WE REALIZE MANY ADVANCES IN MEDICINE HAVE COME NOT THROUGH A STANDARD TRANSLATIONAL PATHWAY. IF YOU LOOK AT THE FIELD OF CORD BLOOD, FOR INSTANCE, THAT WAS VERY FAMILIAR TO EVERYONE IN THE ROOM. IF YOU LOOK AT THE STORY OF ORGAN TRANSPLANTATION, VERY MUCH A STORY OF INNOVATION. AND SOME OF THE MAJOR THINGS WE DO DON'T FOLLOW THAT PATHWAY WE ALL LEARN AND TEACH ABOUT. SO WE WANTED TO ACKNOWLEDGE THE FACT THAT PEOPLE WERE GOING TO BE TRYING STUFF, THEY WERE GOING TO BE DOING THINGS OFF LABEL. THEY WERE GOING TO DO THINGS THAT WERE IN INNOVATION BUT WE WANTED TO CAPTURE THAT IN SOME WAY, AND BE ABLE TO SAY, WHAT'S THE RIGHT WAY, WHAT'S THE RESPONSIBLE WAY, TO GO ABOUT DOING SOMETHING THAT IS IN THE BEST INTEREST IN THE PATIENT IN FRONT OF YOU BUT AT THE SAME TIME NOT SUGGESTING THOUSANDS OF PEOPLE TO SOMETHING THAT'S POTENTIALLY DANGEROUS. SO THE GUIDELINES IN THIS, CURRENT VERSION, CLINICIAN SCIENTISTS MAY PROVIDE UNPROVEN STEM CELL BASED INTERVENTION TO AT MOST A SMALL NUMBER OF PATIENTS OUTSIDE THE CONTEXT OF FORMAL CLINICAL TRIAL AND ACCORDING TO THE HIGHLY RESTRICTED PROVISIONS OUTLINED IN THE SECTION. WHAT ARE THE PROVISIONS? WELL, RATHER THAN JUST WINGING IT, RIGHT, HEY, LET'S TRY SOME OF THIS STUFF, LET'S GET A DOSE OF THIS, THERE NEEDS TO BE A WRITTEN PLAN. YOU HAVE TO PUT TOGETHER A PLAN ABOUT WHAT'S GOING TO HAPPEN. THE PLAN IS APPROVED THROUGH SOME TYPE OF PEER REVIEW. THE PATIENT SHOULD NOT BE ELIGIBLE FOR A CLINICAL TRIAL. SOME PEOPLE COULD ARGUE ABOUT THIS. THE INSTITUTIONS WILLING TO BE ACCOUNTABLE FOR IT'S RESULTS OF WHAT HAPPENED, THE PERSONNEL WITH QUALIFIED, VOLUNTARY AND INFORMED CONSENT, THERE'S AN ACTION PLAN FOR ADVERSE EVENTS, THERE ARE RESOURCES FOR COMPLICATIONS, AND THERE'S A COMMITMENT TO CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. NOW, THAT LAST BIT IS REALLY IMPORTANT. WHEN THINGS GO WELL, THERE'S A RUSH TO STEM -- SEND THAT TO THE NEW ENGLAND JOURNAL. WHEN THINGS GO POORLY THE EXCITEMENT MAY NOT BE THERE, NOT JUST ON THE PART OF THE EDITORS, BUT ON THE PART OF WHAT DID WE DO, WHAT HAPPENED. WELL, IF YOU HAVE -- AS SPECIAL AS EVERYBODY IN THE ROOM IS AND MY COLLEAGUES AT HOPKINS, THE LAKE WOE BEE GONES OF CLINICAL CARE, THINGS GO WRONG AND OTHER PEOPLE WILL COME UP WITH THE SAME IDEA OR SOMETHING SIMILAR. WE NEED TO TELL THE STORIES WHEN THINGS GO WRONG. ENGINEERS LEARN WHEN BRIDGES COLLAPSE. WE CAN STAND TO LEARN AS MUCH WHEN THINGS GO WRONG BUT WE'RE OFTEN NERVOUS AND THERE ARE LOTS OF FORCES TELLING US NOT TO TELL THAT STORY. THE COMMITMENT HAS TO BE ON THE FRONT END TO TELL THE STORY ABOUT WHAT WENT WRONG. BRIEFLY, BECAUSE THE TIME, I KNOW, THE TIMING OF YOUR SESSION IS GOOD BECAUSE IT'S NOT RIGHT AFTER LUNCH, SO I'M GOING TO JUST SMUGGLE IN A LITTLE BIT OF ETHICS HERE BUT NOT MUCH, JUST ENOUGH TO GET YOU THINKING AND THEN I'LL STOP AND WE CAN HAVE QUESTIONS. THERE'S SOME CONCEPTUAL ISSUES IF YOU WANT TO THINK THROUGH WHEN IS IT RIGHT AND TO GET AT THOSE QUESTIONS THAT DAVE POSED, WE REALLY DON'T HAVE SOLID ANSWERS FOR THOSE YET. BIOETHICS HASN'T REPLACED DUG INTO THIS. IN ORDER TO GET AT THESE CONCEPTUAL ISSUES WE HAVE TO AGREE ON DEFINITIONS SO WE'RE TALKING ABOUT THE SAME THING, AND THEN I'M GOING TO JUST GIVE YOU HINTS AT WHAT A CONCEPTUAL MODEL MIGHT LOOK LIKE. WE NEED TO DISTINGUISH INNOVATION FROM VARIATION. THIS COMES FROM THE SURGICAL LITERATURE. IT'S SORT OF A MINOR VARIATION OF A SURGICAL PROCEDURE THAT DOES NOT HAVE EXPECTATION OF INCREASING RISK. SOMETHING IS DIFFERENT IN THE OPERATING ROOM, THE PERSON DOESN'T LOOK LIKE THE OLD DRAWINGS, IT THEY ARE NOT HOOKED UP THE SAME WAY AND YOU HAVE TO MAKE IT UP. THAT'S JUST A VARIATION. IT'S NOT AN INNOVATION. YOU DON'T WANT TO CONSTRUCT AN ENTIRE PROCESS TO OVERSEE THE THINGS WE JUST DO DIFFERENTLY. INNOVATION HAS COME UP WITH SEVERAL DIFFERENT DEFINITIONS IN THE INTEREST OF TIME I'M GOING TO ASK YOU JUST TO SKIM THAT RATHER THAN HAVE ME READ IT. PICKING OUT THE KEY POINTS HERE, THAT SOME INNOVATIONS ARE AD HOC, BUT OTHERS ARE DEVELOPED RIGOROUSLY LIKE THE STORY WE HEARD AT THE BEGINNING OF THE SESSION. McCORNEALLY AND DAAR TALK ABOUT INTERVENTION NOT YET VIEWED BY INSTITUTION, COMMUNITY OR PRO INVESTIGATORS AS MEETING ACCEPTED STANDARDS OF SAFETY, REBY LILT AND FAMILIARITY, WITH EFFECTS, SIDE EFFECTS AND COMPLICATIONS. WE COULD QUIBBL. DAVE MIGHT HAVE MENTIONED AT THE BEGINNING, EVEN IN THE BELMONT REPORT, THERE'S A DESCRIPTION OF THE NEED FOR INNOVATIVE APPROACHES TO CARE. VERY PRESCIENT APPROACH, NOT NECESSARILY EXPERIMENTAL, NOT NECESSARILY CLINICAL CARE. IF IT'S RADICALLY NEW SHOULD A FORMAL RESEARCH PROCESS. BELMONT SAYS A MEDICAL PRACTICE COMMITTEE OUGHT TO REVIEW WHAT'S GOING ON. SO WE DON'T TEND TO HAVE THOSE. WE DON'T CALL THEM THAT. BUT IT WAS SOMEWHAT A MECHANISM OF PEER REVIEW RATHER THAN WINGING IT. ALL RIGHT. IF WE WANTED TO CONSTRUCT A CONCEPTUAL MODEL FOR INNOVATION SO WE COULD ANSWER THOSE QUESTIONS PROPERLY, ONE OF THE THINGS THAT DISTINGUISHES NECESSARILY RESEARCH FROM INNOVATION IS THERE HAS TO BE A REAL PROSPECTIVE BENEFIT TO THE PATIENT. WE REALLY ANTICIPATE A BENEFIT TO THIS PATIENT IN FRONT OF US. IT ALSO RECOGNIZES THE FIDUCIARY NATURE OF THE CLINICIAN-PATIENT RELATIONSHIP. WHAT I MEAN BY THAT IS THE PATIENT'S INTERESTS COME FIRST. WHEN I'M WEARING MY WHITE COAT, TUESDAYS FOR ME, TODAY IS WEDNESDAY SO YOU'RE GETTING THIS, MY OBLIGATION IS TO THAT PATIENT AND I'M SUPPOSED TO PUT ETHICALLY MY PATIENT'S INTERESTS AHEAD OF MY OWN AND THAT RELATIONSHIP IS BUILT ON TRUST THAT THAT'S WHAT I'M DOING. WHEN I'M A RESEARCHER I HAVE TO MINIMIZE RISK TO PATIENTS, I WANT TO MAXIMIZE BENEFITS, BUT ONE OF MY OBLIGATIONS IS PRIMARILY TOWARDS OBJECTIVITY, NOT THE SUBJECTIVITY OF THE PERSON IN FRONT OF ME. WE MEASURE ADVERSE EVENTS RATHER THAN CHANGE MEDICINE TO SOMETHING ELSE, RIGHT? THE INNOVATION SHOULD BE MINIMAL INCREMENTAL RISK. WE GOT TO BE HUMBLE THAT WE CAN REALLY BE SCREWING THIS UP. WE ARE ON TREACHEROUS GROUND. WE ARE ON ICE. AND THAT ICE IS THIN. WE'VE GOT TO BE HUMBLE ENOUGH TO LISTEN TO OUR COLLEAGUES AND TO LOOK REALLY CAREFULLY TO MAKE SURE WE'RE DOING THE RIGHT THING. AND FINALLY, AS YOU MIGHT HAVE GUESSED FROM MY EARLIER SLIDES, THERE HAS TO BE RESPONSIBILITY FOR BALANCE DISSEMINATION OF THE INFORMATION. IN REPORTS IN THE FRONT END, ON CASES, TO CONSIDER PUTTING REGISTRIES TOGETHER AND COMMITMENT TO CONDUCTING RIGOROUS CLINICAL TRIALS. SO, THE COMMON APPROACHES, FEATURES OF APPROACHES PEOPLE HAVE USED, SURGEONS, STEM CELL SCIENTISTS, IS RECOGNITION THAT INNOVATION CAN BE HARMFUL, NOT JUST BENEFICIAL, NOT JUST A COOL SCIENCE STORY. THERE IS A NEED FOR OVERSIGHT. WE SHOULDN'T DECIDE ALONE. PATIENT CONSENT, REALLY CONSENT, IS IMPORTANT. WE SHOULD ACKNOWLEDGE OUR CONFLICTS, BOTH OUR FINANCIAL CONFLICTS, ALSO NON-FINANCIAL CONFLICTS INTEREST, FAVORITE ENZYME, FAVORITE PATHWAY, WE HAVE TO ACKNOWLEDGE THOSE CONFLICTS AND BE COMMITTED TO REPORTING. SO, WHAT I HOPE I'VE SHOWN YOU IN THAT BRIEF FEW MINUTES IS THAT INNOVATION HAS RESULTED IN ENORMOUS BENEFITS AND HARMS. THERE ARE APPROACHES TO RESPONSIBLE INNOVATION THAT SHARE COMMON FEATURESA CLEAR NEED TO SORT THAT OUT. WE KNOW WHAT THE SPHERE LOOKS LIKE OR OUGHT TO LOOK LIKE AND ENHANCED WITH EMPIRICAL APPROACHES OF MAPPING DIFFERENT APPROACHES TO INNOVATION TO SEE WHETHER IN FACT THEY WORK. WE ARTICULATED THAT FRAMEWORK IN THE ISSTR GUIDELINES, WE DON'T KNOW IF PEOPLE ARE DOING IT, HOW WELL IT'S DOING. WE'VE HAD THE IRB SYSTEM, WE BARELY KNOW HOW WELL THAT WORKS. SOME PROCESS MEASURES BUT NOT OUTCOME MEASURES AND SHOULD APPLY THIS A BIT MORE. SO THANKS FOR YOUR ATTENTION. [APPLAUSE] >> JEREMY IS ALREADY TRYING TO ESCAPE. OKAY. SO QUESTIONS FOR JEREMY OR FOR STEVE. >> IN THE TWO CASES YOU MENTIONED, THE ITALIAN CASE OF STEM CELLS AND THE BONE MARROW TRANSPLANT FOR BREAST CANCER, YOU KIND OF NEGLECTED THE PART THAT MOST OF THAT WAS DONE TO PUBLIC PRESSURE. IN THE STAMINA CASE IN ITALY IT WAS PRESSURE FROM THE GOVERNMENT THAT OVERRULED REGULATORY AGENCIES, THERE'S A DANGER GOVERNMENT AND POPULAR PRESSURE CAN IMPEDE GOOD MEDICINE IF PEOPLE AREN'T VERY CAREFUL. IN OTHER WORDS YOU CAN GET A DEMOCRACY SAYING THE PEOPLE WANT THIS, AND IN ITALY THAT'S EXACTLY WHAT HAPPENED IN THIS CASE, AND FINALLY COMMON SENSE AND SCIENTIFIC COMMUNITY WON OUT BUT A GOOD LESSON TO BE LEARNED FOR THE UNITED STATES IN TERMS OF DRUG APPROVAL, ET CETERA. >> THIS WAS NOT THE STAMINA CASE. THIS WAS MACARINA, MORE IN NORTHERN EUROPE BUT HE'S ITALIAN. THE STAMINA WAS AN IMPORTANT STEM CELL CASE WHERE THE GOVERNMENT SHUT DOWN BECAUSE MUCH OF CONCERNS, A MINISTER CONCERNED ABOUT THE APPROPRIATENESS OF STEM CELL THERAPEUTICS AND THE SCIENTIFIC COMMUNITY RALLIED IN AN IMPORTANT WAY, BUT IT'S A DIFFERENT AND COMPLICATED CASE. THIS WAS THE NEGATIVE CASE. THAT WAS NEGATIVE FOR DIFFERENT REASONS BUT ALSO POSITIVE IN THE SENSE OF SCIENCE BRINGING SOME RATIONILITY TO A POLITICAL SYSTEM, WHICH I'M GOING TO STOP RIGHT THERE. >> JEREMY, IN YOUR MID-PORTION OF YOUR TALK YOU HAD A SLIDE HOW TO CORRECTLY DO INNOVATION RESEARCH. NOW, THE STEPS, WRITTEN PLAN, PEER REVIEW, ET CETERA, ET CETERA, SOUNDS VERY MUCH LIKE WHAT WE WOULD CALL A PROTOCOL INSIDE THE INTRAMURAL PROGRAM. AND YOU DISTINGUISH THAT FROM A FULL-BLOWN CLINICAL PROCESS (INAUDIBLE) MULTI-INSTITUTIONAL LARGER SCALE NUMBER OF PATIENTS, ET CETERA. SO IF I UNDERSTAND WHAT STEVE SHOULD DO, HE SHOULD WRITE A PROTOCOL APPROVED BY HIS IRB TO PROCEED WITH WHAT WE'RE CALLING INNOVATIVE SMALL STEP RESEARCH IN THIS PARTICULAR PATIENT? >> SO GREAT AND THANK YOU FOR THE QUESTION. SO, YES, HE SHOULD WRITE DOWN WHAT HE PLANS TO DO. AND ARGUABLY HE SHOULD HAVE IT REVIEWED BY SOME PEERS BEFORE TRYING IT HIMSELF. I DIDN'T SAY IT WOULD NECESSARILY BE IRB APPROVED. THAT'S A SEPARATE QUESTION WHETHER IT CONSTITUTES RESEARCH. YES, THINGS -- THANK YOU VERY MUCH. SO THE REASON FOR THIS IS THAT WE REALLY -- YOU KNOW, WE HEARD A DESCRIPTION, WHAT WOULD BE IN THAT WRITTEN PLANT WOULDN'T BE NECESSARILY A FULL FLEDGED PROTOCOL. THERE'S A SCIENTIFIC BASIS, ARTICULATING WHAT THAT SCIENTIFIC BASIS IS, WHAT WE KNOW ABOUT THE ABLE USED OFF LABEL, THINGS IN HIS HEAD OTHER PEOPLE MAY OR MAY NOT KNOW. THIS WAS A PEER REVIEW, NOT WRITTEN, MAYBE POWERPOINT BUT THIS IS A PEER REVIEW. IF SOMEONE THOUGHT THAT'S CRAZY DEPENDING ON POWER STRUCTURE HERE YOU MAY SAY, STEVE, THAT'S NUTS, DON'T TRY THAT. OR, STEVE, THAT'S GREAT. TRY IT. SO, YEAH, BECAUSE WE DON'T HAVE ANOTHER WAY OF COMMUNICATING OTHER THAN WRITING DOWN AND COMMUNICATING TO OTHERS. THERE'S SOME KIND OF PEER REVIEW, NOT SAYING IRB REVIEW. THERE'S A PUSH BECAUSE WE WERE PRIVILEGING EVIDENCE-BASED PRACTICES. IF THERE'S A TRIAL ON THE SAME THING WE WOULD RATHER MOVE THAT PATIENT, IF POSSIBLE, INTO A CLINICAL TRIAL, IF SHE OR IS HE WILLING, BECAUSE WE CAN STAND TO LEARN IN A CONTROLLED SETTING. SO IT'S NOT EXACTLY BUT WE DIDN'T HAVE SOMETHING ELSE TO TURN TO, RIGHT? WE'RE MAKING IT UP. SO WHAT WE WERE MAKING UP IN THE ROOM IN THE GUIDELINES HOW CAN WE GET THE INFORMATION WE NEED SO WE CAN BE AS OBJECTIVE AS POSSIBLE AND MAKE SURE THAT THE PATIENT'S INTERESTS REALLY ARE UP FRONT. DID I -- >> YES, THAT'S GOOD. PART B OF MY QUESTION COMES TO THAT INFORMED CONSENT. SO, YOU KNOW, THIS ISN'T LIKE A PHASE 1 TRIAL WHERE I MEAN STEVE KNOWS HOW THIS DRUG WORKED IN PEOPLE WITH PSORIASIS BUT ADMITS TO NOT HAVING ANY IDEA HOW IT WILL WORK IN AN INDIVIDUAL WITH THIS PARTICULAR DISORDER. AND SO WHEN YOU SAY TRULY VOLUNTARILY INFORMED CONSENT, WHAT DO WE SAY TO THESE PATIENTS? WE'RE GOING TO TRY THIS, IT WORKED IN A DIFFERENT DISEASE SIMILAR TO WHAT YOU HAVE BUT NOT AT ALL LIKE IT, AND THESE WERE THE COMPLICATIONS THOSE PEOPLE HAD BUT WE HAVE NO IDEA BECAUSE WE'VE NEVER DONE THIS IN AN INDIVIDUAL LIKE YOURSELF? >> SOMETHING LIKE THAT, EVEN SIMPLER, EVEN MORE DIRECT. >> AS TRUTHFUL AS ONE CAN BE. >> WE'VE NEVER USED THIS DRUG IN SOMEONE WITH YOUR DISEASE. WE THINK THE DISEASE WORKS IN A SIMILAR WAY. WE DON'T KNOW. THIS DRUG HAS NEVER BEEN USED IN PEOPLE WITH YOUR DISEASE. WE DON'T KNOW WHETHER IT WILL BE BENEFICIAL OR HARMFUL. WE DON'T HAVE -- BEING AS DIRECT AND SIMPLE AS POSSIBLE ABOUT WHAT WE DON'T KNOW. >> AND THEN FINALLY IT MAY BE UNIQUE TO OUR INTRAMURAL ENVIRONMENT BUT TO HAVE INSTITUTIONAL ACCOUNTABILITY FOR THINGS HERE IS VERY DIFFICULT. WE HAVE AN IRB-APPROVED PROCESS. YOU'RE SUGGESTING SOMETHING THAT SYMPTOMS SLIGHTLY SHORT OF A FULL IRB PEER REVIEW, IF I UNDERSTOOD YOUR ANSWER? >> SO EVERY INSTITUTION CAN CONSTRUCTS WHATEVER -- SO YOU HAVE SIMILAR ISSUES WITH REVIEW OF QI AND QA. RIGHT? HOW YOU HANDLE QUALITY IMPROVEMENT WORK THAT'S GOING ON, SOME OF IT MAY COME TO THE IRB, SOME MAY NOT. SOME INNOVATION MAY COME. I'M AGNOSTIC HOW THAT'S OPERATIONALIZED AT A PARTICULAR INSTITUTION, AND DIGGING INTO THE INSTITUTION, HOW THAT WOULD HAPPEN. SOME PLACES MAY SAY JUST HAVE THE IRB REVIEW IT. OTHERS MAY SAY, NO, WE WANT TO HAVE A MEDICAL PRACTICE COMMITTEE OR INNOVATION COMMITTEE. SO AGAIN FIGURING OUT WHAT WORKS WITH AN INSTITUTION, THIS IS A UNIQUE PLACE, RIGHT? SO CARE, COMPLICATIONS, YOU KNOW, PEOPLE ARE GOING TO BE TAKEN CARE OF IN WAYS THEY MAY NOT AT A PRIVATE INSTITUTION. NOTICE THE OTHER THING IS THE PERSONNEL ARE QUALIFIED ISSUE, THIS IS REALLY INTERESTING. WHAT WE WERE TRYING TO ATTACK HERE, WHICH WASN'T DIRECTED AT THE NIH BUT PEOPLE TRYING STEM CELL INNOVATION IN THE WORLD IN PRIVATE SETTING CLINICS OR OFFERING OR MARKETING STEM CELL THERAPIES BEFORE THEY HAVE BEEN TESTED OR MAY NOT BE ACCOUNTABLE. LOOK ALSO AT THE CASE OF THE CORD BLOOD TRANSPLANT, WHAT WAS DONE. THEY TOOK -- THEY FOUND THE WOMAN WHO HAD DONE THE MOST TRANSPLANTS, SHE HAD NEVER DONE A CORD BLOOD TRANSPLANT, NO ONE HAD. BUT HAD THE MOST EXPERIENCE WITH THE RANGE OF COMPLICATIONS FOR FRANCONEY'S, RIGHT? WHAT DO YOU DO WHEN YOU BUILD A TEAM FOR THIS? EVEN IF NEVER USED IN THIS DISEASE WHO ARE THE PEOPLE WHO KNOW HOW THIS DRUG PERFORMS IN THE RANGE OF PATIENTS WITH PSORIASIS, MAYBE THEY KNOW SOMETHING ELSE. SO YOU WANT TO MAKE SURE YOU CONSTRUCT IT WHERE PEOPLE ARE PREPARED TOP DO IT. >> THANK YOU. >> JEREMY, FOLLOWING UP QUICKLY YOUR FIRST POINT ABOUT MAKING SURE THAT THE UNCERTAINTY IS PRESENTED VERY CLEARLY TO THE PATIENT SEEMS TO ME OBVIOUSLY CRUCIAL. AND I WAS WONDERING, DO YOU THINK THAT THAT'S SUFFICIENT, ARE THERE CASES WHERE YOU THINK IT'S SUCH A LONG SHOT THAT EVEN OFFERING IT, EVEN MAKING THE SUGGESTION TO THIS PATIENT WHO MIGHT END UP THINKING, THIS IS JEREMY SUGARMAN, ENDOWED CHAIR FROM JOHNS HOPKINS, HE'S SAYING IT'S A LONG SHOT BUT THAT'S WHAT HIS LAWYER IS TELLING HIM TO SAY, THERE'S A CHANCE, I'M GOING TO GO FOR IT. ARE THERE CASES YOU SAY IT -- YOU SHOULDN'T EVEN PUT IT ON THE PERSON'S PLATE, THEY ARE IN BAD SHAPE, THEY NEED TO ACCEPT IT AND YOU SHOULDN'T GO THERE? >> SO IF IT'S INNOVATION, FIRST BULLET HERE, IF WE WANT TO THINK ABOUT WHAT JUSTIFIES IT, THERE HAS TO BE A REAL PROSPECT, RIGHT? THIS ISN'T A PHASE 1 TRIAL IN A NORMAL VOLUNTEER TO SEE TOXICITY. THAT'S NOT INNOVATION. THAT'S RESEARCH, IF THERE'S A REASON TO DO THAT TRIAL. THAT'S TOTALLY DIFFERENT. THE ONLY JUSTIFICATION FOR THIS HANDFUL OF PEOPLE THAT GET INNOVATION THERAPIES, YOU REALLY THINK THAT THERE'S A BENEFIT. AND YOU CAN PERSUADE YOUR PEERS THAT THERE'S A PROSPECT. RIGHT? SO THAT'S HOW I WOULD PARSE THAT. OVER HERE. >> MY QUESTION IS BASICALLY THE SAME AS THE SECOND GENTLEMAN. IF WHAT YOUR REPORTING REQUIREMENTS ARE AS FAR AS INITIAL REVIEW, DOCUMENTATION REPORTING, WHEN YOU'RE USING SOMETHING OFF LABEL FOR THE FIRST TIME VERSUS SUBSEQUENT TIMES, YOU KIND OF COVERED THAT. >> YEAH, SO WHAT'S THE BREAK POINT? WE DIDN'T ANSWER THAT. WE DIDN'T KNOW. WE JUST SAID A SMALL NUMBER AND COULDN'T GET THAT FAR. WE'RE PUTTING THIS OUT HERE AS AN INITIAL APPROACH FOR PEOPLE TO TRY. THERE ISN'T REPLACED MUCH. IF YOU DO LOOK AT THE SURGICAL LITERATURE AS WELL, THEY HAVE A SIMILAR STRUCTURE WHICH TALKS ABOUT HAVING PEER REVIEW, RECOGNIZING CONFLICTS, AND THOSE SORT OF FEATURES. BUT THOSE ARE THE ONLY PLACES TO LOOK. >> THANK YOU FOR THE PRESENTATION. I WANTED TO ASK A QUESTION AND FOLLOW UP ON WHAT SORT OF THE DEGREE OF CERTAINTY A CLINICIAN SHOULD HAVE IN ORDER TO OFFER ONE OF THESE THERAPIES. ONE OF THE PHRASES THAT I HEARD MENTIONED A COUPLE TIMES WAS THAT SORT OF THE INNOVATIVE THERAPY SHOULD MAKE SENSE. BUT WHAT DOES THAT MEAN IN THE CONTEXT OF SORT OF MEDICAL BIOLOGICAL CLINICAL UNDERSTANDING, DOES IT MEAN HAVING A HUNCH, DOES ITS MEAN HAVING HEARD SOME CASE REPORTS, AS DAVE MENTIONED, DOES IT MEAN HAVING DONE WORK IN MOUSE MODELS, PRIMATE MODELS, WHAT DOES IT MEAN? WHAT'S THE KIND OF REASONABLE BELIEF THAT A CLINICIAN CAN HAVE TO HAVE A -- THAT THERE'S A REAL PROSPECTIVE BENEFIT IN ORDER TO OFFER? >> SO IT'S A GREAT QUESTION. IT'S A LIFE'S WORK TO SORT THAT. LIKE HOW DO WE KNOW AND HOW GOOD ARE WE AT PREDICTING WHETHER THERE WOULD BE A BENEFIT. WE TEND TO BE PRETTY BAD AT PREDICTING AND WHAT EVIDENCE-BASED MEDICINE TOLD US, WE'RE NOT AS SMART AS WE THINK WE ARE. THE PRACTICES THAT WE DO ANYWAY THAT WE WERE TRAINED TO DO, THE THINGS I WAS TRAINED TO DO AND LEARN AT THE TIME WITH CARDS IN MY WHITE POCKET, NOW REPLACED BY SOME OTHER DEVICES THAT NEED TO BE CHARGED UP PERIODICALLY, RIGHT, WERE ALL TRUTH AND HALF OF THEM HAVE BEEN DEBUNKED, RIGHT? SO THOSE TRUTHS OF EVEN THINGS THAT HAVE MARCHED THROUGH A TRADITIONAL PATHWAY HAVE BEEN SHOWN TO BE WRONG. SO HUMILITY. SO EACH OF THOSE THINGS YOU PUT UP THERE ARE POSSIBLE WAYS TO BUILD AN EVIDENTIARY BASE. THE CASE OF CORD BLOOD WAS DONE THROUGH MOUSE MODELS. OKAY. WE HEARD SOME OF THE SCIENCE TODAY THAT JUSTIFIES IT. WE'RE THINKING, OKAY, SO THAT'S A COMPELLING HYPOTHESIS. HOW MIGHT WE ANSWER IT? AND MAYBE THE ONLY WAY TO ANSWER THAT HYPOTHESIS IS THROUGH SOME TYPE OF INTERVENTION. RIGHT? BUT EACH ONE OF THOSE APPROACHES, WHAT DO WE KNOW FROM INCIDENTAL CASES, WHAT DO WE KNOW FROM CASE REPORTS WHERE SOMETHING -- YOU LOOK AT A FEW CASE REPORTS AND SEE A COMMON FEATURE THAT EACH CASE ALONG DIDN'T SEE AND SAY, IS THAT THE COMMON PIECE? IT'S HOW WE CONSTRUCT KNOWLEDGE, IT'S GREAT QUESTION. IF YOU CAN SOLVE THAT I DON'T KNOW IF IT CAN GET IN THE NEW ENGLAND JOURNAL BUT SOMEPLACE NICE. >> CHRISTINE? >> MY QUESTION IS ABOUT -- YOU SAID THERE'S A NEED TO BE CLEAR ABOUT WHAT INNOVATION ACTUALLY MEANS BUT IT SEEMS LIKE THE RIGOR OF THE REQUIREMENTS THAT YOU PUT TOGETHER FOR THE STEM CELL TRANSPLANT MIGHT BE A LITTLE OVERKILL, IF THAT'S THE RIGHT WORD, FOR AN OFF-LABEL DRUG FOR A DRUG THAT'S USED A LOT AND DOESN'T HAVE A LOT OF SIDE EFFECTS. SO, YOU KNOW, IF YOU'RE TALKING ABOUT -- THAT'S STILL INNOVATIVE TREATMENT, RIGHT, OFF LABEL AND HASN'T BEEN USED IN THIS DISEASE. >> SURE. >> DO YOU THINK THAT THE SAME, YOU KNOW, WRITTEN PLAN, PEER REVIEW, I FORGET THE WHOLE LIST, BUT ALL THOSE THINGS ARE EQUALLY NECESSARY DEPENDING ON WHAT THE OFF-LABEL INNOVATION IS? >> YEAH. >> OR IS THERE SOMETHNG MORE -- I MEAN THERE SEEMS TO BE SOMETHING MORE SIGNIFICANT ABOUT A STEM CELL TRANSPLANT THAN GIVING A DOSE OF A DRUG. >> GREAT. I DON'T KNOW IF I DO OVERTREAT OR OVERKILL, INNOVATION. SO, NO, I THINK YOU'RE RIGHT. IT MAY TOO MUCH, THAT ARCHITECTURE, FOR INNOVATIVE USE OF AN AGENT WE HAVE LOTS OF EXPERIENCE WITH, NOT ONE DISEASE INDICATION BUT TEN. AGAIN, HOW TO PARSE THAT ONE, I'M NOT SURE WHERE YOU DRAW THE POINT. THE PROBLEM WE WERE TRYING TO SOLVE REQUIRES THAT AND ESPECIALLY GIVEN THE SOCIAL FORCES WE HEARD IN THE FIRST QUESTION, YOU KNOW, WE'VE GOT GOVERNMENTS WEIGHING IN ON STEM CELL TRANSPLANTS, THOUSANDS OF PATIENTS RECEIVING UNPROVEN, UNTESTED STEM CELL INTERVENTIONS AROUND THE GLOBE THAT ARE EXTRAORDINARILY HARMFUL. WE'RE TRYING TO SOLVE A DIFFERENT PROBLEM. NOW, A FULLY MAPPED APPROACH TO ETHICS OF INNOVATION WOULD BE ABLE TO ACCOMMODATE WHAT ARE THESE DIFFERENT KINDS, AND IT WOULD PROBABLY DIVIDE THOSE UP INTO DIFFERENT PARADIGMATIC CASES THAT WE COULD USE. >> ALL RIGHT. >> DO WE GET TO HEAR WHAT HAPPENED? >> YEP. TYPICALLY WE END ETHICS GRAND ROUNDS WITH QUESTIONS, AND HEADACHES AS PEOPLE LEAVE AND GET NO CLOSURE, BUT WE HAVE GOOD NEWS. STEVE'S GOT A COUPLE SLIDES TO GIVE US CLOSURE TODAY. PUT UP THE LAST COUPLE SLIDES. >> OKAY. SO WE HAD TWO ENDPOINTS WE WERE FOLLOWING. THE FIRST WAS HIS TEETH. THAT'S WHAT HE CAME IN COMPLAINING ABOUT. AND SO IT WAS IMPORTANT TO ADDRESS HIS ISSUE FIRST. THIS IS WHAT HIS TEETH LOOKED LIKE BEFORE TREATMENT. THIS IS AFTER ONE MONTH. THIS DRUG GETS GIVEN AT THREE MONTHLY INTERVALS. ONE MONTH AFTER TREATMENT YOU CAN SEE HIS GUMS ARE MUCH LESS EDEMATOUS AND LESS RED, AND AFTER TEN MONTHS OF TREATMENT THEY REALLY LOOK TERRIFIC. TO GIVE AN OBJECTIVE MARKER OF THAT, BECAUSE THIS IS A LITTLE BIT HARD TO BE CONFIDENT ABOUT, THIS IS ABOUT BLEEDING. THIS IS A RATHER CRUDE MEASURE. YOU PROBE THE GUMS AND SEE HOW MUCH BLEEDING IT DOES. AND SO THESE ARE THE NUMBER OF BLEEDING SITES. WHEN HE CAME IN HERE, VIRTUALLY EVERY SITE THAT WAS PROBED BLED. BUT AFTER TREATMENT, YOU CAN SEE THE NUMBER OF BLEEDING SITES WENT WAY DOWN. NORMAL PEOPLE, IF YOU FLOSS YOUR TEETH, TEETH BLEED WHEN YOU MESS WITH THEM. I DON'T KNOW WHAT CAN YOU GET DOWN TO AS A LOW LIMIT BUT THIS WAS AN IMPROVEMENT. THEY LOOKED BETTER, FELT BETTER AND CANKER SORES WENT AWAY. MUCH MORE IMPORTANT AND IMPRESSIVE WAS THIS IS WHAT HE LOOKED LIKE AT THE BEGINNING, FOUR MONTHS INTO THERAPY, AFTER TWO DOSES, HE HAD ALREADY STARTED TO HEAL IN AND I'M NOT SURE, 16 MONTHS POST, BUT HE'S COMPLETELY HEALED. NOW, FOR HIM, WHAT HE CAME IN COMPLAINING ABOUT WITH THE TEETH, WHAT HE REALLY WAS INTERESTED IN WAS BEING ABLE TO RIDE HIS LITTLE MOTORCYCLE AGAIN AND COULDN'T DO IT BECAUSE IT WAS UNCOMFORTABLE AND I THINK WE CAN ALL GET THAT. AND NOW HE IS RIDING WITHOUT A HELMET WHICH IS NOT GOOD. [LAUGHTER] BUT IT IS WHAT HE WANTED. SO THAT'S OUR STORY. WE THINK IT WAS REALLY COMPELLING. IT WAS IMPORTANT BECAUSE IT SHOWED US AN ENTIRELY NEW MECHANISM THAT WE HAD NOT ANTICIPATED BEFORE, THROUGH INNOVATIVE WORK DONE BY NIKKI MATSOPOULOS AND HER GROUP IN HUMANS AND MICE THAT LED TO IS A DIFFERENT APPROACH. APROPO OF WHAT JEREMY IS SAYING AND IN AGREEMENT THE FIRST TIME WE DID IT BECAUSE IT WAS THERAPY FOR THIS GUY. HE HAD A PROBLEM. WE NEEDED TO FIX IT. BUT ONCE YOU GET PAST THAT FIRST TIME, AND SO, WELL, NOW I REALLY, REALLY BELIEVE THIS, THEN YOU GOT TO STOP, I THINK, AND SAY, OKAY, IT'S EASY TO BELIEVE WHAT YOU WANT TO BELIEVE, RIGHT? THE WORLD IS FULL OF STUFF LIKE THAT. AND THAT'S WHERE YOU GOT TO PUT THE BRAKES ON AND SAY, OKAY, NOW WE NEED A PROTOCOL. AND SO OUR PROTOCOL WAS WRITTEN, GOES TO ITERATION AND IRB, SO WE CAN TREAT TEN PATIENTS WITH THIS APPROACH. TEN IS NOT A BIG NUMBER. BUT IN THE WORLD OF RARE DISEASE, TEN IS A HUGE NUMBER. AND HOW MANY WOULD YOU NEED TO SEE TO SAY, YOU KNOW WHAT, WE GOT TO CHANGE PRACTICE FUNDAMENTALLY, [ NO AUDIO ] MOST PEOPLE DON'T COME IN WITH THIS PROBLEM BUT THEY ALL COME WITH THIS PROBLEM IF THEY STILL HAVE TEETH. THE GOAL TO TO GET YOUNG ENOUGH TO LET CHILDREN KEEP TEETH INTO ADULTHOOD AND NOW REGULATE INFLAMMATORY PROBLEMS THAT REALLY DO LIMIT THESE PEOPLE'S LIVES. SO I THINK IT'S BEEN A GOOD EXAMPLE HOW WE USE EVIDENCE-BASED MEDICINE IN A IS NOVEL EVIDENCE IN RARE DISEASE TO COME UP WITH MECHANISTIC APPROACHES, DOING IT AS A PROSPECTIVE PROTOCOL IS THE RIGHT AND LOGICAL THING TO DO NEXT. THANK YOU VERY MUCH. [APPLAUSE]