>> GOOD AFTERNOON, IT'S MY PLEASURE TO WELCOME YOU TO OUR OPEN SESSION OF OUR SUBCOMITTEE. AND WE HAVE VERY INTERESTING PROGRAM TODAY AND VERY GLAD TO HAVE DAVID COOPER HERE TO TALK ABOUT PROGRESS IN THE AREA OF XENOTRANSPLANTATION. BEFORE THAT, NAZARINE BOBBY WILL GIVE AN OVERVIEW OF OUR NIAID IMMUNOBIOLOGY OF XENOTRANSPLANTATION PROGRAM. A FEW WORDS ABOUT DIVISION ACTIVITIES THAT HAVE COME UP SINCE LAST COUNCIL MEETING OR COME UP SOON. ONE DR. FAUCI MENTIONED THIS MORNING APPOINTMENT OF DO WAY LYNN WHO IS NOW ASSOCIATE DIRECTOR IN DATE FOR BIOINFORMATICS. HE JOINED US IN FEBRUARY AND COMES TO US FROM UC DAVIS WHERE HE WAS FOUNDING DIRECTOR OF THE BIOINFORMATICS CORE PROGRAM IN THE UC DAVIS GENOME CENTER. HE BRINGS A LOT OF EXPERTISE IN COMPUTATIONAL BIOLOGY, HE WAS IN CHARGE OF THE COMPUTATIONAL BIOLOGY GROUP AT THE UNIVERSITY OF GEORGIA FOR FOUR YEARS AND BEFORE THAT, SPENT FIVE YEARS AT BROOK HAVEN NATIONAL LABORATORY WHERE HE PLAYED A VERY SIGNIFICANT ROLE IN THE MODERNIZATION AND OPERATION OF THE PROTEIN DATA BANK SO WE'RE PLEASED TO HAVE HIM AND I THINK SOME OF YOU WILL BE HEARING FROM HIM ABOUT HIS ACTIVITIES THAT WE HOPE WILL TRANSFORM DATA ACCESS BIG DATA SHARING AND THE LIKE AND YOU WILL SEE SOME PROGRAMMATIC EFFORTS IN THAT DIRECTION IN THE NEXT FEW YEARS. SINCE OUR LAST COUNCIL MEETING THERE HAVE BEEN A NUMBER OF FUNDING OPPORTUNITIES THAT VAN ANNOUNCED OR HAVE BEEN ANNOUNCED AND THE RECEIPT DATES OR APPLICATIONS HAVE ALREADY COME IN. THOSE ARE ON YOUR DIVISION UPDATE WHICH I THINK EACH OF YOU Z HA OR CAN PICK UP HERE. THERE'S OVER A DOZEN SO I'M NOT GOING TO GO INTO THEM IN DETAIL. ALSO SOME BRANCH UPDATES TO VARIOUS WORKSHOPS ON ALLERGY AND IMMUNOTHERAPY AND VARIOUS ACTIVITIES IN THE BASIC IMMUNOLOGY BRANCH RELATED TO INFANT IMMUNITY AND HUMAN IMMUNOLOGY PROJECT CONSORTIUM. SO PLEASE TAKE A LOOK AT THOSE. AND IF THERE ARE FUNDING ANNOUNCEMENTS THAT ARE STILL ACTIVE, PLEASE BRING THEM TO YOUR ATTENTION OF PEOPLE AT UNIVERSITIES OR ELSEWHERE BECAUSE WE WOULD WELCOME AS MANY APPLICATIONS AS WE CAN. SO WITH THAT I'M GOING TO ASK NASRIN TO GIVE THE OVERVIEW OF THE XENOTRANSPLANTATIONI/w PROGRAM AND THEN YOU CAN INTRODUCE DR. COOPER. >> THANK YOU. >> THANK YOU. GOOD AFTERNOON. MY NAME IS NASRIN NABAVI, PROGRAM OFFICER IN OFFICE OF NIAID. I WOULD LIKE TO INTRODUCE YOU TO OUR PROGRAM MY BIOLOGY OF XENOTRANSPLANTATION CALLEDDED RESEARCH PROGRAM OR FOR SHORT, IXCRP. THIS PROGRAM WIDE SUPPORT THE FIRST QUESTION IS WHY SUPPORT XENOTRANSPLANTATION PROGRAM? IN U.S. ALONE, ABOUT 110,000 PEOPLE EVERY DAY ARE WAITING EVERY DAY FOR RECEIVING ORGANS HUMAN ORGANS. AND AGING PEOPLE APPROXIMATELY DIE -- 18 PEOPLE APPROXIMATELY DIE EACH DAY BECAUSE THE WAITING THE RECEIVE AN ORGAN. XENOTRANSPLANTATION OFFERS POTENTIAL FOR SOLUTION TO SHORTAGE OF HUMAN ORGAN FOR TRANSPLANTATION. IN ADDITION 1.5 MILLIMETER PEOPLE WITH TYPE 1 DIABETES CAN BE MADE INSULIN FREE BY PIG ISLET XENOTRANSPLANTATION. OUR PROGRAM WAS ESTABLISHED IN 2005 BY CO-FUNDING FROM NIDDK, THE TYPE 1 DIABETES AND FUNDS AND THE FOCUS OF THE PROGRAM WAS TO CONDUCT XENOTRANSPLANTATION RESEARCH IN LARGE ANIMAL MODEL MEANING SWINE TO NON-HUMAN PRIMATES. WHY PIG ORGAN? BECAUSE PIG ORGANS ARE SIMILAR IN SIZE AND PHYSIOLOGY TO HUMAN ORGANS. AND GENETIC MODIFICATION OF THE PIG MAKES THE ORGANS MORE IMMUNOLOGICALLY COMPATIBLE TO NON-HUMAN PRIMATE AS WELL AS HUMAN. THE GOAL OF OUR PROGRAM WAS TO ADDRESS IMMUNOLOGICAL AND PHYSIOLOGICAL ISSUES RELATED TO XENOGRAFT ENGRAPHMENT SURVIVAL AND FUNCTION AND ALSO TO DEVELOP EVALUATE AND OPTIMIZE THE GENERAL IT CANNILY MODIFIED PIG MODEL FOR TRANSPLANTATION IN NON-HUMAN PRIMATES. IN 2005, THERE WAS FIVE SINGLE PROJECTS AWARDED TO FIVE DIFFERENT ACADEMIC SENT PARS AND THE PI OF DR. COOPER, DR.S COOPER, MCGRUGER PEERSON, ROBSON AND HERRING. FOCUS OF THE PROGRAM WAS ON HEART AND HEART KIDNEY LUNG AND LIVER AND OTHER SOLID ORGANS IN ADDITION TO ISLETS. THE PROGRAM WAS RENEWED, CLINIC PROGRAM RENEWED IN 2010 WITH NIAID FUNDS AND IN THIS ROUND THREE PROJECTS WERE FUNDED, ONE MULTI-PROJECT GRANT PI OF DR. COOPER AN UNIVERSITY OF PITTSBURG AND CO-INVESTIGATORS IN UNIVERSITY OF MARYLAND AND HARVARD. AND ALSO ALAN (INDISCERNIBLE) ARE OTHER PI OF THE OTHER TWO PROJECTS. SO AT THIS POINT I I WOULD LIKE TO INVITE DR. DAVID COOPER LONG STAND LEADER IN THE FIELD OF XENOTRANSPLANTATION TO BRING US UP TO DATE TO ADVANCES OF THE XENOTRANSPLANTATION RESEARCH IN GENERAL AND OUR PROGRESS OF CONSORTIUM IN PARTICULAR. DR. COOPER IS PROFESSOR OF SURGERY AT THE HI RICK TRANSPLANTATION INSTITUTE -- HISTORIC TRANSPLANTATION INSTITUTE, UNIVERSITY OF PITTSBURGH. >> THANK YOU VERY MUCH, INDEED NASRIN. I WOULD LIKE TO THANK NASRIN AN CHRISTY FOR THOSE TREMENDOUS HELP FOR THOSE WHO HAVE GRANTS IN THIS PROJECT. I'LL GIVE A BRIEF SUMMARY OF WHAT'S GOING ON IN XENOTRANSPLANTATION AND THE PURPOSE OF THIS IS TO IMPRESS UPON YOU THE PROGRESS WE'RE MAKING BECAUSE I THINK A LOT OF PEOPLE STILL FEEL THIS IS PIE IN THE SKY BUT IN FACT I CAN -- I HONESTLY THINK THAT WE'LL BE IN THE CLINIC VERY SOON. SO FIRST I'M CHAIRMAN OF THE SCIENTIFICKED VISERY BOARD OF A SMALL BIOTECH COMPANY THAT PROVIDES THE PIGS FOR US FOR SEVERAL GROUPS IN THIS GRANT. BUT I HAVE NO FINANCIAL INTEREST AND DO RECEIVE RENUMERATION FROM THEM. THE OFFSHOOT OF THE COMPANY IN SCOTLAND MADE SHEEPS A FEW YEARS AGO, THE COMPANY WENT OUT BUSINESS AND THEY HAVE INCREASED THE SKILLS NOW OF MICROINJECTION AND CLONING, ET CETERA, ET CETERA. THERE ARE SEVERAL TECHNIQUES THEY CAN USE WITHIN THE LAST FEW YEARS TO MAKE IT MUCH EASIER TO GENETICALLY ENGINEER A PIG, YOU CAN PUT SEVERAL GENES IN SEVERAL TIME KNOCK OUT SEVERAL GENES AT THE SAME TIME SO IT'S GETTING MORE FEASIBLE. THROUGH THESE XENOTRANSPLANTATION COOPERATIVE RESEARCH PROGRAM VIVICORE IS PROVIDING FIVE OF FIVE GROUPS INVOLVED IN IT. AND TO HELP PROGRESS IN XENOTROPE WORLDWIDE THEY PROVIDED PIG FOR GROUPS IN CHINA, GERMANY AND SOUTH KOREA. I WOULD POINT OUT GERMANY AND SOUTH KOREA AND CHINA ARE GETTING LOTS OF FUNDING FOR THIS PURPOSE. SO THE MEMBERS AT THE MOMENT AS YOU CAN SEE MY GROUP WHICH INCLUDES BETH ISRAEL IN HARVARD AND UNIVERSITY OF MARYLAND AND MAYO CLINIC AN EMORY. THIS IS WHAT NASRIN MENTIONED WHAT WE'RE ENTERED IN RESOLVE THE PROBLEM, THERE'S 110,000 PEOPLE WAITING FOR AN ORGAN OF ONE SORT OR ANOTHER. YOU CAN SEE IN BLUE THE NUMBER OF DONOR ORGANS THAT BECOME AVAILABLE IS HARDLY INCREASING AT ALL. ABOUT 30,000 A YEAR FROM 7 OR 8,000 SUITABLE DONORS. SO IT'S NOT REALLY IMPROVED IN TEN YEARS DESPITE MONEY BEING PUT INTO IT INCLUDING THROUGH THE NIH TO TRY TO GENERATE MORE SUITABLE DONORS. SO THE PROBLEM/mœ IS INTRACTABLE I BELIEVE. I USED TO BE A HEART TRANSPLAN SURGEON AND THE BIGGEST PROP I HAD WAS DONORS FOR THE PATIENTS, ONCE THEY GOT A TRANSPLANT THEY DID WELL. BUT GETTING A DONOR WAS THE PROBLEM, A LOT OF PATIENTS DIED WHILE WAITING. THIS GIVES AN IDEA ABOUT THE IMPACT THIS MIGHT HAVE TOO ON THE FINANCIAL AS SPECIFICS OF TRANSPLANTATION. THIS IS SOME DATA ON CHRONIC KIDNEY DISEASE. YOU CAN SEE WE SPEND IN THIS COUNTRY OVER $50 BILLION A YEAR ON PATIENT WITH CHRONIC KID NCI DISEASE. 4/5 THOSE PATIENTS NEVER GET TO RENAL TRANSPLANT ATE WATTING LIST. MOST NEVER GET THAT FAR AND THEY JUST GO ON CHRONIC DIALYSIS WHERE WE SPEND $20 BILLION. THE AMOUNT ON KIDNEY TRANSPLANTATION IS SMALL BECAUSE OF RELATIVELY SMALL NUMBERS BUT IT'S CHEAPER TO GIVE A PATIENT A KIDNEY TRANSPLANT AND THEY FEEL BETTER THAN IF ON DIALYSIS. THE LONGER YOU'RE ON DIALYSIS THE WORSE THE OUTCOME IS AFTER YOU HAVE A KIDNEY TRANSPLANT. THE BEST PATIENTS DO WELL AFTER KIDNEY TRANSPLANT IF NEVER ON DIALYSIS AND XENOTRANSPLANTATION ENABLES THAT TO HAPPEN BECAUSE YOU HAVE UNLIMITED NUMBER OF DONORS. I SAY IT REPRESENTS NEARLY A THIRD OF THE TOTAL MEDICARE uR SOW KNOW TRANSPLANTATION IS NOT A NEW IDEA YOU KNOW MYTHOLOGICAL FIGURES, THIS IS WHAT WE CONSIDER OUR PATRON SAINT OF XENOTRANSPLANTATION. EVEN IN THE 17th CENTURY THEY WERE DOING BLOOD TRANSFUSIONS BETWEEN PATIENT -- BETWEEN ANIMALS AND PATIENTS, USUALLY PATIENTS WITH MENTAL DISEASE AND THEY USE TO CHOOSE THE SHEEP AS A DONOR BECAUSE THINK THOUGHT THE SHEEP WAS DOCILE, GOING TO CALM THE PATIENT DOWN. A LOT OF PATIENTS WERE CALM BUT QUITE A LOT WERE DEAD AT THE END AS WELL. THE FIRST SCIENTIFIC EFFORTS TO IT WERE BY ALEX CORELL ON THE LEFT SUPPORTED BY LINDEBERG WHO WAS THE FIRST MAN TO FLY THE ATLANTIC IN A SIMPLE PLANE. AND THEY -- THEY WORKED ON TRYING TO KEEP ORGANS FUNCTIONING OUTSIDE OF THE BODY BECAUSE LIPIDBERG HAD A SISTER-IN-LAW WHO NEEDED A MITRAL VALVE REPLACEMENT AND HE THOUGHT HE WAS TOLD YOU CAN ONLY DO THIS IF YOU CAN KEEP THE HEART ALIVE THROUGH CARDIO BIPASS MACHINE BUT THEY STARTED LOOKING EXVIVO. ALEXIS CORE WILL BEL SAID THE IDEAL METHOD WOULD BE TO TRANSPLANT IN MAN ORGANS OF ANIMALS EASY TO SECURE AND OPERATE SUCH ADS HOGS FOR INSTANCE. BUT WITHIN ALL PROBABILITY BE P NECESSARY TO IMMUNIZE ORGANS OF HOG AGAINST THE HUMAN SERUM, WHAT WE'RE TRYING TO DO TODAY. WE'RE TRYING TO GENETICALLY MANIPULATE THE PIG SO THAT IT'S PROTECTED AND E O AGAINST THE HUMAN IMMOWN RESPONSE. SO THE FUTURE TRANSPLANTATION OF THERAPEUTIC PURPOSES DEPENDS ON FEASIBILITY OF HETERO TRANSPLANTATION, THE OLE WORD FOR XENOTRANSPLANT. HE SAID IN 1907, WEAR STILL TRYING TO DO IT MORE THAN 100 YEARS LATER. ONE REASON HE WON A NOBEL PRIZE IN 1912 FOR VASCULAR ADVANCE VASCULAR SURGERY. THIS PHYSICIAN WHO WAS A RUSSIAN IMMIGRANT LIVING IN PARIS, HE CAME UP WITH THE IDEA OF TRANSPLANTING CELLS TO PROVIDE HORMONES OR ENZYMES AND SO ON JUST WHAT WE'RE TRYING TO DO WITH ISLET TRANSPLANTS NOW, PUT THE CELL IN, THE CELL PRODUCES WHAT YOU NEED, AND YOU -- AND THAT IS EXACTLY WHAT WE'RE TRYING TO DO WITH DIABETES. HIS IDEA WAS TO PUT IN TESTICULAR CELLS TO AGING MEN WHO WERE RUNNING OUT OF STEAM, SO TO SPEAK. PEOPLE MY AGE OF LIFE THIS CAUGHT ON IN EUROPE AND THIS COUNTRY SEVERAL HUNDRED OR THOUSAND OF THESE OPERATIONS WERE CARRIED OUT. AND HE REPORTED FANTASTIC RESULTS FROM SOME OF THEM, THOUGHT OF HAVING IT DONE MYSELF BUT IT'S NOT -- [LAUGHTER] >> AND I CAN'T BELIEVE THAT ANY DID WELL BECAUSE HE WAS USING CHIMPANZEE KIDNEYS WHICH HE SLICED UP AND HE SLICED UP THE HUMAN -- CHIMPANZEE TESTICLES HE SLICED UP THE HUMAN AND PUT THE SLICES OF CHIMPANZEE IN THE SLICES OF THE HUMAN ONES SO I DON'T THINK TOO MANY PEOPLE CAME BACK FOR RETRANSPLANT AFTER THAT. YOU MAY BE INTEREST TO SEE HERE HE LOOKS TO ME HE NEEDS REJUVENATION HIMSELF. IN FACT JUST AT THIS TIME THIS IS ABSOLUTELY TRUE. HIS SECOND WIFE, A TEXAS OIL HEIRESS DIED AND HE MARRY AD 21-YEAR-OLD FRENCH LADY, I THINK THAT'S HE'S LOOKING A BIT JADED. THE FIRST CLINICAL TRIAL REALLY OF SIGNIFICANCE OF SCIENTIFIC -- CLINICAL TRIALS BACK SINCE 1905 BUT WAS BY KEITH RIMSE A WONDERFUL PERSON, WHEN HE WAS AT TULANE UNIVERSITY IN THE 1960, 63, 64 HE CARRIED OUT 13 KIDNEY TRANSPLANTS FROM CHIMPANZEES TO HUMANS WITH PRIMITIVE NEWSPAPER SUPPRESSION. AND THIS IS MOST OF THE THEM DIED WITHIN ABOUT SIX WEEKS FROM INFECTION OR FROM LACK OF IMMUNOSUPPRESSIVE ABILITY. BUT ONE PATIENT, THESE ARE CHIMPANZEE, PUT BOTH KIDNEYS THESE ARE POSTMORTEM BUT THEY LOOK ABSOLUTELY HISTOLOGICALLY NORMAL. AND THIS WAS NINE MONTHS AFTER THE TRANSPLANT. HERE ARE HER OWN DISEASE KIDNEYS WHICH WERE TAKEN OUT AT THE TIME OF THE POSTMORTEM SO WITH VERY PRIMITIVE IMMUNOSUPPRESSION, IN 1963, CHIMPANZEE KIDNEY SURVIVING, NOT REJECTED FOR NINE MONTHS IN A PATIENT WHO WEPT BACK TO WORK AS TEACHER AND DIED SUDDENLY OF WHAT THEY THOUGHT WAS AN LEK LIGHT DISTURBANCE, POTASSIUM OR SOMETHING. SO IF WE USE CHIMPANZEES WE DO WELL WITH DRUGS AVAILABLE BUT OBVIOUSLY WE'RE NOT GOING TO USE THEM FOR A NUMBER OF REASONS. THESE ARE SOME. IF WE USE PIGS WE HAVE AN UNLIMITED SOLI OF DONOR ORGANS. THEY'RE AVAILABLE ELECTIVELY WHICH IS EQUALLY IMPORTANT, YOU COME INTODAY YOU HAVE YOUR TRANSPLANT TOMORROW MORNING ON ROUTINE OPERATING LIST. YOU WON'T HAVE TO WAIT AROUND FOR THREE, FOUR, MONTHS IF YOU'RE A HEART PATIENT WAITING FOR DONOR IN THE MIDDLE OF THE NIGHT YOU WON'T HAVE TO WAIT SEVERAL YEARS ON DIALYSIS IF YOUR KIDNEY DONOR. IT ALSO WOULD AVOID -- WHEN I WAS WORKING AT CAPE TOWN WITH PROFESSOR CHRIS BALLARD WHO DID THE FIRST HEART TRANS PLANT WE DID BRAIN DEATH ON ORGANS AND THE PROCESS OF BRAIN DEATH DAMAGES ALL THE ORGANS. SO YOU'RE ALREADY DAMAGED ORGANS. ONCE YOU'RE BRAIN DID YOU CEASE TO METABOLIZE, YOU SWITCH OFF AEROBIC YOU ONLY METABOLIZE ANAEROBIC SO A LOT OF HEART IN EARLY DAYS USED TO FUNCTION VERY POORLY AFTER THE TRANSPLANT. SO YOU AVOID THIS BECAUSE YOU TAKE THE PIG TO THE OPERATING ROOM AND ANESTHETIZE THEM AND TAKE THE ORGANS OUT UNDER ANESTHESIA. THERE WOULD BE NO INJURY TO THE ORGANS. THEORETICALLY WE HAVE INFECTION FREE DONORS, EVERY YEAR INFECTION IS TRANSPLANTED WITH ORGANS TO PATIENTS AND PERHAPS FOUR OUR FIVE PATIENTS WHO GOT ORGANS THEN DIE OF INFECTION. WEST NILE FEVER, RABIES, ET CETERA. SO WE WOULD KNOW WHETHER THESE PIGS HAVE ANY INFECTIOUS AGENT WHICH IS GOING TO CARRY AND IF YOU LOOK AT CYTOMEGALY VIRUS AN EPISTEIN BARR VIRUS WE TRANS PLANT TO DONOR WHO GIVES IT. YOU CAN HAVE PIGS C AND V NEGATIVE. SO HUGE ADVANTAGE, WHEN I WAS A TRANSPLANT SURGEON I WOULD SEE 140 PATIENTS REFERRED FOR HEART TRANSPLANT EACH YEAR. I KNEW I WAS NOT GOING TO GET MORE THAN 20, 30 DONORS SO I WAS VERY RIGID IN SELECTION. I WANTED TO SELECT PATIENTS THAT WERE GOING TO DO WELL SO I SELECTED HALF OF THOSE 140 AND I TRANSPLANTED LESS THAN HALF OF THOSE. SOME OF THEM WOULD HAVE DONE OKAY FOR A FEW YEARS, THEY WEREN'T STELLAR CANDIDATES, THEY HAD PERIPHERAL VASCULAR DISEASE OR SOMETHING TO GIVE A DISADVANTAGE SO I WOULD RESULT THEM OUT BUT IF I HAD A LIMITEDDED NUMBER OF DONORS I TRANSPLANT MORE AND GIVE PATIENT GOOD QUALITY OF LIFE FOR A FEW YEARS EVEN IF NOT TO TEN OR 20 YEARS. SO THIS MAKES A HUGE DIFFERENCE TO THE NUMBER OF PATIENTS YOU SHOULD TRANSPLANT. SOME COUNTRIES HAVE CULTURAL BARRIERS TO DONATION, THEY ONLY HAD 20 HEARTS EVER DONATED IN JAPAN SO NOBODY WANT TO DONATE SO THEY'RE FROM LIVING DONORS KIDNEY PARTIAL LIVER, ET CETERA. AS NASRIN MENTIONED 1.5 MILLION WITH TYPE 1 DIABETES, 22 MILLIMETER WITH TYPE 2 DAY BEE TEASE, YOU'LL NEVER SOLVE THAT PROBLEM WITH 7,000 DONORS A YEAR. SO YOU'RE ONLY GOING TO SOLVE THAT WITH XENOTRANSPLANTATION. SO WE'RE INTERESTED TO ALL THESE ORGANS ALL ORGANS ISLETS CORNEASES, THERE'S A HUGE WAITING LIST FOR CORNEASES, THERE'S ESTIMATED 2 MILLION PEOPLE IN CHINA ALONE WHO COULD DO WITH A CORNEA TRANSPLANT. AND I WON'T TALK CORNEAS BUT WE'RE CLOSE WITH GENETICALLY HE CAN NEARED PIGS TO -- ENGINEERED PIGS TO GET THEM FUNCTIONING IN MONKEYS, I BELIEVE BY THE END OF THE YEAR THE GROUP IN SOUTH KOREA WILL START A CLINICAL TRIAL OF CORNEA TRANSPLANTS. IT'S A HUGE PROBLEM, NOT SO MUCH IN THIS COUNTRY BUT WORLDWIDE. NEURONAL CELLS FOR PATIENTS WITH PARKINSON'S DISEASE, THERE'S 8 MILLION PEOPLE WITH PARKINSON, THERE WAS A GROUP IN EUROPE WITH OUTSTANDINGINGLY GOOD ENCOURAGING RESULTS PUTTING PIG NEURONAL CELLS TO MONKEYS THAT HAVE A PARKINSON LIKE CONDITION AND CURING FOR PERIODS OF MORE THAN A YEAR. IF YOU DON'T WANT A LIVER TRANSPLANT (INDISCERNIBLE) RED BLOOD CELL TRANSFUSION. THERE'S A HUGE SHORTAGE OF TRANSFUSION BLOOD WORLDWIDE,PARTICULARLY IN COUNTRIES WHERE HIV IS COMMON BECAUSE MOST DONORS ARE HIV POSITIVE. THOUGH WE'RE NOT THERE YET I FIRMLY BELIEVE IN ONE DAY ALL OF OUR BLOOD TRANSFUSIONS WILL BE USING PIG RED BLOOD CELLS RATHER THAN HUMAN RED BLOOD CELLS WHICH WILL SOLVE THE PROBLEM OF MULTITUDE OF TESTS YOU DO THE MAKE SURE HUMAN IS NOT CARRYING AN INFECTIOUS ORGANISM. WHAT ARE THE PROBLEM? THERE'S A NUMBERND P THE MOST IMPORTANT DEALING WITH AT THE MOMENT IS IMMUNOLOGIC PROBLEM. SO LET' LOOK AT THAT. THE IMMUNOLOGIC ASPECTS INCLUDE INNATE IMMUNE RESPONSE MAINLY ANTIBODIES OMPLIMENT CELLS INNATE IMMUNE CELLS, ADAPTIVE IMMUNE RESPONSE, T-CELLS, B CELLS. IN ADDITION COAGULATION DYSFUNCTION WHICH IS PARTLY PROBABLY SET OFF BY THE IMMUNE RESPONSE BUT THERE ARE COAGULATION DISCREPANCIES BETWEEN PIG AND HUMAN AND BABOON WE'RE HAVING THE DEAL WITH, I'LL COME TO THAT IN A MINUTE. THEN H OOHs INFLAMMATORY RESPONSE, ONGOING INFLAMMATORY RESPONSE WHICH IS LINKED UP WITH IMMUNE RESPONSE BUT WE'RE LOOKING AT SLIGHTLY SEPARATELY. SO WHERE ARE WE WITH PIG ORGAN TRANSPLANTATION? WE LOOK AT ORGANS FIRST. HERE IS A PIG KIDNEY THAT WAS PUT INTO A BABOON, WILD TYPE PIG MODIFIEDD TO A BABOON WITH NORMAL IMMUNOSUPPRESSION YOU GIVE A PATIENT WHICH IS MAINLY AGAINST T-CELL RESPONSE AND WITHIN MINUTES, LITERALLY MINUTES, FIVE OFFER SIX MINUTES IT LOOKS LIKE THIS, BLACK, COMPLETELY DESTROYED THROMBOSED, HEMORRHAGIC INTO THE TISSUES, EDDY MARKS STOP FUNCTIONING. THE SAME HAPPENS WITH THE HEART AND EVERYTHING ELSE. SO THAT'S HOW YORUBAS LINE, FIVE, SIX MINUTES SO REMEMBER THAT. ON THE SURFACE OF VASCULAR ENDOTHELIUM OF THE PIG SHELL ARE SUGARS STICKING OUT WHICH ARE ANGIOGENIC AND ANTIBODIES BIND THE THEM, WE HAVE NATURAL ANTIBODIES AGAINST THE SUGARS BECAUSE THE SAME IS ON VARIOUS MICROORGANISMS THAT INVADE OUR COLONIZED GUT DURING FIRST THROW MONTHS OF LIFE. YOU GET THEM IN THREE MONTHS AS A DEFENSE MECHANISM AGAINST THESE ORGANISMS. AND BECAUSE THE PIG HAS THE SAME SUGARS ON SURFACE YOU IMMEDIATELY GET ANTIBODY BY COMPLIMENT ACTIVATION AND DESTROY THE ORGAN RAPIDLY. THESE NATURAL ANTI-PIG ANTIBODIES ARE MAINLY DIRECTED TOWARD GALACTOSE SUGAR, MY OWN GROUP IN THE 1990s WAS ABLE TO IDENTIFY. AND IF YOU LOOK AT THE PORCINE VASCULAR ENDOTHELIUM OPT LEFT, THE THREE -- ON THE LEFT THE THREE MAIN STRUCTURES HERE, THE IMPORTANT ONES FROM OUR POINT OF VIEW, WHERE WE HAVE THE A, B -- WHERE WE HAVE -- SORRY. WHERE WE HAVE THE ABO STRUCTURES THE VASCULAR ENDOTHELIUM THE PIG HAS GALACTOSE SUGAR SO IT'S AN ABO INCOMPATIBLE TRANSPLANT AND IN HUMANS TWO-THIRDS INCOMPATIBLE TRANSPORT PLANTS IF YOU DON'T PREVENT WILL CAUSE REJECTION. BECAUSE PIG IS 100% FROM PIG TO HUMAN OR PIG -- AND THERE IS -- YOU CAN SEE THE GALACTOSE, THE SIGH LICK ACID ARE IDENTICAL. THERE IS ONE OTHER SUGAR ON THE PORCINE VASCULAR ENDOTHELIUM, AN END GLYCOLYTIC WE HAVE ANTIBODIES AGAINST IT SO CLINICAL TRANSPLANTS WE'LL DEAL WITH THAT AS WELL BUT THERE'S PIG THIS IS'S BEEN KNOCKED OUT AND THE REASON I HAVEN'T GOT IT HERE IS BECAUSE THE PRIMATE, THE NON-HUMAN PRIMATE SUCH AS THE CHIMPANZEE AND BABOON ALSO HAVE SUGAR SO IN THE WORK I'M SHOWING YOU, PIG TO NON-HUMAN PRIMATE IT DOESN'T PLAY A ROLE BUT IT WILL PLAY A ROLE WHEN WE COME TO THE HUMAN. HERE LOOKING AT THE BLOOD -- THE STRUCTURE OF BLOOD GROUP A AND BLOOD GROUP B YOU CAN SEE HOW CLOSE TO IT IS THE -- IT'S ALMOST PART OF THE B SUGAR, THAT'S WHY YOU CAN THINK OF IT ALMOST AS PIG BLOOD GROUP. THE ANSWER TO THIS IS GENETIC ENGINEERING. WE TRIED WAYS TO ABSORB THE ANTIBODY TO BLOCK A COMPLIMENT AND YOU O FIGHTING A LOSING BATTLE. IF YOU DON'T GENERAL IT CANNILY ENGINEER THE PIG TO PROTECT IT YOU'RE NOT GOING TO GET ANYWHERE. THE FIRST APPROACH IN 1993 WAS TO KNOCK OUT THE GENE FOR THE ENZYME THAT PUTS THE SUGAR ON THE SURFACE OF THE PIG BLOOD VESSELS BUT IT WASN'T UNTIL -- WASN'T UNTIL TEN YEARS LATER IT WAS POSSIBLE TO DO WHEN THE CLONING TECHNOLOGY CAME IN. SO THIS WE THOUGHT IF YOU HAVEN'T GOT THIS TARGET SUGAR, YOU'RE MUCH BETTER OFF, THAT PROVED TO BE THE CASE. THE SECOND APPROACH, INTRODUCED BEFORE, WAS TO MAKE THE PIG TRANSGENIC FOR A HUMAN REGULATORY PROTEIN. WE HAVE COMPLIMENT CIRCULATES IN OUR BODY, TO KILL BACTERIA, SO ON BUT WE HAVE HUMAN COMMON REGULATORY PROTEIN ON OUR VASCULAR THAT PROTECTS FROM THE EFFECTS OF HUMAN COMPLIMENT, PIG HAS PIG COMPLIMENT REGULATORY PROTEIN BUT NOT EFFECTIVE AGAINST HUMAN COMPLIMENT SO WE PUT INTO THE PIGS ONE OR MORE HUMAN COMPLIMENT PROTEIN SUCH AS CD 55, DAF OR CD 46 WHICH IS MCP. AND I WANT TO IMPRESS UPON YOU HOW CLEVER THE MOLECULAR BIOLOGISTS AND CLONERS ARE TODAY. THIS BOTTOM HERE IS THE EXPRESSION OF CD 46, ONE HUMAN IN THE HUMAN SO NATURAL EXPRESSED AND HERE IS CD 55 IN THE HUMAN. AND YOU CAN SEE IN THE PIGS THAT WE HAVE GOT AVAILABLE NOW, THE EXPRESSION OF HUMAN CD 46 IS HIGHER THAN IT IS IN THE HUMAN. AND THE EXPRESSION IN HUMAN CD 55 IS HIGHER THAN IT IS IN THE HUMAN. IF YOU LOOK AT SOME OF THE COAGULATION REGULATORY PROTEINS I'LL COME IF TO IN A MINUTE, THROMBO MODULINNING THIS IS HUMAN THIS IS PIG. SO THEY'RE CLEVER WE HAVE PIGS THAT EXPRESS MORE HUMAN PROTEINS THAN WE DO OURSELVES. THESE PIGS ARE HEALTHY AND BREED PERFECTLY WELL IF YOU OUTBREED THEM, TAKE STEPS BUT THEY BREED PERFECTLY. THEY'RE HEALTHY. SO NOW IF YOU HAVE THESE ANTIBODIES THAT YOU HAVE NOW BLOCKED, SO THEY DON'T CAUSE HYPERACUTE REJECTION BUT WHEN YOU PUT A GRAFT IN, UNLESS YOU GIVE GOOD IMMUNOSUPPRESSION YOU WILL GET ELICITED ANTIBODIES JUST AS YOU DO WITH HUMAN GRAFT YOU DEVELOP NEW ANTIBODIES TO NEW TARGETS ON THIS ORGAN. SO AND THAT'S PREVENTED BY IMMUNOSUPPRESSIVE THERAPY AFTER EXPOSURE TO PIG ORGAN OR CELLS, YOU HAVE A T-CELL DEPENDENT IMMUNE RESPONSE AND IT CAN BE 100 TIMES HIGH THEY WERE P THE NATURAL ANTIBODIES YOU STARTED WITH, AND THEY OBVIOUSLY WILL CAUSE REJECTION. BUT LUCKILY WE NOW HAVE IMMUNOSUPPRESSIVE THERAPY PI THAT BLOCKS THAT ELICITED RESPONSE SO IN THE PIG PRIMATE MODEL, IT'S NO LONGER A PROBLEM. WE DO NOT GET ELICIT RESPONSE BUT HERE AGAIN, THE GENETIC ENGINEERING CAN HELP US. THIS IS A PIG THAT HAS THE MHC CLASS 2 TRANSACTIVATOR, C 2 KNOCK DOWN THAT THE TRANSACTIVATOR AND YOU CAN SEE HERE THAT ALTHOUGH YOU HAVE -- WHEN YOU HAVE NO ACTIVATION OF THE PIG ENDOTHELIAL CELLS, YOU HAVE SOME EXPRESSION OF THIS CLASS 2. WHEN YOU ACTIVATE THEM YOU HAVE A BIGGER EXPRESSION. THIS IS IN A NORMAL PIG CELL IN VITRO. BUT WHEN YOU HAVE THE CLASS 2 KNOCK DOWN YOU GET MUCH LESS EXPRESSION TO START WITH, AND WHEN YOU ACTIVATE YOU GET VIRTUALLY -- VERY LITTLE EXPRESSION. EXOGENOUS IMMUNOSUPPRESSION BY MANIPULATING THE PIG. WE CAN PUT IN A A IMMUNOSUPPRESSIVE GENE INTO FIG. WE HAVE PIGS THAT EXPRESS ONE OF THESE CO-STIMULATORY T-CELL BLOCKAID MOLECULES THAT EXPRESS MORE THAN TEN TIMES THE AMOUNT IN THE BLOOD YOU EXPRESS IN A PATIENT. IT WAS RECEIVING THE DRUG. SO THE EXTREMELY EFFECTIVE UNFORTUNATELY BECAUSE THEY EXPRESS SO MUCH THEY IMMUNOSUPPRESS THEMSELVES AND GOT INFECTION SO WE HAD TO STOP. WE PUT THEM JUST INTO THE CELLS ISLETS. I'M IMPRESSING HOW ABLE THIS MOLECULAR BIOLOGY AND THIS TECHNOLOGY IS. THERE'S WAYS TO REDUCE IMMUNOSUPPRESSION WHICH VERY IMPORTANT PARTICULARLY WHEN YOU TREAT PATIENTS SAY YOUNG PATIENTS WITH DIABETES ON IMMUNOSUPPRESSION FOR MANY, MANY YEARS, AS A CURE FOR THEIR DIE BOW TEASE, WE WANT AS LITTLE AS POSSIBLE, THE MORE YOU CAN DO TO THE PIG, THE LESS YOU CAN DO -- YOU HAVE TO DO TO THE PATIENT. THIS IS THE FIRST TIME IN TRANSPLANTATION WE HAVE BEEN ABLE TO MANIPULATE THE DONOR INSTEAD OF MANIPULATE ONLY THE RECIPIENT. WE HAVE A NUMBER OF TECHNIQUES BACK WE HAVE A NUMBER OF TECHNIQUES RATHER THAN HEART TRANSPLANT OR KIDNEY TRANSPLANT PIG TO BABOON, WE HAVE A NUMBER OF TECHNIQUES, THIS IS JUST AN ARTERY PATCH BABOON. IT EXPOSES ENOUGH OF THE SUGARS AND THE PROTEINS ON THE PIG VASCULAR END THEE YUM TO CAUSE A RESPONSE SO IT'S A SIMPLE WAY OF GETTING A RESPONSE, T-CELL RESPONSENESS AND IS THE IMMUNOSUPPRESSION WE'RE GIVING OR THE PATCH GENETICALLY MODIFIED SUFFICIENTLY TO SUPPRESS THAT RESPONSE. SO WE HAVE DONE A LOT OF WORK IN MODELS LIKE THIS. BASED ON A MODEL TOO MUCH WHICH IS SIMPLE. SO WHERE ARE WE WITH USING JUST FAIRLY SIMPLE PIGS AT THE MOMENT, THE KNOCK OUT ONES WHERE THEY DO NOTECASE PRESS THE WHERE THEY HAVE ONE COMPLIMENTARY REGULATORY PROTEIN. AND WE SEE NO OBVIOUS ANTIBODY MEDIATED OR CELLULAR REJECTION. NO REJECTION. KITE DIFFERENT FROM THAT 5 TO 6 MINUTE PICTURE I SHOWED YOU. NO HYPERACUTE REJECTION, NO LATE REJECTION. BECAUSE THE IMMUNOSUPPRESSIVE THERAPY AND THE MANIPULATION OF PIG IS SUFFICIENT TO PREVENT THAT. ONE GOOD THING IS THAT WHEN YOU PUT A COMPLIMENT REGULATORY PROTEIN O KNOCK OUT THE GAL NOT ONLY DO YOU PREVENT THAT ANTIBODY RESPONSE YOU ACTUALLY REDUCE THE T-CELL RESPONSE WHICH IS SOMETHING WE DIDN'T EXPECT BUT THE MORE WE DO TO THE PIG, THE MORE REDUCING THE BASIC T-CELL RESPONSE AS WELL WHICH IS ENCOURAGING. WHICH ARE SEEING CO-ING ALATORY, THROMBOTIC ANGIOPATHY AND THE THE KIDNEY CONSUMPTIVE COING ALOPOTHY DEVELOPED THAT THE BABOON WILL BLEED BECAUSE HE USED UP ALL HIS COAGULATION FACTORS. IN LIVER WE SEE AN IMMEDIATE THROW BOW CYTOPENIA WHICH LEADS TO HEMORRHAGE AND LUNG WE SEE VARIOUS ASPECTS OF CO-AGOLATION DYSFUNCTION. -- COAGULATION DYSFUNCTION. SO HERE IS A PICTURE OF A HEART SINCE MONTHS AFTER TRANSPLANT TO A BABOON. AND THIS WAS JUST A KNOCK OUT HEART BUT YOU CAN SEE THERE IS EXTENSIVE THROMBOSIS IN THE BLOOD VESSELS, SURROUNDED BY ISCHEMIC FIBROSIS BECAUSE THIS HEART HAS SUFFERED MULTIPLE MYOCARDIAL INFARCTIONS OVER THE SIX MONTH PERIOD. EVENTUALLY WILL STOP BEATING. WHAT WE'RE -- THIS IS THE PROBLEM WE'RE FACED WITH NOW, THIS MORE CHRONIC STATE OF THROMBOTIC MICROANGIOPATHY. BUT WE'RE BEGINNING TO OVERCOME THAT EVEN WITHOUT THROMBO REGULAR WILLTY GENES LONGEST SURVIVAL IS EIGHT MONTHS N. NHLBI TODAY THISSER VERY DAY, A GROUP LED BY MOHAMMED (INAUDIBLE) USING THESE CD 46 HEARTS FROM (INDISCERNIBLE) HE WILL EXTEND BEYOND 8 MONTHS TODAY. THE FIST TIME BUT THAT PIG TODAY THE HEART THAT HAS THROMBO MODULIN IN IT AS WELL. SO H IS THE LONGEST SURVIVAL IN THE WORLD. THE KIDNEY WE GET TO THREE MONTHS IS MORE PROBLEM TO OVERCOME THROMBOSIS AND COAGULATION SO ON. THE LIVER WE GET TEN DAYS BECAUSE WE LOSE ALL THE PLATELETS AND THE LUNGS IS PARTLY BECAUSE THEY'RE THIN FRAGILE ORGAN WE ONLY GET UP TO FIVE DAYS. WE USE THE LUNG AS PREDICTOR FOR WHAT HAPPENS IN THE HEART AND KIDNEY, WE SEE THE SAME PATENT BUT MORE RAPIDLY. BUT EIGHT MONTHS IS BETTER THAN FIVE OR SIX MINUTES. SO WHAT COULD WE DO ABOUT THIS? WE THINK THIS IS THE VASCULAR ENDOTHELIAL CELL IS ACTIVATED BY NTP NON-GAL ANTIBODIES THAT WE HAVEN'T IDENTIFIED WHICH ARE WEAKER THAN THE ANTI-GAL INHIBITORS BUT THEY'RE THERE SO WE GET LOW GRADE ACTIVATION WHICH CAUSES A PRO COOINGING A LISTEN STATE THE TAKE PLACE IN VASCULAR ENDOTHELIUM, THEREFORE THROMBOTIC MICROANGIOGRAPHY DEVELOPING. WE KNOW THERE'S BETWEEN PIG AN PRIMATE WHICH ENHANCE THAT VERY SIGNIFICANTLY. SO WE'RE PAYING ATTENTION NOW TO TRY TO MANIPULATE THE PIG TO GIVE IT SOME HUMAN ANTI-COAGULATION FACTORS RATHER THAN JUST PRO COAGULANT ONE. HEARSAY THE APPROACH NOW, THE CD 46 PIGS SOMETIMES WITH OTHER COMPLIMENT REGULATORY PROTEINS AS WELL. TRANSGENIC FOR HUMAN ANTICOAGULANT OR THROMBO MODULIN C RECEPTOR ET CETERA THAT ARE KNOWN TO BE PART OF THE ANTICOAGULATION IN HUMANS THAT MAINTAIN OUR VASCULAR ENDOTHELIUM IN ANTI-CO-ING A LAP STATE SO WE THROMBOSE OUR OWN VESSELS AS THE BLOOD PASSES THROUGH. SO IN JULY I WILL RECEIVE PIGS WITH TWO COMPLIMENTARY PROTEINS AN THREE COAGULATION REGULATORY PROTEINS SO WE'RE GETTING GOOD PIGS AND I SUSPECT WILL DO VERY WELL. WE LOOK AT ALL THESE THINGS INASMUCH AS WE CAN BECAUSE PIG TO PRIMATE WORK IS EXPENSIVE AND SO WE DO AS MUCH AS WE CAN IN VITRO. AND HERE YOU CAN SEE IF YOU TAKE A PLATELET AGGREGATION ASSAY, IN VITRO AGGREGATION ASSAY, MODIFIED PIG CELLS MIXED WITH HUMAN PLATELETS, OR HUMAN BLOOD, YOU WILL GET WITHIN AN HOUR OR TWO YOU WILL GET ABOUT 55 TO 60% AGGREGATION OF THOSE PLATELETS. YOU CAN MEASURE THEM WE DIDN'T SEE HERE. YOU CAN MEASURE THEM IN A MACHINE HERE, YOU GET A CURVE YOU GET ABOUT 60%. WHEN YOU HAVE GET A PIG DOWN HERE, WITH A GAL KNOCK OUT CD 46 WITH THROMBO MODULIN YOU'RE DOWN TO HALF, 25%, NOT AS GOOD AS HUMANS BUT ARCPCR, ACCENTUATES 20 FOLD EFFECT OF THROMBO MODULIN. WE HAVEN'T HAD A PIG YET WITH THROMBO MODULIN AND DPCR AN WE BELIEVE WHEN WE HAVE THESE PIGS THIS WILL DROP RIGHT DOWN ALMOST TO LEVEL OF HUMAN WHEN YOU PUT HUMAN CELLS INTO THIS MODEL. SO WE'RE MAKING STEADY PROGRESS IN THAT RESPECT. HERE IS A SMALL SERIES, THESE ARE SOME PIGS THAT -- THE PIG HEART WAS PUT IN TO A BABOON WITH THE SAME IMMUNOSUPPRESSIVE REGIMEN BUT DIDN'T EXPRESS THROMBO MODULIN WITHIN TWO OR THREE WEEKS WE HAVE A GREAT DROP IN THE NUMBER OF PLATE -- OF FIBRINGEN BECAUSE THE FIBRIN IS STICKING IN THE HEART. HERE IS THREE PIGS, THREE HEART BABOONS THAT HAD PIG TRANSPLANTS THAT DID HE CANS FROM THROMBO MODULIN, YOU CAN SEE NORMAL RANGE OF FIBRINGEN IS MAINTAINED. HERE IS THE SAME WITH THE PLATELET COUNTS WITHIN DAYS THE PLATELET COUNTS START TO DROP BECAUSE THE PLATENESS IS STICKING IN THE HEART. HERE WE MAINTAIN OVER PERIOD OF FOUR MONTHS WITH NO LOSS OF PLATELETS. AND I POINT OUT THAT THE THREE HERE, THAT WE DID, TWO OF THEM HAD VERY LOW LEVELS OF THROMBO MODULIN, THEY WERE NOT FROM THE REVIVICORE BUT A GROUP ABROAD THAT GAVE US THE PIGS BUT ABOUT 10% EXPRESSION INSTEAD OF 90% OF HUMAN THROMBO MODULIN SO WE DID WELL EVEN WITH 10% EXPRESSION. HERE IS A ONE THAT WE DID ON DAY 52, WE HAD A BIOPSY, THIS IS A HIGH EXPRESSOR, THIS IS THE HEART AND NEARLY TWO MONTHS AFTERWARDS YOU CAN SEE ABSOLUTELY NORMAL, NO SIGNS OF THROMBIN GENERATION IN THIS THROMBO MODULIN EXPRESSING HEART. THOUGH WE'RE DOING WELL WITH HEART AND EVEN KIDNEYS WE'RE DOING BETTER WITH PIG ISLETS AND AS THE PIG ISLETS ARE SIMPLE, LESS RISK TO THE PATIENT, THIS IS WHY CLINICAL TRIAL WILL COME EARLIER, WITH ISLETS. IF THE ISLETS DON'T WORK, THE PATIENT IS STILL DIABETIC BUT HE'S NOT THREATENED BY CONSUMPTIVE COAGULOPATHY, JUST HAS TO GO BAG TO INSULIN. SO LET ME TELL YOU WHERE WE'RE GOING. AS WE HEARD THERE'S WELL OVER A MILLION PEOPLE WITH TYPE 1 DIABETES, JUVENILE DIABETES AND WITH 7 OR 8,000 DECEASED HUMAN DONORS PARTICULARLY WHEN YOU HAVE TO USE WITH HUMAN ISLETS YOU HAVE TO OFTEN USE TWO OR THREE DONORS TO PROVIDE ENOUGH ISLETS FOR PATIENT SO WE'RE NEVER GOING TO SOLVE PROBLEM WITH HUMAN DONORS. AND SPENDTURE ON DIABETES IS ALMOST THE SAME AS KIDNEYS. ABOUT 210 BILLION IS EXPENDED ON PATIENTS WITH DIABETES. PATIENTS WITH DIABETES WILL LIVE AT LEAST TEN YEARS LESS THAN THE REST OF US. ABOUT MORE THAN 10% OF ALL IS ON DIABETES SO A HUGE PROBLEM TO PATIENT AND COMMUNITY. PIG INSULIN DIFFERS FROM HUMAN INSULIN BY ONE AMINO ACID, IT WAS USED CLINICALLY FOR DECADES BEFORE WE HAD RECOMBINANT HUMAN SO WE KNOW IT WORKS WELL. AND AS I SAID THERE COULD BE UNLIMITED SUPPLY OF PIGS. I JUST POINT OUT FOR HEPARIN WHICH IS ALSO MADE FROM PIGS. AND MAINLY CHINA THESE DAYS THEY SLAUGHTER 600 MILLION PIGS A YEAR TO GIVE US HEPARIN. SO WE IN THIS COUNTRY SLOGGER 100 MILLION A YEAR FOR FOOD. SO SLOGGERRING PIGS IS SOMETHING WE'RE USED TO, AND IF THEY PROVIDE LIFE SUPPORTING ISLETS THAT'S PROBABLY OKAY. NOW YOU CAN TRANSPLANT M&A WHAT WE KAW FREE ISLETS JUST PUT IN BY#oD THEMSELVES, OR YOU CAN PUT IN ENCAPSULATED ISLETS. THE IDEA BEHIND ENCAPSULATED ISLETS, WORK IS BEING DONE IS CAPSULES AROUND A GROUP OF ISLETS WILL ALLOW I'M SORRY LYNN TO COME OUT BUT THEY WON'T ALLOW ANTIBODY AND T-CELLS TO GET IN SO YOU'LL PROTECT THEM. THERE ARE CLINICAL TRIALS GOING ON, ONE INCLUDING NEW ZEALAND DEPARTMENT OF HEALTH, SMALL NUMBER OF PATIENTS GETTING ENCAPSULATED PIG ISLETS. THEY HAVEN'T REPORTED THE RESULTS WE KNOW THEY PROBABLY FAIL WITHIN A FEW WEEKS OR FEW MONTHS. I'M NOT OPTIMISTIC ABOUT THIS, I THINK CAPSULE TO DO WHAT THEY WANT TO DO IS GOING TO BE DIFFICULT AND WE'RE NOT SURE BECAUSE EVENTUAL HI YOU GET REJECTION OR BECAUSE THE CAPSULE -- OXYGEN OR SUGAR, WHATEVER IT MAYBE. THAT DOESN'T MEAN YOU REQUIRE IMMUNOSUPPRESSIVE THERAPY, HERE I MENTION THE CLINICAL TRIALS, ANOTHER WITHIN JUST BEGINNING IN BELGIUM. TWO BIG PROBLEMS HERE,THE FIRST ONE WITH ISLET -- FREE ISLETS WE PUT INTO THE PORTAL VEIN, MAY NOT BE THE BEST PLACE BUT THAT WHERE WE'RE PUTTING THEM. SO YOU YOU PUT THEM DIRECTLY INTO THE BLOOD NOT SUPPOSED TO BE IN THE BLOOD AND WE GET THIS RESPONSE CALLS BLOOD MEDIATED INFLAMMATORY REACTION. AND HERE YOU CAN SEE, THIS IS RELEASE OF PORCINE C PEPTIDE IN BABOONS, SERIES OF BABOONS, YOU CAN SEE THAT IT GOES UP, IT SHOULD BE ABOUT 1 POINT SOMETHING, IT'S MORE THAN 8 WITHIN 15 MINUTES. THIS IS NOT A GOOD SIGN, ALL THE ISLETS GET DISCORRUPTED BY THIS RESPONSE AND JUST REGURGITATING THE INSULIN OUT AND ISLETS ARE DEAD. IF YOU GET ENOUGH TO SURVIVE THIS HAPPENS TO SOME EXTENT WITH HUMAN ISLETS. BUT IF YOU GET ENOUGH ISLETS TO SURVIVE YOU MAINTAIN A LOW LEVEL OF C PEPTIDE BECAUSE THE ISLETS ARE NOW FUNCTIONING AS THEY'RE SUPPOSED TO DO. SO THIS IS A BIG PROBLEM, BECAUSE WE'RE PROBABLY LOSING 80% ISLETS PUT IN WITHIN THE FIRST FEW MINUTES. AND IT WAS THOUGHT MANY YEARS THIS WAS A NON-SPECIFIC BY PUTTING ISLETS IN THE BLOOD. WORK WE HAVE DONE OURSELVES AND YOU CAN SEE HERE, IN BLUE, I THINK IS INSULIN. AND IN GREEN IS ANTIBODY. WHEN YOU PUT ALLO ISLETS IN, HUMAN ISLETS TO HUMANS OR WHATEVER IT IS, IN VITRO TEST YOU CAN SEE THIS VERY LITTLE ANTIBODY BINDING. WHEN YOU PUT IT IN WITH PIG ISLETS TO HUMAN BLOOD YOU GET A HUGE AMOUNT SO IT'S A FORM OF HYPERACUTE REJECTION. IMMEDIATE REJECTION OF THESE WILD TYPE PIG ISLETS. SO THIS IS ANOTHER METHOD WE HAVE OF DOING WORK E VIVO. YOU CAN ANTI-CO-ING A LATE GIVE ANTICOMPLIMENT AGENT BUT NOT SATISFACTORY. AND WE PREFER TO GENETICALLY ENGINEER THE PIGS PIGS SO WE HAVE PIGS WITH ISLET SPECIFIC ON INSULIN PROMOTER SO THE GENE IN THE ISLET SO WHEN YOU TAKE THEM OUT OF PIG, YOU PUT THEM IN, EXPRESS THE GENE BUT NOT OVERLOADED WITH THIS GENE IN THE WHOLE BODY. WE HAVE CD -- GAL KNOCK OUT CD 46 WITH ISLET EXPRESSION OF TISSUE VECTOR PATHWAY HUMAN COAGULATION REGULATORY PROTEIN OR CD 39 ANOTHER HUMAN COAGULATION AND THIS DRUG THAT I MENTIONED CO-STIMULATORY BLOCKAID IF YOU PUT IN WHOLE PIG IMMUNOSUPPRESSED BUT IN ISLETS, SO WE HAVE LOCAL IMMUNOSUPPRESSION HERE. SECOND T-CELL MOST ARE REJECTD BY T-CELL RESPONSE, NOT T-CELL MEDIATED REJECTION. WE CAN CONTROL THIS WITH RELATIVELY EASILY WITH DOE SYSTEM HIS OR TRY TO MANIPULATE TO REDUCE THAT NEWSPAPER SUPPRESSION. SIX GROUPS REPORTED IN NON-HUMAN PRIMATE INCLUDING THE EMORY GROUP IN OUR GRANT COOPERATIVE AND OUR OWN GROUP AS WELL. NOT FUNDED BY THIS THING. AND HERE IS ONE FROM OUR GROUP, THIS IN BLUE IS THE BLOOD SUGARK YOU CAN SEE FROM THE DAY WE PUT THEM IN, THE PIG ISLETS TO THE BABOON HE REQUIRED INSULIN BECAUSE BLOOD SUGAR REMAINED NORMAL OVER A YEAR, WHEN WE EUTHANIZED BECAUSE WE HAVE DON'T HAVE ENOUGH MONEY TO KEEP HIM GOING. THE BARS HERE COMING UP HERE ARE PIG C PEPTIDE. HE IS NO MONKEY C PEPTIDE BECAUSE WE ABLATED HIS OPEN CELLS IN THE PANCREAS AND YOU CAN SEE HE'S GOT SUSTAINED DECENT LEVELS PORCINE ON PEER REVIEW. WITH RELATIVELY MODEST IMMUNOSUPPRESSION. SO MY FEELING WE HAVE DONE THIS A FEW TIMES NOW, IF WE CAN DO THISjD CONSISTENTLY, IT'S BOUND TO WORK EVENTUALLY CONSISTENTLY. WE LOOK AT REASONS WHY IT'S NOT CONSISTENT. BUT I THINK THIS IS EXTREMELY ENCOURAGING OF PATIENTS WITH DIABETES. THE END OF THE YEAR ARE PERFECTLY HEALTHY PIG ISLET IN THE LIVER OF THE BABOON. NOW, THERE IS A LOT OF DISCUSSION WHERE THE NEONATAL ISLETS IN THE FIRST YEAR OF LIFE AFTER THE PIG IS BORNER ADULT ISLETS ARE PREFERABLE. THERE'S DISCUSSION IN EMORY GROUP SOME OTHER GROUPS AS WELL, WE OOH BEGINNING TO LOOK, MUCH CHEAPER PIG ISLETS FIRST YEAR HOUSING IS EXPENSIVE PROCEDURE, IT'S MUCH EASIER AND CHEAP TORE ISOLATE THE ISLETS FROM A NEONATAL PIG THAN ADULT PIG MUCH CHEAPER AND MUCH EASIER AND I THINK THIS IS ONE OF THE REASONS WE HAVEN'T GOT CONSISTENT SUCCESS BECAUSE WHEN WE ISOLATE THE ADENOVIRUS, (INDISCERNIBLE) IS EXPERT AND SHE KNOWS ISOLATING ADULT ISLETS IS VERY FRAGILE. THERE'S SOME EVIDENCE YOU HAVE INCREASED RESISTANCE TO THIS IMMEDIATE LOSS OF ISLETS WHEN YOU USE NEONATAL ISLETS. THE NEONATAL ISLETS PROLIFERATE BUZZ THEY'RE IMMATURE AND THEY STILL PROLIFERATE YOU PUT IN A CERTAIN NUMBER BUT AFTER A CERTAIN NUMBER OF MONTHS YOU HAVE A BIGGER NUMBER. THERE IS SOME EVIDENCE THEY MAY BE MORE RECESSTANT TO REJECTION SO WE'RE MOVING TO NEONATAL ISLETS. THE OTHER APPROACH IS DON'T PUT IN BLOOD OR PORTAL VEIN PUT THEM SOMEWHERE ELSE AND WE AND OTHER GROUPS LOOKED AT VARIOUS THINGS WE LOOKED AT SUBMUCOSAL SPACE ONLY IN PIG WITH ALLO TRANSPLANTS, YOU CAN DO IT ALL THROUGH GASTROSCOPY, IT TAKES ABOUT FIVE MINUTES TO DO UNIN A BABOON. SO YOU CAN DO THE TRANSPLANT UNDER SEDATION BY ENDOSCOPY T PATIENT GOES HOME A COUPLE OF HOURS LATER WHEN THEY RECOVER FROM THE SEDATION. SO IT WILL BE SIMPLEND EVEN IF YOU ONLY KEEP THEM FUNCTIONENING A YEAR OR TWO, THE PATIENT COMES BECOME IN YEAR OR TWO AND YOU HAVE ANOTHER LOAD OF ISLETS PUT IN. THIS CAN GO ON FOR YEARS IF YOU HAD TO. SO IT IS A SIMPLE PROCEDURE. VERY LOW RISK TO THE PATIENT. SO ONE OF THE REQUIREMENTS FOR CLINICAL TRIAL OF THESE FREE PIG ISLETS OPPOSED TO ENCAPSULATED ISLETS, YOU HAVE TO HAVE CLEAN PIGS. THE FDA MAY INSIST THOSE PIGS HOUSED IN THESE ISOLATED CONDITIONS WHERE THEY NEAT EXPOSED TO INSECTS OR HUMANS WITHOUT SPACE SUITS ON. BUT WONDERING WHETHER THEY ALLOW US TO USE CLEAN ISLETS BECAUSE YOU TAKE THE ISLETS, YOU CULTURE A FEW DAYS, IF THEY'RE STERILE WHY DO YOU HAVE TO HAVE THE PIG STERILE? SO MAYBE CHEAP TORE COTHIS IF YOU DON'T HAVE P PIGS -- CHEAPER TO DO THIS BUT WE HAVE TO DISCUSS THAT WITH THE FDA OF COURSE. YOU NEED A CLINICALLY ACCEPTABLE IMMUNOSUPPRESSIVE REGIMEN WE NOW HAVE, NO WORSE THAN YOU GIVE MORRIS PATIENTS WITH A KIDNEY TRANSPLANT. NO MORE INTENSIVE AND YOU HAVE TO HAVE CONSISTENT SURVIVAL IN THE NON-HUMAN PRIMATE -- SIX MONTHS OR MORE. TO BE SURE WHEN YOU GO TO PATIENT YOU SOLVE THE PROBLEMS. THAT WHERE WE FALL DOWN BUT LARGELY BECAUSE WE FIND IT DIFFICULT TO ISOLATE PIG AND ALL PIG ISLETS. FINALLY AT THE IMMUNOLOGICAL, THE EVIDENCE AT THE MOMENT THOUGH NOT PARTICULARLY STRONG, NOT A LOT OF DATA BUT IF YOU ARE SENSITIZED TO HUMAN GRAPH, A LOT OF PATIENTS WHO HAVE MULTIPLE BLOOD TRANSFUSIONS OR BEING PREGNANT OR HAVE A PREVIOUS KIDNEY TRANSPLANT THEY'RE SENSITIZED AGAINST HUMAN ANTIGENS SO ANTIBODIESES AGAINST HLA ANTIGENS IF YOU PUT (INAUDIBLE) THEY REJECT. THE EVIDENCE IS, THOSE ANTIBODIES DO NOT AFFECT THE PIG TRANSPLANT SO YOU CAN USE THE PATIENTS AND SAY PIG TRANSPLANT. YOU DON'T HAVE THOSE AGAINST THE AVERAGE PERSON AND WE NOW HOW TO DEAL WITH THAT. IT WOULD BE A HUGE ADVANTAGE TO THESE PEOPLE AWAITING 5, SIX YEARS TO A PERFECT MATCH HUMAN TRANSPLANT. THEY DON'T HAVE TO WORRY. FURTHERMORE FROM THE DATA WE HAVE, WHEN YOU PUT A PIG GRAFT IN, EVEN IF YOU DON'T GIVE IMMUNOSUPPRESSION AN SENSITIZED TO THE PIG GRAFT, THAT DOESN'T PREVENT ALLO TRANSPLAN. BIG ADVANTAGE, WE PUT THE PIG CELLS IN PIG ISLETS TO THE PIG KIDNEY, IT DOESN'T WORK VERY WELL, IT DOESN'T SOME THEM FROM HAVING A HUMAN SUBSEQUENTLY. SO THOSE ARE BIG ADVANTAGES. WHAT ARE WE DOING WITH THESE THREE GROUP? UNIVERSITY OF MARYLAND MY GROUP LOOKING PARTICULARLY AT LUNGS AND THE UNIVERSITY COLLEGE LOIN LONDON MAYO CLINIC GROUP AT HEARTS PARTICULARLY ORTHO TOPIC WEo[ PUT THEM INTO THE ABDOMEN BECAUSE IT'S EASIER TO DO, MUCH LESS A PROCEDURE. AND AT THE END OF IT IS THE HEART -- IF THE HEART REJECTS DREW TAKE THE HEART OUT AND KEEP THE BABOON ALIVE. SO WHEREAS THE MAYO CLINIC PUTTING THEM ORTHO TOPICALLY IN POSITION WHERE YOU EXPECT THE HEART TO BE AND THE PROBLEMS ON THE EMORY GROUP LOOKING AT ISLETS. MARYLAND PARTICULARLY AT LUNG AN LIVER, I'LL ONLY TUCK TALK LUNG A MINUTE. REJECTION OR FAILURE, I WOULDN'T COULDN'T IT REJECTION BUT FAILURE OF THE PIG LUNG IS SO WITH THE HEART AND KIMINI LUNG PROVIDES A SCREEN FOR GENETIC THERAPY. SO WE HAVE A NEW PIG, WE CAN TEST IT IN THIS LUNG TRANSPLANT MODEL, AND SEE HOW LONG IT GOES, THAT WILL GIVE US AN INDICATION OF WHETHER IT'S BENEFICIAL IN THE MUCH LONGER SURVIVAL IN THE HEART OR THE KIDNEY. THEY HAVE A PERFUSION SYSTEM PERFUSE HUMAN BLOOD THROUGH THE PIG LUNG FOR FEW HOURS AND THEY ASSESS LUNG FUNCTION BY VARIOUS BLOOD FLOW, BLOOD PRESSURE OPTION, SO ON. ONE EXAMPLE, THIS IS A WILD TYPE, IT FAILS WITHIN ABOUT 30 TO 40 MINUTES. WITH THE BEST PIG SO FAR, CD 36 WITH THROMBO REGULATORY PROTEIN, THEY GET OUT THE FULL FOUR HOURS THEY WANT TO TEST AN THEY'RE GOING ON ORTHO TOPIC TRANSPLANS OF THOSE LUNGS IN BABOONS. Z YOU CAN SEE, EVERY PIG WE GET GETS BETTER AND BETTER AND SO NOW WE ARE BEYOND THE HOPE -- HELP OF THIS PERFUSION SYSTEM, WE'RE NOW GOING ON TO TRANSPLANT. SO IT'S BEEN A VERY VALUABLE THING. THE MAYO CLINIC GROUP, B LOOK AT A LIFE SUPPORTING HEART TRANSPLANTATION BUT ALSO IDENTIFIED ANOTHER NON-GAL ANTIGEN WHICH WE HAVE HUMAN ANTIBODIES WHICH IS AN IMPORTANT STEP FORWARD. HOW IMPORTANT THAT IS WE'RE NOT SURE BUT AT LEAST -- THIS IS A WONDERFUL VIDEO THAT THEY GAVE ME BUT UNFORTUNATELY WE CAN GET IT TO WORK. I'M SORRY. BUT THOSE OF YOU WHO HAVE SEEN HUMAN OR PIG HEART, THIS IS AN EXTREMELY HEALTHY HEART AND BEATS LIKE MAD. I CAN'T SHOW IT TO YOU BUT IF YOU SAW THAT HEART YOU'D THINK THIS IS GOING TO WORK. THIS IS A WONDERFUL HEART. THIS IS A HEART ACTUALLY SUPPORTING THE CIRCUMSTANCE LAKE OF A BABOON -- CIRCULATION OF BABOON AND HERE IS A PICTURE OF BABOON EATING AWAY THERE, IF YOU CAN GET THIS VIDEO TO Q. AS WELL. THIS ONE IS OBVIOUSLY CLEAR HEALTHY, A MONTH AFTER, SO IT'S SUPPORTED ENTIRELY BY THE PIG HEART. WHAT ARE ALTERNATIVES TO XENOTRANSPLANTATION TO SOLVE PROBLEMS OF DONOR SUPPLY. NOBODY ELSE IS ANYWHERE CLOSE TO HAVING A ANIMAL SURVIVING LIKE THIS IS. 100% WELL SUPPORTED BY PIG ORGAN. EMORY LOOKING AT ISLET XENOTRANSPLANTATION, THEY HAVE A RECOGNIZE SYSTEM, THEY CAN PUT WILD TYPE INTO THE LOBE OF LIVER AND THEY CAN PUT GAL INCOME OUT OR CD 46 INTO THE OTHER LIVER AND THEY USE EUTHANIZE THE BABOON AT ONE OR 24 HOURS AND LOOK HISTOLOGICALLY AND THEY CAN SEE WHERE IS THE MOST CELL INFILTRATE INFLAMMATORY RESPONSE, CLEARLY WORSE WITH THE WILD TYPE ISLET THAN WITH GAL KNOCK OUT OR CD 46 ISLETS. WHICH HAS BEEN CONFIRMING WHAT WE ALREADY KNOW WHAT'S GOING ON MANY THIS. THEY HAVE ALSO DONE A STUDY WHERE THEY HAVE COMPARED LONG TERM SURVIVAL WITH GAL KNOCK OUT PIG ISLET AGAINST WILD TYPE, SHOW STATISTICALLY VERY SIGNIFICANT AFFECT FOR THE GA HEALTHCARE KNOCK OUT. AS WE WOULD HAVE ANTICIPATED. SO THEY'RE ADDING DATA TO THE ISLET HERE. THERE ARE A LOT OF OTHER PROBLEMS BUT NOWHERE NEAR AS IMPORTANT AS IMMUNOLOGIC ONES. FZ OWE LOGIC PIG KIDNEYS SUPPORT BABOONS FOR THREE MONTHS. WE KNOW A PIG HEART IN THE ORTHO TOPIC SUPPORT FOR MUCH THE SAME PERIOD OF TIME. SO I DON'T SEE ANY PROBLEM WITH THE PHYSIOLOGY, THERE'S ONE OR TWO DIFFERENCES BETWEEN KIDNEY METABOLISM IN PIG AN HUMAN BUT THEY'RE NOT GREAT. IF YOU HAVE A METABOLIC DIFFERENCE UP TO DO SOMETHING ABOUT SAY IN THE LIVER, IF LIVER IS NOT PRODUCING THE RIGHT AMOUNT OF ALBUMIN OR NOT HUMAN ALBUMIN OR SOMETHING YOU HAVE TO HAVE THIS WHICH DONE THINK YOU WILL HAVE TO YOU CAN GENETICALLY MANIPULATE THE PIG TO PRODUCE HUMAN ALBUMIN. SO YOU CAN SOLVE THESE PHYSIOLOGICAL PROBLEMS IN THE SAME WAY YOU SOLVE THE IMMUNOLOGIC PROBLEMS. SAFETY, RISK OF INFECTION, LOTS OF PAPERS ON THIS PARTICULARLY TEN OR SO YEARS AGO THE VIROLOGISTS TODAY HAVING KEPT IN TOUCH, FEEL A RISK IS VERY, VERY LOW. IF WE HOUSE THESE PIGS UNDER THE RIGHT SITUATIONS, WE WOULDN'T HAVE RISK OF TRANSFERRING INFECTIONS WITH THE PIG ORGAN TO THE HUMAN. AND THEN THERE ARE ETHICAL REGULATORY PROBLEMS WHICH OBVIOUSLY PEOPLE CONSIDER IN GREAT DETAIL. I JUST MENTION EARLY CLINICAL TRIALS, I THINK THERE WILL BE A CORNEA TRANSPLANT LATER IN YEAR IN KOREA AND IN CHINA. FREE IONS NOT ENCAPSULATED PROBABLY FAIRLY SOON. BRIDGING WITH THE PIG LIVER, ONLY GOT TO KEEP A PIG LIVER GOING A WEEK OR TWO BECAUSE YOU CAN GET HUMAN LIVER UNDER EMERGENCY CIRCUMSTANCES KYE QUICKLY BUT THE PATIENT WITH ACUTE LIVER FAILURE MAY DIE P WITHIN THOSE FIRST TWO OR THREE DAYS SO IF YOU CAN BRIDGE WITH A PIG LIVER THIS IS A BIG STEP FORWARD FOR THAT PARTICULAR PATIENT. WE MAY GET INTO CLINIC BRIDGING A PIG HEART. YOU NEED TO KEEP IT FUNCTIONING NINE MONTHS SO WE'RE NOT QUITE THERE YET BUT THAT WILL BE A WAY OF GETTING A WAY TO SAVE PATIENTS' LIVES, PIG LIVER FOR THAT FIRST PERIOD OF TIME UNTIL YOU GET A HUMAN LIVER. THOUGH THE ULTIMATE AIM OF COURSE IS TO TRANSPLANT THESE ORGANS PERMANENTLY. WHERE ARE ALTERNATIVES I MENTIONED A MINUTE AGO? MECHANICAL ASSIST DEVICES IMPROVED THE LAST 10, 15 YEARS, YOU CAN DO IT SEVERAL MONTHS IF NOT TWO OR THREE YEARS WITH MECHANIC DEVICE OR MECHANICAL HEART. BUT YOU HAVE TO HAVE A WIRE COMING OUT PLUGGED INTO THE MAINS OR INTHE A BATTERY TO KEEP THE HEAR FUNCTIONING. I CAN NOT BELIEVE THAT CALL OF LIFE IF YOU HAVE TO BE PLUGGED INTO SOME BATTERIES IS AS GOOD AS IT IS IF YOU HAVE A PIG HEART COMPLETELY ENCLOSE AND WILL FUNCTION AND RESPOND TO YOUR EVERY MOVE. SO ULTIMATELY THE BIOLOGICAL HEART WILL SURPASS THE CHEMICAL HEART. KIDNEYS WE HAVE DIALYSIS BUT I TOLD YOU DISADVANTAGES OF DIALYSIS FOR MANY YEARS. PEOPLE SPENT A LOT OF TIME HYPING HUMAN STEM CELLS AS AN ANSWER. WE'RE GOING THE MAKE ORGANS OUT OF HUMAN STEM CELLS. 'S 50 OR 100 YEARS AWAY IN MY OPINION. I LOOK THAT THE CONSIDERABLY IN THE LAST TWO OR LEE WEEKS KNOWING I WAS GOING TO COME SPEAK TO YOU. SAME FOR REGENERATION MEDICINE. WE'RE GOING THE TAKE THE CELLS OUT, KEEP THE COLLAGEN STRUCTURE AND PUT HUMAN CELLS BACK IN AND HAVE A NEW HEART OR KIDNEY. IT'S PIE IN THE SKY, AND I TACKED TO EXPERTS THEY'RE IN THE CONSIDERING IT IN THE NEAR FUTURE. IF YOU THINK WE CAN DO STEM CELL REGENERATION MEDICINE SHOWS ME HEART THAT LOOKS LIKE THE ONE IN BABOON THAT LOOKS THAT HEALTHY AND SAY HOW CLOSE ARE YOU TO THAT, THEY'RE MILES AWAY, YEARS AWAY SO WE HAVE NO REAL ALTERNATIVES TO THE XENOTROPE A PATIENT. I USED TO LIVE IN OKLAHOMA CITY AND TRIED TO BECOME A GOOD OKIE AND WHAT IMPRESSED ME PARTICULARLY WAS THIS NATIVE AMERICAN PROBLEM, THE TIMING HAS A LOT TO DO WITH. NO PROPERTY RUSHING OUT DOING THIS SAY SHY DANCE, AS YOU LOOK TO -- CRAZY DANCE. BUT TIMING IS BECOMING RIPE NOW, FOR SOW KNOW TRANSPLANTATION. REVIVICORE I LOAN PRODUCED 11, SOME FIVE DID I WANT ONES IN THE SAME PIG, SOON HAVE ONES WITH SIX. ANOTHER 11 FROM PLACES LIKE GERMANY AND KOREA BEING DEVELOPED SO WE HAVE ABOUT 22 DIFFERENT GENETIC MANIPULATIONS, IF WE GET THEM IN THE SAME PIG WE'LL SOLVE THE PROBLEMS SO THE TIMES IS RIGHT AND SOME NEW CO-STIMULATORY BLOCK ATHLETE AID MOLECULES IMPROVED NEWSPAPER SUPPRESSIVE THERAPY. -- IMMUNOSUPPRESSIVE THERAPY. OTHER COUNTRIES WITH MAJOR GOVERNMENT SUPPORTED XENOTRANSPLANTATION, VAIL AUSTRALIA WAS DONE WORK ON PIGS, CHINA, THE EU, THE NEURONAL CELLS, PARKINSON'S GERMANY HAS JUST THEIR GRANT REFUNDED CONSORTIUM FOR 12 YEARS. SO THEY SUPPORT IT WELL. SOUTH KOREA AN SWITZERLAND HAS GOOD WORK GOING ON TOO. SO I THINK ONE DAY MAKING A PIG OF YOURSELF COULD TAKE ON WHOLE NEW MEANING. BUT I THINK THE PIG STILL HAS A FEW TRICKS UP ITS SLEEVE THAT WE HAVE TO RESOLVE BUT I THINK WE'RE SLOWLY GETTING THERE. WE NEED MORE RESEARCH. I LIKE THIS QUOTE, THERE ARE MANY WAYS OF LOSING MONEY, WOMEN MOST FUN GAMBLING IS THE FASTEST AND NIH IS MOST CERTAIN. BY FORMER CHAIRMAN OF ROLLS ROIST. THOUGH GOOD WAY TO THE LOSE MONEY WE NEED A BIT MORE RESEARCH SO I THINK ULTIMATELY I'LL LEAVE YOU THIS QUOTE FROM ANIMAL FARM. THE CREATURES OUTSIDE PIG TO MAN AND MAN TO PIG AN FROM PIG TO MAN AGAIN, BUT ALREADY IT WAS IMPOSSIBLE SAY WHICH WAS. I THINK INVENTORIALLY PATIENTS WILL COME TO DOCTOR'S CLINIC ROOM AND THE DOCTOR WILL HAVE NO IDEA WHETHER HE HAS A PIG OR HUMAN KIDNEY AND THE PROBLEM WILL BE SOLVED. THANK YOU. [APPLAUSE] >> WE HAVE TIME FOR QUESTIONS IF PEOPLE HAVE QUESTIONS. >> WE WORKED A LOT ON C 2TA. THERE'S AT PROTEIN THAT CONTROLS CLASS 1. WHAT'S IT CALLD? >> N LRC-5. (OVERLAPPING SPEAKERS) >> SO I'M CURIOUS. >> YES. >> CAN I JUST SAY WE HAVE TO BE CAREFUL OF COURSE. IF YOU KNOCK OUT THAT GENE COMPLETELY IN THE PIG, IT'S PROBABLY NOT VIABLE. SO WE HAVE KNOCKED IT DOWN BUT NOT OUT. >> THIS GENE MAYBE PERFECT BECAUSE IT ACTUALLY IS NOT QUITE AS POWERFUL AS C 2TA SO DOESN'T KNOCK OUT MHC COMPLETELY BUT ABOUT 80%. >> SOUNDS GOOD TO ME. >> I WANTED TO ASK PIG RETRO VIRUS AND IF THAT IS A POTENTIAL PROBLEM. >> THE EXPERTS FEEL IT'S A WEAK VIRUS, IT'S NOT GOING TO DO ANY HARM AT ALL. AND ALL OF THE DATA AND ONE OR TWO GROUPS OF PEOPLE EXPOSED RECENTLY JUST REVIEWED A PAPER PEOPLE EXPOSED TO PIG SKIN GRAPHS FOR BURN, MANY YEARS AGO AND THEY FOLLOWED THEM UP NOW UP TO 34 YEARS. AND THEY HAVEN'T SEEN ANY SIGN OF A RETRO VIRUS. THOSE PATIENTS WERE NOT NEWSPAPER SUPPRESSED. THEY DIDN'T HAVE ORGANS FOR YEARS SO IT'S DIFFERENT BUT WHAT TRUCK ME PARTICULARLY IS 5, 10 YEARS AGO I WAS ON A COMMITTEE REVIEWING THE WORK OF THE FDA, THEY HAD HAD A LAB THERE AT THE TIME LOOKING AT THE RETRO VIRUSES BECAUSE EVERYBODY WAS WORRIED. THERE WERE EIGHT NON-VIROLOGISTS. AND THEY GAVE A PRESENTATION AN TO A MAN —> ARE YOU WASTING YOUR TIME WITH THIS VIRUS? SO IT STRUCK ME IT CAN'T BE VERY -- THEY WERE NOT IMPRESSED WITH THE DATA SO I THINK THE FDA WILL ASK US TO MONITOR, TO BE SURE THAT WE DOPE SEE SIGNS BUT I DON'T THINK THAT WILL HELP THE BUSINESS. AND I DON'T THINK IT WILL BE A PROBLEM. >> YOU PROBABLY RECALL ABOUT TEN YEARS AGO I GUESS THE HHS SECRETARY CONVENE AD COMMITTEE TO ADVISE ON XENOTRANSPLANTATION. AT THAT TIME CONCERN ABOUT RETRO VIRUS WAS JUST ON BEGINNING TO WANE. SOME DATA SUGGESTED IT WASN'T GOING TO BE THE PROBLEM IT HAD BEEN THOUGHT BUT THE FDA RECOMMENDATIONS AT THAT TIME WERE TO FOLLOW ANY SUBJECTS FOR SOMETHING APPROACHING >> 50 YEARS. >> YEAH. AND THAT IMMEDIATELY POSED PROBLEMS IN TERMS OF DOING THAT ANY TYPE OF GRANT SUPPORT. GIVEN THOUGHT THE THAT IN TERMS OF GOING BACK TO THE FDA? >> YES. I THINK THE FDA WILL WANT MONITORING, MAYBE NOT 50 YEARS BUT IF WE SHOW IT'S DONE AND SELL THESE PIGS COMMERCIALLY AND YOU GET A PIG TO COME IN TOMORROW, I THINK THE PHARMACEUTICAL COMPANY BIOTECHNOLOGY COMPANIES COME TO THE FIELD AND WE REALIZE THEY WILL MAKE MONEY OUT OF THIS. SO I THINK ONCE WE GET -- SHOW THEM IT WILL WORK, THEY'LL COME IN AND DO THE CLINICAL TRIALS. >> YOU AAT THIS POINT SIN YOU BROUGHT UP THE UNENCAPSULATED ISLETS PROBABLY THE FIRST TO GO IN THIS COUNTRY AT LEAST. WHAT WOULD BE THE IMPLANTATION WOULD IT BE GI SUBMUCOSA OR BIOPORTAL VEIN? >> EVERYBODY IS STILL LOOKING AT THAT, SOME INTO THE PERITONEAL CAVITY OR THE -- STITCHED IN, SOME PUT THEM IN SUBCUTANEOUSLY, SOME INTO MUSCLES. WE HAVE A GROUP PUTTING INTO LYMPH NODES SURPRISINGLY AN DONE WELL, NOT EPICAPSLATED EVEN. SO IT'S -- ENCAPSULATED SO IT'S A FLUX WHICH IS OPTIMUM SIDE BUT I'M IN THE A GREAT BELIEVER IN ENCAPSULATION BECAUSE I THINK IT'S VERY DIFFICULT TO SEE HOW YOU TIER GOING TO GET INSULIN OUT AND NOT GET ANTIBODY AND SO ON IN. SO ANSWER IS FREE ISLETS. WE HAVE DONE BETTER WITH FRY ISLETS IN BABOONS WE HAVE TWICE THE SURVIVAL BUT WE HAVE TO IMMUNOSUPPRESS THE BABOON. >> NELSON, YOU HAVE A QUESTION? >> TECHNICAL QUESTIONS BACK INTO THE CHEST ONCE OR TWICE, THE THIRD TIME O -- >> IF YOU REPLACE THE HEART SEVERAL TIMES IT BECOMES TECHNICALLY MORE DIFFICULT EACH TIME BUT SURGEONS ARE USED TO IT BECAUSE THEY HAVE DONE RESURGERIES FOR PATIENTS WITH CORONARY ARTERY SURGERY, SO ON. SO IT'S CERTAINLY NOT GOING TO PREVENT P YOU DOING IT BUT OBVIOUSLY I WOULDN'T SAY YOU WANT TEN HEART TRANSPLANTS BUT YOU CAN HAVE TEN ISLET TRANSPLANTS. >> OKAY. THANK YOU VERY MUCH. WE HAVE THE NEXT HOUR AND A HALF DEVOTED TO DISCUSSION OF THREE RESEARCH CONCEPT CLEARANCES. WE WILL PROBABLY GET THROUGH QUICKER THAN THAT. THE FIRST ON IMMUNOBIOLOGY OF XENOTRANS PLANTATION PROGRAM AND NASRIN WILL PRESENT THAT. >> OKAY. AFTER AN EXCITING WELCOME DR. COOPER I'M GOING TO BE VERY BRIEF ON MY CONCEPT CLEARANCE PROGRAM. MY BIOLOGY XENOTRANSPLANTATION AND RESEARCH. THIS PROGRAM MENTIONED BEFORE ESTABLISHED IN 2005 WITH CO-FUNDING FROM NIDDK AND IN O 2010 WITH AGAIN GOAL OF ADDRESSING IMMUNOLOGICAL AND PHYSIOLOGICAL ISSUES ESSENTIAL FORjMv XENOGRAPH SURVIVAL. AND FUNCTION AND ALSO DEVELOPING NON-HUMAN PRIMATES XENOTRAN PLANTATION MODEL. RATIONALE FOR THIS PROGRAM WAS XENOTRANSPLANTATION OFFER POTENTIAL FOR DEFINITIVE SOLUTION FOR SHORTAGE OF HUMAN ORGAN FOR TRANSPLANTATION. AND IT ALSO COMPLIMENTARY TO STEM CELL AND GENERIC -- AND GENETIC TECHNOLOGY. CONTINUE. THE XENOTRANSPLANTATION WAS VERY MINIMUM INDUSTRY SUPPORT 1990s AND SO THE ONLY SUPPORT IS HIPPOFUNDING FOR -- IN THE US. THE PROJECT USUALLY IS HIGH IMPACT IN A HIGHLY SPECIALIZED FIELD THAT REQUIRES SOLICITATION OF PROGRAM AND ALSO SPECIAL ONLY FA SAYS PAM OR SPECIAL PANEL REVIEW REQUIRED FOR THIS. SO IT'S NOT SOUGHTABLE FOR INVESTIGATOR INITIATED RO-1. THE PROGRAMS USUALLY IS VERY COLLABORATIVE AND PROMOTES SYNERGY AMONG THE PROJECT IN THIS SPECIALIZED SMALL SPECIALIZED SEED. THE LONG TERM INVESTMENT IS REQUIRED TO GENERATE ALL THESE GENETICALLY MODIFIED ANIMALS AND OPTIMIZE THIS IN VIVO SYSTEM. ALSO TO MAINTAIN HIPPOAND U.S. INVOLVEMENT IN PRE-CLINICAL RESEARCH TRANSITION TO CLINICAL RESEARCH IN FUTURE AN CLINICAL TRIALS. OUR CUP PROGRAM IS THREE FUNNED PROJECTS, ONE MULTI-PROJECT AND TWO SINGLE PROJECTS AS MENTIONED BEFORE, EMPHASIS ON SOLID ORGANS HEART LUNG AND LIVER KIDNEY AND ISLET. AND AS PART OF THE SCIENTIFIC PROGRESS CONCERN, THIS GROUP WAS VERY PRODUCTIVE IN THE PAST ALMOST 8 YEARS SINCE 2005 THEY PUBLISHED 74 PEER REVIEW RESEARCH PUBLICATION, THAT DIRECTLY ATTRIBUTED TO THIS PROGRAM. AND ALSO AS DR. COOPER MENTIONED 11 GENETICALLY MODIFIED PIGS DEVELOPED FOR THIS PROGRAM. ALSO OUR INVESTIGATOR ACHIEVEDDED THE LONGEST LIFE SUPPORTING XENOGRAPH, XENOCARDIOGRAPH, CARDIO TRANSPLANT AND ESTABLISH AD CLINICALLY ACCEPTABLE IMMUNOSUPPRESSIVE REGIMEN USED IN HEART MODEL. EVALUATED RECENTLY THE CHICK -- THE TRANSGENIC PIG THAT EXPRESS IN HUMAN COAGULATION REGULATORY PROTEIN THEY IS DR. COOPER, THAT IS BENEFICIAL TO SOW KNOW GRAPH SURVIVAL. LAST BUT NOT LEAST THEY IDENTIFY A NON-G ACTIONL ANN GENERAL INVOLVED IN XENOGRAPH FAILURE. BENEFIT OF CONSORTIUM. WHY THEY HAVE A CONSORTIUM OF INVESTIGATORS. BASICALLY OUR CONSORTIUM WE'RE COLLABORATIVE AND MULTIPLE COLLABORATION AND JOINT PUBLICATION, HAPPENED AMONG THE GROUP. BASICALLY STANDARDIZATION OF THE ASSAY PROTOCOL, SHARING REAGENTS AND PIG MODELS THAT DEVELOP. AND ALSO NOT ONLY COLLABORATION AMONG THIS CONSORTIUM BUT COLLABORATION WITH OTHER CONSORTIUM AN GROUPS INCLUDING COLLABORATION WITH NATIONAL SWINE RESEARCH RESOURCE CENTER THAT IS UNDER OD, THAT DEVELOP GENERAL IT CANNILY MODIFIED PIGGINGS THAT BENEFIT BROADER RESEARCH COMMUNITY. AS WELL AS COLLABORATION WITH OUTSIDE CONSORTIUMS THAT DR. COOPER'S GROUP NHLBI CHEMISTRY AND BIOLOGY, THIS COLLABORATION RESULTED IN DEVELOPMENT OF HEPARIN ANTICIPATED TO HAVE ADVANTAGE OVER THE HEPARIN. BASICALLY THERE IS A NEW ONE FOR 2015, WE'RE LOOKING FOR SUPPORT CONTINUATION OF PROGRAM TOE VALUE WAIT NEW AND EXISTING PIG MODELS, GENETICALLY MODIFIED PIG, AND ORGAN TRANSPLANTATION MODEL OF PIG TO NON-HUMAN PRIMATES. ALSO ELUCIDATION OF CELLULAR MOLECULAR MECHANISM INVOLVED IN XENOGRAPH FAILURE. ALSO DEVELOPMENT OF THE STRATEGIES THAT FOR TREATMENT AND PREVENTION OF THE SOW KNOW GRAPH FAILURE AS DR. COOPER ALSO MENTIONED. THE LAST PART BUT NOT LEAST REFINING ISLET SEE NEE TRANSPLANT MORE ADVANCED THAN OTHER ORGANS TECHNOLOGY, SO THAT IT'S REALLY TO BE TRANSLATED TO FUTURE CLINICAL TRIALS IN HUMAN. SO BASICALLY THIS IS MY PRESENTATION. AND I AM HAPPY TO ANSWER ANY QUESTIONS. THANK YOU. >> MIGHT BE HEARING FROM YOU OR DR. COOPER ABOUT THE RELATIVE SIZE OF THIS PROGRAM COMPARED TO THE INTERNATIONAL EFFORTS YOU MENTIONED IN YOUR TALK. (OFF MIC) >> CONTEXT OF INTERNATIONAL PROGRAMS. >> I THINK MOST -- AUSTRALIA'S GROUP IS FAIRLY SMALL,N'T THE SAME AS OURS. SOUTH KOREAN GROUP IS PROBABLY TWO OR THREE TIMES THE SIZE SO THEY FUNDING IS SUBSTANTIAL. I KNOW ONE OF THE LABS THERE, THERE'S AT LEAST TWO IN THE SAME UNIVERSITY THAT HAS 30 PEOPLE IN IT WHICH IS FAR MORE THAN WE HAVE. THE GERMAN GROUP IS A CONSORTIUM OF ABOUT 8 TO 10 DIFFERENT CENTERS. AND THEIR FUNDING MUST BE SUBSTANTIAL. I SAY THEY HAVE JUST BEEN REFUNNED 12 YEARS WHICH STRUCK ME AT LEAST THE GOVERNMENT HAS SOME FAITH IN WHAT'S GOING ON. THERE SO MOST OF THE PROGRAM, AND CHINA IT'S DIFFICULT THE SAY WHAT'S GOING ON THERE BUT THEY HAVE A LOT OF MONEY BEING PUT INTO IT NOW. I HAVE A COLLEAGUE WHO LEFT PITTSBURGH HE'S CHINESE, WEPT BACK TO CHINA AND -- WENT BACK TO CHINA HE'S NOT SWAMPED IN MONEY BUT HE HAS A LOT OF MONEY FROM THE GOVERNMENT AND THE STATE GOVERNMENT. AND HE PUTS IN A THREE PAGE APPLICATION, GETS THE MONEY BASED ON THAT INSTEAD OF -- SO THEY'RE PUTTING A LOT OF EFFORT INTO IT NOW. SO WE'RE CERTAINLY NOT AT ANY ADVANTAGE OVER ANYTHING. >> I WISH WE COULD OFFER YOU THREE PAGE APPLICATION BUT WE CAN'T. NORMA. >> SO DAVID THAT WAS A GREAT TALK. JUST I REMEMBER BEING ON FDA PANEL WHERE YOU SPOKE SEVERAL YEARS AGO, AND PROGRESS IS TREMENDOUS. SEEMS TO ME A LOT OF THAT THAT WAS ATTRIBUTABLE TO THE PIGS GENERAL IT CANNILY MODIFIED PIGS. HOW MUCH EFFORT AROUND THE WORLD AND THIS GROUP IS ON THOSE PIGS? I THINK THAT'S A BIG PIECE OF IT. >> HOW MANY EFFORT HERE? >> HOW MUCH OF THE EFFORT -- HOW MUCH OF THE FUNDING -- >> THE FUNDING FROM NIH IS VERY LITTLE TO THE PIGS. THE REEVIVICORE IS PART OF MY PROJECT I THINK THEY GET $150,000 OUT OF THAT PER YEAR. ONE REASON IS THEY HAVE ALREADY DEVELOPING THESE PIGS AND THEY WANT -- THEY DON'T WANT TO BE FORCED TO GIVE THE PIGS TO ANYBODY. SO THE NIH FUNDING ALLOWS THEM TO PROVIDE THE PIGS TO US BUT THE VAST MAJORITY OF FUNNING IS NOT FOR THE PIGS. WE'RE FORTUNATE THEY HAVE THEIR OWN FUNDS AND THEY HAVE BEEN SUPPORTING THE COST OF ACTUALLY DEVELOPING THESE PIGS WHICH IS WAY IN EXCESS OF $150,000 A YEAR OF COURSE. (OFF MIC) >> THEY'RE OBVIOUSLY IN THE BUSINESS TO TRY TO GET THIS RESOLVED BUT OBVIOUSLY ANY HELP WE CAN GIVE THEM PARTICULARLY AS THEY GIVE ME THE PIGS FOR NOTHING BECAUSE THEY GET 150,000, THAT'S A HUGE ADVANTAGE BECAUSE I WOULD HAVE TO PAY THEM AT LEAST 6,000 FOR THE PIG JUST LIKE I PAY 6,000 FOR MONKEY. SO IT'S A BIG HELP TO HAVE THEM PART OF THE GRANT THOUGH NOT FUNDED FORD MOST OF WHAT THEY DO FROM THE GRANT. CHRISTY, DID YOU WANT TO SAY SOMETHING? >> I WAS GOING TO FOLLOW-UP ON NOR MA'S QUESTION. I THINK OF THE PEOPLE THAT ARE DOING THE RESEARCH IN GERMANY, SOUTH KOREA, CHINA, I KNOW NEW ZEALAND -- I MEAN AUSTRALIA IS MAKING THEIR OWN ANIMALS PRETTY MUCH BUT ARE THE REVIVICORE ANIMALS PROVIDED TO MOST OTHER INVESTIGATOR? >> NO. WE HELP THEM OUT. THEY CAME TO US SEW SOUTH KOREANS CAME, GERMANS CAME, THEY COULDN'T GET THE KNOCK OUT PIGS THEMSELVESES SO THEY ASKED COULD WE PROVIDE WITH WITH SOME CELLS WHICH WE DID. BUT WITH THESE NEWER TECHNIQUES OF MAKING PIGS, IT'S EASIER, THEY HAVE BOTH GOT THEIR OWN GAL KNOCK OUT PIGS APPROXIMATE PUTTING NEW GENES TO THAT. IN FACT THE TWO PIGS WE USE FORHVF0/W THROMBO MODULIN WORK REVIVIC ORE CELLS L BUT THE GERMANS PUT THROMBO MODULIN BUT IT WASN'T QUITE AS SUCCESSFUL AS THEIR PIGS BUT WITH HAD THOSE PIGS BACK. >> HOW DO YOU ULTIMATELY SEE THIS? WHEN I HEAR A TALK THEY SAY WE HAVE UP LIMIT SID PLY BUT ACTUALLY THESE ARE SPECIALIZED PIGS GENETICALLY MODIFY SOD HOW DO YOU SEE IT PANNING OUT? IT WILL BE -- COMPANIES WILL BE INTERESTED IN MAKING PIGS AVAILABLE IN LARGE SUPPLY BECAUSE OF -- WE'LL BE ABLE TO HAVE LONG TERM SURVIVAL? >> I THINK THEY WILL BE A GREAT DEMAND PARTICULARLY FOR TREATMENT OF PATIENTS WITH SAY DIABETES OR PARKINSON'S DISEASE, SO ON SO I THINK THE COMPANIES WILL MAKE THESE -- AND YOU OWN HAVE TO KEEP THE PIGS LONG, THEY GROW RAPIDLY, BY SIGNATURE MONTHS THEY'RE BIG ENOUGH TO GET A HEART TO ME. IF U YOU'RE USING NEONATAL PIGS FOR ISLETS YOU DON'T HAVE TO KEEP THEM LONG AND THE INURNINGAL CELLS FROM FETAL PIGS SO THEY DON'T EPIGET TO BE BORN. SO YOU WON'T HAVE TO KEEP THESE PIGS VERY LONG. SO YOU CAN THEREFORE HOUSE A LARGE NUMBER OF THEM PRETTY EASILY. SO I DON'T THINK THIS WILL BE A PROBLEM. YOU WILL HAVE PIG CENTERS AROUND THE COUNTRY WHICH SUPPLY REGION IN THEIR AREA. SO I DON'T THINK IT'S A LOGISTIC PROBLEM. >> WHAT ABOUT SMALL BUSINESS GRANTS FUNDING FOR COMPANIES LIKE REVIVICORE? >> FOR A WHILE IT WAS P PURCHASED BY UNIVERSITY OF PIT BURGLARY MEDICAL CENTER THAT OWNS THE HOSPITAL. SO THEY WEREN'T HE WILL I DIDN'T BELIEVE FOR A SMALL GRANT THEY WERE BOUGHT OUT BY OUTED THERAPEUTICS AND THEY'RE A BIG ENOUGH SO THEY OR NOT ELIGIBLE FOR SMALL BUSINESS GRANT. UPMC WAS LIMITED IN AMOUNT OF MONEY. THEY GAVE THEM 3 MILLION YEAR. RE, REVIVICOR HAD THEIR OPEN GRANTS, DEPARTMENT OF DEFENSE WAS INTERESTED IN WHAT THEY WERE DOING WHICH ADDED TO AN EXTRA MILLION BUT THEY RUN THAT BUSINESS ON ABOUT 4 MILLION A YEAR THE LAST 15 YEARS WHICH I THINK IS PRETTY GOOD. THEY HAVE DONE VERY VERY WELL. I THINK. >> IS IT YOUR IMPRESSION THEY HAVE SUCH A SUBSTANTIAL LEAD ON THE,P OF THE RELEVANT KNOCK OUTS AND KNOCK INS THAT ANOTHER COMPANY WOULD FIND IT TREMENDOUS BARRIER, SMALL BUSINESS SEE IT AS TREMENDOUS BARRIER TO GET TYPE THIS FIELD? >> THEY HAD A VERY STRONG IP SITUATION. UNTIL SOME OF THESE NEW TECHNOLOGIES CAME IN OF GENETIC ENGINEERING PIGS AND THEY DON'T ARE THE IP ON THOSE. SO IT WILL DEPEND HOW SUCCESSFUL THOSE APPROACHES ARE THAT THERE MAYBE OTHER COMPANIES NOW THAT WILL HAVE THE IP, WE MAY HAVE TO RELY SENSE THAT BUT SOME THINGS THEY HAVE DONE THEY HAVE TO CROSS-LICENSE. BUT IT'S NOT AS STRONG AS IT WAS ORIGINALLY. BUT THEY BELIEVE THAT THEY CAN STILL DO ALL THESE -- MAKE ALL THESE FOR THEIR ORIGINAL IP WHICH GIVES THEM CONTROL OVER THAT SIDE BUT THERE MAYBE COMPETING TECHNIQUES LATER ON. I DOUBT SMALL BUSINESS WILL GET INTO IT. I THINK WITHIN A SHORT TIME BIG BUSINESSES WILL GET IN. THE FINANCIAL SIDE PERHAPS REPRESENTING -- TO DO SMALL BUSINESS YOU NEED A LOT OF MONEY TO SET THIS UP. >> IF THERE ARE NO OTHER QUESTIONS, WE SHOULD GET A COUNCIL MOTION ON PROCEEDING WITH THIS INITIATIVE. SECOND. OKAY. ALL RIGHT. NEXT INITIATIVE IS ENTITLED RESOURCES TO ASSIST INVESTIGATIONS IN PRIMARY IMMUNODEFICIENT CITY DISEASES AN DAVID JOHNSON WILL BE PRESENTING THAT. SO I'LL BE TELLING YOU ABOUT OUR WISHES TO RENEW THIS RESOURCE TO ASSIST INVESTIGATIONS IN PRIMARY IMMUNE DEFICIENCY DISEASES. LITTLE BACKGROUND. GENETIC PRIMARY IMMUNE DEFICIENCIES MEANS GENETIC IMMUNODEFICIENCIES. IN THE PAST, THESE WERE LARGELY CHARACTERIZED BY KIDS WITH INCREASE SUSCEPTIBILITY TO MULTIPLE MICROBES, HIGH PENETRANTS OF THE DISEASE, FOR EXAMPLE, THE NUCLEAR ROLE, THESE ARE SOYATIONS OF THE RECENT LITERATURE. NUCLEAR ROLE FOR WHICH ISKOT ALDRIDGE SYNDROME PROTEIN OR THE DOCK 8 AUTOSOMAL RECESSIVE HYPERIGE. MORE IN RECENTLY, THERE HAVE BEEN SEVERAL GENETIC OTHER PRIMARY IMMUNODEFICIENCIES THAT ARE -- THAT GIVE RISE TO SUSCEPTIBILITY TO SPECIFIC PATHOGENS AND SOME CASES AUTO-IMMUNITY. EXAMPLES HERE I GIVE ARE FOR ISG 15, WHICH MAKES PATIENTS PARTICULAR ALLELES MAKE PATIENTS SUSCEPTIBLE TO PARTICULAR MYCOBACK TOREIAL DISEASES AN INTERFERON GAMMA COMMUNITY OR THE CYBB IN X LINKED MICROBACTERIAL DISEASE. IN ALL THESE CASES THESE DEFECTS REVEAL SIGNALING PATHWAYS IN HUMAN IMMUNITY, UP PER EXAMPLES SHOW THAT BUT MORE EXAMPLES BELOW HERE IRF-8 IN DENDRITIC CELL IMMUNODEFICIENT SAY, AIR, PARTNERING IN AIR PARTICULAR PROTEIN PARTNERING ACTUALLY FORGET WHAT DNA PK STANDS FOR. SORRY. SEVERAL THINGS CONTRIBUTE TO ACCELERATION OF THE DISCOVERY IN IMMUNE SYSTEM. ONE WE HAVE TALKED EARLIER THIS MORNING NEWBORN SCREENINGIOUSING THESE CARDS TO DETECT NEWBORNS WITH GENETIC DEFICIENCY. THE TECHNOLOGY FOR SEQUENCING HAS INCREASED GREATLY. MOUSE MUTAGENESIS WE HER ABOUT WHERE THERE'S GLOBAL MUTAGENESIS AN ANALYSIS. REGISTRIES AN REPOSITORIES WERE TOGETHER WITH THE NETWORKING THAT'S EXPANDED GREATLY AND SHIPPING ALLOWS WORLDWIDE COLLABORATION CONSORTIA TO FORM. YOU WILL THESE CONTRIBUTE TO MORE RAPID DETECTION,ING A CAT DIAGNOSES, THERAPY AND INCREASED KNOWLEDGE. IT IS A VERY COMPLEX FEEL. PRIMARY IMMUNE DEFICIENCY IT STANDS FOR. IN THE MOST RECENT -- THIS IS BIANNUAL EVERY TWO YEARS THERE'S A SUMMARY OF PED DISEASES THE MOST RECENT TWO YEARS AGO IDENTIFIED A TOTAL OF MORE THAN 150 DISEASES OVER 120 GENES IDENTIFIED. I JUST TO GIVE YOU A FLAVOR HERE, BROKEN DOWN OR TAKEN THEIR SOME OF THE MORE FAMILIAR GENES INVOLVED, GYNOCOMBINE T AN B CELL IMMUNODEFICIENCY, SKIDS COMMON UNDERLYING HERE I HAVE SHOWN SOME OF THE GENES THAT WE TALK -- I MENTION EARLIER, ANTIBODY DEFICIENCIES, OTHER WELL DEFINED INCLUDES WORKISCOTT ALDRIDGE AND HYPERDGE. IMMUNE AT THIS REGULATION, THE AIR, GIVES RISE TO DEFECTS ARISE -- GIVE RISE TO IMMUNE REACTIVITY IN THE PERIPHERY. PHAGOCYTE DEFICIENCIES PARTICULARLY NEUTROPENIAS AN DIFFERENT INNATE IMMUNE SYSTEM DEFICIENCIES. THIS INITIATIVE, THE HISTORY OF THIS INITIATIVE IS THAT IT WAS ESTABLISHED IN 2003 AS A RESOURCE. THERE WAS A CONTRACT TO THE PRIMARY IMMUNE DEFICIENCY RESOURCE CONSORTIUM, ON THE U.S. ID NET, UNITED STATES IMMUNODEFICIENCY NETWORK. THE PI WAS HANS OX. THAT WAS -- THAT ACCOMPLISHED THE NETWORK AND ELECTRONIC REGISTRY TRANSFERRED OLD DATA AND ADDED ABOUT 1,000 INDIVIDUALS. THEY ALSO AWARDED PILOT RESEARCH GRANTS TO THE TUNE OF ABOUT $8 MILLION. IN 2007 THOSE FUNCTIONS, THOSE RESOURCE FUNCTIONS WERE ASSOCIATED WITH THE PILOT RESEARCH GRANTS BEING -- FORMING THE BASIS OF EXPLORATORY OR R-21, SMALL GRANT OR R O-3 FUNDING UP THE ANNOUNCEMENTS. WHAT WE'RE TALKING ABOUT TODAY IS RFA TO EURYON U-24, SO A RESOURCE GRANT COOPERATIVE AGREEMENT I SHOULD SAY. AND THIS WAS AWARDED IN 2008 TO CHARLOTTE CUNNINGHAM AS PE AND GRANTEE IS IMMUNE DEFICIENCY FOUNDATION. WE ARE NOW TALKING RENEWAL. THE PURPOSE OF REGISTRY OF U.S. RESIDENTS WITH PRIMARY IMMUNE DEFICIENCY DISEASES, FOUNDED IN '93 WITH CHRONIC GRANULOMATOUS DISEASE, EXPANDED IN '97 WITH THESE EIGHT PIDs, IN ADDITION, MORE THAN 30 MOLECULAR GENETIC DISORDERS AND SEVERAL OTHER DISEASES ARE TRACKED. WHICH DOES THIS ENCOMPASS? I ADDD THE STEERING COMMITTEE BECAUSE I BELIEVE IT IS A RESOURCE TO THIS COOPERATIVE AGREEMENT. IT'S COMPOSED OF SOME OF THE LEADING PICSD INVESTIGATORS. THREE COMPONENTS ARE REGISTRY, MORE THAN DOUBLED ENROLLMENT IN THE PAST FOUR YEARS, NUMBERS IN A MOMENT ACTUAL ENROLLMENT. THEY ESTABLISHED DISEASE WORKING GROUPS WHICH INCLUDE DATA ENTRY FORMS NEGOTIATED DATA SHARING WITH TWO CONSORTIA, TREATMENT COPSOR SHAH FOR PRIMARY DEFICIENCIES, PARTICULARLY DISEASES AND THEY'RE PROVIDING WEB-BASED QUERY FORM, I'LL SHOW YOU AN EXAMPLE OF THAT IN A MOMENT. THE SECOND COMPONENT IS REPOSITORY WHICH MAINTAINS PATIENT SAMPLES INCLUDING 48 CELL LINES REPRESENTING 15 PIDs CURRENTLY. THESE ARE AVAILABLE FROM THE CORELL INSTITUTE. THERE ARE A TOTAL OF 86 AND 18 DIFFERENT DISEASES REPRESENTED AMONG WHAT THEY HAVE IN THE STORE. 23 CELL LINE'S THIS IS PARTLY WHAT RESOURCE IS AND ALSO WHAT IS OFFERED RIGHT NOW. 23 CELL LINES DISTRIBUTED IN 2012, THEY WERE USED IN STUDIES OF EXPRESSION OF PARTICULAR GENES AND ALSO GENETICS. RESOURCES WORKING ALSO ON MYRIAD LIST OF CELL LINES AN ANTIBODIES AVAILABLE OPT WEBSITE TO HELP DIE KNOWSIS. THE THIRD COMPONENT OF THIS RESOURCE IS EDUCATION AN TRAINING. THEY HAVE AN ANNUAL SCIENTIFIC MEETING IN LAB RATION WITH THE CLINICAL IMMUNOLOGY SOCIETY. WE ALSO HOLD A -- ORGANIZE A SUMMER SCHOOL FOR TRAINEES, 32 TRAINEES IN 2012 AND THEY SPONSOR VISITING PROFESSORSHIP WHERE INDIVIDUALS THAT AS PROFESSORS EXPERTS. TRAVEL TO OTHER SITES AND PROVIDE A LECTURE AS WELL AS BED SIDES ROUNDS, SEVEN OF THOSE FIVE EXPERT MS. 2012. VISITING IMMUNOLOGY SCHOLARS PROGRAM WHERE TRAINEES GO TO EXPERT SITES THE TRAIN FOR ONE TO FOUR WEEKS. THERE WERE 15 OF THESE IN 2012. I SHOULD MENTION NOT ALL OF THIS, IS PAID SMALL PART IS PAID BY THIS RESOUR, A LOT COMES FROM INDUSTRY. ENROLLMENT IN THE PAST LEGACY DATA THE CUP REGISTRY IS DARK BLUE AND THIS REPRESENTS NUMBER OF DIFFERENT PIDs FOLLOWED BY THE RESOURCE. OVER 3,000 ENROLLED FROM 35 ENROLLING INSTITUTIONS INCLUDING FIVE SITES IN 2012 THIS IS AS OF THE END OF 2012 SO INCREASE. THIS SHOWS THE WEB PAGE, HOME PAGE. WHAT I WANT POINT OUT, AS OF A YEAR AGO AGO THERE'S A WEB QUERY FORM AVAILABLE LINK TO THE HOME PAGE, WHERE ANYBODY DO GO, IF YOU'RE RESPONSIBLE INVESTIGATOR, YOU CAN ASK THE QUESTIONS OF THE RECOMMEND INDUSTRY. SO IN THE PAST YEAR, 33 QUERIES, 14 DISEASE, NINE WITHIN THE COLLABORATORS USID NET, 15 FROM ACADEMIC INVESTIGATORS NINE FROM INDUSTRY. AMPLE QUERIES INCLUDE PREVALENCE OF AUTO-IMMUNITY IN GEORGE SYNDROME, THAT IS THE ANSWER. ADVERSE EVENTS, SUBQUEUE TAPEIOUS IMMUNOGLOBULIN, INTRAVENOUS IMMUNOGLOBULIN FACTORS AFFECTING DOSE OF IMMUNOGLOBULIN THERAPY, PID PATIENTS, HAVINGING HEPATOREAL ALREADY CARCINOMA. THE ANSWER IS THERE. SIX ABSTRACTS THREE MANUSCRIPTS TWO STILL IN REVIEW BUT ONE IN JOURNAL OF PEDIATRICS, TITLE OF THAT WAS ABOUT GEORGE SYNDROME. AGAIN, JUST TO GIVE YOU A SENSE OF WHAT THE RESOURCE IS, THIS SHOWS YOU THE DISEASE SPECIFIC WORKING GROUPS WITH THE -- EACH DISEASE FOLLOWED BY CHAIR AND THE MEMBERS OF THE WORKING GROUPS. THE PLAN WOULD BE TO RENEW THE RESOURCE WITH ALL THREE COMPONENTS MAINTAINED. MAIN TAPE REGISTRY,EN ROLE NEW PATIENTS CHECK CHECK MORE CELL TYPES OF DATA AND INCREASE COLLABORATION WITH OTHER REGISTRIES. TWO CHANGES WE'D LIKE TO HAVE HERE WOULD BE TO EPICOURAGE COLLABORATION WITH NBS NEWBORN SCREENING STATES AS I MENTION THIS MOTHERING. SO THERE ARE A NUMBER OF STATES IN THE UNITED STATES THAT DO NEWBORN SCREAMING, WE THINK IF WE CAN HAVE THEM COLLABORATE MORE DIRECTLY WITHVSx THOSE STATES, WE BET LESS BIASED REPRESENTATION IN THE RECOMMENDATION INDUSTRY. ALSO TRACK PEER REVIEWED PUBLICATION USES THE REGISTRY, ENCOURAGE THEM ONCE YOU HAVE THIS METRIC, ENCAN COURAGE THEM TO USE IT FOR THAT PURPOSE. THAT WOULD ALSO ENCOURAGE VALIDATION OF VALUE AND INTEGRITY OF THE DATA. MAINTAIN REPOSITORY HAS MAINTAINED AS CELLS NEEDED DEVELOP REAGENTS AND OTHER MATERIALS FOR THE RESEARCH COMMUNITY. THE ANTIBODIES MENTIONED EARLIER. EDUCATION AND TRAINING CONTINUED TRAINING AND OPPORTUNITIES AND COLLABORATIVE RESEARCH ON PID P. SO QUESTIONS? SUGGESTIONS? >> HOW DO PEOPLE GET ACCESS TO REAGENT PES YOU MEAN REPOSITORY. GOOD QUESTION. ALMOST ALL CELLS ARE AVAILABLE FROM THE COREAL NOT FOR PROFIT INSTITUTION SIMILAR TO ARCTCC SO THERE IS A COST TO THE REQUESTER. IT'S A MODEST COST, CAN'T TELL YOU EXACTLY HOW MUCH. I THINK IT'S DNA, THERE'S SOME LEVEL OF REVIEW AS WELL. SOME IMMORTAL CELL LINE ATCC, ANY QUALIFIED INVESTIGATOR CAN GET AT A LOW COST. I ENCOURAGE TO KEEP CORE ACTIONL BECAUSE EVERYBODY KNOWS ABOUT IT, EASILY FOUND, AND IT WORKS WELL. (OFF MIC) >> YOU KNOW, I DON'T KNOW FOR SURE WHICH SLIDES ARE AVAILABLE. BUT IT INCLUDES WHETHER THEY'RE ALL TRANSFORM NOT SURE, THE INDUCIBLE PLURIPOTENT STEM CELLS ARE BECOMING MORE POPULAR IN TERMS OF THE WAY THE INVESTIGATORS ARE EXCHANGING MATERIAL LIKE THAT. NONE OF THOSE ARE AVAILABLE THAT I'M AWARE OF YET. >> COLD YOU COMMENT ON THE OTHER P ID REGISTRIES WHERE THIS FITS INTO THAT CONTEXT? >> SUCH AS? MCMIC Q. THOSE ARE NOT -- YOU MEAN PITTC AND -- I'M SPACING OUT. THOSE ARE TREATMENT IF I SAID REGISTRY, I'M SORRY, THEY'RE BOTH TREATMENT CONSORTIA. SO IN FACT, THE -- THEY TREAT QUITE A NARROW RANGE OF SKID PATIENTS. >> WE WANT TO ENCOURAGE THEM TO WORK CLOSELY AND THE JAPANESE EQUIVALENT REGISTRY. >> OKAY. IF NO FURTHER DISCUSSION, WE WOULD LIKE TO ASK FOR YOUR RECOMMENDATION ON PROCEEDING WITH THIS. OKAY. THE FINAL INITIATIVE IS A NEW ONE, DEVELOPMENT OF SAMPLE SPARING ASSAYS FOR MONITORING IMMUNE RESPONSES AND KASIA BOURCIER WILL PRESENT THAT. >> THIS IS A NEW INITIATIVE CLEARING CONCEPT FOR FY 15. THIS INITIATIVE ACTUALLY HAS A WORKING GROUP, YOU CAN SEE THE LIST OF MEMBERS FROM EACH BRANCH OF THE DIVISION THAT HAD BEEN WORKING ON THAT. I MUST ACKNOWLEDGE HERE THAT IDEA OF THIS INITIATIVE WAS PUT FORWARD YEARS AGO I GUESS MAYBE NOT TOO MANY YEARS AGO BY HELEN AND WE ARE VERY HAPPY THAT POSSIBLY WILL HAVE AN OPPORTUNITY TO PURSUE THIS OPTION. AND DEVELOP IT A LITTLE FURTHER. THE OBJECTIVE OF THIS INITIATIVE IS TO ACCELERATE DEVELOPMENT OF SAMPLES AND VALIDATED ASSAYS THAT CAN BROAD P AVAILABLE OF WELL CHARACTERIZED TOOLS FOR MONITORING IMMUNE RESPONSES AND WE ARE OBVIOUSLY INTERESTED IN MONITORING IMMUNE RESPONSES IN HEALTHY SUBJECTS AS WELL AS DISEASE INDIVIDUALS AN OBVIOUSLY ALL THE DISEASE THAT OUR DIVISION IS STUDYING. THE ULTIMATE GOAL EVENTUALLY MIGHT BE DEVELOPMENT OF SOME KIND OF TIGHT NOTTIC TOOL -- DIAGNOSTIC TOOL OR BIOMARKER THAT COULD HAVE IMPACT FOR CLINICAL TRIAL DESIGN OR CLINICAL TRIAL MONITORING OF PATIENTS DURING TREATMENT. WE BELIEVE THERE IS A BIG NEED FOR THIS INITIATIVE SINCE CONVENTIONAL APPROACHES FOR IMMUNE MONITORING DO NOT PROVIDE THE OPPORTUNITY TO REALLY FULLY EXPLORE THE MECHANISM OF IMMUNE FUNCTION AND VERY LIMITED AMOUNT OF SAMPLES OR TISSUES. WE KNOW THAT SUCH SAMPLES ARE COLLECTED DURING CLINICAL TRIALS FROM PEDIATRIC OR IMMUNOCOMPROMISED PATIENTS, TISSUE BIOPSY, THESE ARE VERY MANY TYPE OF SAMPLES THAT THE MATERIAL IS REALLY LIMITED AND IT IS VERY HARD TO GET A BIG PICTURE OF IMMUNE FUNCTION AT MANY LEVELS. WE HOPE THE ASSAYS WE DEVELOP BY THIS INITIATIVE WILL HAVE BROAD APPROXIMATELY CASE IN MANY PROGRAMS RUN BY DADE AND BY SPEAKING INFORMALLY WITH OTHER DIVISIONS AND OTHER INSTITUTES, WE MIGHT BE ALSO VERY INTERESTED IN PURSUING THAT. WHAT KIND OF ASSAYS WE MIGHT SUPPORT? THIS IS OBVIOUSLY JUST EXAMPLES, THAT WILL BE MONITORING OF SPECIFIC RESPONSES, VARIOUS SUBPOPULATIONS. AND ASSESSMENT OF T AND B REGULATORY CELLS ANNETTE WORKS. CYTOKINES AND SIGNALING NETWORKS. GENE EXPRESSION STUDY, PROTEOMICS, MANY OTHER TYPE OF OMICS STUDIES. THE BEST WOULD BE TO DEVELOP ASSAY THAT COULD COMBINE OR MULTI-PLEX ALL THE -- SO WE CAN GET A LOT OF INFORMATION COMING OUT FROM LIMITED AM OF SAMPLES. THESE ASSAYS WHAT IS IMPORTANT|„=zy FOR US IS THEY WOULD LEAD TO THE MAXIMUM USE OF THE SAMPLES THAT WE HAVE. BUT ALSO WOULD REQUIRE MUCH MORE INCREASE SENSITIVITY OR SPECIFICITY OF ASSAY ALREADY IN EXISTENCE. I PUT SOME EXAMPLES OF ASSAYS BUT THESE ARE JUST A FEW OF THEM. ONE IS MICROENGRAVING ASSAY, AND WHAT IT ENABLES FOR IS USING VERY LIMITED AMOUNT OF CELLS, EVEN ONE CELL, ONE CAN GET A LOT OF INFORMATION ON CYTOKINE PRODUCTION, CHEMOKINE PRODUCTION, GENE EXPRESSION, GENE SEQUENCING PHENOTYPE ANALYSIS, THIS IS TYPE OF ASSAY MULTI-PLEXING WE WOULD LICK TO SUPPORT. THERE'S A LOT OF INTERESTING INNOVATION IN NANOWIRE AS MICROFLUIDICS AREAS. AND WE HOMOTHAT THOSE MIGHT BE INCLUDED IN STUDIES CELLS REGULATORY NETWORK. THIS IS AN EXAMPLE OF A -- METH USED FOR A WHILE ALREADY. WE KNOW THAT FROM FLOW CYTOMETRY ANALYSIS WE CAN LOOK SIGH MULL TAPEIOUSLY AT 12 TO 19 DIFFERENT MARKERS. AND THAT GIVES US A COMBINATION OF OVER MAYBE 2, 3,000 DIFFERENT SUBPOPULATION. IF WEIOUS THIS TYPE OF TECHNOLOGY MASS DETECTION MASS SPECTROMETRY DETECTION SITE, THIS NUMBER GOES REALLY UP AND P AT THIS MOMENT I THINK THE TECHNOLOGY IS ABLE TO LOOK AT 30 OR UP TO 50 MAYBE MARKERS AT THE SAME TIME. SO THE CELL FUNCTION CAN BE INTERROGATED AT MANY LEVELINGS. WHAT ALSO INTERESTING IS THAT THIS TYPE OF APPROACH MIGHT BE USED FOR HISTOLOGY, I THINK THAT COULD LEAD TO VERY EXCITING TYPE OF DISCOVERY. THE FUNDING MECHANISM WE PROPOS IS U-24,LY SOURCE RELATED PROJECT. DURATION OF AWARDS WOULD BE 3 TO 5 WITH ANTICIPATED NUMBER OF AWARDS, AGE TO 10. THERE IS NO OTHER INITIATIVE SIMILAR TO THAT. SO THIS ONE WOULD BE ONE OF THE HIGH. AND THAT'S THE END OF THE PRESENTATION IF YOU HAVE ANY QUESTIONS. OR SUGGESTIONS. >> ARE THERE NOT COMPANIES IN THE BUSINESS LOOKING TO SEE IF THEY CAN USE SMALLER AND SHALLER SAMPLES OF BLOOD? SHOULDN'T THE COMPANIES WHO PROVIDE THESE ASSAYS AND SO ON BE DOING THIS IF >> THAT'S A GOOD IDEA. ACTUALLY THESE COMPANIES COULD APPLY FOR IR TYPE OF FUNDING. MANY OF THE DEVELOPMENTS FIST HAPPEN IN ACADEMIA AND THEN THEY CAN BE TRANSFERRED TO THE COMPANIES FOR PRODUCT DEVELOPMENT TYPE OF THING. >> THIS IS A CONTROVERSIAL QUESTION. IN THE PRESENT FUNDING SITUATION DO YOU THINK THIS IS HIGH ENOUGH FUNDING PRIORITY TO GIVE SPECIAL ATTENTION? >> ABSOLUTELY. ABSOLUTELY. JUST BECAUSE WE HAVE -- DURING OUR -- THERE'S A LOT OF -- AS YOU KNOW, CONSORTIA RUN BY DADE AND A LOT OF NETWORKS THAT ARE LOOKING INTO HEALTHY INDIVIDUALS, HOW THE IMMUNE RESPONSE IS PROGRESSING AND HOW WHAT ARE THE BEST WHICH TO APPROACH IT SO SOME OF THESE ASSAYS ESPECIALLY ASSAYS THAT ARE VALIDATED, AND HAVE CONSTANT RESULTS, THAT SAY I THINK IT CAN BE VERY USEFUL IN THE APPLICATION TO THESE CONSORTIAS. >> I WOULD LIKE TO ADD THE THAT FROM OUR FEEL FOR AL ALREADY JOY AND ASTHMA, IT'S ABSOLUTELY NECESSARY WE ALLERGY AND ASTHMA, THIS IS WHERE EVERYTHING BEGINS AND IF WE DOPE HAVE THE ABILITY TO GET SAMPLES WE'RE MISSING A TREMENDOUS OPPORTUNITY FOR PREVENTION OF THE DISEASE. Q. I'LL JUMP IN FOR TRANSPLANTATION. WE'RE SO OFTEN STUDYING SUBJECTS WHO HAVE BEEN DEPLETED OF CELLS AND WE'RE TRYING TO UNDERSTAND WHAT'S HAPPENING IN THE EARLY POST TRANSPLANT PERIOD WHEN WE HAVE FEW CELLS TO STUFF DO DI. SO WE WILL BE DEPENDENT ON THIS KIND OF TECHNOLOGY IF WE'RE EVER TO LOOK AT THAT PARTICULAR TIME PERIOD. (OFF MIC) [LAUGHTER] >> WHERE WOULD FUNDING FROM THIS COME? WHAT IF SOMEBODY HAS A GREAT IDEA? >> WE WOULD HAVE RFAs -- >> IF YOU DIDN'T DO THIS, WHAT WOULD HAPPEN RIGHT NOW? >> THERE'S NOTHING THAT -- NOTHING THAT IS AVAILABLE. THIS IS NOT A HYPOTHESIS DRIVEN TYPE OF RESEARCH SO IT WOULD BE VERY DIFFICULT TO PROPOSE SAY RO-1 OR R-21 FOR JUST DEVELOPING METHODS. SO I THINK THAT NEEDS A SPECIAL ATTENTION. >> I THINK IT IS A GREAT QUESTION, IS THERE FUNDING FOR THIS? WOULD BE HEAR TO ENVISION ANYTHING COMPREHENSIVE GETTING THROW STUDY SECTION. OBVIOUSLY SOME OF THE TECHNOLOGIES THAT KASICSA SHOWED EMERGED FROM RO-1 GRANTS OR OTHER CONSORTIUM GRANTS. BUT NOTHING THAT WE CAN POINT TO IN A SYSTEMATIC FASHION. TO VALIDATE AND COMPARE TECHNOLOGIES AND BRING THEM TO THE POINT WHERE THEY CAN BE APPLIED IN RESEARCH SETTING NOT IN A GENERAL CLINICAL SENSE. BUT IN A RESEARCH SETTING IN THE CONTEXT THAT NANCY OR ALKUS HAVE REFERRED TO. >> OKAY. IF THERE'S NO FURTHER QUESTIONS, WITH THAT WE AGAIN NEED COUNCIL RECOMMENDATION ON THIS INITIATIVE. OKAY. THEN WITH THAT, LET ME THANK YOU ALL FOR YOUR PARTICIPATION AND WE LOOK FORWARD TO SEEING YOU AT THE NEXT COUNCIL ROUND IN A FEW MONTHS.