>> GOOD AFTERNOON, LADIES AND GENTLEMEN, I'M BRIAN TRAINER AND IT IS MY ABSOLUTE PLEASURE TO INTRODUCE AND TO HOST BRIAN KASPER TO YOU TODAY BUT FIRST AND FOREMOST I WANT TO DO TWO LITTLE HOUSEKEEPING THINGS. I'VE BEEN ASKED TO TELL YOU THAT THERE IS IN FACT A TOWN HALL MEETING SCHEDULED TO TAKE PLACE HERE AT 1:00 O'CLOCK, SO WE HAVE TO VACATE THIS BEAUTIFUL ESTABLISHMENT AND AMP TEATER AT 1:00 O'CLOCK. JUST TO TELL YOU A LITTLE BIT ABOUT THIS MEETING BECAUSE IT'S AN OPEN TOWN HALL, EVERYBODY'S INVITED TO YOU, IT'S FOR CLINICAL INVESTIGATOR TO DISCUSS THE POSSIBILITY OF COLLABORATION WITH EXTRAMURAL INVESTIGATORS. BUT ENOUGH ABOUT THAT, LET ME JUST TURN MY ATTENTION AGAIN NOW, BACK TO BRIAN AND TELL YOU A LITTLE BIT ABOUT THEM AS AN INTRODUCTION AND THEN HE CAN CONTINUE ON. BASICALLY BRIAN IS AN ASSOCIATE PROFESSOR AT OHIO STATE UNIVERSITY. HE ACTUALLY GREW UP INITIALLY IN SPRING FIELD, ILLINOIS AND THEN MOVED TO CALIFORNIA TO WORK IN A BIOTECH COMPANY, FOCUSED ON GENE THERAPY WHICH ALMOST BECOME HIS LIFE PASSION AT THIS STAGE AND FOR A NUMBER OF YEARS BEFORE HE DID HIS GRADUATE STUDENTS WITH RUSTY GAUGE AND THE STUDENT IN THE USS SAN DIEGO AND THEN ABOUT NINE YEARS AGO, HE MOVED TO OHIO WHERE HE'S BEEN, SINCE, THE TITLE OF HIS TALK TODAY AS BEEN CELLULAR CULPRITS IN NEUROMUSCULAR DISEASE AND IT WILL BE AN INTERESTING TALK FOR US ALL, THANK YOU. >> GREAT, THANK YOU VERY MUCH BRIAN FOR THE OPPORTUNITY TO COME AND VISIT. THIS IS ACTUALLY, DESPITE RUNNING A LABORATORY OVER THE PAST NINE YEARS, THIS IS THE FIRST TIME THAT I'VE ACTUALLY BEEN ON NIH CAMPUS. USUALLY THE MEETINGS ARE IN ONE OF THE NEARBY HOTELS, SO IT'S A REAL PLEASURE TO ACTUALLY SEE THE NIH AND THE CAMPUS AND GET TO MEET MANY OF THE LABORATORIES HERE. THANK YOU ALSO FOR SPENDING SIEBER MONDAY TO LISTEN ABOUT SOME SCIENCE AND I WILL TRY TO KEEP ON TIME HERE SINCE THERE IS 1:00 O'CLOCK, SO WE'LL MOVE THROUGH AND GET TO SOME OF THE NEWEST DATA WE HAVE ON OUR UNDERSTANDING OF SOME OF THE CELLULAR CULPRITS IN LUNG CANCER GERIATRICKIZATION EIGHT--LOW GERIATRICKIZATION EIGHT HOURS' DISEASE,--ULTIMATE DEATH IN MOTOR NEURONS RESULT NOTHING WEAKNESS, PARALYSIS AND DEATH. THE DISEASE IS FATAL IN ALL CASES, USUALLY WITHIN THREE TO FIVE YEARS OF ONSET AND THERE'S ACTUALLY ONLY ONE FOOD AND DRUG ADMINISTRATION APPROVED DRUG TO TREAT ALS AND THAT'S BLOCKS EXCESS GLUTEA MIGHT AND THEN ACTUALLY EXTENDS BY AN AVERAGE OF THREE MONTHS. THERE HAVE BEEN MANY, MANY DRUGS AND THERAPIES TO MOVE FORWARD AS THERAPEUTIC DEVELOPMENTS AND THE FIELD HAS FOUND A LARGER CLINICAL TRIAL, PHASE TWO/THREE CLINICAL STUDIES AND THE STUDY SO THAT'S GREAT. REALLY REGULATING WHETHER THE AS SITES ARE LOOKING FOR IT SO WE CLONED THE H 2 G GENE INTO A [INDISCERNIBLE] WHICH IS A SUB UNIT OF MHC AND INFECTED THE MOTO NEURONS AND ASKED WHETHER THAT COULD RESCUE THE ALS [INDISCERNIBLE] TOWARD MOTOR NEURONS SO MOTOR NEURONS WERE COMPLETELY PROTECTED WHEN WE OVEREXPRESSED. QUITE EXCITING RESULT FOR US. P RESCUED THEM PERFECTLY AND WE MAINTAINED NORMAL LEVELS OF HC ON TOP OF THOSE AS CITES BY PROVEN EXPRESSION. WE'RE GETTING CLOSE. IT'S 12:47 I'VE GOT A COUPLE MORE THINGS TO SAY. WHAT DO WE THINK IS GOING ON IN ALS? WHAT I'VE TOLD YOU HAS BEEN AN UNDESCRIBED MECHANISM, ALMOST A HARD TO BELIEVE AND SCARY THOUGHT THAT ASTROCYTES CAN ADOPT, CONVERGE, TRANSFORM THEMSELVES INTO KILLING MACHINERY THAT IS TYPICALLY UTILIZED IN THE INP NATE IMMUNE SYSTEM AND GUESS WHAT? THEY'RE KILLING IT THIS WAY, MICRO GLIAL CELL DOS NOT USE THIS PATH WAY TO TRY TO ATTACK THE MOTOR NEURON BUT WE'RE TRYING TO UNDERSTAND HOW EACH OF THOSE ARE KILLING THE KNOW MOE TOR NEURON. THIS IS WHAT WE'RE THINKING IS OUR THOUGHT HERE IN THE CONTEXT OF A MOTOR NEURON THAT IS LOSING -- WHATEVER REASON -- THE MHC EXPRESSION DUE TO THE PRESENCE OF AN ALS ASTROCYTE AS WELL AS OTHER POTENTIALLY OTHER CELL TYPES THAT THE ACTIVATING RECEPTOR GETTING TRIGGERED SENDING THE POSITIVE KILL SINGLE TOWARD ASTROCYTES THAT ARE CONVERT INTO THIS NATURAL KILLER-LIKE PROPERTY AND MHC IS NO LONGER THERE TO PREVENT THE ASTROCYTE FROM KILLING [INDISCERNIBLE] GETS ACTIVATED AND DEGRANULATED TOWARDS THE MOTOR NEURON. I NEED PROBABLY TWO OR THREE MORE MINUTES THEN WE'LL GO INTO QUESTIONS AND ANSWERS. BUT I WANTED TO STOP THERE TO BRIEFLY SHOW THE GROUP CARLOS MIRANDA AS WELL AS SONG AND OTHERS HAVE PIONEERED THIS AND LAURA FERIOLO AND KATHERINE MEYER HAVE PUSHED FORWARD AS FELLOWS ON THIS NEWLY-DESCRIBED STORY THEY TOLD YOU TODAY. IN THINKING ABOUT THE MICROGLIAL, WHAT ARE THEY DOING? INFLAMMATION DOESN'T MATTER HERE, DOES IT MATTER HERE? ASHLEY FRANKS WHO IS HERE HAS MAINLY BEEN WORKING ON EVALUATING MICROGLIAL FROM THE ALS MICE. WHAT WE HAVE IS A VERY NICE MODEL OF WHEN WE TAKE A PRIMARY-DERIVED MICRO GLIAL AND CULTURE THEM WITH MOTOR NEURONS, MOTOR NEURONS DIE. IF WE INHIBIT I KAPPA B BY THE DOMINANT NEGATIVE, WE ACTUALLY RESCUE MOTOR NEURON SURVIVAL AND THEN IF WE ISOLATE I KAPPA B ANIMALS WE HAVE A MICRO GLIAL-SPECIFIC KREE -- WE CAN ACTUALLY NOW RESCUE MOTOR NEURON SURVIVAL. WE DID THE STUDY FIRST. THIS IS MICROGLIAL AND MONOCITE DRIVEN. IF WE USE A ROSA 26 -- MICROGLIAL GETTING COMBINED HERE. THE IF WE TAKE A CSF 1 CEIL MOUSE CROSS IN WITH A G 93 CROSS [INDISCERNIBLE] ANIMAL, COULD WE HAVE DISEASE PROGRESSION. ANSWER IS YES. WE FAILED WHEN WE REMOVED INFLAMMATION IN NF KAPPA B SIGNALLING IN ASTROCITES, BUT NOW WE HAVE A 21-DAY INCREASE IN THE [INDISCERNIBLE] MOUSE MODEL. WE'RE EXCITED ABOUT THIS RESULT BECAUSE ULTIMATELY THIS IS VALIDATING THIS VARIOUS CELL TYPES ARE ACTUALLY TRYING TO KILL THE MOTOR NEURON FOR WHATEVER REASONS AGAIN THAT WE DON'T KNOW BY VARIOUS AND DIFFERENT MECHANISMS. WITH A THAT I'D LIKE TO STOP AND ANSWER ANY QUESTIONS IN THE LAST 8-9 MINUTES. THANK YOU. [APPLAUSE] >> [LOW AUDIO] HAVE A PARTICULAR INFLAMMATORY PROFILE, OBVIOUSLY THERE ARE OTHER DISEASES SUCH AS MULTIPLE SCLEROSIS ALSO INVOLVE INFLAMMATION. MY QUESTION IS, DOES THIS PROFILE THAT YOU'RE SHOWING HER FOR ALS DOES IT OVERLAP WITH MS? THERE'S AN AWFUL LOT OF THERAPIES THAT WE COULD USE TO ALTER THAT IMMUNE PROCESS AND WHETHER THEY MIGHT BE MRIKABLE TO ALS. -- APPLICABLE. >> I THINK THAT, YOU KNOW, THE MS FIELD HAS FOCUSED ON THE MICROGLIAL. WE WERE THINKING GOOD CELL/BAD CELL AND THERE'S PROBABLY A LOT OF SPECTRUM IN-BETWEEN, BUT MICROCOMBLEEL FROM THE M # VERSUS M 1 CONVERSION, THIS HAS BEEN SEEN IN ALS AND MS IN TRYING TO PUSH A M 1 IF ONE BELIEVES THAT M 1 IS BAD IN THAT THE MORE SIMPLISTIC VIEWPOINT IF ONE CAN PUSH IT TOWARDS A MORE RESTING MICROGLIAL THAT'S PROBABLY GOING BE GOOD IN MS AND ALS; HOWEVER, THERE'S OTHER CELLS THAT ARE LIKELY, SUCH AS AN ASTROCYTE, SUCH AS WHAT'S HAPPENING IN THE MOTOR NEURON -- WE HAVE HIT MULTIPLE CELLS AND MULTIPLE PATHWAYS FROM WHAT WE CURRENTLY KNOW IS OUR ULTIMATELY, WE HOPE TO FIND THE D 1 FACTOR THAT THE DRIVING THE MAYHEM IN ALL OF THE VARIOUS CELL TYPES. [INDISCERNIBLE] THE FIELD REMAINS TO BE KNOWN OR IS IT SOME OTHER FACTOR OR FACTORS THAT ARE DRIVING BASICALLY MULTIPLE TRAINS GOING TO TRY TO RUN OVER THE MOTOR NEURON. >> EXCELLENT JOB [LOW AUDIO]. >> SO THERE'S CURRENTLY NEURAL STEM -- THE QUESTION IS, IS ANYONE IN HUMAN CLINICAL TRIALS WITH ANY SORT OF STEM CELL REPLACEMENT? NEURAL STEM -- AND THIS IS LED BY EVA FIELDMAN IS THE PI OF MICHIGAN AS WELL AS MANY OTHER INVOLVED INDIVIDUALS INCLUDING [INDISCERNIBLE] THEY ARE IN INITIAL HUMAN CLINICAL TRIALS WITH A NEURAL STEM CELL IMPLANT AND THESE CELLS ARE LIKELY TURNING INTOES TURNING INTOES A -- ASTROCYTES. >> CERTAINLY ONE OF THE BIGGEST READOUTS IN A MOUSE FOR SURVIVAL IS WRITING REFLEX UTILIZED BY HAND LEGS OF ANIMALS. THE HUMAN TRIALS ARE STARTING TO SHOW THAT THE CELLS AREN'T SPREADING OUT AS MUCH AS ONE IMAGINED AND I THINK THIS IS GOING TO BE DIFFICULT TO THINK ABOUT HOW ONE REALLY TRANSLATES THIS. NOW EVERYBODY WANTS TO GO FOR THE GRAND SLAM. FDA HAS TAKEN THE POINT OF SAYING GO LOWER ON THESE PATIENTS SUCH AS LUMBAR REGION OF THE SPINAL CORD WHICH IF PROVEN SAFE THEN YOU CAN THINK ABOUT SOME OF THE RESPIRATORY CENTERS AND TRANSPLANTS IN SOMETHING THAT LIKE SUR VI CALL THORACIC REGIONS. YOU'RE GOING TO HAVE TO DILUTE THE ASTROCYTES WITH THESE STEM CELL BUS CERTAINLY WORTHY OF PURSUIT. >> [LOW AUDIO].