2018 Demystifying Medicine: Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease)

2018 Demystifying Medicine: Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease)


>>>GOOD AFTERNOON. I HAVE A VERY NICE ANNOUNCEMENT TO INFORM YOU AND THOSE WHO ARE LISTENING AND WATCHING. WE HAD TO DO A LITTLE SWITCHING OF THE LAST TWO SESSIONS OF DEMYSTIFYING MEDICINE. SO, ON MAY 1, WE ARE GOING TO HAVE A ROUNDTABLE KIND OF DISCUSSION WITH MICHAEL GODDESS MAN AND SEVERAL OTHERS WHO HAVE BEEN INVOLVED IN THE QUESTION OF, WHAT DO YOU DO AFTER YOU FINISH YOUR POSTDOC AT THE NIH? AND ON THE LAST DAY, ON THE 8th, FRANCIS COLLINS, THE DIRECTOR OF THE NIH, IS GOING TO SPEAK ON THE TOPIC OF THE NATIONAL INSTITUTES OF HOPE. AND FRANCIS TELLS ME HE IS GOING TO PRESENT SOME OF HIS VIEWS ABOUT THE WORLD IN WHICH WE LIVE AND WHERE SCIENCE IS STANDING. SO I’M SURE THAT WILL BE A VERY EXCITING EVENT. IS THERE ANYONE IN THE ROOM WHO DOESN’T KNOW WHAT THIS PICTURE IS? DON’T HESITATE. YOU ALL KNOW, RIGHT? SO HOW ABOUT YOU, SIR? DO YOU KNOW WHAT IT IS? RIGHT. OKAY. SO THAT’S THE BROOKLYN BRIDGE. AND WE SHOW THIS EACH TIME FOR A COUPLE OF REASONS. ONE, THE PICTURE WAS TAKEN BY MY GRANDFATHER. BUT SECONDLY, IT SYMBOLIZES WHAT THE WHOLE PURPOSE OF THE DEMYSTIFYING MEDICINE COURSE IS. ONCE YOU BUILD A BRIDGE, LIFE IS NEVER THE SAME ON EITHER SIDE. THE PEOPLE IN BROOKLYN, THE FAR SHORE HERE, HAD NO IDEA OF WHAT WAS GOING TO HAPPEN TO THAT FARMING COMMUNITY WHEN THE BRIDGE WAS BUILT AND THE PEOPLE IN NEW YORK, ON THE OTHER SIDE, THOUGHT THEY WERE GOING TO BE INVADED BY A BUNCH OF FOREIGNERS AND FARMERS. WELL, THAT DIDN’T HAPPEN. BUT WE ARE LIKE THE TWO GENTLEMAN ON THE CATWALK, SORT OF TRYING TO BRIDGE SOME OF THE AMAZING ADVANCES IN MODERN, CONTEMPORARY, BIOLOGICAL AND ENGINEERING SCIENCES WITH HUMAN HEALTH AND DISEASE. AND I WOULD POINT OUT THAT THE USUAL WAY IN WHICH THIS HAS EVOLVED IN MEDICINE IS THAT PEOPLE DESCRIBE A DISEASE, MAYBE THEY LOOK AT THE PATHOLOGY, THEY GIVE IT A NAME, AND THEN THAT IS A STIMULUS FOR MORE REDUCTIONIST STUDDITIES TRY AND UNDERSTAND MECHANISMS AND TREATMENT. BUT I CALL YOUR ATTENTION TO THE FACT THAT WE ARE LIVING IN A WORLD WHERE THAT BRIDGE IS CHANGING. AND TODAY IS AN EXAMPLE OF THAT KIND OF BRIDGE, IN A WAY. AND WHAT I’M REFERRING TO IS THE FACT THAT WHEN YOU START TO THINK ABOUT RISK FACTORS FOR PEOPLE WHO SEEM TO BE HEALTHY, OR PROGNOSTIC THINKERS, DETECTORS, MARKERS, AND YOU LOOK AT THIS USING SOPHIS INDICATION OF GENOMIC ANALYSIS AND OTHER FORMS OF SEARCH ANALYSIS, IN A WAY, YOU’RE PUTTING THE CART BEFORE THE HOURS COMPARED TO WHAT THE TRADITIONAL PATHWAYS OF MEDICINE HAVE BEEN. SO I THOUGHT THAT WAS AN INTERESTING POINT. THIS IS AN EXAMPLE OF TODAY’S DISCUSSION, IS AN EXAMPLE OF THE FORMER, TRADITIONAL WAY. SHARKO IS CONSIDERED TO BE THE FATHER OF CLINICAL NEUROLOGY. — IF YOU HAVE TIME AND WANT TO READ INCREDIBLE THINGS, YOU CAN READ THE FRENCH OR THE ENGLISH TRANSLATION OF HIS DESCRIPTION OF PATIENTS WHO HAD DISEASES THAT WERE TOTALLY UNKNOWN. AND ONE OF THEM IS THE DESCRIPTION OF A GROUP OF PATIENTS, A SMALL GROUP, THAT HAD MOTOR NEURON DISEASE THAT WAS PROGRESSIVE AND FATAL. THAT WAS IN 1869 AND THE DISEASE WAS CALLED CHARCOT SICKNESS AND IT SORT OF SAT THAT WAY FOR FRANK LONGO TIME WITH THE EXCEPTION OF SOME PATHOLOGY THAT WAS DONE ALONG THE LINE. BUT NOT MUCH ATTENTION WAS PLAYED TO IT, UNTIL AN AMERICAN HERO, LOU GEHREG, BASEBALL’S IRON MAN. HE WAS A WONDERFUL PERSON. I REMEMBER SEEING HIM OFTEN WITH MY FATHER. HE HAD THE LONGEST RECORD FOR CONSECUTIVE PLAYING AND HIS BATTING AVERAGE WAS IN THE 300S ALL THE TIME. AND THEN ON ONE YEAR, IT BEGAN TO FALL. AND THINGS BEGAN TO HAPPEN. AND IT HAPPENED VERY QUICKLY. AND HE GAVE A VERY FAMOUS SPEECH AT YANKIE STADIUM SAYING HE HAD THE BEST LIFE IN THE WORLD, BUT WITHIN 2 YEARS HE HAD DIED OF ALS. THE DISEASE WAS NAMED AFTER HIM, AND MORE PEOPLE KNEW IT AS LOU GEHRIG’S DISEASE RATHER THAN THE ANATOMIC DESIGNATION. AND THEREAFTER, SUDDENLY THIS BECAME RECOGNIZED WIDELY, GLOBALLY. AND THERE WAS GREAT PUBLIC PRESSURE BECAUSE OF THE SEVERITY OF THE DISEASE TO FIND ANSWERS. AND THAT IS KIND OF WHERE WE ARE, THE ERA OF GENOMICS AND MOLECULAR BIOLOGY. WHERE DO THINGS STAND? NOW HERE IS LOU GEHRIG ON THE LEFT. HE WAS THE NUMBER 3 BATTER, THE NUMBER 4 WAS BABE RUTH, PROBABLY THE MOST FAMOUS FIGURE IN BASEBALL HISTORY, THE HOME RUN HITTER. AND THEY WERE GREAT FRIENDS. NOW I SHOW THIS PICTURE BECAUSE LOU GEHRIG DIED AT THE AGE OF 31 HAVING SUFFERED FROM ALS FOR APPROXIMATELY TWO YEARS. ON YOUR RIGHT IS STEPHEN HAWKINS WHO WAS, UNTIL ALMOST THREE WEEKS AGO, A PROFESSOR OF THEORETICAL PHYSICS AT THE UNIVERSITY OF CAMBRIDGE OCCUPIED THE CHAIR FIRST ESTABLISHED BY SIR ISSAC NEWTON. NOW HAWKINS, HIS STORY IS DIFFERENT. HE DEVELOPED A DISEASE 50 YEARS BEFORE HE DIED. FOR THAT NEXT 50 YEARS, HIS PATHWAY WAS VERY DIFFERENT FROM THAT OF LOU GEHRIG’S. AND ONE OF THE THINGS, TO THINK ABOUT IS WHY? HOW? WHAT HAVE WE LEARNED ABOUT THIS? IS ALS LIKE AN ICEBERG? DID THE CLINICAL PICTURE DESCRIBED, IS THAT IT? OR WITH THE NEW KNOWLEDGE AS THE CLINICAL SPECTRUM NOW BROADENED SO THE SYMPTOMS, THE SIGNS AND MAYBE EVEN THE PATHOLOGY HAVE CHANGED. IS THAT HAPPENING? WHAT CAN BE DONE TO DIAGNOSE, TREAT, TO PREVENT? WE ARE FORTUNATE TO HAVE TWO LOCALLY-KNOWN EXPERTS AT THE NIH WHO WILL TALK TO US ABOUT THIS. AND THE FIRST SPEAKER IS MARY KAY FLOETER WHO GOT HER MD AND PH.D. AT THE UNIVERSITY OF CALL — WASHINGTON UNIVERSITY IN ST. LOUIS. AND ENDED RESIDENCY TRAINING IN NEUROLOGY AND A POSTDOC IN PHYSIOLOGY IN CALIFORNIA. SHE CAME TO THE NIH AND PROGRESSIVE NEWLY-ESTABLISHED A RESEARCH CAREER IN 2006 SHE WAS APPOINTED THE NINDS DEPUTY CLINICAL DIRECTOR AND BECAME A SENIOR CLINICIAN IN 2008. HER RESEARCH FOCUSES ON RARE MOTOR NEURON DISORDERS. ONE OF WHICH IS THE TOPIC OF TODAY’S PRESENTATIONS. AND THE SECOND SPEAKER IS BRYAN TRAY NORWHO RECEIVED HIS MD DEGREE AND PH.D. FROM UNIVERSITY COLLEGE IN DUBLIN, IRELAND. AND HE TRAINED IN NEUROLOGY AT MIT AND AT HARVARD. HE WAS A STAFF NEUROLOGIST AT THE MASS GENERAL HOSPITAL, AND CAME IN 2005 TO THE NIH AS A CLINICAL ASSOCIATE. HE IS A SENIOR INVESTIGATOR IN THE LABORATORY OF NEUROGENETICS AND ONE OF THE PRIME MOVERS, IF YOU READ SOME OF THE PAPERS THAT HAVE BEEN POSTED THAT HE SUBMITTED, IN THE GENETIC ANALYSIS OF ALS. SO WE ARE VERY GRATEFUL TO BOTH OF YOU FOR BEING WILLING TO COME AND EDUCATE US.>>CAN YOU HEAR ME IF I SPEAK THROUGH THIS MICROPHONE? GREAT. SO AS DR. AWRYIAS MENTIONED, AMYOTROPHIC LATERAL SCLEROSIS IS ALSO KNOWN AS LOU GEHRIG’S DISEASE IN THE UNITED STATES. AND IN THE U.K. IT’S CALLED MOTOR NEURON DISEASE. THAT’S A LITTLE BIT CONFUSING BECAUSE IN U.S., WE SOMETIMES USE THE TERM MOTOR NEURON DISEASE TO REFER TO A WHOLE FAMILY OF DISORDERS OF WHICH ALS IS ONLY ONE. SO, I HAVE BEEN ASKED TO TALK ABOUT WHAT THE PATIENTS ARE LIKE AND PUT A HUMAN FACE ON THE PATIENTS. SO MY TALK IS REALLY MOSTLY ABOUT THE STORIES OF A COUPLE OF PATIENTS, BUT JUST BEAR WITH ME, I DO HAVE A FEW SLIDES TO PUT US ALL ON THE SAME PAGE. SO, AS MENTIONED, IT WAS FIRST DESCRIBED AS ALS AND DESCRIBED KNOWING PATIENTS AND KNOWING THEIR CLINICAL EXAM AND THEN LOOKING AT THE PATHOLOGY. AND SO WHAT ALS CONSISTS OF IS DEGENERATION OF TWO SETS OF NEURONS. CLINICALLY, HE NOTICED THAT THE PATIENTS HAD WASTING OF MUSCLES CALLED AMY ON THE FEE DUE TO THE DEGENERATION OF THE SPINAL MOTOR NEURONS THAT CONNECT DIRECTLY TO THE MUSCLES AND THE MOTOR NEURONS IN THE BRAINSTEM THAT CONNECT TO MUSCLES AS WELL. SO THESE ARE THE MUSCLES OF THE FACE AND THE TONGUE IN THE BRAINSTEM, THE ARMS AND THE LEGS IN THE SPINAL CORD. HE NOTICED THAT IN THE VENTRAL HORN OF THE SPINAL CORD THOSE LARGE MOTOR NEURONS WERE GONE AND HE ALSO NOTICED THAT THERE WAS SCARRING OR SCLEROSIS FROM THE LATERAL PART OF THE SPINAL CORD WHERE THE AXONS RUN FROM THE NEURONS IN THE MOTOR CORTEX THAT TRAVEL DOWN THE CORTICAL SPINE TRACT TO PROVIDE INFORMATION TO THE SPINAL MOTOR NEURONS. SO CLINICIANS SOMETIMES REFER TO THESE AS UPPER MOTOR NEURONS ALTHOUGH THEY DON’T DIRECTLY CONNECT TO MUSCLE. AND LOWER MOTOR NEURONS, THE ONES THAT DO CONNECT DIRECTLY TO MUSCLE. DEPENDING ON WHERE THE DISEASE BEGINS, WHICH PARTICULAR SETS OF NEURONS ARE FIRST AFFECTED, PATIENTS WILL DEVELOP WEAKNESS OF THEIR MOVEMENTS AND IF IT IS INVOLVING THE NERVE CELLS OF THE BRAINSTEM, THOSE WILL BE PROBLEMS WITH SPEAKING, SWALLOWING, AND MOVING THEIR TONGUE AROUND F THEY DEVELOP IN THE CERVICAL CORD, IT COULD BE A PROBLEM IN MOVEMENTS IN MUSCLES OF THE ARMS AS WELL AS THE DIE PHOTOGRAPH, WHICH IS AN IMPORTANT MUSCLE FOR RESPIRATION AND IF IT’S IN THE LOWER PART OF THE SPINAL CORD IT WILL AFFECT THE LUNGS. SO AN INTERESTING CLINICAL PHENOMENON ON PATIENTS WITH ALS IS THAT IT SEEMS TO BEGIN ALMOST SIMULTANEOUSLY IN LOWER MOTOR NEURONS AND UPPER MOTOR NEURONS AND A NUMBER OF YEARS AGO A CLINICIAN IN SEATTLE DESCRIBED PATIENTS THAT HE HAD FOLLOWED OVER YEARS AND SHOWED THAT THE CLINICAL PROGRESSION OF SYMPTOMS SEEMED TO SUGGEST THAT ALS WAS A DISEASE WHERE THERE WAS SPREADING. SO IF THE MUSCLES WERE AFFECTED, WHICH WOULD SUGGEST THE CERVICAL CORD, AT THE SAME TIME THEY WOULD DEVELOP CLINICAL SIGNS IN THE UPPER MOTOR NEURONS WERE ALSO AFFECTED FOR THE ARM. AND OVER TIME, THE OTHER ARM MIGHT BECOME AFFECTED AND EVENTUALLY IT WOULD SPREAD UP AND DOWN THE LEG TO DIFFERENT SEGMENTS. AND SO THE ALS IS A DISEASE WHICH AFFECTS ADULTS. THEY USUALLY ARE IN THEIR FIRST TO 60s BUT IT IS GOT A VARIABLE ONSET. SOME PATIENTS AS YOUNG AS 30 AND SOME PATIENTS AS OLD AS 80. TYPICALLY PATIENTS WHO DEVELOP ALS WILL HAVE AN AVERAGE& SURVIVAL OF JUST ABOUT 3-4 YEARS. BUT THERE IS A BIG SPREAD INCLUDING PATIENTS SUCH AS STEVEN HAWKINGS WHO SPENT THE LAST 20 YEARS OF HIS LIFE ON A MECHANICAL VENTILATOR BECAUSE HIS RESPIRATORY MUSCLES WERE NOT ABLE TO ACTUALLY WORK. SO, ALS IS A CLINICAL, DIAGNOSED BY CLINICAL FINDINGS. AND SO, WHAT QUI ARE LOOKING IN A UPPER MOTOR NEURON DYSFUNCTION? THEN YOU CHECK IF YOU CAME TO SEE THE NEUROLOGY. SO THE FIRST THING IS THAT THE PATIENTS WHO HAVE HAD — WHERE THE MOTOR NEURONS DIE CONNECTING MUSCLES, THE MUSCLES BEGIN TO ATROPHY. IF THE MUSCLES ARE — THAT ATROPHY ARE IN THE CERVICAL CORD, YOU MAY SEE SOME LOSS OF MUSCLE AROUND THE SHOULDER AREA. YOU CAN SEE THE HALLOWING. IF IT’S A LOWER CERVICAL SEGMENT, YOU CAN SEE THE INTRINSIC HAND MUSCLES WILL ATROPHY. SO NOTICE THE MUSCLE THAT MOVES THE INDEX FINGER LOOKS GOOD ON THIS HAND AND IT’S TOTALLY WASTED ON THE OTHER HAND. THIS IS ONE OF OUR PATIENTS AND IT’S VERY ASYMMETRIC. THIS HAND SEEMS TO BE IN GOOD STRENGTH. THOSE MOTOR NEURONS ARE STILL FAIRLY HEALTHY AND OVER HERE YOU CAN SEE THAT THIS HAND IS STARTING TO LOSE THE MUSCLES THAT MOVE THE THUMB AS WELL AS THE INTRINSIC MUSCLES OF THE FINGER. ONE OF THE THINGS WE LOOK FOR IS WHETHER PATIENTS HAVE WEAKNESS AND ATROPHY. NOW AS THE — THIS IS MY FIRST TIME USING IMOVIE TO MAKE MOVIES SO I HOPE THIS WORKS. SO AS THE MOTOR NEURONS BEGIN TO DIE, THEY BECOME HYPEREXCITABLE AND WHILE THEY ARE STILL CONNECTED TO THE MUSCLE FIBERS, BEGIN TO SEE THESE — I KNOW THAT MANY OF YOU PROBABLY HAD A TWITCH OF A MUSCLE HERE OR THERE BUT IF YOU FOCUS YOUR ATTENTION ON THE UPPER PART OF THE SHOULDER, YOU WILL SEE THAT THE MOTOR — MUSCLE HAS ALL THESE TWITCHES AND WE CONSIDER THESE TO BE A SIGN OF LOWER MOTOR NEURON DYSFUNCTION. NOW IF I HAD A NEEDLE AND I PUT IT INTO THE MUSCLE AND IT WAS CONNECTED TO AN AMPLIFIER, THE MUSCLE FIBERS, THE INDIVIDUAL MUSCLE FIBERS NO LONGER GETTING NERVE INPUT WOULD BEGIN TO GIVE OFF SPONTANEOUS ACTION POTENTIALS AND THOSE ARE CALLED FIBRILLATIONS. THESE ARE THE KINDS OF THINGS WITH THIS EMG, ELECTROMYOPATHY AND CLINICAL EXAM, THAT WE USE SAY THEIR INVOLVEMENT OF THE LOWER MOTOR NEURONS. WHAT I SHOWED YOU WAS INVOLVING THE LIMBS. BUT THERE IS ALSO ATROPHY THAT CAN OCCUR IN THE TONGUE MUSCLES. IN THIS PATIENT HERE HE HAS — LET’S SEE IF I CAN CLICK THAT AGAIN. HE HAS VESTICKALATIONS IN THE TONGUE AND HE ALSO, WHEN I LOOKED TO HIS GAG REFLEX, IT IS VERY BRISK. SO THIS IS A COMBINATION OF THE BRISK REFLEXES OF AN UPPER MOTOR NEURON DYSFUNCTION AND HIS TONGUE IS WASTING AWAY. SO THIS SIA PATIENT WHERE WE CAN SEE THE CLINICAL SIGNS OF BOTH SETS OF NEURONS BEING AFFECTED. NOW WHAT ARE UPPER MOTOR NEURON SIGNS WE MIGHT SEE IN A LIMB? AND HERE I’M GOING SHOW YOU
SOME& EXAMPLES OF HYPERACTIVE REFLEXES. SO HERE IS A GENTLEMAN AS I TAP HIS BICEPS TENDON, YOU WILL SEE THAT IT JERKS TWO TIMES INSTEAD OF ONE TIME. WHEN THERE IS REPEATED JERKS, THAT IS CALLED CLOTIS. I TAP THE TRICEPS REFLEX AND YOU’LL SEE THE TIP OF THE THUMB IS WIGGLING. SO THERE IS HYPEREXCITABILITY OF THE INPUT TO THE MOTOR NEURONS. SIMILARLY IN THE LEGS, I CAN PLAY THIS AGAIN. SO HERE IS SHOWING THE REFLEXES ARE HYPEREXCITABLE AND THEY SPREAD. THIS IS IN THE LEGS. I TAP THE RIGHT LEG AND THE LEFT LEG JERKS AS WELL. AND THEN THERE IS A RETURN OF PATHOLOGICAL SIGNS THAT YOU SEE IN INFANTS BEFORE THE CORTICAL SPINAL GOES. THE FANNING OF THE TOES AND RISING OF THE BIG TOE. SO WHEN I SEE A PATIENT IN THE CLINIC AND I’M DOING AN EXAM AND TRYING TO LOOK IN ALL THE DIFFERENT SEGMENTS OF THE BODY, THAT THERE IS EVIDENCE FOR CLINICAL EVIDENCE FOR DYSFUNCTION OF BOTH UPPER AND LOWER MOTOR NEURONS. SO NOW I SHOWED YOU WHAT I WOULD LOOK FOR IN THE CLINIC. I’D LIKE TO TELL YOU THE STORIES OF A COUPLE OF PATIENTS. AND I WANT TO MAKE A DISCLAIMER THAT THESE VIDEOS WERE NOT MADE FOR PRESENTATION OR FOR PRODUCTION. WHEN YOU SEE A PATIENT IN THE CLINIC, WE OFTENTIMES WILL TAKE VIDEOTAPES OF CERTAIN ACTIONS SO WE CAN MAKE MEASUREMENTS LATER AND AS A PART OF THIS, MY POST BACKS AND I WILL TRY TO ILLICIT SPONTANEOUSNESS TO SEE IF THEIR SPEECH IS OKAY. IN THE PROCESS OF DOING THAT, WE OFTENTIMES WILL ASK THEM QUESTIONS WHICH GIVE US INSIGHT INTO THEIR MEMORY OR WHETHER THEY ARE ABLE TO UNDERSTAND THE KINDS OF THINGS THAT WE ARE ASKING. SO THIS FIRST PATIENT HERE IS A GENTLEMAN THAT I FIRST SAW IN 2004. HE WAS SENT TO ME BY A NEUROLOGIST AT GEORGETOWN BECAUSE HE HAD ABOUT TWO YEARS OF HIS RIGHT LEG BECOMING PRO AGGRESSIVELY STIFF. AND HE HASN’T DEVELOPED LOWER MOTOR NEURON SIGNS AND WE WONDERED IF HE HAD A PRIMARY LATERAL SCLEROSISES IN WHICH THE NEURONS OF THE BRAIN DEGENERATE BUT NOT THE ONES IN THE SPINAL CORD. AND AT THAT POINT, WE REALLY DIDN’T HAVE A GOOD TEST TO DISTINGUISH BETWEEN THESE TWO DISORDERS EXCEPT TO LET ENOUGH TIME GO BY TO KNOW IT IS NOT LIKELY TO BE ALS. I ASKED HIM TO COME BACK A YEAR LATER. SO THIS IS A VIDEO OF HIM WALKING AT THREE YEARS. AND YOU CAN SEE THAT AS HE IS WALKING, THAT HIS RIGHT LEG IS STIFF. THE REFLEXES WERE VERY BRISK. BUT THERE WERE NO EVIDENCE OF ANY LOWER MOTOR NEURON SIGNS. SO AT THAT POINT, I SAID IT COULD BE THAT YOU IN FACT DO HAVE PRIMARY LATERAL SCLEROSIS. AND WE’LL SEE YOU IN A YEAR AND SEE IF THAT IS STILL THE CASE. NOW HERE IS THE VIDEO OF THE CONVERSATIONAL SPEECH THAT WE RECORDED.>>TELL ME ABOUT THIS PERSON WHO CAME WITH YOU TODAY.>>THAT’S MY SON, MICHAEL. HE IS — I HAVE THREE SONS, THIS IS MICHAEL. HE’S — HE LIVES NEAR –>>SO THAT’S GOOD TO KNOW. HOW HAVE THINGS BEEN CHANGING WITH YOU OVER THE PAST FEW YEARS?>>WELL, FOR THE MOST PART I FEEL I’M WEAKER. I’M FALLING MORE AND MORE OFF BALANCE AND NOT RESPONDING TO ANY KIND OF THERAPY. LIKE I FEEL I SHOULD BE. GENERALLY WEAKER.>>GENERALLY WEAKER. OKAY. HOW IS YOUR THINKING? ANY PROBLEMS?>>I THINK IT’S OKAY.>>ALL RIGHT. MEMORY IS OKAY?>>I THINK SO. YES.>>OKAY, GOOD.>>SO YOU CAN SEE FROM THIS DISCUSSION HERE THAT HE IS VERY ENGAGED WITH US. HIS SPEECH IS UNAFFECTED. AND HE HIMSELF SAYS THAT HE THINKS HIS MEMORY IS FINE. AND THE MAIN PROBLEM NOW IS THE BALANCE AND THE PROBLEM WITH HIS WALKING. WHEN I ASKED HIM TO COME BACK A YEAR LATER, HE SAID I’M REMODELING MY HOUSE. I CAN’T COME. AND I SAID OKAY, JUST LET US KNOW AS SOON AS YOU CAN COME. SO THEN HE CAME BACK NOT QUITE TWO YEARS LATER AND THIS IS HOW HE APPEARED AT THAT TIME.>>I ENLISTED IN THE NAVY AND WENT THROUGH FLIGHT TRAINING AND GOT MY COMMISSION AND SPENT 31 YEARS. I FLEW HELICOPTERS THROUGHOUT TOUR, AND I ENDED UP IN THE PENTAGON, AND MY LAST JOB WAS AS THE INSPECTOR GENERAL FOR THE CHIEF OF NAVAL PERSONNEL. SO I GOT TO TRAVEL A LOT AND SOLVING PEOPLE’S PROBLEMS.>>OKAY. SO THE FIRST THING THAT WILL YOU’RE GOING TO NOTICE IS THAT FIRST OF ALL HE IS HOLDING HIS HEAD FORWARD BECAUSE THE MUSCLES THAT EXTEND THE NECK ARE SO WEAK, THIS IS A VERY CHARACTERISTIC SIGN IN ALS. AND YOU CAN SORT OF GET AIR SENSE, HE IS WEARING THE SAME SHIRT THAT HE LOST A LOT OF MUSCLE BULK, PARTICULARLY IN THE UPPER PART OF HIS ARMS. HE IS TALKING HERE AND HE IS A LITTLE BIT SLOWER BUT HE IS STILL VERY CLEAR IN WHAT HE IS SAYING. AND I CUT IT OFF BECAUSE RIGHT AFTER THIS POINT, HE SAID WHERE HAVE YOU BEEN STATIONED IN YOUR CAREER? HE WAS ABLE TO NAME OFF ABOUT 20 PLACES. SO AT THIS TIME, I WAS DOING A STUDY TO LOOK WHETHER THERE WERE COGNITIVE CHANGES IN ALS PATIENTS AND TO SEE HOW FREQUENTLY THESE PATIENTS HAVE COGNITIVE IMPAIRMENT. THIS WAS QUITE AN ISSUE IN THE EARLY TWO THOUSANDS. AND SO WE DID FULL COGNITIVE TESTING WITH OUR NEUROPSYCHOLOGIST AND HE HAD NO PROBLEMS WITH HIS THINKING OR MEMORY. WE SAW HIM AGAIN ONE YEAR LATER AND I WILL SHOW YOU THIS LAST VIDEO AND I WANT TO APOLOGIZE BECAUSE IT IS VERY SHAKEY BUT I THINK IT IS VERY INSTRUCTIVE.>>CAN YOU TELL ME YOUR NAME?>>IT’S –>>WOULD YOU TELL ME YOUR NAME?>>SURE. MY NAME IS [ INAUDIBLE ]>>WHAT IS YOUR NAME?>>MY NAME IS LUCAS.>>I WANTED TO PAUSE THAT THERE BECAUSE HE IS TEASING ME ABOUT MY INTERVIEWING TECHNIQUE THAT I SHOULDN’T SAY CAN YOU TELL ME YOUR NAME BUT WILL YOU TELL ME YOUR NAME IS THE PROPER WAY TO ASK THAT QUESTION. ONE THING YOU CAN SEE IS HE HAD A LOT OF DETERIORATION IN NA ONE YEAR. THE MUSCLES ON HIS HANDS, THEY ARE QUITE WASTED AWAY. THE UPPER ARMS AS WELL AND HE MUST USE A JOYSTICK TO MOVE HIS CHAIR UP AND DOWN. THE NECK MUSCLES ARE SO WEAK HE NOW NEEDS TO USE A BRACE TO HOLD HIS HEAD UP RIGHT. I’M JUST GOING TO CONTINUE THIS BECAUSE INTERESTINGLY, HE STILL HAS A GOOD SENSE OF HUMOR AND PERSONALITY COMES THROUGH.>>AND WHAT IS THE DATE TODAY?>>I HAVE NO IDEA. IT’S PROBABLY THE 23rd OF — OF APRIL.>>WHAT YEAR IS IT?>>2008.>>OKAY. AND HAVE YOU EVER SEEN ME BEFORE?>>YES.>>WHERE HAVE YOU SEEN ME BEFORE?>>HERE AT THE NIH.>>OKAY. SO TELL ME A LITTLE BIT ABOUT YOUR SIX GRANDCHILDREN.>>ACTUALLY I HAVE EIGHT.>>EIGHT?>>THE OLDEST IS 13 AND THE YOUNGEST NOW IS 9. 13, 14, 13, 12, 11, 10 AND 9.>>SO COGNITIVELY, I MEAN IF YOU CAN REMEMBER THE AGES OF YOUR EIGHT GRANDCHILDREN ON SOME RANDOM DAY WHEN YOU’RE THISIL, YOU CAN SEE THAT HE IS PROBABLY GOT FAIRLY GOOD COGNITION. SOMETHING ELSE YOU MIGHT HAVE NOTICED IS HE IS ABLE TO MOVE HIS EYES NORMALLY. THE OCULAR MUSCLES ARE GENERALLY UNAFFECTED IN ALS UNTIL PROBABLY AS LATE AT 20 YEARS INTO YOUR DISEASE, IF HE MANAGED TO SURVIVE THAT LONG. SO THIS IS A GENTLEMAN WHO WOULD FIT THE CLASSIC ALS THAT MOST PEOPLE KNOW. NOW HE HAS A COUPLE OF RISK FACTORS HERE. SO HE MENTIONED THAT HE WAS IN THE MILITARY AND SO WE DON’T KNOW WHY, BUT WE DO KNOW THAT BEING IN THE MILITARY, WHETHER YOU’RE IN COMBAT OR NOT, DOES SLIGHTLY INCREASE THE RISK FOR ALS. HE ALSO PLAYED SPORTS IN HIGH SCHOOL AND COLLEGE, MAYBE NOT SURE WHICH ONES BUT PLAYED FOOTBALL. SO CONTACT SPORTS IS SOMETHING THAT EPIDEMIOLOGICALLY THERE IS A LITTLE BIT OF ASSOCIATION WITH INCREASED RISK FOR AL. AND NOW WE WONDER IF IT HAS SOMETHING TO DO WITH SMALL HEAD INJURIES. BUT THAT PART OF IT IS REALLY NOT YET CLEAR. NOW HE DID NOT HAVE ANY FAMILY HISTORY OF ALS. BUT INTERESTINGLY, HIS MOTHER HAD DIED IN HER 80s OF DEMENTIA AND THAT WILL PERHAPS MEAN SOMETHING AS WE TALK ABOUT THE NEXT CASE. AND HE HAD SAID THAT HUNTINGS TONSE DISEASE RAN ON HIS FATHER’S SIDE OF THE FAMILY BUT NO ONE IN HIS GENERATION WITH HUNTINGTON’S DISEASE. SO DOES ANYBODY HAVE ANY QUESTIONS ABOUT THIS AT THIS POINT? [ OFF MICROPHONE ]>>IT OFTEN WILL BEGIN ON ONE SIDE. OF COURSE WHEN IT IS BULL VAR, INVOLVING THE TONGUE, OF COURSE IT IS MID LINE. BUT IT GENERALLY GENERALIZES.>>[ OFF MICROPHONE ]>>SO CENTURY NEURONS ARE GENERALLY UNAFFECTED IF WE MEASURE THE AMPLITUDE OF SENSORY NERVE RESPONSE OR TEST BY PINPRICK OR VIBRATION SENSITIVITY, THEY ARE GENERALLY UNAFFECTED. PEOPLE HAVE REPORTED SOME VERY SLIGHT SENSORY ABNORMALITIES BUT THEY ARE VERY SUBTLE AND THEY DON’T TYPICALLY HAVE A CLINICAL — NOT CLINICALLY RECOGNIZED BY THE PATIENT. AND WE KNOW THAT PATH LOGICALLY, THERE IS A LITTLE BIT OF SPREAD OF SOME OF THE PATHOLOGY THROUGH THE POST CENTRAL GYRUS.>>[ OFF MICROPHONE ]>>SO THIS GENTLEMAN, BACK IN THAT TIME, WE ONLY HAD DISCOVERED FOR ALS WAS SOD1 AND HE WOULD NOT GET THAT.>>[ OFF MICROPHONE ]>>IN THIS GENTLEMAN? I DON’T THINK SO, NOT THAT I ILLICIT THAT THE TIME.>>[ OFF MICROPHONE ]>>I THINK THIS COMES DOWN TO THE QUESTION OF WHETHER ALS IS A SINGLE DISEASE. SO THAT WE — THIS CLINICAL PICTURE TYPICALLY THAT AND THE PROGRESSION OF THE DISEASE ARE WHAT WE USE TO SAY THAT IT IS ALS. NOW ALS OCCURS THROUGHOUT THE WORLD AND I KNOW BRYAN WILL TALK ABOUT THE GENES AND THOSE HAVE DIFFERENT FREQUENCIES AND DIFFERENT POPULATIONS THROUGHOUT THE WORLD. SO IT MAY BE THAT THERE ARE MULTIPLE DIFFERENT WAYS TO GET TO VIEW THIS PICTURE OF THE DEGENERATION OF THE UPPER AND LOWER MOTOR NEURONS. ALSO, IT’S THE CASE THAT CLINICALLY WHAT WE SEE ARE THINGS RELATED TO THE UPPER AND LOWER MOTOR NEURONS BUT THERE ARE PROBABLY CHANGES IN INTRANEURONS AS WELL AND IT’S PROBABLY MUCH MORE THAN JUST THOSE TWO CLASSES OF NEURONS THAT ARE AFFECTED BY THE DEGENERATION. YES? [ OFF MICROPHONE ] SO WE DON’T HAVE POST MORTEM ON THIS GENTLEMAN IN PARTICULAR. BUT, THIS IS A VERY INTERESTING QUESTION AND MAYBE THE SECOND PATIENT I CAN SHOW YOU SOMETHING WHERE I HAVE ACTUALLY — I THINK I HAVE A LITTLE HEAT MAP OF SOME PATHOLOGY. SO WE KIND OF THINK OF ALS AS BEING SOMEWHERE ON A SPECTRUM OF NEURODEGENERATIVE DISORDERS. AND SO THE MOTOR NEURON DISORDER SPECTRUM REALLY HAS COME ABOUT WITH THE RECOGNITION THAT THERE IS CLINICAL, PATHOLOGICAL AND SOME OVERLAP BETWEEN DISORDERS THAT CAUSE FRONTO TEMPORAL DEMENTIA AND ALS. SO YOU READ DIFFERENT NUMBERS FOR THE OVERLAP OF CLINICAL CHANGES. THERE WAS VERY NICE STUDY BY CATHY AT UCS WITH RESPECT SHE EXAMINED PATIENTS IN DEMENTIA CLINIC AND FOUND A THIRD OF THEM — I THINK 15% OF THEM MIGHT MEET CRITERIA FOR ALS. BUT WHEN YOU RUN A MEMORY CLINIC, YOU’RE NOT ACTUALLY LOOKING AT ALL OF THESE ASPECTS OF MOTOR FUNCTION. BRUCE MILLER EXAMINED THE PATIENTS IN THE ALS CLINIC AND 15% OF THEM COULD MEET CRITERIA FOR DEMENTIA. WHEN THEY LOOKED FOR WHAT PERCENTAGE OF PATIENTS HAD SOME COGNITIVE OR MOTOR IMPAIRMENT, YOU’LL READ NUMBERS THAT GO FROM ANYWHERE FROM 15-50%. IN OUR STUDY UABOUT A THIRD OF THE ALS PATIENTS HAD SOME IMPAIRMENT OF THEIR COGNITION AND I THINK THAT IS ABOUT WHERE MANY OF THE NUMBERS FALL. THE SECOND THING IN 2006, THAT KIND OF BROUGHT TOGETHER ALS AND FRONTO TEMPORAL DEMENTIA WAS PATHOLOGY WORK WHERE THEY WERE FINALLY ABLE TO IDENTIFY THE UBICINATED INCLUSIONS THAT WERE IN NEURONS IN ALS. AND THAT WAS WHEN THEY DISCOVERED THAT THE PROTEIN THAT THEY HAD WAS THE RNA BINDING PROTEIN GDP43. — TDP43. AND IT TURNS OUT THAT WHEN THEY LOOKED AT SPORADIC ALS AND AS WELL AS THE GENETIC FORMS OF ALS THAT WERE THEN KNOWN, THAT ABOUT 97% OF THE ALS PATIENTS REPORTED TDP43 ONE OF THE MISFOLDED PROTEINS IN THE UBICINATED INCLUSIONS. AND INTERESTINGLY, THE TWO DISEASES THAT THEY WERE ABLE TO LOOK AT THAT DIDN’T HAVE THOSE WERE SOD1 AND 5. I BRING THIS UP BECAUSE SOD1 WAS THE FIRST GENE DESCRIBED FOR ALS AND FOR 20 YEARS, ALL THE ANIMAL WORK HAS BEEN ON MICE WHO HAVE PATIENTS IN SOD1. BUT INTERESTINGLY, THERE WAS AT THAT TIME IN FIBERALL DEMENTIA SOME UBICINATED INCLUSIONS THAT WERE UNIDENTIFIED AND THEY WERE ABLE TO SHOW THAT THEY ALSO HAD THE SAME RNA BINDING PROTEIN. SO THE OTHER PATIENTS WITH FRONTO TEMPORAL DEMENTIA HAVE INCLUSIONS OF TAU, THE SAME PROTEIN WE SEE IN ALZHEIMER’S DISEASE. SO PATH LOGICALLY THERE IS SOMETHING SIMILAR GOING ON AT THE CELLULAR LEVEL BUT WHEN THEY LOOKED AT THE DISTRIBUTION, THE ALS PATIENTS HAVE MUCH MORE FOCAL DISTRIBUTION OF THE PATHOLOGY AND THE PRIMARY MOTOR CORTEX AND IN THE BRAINSTEM, A LITTLE BIT THAT IS OVER INTO THE POST CENTRAL GYRUS WHEREAS PATIENTS THAT HAVE FRONTO TEMPORAL DEMENTIA ARE MORE WIDESPREAD THROUGHOUT THE CORTEX. I DON’T KNOW IT THAT ANSWERS YOUR QUESTION. AND THEN THE THIRD PIECE OF THIS CLINICAL PATHOLOGICAL IS THE GENETICS. BRYAN WILL TALK ABOUT IT BUT INTERESTINGLY, I’LL JUST POINT OUT THAT SOME OF THE FIRST MUTATIONS, GENE MUTATIONS THAT CAUSE ALS STEAM CAUSE A PRETTY PURE ALS. SOME OF THE FIRST GENE MUTATIONS THAT CAUSE FTD CAUSE YOUR FRONTO TEMPORAL DEMENTIA BUT A LOT OF THE NEW GENES DISCOVERED ARE IN THE MIDDLE WHERE PROTEINS HAVE A MIXTURE OF COGNITIVE AND MOTOR DYSFUNCTION. SO I’M GOING TO TALK A LITTLE BIT ABOUT THE NEXT PATIENT WHO HAS A MEW NATION A GENE C9ORG WHICH BRYAN WILL SPEND MORE TIME ON. NOW THOSE PATIENTS HAVE BOTH, COULD HAVE COMPLETE PRACTICES TICK ALS WITH NO COGNITIVE IMPAIRMENT OR THEY COULD HAVE A MIXTURE OF THE TWO. SO THIS NEXT PATIENT WAS IN OUR STUDY AND HE HAS A MIXTURE OF THE TWO. SO, LET ME TELL YOU ABOUT THIS GENTLEMAN A LITTLE BIT FIRST. HE HAD BEEN IN GOOD HEALTH UP UNTIL — WELL, HE STILL THOUGHT HE WAS IN GOOD HEALTH, LET ME JUST SAY THAT. HE HAD BEEN WORKING — AND I’LL SHOW YOU A CLIP OF HIS SPEECH WHEN HE WAS WORKING AS A LOBBYIST FOR THE AUTOWORKER INDUSTRY. AND HE WAS ABRUPTLY FIRED AT THE AGE OF 57. NOT CLEAR WHAT REALLY HAPPENED THERE. BUT THEN HE DID GET ANOTHER JOB FOR ABOUT ANOTHER SIX MONTHS OR SO AND WHEN HE WAS AROUND THE AGE OF 59, HIS WIFE REALIZED THAT HE HAD DONE SOME FINANCIAL MISMANAGEMENT AND HAD SOMEHOW SPENT DOWN ALL THEIR RETIREMENT FUNDS AND THAT HE HAD A PERSONALITY CHANGE. HE WAS MORE PLACID AND HE WAS LESS INTENSE. HE WASN’T AS HIGH FOCUSED AS HE USED TO BE. AND HE HAD SOME INAPPROPRIATE BEHAVIORS MAKING INAPPROPRIATE REMARKS TO A FAMILY FRIEND AT THAT TIME. SO WE SAW HIM WHEN HIS FIRST SYMPTOMS WERE ABOUT FIVE YEARS BEFORE WE FIRST SAW HIM. AND I JUST WANT TO SHOW YOU A LITTLE BIT OF WHAT HE WAS LIKE BEFORE HE BECAME ILL BECAUSE I WANT YOU TO LISTEN TO THE DIFFERENCE IN HIS SPEECH. SO THIS IS HIS CONGRESSIONAL TESTIMONY WHERE HE HAD ILLNESS.>>THERE ARE OVER 220 MILLION VEHICLES REGISTERED IN THE UNITED STATES. TO REPAIR AND SERVICE VEHICLES QUICKLY AND PROPERLY, WE NEED A BROAD NETWORK OF INDEPENDENT REPAIR SHOPS AFTER MARKET PART SUPPLIERS AND DEALERSHIPS AS PARTNERS.>>OKAY SO HE CAN TALK PRETTY QUICKLY AND PRETTY SMART. HE IS DOING VERY WELL. SO HERE HE IS WHEN HE FIRST ENROLLED IN OUR STUDY IN 2013.>>WHAT DID YOU LIKE TO DO FOR FUN IN MICHIGAN?>>GENEALOGY AND SKIING.>>OKAY. DO YOU HAVE A ANY INTERESTING GENEALOGY STORIES TO SHARE?>>YES. RELATED TO THE GUY WHO SIGNED THE DECLARATION OF INDEPENDENCE.>>I DIDN’T CATCH THAT. IS THAT WHY DR. TURNYER CAME TO MEET WITH YOU.>>HE CAME TO MEET WITH ME BECAUSE OF THE KINS AND CONVENIENCE OF ENGLAND I’M RELATED TO.>>WHO ARE YOU RELATED TO?>>HENRYS AND LOUIES. I DON’T KNOW WHICH ONES. I CAN’T REMEMBER WHICH ONES IT IS.>>OKAY. SO HIS SPEECH IS A LITTLE BIT MORE SLURRED AT THIS POINT AND HE WAS HAVING SOME INITIAL PROBLEMS WITH HIS SWALLOWING. I DON’T KNOW IF YOU PICKED IT UP BUT HE ALSO HAS SOME STEREOTYPED MOVEMENTS HE IS DOING REPETITIVELY AT THAT POINT. ON HIS COGNITIVE TESTING, HE HAD CONSIDERABLE COGNITIVE IMPAIRMENT AND HE MET THE CRITERIA FOR THAT. SO WE SAW THIS GENTLEMAN, I THINK 4-5 MORE TIMES OVER THE NEXT SEVERAL YEARS AND WHAT IS KIND OF AN INTERESTING ASSAY THAT WOULD BE ABOUT HIS EXECUTIVE FUNCTION, THE COGNITIVE FUNCTION THAT IT TAKES TO DO A SEQUENCE OF ACTIONS, IS HIS WIFE’S DESCRIPTION OF THE COOKING. SO INITIALLY, BECAUSE HE HAD SPENT OUT ALL THE MONEY, HE WAS WORKING AT A VERY MENIAL JOB AT A LOCAL STORE BUT SHE WOULD HAVE HIM DO THE COOKING. AND HE COULD INITIALLY DO THE COOKING IF SHE MADE A LIST OF WHAT TO PUT IN THE INGREDIENTS. AND THEN, A FEW MONTHS LATER, ABOUT 18 MONTHS LATER, HE REALLY WASN’T ABLE TO DO THAT SO EVERYTHING HAD TO BE COOKED IN THE CROCK POT AND THEN AFTER THAT, WHEN WE SAW HIM IN 2016, HE COULDN’T DRIVE ANYMORE. HE HAD TOTALED THE CAR. HE WAS BURNING THE FOOD WHEN HE WAS COOKING. SO THIS IS THE KIND OF COGNITIVE CHANGES THAT HE WAS HAVING. MEMORY IS PRETTY GOOD. THIS IS DIFFERENT FROM ALZHEIMER’S DISEASE. HE HAD PRETTY GOOD MEMORY AT THAT TIME. AND SO I’M GOING TO SHOW YOU THE LAST TIME THAT WE SAW HIM IN 20 2017.>>WHAT TYPES OF THINGS DO YOU PAINT?>>AN ANGEL.>>WHAT ELSE HAVE YOU PAINTED? WHAT KIND OF THINGS DO YOU ENJOY ENJOY?>>WATCHING T.V.>>WHAT DO YOU LIKE TO WATCH ON T.V.?>>THE “TODAY SHOW.”>>SO THE THINGS THAT YOU NOTICE HOW SLOW HE IS TO RESPOND. WE ACTUALLY EDITED OUT SOME PIECES HERE BECAUSE AFTER TWO OR THREE MINUTES IF HE HASN’T RESPONDED WE JUST GO TO THE NEXT QUESTION. BUT HE DOES EVENTUALLY SAY, I LIKE TO WATCH T.V. I WATCH THE “TODAY SHOW.” HE HAS A LOT MORE DIS ANOTHERRIA AND EXHIBITS SOMETHING CALLED FORCED YAWNING WHICH IS AN INTERESTING NEUROLOGIC SIGN WHICH IS CONSIDERED TO BE AN UPPER MOTOR NEURON SIGN OF THE BULL BAR MUSCLES. AND HE HAS AGAIN AS HE HAD BEFORE, THESE SORT OF STEREOTYPED MOVEMENTS AS WELL. SO THIS GENTLEMAN EVENTUALLY HAD GONE THROUGH — AND ONE OTHER THING I COULD SAY IS HE DEVELOPED A FUNNY HABIT OF NOT COMPLETELY SWALLOWING HIS FOOD. SO HE WOULD TAKE SIPS OF ICED TEA AND HOLD IT IN HIS MOUTH FOR HOURS AND HOURS. I BRING THIS UP — I’M NOT ACTUALLY 100% SURE ABOUT HIS FINAL DAYS BUT IN ONE OF OUR OTHER PATIENTS, THIS INABILITY TO SEQUENCE THE MOVEMENTS OF SWALLOWING HAVE LED TO CHOKING TO DEATH. AND THAT TURNS OUT TO BE THOUGHT TO BE ONE OF THE MORE COMMON CAUSES OF DEATH IN FRONTO TEMPORAL DEMENTIA PATIENTS THAT IS UNEXPLAINED. SO THE LAST THING I WOULD LIKE — SO THIS IS AN EXAMPLE OF SOMEBODY WHO HAS FRONTO TEMPORAL DEMENTIA AND BECOMING VERY APATHETIC OVER TIME BUT ALSO DEVELOPING SOME SLIGHT MOTOR SYMPTOMS. HE FALLS SOMEWHEREOONS THAT SPECTRUM E-MAIL MORE TO THE FTD SIDE BUT A COMBINATION — SO THE LAST VIDEO I WANT TO SHOW HERE IS ONE THAT I HAVE EDILATEED FROM SOME UTHAT I HAVE EDITED AND I GAVE THE ACTUAL VIDEOS IN THE HAND OUT IF YOU WANT TO WATCH THE FULL THING. MANY OF THE PEOPLE IN THE U.S. REALLY FIRST HEARD ABOUT ALS IN 2014 WITH THE ICE BUCKET CHALLENGE. AND ICE BUCKET CHALLENGE WAS STARTED — THERE IS THREE YOUNG MEN WHO RECENTLY WERE AWARDED THE HUMANITARIAN AWARD FOR THE ICE BUCKET CHALLENGE AND THE MOTHER OF THEM WAS THE ONE WHO ACCEPTED IT IN DECEMBER FROM THE INTERNATIONAL ALS FOUNDATION. THE FIRST PERSON WHO STARTED THIS YOU’LL SEE IN THE NEXT BIT OF THE VIDEO, WAS A GUY NAMED ANTHONY. HIS WIFE WAS A SISTER OF A PROFESSIONAL GOLFER AND THAT GOLFER, CHRIS KENNEDY SENT HER A FACEBOOK CHALLENGE FOR ICE BUCKET CHALLENGE. THE PAT KWINN, WHO WAS ANOTHER ALS PATIENT IN NEW YORK SAW IT AND HE PASSED ON TO HIS FRIEND, PETER FREIGHTIES, A BASEBALL PLAYER IN BOSTON. PETER FREIGHTIES WAS FRIENDS WITH SOME NFL PLAYERS LIKE TOM BRADY WHO THEN PUT IT ON TO THEIR FACEBOOK PAGE AND THE NEXT THING YOU KNOW, IT BECAME A SOCIAL MEDIA PHENOMENA. IT WAS A VERY SUCCESSFUL FUNDRAISING CAMPAIGN THAT RAISED 115 MILLION DOLLARS. WHEN NANCY SHOWED A VIDEO AT THE DECEMBER MEETING OF THE INTERNATIONAL SYMPOSIUM ON ALS, I WAS VERY STRUCK THAT THE VIDEO SHOWED YOU A LOT OF WHAT A DAY IN THE LIFE OF A PATIENT WITH ALS IS, AND THAT IS WHY I DECIDED TO SHOW PART OF THIS VIDEO AND THEN I HAVE VERY POORLY EDITED ON SOME BITS FROM A NEWS SHOW THAT SHOWED HIM TOWARDS A MORE SEVERE TIME OF HIS LIFE. SO THIS LAST VIDEO IS ABOUT –>>STARTED THE END OF ALS.>>ANTHONY HAS WEAKNESS IN HIS UPPER BODY. HE HAS NO USE OF HIS HANDS ANYMORE. WE FEED HIM THROUGH A TUBE.>>I HAVE TO HAVE MY BROTHER, MY FATHER, OR MY WIFE SHOWER ME, GET ME DRESSED. THERE IS A REASON WHY HE IS NOT TALKING BECAUSE HE CAN NO LONGER TALK. HE IS IN THIS A CHAIR BECAUSE HE CAN NO LONGER WALK. THERE ARE MANY DIFFERENT DEVICES HE HAS AT THIS TIME BECAUSE WITHOUT THEM, HE WOULDN’T BE ABLE TO LIVE.>>YOUR MIND IS NOT AFFECTED AT ALL AND YET YOUR BODY IS JUST COMPLETELY SHUTTING DOWN AND THERE IS NOTHING YOU CAN DO ABOUT IT.>>HE WAS A DIVISION 1 BASEBALL STAR.>>A HOME RUN! [ APPLAUSE ]>>I REALLY CAN’T PUT INTO WORDS WHAT I FEEL RIGHT NOW.>>HERE WE WERE, NEWLY MARRIED AND WHAT ARE WE GOING TO DO? IS THERE A CURE? ANYTHING? WHAT CAN YOU TAKE? THERE WAS NOTHING. NO HOPE. THERE WAS NOTHING.>>THE MAN BEHIND THE ICE BUCKET.>>FOR A YOUNG GUY LIKE MYSELF TO BE DIAGNOSED –>>RATHER THAN TEARING THEM APART, PETE AND JULIE PROMISED TO SPEND THE REST OF THEIR LIVES.>>PETER FRATES. [ APPLAUSE ]>>IT IS LIKE EMPOWERED. LIKE WE ARE DOING THIS IN SICKNESS AND HEALTH.>>PETE ALWAYS THE FIGHTER. BY THIS TIME IN A WHEELCHAIR, STOOD UP TO WALK HIS WIFE DOWN THE AISLE.>>IT’S NOT COVERED. THESE PATIENTS NEED SOMEONE WATCHING THEM 24 HOURS A DAY.>>IT’S THIS KIND OF PHASE II OR III OR SOMETHING OF YOUR CAMPAIGN?>>IT’S NOW BEEN NEARLY SIX YEARS SINCE PETE’S DIAGNOSIS BUT THANKS TO MODERN TECHNOLOGY WITH JULIE BY HIS SIDE, HE ALREADY OUTLIVED THE AVERAGE LIFE EXPECTANCY.>>WHAT DO YOU THINK OF THIS DISEASE?>>I HATED IT. IT IS AN EXTREMELY CRUEL WAY FOR SOMEONE TO LIVE. YOU ARE LITERALLY TRAPPED INSIDE OF YOUR BODY. NO ONE SHOULD HAVE TO LIVE THROUGH THAT. ESPECIALLY SOMEONE WHO YOU KNOW, OTHERWISE YOU THOUGHT HE HAD HIS WHOLE LIFE AHEAD OF HIM.>>I WAS GOING TO BE EVERYTHING THATTING THE PATIENTS WHO PARTICIPATED — THANKING THE PATIENTS WHO PARTICIPATED IN OUR STUDIES. SO NOW I GUESS I’LL TURN IT OVER TO BRYAN. [ APPLAUSE ]>>HOW LONG HE LIVE AFTER HIS DIAGNOSIS?>>SO HE DIED ABOUT A YEAR AND A HALF AFTER THAT LAST VIDEO THERE SO, IT WOULD BE ABOUT 6 1/2 YEARS.>>[ OFF MICROPHONE ]>>[ OFF MICROPHONE ]>>UNFORTUNATELY I REALLY CAN’T SAY. ONE THING IS THAT FOR MOST PATIENTS WHO HAVE ALS, IT’S THE LOSS OF THEATIONAL TOW BREATHE, WHICH IS REALLY RELATED TO THEIR EVENTUAL DEATH. AND BY STAYING ON A VENTILATOR, PATIENTS CAN BE KEPT ALIVE FOR A LONGER PERIOD OF TIME. BUT HE EVEN BEFORE THAT, WAS SORT OF, FOR ALS, AT SORT OF THE LONG END OF THE BELL CURVE IN TERMS OF SURVIVAL.>>SO, GOOD AFTERNOON LADIES AND GENTLEMEN. LET ME JUST GET THIS GOING HERE. SO CAN YOU HEAR ME? CAN YOU HEAR ME WITH THIS? OKAY. SO WHAT I WANT TO TALK TO YOU ABOUT TODAY IS I THINK THAT MARY KAY HAS DONE A REALLY GOOD JOB EXPLAINING THE CLINICAL SIDE OF THINGS. SO I’M GOING TO GET INTO MORE INTO THE SCIENCE SIDE OF THINGS SO FEEL FREE TO STOP ME AT ANY STAGE AND ASK ME QUESTIONS. EXCEPT ANYBODY FROM MY LAB. YOU CAN’T ASK ME QUESTIONS. OKAY? I JUST WANT TO STATE THAT UPFRONT. THIS IS MY FUNDING SOURCES. IF ANYBODY WANTS TO ASK ME ABOUT THE ITALIAN FOOTBALL FEDERATION OR WHY THEY FUNDED US AT THE END, IT’S A GREAT STORY. SO I’LL TELL YOU. SO SOME OF THIS HAS ALREADY BEEN COVERED SO JUST VERY QUICKLY, ALS WAS FIRST DESCRIBED BY THIS GENTLEMAN HERE, CHARCOT WORKING IN A HOSPITAL IN 1869 AND IN FACT, AS DR. IRWIN SAID, IN FRANCE IT IS STILL KNOWN AS — BUT IN THE UNITED STATES, THE DISEASE IS MORE COMMONLY KNOWN AS LOU GEHRIG’S DISEASE AFTER THE BASEBALL PLAYER WHO DIED AT A VERY YOUNG AGE. WE ALWAYS THINK OF ALS AS BEING ONE OF THESE DISEASE THAT IS AFFECT MIDDLE AGE AND ELDERLIES AND THE INDIVIDUALS THAT WE NAMED THE DISEASE AFTER, HE DIED VERY YOUNG OF THIS CONDITION. AND I PUT UP A FEW OTHER IMAGES OF OTHER PEOPLE WHO SUCCUMBED TO THE DISEASE OVER THE YEARS. THE FIRST OF COURSE IS DAVID NIVEN. WHO KNOWS WHO HE IS? KEEP YOUR HANDS UP. NOW EVERYBODY LOOK AROUND AND NOTICE IT’S ALL THE OLD PEOPLE IN THE ROOM. SO HE WAS THE GEORGE CLOONEY OF HIS TIME. HE WAS AN ENGLISH ACTOR, A FAMOUS ACTOR. THE ORIGINAL JAMES BOND IN THE ORIGINAL CASINO ROYAL MOVIE AND HE DIED OF ALS AND HE IS VERY CLOSE TO THE HEART OF A LOT OF US IN THE ALS COMMUNITY BECAUSE HE GAVE THE MONEY IN HIS WILL TO FUND THE VERY FIRST ALS ASSOCIATION, WHICH IS THE ENGLISH ASSOCIATION. AND THEY STILL ARE HOUSED IN THE DAVID ENOUGH EN HOUSE IN LONDON. SO VERY CLOSE TO OUR HEART. OTHER PEOPLE — MAS ALLEGED TO HAVE DIED OF ALS AS WELL AS CARDIAC ISSUES. WE DON’T KNOW FOR SURE AND THEN THERE IS THIS GENTLEMAN HERE, HENRY WALLACE. ANYBODY KNOW WHO HE IS? OKAY. DO YOU KNOW WHO HENRY WALLACE WAS? [ OFF MICROPHONE ]>>HE WAS VICE PRESIDENT. HE WAS THE 33rd VICE PRESIDENT. AND HE WAS VICE PRESIDENT TO ROOSEVELT, TO FDR. AND HE MISS — AND FDR DIED ACTUALLY, REMEMBER FDR DIED IN OFFICE? AND ACTUALLY HE HAD JUST REPLACED HENRY WALLACE WITH TRUMAN. AND TRUMAN BECAME PRESIDENT. SO HE ACTUALLY REPLACED HENRY WALLACE AS THE VICE PRESIDENT 82 DAYS BEFORE HE DIED. SO HENRY WALLACE ACTUALLY MISSED OUT. HE WENT ON TO DIE OF ALS AND HE MISSED OUT ON BEING PRESIDENT OF THE UNITED STATES BY 82 DAYS. COULD YOU IMAGINE HOW MUCH FUNDING WE WOULD HAVE IF A PRESIDENT OF THE UNITED STATES FOR RESEARCH INTO ALS HAD ACTUALLY DIED OF AL! I PUT THIS UP HERE AS A LITTLE BIT OF A — TO LIGHTEN THE MOOD A LITTLE BIT AND TO GET A POINT ACROSS THAT ACTUALLY MEET — SOMETIMES THINK OF ALS AS BEING A RARE DISEASE. AFFECTIONATELY IT’S MORE COMMON IN THE GENERAL POPULATION THAN WE APPRECIATE. BUT TO PUT SOME ACTUAL SCIENCE ON IT, WE HAVE VERY TALENTED MEDICAL INSTITUTE WORKING IN OUR LAB DID SOME CALCULATIONS AND SHE WORKED OUT THAT AT I CAN’T RECOLLECT OVER THE NEXT 25 YEARS, BY 2040, THE NUMBER OF CASES OF ALS AROUND THE WORLD IS GOING TO RISE TO ABOUT 350,000 CASES. AND THAT REPRESENTS INCREASE OF ABOUT 69%. NOW, WE ARE NOT SAYING THAT THAT INCREASE OF 69% IS DUE TO AN INCREASE IN THE WORLD POPULATION OF 69%. BECAUSE THAT WOULD BE A REALLY MASSIVE INCREASE. ACTUALLY WHAT IT IS DUE TO IS AGING OF THE POPULATION. BECAUSE WE HAVE GOT A WHOLE BOLUS OF PEOPLE THAT ARE NOW IN THEIR 20s AND 30s AND THEY ARE GOING TO START HITTING THAT MIDDLE AGE WHICH IS THE RISQUE FACTOR, PRIME RISK AGE FOR DEVELOPING ALS. AND I THINK THAT THIS IS INDICATIVE FOR A LOT OF OTHER NEURODEGENERATIVE DISEASES THAT ARE OUT THERE AND I THINK THAT IT IS NOT JUST ALS. WHAT WE WORRY GOING TO SEE MASSIVE INCREASE IN THE NUMBER OF CASES BUT ALSO ACROSS THE WHOLE SPECTRUM OF NEWO DEGENERATION. NOW, I SHOULD POINT OUT THAT THAT CALCULATION OF 350,000 CASES IS PREDICATED ON THE IDEA THAT THE AVERAGE OR MEDIAN SURVIVAL OF ALS PATIENTS IS ABOUT THREE YEARS. THAT’S WHAT THIS CHART HERE SHOWS. THE SURVIVAL GRAPH SHOWING THE SURVIVAL OF ALS PATIENTS. NOW ONE OF OUR JOBS, ONE OF MY JOBS IS WHEN I GO OUT AND I TALK TO PHARMACEUTICAL COMPANIES, I’M TRYING TO GET THEM TO PUT THEIR DOLLARS AND TO INVEST THEIR DOLLARS INTO WHAT SEEMS LIKE RARE DISEASES SUCH AS ALS, BECAUSE OBVIOUSLY THAT IS WHAT WE WANT. WE REALLY WANT THE BIG HITTERS LIKE MERCK AND PFIZER TO COME IN AND START PUTTING MONEY INTO THIS. THE ONE POINT I MAKE IS WHEN I SHOWED THEM THAT SLIDE IS, LOOK, IF YOU COME UP WITH A DRUG THAT PROLONGS SURVIVAL BY ONE YEAR, YOU’RE GOING TO INCREASE THE NUMBER OF PATIENTS THAT YOU CAN SELL YOUR DRUG TO BY 1/3 WITHIN ONE YEAR. YOU CAN SEE THE DOLLAR SIGNS LIGHT UP IN THEIR EYE WHEN IS THEY REALIZE THAT. AND ACTUALLY, I THINK THAT THAT IS A VERY IMPORTANT THING. THAT REALLY IF YOU THINK ABOUT IT, IF WE ARE ABLE TO PROLONG THE LIFE OF THESE PATIENTS, THEY ARE GOING TO ACCUMULATE WITHIN THE POPULATION. WE ARE GOING TO SEE A LOT MORE BIGGER POPULATION OVER TIME. AND OF COURSE TREATING ALS PATIENTS IS ONE OF THE MOST EXPENSIVE DISEASES TO DEAL WITH. SO THAT IS ALSO SOMETHING THAT IS VERY IMPORTANT. NOW, AGAINST THAT I THINK IT IS FAIR TO SAY THAT WE BOTH THE NIH AND OTHER INSTITTIONS AND OTHER FUNDING INSTITUTIONS, SPEND A LOT OF MONEY ON FINDING GENES. I MEAN IT IS AN EXPENSIVE BUSINESS. AND I THINK THAT IT IS A WORTHWHILE TIME AND EXERCISE, INTELLECTUAL EXERCISE EVERY SO TOO OFTEN TRY AND THINK, WHY DO WE WANT TO FIND THESE GENES? WHAT IS THE POINT BEHIND IT? SO I ROUGHLY DIVIDED INTO CLINICAL AND SCIENTIFIC. SO ON THE CLINICAL SIDE OF THINGS, I THINK IT IS VERY IMPORTANT FROM THE PERSPECTIVE OF DIAGNOSIS OF PATIENTS. SO OFTENTIMES WHEN A PATIENT COMES TO YOU, YOU KIND OF KNOW WHAT THE THING YOU DO THE EXAM AND YOU KNOW WHAT IT IS. BUT THERE ARE FAIRLY SIZEABLE CHUNK OF PATIENTS PROPORTION OF PATIENTS WHERE WHEN THEY FIRST COME INTO YOU, YOU’RE NOT 100% SURE OF WHAT IS GOING ON. AND IF YOU KNEW WHAT THE GENES WERE THAT CAUSED THAT DECEASED AND YOU COULD TEST FOR THEM, THAT WOULD GIVE YOU SOME SURETY AND CERTAINTY AS YES, OKAY, I’M TELLING YOU YOU HAVE AL. AND I KNOW YOU HAVE C9472 AND I’M PRETTY SURE YOU HAVE ALS. THAT IS VERY IMPORTANT FOR PATIENT BECAUSE THEY REALLY WANT A DIAGNOSIS BUT ALSO I WOULD IMAGINE THAT IF YOU FAST FORWARD 10 YEARS FROM NOW WHEN WE FINALLY START TO GET TREATMENTS FOR NEURODEGENERATION, HOPEFULLY BEFORE 10 YEARS, HOPEFULLY 5 YEARS. HOPEFULLY NEXT YEAR. AND BUT IF YOU FAST FORWARD UNTIL THE TIME WHEN WE ACTUALLY HAVE THOSE TREATMENTS THAT ARE AVAILABLE, AND I WOULD IMAGINE THAT THE SOONER YOU ARE ABLE TO START THAT TREATMENT, THE MORE EFFECTIVE IT IS GOING TO BE. BECAUSE NO MATTER HOW GOOD ANY TREATMENT IS, IT AIN’T GOING TO WORK ON A DEAD NEURON, RIGHT? SO YOU REALLY NEED TO HAVE PRESERVED NEURONS AND START YOUR TREATMENT AS QUICKLY AS POSSIBLE TO HAVE AN AFFECT. ONE OF THE THINGS THAT DIAGNOSIS THAT GENETICS ALLOW LOSE US TO DO IS REALLY START TO COME TO THE FORENOW WITH MACHINE LEARNING AND WITH DEEP LEARNING OF THE DATA AND DEEP MINING OF THE DATA IS THIS IDEA OF PREDICTIVE DIAGNOSIS. THIS IS SOMETHING YOU SEE IN STAR TREK AND GALACTICA. BUT IT’S NOW BECOMING A REALITY. I WILL GIVE YOU AN EXAMPLE. THIS WAS A PAPER THAT WAS PUB ENGLISH BY A TALENTED SCIENTIST WORKING IN OUR LAB, DATA SCIENTIST. HE LIKES TO CALL HIMSELF A DATA SCIENTIST. MODIFICATIONY KNOWLES AND HE PUBLISHED IN LANCET NEUROLOGY. HE TOOK CLINICAL DATE AND GENETIC DATA AND WORKED OUT A MODEL BY WHICH HE WILL BE ABLE TO DIAGNOSIS PATIENTS AND SAY, YOU HAVE OR YOU WILL HAVE DEVELOPED PARKINSON’S DISEASE. NOT ALS. PARKINSON’S DISEASE, BY SUCH AND SUCH A DATE. AND HE WAS ABLE TO DO IT WITH 92% ACCURACY AND SAY SOMEBODY SITTING IN FRONT OF THEM THAT ARE COMPLETELY NORMAL AND SAY TO THEM, OKAY BASED ON THIS AND BASED ON A FEW OTHER CLINICAL FINDINGS, I CAN PREDICT THAT WITHIN TWO YEARS, YOU WILL HAVE A 92% CHANCE OF DEVELOPING PARKINSON’S DISEASE. AND OF COURSE THE WHOLE IDEA THERE IS IF WE ACTUALLY DID HAVE A TREATMENT FOR PARKINSON’S DISEASE, WE COULD INSTITUTE IT AND ACTUALLY MOVE FORWARD WITH THAT. AND NEWS ONE OF THE OTHER BEAUTIES OF THIS IDEA OF MACHINE LEARNING IS THAT AS WE AMASS MORE AND MORE DATA, THOSE MODELS ARE GOING TO GET BETTER AND BETTER AND I KNOW THAT MIKE IS WORKING ON THIS AND MAKING IT EVEN BETTER THAN WHAT IT IS. I WILL SAY TO ALL OF THE YOUNG PEOPLE IN THE AUDIENCE WHO WANT TO GO FORWARD TO MEDICAL SCHOOL OR ALREADY IN MEDICAL SCHOOL, THIS IS GOING TO TRANSFORM HOW WE DO MEDICINE. IT REALLY IS GOING TO CHANGE EVERYTHING BECAUSE WE WILL BE DIAGNOSING PEOPLE BEFORE THEY COME TO DISEASE. GENETIC COUNSELING. MOST COMMON QUESTION I GET ASKED BY MY PATIENTS IS, ARE MY CHILDREN GOING TO GET THIS? AND OF COURSE IF YOU KNOW THE GENES THAT CAUSE THE DISEASE, YES, YOU CAN ACTUALLY GO AND TEST FOR THEM IF YOU WANT TO DO IT. AND THEN FROM A SCIENTIFIC PERSPECTIVE, IF YOU KNOW THE GENE, YOU CAN MODEL IT. A LITTLE BIT DIFFICULT TO BUILD A MOUSE IF YOU DON’T KNOW WHAT THE GENE IS. RIGHT? BUT IF YOU KNOW THE GENE, YOU DOCK THAT AND THE SAME THING APPLIES TO CELLULAR MODELS AND GIVING YOU AN INSIGHT INTO THE PATHOGENESIS. AND THEN OF COURSE THE FINAL THING AND I THINK THIS IS THE MOST IMPORTANT ASPECT OF THIS. AND IT IS ALMOST LIKE U.S. MILITARY SPEAK. THERE IS THIS THING IN U.S. MILITARY, IF YOU CAN SEE IT, YOU CAN KILL IT. SAME THING APPLIES WITH MEDICINE AND WITH NEUROLOGICAL DISEASES. IF YOU CAN SEE IT, YOU KNOW WHERE THE GENE IS, YOU CAN PROBABLY KILL IT AND PROBABLY CURE THAT PARTICULAR DISEASE. BUT UNLESS YOU KNOW WHAT GENES ARE UNDERLYING IT, YOU ARE PROBABLY SHOOTING A LITTLE BIT IN THE DARK JUST TO BRING BACK ANOTHER MOVIE THAT DAVID NIVEN WAS IN. VERY IMPORTANT THING THAT I REALLY WANT TO GET ACROSS HERE AND THAT IS GENETICS IS NOT THE BE-ALL AND END-ALL. IT IS IN FACT THE VERY FIRST STEP. IT’S A VERY IMPORTANT FIRST STEP. MOST IMPORTANT STEP ON A JOURNEY IS THE FIRST ONE AND THE LAST ONE, RIGHT? BUT IT IS ONLY JUST THE BEGINNING. THERE IS USUALLY TYPICALLY A 10-YEAR JOURNEY FROM THE DISCOVERY OF THE GENE TO THE FIRST IN-HUMAN CLINICAL TRIALS. AND I SHOULD SAY 10 YEARS PLUS A BILLION DOLLARS. THAT’S IMPORTANT. THAT’S QUITE IMPORTANT. BUT EVERY SO OFTEN YOU GET LUCKY. ALL RIGHT? SO THIS IS AN EXAMPLE OF WHERE WE ACTUALLY GOT EXTREMELY LUCKY. THIS IS A DISEASE THAT IS A FORM OF MOTOR NEURON DISEASE CALLED — IT IS ALS PLUS DEAFNESS AND SOMETIMES PLUS BLINDNESS. AND A NUMBER OF STUDIES THAT CAME FROM OUR LAB AND FROM OTHER LABS AROUND THE WORLD, INPATIENTS WITH THIS SYNDROME FOUND THAT THOSE PATIENTS HAD MUTATIONS IN TWO GENES. IT TURNED OUT THAT THOSE TWO GENES WERE ACTUALLY IN THE RIBOFLAVIN PATHWAY. SO WHAT IS THE RIBOFLAVIN PATHWAY? IT AIN’T NOTHING EXCEPT VITAMIN B2. SO IT TURNS OUT IF WE REPLACE AND GIVE HIGH DOSE REPLACEMENT VITAMIN B2 THERAPY TO THESE PATIENTS, AND THAT IS BEING DONE IN QUEEN’S SQUARE BY HENRY HOLDEN, ONE OF THE AUTHORS OF THESE PAPERS, IT REALLY WORKS. A VERY SMALL PERCENTAGE OF PATIENTS BUT IT IS REALLY VERY, VERY IMPORTANT AND POWERFUL. OKAY. SO WHAT AM I GOING TO TALK ABOUT TODAY? TODAY I’M GOING TO TALK ABOUT EXOME SEQUENCING AND THERE HAS BEEN A FAIR AMOUNT OF TIME TALK TALKING ABOUT OUR MOST RECENT GENOME-WIDE ASSOCIATION STUDY WHICH HAS JUST COME OUT AND WE ARE A BIT EXCITED ABOUT. SO JUST VERY BRIEFLY. EXOME SEQUENCING IS WHERE YOU TAKE, INSTEAD OF SEQUENCING ONE GENE IN THE GENOME, YOU SEQUENCE ALL OF THE GENES AT THE SAME TIME. ALL 20,000. IT REPRESENTS ABOUT 1% OF THE HUMAN GENOME THAT YOU’RE SEQUENCING. AND I THINK THAT THIS IS A VERY GOOD — SO ONE OF THE REAL GOOD THINGS ABOUT WORKING IN THE IRB, INTRAMURAL RESEARCH PROGRAM, WE GET OUR MONEY UPFRONT. THAT’S THE WHOLE POINT BEHIND IT. WE GET OUR MONEY. NOW WE HAVE TO JUSTIFY OURSELVES FOUR YEARS LATER WITH A BSE, WHICH MINE IS IN TWO WEEKS FROM NOW SO WE HAVE TO JUSTIFY IT. BIG STRESS AND SO FORTH. BUT YOU GET YOUR MONEY UPFRONT. WHAT WE DON’T HAVE TO DO IS WE DON’T HAVE TO WRITE A GRANT WHICH TAKES A COUPLE OF WEEKS IF NOT MONTHS, SUBMIT IT, WAIT A FEW MONTHS UNTIL IT IS BEEN REJECTED — [ LAUGHS ] REWORK THE GRANT, SUBMIT IT FOR ANOTHER FEW WEEKS AND MONTHS, SUBMIT IT, WAIT FOR ANOTHER MONTHS TO HEAR THAT YOU HAVE BEEN REJECTED AGAIN. AND THEN MAYBE, AFTER THE THIRD TIME THAT YOU SUBMITTED IT, YOU GET THE MONEY TO ACTUALLY DO THE — SO WHAT DOES THAT DO? IT SLOWS YOU DOWN. IT MEANS YOU CAN’T BRING YOUR RESOURCES TO BEAR. BUT IN THE INTRAMURAL PROGRAM, WE HAVE THE MONEY UPFRONT SO WE CAN BRING OUR RESOURCES TO BEAR AND I THINK IT IS A REALLY GOOD THING ABOUT THEM, THE IRN WE ARE SO NIMBLE. WE WERE AMONG THE FIRST TO APPLY EXOME SEQUENCING TO NEURODEGENERATION AND THIS WAS THE STUDY THAT CAME OUT AS A CONSEQUENCE OF IT, TO USE EXOME SEQUENCING IN THIS ITALIAN FAMILY BEING COLLECTED BY A GOOD FRIEND AND COLLABORATOR OF MINE IN ITALY AND IT TURNED OUT THAT THERE WAS A MUTATION IN A GENE CALLED VCP. AND IT WAS VERY COOL FROM A TECHNOLOGICAL PERSPECTIVE TO DO THAT. BUT ACTUALLY FROM A SCIENTIFIC PERSPECTIVE, IT WAS ALSO INTERESTING AND THE REASON WHY I SAY THAT, IS VCS A KNOWN GENE, KNOWN CAUSE OF ANOTHER CONDITION CALLED FRONTO TEMPORAL DEMENTIA. NOW LET ME SAY THAT IF YOU SEE ALS AND YOU SEE A PATIENT WITH FRONTO TEMPORAL DEMENTIA IN THE CLINIC, YOU WILL NOT GET THOSE TWO CONFUSED. THEY ARE TWO TOTALLY DIFFERENT DISPARATE NEUROLOGICAL DISEASES. AND YET, HERE WE ARE WITH A GENE THAT WITH MUTATIONS IN THE SAME GENE CAUSING BOTH OF THOSE DISEASES. THEY REALLY SPARKED MY INTEREST ON A SCIENTIFIC BASIS OF TRYING TO UNDERSTAND AND UNRAVEL THE GENETICS THAT UNDERLAY IT. AND THIS BRINGS US ON TO C9ORF72. I’M IRISH AS SOME PEOPLE POINT — MANY PEOPLE CAN TELL FROM MY ACCENT I’M IRISH BUT IRISH PEOPLE LOVE TELLING STORIES. SO I’M GOING TO TELL YOU A STORY ABOUT THIS LOCUS. AND IT REALLY STARTS IN 2006 WHEN THE PUBLICATION OF TWO PAPERS. BOTH OF WHICH WERE BASED ON TRADITIONAL OLD-FASHIONED, SORRY, I HATE THAT TERM. I GET INTO TROUBLE WHEN I CALL IT OLD-FASHIONED BUT STILL, OLD-FASHIONED LINKAGE STUDIES AND THEY IDENTIFIED A LOCUS ON THE SHORT ARM OF CHROMOSOME 9. AND THOSE TWO STUDIES TOGETHER WITH A COUPLE OF OTHER STUDIES THAT CAME OUT ABOUT THE SAME TIME, IDENTIFIED A REGION OF ABOUT 7.2 MILLION BASE PAIRS. NOW WHEN WE KNEW IT WAS LINKED IN TO PATIENTS WITH ALS AND WITH FRONTO TEMP ROW DEMENTIA. TO PUT THAT IN PERSPECTIVE, THERE ARE 3 BILLION BASE PARIS IN THE HUMAN GENOME. IF YOU WANT GEE NO ONE SEQUENCE THEM, YOU HAVE TO SEQUENCE THE MOMS AND DADS. THAT’S 6 BILLION BASE PAIRS. SO ABOUT 6 BILLION INDIVIDUALS ALIVE IN THE WORLD. SO 7 MILLION BASE PAIRS IS ABOUT THE SIZE OF THE CITY OF LONDON. THAT’S WHAT WE WERE LOOKING AT. IN GENETIC TERMS, IT WAS 130 GENES IN THERE WE COULD WORK OUR WAY THROUGH IT AND IT IS DOABLE. THE PROBLEM WAS THAT ALL OF THESE DIFFERENT LABORATORIES AROUND THE WORLD WERE TRYING TO FIGURE OUT WHAT THE UNDERLYING MUTATION IS BECAUSE KNOWING WHERE THE MUTATION IS KIND OF INTERESTING, BUT WHEN YOU REALLY WANT TO KNOW IS WHAT IS THE GENE AFFECTED AND WHAT IS THE UNDERLYING MUTATION. NOBODY WAS HAVING ANY LUCK WITH RESPECT TO THAT. SO IT WAS REALLY TAKING ON THIS YEARA OF A HOLY GRAIL IN THE ALS AND FTD COMMUNITY. SO OUR INVOLVEMENT IN THE HUNT STARTED WITH THIS GENOME-WIDE ASSOCIATION STUDY OF AL. THAT WE DID IN FINLAND. IT’S ONLY DONE — REMEMBER THESE NUMBERS FOR LATER ON WHEN I’M TALKING ABOUT OUR GWAS. IT’S ONLY DONE ON 300 CASE SYSTEM AND 300 CONTROLS. JUST LIKE STAGGERING SMALL! AND YET, THIS WAS THE FIRST GENOME-WIDE ASSOCIATION STUDY WHERE WE REALLY SAW REALLY ROBUST SIGNALS. WE SAW A SIGNAL RIGHT THERE ON THE SHORT ARM OF CHROMOSOME 9. RIGHT IN THE MIDDLE OF WHERE THAT OTHER LOCUS WAS. LOW AND BEHOLD BECAUSE OF THE DENSE NATURE OF THE SNPS ON THOSE CHIPS WE USED FOR THE GWAS WE WERE ABLE TO NARROW IT FROM 7 MILLION BASE PAIRS DOWN TO JUST 230,000 BASE PAIRS. WHICH IN GENETICS TERMS IS NOTHING. IT’S A BLINK OF AN EYE. TELL CONTAINS THREE GENES. I MADE MY POOR GRAD STUDENT AT THE TIME, JENNIFER, STAY IN THE LAB FOR TWO WEEKS SOLID WITHOUT GOING HOME SEQUENCING THOSE TWO GENES BECAUSE I REALLY THOUGHT THAT WE WOULD HAVE IT WITHIN THE NEXT COUPLE OF DAYS. WHEN I RAN INTO HER FOUR YEARS LATER SHE MOVED ON TO MEDICAL SCHOOL AND TO REMIND HER OF THAT, TO TELL HER WE FOUND IT, SHE REMINDED ME ABOUT THE TIME THAT I MADE HER ACTUALLY STAY THERE. THAT WAS THE FIRST THING SHE REMINDED ME OF. SO ANYWAY, WE TRIED, WE REALIZED FROM AN EARLY STAGE THAT THIS IS GOING TO BE A DIFFICULT NUT TO CRACK. WHAT WE SAID IS WE ARE THE NIH. WE DO THINGS DIFFERENTLY. WE ARE SUPPOSED TO DO THINGS DIFFERENTLY. THAT’S WHY THEY GIVE US THE MONEY UPFRONT. SO OKAY, INSTEAD OF COMPETING WITH PEOPLE, WE REACHED OUT TO DIFFERENT GROUPSAROUND THE WORLD IN MANCHESTER AND LONDON AND AMSTERDAM AND HELSINKI AND IN CARDIA, AND WE SAID, LOOK, THESE CASES WERE DIRECT COMPETITORS OF OURS AND WE SAID LOOKS WORK TOGETHER AND TRY AND FIND THIS. WE HAVE RESOURCES. SEND US DNA SAMPLES YOU COLLECTED. WE RUN THEM ON THE MACHINE AND THEN PUSH ALL THE DATA OUT AND ANALYZE IT TOGETHER. THEN WE TEAMED UP WITH ANOTHER CONSORTIUM RUN BY ROSIE WHO IS WORKING AT THE MAYO CLINIC IN FLORIDA. AND FROM AN EARLY STAGE, WE FOCUSED ON THIS PARTICULAR FAMILY HERE WHO WE CALLED THE — IT WAS COLLECTED BY THIS MARVELOUS NEUROLOGIST HERE IN. AND WILL HUE MORRIS SPENT 10 YEARS IN CARTIVE GETTING THIS. IT’S A SMALL TOWN JUST SOUTH OF CARDIA AND EVERY WEEKEND HE WOULD GET IN HIS CAR AND DRIVE DOWN AND MEET WITH THE FAMILY AND HE WOULD COLLECT SAMPLES AND PHENOTYPE THEM. AND I THINK IT IS VERY IMPORTANT TO ANYBODY HERE WHO WANTS TO GO TO MEDICAL SCHOOL, THAT REALLY COLLECTING THOSE SAMPLES IS CRUCIAL TO THE SUCCESS OF GENETICS. BUT HE COLLECTED THIS FAMILY AND BECAME REALLY OUR CORE FAMILY FOR DOING IT. AND WE TRIED EVERYTHING ON THIS FAMILY. ANY TECHNIQUE THAT YOU CAN THINK OF, WE TRIED IT. OKAY? AND NOTHING WAS SHOWING UP. NOW THAT WAS NOT WASTED EFFORT BECAUSE IT TOLD US THAT IT WAS GOING TO BE EITHER ONE OF TWO TYPES OF MUTATIONS. IT WAS EITHER AN INSERT OF A NEW PIECE OF DNA THAT WE KNEW NOTHING ABOUT OR ELSE THE ENTIRE REGION WAS FLIPPED. WE KNEW THAT KIND OF FLIP COULD OCCUR IN NEUROLOGICAL DISEASE ESPECIALLY FRONTO TEMPORAL DEMENTIA. SO WHAT WE DID, WE SENT CELL LINES FOR ONE OF THE SAMPLES, THIS ONE DOWN HERE, WE SENT IT OFF TO A COMMERCIAL COMPANY IN GERMANY. AND THEY FLOW SORTED OUT CHROMOSOME 9 AND SENT US BACK DNA THAT WAS ENRICHED FOR CHROMOSOME 9. THE REASON WHY THAT WAS IMPORTANT IS BECAUSE IN THOSE DAYS, NEXT GENERATION SEQUENCING WAS STILL REALLY EXPENSIVE. SO WHAT WE DID IS WE JUST KEPT PUTTING THIS ENRICHED DNA AND GENERATING MORE AND MORE AND MORE DATA. WE ACTUALLY HAVE A TECHNICAL TERM FOR THAT. WE SEQUENCED THE IS NOT OUT OF IT. WE JUST KEPT PUTTING IT ON FLOW CELL AFTER FLOW CELL. AND EVENTUALLY WE ANALYZED IN A VARIETY OF WAYS. IT WASN’T AN INVERSION. WHAT FINALLY GAVE IT TO US WAS I LOOKED IN THAT AREA AND SAID OKAY, WHICH POLYMORPHISMS HAVE NEVER BEEN DESCRIBED BEFORE? WHAT CHANGES HAVE NEVER BEEN DESCRIBED BEFORE? AND THE TOTAL AREA OF 230,000 BASE PAIRS, THERE WAS ONLY EIGHT. AND SIX OF THEM WERE ALL WITHIN 30 BASE PAIRS OF EACH OTHER. OKAY. THAT’S A BIT UNUSUAL. SO I WENT IN AND TOOK A LOOK TAT AND THIS IS A SCREENSHOT FROM WHAT I SAW THAT DAY. EACH OF THOSE BARS REPRESENTS A READ. THE WAY NEXT GENERATION SEQUENCE WORKS IT’S A READ. AND IT’S 300 DEEP. IT WILL GO IF YOU WERE TO DIG INTO THE BASEMENT, THAT IS HOW FAR DOWN IT GOES. SO YOU SEE 300 BASE PAIRS, EVERY PAIR IS SEQUENCED 300 TIMES AND THEN BACK UP TO 300 OR 400. AND THAT’S A PASSION THAT WE TEND TO SEE WHENEVER THERE IS A PROBLEM WITH UNDERLYING STRUCTURE OF THE DNA. THAT WAS THE FIRST THING I NOTICED. SECOND THING I NOTICED WAS SEE THOSE TWO LONELY BREEDS UP THERE? THE OBJECTION IN THE CENTER? IT TURNS OUT, REMEMBER HOW THIS WORKS. WE ARE GENERATING LITERALLY TRILLIONS OF READS. I’M NOT KIDDING YOU. AND THEY HAVE TO BE IN LINED BY A COMPUTER ALGORITHM BACK TO THE HUMAN GENOME. BUT EVERY SO OFTEN IT GETS IT WRONG. SO WHAT WE DID IS WE GOT OUR PENCIL AND PAPER AND REALIGNED THOSE TWO READS MANUALLY AND IT TURNED OUT THAT WHAT IT SHOWED US WAS THAT INDIVIDUAL CARRIED MORE OF THIS GGGCCC MOTIF THAN WAS INDICATED IN THE REFERENCE HUMAN GENOME. THE REFERENCE HUMAN GENOME SAYS THESE GUYS SHOULD ONLY HAVE THREE AND WE WERE SEEING THERE WERE MANY MORE AND IT WAS TRUNCATED. SO WHAT IT TURNED OUT TO BE WAS AN INSERT OF A NEW PIECE OF DNA, IN THIS CASE A REPEAT EXPANSION CONSISTING OF THESE GGGCCCs, RIGHT HERE AT THE START OF THAT GENE. AND IT TURNED OUT IT WAS A MASSIVE ONE. NOW THAT WAS A VERY EXPENSIVE THING. WE COULDN’T DO THAT FOR EVERY SAMPLE SO WE DESIGNED ANOTHER ASSAY TO LOOK AT IT. WE ALSO DID FISH, FLORESCENT IN SITU HYBRIDIZATION USING A PROBE TO JUST SEE THE CHROMOSOME 9 LIGHTING UP THERE. AND I LOVE THE FACT THAT THIS IS A TECHNOLOGY THAT CAME INTO EXISTENCE ABOUT 100 YEARS AGO. THE IN SITU HYBRIDIZATION. AND WE WERE USING BOTH THIS REALLY OLD TECHNOLOGY AND THIS REALLY NEW TECHNOLOGY TOGETHER. SO THIS ENDED UP GETTING PUB ENGLISH BACK-TO-BACK WITH ROSA’S GROUP WHO FOUND THE SAME GENE USING A DIFFERENT TECHNIQUE IN 2010. — SORRY 2011. AND IT’S FAIR TO SAY THAT IT IS ACTUALLY BEEN A REAL WATERSHED MOMENT IN THE ALS RESEARCH COMMUNITY. IT’S REALLY SORT OF SPARKED THIS ALMOST MINIINDUSTRY SURROUNDING THIS AND THERE ARE SEVERAL REASONS FOR THIS. FIRST OF ALL, IT WAS THE FIRST TIME THAT A LARGE REPEAT EXPANSION HAD BEEN SHOWN TO BE CAUSATIVE IN A COMMON NEUROLOGICAL DISEASE LIKE ALS. SECONDLY, IT WAS INCREDIBLY COMMON. IT CAUSED ABOUT 40% OF THE FAMILIAL ALS IN AWE INDICATION CASES AND ALSO CAUSED ABOUT 8% OF SPORADIC DISEASE AL. AND THAT WAS REALLY A MODEST THING FOR ME. I SHOULD SAY THAT I HAD SPENT YEARS GOING TO FUNDING ORGANIZATIONS AND CHARITABLE ORGANIZATIONS GOING LOOK, TELLING YOU, IT’S GENETIC. GIVE US MONEY AND WE’LL SHOW YOU. AND WE WERE TAKING MILLIONS OF DOLLARS AND TRYING TO FIND SHOWING THAT THIS IS GENETIC WITHOUT MUCH SUCCESS AND MANY OTHER GROUPS WERE DOING THE SAME. AND FINALLY, WE COME ALONG WITH THIS CNORF72 REPEAT EXPANSION AND SHOWED A SIGNIFICANT CHUNK OF SPORADIC DISEASES ASK DUE TO THIS PARTICULAR GENETICS. THE OTHER REASON IS, ACTUALLY IT CAUSES ABOUT THE SAME PROPORTION OF DISEASE IN FTDB40% OF FAMILIAL FDA AND 8% OF SPORADIC FTD. SO WE ACTUALLY HAVE A GENE THAT UNITES THESE TWO VERY DISPARATE NEURODEGENERATIVE DISEASES TOGETHER. NOW I WILL SAY THAT IT WAS PRETTY AMAZING TO BE SITTING IN FRONT OF THE COMPUTER AND THE SEEING WHAT THE RESULT OF THAT WAS AND TO BE — TO REALLY KNOW WHAT THIS GENE THAT EVERYBODY HAD BEEN SPENDING YEARS LOOKING FOR. I THINK THERE IS REALLY ONLY ONE OTHER THING THAT COULD BE COMPARABLE TO THAT AND THAT WILL BE KNOWING WHO REALLY WON FLORIDA IN THE 2000 PRESIDENTIAL ELECTION, WAS IT BUSH OR GORE? SO I SAY IT WAS A REAL EUREKA MOMENT AND I SAY THAT FOR THE GRAD STUDENTS AND FELLOWS IN THE AUDIENCE BECAUSE IT IS REALLY SOMETIMES VERY EXCITING IN GENETICS. BUT I DON’T WANT TO MISLEAD YOU BECAUSE WE DON’T FIND A NEW GENE EVERY SINGLE DAY OF THE WEEK. RIGHT? SOMETIMES IT’S AN UNUSUAL THING. AND BUT THERE IS OTHER THINGS THAT YOU CAN DO IN GENETICS AND I THINK THAT THIS GRAPH HERE SHOWS YOU ONE OF THOSE THINGS. IT’S ALMOST LIKE A TIME MACHINE, ALMOST. AND SO WHEN WE DISCOVERED THAT PIECE, ASSOCIATION SIGNAL IN ALS IN THE FINISHED POPULATION, WE FOUND THAT ALL OF THOSE CASES HAD A PARTICULAR HAPLOTYPE OR A ARRANGEMENT OF SNIPPS ACROSS THE LOCUS. SO WE FOUND THE REPEATED EXPANSION, OF COURSE AT THAT TIME WE DIDN’T KNOW WHAT THE UNDERLYING PROVEITATION WAS BUT ONCE WE FOUND IT — MUTATION — I WONDER IF ALL THE OTHER CASES THAT ARE KAYEING THIS ALSO ARE CARRYING THE SAME HAPLOTYPE AND THE SAME FINNISH HAPLOTYPE. THAT IS WHAT THIS PARTICULAR GRAPH IS SHOWING HERE. THIS REPRESENTS 240 CASES. ALL THE BLUE ONES ARE FINNISH CASES. THE ORANGE ARE AMERICANS. THE RED ARE ITALIANS AND AT THE TOP IS THAT LONELY JAPANESE INDIVIDUAL SAMPLE THAT WE FOUND THE C9ORF72 IN. AND THE LENGTH OF THE LINE TELLS YOU HOW MUCH OF THAT HAPLOTYPE OF THE FINNISH HAPLOTYPE DID THEY CARRY. SO THIS VERY CARRIES IT FROM HERE TO HERE. THIS INDIVIDUAL CARRIES THE HAPLOTYPE FROM HERE TO HERE AND THIS IS THE ACTUAL LOCATION OF THE REPEAT EXPANSION. AND VIRTUALLY EVERY SINGLE CASE THAT WE FOUND THE EXPANSION IN, ALSO CARRIED THE SAME HAPLOTYPE. NOW THERE ARE MANY WAYS TO INTERPRET IT BUT THE WAY I CHOSEN TO INTERPRET IT BECAUSE BEING AN IROBBER MAN I LOVE TELESTORIES. THE WAY I HAVE CHOSEN TO INTERPRET IT IS THAT PROBABLY WHAT HAPPENED IS THIS EVENT HAPPENED ONCE IN HUMAN HISTORY. AND IT HAPPENED BY OUR GUESS, BY OUR ESTIMATES, ABOUT THE TIME OF THE FALL OF THE ROMAN EMPIRE, 1500 YEARS AGO IN SCANDINAVIA. SO THE QUESTION IS, WAIT A MINUTE. IS HAPPENED IN SCANDINAVIA T IS PRETTY ISOLATED. HOW DID IT END UP ALL AROUND THE REST OF THE WORLD? WE THINK THAT THESE GUYS ON THEIR SUMMER VACATIONS BROUGHT IT WITH THEM WHEN THEY ARE TRAVELING AROUND EUROPE. AND IT IS REALLY QUITE INTERESTING. BY THE WAY, IF THERE IS ANYTHING FINNISH PEOPLE IN THE AUDIENCE, YES, I KNOW THAT THE FINNISH WERE NOT THE VIKINGS. I KNOW THAT. TURNS OUT THAT IF YOU LOOK AT A MAP OF WHERE THE VIKINGS CONQUERED IN THE MIDDLE AGES, IT MATCHES REALLY WELL WHERE WE CURRENTLY MODERN DAY WORLD, FIND C9ORF72. IT’S STRIKING. IT’S QUITE INTERESTING. LIKE I SAID, ALMOST LIKE A TIME MACHINE. NOW I WOULD SAY UPFRONT, I SAID IT AT THE BEGINNING AND I’LL SAY IT AT THE END, NOT EVERYBODY AGREES WITH ME AND THERE IS A POSSIBILITY IT’S NOT TRUE BUT IT IS AN INTERESTING STORY. SO LET’S END HERE A LITTLE BIT QUICKLY. I HAVE ABOUT 10 MINUTES LEFT. GENOME-WIDE ASSOCIATION STUDIES THAT WE JUST RECENTLY PUBLISHED ON ALS. AND THIS INVOLVED, REMEMBER THE FINNISH GWAS OF THE 300 CASES AND 300 CONTROLS. ALL RIGHT? THAT WAS BECAUSE IT’S A CONSERVED POPULATION AND THAT’S WHY IT WAS SO AFFECTIVE. IT TURNS OUT NOW WE ARE UP TO 20,000 CASES AND 60,000 CONTROLS. AND YOU CAN SEE THAT WE FIND SEVERAL LOCI AND A LOT WERE KNOWN INCLUDING C9ORF72 BUT THERE WAS ONE NEW LOCUS RIGHT THERE ON CHROMOSOME SHOWN IN BLACK AND IT’S ON THE LONG ARM OF CHROMOSOME 12 AND IT’S IN THE REGION OF THE KIF5A GENE. AND THE REASON WHY WE KNOW IT IS THE KIF5 GENE FOR SURE IS BECAUSE JOHN LANDERS WHO IS WORKING AT THE UNIVERSITY OF MASSACHUSETTS, HE WAS WORKING ON ALS AT THE SAME TIME. WE HAVE THESE RESULTS ABOUT THE MIDDLE OF 2017 AND THEN JOHN SORT OF, WE BUMPED INTO EACH OTHER AT A CONFERENCE. AND HE ACTUALLY FOUND EXACTLY THE SAME GENE USING IN THIS CASE, GENE BURDEN ANALYSIS BASED ON EXOME SEQUENCING. WHAT THAT TOLD US WAS THAT REALLY THIS WAS A ROBUST FINDING. BECAUSE WE WERE FINDING TWO DIFFERENT WAYS AND KIND OF WAS REMINISCENT ALMOST OF OTHER GENE STORIES LIKE ELEC 2 AND T9 WHERE MULTIPLE INDIVIDUALS ARE COMING TOGETHER ON THE SAME GENE AT THE SAME TIME. AM I OKAY? I HAVE ANOTHER FEW MINUTES? THANK YOU. SO WE WERE REALLY SORT OF HAPPY WITH THAT AND SO IT TURNS OUT THAT KIF5A IS PART OR SUBUNIT OF KIF1. AND THAT IS THE PROTEIN COMPLEX THAT IS RESPONSIBLE FOR INTEGRATE EXOMEAL TRANSPORT. AND THIS VIDEO SHOWS VERY NICELY THE KIF1 COMPLEX WALKING DOWN THE MICROTUBUAL OF THE AXON DRAGGING THE VESICLE BEHIND IT. IT TURNS OUT THAT ALL OF THE MUTATIONS THAT WE FOUND IN ALS ARE ALL UP HERE IN THE CARGO BINDING DOMAIN OF THE PROTEIN. WHICH IS REALLY COOL. WHAT THIS STUDY WAS NOTABLE FOR WAS THE FACT THAT IT INVOLVED JUST AFTER COMING OUT IN NEURON, SITTING IN THE AUDIENCE IS THE FIRST AUTHOR ON THIS PARTICULAR PAPER. SHE DID A GREAT JOB DURING THE ANALYSIS. AND IT INVOLVED 125,000 SAMPLES. THAT’S A LOT OF SAMPLES. AND IT WOULD ONLY BE POSSIBLE THROUGH THE COLLABORATION OF MAJOR GENETIC GROUPS. AND I THINK THAT IS A THING WE SEE PERMEATING THROUGH THE GENETICS FIELD BUT REALLY WE ARE INTO THIS COLLABORATIVE SPIRIT NOWADAYS AND GONE ARE THE DAYS OF THE SCIENTISTS WORKING LATE AT NIGHTTIME ON THE LAB. AND THE OTHER THING WE WERE ABLE TO GO TO THE GWAS HIT TO THE GENE. I JUST A FEW MINUTES LEFT AND I WANT TO TALK, THIS IS A TIMELINE OF ALS GENETICS STARTED IN 1993 WITH BOB BROWN WHO WAS ONE OF MY MENTORS, FINDING THE GENE AT A CAUSE OF FAMILIAL ALS AND THEN THERE WAS FRANK LONGO HIATUS UNTIL THE DISCOVERY OF TDP43, AND THEN T9ORF72 IN 2011. TODAY, FAST FORWARD TODAY, I THINK IT IS FAIR TO SAY THAT WE KNOW ABOUT TWO CAUSES OF FAMILIAL ALS AND ABOUT 15% OF THE CAUSES OF SPORE ADDIC DISEASE. NOW HONESTLY, I’M NOT TERRIBLY CONCERNED ABOUT THE FAMILIAL SIDE OF THINGS BECAUSE I THINK WE ARE GOING TO GRIND THAT OUT OVER THE NEXT FEW YEARS AS WE HAVE PROGRAMS GOING ON. WHAT KEEPS ME AWAKE AND WORRIED AT NIGHTTIME IS HOW ARE WE GOING TO NARROW THIS GAP HERE, THE SPORADIC DISEASE? THAT IS A MUCH MORE DIFFICULT NUT TO CRACK, I THINK. OF COURSE WE ARE NOT JUST INTERESTED IN FINDING GENES FOR THE SAKE OF FINDING GENES, WE ALSO WANT TO TRY TO PUT THEM TOGETHER ON PATHWAYS AND THING IS A LOVELY ILLUSTRATION DONE BY RICH, WHO IS SEEMS TO BE A STAFF SCIENTIST IN OUR LAB AND SHE HAS DONE A REALLY GOOD JOB SHOWING THAT NOT ONLY HAVE WE GENES AND PUTTING THEM ON THE VARIOUS CHROMOSOMES, BUT ALSO WE ARE ABLE TO IDENTIFY THE PATHWAY OF THOSE GENES AND THAT WOULD INCLUDE RNA METABOLISM, AUTOPHAGY AND OTHERS. I DON’T KNOW WHAT HAPPENED THERE BUT IT SEEMS — LET ME GO BACK FOR A SECOND. SO VERY NICE SORT OF GRAPH THERE SHOWING THE DIFFERENT PATHWAYS COMING OUT. AND I’LL END WITH THIS SLIDE SAYING, LOOK, THESE ARE GROUP EFFORTS. THERE IS A LOT OF PEOPLE INVOLVED IN ALL OF THESE. AND THESE ARE PICTURES OF THEM HERE. AND IT REALLY IS IMPORTANT TO TRY AND WORK TOGETHER, ESPECIALLY WHEN WE ARE TALKING ABOUT A RARE DISEASE LIKE ALS. SO I’LL PAUSE THERE AND CATCH MY BREATH AND IF THERE ARE ANY QUESTION SYSTEM, I’M HAPPY TO TAKE THEM. [ APPLAUSE ]>>[ OFF MICROPHONE ]>>IT’S A KNOWN JEAN. THAT WHAT YOU’RE TALKING ABOUT? ORF72. SO C9 MEANS CHROMOSOME 9. ORF STANDS FOR OPEN READING FRAME AND THEN 72, BECAUSE IT WAS THE 72nd OPEN READING FRAME THAT WAS FOUND IN CHROMOSOME 9. SO LET ME EXPLAIN A LITTLE BIT OF HISTORY HERE. SO IT TURNS OUT THAT WHENEVER A GENE IS FOUND, UNTIL IT IS FIGURED OUT WHAT THAT GENE DOES, IT HAS AN ORF DESIGNATION. SO C21ORF2 FOR EXAMPLE. C9ORF72. AND IT FOLLOWS THAT PATTERN OF CHROMOSOME AND THE NUMBER ALONG THE CHROMOSOME. THE VAST, VAST MAJORITY OF GENES NOWADAYS WHEN YOU ACTUALLY FIND THEM, YOU CAN GO IN AND LOOK AT THE DOMAINS OF THOSE PROTEINS AND THAT TELLS YOU WHAT THE PROTEIN DOES. RIGHT? C9ORF72 IS ONE OF THOSE THINGS THAT YOU WENT IN AND WE WERE LIKE OKAY, WHAT DOES IT DO? THERE IS NO INFORMATION. THAT WAS IN 2011. THER2500 PAPERS ON C9ORF72 AND NOBODY STILL KNOWS WHAT THE PROTEIN DOES. IT’S ALL ABOUT THE REPEAT EXPANSION. THERE HAS BEEN SOME TALK THERE MIGHT BE A DENT PROTEIN AND THERE WAS A MOVE TO ACTUALLY TRY AND CHANGE THE NAME OF IT BY HUGO. BUT WHEN THEY REACHED OUT TO THE ALS AND FTD COMMUNITY I THINK THEY MORALS SAID WE HAVE 2500 PUBLICATIONS ON THIS AND IT WILL ALWAYS BE CALLED C9ORF72 SO DON’T CHANGE THE NAME. SO THERE IS A LITTLE BIT OF HISTORY TO IT. IF THEY DO CHANGE IT, I’M GOING TO USE THE PRINTS MONIKER AND CALL IT THE GENE FORMERLY KNOWN AS C9ORF72.>>[ OFF MICROPHONE ]>>IT’S BOTH. ALTHOUGH IF YOU BELIEVE ME, I THINK THAT ALL OF THOSE SPORADIC CASES ARE ACTUALLY REALLY TRULY FAMILIAL CASES. AND THAT WHAT WE ARE SEEING HERE IS THAT THE BORDER — AS CLINICIANS WE USE THIS DEFINITION OF FAMILIAL AND SPORADIC BUT IN REALITY THAT BORDER IS MUCH MORE COURSE THAN WE THINK.>>[ OFF MICROPHONE ]>>YOU HAD SAID EIGHT DIFFERENT PATH IOWAS IN WHICH THE VARIOUS DISCOVERED GENES ARE THOUGHT TO BE FUNCTIONALLY IMPORTANT. WHAT IS THE CONVERGENCE OF THOSE ON A SINGLE PATHOLOGICAL MECHANISM?>>OKAY. THAT IS AN ABSOLUTELY EXCELLENT QUESTION. AND I WISH I COULD USE THE MICROPHONE LIKE THAT. IT’S LIKE A ROCK STAR. THAT WAS AN ABSOLUTELY EXCELLENT QUESTION AND I THINK IT REFERS BACK TO EXACTLY WHAT MARY KAY SAID AT THE VERY BEGINNING AND THAT IS, WE USED TO THINK OF ALS AS A MONOLITHIC DISEASE. NOW WE KNOW THAT IT IS NOT ONE DISEASE. OF THE IT IS A GROUP OF DISEASES. ALL AFFECTING BOTH MOTOR NEURONS TO ONE EXTENT OR ANOTHER BUT IT DOES APPEAR TO BE DIFFERENT DISEASES. SO WE ARE NOT LOOKING FOR ONE PARTICULAR PATHWAY. WE ARE LOOKING FOR A GROUP OF PATHWAYS. AND WE CAN DIVIDE THE ALS INTO THE CYTO– AND DIVIDE THEM INTO THE RNA METABOLISM SIDE OF THINGS. SO IT IS NOT REALLY THAT WE ARE LOOKING FOR ONE. I THINK WE ARE LOOKING FOR A SMALLER NUMBER. [ OFF MICROPHONE ]>>SO THE SHORT ANSWER IS, NO. THE LONG ANSWER IS, SO IT IS NOT WITHOUT ITS CONTROVERSY THE IDEA THAT IT SPREADS. I THINK THAT IT IS CLEAR THERE IS A CERTAIN ELEMENT OF SPREAD BUT HOW MUCH IS GOING ON WE DO NOT KNOW. AND IF I HAD HALF HOUR AND A COUPLE OF SHEETS EVER PAPER, I COULD PROBABLY EXPLAIN THAT IN MORE DETAIL. BUT I THINK THAT WE ARE ALL STRUGGLING TO GET CLARITY ON THAT. WHAT WORRIES ME ABOUT ALL OF THIS, AND YOU REFERRED TO JOHN’S WORK. WHAT WORRIES ME ABOUT THIS IS WHEN WE DO AN AUTOPSY, WHAT IS AN AUTOPSYEND? -STAGE. WHAT IS GOING ON OVER THERE? WHEN THEY STARTED? AND HOW MUCH DOES THE AUTOPSY REFLECT WHAT WAS HAPPENING AT AND I THINK THAT THAT IS ACTUALLY A PROBLEM THAT FACES THE ENTIRE FIELD, NOT JUST IN ALS. I THINK IT FACES — I THINK THAT ALZHEIMER’S MAY BE A LITTLE BIT BETTER OFF BECAUSE THEY HAVE GOT LIGANDS NOW THAT CAN FOLLOW THOSE THINGS. I WISH, I DREAM FOR THE DAYS WHEN WE ACTUALLY HAVE A TDP3 LIGAND AND THAT WILL ANSWER A LOT OF QUESTIONS AND MAYBE IT WILL TURN OUT THE SPREAD IS GOING ON. BUT I’M NOT 100% SOLD ON THAT IDEA JUST QUITE YET. YES, SIR? [ OFF MICROPHONE ]>>ON THE BIOCHEMICAL SIDE OF THINGS, I THINK IT’S FAIR TO SAY THEY HAVE NOT BEEN TERRIBLY SUCCESSFUL. HOWEVER, THERE IS A LOT OF EXCITEMENT IN THE FIELD. I’LL TELL YOU WHY. IT TURNS OUT THAT A COMPANY THAT TALKING ABOUT CHANGING NAMES KNOWN AS IONS PHARMACEUTICALS AND THEY WERE PREACHESLY KNOWN AS ISIS. THEY CHANGE TODAY BECAUSE OF A SATURDAY NIGHT LIVE SKIT, WOULD YOU BELIEVE? THEY CHANGED IT ON THE MONDAY AFTER THE SATURDAY NIGHT LIVE SKIT. IT TURNS OUT THEY DEVELOPEDAL GO THERAPY AGAINST SOD 1 AND ALSO AGAINST C9ORF72. AND THERE IS A LOT OF EXCITEMENT IN THE FIELD THAT THOSE PARTICULAR FORMS OF GENE THERAPY MIGHT BE SUCCESSFUL. SO STAY TUNED. MAYBE OVER THE NEXT 1-3 YEARS, WE MAY HAVE PRETTY GOOD SUCCESS STORIES TO THE THAT.>>[ OFF MICROPHONE ]>>RIGHT.>>[ OFF MICROPHONE ]>>NONE OF THAT. I THINK THAT IT IS FAIR TO SAY THAT RID SOLHAS AN AFFECT. I THINK IT’S FAIR TO SAY UDEXA HAS AN AFFECT ON SYMPTOMS AND HOPEFULLY ALSO AN AFFECT ON MAYBE THE RATE OF PROGRESSION. I THINK THERE IS ANOTHER DRUG OUT THERE CALLED ADAIRA ZONE. BUT MAYBE MARY KAY — I’LL GIVE YOU THE MICROPHONE AND MAYBE YOU WANT TO COMMENT ON THAT? [ OFF MICROPHONE ]>>I HAVE TO PUT IN A SECOND SLIDE, WHAT STARTS OUT WITH 20 YEARS OF TREATMENT TRIALS IN ALSY HAVE WE NOT HAD ANY SUCCESS? AND IT IS REALLY THE CASE THAT REALLY ALL OF THE TREATMENTS THAT WERE INITIALLY BROUGHT UP WITH THE IDEA OF EXCITEO TOXICITY, LOOKING AT OXIDATIVE STRESS AND OTHER SORTS OF GROWTH FACTORS ON THE MUSCLE REALLY HAVE NOT AT ALL CHANGED THE COURSE OF THE DISEASE. AND SO IN TERMS OF SMALL MOLECULES, THEY ARE ACTUALLY, PEOPLE ARE WORKING ON SMALL MOLECULES WHO INTERACT WITH THE ABNORMAL ACCUMULATIONS OF RNA TO PREVENT SOME OF THE EFFECTS WHICH THE RNA ACCUMULATIONS ARE THOUGHT TO BE POTENTIALLY TOXIC.>>[ OFF MICROPHONE ]>>I WAS AWARE THEY ALSO CAUSE SOME FORM OF PEDE AT RICK NEUROLOGICAL DISEASE AS WELL. — PEDIATRIC. IT’S MORE METABOLIC? THAT’S INTERESTING, ISN’T IT?>>SO TO RETURN TO THESE MUTATIONS CAUSING TWO VERY DISTINCT DISEASES. CAN YOU EXPLAIN WHAT THE THINK THE MECHANISM IS, ATS GENE THAT CAN CAUSE TWO EXTREMELY DISTINCT DISEASES?>>OKAY. SHORT ANSWER, NO. I WISH I COULD. NOW, THE LONGER ANSWER IS THAT I THINK THAT THAT IS A BURNING QUESTION WITHIN THE FIELD. AND I THINK THAT THERE ARE TWO APPROACHES THAT HAVE BEEN ADOPTED LARGELY TO TRY AND ANSWER THAT. NUMBER 1 IS PICKING OUT CANDIDATE GENES AND TRYING TO SAY, WE THINK THIS GENE IS MORE ASSOCIATED. IF YOU HAVE VARIANCE IN THERE IT PUSHES YOU TOWARDS ALS AND IF YOU DON’T IT PUSHES YOU TOWARDS FTD. THERE IS A GENE CALLED TRIM 106B THAT SEEMS TO FIT SOME PRELIMINARY DATA ON CANDIDATE GENE STUDY DATA TO SUGGEST THAT. THE OTHER ASPECT, THE WAY WE TRY TO APPROACH THIS IS WE TRY TO AVOID CANDIDATE GENE STUDIES AND DO OMIC-WIDE STUDIES. LOOKING FOR GENES THAT INFLUENCE EITHER AGE OF ONSET OR THE DISEASE. WE HAVE GOT — ANDOTIS IS PIONEERING THIS WORK. AND WE HAVE INTERESTING HITS THAT ARE SUGGESTIVE BUT DO NOT REACH AS OF YET, AT LEAST WITH OUR NUMBERS, GENOME-WIDE SIGNIFICANCE. BUT NOT ONLY IS IT INTERESTING FROM THE SCIENTIFIC PERSPECTIVE, IT IS CRUCIALLY IMPORTANT FROM A GENE — FROM A THERAPEUTIC PERSPECTIVE BECAUSE IF YOU COULD IDENTIFY A GENE THAT INFLUENCES THE AGE OF ONSET OF SOMETHING THAT DELAYS THE AGE OF ONSET, YOU COULD THEN HIT IT WITH A SMALL MOLECULE AS SUGGESTED, THAT IS A BIG DEAL AND THAT IS SOMETHING THAT WE ARE ALL VERY EAGER FOR THAT AND WHEN I TALK TO PHARMACEUTICAL COMPANIES AND INDIVIDUALS VERY CLEVER SCIENTISTS WORKING WITH THOSE INDUSTRIES, THAT’S WHAT THEY ARE INTERESTED IN. THAT’S WHAT THEY REALLY WANT TO DO.>>[ OFF MICROPHONE ]>>AND I THINK THAT IS PART OF THE INTEREST? IDENTIFYING GENETIC CAUSES OF DISEASE. AND THEN THE QUESTION WILL BE FOR SOMETHING FOR EXAMPLE, THE ANTI-SENT WHERE IT MAY HAVE TO BE GIVEN REPEATEDLY. WHAT IS THE CORRECT TIME POINT? AND THERE ARE SOME MARKERS, BIOMARKERS IN CFS THAT HAVE BEEN SHOWN TO BE PRESENT ONCE PEOPLE BECOME SYMPTOMATIC BUT NOT INCREASED SYMPTOMATIC, WHEREAS OTHER ONES ARE PRESENT THROUGHOUT THE COURSE OF THE DISEASE. BUT THERE WAS A CONFERENCE TWO YEARS AGO LOOKING AT WHY THE 20 YEARS OF FAILURE AND OTHER THINGS THAT HAVE TO BE CONSIDERED ARE THE FACT THAT MAYBE WE HAVE HAD THE WRONG DESIGN. WE PUT IN PATIENTS TOO LATE IN THE DISEASE. DON’T REALLY HAVE GOOD MARKERS FOR WHETHER THE TREATMENTS EVER ENGAGE THE TARGET AND THAT REALLY IS SOMETHING THAT HAS TO BE WORKED ON AND THEN ALSO THE ISSUE ABOUT ANIMAL MODELS BECAUSE IT IS VERY DIFFICULT TO HAVE A ANIMAL MODEL THAT REALLY COMPLETELY RECAPITULATES THE DISEASE.>>[ OFF MICROPHONE ]>>NO, YOU SCREEN THOSE OUT. SO YOU WANT A COLLECTION OF ONE SIDE OF CASES. AND YOU DON’T WANT THEM RELATED TO EACH OTHER BECAUSE IT ACTUALLY INFLATES UP THE SCORE AND THEN ON THE OTHER SIDE IS THE COMPARISON. YOU WANT THE COHORT OF CONTROLS WHO YOU KNOW DON’T HAVE DISEASE. NOW, TO BE FAIR, YOU KNOW THAT A CERTAIN — IF YOU HAVE 100,000 CONTROLS, YOU KNOW THAT THERE IS GOING TO BE A PORTION OF THOSE WHO ACTUALLY WOULD GO ON TO DEVELOP ALS. BUT GWAS IS SO ROBUST THAT IT ALLOWS YOU TO OVERCOME THAT AND IT GETS BUILT INTO A MODEL.>>[ OFF MICROPHONE ]>>SURE. AND IS I THINK THAT THAT WAS ONE OF THE THINGS THAT MARY KAY WAS VERY CAREFUL TO INCLUDE IN THE C9ORF72 CLINIC. SO WE HAVE AT THIS STAGE 5-10 INDIVIDUALS WHO ARE ACTUALLY CARRYING THE C9 GENE. 15? SO 5 PLUS 10. 15. AND THEY HAVE NOT YET DEVELOPED DISEASE. HOPEFULLY THEY NEVER WILL. BUT WE COLLECTED BIOSPECIMENS FROM THEM THAT WILL SORT OF, WE HOPE, WILL BE A BUILDING BLOCK TOWARDS DEVELOPMENT OF SOME SORT OF BIOMARKER THAT WILL PREDICT IF THEY ARE GOING TO GO ON TO DISEASE OR WHEN THEY ARE GOING TO GO ON TO DISEASE.>>[ OFF MICROPHONE ]>>SO, NOT REALLY AT THE MOMENT. NO. I CAN’T SEE A GOOD USE FOR THEM, PER SE. THEY GET INCLUDED IN CERTAIN ASPECTS OF WHAT WE DO BUT NOT — I WOULDN’T DO IT JUST ON THEM ALONE. I’D ALWAYS INCLUDE ALS CASES AS WELL ON TOP OF THAT. DOES THAT MAKE SENSE? [ OFF MICROPHONE ]>>IS THERE ANY FACTOR MRI IMAGING THAT COULD LOCALIZE AND SENSITIVITY AND SPECIFICITY OF THOSE IMAGING FOR ALS?>>IN TERMS OF PET STUDIES, THE ONLY THING THAT HAS BEEN DONE IS LOOKING AT FTG UPTAKE WHICH MAY BE LESS IN THE FRONTAL LOBES BUT IT IS VERY, VERY NON-SPECIFIC. I THINK WE SEE THAT IN OTHER DEMENTIA DISORDERS. THERE IS NO PET LIGAND FOR SOMETHING LIKE TDP43 THAT WOULD ALLOW US TO LOCALIZE. IN TERMS OF MRI, THAT IS AN AREA THAT WE HAVE BEEN WORKING ON FOR THE LAST 4-5 YEARS NOW. IT DOES SEEM THAT THERE ARE A NUMBER OF CHANGES THAT HAPPEN IN THE BRAINS AND WHEN WE START TO PARSE THEM OUT IN TERPS OF GRAY MATTER AND CHANGES AND ATROPHY ATROPHY — IT SEEMS THERE ARE MUCH MORE GRAY MATTER CHANGING IN PATIENTS WHO HAVE DEMENTING CHARACTERISTICS. WHEN WE LOOK AT THE WHITE MATTER TRACKS, IT IS VERY INTERESTING THAT THE CHANGES IN THE CORTICAL SPINAL TRACT AND THE MIDDLE PORTION OF THE CHORPUS CLOSE UP UM SEEM TO CORRELATE WITH THE SCORE AND CHANGES IN MORE AN TEARIER PORTIONS OF THE CHORPUS CALLOSUM SEEM TO CORRELATE BETTER WITH THE COGNITIVE CHANGES. SO THESE ARE NOT AT A POINT WHERE WE CAN TALK ABOUT SENSITIVITY AND SPECIFICITY. WE ARE STILL AT THE POINT OF DISCOVERING THEM AND DISCOVERING THEM BY COMPARING PATIENTS TO HEALTHY CONTROLS.>>IT SEEMS THE DISEASE PROGRESS FROM BRAIN ALL THE WAY TO THE SPINAL CORD. COULD YOU ALSO SEE THE PATHOLOGY ALONG THE SPINAL CORD BESIDES THE BRAIN?>>IT DOESN’T NECESSARILY PROGRESS THAT WAY. THE BUT THERE IS A LOT OF INTEREST IN LOOKING AT THE SPINAL CORD F A POINT OF VIEW OF MRI, IT IS VERY — YOU HAVE MUCH LESS — IT’S VERY DIFFICULT TO GET GOOD HIGH RESOLUTION SPINAL CORD IMAGES. YOU KNOW, SO THE MAGNET FEVER COILS ARE ON THE OUTSIDE OF THE BODY AND THE SPINAL CORD IS ABOUT THIS LARGE. BUT THERE ARE SOME PEOPLE WHO ARE STARTING TO SHOW SOME CHANGES BUT AGAIN IT IS STILL CLEARLY MUCH IN THE RANGE OF DISCOVERY, OF DIFFUSION CHANGES IN THE CORTICOSPINAL TRACKS AND THE CERVICAL CORD FOR EXAMPLE.>>MANIPULATIONS FOR FINDING AND MORE POWERFUL — [ APPLAUSE ]

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