>> GOOD AFTERNOON. IT'S MY PLEASURE TO INTRODUCE TODAY'S NIH DIRECTOR'S SPEAKER, BRYAN TRAYNOR. BRYAN WAS TRAINED INITIALLY IN DUBLIN, GOT HIS MEDICAL DEGREE AT THE UNIVERSITY COLLEGE DUBLIN, AND THEN WENT ON TO OBTAIN AN ADVANCED MEDICAL DOCTORATE AND BEGAN THEN HIS INTEREST IN THE EPIDEMIOLOGY AND GENETICS OF AMYOTROPHIC LATERAL SCLEROSIS, WHICH HAS BEEN A SUBJECT OF HIS INTEREST EVER SINCE. HE COMPLETED HIS MEDICAL RESIDENCY IN DUBLIN, AND THEN DID A NEUROLOGICAL RESIDENCY AND NEUROMUSCULAR FELLOWSHIP AT MASS GENERAL AND PETER BRIGHAM HOSPITAL IN BOSTON. SOMEWHERE HE GOT A MASTER'S IN DRUG DISCOVERY AND CLINICAL TRIAL DESIGN SAND A Ph.D. IN THE GENETICS OF ALS FROM UNIVERSITY COLLEGE DUBLIN. HE'S BEEN HERE SINCE 2005 AND MADE PHENOMENOL CONTRIBUTIONS TO UNDERSTANDING YOU GENETICS OF ALS, SOME OF WHICH HAVE BEEN IN THE NEWSPAPERS AND SO YOU PROBABLY KNOW ABOUT THESE THINGS. AND I THINK RATHER THAN GO INTO SOME DETAIL ABOUT WHAT HE'S ACCOMPLISHED, I WILL LET HIM GIVE HIS OWN TALK, WHICH IS ENTITLED GENOMICS OF AMYOTROPHIC LATERAL SCLEROSIS. BRYAN? >> GOOD AFTERNOON, EVERYONE. I WANT TO SAY THANK YOU TO THE ORGANIZING COMMITTEE FOR INVITING ME TO SPEAK THIS MORNING. AS YOU CAN SEE, THE SUBJECT OF MY TALK IS GOING TO BE ON ALS, WHICH IS REALLY A PASSION OF MINE SINCE MOVING DOWN TO THE NIH IN 2005. I MUST SAY IT'S REALLY BEEN A VERY EXCITING FIELD, WE'LL HOPEFULLY GET THAT ACROSS TO YOU AS WE GO ALONG. A QUICK OUTLINE OF WHAT I'M GOING TO TALK ABOUT TODAY, I'M GOING TO TALK FIRST OF ALL GIVE YOU A VERY BRIEF DESCRIPTION OF WHAT IS ALS, AND WHY IT'S IMPORTANT FOR US TO ACTUALLY FIND GENES, WHY WE THINK THIS IS SOMETHING CRUCIAL TO OF MOOING FORWARD IN THE FIELD. I'M GOING TO TALK ABOUT GENE DISCOVERY IN TERMS OF MENDELIAN FAMILIAL GENES, DESCRIBE HOW WE DISCOVERED THE C9ORF72 REPEAT EXPANSION AND TOUCH ON SPORADIC ALS IN TERMS OF GENE OH-WIDE ASSOCIATION STUDIES AND END UP WITH FUTURE STUDIES AND HOW WE THINK THE FIELD IS GOING TO EVOLVE IN THE FUTURE. SO WHAT IS ALS? ALS IS A DEVASTATING NEURODEGENERATIVE DISEASE AFFECTING THE UPPER AND LOWER MOTION NEURONS, LEADS TO PROGRESSIVE PARALYSIS AND RESPIRATORY FAILURE LEADING TO DEATH TYPICAL IN TWO TO THREE YEARS OF SYMPTOM ONSET, IT'S QUITE A RAPIDLY PROGRESSIVE ALMOST -- IT'S FAIR TO SAY A HORRIBLE DISEASE. IT WAS DESCRIBED THIS GENTLEMAN OVER HERE, CHARCOT, IN 1869 WORKING IN THE HOSPITAL IN FRANCE. IN FACT IN FRANCE, THE DISEASE IS STILL KNOWN AS MALADY DU CHARCOT, IN AMERICA KNOWN AS LOU GEHRIG'S DISEASE AFTER THE FAMOUS BASEBALL PLAYER WHO DIED AT THE AGE OF 38 FROM THE CONDITION. OTHER NOTABLE INDIVIDUALS WHO HAVE ALSO DIED OF ALS INCLUDE DAVID NIVEN. ANYBODY IN THE ROOM KNOW WHO DAVID NIVEN IS? YES, THERE'S A REAL AGE GAP HERE. [ LAUGHTER ] DARE I SAY MORE MATURE INDIVIDUALS IN THE ROOM KNOW WHO DAVID NIVEN IS, THE YOUNGER CROWD, I HAVE NO IDEA. DAVID NIVEN IS THE GEORGE CLOONEY OF THE PAST, OKAY? THAT'S WHO DAVID NIVEN IS. VERY FAMOUS. HE WAS ONE OF THE BOND -- HE PLAYED JAMES BOND ON ONE OCCASION. MAO TSE TUNG IS ALSO ALLEGED TO HAVE DIED OF ALS, AND IN FACT HENRY WALLACE, WHO WAS THE 33rd VICE-PRESIDENT OF THE UNITED STATES, UNDER ROOSEVELT, DIED OF ALS AND MISSED OUT ON BEING PRESIDENT BY JUST 88 DAYS TO HARRY TRUMAN. SO ONE OF THE REASONS I PUT THIS UP HERE IS JUST TO PUT IN CONTEXT, BUT ALSO I'M TRYING TO MAKE A SERIOUS POINT HERE, WHICH IS THAT WE HAVE THIS PERCEPTION THAT ALS IS A RARE DISEASE, I THINK IT'S MORE COMMON THAN WE APPRECIATE. I THINK WE HAVE SEEN MORE CASES CERTAINLY THE ALS CLINICS TEND TO BE STUFF FULL OF PATIENTS SO I THINK IT'S GOOD TO APPRECIATE THAT IT'S ACTUALLY A MORE COMMON CONDITION THAN MAYBE OTHERS MIGHT THINK. SO WHY FIND GENES? IT'S AN EXPENSIVE ENDEAVOR, IT TAKES A LOT OF TIME, A LOT OF EFFORT, AND A LOT OF HYPE SURROUNDING IT, A LOT OF PROMISES AND SO FORTH, AND A LOT OF MONEY. WHY DO WE DO IT? WELL, I THINK WE CAN DIVIDE IT INTO TWO GENERAL CATEGORIES. THE FIRST IS THE CLINICAL ARENA. SO GENERALLY SPEAKING, IF YOU'RE SEEING AN ALS PATIENTS TOWARDS THE MIDDLE OR END OF THEIR ILLNESS IT'S EASY TO MAKE THE DIAGNOSIS, QUITE EASY. BUT THAT'S NOT ALWAYS THE CASE WHEN THEY INITIALLY PRESENT. SOMETIMES IT'S QUITE CHALLENGING. YOU REALLY DON'T KNOW WHETHER THEY HAVE ALS OR NOT. KNOWING THE GENE AND ESTABLISHING THAT DIAGNOSIS, WHY IS THAT IMPORTANT? WELL, IF WE WANT TO INSTITUTE THERAPY BY AND LARGE INSTITUTING THERAPY AT AN EARLIER DISEASE TENDS TO LEAD TO BETTER OUTCOMES SO KNOWING THE DIAGNOSIS EARLIER IS CRUCIAL TO SUCCESSFUL OUTCOME. FOR EXAMPLE, INSTITUTING THE DRUG, ONE THAT EXISTS FOR ALS. THE OTHER IS GENETIC COUNSELING OF FAMILY MEMBERS. MOST COMMON QUESTION I GET ASKED BY PATIENTS AND THEIR FAMILY IN THE CLINIC, ARE MY KIDS GOING TO GET THIS? WHAT IS THE RISK TO MY KIDS? BY IDENTIFYING AND BEING ABLE TO SCREEN FOR THE GENES IT ALLOWS US TO GIVE THEM MORE DETAILED GENETIC COUNSELING, FINITE GENETIC COUNSELING AS TO WHAT THEIR RISK IS. THAT REALLY -- IT'S VERY IMPORTANT, PATIENTS REALLY APPRECIATE THAT. THEY REALLY WANT TO KNOW WHAT THE RISK IS TO THE FAMILY. THEY KNOW THEY HAVE IT THEMSELVES AND THEY DON'T WANT THEIR LOVED ONES TO GO THROUGH THE SAME THING. THE SECOND ARENA THAT WE THINK ABOUT IN TERMS OF WHY IT'S IMPORTANT TO FIND GENES IS THE SCIENTIFIC ARENA. OF COURSE, WE WANT TO UNDERSTAND HOW THE MOTOR NEURONS ARE DYING, BY IDENTIFYING DEFECTS AND KNOWING WHICH GENE IS INVOLVED THAT GIVES A CLUE. ALSO ALLOWS US TO MAKE CELL-BASED AND ANIMAL-BASED MODELS AND FURTHER LOOK INTO THE PATHOGENESIS AND PERHAPS HOPEFULLY TEST THERAPEUTIC AGENTS. BUT IT'S WORTH NOTING THIS IS REALLY ONLY THE START. FINDING THE GENE IS ONLY THE STARTING POINT. THERE'S A LONG JOURNEY, A LONG ROAD AHEAD OF US TO GO FROM FINDING THE GENE TO ACTUALLY HAVING AN EFFECTIVE THERAPY. AS MANY OF US KNOW AND HAS BEEN DISCUSSED WIDELY HERE AT THE NIH, IT'S OFTEN A DECADE BETWEEN THE DISCOVERY OF THE GENE AND FIRST IN HUMAN STUDIES. HOWEVER, EVERY SO OFTEN, EVERY SO OFTEN YOU GET LUCKY. THIS IS THE SET OF PAPERS FROM JOHNSON AND SINGLETON OF THE LABORATORY OF NEUROGENETICS IN WHICH THEY IDENTIFIED MUTATIONS IN TWO GENES, IN PATIENTS WHO HAVE A FORM OF MOTOR NEURON DISEASE NOUN AS BROWN-VIALETTO-VANLEARE SYNDROME, BOTH GENES LIE IN THE RIBOFLAVIN PATHWAY. HENRY HOLDEN, CO-AUTHOR ON THE PAPER, IS NOW TREATING A SET OF PATIENTS WITH BVVL WITH HIGH DOSES OF RIBOFLAVIN AND REPORTS BACK TO US, NOT YET PUBLISHED, THEY ARE DOING BETTER. SO EVERY SO OFTEN, YOU CAN JUMP OVER THAT DECADE OF RESEARCH AND SOMETIMES YOU JUST GET LUCKY. THAT OF COURSE IS WHAT WE ALWAYS HOPE FOR OUR ALS PATIENTS BECAUSE REMEMBER THEY HAVE A LIMITED LIFESPAN. NOW, IN TERMS OF ALS, WE LIKE TO CLASSIFY IT CLINICALLY AND GENETICALLY INTO FAMILIAL AND SPORADIC. LIKE MANY OTHER NEUROGENETIC DISEASES 10% IS FAMILIAL IN NATURE, SO YOU SEE THE SAME IN PARKINSON'S, THE SAME IN ALZHEIMER'S DISEASE. AND WE SAY WE MEAN OTHER MEMBERS OF THE FAMILY ACTUALLY CARRY THE MUTATION AND HAVE THE DISEASE. THE OTHER 90% ARE KNOWN AS SPORADIC AND APPEAR TO OCCUR RANDOMLY IN THE COMMUNITY, OFTEN MUCH MORE DIFFICULT TO GET A HOLD ON, TRACTION ON GENETICALLY. I SHOULD SAY THAT THE BARRIERS, AS YOU WILL SEE AS I GO ON WITH THE TALK BETWEEN THE TWO TYPES OF ALS IS ACTUALLY MUCH MORE POROUS THAN WE PREVIOUSLY APPRECIATED BUT NEVERTHELESS THIS CLASSIFICATION IS VERY USEFUL TO US, BECAUSE IT GUIDES US INTO WHAT FORM OF TECHNOLOGY WE WANT TO USE IN ORDER TO TRY AND FIND GENES IN THERE. WE USE A DIFFERENT TYPE OF TECHNOLOGY FOR FAMILIAL AND DIFFERENT TYPE OF TECHNOLOGY FOR SPORADIC. SO THIS IS THE SORT OF SETTING, WHAT WAS KNOWN ABOUT ALS GENETICS IN 2005, WHICH IS WHEN I WAS MOVING DOWN TO THE NIH. THESE ARE THE CHROMOSOMES ARRANGED, 1 TO 22 WITH X AND Y AT THE TOP. YOU CAN SEE THERE'S ONLY ONE LONELY GENE THERE, THAT WAS A COMMON CAUSE OF ALS. THERE WERE A LOT OF OTHER GENES THAT WERE RARE CAUSED OR CAUSED OTHER FORMS OF MOTOR NEURON. I'M JUST SHOWING THE GENE THAT REALLY WAS KNOWN TO BE A COMMON, COMMON CAUSE OF FAMILIAL ALS, AND I JUST KICKED SOMETHING HERE ON MY SCREEN. OKAY. OKAY. BUT THAT LEADS US NICELY ON TO MENDELIAN GENES AND ALS. NOW, ONE OF THE THINGS THAT WE REALLY STRIVE TO DO IN THE LABORATORY OF NEUROGENETICS IS APPLY NEW GENETIC TECHNIQUES, GENOMIC TECHNIQUES, AS QUICKLY AND RAPIDLY AS POSSIBLE TO DISEASE OF INTEREST, IN THIS CASE ALS. THIS IS A PAPER WE PUBLISHED IN 2010 WHERE WE USED EXOME SEQUENCING TO IDENTIFY MUTATIONS IN A GENE CALLED VCP AS A CAUSE OF ALS IN THOSE FAMILIES THAT WE SEE THERE. THIS WAS THE FIRST TIME THAT EXOME SEQUENCING HAD BEEN APPLIED IN ALS, IN FACT I THINK IN GENERAL ONE OF THE FIRST TIMES EXOME SEQUENCING HAD BEEN APPLIED IN NEUROGENERATION, WE CAN BRING THE RESOURCES TO BEAR RAPIDLY. TECHNOLOGY IS INTERESTING BUT WHAT IS ALSO INTERESTING WAS THAT VCP WAS A KNOWN CAUSE OF FRONTOTEMPORAL DEMENTIA, TWO DISPARATE ENTITIES. I STARTED TO UNRAVEL THAT LINK BETWEEN THESE TWO DISEASES AND SPARKED OUR INTEREST IN TRYING TO UNDERSTAND WHAT WAS GOING ON THERE AND WHY PATIENTS GETTING ALS WERE ALSO GETTING FTD. WE'VE CONTINUED USING EXOME SEQUENCING IN ADDITIONAL FAMILIES AND RECENTLY PUBLISHED MATR3 AS A CAUSE, A NUCLEAR MATRIX PROTEIN WITH RNA AND DNA BINDING DOMAINS SIMILAR TO TTP 43. SOME OF YOU MAY KNOW FOR WORK AT THE UNIVERSITY OF PENNSYLVANIA, TDP 43 IS CENTRAL TO THE PATHOGENESIS OF ALS AND FTD AND IT'S REALLY THE NEUROPATHOLOGICAL HALLMARK OF THE TWO CONDITIONS. I'M GOING TO TALK ABOUT THAT LATER AND PUT IT IN CONTEXT. SO WHAT I REALLY WANT TO SPEND A FAIR AMOUNT OF TIME THOUGH TALKING ABOUT THIS AFTERNOON IS THE DISCOVERY OF THE C9ORF72 REPEAT EXPANSION WHICH HAS DARE I SAY EMBOLDENED THE FIELD AND LIVENED THINGS UP IN THE ALS RESEARCH COMMUNITY. UNTIL THEN WE HAD INFREQUENTLY CAUSING GENES IN ALS. SO OUR STORY REALLY BEGINS BACK IN 2005, 2006, WITH THE PUBLICATION OF TWO FAMILIES, ALS/FTD FAMILIES, TRADITIONAL LINKAGE STUDIES THAT IDENTIFIED A LOCUS ON THE SHORT ARM OF CHROMOSOME 9. THOSE TWO STUDIES TOGETHER WITH A VARIETY OF OTHER LINKAGE STUDIES IDENTIFIED A REGION OF ABOUT 7 MILLION BASE PAIRS ON THE SHORT ARM OF CHROMOSOME 9. PUT THAT IN CONTEXT, 6 BILLION BASE PAIRS IN THE HUMAN GENOME, 3 BILLION FROM MOM, 3 BILLION FROM DAD, AND 6 BILLION PEOPLE ON THE FACE OF THE PLANET. 7 MILLION IS ABOUT THE SIZE OF THE CITY OF LONDON, JUST TO PUT THAT IN A GEOGRAPHICAL PERSPECTIVE. NOW, THERE WAS A LOT OF EXCITEMENT ABOUT THIS AT THE TIME BECAUSE IT WAS CLEAR THAT THIS ACCOUNTED FOR A LARGE PROPORTION OF FAMILIAL ALS. THERE WAS A LARGE NUMBER OF REALLY GOOD NEUROGENETICS LABORATORIES AROUND THE WORLD WORKING ON THIS NOBODY COULD FIND WHAT THE UNDERLYING MUTATION WAS. IT WAS GREAT TO KNOW IT WAS IN THE 7 MILLION BASE PAIRS BUT YOU HAVE TO KNOW WHICH GENE IS INVOLVED. IT'S TAKING ON THIS AURA OF THE HOLY GRAIL, SORT OF THING. OUR INVOLVEMENT IN THE HUNT FOR C9 STARTED WITH OUR GENOME-WIDE ASSOCIATION STUDY OF ALS IN FINLAND. FINLAND IS AN IDEAL PLACE TO DO A GENETICS STUDIES OF ALS FOR TWO REASONS. FIRST AND FOREMOST IT'S A HIGHLY CONSERVED POPULATION WHICH HELPS US IN FINDING GENES BECAUSE IT DECREASES GENETIC AND ALLELIC HETROGENEITY AND SECONDLY IT HAS ONE OF THE HIGHEST RATES OF ALS ANYWHERE IN THE WORLD, FOR REASONS THAT WILL BECOME CLEAR AS WE GO ON. WHEN WE DID THIS GENOME-WIDE ASSOCIATION STUDY WE WERE REALLY PLEASED TO SEE A SPIKE ON THE SHORT ARM OF CHROMOSOME 9 RIGHT IN THE MIDDLE OF WHERE THAT 7 MILLION BASE PAIR INTERVAL WAS, BECAUSE OF THE DENSE NATURE OF THE SNPs ON THE CHIP THAT DALE IN THE FRONT SOLD TO US, BECAUSE OF THE DENSE NATURE OF THOSE, WE WERE ABLE TO NARROW IT DOWN FROM 7 MILLION BASE PAIRS DOWN TO JUST 232,000 BASE PAIRS WHICH REALLY GUESS IF YOU WANT TO PUT IT THIS WAY IS LIKE A STREET IN LONDON. I WILL ADMIT I MADE MY -- I WAS REALLY EXCITED WHEN I SAW THIS. I MADE MY POOR GRAD STUDENT JENNIFER STAY IN THE LAB FOR A WEEK SOLID WITHOUT GOING HOME SEQUENCING THREE GENES IN THERE BECAUSE I THOUGHT WE WERE GOING TO HAVE IT. IN A WEEK WE'LL KNOW WHAT THE GENE THAT UNDERLIES THIS COMMON CAUSE OF ALS IS. AS I REMINDED HER, SHE REMINDED ME WHEN I RANG HER UP TO TELL HER WE FOUND IT THEY YEARS LATER SHE REMINDED ME OF THAT FACT IT ONLY TOOK US THREE YEARS, NOT A WEEK TO FIND IT. BUT I THINK WE REALLY -- WE'VE STARTED TO REALIZE VERY EARLY THIS WAS GOING TO BE MORE DIFFICULT NUT TO CRACK THAN WE PREVIOUSLY APPRECIATED. WHAT WE DID IS WE REACHED OUT TO OTHER LABORATORIES AROUND THE WORLD THAT WERE ALSO WORKING ON CHROMOSOME 9 WHO COLLECTED FAMILIES AND WE SAID TO THEM WE'VE GOT RESOURCES HERE AT THE INTRAMURAL PROGRAM, SEND THE DNA SAMPLES TO US, WE'LL SEQUENCE THEM, AND WE'LL SEND THE DATA OUT AND WE'LL ALL ANALYZE IT TOGETHER. I THINK THAT'S ONE OF THE STRENGTHS OF THE INTRAMURAL PROGRAM AGAIN TO BE ABLE TO RAPIDLY BRING RESOURCES TO BEAR ON A PROBLEM. THIS INCLUDED HUGH MORRIS, DREW PICKENBRAND, THE UNIVERSITY OF HELSINKI, PETER IN AMSTERDAM AND JOHN HARDEE AT QUEENS SQUARE AND WE ALSO REACHED OUT AND FORMED A COLLABORATION WITH ANOTHER CONSORTIUM THAT WAS LED BY ROSA IN THE MAYO CLINIC. AND FROM AN EARLY STAGE ONE OF THE FAMILIES THAT WE FOCUSED ON WAS THIS FAMILY HERE CALLED AFTER A SMALL LITTLE VILLAGE SOUTH OF CARDIFF. I'VE NOT BEEN THERE BUT IF YOU BLINK AS YOU DRIVE THROUGH YOU'LL MISS THE VILLAGE. HUGH MORRIS SPENT A DECADE GOING DOWN TO THE VILLAGE COLLECTING AND PHENOTYPICALLY CHARACTERIZING PATIENTS AND MEMBERS OF THE FAMILY. SO WE KNEW FROM AN EARLY STAGE THIS WAS AN IMPORTANT FAMILY AND THREW EVERYTHING AT THIS, EVERY PIECE OF TECHNOLOGY WE THREW IT AND THE KITCHEN SINK, NOTHING WAS SHOWING UP. REALLY NO MUTATIONS WERE SHOWING UP. THAT WAS NOT WASTED EFFORT. I'LL TELL YOU WHY. IT TOLD US THAT IT HAD TO BE ONE OF TWO TYPES OF MUTATIONS, EITHER THE ENTIRE AREA INVETRIS OR THERE WAS AN INSERT OF A NEW PIECE OF DNA INTO THE REGION. IT HAD TO BE ONE OF THOSE TWO BECAUSE ANY OTHER TYPE OF MUTATION WOULD HAVE SHOWN UP WITH EVERYTHING WE HAD DONE. SO WHAT FINALLY WORKED? WHAT FINALLY WORKED, WE TOOK DNA FROM ONE OF THOSE AFFECTED INDIVIDUALS, I THINK THE BOTTOM LEFT, SENT IT OFF TO A COMPANY IN GERMANY AND THEY FLOW SORTED TECHNICAL DIFFICULTIES WITH VIDEO THAT WAS THE FIRST THROUGH AFTER THREE YEARS OF HARD SLOG AS TO WHAT WAS GOING ON IN THIS CHROMOSOME 9. THIS IS REALLY -- IT WAS ABSOLUTELY AMAZING TO BE SITTING IN FRONT OF THE COMPUTER AND KNOW THIS IS IT. THIS IS WHY WE COULDN'T FIND IT. IT ALL MAKES SENSE, A BIG REPEAT EXPANSION WE WEREN'T ABLE TO SEQUENCE ACROSS. IN FACT, I'M SAYING THIS FOR THE FELLOWS AND GRAD STUDENTS IN THE ROOM THINKING OF GOING INTO GENETICS. I CAN THINK OF ONLY ONE THING THAT MIGHT BE SIMILAR IN NATURE TO THIS. THAT WOULD BE KNOWING WHO REALLY WON THE FLORIDA IN THE 2000 PRESIDENTIAL ELECTION, BUSH OR GORE, THE ONE THING. THAT'S HOW GOOD IT WAS. IT'S A MASSIVE HEXONUCLEOTIDE REPEAT EXPANSION AT THE START OF THIS GENE C9ORF72. THIS GAVE RISE TO PUBLICATIONS BACK TO BACK IN "NEURON" IN SEPTEMBER OF 2011, BACK TO BACK WITH ROSA WHO FOUND THE SAME HEXONUCLEOTIDE REPEAT EXPANSION. IT ACCOUNTS FOR 40% OF FAMILIAL ALS, ABOUT 25% OF FAMILIAL FRONTOTEMPORAL DEMENTIA, UNHEARD OF NUMBERS. THE HIGHEST ONE BEFORE THAT WAS 12%, AND HERE WE ARE WITH A SINGLE GENE ACCOUNTING FOR NEARLY HALF OF ALL OF THE FAMILIAL ALS. WHAT WAS EVEN MORE EXCITING WAS IT ACTUALLY ACCOUNTED FOR 8% OF APPARENTLY SPORADIC CASES. CASES THAT DID NOT HAVE A FAMILIAR HISTORY OF DISEASE. I WILL TELL YOU FROM A PERSONAL PERSPECTIVE THAT AS ONE WHO HAS TO GO TO ALL OF THESE CHARGEABLE ORGANIZATIONS AND GET MONEY AND BEG FOR MONEY AND SAY, NO, LOOK, SPORADIC ALS IS GENETIC AND SPEND A FEW MILLION DOING THIS IT WAS MARVELOUS TO HAVE PROOF THAT GENETICS ACTUALLY PLAYED A SIGNIFICANT ROLE IN SPORADIC DISEASE. LOOK, IT REALLY IS GENETICS, WHICH IS REALLY ALL BREATHING A SIGH OF RELIEF WITH RESPECT TO THAT. IT TURNS OUT THAT IT REALLY IS -- IT'S ONE OF THE MOST COMMON CAUSES OF ALS, ONE OF THE MOST COMMON CAUSES OF FRONTOTEMPORAL DEMEANTA AND ACCOUNTS FOR ALL OF THOSE CASES THAT SIT IN BETWEEN ALS/FTD CASES. LIKE ANY GOOD SCIENCE, THE DISCOVERY OF C9ORF72 RAISES MORE QUESTIONS THAN IT ANSWERS. I'M GOING TO GO OVER SOME OF THEM HERE, THERE ALREADY MORE IN THE AUDIENCE, ASK AT THE END. THERE'S SOME GLARING GAPS. THESE ARE THE ONES THAT COME TO MIND WHICH ARE CLOSE TO MY HEART. FIRST IS WHERE DID THE C9ORF72 MUTATION COME FROM? IT TURNS OUT THAT REMEMBER I SHOWED YOU THAT GENOME-WIDE ASSOCIATION STUDY OF ALS IN FINLAND? THERE WAS A BLOCK, A HAPLOTYPE BLOCK OF 230 BASE PAIR, 230,000 BASE PAIRS, THAT ALL THOSE CASES SHARED. ONCE WE FOUND THE ACTUAL REPEAT EXPANSION, WE ASKED A SIMPLE QUESTION. THAT IS, DOES EVERYBODY WHO CARRIES THE REPEAT EXPANSION ALSO CARRY THAT FINNISH HAPLOTYPE? THAT'S WHAT THIS GRAPH IS SHOWING YOU. LET ME WALK YOU THROUGH IT. I DON'T HAVE A POINTER. OKAY. SO HERE IS THE HAPLOTYPE AT THE BOTTOM. THERE'S 260 CASES CARRYING THE EXPANSION REPRESENTED HERE, EACH REPRESENTED BY A LINE GOING ACROSS. THE LENGTH OF THE LINE TELLS YOU HOW MUCH OF THE FINNISH HAPLOTYPE THIS CARRY. THIS INDIVIDUAL HAS ALL EXTENDING FROM HERE TO HERE. THIS INDIVIDUAL HAS IT EXTENDING FROM HERE TO HERE. THIS IS THE LOCATION OF THE ACTUAL REPEAT EXPANSION. THE BLUE LINES ARE THE FINNISH CASES, ORANGE LINES ARE AMERICANS, RED ARE THE ITALIANS. RIGHT HERE AT THE TOP IS THIS LONELY SINGLE SOLITARY JAPANESE PATIENT THAT WE FOUND THE C9ORF72 REPEATER. WHAT YOU SEE FROM THIS IS EVERY SINGLE CASE THAT CARRIED THE C9ORF72 REPEAT EXPANSION ALSO CARRIED THE FINNISH HAPLOTYPE TO A GREATER OR LESSER EXTENT TELLING US TWO THINGS. YOU CAN LOOK AT THIS AND FIGURE OUT HOW OLD OR HOW LONG AGO IT WAS SINCE THIS ACTUAL MUTATION OCCURRED, WE THINK IT OCCURRED ABOUT 1500 YEARS AGO, ABOUT THE TIME OF THE FALL OF THE ROMAN EMPIRE. IT ALSO TELLS US THAT IT'S LIKELY THIS OCCURRED ON ONE OCCASION AND THEN SPREAD OUT. WHAT WE THINK HAPPENED IS THAT IT OCCURRED IN FINLAND, SCANDINAVIA, AND SPREAD AROUND THE REST OF EUROPE. THE QUESTION IS HOW DID IT SPREAD AROUND THE REST OF EUROPE? SO WHAT WE THINK HAPPENED IS THESE GUYS, ON THEIR SUMMER HOLIDAYS, TOOK IT WITH THEM AS THEY WERE GOING AROUND THE REST OF EUROPE. I SHOULD EMPHASIZE THAT THIS IS A THEORY, ON MY PART. I HAVE APPLIED FOR MONEY AND FUNDING TO BUILD A TIME MACHINE TO GO BACK. [ LAUGHTER ] I WAS TOLD THAT AS IN TYPICAL FORM WE HAD TO DO IT IN MILESTONES, THE FIRST BEING TO GO BACK IN TIME ONE HOUR AND UNASK FOR THAT ACTUAL MONEY. [ LAUGHTER ] BUT I SUPPOSE IN SOME WAYS GENOMICS IS A BIT OF A TIME MACHINE, ALLOWS US TO LOOK AT THAT. WHAT'S PARTICULARLY STRIKING ABOUT THIS, THIS IS A MAP SHOWING THE CONQUESTS OF THE VIKINGS DURING THE MIDDLE AGES. WHAT'S PARTICULARLY STRIKING ABOUT THIS IS THAT IF YOU LOOK AT THE MAP OF WHERE C9ORF72 IS, IT REALLY MATCHES UP WITH WHERE THE VIKINGS WERE. IT'S CRAZY. REMEMBER, THE VIKINGS WERE SEA-FARING NATION, THEY DIDN'T MARCH ACROSS LAND LIKE NORMAL ARMIES. THEY WENT ACROSS IN BOATS, SO THEY STUCK TO THE COASTS. THAT'S WHERE YOU SEE C9ORF72, THERE'S MORE HISTORICAL FACTS I CAN BRING FORTH DURING QUESTION TIME IF YOU WANT. WHAT OTHER PHENOTYPES ARE ASSOCIATED WITH C9ORF72? REMEMBER THAT WE'VE GOT ALS AND FTD, THE TWO VERY DISPARATE CLINICAL SYNDROMES, MAYBE C9ORF72 CAUSES OTHER ONES. WELL, FOR THE PURPOSES OF THIS TALK I'VE DIVIDED IT INTO TWO GROUPS, THERE'S NO DOUBT THAT C9ORF72 CAUSES THIS, DEFINITE, IMPOSSIBLE. THERE'S A HINT IT MIGHT BE INVOLVED BUT WE'RE NOT TOTALLY SURE. TOP IS ALS AND FTD AND WE'RE GLAD IT WAS REPLICATED BY CHRISTINA VAN BROOK HOVEN'S GROUP IN THE NETHERLANDS. THE OTHER ONE THAT FALLS INTO THE DEFINITE CATEGORY IS HUNTINGTON DISEASE, NOT THE CASES THAT HAVE THE CAG REPEAT. I'M TALKING ABOUT THOSE CASES THAT DON'T CARRY THE CAG REPEAT. WHAT'S THE CAUSE OF THOSE? WELL, SOMEBODY WENT AND COLLECT THE ABOUT 100 OF THOSE AND LO AND BEHOLD C9ORF72 ACCOUNTED FOR THE VAST MAJORITY. C9ORF72 CAN GIVE RISE TO A HUNTINGTON-LIKE SYNDROME. AND THEN IN THE POSSIBLE AREA ALZHEIMER'S DISEASE AND A HOST OF NEUROPSYCHIATRIC CONDITIONS, SCHIZOPHRENIA, BIPOLAR AND PARKINSON'S. THAT'S A LONG LIST. ALMOST A CRAZY LONG LIST UNTIL WE REALIZE SOMETHING, THANKED IS WHEN YOU TALK TO A NEUROPATHOLOGIST, ABOUT A C9ORF72 BRAIN, THEY ACTUALLY TELL YOU THAT THEY CAN DIAGNOSE A C9ORF72 BRAIN BY LOOKING UNDER THE MICROSCOPE BEFORE THEY KNOW THE GENOTYPE. THE REASON WHY IS BECAUSE IN C9ORF72 CASES, THE PATHOLOGY IS EVERYWHERE. IT'S MUCH MORE PROFUSE AND DIFFUSE THAN IT ACTUALLY IS IN OTHER FORMS OF ALS. SO ONE OF THE IDEAS HERE IS THAT BECAUSE IT'S SO DIFFUSE AND IT'S AFFECTING SO MANY STRUCTURES IN THE BRAIN, MAYBE THAT'S WHY YOU'RE SEEING ALL OF THESE DIFFERENT PHENOTYPES THAT ARE INVOLVED. I THINK THAT'S A RATHER INTERESTING IDEA PEOPLE ARE WORKING ON. NOW, OUR OWN WORK WAS REALLY LOOKING AT ALZHEIMER'S DISEASE, BECAUSE IMMEDIATELY AFTER WE DISCOVERED THAT IT CAUSED A LARGE PORTION OF FRONTOTEMPORAL DEMENTIA WE ASKED DOES IT CAUSE ANY OTHER TYPES OF DEMENTIA? WE HAD IN OUR FREEZER THE NIMH COHORT OF 770 CASES THAT HAD BEEN CLINICALLY, I EMPHASIZE THAT WORD, CLINICALLY DIAGNOSED WITH ALZHEIMER'S DISEASE. WE SCREENED THEM FOR THE REPEAT EXPANSION AND 6 OF THEM, ABOUT 1%, CARRIED THE REPEAT EXPANSION. NO, THAT'S RATHER INTERESTING BECAUSE IF YOU LOOK ACROSS ALL OF THE OTHER A-D GENES THAT HAVE BEEN IDENTIFIED IN THAT COHORT, THAT COHORT WAS THE STALWART BEING USED ACROSS ALL OF THE A.D. COMMUNITY FOR FINDING GENES. THIS WAS THE MOST COMMON GENE DEFECT THAT HAD BEEN FOUND WITHIN THE 700. IT TURNS OUT THAT TWO OF THOSE 6 PATIENTS CAME TO AUTOPSY, REDIAGNOSED HAVING FRONTOTEMPORAL DEMENTIA. HERE IS WHAT I THINK IS GOING ON HERE. I THINK IT'S NOT CLEAR IN THE LITERATURE WHETHER IT REALLY CAUSES A.D. BUT MY GUT IS TELLING US THAT REALLY WHAT IS GOING ON HERE IS THAT THESE PATIENTS ACTUALLY HAVE AMNETTIC FTD MISDIAGNOSED AS ALZHEIMER'S DISEASE. CLINICAL ACCURACY BEFORE THE BRAIN IS LOOKED AT BY NEUROPATHOLOGY IS 85, 86%. THE C9ORF72 AND ABILITY TO SCREEN ALLOWS US TO INCREASE OUR ACCURACY OF DIAGNOSIS FOR A.D. BECAUSE IT WEEDS OUT THOSE CASES THAT ARE ACTUALLY FTD AND THAT HAS IMPLICATIONS FOR THE FAMILY, YOU HAVE TO COUNSEL THEM DIFFERENTLY COMPARED TO ALZHEIMER'S DISEASE, IT REPRESENTS IN RUNNING CLINICAL TRIALS, AS HOMOGENOUS A POPULATION AS POSSIBLE. WHAT ABOUT THE PENETRANTS OF -- PENETRANCE OF C9ORF72. THIS IS THE GRAPH OF AGE OF ONSET IN 162 IS 162 CASE IS. MEDIAN OF 57, PLATEAUS ABOUT 80%. WHAT THAT'S SHOWING US, YOU IT CARRY THIS MASSIVE REPEAT EXPANSION AND SURVIVE TO YOUR NINTH DECADE OF LIFE WITHOUT GETTING SICK. THAT'S KIND OF COOL, ISN'T IT? THERE ARE PATIENTS WHO GET IT REALLY EARLY AND PATIENTS WHO GET IT REALLY LATE. OUR THOUGHT WAS, WELL, I WONDER IF THERE'S SOME OTHER GENETIC VARIATION GOING ON IN THERE THAT MIGHT BE DRIVING THAT? SO ONE OF THE PROJECTS WE'RE UNDERTAKING IS COMPLETE GENOME SEQUENCING ON A SET OF CASES THAT ARE OLD ONSET AND SET OF CASES YOUNG ONSET, AND LOOK AND SEE IF WE CAN FIND SOMETHING THAT'S ACTUALLY INFLUENCING. IF WE DO FIND THAT, IT'S QUITE POSSIBLE THAT IT HAS SOME INFLUENCE, IT'S A WAY OF FINDING THE FINAL COMMON PATHWAY IN ALL OF ALS, MIGHT HAVE SOME INFLUENCE AND BE A GOOD TARGET FOR ALL OF ALS, NOT JUST A SPECIFIC COHORT OF PATIENTS CARRYING A PARTICULAR MUTATION. OF COURSE, A LOT OF WORK HAS BEEN DONE IN THE FIELD WITH METHYLATION BEING SUGGESTED AS BEING A MODIFIER OF AGE OF ONSET AND VARIETY OF OTHER GENES BUT I THINK IT'S GOING TO BE INTERESTING TO SEE WHAT BEARS OUT AN COMES OUT OF THAT PARTICULAR TYPE OF ANALYSIS. THEN OF COURSE I'M A NEUROLOGIST. I SEE THESE PATIENTS WHO ARE DEVASTATED WITH THIS NEURODEGENERATIVE DISEASE ALL THE TIME IN MY CLINIC. IT'S CLOSE TO MY HEART, THIS IDEA OF TRYING TO BRING BACK WHAT WE LEARNED AT THE BENCHSIDE TO THE PATIENT, TRYING TO HELP THEM. WHETHER WE CAN LEVERAGE THAT DATA. I'M HAPPY TO SAY THAT NINDS HAS BEEN STELLAR IN TERMS OF SUPPORTING THIS EFFORT. THEY HAVE ALLOWED US TO SET UP A C9ORF72 CLINIC, AND I DO THIS IN COLLABORATION WITH MARY KAY FLOATER OF NINDS, AND THIS IS REALLY SORT OF SOMETHING THAT'S VERY CLOSE TO OUR HEARTS, BOTH OUR HEARTS, BECAUSE I THINK THAT WE NEED TO KNOW THE NATURAL HISTORY OF THE DISEASE BEFORE WE CAN PROCEED TO CLINICAL TRIALS. I MEAN, IT'S CLEAR IT CAUSES A WIDE PHENOTYPE BUT WE NEED TO NAIL THAT DOWN BECAUSE IF YOU ACTUALLY DO HAVE A DRUG, YOU NEED TO HAVE SOME SORT OF READOUT TO KNOW THE PATIENTS ARE GETTING BETTER. IF THE PHENOTYPE IS ALL OVER THE PLACE THAT'S GOING TO BE DIFFICULT TO DO. ANOTHER THING, ANOTHER WAY TO GET AT THAT WILL BE TO DISCOVER BIOMARKERS, SO ONE OF THE THINGS WE'RE WORKING ON IS COLLECTING ALL OF THESE SPECIMENS, PLASMA, SERUM, BLOOD, CSF, NEUROIMAGING AND SO FORTH FROM THESE PATIENTS AND WE'RE HAPPY NEITHER MARY KAY NOR MYSELF ARE INTO BIOMARKER DISCOVERY, THE IDEA IS WE SEND OUT AND COLLABORATE WITH OTHERS TO ACT AS AN INFRASTRUCTURE FOR THAT VERY IMPORTANT EFFORTS. WE'RE PLEASED WE WERE PART OF AN EFFORT IN EUROPE, IN MAYO CLINIC JUST RECENTLY PUBLISHED IN "NEURON," THEY USED OUR CSF SAMPLES TO IDENTIFY A PARTICULAR DIPEPTIDE THAT MIGHT BE A POTENTIAL BIOMARKER. THAT'S ALL WELL AND GOOD, BUT THE WHOLE IDEA HERE IS THAT WE WANT TO HAVE A REALLY WELL PHENOTYPED COHORT READY FOR CLINICAL TRIALS IF AND WHEN AGENTS COME UP, GENE THERAPY OR SMALL MOLECULES. WE'RE STILL ENROLLING. GET MORE DETAILS ABOUT THIS PARTICULAR TRIAL AT THE clinicaltrials.gov WEBSITE LISTED BELOW. THIS IS TO COME BACK TO WHERE WE WERE NOW IN TERMS OF THE GENETICS IN 2005. THAT'S LONELY SOD1 IN 2005, AND THIS IS NOW POPULATED WITH ALL OF THE MORE RECENTLY FOUND GENES UP TO THE REGION OF 2014. THERE IS QUITE A LOT MORE THERE. BUT IT CAN BE EVEN MADE MORE INTERESTING BY GOING BACK AND LOOKING AT MATR3 THAT INTERACTS WITH 43, AND WORK DONE IN MARK COOKSON'S LAB SHOWS IDENTIFIED THAT ALTERED INTERACTION WITH TDP 43, SO WE KNOW MAPR 3 AND TDP 43 ARE INTERACTING. IF GO BACK TO THE GRAPH AND DRAW IN THE INTERACTIONS, AND WE KNOW TDP 43 INTERACTS WITH FUS FROM WORK IN FRANCE, AND YOU'RE STARTING TO SEE INTERACTIONS EMERGE, IT'S ALMOST AS IF THE PATHWAYS ARE STARTING TO COME OUT AND WE'RE BEGINNING TO LEARN WHAT IS IMPORTANT AND RELEVANT TO MOTOR NEURON DEGENERATION WHICH IS VERY EXCITING. UP UNTIL NOW I'VE BEEN TALKING ABOUT FAMILIAL AND MENDELIAN DISEASE. WHAT ABOUT SPOREATIC? WE GET AT THAT WITH GENOME-WIDE ASSOCIATION STUDIES. WE'VE DONE SEVERAL OVER THE YEARS, INCLUDING THE VERY FIRST GENOME-WIDE ASSOCIATION STUDY UP THERE IN THE TOP LEFT-HAND SIDE. THESE ARE CALLED MANHATTAN PLOTS, JUST FOR THOSE NOT FAMILIAR WITH THEM. THE IDEA IS THAT THE ASSOCIATION IS SUPPOSED TO STICK UP LIKE A SKYSCRAPER FROM THE MANHATTAN SKYLINE, ALL RIGHT? THE PROBLEM IS THAT IF YOU GO BACK AND LOOK AT THOSE GENOME-WIDE MANHATTAN PLOTS, NOTHING IS REALLY SHOWING UP. IT'S NOT REALLY ASSOCIATED. IN FACT, YOU COULD SAY IT'S ALMOST LIKE A DUBLIN PLOT BECAUSE THERE ARE NO SKYSCRAPERS IN THE DUBLIN SKYLINE, SO THESE ARE COMPLETE DUBLIN SKY PLOTS. THE ADVANTAGE BEHIND THIS, HAVING DONE THAT, WE MADE IT POSSIBLE IN dbGAP, IT'S BEEN DOWNLOADED AND INCORPORATED INTO OTHER GWAS'ES. OUR GENOME-WIDE ASSOCIATION STUDY OF ALS IN FINLAND FINALLY GAVE US SOME GOOD ASSOCIATION STUDY WHICH WAS VERY EXCITING AND WHAT ULTIMATELY LED TO THE DISCOVERY OF C9ORF72. WE'VE CONTINUED ON WITH GWAS. THIS IS A -- IT'S MORE AN EWAS, EXOME-WIDE ASSOCIATION STUDY ON 5000 CASES AND CONTROLS IN OUR LAB. WE'VE COMPLETED THAT LAST YEAR. AND UNFORTUNATELY REALLY AT THIS STAGE ALL THAT'S SHOWING UP IS C9ORF72 RIGHT THERE ON CHROMOSOME 9. THAT'S UNPUBLISHED DATA AS OF YET. LET'S QUICKLY SUMMARIZE WHERE WE STAND IN TERMS OF ALS GENETICS AT THE MOMENT. WE START BACK IN 1993, WITH THE DISCOVERY OF THE FIRST GENE SOD1 DISCOVERED BY BOB BROWN UP IN MASS GENERAL HOSPITAL. THERE'S A LONG HIATUS UNTIL WE STARTED PULLING IN A FEW OTHER GENES, TDB 43, FOS, VCP, YOU CAN SEE REALLY IT'S LIKE THERE'S BEEN AN EXPLOSION IN THE PACE OF DISCOVERY, I THINK THAT REFLECTS THE DEVELOPMENT IN TECHNOLOGY THAT REALLY HAVE ADVANCED THE FIELD ALONG. THIS IS THE MOST RECENT GENES HERE, TBK 1 AND TUB4A, WE CAN PAT OURSELVES ON THE BACK BECAUSE WE'VE DONE A GOOD JOB, 15% COMPARED TO A FEW AGO WHEN WE DIDN'T KNOW THAT MUCH AT ALL. ON THE OTHER HAND, YOU COULD LOOK AT ANOTHER WAY, AND THAT IS THERE'S STILL 85% OUT THERE THAT YOU DON'T KNOW ABOUT, AND HOW ARE YOU GOING TO GET AT THAT? OKAY. SO THAT SEGUES NICELY ONTO OUR FUTURE PROJECTS, AND HOW WILL WE TRY AND TEASE APART THE REMAINING GENETICS OF ALS? OBVIOUSLY I COULD SPEND AN HOUR, ANOTHER HOUR, GOING OVER ALL OF THESE DIFFERENT PROJECTS BECAUSE THEY ARE ALL VERY EXCITING, SOME ARE IN DIFFERENT STAGES OF PROCESS, SOME ARE NEARING COMPLETION, SOME ARE IN GESTATION STAGE, AT THIS STAGE. BUT THE ONE I WANT TO HE CAN TO US ON IS GENOME-WIDE ASSOCIATION STUDIES. THIS IS A GWAS PUBLISHED BY ANNIE SINGLETON AND MIKE NOLDS FROM LABORATORY OF NEUROGENETICS THAT I WORK IN AND THEY DID THAT ON PARKINSON'S DISEASE, RIGHT? AND NOTICE THE NUMBERS. THEY DID 13,000 CASES AND NEARLY 100,000 CONTROLS. WHEN THEY HIT THAT LEVEL, THEY SAW 26 LOCI SIGNIFICANTLY ASSOCIATED WITH PARKINSON'S DISEASE, A HUGE PORTION AND WHAT'S GOING ON IN PARKINSON'S DISEASE. I SHOW THIS BECAUSE I'M TRYING TO MAKE THE POINT IF WE CAN GET SIMILAR NUMBERS FOR ALS, THAT WE MIGHT BE ABLE TO ACTUALLY DISCOVER THE SAME AMOUNT. I WOULD ACTUALLY MAINTAIN WE REALLY HAVEN'T DONE THE ULTIMATE GENOME-WIDE ASSOCIATION STUDY IN ALS AS OF YET, SOMETHING WE HAVE ONGOING IN OUR LAB AT THE MOMENT, HOPEFULLY FINISHED TOWARDS THE END OF THIS YEAR, PUBLICATION IN THE BEGINNING OF NEXT YEAR. WE'RE VERY EXCITED ABOUT HOPEFULLY WHAT THAT'S GOING TO SHOW. AND I'M GOING TO STOP NOW AND LET YOU ASK SOME QUESTIONS BUT BEFORE I DO THAT I WANT TO MENTION MY STAFF THAT HAVE BEEN WORKING ON ALL THESE PROJECTS OVER THE YEARS. IT'S GREAT THAT I GET TO STAND UP HERE AND WAX LYRICAL BUT THESE ARE THE GUYS WHO DO ALL OF THE HARD WORK AND THEY HAVE BEEN FANTASTIC AND AMAZING OVER THE YEARS SHOWING US HOW TO DO IT. SOME HAVE GONE ON TO DO MUCH BETTER AND GREATER THINGS, JENNY HAS GONE ON TO MEDICAL SCHOOL, JENNA WENT TO UNIVERSITY OF MARYLAND, NOW COMING BACK TO BE OUR GRAD STUDENT, THEY ARE REALLY GOOD CAREER AND WORK TOGETHER VERY WELL. I'VE MENTIONED MANY OF OUR COLLABORATORS, AS I'VE BEEN GOING THROUGH THE TALK. I'M NOT GOING TO MENTION THEM ALL AGAIN. THIS IS A MAP SHOWING WHERE THEY MIGHT ACTUALLY -- WHERE MANY ARE LOCATED AROUND THE WORLD. I SHOW IT FOR TWO REASONS. FIRST, TO SHOW THAT REALLY THERE ARE A LOT OF COLLABORATORS ALL OVER THE WORLD. YOU NEED TO BE -- IN ORDER TO BE A SUCCESSFUL GENETICIST YOU NEED TO BE PART DIPLOMAT BECAUSE THIS IS A NUMBERS GAME. YOU NEED THE NUMBERS. YOU CAN HAVE ALL THE MACHINES IN THE WORLD, BUT IF YOU DON'T HAVE THE DNA SAMPLES COMING IN THE FRONT DOOR YOU'RE NOT GOING TO GET ANYWHERE. GONE ARE THE DAYS OF THE LONELY SCIENTIST WORKING IN HIS LAB LATE AT NIGHTTIME. THESE ARE ALL CONSORTIUM EFFORTS AND TEAM EFFORTS, IT'S IMPORTANT TO REALIZE THAT AND I'M FORTUNATE TO HAVE SOME VERY, VERY CLOSE FRIENDS AND COLLABORATORS INCLUDING ADRIAN AND PENTI WHO HAVE BEEN FANTASTIC. FINALLY, ENDING WITH FUNDING AND DISCLOSURES, A PATENT PENNING ON THE C9ORF72 REPEAT EXPANSION, WE'VE RECEIVED FUNDING FROM THE INTRAMURAL PROGRAM OF NII AND NINDS AND OTHER INTENTS, THESE ARE EXPENSIVE STUDIES TO TRY AND DO. WITH THAT I WILL STOP AND MAYBE THERE ARE QUESTIONS IN THE AUDIENCE IN AREAS I MAY NOT HAVE COVERED IN FULL DETAIL. THANK YOU. [APPLAUSE] >> QUESTIONS, BRYAN? GO TO THE MICROPHONE BECAUSE THERE ARE HUNDREDS OF THOUSANDS OF PEOPLE LISTENING IN. >> NOT HUNDREDS. >> ALL YOUR COLLABORATORS. >> SO LOVELY. OBVIOUSLY BEAUTIFUL. SO WHAT DO WE KNOW ABOUT THE PRODUCT OF C9ORF72 AND WHAT THAT PRODUCT NORMALLY DOES? >> YES, AN ABSOLUTELY -- THANK YOU FOR ASKING THAT QUESTION. I DID NOT PAY HIM ANY MONEY TO ASK THAT QUESTION. HERE IS AN INTERESTING THING. WHEN YOU FIND MUTATION IN THE GENE BY AND LARGE YOU CAN GO ON PubMed OR WHATEVER WEBSITE IS YOUR FAVORITE AND FIND INFORMATION ABOUT A GENE. IF THERE'S NO INFORMATION, YOU CAN LOOK AT THE DOMAINS AND FIGURE OUT MAYBE THIS IS WHAT THIS GENE DOES BECAUSE IT'S GOT AN RNA-BINDING DOMAIN AND SO FORTH. C9ORF72 FALLS INTO THE CATEGORY WHERE NOT ONLY DOES NOBODY KNOW WHAT IT DOES, IT ALSO WHEN YOU LOOK AT THE DOMAIN, THERE ARE NO DOMAINS. THERE HAS BEEN SOME PUBLICATIONS SUGGESTING IT MAY BE A DENM PROTEIN OR HAVE A ROLE THERE, THERE ARE OTHERS SUGGESTING THAT IT IS PRESENT IN VARIOUS MEMBRANES AND MAY HAVE SOMETHING TO DO WITH IMPORT/EXPORT. NOT CLEAR IS THE SIMPLE ANSWER TO THAT QUESTION. >> IS THERE A KNOCKOUT MOUSE? >> AH, SO THERE ARE SEVERAL MICES, MOUSESES, MICE, THAT HAVE BEEN MADE, SO LET ME JUST SAY THAT WE -- MY LAB REALLY, REALLY FOCUSES ON GENETICS AND GENOMICS. I DON'T DO CELL-BASED MOLECULAR CELL BIOLOGY OR ANIMAL MODELS. THIS IS WORK I'M INTERESTED IN SO I COLLABORATE WITH PEOPLE IN TERMS OF DOING IT BUT DON'T DO IT MYSELF. SO REALLY I'M TALKING ABOUT OTHER PEOPLE'S WORK HERE. THERE ARE SEVERAL MICE THAT ARE IN PRODUCTION. THERE ARE ONE OR TWO OF THEM, THERE'S ONE THAT I'VE HEARD HAS A PHENOTYPE. THERE ARE ANOTHER TWO THAT DO NOT HAVE A PHENOTYPE, EVEN THOUGH THEY HAVE BEEN AGED QUITE SIGNIFICANTLY. SO IT'S NOT CLEAR WHAT'S GOING ON. OF COURSE, ONE OF THE PROBLEMS IS THAT WHEN IT COMES TO PUTTING IN TO CLONING IN THE REPEAT EXPANSIONS, THE CELLS REALLY DISLIKE THE VERY LONG REPEAT EXPANSION, SO IT'S DIFFICULT TO GET THE LONG REPEAT EXPANSIONS IN. THEY JUST KEEP DYING AND SO YOU'RE STUCK WITH THESE MUCH SMALLER REPEAT EXPANSIONS THAT MAY OR MAY NOT BE COMPLETELY IN THE REALM OF HUMAN PATHOGENESIS. >> I HAD A QUESTION ABOUT THE PHENOTYPIC VARIABILITY IN THE GWAS. ARE YOU INCLUDING PEOPLE WITH FTD OR ALS OR SOME OR HOW ARE YOU -- >> IN ORDER TO GET INTO THE GWAS, THE FIRST DIAGNOSIS YOU HAVE HAS TO BE ALS. IF YOU COME WITH A DIAGNOSIS OF FTD AND DEVELOP ALS LATER WE TEND NOT TO INCLUDE THOSE PATIENTS. YOU FIRST HAVE TO COME WITH ALS. IF YOU DEVELOP COGNITIVE DIFFICULTIES AFTER THAT DIAGNOSIS IS ESTABLISHED, WE WILL STILL INCLUDE YOU IN THE GENOME-WIDE ASSOCIATION STUDY. ONE THING, AND IT'S ACTUALLY A VERY GOOD QUESTION, MANY LEVELS, BECAUSE AS A CLINICIAN, YOU KNOW, IT'S FUNNY. AS A CLINICIAN AND NEUROLOGIST, WE'RE ALWAYS TAUGHT TO SILO PATIENTS. PATIENTS HAVE ALS. PATIENTS HAVE MYOPATHY. PATIENTS HAVE NEUROPATHY AND NEVER THE TWAIN SHALL MEET. THROUGH THE GENETICS AND WHAT I'M BEGINNING TO APPRECIATE MYSELF FROM THE NEUROGENETICS IS REALLY THE BARRIERS ARE MUCH MORE POROUS, THE OVERLAP IS MUCH MORE THERE THAN WE PREVIOUSLY APPRECIATED. WE HAVE TO BE OPEN MINDED ABOUT THAT. THE SECOND POINT IS WHEN YOU'RE DOING FAMILY-BASED STUDIES, YOU HAVE TO BE INCREDIBLY PRECISE ABOUT THE DIAGNOSIS BECAUSE IF YOU GET ONE INDIVIDUAL WRONG WHEN YOU'RE DOING EXOME SEQUENCING, IT SCUPPERS THE ENTIRE PROJECT. IN CONTRAST WITH GENOME-WIDE ASSOCIATION STUDIES, IT IS MUCH MORE TOLERANT OF MAKING WRONG DIAGNOSES. YOU CAN HAVE UP TO 10% WRONG DIAGNOSEES IN THERE AND IT PROBABLY WON'T DAMAGE YOU TOO MUCH IF YOU'VE GOT SUFFICIENT COHORT SIZES. IT'S MUCH MORE TOLERANT. >> TO FOLLOW ON THE ISSUE OF WHAT THESE GENES ARE DOING, EVAN EICHLER WAS HERE A FEW WEEKS AGO TALKING ABOUT AUTISM, MAKING THE CASE THEY ALL FELL INTO PATHWAYS INVOLVED IN NEURODEVELOPMENT. DO YOU SEE ANYTHING LIKE THAT WITH ALL THE GENES THAT ARE ALS AND DO THEY OVERLAP AT ALL WITH OTHER NEURODEGENERATIVE DISEASES? >> THAT'S AN EXCELLENT QUESTION, AND I THINK THAT, YES, ONE OF THE POWERS BEHIND GENETICS IS PATHWAYS ARE STARTING TO EVOLVE, BY LOOKING AT THE FUNCTION OF THE DIFFERENT GENES. AND THE TWO AREAS THAT ARE COMING TO THE FRONT ARE RNA METABOLISM, YOU'VE GOT TDP 43, POSSIBLY C9ORF72, FUS, MAPT 3 IMPACTING ON RNA METABOLISM AND DYSREGULATION OF THAT PARTICULAR PROCESS. THAT'S ONE SIDE. THE OTHER SIDE IS PROTEIN -- HANDLING OF PROTEINS AS THEY HAVE BEEN DEGRADED THROUGH THE PROTEOSO MANY, VCP, UBIQUITIN 2. THERE'S A LOT OF EFFORT TO LINK THE TWO PATHWAYS UP. I'VE SEEN SOME PRELIMINARY DATA THAT MIGHT LINK THEM UP BUT IT'S PRELIMINARY AT THE MOMENT AND I DON'T KNOW WHETHER IT'S GOING TO GO. BUT, YOU KNOW, I THINK WE SHOULD NOT BE -- SO WE SHOULD NOT BE SURPRISED. IT IS BECOMING CLEARER AND CLEARER TO ME AND I THINK TO THE REST OF THE ALS RESEARCH COMMUNITY THAT ALS IS NOT ONE DISEASE. IT IS A GROUP OF DISEASES. SO BASED ON THAT WE SHOULD NOT BE TERRIBLY SURPRISED THERE WOULD BE MORE THAN ONE SET OF PATHWAYS INVOLVED BECAUSE IT'S JUST -- IT'S A VERY BROAD DEFINITION. MOTOR NEURONS CAN ONLY DO ONE OF TWO THINGS, THEY CAN WORK OR DIE. THAT'S WHY YOU SEE THE SAME CLINICAL PATTERN FOR A WHOLE HOST OF DIFFERENT REASONS. >> ANY OTHER QUESTIONS? IF NOT, THE SHY PEOPLE WILL COME UP AFTER THE SEMINAR. LET'S THANK BRYAN. [APPLAUSE] >> THANK YOU VERY MUCH.