>> I THINK WE'LL BEGIN. I HAVE JUST A COUPLE OF ANNOUNCEMENTS. I SEE SOME NEW FACES WHO HAVE NOT BEEN HERE BEFORE SO WE'LL JUST SPEND 30 SECONDS. DO YOU ALL RECOGNIZE WHAT THAT STRUCTURE IS? WHAT IS IT? YES, THAT'S THE BROOKLYN BRIDGE. SO WHY SHOULD WE BE SHOWING THE BROOKLYN BRIDGE IN A COURSE CALLED DEMYSTIFYING MEDICINE. >> [INDISCERNIBLE] IT LOOKS LIKE TWO I'S [INDISCERNIBLE] >> THAT'S AN INTERESTING IDEA. WELL YOU'RE ACTUALLY LOOKING AT NEW YORK. THIS IS AROUND 1863. THE REASON WE DO IT IS VERY SIMPLY THE WHOLE PURPOSE OF THIS COURSE IS TO MATCH TOGETHER AT THE SAME TIME AND THE SAME PLACE PEOPLE WHO ARE REALLY DOING VERY EXCITING RESEARCH AND THINKING ABOUT SOME OF THE FUNDMENTAL BIOLOGICAL AND ANALYTICAL PROBLEMS THAT CONFRONT MAJOR HEALTH DISEASE, MAJOR HEALTH PROBLEMS. SO THE IDEA IS BY BEING ABLE TO DISCUSS THIS MUTUALLY AND THINKING ABOUT IT FROM THE TWO SIDES OF THE BRIDGE YOU CREATE SOMETHING THAT DIDN'T EXIST BEFORE. THAT'S WHAT HAPPENS WHEN YOU BUILD THE BRIDGE, IT'S NEVER THE SAME ON EITHER SIDE. AND IT CERTAINLY NEVER THE SAME BACK IN THE 19TH CENTURY WHEN NEW YORK WHICH LOOKED LIKE THAT AND OVER HERE WERE PASTURES AND COWS. ANY WHO HAVE EVER BEEN TO BROOKLYN IN MORE RECENT TIME REALIZE THERE HASN'T BEEN A COW OR PASTURE IN BROOKLYN PROBABLY FOR A HUNDRED YEARS. OKAY. SO THAT'S THE POINT OF IT. I WANTED TO MENTION ON OUR SCHEDULE THERE WAS NOTHING OFFICIALLY PRINTED FOR NEXT TUESDAY SESSION. NOTICES HAVE BEEN SENT OUT ELECTRONICALLY AND SO FORTH THAT THE TOPIC IS GOING TO BE PARKINSON'S DISEASE AND THE SUBTITLE IS SEEING HOW BASAL GANGLION NEURONS WORK. ACTUALLY SEEING THEM AND WHAT HAPPENED WHEN THEY FAIL. AND THE TWO SPEAKERS ARE FROM THE NIH INVESTIGATORS MARK -- FROM NINDS AND HEADS THE PARKINSON RESEARCH AND CLINICAL EFFORT HERE. AND -- WHO HAS DONE ABSOLUTELY AMAZING WORK AND HOW NEURONS IN THE BASAL GANGLIA COMMUNICATE WITH ONE ANOTHER. ON THE 30TH, WHICH IS THE LAST PRESENTATION. WE'LL HAVE AN EXCITING PROGRAM ON THE MITOCHONDRIA AND THE DISEASES AND THE SPEAKERS ARE -- FROM NICHD, OUTSTANDING SPELL BIOLOGIST AND IS DOING A LOT TO UNRAVEL MITOCHONDRIAL STRUCTURE AND FUNCTION. AND LANE WOLF WHO IS IN THE GENOME INSTITUTE, WHO HAS BEEN STUDYING PATIENTS WITH A VARIETY OF SOME OLD AND SOME NEWLY DISCOVERED INHERITABLE DISORDERS. LASTLY ON THE 7TH OF MAY THERE'S THE FINALE. THAT'S THE SYMPOSIUM ENTITLED WHAT ARE THE OPPORTUNITIES FOR PH.D.'S AND BIOMEDICAL SCIENCE. AS A MATTER OF FACT IN ALL KINDS OF SCIENCE. AND AS YOU KNOW, THESE ARE TOUGH TIMES AND DOESN'T LOOK AS IF BY TOMORROW THEY'RE GOING TO GET ENORMOUSLY BETTER. SO I'VE ASKED SEVERAL INSTITUTE DIRECTORS WHO HEAD VERY EXCITING PROGRAMS TO TAKE PART IN A SYMPOSIUM AND DISCUSS WHAT THEIR FIELD HAS TO OFFER BOTH SCIENTIFICALLY AND FROM A PRACTICAL OCCUPATIONAL STANDPOINT. AND THEY ARE STORY LANDES WHO IS THE DIRECTOR OF NINDS AND BOBBALANCEEN WHO IS THE DIRECTOR OF THE HEART INSTITUTE AND TOM ENSELL WHO IS THE DIRECTOR OF THE MENTAL HYGIENE AND JOHN GALLON WHO IS THE DIRECTOR OF THE CLINICAL CENTER. THIS IS A FREE WHEELING DISCUSSION OF WHAT IS THE FUTURE LOOK LIKE, WHAT ARE THE OPPORTUNITIES AND WHAT PARTICULARLY CAN PH. PH.D.s DO TO TAKE ADVANTAGE OF THESE EXTRAORDINARY OPPORTUNITIES. SO TODAY'S TOPIC IS VISION AND BLINDNESS IN THE GENOMIC ERA. I GUESS ANYBODY WHO EVER THINKS ABOUT A VISION HAS GOT TO BE IMPRELINGSED -- IMPRESSED BY SOMETHING HAPPENS WHEN WE SEE WHITE AND SUDDENLY IT'S CONVERTED INTO IMAGES. THE MOST POETIC AND DIRECT THING I EVER SAW JUST IN READING A LITTLE BIT, THIS MEETING WAS THIS QUOTE FROM BOB RODIC WHO WAS THE LEADER IN OPHTHALMOLOGY RESEARCH AND DIED IN 2003 WHO SAID OUR MOST CHERISHED SENSE VISION BEGINS WITH THE PROCESS OF PHOTO TRANSDUCTION, A PROCESS FORMED BY THE HIGHLY SPECIALIZED PHOTO RECEPTOR CELLS OF THE RODS AND CONES. NOW IN MODERN TIMES PARTICULARLY POST GENOMICLY HOW RODS AND CONES ACTUALLY FUNCTION AND HOW TRANSDUCTION ITSELF FUNCTIONS. AND WHAT ARE DISEASES THAT CAN BE RECOGNIZED THAT REPRESENT DEFECTS, MANDELIAN DEFECTS, WHAT ARE THEY AND CAN WE USE GENOMIC TECHNOLOGY TO FIND OUT WHAT THEY ARE AND PERHAPS EVEN TO DO SOMETHING ABOUT IT. THE EYE BEING WHERE IT IS AND THE RETINA BEING WHERE IT IS THERE'S ALWAYS THE POSSIBILITY ONE CAN DELIVER THINGS DIRECTLY TO THE RETINA WITHOUT HAVING TO GO THROUGH THE SYSTEMIC CIRCULATION WHICH MAY HAVE SOME GREAT ADVANTAGES IF YOU'RE TALKING ABOUT THINGS LIKE VIRAL VECTORS AND SO FORTH. TODAY'S SPEAKERS ARE TWO LEADERS THAT REPRESENT BOTH SIDES OF THE BRIDGE AND REALLY AT THE HIGHEST LEVEL. SO OUR FIRST SPEAKER WHO IS GOING TO BE EMILY CHEW AND EMILY IS A PHYSICIAN WHO TRAINED IN TORONTO, DID A FELLOWSHIP AT HOPKINS AND IN HOLLAND AND THE DIRECTOR OF THE DIVISION OF EPIDEMIOLOGY AND CLINICAL APPLICATIONS. SHE'S THE CHIEF OF THE CLINICAL TRIALS BRANCH AND FROM THE LITERATURE ALL OF WHICH IS POSTED ON THE WEBSITE BY THE WAY WHICH CONTAINS ALL OF THE POWER POINTS OF THIS AND ALL PREVIOUS SESSIONS FOR 11 YEARS, YOU CAN OBTAIN A VALUABLE SOURCE OF INFORMATION. ONE OF THE PAPERS THAT EMILY GAVE WHICH WE POSTED HAS TO DO WITH HOW YOU KNEW, SORT OF LIKE THE GOLD STANDARD OF CLINICAL TRIALS. AND THIS IS HOW YOU DO A RANDOMIZED CLINICAL TRIAL. I THINK THAT'S, IT'S A SHORT ARTICLE AND VERY THOUGHTFUL AND WORTH READING. THIS IS ONE SIDE OF THE SPECTRUM. CLINICAL TRIALS BASED UPON OBSERVATIONS EPIDEMIOLOGICALLY BASIC SCIENCE AND SO FORTH. AND SORT OF AS THEY SAY WHERE RUBBER MEETS THE ROAD. IS IT GOING TO WORK AND IF NOT WHY AND IF SO WHY TOO. SO THEN ON THE OTHER SIDE OF THE BRIDGE OF COURSE IS THE GENOMIC ASPECT OF IT. AND THE MORE BASIC ASPECTS OF WHAT DOES THE RETINA CONSISTENT OF WHAT THE STANDPOINT OF GENES AND THEIR EXPRESSION AND THE IDENTIFICATION OF GENETIC ARTICLITIES THAT ARE COMMON AND NOT SO COMMON IN ORDERS OF VISION. HERE WE'RE VERY FORTUNATE TO HAVE THE DIRECTOR OF THE EYE INSTITUTE PAUL SIEVING WHO IS AN MB PH.D. AND HE'S BEEN DIRECTOR OF THE INSTITUTES SINCE 2001 WHEN HE CAME HERE FROM MICHIGAN WHERE HE WAS PROFESSOR OF OPHTHALMOLOGY AND GENETICS AND PRIOR TO THAT, HIS BACKGROUND IS AT NUCLEAR PHYSICS AT YALE. FURTHER EFFORT TO GO TO LAW SCHOOL WHICH THANK GOD HE DECIDED WAS NOT THE PROPER THING AND THAT WAS FOLLOWED BY A MEDICAL DEGREE AT THE UNIVERSITY OF ILLINOIS TRAINING AT OPHTHALMOLOGY AND POST DOC FELLOWSHIPS AT UC SAN FRANCISCO. AND HARVARD. AND THEN CAME TO NIH IN 2001. AND PAUL IS ONE OF THE GREAT LEADERS IN THIS AREA OF THE POST GENOMIC ERA IN OPHTHALMOLOGY. SO WE'RE VERY GRATEFUL TO BOTH OF YOU FOR BEING WITH US AND EMILY HAVE BEEN KIND ENOUGH AND TWO OF HER PATIENTS HAVE BEEN KIND ENOUGH TO COME AND TELL YOU A LITTLE OF THEIR ILLNESS. SO WHY DON'T WE BEGIN. >> OKAY, GREAT. THANK YOU VERY MUCH FOR THIS KIND INTRODUCTION TO ALL OF US. IT'S A GREAT PLEASURE TO BE HERE TO REPRESENT THE NATIONAL EYE INSTITUTE. WHAT WE DO IS REALLY A TEAM EFFORT AND MANY OF YOU ARE HERE AS PART OF THE TEAM SO WE'RE VERY GLAD TO BE SHOWING OFF OUR WARES TODAY. AND WE'RE ESPECIALLY PROUD TO HAVE TWO OF MY FAVORITE PATIENTS HERE, MR. AND MRS. HAMMER. MR. HAMMER, HOW ARE YOU TODAY? YOU ALWAYS TELL ME THAT YOU ARE -- MAGNIFICENT. >> EXACTLY. HOW ABOUT. >> HOW AM I? I GUESS I HAVE TO SAY MAGNIFICENT TOO. >> HE'S ALWAYS MAGNIFICENT WHEN HE COMES. SO HOW YOUNG ARE YOU, SIR? >> OH GOSH I HAVE TO COUNT. GETTING CLOSE TO 94. >> OKAY. SO HE'S REALLY A YOUNGSTER. ABOUT TEN YEARS AGO IS WHEN YOU STARTED HAVING TROUBLE WITH HIS VISION. SO HE'S 94. I THINK I TELL HIM THIS ALL THE TIME, THA WAS BORN LUCKY. I THINK YOU KNOW THE RESEARCH HAS GONE ON AND 20 YEARS AGO WE WOULDN'T HAVE BEEN ABLE TO DO VERY MUCH. WE WOULD SAY MR. HAMMER YOU HAVE MACULAR DEGENERATION AND UNFORTUNATELY THERE ISN'T MUCH WE CAN DO. GO TO A LOW VISION SPECIALIST AND HELP YOU BUT IN THIS DAY AND AGE THINGS HAVE CHANGED. THE THERAPY WHICH YOU LOVE GETTING. YOU GET INJECTIONS. WHAT ABOUT THOSE INJECTIONS. >> THEY'RE A LOT OF FUN. [LAUGHTER] RIGHT IN THE EYEBALL. >> TELL US HOW YOU STARTED. WHEN YOU FIRST STARTED WITH THE PROBLEM WITH YOUR MAC GENERATION, WHAT DID YOU NOTICE AT THE BEGINNING. >> DIFFICULTY IN READING AND DIFFICULTY IN JUST GENERAL VISION. >> YOU WOULDN'T KNOW THIS BUT THE TWO ARE NOT RELATED BY BLOOD BUT THEY BOTH HAVE MAC DEGENERATION. WHEN DID YOURS START MRS. HAMMER. >> WHEN I LOOKED AT THE CHART AND I SAW SOME WAVY LINES AND I DIDN'T WANT TO BELIEVE IT. THAT I HAD AN IDEA WHAT IT MIGHT BE. AND OF COURSE IT WAS DIAGNOSED AS THE DRY MAC INCLUDE DEGENERATION. HIS IS THE WEB KIND. >> RIGHT. AND WHO DRIVERS IN THE FAMILY. >> ME. >> -- THEY'VE BEEN WONDERFUL TO COME TO OUR STUDIES AND HEVE BEEN CONTRIBUTING A GREAT DEAL TO NIH. DOING CLINICAL TRIALS WITHOUT OUR PATIENTS IS IMPOSSIBLE. THEY ALWAYS CONTRIBUTE A GREAT DEAL. THEY ARE ALWAYS WILLING TO COME D TY'RE EXTMELY EDUCATED. THEY BRING THEIR WHOLE FAMILY SO I'VE ACTUALLY SEEN EVERY ONE OF THEM. WE ACTUALLY PHENOTYPE AL THE FAMILY. IT'S IMPORTANT THEY CONTRIBUTE A GREAT DEAL TO OUR KNOWLEDGE OF MAC DEGENERATION. THANK YOU VERY MUCH. IS THERE ANYTHING ELSE YOU'D LIKE TO SAY. >> IT'S BEEN GREAT. SAVED MY VISION AND KEPT ME DRIVING SAFELY. >> AND MRS. HAMMER, ANYTHING YOU HAVE TO ADD TO THAT? >> LET'S SEE. WELL, I DON'T DRIVE. AND NO, IT'S NO FUN. I MEAN THE DRY MAC DEGENERATION, I SEE MY VISION GRADUALLY DISAPPEARING. I REMEMBER WHEN I FIRST CE TO EMILY AND SHE SAID YOU'LL NEVER GO BLIND, YOU'LL ALWAYS HAVE YOUR PERIPHERAL VISION. I DIDN'T KNOW WHETHER THIS WAS GOOD OR BAD. BUT I DO MANAGE, AND I HOPE SOME DAY THAT THERE WILL BE SETHING THAT WILL REALLY HELP AND BE A CURE. >> IT'S INTERESTING THAT THEY BOTH HAVE IT BUT THE CHILDREN ARE NOW IN THEIR 50'S. >> 60'S. >> 60'S, OKAY. THEY DON'T HAVE ANY SIGNS OF ANYTHING THAT I'VE SEEN. I'VE EXAMINED ALL OF THEM. SO THE GENETICS IS VERY COMPLEX. THESE AR COMPLEX TRAITS AND IT'S HARD TO STUDY FAMILIES BECAUSE IT OCCURS IN OLDER INDIVIDUALS. YOUNGER INDIVIDUALS USUALLY DO NOT HAVE THIS DISEASE. IT'S LUCKY FOR THEM THEY DON'T HAVE ANYTHING BUT THEY'RE ALWAYS ON THE LOOKOUT TO MAKE SURE THEY'RE BEING WATCHED AND ETCETERA. BUT THANK YOU VERY MUCH FOR COMING. WE REALLY APPRECIATE YOU BEING HERE. >> OKAY, THANK YOU. >> DO YOU HAVE ANY QUESTIONS FROM THE AUDIENCE? ANY QUESTIONS FROM THE AUDIENCE? ONE OF MY STUDENT SESSIONS ABOUT TWO AND-A-HALF YEARS AGO, WHAT WAS THE MOST IMPORTANT QUESTION THEY ASKED YOU, DO YOU REMEMBER. >> THEY WANTED TO KNOW HOW LONG WE'VE BEEN MARRIED. [LAUGHTER] AND HOW WE MET. >> CAN YOU TELL THEM HOW LONG YOU'VE BEEN MARRIED. >> WELL, I SHOULDN'T TELL YOU BUT WE'VE BEEN MARRIED 70 YEARS. >> CHILD BRIDE. >> ANYONE IN YOUR FAMILY WHO HAS THIS PROBLEM? IS THERE ANYONE IN YOUR FAMILY. >> YES, MY MOTHER HAD THE DRY KIND AND MY TWO BROTHERS WERE IN THE EARLY STAGES WHEN THEY DIED. BUT YES, IT IS IN THE FAMILY. I DON'T KNOW, I HOPE MY CHILDREN DON'T HAVE IT. >> HOW OLD WERE YOUR BROTHERS WHEN THEY PASSED AWAY? >> IN THEIR LATE 70'S. >> DID THEY CARDIOVASCULAR DISEASE OR D THEY HAVE OTHER DISEASES. >> YES. THEY BOTH HAD CARDIOVASCULAR DISEASE. >> ANY QUESTIONS FROM THE AUDIENCE? OKAY, GREAT. THANK YOU VERY MUCH. THANK YOU VERY VERY MUCH. [APPLAUSE] AGAIN, THANK YOU FOR INVITING ME TO SPEAK. I'M GOING TO CONCENTRATE ON MAC DEGENERATION, AGE-RELATED MAC DEGENERATION BECAUSE IT REALLY IS A HEALTH PROBLEM IN THE U.S. YOU CAN SEE THIS IS A PIE CHART TAKEN FROM THE EYE DISEASE STUDY GROUP IN 2004. WE TOOK ALL THE COMPANIES, ALL THE DIFFERENT -- IS THIS BETTER? CAN YOU HEAR BETTER? OKAY. SO WE TOOK ALL THE STUDIES THAT WE COULD FIND THAT WERE POPULATION-BASED BOTH FROM THE U.S., FROM EUROPE AND FROM AUSTRALIA. AND THERE'S SOME OTHERS THAT THERE WERE A FEW PARTICULARLY IN ASIA BUT MOST OF THEM WERE REALLY NORTHERN EUROPEAN PERCENT LOOKING AT WHITE PERSONS IN THE USA THAT WE PREDICTED. IN FACT HALF OF BLINDNESS IS DUE TO MAC DEGENERATION. THE INCLUDES REP KNOW THEY, GLAUCOMA AND CAT RATHER. THOSE ARE THE FOUR MAIN CAUSES OF VISION LOSS. THERE ARE OTHERS THAT ARE ALSO VERY IMPORTANT AND DR. SEIVING WILL TALK ABOUT THAT AS WELL. IF YOU'RE AFRICAN AMERICAN THAT'S NOT YOUR PROBLEM. LOOKING AT MAC DEGENERATION PATIENTS, IT MAY CAUSE LACK OF VISION USUALLY GLAUCOMA AND CAT RATHER ARE NUMBER ONE AND TWO CAUSES OF VISION LOSS. AND MAC DEGENERATION IS A VERY SMALL PROPORTION, ONLY 4%. SO THERE'S SOME RACIAL DIFFERENCES IN THIS PARTICULAR DISEASE. THE PREVALENCE IN POPULATIONS ARE FOUR YEARS AND OLDER. IT'S 1.47% BUT IF YOU LOOK AT OLDER IT'S MUCH HIGHER. 15% OF WOMEN AGE 80 OR OLDER WERE WHITE HAVE ADVANCED MAC DEGENERATION. AND IT'S A DISEASE IN WHICH IT'S HIGHLY PREVALENT, 8 MILLION WITH INTERMEDIATE, THERE ARE TWO MILLIONS WITH MAC DEGENERATION IN 2020 AND OF COURSE AGING IS ONE OF THE NUMEROUS FACTORS OF THIS CONDITION. WORLDWIDE IT'S RANKED THIRD IN THE WORLD, HEALTH ORGANIZATIONS REVIEW OF LEADING CAUSES OF BLINDNESS WORLDWIDE. IN A DEVELOPED WORLD AMD LEADS THE CAUSE DUE TO A GROWING NUMBER OF PEOPLE OVER THE AGE OF 70. AS THE POPULATION GROWS AND DEMOGRAPHIC SHIFTS TOWARDS THESE INCREASING PAGE, THERE'S A PREDOMINANCE OF OLDER AGE GROUPS. IT WILL DEFINITELY INCREASE WORLDWIDE. THIS IS AN EPIDEMIC THAT WILL INCREASE AS WE ALL ESPECIALLY THE BABYBOOMERS ARE GETTING OLDER AND OLDER. SO NOW THIS WAS A GRAPH SHOWING YOU THE DIFFERENT AREAS MOSTLY. THIS IS FROM FRAMINGHAM FROM THE U.S., BEAVER DAM FROM THE U.S., BROADER DAM FROM HOLLAND, BLUE MOUNTAIN FROM AUSTRALIA, THE URI WHICH IS A COMBINATION OF EUROPEAN COUNTRIES, BEIJING IN CHINA, BARBADOS, JAPANESE AND INDIAN. THESE ARE ALL A POPULATION BASE STUDIES. THEY SHOW WITH INCREASING AGE AS YOU GET TO ABOUT 65 AND 70 THERE'S A LARGE JUMP IN TERMS OF PREVALENCE OF ADVANCED MAC DEGENERATION. WE LOOK FOR THIS IN THE EARLIER DISEASES, EARLIER AMD, THERE'S A LITTLE BIT OF A DIFFERENCE IN THE NUMBER OF STUDIES. AND IT'S THE WAY THAT THEY DEFINE EARLY MAC DEGENERATION. BUT IN OTHER WORDS IT DOES INCREASE OVER AGE AND YOU CAN SEE THAT BY THE TIME YOU GET INTO 80'S THE NUMBER OF PATIENTS WILL ACTUALLY HAVE EARLY AMD AS WELL AS ADVANCED AMD. I'M JUST GOING TO TALK A BIT ABOUT THE AREA THAT WE'RE INTERESTED IN. THE PHOTO TRANSDUCTION IN THE EYEBALL AND THE EPITHELIAL PLAYS AN IMPORTANT ROLE SO THAT THIS COMBINATION AND SOMETHING OCCURS IN THAT AREA OF MAC DEGENERATION. THOSE WHO ARE NOT OPHTHALMOLOGISTS, THE ANGLE IS VERY IMPORTANT -- CAUSE OF THE BLINDNESS IN STRUCTURES OF THE EYE. WE'RE LOOKING AT THE MACULA AND THE BLOOD VESSELS AS WELL AS THE OPTIC NERVE. IN MAC DEGENERATION YOU SEE THESE SMALL POTS. IN THE MOST WE THOUGHT THESE WERE PRETTY INNOCUOUS. WHEN WE STUDIED THE PATIENTS FOR TEN YEARS 70% OF THEM BECOME LARGE DRUSEN AND -- WILL DEVELOP THE DISEASE. MAC DEGENERATION IS WHEN THE DRUSEN IS OF SIGNIFICANT SIZE. THESE ARE EXTENSIVE INTERMEDIATE SIZE DRUSEN AND WE CAN TELL BY LOOKING AT THE RULER HERE YOU GO RIGHT AT THE NERVE WHERE THE BLOOD VESSEL THIS VEIN WHICH IS THE FATTER OF THE TWO CROSSES THE MICRONS AND THAT'S SORT OF OUR MEASUREMENTS. THIS PATIENT HAS LARGE DRUSEN. THE MORE DRUSEN YOU HAVE THE MORE LIKELY YOU'RE GOING TO HAVE MAC DEGENERATION. IT MAY BECOME ARE MORE SIGNIFICANT. IN THE ADVANCE STAGES WE TALKED ABOUT ARE THE NEO VASCULAR FORM WHICH IS DEVELOPED BECAUSE OF BLOOD VESSEL FORMATION AND ATROPHY WHICH IS A SLOW ATROPHY OF THE RETINAL PIGMENT AS WELL AS THE LOSS OF THE PHOTORECEPTORS IS A GRADUAL PROCESS -- IN TERMS OF LOW VISION IT'S HARD TO REHABILITATE COMPLETELY. THESE ARE THE RISK FACTORS WE LOOKED AT. WE LOOKED AT WHAT'S IMPORTANT AND WHAT INCREASES THE RISK, AGING IS SOMETHING THAT'S IN EVERY STUDY AND CERTAINLY WE CAN'T DO ANYTHING ABOUT. SMOKING IS VERY IMPORTANT ASPECT. IT USUALLY TRIPLES OR DOUBLES OR TRIPLES THE RISK OF HAVING MAC DEGENERATION. THE GENETICS I'LL TOUCH A LITTLE BIT ON THAT AND DR. SIEVING WILL TALK MORE ABOUT GENETICS. THERE'S AN INCREASE RISK OF BODY MASS INDEX THE BIGGER YOU ARE THE MORE LIKELY. SO SMOKING, YOU KNOW, HAVING A HEAVY WEIGHT, SO HEALTHY LIVING IS ACTUALLY VERY IMPORTANT PART IN PREVENTING MACULAR DEGENERATION. INTERESTINGLY, THERE'S SOME CARDIOVASCULAR THAT'S SIMILAR TO VASCULAR AMD. SO IT'S SOMETIMES HARD TO SORT OUT. FOR EXAMPLE THERE'S BEEN A LOT OF PRESS RECENTLY ABOUT MAC DEGENERATION AND THERE'S A QUESTION THAT ASPIRIN MIGHT ACTUALLY INCREASE YOUR RISK OF LATE MAC DEGENERATION. BUT WE DON'T THINK THAT'S REALLY TRUE. THE RICK FACTORS ARE COMMON IN BOTH TYPES OF DISEASES, BOTH FOR THE CARDIOVASCULAR AS WELL AS MAC DEGENERATION. SO IT'S QUITE CONFOUNDING THAT PEOPLE WHO HAVE AMD ARE TAKING ASPIRIN NOT BECAUSE THEY'RE TAKING ASPIRIN DOESN'T MAKE THE AMD WORSE. THERE ARE SEVERAL PAPERS THAT HAVE KIND OF BATTED THIS CONTROVERSY AROUND AND IT'S IMPORTANT TO SORT THAT OUT FOR OUR PATIENTS. NUTRITIONAL RISK FACTORS ARE ALSO SEEN IN A NUMBER OF OBSERVATIONAL DATA AND WE'RE NOW IN YOUR SECOND, IN OUR SECOND TRIAL. AND THE FEATURES WHICH I'M NOT GOING TO TALK MUCH ABOUT BUT THE FACT THERE'S LARGE DRUSEN AND HAVING DISEASE IN ONE EYE WILL INCREASE YOUR RISK FOR MAC DEGENERATION. FOR SMOKING IT DOUBLE THE RISK. THERE'S A DOSE RESPONSE. THIS IS FROM THE EUROPEAN STUDY IN WHICH YOU LOOK AT THE PACK YEARS. 1-19 ODDS RATIO OF 1.8. IF YOU GO UP AS HIGH AS 40 PACK YEARS YOU'RE UP TO ALMOST THE FIVE TIME OR FIVE FOLD INCREASE HAVING MAC DEGENERATION. SO SMOKING IS NEVER GOOD FOR YOU. IN TERMS OF TREATMENT, I WANT TO GO THROUGH SOME INTERESTING HISTORY OF WHAT WE'VE DONE IN THE PAST, AND WHERE WE ARE. AND TO GIVE YOU A SENSE OF WHAT'S GONE ON. I SAID EARLIER MORE THAN 30 YEARS AGO THERE WAS NO EFFECT OF TREATMENT UNTIL THERE WAS INTRODUCTION OF LAYERS. COAGULATION HAS REVOLUTIONIZED DIABETIC RETINOPATHY. FOR MAC DEGENERATION IS A TRIAL WHAT WE CALL -- OUTSIDE THE CENTER OF THE RETINA AND SUBFOAF YELL -- IN THOSE DAYS WE DID LASER RIGHT IN THE CENTER OF THE MACULA. AND TREATMENT WAS NOT TERRIFIC. THIS IS THE RESULTS OF TWO YEAR RESULTS FROM PATIENTS. IT'S ONE OF THE FIRST EARLIER TRIAL NOT THE FIRST TRIALS BUT ONE OF THE EARLIER TRIALS IN OPHTHALMOLOGY LOOKING AT PHOTO COAGULATION FOR MAC DEGENERATION. SO WE ACTUALLY USE A HOT LASER PRODUCE THESE WHITE SPOTS AND THE PATIENT ON THE SPOT WOULD DEVELOP A BIG -- OR A BLIND SPOT. SO OUR METRICS FOR MEASUREMENT OF ACTUAL IMPROVEMENT OR SUCCESS IS THE RATE OF SIX LINE LOSS. YOU LOSE A LOT OF VISION. PEOPLE WHO ARE TREATED STILL LOST VISION QUITE A BIT. NOBODY GAINED VISION. EVERYBODY WAS ALWAYS IN THE LOSS. I CAN SLOW DOWN THEIR LOSS. IT WAS UNTREATED 60% BY 18 MONTHS WILL HAVE SIX LINES OF VISION LOSS. SO THAT WAS A PRETTY BIG DEAL IN THOSE DAYS. AND WHEN YOU LOOK AT PATIENTS, THAT WAS FOR THE EXTRA FOVEAL. IF YOU LOOK AT SUBFOVEAL YOU LOSE YOUR VISION QUICKLY. WITHOUT TREATMENT YOU END UP GOING SLOWER BUT YOU STILL HAVE A HIGHER. THAT WAS THE JUSTIFICATION FOR DOING THAT SORT OF LASER AND YOU HAVE A NEW VASCULARIZATION. IN THE CENTER YOU WOULD ACTUALLY LASER THAT DIRECTOR. AS I SAID SIX LINE LOSS IS HUGE. NOW IT COMES UNDER -- THERAPY WHICH IS AN INTRAVENOUS -- PHOTO SYNTHESIZER THAT GOES INTO THE AREA OF THE NEW BLOOD VESSELS AND THE LASER, A COLD LASER IS APPLIED TO THE RETINA AND THAT WOULD CAUSE THE DEMISE OF THAT PARTICULAR REVASCULARIZATION BUT IT MEANT THE PATIENT HAD TO GO OUT IN THE SUN AND WEAR LONG SLEEVES AND GLOVES AND HOTS. YES, SIR, DO YOU HAVE A QUESTION. >> JOB. >> IN THIS CASE IN THE PDT OR THE OTHER LASER YOU'RE TALKING ABOUT? THE COLD LASER. ARGON LASER, THE OTHER LASER IS WHAT WE CALL PHOTO ABLATION. YOU CAN IMAGINE THE DESTRUCTIVE TREATMENT. SO WHAT HAPPENS IS IT'S LIGHT THAT'S ABSORBED BY THE BLOOD VESSELS. ALSO THE OVERLYING SORT OF RECEPTORS ARE ALSO GONE. SO YOU ARE BASICALLY CREATING A BIG BLIND SPOT. YOU'RE DESTROYING THAT AREA. THAT WAS THOUGHT TO BE THE STRUCTURE TREATMENT TO GET RID OF THOSE BLOOD VESSELS WHICH YOU CAN SEE THERE'S ALWAYS RECURRENCE, WE NEVER GOT RID OF IT SO EVERY TIME YOU TREAT IT YOU END UP PROBABLY TREATING IT A LITTLE BIT MORE. WE JUSTIFY IT BY SAYING YOUR BLANK SPOT WAS A LITTLE BIT SMALLER THAN IT WOULD BE IF IT WAS NATURALLY LEFT ALONE. BY MAKING IT SMALL YOU MIGHT CONFINE YOUR AREA TO A SMALLER AREA. CLEARLY THIS NEW BLOOD VESSEL THAT WAS NOT THE ANSWER. BECAUSE FURTHER COAGULATION JUST CONTINUED TO HAVE RECURRENCES. PATIENTS GET MORE AND MORE LASER, GET LARGER AND LARGER. SO PATIENTS EVENTUALLY ALL LOSE VISION EVEN THOSE WHO ARE TREATED ESPECIALLY IF THEY'RE IN THE SUBFOVEAL RIGHT UNDER THE CENTER THAT THE PATIENTS DID LOSE A LOT OF VISION OVER TIME. BUT THIS LASER'S A LITTLE BIT. THIS LASER ACTIVATES THAT DRIVE FOR PHOTO DYNAMIC THERAPY AND CAUSES THE BLOOD VESSELS TO CLOSE OFF. WHEN YOU DO ACTUAL -- WE DON'T KNOW IF IT CLOSES OFF OR CAUSES CALCULATING IN THAT AREA. IT HAS A TEMPORARY DECREASE IN THE BLOOD FLOW BUT AGAIN THERAPY WOULD MEAN MORE TREATMENT AND YOU WOULD DO MORE TREATMENT WITH TIME. AND AGAIN THAT WAS NOT PARTICULARLY SUCCESSFUL. WE'RE STILL LOOKING AT VISION LOSS, SO THIS IS THE THERAPY OF PDT WHICH STILL HAVING PATIENTS LOSING VISION AND THAT WAS OUR METRIC FOR MEASUREMENT OF SUCCESS. AND NOBODY GAINED VISION, NOBODY STAYED STABLE BUT THEY ALL LOST VISION. IF YOU COMPARE PATIENTS WITH THERAPY AND SUBFOVEAL I LOOKS LIKE THE LASER TREATMENT WHICH WE'RE NOT THAT MUCH BETTER OFF. A VARIETY OF THINGS CAME ALONG. ANTI-ANGIOGENIC THERAPY, NOT THE ONES WE'RE TALKING ABOUT, TALKING ABOUT THINGS LIKE -- RADIATION WAS TRIED. PDT. WE TALKED ABOUT STEROID BECAME AN IMPORTANT PART OF THIS. PEOPLE WERE INJECTING STEROIDS INTO THE RETINA INTERFERON ALPHA 2A WAS USED FOR OTHER ILLNESS FOR EXAMPLE AND WE STARTED USING THAT FOR AMD. UNTIL FINALLY A TRIAL WAS DONE IT SHOWED THAT IT ACTUALLY DID NOT HAVE ANY EFFECT ON AMD. IT WAS A SMALL TRIAL, REMEMBER -- AND IT WAS CERTAINLY NOT WELL TAKEN AND NOT EASY. IT WASN'T EFFECTIVE FOR MAC DEGENERATION. AND WE HAD OTHER ORAL AND INDIVIDUAL STEROIDS AS WELL. THE FIRST BREAK THROUGH CAME IN 2004 AND IT WAS FOUND THAT GROWTH NARC IS AN IMPORTANT FACTOR IN THE GROWTH OF THESE NEW BLOOD VESSELS. AND THE FIRST DRUG TO REALLY TRY THIS IS CALLED MACUGEN OR IT WAS INTRODUCED IN 2004. AND THE TREATMENT WAS NOT ABSOLUTELY TERRIFIC AS THE WAY WE HAVE IT NOW BUT IT WAS AT LEAST THE FIRST STEP. THIS LED TO A BETTER TREATMENT. IN 2006, THE FDA APPROVED OF THE PLACENTAS OR -- WHICH IS MADE BY GENENTECH, AN ANTI-BODY AGAINST. AND YOU CAN SEE THAT I'M TREATED THE GROUP HERE PATIENTS WHO HAVE PDP I TALKED ABOUT THE STANDARD TREATMENT AT THAT TIME. THEY LOSE VISION. AGAIN THAT SAME THEORY, SAME THEME RECURRED. THERE WAS A CONSTANT LOSS OF VISION WHEREAS FOR THE FIRST TIME WE SAW PATIENTS IMPROVING. IT'S GIVEN MONTHLY AND THIS IS UP TO TWO YEARS. YOU CAN SEE THEY GAINED VISION BY AS MUCH AS TWO LINES. SO 40% OF PATIENTS GAINED VISION, 95% OF THE PATIENTS REMAINED THE SAME. FOR THIS IS THE FIRST REAL BREAK THROUGH AND THIS IS WHAT MR. HAMMER'S HAVING SOME OF THESE TREATMENTS WHICH IS IMPROVING OUR PATIENT'S VISION DRAMATICALLY BUT INCREASE OUR WORK LOAD AND ALSO THE COST OF HEALTHCARE BECAUSE THESE DRUGS ARE VERY EXPENSIVE. AND THIS IS ONLY ALSO IN ADDITION TO DEVELOPING DRUGS, WE ALSO HAD TECHNOLOGY TO GO ALONG WITH THIS. AND WE'RE VERY FORTUNATE THE OPTICAL COHERENCE TOMOGRAPHY I'LL SHOW YOU WHICH IS AN ULTRASOUND, A SOUND WAVE BUT WE DO THIS WITH LATE. IT'S AN OPTICAL COHERENCE AND WE GET A PICTURE OF THE PATIENT -- YOU SEE THE NEXT PICTURE RIGHT THROUGH THAT AREA IS THE ACTUAL OCT. YOU CAN TELL THAT THE PATIENT HAD A THIN RETINA. YOU CAN SEE THERE'S ACTUALLY LITTLE POCKETS OF FLUID -- NO FLUID UNDERNEATH THE RETINA -- YOU CAN SEE SOME FLUID. WE CAN ACTUALLY MEASURE FOR THE FIRST TIME THE IMPORTANCE OF THIS AND SEE SUBTLE CHANGES THAT WE DON'T WAIT UNTIL THE VERY SEVERE TO COME ON TO ACTUALLY GIVE THE TREATMENT. SO THIS IS REALLY VERY IMPORTANT AS WELL, THIS DEVELOPMENT. IT PROMOTES THE VEGF MOSTLY VASCULARIZATION AND AMD. IT'S PERMEABILITY AND THAT'S ONE OF THE MAIN THINGS WE ACTUALLY TREAT WHEN WE TREAT WITH A DRUG. IT STIMULATES PROLIFERATION MIGRATION AND SURVIVE OF THE ENDOTHELIAL CELLS AND IT'S VERY IMPORTANT TO BLOCK IT AND CREATE THE LEUKOCYTES AS WELL. THERE ARE A NUMBER OF DRUGS THAT HAVE A NUMBER OF DISEASES WHICH THIS HAS BEEN TRIED ON. IT'S BEEN NOW APPROVED FOR VEIN OCCLUSIONS. LIKE RETINOPATHY THAT'S BEEN APPROVED FOR. RADIATION RETINOPATHY IS BEING USED OFF LABEL FOR THAT AND DIABETES IS IMPORTANT -- SICKLE CELL RADIATION, GLAUCOMA IS ALSO BEING USED ALTHOUGH NOT PROVEN. THERE ARE PEOPLE TRYING TO GET A TRIAL LOOKING AT RETINOPATHY MATURITY. THE VEG F DRIVE IS VERY IMPORTANT. AND THE USE OF PRESURGICAL TREATMENT OF THE ANTI-VEG FOR PROLIFIC DISEASE. AND FOR PERSISTENT RECURRENT HEMORRHAGES FOR PEOPLE WITH DIABETES. THIS DRUG HAS TAKEN OFF ON IT'S OWN FOR VARIOUS DISEASES IT'S BEEN CONSIDERED FOR. I'LL SHOW YOU A 63 YEAR OLD WOMAN WHO HAD -- THIS IS ACTUALLY A CASE GIVEN TO ME BY ROSENTHAL. IT'S ONE OF THE FIRST CASES HE INJECTED. THIS IS NOT LIEU SENT TICE. IT WAS ACTUALLY FDA APPROVED IN 2006. DURING THAT PERIOD OF TIME AFTER THE STUDIES ARE FINISHED THE CLINICIAN KNEW THIS DRUG WAS VERY POWERFUL BUT THEY DID NOT HAVE ACCESS TO IT BECAUSE THE FDA PROCESS TAKES SOME TIME. CLINICIANS HAVE TAKEN THE PARENT DRUG, THAT WAS A SMALL PART OF THE MONO CLONAL ANTI-BODIES SO THEY'VE TAKEN THE WHOLE BIG THING AND INJECTED IN THE EYE AND FOUND IT TO BE EFFECTIVE. SO THIS IS A PATIENT ONE OF THE FIRST PATIENTS BEING INJECTED. YOU CAN SEE EARLY FLOURISHING ANGIOGRAM YOU SEE EARLY LEAKAGE DUE TO NEW VESSELS OCCURRING. THE OCT YOU SEE THERE'S A LOT OF FLUID IN THIS PATIENT. THE PATIENT HAS EXUDATIVE AMD. ONE MONTH LATER THERE WAS NOTHING GIVEN AND IT WAS OBSERVATION. AND AGAIN FOUR MONTHS LATER THERE'S OBSERVATION BUT YOU COULD SEE THAT THE LEAKAGE IS GETTING LESS. THERE'S AN EFFECT IN THIS. AND AS YOU GO ON, THERE'S TO BE NO TREATMENT GIVEN UNTIL TEN MONTHS AFTER AVASTEN WAS GIVEN. AVASTEN WAS THEN GIVEN. YOU CAN SEE THE PATIENT GOES BACK TO 20/60 AND THERE'S LESS LEAKAGE. SO THIS DRUG HAS BEEN VERY VERY IMPORTANT IN KEEPING OUR PATIENTS SEEING THAT WE HAVEN'T LEARNED EVERYTHING ABOUT IT YET. THERE ARE A LOT OF PROBLEMS AND THE FACT WE HAD TO GIVE CHRONICALLY SOME PATIENTS REQUIRE ALMOST MONTHLY INJECTIONS, OTHERS MAY BE FUMING LIKE THIS PATIENT ONLY HAD TWO. WE HAD TO FIND DRUG DELIVERY THAT MAY BE BETTER. THERE ARE PEOPLE WHO FILLS THE VISION AFTER THIS PARTLY BECAUSE THE ONGOING PROCESS OF MAC DEGENERATION CONTINUES ON. THEY STILL HAVE GEOGRAPHIC ATROPHY WHICH NEEDS TO BE WORKED. AND HERE THIS IS THE FIRST THE OCT SHOWING THE CHANGES OVER TIME, LOOKING AT INDIVIDUAL INJECTION GIVEN. YOU CAN SEE ONE WEEK LATER THAT FLUID GOES AWAY AND WITH TIME IT PRESERVES ITSELF AND WITH ONE MORE TREATMENT IT'S DONE VERY WELL. I TALKED A BIT ABOUT ANTI-OXIDANTS WHICH IS PROPREVENTION OF E SENSE FOR MAC DEGENERATION WE UNDERTOOK IN THE INTRAMURAL PROGRAM HERE AT NIH. THE DISEASE STUDY. THIS WAS A CLINICAL TRIAL, FIRST IT STARTED OF AS A PROSPECTIVE NATURAL HISTORY DAY LOOKING AT MAC DEGENERATION AND CATARAT. WE OURSELVES ARE INTERESTED IN DOING SOMETHING RATHER THAN JUST OBSERVING PATIENTS. SO WE GOT TOGETHER A NUTRITIONAL GROUP AND DECIDED ON THIS PARTICULAR SUPPLEMENT WHICH IS VITAMIN C, E, BETA CAROTENE ZINC AND COPPER. THIS WAS WHERE ONE QUARTER GOT A PLACEBO ONE QUARTER GOT ZINC AND ONE QUARTER GOT A COMBINATION. THIS WAS DONE IN PATIENTS WHO HAD CATEGORY ONE NO MAC DEGENERATION. THESE ARE PATIENTS WHO ARE INTERESTED IN LOOKING AT WHAT HAPPENS WITH CATARACTS. WE HAVE PATIENTS WITHOUT DRUSEN. HERE IS VARYING DEGREES OF DRUSEN, LARGE DRUSEN, INTERMEDIATE SIZE AND ADVANCED DISEASE. AMD1I AND THIS IS DRUSEN IN THE OTHER EYE. GEOGRAPHIC ATROPHY IS THE DRY FORM. AND THE TREATMENT AT SEVEN YEARS SHOWED THAT THERE WAS -- SHOWED THE COMBINATION OF THE TWO BOTH THE ANTI-OXIDANTS AND THE VITAMINS AND THE ZINC WERE PROTECTIVE IN REDUCING THE RISK OF ADVANCED MAC DEGENERATION BY APPROXIMATELY 25%. IF THE VISION WAS ALSO SIMILAR. WE THEN FOLLOW THE PATIENTS AND STOP THE STUDY IN TERMS OF THE VITAMINS, SIX AND-A-HALF YEARS. AND IN FACT FOR THE NEXT TWO YEARS THE DRUG WAS NOT EVEN AVAILABLE. WE COULDN'T MAKE IT IN THE RIGHT WAY OR IT WAS DONE IN CANADA. WE COULDN'T GET IT INTO THE FDA SO WE WERE ACTUALLY WITHOUT DRUGS FOR TWO YEARS. AND THEN PATIENT WERE THEN GIVEN THE DRUGS THE REMAINING OF THE TEN YEARS. YOU CAN SEE EVEN WITHOUT HISTORY AND IT'S NO LONGER RANDOMIZED THAT THE GRIP IS NOW TAKING THE ANTI-OXIDANTS. THERE'S STILL A REDUCTION IN THE RISK OF ADVANCED MACRO DEGENERAL RACE IN THESE PATIENTS WHO ARE AT RISK. SO THE COMBINATION RULES THE RISK BY 34% ONLY DEVELOPED IT. AND 44% ACTUALLY IN THE PLACEBO GROUP DEVELOPED ADVANCED DISEASE. SO THERE WAS A REDUCTION BY ABOUT 27%. SO INTERESTINGLY, EVEN THOUGH THE STUDY HAD STOPPED, WE HAD DRUGS, WE HAD PLACEBO. WE STILL HAD A TREATMENT EFFECT. WHETHER THIS IS SIMILAR TO WHAT WE'VE SEEN WITH DIABETES WITH THE GLYCEMIC CONTROL YOU SEE, THE DIABETES CONTROL AND COMPILATIONS TRIAL, VERY TIGHT CONTROL FOR SIX YEARS. AND TEN YEARS LATER THEIR EYES STILL CONTINUE TO IMPROVE. THEY CALL IT MEMORY IMPRINT FOR WHATEVER THAT IS. I DON'T UNDERSTAND WHY THIS HAS OCCURRED IN THIS AS WELL. SIMILAR WE HAVE VISUAL ACUTEY CHANGES. PATIENTS WITH THE TREATMENT HAD REDUCTION IN VISUAL ACUTITY. WE RECOMMEND THEM TO TAKE THIS. THE IMPACT IS ONE AND-A-HALF OR 1.3 MILLION PEOPLE WHO DEVELOPS ADVANCED DISEASE IN THE NEXT FIVE YEARS WHICH YOU ACTUALLY GIVE THE TREATMENT OF 25% REDUCTION WOULD REDUCE BY 300,000 PEOPLE NOT GETTING THE VASCULAR DISEASE. IT'S A PUBLIC HEALTH ISSUE. WE LOOKED AT THE DIETARY QUESTIONNAIRE AND WE LOOKED AT PATIENTS WHO HAD DISEASE VERSUS THOSE WHO DIDN'T. SO THE CONTROL GROUP DID NOT HAVE MAC DEGENERATION OR THEY HAD LARGE DRUSEN OR GEOGRAPHIC -- WHAT WE FOUND -- NOT THE CARROTS BUT THE GREEN LEAFY VEGETABLES ARE BETTER FOR YOUR EYES -- IN TERMS OF FISH. IN OUR STUDY ANYTHING IN THIS SIDE IS PROTECTIVE SO THIS IS FOR LUETIN, THE HIGHEST INTAKE OF LUETIN. THERE'S AMD ATROPHY, EVEN LARGE DRUSEN. AND FOR HIGH INTAKE OF THE LIPIDS, YOU CAN SEE THAT PATIENTS AHEAD OF REDUCTION IN THE VASCULAR AMD. PEOPLE WHO TOOK THE HIGHEST -- THAT IS THE PATIENTS WHO ARE TAKING ON A LOT OF RED MEAT. THERE WAS AN INCREASED RISK OF A.M. D AND GEOGRAPHIC ATROPHY WAS ALSO PROTECTED BY THE HIGHEST INTAKE OF OMEGA 3. THEN WE HAVE -- WE HOPE TO HAVE THE RESULTS OUT SOON. TEN MILLIGRAMS OF LUETIN AND -- IN 80 CLINICS. AND AGAIN WE HAVE PATIENTS WHO ARE AT RISK. THESE ARE PATIENTS WITH A LARGE DRUSEN OR ADVANCED DISEASE IN ONE EYE. AGAIN IT'S A FACTORIAL DESIGN. PATIENTS WE CALL IT THE -- THEY'RE AT RISK AND WE NEED TO GIVE THEM ACRED SUPPLEMENT. WE WANT LUETIN -- OR COMBINATION VERSIONS THE CONTROL OR THE PLACEBO IN THAT CASE. WE WERE INTERESTED IN PATIENTS AT RISK REDUCE BETA CAROTENE BECAUSE BETA CAROTENE INCREASES THE RISK OF LUNG CANCER IN PATIENTS. WE'RE ALSO LOOKING AT LOWERING THE DOSES OF, INC. -- EVERYBODY'S IN THIS ONE. WE ASKED THEM WHAT WOULD THEY PREFER. A QUARTER OF THEM WANTED TO TAKE THEIR VITAMINS AND THE MINERALS SO THEY STUCK WITH IT AND RANDOMIZED. THAT COULD BE WOMEN MORE EDUCATED PEOPLE ARE IN THIS PARTICULAR GROUP WHEREAS THIS GROUP PATIENTS WHO SAY FINE I'M HAPPY TO BE RANDOMIZED. AND THEY MAY PARTICIPATE IN THE SECOND RANDOMIZATION. WE LOOKED AT PROGRESSIONS IN MAC DEGENERATION AND VISION LOSS IN CATARAT SURGERY. WE ALSO LOOK AT CARDIOVASCULAR DISEASE WHICH IS ALSO IMPORTANT. I THINK THE IMPORTANT ASPECT THAT WE HAVE A LOT OF STUDIES BUT WE'RE VERY GRATEFUL WE'RE ABLE TO DO A GENETIC STUDY AND WE HOPE TO GET MORE INFORMATION ON THAT. SINCE I THINK THIS WILL BE A VERY IMPORTANT ASPECT. AND IN 2005, WE WERE VERY FORTUNATE IN THE STUDY WHICH TOOK 150 PATIENTS. WE TOOK A G WAS LOW HANGING FRUIT FACTOR WAS AN AGE. NOT ONLY DID WE FIND IT BUT FOUR OTHER GROUPS WERE RIGHT ON THE MARK. SINCE THEN THERE'S BEEN A NUMBER OF GENES THAT HAVE BEEN ASSOCIATED, PROBABLY ONE OF THE BEST GENETICALLY CHARACTERIZED GENETIC COMPLEX TRAITS IN MEDICINE. A COMPLEMENT PATHWAY WITH THE CHOLESTEROL METABOLISM -- ANTIGENSUS PATHWAYS AS WELL. IT HAS A HIGH EFFECT IN PATIENTS WHO HAVE MAC DEGENERATION. A LARGE NUMBER WILL HAVE THE POSITIVE FACTOR H AND THE CHROMOSOME TEN, HETERO ONE. THERE'S THE MORE RARE VARIANCE WE NEED TO LOOK AT. AND THERE'S SOME RARE VARIANCE THAT WE DISCOVER NOW. SO THE STORY IS NOT IN YET COMPLETELY. THERE'S STILL A LOT OF THINGS TO LEARN. WE HAVE 19 LOCI, HOW DO THEY ACTUALLY ARE IN THE CAUSAL PATHWAY. WE ACTUALLY GOT THE GENES. WE GOT THE -- ARE INVOLVED, DO WE ACTUALLY KNOW WHAT THEY REALLY MEAN. SO THERE'S A LOT WE LEARN FROM THIS. I THINK WE'RE VERY FORTUNATE WE'RE HAD ALL THIS AND I WOULD LIKE TO THANK MY COLLEAGUES FROM THE CORNING CENTER WHO HELPED US WITH THE STUDIES MY COLLEAGUES AT NEI, DR. -- FOR HIS SUPPORT AND THE RESEARCH TEAMS AND PHYSICIANS. AGAIN THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> MY QUESTION IS ABOUT THE -- JUST TO CLARIFY YOU SAID THE -- IS PART OF THE BROADER MOLECULE -- SO THEY'RE NOT EQUIVALENT, RIGHT. >> THEY'RE NOT EQUIVALENT. >> YOU ALSO MENTIONED THE BIG -- AND THERE WAS A BIG TRIAL, RIGHT. >> ONE TRIAL WAS DONE, I DIDN HAVE TE TO TALK ABOUT THE CAT STUDY WHICH SHOWED THEY REALLY WERE VERY SIMILAR IN TERMS OF THEY DID IT JUST WHENEVER THEY NEEDED. THEY BOTH HAD VERY SIMILAR VISION IMPROVEMENTS. THERE WAS REALLY NO DIFFERENCE BETWEEN THE TWO OF THEM. AND THE COST DIFFERENTIAL IS HUGE, YOU KNOW. THEY SPENT A LOT OF MONEY DEVELOPING THIS DRUG AND THEY FELT LIKE -- EXPENSIVE SO IT'S $2000 FOR THE -- AND FOR -- IT COULD BE IN THE NEIGHBORHOOD OF $50 A SHOT. OF COURSE THERE ARE A NUMBER OF OTHER ISSUES ASSOCIATED WITH THAT. THE COMPOUNDING PHARMACIES, YOU'VE HEARD A LOT ABOUT MENINGITIS AND ALL THOSE OTHER THINGS. AND WE'VE HAD LOTS OF PROBLEMS WITH COMPOUNDING -- CAUSING INFECTIONS IN THE EYE BECAUSE OF THE FACT THAT THIS IS DONE IN SUCH A MANNER. SO THEY ARE PROTEIN FOR EVERYTHING. IN CERTAIN COUNTRIES LIKE ENGLAND THEY DECIDE LUSENTA IS THE ONLY THING PROVEN AND WILL ONLY USE IT IN ENGLAND. HERE IN THE U.S. I THINK IT'S MORE IN USE -- THAT'S BEING AT LEAST 60% ARE AVASTEN. THERE ARE PEOPLE WHO FEEL STRONGLY -- THAT'S AN INTERESTING STORY BECAUSE I THINK, IT'S THE SAME COMPANY THAT ACTUALLY MAKE BOTH DRUGS. AND OBVIOUSLY YOU KNOW WHAT SIDE THEY WOULD BE ON. THEY WOU LIKE TO PROMOTE WHAT THEY THINK IS IMPORTANT. SO IT IS AN INTERESTING STORY. >> IN YOUR VIEW THE CAT TRIAL DID HAVE AN EFFECT ON CLINICAL PRACTICE. >> WELL THAT'S A GOOD QUESTION. DID THE CAT TRIAL ACTUALLY HAVE AN ACTUAL CHANGE. YOU WOULD THINK PEOPLE WOULD LOOK AT IT AND SAY AVASTEN IS JUST AS GOOD S LIEU SENT TICE, MAYBE I SHOULD SWITCH OVER. AS DAN MARTIN SAY IT LOOKS GOOD I'LL STICK -- I DON'T THINK IT'S CHANGED DRAMATICALLY BUT I DON'T THINK WE HAVE A GOOD WAY OF ACTUALLY MONITORING THAT. WE HAVE A VERY CRUDE WAY WHERE WE DO A SURVEY THROUGH A COUPLE OF THE SOCIETIES. AND IT REALLY HASN'T CHANGED DRAMATICALLY. AVASTEN IS STILL A MORE PREFERRED USE AT LEAST IN THE RETINAL SOCIETY THAT WE'VE LOOKED AT. I DON'T KNO OTHER PEOPLE WERE ACTUALLY -- ALSO I THINK IT WAS IMPORTANT, OTHER COUNTRIES HAVE DONE -- PRETTY GOOD IN LEAGUE SHOWING VERY GOOD RESULTS. IN VIENNA OR RATHER IN AUSTRIA. ALSO VERY SIMILAR SO I THINK IT'S THE SAME STORY OVER AND OVER AGAIN. IT DEPENDS ON AGAIN THE GOVERNMENT'S PHILOSOPHY, AS I SAID IN ENGLAND, THEY WERE I THINK THEY GOT SOCIALIZED MEDICINE. BUT YET THEY ARE GIVING THEM THE PRIMITIVE CROP THERE. THERE'S A QUESTION BACK HERE. >> WOULD YOU PLEASE EXPLAIN THE DIFFERENCE BETWEEN WET AND DRY MACULAR DEGENERATION, THE FREQUENCY OF BOTH AND PREVALENCE OF BOTH RATHER. CAN ONE CROSS OVER INTO THE OTHER. >> THAT'S A VERY GOOD QUESTION. SO DRY IS A VERY FUNNY TERM. WE'RE TRYING TO NOT USE IT QUITE AS MUCH BUT DRY MEANS THAT THERE'S A LACK OF NEW BLOOD VESSELS. IT'S WHAT MOST PEOPLE TRY TO REFER TO IT. BUT DRY COULD MEAN A NUMBER OF THINGS. IF YOU HAVE DRUSEN WHICH ARE THE EARLY STAGES, YOU CAN ALSO REFER TO THAT AS DRY. AND SOMETIMES PATIENTS HAVE ABSOLUTELY NO SYMPTOMS AT ALL. BUT AS THEY PROGRESS, THEY HAVE THIS ATROPHY AND EVENTUALLY LOSE SOMING VISION CENTRALLY. STILL CALLED DRY BUT WHAT WE LIKE TO SAY THIS IS CENTRAL, GEOGRAPHIC ATROPHY AFFECTING THE CENTER SO THAT MEANS IT'S GOING TO CAUSE VISION LOSS. AND YES, THEY CAN BOTH OCCUR. WHEN WE LOOK AT THE DATA WHICH IS A LONG TERM TENURE FOLLOW UP, 40% OF FAKERS WHO -- PATIENTS WHO HAVE DRY TYPE -- YOU CAN HAVE IT IN THE ONE EYE AND THE OTHER EYE IS DRY SO YOU CAN ACTUALLY HAVE BOTH. I THINK THE UNDERLYING DISEASE OF MAC DEGENERATION IS THE ATROPHY. A LOSS OF THE PHOTO RECEPTORS THESE RELENTLESS NO MATTER WHAT YOU DO UNTIL WE FIND SOMETHING THAT WILL HELP THE DEGENERATION WHAT THAT REALLY IS WE REALLY CAN'T TREAT MAC DEGENERATION. WE HAVE A STOP GAP OF TREATING THE NEW VASCULAR PART BUT THE DRY TYPE OR THE ACTUAL YOU KNOW ONGOING NEEDS MORE THERAPY. >> WITH ALL OF THE OXIDANTS THAT ARE PART OF THE THERAPEUTIC REGIMEN, ARE THERE DIFFERENCES IN EITHER THEIR PHARMACOLOGY OR THEIR DISTRIBUTION. WHY IS THERE A COLLECTION OF ANTI-OXIDANTS RATHER THAN ONE. AND WHAT IS THE MAGIC OF LUETIN FOR EXAMPLE. >> I GET ASKED THAT QUESTION ALL THE TIME BY PATIENTS AND CLINICIANS. THE ONLY PROVEN FORMULATION IS THE -- FORMULATION WHICH IS THE DRUG WE TALKED ABOUT WITH ANTI-OXIDANTS AND SPECIFIC AMOUNT OF VITAMINS AND ZINC. IT'S ALL OBSERVATIONAL THAT LUETIN MIGHT BE GOOD. WE DON'T KNOW THAT UNTIL WE'VE DONE OUR STUDY. BUT PEOPLE HAVE JUMPED ON TO THE BAND WAGON, NOT BECAUSE THEY HAVE DONE IT BUT THE DRUG COMPANIES HAVE REALLY PROMOTED IT. SO THEY'VE ALREADY MADE AN ERROR IN FORMULATION, WE HAVEN'T FINISHED OUR STUDY THEY MADE IT ALREADY IT'S OUT IN THE MARKET. IT'S ALSO VERY CONFUSING. THERE'S THE INTEREST IN LUETIN. THEY PUT LUETIN IN VARIOUS LITTLE THINGS. BUT LUETIN'S VERY EXPENSIVE AND THIS IS NOT A REGULATED INDUSTRY. WE ACTUALLY HAD THE OPPORTUNITY TO TEST SOME OF THESE, BUT THINGS WE'VE TESTED SOME ARE RIGHT ON THE MONEY BUT SOME COULD BE AS MUCH AS, IT SAYS 20 MILIGRAMS OF LUETIN. IT HAS .2 MILLIGRAMS OF LIEU -- LUETIN. THEY THEMSELVES HAVE CREATED A MAJOR HEADACHE BY CREATING THESE DIFFERENT TYPE OF THINGS. ONE'S FORSMOKS, ONE IS FOR LUETIN AND THIS IS FOR EYE HEALTH, THEY THEY ARE IT'S FOR PEOPLE WITH OFFSPRING. THE ANTI-OXIDANTS AND THE ZINC MADE NO DIFFERENCE SO WE COULDN'T PREVENT IT FROM PROGRESSING FROM AN EARLY STAGE. SO THERE'S RELY NO PREVENTIVE THERAPY THAT WE HAVE. SO I THINK THE ONLY GOOD THING ARE PEOPLE WHO HAVE LARGE DRUSEN WHO ARE AT A CERTAIN STAGE OR ADVANCED DISEASE IN ONE EYE THEY SHOULD TAKE IT. AND MOSTLY FROM PREVENTION AMD RATHER THAN GEOGRAPHIC ATROPHY. >> DO YOU DO SCREENING POPULATIONS NOW FOR RIGHT IN THE CONTROL GROUP, IS IT OF VALUE TO KNOW WHETHER THEY HAVE DIFFERENT GENE PATTERNS OF SUSCEPTIBILITY. HOW DO YOU DIVIDE THEM OUT. >> WE'RE VERY FORTUNATE IN ERROR ONE WE DID A LARGE GENETIC STUDY AND THAT'S HELPED US A LOT IN SOME OF THE STUDIES WE'VE DONE. WE HAVE A DNA COLLECTED ON THE PATIENT. SO THE -- HAVE CONTROL SO WE'VE BEEN LOOKING AT THEM. THERE'S STILL LOTS TO LEARN. WE STILL HAVEN'T FINISHED AND WE DO HAVE OTHER STUDIES POPULATION BASE STUDIES THAT I FOLLOW FOR A LONG TIME. LIKE BEAVER M A THE BLUE MOUNTAINS. WE HAVE MATERIAL AND FOLLOW THROUGH AND WE'VE SEEN THESE PATIENTS OVER 20 YEARS. THERE'S VERY VALUABLE DNA WE CAN LOOK AT. IF IT'S ONLY YOU LOOKING AT CASES AND CONTROLS. BUT WE HAVEN'T LOOKED AT OTHER THINGS THAT MIGHT BE VERY IMPORTANT THAT WE NEED TO DO SOME MORE WORK ON. >> THE OTHER THING I WONDERED ABOUT IS WHAT IS THAT DATE FROM CHINA IS IT REALLY CHEW THE INCIDENCE IS SO LOW AND IT'S NOT INCREASING. >> I THINK IN CHINA THEY HAVE SOME POPULATION-BASE STUDIES BUT THEY'RE NOT AS BIG AS THE ONES HERE AND THEY HAVEN'T FOLLOWED THEM. I DON'T KNOW IF WE KNOW THAT FOR SURE. THEY DO HAVE MAC DEGENERATION IN CHINA, THEY ABSOLUTELY DO HAVE THAT. WE SEE CASES SOCIETAL PREVALENCE MIGHT NOT BE AS RIGOROUSLY EVALUATED. >> -- REGARDING THE SUPPLEMENTS. WHEN WE HEAR ABOUT THESE STUDIES AND WE FOLLOW SELF PRESCRIBED -- SO YOU HAVE ZINC 80 MILLIGRAMS. SO I USUALLY TAKE ONE ZINC 20 MILLIGRAMS THE OTHER DAY. AND OF COURSE I ALSO TAKE LIKE VITAMIN SEE. >> VITAMIN C HALF A GRAM DAILY. WE NEVER TESTED, WE COULDN'T TEASE IT OUT WE JUST TESTED AS A QUOTIENT TOGETHER. I DON'T THINK WE'LL EVER HAVE THAT OPPORTUNITY BECAUSE IT'S BECOME A STANDARD OF CARE. >> THE LUETIN IS 20 MILLIGRAM IN YOUR STUDY. >> 10 MILLIGRAMS. >> BECAUSE WHEN I WAS IN THE LAST YEAR EY HAVE THIS CAPSULES AVAILABLE PROVIDED BY -- THEY ALSO HAVE THIS COMBINATION -- WITH LUETIN AND I THINK -- SO I GUESS ONCE IN A WHILE I THINK THAT BECAUSE I'M THE DIABETIC GROUP, THINKING ABOUT THE -- I THOUGHT THAT BY TAKING EVEN A SMALL AMOUNT, IS IT BENEFICIAL BY TAKING A SMALL AMOUNT. >> WE DIDN'T TEST IN DIABETICS SO I REALLY DON'T KNOW, YOU KNOW. THERE'S THEORETICAL ASPECTS TO THAT. WE DON'T REALLY HAVE ANY ANSWERS TO THAT. >> THANK YOU. PAUL, DO YOU WANT TO CONTINUE? >> THANK YOU FOR THE INVITATION TO SPEAK FOR A FEW MINUTES. THE ANSWER TO YOUR QUESTION ABOUT THE BROOKLYN BRIDGE, THAT IS THAT IT REFLECTS AN ULTIMATE STANDARD IN THE ENGINEERING AND THE EYE ALSO REFLECTS AN ULTIMATE ADVANCE IN ENGINEERING. I WANT TO TURN ATTENTI FOR A FEW MEMBERS TO GENETICS, GENOMICS AND PATHOPHYSIOLOGY OF EYE DISEASE. I THINK ALL OF US KNOW THAT EYE CARE IS A BURDEN. WE WANT TO HAVE GOOD VISION. FORTUNATELY MOST PEOPLE DO. BUT UNFORTUNATELY THERE ARE SOME NEARLY 40 MILLION CURRENT PEOPLE IN THE UNITED STATES WHO SUFFER FROM VISION IMPAIRMENT IN SOME FORM AND THIS ADDS UP TO A SUBSTANTIAL COST TO THE COUNTRY, $60 BILLION CURRENTLY. AND SINCE EACH OF US TO MY KNOWLEDGE HAVE A BIRTHDAY ONCE A YEAR, THE POPULATION IS AGING AND THESE PROBLEMS WILL BE BECOMING MORE SEVERE AND MORE COMMON IN THE YEARS AHEAD. HERE'S AN INTERESTING FACT AND THAT IS THAT MANY OF THE DISEASE THAT WE TREAT IN THE EYE CLINICS HAVE A GENETIC BASIS. SOME OF THESE ARE QUITE OVERT. IN FACT ALL OF THESE CONDITIONS SHOWN HERE, THESE SIX CONDITIONS HAVE KNOWN GENETIC FACTORS. CATARACTS. LET'S SEE, WHERE IS THE POINTER ON THIS. SO HERE'S THE CATARAT AND YOU CAN SAY THE CLOUDING OF THE LENS. OBVIOUSLY THE CALCULATOR OF A CAMERA THE PICTURE IN THE CAMERA IS NOT GOING TO BE VERY GOOD IF YOU TAKE IT TO A CLOUDY LENS. OOPS. THIS CHILD IS NOT EXACTLY LOOKING STRAIGHT AT YOU. THE MUSCLES THAT MOVE THE EYE THOSE ARE UNDER GENETIC CONTROL. THE SMALL DEFECT WHERE THE IRIS IS INSERTED THAT OFTEN LEADS TO GLYCOMA. THIS IS A YOUNGER PERSON WHO HAS LOST AND IS LOSING CENTRAL VISION. THOSE ARE THE DISEASES OBVIOUSLY BECAUSE WE HAVE GENES IN BOTTLES ON LABORATORY SHELVES THAT CAUSE THESE PROBLEMS. THE GENETIC ERA REALLY STARTED IN THE 1980'S. AT THAT POINT THERE WERE FEW GENES KNOWN AND NOW YOU CAN APPRECIATE BY 2007, 8, 9 AND 10, 2010, THERE ARE 170 GENES KNOWN TO CAUSE RETINA DISEASE. THE 120 OR 30 GENES CAUSING CLOUDING OF THE LENS AND THE CORNEA IS ALSO IS UNDER DURESS. WE HAVE MORE GENES IN OPHTHALMOLOGY AND VISION DISORDERS THAN ONE CAN SHAKE A STICK AT. IN FACT ABOUT ONE IN FIVE KNOWN HUMAN DISEASED GENES THAT ARE CLONED INVOLVE THE EYE. IN FACT THE KNOWLEDGE OF GENES AND GENETICS HAS BECOME OVERWHELMING. I USE TO IN THE 1909 KNOW MANY OF -- 1990 I KNEW MANY OF THESE. YOU GET TO MAKE SENSE OF THEM BECAUSE THEY COME IN FAMILIES AND PACKAGES. HERE IS PHOTO TRANSDEDUCTION GENES, INCLUDING ONE OF MY FAVORITES ROW OR ROW DOBSON THE LIGHT SENSITIVE MOLECULE OF THE EYE. AND MUTATIONS IN THOSE GREENS CALLED -- THIS IS A MACULAR DEGENERATION CONGENITAL STATIONARY NIGHT BLINDNESS ETCETERA ETCETERA. GENES THAT CYCLE THE VITAMIN IN THE EYE. I'LL SPEAK OF ONE, ABCA4 AND SHOW YOU GENE THERAPY FOR RPE65. PUT A LENS ON THE PIGMENT EPITHELIUM. YOU CAN GO ON AND ON. YOU CAN SEE THAT WHEN YOU HAVE A LOT OF GENES AND YOU KNOW SOMETHING ABOUT THEIR FUNCTION, YOU CAN BEGIN TO PUT THEM IN CATEGORIES OF THE PROBLEMS THEY ARE CAUSING. SO WE'VE GOT A LOT OF GENES AND WE STILL HAVE MANY MORE TO COME. OPHTHALMOLOGY LIKE ALL OF MEDICINE IS EMPLOYING THE NEWEST TECHNOLOGIES AND HERE IN THIS CASE, THIS FAMILY, THE LID SKI FAMILY. I THINK SEVERAL PEOPLE IN THE AUDIENCE KNOW THEM. THEY'RE CERTAINLY FRIENDS OF MINE. THEY LIVE IN MIAMI. THEY WERE LOOKING FOR THEIR GENE FOR 20 YEARS UNTIL FINALLY PUBLISHED IN SCIENCE IN 2010 USING WHOLE EXOME SEQUENCING, A DHDDS GENE WAS FOUND. I DON'T KNOW WHAT DHDDS MEANS BUT WHAT IT DOES IS TO PUT A SUGAR MOLECULE ON THE ROW DOBSON MOLECULE AND MAKE IT FUNCTION. IF THE GENE IS NOT PRESENT, IF THE ENZYME IS NOT THERE, ONE WILL BE BLIND BECAUSE THE ROW DOBSON MOLECULE IS NOT WORKING. NOW ALL OF IF I THINK ALL OF US IN THE ROOM RECOGNIZE THAT IS ADDING UP TO THE GENOMIC ERA OF MEDICINE. CURRENTLY THERE ARE MANY PEOPLE HERE COMING ON TO THIS CAMPUS NIH WHO ARE DIAGNOSED BY GENETICS. AND WITHIN 50 YEARS, IT WILL BE STANDARD. YOU WALK IN, YOU HAVE A PROBLEM. MAYBE FIRST TIME IN YOUR LIFE THE GENE SCAN IS DONE AND A DIAGNOSIS WILL BE MADE. WE ARE REALLY MOVING FORWARD QUICKLY. IN MEDICINE. I WOULD LIKE TO TURN NOW TO A CASE. LET'S TALK ABOUT WHAT THE GENE DOES. I'M GOING TO BE INTRODUCING THE TERM RENT INDEMNIFY TICE PIGMENT TOE SAW. RENT INDEMNIFY TICE -- HERE YOU CAN SEE PIGMENT, THE BLACKISH SPECS OF PIGMENT IMBEDDED IN THE RETINA. THEY SHOULDN'T BE THERE. EMILY HAS SHOWN YOU A NICE PRISTINE RETINA AND THIS PIGMENT IS THERE BECAUSE OF INJURY TO THE UNDERLYING CELLS OF THE EYE. THEY HAVE THE CURIOUS TERM BONE SPECKULE. SOMEONE LOOKED AT THE EYE AND SAID THESE PIGMENT GRANULES LOOK LIKE BONE-IN STRUCTURES. THEY'RE NOT. BUT THIS IS THE ARCHAIC LANGUAGE WE DEAL WITH. NOW WE DEAL INSTEAD WITH THE LANGUAGE OVER MODERN BIOLOGY WHICH IS THIS IS A PATIENT WHO IS GOING BLIND FROM A MUTATION IN THE PROTEIN ROW DOBSON. AND IT'S A SPECIFIC MUTATION P25H. A PROTEIN IS THE NORMAL AMINO ACID AND UNFORTUNATELY THIS WOMAN HAS A HISTIDINE INSTEAD. NOW JUST TO PUT THIS IN REFERENCE, WE ARE LOOKING AT THE BACK OF THE EYE. THAT CAMERA WAS TAKING A PICTURE FROM THE FRONT OF THE EYE, TAKING A PICTURE HERE OF THE BACK OF THE EYE. THE MACULA, THE FOVEA, THE BLOOD VESSELS, THE OPTIC NERVE. BUT I RIGHT NOW FOR A FEW MINUTES WANT TO FOCUS ON THE STRUCTURE OF THE RETINA, RIGHT HERE. HERE'S A FIRST EXPANDED VIEW IN THE MIDDLE AND A SECOND EXPANDED VIEW ON YOUR RIGHT SIDE. WHEN YOU LOOK AT THE INTRAINDICATE SEE ALL OF THESE ARE DIFFERENT TYPES OF NEURO PROCESSING. THEY SEND A SIGNAL THEN THROUGH THE OPTIC NERVE TO THE BRAIN THAT'S A PRETTY PICTURE. THAT STARTS WITH THE LIGHT ACTIVATING THE RODS AND CONES PHOTORECEPTORS. LET'S RETURN TO THE THE PATIENT THAT I -- BEFORE SHE DIED. SHE HAD MANY RELATIVES MEN AND WOMAN. THIS IS FOR THE YOUNG PEOPLE OR ALLLY THE OLD PEOPLE. IF MEN ARE INFECTED AND WOMEN ARE INFECTED AND MULTIPLE GENERATIONS, IT SPEAKS OF AN AUTOSOMAL DOMINANT PROBLEM WHICH MEANS HER CHILDREN ARE AT 50% RISK. ACUITY 20/60. COULD SHE DRIVE? SHE CAN GET A DRIVERS LICENSE. SHOULD SHE DRIVE? I SURE HOPE NOT BUT SHE HAS NO PERIPHERAL VISION. SHE'S HAD A NUMBER OF AUTOMOBILE ACCIDENTS PEOPLE COMING FROM THE SIDE, SHE DOESN'T SEE THEM. AND HAD THEY HIT HER AND SHE HITS OTHER PEOPLE. ONE OF THE PIGMENT IS NIGHT BLIND WAS OF THE PHOTORECEPTOR CELLS ARE LYING AND THE PHOTO RETINA GRAM IS A FANCY TOO MANY TO MONITOR WHAT IS HAPPENING TO THE EYE. LET'S TAKE ANOTHER LOOK AT HER RETINA. AND YOU CAN SEE THAT ALL OF THIS IS DEGENERATED IN THE PERIPHERY. SHE HAS LOST HER PERIPHERAL VISION, AND PERHAPS YOU CAN IMAGINE THAT HERE IN THE CENTER, THE NERVE TISSUE LOOKS FAIRLY IN TACT. AND IN FACT IT IS, WHICH GIVES HER A CENTRAL TUNNEL OF VISION. HERE IS HER VISUAL FIELD, YOUR FIELD BY COMPARISON WOULD BE OUT 90 DEGREES TO EACH SIDE. 180 DEGREES OF FIELD. SHE'S JUST LOOKING THROUGH THE CENTRAL SPOTLIGHT. INSTEAD OF HER SEEING THE MARCHING BAND, SHE JUST SEES RIGHT DOWN THE CENTRAL TUNNEL OF VISION. THIS IS NOT HER EYE I'LL SHOW YOU THAT IN THE NEXT SLIDE, BUT IF ONE TAKES A HUMAN RETINA, DIE -- DISSECT IT EACH EYE HAS 120 MILLION OF THESE CELLS. THEY'RE GOING TO GIVE YOU VISION TONIGHT WHEN THE MOON IS OUT. WE HOPE THE MOON IS OUT. THESE CELLS, EACH CELL, PICK A CELL, ONE CELL HAS 100 MILLION ROW DOBSON MOLECULES IN IT. THOSE ROW DOBSON MOLECULES ARE WAITING FOR LIGHT TO COME AND ACTIVATE THE CELL AND TO STIMULATE THE CASCADE OF VISION. THEY'RE SINGLE PHOTON DETECTORS WHICH IS WHY THE DISCUSSION BEFORE ABOUT THE SIGNAL PROCESSING AT THE BIOLOGIC BEST. BEATS THE PHONE COMPANY. BEATS CELL PHONES. AND THEN THERE ARE CONE PHOTORECEPTORS, THEY SEE IN COLOR, RED, BLUE AND GREEN. THEY'RE NOT NEARLY AS MANY, ONLY 6 MILLION OF THOSE, BUT THEY'RE CONCENTRATED RIGHT IN THE CENTER OF VISION SO THAT I CAN LOOK AT YOU WITH HIGH PRECISION OR YOU CAN READ A BOOK WITH HIGH PRECISION. NOW, LET'S LOOK AT THIS WOMAN. SHE WAS GENEROUS WITH HER DONATION. 20/60 VISION, REMEMBER. AND A SLICE, A HISTOLOGY SLICE RIGHT THROUGH THE CENTER OF VISION IS THIS. THIS IS HER PICTURE, COMPARED TO SOMEONE WHO DOES NOT HAVE THE DISEASE, AND I'VE DRAWN OUT THE ROD, ACTUALLY THIS IS IN THE FOVEA. THIS IS THE CONE. HERE IS THE LIGHT SENSITIVE PART OF THE CONE CELL. THE CENTER SEGMENT, METABOLIC ACTIVITY, THE LIGHT SENSITIVE SECTION AND EACH OF THESE IS CONNECTED WITH THE NUCLEUS SO IT CAN FUNCTION. BY COMPARISON, SHE HAS VERY FEW OF THOSE. SHE'S LOST 60% OF THEM NOMINALLY. AND INSTEAD OF THIS ELEGANT LONG STRUCTURE, LOOK WHAT'S LEFT. IT'S A NUB AND IT'S ALL CHEWED UP. WHAT I FIND REMARKABLE IS SHE STILL HAS 20/60 ACUITY. SO YOU CAN IMAGINE THAT IF YOU COULD SIMPLY SAVE A FEW OF THESE CONE CELLS, SHE'D BE VERY HAPPY. AND THAT IN FACT IS THE CHALLENGE GOING FORWARD FOR ONE OF THE CHALLENGES FOR VISION. BUT JUST TO COMPLETE THE PICTURE, LET'S LOOK IN THE PERIPHERY WHERE THERE IS THE PIGMENT ACCUMULATION. HERE YOU CAN SEE THE PIGMENT. IT'S SCATTERED AROUND. YOU DIDN'T SEE IT IN THE PREVIOUS SLIDE. THIS IS ABNORMAL INJURY PIGMENT. AND FURTHER, THERE ARE NO RODS AND CONE LEFT. SHE IS TOTALLY BLIND IN THE PERIPHERY AND EVEN THE SIGNAL PROCESSING NEURONS IN THE PROXIMAL RETINA ARE ALL SCRAMBLED AS THOUGH YOU HAD TAKEN AN EGG BEATER AND JUST RANDOMLY SCATTERED THEM AROUND. IT'S VERY UNLIKELY THAT YOU CAN DO ANYTHING TO PRESERVE OR EVEN RESTORE THIS PERIPHERAL VISION AT LEAST IN THE NEAR FUTURE. SO THAT'S THE PROBLEM WE ARE FACING. WE ARE FACING MANY DIFFERENT KINDS OF GENES THAT CAUSE DEATH OF ROD PHOTO RECEPTORS. I MENTIONED ONE. OR CONE PHOTORECEPTORS. THERE'S PROBABLY SOME POOR MAN IN THE AUDIENCE WHO DOESN'T HAVE NORMAL RED OR GREEN VISION BECAUSE ABOUT FIVE OF US POOR MEN SUFFERED FROM THAT. WOMEN DON'T. COURTESY OF WOMEN HAVE TWO X CHROMOSOMES AND TWO CHANCES TO HAVE COLOR VISION. WE ONLY HAVE ONE X CHROMOSOME AND WE'RE VULNERABLE. MACULAR, STAR GOT MACULAR DEGENERATION. AND THEN THERE ARE CASES, MANY CASES IN WHICH IT'S THE VISION PLUS OTHER ORGAN SYSTEMS. VISION AND HEARING, DEAF BLINDNESS IS USHER. OCULAR CUTANEOUS ALBINISM, THE PERSON ON THE STREET WHO IS 20 YEARS OLD WITH WHITE HAIR. AND DOESN'T HAVE PIGMENT IN THE HAIR OR SKIN OR BACK OF THE EYE WHERE THERE SHOULD BE PIGMENTED OR A MITOCHONDRIAL PROBLEM THAT CAUSES CARDIUM MYOPATHY AND RETINOPATHY. SO THE BASKET OF EYE DISEASES IS VERY BIG AND INCREASINGLY UNDERSTOOD NOW AT A GENETIC LEVEL. LET ME TURN ATTENTION FIRST TO GENE THERAPY. THERE ARE MANY WAYS YOU CAN DO IT BUT I WANT TO IN JUST THE NEXT FEW MINUTES TALK ABOUT GENE REPLACEMENT. IF THE GENE IS DEFECTIVE, IT MAKES A-OOPS. I HOPE IT COMES BACK. CHECK THE CABLE, WE'LL SEE. NO. IT'S ONLY HERE, SORRY. I WAS COMMENTING MY MONITOR JUST WENT BLANK. SO WE'RE GOING TO TURN ATTENTION TO THE RPE65. I'VE GOT TO PUT THIS IN CONTEXT. THANK YOU. THIS IS CALLED LABOR CONGENITAL AM ROSES. LABOR, DR. THEODORE LABOR, ABOUT, HERE IT IS. HE LIVED -- CONGENITAL MEANS FROM BIRTH. AND THIS MEANS NO VISION. THESE ARE CHILDREN BORN BLIND. THEY HAVE SOME CHARACTERISTIC FEATURES BUT ONE OF THE CHARACTERISTICS IS THERE'S NOT MUCH TO SEE IN THE EYE. IT LOOKS PRETTY GOOD DESPITE THE FACT THAT THEY ARE NOT SEEING. THIS IS WHAT I SAW WHEN I WAS TRAINING AS A RESIDENT 30 YEARS AGO. NOW, THIS IS WHAT THE NEW RESIDENCE LOOK AT. THEY SAY OH LABOR CONGENITAL AMAUROSIS. TELL ME WHICH OF THE 15 GENES YOU HAVE. AND WE CAN TEST THESE VERY READILY. AND THE GENES HERE ARE THE ROD PHOTO RECEPTOR AND THE CONE PHOTORECEPTOR AND THE RETINAL PIGMENT EPITHELIUM. THE GENES ALL SERVE SOME PARTICULAR FUNCTION RIGHT BACK AT THE ROD AND THE CONE AND THE PIGMENT EPITHELIUM LEVEL. THE GENE THAT WE'RE GOING TO TALK ABOUT IS RPE65. 65 IS THE WEIGHT, RPE IS THE CELL IT'S IN. IT KIND OF MAKES SENSE. YOU'RE GOING TO CALL IT THE CELL AND THE PROTEIN RP65. IT TURNS OUT TO BE AN EYESOME RAISE, AN ENZYME THAT TAKES VITAMIN A AND TWISTS IT AROUND SO IT'S THE RIGHT SHAPE TO BE LIGHT SENSITIVE. WELL, THIS IS AN NIH AND NEI SUCCESS STORY. MIKE REDMAN LOOKING RIGHT ACROSS THE MARKING LOT IN BUILDING SIX. IN 1993, CLONED A NEW GENE. NOW CLONING A GENE 1993, THAT WAS A REAL ACCOMPLISHMENT. IT STILL IS, BUT MUCH EASIER NOW. AND THAT GENE WAS EXTREMELY ABUNDANT IN THE RETINAL PIGMENT EPITHELIUM CELLS OR THE BACK OF THE EYE. IT TURNED OUT TO BE ABUNDANT BECAUSE IT WAS SO CRITICAL FOR THE VITAMIN A CYCLINE THROUGH THE PIGMENT EPITHELIUM. HE MADE A KNOCKOUT MOUSE IN 1998, THE MOUSE WAS BLIND. A DOG WAS FOUND. THE SWEDISH DOG, TURNS OUT TO HAVE AN INBRED GENE. IT WAS THE ANIMAL WITH THE LARGE EYE THAT PROVIDED AN OPPORTUNITY TO DO GENE THERAPY. THAT GENE THERAPY WAS DONE IN 2001 ON THE DOG. AND JUST FOR REFERENCE HERE, TAKE A LOOK AT WHAT THAT GENE THERAPY ACCOMPLISHED. IN THE MIDDLE IS THE DOG BEFORE GENE THERAPY, AND THESE ARE FLAT RESPONSES COMPARED TO THE CONTROL, LIGHT FLASHES, THE ELECTRICAL ACTIVITY OF THE EYE GIVES A SIGNAL, GIVES A WAVE FORM. AND UNFORTUNATELY, THAT DOG WITH A LOT FLASH DOESN'T DO VERY MUCH. BUT WHEN THE GENE IS PUT BACK INFORM, THE VITAMIN A EYESOME RACE GENE IS PUT BACK IN. THE EYE AGAINST TO FUNCTION SO GENE THERAPY HAS THE POTENTIAL TO RESTORE VISION IN CHILDREN WHO ARE BORN BLIND. AND IN FACT, TAKES MY BREATH AWAY. IT WAS DONE BY THREE SEPARATE GROUPS IN THE SAME YEAR. ALL THREE WORKING INDEPENDENTLY PUT A GENE IN THE EYE OF SEPARATE PEOPLE WHO ARE BORN ESSENTIALLY BLIND, AND RESTORED VISION. LET ME JUST SHOW YOU WHAT THAT AMOUNTS TO. LET'S HOPE THIS VIDEO WILL PLAY HERE. HERE IT IS, WONDERFUL. THIS IS CORY. CORY WAS BORN WITHOUT VISION. AND YOU'RE NOW WATCHING HIM WALK THROUGH A MAZE WITH THE UNTREATED EYE. HIS TREATED EYE HAS BEEN PATCHED. HERE YOU CAN SEE. HE'S KIND OF STUCK, HE'S CAUGHT. HE CAN'T SEE WHERE HE'S GOING. HE'S NOT MOVING BECAUSE HE CAN'T SEE ANYTHING. WE COULD WATCH TO THE END OF THIS BUT I THINK YOU GET THE IDEA THAT HE IS NOT SEEING IN THE UNTREATED EYE. NOW LET'S LOOK WHAT HAPPENED IN THE TREATED EYE. >> PERFECT, ALL RIGHT. PRETTY REMARKABLE ISN'T IT. THIS IS A CHILD WHO SIX MONTHS AGO COULDN'T GET AROUND. NOW HE'S ON HIS OWN. THREE INDEPENDENT VISION GROUPS ACCOMPLISHED THE SAME OUTCOME RESTORING VISION IN YOUNG PEOPLE WHO WERE BORN BLIND FROM LABOR CONGENITAL AMAUROSIS FROM A MUTATION IN THE RPE65 GENE. THAT'S WHAT MEDICINE IS NOW. IT NETTED MENTIONED IN SCIENCE AS A BREAK THROUGH OF THE YEAR. HERE? FACT IS CORY THE BOY YOU JUST SAW. THE NEEDLE IS INJECTED INTO THE EYE, IT'S HOLLOW. THE NEEDLE IS INSERTED INTO THE SPACE BENEATH THE RETINA. THE FLUID IS INJECTED WITH VECTOR GENE PARTICLES, HE GOES HOME AND SIX MONTHS LATER HE'S PRETTY MUCH DOING A LOT BETTER. VISION HAS A LOT OF GENE THERAPY TRIALS GOING ON. RP65 THE EXAMPLE I JUST SHOWED YOU IS THE ONLY CERTIFIED SUCCESS. IT IS LABOR CONGENITAL AMAUROSIS FOR THE. RP65 GENE. BUT THERE ARE A NUMBER OF OTHER TRIALS GOING ON INCLUDING FOR AMD STAR GOT MACULAR DEGENERATION. USHER SYNDROME DEAF BLINDNESS, OPTIC MOROPATHY AND CORNEAL PROBLEMS. IT'S NOT JUST THE RETINA THAT IS GETTING ATTENTION. THE GENES I TALKED ABOUT RP65 BUN GENE THE MUTATION IN THAT GENE CAUSES THE FAILURE OF THE CELLS. AS EMILY MENTIONED AGE RELATED MAC DEGENERATION IS A COMMON DISEASE BUT IT IS GENETICALLY COMPLEX, HETEROGENOUS. IT'S CALLED A COMPLEX DISEASE. AND AS EMILY HAS SHOWN YOU IT STARTS WITH A NORMAL LOOKING EYE. ADVANCES TO THE ACCUMULATION OF THESE DRUSEN AND THEN TO ATROPHY AND THEN TO HEM IMAGE. IT AFFECTS TOO MANY PEOPLE AND UNTIL RECENTLY THERE WERE NO THERAPIES AVAILABLE. AGAIN AS EMILY HAS SAID AND AS THE HAMMERS HAVE ATTESTED, IT DISTORTS VISION AND IF A HEMORRHAGE HAPPENS IT TOTALLY BLOCK THE CENTRAL MOST PART OF VISION. ALSO AS EMILY HAS SAID IN 25005 LIGHTENING STRUCK. AGAIN NOT ONE TIME OR THREE TIMES, FIVE TIMES. SIMULTANEOUSLY WITHIN THE MATTER OF A FEW MONTHS A GENE COMPLEMENT FACTOR H IN THE IMMUNE SYSTEM CASCADED WAS IDENTIFIED AS CAUSING RISK OF DEVELOPING AMD. WHAT EMILY DID NOT QUITE SAY IS THE PAPER BY CLINE AND THE PHOTOGRAPHS HERE ARE EMILY'S WORK. SHE WAS PART OF THE GROUP THAT IDENTIFIED THIS COMPLEMENT FACTOR H GENE. TREMENDOUS SUCCESS HERE AT THE EYE INSTITUTE AND NIH. AND WITHIN SHORT ORDER BY 2006, TWO MORE GENES WERE FOUND AND REMARKABLY BOTH OF THEM WERE IN THE COMPLEMENT CASCADE. SO NOW THERE ARE THREE GENES. THAT KIND OF POINTS TO A PROBLEM IN THE COMPLEMENT SYSTEM, DOESN'T IT. THREE GENES CAN INDEPENDENTLY CAUSE RISK FOR MACULAR DEGENERATION. THOSE THREE GENES EXPLAIN 74 MERSE PERCENT ABOUT THREE QUARTERS OF THE RISK OF AMD. THE STORY GETS A LITTLE MORE COMPLICATED IN A MINUTE, HOWEVER. WELL, JUST TO PUT THIS IN CONCESSION, HERE'S WHAT WAS HAPPENING TO RPE65 AND ALL THE SINGLE GENE DISEASES MANDELIAN TRAITS, THERE WERE 1300 GENES CLONED AND 20% OF THEM INVOLVED VISION. BY 2005, THERE ARE 1700 GENES CLONED. BUT FOR THE COMMON COMPLEX DISEASES, CARDIOVASCULAR DISEASE, RENAL DISEASE, PULMONARY OWE DISEASE, AGE-RELATED MACRO DEGENERATION. THERE ARE ONLY EIGHT. AND IN 2005, AMD RETAINED GENE NUMBER 9 TO EXPLAIN COMMON COMPLEX DISEASE. A TREMENDOUS SUCCESS AND THAT WAS COURTESY OF FRANCIS COLLINS THE FRUITS OF THE GENOME PROJECT AND THE INTERNATIONAL MAP THAT HAS MADE ALL OF THE DIFFERENCE TO MEDICINE. NOW, 2005, 2012, SEVEN YEARS LATER, THERE WERE 250 OF THESE RISK GENES IDENTIFIED AND SOME 1500 STUDIES. AND PEOPLE ARE SAYING WE'RE ACTUALLY APPROACHING THE END OF THE G WAS APPROACH TO FINDING GENES. LET'S TURN BACK TO AMD FOR A MOMENT. AS I MENTIONED COMPLEMENT FACTOR H, HERE IT IS IN THE PINK BOX WAS THE FIRST OF THE RISK GENES AND YOU CAN SEE THAT IT IMPINGES ON THE CLASSICAL PATHWAYS A REGULATOR, THE -- PATHWAY AS A REGULATOR. HERE AND ON THE ALTERNATIVE PATHWAY AS A REGULATOR. IT IS FRONT AND CENTER A CONTROLLING MOLECULE FOR THE IMMUNE RESPONSE SURVEILLANCE OF CELLS IN THE EYE. AND A LOT IS KNOWN ABOUT THIS HERE AT NIH THERE'S A VERY STRONG IMMUNOLOGY SET OF PHYSICIANS AND DIANE SISTS. SO A LOT IS KNOWN ABOUT WHAT'S HAPPENING WITH COMPLEMENT CASCADE AND IT MAKES SENSES THAT PERHAPS YOU WANT TO PAY ATTENTION TO C5 WHICH ALSO IS RIGHT IN THE CRITICAL PATHWAY. PERHAPS MODULATING C5 WOULD HELP DAMPEN DOWN THE INCIDENCE OF AMD. AND SUCH TRIALS ARE UNDER WAY BECAUSE IN FACT THERE ARE FDA APPROVED DRUGS THAT WILL MODULATE THE C5 FACTOR. THERE ARE OTHER THINGS THAT YOU CAN DO ONCE YOU KNOW ABOUT GENES. FIRST OFF, CFH, THE FIRST GENE WE'VE MENTIONED INCREASES YOUR RISK OF DEVELOPING AMD BY FOUR FOLD. IF YOU HAPPEN TO HAVE THE UNFORTUNATE GENOTYPE OR ANOTHER GENE, SIX FOLD. BUT IF YOU ADD SMOKING TO THIS, THINGS REALLY GO BAD, GO SOUR QUICKLY. IF YOU HAVE CFH AND SMOKE, YOUR RISK IS DOUBLED. IF YOU HAVE THIS GENE AND SMOKE YOUR RISK IS TRIPLED. SO YOU CAN SEE THAT THERE'S AN INTERPLAY BETWEEN GENES AND ENVIRONMENT. A COUPLE YEARS AGO THE EYE INSTITUTE WENT INTO HIGH GEAR COURTESY OF EMILY AND HER COLLEAGUES POINTING OUT THAT AMD IS A STRONGLY GENETIC DEPENDENT DISEASE. AND THE EYE INSTITUTE MANAGED TO GET MANY COMPETING RESEARCH GROUPS SITTING AMICABLY IN THE SAME ROOM HERE AT NIH. AND TO POOL THE RESOURCES AND POOL THE TALENT AND POOL THE CASES AND POOL THE EXPERTISE, AND A NUMBER OF GENES HAVE COME OUT OF THIS. IN FACT THE PAPER HAS JUST BEEN ACCEPTED AND JUST PUBLISHED WHICH HAS ANOTHER 17 GENES FOR AMD. SO THE FIRST THREE CFHC2C3 ACCOUNT FOR MUCH OF THE RISK. AND THESE ADDITIONAL GENE ARE GOING TO HELP FILL IN THE RISK POOL. AND AS EMILY HAS MENTIONED, THESE GENES BEGIN TO SEGREGATE IN, WELL, COMPLEMENT PATHWAY OR A LIPO PROTEIN PATHWAY. OR MAY PATHWAY OR AN GENESIS PATHWAY. WE BEGIN TO SEE BIOLOGICAL PATHWAYS THAT PLAY, ALL OF THE INVESTMENT IN FINDING GENES. WE'RE DOING THE SAME THING WE MEANING THE EYE INSTITUTE. MORE IMPORTANTLY THE VISION COMMUNITY IS DOING THE SAME THING FOR GLAUCOMA. AND HERE IS A GROUP OF GLAUCOMA INVESTIGATORS 12 INSTITUTIONS WITHIN THE U.S., 22 INVESTIGATORS PUTTING TOGETHER ABOUT 4,000 ADVANCED DEFINITIVE CASES OF GLAUCOMA FOR STUDY. BUT DESPITE SEVERAL YEARS OF WORK, IT'S PROVEN SO FAR TO BE RATHER DISAPPOINTING. THERE ARE TWO SIGNALS THAT HAVE COME OUT OF VAST AMOUNTS OF CASES AND VAST EXPERTISE AND ENERGY AND MONEY BUT ONLY TWO. AND NEITHER OF THOSE REALLY AT THE MOMENT MAKE MUCH SENSE FOR GLAUCOMA. BUT THIS IS THE WAY THAT ONE TACKLES COMMON COMPLEX DISEASES. SO IT'S WORTH ASKING A QUESTION. WE'VE GOT ALL THESE GENES, WHEN DO WE QUIT. HOW MANY GENES ARE ENOUGH. ANYBODY WANT TO VOLUNTEER AN ANSWER? NEVER? OR DO YOU FINALLY SAY WELL IF YOU'VE GOT 40 GENES, DOES GENE 41 IS IT GOING TO HAVE SOMETHING REALLY CRITICAL OR IS IT NOW TIME TO TAKE THE 40 GENES AND TO FOCUS THE SPOTLIGHT IN THE LABORATORIES IN THIS BUILDING AND ELSEWHERE ON THE CELL BIOLOGY AND THE PATHOPHYSIOLOGY OF WHAT'S HAPPENING. THERE'S ANOTHER WAY YOU CAN LOOK AT THIS AND THAT IS TO SAY WELL MAYBE WE ALREADY HAVE A LOT OF INFORMATION THAT CAN BE HELPFUL TO THE PATIENTS WHO HAVE AMD. IN FACT JUST THREE GENES ACCOUNT FOR 74% OF THE GENETIC RISK OF DEVELOPING AMD. BUT THERE'S A REAL PROBLEM WITH USING THIS DIAGNOSTICALLY. I THINK WHEN YOU ASKED THE QUESTION, WHAT IS THE VALUE OF GENE TYPING. THE PROBLEM IS, IF YOU LOOK AT THIS NUMBER 20-1, FOR EVERY ONE AMD CASE, TRUE AMD CASE, THERE ARE 20 WHO DO NOT HAVE AMD. WHEN YOU TAKE 74% CHANCE OF A RATIO OF 20-1, WHAT HAPPENS IS YES YOU FIND MANY PEOPLE WHO HAVE TRUE AMD BUT IF YOU ENSNARE AND WRONGLY CLASSIFY VAST NUMBERS OF PEOPLE WHO WILL NEVER GET AMD. AND THAT'S BECAUSE 74% IS NOT A STRONG ENOUGH PREDICTOR YET. SO WHAT WE NEED IS TO GO TO GENE 40 AND TO GO TO GENE 80 BECAUSE ONLY WHEN WE HAVE NEARLY THE ENTIRE SET OF GENES ARE WE GOING TO BE ABLE TO USE THIS AS A DEFINITIVE FORWARD PREDICTOR OF RISK FOR ANY ONE INDIVIDUAL WHICH IS WHAT WE AS PATIENTS WANT TO HAVE. BUT STILL ONE DOES HAVE TO ASK THE QUESTION AT WHAT POINT DO YOU FOCUS YOUR ATTENTION ELSEWHERE. LET ME TURN TO A DIFFERENT STRATEGY WHICH IS A GENE BASED SYSTEM FOR A CELL CALLED -- TROPIC FACTOR. THIS TAPS INTO A RICH 70 YEAR HISTORY OF NEUROTROPIC FACTORS FOR NEURODEGENERATIVE DISEASES SET OFF IN THE 1950'S BY -- WHO JUST DIED I THINK IT WAS LAST FALL AT A GRANT OLD AGE OF 92. 91 OR 2, THANK YOU. SHE HAD THE LONG JEFFITY GENE. I NEED THE HEARING AGAIN. GOT AN OVER ALL PRIZE FOR HER WORK. A NUMBER OF THESE NEUROTROPIC NARCOTICS WERE FOUND INCLUDING A VERY INTERESTING ONE -- FACTORS WERE FOUND INCLUDING A VERY INTERESTING ONE BASIC FINE GLASS GROWTH FACTOR BFGF WHICH RESCUES PHOTO RECEPTOR CELLS IN THE EYE OF AN ANIMAL WHO HAS RP. YOU'VE NOW SEEN SLIDES LIKE THIS FROM THE WOMAN WHO DIED. SHE DIDN'T HAVE VERY MANY IN FACT SHE LOOKED LIKE THIS. SHE HAD VERY FEW LEFT. IF SHE HAD RECEIVED AN INJECTION OVER BASIC FINE BLAST GROWTH FACTORS PERHAPS HER CELLS WOULD HAVE BEEN RESCUED. THAT WOULD HAVE BEEN WONDERFUL. JUST FOR REFERENCE I'M PLEASED TO HAVE DONE MY POST DOC WITH ROSE STEINBERG AND IT WAS HE WHO HAD THIS IDEA AND HEARING A LECTURE AT UCSF TO TRY A NEUROTROPIC FACTOR FOR RP. IN FACT HIS COLLEAGUE MATT ALSO USED CSF BUT HAVE WORKED DILIGENTLY FOR MANY YEARS AND HAS TESTED 12 YEARS BFGF AND HERE IS CILIARY NEUROTROPIC FACTORS CNTF. HEPARIN HAS MODEST EFFECTS AND OTHERS THE TALLER BARS ARE MORE POTENT IN RESCUING BUT CMTF IS PART OF THE CYTOKINE FAMILY AND IT HAD SOME VERY POWERFUL FACTORS TO IT WHICH MEANT WHICH MEANT THE FACTORS WERE CLEAN TO MOVE FORWARD WITH IT. THERE WAS ANOTHER POWERFUL FACT GOING FORWARD AND THAT IS THE CNTF IN RAT, MOUSE, CHAT AND DOG RETINAL DEGENERATION GAVE RESCUE. AND AS I MENTIONED THE WOMAN WHO DIED AT AGE 74 HAD A -- MUTATION. SO PERHAPS IN FACT, HERE'S HER MUTATION. WHEN THAT WAS TRIED WHEN CNTF WAS TRIED ON ROW DOBSON, IT RESCUES THE PHOTORECEPTORS. SO TOO BAD THAT SHE DIDN'T SURVIVE LONG ENOUGH TO HAVE THIS MOLECULE INJECTED. SO IT WORKS IN THESE ANIMALS AND THESE SPECIES. WHAT ABOUT THE HUMAN SPECIES, DOES IT WORK FOR US. I HAD THE PLEASURE OF LEADING THE GROUP HERE AT NEI IN 2004 AND 5. WE TRIED CILIARY NEUROTROPIC FACTORS FOR PATIENTS WITH RETINITIS PIGMENT TOE SAW. I THINK THE VERY NOVEL DELIVERY SYSTEM DEVELOPED BY A COMPANY NEUROTECH. IT'S THIS LITTLE CAPSULE AND HERE IN THE EYE OF ONE OF OUR PATIENTS YOU CAN SEE THE CAPSULE THAT'S BEEN SURGICALLY IMPLANTED INTO THE CENTER OF THE EYE. IT'S JUST POKING THROUGH. THAT CAPSULE WHOSE A POUROUS MEMBRANE. THEY ARE FILLED WITH CELLS. THE CELLS. THEY ARE TRANSVECTOR -- THEY RELEASE THE PROTEIN INTO THE EYE AND CASE CLOSED. AT LEAST FOR DELIVERY. THE QUESTION IS, IS THE CASE CLOSED FOR RESCUE. HERE IS MY PAPER IN 2006. CILIARY NEUROTROPIC FACTOR PHASE ONE HUMAN CLINICAL TRIALS -- ENCAPSULATED CELL, DA DA DA, 10 SUBJECTS, TWO DOSES, IMPLANTED SIX MONTHS. WHAT WAS THE OUTCOME. WELL, THESE COLUMNS LOWER DOSE AND HIGHER DOSE, FIVE INDIVIDUALS AND FIVE INDIVIDUALS. YOU CAN SEE THAT IN THE UNTREATED EYE OVER SIX MONTHS WHEN WE TESTED THEIR VISUAL ACUITY ON CONSECUTIVE EXAMINATIONS, IT'S REALLY GOING NO WHERE. WOULDN'T EXPECT IT TO. WE DIDN'T DO ANYTHING TO THE ISO THE ACUITY STAYS THE SAME. BUT IF YOU ARE AN OPTIMIST, YOU CAN PERHAPS THINK THAT IN THE I'D WITH THE CAPSULE THERE'S AN UPWARD TREND, A BENEFIT TO VISUAL ACUITY. IN FACT FOR A FEW PEOPLE HERE IS ONE WITH THE LOW DOSE, A TREMENDOUS INCREASE, THREE LINES ON A NIGHT CHART. THIS IS A DIFFERENT STORY I'M GOING TO SLIP OVER THAT FOR A MOMENT. ARE ACTUALLY WHAT HAPPENED HERE WAS A SURGICAL ADVENTURE THAT HAD NOTHING TO DO WITH THE CAPSULE ITSELF OTHER THAN TO PARTICIPATE IN THE TRIAL. BUT IT LOOKED HOPEFUL THAT IN FACT CNTF WOULD HELP PEOPLE WHO HAD RETINITIS PIGMENT TOSA. SO PHYSICIAN ONE NOW WE'RE IN PHASE TWO AND WE DESIGNED THE STUDIES AND I THINK EMILY, ONE OF E LISA MEASURES WAS THE FIRST TO RECEIVE AN IMPLANT FOR AMD. AND THE STUDIED WAS PUBLISHED AND UNFORTUNATELY IT GAVE ONLY A WEEK POSSIBILITY OF SHOWING SOME SUCCESS. IT WAS NOT A RIP ROARING SUCCESS. SO WE ARE STILL IN A PERIOD OF EXPLORING ALL OF THE FACTORS AROUND THE VAGARIES OF BIOLOGY. BECAUSE THE DOSE RIGHT, WAS THE APPLICATION RIGHT WAS THE OUTCOME MEASURE RIGHT. ALL OF THOSE THINGS HAVE TO BE ATTENDED TO FOR CLINICAL TRIAL. I WANT TO NOW CONCLUDE WITH THREE, FOUR, FIVE SLIDES JUST QUICK TO SHOW YOU SOME VERY INTERESTING BIOLOGY THAT I THINK MANY OF US IN THE ROOM ARE AWARE OF. IN 2006, THE DENTIST IN JAPAN FIGURED OUT A WAY TO TAKE SKIN CELLS, FIBROBLASTS SKIN CELLS AND REDUCE THEM TO REGRESS TO AN EMBRYO LOGIC STATE WHICH THEY COULD DEVELOP ALONG ONE OF A NUMBER OF PATHWAYS. THEY COULD BECOME CARDIAC CELLS, EYE CELLS, KIDNEY CELLS. THE INDUCED PLURIPOTENT STEM CELL. THIS IS THE CELL THAT HAS CAUGHT THE ATTENTION OF MEDICINE AND WE HOPE IN FACT WILL HELP US IN THE DECADES AHEAD RESCUE MANY PEOPLE FROM RATHER HORRIBLE DISEASE. AGAIN, I'M PLEASED FOR THE VISION COMMUNITY BECAUSE THE VISION COMMUNITY WAS THE FIRST TO TRY ANY STEM CELL AS THERAPY. IN THIS CASE, IT WAS PUBLISHED JUST A YEAR AGO IN FEBRUARY, HUMAN EMBRYONIC STEM CELL THERAPY FOR MACULAR DEGENERATION. ONE HAD AGE RELATED. ANOTHER HAD DEGENERATION OF THE STAR GUARD FORM, ABC84. IT'S A FLIPASE IN THE PHOTO RECEPT CELLS AND MOVE VITAMIN A AROUND, RECURRING THEMES I HOPE YOU'RE AWARE. AGAIN I AM PLEASED TO SAY IT WAS ENVISION IN EYE DISEASES THAT THE OUTSTANDING OPPORTUNITY OF STEM CELL WAS FIRST TRIED. INFECTED IN -- INJECTED IN THE BACK OF THE EYE YOU CAN SEE THE RETINA BY THE OPTICAL COHERENCE TOMOGRAPHY. AFTER SEVERAL MONTHS, THREE MONTHS, THERE ARE STILL CELLS THAT ARE REMAINING UNDERNEATH THE RETINA. SO IN THE LEAST, WHAT YOU ARE SEEING HERE IS A DEMONSTRATION THAT ONE CAN PUT CELLS INTO THE AREA OF NEED AND THE IMMUNE SYSTEM DOESN'T IMMEDIATELY CANNIBALIZE THEM. WHETHER THIS IS SUCCESSFUL AS THERAPY, IT'S GOING TO TAKE A NUMBER OF YEARS TO FIGURE THAT OUT. AND THEN FINALLY SOMETHING THAT ALSO MANY PEOPLE HERE AT NIH AND ELSEWHERE ARE ENTHUSIASTIC ABOUT REGENERATIVE MEDICINE. EMBRYONIC STEM CELLS, IN THIS CASE -- WHO WE INVITED AND WHO SPOKE HERE LAST YEAR PUBLISHED THIS REMARKABLE PAPER IN NATURE MAC SEEN WITH, AS I PUT IT, GREEN EYE BALLS. THESE ARE MOUSE EYE BALLS OR AT LEAST THE NEURO RETINA IN AN EYE CUP, THREE DIMENSIONAL CULTURE COMING FROM EMBRYONIC STEM CELLS. THIS HAS ALL OF THE FORMATION, THE RODS, THE CONES, THE BIPOLAR, ALL AT THE NEUROELEMENTS OF THE RETINA OF THE MOUSE MADE FROM MOUSE EMBRYONIC STEM CELLS. THIS IS NOW THE REPLICATED WITH HUMAN STEM CELLS AND SHORTLY WE WILL HAVE EYE BALLS IN A DISH THAT WE CAN STUDY MADE FROM ES CELLS. SO THE QUESTION IS IF ANYBODY WANTS TO PLACE A BET HOW MANY YEARS BEFORE WE MAKE OUR OWN TISSUE BEFORE WE REPLACE THE RETINAL DISEASE. REMARKABLE OPPORTUNITIES. SO THEN JUST THE LAST SLIDE AND SOME CLOSING THOUGHTS. I WOULD REALLY LIKE TO FOCUS ON THE REMARKABLE BIOLOGY THAT'S HAPPENED OVER THE PAST DECADE STARTING IN 2001 WITH FRANCIS COLLINS PUBLISHING THE FIRST -- IT IS FROM THAT THE INTERNATIONAL HAT MAP AND 2005 EMLY AND OTHERS FOUND THE FIRST GENES FOR AMD. 2006 INDUCED PROTOCOL STEM CELLS. 2007, EIGHT, NINE, GENE THERAPY, 2011, GREEN EYE BALLS. WE'RE MOVING AHEAD. SO THANK YOU AND I HOPE I CAN INDUCE A YOUNG FACES INTO ENGAGING IN OPHTHALMOLOGY. THANK YOU. [APPLAUSE] >> WITH LEPER -- AND STILL RESTORE VISION ALTHOUGH THIS IS NOT MY AREA OF EXPERTISE BUT I UNDERSTAND THE VISION DEVELOPMENT REQUIRED VISUAL INPUT AND IF YOU DON'T HAVE THAT EARLY ON YOU ARE NOT DOING SO WELL SO HOW LONG CAN YOU DELAY THE THERAPY AND STILL HAVE USEFUL RESTORATION OF VISION. >> I HOPE IT'S NOT TOO LATE FOR US OLD GUYS BUT THE INTEREST IS IN BECAUSE VISUAL DEPRIVATION, IF YOU PATCH A YOUNG PERSON'S EYE FOR 20 YEARS, THE BRAIN CAN'T PROCESS THE SIGNAL SO YOUR QUESTION IS WHAT IF YOU TREAT AT AGE 20. THE ANSWER TO THAT IS COMING OUT OF A PROJECT IN INDIA THAT THE EYE IS SPONSORING FOR A PROJECT -- AND IT IS THE UNFORTUNATE NUMBER OF INDIAN PEOPLE WHO ARE BORN WITH CONGENITAL CATARACTS SO THEY HAVE BLINDERS ON. WHEN SURGERY IS DONE AT AGE 20, IT'S THE SAME QUESTION THAT YOU ASKED. DOES THE PERSON ACTUALLY HAVE VISION THAT IS USEFULLY PERCEIVED BY THE BRAIN AND THE ANSWER IS YES, TAKES A FEW DAYS BUT STILL WORKS. SO IN FACT GENE THERAPY FOR LABOR CONGENITAL AMAUROSIS COULD BE DONE FOR US OLD GUYS TOO. >> [INDISCERNIBLE] CONDITION OF THE VECTOR. >> THAT'S AN INTERESTING QUESTION. WHAT IS THE LONG JEFFITY JEFF -- LONGEVITY -- INCORPORATES INTO THE CELLULAR GENOME OR WHETHER IT REMAINS EPI SOMAL. ONE COMES FROM THE GENE THERAPY IN THE DOG THAT HAS THE -- MUTATION. THAT DOG WAS INJECTED IN 2001. IT DIED A YEAR AND SOME AGO AND IT HAD AS GOOD VISION A YEAR AND SOME AGO AS A DECADE EARLIER. SO IT'S A LONG TERM SOLUTION A LEAST IN THE DOG AND PROBABLY IN THE HUMAN. >> DO THEY ANALYZE TO SEE IF IT IS -- IN THE CELL. >> I KNOW THAT THE GROUP AND OTHERS AT THE UNIVERSITY OF PENNSYLVANIA PHILADELPHIA ARE ASKING YOUR QUESTION BUT I DON'T HAVE AN ANSWER. >> I WANT TO KNOW TO WHAT EXTENT THE -- DATA IS BEING USE IN THE EYE INSTITUTE. MICRO RAY DATA, MASS SPECTROMETRY, DNA SEQUENCING AND HOW MUCH IT'S BNG USED AND WHAT SUCCESS IS IT GOING TO BE REPORTED ASSOCIATED WITH THAT KIND OF THING. >> EMILY AND OTHERS ARE USING THOSE APPROACHES FOR AMD. ONE ANSWER TO THE OMIX I SHOWED SLIDES ABOUT FIVE SIX OR SEVEN THE PHOTO TRANUCTION PHWAY GENES, ALL OF THESE GENES THAT FIT UNDER THAT RUBRIC, ALL OF THE GENES THAT FIT OVER THE VITAMIN A RUBRIC, THAT IS A POWERFUL OWEMIX APPROACH AND WHEN IT'S APPLIED TO AMD IT IS POINTING A FINGER THAT EXTRA CELLULAR MATRIX. IT'S BEING VERY ACTIVELY USED AND IT IS PROVIDING SOME VALUABLE INFORMATION. >> THANK YOU VERY MUCH. >> THANK YOU BOTH.