2018 Demystifying Medicine: The Great Neglected Diseases

SOME OF YOU HAVE NOT BEEN HERE BEFORE. SO I WOULD LIKE TO POSE TWO QUICK QUIZZES. DOES EVERYONE KNOW WHAT THAT IS? THAT’S THE BRIDGE ACROSS THE SAN FRANCISCO BAY. RIGHT? EVERYBODY AGREE? COME ON. WHAT IS IT, ALAN? IT’S THE BROOKLYN BRIDGE. SO THIS IS THE MOST FAMOUS BRIDGE IN PROBABLY BRIDGE HISTORY. AND IT’S THE LOGO FOR THIS COURSE THAT WE HAVE. BECAUSE WE ARE ALL, LIKE THE TWO GENTLEMAN ON THE CATWALK, CROSSING BETWEEN BROOKLYN AND NEW YORK.& LIFE IS NEVER THE SAME ON EITHER SIDE OF THE BRIDGE. ONCE IT’S BEEN CONSTRUCTED. AND IN FACT, IF BROOKLYN, ON THE OTHER SIDE THERE, REPRESENTS ADVANCES IN BASIC BIOLOGICAL MATHEMATICAL AND ENGINEERING SCIENCES, AND OVER HERE IN NEW YORK WE HAVE PATIENTS WITH SICKNESSES THAT WE’D LIKE TO UNDERSTAND AND TREAT, MANY OF US THINK THAT THE BIGGEST PROBLEM OR A HUGE PROBLEM IN BIOMEDICAL RESEARCH, IS THERE AREN’T ENOUGH BRIDGES. AND WE ALL SPEAK OUR OWN LANGUAGE. WE ALL HAVE OUR SMALL PIECE OF THE PIZZA PIE. SO THE PURPOSE OF THIS COURSE IS TO HELP STIMULATE, PARTICULARLY YOUNG BASIC PH.D. SCIENTISTS, BUT EVERYBODY, IN WHAT THE PROBLEMS ARE AND WHAT DO WE KNOW. SO THE GOAL IS TO EXCITE YOU, NOT FILL YOUR HEADS FULL OF NUMBERS AND SO FORTH. THIS IS NOT A MEDICAL SCHOOL. I HAVE ANOTHER QUESTION. DOES ANYONE KNOW THE ORIGIN AND MEANING OF THE WORD PARASITE? BYRON DO YOU KNOW? I DIDN’T KNOW EITHER. SO I LOOKED IT UP. AND IT’S REALLY FASCINATING. OF COURSE WHAT IS UNDERLYING OUR TOPIC OF TODAY ARE PARASITES. SO THE MEANING OF THE WORD, PARASITE. PARA– MEANS TO SIT OPPOSITE. REMEMBER IN CHEMISTRY, THE PARA-POSITION. AND SITE REFERS IN LATIN, TO SHARING A MEAL. SO SOMEBODY WHO CAME AND SPONGED A MEAL, IN OTHER WORDS THEY CAME, THEY DIDN’T CONTRIBUTE VERY MUCH BUT YOU FED THEM, THAT’S THE ORIGIN OF THE WORD PARASITE. AND OF COURSE IT’S MATURED GREATLY. AND NOW WE ARE DISCUSSING PARACYTOLOGY, THE STUDY OF HOW BIOLOGIC SPECIES INFECT THE HOST, UTILIZE THE ENERGY SOURCES OF THE HOST, ESTABLISH SOME CHRONIC SYMBIOTIC RELATIONSHIP, WHICH MANY EVENTUALLY IN SOME DISEASES, KILL THE HOST AND IT CERTAINLY CAN CONTRIBUTE TO IMPAIRED HEALTH AND SURVIVAL. AND THESE ARE THE GREAT NEGLECTED DISEASES, WHICH AS A TOPIC IS AN OUTSTANDING EXAMPLE, WHICH WE’LL DISCUSS TODAY, OF BRIDGING BASIC SCIENCES AND TRULY MAJOR HUMAN HEALTH PROBLEMS. AS MOST OF YOU KNOW, THESE ARE THE DISEASES THAT ARE MOST ABUNDANT, MOST CHRONIC, MOST DISTRIBUTED, AROUND THE WORLD PARTICULARLY IN SO-CALLED UNDERDEVELOPED WORLDS. IN THEIR OWN WAY, THEY ARE DEVASTATING. NOW WHY ARE THEY NEGLECTED? WHAT WE ARE GOING TO TALK ABOUT IS A BEAUTIFUL DEMONSTRATION THAT BUILDING A BRIDGE REQUIRES MORE THAN JUST MONEY. IT REQUIRES HUMAN CATALYSTS WHO SEE BEYOND THE CURVE. SO WE HAVE TO GIVE YOU A LITTLE STORY. SO KEN WARREN WAS ACTUALLY A STUDENT OF MINE. I WAS HIS INTERN WHEN HE WAS A FOURTH-YEAR STUDENT. I WAS HIS RESIDENT WHEN HE WAS AN INTERN. AND WE REMAINED FRIENDS THROUGHOUT HIS ENTIRE LIFE. NOW, KEN WAS A VERY DYNAMIC PERSON WHO WAS TRAINED IN PARASITOLOGIY AND MEDICINE. AND IN THOSE DAYS, PARACYTOLOGY WAS MAINLY THE CATEGORIZING THE BRILLIANT WORK DONE ON EPIDEMIOLOGY AND THE EXTRAORDINARY LIFE CYCLES ASK SO FORTH BUT MECHANISTICALLY, IN TERMS OF ACTUAL CELLULAR PROCESSES THAT WERE GOING ON, THERE WAS A HUGE GAP. IT NEEDED A BRIDGE. AND KEN, LARGELY THROUGH SOME WORK THAT WAS STARTED HERE WHEN HE WAS A FELLOW FOR A SHORT TIME, HE CONVINCED THE ROCKEFELLER FOUNDATION TO BUY INTO A PROJECT HE CALLED, THE GREAT NEGLECTED DISEASES. AND THAT LED TO A TRANSFORMATION OF TROPICAL AND GLOBAL MEDICINE. SO HERE HE IS. A VERY DYNAMIC MAN. WHAT DID IT DO? IN THE COURSE OF 10 YEARS, IT CHANGED PARACYOLOGY FROM TAXONOMY TO WHAT YOU MIGHT CALL MODERN SCIENCE. THEY PROVIDED FUNDING FOR, I THINK IT IS 14, OUTSTANDING BASIC SCIENCE LABORATORIES. MOST OF WHICH WERE IN IMMUNOLOGY. AND THE ONLY REQUIREMENT WAS THAT PEOPLE CAME TO AN ANNUAL MEETING AND PRESENTED REAL WORK. AND IF IT WASN’T GOOD, THEY DIDN’T GO VERY FAR. SO HE WAS CONVINCED THAT NON-PARASIGHTOLOGISTS, MAINLY LEADING IMMUNOLOGISTS, COULD GET INVOLVED IN UNDERSTANDING DISEASES SUCH AS MALARIA, WORMS, ET CETERA. AND HE CONVINCED THEM. THOSE WHO KNEW NOTHING ABOUT PARACYTOLOGY, MANY WERE SENT FOR A SHORT PERIOD OF TIME TO THE LONDON SCHOOL OF TROPICAL MEDICINE WHERE THEY LEARNED AT LEAST THE BALLPARK. THE PROGRAM PRODUCED MAJOR ADVANCES AND IT PRODUCED WHAT YOU MIGHT CALL THE NEXT GENERATION OF LEADERS IN GLOBAL RESEARCH. NOW THE INTERESTING THING IS IT WAS REALLY THE PRODUCT OF NOT JUST ONE MAN. KEN WAS THE CATALYST BUT HE WAS ALSO INFLUENCED BY FRANKLIN WHO WAS HERE AND BELOVED AT THE NIH AS THE DIRECTOR OF THE LABORATORY OF PARACYTIC DISEASES FOR MANY YEARS. AND OTHERS. BUT HE CARRIED IT THROUGH. HE HAD IDEAS, CONVICTIONS AND IMAGINATION, AND HE HAD ASSURED FUNDING. HE DIDN’T HAVE TO WRITE A GRANT — FOR PRODUCTIVE RESEARCH. AND THEN AS FOUNDATIONS DO, THEY GET THE BALL ROLLING AND THEN THEY ROLE IT TO SOMEONE ELSE AND THE PROGRAM ENDED WITH A NEW ROCKEFELLER PRESIDENT BUT IT SET THE STAGE WHO HAD OTHER IDEAS. BUT SET THE STAGE FOR WORK WHICH REMAINS IMPORTANT AND EXCITING AND NEW APPROACHES TO THE TREATMENT OF THE GREAT TRULY NEGLECTED DISEASES. LAST THING. THIS PAPER BY ANOTHER COLLEAGUE, IS IN MY VIEW A CLASSIC: — SO, OUR SPEAKERS TODAY ARE WORLD-KNOWN EXPERTS IN THIS EXCITING FIELD. AND ALAN RECEIVED HIS PH.D. FROM THE UNIVERSITY OF CALIFORNIA AND SAN DIEGO, DID A POSTDOC IN PARACYTOLOGY AT THE MEDICAL RESEARCH COUNCIL LABORATORY IN MILL HILL, LONDON, WHICH WAS A CENTER FOR IMMUNOLOGY. IN 1980, AFTER HAVING BEEN AT HARVARD FOR SEVERAL YEARS, HE CAME TO NIAID AS A SECTION CHIEF IN THE LABORATORY OF PARASITIC DISEASES. HE HAS BEEN PROMOTED AND AN NIH DISTINGUISHED INVESTIGATOR AND HIS WORK IN PARTICULARLY IMMUNOLOGY STUDYING HOST RESISTANCE AND IMMUNE REGULATION, IS WIDELY CITED AND I PRESUME THAT IS WHAT HE IS GOING TO DISCUSS TODAY. NOW OUR SECOND SPEAKER, THOMAS, GOT HIS MEDICAL DEGREE AT THE UNIVERSITY OF CINCINNATI, DID MEDICAL TRAINING AT NEW YORK UNIVERSITY, CAME HERE IN 1982 AS A POSTDOCTORAL FELLOW IN THE LABORATORY, WHICH HE NOW HEADS THE LABORATORY OF PARACYTIC DISEASES. HE IS ALSO THE DIRECTOR OF AN NIAID INTERNATIONAL PROGRAM AND RESEARCH IN INDIA AND ALSO IN BALI. HE IS ALSO WIDELY KNOWN, RECOGNIZED AND HIS CONTRIBUTIONS, PARTICULARLY RELATED TO HELMET INFECTION, ARE WIDELY CITED. SO WE ARE VERY GRATEFUL TO BOTH OF YOU FOR BEING HERE AND IN PARTICULAR, WE ARE GRATEFUL TO A YOUNG LADY WHO WILL BE INTERVIEWED AND DISCUSS HER ILLNESS WITH YOU. >> SO THANK YOU VERY MUCH. I’M TOM LITTMAN AND TODAY WE ARE — I’M JUST GOING TO HAVE ONE OF OUR PATIENTS WHO ACTUALLY HAS HAD ONE OF THESE, WHAT I’M NOW GOING TO TALK ABOUT TODAY, ONE OF THE NEGLECTED TROPICAL GREAT NEGLECTED DISEASES, GOING TO TELL US A STORY ABOUT HOW SHE ACQUIRED THIS INFECTION AND THEN OBVIOUSLY IF THEE ARE QUESTIONS, FEEL FREE TO ASK OF HER. BUT MAYBE — BECAUSE I THINK THIS IS — HER STORY IS VERY ANALOGOUS TO MANY OF THE KINDS OF PATIENTS WE SEAR HERE AT THE NIH AND AS I HOPE YOU’LL HEAR AT THE END, WE’LL ALSO GIVE YOU A SENSE FOR HOW WE HAVE BEEN ABLE TO, BY CLOSELY OBSERVING AND TREATING SOME OF THESE PATIENTS COME UP WITH NEW AND INTERESTING OBSERVATIONS, TAKEN US FROM THE CLINIC TO THE LAB AND THEN BACK AGAIN. SO MAYBE YOU COULD JUST START BY TELLING US YOUR AGE AND THEN WHERE YOU TRAVELED AND YOUR PROFESSION AND THEN WHAT HAPPENED TO YOU. >> SURE. SO, I AM 29 YEARS OLD. I WORK FOR A NON-PROFIT ORGANIZATION THAT DOES WORK IN CENTRAL AFRICA REPUBLIC AND DEMOCRATIC REPUBLIC OF CONGO SO I HAD TRAVELED WITHIN SIX MONTHS OF EACH OTHER, I TOOK TWO TRIPS, ONE TO UGANDA AND THEN CENTRAL AFRICAN REPUBLIC AND THEN THE NEXT TO UGANDA, CENTRAL AFRICAN REPUBLI AND CONGO. BOTH OF THESE TRIPS HAPPENED IN OR ONE HAPPENED IN LATE 2015 AND THE OTHER ONE HAPPENED IN APRIL OF 2016. WHEN I RETURNED FROM MY TRIP IN APRIL, 2016, I CAME BACK ON A LONG FLIGHT AND HAD THE USUAL JUST SOME GENERAL SWELLING OVERALL LIKE IN MY ANKLES. I DIDN’T REALLY THINK ANYTHING OF IT. I WENT HOME, SLEPT IT OFF, KIND OF NOTICED IT WAS STILL THERE, AND THEN NOTICED THAT IT WAS PERSISTENT IN MY LEFT LEG, ESPECIALLY MY LOWER LEFT LEG FOR A PERIOD OF TIME AND THEN ONE OF MY FRIENDS ACTUALLY CONVINCED ME, YOU PROBABLY SHOULD GO GET THAT CHECKED OUT BY A DOCTOR JUST TO MAKE SURE YOU DON’T HAVE A BLOOD CLOT. SO I ENDED UP GOING TO MY PRIMARY CARE PHYSICIAN. SHE HAD TESTED ME FOR A BLOOD CLOT. WE DID A COUPLE OF ULTRASOUNDS AND CAME BACK NEGATIVE. DIDN’T FIND ANYTHING WRONG. MY PRIMARY CARE PHYSICIAN JUST WAS LIKE, I’M NOT SURE WHAT IS HAPPENING HERE BUT NOTHING ELSE IS GOING ON. MAYBE YOU JUST HAVE WEAK VEINS. WE ARE NOT REALLY SURE. LET’S MONITOR THIS OVER A PERIOD OF TIME. IF ANYTHING ELSE COMES UP, PLEASE LET ME KNOW AND COME BACK. LET ME FINISH YOU HAVE ANY ADDITIONAL SYMPTOMS. NOTHING ELSE HAPPENED FROM APRIL 2016 UNTIL AROUND LATE OCTOBER OF 2016. SO ALMOST SIX MONTHS LATER, WHEN I STARTED TO GET SOME — AT THE TIME I DIDN’T KNOW BUT NOW I KNOW IT IS SOME REALLY RANDOM ALLERGIC REACTIONS. SO I WAS JUST BECOMING REALLY ITCHY ALL OVER IN RANDOM PLACES. I WAS HAVING SOME REDNESS ON MY SKIN. I’VE NEVER BEEN ALLERGIC TO ANYTHING BEFORE SO I WASN’T SURE WHAT IT WAS. IT WAS KIND OF JUST DEALING WITH IT. FIGURED THAT I DEVELOPED SOME TYPE OF ALLERGY BUT THAT MY DOCTOR WASN’T REALLY GOING TO BE ABLE TO DO MUCH FOR ME. SO I TRIED SWITCHING ALL OF MY PRODUCTS, HYPOALLERGENIC PRODUCTS. NOTHING WAS GOING AWAY. SO THAT LASTED FOR ABOUT SIX MONTHS UNTIL APRIL OF 2017, WHEN I WAS AT MY OFFICE. I WAS WORKING. MY COLLEAGUES WERE AROUND ME AND I HAD FELT IN MY RIGHT EYE IN THE CORNER OF MY RIGHT EYE, I FELT LIKE WHAT FELT LIKE WAS AN EYELASH STUCK THERE. I FELT SOME IRRITATION. IT WAS JUST LIKE OKAY THAT IS INTERESTING. WENT TO THE BATHROOM, DIDN’T SEE ANYTHING THERE. MY EYE WAS DEFINITELY IRRITATED. IT WAS A LITTLE RED AND BLOODSHOT BUT WASN’T FEELING ANYTHING ELSE. DECIDED THAT I WAS PROBABLY TIME FOR ME TO TAKE A STEP AWAY FROM MY COMPUTER FOR A BIT. I WENT OUT AND WENT FOR A DRIVE AND I PULLED INTO A PARKING GARAGE AND I WAS STARTING TO FEEL SOMETHING A LITTLE DIFFERENT IN MY EYE. IT WAS ACTUALLY ON THE INSIDE OF MY RIGHT EYE. WHAT I WOULD DESCRIBE AS FELT LIKE A — ONLY DESCRIBE IT AS A PULSING OR THROBBING SENSATION AND I WAS LIKE, THAT IS INTERESTING AND IT FEELS DIFFERENT. I IMMEDIATELY PULLED THE MIRROR DOWN AND SAW SOMETHING IN MY EYE WHICH AT THE TIME, WAS IN MY HEAD, I WAS LIKE THAT IS NOT WHAT YOU’RE SEEING. YOU’RE STRESSED OUT. YOU’RE TOTALLY OKAY. IT LOOKED LIKE A SMALL WORM. SO IT WAS VERY VISIBLE. IT WAS MOVING IN MY EYE. SO MY FIRST REACTION WAS, THAT’S NOT YOU’RE SEEING. BUT THEN I DID A QUICK GOOGLE SEARCH OF WORM IN EYE AND THE FIRST PHOTO THAT CAME UP MATCHED EXACTLY WHAT I WAS SEEING. I WENT TO THE CDC WEBSITE AND ALL OF THE SYMPTOMS AND THE TIMELINE MATCHED. SO IT HAD BEEN ABOUT A YEAR SINCE I WAS BACK FROM MY TRIP. EVERYTHING MATCHED UP. SO, THEN THAT IS WHEN I DECIDED TO RETURN TO MY DOCTOR AND SAY, I FOUND THIS THING CALLED LOWA LOWA. IT SEEMS THAT I HAVE ALL THE SYMPTOMS HERE. THE TIMELINE MATCHES UP AND WE ARE PRETTY MUCH WENT TO MY PRIMARY CARE DOCTOR AND SAID I WANTED TO BE TREATED FOR THIS OR CAN YOU DO A BLOOD TEST FOR THIS? AND THEN A SERIES OF SEEING MY PRIMARY CARE PHYSICIAN AND THEN AN INFECTIOUS DISEASE PHYSICIAN WAS THEN REFERRED TO NIH. >> CAN YOU JUST DESCRIBE I A LITTLE BIT MORE ABOUT WHEN YOU HAD THE WORM CRAWLING ACROSS YOUR EYE. DID YOU HAVE ANY OTHER SYMPTOMS? MANY PATIENTS DESCRIBE SIGNIFICANT ITCHINESS OR PAIN WITH ANY OF THAT PART OF IT. >> AT THAT TIME, WHEN IT WAS LOCALIZED IN MY EYE, NO. I DIDN’T HAVE ANYTHING BESIDES THE IRRITATION THAT I WAS EXPERIENCING EARLIER WHICH AGAIN TO ME THE BEST WAY TO DESCRIBE THE PAIN LEVEL WAS LIKE IF YOU HAVE AN ANNOYING EYELASH STUCK IN YOUR EYE. YOU CAN’T GET IT OUT. YOU DON’T KNOW WHERE IT IS. BUT BESIDES THAT, NOT REALLY A LOT OF ITCHINESS. THERE WAS A LOT OF REDNESS. MY EYE WAS PRETTY BLOODSHOT FROM THE OUTSIDE. BUT YOU COULDN’T SEE ANYTHING ELSE. I ACTUALLY — I WAS AT THE GROCERY STORE, WENT BACK TO MY OFFICE, BY THE TIME I CAME BACK AND TOLD MY COLLEAGUES WHAT I HAD SEEN, NOTHING WAS PRESENT IN MY EYE. THEY WERE CONVINCED THAT I DID NOT SEE A WORM IN MY EYE. IT WASN’T POSSIBLE. SO, THERE WAS NOTHING ELSE ASSOCIATED WITH THAT. HOWEVER, I WAS STILL HAVING A QUITE SEVERE FOR ME, ALLERGIC REACTION THROUGHOUT MY COULD JUST DURING THAT TIME PERIOD. ON MY ARMS, I CAME BACK WITH SOME BAGS I WAS CARRYING AND IMMEDIATELY WHEN YOU PUT THEM DOWN, YOU COULD SEE THE REDNESS ON MY ARMS JUST FROM OLDING THE BAGS. >> AND THEN ONE LAST QUESTION AND WE’LL CUT TO THE FACT WE DID TREAT YOU OVER TIME. BUT SOMETHING HAPPENED ALONG THE WAY AFTER OR DURING THE TREATMENT. DO YOU WANT TO MAYBE TELL EVERYBODY ABOUT THAT. >> YES. SO, I WAS REFERRED TO NIH. WE STARTED GOING THROUGH THE PROCESS OF TREATMENT. I WAS BRIEFED BY THE DOCTORS VERY WELL. VERY WELL INFORMED ON WHAT THE PROCESS WAS AND HOW LONG TREATMENT WAS. AND THE PROCESS OF WHAT IS THE MEDICINE WOULD DO TO THE WARMS THAT WERE IN MY BODY. AND SO ONE OF THE THINGS THAT I WAS TOLD WAS ABOUT HOW THE ADULT WORMS ARE KILLED BY THE DRUG THAT I WAS TAKING. AND I WAS TOLD THAT THEY WOULD — I WOULDN’T NOTICE THEM. THEY WOULD CALLSIFY UNDER MY SKIN. I MIGHT HAVE A SMALL BUMP SOMEWHERE. SO IT WAS IMPORTANT TO NOTE THAT WHILE I WAS EXPERIENCING THE SWELLING? MY LEFT LEG AND IT WAS REALLY ONLY IN MY LEFT LEG THAT I EVER EXPERIENCED IT, IN RECOLLECTION, I DO REMEMBER HAVING A BITE THERE WHEN I CAME BACK. THAT WAS KIND OF ON MY BACK LEFT THIGH. AND SO THAT HAD BEEN KIND OF AN AREA OF FOCUS EVERY TIME I RETURNED TO NIH TO SEE IF THE SWELLING WAS CHANGING. IF IT MOVED ANYWHERE ELSE. AND IN MY FIRST COURSE OF TREATMENT, I NOTICED ONE DAY JUST IN MY UPPER THIGH THAT I WAS FEELING SOME IRRITATION THERE AND I WAS LIKE THAT IS INTERESTING. I WENT HOME. DIDN’T REALLY THINK ANYTHING OF IT. IT WAS DURING THE SUMMER SO IT WAS HOT AND SWEATY TIME. SO JUST LIKE, MAYBE I’M JUST IRRITATED FROM WEARING SOME TIGHT PANTS. I WAS GETTING CHANGED AND I THOUGHT WHAT I SAW WAS A PIECE OF ELASTIC. SO THAT IS WHAT TO ME IN MY BRAIN I DIDN’T THINK ANYTHING OF IT. SO I JUST WAS LIKE, THERE IS A PIECE OF ELASTIC STUCK TO MY SKIN. PULLED IT OFF IMMEDIATELY. WAS NOT FEELING ANYMORE IRRITATION OR PAIN AND THEN I REALIZED WHEN I HAD SET IT DOWN THAT IT WAS MOVING. AND SO, THEN FROM THERE RECOGNIZED THAT THAT WAS LIKELY A WORM. I GOT IN TOUCH WITH THE DOCTORS HERE. I WAS LIKE IS THIS POSSIBLE? COULD THIS HAPPEN? AND WAS TOLD IT IS PRETTY RARE BUT IS POSSIBLE. AND THEN FROM THERE WAS PAYING A LOT OF ATTENTION TO WHAT WAS HAPPENING IN THAT LEG AS MY TREATMENT WAS HAPPENING AND I NOTICED ANOTHER SMALL BUMP, THE BEST WAY TO DESCRIBE IT IS IT LOOKED LIKE ALMOST LIKE A PIMPEL ON MY LEG. AND I ACCIDENTLY SCRATCHED IT AND ANOTHER WORM THAT WAS THERE AS WELL. >> OKAY. I THINK THAT GIVES YOU THE FLAVOR AT LEAST OF THE INFECTION. DOES ANYBODY HAVE ANY QUICK QUESTIONS AND WE’LL JUST GO FROM THERE. THANK YOU VERY MUCH. >> [ OFF MICROPHONE ] >> I WOULD DEFER TO YOU TO DESCRIBE A LITTLE BIT MORE IN THE TECHNICAL SCOPE. FOR ME THEY WERE LIKE THAT LONG, LIKE MAYBE AN INCH OR INCH AND A HALF. >> THEY ARE USUALLY ONE TO TWO CENTIMETERS, VERY THIN AND OBVIOUSLY VISIBLE TO THE HUMAN EYE. >> [ OFF MICROPHONE ] >> TALK ABOUT YOUR EXPOSURE. >> SO — >> [ OFF MIC ] >> I’LL JUST REPEAT THE QUESTION. THE QUESTION WAS, WHAT KIND OF EXPOSURE DID YOU HAVE IN CENTRAL AFRICA? >> SO, I WAS NOT IN ANY OF THE CAPITAL CITIES. MY ORGANIZATION WORKS IN EASTERN CENTRAL AFRICAN REPUBLIC. IT’S VERY FAR FROM THE CAPITAL T IS A VERY REMOTE AREA CONSIDERED THE BUTCH OR THE JUNGLE. THE SAME THING IN DEMOCRATIC REPUBLIC OF CONGO. I WAS IN A PLACE CALLED DENNING YOU, WHICH IS ALSO FAIRLY FAR FROM THE CAPITAL, CONSIDERED MORE — IT’S MORE — DENGU — IT’S MORE POPULATED THAN WHERE I WAS BEFORE BUT I WAS ALSO IN GRAMBA NATIONAL PARK AS WELL. SO IF YOU KNOW ANYTHING BUT REGION, THAT IS A PROTECTED PARK THERE. BUT BASICALLY JUST WILDLIFE, A LOT OF JUNGEL AND A LOT OF FORREST. >> ANY OTHER QUESTIONS? >> WHEN WAS THE SECOND WORM ISOLATED? >> WHAT WAS IT? DID WE GET THE DIAGNOSIS FOR THE SECOND ONE? >> SHE HAD A DIAGNOSIS ALREADY. THIS IS LOWA LOWA AND IT WAS AN ADULT LOWA LOWA PARASITE THAT CAME OUT FOLLOWING TREATMENT THAT CAME TO THE SKIN AND IN THE PROCESS OF DYING PROBABLY SET UP A LITTLE BIT OF INFLAMMATION THAT WAS SO SUPERFICIAL THAT WHEN SCRATCHED IT POPPED UP. >> OKAY — >> YES. >> OKAY. GREAT. >> THANK YOU VERY MUCH. [ APPLAUSE ] >> THANK YOU VERY, VERY MUCH FOR SHARING YOUR STORY WITH US. >> SO, WE ARE GOING TO USE OUR PATIENT AS A SORT OF A LEAD-IN TO DISCUSSING REALLY NEGLECT THE TROPICAL DISEASES IS THE TITLE. AND WE ALREADY HEARD EARLIER THAT IT REALLY, I THINK IN THE MODERN AGE BEGAN WITH THIS GREAT NEGLECTED DISEASE NETWORK THAT KEN WARREN STARTED. AND IT LASTED REALLY MAYBE 10 YEARS. I THINK WHEN THEY REALLY GOT STARTED, IT REALLY WAS IN PROGRESS FOR ABOUT EIGHT YEARS AND THE IMPORTANT PIECE I THINK HERE WAS THAT IT FOLLOWS ON THE CAREER OF PARASITE-ORIENTED SCIENTISTS. AT THE TIME, THE DISEASE FOCUS WAS PARACYTIC INFECTIONS BUT IT INCLUDED MALARIA. AND YOU’LL SEE WHERE THAT BECOMES IMPORTANT IN A LITTLE WHILE. SO, FAST FORWARD TO THE YEAR 2000 OR 1999, AND JEFFREY SACHS ON AND A GROUP OF CONVENED A CONFERENCE IN THE UNITED NATION TO DEVELOP THE MILLENNIUM DEVELOPMENT GOALS OR MDGs. AND THIS WAS A 15-YEAR PROGRAM TO SORT OF MAKE THE WORLD A BETTER PLACE. THAT WENT FROM ERADICATING EXTREME POVERTY AND HUNGER TO DEVELOPMENT. AND IT WAS SUPPOSED TO HAPPEN ALL BY 2015. AND IF YOU SEE THERE, THERE WAS SOME THINGS THAT WERE HEALTH RELATED AND IMPROVED MATERNAL HEALTH AND CHILD HEALTH MORTALITY BUT NUMBER 6 WAS COMBAT, HIV/AIDS AND MALARIA AND OTHER DISEASES. AND SO, AS WE ALL KNOW, THERE WAS EVEN BEFORE THAT A HUGE EFFORT AND DOLLARS GIVEN TO HIV/AIDS AND MALARIA AND TUE BERK LOWSIS AND THEY LUMPED ALL — TB AND THEY LUMPED ALL THESE OTHER DISEASES. AND THIS GOT A NUMBER OF PEOPLE BOTHERED AND FROM THESE NTBs THIS HAPPENED. AND IT IS TRUE IT ATTRIBUTED TO AND POPULARIZED BY THREE COLLEAGUES OF OURS, SPIRIT ALAN AND DAVID AND IT GREW OUT OF FRUSTRATION FROM THE USE OF THE TERM, OTHER DISEASES, IN THIS MDG NUMBER 6 BECAUSE IT CREATED A VERY CLEARLY A TWO-TIERED SYSTEM WHERE HIV AND MALARIA WAS VERSUS EVERYTHING ELSE. AND IT REALLY MADE PUBLIC ADVOCACY FOR THESE OTHER DISEASES, THESE NEGLECTED DISEASES REALLY IMPOSSIBLE. AND IT REALLY LEFT OUT THESE OTHER DISEASES AND MOST DISCUSSIONS ON GLOBAL HEALTH. AND SO, IT REALLY TURNED OUT TO BE A MARKETING STRATEGY IF YOU WILL. AND IT HAS ACTUALLY, AND I’LL GIVE YOU A COUPLE OF REASONS WHY. REALLY DRIVEN A HUGE BOOST IN FUNDING AND IDENTITY FOR A LOT OF PEOPLE WHO STUDY THESE NTDS AND IT’S NOT UNCOMMON NOW TO HAVE DEPARTMENTS AND UNIVERSITIES AND OTHER PLACES THAT HAVE AN NTD-FOCUS. SO WHAT ARE THESE NTDs? SO, THE REASONS THEY ARE NEGLECT SAID THAT THEY ARE THE MOST PREVALENT INFECTIONS OF POOR PEOPLE AND UP TO HALF OF THE 2.7 BILLION BEAM LIVE ON LESS THAN TWO DOLLARS A DAY, ARE AFFECTED BY THESE OR INFECTED BY THESE. THESE ARE NON EMERGING ANCIENT CONDITIONS. THEY HAVE BEEN AROUND — THERE IS BIBLICAL TEXT AND PRE-BIBLICAL TEXT OF MANY OF THESE CONDITIONS. THEY TEND TO OCCUR IN INDIGENOUS POPULATIONS. AND THE OTHER THING THAT THEY DON’T DO IN LARGE PART, IS THEY DON’T KILL. THEY ARE CHRONIC DISABLING CONDITIONS THAT CAUSE GROWTH DELAYS, BLINDNESS, SOCIAL STIGMA, DISFIGUREMENT. SHOWN ON THE RIGHT IS THE PATIENT WITH A LYMPHATIC — AND YOU CAN SEE THE MASSIVE ELEPHANTITIS IN THAT PATIENT AS — TAKEN IN INDIA AS PART OF A HYGIENE CAMPAIGN TO TREAT THIS. AND WE KNOW NOW FROM A LOT OF SOCIOECONOMIC STUDIES THAT THESE ARE POVERTY-MOW MEETING CONDITIONS DRIVING POOR PREGNANCY OUTCOMES, PRODUCTIVE CAPACITY AND CHILD DEPARTMENT AND EDUCATION. SO — CHILD DEVELOPMENT. WHEN YOU LUMP ALL OF THESE NEGLECTED TROPICAL DISEASES TOGETHER IN ONE SORT OF MONA KER, AND THEN YOU LOOK AT THE 10 LEADING CAUSES OF LIFE YEARS LOST DISABILITY AND PREMATURE DEATH, YOU CAN SEE THESE NTDs FALL ABOVE MALARIA AND TB AND BELOW SOME OF THESE OTHERS. BUT SUFFICE IT TO SAY IT MAKES A VERY POWERFUL AUGMENT THAT ACTUALLY DEALING WITH THESE INFECTIONS ACTUALLY WILL LEAD TO IMPROVED QUALITY OF LIFE. SO WHAT ARE THEY? SO IT TURNED OUT THAT AS YOU CAN IMAGINE, EVERYBODY WANTED A PIECE OF THE NTD PUZZLE AND/OR PORTFOLIO. AND IT STARTED OUT WITH 13 OR 14 TARGETED INFECTIONS AND NOW HAS EXPANDED TO INCLUDE 18 OR 20 DIFFERENT CONDITIONS THAT ARE CAUSED BY PROTOZOA, A SINGLE-CELL PARACYTIC ORGANISM. VIRUSES SUCH AS RABIES AND DENNINGY AND CHIKUNGUNYA, SOME OF THE BACTERIA, PARTICULARLY LEPROSY AND TRACKOMA. AND A WHOLE BUNCH OF HELMINTH INFECTIONS AND THEN RECENTLY ADDED ON TO THESE ARE SCABIES, SOME OF THE DEEP MYCOSIS AND SNAKE BITE AS A SERIOUS PROBLEM IN THE TROPICAL WORLD. SO OUR FOCUS HERE AT THE NIH OR MY GROUP FOCUS ARE THESE HELMINTH OR WORM INFECTIONS IS A FANCY WORD FOR WORM, REALLY. AND YOU CAN SEE THEY GET CATEGORIZED INTO CODES AND NEMATODES AND YOU CAN SEE THE MAJOR SPECIES THAT EFFECT HUMANS AND HOW MANY PEOPLE ARE INFECTED WITH EACH OF THESE. AND JUST SUFFICE IT TO SAY OUR GROUP HAS FOCUSED LARGELY ON THESE INFECTIONS UP ON YOUR LEFT IN THE MIDDLE LEFT AND SPECIES OF MALARIA PARASITES. AND THE NUMBER OF PEOPLE INFECTED OF LOWA LOWA ARE CONSIDERED MAJOR HUMAN PATHOGENS. AND I NEED TO POINT OUT THAT THEY ARE THE SECOND LEADING CAUSE OF DISABILITY WORLDWIDE AND THIRDLY, IT’S IMPORTANT TO NOTE THAT WITH THE EXCEPTION ABOUT ONE SPECIES OF FEARINGIA, ALL OF THESE HAVE ONLY HUMANS AS THEIR RESERVOIR. SO THESE ARE VECTOR-BORN DISEASES. AND SO PRETTY MUCH EVERYTHING THAT THAT WE HAVE TO DO TO STUDY THESE INFECTIONS HAVE TO BE DONE IN HUMAN POPULATIONS. SO THEY ARE NEGLECTED BY EVERYBODY BUT HEAVY METAL BANDS IN GERMANY PRIMARILY BUT THAT BEING SAID, THEY HAVE MADE IT TO BE TO THE BIG TIME AS SHOWN BY THESE ALBUM COVERS. WHAT WE WILL FOCUS IN ON TODAY IS THE UPPER RIGHT-HAND CORNER, LOWA LOWA. SO THIS IS WHAT OUR PATIENT TODAY HAD AND I THINK IT’S A GREAT EXAMPLE OF HAVING PAID VERY CLOSE ATTENTION TO THE CLINICAL MANIFESTATIONS OF THIS INFECTION, HAS ALLOWED US TO LEARN A LOT ABOUT THE SORT OF BASIC SCIENCE SURROUNDING THIS AND ALSO TO THEN USE THAT BASIC SCIENCE FOR THERAPEUTIC GOOD. AND THAT IS THE KIND OF STORY I’M GOING TO TRY TO TELL TODAY. SO LOWA LOWA IS CAUSED BY THE PARASITE, LOW ISIS. IT’S TRANSMITTED BY A DEAR FLY. I’LL SHOW YOU A PICTURE IN A SECT. IT HAS A COMPLICATED LIFE CYCLE BUT THE MICROIF ILARIA, THE STATE THAT PASSES FROM THE HUMAN TO THE FLY AND THEN BACK TO THE HUMAN AGAIN IS CALLED A MICROIF ILARIA. THAT’S NOT THE ADULT WORM. THE ADULT WORM LIVES IN THE SUBCUTANEOUS TISSUE LARGELY AND MIGRATES. IT HAS A GEOGRAPHIC DISTRIBUTION THAT IS PRIMARILY CENTRAL AFRICA, A LITTLE BIT IN WEST AFRICA AND PREVALENCE SOMEWHERE BETWEEN 13-15 MILLION PEOPLE AND ONLY HUMANS ARE INFECTED. SO THIS IS JUST A GEOGRAPHIC DISTRIBUTION MAP OF LOWA LOWA INFECTION AND THE BRIGHTER THE ORANGE OR BROWN COLOR, THE MORE INTENSE THE INFECTION OR MORE PREVALENT THE INFECTION IN THESE VARIOUS COUNTRIES AND YOU CAN SEE CAR AND DRC WHERE OUR PATIENT TODAY ACQUIRED THIS INFECTION, ARE REALLY TWO OF THE MOST HIGHLY-ENDEMIC COUNTRIES FOR THIS INFECTION. THIS IS THE LIFE CYCLE. THIS IS THE DEER FLY THAT TRANSMITS THE INFECTION AND SUFFICE IT TO SAY THAT THE FLY PICKS UP THE MICROIF ILARIA IN THE BLOOD MEAL OVER A TWO-WEEK PERIOD OR SO. THEY DEVELO INTO THOSE L3s, THE BOTTOM ONE, THE INFECTED STATE, THE PARASITE AND THEN THOSE ARE TRANSMITTED TO ANOTHER HUMAN AND THEN THEY DEVELOP. AND IT TAKES SOMEWHERE BETWEEN PROBABLY 6-12 MONTHS BEFORE THE ADULT MALES AND FEMALES PRODUCE. SO FROM THE TIME YOU ARE INFECTED TO THE TIME YOU’RE ASYMPTOMATIC, IT CAN OFTEN BE A YEAR OR 18 MONTHS. IT’S IMPORTANT TO KNOW LOOKING AT PATIENTS, THAT THE TIME OF TRAVEL TO THE TIME OF SYMPTOMATOLOGY OFTEN TAKES A GOOD SIGNIFICANT PERIOD OF TIME AND THAT HAS TO DO WITH THE PARASITE DEVELOPMENT. SO CRIN CALL MANIFESTATIONS ARE DEPICTED HERE. AND INTERESTINGLY — CLINICAL — THIS IS TRUE OF MOST PARACYTIC INFECTIONS, THE LARGE NUMBER OR LARGEST NUMBER OF PEOPLE WHO ARE TRULY INFECTED HAVE A CLINICALLY ASYMPTOMATIC CONDITION OR A SUB CLINICAL CONDITION. AND WHEN YOU GET PATHOLOGY, IT’S EITHER NON-SPECIFIC IN THE CASE OF LOWA LOWA, YOU GET ITCHINESS, AS OUR PARITY HAD TODAY, HIVES, OCCASIONALLY MYALGIA. AND THE TWO CLASSIC SYMPTOMS THAT SORT OF MAKE US UNDERSTAND WHAT THIS IS SOMETHING CALLED OCALA BAR SWELLING AND THIS EYE WORM. AND THE OTHER PIECE TO REMEMBER IS THAT YOU CAN, BECAUSE OF THE HOST’S RESPONSE TO THESE PARASITES, YOU CAN END UP GETTING SIGNIFICANT COMPLICATIONS OF THINGS LIKENED OH, MY CARDIAL FIBROSIS OF THE HEART, RENAL DISEASE, CNS INVOLVEMENT WITH ENCEPHALOPATHY OR EN TRAMPMENT NEUROPATHY MUCH LIKE CARPAL TUNNEL. YOU COULD ARGUE HAVE A ASYMPTOMATIC CONDITION. WHY BOTHER? IT’S NOT DOING TOO MUCH HARM APART FROM THE OCCASIONAL WORM ACROSS YOUR EYE BUT TO PREVENT SOME OF THESE SIGNIFICANT COMPLICATIONS WE WANT TO TREAT AS EARLY AS POSSIBLE. SO THIS IS WHAT A CALL BAR SWELLING LOOKS LIKE. AREAS OF MIGRATORY AND ANGIOEDEMA THAT TYPICALLY OCCUR ANYWHERE ON THE BODY. IT’S HARD TO PHOTOGRAPH SOMETIMES BUT I THINK YOU CAN APPRECIATE THE TOP OF THE HAND ON THE RIGHT THERE BEING QUITE SWOLLEN OR YOU CAN SEE THE WRIST ON THE OTHER SIDE ON YOUR LEFT THAT ALSO IS THIS SWELLING. IT OFTEN WILL COME AND LAST FOR 3-4 DAYS AND MIGRATE TO ANOTHER AREA AND WE THINK THAT THIS IS — WE KNOW THIS IS PROBABLY RELATED TO THE ADULT PARASITE’S MOVING ACROSS THE SUBCUTANEOUS TISSUE AND LEAVING ITS ANTIGENS BEHIND IN OUR BODY HAVING, LET’S CALL IT AN ALLERGIC-TYPE REACTION TO THOSE ANTIGENS. THE THING THAT EVERYBODY REMEMBERS AND WAS DESCRIBED BEAUTIFULLY BY OUR PATIENT TODAY, IS THE EYE WORM. AND IT IS NOT IN THE EYE, PER SE. WELL, IT IS. BUT IT’S SUBCONGENTYPHA OF YOUR EYE. AND IT MOVES. SO THINK ABOUT THIS AS THE SAME PLANE AS THE SKIN OF THE EYE. AND SO PROBABLY IT’S JUST LIKE IT’S MOVING IN OUR SUBCUTANEOUS TISSUE, EVERY NOW AND THEN IT CROSSES THE EYE AND THIS IS REALLY THE HALLMARK OF THE INFECTION AND OBVIOUSLY WHAT MOST PEOPLE REMEMBER ABOUT IT. LOW ICE SIS ALSO CALLED THE AFRICAN EYE WORM AND YOU CAN IMAGINE WHY. THIS IS HOW OFTENTIMES PATIENTS GET TO REFERRED TO US IN THIS COUNTRY: THIS IS A TAXI DRIVER IN WASHINGTON, D.C. AND MADE HIS WAY TO ER AT GEORGETOWN AND WAS TOLD HE DIDN’T HAVE ANYTHING TO WORRY ABOUT AND THEN HE INSISTED. HE SAID, I KNOW I’M FROM CAMEROON AND I HAVE LOWA AND THEY CALLED THE OPTIMAL JUST THEY POPPED IT OUT. THIS IS JUST LIKE OUR OWN PATIENT TODAY, FOR EVERY ONE YOU HAPPEN TO SEE, THERE IS
PROBABLY& MANY MORE LYING ELSEWHERE. SO, ONE OF THE BEAUTIFUL THINGS ABOUT THE NIH AND OUR CLINICAL PROGRAM HERE IS THAT IT GAVE US THE OPPORTUNITY TO BE REFERRED PATIENTS WITH INFECTIONS AND WHEN I FIRST STARTED HERE, I GOT REFERRED PRIMARILY PEOPLE WHO WERE MISSIONARIES AND PEACE CORPSES AND PHOTO JOURNALISTS WHO PRESENTED WITH LOWA LOWA. AND IT WAS INTERESTING WAS IT WASN’T ANYTHING LIKE I HAD READ IN THE TEXTBOOKS ABOUT THE MANIFESTATION OF LOWA LOWA. SO WE COMPARED THOSE WHO ARE BORN AND BRED TO THOSE WHO ACTUALLY ACQUIRED IT DURING TRAVEL. AND COMPARED TO STANDARD SYMPTOMS. WHEN YOU CAN SEE IS IN OUR FIRST SET OF PATIENTS WHEN WE WERE COMPARING PATIENTS WE SAW HERE TO PATIENTS WE STUDIED IN WEST AFRICA, THAT THE LIKELIHOOD OF HAVING CALL BAR SWELLING WAS MUCH GREATER IN THE TRAVELERS THAN IT WAS IN THOSE BORN TO EN DEMIC REGIONS. AND SIMILARLY, THOSE PEOPLE WITH RELATIVELY ASYMPTOMATIC INFECTIONS, NO SYMPTOMS WHATSOEVER WAS REALLY JUST THE OPPOSITE. SO, PATIENTS WHO TRAVELED AND NOW WE HAVE A SENSE OF THIS HAS TO DO WITH THE RELATIVE ACUTENESS OF THEIR EXPOSURE, OR WHERE THEY ARE IN THE EVOLUTION OF THE INFECTION, WERE MUCH MORE LIKELY TO HAVE SIGNIFICANT CLINICAL REACTIVITY TO THE PARASITE. SO, WE WERE ABLE WITH A FELLOW IN THE LAB, JUST RECENTLY TO PULL OUR MUCH-GREATERRER EXPERIENCE OF ONLY PATIENTS WE SAW AT THE NIH AND A LOT OF OUR ORIGINAL OBSERVATIONS WERE FOUND TO BE QUITE SIMILAR. CALL BAR SWELLING MUCH MORE FREQUENT IN THE TRAVELERS. BOTH EYE WORM IN THE ASYMPTOMATIC MICROFILAR AREA PATIENTS MUCH MORE COMMON BORN IN ENDEMIC REGIONS AND THEN THE REST WAS PRETTY MUCH SIMILAR. AND IF YOU THINK ABOUT THE COMPLICATIONS ASSOCIATED WITH THIS, THEY WERE PRETTY MUCH IDENTICAL. SO ONE OF THE THINGS THAT IS SORT OF NICE ABOUT BEING ABLE TO STUDY SOME OF THESE PATIENTS IN DEPTH IS THAT WE WERE ACTUALLY ABLE TO BEGIN TO UNDERSTAND SOME OF THE PATHOGEN SIS OF SOME OF THE COMPLICATIONS. AND THIS IS A BIOPSY OF A PATIENT WITH ENDOMYOCARDIAL FIBROSIS SECONDARY TO LOWA LOWA HERE. AND WHAT YOU CAN SEE ON THE RIGHT IN THE GREEN THERE IS THE HEART MUSCLE ON THE BIOPSY THAT IS STAINED BY GRANUAL PROTEINS. SO THESE PARASITES ARE VERY CAPABLE AND YOU’LL HEAR THIS FROM DR. SHARIA IN THE NEXT TALK, REALLY DRIVING A RESPONSE THAT IS CALLED A TH2-TYPE RESPONSE. AND IN THIS SITUATION, THIS TH2 RESPONSE, DROVE ASCENTA FILLS IN THE HEART AND GOT ACTIVATED AND DUMPED THEIR GRANULAR PROTEINS ON TO THE HEART MUSCLE AND INDUCED FIBROSIS. SO, ONE OF THE OTHER THINGS THAT ALLOWED US TO DO WAS TO STUDY PATIENTS LONGITUDINALLY AND COME UP WITH THIS KIND OF SORT OF UNDERSTANDING OF HOW THE PARASITE SET UP AN IMMUNE RESPONSE. WHAT THE NATURE OF THAT IMMUNE RESPONSE IS AND WHAT HAPPENS OVER TIME. AND I WON’T DWELL ON THIS BECAUSE I THINK ALAN IS GOING TO TALK ABOUT THIS IN MUCH MORE GREAT DETAIL. BUT SUFFICE IT TO SAY THAT EARLY ON IN THE INFECTION FROM ZERO-6 MONTHS OR ZERO TO A YEAR, THERE IS A MARKED INDUCTION OF THINGS THAT ARE ASSOCIATED WITH WORM INFECTIONS, LIKE IG. AND IGT4, AND THEN OVER TIME, MANY OF THESE RESPONSES GET DAMPENED. AND BEING ABLE TO STUDY PATIENTS OVER TIME HAS KIND OF ALLOWED US TO SORT OF FILL IN THAT GRAPHIC I SHOWED YOU WAS A GRAPH THAT WAS 1995 OR 2000. AND NOW WE HAVE MUCH — WE CAN FILL IN MANY MORE DETAILS AND I’M NOT GOING TO GO INTO THIS AT ALL BUT SUFFICE IT TO SAY THAT IT TAKES A VERY LONG PERIOD OF TIME, DECADES, TO DAMPEN DOWN THE INFLAMMATORY RESPONSE SUCH THAT YOU END UP WITH A RELATIVE ASYMPTOMATIC CONDITION ASSOCIATED WITH THIS INFECTION. SO W ALL OF THIS DATA TOGETHER, WE UNDERSTAND THAT WHEN THE PARASITE AND THE HOST IN THE CONTEXT OF THESE MA LARIAL INFECTIONS, THE NORMAL RESPONSE IS TO HAVE A MODERATED OR A SUPPRESSED AIMED MUNE RESPONSE. AND AS A CONSEQUENCE, YOU END UP WITH THIS ASYMPTOMATIC SUBCLINICAL INFECTION. AND IF YOU FAIL TO MODULATE THAT RESPONSE, YOU END UP WITH INFLAMMATION AND THAT INFLAMMATION DRIVES IMMUNE MEDIATED PATHOLOGY. SO IN THE CASE OF LOWA LOWA, THIS CALL BAR SWELLING. IN THE CASE OF ONCOVIRE SIS OR LYMPHATIC INFECTIONS, THINGS LIKE ELEPHANTITIS AND HYDROSEAL. AND WE KNOW THAT A LOT OF THIS SAID ACTUALLY THE SUPPRESSION IS DRIVEN BY THINGS LIKE IL10 AND OTHER IMMUNOSUPPRESSIVE CYTOKINES. SO, WE DON’T JUST SORT OF STUDY PATIENTS. WE OBVIOUSLY WANT TO TREAT THEM AND THERE ARE CURRENTLY TWO DRUGS THAT WE USE AND THE DRUG OF CHOICE IS SOMETHING CALLED DEC. WE DON’T UNDERSTAND ITS MECHANISM OF ACTION BUT WE KNOW THAT IT KILLS BOTH THE ADULTS AND THE MICROIF ILARIA. AND LIKE MOST OF THESE INFECTIONS, THERE ARE POST-TREATMENT OFTENTIMES SEVERE SIDE EFFECTS IN PATIENTS WITH HIGH LEVELS OF CIRCULATING PARASITES BECAUSE THE DRUG SO EFFECTIVE AT KILLING THE MICROIF ILARIA THAT THEY RAPIDLY KILL THEM AND RELEASE ALL THEIR ANTIGENS AND DRIVE INFLAMMATION AND PEOPLE CAN HAVE SEVERE SIDE EFFECTS, AND PARTICULARLY IN THE CASE OF THE LOWA LOWA, WHERE WE ARE VERY CONCERNED ABOUT CENTRAL NERVOUS SYSTEM PROBLEMS. IVERMECTIN WHICH IS A DRUG THAT RECENTLY WON THE NOBEL PRIZE OR DISCOVERY OF WHICH WON THE NOBEL PRIZE A COUPLE OF YEARS AGO, IS ALSO CAN BE USED IN LOWA LOWA BUT IT IS ONLY MICROIF I LAYER SIDEAL AND IT IS ALSO ASSOCIATED WITH SEVERE SIDE EFFECTS. SO WHAT DO YOU DO IN PATIENTS HAVE HIGH LEVELS OF THESE MICROIF ILARIA AND THE ONLY DRUGS YOU HAVE ARE ASSOCIATED WITH A SERIOUS SIDE EFFECTS AND YOU WANT TO TREAT PEOPLE SAFELY? SO ONE OF THE THINGS THAT HAPPENS AND I’LL GOAT THAT OTHER POINT IN A SECOND, AND THIS IS WHAT WAS DESCRIBED BY OUR PATIENT TODAY, IS FOLLOWING TREATMENT, YOU END UP WITH OCCASIONALLY POST-TREATMENT. THIS ERUPTION ON THE SKIN, AND THIS IS THE PATIENT THAT WAS AN IN-PATIENT AT THE NIH THAT WE JUST NICKED AND PULLED THE WORM OUT. SO TO PREVENT SOME OF THESE SORT OF EFFECTS, WE SOMETIMES TREAT PATIENTS WITH CORTICOSTEROIDS AND ONE OF THE THINGS WE DEVELOPED HERE WAS APHERESIS. SO USING BLOOD BANKING MATERIAL, WE CAN REMOVE THE MICROIF ILARIA SUCH WE LOWER THE LEVELS TO THE POINT WHERE WE CAN TREAT PATIENTS AND DO IT SAFELY. SO OVER THE PAST MANY YEARS, WE HAVE DONE THIS IN 46 HEAVILY-MICROFILL REAMIC PATIENTS. AND YOU CAN SEE THAT THESE LEVELS GO DOWN FOLLOWING FERRIESIS AND THE POINT IS WE HAVE TO DO THEM WITH THE PARASITES ARE IN THE BLOOD. AND ONE OF THE FASCINATING THINGS ABOUT MOST OF THESE PARASITES IS THE PERIODISSITY. IF YOU LOOK AT THE UPPER RIGHT-HAND CORNER, LL, IF YOU FOLLOW A SINGLE PERSON AND COUNT THEIR MICROIF ILARIA DURING THE 24-HOUR PERIOD FROM MIDNIGHT TO MIDDAY, AND THEN MIDNIGHT AGAIN, YOU CAN SEE THAT IN THE CASE OF LOLA LOWA, AT 12:00 NOON ON EACH SUCCESSIVE DAYS THE PARASITES ARE IN THE BLOODSTREAM. AND THIS PERIOD WE ARE BEGINNING TO GET AN UNDERSTANDING OF WHAT DRIVES IT BECAUSE AS YOU WILL SEE IN A SECOND, NOW WE HAVE THE GENOME FOR NICE AND WE CAN BEGIN TO SORT OF UNDERSTAND THAT. SO WHEN YOU DO THESE APHORESIES OF THE PATIENTS, THIS IS LOOKING AT A PICTURE FROM A CELL PHONE ON THE — THINK OF THIS, THE BLOOD PACK YOU GET FROM THE BLOOD BANKING MACHINE. YOU CAN SEE THE PARASITES JUST WIGGLING IN THE BLOOD. SO WE CAN ACTUALLY THEN USE THIS TO OUR ADVANTAGE AND WE CAN JUST PURIFY THEM. SORRY. PURIFY THEM. IT’S NOT GOING TO WIGGLE. SORRY. AND WE ACTUALLY THEN DID THIS FROM SEVERAL PATIENTS WHERE WE COLLECTED PURIFIED ALL OF THESE WIGGLING MICROFILARIA — SORRY IT’S NOT MOVING. MAC PROBLEM. AND WE ARE ABLE THEN TO MAKE A SUFFICIENT DN TOO. ACTUALLY DO THE GENOME. AND SO FROM THIS SORT OF ABSOLUTELY KIND OF CLINICALLY-DRIVEN NEED TO REDUCE THE MICROFALARIA, WE ARE ABLE TO COLLECT ENOUGH PARASITES TO AT THE TIME COMPLETE THE LOWA LOWA GENOME. AND SO THE REMAINING A LITTLE BIT OF TIME I HAVE, I’M GOING TO TELL YOU A LITTLE BIT OF A STORY OF HOW WE UTILIZED THAT TO GET TO SOMETHING OF THERAPEUTIC VALUE. SO, WHEN WE DID THE GENOME, WE LOOKED ACROSS THE GENOME AND ALL OF A SUDDEN WE SAW THAT THE PARASITE CONTAINED A SET OF ENZYMES, KINASES, THAT ARE ALREADY TARGETED OF FDA-APPROVED DRUGS AND IN THE RED THERE THE TYROSINE KINASE THAT ARE EXPRESSED BY ALL THE IF I LARIAL PARASITES. IN A SINGLE COPY AND THE TARGET IS A DRUG CALLED, AMONG THEM A DRUG CALLED IMMAT NIB WHICH REVOLUTIONIZED THINGS LIKE LEUKEMIA. SO LISA, AT THE TIME A FELLOW IN THE LAB, TOOK THIS ON AND FIRST WE WERE ABLE TO SHOW THAT THE LOWA LOWA KINASE AS PREDICTED BY THE GENOME, STRUCTURALLY WAS IDENTICAL TO THE CATALYTIC OF THE HUMAN BCR-ABL KINASE. IF YOU LOOK ON THE RIGHT WHERE THE OVERLAP IS, YOU CAN SEE THAT THEY BASICALLY OVERLAP WITH UNBELIEVABLY HIGH DEGREE OF SIMILARITY. AND SUGGESTED THAT WE COULD USE IMMAT NIB, A FOR SAFE ORALLY-DELIVERED DRUG PERHAPS TREAT LOWA LOWA. SO THIS IS A PICTURE THAT IN A SECOND THE MOVIE WILL START. SO SHOWN HERE ARE THE LOW RELATED PARASITES. SORRY. SO SHOWN AT THE TOP IS IN THE ABSENCE OF THE DRUG AND SHOWN AT THE BOTTOM AT THE SAME TIME YOU CAN SEE A LITTLE BIT OF WIGGLING AND MORE ABUNDANT PARASITES IN THE PRESENCE OF THE DRUG. AND THEN FINALLY, WE ARE ABLE TO USE ANTIBODIES TO LOCALIZE IN THE PARASITE WHERE THIS ENZYME IS EXPRESSED AND LARGELY IT IS EXPRESSED IN THE FEMALE REPRODUCTIVE TRACT OF THE IF ILARIA. WHAT YOU ARE SHOWN IS A ADULT WORM IN CROSS SECTION WITH THAT LITTLE RED THING THAT YOU CAN SEE ACROSS IS SEPARATING ONE OF THE PARASITE UTERUS FROM THE OTHER AND WHERE THE MICROIF I LARIAL LIVE IN THE ADULT FEMALE AND WE CAN SHOW THIS IF I LARIAL, TARGET OF THIS WOULD STRONGLY EXPRESSED IN THE REPRODUCTIVE TRACK IN THESE FAYLARIA AND MICROIF ILARIA IN PARTICULAR. SO TO FINISH UP, WHAT WE DID WAS WE PROPOSED THAT WE SHOULD ACTUALLY THINK ABOUT USING OR GETTING A CLINICAL PROTOCOL TO USE AS A SINGLE — ORAL DRUG ACTUALLY REDUCE THESE MICROIF ILARIA TO LEVELS THAT WERE SAFE FOR US TO TREAT WITH ANOTHER DRUG. AND THE REASON THESE SEVERE ADVERSE REACTIONS IS ABSOLUTELY RELATED TO THE LOWA LOWA MICROIF ILARIA COUNT AND THE REPIDILITY WITH WHICH IT DECREASES FOLLOWING TREATMENT. SO SHOWN IN THAT CARTOON OVER THERE IS THE DANGER ZONE SO ANYTHING OVER ABOUT 20,000 MICROIF ILARIA PER MILL AND IF YOU GIVE IVERMECTIN OR ONE OF THE MICROIF ILARIA SIDE EFFECTS, YOU CAN SEE YOU DROP THE LEVEL TO ALMOST ZERO WITHIN 24 HAD OF 48 HOURS. THE IDEA WAS, CAN WE USE THIS OTHER DRUG TO LOWER THE LEVELS DOWN A LITTLE BIT MORE SLOWLY BUT TO A POINT SAFELY WHERE WE CAN NOW TREAT WITH THIS? AND WITHOUT GIVING TOO MUCH AWAY AWAY, OUR PATIENT TODAY ACTUALLY WAS WILLING TO ACTUALLY, PRIOR TO HER BEING DEFINITIVELY TREAT TREATED IN A OBVIOUSLY CONSENSUAL WAY TO, TRY A SINGLE DOSE OF THIS DRUG TO SEE WHAT HAPPENED. AND WHAT YOU CAN SEE IS OVER A SEVEN-DAY PERIOD WITH A SINGLE ORAL DRUG WITH ASSOCIATED WITH ESSENTIALLY NO SIDE EFFECTS AT THE DOSES WE USED, THAT YOU LOWERED THE LEVEL DOWN TO LESS THAN 100 OR SO. AND IS NOW ALLOWING US TO DO A RANDOMIZED CONTROL STUDY FOR THIS IN CAMEROON WHERE OBVIOUSLY THIS HIGH LEVEL OF MICROIF ILARIA IS A PROBLEM. I HOPE I CONVINCED YOU THAT THESE NEGLECTED TROPICAL DISEASES, THE STUDY OF THESE ARE IMPORTANT AND ALSO I’M ABLE VERY CLEARLY TO BE A MODEL TO SORT OF GO FROM THE CLINIC TO THE BENCH AND THEN BACK AGAIN AND HOW I THINK PLACES THAT ALLOW FOR VERY CLOSE OBSERVATION OF THE PATIENT AND A MARRIAGE BETWEEN GOOD CLINICAL CARE AND AT THE SAME TIME, LET’S CALL IT ADJUNCT BASIC SCIENCE SORT OF GETS YOU TO WHERE YOU WANT AND MAYBE A PARADIGM FOR MANY OF THESE OTHER INFECTIONS. THIS THE IS NOT MY CAR BY THE WAY. AND BEFORE I END, I WANT TO MAKE THE CASE THAT THIS IS — ALL THE SCIENCE AND MEDICINE IS A TEAM SPORT. OBVIOUSLY I WANT TO THANK THE MANY, MANY PATIENTS BOTH HERE AND ABROAD THAT HAVE CONTRIBUTED TO OUR UNDERSTANDING, MANY OF MY COLLEAGUES AND ALL OF THESE PLACES, MY CURRENT LAB, MANY OF WHOM SHOWN UP HERE TODAY WHICH I APPRECIATE, AND I WANTED TO JUST POINT OUT ALEASE O’CONNELL IN THE FRONT ROW ON THE RIGHT OF THE LAB GROUP WHO ACTUALLY DID A LOT OF THIS SORT OF WORK ON THE TYROSINE KINASE INHIBITORS AND ITS USE FOR WHAT I TOLD YOU TODAY. SO WITH THAT, I WILL LEAVE YOU. [ APPLAUSE ] >> THANK YOU VERY MUCH. THAT WAS REALLY VERY EXCITING. ANYBODY, PLEASE DON’T HESITATE. IF YOU HAVE A QUESTION — >> SO, REGARDING THE ALLERGY SYMPTOMS. DO YOU THINK THIS IS ALL FROM THE PRODUCT FROM THE WORM? THE WORM AFFECTS THE SYSTEM AND THEN IMMUNE CELLS RESPOND MORE SINCATIVELY TO THE STIMULI? >> RIGHT. SO I THINK THAT THE EFFECTOR PHASE OF THE ALLERGY IS OBVIOUSLY HOST DERIVED. AND MUCH OF THIS IS WE THINK IS IGE MEDIATED. SO AS IS MUCH ALLERGIC REACTIONS ARE. WE THINK THAT THE PARASITES THEMSELVES, THE PARASITE ANTIGENS THEMSELVES ACTUALLY DRIVE BOTH A TH2-TYPE ENVIRONMENT BUT THAT TH2 ENVIRONMENT ALSO INDUCES PARASITE-SPECIFIC IGE. AND THAT PARASITE IGE MEDIATES ON HUMAN MASS CELLS AND OTHER CELLS, A LOT OF THE ALLERGIC REACTIVITY THAT OCCURS. AND IT’S ONE OF THE THINGS WE ARE TRYING TO UNDERSTAND THE INTERRELATIONSHIP BETWEEN HELL MONTHS INFECTIONS AND ALLERGIC DISEASES BECAUSE WITH CHRONIC LONG-STANDING HELL MYTH INFECTIONS IT APPEARS THE ALLERGIC SYMPTOMS ARE DOWN REGULATED. BUT WHAT WE THINK IS ACTUALLY HAPPENING, AT LEAST WHEN YOU GET ALLERGIC SYMPTOMS IS THAT IT’S THE PARASITES DIVING THAT ALLERGIC REACTIVITY. >> SO LET ME ASK YOU A QUESTION. ON YOUR LAST SLIDE THERE, THE NUMBERS ON THE ORDINANT WHERE IN THE PATIENT IT COMES WAY, WAY DOWN, WHAT IS THAT ORDINANT? IS IT SO MANY IF ILARIA. >> SO PER MILL. RIGHT. >> SO THERE ARE 2000? >> 2000 IN OUR — WE WOULD THINK OF THOSE AS A RELATIVELY MODEST NUMBER. SO IN STUDIES THAT I DIDN’T TALK ABOUT TODAY WHERE IN PLACES LIKE IN CAMEROON, FOR EXAMPLE, WHERE WE WORK, IT IS NOT UNCOMMON TO SEE PATIENTS WITH HUNDREDS OF THOUSANDS OF MICROFILARIA PER MILL OF BLOOD. IT HAPPENS ABOUT 2% OF MICROFILARIA POSITIVE PATIENTS BUT YOU CAN GET LEVELS THAT EXCEED TWO OR THREE 100,000 PER MILL OF BLOOD. >> ARE THEY ASYMPTOMATIC TOO? >> SO IT’S REALLY INTERESTING. SO THE HIGHER THE BURDEN OF INFECTION, THE MORE LIKELY THEY ARE TO BE ASYMPTOMATIC. AND WE THINK IT IS ACTUALLY WITH THE EXCEPTION OF THE FACT THAT THEY END UP BEING THE RESERVOIR FOR CONTINUED TRANSMISSION, THAT PROBABLY IT’S TEACHING US SOMETHING ABOUT HOW THE PARASITES ACTUALLY DOWN REGULATE OR SUPPRESS THE IMMUNE SYSTEM AND ALSO SUGGESTS THAT WE KNOW THERE ARE PARASITE ENCODED PRODUCTS THAT MAY ACTUALLY BE USED THERAPEUTICALLY TO DAMPEN EITHER AUTOIMMUNE DISEASES OR OTHER THINGS. THAT’S STILL A WORK IN PROGRESS. >> SO DO OTHER PARASITES WITHIN THIS BIG FAMILY HAVE BCRA? >> SO THEY DO. SO THE IF I LARIAL PARASITES ALL HAVE A SIMILAR OR ALMOST IDENTICAL TYROSINE-LIKE KINASE. AND THEN THE RELATED, SUCH AS SCHISTOSOMES OR THE TREMA TOWEDS HAVE A SIMILAR NOT QUITE AS — IT’S A LITTLE LESS HOMOLOGOUS FROM THE HUMAN BCR THAN THE FLAIRIAL ONES BUT IN THE 60% RANGE OF THE IDENTITY OF THE AMINO ACID LEVEL. SO, IT IS A POTENTIAL, NOT PAN PARASITE, BUT TARGETED PARASITE DIRECTED APPROACH. AND WE ARE DOING THIS WITH SOME OF THE OTHER — SO MAT NIB IS SAVER THAN SOME OF THESE OTHER DRUGS THAT TARGET DIFFERENT KINASES AND SO THERE IS ALWAYS THIS THERAPEUTIC WINDOW WHERE THE BENEFIT AND THE SIDE EFFECTS HAVE TO BE SORT OF BALANCED. >> WHAT IS BRR-ABL DOING IN THE PARASITE? >> SO WE DON’T THINK IT HAS ANYTHING — SO JUST REMEMBER, THE BCR-ABL IN CMV A FUSION PROTEIN BETWEEN A KINASE ENCODED ON ONE SIDE OF THE PHILADELPHIA CHROMOSOME AND FUSED TO — >> THEY HAD A PHILADELPHIA CHROME SNOWSTORM. >> THEY DID NOT. THIS IS — CHROMOSOME — THIS IS JUST LIKE THE HOMOLOGOUS TYROSINE KINASES IN HUMANS THAT ARE NOT ACTIVE, THESE ARE PROBABLY HAVE A ROLE IN THE METABOLISM OF THE CELLS OF THE PARASITE. SO THE FACT THAT IT — THE ONLY ISSUE HAD TO DO WITH THE FACT THAT THE BRC ABLE WAS USED AS TO DISCOVER ESSENTIALLY THESE CLASS OF DRUGS THAT HAVE BEEN HUGELY SUCCESSFUL BUT — AND WE ARE LEVERAGING LARGELY THE PHARMACEUTICAL INDUSTRY IN A SENSE FOR HAVING DONE ALL OF THE SORT OF SAFETY AND STRUCTURE FUNCTION RELATIONSHIPS THAT ALLOWED US THEN TO FIGURE OUT THAT WE COULD PROBABLY GO FOR THIS. THE ISSUE OF COURSE THEN BECOMES COST. SO WE ARE TALKING ABOUT THINGS — RIGHT NOW IMMAT NIB IS EVEN NOW THAT IT IS OFF PATENT IS EXPENSIVE IN MOST PLACES BUT IT IS ACTUALLY A SINGLE DOSE SO IT’S NOT LIFELONG AS IS CML AND THE OTHER THING IS THAT IT IS NOW LISTED AS WON’T W.H.O. ESSENTIAL DRUGS. THEY ARE NOT THINKING ABOUT GIVING IT OUT TO PEOPLE WITH LOWA ALL OVER THE WORLD BUT THE POINT IS IT IS SUBSIDIZED TO A POINT WHERE IT CAN BE GIVEN RELATIVELY IN EXPENSIVELY TO ANYBODY IN THE WORLD. >> SO LAST YEAR, ONE OF OUR SPEAKERS WAS JONATHAN SLIM ATHE DIRECTOR OF THE UNITED STATES GEOLOGIC SURVEY. THEY DO MORE THAN MAKE MAPS. THEY SURVEY THE AFFECT OF GLOBAL WARMING ON THE MIGRATION OF VARIOUS VECTORS. AND ONE OF THE VECTORS THAT IS ON HIS LIST IS THE DEER FLY. AND MY UNDERSTANDING IS, MAYBE IN ERROR FROM THIS, BUT THE DEER FLY, LIKE OTHER FLY VECTORS HAS BEEN DETECTED PARTICULARLY IN SOUTHERN STATES AND SO FORTH. >> SO WE HAVE — CRISIS OPS IN MARYLAND. SO WE DON’T HAVE THE RIGHT SPECIES — [ MULTIPLE SPEAKERS ] >> SO YOU NEED HAVE ENDOGENOUS LOWA LOWA? >> WE TAKE A HUGE RESERVOIR OF PATIENTS WHICH IS PROBABLY NOT GOING TO HAPPEN AND IT ALSO TAKES THE RIGHT CRISIS OPS SPECIES. SO THE ONES THAT WE HAVE HERE IN MARYLAND, FOR EXAMPLE, ARE NOT CAPABLE OF TRANSMITTING IT. SO THERE IS A VECTOR SPECIES SPECIFICITY FOR BOTH THE VECTOR AND THE PARTICULAR PARASITE. SO, YES. >> ANY QUESTIONS? WE DON’T HAVE TIME AFTER DR. SHERA IS FINISHED. SO THANK YOU VERY MUCH. REALLY EXCITING. [ APPLAUSE ] >> I’D LIKE TO BEGIN BY THANKING IRWIN FOR INVITING TOM AND I TO SPEAK TODAY. I HAVE BEEN IN THE AUDIENCE LIKE YOU PEOPLE AND ON MANY OCCASIONS AND THROUGHLY ENJOYED THIS WHOLE SERIES AND IT’S NICE TO BE PART OF IT ON THE OTHER SIDE. SO ANYWAY, I’M GOING TO SORT OF DO A NOW FOR SOMETHING COMPLETELY DIFFERENT SWITCH HERE AND TALK ABOUT MORE OF THE BASIC SIDE OF WORK IN PARACYTOLOGY AND PARTICULARLY IMMUNE RESPONSE TO PARASITES. AND THE BASIC PREMISE OF MY TALK IS SHOWN HERE AND MAYBE A LITTLE BIT ARROGANT, I DON’T KNOW. AND THAT IS REALLY BY STUDYING THE IMMUNE RESPONSE TO PARASITES, WHICH IS SOMETHING THAT WAS SPURRED ON BY THE QUEST TO MAKE VACCINES AGAINST THESE ORGANISMS, THIS HAS PROVIDED FUNDAMENTAL INSIGHT INTO THE NATURE OF BOTH THE INNATE AND ADAPTED COMPONENTS OF THE IMMUNE SYSTEM. PARACYTOLOGY, HAS TOLD US A LOT ABOUT IMMUNOLOGY. AND I’D LIKE TO GO FURTHER AND SAY THAT THIS REPRESENTS A MAJOR CONTRIBUTION OF PARACYTOLOGY TO MODERN BIOMEDICAL SCIENCE. PRETTY ARROGANT, I THINK. SO, THE FIELD THAT I WORK IN AND ACTUALLY A NUMBER OF PEOPLE INCLUDING TOM IS IMMUNOPARACYTOLOGY. AND I HAVE TO SAY THAT WHEN I STARTED OUT IN THE FIELD, THIS WORD DID NOT EXIST. IT WAS SORT OF COBBLED TOGETHER BY SOME PEOPLE. WITH YOU THE DEFINITION IS VERY INSIGHTFUL AND THAT IS IT’S A BRANCH OF IMMUNOLOGY THAT DEALS WITH ANIMAL PARASITES AND THEIR HOSTS. IT’S NOT PART OF PARASIGH TOLLING. IT’S PART OF IMMUNOLOGY. AND THAT IS GOING TO BE KIND OF ANGLE I’M GOING TO TALK TODAY HOW DOES THIS EVOLVE? TWO DIFFERENT FORCES. SOMETHING CALLED THE IMMUNOBIOLOGICAL REVOLUTION. A GREAT EXPLOSION IN IMMUNOLOGIC RESEARCH THAT OCCURRED IN THE 60s AND 70s. AND THIS SLIDE JUST LIST SOME OF THE KEY DEVELOPMENTS DEMONSTRATION THAT LYMPHOCYTES ARE KEY MEDIATORS OF ADAPTIVE IMMUNITY AND THE IDENTIFICATION OF B AND T LYMPHOCYTES AND COOPERATION IN HUMORAL IMMUNITY AND ANTIBODY RESPONSES AND THEN IMPORTANTLY THE DEVELOPMENT OF MONOCLONAL ANTIBODIES AND T-CELL LINES AND CLONES WHICH ENABLE US TO IDENTIFY TARGETS OF IMMUNE RESPONSE. AND THEN, THIS ONE WHICH I’M PARTICULARLY FOND OF WHICH IS DEVELOPMENT OF INBRED AND CONGENIC MOUSE STRAINS AND THE DISCOVERY OF MHC RESTRICTION, WHICH ENABLED US TO DEVELOP PHENOMENAL IMMUNOLOGIC MODELS TO STUDY DISEASE. SO THIS WAS THE IMMUNOBIOLOGICAL REVOLUTION. BUT SIMULTANEOUSLY, WITH THIS WAS AN ENORMOUS EXPLOSION IN THE USE OF VACCINES AND VACCINOLOGY. AND YOU ALL KNOW THIS PRETTY WELL. BUT THIS SLIDE ALWAYS AMAZES ME. AND IF YOU EVER HAVE ANYBODY WHO DOESN’T BELIEVE IN VACCINES OR IS ANTI-VACCINE, SHOW THEM THIS SLIDE. SO THIS IS THE IMPACT OF VACCINATION ON ALL OF THESE MAJOR HUMAN INFECTIONS AND YOU JUST HAVE TO GO OVER IT TO THE FAR RIGHT HERE AND SEE THE ENORMOUS IMPACT ON THE PREVALENCE OF THESE DISEASES THAT VACCINES HAVE CREATED IN HUMAN HEALTH. IT’S A FACT THAT SING OFTEN OVERLOOKED. SO, AT THIS PARTICULAR TIME IN HISTORY, THERE WAS A LOT OF OPTIMISM. AND IN FACT, THERE WAS THIS VERY FAMOUS QUOTE FROM WILLIAM STEWART WHO WAS THE SURGEON GENERAL OF THE UNITED STATES IN 1965 THROUGH 1969. AND HE IS SAID TO HAVE SAID THIS BUT THERE IS A LOT OF CONTROVERSY AS TO WHETHER HE REALLY USED THESE WORDS. AND HE SAID, “IT IS TIME TO CLOSE THE BOOK INFECTIOUS DISEASE. THE WAR AGAINST PESTILENCE IS OVER. ” NOW WE ALL KNOW IN RETROSPECT THIS IS A VERY FOOLISH STATEMENT BECAUSE A FEW YEARS LATER, HIV CAME AROUND THE CORNER AND BLEW EVERYBODY AWAY. THIS MIGHT BE THE FIRST EXAMPLE OF FAKE NEWS. SO ANYWAY, YOU CAN SEE THIS IF YOU WANTED TO BASED ON THE DATA THAT I JUST SHOWED YOU. THE INFECTIOUS DISEASE VACCINATION DATA. BUT ONE AREA WHERE YOU COULDN’T SAY IT WAS IN THE AREA OF PARACYTIC DISEASES AND THIS IS ALREADY BEEN EXPLAINED TO YOU OR INTRODUCED BY BOTH IRWIN AND TOM. AND THIS IDEA OF GREAT NEGLECTED DISEASES OF MANKIND, PARACYTIC INFECTIONS. AND THIS IS AN OLD SLIDE AND THE PREVALENCE OF THESE DISEASES HAS GONE DOWN. AND THE CONTROL MEASURES VARIABLE AT THE TIME AND STILL ARE TODAY, ARE VECTOR-CONTROLLED CHEMOTHERAPY AND HYGIENE. AND AT THIS PARTICULAR PERIOD IN HISTORY WE ARE TALKING ABOUT, THERE WERE NO VACCINE AND AS YOU’LL SEE THEY ARE REALLY FOR ALL PRACTICAL PURPOSES AREN’T TODAY EITHER, WHICH IS A SAD PART OF THIS STORY. SO, AT THE TIME I WAS A YOUNG GRADUATE STUDENT AND TRYING TO DECIDE WHAT TO DO WITH MYSELF FOR MY POSTDOC AND I WANTED TO GET INVOLVED IN SOMETHING THAT WAS MORE TRANSLATIONAL AND HAD MORE TRANSLATIONAL IMPORT FOR HUMAN HEALTH AND WITH SEVERAL OF MY COLLEAGUES WHO ARE SHOWN HERE, WHO ARE FELLOW IMINOLOGYISTS, THERE WILL BE ONE QUIZ IN THIS LECTURE WHICH IS TO FIGURE OUT WHICH ONE OF THESE FOUR PEOPLE IS ME. I CAN TELL YOU IT’S NOT THIS GUY HERE BECAUSE — I CAN’T USE THE POINTER. BUT IT’S NOT THIS GUY BECAUSE HE WAS ONE OF TOM’S MENTORS AT BROWN UNIVERSITY. WE WERE ALL LOOKING FOR SOMETHING TO WORK ON THAT WOULD BE — AND ALL FOUR OF US WENT INTO IT AND WORKING ON A DISEASE CALLED SCHISTOSOMIASIS WHICH EVERYONE USED TO WORK ON YEARS AGO. SO THAT WAS OUR CRUSADE. AND REALLY THIS HIGHLIGHTS THE GOAL-ORIENTED PART OF THIS RESEARCH, WHICH IS TO ELUCIDATE MECHANISMS OF HOST RESISTANCE AND IMMUNOPATHOLOGY IN PARASITIC INFECTION IN ORDER TO DEVELOP VACCINES AND OTHER FORMS OF IMMUNOLOGIC INTERVENTION IN HUMAN AND VETERINARY DISEASE, JUST TO EMPHASIZE TO YOU THAT PARASITES ARE VERY IMPORTANT CAUSES OF VETERINARY DISEASE AND THAT BOTH QUESTS CAN BE LINKED AT CERTAIN LEVELS. SO, WE WENT TO WORK ON SCHISTOSOMIASIS TRYING TO UNDERSTAND THIS VERY COMPLICATED ORGANISM BUT ABOUT 10 OR 15 YEARS LATER, THERE WAS AN ENORMOUS BREAKTHROUGH IN THE FIELD THAT KIND OF HAD THE KERNELS OF EVERYTHING YOU WANTED FROM WHAT I JUST DESCRIBED. THIS IS WORK OF RUTH AND VICTOR WHO ARE THE SWEETHEARTS AND THE FIELD AS YOU CAN SEE HERE. AND THEY WERE BOTH — THESE ARE BOTH SCIENTISTS WORKING ON MALARIA. SOOTH A MALARIOLOGIST AND VICTOR MORE OF A BASIC IMMUNOLOGIST. AND WHAT THEY SHOWED WAS REALLY BASED ON RUTH’S WORK AND I SHOULD MENTION AGAIN THAT THIS IS ANOTHER SET OF MANY TORS FOR TOM. NOT ME. RUTH WAS, RIGHT? AND WHAT SHE SHOWED WAS THAT THERE IS AN INFECTED STAGE OF AND IF YOU IMMUNIZE BYES A IRRADIATED SPORE ZEROITE TO& PROTECT THEM AGAINST CHALLENGE INFECTION, OR EVEN IN EFFECTED MOSQUITOES AND SHE WENT ON TO SHOW THIS WAS MEDIATED BY ANTIBODIES. AND ACTUALLY MADE WHAT WAS THEN A NEW KIND OF TOOL USED A NEW TOOL, MONOCLONAL ANTIBODIES TO SHOW THAT A MONOCLONAL ANTIBODY COULD TRANSFER PROTECTION TO THE DISEASE. AND THIS MONOCLONAL ANTIBODY RECOGNIZED A SERIES OF REPEATS ON THIS MOLECULE WHICH IS CALLED CS. AND THEY THEN CLONED THE ANTIGEN WHICH AGAIN WAS A TECHNICAL FEET AT THE TIME TO CLONE AND EXPRESS AN ANTIGEN. AND THEY DID SO. AND WERE ABLE TO USE THIS ANTIGEN OR PARTS OF IT, TO IMMUNIZE MICE AND GET PROTECTION AND DEVELOP AN EXPERIMENTAL VACCINE AGAINST MALARIA. AND THIS OF COURSE WAS — I MEAN IT WAS VERY EXCITING AND IT WAS — THE LATEST TECHNOLOGY. BUT UNFORTUNATELY, THESE EARLY EXPERIMENTS TURNED OUT NOT TO GO VERY FAR BECAUSE — AND I SHOULD SAY THIS STRATEGY OF USING MONOCLONAL ANTIBODIES TO IDENTIFY ANTIGENS, CLONING AND EXPRESSING THEM, BECAME LIKE A FACTORY EFFORT. EVERY LAB STARTED DOING THIS WITH THEIR PARTICULAR BUG AND WITH THE IDEA THAT IT COULD SIMPLY TAKE THE ANTIGENS THEY GOT, IMMUNIZE AND YOU’LL HAVE A VACCINE AGAINST THE DISEASE THAT YOU WANT. SO, WHEN THIS WAS TRIED WITH OTHER HOST PARASITE MODELS, SUCH AS SCHISTO SEEMS WHICH I WAS WORKING ON AT THE TIME, IT DIDN’T REALLY WORK WELL AT ALL. AND EVEN IN THE MALARIA SYSTEM, PROTECTION BY DEFINED ANTIGEN IN MICE WAS MUCH LESS THAN THAT CONFERRED BY THE LIVE INTACT IRRADIATED PARASITES. FOR SOME REASON THE IRRADIATED ORGANISMS STIMULATED MUCH BETTER IMMUNITY AND THEN WHEN THEY WENT INTO HUMANS, OF COURSE, THERE WAS VERY POOR TRANSLATION IN VACCINE TRIALS. HOWEVER, AS WE’LL SEE AT THE END OF THE LECTURE, THERE IS SOME RECENT ENCOURAGEMENT WITH A KIND OF NEW VERSION OF THIS TYPE OF VACCINE CALLED RTSS. SO THE QUESTION THEN, WE WERE LEFT WITH, WAS HOW TO DESIGN EFFECTIVE VACCINES? AND I HAVE ALWAYS FELT THIS SHOULD BE THE STRATEGY, WHICH IS TO IDENTIFY THE MECHANISMS BY WHICH THE IMMUNE SYSTEM CAN CONTROL A PARASITIC INFECTION AND THEN LEARN HOW TO TRIGGER THOSE IMMUNE RESPONSES AT THE CORRECT LEVEL AND MAINTAIN THEM IF A FORM THAT CAN BE RECALLED UPON PARASITE CHALLENGE. THAT GIVES YOU MEMORY SO YOU CAN HAVE A VACCINE THAT WILL LAST FOR A LONG TIME AND DOESN’T REQUIRE A CONSTANT BOOSTING BY MEDICAL WORKERS. SO, HERE, ONE CONFRONTS SOMETHING ABOUT PARASITES THAT IS VERY SOPHISTICATED. EUKARYOTIC INFECTIOUS AGENCY THAT ARE COMPLICATED AND CO-EVOLVE WITH THE IMMUNE SYSTEM AND GOOD AT EVADING HOST EFFECTOR MECHANISMS REGULATING IMMUNOPATHOLOGY IN ORDER TO PRODUCE LONG-LASTING INFECTIONS. THEIR GOAL IS TO NOT KILL YOU BUT KEEP YOU ALIVE SO THEY CAN TRANSMIT THEMSELVES TO THE NEXT HOST. AND THIS IS A FAMOUS ARTICLE BY BARRY, CALLED GAMES PARASITES PLAY. AND THIS IS PART OF THIS GAMING STRATEGY. SO, BUT SO THAT IS THE NEGATIVE SIDE. ON THE POSITIVE SIDE, THOUGH, PARASITES IN COMMON WITH SOME OTHER PERSISTENT PATHOGENS ARE REALLY VENERABLE SCHOLARS OF THE IMMUNE RESPONSE. AND UNLIKE US, THEY ARE UNDAUNTED BY COMPLEXITY. SO PARASITES LEARNED TO MANIPULATE THE IMMUNE SYSTEM. THEY ARE GOOD IMMUNOLOGISTS. THAT’S WHY BY STUDYING THEM, I THINK WE CAN LEARN A LOT ABOUT THE IMMUNE SYSTEM. SO, THEY SEEM TO BE PARTICULARLY GOOD AT TWO THINGS. AND I CALL THEM EFFECTOR CHOICE. AND WHAT THAT MEANS IS WHAT DIRECTS THE IMMUNE TOSS PRODUCE DIFFERING CLASSES OF IMMUNE RESPONSES? NOT ALL IMMUNE RESPONSES ARE THE SAME. WE HAVE ANTIBODIES. WE HAVE T-CELL MEDIATED IMMUNITY IMMUNITY. WE HAVE A DIFFERENT FLAVORS OF IMMUNE RESPONSES AS I’LL EXPLAIN IN A MINUTE. AND PARASITES SEEM TO REALLY KNOW HOW TO DIRECT EFFECTOR CHOICE. AND THE OTHER THING THAT THEY ARE VERY GOOD AT IS IMMUNE REGULATION. AND YOU HEARD A LITTLE BIT ABOUT THIS IN THE LECTURE IN THE CASE OF HUMAN DISEASE. AND THAT IS HOW EFFECTOR RESPONSES ARE CONTROLLD WHILE MEDIATING HOST PROTECTION AND THE PROBLEM HERE IS THAT YOU CAN INDUCE IMMUNE RESPONSE BUT THERE IS ALWAYS THE POSSIBILITY THAT IN ADDITION TO CAUSING PROTECTION, IT IS GOING TO CAUSE INFLAMMATION AND DISEASE. AND PARASITES SEEM TO HAVE LEARNED HOW TO FIGURE THAT OUT. SO THAT THEY KEEP THE HOST ALIVE AND SO THEY CAN TRANSMIT THEIR CYCLES. SO THE PLACE WHERE ALL OF THIS BEGINS IS IN THIS. THIS IS THE ULTIMATE EFFECTOR CHOICE, I THINK, IN THE INFECTIOUS DISEASE WORLD. AND IT OCCURS IN PARASITES. AND THIS IS SOMETHING THAT I CONFRONTED WHEN I STARTED OUT IN THIS FIELD. AND THAT IS THAT WE REALLY HAVE TWO BASIC FLAVORS OF ORGANISM AND PARASITOLOGY. AND THE IMMUNE RESPONSE TO THEM IS REALLY QUITE DIFFERENT. AS YOU HEARD FROM TOM, HELMINTHS ARE FAMOUS FOR THEIR ABILITY TO INDUCE RESPONSES THAT ARE CLASSICALLY ASSOCIATED WITH ALLERGY. THIS IS IMMEDIATE HYPERSENSITIVITY, IGE, AND MASTO CYTOSIS, AND IN CONTRAST, MOST PROTOSTOME INFECTIONS AND IN PARTICULAR, INTRACELLULAR ARE FAMOUS FOR STIMULATING CELL MEDIATED IMMUNITY AND DELAYED HYPERSENSITIVITY AND LYMPHOCYTE PROLIFERATION. AND THESE ARE IN THE CASE OF THE PROTOZOA, NOT UNLIKE SOME OF THE RESPONSES STIMULATED BY BACTERIA AND IN PARTICULAR INTRACELLULAR BACTERIA. AND THIS WAS ALWAYS A FASCINATING DISTINCTION. AND IT BECAME EVEN MORE INTERESTING WHEN IT WAS FOUND OUT BECAUSE OF THE IMMUNOLOGIC REVOLUTION AND ANALYSIS OF THE ROLE OF T-CELLS THAT BOTH OF THESE RESPONSES WERE HIGHLY DEPENDENT ON CD4 T-CELLS WHICH ARE CALLED HELPER CELLS. AND THEY ARE — AND CD4 T-CELLS AS YOU REMEMBER ARE CELLS THAT ARE CRITICAL IN HOST DEFENSE AND WHY AIDS PATIENTS BECOME SUSCEPTIBLE TO MANY INFECTIONS. SO, THIS WAS REALLY INTERESTING. BUT WHEN YOU THOUGHT ABOUT IT, AT THE TIME, AND IT JUST SEEMED STRANGE THAT YOU COULD HAVE ONE T-CELL THAT WAS MEDIATING BOTH OF THESE EFFECTS. AND IT WASN’T UNTIL LATER ON IN THE 1980S, SO HERE IS THE QUESTION. HOW CAN THE CD4T LYMPHOCYTE GENERATE SUCH DIVERGENT IMMUNOLOGICAL OUTCOMES. AND THE ANSWER CAME FROM SOME VERY IMPORTANT WORK BY THESE TWO GENTLEMAN, TIM MONTHS MAN AND BOB COFFMAN IN THE LATE 80s. AND THEY SHOWED ACTUALLY THAT THERE IS NOT JUST ONE CD4 T-CELL BUT THERE IS AT LEAST TWO, AND THEY WERE DISTINGUISHED BY THEIR PRODUCTION OF CYTOKINES, IMMUNOLOGIC MEDIATORS. AND TH1 CELLS MADE INTERFERE GAMMA AND IL-2, TWO VERY IMPORTANT CYTOKINES WHEREAS THE TH2 CELLS PRODUCE IL4, IL5 AND IL13. ELEGANT WORK WITH T-CELL CLONES. AND THOSE RESPONSES IN TURN WERE ASSOCIATED WITH CLASSICAL CELL MEDIATED IMMUNITY AND ALLERGY. AND SO YOU CAN IMAGINE THAT THIS RIGHT AWAY PROVIDED AN EXPLANATION FOR THIS DICHOTOMY THAT WE SAW IN PARASITIC INFECTION, AND WE WERE ABLE TO — WE AND OTHER LABS, WERE WORKING WITH MONTHS MAN AND COFFMAN, WERE ABLE TO DEMONSTRATE THAT IN FACT THIS WAS THE CASE. THAT HELMINTHS STIMULATE THESE PARTICULAR TH2-TYPE CD4 T-CELLS WHERE INTRACELLULAR PROTOZOA ARE TH1-TYPE RESPONSE. SO THIS IS EFFECTOR CHOICE. AND THE CONCEPT HAS BEEN EXTENDED OVER THE YEARS AND IT TURNS OUT THAT THERE IS MORE THAN ONE TYPE OF T HELPER OR TWO TYPES OF HELPER CELLS. WE NOW HAVE AT LEAST 6 OR 7 OF THEM. THAT IS PROBABLY A LOW-BALL ESTIMATE. AND THEY ARE ALL BASED ON THEIR CYTOKINE SECRETION PATTERNS. AND VERY OFTEN THEY ARE ASSOCIATED WITH THE RESPONSE TO A PARTICULAR TYPE OF ORGANISMS. SO FOR EXAMPLE, TH17 CELLS SEEM TO BE PROMINENT IN THE RESPONSE TO EXTRACELLULAR BACTERIA AND FUNGI AND IN ALMOST THE SAME WAY THAT TH CELLS FAVOR THE RESPONSE TO WORMS AND TH1 INTRACELLULAR PATHOGENS. SO THE CONCEPT REALLY STARTED WITH PARASITES AND HAS BEEN EXTENDED TO OTHER TYPES OF PATHOGENS AND OTHER TYPES OF T-CELL RESPONSES. SO, WHAT WE HAVE DONE IN THE LAB OVER THE YEARS IS TO ADDRESS A NUMBER OF CENTRAL QUESTIONS ABOUT THIS. WE HAVE FOCUSED LARGELY ON THE TH1 AND TH2 RESPONSE DIFFERENCE. AND SO WE WANT TO KNOW WHAT ARE THE FUNCTIONS OF THESE RESPONSES IN HOST RESISTANCE AND DISEASE? PARTICULARLY IN PARASITIC INFECTION? WHAT ARE THE HOST SIGNALING EVENTS THAT DICTATE TH1 VERSUS TH2 OUTCOMES? WHAT SIGNALS OCCUR WITHIN IMMUNE CELLS THAT DRIVE THEM TOWARDS ONE OR THE OTHER OUTCOME? AND THEN WHAT ARE THE PARASITE TRIGGERS OF TH1 VERSUS TH2 DIFFERENTIATION AND HOW ARE THEY RECOGNIZED BY THE HOST? SO WHAT IS IT ABOUT A WORM THAT MAKES IT STIMULATE TH2 AND A PROTOZOA TH1? WHAT IS IT CHEMICALLY OR PHYSICALLY ABOUT IT THAT MAKES IT GO IN EITHER OF THOSE TWO DIRECTIONS? SO THAT IS A KIND OF FUNDAMENTAL QUESTION THAT YOU CAN USE PARASITES TO STUDY. SO, ONE OF THE FIRST THINGS THAT WAS DONE, AND A LOT OF IT HERE IN THE LPD, WAS TO ACTUALLY CHARACTERIZE THE ROLE OF A LOT OF THESE CYTOKINES PRODUCED BY TH1 AND TH2 CELLS IN THE RESPONSE TO THESIS PARASITES, AND INTERFERON GAMMA AND TNF WERE SHOWN TO BE VERY IMPORTANT IN INTRACELLULAR CONTROL OF PARASITE GROWTH AND INFECTIONS LIKE TOXO PLASMA AND OF COURSE IL-2 PRODUCED BY TH1 CELLS IS IMPORTANT FOR LYMPHOCYTE EXPANSION AND DELAYED HYPERSENSITIVITY. A LOT OF WORK ON THE TH2 RESPONSE WHICH IS THE MOST UNIQUE THING ABOUT PARASITES, AND HERE IL4 HAS BEEN SHOWN TO BE IMPORTANT IN THE GENERATION OF THE IGE RESPONSE, WORM EXPULSION. IL75 HELMINTH INDUCED SIN PHILIA AND IL13 IN WORM EXPULSION AND IMPORTANT WORK BY TOM HERE AT THE NIH TISSUE FIBROSIS. SO WE COULD EASILY DEFINE WHAT THESE CYTOKINES WERE DOING IN TERMS OF THEIR RESPONSE THAT WE SEE, BUT THERE WAS A BIG QUESTION AND THAT WAS, IS THE FUNCTION OF THESE TH1 AND TH2 CYTOKINE RESPONSES TO CONTROL A PARASITIC INFECTION? AND THIS IS STILL KIND OF CONTROVERSIAL BUT I THINK THIS REFLECTS MY FEELING AND THE FEELING OF A LOT OF PEOPLE IN THE FIELD, IS THAT IN THE CASE OF TH1 RESPONSE, IT’S FAIRLY CLEAR-CUT THAT THE TH1 CYTOKINES ARE PROTECTIVE. THEY ARE ABLE TO MEDIATE KILLING OF INTRACELLULAR PROTOZOA AND ARE IMPORTANT FOR IT AND OF COURSE THEY PERFORM A SIMILAR ROLE WITH INTRACELLULAR BACTERIA. THE TH2 RESPONSE IS THE ONE THAT IS COMPLICATED. AND ALSO QUITE INTERESTING. SO, DESPITE WORK BY MANY GROUPS, INCLUDING MYSELF WHEN I FIRST STARTED OUT IN THIS FIELD, IT REALLY IS A VERY HARD TO SHOW DIRECT HELMINTH KILLING MECHANISMS THAT ARE INVOLVED WITH TH2 RESPONSE THAT ARE BELIEVABLE AND HOLD UP IN-VIVO. BUT, THE TH2 RESPONSE CLEARLY HAS A MAJOR IMMUNOREGULATORY ROLE AND INFECTION, AND IT PLAYS IMPORTANT ROLLS IN TISSUE HOMEOSTASIS AND REPAIR. SO, IF YOU CONSIDER THE TH2 RESPONSE IN THE OLD DAYS IT WAS THOUGHT THAT ALL TH2 RESPONSES DID WAS MEDIATE ALLERGY AND HELMINTH AND RESISTANCE TO HELMINTHS AND YOU CAN SEE NOW THAT IN FACT THE TH2 RESPONSE, EVEN OR TH2 CYTOKINES, EVEN AT STEADY STATE, PLAY A VERY IMPORTANT ROLE IN TISSUE HOMEOSTASIS AND ALL THESE DIFFERENT PROCESSES LISTED ON THIS SLIDE. AND HELMINTH INFECTION IS REALLY ONLY ONE OF THEM. SO, THIS RAISES ALWAYS FASCINATING QUESTION OF WHERE TYPE II IMMUNITY CAME FROM. AND IF YOU GO BACK AND READ TEXTBOOKS, PROBABLY UP UNTIL JUST A FEW YEARS AGO, IT WILL SAY IN THE TEXTBOOK THAT TYPE II IMMUNITY EVOLVED TO CONTROL HELMINTHS AND I THINK THAT FEELING IS NOW OR THAT IDEA IS NOW KIND OF FADING AWAY. AND IF ANYTHING, YOU MIGHT GO IN THE OPPOSITE DIRECTION AND SUGGEST THAT HELMINTH, THE CONTROL OF HELMINTH INFECTION AND SOMEHOW A SPIN OFF OF THESE OTHER FUNCTIONS OF TYPE II IMMUNITY IN TISSUE HOMEOSTASIS. IN OTHER WORDS BASIC PHYSIOLOGIC ROLE RATHER THAN IN HOST DEFENSE. SO IT’S A FASCINATING QUESTION THAT IS DEBATED A LOT IN THE FIELD. SO, I’M GOING TO NOW MAKE A QUICK SWITCH INTO TH1 AND INTRODUCE A PATHOGEN THAT STIMULATES THE OPPOSITE TYPE OF RESPONSE, WHICH IS TH1. AND THIS PATHOGEN IS T GONDO,& WHICH WORKED ON BY A NUMBER OF INVESTIGATORS AT LPD. AND WHAT IS SO WONDERFUL ABOUT THIS PARTICULAR ORGANISM, IT’S AS A DISEASE IT IS A MAJOR OPPORTUNISTIC INFECTION IN HIV PATIENTS AND THAT IS HOW WE GOT INVOLVED IN IT FROM THE BEGINNING. BUT THE FACT THAT THE TYPE OF IMMUNE RESPONSE THAT INDUCES IS SO POLARIZED TOWARDS TH1, AND THAT IS SHOWN HERE. BASICALLY WHAT HAPPENS IS EARLY IN THE INFECTION, THERE IS A CYTOKINE PRODUCED FROM INNATE CELLS CALLED INTERLEUKIN 12, WHICH DRIVES THE PRODUCTION OF INTERFERON GAMMA, A HOST PROTECTIVE CYTOKINE, AND CONTROLS THE GROWTH OF THE PARASITE IN HOST CELLS AND MEDIATES INTRACELLULAR KILLING. AND IT ALSO PROTECTS THE — AND HELPS TO MAINTAIN DORMANCY BECAUSE OF THE PARASITE DOES REACTIVATE OR COME OUT OF ITS ASSIST FORM, WHICH IS — SIFT FORM, IT’S CHRONIC STAGE. THIS TH1 QUICKLY CONTROLS THE ORGANISM KEEPS IT FROM REEMERGING. AND THIS IS A VERY POTENT RESPONSE AS YOU CAN SEE AT THE BOTTOM HERE. YOU CAN NOT DETECT ANY TH2 CYTOKINES IN THIS INFECTION AT ALL. IT’S SO POLARIZED INTO THE TH1 SPHERE. SO WHEN WE WERE STUDYING THIS BACK IN THE 90s WHEN IT FIRST STARTED BEING STUDIED. THERE IS SOMETHING VERY FLAG WE THOUGHT ABOUT AND THAT IS THAT IT WAS KNOWN THAT INTERFERON GAMMA CAN ACTUALLY FEEDBACK ON THESE IL12-PRODUCING CELLS AND ACTUALLY GENERATE MORE INTERFERON GAMMA SO YOU HAVE A VICIOUS LOOP WHERE INTERFERON GAMMA CAN INTRODUCE MORE INTERFERON GAMMA AND THAT RESPONSE IS ALMOST CERTAINLY BAD FOR THE HOST. THIS IS INTERFERON GAMMA THAT IN ADDITION TO CONTROLLING INFECTION, CAN CAUSE TISSUE DAMAGE AND BE LETHAL. AND SO, A FELLOW AT THE TIME, RICARDO, AND I, REASONED THERE MUST BE SOMETHING HOLDING THIS RESPONSE BACK. AND I NEW CYTOKINE HAD JUST BEEN DISCOVERED AND TOM REFERRED TO IT IN HIS TALK AND THAT IS INTERLEUKIN 10. AND IT SUPPRESSES A CYTOKINE RESPONSE, THAT WAS ITS ORIGINAL NAME, ACTUALLY. AND SO WE DECIDED TO LOOK IN MICE THAT LACK ENTER 15 — I’M SORRY, THAT LACK IL10, AND JUST WHAT I WANT TO JUST POINT OUT TO YOU VERY QUICKLY IS THIS IS AN ACTUAL EXPERIMENT NOW FOR A CHANGE. THIS IS WHAT HAPPENS WHEN YOU INFECT MICE. SOME REASON I CAN’T GET THE POINTER TO WORK HERE. I DON’T KNOW WHAT I’M DOING WRONG. BUT ANYWAY, MAYBE THAT IS IT. THERE WE GO. SO IF YOU INFECT WILDTYPE MICE, THEY CONTROL THE INFECTION QUITE NICELY AND INTERFERON GAMMA KNOCKOUT MICE DIE BECAUSE THEY NEED INTERFERON GAMMA TO SURVIVE. THESE IL10 KNOCKOUT MICE ALSO DIE. AND WITH ALMOST THE SAME GENETICS AS THE INTERFERON GAMMA KNOCKOUT MICE. AND THAT WAS SURPRISING TO US. AND IT TURNED OUT THAT IN FACT THE MICE WERE DYING FROM DIFFERENT REASONS. THE AIRPORT FOREIGN GAMMA KNOCKOUT MICE HAD CLEARLY MORE PARASITES AND WERE DYING OF INFECTION N CONTRAST, THE IL10 KNOCKOUT MICE HAD STRONGLY ELEVATED CYTOKINE TH1-TYPE CYTOKINE RESPONSES AND THERE WAS EVIDENCE OF TISSUE DAMAGE. SO IL10 WAS ACTUALLY A REGULATING PROTECTIVE RESPONSE. AND THIS IS ILLUSTRATED IN A SIMPLE-MINDED FASHION. HERE AND SO NORMALLY YOU HAVE BOTH OF THESE CYTOKINES MADE AND THE IL12 HELPS IN MAINTAINING INTERFERON GAMMA DEPENDENT HOST RESISTANCE. BUT IF YOU GET RID OF IL10, YOU HAVE INCREASED PATHOGEN CONTROL BUT ALSO INTERFERON GAMMA DEPENDING ON IMMUNOPATHOLOGY. AND THIS MAY SEEM LIKE A SIMPLE-MINDED KIND OF CONCLUSION BUT IT’S ACTUALLY MORE PROFOUND BECAUSE WHAT IT MEANS IS THAT A CYTOKINE IN INTERFERON GAMMA WHICH CONTROLS INFECTION, IS IMPORTANT BUT IL10 CYTOKINE THAT REGULATES THAT RESPONSE, IS EQUALLY IMPORTANT FOR THE SURVIVAL OF THE HOST. THEY ARE BOTH HIGHLY PROTECTIVE CYTOKINES BUT THEY WORK IN TOTALLY DIFFERENT FASHIONS. OKAY. SO, I’LL JUST QUICKLY GO OVER THIS. WHICH IS A QUESTION THAT WE HAVE BEEN INTERESTED IN FOR MANY YEARS AND THIS IS MOSTLY THE WORK OF MY COLLEAGUE. AND THAT IS, WHAT MAKES THIS IL10? WHAT HOW IS IT REGULATED AND WHAT IS ITS TRIGGER? I’LL JUST JUMP TO THE CONCLUSION. I’LL SAY THAT IT IS ACTUALLY THE TH1 CELLS THEMSELVES THAT ARE MAKING THE IL10. SO WHEN YOU HAVE AN INFECTION AND YOU START OUT WITH MAKING TH1 CELLS, AND THEN YOU INDUCE THE PRODUCTION OF IL10 AND IL10 GOES BACK AND FEEDS BACK ON THE MECHANISMS INVOLVED IN THE GENERATION OF NEW TH1 CELLS. AND IN OTHER WORK, WE HAVE UNCOVERED ANOTHER LOOP OF THIS REGULATION OF THE TH1 RESPONSE WHICH ACTUALLY INVOLVES THE NEUROENDOCRINE SYSTEM AND BOTH OF THESE MECHANISMS PLAY A IMPORTANT ROLE IN DAMPENING THE IMMUNE — VERY POTENT RESPONSE TO THIS INFECTION IN THE HOST. OKAY. SO, FINALLY, WE ARE GOING TO SWITCH TO THE LAST QUESTION HERE, WHICH IS TO GO BACK TO THE BEGINNING AND REALLY ASK, WHAT IS IT THAT DRIVES THESE DIFFERENT TYPES OF OR THESE TWO VERY DISTINCT OUTCOMES? AND THIS HAS BEEN PROBABLY ONE OF THE MOST VASINATING QUESTIONS IN — FASCINATING QUESTIONS IN THE FIELD. AND WHAT WE AND MANY OTHERS BELIEVE IS THAT WHAT THIS INVOLVES IS SIGNALS DELIVERED TO PRECURSOR HELPER CELLS, THPs, THAT DRIVE THEM IN ONE DIRECTION OR ANOTHER. SO WHAT ARE THESE SIGNALS AND WHERE DO THEY COME FROM? SO THE GENERAL FEELING IS THAT THERE ARE WHAT WE CALL ACCESSORY CELLS THAT RECOGNIZE DIFFERENT MICROORGANISMS AND THERE IS A BUNCH OF THEM LISTED IN THIS POT IN THE CENTER HERE. AND SO THE IDEA WOULD BE THAT THESE CELLS HAVE RECEPTORS OR SOMEHOW TRIGGERED BY DIFFERENT PATHOGENS AND THEY MAKE DIFFERENT FACTORS THAT DRIVE THE PRODUCTION OF ALL THESE DIFFERENT T-CELL SUBSETS THAT WE WERE TALKING ABOUT SO THIS IS AN IMPORTANT IDEA IN THE FIELD FOR THE EFFECTOR CHOICE. WE DECIDED TO FOCUS ON ONE PARTICULAR CELL AND THAT IS AN IMPORTANT CELL CALLS THE DENDRITIC CELL. AND WHAT IS IMPORTANT ABOUT DENDRITIC CELLS AS YOU MAY KNOW, IS THAT THEY PLAY A BASIC ROLE IN THE IMMUNE RESPONSE ANYWAY. VERY IMPORTANT TO PRESENT ANTIGEN TO GENERATE T-CELL RESPONSES PERIOD. REGARDLESS OF WHETHER THEY ARE TH1 OR TH2. SO IF YOU COULD GET OR SOMEHOW STIMULATE A DENDRITIC STOLE MAKE A SIGNAL, YOU COULD NOT ONLY PRESENT ANTIGEN BUT ALSO DICTATE THE EFFECTOR CHOICE IN ONE DIRECTION OR ANOTHER. AND THIS IS WHAT WE HAVE BEEN STUDYING. AND WE HAD A REALLY NEAT SYSTEM BECAUSE UNLIKE MANY OTHER ORGANISMS, THE TWO ORGANISMS, THE TWO PARASITES THAT ARE STUDIED IN THE LAB WHICH IS TOXO, WHICH I JUST TALKED ABOUT AND SCHISTO, WHICH IS A HELMINTH INFECTION, THEY ACTUALLY — YOU CAN ACTUALLY GRIND UP THESE ORGANISMS AND GET OUT A SOLUBLE EXTRACT THAT WILL STIMULATE TH1 OR TH2. YOU DON’T EVEN NEED THE ORGANISMS THEMSELVES. SO WE ARE IN A SITUATION TO BIOCHEMICALLY CHARACTERIZE WHAT IT WAS IN THE ORGANISMS THAT MAKES THEM GO IN ONE DIRECTION OR ANOTHER. AND I’M JUST GOING TO SUMMARIZE YEARS OF WORK IN TERMS OF THESE MOLECULES AND HOW THEY WORK AND HOW THEY WORK ON DENDRITIC CELLS. THAT IS SHOWN HERE. SO HERE IS THE TOXO MOLECULE. AND THIS WAS WORK OF FELIX, POSTDOC IN OUR LAB. AND HE PURIFIED THE ACTUAL COMPONENT IN THE SOLUBILITY EXTRACT OF TOX OH, AND IT TURNED OUT TO BE A STRUCTURAL THING OF ALL THINGS. AND IN THE PROCESS OF IDENTIFYING THE LIGAND, HE ALSO IDENTIFIED ITS RECEPTOR OR RECEPTORS ON DENDRITIC CELLS WHICH IS A NEWLY DISCOVERED TOLL-LIKE RECEPTOR CALLED TOLL 11 AND 12 WHICH SIGNAL THROUGH ADAPTER MOLECULE CALLED MYDE SKATE STIMULATE THE PRODUCTION OF IL12 WHICH DRIVES T HELPER PRECURSOR CELLS IN THE TH1 CELLS. SO THIS WAS PRETTY STRAIGHTFORWARD AND PRO FILL IN IS A VERY, VERY POTENT MOLECULE. AT LEAST IN THE MOUSE. AND IS ABLE TO STIMULATE LIKE L LPS SO THE TH1 SIDE SEEMED PRETTY STRAIGHTFORWARD. TH2 SIDE, HOWEVER, IS COMPLICATED. BUT THAT BEING SAID, WE WERE ABLE TO IDENTIFY THE MAJOR MOLECULE IN THIS EXTRACT. AND INTERESTINGLY, THIS IS A TOTALLY DIFFERENT MOLECULE. THIS IS A T2 NUCLEASE CALLED OMEGA 1 AND THIS JUST SHOWS THE PURIFICATION. AND KIND OF VERY LONG STORY SHORT, OMEGA 1 SHOWN HERE STIMULATES DENDRITIC CELLS IN A VERY, VERY DIFFERENT WAY THAN PRO FILL IN. SO PRO FILL IN, HIGHLY ACTIVATES DENDRITIC CELLS AND YOU GET A STRONG T-CELL ACTIVATION SIGNAL. IN CONTRAST, OMEGA 1 GIVES YOU A VERY WEAK ACTIVATION SIGNAL AND IN CERTAIN CASES EVEN LOOKS LIKE IT IS INHIBITING DENDRITIC CELL FUNCTION AND THAT WEAK T-CELL ACTIVATION SIGNAL IS ASSOCIATED WITH THE GENERATION OF A TH2 RESPONSE. SO THIS IS HOW WE THINK EFFECTOR CHOICE IS WORKING IN A MODEL HELMINTH AND PROTOZOAN SYSTEM. I’M GOING TO END AND COME BACK TO THE BEGINNING OF ALL OF THIS AND POSE A QUESTION THAT KIND OF HAUNTS ME, PROBABLY MORE THAN IT HAUNTS TOM. AND THAT IS SHOWN HERE. AND SO WE HAD THIS ENORMOUS INTEREST IN THE IMMUNOLOGY OF PARASITES. AND THIS IS ACTUALLY A QUOTE FROM A FAMOUS BRAZILIAN PATHOLOGIST, WHO ACTUALLY USED — THIS WAS IN A SCHISTO ZOME MEETING. HE SAID, HAS SHIFT MICE SIS DONE MORE FOR IMMUNOLOGY THAN IMMUNOLOGY HAS DONE FOR SHIFT MICE SIS? AND HE RAISED A VERY, VERY GOOD POINT BECAUSE WE HAVE — WE REALLY STILL DON’T HAVE MAJOR VACCINES FOR PARASITIC INFECTION EXCEPT FOR ONE, WHICH I PROMISED TO COME BACK AND TELL YOU ABOUT. AND THAT IS A VACCINE CALLED RTSS. AND IT HAS ABOUT THE WORST NAME FOR A BIOLOGICAL I HAVE EVER SEEN. THIS IS SUPPOSED TO REMIND YOU OF MOSQUITOES AND MALARIA AND ALL OF THAT. BUT SO WHAT IT IS YOU REMEMBER THE NUISANCE BUGS AND THEIR DISCOVERY OF THIS CS MOLECULE? THIS IS WHAT HAPPENED TO IT. SO, IN TERMS OF VACCINE ENGINEERING, THEY TOOK THE CENTRAL REPEAT THAT I SHOWED YOU WHICH IS THE MONOCLONAL ANTIBODY RECOGNIZED A TAX AND T-CELL EPITOPES ON TO IT, AND THEY GENETICALLY ENGINEERED THIS INTO THE SURFACE ANTIGEN, HEPATITIS B VIRUS AS BOTH A CARRIER AND A WAY TO, I THINK, TO TARGET INTO THE LIVER, WHICH IS WHERE THIS PARTICULAR STAGE OF MALARIA TAKES PLACE. AND SO THE INITIALS ARE AWARE OF THE RTSS COMES FROM. SO WHAT I WANT TO SAY IS THAT THIS CONSTRUCT WAS MADE AROUND 1980, 1982. AND IT WAS STUDIED BY THE ARMY AND IT DIDN’T REALLY GO ANYWHERE. THERE WAS VACCINE TRIALS DONE WITH IT BUT THEN SOMEONE HAPPENED TO PUT THE RIGHT ADJUVANT TOGETHER WITH THIS MOLECULE. AND SUDDENLY THEY STARTED GETTING A PROMISING RESULT. AND THAT ADJUVANT IS SOMETHING CALLED ASL1 MADE BY GLAXOSMITHKLINE AND IT IS STILL TO ME, PRETTY MUCH VOODOO. IT’S A LIPOSOMAL FORMULATION OF MONOLIPID A. A KNOWN ADJUVANT AND A INFRACTION FROM A CHILEAN SOAP BARK TREE. BUT THIS WORKS. AND IT WORKS NOT PARTICULARLY WELL AS I’M ABOUT TO DESCRIBE. SO THE IDEA AND IT WAS JUST DESCRIBED TO ME IN A CONVERSATION I HAD WITH A MALARIA VACCINE GUY. YOU HAVE YOUR RTS. AND YOU HAVE YOUR ADJUVANT AND YOU MIX THEM AT THE TIME OF THE VACCINATION. AND THIS HAS BEEN STUDIED NOW FOR AT LEAST ABOUT 15 YEARS OF VACCINE TRIALS. AND THIS IS THE WAY THEY ARE NOW. THEY HAVE A THREE-DOSE SCHEDULE. THIS WAS I THINK PUBLISHED IN LANCET A COUPLE OF — IN TWO OR THREE YEARS AGO. SO A THREE-DOSE SCHEDULE OF VACCINE AND YOU CAN IMAGINE COMING BACK AND VACCINATING PEOPLE THREE TIMES. AND THEY ADDED A FOURTH BOOST, WHICH SEEMS TO BE VERY IMPORTANT IN GETTING A SIGNIFICANT PROTECTION. AND THAT BOOST GIVES YOU A 36% REDUCTION IN CLINICAL MALARIA IN CHILDREN AGE 5-17 MONTHS. AND 26% IN INFANTS. SO THIS ISN’T REALLY MUCH. THE WAY IT HAS BEEN DESCRIBED TO ME, YOU HAVE 198 MILLION CASES OF EPISODES OF CLINICAL MALARIA AND YOU CAN ELIMINATE 30 MILLION OF THEM WITH THIS. AND I THINK THE KEY THING IS WE REALLY DON’T STILL DON’T UNDERSTAND HOW THIS VACCINE WORKS. IT SEEMS TO BE ASSOCIATED WITH ANTIBODY BUT THERE IS EVIDENCE IN ANIMAL MODELS THAT CD8 T-CELLS ARE IMPORTANT AND THE ONLY RECENT CLUE IS THE BOOSTER SEEMS TO BE VERY IMPORTANT. THE LAST BOOSTER. AND IF YOU LOWER THAT BOOST, YOU CAN — IT CAN PLAY A MAJOR ROLE IN THE OUTCOME BY INCREASING ANTIBODY AFFINITY IS THE ONE THING THEY HAVE BEEN ABLE TO MEASURE. SO ALL OF THIS WORK THAT I HAVE BEEN TELLING YOU OVER ALL THESE YEARS AND GREAT NEGLECTED DISEASES HAS GIVEN US THIS. AND YOU CAN JUST SEE — I SEE YOUNG PEOPLE IN THE ASIENCE I KNOW. WHAT AN ENORMOUS CHALLENGE THIS IS. THIS FIELD IS STILL SITTING THERE WAITING FOR US TO UNDERSTAND HOW TO MOVE FORWARD AND GENERATE IMPORTANT FORMS OF IMMUNOLOGIC INTERVENTION. I SHOULD ALSO MENTION THAT THESE RESULTS WERE IN THE CONTEXT OF REGULAR MALARIA PREVENTION. SO BED NETS AND EVERYTHING. SO YOU’RE LOOKING AT THE COMBINED EFFECT OF A VACCINE WITH EVERYTHING ELSE. BUT ANYWAY, THEY ARE GOING AHEAD WITH IT AND THERE IS GOING TO BE A TRIAL OR MUCH LARGER TRIAL THE GSS SPONSORING IN THREE DIFFERENT AFRICAN COUNTRIES JUST TO SEE IF THEY CAN AGAIN, JUST BY HELPING THOSE 30 MILLION CASES, WHETHER THIS IS GOING TO BE OR MAKE A SIGNIFICANT IMPACT ON MALARIA ITSELF. SO YOU CAN SEE THE CHALLENGE THAT REMAINS IN THIS FIELD. AND SO THIS IS A STATEMENT OF IT. IT’S REALLY, I THINK WE STILL NEED TO UNDERSTAND MORE ABOUT, A LOT MORE ABOUT THE EFFECTOR MECHANISMS THAT MEDIATE HOST RESISTANCE AND PARASITES AND WE NEED BIOMARKERS FOR THESE PROTECTIVE RESPONSES IN HUMANS. IT’S REALLY IMPORTANT TO KNOW IN ALMOST ANY HUMAN INFECTIOUS DISEASE VACCINE, A SITUATION WE NEED WAYS TO FIND OUT WHETHER A RESPONSE IS PROTECTIVE OR NOT WITHOUT EXPOSING SOMEONE TO THE DISEASE. AND THEN ALSO I THINK THOSE OF US WHO WORK ON MOUSE MODELS AND OTHER MODELS, YOU REALLY NEED TO BE THINKING MORE ABOUT HOW TO TRANSLATE THEM INTO ACTUAL TRANSLATIONALLISH VENTIONS. SO I’LL END THERE. THIS IS JOUST – INTERVENTIONS. THIS IS A HUGE LIST OF PEOPLE WHO WORKED WITH US OVER THE YEARS ON THE WORK I’M DESCRIBING AND I’M VERY FORTUNATE TO BE HERE AT THE NIH AND TO BE IN THE LPD, WHICH IS A GREAT PLACE TO WORK AND GREAT COLLEAGUES. AND WE HAVE HAD VERY WONDERFUL EXTERNAL COLLABORATORS OVER THE YEARS THAT ARE ALSO MENTIONED HERE. I ALSO WOULD LIKE TO ACKNOWLEDGE BILL PAUL WHO IS A VERY IMPORTANT COLLEAGUE IN A LOT OF THE IMMUNOLOGIC WORK THAT WE DID AND UNFORTUNATELY HE IS NO LONGER WITH US. SO I’LL STOP THERE AND IF THERE IS ANY QUESTIONS. I THINK WE ARE RIGHT ON THE NOSE, 6:00. [ OFF MIC ] >> I FORGOT TO MENTION A WHOLE WORLD OF VETERINARY VACCINES THAT, WHERE THERE HAS BEEN MORE PROGRESS AND THAT IS SIMPLY CAN BE CREDITED TO THE FACT THAT IT IS EASIER TO DO TRIALS AND TO TEST HYPOTHESES IN ANIMALS THAN IN HUMANS. SO BUT WHAT TED IS ALLUDING TO IS THE FACT THAT IN SOME PARASITES IT’S NOT SO DIFFICULT TO IMMUNIZE. BUT THEY ARE NOT ONES THAT ARE LIKE THE BIG GUYS, SOME OF THE BIG GUYS THAT WERE MENTIONED HERE. BIG DISEASES. HE MAY DIFFER ON THAT, I DON’T KNOW. >> SO THE IDEA THAT A PARASITE — I’M CURIOUS ABOUT THE RELATIONSHIP OF — TO PARASITES WHICH INVADE TISSUE AS DISTINGUISHED TO THOSE THAT DON’T. NOW MANY YEARS AGO WE WERE TAUGHT IN MEDICAL SCHOOL THAT THAT WAS AN IMPORTANT FINDING. IS THAT TRUE ANYMORE? >> WELL, I THINK TOM IS A BETTER PERSON TO ANSWER THAT THAN I. I MEAN, INK IT IS A RESPONSE TISSUE INVASION, FOR SURE. — I THINK. AND ALTHOUGH AS I WAS TRYING TO POINT OUT — IT OCCURS IN OTHER SITUATIONS AND BUT I THINK THE IDEA OF TISSUE DAMAGE IS ALSO VERY IMPORTANT THING IN THE TH2 RESPONSE. REMEMBER THE TH2 RESPONSE IS NOW THOUGHT TO BE A HEALING PROCESS. TISSUE REPAIR PROCESS. I’M SORRY. FOR OTHER PEOPLE, YES. SO IT IS THOUGHT TO BE A TH2 RESPONSE AS I SHOWED YOU ON ONE OF THE SLIDES IS MEANT TO INVOLVE TISSUE REPAIR. THAT MAY BE ITS REAL FUNCTION. AND HELMINTHS ARE GREAT AT TEARING UP TISSUE. IT’S ONE OF THE THINGS THEY DO. AND YOU EXPERIENCE THEM TEARING UP YOUR TISSUE — [ LAUGHS ] SO I THINK WHAT YOU JUST SAID IS PROBABLY STILL THOUGHT TO BE THE CASE AND TOM CAN CLARIFY THAT. >> I COMPLETELY AGREE. I THINK YOU HAVE TO THINK ABOUT TWO DIFFERENT THINGS. SO WHAT DRIVES IT IN THE BLOOD IS LARGELY WE KNOW IS IL5 AND IT ACTS AS A HORMONE ESSENTIALLY ON PRECURSOR SELLS IN THE BONE MARROW. BUT THEY ARE REALLY TISSUE RESIDENT CELLS AND IN HUMANS AT LEAST, YOU CAN’T REALLY STUDY THAT. YOU PRETTY MUCH HAVE ACCESS ONLY TO THE PERIPHERAL BLOOD COMPARTMENT AND I THINK LARGELY, ALL THE TISSUE DAMAGE DONE BY THE SCENFILLS HAPPEN UNTIL SIGHT YOU. SO I THINK ONE IS THE REGULATION OF PHILIA WHICH WE UNDERSTAND A LOT ABOUT. IT’S REALLY THE REST OF THAT AND PROBABLY DRIVING EVEN THAT IS TISSUE INVASION BECAUSE THOSE ORGANISMS THAT DON’T INVADE THE TISSUE REALLY DON’T DRIVE OF THE SEN FILLS. >> I JUST WANTED TO MAKE THE POINT AND SAY IT AGAIN AND JUST GENERAL POINT, IS HOW IMPORTANT HELMINTHS HAVE BECOME FOR STUDYING ALL OF THESE TH2-ASSOCIATED RESPONSES. I MEAN MY STARTING POINT WAS THE STUDY OF IMMUNE RESPONSE TO PARASITES HAS TAUGHT US A LOT ABOUT IMMUNOLOGY AND ONE OF THE BIG THINGS, UNIQUE THINGS IS THE TH2 RESPONSE BECAUSE IT REALLY DOESN’T EXIST IN ANY SUBSTANTIAL WAY TO ANY OTHER ORGANISM, TYPE OF ORGANISM. SO, WE LEARNED A LOT FROM STUDYING THIS. BUT WE HAVE OR WE ARE LEFT WITH THIS FASCINATING IDEA ABOUT WHO CAME FIRST? THE PARASITES AND THEN THE NEED TO CONTROL THEM? OR THE NEED REPAIR AND MAINTAIN TISSUE HOMEOSTASIS? >> THE ROUNDWORM HAS BEEN A STALWART IN THE STUDY OF AGING, DEVELOPMENT, GENETICS, AND IT’S ALL BASED ON THE PRINCIPLE THAT YOU CAN FEED THE WORM A BACTERIUM, WHICH CONTAINS WHATEVER IT IS YOU WANT TO PUT IN THAT IT IS GOING TO PERMIT YOU TO IDENTIFY AND STUDY IT. SO THAT SORT OF PROMISE SOMETHING IN MY HEAD ABOUT A RELATIONSHIP, IF ANY, BETWEEN THE BACTERIAL MICROBIOME AND THE PARASITIC INFECTION OF THE INTESTINAL TRACT. IS THERE SORT OF A YIN-YANG THERE? OR IS THIS — ARE THESE TWO SEPARATE WORLDS? >> I THINK TOM CAN SPEAK TO THAT BETTER THAN I. >> WELL, I THINK IT IS CLEAR THAT THERE IS AN AFFECT OF PROBABLY A TWO-WAY AFFECT OF THE — SOME OF THE INTESTINAL WORMS AND THE COMPOSITION OF THE MICROBIOME AND PROBABLY THERE IS SOME INFLUENCE WE HAVE TO ASSUME, IN THE OTHER DIRECTION AS WELL THAT IS SOME OF THESE BACTERIA MAY INFLICT INFLUENCE THE GROWTH AND DEVELOPMENT OF A PARTICULAR PARASITE. I THINK WHAT IS LESS CLEAR AT THE MOMENT AT LEAST, IS ARE THESE WHAT TURNED OUT TO BE RELATIVELY SUBTLE CHANGES IN THE MICROBIOME INDUCED BY HEAVILY-INFECTED PAIR SA TIESED INDIVIDUALS, IS THAT REALLY ACTUALLY ALTER IN ANY WAY THE IMMUNE HOMEOSTASIS SYSTEMICALLY? AND THAT IS WHERE THE NEXT HURRAH, IN A SENSE FOR HOW PEOPLE ARE GOING TO BEGIN TO UNDERSTAND THESE SORT OF COMPLEX INTERRELATIONSHIPS BETWEEN HOST TISSUE, HOST MICROBIOME AND THESE EXTERNAL PATHOGENS. >> SO THE OTHER RINK TOLL THIS, WHAT YOU’RE ASKING IS — WRINKLE TO THIS — AND YOU HAVE TO THINK OF PARASITES THEMSELVES AS COMMENSALS. JUST LIKE THE — THERE MAY BE A WORMY — WE KNOW THERE ARE PROTOZOA THAT ARE VERY IMPORTANT COMMENSALS NOW THAT ARE DESCRIBED. AND THEN THERE IS ALSO THIS WHOLE FASCINATING IDEA OF THE HYGIENE HYPOTHESIS THAT WE CARRIED THESE AROUND FOR YEARS AND THEY ARE PART OF OUR IMMUNOLOGIC MAKEUP AND OF COURSE WE STOPPED HAVING PARASITIC INFECTIONS OR WORM INFECTIONS. WE COMPLETELY CHANGE OUR IMMUNE RESPONSES AND THAT COULD BE IN A BAD DIRECTION. SO THAT IS ANOTHER FASCINATING ASPECT OF WHICH YOU CAN GET TOM BACK TO TALK TO YOU ABOUT ANOTHER TIME. >> WELL, I WANT TO THANK YOU BOTH AND THANK YOU VERY MUCH FOR COMING AND SHARING YOUR EXTRAORDINARY EXPERIENCE, WHICH I SUSPECT THAT MANY OF US, AT LEAST ME, HAD NEVER SEEN BEFORE. SO THANK YOU ALL VERY MUCH AND WE HOPE TO SEE YOU NEXT WEEK WHEN IT IS DIABETES AND ARTIFICIAL SWEETENERS. MAY THEY EFFECT THE HELMINTHS TOO. >> IT ALL HAS TO DO WITH HELMINTH.

2 comments

  1. @5:42 The photo is of the author Conrad Keating, not Kenneth Warren. Deviating from the truth only opens the door to parasites…

  2. For anyone who's interested, "Kenneth Warren and the Great Neglected Diseases of Mankind Programme" by Conrad Keating 😃 Book Link(Amazon): https://amzn.to/2KIay6y

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