>> GOOD AFTERNOON, EVERYONE. WELCOME TO THE WEDNESDAY AFTERNOON LECTURE, THIS AFTERNOON WE'RE GOING TO HEAR ABOUT CRYPTOCOCCUS NEOFORMANS FROM A DISTINGUISHED INVESTIGATOR, DR. ARTURO CASADEVALL WHO JUST MOVED FROM ALBERT EINSTEIN WHERE HE'S BEEN FOR 22 YEARS AND ARRIVED AT HOPKINS, CHAIR OF MICROBIOLOGY AND IMMUNOLOGY IN THE BLOOMBERG SCHOOL OF PUBLIC HEALTH. ARTURO HAS A DISTINGUISHED ACADEMIC CAREER, Ph.D. AND M.D. FROM NYU, AND AS I MENTIONED, THEN TAKING A POSITION AT ALBERT EINSTEIN, RISING TO BECOME A NAMED PROFESSOR AND CHAIR OF THE DEPARTMENT OF MICROBIOLOGY AND IMMUNOLOGY THERE. AN ELECTED MEMBER OF THE AMERICAN ASSOCIATION OF PHYSICIANS AND OF THE INSTITUTE OF MEDICINE, AND I MUST SAY FROM MY PERSPECTIVE AS NIH DIRECTOR, I'D LIKE TO POINT OUT HE'S ALSO BEEN A VERY DEDICATED SERVANT WHEN WE'VE CALLED UPON HIM TO HELP OUT WITH MANY DIFFERENT NIH TASKS, INCLUDING HIS CURRENT ROLE, AS CO-CHAIR OF THE NIAID BOARD OF SCIENTIFIC COUNSELORS, AND HIS SERVICE PREVIOUSLY ON THE NSABB, THE NATIONAL SCIENCE ADVISORY BOARD ON BIOSECURITY. HE'S DONE IMPORTANT WORK OVER MANY YEARS ON FUNGAL PATHOGENESIS AND ECLECTIC INTERESTS IN OTHER THINGS INCLUDING THE SCIENTIFIC ENTERPRISE, SOMETHING ABOUT DINOSAURS, CONCERNS ABOUT RESEARCH MISCONDUCT AND HOW WE'RE HANDLING THAT VERY TROUBLING ISSUE IN OUR COMMUNITY. AND HE'S ALSO CURRENTLY EDITOR IN CHIEF OF M-BOI FROM THE AMERICAN SOCIETY OF MICROBIOLOGY AND PUBLISHING INTERESTING STUFF OF LATE. WE'RE FORTUNATE TO HAVE HIM HERE FOR THIS AFTERNOON, SO PLEASE JOIN ME IN GIVING A WARM WELCOME TO DR. ARTURO CASADEVALL. [APPLAUSE] >> THANK YOU, DR. COLLINS, FOR THE NICE INTRODUCTION. I'M TALKING PRIMARILY ABOUT CRYPTOCOCCUS NEOFORMANS BUT I WARN YOU THIS IS A SEMINAR THAT'S GOING TO BE ALL OVER THE PLACE, INCLUDING GLOBAL WARMING IN THE NEXT 45 MINUTES. IT WILL ALL COME TOGETHER. ONE OF THE THINGS I REBELLED AGAINST IN TODAY'S SCIENCE, THEY FORCE YOU TO SPECIALIZE. I REFUSE. I THINK YOU'LL SEE THAT I'M ALL OVER THE PLACE. THERE'S A LOT I WILL NOT TALK ABOUT. I WILL NOT TALK ABOUT ANTIBODY FUNCTION, DINOSAURS, H1N1, PUBLICATION RETRACTIONS. SO THE PROBLEM OF FUNGAL PATHOGENESIS IN AN ESSENCE IS IF YOU LOOK AT IT FROM THE BIG PICTURE, THERE ARE TOO FEW FUNGAL PATHOGENS. THE MAJORITY OF FUNGAL DISEASES ARE ACQUIRED PRIMARILY FROM OTHER HOSTS. FROM THE ENVIRONMENT WE GET OTHER ORGANISMS WHERE INFECTION IS FREQUENT, DISEASE IS RARE. WHEN THERE'S DISEASE IT'S PROGRESSIVE, OFTEN LETHAL. ABRAHAM DIED IN A CONCENTRATION CAMP TIEING THIS TO A HORROR OF THE CENTURY. IN THE 1950s, THERE IS MAJOR PROBLEMS IN DIAGNOSIS AND THERAPY, HEE I -- HERE I WANT TO CELEBRATE THE INTRAMURAL PROGRAM. I COULD ONLY IMAGINE WHERE WE HAD BEEN IN 1981 WITHOUT THE WORK DONE. WE HAD A GREAT DIAGNOSTIC TEST, WORKING OUT THE NEURONS, AND BY THE 1980s, A MAJOR PATHOGEN, MOLECULAR TOOLS BEGAN TO BE DEVELOPED HERE IN THE INTRAMURAL PROGRAM AND TODAY THIS ORGANISM CAUSES OVER A MILLION DEATHS WORLDWIDE, THE MAJORITY BECOME INCURABLE AND LEAD TO DEATH. WITHOUT THIS THE ORGANISM IS -- [LOW AUDIO] IN THE BIG PICTURE INFECTION IS ACQUIRED FROM THE ENVIRONMENT. YOU'VE BEEN INFECTED WHETHER IT COMES FROM DESECRATED CELLS, WE DON'T KNOW, BUT IN THE MAJORITY OF US THIS IS CLEARED OR GOING INTO A GRANULOMA WHERE IT MAY STAY THE REST OF YOUR LIFE, AND LATER HOPEFULLY WHAT HAPPENS, IMMUNOCOMPROMISED BY A VARIETY OF MECHANISMS, ONE OF THE MAJOR AREAS WITH A LOT OF ACTIVITY GOING ON NOW, OFTEN NORMAL PEOPLE WILL COME DOWN WITH THIS AND NOBODY KNEW WHY. WELL, THE GROUP HEADED BY STEVE HOLLAND IS PRETTY MUCH SHOWING SOME OF THESE INDIVIDUALS DEVELOP AND AUTOIMMUNE MUTATION, WE CAN MAKE ANTIBODIES, THE INTRAMURAL PROGRAM MAKING A MAJOR CONTRIBUTION AGAIN TO THIS DISEASE. MANY YEARS AGO WE BECAME INTERESTED IN WHAT WAS THE RELATIONSHIP. YOU CAN SEE THE WHITE CIRCLES, THE OTHER PLACES ARE CONTAMINATED. SUGGESTING THE DISEASE IS COMING FROM LOCAL SOURCES. BOTH SOURCES INFECTED FROM A THIRD. WE TRIED TO DO WORK ON SEROLOGY. [LOW AUDIO] I THINK THAT IS THE BEAUTY OF HUMANITY. YOU GET SOME PEOPLE THAT CAN GIVE YOU MULTIPLE INTERPRETATIONS. SO A SPECIAL COCKATOO TAUGHT US YOU COULD BE INFECTED AT HOME, A PATIENT IN BOSTON, A RENAL TRANSPLANT, WE WERE ABLE TO LINK THE ISOLATE IN THE COCKATOO IN THE APARTMENT. SO HOW DID I GET TO CRYPTOCOCCUS? HOW DOES IT GET HERE? I HAD NO IDEA I WOULD WORK ON THIS. WHEN I WAS A GRADUATE STUDENT, THIS IS WHAT I LOOKED LIKE IN THE EARLY '80s, I WAS INTERESTED IN PHYSICAL CHEMISTRY. I WENT TO WORK AS A PHYSICAL CHEMIST INTERESTED IN MAKING MEASUREMENTS, MAKING THE SAME MEASUREMENT EVERY DAY OF YOUR LIFE AND SEE HOW CLOSE YOU CAN DO IT. I LIKE TO DO THAT. I WAS VERY INFLUENCED GOING ACROSS THE STREET TO BELLEVUE, THAT'S WHAT I ALSO LOOKED LIKE WITH THE BIG GLASSES FROM THE 1970s. AND THE AIDS EXPERIENCE, AIDS EPIDEMIC WAS A FORMIDABLE EXPERIENCE. I COULD NOT BELIEVE WHAT I SAW. I DON'T THINK ANY OF YOU, EXCEPT IF YOU LIVED THROUGH THAT TIME, WOULD HAVE A MEMORY. BASICALLY THE HOSPITAL FULL OF PEOPLE, YOU COULDN'T DO ANYTHING ABOUT IT. PEOPLE JUST DIED. I DECIDED TO GET RETRAINED AND WENT TO THE IMMUNOLOGY LAB WITH MATT SCHARFF. I TOLD HIM I WANTED TO DO SOMETHING CLINICALLY, AND A 30-SOMETHING CAMBODIAN MAN WITH CRYPTOCOCCUS, WE GAVE HIM 3 OR 4 GRAMS OF AMPOTHERICINB AND HE STILL DIED. THIS WAS A NEW FAILURE. THE QUESTION WAS COULD YOU MAKE ANTIBODIES. I WANTED TO MAKE ANTIBODIES. THIS WAS AN ANTIBODY LAB. MATTIE WAS NOT HAPPY ABOUT THIS. I WENT TO TALK TO THREE EMINENT IMMUNOLOGISTS, ALL THREE MEMBERS OF THE NATIONAL ACADEMY, THIS IS THE ADVICE I GOT. WORK ON WELL IMMUNOLOGY, IMMUNITY, WE KNOW ABOUT ANTIBODY AND YOU'RE WASTING YOUR TIME. IF YOU WANT TO HAVE A CAREER, THE MORE BASIC IT IS, THE BETTER YOU'LL DO AND GET A DIFFERENT PROJECT. YOU'LL LEARN EVERYTHING WE KNOW AGAIN. I DIDN'T TAKE THE ADVICE, TEN YEARS LATER WE'RE ABLE TO DO A CLINICAL TRIAL. THERE ARE MANY PEOPLE TO THINK, DENNIS DIXON, RICHARD HAFNER, THE PEOPLE AT THE NIAID. AND THEN THIS COMPOUND ENTERED INTO THE VALLEY OF DEATH, ALSO BECAUSE THE PROBLEM HAD LARGELY -- WAS MUCH LOWER THAN WHEN I BEGAN. BECAUSE OF THE DEVELOPMENT OF HIGHLY RETROACTIVE THERAPY. WE HAD NOT GIVEN UP, WE HAD OTHER IDEAS, RIGHT NOW WE'RE LOOKING TO GO FORWARD. SO IN THE '90s, THIS THING WAS BEING DEVELOPED. I TOOK HEART ADVICE I WAS GIVEN, BASICALLY STICK TO BASIC SCIENCE, WORK ON THE BASIC PROBLEMS. WE WERE ABLE TO DO THAT SUCCESSFULLY AND FOUND A LOT OF STUFF IN IMMUNOLOGY THAT WOULD NOT HAVE BEEN SUSPECTED FROM WORK WITH PNEUMOCOCCUS, THEN THE POSTER CHILD OF AN ENCAPSULATED ORGANISM. THE RESPONSES WERE RESTRICTED, ONE TYPE OF IgG WORKED, ONE DIDN'T WORK. IF YOU TAKE THIS IgG AND SWITCH TO THE OTHER, ANTIBODY PROTECTION DEPENDED ON SPECIFICITY EXCLUSIVELY. YOU MOVED IT A LITTLE BIT IN THE POLYSACCHARIDE, IT DIDN'T WORK. STRANGELY, ANTIBODY PROTECTION REQUIRED T-CELLS. THAT'S NOT SUPPOSED TO HAPPEN. BASICALLY GOING BACK AND QUESTIONING SOME IDEAS TO THE WORK OF PORTER WHO GOT THE NOBEL PRIZE TO SHOWING THERE WERE TWO PARTS TO THE MOLECULE, BUT I ALWAYS GO BACK TO CONCEPT, THE MOST IMPORTANT THING YOU CAN CONTRIBUTE. YOU CAN TAKE AN ORGANISM FOR WHICH IMMUNOLOGY TELLS YOU THAT IMMUNITY WAS DOMINANT AND ANTIBODY IMMUNITY HAD NO ROLE AND YOU COULD MAKE A PROTECTIVE ANTIBODY. THIS WAS NOVEL THEN. IT IS ACCEPTED NOW. WE WENT ON TO REPEAT THIS AND TO SHOW IN TUBERCULOSIS, NOW REPEATED IN MANY OTHER AREAS. THIS LEADS TO A RETHINKING OF THE OLD DIVISION OF LABOR THAT DOMINATED IMMUNOLOGICAL THOUGHT IN THE 20th CENTURY. I DON'T THINK PEOPLE TALK ANYMORE THAT WAY. ONE WAY OR THE OTHER WAY. IN FACT, I THINK WE NOW ACCEPT THIS WAS -- WHAT SHOULD HAVE BEEN ALL ALONG, THE IMMUNE SYSTEM AND EFFECTIVE RESPONSE IS AN ALL ARMS RESPONSE. BY THE LATE 1990s WE HAD A PROBLEM, AND THIS FORCED ME TO GO FROM IMMUNOLOGY TO BASICALLY WORK PRIMARILY IN A CELL BIOLOGY, AND THE PROBLEM WAS WE COULD NOT EXPLAIN THE FINDINGS IN IMMUNOLOGY. AND AB MEDIATED PROTECTION WAS NOT UNDERSTOOD. SO CLEARLY IT WASN'T THIS CAPSULE, ONCE YOU OVERCOME IT, THIS WOULD WORK. WHY DO YOU NEED T-CELLS TO PROTECT IN THIS SITUATION? ONE WAY TO RESULT THE DILEMMA WAS THINK CRYPTOCOCCUS MAY BE AN INTRACELLULAR PATHOGEN. IS IT? THIS WAS QUITE CONTROVERSIAL. YOU CAN SEE THE HISTOLOGY. THIS LOOKS EXTRACELLULAR. IF YOU GET A -- THIS IS A GRANULOMA FROM A CHILD, IT'S INTRACELLULAR. IF YOU DO IT IN A MOUSE YOU COULD GO EITHER WAY, ARGUE MAYBE THESE ARE DEAD SO WE TRIED TO DO A LOT OF WORK. JACK BENNETT IN 1973 HAD IN FACT NOTED IT GREW MUCH MORE RAPIDLY IN THE INSIDE CELLS THAN IT DID IN SERUM, SUGGESTING SOMETHING MORE WAS GOING ON HERE IN THE PATHOGENESIS. SO BY THE EARLY 2000s, THIS WAS ESTABLISHED THAT IN FACT THIS WAS A FACULTAVIVE INTRACELLULAR PATHOGEN, IT WILL HIDE OUT IN YOUR MACROPHAGES, LIVE THERE FOR YEARS. THE MASS SUSCEPTIBILITY WAS PROPORTIONAL, AND IN THE LAST COUPLE YEARS THE ABILITY TO CORRELATE MACROPHAGE CORRELATES IN LETHALITY IN HUMANS. YOU GO INTO THE LITERATURE AND SAY THIS IS THE TYPE OF STRATEGIES OUT THERE USED BY LISTERIA, LEGION ONELLA, IT DID NOT MATCH ANYTHING DONE BY OTHERS SO WE WERE CLEARLY DEALING WITH SOMETHING DIFFERENT. WHEN WE BEGAN TO LOOK AT THIS, WE FOUND THAT THIS ORGANISM DOESN'T DO ANYTHING AT THE TIME, IT ABSORBS THE FIT, GOES INTO THE MACROPHAGES AND IS ABLE TO TAKE IT. IT TAKES THE OXIDATIVE BURST, IT TAKES THE PROTEASE. WHAT'S GOING ON? THE POLYSACCHARIDE PROVIDES THE TREMENDOUS AMOUNT OF PROTECTION, HERE AN EXPERIMENT ADDING POLYSACCHARIDE, EXPOSING TO OXIDATIVE BURST, THE POLYSACCHARIDE CAN ABSORB IT. IT DOESN'T THE MEMBRANE. YET IT RESIDES THERE. IT ALSO HAS VERY POWERFUL ANTIOXIDANT SYSTEM INCLUDING LACCASE, AND IN FACT HELPS DEACTIVATE OXIDATIVE BURST. HERE IS THE PROBLEM. THE PROBLEM ALSO IS THAT YOU HAVE A HUMONGOUS VACUOLE, LOWER IN VOLUME. WHATEVER YOU'RE MAKING IS GOING TO GET DILUTED, LAST TO GET THROUGH THE CAPSULE AND MELANIN. THEN IT ALSO HAS AN UNUSUAL THING, SECRETED VESICLES, ESSENTIALLY THE CELL RUNS OUT OF MEMBRANE, AND CAN PROMOTE LATER DEATH, AND CIRCA 2003, WE WERE PRETTY HAPPY, YOU COULD DRAW DIAGRAMS, GET FEATURED IN TRENDS, BUT THIS WAS A VERY INCOMPLETE STORY SO I'LL HAVE TO SHOW YOU. THERE IS NO PROBLEM GOING IN, YOU GET A MATURE PHYTOZOME, AND THE CYCLE WOULD CONTAIN ITSELF WE THOUGHT, BUT THE MOVIES WOULD SHOW SOMETHING DIFFERENT. I WANT TO POINT OUT EVERYTHING, MOST OF THE FINDINGS IN MY LAB ARE THE RESULT OF SERENDIPITY. SOMEBODY LET THE MOVIE RUN, TWO TO FOUR HOURS. WHAT HAPPENS IF YOU RUN THE MOVIE OVERNIGHT? WELL, THIS IS WHAT HAPPENED. HERE YOU SEE A MACROPHAGE, YOU'RE GOING TO SEE IN A MINUTE IT'S GOT A BUNCH OF CRYPTOCOCCUS INSIDE, SOMETHING'S GOING TO HAPPEN HERE, IN WHICH THE MACROPHAGE, THE CRYPTOCOCCUS, ARE GOING TO COME OUT AROUND 8 HOURS, AND THERE THEY GO. THEY ARE GOING TO GO ABOUT NOW. LOOK AT THE CELL. THE CELL IN THE LACK LEFT ALIVE, IF YOU DON'T WATCH IT, KEEP WATCHING. IT DIVIDES, ONE WILL WALK OFF THE EDGE. THAT'S ONE OUTCOME. HERE IS ANOTHER OUTCOME. THESE CELLS WILL BURBS. HERE IS SOMETHING THAT TODAY REMAINS UNCOMPLAINED BUT IT IS A MAJOR PROBLEM IN CELL BIOLOGY. YOU'RE GOING TO SEE A MACROPHAGE CAN TRANSFER. THIS THING MOVES. IT'S FREQUENT. I'M NOT SHOWING YOU EVENTS. WE'VE-LOOKING PRIMARILY TO TRY TO UNDERSTAND, BECAUSE CLEARLY FROM A CELL BIOLOGY THERE HAS TO BE A LOT OF SCIENCE TO UNDERSTAND THIS. AND ONE OF THE THINGS, ONE OF THE PROBLEMS TODAY IN SCIENCE, IF YOU GET A MOVIE LIKE THAT, YOU CAN ENJOY IT FOR FIVE MINUTES BEFORE SOMEBODY SAYS TO YOU, WHAT'S THE MECHANISM? [ LAUGHTER ] IF YOU GIVE THE MECHANISM, DOES IT HAPPEN IN VIVO? BOTTOM LINE, YOU'RE A SCIENTIST. WE SHOULD BE ABLE TO ENJOY THE MOVIE. [ LAUGHTER ] IN FACT, WHAT'S IMPORTANT IS THE MOVIE. I CAN THINK OF 10, 20 MECHANISMS BY WHICH THIS CAN HAPPEN. YOU COULD HAVE SNARES, YOU KNOW, WE LIVE IN THE REALITY OF TODAY. IF YOU'RE GOING TO WORK ON THIS YOU HAVE TO ANSWER THE TWO QUESTIONS AND YOU'RE FREE TO GO ON TO WHEREVER YOU'RE GOING TO GO. BOTTOM LINE, IT DOES HAPPEN IN VIVO AND IT HAPPENS IN 50% OF THE MACROPHAGES. SO IT'S A VERY, VERY COMMON PHENOMENON. THE MECHANISM IS INCREDIBLY COMPLEX. THIS IS A GENERAL TALK BUT I'LL SHOW YOU, THIS IS ONE OF THE MOVIES. HERE WE HAVE THE OPPOSITE. I DON'T KNOW HOW MANY OF YOU HAVE SEE THE MOVIE "ALIEN" BUT THE ALIEN HAS THE SAME PROBLEM AS CRYPTOCOCCUS, IT WANTS TO GET OUT, AND IT DOES A TREMENDOUS AMOUNT OF DAMAGE TO ITS HOST. THIS MAKES GIANT -- YOU'LL SEE THE LC3, THIS IS A VERY, VERY SOPHISTICATED PROCESS. AT SOME POINT THIS THING WILL NOW FUSE AND THESE THINGS WILL COME OUT. TURNS OUT THE ACTIN REARRANGEMENT, ALL THESE THINGS ARE INTEGRALLY ASSOCIATED, NONE OF THEM IS ALL OR NONE. YOU'RE TALKING ABOUT REDUNDANCY IN THIS SYSTEM. SO ONE OF THE THINGS WE'VE BEEN FOCUSING ON IS PHYTOSOME. THE CELL IS ALIVE AND WILL LIVE FOR TWO OR THREE DAYS BUT WILL DIE, IT'S UNDERGONE DAMAGE. IF YOU, FOR EXAMPLE, WERE MAKING MORE LEAKY, YOU COULD PROMOTE ALL EXOCYTOSIS. A BEAUTIFUL PAPER IS CURRENTLY IN PRESS, SHOWING IN FACT IT TAKES A GAMMA INTERFERON THAT INHIBITS EXOCYTOSIS, MAINTAINING THE INTEGRITY OF THE CELL. THE MACROPHAGES ARE STAINING DAMAGE, MITOCHONDRIA ARE DEPOLARIZE. CASPASES HAVE BEEN ACTIVATED BUT NOT ACTIVATED AT A LEVEL LEADING TO NECROSIS, APOP -- APOPTOSIS, THE ORGANISM CAN REPLICATE FASTER AND TAKE CARE OF THE CELL, AND THIS IS A PAPER THAT IS NOW IN PRESS, DOCUMENTING THIS PHENOMENON. IT TURNS OUT THE CRYPTOCOCCUS IS SECRETING LARGE NUMBERS INTO THE PROTOPLASM. LIFE OR DEATH CELLS, VERY DIFFERENT CELLS, PROTEIN CELLS, RECOVER FROM THE CYTOPLASM, IN THIS CASE THE RESULT OF DIGESTION. WHAT I'M GETTING AT IS I WANT YOU TO THINK ABOUT THE BIG PICTURE. THIS IS AN ORGANISM THAT LIVES IN THE SOIL. IT HAS ABSOLUTELY NO NEED TO DO ANY OF THIS. WHY IS IT DOING IT? TO ME, THAT IS A VERY COMPELLING QUESTION, BECAUSE WHAT YOU HAVE IS GREAT SOPHISTICATION, THIS ORGANISM IS KEEPING THE CELL ALIVE, DAMAGING THE MEMBRANE, ACTIVATING CASPASES, DEPOLARIZING MITOCHONDRIA AND NOT KILLING IT BECAUSE IT'S REPLICATING. THIS CAN GET INTO INSECTS, REPTILES, WORMS, MAMMALS, EVEN PLANTS. YOU HAVE SOPHISTICATION AND NONSPECIFICITY. HOW DO YOU RECONCILE THAT? GENERALLY WE SEE HIGHLY SOPHISTICATED VIRAL STRATEGIES, WE SAY, OH, THEY CO-EVOLVE, THIS IS A MECHANISM TO MAINTAIN ITSELF. THIS IS THE COMPLETE OPPOSITE. THIS IS DOING TO HOSTS THINGS THAT IT DOESN'T EVEN NEED TO DO, IF YOU REMOVE ALL THE ANIMALS FROM THE EARTH, THIS ORGANISM WILL PROBABLY STILL BE FINE, WHEREVER IT IS IN THE ENVIRONMENT. WELL, WE BEGAN TO THINK YOU HAVE TO GO BACK INTO THE ENVIRONMENT TO THINK ABOUT THIS. THIS IS INCIDENTALLY THE BACK OF A NEW YORK CITY HOSPITAL IN 1992, YOU CAN SEE HOW MUCH MATERIAL THERE WAS. SO YOU ASK THE QUESTION, WHAT IS GOING ON HERE? WE ANSWER, COULD THE COMMON DENOMINATOR BE AMOEBA? AMOEBA WERE KNOWN TO BE PREDATORS, THERE WAS THE LEGIONELLA STORY AROUND 1998. WE SET OUT TO LOOK AT THE PROBLEM AND IMMEDIATELY WE SAW EVERYTHING WE WERE SEEING IN THE MACROPHAGE, REPLICATED IN AMOEBA, FIBROSOMAL DAMAGE, SUGGESTING CRYPTOCOCCUS LEARNED TO BE A PATHOGEN NOT BECAUSE IT NEVER CARED ABOUT A MAMMAL BUT RATHER TO SURVIVAL PREDATORS IN THE SOIL. WHEN YOU LOOK AT THE GENES REGULATED, YOU FIND IN MACROPHAGES, THEY ARE ALMOST IDENTICAL. WHEN IT'S IN A MACROPHAGE IN AMOEBA, IT'S DEAL WITH THE SAME PROBLEM, SOMETHING THAT ATE IT, IT'S HAVING TO DEAL WITH OXIDATIVE BURSTS AND MICRO CYTOPROTEIN. ANOTHER EXAMPLE, YOU CAN TAKE A STRAIN, RECOVER PASSING AFTER FOUR DAYS SUGGESTING SOME THINGS -- I CAN ONLY IMAGINE GENETIC CHANGES. SO YOU GET TO INTRACELLULAR REPLICATION, BOTH SYSTEMS, BOTH ARE TOXIC TO AMOEBA AND MACROPHAGES, PHOSPHOLIPID TRIGGERED CAPSULE AND CAPSULE PROTECTS. THIS IDEA HAS BEEN EXTENDED TO MANY FUNGI. WHEN YOU THINK ABOUT ASPERGILLUS, THEY COME WITH READY MADE VIRULENCE, THIS HAS BEEN ELECTED IN THE ENVIRONMENT, NOTHING TO DO PROBABLY WITH ANY OF THE ANIMALS. IN FACT, IT'S NOW BEEN DEMONSTRATED IN DROSOPHILA, AMOEBA, MOUSE CELLS. WHEN IT GETS INTO THE CELLS IT HAS REDUNDANCY TO DEAL WITH PROCESSES THAT ARE SEPARATE BY A BILLION YEARS IN EVOLUTION. WHAT DO WE THINK IS GOING ON? A LOT IS GOING ON IN THE SOIL, AND THINGS ARE BEING GENERATED, AND OCCASIONALLY THEY MAY CYCLE THROUGH ANIMALS AND THEN WHAT WE SEE AS A HUMAN PATHOGEN, THAT OCCASIONAL ONE WHERE THERE'S BEEN A BREAKDOWN IN IMMUNITY, IT CANNOT BE CONTAIN AND APPEARS TO HOST AN ORGANISM THAT'S DEADLY. TO MY KNOWLEDGE, THIS IS THE ONLY ORGANISM FOR WHICH THIS TYPE OF ANALYSIS HAS BEEN MADE. MANY PEOPLE WORK IN A VIRULENCE, IF THEY KNOCK IT OUT IT IS NOT VIRULENT. WHAT I URGE EVERYONE THAT'S INTERESTED IN PATHOGENESIS IS TO TRY TO DO THIS TYPE OF ANALYSIS AND SURROUND WHAT'S IMPORTANT. THE FACT IS, OUR EXPERIENCE IS CONSISTENT WITH IT. IF YOU GIVE ANTIBODIES, YOU'RE ABLE TO NEUTRALIZE, YOU'RE ABLE TO IN FACT NEUTRALIZE VIRULENCE. ONE OF THE FASCINATING THINGS ABOUT THIS ORGANISM, IT'S ABLE TO RAPIDLY ENLARGE THE CAPSULE, SO YOU TAKE A CULTURE, PUT IT INTO A MOUSE, 18 HOURS LATER THE CELLS ARE MUCH LARGER. YOU TAKE THE SAME THING, THROW AMOEBA IN THERE, AND YOU ALSO GET THE SAME PHENOMENON. HOWEVER, THESE CELLS CAN NOW BECOME VERY, VERY LARGE. THIS IS THE SIZE, 50 MICRONS, A FORMIDABLE PROBLEM FOR THE IMMUNE SYSTEM. IF THEY WERE COLORED, YOU WOULD SEE THEM WITH THE NAKED EYE. ONE OF THE THINGS WE WORK ON IS WORKING FROM AMOEBA NOW, WE'RE ABLE TO WALK BACKWARDS AND SEE WHAT THE SENSOR IS. WHAT HAPPENS IS THAT MANY CRYPTOCOCCUS IS SECRETING THINGS AND THEY BEGIN TO CAUSE DAMAGE ON THE AMOEBA, AND THE AMOEBA BEGINS TO RELEASE PHOSPHOLIPIDS, TRIGGERING THE CAPSULE TO ENLARGE, ALMOST LIKE A DANGER SENSOR. IF YOU SENSE PHOSPHO-LIPASE, THERE'S PROBABLY A PREDATOR, THE SAME MECHANISM IS USED FOR AMOEBA AND MACROPHAGES. WE WENT ON TO WORK OUT THIS QUOTE/UNQUOTE MECHANISM. IT HAPPENS TO BE FISSION. REPLICATION WITHOUT FISSIO, IN. THE RATIO BETWEEN VOLUME AND SURFACE GROWS DISPROPORTIONATELY, BUT THE ORGANISM MAKES A LARGE VACUOLE AND SQUEEZES THE CYTOPLASM ON THE SURFACE SO YOU HAVE A SURFACE YOU CAN WORK WITH. I WANT TO THROW YOU A LITTLE HISTORY HERE. IT'S 2008, THE SUMMER. I'M IN A CONFERENCE, IN THE BACK OF THE ROOM ANSWERING E-MAIL. WHY? BECAUSE I LIVE TO ANSWER E-MAIL. IN FACT, I HAVE MASTERED THE CAPACITY TO LISTEN TO TALKS AND ANSWER E-MAIL. AND I'M LISTENING, A YOUNG SCIENTIST, A STUDENT PROFESSOR AT THE TIME, IS PRESENTING. I'M SHOCKED BECAUSE SHE'S DISCOVERED THE SAME THING AND HAS THE SAME DATA. AND I ASK HER THE QUESTION, WHAT DO YOU THINK I DID? I COULD HAVE TAKEN MY CELL PHONE OUT, GONE OUTSIDE AND CALLED THE POSTDOC, YOU'RE ABOUT TO GET SPOOKED, YOU BETTER SHOW UP EVERY WEEKEND, YOU'RE GOING TO HAVE NO YEAR, YOU GOT TO GET THIS OUT, RIGHT? THAT'S ONE. YOU COULD HAVE ALSO WALKED AROUND THE MEETING AND SAID NOTHING. OR APPROACHED THE SCIENTIST AND SAID, YOU KNOW, WE HAVE THE SAME DATA. LET'S TRY NOT TO SCOOP EACH OTHER AND GET THE BEST WORK DONE. AT FIRST, I THINK I HAVE A BIG LAB, SHE WAS JUST STARTING OUT. THIS WAS ONE OF THE MANY THINGS I WAS DOING. WE BEGAN TO GET TOGETHER, AND WE BEGAN TO WORK TOGETHER AND WE WAITED FOR THE OTHER ONE TO COMPLETE THE EXPERIMENT. AND THEN WE SUBMITTED TOGETHER THE PAPERS AND THEY WERE PUBLISHED AT THE SAME TIME. NOBODY GETS SCOOPED. SCIENCE IS CONFIRMED AT THE SAME TIME. AND THE WORK GETS TO A HIGHER LEVEL OF COMPLETION THAN IF WE HAD GONE OUT THERE AND TRIED TO SCOOP EACH OTHER. WHAT IS THE MONEY IN SCIENCE? PRESTIGE. HOW DO YOU GET PRESTIGE? YOU GET PRIORITY. IT CAN BE RELATED TO CREDIT. YOU GET PRESTIGE, PRIZES, GRANTS, PUBLICATION VENUE THAT RESULTS IN MORE PRESTIGE. THIS IS OUR ECONOMIC SYSTEM. THIS IS HOW WE DO SCIENCE. I ASK YOU, IS THIS THE BEST WAY TO DO IT? WELL, WE HAVE WRITTEN THIS, IN FACT SCIENCE FOLLOWS A WINNER TAKE ALL ECONOMY. AND I ARGUE THAT WE SHOULD RETHINK IT IN MANY WAYS, BECAUSE THERE MAY BE BETTER WAYS TO DO THIS. WHY, FOR EXAMPLE, COMPETING LABS, WHY NOT WAIT FOR THE OTHER AND PUBLISH AT THE SAME TIME. WHAT IF WE GAVE CREDIT TO GROUPS THAT COOPERATE AND PRODUCED BETTER DATA RATHER THAN GROUPS THAT PUBLISH FIRST? I HAVE DONE THIS FOUR TIMES, AND EVERY TIME IT'S BEEN A WONDERFUL EXPERIENCE. IT'S RIGHT HERE. I DID IT WITH ROBIN MAY, WITH WHERE WE PUBLISHED ON CYTOSIS. THIS IS THE EXAMPLE I WAS TELLING YOU ABOUT, CELL TO CELL TRANSFER, WE HAD JUST DONE IT, THE PAPERS ARE IN PRESS. IT'S WONDERFUL. I WILL TELL YOU AN ANECDOTE ON THIS. THE SYSTEM TRIES TO DEFEAT THIS. IT TURNS OUT THAT ONE OF THESE SETS, I'M NOT GOING TO GET INTO IT, WENT INTO A HIGH PROFILE JOURNAL. AND WHERE THE EDITOR HAS NO -- GETS NO GAIN BY PUBLISHING TWO PAPERS THAT HAVE THE SAME THING, WHY? BECAUSE THE EDITOR IS CONCERNED ABOUT THE IMPACT FACTOR. SO IF IT GETS TWO PAPERS ON THE SAME THING, THE SAME THING DIVIDED BY TWO. THE EDITOR TRIED TO CUT A DEAL WITH THE OTHER GROUP. BECAUSE TRUST HAD BEEN ESTABLISHED, AND WE WORKED TOGETHER, THE OTHER GROUP PULLED OUT. AND THEN WE WENT TO ANOTHER JOURNAL. I THINK THIS IS WHAT I WOULD ARGUE, I COULD LEAVE YOU WITH ONE THING IN THIS TALK, IF YOU THINK YOU'RE GOING TO GET SCOOPED, YOU HAVE A SITUATION LIKE THAT IN YOUR LAB, PICK UP THE PHONE AND TRY TO SEE IF YOU CAN WORK SOMETHING OUT, DO IT TOGETHER, SHARE THE DATA LATER SO YOU CAN COME OUT INDEPENDENTLY BUT YOU CAN END UP BENEFITTING. THERE ARE NO LOSERS, YOU END UP WITH A MUCH BETTER RELATIONSHIP, SCIENCE BENEFITS, AND HE IT END OF THE DAY EVERYBODY IS A WINNER INCLUDING SOCIETY THAT DOESN'T HAVE TO DEAL WITH THE REPRODUCIBLE RESULTS. SO I HAVE WRITTEN ABOUT THIS. ONE OF THE THINGS ABOUT COMPETITION, PEOPLE THINK YOU NEED TO COMPETE TO PROMOTE PEOPLE IN SCIENCE. THE FACT IS, THERE'S NO EVIDENCE. WELL, TRANSFORMERS OF DISCOVERY ARE MADE OFTEN IN THE ABSENCE OF ANY COMPETITION. WHEN YOU CREATE COMPETITION, WHAT YOU DO IS YOU OFTEN CREATE PEOPLE TO SOLVE THE PROBLEMS BY THE MEANS THEY KNOW HOW TO DO IT. AND YOU'VE STIFLED CREATIVITY, THERE'S SOME DEGREE ABOUT THAT. I WISH YOU WOULD THINK HARD AS WE GO FORWARD ON HOW THERE ARE WAYS TO DO SCIENCE BETTER. TALKING ABOUT MELANINS, WE COVERED ETHICS. MELANINS ARE MADE BY ALL BIOLOGICAL KINGDOMS, INCLUDING MUSHROOMS AND CRYPTOCOCCUS MAKES THE SAME TYPE OF MELANIN IN YOUR SKIN. THIS STUFF IS PUT ON THE CELL WALL AND PRETTY MUCH SERVES AS A BARRIER, A NONSPECIFIC BARRIER THAT CAN PROTECT IT AGAINST PRACTICALLY ANYTHING YOU CAN THROW AT IT. THIS COULD BE A CAUSE OF ACQUIRED PERSISTENCE, DEFENSEINS, ON AND ON. ONE OF THE THINGS FASCINATING ABOUT MELANIN, IT'S TOTALLY RESISTANT TO BIOLOGY IN HYDROCHLORIC ACID. THIS HAS BEEN A USE UNTIL PROCEDURE ALLOWING US TO STUDY. THE STRUCTURE OF MELANIN IS UNKNOWN, IT'S AN AMORPHOUS COMPOUND. SCIENCE IS GOOD AT SOLVING STRUCTURES THAT CAN GO INTO SOLUTION OR BE CRYSTALLIZED. THEREFORE, THIS IS BEYOND THE SCIENTIFIC HORIZON. THIS IS WITH ATOMIC MICROSCOPY, IT IS COMPOSED OF SMALL THINGS AND WE THINK IT'S MADE IN VESICLES AND SHIFTS TO THE CELL WALL. I'M GOING TO TELL BUT TWO MELANIN TALES FROM THE FAR SIDE. FIRST, INITIAL INCREDULITY. THERE IS DIFFICULTY IN FUNDING. NONE HAVE BEEN FUNDED TO DATE. CONFIRMED BY OTHER GROUPS AND POTENTIALLY FAR-REACHING, AND THIS IS WHY ALL THIS ADVICE YOU TAKE SOME PART OF YOUR DAY AND READ OUTSIDE YOUR AREA AND TRY TO MAKE A LINK BETWEEN SOME CRAZY THING AND SOMETHING THAT YOU'RE DOING BECAUSE SCIENCE WILL BE MORE FUN THAT WAY, AND BASICALLY READING ALWAYS INTO YOUR FIELD. TALE ONE BEGINS WITH CHERNOBYL, 1986. SOMEBODY SENDS IN A ROBOT. THE REASON THE WALL IS BLACK. THIS IS THE MELTING REACTOR AREA, FUNGI ARE ON IT. IT'S A GOOD IDEA TO CULTURE AND FIND FUNGI ARE GROWING ALL AROUND AND AREA WHERE IF YOU WALK IN YOU'RE LETHALLY IRRADIATED. THIS GETS PUBLISHED IN A JOURNAL WITH AN IMPACT FACTOR LESS THAN TWO. WE BEGAN TO THINK OF THE ANSWER, RADIATION SHIELDED BY MELANIN. CLASSICAL RADIATION SHIELDING EXPERIMENT, LOW TECH, 96 WALL PLATE, PUT A FILM AND DO RADIATION. MELANIN ALONE GIVES YOU TWICE THE AMOUNT OF -- I'M SORRY, HALF THE AMOUNT OF PROTECTION AS LEAD. THINK ABOUT THAT. THIS IS A CARBON-BASED SUBSTANCE AND YOU'RE GETTING HALF OF WHAT LEAD GIVES YOU, SO IF YOU DOUBLE THE SIZE OF IT, IT BEGINS TO FUNCTION ALMOST AS LEAD. SO AGAIN, THAT GETS PUBLISHED, AND THAT COULD NOT BE THE EXPLANATION. WHY? FUNGI ARE RESISTANT TO RADIATION. THE FUNGI WON'T EVEN CARE ABOUT THE FLUX, SO THEN WE HAVE ANOTHER HINT FROM AGAIN ANOTHER NOT WELL KNOWN JOURNAL, IN THAT FUNGI BEGIN TO DEVELOP A PHENOMENON RADIOTROPISM, GROWING TOWARDS RADIATION SOURCES. ISN'T THAT INTERESTING? THINK ABOUT IT. WHY WOULD A FUNGUS GROW TO A RADIATION SOURCE? WE BEGAN TO ASK THE QUESTION, COULD THE FUNGUS BE USED IN RADIATION FOR GROWTH? AND WE ARE GOING THROUGH THE DATA. IT'S PUBLISHED IN AN OPEN ACCESS JOURNAL, DOWNLOAD IT IF YOU'RE INTERESTED. THE ANSWER SEEMS TO BE YES, BASICALLY RADIATION CHARGES OF MELANIN, CONVERTING, WE THINK THIS IS AN OXIDATION REDUCTION LOOP THAT ALLOWS IT TO -- THIS PAPER, BY THE WAY, THOSE OF YOU WHO HEARD MY LECTURE LAST YEAR, THE GORY DETAILS OF TRYING TO PUBLIC THIS. THREE YEARS DEALING WITH SINGLE AWARD JOURNALS, IN THE END WE DIDN'T SUCCEED BUT I'M HAPPY BECAUSE THE SAME DATA, AND THE SAME PEOPLE THAT TURNED US DOWN HAD TO WRITE STORIES ABOUT IT. IN FACT, I OFTEN ASK PEOPLE, YOU KNOW, WOULD YOU RATHER HAVE YOUR PAPER IN THE REPORTS ARE IN THE NEWS? YOU SHOULD ALWAYS TAKE THE NEWS BECAUSE THE JOURNALS HAVE HIGH RETRACTION RATES. SO LOOSE ARTICLES DON'T -- NEWS ARTICLES DON'T SEEM TO BE RETRACTED. AND THIS ARTICLE BOTHERED ME, GAMMA RADIATION, WHAT ARE YOU TALKING ABOUT? WE BEGAN TO SPEND FIVE TO SIX YEARS TO SHOW IN FACT GAMMA RAYS COULD CHANGE THE STRUCTURE OF MELANIN, IT HAD TO INTERACT, BUT THAT WAS NOT PROOF I WANTED. PROOF I WANTED CAME FROM THIS INDIVIDUAL WHO BASICALLY CREATED A MELANIN ELECTRODE AND IRRADIATED IT AND GET WHAT HE GOT? A CURRENT. THERE IS NO WAY OUT OF IT. MELANIN HAS THE CAPACITY TO CAPTURE THIS MATERIAL BY WAYS IN WHICH WE DON'T UNDERSTAND, WITH A CURRENT. IF THAT INDIVIDUAL COULD MEASURE A CURRENT, PUBLISHED IN A SINGLE AWARD JOURNAL BUT NOT ONE OF THE OTHERS, BIOLOGICALLY THIS COULD BE USED. IT'S NOW BEEN CONFIRMED BY ANOTHER GROUP, THERE IT IS OUT THERE, WE HAVE EXTENDED TO THE SPECTRUM, BLUE LIGHT DOES THE SAME THING, AND THIS IS A PICTURE I TOOK. YOU CAN SEE WHAT I THINK IS HAPPENING IS THE ORGANISMS ARE PROBABLY HAVING SOME FORM OF PHOTOSYNTHESIS COMPLEMENTARY AND PROBABLY DIFFERENT THAN THE ONE GOING ON BY CHLOROPHYL BASED, AND THIS IS SOMETHING I SAW IN CENTRAL PARK THIS SUMMER AND I CANNOT BELIEVE THESE ORGANISMS ARE NOT HARVESTING SUNLIGHT WITH THEIR MELANIN. THESE ARE USING CHLOROPHYL, THESE ARE USING A DIFFERENT SYSTEM, I BELIEVE, AND I THINK THIS IS SOMETHING VERY DIFFERENT THAT CAME OUT OF WORKING AND BEEN INTERESTED IN LINKING THINGS DIFFERENTLY. THE BLACK MOUNTAINS OF ANTARCTICA, WHAT'S GOING ON HERE? THE REASON THEY ARE BLACK IS BECAUSE THEY HAVE LICLENS GROWING ON THEM. I THINK THEY ARE GETTING THEIR ENERGY FROM THE SUN, A MELANIN-BASED PHOTOSYNTHESIS. THE SPACE STATION IS CONTAMINATED WITH FUNGI, HERE YOU SEE MELANOTIC FUNGI GROWING, THEY GROW WELL IN SPACE, ALSO CONSISTENT WITH GROWTH IN HIGH RADIATION ENVIRONMENT. SO THE TALE, THE SECOND TALE FROM THE FAR SIDE IS REMEMBER I TOLD YOU, I SHOWED YOU THE DATA, MELANIN HAS ROUGHLY HALF THE SHIELDING CAPACITY AS LEAD. COULD WE USE IT TO PROTECT MICE AGAINST LETHAL RADIATION? THE EXPERIMENT WORKED INCREDIBLY BELL. YOU TAKE MICE BASICALLY AND FEED THEM BLACK MUSHROOMS, WHITE MUSHROOMS, AND WHITE MUSHROOMS WITH MELANIN AND YOU CAN PROTECT THE MOUSE AGAINST A LETHAL RADIATION DOSE. WHAT IS GOING ON HERE? WELL, IT'S COMPLICATED. I THINK WHAT'S HAPPENING, MELANIN IS PROVIDING LOCAL SHIELDING TO THE GUT, AND THEN THE GUT IS ALLOWING TO DO AN AUTOTRANSPLANT, SO THE MICE ARE ABLE TO REPOPULATE THEMSELVES. THIS, WE TOOK THIS DATA AND SENT IT TO JAPAN, FUKISHIMA AND I DON'T KNOW IF THEY DID ANYTHING ABOUT IT BUT THIS IS A WAY TO HAVE RADIATION PROTECTION. YOU SAY I DON'T BELIEVE IT? IT'S BEEN CONFIRMED BY THE OTHER GROUP, THE SAME DATA. IF YOU CAME UP WITH A SMALL MOLECULE, ONE OF THE SIGNALING PATHWAYS, AND GOT 20%, PEOPLE WOULD THINK IT'S A BREAKTHROUGH. IF YOU TELL THEM BLACK MUSHROOMS WILL PROTECT THE MOUSE AGAINST RADIATION, HMM, I DON'T KNOW WHAT THAT MEANS. [ LAUGHTER ] IT'S PUBLISHED. I'M GOING TO TELL YOU ONE MORE TALE, BUT THIS IS NOT VERY DIFFERENT. SO FROM ONE OF THE THINGS FROM "GHOSTS," WE MADE ANTIBODIES, WE HAD AN IDEA, COULD THIS ANTIBODY BE USED TO TREAT MELANOMA? HERE IS SKIN MELANOMA. PEOPLE SAY, OH, IT COULD NEVER WORK BECAUSE MELANIN IS AN INTRACELLULAR PIGMENT. IT WILL NEVER REACH IT. WE KNOW ANY TUMOR IS MOSTLY DEAD CELLS. WHEN YOU STAIN IT YOU CAN SEE THE ANTI-BODIES, SO THE IDEA WAS COULD YOU TAKE THE ANTIBODIES TO FUNGAL MELANIN, AND USE THEM TO TREAT MELANOMA? WE DID THIS IN MICE, PUBLISHED IN 2004 IN PNAS, IT WORKED BEAUTIFULLY. THE MELANOMAS HAVE BECOME ESSENTIALLY SCAR TISSUE, THIS WAS TAKEN INTO HUMANS, AND IT'S BEEN GIVEN TO ABOUT 22 PATIENTS, AND THIS PROJECT IS CURRENTLY STALLED. WE'RE TRYING TO GET IT BACK. WE AGAIN SEE THE VALUE OF THAT, BUT WE THINK THIS IS A POTENTIAL THERAPY AGAINST MELANOMA, AND WE'LL BASICALLY ADD SOME OF THESE THINGS THAT ARE ALREADY AN AREA WHERE THERE'S BEEN A LOT OF DEVELOPMENT, BUT I WOULD POINT OUT TO YOU HOW THE DISCOVER CAME FROM A VERY DIFFERENT ANGLE, NOT ALL RELATED TO CANCER RESEARCH. SO AS WE GO FORWARD HERE, THE NEXT FIVE MINUTES OR SO, I WANT TO GIVE YOU A BIGGER PICTURE SO YOU HAVE SOILS, IN SOILS YOU HAVE A LOT OF ORGANISMS, AND THEY ARE ALL SELECTION PRESSURE BY RAIN, SUN, AMOEBA, TRACTORS, ET CETERA. MOST SOIL ORGANISMS MUST HAVE THE CAPACITY TO SURVIVE PREDATORS OR THEY WOULDN'T BE THERE BUT ONLY A FEW ARE VIRULENT. WHAT IS THE MECHANISM? WHEN YOU LOOK AT THE SOILS, YOU FIND AN ENORMOUS -- ALL THE FACTORS ARE THERE. THE BOTTOM OF THE OCEAN, THEY ARE THERE. WE BEGIN TO THINK THE MICROBES WERE IN FACT PLAYING CARDS, IN SOME CASE, A RANDOM GAME. THE MAMMALIAN HAND, THE PLANNED HAND DOESN'T NEED THAT BECAUSE PLANTS ARE ROOM TEMPERATURE, YOU CAN IMAGINE THE INSECT HAND DOESN'T NEED THE SAME THING. IT'S A VERY USEFUL WAY TO THINK HOW THESE THINGS MAY EMERGE. THEN I REALIZED THIS HAS ALREADY BEEN DESCRIBED, IT WAS DESCRIBED AT THE END OF THE 19th CENTURY BY A MARTIAN HAND. IF YOU READ WAR OF THE WORLDS, THE MARTIANS INVADED, THEY BASICALLY GOT SICK. THEY HAD NEVER BEEN TO THE PLANET BEFORE, PATHOGENIC ORGANISMS COULD TAKE OUT THE MARTIANS. THE MORE DIVERSITY MICROBIAL LIFE YOU WILL HAVE ALWAYS HAVE A DEGREE OF PATHOGENS, THEY MAY BE REEMERGING BY THE RANDOM COMBINATION OF VIRULENT FACTORS. ONE OF THE THINGS WE'RE PROTECTED, WE GO BACK, WHY ARE THERE SO FEW FUNGAL PATHWAYS? ADAPTIVE IMMUNITY CANNOT BE THE ANSWER BECAUSE FROGS ARE SUSCEPTIBLE. THE MAJORITY OF FUNGI LOOSE ABILITY RAPIDLY IN THE RANGE OF 30 TO 40 DEGREES, AND IN FACT IF YOU TAKE THIS DATA, THAT IS THE BENEFIT OF BEING HOT AND TOOK THE CAUSE AND HAVE THE TWO SIMULTANEOUS EQUATIONS, LOOK AT THE TEMPERATURE THAT POPS OUT, YOUR TEMPERATURE. IN THE PAST WE TALKED ABOUT DINOSAURS, WE ARGUED PERHAPS THE REASON THERE WERE SO FUNGAL DISEASES, THEY WERE THE DISEASE DISEASES BY WHICH WE GET HERE. THE WORLD IS GETTING WARMER. MOST OF THE DISEASES CURRENTLY COME FROM THE TROPICS. MAKES SENSE. THAT'S AN AREA WHERE THE FUNGI WILL ADAPT TO HIGHER TEMPERATURES. SO ALL PROJECTIONS ARE THE GLOBE IS GETTING WARMER, AND THE QUESTION IS HOW WARMER IT WOULD GET, AND WE HAVE LOOKED AT THERMAL TOLERANCE, COULD WE IDENTIFY THE NEXT PATHOGENS? MOST ORGANISMS IN THE FUNGAL KINGDOM ARE NOT SUSCEPTIBLE TO OUR DRUGS. WE'VE BEEN PROTECTED BY THE TEMPERATURE DIFFERENCE AND OUR IMMUNE SYSTEM. THE FUNGI CAN ADAPT RAPIDLY TO TEMPERATURES. HERE IS AN EXPERIMENT DONE BY A COMPANY IN FLORIDA, THEY HAVE A FUNGUS, THEY WANT TO USE IT TO KILL INSECTS. INSECTS LEARN TO SUN THEMSELVES AND BY SUNNING THEMSELVES THEY KILL THE FUNGUS, THEY ADOPT TO THE FUNGUS IN SIX WEEKS TO BE ABLE TO GROW AT 47 DEGREES. THE MESSAGE IS THESE THINGS ARE RAPIDLY ADAPTING, WE PUBLISHED DATA THAT'S CURRENTLY BEING REVIEWED SHOWING IF YOU TAKE THE AVERAGES, SUGGESTING THIS PROCESS IS ALREADY HAPPENING AS THE GLOBE IS BEGINNING TO WARM. CAN WE PREDICT ANYTHING? WE TOOK CRYPTOCOCCUS, THIS IS WORK DONE HERE AT THE NIH, AND WE TOOK THREE OF THEM THAT WERE RELATIVES, WE HAD TO HAD A HOST TO COMPARE INFECTIVITY, YOU HAD TO GO TO GALAREA, YOU COULD NOT DO EXPERIMENTS IN A MOUSE. CAPSULE AND MELANIN GIVES YOU HALF. WE WERE PREDICTING ON THE BASIS OF THIS, HERE YOU HAVE CRYPTOCOCCUS THAT KILLS THE GALAREA, THIS ORGANISM WITH NO CAPSULE AND NO MELANIN WAS MORE VIRULENT. PRESUMABLY, THE HAND OF THIS ORGANISM INCLUDED CARDS THAT ALLOW THEM TO MAKE THIS EXTINCT. THE QUESTION IS, WILL IMMUNOLOGY AND INFECTIOUS DISEASE EVER BECOME A PREDICTIVE SCIENCE? IF YOU KNOW THE IMMUNE SYSTEM, WHAT'S OUT THERE, COULD YOU PREDICT WHETHER THINGS WOULD BE PATHOGENIC OR NOT? THE CONCEPT OF EMERGENCY GOES BACK, THE WHOLE IS CREATED IN THE PART. THE FACT IS IF YOU KNOW ALL ABOUT THE LAWS OF PHYSICS, YOU CANNOT PREDICT THIS. YOU CAN STILL NOT PREDICT THIS FEATURE OVER HERE. YOU MAY BE ABLE TO EXPLAIN IT AFTERWARDS BUT THIS SUGGESTS THERE MAY BE LIMITS TO WHAT WE CAN KNOW IN THESE SYSTEMS. SO THE CONSEQUENCES OF VIRULENCE OF AN EMERGENT PROPERTY, IT'S NOT REDUCIBLE, SCARY BECAUSE MICROBIOLOGISTS, KEEP THE HOSTS CONSTANT, IMMUNOLOGIES KEEP THE MICROBE CONSTANT. WE NEED NEW APPROACHES, AND I THINK I AM OPTIMISTIC, WE MAY GET SOMETHING SIMILAR TO WEATHER DICTION TO WEATHER PREDICTION. SO WE MAY NEVER GET TO A POINT WE MAY HAVE A PREDICTION, INFECTIOUS DISEASE WILL BE WITH US, WILL ALWAYS BE A THREAT. THE ENVIRONMENT IS PROBABLY THE GREATEST THREAT WE FACE. AT THE END, SOME INSIGHT FROM THIS WORK, NO SPECIFIC ENVIRONMENTAL PATHOGENS BUT HAVE VERY SOPHISTICATED STRATEGY, THE SOIL, WAYS YOU MAY NOT HAVE IMAGINED. MELANIN IS A NOT RADIOPROTECTOR AND ENERGY HARVESTING MOLECULE. THIS IDEA, BY THE WAY, THAT THE FUNGI MAY USE RADIATION FOR FOOD CHANGES WITH THE ECOLOGY OF THE EARTH. WE THINK OF FUNGI AS DIGESTORS BUT IF THEY PRODUCE ENERGY BY HARVESTING RADIATION FROM THE SUN YOU HAVE TO RECALCULATE THE ENERGY FLOWS. HUMAN MAMMALIAN TEMPERATURES RESTRICTS MOST FUNGAL SPECIES. THANK YOU VERY MUCH. [APPLAUSE] >> THANKS, ARTURO, THROUGH A ROMP THROUGH A HOST OF DELIGHTFUL ISSUES. WE'RE OPEN TO QUESTIONS. PEOPLE WHO HAVE QUESTIONS PEOPLE COME TO THE MICROPHONE SO PEOPLE ON THE WEB CAN HEAR YOU. >> VERY NICE TALK. I HAVE A QUESTION. WHAT DO YOU THINK, I INCLUDE MYSELF, WHY DO SCIENTISTS HAVE SUCH A DIFFICULT TIME IDENTIFYING AND RECOGNIZING INNOVATION, ESPECIALLY WITHIN COMMITTEE? AND DO YOU KNOW OF ANY SYSTEMATIC STUDY OF SUCH A THING? >> YOU KNOW, THIS IS A CENTRAL PROBLEM, THE DIRECTOR IS RIGHT HERE. WE NEED TO SOLVE THIS. THE WAY WE TRY RECOGNIZE INNOVATION IS WE GIVE ESTABLISHED SCIENTISTS THE LOOKOUT, THEY ARE WORKING FROM THE CURRENT MODEL. IT'S VERY, VERY HARD, AND THE MORE CHALLENGES, THEY ARE MORE LIKELY TO REJECT IT. THIS IS THE HISTORY OF SCIENCE. I THINK WE NEED TO BE MORE OPEN-MINDED, INSTEAD OF REJECTING SOMETHING LIKE THIS, THIS IS THE DATA YOU HAVE TO APPROVE AND BELIEVE IT. YOU KNOW, BASICALLY THE QUESTION AROUND, I QUESTION HOW MUCH INNOVATION ARE WE JUST -- WHAT ARE WE KILLING BY THE FACT THAT WE KNOW WHAT SAFE SCIENCE IS, WE KNOW WHAT WE NEED TO CONVINCE, THIS IS NOT THE KIND OF THING YOU WOULD PUT IN A GRANT. [LOW AUDIO] >> ANOTHER AREA WHERE ONE OFTEN SEES INNOVATION, IF YOU'RE LOOKING HISTORICALLY AND RETROSPECTIVELY IS TWO DISCIPLINES WORKING TOGETHER ON A PROBLEM WHERE THEY HAVEN'T PREVIOUSLY PARTNERED BEFORE AND NOW EACH ONE BRINGS A PERSPECTIVE TO THE PROBLEM THAT NEITHER ONE ALONE COULD HAVE ACHIEVED. DO ANY OF THESE EXAMPLES FIT THAT OR IS THAT SOMETHING DIFFERENT? >> THANK YOU, DR. COLLINS. THEY DO FIT THAT. I DO COME FROM A PHYSICAL CHEMICAL BACKGROUND AND THINK DIFFERENTLY WHEN I APPROACH THE PROBLEM, I DON'T THINK GENETICIST. TRY TO CHANGE FIELDS AND SEE WHAT HAPPENS. YOUR OLD FIELD ABOUT SAY YOU ABANDONED THEM AND THE NEW FIELD WILL WORK HARD TO KEEP YOU OUT. WHAT IS GOING ON HERE? WELL, WE KNOW VERY WELL THIS IS EXACTLY WHAT WE SHOULD BE ENCOURAGING. THE FIELDS WORK AS A UNIT THAT KEEPS INFORMATION EITHER OUT AND THEN SAYS WE MORE PEOPLE TO BE INTERESTED IN MY FIELD BUT WOULD THEY WELCOME ANYBODY? THINK ABOUT THAT. DO THEY WELCOME ANYBODY? THIRST THING YOU DO, YOUR FIRST PAPER, SOME MINOR THING, YOU USED A PH, THIS IS CRAZY. WE NEED TO FIGHT THIS. WE NEED TO -- WHEN ANYBODY COMES UP WITH, IN YOUR FIELD, THEY SAY, WELL, YOU KNOW, THAT'S AN ENTOMOLOGIST, I DON'T KNOW WHAT THEY ARE DOING, LET'S SEE WHAT WE THINK IS RIGHT ABOUT WHAT IS GOING ON AND EMBRACE IT AND WE COULD PUSH SCIENCE SO MUCH FARTHER THAN IF WE TRY TO SQUELCH IT EVERY TIME WE RUN INTO IT. >> I'M INTRIGUED WITH YOUR COMMENTS ON THE MELANIN EFFECT ON RADIO PRODUCTION. THE DEPARTMENT OF ENERGY SPENT MILLIONS TO DEVELOP NEW PROTECTANTS. I WAS WONDERING IF YOU FIND ANY APPLICATION? >> WE HAVE APPLIED FOR FUNDING AND THINGS LIKE THAT. LISTEN, THE IDEA THAT SOMETHING, THAT MELANIN IS GOING TO PROTECT, YOU KNOW, IT SIMPLY HASN'T CONNECTED. THE DATA IS THERE. CONFIRMED BY ANOTHER LAB. EXPERIMENTS ARE SIMPLE. I INVITE ANYONE TO DO THE EXPERIMENTS. IT'S REMARKABLE. THIS THING IS PROTECTING THE GUT, THE ANIMAL SURVIVES. >> IS IT ANY SPECIFIC TYPE OF RADIATION? >> YES, THESE ANIMALS FORGOT THEY WERE BLASTED WITH ONE THAT ABLATES THE BONE MARROW, THEY DIE OF SEPSIS IN 14 DAYS, THE GUT LEAK, SO ANOTHER MECHANISM PROBABLY WORKING IS PROTECTING THE GUT LOCALLY SO YOU DON'T HAVE THE LEAKAGE THAT CAUSES THE DEATH. >> THANK YOU. >> TIMETABLES, SURELY THERE MUST BE A WINDOW WHERE YOU HAVE TO APPLY THE MELANIN AND WAIT A CERTAIN PERIOD AND ZAP WITH RADIATION. HOW DOES THAT WORK? IT MUST BE A LONG-TERM EFFECT. >> YOU'RE RIGHT, MELANIN IS NOT ABSORBED, IT BASICALLY GOES RIGHT THROUGH, SITS THERE AND WHAT I THINK IS HAPPENING IS THE LITTLE MELANIN GRANULES ARE PROVIDING LOCAL PROTECTION, THAT'S ENOUGH FOR YOU TO BOUNCE UP. >> LET ME ASK ABOUT THE STRAINS THAT HAVE THE MELANIN WHICH SEEM TO LOVE RADIATION, AND IT DOES MAKE YOU WONDER IN TERMS OF THE EVOLUTIONARY EFFECT, WHY WOULD THE PARTICULAR FUNGI HAVE BEEN EXPOSED TO THOSE LEVELS OF RADIATION DURING EVOLUTIONARY TIME OR IS IT JUST THAT THEY HAVE A SYSTEM THAT DOESN'T PARTICULARLY CARE ABOUT THE WAVELENGTH AND ANYTHING WILL DO? >> THAT'S ACTUALLY A VERY INSIGHTFUL QUESTION WE'VE HEARD A LOT ABOUT. MELANIN IS CHEAP TO MAKE, YOU NEED TO POLYMERIZE. IT'S PROBABLY A PIGMENT FROM THE EARLY DAYS THAT'S GOT MANY, MANY FUNCTIONS, ADAPTED FOR MANY USES. AND I THINK THAT IT'S PROBABLY A LOW TECH ENERGY ABSORPTION MECHANISM. LOOK, IT STANDS TO REASON, IS BIOLOGY GOING TO WASTE THINGS THAT HAVE BEEN ANSWERED? COME ON. THESE THINGS LIVE ON CAVES, ELECTRONS, BIOLOGY, WHEREVER YOU CAN FIND AN ELECTRON IT TENDS TO USE IT. MY VIEW, THIS IS A REMNANT FROM A VERY DISTANT TIME WHEN THERE WAS NO OXYGEN, THE WORLD WAS VERY DIFFERENT AND LIFE WAS SMALL. YES, SIR? >> THANK YOU, VERY MUCH, DR. CASADEVALL. I WAS WONDERING, CRYPTOCOCCUS IN THE NONHIV PATIENT, YOU HAVE SHOWN IN SOME OF YOUR WORK VERY ELEGANT PICTURES DEPICTING TO DISEASE PROCESS. WHERE DO YOU SEE THAT CURRENTLY IN WHAT'S KNOWN ABOUT CRYPTOCOCCUS IN NONHIV. >> THE DAMAGE FRAMEWORK IS A THEORETICAL CONCEPT WE PROPOSED 15 YEARS AGO TO TRY TO RECONCILE THE HOST AND MICROBE IN MICROBIAL PATHOGENESIS, USEFUL TOOLS TO THINK ABOUT IT. IN WEAK IMMUNITY THE ORGANISM REPLICATION, YOU SEE AIDS. AT THE OTHER END WE DON'T SEE EVIDENCE, AT LEAST THERE'S EVIDENCE OF ASSOCIATION, THIS ORGANISM MAY BE RELATE TO THE ASTHMA ESPECIALLY IN THE INNER CITIES, THE HYGIENE HYPOTHESIS, ALL THE KIDS ARE GETTING INFECTED. REMOVE THE DISEASES THAT USED TO GIVE YOU TH 1, THEY ARE STILL GETTING INFECTED WITH CRYPTOCOCCUS. THERE'S TROUBLE AT EITHER END. >> I LIKE YOUR EXAMPLE, IF YOU HAVE THE GUARD CHOSEN BY CRYPTOCOCCUS. >> I THINK WE DON'T KNOW ENOUGH THERE TO KIND OF -- THEY CLEARLY ARE DIFFERENT IN THAT SOME OF THEM -- ONE IS ASSOCIATED WITH IMMUNODEFICIENCY, THE COMPARISON IS GOING TO BE VERY INTERESTING. >> THANK YOU VERY MUCH. [APPLAUSE] >> FOR THOSE INTERESTED, THERE WILL BE A RECEPTION IN THE NIH LIBRARY RIGHT DOWN THE HALL. PLEASE COME AND CONTINUE THE CONVERSATION WITH THIS SPEAKER IF YOU WOULD LIKE TO ASK MORE QUESTIONS. THANK YOU.