>> GOOD AFTERNOON. WELCOME TO THE KINYOUN LECTURE. HE HAD A ONE-ROOM LABORATORY ON STATEN ISLAND WHICH OPENED THE NEW ERA OF BATTLING INFECTIOUS DISEASES THROUGH HIS VIGOROUS SCIENTIFIC RESEARCH AND HIS VISION AS IT CONTINUES TO INSPIRE OUR APPROACH TO IMPROVING HUMAN HEALTH. IN 1979, WE AT NIAID LAUNCHED THE KINYOUN MEMORIAL LECTURE SERIES TO HONOR HIS PIONEERING EFFORTS. LAST YEAR, TO MARK THE 125TH ANNIVERSARY OF THE FOUNDING OF THE HYGIENIC LABORATORY ON STATEN ISLAND, NIAID CREATED A MULTIMEDIA WEBSITE DEVOTED TO THE LIFE AND LEGACY OF DR. KINYOUN, WHICH I ENCOURAGE YOU TO VISIT. HERE IS THE WEBSITE HERE AND IT IS REALLY QUITE A FASCINATING AND INFORM TIM. INFORMATIVE, SO I ENCOURAGE YOU VERY MUCH TO VISIT IT. SO TODAY WE WELCOME THE FOUNDING AND CURRENT EDITOR-IN-CHIEF OF THE ONLINE OPEN ACCESS JOURNAL AND BIO, DR. ARTURO CASADEVALL. LIKE DR. KINYOUN, DR. CASADEVALL'S INTEREST ENCOMPASSES BOTH BASIC INQUIRIES IN MICROBIOLOGY AND THE DEVELOPMENT OF NOVEL INTERVENTIONS FOR HUMAN ILLNESSES. DR. CASADEVALL WAS BORN IN CUBA AND CAME TO THE UNITED STATES IN 1968. HE RECEIVED HIS M.D. AND P.H.D. FROM NYU AND COMPLETED AN INTERNSHIP IN RESIDENCY IN INTERNAL MEDICINE AT BELLEVUE HOSPITAL IN NEW YORK CITY. HE THEN WENT TO ALBERT EINSTEIN COLLEGE OF MEDICINE AS A POSTDOCTORAL FELLOW IN 1989 AND JOINED THEIR FACULTY IN 1992, AND SINCE 2006, ARTURO HAS BEEN PROFESSOR AND CHAIR OF THE DEPARTMENT OF MICROBIOLOGY AND IMMUNOLOGY AT EINSTEIN. HE ALSO WAS ATTENDING PHYSICIAN IN MEDICINE AT UNIVERSITY HOSPITAL AND ACADEMIC MEDICAL CENTER FOR EINSTEIN. EARLY THIS YEAR, HE ASSUMED AN ADDITIONAL ROLE AS DIRECTOR OF THE NEWLY ESTABLISHED CENTER FOR IMHUE KNOW LOGICAL SCIENCES. A KEY GOAL OF THAT CENTER IS TO ENHANCE THE UNDERSTANDING OF BASIC IMMUNOLOGY AND TO TRANSLATE THAT KNOWLEDGE INTO TREATMENTS FOR IMMUNE DISORDERS. ARTURO HAS RECEIVED NUMEROUS HONORS, BUT PARTICULARLY I WANT TO POINT OUT HIS MULTIPLE RECOGNITION FOR HIS EXTRAORDINARY MENTORING SKILLS. IN 2008, HE RECEIVED BOTH THE ALBERT EINSTEIN COLLEGE OF MEDICINE FACULTY MENTORING AWARD AND THE AMERICAN SOCIETY OF MICROBIOLOGY'S WILLIAM HINTON AWARD FOR MENTORING SCIENTISTS FROM UNDERREPRESENTED GROUPS. ARTURO IS A FELLOW OF THE AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SIG SCIENCE AND WAS ELECTED TO MEMBERSHIP IN THE ASSOCIATION OF AMERICAN PHYSICIANS AND AMERICAN ACADEMY OF MICROBIOLOGY. HE ALSO SERVES ON THE NATIONAL SCIENCE ADVISORY BOARD FOR BIOSECURITY AND IS A CO-CHAIR OF THE BOARD OF SCIENTIFIC COUNSELORS. BUT MOST IMPORTANTLY, HE HAS BEEN A VERY IMPORTANT CONTRIBUTOR TO NIAID AND TO ME PERSONALLY AS A VALUED FRIEND AND ADVISOR ON A VARIETY OF SCIENTIFIC AND POLICY ISSUES. HIS RESEARCH FOCUSES ON THE FUNDAMENTAL ISSUE OF VIRULENCE IN MICROORGANISMS, WHY ARE SOME MICROBES BA POEGENIC WHILE OTHERS ARE HARMLESS? STUDYING THE INTERPLAY BETWEEN THE HOST AND MICROBE. MORE RECENTLY, HE'S ADVANCED AN ARGUMENT THAT FUNGAL DISEASE PLAYED A ROLE IN THE DEMISE OF THE DINOSAURS AND RISE IN MAMMALS. PLEASE JOIN ME IN WELCOMING ARTURO. [APPLAUSE] >> THANK YOU FOR THAT VERY NICE INTRODUCTION, THANK YOU FOR INVITING ME. IT'S A GREAT HONOR TO BE HERE AND AMONG SOME OF MY FRIENDS. THE LAST YEAR I GAVE A TALK ON IMMUNOLOGY SO I THOUGHT THIS YEAR WE WOULD TALK ABOUT OTHER THINGS, BUT FIRST I THOUGHT WE SHOULD SAY -- I SHOULD SAY SOMETHING ABOUT DR. KINYOUN. THIS WAS A BEAUTIFUL ARTICLE WRITTEN LAST YEAR, WHICH IS IN M BIO, YOU CAN READ IT, AND THIS IS A REMARKABLE INDIVIDUAL WHOSE LIFE SAW THE GERM THEORY REVOLUTION, AND SO HE WENT FROM BEING A PHYSICIAN WHO COULDN'T DO ANYTHING ABOUT INFECTIOUS DISEASE TO BE ABLE TO TREAT IT WITH SERUM THERAPY AT THE TURN OF THE CENTURY. HE SAW HIS DAUGHTER DIED -- PER PERFECTED A STRAIN FOR TUBERCULOSIS. WHEN I LOOK AT HIS LIFE, WHAT I SEE IS THAT IT'S SPAWNED ONE OF THE GREAT HUMAN REVOLUTIONS IN THAT PHYSICIANS WERE ABLE TO ASSOCIATE DISEASES WITH SPECIFIC MICROBES, AND IT'S NOT UNLIKE THE REVOLUTION THAT SOME OF YOU ARE LIVING IN, WHERE WE'RE IN FROM COMPUTERS, THINGS THAT WERE FAR AWAY, TO BEING IN EVERY PART OF OUR LIVES. I'M GOING TO BEGIN WITH SOME QUESTIONS THAT AREN'T PART OF ANY USUAL SEMINAR. WHY ARE WE HERE? WHY ARE WE SO HOT? WHY DO WE EAT SO MUCH? WHY WHEN YOU DRIVE IN THE M.D. COUNTRYSIDE, MOST OF THE LARGE ANIMALS ARE MAMMALS? YOU WOULD ARGUE THOSE ARE IMPORTANT QUESTIONS YET YOU DON'T SEE THEM ADDRESSED IN SEMINARS. I'M GOING TO GIVE YOU THE ANSWER SO YOU DON'T HAVE TO STRESS OUT, IT'S A SINGLE WORD, AND IT'S FUNGI. I HOPE TO CONVINCE YOU AT THE END THAT THIS ALL MAKES SENSE. SO SOME OF THE GOALS, ONE IS TO SHOW THAT SCIENCE CAN BE FUN, AND THE SECOND TO ARGUE FOR MUCH THOUGHT IN BIOLOGY. IN BIOLOGY, WE DON'T THINK ANYMORE, IN FACT, WE CAN'T THINK WITHOUT DATA, AND I THINK THAT'S ONE OF THE THINGS THAT WE HAVE LOST. SO INFECTIOUS DISEASE FORM THED GERM THEORY, DISEASES WILL COME AND GO AND PEOPLE WOULD DIE AND THERE WAS VERY LITTLE ANYONE COULD DO. THE GERM THEORY REVOLUTION BEGINS WITH A TECHNOLOGICAL INNOVATION, THE MICROSCOPE, BUT IT TAKES 200 YEARS BETWEEN MICROBES THAT ARE ASSOCIATED WITH DISEASES. CAUSATION ESTABLISHED IN THE LATE 19TH CENTURY AND WITHIN SIX OR SEVEN GENERATIONS, MANY OF THE DISEASES THAT KILLED HUMANS SINCE WE HAVE HAD HISTORY TEND TO GO AWAY. SO WE HAVE INTERVENTION, SERUM THERAPY, VACCINE, ANTIBIOTICS, AND THEN MECHANISMS. PEOPLE HAVE BEEN WORKING ON MECHANISM PRETTY MUCH EVER SINCE. SO ARE PATHOGENIC MICROBES DIFFERENT? IN THE EARLY DAYS, IT APPEARED TO BE SO. THEY MADE TOXINS AND THEY HAD CAPSULES, BUT THERE IS A DIE DIVERGENT VIEW BY PASTURE, THE ONE WHO DISCOVERED -- AND HE ALSO CONTRIBUTED TREMENDOUSLY TO COMPLEMENT, ARGUED THERE WAS NO FUNDAMENTAL DIFFERENCE BETWEEN PATHOGENS AND NON-PATHOGENS. VIRULENCE WAS NOT A STABLE TRAIT. YOU COULD TAKE AN ORGANISM, ATTENUATE IT AND BRING IT BACK TO VIRULENCE AND ALSO IMMUNIZATION AGAINST -- THEN IT BECOME A VERY CONFUSING EVOLUTION IN THOUGHT FROM THE 1670s TO 18 SICTS 60s, MICROBES WERE SEEN AS ANIMALS, THEN WE SEPARATED THEM INTO PATHOGENS AND NON-PATHOGENS. BY THE LATE 20TH CENTURY, WE HAD TREMENDOUS CONFUSION. I WOULD ARGUE ULTIMATELY THIS LAST BUSINESS IS LARGELY AN ERROR IN THOUGHT AND LOGIC. SO A PROBLEM BEGINS CAN THIS MOVE IN ONE DIRECTION OR ANOTHER, PATHOGENS COULD BECOME NON-PATHOGENS AS ALLUDED TO BY VACCINATION. BY THE 1990s, IT DEPENDS WHO YOU ASK. IF YOU ASK A MICRO BIOLOGIST HOW DO YOU MAKE A PATHOGEN, THEY SAY TAKE A MICROBE AND PUT SOMETHING ON IT LIKE A VIRULENCE FACTOR. IMMUNOLOGISTS WILL TAKE A MICROBE AND MAKE IT A HOST BUT NEITHER HAD THE STORY. FOR IMMUNIZATION NEGATED -- MAJOR IS A NON-PATHOGEN? HOST GIVEN VACCINE. ON THE OTHER PART OF THE COIN, PATIENTS WITH AIDS GET ALL MICROBES SO THE PROBLEM WAS THAT NEITHER VIEW COULD ACCOUNT FOR IT. BUT IN FACT THE CENTRAL PROBLEM WAS THAT A MICROBE, IF YOU CALL A MICROBE A PATHOGEN, YOU'VE GIVEN IT A TRAIT THAT IS NOT ITS OWN. FOR A MICROBE THAT IS PATHOGENIC ONLY IN A SUSCEPTIBLE HOST. SO WE SET OUT TO TRY TO RECONCILE SOME OF THIS IN THE LATE 1990s, AND IN PARTICULAR SOME OF THE PAPERS THAT APPEARED, YOU A YOU CAN PUT ALL MICROBIAL PATHOGENESIS -- IN THIS DIAGRAM. IF YOU FOCUS ON THE ARROWS WHERE THE HOST GOES DOWN, THAT IS WHERE MICROBIAL PATHOGENESIS WILL BE AT. WE CAME UP WITH THE DAMAGE RESPONSE FRAMEWORK. THIS WAS ORIGINALLY A TEACHING TOOL. WE USED IT TO TEACH GRADUATE STUDENTS AND AFTER A WHILE, WE REALIZED THAT IN THE TEACHING NOTES, WE HADAL THOUGHT SO WE WENT ON AND PUBLISHED T SO IT'S VERY SIMPLE, YOU HAVE TWO ENTITIES, A HOST AND A MICROBE, YOU HAVE IN THIS CASE THE RELEVANT OUT COME IS DAMAGE AND DAMAGE CAN COME FROM THE HOST, THE MICROBE OR BOTH, AND THE INSIDE WAS THAT THERE HAD TO BE A RELATIONSHIP. AFTER DOING A LOT OF READING, WE REALIZED THAT THE RELATIONSHIP IS A PROBLEM. PEOPLE GET INTO TROUBLE AT EITHER END AND IF YOU DRAG IT BELOW THE X AXIS, YOU CAN SEE AN ORGANISM THAT CAN BE BENEFICIAL AT A CERTAIN IMMUNE RESPONSE, CAN BECOME PATHOGENIC IN A VERY WEAK IMMUNE RESPONSE OR ALTERNATIVELY, IF YOU HAVE A DISPROPORTIONATELY STRONG IMMUNE RESPONSE. SO HOW COULD YOU USE IT? YOU CAN BUY THIS IN THE STORE, DOWNT NEED A LICENSE, DON'T HAVE FILL OUT ANY APPLICATIONS, YET IF YOU LOOK IN PUBMED, YOU MAY FIND THAT THIS CAUSES DISEASE. SO IT CAUSES DISEASE -- IN THE OLD DAYS, NOW WE DON'T SEE THIS ANYMORE, SO YOU'RE GOING TO CALL IT OPPORTUNISTIC OR YOU KEEP RIDING AND FIND IT CAUSES IDENTICAL DISEASE TO VAGINITIS AND THIS IS IN NORMAL WOMEN, SO WHAT ARE YOU GOING TO CALL IT NOW? A PRIMARY PATHOGEN? LONG TAKEN OUT BECAUSE OF MASSIVE INFLAMMATION, A PROBLEM AT THE OTHER END. SO IF YOU LOOK AT THE DAMAGE RESPONSE, YOU CAN PUT THE AIDS PATIENT THE AT ON AT ONE END, I DON'T KNOW WHERE NORMAL WOMEN WOULD BE WITH VAGINITIS, THE DAMAGE FRAMEWORK ALSO INTELLECTUALLY ALLOWS YOU TO TRANSCEND A LOT OF THESE THINGS THAT ARE CONFUSING. FOR EXAMPLE, IF YOU LOOK AT DAMAGE AS A FUNCTION OF TIME, WE SEE ALL THESE STATES ARE CONTINUOUS EXCEPT FOR THE AMOUNT OF DAMAGE TO THE HOST, SO IT'S DIFFERENT FROM DISEASE ONLY IN THE DEGREE OF DAMAGE. AND YOU CAN SEE, FOR EXAMPLE, IF YOU WERE TO -- BASICALLY WE GET INFECTED, WE BECOME COLONIZED, THEN IT GETS CONTROL, BUT IT'S -- IN LIFE IT'S BASICALLY MOVING ALONG THE STATES. THE DAMAGE FRAMEWORK HAS SOME IMPORTANT CONSEQUENCES IF YOU ACCEPT IT. IT SHIFTED THE BASE FROM PATHOGEN TO NON-PATHOGEN TO THE OUTCOME OF THE INTERACTION. ACCORDING TO THE DAMAGE FRAMEWORK, THERE ARE NO PATHOGENS. THERE ARE NO COMEN TALLS. IT IS AMAZING HOW YOU CAN GO OVER A TALK OVER AND OVER AGAIN MOUNTAIN COMPUTER AND NEVER CATCH THE ERRORS, THEN WHEN IT'S PROJECTED, THEY ARE APPARENT. I THINK THAT'S FASCINATING. YOU KNOW? SO VIRULENCE IS ONE OF THE OUTCOMES OF THE INTERACTIONS. TO US, THERE ARE ONLY MICROBES AND HOSTS. THE OUTCOME OR STATES CONTINUED. WE SEE VIRULENCE AS AN EMERGENT PROPERTY. I WILL COME BACK TO THAT. IT BASICALLY FREES YOU TO BE -- VERY DIFFERENTLY, IF YOU THINK ONLY IN TERMS OF MICROBES AND HOSTS. SO ONE OF THE THINGS THAT IT DOES IS THAT ONE OF THE PROBLEMS IN MICROBIOLOGY TODAY IS THAT WE'RE LIVING IN A MICRO BIOLOGICAL ARCHIPELAGO. THEY BARELY INTERACT WITH ONE ANOTHER. IN FACT, MOST OF MICROBIOLOGY BECOMES NO DIFFERENT THAN STAMP COLLECTION. IF YOU LOOK AT DARWIN, DARWIN LOOKED AT PATTERNS. ONE OF THE THINGS THEY TELL YOU TODAY IS TO FOCUS -- IF YOU HAD FOCUSED ON THE PIGEONS OR ON THE SHELLS OR ON THE FINCHES OR THE INSECTS, HE WOULD HAVE MISSED THE THEORY OF EVOLUTION. WHAT HE DID IS HE FOCUSED ON THE PATTERNS, THIS WAS ALL THOUGHT, HE HAD DONE VERY FEW EXPERIMENTS, IT'S ALL DESCRIPTIVE, THERE IS NO MECHANISM AND IT WILL NOT BE PUBLISHABLE TODAY BECAUSE HE HAD NO MECHANISM. AND THAT ACTUALLY TELLS YOU SOMETHING ABOUT THE STATE OF SCIENCE TODAY. NOW, IF YOU LOOK AT THE END OF THE 19TH CENTURY, YOU WOULD HAVE SEEN A LOT OF DISEASE, SOME OF THEM HAVE GONE AWAY, SOME OF THEM ARE VERY MUCH WITH US. BUT THERE WOULD HAVE BEEN ONE BIG DIFFERENCE FROM LIFE TODAY, AND THAT IS INVASIVE FUNGAL DISEASES WOULD HAVE BEEN EXTREMELY RARE. YOU GO FORWARD 100 YEARS AND YOU SEE THESE DISEASES ARE VERY COMMON. THE QUESTION IS, WHAT HAPPENED? WHAT HAPPENED IS THAT WE CHANGED THE HOST. SO WE HAD THE MEDICAL PROGRESS, GAVE US ANTIBIOTICS, ALTERED THE THE FLUORA, IMMUNOSUPPRESSANT, CHEMOTHERAPY, ICUs, THEN THE CAT CLISM OF AIDS, SUCH THAT UNTIL RECENTLY, CRYPTOCOCCUS IS ONE OF THE LEADING CAUSES OF DEATH IN AFRICA, ECLIPSING TUBERCULOSIS, AND YET YOU DON'T HEAR ABOUT IT. TWO DAYS AGO, WE HAD A "NEW YORK TIMES" EDITORIAL, FUN CAL FUNGAL INFECTIONS NOT THERE. FUNGAL FACTS. ES TH IS THE MOST SUCCESSFUL KINGDOM WITH 1.5 MILLION SPECIES. THEY ARE THE MAJOR PATHOGENS OF PLANTS, REPTILES, INVERTEBRATES AND AMPHIBIANS. HOWEVER, FUNGI ARE DEVASTATING ENTIRE ECOSYSTEMS FROM CORAL TO THE FROGS, THE AMPHIBIANS MADE IT THROUGH ALL THE MAJOR EXTINCTIONS OF LIFE AND THEY ARE NOW IN TROUBLE FROM A SINGLE FUNGUS. RICE, SALAMANDERS, TURTLES, WHEAT, THE LIST CAN GO ON AND ON. SO WHAT THE PATTERN IS, ALL THESE HOSTS ARE ECTOTHERMIC. HERE IS THE HOST THAT IS IN TROUBLE FROM A FUNGAL INFECTION THAT ARRIVED IN THE UNITED STATES IN 2006, BAT WHITE NOSE SYNDROME. BUT IT HAS NO PROBLEM IN THE SUMMER. IN THE WINTER, THE TEMPERATURE DROPS 10 TO 12 DEGREES AND THEY BECOME SUSCEPTIBLE TO THIS ORGANISM. WE ARE GOING TO SEE EXTINCTIONS OF SEVERAL BAD SPECIES AS A RESULT OF THIS ORGANIZE NI. AND THERE IS NOT MUCH THAT ANYONE HAS MANAGED TO DO ABOUT IT. SO WHY ARE MAMMALS SO RESISTANT TO FUNGAL DISEASES AND COULD THE ANSWER BE IN THE DISTANT PAST? IF YOU LOOK IN THE DISTANT PAST, WHAT IS VERY APPARENT IS THAT THE K-T EVENT, THE REPLACEMENT OF THE REP TILLIAN MEG GAFORNA, WHY WHEN YOU DRIVE IN M.D. YOU SEE PRIMARILY LARGE MAMMALS AND BIRDS, AND YOU CAN SEE THAT THERE WAS A REVERSAL BETWEEN ECTOTHERMS AND ENDOTHERMS, THE ORGANISMS THAT IS MADE IT THROUGH THIS EVENT WERE LARGELY WARM BLOODED. SO THERE ARE THREE QUESTIONS THAT HAVE TROUBLED ME AND I ASK COULD THEY BE RELATED. IF THE REPTILES WERE SOFFIT, WHY DID THEY NOT RECLAIM THE EARTH? THEY NEED ABOUT ONE-TENTH THE ENERGY THAT YOU DO, IF YOU WERE REPTILIAN, YOU WOULD PROBABLY HAVE TO EAT ONCE A WEEK. THEY HAVE MANY PROGENIES, THEY DO EXTREMELY WELL. AND WHY ARE THERE SO FEW PATHOGENS FOR MAMMALS AND IT'S ALL RELATED TO WHY IS MEDICAL MYCOLOGY -- BUT YOU CAN SEE HOW MY OWN ISSUES DROVE SOME OF THIS. SO I GOT TO THE IMMUNITY CANNOT EXPLAIN THE -- OF FUNGAL DISEASES. ALL VERTEBRATES HAVE ADAPTIVE IMMUNITY WITH CELL RAR AND HUMERAL ARMS. I MENTIONED THE CATASTROPHIC FUNGAL DECLINE. NOW IF YOU TAKE A BUNNY AND YOU INFECT IT WITH CRYPTOCOCCUS, IT DOESN'T MATTER IT WHERE YOU PUT KANSACRYPTOCOCCUS IN IT, IT CLEARS INFECTION. BUT IF YOU PUT IT IN THE TESTICLE, ONE CAN GET A CHRONIC ORCHITIS THAT DOES NOT DISSEMINATE. THAT SUGGESTS AN EMERGENT PATTERN THAT PERHAPS MAMMALS FACE ADAPTIVE I -- A FEW YEARS AGO, HE DESIGNED INFORMATIC TOOLS AND LOOKED AT THERMAL TOLERANCE OF 4,000 FUNGI IN ONE COLLECTION AND IMKA U CAME UP WITH THAT RELATIONSHIP SUCH THAT YOU COULD SEE A DRAMATIC IT DROP IN VIABILITY AS YOU GO FROM 30s TO THE 40s, SO FOR EVERY DEGREE OF TEMPERATURE, ONE CAN EXCLUDE ROUGHLY 6% OF FUNGAL SPECIES. THEN WE TOOK THAT DATA AND WORKED WITH BERGMAN, MATHEMATICIAN, AND SOLVED THOSE TWO EQUATIONS TOGETHER. THE BENEFIT OF INFECTIOUS AGAINST FUNGAL DISEASES -- THE HOTTER YOU ARE, THE MORE YOU NEED TO EAT. LOOK AT THE TEMPERATURE THAT CAME OUT. THAT'S THE MAXIMUM. THE OPTIMA APPEARS TO BE A MAMMALIAN TEMPERATURE. NOW, IT COULD BE COINCIDENCE, BUT IT IT ISN'T 27 AND IT IS IN 48. IT HAPPENS TO BE VERY CLOSE TO YOUR CORE TEMPERATURES SUGGESTING THAT THERE MAY BE MORE TO THIS. SO WHAT KILLED THE DINOSAURS? WELL, IT DEPENDS WHO YOU ASK. IT USED TO BE THAT PEOPLE THOUGHT IT WAS SMALL MAMMALS THAT ATE THE EGGS. THAT ABSOLUTELY MAKES TO SENSE. I FOUND THIS IN THE WEB WHICH ACTUALLY MAKES NO SENSE EITHER, BUT IT WAS FROM A CRITICISM IN THE ANTISMOKING PROGRAM. IT COULD BE INCREASED VULCANISM, THERE WAS A LOT OF VULCANISM RIGHT ABOUT 100,000 YEARS BEFORE THE ASTEROID HIT AND IT COULD HAVE BEEN A TWO-HIT SCENARIO WHERE IT WAS VOLCANIC AND IT COULD HAVE BEEN THE DINOSAURS NOW. THE NEXT ONE IS TRUE, THIS WAS BELIEVE IT OR NOT PUBLISHED IN CURRENT BIOLOGY LAST YEAR, SOMEBODY CALCULATED THAT THE LARGE DINOSAUR MASS COULD HAVE TRIGGED GLOBAL WARMING THROUGH PUTTING OUT THE AMOUNT OF METHANE TO GET A RUNAWAY CLIMATE CHANGE, SO -- AND THEN THERE IS ONE MORE EXPLANATION THAT I'LL SHOW YOU BUT YOU WON'T COMMENT ON IT BECAUSE I HAVE NO DATA FOR OR AGAINST IT. SO THE KRETACEOUS WORLD, YOU HAD A REPTILIAN MEGAFAUNA. NEXT TIME YOU GO TO CANCUN, YOU SEE THEY OCCUR ONLY THERE BECAUSE BASICALLY THE LIMESTONE AND EVERYTHING ENDED UP GETTING MELTED. WHAT WAS THE POST IMPACT WORLD? OVERNIGHT, YOU HAD FIRE, SMOKE AND THE DUST OBSCURE THE SUN, PHOTOSYNTHESIS WAS SHUT DOWN FOR SIX MONTHS AND GLOBAL TEMPERATURES DROPPED. THERE IS PRETTY GOOD DATA FOR THIS. THERE IS ALSO GOOD DATA THAT THERE WAS A GLOBAL FUNGAL COMPOST. SO IMAGINE A WORLD WHERE ALL THE TREES COME DOWN. YOU WOULD HAVE A MASSIVE EXROAS, YOU WOULD HAVE IT MASSIVE SPORES, AND I COULD IMAGINE THAT ORGANISMS THAT WERE WARMER MAY HAVE BEEN SUSCEPTIBLE TO THE MASSIVE INOCULA THAT THEY WOULD HAVE BEEN EXPOSED TO. I WROTE THIS A FEW YEARS AGO TONGUE IN CHEEK BUT THE MORE I THOUGHT ABOUT IT, THE MORE IT MADE SENSE. SO IF YOU THINK ABOUT THE POST IMPACT WORLD, I HEAR BY THE WAY SOME OF THIS BEAUTIFUL ART COMES FROM JULIE MARQUARDT, SHE SHARED IT WITH ME WHEN SHE WAS MAKING THE POSTER SO I BENEFITED IN MULTIPLE WAYS FROM COMING HERE. SO THE REPTILIAN MEGAFAUNA -- YOU SAY AREN'T THE DINOSAURS SUPPOSED TO BE WARM BLOODED? I SAID SURE, BUT THEY ARE WARM BLOODED BECAUSE THEY ARE SACKS OF CYTOPLASM. AS SOON AS YOU STOP FEEDING THEM, THERE IS NO EVIDENCE THAT THEY COULD HAVE REGULATED THEIR TEMPERATURES THE WAY YOU DO. REPTILES USUALLY FIGHT OFF INFECTIONS WITH INDUCED FEVERS, BUT THERE WAS NO SUN. REPTILIAN EGGS ARE SUSCEPTIBLE TO FUNGAL DISEASES, THEY DID GO RIGHT THROUGH THE SHELL. ENDOLY THICK FUNGI ATTACKING A DINOSAUR. THIS MAY NOT ALL BE FROM THE K-T EVENT BUT AT LEAST IT'S MORE CIRCUMSTANTIAL EVIDENCE. SO SOME SMALL REPTILES SURVIVE, IF THEY WERE SOFFIT, WHY DID WE NOT HAVE A SECOND REPTILIAN AGE? I ARGUE THERE WAS A FILTER PRETTY MUCH AT THE K-T BOUNDARY, IT'S A GREAT GLOBAL COMPOST SELECTED FOR WARMER ORGANISMS. HERE IS ANOTHER ONE OF JULIE'S DESIGNS AND I THINK SHE CATCHES IT VERY NICELY, YOU HAVE THE REPTILIAN MEGA FAUNA CREATE A FILTER FOR THE EMERGENCE OF MAMMALS, NOW YOU HAVE THESE ORGANISMS SELECTED FOR IT AND THAT'S WHY THEY ARE SO RESISTANT TO WHAT IS ONE OF THE MAJOR TYPES OF PATHOGENS ON THE PLANET. SO I HAVE NO PROOF, IS IT PLAUSIBLE? I THINK SO. I HAVE NO EXPERIMENT, IT'S ALL THOUGHT, IT'S A LOT OF FUN. I THINK IT'S INTERNALLY CONSISTENT, I THINK IT'S SATISFYING TO ME, I HAVE NO IDEA IF IT'S ACCEPTED AND I FRANKLY DON'T CARE. I NEVER HAVE TO APPLY FOR FUNDING ON IT, SO IT'S SOMETHING THAT I -- AND THIS IS WHY I WANTED TO -- SCIENCE SHOULD BE FUN. WE SHOULD BE ABLE TO THINK RIGHT ABOUT IT AND DEBATE THINGS, AND THIS IS SOMETHING THAT YOU OFTEN DON'T SEE TOO MUCH ANYMORE. IT'S ALL WRITTEN DOWN ON A FEW PAGES, THAT STORY. SO NOW I'M GOING TO FOCUS ON KANSACRYPTOCOCCUS NEOFORMANS. HERE I WANT TO ACKNOWLEDGE MY PROGRAM. THEY'VE BEEN ENORMOUSLY HELPFUL TO ME WHEN I BEGAN, AND A LOT OF WHAT WE KNOW ABOUT THIS ORGANISM WAS, IN FACT, GENERATED HERE. IT'S AN ORGANIZE NI. THAT ACTUALLY, AS YOU CAN SEE, THE PATHOGENESIS VERY SIMILAR TO T.B., EVERYONE IS INFECTED BUT FEW GET DISEASE UNLESS ONE BECOMES IMMUNOSUPPRESSED. IT'S ALSO A PATHOGEN OF PLANTS -- IT HAS A VERY COMPLICATED LIFE CYCLE THAT WE HAVE BEEN WORKING ON FOR ABOUT 20 YEARS. 19 PAPERS FROM US AND OTHER GROUPS, BUT I WANT TO SHOW YOU IS THAT IT CAN PRETTY MUCH GET INTO A MACROPHAGE AND -- YOU'RE GOING TO SEE THAT IT BURST IT, IT'S DEAD, PART OF THE REASON IS THE IT'S NOT MOVING. THIS IS A MUCH MORE INTERESTING MOVIE. WHAT YOU SEE HERE IS A MACROPHAGE AND THE CRYPTOCOCCUS ARE REPLICATING INSIDE, AND WHAT IT'S GOING TO DO IS THEY'RE GOING TO COME OUT AND THEY'RE GOING TO LEAVE THE MACROPHAGE ALIVE. WHAT I WOULD ASK YOU IS TO STOP FOR A MINUTE AND THINK, WHY SHOULD A SOLO ORGANISM THAT HAS NO NEED FOR MA MILLIAN VIER EU LENS NEED A STRATEGY LIKE THIS? KEEP WATCHING. IT'S GOING TO RE REPLICATE AND ONE OF THEM WALK OFF THE FIELD. THIS IS SOPHISTICATION, AND YET THIS IS LEARNED IN THE SOIL. IF YOU REMOVE ALL ANIMALS FROM THE WORLD, I AM SURE THIS ORGANISM WILL STILL HAVE THAT CAPACITY. SO TODAY WE LIVE IN A SAD TIME BECAUSE IF YOU HAVE A MOVIE LIKE THAT, YOU CAN ENJOY IT FOR ABOUT FIVE MINUTES BEFORE SOMEBODY COMES UP TO YOU AND SAYS, WHAT'S THE MECHANISM, WHAT'S THE MECHANISM? IF YOU ANSWER THAT QUESTION, THEY SAY DOES IT HAPPEN IN VIVO? WELL, THIS IS REALITY. WE HAVE BEEN WORKING ON THE MECHANISM, IT'S COMPLICATED, WE TOOK A HINT FROM VIROLOGY, IN WHICH THEY ALLOW FUSION, IT DOES HAPPEN IN VIVO AND THIS LED TO VERY COMPLICATED FIVE YEARS OF WORK. BASICALLY WE HAD TO LEARN HOW TO LABEL MACROPHAGES, LOAD THE MACROPHAGES, PUT THEM INTO A MOUSE, TAKE THEM OUT, AND YOU CAN SEE IN THE BOTTLE ABOUT HALF OF THEM WERE EMPTY 24 HOURS LATER. SO THIS MECHANISM IS OUT THERE AND WHERE DOES IT LEARN TO DO IT? THE ORGANISM LEARNS, WE BELIEVE, TO DO THIS IN AMOEBA. SO IF YOU LOOK -- YOU CAN DEMONSTRATE PRETTY MUCH EVERYTHING THAT HAPPENS IN A MACROPHAGE IN AMOEBA. YOU CAN DO IT WITH -- TOO IF YOU WANT GENETICALLY TRACKABLE HOST AND IF YOU LOOK AT EVOLUTION, THESE ORGANISMS WERE INTERACTING WITH EACH OTHER FOR AT LEAST HALF A MILLION YEARS FOR THE FIRST TYPE OF ANIMAL EMERGED, SO WHEN THE ANIMALS EMERGED, SOME OF THE FUNGI WERE THERE ALREADY LEARNED HOW TO BE PATHOGENS. IF YOU LOOK AT EXPRESS, I'D LIKE TO THINK THAT THESE TWO ARE SEPARATED BY OVER A BILLION YEARS OF EVOLUTION. LOOK HOW THE GENE EXPRESSION OF THE ORGANISM, IT'S ALMOST IDENTICAL IN THE GENES THAT IT SELF REGULATES, THERE ARE MORE DIFFERENCES IN THE DOWN REGULATED GENE BUT THIS TYPE OF CONSERVATION SUGGESTS THAT, IN FACT, OUR COMMON -- THERE ARE TWO MAJOR VIRULENCE FACTORS, THE CAPSULE AND THE DB SYSTEM THAT HAVE BEEN STUDIED HERE. TREMENDOUS AMOUNT OF WORK ON THAT. AND THEY CONTRIBUTE ABOUT 40% OF THE TOTAL VIRULENCE. INCIDENTALLY, THIS KIND OF ANALYSIS IS ONLY DONE FOR CRYPTOCOCCUS NEOFORMANS, THERE IS THERE ARE DIFFERENT WEIGHS YOU CAN WEIGH THE VIRULENCE FACTORS, GIVES YOU ALL OR NONE, CONTRIBUTING ONLY 1% TO THE TOTAL VIRULENCE. BECAUSE IT MAY BE NEEDED BUT WHAT IT TELLS YOU IS THAT A LOT OF THE VIRULENCE IS COMING FROM THESE TWO AGENTS. THE POLYSACCHARIDES ACCUMULATE IN VIVO. THE BROWN MATERIAL IS POLYSACCHARIDES, IT GETS INTO THE MACROPHAGES AND IT IT MESSES THEM UP, AND THIS IS A STRIKING PICTURE OF A CRYPTOCOCAL BIOFILM, NOTICE THE COMPLETE ABSENCE OF INFLAMMATION. PART OF THIS IS THE DIFFICULTY TREATING THE DISEASES WITH FUNGAL AGES ALONE, THERE IS NO IMMUNE SYSTEM TO HELP YOU. NOW, IF YOU LOOK AT THE CAPSULE AND YOU WERE TO PLOT MOLECULAR MASSES AS A FUNCTION OF IGNORANCE, YOU FIND WE KNOW A LOT AT THE PLEK LEVEL AND WHAT WE CAN SEE. THE PROBLEM IS AT THE MIDDLE, THE CAPSULE IS ONE OF THOSE STRUCTURES THAT IS VERY HARD TO STUDY, AND I GIVE YOU AN EXAMPLE WHY. THIS IS AN -- LOOK WHAT HAPPENS WHEN YOU DRY IT UP. THESE ARE STRUCTURES AND 99% PLUS WATER, SO YOU NEED TO HAVE DIFFERENT APPROACHES. I ORIGINALLY TRAINED AS A CHEMIST AND I NEED TO LET YOU KNOW HOW WE THINK. YOU ACCEPT IT, YOU LEAVE IT ALONE. YOU -- THE APPROACH IS TO MAKE ACCURATE MEASUREMENT, THE MEASUREMENT TEMEASUREMENT DEFINES THE PARAMETERS OF THE STUDY, REALITY IS APPROXIMATED. I WILL TELL YOU PRECISELY WHAT WAS DONE HERE, THESE TWO GENTLEMEN USED RULES, THEY BORROWED SOME DATA AND GENERATED A MODEL, A MODEL THAT RESISTED FALSIFICATION, AND THAT'S WHY IT WAS ACCEPTED VERY RAPIDLY. EVERY EXPERIMENT THAT WAS DONE WAS CONSISTENT WITH THE STORY. AS COUNTER EXAMPLE, 20TH CENTURY, ENDED UP WITH A 300 HELIX BECAUSE -- THAT STRUCTURE WAS RAPIDLY INVALIDATED. A LITTLE BIT ABOUT LIGHT SCATTERING, THE REASON THAT THE SUN IS RED BECAUSE BLUE LIGHT IS REMOVED, THE SKY IS BLUE BECAUSE BLUE LIGHT IS -- THAT IS BECAUSE THE SCATTERING FUNCTION IS TO THE FOURTH POWER OF THE WAVELENGTH AND BLUE LIGHT IS THE SMALLEST PART OF THE VISIBLE SPECTRUM. NEXT TIME YOU SEE A LUNAR ELLIPSE, YOU WILL SEE THAT THE MOON IS REDDISH, THE REASON IS BECAUSE THE LIGHT THAT FALLS ON IT HAS BEEN FILTERED TO REMOVE BLUE LIGHT. IF YOU COULD DO LIGHT SCATTERING MEASUREMENT, STATIC AND DYNAMIC, THIS WILL GIVE YOU A BUNCH OF PARAMETERS I WILL TELL YOU SOME OF THE THINGS WE HAVE LEARNED. ONE OF THE THINGS WE LEARNED IS THAT A SINGLE MOLECULE SPANS THE CAPSULES. WE DID THIS BY MAKING A MEASUREMENT IN OUR WORLD, A MICROSCOPE MEASUREMENT, AND A MEASUREMENT IN THE QUANTUM WORLD FROM DYNAMIC LIFE SCATTERING. WE GOT A BEAUTIFUL STRAIGHT LINE SUGGESTING THAT THE MODEL INVOLVED, A SINGLE MOL COOL WILL ROLE AS A COUPLE EXPANDED. WE FIRST TRY TO EVALUATE THE MODEL AND ONE OF THE THINGS WE DO, THIS IS A VERY TOUGH PROBLEM. AND YOU CAN DO IT IF YOU HAVE ACCESS TO LIGHT SCATTERED INSTRUMENTS AND YOU CAN MEASURE, WHEN THINGS BECOME BRANCHED, YOU HAVE A REVERSAL. SUCH THAT THE HYDRODYNAMIC RAISH HORATIOIS OUTSIDE. A BALLERINA'S -- I WAS WARNED NEVER TO DO THIS, THAT IS, NEVER TO BRING EXAMPLES FROM THE REAL WORLD FROM THE QUANTUM WORLD BECAUSE THAT WASN'T RIGHT, BUT I THINK THAT I CAN TAKE SOME LIBERTY HERE AND GIVE YOU A SENSE OF WHAT I'M THINKING ABOUT, WHERE THE HYDRODYNAMIC RADIUS WILL BE THE RADIUS OF MASS AND THE AIR AROUND IT. WHAT WE FIND ARE THE CRYPTOCOCCAL CAPSULE IS INCREDIBLY UNUSUAL IN BRANCH, IT APPEARS TO BE A STRUCTURE THAT IS NOT ONLY NEAR POLL LISA SACCHARIDES, NOT A SIMPLE BRANCH, APPEARS TO BE A DEN DROA MER. YOU CAN IMAGINE THAT'S WHAT HAPPENS, YOU HAVE A VERY LARGE RADIUS OF HYDRATION AND A SMALL RADIUS OF MASS. THIS IS THE ONLY MICROBIAL CAPSULE THAT IS COMPOSED OF DEN DROA MERE AND IT RAISES HUGE BASIC SCIENCE QUESTIONS ON HOW DO YOU ASSEMBLE THE STRUCTURES AND GET THEM OUT. AND IN FACT WE HAVE NOW MODIFIED THIS VIEW TO THINK THIS IS A DEN DROA MERE AND THE CAPSULE GROWS TO EFFICIENTLY CREATE AN EXCLUSION ZONE. WHY CARE BECAUSE BRANCHING -- INTERACTION WITH THE CELLS. SO IT'S VERY BIOLOGICALLY RELEVANT. IN COLLABORATION WITH PETER WILLIAMS, YOU CAN SEE WE HAVE GENERATED A NEW MODIFICATION OF THE CAPSULE. HE HAD THE UNUSUAL RESULT THAT HE KNOCKED OUT AN ENZYME THAT HE DID NOT EXPECT WILL BE INFECTING THE CAPSULE AND ENDED UP WITH A VERY LARGE CAPSULE AND HIS MUTANTS ARE VERY DIFFERENT THAN THE ORIGINAL ONE. I GUESS WHAT I'M GETTING AT HERE IS THAT THE POWER OF COMBINING DIFFERENT THINGS, COMBINING GENETICS WITH CHEMISTRY TO GET NEW INSIGHT. IS IT COTTON CANDY, STYROFOAM BALL OR A SOCCER BALL? HOW WOULD YOU GET SOMETHING LIKE THIS, YOU BEGIN TO THINK ABOUT IT, THAT IS A VERY DIFFICULT PROBLEM. SO WORKING WITH SOME BIOPHYSICISTS, WE CAME TO A NOVEL APPROACH TO DO THIS. YOU TAKE CRYPTOCOCCUS AND YOU IMMOBILIZE IT, PUT A LATEX FEET ON IT AND THIS WHAT HAPPENS. YOU CAN TAKE ALL KINDS OF MEASUREMENTS, YOU CAN MOVE THE CRYPTO AWAY FROM IT AND AT SOME POINT THIS, WILL SNAP. FROM THAT, YOU CAN CALCULATE THE -- MODULUS AND THAT GIVES YOU A SENSE OF WHAT THIS CAPSULE IS LIKE. WHEN THEY'RE YOUNG, THEY APPEAR TO BE A LITTLE BIT LIKE THE CAPSULE IS VERY FLUFFY, AS IT GETS OLD, IT BECOMES FIRMER, AND IF YOU EVER PUT ANTIBODY ON IT, IT BECOMES LIKE A SOCCER BALL, VERY RIGID, AND IN FACT THE PROTECTIVE ANTIBODIES ARE THE ONES THAT IMMEDIATE THE CHANGE IN UNPROTECTED ANTIBODIES TO -- SO NOW I'M GOING TO SWITCH OVER TO THE WORLD OF MEL NIN. IT'S A PIGMENT, NOT A PROTEIN THE ONLY ONES THAT LACK IT ARE VIRUSES. THE COLOR OF YOUR SKIN IS DETERMINED BIFFLE NIN, CERTAINLY FUNGI MAKE MELANIN. CRYPTOCOCCUS MAKES THE SAME MELANIN FOUND IN YOUR SKIN. THIS MELANIN IS DEPOSITED IN THE CELL WALL AND CAN PROTECT IT AGAINST MANY TYPES OF INSULTS FROM ANTIFUNGALS, AND WE HAVE SHOWN THAT THIS IS A CAUSE OF ACQUIRED ANTIFUNGAL RESISTANCE TO HEAVY METALS, PRETTY MUCH EVERYTHING. WHAT I'M GOING TO TELL BUT IS A NEATER STORY, IT CAME FROM WHAT I THINK WE SHOULD ALL BE READING OUTSIDE OUR FIELDS. SO I WAS READING ABOUT CHERNOBYL. AND IT TURNS OUT THAT IN CHERNOBYL, THERE WAS A CHEMICAL EXPLOSION IN 1986 THAT CAUSED THIS STRUCTURE TO BECOME RADIOACTIVE. SO THE OLD SOVIET UNION COULD NOT SHUT DOWN THE REACTORS, SO THEY CREATED WHAT THEY CALL A SARCOPHAGUS AROUND IT. THIS IS IN DANGER OF FALLING APART AND I'LL GET BACK INTO IT. THEY'RE NOW GOING TO CREATE SOMETHING TO BE IN THE OUTSIDE SO WHEN THIS CRASHES DOWN AND ALL THE DUST GETS OUT, THAT IT WILL AT LEAST BE CONTAINED WITH IT. SO THEY SEND IN A ROBOT AND COLLECTED SAMPLES FROM THE SPENT CORES AND FOUND THERE WERE 37 FUNGAL SPECIES GROWING IN THE REACTOR, OF WHICH ALL OF THEM WERE HIGHLY MELANOTIC, IT DOES PROTECT AGAINST RADIATION, IT'S REMARKABLE, BUT THIS COULDN'T BE THE EXPLANATION, BECAUSE EVEN THOUGH YOU'RE LETHALLY RADIATED, IF YOU WALK INTO THE AREA, THIS FUNGI CAN TOLERATE THAT RADIATION. THE HIGHLY RADIOACTIVE AREAS WERE TURNING BLACK. THEY WOULD DO SO BECAUSE WE THOUGHT THAT THE MICRO FAUNA WAS BEING REPLACED WITH MICROORGANISMS. SO WITHOUT GOING THROUGH A LOT OF WORK, I'M JUST GOING TO TELL YOU AFTER FIVE YEARS, WE THOUGHT WE ESTABLISHED THAT MELANIN WAS ALLOWING THE FUNGI TO CONVERT LEK FRTROA MAGNETIC RADIATION TO FOOD. SO THE FUNGI WERE USING RADIATION FOR FOOD. WHEN YOU THINK ABOUT IT, IT SHOULDN'T SURPRISE YOU TOO MUCH BECAUSE BIOLOGY CAN ALWAYS USE AN ELECTRON. WE SHOW FOR EXAMPLE THAT IF YOU TAKE MELANIN AND RADIATE IT, IT WILL ALLOW THE OXIDATION REDUCTION OF NNAD AND NNID, SO WE THOUGHT WE HAD A MAJOR DISCOVERY, AND WE SENT IT TO A SINGLE WORD JOURNAL. THE SINGLE WORD JOURNAL REVIEWED IT AND AFTER SIX MONTHS GAVE US A LOT OF WORK AND THEN AFTER ANOTHER SIX MONTHS, REJECTED IT. AND THEN WE DECIDED, GEE, THERE ARE OTHER SINGLE WORD JOURNALS OUT THERE, SO WE WENT TO YOU A 'NOTHER SINGLE WORD JOURNAL AND THE OTHER SINGLE WORD JOURNAL DID THE SAME THING US TO. BUT THERE WERE MANY MEMORABLE REVIEWS, BUT ONE OF THE MOST MEMORABLE REVIEW WAS A REVIEWER WHO WROTE SOMETHING TO THE EXTENT OF I CAN FIND NOTHING WRONG WITH THE WORK BUT I DON'T BELIEVE IT. WHAT DO YOU DO? I MEAN, ANYWAY, I ASK YOU THE QUESTION, IF YOU HAD A CHOICE BETWEEN BEING IN THE SCIENCE PARTS -- IN THE REPORT PARTS OF A SINGLE WORD JOURNAL OR BEING IN THE NEWS, WHAT WOULD YOU TAKE? THINK ABOUT IT. IT'S ACTUALLY AN IMPORTANT QUESTION, EVEN THOUGH WE ENDED UP PUBLISHING IN -- ONE, THEY HAD TO ALL OF IT COVER IT. SO WE DIDN'T MAKE IT INTO THEIR SCIENCE PART BUT WE MADE IT INTO THE NEWS PART, BUT IT MAY HAVE BEEN GOOD BECAUSE RECENTLY WE FOUND THIS VERY INTERESTING RELATIONSHIP, THE RETRACTION INDEX AND THE IMPACT FACTOR, AND THE SINGLE WORD JOURNALS TEND TO BE IN THIS AREA. SCIENCE WENT ON AND REPRINTED IT AND CHALLENGED US, THAT PERHAPS IT WAS BECAUSE MORE PEOPLE READ THE JOURNAL, AND WE WERE KIND OF SKEPTICAL ABOUT THAT SO WE DECIDED TO FOLLOW UP THE STUDY. WE OF COURSE THOUGHT THAT EVERYDAY SCIENCE -- THEY MAY ENCOURAGE AND MANIPULATE THEIR DATA, RECENTLY WE HAVE FOUND UNFORTUNATELY THAT MISCONDUCT -- WE HAVE FOUND THAT MALES ARE RESPONSIBLE FOR A LOT OF THIS. NOW, FOR THE FEMALES, THERE IS A CAVEAT IN THE STUDY, ALL WE SHOW IS THAT THE FEMALES ARE MISSING. IT MEANS -- IT DOESN'T MEAN THAT THEY DON'T COMMIT MISCONDUCT AT THE SAME RATE AND THEY JUST DON'T GET CAUGHT. SO IT'S IN THE DISCUSSION, IT'S OUT THERE, SOMETHING TO THINK ABOUT. HOWEVER, THIS -- I REALLY WASN'T BOTHERED TOO MUCH, SOME OF THE REVIEWERS WANTED YOU TO GIVE THE ENTIRE MECHANISM, ANOTHER REVIEWER WANTED TO YOU TRACK AN ELECTRON DOWN ALL THE WAY TO ATP, I SAY YOU CAN'T DO THAT FOR COLOR PHIL TODAY, BUT ONE PERSON TOLD ME, ARTURO, X-RAYS GO THROUGH EVERYTHING, HOW IS GAMMA RAYS GOING TO BE REACTING WITH MELANIN? THE SOLUTION TO THAT CAME FROM THIS INDIVIDUAL, WHO WE COLLABORATED AND HE MADE A MELANIN ELECTRODE. THEN WHEN YOU TURN ON THE RADIATION, HE GOT A CURRENT. THERE IS NO WAY OUT. IF YOU CAN GET A CURRENT, IT CAN DO SO. WE PUBLISHED IN IN ANOTHER ONE WORD JOURNAL BUT IT'S NOT ONE OF THE ONES THAT YOU USUALLY SUBMIT TO. I WILL TELL YOU THIS HAS NOW BEEN CONFIRMED BY ANOTHER GROUP AND WE'RE VERY HAPPY ABOUT THIS INDEPENDENTLY. WHICWE HAVE EXTENDED IT INTO THE -- RANGE SO WE THINK FUNGI HAVE A LIMITED CAPACITY THE FOR PRIMITIVE PHOTOSYNTHESIS AND MAYBE THAT'S WHY THEY EXPRESS ALL THESE PIGMENTS AND HERE IS SOMETHING I TOOK WHEN I WAS TRAVELING, YOU CAN SEE THE -- NEXT TO THE ONES THAT HAVE COLOR FILL, WE THINK THESE ARE CAPTURING ENERGY AND HERE IS ANOTHER PICTURE FROM ANTARCTICA, IN ANTARCTICA, SOME OF THE HILLS, THE MOUNTAINS ARE COMPLETELY BLACK AND THEY ARE COMPLETELY BLACK WITH -- ORGANISMS AND YOU ASK YOU WHAT DO YOU THINK IS GOING ON THERE AND THINK IT'S A FORM OF PHOTOSYNTHESIS. HERE IS A ANOTHER FASCINATING THING THAT MELANIN CAN DO. IF YOU PUT MELANIN, BLACK MUSHROOMS, INTO A MOUSE, YOU CAN LETHALLY RADIATE THE MICE AND THEY CAN SURVIVE. YOU TAKE THE MELANIN AND MIX IT WITH THE WHITE MUSHROOMS, YOU GET THE SAME RESULTS. WHAT HAPPENS IS THAT MELANIN PROTECTS THE GUT AND BY PROTECTING THE GUT, ALLOWS THE MICE TO HAVE PROBABLY AN AUTO TRANSPLANTATION, SO THE THEY GET SEPTIC, WE ARE DEVELOPING THIS, WE HOPE THEY'RE GOING TO CLINICAL TRIAL IN RADIATION THERAPY AND RADIATION PROTECTION, LAST YEAR WE SENT ALL THIS DATA TO THE PEOPLE IN THE DAMAGED REACTOR IN JAPAN BUT I HEAR IT'S SOMETHING RELATIVELY SIMPLE. THAT COULD HAVE TREMENDOUS USE. I WILL COME BACK TO THE FUNGAL INFECTIONS AND THE BIG PICTURE, SO THE FUNGI ARE FOUND PRIMARILY MOST OF THE FUNGAL DISEASES ARE FOUND PRIMARILY IN THE EQUATOR, AND THAT'S CONSISTENT WITH FUNGI THAT WOULD HAVE EVOLVED TO BE MORE THERMAL-TOLERANT. NOW ALL THESE STUDIES PREDICT THAT THE CLIMATE IS GOING TO GET WARMER. AS THE CLIMATE GETS WARMER, THE DIFFERENCE BETWEEN YOU AND AMBIENT TEMPERATURE IS GOING TO BECOME SMALLER. FUNGI CAN ADAPT AND WE MAY HAVE MANY ORGANISMS THAT ARE TODAY NON-PATHOGENIC BECOME PATHOGENIC. HERE IS AN EXPERIMENT DONE BY A COMPANY, THEY BASICALLY WANTED TO DEVELOP A FUNGUS TO KILL INSECTS AND WHAT THEY FOUND IS THAT THE INSECTS ARE PRETTY SMART. THEY SUN THEMSELVES. AND AS SOON AS THEY SUN THEMSELVES, THEY FRY THE FUNGUS. SO THEY ADAPTED AFTER ONLY A FEW MONTHS THE FUNGUS TO BE ABLE IT TO GROW AT 37 DEGREES. IF THIS CAN BE DONE, AND WE HAVE ALL THE SPECIES OUT THERE, ANTI & THE CLIMATE IS GOING TO GET WARMER, I THINK THIS CENTURY THE SITUATION MAY CHANGE DRAMATICALLY WITH REGARD TO FUNGI THAT COULD TAKE DOWN IMEU LOGICALLY INTO HUMANS. ONE OF THE THINGS WE TRY TO DO IS WE HAVE PROPOSED THAT IN FACT VIEWER LANCE IS AN EMERGING PROPERTY THAT IS NOT PREDICTABLE. WE SET OUT TO DO SOME EXPERIMENTS IN THIS REGARD BY COMPARING THREE SPECIES BUT THEY WERE VERY DIFFERENT IN THERMAL TOLERANCE, SO WE HAD TO GO TO A HOST THAT ALLOWED THAT, AND WHAT WE FOUND WAS THAT EVEN THOUGH ALL THE STUDIES IN CRYPTOCOCCUS WOULD HAVE SUGGESTED THAT THESE WERE THE CRITICAL VIRULENCE FACTORS, CAPSULES -- THAT, IN FACT, WAS NOT PREDICTIVE. IN FACT, THE MOST VIRULENT ORGANISM TURNED OUT TO BE AT THE LOWER TEMPERATURE, THE ONE THAT DID NOT HAVE A CAPSULE AND DID NOT HAVE MELANIN. THE POINT OF THIS IS A VERY SIMPLE EXPERIMENT BUT I DON'T BELIEVE THERE'S GOING TO BE PREDICTABILITY. I BELIEVE INTO THE FUTURE, THERE MAY BE MODELS BUT I DON'T THINK THEY WILL ACCOMMODATE WHEN YOU HAVE AN ENTIRE GENOME OF ONE, AN ENTIRE GENOME OF THE OTHER, YOU KNOW ALL THE EPIGENETIC CHANGES, THE YOU KNOW THE IMMUNE SYSTEM, AND YOU'RE GOING TO BE ABLE TO SAY THIS IS A PATHOGENIC ORGANISM. LAST THING I WANT TO LEAVE YOU WITH IS THE QUESTION IS VIRULENCE A CHAOTIC SYSTEM. SO CHAOS PRETTY MUCH HAS BEEN DISCOVERED A FEW TIMES, IT PROBABLY WAS DI COVERED BY MUTANTS WHO SAID THE TREE BODY PROBLEM GAVE HIM A HEADACHE -- PUBLISHED A SOLUTION TO THE THREE-BODY PROBLEM AND HE TURNED OUT TO BE WRONG. THE BOTTOM LINE IS IT CANNOT RESOLVE, BECAUSE SMALL DISS IN THREE BODIES RESULT IN THE SYSTEM BECOMING UNSTABLE IN TIME. THE ONE THAT THIS IS CREDITED TO IS EDWARD LAUREN, WHO WAS AN ACCIDENTAL DISCOVERY OF -- BECAUSE HE WAS DOING MATHEMATICAL MODELS AND SIMULATION, AND WHAT HE WAS LETTING THE COMPUTER RUN, BUT HE WANTED TO SHORTEN THE EXPERIMENT SO HE BEGAN TO TAKE THE VALUES, THREE OR FOUR DAYS LATER. WHAT HE DID NOT KNOW WAS THE COMPUTER TRUNCATED THE NUMB WE NUMBERS BECAUSE IT DID NOT HAVE CAPACITY MEMORY AND BASICALLY I SAY PUT THEM TOGETHER, THINGS WILL BE FINE FOR A WHILE, THEN IT WILL HAVE PRETTY MUCH COMPLETE HELTER SKELTER. AND THIS BECAME WHAT IS THE BASIS OF CHAOS. CHAOS MEANS SMALL DIFFERENCES IN A SYSTEM WILL HAVE BIG DIFFERENCES OUT THERE. IF YOU THINK ABOUT IT, THIS IS A FUNDAMENTAL ASPECT OF ALL BIOLOGY. WHETHER YOU'RE STUDYING IMMUNE RESPONSE, VIRULENCE, HA HAS NEVER BEEN LOOKED AT BEFORE. IT'S IN FACT VERY DIFFICULT TO LOOK AT THE PROBLEM OF CHAOS BECAUSE YOU CANNOT REDO THE EXPERIMENT OVER AND OVER AGAIN. SO OUR SYSTEMS -- SIX EXPERIMENTS, I'M NOT GOING TO TAKE YOU THROUGH THE MATH BUT I'M GOING TO SHOW YOU THE RESULT. SO WE WERE -- THIS HAS JUST BEEN PUBLISHED. WE WERE ABLE TO SHOW -- FIND NO CHAOTIC SIGNATURES IN THIS INTERACTION. BUT THE IMPORTANT THING HERE IS, NOT THE RESULT, THAT THERE WAS A METHOD TO ASK THE QUESTION. THINK ABOUT IT. WE CAN MAKE VACCINES VERY EASILY TO SOME ORGANISMS, AND WE CANNOT MAKE THEM TO OTHERS. AND WE DON'T REALLY UNDERSTAND THAT. WOULDN'T YOU WANT TO KNOW WHETHER THE SYSTEM YOU'RE WORKING WITH IS CHAOTIC OR NOT? IF IT WAS CHAOTIC, WOULD YOU HAVE A VERY DIFFERENT -- YOU WOULD HAVE A VERY DIFFERENT VIEW OF VIEWING IT. IN FACT, IF THE WEATHER WAS NOT KAY OH IT TICK, WE COULD HAVE WEATHER PREDICTION FAR INTO THE FUTURE. WHAT HAPPENS IS THAT SMALL DIFFERENCES TRANSLATE INTO BIG CHANGES. WE HAVE BEEN ABLE TO COMPENSATE THAT A LOT BY COMPUTING POWER, BUT SOMETHING SO FUNDAMENTAL HAS NEVER REALLY BEEN ASKED. OUR IMMUNE RESPONSE IS CHAOTIC. DOES IT VARY WITH -- AND I THINK THIS IS AN AREA THAT IF WE KNEW THE ANSWERS TO THIS, IT MAY, IN FACT, GUIDE A LOT OF HOW WE GO FORWARD. SO I'M ALMOST AT THE END AND I PROMISED YOU I'D COME BACK TO THE QUESTIONS. SO WHY ARE WE HERE, WHY ARE WE SO HOT? TO KEEP THE FUNGI AWAY. WHY DO WE EAT SO MUCH? TO MAINTAIN THIS VERY HIGH TEMPERATURE. MAMMALS MAKE NO SENSE. MAMMALS WERE NOT GOING ANYWHERE UNTIL THE KT EVENT. THEY HAVE BEEN AROUND FOR PROBABLY OVER 100 MILLION YEARS. IT WAS AN EXPERIMENT THAT IT IN MY VIEW WAS GOING NOWHERE, AND YET ALL OF A SUDDEN BECOMES DOMINANT. AND I THINK FOR THAT TO HAVE HATCHED, IT HAD TO BE SELECTED FOR. AND NOW THAT BEGINS TO EXPLAIN WHY THEY'RE SO RESISTANT TO FUNGAL DISEASES AND WHY THIS LIFESTYLE, THAT IN REALITY REQUIRES A TREMENDOUS AMOUNT OF FOOD AND IS VERY WASTE FULL, BECOMES A DOMINANT. SO FUNGAL SELECTION KEPT DOWN THE REPTILES AND WE NEVER HAD A SECOND REPTILIAN AGE. SO A FINAL THOUGHT, MAMMALS MAKE NO SENSE WITHOUT THE FUNGI, MOSTLY A CALORIC INTAKE IS TO KEEP YOUR BODY TEMPERATURE. YOU EAT PROBABLY FOUR OR FIVE TIMES A DAY TO KEEP THE FUNGI AWAY. I'LL POINT OUT TO YOU THAT EMERGING DISEASES IN AMPHIBIANS CAN BE CURED BY ELEVATED BODY TEMPERATURE. YOU CAN TAKE THE FROGS INTO A 37 DEGREE ROOM AND COMPLETELY ERADICATE THE FUNGUS. YOU CAN GO INTO A CAVE AND TAKE THE BATS AND BRING THEM INTO THE LAB AND JUST FEED THEM SO THAT THEY CAN GET THEIR METABOLIC RATE UP AND THEY CAN CLEAR THE FUNGAL INFECTION. SO PERHAPS GLOBAL WARMING WILL SAVE THE FROGS BY ROASTING THE -- AND I LEAVE WITH YOU THAT IMAGE, THAT PERHAPS SOMEBODY WILL BENEFIT FROM ALL THAT POLLUTION. THANK YOU VERY MUCH. [APPLAUSE] >> THAT WAS AMAZING. QUESTIONS OR COMMENTS FOR ARTURO? >> I'M GOING TO ASK YOU AN EDITORIAL QUESTION. SO WHEN THE REVIEWERS OF THE PAPER COME BACK AND SAY YOUR DATA DON'T LOOK VERY REPRODUCIBLE, YOU EXPLAIN IT AS CHAOTIC. >> ACTUALLY -- NO, NO, I'M SORRY. CHAOS IS REPRODUCIBLE. CHAOS IS BOTH DETERMINISTIC AND REPRODUCIBLE. ONE OF THE GREAT PROBLEMS THAT WE WITH CHAOS THEORY IS THE WORD CHAOS. IN OUR EVERYDAY LANGUAGE, IT DOESN'T MEAN THE SAME THING IN MATHEMATICS. AND THAT -- A TREMENDOUS AMOUNT OF UNCERTAINTY IN HOW WE SPEAK. >> NOW THE SERIOUS PART OF THE QUESTION. >> ALL RIGHT. >> WHICH IS, WE'VE ALL -- ESPECIALLY HAVING JUST DONE OUR ETHICAL CONDUCT OF SCIENCE TRAINING TODAY AWARE OF THIS ISSUE OF REPRODUCIBILITY IN SCIENCE, AND THE PUBLICATIONS RECENTLY ABOUT THE EAR REPRODUCIBILITY OF SCIENCE. BUT AS YOU SAID, VERY SMALL EFFECTS CAN GIVE YOU VERY BIG DIFFERENCES. SO DO YOU THINK A LOT OF THE IRREPRODUCEABILITY IS NOT THE MAKE IT UP KIND THAT YOU POINTED OUT HERE DOES OCCUR, BUT THE FACT THAT WE ARE NOT AS CAREFUL AS WE MIGHT BE ABOUT WHETHER WE REALLY ARE PRECISELY REPLICATING AN EXPERIMENT AND WE'RE GETTING INTO THESE REGIMES WHERE VERY SMALL DIFFERENCES GIVE YOU VERY BIG READOUT DIFFERENCES, AND WE SHOULD USE THAT AS A GUIDE TO BETTER UNDERSTANDING THE BIOLOGY AND HOW THINGS DIVERGE? >> SO RON, I THINK YOU'RE HITTING ON SOMETHING REALLY, REALLY IMPORTANT, SOMETHING THAT AFFECTS EVERYONE IN THIS ROOM. WE HAVE BEEN LOOKING AT THE ISSUE OF RETRACTIONS. RETRACTIONS ARE EVIDENCE FOR FAILURE OF SCIENCE. EVEN THOUGH IT'S GOOD THAT YOU CAN RETRACT IT AND CORRECT SCIENCE TO FIGURE OUT WHAT'S GOING ON. SO THE WAY WE GOT THIS DATA, BY THE WAY, IS WE REVIEWED EVERY SINGLE RETRACTION NOTICE OUT THERE, WE FOUND THE RETRACTION NOTICES WERE OFTEN FRAUDULENT. IN HA PEOPLE LIO LIE ON THE RETRACTION NOTICES, BASICALLY BECAUSE I CAN'T PRODUCE TABLE 2, THEN YOU CORRELATE THE NAMES WITH THE OFFICE OF RESEARCH INTEGRITY AND YOU FIND THAT A LOT OF THAT WAS MISCONDUCT. SO ONE OF THE THINGS WE'RE DOING TO ADDRESS YOUR QUESTION IS WE'RE GOING BACK AND ANALYZING THE HONEST RETRACTIONS, GOING ONE BY ONE TO TRY TO SEE PATTERNS, AND I THINK IT'S A COMPLICATED STORY. ONE OF THE MOST COMMON CAUSES OF ERROR IS CONTAMINATED CELL LINE. AND CONTAMINATED SAMPLES OFTEN LEAD TO MULTIPLE RETRACTIONS. AND I THINK THE ANSWER TO SOME OF THIS IS YES, SOME OF IT CAN BE ERROR, IT'S ALSO -- WE ARE UNDER TREMENDOUS PRESSURE OF FUNDING, ALSO CAREERS HAVE BEEN MADE WHETHER YOU PUBLISH IN A SINGLE WORD JOURNAL OR NOT AND YOU CAN IMAGINE THE PRESSURE IT'S PUTTING ON PEOPLE TO OFTEN NOT NECESSARILY PUT THE WHOLE DATA OUT THERE. PART OF THE REPRODUCIBILITY. I WOULDN'T GO AS FAR AS CALLING THAT MISCONDUCT, BUT I THINK WE HAVE REALLY MESSED UP PRIORITIES IN SCIENCE INCLUDING THE FACT THAT WE JUDGE THE VALUE OF THE WORK BASED ON WHERE IT'S PUBLISHED RATHER THAN CONTENT. SO IT'S A PERFECT STORM. IT'S FUNDING PROBLEMS. IT'S THE FACT THAT WE JUDGE WORK VERY DIMPLE. IT'S AOS IN TH CHAOS IN THE NUMBERS. WHY DON'T YOU PUBLISH A WORSE EXPERIMENT? BECAUSE YOU CAN'T GET IT PUBLISHED. ALSO IF YOU LIKE TO -- NOBODY WANTS TO PUBLISH YOUR WORK. SO I THINK THAT WHAT YOU'RE GETTING AT IS ALMOST WE NEED TO AS A SCIENTIST, WE NEED TO SIT DOWN AND BASICALLY TRY TO WORK THESE THINGS OUT BECAUSE THE LITERATURE, WHICH IS OUR LIFE BLOOD, IS IN TROUBLE. AND THIS MAY BE PART OF IT. CHAOS. BUT I THINK THERE'S A LOT OF OTHER ISSUES OUT THERE. INCIDENTALLY, DID YOU SEE IN THE PAPER, IT SAYS THAT HOW BASICALLY WE JUDGE SIGNIFICANCE AT .05? WE ARGUE THAT IN BIOLOGY, WITH ALL THESE CHANGES, THAT WE SHOULD BE A LOT MORE STRINGENT AND USE A GREATER SIGNIFICANCE BEFORE WE ACCEPT THE ONE IN 20. SO IT'S A LOT OF THINGS THAT I THINK WE NEED TO -- THIS IS A BIG DISCUSSION AND A BIG ISSUE, AND WE NEED TO AS A COMMUNITY BEGIN TO ADDRESS IT. >> YOU MENTIONED SEVERAL FUNGAL DISEASES THAT ARE EXTINGUISHING OR ALMOST EXTINGUISHING COLD BLOODED AND WARM BLOODED SPECIES. THE FROG WHICH I CAN'T PRONOUNCE AND THE WHITE NOSE BAT SYNDROME. IS THERE ANY WAY YOU CAN SAY THAT SOME EMERGING INFECTIOUS FUNGAL DISEASE WON'T BEGIN TO EXTINGUISH HUMAN BEINGS? ARE WE IMMUNE TO THAT? >> NO, WE'RE NOT. IN FACT, ONE OF THE THINGS WE HAVE BEEN DOING IS WE'RE TAKING THAT COLLECTION AND WE HAVE BEEN LOOKING AT WHERE ARE THE ORGANISMS THAT ARE THERMOTOLERANT. THERMOTOLERANCE APPEARS TO BE SPREAD THROUGHOUT THE FUNGAL KINGDOM. SOME OF THESE ORGANISMS ARE COMPLETELY RESISTANT TO OUR ANTIFUNGAL AGENTS. AND IF ONE OF THOSE EMERGES, WE ARE GOING OH HAVE A HUGE PROBLEM. BUT I DON'T BELIEVE -- BECAUSE THERE ARE PLENTY OF FUNGI, THERE ARE 1.5 MILLION SPECIES, AND AT LEAST FIVE TO 10% OF THOSE CAN LIVE AT TEMPERATURES GREATER THAN 45 DEGREES. SO THE POTENTIAL NUMBER OF ORGANISMS OUT THERE IS ENORMOUS. AND IF YOU DON'T BELIEVE THE TWO CAN HAPPEN, GO TALK TO THE FROGS. [LAUGHTER] >> OR TO THE BAT, WHO ARE DOING WELL UNTIL THIS THING GOT INTRODUCED INTO THE UNITED STATES. >> THAT WAS THE MOST ELEMENT ARGUMENT FOR INCREASING FUNDING FOR FUNGAL DISEASES THAT I'VE EVER HEARD. >> I DIDN'T SAY ANYTHING ABOUT THAT. >> WELL, THE REASON THAT IT WAS ASSOCIATED WITH GLOBAL WARMS WAS FASCINATING BECAUSE WHAT HAPPENS IS THAT AS THE PLANET GETS WARMER, IT CLIMBS OFF THE MOUNTAINS. SO WHAT YOU SEE IS THAT IT CLIMBS UP -- IT USED TO BE THAT IT'S RESTRICTED PRIMARILY TO THE AREAS AROUND SEA LEVEL. SOME PEOPLE THINK THAT THIS WAS SPREAD WHEN -- WAS SENT ALL OVER THE WORLD ASSOCIATED -- BECAUSE IN THOSE DAYS, IT WAS USED FOR PREGNANCY TESTING. IT WAS AN EXAMPLE OF THAT. I THINK IT WAS PREGNANCY TESTING, SOMEBODY COULD CORRECT ME ON IT. BUT THE IDEA IS THAT WE PRETTY MUCH SPREAD IT ALREADY, AND HUMANS -- WE'RE THE VECTOR FOR DISSEMINATING IT. >> RIGHT. >> AS IMMUNOLOGISTS, WE DO A LOT OF STUFF -- ARE HOUSED IN TEMPERATURES -- SO HOW MUCH EFFECT DO YOU THINK THIS IS HAVING AS A BROAD PRINCIPLE IN ALL OF IMMUNOLOGY? IF WE'RE OFF IN SOME -- I MEAN, THE IMPLICATIONS OF IT COULD BE REALLY PROFOUND, RIGHT? >> ABSOLUTELY. THE ARGUMENT GOES LIKE THIS: MICE NORMALLY LIVES AT TEMPERATURES UNDERGROUND IN WHICH THEY HUDDLE TOGETHER OF 37, 38, EVEN 39 DEGREES. WHEN WE ADAPTED IT, WE ADAPTED IT TO OUR TEMPERATURES BECAUSE WE DON'T WANT TO GO INTO A WARM ROOM TO DO A MOUSE EXPERIMENT, SO NOW WE HAVE MOUSE, WE HAVE 100 YEARS OF SELECTIVELY BREED MOUSE THAT ARE FULL STRESS, AND IT RAISES THE QUESTION WHETHER SOME OF THE PROBLEMS IN RELATING SOME OF THE IMMUNOLOGICAL STUDIES IN HUMANS TO MICE MAY HAVE THE ORIGIN IN THE FACT THAT WE'RE WORKING WITH A COLD STRESSED ORGANISM. THE THINK THE JURY IS OUT THERE, I KNOW MICE ARE GETTING A BAD RAP BUT IT'S IMPORTANT TO THINK OF THE MANY WAYS IN WHICH THEY HAVE GUIDED US CORRECTLY. >> SO MAMMALS HAVE BEEN HERE FOR MAYBE 65 MILLION YEARS? >> NO, NO, MUCH LONGER. >> OKAY. SO IN ANY CASE, WHAT HAS BEEN THE CONSTRAINTS ABOUT FUNGI TO EVOLVE THAT THERMAL TOLERANCE OVER THOSE MILLIONS OF YEARS AND NOT BE AS GOOD AS BACTERIAL VIRUSES AT INFECTING MAMMALS? >> I THINK YOU'RE THINKING OF VIEWER EU LENS ALMOST FROM A MISSION. THE FUNGI DON'T CARE. THEY LIVE IN THE GROUND, THEY DIGEST STUFF. WHEN THEY GO INTO AN ANIMAL, THEY GO INTO A NEW ECOSYSTEM. AND IT JUST HAPPENS THAT THROUGH SELECTION, THEY HAVE BEEN FIGHTING WITH PROTOZOA, BACTERIA ALL THIS YEAR -- THAT CAN OCCASIONALLY CAUSE DISEASE IN MAMMALS. BUT I DON'T THINK THAT NECESSARILY YOU SHOULD THINK OF THEM EVOLVING TO HAVE THERMAL TOLERANCE. WE DON'T UNDERSTAND WHY THERMAL TOLERANCE. FOR EXAMPLE, THE ORGANISMS THAT LIVE IN A COMPOST CAN GET PRETTY HOT AND THEY SURVIVE IT THERE. BUT I DON'T THINK THAT THE -- VIRULENCE IS AN OUTCOME, IT IS HARD TO ARGUE THAT AN ORGANISM WILL BECOME THERMAL TOLERANT BECAUSE THEY'RE GOING TO ANOTHER SITE. >> THANK YOU. >> YOU'RE WELCOME. >> ALL RIGHT. >> THANK YOU VERY MUCH.