WELCOME TO THE FIRST SUMMER LECTURE SERIES, I AM Dr. CHUN FROM THE OFFICE OF TRAINING AND EDUCATION AND IT IS MY PLEASURE TO HAVE AN OPPORTUNITY TO INTRODUCE Dr. JULIE SEGRE, SENIOR INVESTIGATOR AT THE NATIONAL HUMAN GENOME RESEARCH INSTITUTE. SHE RECEIVED HER BACHELOR DEGREE WITH HIGHEST HONORS FROM AMHERST COLLEGE AND RECEIVED HER PHD FROM MIT. THEN SHE PERFORMED POST-DOCTORAL TRAINING AT THE UNIVERSITY OF CHICAGO. SHE SAUCES SEQUENCING AND DEVELOPS AGO RHYTHMS TO STUDY MICROBIAL DIVERSITY OF HUMAN SKIN IN BOTH HEALTHY AND DISEASED STATES WITH A FOCUS ON ECZEMA AND OTHER MICROBIAL-ASSOCIATED INFECTIONS. SHE IS A LEADER IN THE NIH ROAD MAP HUMAN MICROBIOME PROJECT COMMUNICATING WITH MULTIPLE MEDIA SOURCES TO PROMOTE THE CONCEPT OF HUMANS AS ECOLOGICAL LANDSCAPES. TDAY SHE WILL TELL THE STORY OF HER CAREER IN SCIENCE, HIGHLIGHTING THE HUMAN MICROBIOME PROJECT. PLEASE JOIN ME IN WELCOMING Dr. JULIE SEGRE. >> OKAY, THANK YOU ALL AND THANK YOU FOR COMING OUT ON THIS HOT DAY. SO THANK YOU FOR THAT NICE INTRODUCTION AND WHAT CAN I PICK APART FROM THAT? I DID FEEL LIKE FROM THE COLLEGE LEVEL, MY UNDERGRADUATE DEGREE WAS IN MATH AND I REALLY DID FEEL IT WAS REALLY USEFUL TO HAVE STRONG QUANTITATIVE SKILLS TO BE ABLE TO DO THE WORK I WANTED TO DO AND I WOULD ENCOURAGE, IF YOU GUYS ARE SUMMER STUDENTS, POST-BACCS, DEFINITELY TAKE THE CLASSES AND LOVE THE CLASSES ON COMPUTER SCIENCE, STATISTICS, LIKE THAT IS REALLY THE CHALLENGE FOR ME, HAS BEEN TO FIGURE OUT HOW DOES MY BRAIN WORK AND MY BRAIN LIKES TO ORGANIZE LARGE DATA SETS AND IT IS EASIER TO DO THAT FOR ME IN THE CONTEXT OF COMPUTATIONAL BIOLOGY THAN ANYWHERE ELSE. SO THAT IS SORT OF WHAT I WILL TALK ABOUT. I WILL TALK ABOUT THE SCIENCE AND A LITTLE ABOUT WHY DO I DO THESE THINGS BUT I THOUGHT I WOULD START BY SAYING THAT IN 2000 -- SO MY TRAINING INFORMS GENOMICS AND SKIN BIOLOGY AND WE STARTED WORKING ON THESE MOUSE MODELS OF SKIN BARRIER IMPAIRMENT WHEN THE SKIN IS IMPAIRED AND KEPT SEEING ANTIMICROBIAL PEPTIDES COMING UP AND SO THAT WOULD ASK WHAT ARE THE MIKE CONTRACEPTIVES IN THE MOUSE SKIN OR HUMAN SKIN AND THAT WAS RIGHT WHEN THE HUMAN MICROBIOME PROJECT WAS STARTING SO I HAD DONE MY PHD AT MIT WHEN THAT WAS STARTING AND I LIKE TO BE IN ON THE BEGINNING OF PROJECTS BECAUSE THEN YOU CAN ORGANIZE THEM AND DEVELOP THESE REALLY LARGE, HIGH-QUALITY DATA SETS. SO I PRETTY MUCH DID -- CHANGED DIRECTIONS IN 2007 AND AT THIS POINT FOR THE LAST TEN YEARS, I HAVE REALLY EXCLUSIVELY ONLY WORKED ON THE HUMAN MICROBIOME PROJECT WHEREAS BEFORE I WAS WORKING ON TRANSCRIPTIONAL REGULATION AND BARRIER FUNCTION SO THAT IS ONE OF THE ADVANTAGES OF BEING HERE AT NIH, THAT YOU CAN CHANGE DIRECTIONS AND IT REALLY HAS OPENED UP NEW WAYS OF WORKING FOR ME SO I WILL INTEGRATE THAT IN, TOO. WHEN WE TALK ABOUT THE HUMAN MICROBIOME PROJECT, I THINK A WILL THE OF -- A LOT OF PEOPLE TALK ABOUT BACTERIA BUT REALLY, IT IS A NUMBER OF ITEMS AND I WILL TELL YOU A STORY OF THREE OF THOSE FOUR. WE HAVE NOT FOUND EUKARIA ON THE SKIN TO DATE. IT IS TYPICAL TO THINK THAT THESE ARE TINY LITTLE THINGS BUT THE IMPACT IS HUGE. HERE WE ARE, HERE IS THE FUNGI, THE DIFFERENT KINDS OF BACTERIA AND THE BIOGENETIC DIVERSITY OF THESE MICROORGANISMS IS HUGE AND THEY HAVE EXISTED ON THIS PLANET FOR, YOU KNOW, MILLIONS OF YEARS BEFORE WE DID. AND I WOULD SAY THAT THERE IS STILL A LOT OF, YOU KNOW, GENETIC DIVERSITY AND WAYS OF THINKING THAT THESE BAGUETTE TEAR, FUNGI, VIRUSES UTILIZE THAT ARE ANTHROPORMOPHIC SCIENCE HAS NOT YET GENERALIZED YET. SO WHAT IS THIS REALLY? SO IF A HUMAN BEING IS 30 TRILLION CELLS, THE BACTERIA THAT COLONIZE THE HUMAN IN MANY OF THOSE ARE FOUND IN THE GUT AND WILL BE IN EQUAL NUMBER AS THE HUMAN CELLS AND THEN THE VIRUSES ARE PROBABLY GOING TO BE EVEN MORE THAN THAT BUT THE VIRUSES, LIKE THEY ARE MULTIPLEPHAGE THAT COULD LIVE WITHIN A VIRUS CELL AND HUMAN HOST CELLS. SO JUST TO KIND OF, YOU KNOW, HOW DOES THIS ALL COME BOOT, IF THE HUMAN GENOME IS 24,000 BREATHE TEEN CODING GENES, EACH CELL CONTAINS THE SAME GENETIC MATERIAL. YOU CAN KIND OF REGULATE THAT BUT WHAT IS THE GENETIC MATERIAL OF A HEART CELL IS THE SAME AS A SKIN CELL. IN CONTRAST, LIKE A BACTERIAL GENOME IS THREE MILLION BASE PAIRS WITH 2400 BREATHE TEEN BASE CODEING GENES. SO IT SOUNDS LIKE A LOT LESS BUT THINK ABOUT IT, THAT THESE BACTERIA ARE QUITE DISTINCT THAT LIVE ON AND IN YOUR HUMANS. SO IF YOU LOOK AT THE BACTERIA THAT LIVE IN THE GUT AND YOU ADD UP ALL THE PROTEIN CODEING GENES IT, PROBABLY FAR EXCEEDS WHAT IS THE HUMAN GENOME. SO IT IS REALLY -- WE TALK ABOUT IT LIKE THESE TWO GENOMES THAT ARE CO-EXISTING SIMULTANEOUSLY OF THE HUMAN CELLS AND MICROBIAL CELLS. WHEN I FIRST GOT INTO THIS PROJECT OR GOT INTO SCIENCE AS A PHD STUDENT AS PART OF THE GENOME PROJECT, I REALLY THOUGHT THAT WE WERE GOING TO USE -- YOU KNOW, MAP GENES ON THE HUMAN GENOME, FIND THE GENE FOR LIKE CYSTIC FIBROSIS AND CURE THE DISEASE. AND THERE WAS A LOT OF HOPE THAT GENE THERAPY WOULD COME IN AND WE WOULD BE ABLE TO MAGICALLY RESTORE THE FUNCTION. ALL WE HAD TO DO WAS IDENTIFY THE GENE CAUSING CYSTIC FIBROSIS AND WE COULD CURE THAT DISEASE. AND AS YOU HAVE PROBABLY SEEN AND HEARD IN THE NEWS, THE GENE THERAPY HAS GOTTEN STALLED AND VERY COMPLEX AND NOW WE HAVE A NEW DELIVERY SYSTEM WITH CHRIS BURKASS BUT THERE ARE STILL A LOT OF ISSUES WITH CHANGING SOMEONE'S GERMLINE GENOME. MEANWHILE, WE HAVE ACTUALLY MADE TREMENDOUS ADVANCES IN THE LIFESPAN AND DISEASE COURSE OF PATIENTS WHO HAVE CYSTIC FIBROSIS. AND HOW HAVE WE DONE THAT? WE HAVE DONE THAT BY CONTROLLING THE MICROBIAL COLUMNS OF THESE PATIENTS. THEY OFTEN BECOME MUCOUSY, THEY GET A LOT OF INFECTIONS AND ACTUALLY THROUGH CONTROLLING THE COLIZATION COLONIZATION OF A BUILDUP AND WITH THE CARE, THE LIFESPAN OF A KID BORN WITH CF TODAY FAR EXCEEDS THAT WHEN I FIRST STARTED THAT BUT THAT IS THROUGH UNDERSTANDING THE MICROBIAL INTERACTION BETWEEN THESE PATIENTS. SO THE MICROBIOME, THE IMMUNE SYSTEM, EACH OF THESE MICROBES BASICALLY KEEPS LIKE THE IMMUNE SYSTEM KIND OF ON ALERT BUT NOT SUPER-ACTIVATED, AIDS IN DIGESTION, RIGHT, SO A LOT OF INTEREST IN THE REALM OF DIET AND OBESITY AND PERHAPS SOME OF PROVIDING PROTECTION FROM PATHOGENS SO IF YOU ARE CONSTANTLY BEING EXPOSED TO THINGS THAT COULD BE POTENTIAL PATHOGENS BUT YOU HAVE RESIDENT MICROBES THAT ARE MORE -- ATLANTA ARE ADAPTED TO LIVE ON THAT ENVIRONMENT, SO I REALLY THINK IT COULD BE, YOU WOULD THINK THAT, YOU KNOW -- WELL, I THINK THE MICROBIAL COLONIZATION, IT IS MORE EFFICIENT TO COLONIZE WITH NEUTRAL MICROBES THAN STERILITY BUT WE ARE CONSTANTLY BEING EXPOSED TO POTENTIAL PATHOGENS. SO YOU THINK ABOUT THE BACTERIA BEING NEUTRAL, THAT IS AWESOME, BUT THEY MAY DO MORE THAN THAT BY ALSO, YOU KNOW, OFFLOADING FUNCTIONS THAT THE HUMAN GENOME HAS NOT EVOLVED LIKE AIDING AND DIGESTION AND BREAKING DOWN CELLULAR MATERIAL FOR US. OKAY, SO HOW DO WE CHARACTERIZE THIS MICROBIOME, RIGHT? AND BECAUSE I HAVE TOLD YOU ABOUT ALL THESE MICROBES THAT COLONIZE THE SURFACES SO IF YOU ARE THINKING THIS IS THE WAY WE USED TO DO IT, PLACE THEM ON THE AUGER DISHES AND THEN COUNT, WOULD YOU DO THIS IF I JUST TOLD YOU THERE SHOULD BE 10 TO THE 14TH CELLS? YOU CAN'T CULTURE AND COUNT EVERYTHING. AND THE MICROBES WHEN YOU PLACE THEM ON THESE AUGER DISHES, THEY GO THROUGH THESE TREMENDOUS BOTTLENECK THAT REALLY WHAT YOU ARE GROWING THERE ARE LAB WEEDS, THINGS THAT HAVE OPTIMIZED THEMSELVES TO LIVE ON BLOOD AUGER OR LB, NOT THE NUTRIENTS AND RESOURCES THAT YOU WOULD SEE WHEN THEY ARE LIVING ON YOUR SKIN OR IN YOUR GUT. SO FROM THE GENOME INSTITUTE, THE WAY THIS WHOLE THING REALLY BUST OPEN FOR US, WAS THAT WE'RE NOT GOING TO THINK ABOUT CULTURING, WE'RE GOING TO THINK ABOUT DIRECT SEQUENCING. SO I SWAB SOME SKIN, PUT IT DIRECTLY IN THE LICENSE BUFFER, MAKE DNA AND THEN WE HAVE THESE CONSERVED REGIONS IN BACTERIA AND ALSO IN FUNGI, WHICH THERE ARE CONSERVED REGIONS THAT I CAN SINK PRIMERS INTO AND AMPLIFY. THIS IS THE 16TH RNA GENE, I DO A PCR AMPLIFICATION AND THAT AMP PHASE THE 16S GENE OF EVERY BACTERIA AND THERE ARE LESS CONSERVED REGIONS IN THE MIDDLE OF THE 16S GENE AND THOSE HAVE SIGNATURE NUCLEOTIDES WHICH THEN ALLOW ME TO BIN THEM AND SAY TWO BACTERIA THAT BELONG SO THE SAME PHYLUM ARE MORE SIMILAR, SAME SPECIES, ALL THE WAY DOWN WHERE I CAN GET A SPECIES-LEVEL IDENTIFICATION AND SAY THIS IS STAPH OREUS, AND SO WITH SEQUENCING, WE CAN DO ONE AMPLIFICATION AND THEN SEQUENCE THE PRODUCT AND GET EACH OF THOSE READS WHICH BECOMES THIS WAS ONE BACTERIA THAT WAS PRESENT HERE. SO WE HAVE THE TECHNOLOGY AND I GUESS BEFORE WE EVEN EMBARKED ON THIS, OUR QUESTION WAS BUT WOULD I SEE ANYTHING DIFFERENT? WHEN YOU HAVE A NEW TECHNOLOGY, YEAH, WE ALL WANT TO USE IT BUT IS IT GOING TO TELL YOU ANYTHING DIFFERENT? SO THIS IS THE FIRST EXPERIMENT I SET UP WITH MY CLINICAL MICROBIOLOGY COLLEAGUES. WE SORT OF DID THIS LIKE HEAD-TO-HEAD EXPERIMENT WHERE WE SWABBED FROM SOMEONE'S ARM AND THEN I CALCULATED THE DIVERSITY JUST FROM DIRECT SEQUENCING AND PAT TOOK IT BACK TO HIS LAB AND GREW IT ON BLOOD AND CHOCOLATE AND BASICALLY TRIED TO PICK WHAT HE THOUGHT WAS THE MOST DIVERSE COMMUNITY FROM THESE DIFFERENT PLATES AND THEN WE ACTUALLY SEQUENCED EACH OF THOSE JUST TO MOLECULARLY-I.D. EACH OF THOSE ORGANISMS. AND THIS IS THE KIND OF THING WE SAW. FROM THE SIDE OF SOMEONE'S NOSE FROM CULTUREING, IT WAS BASICALLY THIS. FROM THE DIRECT SEQUENCING, I ACTUALLY SAW LESS STAPH, DEFINITELY THE LAB WEED. I ALSO SAW THESE AACTENOBACTERIUM. THEY NEED THOSE LIPIDS, THEY SCAVENGE THEM SO THEY GET THEM FROM THE SKIN SO WE GOT VERY FEW OF THEM AND WE DIDN'T KNOW THEY WERE DOMINANT MEMBERS OF THE SKIN COMMUNITY. WHEN WE CULTURE FROM THE PERSON'S UMBILICUS, OR BELLY BUTTON, HE COULD CULTURE A FEW, NOT LIKE THEY WOULD NEVER GROW BUT REALLY UNDER REPRESENTED COMPARED TO POSTULATING THEY COULD BE UP TO 50 PERCENT. SO WE WENT FORWARD, SAID OKAY, THIS IS A GO, WE WILL GET INFORMATION WE CAN USE AND WE STARTED THE FIRST CLINICAL STUDY WHICH WAS 1500 HEALTHY ADULTS AND WE DID A SURVEY OF THESE 18 DIFFERENT BODY SITES. AND THE REAL IMPETUS FOR THIS STUDY WAS Dr. TURNER AND Dr. KUNG TALKING ABOUT HOW THERE ARE DERMATOLOGIC MANIFESTATIONS. KIDS HAVE IT IN THE BEND OF THEIR ELBOW BUT 10 TO 30 PERCENT OF OTHERS WHO HAVE SORE RICE SASS WILL -- PSORIASIS WILL HAVE IT ON THEIR ELBOWS AND SO WHY AND COULD WE USE THIS TO UNDERSTAND WHAT ARE THE DISEASES WE'RE SEEING? SO REALLY AWESOME POST-DOC IN MY LAB WHO ACTUALLY HAS ALREADY GOTTEN TENURE SO THAT TELLS YOU HOW LONG AGO THIS WAS, ABOUT TEN YEARS AGO, SET UP TO DO THE STUDY OF LOOKING AT THE 16S GENE OF THESE 18 DIFFERENT BODY SITES. AND REALLY WHAT STANDS OUT HERE IS THAT THE BACTERIAL COMMUNITY IS NOT SPECIFIC TO THE INDIVIDUAL. IT IS NOT LIKE YOU HAVE, YOU KNOW, ONE BACTERIAL COMMUNITY AND I HAVE A DIFFERENT ONE. THE BIGGEST DIFFERENCE IS THE BODY SITE AND THAT COMES DOWN TO WHAT ARE THE NUTRIENTS AVAILABLE TO THE BACTERIA THAT WOULD LIVE THERE? SO THE BEND OF MY LEFT ELBOW IS MOST SIMILAR TO THE BEND OF MY RIGHT ELBOW AND AFTER THAT, THE BEND OF MY ELBOW WOULD BE LIKE YOURS BECAUSE THIS IS A MOIST CREASE, SWEATY ENVIRONMENT WITH LARGE HAIR FOLLICLES, AN OILY REGION, AND THE BACTERIAL COMMUNITIES ARE REALLY DEPENDENT ON WHAT NUTRIENTS CAN THEY SCAVENGE? THEY ARE LOOKING TO HUMANS AS A FOOD SOURCE. SO THAT ACTUALLY WAS QUITE REVEALING IN TERMS OF GIVING THIS KIND OF TOPOGRAPHIC LANDSCAPE, SINK SYNCHED WITH WHAT WE KNEW ABOUT DERMATOLOGIC DISEASES. WE USED THIS TO LOOK AT FUNGAL HEALTH AND USE A DIFFERENT REGION. IF YOU RUN A NORTHERN BLOT WHICH NONE OF YOU PROBABLY DO ANYMORE BUT YOU SEE THESE BANDS LIKE THE 23S, 18S, 5S, THOSE ARE THE RHIBOZOMAL ENTITIES. SO WE USED A DIFFERENT REGION O THE FUNGAL CLUSTER, ITS1 REGION AND DID A VERY SIMILAR TYPE OF ANALYSES BUT INSTEAD WHAT WE DID HERE IS BASICALLY THE PURPLE HERE IS THE DOMINANT FUNGI FOR THE WHOLE HUMAN BODY. THERE ARE SOME DIFFERENCES IN TERMS OF SPECIES BUT REALLY THE ONLY PLACE WE WERE SEEING FUNGAL DIVERSITY WAS ON THE FEET. AND IN FACT WHEN WE WENT BACK AND THOUGHT ABOUT IT, THIS PROBABLY DIDN'T HUGELY SURPRISE US BECAUSE WHERE DO YOU SEE FUNGAL DISEASE? YOU SEE ATHLETE'S FOOT, TOE NAIL INFECTIONS, SO THAT PROBABLY ACTUALLY DOES MAKE SENSE. SO I WILL SWITCH AND TALK ABOUT KIND OF LIKE SO WHAT DO I DO WITH THIS AND WHAT DO I DO AT NIH? SO ABOUT THREE YEARS AGO, WE IDENTIFIED AT THE CLINICAL CENTER A NOVEL EMERGING FUNGAL PATHOGEN. THE CDC WAS ALREADY AWARE OF IT. THIS IS THE FUNGI HERE CALLED CANADA -- CANDIDA AURIS. THERE WAS ONE FUNGI THAT MADE THE LIST AND IT IS BECAUSE THEY ALSO HAVE EVOLVED TO A FAIRLY HIGH LEVEL OF RESISTANCE BUT WE ACTUALLY HAD NEVER SEEN CANDIDA AURIS IN THE U.S. IT CAME OUT OF NOWHERE ABOUT TEN YEARS AGO. CASES WERE PICKED UP IN SOUTH ASIA, AFRICA AND SOUTH AMERICA AND THREE DIFFERENT STRAINS OF CANDIDA AURIS. BUT WE HAD A PATIENT WHO CAME IN AS A TRANSFER FROM ANOTHER HOSPITAL WHO WAS THE THIRD PARROT PATIENT IN THE U.S. IDENTIFIED AS COLONIZED WITH CANDIDA AURIS. THERE WAS A LARGE STORY ABOUT THIS IN THE NEW YORK TIMES ON SUNDAY TWO MONTHS AGO BECAUSE IT IS NOW CAUSING OUTBREAKS IN SKILLED NURSING FACILITIES WHERE PATIENTS STAY OFTEN FOR A LONG PERIOD OF TIME AND BY OUTBREAKS, I MEAN CLUSTER OF COLONIZATION AND INFECTION AND IN BOTH OF THESE CASES, WE HAVEN'T REALLY FIGURED OUT YET HOW TO BREAK THE TRANSMISSION. AND OUR CONCERNS ABOUT CANDIDA AURIS ARE THE HIGH LEVELS OF MICROBIAL RESISTANCE. CLINICALLY THE ISSUE IS THE BLOODSTREAM INFECTIONS ARE VERY DIFFICULT TO TREAT BECAUSE OF THE HIGH LEVELS OF ANTIMICROBIAL RESISTANCE AND REALLY A LOT OF THAT HAS TO DO WITH YOU THINK ABOUT ANTIBIOTICS AND THE TARGET BACTERIA, BECAUSE BACTERIA DON'T HAVE A NUCLEUS AND THERE ARE A& LOT OF WAYS IN WHICH BACTERIA IS SUPER DIFFERENT FROM A HUMAN CELL IN WAYS THAT YOU CAN INTERRUPT BIOSYNTHESIS AND SO YES, WE HAVE DRUGS THAT YOU CAN USE AGAINST THEM BUT THEY ARE PRETTY TOXIC TO THE HUMAN AS WELL. SO WE ACTUALLY ONLY HAVE THREE CLASSES OF ANTI-FUNGALS AND ONE OF THEM IS AZOLES AND RESISTANT SO WE'RE DOWN TO TWO DRUGS. IF YOU HAVE EVER SEEN ANYONE TRYING TO GET RID OF A TOE NAIL INFECTION, THEY ARE FUNGAL BUT THEY ARE REALLY HARD TO GET RID OF AND PEOPLE WILL TAKE THESE SYSTEMIC DRUGS ATLANTA ARE FAIRLY TOXIC AND YOU CAN'T DRINK FOR A WHILE BECAUSE THEY INHIBIT LIVER AND KIDNEY FUNCTION. OUR PART OF IT IS WE'RE ALSO INTERESTED IN THE FACT THAT CANDIDA AURIS PRIMARY SITE OF COLONIZATION GO IS THE SKIN AND IF YOU PUT IN LIKE A LINE, THAT IS WHERE IT IS GETTING INTO THE BLOODSTREAM. ANY TIME YOU PUT IT IN AN IV OR ANYTHING. BUT IT ALSO MEANS IT IS HARD TO CONTROL AND IF SOMEONE IT HAS ON THEIR SKIN, THEY ARE SHEDDING IT IN THEIR ENVIRONMENT AND THAT HAPPENS IN PARTICULR WHEN THEY CHANGE THE SHEETS IN A NURSING HOME. AND THE CDC CAME TO US, WELL, WE STARTED WORKING TOGETHER BECAUSE THEY DIDN'T HAVE -- THEY WERE STILL USING CULTURING TO TEST FOR CANDIDA AURIS AND THAT WAS TAKING SEVEN DAYS TO RETURN FOR RESULTS SO IN THE MEANTIME, IF YOU WERE TESTING NEW PATIENTS COMING INTO THE FACILITY FOR SEVEN DAYS WHILE YOU ARE GETTING THE CULTURE RESULTS, YOU JUST HAD THESE PEOPLE IN THE REGULAR PATIENT POPULATION. SO WE CAME UP WITH SOME SEQUENCING METHODS THAT WOULD BE FASTER AND GENERATED LIKE PCR-BASED ASSAYS AND THESE ARE THE FIRST TWO NURSING HOMES WE WENT IN TO, ONE IN NEW YORK ON THE LEFT AND ONE IN CHICAGO ON THE RIGHT AND THE WAY THESE CHARTS WORK IS AGAIN, IT IS LIKE 100 PERCENT OF THE POPULATION SO I SEQUENCE THAT ITS1 AMPLICON AND SAY OKAY, YOU ARE ONE OF THESE THREE AND WHAT WE SAW IS COMPARING SEQUENCING WITH THE CULTURING AND THEN USING THAT WITH THE PTR ASSAYS THAT WE HAD VERY STRONG CONCORDANCE BUT IF YOU LOOK ON THE RIGHT, THIS IS THE CHICAGO NURSING HOME WHERE THEY JUST HAD TWO PATIENTS AND THEN GOT MULTIPLE NEGATIVES AFTER THAT. AND SO THIS IS ONE OF THE PATIENTS IN HERE, THE RED IS THE CANDIDA AURIS AND YOU CAN SEE THEY ARE STILL BY AND LARGE COLON IZED, THE BLUE IS A DIFFERENT CANDIDA BUT IN NEW YORK THEY WERE IN A FULL OUTBREAK SCENARIO WHERE ANYTHING ON THEIR SKIN HAD BEEN OUTCOMPETED BY CANDIDA AURIS AND IF IT WASN'T AURIS, IT WAS A DIFFERENT KIND OF CANDIDA. SO WE IDENTIFIED THE DOMINANT FUNGI BUT IT IS A TOTALLY DIFFERENT SITUATION WHEN WE GO INTO THESE SKILLED NURSING FACILITIES WHICH HAVE NOT VERY AMBULATORY, MULTIPLE PATIENTS ON MULTIPLE MEDS. SO RIGHT NOW WE HAVE KIND OF GONE FROM LIKE HAVING THIS ONE PATIENT AT THE HOSPITAL TO NOW AT LEAST 25 PERCENT OF MY LAB WORK IS ON CANDIDA AURIS LOOKING FOR COLONIZATION RESISTANCE OR BACTERIA AND A LOT OF MY WORK HAS BEEN WORKING WITH CLINICIANS TO IDENTIFY WHAT IS THE SITE OF SKIN COLONIZATION BECAUSE THEY NEED TO KNOW WHERE SHOULD THEY BE LOOKING, LIKE INSIDE THE PATIENT'S NOISE, PATIENT''S 'S NOSE, WHERE SHOULD WE BE LOOKING? SO WE HAVE BEEN DOING THIS AT CHICAGO FACILITIES WITH TEN DIFFERENT BODY SITES AND CULTURING THEM AND ONE OF OUR FINDINGS IS THE NOSE WAS A SITE THEY WEREN'T TESTING BUT AS WELL, THESE PATIENTS HAVE IT ON THEIR HANDS AND FEET BECAUSE IT IS SO MUCH IN THE ENVIRONMENT. SO A LOT OF OUR WORK, I TALKED ABOUT HOW WE SEQUENCE THE 16S AND THE FUNGAL BUT A LOT OF OUR WORK IS DOING REALLY HIGH-TECH WORK AND GOING STRAIGHT TO GENOMIC SEQUENCING WHERE WE SEQUENCE EVERYTHING AND TRY TO REASSEMBLE THE GENOMES FROM THAT. SO BEING IN THE SEQUENCING CENTER, WE HAVE JUST LIKE MOVED THROUGH THE LAST TEN YEARS, THIS AMAZING ALTERATION IN INSTRUMENTS THAT ARE AVAILABLE FOR DOING SEQUENCING. AND WE ARE NOW SEQUENCING MOSTLY ON A ILLLLUMINA NOVASEQ600 WHICH IS LIKE A BEAST, I GET A HUNDRED MILLION READS PER SAMPLE AND THEN REASSEMBLE THEM. SO THE FIRST THING WE DO IS TAKE OUT THE HUMAN DNA AND THEN TRY TO SEPARATE OUT THE VIRUSES AND FUNGI AND SEE WHAT THE RELATIVE ABUNDANCE IS. IT HAS REALLY BROUGHT TO LIGHT SOME IDEAS FOR US WHERE I TALKED ABOUT HOW THERE WAS THIS DIFFERENCE IN THE BODY BUT IT HAS REVEALED HOW MUCH DIFFERENCE THERE IS BETWEEN PEOPLE. SO IF YOU JUST EVEN LIKE -- THESE ARE THREE DIFFERENT HEALTHY VOLUNTEERS AND I HAVE PULLED OUT THREE DIFFERENT BODY SITES AND LIKE IF YOU LOOK AT VOLUNTEER NUMBER 1 ON THE SIDE OF THEIR NOSE, YOU CAN SEE THAT PURPLE, GO THEY ARE COLONIZED WITH THIS BACTERIA AND WE WOULDN'T HAVE THOUGHT THERE WOULD BE THAT MUCH PHAGE ON SOMEONE AND THAT PERSON LOOKS TOTALLY HEALTHY. SO YOU THINK OKAY, THIS IS SOME WEIRD PHAGE BLOOM. BUT WE COME BACK A YEAR LATER, DO THE SKIN MICROBIOME AGAIN AND THEN COME BACK A MONTH LATER AND SEE WHAT IS THE CHANGES, BOTH SHORT AND LONG-TERM. AND THIS PERSON JUST HAS A LOT OF PHAGE AND THEY ARE CONSISTENT THAT WAY. IF YOU LOOK AT HEALTHY VOLUNTEER NUMBER 2, THERE IS VERY LITTLE PHAGE. INSTEAD, WHAT IS REMARKABLE ABOUT THAT PERSON IS THAT TOE COLOR. THIS IS THE PATIENT WHO HAS THE LARGEST AMOUNT OF FUNGI ON THEIR SKIN, NOT SOMETHING YOU WOULD SEE BUT THE DEFAULT MICROBIAL COMMUNITY HAS A LOT MORE FUNGI THAN HEALTHY PEOPLE. AND THEN THIS THIRD, THEY HAVE BACTERIA AND PHAGE BUT NOT MUCH ELSE. SO WHAT WE'RE SEEING HERE IS A LOT OF INTERINDIVIDUAL VARIATION BUT PEOPLE ARE CONSTANT THEMSELVES WHICH MEANS THAT OUR POWER TO DO THESE LONGITUDINAL STUDIES WHERE WE LOOK AT SOMEONE OVER TIME AND SAY HOW HAS THAT CHANGED AND HOW DOES IT RELATE TO DISEASE? ONE OF THE OTHER FEATURES WE SAW, WE HAVE ENOUGH DATA THAT WE CAN ACTUALLY NOT JUST SAY WHAT BACTERIAL SPECIES IT IS BUT WHAT STRAIN IT IS. SO BACTERIAL STRAINS, YOU KIND OF HAVE SENSE ABOUT. LIKE SOME STRAINS OF STAPH ARE RESISTANT, SOME AREN'T, SOME ARE MORE INFLAMMATORY, YOU THINK ABOUT E. COLI, SOME OF THEM COLONIZE THE URINARY TRACT MORE, SOME COLONIZE THE GUT MORE. THERE IS A GENE THAT ACTUALLY ALLOWS THEM TO ADHERE TO THOSE KIND OF EPITHELIAL CELLS. SO WE -- THIS IS THE PHYLOGENETIC DIVERSITY OF THE P.ACNES ON THE LEFT. AND THEY HAVE DIFFERENT STRAINS. C WOULD MEAN 20 PERCENT OF THE STRAINS ARE THESE BROWN STRAINS AND 10 PERCENT IS THIS AQUAMARINE AND THEY HAVE DIFFERENT STRAINS OF P. ACNES ON THEIR SKIN AND THOSE STRAINS ARE CONSTANT WHICH MEANS IT IS NOT JUST THAT YOU HAVE SKIN MICROBIOME, YOU GO ABOUT YOUR DAY, YOU TAKE A SHOWER, WHEN YOU WAKE UP THE NEXT MORNING, YOU DO NOT HAVE LIKE A NEW SKIN MICROBIOME. THE SKIN MICROBIOME IS CONSTANTLY BEING REPLENISHED FROM UNDERNEATH. SO FROM THIS KIND OF SHOCK ON METAGENOMICS, WE BEGAN LOOKING AT PATIENTS WITH THESE PRIMARY IMMUNE DEFICIENCIES SEEN HERE AT THE MEDICAL CENTER. AND WHAT WE KNEW ABOUT THE PATIENTS CLINICALLY IS THEY HAD A LOT OF VIRAL INVOLVEMENT. SO ON THE LIPS, THAT IS HERPES SIMPLEX, ON THE HANDS, WARTS, HUMAN PAPILLOMA VIRUS USUALLY AND ON THE KNEES, A POX VIRUS. SO HEALTHY VOLUNTEERS ARE GOING TO BE MOSTLY BACTERIAL AS I SAID AND THEN THEY WILL HAVE A LITTLE BIT OF FUNGI. SO THIS IS LIKE FIVE DIFFERENT REPRESENTATIVE HEALTHY VOLUNTEERS. WHEN WE DID THIS METAGENOMIC SEQUENCING ON THESE PATIENTS WHO ALL HAD AN INDICATOR IN THE DOCK8 PROTEIN ON THE EXOSKELETON AND AS THE IMMUNE CELLS TRY TO IT MIGRATE INTO THE SKIN, THEY ACTUALLY CAN'T MAKE THE SQUEEZE, IS WHAT IT LOOKS LIKE IN MY CROSS -- MICROSCOPY AND THEY SHATTER. SO THESE PATIENTS HAVE PROBLEMS WITH THEIR SYSTEMIC IMMUNITY BUT DIFFICULTIES IN THEIR PERIPHERAL IMMUNITY AS FAR AS THE SKIN IMMUNE COMMUNITIES. AND, GO YOU KNOW, RUNNING THROUGH JUST THE FIRST FEW CAN DO 8 PATIENTS THAT WE SEQUENCED AND THEY LOOK NOTHING LIKE HEALTHY VOLUNTEERS. EVERY READ WE GET OFF THE SEQUENCER IS FROM A VIRUS -- WELL, NOT EVERY ONE BUT LIKE 99 PERCENT OF THEM. SO THAT WAS REALLY FASCINATING TO US BECAUSE WE REALLY DON'T KNOW -- I MEAN, GO WE DON'T KNOW MUCH ABOUT VIRAL DIVERSITY BECAUSE WITH THE BACTERIA AND THE FUNGI, WE HAVE THE 16S OR THESE ITS1 GENES SO YOU CAN CAPTURE THEM. BUT VIRUSES DON'T HAVE ANY COMMON ELEMENT. LIKE YOU KNOW, SO IT HAS BEEN REALLY HARD TO KNOW WHAT IS THE DIVERSITY OF VIRUSES THAT COLONIZE AND REALLY METAGENOMICS IS THE ONLY WAY WE'RE GOING TO GET TO THAT. SO WE COULD CHARACTERIZE SOME OF THE READS AS BEING PAPILLOMA VIRUSES, BUT REALLY WHAT WE DID WAS TAKE ALL THE READS THAT MAP TO VIRUSES AND ALL THE READS THAT WERE UNASSIGNED WHICH WE CALL DARK MATTER, AND WE DID DENOVO ASSEMBLY. SO WE HAVE 100 BASE PAIR READS COMING OFF THE SEQUENCER AND LOOKING FOR REGIONS WHERE THEY HAVE LIKE 20 BASE PAIR OVERLAP AND YOU CAN KIND OF STRING THEM ALONG. WHEN WE USE COMPUTATIONAL METHODS, WE WERE ENDING UP WITH CONTIGUOUS PIECES OF DNA WHICH WE CALLED CONTIGS, 7-8KB AND NEARLY FULL LENGTH HUMAN PAPILLOMA VIRUSES. SO WE WOULD GET THESE IT, YOU KNOW, ALE 8KILOBASE CONTEXTS AND THE WAY YOU CHARACTERIZE IT IS ON THE L1 GENE WHICH IS HIGHLY CONSERVED. SO WE TAKE THE L1 SEQUENCE TO DO PHYLOGENETICS. SO BASICALLY IF THE L1 IS LESS THAN 70 PERCENT IDENTICAL TO ANYTHING ELSE IN THE DATABASE, YOU SAY IT IS A NEW SPECIES AND THEN THERE'S TYPES AND VARIANTS. AND WITH THIS METHOD, WE COULD FIND -- SO I AM GOING TO -- YOU CAN SEE HERE THE GAMMA HPVS AND THE LIGHTER BLUE COLOR IS THE NOVEL GAMMA HPVS. SO WE FOUND 200 NEW HPV TYPES AND ONE NEW HPV SPECIES THAT HAD 25 TYPES SO A FAIRLY COMMON ONE, JUST HAD NEVER BEEN SEEN OR NOTED BEFORE. AND YOU CAN SEE THE WAY THAT IS READING OUT WHERE THIS DARKER BLUE IS WHAT WE KNEW, IF WE JUST WERE SING REFERENCE GENOMES AND THIS LIGHTER BLUE IS ALL WE'RE FINDING BECAUSE WE HAVE THESE NEW REFERENCES. AND THIS IS THE KIND OF THING THAT WE FIND HERE IN THE CAN DO 8 PATIENTS BUT THEN WE CAN PRETTY QUICKLY MOVE THIS TO A PCR ASSAY AND SAY DO WE FIND THESE IN OTHER PATIENTS AND THAT IS HOW THEY FOUND SOME OF THE OTHER VIRUSES AND THEN COULD SEE WHAT THE POPULATION PREVALENCE WAS. OKAY, I AM NOT DOING WELL ON TIME BUT I, YOU KNOW, FOR THIS PART, I WANT TO TALK ABOUT BACTERIA, FUNGI, VIRUSES AND HOW, YOU KNOW, THE DATA WE USE, WE OBTAIN FROM HUMANS COULD GENERATE HYPOTHESIS ABOUT THE MICROBIAL COLONIZATION. I AM GOING TO TALK FOR A MINUTE ABOUT HEALTHCARE-ASSOCIATED INFECTION BUS WHEN I WHEN -- BECAUSE WHEN I STARTED WORKING WITH MY COLLEAGUE IN CLINICAL MICRO, PAT MURRAY WAS SOMEONE I JUST REALLY LIKED WORKING WITH AND I WAS LIKE PAT, IS THERE ANYTHING ELSE WE CAN WORK ON TOGETHER AND HE WAS LIKE WE DO GET THESE HOSPITAL INFECTIONS EVERY ONCE IN A WHILE AND I WAS LIKE OKAY, LET'S DO IT. AND IN PARTICULAR, HE WAS INTERESTED IN WHEN A PATIENT COMES IN TO A HOSPITAL, LET ME JUST TELL YOU THAT STORY. SO YOU KIND OF ALL KNOW, GO YOU KNOW, THE JOHN SNOW STORY ABOUT HOW THEY FOUND THIS CHOLERA OUTBREAK AND LINKED IT TO THIS PUMP AND THEY DID THAT BASED ON WHERE WERE THE CASES THAT THEY WERE SEEING AND THE INCIDENTS. AND WE REALLY WANTED TO BRING GENOMIC SEQUENCING IN TO HOW YOU TRACK TRANSMISSIONS. SO HERE IS THE CASE. THERE IS A PATIENT WHO COMES INTO THE HOSPITAL CARRYING A RESISTANT PNEUMONIA. THIS BACTERIA IS SO RESISTANT, WE HAVE NO DRUGS TO TREAT THIS. THE ONLY THING WE CAN DO IS IN INFECTION CONTROL. AND SHE IS STILL ALIVE. SO WE HAVE PATIENT 1 COME IN AND WE PUT HER IN THE LAST ROOM OF THE ICU AND WE DIDN'T KNOW WHERE TO SCREEN FOR KPC SO WE WERE SCREENING AXILLA AND GROIN AND ACTUALLY SHOULD HAVE BEEN SCREENING IN THE GI TRACT. SO FOR THE MONTH OF JULY, WE THOUGHT WE HAD NO CASES. THEN IN AUGUST AND SEPTEMBER, WE FOUND PATIENTS 2, 3, 4 AND 5 WHO WERE COLONIZED OR INFECTED WITH THE SAME KLEBSIELLA PNEUMONIAE. THERE ARE TWO HYPOTHESIS HERE. ONE IS THAT PATIENT 1 IS TOTALLY, YOU KNOW, RELATED TO PATIENT 2, 3, 4 AND 5 AND THAT MEANT THE CONTACT ISOLATION WAS INSUFFICIENT AND THE SCREENING OF PATIENTS WAS INSUFFICIENT AND WE NEED TO CHANGE THE HOSPITAL PRACTICE. THE OTHER POSSIBLE HYPOTHESIS WAS THAT PATIENT 1 DOESN'T MATCH PATIENT 2, 3, 4 AND 5 AND WHAT HAD HAPPENED WAS THAT WE HAD PICKED UP 2, 3, 4 AND 5, PATIENT 1 PUT US ON ALERT SO WE WERE STARTING TO DO MORE INTENSIVE SCREENING SO WE HAD PICKED UP THIS LITTLE CLUSTER EARLY WHICH WOULD MEAN CONTACT ISOLATION IS SUFFICIENT, AND WE SHOULD STAY THE COURSE. SO AND THE PROBLEM IS WHERE THE TRADITIONAL MICROBIOLOGY TECHNIQUES, THEY REALLY CAN'T TELL THE DIFFERENCE BECAUSE WHAT THEY WERE DOING IS RUNNING GELS AND SAYING THESE LOOK SIMILAR TO ONE ANOTHER. BUT THIS SEQUENCE IS 70 PERCENT OF HEALTH SQUARE-ACQUIRED INFECTIONS SO IT IS EQUALLY LIKELY YOU WOULD HAVE GOTTEN THAT SAME STRAIN TWICE, ONCE FROM NEW YORK, ONE FROM FLORIDA, YOU KNOW, INTO YOUR HOSPITAL, WHEREVER, AS YOU HAD GOTTEN TRANSMISSION. SO WE SEQUENCED THE PATIENT, THE INDEX PATIENT AND SHE HAD BEEN COLONIZED FOR SO LONG THAT WE ACTUALLY COULD GET BISOLATES FROM THE URINARY TRACT, THROAT AND SKIN INGUINAL AREA. AND WE SEQUENCED THIS 16 META GENOME AND FOUND THERE ARE FOUR DIFFERENT CHANGES TO THE GROIN AND THREE TO THE THE THREE. -- THE THROAT. SHE HAD BEEN COLONIZED FOR SO LONG, THOSE CHANGES OCCURRED WHILE SHE WAS COLONIZED SIX MONTHS WHICH ISN'T UNEXPECTED. YOU ARE EXPECTING TO SEE ONE NEW ONE PER MONTH BECAUSE WHILE THEY ARE REPLICATING THEIR BACTERIA, YOU WILL SEE SMALL ERRORS. SO WHEN WE LOOKED AT PATIENTS 1, 2, 3, 4, 5, AFTER ISOLATING PATIENT 1, WE SAW PATIENT 3 WAS AN IDENTICAL MATCH TO THE PATIENT 1 THROAT ISOLATE AND PATIENT 2 HAD A CHANGE. SO WE BASICALLY ARE SEQUENCING THESE AND SITTING DOWN WITH THE HOSPITAL EPIDEMIOLOGIST THE SAME WEEK AND SAYING WE THINK WE HAVE A MATCH BUT WE THINK IT'S -- BUT -- THEY THINK THERE IS A PROBLEM WITH OUR METHOD BECAUSE OUR GENETICS WOULD SAY PATIENT 1 TRANSMITTED TO 3 WHO THEN TRANSMITTED TO PATIENT 2 SO WE THINK WE HAVE A PROBLEM WITH OUR ALGORITHM AND WE'RE STILL WORKING ON IT. AND SHE SAYS BASED ON PATIENT TRACE DATA, WE RECORD WHAT WARD EVERY PATIENT WAS ON, WHAT BED THEY HAD, THERE IS A LOT OF TRACKING, THE VENTILATOR THEY USE, WHATEVER. SHE RECORDS WHAT ROOM THEY WERE ON AND IN FACT LOOKING AT THE DATA, PATIENT 1 WAS IN THE ICU TWICE AND OVERLAPPED BOTH TIMES WITH PATIENT 3. AFTER PATIENT 1 WENT BACK TO A REGULAR WARD IN THE HOSPITAL, PATIENT 2 CAME IN TO THE ICU AND OVERLAPPED WITH PATIENT 3. SO THIS WOULD SUGGEST THAT PATIENT 1 TRANSMITTED TO 3 WHO TRANSMITTED TO 2 WHICH WAS THEIR HYPOTHESIS ALSO AND THAT PATIENT 3 HAD BEEN ASYMPTOMATICALLY COLONIZED AND HAD NOT BEEN PICKED UP FOR QUITE A WHILE BUT THEN PATIENTHAD A CLINICAL CULTURE AND WAS PICKED UP. WE KEPT HAVING PATIENTS IDENTIFIED WITH THE KLEBSIELLA PNEUMONIAE OVER SIX MONTHS AND BASICALLY IF YOU JUST HAD THE PATIENT TRACE DATA, YOU WOULD HAVE THIS PLATE OF SPAGHETTI WHERE THERE WAS LIKE ALL THESE POSSIBLE CONNECTIONS BETWEEN THE PATIENTS BECAUSE A LOT OF THE SICKEST PATIENTS WERE COMING IN AND OUT OF THE ICU AND OVERLAPPING WITH EACH OTHER AND THERE WAS ALSO A LOT OF SHARED EQUIPMENT BEING USED WITH THE PATIENTS SO THERE WAS THIS WHOLE STORY DEVELOPING WHERE TWO PATIENTS USED THE SAME WOUND CART AND THAT MUST BE THE SOURCE OF TRANSMISSION BARGAINING UNIT WHEN WE INTEGRATED THAT WITH GENOMIC SEQUENCING, WHAT YOU CAN SEE IS THOSE SNPS THAT I WAS TALKING ABOUT, THE ONES THAT COME FROM THE GROIN AND THE THROAT, THOSE BASICALLY FORMED TWO SEPARATE CLUSTERS OF INFECTION AND BASICALLY THE THROAT ONE DIDN'T KEEP GOING AFTER THAT. BUT YOU CAN SEE EVEN LIKE THESE SNPS, YOU CAN SEE 12, 13, 18, THOSE PATIENTS ARE A NEW TYPE NODE OF -- YOU COULD REALLY SAY WHAT DO 12, 13 AND 18 HAVE IN COMMON BECAUSE THAT WAS CLEARLY A DIRECT TRANSMISSION AMONGST THOSE. SO WITH THIS KIND OF SEQUENCING, WE WERE ABLE TO IDENTIFY WHAT WERE THE LIKELY MODES OF TRANSMISSION AND A LOT OF THIS CAME DOWN TO REALLY INCREASED EDUCATION OF HOSPITAL PRACTICES, A LOT MORE HAPPENED WASHING BUT REALLY WHAT WE ENDED UP DOING WAS TO MOVE THE COLONIZED PATIENTS INTO A COHORTED AREA WHERE THOSE NURSES ONLY TOOK CARE OF THEM, THAT EQUIPMENT WAS NOT USED IN THE GENERAL POPULATION AND REALLY UP OUR GAME. SO THAT IS KIND OF A STORY ABOUT HOW IT SEEMS OPPORTUNISTIC BUT THAT IS THE KIND OF RESEARCH PROJECT THAT WE'RE ABLE TO DO HERE AT THE CLINICAL CENTER WHERE WE JUST LIKE, YOU KNOW, THERE'S A CLINICAL ISSUE, WE USED GENOMIC SEQUENCING AND THINK ABOUT HOW ARE WE GOING TO WORK TOGETHER ON THIS AND I HAD ONE OTHER LITTLE STORY AT THE END TO TELL. SO THIS WILL HELP REVOLUTIONIZE WHAT IT MEANS TO BE HEALTHY AND HUMAN AND TAKING CARE OF THE MICROBIAL COMMUNITIES THAT COLONIZE US AND I HOPE IT WILL GIVE US NEW INSIGHTS ON HOW TO FIGHT OUR MICROBAL FOES AND AS I THINK ABOUT THE BENEFICIAL MICROBES, I AM CONCERNED ABOUT THE INCREASE OF BOYS RESISTANCE WE'RE SEEING. AND I WILL JUST GO THROUGH THIS QUICKLY, SO WHAT IS DIFFERENT ABOUT THIS KIND OF WORK AND IN MY MIND, THE DIFFERENCE IN WHAT I DO IS REALLY PARTNERING WITH PHYSICIANS IN THAT I HOPE THAT WAS OBVIOUS FROM THE PROJECT BUT IT IS THIS KIND OF COMBINATION OF WHAT IS A GENOMIC APPROACH BUT HOW DO YOU ANSWER THAT IN A CLINICAL QUESTION. AND I KNOW THERE IS A LOT OF INTEREST IN TRANSLATIONAL RESEARCH AND A LOT OF SORT OF PUSH TO DO TRANSLATIONAL RESEARCH BUT THERE IS THIS SORT OF VALUE AND WHY IS IT SO HARD? WHY DON'T PEOPLE DO IT MORE OFTEN? SO HEIDI AND I ACTUALLY SAT DOWN ONCE WE STARTED WORKING TOGETHER AND STARTED THINKING WHY DID THIS WORK FOR US? SO WE CAME UP WITH A FEW IDEAS AND THE FIRST WAS LIKE HOW WE EVEN MET EACH OTHER AND THAT HAD TO DO WITH THESE CONNECTORS œWHERE WE WOULD LIKE TALK TO PEOPLE AND SAY THIS IS WHAT I WANT TO DO AND, YOU KNOW, THEY WOULD START US ON THESE, WELL, YOU SHOULD MAYBE MEET SO-AND-SO AND ACTUALLY BEING WILLING TO GO AND TALK TO PEOPLE OUTSIDE MY FIELD AND BE OPEN TO WHAT ARE THEIR IDEAS, WHAT ARE THE BIG QUESTIONS THEY ARE THINKING ABOUT. BUT YOU KNOW DOING IT WITH PEOPLE WHO ACTUALLY WILL TAKE THE TIME TO THINK ABOUT HOW ARE YOU, -- WHO ARE YOU, WHO WOULD YOU WORK WELL WITH. AND THEN HEIDI AND I STARTED A PILOT PROJECT TO DETERMINE IF WE WOULD WORK WELL AND THAT WAS KEY BECAUSE THERE ARE A NUMBER OF PEOPLE I WORKED ONCE WITH AND WOULD NOT WORK AGAIN WITH BECAUSE IT JUST NEVER ADDED UP. THEY WERE HANDING ME SOMETHING AND IT WAS LIKE SPIN THIS INTO GOLD AND I AM LIKE THAT DOESN'T WORK. OR YOU KNOW THEY WOULD DO SOMETHING ELSE LIKE WAIT, YOU DIDN'T CONSENT THE PATIENTS FOR THIS, YOU JUST LIKE -- I MEAN, NOT LIKE THAT BUT MORE LIKE, YOU KNOW, I DON'T KNOW, JUST DIDN'T HAVE LIKE A VIEW OF WHAT REALLY WAS POSSIBLE. OKAY AND THEN THE OTHER REASON TO DO IT, FOR HEIDI AND I, WE GOT IN EARLY. REALLY WHEN THE HUMAN MICROBIOME WAS GROWING IS WE KIND OF THOUGHT ABOUT IT LIKE WE COULD EACH HAVE HAD THIS TINY ST. LOUIS TINE -- TINY SLICE OF PIE AND GROW OURSELVES IN THIS MICROBIOME. SO WHERE IT HAS BEEN RELEVANT RECEIVED AND WHERE I SEE A DIFFERENCE, BEFORE I WORKED W ITH HEIDI, WE WOULD FIND THESE FORMS OF LIKE DERMATITIS AND WORK TO GET IT PUBLISHED AND NO ONE WOULD PICK IT UP BECAUSE I HAD NOT BROUGHT IT TO A POINT WHERE A CLINICIAN COULD USE THAT MODEL OR GLEAN ANYTHING FROM IT THAT EVER MIGHT BE USEFUL TO THEM IN THEIR CLINICAL PRACTICE OR SETTING UP A CLINICAL TRIAL. SO TALKING WITH HEIDI AND BAKING THAT INTO OUR STUDIES HAS REALLY BEEN USEFUL. SOMETIMES WE THINK ABOUT, LIKE IF WE HAVE NEW INFORMATION, LIKE YOU SAW THE CANDIDA AURIS STUDY, WE'RE SPENDING SO MUCH TIME MAKING MOUSE MODELS OF THIS BUT IN THE MEANTIME, WE SPUN OFF WE'RE THE CLINICAL ASSAY HERE AND HOW DO WE GET THIS TO THE PEOPLE WHO NEED IT, SETTING UP WHAT IS POSSIBLE AND DOING THE RESEARCH QUESTIONS. SO WHY NOT TEAM SCIENCE? IT IS REALLY DIFFICULT. AND HEIDI AND I WROTE ABOUT THIS. SHE WENT TO MEDICAL SCHOOL AND I WENT TO GRADUATE SCHOOL AND THE TRAINING IS SO DIFFERENT. I AM ALWAYS TRYING TO ENCOURAGE THE PEOPLE IN MY LAB LIKE WOULDN'T YOU WANT TO KNOW THE ANSWER TO THAT? AND HEIDI IS MORE LIKE WHEN I WALK INTO A ROOM TO SAMPLE THIS PATIENT, I NEED THIS, THIS, THIS AND THIS AND I AM LIKE I REALLY FEEL UNCOMFORTABLE GIVING PEOPLE ORDERS. BUT IF YOU HAVE SOMEONE WALKING IN AND THEY NEED THEIR BLOOD DRAWN, YES, YOU NEED TO GIVE PEOPLE ORDERS AND TELL THEM THIS IS THE CHECKLIST AND YOU HAVE TO DO THIS. SO WE HAD TO GET OVER THAT SORT OF STUFF AND IT TAKES A LOT OF TIME AND WE NEEDED TO LIKE CROSS TRAIN EVERYONE, THIS IS THE TUBE AND PRINTOUT ONE OF THOSE BAR CODES, THESE ARE THINGS THAT I HOPE YOU WILL -- YOUR GENERATION WILL SOLVE BECAUSE WE'RE FIGHTING THIS BUT I DON'T THINK SCIENCE RIGHT NOW IS REALLY SET UP FOR PEOPLE TO WORK TOGETHER IN TEAMS. THERE IS THIS IDEA THAT SCIENTISTS ARE LIKE THESE LOAN INDIVIDUALS WHO -- -- LONE INDIVIDUALS THAT SIT IN THEIR LABS AND ASK QUESTIONS. NOTHING I HAVE SHOWN YOU TODAY IS ME SITTING DOWN WORKING ON THE COMPUTER AND PERUSING THROUGH THOSE BEAUTIFUL FIGURES. SCIENCE IS A TESTIMONY AND REALLY ALL ABOUT HOW PEOPLE CAN WORK TOGETHER. BUT YOU KNOW, WE HAVE HAD TO BE VERY TACTICAL ABOUT HOW WE WORK TOGETHER AND ESPECIALLY BECAUSE THE TWO CLINICIANS I WORKED WITH MOST CLOSELY ARE ON TENURE TRACK AND I HAVE TENURE SO I HAVE TO MAKE SURE THAT EVERYTHING IS ABOUT HIGHLIGHTING THEIR ROLE, BECAUSE TOO OFTEN PEOPLE THINK WELL, YOU JUST RUN THE SAMPLES AND HEIDI DESIGNS THE STUDIES OR THEY WILL SAY, WELL YOU ARE THE EXPERT ON THE SKIN MICROBIOME AND SHE JUST ACQUIRES THE SAMPLES AND NO MATTER WHAT THEY ARE SAYING, THEY ARE DISCOUNTING THE CONTRIBUTION TO THE BOTH OF US TO THIS PROJECT AND I WON'T GET INTO IT BUT THERE HAVE BEEN TIMES WHEN PEOPLE HAVE CONFUSED ME WITH A DOCTOR AND ASKED ME FOR MEDICAL ADVICE. NOW I LOOK AT THEM LIKE OOH, THAT LOOKS BAD, I WOULD TALK TO A DOCTOR BECAUSE THEY ALWAYS WANT ME TO TELL THEM WHAT IS WRONG WITH THEIR SKIN AND I AM LIKE I DON'T KNOW, LOOKS LIKE POISON IVY TO ME AND THEY ARE LIKE WELL, I HAVE HAD IT SINCE I WAS 7 AND WELL, IT LOOKS LIKEPOISON POISON IVY. SO THESE ARE THE PEOPLE WHOSE WORK I REALLY HAVE VALUED AND WORKED WITH AND MY LAB, THIS WAS OUR ANNUAL HIKE AND I AM HAPPY TO TAKE QUESTIONS IF PEOPLE HAVE THEM. [APPLAUSE] >> AND YOU CAN BE SCIENTIFIC OR NOT. ARE WE JUST GOING TO SIT HERE? OH, GOOD. [ OFF MIC ] >> HAVE I EVER WORKED WITH A MD/PHD AND HOW IS THAT DIFFERENT. I HAVE ONE IN MY LAB RIGHT NOW. HAD ANOTHER MD IN MY LAB AND I DON'T THINK I CAN ANSWER EXACTLY THAT QUESTION BUT I WILL TELL YOU A RELIED QUESTION -- RELATED QUESTION TO THAT. I HAVE BEEN WITH LAB PHD/MDS AND THEY WILL JUST SAY THINGS. HEIDI AND I ARE LIKE TWO BODIES AND IT HAS THIS ADVANTAGE THAT WHEN WE TALK ABOUT THINGS, WE HAVE TO EXPLICITLY HAVE THOSE CONVERSATIONS, LIKE AN MD/PHD MIGHT HAVE AN IDEA ABOUT THE HYGIENE HYPOTHESIS AND SAY SOMETHING IN LAB MEETING BUT AT LAB MEETING, I WILL BE LIKE HEIDI, DO YOU BELIEVE IN THE HYPOTHESIS AND SHE WILL GO HERE IS WHAT I DO AND WHY I DON'T BELIEVE IN IT AND SO WE HAVE EXPLICIT CONVERSATIONS AND THINK WE'RE TRAINING PEOPLE TO BE ABLE TO HAVE THOSE CONVERSATIONS BUT IN TERMS OF BEING AN MD PHD, I MEAN, IT IS AWESOME, IT IS JUST A LONG ROAD AND IT, YOU KNOW, IF THAT IS IN YOUR FUTURE, THAT IS GREAT. I THINK FOR HEIDI AND I, IT HAS ALLOWED US BOTH TO HAVE CLINICAL RESEARCH AS PART OF OUR PORTFOLIO BUT ALSO WE OFTEN THINK ABOUT IT LIKE WE BOTH WORK LIKE 50 HOURS A WEEK AND SPEND FIVE TOGETHER AS AN MD/PHD AND, YOU KNOW, RAISE KIDS AND HAVE LIVES AND YOU KNOW, WITH AN MD/PHD, YOU HAVE TO KEEP BOTH THOSE PRACTICE GOING AT THE SAME TIME AND THIS IS THE WAY TO HAVE THAT INTELLECTUAL WORKLIFE WITHOUT HAVING THE 100-HOUR WORKWEEK. [ QUESTION OFF MIC ] >> WHO OWNS IDEAS? YOU KNOW, THERE ARE CON CONFLICTS LIKE THAT AND I HAVE SEEN THAT WHEN WE HAD PEOPLE BE COFIRST AUTHORS ON PAPERS AND I THINK -- THEY AGREE TO BE COFIRST AUTHORS AND PEOPLE WANT TO BE THE FIRST OF THE COFIRST AND IT IS LIKE -- AND I THINK THERE IS THIS IDEA -- I GUESS THERE ARE A LOT OF IDEAS THAT PEOPLE CAN INDEPENDENTLY COME TO MORE OR LESS AT THE SAME TIME. THERE ARE IDEAS THAT DO JUST FLOAT. AND SO, YOU KNOW, LIKE THE IDEA OF BRINGING THE PEOPLE BACK AND SAMPLING THEM AGAIN A YEAR LATER, A MONTH LATER, YOU KNOW TWO, PEOPLE, THREE PEOPLE COULD HAVE THOUGHT THEY HAD THAT IDEA AND YOU CAN LOOK BACK AND SEE THAT I WROTE THAT IN A GRANT TWO YEARS AGO AND THEN FORGET ABOUT IT. SO WHO OWNS THESE IDEAS? IT IS LIKE THERE IS SOMETHING TO THAT BUT IT IS ALSO LIKE, YEAH, WHO IS GOING TO GET THE PROJECT DONE AND OWNING IDEAS, IT'S... YOU KNOW, SHARING IDEAS IS GREAT, TOO. SO YEAH, WE HAVE THOSE ISSUES AND I OFTEN DEAL WITH IT IN A VERY FORMAL WAY BECAUSE I THINK THERE'S A LOT OF THAT, THAT PEOPLE DON'T, YOU KNOW, I DON'T THINK IT IS IDEAS AS MUCH. I THINK PEOPLE UNDER RECOGNIZE HOW MUCH WORK I PUT INTO DEVELOPING A COMPUTATIONAL FRAMEWORK TO ANALYZE SAMPLES BUT I THINK PEOPLE UNDERVALUE HOW MUCH HEIDI PUTS INTO, YOU KNOW, LIKE REALLY CLEANLY DEFINING A PATIENT POPULATION. SO YEAH, I FEEL LIKE A LOT OF TIMES PEOPLE FEEL LIKE THEIR IDEAS ARE UNDERVALUED AND WE SHOULD BRING THAT OUT MORE INTO THE LIGHT. [ QUESTION OFF MIC ] >> RIGHT, THERE ARE HIGH RISK HPV'S, HOW THEY ARE DISCUSSED CLINICALLY IN CERVICAL CANCER AND THEY ARE BY AND LARGE THE ALPHA HPV'S AND THE RISKING THERE IS THEY HAVE INTEGRATED INTO THE HUMAN GENOME AND BROUGHT WITH THEM STRONG PROMOTERS WHICH MAY ACTIVATE GENES IN THE REGION AND UNCONTROLLED PROLIFERATION AND WE DIDN'T FIND ALPHA HPV'S ON THE SKIN ALTHOUGH WE HAVE REALLY BEEN LOOKING FOR THEM BECAUSE THERE ARE SOME CASES OF PATIENTS HAVING KWAME SQUAMOUS CELL CARCINOMA. CERVICAL TISSUE AND SKIN ARE REALLY THE ONLY TWO STRAT IFIED, QUANTIFIED EPITHELIA SO IT IS SOMETHING THAT NO ONE OWNS BUT WE HAVE BEEN LOOKING FOR THAT AND HAVEN'T FOUND IT. [ QUESTION OFF MIC ] >> YOU KNOW I THINK A LOT OF IT -- I ACTUALLY AM CONCERNED ABOUT EARLY CHILDHOOD PERIODS AND TRYING TO THINK ABOUT WHEN WE USE ANTIBIOTICS ON A LOT OF THE CHILDHOOD RESPIRATORY INFECTIONS ARE VIRAL YET PARENTS WANT ANTIBIOTICS AND DOCTORS WANT TO GIVE YOU ANTIBIOTICS SO I THINK A LOT OF MY INTEREST IS IN THESE EARLY YEARS AND KIND OF UNDERSTAND MICROBIAL SUCCESSION. AND THEN AFTER THAT, I MEAN, YOU KNOW, I WOULD SAY TRY TO AVOID USING ANY YOU KNOW ANTIMICROBIAL PRODUCTS AS MUCH AS POSSIBLE. I DON'T MYSELF UNDERSTAND WHY WE AS AMERICANS ARE SO OBSESSED WITH THESE ANTIMICROBIAL PRODUCTS THAT SOAP WOULD HAVE ANTIMICROBIALS IN IT. LIKE WHAT IS THE MATTER WITH JUST SOAP? WE WANT TO COLONIZE OUR GUTS BUT ON THE SKIN DESTROY ALL OUR MICROBES? SO JUST BEING AWARE OF WHEN YOU ARE USING ANTIMICROBIAL PRODUCTS AND BESIDES THAT, TO LIKE THINK ABOUT TAKING CARE OF YOUR MICROBIAL COMMUNITIES BUT PROBABLY ANTIBIOTICS WHICH SHOULD BE USED IF YOU HAVE A TESTED INFECTION BUT YOU KNOW OTHERWISE TO THINK ABOUT NOT REACHING FOR ANTIBIOTICS. >> OKAY, LAST QUESTION. [ OFF MIC ] >> RIGHT, SO WE DO THAT FOR MRSA. YOU COME INTO THE HOSPITAL, HAVE A NOSE SWAB AND WITHIN 6 MINUTES, THEY HAVE A VERY GOOD PCR TO TELL YOU WHETHER OR NOT YOU ARE COLONIZED WITH MRSA -- 60 MINUTES. THERE IS VERY LITTLE MONEY TO BE MADE IN INFECTION CONTROL AND, YOU KNOW, THESE SORT OF TESTS OF ORGANISMS ARE YOU COLONIZED BY. WE'RE DEVELOPING THESE BECAUSE THE MICROLABS THAT HAVE TO PROCESS HUNDREDS OF THOUSANDS OF CULTURES ARE JUST OVERWHELMED. SO YEAH, WE'RE -- IT WOULD NOT BE US BUT IT WOULD BE OUR COLLEAGUES WHO WOULD REALLY BE DEVELOPING THIS AS KIND OF A VERSION OF THE PCR-BASED ASSAY THAT EVERY HOSPITAL COULD RUN. OKAY, THANKS.