>> I WANT TO THANK YOU FOR BEING HERE PARTICULARLY WANT TO THANK THE PEOPLE FROM THE WEST COAST FOR EVEN BEING AWAKE SINCE IT'S 4:30 IN THE MORNING FOR YOU BUT I WANT TO THANK YOU FOR TAKING TIME FROM OBVIOUSLY VERY BUSY LIVES. YOU ARE NOT A RANDOM ASSORTMENT OF FOLKS. WE GATHERED PEOPLE WHO WE KNEW HAVE RATHER BUSY OTHER LIVES THAT'S WHY YOU'RE HERE. I WANT TO THANK YOU FOR BEING HERE BUT I WANT TO THANK A NUMBER OF YOU IN THE ROOM ARE THE REASON WHY WE ARE HERE. IF IT WERE NOT FOR YOUR CAREERS, AND YOUR INVESTMENT OF TIME, ENERGY, INTELLECT OVER DECADES IN SOME CASES, WE WOULD NOT HAVE THE SCIENTIFIC OPPORTUNITY THAT CURRENTLY PRESENTS ITSELF TO US AND SOME OF THE CHALLENGES AS WELL THAT WE'RE HERE TO THINK ABOUT OVER THE NEXT COUPLE OF DAYS. SO WE ARE OF COURSE BUILDING ON THE FOOT STEPS OF THOSE WHO HAVE BEEN WORKING IN THIS AREA FOR SO LONG. BUT WE'RE NOT HERE TO SIMPLY THANK AND CONGRATULATE YOU FOR THE GREAT INSIGHTS THAT YOU'VE HAD. WE'RE HERE IN FACT TO SAY, CAN WE DO SOMETHING MORE? AND BY MORE WE DON'T JUST MEAN, MORE OF THE SAME, BUT CAN WE BRING TO BEAR SOME NEW TOOLS, APPROACHES, OTHER KINDS OF THICKS TO THE UNDERSTA OF THE PLACENTA IN A WAY THAT WILL REALLY CHANGE THAT UNDERSTANDING AND ALLOW US TO APPLY IT TO BASIC PROBLEMS AND BIOLOGY BUT ALSO TO IMPROVE IN HUMAN HEALTH IN WAYS WE'VE NEVER BEEN ABLE TO BEFORE. IN FACT THERE ARE SOME PEOPLE IN THIS ROOM THAT WE HAD TO SORT OF DRAG HERE BECAUSE YOU KEPT HAVING THE IMPRESSION THAT WE HAD SOMEHOW CONFUSED YOU WITH SOMEBODY ELSE WITH THE SAME NAME OR SOMETHING THAT YOU KNOW, WHAT WERE YOU DOING IN THE MEETING ABOUT THE PLACENTA? YOU'RE ONLY ATTACHMENT HAD EVER BEEN ONCE MANY, MANY YEARS AGO. IN SOME CASES, A LITTLE BIT MORE RECENTLY, YOU HAD OTHER IN THE PLACENTA BUT THAT WAS NOTHING YOU EVER THOUGHT ABOUT VERY MUCH AND THAT'S WHY SOME OF YOU ARE HERE. WE WANTED TO HAVE SOME FOLKS HERE WHO WE THOUGHT WERE GREAT THINKERBIOLOGY AND HEALTH WHO HAD NOT SPENT MUCH TIME THINKING ABOUT THE PLACENTA TO COME IN WITH DIFFERING PERSPECTIVES TO HELP US THINK ABOUT THOSE THINGS WE WOULDN'T THINK ABOUT OTHERWISE AND I'VE BEEN ASKED, YOU KNOW, SO WHY A HUMAN PLACENTA PROJECT? IT IS BECAUSE, AS MANY OF YOU IN THE ROOM KNOW, IT'S BECAUSE THE HUMAN PLACENTA IS REALLY THE LEAST UNDERSTOOD HUMAN ORGAN AND ARGUABLY ONE OF THE MORE IMPORTANT. AND AS WE'RE LEARNING MORE AND MORE RECENTLY NOT JUST FOR MATERNAL AND FETAL WELL BEING BUT FOR THE LIFE LONG HEALTH OF BOTH MOTHER AND CHILD THAT RESULTS FROM THE PREGNANCY. AND ALSO WE THINK HAS THINGS TO TELL US ABOUT OTHER ASPECTS OF BIOLOGY, WHETHER IT'S PROGRAM CELL DEATH, OBVIOUS IMPLICATIONS FOR CANCER AND OTHER THINGS ABOUT THE REALLY UNIQUE IMMUNE FUNCTION OF THIS ORGAN THAT CREATES THE SYMBIOTIC REQUIREMENT AND WHAT IT SAYS ABOUT OTHER FORMS OF THE NEW FORM, ET CETERA. IN FACT THE IDEATION FOR THIS CAME FROM OUR SCIENTIFIC WORKSHOPS THAT NICHD HAD A FEW YEARS AGO AND SOME OF YOU PARTICIPATED AND 10 OR 11 DIFFERENT WORKSHOPS AND DIFFERENT THINGS, THE PLACENTA CAME UP IN THE MOST DIFFERENT I HAD THIS FEELING BY THE END OF THE WORKSHOPS, THOSE OF YOU--I DON'T OFTEN COMPARE MYSELF TO A YOUNG DUSTIN HOFFMAN BUT BY THE END OF THOSE MEETINGS, I FELT LIKE DUSTIN HOFFMAN AND THE GRADUATE AND YOU MAY REMEMBER THE FAMOUS SCENE WHERE THEY'RE OUTSIDE IN AN OLDER GENTLEMAN SAYING TO HIM, I WANT TO SAY ONE WORD TO YOU, JUST ONE WORD: PLATTICS. THERE'S A GREAT FUTURE IN PLASTICS. AND I FELT LIKE I WAS GETTING THE SAME MESSAGE BUT IT WASN'T THE PLASTICS, IT WAS PLACENTA. WHAT A DIFFERENCE A FEW LETTERS MAKES. OVER AND OVER AGAIN, THIS KEPT COMING UP AS A SCIENTIFIC OPPORTUNITY, SO ALONG WITH OUR ADVICERY COUNSELS AND I WILL OTHERS, WE'VE BEEN THINKING FOR SOMETIME ABOUT HOW CAN WE PULL THIS TOGETHER. AND THAT'S REALLY THE REASON FOR THIS MEETING. WE BELIEVE THAT THERE IS A SCIENTIFIC OPPORTUNITY RIGHT NOW BECAUSE OF THE CURRENT STATE OF KNOWLEDGE ABOUT THE PLACENTA AND BECAUSE OF SOME OF THESE NEWER APPROACHES, ET CETERA, THAT IF WE HAVE A COORDINATED APPROACH, THIS DOES NOT MEAN THIS SHOULD ALL BE TOP DOWN SCIENCE AND INVESTIGATOR INITIATED WORK INTO THE PLACENTA THAT SHOULD CONTINUE BUT THERE ARE CHANCES IN A COORDINATED KIND OF WAY TO SET SOME SPECIFIC GOALS AND OBJECTIVES, IDEALLY, THE ULTIMATE GOAL WOULD BE ABLE TO STUDY AND MONITOR PLACENTAL STRUCTURE AND FUNCTION IN THE HUMAN IN REALTIME, WHICH IF WE COULD DO THAT, OBVIOUSLY WOULD HAVE MUCH TO TELL US NOT JUST ABOUT THE PLACENTA BUT OTHER APPLICATIONS AND BIOLOGY AND HEALTH BUT THAT KIND OF THING, SO REALLY OUR GOAL OVER THE NEXT KIND OF DAY SYSTEM TO HEAR IDEAS AND THEN VERY MUCH IN THE BREAK OUT GROUPS TO BE VERY CREATIVE IN THINKING ABOUT WHERE DO WE WANT TO GET AND TO THINK ABOUT ACTUAL STEPS TO GET THERE. WE WANT TO BE BASED IN REALITY IN DO THANKSGIVING BUT AT THE SAME TIME WE WANT TO SPEND THE ARC OF FUTURE REALITY IN A WAY WE THINK IT WOULD TAKE A COORDINATED APPROACH OF THINKERS LIKE YOU TO TRY TO HELP US FIGURE OUT. UNDOUBTEDLY WILL BE AN ITERATIVE PROCESS. WE DON'T EXPECT TO WALK AWAY TOMORROW WITH A COMPLETE ROADMAP OF WHAT YOU FUTURE SHOULD LOOK LIKE IN PLACENTAL STUDIES BUT WE DO HOPE WE WILL HAVE A PRETTY GOOD ROADMAP COMING OUT AND ONE WE CAN PARTICULAR TO PERFECT AS WE GO FORWARD. SO I GUESS MY LAST INSTRUCTION TO YOU OR SOMETHING IS TO BE AMBITIOUS OVER THE NEXT COUPLE OF DAYS, TO THINK BOLDLY, TO THINK CREATIVELY TO TALK ABOUT THE KINDS OF THINGS YOU WOULD LIKE TO BE ABLE TO DO IF ONLY WE HAD THE TECHNOLOGY OR THE SOMETHING TO DO THAT. WHAT ARE THE KEY THINGS WE LACK? AND HOW MIGHT WE ACTUALLY CONSTRUCT THOSE THINGS? SO THAT WE WOULD NO LONGER LACK THEM, BUT INSTEAD COULD BE APPLYING THEM. THAT'S REALLYY WHAT WE WANT YOU TO BE THINKING ABOUT. IT SHOULD BE A GREAT TIME. NO IDEA IS TOO CRAZE TOW BRING UP IN THIS COUPLE DAYS, I HOPE, SO FEEL FREE TO DO THAT AND WE WILL TRY TO BE BASE INDEED REALITY BUT SOME OF IT BE BASED IN THE FUTURE REALITY RATHER THAN A PRESENT ONE. SO THANKS AGAIN FOR BEING HERE, I WILL TURN IT OVER TO CATHY SPAWN, DIRECTOR OF EXTRAMURAL PROGRAMS AT NICHD WHO HAS BEEN A PRIME ARCHITECT AT THIS MEETING BUT THE PLACENTA AND HOW WE PLIGHT STUDY IN THE FUTURE IN GENERAL, SO CATHY IT'S ALL YOURS. >> THANK YOU SO MUCH ALAN AND I TIETH TO WELCOME YOU. I KNOW HOW MUCH CAJOLING IT TOOK A COUPLE OF YOU TO COME AND I REALLY LOOK FORWARD TO GAINING THE EXPERTISE OF EVERYONE IN THE ROOM. THOSE WHO SPENT A LIFETIME OF WORK ON THE PLACENTA AND THOSE WHO OF YOU WHO HAVE NOT HAD A HUGE AMOUNT OF WORK IN THE PLACENTA SENT AALBIET MANY, MANY YEARS AGO, PERHAPS. THE GOAL OF THIS WORKSHOP AND THE GOAL OF THE HUMAN PLACENTA PROJECT IS TO DEVELOP WAYS TO MEASURE AND UNDERSTAND THE STRUCTURE AND FUNCTION OF THE PLACENTA IN REALTIME AND THE KEY HERE IS IN REALTIME, MEANING DURING THAT PREGNANCY. AND THAT'S A CONCEPT THAT WE ALL WOULD LOVE TO BE ABLE TO ACHIEVE BUT IS SOMETHING WE HAVE NOT BEEN ABLE TO ACHIEVE TO DATE. AND I THINK, YOU KNOW WE HAVE THE ABILITY AND THE TECHNOLOGIES IN OTHER FIELDS THAT WE CAN APPLY TO THE PLACENTA PERHAPS AND BE ABLE TO MOVE IN AREA FORWARD. AS IS LISTED IN THE AGEND AI WANT TO GO OVER THE OVERALL OBJECTIVES WE DEVELOPEDOT HUMAN PLACENTA PROJECT AND I WANT TO WELCOME YOU DURING THE NEXT TWO DAYS TO MAKE RECOMMENDATIONS TO THOSE OBJECTIVES, MODIFICATIONS IF DESIRED, PERHAPS ADDING THINGS TO THEM. THESE INCLUD IMPROVING CURRENT METHODS AND DEVELOPING TECHNOLOGIES OF REALTIME ASSESSMENT OF PLACENTAL DEVELOPMENT AND APPLYING THESE TO UNDERSTAND AND MONITOR IN REALTIME, PLACENTA DEVELOPMENT AND FUNCTION IN BOTH NORMAL AND ABNORMAL PREGNANCIES. DEVELOP AND EVALUATE NONINVASIVE MARKERS FOR PREGNANCY OUTCOMES, UNDERSTAND THE CONTRIBUTIONS OF PLACENTAL DEVELOPMENT OF LONG-TERM HEALTH AND DISEASE AND ULTIMATELY DEVELOP INTERVENTIONS TO DEVELOP ABNORMAL DEVELOPMENT AND ENHANCE IMPROVE PREGNANCY OUTCOME. WHAT WE'RE HOPING WITH THIS WORKSHOP IS TO GENERATE A ROADMAP FOR WHAT THE HUMAN PLACENTAL WORKSHOP SHOULD LOOK LIKE IN ORDER TO MEET THESE GOALS AND WE DO ANTICIPATE THIS MEETING IS SIMPLY A BEGINNING OF WHAT WE ANTICIPATE IS GOING TO BE A MUCH LARGER EFFORT. WE ARE VIDEOTAPING THIS CONFERENCE, THE LARGER SESSIONS SO THAT THOSE WHO COULD NOT BE HERE, THERE'S BEEN A LOT OF INTEREST IN THIS MEETING, ARE GOING TO BE ABLE TO VIEW IT AND PROVIDE US FEEDBACK AS L. AND WE ENCOURAGE TO YOU HAVE OTHERS VIEW THE WORKSHOP SO THAT WE CAN GET THEIR INPUT AS WELL. AS ALAN MENTIONED WE BROUGHT TOGETHER BOTH PEOPLE WHO HAVE RESEARCHING PLACENTA AS WELL AS PEOPLE WITH EXPERTISE OUTSIDE OF THE PLACENTA WITH A HOPE THAT BRING THE TWO TOGETHER, WE WILL MOVE THE FIELD FORWARD. REALIZING THAT WE WILL START THE MORNING AND WORKSHOP WITH THREE LECTURES TO KIND OF PROVIDE THE BASIS AND BACKGROUNDOT PLACENTA FOR THOSE OF YOU WHO MAY NOT HAVE THAT EXPERT OOZE AND TO FRESHEN UP OUR PLACENTAL KNOWLEDGE AND UNDERSTANDING FOR THOSE WHO OF US WHO MORE OF A KNOWLEDGE OF THE PLACENTA.NG THAT THE ENTI RE STRUCTURE OF THE MEETING WILL BE A SERIES OF PANEL PRESENTATION, FOLLOWED BY BREAK OUTS AND IT'S AT THOSE BREAK OUT SESSIONS THAT THE BULK OF THE WORK WILL BE DONE. THERE WILL BE A SERIES OF QUESTIONS THAT THOSE BREAK OUT GROUPS WILL BE ADDRESSING AND THEY WILL BE DEVELOPING A PRESENTATION THAT WILL COME BACK TO THE LARGER GROUP FOR THE INPUT OF THE LARGER GROUP BECAUSE WE KNOW THAT MANY OF YOU HAVE EXPEREASE IN DIFFERENT AREAS OF THOSE BREAK OUT GROUPS SO WE WANT YOUR INPUT ON ALL OF THEM. SO WE WILL HAVE PRESENTATIONS FROM EACH BREAK OUT GROUP TO THE LARGER GROUP FOR YOUR INPUT AS WELL. AT THE END WE'RE HOPING TO COME TOGETHER AND DESIGN AND DEVELOP THE HUMAN PLACENTAL PROJECT BEFORE WE MOVE TO THE INTRODUCTIONS OF EACH OF US IN THIS ROOM, I'D LIKE TO THANK A NUMBER OF PEOPLE WHO HAVE MADE THIS MEETING POSSIBLE. THEY'RE INVALUABLE ASSISTANCE AND BEHIND THE SCENES WORK HAS BEEN JUST INCREDIBLE. MISS KRISTI ROGERS, MISS ROSA LYNNA BRAE AND CAROLINE SIGNORE, OTHERS, THANK YOU FOR YOUR HARD WORK. WITHOUT ALL OF YOU WE WOULD NOT BE HERE AND HAVE A WONDERFUL MEETING PUT TOGETHER. I WANT TO WELCOME SEVERAL SCIENCE JOURNALISTS, SARRA REARAND DENISE GRADE FREE RADICALS THE NEW YORK TIMES, WELCOME, WE ARE HAPPY TO HAVE YOU WITH US. I ALSO WANT TO LET YOU KNOW WE WILL HAVE INHOUSE VIDEOTAPING TOMORROW. KERRY CHILDRESS OR KATIE RUSH FROM THE NICHD COMMUNICATIONS TEAM MAY APPROACH YOU WITH A COUPLE OF QUESTIONS. IF YOU COULD TAKE A MOMENT TO SHARE WITH THEM YOUR THOUGHTS ABOUT THE HUMAN PLACENTA PROJECT. NOW GIVEN THE DIVERSE GROUP THAT WE HAVE IN THE ROOM, YOU MAY NOT KNOW EVERYONE AND SO WHAT WE WOULD LIKE TO DO IS HAVE EVERYONE BRIEFLY INTRODUCE THEMSELVES, JUST YOUR NAME, YOUR AFFILIATION AND YOUR AREA OF SCIENTIFIC EXPERTISE AND THEN PRESENTATIONS WILL START AT EIGHT. SO THIS WILL BE A NICE LITTLE BRIEF INTRODUCTION. DO WE HAVE A WALKING MIC? WONDERFUL. THANK YOU. >> AGAIN I'M CATHY SPONG, I'MAN OBSTETRICIAN GYNECOLOGIST WITH MATERNAL FETAL MEDICINE AND MY INTEREST IS ALL OF THAT. GIL MOR . I'M WITH YALE UNIVERSITY AND IN PRODUCTIVE TECHNOLOGY. >> I'M MIC GILL MER, STUDYING PLACENTAL FUNCTION AND METABOLISM FOR MANY YEARS NOW. SALLY COLLINS. FROM THE UNIVERSITY EVER OXFORD, STUDYING IMAGING IN THE PLACENTA FOR A LITTLE WHILE NOW. BRIAN COX. BRIAN COX FROM UNIVERSITY OF TORONTO, I WORK ON HYPER TENSIVE DISORDERS OF PREGNANCY. DEPUTY DIRECTOR OF NICHD. >> CONSTANTINE AND DIRECTOR FOR INTRAMURAL LABS HERE. SUSAN FISHER. ISM A LIFER WITH IT IS PLACENTA BUSINESS AND WE STUDY NORMAL AND ABNORMAL PLACENTA BOTH AND TRY TO FIGURE IT OUT AND I'M FROM THE UNIVERSITY OF CALIFORNIA SAN FRANCISCO. DIANA BIANCHI. MY INTERESTS ARE IN PRENATAL DIAGNOSE AND I GUESS FETAL THERAPY. --DIAGNOSIS AND FETAL THERAPY. >> I'M FROM UNIVERSITY OF CAME BRIDGE, I STUDY PLACENTAL DEVELOPMENT AND I THINK I'M ALSO A LIFER. >> I'M WITH THE PREGINANC PREG--PREGNANCY BRANCH AND DEALING WITH GENETICS AND THINGS LIKE THAT. DAVID WEINBERG. I'M WITH NICHD AND I REACH OUT AND ASK YOU TO HELP ME AND WORK WITH ME ON BACKGROUND METABOLIC DISORDERS. GILMAN GRAVE. INTERESTED IN NUCLEOTIDES--NUTRIENT SUPPOR T FOR THE PLACENTA. >> GOOD MORNING, I'M SITTING NEXT TO THE NICHD PEOPLE HOPING FUNDING ROLLS OFF. THANKS FOR LAUGHING. KOJI YOSHINAGA. I WORK ON UTERINE FUNCTIONING AND IMPLANTATION BIOLOGY. >> I'M MIKE VANNER AND I'M INTERESTED IN CLINICAL TRIALS AND INTERGENERATIONAL OBSTETRIC PROBLEMS. >> I STUDY SMALL PRIMATES TERM BIRTH STARTING OUT WITH OMICS TECHNOLOGIES. >> GOOD MORNING KIM LESLIE FROM THE UNIVERSITY EVER IOWA, I STUDY CANCER AND THIS LADY SENDS ME. >> I'M WEI ZANNG, AND I'M WITH IMAGING AND MARKER IMAGING. >> TOP OF THE MORNING TO YOU, MIKE NELSON WASHINGTON UNIVERSITY IN ST. LOUIS, I DELIVER LOTS OF BABIES BECAUSE I TRAIN AND I'VE BEEN STUDYING THE PLACENTA FOR 40 YEARS SO GRAHAM BURTON AND SUSAN FISHER ARE NOVICES FOR THE LENGTH OF TIME OR THEY'RE YOUNG PEOPLE COMPARED TO MEET. >> GOOD MORNING, KIMBERLY GRAY, FROM NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES, PROGRAM DIRECT FOR FOR THE NIEHS AT EPA CHILDREN CENTERS SO HERE ON BEHALF OF OUR INSTITUTE AND GREAT INTEREST IN THE MECHANISM OF BIOLOGY, MAYBE INFLUENCE OF ENVIRONMENTAL EXPOSURES ON HEALTH OF THE MOTHER AND THE CHILDREN. JOCELYN KAISER. REPORTER WITH SCIENCE MAGAZINE. >> KRISTI ROGERS, SPECIAL ASSISTANCE TO DR. GUTTMACHER. >> I'M MIKE SORES AND UNIVERSITY OF KANSAS MEDICAL CENTER AND I STUDY PLACENTAL DEVELOPMENT. >> I'M WITH THE CHEMISTRY AND RESEARCH MEDICAL BRANCH FROM THE UNIVERSITY OF TEXAS. MY SPECIALTY IS ANIMAL MEDICINE. >> I'M PETER BASSER ON PETEIAD ON--PEDIATRIC TISSUE AND IMAGING. MAHMOUD AHMED. WE ARE INTERESTED IN UNDERSTANDING FETAL EXPOSE TOWER GENOBIOTICS AND MEDICATION, SPECIALLY MEDICATION AT THIS TIME. THANK YOU. >> CARL P A LLINEAN E AND I'M WITH IMAGES AND QUANTITATIVE MATTERS. >> I'M JOHN, I'M AT THE HOSPITAL FOR SICK CHILDREN IN TORONTO AND MY RESEARCH INTERESTS NEAR MRI, X-RAYS, CT, PLACENTA AND OTHER ORGANS. JAMES COULOMBE. PROGRAM OFFICER AT NICH D AND I HANDLE A PORTFOLIO OF DEVELOPMENTAL GENETICS AND DEVELOPMENTAL SYSTEMS BIOLOGY, I'M TRAINED AS A DEVELOPMENT DEVELOPMENTAL BIOLOGIST. SO IT FITS. ISABELLE PETER. I AM STUDYING SEA URCHIN GUTS BUT WHAT IS RELEVANT HERE IS I AM STUDYING HOW GENE REGULATORY NETWORKS DETERMINE HOW TO FORM COMPLEX ORGANS FROM PRECURSOR CELLS, WHAT CELLS THESE ORGANS CONSIST OF AND WHAT GENES THAT EXPRESS. JOSH ZIMMERBERG. DIRECTOR OF PHYSIOLOGY PROGRAM AT THE INTRAMURAL STUDY AND THE THINGS WE STUDY WITH PLACENTA MOSTLY DO WITH THE MEMBRANE FUSION, TROPOBLAST FUSION AND WE STARTED A NEW PROJECT WITH ROBERTO ROMERO TO LOOK AT THE MOLECULAR ANATOMY OF PLACENTA BIOPSIES. GEORGE SIBERRY. >> PEDIATRIC DISEASE SPECIALIST FOCUSING ON MA TERN AFRONS TRANSMISSION OF HIV AND OTHER INFECTIONS. >> I'M THE CHIEF OF THE MEDICINE BRANCH AND I'M AN OBGYN. >> I AM WITH THE OBGYN AND MEDICINE, I STARTED MY MEDICAL LIFE IN THE PLACENTAL CLASS PROJECT AND CHAIRING THE SCHOOL IN THE [INDISCERNIBLE] IN THE EARLY 70S. MY INTEREST CONTINUES TO BE IN THE [INDISCERNIBLE], INVOLVED IN IT AND STILL RESEARCH THE PLACENTAL AREA. THANK YOU. ELIZABETH HILLMAN. >> I'M FROM YALE UNIVERSITY AND I WORK ON THE VASCULAR ENDOTHELIUM AND DEVELOPED ALL KINDS OF DIFFERENT TOOLS FOR DOING IN VIVO MICROSCOPY, PROFUSION AND CELLULAR FUNCTION AND METABOLISM ALL THE THINGS UP TO [INDISCERNIBLE], I PRODUCED TWO PLACENTAS IN THE LAST FIVE YEARS ALONG WITH TWO BEAUTIFUL LITTLE BOY WHICH IS MADE WE UTTERLY OBSESSED WITH ALL THINGS LABOR AND DELIVERY AND, BRAIN DEVELOPMENT, PREGNANCY, ALL OF IT SO I'M PLEASED TO BE HERE, THANKS. >> [INDISCERNIBLE]. [LAUGHTER] MIKE VARNER. JOE LEIGH SIMPSON. >> I CAN'T CLAIM I STUDIED THE PLACENTA DURING THE ARCHITECTURE OF MY CAREER BUT I SPENT A GOOD BIT OF TIME TAKING SMALL SNIPITS OF THE PLACENTA DURING PREGNANCY AND LIKE THE OTHER DOCTORS WE'RE INTERESTED IN WHAT SHEERS OFF THE PLACENTA AND WHAT GOES THROUGH THE PLACENTA THROUGH MOST OF PREGNANCY. I AM CURNOTLY SEEN YORE VICE PRESIDENT FOR RESEARCH AND GLOBAL PROGRAMS AT THE MARCH OF DIMES. >> GOOD MORNING I'M EMILY SU, NORTHWESTERN UNIVERSITY OF CHICAGO AND INTERESTED IN MECHANISMS REPRESENTING PLACENTAL FETAL BLOOD FLOW. >> I'M VIRGINIA WIN, BIOCHEMIST IN MFN TRAINED. CURRENTLIA AT COLORADO BUT SHORTLY WILL BE CHIEF OF PERINATAL BIOLOGY AT STANFORD AND STUDY ABNORMAL AND NORMAL PLACENTATION. >> I AM THE PROGRAM DIRECTS FOR FOR NIAIB AND BIOENGINEERING AND MRI, MR-SPECTROSCOPY PROGRAM AND I AM HERE REPRESENTING NIBIB, AND OBVIOUSLY WE'RE INTERESTED IN KNOWING, AND LEARNING FROM YOU AND WORKING TOGETHER WITH NICHD AND EVERYONE OF YOU IN TERMS OF TECHNOLOGIES AND WHAT WE SHOULD DO AND CAN DO TO DEVELOP TECHNOLOGY, IMPROVE THEM, FOR THE HUMAN PLACENTA PROJECT AND I'M SO GLAD TO SEE SOME OF OUR GRANTEES ARE HERE AND THE SUMMER FOR MY FORMER GRA FROM NCI AND HERE AS WELL. >> HI, LISA KAISER, DIRECTOR OF PUBLIC POLICY AND DIRECTION FOR NICH D. >> CHRISTINE COLPUS, MY PORTFOLIO FOCUSED ON THERAPEUTIC DEVELOPMENT. >> GOOD MORNING. SUSAN MEYER, DEPUTY DIRECTSOR OF THE OFFICE OF RESEARCH ON WOMEN'S HEALTH AND PART OF OUR MISSION IS TO INTEGRATE WOMEN'S HEALTH AND SEX AND GENDER DIFFERENCES, IN RESEARCH ACROSS ALL OF THE INSTITUTES AT NIH. WE'RE WITHIN THE OFFICE OF THE DIRECTOR AND WE HAVE MANY, MANY COLLABORATIONS WITH MANY OF THE INSTITUTE WHO IS ARE REPRESENTED HERE AND I CAN THINK OF NO BETTER WAY TO END A LONG WEEKEND THAN TO BE AT THIS WORKSHOP. THIS IS MY DREAM COME TRUE. >> HI, I'M MONA ROWE, SCIENCE DIRECTOR FOR POLICY AND COMMUNICATIONS AT NICH D. >> FRAN SIGN EINSTEIN, FROM ALBEATERS EINSTEIN IN NEW YORK AND MY INTEREST IS IN EPIGENETICS AND EARLY LIFE EXPOSURES AND AGE-RELATED DISEASE. >> MORNING PATRICK AND I'M ENTERED IN FETAL GROWTH. >> I'M NONA GRANT AND I'M FROM BOSTON CHILDREN'S HOSPITAL CLINICALLY AND RESEARCH WISE I RUN A GROUP AND NEONATAL IMAGING, I WAS FRUSTRATED WITH THE LACK OF TOOLS IN THE NEOINATE OPEN SOURCE SOFTWAREY WE STARTED A RESEARCH CENTER AND WITH NSF FUNDING WE'RE BUILDING A THREE YEAR-OLDS, WE WORK WITH PROFESSIONALS OR SCIENTISTS LIKEI LIZ BETH WITH NEOS AND APPLY IT TO INSTANTS AND GOING INTO THE CARDIAC SURGERY SUITE TO MONITOR BRAIN HEALTH AND SCREEN FOR BRAIN INJURY THROUGH NIH FUNDING AND WE'RE WORKING WITH GE WITH AN MRI TO GET CLOSE TORE INFANTS AND WE'VE GOTTEN FUNDINGS FROM NIBIB TO PARTNER WITH M. I.T. A THE MARTIN O CENTER TO DEVELOP COILS AND PULSE SEQUENCES TAYLORED TO THE FETUS BECAUSE WE THINK WE NEED TO UNDERSTAND THAT TIME PERIOD REALLY WELL AND MOTION IS A CRITICAL THING SO A LOT OF OUR INITIAL EFFORTS WILL BE PUT ON MOTION BUT ALTHOUGH WE STARTED FOCUSING ON BRAIN WE STARTED TO REALIZE VERY EARLY ON THAT YOU CAN'T SEPARATE THE BRAIN FROM THE REST OF THE BODY OR THE SO STARTING AS A NEURORADIOLOGIST AS I DO NEOINATES IT'S A WHOLE BODY SYSTEM AND GOING TO FETUS IS A WHOLE UNIT SO JUST START TO LOOK AT PLACENTAS, SO I'M INTERESTED IN TALKING TO SOME OF THE PEOPLE I MET ON THE PHONE AND HOPING TO LEARN MORE HERE. KATHLEEN SCHMAINDA. I'M FOCUSING ON BRAIN, AND OUTSIDE THE BRAIN LIVER CANCERS. >> GOOD MORNING I'M FROM THE UNIVERSITY IN PORTLAND, I DIRECT THE MOORE INSTITUTE THERE, I'M INTERESTED IN PLACENTA TRANSPORT AND IN REASON YEARS JOINED FORCES WITH PEOPLE IN EPIDEMIOLOGY TO BRING EPIDEMIOLOGY BACK TO THE BASIC SCIENCE LACK LAB SO THAT THE WORK WE DO WILL APPLY TO PROBLEMS WE ALREADY KNOW. THOMAS JANSSON. >> PARTICULARLY INTERESTED IN PLACENTA TRANSPORT FROM SAN ANTONIO. >> I'M AT THE NATIONAL CANCER INSTITUTE, SO THE TISSUE THAT NORMS THE PLACENTA THAT'S NOT THE TROPOBLAST THAT GETS IGNORED A LOT OF THE TIME BUT I'M WORKING ON ALAN'S TOE'S DEVELOPMENT FOR A FEW YEARS NOW AND I'M NOW TRYING TO FIND MY FIRST INDEPENDENT POSITION. >> I'M DENIES GRADY, WRITER AT THE NEW YORK TIMES AND I'M GRATEFUL TO HAVE A CHANCE TO BE HERE AND LEARN ABOUT THE RESEARCH. >> GOOD MORNING, I'M DRUCILLA ROBERTS. SPENT MY CAREER ON CLINICAL PATHOLOGY OF PLACENTA. >> HI, SARA REARDON, REPORTER AT NATURE MANAGE VENE. >> CAROLYN OTT, INTRAMURAL SCIENTIST IN THE INSITUITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT. I AM A CELL BIOLOGIST WHO SPECIALIZES IN MICROSCOPY AND MY RESEARCH INTEREST IS PRIMARY CILIA. SO I'M--NEW TO THE PLACENTA WORLD. >> GOOD MORNING, I'M INTERESTED IN MEDICAL COMPLICATIONS OF PREGNANCY AND WHY TROPOBLASTING INVADES MORE THAN IT SHOULD BE PLACENTA IN PARTICULAR. >> GEORGE GEORGE SAADE. UNIVERSITY OF TEXAS AT GALVESTON AND PARTICULARLY HOW FETAL OUTCOME RELATES TO PROGRAMMING. >> ALFRED ABUHAMAD, AND I'M INTERESTED IN MEDICAL IMAGES. >> I WANT TO THANK EVERYONE SO MUCH FOR YOUR BRIEF INTRODUCTIONS. IT ALLOWEDITOUS PRETTY MUCH BE ON TIME. WE'LL START WITH OUR THREE OVERARCHING PRESENTATIONS. WE'LL START WITH DR. GRAHAM BURTON WHO WILL GIVE US AN OVERVIEW OF PLACENTAL FORMATION AND STRUCTURE FOLLOWED BY GEORGE SAADE, MATERNAL-PLACENTAL SYNDROMES, CONDITIONS DUE TO PLACENTAL ABNORMALITIES AND THEN WE'LL FINISH WITH YOEL SADOVSKY, CURRENT METHODS FOR ASSESSING PLACENTAL DEVELOPMENT IN FUNCTION AND THEIR LIMITATIONS. >> OKAY, THANK YOU VERY MUCH. TODAY WILL BE AN EXCITING MEETING. I'VE BEEN CHARGED WITH GIVING AN OVERVIEW OF MUSEUM MAN PLACENTAL DEVELOPMENT AND INSTRUCTION WHICH IS A CHALLENGE IN 3 30 MINUTES. BUT WHAT I CONCENTRATED ON HERE IS THE KEY ASPECTS OF DEVELOPMENT, SORT OF LAY THE FOUNDATIONS OF PATHOPHYSIOLOGY OF COMPLICATIONS OF PREGNANCY AND ALSO SOME OF THE TECHNIQUES--EXCUSE ME. SO MY AIM IS TO OUTLINE THE STRUCTURE OF THE HUMAN PLACENTA, I MEAN WHERE ARE WE GOING WITH THIS DEVELOPMENT, WHAT ARE WE TRYING TO ACHIEVE AND THEN TO OUTLINE THE DEVELOPMENT ELABORATION, AND THE ENVIRONMENT DURING THE FIRST TRIMESTER WHEN THE FOUNDATION OF THE PLACENTA ARE ESTABLISHED AND HOW WE ESTABLISH THE MATERNAL CIRCULATION TO THE PLACENTA WHICH IS ONE OF THE VERY KEY ASPECTS OF HUMAN TRANSPLANTATION AND FINALLY TO CONSIDER REMODELING OF THE EARLY PLACENTA AND THE FORMATION OF THE SMOOTH MEMBRANE WHICH IS AN IMPORTANT ASPECT. TO START OFF WITH AN OVERVIEW OF THE PLACENTA, THIS IS A DELIVERED PLACENTA, SOMETHING LIKE 25-25-CENTIMETERS IN DIAMETER, SOMETIMES ELLIPTICAL AND IF YOU WANT TO APPRECIATE THE INTERNAL STRUCTURE, I DON'T THINK YOU CAN DO BETTER THAN THIS ICONIC IMAGE FROM ELIZABETH RAMSEY WHERE SHE TAKE AS I SLICE THROUGH ON THE CHORIONICS PLATE WHICH IS FACING THE BABY THROUGH TO THE PLACAL PLATE WHICH IS A--BAIZAL PLATE WHICH IS FROM THE UTTERRINE WALL AND AS CAN YOU SEE INSIDE THE PLACENTA THERE IS A WHOLE MASS OF FETAL BILLUS WHICH RUNS REPEATEDLY TO GIVE US AN ELABORATE STRUCTURE AND THOSE ARE BATHED BY MATERNAL BLOOD WHICH IS DELIVERED FROM THE UTTERRINE ARTERIES THROUGH THE BASAL PLATE, TO THE INSIDE SPACE PERK O LAYS BETWEEN THE THE VAIN VAIS SO WE CALL IN A CORAL AREA. THIS IS NOT ACROSSAL MAMMALIAN SPECIES. WE'RE PRETTY UNIQUE AND THAT MAY EXPLAIN SOME OF THE COMPLICATIONS OF PREGNANCY. SO I THINK THE MAIN FUNCTION OF THE PLACENTA MUST BE MATERNAL FETAL EXCHANGE, THE RESPIRATORY IS PROBABLY THE MOST IMPORTANT OF THOSE OXYGEN DIFFUSES MORE, IT'S MORE DIFFICULT FOR DIFFUSION THAN CARBON DIOXIDE AND IT IS REALLY REQUIREMENTS FOR OXYGEN EXCHANGE WHICH DICTATE THE ARCHITECTURE OF THE PLACENTA SO WE NEED A LARGE SURFACE AREA SO WE HAVE THESE VERY ELABORATELY BRANCHED VILL I AND WE HAVE ABOUT 12 TO 14 SQUARE METERS AT--INSIDE THOSE VILLI, WILL BE A NETWORK OF FETAL CAPILLARIES. WE CAN SEE THEM HERE. WE CAN SHOW THE NETWORKS THERE. WE HAVE THE NETWORK, THE MATERNAL BLOOD OUTSIDE. THE DIAMETER IS NOT UNIFORM AS CAN YOU SEE THERE ARE LOCALIZED DIAALATIONS, AND THEY WILL BRING THE CAPILLARIES VERY CLOSE TO THE SURFACE OF THE VILLI, SO THAT IF WE TAKE A CROSS SECTION THROUGH HERE, WHAT WE SEE IS THE MATERNAL BLOOD IN THE INTRA VILLAR SPACE, THE BABIES BLOOD IN THE FETAL CAPILLARIES AND I MENTIONED THE MEMBRANE SEPARATING THE TW IS REDUCED TO AS LITTLE AS TWO-THREE MICRO METERS. SO WE HAVE A LARGE SURFACE AREA, WE HAVE A VERY THIN BARRIER. THESE VILLI ARE NOT ARRANGED AT RANDOM, THEY'RE ARRANGED IN A SERIES OF GLOBULES EACH OF WHICH IS CENTERED AROUND THE OPENING OF ONE OF THE MATERNAL ARTERIES. SO WE HAVE ABOUT 30-40 LITTLE INDIVIDUAL MATERNAL FETAL EXCHANGE UNIT WITHIN THE FULL PLACENTA. SO YOU CAN SEE THAT THESE ARE TRANSFERRED TO THE MATERNAL FEEL AT LOCATION, AND SORT OF LIKE A TRANSCONTINENTAL FLIGHT. IT IS A WHOLE DIFFERENT ACTIVITY, MAINLY THE TROPOBLAST HERE, IT IS EMPHASIZING A LARGE AMOUNT OF HORMONES, IT IS DOING AND METABOLIC REGULATION AND IONIC HOMEOSTASIS. SO IT USES AN AWFUL LOT OF OXYGEN. SO IT DOES HAVE HIGH METABOLIC PARTS AND DOES CONSUME 30-40% OF OXYGEN COMSUMPTION BY THE FETAL PLACENTAL UNIT. OKAY, LET'S MOVE ON TO DEVELOPMENT. THE ELABORATION OF THESE AND THERE ARE TWO PLAYERS IN DEVELOPMENT OF THE PLACENTA. THERE IS OF COURSE A PRECEPTUS THAT PROVIDES THE CELLS OF THIS, AND THERE IS THE ENDOMETRIUM AND LIKE ANY SEED, THE SUCCESS OF THAT SEED DEPENDS ON THE SOIL IN WHICH IT IMPLIES, IT WILL PROVIDE NUTRITIONAL SUPPORT AND GROWTH FACT STIMULATION IN EARLY PREGNANCY, AND LATER THE MATERNAL ARTERIES. SO LET'S START WITH THE COB SEPTORSORS TO INDUCE THE TERMS. WE HAVE THE TRIFECTA DERM WHICH ARISES FROM THE OUTER WALL OF THE BLASTOCYST. THIS GIVES RISE TO CYTOTROPOBLAST CELLS WHICH ARE A HOMOGEANIOUS POPULATION AND THOSE CAN DIVIDE INTO VILLUS OR EXTRA VILLUS. THE VILLUS, COMPARED TO THE ACTUAL PLACENTA, THE EXTRA VILLA WILL CONTRIBUTE TO THE INVASIVE CELLS, WHICH WILL INVADE FROM THE MATERNAL WALL, EITHER BETWEEN THE ARTERIES, OR DOWN THE LUMEN OF THE ARTERIES, AND ESTABLISH THE MATERNAL ARE--ADMINISTRATIVE TORIOLE CIRCULATION. THERE ARE ALSO OTHER CELLS OF COURSE THERE ARE THE FAITHS O DERMAL CELLS WHICH COME FROM THE INNER CELL MASS AND THESE WILL GIVE RISE TO THE STROMAL CELL CORE AND THE SMOOTH MUSCLE CELLS THAT CONTRIBUTE TO THAT VASCULAR TREE AND WILL ALSO GET HEMATOPOIESIS IN THE PLACENTAL TISSUES. SO THESE ARE THE--THE FETAL COMPONENTS, SAME GENO TYPE OBVIOUSLY, AS THE BABY AND THIS IS REALLY A SUMMARY OF HOW WE ESTABLISH THE VILLUS TREE. THE UTERINE EPITHELIUM, WE GET A DIFFERENTIATION INTO THE TROPOBLAST AND THE TRUE MULTINUCLEATED TISSUE. THIS IS ABOUT SEVEN-EIGHT DAYS AFTER IMPLANTATIO AND CAN YOU SEE THAT SOON SPACES BEGIN TO APPEAR IN THE [INDISCERNIBLE] TROPOBLAST AND WE DIVIDE THIS TISSUE INTO A SERIES OF PLATES OR TRIBECULAE WHICH ARE ILLUSTRATED HERE. THOSE CELLS THEN TRAVEL DOWN HERE WHERE THEY REACH OUT AND FORM BODIES KNOWN AS TROPOBLASTIC SHELL WHICH FORMS THE INTERFACE BETWEEN THE DEVELOPING PLACENTA AND THE ENDOMETRIUM AND THAT'S A KEY ASPECT OF EARLY LA SENTAL DEVELOPMENT AS WE WILL SEE LATER. SO WE HAVE INITIALLY INSIDIAL TROPOBLAST, SPLIT THAT INTO PLATES, THE SIDES PENETRATE DOWN AND FOLLOWED THEN BY MESODERM FROM THE INNER COAT MASS AND IN THAT, IT WILL DIFFERENTIATE, AND THAT BASICALLY IS THE FETAL VILLUS, AND IT WILL GIVE US ELABORATE VILLI AND THAT IS JUST A BRANCHING PROCESS DRIVEN BY ANGIOGENESIS, THE PROLIFERATION OF THESE BLOOD VESSELS. SO NOW AND THIS IS THE TROPOBLAST REALLY GIVE US WHICH IS FACING THE BABY AND THE BASAL PLATE WHICH IS OPPOSED TO THE UTIERINE WALL. SO I DON'T PROPOSE TO SAY MUCH MORE ABOUT THE ELABORATION OF THE VILLUS TREE EXCEPT IN THE MATERIAL FORM, THEY FORM IN GLOBULAR ARRANGEMENT ENTERING INTO THE CENTER AND AS A BRANCH, BRANCH, BRASH BRANCH. SO THE FINAL BRANCHES ARE THE TERMINAL VILLI WHICH ARE REALLY THE BUSINESS END OF THE PLACENTA AS FAR AS MATERNAL FETAL EXCHANGES AND THAT'S WHERE YOU GET A THIN MEMBRANE AND THE LARGE SURFACE AREA. SO THEN WE HAVE THE TERMS OF THE PLACE SURFACE AREA IS ALWAYS INCREASING. THERE'S NO REAL EVIDENCE OF PLACENTAL SENESCENCE OF SUCH AND THAT BEGINS TO TAKE OFF REALLY AT ABOUT 20 WEEKS OF GESTATION. SO THIS IS THE ELABORATION REALLY OF THE VILLUS TREE. THE OTHER PLAYER, THE ENDOMETRIUM, THERE ARE FOUR KEY ASPECTS. I THINK WE NEED TO BEAR IN MIND AND TO THINK ABOUT WHEN WE'RE DOING THE BREAK OUT SESSIONS IN TERMS OF WHAT CAN WE PERHAPS IMAGE. CERTAINLY THE UTERINE GLANDS ARE VERY IMPORTANT. WE KNOW THAT THEY CHANGE IN SYSTEM, NORMAL MENSTRUAL CYCLE, THEIR ACTIVITY ACTUALLY INCREASES DURING EARLY PREGNANCY. WE NOW KNOW THEY PROVIDE NUTRIENT AND GROWTH FACTOR SUPPORT DURING THE FIRST TRIMESTER OF PREGNANCY AS I'LL SHOW NUCLEOTIDES A MINUTE. SO THE PLANS ARE A KEY ASPECT, THE ENDOMETRIUM ALSO UNDERGOES IN THE HUMAN PROFOUND CHANGE, CALLED DISCIPLINARY SIDUALIZEATION WHEREBY THE STROMAL CELLS UNDERGO TRANSFORMATION TO BECOME HIGHLY SECRETORY CELLS, THAT HAPPENS IN THE LATE SECRETING PHASES OF THE NORMAL CYCLE BUT MUCH MORE DURING EARLY PREGNANCY. THESE ARE DESIDDUAL CELLS, THEY EXCRETE A LOT OF HORMONE PROLACTIC ACIDOSEISIN FOR EXAMPLE AND WE BELIEVE THEY ARE ESSENTIAL PROBABLY FOR THE CORRECT FUNCTIONING OF THE GLANDS IN EARLY PREGNANCY. AND CERTAINLY DISCIPLINARY SIDUALIZEATION IS RELATED TO A LOT OF THE COMPLICATIONS OF PREGNANCY. I KNOW WE WILL HAVE SESSIONS ON IMOLOGY CELLS AND THE INFORMATION ON THE KILLER CELLS BECAUSE THEY ACCUMULATE IN ANTICIPATION OF IMPLANTATION IN A NORMAL CYCLE AND THEIR NUMBER IS VERY MUCH HIGHENER EARLY PREGNANCY AND THEY REPRESENT ABOUT 70% OF THE LYMPHOCYTES AT THE IMPLANTATION SITE. SO WHEN OUR TROPOBLAST INVADES IT WILL COME ACROSS THESE MATERNAL IMMUNE CELLS. AND LASTLY OF COURSE, WE HAVE [INDISCERNIBLE] WHICH ARE GOING TO BE TAPPED INTO BY THE INVADING PLACENTA AND ULTIMATELY GIVE US THE BLOOD SUPPLY TO THE PLACENTA BUT THAT DOESN'T START UNTIL THE END OF THE FIRST TRIMESTER ABOUT 10-12 WEEKS. SO HOW DO ALL THESE PLAYERS INTERACT TOGETHER? WELL, THIS DIAPHRAGMATIC ILLUSTRATION HERE BASED ON THESE CARNEGIE SLIDES WHICH I SUPPOSE ARE HERE IN WASHINGTON SHOWS THAT DURING THE EARLIER STAGES OF IMPLANTATION, IT'S INSIDIO TROPOBLAST SURROUNDING THE CONCEPTUS INVADES INTO THE ENDOMETRIUM, IT WILL INVADE INTO MAUL DIAMETER CAPILLARIES IT COMES ACROSS BUT IT ALSO INVADES INTO THE UTERINE GLAND AND THAT IS THE UTERINE GLAND THERE. AND WE NOW KNOW THAT THESE GRANDS PROVIDE NUTRIE TO THE PLACENTA NOT JUST IN THOSE INITIAL STAGES, BUT PROBABLILY FOR THE FIRST THREE MONTHS OR TWO AND HALF MONTHS OF PREGNANCY. SO THIS IS A PLACENTA INSITU SECTION THAT WE HAVE IN CAM BRIDGE AT SIX WEEKS GUESTATION AGE, FOUR WEEKS POST FERTILIZATION AND HERE IS THE CONCEPTUS WITH THE DEVELOPING PLACENTA WITH ALL THE VILLI I'VE BEEN TALKING ABOUT, SITTING ON TOP OF A VERY ACTIVE ENDOMEET RICK, 5-MILLIMETERS THICK AT LEAST AND THAT'S IN A CHUNKEN PARAFFIN EMBEDDED SECTION AND I FOR A SUCCESSFUL PREGINANCE O ULTRASOUND. SO CAN YOU SEE THAT THESE SECRETIONS FROM THE GLANDS ARE DELIVERED THROUGH THE DEVELOPING BASAL PLATE INTO THE INTERVILLAR SPACE SURROUNDING THE VILLI AND WE'VE SHOWN THAT THOSE FACTORS AND THOSE SECRETIONS ARE TAKEN UP BY THE VILLI, BROKEN DOWN PROVIDING NUTRIENTS BUT ALSO THEY ARE VERY RICH IN A NUMBER OF DIFFERENT GROWTH FACTORS, FGF EGF, VEG F ARE ALL SECRETED BY THESE GLANDS. WHAT IS MORE EVIDENCE ON DOMESTIC ANIMALS AND NOW WE HAVE PILOT STAGE IN THE HUMAN IS THAT THE PLACENTA SIGNALS FROM THE DEVELOPING PLACEN SIGNALS TO THESE GLANDS TO INCREASE THE SECRETIONS AND INCREASE THE EXPRESSION OF PEEK GROWTH FACTORS. SO WE HAVE A SORT OF SURVEY MECHANISM BY WHICH THE PLACENTA CAN STIMULATE IT'S OWN DEVELOPMENT IN ASSOCIATION WITH THE ENDOMETRIUM. SO THERE'S A TRUE COOPERATION GOING ON. SO WE THINK THE HCG COMING FROM THE TROPOBLAST CAN STIMULATE GLANDULAR, FROM THE EPITHELIUM THAT SECRETE IT FROM THE KESIDUAL CELLS THAT SECRETE PROLACTIC ACIDOSEISIN AND THEY MAY BE THE INVADING TROPOBLAST AND THE IMMUNE CELLS AND THE NET RESULT IS THAT YOU GET AN INCREASED ACTIVITY OF THESE SECRETORY CELLS AND THEY PRODUCE THE MILK AND WE KNOW THAT HAS PROLIFERATIVE ACTIONS ON THE TROPOBLAST WHICH ARE SURROUNDING THE VILLI AND THESE CELLS OF THE TIPS OF THE VILLI WHERE WE FORM THIS CYTOTROPOBLASTIC SHELL AT THE INTERFACE. SO THIS IS A KEY FACTOR. WE'RE JUST BEGINNING TO EXPLORE THE SIGNALING PATHWAYS FOR THIS SERVER MECHANISM IN THE HUMAN. ULTIMATELY WE NEED A BLOOD SUPPLY FROM THE PLACENTA. WHERE DOES THAT COME FROM? FROM THE BRACHS OF THE UTERINE ARCH WAYS, ALONG THE LIGAMENT UTERROUS AND WE GET THE ARTERIES WITHIN THE ENDOMETRIUM. TAP INTOG THE MATERNAL ARTERIAL SUPPLY IS A DANGEROUS THING TO DO BECAUSE THE PRESSURE WILL BE MUCH, MUCH, HIGHER WITHIN THE FETAL CIRCULATION AND THERE IS A DANGER THAT IF HAVE YOU TOO MUCH ARE--ADMINISTRATIVE TERIOLE PRESSURE, YOU COULD BLOW THE CONCEPT ARE OFF THE ENDOMETRIUM SO THESE NEED TO UNDERGO CONSIDERABLE REMODELING BEFORE WE CAN ESTABLISH BLOOD FLOW. AND SO REMODELING IS ONCE AGAIN A KEY EVENT IN A HEMOCORRIDOR PLACENTA AS IN HUMAN AND WHAT WE MEAN BY THAT IS THERE IS A LOSS OF THE SMOOTH MUSCLE IN THE SUPERFICIAL PORTIONS OF THESE SPIRAL ARTERIES AND AS A RESULT, THE HUMAN DILATES AS IT APPROACHES THE PLACENTA. THAT REMODELING IS ASSOCIATE WIDE THE INVASION OF THE TROPOBLAST CELLS FROM THE PLACENTA INTO THE INTERSTITIAL RUDE BETWEEN THE ARTERIES OR DOWN THE LUMEN OF THE ARTERIES AND IT IS THOSE CELLS WHICH ARE GOING TO INTERACT WITH THE NK CELLS. SO THIS IS AN UNMODDIFIED SPIRAL ARTERY IN THE METRIUM HERE AND IT HAS A THICK WALL IN THE LUMEN, THIS BY CONTRAST IS A MODIFIED ARTERY. WE'VE REMOVED THE SMOOTH MUSCLE, REPLACED BY A MORPHUS SPINNOID DEPOSIT AND EMBEDDED IN THAT, WE SEE THESE EXTRA VILLAS. THE CONSEQUENCES OF THAT BLOOD FLOW ARE PROFOUND. WE DID MATH MODELING AND TAKING DIMENSIONS FROM THIS PAPER, FROM HAROLD RAMSEY WHO HAD SEVERAL SECTIONS OF PREGNANCY UTERI, THIS IS A LOGARITHMIC SCALE OF THE SPEED OF BLOOD FLOW, IF YOU DON'T HAVE ANY DILATION, THEN THE VILLS ONITY IS ABOUT TWO-THREE--VELOCITY IS TWO-3-METERS PER SECOND DEPENDING ON THE VISCOSITY OF THE BLOOD AND THESE ARE MAXIMUM AND MINIMUM VALUES WITHIN THE LITERATURE. BUT IF YOU HAVE DILATION TO SORT OF DIAMETER ABOUT 2.4-MILLIMETERS AND YOU REDUCE THE VELOCITY BY ORDER OF MAGNITUDE, ABOUT 10-CENTIMETERS PER SECOND. SO INSTEAD OF HAVING THIS HUGE BRUSH OF MATERNAL BLOOD INTO THE PLACENTA WE NOW HAVE A SLOW SEEPAGE AND A LOW VELOCITY AND ALSO A LOW PRESSURE. AND THAT IS [INDISCERNIBLE]. THESE DOTTED LINES ARE THE REYNOLDS NUMBER INDICATING TURBULENT FLOW. AND WE KNOW FROM NUMEROUS STUDIES THAT INCOMPLETE DEFICIENT MODELING OF THOSE ARTERIES IS ASSOCIATED WITH IUG GR AND PREELAMPSIA AND READING TO HIGH FUSION AND CREATEOXIDATIVE STRESS THROUGH HIGH SHEER RATES AND ALSO FLUCTUATIONS IN BLOOD FLOW BECAUSE YOU MAINTAIN CONTRACTILE PORTIONS OF THE ARTERY. SO WHY SHOULD REMODELING BE DEFICIENT IN SOME CASES, THERE MAY BE MANY DIFFERENT REASONS BUT OF COURSE, WE SHOULD LOOK AT THOSE IMMUNE RESPONSES, THE TROPOBLAST CELLS INVADING DO COME INTO CLOSE CONTACT WITH MOVEET'S GROUP HAS SHOWN THAT CERTAIN COMBINATIONS OF HCG ANTIGENS EXPRESSED BY THESE TROPOBLAST CELLS AND THE RECEPTORS ON THE NK CELLS DOES PREDISPOSE TO RECURRENT RISK CARRIAGE FOR PRERISK OF IUGR. SO THERE IS SOME EVIDENCE OF A IMMUNE PREDISPOSITION BASED ON THE GENETICS OF THE--IT'S THE PATERNAL CTWO ANTIGEN WHICH IS THE KEY ANTIGEN AS FAR AS THIS IS CONCERNED. SO WHEN DOES THE CIRCULATION ACTUALLY START? WELL BACK IN THE LATE 1980S, HUGH STANDON LOOKED INTO THIS, PRIOR TO DETERMINATION OF PREGNANCY WITH A HISTORY OF RISK, SHOWED AT EIGHT-NINE WEEKS THE SPACE IS FILL WIDE A CLEAR FLUID. AT 12-13 WEEKS IT IS FULL OF THIS PINK BLUSH OF MATERNAL BLOOD. SO SOMETHING WAS DIFFERENT BETWEEN EIGHT-NINE WEEKS AND 12 TO 13 WEEK ASKS IT TRANSPIRED THAT THESE INVADING TREPPE O BLAST CELLS, PARTICULARLY THE ENDOVASCULAR TROPOBLAST CELLS COME DOWN IN SUCH A LARGE NUMBER THAT THEY OCCLUDE THE ARTERIES IN THE FIRST TRIMESTER AND SO, INSTEAD OF THAT MATERNAL BLOOD, WE HAVE THE ENDOMETRIAL GLANDS PROVIDING THE NUTRIENTS. AND THE START OF THE SECOND TRIMESTER, THE ARTERIES ALLOWING THE INFLOW OF MATERNAL BLOOD. NOW THESE GLANDS SUPPLY ALL THE NUTRIENTS YOU NEED. THE ONE THING THEY DON'T SUPPLY OF COURSE IS OXYGEN AND SO THERE IS A THREE FOLD RISE IN OX GENERATEDDATION WITHIN THE INTERVILLUS SPACE, WITHIN THE CENTER, BETWEEN THE DISPAREIGHT HERE WHEN IT'S FULL OF THE CLEAR FLUID AND 12-14 WEEKS WHERE IT FULL OF MATERNAL BLOOD AND THIS ISN'T DUE TO AN INCREASE IN UTERINE BLOOD FLOW NECESSARILY BECAUSE THE PO2 WITHIN THE UNDERLYING DECIDUA DOES NOT REALLY CHANGE TO THAT EXTENT. IT IS IN A CHANGE FROM THE BLOOD FLOW IN THE ENDOMEET REUMKC INTO THE PLACENT--ENDOMEET I ENDOMETRIUM IN THE PLACENTA. WE HAVE A UNIQUE EXCHANGE HAPPENING IN THE FIRST TRIMESTER. WE HAVE LOW OXYGEN CONCENTRATION, WE HAVE IT SUPPORTED BY THE GLANDS AND WE THINK THIS IS WHEN WE FIRST CAME ACROSS LOW OXYGEN, WE THOUGHT THIS WAS PROTECTING THE FETUS AGAINST FREE RADICAL GENESIS AND THEY PREFER TO BE IN A LOW OXYGEN ENVIRONMENT AND NOT NECESSARILY HIPOXIC BECAUSE THE PLACENTAL OF THIS STAGE IS USING DIFFERENT METABOLIC PATHWAYS BUT THEY LIKE A LOW AUCTION ENVIRONMENT. AND SO WHEN WE LOOK AT MARKERS OF STEMNESS OF TROPOBLA CDX TWO IS ONE OF THE TRANSCRIPTION FACTORS THAT REALLY LOCKS YOU INTO THE TROPOBLAST LINEAGE. WE SEE GOOD EXPRESSION DURING THE FIRST TRIMESTER, BUT IT CUTS OFF ALMOST IMMEDIATELY AT THE START OF THE SECOND TRIMESTER. AND THIS MAY BE BECAUSE WE'RE LOSING THE KEY GROWTH FACTORSOT GLAND OR IT MAY BE THIS RISE INOX GENERATEDDATION, WE DON'T KNOW YET. WE ARE TRYING TO TEASE THOSE APART BUT IT DOES IMPLY THAT THE FOUNDATIONS ARE REAL LE LAID DOWN IN THIS HERE AND CERTAINLY AS FAR AS TROPOBLAST STEM CELLS CONCERNED, YOU'RE PROBABLY NOT GETTING TRUE STEM CELLS PASSED THE END OF THE FIRST TRI METER AND THAT HAS CERTAINLY--CERTAINLY SIMILARITIES TO THE SITUATION IN THE MOUSE. THAT'S REALLY ALL I CAN SAY, FOR THE REMODELING OF THE EARLY PLACENTA AND THE SMOOTH MEMBRANES, WHEN WE GET THE EARLY PLACENTA WE GET VILLI OVER THE WHOLE OF THE CHORIONIC SACK, THESE NEED TO REGRESS DOWN SO WE GET SOME SMOOTH MEMBRANES, OTHERWISE YOU CAN'T BE BORN WITHOUT TEARING THROUGH THE PLACENTA AND CAUSING A MASSIVE HEMORRHAGE SO WHAT REMODEL THIS IS SITUATION THROUGH HERE TO THE DISKOID CENTER IS SMOOTH MEMBRANE. WELL A FEW YEARS AGO, NOW, ERIC AND I, WE DID A SIMPLE STUDY BUT TOOK NORMAL PLACENTAS AND HE SCANNED THEM AND SAID, JUST WITH GRAY SCALE ULTRASOUND DO I SEE EVIDENCE OF SIGNIFICANT BLOOD FLOW WITHIN THE PLACENTA, EIGHT TO NINE WEEKS, 10-11, 12-13 WEEKS AND DIVIDED THE PLACENTA SEBTA INTO THREE REGIONS DEPENDING ON WHERE THE UMBILICAL CORD WAS INSERTING ON THE CENTRAL REGION, PERIPHERAL REGION AND WHAT HE FOUND IS THAT THERE WAS THIS PROGRESSIVE INCREASE IN BLOOD FLOW WITH GESTATIONAL AGE WHICH IS TO BE EXPECTED. BUT MORE IMPORTANTLY WHEN THE BLOOD FLOW STARTS, IT STARTS MAINLY IN THE PERIPHERY OF THE PLACENTA, VERY, VERY RARELY IN THE CENTRAL REGION AND THAT MAPS TO THE DEGREE OF INVASION ACROSS THE BED WHICH IS GREATEST IN THE CENTRAL REGION AND YOU MIGHT EXPECT THE PLUGGING OF THE ARTERIES TO BE BIGGER, TO BE MORE EXTENSIVE IN THAT AREA. SO WE CAME UP WITH THIS--WELL HE GAVE US SAMPLES AND WE LOOKED AT THOSE AND WE SAW INCREASE THEOXIDATIVE STRESS AND APOPITOSPOPIS AND PERIPHERAL REGIONS COMPARED TO VILLI IN THE CENTRAL REGION. SO WHAT WE THOUGHT WAS AS THE BLOOD FLOW STARTS IN IN PERIPHERAL REGION, HIGH LEVELS OF OXIDATIVE STRESS CAUSE INCREASE APOPTOSIS, REDUCE PROLIFERATION, LEADING TO REGRESSION OF THOSE PERIPHERAL VILLI AND I THINK THAT'S ONE OF THE KEY THINGS THAT SEPARATES THE HUMAN FROM OTHER SPECIES. OTHER SPECIES HAVE VARIOUS SHAPES IN THE CENTER BUT NONE OF THEM SHOW REGRESSION OF VILLI, OUT INTO TH OSE DIFFERENT SHADES. SO THIS IS A PECULIAR ASPECT OF THE HUMAN. AND LASTLY JUST TO SHOW YOU, THE IMPORTANCE OF THAT CYTOTROPOBLASTIC SHELL WHEN WE DID THE SAME EXPERIMENT BUT LOOKED AT CASES OF THE MISCARRIAGE, NOW INSTEAD OF SAYING BLOOD FLOW IN ONLY NINE OUT OF 25 PLACES HE SAW IT IN 22, OUT OF 25 CASES. AND THAT BLOOD FLOW WAS THROUGHOUT THE PLACENTA, AND NOT JUST IF THE PERIPHERAL REGION. AND SO WE THINK THERE IS OVERWHELMINGOXIDATIVE STRESS IN THIS PLACENTA AND THAT IS ASSOCIATED AGAIN WITH POOR DEVELOPMENT OF THAT CYTOTROPOBLASTIC SHELL AND POOR PLUGGING OF THESE ARTERIES. SO THOSE EARLIER STAGE WHEN IS THE GLANDS ARE PROVIDING NUTRIENTS AND STIMULATION OF THE TROPOBLAST WHICH GIVES US THIS GOOD SHELL WHICH PROTECTS THE CONCEPTUS AGAINST THE MATERNAL ARE--ADMINISTRATIVE TARIOL FLOW, THAT--ARTERIAL FLOW, IT'S KEY, IF IT GOES WRONG WE END WE END UP WITH MISCARRIAGE OR PREELAMPSIA. THESE ARE MY CONCLUSIONS. FOR A WE YOU WANT A LARGE CIRCUIT AREA, THIN BARRIER FOR DIFFUSION EXCHANGE. DURING THE FIRST TRI MEMORY RESPONSER PLACENTA SEBTA DEVELOPS IN LOW OXYGEN ENVIRONMENT, STIMULATE THE BY THESE PLANS AND THAT MAY BE FUNDAMENTAL FOR STIMULATING TROPOBLAST AND OTHER STEM CELLS AND AND EARLY PROLIFTION. ONSET OF MATERNAL CIRCULATION STARTS AT THE START OF THE SECOND TRIMES AND IT'S ASSOCIATED WITH REGRESSION OF VILLI FORMATION AMONG THE DINGOID CENTER AND THE--DISKOID CENTER AND REMODELING OF THE MATERNAL ARTERIES BY THE EXTRA VILLAR CELLS SENT OUT FROM THE PLACENTA, KEY EVENTS IN EARLY PREGNANCY AND AS WE KNOW DEFICIENCY IS ASSOCIATED WITH THE GREAT [INDISCERNIBLE]. SO I MUST STOP THERE. AND I THEREIN IS A PERIOD OF DISCUSSION. >> THANK YOU GRAHAM, THAT WAS A WONDERFUL KICKOF TO THIS WORKSHOP. WE HAVE A FEW MINUTES FOR CONVERSATIONS MPLET. >> GREAT, GRAHAM, FANTASTIC OVERVIEW OF THE WORLD OF WHERE VIEW CANS BE INDUCED AND GIVEN EARLY PLACENTAL DEVELOPMENT, THAT VILLUS FORMATION, THERE SEEMS A FEW TIME PERIODS THAT WOULD BE PRACTICAL FOR INTERVENTION, AND I ALWAYS THINK ABOUT IS SMALL DRUG INTERVENTIONS OR INTERVENTION OF GROWTH FACTORS, WHAT HAVE YOU SO CORRECT ME IF I'M WRONG, A GOOD A OR PRACTICAL TYPE FOR INTERVENTION FOR REMODELING SPIRAL ARTERIES WOULD BE ABOUT 12-13 WEEKS? BUT THE EARLIER, THE BETTER, BUT PRACTICALLY SPEAKING YOU MAY NOT SEE A PATIENT UNTIL LATER. >> PEOPLE HAVE LOOKED AT THE VIALS AND THEY HAVE SAID THERE'S MORE OR LESSER DEGREE OF INVASION. [INDISCERNIBLE] THAT I THINK IS A KEY THING THAT WE HAVEN'T REALLY THOUGHT OF BEFORE SO YOU SAY 12-14 WEEKS MIGHT BE KEY IN REMODELING AND PERHAPS THE OPENING OF THE PLUGS BUT PROBABLY THE KEY [INDISCERNIBLE] >> MUCH EARLIER. >> EARLY. >> BUT BEING PRACTICAL YOU WON'T SEE A PATIENT UNTIL-- >> NO, MAY NEED TO BE-- >> UNLESS YOU CHANGE PRACTICE A BIT AND COME IN AS SOON AS YOU'RE PREGNANT AND WE COULD MONITOR YOUR PLACENTA IN REALTIME AND TELL YOU WHETHER WE COULD INTERVENE. >> AND ABOUT THE VILLUS TREE ALSO, THAT WOULD BE PROBABLY 18-20 WEEKS? START INTERVENTION? >> IT'S DIFFICULT TO KNOW WHAT IS STIMULATING THE VILLUS TREE. >> EARLIER BETTER. >> THE ELABORATION OF THE CAPILLARIES IS GOING ON THROUGHOUT THE TERM. SO YOU MAY HAVE OPPORTUNITIES FOR INTERVENTION. >> OR LEEWAY IN THAT REGARD. >> --AND REDUCING STRESS. WHICH IS [INDISCERNIBLE]. >> OKAY, THANK YOU. >> SO GRAHAM TOOK A VERY PATERNALISTIC TERM WHEN HE SAID HE HAD BEEN WORKING ON THIS FOR 40 YEARS. HIS CHILDREN LIVE, HOWEVER, ACROSS THE WORLD, THEY'RE CALLED HTR-EIGHT FELLEDS, THEY LIVE IF MY LAB AND MANY OTHERS SO I'M WONDERING ABOUT CELL LINES IN FACT TO HELP WITH UNDERSTANDING SOME OF THESE CONCEPTS, THEY'RE MULTIPLE TROPOBLAST PHENOTYPES, THERE AREN'T THAT MANY CELL LINES, THERE ARE MANY GENES WE'RE WORKING ON THAT ARE ACTUALLY NOT EXPRESSED IN THE AVAILABLE CELL LINES, WOULD THAT HELP OUR FIELD IF WE ASKED THE RESOURCES TO DEVOTE THEMSELVES TO DEVELOPING CELL LINES THAT WE COULD WORK ON? >> FIRST OF ALL I THINK YOU HAVE TO DECIDE WHOO IS A TROPOBLAST CELL? >> MAYBE SOMETHING LIKE MIAMI, MINIMAL INFORMATION ABOUT MICROARRAY EXPERIMENTS. >> [SPEAKING AT ONCE. >> --THEY'VE SHOWN THAT ALL THESE CELL LINES ARE VERY DIFFERENT FROM PRIMARY ACEOLATES THEN WHEN YOU LOOK AT METHOALATION PATTERNS, MANY OF THESE INDUCED CELL LINES, DO NOT HAVE NORMAL METHYLATION AND NORMAL MicroRNA AND WHEN I SAY NORMAL, COMPATIBLE WITH PRIMARY ISOLATES, SO I THINK WE HAVE A MAJOR CHALLENGE IN IDENTIFYING [INDISCERNIBLE]. SO IT'S IN SOME WAYS A PRIMITIVE CELL AND IN SOME WAYS THE BEST OF THE CELL, IT'S A CELL THAT EXPRESS IN HLAA AND HLAAB, BECAUSE VERY FEW CELL LINES WILL PUT OUT HLA AND THEN SUPPRESS IT. SO I KNOW PEOPLE USE CELL LINES, I THINK WE HAVE TO BE EXTREMELY CAUTIOUS. BUT PRODUCING A TRUE TROPOBLAST CELL IS SOMETHING WE'RE TRYING AT THE MOMENT. IT WOULD BE A WORTH WHILE OBJECTIVE, YES. >> GRAHAM, OVER LEER, WHENEVER, YOU POINTED OUT APPROPRIATELY HOW THE HUMAN PLACENTA IS, SO UNLIKE WHAT WE SEE IN OTHER SPECIES, FROM AN EVOLUTIONARY POINT OF VIEW, WHY DO YOU THINK THAT IS? >> WE DON'T KNOW YET, I THINK WHAT THE BENEFITS OF THE HUMAN PLACENTAL ARE. MIC ELLIOTT HAS DONE SOME VERY NICE WORK SO PLACENTAS CAN BE HIGHLY INVASIVE AS OUR OWN OR NONINVASIVE AS THE [INDISCERNIBLE], THE SORT OF 19th CENTURY ANATOMIST VIEW IS THAT THE EVOLUTION WENT FROM THE NONINVASIVE TO THE MODERATELY INVASIVE TO THE HIGHLY INVASIVE SITUATION AS WE ARE HERE. THAT HAS BEEN COMPLETELY OVERTURNED IN THE LAST DECADE BY MOLECULAR FILE O GENERATEDET CLINICA--PHILOGENETICSAND IT IS AN ACQUIRE D STATE. WHY SHOULD THAT BE THE CASE WHEN Mc ELLIOTT COMPARED THE GENES THAT ARE EXPRESSED IN THESE DIFFERENT INVASIVE SPECIES AND CAME UP WITH A LIST OF WHAT EXPRESSED OF NONINVASIVE ONES AND THEN LOOKED AT THE GENES ASSOCIATE WIDE PREELAMPSIA AND FOUND--PREECLAMPSIA AND THE SPECIES THAT ARE TRYING TO PROTECT THEMSELVES AGAINST COMPLICATIONS OF PREGNANCY SUCH AS PREECLAMPSIA. >> SO YOU'RE SAYING THAT THE HUMAN PLACENTA IS VERY DIDN'T AND GIVEN EXAMPLES IN WHAT WAY, ARE THERE ANIMAL MODELS, WHAT WOULD BE A SUITABLE ANIMAL MODEL TO STUDY IN IF IT WAS ALL WE COULD DO. >> OF COURSE AS ALWAYS THE MOUSE IS A VERY POWERFUL GENETIC TOOL, I MEAN A LOT OF RESOURCES AVAILABLE THERE. IT HAS A DISKOID HEMOCORAL CENTER, HAS A BIT OF A DIFFERENT STRUCTURE, DIFFERENTIATED, SO IT HAS THE EXACT TRANSPLANTATION OF THE FIRST TRIMESTER, AND THE UTERINE GLANDS SIMILAR TO THE HUMAN. SHEEP LONGER GUESTATION, GOOD FOR FETAL--I MEAN ALL SPECIES WILL HAVE SOME BENEFITS AND I THINK IT DEPENDS ENTIRELY REALLY ON THE QUESTION THAT YOU'RE ACTUALLY ADDRESSING. >> WE LOOKED AT A NUMBER OF PLACENTA SEBTAS, FEWER THAN 40, AND WE LOOKED AT HOW THE PLACENTA GROWS AND BLOOD PRESSURE LATER IN LIFE, CAN YOU GIVE INSIGHT ABOUT HOW THE NUMBERS ARE FORMED AND HOW THESE RELATE TO SPIRAL ARTERIES WHEN THERE ARE FEW? >> I THINK WE COME BACK TO A LACK OF KNOWLEDGE TO A CERTAIN EXTENT ABOUT BASICALLY YOU TRYING TO ASK ME AND I TRIED TO FIND IN THE LITERATURE INFORMATION ON THE DENSITY AS SPIRAL ARTERIES IN THE NONPREGNANT UTERROUS, I COULD NOT FIND IT. YOU WOULD THINK IN THE 19th CENTURY WE WOULD HAVE DOCUMENTED YOU THIS BUT ON THE FUNDUS OF THE UTERROUS, THE LATERAL WALL DEPENDING ON WHERE IMPLANTATION IMPLANTATI ON OCCURS YOU MIGHT EXPECT DIFFERS DENSITY WITH THE ARTERIES. SO TO ME, I THINK THE PLACENTA HAS PROBABLY TAPPED INTO AS MANY SPIRAL ARTERIES AS IT'S GOING TO BY THE END OF THE FIRST TRIMESTER AND THEN YOU GET AN EXPANSION OF THE UTERROUS AND THE PLACENTA. TOGETHER BUT NOBODY AGAIN HAS MODEL THE THAT COMPUTER ANIMATION ON SOMETHING AND THAT AGAIN IS SOMETHING THAT I THINK NEEDS TO BE DONE. BECAUSE YOU WOULD EXPECT FROM THE DENSITY FOR THE SPIRAL ARTERIES, THE LOBULE AND THE EXTENSION. >> WE WILL TAKE ONE LAST QUESTION. >> [INDISCERNIBLE]--WHAT'S THE SIZE OR CHANGING AS OF TIME AND ALSO HOW HOMOGENEITY OF THE WHOLE HOPE AND PERCENTILE ACROSS THE WHOLE STRUCTURE THERE IN TERMS OF FUNCTION. SO WHY IS IT ASSIGNED 10 YEARS AT A TIME AND THE ANOTHER ONE IS HOMOGENETIC FUNCTIO ACROSS THE WHOLE OBJECT? >> EACH LOBULE IS A FETAL MATERNAL EXCHANGE UNIT. NOBODY'S BEEN AND WE MEASURED A LEVEL AND EXPRESSION OF THE ANTIOXIDANT ENZYMES AND THEY ARE HIGHER IN THE CENTRAL REASON AND AND AND WHOLE FUNCTIONING EACH OF THOSE UNITS WITH THE MATERNAL EXCHANGE UNIT WORK FROM THE [INDISCERNIBLE] AND SHOW NOT ALL PREVIOUS AT THE SAME TIME. >> THE SIZE--AND A WEEK OF 38 AND WHAT'S THE BEGINNING FROM BEGINNING GOING TO MOVING TO A 38 WEEKS, SIZE IS CHANGING THAT'S CRITICAL FOR THE IMAGES PART. HOW IS THE PLACENTA? >> NOW DOES IT GROW IN SIZE I MEAN PEOPLE HAV TRIED TO MEASURE THAT WITH ULTRASOUND. AS I UNDERSTAND IT. THE FOOTPRINT IS SMALLER, AT THE END OF THE FIRST TRIMESTER AND THOSE PREGNANCIES GOING TO BE COMPLICATED BY PRE-ECLAMPSIA AND IUGR. HOW DOES IT GROW? I THINK IT'S DIFFICULT TO SAY BECAUSE AS FAR AS MY COLLEAGUES TELL ME, YOU CANNOT IMAGE THE WHOLE PLACENTA IN ONE PHRASE WITH ULTRASOUND AND SO IT'S VERY DIFFICULT TOGETHER WITH THE PICTURE, HOW YOU GET IT UP TO--YOU GET UP TO 30 WEEKS, 16 WEEKS AND THEN AFTER THAT YOU CANNOT SEE THE WHOLE THING IN ONE FRAME. SO WE HAVE A GENDERING PROBLEM IN THAT RESPECT. >> THANK YOU SO MUCH. APPRECIATE IT. [ APPLAUSE ] >> BEFORE DR. SAADE GIVES HIS PRESEN ILLEGALSEN EGG I WILL ASK TWO DR. ROSAS WHO JOINED US TO GIVE BRIEF INTRODUCTION. >> I'M WITH THE UNIVERSITY OF BOSTON AND I'M HERE ON WORK ON BEHALF OF THE PRE-ECLAMPSIA. >> I'M ROBERTO ROMERO, INTRAMURAL RESEARCH AND NICHD AND PLACENTAL GROWTH FROM EVOLUTION TO PLACENTA DEVELOPMENT AND IMAGES, SO THANK YOU GUYS. >> GOOD MORNING, I'M PROGRAM DIRECTOR OF THE NHGRI AND NHLBI CENTERS FOR THE GENOMICS. >> THANK YOU DID ANYONE ELSE JOIN US THAT I MISSED OR DIDN'T GIVE AN INTRODUCTION? CHERYL ANNE BOYCE. WITH NICHD. >> THANK YOU SO MUCH, DR. SAADE? >> ALL RIGHT, GOOD MORNING AND FIRST I WANT TO THANK NICH D FOR PUTTING THIS WORKSHOP TOGETHER. AND FOR INVITING ME AND ALL OF YOU AND I SPEAK FOR ALL OF US HERE TO SAY THAT THIS IS AN IMPORTANT MILESTONE IN THE STUDY OF PREGNANCY AND I'M SURE IN THE YEARS TO COME WE WILL LOOK BACK AND SAY IT ALL STARTED HERE. YOU'VE EXPERIENCED AN ENGLISH ACCENT NOW YOU EXPERIENCE A TEXAN ACCENT. [LAUGHTER] NOT REALLY. THERE WILL BE ANOTHER ACCENT AFTER ME, RIGHT? BUT MY PERPS ON IN THIS TALK IS TO--PURPOSE IN THIS TALK IS TO INTRODUCTION SOME OF YOU WHO DON'T KNOW THE PREGNANCY COMPLI INTRODUCE YOU TO THESE PREGNANCY COMPLICATIONS AND RELATE THEM SOMEHOW TO THE PLACENTAL DYSFUNCTION BECAUSE THE OVERALL GOAL IS SUCH A BASIC GOAL, SOME OF THIS YOU MAY ALREADY KNOW AND I APOLOGIZE FOR THAT AHEAD OF TIME. OBVIOUSLY IN 30 MINUTES I CANNOT SHOW A LOT OF DATA, MOSTLY DAT BAH MOSTLY BULLET ON A POWER POINT PRESENTATION. I LIKE TO CATEGORIZE ADVERSE PREGNANCY OUTCOME AND THE PLACENTAL CAUSES INTO THE WHETHER THEY'RE DEFINITE LEE OR SUSPECTED OR LIKELY AND SOME OF THESE ARE CLEARLY PLACENTAL CAUSES, PLACENTA PLEFFIA, TUMORS OF THE PLACENTA AND I HAVE PERCENTAGES HERE AND IF I DON'T HAVE A PERCENTAGE IT'S BECAUSE THEY'RE RARE. SO THESE ARE PROBABLY FEW THAT ARE DEFINITE CAUSES OF ADVERSE PREGNANCY OUTCOMES, THEY'RE SOME OF THE LIKELY ONES THAT WE ALL THINK ABOUT WHEN TRANSFUSION AND CARRIAGES, FETAL DEATH, PREELAMPSIA, ABSTRACTION AND ABRUPGZ AND PRETERM BIRTH, WE MAY MATT HOLT QUACKLE HERE BUT MAY PUT IT AS LIKE LEER OR CHANGE SOME OF THESE BUT THAT'S HOW I PUT THEM. WHEN WE TALK ABOUT PLACENTAL SYNDROMES AND ADVERSE PREGNANCY OUGHPREGINANCEOUTCOMES RELATING TO CAUSES, MOST OF US THINK OF FETAL DEATH, PLUS OR MINUS PRETERM BIRTH, THESE ARE THE SEXY ADVERSE PREGNANCY OUTCOMES THAT WE ALL WANT TO STUDY, BUT I ALSO WANT TO BRING TO YOUR ATTENTION AND I HOPE WE WILL NOT FORGET THE OTHER PLACENTAL PROBLEMS THAT COMPLICATE MANY PREGNANCIES EACH MORE THAN THE SEXY ADVERSE PREGNANCY OUTCOME AND ACTUALLY KEEP US ALL UP AT NIGHT, AND TAKING CARE OF PATIENT AND AFTER SPEAKING OF THESE COMPLICATIONS. I ALSO DON'T UPON YOU TO FORGET THERE ARE OTHER CONDITION WEES DON'T TALK ABOUT VERY OFTEN, IS A PLACENTAL CONDITIONMY BECAUSE THE INSULIN RESISTANCE IS DRIVEN BY THE PLACENTA THERE'S HYPER TENSIVENESS, NAUSEA, VOMITING COAL O STASE AND I GUESS THESE ARE CONDITIONS THAT ARE A NUISANCE TO SOME PREGNANT WOMEN BUT CARRY SOME MORBIDITY AND MORTALITY BUT I'M NOT GOING TO TALK A LOT ABOUT THESE CONDITIONS. SO LET ME START WITH THE ONES THAT I SAID MAY NOT BE VERY SEXY BUT THEY'RE VERY IMPORTANT AND CLINICALLY, FIRST ONE BEING SENTIA PREVENT IVIA, BI DEFINITION THAT MEANS IT IS PLACENTA COVERS THE INTERNAL WALLS. SEVERAL RISK FACTORS FOR PLACENTA SEBTA PREVENTIVIA, FIRST ADVANCE MATERNAL AGE, MULTIPARITY, MULTIPLE GUESTATION, PRIOR UTERINE SURGERY, BE IT SESARRIAN, MILECTOMY, KERITTAGE OR SMOKING OR SUBSTANCE ABUSE OR MOM AT PLACENTAL DEVELOPMENT AND I'LL SHOW YOU SOME OF THESE MORPH LOGICAL ABNORMALITIES THAT CAN LEAD TO PLACENTA PREVIOUS, ALL THESE PATES WILL BE DELIVERED BY CESSARRIAN SORE THAT ITSELF IS A MORBIDITY ALREADY, AND THEN THERE ARE SOME RISKERS AND OTHER MORBIDITYS LIKE LEADING FETAL GROWTH ABNORMALITIES, MOST OF THESE PATIENS DELIVER PRETERM SO THAT THE PRETERM BIRTH AND THEN ACRETA, THIS IS THE ULTRASOUND OF PLACENTA PREVIA, THERE IS NO WAY FOR THE BABE TO COME OUT EXCEPT BY CESSARRIAN DELIVERY, THAT'S THE PLACENTA PREVENTIVIA AND THIS IS THE CONNAL OVER THE PLACENTA OVERLYING IT. PLACENTA ACCRETA IS A ANOTHER ABNORMALITY WE SHOULDN'T FORGET ABOUT. THIS IS A PLACENTA, BUT THEY COULD BE AKRETTA AND KRETTA WHICH IS INTO THE MYOMET REUMKC AND THE LINING, THE OUTSIDE OF THE UTERROUS WHICH THEN BECOMES [INDISCERNIBLE]. AND THE RISK FACTOR, TWO MOST IMPORTANT RISK FACTORS FOR AN ACCRETA ARE PRIOR TO UTERINE SURGELY, CESS ANIAR MY OECTOMY AND KERITAGE AS I SAID BEFORE AND THE OTHER BIG ONE IS PLACENTA PREVENTIVIA. ALMOST ALL THESE PATIENTS WILL BE DELIVERED PRETERM AND THEA DOESN'T COME OUT, IT WILL RESULT IN BLOODING AND MOST OF THESE ULTIMATELY THE TRUE TEST OF A PLACENTA IS THE HYSTERECTOMY. THIS IS AN ULTRASOUND OF A THERE IS NO DIFFERENTIATION ANYMORE AROUND HERE BETWEEN THE MY O MEETRIUM AND THE PLACENTA, YOU TYPICALLY ALSO SEE THESE LARGE LAKES IN THE PLACENTA. THIS IS ANOTHER ONE LOOKING AT THE LAKES AND THE BLOOD FLOW CLOSE TO THE BLADDER IS NORMAL BLOOD FLOW IN THE PLACENTA, THIS IS AN MRI PICTURE OF THE PLACENTA, AGAIN SEEING THESE LAKES AND ABNORMAL ADHERING PLACENTA, THIS IS THE SPECIMEN WITH THE FUNDUS HERE AND THE PLACENTA INNOVATING THROUGH THE UTERINE WALL. NOW THE OTHER ONES ARE THE NORMAL MORPHOLOGIES I CALL THEM. THESE ARE [INDISCERNIBLE] PLACENTA FOR THE CORD INSERTION FOR THE PREVENTIVIA, THE REASON I MENTION THEM IS FOR TWO REASONS: FIRST, THEY HELP US UNDERSTAND A LITTLE BIT ABOUT PLACENTAL DEVELOPMENT BUT THEY'RE ALSO ASSOCIATE WIDE ADVERSE PREGNANCY OUTCOMES LIKE STILL BIRTH, FETAL BLEEDING, GROWTH RESTRICTION, AND NEED FOR CESS ANIAR DELIVERY. THIS IS FOR EXAMPLE, A CIRCUMVELLATE PLACENTA, THIS IS ABNORMAL CAUSES RESTRICTION OF THE FETAL MATERNAL BLOOD FLOW AND RESULTS IN GROWTH RESTRICTION AND STILL BIRTH. THIS IS THE LAMENTUS CORD INSERTION, INSTEAD OF THE CORD INSERTING CENTRALLY, IT'S INSERTINGOT MEMBRANE WITH FETAL BLOOD VESSELS COARSING THROUGH THE MEMBRA WHEN THERE'S MEMBRANE RUPTURE, THERE'S RUPTURE OCCURS OVER THE CERVIX, OR THESE MEMBRANES OF COURSE OVER THE CERVIX WHICH ARE CALLED PREVENTIVIA AND THIS WOULD THE BLOOD VOLUME THAT WILL BE A CATASTROPHIC EVENT FOR THE FETUS AND THIS IS A [INDISCERNIBLE] MOVE, ANOTHER BEING ACCESSORY LOBE AND AGAIN YOU CAN SEE HOW THESE VESSELS THAT COURSE BETWEEN THESE TWO LOBES ARE AT RISK FOR RUPTURE AND FETAL HEADACHE SANGUINATION. NOW I'M GLAD THAT DR. BURTON SHOWED THAT IN HIS TALKS. I DON'T HAVE TO SPEAK TOO MUCH ABOUT IT BUT MANY OF THESE ARE THE RESULT OF IMPLANTATION ABNORMALITIES. AS THE DOCTOR SHOWED THE INITIAL BLASTOCYSTS OR EMBRYO IS EMBEDDED IN THE DECIDUA, THERE IS NO FREE PART OF THE EMBRYO OR BLASTOCYST. THE TROPOBLASTS ARE ALL AROUND THIS STRUCTURE. AND THIS IS ANOTHER EXAMPLE WHERE YOU CAN SEE ALL THE TROPOBLASTS OR WHATEVER BECOMES THE TROPOBLASTS, WITH THE INSITU TROPOBLAST OR ALL AROUND THE STRUCTURE AND ULTIMATELY, AS THESE GO AWAY, YOU WILL HAVE A CENTRAL PLACENTA AND THE CORE IN THE CENTER, HOWEVER, FOR SOME REASON, ONE REASON OR ANOTHER, THE PLACENTA DOES DEVELOP RIGHT UNDER THE CHORD MAY DEVELOP OVER HERE AND YOU MAY HAVE CORD INSERTION OR YOU MAY HAVE SOME REMNANTS OF THE TROPOBLAST AND YOU HAVE A LOBE, SO IN A SENSE THESE HELP US IDENTIFY SOME OF THESE CHANGES THAT OCCUR IN ABNORMALITIES IN EARLY IMLABORATORIATION, AND I AGREE WITH DR. BURTON WHEN HE SAID THIS IS ONE OF THE MOST IMPORTANT CHANGES THAT HELP US UNDERSTAND ADVERSE PREGNANCY OUTCOME. WE HAVE TO ASK YOURSELF, WE ASK STOCK EXCHANGE ASK OURSELVES, WHY IS IT THEN THAT MOST PREGNANCIES, ONLY FEW OF THESE REMAIN IN A CENTRAL LOCATION. WHY DOES THIS HAPPEN. AND WHY DOESN'T IT HAPPEN IN OTHER CASES. LET ME MOVE TO ANOTHER SYNDROME WHICH WE DON'T TYPICALLY SEE AS SYNDROME WHICH IS A TWIN-TWIN SYNDROME AND THAT OCCURS IN MONOZYGOTIC OR ONLY IN MONOZYGOTIC PREGNANCIES AND IT'S AT THIS EQUILIBRIUM BETWEEN THE FETAL BLOOD CIRCULATION BETWEEN THE TWO TWINS, IT'S A FLUID OVERLOAD AND THE RECIPIENT TWIN OR WHAT WE CALL THE RECIPIENT TWIN AS A FLUID OVERLOAD OR A BLOOD VOLUME OVERLOAD AND INTE VOLUME DEPLETION OR CONTRACTION OR A DONOR TWIN. THESE ARE ASSOCIATE WIDE STILL BIRTH, PRETERM BIRTH AND NEUROLOGIC DAMAGE PARTICULARLY FOR ONE OF THE TWINS DIES AND THE OTHER ONE SURVIVES. AND THESE ARE SOME EXAMPLES OF THE PLACENTAL PATHOLOGY IN THIS CASE WHICH IS AN IMBALANCE BETWEEN THE PROFUSION, BETWEEN THE TWO SIZE OF THE TWIN ARTERIAL, ARTERIAL COMMUNICATION AND THIS IS THE OTHER SIDE OF THE PLACENTA WHERE YOU CAN SEE THE PLACENTA ON ONE SIDE AND THE RECIPIENT AND THE PALE PLACENTA OR PLACENTAL PART AND THE DONEAR TWIN. LET ME MOVE THEN TO PREGNABSY LOSS AS ANOTHER CONDITION THAT RELATES TO PATHOLOGY OBVIOUSLY AND PREGNANCY LOSS FROM A CLINICAL PERSPECTIVE IS DIVIDED INTO THREE CATEGORIES. IT'S EARLY PREGNANCY LOSS CHRKS IS LOSS BEFORE 10 WEEKS, EVEN IF THERE IS NO FETUS OR EMBRYO AT THAT STAGE. IT'S STILL CALLED EARLY PREGNANCY LOSS, FETAL DEATH, IS TYPICALLY BETWEEN 10 WEEKS AND UP TO 20 WEEKS, LESS THAN 20 WEEKS AND THEN STILL BIRTH WHICH TYPICALLY CLINICALLY WE CALL A STILL BIRTH AT LEAST 20 WEEKS OR 20 WEEKS AND LATER IS CALLED STILL BIRTH. WHILE CLINICALLY WE DEFINE THESE IN CATEGORIES WE THINK OF IT AS A CONTINUUM OF PLACENTAL PERSPECTIVE. LET ME SPEND A FEW MINUTES TALKING ABOUT STILL BIRTH BECAUSE THAT'S ONE OF THE LARGER PROBLEMS WE DEAL WITH CLINICALLY. IN THIS ABOUT ONE IN SEIVET PREGNANCIES WHILE YOU THINK THE NUMBER DOESN'T SEEM TOO LARGE THERE ARE ABOUT 26,000 STILL BIRTHS PER YEAR, THAT'S A SIGNIFICANT NUMBER WHEN YOU PUT IT IN THAT PERSPECTIVE AND WHEN YOU LOOK AT THIS OUTCOME COMPARED TO OTHER IT IS THAT WE CARE ABOUT, IT'S ACTUALLY THE EQUAL TO THE NUMBER OF DEATHS, TOTAL NUMBER OF DEATHS DUE TO PRETERM BIRTHS PLUS THE NUMBER OF DEATHS DUE TO SIDS. SO EVEN THOUGH WE DON'T TALK ABOUT MUCH OR WE DON'T DO A LOT OF RESEARCH IN STILL BIRTH IT IS AS IMPORTANT AS THESE OTHER CONDITIONS. EQUAL THE TOTAL NUMBER OF BIRTHS AND EQUAL TO THE NUMBER OF INFANT DEATHS. NOW STILL BIRTHS AND DIVIDED WHERE THE PREGNANT PATIENT COMES IN WITH A DEAD BABY BUT SHE'S NOT LABOR OR INTERPART UMKC STILL BIRTH WHERE THE WOMAN COMES IN WITH A LIVE FETUS AND THEN THROUGH THE PROCESS OF LABOR THE FETUS DIES. OBVIOUSLY NOWADAYS WITH MONITORING THIS DOESN'T HAPPEN VERY OFTEN UNLESS THE FETUS IS PREVIABLE. NOW THESE ARE THE RATES OF STILL BIRTH IN THE UNITED STATES FROM NICHD FROM MARY WILLING HAM, AND THIS IS THE HAZARD RATIO OF THE STILL BIRTH, NOT THE RATE OF STILL BIGGER BUT THE RISK OF STILL BIRTH BY ONGOING GUESTATION AND YOU CAN SEE TWO PEEKS EARLY IN GUESTATION AND THEN LATE IN GUESTATION TOWARDS TERM AND POST TERM. FORTUNATELY NICHD FUNDED A NETWORK LOOKING AT STILL BIRTHS BECAUSE THEY REALIZE THE IMPORTANCE OF THIS PROBLEM AND I WAS FORTUNATE TO BE PART OF THIS NETWORK AND THIS IS ONE OF THE PUBLICATIONS THAT CAME OUT IN JAMA FROM THIS NETWORK LOOKING AT PROBABLE OR POSSIBLE CAUSES OF DEATH. NOW FIRST THING YOU REALIZE HERE IS IT SAYS PROBABLE AND POSSIBLE. AND WE'RE GOING TO SEE THAT OFTEN IN THESE TWO DAYS WHICH IS THE DEFINITION OF THE OUTCOME OR THE ASCERTAINMENT OF THE OUTCOME IS NOT ALWAYS AS WE LIKE IT. IT'S NOT LIKE A LAB, IT'S NOT LIKE BASIC SCIENCE, THIS IS CLINICAL MEDICINE. SO PROBABLY OR POSSIBLE CAUSES OF DEATH ACCORDING TO THIS STILL BIRTH NETWORK WHICH BY THE WAY HAD 600 STILL BIRTH AND 1800 CONTROLS OVER GEOGRAPHIC SEVERAL--SEVERAL GEOGRAPHIC AREAS THROUGHOUT SO SO IT'S A POPULATION BASED STUDY. YOU CAN SEE THAT PLACENTA IS ONE OF THE IMPORTANT PROBABLE AND POSSIBLE CAUSES OF DEATH. NOW LOOK AT OBSTETRIC CAUSES HERE, IS ANOTHER ONE AND I'M GOING TO TALK ABOUT IT SOME MORE LATER BUT PLACENTA WAS STILL NUMBER TWO OR VERY HIGH UP THERE AS A PROBABLE OR POSSIBLE CAUSE OF DEATH IN THESE CASES. NOW THE SAME COHORT THEN WE DIVIDED THEM INTO THE GUESTATIONAL AGES AT LEAST WHAT WE SUSPECTED WERE THE GUESTATIONAL AGES WHEN THESE STILL BIRTH OCCURRED AND THEN DIVIDED THEM INTO ANTEPARTUM AND UMKC AND ANTEPARTUM IS IN THE YELLOW WHAT NOTICE RIGHT AWAY IS THAT THE EARLY GUESTATIONAL AGES WERE MOSTLY INTERPART UMKC STILL BIRTH, THESE ARE AGAIN, AGAIN THE PREGNANCIES THAT CAME IN WITH A LIVE FETUS AND THEN THE FETUS DIED DURING LABOR. DURING THE PROCESS OF LABOR. THESE ARE MOSTLY, MOSTLY CONFINED TO THE 20-24 WEEKS OPPOSE TO THE OTHER AND THEN THE ANTEPARTUM STILL BIRTHS ARE THE ONES WE THINK ABOUT AS THE PLACENTAL CONDITIONS WERE ALMOST EQUALLY DISTRIBUTED THROUGHOUT GUESTATIONAL AGES AND THEN WHEN YOU LOOK AT THE PROBABLE AND POSSIBLE CAUSE OF DEATH ON ANTEPARTUM AND INTERPART UMKC CAUSES, YOU SEE THAT OBLIGATIONS STETRICLE CAUSES OR POSSIBLE PROBABLE CAUSES ARE REALLY SIGNIFICANTLY HIGH IN THE INTRA PART UMKC CONDITIONS. AND NOT AS MUCH IN THE OTHER CAUSES. AND THE--BUT THE PLACENTAL CONDITIONS ARE MORE IMPORTANT THAN THE ANTEPARTUM CAUSES. WHY DID I SPEND SO MUCH TIME ON THIS? THE REASON I DID IT IS BECAUSE I WANT TO IMPRESS UPON YOU MOST OF THE STILL BIRTHS EARLY ON ARE REALLY PRETERM LABOR. THESE ARE PREGNANCIES THAT CAME IN WITH BLEEDING, CERVICAL DILATION AND THEN THE BABY DIED DURING LABOR BECAUSE THE BABY WAS PREVIABLE. SO LET'S NOT FOR GET THIS ASSOCIATION BETWEEN STILL BIRTH, PRETERM REHABILITATIO LABOR, I WILL COME B ACK TO IT A LITTLE LATER. OKAY, SO LET'S GO NOW TO PREELAMPSIA. AND I CONSIDER PREELAMPSIA AS THE POSTER CONDITION FOR A PLACENTAL CONDITION, RIGHT? I MEAN WE ALL THINK ABOUT IT THAT WAY. NOW PREELAMPSIA, HAS BEEN REPORTED THIS WAY OR SOME PRIMATE SOMEWHERE THAT GEEPED SOMETHING SIMILAR TO PREELAMPSIA. WE AS WELL AS OTHERS INDUCED SIMILAR TO PREELAMPSIA TO ANIMALS IN THE LAB, BUT THE TRUE PREELAMPSIA IS LIMITED TO HUMAN PREGNANCIES. AND THERE WAS SOME QUESTIONS EARLIER AS TO WHERE IS THE PLACENTAL PREGNANCY SO DIFFERENT, THE PLACENTA--HUMAN PLACENTA SO DIFFERENT THAN THE ANIMAL PLACENTA, WHY IS IT MORE INVEIGHS AND I HAVE MAYBE THAT'S THE REASON WHY PRE-ECLAMPSIA IS REALLY ONLY SEEN IN MUSEUM MANS AND MOSTLY SEEN IN HUMANS, BY THE WAY, I THINK THE HUMAN PLACENTA IS DIFFERENT THAN OTHER ANIMALS OR ONE OF THE HYPOTHESIS IS BECAUSE OF CIVILIZATION IN THE HUMAN BECAUSE THE BRAIN OF THE HUMAN NEEDS A LOT MORE NUTRIENT OR OXYGEN AND THE PLACENTA HAS THE ONLY WAY IT COULD RESULT IN THIS WAS TO INVA MORE AND MORE AND MORE AND MORE INVADE INTO THE--THE ENDOMETRIUM OR INTO THE UTERROUS AND OTHER EVEN PRIMATES, DON'T HAVE THE SAME SIZE OF THE BRAIN AS THE HUMAN SO IT DOESN'T NEED TO BE AS INVASIVE AS IN THE HUMAN. NOW PRE-ECLAMPSIA CLINICALLY IS A MULTIORGAN DISEASE. I KNOW IT'S THE DEFINITION OF PREELAMPSIA IS BASED ON HYPERTENSION AND PROTEIN URIA AS I WILL SHOW YOU LATER BUT IT'S NOT ONLY HYPERTENSION AND PROTEINERRIA, IT'S A MULTIORGAN DISEASE. ACTUALLY I THINK OF PREELAMPSIA OR DEFICIENCY PREELAMPSIA AND I COMPARE IT TO CORONARY ARTERY DISEASE OR MYOCARDIAL INFARCTION. DO ANYBODY HERE DEFINE CORONA ARTERY DISEASE AS AN GUINA? NOBODY DEFINES IT AS ANG INACIN. IT IS A MAJOR CAUSE OF MATERNAL AND PERINATAL MORTALITY, PARTICULARLY WORLD WIDE, MAYBE NOT IN THE U.S. AS MUCH AS WORLD WIDE BUT SPECIFICALLY WORLD WIDE. >> RECENTLY ACOG PUT A TASK FORCE TOGETHER FOCUSED ON LOOK AT PREGNANCY AND DR. STRONG WAS PART OF THE TASK FORCE AND THEY DIVIDED IT AND OTHER PEOPLE DIVIDE IT THE SAME WAY SO IT'S IMPORTANT TO KEEP IN MIND THIS TERMINOLOGY BECAUSE I'M SURE IN THE NEXT TWO DAYS WE WILL TALK A LOT ABOUT IT SO THE TERMINOLOGY IS OVERALL PREGNANCY RELATED HYPER ATTENTION AND PREELAMPSIA IS AWE CATEGORY OF THISHYPERTENSION SO WE HAVE GUESTATIONAL HYPERTENSION WHICH IS HYPER ATTENTION WITHOUT PROTEINERRIA, BECAUSE THERE IS NO PROTEINERRIA, THE AFFECT ON OTHER ORGANS OTHE ORGANS ARE MUCH LESS SO IT'S BASICALLY HYPER ATTENTION AND NO OTHER ORGAN DAMAGE OR DYSFUNCTION AND THEN HAVE YOU PREECLAMPSIA WHICH IS THE PRACTICES TEEN URWHY AND HYPER PREELAMPSIA IS DIVIDED WITHOUT SEVERE FEATURES AND WITH SEVERE FEATURES AND I'LL SHOW YOU LATER WHAT THESE ARE AND THEN THE TERMINOLOGY OF THESE SUPERIMPOSED PREELAMPSIA WHICH IS WHEN A WOMAN HAS CHRONIC HYPERTENSION OR PREPREGNANCY HYPER ATTENTION AND THEN DEVELOPS SUPER IMPOSED PREELAMPSIA DHS IS A RISK FACTOR FOR PREELAMPSIA OR HYPER CHRONIC TENSION AND THEN ELAMPSIA WHICH IS A MANNESTATION OF END ORGAN DAMAGE BUT THE END ORGAN HERE IS THE BRAIN AND THAT'S WHEN YOU HAVE SEIZURES IN ADDITION TO THE HYPER ATTENTION AND PROTEINURIA. THIS IS THE DIAGNOSTIC CRITERIA FOR THE TASK FORCE, BLOOD PRESSURE IS THE MAIN AT A HERE AND TYPICALLY, IT'S--HONESTLY AN ORBCONTRARY NUMBER, 140 OVER 90. IT'S CLINICALLY USEFUL BUT I'M NOT SURE HOW USEFUL IT IS FOR RESEARCH. AND THEN THE PROTEINURIA, HERE AND ANOTHER ONE, ALSO AGAIN ANOTHER ARBITRARY MEASURE OF SOMETHING THAT PATHOLOGICALLY MAY NOT MAKE TOO MUCH SENSE. AND THESE ARE THE SEVERE FEATURES, THE SEVERE FEATURES OF BASICALLY END ORGAN DAMAGE THAT OCCURS BECAUSE OF WHAT WHATEVER THE PATHOPHYSIOLOGY OF PREELAMPSIA IS AND IT RELATES TO THE HEMOST AND BLOOD COMPONENTS AS IN THROMBOW CYTOPENIA, RENAL FUNCTION, LIVER FUNCTION, PULMONARY FUNCTION AND CNS FUNCTION SO AS CAN YOU SEE THESE ARE THE END ORGAN DAMAGE BUT ALL OF THESE ARE CLINICALLY IMPORTANT BUT FROM A RESEARCH PERSPECTIVE. WE NEED TO THINK DIFFERENT AND NOT BOX OURSELVES INTO THE CLINICAL COMPONENTS OF THE DEFINITION. DR. BURTON MENTIONED THE PRESENTATION AND INVASION INTO THE ARTERIALS AND TO THE ABNORMAL PLACENTATION THAT OCCURS THAT'S RELATED TO PREELASMTIONIA SO I'M NOT GOING TO SPEND TOO MUCH TIME ON THAT AS ABNORMAL PRESENTATION AND PRE-ECLAMPSIA SO ONE OF THE IMPORTANT COMPONENTS THAT'S BEEN TALKED ABOUT VERY FREQUENTLY IS THIS ABNORMAL INVEIGHS LEADING TO REDUCED PROFUSION, HOWEVER THIS REDUCED PROFUSION CAN ALSO BE CAUSED BY OTHER THINGS LIKE ON THE MATERNAL SIDE INDEPENDENT OF THE TROPOBLAST INVASION, ANY ABNORMALITY IN THE UTERINE BLOOD FLOW WILL CAUSE REDUCED PLACENTAL PROFUSION. THE OTHER WAY TO GET THE REDUCED PROFUSION IS HAVING EXCESS TROPOBLAST AS YOU HAVE IN TWINS OR GUESTATIONAL TROPOBLASTICNY O PLACIA OR ANY REASON FOR ENLARGEMENT OF THE PLACENTA AND THIS WILL BE A RELATIVE REDUCTION IN PLACENTAL PROFUSION, SO EVERYTHING HERE IS RELATIVE. HOW DO THESE CAUSE PREELAMPSIA, THIS THEN CAUSES ENDOTHELIAL INJURY. ENDOTHELIAL INJURY ALSO CAN CAUSE RELATIVELY REDUCED PLACENTAL PROFUSION WHICH IT'S GOING TO AFFECT THE ENDOTHELIUM IS INVOLVED IN THE PLACENTAR PROFUSION. THIS ENDOTHELIAL INJURY WE BE EVEN IN NONPREGNANT INDIVIDUALS CAN RESULT IN THE MANIFESTATIONS SIMILAR TO PRE-ECLAMPSIA, AND ACTIVATION OF THE COAGULATION, ALL OF THESE CAN BE CAUSED BY ENDOTHELIAL INJURY INJURY, NOW WE TYPICALLY LOOK AT HYPER ATTENTION, THIS IS EVIDENCE OF BASAL SPASM BUT ALL OF THE OTHER FINDINGS IN PRE-ECLAMPSIA CAN BE EXPLAINED BY THIS ENDOTHELIAL INJURY, SO TO SUMMARIZE IN A NORMAL REG NANCY AND THERE IS A BALANCE BETWEEN PROFUSION AND METABOLIC NEEDS AND PREELAMPSIA, THERE IS AN IMBALANCE BETWEEN PROFUSION AND METABOLIC NEEDS THAT WILL RELEASE FACTORS INTO A MATERNAL CIRCULATION THAT'S GOING TO RESULT IN ENDOTHELIAL DYSFUNCTION AND THEN BLOOD PRESSURE INCREASE AND ORGAN DAMAGE. SO LET'S TALK A LITTLE BIT ABOUT ANOTHER PLACENTAL CONDITION THAT'S RELATED TO PLACENTAL OUTCOMES AND WHICH ABRUPG ABRUPTION AND THIS IS CLINICAL AND SUBCLINICAL, IT DOESN'T HAVE TO BE CLINICALLY EVIDENT. NOW PLACENTA SEBTAL ADOPTION IS A SPECIAL CATEGORY BECAUSE IT OVERLAPS WITH OTHER PREGNANCY OUTCOMES. COMES THAT I SHOWED YOUHESE OR THESE OTHER PLACENTAL ABNORMALITIES SO MAYBE BY ITSELF IT'S NOT A PURE CONDITION, IT'S A CONDITION THAT'S RELATED TO ALL THE OTHER CONDITIONS, IT'S A MAJOR CAUSE OF MATERNAL MORTALITY AND MORBIDITY BECAUSE OF THE BLEEDING, ALSO BECAUSE OF THE DISSEMINATED THAT OCCURS WITH PLACENTAL APOPULATION. ONE THING TO KEEP IN MIND WITH THIS CONDITION IS THAT THE DIAGNOSIS IS CLINICAL AND IT'S IMPRECISE, IT'S CLINICAL SUBJECTIVE FEELING. THIS IS AN EXAMPLE OF A PLACENTAL ABRUPTION BUT IT DOESN'T HAVE TO BE THAT BIG, DOESN'T EVEN HAVE TO BE MICROSCOPEICALLY EVIDENT. YOU MAY LOOK AT A PLACENTAL AND IT MAY LOOK PERFECTLY DEVELOPED AND YOU MAY STILL HAVE MA ISSUES IN THE PLACENTA SEBTA. NOW NEXT IS FETAL GROWTH AND THAT'S A BIG CAN OF WORMS THAT I CAN'T TALK ABOUT IN FIVE MINUTE BUS I WILL TRY TO GIVE A FLAVOR OF THIS. FIRST OF ALL TALKING ABOUT ONE OF THE MAJOR ONES THAT WE HAVE PROBLEMS WITH DEFINITIONS AND SEVERAL DEVELOPMENTAL ENDOCRINOLOGYINATIONS HAVE BEEN--SEVERAL DEVELOPMENTAL ENDOCRINOLOGDEVELOPMENTAL--DEFIN ITIONS HAV E BEENPROPOSED AND PEOPLE USE THEM INTERCHANGEABLILY ALTHOUGH THEY SHOULDN'T BE USED INTERCHANGEABLILY BUT THE MOST COMMON DEFINITION OF FETAL GROWTH RESTRICTION IS AN ESTIMATED FETAL WEIGHT OR BIRTH WEIGHT LESS THAN 10%ILE. SO BASICALLY WE'RE JUST SAYING THIS MAYBE LESS THAN THE 10th PERCENTILE FOR THAT POPULATION, THAT'S WHAT WE'RE SAYING WHEN WE SAY FETAL GROWTH RESTRICTION, NOW WITH THE PERINATAL MORTALITY AND MORBIDITY BUT PARTICULARLY AS THE TILE GETS SMALLER AND SMALLER, LESS THAN THE FIFTH PERCENTILE AND LESS THAN THE 10th, LESS THAN THE THIRD AND LESS THAN THE FIFTH AND MANY PEOPLE USE THE THIRD OR THE FIFTH, BECAUSE OF THE PERINATAL MORTALITY AND MORBIDITY. AND IT'S A PRETERM DELIVERY AND WE TALK ABOUT PRETERM DELIVERY, MOST OF THE TIME WHEN WE'RE DOING RESEARCH ON PRETERM DELIVERY, WE'RE TALKING ABOUT SPONTANEOUS PRETERM DELIVERY BUT THERE IS ALSO THE INDICATED PRETERM DELIVERY. OBVIOUSLY PREELAMPSIA IS A CAUSE OF THE DELIVERY BUT IUGR IS ANOTHER CAUSE OF INDICATE WIDE WE INDUCE THE PATIENT. THE CHALLENGES WITH FETAL GROWTH RESTRICTION IS TO DIFFERENTIATE BETWEEN WHAT IS A SMALL GUESTATIONAL AGE, REMEMBER I SAID THE DEFINITION BASICALLY JUST TELLS YOU HOW IT RELATES TO A NORMAL GRAM AND MANY OF THESE BABIES ARE NOT GROWTH RESTRICTED THEY JUST FALL BELOW THE 10th PERCENTILE OR THE FIFTH PERCENTILE AND THAT SHOULD BE CALLED SMALL FOR GUESTATIONAL AGE VERSES THROUGH GROWTH RESTRICTION. TYPICALLY IF YOU TAKE 10th PERCENTILE AS THE CUT OFF, ABOUT 80% OF THESE BABIES WILL BE SMALL FOR GUESTATIONAL AGE. THERE IS NOTHING WRONG WITH THEM, THEY'RE JUST SMALLER THAN THE 10th PERCENTILE AND ONLY 20% WILL BE TO GROWTH RESTRICTION. AND THEN IN THE TRUE GROWTH RESTRICTION, WE HAVE TO DIFFERENTIATE BETWEEN THE INTRINSIC AND THE STRUCTURE AND ANOMALIES, WE CAN SAY CHROMOSOMAL AND THEY AFFECT THE PLACENTA OR THE EXTRINSIC WHICH ARE THE ONES THAT AFFECT THE PLACENTA AND THAT WE'RE GOING TO TALKING A BOUT THE IN THE NEXT TWO DAYS. SO NOW MOVING ON AND DELIVERY BETWEEN 16 WEEKS AND LESS THAN 37 WEEKS, I SPECIFICALLY PUT 16 WEEK ASKS HERE AND PREVIOUSLY, STILL SOME PEOPLE BELIEVE THAT 20 WEEKS OR 24 WEEKS SHOULD BE THE CUT OFF BUT I HOPE I SHOWED YOU ENOUGH DATA THAT PRETERM DELIVERY IS ALSO EARLIER THAN 20 OR 24 WEEKS. WE DON'T THINK OF IT THIS WAY BECAUSE THE BABIES ARE VIABLE BUT WE SHOULD KEEP IN MIND THAT THE PATHOGENESIS OF PRETERM DELIVERY OR BIRTH MAY EXTEND ALL THE WAY TO 16 WEEKS NOW WE TYPICALLY CLASSIFY AS I MENTIONED PRETERM BIRTH IN SPONTANEOUS AND NONSPONTANEOUS, UNDER THE SPONTANEOUS WE TYPICALLY CLASSIFY AS INTACT MEMBRANE AND FOLLOWING PREMATURE MEMBRANES SO LET'S NOT FORGET THE MEMBRANES IN THESE TWO DAYS. AND IF YOU LOOK AT THE MORPHOLOGY OF THE PRETERM BIRTH, AND THE MULTIPLES, TWINS, AND ADAPTIVE DISORDERS, THESE CONDITIONS OVERLAP OR PUT ON THE SAME PAGE SO NOW YOU'RE ASKING YOURSELF HOW IS PRETERM BIRTH RELATED TO THE PLACENTA. WELL WE SEE THAT HYPER TENSIVE DISORDERS, FETAL GROWTH RESTRICTION, HEMORRHAGE AND EACH TWINS MAY BE RELATED TO THE PLACENTA, BUT HOW DOES SPONTANEOUS PRETERM BIRTH RELATE TO THE PLACENTA. SO WHAT I WILL TRY TO DO IS CONVINCE YOU THAT AT LEAST THE GOOD PROPORTION OF THE SPONTANEOUS PRETERM BIRTH RELATE TO PLACENTAL MORPHOLOGY OR DYSFUNCTION? NOW ONE WAY TO SHOW THAT IS AN INDIRECT WAY IN SHOWING THAT BABY WHO IS ARE BORN AFTER SPONTANEOUS PRETERM BIRTH, ACTUALLY GROWTH RESTRICTED, RIGHT? THAT'S INDIRECT WAY TO SHOW IT. LHOW DO YOU DETERMINE GROWTH RESTRICTION AS I MENTIONED BEFORE. TYPICALLY IN THE UNITED STATES, WE FOLLOW OR WE COMPARE TO A NORMAL GRAM BY ALEX ABDOMENNER PUBLISHED BY 1986 BY ALEXANDER, IT'S A POPULATION, HUGE NUMBER OF PATIENTS THAT WERE BORN AT DIFFERENT GUESTATIONAL AGE, THEY WERE PLOTTED. THEIR MEAN WAS PLOTTED AND THE 95% COMPETENCE INTERVAL WAS PLOTTED ACCORD TO GESTATIONAL AGE. SO THESE ARE BABIES THAT ARE ACTUALLY BORN AND BIRTH WAY WAS PLOTTED AND IF YOU DO THAT YOU DON'T FIND SPONTANEOUS [INDISCERNIBLE] IN PRETERM BIRTH THAT. IS A FALLACY HERE BECAUSE YOU'RE OBVIOUSLY NOT GOING TO DETECT GROWTH RESTRICTION IF YOU COMPARE IT TO A NORMAL GRAM OF AFTERBIRTH OR BIRTH WEIGHT, NORMAL GRAM, WHAT W WE NEED TO HAVE A NORMAL RATE IN PREGNANCY OR IN UTERO IN A NORMAL BIRTH WAY. AND WE HAVE SEVERAL OF THESE, ONE OF THESE IS THE CUSTOMIZED GROWTH PROTENTIAL AND THAT TAKES INTO ACCOUNT EACH BABY'S GROWTH POTENTIAL AND THEN CAN YOU IT BASED ON SOME MATERNAL CHARACTERIZISTICS. YOU CAN THEN--YOU CAN DRAW THE POTENTIAL CURVE FOR THAT BABY AND THEN COMPARE IT TO THAT BABY, SO THIS BABY WITH THAT WEIGHT, 2500 IS WITHIN THE NORMAL RANGE, THE SAME 2500-GRAM BABY FOR A DIFFERENT MATERNAL CHARACTERISTICS WOULD FALL UNDER THAT GROWTH POTENTIAL. SO THAT'S ONE WAY TO DO IT. I'M NOT SAY THANKSGIVING IS THE WAY TO DO IT BUT THAT'S ONE WAY TO DO IT. IF YOU DO IT THIS WAY, WE DID IT THIS WAY AND LOCK AT PRETERM BIRTH AND OTHER VS DONE THIS, IS NOT ONLY US WHO DID THAT BUT IF YOU LOOK AT PREMATURITY AND ARDIZEED NORM, YOU SEE THERE IS NO DIFFERENCE IN THE PERCENTILES HOW MANY ARE LESS THAN THE PERCENTILES THAN TERM AND PRETERM. IF YOU USE INDIVIDUALIZED GROWTH RESTRICTION, THEN AFTER A QUARTER OF THESE PRETERM BABIES, WERE ACTUALLY GROWTH RESTRICTED. AS I SAID WE'RE NOT THE ONLY ONES LITTLER OTHERS HAVE SHOWN IT, THIS IS A SWEDISH STUDY LOOKING AT LARGE DATA SET AND THIS IS STANDARD DEVIATION AWAY FROM THE MEAN MEANING THE LOWER STANDARD DEVIATION, THE GROWTH RESTRICTION AND ACROSS PRETERM GUESTATIONAL AGES, THE ODDS RATIO FOR GROWTH RESTRICT SIDE VERY, VERY HIGH COMPARED TO TERM GESTATION. SO THERE'S NO QUESTION ABOUT IT THAT PREMATURE BABIES, AND BIG PROPORTIONS OF PREMATURE BABIES ARE GROWTH RESTRICTED. NOT IBT--INTEGRATE DIRECT EVIDENCE OF PLACENTA FUNCTION AND IF YOU LOOK AT THE TRADITIONAL DIAGRAM OF PREMATURE BIRTH AND CAUSES AND THE DIFFERENT PATHWAYS FOR PRETERM BIRTH, I THINK AT LEAST THESE ARE PLACENTAL IN ORIGIN. NO AUTOMATTURATION AND STRESS MEANING THAT'S HOW THE PLACENTA AND THE FETUS IN A GROWTH RESTRICTED ENVIRONMENT WOULD RESULT IN PRETERM BIRTH. SO I DESCRIBE THE DIFFERENT CONDITIONS THAT RELATE TO THE PLACENTA. HOWEVER, I BELIEVE THAT THERE IS A UNIFYING THEORY OF THE CENTRAL CONDITIONS, MAYBE WE'LL BE LIKE EINSTEIN AND OTHER PHYSICISTS TRYING TO FIND THE UNIFYING THEORY BUT I LIKE TO THINK WE WILL FIND THE UNIIFYING THEORY IF WE REALLY LOOK FOR ONE AND LOOK CAREFULLY AT PLATSENTA. WHY DO I THINK LIKE THAT? BECAUSE SOMETIMES THEY OCCUR IN THREE OR FOUR OF THE SAME PATIENT. THERE ARE OVERLAPPING RISKER FACTORS, MATERNAL AGE, MULTIPARITY. HYPERTENSION, ALL OF THESE ARE RISKER FACTORS FIR THESE DIFFERENT CONDITIONS AND I THINK THE MOST IMPORTANT REASON FOR UNIFYING THEOR SETHAT IF ONE OF THESE CONDITIONS OCCUR IN THIS PREGNANCY THAT WOMAN IS AT RISK FOR ALL CONDITIONS IN THE NEXT PREGNANCY, NOVELTY JUST THE SAME--NOT THE SAME CONDITION, ALL THE OTHER PLACENTA CONDITIONS IN THE NEXT PREGNANCY ARE INCREASED SO HERE'S MY UNIIFYING THEORY OF PLACENTAL CONDITIONS: FIRST STARTS WITH IMP PLANTATION. I'M GLAD THAT GRAHAM MENTIONED IMPLANTATION. ABNORMAL IMPLANTATION IS GOING TO RESULT IN ABNORMAL STRUCTURE OF NORMAL LOICATION, SOME OF THESE CONDITIONS I SHOWED YOU, THESE AND YOU CAN EACH PUT EARLY LOSSES IN HERE AND ABNORMAL PLACENTATION AND IMPLANTATION. ABNORMAL IMPLANTATION IS GOING TO ALSO AFFECT FUNCTION, GOING TO RESULT IN ABNORMAL FUNCTION AND EVEN STRUCTURE AND LOCATION COULD ALSO AFFECT FUNCTION. SO FUNCTION IS ACHGHTED. THERE WIL--IS AFFECTED. THERE WILL BE MATERNAL COMPENSATION, THIS IS SUCH AN IMPORTANT--REPRODUCTION IS SUCH ACTIVITIES AND PROJECTS IMPORTANT THING FOR SURVIVAL OF THE SPECIES, YOU COULDN'T THINK THERE WOULDND BE PLACENTA TERNAL COMPENSATION FOR THIS. IT WOULD BE ADEQUATE, INADEQUATE OR EXCESSIVE. IF IT'S ADEQUATE, THEN HAVE YOU GESTATIONAL HYPERTENSION, GESTATIONAL HYPERTENSION IS ACTUALLY AN APPROPRIATE AND PHYSIOLOGIC COMPUTATION. FOR NORMAL PLACENTATION. AT LEAST IN MY OPINION. THE MATERNAL COMPENSATION IS INADEQUATE. WE HAVE TO LOOK AT FETAL COMPENSATION. THERE IS INTERPLAY, IF ONE IS NOT INADEQUATE, THE OTHER MAY MAKE UP FOR IT. IF THE FETAL COMPENSATION IS ADEQUATE--SOMEHOW THIS CHANGES A LITTLE BIT OF WHAT THE COMPUTER CHANGED A LITTLE BIT BUT FOLLOW ME, DON'T FOLLOW THE SLIDE. [LAUGHTER] SO IF THE FETAL COMPENSATION IS ADEQUATE, THEN YOU GET FETAL GROWTH RESTRICTION THAT'S WHAT DAVID PARKER HAS BEEN TALKING ABOUT ALL ALONG, ABOUT THE FETAL DEVELOPMENTAL PROGRAM. IT'S A COMPENSATION BUT IT RESULTS IN FETAL GROWTH RESTRICTION. IF THE FETAL COMPENSATION IS INADEQUATE, THEN CAN YOU HAVE A STILL BIRTH OR A PRETERM BIRTH TO PREVENT THE STILL BIRTH. AND THEN IF THE MATERNAL IS EXCESSIVE THEN YOU GET PRE-ECLAMPSIA AND END ORGAN DAMAGE. SO THIS IS THE THEORY OF PLACENTAL CONDITIONS. LET ME BE PHILOSOPHICAL HERE. I THINK WHAT I TALKED ABOUT AND WHAT WE MOST THINK ABOUT WITH ADVERSE OUTCOMES, IS REALLY THE TIP OF THE ICEBERG, PLACENTAL ABNORMALITIES AND DYSFUNCTION AFFECT THE WHOLE ICEBERG, NOT THE TIP OF THE ICEBERG. FOR EXAMPLE, IT ALSO HAS AN IMPACT ON LONG-TERM OUTCOMES AND LONG-TERM OUTCOMES FOR BOTH THE OFFSPRING AND THE MOTHER. THIS IS THE BOTTOM PART OF THE ICEBERG THAT WE DON'T TYPICALLY PAY ATTENTION TO BUT TO ME IS THE BIGGER PROBLEM THAN THE TIP OF THE ICEBERG. NOW OFFSPRING, THERE ARE LONG-TERM OUTCOMES TO THE OFFSPRING THAT ARE DIRECTLY RELATED TO PRETERM BIRTH, IUGR, PREELAMPSIA, LIKE NEURAL MOTOR DYSFUNCTION, PREMATURITY AND NETOINATEOLOGYST DEAL WITH THAT AND DO RESEARCH THERE. THE OTHER BIG COMPONENT AND THANKS TO DAVID BARKER FOR BRING THANKSGIVING UP TO OUR ATTENTION IS THE DEVELOPMENTAL PROGRAM, THAT'S THE PLACENTAL CONDITION. THAT'S MORE THAN THE TIP OF THE ICEBERG BUT LET'S LOOK ALSO AT THE MOTHERS. DON'T FORGET THE MOTHER, IT'S ALWAYS A MOTHER THERE. AND THERE ARE OBVIOUSLY ADVERSE OUTCOMES THAT ARE LONG-TERM OUTCOMES TO ARE DIRECTLY RELATED TO THE CONDITION, TO THE PLACENTAL CONDITIONS LIKE STROKE AND PATIENT WHO IS HAVE PRE-ECLAMPSIA AND CAN HAVE STROKE AND LONG-TERM OUTCOMES FROM THE STROKE. THEY CAN HAVE RENAL FAIL AND YOU ARE LONG-TERM OUTCOMES, MOST OF THESE PREGNANCY OUTCOMES END UP IN A CESSARRIAN DELIVER SCHEALL OF THESE COMPLI AND LONG-TERM OUTCOMES OF THESE OPERATIVE DELIVERIES, DON'T FORGET OUR DELIVERY VS LONG-TERM OUTCOMES. BUT IN MY OPINION, THE ONE THING THAT WE ALWAYS FOR GET AND AT THE BOTTOM OF THIS ICEBERG IS THE M MAMA TERNAL PROGRAMMING, MANY OF THESE PLACENTAL CONDITIONS, RESULT IN LONG-TERM OUTCOMES THAT ARE NOT DIRECTLY RELATED TO THE PLACENTAL CONDITIONS AND I'D LIKE TO CALL IT MATERNAL PROGRAMMING IN HONOR OF DAVID BARKER ALSO BECAUSE HE CALLED FETAL PROGRAMS OR DEVELOPMENTAL PROGRAMMING AND THESE ARE CARDIOVASCULAR ISSUES LATER IN LIFE. WE KNOW THAT WOMEN WITH SYNDROME VS INCREASED RISK OF CARDIOVASCULAR DISEASE AND METABOLIC DYSFUNCTION LATER IN LIFE AND BEFORE HIS UNTIMELY DEATH, DAVID AND I SPOKE A LOT ABOUT THIS PLACENTAL PROGRAMMING AND I'M GLAD TO SEE THAT HE AND KIN FROMBERG PUBLISHED A PAPER TOGETHER BEFORE HIS UNTIMELY DEATH RELATING THE DEVELOPMENT OF THE PLACENTA AND THEY DID ELEGANT STUDIES LOOKING AT WEIGHT, CIRCUMFERENCE OF THE PLACENTA, WIDTH AND DEPTH AND LENS OF THE PLACENTA SENT S ANTIAND ALL THESE CHANGES IN THE PLACENTA RELATE TO LONG-TERM MATERNAL OUTCOME THAT WE SHOULD NOT FORGET ABOUT. FINALLY I WANT ADD ONE PLUG FOR MATERNAL PROGRAMMING RELATI TO PARTICLES AND MICRO CHIMERS AND I KNOW WE WILL MAYBE TALK ABOUT MEAS MICROPARTICLES IN EVALUATING THE PLACENTAENTA OR LOOKING AT PLACENTA IN REALTIME BUT THESE MICROPARTICLES SEPARATE TO THE MATERNAL CIRCULATION HAVE PATHOLOGIC IMPLICATIONS. THEY REMAIN IN THE CIRCULATION OF THESE WOMEN AND CAUSE ALL KINDS OF ADVERSE LONG-TERM OUTCOMES. THE OTHER ONE AND WE KNOW THAT THESE ARE MICROPARTICLES ARE INCREASED THESE PLACENTA SYNDROMES AND THE OTHER ONE IS MICRO CHIMERISM WHERE THESE ARE CELLS THAT SEPARATE FROM THE PLACENTA, GO INTO THE MATERNAL CIRCULATION IS ACTUALLY STAY IN THE ORGANS OF THESE MOTHERS FOREVER. AND CAN CAUSE ALL KINDS OF AUTOIMMUNE DISEASES CANCERS OR ANYTHING RELATING TO THE IMMUNE SYSTEM. I KNOW WE MAY BE TALKING ABOUT THIS LATER FOR EVALUATION OF THE PLACENTA IN REALTIME BUT DON'T FORGET THE IMPLICATION FOR LONG-TERM HEALTH OF THE MOTHER. >> THERE ARE CHALLENGES LOOKING AT THE CLINICAL OUTCOME OF PLACENTAL DYSFUNCTION. THE EVIDENCE OF PLACENTAL INVOLVEMENT IN ALL OF THESE CONDITIONS THAT I SHOWED YOU IS DULY INDIRECT. WE DON'T HAVE A DIRECT EVIDENCE THIS IS A SLIDE I WORK FROM GORDON SMITH LOOKING AT HOW WE LOOKED AT THESE PLACENTA FROM THE OUTCOME, BIOCHEMICAL, ULTRA SONOGRAPHIC, MRI, OR THROUGH ASSESSMENT OF FETAL GROWTH. THAT'S THE BEST EVIDENCE WE HAVE BUT ALSO OF THESE ARE INDIRECT. EVEN PLACENTAL PATHOLOGY AFTER BIRTH AND I KNOW ALAN MAKES THAT POINT ALL THE TIME IN THAT STUDYING THE PLACENTA AFTER BIRTH IS LIKE STUDYING A DISEASE THROUGH NEUROECTODERMAL CROPSY AND ALL OF THESE ARE INDIRECT MEASURES OF IMPLANTATION. THE OTHER CHALLENGE IS THAT THESE ABNORMALITIES OR WHATEVER SETS THE PLACENTA LIKELY STARTS EARLY AS WE'VE HEARD IN THE PREVIOUS TALK SO WE HAVE TO HAVE SOMETHING THAT WE CAN LOOK AT AND EVALUATE EARLY IN PREGNANCY AND MAYBE EVEN BEFORE PREGNANCY. THE OTHER CHALLENGE AND RESEARCH IN GENERAL, WE RELY ON SIMILARITY AND AVAILABILITY OF THE DIFFERENT THINGS IN OUR RESEARCH AND I HOPE IN THE TWO DAYS IN THE NEXT COMING YEARS WE MOVE OUTSIDE THE [INDISCERNIBLE] KNOWLEDGE OUTSIDE THE FAMILIAR AND AVAILABLE AND BECAUSE OF THIS THERE IS TOO MUCH HUBEROUS IN THE FIELD, TOO MUCH NOISE IN RESEARCH IN THE PLACENTA AND MANY OF THE THINGS I SHOW YOU, I SAID ARE WRONG, I CAN ASSURE THAT YOU MANY OF THE THINGS WE SAY WILL BE WRONG. WILL BE PROVEN WRONG ONCE WE DEVELOP THE RIGHT TECHNIQUES TO STUDY THE PLACENTA. WE MAY HAVE STRAYED TOO FAR AWAY FROM THE TARGET. THE OTHERICAL THEANCH WE HAVE TO KEEP IN MIND IS THAT THE PLACENTA IS NOT ALONE. THERE ARE MANY INTERACTIONS AND COMPENSATIONS, I SHOWED YOU SOME OF THESE IN MY UNIFYING THEORY. BUT THIS IS FOR EXAMPLE IN PREELAMPSIA, WE SHOW THESE STAGES AND RELATIONSHIP BETWEEN PLACENTAL PROFUSION AND THE OUTCOMES BUT LET'S NOT FORGET THAT THE MOTHER ALSO HAS DIFFERENT COMPENSATIONS AND DIFFERENT THINGS THAT COULD CAUSE THE SAME THING WITHOUT ANY PLACENTAL ABNORMALITIES. GORDON SMITH IN THE PROCESS,s I SAID ALL OF THIS START INDEED THE PROCESS, GORDON SMITH HAD THIS NICE SLIDE AND THIS IS THE BASE OF TECHNOLOGICAL CHANGE MILLIONINGS OF YEARS AGO, THE STATE OF THE TECHNOLOGY WAS IT IS ACTS AND FOR NEXT MILLIONS OF YEARS AGAIN, THE AX AND ANOTHER MILLION OF YEARS, THE AX. [LAUGHTER] SO BASICALLY 96% OF THE HUMAN HISTORY HAS BEEN IN PERFEC THE AX AND LESS FOUR% WAS THE TECHNOLOGICAL ADVANCES, I'M AFRAID IN THE PLACENTA WE'RE STILL DEVELOPING THE AX, AND I FEEL LIKE AS A CLINICIAN THAT WE ARE IN A FOG. THE FOG OF WAR, THE FOG OF PLACENTA, AFTER THESE TWO DAYS IN THE COMING YEARS BECAUSE THIS WAS INITIATED THIS FOG WILL BE LIFTED. >> THANK YOU. >> THANK YOU SO MUCH GEORGE WE HAVE TIME FOR ABOUT THREE QUESTIONS. >> EVERYONE'S GOING FOR A QUICK BREAK. [LAUGHTER] >> DR. SADOVSKY, IF YOU COULD SET UP WHILE GEORGE IS ANSWERING QUESTIONS. >> SO GEORGE AS AN MFN PERSON, I LEARNED SOMETHING FROM YOU. IT WAS AN EXCELLENT TALK. SO THE ONE THING I TOOK FROM GRAHAM AND FROM YOU, MAYBE IT IS FIRST PROBLEM WITH [INDISCERNIBLE] IS NOT HYPOPERFUSION OF THE TROPOBLAST BUT HYPER PERFUSION, HYPER PERFUSION WHICH LATER LEADS TO HYPOPERFUSION AND THE OTHER POINT IS THAT WE THINK AN O. B. OF THE MOTHER IS THE PROBLEM OF PROTEINERRIA, BLAH, BLAH, BLAH BUT THE PLACENTA IS DICTATING HER PRESPONSE AS HAVE YOU POINTED OUT SO BEAUTIFULLY. MICRO RNAs ARE BATHING HER SYSTEM. MANY OTHER HORMONES AND FACTORS ARE REALLY PROBABLY ACCELERATING HER VASCULAR DISEASE AND PLACENTAL IN ORIGIN AND I JUST FELT LEAK I HAD TO SAY HOW GREAT THAT WAS TO HEAR IT. >> THANK YOU. >> I HAVE JUST A QUICK ONE. EXCELLENT PRESENTATION. DO YOU THINK WE SHOULD THINK ABOUT FETAL MEMBRANES ALSO? AS PART OF THE PLACENTA? , I NOTICED THE P-PROMULGATE FOR EXAMPLE DIDN'T PUT IN AS A PLACENTAL BUT AS A GROUP IS THAT PLACENTA? >> I SAID IT QUICKLY BUT I'M GLAD YOU ASKED THE QUESTION AND I'D SAY IT AGAIN, WE SHOULDN'T FORGET THE MEMBRANES, I MEAN THE MEMBRANES TO ME MAY BE ONE OF THE WAYS THE PLACENTA SIGNALS THE DELIVERY PROCESS. SENESCENCE IN THE MEMBRANE IS VERY IMPORTANT MECHANISM FOR RUPTURE. ALSO FOR STARTING THE KASP CASCADE OF PRETERM BIRTH AND THAT SIGNAL FOR SE SENESCENCE COULD BEING COMING FROM THE PLACENTA OR THE [INDISCERNIBLE]. >> I THINK YOUR TALK SHOWS AS LWHAT WE MEASURE IS REALLY BASICALLY PHYSIOLOGY BUT THE PROBLEM IS PROBABLY CAUSED MUCH EARLIER DEVELOPMENT OF THE PLACENTA. IS IT POSSIBLE TO SAY, I WAS THINKING OF THE GENOMIC OF THE WAY IN THE SEQUENCE MIGHT BE MUTATED TO SAY IF THIS COMES FROM THE EMBRYO PART OF THE PLACENTA? OR WHETHER PROBLEMS MIGHT ARISE BOTH OF MATERNAL SITES OR THE FETAL SIDE. SNORE CURRENTLY WE DON'T HAVE THE TOOLS TO DIFFERENTIATE BETWEEN THESE TWO EXCEPT TO LOOK AT DNA OF THE MOTHER AND THE CIRCULATION. AND DNA OF THE FETUS AFTER BIRTH BUT THAT'S NOT THE IDEAL WAY TO IT. WE NEED TO BE LOOKING IN REALTIME AT THESE CHANGES AND BOTH IN THE SIGNIFY SIDUEA AS WELL AS MEMBRANES NOT FORGET THE MEMBRANES AND IT MAY NOT BE MUTATIONS IT COULD BE METHYLATION OR SOME OTHER EPIGENETIC CHANGES IN THE DNA, HAVE TO BE ABLE TO MONITOR IT IN REALTIME. >> SO IT SEEMS FROM YOUR TALK THAT ALTHOUGH WE WOULD LIKE TO KNOW WHAT CAUSES WHAT, ALMOST EVERYTHING IS JUST A CORRELATION AT THIS POINT. WE DON'T--WE DON'T--THEY DON'T SEEM TO BE MANY INSTANCES IN WHICH EXPERIMENT CANS BE DONE TO IS THERE ANY MOPE FOR A MODEL SYSTEM AT LEAST FOR YOU KNOW NOT THE WHOLE THING OF COURSE BUT FOR DISCREET ELEMENTS THAT COULD BE USEFUL IN TESTING THE CAUSALITY OF SOME OF YOUR HYPOTHESIS? >> I, GHEE, EVERYTHING IS GOING TO BE--AGREE EVERYTHING IS ASSOCIATIONS. WE LOOK AT ASSOCIATIONS. IT'S HUMAN IS AND THESE HUMANS THESE CONDITIONS DO NOT OCCUR IN AS GOOD AS IN HUMAN OPEN SOURCE SOFTWAREY WOO KOOBT PERFORM EXPERIMENTS TO SHOW CAUSALITY. SO ALL WE CAN DO IS JUST SHOW ASSOCIATIONS THAT PERSIST IN CONDITIONS AND PERSIST IN DIFFERENT POPULATIONS AND ALSO PERSIST UNDER DIFFERENT RISK FACTORS. >> HOW CAN YOU DO SPECIFIC RESEARCH WITHOUT EXPERIMENTALLATION. >> WE WILL LEAD RIGHT INTO THAT. >> OKAY. >> I'LL DO THAT; I WILL LEAVE IT AT THAT. >> YOUR QUESTION IS SO RIGHT ON TARGET AND YOU REALLY TEED IT UP FOR DR. SADOVSKY, TO TALK ABOUT CURRENT METHODS FOR ASSESSING PLACENTA SEBTAL DEVELOPMENTAL FUNCTION AND THEIR LIMITATIONS. [ APPLAUSE ] >> THANK YOU CATHY AND THANK YOU FOR PUT THANKSGIVING TOGETHER AND EVERYBODY AT NICHD. MY TASK IS TO TALK ABOUT METHODS FOR ASSESSING PLACENTAL DEVELOPMENT AND FUNCTION AND BRIEFLY ABOUT THEIR LIMITATIONS SO I WILL TRY TO BE ON TIME, I REALIZE WE'RE A BIT BEHIND AND I WANT TO JUST START BY REMINDING EVERYBODY WHAT A PLACENTA IS, THIS IS ALSO TO MENTION AND SHOW YOU MY DRAWING CAPABILITY, IS THE EXTENT, MAXIMUM I CAN DO. LIKE GRAHAM, WE HAVE A LOGO FOR OUR INSTITUTE AND IF IN HONOR EVER THE MEETING AND I CHANGE TODAY AND FOR THE REST OF THE MEETING, I WILL USE A DIFFERENT LOGO HONORING THE SIGNIFICANCE OF OUR DISCUSSION TODAY. AS MUCH AS I LIKE TO THINK THIS ALL STEMS FROM THE VISION MEETINGS WE HAD SEVERAL YEARS AGO, I THINK ELEN AND CATHY'S INTEREST IN THE PLACENTA ALSO STEMS FROM CURRENT LITERATURE IN SPORTS ILLUSTRATED AND OTHER SOURCES SHOW NEW RECENT EMERGING INTEREST IN THE PLACENTA AS A WAY TO TREAT ALL KINDS OF ORTHOPEDIC LIGAMENT TEARS AND OTHERS AND THESE ARE PICTURES OF FAMOUS SOCCER PLAYERS. >> [INDISCERNIBLE]. >> EXACTLY SO THE IT'S WITH THE WORLD CUP, I WANT TO PROPOSE ONE OF THE OUTCOMES OF THIS MEETING IS NOT ONLY TO USE THE HORSE PLACENTA, THAT WAS USED IN THIS CASE, AS A THERAPY BUT ALSO THE PREVENTIVE MEASURE FOLLOWING THE WORK UP OF PLAYERS, I THINK NIH CAN MAKE AT LEAST A MOUNT OF MONEY BY PATENTING THIS IDEA OF USING PLACENTA AS A PROPHYLACTIC TREATMENT PRIOR TO GAMES. ANYWAY I HAVE A FEW DISCLAIMERS TO SAY THAT JUST THIS IS GENERAL BRIEF REVIEW OF BECAUSE OF STYMIED LIMITATIONS WE DID NOT HAVE DETAILED ANALYSIS BUT EACH OF THE TOOLS THAT I WILL BE DESCRIBE BRIEFLY AND MANY OF HEWS IN THE AUDIENCE DISCIPLINARY SEC AS A CAREER IS WORTH THE FULL HOUR PRESENTATION. I'LL HAVE A MINIMUM DECUSHION OF LIMITATIONS AND I'LL TRY TO MENTION ALL COMMON TECHNIQUES ALTHOUGH I REALIZE I MAY BE MISSING A FEW AND NOT BE ABLE TO GET IN THERE AND THEY HAVE NO CONFLICTS OF INTEREST. SO THIS IS HOW I MENTION LIMITATIONS AND I BRIEF STAR HIGHLIGHTING SELF-LIMITATIONS. WHEN WE TALK ABOUT ALL KINDS OF ADVANCED TECHNIQUES ONE HAS FROM THE VERY BEGINNING, DRUCILL ROBERT SYSTEM HERE FROM MASS GENERAL, WHEN WE ANALYZE THE HUMAN PLACENTA IS TO LOOK AT IT AND GREAT DIAGNOSES THAT CAN BE MADE BY LOOKING AT THE PLACENTA AND SUCH AS COLLECTION OF FLUIDS, CLASSIFICATIONS AND HEMATOMAS THAT ARE SHOWN IN THE CARTOON HERE IN THE CROSS SECTION HERE. SO, GROSS ANAL SILLS OF THE PLACENTA, HUMAN PLACENTA IS ABSOLUTELY ESSENTIAL FOR ANY NORMAL AND ABNORMAL PREGNANCY. NOW TWO OF THE PREVIOUS SPEAKERS ALLUDED TO, KEN THORTON BURG AND BARKER HAS DONE RECENT WORK ON THE PLACENTAL SHAPE IN VERY SIMPLISTIC WAY, SHOWN HERE IN MENTIONED FROM THEIR STUDIES, OF REDUCED IT WITH ASSOCIATION WITH THE ADULT DISEASE AND MEASURE OF NUTRIENTS SENSING NUTRIENTS, THE CELL SIN ESTIMATE THAD ASSOCIATION WITH CARDIAC DISEASE AND ALSO IT WAS MENTIONED IN KEN'S QUESTION ABOUT THE CARDIAC DISK AND THESE ARE VERY INTERESTING ASSOCIATIONS, WE DON'T UNDERSTAND HOW THEY WORK AND WE WILL CONTRIBUTE TO THOSE DISCUSSIONS AS WE LOOK DEEPENER THE GAME, OTHER PEOPLE WHO ACKNOWLEDGE PATHOLOGY, WE KNOW THIS IS THE CURRENT MOST IMPORTANT TOOL TO INTERROGATE THE PLACENTA, MOST COMMONLY DONE BY IT BUT NOT ALWAYS HAVING A DEEP LOOK AS BIOPSIES AND THIS SHOULD BE DUS CUSSED TODAY BUT COMMONLY STRUCTURE AS HERE WE CAN SEE THE DEPOSITS, LARGE AND SMALL VILLI AND INDICATING ENHANCED AND THIS IS TYPICALLY CARING PREECLASMTIONIA AND RESTRICTION AND ALSO ELECTROMICROSOPEN MEETINGY OF A NORMAL PLACENTA SHOWING THE STRUCTURES IN ACTUAL TERM AND I WANT TO USE THIS SLIDE FOR THE NON[INDISCERNIBLE], PEOPLE TO REMIND US--WHAT REALLY SEPARATES THE MOTHER AND THE FETUS, IS JUST THESE SMALL AREAS HERE, MOTHER HERE, EXTENSION OF ONE CELL TYPE, EXTENSION OF THE BASAL MEMBRANE, EXTENSION OF THE ENDOTHELIAL CELLS AND THAT'S IT, THAT'S THE CELLS RIGHT THERE. SO THIS IS VERY SIMILAR TO THE LUNG. THIS IS THE STRUCTURE WHICH IS KEY FOR FETAL DEVELOPMENT BEYOND THE FIRST SEMESTER. SO OF COURSE MATHOLOGY IS LIMITED, IS NOT USUALLY AND PROVIDES LIMI LIMITED DATA FOR THE MOLECULAR ACTION BETWEEN THE PLACENTA, THAT ARE CRITICAL FOR DEVELOPMENTAL INFARCTION OF THIS ORGAN. NOW THIS IS A LAST QUESTION, CAUSE AND EFFECT STUDIES WE CANNOT DO CAUSE AND EFFECT STUDIES IN LIVE WOMEN CARRYING PREGNANCY BUT WE CAN DO--WE CAN USE MANY OTHER SYSTEMS THAT ARE SERVE AS SURROGATE IN VIVO IN OUR LAB AND MANY OTHER LABS, MANY OF US SITTING HERE IN THE AUDIENCE WE USE PRIMARY HUMAN TROPOBLAST CELLS. THESE ARE REAL CELLS FROM REAL PLACENTA AND WE CAN GROW THEM IN ULTIMATE GOAL CUR, THEY DIFREBTIATE NICELY IN CULTURE AND MULTINUCLEATED SEDDED CELLS AND HERE'S A TICKETTURE OF THE CELLS AND THEY CAPTURE THE FEATURES OF THE NORMAL PLACENTA AND WE MIMIC PRE-ECLAMPSIA ON A PLASTIC DISH, PROBABLY NOT FULLY BUT WE CAN TRY TO MIMIC SOME ASPECTS OF NORMAL AND ABNORMAL CELL DIFFERENTIATION INVITRO USING THE CELL SYSTEM, NOW IT'S SOME LIMITATIONS OF COURSE AND IT'S DIFFICULT TO MANIPULATE THEM MOLEC LECULARLY AND IT'S DO YOUABLE AND WE DO IF IN OUR LAB AND OTHERS ARE DOING IN. IT WAS ASKED ABOUT THE LAST TALK OF THE CELL LINE, IT WAS CORRECTLY NONE OF THIS ALLIANCE CAPTURES THE PRIMARY HUMAN ADVANTAGES, SOME OF THEM, THE EXTRA VILLAR TROPOBLAST, OTHER CELLS CAPTURE MORE OF THE TROPOBLAST, SOME DIFFERENTIATE BETTER SOUTH AMERICA DIFFERENTIATE NOT SO WELL BUT EACH ONE OF THEM MAY CAPTURE AN ASPECT OF HUMAN BIOLOGY THAT IS VERY, VERY IMPORTANT FOR DIFFERENT STUDIES, SO THE KEY THING IS NOT TO NEGLECT THEM BUT TO IDENTIFY SPECIFICALLY WHAT SYSTEM THEY MAY BE USED FOR TESTING AND THAT'S ACTUALLY WHAT MANY INVESTORS ARE DOING NOW. SUSAN FISHER HERE, SUSAN WILL CONTRIBUTE OUR DISCUSSIONS. SUSAN'S WORK WITH OTHERS, HAVE CHARACTERIZED THE HUMAN PLACENTAL STEM CELLS AND I'M SURE IT WILL COME UP WITH DISCONGRATULATIONS--DISCUSSIONS FOLLOW THANKSGIVING SESSION AND I THINK THESE CELLS WHICH ARE VERY FRESH IN PLACENTAL RESEARCH WILL BECOME VERY USEFUL AND DERIVATIVES WILL BE USEFUL TO UNDERSTAND NORMAL DEVELOPMENT AND DISEASE AND ALREADY BASED ON SUSAN'S WORK WE BE THEY CAPTURE KEY FEATURES AND PROTEINS AND FEATURES OF NORMAL AND ABNORMAL PLACENTAL DIFFERENTIATION. AGAIN THESE ARE LIMITED SYSTEMS, THEY'RE NOT REALTIME AND THEY'RE VERY MUCH TISSUE DEPENDENT CELL TYPE DEPENDENT AND EACH ONE HAS ITS OWN LIMITATIONS INDIVIDUALLY. NOW TO OVERCOME TISSUE ISSUE, SOME PEOPLE TRY TO STUDY CELL EXPLANTS AND CAN YOU SEE HERE AN EXAMPLE OF EXPLANTS FROM THE FIRST TRIMESTER GROWING ON PLASTICS OR MATRIX AND THIRD TRI TRIMESTERS GROWN IN MESH TO THE BOTTOM OF THE PLATE. THE ADVANTAGE OF AN EXLABORATORY IS THAT IT'S ABLE TO CAPTURE THE TISSUE ARCH 10thURE AND BETTER THAN JUST ISOLATED CELLS. SO IT'S--IT TRIES TO MAKE MAIN TREASURE CONTEXT IN A MORE MEANINGFUL WAY AND A MAJOR DISADVANTAGE THOUGH IS NO REALTIME AND ALSO THE ARCHITECTURE MAY BECOME LIMITED BECAUSE WHAT HAPPENS IN THE PERIPHERAL AREA OF THE PLANT MAY NOT BE WHAT HAPPENS IN THE CENTER OF THE PLANT BASED ON NUTRIENT PROVISION AND OTHER BIOCHEMICAL AND FLOW, SHEER FLOW ASPECTS SO THEY CAN BE USEFUL AND THEY'RE VERY DIFFICULT TO MANIPULATE AND ONE HAS TO BE CAREFUL BEFORE INTERFERING MAJOR CONCLUSIONS FROM STUDYING EXPENSES WITH THE WHOLE WHERE THERE A ARE CELL TYPE DIVERSITY WESTBOUND THE--WITHIN THE [INDISCERNIBLE]. SO ONE OF THE TECHNIQUES USED RECENTLY IS A NUMBER OF YEARS MANY YEAR SYSTEM TO TRY TO STUDY A SORT OF FREE RADICAS TIME--THE CELL PROFUSON IN A HAPPY THAT THE AHMAD IS HERE AND THESE PICTURES ARE FROM OF [INDISCERNIBLE] IN THE AREA AND AS CAN YOU SEE HERE. --UNDERSTANDING CELL FUNCTION NOT FROM A CERTAIN PREGNANCY --TO MENTION THIS IS HERE AND THIS IS A FETAL ARTERY AND VAIN WITH THE ONE SIDE AND THE OTHER SIDE AND EVERYTHING OCCURS IN THIS UNITS AND THROUGH THE METRICS TAKEN--THEY TAB O LIGHTS AND ANALYZING THE ANALYTES FROM THIS SYSTEM, ONE CAN TRY TO INFER AGAIN NORMAL BIOLOGY AND HISTOLOGY. BUT THIS IS A LIMITED SYSTEM NOT ONLY BY THE REALTIME FOR CERTAIN PREGNANCY BUT MAINLY BECAUSE OF IT'S COMPLEXITY. CEREBELLUMS PETTERS IN THE FIELD AND MORE CONTRIBUTIONS TO THE DISCUSSIONS, THAT A SMALL FRACTION, LESS OF THE PLACENTAS DERIVED AND USED FOR THE PROFUSION ARE USEFUL FOR CAPTURING THE BIOLOGY AND MANY OF THEM ARE JUST HAVING A LOT OF TECHNICAL PROBLEM PROBLEMS AND I THINK IT'S A USEFUL SYSTEM BUT THERE'S FEW CENTERS DOING IT RIGHT NOW BUT IT SHOULD BE MAINTAINED BUT IT'S NOT TIME FOR CERTAIN PREGNANCY. SO BEFORE THERE ARE HUMAN MODELS USED TO STUDY THE PLACENTA, MOST COMMON ONES ARE THE SHEEP, MICE, RATS AND GUINEA PIGS. EACH ONE OF THEM IS GRAHAM ALLUDED TO BRIEFLY THE FIRST TALK, EACH ONE OF THEM HAS ITS OWN ADVANTAGES AND DISADVANTAGES, MANY OF US INCLUDING OUR LAB WE LIKE TO USE THE MICE BECAUSE THEY HAVE SO MANY STRUCTURAL ANALOGIES TO THE HUMAN PLACENTA WHICH I'LL SHOW IN A MINUTE BUT IN ADDITION BECAUSE OF THE AMOUNT OF INFORMATION WE HAVE ON MOUSE GENOMICS AND AABILITY TO MANIPULATE THE MOUSE GENOME TO MIMIC NORMAL AND PATHOLOGICALLIZATIONS IN THE PLACENTA. GUINEA PIG VS BEEN USED AND HAVE BEEN CLAIMED TO MIMIC SOME OF THE EFFORTS OF YO HUMAN PLACENTA MAYBE BECAUSE THEY HAVE A LONGER GUESTATION THAN MICE AND TWENTIES, 21 DAYS AND GUINEA PIG IS ABOUT NINE WEEKS AND THE GUINEA PIG ALSO THE EMBRYO HAS A LONGER PERIOD OF THE INTRO UTERINE DEVELOPMENT WHICH IS SIMILAR TO THE EMBRYO, HOWEVER OUR INFORMATION FOR THE GUINEA PIG GENOME LAGS BEHIND WHAT WE KNOW ABOUT THE MOUSE. RATS CAN BE USED AND MICHAEL HAS A LOT OF USE WITH THE PLACENTAL DEVELOPMENT, I'M SURE HE WILL TRIBUTE CONTRIBUTWILL--CONTRIBUTE FROM THE DIGS CUSHIONS. SO THERE ARE LIMITATIONS AND AGAIN, IT'S NOT HUMAN, SO NONE OF THESE MODELS FULLY CAPTURES THE HUMAN PLACENTA SEBTA AND I'LL TOUCH ON THIS IN THE NEXT SLIDE AND OF COURSE NONE OF THIS IS TO LIKE THE HUMAN PREGNANCY. SO TO EXPABD A BIT MORE, THE HUMAN PLACENTA AND THE ROLE PLACENTA, THE MOUSE HAS A HUMAN TRI CORRIAL PLACENTA MEANS HREE LAYERS OF TROPOBLAST SEPARATING BETWEEN THE MATERNAL BLOOD AND THE FETAL CELLS, CAN YOU SEE THEM HERE, THE MONONUCLEEIGHTED CELLS AND TWO LAYERS OF MODEL NUCLEEIGHTED CELLS IN A MOUSE AND IN THE FIRST TRIMESTER PRIMARILY THERE'S TWO LAYERS OF TROPOBLAST AND THEN THEY CHANGE TO A MONOLAYER OF ALMOST ONE LAYER WITH SOME OCATIONAL TROPOBLAST WITH THE LAYER OF THE SUPERSITTIAL TROPOBLAST, CAN AND THIS IS AN ADVANTAGE OF USING THE GUINEA PIG BUT THE MOUSE BECAUSE OF THESE STRUCTURES SIMILAR TO THE HUMAN AND BECAUSE OF SHORT GUESTATION AND THE GENOMICS KNOWLEDGE HAS BEEN THE CURRENT MAJOR SYSTEM TO BE USED. WE'RE ALSO USING THE MOUSE IN OUR LAB AND TO ANSWER THE PREVIOUS QUESTION, YES WE CAN USE THE MOUSE FOR CAUSE AND EFFECT STUDIES AND YOU CAN SEE HERE BY KNOCKING DOWN SPECIFIC GENE, THREES ARE DAT FRANCIS COLLINS BRIAN COX, I'M HAPPY HE IS SITTING HERE AND HE AS CHARACTERSIZED THE MOUSE AND MUSEUM MAN GENOME AND SHOW THAD NEARLY 80% SIMILARITY IN GENE EXPRESSION BETWEEN THE TWO SYSTEMS AND I'M SURE BRIAN WILL CONTRIBUTE TO LEAD THE DISCUSSIONS IN THIS AREA. SO MOVING ON, AGAIN TO BRAG ON MY JOINT ABILITY, THIS IS OBVIOUSLY THE MAIN STAY OF STUDYING THE HUMAN PLACENTA IN REALTIME IS ULTRASOUND AND URLT RASOUND THERE'S GREAT EXPERTS HERE, ALFRED AND OTHERS WHO HAVE REALLY CONTRIBUTED TO THE FIELD. THIS IS JUST A STRUCTURAL DEPICTION OF PLACENTA AS GEORGE SAID WITH IT LOBE AND THE ASSOCIATE PATHOLOGY WITH THIS. THE MAJOR ADVANCE WITH STUDYING THE PLACENTA IS NOT ONLY THE ANALYSIS ANATOMY AND ALSO ANALYSIS OF BLOOD FLOW, MOST IMPORTANT REALTIME TOOLS TO USE TO SURROGATE THE PLACENTA, WE TRY TO STUDY CELL PROFUSION BY FLOW FROM THE MATERNAL SIDE, THE UTERINE ARTERY OR THE FEELAL SIDE, THE VEIN AND THEN WE TRY TO STUDY THE INTERVAL SPACE WITHIN THE PLACENTA. SO JUST TO CHARACTERIZE THOSE, IF THIS IS A CARTOON OF THE HUMAN PLACENTA, THIS IS THE FETAL SIDE AND IN HERE WE USE A TRACTION DUCER TO INFER FLOW IN THE FIELD SIDE IN THE UMBILICAL ARTERY AND THE VEIN AND ALSO FROM THE MATERNAL SIDE, WE TRY TO UNDERSTAND FLOW IN THE SPINE ARTERIES AND THE MEAN TO UNDERSTAND FLOW CHARACTERISTICS AND ALSO RESISTANCE IN THE MATERNAL SIDE AND CHARACTERIZE AND TRY TO DIAGNOSE PRE-ECLAMPSIA AND ALSO WE MAKE SOME USUALLY NOT VERY SUCCESSFUL ATTEMPTS TO UNDERSTAND FLOW WITHIN THE INTERVAL SPACE BY USING DOPPLER. SO THIS IS A TYPICAL EXAMPLE AND REFLECT INVASION OF THE UTERINE ARTERIES THAT GRAHAM AND GEORGE ALLUDED TO AND IN APPEARANCE OF THE NOTCH FOR THE FLOW, WHICH CHARACTERISTICALLY OCCURS IN PRE-ECLAMPSIA, WE CAN ALSO COMBINE THIS CASE OF THE FLOW AND THE NORMAL FLOW, WITH HISTOLOGICAL CHARACTERISTICS AFTER DELIVERY TO TRY TO UNDERSTAND BETTER WHAT MIGHT BE THE CAUSE OF THE ABNORMAL FLOW WITHIN THE PLACENTA. AS I SAID LOOKING AT THE INTERVAL SPACE HAS BEEN DISAPPOINTING THIS IS THE ULTRASOUND AT 32 WEEKS, BUT THE ASSOCIATION OF INTERVILLUS FLOW, WITH DISEASE HAS BEEN REALLY LIMITED AND UNLIMITED USE RIGHT NOW. WE ARE TRYING TO INTEGRATE THOUGH, PLACENTAL IMAGES, TO UNDERSTAND AGER AN ANALYSIS AS A WHOLE AND IT'S JUST ONE PICTURE TRYING TO INFER FROM INDIVIDUAL ULTRASOUND PICTURES, INTO TRYING TO GENERATE A THRE DIMENSIONAL PLACENTAL STRUNGURE AND IN REALTIME, TRY TO MAKE AN ASSOCIATION WITH DISEASES BECAUSE IT'S LIMITED, LIMITATIONS MAINLY, THE RESOLUTION AND THE INDIRECT NATURE OF THESE STUDIES TO INFER ON PLACENTAL FUNCTIONS. SO, AS MANY OF YOU IN THE AUDIENCE WITH YOUR EXPERTISE CAN IMAGINE, MRI BASED TECHNIQUES BECOME A KEY TOOL NOW AS FUTURE TIME ANALYSIS OF THE PLACENTA, PETER BASSER IS HERE AND OTHERS, WITH IMAGING APPLIED TO THE BRAIN AND OTHER CARDIAC OTHER SYSTEMS, THE QUESTION IS CAN WE APPLY THOSE TO UNDERSTAND PLACENTAL FUNCTION AND KEY CONCERNS THAT ARE BEING INTERROGATED OBVIOUSLY COST, ACCESSIBILITY, YOU KNOW THYSELF MACHINES ARE NOT READILY AVAILABLE, THEY'RE NOT BEDSIDE LIKE ULTRASOUND. HOW MUCH THEY TELL US ABOUT PLACENTA FUNCTION AND ALSO SOME QUESTION ABOUT SAFETY, NOT TO SAY IT'S UNSAFE BUT JUST AS WE DON'T HAVE ENOUGH EXPERIENCE WITH THESE TECHNOLOGIES TO INFER SAFETY. JUST BRIEFLY THE CURRENT APPLICATIONS WE USE FOR PLACENTAL MRI TO LOOK AT LOCATION, PLACENTA PREVIOUS, KREDDA IS ONE EXAMPLE, AND VOLUME, AND SALLY COLLINS CAN TELL US ABOUT THAT AND ESPECIALLY IN OBESE PATIENTS WHERE ULTRASOUND IS MORE LIMITED. SO THERE ARE NOW NEW TOOLS THAT REALLY LIKE THE EXPERTISE BUT MANY OF YOU ACTUALLY ARE ENGAGED IN DEVELOPING TOOLS, TRANSLATED HERE AND THEY KNOW--I'M REALLY LOOKING FORWARD TO JOHN'S PRESENTATIONS AND DISCUSSIONS ABOUT SOME OF THE FUNCTIONAL MRI TECHNOLOGIES BUT CAN BE USED TO PUBLISH THIS WITH THE OTHERS TRYING TO USE DIFFERENT MODEL--MODALITIES CHANGING GENETIC FIELDS BASED ONOX GENERATEDDATION AND FLOW AND HOW THEY CHANGE THE MRI SIGNAL TO UNDERSTAND REALTIME ANALYSIS OF PLACENTAL BLOOD FLOW AND MOST IMPORTANTLYOX GENERATEDDATION WHICH IS A KEY--IMPORTANTLY OX GENERATEDDATION THAT GRAHAM ALLUDED TO. THESE ARE BEING TESTED, NONE IS BEING USED IN CLINICAL PRACTICE. BOLD TECHNIQUES OF BLOOD OXYGEN LEVEL MRI IS ONE OF THE MOST TALKED ABOUT TECHNIQUES BUT AGAIN THESE ARE LIMITED BY EXPERIENCE, COST ACCESSIBILITY AND POTENTIAL RISKS. AGAIN NOT TO SAY THEY'RE NOT AS RISKY BUT TO SAY WE DON'T HAVE ENOUGH ABOUT THEM TO ASSESS RISKER. ANOTHER TECHNIQUE, MAINLY PUSHED BY INVESTIGATOR IN JAPAN THIS, IS ONE THE PARENT THE PAPERS IN THIS GROUP , IS USING INNER UTERROUS SPECTROSCOPY IN RELYING ON THE SPECTRAL ANALYSIS OF HEMOGLOBIN, USING THE CHROMOFOREHEMOGLOBIN AS OX GENERATEDDATION AND THIS--OXOX GENERATEDDATED VALUE AND THESE HAVE LESS OBSTRUCTION OF OXYGEN FROM THE SPACE, BUT THEN SUGGESTS WHY THEY TISSUE MAY BE MORE MIRROR IMAG MIRRORMORE HIPOXIC FROM T HE PLACENTA. THIS IS INTERESTING. AGAIN EXPERIMENTAL, VERY FEW PAPERS ABOUT IT BUT IT'S AN IMPORTANT TOOL TO CONSIDER. CAN WE USE MORE TECHNIQUES IN VIVO IN TIME. THIS IS INVASIVE OMNIO SIN THESIS OR A TECHNOLOGY TO OBTAIN A BIOPSY OF THE PLACENTA, I MENTION IT ROUTINELY BUT ANYBODY WHO'S NOT FROM THE FIELD HERE WOULD THINK ABOUT THE CELL BIOPSY, AND RENAL BIOPSY AND LIVER BIOPSY AND OTHER BIOPSY AS A WAY TO OBTAIN INFORMATION ABOUT REAL MOLECULAR ENVIRONMENTS WHO DIDN'T KNOW ORGAN IN THE TYPE. WELL AS CAN YOU IMAGINE PLACENTAL BIOPSIES NOT NECESSARY ALWAYS SAFE AND THE SAFETY HAS BEEN TESTED IN THE SECOND, THIRD TRIMESTER OF PREGNANCY BEYOND THE FIRST TRIMESTER WHEN IT'S DONE AND THROUGH CVS, AND THE HORRIBLE. MOTHERS OR BABIES USUALLY DIE IF YOU DO A BIOPSY BUT THE RISK IS HIGHER THAN JUST CVS AND THE RISK MAY BE HIGHER AS PREGNANCY PROGRESSES SO WE CAN TALK IF WE HAVE TIME ABOUT NUMBERS BUT I THINK THIS IS A REALTIME ASSESSMENT OF THE POETIC PLACENTA BUT BECAUSE IT'S INVASIVE PROCEDURE, NOT MOST MOTHERS WOULD AGREE TO HAVE IT ROUTINELY DONE, TO HAVE REPEAT BIOPSIES TO GET ASSESSMENT OF PLACENTA SEBTA FUNCTION. BUT I WANT TO CONSIDER THE NEXT FEW DAYS VERY DEEP FUNCTION CAN BE OBTAINED BY STUDYING THE PLACENTA IN VIVO. THIS IS JUST A CARTOON FROM A PAPER THAT WE PUBLISHED FROM OUR LAB, MIKE NELSON AND I WHEN I SERS IN ST. LOUIS AT WASH-U, AND WE CAN OBTAIN NICE VILLI, INTERROGATE THEM PATHOLOGICALLY BUT WE CAN INTERROGATE THEM USING A VARIETY OF MOLECULAR MARKERS EBBS TENSIVE ANALYSIS OF THE TRANSCRIPT OHM OF THOSE PLACENTAS AND WANTING TO REMEMBER THIS ONE IS NOT WITH THE OTHER. AND IN OUR STUDY WE DEVELOP THE DIFFERENT SITES AND WE SHOW THAT GENE EXPRESSION IN THIS AREA AND DIFFERENT FROM GENE EXPRESSION IN THIS AREA, AND THIS IS PROFUSION AND PROXIMITY TO THE CORE DEVELOPMENT EVENTS. SO, I THINK IT'S A AN IMPORTANT TOOL BUT AGAIN, I DOUBT TELL BE USEFUL AS A ROUTINE WAY TO LOOK AT PLACENTAL FUNCTION IN VIVO. SO WHAT CAN WE DO AS A SIMPLE TEST, VUBSLY WE WOULD LIKE TO--OBVIOUSLY WE WOULD ALL LIKE TO THINK ABOUT BLOOD TEST, URINE TEST, SALIVA TEST TO ASSESS AN WILL BE THE KEY FOCUS OF OUR DISCUSSION IN ADDITION TO IMAGING IN THE NEXT FEW DAYS. AS GEORGE ALLUDED TO AT THE END OF THIS TALK, THE PLACENTA DOES SHED PARTICLES, THE PLACENTA ALSO SHEDS RNA, DNA AND PROTEINS AND THESE CAN BE USEFUL FOR STUDYING THE PLACENTA AND THE FUNCTION OF THE PLACENTA IN VIVO THE OLD FASHIONED TESTS, SUCH AS THE URINAR SHIELDND DEPEND PROSENTAL PRODUCTION OF ORMOANS AND UP TILL ABOUT 30 YEARS AGO WE DIDN'T USE TO MEASURE THE THIS AND MAYBE YOU MIGHT REMEMBER THIS MPLET SO BECAUSE OF THE LOCATION IN THE HUMAN PLACENTA SENT ACIN THE HUMAN PLACENTA BECAUSE OF THE LOCATION OF TROPOBLASTS WHICH ARE DIRECTLY BATHED WITHIN MATERNAL BLOOD IT IS VERY DEFEATING TO US WE CAN DO THE BLOOD TESTS OR URINE TESTS TO AND ABNORMALITIES TAN ANALYTES FROM THE PLACENTA SO MANY OF US INCLUDING OUR LAB, WE'RE INTENSELY RIGHT NOW TODAY STUDYING THE COMMUNICATION OF VESICLES AND PARTICLES TWEAK THE PLACENTA INTO THE MOTHER AND MAYBE POTENTIALLY INTO THE FETUS ALTHOUGH I REMIND TO YOU GO FROM TROPOBLAST INTO THE FETUS, YOU HAVE TO CROSS A BASAL MEMBRANE AND FILL THE FETAL SALES. TO GO FROM TROPOBLAST TO THE MOTHER, DIRECT SHEDDING INTO THE MATERNAL SYSTEM. SO, THE KEY LIMITATIONS HERE WILL BE THE SELECTION OF THE RIGHT MARKERS AND FIGHTING ALSO FETAL MARKERS AND ALSO PREDICTIVE VALUES. SO JUST BECAUSE THE PLACENTA INDICATES DOESN'T MEAN IT'S THE RIGHT FUNCTION, THE PLACENTA PRODUCES ESTRIOLE BUT NOTES A GOOD MARKER OF PLACENTAL DEVELOPMENT FUNCTIONAL AND THIS, CG ALSO. THERE IS ALSO ANOTHER TYPE OF VESICLE SUCH AS THE VESICLES, THE EXOSTUDIES OF MULTIPLE ENDOCRINES AND ALSO THE LARGER VESICLES, THESE ARE MORE THAN ONE MICROMETER IN SIZE. THESE ARE ABOUT A HUNDRED NANOMETER IN SIZE, AND THESE ARE THE VESICLES IN THE ABOUTS CARRY SIGNIFICANT AMOUNT OF INFORMATION FROM THE PLACENTA NOT ONLY PROTEINS, NOT ONLY METABOLITES BUT ALSO NUCLEIC ACIDS FROM THE PLACEN AND IN OUR LAB WE HAVE PROFILES EACH OF THOSE VESICLES WE CAN SEPARATE THEM AND PROFILE THEM AND OBTAIN REALTIME INFORMATION, AND READ REALTIME INFORMATION FOR THE TAKEN--THEY WE HOPE TO DISCUSS LATER ON IN THESE TWO DAYS. SO HERE ARE EXAMPLES OF THE BLOOD PROTEIN MARKERS OF THE FUNCTIONS OVER THE YEARS AND SOME OF THEM HAVE BEEN USED TO IDENTIFY PRE-ECLAMPSIA, THESE ARE STUDIES BY CARL MANCHU, SITTING HERE SOME OF THEM ARE HOTLY DISCUSSED AND DEBATED. ALSO WE CAN MEASURE DNA AND I THINK DAN BIANNCCI, WILL TALK ABOUT THIS, THE FETAL ASSUMPTION, BUT PLACENTAL FUNCTIONS AND THERE'S OTHER--THERE'S SPECIFIC DNA PRODUCTS THAT CAN BE TESTED FOR GENOMIC FUNCTION, I WOULD SAY BUT ALSO EPIY GENOME EPICENTER FOR THE FUNCTION WITH THE TOTAL EXTRA CELLULAR DNA AND TO MEASURE THEM AS AN INDICATOR OF DISEASE. IN OUR LAB BUT ALSO OTHER LABS AROUND THE COUNTRY THERE,'S BEEN TREMENDOUS WORK ON THE RNA AND THE MA SENTA AND A MEASURE OF PLACENTA SEBTAL FUNCTION SO FETAL WELL BEING, THIS GRAPH IS FROM A RECENT INTERESTING MATHEMATICAL TECHNOLOGIES TO SEPARATE FETAL RNA FROM MATERNAL RNA, THIS IS THE PICTURE FROM THE STEPHEN QUAKES RECENT PAPER SHOWING TOTAL RNA THAT BE FOUND IN THE MATERNAL BLOOD THAT IS A FETAL ORIGIN IN A STRAIKS OF THE--FRACTION OF THE 50% IS THE NONCODING RNAs THAT INCLUDE DIVERSE TYPES OF RNAs AND AND STEPHEN AND HIS PAPER SHOWED THAT THE RELEASE OF RNA GOES UP DURING PREGNANCY AND A MAXIMUM RELEASE IN THE THIRD TRI METER AND IN OUR LAB WE SHOW THAT MOST OF THIS IS IN A FORM OF VESICLE BUT FREE RNA BOUND BY THIS AND OTHERS SO SOME OF THESE RNS ENCODE DIFFERENT PROTEINS IN OUR--HAVE BEEN ASSOCIATED AND CAN YOU SEE HERE IN PARENTHESES HAVE BEEN ASSOCIATE WIDE FETAL GROWTH RESTRICTION AND OTHER DISEASES BUT THESE ARE MERE ASSOCIATIONS WITH VERY POOR UNDERSTANDING OF MECHANISMS. STEPHEN QUAKE IN HIS PAPER WENT FURTHER AND CHARACTERIZED A NUMBER OF TRANSCRIPTS NOT OLDSMOBILE CHASTISTIC OF THE PLACENTA AND A FETAL TISSUES AND HE CAN SHOW IN HIS PAPER, OR CLAIM THAT SOME OF THE SPECIFIC FETAL BRAIN RNAs CAN RELEASE THROUGH THE PLACENTA INTO THE MATERNAL BLOOD AND WITH SOPHISTICATED INTERROGATION OF MATERNAL BLOOD WE CAN ACHIEVE BETTER ANALYSIS OF FETAL PLACENTA SO I HAVE TO CONCLUDE MY TALK WITH THOUGHTTHE FUTURE. EVERY TIME WHEN I THINK ABOUT THE FUTURE I THINK ABOUT THIS GUY. I THINK ABOUT YOGI BARRA, HE SAYS IT IS TOUGH TO MAKE PREDICTIONS ABOUT THE FUTURE. >> THIS IS A-- >> [LAUGHTER] >> YEAH. >> THAT'S RIGHT. >> SO KEEPING THIS IN MIND I THINK JUST I WANT TO SHARE WITH YOU REALLY MY LAST TWO OR THREE SLIDES. , KACCT TOONS WHAT NEW MINES WHAT IT MEANS TO INTERROGATE PLACENTA. ONE OF THE THINGS THAT CAME UP IN OUR MEETING AND WE TALKED ABOUT QUITE A BIT WAS PLACENTA ON A CHIP, I KNOW ALAN GUTTMACHER DID LIKE THAT, I DID THAT IN THE SECOND MEETING SO I COULD CONVINCE ALAN THAT THE CENTER WAS IMPORTANT FOR STUDIES. BUT ON A MORE SERIOUS NOTE THIS CATCHES TWO IDEAS. NUMBER ONE IS CAN WE USE AN CULTURE SYSTEM EXVIVO AND BIOENGINEER IN A WAY TO UNDERSTAND TISSUE ARCHITECTURE AND ITS FUNCTION IN REALTIME. OBVIOUSLY WE DON'T FORSEE THE STUDIES TOMORROW WE WILL DO BIOPSY ON A WOMAN GROW CELLS INVITRO, PUT IT ON A CHIP AND HAVE AN ONGOING ANALYSIS OF THAT PREGNANCY BUT ACTUALLY WHY NOT, THAT WOULD BE NICE THING TO CONSIDER. COULD WE IMPLANT THESE TOOL INTO'S PEG FRANCE SCHETHESE CAN PROVIDE TO US REALTIME INFORMATION ABOUT THE ONANYTHING PROGRESS OF PREGNANCY, THIS IS SCIENCE FICTION BUT NOWA DAYS IN MODEL ORGANISMS WE CAN INTRODUCE TOOLS TO INTERROGATE SPECIFICALLY THE PLACENTA. THIS IS ONE EXAMPLE FROM OUR LAB BUT OTHER LABS ARE DOING THE SAME THING AND PRIMATES AN YOU ARE INVOLVED IN KNEES STUDIES OF USINGULENTY I HAVE RAWS MEDIATED TRANSDUCTION TO INFECT ONLY THE TROUGH TECTOR DERM CELLS OF THE MOUSE PLACENTA REGREWS THEM USING THE IDEA FOR TECHNIQUES INTO THE MOUSE AND USING THIS TECHNIQUE WE CAN INSERT GENES SELECTIVELY INTO THE PLACENTA AS YOU SEE HERE BY GFP EXPRESSION AND YOU CAN SEE IT'S NOT EXPRESS INDEED THE EMBRYO PROPER, ONLY IN THE PLACENTA, IF USED THIS TECHNIQUE BEING THIS SUFFICIENCY ONE OF DEVELOPERS WITH THE LAB, BUT ALSO FEW OTHER GROUPS ARE USING IT. CAN WE ACTUALLY INTRODUCE MOLECULAR PROBES INTO THE US REALTIME ANALYSIS OF PLACENTAL FUNCTION IN HIGH RISK PREGNANCIES AND OBVIOUSLY THE DREAM WOULD BE TO THEN ONCE WE HAVE ANY KIND OF PROBES IS DUE TO A DEVICE, IPHONE ATTACHED TO THE PLACENTA FROM THE OUTSIDE, CAN WE ACTUALLY OBTAIN REALTIME INFORMATION THAT'S ON AN ONGOING BASIS, GIVE US DATA ON THE WELL BEING OF POTENTIAL DEVELOPMENT OF THIS IN THE PLACENTA. THIS SOUNDS LIKE SCIENCE FICTION BUT IF YOU SHOW ME AN IPHONE 20 YEARS AGO, I WOULD SAN FRANCISCO THAT'S SCIENCE FINKS SO WE MADE PROGRESS BASED ON GEORGE'S VIEW OF THE HUMAN DEVELOPMENT. I WILL END WITH THIS AND HAPPY TO TAKE QUESTIONS. THANK YOU. KD--SALL[ APPLAUSE ] >> THANK YOU SO MUCH YOEL, A FRY QUESTIOA--FEW QUESTIONS AND THEN WE'LL GO INTO THE BREAK. >> THANK YOU, SO MUCH, YOU MENTIONED TOPLER FOR BLOOD FLOW--DOPPLER FOR BLOOD FLOR, MRI FOR--ONE THING WE WOULD USE IS MR, NUCLEAR MAGNETIC RESONANCE, TO STUDY PATHWAYS, SIGNALING PATHWAYS BECAUSE NMR IS USEFUL FOR MONITORING PHOSPHOROUS CONTAINING MOLECULES AND THAT'S A BIG PLAYER IN SIGNAL SUGGES PHOSPHOROUS AND I WANT TO BRING THAT UP AND I HOPE ONE OF OUR OUTSIDE EXPERTS WOULD SHED LIED ON THE USE OF THAT NMR IN THAT REGARD. >> I AGREE WITH YOU AND JUST BECAUSE OF TIME I ONLY TOUCH OFFICE OF DIVERSITY IT BUT I THINK THERE ARE EXPERTS HERE IN THE FIELD. I MEKSED A FEW OF THEM BUT PEOPLE THAT GETTIN SEPARATE FROM NIH AND OTHER PLACES ARE EXPERTS IN THIS FIELD AND MOST OF THOSE TECHNOLOGIES ARE UP TELL NOIL HAVE BEEN APPLIED TO THE PLACENTA SO I THINK IT'S TIME TO SERIOUSLY CONSIDER AND I HAVE NO DOUBT THAT IMAGING AND PLOD AND OTHER--BLOOD AND OTHER URINE AND OTHER AN LIGHTS WILL BE THE KEY POINTS OF DISCUSSION NEXT TO THESE, THANK YOU FOR YOUR POINT. >> I'M WONDERING ABOUT ASSESSING BASELINE WITH SOME KIND OF PROVOCATIVE TESTING? YOU'LL AGREE WITH THAT THAT'S DONE FOR HYPOTHALAMIC FUNCTION AND FOR A VARIETY OF THINGS THAT'S WHAT LABOR REPRESENTS PERHAPS? THIS IS A CONUNDRUM. >> YOU'RE GRINNING WHAT DO YOU THINK? >> I AGREE, ONCE WE DEVELOP TOOLS AND THEY RELIAISONNABLY MEASURE FUNCTION, DOING SIMPLE PROVOCATIVE TESTS INI HAVE O, POTENTIALLY UNCOVER THEM THROUGH THE NEXT STEP,. >> [INDISCERNIBLE]. SO THEY'RE TALKING ABOUT METABOLIC STUDIES IN INVO IN TIME AND THE I THINK THE KEY HURDLE, HAS BEEN THE ACCURATE VALIDATED MEASUREMENTS, ONCE WE HAVE THEM, WHAT CANACILY SEE THINGS LIKE TREADMILL OR DIFFERENT SIDES OR DIFFERENT INTERVENTION THAT CAN BE USED TO INTERROGATE THE PLACENTA IN REAL TEEM IN THE REALTIME. >> CAN I--IN YOUR PRESENTATION, YOU COMMENTEDOT PAPER, ON THE ISSUE OF SAMPLING AND THE PAPER YOU PUSHLISH WITH MIKE SAYING THAT THE GENE EXPRESSION OR THE TRANSCRIPTION IS DIFFERENT IN TWO DIFFERENT SITES. IN GRAHAM AND A GROUP OF YOU PUBLISHED, YOU CAME DOWN TO RECOMMENDING FOUR SITES SO I WONDER HOW THIS CAN BE RECONCILED EMPLOY WHAT IS METHOD OF SAMPLING, HOW MUCH VARIATION IS THERE AND IS THERE EVIDENCE OF THOSE FOUR SIZE YOU RECOMMENDED WILL AS THE ISSUE SAMPLE YOU ALLUDED TO IN YOUR PRESENTATION. >> THANK YOU, SO, I THINK--I THINK THE KEY THING, WE CAME UP WITH SEVERAL SITES IN THE PAPER WE PUBLISHED BECAUSE WE WANT TO TRY TO STANDARDIZE THE MEASUREMENT BUT THAT IS NOT TO SAY THAT THERE'S NOT--THERE IS OUR HUMAN WAY TO OVERCOME OUR ABILITY. THAT IS NOT TO SAY THAT THERE'S NO VIABILITY. SO HOW MUCH--SO THE REAL QUESTION IS WHAT WOULD BE THE BEST SITE DIMINISH AMONG PLACENTAS AND ALSO REFLECTS THE PATHOLOGY YOU'RE LOOKING FOR. AND I REALLY THIS MAY SEEM THE TIME WE HAVE RIGHT NOW FOR DISCUSSION, BUT I THINK THE--EXCELLENT, BECAUSE THE PAPER WE PUBLISHED ABOUT 10 YEARS AGO WHEN I WAS WITH WASH-UE, DEDICATED AND CAREFULLY I THINK AND TRANSCRIPT OHM DIFFERENT SITES, AND IT'S DONE TERRIFIC WORK AND A NUMBER OF SIDES LOOKING ATSTERROLOGY IN PERCENTAGE ALL STEMS FROM THE BIOLOGY THAT'S GRABBED UP TO DR. RAMSEY'S PROFUSION STUDIES, I THINK THE ANSWER ROBERTO WILL BE, WHAT ARE YOU LOOKING FOR, IF YOU TRY TO STANDARDIZE FOR CLINICAL USE, WE MAKE RECOMMENDATION. IF YOU WANT TO USE A BIOPSY AS A WAY TO INTERROGATE BIOLOGY, WE THEY'D TO BE MUCH MORE COMPREHENSIVE IN THE RECOMMENDATION WE MADE. >> SO SHORT QUESTION. >> YEAH COUPLE QUICK THINGS. >> JIM'S POINT ABOUT CHALLENGE? I THAT'S ONE OF THE THICKS THAT FOR EXAMPLE ONE COULD DO WITH BOLD MRIs IN THE SENSE THAT CAN YOU HYPEROX GENERATED EIGHT THE WOMAN, YOU CAN BE THE--YOU MAY NOT BE ABLE TO LOOK AT PILOT PROJECT POXIA BUT IF YOU CAN LOOK AT PLACENTAL RESPONSE AND INTERVILLUS BLOOD SPACE RESPONSE TO HYPEROX GENERATEDDATION, CAN YOU LOOK AT SOMETHING THAT IS--THAT CAN COMPARE ABNORMAL TO NORMAL AND GET SOMETHING,. >> WELL THAT'S THE WHOLE POINT YOU CAN BE THE MAKE PEOPLE HIPOXIC BUT CAN YOU GIVE THEM OXYGEN AND SEE CHANGES IN INTERVILLUS SPACE POTENTIALLY IN THE OXYGEN HOW QUICK IT GOES GOES UP AND DOWN AGAIN. >> SAFE AND A MATTER OF THE MAGNETIC FIELD, MOTION PROBLEMS AND SO ON. >> YEAH. >> THE OTHER QUESTION I WANTED ABOUT WAS THE WAS YOU MENTIONED THE NANO PARTICLE TARGETING REPORTERS TO INTERSTITIAL CELLS AND THIS SORT OF THING BECAUSE THAT'S--SORT OF THING LINDA HELIOS POSITIVEISON AND LINDA JONES ARE DOING NOW. SO YOUR QUESTION YOU TALK ABOUT THE USE OF NANO VESICLES AND NONE O PARTICLES ESPECIALLY FOR DIAGNOSTIC AND THERAPEUTICS, IT IS IT'S RIGHT FOR THIS INTERROGATION, I KNOW ROBERTO AND HIS INTEREST, HIGHLY STUDIED WITH THIS THERAPEUTICS AND OUR LAB WE DO THE CAMMING THING SO I THINK AS WE USING THOSE TOOLS TO TREAT THE DISORD WILL BE THE NEXT PHASE OF RESEARCH. >> THANK YOU, I WANT TO THANK ALL OF THE DOCTORS FOR THEIR OVERVIEWS. I SET THE STAGE AND PROVIDED A LOT OF INFORMATION THAT NOT ONLY FOR THOSE OF YOU WHO ARE NOT AS FAMILIAR WITH THE PLACENTA, FOR THOSE WHO ARE, I THINK WE ALL LEARNED SOME NUGGETSA AS WELL AND I APPRECIATE THE THOUGHT THAT THEY PUT INTO THOSE PRESENTATIONS. WE'RE NOW GOING TO MOVE INTO A BREAK. WE GIVE YOU 10 MINUTE FIST YOU COME BACK AT 10:35. WE WILL HAVE AN OVERVIEW PANEL DISCUSSION BEFORE OUR FIRST SET OF BREAK OUTLETS SO COME BACK AT 10:35. WE WILL START PROMPTLY. THANK YOU SO MUCH. WE'RE GOING TO GO AHEAD AND START WITH OUR PANEL PRESENTATION. AS I MENTIONED IN THE OPENING, THE NEXT -- THE REST OF THE WORKSHOP IS GOING TO BE A SERIES OF PANEL PRESENTATIONS WHERE WE'RE GOING TO HAVE EXPERTS KIND OF PRESENT AN OVERVIEW OF WHAT'S GOING TO BE DISCUSSED IN THEIR WORKING GROUP, JUST TO KIND OF HIGHLIGHT TO EVERYONE WHAT THOSE DIFFERENT BREAK OUT GROUPS ARE GOING TO BE COVERING. WE REALIZE THAT MANY OF YOU HAVE EXPERTISE THAT SPANS SEVERAL OF THE BREAK-OUT GROUPS. AND WE HAVE IN YOUR PACKETS YOU WILL SEE A LISTING OF WHAT BREAK-OUT GROUP YOU ARE ASSIGNED TO. YOU MAY NOT LIKE THE BREAK OUT GROUP YOU ARE ASSIGNED TO. I UNDERSTAND THAT. OUR HOPE WAS TO USE YOUR EXPERTISE AND SPREAD THAT OUT ACROSS THE DIFFERENT BREAK-OUT GROUPS THAT WE'RE HAVING. THE GOOD NEWS IS THAT YOU'RE GOING TO GET AN OVERVIEW OF ALL -- OF THE BREAK OUT GROUPS THAT WILL BE HELD BY THE SIX MINUTE PANEL PRESENTATIONS AFTER WHICH WHEN THE -- AFTER THE BREAK OUT GROUPS OCCUR WE WILL THEN HAVE REPORT BACKS FROM EACH OF THESE BREAK OUT GROUPS. AND WE WILL ASK FOR YOUR INPUT ON THOSE REPORT BACKS SO THAT IF YOU HAVE EXPERTISE ON TWO OF THE DIFFERENT BREAK-OUT GROUPS AND YOU'RE ONLY IN ONE OF THEM OR YOU MAY NOT EVEN BE IN ONE THAT YOU HAVE SPECIFIC EXPERTISE IN, WHEN THAT PRESENTATION OCCURS AND THE REPORT OUT OCCURS WE WANT YOU TO GIVE FEEDBACK TO THOSE OTHER BREAK-OUT GROUPS SO WE CAN GET AS MUCH INFORMATION FROM YOU AS WE CAN AND REALLY GET A ROBUST DISCUSSION OF EACH OF THE BREAK-OUT GROUP PRESENTATIONS. I HOPE THAT MAKES SENSE, EVERYONE, HAPPY TO DISCUSS THAT FURTHER DURING THE LUNCH IF YOU WISH. BUT BEFORE LUNCH WE'LL HAVE THE FIRST PANEL SET OF PRESENTATIONS AND THIS SET OF PANEL PRESENTATIONS IS ON THE SHARED PATHOPHYSIOLOGIC PROCESSES THAT CAN BE ASSESSED USING KNOWLEDGE AND TECHNOLOGIES FROM OTHER FIELDS. WE'RE GOING TO HAVE FOUR BREAK-OUT GROUPS, ONE ON AGNATTY AND TISSUE STRUCTURE, ONE IS PRO FUSION, ONE IS TISSUE AND CELLULAR METABOLISM AND ONE IS IMMUNOLOGY AND INFLAMMATION. AND WE HAVE ASKED A HERCULEAN OF FOUR PRESENTERS TO GIVE A SIX MINUTE OVER VIEW STARTING WITH DR. FISHER. >> FIRST I WANT TO SAY WHAT AN ABSOLUTE THRILL IT IS TO BE HERE DISCUSSING MY FAVORITE ORGANS. SO THANK YOU VERY MUCH FOR ORGANIZING THIS. SO I'M GOING TO PROBABLY SAY SOME OF THE SAME THINGS THAT GRAHAM SAID BUT I'M GOING TO TRY TO PUT MORE A FUNCTIONAL SPIN ON THIS. SO JUST FOR PEOPLE WHO DON'T NORMALLY THINK ABOUT THIS, I WANTED TO POINT OUT, WHICH I'M NOT DOING VERY WELL, THE PLACENTA HERE THAT'S CONNECTED TO THE BABY BY THE UMBILICAL CORD. SO I THINK WE'RE IN THE FIELD AND A LOT OF THOSE PEOPLE ASK ME, WHERE IS THE PLACENTA AND WHERE IS THE BABY? SO I ALWAYS START OUT THERE. JUST TO REVIEW, THE PLACENTA HAS A FETAL SURFACE FACING THE BABY AND A MATERNAL SURFACE. AND IF WE STEP BACK A MOMENT, I THINK ONE OF THE MOST INTERESTING THINGS TO CONSIDER ABOUT THE PLACENTA IS THAT IT IS FROM THE BABY. THIS ORGAN IS OUR BEST NO, SIR THE MOST SUCCESSFUL TRANSPLANT. SO IT HAS HALF THE GENES FROM THE FATHER. YET WE DON'T THINK IT'S REJECTED. ROUTINELY. THIS IS WHAT IT LOOKS LIKE. I WON'T BELABOR IT, THE PLACENTA HAS -- WE'RE NOW GOING BACK AND LOOKING AT THE SIDE FACING THE BABY WITH THE UMBILICAL CORD AND THE SIDE FACING THE MOTHER. SO IT'S A VERY LARGE ORGAN AND I ALWAYS LIKE TO SAY IT'S PERHAPS THE MOST IMPORTANT ORGAN OF THE HUMAN BODY BUT YET WE HAVE YET’R TO STUDY ITS MANY, MANY FUNCTIONS. ONE OF IT'S INCREDIBLE FUNCTIONS, THIS IS ACTUALLY TOO SCALE, ONE OF THE FUNCTIONS IS THIS ENORMOUS GROWTH BETWEEN 20 WEEKS AND 40 WEEKS SO THE PLACENTA GOES FROM BEING JUST A VERY FEW CELLS, PERHAPS 20 TO 30 AT THE TIME OF IMPLANTATION TO THIS VERY ENORMOUS E RAN LATE STRUCTURE THAT ONLY LIVES FOR NINE MONTHS. -- ELABORATE STRUCTURE THAT ONLY LIVES FOR NINE MONTHS AND HOW IS THIS EXPLOSIVE DEVELOPMENT DONE AT A GENETIC AND EPIGENETIC LEVEL? I THINK THIS IS ONE OF THE PRIMARY QUESTIONS WE'RE HERE TO PUT ON THE TABLE. SO TO GO OVER THE FUNCTION OF THE INDIVIDUAL CELLS WHICH I THINK IS -- REALLY BARES SAYING ONE MORE TIME. THE TROPOBLAST POPULATION -- I LOST THE LASER, DO WE HAVE ANOTHER LASER? I'LL GO UP HERE. I THINK PEOPLE CAN HEAR ME, RIGHT? SO ONE OF THE MOST IMPORTANT THINGS IS THESE PROGENITORS ARE MONONUCLEAR TROPOBLAS THETS IN THE CHOREIONIC VILLI CAN DIFFERENTIATE ALONG TWO PATHWAYS. IN ONE PATHWAY THE CELLS FUSE TO FORM THIS MULTI-NUCLEATEED SICSHM AND ANOTHER PATHWAY INVADE THE UTERINE WALL. THIS IS PERHAPS ONE OF THE MOST INTERESTING PROCESSES IN ALL OF BIOLOGY. DURING THIS INVASION THEY EXECUTE ONE OF THE FEW EXAMPLES OF WHAT'S AN EPITHELIAL TO ENDOTHELIAL TYPE DIFFERENTIATION PROGRESS IN WHICH THEY BECOME VERY VASCULAR IN THEIR FUNCTION. THEY ALSO HAVE AN INCREDIBLE TROPISM FOR ARTERIES, RATHER THAN VEINS. SO YOU CAN SEE THE BIG EMPHASIS THAT WAS PLACED BY FORMER SPEAKERS ON ARTERIES BUT THESE CELLS, THE TROPOBLAST CELLS HAVE MOLECULAR MACHINERY IN TERMS OF NOTCH MOLECULES AND EPINEPHRINE TOv # ACTUALLY SINGLE OUT ARTERIES. PEOPLE IN MY LAB HAVE BEEN TAKINGING A LOT OF PICTURES, THIS IS A FIRAL ARTERY PER FUSING A PLACENTA AT 16 WEEKS. SO I THINK YOU CAN SEE THIS IS REALLY A VERY STUNNING ANATOMICAL FEED THAT IS GOING ON HERE. THERE'S SO MANY INTERESTING AND SPECIALIZED STRUCTURES IN THE PLACENTA. THIS IS ONE OF MY FAVORITE THAT TO MY KNOWLEDGE IS COMPLETELY UNSTUDIED. THE TROPHOBLAST AND SCHISM IS THE ONLY EXAMPLE IN OUR ENTIRE BODIES WHERE WE HAVE BRANCHED MICROVILLI SO THE CELL BIOLOGY OF THIS ALONE IS QUITE AMAZING. IF YOU LOOK IN THE SCANNING EM, YOU CAN SEE THERE WAS EVIDENCE ON SOME OF THE OTHER PICTURES PEOPLE SHOWED THAT THESE TENTH OF A MICRON PROJECTIONS REALLY GO ON THEMSELVES TO BRANCH. SO THE TEAM OF THE PLACENTA IS VERY MUCH BRANCHING. AND HERE IS AGAIN, THIS INCREDIBLE SYSTEM IN WHICH THIS IS A UTERINE VESSEL BEFORE PREGNANCY AND AFTER PREGNANCY AND WE CAN SEE IT'S NO LONGER LINED BY ENDOTHELIUM, THESE FLAT GLASS LIKE CELLS INSTEAD OF ENTIRELY LINED BY TROPHOBLAST CELLS WHICH IS NOT AN ENGINEERING DECISION I THINK YOU WOULD EVER MAKE BECAUSE OF THE THE TURBULENT BLOOD FLOW THAT ENSUES. HERE IS ANOTHER REALLY INTERESTING THING, IF WE LOOK AT THE TROPHOBLAST CELLS INSIDE THE VESSELS WE CAN SEE THEY'RE ALL DIFFERENT SIZES. THIS THE REFLECTION OF THE FACT THAT AS THE TROPHOBLAST CELLS INVADE THE UTERINE ARTERIES AND THE UTERUS ITSELF, THEY BLOW UP THEIR CHROMOSOME NUMBER SO THEY NO LONGER HAVE A NORMAL CHROMOSOME NUMBER, YOU CAN SEE THIS IN THE DIFFERENT SIZES OF THE CELLS REFLECTING THE DIFFERENT CHROMOSOME NUMBERS. I WANT TO ALSO MENTION PEOPLE HAVE BEEN TALKING VERY MUCH ABOUT THE PLACENTA THAT'S OUR THEME, HERE IS THE MICROANATOMY BUT MEMBRANES ARE ALSO INCREDIBLY IMPORTANT IN THE SMOOTH CHORION THEY'RE CYTOCHROME BLAST STRIATAL BACKING AND THEY FORM A FUNCTIONAL UNIT WITH THE AMNION AND ITS STROMAL BACKING. SO I THINK THESE PICTURES CAN TELL US A LOT ABOUT QUESTIONS WE NEED TO BE ASKING AND ANSWERING. I WANT TO THANK MATTHEW GORMLEY IN OUR LAB, WE HAVE LOTS OF BABIES AND PLACENTAS. HE HELPED ME TAKE THESE PICTURES. THANKS A LOT. [APPLAUSE] >> GOING TO MOVE TO THE NEXT PRESENTATION AN AT THE END WE'LL HAVE SOME TIME FOR DISCUSSION FOR ALL FOUR OF THE PANELISTS. THERE WE GO. DR. SHANDA. >> THANK YOU, VERY MUCH AND THANK YOU FOR THE INVITATION. I'M GOING TO SPEAK ABOUT THE PERFUSION MRI TOOLBOX THAT WE HAVE. I COME FROM A COMPLETELY DIFFERENT AREA OF RESEARCH SO I WANT TO PRESENT TO THE GROUP, THIS IS THE WEALTH OF PARAMETERS WE CAN MEASURE WITH, MRI PERFUSION TECHNIQUES AND AS WE DISCUSSION THINGS, HOPEFULLY WE'LL DECIDE ON WHICH NEED TO BE DEVELOPED FURTHER FOR THESE PURPOSES. SO SINCE I ONLY HAVE SIX MINUTES A LOT IS GOING TO BE THIS IS WHAT IT IS, THIS IS DEFINITION WITH THE COUPLE OF EXAMPLES. SO FIRST STARTING OFF, MR WE HAVE DIFFERENT LEVELS OF FLOW WE CAN MEASURE SO I WANT TO START OFF BY SAYING WE'RE NOT TALKING ABOUT THE LARGE ARTERIAL FLOW THAT WE MEASURE WITH ANGIOGRAPHY, I'M TALKING ABOUT ESSENTIALLY DELIVERY OF BLOOD TO TISSUES SO PERFUSION AS DEFINED BY MOST PEOPLE BUT I HAVE TO MAKE THAT EXPLICIT DISTINCTION FOR MRI. THIS IS A GENERAL SAMPLING OF THE MRI PERFUSION METHODS. I HAVE IT DIVIDED TO TWO CATEGORIES. FIRST, THOSE THAT USE EXOGENOUS CONTRAST AGENTS, CONTRAST ENHANCE AND SUSCEPTIBILITY CONTRAST, I KNOW THAT WE WANT TO AVOID CONTRAST BUT THERE'S SOME AREAS WHERE IT COULD BE USEFUL AND PROVIDE INFORMATION WE CAN'T GET WITH THE OTHER METHODS TESTIMONY OTHER METHODS USE ENDOGENOUS)a6z CONTRAST SO ESSENTIALLY THE BLOOD WATER IN OUR BODIES. THOSE ARE CELLS BOLD METHOD AS WE MENTIONED AND IF I HAVE TIME ISLE BRIEFLY MENTION SOMETHING ABOUT THIS IVIM METHOD. SO FIRST FOR THE EXOGENOUS METHODS, THE CONTRAST AGENT APPROVED FOR CLINICAL USE FOR SOME TIME IS GAD LID YUM CONTRAST AGENT, A TRANSITION METAL KEYLATED BY VARIOUS MANUFACTURERS SO IT'S NON-TOXIC TO THE BODY. UNDER MOST CONDITIONS. WE HAVE VARIOUS FORMULATIONS OF THIS, THIS IS A STANDARD CONTRAST MRI AS SHOWN HERE IN THIS GADOLINIUM ENHANCED MRI BEFORE CONTRAST AND THE PATIENT WITH THE BRAIN TUMOR AN AFTER CONTRAST, SO IT'S OUR ONLY WAY TO ACTUALLY SEE THE LESION EXISTEDS, SHAPE AND WHERE IT IS. THIS IS PERFORMED UNDER STEADY STATE CONDITIONS SO INJECT THE CONTRAST AND YOU IMAGE. PRE AND POST. HOWEVER PERFUSION WE'RE ESSENTIALLY IMAGING AS WE INJECT THE CONTRAST AGENT. THAT'S THE DYNAMIC PART OF THESE METHODS. THE FIRST METHOD IS I CAN MENTION THE DYNAMIC CONTRAST ENHANCE METHOD AND THIS IS THEN THE OLDER THE TECHNIQUE AND THAT WE ACTUALLY USE MRI SEQUENCES THAT WE SEE CONTRAST ENTERING THE TISSUE AND THE SIGNAL BECOMES BRIGHTER. AND SO THIS IS THE T-1 METHOD. WE CAN USE NICE HIGHER RESOLUTION IMAGING TECHNIQUES. FLOSS THE OTHER METHOD IS A METHOD WE IMAGE FASTER AND THE AREA WHERE IT TAKES UP MORE CONTRAST AGENT BECOMES BETTER AND THIS IS WITH T-2 METHOD. I'M GOING TO TALK ABOUT EACH QUICKLY IN TURN. THE PRIMARY APPLICATIONS OF THESE PROFUSION METHODS ARE IN ISCHEMIA, CARDIAC AND CEREBRAL ISCHEMIA AND IN CANCER. SPECIFICALLY IN TUMOR ANGIOGENESIS. THESE ARE EXAMPLES I'LL BE USING. SO FIRST DYNAMIC CONTRAST ENHANCE, IT WAS USED FOR CARDIAC PROFUSION STUDIES. YOU CAN SEE PRE-CONTRAST THE IMAGE SET UP IS VERY DARK, WHEREAS WITH CONTRAST AGENT GOES IN WE USE T-1 SEQUENCES YOU CAN SEE THAT IT'S PER FUSING THROUGH THE CARDIAC TISSUE RIGHT VENTRICLE LEFT VENTRICLE MYOCARDIUM AND WASH OUT SO WE CAN GET A LOT OF INFORMATION FROM THESE CURVES, IT'S ALSO BEING USED FOR BREAST MRI ANALYSIS AND HAS BECOME A PRODUCT WHERE THEY LOOK AT IF YOU LOOK AT IN EACH TISSUE VOXEL, THE SIGNAL AS IT CHANGES OVER TIME AS THE CONTRAST PROFUSES THE TISSUE YOU CAN CATEGORIZE THE LESION IN THOSE INVASIVE CARCINOMA VERSUS LESS VERSUS MORE BENIGN. THIS INFORMATION IS COLORIZED AND SUPERIMPOSEDDED ON THE BREAST TO DIRECT RADIOLOGIST TO WHAT MIGHT BE MORE WERE SRI COUNTRYSOME. THIS IS A HEURISTIC ANALYSIS USED FOR DC MRI. WE CAN ALSO USE THIS IN LIVER AND DISTINGUISH BETWEEN NORMAL AND PLASTIC TISSUE. MORE OFTEN PEOPLE LOOK AT THE HEURISTIC PARAMETERS SUCH AS ENHANCEMENT SLOPES, PEAK ENHANCEMENT BUT THAT CAN BE CONFOUNDING ESPECIALLY BECAUSE THE GADOLINIUM CONTRAST AGENT STAYS OUTSIDE THE CELLS SO THERE'S A CERTAIN PHARMACOKINETIC ANALYSIS DONE TO PROVIDE MORE SPECIFIC INFORMATION AND YOU START TO APPLY SOME EQUATIONS TO GET MORE SPECIFIC PARAMETERS TO CHARACTERIZE SOME OF THE METHODS. THIS IS A PAPER PUBLISHED BY MANY AUTHORS CALLED THE TOX METHOD AND IT IS THE METHOD THAT GIVES SPECIFIC PARAMETERS FROM THE PHARMACOKINETIC MODEL. THE ONE BEEN FOUND MOST USEFUL IS THIS K TRANSPARAMETER, IT'S ACTUALLY THE PRODUCT OF THE EXTRACTION FRACTION IN THE FLOW. SO YOU CAN LOOK AT THE DELIVERY OF THE GADOLINIUM TO THE TISSUE. THIS IS VERY USEFUL IN CHARACTERIZING DIFFERENT DISEASE PROCESSES. THIS IS AN EXAMPLE K TRANSTO SHOW THE EFFECT OF AGENT AND THE VALUE GOES DOWN THAT, TEASE MOST USEFUL PARAMETER IS DC, EVIDENCE. WITH THEKINE MIC SUSCEPTIBILITY CONTRAST METHOD USED MOST OFTEN IN BRAIN AND SPECIFICALLY BRAIN TUMOR, AGAIN WE COLLECT IMAGES VERY QUICKLY OVER ABOUT EVERY ONE SECOND F. YOU LOOK IN EACH VOXEL YOU SEE A SIGNAL TRANSIENT DECREASE. FROM THAT WE CAN CALCULATE A PARAMETER SUCH AS THE RELATIVE CEREBRAL BLOOD VOLUME MAP. THIS IS COMPARED TO THE STANDARD POST CONTRAST IMAGE. SO FROM TIP N TYPE OF DATA WE CAN LOOK AT THE HETEROGENEITY OF THE VASCULARITY IN THE BRAIN TUMOR INDICATOR OF THE GROWING BLOOD VESSELS IN THE BRAIN TUMOR ANGIOGENESIS. THE FEASIBILITY OF THIS HAS BEEN SHOWN BY CORRELATION WITH BRAID, THE SIZE OF BLOOD VOLUME CAN ALSO GET MEASURES OF BLOOD FLOW MEASURING ARTERIAL FUNCTION AN ANOTHER PARAMETER CALLED MEAN TRANSIT TIME. DRAW YOUR ATTENTION TO THIS BECAUSE MEAN TRANSIT TIME IS A PARAMETER USED TO LOOK AT BUDDING VESSELS AS THE PROCESS OF ANGIOGENESIS GOES FORWARD THIS CAN BE VERY INTERESTING WITH PLACENTAL GROWTH AND VASCULAR GROWTH. AN EXAMPLE OF THE DIFFERENT PARAMETERS, CBS MEAN TRANSIT TIME AND CBV DERIVE FROM THE PROFUSION CURVE. SO IN SUMMARY, WITH METHODS WE HAVE DCE DFE, ONE IS BRIGHTER ONE IS DARKER THIS IS USED THE IN BODY AND THIS IN BRAIN. BECAUSE OF THE FACT THE BRAIN AS A BLOOD BRAIN BARRIER, CONTRAST STAYS IN THE VASCULATURE BUT FOR PRE-CLINICAL STUDIES WE USE IRON OXIDE AGENTS VASCULATURE SOMETHING ELSE TO CONSIDER FOR PRE-CLINICAL STUDIES. SO COUPLE OF SLIDES ON THE ENDOGENOUS METHOD SO BY ENDOGENOUS ESSENTIALLY MR IS PRETTY NEAT IN THE WAY THAT WE CAN USE THE BLOOD WATER, WE CAN LABEL THE RF SIGNAL WE CAN LABEL THE BLOOD WATER SO BASICALLY LABELING THE WATER INTO THE IMAGING SLICES AND WE CAN GET A MEASURE OF FLOW. SO IT'S A LITTLE NEWER TECHNIQUE, A LITTLE MORE COMPLEX, THIS IS A COMPARISON OF ASL TO PET TRACER METHODS, THE BLOOD OXYGENATION METHOD AS MENTIONED SENSITIVE TO THE OXYGENATION LEVEL OF THE BLOOD. SO THIS IS THE STEADY STATE SIGNAL AS OXYGENATION INCREASES MR SIGNAL INCREASES AS DIAGRAMS SHOW HERE ALSO. THIS IS USED TO LOOK AT BRAIN ACTIVATION SO WITH LIGHTS OFF VERSUS ON YOU SEE THE INCREASE IN THE SIGNAL AND THE CORTEX -- PARIETAL CORTEX. WE USE IT ALSO IN RAT MODELS. SO THE DIFFERENCE BETWEEN ASL AND BOLD IS ASL IS MORE SENSITIVE TO THE ARTERIAL CIRCULATION WHEREAS BOLD IS SENSITIVE TO THE VENOUS END OF THE CIRCULATION. THEN THE FINAL TECHNIQUE WHICH I'M NOT GOING TO GO INTO IN MUCH DETAIL IS DERIVED FROM DIFFUSION IMAGING METHODS. WHICH ALSO HAD ANOTHER WHOLE REALM OF TOOLS THAT CAN BE APPLIED TO PLACENTAL PERFUSION AN DIFFUSION AND MAYBE WE CAN SPEAK ABOUT THOSE IN OUR BREAK-OUT GROUPS. SO IN SUMMARY, WE HAVE THE TWO GENERAL METHODS EXOGENOUS AND ENDOGENOUS CONTRAST AGENT, THESE HAVE BEEN MORE DEVELOPED IN MRI AN THESE ARE UP AND COMING BUT DEFINITELY BOTH HAVE AREAS OF APPLICATION TO PLACENTAL PERFUSION. THANK YOU. [APPLAUSE] >> >> PLACENTAL TISSUE AND CELLULAR METABOLISM, DR. ILLSLEY. >> I'M ANOTHER LIFER ONLY 30 PLUS YEARS THOUGH. SO WHAT I'M GOING TO START OUT BY DOING IS TRYING TO DESCRIBE WHY IT'S IMPORTANT TO LOOK AT TISSUE AND CELLULAR METABOLISM THE PLACENTA. PLACENTAL METABOLIC FUNCTIONS ARE VITAL FOR THE GROWTH AND DEVELOPMENT OF THE PLACENTAL SUPPLY LINE AS YOU MIGHT IMAGINE. BUT AGAIN, YOU GOT TO REMEMBER THE PLACENTA IS METABOLICALLY ACTIVE AND CONSUMES A SIGNIFICANT FRACTION OF METABOLIC SUBSTRATES IT TAKE UP SO IT ALTER IT IS OUTPUT TO THE FETUS. FINALLY THE PLACENTA ALSO ACTS AS A METABOLIC SENSOR UNDER ABNORMAL OR STRESS CONDITIONS SUCH AS HYPOXIA, PLACENTAL METABOLISM IS MODIFIED BY THE TISSUE ITSELF RESULTING AGAIN, IN AN ALTERATION IN THE SUBSTRATE PROFILE WHICH IS PRESENTED TO THE FETUS. PERHAPS FINALLY, I DIDN'T PUT IT ON HERE, ONE OF THE IMPORTANT POINTS THE TO NOTE ALSO IS THAT AT LEAST IN LATER IN PREGNANCY, CHANGES IN TISSUE AND CELLULAR METABOLISM CAN BE THE THINGS THAT CAN LEAD TO SIGNIFICANT PREGNANCY COMPLICATIONS AND FETAL DEMISE. SO I CAN'T REALLY GO INTO METABOLISM IN GENERAL. I'M GOING TO LIMIT MYSELF TO A COUPLE OF THINGS AND WE CAN DISCUSS MORE LATER BUT WHAT I WANT TO DO IS TALK PLACENTAL METABOLISM AS IT INTERSECTS PLACENTAL PATHOLOGIES. SO THE PATHOLOGIES THAT I'M GOING TO TALK ABOUT ARE ONES YOU HAVE HEARD ALREADY INTRAUTERINE GROWTH RESTRICTION, PREECLAMPSIA AND DIABETES IN PREGNANCY. THE PATHOLOGIC PROCESS I'M GOING TO TRY AND TALK ABOUT ARE THOSE THAT ALTER THE DISTRIBUTION AND UTILIZATION OF ENERGY GENERATING SUBSTRATES. PRIMARILY OXYGEN AND GLUCOSE. SO LET'S THINK ABOUT THESE FOR A MOMENT. OXYGEN OF COURSE IS GOING TO BE TAKEN UP BY THE PLACENTA FROM THE MATERNAL CIRCULATION AND MOVED INTO THE FETAL CIRCULATION. IN SOME OF THESE PATHOLOGIES PREECLAMPSIA AND IGFR FOR EXAMPLE REDUCE PLACENTAL BLOOD FLOW IS A MAJOR ISSUE. THAT REDUCED UTERINE BLOOD FLOW LEADS TO HYPOXIA, ALTERED METABOLISM AND ULTIMATELY TO THESE PATHOLOGIES HERE OR HIGH POXICS AND ALSO REACTIVE OXYGEN SPECIES OXIDATIVE DAMAGE IN THE BLAH STEAN AND BEYOND AND AGAIN, INVOLVEMENTAP)?HR' THESE PATHOLOGIES. THE PROBLEM REALLY IS, WE CAN MEASURE THIS ONE, IT'S FOR ANY -- ONE INDIVIDUAL YOU CAN MEASURE IT, BUT AGAIN BETWEEN INDIVIDUALS THERE ARE QUITE SUBSTANTIAL VARIATIONS. WE CAN OF COURSE MEASURE THIS BUT BY THE TIME WE MEASURE THIS IT'S TOO LATE. WE HAVE ALREADY LOST OUT. THE PROBLEM IS WHAT WE CAN'T MEASURE ARE ANY OF THESE IMPORTANT THINGS IN THE MIDDLE HERE. THIS IS PERHAPS WHERE WE NEED TO THINK ABOUT GOING. CAN WE MEASURE HYPOXIA AN OXIDATIVE DAMAGE? SIMILARLY FOR GLUCOSE, WE CAN MEASURE THE MATERNAL GLUCOSE CONCENTRATION BUT THAT'S ABOUT IT. BUT REMEMBER IN THE PLACENTA WE CAN'T MEASURE GLUCOSE CONCENTRATION, TRANSFER CONSUMPTION AND WE CERTAINLY CAN'T MEASURE FETAL GLUCOSE CONCENTRATION BUT WE NEED TO BECAUSE DIABETES AFFECTS MATERNAL GLUCOSE CONCENTRATION, IT AFFECTS THESE PARAMETERS ON THE WAY THROUGH TO AN INCREASE IN FETAL GLUCOSE CONCENTRATION WHICH WE CAN LEARN ABOUT LATER ON IF YOU LIKE. AND MACROSOMEIA WHICH IS ONE OF THE END POINTS OF THAT. AND ON THE OTHER HAND, HYPOXIA ALSO LEADS TO CHANGES, DIFFERENT CHANGES BUT CLEARLY CHANGES IN GLUCOSE CONCENTRATION PLACENTA IN THE TRANSFER AND IN CONSUMPTION OF THE PLACENTA, AGAIN, LEADING TO CHANGES IN FETAL GLUCOSE CONCENTRATION AN LEADING TO CHANGES IN FETAL GROWTH. SO WHAT SORT OF QUESTION ARE ONES WE NEED TO ANSWER WHEN THINKING ABOUT THESE THING? QUESTIONS LIKE WHEN DOES PLACENTAL HYPOXIA OCCUR? WE JUST DON'T KNOW REALLY. CAN WE MEASURE OXYGENATION AND OXYGENATION IN OTHER PLACENTAL BLOOD SPACES? WHAT IS PLACENTAL GLYCEMIC STATUS? HOW CAN WE MEASURE PLACENTAL GLUCOSE TRANSFER AND CONSUMPTION IN VIVO? ALL IN THIS ELEMENTS ARE REALLY IMPORTANT TO HOW PLACENTA DOES AND THEREFORE HOW THE FETUS DOES. WHAT IS THE BALANCE BETWEEN GLYCOLYTIC AND OXIDATIVE ENERGY METABOLISM IN THE PLACENTA? CAN WE MEASURE THIS IN REAL TIME? AS THE PLACENTA SHIFTS FROM OXIDATIVE TO GLYCOLYTIC FUNCTION WE'RE LOSING THINGS. THE BLAH STEAN IS BEGINNING TO STRUGGLE. -- PLACENTA IS BEGINNING TO STRUGGLE. WHEN DOES FLOW REDUCTION HYPOXIA REPERFUSION LEAD TO GENERATION OF REACTIVE OXYGEN SPECIES? CAN WE MEASURE SOME ONGOING -- GET ONGOING MEASURE OF OXIDATIVE STRESS? BECAUSE ALL WE'RE LOOKING AT RIGHT NOW ARE FINGERPRINTS, INDIVIDUAL COMPONENTS WHICH MAY OR MAY NOT REPRESENT THE OXIDATIVE STRESS PROFILE. WHAT ARE THE OTHER CONDITIONS IN WHICH ASSESSMENT OF THESE PATHOPHYSIOLOGIES IS IMPORTANT? CLEARLY THINGS LIKE ISCHEMIC HEART DISEASE, PLACES WHERE PERFUSION REPERFUSION INJURY CAN TAKE PLACE AS WELL AS CEREBELLAR HYPOXIA AND ISCHEMIA, SOLID TUMOR DEVELOPMENT IS A PLACE ANGIOGENESIS BUT ALSO GLYCOLYTIC FUNCTION, OXIDATIVE FUNCTION IS VERY IMPORTANT. WE'RE LEARNING A LOT ABOUT HOW THINGS CHANGE BECAUSE IN SOLID TUMORS WHEN THERE'S NOT ENOUGH VASCULARIZATION, METABOLISM CHANGES, IT ADAPTS TO A LOW OXYGEN ENVIRONMENT. WE NEED TO LEARN FROM THAT. OF COURSE, CLEARLY WHAT'S HAPPENING IN OBESITY AND TYPE 1 AND TYPE 2 DIABETES IN ADULTS, AND CHILDREN AS WELL, NORMALLY ARE THE SORT OF AREAS WHERE THESE TOOLS ARE BEING DEVELOPED. SO WHAT METHODOLOGIES AND TECHNIQUES ARE BEING USED IN THESE CONDITIONS? SO FOR OXYGEN IF WE HAVE ACCESS TO THE TISSUE, IS OXINETRY, ELECTRO SPECTROSCOPY ELECTRODES CAN BE USED. CLEMLY THE NITRO -- PEOPLE KNOW THEM AS HYPOXY PROBE FOR EXAMPLE. THAT'S WITH ACCESS TO THE TISSUE WHICH WE DON'T HAVE. WITH ACCESS TO BLOOD, ELECTRODES ARE THE PHYSICAL PROBES -- OTHER PHYSICAL PROBES, YES, THAT'S MATERNAL BLOOD ONLY AND NOT WHERE WE WANT TO HAVE ACCESS. HERE IS ONE AREA WHERE PERHAPS THERE'S MORE THAT WE CAN DO. FINALLY WHEN WE HAVE NO ACCESS OF COURSE MAGNETIC RESONANCE SPECTROSCOPY IN TERMS OF LOOKING AT LACTATE OR BOLD AS ALREADY DISCUSSED HERE ARE METHODS THAT ARE CLEARLY IMPORTANT. CHEMICALLY I WOULD SAY YES WE CAN DO THE SAME THING WITH SPECTROSCOPY WITH 19 FLUOROCARBONS BUT THESE ARE METHODS THAT ARE USED WHEN PROBES ARE AVAILABLE WHEN WE CAN GET IN THERE AND DO THINGS NOW WE HAVE TO CONSIDER WHAT WE CAN DO WHEN WE DON'T HAVE ACCESS WITH CONTRAST PROBES AND THIS SORT OF THICK. THESE ARE THE ONES RIGHT NOW WE HAVE TO CONSIDER ACCESS WITHOUT PROBES, FOR GLUCOSE SIMILAR THINGS, SPECTROSCOPY, ELECTROENZYMATIC MEASURES, VARIOUS SENSORS FOR GLUCOSE CAN BE USED BUT YOU HAVE TO GET ACCESS FOR THEM. AGAIN, MAYBE ACCESS TO THE BLOOD BUT RIGHT NOW ONLY MATERNAL BLOOD, AND PERIPHERAL CIRCULATION. SO AGAIN, THE MICRORNAs AND THE METABALOMICS IN THE MATERNAL CIRCULATION MATERIALS THAT HAVE BEEN PUSHED OUT BY THE PLACENTA, THAT ARE THE PRODUCTS. AGAIN, MRS LACTATE AND ANOTHER METHODOLOGY WHICH I WON'T GO INTO NOW BUT IS VERY INTERESTING, SO FAR THE MRS WORK THAT I HAVE SEEN REQUIRES THINGS LIKE NINE TESLA MAGNETIC FIELDS WHICH WON'T BE ALLOWED NEAR FUTURE, BUT AGAIN THE POSSIBILITY OF GLUCOSE MEASUREMENT USING CHEMICAL EXCHANGE SATURATION TECHNIQUE. THE CHEMICAL METHODS MISSION TOMOGRAPHY AND SO ON ARE GREAT BUT AGAIN, WE CAN'T PUT THE PROBES IN. SO I THINK AGAIN HERE, THESE ARE THE METHODS WE HAVE TO BE THINKING ABOUT FOR LOOK AT TISSUE AND CELLULAR METABOLISM, JUST TO CONCLUDE IT'S IMPRACTICAL TO SCREEN FOR EVENTS WHICH LEAD TO PLACENTAL METABOLIC DISTURBANCES IN THE ABSENCE OF OTHER CLUES SUCH AS PRIOR HISTORY. BY THE TIME A PATHOLOGY SUCH AS IUGR IS DETECTED CLINICALLY, IT'S PROBABLE SIGNIFICANT IRREVERSIBLE FETAL PLACENTAL DAMAGE HAS OCCURRED. SO IT'S NECESSARY FOR US TO DEVISE NEW METHODS OF IN UTERO ASSESSMENT WHICH ENABLES THERAPEUTIC INTERVENTION PRIOR TO ESTABLISHMENT OF THE DISEASE. THANK YOU. [APPLAUSE] >> I THINK WE'LL HAVE A WONDERFUL ROBUST DISCUSSION IN BREAK OUT GROUPS THIS AFTERNOON. DR. MOR WILL TALK IMMUNOLOGY AND INFLAMMATION, A VERY SMALL TOPIC. >> THANK YOU VERY MUCH. THIS IS A REAL TALENT. LET'S GO DIRECTLY TO THE POINT. 50 YEARS WE HAVE BEEN DEALING OF REPRODUCTIVE IMMUNOLOGY WITH THE META WORD WHO GOT ANOTHER PRIZE, WHEN THE TIME LET ME TELL YOU, HE WAS A TRANSPLANT IMMUNOLOGY, REMEMBER ABOUT THAT. HE DEFINE PREGNANCY AS -- THE PRESENCE OF THE IMMUNE CELL OF IMPLANTATION HAS BEEN USED AS A PROVE THAT INDEED THE MOTHER IS ATTACKING THE HUSBAND, IS THE HUSBAND REPRESENTED IN THE PLACENTA. AND IN ORDER TO STUDY THOSE -- THE WHOLEAREA OF PREGNANCY FROM IMMUNOLOGICAL POINT HAS BEEN FOCUSED IN THE GUT HOST RESPONSE. AND I BROUGHT -- BECAUSE OF THE TIME THREE MAJOR EXAMPLES OF THIS GRAFT HOST RESPONSE. ONE IMMUNE PRIVILEGE ORGAN OR MECHANICAL BARRIER SUPPRESSION OF THE IMMUNE SYSTEM AND THE IMMUNE RESPONSE. SO THE PLACENTA WAS SUPPOSED TO BE A MECHANICAL -- THAT CREATES A NEW ORGAN WHERE IMMUNE CELLS OF THE MOTHER NEVER WERE CLOSE TO FETUS AND FETAL CELLS CLOSER GOING TO THE MOTHER, COMPLETELY WRONG. WE KNOW THAT I KNOW WHAT I SAY IS HAPPENING. MATERNAL IMMUNE CELLS MIGRATE TOWARDS THE FETUS AND FETAL CELLS GO TO THE MOTHER AND LIVES WITHIN THE MOTHER. THE SECOND, THAT'S SOMETHING I JUST HEARD A MONTH AGO, IN A MAJOR MEETING. WHEN SOMEBODY SAYS WAS GIVING A TALK IN SAY PREGNANT WOMAN ARE IMMUNE SUPPRESS. THAT IS THE REASON THE FETUS IS NOT REJECTED. LET ME TELL YOU, IF THAT WILL BE THE CASE WHEN MY GRANDMOTHER WAS PREGNANT WHEN MY MOTHER -- WITH MY MOTHER AND SHE WAS IMMUNE SUPPRESSED I WILL NOT BE HERE. TRUST ME. BECAUSE HER CONDITION AS WELL AS CONDITIONS OF MANY PEOPLE -- MANY PREGNANT WOMAN IN THE WORLD IS THEY LIVE IN CONDITIONS THAT REQUIRE VERY STRONG IMMUNE SYSTEM. IN AFRICA, ANTI-IMMUNITY IS NOT AFFECTED HIV PREGNANT WOMAN DO NOT DEVELOP AIDS. THE IMMUNE SYSTEM DURING PREGNANCY IS A STRONGER THAN EVER. THE LAST ONE, TH-2 CONDITION. AGAIN, BECAME A NEW DOGMA, PREGNANCY IS AN ANTI-INFLAMMATORY CONDITION. INFLAMMATION IS BAD FOR PREGNANCY. GUESS WHAT, NOT TRUE ALSO. INFLAMMATION IS NECESSARY FOR PREGNANCY. WE KNOW WITHOUT INFLAMMATION THERE'S NO IMPLANTATION AND WITHOUT INFLAMMATION THERE IS NO MATURATION SO WE NEED INFLAMMATION. THERE IS A TIME, THE BEST TIME OF PREGNANCY IN THE SECOND TRIMMEST THEIR IS TRUE. AT THAT TIME THERE IS NO INFLAMMATION. WHY INFORMATION IS GOOD FOR -- PLAINMATION IS GOOD FOR PREGNANCY, ESPECIALLY IMPLANTATION SITE? BECAUSE IMPLANTATION IS LIKE WOUND REPAIR. EVERYTHING, ALL IMMUNOLOGICAL COMPONENTS, ALL THE PROCESS THAT WE SEE IN THE WOUND REPAIR THAT IS EXACTLY WHAT WE SEE IMPLANTATION SITE. SO INFLAMMATORY PROCESS WE CAN CALL IMPLANTATION IS A WOUND REPAIR PROCESS. NEW ASPECTS OF PLACENTAL IMMUNE INTRODUCTION WE NEED TO DEFINE INDEED WHAT IS THE ROLE OF THE MATERNAL SYSTEM, WHAT IS THE ROLE OF THE PLACENTA THE AS IMMUNE REGULATOR AND DURING THE INFECTION? I'M GOING TO COVER THOSE THREE MAJOR QUESTIONS, IN THE KNOWLEDGE OF IMPLANTATION SO LET'S GO OVER THE RULE OF PREGNANCY. MANY PEOPLE INCLUDING US TRY TO DELETE IMMUNE CELLS IN ORDER TO HELP THE PREGNANCY. WHAT IMMUNE CELLS ARE ATTACKING THE PREGNANCY. GUESS WHAT, WHEN WE REMOVE IMMUNE CELLS INSTEAD OF HELPING THE PREGNANCY YOU TERMINATE THE PREGNANCY. SO WE KNOW NOW THE NK CELLS ARE IMPORTANT FOR BLOOD VESSELS. WE HEAR AT THE BEGINNING. WE KNOW MACROPHAGE THERE IS IS NO PREGNANCY. OF COURSE TREG IMMUNOLOGICAL PROBLEMS AND RECENTLY WE SHOW IF WE DEPLETE DENDRITIC CELLS THERE IS NO IMPLANTATION. IN OTHER WORDS, IMMUNE CELLS ARE VITAL FOR SUCCESSFUL PREGNANCY. MATERNAL IMMUNE CELLS. LET'S REDEFINE THE KNEW IMMUNOLOGY OF PREGNANCY. PLACENTA OR THE TROPHOBLAST IS AN IMMUNE REGULATORY ORGAN. I SAY IMMUNE REGULATORY ORGAN BECAUSE IT'S SECRETING A LOT OF FACTORS THAT EDUCATE THE IMMUNE CELL PRESENT AT IMPLANTATION SITE. WHEN I SAY EDUCATE, IT'S INDUCE THE DIFFERENTIATION AND FUNCTION OF THOSE IMMUNE CELLS AND IN UNIQUE CHARACTERISTIC WE ONLY FIND DURING PREGNANCY. AND IT'S UPCOMING FROM THE FACTOR SECRETED BY THE PLACENTA. LET ME POSE YOU THE CHALLENGE, IT'S REALLY THE IMMUNOLOGICAL ASPECT OF PREGNANCY, GRAFT HOST RESPONSE OR MAYBE SOMETHING RELATED TO TUMOR IMMUNE INTERACTION. WHEN WE SEE FACTOR ASSOCIATED WITHIJWTHE TUMOR ABOUT HOW INTERACT ON THE IMMUNE SYSTEM FOR EXAMPLE IMMUNE REGULATION ANGIOGENESIS, VASCULARITY INVASION, IMMUNE CELLS MACROPHAGE CAN HAVE THE TROPO BALANCE SHEET TO INVADE. ALL THOSE PHYSIOLOGICAL FUNCTION AND EVIDENCE WE SEE IN THE TUMOR ARE ALSO HAPPENING AT IMPLANTATION SITE. IMMUNE CELLS THAT YOU FIND IN THE TUMOR (INAUDIBLE) THAT WE CAN SEE AT IMPLANTATION SITE. SO THE LAST ASPECT THAT I WANT TO LEAVE YOU IS ABOUT INFECTION AND PREGNANCY. THE OLD PARADIGM OF INFECTION AND PREGNANCY IS THE RESPONSE INFECTION TO PREGNANCY IS MAINLY ASSOCIATED WITH RESPONSE OF THE MOTHER. SO WE ALWAYS LOOK WHAT HAPPEN WITH THE MOTHER GETS INFECTED. AND WE LOOK -- TALK BEFORE THE MATERNAL IS SUPPRESSED, BECAUSE OF IMMUNE SUPPRESSION WE ALWAYS THOUGHT THAT A PREGNANT WOMAN IS MORE -- IS MORE SENSITIVE TO VIRAL AND BACTERIAL INFECTIONS. THIS IS THE WAY WE HAVE STUDIEDED, AND STILL WE ARE EVALUATING A PREGNANT WOMAN. WHEN THERE IS A VIRUS BACTERIA OR MICROORGANISM WE SEE THE RESPONSE OF THE MOTHER. WE SAW THAT THE PLACENTA AND THE FETUS AS JUST STANDING, THAT HAVE ABSOLUTELY NO ROLE IN THE IMMUNOLOGICAL RESPONSE. SO AGAIN, THE NEW PARADIGM, THE MATERNAL IMMUNE -- IS NOT SUPPRESSED, I TOLD YOU BEFORE. THE PLACENTA PLAYS A CRITICAL ROLE IN THE RESPONSE TO INFECTION. AFFECTING NOT ONLY THE FETUS BUT ALSO AFFECT THE MATERNAL IMMUNE RESPONSE. THEREFORE THERE ARE MAJOR LIMITATIONS TO OUR UNDERSTANDING OF THE ROLE OF INFECTION IN PREGNANCY. WE HAVE ABSOLUTELY NO IDEA. THIS LIMITATIONS HAVE SEVERE IMPACT ON HOW WE IDENTIFY WOMAN AS (INDISCERNIBLE) DURING PANDEMICS. WE KNOW HOW TO TREAT PREGNANT WOMAN OR PREGNANCY COMPLICATIONS DURING INFECTIONS AND WE KNOW HOW TO PREVENT MATERNAL IMMUNITY DURING PANDEMICS. HERE IS THE NEW ASPECT ABOUT THE IMMUNE RESPONSE TO INFECTION. AS I'LL SHOW YOU BEFORE, ONLY MOTHER, DURING PREGNANCY THERE IS A COMPLETE NEW IMMUNE SYSTEM. THAT IMMUNE SYSTEM IS THE COMPOSITION OF ALL THESE THREE. MATERNAL IMMUNE SYSTEM INFLUENCE RESPONSE OF FETUS WHO ARE GOING TO AFFECT THE MOTHER AS WELL AS FETUS. HERE IS A PICTURE. YOU HAVE PLACENTA. AN IMMUNE REGULATORY ORGAN, IF THERE IS INFECTION WHAT IS PRODUCED IN THE INFLAMMATION IS GOING TO AFFECT THE FETUS. ESPECIALLY DEVELOPMENT OF THE FETAL IMMUNE SYSTEM. AND THAT MAYBE RELATED TO SENSITIVITY TO ALLERGIES, TO RESPONSE TO VACCINATION AND SO ON. IT'S HAPPENING HERE. THE PLACENTA MAYBE DIRECTING THE DEVELOPMENT OF THE FETAL IMMUNE SYSTEM. AND THE LAST ONE, THIS INFLAMMATION MAY HELP THE MOTHER BUT ALSO MAY KILL THE MOTHER. SO WE NEED TO UNDERSTAND HOW THE PLACENTA RESPONDS IN ORDER TO UNDERSTAND THE RESPONSE OF THE MOTHER TO INFECTION. THANK YOU. [APPLAUSE] >> I WOULD LIKE TO INVITE OUR FOUR PANELISTS SO THE CHAIRS UP FRONT. WE WILL HAVE A COUPLE OF MOMENTS FOR DISCUSSION AS THEY COME FORWARD I WANT TO GIVE A LITTLE OVERVIEW FOR THE BREAK-OUT PRESENTATION, BREAK OUT GROUPS. WE WILL HAVE RIGHT AFTER LUNCH PLEASE COME TOGETHER TO YOUR SPECIFIC BREAK-OUT SESSION YOU WILL SEE IN THE FOLDER THE BREAK-OUT GROUPS YOU ARE EACH ASSIGNED TO A SPECIFIC BREAK-OUT GROUP. WE'LL GO STRAIGHT TO YOUR BREAK-OUT GROUPS AND DISCUSS IN DEPTH A SERIES OF QUESTIONS WHICH ARE LISTED ON YOUR AGENDA, WHICH I WON'T READ AND DEVELOP A PRESENTATION TO COME BACK AND PRESENT TO THE GROUP. WE -- THAT POINT WE'LL HAVE DISCUSSION OF THOSE BREAK-OUT PRESENTATIONS AS WELL SO WE'LL BE ABLE TO HAVE INPUT INTO EACH OF THESE FOUR GROUPS AND THEIR DISCUSSIONS. WE'RE GOING TO MOVE THE LAUNCH BREAK TO 11:30 TO ALLOW US SOME TIME FOR DISCUSSION NOW AND WE WILL ALLOW YOU THEN TO START YOUR BREAK-OUT SESSIONS AT 12:30. 12:30 UNTIL 2 O'CLOCK WILL BE THAT BREAK-OUT SESSION. THE LUNCH IS IN THE MAIN BUILDING SO IT IS A LITTLE BIT OF WALK TO GET THERE. AND A LITTLE BIT OF A WALK TO GET BACK SO TAKE THAT INTO ACCOUNT TO GET BACK TO YOUR BREAK-OUT GROUP AT 12:30 EXACTLY. A LITTLE BEFORE WOULD BE GREAT. IN THE MEANWHILE WE HAVE TIME FOR SOME DISCUSSION. I KNOW THESE WERE REALLY INTERESTING PRESENTATIONS FILLED WITH A LOT OF INFORMATION. SO QUESTIONS. ROBERTA, DO YOU WANT TO START? (OFF MIC) >> QUESTION REPEAT THE QUESTION, SUSAN? >> SURE. SO ROBERTO ASKED ABOUT THE PARALLELS BETWEEN IMPLANTATION AN TUMORS AND ALSO TO BRING IN SOME CONCEPTS ABOUT STEM CELL BIOLOGY. THERE ARE A GRAVE MANY PARALLELS BETWEEN HOW THE TROFOBLAST CELL APPROACHES THE PROBLEM OF GETTING A MATERNAL SUPPLY OF BLOOD AND HOW A TUMOR CELL APPROACHES THE PROBLEM OF GETTING BLOOD SUPPLY FROM THE HOST. SO WE PUT A MOLECULAR CORRELATE TO THE PROCESS I SHOWED OF BLOOD VESSEL INVASION AND AFTER WE DID THAT TUMOR PEOPLE STARTED LOOKING FOR THE SAME PHENOMENA. IF YOU PUT TUMOR CELLS IN VASCULAR FLOW CAN THEY CHANNEL BLOOD SUCCESSFULLY? NOW THERE ARE SEVERAL EXAMPLES OF TUMORS THAT DO THIS. MARY HENDRICKSON HAS DONE A LOT OF WORK ON THIS IN MELANOMA. I THINK THAT'S A REALLY INTERESTING EXAMPLE. AND IF YOU GO AS FAR AS TUMOR CELLS, THERE ARE NOW REPORTS THERE WAS A REPORT IN PNAS WITHIN THE LAST SIX MONTHS OF TUMORS ACTUALLY CONTAINING PLURIPOTENT CELLS THAT EXPRESS ALL THE STEM CELL MARKERS. AND THAT THEY ACTUALLY CAN GROW IN TO NORMAL SORTS OF ORGANISMS AND PRODUCE NORMAL SORTS OF PROGENY. SO I THINK IT'S AN INTERESTING AND VERY UNTAPPED AREA OF PLACENTAL RESEARCH, THE EXTENT TO WHICH THE EMBRYONIC AND TUMOR PROGRAMS ARE SHUT DOWN AS COMPARED TO THE PATHOLOGICAL COUNTER PARTS. >> OKAY. I HAVE A COMMENT FOR THAT TISSUE CELLULAR METABOLISM, ACTUALLY THERE'S NEW IMAGE MODALITY,ED IN CANCER FOR A LOT, RECENTLY IN FEW YEARS AS HYPERPOLYRIDE MAGNETIC RESONANCE IMAGING SO YOU'RE USING CARBON PYRUVATE OR VITAMIN C OR GLUTAMATE, YOU CAN LOOK AT GLUCOSE AND METABOLIC SWITCH AND ALSO THAT REDOX STATUS. SO THE ONLY THING I DO KNOW FOR THIS PARTICULAR SYSTEM YOU HAVE MOTHER AN BABY THERE, THIS PROBE CAN BE TOLERATED BY MOTHER AND THE BABY. THIS IS BASICALLY SOME SMALL MOLECULE OF AMINO ACID OR SOMETHING. >> YES. I MEAN, I THINK ONE OF THE PROBLEMS IS NOT THAT THERE ARE NOT PROBES AVAILABLE. BUT I MEAN BELIEVE ME, I HAD A HELL OF A TIME TRYING TO BE ABLE TO USE STABLE ISOTOPES, STABLE ISOTOPE LABELED AMINO ASITS. IN PREGNANCY -- ACIDS IN PREGNANCY. NOT THAT THE PROBES ARE NOT AVAILABLE, IT'S THE PREGNANCY IS A PRIVILEGE CONDITION IF YOU LIKE IN THE SENSE OF BEING ABLE TO USE THESE PROBES WITH. THERE ARE LOTS OF THINGS THAT ARE USED, LOTS OF SYSTEMS THAT ARE USED IN ADULT HUMAN BEINGS THAT WE COULD USE IN PREGNANCY. BUT AS I WAS SAYING TO JIM EARLIER, TRY AND FIND ME A DRUG COMPANY THAT IS PREPARED TO PRODUCE CONTRAST PROBES OR OTHER THINGS LIKE THAT, WHICH ARE GOING TO BE PUT INTO PREGNANT WOMEN ON REGULAR AND ROUTINE BASIS. ONE OF THE REASONS WE HAVE THE PROBLEMS WE DO IS BECAUSE PEOPLE ARE SCARED OF DOING THINGS TO PREGNANT WOMEN. IT'S NOT -- WE HAVE TWO PROBLEMS. ONE THEY'RE SCARED TO DO THINGS TO PREGNANT WOMEN AND SECOND, THE PROBLEM OF ACCESS. AND SO WHEN YOU COMBINE THOSE TWO, YOU GET TO WHERE WE ARE NOW. IT'S NOT THAT SOME OF THE TOOLS AREN'Ta/Y AVAILABLE. IT'S THAT IF YOU WANT TO FIND A CLINICIAN WHO # >> I HOPE EVERYONE ENJOYED A NICE LUNCH AND GOT TO SEE SOME OF THE BEAUTIFUL WASHINGTON SUNSHINE. OUR GOAL WITH THESE REPORT OUTS FROM THE BREAK-OUT SESSIONS IS TO REALLY START THE DISCUSSION AND GET THE INPUT FROM THE PEOPLE WHO WERE NOT NECESSARILY IN THAT GROUP. ALSO WELCOME ANY ADDITIONAL DISCUSSION FROM PEOPLE WHO WERE IN THAT GROUPS, SOMETIME THERE'S MORE TO BE SAID. WE ARE WAITING FOR ONE FINAL PRESENTATION BUT IF WE DON'T GET IT WE WILL GO AHEAD AND GET STARTED AND THEN IT WILL SHOW UP I'M CERTAIN. DOING THE BEST I CAN, RIGHT? WHAT WE'RE GOING TO DO, THESE PRESENTATIONS SHOULD -- ARE PLANNED TO BE TEN MINUTES IN LENGTH AND THEN WE WILL HAVE TIME FOR QUESTIONS AND ANSWERS AND DISCUSSION. SO IF I DON'T SEE THAT FINAL PRESENTATION WE'LL GET START -- DO YOU HAVE IT? SHE'S BRINGING IT? OKAY. THAT'S FINE. LET'S START WITH DR. FISHER'S GROUP. I KNOW DR. FISHER WAS READY. YOU HAVE TEN MINUTES. >> OKAY. SO WE HAVE THE SAME QUESTIONS BUT I'LL REITERATE THE FIRST BULLET WHICH WAS WHAT FUNCTIONS ARE IMPORTANT TO EVALUATE IN REAL TIME. WE STARTED TALKING THE MORE MICROSCALE AND MOVE TO THE GROSS ARCHITECTURE BUT SO THAT'S SORT OF THE ORGANIZATION OF THIS SLIDE. SO WE WANTED TO KNOW ABOUT TROPHOBLAST REMODELING OF SPIRAL ARTERY, UTERO AND PART AND PARCEL WITH THAT COMES UTERO PLACENTAL PERFUSION. FORMATION OF THECOID PLACENTA IS IF THE SHAPE OF THE PLACENTA REFLECTS FUNCTION AND PREGNANCY OUTCOME, CAN THIS BE UNDERSTOOD MORE IN REAL TIME. EVERYONE WANTED TO MONITOR TROPHOBLAST DIFFERENTIATION MORE LIKE TROPHOBLAST ENVISUALIZATION AND INTO THIS ALL WENT FUNCTION. SO IN THE END WE CAME DOWN TO MONITORING THE ARCHITECTURE OF DEVELOPMENT]  AND BEING ABLE TO MONITOR THAT,W ARCHITECTURE AT DIFFERENT SITES IN THE UTERUS. INCLUDING BRANCHING MORPHOGENESIS AND THEN AS I'LL COME BACK TO ON THE LAST SLIDE, MAPPING FUNCTION TO FORM. SO WHAT ARE THE CURRENT STATE-OF-THE-ART APPROACHES FOR ASSESSING THESE FUNCTIONS? I AM ABSOLUTELY SURE THIS NEEDS TO BE ADDED TO SO THIS IS NOT MEANT TO BE EXHAUSTIVE SO THIS COULD BE A POINT OF DISCUSSION. UTERINE DOP PLIERS, EXAMINING PLACENTAS FROM DIFFERENT GESTATIONAL AGES SO PATHOLOGY IS STILL THE MAIN STAY. MRI. AND THEY'RE LIMITED BIOMARKER PANELS. ONE THAT I CAN THINK OF RIGHT NOW THAT'S NOT ON HERE WOULD BE USING THE FETAL DNA FOR AANYPLOIDY WHICH SOMEHOW WE MISSED OUT. HOW ARE THE PROCESSES ASSESSED IN OTHER FIELDS? WE TALKED ABOUT THINGS THAT ARE BEING APPLIED, PARTICULARLY IN CANCER FOR EXAMPLE, LIQUID BIOPSIES IN WHICH WHAT IS SHOWING UP IN BLOOD IS REPRESENTATION OF EITHER THE TUMOR OR HOW THE PATIENT IS REACTING TO THE TUMOR. PROJECTS LIKE THE CANCER GENOME ATLAS WHICH TAKE IT IS GENOME TO PERSONALIZED TREATMENT. IN THAT CASE WE KNOW MOST OF THE ANSWERS WERE EXPECTED ONES BUT THE EXCEPTIONS HAVE BEEN IMPORTANT AND IT SEEMS TO US NOW WE KNOW THE FETAL GENOME AND MATERNAL GENOME ARE EASILY ACCESSIBLE IN THE BLOOD, THAT THOSE KIND OF APPROACHES SINCE THE MATERIAL IS EASY TO GIVE GET, EASIER THAN CANCER THAT WE SHOULD EXPLOIT THAT MATERIAL. THEN FOR IMAGING WE TALKED ABOUT PHOTON MIGRATION WHICH IS BEING USED TO TRACK PRIMARILY OXYGEN SATURATION AND BLOOD FLOW IN TISSUES. IF I GOT THAT HORRIBLY WRONG, PLEASE IMAGING COLLEAGUES CORRECT ME BECAUSE I HAVE NO IDEA WHAT THIS IS. AND ALSO PET FOR IMMUNE ACTIVATION AND I'M GOING TO GO DOWN TO AT THE LAST BULLET WHICH WAS IMAGING STUDIES BOLD MRI WHICH WAS DISCUSSED BY A LOT OF PEOPLE THIS MORNING. FINALLY PLACENTAL SHED PRODUCTS INTO THE BLOOD, I JUST MENTION FETAL DNA FOR ANNIEPLOIDY ANALYSIS BUT OTHER PRODUCTS BE ARE BEING SHED INTO BLOOD THAT SHOULD BE ENABLE RNA P AND PROTEIN ANAL SIZE. WE COMBOD THE LAST TWO BULLETS WHICH ARE WHAT TECHNOLOGIES MIGHT BE APPLICABLE AND NEED TO BE DEVELOPED. SO SOME OF THESE I THINK ALMOST ANY GROUP WOULD COME UP WITH. IF WE KNOW MORE SPECIALIZED FUNCTIONS OF PARTICULAR AREAS OF THE PLACENTA, CAN WE COME UP WITH ANIMAL AND EXVIVO MODELS FOR ASSAYING THOSE FUNCTIONS? SO I THINK WE ALL KNOW ANIMAL MODELS FALL SHORT IN CERTAIN AREAS BUT IF THEY'RE APPLIED JUDICIOUSLY, THEY CAN BE INCREDIBLY VALUABLE. KNOWING THE FUNCTION, ARCHITECTURE AND FUNCTION WOULD BE ALLOWED TO BETTER SUIT THE MODEL TO THE PROBLEM. P AND PEOPLE WOULD LOVE TO HAVE TRACERS, VARIOUS KINDS OF TRACERS FOR FOLLOWING VARIOUS BLOOD FLOW AND FOR LABELING VARIOUS KINDS OF CELLS. PROTEOMIC IMAGING WHERE WE'RE BE ABLE TO VISUALIZE CELLS BASED ON THEIR PROTEIN EXPRESSION. BUT I THINK THE LAST POINT COMES DOWN TO WHAT WE ALL FELT WAS THE MOST IMPORTANT THING. IT'S NOT A TECHNOLOGY TO BE DEVELOPED BUT MORE APPLICABLE THAT WE REALLY NEED A GENOME, AN EPIGENOME ATLAS, EVEN PERHAPS DOWN TO THE CELLULAR LEVEL OF THE PLACENTA AND DISIDUA THROUGHOUT GESTATION. BECAUSE FROM THIS WILL FLOW ALL THE OTHER TECHNIQUES. IT WILL ALLOW US TO UNDERSTAND CHANGES THAT ARE HAPPENING IN REAL TIME OVER GESTATION, APPLY SYSTEMS BIOLOGY APPROACHES. COME UP WITH BIOMARKERS,„u(T‡‡U( WITH MOLECULAR BASED HYPOTHESES. SO THAT WAS OUR CONCLUDING STATEMENT. >> THIS IS NOW OPEN FOR DISCUSSION. SUGGESTIONS THOUGHTS FROM OTHERS IF YOU WILL OR NOT IN THIS GROUP? (OFF MIC) >> EXPRESSION LAYER TO THE LAST >> ADD THE EXPRESSION LINEAR TO THE LAST BULLET, GENOME, EPIGENOME AND TRANSCRIPTOME. >> OH. >> FRIENDLY SUGGESTION. >> YEAH I KNOW. I WOULD ADD TO THAT PROTEOMIC METABALOME AND -- I AGREE TOTALLY. >> SO THAT WE UNDERSTAND THE PLACENTAL >> I WAS CURIOUS IF THE GROUP HAD ANY INTERESTING DISCUSSION ON WHETHER WE SHOULD LOOK AT IMPROVING CURRENT ANIMAL MODELS OR NEW ANIMALS THAT HAVE NOT BEEN ASSESSED DURING PREGNANCY? >> WE TALKEDDED ABOUT NEITHER. DO YOU HAVE IDEAS TO SUGGEST SUGGEST? >> COMPARING BETWEEN EACH OTHER AND REALLY GOING AND SAYING THIS IS GOOD FOR THIS. SO LOOKING AT WHAT ANIMAL -- INDEXING ALL ANIMAL MODELS AND JUST HAVING A DATABASE OF WHAT ACCEPTABLE RESEARCH IS ONE AND NOT WITH OTHERS, IT WILL RECONSTITUTE STUDY SECTIONS THAT SOMETIMES THE REVIEWERS DON'T AGREE AT ALL ON WHETHER THE ANIMAL MODEL IS GOOD OR NOT. >> IN ANSWER TO YOUR QUESTION WE HAVE BEEN DOING THE BABOON WHICH IS MY COUSIN PRIMATE, 96% DNA AND I THINK THE LESSON WE LEARNED FROM IT IS LIKING FOR THE SAME MEDICATION WE SAW PREGNANT WOMEN METABOLIZEING IT IN THE BABOON, THE PREGNANT BABOON WAS DIFFERENT. CIP 384 IN THE PLACENTA OF THE PREGNANT WOMAN IS NOT THERE IN THE BABOON, IT DOESN'T HAVE SIP 3 BUT ALSO ANOTHER ENZYME TAKING OVER THAT FUNCTION. SO EVEN FOR MAN AL MODEL I THINK BABOON IS MUCH MORE INFORMATIVE, YOU HAVE TO LOOK AT EACH FUNCTION BY ITSELF. (OFF MIC) >> I THINK THE LAST POINT WAS EXACTLY ABOUT THIS, HAVING A DATABASE OF GENE EXPRESSION AFTER TRANSCRIPTOME LEVEL AND FOCUS THOSE REGULATORS OF DEVELOPMENT. IF YOU HAVE A SIMILAR TIME COURSE OF EXPRESSION OF IMPORTANT TRANSCRIPTION FACTORS IN SIGNALING MOLECULES, FOR EXAMPLE FOR ALL THE IMPORTANT MODEL SYSTEM, YOU CAN MAKE COMPARISON AND ALSO GET FROM THAT A SET OF REGULATORS THAT YOU COULD STUDY IN THE EXPERIMENTAL SYSTEM LIKE MICE THOUGH THERE IS SOME VARIATION IT'S GOOD IF YOU CAN START WITH WHAT'S IN COMMON, WHAT YOU CAN BEFORE ADDRESSING BEFORE ADDRESSING WHAT IS DIFFERENT. >> I WOULD ASK IF YOU CONSIDERED THE NEED FOR BETTER GENETIC TOOLS IN THE PLACENTA, PARTICULARLY THE COMMONLY USED TRACERS, ROSA CRE TRACERS DON'T WORK WELL IN EXTRA EMBRYONIC TISSUES AND THERE'S FEW CRE LINES AVAILABLE TO LOOK AT PARTICULAR TISSUES OR MANIPULATE GENES IN PARTICULAR SUBTYPES OF THE PLACENTA. THERE'S SOME FOR THE TROPHOBLAST AS A WHOLE BUT NOT GOOD FOR THE CHORION AND I THINK THERE'S NOT MUCH AVAILABLE FOR SUBTYPES OF TROPHOBLASTS. >> I THINK THAT WOULD BE ONE OF THE WONDERFUL THINGS THAT COME OUT OF MAKING AN ATLAS BECAUSE AS YOU SAY, THERE'S VERY FEW PROMOTERS FOR TBBP FOR TROPHOBLAST CELLS BUT THERE'S LOTS OF PROBLEMS WITH THAT. IF WE HAD A GENE ATLAS WE WOULD KNOW HOW BETTER TO DO THAT. SO WE DIDN'T TALK ABOUT IT BUT IT'S A GREAT POINT. >> I WANT TO GO BACK TO THE ANIMAL MODEL. I THINK WE SHOULD ALSO STUDY THE DIFFERENCES, NOT ONLY WHAT WE CAN USE THEM FOR BUT ALSO EVOLUTIONARY AND COMPARATIVE BIOLOGY IS IMPORTANT. WE HAD A QUESTION THIS MORNING, WHY IS THE HUMAN PLACENTA SO INVASIVE? THESE -- THE RESEARCH IN THIS FIELD ALSO COULD HELP US UNDERSTAND BETTER THE HUMAN PLACENTA. >> WHILE THE MICROPHONE IS MOVING AROUND, I THINK I WOULD LIKE TO SECOND THAT POINT, SO MANY FIELDS HAVE LEARNED SO MUCH FROM EVOLUTION. AND EVOLUTION IS SO FAST IN THE PLACENTA THAT I THINK THAT WE HAVE MUCH MORE DIRECTIONALITY THAN OTHER FIELDS IN THAT REGARD. >> CAN I JUST MAKE A COMMENT IN RESPONSE TO THE QUESTION ABOUT CRE LINES? JUST TO SAY THAT THE TROPHOBLAST RESEARCH HAS GOT APPLICATION TYPE THE WELCOME TRUST AT THE MOMENT TO DEVELOP NINE MORE PLACENTAL SPECIFIC CRE LINES WHICH WOULD ADDRESS MOST INDIVIDUAL CELL POPULATIONS. IF WE ARE SUCCESSFUL THOSE HAVE BEEN MADE FREELY AVAILABLE. >> THAT IS GREAT NEWS. >> DEPENDS WHAT THE WELCOME DECIDE. WE ARE THINKING ABOUT THOSE SORT OF ISSUES. >> ANOTHER COMMENT ABOUT ANIMAL MODEL? >> I DON'T WANT TO OFFEND ANY COLLEAGUES THAT ARE NIH STAFF BUT WE OR STUDY SECTION I SUPPOSE BUT WE PROPOSED LOOKING AT PLANTS AND IN PARTICULAR LOOKING AT THE ENDOSPERM, THE HOMOLOGUE TO THE PLACENTA IN PLANTS. IN A GRANT APPLICATION. THEY DIDN'T GET IT. IN FACT THEY POUNDED US, I'M ONLY SAYINGING THAT BECAUSE WE'RE SUPPOSED TO STIR IS THE IS THE THE SOUP, BUT SINCE THAT APPLICATION GONE IN I'M MORE CONVINCED IT'S OOH GOOD IDEA TO LOOK AT OTHER LOGS IN PLANTS. THE PLANT GENETICISTS ARE WAY AHEAD OF US IN TOOLS AND UNDERSTANDING. >> ALL RIGHT. THANK YOU. >> I'LL ADD THAT AS A LAST BULLET. >> THANK YOU SO MUCH. MOVE TON GROUP 2. WE CAN GO TOO THREE IF YOU WANT. HOT OFF THE PRESS. GOOD FAULK SOMEONE CAN ALWAYS GIVE, RIGHT? PERFUSION. LOOK AT THAT PRETTY SLIDE. DIDN'T KNOW, WHAT A SURPRISE. THIS IS BEAUTIFUL. NICE SURPRISE. SO WE HAD A VERY GOOD ACTIVE DISCUSSION, SO THINGS MENTIONED FOR REAL TIME FUNCTIONS, PERFUSION AND OXYGENATION OF PLACENTAL TISSUE AND LACTIC CONCENTRATION, THERE ARE A COUPLE OF MENTIONS, SOME DISCUSSION AN THAT. THE VASCULAR DEVELOPMENT BOTH IN SPECIFIC AREAS IN THE WHOLE BLAH STEAN SO THE THOUGHT THERE WAS TO GET WITH THE SPATIAL INFORMATION DETERMINE THE FRACTION OF PLACENTA THAT HAS A CERTAIN STATE OF OXYGENATION AND THEREFORE PREDICT OUTCOMES BASED ON THAT, I THOUGHT THAT WAS A GREAT IDEA. THE SAME ASSESSMENTS ON A SINGLE CELL LEVEL, SINCE WE DON'T WANT TO JUST GENERAL ORGAN LEVEL BUT SINGLE CELL LEVEL. MAPPING OF EVIDENCE OF PLACENTAL COMPROMISE AN AMOUNT REQUIRED RESULTS IN AT VERSE OUTCOMES. THAT'S SOMEWHAT RELATED TO WHAT I JUST MENTIONED ABOUT MEASURING THESE THINGS IN SPECIFIC AREAS. PERFUSION AND ANGIOGENESIS IN THEVILLE PLUS TREE DEVELOPMENT IN 3-D. SO THIS MAY LEAD TO DEVELOPMENT OF BIOMARKERS SO AS WE UNDERSTAND THESE BETTER ORGAN STRUCTURAL LEVEL WE MIGHT CORELITE THOSE WITH OTHER BIOMARKERS THAT ARE MORE ACCESSIBLE. SO THOSE ARE THE MAIN ONES FOR REAL TIME FUNCTION. COUPLE ADDITIONAL FOR REAL TIME FUNCTION INCREASE DIFFERENT REGIONS OF PLACENTA, IMMEDIATE MARKERS THAT DIFFERENTIATE TRANSPORT MEDIUMS, GLUCOSE, AMINO ACIDS, CHANGES IN FUNCTION WITH REAL TIME STRESS TESTING. EPINEPHRINE. THIS IS ALONG THE LINES OF PERTURBATIONS THAT WE LIKE TO INDUCE WHEN WE DO OUR BOLD IMAGING AS WE'LL TALK ABOUT IN TECHNOLOGY. RECOMMENDATION T OTHER THING WAS ALL THESE TESTS ARE DONE IN THE SUPINE POSITION S YOU HAVE UP RIGHT -- CHANGES IN PERFUSION THAT OCCUR STANDING VERSUS SITTING FOR EXAMPLE. SO WHAT ARE THE CURRENT STATE OF ART APPROACHES FOR THESE PROCESSES, ULTRASOUND WITH MICROBUBBLES, SUPPORT FOR WHAT'S CURRENTLY EXISTS AND CONTINUED RESEARCH TO ACTUALLY IMPROVE THIS TO GREATER DEGREES WITH REGARD TO MICROBUBBLES AN PERFUSION, IT CAN DO SO MUCH. SO THERE'S STILL CONTINUED ROLE FOR ULTRASOUND. ULTRASOUND 2D GRAY SCALE AND COLOR DOPPLER, COLOR AND POWER DOPPLER SO THIS IS SALLY'S EXPERTISE SO IF THERE'S SPECIFIC QUESTIONS WE CAN ASK SALLY FOR MORE INFORMATION ON THIS. NON-CONTRAST MRI, THIS REALLY IS ONE OF THE CLEAR WINNERS AS THE GROUP DISCUSSED MORE AND MORE ARTERIAL SPIN LABELING TECHNIQUE. SEEMS MOST PROMISING IN TERMS OF GIVING A LOT OF ADDITIONAL INFORMATION WITH REGARD TO BLOOD FLOW, BLOOD VOLUME, DEVELOPMENT OF VASCULATURE AND BEAUTY OF IT OF COURSE IS IT DOESN'T NEED CONTRAST AGENTS, ANY EXOGENOUS CONTRAST AGENTS SO THAT'S VERY NICE AND THERE ARE FDA APPROVED VERSIONS OF THIS ALREADY EXISTING ON MRI SCANNERS. SO THERE'S A LOT IN THAT SUPPORT OF THAT METHOD THAT CURRENTLY EXISTS. BOLD MRI OXYGENATION LEVEL INDEPENDENT MRI THAT LOOKS AT CHANGES IN PERFUSION INDIRECTLY BY LOOKING AT CHANGES IN BLOOD OXYGENATION. SO THAT'S BEING USED PRETTY ROUTINELY TO LOOK AT BRAIN ACTIVATION. SO THERE'S POTENTIAL FOR LOOKING AT THAT PLACENTA BUT IN ORDER FOR YOU TO LOOK AT CHANGES YOU NEED SOME SORT OF PERTURBATIONS THAT SPEAKS TO THE PREVIOUS SLIDE ABOUT DIFFERENT WAYS TO INDUCE PER THE TRABEATION. THE CONTRAST MRI IS USED PRIMARILY IN BRAIN TUMORS AND STROKE. IT'S SORT OF COMES IN AT LEAST THIRD BECAUSE OF THE FACT THAT YOU NEED CONTRAST AGENT AND DSC METHODS ARE MORE COMPLICATED OUTSIDE THE BODY BECAUSE OF THE LEAKAGE OF CLINICALLY APPROVED -- GADOLINIUM IS THE MOST COMMONLY USED PROBE CONTRAST AGENT BUT IT'S NOT APPROVED FOR FETAL IMAGING. MRI ARTERIAL SPIN LABELING ADDRESSED A BIT ABOVE WITH NON-CONTRAST MRI. BUT ONE THING NOT ON THE LIST WE DIDN'T REALLY DISCUSS IN GREAT LENGTH BUT IT'S STILL DUMMIESTLY SHOULD BE CONSIDERED IS DIFFUSION MRI METHOD. DIFFUSION MRI METHOD IS REALLY THE ONLY IMAGING MODALITY THAT'S SENSITIVE TO THE THE MICROMOLECULAR MOTION OF WATER MOLECULES SO A LOT OF INFORMATION ABOUT TISSUE STRUCTURE BUT THERE'S ALSO CAN BE MADE SENSITIVE TO TISSUE PERFUSION ALSO SO KEPT P ON THE OUR LIST OF WHAT IS OUT THERE. AND HOW THE PROCESS ASSESS IN OTHER FIELDSES SO CONTRAST AGENTS, AT THE FIRST GO AROUND TRYING TO STAY AWAY FROM CONTRAST AGENT THERE'S ISSUE THERE GETTING IRB APPROVAL BUT THERE'S MICROBUBBLE AGENTS THAT MAYBE MORE LIKELY USED WITH ULTRASOUND TECHNIQUES SO THE TECHNIQUES, NOT A LOT IN THE HUMAN MODEL DUE TO JUST POTENTIAL, ACTUALLY MR CONTRAST AGENT THERE'S NO RADIATION EFFECT, IT'S JUST A MATTER OF AGENTS UNKEYLATED AS THEY DO IN RARE CASES BUT OF RENAL FAILURE. WHAT TECHNOLOGIES MIGHT BE APPLICABLE TO THE HUMAN PLACENTAL PERFUSION PROJECT? THE 3-D ULTRASOUND, ULTRASOUND WITH MICROBUBBLE, PHASED CONTRAST MRI. PHASE CONTRAST MRI IS DIFFERENT IN THE ARTERIAL SPIN LABELING. BASIC PRINCIPLES ARE THE SAME BUT WHEN YOU LOOK AT LARGER VESSEL FLOW ARTERIAL FLOW, UTERINE VASCULAR FLOW AND ALSO IT CAN GIVE US INFORMATION AT THE LEVEL THAT YOU CAN ACTUALLY SEE THE ARTERIAL REMODELING. SO THE SIZE I LEARN THE SIZE OF THE SPIRAL ARTERIALS ARE OF A SIZE THAT IS IMAGEABLE WITH MRI AND SPECIFICALLY WITH THESE PHASE CONTRAST METHODS. MR SPECTROSCOPY GIVES US INFORMATION ABOUT TISSUE CHEMISTRY ESSENTIALLY IF YOU LOOK AT CHOLINE FOR EXAMPLE, THERE'S RECENT STUDIES THAT CAN GIVE US INFORMATION ABOUT CHOLINE, LACTATE, TISSUE OXYGENATION, SO FORTH. DSCMRI WE SPOKE ABOUT AND ARTERIAL SPIN LABELING. PHOTO ACOUSTICS IS ALSO APPLICABLE TO PLACENTAL PERFUSION. SO WHAT DO WE SEE TECHNOLOGY THAT NEED TO BE DEVELOPED? ALL MRI FUNCTIONAL MODALITIES HAVE THEIR PROVEN APPLICATION, MANY WHICH ARE IN THE BRAIN BUT IN ORDER TO ADAPT IT TO PLACENTA, THERE NEEDS TO BE SOME OPTIMIZATION AND VALIDATION SO THAT'S EACH TECHNIQUE I MENTIONED BOLD HOW EXACTLY DO YOU DO IT AND WHAT DOES IT MEAN BECAUSE IT'S AN INDIRECTM/] MEASURE OF PERFUSION. THE PERFUSION WAVE METHODS THE ASL, WE NEED TO OPTIMIZE HOW ARTERIES ARE LABELED, BY LABELED I USING THE RF PULSE TO LABEL. AND MODELED. SO SOME IS MODELING AND UNDERSTANDING THE DIFFERENCES, OPTIMIZATION YOU NEED TO DO IT IN PLACENTA. OTHER TECHNOLOGIES THAT ARE SUGGEST FORD DEVELOPMENT OR VASCULAR MARKERS OF INFLAMMATION. NEW PROBES FOR IMAGING, PHOTO ACOUSTICS AND ULTRASOUND TECHNIQUES ESPECIALLY AS SCREENING TOOLS. MORE ALONG THE LINES OF SOME OF THE 3-D, COLOR DOPPLER AND THE ULTRASOUND MICROBUBBLE TECHNIQUES WERE SUGGESTED. SO I MENTIONED MATHEMATICAL MODELING OF SOME OF THESE TECHNIQUES, MODELING OF SHAPE AND DEVELOPMENT OF THE PLACENTA. SO THIS IS SOMETHING GOING BACK TO THE STRUCTURAL IMAGING METHOD THAT COULD BE USEFUL. MATHEMATICAL AND ENGINEERING COLLABORATION TO IMPROVE IMAGING TECHNIQUE, ESPECIALLY COMPUTATIONAL MODELING. THAT'S MODELING SOME OF THE PERFUSION MARKERS THAT WE'RE MEASURING. COLLABORATION WITH INDUSTRY TO DEVELOP THE BEST TOOLS LED BY THE RESEARCH NEEDS RATHER THAN THEM DEVELOPING TOOLS OR NOT HAVING THE TOOLS WE NEED. TRANSLATIONAL RESEARCH DEVELOPING TECHNOLOGIES SUCH AS ULTRASOUND. SO A LITTLE BIT REDUNDANT WHAT I SAID BEFORE. SO THOSE ARE THE MAIN POINTS. I DON'T KNOW IF I COMPLETELY MISSED ANYTHING BASED ON MY DESCRIPTION OF THESE POINTS, ANYBODY FROM THE GROUP WANTS TO ADD SO FEEL FREE TO ADD OR FURTHER EXPLAIN. >> WONDERFUL. THANKS. ANYONE FROM THE GROUP WANT TO ADD ANYTHING BEFORE WE MOVE ON TO THE DISCUSSION? >> TWO POINTS, I WANT TO MENTION WITH BOLD IMAGING THERE'S BASELINE FLUCTUATIONS IN PERFUSION SO YOU DON'T ALWAYS HAVE TO GIVE PERTURBATION SO YOU CAN LOOK AT REGIONAL VARIATION AND FLOW. A LOT OF THOSE TECHNIQUES THAT ARE USED ELSEWHERE IN THE BODY WHEN WE GET TO PLACENTA, ANYTHING UTERINE LIMITED BY TIME, SO MOST FEEL IMAGES DONE TIME SCALE OF 15 TO 20 SECONDS SO ASL FOR EXAMPLE IN THE BRAIN TAKES 6 MINUTES AND SUBTRACTION TECHNIQUE SO YOU NEED THEM REGISTERED SO A LOT OF WHAT OPTIMIZATION NEEDED FOR ACCURATE PLACENTAL IMAGING RELIES ON ADEQUATE MOTION, MITIGATION AND INCREASING SPEED. >> ABSOLUTELY. YES. THOSE ARE DEFINITELY TECHNICAL CHALLENGES. WE TALKED ABOUT SOME OF THE GATING THAT WOULD NEED TO BE DONE. HOW YOU CAN HAVE MR GATED ECG ESSENTIALLY RETROSPECTIVE TO YOUR CORRECTIONS AND SO FORTH. >> JUST THE NEGATING PART IS HARD TO GATE THE FETUS HEART BECAUSE YOU CAN'T PICK IT UP FROM THE MOTHER HEART SO THERE'S SOME PEOPLE TRIED TO DO WITH ULTRASOUND PROBES BUT THEY'RE NOT THAT ACCURATE AND NOT IN PRODUCTION TO -- SO THEY'RE EASILY ACCESSFUL. SO MOST FETAL CARDIAC GATING IS RETROSPECTIVE. >> THIS MAYBE A DUMB QUESTION BUT WHATEVER HAPPENED TO MAGNETO MAGNETICOMETRY. >> WASN'T THERE MAGNETOMETRY. >> MAGNETIC RESONANCE TOPOGRAPHY. >> NOT SURE. (OFF MIC) >> THAT WOULD BE GOOD FOR FETAL BRAIN. ARE YOU TALKING MRE? >> THAT IS MEG. THERE IS ANOTHER TECHNIQUE TALKED ABOUT. M RE ACTUALLY USED MORE OFTEN NOW IN LIKE LIVER STIFFNESS, A COMBINATION OF ULTRASOUND WAVES. YOU CAN IMAGE THOSE WITH MRI. SOMETHING WE'RE USING IN LIVER, SOMETHING IN LIVERS MIGHT BE USEFUL IN PLACENTA. SOMETHING ELSE TO THROW OUT THERE. >> TOTALLY OFF THE WALL QUESTION BUT IN MANY PLACENTAL PATHOLOGY THERE'S A LOT OF INTEREST IN THE FETAL PLACENTAL PERFUSION, NOT JUST THE UTERINE PLACENTAL PERFUSION. WAS THERE DISCUSSION ABOUT THAT END OF THE SPEAKER FUSION SPECTRUM? >> YES, THAT WAS DEFINITE BROUGHT UP. WE DIDN'T HAVE A LENGTHY DISCUSSION ON IT BUT SEVERAL TECHNIQUES WE MENTIONED HERE COULD SPEAK TO THAT'S SPECIALLY ASL AND SOME OF THE DIFFUSION METHODS WE DIDN'T GET INTO IN GREAT DETAIL. I DON'T KNOW IF -- YOU HAVE A SUGGESTION ALONG THOSE LINE? SUSCEPTIBILITY MAP SOMETHING YES. THAT'S SOMETHING WE MENTION IN DISCUSSIONS OF THE BULL TECHNIQUE. THAT'S A BASELINE TECHNIQUE YOU CAN USE BASED ON T-2 STAR MAPPING. AND IT CAN GIVE DIFFERENT LEVELS OF PEOPLE LOOK AT DIFFERENT LEVELS OF IRON SCONATION BUT DIFFERENT -- CONCENTRATION LEVELS BUT DIFFERENT OKAY JOE NATION LEVELS, THAT'S A TECHNIQUE THAT HAS POTENTIAL IN THE PLACENTA. >> I WANTED TO ASK A QUESTION ABOUT THE FEASIBILITY. I HAVE NO IDEA, WE'RE TALKING ABOUT BOLD AND THIS SORT OF THING. WHAT'S THE -- IS THIS -- ARE THESE TECHNOLOGIES THAT CAN IF USED IN LARGE QUANTITY IF YOU LIKE, REDUCE THE SIZE, THE COST, BRING THESE DOWN TO TECHNIQUES THAT CAN BE USED REGULARLY IN MATERNALTY HOSPITALS, SO FORTH, OPPOSED TO PRESUMABLY WHAT THEY ARE TO SOME DEGREE NOW, SPECIALIZED RESEARCH TOOL? >> SO YOU ASK IN TERMS OF VOLUMES OR ASK IN TERMS OF FOCUS --? VOLUMES AND WHAT'S VOLUME AND HOW -- IT'S GOING FROM THE $1 MILLION GENOME TO THE $1,000 GENOME, IS THE SAME THING POSSIBLE WITH TECHNOLOGY HERE? >> YES, HERE ALL THINGS ARE POSSIBLE. >> PUTTING IN CONTEXT THE BAY WE DO CLINICALLY, DOING TESTING TWICE A WEEK. WE PUT PEOPLE THROUGH NON-STRESS TESTING WHICH IS HEART RATE MONITORING, WHEN THEY HAVE NO REASSURING PARAMETERS OF FETAL WELL BEING WE PUT THEM THROUGH BIOPHYSICAL PROFILES. AS OUTPATIENT THEY MAY SPEND THREE OR FOUR HOURS THERE, THEY'LL Q. CHARGED SOMEWHERE AROUND DEPENDING WHAT INSTITUTION IT IS, 250 TO $500 FOR ANTI-PARTUM TESTING BY HEART RATE TESTING AND SOMEWHERE AROUND $500 FOR THE FULL BIOPHYSICAL PROFILE. AND SO IF YOU PUT IT IN THE CONTEXT TWICE A WEEK TESTING FOR THIS INDIRECT MEASURE, SUPPOSEDLY OF FETAL WELL BEING, SUPPOSEDLY IS TELLING YOU SOMETHING VERY INDIRECTLY ABOUT OXYGENATION. SO IF YOU SCAN SOMEBODY AND TRYING TO DO IT FOR LACTATE OR FOR OXYGEN, YOU'RE TALKING"O" ABOUT MINUTES. IN THE SCANNER. AND THAT NOW THEY HAVE TO BE IN SPECIALLY ISOLATED ROOMS OBVIOUSLY BUT FOR EXAMPLE IN INSTITUTION WE HAVE -- LABOR AND DELIVERY FIFTH FLOOR AND SCANNER IS ON THE 10TH FLOOR SO IT'S TWO MINUTE RIDE UP THE ELEVATOR AND THEY CAN BE SCANNED. SO I THINK IT IS FEASIBLE. BECAUSE FIRST BRUSH THERE'S NO WAY WE'RE GOING TO BE PUTTING EVERYBODY THROUGH MRIs OR MR IN THIS CASE. BUT I THINK IT IS FEASIBLE. >> I WAS GOING TO MAKE A COMMENT TOO I THINK THINGS ARE SHIFTING, STARTING TO BE MRI IN THE ADJACENT ICU, WE'RE DEVELOPING NEONATAL MRI SO THE MODEL WILL BE SHIFTING TO NOT JUST OUTPATIENT HIGH THROUGH PUT HIGH COST BUT PROBABLY TO MORE OF MANAGED CARE. >> ONE MORE COMMENT. >> THAT WAS WHAT I MENTIONED ABOUT MEASURING THE CHOLINE IN THE LACTATE. WHEN WE THINK ABOUT SPEAKING TO YOUR QUESTION ABOUT IS IT FEASIBLE, IS IT COST EFFECTIVE TO USE MRI. MRI IS COMPLETELY BIASED BUT THE DIFFUSION METHODS TO MEASURE MICROSTRUCTURE, YOU CAN MEASURE PERFUSION, YOU CAN MEASURE TISSUE STRUCTURE WITH MRS. YOU CAN GET EASY NON-CONTRAST MULTI-FUNCTIONAL EXAM THAT CAN GIVE YOU INFORMATION AND IT'S EASY TO CONVINCE ANYBODY OF THAT, THIS ONE EXAM IS REALLY IMPORTANT. MAYBE NOT SCREENING BUT DEFINITELY FOR EVALUATION. YES. >> WHAT ABOUT DATA SIZE, P IF YOU DID 500 PATIENT COHORT ALL THESE DIFFERENT IMAGING MODAL DIS AND YOU WANTED TO DEPOSIT THE RAW DATA WITH MICROEXPERIMENT, HOW MUCH STORAGE DO YOU NEED? >> LOTS. >> SO TERABYTE RANGE OF STORAGE. >> YES. THE FUNCTIONAL EXAM YOU DEFINITELY -- >> IS THERE ANY WAY OF USING SOME KIND OF, I DON'T KNOW MAYBE DO SOME ALGORITHMIC COMPRESSION OF THE DATA? OR SELECTION OF THE DATA THAT YOU DON'T NEED ALL THAT VOLUME SPACE BUT YOU JUST ONLY NEED TO ISOLATE CERTAIN VOLUMES? >> AS RESEARCHER I LIKE TO KEEP ALL MY DATA BUT FOR EVALUATION PURPOSES, YES. YOU CAN DEFINITELY JUST KEEP THE PARAMETER MAPS LONG TERM I SUPPOSE. I THINK PETER WILL BE TALKING TO SOME OF THAT, RIGHT? IN SOME OF THE DATA MANAGEMENT ISSUES WITH IMAGING BUT YES, THERE'S DEFINITELY THAT OPTION. >> I THINK THAT GOES -- THAT POINTS EXACTLY TO THE WHOLE PURPOSE OF THIS MEETING IS TO REALIZE, OKAY, WHAT COULD DOE AND WHAT ARE THE IMPLICATIONS IF WE WERE TO DO THAT. THANK YOU FOR BRINGING THAT UP. >> ONE THING I WANTEDDED TO SAY HAS TO DO WITH STANDARDIZATION. WE HAVE KNOWN FOR A LONG TIME IF THE PLACENTA DOESN'T DEVELOP QUITE RIGHT AND VASCULAR RESISTANCE GOES UP, THE FETAL HEART IS ALTERED FOR THE REST OF THE LIFE OF THAT INDIVIDUAL. IT SEEMS TO ME ONE THING THAT WE NEED TO PUT ON THE RADAR SCREEN IS HAVING SOME PARAMETERS THAT WE KNOW FIT IN WITH THE NORMAL RANGE AND THOSE WE DON'T. WE HAVE DONE THIS WITH PULSEATILITY INDICES BUT WHAT WE HAVEN'T DONE IS TO SAY WHAT VASCULAR AND FLOW RELATIONSHIPS OUGHT TO BE FOR ANY GIVEN SIZE FETUS. ONCE WE COULD DO THAT WE CAN DO IT ON THE MATERNAL SIDE AND THESE FLOW MATCHING PARAMETERS ARE SOMETHING THAT WE'RE CLOSE TO DOING NOW AND IF WE DECIDE TO DO MRI IN THE FUTURE WE CAN DO THIS IN WAY THAT WOULD ALLOW US TO MONITOR THE HEALTH OF AN INDIVIDUALITY IN THIS WAY WE DON'T DO NOW. GREAT POINT WE SHOULD ADD THAT TO OUR TECHNOLOGY NEEDS. RIGHT ON TIME. >> YOU HAVE THE LOGO IN THE FRONT. >> TO MAKE UP FOR WHAT COMES AFTER. I THINK OURS IS MORE STREAM OF CONSCIOUSNESS STUFF HERE UNLESS -- LESS ORGANIZED AND BEAUTIFUL. BUT I THINK ONE POINT MADE EARLY ON, IT'S WORTH US REMEMBERING IS THE PLACENTA FORMS WITHIN THE MATERNAL ENVIRONMENT SO IT'S NOT SOMETHING THEY ALL START OUT THE SAME AND THEN DIVERGE SOMEHOW. BUT THE MOTHER FORM AS UNIQUE ENVIRONMENT THAT CONDITIONS THE PLACENTA AND THE FETUS. WE HAVE TO REMEMBER THAT THEY DIFFER TO BEGIN WITH. EVEN AMONG NORMALS, NOT ONLY ABNORMALS. WE HAVE TO REMEMBER THE PLACENTA AS TRANSPORTER AND CONSUMER WHEN IT COMES TO METABOLISM. SO FUNCTION IS IMPORTANT TO EVALUATE. TRANSPORT OF EVERYTHING IMPORTANT,&TZ CLEARLY. OXYGEN NUTRIENTS LIKE GLUCOSE, AMINO ACIDS AND LIPS WE WOULD LOVEAm3m TO LOOK AT, BOTH THE MACRO AND THE MICRO LEVEL WE WOULD LOVE TO LOOK AT LACTATE TO BE ABLE TO DETERMINE OXIDATIVE STATUS N TERMS OF ENERGY STATUS. IN TERMS OF BIOSYNTHESIS BECAUSE METABOLISM HAS BEEN POINTED OUT IS NOT ONLY CATABOLISM, IT'S ANABOLISM. SO WE NEED TO BE LOOKING AT BOTH SIDES TO SOME EXTENT TO ASSESS HOW THE PLACENTA IS DOING. THE STATE OF THE ART. WELL, STATE-OF-THE-ART IS SOMEWHAT LIMITED. WE HAVE MATERNAL FLUID, SERUM, PLASMA, URINE, AND I THINK WE CAN ADD AMNIOTIC FLUID TO THAT AS A POTENTIAL WAY OF LOOKING AT THINGS THAT'S CURRENTLY USED. WE ARE BEGINNING TO LOOK AT MICROPARTICLES IN THE MATERNAL CIRCULATION. WE ARE LOOKING AT CELL-FREE RNA AND DNA. THERE IS LIMITED IMAGING SO FAR MIKE IS TALKING ABOUT WHAT HE'S DOING PROBABLY VERY ADVANCED COMPARED TO ALMOST EVERYTHING GOING ON AND THERE'S METABALOMIC STUDIES ONE SORT OR ANOTHER GOING ON THOUGH I THINK THERE ARE LIMITATIONS TO THOSE THAT SO FAR HAVE NOT BEEN ADDRESSED AND PERHAPS WHY THEY'RE NOT HIGHER UP THE TREE IN TERMS OF DIAGNOSTIC. CAPABILITIES. SO HOW ARE THINGS ASSESSED IN OTHER FIELDS? WELL, WE HAVE ALREADY GONE THROUGH THIS BUSINESS IN TERMS OF MRI OR MRS SPECTROSCOPY. LACTATE, PYRUVATE, THE CHEMICAL EXCHANGE SATURATION TRANSFER METHODS. FOR LOOK AT GLUCOSE, PH, METABOLITES. WHO WAS THE NANOPARTICLE INTERROGATION? (OFF MIC) >> YEAH. THAT THIS HAS BEEN DONE IN OTHER FIELDS AND MICROFLUIDICS THAT ARE ALSO USED IN OTHER FIELDS. BUT NOT A LOT THAT IS NECESSARILY RELEVANT EXCEPT FOR THE MRI STUFF IN SOME WAYS. WHAT IS APPLICABLE TO WHAT WE WANT TO DO NOW? ONE THING THAT CAME UP CLEARLY WAS THAT ACCESS TO MICROPARTICLES IN THE MATERNAL CIRCULATION ARE LIKELY TO BECOME VERY IMPORTANT PART OF WHAT WE'RE DOING. WE'RE GOING TO BE ABLE TO SAMPLE THEM LONGITUDINALLY AND LOOK NOT ONLY AT THE AMOUNT IN TERMS OF MICROPARTICLE BUT ALSO THE CONTENT TO PROFILE EXOSOMES FOR MICRORNA CONTENT. CLEARLY IN A VARIETY OF IMAGING POSSIBILITIES APPLICABLE TO THE PLACENTA, CLEARLY NANOPARTICLE DIRECTED PROBES, BUT ALSO THE QUESTION IS WHETHER THERE ARE OTHER SOURCES WE CAN BEGIN TO LOOK AT IN TERMS OF DIAGNOSIS, VOLATILE AGENTS IN BREATH, LOOK AT SWEAT, SALIVA, VERY FEW OF THESE THINGS HAVE BEEN CONSIDERED THUS FAR. SO WHAT DO WE NEED TO DETERMINE? WHAT DO WE NEED TO DEVELOP, RATHER? CLEARLY THE IMAGING PROGRAMS ARE ON THEIR WAY. WE NEED TO DO A LOT MORE IN TERMS OF GETTING THOSE IMAGING CAPABILITIES ESTABLISHED. CLEARLY WE NEED TO BE ABLE THE TO DEFINE PLACENTA SPECIFIC MARKERS BECAUSE IF WE'RE GOING TO BE LOOKING AT MICROPARTICLES, EXOSOMES AND OTHER THINGS IN THE MATERNAL CIRCULATION WE NEED TO BE ABLE TO LOOK FOR THOSE ONES THAT REFLECT PLACENTAL FUNCTION AND PLACENTAL OPERATION. WE NEED TO BE ABLE TO DEVELOP -- THINKING ABOUT NUMBER FOP FOUR WAS SOMEONE ELSE REMIND ME. I THINK ONE OF THE PROBLEMS THAT WE ALL UNDERSTAND WE HAVE IS THE RELUCTANCE OF VARIOUS ORGANIZATIONS TO ALLOW US TO DO THINGS TO PREGNANT WOMEN. SOME OF THESE ARE THROUGH THE PROBLEMS WITH USING DRUGS OF ONE OR NOT NOT USED IN PREGNANT WOMEN BEFORE, PROCEDURES NOT USED IN PREGNANT WOMEN BEFORE. IT MAYBE IMPORTANT WE THINK JUST TO DEVELOP A NETWORK FOR EXAMPLE, A DATABASE OF NEW TECHNIQUES. TECHNIQUES SUCH THAT IF I'M GOING TO BE ADMINISTERING THIS DRUG OR THESE -- THIS CLASS OF DRUGS OR MOLECULES TO A PREGNANT WOMAN I CAN GO TO UL AND MIKE AND GIL AND THEY HAVE GOT IRBs ALREADY DONE FOR THESE THINGS. SFROM I CAN SAY GIVE ME A7 – COPY OF YOUR IRB, I CAN GO TO MY IRB AND SAY LOOK, EVERYBODY ELSE IS DOING THIS ALREADY. NO PROBLEMS, NO ADVERSE OUTCOMES. IN OTHER WORDS, INSTEAD OF AN INDIVIDUAL INVESTIGATOR STANDING ALONE AND HAVING TO WITHSTAND THE IRB OR WHOEVER, THERE IS SOME COOPERATIVETY ACROSS OUR NETWORKS TO ALLOW US TO USE THOSE NETWORKS A LITTLE AND GET THOSE TECHNIQUES AVAILABLE A LITTLE MORE EASILY. NANOPARTICLE, FUNCTIONAL TESTING. I THINK ONE OF THE MOST IMPORTANT THINGS THAT WE THOUGHT ABOUT WAS THE POTENTIAL FOR USING SINGLE CELL ANALYSIS. WE'RE USING EXOSOMAL ANALYSIS FROM FROM PLASMA SAMPLES FOR EXAMPLE BUT IN THEORY THERE IS THE POSSIBILITY OF ISOLATING CELLS, CELL FRAGMENTS CELLS OR CELL FRAGMENTS FROM MATERNAL CIRCUMSTANCELATION FOR EXAMPLE. NOT HIGH VOLUME, MAYBE MORE THAN SINGLE CELL BUT POTENTIAL FOR LOOKING AT SINGLE CELLS, AND FOR LOOKING AT THINGS LIKE METABALOMICS IN THAT'S WHEN WE'RE LOOK NOT AT A PROCESS WHERE MATERNAL METABOLISM OVERWHELMS WHATEVER FETAL THINGS ARE GOING ON, WE'RE LOOKING AT FETAL OR PLACENTAL CELLS AND THAT'S WHERE WE CAN SEE WHAT'S GOING ON WITHOUT THE INTERFERENCE FROM THE MATERNAL SYSTEM. SO WE THOUGHT ABOUT CELLS FROM OTHER POTENTIALITIES. WE DISCUSSED POTENTIALLY USING CERVICAL CELLS. CELLS NON-INVEIGH SLY USING THE SAME MECHANISM'S NON-INVASIVELY USING THE SAME MECHANISMS FROM PAP SMEAR BUT FROM THE CERVIX WHICH AGAIN THE SORT OF THING MAY NOT BE LARGE IN NUMBER BUT CERTAINLY REPRESENT -- COULD REPRESENT THE PLACENTA AND WHAT'S GOING ON ESPECIALLY PROBABLY EARLY IN PREGNANCY. SO THERE ARE A VARIETY OF POSSIBILITIES HERE. BUT OF COURSE, PAT CATALANO CAME ONE THE SLOGAN YOU'RE GOING TO HAVE TO APPEND UNDER THE LOGO, DON'T LET THE AFTER BIRTH BE AN AFTER THOUGHT. [APPLAUSE]kO QUESTIONS, THOUGHTS, IDEAS? >> THAT MIC IS GOING? >> JUST TO RIF OFF WHAT YOU SAID ABOUT IRB. I ENCOUNTERED A SIMILAR PROBLEM BY CONTACTING A BIOBANK IN THE UNITED STATES I COULD IMPORT HUMAN SERUM INTO CANADA WHICH I CAN BUT IT TAKES APPROXIMATELY SIX MONTHS TO GET APPROVAL FOR IMPORTATION LICENSE OF HAZARDOUS GOOD. WHICH JUST SEEMED STRANGE GIVEN THE FLOOD OF PEOPLE COMING OFF AIRPLANES ON ADDICTION CARRYING A HUGE RANGE OF PATHOGENS AND THAT I WANTED BLOOD THAT WAS COLLECTED IN A BIOBANK UNDER CONTROLLED CLINICAL CONDITIONS. SO I DON'T KNOW IF THERE'S A REGULATORY FRAMEWORK THAT CAN BE WORKED OUT FOR MOVING HUMAN SPECIMENS BETWEEN COUNTRIES THAT ARE COLLECTED, IT'S NOT AIDS, NOT INFECTIOUS AGENT, IT'S JUST A PREGNANT WOMAN'S SERUM. >> IT'S PART OF THAT PROBLEM, AGAIN, YOU'RE WORKING BY YOURSELF. AND WE SHOULD BE ABLE TO UTILIZE OUR KNOWLEDGE TO BE ABLE TO HELP YOU RATHER THAN YOU HAVING TO SPEND THAT SIX MONTHS DOING IT. P IF YOU CAN SAY THE GUY TWO FLOORS BELOW IS DOING IT TOO ALREADY. IT COULD PROBABLY HELP. >> ARE THERE TOOLS AVAILABLE TO -- IS THIS ON? ARE THERE TOOLS AVAILABLE TO LOOK AT WHERE METABOLITES ARE BEING DIRECTED, WHETHER CYTOKINES ARE BEING USED WITHIN THE PLACENTA OR SENT TO THE FETUS? NUTRITION -- IS THAT HAPPENING PAIR KIN OR AUTOCRINE OR HOW METABOLITES ARE BEING DISTRIBUTED? >> NOT REALLY, NOT TO MY KNOWLEDGE. AGAIN, MOST OF THAT REQUIRES FORM OF A PROBE OR SOME MECHANISM OF SEEING IT. AND WHAT WE'RE SEEING NOW IS A LOT OF IMAGING TECHNIQUES ARE GOING TO BE THE WAYS IN WHICH WE CAN DO THAT. IT'S EASY TO DO IF YOU CAN TAG SOMETHING. SOON AS YOU TAG SOMETHING YOU'RE INTRODUCING SOMETHING FOREIGN, SOON AS YOU INTRODUCE FOREIGN THE WEIGHT OF THE WORLD COMES DOWN ON YOU. WHEN WE CAN GET PAST THAT, IT WILL CERTAINLY BE VERY HELPFUL. >> ONE POINT THAT WE DIDN'T MENTION IS TO EMPHASIZE THE BIODIRECTIONAL REPORT BY PLACENTA. EVERYONE TALKS UPTAKE AND NOT MANY THINK ABOUT THE eFLUX SO IT'S THE BIODIRECTIONAL TRANSPORT OF THE PLACENTA. >> I SHOULD EMPHASIZE THAT, BECAUSE AGAIN T PLACENTA IS EXPORTING VAST AMOUNTS OF MATERIAL. ALL WHICH MUST HAVE COME FROM THE MOTHER TO BEGIN WITH. AND THOSE THAT e-FLUX IS WHAT WE'RE INTERESTED IN. >> SO WE DISCUSSED A LOT ABOUT THE IMPORTANCE OF NICHD IN IMPROVING COMMUNICATION TO -- WE WILL NEED ESPECIALLY FOR THIS, WE WILL NEED ACCESS TO VOLUNTEERS SO WHICH MEANS WOMEN THAT MIGHT HAVE HAD POOR PREGNANCY OUTCOME THAT NOW WILL VOLUNTEER FOR SPECIAL IMAGING THAT HAVE BEEN PROVEN SAFE BUT WE WILL NEED TO IMPROVE THE WAY OUR COMMUNITY PERCEIVES THE PLACENTA AS IMPORTANT TO THE BABY. WE SPENT A LOT OF TIME. >> YOU MENTION IN YOUR SIX MINUTE PIECE BUT NOT ON HERE THE ORGAN ON A CHIP. YOU SAID PLACENTA. AND THAT IS ACTUALLY A HIGHLY REFINED ALREADY -- GOT AN ENTERPRISE CALLED THE VICE INSTITUTE THAT IS BUILT NUMBERS OF THESE, PARTICULARLY USEFUL FOR BIDIRECTIONAL TRANSPORT FOR XENOBIOTICS, POPULATING THE ON -- DIFFERENT CO-CULTURED THINGS, LUNG ON A CHIP, KIDNEY ON A CHIP, BONE MARROW ON A CHIP, I HAVE SEEN THIS PRESENTED TWICE, IT'S EXCEPTIONAL AND WOULD BE VERY SUITABLE TO SOME OF THE QUESTIONS BEING ADDRESSED. >> I THINK THERE'S ONE ASPECT OF THAT WHICH WE DISCUSSED AT LUNCHTIME, THE IDEA THAT PEOPLE HAVE BEEN TRYING SINCE THE '70s TO GET THE MONOLAYER SINSITIUM AND WE DON'T HAVE ONE YET. WE DON'T HAVE ANYTHING WE CAN USE FOR THAT BIDIRECTIONAL TRANSPORT, THE BEST WE HAVE GOT ARE CULTURES OF BWO CELLS ARE BEST FOR TRANSPORT, WE KNOW THEY'RE NOT THAT GOOD. AGAIN, THAT IS -- THOSE TWO COIN SIDE OR OVERLAP, WE WOULD LIKE TO BE ABLE TO -- ONCE WE CAN DEVELOP SINSITIAL MONOLAYER, WE'RE ABLE TO BUILD ON THAT MONOLAYER TO SOME DEGREE. BUT RIGHT NOW, THAT PROCESS IS DEFEATED MANY ATTEMPTS. I DON'T KNOW -- >> ACTUALLY YOU CAN USE A BIO BIOREACTOR FOR CELLS IN TISSUES INSIDE A MAGNET OR IMAGE THOSE FUNCTIONS. >> THE PROBLEM TO SOME DEGREE IS AGAIN, THE IF WE'RE LOOKING AT TRANSPORT WE CAN'T USE IT BIDIRECTIONALLY. TO LOOK AT METABOLISM PER SE IS POSSIBLE WITHIN THE CELLS. AND IT IS DONE THOUGH THE PERIOD DURING WHICH WE CAN USE THEM, AGAIN, IS FAIRLY LIMITED IF WE'RE TALKING ABOUT PRIMARY CELLS. BECAUSE YOU HAVE A WINDOW OF, WHAT, 72 TO 120 HOURS MAYBE, SOMETHING LIKE THAT. AFTER THAT YOU'RE NOT LOOKING AT ANYTHING THAT HAS RESEMBLANCE TO IN VIVO. SO WE HAVE THAT OTHER PROBLEM, NOT ONLY CAN WE NOT GET A MONOLAYER BUT WE HAVE THIS DYNAMIC SYSTEM, THAT DYNAMIC SYSTEM I DON'T THINK HAS BEEN EXPLORED IN MANY WAYS YET IN TERMS OF WHAT HAPPENS TO TRANSPORT AND METABOLISM, 72, 78, 84, 90 AND 96 AND SO ON IN TERMS OF COMPARISON. >> TO FOLLOW-UP ON GEORGE'S COMMENT FROM THIS MORNING NOT FORGETTING THE MEMBRANES. I HOPE WE DON'T FORGET MEMBRANES WHEN IT COMES TO CELLULAR GROWTH AND METABOLISM BECAUSE SINGLE MOST COMMON RECOGNIZABLE CAUSE OF PREMATURE LABOR IS RUPTURED MEMBRANES, IT'S JUST A LOT MORE THAN ASCENDING INFECTION. WE NEED TO STUDY THE MEMBRANES FOR THAT TOO. >> POINT TAKEN. >> THANK YOU SO MUCH. ALL RIGHT. GIL, YOU'RE UP. >> OKAY. NOT COVERED HERE. SO WHAT FUNCTIONS ARE IMPORTANT TO REAL TIME? ONE OF THE DISCUSSING THIS ASPECT I THINK ONE IMPORTANT MESSAGE WE LEARN IS THAT WHEN WE TALK ABOUT THE ROLE OF THE IMMUNE SYSTEM PREGNANCY, IS TOO GENERAL. THE IMMUNE SYSTEM HAS A SPECIFIC FUNCTION DEPENDING ON THE STAGE OF THE PREGNANCY. SO WE TRY TO DIVIDE THE DIFFERENT STEPS, DIFFERENT STAGES OF THE PREGNANCY, MAYBE LOOK AT WHAT IS THE ROLE OF THE IMMUNE SYSTEM ON THOSE STAGES. THERE IS LACK OF BASIC GLOBAL KNOWLEDGE FOR EXAMPLE OF PLAINMATION IN TROPHOBLAST IN UTERINE ENVIRONMENT. ONE OF THE EARLY STAGES OF INFLAMMATION IS RELATED TO IMPLANTATION. THE KNOWLEDGE ABOUT THE ROLE OF IMMUNE CELLS AND IMPLANTATION IS JUST AT THE BEGINNING AND IS VERY POOR. THERE IS NO MUCH KNOWLEDGE ABOUT THAT. THERE IS ALSO THE ASPECT OF HOW HORMONES ESPECIALLY PROGESTERONE , AND OTHER MOLECULES MAYBE REGULATING OR AFFECTING THE IMMUNE CELL FUNCTION AND DIFFERENTIATION. THE ANIMAL MODEL INVESTIGATE MECHANISMS ESPECIALLY USING CONDITIONAL MUTANTS, AGAIN ASSOCIATED WITH EARLY STAGE PREGNANCY IN TERMS OF THE ROLE OF IMMUNE SYSTEM AND HOW THE UTERINE ENVIRONMENT REGULATES IMMUNE CELL DIFFERENTIATION AND FUNCTION. EVALUATING THE FUNCTIONS THAT ARE IMPORTANT TO REAL TIME. WHAT IS EVOLUTION OF THE MATERNAL AND TROPHOBLAST EDUCATION AFFECTING IMMUNOLOGY S MUCH OF THE WORK FOCUS AT LEAST SO FAR WE HAVE FOCUS A LOT LOOKING AT THE ASPECT OF A PLACENTAL MATERNAL IMMUNE SYSTEM AND WE HAVE LEFT EVERYTHING THAT IS THE AREA OF THE FETAL IMMUNE SYSTEM AS COMPLETE, INDEPENDENT OR SEPARATE. QUESTION IS HOW CAN WE EVALUATE WHAT IS HAPPENING AT TIME OF INTERACTION BETWEEN PLACENTA AND THE MATERNAL IMMUNE SYSTEM, HOW THAT THEN WILL AFFECT THE FETAL IMMUNE SYSTEM AND THE DEVELOPMENT OF THE FETAL IMMUNE SYSTEM. THE EPIGENETIC MODULATION OF IMMUNE CELLS DURING PREGNANCY. WE KNOW IMMUNE CELLS DURING PREGNANCY HAVE SIGNIFICANTLY MODIFICATIONS OR WHAT WE SEE IMMUNE CELL IN THE PERIPHERAL BLOOD OR OTHER TISSUES. THOSE CHANGES MUST BE ASSOCIATED WITH EPIGENETIC CHANGES. WE HAVE ABSOLUTELY -- VERY LITTLE WHAT IS KNOWN ABOUT THE EPIGENETIC MODIFICATIONS. THE QUESTION IS, HOW CAN WE EVALUATE AND (INAUDIBLE). SO THAT IS THE FIRST EARLY PREGNANCY, THEN WE MOVE LATER STATUS, WHAT HAPPENED WITH MATERNAL AND PLACENTAL RESPONSE TO INFECTION. DURING SECOND AND THIRD TRIMESTER OF PREGNANCY AND RELATIONSHIP TO PRE-TERM BIRTH. WE NEED TO IMPROVE METHODS FOR ASSESSING INFECTION AND INFLAMMATION DURING PREGNANCY. THERE IS CLEARLY CRITICAL IMPORTANT ROLE OF INFECTION AND CHANGES ON THE IMMUNE FUNCTION DURING PREGNANCY, AND STILL WE DON'T UNDERSTAND THAT ASPECT. CHARACTERIZATION OF THE UTERINE PLACENTAL AND AMNIOTIC MICROBIOME, THERE WAS ALSO THE SUGGESTION THAT MAYBE WITH NEW TECHNIQUE WE NEED TO GO BACK TO LOOK AT THE AMNIOTIC FLUID AND USING MORE SENSITIVE METHODS TO DETECT FOR MICROBIOME THERE. WHAT CONTROLS IMMUNE INFLAMMATORY RESPONSES FROM PHYSIOLOGICAL TO PATHOLOGICAL CONDITIONS. WHAT ARE THE CURRENT STATE OF THE APPROACHES FOR ASSESSING THIS PROCESS. THE MAJORITY OF STUDY WAS FOCUSED ON MONITORY PERIPHERAL BLOOD. WE KNOW THE PERIPHERAL BLOOD DOESN'T TELL US WHAT IS GOING AT IMPLANTATION SITE SO REALLY WE HAVE A NEED TO DEVELOP NEW SYSTEMS THAT CAN EVALUATE WHAT IS HAPPENING AT IMPLANTATION SITE. THE QUESTION IS IN THE CERVICAL SWABS ANALYSIS OF TROPHO BLAST, AMNIOCENTESIS MORE SENSITIVE TECHNOLOGIES OR CBS AND TO POTENTIALLY VARIOUS OMICS. HOW THIS PROCESS ASSESS IN OTHER FIELDS. SO WHAT I MENTION ALSO THIS MORNING MUCH OF THE STUDIES OF THE IMMUNE SYSTEM ON PREGNANCY HAS FOCUS ON THE MODEL OF GRAFT VERSUS HOST DISEASE SO MAYBE NOW WE NEED TO RE-EVALUATE THAT AND START LOOKING AT OTHER FIELDS, ESPECIALLY THE FIELD OF CANCER WHERE THERE IS SIGNIFICANT IMPROVEMENT IN THAT AREA. TUMOR KNEW TUMOR IMMUNOLOGY DEVELOP SIGNIFICANTLY. WHAT ARE WE DOING THAT? ONE IS POTENTIAL AVAILABILITY OF RESOURCES, FINANCIAL ASPECT UNDERSTANDING WHAT IS IMMUNE -- THE INTERACTION BETWEEN IMMUNE SYSTEM AND THE TROPHOBLAST AND SAFETY ISSUES RELATED TO PRESENCE OF FETUS WHEN WE WANT TO DO INTERVENTION. WHAT I MENTION, LOOK AT THE FIELD OF CANCER IMMUNOLOGY APPLICATION OF PET SCAN THAT HAS BEEN DONE IN TUMORS WHETHER APPLICABLE BEFORE MENTIONING. THERE IS AN IMPORTANT INTERESTING ASPECT. WE KNOW THAT THE TUMORS ARE HETEROGENEOUS IN THE SAME TYPE OF TUMORS IF YOU TAKE BREAST CANCER A LOT OF HETERO GENICITY SO THE QUESTION THAT WAS BROAD IN THE DISCUSSION IS, IS THERE ALSO A HETERO GENICITY IN THE PLACENTA, IN THE DIFFERENT PREGNANCIES, IN THE HETERO GENICITY IN ONE GROUP OF PEOPLE OR REGIONAL PEOPLE. WE KNOW EVEN THE MICROBIOME OF THE VAGINA OR THE REPRODUCTIVE TRACK IS DIFFERENT BETWEEN REGION, NOT THE SAME IN NORTH AMERICA, IN THE NORTH, SOUTH OR AFRICA, IS THE PLACENTA ALSO HETEROGENEOUS WITHIN A POPULATION WITHIN AREAS, SO ON. THAT IS A VERY CHALLENGING QUESTION, ESPECIALLY WE WANT TO COMPARE WITH TUMOR HETERO GENICITY. THAT IS GOING TO AFFECT HOW THE IMMUNE SYSTEM BEHAVES. THE IMMUNE SYSTEM, SAY IN PREGNANCY AND IN A STERILE ENVIRONMENT IS GOING TO BE COMPLETELY DIFFERENT HOW THAT PLACENTA BEHAVES. IN A KNOWN STEADY STATE CONDITION LIKE SOUTH AFRICA AND OTHER REGIONS. WHAT TECHNOLOGY MAYBE APPLICABLE? THAT WAS A SERIOUS PROBLEM, I DON'T THINK WE CAN -- SOMETHING -- BUT ANYWAY EVALUATION OF TECHNOLOGIES USED TO EVALUATE CANCER IMMUNOLOGY. PET SCAN AND AGAIN WAS MENTIONED IN THE OTHER CONCLUSIONS. EVALUATION OF TECHNOLOGY DURING PREGNANCY IS CRITICAL. CONTRARY TO CANCER IMMUNOLOGY. THERE IS NOT A BABY IN THE TUMOR. HERE WHEN WE TALK ABOUT PLACENTA, I WAS GOING TO SAY UNFORTUNATELY, FORTUNATELY WE HAVE A BABY. MANY TECHNIQUE WE APPLY TO CANCER WE CANNOT APPLY HERE BECAUSE WE MAY AFFECT THE BABY. WHAT TECHNOLOGY NEED TO BE DEVELOPED TO AT RISK PATHOLOGICAL PROCESSES IN PLACENTA? PHENOTYPING OF PLACENTAL DISEASE. IN COOPERATION OF SENSORS TO DETECT INFLAMMATION, PROGRAM LYMPHOCYTES, NANOPARTICLES. THERE WAS SOME DISCUSSION ABOUT HUMAN IN THE MOUSE PLACENTA, MAJOR PROJECTS GOING NOW IN IMMUNOLOGYTOR THE HUMANIZATION OF THE IMMUNE SYSTEM IN THE MOUSE, QUESTION CAN WE ALSO DO IN THE MOUSE -- MOUSE PLACENTA, AND EXPANDING ANIMAL MODELS. ONE PROBLEMS ALSO DISCUSSED, AS A POLITICAL PROBLEM STUDYING EARLY STAGES OF IMPLANTATION IS THAT WE CANNOT WORK WITH BLAST CYSTS. SO HOW CAN CAN WE EXPLAIN TROPHO BLAST IMMUNE INTERACTIONS WHEN WE ARE MISSING ONE IMPORTANT COMPONENT THAT IS THE BLASTOCYST, HOW DO WE REPLACE THAT? IS THE ANIMAL MODEL GOING TO REPLACE THE REALITY OF A BLASTOCIST? IS WORKING WITH THE TROPHO ECTO DETERMINE REAL WHEN CELL MASS IS MISSING, THEN WHAT IS THE ROLE OF THE MASS CONTROLLING OR SIGNALING THE TROPHO BLAST THAT THEN SIGNAL THE IMMUNE CELL. WE ARE FORBIDDEN TO WORK WITH THAT COMPONENT SO WE ARE LEFT WITH ONE LEFT HAND WHEN I WRITE WITH MY RIGHT. IT IS A PROBLEM. WITH THAT, I FINISH. [APPLAUSE] >> THOUGHTS? >> THIS MORNING YOU BEGAN WITH ANALOGY WITH TRANSPLANTATION SO THEY HAD SEEN SOME VERY INTERESTING WORK GOING ON AT THE UNIVERSITY OF CAMBRIDGE BY ASHLEY MOFFET ABOUT HLAC AND CUR AND THE POSSIBILITY OF MATERNAL FETAL INCOMPATIBILITY. I WONDER IF THAT WAS COVERED IN THE DISCUSSION. AND IF YOU HAVE MECHANISM OF DISEASE. >> IT WAS NOT IN DISCUSSION, IT WAS PUT IN THE SUBJECT THAT OUR UNDERSTANDING OF THE MAJORITY OF IMMUNE CELLS, PRESENT AT IMPLANTATION SIGNED NEEDS TO BE FURTHER DEVELOPED ESPECIALLY NOW WITH IDEA THAT THE IMMUNE CELLS ARE HELPING THEg PLACENTA IN ORDER TO DEVELOP AND GROW. I THINK THERE IS GROWING EVIDENCE THAT THEJ3$MAJORITY OF THE HYPOTHESIS IS REALLY MAYBE IT WAS WRONG. >> CAN I COMMENT ON THAT? ASHLEY MOFFET HAS SHOWN IT IS THE C-2 WHICH IS HARMFUL TO PREGNANCY. AND INTERESTINGLY THE EXPRESSION OF C-2 IS HIGHER IN THE AFRICAN POPULATION WHERE THEY HAVE HIGHER PREECLAMPSIA SO THERE IT'S NOT A TECHNOLOGY, WE NEED BETTER DEFINED COHORTS OF PATIENTS FROM DIFFERENT COUNTRIES. FROM DIFFERENT ALTITUDE LEVELS EVEN. BECAUSE THAT IS ANOTHER EXPERIMENT OF NATURE WHERE YOU DO GET HYPOXIA AND IT CAN TELL US ABOUT HOW THE PLACENTA ADAPTS. AS NICK AND STACY HAVE SHOWN. SO WELL DEFINED COHORTS FROM DIFFERENT PARTS OF THE WORLD WIDOW EXPRESS MUCH HIGHER LEVELS OF PLACENTAL PATHOLOGY THAN WE SEE IN THE WEST WHERE MOST OF THE RESEARCH IS ACTUALLY CONDUCTED WOULD BE VERY HELPFUL. >> HETERO GENICITY OF THE PLACENTA. THAT IS A GOOD POINT. FOR THE SIMPLE ADS YOU SAY, PREECLAMPSIA, 5 TO 10% BUT IN HAITI IT'S 60%. YOU GO TO PAIRAGUA, 65%, COLUMBIA, ALMOST 48%, THE NUMBERS WE CAN CONTINUE. SO GREAT HETERO GENICITY IN THOSE DISEASES. SO JUST FOCUS IT IN HLAG OR VERY DIFFICULT TO EXPLAIN THAT. >> FOLLOWING FROM THAT GIL, IN TERMS OF POPULATION, BRINGING IT DOWN TO A MICRO LEVEL, IT SEEMS TO ME FOR BOTH YOURS AND FOR SOME OF THE OTHER DISCUSSIONS HERE TODAY, THERE'S SOMEWHAT A NEED TO DESCRIBE WHAT CELL POPULATIONS THERE ARE IN THE PLACENTA. AND SUBPOPULATIONS WITHIN -- IN OTHER WORDS, IF THERE'S A VIELLES TROPHO BLAST POPULATION IS IT ONLY ONE POPULATION. NC WELLS, IS IT ONLY ONE -- IF WE'RE GOING TO LOOK FOR SAMPLES ELSEWHERE, OF SOME OF THESE CELLS, WE NEED TO KNOW WHAT WE'RE LOOKING AT WHEN WE GET THERE. SOME SORT OF CELLULAR ATLAS IS PERHAPS SOMETHING THAT MIGHT BE INTERESTING. >> FINAL QUESTION OR COMMENT. DR. MALIK. >> I GUESS WE'LL DO ONE MORE AFTER -- >> WHEN YOU TALK ABOUT HUMANIZING THE MOUSE BLAH STEAN, WHAT ASPECTS OF THE MOUSE PLACENTA DO YOU THINK WOULD BE MOST IMPORTANT TO TRY AND REPLICATE THE HUMAN, AND HOW WOULD YOU VALIDATE THAT IT'S REALLY REALLY A CHANGE THAT RECAPITULATES HUMAN DEVELOPMENT OR SOMETHING THAT'S JUST AN ARTIFICIAL SYSTEM? >> WHO WAS THE PERSON -- [LAUGHTER] >> I HAVE NO IDEA. I THINK IT WAS GRAHAM BROUGHT UP THE FACT WHAT'S BEEN HAPPENING IS SPECIES ARE EVOLVING AWAY FROM THE INVASIVE PHENOTYPE WHICH MEANS THEN THEY'RE LOSING AND GAINING GENE EXPRESSION PATTERNS TO PREVENT THAT FROM HAPPENING. SO CAN YOU START TO REVERSE THAT PROCESS BY ADDING THOSE GENES BACK IN? AND SEE IF YOU CAN GET SOMETHING THAT BECOMES MORE INVASIVE. COULD YOU GET SOMETHING THAT HAD A TROPHOBLAST LAYER THAT PROTRUDES THROUGH -- IN THE CONTEXT OF IT BEING RELATIVELY NORMAL AND FUNCTIONAL AND THEN START TO ADDRESS SPECIFICS OF HUMAN PATHOLOGY. WE WERE ASKED TO COME UP WITH FANTASY. A BIT OF FANTASY BUT IN REALITY THERE'S A ROLE FOR THESE TRANSGENESIS AND MOLECULAR STUDIES TO TRY TO REINTRODUCE HUMANESQUE FEATURES TO ANIMAL SPECIES. >> I THINK THERE IS THE ASPECT I DON'T KNOW IF I MADE CLEAR, THERE IS THIS FIELD OF INFECTION AND PREGNANCY, THAT WE DON'T KNOW WHAT IS PLACENTA RESPONDING AND THE MODELS TO CITY THAT, IS A CHALLENGE. IF YOU TAKE JUST THE MOUSE, I THINK THEY MENTION THE CONDITIONS THAT WE KEEP IS DIFFERENT. HOW CAN WE REALLY TRANSLATE THAT HUMANIZATION OF THE MOUSE PLACENTA, WITH HUMANIZATION OF IMMUNE SYSTEM. I DON'T KNOW, MAYBE WE WILL GET CLOSER TO THAT'S SPECIALLY BECAUSE OF THE REGULATORY LIMITATIONS THAT WE HAVE. >> FINAL. >> JUST A QUESTION. LITTLE COMMENT. FIRST OF ALL, QUITE A FANTASTIC DAY SO FAR. GIVEN THE CONCENTRATION OF KNOWLEDGE WE HAVE IN THISn  ROOM, QUESTION IS, VERY BASIC. ON ALL CASES OF PREECLAMPSIA OR FETAL GROWTH RESTRICTION WILL HAVE FAILURE OF REMODELING OF THE SPIRAL ARTERIES. >> SO WE HAVE BEEN SUBSETTING OUR PREECLAMPSIA CASES. I SHOWED THAT PICTURE THIS MORNING OF THE SPIRAL ARTERY PROFUSING A PORTION OF PLACENTA. IN ADDITION TO JUST THE HISTOLOGY, WE HAVE BEEN TAKING OUR PREECLAMPSIA PLACENTAS AND RECORDING WHETHER WE SEE PERTURBATIONS IN THAT RELATIONSHIP VISUALLY, JUST LIKE I SHOWED YOU. THAT WAS NORMAL BUT WE HAVE BEEN DOING THAT IN PLACENTA. AND WE'RE TRYING TO -- WE DON'T -- WE HAVEN'T DONE IT BUT WE HAVE THE SAMPLES WE'RE ACCUMULATING THE SAMPLES TO COORDINATE THAT WITH GENE EXPRESSION. SO WHETHER OR NOT WE'LL FIND ANY DIFFERENCES, I DON'T KNOW. BUT WE CERTAINLY FIND CASES OF PREECLAMPSIA THAT ARE LACKING -- THAT LOOK PRETTY NORMAL IN CASES OF PRE-TERM LABOR THAT LOOK VERY MUCH LIKE PREECLAMPSIA. SO WE'RE VERY INTERESTED IN GENE EXPRESSION CORRELATIONS THAT GO TOGETHER WITH THOSE PHYSIOLOGIC PARAMETERS. >> HATE TO CUT OFF GOOD DISCUSSION. QUICKLY. >> RELATED TO THAT, AND IT WASN'T EXPLICITLY SAID IN OUR PRESENTATION FROM OUR GROUP, WHAT IS NORMAL? BRIAN MENTIONED THAT WHAT REALLY MOVED THE CANCER FIELD FORWARD WAS THAT PEOPLE BEGAN TO REALIZE THAT THE SAME TUMOR WAS NOT THE SAME BIOLOGICALLY. THERE'S CERTAINLY BEEN AN ASSUMPTION THAT NORMAL IS THE SAME FOR EVERYBODY. I THINK THAT THAT ASSUMPTION NEEDS TO BE CHALLENGED. WE DON'T REALLY EVEN KNOW WHAT NORMAL IS. AND WHAT ACTUALLY DRIVES NORMAL, WHAT COMBINATION OF FACTORS, WHETHER IT'S GENOTYPE, WHETHER IT'S ENVIRONMENT, WHETHER THERE ARE DIFFERENT COMBINATIONS THAT WHEN THEY COME TOGETHER MAKE A NORMAL PLACENTA. BUT I THINK WE HAVE TO ANSWER THAT QUESTION TOO. >> JUST A COMMENT. YOU MENTION TROPICAL POPULATIONS REMINDED ME THAT PLACENTAL MALARIA SAN INTERESTING PHENOMENA THAT CAUSES DRAMATIC REMODELING OF THE PLACENTA AND MAKES AN INTERESTING ASPECT TO THIS ISSUE. >> AGAIN, FROM THE PLACENTA MALARIA YOU CAN GO ALSO TO THE VIRAL INFECTION OF PLACENTA WHICH HAVE NO IDEA EXACTLY IT IS A GROWING AREA BUT IT NEEDS A LOT OF SUPPORT TO FIND WHAT OBJECTIVES WE SHOULD STUDY IN THAT AREA. >> GEORGE, KIM. AND WE'RE GOING TO TAKE A BREAK. >> I JUST WANT TO ANSWER DEV'S QUESTION, I'M SORRY, IT'S THREE QUESTIONS AFTER THAT BUT I'M TRYING TO ANSWER IT. I REALLY DON'T SEE HOW IT COULD ONLY BE FAILURE OF REMODELING OR ABNORMAL REMODELING. AS I SAID IN MY TALK, IT'S ALL RELATIVE, IT'S RELATIVE IMBALANCE. THAT RELATIVE IMBALANCE COULD BE STILL PRESENT IN THE PRESENCE OF ADEQUATE REMODELING BECAUSE THERE IS SOMETHING ELSE IN THE MATERNAL CIRCULATION OR IN THE MATERNAL SITUATION THAT AFFECTS THIS IMBALANCE. SO I THINK IT'S IMPORTANT TO KEEP IN MIND THE COMPENSATION AND BALANCE OF THE DIFFERENT SYSTEM, IT'S NOT ONE SYSTEM ALONE. >> I HAVE ONE PLEA FOR PATHOLOGIST COLLEAGUES. WHEN I SEND PLACENTA, I GET WEIGHT AND THREE VESSEL CORD. LITERALLY. I SAT IN ON A CONFERENCE AT YALE WHEN A GREAT PLACENTAL PATHOLOGIST, THERE WAS A PATIENT WITH LUPUS, WITH FETAL DEATH IN UTERO AND THERE WAS A LONG DESCRIPTION OF VASCULAR PROBLEMS, DISEASE, ET CETERA. WE NEED BETTER SERIOUS PATHOLOGY. WE CAN DO IT RIGHT NOW IF WE ASK AND DEMAND IT. >> WITH THAT WE'RE GOING TO TAKE A BREAK. WE'LL COME BACK AT 3:35. YOU HAVE TEN MINUTES THEN WE'LL HAVE TWO PRESENTATIONS AND ANOTHER SET OF BREAK-OUTS. THANK YOU.