>>> GOOD MORNING, EVERYONE. I'M GOING TO ENCOURAGE EVERYONE TO TAKE YOUR SEATS. I WANT TO WELCOME YOU TO THE NIH FOR OUR THIRD ANNUAL WORKSHOP ON THE HUMAN PLACENTA PROJECT. I'M CATHY SPONG, THE ACTING DIRECTOR OF THE A EUNICE KENNEDY SHRIVER AND NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT AND WE ARE DELIGHTED YOU ARE HERE TODAY TO HELP US MOVE THE HUMAN PLACENTA PROJECT FORWARD. THERE ARE A GROUP OF SCIENTIFICALLY DIVERSE PEOPLE IN THIS ROOM. BRINGING DIFFERENT PERSPECTIVES TO THIS MEETING, WHICH IS WHAT WE REALLY WANTED. WE ARE EXTREMELY HAPPY ABOUT THIS BECAUSE WE KNOW WE NEED AN INTERDISCIPLINARY APPROACH TO CONTINUE TO MOVE THIS PROJECT FORWARD. DON'T WORRY, FOR THOSE OF YOU WHO MIGHT BE FEELING A LITTLE BIT UNEASY ABOUT HOW THE PLACENTA WORKS AND ROLE IN PREGNANCY. I'M GOING TO TALK A LITTLE BIT ABOUT THAT IN MY FIRST PRESENTATION ALONG WITH MORE DETAILS ABOUT THE PROJECT ITSELF. I WOULD LIKE TO DO A LITTLE EXERCISE, A LITTLE OPENING EXERCISE SIMILAR TO WHAT WE DID LAST YEAR TO DEMONSTRATE THE VARIETY OF INTERESTS THAT ARE REPRESENTED IN THE ROOM AND TO PROVIDE AN OPPORTUNITY FOR YOU TO SEE WHO MIGHT BE A POTENTIAL PARTNER TO COLLABORATE ON A FUTURE HUMAN PLACENTA PROJECT INTERDISCIPLINARY EFFORT. I'M GOING TO NAME SOME CATEGORIES AND I'M GOING TO ASK YOU YOU TO PLEASE STAND IF YOU CLASSIFY YOURSELF AS SOMEONE WHO HAS AN INTEREST IN THAT AREA. AND I DID EXPECT THAT SOME OF YOU ARE GOING TO NEED TO STAND UP MORE THAN ONCE BECAUSE SOME OF YOU HAVE MORE THAN ONE AREAS OF EXAPPROXIMATERRITIES. SO THOSE -- EXPERTISE -- THOSE WHO HAVE AN INTEREST INO MIX, INCLUDING GENOMICS, METABOLOMICS TRANSCRIPTOMICS AND ANY OTHER KIND OF OMICS YOU WANT TO NAME, PLEASE STAND. LOOK AROUND AND SEE WHO IS INTERESTED IN DOING SOMETHING WITHO MIX. THIS IS A LITTLE CALL STENNICS FOR SOME OF YOU. THE NEXT GROUP IS IMAGING. ANYONE INTERESTING IN ANY FORM OF IMAGING. TAKE A STAND AND LOOK AROUND. AND THOSE WHO ARE SEATED, LOOK AT THE PEOPLE WHO YOU CAN COLLABORATE WITH WHO ARE INTERESTED IN IMAGING. WAVE TO YOUR FRIENDS. HAVE A SEAT. NOW, THE TECHNOLOGY EXPERTS, PEOPLE WHO FEEL THEY HAVE AN INTEREST IN EXPERTISE IN TECHNOLOGY. FABULOUS. ALL RIGHT. WAVE TO YOUR FRIENDS. LOOK AND SEE WHO TO COLLABORATE WITH. OKAY. TAKE A SEAT. THOSE WHO ARE CLINICIANS. TAKING CARE OF THE PREGNANT WOMEN, TAKING CARE OF KIDS, TAKING CARE OF ANYONE YOU WANT TO TAKE CARE OF, HERE IS THE CLINICIANS IN THE ROOM WHO CAN PROVIDE THAT CLINICAL EXPERTISE TO YOU. THOSE OF YOU WHO ARE RESEARCHERS, SOME OF WHOM ALSO MAY BE CLINICIANS. EXCELLENT. LOTS OF RESEARCHERS IN THE ROOM. THOSE OF YOU WHO ARE INDUSTRY REPRESENTATIVES. SO WE HAVE SOME INDUSTRY REPRESENTATIVES HERE. TAKE A LOOK AROUND THE ROOM. IT'S A SMALLER GROUP. YOU GUYS ARE GOING TO BE SOUGHT AFTER. NOW ANYONE WHOEVER BEEN ATTACHED TO A PLACENTA ESTIMATE POINT IN YOUR LIFE, PLEASE STAND UP. AND NOW I WANT YOU TO JUST TAKE ONE MINUTE TO INTRODUCE YOURSELF TO SOMEONE WHO IS STANDING CLOSE BY YOU OR SITTING CLOSE BY YOU SINCE YOU DID NOT FOLLOW THAT DIRECTION. ALL RIGHT. THIS IS QUITE A CHATTY GROUP. OKAY, OKAY. ENOUGH LOVE. ENOUGH LOVE. COME ON BACK. NOW MANY OF YOU MAY HAVE ALREADY PICTURED UP COLOR-CODED DOTS -- OKAY. ENOUGH. THANK YOU FOR THE LOVE. I APPRECIATE THE LOVE. WE ARE GOING TO COME BACK NOW. MAYBE NOT. IF DR.Y IS DOS KEY COULD PLEASE TAKE HIS SEAT. THANK YOU. I'M DELIGHTED THAT WE ARE ALREADY HAVE THAT MUCH INTERACTION. THAT IS FABULOUS. SOME OF YOU MAY HAVE ALREADY PICKED UP THE COLOR-CODED DOTS FOR THOSE DIFFERENT AREAS DURING THE BREAK YOU CAN ALSO PICK UP A COLOR-CODED DOT THAT CORRESPONDS TO YOUR AREAS OF INTEREST TO STICK ON YOUR NAME BADGE AND A PRINTED KEY IS ALSO AT THE REGISTRATION TABLE. THIS WILL ALLOW YOU TO KNOW PEOPLE WHO HAVE SIMILAR AND DIFFERENT INTERESTS FROM YOU TO HELP YOU INTERACT. WILL YOU HAVE MUCH MORE TIME FOR MINGLING AND GETTING TO KNOW EACH OTHER, WHICH CLEARLY YOU WANT TO DO, LATER IN THE DAY, BOTH AT THE LUNCH AND THEN AT OUR POSTER AND TECHNOLOGY DEMONSTRATION SESSIONS THIS AFTERNOON. FOR THIS YEAR'S WORKSHOP, WE WANT YOUR INPUT TO HELP US DETERMINE HOW BEST TO INCORPORATE TECHNOLOGY INTO THE HUMAN PLACENTA PROJECT. WE PROVIDED A NUMBER OF OPPORTUNITIES FOR YOU TO GET TO KNOW OTHERS IN THE FIELDS OF SCIENCE THAT YOU MAY NOT BE FAMILIAR WITH TO SHARE YOUR IDEAS WITH US. THROUGHOUT THE BAKE OUT SESSIONS, POSTER AND TECHNOLOGY DEMONSTRATIONS SESSION AND OUR IDEAS BOARDS LOCATED OUTSIDE OF THE AUDITORIUM, WE HOPE TO GENERATED INNOVATIVE IDEAS TO HELP US CONTINUE TO REVOLUTIONIZE OUR UNDERSTANDING OF THE PLACENTA AND ULTIMATELY IMPROVE THE HEALTH OF MOTHERS AND CHILDREN. WITH THAT END IN MIND, THE GOALS OF THE MEETING ARE TO IDENTIFY SCIENTIFIC PROCESSES THAT WITH NONINVASIVE MONITORING WILL ALLOW UNDERSTANDING OF PLACENTAL DEVELOPMENT AND FUNCTION, TO IDENTIFY NEW AND EMERGING TECHNOLOGIES AND IMAGING METHODS TO ACHIEVE THE HUMAN PLACENTA PROJECT GOALS, TO DEVELOP PARTNERSHIPS BETWEEN SUBJECT MATTER AND TECHNOLOGY EXPERTS, AND TO LEVERAGE THIS BREATH OF EXPERTISE TO INFORM THE BROADER PROJECT ROADMAP AND TO PRIORITIZE THE NEXT STEPS. TO HELP US ACHIEVE THESE GOALS, WE COLLABORATED WITH THE NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING WHO ARE THE EXPERTS AT NIH WHEN IT COMES TO CREATING BIOMEDICAL USING MRI. HIS CURRENT RESEARCH FOCUSES ON INTEGRATED IMAGING AND PREDICTIVE BIOMEDICAL MODELING OF CORONARY ARTHEROSCLEROTIC DISEASE. NATIONAL COLLABORATIVE AND INTERNATIONAL INITIATIVES HAVE BEEN ISSUED TO DEVELOP LOW COST AND POINT OF CARE MEDICAL TECHNOLOGIES AND HE LEADS AN EFFORT TO REDUCE CT RADIATION DOSE TO BACKGROUND LEVELS. HE ALSO LEADS A RECENT U.S. INDIA COLLABORATION TO DEVELOP UNOBTUSIVE TECHNOLOGIES FOR FREEIENT RECORDING OF BLOOD PRESSURE TO ADDRESS THE WORLDWIDE PROBLEM OF HYPERTENSION. NOW I'D LIKE TO INVITE DR. RODERICK PETTIGREW TO COME UP AND SAY A FEW WORDS. [ APPLAUSE ] >> THANK YOU, CATHY. I ONLY EXPECTED YOU TO SAY RODERICK PETTIGREW, DETECTOR OF NIBIB. BUT, GOOD MORNING, EVERYBODY. INDEED, IT IS A DELIGHT TO BE HERE AND TO BE A PART OF THIS IMPORTANT SYMPOSIUM AND MEETING. AS CATHY INDICATED, I AM THE DIRECTOR OF THE NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING, BUT I REALLY WOULD LIKE TO SHARE A SECRET WITH YOU. I'M NOT FOND OF OUR NAME BECAUSE I THINK OUR INSTITUTE IS BROADER THAN THE TITLE STATES. WE INDEED DO FOCUS ON IMAGING AND BIOENGINEERING. BUT I THINK OF US AS MORE OF AN INSTITUTE THAT LEADS THE DEVELOPMENT AND ACCELERATES THE APPLICATION OF EMERGING TECHNOLOGIES ACROSS-THE-BOARD. BIOMEDICAL PROBLEMS ARE ALSO A PART OF OUR COMMUNITY. ABOUT FOUR YEARS AGO, SOMEWHERE IN THE 3-4 YEAR RANGE, I WAS INVITED TO A MEETING BY THE DIRECTOR OF NICHD AT THAT TIME, ALLEN GUTTMACHER. I DIDN'T KNOW EXACTLY WHAT THIS MEETING WAS ABOUT. SO I ARRIVED IN HIS OFFICE, HE WAS THERE AND SEVERAL OF HIS KEY STAFF WERE THERE, INCLUDING CATHY SPONG. HE SAYS SOMETHING TO ME THAT WAS SO SIMPLE AND PROFOUND I'VE NEVER FORGOTTEN IT. IT SIMPLY WAS, DESPITE THE CRITICAL ROLE THAT THE HUMAN PLACENTA PLAYS IN ALL OF OUR LIVES, IT IS THE LEAST UNDERSTOOD AND THE LEAST STUDIED ORGAN IN THE BODY. AND THAT JUST HIT ME. AND THEN, HE BEGAN TO TALK ABOUT THIS PROJECT, WHICH INTENDS TO MEET THAT CHALLENGE AND ADDRESS THAT NEED, AND ASKED FOR OUR COOPERATION AND COLLABORATION. AND I WAS IMMEDIATELY HAPPY TO DO THAT AND SAID, CERTAINLIY AND FOR SURE. AND WE HAVE BEEN PARTNERS SINCE THEN. THIS IS THE THIRD MEETING ON THIS PARTICULAR TOPIC, AND THE SUBTITLE OF THIS PARTICULAR MEETING, WHICH IS INNOVATION OR INCORPORATING NOVEL TECHNOLOGIES IN THE HVP, IS VERY APROPOS AND CERTAINLY ADDRESSES A WAY FORWARD IN MEETING THIS CHALLENGE. IN REVIEWING THE GRANTS THAT HAVE BEEN FUNDED TO DATE, SOME 20 OR APPROXIMATELY OR SO GRANTS, FUNDED IN THIS PROJECT, I WAS BOTH GRATIFIED AND IMPRESSED BY THE LARGE PERCENTAGE OF THOSE GOING TO MEMBERS OF OUR COMMUNITY AND SPECIFICALLY THE IMAGING COMMUNITY, ABOUT 80% OR SO. BUT ALSO LOOKING AT THE SPECIFIC APPLICATIONS AND GRANTS THAT HAVE BEEN FUNDED, I WAS ALSO STRUCK BY THE SOPHIST INDICATION OF THE TECHNOLOGY THAT IS BEING DEVELOPED TO HELP US BEGIN TO GET A BETTER UNDERSTANDING OF THE HUMAN PLACENTA. SOME PRETTY SOPHISTICATED COIL DEVELOPMENT WITH THE MRI, SPECIFICALLY FOR IMAGING THE PLACENTA. ADVANCES IN HIGH SPEED IMAGING TO ADDRESS THE PROBLEM OF MOTION AND MOTION DEGRADATION THAT HAPPENS WITH A VARIETY OF IMAGING TECHNIQUES, PARTICULARLY, MORE. R. AND ALSO IN THE METABOLIC FRONT USING HYPERPOLARIZED CARBON 13 TO OBTAIN IN-VIVO, NONINVASIVE METABOLIC INFORMATION. SO, THAT I FOUND VERY IMPRESSIVE. AND WOULD LIKE TO ENCOURAGE THE CONTINUATION OF THAT. I'D ALSO LIKE TO MENTION THOSE OF YOU WHO ARE GRANTEES OR POTENTIAL GRANTEES, THAT THE RESEARCH MECHANISM KNOWN AS BIOMEDICAL RESEARCH PARTNERSHIPS, BRPs, WHICH REQUIRE AN ENGINEERING-TYPE PERSON, A PHYSICAL SCIENTIST, TO COLLABORATE WITH A CLINICIAN AND CATHY INDICATED WE HAVE BOTH OF THOSE TYPES OF PEOPLE IN THE AUDIENCE; HAS BEEN RE-ISSUE THE THIS YEAR AND THIS RE-ISSUANCE WHICH ALSO INCLUDES NICHD NOW SPECIFICALLY HAS LANGUAGE ADDRESSING THIS PARTICULAR PROBLEM AND THIS PARTICULAR PROJECT, HUMAN PLACENTA PROJECT. THERE ARE TWO RECEIPT DATES FOR THE BRPs NOW, IN MAY AND SEPTEMBER. SO, DO TAKE NOTE AND WE WELCOME YOUR APPLICATIONS. AND THE FINAL THING I'D LIKE TO MENTION IS SPECIFIC TO OUR INSTITUTE, ALTHOUGH CHILD HEALTH MAY DO SOMETHING SIMILAR. AND THAT IS, A FEW YEARS AGO, WE ANNOUNCED A POLICY IN WHICH WE ARE MORE ACTIVE NOW IN IDENTIFYING HIGH PRIORITY APPLICATIONS AND SELECTING THEM FOR PAY, INCLUDING THOSE THAT ARE BEYOND THE NOMINAL PERCENTILE PAY LINE. IN FACT, WE INSTITUTE WHAD WE CALL THE EXPANDED OPPORTUNITY ZONE. THIS IS THE ZONE IN THE PERCENTILE TERMS THAT IS TWICE OUR NOMINAL PERCENTILE PAY LINE. SO IF OUR PAY LINE IS 12% AS IT WAS LAST YEAR, WE WILL LOOK FOR APPLICATIONS IN THE 12-24th PERCENTILE RANGE AND IDENTIFY THOSE BASED ON PRIORITIES FOR OUR INSTITUTE AND THIS IS ONE OF THEM AND INDEED, GRANTS HAVE BEEN IDENTIFIED AND FUNDED USING THAT PARTICULAR POLICY. SO, I'M DELIGHTED TO BE HERE. I SEE ALLEN GUTTMACHER IS HERE WHO I REFERENCED IN MY OPENING COMMENTS. AND I THINK THIS IS A TESTAMENT TO THE SINCERITY WITH WHICH HE ADDRESSED ME IN IDENTIFYING THIS PROBLEM BACK WHEN HE WAS NICHD DIRECTOR, AND THE FACT THAT HE IS NOW HERE AND HAS COME HERE OUT OF RETIREMENT, I THINK UNDERSCORES THAT THAT CONVERSATION WAS JUST NOT ONE OUT OF OBLIGATION BUT ONE OUT OF SINCERE INTEREST AND INVOLVEMENT. SO, I LOOK FORWARD TO CONTINUING THIS MEETING AND LEARNING FROM YOU AND SEEING EACH OF YOU LEARN FROM EACH OTHER. THANK YOU. [ APPLAUSE ] >> THANK YOU VERY MUCH FOR THAT WONDERFUL SET OF REMARKS. I WANT TO ADD MY WELCOME TO ALL OF YOU HERE. MY NAME IS DAVID WEINBERG AND I'M THE PROJECT LEAD FOR THE HPP. I THINK THIS IS GOING TO BE A FABULOUS MEETING AND SO I JUST WANT TO GIVE YOU A BRIEF OUTLINE OF THE DAY. SO WE'LL HAVE A SERIES OF TALKS WHICH TOUCH ON ASPECTS OF PLACENTAL BIOLOGY AND INNOVATIVE TECHNOLOGY, SOME OF WHICH IS BEING APPLIED TO THE PLACENTA AND SOME OF WHICH IS NOT CURRENTLY, BUT MAY INSPIRE, AND I HOPE WILL INSPIRE, CREATIVE NEW APPROACHES. THEN WE WILL HAVE BREAKOUT SESSIONS WHERE YOU WILL ASSEMBLE IN SMALL GROUPS TO REALLY GET INTO WHAT WE MOST WANT TO MEASURE, WHAT TECHNOLOGIES MAY BE APPLIED AND WHERE THE TECHNOLOGY AND TECHNOLOGY GAPS ARE. BREAKOUT ASSIGNMENTS BASED ON YOUR REQUESTS ARE IN THE PACKET. LATER WE WILL HAVE A TALK FROM DR. TOGA ABOUT MANAGING AND VIEWING COMPLEX DATA, LESSONS LEARNED FROM THE FIELD OF NEUROSCIENCES. AND WE LISTENED WHEN YOU TOLD US YOU WANTED MORE TIME FOR NETWORKING AND UNSTRUCTURED DISCUSSION. SO WE HAVE SET UP AT THE END OF THE DAY, A NICE RELAXED POSTER DEMONSTRATION SESSION. JUST A COUPLE OF HOUSEKEEPING COMMENTS. PLEASE SILENCE YOUR PHONES, ALSO WE WILL HAVE TIME FOR A BRIEF QUESTION OR TWO AFTER EACH TALK BUT THE SCHEDULE IS PRETTY PACKED AND SO I'D INVITE YOU TO SEEK OUT THE SPEAKERS AT THE BREAKS OR AT LUNCHTIME FOR MORE EXTENSIVE DISCUSSIONS. I SHOULD ALERT YOU THAT THIS MEETING IS BEING RECORDED FOR FUTURE PLAYBACK ON THE NIH VIDEO CAST WEBSITE. ONE FEATURE THAT WE REALLY HOPE THAT YOU'LL UTILIZE IS THE DREAM BOARDS WE HAVE SET UP IN THE LOBBY. DON'T HESITATE TO LET US KNOW WHAT YOU LOVE ABOUT THE CURRENT HPP APPROACHES AND AS WELL AS WHAT YOU THINK NEEDS MORE ATTENTION. AND FOR THE SPEAKERS, WE HAVE A SYSTEM HERE THAT I'LL ATTEMPT TO USE WHERE BLINKING LIGHTS WILL ALERT YOU WHEN YOU START TO RUN OUT OF TIME. BUT I KNOW THAT YOU'LL FORGIVE ME IF I START TO HOVER IF YOU'RE STARTING TO GO OVER. WE HAVE A CAFETERIA AND A SNACK BAR RIGHT UPSTAIRS FOR FOOD AND DRINK NEEDS AND IMPORTANTLY, WE ARE GOING TO DO A PICTURE AT LUNCHTIME SO BEFORE WE BREAK, WE'LL ASK EVERYBODY TO COME TO THE FRONT TO GET A PHOTOGRAPH. AND WITH THAT, I'M DONE AND I WANT TO WELCOME DR. SPONG BACK TO GIVE US THE OPENING LECTURE. [ APPLAUSE ] >> CATHERINE SPONG: DO I HAVE A CLICKER THAT MOVES AROUND? SO GOOD MORNING. I'M DELIGHTED TO SEE YOU ALL HERE AND ALL OF THE ENERGY IN THE ROOM. MY APOLOGIES FOR MY VOICE. CAN YOU HEAR ME ALL RIGHT? THE LAST TIME I WAS ATTACHED TO A PLACENTA WAS ABOUT 2 1/2 YEARS AGO AND THAT WILL LITTLE PERSON IS A GREATER VECTOR AND HAS GIVEN ME A NICE COLD SO I APOLOGIZE FOR MY VOICE. WHAT I WOULD LIKE TO DO IN THIS PRESENTATION IS SET THE STAGE OF WHY ARE WE UNDERTAKING THIS PROJECT OF THE HUMAN PLACENTA PROJECT? WE BELIEVE THE HPP WILL REVOLUTIONIZE HOW WE VIEW PREGNANCY AND UNDERSTAND AND OPTIMIZE PREGNANCY OUTCOMES AND IT IS ALSO GOING TO PROVIDE INCREDIBLE INSIGHTS FOR MEDICINE IN GENERAL. AND I LOOK FORWARD TO THE NEXT DAY AND A HALF AS YOU HELP TO WORK WITH US IN TRYING TO FIGURE OUT ALL OF THOSE STEPS. I KNOW SOME OF YOU FEEL A LITTLE BIT UNCOMFORTABLE ABOUT THE PLACENTA, BUT WHAT I HOPE TO DO IN THIS PRESENTATION IS TO GIVE YOU A LITTLE BIT OF INSIGHT INTO THE PLACENTA ITSELF AND INTO UNDERSTANDING WHY THE PLACENTA IS IMPORTANT AND HOW THIS PROJECT IS GOING TO HELP US MOVE ALL OF THIS FORWARD. BEFORE I BEGIN THAT, I WANT TO START WITH A STORY BECAUSE SOMETIMES IT'S EASIER TO UNDERSTAND THE IMPORTANCE OF AN AREA OR AN ASPECT IF WE START WITH A STORY. SO I'M GOING TO START WITH A STORY OF CAROLINE. THIS IS CAROLINE. A BEAUTIFUL YOUNG LADY. A HIGH SCHOOL SENIOR. SHE IS AN HONOR STUDENT IN ADDITION TO BEING A VERY KIND AND AND THOUGHTFUL YOUNG LADY. SHE IS A 5 FOOT 8 VARSITY VOLLEYBALL PLAYER AND ULTIMATE FRISBEE PLAYER AND I BELIEVE THEIR TEAM WON THE STATE CHAMPIONSHIP IN ULTIMATE FRISBEE LAST YEAR. BUT SHE IS, I'LL TELL YOU THE STORY IS A GOOD ONE BECAUSE SHE IS A SUCCESS. AND I THOUGHT IT WAS BETTER TO HAVE A SUCCESSFUL STORY FOR YOU TODAY. BUT PLEASE UNDERSTAND THAT THIS IS NOT THE NORMAL OUTCOME FOR THE STORY I'M GOING TO TELL YOU ABOUT AND THIS WAS CERTAINLY NOT WHAT HER PARENTS EXPECTED NECESSARILY WHEN THEY BEGAN THEIR JOURNEY NOW 18 YEARS AGO. THESE ARE HER PARENTS, SUZI AND TIM. LIKE MANY COUPLES, WE ARE EXCITED ABOUT HAVING A FAMILY AT SOME POINT. SUZI IS LIKE ANY TYPICAL PATIENT OF MINE. I'M AN OBSTETRICIAN. SHE COMES INTO PREGNANCY AS WE ALL DO WHEN WE ARE PREGNANT WITH SOME RISKS. BECAUSE PREGNANCY ITSELF HAS MANY DIFFERENT RISKS ASSOCIATED WITH IT. AND ONE OF THOSE RISKS FOR HER OF COURSE BECAUSE IT WAS HER FIRST PREGNANCY WAS A RISK OF PREECLAMPSIA. NOW FOR THOSE OF YOU WHO DON'T KNOW WHAT PREECLAMPSIA IT IS, IT'S A SPECIFIC CONDITION TO PREGNANCY ITSELF AND IT HAS ORIGINS IN THE PLACENTA. SOME OF YOU MAY HAVE HEARD OF IT AS TOXEMIA AND PREECLAMPSIA CAN AFFECT MANY DIFFERENT ORGANS AND CAN BE LIFE-THREATENING TO BOTH MOM AND BABY. IT OCCURS 10-14% OF PREGNANCIES. SO SUZI HAD THAT RISK. SHE HAD OTHER RISKS. SUZI HOWEVER, IS A LITTLE BIT DIFFERENT THAN MANY PATIENTS THAT I HAVE BECAUSE SUZI IS ALSO AN OBSTETRICIAN AND ALSO A MATERNAL FETAL MEDICINE SPECIALIST. SO SHE KNOWS ABOUT THESE RISKS PRETTY INTIMATELY. SHE TALKS TO PATIENCE ABOUT THEM. AND SHE KNOWS WHAT IS IMPORTANT TO DO IN PREGNANCY TO HAVE A GOOD OUTCOME. WHAT ARE THE STEPS WE CAN TAKE, GOOD DIET, SHE EXERCISED THROUGHOUT HER PREGNANCY, ET CETERA. AND SO IF SOMETHING BAD COULD HAPPEN TO SUZI, TO ME, THAT MEANS IT CAN HAPPEN TO ANYONE, RIGHT? SO TO ME, IT'S EVEN MORE POIGNANT THAT WE USE HER STORY TO ILLUSTRATE THIS. SO SUZI AND TIM DID BECOME PREGNANT AND THE DUE DATE WAS DECEMBER 25th. SO FOR THEM, THE GOAL WAS TO GET THROUGH THE FALL HOLIDAYS AND THEN CELEBRATE CHRISTMAS A LITTLE EXTRA SPECIAL THAT YEAR WITH THE BIRTH OF THEIR DAUGHTER. AND PREGNANCY WAS GOING VERY WELL. THERE WEREN'T ANY COMPLICATIONS. SHE DIDN'T HAVE DIABETES REMEMBERS SHE WAS EXERCISING AND THINGS WERE GOING INCREDIBLY WELL. NOW AT 30 WEEKS, WHICH IS ABOUT 3 QUARTERS OF THE WAY THROUGH PREGNANCY, PREGNANCY LASTS 40 WEEKS. AT ABOUT 30 WEEKS, SUZI STARTED TO NOTICE SOME SWELLING. AND AS A CLINICIAN, WE KNOW THAT SWELLING CAN BE ASSOCIATED WITH PREECLAMPSIA AND ALSO IS JUST COMMON IN PREGNANCY. WHICH SHE WENT IN TO SEE HER PHYSICIAN, HER BLOOD PRESSURE WAS UP. SO SHE WENT AND HAD SOME LABS DONE AND COLLECTED SOME URINE TO LOOK AT HER KIDNEY FUNCTION AND YES, IN FACT, SHE WAS SPILLING A LOT OF PROTEIN IN HER URINE. AND HER LABORATORY VALUES STARTED TO INCREASE AND SHE DEVELOPED SOMETHING CALLED HELP SYNDROME. NOW WHO WOULD WANT HELP SYNDROME? THE NAME ITSELF IS NOT GOOD. HELP SYNDROME IS A VARIANCE OF PREECLAMPSIA, A SEVERE FORM OF PREECLAMPSIA. THE H STANDS FOR HEMOLYSIS BREAKING DOWN BLOOD. EL FOR ELEVATED LIVER ENZYMES AND LP FOR LOW PLATELETS. THIS IS VERY CONCERNING. AND IT IS LIFE THREAT KNOWING FOR BOTH MOM AND BABY. -- LIFE-THREATENING FOR BOTH MOM AND BABY. ALTHOUGH THEY WERE EXPECTING TO DELIVER AROUND A BIG HOLIDAY, THEY STILL GOT THAT WISH, SORT OF. THEY DELIVERED ON HALLOWEEN IN AN EMERGENCY CESAREAN BECAUSE CAROLINE WAS SHOWING SIGNS OF INTOLERANCE TO LABOR. SO, IT WAS VERY DIFFERENT STORY THAN THEY HAD EXPECTED. AND HERE IS SUZI WITH CAROLINE IN THE ICU ALL THREE POUNDS OF HER. AND YOU KNOW, BABIES WHO ARE BORN SMALL LIKE THIS HAVE LOTS OF RISKS IN THE ICU AND NOT TO FORGET WE HAVE DAD HERE ALSO HOLDING CAROLINE. SO A LITTLE OVER THREE POUNDS, CAROLINE SPENT 26 DAYS IN THE INTENSIVE CARE UNIT AND SHE DID REQUIRE ABOUT 3-4 DAYS OF VENT TORY SUPPORT. BUT OVERALL, DID INCREDIBLY WELL. BUT THIS IS NOT NECESSARILY THE CASE. IN FACT, MANY, MANY TIMES, THE OUTCOMES ARE FAR WORSE FOR BABY AND FOR MOM FROM THIS CONDITION. AND AGAIN, THIS CONDITION HAS IT'S ORIGINS IN THE PLACENTA. SO THIS IS THE OUTCOME THAT WE WANT. THE GOAL OF THE HUMAN PLACENTA PROJECT IS TO TRY TO PROVIDE THIS OUTCOME FOR ALL OF OUR PATIENTS. CERTAINLY BACK IN THE ICU, THEY HAD NO IDEA THAT THIS IS WHAT THEY WERE GOING TO HAVE AS THE OUTCOME AND THEY ARE THRILLED WITH IT, BUT THEY TOO AS I ASKED THEM COULD I SHARE THEIR STORY, THEY TOO ARE EAGER FOR WHAT YOU ALL ARE GOING TO DO TO BE ABLE TO HELP US TO DETECT THAT PREECLAMPSIA EARLIER AND ULTIMATELY EVEN TO PROVIDE INTERVENTIONS TO BE ABLE TO PREVENT IT. SORRY, I'M GOING TO HAVE TO TAKE A WATER BREAK. SO WHAT EXACTLY IS THE PLACENTA AND WHAT DO WE KNOW ABOUT IT? WELL, THE PLACENTA IS FORMED FROM THAT DEVELOPING EMBRYO. THE BLASTOCYSTS AS IT COMES DOWN INTO THE UTERINE CAVITY FROM THE FALLOPIAN TUBE, IS LOOKING FOR A NICE PLACE TO IMPLANT AND THAT LUSH AREA IS THERE AND THE BLASTOCYST WILL BURY INTO THAT AREA TO IMPLANT AND THEN FORM THE PLACENTA. AND THIS WHOLE PROCESS AND HOW THIS HAPPENS IS INCREDIBLY REMARKABLE. THERE WAS A REALLY NICE VIDEO BY JOEL FLOYD WHO PUT THIS INTO PERSPECTIVE. HERE IS THE BLASTOCYST GOING INTO THE UTERINE WALL, INVADING IN. AND HE POINTS OUT THE CYTOTROPHOBLAST AND TWO DISTINCT CELL LAYERS COMING INTO THE UTERINE LINING. AND THEN THESE CELLS COMING OUT AND LOSING THEIR SHELLS SO THAT WE CAN MAKE THE MULTINUCLEATED UNIQUE STRUCTURE. ENZYMES ALLOW THAT BEARING TO CONTINUE AND WITHIN THAT THERE WILL BE DIFFERENT LA COONEY THAT WILL FORM, THE SPACES, AND THOSE WILL JOIN TOGETHER AND FILL WITH THE MATERNAL BLOOD THAT WILL THEN BATHE THE EMBRYO. AND THIS IS THE RUDIMENTARY, INITIAL FORM OF THE PLACENTA. THIS IS THE BEGINNINGS OF IT. THEN AS THIS GOES FORWARD AND INVADES INTO THE SPIRAL ARTERIES, AND THE PLACENTA PROPER IS DEVELOPED, BUT AS YOU CAN SEE FROM THIS PICTURE, THIS INITIAL FORMATION OF THE PLACENTA AND THE WAY THAT THE DEVELOPING EMBRYO IS GETTING ALL OF ITS NUTRIENTS AND ALL OXYGEN AND EVERYTHING FROM THE MOTHER, LOOKS VERY, VERY DIFFERENT THAN THIS PICTURE, ALSO FROM HIS VIDEO, OF A PLACENTA MUCH LATER IN GESTATION. SO IT'S VERY CLEAR THAT THE PLACENTA CHANGES ACROSS PREGNANCY. NOW WE KNOW A LOT ABOUT THE PLACENTA AND MANY OF YOU IN THIS ROOM HAVE PROVIDED HUGE AMOUNTS OF INFORMATION UPON WHICH WE ARE BASING WHAT WE NEED TO LEARN. BECAUSE WHAT YOU ARE ABLE TO DO IS TO STUDY THIS PLACENTA AFTER IT IS DELIVERED, WHICH IS CRITICALLY IMPORTANT AND THAT WORK THAT IS DONE AND IS CONTINUING TO BE DONE AND NEEDS TO CONTINUE TO BE DONE IS GOING TO HELP INFORM US EVERY STEP OF THE WAY OF WHAT DO WE NEED TO LOOK FOR AND BE ABLE TO ASSESS NONINVASIVELY IN THE PLACENTA. WHEN WE TRY AND LOOK AT THE PLACENTA LIKE THIS, AND UNDERSTAND THE PLACENTA EARLIER ON IN PREGNANCY, IT'S AKIN TO PERHAPS HAVING AN AUTOPSY AND TRYING TO UNDERSTAND WHAT HAPPENED TO THAT PERSON THROUGHOUT THEIR LIFE. YOU CAN GET A LITTLE BIT OF A HINT FROM IT IF THEY HAD PLAQUES IN CORONARY VESSELS. YOU MIGHT UNDERSTAND A LITTLE BIT ABOUT THEIR DIET OR ACTIVITY LEVEL. BUT YOU REALLY DON'T KNOW EVERYTHING THAT HAPPENED IN THAT PERSON'S LIFE. OR PERHAPS A LESS MORE BID WAY TO THINK ABOUT IT IS TO LOOK AT THE TREE STUMP. ALSO ROUND LIKE THE PLACENTA AND CERTAINLY WHEN I WAS LITTLE, I WAS TAUGHT THAT IF YOU COUNTED THE RINGS ON THE TRY YOU COULD TELL HOW OLD IT WAS AND IF THEY WERE THICK, YOU KNEW THERE WAS LOTS OF GROWTH AND LOTS OF NUTRIENTS THAT THE TIME OR THIN, THERE WAS PERHAPS A TIME OF LITTLE WATER. BUT REALLY, LOOKING AT A TREE TRUNK AND JUST LOOKING AT THIS STUMP AND TRYING TO UNDERSTAND WHAT DID THAT TREE LOOK LIKE WHEN IT WAS LITTLE? OR EVEN AS AN ADOLESCENT? OR WHAT CAN THAT STUMP TELL US ABOUT THE MA JECTIC LIFE OF THIS FREE FOR MANY, MANY YEARS, IS VERY, VERY LITTLE. SO WE NEED TOOLS TO BE ABLE TO DO THAT WILL ASSESSMENT THROUGHOUT PREGNANCY FOR THE PLACENTA ITSELF. BECAUSE JUST AS THE FT. US CHANGES AND GROWS ACROSS PREGNANCY AND YOU CAN SEE THAT THE BLASTOCYST DOESN'T EVEN LOOK LIKE WHAT WE WOULD CONSIDER A FETUS, ALL THE WAY THROUGH A TERM FETUS GROWS AND CHANGES AND WE KNOW THIS WELL, THE PLACENTA DOES THAT AS WELL. AND IT CHANGES NOT ONLY IN WHAT IT LOOKS LIKE, BUT IT CHANGES IN ITS FUNCTION AS WELL AS ITS STRUCTURE. AND SO IT WILL BE ABSOLUTELY WONDERFUL TO HAVE THE TOOLS AND TECHNOLOGIES TO BE ABLE TO DO THIS ASSESSMENT THROUGHOUT PREGNANCY AND THAT IS REALLY WHAT THE GOAL IS OF THE HUMAN PLACENTA PROJECT. SO WHAT DO WE KNOW ABOUT THE PLACENTA? WE KNOW THAT IT GROWS AND DEVELOPS ACROSS PREGNANCY. WE KNOW IT'S FUNCTION CHANGES ACROSS PREGNANCY AND WE CONTINUE IS CRITICAL FOR PREGNANCY GROWTH AND DEVELOPMENT. AND THAT WHAT THE PLACENTA DOESN'T GROW NORMALLY PREGNANCY OUTCOME IS ALTERED. WE KNOW THAT THE PLACENTA FUNCTIONS AS MULTIPLE ORGANS. THE PLACENTA IS THE ONE THAT PROVIDES THE OXYGEN TO THE FETUS; THEREBY IT FUNCTIONS AS THE LUNGS. THE PLACENTA PROVIDES THE NUTRIENTS TO THE FETUS, HAS SOME OF THE GI ROLE. THE PLACENTA HAS AN ENDOCRINE ROLE. IT MAKES HORMONES ITSELF. THE PLACENTA ALSO REMOVES THE WASTE SO IT HAS FUNCTIONS OF BOTH THE LIVER AND THE KIDNEYS. AND THE PLACENTA HAS AN IMMUNOLOGIC FUNCTION. THE PLACENTA IS THE ONE THAT ALLOWS THE FETUS AND THE MOTHER TO GENETICALLY DISTINCT ENTITIES, TO GROW AND COEXIST. THE PLACENTA THEN IS REALLY A MODEL ORGAN FOR MANY, MANY DIFFERENT ORGANS. SO WHAT I'D LIKE TO DO IS TO TRY AND EXCITE YOU A LITTLE BIT ABOUT THIS AND THE POSSIBILITIES OF THIS. AS I WAS MENTIONING EARLIER, WHEN THE BLASTOCYST IMPLANTS INTO THE WOMAN, IT INVADES INTO THE MATERNAL SPIRAL ARTERIES AND THE INVADING CYTOTROPHOBLASTS GO TO THE SPIRAL ARTERIES AND TRANSFORM THEM. THEY TAKE OVER THE LINING ENDOTHELIUM AND THEY MAKE THESE SPIRAL ARTERIES TRANSFORMING THEM FROM LITTLE TINY SPIRAL ARTERIES INTO MUCH LARGER BORE VESSELS TO ALLOW LOTS OF BLOOD FLOW TO COME TO THE EMBRYO. SOMETIMES, THAT DOESN'T HAPPEN NORMALLY AND THAT IS WHEN YOU CAN GET PREGNANCY ADVERSE OUTCOMES. BUT LET'S JUST THINK ABOUT IT IF WE WEREN'T EVEN INTERESTED IN THE PREGNANCY ITSELF. WHAT DOES SOMETHING THAT IS COMING IN AND INVADING AND TAKING OVER SOUND LIKE TO YOU? TO ME, IT'S A TUMOR, RIGHT? OR A CANCER. SO HOW IS IT THAT THESE INVADING CYTOTROPHOBLASTS CAN DO THIS, CAN INVADE INTO THE SPIRAL ARTERIES AND TAKE THEM OVER AND TRANSFORM THEM AND THEN STOP? IF WE COULD UNDERSTAND THAT, DON'T YOU THINK WE WOULD HAVE A LITTLE BIT OF INSIGHT INTO TUMOR BIOLOGY AND CANCER BIOLOGY? AND MAYBE WE WOULD BE ABLE TO TAKE SOME OF THAT AND PUT THEM INTO SOME THERAPEUTICS. SO JUST TO DEPICT THAT AS PICTORALLY, HERE IS THE NORMAL NON-PREGNANT UTERUS IN A SIMPLE GRAPHIC SHOWING THAT SPIRAL ARTERY. IN PREGNANCY, WE HAVE GOT THIS ON THE BOTTOM WITH THE TROPHOBLASTS GOING INTO TO INVADE AND TAKE OVER THAT SPIRAL ARTERY, AGAIN REPLACING THE ENDOTHELIUM AND MAKING THAT SPIRAL ARTERY A LARGER BORE, ALLOWING MORE BLOOD FLOW TO COME IN. INVADING LIKE A TUMOR OR A CANCER. NOW, IN SOME SITUATIONS, THAT TRANSFORMATION AND THIS IS WORK THAT YOU ALL IN THE AUDIENCE HAVE DONE TO SHOW US, THAT IN FACT SOMETIMES THAT DOESN'T HAPPEN NORMALLY. AND IT MAKES THAT SPIRAL ARTERY NOT AS LARGE. SO THE BLOOD IS NOT ABLE TO COME IN AS EASILY, AND THEN WE CAN GET ADVERSE PREGNANCY OUTCOMES SUCH AS PREECLAMPSIA OR SMALL BABIES. AND LET'S JUST TAKE IT ONE STEP FURTHER. AGAIN, IF YOUR GOAL IN LIFE ISN'T TO IMPROVE PREGNANCY OUTCOMES, NOT SURE WHY IT WOULDN'T BE BUT IF IT WASN'T, WHAT COULD WE LEARN FROM THE PLACENTA? IF WE WERE ABLE TO NONINVASIVELY UNDERSTAND THE IMMUNOLOGY OF HOW DOES THE PLACENTA ALLOW THESE TWO GENETICALLY DISTINCT ENTITIES TO NOT JUST COEXIST, BUT TO THRIVE, TO DO WELL, AND TO GROW, DON'T YOU THINK WE COULD TAKE THE THINGS WE LEARNED AND IMPROVE AREAS OF TRANSPLANT MEDICINE AND MAKE IT EASIER FOR US TO TRANSPLANT ORGANS AND TO HELP THEM TO NOT JUST COEXIST, BUT ALSO TO THRIVE. THE IMPLICATIONS OF THE HUMAN PLACENTA PROJECT GO FAR BEYOND IMPROVING PREGNANCY OUTCOME. THE INSIGHTS YOU ALL ARE GOING TO HELP US GENERATE ARE GOING TO HELP US UNDERSTAND AND ADVANCE MANY, MANY ASPECTS OF MEDICINE. SO WHY DOES THE PLACENTA MATTER STEPPING BACK INTO PREGNANCY? A PLACENTA THAT DOESN'T FORM NORMALLY IS A PLACENTA THAT CAN RESULT IN A PREGNANCY THAT CAN HAVE ADVERSE OUTCOMES. AND WHAT ARE THOSE ADVERSE OUTCOMES? WHAT IS THE PLACENTA CRITICAL FOR? IT'S CRITICAL FOR FETAL GROWTH. AND A PLACENTA THAT ISN'T NORMAL, YOU WILL OFTEN GET GROWTH RESTRICTIONS WHERE A BABY IS SMALL. SIMILARLY, WE CAN GET PREECLAMPSIA AS I HIGHLIGHTED ALREADY. WE CAN ALSO GET OTHER COMPLICATIONS SUCH AS PLACENTAL AB ERUPTION WHERE THE PLACENTA SEPARATES FROM THE WALL OF THE UTERUS AND CAUSES HEMORRHAGE AND AGAIN, LIKE OTHER CONDITIONS, CAN BE LIFE-THREATENING FOR THE MOM AND THE BABY. THE PLACENTA IS ALSO CAN RESULT IN ABNORMALITIES IN THE PLACENTA IN GESTATIONAL DIABETES AND IN PRE-TERM BIRTH. THESE ALL HAVE IMPLICATIONS NOT ONLY FOR THE PREGNANCY ITSELF, BUT ALSO FOR THE MOM. BABIES WHO ARE BORN SMALL HAVE HIGHER RISKS OF COMPLICATIONS LATER IN LIFE. THOSE COMPLICATIONS INCLUDE HEART DISEASE AND DIABETES. AND THIS IS CALLED THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE. SO IF WE COULD OPTIMIZE PREGNANCY OUTCOME BY OPTIMIZING PLACENTAL HEALTH AND PREVENT THOSE BABIES FROM BEING BORN SMALL, SUCH AS YOU SEE WITH GROWTH RESTRICTION OFTEN WELL PREECLAMPSIA OR PRE-TERM BIRTH, WE CAN IMPROVE NOT ONLY THE HEALTH OF THE NATION BUT THE THE HEALTH OF THE WORLD. SO OPTIMIZING PREGNANCY OUTCOME HAS LIFELONG IMPLICATIONS OF HEALTH FOR THAT BABY. NOW I WANT TO TAKE IT ONE STEP FURTHER. BECAUSE PREGNANCY ITSELF IS A STRESS TEST ALSO FOR MATERNAL HEALTH. WE KNOW THAT WOMEN WHO HAVE PREECLAMPSIA ARE AT HIGHER RISK FOR HAVING HEART DISEASE LATER IN LIFE. AND WOMEN WHO HAVE GESTATIONAL DIABETES ARE AT HIGHER RISK FOR HAVING DIABETES LATER IN LIFE. SO IF WE CAN OPTIMIZE PREGNANCY OUTCOME AND OPTIMIZE THAT PLACENTA, NOT ONLY CAN WE IMPROVE THE HEALTH FOR THE CHILD, POTENTIALLY WE CAN IMPROVE THE HEALTH FOR THE MOTHER. JUST MANAGE WHAT I KNOW YOU ALL ARE SET AND POISED TO DO. IT'S INCREDIBLE. THESE ARE LIFELONG IMPLICATIONS FOR BOTH THE MOM AND THE BABY. SO WHAT IS THE HUMAN PLACENTA PROJECT? THE HUMAN PLACENTA PROJECT IS TRYING TO DEVELOP THE TOOLS AND THE TECHNOLOGIES TO BE ABLE TO UNDERSTAND THE PLACENTAL FUNCTION, STRUCTURE AND DEVELOPMENT ACROSS PREGNANCY. IN A NONINVASIVE MANNER. WHY ARE WE DOING THIS? WHY NOW? WELL, WE ARE AT A UNIQUE POINT IN TIME WHERE WE HAVE THE TOOLS AND THE TECHNOLOGY TO DO THIS. WE HAVE THE ABILITY, WHO WOULD HAVE THOUGHT 10 YEARS AGO THAT YOU COULD HOLD IN YOUR HAND A PHONE, A COMPUTER, WALK AROUND, GET YOUR E-MAILS, TAKE PICTURES, SEND THEM TO SOMEONE ELSE INSTANTLY? I USED TO THINK THE FAX MACHINE WAS COOL. IMAGINE WHAT WE CAN DO NOW. 10 YEARS AGO I WOULD HAVE THOUGHT THAT WAS CRAZY, RIGHT? SO WHAT CAN WE DO NOW? TAKE ALL OF THAT ENERGY THAT WE HAVE, ALL OF THAT INNOVATIVE THINKING AND BE ABLE TO DEVELOP THESE TOOLS AND TECHNOLOGIES TO BE ABLE TOL ASSESS THE PLACENTA IN REALTIME. WE CAN DO IT. WE HAVE THAT NOW. WHAT HAVE WE DONE TO DATE? THIS IS OUR THIRD WORKSHOP AND EACH TIME WE FOCUSED ON DIFFERENT SPECIFIC AREAS. WE HAD A NUMBER OF CALLS FOR APPLICATIONS AND HAVE STARTED FUNDING PEOPLE TO WORK AGGRESSIVELY ON THIS PROJECT. FIRST WE STARTED WITH, WHAT ARE THE TECHNOLOGIES THAT ARE OUT THERE THAT JUST ARE NOT BEING APPLIED TO THE PLACENTA? SOMETIMES DIFFERENT AREAS IN MEDICINE MOVE FORWARD AND OTHERS DON'T EVEN KNOW THEY ARE DOING THAT. SO WE RECOGNIZE, WE NEED A MULTIDISCIPLINARY APPROACH TO BE ABLE TO DO THIS AND LET'S TAKE THOSE TECHNOLOGIES THAT ARE ALREADY AVAILABLE AND APPLY THEM TO THE PLACENTA. WE HAVE ALSO FUNDED PEOPLE TO DEVELOP NEW TECHNOLOGIES AND THESE TECHNOLOGIES CAN INCLUDE IMAGING, BIOSENSORS, NOVEL TECHNOLOGIES, THE LITTLE NANOBOTS AND THINGS LIKE THAT, ANYTHING THAT YOU WOULD WANT TO DEVELOP. AND ONE OF THE -- LOOKING AT OMICS AS WELL. IT IS ALWAYS FASCINATING TO ME AS I TALKED TO MY PATIENTS TO EXPLAIN TO THEM THAT THERE ARE CIRCULATING IN MOM'S BLOOD, PARTS OF THE PREGNANCY. THE PLACENTA SHEDS THINGS INTO THE CIRCULATION. THAT IS WHY WE CAN DO THAT PRENATAL TEST JUST FROM MOM'S BLOOD TO LOOK FOR ANEUPLOIDY. SO WHAT CAN WE TAKE FROM MOM'S BLOOD AND UNDERSTAND WHAT IS GOING ON? BECAUSE THE PLACENTA IS SENDING CLUES TO US. SO THERE IS SO MUCH OPPORTUNITY FOR US THAT WE ARE ABLE TO HARNESS NOW TO MOVE THIS FORWARD. THIS IS AN INTERNATIONAL EFFORT AND I'M DELIGHTED THAT WE HAVE HAD TWO WORKSHOPS OUTSIDE OF THE U.S. IN ADDITION TO THE TWO PRIOR TO THIS WORKSHOP, ONE IN INDIA AND ONE IN CHINA LAST YEAR. SO WE ARE EXCITED AROUND THE WORLD, PEOPLE ARE INTERESTED IN THIS PROJECT AND ARE GOING TO WORK ALL OF US TOGETHER TO MOVE THIS FORWARD. BECAUSE IT'S SO IMPORTANT TO REALLY BE ABLE TO TAKE THE OPPORTUNITY AS WE CAN SEIZE IT NOW, AND BE ABLE TO HARNESS THIS AND MOVE IT FORWARD. THIS IS A PICTURE FROM GRAHAM BURTON'S SLIDES THAT I THINK FROM ONE OF THE PRIOR PRESENTATIONS THAT HE GAVE AT ONE OF THESE MEETINGS. AND IT'S A TERMINALVILLE I IN THE CAPILLARIES INSIDE. AND WOULDN'T IT BE JUST AMAZING IF WE COULD BE ABLE TO DO THIS IN A NON-INVASIVE MANNER AND SEE THIS LEVEL OF DETAIL? TO TAKE ALL OF THE TALENT THAT IS IN THIS ROOM, TO THINK OUTSIDE OF THE BOX AND COME UP WITH WAYS TO MEASURE BLOOD FLOW, OXYGENATION, METABOLISM, NUTRITION. TO UNDERSTAND WHAT GENES ARE TURNED ON AND OFF AT DIFFERENT TIMES ACROSS DEVELOPMENT IN THE PLACENTA. AND TO IDENTIFY DIFFERENT COMPOUNDS SPECIFICALLY. WHAT IS BEING MADE AT DIFFERENT TIME POINTS AND TO UNDERSTAND THE IMMUNE RESPONSE. FOR ME, THIS IS TO CRITICALLY UNDERSTAND FROM WHAT GREAT WORK HAS BEEN DONE WE KNOW THE PLACENTA CAN DO AND HOW IS THAT HAPPENING AND WHAT IS DIFFERENT ACROSS THE TIME PERIODS IN PREGNANCY ITSELF? SO I WANT TO END WITH JUST SOME THOUGHTS ABOUT WHAT COULD THE HUMAN PLACENTA PROJECT PROVIDE IF THE GOALS ARE ACHIEVED? WE CAN PROVIDE NOVEL TECHNOLOGIES TO MONER AN ORGAN FOR US IT IS THE PLACENTA. BUT IN REALITY, IT CAN BE ANY ORGAN. ONCE THESE TECHNOLOGIES HAVE DEVELOPED, THEY COULD BE USED FOR ANY ORGAN AND ADVANCE MANY OTHER ASPECTS OF MEDICINE. THE HUMAN PLACENTA PROJECT OVERALL IS GOING TO GIVE US A BETTER UNDERSTANDING OF DISEASE PROCESSES ITSELF AND PROVIDE INSIGHTS FOR OTHER ASPECTS OF MEDICINE THAT I THINK WE ARE NOT NECESSARILY ANTICIPATED BY MANY PEOPLE WHEN WE STARTED THIS PROJECT. IT ALSO WILL PROVIDE US AN OPPORTUNITY TO IMPROVE THE HEALTH OF THE WORLD BY OPTIMIZING HEALTH FOR MOMS AND BABIES AND FAMILIES AND TO GIVE HOPEFULLY, THE ABILITY THAT IF WE CAN IDENTIFY EARLY ON IN PREGNANCY, THAT SOMEONE MIGHT BE HAVING AN AT RISK FOR A COMPLICATION, WE CAN UNDERSTAND THE NORMAL AND WE CAN UNDERSTAND WHAT IS ABNORMAL. WE CAN THEN IDENTIFY INTERVENTIONS AND WITH THOSE INTERVENTIONS, BE ABLE TO HOPEFULLY OPTIMIZE THAT OUTCOME. SO THAT WE CAN HAVE MORE SUCCESS STORIES LIKE CAROLINE AND SUZI AND TIM. SO THANK YOU VERY MUCH. I NOW LIKE TO IN VIOLATE DIVED COME BACK UP AND INTRODUCE THE NEXT SPEAKER. [ APPLAUSE ] >> DAVID WEINBERG: THANK YOU VERY MUCH, CATHY. THAT WAS A WONDERFUL AND VERY INSPIRING OVERVIEW. SO NOW WE'LL START TO GET INTO SOME OF THE DETAILS THAT CATHY HAS INTRODUCED US TO AND THE FIRST SPEAKER WILL BE ANTONIO FRIAS FROM THE OREGON HEALTH AND SCIENCES UNIVERSALITIY AND GIVE US A INTRODUCTION TO OXYGENATION AND PERFUSION IN PLACENTAL DEVELOPMENT AND FUNCTION. >> ANTONIO FRIAS: GOOD MORNING. I'M SO HAPPY TO BE HERE. IT'S HARD TO FOLLOW THAT TALK. BUT, I'M VERY EXCITED TO SPEAK WITH YOU ABOUT HOW WE CAN USE IMAGING TO HELP US ENHANCE OUR UNDERSTANDING OF THIS VITAL ORGAN AND NAMELY, HOW TO HELP US BETTER UNDERSTAND TWO CRITICAL COMPONENTS OF DEVELOPMENT WHICH ARE BLOOD FLOW AND OXYGENATION. I'M NOT GOING TO SPEND A LOT OF TIME HERE SINCE DR. SPONG GAVE AN INTRODUCTION. BUT, THE HUMAN PLACENTA CONTAINS TWO VASCULAR COMPARTMENTS. THERE IS THE MATERNAL BLOOD COMES FROM THE SPIRAL ARTERIES AND PER FUSES THE SPACE AND FACILITATES OXYGEN EXCHANGE ACROSS THE CORE ONTICVILLE I. NOW IN ORDER FOR THIS TO HAPPEN, A LOT OF THINGS NEED TO OCCUR. AS DR. SPONG SUGGESTED IN HER LAST TALK, THERE IS A LOT OF REMODELING IN THE MATERNAL VASCULAR COMPARTMENT SHOWN HERE. INTENDED TO MAXIMIZE BLOOD FLOW TO THE PLACENTA BY CREATING A LOW RESISTANCE CIRCUIT. SO WHAT HAPPENS IS THAT A SERIES OF IMPORTANT ARTERIAL PERTERBATIONS THAT ARE INCOMPLETELY UNDERSTAND WHERE THERE IS IN INITIALLY DIATION OF THE SPIRAL ARTERIES INDEPENDENT OF TROPHOBLAST INFLATION AND THEN THEY SECRETE NITRIC OXIDE AND DIALATE THE VESSELS AND THEN THERE IS THE INVASIVE COMPONENTS THEY INVADE INTO THE ARTERIAL LUMEN AND BECOME ENDOVASCULAR TROPHOBLASTS CREATING A MAXIMAL DILATION. AS DR. SPONG ALSO HIGHLIGHTED, WHEN THIS PROCESS GOES AWRY, IT IS ASSOCIATED WITH MANY ADVERSE OBSTETRIC OUTCOMES INCLUDING PREECLAMPSIA, FETAL GROWTH RESTRICTION, PRETERM LABOR, PRETERM PREMATURE RUPTURE OF MEMBRANES. SO CLEARLY A BETTER UNDERSTANDING OF BOTH THE IMMUNOLOGIC COMPONENTS OF THIS AS WELL AS WHAT IS HAPPENING TO THE ARTERIES IN REALTIME WOULD BE FANTASTIC. SIMULTANEOUSLY, THE FEELS VASCULAR COMPARTMENT MUST DEVELOP DURING THIS PROCESS AS HIGHLIGHTED ON THIS SLIDE. SO, IN THE FIRST TRIMESTER, THERE IS SUBSTANTIAL NEOANGIOGENESIS WHICH OCCURS IN THE LOW OXYGEN VIRAL. IN THE SECOND TRIMESTER, THERE IS CONTINUED SIGNIFICANT ANGIOGENESIS OF THEVILLE I, WHICH WITH CONTINUED ENHANCEMENT AND GROWTH IN THE THIRD TRIMESTER, IN THE TERMINALVILLE I SO THAT AT TERM, ABOUT 13 METERS SQUARED OF SURFACE AREA IS AVAILABLE FOR EXCHANGE. AND SO, ALSO AT TERM, 25-30% OF THE FETAL VASCULAR COMPONENT IS IN THE PLACENTAL CIRCULATION. WHAT THIS SLIDE ALSO ILLUSTRATES IS THAT DIFFERENT ENVIRONMENTAL PERTERBATIONS AT DIFFERENT TIMES DURING GESTATION CAN AFFECT DIFFERENT PROCESSES OF THIS FEELS VASCULAR DEVELOPMENT. THIS SLIDE ALSO SUGGESTS THINGS THAT HAVE BEEN SUGGESTED BY MANY IN THIS ROOM IN SEMINOLE WORK THAT BLOOD FLOW AND OXYGEN FROM THE SPIRAL ARTERIES, BY EITHER BEING LOW OR HIGH OR TOO LITTLE FLOW OR TOO FAST FLOW, COULD CREATE SHEAR STRESS, OXIDATIVE STRESS, THAT COULD AFFECT BOTH THE STRUCTURAL DEVELOPMENT OF THE TERMINALVILLEY, PROCESS WE JUST REALLY DON'T UNDERSTAND IN REALTIME. SO WHY DON'T WE KNOW MORE ABOUT OUR RULE TIME IMAGING? WHY AREN'T WE DOING BETTER? OUR CURRENT ASSESSMENTS OF THIS SPACE ARE INHIBITED BY THE FACT THAT OUR CURRENT SCREENING TECHNOLOGIES WHICH IS ULTRASOUND, A VERY IMPORTANT SCREENING TOOL, CANNOT YET LOOK AT WHAT IS HAPPENING IN THE INTERVILLA SPACE. THEREFORE, WE NEED TO WORK ON SOME TECHNOLOGY DEVELOPMENT TO HELP US BETTER UNDERSTAND BOTH PERFUSION, OXYGENATION AND NUTRIENTS TRANSPORT IN THE INTERVILLEY SPACE. SO MULTIPLE IMPORTANT PROJECTS IN THE HUMAN PLACENTA PROJECT LOOKING AT IMPROVEMENT IN CURRENT TECHNOLOGIFUL ULTRASOUND TO HELP US WITH IMPROVING ACQUISITION METHODS AND ANALYSIS TOOLS THAT WILL BETTER DEFINE BOTH PERFUSION THAT THE SPACE THAT WILL ALWAYS BE AN IMPORTANT COMPONENT AS A SCREEN. I'M NOT GOING TO TALK ABOUT THOSE. WHAT I'M GOING TO TALK ABOUT IS NEUROAPPLICATIONS OF KNOWN TECHNOLOGY AND FOCUS ON MRI TO SHOW HOW WE CAN HELP US BETTER UNDERSTAND THIS INTERVILLA SPACE. I'M SHOWING HERE IN THESE AXEIO AND COLONIAL IMAGES OF A RHESUS MACAQUE PLACENTA, YOU CAN SEE THE PLACENTAL LOBES OUTLINED IN RED AND BLUE. I DON'T WHY THE HIGHLIGHTER IS NOT WORKING. BUT THE IMPORTANT THING FOR THOSE WHO AREN'T USED TO SEEING MRI IMAGES, IS THAT IT PROVIDES NICE ANATOMIC STRUCTURE. IT'S VERY EASY TO CAPTURE THE ANATOMIC INFORMATION QUICKLY AND THEN MRI IS MULTIPURPOSE. DEPENDING ON HOW YOU ACQUIRE THE IMAGES CAN GIVE YOU DIFFERENT INFORMATION ABOUT THE SAME ORGAN. NOW, MANY YEARS OF WORK, MRI HAS BEEN USED FOR MORE THAN 30 YEARS TO LOOK AT THE PLACENTA. PART OF THE ISSUE IS WITH WHY IT HASN'T HELPED US MORE IN TERMS OF UNDERSTANDING PLACENTAL FUNCTION IS THE LACK OF DEVELOPMENT OF ACQUISITION AND ANALYSIS TOOLS THAT SPECIFICALLY FOCUS ON PLACENTAL PHYSIOLOGY AND PLACENTAL STRUCTURE. I'M SHOWING HERE THIS IMAGE OF HIGH RESOLUTION IMAGE OF A CONTRAST AGENT AS IT GOES INTO A PLACENTA AND WHAT I WOULD LIKE TO DRAW YOUR ATTENTION TO IS THOSE BRIGHT POINTS HERE WHERE YOU CAN SEE THE SPIRAL ARTERIES GOING INTO THESE LOBULAR STRUCTURES IN THE PLACENTA. GAD LIN YUM CONTRAST AGENTS ARE USED ROUTINELY OUTSIDE OF OBSTETRICS TO MEASURE PROFUSION AND WHEN YOU LOOK THAT THE IN REALTIME, YOU CAN SEE THE BLOOD ENTER THE SPIRAL ARTERIES FROM THE SPIRAL ARTERIES INTO THE SPACE. NOT ONLY DOES IT CREATE NICE IMAGE AND TELLS YOU SOME INFORMATION ABOUT HOW BLOOD FLOW OCCURS IN THE SPACE BUT USING THAT KINETIC DATA, YOU CAN USE TO BUILD MODELS THAT CAN GIVE YOU INFORMATION ABOUT THE KINETIC BLOOD FLOW FROM THE SPIRAL ARTERIES TO THE PROFUSION DOMAINS AS SHOWN HERE. SO, OUR GROUP DEVELOPED SOME ANALYSIS TOOLS THAT ALLOWS YOU TO CALCULATE BLOOD FLOW FROM EACH SPIRAL ARTERY AND THEN SEGMENTATION ANALYSIS THAT WE VERIFIED BECAUSE THIS WAS DELIVERY POST DELIVERY OF A RHESUS MACAQUE PLACENTA AFTER ACQUIRING OUR IMAGES THAT ALLOWED OR CONFIRMED OUR SEGMENTATION ANALYSIS WITH WHAT IT LOOKS STRUCTURALLY. SO USING THIS METHOD, YOU CAN THEN START THINKING ABOUT LEARNING SOME INFORMATION ABOUT HOW BLOOD FLOW IS TO THAT, FROM THAT SPIRAL ARTERY SOURCE AND START LOOKING AT EACH INDIVIDUAL PROFUSION DOMAIN AND SEE WHAT HAPPENS TO STRUCTURE AND GENOMIC EXPRESSION. NOW, THE OTHER THING THAT THIS ALLOWED US TO DO IS IT PROVIDED SOME SUGGESTION THAT USING THESE TYPES OF PROCESSES COULD ALLOW YOU TO IDENTIFY PLACENTAS THAT ARE INJURED AS SHOWN HERE. THERE IS AN AREA OF NO PERFUSION, WHICH CORRELATED WITH THIS POST DELIVERY. SO IT WAS PRETTY EXCITING AS A PROOF-OF-CONCEPT. WE DEMONSTRATED MINIMAL FETAL EXPOSURE FOLLOWING MATERNAL GAD LIN YUM INFUSION IS SHOWN HERE. THIS IS PERCENT INJECT FRIDAY CLINICAL DOSE IN THE FEELS TISSUES. I DEALY, WE WOULD WANT TO ACQUIRE SIMILAR INFORMATION WITHOUT THE USE OF CONTRAST AGENT. BUT THAT CONTRAST AGENTS ALLOWED US TO MAKE A DISCOVERY. AS SHOWN ON THE RIGHT HERE, THESE ARE THOSE PROFUSION DOMAINS I SHOWN YOU WITH THE CONTRAST. YOU DON'T NEED TO DO ANY REAL ANALYSIS TO LOOK THAT THIS WAS ACQUIRED WITH A T2-BASED CONTRAST AND THIS IS THE RELAXATION TIME OF GRADIENT ECHO TECHNIQUE THAT IS CORRELATED WITH THE OXYPEOPLEO GLOBIN IN THE BLOOD THAT LOOKED VERY SIMILAR. AND THEN WE -- WEEKSY HEMOGLOBIN -- AND WE SPENT SOME TIME FIGURING OUT WHICH ECHO TIMES GAVE US THE BEST SPACIAL HETEROGENEITY THAT CORRELATED WITH OUR PROFUSION DOMAINS IDENTIFIED BY CONTRAST SO THAT OUR MAXIMAL SIGNAL FROM THIS T2 STAR CORRELATED WITH OUR MAXIMAL BLOOD FLOW AND. AND WHEN WE DID OUR THREE-DIMENSIONAL MODELING USING SEGMENTATION OF THE ISOSURFACES TO LOOK AT EACH PROFUSION DOMAIN AND THEN SUPERIMPOSED THE MAXIMAL SIGNAL WITH T2 STAR OVER THE PROFUSION DOMAIN, IT IDENTIFIED THE SPIRAL ARTERIES VERY WELL. WHAT IS NICE ABOUT THIS YOU'LL NOTICE IS SOME MISREGISTRATION THAT IS BECAUSE THE T2 STAR WAS ACQUIRED WITH BREATH HOLD AND THE PROFUSION DATA WAS WITH FREE BREATHING SO THAT IS TO BE EXPECTED. SO, WITH THIS INFORMATION WE HAVE A PARAMETER THAT CONNECTED TO BLOOD FLOW GIVES US INFORMATION ABOUT OXYGEN AT THE POINTED OF ENTRY IN THE INTERVILLA SPACE WHICH WE CAN THEN MODEL AND TEST UNDER DIFFERENT PHYSIOLOGIC CONDITIONS AND THAT IS WHAT WE'LL BE DOING AS PART OF OUR TRANSLATIONAL STUDY. OPTIMIZING ACQUISITION SEQUENCES, OPTIMIZING ANALYSIS TOOLS WHICH WILL FREELY PROVIDE TO OTHERS AND THEN USING THAT TO HOPEFULLY IDENTIFY PATIENTS AT INCREASED RISKS FOR ADVERSE OUTCOME AND USE THAT TO HELP THE OTHER GROUPS THAT YOU'LL -- THAT NOTICE HERE SEARCH FOR BIOMARKERS OF THE DISEASE SO I WANT TO THANK THE TEAM THAT ORIGINALLY WAS VERY IMPORTANT IN THIS WORK, ACKNOWLEDGE CHRIS WHOSE WORK I SHOWED HERE AND OUR GENEROUS FUNDING. [ APPLAUSE ] >> SO WE HAVE TIME FOR A COUPLE OF QUESTIONS. THERE ARE IS MICROPHONES. PLEASE. >> VERY ELEGANT STUDY. HOW DO YOU ANTICIPATE TRANSLATING TO THE GAD LIN YUM TO HUMANS? BECAUSE THE A COG JUST CAME OUT WITH A STATEMENT THAT IT SHOULD NOT BE USED UNLESS IT'S A CLINICAL INDICATION. >> SO I DIDN'T MEAN TO INFER OR IMPLY THAT WE ARE GOING TO USE GAD LIN YUM FOR THIS PROCESS. I MEAN, WHAT WE DID IS WE USED THE GAD LIN YUM TO HELP US MODEL THE KINETICS SO WE COULD THEN USE A METHOD THAT DOES NOT REQUIRE THE CONTRAST THAT GIVES US SIMILAR INFORMATION. ALTHOUGH WE ARE COLLECTING DATA ABOUT THE LIMITED TRANSPORT OF GAD LIN YUM ACROSS THE PLACENTA AND HAVE A PAPER WHICH WILL BE COMING OUT LOOKING AT LONG TERM EXPOSURE RISK IN JUVENILES. >> THANK YOU. >> THANK YOU ANTONIO. THAT WAS GREAT. COULD YOU JUST GIVE US A REAL QUICK OVERVIEW OF WHAT KIND OF DIFFERENCES YOU ANTICIPATE IN THE HUMAN PLACENTA VERSUS THE MACAQUE? I'M NOT TERRIBLY FAMILIAR WITH THE PRIMATE PLACENTAS BUT THAT LOOKED MUCH MORE COD LEANIARY THAN THE HUMAN PLACENTA AND ALSO LOOKED LIKE PERHAPS YOU HAD A SINGLE SPIRAL ARTERY PER FUSING EACH SEPARATE -- WHICH IS NOT THE CASE IN A HUMAN. >> THAT'S ALSO KIND OF NOT THE CASE IN MACAQUES. SO, THERE ARE MULTIPLE SPIRAL ARTERIES TO THE PROFUSION DOMAINS AND WE HAVE DEMONSTRATED THAT AS WELL AS REPORTED IT, THAT WAS AN ARGUMENT THAT OCCURRED 50 YEARS AGO WITH DR. ELIZABETH RAMSEY AND OTHERS. SO IT'S NOT JUST A COD LENIARY STRUCTURE. IT'S SOMETHING THAT WE'LL HAVE TO OPTIMIZE AND LOOK AT THE DATA BUT IT'S AN IMPORTANT QUESTION. LIKE HOW MANY PROFUSION DEMANES ARE THERE? HOW DO THEY GROW DURING PREGNANCY? HOW DOES IT CHANGE IF ONE IS INJURED? DOES ANOTHER GROW? AND THOSE ARE THINGS THAT YOU CAN NOW FOLLOW AND THEN MODEL HOW IT RELATES TO OXYGEN TRANSPORT ACROSS THE FETAL VASCULAR SPACE. >> HI. I'M PAUL THOMPSON FROM USC IN L.A. MY FIELD IS MORE IN NEUROIMAGING AND I ENJOYED THE IMAGES OF AUTOMATIC QUANTIFICATION EVER MRI. MY QUESTION IS, WHAT ARE THE BARRIERS YOU FORESEE TO DOING LARGE-SCALE AUTOMATED QUANTIFICATION OF PLACENTAL IMAGES? OF COURSE THE IMAGING LOOKS TERRIFIC AND YOU SHOWED SOME REALLY GREAT EXAMPLES OF AUTOMATIC FINDING AND QUANTIFICATIONS OF STRUCTURES. COULD THAT BE DONE ON A VERY LARGE-SCALE OR ARE NEW TECHNOLOGIES NEEDED? >> OUTSTANDING QUESTION. ANY TIME YOU BUILD LARGE IMAGING DATASETS, THE PART IS THE PROCESSING AND HOW DO YOU ANALYZE IT? WE CLEARLY HAVE STARTED TO DO THAT BUT I THINK THE NEED IS SIGNIFICANT AND VAST IMPROVEMENTS IN TERMS OF AUTOMATION OF THAT PROCESS. NOT ONLY THE STORAGE OF THE DATA SO THAT IT CAN BE COMPARED, HOW DO WE COMPRESS THE DATA SO IT CAN BE SHARED? AND THEN, HOW DO WE AUTOMATE THE ANALYSIS SO IT IS SIMPLE? I THINK THOSE ARE IMPORTANT LONG TERM GOALS THAT WILL NEED TO BE DONE FROM THE HPP PROJECT GIVEN MULTIPLE IMAGING STUDIES. >> WONDERING IF YOU HAD AN OPPORTUNITY TO LOOK AT THESE PROFUSION STUDIES DURING ANY UTERINE ACTIVITIES SINCE WE KNOW THAT AT REST, THE SUFFICIENCY MAY NOT BE IDENTIFIABLE BUT DYNAMICS OF THE PROFUSION MAY CHANGE WITH CONTRACTIONS. >> GREAT QUESTION. THE ANSWER IS, WE HAVE NOT REPORTED YET BUT WE HAVE MULTIPLE MODELS OFUTE RECALL PLACENTAL SAFES NEOUR MACAQUES WHERE WE ACQUIRED THAT DATA AND ARE IN THE PROCESS OF ANALYSIS TO SEE HOW IT CHANGES. AND NUMBER 2, WE ARE CURRENTLY DOING STUDIES WHERE WE WILL DO PHYSIOLOGIC PERTERBATIONS AND SEE HOW SENSITIVE THESE MEASURES ARE TO BOTH CHANGES IN BLOOD FLOW AND CHANGES IN OXYGENATION. >> I KNOW OBVIOUSLY THAT YOU PLAN AND YOU WILL BE DOING ALL KINDS OF ANALYSIS ON THE BLOOD FLOW ON THE JETS COMING INTO THE PLACENTAL CRYPT. CATHY ALLUDED EARLIER ON TO SOMETHING WHICH IS EXCEPTIONALLY IMPORTANT AS WELL AND THAT IS NORMAL AMOUNT OF INVASION OF TROPHOBLASTS INTO THE VESSEL AND OBVIOUSLY THAT CAN BE IMPAIRED IN CERTAIN CONDITIONS. NOW YOUR IMAGING WILL GIVE YOU THE FLOW, THE JET SPEED AND DIAMETER. ARE YOU GOING TO ALSO LOOK AT IN THOSE MACAQUE PREGNANCY, THE EXTENT OF THE TROPHOBLAST INVASION TO SO YOU CAN SEE GOOD AND BAD PERFORMING JETS AND WHETHER THAT RELATES TO TROPHOBLAST INVASION? >> WE COLLECTED THE DATA IN THAT WAY TO LOOK PESPIRALS. SPECIFICALLY MY HOPE IS THAT SOME POINT WE CAN DO THAT IN REALTIME WHICH I THINK IS AN ABSOLUTELY ATTAINABLE GOAL. [ APPLAUSE ] >> SO THANK YOU ANTONIO AND I WANT TO THANK THE AUDIENCE. THESE ARE SUPER DISCUSSION QUESTIONS AND I LOVE THIS. SO OUR NEXT SPEAKER -- NOW WE HAVE AN INTRO AND NOW WE'RE GOING TO HAVE SOME TALKS THAT LOOK AT TECHNOLOGY AND THE FIRST ONE IS FROM ARJUN YODH OF UNIVERSITY OF PENNSYLVANIA TALKING ABOUT NOVEL TECHNOLOGY FOR STUDYING PLACENTAL OXYGENITION OF PERFUSION-NEAR INFRARED SPECTROSCOPY. >> THANK YOU AND GOOD MORNING, EVERYONE. SO, WHAT I WANT TO DO TODAY IS TO JUST GIVE YOU A FLAVOR OF THE OPTICAL PIECE OF A -- THE PLACENTA EXPLORED ROUTE PROJECT LED BY OTHERS. IT SORT OF, I'M A PHYSICIST SO IT WILL BE A LITTLE BIT PERHAPS MORE MYOPIC THAN WHAT WE HEARD SO FAR. BUT OUR LONG-RANGE GOAL WITH THIS IS ULTIMATELY TO DEVELOP AND DEMONSTRATE THE POTENTIAL OF OPTICAL TECHNIQUES, DIFFUSED OPTICAL TECHNIQUES IN PARTICULAR WITH ULTRASOUND AND PERHAPS WITHOUT ULTRASOUND AT THE BEDSIDE TO NONINVASIVELY PROBE OXYGENATION IN THE PLACENTAL TISSUES. SO, BEFORE I START, I WANTED TO ACKNOWLEDGE, WE MADE A FAIR AMOUNT EVER PROGRESS IN THE LAST SIX MONTHS OR SO AND IT'S BEEN LED BY TIFFANY, A PH.D. STUDENT AND OTHERS WHO ARE POSTDOCS. OKAY. SO MY PLAN THEN IS TO TELL YOU A LITTLE BIT ABOUT A BUNCH OF THINGS. AND SO, I WANT TO GIVE SOME PERSPECTIVE ON DIFFUSE OPTICAL SUSPECT SCOPEY AND THERE HAS BEEN WORK THAT WE FOUND SOME YEARS AGO BUT I WANT TO SHOW YOU WHAT THEY DID AND THEY HAD GOOD VISION. AND THEN I'LL SHOW YOU WHAT WE HAVE DONE AND SOME OF OUR PROGRESS AND THINKING. OKAY, SO, BASICALLY, WHAT WE ARE TRYING TO DO IS TO DO SUSPECT SCOPEY AND THIS IS A VENERABLE TECHNIQUE IN OPTICS. AND IT IS THIN. I CAN MEASURE THE TRANSMISSION THROUGH THE COUP VET AND FROM THE DEPENDENCE WITH THE THICKNESS, YOU CAN DETERMINE THE ABSORPTION COEFFICIENT WHICH DEPENDS ON THE CONCENTRATIONS OF CHROMO4S IN YOUR SAMPLES. AND ON THE EXTINCTION COEFFICIENT, THE SPECTRUM OF THOSE. AND IF YOU MEASURE IT AS A FUNCTION OF WAVELENGTH THEN YOU CAN LEARN ABOUT WHAT COMA FORES ARE THERE AND YOU CAN ALSO LEARN ABOUT WHAT IS THE CONCENTRATION OF THESE THINGS. AND SO, THE TISSUE CHROMOFORES THAT ARE OF INTEREST FOR US ARE PRIMARILY OXYHEMOGLOBE IN AND IN TISSUE YOU HAVE OXYAND DEOXYHEMOGLOBIN. YOU HAVE WATER AND LIPIDS. HERE IS A PLOT PROBABLY MANY OF YOU HAVE SEEN OF THE ABSORBANCE OF THESE CHROMOFORES IN TISSUE AS A FUNCTION OF WAVELENGTH AND THE MAIN THING WE WANT TO TAKE ADVANTAGE OF WITH THESE TECHNIQUES IS THAT THE ABSORPTION IS FAIRLY LOW IN THE NEAR INFRARED. SO IT IS RELATIVELY LOW AND SO WE CAN HAVE OUR LIGHT PENETRATING INTO THE TISSUES. ON THE OTHER HAND, THOUGH, AS ALSO YOU PROBABLY KNOW, THERE IS A LOT OF SCATTERING THAT ACCOMPANIES THAT ABSORPTION IN THE TISSUES SO JUST TO GIVE YOU SOME NUMBERS, YOU MIGHT HAVE A SO-CALLED RANDOM WALK STEP FOR THE PHOTON OF THE ORDER OF A MILLIMETER IN TISSUE AND THE ABSORPTION WOULD BE MUCH LONGER. BUT IN THIS REGIME WHERE THE SCATTERING IS VERY LARGE AND THE ABSORPTION IS RELATIVELY LOW, THE PHOTONS UNDERGO THE TRAJECTORIES OF THE PHOTONS ARE RANDOM WALKS. AND SO, YOU CAN APPLY DIFFUSION THEORY FOR UNDERSTANDING HOW THE LIGHT IS TRANSPORTED THROUGH TISSUE AND SO IF WE SORT OF ABANDON THE TRADITIONAL OPTICS WE USE WITH THE QUEUE VET AND ADOPT THE FUSION MODELS FOR ANALYZING YOUR DATA, THEN YOU CAN ACTUALLY MAKE PROGRESS AND LEARN ABOUT THE CONCENTRATIONS OF STUFF INSIDE SCATTERING MATERIALS. AND SO, THE TECHNIQUES THEN THAT WE USE ARE ALL BASED ON THE LIGHT DIFFUSION EQUATION AND THE TWO KINDS OF GEOMETRIES, THE NATURAL GEOMETRIES FOR THESE EXPERIMENTS IS YOU CAN DO IT IN TRANSMISSION, WHICH YOU MIGHT DO IF YOU'RE DOING BREAST IMAGING, BREAST CANCER IMAGING, OR DO IT IN REMISSION WHICH IS CERTAINLY MORE LIKELY, WHAT WE ARE GOING TO BASICALLY BE THE GEOMETRY OF CHOICE FOR THE PLACENTAL STUDIES OR ALSO GEOMETRY THAT IS TYPICALLY USED AS YOU LOOK AT THE BRAIN WITH LIGHT. AND SO, IN THAT CASE, JUST TO GET YOU ORIENTED, IF I HAVE A DETECTER ON THE SURFACE AND THEY HAVE SOME SEPARATION, TYPICALLY THE PENETRATION MIGHT BE ABOUT HALF OR A THIRD OF THE SEPARATION BETWEEN THE SOURCE AND THE DETECTERS. SO I CAN CHANGE THE PENETRATION BY CHANGING THE SOURCE DETECTOR SEPARATION AND ALSO OF COURSE NOT JUST ONE DISTANCE THAT THE PHOTONS TRAVEL. THEY SORT OF HAVE A SPREAD OUT, DIFFUSE. AND THE WIDTH OF THE DIFFUSION ALSO PATHWAYS IS ALSO OF ORDER 1/3 TO 1 1/2 OR 1/3 OR SO OF THE SOURCE DETECTER SEPARATIONS. SO, GIVEN THIS GEOMETRY, THERE ARE DIFFERENT TECHNOLOGY THESE HAVE BEEN DEVELOPED. ONE OF THE MAIN TECHNIQUES IS TO USE THESE TECHNOLOGIES TO LOOK AT THE BRAIN AND THE MOST SIMPLE ONE USES CONTINUOUS WAVES. SO BASICALLY, THIS IS LIGHT THAT YOU JUST SHINE IN THE SAMPLE. YOU DON'T DO ANYTHING TO THE LIGHT. YOU JUST MEASURE THE TRANSMISSION AND YOU MIGHT MEASURE THAT AS A FUNCTION OF THE SOURCE DETECTOR SEPARATION OR AS A FUNCTION OF WAVELENGTH. AND THIS IS BASICALLY THE BASIS OF MOST COMMERCIAL SO-CALLED MERES DEVICES. NEAR INFRARED SPECTROSCOPY DEVICES AND IT'S USEFUL. IT CAN MEASURE CHANGES REASONABLY WELL, BUT IT DOES HAVE A LOT OF LIMITATIONS. ONE OF THEM IS IT DOESN'T SEPARATE SCATTERING FROM ABSORPTION IN A QUANTITATIVE WAY AND THAT IS A SIGNIFICANT LIMITATION IN MY VIEW. SO, IF YOU USE A LITTLE BIT MORE SOPHISTICATED TRICKS, YOU CAN EITHER AMPLITUDE MODULATE THE LIGHT THAT YOU SEND IN AND SO YOU MAKE A DIFFUSIVE WAVE YOU LAUNCH INTO THE MEDIAN AND THEN YOU WOULD MEASURE THE CHANGE IN THE AMPLITUDE AND THE FACE SHIFT OF THIS WAVE AT DIFFERENT SOURCE DETECTOR SEPARATIONS AND AT DIFFERENT WAVE LENGTH OR PUT IN -- AND THAT'S THE TECHNIQUE WE ARE GOING TO BE USING HERE. THAT IS CALLED A FREQUENCY DOMAIN DIFFUSE OPTICAL SPECTROSCOPY. THE OTHER LIMIT OF THAT IS TO PUT IN THE SHORT POLES AND MEASURE THE BROADENING OF THAT PULSE. AND THEREFORE YOUR TRANSFORMS OF EACH OTHER. SO, THIS WORKS PRETTY WELL. IF YOU DID THIS PREAK SEE DOMAIN OPTICAL TOMOGRAPHY IT WORKS PRETTY WELL. A WORKHORSE MEASUREMENT IS TAKE A PAD AND PUT IT ON THE HEAD OF A SUBJECT AND YOU HAVE A BUNCH OF DIFFERENT SOURCE DETECTOR SEPARATIONS AND YOU USE A BUNCH OF DIFFERENT OPTICAL WAVE LENGTH. IN THIS CASE, WE ARE JUST USING ONE WAVELENGTH BUT USE DIFFERENT SOURCE DETECTOR SEPARATIONS AND SAY THE AMPLITUDE OF THAT WAVE VERSUS SOURCE DETECTOR DISTANCE AND THE PHASE OF IT, I GET TWO LINES AND IF I GOET THE SLOPES OF THOSE LINES, I CAN FIGURE OUT WHAT IS THE AVERAGE ABSORPTION OF THE MEDIAN AND WHAT IS THE AVERAGE SCATTERING? THAT IS A GAIN BECAUSE WE HAVE BEEN ABLING TO DO THAT IN A MEDIUM. BUT THE REAL POWER COMES WHEN WE DO THIS VERSUS WAVELENGTH AT MULTIPLE WAVE LENGTH. AND THEN WE CAN GENERATE ESSENTIALLY A STET OF EQUATIONS WHICH LETS US FIGURE OUT THE CONCENTRATIONS OF STUFF. AND SO, IN PARTICULAR, YOU CAN FIGURE OUT FOR EXAMPLE, THE OXYAND DEOXYHEMOGLOBIN CONCENTRATIONS FROM WHICH YOU CAN GET THE TOTAL HEMOGLOBIN CONCENTRATION AND THE OXYGEN SATURATION AND THAT IS WHERE WE ARE OR WHAT WE WILL BE DOING TODAY. AND SO, THIS IS -- THESE ARE WELL-KNOWN TECHNIQUES. I'M NOT -- HOPEFULLY SOME PEOPLE KNOW THIS AND SOME PEOPLE DON'T. I WANT TO EMPHASIZE THAT THESE ARE IDEAS THAT ARE USED IN THIS COMMUNITY. THESE ARE MEASUREMENTS FROM OUR LAB BUT THERE ARE LABS ALL OVER THE WORLD THAT USE THIS TO LOOK FOR IMAGING AND CANCERS, TOMOGRAPHY, TO LOOK AT THE BRAIN WITH MORE MONITORING. WE ARE HERE TRYING TO THINK OF IT MORE AS A MONITORING APPLICATION RATHER THAN IMAGING APPLICATION. THESE ARE RELATIVELY LOW RESOLUTION TECHNIQUES. BUT YOU CAN PENETRATE CENTIMETERS INTO TISSUE AND YOU CAN PROBE SAY REGIONS OF ORDER HALF CENTER METER AND SO ON AND THE CHANGES IN THE OXY AND DEOXYHEMOGLOBIN. ALSO MEASURE FLOW WHICH I WON'T TALK ABOUT AND THEN YOU CAN RELATE THOSE TO METABOLISM. SO THOSE ARE -- THIS IS THE TECHNOLOGY. AND THEN, LET ME JUST GIVE YOU A IDEA OF WHAT HAS BEEN DONE BECAUSE THERE HAS BEEN, TO OUR KNOWLEDGE AT LEAST, A FEW STUDIES THAT COME OUT QUITE A WHILE AGO NOW OUT OF JAPAN, ACTUALLY. WHERE THEY HAD THE VISION TO TRY TO LOOK FOR THE TISSUE OXYGENATION AND PLACENTAL TISSUES AND THEY BASICALLY DID IT USING NEARS DEVICES. THESE ARE CW COMMERCIAL INSTRUMENTS. AND THEY MADE A PROBE AND THEY SET THEIR SOURCE DETECTOR SEPARATION AT 4 1/2 CENTIMETERS WHICH IS A LITTLE BIT TO MY MIND, AND I'LL TELL YOU ABOUT THE CHALLENGES, A LITTLE BIT ON THE SHORT SIDE BECAUSE IT DOESN'T -- THAT LIMITS YOUR PENETRATION AND OFTEN THE PLACENTAL TISSUE MIGHT BE QUITE A BIT DEEPER. BUT THEN THEY BASICALLY MADE MEASUREMENTS, WHY. W MEASUREMENTS, AS A FUNCTION OF WAVELENGTH IN THIS NEAR INFRARED REGION AND EXTRACTED IN MAIN KEYSES, A KIND OF INDEX OF OXYGENATION NOT EXACTLY -- THEY DIDN'T SEPARATE THE SCATTERING FROM THE ABSORPTION BUZZ IT'S A CW MEASUREMENT BUT GOT SOMETHING THAT CERTAINLY, IS RELATED TO OXYGEN SATURATION. THE TOTAL OPTICAL OXYGENATION INDEX WHAT THEY CALLED IT. AND, THEY WERE ABLE TO IN SOME CASES SHOW THAT THERE WAS SOME SENSITIVITY TO DIFFERENT PHYSIOLOGICAL STATES. SO HERE IS A MEASUREMENT WHICH IS AGAIN I DON'T WANT TO GO INTO THE DETAILS OF THIS, BUT BASICALLY, THEY LOOKED AT THIS TISSUE OBSTACLE INDEX AND COMPARED NORMAL PATIENTS TO PATIENTS WITH GRANDOSEIS AND THEY CAN SEE CHANGES IN THE OXYGENATION OF THE PLACENTAL TISSUES. I WANT TO WARN YOU THOUGH, THAT THEY MADE APPROXIMATIONS WHERE THEY CONSIDER THE MEDIUM SEMI-INFANT. SO INTEGRATING OVER THE WHOLE VOLUME FOR THAT. HERE IS ANOTHER MEASUREMENT THAT WAS DONE WHERE THEY SAW SOME SENSITIVITY TO IUGR AND COMPARED TO NORMAL WOMEN. USING THIS TISSUE OXYGENATION INDEX. OKAY. SO, LET ME NOW -- SO THAT WAS QUITE A NUMBER OF YEARS AGO AND THE TECHNOLOGY HAS IMPROVED AND OUR UNDERSTANDING OF THE PROBLEM IS IMPROVED AS WELL. THE PHYSICS PROBLEM AT LEAST. SO, RIGHT NOW OUR GOAL IS ESSENTIALLY SIMILAR TO THOSE ORIGINAL GOALS. WE WANT TO FIGURE OUT WHAT ARE THE CONCENTRATIONS OF OXYGENATED AND DEOXYGENATED HEMOGLOBIN IN THE INTERIOR PLACENTA. ONE OF THE BIG CHALLENGES IS THE PENETRATION DEPTH IS LIMITED. YOU CAN ONLY PENETRATE DISTANCE OF ORDER 1/3 TO ONE-HALF OF THE SOURCE DETECTOR SEPARATION AND SO FOR A TYPICAL GEOMETRY, YOU'RE GOING TO BE REALLY JUST LOOKING AT THE EDGE OF THE BLAH SENTAL TISSUE. EVEN IN SORT OF THE OPTIMAL CASES WITH THE 4 1/2 SEPARATION DEVICE. AND SO, ONE OF THE THINGS THAT WE WANT TO DO IS TO FIGURE OUT WAYS TO INCREASE THAT DISTANCE. AND I'LL SHOW YOU WHAT WE ARE DOING. THEN THE OTHER THING, ANOTHER THING THAT SORT OF WAS GLOSSED OVER IS THAT OF COURSE YOU HAVE EXTRA PLACENTAL TISSUES BUT YOU HAVE THIS HUGE OVERLAYER OF OTHER TISSUES, WHICH ARE ESSENTIALLY CONTAMINATION OF THE SIGNAL THAT YOU WANT. AND ONE NEEDS TO SORT OF DERIVE WAYS TO SORT OF COPE WITH THAT PROBLEM AND PERHAPS EXTRACT THE PLACENTAL TISSUES BETTER. THIS IS A PROBLEM ACTUALLY THAT OCCURS WHEN YOU'RE LOOKING AT THE BRAIN. YOU WANT TO GET THE SIGNAL FROM THE CEREBRAL TISSUES NOT FROM THE SKULL AND THE SCALP SO WE HAVE TO ALSO HAVE A SIMILAR PROBLEM THERE AND TAKE ADVANCE THAT IS HAVE BEEN MADE IN THAT AREA AND APPLY THEM HERE. AS I SAID, THE CW NEARS DID NOT SEPARATE SCATTERING FROM ABSORPTION AND SO, WE WOULD, BY DOING THIS FREQUENCY DOMAIN MEASUREMENTS WE ARE ABLE TO DO THAT AND ESSENTIAL WHAT HE IS MISSING ALSO IS THAT WE NEED TO REALLY DO QUANTITATIVE BASELINE MEASUREMENTS IN MANY SUBJECTS TO UNDERSTAND WHAT IS THE VARIATIONS OF THESE SIGNALS, WHAT ARE THE SIGNALS YOU MIGHT EXPECT IN HEALTHY PATIENTS AND SO ON? OKAY. SO, THEN JUST AS ONE POINT OF REFERENCE, YOU CAN ASK, HOW DEEP CAN PEOPLE -- HAVE PEOPLE PENETRATED IN THIS REFLECTION GEOMETRY IN THE BODY? AND I THINK IF I LOOKED AT THE FREQUENCY DOMAIN MEASUREMENTS THAT HAVE BEEN DONE, I THINK THE BIGGEST OR LARGEST REMISSION SEPARATION THAT HAS BEEN USED FOR BRAIN IS THE BRAIN STUDY WHICH IS ABOUT 7 CENTER METERS AND AT 7 CENTIMETERS THE SIGNAL TO NOISE IS GETTING PRETTY LOW. THIS IS WHERE WE WANT TO BE. 7 CENTIMETERS WE CAN PENETRATE AND GET A GOOD FRACTION OF THE PHOTONS TRAVELING THROUGH THE PLACENTA. SO, LET ME NOW THEN JUST FINISH UP WITH SOME PROGRESS. AND SORT OF WE HAVE TAKEN, TRYING TO DO TWO THINGS IN PARALLEL. ONE IS JUST TO TRY TO MAKE BETTER INSTRUMENTATION SO WE CAN MAKE THIS MEASUREMENT AT LARGER SEPARATIONS WITH BETTER SIGNAL TO NOISE AND PENETRATE FURTHER AND ALSO TO DO A LITTLE BIT OF WORK WITH THE ALGORITHMS RELATED TO THAT. AND THEN THE OTHER ASPECT OF THE WORK IS TO START TO MAKE MEASUREMENTS. BECAUSE WHEN WE START TO DO THAT, TO -- AND I'LL SHOW YOU SOME FIRST EXAMPLES OF THAT. THEN WE CAN ALSO FIND OUT WHAT THE PROBLEMS ARE AND WHAT THINGS WE HAVE TO IMPROVE IN THE CLINICS. AND SO, BUT UNFORTUNATELY FOR THAT CASE, WE ARE NOT USING THE OPTIMIZED INSTRUMENT BECAUSE WE ARE WORKING ON THAT IN PARALLEL. HOPEFULLY IN A YEAR I WOULD HAVE SOME NEW THINGS TO TELL YOU ON THAT LINE. LET ME JUST TELL YOU ABOUT INSTRUMENT DEVELOPMENT FIRST. SO, BASICALLY WHAT WE WANT TO DO IS TO MEASURE DEEPER. THAT IS THE BIGGEST CHALLENGE. AND WE CAN DO A LOT BETTER THAN HAS BEEN DONE IN THE PAST FOR A NUMBER OF REASONS AND SO THAT -- AND SO ONE IS THAT WE HAVE BETTER DETECTORS NOW AND MORE SENSITIVE DETECTORS WITH LOWER NOISE. ANOTHER ONE IS THAT WE CAN WORK HARDER THAN HAS BEEN DONE CERTAINLY NECOMMERCIAL INSTRUMENTS TO STABILIZE THE SOURCES AND TO MAKE THE DETECTION HAVE LOWER NOISE. SO THIS IS WHAT WE ARE DOING AND THESE FIRST SETS OF MEASUREMENTS WITH THESE INSTRUMENTS ARE REALLY JUST AT THE BENCH IN THE LAB WITH TISSUE PHANTOMS. SO THESE INSTRUMENTS DON'T WORRY TOO MUCH ABOUT THE DETAIL BUT BASICALLY, HAS TWO SIDES OF IT, ONE IS THE SIGNAL GENERATION, SOURCE LIGHT GENERATION AND THE OTHER IS THE DETECTION. AND SO, ON THE SIGNAL GENERATION SIDE, WE HAVE MUCH MORE -- WE WORKED PRETTY HARD TO HAVE STABLE OR LASER SOURCES STABLER OSCILLATORS AND PHASE LOCKED OSCILLATORS, WHICH REALLY REMOVE A LOT OF PHASE NOISE. THE KEY IS WE CAN MEASURE THE PHASE OF THESE HIGH DISTANCES AND THAT IS THE HARDEST THING TO MEASURE. AND SO, WE THINK THAT AT THE FRONT END OF THIS, WE IMPROVE IT AND THEN AS I SAID, THE LIGHT WILL GO INTO THE TISSUE AND THEN WE'LL HAVE TO DETECT IT AND WE CAN DETECT IT BETTER NOW WITH SOME MORE RECENTLY DEVELOPED PHOTO MULTIPLIER TUBES WHICH ARE, WE BELIEVE WILL GAIN ABOUT A FACTOR OF 10 IN SIGNAL TO NOISE. AND, THEN THE LAST PART EVER THAT IS TO TAKE THESE SIGNALS FROM OUR PHOTO MULTIPLIER TUBES AND FIND -- DO DETECTION AND FIND THE ACTUAL -- EXTRACT THE INFORMATION AND THERE HAS BEEN ADVANCES AND WE WORKED A LOT HARDER IN THIS CASE TO TRY TO REDUCE THE NOISE ON THIS END OF IT AS WELL. SO, THERE IS VERY DEFINITE HARDWARE IMPROVEMENTS THAT WE ARE TESTING NOW AND WE HAVE MADE -- WE THI NK WE WILL BE ABLE TO HAVE A LOT LARGER SOURCE OF DETECTOR SEPARATION. THEN, ANOTHER THING AS I SAID, EARLIER, ALL OF THESE MEASUREMENTS IN THE PAST GENERALLY THE FIELD USES JUST A SEMI-INFINITE APPROXIMATION. AND SO, THAT HAS OR DOESN'T DISTINGUISH BETWEEN THE OVERLAYERS AND THE REGION THAT YOU CARE ABOUT. SO, ESPECIALLY DUE TO THE FACT THAT WE HAVE ALL THESE OTHER MEASURE INDEPENDENTS THIS EXPLORE GROUP BEING DONE, ESPECIALLY ULTRASOUND, WE HAVE SORT OF INFORMATION ABOUT THESE LAYERS. WE HAVE INFORMATION ABOUT THE DEPTH, SIZE, THE THICKNESSES AND SO ON. AND SO WE CAN USE THAT. SO PART OF WHAT WE ARE ALSO DOING IS TO SORT OF TEST OUT DIFFERENT KINDS OF SEGMENTATION ALGORITHMS. SO WE'LL MAKE MANY MEASUREMENTS AT MANY DIFFERENT SEPARATIONS AND MULTIPLE WAVE LENGTH AND ALSO IF WE KNOW THAT THE REGION WE CARE ABOUT IS THE COUPLE OF CENTIMETERS DOWN AND THEN THIS IS THE NATURE OF THE REGION ABOVE, WE CAN START TO FORMULATE A BETTER PROBLEM -- BETTER AND HAVE BETTER INVERSE PROBLEM SOLUTION. AGAIN, THIS IS SOMETHING THAT IS NOT -- IT'S A PROBLEM THAT IS VERY IMPORTANT WHEN YOU'RE LOOKING AT THE TISSUES IN THE BRAIN AND SO, THIS IS SOMETHING THAT WE AND OTHERS WORKED ON IN THIS AREA. SO THE BASIC IDEAS, THE SHORT MEASURE INDEPENDENTS SHORT SEPARATIONS AND LONG SEPARATIONS. YOU CAN USE THAT MORE INTELLIGENTLY IF YOU HAVE SEGMENTED MODELS. AND THEN THE OTHER THING THAT MIGHT BE INTERESTING THAT WE ARE GOING TO EXPLORE IS IF YOU DO A TINY PRESSURE MODULATION, IT IS VERY WELL IN THE BRAIN BUT IT MIGHT WORK ALSO IN THE CASE OF THE PLACENTA PROBLEM. BASICALLY, WE CAN HAVE IT IMPROVE SIGNAL TO NOISE AS WELL. THESE ARE THINGS THAT WE ARE GOING TO TAKE FROM WHAT PEOPLE ARE DOING WITH THE BRAIN AND DIFFUSE OPT KEL SPECTROSCOPY AND ADAPPED THEM HERE. SO, THAT IS VERY QUICKLY WHAT SOME OF THE THINGS WE ARE DOING WITH INSTRUMENTS AND ALGORITHMS. THEN WE JUST STARTED VERY RECENTLY TO MAKE SOME MEASUREMENTS USING IN THIS CASE, WE ARE USING COMMERCIAL INSTRUMENT BUT IT'S A FREQUENCY INSTRUMENT. SO IT IS SOMETHING THAT WE USE IN PEDIATRIC CONTEXT ALREADY. BUT IT IS NOT AS SENSITIVE REALLY AS THE ONE THAT WE ARE BUILDING IN THE LAB. BUT WE JUST THOUGHT LET'S JUST COMBINE IT WITH AN ULTRASOUND AND SO HERE IS ONE VERSION OF THIS. SO WE HAVE THE ULTRASOUND AND THEN ON THE OUTSIDE OF THE ULTRASOUND, WE HAVE A BUNCH OF YOU CAN SEE HOLES HERE CORRESPONDING TO REGIONS WHERE YOU COULD HAVE YOUR LIGHT SOURCES FIBERS COME IN OR LIGHT DETECTION FIBERS COME OUT. THERE IS A RANGE OF SEPARATIONS THAT WE HAVE AND THE RANGE OF REGIONS THAT WE CAN MONITOR WITH THIS. AND IN THIS WAY, WE CAN AGAIN JUST VERY CRUDELY SPEAKING, SHORT SEPARATIONS WILL PROBE THE SUPERFICIAL LAYERS AND THE LARGE SEPARATIONS WILL PROBE THE DEEPER LAYERS. RIGHT NOW, WE HAVEN'T PUT IN THE SEGMENTATIONAL GO RHYTHMS YET BUT WE WERE ABLE TO VERY RECENTLY GET THIS TO WORK. SO, WHAT WE DID FIRST IS WE JUST TOOK THIS THING AND PUT IT ON THE MOTHER AND TRIED TWO DIFFERENT POSITIONS AND THEN YOU CAN ALSO ROTATE IT AND HAVE DIFFERENT ANGLES. AND YOU KNOW, SO, I'M NOT GOING TO -- THIS IS JUST WHERE WE ARE. THIS IS A PROGRESS REPORT. BUT BASICALLY, HERE IS TWO DIFFERENT POSITIONS AT THE THREE DIFFERENT ANGLES AND AGAIN, YOU GET THE ULTRASOUND IMAGE WHICH IS GREAT BECAUSE NOW WE CAN KNOW HOW FAR BELOW THE TISSUE, THE PLACENTAL BED IS, WHERE IS THE MIDDLE OF THE PLACENTA THAT HELPS US IN OUR ANALYSIS T ALSO GIVES YOU AN IDEA OF THE NUMBERS. IN ONE CASE, THE PLACENTAL BED STARTED LESS THAN TWO CENTIMETERS AND ANOTHER CASE IT WAS MORE. BUT THIS IS A GOOD NUMBER TO BE NOT HAVING TO ASSUME WHEN YOU DO THESE KINDS OF MEASUREMENTS AND SO WE ARE GLAD ABOUT THAT. AND THEN WE OTHER STAKED TO EXTRACT INFORMATION NOW ABOUT TOTAL HEMOGLOBIN CONCENTRATION AND TISSUE OXYGEN SATURATION. I DON'T THINK THAT THERE IS ANY BIG CONCLUSION THAT I WANT TO MAKE HERE. WE ARE GETTING NUMBERS THAT ARE REASONABLE BUT AGAIN, REMEMBER, THAT WE ARE USING A SEMI-INFINITE MODEL RATHER THAN A SEGMENTED MODEL AND SO THIS IS ONE PROBE THAT WE HAVE. IT'S A 2HD.D PROBE -- A 2D PROBE. WE TRIED TO COMBINE THE SAME KIND OF IDEA WITH THE OPTICAL AND ULTRASOUND FOR 3D ULTRASOUND PROBE. WE THINK THIS MAY BE BETTER, YOU CAN GET MORE INFORMATION WITH ONE SITTING BUT IT REMAINS TO BE SEEN WHICH IS GOING TO WORK THE BEST. AND SO, HERE IS SORT OF A SCHEMATIC OF THAT. SO LET ME THEN JUST STOP THERE AND SORT OF REMIND YOU BASICALLY WHAT WE ARE AIMING TO DO IN THE NEAR FUTURE IS TO COMBINE THIS OPTIMIZED INSTRUMENT THAT WE HAD AT THE BED OR AT THE BENCH INTO THE CLINICAL ULTRASOUND PROBE AND START TO DERIVE SOME BASELINE DATA IN PATIENTS. WE ARE FOCUSING ON ANTERIOR PLACENTAS ONLY. WE ARE STILL REALLY IN A VERY EARLY LEARNING PART OF THE CURVE FOR THIS. BUT WE ARE GOING TO START GETTING NUMBERS AND WE'LL START TO SEE, ARE THERE CHANGES EVEN IN THIS LIMITED SUBSET OF CASESES? AS FAR AS SAFETY, I'LL MENTION THAT THE POWERS THAT WE ARE USING ARE LESS THAN OR EQUAL TO THE POWERS THAT PEOPLE ARE TYPICALLY USING ALREADY IN NEARS FOR NEONATAL STUDY OF BRAIN. I DON'T THINK THAT WILL BE AN ISSUE. SO FINALLY HERE ARE THE PEOPLE THAT ARE DOING THE WORK. THANK YOU. [ APPLAUSE ] >> SO THANK YOU VERY MUCH. THAT WAS A REALLY INTERESTING TALK ABOUT TECHNOLOGY. I KNEW NOTHING ABOUT THAT. OF COURSE YOU STOLE MY QUESTION, WHICH WAS ABOUT SAFETY. BECAUSE I THINK A LOT OF US ARE FAMILIAR WITH SAFETY ISSUES WITH ULTRASOUND AND MRI AND SO, I DON'T KNOW IF HEAT DEPOSITION FOR INSTANCE IS AN ISSUE. IS THERE ANY SPECIAL CONSIDERATIONS WITH NEARS OR IF YOU WANT TO -- LIKE IF THERE WAS A TECHNOLOGY DEVELOPED SO YOU COMBINE NEARS WITH ULTRASOUNDS OR USE THEM SIMULTANEOUSLY WHETHER THAT WOULD BE A PROBLEM? COULD YOU COMMENT BRIEFLY? >> I MEAN, I THINK IT IS SOMETHING YOU ALWAYS WANT TO WOR AREY ABOUT. BUT I THINK WE ARE CERTAINLY AT THIS POINT -- WE HAVE TO BE VERY CAREFUL ABOUT WHAT WE CALCULATE AND SO ON BUT BASICALLY WE CAN PIGGYBACK ON A LOT OF WORK THAT HAS BEEN DONE USING OPTICS TO LOOK AT BRAIN AND WE CAN EASILY STAY BELOW THE NUMBERS, ESPECIALLY WITH THESE VERY HIGH SENSITIVITY INSTRUMENTS AND SO WE ARE. >> YES, OBVIOUSLY IN TERMS OF THE SIZE AND THE DEPTH OF PENETRATION YOU CAN WORK WITH. OBVIOUSLY THIS MIGHT BE VERY APPLICABLE TO MALL ANIMAL MODELS? VERY SIMPLE GEOMETRY. BUT THE SECOND THING THAT OCCURS IT ME COMES FROM THE FIELD OF GEOLOGY WHEN GEOLOGISTS MAP OUT UNDERGROUND STRATA OF ROCKS THEY RELY ON THE FACT THAT THE SAND WHICH COMES FROM AN EXPLOSIVE THUMPER ON THE GROUND CAN PROPAGATE AT DIFFERENT SPEEDS AND THEY MEASURE THE DIFFERENT DETECTION TIMES AND MAP OUT WHAT IS LIKELY UNDER THE GROUND. NOW OBVIOUSLY, ALL HUMAN TISSUES ARE WATER BASED BUT THE WAY YOU DESCRIBED SCATTERING AND THE PROPERTIES OF THE DIFFERENT THINGS THAT WILL SCATTER WHETHER IT IS ARITHROW SITE IN A BLOOD VESSEL BUT PRIMARILY THOSE MOLECULES IN MONPRO FUSED CELLS, WOULD YOU EXPECT THERE TO BE TIME DIFFERENCES AND PROPAGATION DISTANCE DIFFERENCES THROUGH DIFFERENT LAYERS OF TISSUE? WHETHER THEY ARE HEAVILY VASCULARIZED OR NOT? AND IF YOU WERE TO DIGITIZE THE INPUT LIGHT, SO YOU KNOW THE DELAY BETWEEN WHEN THE LIGHT ENTERED AND WHEN IT IS DETECTED, COULD YOU WORK THAT OUT? COULD YOU CREATE IMAGE LAYERS BASED ON TIME OF SCATTER? >> RIGHT. SO THIS IS A GREAT QUESTION AND I TALKED TO PEOPLE WHO DO THAT PROBLEM. BASICALLY THAT IS THE -- YOU'RE BASICALLY DESCRIBING A PROBLEM IN THE TIME DOMAIN. IF YOU USE THESE WAVES, BASICALLY THEY ARE LOOKING AT PHASE SHIFTS AND THAT IS THE ANALOGOUS THING. SO BASICALLY THIS COMMUNITY HAS EMBRACED THAT. THOSE IDEAS. AND THE SCATTERING BY THE WAY IS FROM ORGANELLES LIKE MITOCHONDRIA AND CELLS AND INTERFACES BUT BASICALLY, AND IT CAN BE DIFFERENT IN THE DIFFERENT LAYERS AND SO YOU CAN INCORPORATE ALL OF THAT INTO THESE DIFFUSION MODELS AND EVEN MORE SOPHISTICATED TRANSPORT MODELS. SO THE EARTH PROBLEM IS ACTUALLY A LITTLE BIT HARDER IN A WAY BECAUSE DIFFUSION IS GOOD. IT'S A KIND OF SIMPLE MODEL. BUT BASICALLY, THOSE GUYS ARE IN BETWEEN SOMETIMES DIFFUSION AND SOMETIMES TRANSPORT. THERE IS CERTAINLY EXPERTS HERE WORKING ON TRANSPORT. BUT BASICALLY, THAT IS EXACTLY WHAT WE ARE DOING. I SORT OF HID THAT, MAYBE. >> I WAS CURES IF IT IS IMPORTANT FOR THIS -- CURES -- TO KNOW WHETHER THE SIGNAL IS FROM FETAL OR MATERNAL BLOOD, WHETHER A SIGNATURE BETWEEN THE TWO? AND IDENTIFY WHAT YOU'RE SEEING? >> YES. SO, AGAIN, THAT IS PART OF THE FIRST, LOWEST ORDER OF THING TO DO IS TO GO FROM BEING A SEMI-INFINITE MEDIUM TO BEING A SEGMENTED MEDIUM BASED ON WHAT WE KNOW FROM THE ULTRASOUND. BUT THEN, THERE MIGHT BE OTHER TRICKS THAT ONE COULD USE, FOR EXAMPLE YOU COULD LOOK AT THE FREQUENCY MODULATION, THE HEARTBEAT DIFFERENCE. BUT IN THE END, AT THE FIRST LEVEL, WE ARE INTEGRATING OVER ALL OF THAT. SO IN THESE MONITORS WE HAVE TO FIGURE OUT HOW TO SEPARATE THEM BETTER AND PART OF IT WILL BE DOING THESE MULTIDISTANCE MEASUREMENTS. IT'S GETTING CLOSER TOWARDS OPTICAL IMAGING. >> GOING TO USING THE TRICKS, I HAVE A QUESTION ABOUT WHETHER YOU CAN SPECIFICALLY FOCUS ON A PARTICULAR ZONE FOR SAMPLING AND THEN I CAN TELL YOU A TRICK. >> WELL, I GUESS LIKE I SAID, SO JUST SUPERFICIALLY, RIGHT. IF YOU HAVE A SHORT SEPARATION AND A LONG SEPARATION, IF IT'S TWO LAYERS, THEN YOU CAN -- VERY, VERY CRUDELY, YOU CAN THINK OF SEPARATING THE LONG FROM THE SHORT SEPARATION. THAT'S A TRICK TO LOOK DEEPER TO SEPARATE THE DEEPER SIGNAL FROM THE SHORTER SIGNAL. IF YOU WANT TO LOCALLY LOOK AT THINGS, THEN THERE ARE -- YOU COULD SAID UP YOUR SOURCES AND DETECTERS IN A WAY AGAIN, PEOPLE HAD IDEAS ABOUT PHASE TO RAYS, WHICH MIGHT BE ABLE TO DO STUFF LIKE THAT. >> SO ONE OF THE TRICKS WOULD BE THAT ULTRASOUND ACTUALLY WHEN YOU TURN ON THE MONOCHROMATIC FLOW PROBE. SO EVERY PROBE IN MODERN ULTRASOUND ALLOWS YOU TO DO FLOW. WHEN YOU DO THAT, YOU CAN ACTUALLY MEASURE THE THICKNESS OF THE DECIDED YUM IN THE VESSELS AND SEPARATE IT FROM THE WHEN IT ACTUALLY ENTERED THE FEELS ZONE. SO YOU KNOW MORE PRECISELY WHERE YOU ARE IN MATERNAL ZONE AND WHEN YOU ARE IN FETAL ZONE. >> THAT'S INTERESTING. SO THERE IS PHOTO ACOUSTIC AND THE OTHER INVERSE OF THAT WHICH IS WHAT YOU'RE SAYING. SO, I HAVE NOT REALLY WORKED ON THAT. I THINK THAT THAT IS A GOOD IDEA. WE ARE BASICALLY AT THIS POINT, TRYING TO TAKE WHAT IS THE LOWEST HANGING TECHNOLOGIES AND SEE HOW WELL WE CAN MAKE THEM WORK. BUT THAT IS A GOOD R01 PROJECT. >> OKAY. >> THIS WILL BE MORE OF A BIOLOGY QUESTION I GUESS. IN ONE OF YOUR SLIDES YOU SHOWED TISSUE OXYGENATION INDEX WAS HIGHEST FOR THE WOMAN WITH [ INDISCERNIBLE ] SO I WAS WONDERING THAT WHEN IT IS SETTING IN, WILL YOU SEE A DIFFERENCE IN TISSUE OXYGENATION INDEX AT THAT POINT OF TIME VERSUS WHEN IT IS ALREADY ESTABLISHED? >> SO HERE I REALLY ACTUALLY DON'T KNOW THE ANSWER TO THAT QUESTION. I DON'T KNOW IF -- DO YOU KNOW? [ OFF MIC ] >> THANK YOU. [ APPLAUSE ] >> DAVID WEINBERG: THANK YOU VERY MUCH. THAT WAS INTERESTING. WE ARE GOING TO MOVE ON. ONE MORE TALK BEFORE THE BREAK. YET ANOTHER TALK THAT I THINK SORT OF TOUCHES ON NOVEL TECHNOLOGY. THAT IS ANANTH ANNAPRAGADA TALKING ABOUT NOVEL PARTICLE CONTRAST AGENTS. -- NANOPARTICLE CONTRAST AGENTS. >> ANANTH ANNAPRAGADA: >> THANK YOU FOR THE OPPORTUNITY TO BE HERE, DAVID. AYE LIKE TO TALK TAU TODAY ABOUT SOME OF THE WORK WE HAVE BEEN DOING IN THE LAST COUPLE OF YEARS OR SO GETTING INTO LEARNING HOW TO IMAGE THE PLACENTA. AM I NOT AUDIBLE? I TEND TO BE RATHER SOFT SPOKEN SO PLEASE, HOLLER IF THAT HAPPENS. SO THIS IS A JOINTED PROJECT A NUMBER OF PEOPLE IN MY GROUP AS WELL AS COLLABORATORS. WESLEY IS THE CHIEF OF MATERNAL FETAL IMAGING. CHANDRA IS A LONG TERM PLACENTAL RESEARCHER. I KNOW SHE IS A PHYSICIST. I'M REQUIRED TO DECLARE MY CONFLICTS. A COUPLE OF COMPANIES I STARTED THAT HAVE AN INTEREST IN THIS TECHNOLOGY. AND COMPANIES THAT I WISH I HAD STARTED BUT -- [ LAUGHS ] SO THE CORE TECHNOLOGY THAT WE WORK WITH IN THE NANOPARTICLE DOMAIN IN MY LAB AND WE HAVE BEEN HAVING THIS FOR A LONG TIME IS CALLED A LIPOSOME. WE WERE WORKING ON THIS BEFORE THE TERM, NANOTECHNOLOGY, HAD BEEN INVENTED. SO THE LIPOSOME ITSELF IS A LIPID BILAYER. AND YOU CAN PUT ALL KINDS OF DIFFERENT COMPENSATIONS OF LIPIDS IN HERE TO DO DIFFERENT THINGS. YOU CAN LOAD STUFF IN THE CORE OF THE PARTICLE AND USUALLY PEOPLE LOAD DRUGS OF SOME KIND IN THERE. THERE HAS BEEN A LOT OF WORK DONE ON CANCER DRUGS. AND SO THE CORE CARRIES THOSE MATERIALS. YOU CAN LOAD STUFF INTO THE BILAYER SO IF YOU HAVE A LIPOPHILIC MOLECULE OR HYDROPHOBIC MOLECULE, YOU CAN LOAD IT INTO THE BILAYER. THE CAPACITY IS LOWER THAN THAT OF THE LUMEN. WHEN YOU INJECT THESE PARTICLES INTO THE BLOODSTREAM THEY ARE USUALLY OPTIMIZE QUICKLY AND CLEARED AND SO IT WAS FIGURED OUT IN THE 90s OR SO YOU COULD PUT A HYDROPHILIC COATING ON THE SURFACE OF THESE PARTICLES AND THAT EXTENDS THEIR CIRCULATION HELPFUL LIFE TRAUMICALLY AND CHANGES ORGAN DISTRIBUTION AND CONTROLS THE PHARMACOKINETICS. THE OTHER THING YOU CAN DO WITH THESE PARTICLES IS YOU CAN ADD ANOTHER LAYER OF TARGETING LIGANDS SO THESE PARTICLES IN CIRCULATION WILL THEN HAVE THE OPPORTUNITY TO BIND TO SPECIFIC MONONUCLEAR RECEPTORS. AND IF YOU WAIT LONG ENOUGH FOR WHATEVER IS IN THE BLOOD POOL TO HAVE CLEARED OUT, THEN YOU CAN HIGHLIGHT WHERE THESE PARTICLES HAVE ADHERED AND SPECIFICALLY IMAGE THOSE SITES. AND THIS IS ALL BEEN DONE IN DIFFERENT CONTEXT FOR DIFFERENT PURPOSES. AND WHAT I'M GOING TO TALK ABOUT FOR THE MOST PART TODAY IS VERY BRIEF BACKGROUND ON THAT AS WELL AS SOME MORE WORK SPECIFIC TO PLACENTAL IMAGING. SO LET'S TALK ABOUT THE SAFETY OF THESE PARTICLES. ANY TIME YOU'RE INTRODUCING A FOREIGN BODY INTO THE BLOODSTREAM YOU HAVE TO WORRY ABOUT THIS. SO THE CIRCULATION HALF-LIFE IS RELATIVELY LONG. WE DID THIS WITH A GAD LIN YUM LOADED PARTICLE THAT WE USE FOR BLOOD POOL IMAGING IN MONKEYS. THE HALF-LIFE, AND I APOLOGIZE FOR THE CLARITY HERE. IT'S POOR. IT'S ABOUT 32 HOURS IN MONKEYS. DIFFERENT SPECIES IT VARIES BETWEEN ABOUT 18-36 HOURS OR SO IS WHAT I HAVE SEEN. THE OREGON DISTRIBUTION, TYPICALLY THE PARTICLES GO TO THE LIVER AND THE SPLEEN. THEY ARE CLEARED BY PARTICULAR ENDOTHELIAL SYSTEM IN SPITE OF WATER PEGALATION OR HYDROPHILIC COATING, ITS PARTICLES END UP GETTING OPTIMIZED AND THEY ARE TAKEN UP BY THE RES. RETENTION IN THE PLACENTA TURNS OUT IS VERY LOW. HERE IS A STUDY THAT CAME OUT RECENTLY IN TOXICOLOGY. LESS THAN 1% OF THE INECT JUDGED DOSE WAS DETECTED IN THE PLACENTA ITSELF AND IT IS NOT CLEAR WHETHER THAT WAS LEFT OVER BLOOD THAT WAS WITHIN THE PLACENTA. HERE IS ANOTHER RECENT STUDY THAT WAS DONE AT THE METHODIST HOSPITAL ACROSS THE STREET FROM MY LAB WHERE RETENTION OF THE PARTICLES IN THE PLACENTA ITSELF WAS VERY, VERY LOW. AND THIS WAS ACTUALLY DONE IN THE CONTEXT OF DELIVERING ENDOMETH SIN TO THE MOTHER WITHOUT EXPOSING THE FETUS TO THE DRUG. AND AGAIN, THE FETUS HAS NO SIGNAL AT ALL. BY FAR THE BIGGEST PROBLEM WITH INTRODUCING LARGE CONCENTRATIONS OF PARTICLES LIKE THIS INTO THE BLOODSTREAM HOWEVER, IS COMPLEMENTARY ACTION. SO COMPLIMENT ASSOCIATED -- PSEUDOALLERGIES ARE THE BIGGEST SIDE EFFECT OF THESE PARTICLES AND IT IS TURNED OUT IT IS SIZE DEPARTMENT. SO DEPENDING ON THE SIZE OF THE PARTICLES THAT YOU PUT IN WHETHER YOU'RE LOOKING AT CELLS OR LARGER LIPOSOMES, YOU ACTIVATE DIFFERENT PATHWAYS AND THE BEST SOLUTION TO THIS AND WE HAVE DONE THESE STUDIES IN MANY, MANY DIFFERENT CONTEXT. PROBABLY THE MOST SENSITIVE SPECIES ARE STUDIES IN THE SWINE. AND THERE THE SIMPLEST SOLUTION WE COME UP WITH IS TO DO A PREDOSE OF MICRODOSE SUBCUTANEOUS AND THEN IF IS THERE GOING TO BE A REACTION, IT COMES UP AND GOES AWAY IN A COUPLE OF MINUTES AND THEN YOU INJECT IV AND NO MORE PROBLEM ANYMORE. WHAT YOU DON'T WANT TO DO IS INJECT A LARGE DOSE IV WITHOUT PRECONDITIONING THE ANIMAL. SO, LET'S SWITCH TO SOME APPLICATIONS THAT WE HAVE DONE. THIS HAS BEEN DONE A LONG TIME AGO. LET'S SEE IF I CAN GET THE REST OF THE MOVIES TO GO. SO, BACK IN 2002, THIS IS THE FIRST AMAGE WE EVER COLLECTED USING LIPOSOMAL CT PARTICLES. SO YOU COULD DO LONG TERM COMPUTER TOMOGRAPHY IMAGING. AGAIN SHOWING THAT UP TO 3 1/2 HOURS POST INJECTION, YOU GET A CLEAR CARDIAC IMAGE. 2004, WE SHOWED THESE PARTICLES WOULD LOCALIZE INTO TUMORS AND YOU COULD SEGREGATE INDIVIDUAL LYMPH NODES IF YOU WANTED TO AS WELL AS HETEROGENOUS DISTRIBUTION WITHIN THE VASCULAR STRUCTURES AND THE STRUCTURES WITHIN THE TUMORS. 2006 WE MADE OUR FIRST MR CONTRAST PARTICLE. THIS IS A NAVIGATOR SEQUENCE IN A RAT RELATIVELY SMALL SIZE HEART BUT WE ARE ABLE TO RESOLVE THE CARDIAC MOTION AS WELL AS PARTICULARLY LIKE HOW YOU SEE THE PULSATION IN THIS PARTICULAR IMAGE. 2007, WE WERE LOOKING AT SPINAL CORD INJURY AND THIS IS AGAIN IN A RAT AND WE WERE ABLE TO RESOLVE INCOMPLETE DETAIL -- INCOMPLETE DETAIL. CAN'T SEE IT WELL IN THIS PARTICULAR IMAGE BUT 100% OF THE TIME ABLE TO RESOLVE THIS WHICH IS CRITICAL IMPORTANCE IN SPINAL CORD INJURY. AT SOME POINT WE SPUN OFF A COMPANY THAT SCALED US UP INTO MULTIPLE LITTERS. WE MAKE LITTERS IN MY LAB. THIS IS IN A SHEEP SHOWING SINGLE INJECTION YOU CAN IMAGE THE COMPLETE VASCULATURE WITH A SINGLE SCAN. THIS WAS A TOUR DE FORCE DONE WITHAL JOHNSON AT DUKE. THIS IS ATTACKA CARTIC MOUSE BEATING 700 BEATS PER MINUTED AND WE ARE ABLE TO TIME RESOLVE THE CARDIAC IMAGE THERE SIMULTANEOUSLY RESOLVING CARDIAC AND RESPIRATORY MOTION. THIS WAS MORE RECENTLY HERE AT TEXAS CHILDRENS LOOKING AT CEREBRAL VASCULATURE LOOKING AT MOIIA MOIIA DISEASE AND TRYING TO UNDERSTAND THE DIFFERENCES IN CEREBRAL VASCULAR MORPHOLOGY IN MOIIA MOIIA. SO THAT IS ANOTHER COOL APPLICATION. AND THIS WAS PROBABLY OUR MOST RECENT APPLICATION WHICH I THINK IS INTERESTING IN THIS CONTEXT. WE WERE TRYING TO IMAGE AMYLOID PLAQUES IN THE BRAIN AND ALZHEIMER MODELS. IT TURNS OUT THESE PARTICLES IN AGING WILL GET PAST THE VBB AND THEY WILL LABEL AMYLOID PLAQUES RATHER WELL. I THOUGHT IT WAS FASCINATING ESPECIALLY IN THE RECENT CONTEXT WHERE I LEARNED THAT AMYLOID DEPOSITS TAKE PLACE IN THE PLACENTA. REALLY SURPRISES ME AND I-TRYING TO LEARN MORE ABOUT THIS AND I'D LOVE TO TALK TO ANYONE WHO KNOWS ABOUT THIS. BUT WE DO HAVE A PARTICLE ALREADY MADE THAT WILL LABEL AMYLOID PLAQUE SO IF YOU WANT TO IMAGE AMYLOID IN THE PLACENTA WE HAVE A WAY TO DO IT. OKAY. SO, THE FIRST SET OF DATA THAT I'LL SHOW YOU WITH RESPECT TO PLACENTA IS USING THE BLOOD POOL VERSION OF THIS AMOUNT AND IT'S SLIGHTLY DIFFERENT THAN WHAT WE TALKED ABOUT SO FAR. THIS IS NOTHING IN THE LUMEN. JUST SALINE. AND THE ONLY PLACE WHERE WE PUT SOME GAD LIN YUM IS ON THE SURFACE OF THE PARTICLE AND THE REASON FOR THAT IS THAT GAD LIN YUM IS ACCESSIBLE TO EXTERNAL WATER AND THEREFORE HAS VERY, VERY HIGH SIGNAL. FIRST THING WE DID WAS TRY TO SEE IF IT GETS PAST THE PLACENTAL BARRIER. AND THIS IS IN A PRO FUSED PLA SENTAL MODEL, HUMAN PLACENTA. AND UNDER A NORMAL PREGNANCY OR A PREGNANCY WITH GESTATIONAL DIABETES, AND WITH KNOWN GROWTH RESTRICTION, THIS HUGE AMOUNTS OF SIGNAL OBVIOUSLY FROM THE MATERNAL CIRCULATION. THIS IS NOT LINEAR. AND A VERY, VERY SMALL FRACTION, THREE HOURS OF MAGNITUDE LOWER SHOWS UP IN THE FETAL CIRCULATION AND THIS AMOUNT IS LOWER THAN THE KNOWN LEAK IN THE PER FUSED MODEL BECAUSE YOU CAN'T GET THESE TISSUES TO SEE PERFECTLY IN YOUR PROFUSION CELL ANY WAY. SO THE KNOWN LEAK IS LARGER THAN THIS. GIVES HIGH DEGREE OF CONFIDENCE THESE PARTICLES WERE NOT EASILY GETTING PAST THE PLACENTAL BARRIER. ONLY, WE CAN DO DC. -- OBVIOUSLY WE CAN DO DCE WITH THESE PARTICLES AS WELL AS WITH CONVENTIONAL CONTRAST AS DR. FREE AS SHOWED EARLIER. THIS IS IN A MOUSE. WE WERE DOING DYNAMIC CONTRAST ENHANCEMENT AND WHAT WE WERE ABLE TO SHOW IS THAT WITH CONVENTIONAL GAD LIN YUM AGENTS YOU GET DYNAMICS THAT YOU NORMALLY EXPECT. THEILABLE RING ENHANCES AND THEN -- THE LA BYRINTH ENHANCES AND THEN THE OUTER ZONE WHICH IS CLOSER TO THE DECIDEDDIA ALSO ENHANCES BUT HAS A DIFFERENT DYNAMIC BECAUSE BLOOD IN MICE IN THE PLACENTA FILLS THE LABYRINTH AND COMES BACK UP IN THE SPACE. AND THE FETAL SIGNAL YOU SEE A LITTLE BIT OF A HUMP HERE AND I'LL COME BACK TO THAT IN A LITTLE BIT. THIS IS WITH CONVENTIONAL CLINICALLY APPROVED GAD LIN YUM AGENTS. DO YOU THIS WITH THE NANOPARTICLE LIPOSOMAL GAD LIMB YUM AND YOU GET DIFFERENT DYNAMICS. THE LABYRINTH FILLS QUICKLY AND THE OUTER ZONE FILLS ALMOST THE SAME TIME BECAUSE NO OBVIOUS DK. AND THEN THE FETAL SIGNAL IS COMPLETELY FLAT. IN FACT, IF YOU LOOK AT CONVENTIONAL GAD LIN YUM VERSUS LIPOSOMAL GAD LIN YUM IN THE FT. US, SIGNAL WITH CONVENTIONAL GOES UP AND COMES DOWN BASED ON THE -- PASSING THROUGH THE PLACENTA WHEREAS WITH LIPOSOMAL GD, THE SIGNAT IN THE FEET SUSIN DISTINGUISHABLE FROM SALINE SO INDICATION ALTERNATE NOT GETTING PAST THE PLACENTAL BARRIER. SO AFTER THIS EXPERIMENT, YOU CAN PULL OUT THE PLACENTA AND THE FETUS AND THEN RUN ICP ON THEM TO MEASURE FAR HIGHER SENSITIVITY AND AGAIN, THE LIPOSOMAL PARTICLES JUST DON'T GET PAST THE BARRIER AT ALL. WE CAN DO ALL KINDS OF INTERESTING MODELING WITH THE DYNAMICS AND WHAT WE HAVE BEEN ABLE TO SHOW, THIS PAPER IS GOING TO COME OUT SHORTLY IN SCIENTIFIC REPORTS. THAT THE K TRANS, INDICATION OF HOW QUICKLY THE SIGNAL COMES INTO THE REGION, WHILE KAP, AN INDICATION OF HOW QUICKLY THE SIGNAL IS LEAVING, YOU CAN SEE THAT LIPOSOMAL AGENT FILLS FASTER -- AND THIS IS AN ARTIFACT FOR THE FACT THAT THERE IS NO TRANSPORT FROM THE PLA SENTA INTO THE FETUS. THIS REDUCTION WITH THE CONVENTIONAL AGENT IS BECAUSE OF THAT ARTIFACT. AND THEN SIMILARLY, YOU GET A MUCH FASTER DECAY WITH THE CONVENTIONAL AGENT BECAUSE CLEARING FROM THE CIRCULATION FASTER AND THEN THIS IS SLOW BECAUSE THE DECAY -- CLEARS OF THE LIPOSOMAL PARTICLE IS MUCH LOWER. NOW, AT SOME POINT, WE FIGURED OUT THAT WE CAN MAKE THESE PARTICLES EVEN MORE INTENSE IN THEIR SIGNALS SO YOU CAN USE FAR LESS GAD LIN AND HAVE HIGH SIGNAL. THIS IS A TECHNOLOGY WE CALL HYPERGAD. SO THE LIPID ANCHOR THAT FITS INTO THE LIPOSOMAL PARTICLE NOW HAS A HYDROPHILIC CATHETER AT THE END OF WHICH WE ANCHOR. THAT INHIBITS THE FLIPPING MOTION LEADING TO A FAR LONGER ROTATIONAL CORRELATION TIME WITHOUT GETTING INTO THE QUANTUM MECHANICS OF THIS IN GREAT DETAIL, LET'S JUST SAY A LONGER ROTATIONAL CORRELATION TIME INCREASES THE SIGNAL THAT YOU GET FROM A GAD LIN YUM AGENT AND IT ALSO WORKS REALLY WELL AT CLINICALLY RELEVANT FIELD STRENGTHS. SO THESE ARE 1 1/2 TESLA MEASUREMENTS AND THE RELAX ACTIVITY IS 8 OR SO LARGER THAN WHAT YOU GET WITH CONVENTIONAL GAD LIN YUM SO YOU CAN GO FROM AUTOMATIC TO LOWER AMOUNTS OF GD. SO WE HAVE BEEN DOING A LOT OF MORE RECENT MEASUREMENTS USING A ONE TESLA INSTRUMENT. SO, THAT IS WHAT IS SPINNING OFF HERE RIGHT NOW. THIS IS A TABLE TOP MRI THAT SITS IN OUR OPEN LAB. COMPARE THAT WITH A HIGH-END CRYO-COOLED MRI AND EXTREMELY HIGH FIELD STRENGTH, 9.4 TESLA. THESE ARE IN RATS BY THE WAY. USING THE LIPOSOMAL GD AGENT. WHAT YOU CAN SEE IS THE MULTIPLE PLACENTA IN THIS PREGNANCY. YOU CAN SEE ALL THE VASCULAR STRUCTURES LEADING INTO THE PLACENTA AS WELL AS AT THE SURFACE YOU CAN SEE THE MR. SENTAL LAP RING AND THE REST OF THE VASCULAR POOL WHICH CONSTITUTES THE BULK OF THE PLACENTA. SO THESE ARE DONE IN LIVE ANIMALS. SO WE CAN DO THIS LONGITUDINALLY AND THEN OF COURSE START DOING INTERVENTIONS AND SEE WHAT HAPPENS. IF YOU LOOK AT SOME OF THE DETAILS, SO THIS IS NOT YOUR IPHONE EAR BUD. THIS THE IS A INDIVIDUAL PLACENTA FROM THIS IMAGE SHOWING PENETRATING ARTERIES AND VEINS AND ONE OF THE ISSUES WITH THIS PARTICULAR AGENT IS IT IS A BLOOD POOL AMOUNT SO YOU SEE ALL THE VESSELS SIMULTANEOUSLY. SO YOU CAN'T DIFFERENTIATE ARTERIES AND VEINS UNLESS YOU DO A TIME-BASED MEASUREMENT. BUT THEN YOU SEE THE ENHANCEMENT DEFEATS INTERFACE. THE LABYRINTH ZONE AND THEN THE LOWER CONCENTRATIONS DENOTED BY THE YELLOW AND ORANGE TINT HERE CLOSER TO THE DESID YUM. THE NICE THING IS YOU GET SUPER HIGH RESOLUTION. SO, THE RAT PLACENTA TURNS OUT HAS A CENTRAL PENETRATING VESSEL LEADING TO THE LABYRINTH AND IT SPREADS OUT FROM THERE AND COMES BACK UP TO THE DISIDDUAL FACE AND THAT PENETRATING VESSEL SELL CLEARLY HERE AND WE HAVE BEEN ABLE TO MEASURE DIAMETERS AND LENGTHS AND WHAT NOT. VERY ACCURATELY. SO, SO I'LL MOVE ON TO A SLIGHTLY DIFFERENT TOPIC OF TRYING TO DO MOLECULAR IMAGING USING SAME PARTICLES AND IF YOU COME BACK TO THE VASCULAR IMAGING LATER, I'LL BE HAPPY TO HAVE THOSE DISCUSSIONS WITH YOU. SO, THE NOTION OF FOLATE TARGETING OF THESE PARTICLES HAVE BEEN AROUND FOR A HAVING LONG TIME IN THE CONTEXT OF DRUG DELIVERY AND WE HAPPEN TO HAVE TEMPLATES TO MAKE THIS PARTICLE VERY EASILY IN THE LAB. SO WE SAID, WHAT THE HECK. LET'S SEE WHERE THE FOLATE RECEPTOR IS IN THE PLACENTA AND IF IT'S KIND OF A CASUAL EXPERIMENT SO TO SPEAK. SEE IT TURNED OUT REMARKABLY INTERESTING. THE WAY WE DO THIS EXPERIMENT IS COLLECT AN MR IMAGE PRECONTRAST AND THIS WAS DONE GESTATIONAL DAY 11. AND THEN, AN ACUTE PHASE POST CONTRAST. SO INJECT THE AGENT AND IMMEDIATELY COLLECT AN IMAGE AND THEN YOU WAIT FOUR DAYS AND THIS IS THE REASON WE WAIT FOUR DAYS IS SO THAT THE AGENTS CIRCULATES HAS AN OPPORTUNITY TO BIND AND THEN WHATEVER IS IN THE BLOODSTREAM CLEARS OUT BECAUSE OF THE CLEARANCE. AND THEN WHAT IS LEFT AT THE END OF FOUR DAYS? WHATEVER HAS BOUND TO ITS MOLECULAR TARGET OR IF SOMETHING IS PASSIVELY DUE TO SOME KIND OF VASCULAR INJURY OR WHATEVER. WHAT WE FOUND WAS IN THE PLACENTA ITSELF, YOU SEE THIS UNIQUE PATTERN OF ENHANCEMENT. THERE IS SORT OF DULL ENHANCEMENT IN THE LABYRINTH ZONE BUT THEN THERE IS MUCH MORE INTENSE ENHANCEMENT RIGHT AT THE INTERFACE. AND WE FOUND THIS IN EVERY PLACENTA WE LOOKED AT AND THAT WAS EFFECTIVELY OUR NORMAL PATTERN FOR THE FOLATE RECEPTOR THAT WE WERE ABLE TO IDENTIFY. WE CONFIRMED THIS BY IMMUNOHISTOCHEMISTRY AS WELL AS LIZA. AND THEN I DIDN'T TELL YOU THIS. IN THE PARTICLES, WE ALSO INCORPORATED A SMALL AMOUNT OF ENDOCYTE GREEN, A NEAR INFRARED DYE. SO ONCE WE EXCISED THE PLACENTA, POST SACRIFICE, WE CAN IMAGE THEM WITH A NEAR INFRARED CAMERA, WHICH ALLOWS US TO CONFIRM THE LOCATION OF THE PARTICLES THAT WE WERE ABLE TO DEDUCE FROM THE MRI. AND THAT IS EXACTLY WHAT WE SEE. SO, HERE IS OUR INTENSE DISIDDUAL ZONE AND RELATIVELY LIGHT FILLED LABYRINTH. AND THESE ARE JUST THREE DIFFERENT VIEWS. CONFIRMED IN THE IMMUNOHISTOCHEMISTRY. TOOK THE TISSUES UP AND GROUND THEM UP AND THEN RAN PCR ON THEM. SO, THE JUNCTIONAL ZONE HAS A FAR HIGHER CONCENTRATION WHICH IS WHAT WE EXPECTED THAN THE LABYRINTH AND THEN PREDICTING THE PLACENTA AND YOU IMAGE THEM, DISIDDUAL FACE UP AND FETAL FACE UP. THIS IS WHAT YOU'RE SEEING HERE. AND YOU CAN SEE THAT THIS IS WHERE ALL OF THE FOLATE RECEPTOR IS COMPARED TO AT THE FETAL INTERFACE. SO YOU CAN ACTUALLY GO INTO SUPER HIGH RESOLUTION IN A GIVEN PLACENTA AND WE CAN IMAGE THE FOLATE RECEPTOR DISTRIBUTION IN THAT PLACENTA USING THE MR TECHNIQUES SO WE CAN DO THIS IN LIVE ANIMALS NOW. SO, IT IS JUST A QUESTION OF TARGETING THESE PARTICLES TO WHATEVER RECEPTOR WE WANT TO STUDY AND WE CAN DO THAT. WE DID A COUPLE OF LONGITUDINAL STUDIES AND I FOUND THIS REALLY INTERESTING. SO, CHANDRA, MY COLLABORATOR, IS INTERESTED IN LOAD WORKING DIETS. AND WE WANTED TO COMPARE A NORMAL PROTEIN DIET WITH THE LOW PROTEIN DIET CASE AND SO NORMAL PROTEIN AT GESTATIONAL DAY 15 YOU GET THAT NORMAL DISTRIBUTION I SHOWED YOU BEFORE. ENHANCE FOLATE RECEPTOR, DESIDDUAL ZONE RELATIVELY LOW ELSEWHERE. IF YOU GO PRETTY MUCH TO TERM, 21.5, YOU SEE VERY, VERY LOW EXPRESSIONS OF THE FOLATE RECEPTOR IN THE PRESENT SENTA BECAUSE IT IS UPREGULATED IN MID GESTATION AND NOT TO TERM. BUT IF YOU GO TO THE LOW-PROTEIN DIET, YOU SEE THE SAME BEHAVIOR AT 15 BUT WHEN YOU GET TO TERM, THERE ARE SOME PLACENTA THAT JUST HAVE HUGE AMOUNTS OF FOLATE RECEPTORS STILL ACTIVE. AND WE SEE THIS OVER AND OVER AGAIN. SUGGESTING THAT THIS PLACENTA IS SOMEHOW CORRESPONDING TO A FETUS THAT JUST NEEDS MORE FOLATE AT THIS THE POINT IN TIME. THAT'S WHY IT'S BEING UPREGULATED. VERY EARLY STAGE DATA. WE'D LIKE TO BE ABLE TO CONFIRM THIS BY LOOKING AT BIRTH WEIGHTED CORRESPONDING TO THESE FETUSES AND SO ON AND SO FORTH. SO, COMING UP, WE'LL BE LOOKING AT DETAILED CHARACTERIZATION, OTHER RECEPTORS, LOOKING AT DIFFERENT CONDITIONS. I'LL TAKE QUESTIONS. THIS IS ONE OF THE GUYS TRYING TO SHOW OFF IN THE LAB. MADE A CD VERSION OF THESIS PARTICLES THROUGH THE ANIMAL MICROCT AND JUST TO SHOW THAT WE CAN GET -- THIS IS ULTIMATE RESOLUTION OF ABOUT 20 MICRON NEGLIGENCE A LIVE ANIMAL. WE CAN IMAGE VASCULATURE, PLACENTA, YOU CAN SEE FETAL STRUCTURES AND SO ON AND SO FORTH. I'LL STOP THERE AND TAKE QUESTIONS. [ APPLAUSE ] >> VERY NICE. WE HAVE TIME FOR SOME QUESTIONS BEFORE THE BREAK. >> HI. JOHN FROM TORONTO. VERY ELEGANT. THANK YOU. MY UNDERSTANDING IS THE CONCERNS WITH GAD LIN YUM ARE STABILITY OF THE VECTOR. SO I WANTED TO ASK YOU WHETHER THIS MODEL, YOU'RE LIKELY TO HAVE MORE STABLE GAD LIN YUM SO YOU WILL GET FREE GAD LIN YUM IN THE FEELS BRAIN? >> SO WE ACTUALLY USE MACK CYCLIC HEELIATS FOR OUR PARTICLES. BUT ABSOLUTELY GAD LIN YUM IS A CONCERN. AT THIS EARLY STAIN OF THE GAME, WE ARE MORE INTERESTED IN WHAT THE PARTICLES DO RATHER THAN THE ACTUAL RAD OUT WE USE. THERE IS OBVIOUSLY OTHER READ OUTS WE ARE LOOKING AT. I DIDN'T GET INTO THAT TODAY. BUT WE ARE LOOKING AT FLUORINE COMPOUNDED TO DO FLUORINE MR AS WELL AS OTHER WAYS OF GREATLY MITIGATING GAD LIN YUM TOXICITY BUT THE OBVIOUS ONE IS USING DOSE SO THE MR TO GAD LIN YUM WE USE IN THESE IF YOU LOOK AT ON A WEIGHT BASIS, IS ABOUT 100 OF THE CLINICAL DOSE THAT YOU WOULD USE. >> DO YOU HAVE ANY SPENCE OF SPONTANEOUS DISASSOCIATION FROM THE VECTORS YOU DESIGNED? >> ARE YOU TALKING ABOUT ASSOCIATION FROM THE PARTICLE? >> YES. >> OR THE ASSOCIATION FROM THE KEEL AT? >> SO IT BECOMES MORE TOXIC BECAUSE IT WILL PENETRATE. >> SO THE TOXIC GAD LIN YUM IS AFTER IT IS DISASSOCIATE THE FROM THE KEEL 8. THAT'S WHY WE USE MACRO CYCLES AND THOSE THAT WE USE HAVE A BINDING CONSTANT 10-16. SO SUBSTANTIALLY BETTER THAN THE ONES THAT ARE OR HAVE BEEN USED CLINICALLY UP UNTIL NOW. JUST RECENTLY THERE HAVE BEEN A COUPLE OF THOSE APPROVED FOR CLINICAL USE. >> THANK YOU VERY MUCH. >> I HAVE A QUESTION FOR YOU. TWO CONTRAST AMOUNT TO COMPARE THAT [ INDISCERNIBLE ] ONE IS FLAT AND ONE IS REGULAR CURVE. IF YOU USE CONTRAST AGENT IT SEEMS DIFFICULT TO DO PROFUSION STUDIES -- FLOW. VOLUME. IS THIS CORRECT? >> NOT TRUE ACTUALLY BECAUSE AS WE SHOWED YOU, WE CAN APPLY EXACTLY THE SAME REFERENCE TYPE MODELS. YOU JUST HAVE THE A DIFFERENT DK CONSTANT THAT YOU'RE LOOKING AT. YOU CAN'T DO WASH AND WASH OUT STUDIES THE WAY YOU USUALLY LIKE TO DO WITH CONVENTIONAL CONTRAST BECAUSE THE VENUS CONTAMINATION IS HIGH. BUT, OTHER THAN THAT, YOU CAN DO EVERYTHING ELSE. AND IF YOU'RE DOING FIRST PASS, THAT IS NOT AN ISSUE. YOU CAN RELEASE THESE PARTICLES THE SAME WAY YOU WOULD WITH CONVENTIONAL. >> SO GAD LIN YUM -- DEVELOP NEW MATHEMATICAL MODEL BECAUSE FROM TRADITIONAL MATHEMATICAL MODEL YOU COULDN'T CALCULATE -- [ INDISCERNIBLE ] >> SO IT'S NOT A NEW MODEL. THE SAME MODEL JUST DIFFERENT CONSTANTS. >> OKAY. >> HELLO, TERRY MORGAN FROM OREGON. AWESOME TECHNOLOGY. VERY IMPRESSIVE TO ME. YOU CAN DO RATE, VOLUME, AND ARCHITECTURE ALL AT THE SAME TIME WHICH IS AWESOME. QUESTION I HAVE FOR YOU IS, IN YOUR RAT, WITH MULTIPLE PLACENTAL UNITS, HAVE YOU STARTED TO LOOK FOR DIFFERENCES IN SPIRAL ARTERY ARCHITECTURE AND RATE OF FLOW TO THE PLACENTA WEATHER PROXIMAL TO CERVIX VERSUS DISTAL HORN? IT WOULD BE INTERESTING TO ASK HOW DOES THE ARCHITECTURE ADAPT TO RATE OR DOES IT DETERMINE RATE? >> SO, TO GO BACK TO YOUR ORIGINAL STATEMENT, YES, WE CAN DO RATE, VOLUME, ARCHITECTURE AND MOLECULAR PROFILES. ALL IN THE SAME MEASUREMENT. TWO, WE ARE ABSOLUTELY LOOKING AT THE DETAILS OF THE VASCULAR MORPHOLOGY IN MANY OF THE SITUATIONS THAT YOU'RE TALKING ABOUT. IT'S JUST EARLY DAYS. WE DON'T HAVE ANYTHING TO TALK ABOUT. >> IF YOU DON'T MIND ME ASKING, SOWY COMPAREDOY LOW PROTEIN TO NORMAL DIET. DID YOU HAPPEN TO SEE ANY DIFFERENCE IN FLOW, RATE, VOLUME -- >> WE HAVE THE DATA BUT HAVEN'T ANALYZED. >> I CAN'T WAIT. THANK YOU VERY MUCH. >> RICH MILLER, ROCHESTER. THANK YOU. I HAD TWO COMMENTS. ONE WAS RELATED TO THE COATINGS THAT ARE ON YOUR LIPOSOMES AND IT MAY NOT BE DIRECTLY SPECIFIC BUT IN OUR STUDIES WITH GOLD PARTICLES, WE HAVE FOUND THAT THE COATINGS TAKEN UP FROM THE BLOOD WHETHER IT IS IGG OR IN FACT ALBUMEN, CAN MAKE A DIFFERENCE IN TERMS OF THE SELECT ACTIVITY IN UPTAKE OF THE NANOPARTICLES. HAVE YOU EXPLORED ANY INTERACTIONS WITH YOUR LIPOSOMES RELATIVE TO BLOOD PRODUCTS? >> YES. SO, THERE HAVE BEEN -- SO, LET ME BACK UP. THE STUDY OF LIPOSOMES AND WHAT HAPPENS WHEN YOU EXPOSE THEM TO BLOOD PRODUCTS WAS DONE YEARS AND YEARS AGO IN THE CONTEXT OF DRUG DELIVERY LONG BEFORE WE CAME ON THE SCENE AND STARTED USING THEM FOR IMAGING. SO, THE FUNDAMENTAL DIFFERENCE BETWEEN GOLD NANOPARTICLES AND THESE PARTICLES ARE THE SIZE. AND THAT ACTUALLY HAS A LOT TO DO WITH THE UPTAKE. IT'S PRETTY HARD TO TAKE UP THESE PARTICLES INSIDE CELLS UNLESS YOU DO SOMETHING FAIRLY DRASTIC. TYPICALLY, GOLD NANOPARTICLES ARE 5-10 NANOMETERS. THESE THINGS ARE 120-150 NANOMETERS. AND SO, THAT ACTUALLY MAKES ALL THE DIFFERENCE. IF THERE WERE A GOOD WAY OF GETTING THESE PARTICLES INTO THE DIFFERENT CELL TYPES, THERE ARE FAR MORE INTERESTING USES FOR THAT. >> AND JUST ONE COMMENT ABOUT GAD LIN YUM AS PART OF THE NATIONAL CHILDREN'S STUDY, WE EXAMINED GAD LIN YUM IN PLACENTAS AND SINCE THEN, ROCHESTER LOOKED AT BLOOD AND WHAT WE HAVE FOUND IN PATIENTS HAS BEG YOUR PARDON OR IN WOMEN'S PLACENTA AS WELL AS IN THE CORD BLOODS, HAS BEEN FREE GAD LIN YUM IN A VERY SMALL PROPORTION OF PATIENTS ABOUT 5-6% THAT ARE 1000 TIMES HIGHER BUT IN ALL OF THE INSTANCES, THEY WERE FREE RATHER THAN BOUND. SO JUST INDICATE IN FOLLOW-UP TO MIKE NELSON'S COMMENTS THAT THERE ARE DIFFERENT RISKS THAT WE ARE LOOKING AT BECAUSE OF IT BEING BOUND TO BONE AND THEN PERHAPS PULLED OUT DURING PREGNANCY MUCH LIKE LEAD IS. >> YES. SO ABSOLUTELY RIGHT. AND WHEN IT COMES TO GAD LIN YUM, WE ARE LOOKING AT IT AS A WINDOW. MUCH MORE INTERESTED IN WHAT THE PARTICLES ARE DOING. [ APPLAUSE ] >> DAVID WEINBERG: SO, I THOUGHT THIS WAS A REALLY WONDERFUL START TO THE DAY. I'M ALL ENERGIZED AND HOPE YOU ARE TOO. NOW I'M SURE YOU'RE READY FOR A BREAK SO I INVITE YOU TO TAKE ONE. WE WERE WAY AHEAD OF SCHEDULE AND NOW WE ARE ALMOST BEHIND SCHEDULE SO TRY TO BE BACK AROUND 10:20 OR SO. AND I'LL COME CHASE YOU. >> WELCOME BACK. I THOUGHT THIS MORNING WAS GREAT AND I CAN PROMISE YOU THE REST IS GOING TO GO EQUALLY WONDERFULLY. IN KEEPING WITH THE THEME OF BEING OPEN AND EXPLORING NEW TECHNOLOGIES THAT WE MIGHT ULTIMATELY BE ABLE TO APPLY FOR PLACENTA, OUR NEXT SPEAKER IS JENNIFER MULEYER WHO WILL TALK ABOUT ELECTRICAL IMPEDE ENT TOMOGRAPHY, A NOVEL METHOD FOR IMAGING. >> THANK YOU VERY MUCH. THANK YOU FOR INVITING ME AND FOR THE OPPORTUNITY TO SPEAK HERE. THIS IS REALLY EXCITING AND I'M VERY STIMULATED. I'D LIKE TO TELL BUT ELECTRICAL IMPEDENCE IMAGING. FIRST I'LL GIVE YOU AN INTRODUCTION TO WHAT IT IS BECAUSE IMAGINE MANY PEOPLE HAVEN'T HEARD OF IT. I'LL GO OVER CURRENTLY USED MEDICAL APPLICATIONS AND OPPORTUNITY USE I SEE FOR PLACENTAL IMAGING. SO THAT WILL BE SPECULATIVE. SO, ELECTRICAL IMPEDENCE TOMOGRAPHY USES ELECTRIC CURRENTS TO FORM IMAGES OF THE CONNECT ACTIVITY AND PER MI ACTIVITY IN A PERSON'S BODY WHICH CHANGE IN TIME. SO VOLTAGE IS MEASURED ON ELECTRODES ON THE BODY. THIS LITTLE VIDEO HERE SHOWS HOW CURRENT IS APPLIED PAIR WISE ON THE ELECTRODES SEQUENTIALLY AROUND THE DOMAIN. IT CAN BE USED FOR 2D OR 3D IMAGING. I'M FOCUSED A LOT ON THE LUNGS SO THIS IS A GEOMETRY THAT YOU USE FOR 2D IMAGING OF A CROSS SECTION OF A PERSON'S CHEST. ON THE LEFT YOU SEE A PERSON, HEALTHY HUMAN SUBJECT IN THE LAB AT COLORADO STATE UNIVERSITY BEING IMAGED IN THEIR LUNGS. SO ONCE YOU HAVE RECOVERED, THE CONNECTIVITY AND THE PERM ACTIVITY DISTRIBUTIONS IN THE INTERIOR BY SOLVING WHAT IS CALLED INVERSE PROBLEM. YOU CAN PLOT THOSE IN TIME TO FORM FUNCTIONAL IMAGES OF AIR FLOW MOVING IN AND OUT OF THE LUNGS AND PROFUSION AND OTHER APPLICATIONS AS WELL. SO, FOR THIS TO WORK, THERE HAS TO BE CONTRAST. I HAVE INCLUDED THE CONTRAST IN CONNECTIVITY AND HUMAN TISSUES IN THE BODY. AIR IS VERY RESISTIVE AND AS AIR MOVES IN AND OUT OF THE LUNGS, THE CONDUCT ACTIVITY CHANGES BY A FACTOR OF 2. YOU CAN SEE IN THIS CHART SOME OF THE DIFFERENTS IN THE BODY THAT MAY BE OF INTEREST. LUNGS, BONE IS HIGHLY RESISTIVE. CARDIAC MUSSEL, CHANGE IN THE LONGITUDINAL VERSUS TRANSVERSEAL DIRECTIONS. HERE IS THE CONNECTIVITY OF THAT. BLOOD HAVE VERY RELEVANT FOR THE PLACENTA AND THEN WE HAVE THE HIGHLY RESISTIVE SKIN, CONNECTIVITY OF THE BLADDER AND AMNIOTIC FLUID IS THE MOST CONDUCTIVE MEDIUM IN THE HUMAN BODY AND IT CHANGES OVER THE PERIOD OF GESTATION SO FROM 0-30 WEEKS YOU CAN SEE IT IS 12.8 AND THEN IT DROPS OFF AFTER 30 WEEKS THROUGH DELIVERY. THE PLACENTA I COULD NOT FIND ANY CONCLUSIVE DATA ON WHAT ITS CONNECT ACTIVITY IS. AGAIN IT IS RATHER COMPLEX BUT IT IS LESS THAN BLOOD ALONE ALTHOUGH IT IS VERY HIGHLY PRO FUSED SO SOMEWHERE BETWEEN BLOOD AND OTHER TISSUES. SO, I WANT TO GIVE YOU AN IDEA OF WHAT EIT HAS POTENTIAL TO DO AND WHAT IT CAN DO, WHAT IT IS BEING USED FOR. SO, IT CAN FORM IMAGES WITH EXCELLENT TEMPORAL RESOLUTION, UP TOIST IFFY FRAMES A SECOND IS CURRENT STATE-OF-THE-ART WITHOUT COMPROMISING TOO MUCH SIGNAL TO NOISE RATIO. IT'S NONINVASIVE AND NONIONIZING SO GOOD FOR MONITORING AND DIAGNOSIS AT THE BEDSIDE. IT IS A LOW-COST AND PORTAL MODALITY. IT CAN BE USED DURING OTHER TESTS. I'LL SHOW YOU SUCH AS PULMONARY FUNCTION TESTS. AND YOU CAN OBTAIN REGIONAL INFORMATION IN REALTIME. ANOTHER USE IS IT'S NOT LOCKED INTO ONE FREQUENCY. YOU CAN DO SPECTROSCOPY AS WE SAW WITH DOTS AND THE MULTIFREQUENCY INFORMATION CAN PROVIDE INFORMATION THAT THE IMAGES ALONE DON'T PROVIDE. SO, HERE IS AN EXAMPLE OF EIT DATA BEING COLLECTED DURING A PULMONARY FUNCTION TEST AT CHILDREN'S HADN'T OF COLORADO. SO THE SUBJECT IS A HEALTHY HUMAN VOLUNTEER FOR THE PURPOSES OF THIS DEMONSTRATION. HE IS BREATHING INTO A SPAROMETER WHICH MEASURES AIR FLOW VOLUME AND AIR CAPACITY, AIR VOLUME. AND FLOW RATE. I THINK I JUST SAID VOLUME. FLOW RATE. SO, WHAT THE SUBJECT DOES OR THE PATIENT, THEY TAKE A BIG BREATH INTO THE SIRROMETER. IT SEALS OVER THEIR LIPS SO NO AIR ESCAPES SO THEY CAN GET THE VOLUME THROUGH THIS DEVICE AND THEN THEY BREATHE OUT FAST AND HARD UNTIL ALL THE AIR IS EXMELD FROM THEIR LUNGS: AND THEN THE NUMBER THAT IS THEY GET OUT OF IT ARE THINGS LIKE THE LUNG CAPACITY, HOW MUCH AIR WAS EXPELLED IN THE FIRST SECOND IS OF INTEREST. HOW FAST THAT AIR WAS EXPELLED AND RATIOS OF SOME OF THOSE. FROM THOSE, THEY CAN DIAGNOSIS VARIOUS PROBLEMS SUCH AS OBSTRUCTION. SO THESE TESTS ARE COMMONLY DONE IN PATIENTS WITH ASTHMA, COPD, CYSTIC FIBROSIS, AND OTHER OBSTRUCTIVE DISEASES. SO, WE ARE COLLECTING THE EIT DATA SIMULTANEOUSLY. ELECTRODES ARE AROUND THIS PERSON'S CHEST BUT IT'S OBSCURED BY THIS MONITOR AND HIS ARM. YOU CAN SEE A FEW EVER THEM THERE. AND THEN, IMAGES ARE FORMED AT THE CONNECTIVITY. THESE ARE ALL RELATIVE TO ONE IMAGE THAT WAS ALMOST AT MAXIMAL EXPIRATION. SO, HIGH CONNECTIVITY REGIONS ARE PLOTTED IN READ. YOU CAN SEE THE HEART AT THE TOP AND LOW REGIONS ARE PLOTTED IN BLUE. SO THESE ARE JUST SOME TIME SNAPSHOTS. I'LL SHOW YOU A MOVIE LATER ON. AS THEY BREATHE IN, THE AIR GOES INTO THEIR LUNGS MAKING THEM MORE RESISTIVE AND IMAGES MORE BLUE. THESE ARE JUST A FEW TIMED SNAPSHOTS BUT DURING RAPID EXHALATION, THE LUNGS BECOME MORE CONDUCTIVE EVENTUALLY THAN THE REFERENCE IMAGE HERE. THE REFERENCE IMAGE ISN'T SHOWN AND IT WAS SLIGHTLY BEFORE MAXIMUM EXPIRATION. AND THEN THEY HAVE RECOVERY BREATHS WHERE THEY BREATHE IN AND OUT AGAIN. SO, WHAT ARE THE LIMITATIONS OF EIT? THE FROM THE PREVIOUS SLIDE YOU ALREADY SEE THAT THE SPACIAL RESOLUTION IS NOT COMPETITIVE WITH CT SCANS OR MRI. IT'S MUCH MORE GLOBAL IN TERMS OF WHAT YOU CAN SEE. IT'S VERY LIMITED WHEN IT IS USED AS A STAND ALONE TECHNIQUE, THAT MEANS WHEN YOU'RE NOT USING ANY EXTRA INFORMATION ABOUT THE ANATOMY THAT YOU COULD OBTAIN FROM FOR EXAMPLE CT SCAN OR MAYBE AN ULTRASOUND IMAGE, THAT YOU HAVE IN ADVANCE OR COLLECTED AT THE SAME TIME. SO, JUST TO COMPARE, THIS IS AN INSPIRATION TORY HIGH RESOLUTION CT IMAGE OF A PATIENT WITH CYSTIC FIBROSIS AT CHILDREN'S HOSPITAL WHO WAS HOSPITALIZED. SHE HAS LINEAR CONSOLIDATION HERE. THIS IS THE EXPRI TORY IMAGE. IN A BETTER MONITOR YOU CAN SEE SOME DIFFUSED AIR TRAPPING. AND THESE ARE THREE FRAMES AGAIN IN THE DIFFERENCE IMAGE IN THE SEQUENCE OF FUNCTIONAL EIT IMAGES ON THIS SUBJECT. SO, YOU CAN SEE RELATIVE SIZES OF THE LUNGS, LINEAR CONSOLIDATION ISN'T PRESENT. THERE IS SOME EVIDENCE OF AIR TRAPPING THAT ONE CAN DISCERN FROM SECONDARY IMAGES BUT FROM THESE YOU DON'T REALLY SEE THAT. SO IT'S STILL AN EMERGING TECHNOLOGY. STILL A LOT OF RESEARCH BEING DONE TO IMPROVE THE QUALITY OF THE IMAGES AND FOR CLINICAL APPLICATIONS. HOWEVER, THERE ARE COMMERCIAL SYSTEMS AVAILABLE. THIS TECHNOLOGY DOESN'T HAVE FDA APPROVAL IN THE UNITED STATES FOR USE IN HOSPITALS. BUT IN EUROPE IT DOES. SO, HERE FROM THIS BROCHURE, YOU CAN SEE THE SYSTEM BEING USED IN GERMANY AT BEDSIDE IN THE ICU TO IMAGE PATIENTS. HERE THEY HAVE ELECTRODES BELT AND YOU CAN SEE THE OUTPUT THE SCREEN. AND SWISS TOM IS A SWISS COMPANY THAT ALSO MAKES AN EIT SYSTEM. THEY ARE 800 SYSTEM IS INTEGRATED WITH A VENTILATORS SO IT'S AN VENTILATOR AND EIT SYSTEM AND DRAYINGER HAS SOMETHING SIMILAR. SO HERE YOU CAN SEE THE 2D LUNG IMAGE ON THE EIT MONITOR. AND TIM PEL IS A BRAZILIAN COMPANY THAT HAS A PRODUCT IN SOUTH AMERICA FOR USE IN HOSPITALS, ESPECIALLY IN THE BRAZIL. SO, IN THE LAP LABORATORY, SYSTEMS MAY NOT LOOK ADDS SLICK. THIS IS OUR SYSTEM IN THE LAB. BUT THEY HAVE TECHNOLOGICAL ADVANTAGES OVER THE COMMERCIAL SYSTEMS. FOR EXAMPLE, THE COMMERCIAL SYSTEMS ARE ONLY IMAGING CONNECTIVITY AT THE TIME BEING WHEREAS THE PERM ACTIVITY IS A PERMANENT ELECTRICAL PROPERTY THAT PROVIDES ADDITIONAL INFORMATION. SO, JUST IN CASE YOU'RE NOT FAMILIAR THE CONNECTIVITY IS WHAT YOU OFTEN THINK ABOUT. IT'S THE ABILITY OF THE MATERIALS TO CONDUCT ELECTRIC CURRENT. BUT THE PERM ACTIVITY IS THE MATERIALS ABILITY TO STORE A CHARGE LIKE A CAPACITOR AND CELLS HAVE THIS PROPERTY. SO FOR EXAMPLE, WHEN YOU HAVE AIR IN THE LUNGS, NOT ONLY ARE THEY VERY RESISTIVE, BUT THEY ALSO REDUCE PERM ACTIVITY WHEN THEY ARE FILLED WITH AIR VERSUS WHEN YOU EXHALE. REGIONS OF -- WILL HAVE HIGHER PERMIA ACTIVITY THAN REGIONS OF NONE AND LIKEWISE THEY'LL HAVE HIGHER PERMIA ACTIVITY THAN A FLUID-FILLED REGION OF THE SO IT CAN BE VERY IMPORTANT FOR DIAGNOSIS. SO OUR SYSTEM DOES HAVE THAT CAPACITY AND THIS IS A HEALTHY 8-YEAR-OLD BOY BEING IMAGED IN THE LAB. WE DON'T HAVE ALL THE BELLS AND WHISTLES THE COMMERCIAL SYSTEMS DO IN TERMS OF ELECTRODES BELTS SO THERE IS A LOT TO BE DONE WITH THE INTERFACE AS WELL. SO THIS IS KIND OF A LIST OF SOME OF THE NONINVASIVE MEDICAL APPLICATIONS OF EIT AND I'LL GO THROUGH SOME OF THESE IN A BIT MORE DETAIL BUT I'D LIKE TO READ THEM OFF TO YOU AND PROVIDE YOU WITH A LIST. SO MONITORING VENTILATION AND PERFUSION IN PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME. THAT IS ONE OF THE APPLICATIONS THAT THE SYSTEM SWISS TOM, DRAYINGER AND TIM PEL ARE LOOKING AT ABROAD. REALTIME DIAGNOSIS OF ATE ELECTA SIS, PNEUMOTHORAX AND LUNG COLLANS AND HYPERDISTENSION IS AND PLEURAL EFFUCION. SOME OF THE DIAGNOSIS THAT THE COMMERCIAL SYSTEMS ARE GEARED TOWARD. VISUALIZATION AND QUANTITATIVE MEASURES FROM PULMONARY FUNCTION TESTS. OUR LAB IS CURRENTLY INVOLVED IN THOSE STUDIES WITH CHILDREN'S HOSPITAL OF COLORADO. IDENTIFYING REGIONS OF OBSTRUCTION OR CONSOLIDATION IN CHILDREN WITH CYSTIC FIBROSIS. THAT'S ALSO PART OF OUR CURRENT PROJECT FUNDED BY THE NIH. BREAST CANCER DETECTION. IT TURNS OUT THAT BREAST TISSUE IS 2 -- CANCEROUS BREAST TISSUE IS 2-4 TIMES MORE CONDUCTIVE THAN HEALTHY BREAST TISSUE AND THE PERM ACTIVITY PROPERTIES ALSO DIFFER SIGNIFICANTLY. NEONATAL LUNG MONITORING. AND DETECTION OF NEONATAL CEREBRAL HEMORRHAGE. SO, I'D LIKE TO SHOW YOU A VIDEO. THIS DEPICTS BLOOD FLOW BETWEEN THE HEART AND LUNGS RECONSTRUCTED THROUGH EIT DATE ON AN ATHREAT SIDES PIG. THIS IS COURTESY OF MY COLLABORATOR IN SAO PAULO. WHAT YOU'LL SEE IS THIS IS THE HEART REGION AND THESE ARE THE LUNGS AND YOU'LL SEE CHANGES IN BLOOD FLOW AS THE HEARTBEATS. ONE THING ONE CAN LOOK FOR IS CHANGES IN THE VENTILATION PROFUSION OR VQ RATIO IN SUBJECTS WITH PROBLEMS LIKE PLEURAL EFFUCION, OR PULMONARY EMBOLISM. SO PULMONARY EMP LIMP, A BLOOD CLOT IN THE LUNG WILL REVEAL THE REGION THAT IS BEING VENTILATED BUT NOT PER FUSED. LIKEWISE, IF YOU HAVE A REGION THAT IS FILLED WITH FLUID, THAT WILL BE PER FUSED BUT NOT VENTILATED. SO BY LOOKING AT THESE RATIOS, YOU CAN GET VALUABLE INFORMATION. NOW TO GET SOME REGIONAL INFORMATION ABOUT THE PERFUSION, A BOLUS OF SAIL EN WAS INJECTED INTO THE HEART OF THE PIG AND THE EIT RECONSTRUCTION SHOW THE PATH OF THIS IS A LEAN FROM THE HEART TO THE LUNGS AND THEN BACK TO THE HEART. AUTO -- SALINE. SO NOT TO PANIC. I KNOW THIS VIDEO TAKES A MINUTE TO GET STARTED. SO THAT WAS THE HEART IN THE CIRCLE UP THERE. AND THEN THE SALINE TRAVELS INTO THE LUNGS AND BACK AGAIN TO THE HEART. SO THAT IS WITH THE CONTRAST. THE SALINE IS A HIGH-CONTRAST AGENT IF YOU PUT ENOUGH SALT IN THERE. PULMONARY MONITORING. THIS IS FROM A PAPER IN CRITICAL CARE MEDICINE ALSO BY MY COLLABORATORS AT UNIVERSITY OF SAO PAULO. AND YOU SEE A COMPARISON AGAIN THIS IS DATA IN A PIG, FROM THE CT SCAN AT BASELINE VERSUS THE CT SCAN AFTER 100 MILLIMETERS OF AIR HAVE BEEN INJECTED INTO THE PLURAL SPACE OF THIS LEFT LUNG. AND, THAT IS INDUCING A PNEUMOTHORAX IN THE PIG. AT THE SAME TIME, EIT DATA WAS COLLECTED -- NOT SIMULTANEOUSLY WITH THE CT SCAN BUT ALTERNATIVELY BEFORE THE AIR WAS INJECTED INTO THE PLURAL SPACE AND AFTER. WHAT YOU SEE IS A SILENT ZONE, THE VENTILATION MAP AGAIN THIS IS JUST A STILL IMAGE BUT IT SHOWS THE REGION THAT IS BEING VENTILATED IN THE PIG AND IT'S BEEN SEGMENT JUST TO SHOW THE LUNGS HERE. SO THIS IS CALLED A SILENT ZONE. THERE IS NO CHANGE IN THAT REGION RIGHT HERE WHERE IT IS BLACK. BECAUSE IT IS NOT BEING VENTILATED. AND THE AERATION MAP HERE WHICH IS A DIFFERENCE IMAGE SHOWS A HIGH RESISTIVE AREA THAT IS NOT CHANGING. SO THAT IS THE PNEUMOTHORAX RIGHT THERE. SO THESE CAN BE DETECTED IN REALTIME AT THE BEDSIDE. BREAST CANCER DETECTION. IN THIS CASE, WE HAVE A ENTIRELY DIFFERENT GEOMETRY INSTEAD OF BELT TO GET 2D CROSS SECTION IMAGES, THERE IS TWO PLANES OF RADIO ELUC WANT ELECTRODES. THIS IS BY THE GROUP AT RPI ON A SYSTEM THEY CALL ACT 4. AND THE EIT DATA IS COLLECTED AT THE SAME TIME AS THE MAMMOGRAPHY DATA SO IT CAN BE COMPARED AND FUSED. AND WHAT I'LL SHOW YOU IS RESULTS IN THIS MIDDLE LAYER SO, A 3D RECONSTRUCTION OF THE CONNECT ACTIVITY AND PERMIA ACTIVITY IN THE REGION BETWEEN THE TWO PLATES OF THE COMPRESSED INTEREST COMPUTED AT MULTIPLE FREQUENCIES. SO THEY TAKE THIS DATA BETWEEN 5 KILOHERTZ AND ONE MEGAHERTZ AT DISCRETE FREQUENCIES AND COMPUTE RECONSTRUCTIONS AND THEN COLD COLD PLOTS CONNECTIVITY VERSUS PERMIA ACTIVITY ARE PLOTTED AND IT TURNS OUT THAT THEY HAVE A CERTAIN SIGNATURE WHEN THE TISSUE IS MALIGNANT VERSE WHEN IS IT IS NOT. SO STUDIES OF EXIDES TISSUE IN 1999 IS THE SEMINOLE PAPER BUT THERE HAS BEEN OTHER WORK AS WELL, SHOWING THAT THERE IS A LINEAR RESPONSE TO THE ELECTRIC FEEDS IN THE COAL COAL PLOTS, MULTIFREQUENCY PLOTS, WHEN THE CASH IS MALIGNANT VERSUS A NONLINEAR RESPONSE WHEN IT'S NOT. SO, IN IT PARTICULAR PAPER, THEY LOOKED AT 4 SUBJECTS. THERE WAS A SLIGHTLY LARGER STUDY THAT FOLLOWED IT BUT I PARTICULARLY LIKE THESE PLOTS. I HOPE YOU CAN SEE THEM. WHAT IS SHOWN HERE IS THE MESH AT ONE LAYER BETWEEN THE TWO PARALLEL ELECTRODES ARRAYS AND THEN ZOOMING IN TO SHOW THE COAL COAL PLOTS ON SOME OF THOSE PIXELS BECAUSE YOU CAN PLOT THEM FOR EACH AND EVERY PIXEL BY HAVING THE CONNECTIVITY AND THE PERM ACTIVITY IN EACH OF THE FREQUENCIES. SO IN IT PARTICULAR PATIENT, THEY HAD NORMAL BREAST TISSUE AND YOU CAN SEE THE CURVED COAL COAL PLOTS OF CONNECTIVITY ON THIS AXIS AND PERM ACTIVITY ON THIS AXIS. SO EACH POINT REPRESENTS THE DATA AT ANOTHER FREQUENCY. OKAY, PATIENT TWO R HERE RECEIVED A BIOPSY AND THEIR TISSUE TURNED OUT TO BE BENIGN. IT WAS A FIBROADENOMA AND AGAIN IN THIS SUSPICIOUS REGION YOU CAN SEE THE NONLINEAR RESPONSE TO THE ELECTRIC FIELDS. AND THIS PLOT DOWN HERE HOWEVER, THIS PATIENT WAS BIOPSIED AND FOUND TO HAVE INVASIVE DUCTAL CARCINOMA AND THE PLOTS ARE MUCH MORE LINEAR. IN THIS REGION WHERE THE TISSUE IS NORMAL, YOU CAN SEE THAT CHARACTERISTIC CURVED SHAPE BUT HERE YOU HAVE A MUCH MORE LINEAR RESPONSE. AND FINALLY, THIS ONE ALSO HAD INVASIVE DUCTAL CARCINOMA IN A MORE WIDESPREAD REGION AND YOU CAN SEE THE LINEAR RESPONSE. SO, THESE FREQUENCY RESPONSES I THINK SHOW A LOT OF PROMISE FOR TISSUE CHARACTERIZATION. NEONATAL IMAGING. ONE OF THE REASONS I INCLUDED THIS WAS TO ADDRESS THE ISSUE OF SAFETY WHICH IS OF COURSE OF PARAMOUNT IMPORTANCE. EIT HASN'T BEEN TESTED FOR FETAL IMAGING BUT IT HAS BEEN USED FOR NEONATAL IMAGING. SO CRITICAL ILL NEONATES TYPICALLY REQUIRE VENT SUPPORT. WE SAW IN THE OPENING TALK BY DR. SPONG. SO, PROBABLY CAROLINE WAS ON A VENTILATOR FOR SEVERAL WEEKS OR -- I CAN'T REMEMBER HOW MANY WEEKS EARLY SHE WAS. SHE WAS BORN AT 30 WEEKS YOU SAID? SO MAYBE SIX WEEKS OR SO ON A VENTILATOR. AND THEIR IMMATURE LUNG TISSUE IS VERY VULNERABLE TO CHRONIC LUNG DISEASE AND IRREVERSIBLE DAMAGE THAT CAN CAUSE A LIFETIME OF PROBLEMS. AND BOTH VENTILATOR AND THE PATHOLOGIES THEY HAVE CAN CAUSE REGIONAL DIFFERENCES IN THEIR VENTILATION. SO, IT IS DESIRABLE TO SEE THESE SO THAT THE TECHNICIANS AND THE DOCTORS CAN RESPOND TO GIVE A PERSONIDES VENTILATION STRATEGY TO CAREFULLY SET THE SEPTEMBER LATERS AND PROTECTIVE STRATEGIES SO AS NOT TO OVER STRESS THE LUNGS AND NOT TO HYPERINFLATE AND THE NOT CAUSE CYCLIC COLLANS AND INFLATION THAT CAN CAUSE PERMANENT DAMAGE. SO THIS FIGURE FROM THIS PAPER BELOW. IT'S NOT MY OWN WORK BUT I THINK IT IS VERY PROMISING. I SHOWED YOU WHAT THIS IS A MOMENT AGO BUT YOU CAN SEE A VIDEO OF IT. THAT'S THE BIG INHALE AND THE EXHALE, EXHALE, AS HARD AS THEY CAN. THERE IS INNOCENTIST ON THE MONITOR SUCH AS BLOWING OUT CANDLES OR SOMETIMES THERE IS FIREWORKS. AND BECAUSE THEY HAVE GOT THIS TUBE OVER THEIR NOSE AND AROUND THEIR MOUTH, NO AIR ESCAPES THEY CAN GET A GOOD READING OF THE VOLUME. SO NOW I HAVE A VIDEO I'D LIKE TO SHOW YOU. HERE COMES THE AMBIGUOUS BREATH IN, INHALE, NOW EXHALE LONG AND HARD. AND YOU CAN SEE SOME REGIONAL INFORMATION HERE. WE CAN DERIVE MORE BY DOING SOME SEGMENTATION AND SECONDARY ANALYSIS. SO THE EXHALE IS VERY LONG TO BREATHE LONG AND HARD OUT AS LONG AS YOU POSSIBLY CAN UNTIL THERE IS NO AIR LEFT AND THEN YOU CAN BREATHE BACK IN AND BREATHE NORMALLY. OKAY. SO THIS PARTICULAR PATIENT WAS NOT HOSPITALIZED. THEY ARE IN FOR ANNUAL VISIT BUT THEY HAD AIR TRAPPING IN ONE OF THEIR LUNGS. I WANT TO MAKE SURE THEY HAVE TIME TO SPECULATE A LITTLE BIT ON THE POTENTIALS FOR PLACENTAL IMAGING. SO SOME THINGS I SAW AS POSSIBLE APPLICATIONS OF THIS TECHNOLOGY WOULD BE TO DETERMINE THE PLACENTAL POSITION. I KNOW THAT CAN ALSO BE DONE THROUGH ALL THERA SOUND. BUT -- ULTRASOUND -- ESPECIALLY WITH INTERIOR PLACENTAS, THEY WOULD BE THE LOW-LYING FRUIT AGAIN BECAUSE THEY ARE SO ACCESSIBLE. ELECTRODES PLACED ON THE FRONT OF THE STOMACH CAN EASILY PROVIDE CURRENT THAT WOULD PENETRATE THE PLACENTA AND ONE COULD DETERMINE I BELIEVE, REGIONAL PROFUSION INFORMATION FROM THAT DATA IN THREE DIMENSIONS. DETECTION OF AB PRESUMPTION IN IMPLANTATION ISSUES ARE A POSSIBLY. AND MAYBE EARLY DETECTION OF PREECLAMPSIA. SINCE THAT IS IS A PROFUSION ISSUE THAT MIGHT BE SOMETHING THAT CAN BE DETECTED EARLY ON WITH THIS TECHNOLOGY. I'M SPECULATING. SAFETY IS REALLY IMPORTANT OF COURSE AND I'M NOT SURE WHAT KIND OF ANIMAL MODELS ARE AVAILABLE IF ARE THIS. I KNOW THEY DIFFER VERY MUCH FROM DIFFERENT SPECIES SO I WOULD BE INTERESTED IN TALKING WITH PEOPLE ABOUT THAT. WAWOULD BE A GOOD FIRST STEP THERE? AND HERE IS A PICTURE OF PLACENTAL AB ERUPTION I THOUGHT MIGHT BE ENLIGHTENING BECAUSE OF THE FACT THAT BLOOD SAID SO CONDUCTIVE IT IS VERY STRAIGHTFORWARD TO GET THAT KIND OF IMAGE. SO THANK YOU VERY MUCH. I'M HAPPY TOP HAVE YOUR ATTENTION. THANK YOU FOR YOUR TIME. [ APPLAUSE ] >> ANOTHER SORT OF NOVEL TECHNOLOGY TO THINK ABOUT. WE HAVE TIME FOR JUST A COUPLE OF QUESTIONS. >> HELLO. I'M A PATHOLOGIST SO I SEE BREAST CANCER EVERY DAY. ON YOUR CONDUCTANTS CURVES WHEN YOU'RE SCREENING FOR BREAST CANCER VERSUS FIBROADENOMA, COULD YOUR CURVE SHAPE BE DEPENDENT ON WHAT YOU'RE GAINING ON OR IS THAT CURVE SHAPE DEPENDING UPON THE CONDUCTANT THROUGH THE WHOLE BREAST. >> THE PLOTS THAT ARE SHOWN ARE PIXEL BY PIXEL. NOW DEPENDING ON WHAT KIND OF RECONSTRUCTION ALGORYTHM YOU USE, IT MAY OR MAY NOT BE INFLUENCED BY NEIGHBORING PICTURE ILS. >> I NOTICED YOU WERE DRAWING BOXES AROUND THE STRUCTURES. ARE YOU GATING ON SOMETHING THAT IS CREATING YOUR CURVE. >> NO NO GATING. SO I DIDN'T CREATE THOSE BUT I'M QUITE FAMILIAR WITH THAT WORK AND HOW IT WOULD BE DONE. SO IT'S NOT GATED. THEY ARE INDEPENDENTLY RECONSTRUCTING THE CONTEXT AND I HAVE PERM ACTIVITY IN EACH PIXEL. >> IF YOU'RE LOOKING AT INNOVATIVE DUCTAL PLASTIC STROMA VERSUS A FIBROADENOMA AND GLANCED AND DENSE TISSUE. YOU WOULDN'T EXPECT TO CONDUCTANTS TO BE DIFFERENT UNLESS ITS FIBROADENOMA IS IN THE BACKGROUND OF FAT, THEN YOU EXPECT THE CONDUCTANTS TO BE DIFFERENT. SO IT MIGHT BE JUST BE WHAT THE BACKGROUND MILL YOU IS OF YOUR DISTINCT MODULE. >> YES. I THINK FURTHER STUDIES WOULD BE WARRANTED. AND IN THOSE PARTICULAR ONES, THE -- IT'S TECHNICAL ON HOW THE RECONSTRUCTION ALGORIYHM WORKS BUT THAT ONE DOES INVOLVE NEIGHBORING PIXELS SO THEY COULD BE INVOLVED. >> THANK YOU FOR YOUR TIME. >> I HAVE A QUESTION ABOUT THE MECHANICS OF HOW YOU GET TO A 3D IMAGE. BECAUSE ESSENTIALLY YOU'RE GETTING A 2D RECONSTRUCTION IN THE PLANE DEFINED BY THE BELT. >> RIGHT. SO -- >> DO YOU HAVE TO MOVE THE BELT? >> THE ONES I HAVE SHOWED YOU, THERE WAS JUST A SINGLE BELT AND SO IT IS JUST IN THE PLANE OF THE ELECTRODES BUT YOU CAN HAVE MULTIPLE BELTS AND DO IT THAT WAY. >> NO CROSS TALK BETWEEN THE BELTS? >> THERE IS THE ISSUE OF OUGHT OF PLAIN CURRENTS AND YOU HAVE TO WATCH FOR THAT. BUT THE IDEAL WAY TO DO THAT IS TO APPLY CURRENT AND DO A FULL 3DD RECONSTRUCTION SO NOT TREAT EACH BELT AS A SEPARATE PLANE BUT DO A RECONSTRUCTION OF THE WHOLE REGION AS A WHOLE ALLOWING CURRENTS TO FLOW OUT OF THE PLANE AS THEY WOULD. DOES THAT HELP? AND YOU MEASURE THE VOLTAGE ON ALL THE ELECTRODES SO SURRUNEDDING AND SAME IN THE PARALLEL PLATE GEOMETRY. >> SO RECONSTRUCTION ALGORIYHM FOR OUT OF PLANE MOVEMENT IS THAT WHAT YOU'RE SAYING. >> I COULDN'T HEAR NEW SO REDOING THE RECONSTRUCTION ALGORIYHM TO ALLOW FOR OUT OF PLANE OCCUR INCIDENTS. >> IT'S A DIFFERENT ALGORIYHM. IT'S DIFFERENT FROM THE 2D TO ALLOW THE FULL 3D FREEDOM OF MOVEMENT OF THE CURRENT. >> CONTRAST BETWEEN AIR AND WATER BASED TISSUES AND I'M CURIOUS IF YOU CAN COMMENT ON THE TYPES OF LIKE SOFT WATER-BASED TISSUE CONTRASTS THAT YOU'RE ABLE TO RESOLVE WITH EIT, FOR EXAMPLE LIKE WOULD YOU BE ABLE TO SEE AMNIOTIC FLUID VERSUS MUSCLE FOR EXAMPLE? >> SO IT HAS NEVER BEEN TESTED IN FETAL IMAGING OR PLACENTAL IMAGING OR ANY OF THAT. BUT, I SPECULATE THAT YES, YOU WOULD BE ABLE TO SEE THE DIFFERENCE. IT'S KIND OF LIKE THE PARALLEL WOULD BE TO ULTRASOUND. YOU'RE FORTUNATE TO HAVE A REGION THERE, THE AMNIOTIC FLUID WHICH IS HIGHLY ACOUSTIC CONDUCTIVE. SAME THING FOR EIT. IT'S HIGHLY ELECTRICALLY CONDUCTIVE. IT'S GREAT. RATHER THAN IF YOU HAD A BIG RESISTER IN THERE IT WOULD BE MUCH MORE DIFFICULT. >> THANK YOU. [ APPLAUSE ] >> SO THAT WAS GREAT AND NOW WE'RE GOING TO GO OFF IN A SLIGHTLY DIFFERENT DIRECTION AND WE ARE GOING TO HAVE YOEL SADVOSKY FROM UNIVERSITY OF PITTSBURGH TALKING ABOUT PLACENTALY DERIVED SUBSTANCES AS WINDOWS INTO PLACENTAL DEVELOPMENT AND FUNCTION. >> THANK YOU VERY MUCH, DAVID. GREAT TO BE HERE. DAVID ASKED ME OVER 10 MINUTES TO TALK BRIEFLY ABOUT PLACENTAL SUBSTANCES SO I'M NOT GOING TO TALK ABOUT OUR OWN REACH BUT JUST TO GIVE YOU A PRELUDE TO THESE CHEMICALS AND OTHER MOLECULES WE CAN MEASURE AS A INDICATOR OF PLACENTAL HEALTH. AND HOPEFULLY TALK JUST NOT ABOUT THOSE WHAT THEY ARE BUT ALSO A FEW THERAPY PITFALLS AND ALSO WILL BE A PRELUDE TO TONY, AND WE COLLABORATE. TONY WILL GIVE A MUCH MORE COMPREHENSIVE TALK ABOUT OUR TECHNOLOGY. SO, I JUST WANTED TO REMIND EVERYBODY THAT CHEMICALS THAT ARE PRODUCED BY THE PLACENTA WERE NOT DESIGNED NECESSARILY TO SERVE AS BIOMARKERSER FOR DIAGNOSTIC PURPOSES. THEY ARE SHAPED BIOLOGY AND AS WE TALK ABOUT THE HPP, IT'S IMPORTANT FOR US TO REMEMBER THAT AS WE TALK ABOUT DIAGNOSIS AND A WINDOW TO UNDERSTAND THE PLACENTA, THIS CHEMICALS HAVE PATHOPHYSIOLOGICAL FUNCTION AND ALSO SOME OF THEM AS WE HEARD THIS MORNING ALREADY, CAN SERVE AS THERAPEUTIC TOOLS TO POTENTIALLY AMEND INJURIES OR EVEN CORRECT INJURIES IN THE PLACENTA. SO THE CHEMICALS ARE GOING TO BE RELEASED WITHIN THE PLACENTA. SOME OF THEM MAY TRAVEL INTO THE FETUS AND MAJORITY WILL PROBABLY TRAVEL INTO MATERNAL TISSUES AND SHAPE THEM PHYSIOLOGICALLY AND PATHOPHYSIOLOGICALLY TO AS PART OF NORMAL PREGNANCY OR DISEASE. AND WHEN WE THINK ABOUT WHERE THESE CHEMICALS TRAVEL TO OR TRAFFIC TO, IF THEY ARE MADE IN THE TROPHOBLAST, THEY ARE NATURALLING GE TO TRAVEL INTO THE MATERNAL CIRCULATION BECAUSE THE TROPHOBLAST IN THE HUMAN AND IN THE MOUSE IS BATHED IN MATERNAL BLOOD SO IT IS QUITE NATURAL FOR US TO EXPECT THE CHEMICALS, VESICLES, NUCLEIC ACIDS RELEASED FROM TROPHOBLASTS TRAVEL INTO MATERNAL BLOOD. IF CHEMICALS OR SUBSTANCES RELEASED FROM THE TROPHOBLASTS, IN A HUMAN HERE, OR IN A MOUSE HERE, THEY HAVE A MUCH MORE DIFFICULT PATHWAY TO TRAVERSE THE BASEMENT MEMBRANE YOU CAN SEE HERE OR NEAR A MOUSE AND TRAVERSE IN THE CELLS IN A HUMAN AND HERE IN A MOUSE BEFORE THESE CAN BE FOUND IN CIRCULATION. SO BECAUSE WE ARE DEALING ABOUT EASE OF AXIS INTO MATERNAL BLOOD AND BECAUSE THIS MEETING IS ABOUT DIAGNOSIS AND UNDERSTANDING CHEMICALS AS A WINDOW TO UNDERSTAND PLA SENTAL FUNCTION, WE MAINLY FOCUS ON THOSE CHEMICALS RELEASED INTO THE MATERNAL CIRCULATION BUT WE HAVE TO REMEMBER THEY ARE ALSO RELEASED ELSEWHERE. SO, THIS IS A CARTOON FROM ONE OF OUR RECENT REVIEWS SHOWING HOW CHEMICALS AND VESICLES CAN BE ERASED FROM THE PLACENTA AND THE MOST INVESTIGATED WAY IS BY RELEASE OF PROTEINS, GLYCOPROTEINS AND OTHERS DIRECTLY THROUGH THE MEMBRANE AND BECOME FREE HORMONES AND CHEMICALS WE CAN MEASURE AND THOSE MEASURED OVER MANY YEARS. IN ADDITION IN THE LAST SEVERAL YEARS, WE FOUND THE PLACENTA MAKES FREE CHEMICALS AND SUBSTANCES BUT ALSO VESICLES OF DIFFERENT TYPES CONTAIN PLACENTAL CONTENT AND CAN POTENTIALLY SHAPE MATERNAL FIZZ OLE AND RISK DISEASE. SOME OF THEM ARE BODIES ORGANISMS CONTAIN WHATEVER GETS FRACTURED AND CONTAINED WITHIN THEM. SOME OF THEM ARE MICROVESICLES THAT ARE THE SMALLER ONES AND THEY ARE RELEASED TO THE CIRCULATION THROUGH BUDDING WITH A PIECE OF THE CELL MEMBRANE N THIS CASE, A TROPOPLAST AND ALSO EXOSOMES THE SMALLEST ONES MEASURING NANONEARLY DIAMETER IN AVERAGE AND THEY ARE FORMED WITHIN PARTICULAR BODIES IN THE CELLS AND CONTAIN NEW CLAYIC ACID PROTEINS AND OTHER PRODUCTS WE MAY BE INTERESTED IN CAPTURING AND MEASURING. SO, THIS IS SOME EXAMPLES OF BIOCHEMICAL MARKERS THAT MANY OF US IN THE AUDIENCE HAVE BEEN USING CLINICALLY TO ASSESS FEELS GENOME GENETIC CHANGES AND ALSO PLACENTAL HEALTH FROM THE PROTEIN, ACG DERIVATIVES, OTHER HORMONES LIKE HPL, AND ALSO SPECIFIC PLACENTAL PROTEINS, SOME OF THEM WE HAVE NOT EVEN FULLY INVESTIGATED BUT THEY SEEM TO INDICATE PLACENTAL HEALTH AND DISEASE AND ALSO INDICATE POTENTIAL CONDITIONS THAT AFFECT THE FETUS AND MAYBE OTHER MARKERS SIMPLER CHEMICALS SUCH AS LACTATE WHICH ARE LARGELY DILUTED BY OTHER TISSUES THAT MAKE THOSE CHEMICALS BUT MAY POTENTIALLY IN EXTREME CASES SERVE AS INDICATORS OF PLA SEVEN. AL HEALTH N SPECIFIC SITUATIONS SUCH AS PREECLAMPSIA AND OTHER DISEASES, SOME OTHER FACTORS SUCH AS ANGIOGENIC FACTORS IN RECENT YEARS HAVE RECEIVED SIGNIFICANT ATTENTION LIKE VGF, PLACENTAL GROWTH FACTOR AND SOLUBLE RECEPTOR PRODUCED BY TROPHOBLASTS MAY INDICATE PLACENTAL DYSFUNCTION AND BEING INVESTIGATED INTENSELY BY NUMEROUS LABS. UNFORTUNATELY OTHER TISSUES AND SOME PEOPLE HERE IN THE AUDIENCE CONTRIBUTED TO STUDIES SHOWING SOME OF THESE MARKERS ARE MADE BY OTHER TISSUES AND THEREFORE NOT SPECIFIC TO PLACENTA BUT MAY STILL INDICATE WHEN THE PLACENTAL FUNCTION BECOMES EXTREME, MAY STILL INDICATE PLACENTAL HEALTH IN DISEASES SUCH AS PREECLAMPSIA. WORK FROM STAN FORMED PUBLISHED FROM STEVEN QUAKE'S LAB TWO YEARS AGO SHOWING THAT A LARGE PERCENT EVER PLASMA CAN BE FOUND IN PLASMA -- NOT ONLY MATERNAL RNA BUT ALSO FETAL DNA. AS WE ADVANCE IN TRIMESTERS DURING PREGNANCY, THE AMOUNT OF FETAL, WHICH USUALLY MEANS PLACENTAL ALMOST EXCLUSIVE LOO, THE AMOUNT OF FEELS PLACENTAL RNA INCREASES DURING PREGNANCY FROM .4% IN THE FIRST SEMESTER UP TO 15% COMING FROM THE FEELS PLACENTAL UNIT AND MAY INFORM PLACENTAL HEALTH. THE PECKAGES ALSO CONTAIN SOME OF THE THESE AND OTHER INFORMATION AND THIS IS AN EXAMPLE FROM OUR LAB THAT WE DID OR CAPTURED SPECIFICALLY PLACENTAL VESICLES COMING FROM TROPHOBLASTS CELLS. YOU CAN SEE THE NANOMETER SITES EXOSOMES, LARGER MICROVESICLES AND THE LARGER APOPTOTIC BODIES. Y WOO CAN MEASURE THEM AND THE AMOUNTS AND PUTERY AND ALSO THIS SPECIFIC CASE IS A NICE ILLUSTRATION FROM OUR LAB SHOWING THAT IF WE CORRELATE THE CONTENT OF THIS CASE MICRORNAs IN TROPHOBLAST CELLS VERSUS CONTENT IN DIFFERENT VESICLES, THE CORRELATION WAS EXCELLENT IN THE APOPTOTIC BODIES IN MICROVESICLES AND EXOSOMES BUT NOT SO GREAT IN PROTEIN-BOUND FREE NONPACKAGED CONTAINERS INDICATING THAT THE MICRORNAs MEASURED BY PROTEINS ARE NOT AS ACCURATELY REFLECTING TROPHOBLAST CELLS AS COMPARED TO WHAT WE CAN FIND IN VESICLES. WHICH SUGGEST TO US AND THAT IS TRUE FOR OTHER SUBSTANCES THAT WHATEVER GETS IN PACKAGE IN VESICLES GETS PROTECTED AGAINST THE DEGRADATION AND MAY POTENTIALLY DIRECTLY REFLECT MORE ACCURATE FASHION THE HEALTH OF TROPHOBLAST CELLS IN CULTURE AND ALSO POTENTIALLY IN-VIVO. THIS HEAT MAP ALSO SHOWS EXCELLENT CORRELATION BETWEEN TROPHOBLAST CELLS AND DIFFERENT PACKAGED MICROVESICLES -- microRNAs COMPARED TO WHAT CAN BE FOUND IN PLASMA. THESE VESICLES AND THE CHEMICALS PACKAGED WITHIN THEM ARE NOT JUST FOR PLACENTAL HEALTH. THEY HAVE A FUNCTION. IN OUR LAB TWO YEARS AGO ONE OF THE FUNCTIONS WAS ANTIVIRAL AFFECT OF SOME OF THESE EXOSOMES WHICH EMERGE FROM TROPHOBLASTS GET TO RECIPIENT CELLS AND STIMULATE ANTIVIRAL RESPONSE AND DEGRADATION OF VIRAL VESICLES AND RECENTLY TWO WEEKS AGO, WE PUBLISHED AN ADDITIONAL PAPER SHOWING VESICLES AND OTHER CHEMICALS SUCH AS INTERFERONS HAVE VERY SPECIFIC ACTIVITY AGAINST VIRUSES INCLUDING ZIEKA VIRUS TO ATTENUATE INFECTION OF TROPHOBLAST CELLS. SO THESE CHEMICAL SUBSTANCES READS LEADS ARE VERY IMPORTANT DIAGNOSTICALLY BUT SOME ARE DISCRETE FUNCTION. SO I WANT TO JUST CONCLUDE WITH A FEW SLIDES TALKING ABOUT SOME OF THE HURDLES WE FACE WHEN WE MEASURE SUBSTANCES. THIS IS RNA-SEQ PROFILING QUI IN OUR LAB FOR microRNAs FOUND IN MATERNAL CIRCULATION COMPARED TO FETAL CIRCULATION AND ON THE X AXIS LOOK AT 25 SUBJECTS. Y AXIS LOOKS AT THE LEVEL. THE LEVELS WERE ALL OVER THE PLACE. MOST IN THE MA TERNITY CIRCULATION BUT STILL QUITE VARY ABLE IN THE FIELD CIRCULATION. SO WE THINK THE VARIABILITY GREATLY CONTRIBUTE TO IN 80 TO USE MANY SUBSTANCES TO INFORM PLACENTAL HEALTH. EACH ONE OF THESE ON THE X AXIS IS ONE INDIVIDUAL. SO AS YOU CAN SEE FOR EXAMPLE, IN THIS INDIVIDUAL, ALL OF THE MARKERS ARE THE EVALUATED AND THE SAME KIND OF PATTERN IN MATERNAL PLASMA. SO TO DEPICT IN A DIFFERENT WAY. IF YOU LOOK AT INDIVIDUALS IN EACH LINE HERE REFLECTS A HYPOTHETICAL INDIVIDUAL, THAT YOU WILL THOUGH EACH AREA IS VERY DIFFERENT CONTRIBUTING TO THE VARIABILITY, WHEN YOU LOOK AT THE RATIOS OF THESE ANNA LIGHTS WITHIN EACH INDIVIDUAL, THEY ARE QUITE PRESERVED. WHICH IMPLIES AND NOW GENERALIZING FOR OTHER SUBSTANCES IF YOU WANT TO MEASURE THEM, YOU HAVE TO EITHER NORMALIZE WITH SOMETHING THAT DOESN'T CHANGE OR LOOK AT RATIOINGS AND LOOK AT HOW RATIOS CHANGE AMONG microRNAs OR AMONG OTHER ANNA LIGHTS TO BE ABLE TO INFORM HOW THEY CAN POTENTIALLY REFLECT PLACENTAL FUNCTION. microRNAs ARE NOT ONLY TYPES CONTAINED IN VESICLES. OTHER TYPES SUCH AS LINK NONCODING RNAs AND CIRCULAR RNA WAS. THEY ARE NOT PACKAGED PASSIVELY. THERE IS AN ACTIVE PROCESS THAT LEADS TO DIFFERENT LEVELS OF THE RNA MOLECULES IN DIFFERENT TYPES OF VESICLES. RIGHT NOW WE DON'T KNOW WHAT LEADS TO THIS SPECIFIC PACKAGING BUT THOSE PACKAGES AND THE WAY THINGS ARE PACKAGED, THE VESICLES, MAY POTENTIALLY BE PART OF A NORMAL PHYSIOLOGY OR ALSO PATHOLOGY. SO JUST TO SUMMARIZE SOME OF THE ISSUES THAT LEAD TO THE PITFALLS AND MEASUREMENTS INCLUDING BIOLOGICAL REPLICATES OR LACK OF THEM, HOW DO WE NORMALIZE DIFFERENT TISSUES? NORMALIZING IN BLOOD AND TISSUES IS VERY DIFFERENT. HOW DO WE COLLECT AND WHICH DISEASE WE ARE ACTUALLY INVESTIGATING. WHICH LEADS TO A VERY SIMPLE PRINCIPLE. I'LL FINISH WITH THIS. THIS IS VERY SIMPLE PRINCIPLE. IF YOU WANT TO MEASURE THINGS THAT ARE CIRCULATING IN THE BLOOD, IF THERE IS A WAY TO CLEARLY IDENTIFY THEM THEN IT IS NOT A PROBLEM. YOU CAN FIND THAT WAY TO CLEARLY IDENTIFY THEM AND POTENTIALLY USE THAT FEATURE TO BE ABLE TO CONDUCT THE MEASUREMENTS. FOR EXAMPLE, AS TONY WILL TALK ABOUT VERY SOON, IF YOU CAN FIND A WAY TO TAKE THOSE VESICLES, WHATEVER THEY ARE, AND ISOLATE THEM, THEN WE CAN HAVE A MEASURE OF PLACENTAL FUNCTION IN A TEST TUBE WE GET. NOW, IF THOSE PACKAGES ARE UNIQUE TO THE PLACENTA, AND CONTAIN CHEMICALS THAT ARE ONLY APPEARING IN THE PLACENTA, IT MAY BE IMPORTANT FOR US TO ISOLATE BECAUSE THEY ARE ONLY COMING FROM THE PLACENTA AND WHATEVER WE MEASURE IN THE BLOOD, EVEN IN THE MIX WILL BE ONLY REFLECTIVE OF THE PLACENTA. USUALLY, THOSE CHEMICALS ARE NOT COMING ONLY FROM THE PLACENTA. BUT REPRESENTS MANY OTHER TISSUES SO THEREFORE ISOLATION PROVIDES A GREAT LEVEL OF ACCURACY AND ALSO SPECIFICITY. THANK YOU VERY MUCH AND TONEY IS PART OF OUR GROUP HERE. THIS IS TONY AND WE ARE GOING TO TALK ABOUT OUR SHIRT PROJECT WITH OTHER INVESTIGATORS WHERE WE LOOK AT THE VESICLES. SHOULD I TAKE QUESTIONS? >> YES, PLEASE. [ APPLAUSE ] >> FIRST I WANT TO SAY THAT WAS A WONDERFUL TALK. SO I HAVE A QUESTION. YOU SHOWED THE RATIOS AND I THINK THAT USING RATIOS TO NORMALIZE IS REALLY INTERESTING. IF YOU LOOK AT HEALTHY VERSUS PATHOLOGICAL CONDITIONS, DO YOU SEE RATIO CHANGES. >> YES SO DAVID IS ASKING SPECIFIC ABOUT RATIOS OF ANNA LIGHTS IN OUR CASE WE DID IT TO microRNAs AND THE ANSWER IS YES. WE SAW DIFFERENCES IN A RATIOS WHEN YOU LOOK AT DISEASE STATES OR INJURED TROPHOBLAST CELLS. THAT WILL BE A MORE SOPHISTICATED WAY TO LOOK AT ANALYZING AS OPPOSED TO SINGLE MEASUREMENT IN A SINGLE INDIVIDUAL. >> GREAT. SO, FOLLOWING THAT INTRODUCTION NOW WE'LL HEAR SOME MORE IN-DEPTH OF THE TECHNOLOGY WITH DR. TONY WANG WHO WILL TALK ABOUT ACOUSTIC TWEEZERS MANIPULATING CIRCULATING FACTORS AND OTHER TINY ON JECT USING SOUND WAVES. >> THANK YOU VERY MUCH AND GREAT TO BE HERE. SO TODAY I'M GOING TO SHARE WITH YOU TECHNOLOGY DEVELOPED IN OUR LABORATORY AND ALSO IN COLLABORATION WITH OUR COLLABORATORS WHICH WE BELIEVE ARE VERY USEFUL FOR PLACENTA HEALTHING. AND THIS TECHNOLOGY IS CALLED ACOUSTIC TWEEZERS. IT CAN USE SOUND WAVESES TO MANIPULATE FACTORS AND OTHER TINY OBJECTS. BEFORE I SHARE WITH YOU OUR ACOUSTIC TWEEZERS, I LIKE TO SHARE SOME EXAMPLES. MY FAVORITE SOCCER TEAM WAS BRAZILIAN NATIONAL DISPEOPLE MY FAVORITE PLAYER WAS ROBERTO CARLOS. HE IS EXTREMELY GOOD IN DOING [ INDISCERNIBLE ] SO I'M GOING TO SHOW YOU BEND FREE KICK HE DID IN A MATCH BETWEEN BRAZILIAN NATIONAL TEAM AND A FRENCH NATIONAL TEAM. IT IS THE CURVE. WE CAN WATCH IT AGAIN. BELIEVE ME. THIS VIDEO IS SO MUCH BETTER THAN THE REST OF MY PRESENTATION SO PLEASE ENJOY. [ LAUGHS ] SO THERE IS NO WAY FOR PEOPLE LIKE US TO DO SUCH A BEAUTIFUL BENDY FREE KICK. WE CAN DO SOMETHING HE CANNOT DO. SO THIS IS A MICROFLUIDIC CHIM CHIP THAT WAS GOING ON THE SOCCER FIELD. THIS IS WHAT A JOB REPRESENTS A SOCCER BALL AND THIS TRIANGLE REPRESENTS BRAZILIAN PLAYER AND THIS GUY IS ROBERTO CARLOS AND THEN THEY ARE HERE AND THE ACOUSTIC TRANSDUCER HERE DRIVES THIS KICK. SO, THE TAKE HOME MESSAGE IS, IF WE DO IT RIGHT, IF WE KNOW HOW TO DO IT ISSUE YOU CAN USE ACOUSTIC WAVE TO PRECISELY MANIPULATE TINY OBJECTS. THAT IS ONE FINE EXAMPLE. AND THE SECOND EXAMPLE WE DO SINGLE PILOT MANIPULATION. THIS IS A CHIP WE FABRICATED AND PUT A DROP OF PARTICLE SOLUTION INTO THIS MICROFLUIDIC CHANNEL AND WE HAVE ACCUSIST TRANSDUCERS. WE CAN MOVE A SINGLE PARTICLE. AND WE CAN CHOOSE HOW BIG THE DEVICE IS. AND I COME FROM THE PENNSYLVANIA STATE UNIVERSITY. PSU. SO WE WRITE PSU. [ LAUGHS ] WE ALSO WRITE SOMETHING MORE COMPLEX AND THAT WAS A JOURNAL WE FIRST SUBMITTED OUR PAPER TO. AND IT WAS DECLINED. [ LAUGHS ] SO WE CHANGE TO A DIFFERENT JOURNAL. SO, THE REASON WHY WE WRITE TO NATURE WE WANT TO PLEASE EDITORS. VERY IMPORTANT TO PLEASE EDITORS OTHERWISE THEY WOULDN'T SEND OUT FOR REVIEW. BUT WE ALSO HAVE OTHER REASONS TO DO IT. WE WRITE PSU AND ONLY NEED TO WRITE ALONG X AXIS OR Y AXIS BUT WE WRITE MATCH, WE HAVE TO WRITE LONG. IF THERE IS A NEED TO WRITE A LONG TIER, WE CAN DO THAT. SO THOSE ARE THE FINE EXAMPLES. BUT THEN I'M GOING TO OCCUR QUESTION WHY DO YOU DEVELOP ACOUSTIC TWEEZERS? WHY USE SOUND WAVE TO MANIPULATE TINY OBJECTS? I REALIZE A LOT PEOPLE HERE ARE EXPERTS ON IMAGING. I DON'T DO IMAGING BUT I DECIDED TO USE A EXAMPLE IMAGING TO ILLUSTRATE WHY WE USE SOUND WAVE TO MANIPULATE TINY OBJECTS? IMAGING IS NOT THE MOST POWERFUL HIGH RESOLUTION IMAGING IN THE WORLD. HOWEVER, IF ULTRASONIC IMAGING CAN GET THE JOB DONE, GET THE KIND OF INFORMATION YOU NEED, A LOT OF PEOPLE WOULD LIKE TO USE ULTRASONIC IMAGING FOR TWO REASONS. NUMBER 1, ULTRASONIC IMAGAING IS VERY COMPACT, VERY, VERY IN EXPENSIVE. IT IS ONLY COST 10,000 DOLLARS A FEW THOUSAND DOLLARS? IT DOESN'T COST $500,000. THE NURSES CAN PUT ULTRASONIC IMAGING DEVICE INTO THEIR POCKET BECAUSE IT'S AS SMALL AS YOUR CELL PHONE AND LAPTOP. AND MANY OTHER TECHNOLOGIES CANNOT DO THIS. NUMBER 2 IT IS VERY GENTLE. USED BY HALF OF THE POPULATION IN THE WHOLE WORLD FOR HALF A CENTURY. PREPRETTY MUCH NO SIDE EFFECT EVERY REPORTED. SO WE USE SIMILAR ACOUSTIC POWER AND SIMILAR FREQUENCY AS ULTRASONIC IMAGING. THEN YOU WILL KNOW THERE IS VERY LIKELY YOU WILL GET THE TWO ADVANTAGES AS ULTRASONIC. NUMBER 1 ADVANTAGE IS VERY COMPACT, VERY IN EXPENSIVE AND NUMBER 2 IS VERY GENTLE. WHATEVER BIOSUBSTANCE OBJECTS, BIOPARTICLES, YOU LIKE TO MANIPULATE, YOU DO NOT CHANGE ITS PROPERTIES WHICH CAN BE VERY IMPORTANT FOR SOME APPLICATIONS. SO, TO TODAY I'M GOING TO SHARE, FIRST THREE FACTORS WE USE TO USE OUR ACOUSTIC COUNTRIES TOURS MANIPULATE. NUMBER 1 IS TUMOR CELLS AND NUMBER 2 IS [ INDISCERNIBLE ] NUMBER 3 IS VESICLES. I WILL START WITH THE FIRST ONE. SEPARATING TUMOR CELLS. IT IS A IMPORTANT TARGET FOR CANCER AS WE TRY TO UNDERSTAND TRY TO BETTER DIAGNOSIS AND TREAT CANCER. BUT THEY ARE VERY DIFFICULT TO SEPARATE BECAUSE THEY ARE VERY RARE. YOU ONLY GET ONE-TO-ONE00 OUT OF ONE MILLILITER OF BLOOD. WE DEMONSTRATED WE CAN USE ACOUSTIC TO DO IT. SO HERE WE USE A VERY CONCENTRATED CANCER CELL LINE TO DEMONSTRATE IT WORKS. SO BECAUSE CANCER CELLS ARE BIGGER THAN WHITE AND RED BLOOD CELLS, THEY GO TO DIFFERENT OUTLETS. WE CAN SEPARATE THEM. ONCE WE DEMONSTRATE OUR DEVICE WORKS FOR CELL LINE, THEN WE DIRECTLY WORK WITH HUMAN CANCER PATIENTS BLOOD SAMPLES. WE DEMONSTRATED TO ISOLATE SEPARATING TUMOR CELLS AND WE DEMONSTRATE OUR DEVICE WORKS FOR BREAST CANCER, FOR PROSTHETIC CANCER AND OVARIAN CANCER. THERE ARE MANY TECHNIQUES THAT CAN ISOLATE SEPARATING TUMOR CELLS. WHY DO WE USE ACOUSTIC? WE BELIEVE OUR TECHNOLOGY HAS ADVANTAGES TO PRESERVE THIS CELL INTEGRITY. OUR TECHNOLOGY DO NOT ALTER THE PROPERTY OF THE CELLS. WHICH IS IMPORTANT BECAUSE ALL THE INFORMATION YOU LIKE TO GET FROM THE CELLS REGARDING THAT YOU CAN USE FOR DIAGNOSIS OR TREATMENT IS ENCODED IN THE CELL. IF WE CHANGE THE PROPERTY, THEN YOU LOSE A LOT OF INFORMATION OR YOU GET WRONG INFORMATION. SO WE ARE DEMONSTRATED DATA IS VERY, WE CAN PRESERVE THE PROLIFERATION AND LONG TERM CULTURE AND DO SOME GENE EXPRESSION AND FOUND OUR DEVICE DO NOT CHANGE GENE EXPRESSION THAT MUCH. SO THAT IS THE FIRST SEPARATING FACTOR TUMOR CELLS. THE SECOND ONE IS FERRELL CELLS. WHICH COULD BE IMPORTANT TARGET OF STUDY FOR OUR PRENATAL DIAGNOSIS. FETAL CELLS IS AGAIN DIFFICULT TO ISOLATE BECAUSE OF VERY, VERY RARE AND SO WE USE THE SAME TECHNOLOGY WE DEMONSTRATED CAN DO IT BECAUSE BIGGER MATERNAL CELLS AND THIS TIME WE DIRECTLY USED MATERNAL CELLS FROM PREGNANT WOMEN AND THAT IS THE RESULTS WE GET FROM THE OUTLETS. WE FIRST MATERNAL BLOOD COME IN AND WE HAVE COLLECTION OUTLET. WE ALSO HAVE WASTE OUTLET. YOU CAN SEE COLLECTION OUTLET WE GET A MAJORITY OF FETAL CELLS SO THEY ARE LABELED WITH THIS ANTIBODY AND THE MATERNAL BLOOD, THIS YOU CAN SEE VERY, VERY LITTLE MAJORITY OF THEM ARE MATERNAL CELLS AND VERY, VERY FEW FETAL CELLS. AND THE BEAUTY SO FAR WE GET IS VERY CLOSE TO 40%. OUR EFFICIENCY RECOVERY RATE IS 85%. WHICH IS GOOD BECAUSE FETAL CELLS CARRIES PRETTY MUCH COMPLETE GENET IKE -- ALL THE COMPLETE GENETIC INFORMATION. WE CAN USE IT AND DO RNA-SEQ, WE CAN DO COMPLETE GENOME ANALYSIS. SO SECOND, THE SECOND FACTOR FETAL CELLS. THE THIRD ONE IS VESICLES. THIS WORK IS IN COLLABORATION WITH DR. YOEL SADVOSKY. I'M VERY GRATEFUL FOR HIM BECAUSE HE BROUGHT ME INTO THIS FIELD, THIS PROJECT. AND SO WE ARE USING ACOUSTIC TWEEZERS TO ISOLATE EXTRACELLULAR VESICLES FROM BIOFLUIDS. SO, NOW, PEOPLE USE [ INDISCERNIBLE ] YOU CAN GET THE JOB DONE. IT WORKS GREAT. HOWEVER, IT HAS SOME DRAWBACKS T TAKES TOO LONG, 5 DAYS. ALSO NEED PEOPLE HIGHLY TRAINED PEOPLE TO DO IT. SO WE THINK OUR BIGGEST ADVANTAGE IS VERY SIMPLE AND IT'S AUTOMATED. OUR TARGET IS SOMEBODY WHO HAS VERY LITTLE TECHINAL SKILLS, SUCH AS MY GRANDMA, PUSH BUTTON AND BLOOD COME IN AND YOU GET 20 MINUTES LATER WE CAN GET DIFFERENT KIND OF VESICLES OUT, MICROVESSELS AND EXOSOMES. IN 20 MINUTES. AND A POINT OF CARE DEVICE IS VERY -- AND ALSO CAN BE VERY, VERY IN EXPENSIVE. SO, ALSO HAVE SOME OTHER ADVANTAGES. SO FOR EXAMPLE, YOU HAVE LITERATURE THAT TALK ABOUT RECOVERING 5-25% OF VESICLES BUT OUR PRELIMINARY RESULTS ALREADY SHOW WE CAN RECOVER MORE THAN 90% OF VESICLES. WHICH IS ALREADY BETTER ALTHOUGH THE FIRST DAY OF THIS PROJECT. AND ALSO, WE BELIEVE WE CAN OR WE HAVE SO MUCH BETTER IN TERMS OF PRESERVING INTEGRITY OF VESICLES BECAUSE EACH VESICLE ONLY EXPERIENCE A ACOUSTIC WAVE WHICH IS VERY, VERY GENTLE FOR A FRACTION OF A SECOND. IT DOESN'T EXPERIENCE VERY, VERY HIGH STRESS FOR 5 DAYS. SO IT IS VERY, VERY GENTLE BUT OF COURSE WE NEED TO CHARACTERIZE MORE. AND SO WE ALREADY HAVE PRELIMINARY RESULTS. BEFORE WE CHARACTERIZE VESICLES, WE FIRST USE PARTICLES AND MIMIC. WE USE 5 MICRON PARTICLES AND 110 NANOMETER PARTICLES. THIS ONE IS TO MIMIC VESICLES. THIS ONE IS TO MIMIC BLOOD CELLS. WHEN THE ACOUSTIC WAVE IS OFF, BOTH 5 MICRON AND 110 NANOMETER PARTICLES GOES TO THIS OUT LET. BUT ONCE WE TURN ON THE ACOUSTIC WAVE, THE BLAST CELLS WILL BE PUSHED TO THE BOTTOM OUTLET BUT 110 NANOPARTICLES REMAIN IN THE OUTLET. SO THAT IS THE PARTICLE RESULTS. AFTER THAT, WE MOVE TO ISOLATE VESICLES FROM WHOLE BLOOD. YOU CAN SEE WHOLE BLOOD COMING IN WITH ACOUSTIC WAVE IS OFF, EVERYTHING GOES TO THE OUTLET. ONCE WE TURN ON ACOUSTIC WAVE, THE BLOOD CELLS MOVE TO THE LOWER OUTLET. SO HERE WE SET A THRESHOLD. EVERYTHING ABOVE 2NANOMETER IS MOVED DOWNWARDS. SO VESICLE IS RELATIVELY MORE DIFFICULT TO ISOLATE BECAUSE OF THE SIZE NANOMETER. THAT IS WHY IF WE INDUCE THIS, VERY, VERY HIGH SPEED. IT STILL TAKES YOU 5 DAYS TO DO IT. AND BUT OUR DEVICE WE CAN WORK VERY EFFICIENTLY AND TAKE JUST A FEW MINUTES. PROBABLY DON'T EVEN NEED 20 MINUTES. SO, AND WE CHARACTERIZE THE VESICLES WE ISOLATE AND USE NANOPARTICLES TRACKING ANALYSIS AND A WESTERN BLOOD TO CHARACTERIZE THOSE ARE VESICLES. THE THINGS WE COLLECT. SO, AFTER WE DEMONSTRATE WE HAVE THE ABILITY TO ISOLATE VESICLES FROM BLOOD, THEN WE MOVE TO THE NEXT STEP WHICH IS TO ISOLATE OR TWO SEPARATE DIFFERENT KINDS OF VEHICLES, EXOSOMES FROM APOPTOTIC BODIES. SO AGAIN WE FIRST USE PARTICLES TO CHARACTERIZE. WE HAVE TWO DIFFERENT KIND OF PARTICLES, 500 NANOMETER AND 110. THIS ONE MIMIC MICROVESICLES. THIS MIMIC EXOSOMES. YOU CAN SEE ONCE WE -- WHEN THEY COME IN, THEY COME TOGETHER BUT ONCE WE TAKE ACOUSTIC WAVE, THESE 500 WAVES GOES TO OUT LET AND 110 GOES TO BOTTOM OUTLET AND THEN WE MOVE TO OR MIX EXOSOMES AND MACRO VESICLES TOGETHER IN THE INDEX. AND THEN OUTLET, WE COLLECT THIS IS OUTLET 1. YOU CAN SEE MAJORITY OF EXOSOMES. THIS IS WE JUST TRIED FOR FIRST TIME SO RESULTS STILL THINGS WE DON'T UNDERSTAND. FOR EXAMPLE, WE DON'T KNOW WHAT THESE PEEKS ARE BUT WHAT OUTLET, MAJORITY ARE EXOSOMES AND THE OTHER IS MAJORITY OF THEM ARE MICROVESICLES. SO ALREADY SHOW VERY PROMISING RESULTS. WE HAVE THIS TO DIFFERENTIATE DIFFERENT KIND OF VESICLES BASED ON THE SIZE AND MECHANICAL PROPERTIES. SO SO FAR TALK ABOUT THE ABILITY TO ISOLATE THREE DIFFERENT KIND OF FACTORS, TUMOR CELLS AND FETAL CELLS AND VESICLES THAT RANGE FROM NANOMETER SIZE TO MICROMETER SIZE BUT THEY ALL SEPTEMBER RATED BASED ON SIZES AND PHYSICAL PROPERTIES AND DEMONSTRATE OUR ACOUSTIC WAVE CAN SEPARATE CELLS OR PARTICLES BASED ON THEIR CHEMICAL PROPERTIES. BASED ON THE SURFACE MARKER AND FLORESC EXPENSE IS WE USE ACOUSTIC WAVE TO MAKER IT FAST. WHY DO YOU NEED NEW FAST? I CAN TELL YOU WHY. SO FIRST OF ALL, OUR -- EVERYTHING ELSE IS THE SAME BUT WE DO NOT USE HYDRODYNAMIC FORCE. WE USE ACOUSTIC WAVE TO FOCUS IT. WE DO NOT USE ELECTRIC STATIC FORCES TO DEFLECT CELLS. WE USE ACOUSTIC FORCE TO DO IT. BY DOING THAT, WE CAN REDUCE THE PRESSURE BY 10 TIMES AND VOLTAGE BY 1000 TIMES. AT THE SAME TIME WE ACHIEVE THE SAME THROUGH PUT. SO, A LOT OF FACS, FACS DAMAGE CELLS, CHANGE EXPRESSION. SOMETIMES IT DRAMATICALLY CHANGE THE REDUCED VIABILITY BY A LOT. WELL FACS WAS INVENTED 40 YEARS AGO PEOPLE DON'T CARE. THEY HAPPY TO HAVE EQUIPMENT THAT CAN SORT THINGS. BUT NOW, WE HAVE NEEDS TO SORT VERY, VERY GENTLE OBJECTS. NEURONS, STEM CELLS, SPERMS, THOSE CELLS ARE VERY GENTLE. AND THIS REPORT SAYS THESE CELLS VIABILITY REDUCED BY 30%, BY 99%, BY DOING THIS. AND ALSO ANOTHER THING IS PEOPLE DON'T TALK THAT MUCH. PEOPLE REALLY CARE AND [ INDISCERNIBLE ] PEOPLE DON'T TALK ABOUT IS GENE EXPRESSION. FOR A LOT OF CELLS THE GENES THAT FACS PROCESSED CHANGED GENE EXPRESSION. 40 YEARS AGO PEOPLE DON'T CARE BUT NOW WE HAVE TO CARE BECAUSE SO MANY ARE INTERESTED IN OMICS STUDIES AND THE FACS CHANGED GENE EXPRESSION AND WHAT OMICS STUDY YOU GET MAY NOT BE ACCURATE AND I HAVE VERY PRELIMINARY NEWS TO SHOW YOU. WE BELIEVE WE HAVE THE HIGHEST BIOCOMPATIBILITY MEANING WE DON'T CHANGE THE PROPERTY OF THE CELLS. AND ALSO VERY SMALL SIZE AND LOW COST AND SAFETY IS BETTER BECAUSE WE SORT IN LIQUID NOT IN AIR. SO WE DO NOT WORRY BEG YOUR PARDON GENERATING AEROSOLS. AND ALSO ANOTHER ADVANTAGE HERE WE CAN DO VERY HIGH-THROUGHPUT. WE CAN -- VERY CLOSE TO COMMERCIAL FACS. 5000 EVENTS PER SECOND. 5000 CELLS PER SECOND. WE CAN ALSO DO 100 BASE MORE AMOUNT OF FLUIDS. IF YOU ONLY HAVE A SMALL -- FOR EXAMPLE YOU TRY TO GET PLACENTA FROM MOUSE, YOU JUST VERY DIFFICULT FOR YOU TO DO FACS BECAUSE YOU DON'T HAVE ENOUGH SAMPLE TO START WITH. SO, BUT OUR DEVICE, POTENTIALLY CAN DO IT. SO, THAT IS FACS. ALSO WE CAN MANIPULATE OR DOUGH DO HIGH-THROUGHPUT SINGLE CELL MANIPULATION AND PRECISELY CONTROL SELL SELL DISTANCE WHICH EN -- CELL CELL DISTANCE. TWO CELLS WHEN THEY ARE IN CONTACT WITH EACH OTHER, AND THE [ INDISCERNIBLE ] OCCURS. IF WE HOLD THESE TWO CELLS AND USE SOUND WAVE, THREE MICRONS APART, THE TRANSFER DOES NOT OCCUR. OUR DEVICE CAN ACHIEVE HIGH-THROUGHPUT, HIGH PRECISION AT THE SAME TIME AND ABILITY TO PRESERVE CELL INTEGRITY. SO THREE THINGS AT THE SAME TIME. WE CAN ALSO DO BIOPRINTING. 3D BIOPRINTING. OUR PRINTING WAY IS DIFFERENT FROM -- IT IS NOT PRINTING. IT'S OUR MECHANISM IS PEEK AND PLACE -- PICK AND PLACE. SO, WE ARE STILL WORKING ON THROUGH PUT. YOU CAN SEE HERE WE WRITE. THIS DAT. WHICH STANDS FOR THREE-DIMENSIONAL ACUTIC WISERS. BUT OUR TECHNIQUES HAVE SOME ADVANTAGES. WE CAN ACHIEVE SINGLE CELL RESOLUTION AND WE CAN PRESERVE THE INTEGRITY OF THE CELLS WHICH AGAIN IS THE IMPORTANT FOR BIOCOMMUNITY. SO WE CAN ALSO NOT ONLY DO TRANSLATION, [ INDISCERNIBLE ] WE CAN DO ROTATION. WE CAN ROTATE XY PLAN, WE CAN ROTATE NZ PLANE. WE CAN ALSO ROTATE ORGANISMS. WE CAN CONTINUOUSLY ROTATING AND ROTATE, STOP, TAKE IMAGE, ROTATE, STOP, TAKE IMAGES. SO HAVING THIS TOOL THEN WE CAN TAKE THREE-DIMENSIONAL IMAGES WITHOUT CONFOCAL MICROSCOPE. YOU CAN USE -- BECAUSE NOT EVERY LAB AS RICH OF YOU GUYS HAVE CONFOCAL MICROSCOPE. YOU CAN USE YOUR CELL PHONE TO TAKE 3D IMAGES WITHOUT POST IMAGING PROCESSING. SO, IN SUMMARY, OUR ACOUSTIC TWEEZERS, WE REALIZE MANY FUNCTIONS THAT THINGS I TALK MORE ABOUT IS WE CAN ISOLATE VESICLES, FETAL CELLS AND TUMOR CELLS AND DO FACS AND CONTROL CELL CELL DISTANCE, 3D PRINTING, ROTATIONAL MANIPULATION. WE BELIEVE THAT THE BIGGEST ADVANTAGE OF OUR TECHNIQUE IS ABILITY TO PRESERVE CELL INTEGRITY BUZZ OUR POWER INTENSITY IS 10 MILLION TIMES SMALLER THAN THAT OF OPTICAL TWEEZERS. THAT IS THE WAY TO DO MANIPULATION AND OUR ACOUSTIC POWER INTENSITY AND FREQUENCY IS VERY SIMILAR TO ULTRASONIC IMAGING WHICH YOU ARE CONVINCED IS VERY SAFE AND GENTLE TECHNIQUE. IT IS ALSO VERY VERSATILE. APPLIED TO ALMOST ANY KIND OF BIOPARTICLES FROM NANOMETER SCALE TO MICROMETERED SCALE TO MILLIMETER SCALE. AND WE CAN DO SINGLE CELL MANIPULATION AND [ INDISCERNIBLE ] WE CAN ACHIEVE VERY HIGH-THROUGHPUT. OUR DEVICE WORKS TO BLOOD, SUTUM AND ALSO DEVICES VERY COMPACT AND SIMPLE AND IN EXPENSIVE. PICTURE SOMETHING CLOSE TO YOURSELF. SO, I WANT TO THANK THE STUDENTS AND POSTDOCS WHO DID THE WORK AND MY COLLABORATORS I REALLY LOOK FORWARD TO WORKING WITH YOU AND COLLEAGUES IN THIS FIELD. I REALLY BELIEVE OUR TECHNIQUE HAVE ADVANTAGES TO MAKE IMMARKET IN THIS FIELD. THANK HPP FOR FUNDING THIS PROJECT. SOME OF OUR PRELIMINARY RESULTS, EARL I STAGE WAS FUNDED BY NIH DIRECTOR NEW INNOVATOR AWARD. THANK YOU VERY MUCH. [ APPLAUSE ] >> VERY NICE. WE HAVE TIME FOR JUST A COUPLE OF QUESTIONS. >> TERRY FROM ORGAN. FASCINATING WORK. WE HAVE BEEN PLAYING WITH HIGH RESOLUTION FACTS SO I HOPE YOU COME TO SEE ME LATER TO SEE WHAT WE ARE DOING WITH THAT. MY QUESTION TO YOU IS, SO YOU SAID THAT YOU COULD DO CELL SPECIFIC. V SORTING AND THAT YOU STARTED TO DO THAT. WHAT KIND OF YIELD ARE YOU GETTING OUT OF MATERNAL BLOOD? SO LET'S SAY A 10-WEEK MATERNAL BLOOD PLASMA SAMPLE. WHAT KIND OF PLACENTAL SPECIFIC AV NUMBERS ARE YOU GETTING? >> SO IN A YEAR OF VESICLES? >> NUMBER OF -- SO YOU COULD SIZE THEM AND COUNT THEM SO YOU CAN TELL ME WHAT PERCENTAGE OF THAT BLOOD IS PLACENTA-SPECIFIC EXOSOMES FOR EXAMPLE. ARE YOU THERE YET? THE. >> WE HAVE NOT TRIED YET FOR THE VESICLE WORK. NOW WE ARE STILL VERY EARLY STAGE. STILL VALIDATED OUR TECHNIQUE. WITHOUT USING PATIENT SAMPLE BUT WE ARE GOING TO DO IT VERY, VERY QUICKLY WITH YOU AFTER WE VALIDATE OUR TECHNOLOGY. BUT NOW WITHOUT USING THE CLINICAL SAMPLES, WE JUST MIX VESICLES -- BECAUSE VESICLES AND EXOSOMES, THAT'S A VERY EASY WAY AND ALSO WE USE WHOLE BLOOD FROM -- THE BL OOD WE BOUGHT. BECAUSE THOSE ARE THE EASY WAY TO CHARACTERIZE RISE. USING THOSE SAMPLES AND OUR YIELD IS MORE THAN 90%. WE RECOVER MORE THAN 90% OF THE VESS ELSE. >> THAT YOU PLUG IN AND THESE ARE THE SIZE BEADS. ARE YOU USING LIPOSOMES. >> THOSE ARE VESS NELS BLOOD. >> I SEE WHAT YOU MEAN AND THEN, OKAY. THANK YOU VERY MUCH. >> OKAY. WE ARE SLIPPING BEHIND BUT WE ARE DOING OKAY. THESE ARE GREAT TALKS AND GREAT DISCUSSION. SO I'LL NOW ASK CHARLES McKINSTOW COME UP, UNIVERSITY OF WESTERN ONTARIO AND WE WILL SWITCH GEARS AGAIN AND NOW WE ARE GOING TO TALK ABOUT NONINVASIVE MEASUREMENT OF PLACENTAL METABOLISM. >> THANK YOU VERY MUCH. IT'S A PLEASURE TO BE HERE. AND I THANK THE NIH TO INVITE ME TO GIVE THIS TALK. I WAS A LITTLE INTIMIDATED GIVING ME THIS TALK. MY GOING IS AN MR PHYSICIST SO I'M USED TO PUSHING PROTONS AROUND AND TRYING TO MAKE PRETTY IMAGES AND NOW I HAVE TO TALK ABOUT METABOLISM AND BIOCHEMISTRY AND A LOT OF AREAS I'M NOT TERRIBLY FAMILIAR WITH. SO I HOPE I'M NOT GOING TO MAKE TOO MANY ERRORS AS I GO THROUGH THE TALK TODAY. SO PART WHAT HAVE I WAS TASKED WITH IS TALKING ABOUT THINGS THAT ARE GOING TO STIMULATE DISCUSSION WITH WHEN WE DO THE METABOLISM BREAKOUT SESSION LATER TODAY. SO I WANTED TO GO THROUGH IN DISCUSSION OF WHAT DO WE WANT TO MEASURE? I'M GOING TO TALK ABOUT WHAT WE ARE ABLE TO MEASURE RIGHT NOW. AND THEN I'M GOING TO FOLLOW ON THAT BY NEW TECHNIQUES THAT ARE GOING TO ALLOW US TO MEASURE NEW THINGS THAT WE ARE INTERESTED IN. SO WE START OFF WITH WHAT SORT OF QUESTIONS DO WE WANT TO ANSWER WHEN WE ARE TALKING ABOUT PLACENTAL METABOLISM. QUESTIONS WE MIGHT BE INTERESTED IN IS HOW DOES METABOLISM CHANGE ACROSS NORMAL GESTATION? WHAT ARE THE IMPORTANT METABOLIC PATHOLOGIES WE WANT TO LOOK AT? HOW IS THAT NORMAL METABOLISM CHANGED WHEN WE HAVE PATHOLOGIY? HOW DOES NORMAL OR ABNORMAL METABOLISM RELATE TO PREGNANCY OUTCOMES? WHEN WE SEE A CHANGE IN METABOLISM, WHAT DOES THAT MEAN FOR THE FATE OF THAT PREGNANCY? HOW DO WE GET ANSWERS TO THESE QUESTIONS? SO NUTRIENT TRANSPORT ACROSS THE PLACENTA TRYING TO BE ABLE TO DISTINGUISH GLIKE LYTIC VERSUS OXIDATIVE. GENETICS OF KEY METABOLIC REGULATORY GENES THINKS FATTY ACID LIPID COMPOSITION, HORMONE COMPOSITION, MITOCHONDRIAL STATUS. OXIDATIVE STRESS AND MANY MEN MORE PEOPLE IN THE AUDIENCE ARE INTERESTED IN POTENTIALLY MEASURING. SO A LONG LIST OF THINGS WE LIKE TO TRY TO MEASURE. BUT WHAT CAN WE MEASURE RIGHT NOW? I'M PARTICULARLY LOOKING AT TALKING ABOUT NONINVASIVE MEASUREMENTS. SO WHAT CAN WE DO NONINVASIVELY SO WE CAN DO THIS IN PREGNANT WOMEN DURING THEIR PREGNANCY TO GET ANSWERS TO THESE QUESTIONS? >> AND SO NONINVASIVELY, WE REALLY HAVE QUITE THE LIMITED OPTIONS. I'M GOING TO TALK ABOUT MEDICINE AND SPECT IMAGING AND WHETHER THERE THAT IS AN ONES. WE CAN LOOK AT BLOOD AND URINE AND PLACENTAL TISSUE SAMPLING AND I'M GOING TO TALK ABOUT MR SPECTROSCOPY AS A METHOD WE CAN USE RIGHT NOW TO LOOK AT SOME OF THE METABOLISM IN THE PLACENTA. SO, PET AND SUSPECT. THESE ARE THE GOLD STANDARD METABOLIC IMAGING TECHNIQUES THAT ARE VERY WELL ESTABLISHED FROM METABOLISM IN ADULTS AND CHILDREN AS WELL. SEEN SOME USE IN ANIMAL PREGNANCY AND SO THERE HAVE BEEN PAPERS ON USING PET TO LOOK AT PLACENTAL METABOLISM IN ANIMAL MODELS. THESE TECHNIQUES ARE HIGHLY SENSITIVE. YOU CAN DETECT NANOMOLOR CONCENTRATIONS OF METABO LIGHTS AND THEY INVOLVE RADIATION AND SO THESE RADIATION CONCERNS REALLY HAVE LIMITED THEIR USE IN PREGNANCY TO ANIMAL MODELS AND THIS IS NOT SOMETHING WE REALLY ARE LOOKING AT DOING IN HUMANS SO THERE HAS BEEN SOME WORK THAT SUGGESTS THAT WITH PET IMAGING YOU CAN KEEP THE DOSE TO THE FETUS TO ACCEPTABLE LIMITS FOR WHATEVER WE DECIDE ACCEPTABLE LIMITS MEANS. I WOULD SAY LIKELY HIGHLY CONTROVERSY. THIS IS AN IMAGE OF A WOMAN WHO HAD BREAST CAPSER AND WAS GIVEN A PET EXAM AND YOU CAN SEE SOME OF THE PET AGENT UPTAKE IN THE FEETINOUS THIS CASE. SHE WAS UNFORTUNATELY HAD TO HAVE THE SCAN DURING PREGNANCY. SO THERE ARE SUGGESTIONS YOU CAN KEEP THE LIMITS TO THE FETUS OR DOSE TO THE FETUS WITHIN THESE ACCEPTABLE LIMITS BUT I DON'T THINK THIS IS A DIRECTION THAT WE REALLY LIKELY TO PURSUE BECAUSE THERE IS WILL BE A LOT OF CONCERNS ABOUT RADIATION. THERE IS ALWAYS OPTIONS FOR BLOOD AND URINE SAMPLING VERY NONINVASIVE METHODS. IN TERMS OF DIFFERENT KINDS OF BLOOD YOU MIGHT WANT TO COLLECT, COLLECT CORD AND BLAH SENTAL BLOOD. IF YOU WANT TO DO THAT NONINVASIVELY THAT IS SOMETHING TO REALLY ONLY DO AT BIRTH. IF YOU ARE COLLECTING THE LABOR PLACENTAL MAY TO BE LIMP SO COLLECT AFTER NORMAL BIRTH VERSUS CESAREAN SECTION THERE CAN BE DIFFERENCES IN THE METABOLITES BECAUSE OF THE LABOR OR LACK THEREOF. YOU CAN LOOK AT TRYING TO GET BIOMARKERS OUT OF MATERNAL BLOOD AND URINE. THE CHALLENGES HERE ARE REALLY DISTINGUISHING THE PLACENTAL VERSUS MATERNAL METABOLITES YOU'RE SEEING SO THESE ARE VERY CHALLENGING TECHNIQUES TO DISTINGUISH AND SEE THE PLACENTAL METABOLITES WE WANT TO SEE VERSUS MATERNAL BACKGROUND. THERE IS PLACENTAL TISSUE SAMPLING. ONLY NONINVASIVE AT THE END OF THE PREGNANCY. WE ARE COLLECTING THAT PLACENTA AFTER BIRTH. SO THIS IS GOING TO GIVE US LIMITED INFORMATION ABOUT METABOLISM ACROSS PREGNANCY. YOU REALLY ONLY WILL GET INFORMATION AT THAT VERY END OF PREGNANCY TIME POINT. AND THE ISSUES IF THERE HAS BEEN LABOR OR NOT, THAT CAN AFFECT THE TISSUE AND IT'S GOING TO AFFECT THE METABOLISM AND THE METAB LIGHTS YOU MIGHT SEE DURING THIS. THERE IS ALSO THE OPTION OF MR SPECTROSCOPY. MRI SPECTROSCOPY CAN SEPARATE A WIDE VIREY OF THINGS. LACTATE, GLUTAMINE, ATP, MANY MORE. NORMALLY WE LOOK AT HYDROGEN. BUT THERE ARE OTHER OPTIONS. WE CAN LOOK AT 31 PHOSPHORUS, CARBON 13. THESE NONPROTON TECHNIQUES -- NONHYDROGEN TECHNIQUES ARE NOT WIDELY AVAILABLE. MOST CLINICAL SITES ARE NOT GOING TO HAVE THESE THAT REQUIRE SPECIALIZED HARDWARE SPECIALS SPECIALIZED SOFTWARE. THEY ARE USED IN RESEARCH ALTHOUGH. THE OTHER MAJOR ISSUE WITH SPECTROSCOPY, MRI IS NOT A TERRIBLY SENSITIVE TECHNIQUE UNLIKE NUCLEAR MEDICINE TECHNIQUES. IT'S NOT TERRIBLY SENSITIVE AND SO THAT MEANS THAT THE ACQUISITIONS ARE VERY SLOW. THEY TEND TO HAVE VERY LIMITED SPACIAL COVERAGE SO LOOKING AT ACQUISITION THAT IS MIGHT BE 10 MINUTES OR MORE AND IN THE TENS OF MILLIMETERS. THAT'S AN EXAMPLE HERE. THIS IS A SINGLE BOXIL WITHIN THE PLACENTA AND IT'S THE SIZE OF THE VOXEL RELATIVE TO THE PLACENTA. IT'S NOT TERRIBLY -- IT'S DIFFICULT TO ADD THIS ON TO A TYPICAL CLINICAL EXAM. ON TOP OF ALL THE OTHER TECHNICAL PROBLEMS. A LOVELY RESEARCH TOOL BUT VERY CHALLENGING TO TRANSLATE THIS SORT OF THING INTO THE CLINIC. SO, LET'S TALK ABOUT NEW MEASUREMENT TECHNOLOGIES. SO JUST WIDE VARIETY OF TECHNOLOGIES THAT ARE BEING DEVELOPED RIGHT NOW. THEY OFFER THE PROMISE OF DIRECT AND NONINVASIVE MEASUREMENT OF METABOLISMS RATHER THAN LOOKING AT PRODUCTS, LOOKING AT METABOLIC FUNCTION. SOME EXAMPLES WE HEARD MAYBE A LITTLE BIT ABOUT THIS, OPTICAL NEAR INFRARED IMAGING, NONINVASIVE MEASUREMENT OF OXIDATION. VERY INTERESTING WORK WITH SPECTROSCOPY LOOKING AT REALTIME MEASUREMENT OF LIPID BY OR MARKERS AND WORK WE ARE DOING IN MY LAB ON METABOLIC MR I AND USING A NEW TECHNIQUE CALLED HYPERPOLARIZED IMAGING TO DIRECTLY IMAGE METABOLISM USING MAGNETIC RESONANCE IN PREGNANCY. SO I'M GOING TO START OFF WITH BACKGROUND ON HOW HYPERPOLARIZED MRI WORKS. IT'S A DIFFERENT TECHNIQUE. NORMAL MR SYMPT LOOKING AT HYDROGEN, WATER OR LIPIDS. HYPERPOLARIZED MIR WORKS ON THE MOST COMMON NUCLEUS WE USE INSTEAD OF HYDROGEN IS CARBON 13. CARBON 12 INVISIBLE TO MRI BUT CARBON 13 IS NOT. IT'S A NATURALLY ABUNDANT AND HAS NATURAL ABUNDANCE, 1% OF ALL CARBON. UNFORTUNATELY THAT MEANS THAT WE REALLY CAN'T USE ENDOGENOUS CARBON 13 FOR OUR IMAGING BECAUSE THERE IS NOT ENOUGH OF IT TO GET ANY REASONABLE SIGNAL FROM IT BUT WE CAN TAKEN DODGINESS SUBSTRATE AND I'LL TALK ABOUT PYRUVATE MOLECULES AND WE CAN LABEL IT WITH A STABLE CARBON 13 ISOTOPE. SO CARBON 13 IS STABLE. IT'S NONRADIO ARCHITECTIVE AND IT LEAVES THE MOLECULE CHEMICALLY IDENTICAL TO THE CARBON 12 VERSION OF THAT MOLECULE. SO THIS FUNCTIONS IDENTICAL IN THE BODY SO NO SAFETY CONCERNS. PYRUVATE IS A COMMON MOLECULE IN ALL OF OUR CELLS. SO DURING THE CARBON 13 LABELING RAISES NO SAFETY ISSUES FROM THAT PERSPECTIVE. SO, WE CAN TAKE A MOLECULE LIKE PYRUVATE AND LABEL WITH CARBON 13 AND POTENTIALLY INJECT THAT BUT STILL WON'T GET ENOUGH SIGNAL TO DO ANY KIND OF REASONABLE METABOLIC IMAGING WITH IT. SO NOW WE USE DYNAMIC NUCLEAR POLARIZATION. WE TAKE PYRUVATE SAMPLE AND PUT IT IN A DEVICE THAT LOOKS LIKE THIS. THIS IS A HYPERSENSE POLARIZER T HAS A STRONG MAGNETIC FIELD, 3 TESLA. WE PUT THE PYRUVATE IN THAT FIELD AND WE THEN COOL IT TO HEAL YUM TEMPERATURES SO 1.4 KELV IN. AND ERADIATE THAT MOLECULE WITH MICROBEHAVES THEY POLARIZE THE ELECTRON ON THAT MOLECULE AND THEN IT IS TRANSFERRED TO CAR BONE 13 NUCLEUS ITSELF AND LOOKS LIKE. WE HAVE HYPERSENSE POLARIZER AND IT IS LOCATED ABOUT 10 METERS AWAY FROM OUR MRI SYSTEM AND SO WE PUT OUR SAMPLE IN THERE AND IT POLARIZES 45 MINUTES AND THEN WE GET TOWARDS THE END AND THE POLARIZATION PROCESS IS FINISHED AND THEN EJECT THE SAMPLE. WE PUSH A BUTTON AND PRESSURES START TO RISE AND YOU COUNT PRESSURES AND 10, 9, 8 -- HERE IT COMES. AND THEN WE TAKE THE SAMPLE OUT OF OUR HYPERSENSE AND THEN WE RUN IT IMMEDIATELY OVER TO OUR MAGNET. THE REASON FOR THIS IS THAT THE RELAXATION TIME OF OUR HYPERPOLARIZED STATE IS ABOUT 40 SECONDS SO IT'S EQUIVALENT WE HAVE A HALF-LIFE IN NUCLEAR MEDICINE TERMS OF ABOUT 30 SECONDS. SO WE ARE TIME IS MONEY AND WE ARE LOSING SIGNAL VERY, VERY QUICKLY AS WE DO THESE EXPERIMENTS. SO WHEN I'M LOOKING AT GRADUATE STUDENTS I ASK THEM WHAT THEIR ONE HUNDRED METER TEAM IS SO THEY CAN GET QUICKLY FROM THE POLARIZER TO THE MAGNET. SO WE THEN DO A INJECTION AND THEN IMMEDIATELY START IMAGING. AND WE ARE TRYING TO GET OUR METABOLIC INFORMATION. I'M GOING SHOW SOME EXAMPLES IN A FEW MINUTES. SO, WHY PYRUVATE? AND IT'S BECAUSE PYRUVATE SITS AT A VERY INTERESTING CROSSROADS OF METABOLISM GLUCOSE CONREPORTS PYRUVATE AND IT WILL ENTER THE MITOCHONDRIA AND THEN GO A COUPLE OF DIFFERENT PATHWAYS. SO IT CAN GO THROUGH AEROBIC METABOLISM GOING THROUGH THE IT. CA CYCLE AND THAT CARBON SO WE LABEL. C1 POSITION CARBON ON PYRUVATE AND IT GOES OVER TO CARBON OXIDE AND COMES BICARBONATE. GOING THROUGH ANAEROBIC METABOLISM, IT WILL WIND UP OVER HERE AND THAT CAN THROUGH OTHER MECHANISMS WIND UP OVER HERE ON ALANIN. NOW REALLY EXCITING THINGS FOR US WHEN WE ARE DOING MRI IS AS THAT MOLECULE GETS METABOLIZED, THE SIGNAL WE GET FROM THE CARBON CHANGES SUDDENLY SO WE DO A FREQUENCY SENSITIVE DETECTION. AND SO, THIS SIGNAL WE GET THE CARBON ON PYRUVATERS HAVES CARBON VERSUS ALANIN VERSUS LACTATE, THEY GIVE US DIFFERENT SIGNALS SO WE CAN AWIRE DATA TO SEPARATE OUT THE SIGNALS. WE CAN FORM IMAGES OF PYRUVATE AND LACTATE AND ALANIN AND WE CAN GET ALL FOUR POTENTIALLY SIMULTANEOUSLY. SO WE CAN WATCH ALL OF THESE PROCESSES GOING ON AT THE SAME TIME WHEN WE CAN DISTINGUISH THE SILLINAL FROM ALL THE DIFFERENT METABOLITES. SO, WE DECIDED TO TRY THIS EXPERIMENT AND SO WE WORKED IN ANIMAL MODELS SO WE USE PREGNANT GUINEA PIGS. THEY ARE A PRENATAL DEVELOPER SO SIMILAR TO THE HUMANS IN THAT SENSE. THEY HAVE HEMOCORIAL PLACENTA. SO THIS IS A HYDROGEN IMAGE OF OUR GUINEA PIGS HERE AND WE HAVE GOT 1, 2, 3 FETUSES HERE. I THINK THERE IS A FOURTH FETUS THAT DIDN'T WIND UP IN THE PLANE HERE. SO WE TAKE THESE ANIMALS AND ANNETTE TIES THEM AND WE PUT A CATHETER IN THEIR HIND LIMB WE WILL DO OUR IN INTRAVENOUS INJECTION. IN TERMS OF MRI, IT'S A CLINICAL 3T SCANNER EQUIPPED TO DO MULTINUCLEAR IMAGES TO IMAGE CARBON 13. WE HAVE A CUSTOM BUILT RF COIL AND THE CUSTOM BUILT HYDROGEN CARBON BIRD CAGE COIL USED FOR SIGNAL TRANSMISSION. SO, WE GET F1 WEIGHTED IMAGES TO DETERMINE WHEN THE PRESENTA IS BECAUSE THEY CAN WIND UP IN DIFFERENT SPOTS AND THAT WILL HELP US TO LOCALIZE OUR CARBON 13 IMAGING. CARBON 13 WE USE C1 LABELED PYRUVATE. WE HYPERPOLARIZE LOSING DNP POLARIZER AND IN JUDGEECT 250 MICROLITERS OF PYRUVATE AND THEN WE ARE GOING TO DO TIME RESULT CARBON 13 SPECTROSCOPIC IMAGING. WE USE A MODIFIED VERSION OF THE IDEAL SEQUENCE. THIS IS USED FOR FAT WATER IMAGING WITH HYDROGEN. CONVERTED SO WE CAN DO CARBON 13 IMAGING WITH IT. WE HAVE RELATIVELY LOW RESOLUTION SO THE HYDROGEN IMAGE OF THE GUINEA PIG HERE HAS RESOLUTION OF ABOUT .5 MILLIMETERSIZESO TROPIC. WITH CARBON 13 WE ARE SIGNAL STARVED AND WE ARE TALKING RESOLUTIONS OF SOMETHING LIKE 6 BY 6 BY 7 MILLIMETERS. AND THEN WE GET A TON OF RESOLUTION OF 10 SECONDS. COLLECTING ONE IMAGE EVERY 10 SECONDS. ULTIMATELY, WE ARE ABLE TO SEE THIS. THIS IS OUR IMAGE OUTLINED IN RED IS THE FETAL LIVER. WHITE IS THE PLACENTA. THERE IS ALSO MATERNAL ORGANS SO WE CAN SEE THE KIDNEYS HERE AND THE LIVER UP HERE. THE MATERNAL ORGANS TAKE UP PYRUVATE AND METABULATE IT. SO WE GET SIGNAL FROM THAT AS WELL. IF WE LOOK -- THESE IMAGES ARE METABOLIC. 20 SECONDS AFTER INJECTION OF OUR PYRUVATE. AND WE GET A LOT OF PYRUVATE SIGNALS. THAT'S WHAT WE ARE INJECTING. WE HAVE TO DIVIDE THE SIGNAL BY FOUR SO WE ARE ANAL TO COMPARE. AND WHAT WE SAW IN THIS CASE WE ARE SEEING PYRUVATE GET MA TABALIZED TO LACTATE AFTER INJECTION. SO YOU CAN SEE THERE IS PYRUVATE IN THE PLACENTA HERE. LOTS OF LACTATE PRODUCTION IN THE PLACENTA. INTERESTING, WE ALSO SEE CONSIDERABLE LACTATE IN THE FETAL LIVER. SO, THAT LACTATE IS BEING PRODUCED IN THE PLACENTA AND IT IS TRANSFERRING OVER AND WE ARE SEEING THAT LACTATE IN THE FETAL LIVER DURING THESE EXPERIMENTS. SO WE WERE VERY EXCITED ABOUT THIS. THIS WAS OUR FIRST ATTEMPTS AT DOING THESE SORTS OF EXPERIMENTS IN PREGNANT ANIMALS. WE HAD NO ISSUES WITH THE ANIMALS IN TERMS OF SAFETY. THE PUPS SURVIVE. SO THEY BIRTH NORMALLY. AND SO, IT LOOKS LIKE WE ARE FEASIBLY ABLE TO DO THIS EXPERIMENT WHERE WE CAN LOOK AT METABOLISM IN REALTIME WITH THIS TECHNOLOGY. WE CAN GET TIME RESOLUTION OUT OF THIS. SO I WAS SHOWING YOU ONE FRAME FROM 20 SECONDS. SO THIS IS WHAT IT LOOKS LIKE. THIS IS OUR TIME COURSE. THIS IS IN THE PLACENTA OF THE GUINEA PIG. WE CAN WATCH THE PYRUVATE WASH IN AND WATCH THE LACTATE BEING CONVERTED FROM THE PYRUVATE AND WE CAN TAKE THIS DATA AND TRY TO FIT MODELS TO IT AND GET RATE CONSTANTS OUT OF IT AND SO LOOK AT COMPENSATE FOR THE PROFUSION EXPIRATE LOOK AT RATES OF HOW QUICKLY PYRUVATE IS BEING CONVERTED AND SO FORTH. WE HAVEN'T SEEN THIS IN PREGNANCY IN OTHER MOTED ELSE OF THIS. WE DO ALSO SEE PYRUVATE CONVERSION TO ALANIN. WE SOMETIMES SEE RARE PATHWAYS AND SEE IT GET CONVERTED TO THINGS LIKE ASPARTATE. WE HAVEN'T SEEN THAT IN PREGNANCY YET BUT HOPING AS WE IMPROVE THE IMAGING THAT WE ARE DOING AND IMPROVE OUR SENSITIVITY, WE MIGHT BE ABLE TO START TO SEE THAT SORT OF THING. SO LIMITATIONS TO THE HYPERPOLARIZED TECHNIQUE. ONLY INVESTIGATE SMALL MOLECULES SO THINGS LIKE PYRUVATE LACTATE THAT HAVE 3-4 CARBONS ON THEM, WE HAVE BEEN ABLE TO DO GLUCOSE. SO POTENTIALLY LOOK AT MAYBE A MOLECULE THAT BIG. WE DO HAVE LIMITED RESOLUTION BECAUSE EVEN DESPITE THAT 100,000 FOLD INCREASE IN SIGNAL TO NOISE WE GET FROM HYPERPOLARIZATION WE ARE STILL INJECTING A SMALL AMOUNT OF THE SUBSTRAIGHT SO LIMITED SIGNALS AND LIMITED RESOLUTION. RIGHT NOW THE TECHNIQUE IS NOT PARTICULARLY AVAILABLE. ABOUT 40 SITES IN THE WORLD THAT HAVE ANIMAL READY POLARIZERS. THERE HAS BEEN HUMAN WORK DONE WITH HYPERPOLARIZATION. ABOUT A DOZEN HUMAN READY HYPERPOLARIZERS OUT THERE AND USED TO INVESTIGATE PROSTATE CANCER IN HUMANS. THIS IS NOT LIKE PET. THIS IS NOT A TRACER TECHNIQUE. WE INJECT A LARGE AMOUNT OF THE HYPERPOLARIZED SUBSTRATE AND TEND TO SWAMP THE PHYSIOLOGIC SYSTEM SYSTEM THAT ARE THERE. SO, WHAT WE ARE LOOKING NAT THIS CASE RATHER THAN A TRACER, WE ARE LOOKING AT ALMOST ENZYMATIC ACTIVITY. SO WHAT IS THE BALANCE OF LACTATE TO PYRUVATE? THAT'S VERY COMMON. AS WE HAVE DONE -- HAVE BEEN WORK DONE IN HUMANS. VERY LIMITED EXPERIENCE SO FAR. OUR GROUP IS HOPING TO TAKE THIS KIND OF TECHNOLOGY AND MOVE THIS INTO HUMAN STUDIES IN PREGNANCY IN THE NEXT SEVERAL YEARS THANKS TO FUNDING FROM NIH. BUT THERE IS A LOT OF REGULATORY HURDLES AS CAN IMAGINE AS WE GO DOWN THAT PATH. SO CONCLUSIONS HERE SO WITH METED BOLLIC MRI WE CAN DO HYPE OR POLARIZED TIME RESULTS AND NONINVASIVELY DETECT METABOLIC ACTIVITY IN THE PLACENTA AND FETUS. WE THINK THAT HYPERPOLARIZED PYRUVATE MAY PROVIDE A MEANS OF INVESTIGATING ABNORMAL PLACENTAL METABOLISM AND WE ARE LOOKING AT THE AFFECT OF WESTERN DIET AND THE SEE IF WE CAN SEE METABOLIC DIFFERENCES IN THE PLACENTA OF ANIMALS. JUST TO BRING THIS BACK TO THE GENERAL THEME. CURRENT CAPABILITIES FOR INVESTIGATING METABOLISM ARE CONSTRAINED AND EMERGING TECHNOLOGIES LIKE THE ONES I HAVE BEEN TALKING ABOUT WILL PROVIDE YOU NEW AVENUES FOR NONIN VASE AND I HAVE METABOLIC INVESTIGATION. LIKE TO JUST ACKNOWLEDGE MY RESEARCH TEAM HERE, THE VERY BLESSED WORK WITH A LOT OF VERY SOME ARE PEOPLE THAT KNOW A LOT MORE ABOUT PREGNANCY AND BIOCHEMISTRY THAN I DO. AND THANK THE NIH FOR INVITING ME AND PROVIDING FUNDING. THANK YOU VERY MUCH. [ APPLAUSE ] >> SO ONE QUICK QUESTION AND THEN I'LL INVITE YOU TO FIND DR. McKENZIE AT THE BREAK. >> IT'S BRILLIANT EXTRAPOLATION OF WHAT YOU'RE DOING. THE OTHER OTHER THING I LAT OF PEOPLE ARE INTERESTED IN IS OX JANUARY TENSION. HAVE YOU CONSIDERED USING UNSATURATED CARBON-CARBON BOND THAT COULD BE ATTACKED BY OXYGEN AND WOULD THAT GIVE YOU A MEASURE OF OXYGEN STATUS? -- >> I'M NOT SURE I KNOW ENOUGH TO BE ABLE TO ANSWER THAT. IT'S SOMETHING I WILL GO BACK AND LOOK AT NOW BUT I'M NOT SURE. >> SO AGAIN, SORRY. TRYING TO GET US SORT OF BACK IN THE DIRECTION OF BEING ON TIME. SO OUR NEXT SPEAKER IN DR. NICK ILLSLEY FROM HACKENSACK UNIVERSITY MEDICAL CENTER, UNDERSTANDING NORMAL AND PATHOLOGICAL PLACENTAL INVASION. [ APPLAUSE ] >> OKAY. AS GROWTH CATHY AND ANTONIO INDICATED EARLIER ON IN THEIR PRESENTATION WHEN'S THEY SET THIS ONE UP, INVASION IS A VERY IMPORTANT COMPONENT OF WHAT IS HAPPENING TO THE PLACENTA. INVASION INTO THE UTERUS. AND I'D LIKE TO GO THROUGH THAT TODAY AND I'M GOING TO TRY AND GIVE THIS AS PLA SENTOLOGY FOR PHYSICIST, SO IT IS GOING TO INVOLVE A TEACHING MOMENT SHOULD WE SAY? AND THE QUESTIONS I'D LIKE TO ASK ARE, WHY IS TROPHOBLAST INVASION AND DEVELOPMENT OF THE MA TERNITY CIRCULATION IMPORTANT? HOW DOES THE INVASION AND THE ESTABLISHMENT OF THE UTERINE PLACENTAL CIRCULATION TAKE PLACE? WHAT IS THE UNDERLYING MOLECULAR MECHANISM? AND FINALLY INVESTIGATING INVASION AND DEVELOPMENT OF THE MATERNAL CIRCULATION. WHAT IS AVAILABLE AND WHAT MIGHT BE POSSIBLE? SO FIRST, LET'S GO TO THE FIRST QUESTION. WHY IS TROPHOBLAST INVASION AND DEVELOPMENT OF THE MATERNAL CIRCULATION IMPORTANT? SO THIS IS THE CLASSIC PICTURE BY ELIZABETH RAMSEY, OF THE PLACENTA WITH THE FETAL CIRCULATION COMING IN THROUGH HERE INTO THE VILLA TREE GOING OUT THROUGH THE VESSEL HERE. AND HERE IS THE MATERNAL BLOOD COMING IN THROUGH THE SPIRAL ARTERIES AND CIRCULATING AROUND THATVILLE US TREE IN THIS SORT OF MANNER AND IT IS BROKEN DOWN NICELY WE ARE INTERESTED IN HOW THE BLOOD COMING IN GETS THERE. THERE ARE A NUMBER OF PATHOLOGY GEES WHICH ARE RELATED TO INVASION. SO, PATHOLOGIES RELATED TO UNDERINVASION BY THE PLACENTA AND THERE IS REDUCED INVASION OBSERVED IN GROWTH RESTRICTION SHALLOW IMPLANTATION AND DECREASED INVASION IS OBSERVED IN PREECLAMPSIA. IN TERMS OF OVERINVASION, LESS STUDIED AREA BUT ONE WE ARE VERY INTERESTED IN, INCREASED TROPHOBLAST INVASION IS FOUND IN ABNORMALLY INVASIVE PLACENTAL PATHOLOGIES SUCH AS PLACENTA, IN CRETA AND PER CRETA. SO WHAT DOES THIS MEAN? FOR EXAMPLE, HERE IS A QUICK LOOK AT BLOOD FLOW IN THE SECOND AND THIRD TRIMESTERS IN NORMAL AND GROWTH RESTRICTED PREGNANCIES. AND WHAT CAN YOU SEE IS THAT UTERINE ARTERY BLOOD FLOW COMPARED TO THE FETAL GROWTH RESTRICTION IS MUCH, MUCH LOWER. IN OTHER WORDS, FAULTY INVASION LED TO THIS REDUCED BLOOD FLOW AND GROWTH IN THE FETUS. YOU CAN SEE A SERIES OF STUDIES FROM WAY BACK USING A VARIETY OF DIFFERENT METHODS BUT ALL LOOKING AT EITHER PREECLAMPSIA, PREECLAMPSIA WITH HYPERTENSION, SEVERE PREECLAMPSIA, INTERUTERINE GROWTH RESTRICTION, HIGH ALTITUDE, AND SO ON. AND WHAT THEY HAVE IN COMMON IS VARYING DEGREES BUT NEVERTHELESS MAJOR DECREASES IN BLOOD FLOW TO THE PLACENTA. IN TERMS OF THE OVER INVASION, I WOULD JUST GIVE YOU THIS EXAMPLE OF PLACENTA WHICH WAS OVER INVADING INTO THE UTERUS AND THIS ONE IN FACT IS GOING OR HAS GONE RIGHT TO THE UTERINE SEROSA. BUT THE THREE DIFFERENT GRADES IF YOU LIKE, OF OVERINVASION WOULD BE SOMETHING LIKE THIS, ACCRETA GETTING DOWN TO AND STICKING TO THE MYOMEET RUM IN CRETA INVADING INTO THE MYOMEET RUM AND PER CRETA GOING RIGHT TO ALL 3 THE UTERINE SEROSA. SO IN THIS CASE, HAVE YOU GOT A PATHOLOGY WHERE THERE IS NO LONGER A DIFFERENCE IF YOU LIKE BETWEEN THE PLACENTA AND UTERUS. THIS REQUIRES IN MAINTENANCE CASES HYSTERECTOMY. IF IT IS NOT RECOGNIZED, IT MEANS THAT THE MOTHER CAN QUITE OFTEN HAVE MAJOR HEMORRHAGE BECAUSE PEOPLE TRY TO REMOVE THE PLACENTA ONE WAY OR ANOTHER AND THE VESSELS THAT ARE INVADED DOWN HERE, THAT ARE NORMALLY NOT INVADED BY THE PLACENTA, PROVIDE A VERY GOOD SUPPLY FOR THAT HEMORRHAGE. SO HOW DOES THE INVASION AND ESTABLISHMENT OF THE MATERNAL CIRCULATION TAKE PLACE? I'M GOING TO DRAW ON ILLUSTRATIONS FROM GRAHAM BURTON HERE AND FROM BOB, BECAUSE MY DRAWING SKILLS ARE NOT THAT GOOD. SO THE FIRST INITIAL MATERNAL CIRCULATION TAKES PLACE VIA INVASION OF THE MATERNAL CAPILLARIES WITHIN THE SUPERFICIAL ENDOMETRIUM. BUT THE SPIRAL ARTERIES LATER ON PROVIDE THE DEFINITIVE MATERNAL CIRCULATION. AND THAT CIRCULATION IS ESSENTIAL IT SHOULD BE INDEPENDENT OF MATERNAL VASOMOTOR CONTROL. YOU DON'T WANT SOMEONE SAYING BOO TO THE MOTHER AND BLOOD VESSELS TO THE BABY SHUTTING DOWN. AND IT HAS TO BE LOW PRESSURE BECAUSE YOU DON'T WANT PRESSURE FROM THE MATERNAL CIRCULATION CRUSHING THOSE NICE SMALL FETAL CAPILLARIES IN THE BLAH SENTA. AND THE ANSWER THAT NATURE FOUND AT LEAST IN THE HUMAN, IS THAT THESE FEATURES ARE ACHIEVED BY TRANSFORMATION OF THE SPIRAL ARTERIES WHICH IS ASSOCIATED WITH EXTRA VILLA TROPHOBLAST MIGRATION INTO THE ENDOMETRIUM AND INTO THE SPIRAL ARTERIES. THIS IS A PICTURE THAT IS COMMONLY USED AND YOU'LL SEE VARIATION ISES OF IT EVERYWHERE. HERE ARE THE SPIRAL ARTERIES LEADING UP THROUGH THE MYOMEET RUM AND INTO THE DISSIDDIA IN THE NONPREGNANT. HERE IS THE IN INITIATION OF INVASION AZEOTROPE'S BLASTS INVADE INTO THE ENTER STITIAL SPACE HERE AND ALSO DOWN THE SPIRAL ARTERY. EVENTUALLY TRANSFORMING THAT SPIRAL ARTERY INTO A MUCH BIGGER CONDEWED DUTY THAT IS ABLE TO CARRY THE BLOOD FLOW NECESSARY FOR FETAL GROWTH. THE PORTION OF THE ARTERY MOST PROXIMAL, WILL BE THE RATE LIMITING SECTION FOR ALL BLOOD FLOW. CONFAILURE OF CONVERSION IS ASSOCIATED WITH COMPLICATIONS. AND OVER INVASION IS ASSOCIATED WITH ACCRETA RELATED PATHOLOGIES. EXTRA VILLOUS TROPHOBLASTS ARISE FROM THE CYTOTROPHOBLAST CELL COLUMNS AT THE TIPS OF ANCHORINGVILLE I HOLDING THE REST OF THE PLACENTA ON TO THE UTERUS AND THESE CELLS ARE PROLIFERATING AND AS THEY MOVE DOWN THE COLUMN, THEY BEGIN TO DIFFERENTIATE INTO THE EXTRA VILLOUS TROPHOBLAST TYPE AND THEN THEY START TO MIGRATE INTO THE UTERUS. AND AS THEY DIFFERENTIATE, THE TROPHOBLAST LOSE SELL H. SELL ADHESION. THEIR POLARITY CHANGES. IT DISAPPEARS. THEIR INTEGRIN EXPRESSION CHANGES. THEY INCREASE THEIR EXPRESSION OF MATRIX PRO TINAISES. ALL DESIGNED TO ENABLE THEIR MOVEMENT AWAY FROM THE CELL COLUMN AND DOWN INTO THE TISSUE BELOW. SO, THESE ARE TAKEN FROM BOB. AND THEY SHOW THE VARIOUS STAGES AS HE SAW IT OF INVASION. THE NONPREGNANT HERE IS THE ARTERY AND HERE IS THE ENTER STITIAL SPACE AND ENDOTHELIUM AND THE VASCULAR SMOOTH MUSCLE. THERE APPEAR TO BE CHANGE THAT IS TAKE PLACE BEFORE THE EXTRA VILLOUS TROPHOBLAST GET THERE. CHANGES WHICH BEGIN TO DISRUPT THE VEHICULAR SMOOTH MUSCLE AND THE ENDOTHELIUM. BUT AS THAT CONTINUES, YOU GET TROPHOBLAST INTERSTITIAL TROPE'S BLAST MOVING DOWN AND THEY BEGIN TO REALLY BREAKDOWN THE VASCULAR SMOOTH MUSCLE WHICH SURROUNDS THESE ARTERIES. AT THE SAME TIME, OR LATER, YOU HAVE ALSO GOT ENDOVASCULAR TROPHOBLASTS COMING IN RETROGRADE FASHION INTO THE SPIRAL ART EXPRESS THEY BEGIN TO BREAKDOWN THE WALL OF THE SPIRAL ARTERY. FINALLY, LATER ON, YOU BEGIN TO HAVE THIS WHOLE SPIRAL ARTERY CHANGE WHERE THE MUSCLE IS ESSENTIALLY REMOVED. FIBRINOIDING ARE GENERATED. TROPHOBLAST CELLS ARE INCORPORATED INTO THAT FROM THE INTRAMURAL OR FROM THE ENTER STITIAL TROPOO BLAST END ENDING UP WITH A CHANGED ARTERY WHERE THERE IS NO SMOOTH MUSCLE. WHERE THERE MAY BE REENDOTHELIALIZATION HERE BUT YOU'RE ALSO LEFT WITH A LAYER OF FIBRINOID WHICH HAS TROPHOBLAST EMBED FRIDAY IT AND THERE IS A VERY NICE DIAGRAM -- EMBEDDED IN IT -- WHICH WAS PRODUCED SHOWING THE SORT OF CROSS SECTION AND THE CHANGE IN CROSS SECTION BETWEEN THE UNREMODELED SPIRAL ARTERY AND THE REMODELED SPIRAL ARTERY TAKEN DIRECTLY FROM OBSERVATION AND DRAWING AND YOU CAN SEE HERE IS THE VASCULAR SMOOTH MUSCLE. HE IS EXTRACELLULAR MATRIX AND THE ENDOTHELIAL CELLS AND FIRST, LOOK AT THE SIZE CHANGE AND ALSO LOOK AT THE DIFFERENT COMPONENTS THAT ARE NOW PART OF THIS VESSEL. THE EXTRA VILLOUS TROPHOBLAST. YOU ALSO GOT ACCESSORY CELL SUCH AS MACROPHAGES AND NATURAL KILLER CELLS ALSO INVOLVED IN THIS TRANSFORMATION. SO I'LL GO BACK TO THAT PREVIOUS ONE. SO, THERE WAS ORIGINALLY, HYPOTHESES ABOUT TWO WAVES OF INVASION. AND YOU'LL STILL FIND A LOT OF THAT IN OBSTETRIC TEXTBOOKS FOR EXAMPLE. BUT THERE IS LATER WORK SUGGESTED THAT THERE IS REALLY NOT A DIFFERENTIATION IN THE SAME WAY THAT THEY TALKED ABOUT THE TWO WAVE HYPOTHESES. BUT, THAT THERE MAY BE DIFFERENT DEGREES OF INVASION BY DIFFERENT PARTS OF THE INVADING TROPHOBLAST. INTERSTIRAL TROPHOBLAST MAY HAVE RAY GREATER ROLE TO PLAY EARLIER ON WHILE THE ENDOVASCULAR TROPHOBLAST MAY PLAY A GREATER ROLE FURTHER INTO THE INVASION PROCESS. SO, HERE WE HAVE SOME PICTURES TAKEN FROM PAPERS OF THE REMODEL SPIRAL ARTERY. THIS IS EARLIER IN GESTATION. ONE LATER IN TERM. AND YOU MAY NOT BE ABLE TO SEE IT REALLY THAT WELL BECAUSE IT IS COMPRESSES BUT THIS IS EARL CHOOY A MUCH BILLINGER OPENING THAN THE ONES THAT ARE DOWN HERE IN THESE UNREMODELLED SPIRAL ARTERIES, NEITHER PREECLAMPSIA -- PREECLAMPSIA AND SUPERIMPOSED HYPERTENSION. BUT CLEARLY YOU CAN SEE COMPARED TO THESE, YOU CAN SEE THESE TIGHT BANDS OF MUSCLE FOR EXAMPLE, AROUND THE VESSELS SHOWING THAT THEY HAVE NOT BEEN REMODELED IN THE FASHION THEY OUGHT TO BE. WHAT ABOUT THE TIMING OF THE INVASION? WELL, THIS IS SORT OF A FEW LIKE, A FUNCTIONAL MEASURE OF THE TIMING OF THE INVASION OR AT LEAST WHEN IT BECOMES IMPORTANT. AND THE THAT IS LOOKING AT OXYGENATION, OXYGEN TENSION IN THE PLACENTA VERSUS THE UTERUS. AND WHAT CAN YOU SEE HERE IS THAT DURING THIS PERIOD HERE FROM THE EIGHTH TO 15th WEEK YOU'RE SEEING A HUGE INCREASE IN OXYGENATION IN THE INTERVILLA SPACE THAT IS BECAUSE THOSE VESSELS HAVE BEEN OPENED UP AND YOU'RE NOW GETTING A LOT MORE FLOW THROUGH THE INTERVILLA SPACE. SO WHAT IS THE UNDERLYING MECHANISM FOR INVASION? HOW DO CELLS KNOW WHAT TO DO, WHERE TO DO IT AND WHERE TO STOP? AND THAT IS SOMETHING THAT HAS BEEN PUZZLING A LOT OF PEOPLE FOR A LONG TIME AND CERTAINLY NOT YET RESOLVED. THIS IS A NICE DIAGRAM FROM PETER'S GROUP. HE ALWAYS DRAWS VERY NICE DIAGRAMS IN HIS PAPERS. AND WHAT IT SHOWS IS HERE THE CELLS, PROLIFERATIVE CELLS AT THE BOTTOM OF THE TROPHOBLAST CELL COLUMN, THE DETACHED DAUGHTER CELLS HERE THAT ARE POST-PROLIFERATIVE, DIFFERENTIATING INTO EXTRA VILLOUS TROPHOBLAST, TRANSFORMING INTO POL IGINAL EXTRACELLULAR MATRIX AND FINALLY FUSING INTO MULTINUCLEAR TROPHOBLAST GIANT CELLS. THIS IS THE PROCESS THAT HAS BEEN SEEN BY HISTOCHEMISTRY, ANATOMY, BY VERSE METHODS LOOKING AT THE PLACENTA WHEN YOU CAN GET THE SAMPLES BUT AGAIN, METHODS YOU CAN'T USE IN REALTIME. WE KNOW THAT AS PART OF CYTOTROPHOBLAST DIFFERENTIATION, THERE IS DISSOLUTION OF JUNCTIONS AND LOSS OF POLARITY, REARRANGE. , LOSS OF EPITHELIAL MARKERS AND A SWITCH IN INTERGRAIN EXPRESSION FROM LAMINANT TO FIBER IN EFFECT IN BINDING INTERGRINS AND SECRETION OF METALLA PRO TIN ACES AND A DIAGRAM LOOKS LIKE THIS PROCESS. CELLS GOING FROM ANGERED EPITHELIAL CELLS WITH NICE JUNCTIONS WITH AN BASAL MEMBRANE, BREAKING DOWN, BECOMING NONPOLAR AND EVENTUALLY BECOMING INVASIVE AND THESE MESENCHYMAL TYPE CELLS. THE INTERESTING THING IS I FOUND THIS DIAGRAM WHEN WE WERE LOOKING AT THE EPITHELIAL TO MESENCHYMAL TRANSITION. THIS IS TAKEN FROM A PAPER LOOKING AT EPITHELIAL TO MESENCHYMAL TRANSITION AND THIS PROCESS IS SOMETHING THAT HAS BEEN KNOWN FOR A LONG TIME. IT'S A PROCESS THAT AND YOU CAN SEE THE MARKERS THERE FOR TROPHOBLASTS AND AS THEY SWITCH MARKERS, WHICH YOU PROBABLY CAN'T SEE THAT WELL BUT MARKERS FOR PLEASE EN CAMEAL CELLS, THOSE TRANSITIONS LOOK VERY LIKE -- MESENC HYMAL CELLS -- LIKE WHAT YOU SEE IN THE HUMAN TROPOPLAST. AND IN FACT, THIS IS TAKEN FROM ANOTHER PAPER BY THE PEOPLE LOOKING AT EMT AND DEFINES THREE DIFFERENT TYPES OF TRANSITION. ONE THAT TAKES PLACE IN EMBRYONIC DEVELOPMENT, GASTROALATION, NEURAL CELL MIGRATION AND SO ON AND SO FORTH WHERE CELLS WILL MOVE FROM ONE PLACE TO ANOTHER, REIMPLANT IF YOU LIKE, AND GROW SECONDARILY. AND THEY GO THROUGH THIS EPITHELIAL TO MEAS AN CAMEAL TRANSITION AND FIND THEIR NEW HOME AND GO THROUGH THE REVERSE PROCESS, MEAS AN CAMEAL AND REIMPLANT AND START A NEW TISSUE. TYPE II IS THE WOUND HEALING, CELLS CLOSE TO A DAMAGED AREA WILL BECOME MORE FIBROBLASTIC AND MOVE AND START TO SECRETE FIBROINOID AS PART OF THE WOUND-HEALING PROCESS. THE THE ONE PEOPLE ARE MOST PROBABLY FAMILIAR WITH, IT COMES BACK TO WHAT CATHY WAS TALKING ABOUT EARLIER, THE PARALLELS BETWEEN CANCER BIOLOGY AND THE PLACENTA, IS WHERE EPITHELIAL CARCINOMA HAS BECOME METASTATIC AND THEN METASTATIC CELLS MIG EXPIRATE FORM SECONDARY TUMORS. NOW, WE HAVE DONE WORK ON THIS WORKING HARD TO GO FURTHER. BUT OUR INITIAL IMPRESSIONS ARE THAT WE DO SEE SOMETHING VERY MUCH LIKE THIS. SO, WE DID A COMPARISON OF FIRST TRIMESTER CYTOTROPHOBLASTS AND EXTRA VILLOUS TROPHOBLAST CELLS AND LOOKED AT A VARIETY OF GENES ASSOCIATED WITH THE EPITHELIAL TO MESENCHYMAL TRANITION. WE HAVE A SERIES OF EPITHELIAL MARKERS, EGF RECEPTOR, OCL, PART OF THE TYPE JUNCTION. MESENCHYMAL MARKERS, FIBROCONNECT IN AND OTHERS. WHAT CAN YOU SEE IS BETWEEN THE CYTOTROPHOBLASTS AND THE EXTRA VILLOUS TROPHOBLASTS, HUGE DECREASES IN THE EPITHELIAL MARKERS EVEN BIGGER INCREASES IN THE MESENCHYMAL MARKERS AND INCREASES MAJOR INCREASES IN THESE METAB LOW APPROPRIATE EN ACES. AND OUR CONCLUSION IS THAT THE PROCESS WHEREBY SUCH TROPHOBLASTS DIFFERENTIATE INTO EXTRA VILLOUS TROPHOBLAST IS AN EPITHELIAL TO MESS AN CAMEAL TRANSITION BUT IT'S NOT LIKE THE OTHERS. IT'S GOT A LOT OF SIMILARITIES. ALL OF THOSE TYPE I AND TWO AND 3 HAVE SIMILARITIES AND OURS HAS SIMILARITIES TO THOSE BUT THEY ARE ALL DIFFERENT AS WELL. WE THINK WE MAY BE LOOKING AT TYPE 4 EPITHELIAL TO MESENCHYMAL TRANSITION. SO, THAT'S A LITTLE BIT ABOUT STARTING TO LOOK AT THE UNDERLYING MOLECULAR MECHANISMS. WHAT ABOUT WHERE CAN WE GO? HOW CAN WE GO FURTHERED? WHAT IS AVAILABLE AND WHAT MIGHT BE POSSIBLE? WELL, THERE ARE A NUMBER OF WAYS OF LOOKING AT THIS. THIS IMAGING FOR EXAMPLE. NEW ULTRASOUND TECHNIQUES, ULTRAFAST POWER DOPPLER, COHERENT FLOW POWER DOPPLER AND WHAT SALLY AND STACEY IS DOING, THIS AUTOMATED QUANTITATIVE ANALYSIS EVER 3D PUP DOPPLER. I'LL SHOW YOU A COUPLE OF EXAMPLES FROM THE LAST THERE BECAUSE I AM ABLE TO USE THEM. AND SO HERE WE ARE LOOKING AT IMAGING OR AN IMAGE OF THE PLACENTA WITH THE MATERNAL VASCULAR SPACE FEEDING INTO THIS PLACENTA AND NOW YOU CAN SEE THOSE OUTLINED AREAS ARE THE PLACES WHERE THE BLOOD IS FEEDING INTO THE PLACENTA. WHERE THE SPIRAL ARTERY JETS ARE GOING INTO THE PLACENTA. LET ME JUST RUN THAT ONE MORE TIME. AND YOU'LL SEE AGAIN, YOU CAN SEE THE OVERLAY OF THAT VASC LA SPACE UNDER THE PLACENTA AND THEN AS IT COMES UP, YOU SEE ALL THE SPACES WHERE THE SPIRAL ARTERY JETS ARE COMING IN. SO WE ARE BEGINNING TO BE ABLE TOL VISUALIZE THE WHERE. AND THIS NEXT IMAGE IS TAKEN FROM SALLY COLLINS WORK AS WELL. AND THAT IS VISUALIZATION OF THE SPIRAL ARTERY JETS ENTERING THE ENTER VILLOUS PLACE. SO THE UTERINE PLA SENT INTERDAYS AND HERE IS THAT SPIRAL ATTAR REJET COMING INTO THE INTERVULUS SPACE. AND THOSE JETS CAN BE IMAGED OVER GESTATION TO BUILD A PATTERN OF FLOW INTO THE INTERVILLOUS PLACE. THE PROBLEM IS THAT BY THE TIME YOU SEE BAD FLOW, IT MAY BE A LITTLE TOO LATE AND WE LIKE TO BE ABLE TO GO EARLIER AND TO LOOK AT THE ESTABLISHMENT, DEVELOPMENT OF INVASION AND THAT CIRCULATION. AND SO, WHAT CAN WE LOOK AT? THE WE HAVE GOT THE POTENTIAL FOR LIQUID BIOPSY PRODUCTS SECRETED FROM THE EXEXTRA VILLOUS TROPHOBLAST. WHEN DO WE START TO SEE THEM. EXOSOMES FROM THE EXTRA VILLOUS TROPHOBLAST. AND ALL ASSISTED IMAGING TECHNOLOGIES WHERE YOU ARE USING SOMETHING NOT JUST A DIRECT IMAGING AND SO PERHAPS DIRECT VISUALIZATION OR DIRECT CONTRAST PROBES OF SOME SORT AROUND TO BE ABLE TO SEE WHAT IS GOING IN THERE. EVT HOMING BROKES. ANTIBODIES. A VARIETY OF THINGS WE CAN THINK OF THAT WE NEED TO BE EXPLORING TO TRY AND GET TO THOSE VERY, VERY EARLY STAGES OF GESTATION AND INVASION. AND SO, THE CHALLENGES I THINK RIGHT NOW ARE FIRSTLY THAT WE HAVE VERY LOW RESOLUTION ON THE ENTITIES AND THE PROCESSES INVOLVED, THE TYPES OF EVT AND MECHANISMS SYSTEM OF DIFFERENTIATION AND BY WHICH VASCULAR SMOOTH MUSCLE ARE DISRUPTED. AND ALSO WE HAVE A VERY SMALL VOLUME OF CELLS AFFECTING AND BEING AAFFECTED BY THE INVASION OF MEDIATED CHANGES COMPARED TO THE MOTHER WHO JUST DILUTES OUT LARGE AMOUNTS OF SIGNAL. AND THEN OF COURSE THERE IS THE REALLY, REALLY BIG PROBLEM OF THE USE OF CONTRAST AMOUNTS, PROBES AND ANTIBODIES AND OTHER XENOBIOCHEMICALS WHICH WHILE SOMEWHAT DIFFICULT IN GENERAL ARE EVEN MORE RESTRICTED IN PREGNANCY AND I HAD DISCUSSIONS WITH THE PEOPLE LOOKING AT GADOLINIUM AND THE MANUFACTURERS SAY THEY WON'T TOUCH THIS STUFF WITH A BARGE POLE BECAUSE THEY DON'T WANT TO GET ANYWHERE NEAR PREGNANCY IT'S A BLACK BOX WARNING. THAT'S IT AS FAR AS THEY ARE CONCERNED. SO, I JUST LIKE TO UNCLE THAT THE PEOPLE WHO CONTRIBUTED TO THIS AT HACKENSACK. STACEY, SONIA, MICHIGAN STATE AND TORONTO AND OXFORD AND AUCKLAND. AND I PROBABLY HAVEN'T GOT ANY TIME FOR QUESTIONS. SO I HOPE TO SEE YOU AFTERWARDS. [ APPLAUSE ] >> SO I DO WANT TO SAY WE WON'T TAKE ANY QUESTIONS BUT THAT WAS REALLY A BEAUTIFUL OVERVIEW AND FOR THOSE OF YOU GOING TO THE BREAKOUT SESSION, I THINK IT DID A PANEL TAFTIC JOB OF LAYING THE GROUNDWORK FOR THAT DISCUSSION. -- A FANTASTIC JOB -- NOW WE'LL HAVE ONE MORE TALK BEFORE LUNCH. AND THIS IS GOING YET IN ANOTHER DIRECTION TO STRETCH YOUR CREATIVE MINDS AND THIS IS DR. SHAOCHEN CHEN FROM UNIVERSITY OF CALIFORNIA SAN DIEGO, BLUE SKY TECHNOLOGY NANOBOTS. >> FIRST I LIKE TO THANK DR. WEINBERG FOR INVITING ME HERE. THIS IS NEW TERRITORY FOR ME. RHYME ENGINEERING DEPARTMENT AND CODIRECT TISSUE CENTER FROM UNIVERSITY OF SAN DIEGO. RECENTLY THE WASHINGTON JOURNAL GAVE ME A NICKNAME [ INDISCERNIBLE ] SO IF IT IS DIFFICULT FOR YOU TO PRONOUNCE MY NAME, JUST CALL ME MICROFISH MAKER. SO I TELL YOU THE STORY. HOW MANY OF YOU HAVE SEEN THIS MOVIE CALLED FANTASTIC VOYAGE? IT'S GREAT. SO, YOU KNOW THAT IT'S ABOUT A SCIENCE FICTION MOVIE ABOUT A CREW OF SCIENTISTS, MEDICAL DOCTORS AND ENGINEERS BOUGHT INTO A SUBMARINE AND THEN THE WHOLE THING GOT SHRUNK INTO ONE MICRON SIZE AND THEN INJECTED INTO THE BODY TO FIX A PATIENT'S BLOOD CLOT IN THE BRAIN. SO, I LOVE SCIENCE FICTION STORIES AND MOVIES AND EVERY TIME I ALWAYS THINK OR WONDER WHAT CAN I DO TO MAKE THIS HAPPEN? THAT IS WHAT WE DID RECENTLY BY USING 3D PRINTING TO CREATE A MICROFISH THAT CAN PROPEL BY ITSELF. YOU CAN SEE THIS FISH, THERE IS A NANOPARTICLES IN THE TAIL OF THE FISH THAT CAN REACT WITH THE SOLUTION THAT GENERATES ABUBBLE AND THE BUBBLE WILL PUSH THE FISH FORWARD. I CAN PLAY THIS AGAIN. THE SIZE OF THE FISH IS ABOUT 100 MICRO. THIS IS JUST FOR THE PURPOSE OF VIDEOTAPING BECAUSE IT IS TOO SMALL YOU CAN NOT SEE. SO WE CAN MAKE AS SMALL AS 100 NANOMETER IF YOU WANT. AND THEN IN THE FISH BODY WE ENCAPSULATE THESE NANOPARTICLE THESE POLYDIE SETA LEAN AND CAPTURE TOXIC MOLECULES IN THE SOLUTION. THAT TRANSPIRING BETWEEN THE POLYBY SET LEAN PARTICLE AND TOXIC MOLECULE WILL GENERATE FLUORESCENCE COLOR. SO YOU CAN SEE THIS TRANSPARENT MICROFISH BECOMES RED ONCE IT TAKES THE TOXINS IN THE SOLUTION. SO IT CAN BE USE TO DEFOXIFY THE MATERIAL IN THE SYSTEM. SO, AND THIS IS "WALL STREET JOURNAL" SAYING YOU CAN USE THIS TECHNOLOGY TOW REMOVE STUFF IN THE BLOODSTREAM AND CERTAINLY IT CAN BE SELF PROPELLED. DO SENSING. AND ALSO CAPTURE DRUGS SO NANOPARTICLES IN THE FISH WHEN THE FISH MOVE, THEY CAN DELIVER THE DRUG LOCALLY TO THE POINT AND THEN RELEASE THEM AT THAT SPECIFIC TARGET AND ALSO DO NANOSURGERY. THINK ABOUT THIS IN A MOSQUITO. MOSQUITO IS VERY SMART WITH THIS MOSQUITO PRO BOSSIS TIP IS ABOUT 35 MICRONS BUT IT IS VERY COMPLICATED STRUCTURE. IT HAS TWO CUTTERS TO CUT YOUR SKIN AND THEN THERE ARE TWO TUBES ALSO IN THE TUBE. ONE TUBE SUCKS THE BLOOD WHEN YOU'RE CUT AND THE OTHER TUBE IS TO DELIVER THE CHEMICALS SO THE BLOOD CAN CONTINUE TO USUALLY FLOW INTO THE MOUTH OF THE MOSQUITO. SO WE CAN ACTUALLY -- BIOMEDDIC SURGERY TOOLS FOR LIFE. IF YOU WANT TO USE THIS FISH-TYPE NANOROBOTS TO DO SURGERY. SO THE TECHNOLOGY, THE WORK FOR THIS ONE IS BEHIND THIS PRINTING TECHNOLOGY WE DEVELOPED IN OUR OWN LAB. I THINK IT'S THE FASTER 3D PRINTING SYSTEM IN THE WORLD. THE IDEA IS TO USE SO-CALLED ADDITIONAL TALL MICROMETER ARRAY LIKE YOU PROJECT THESE IMAGES FROM THE SITES TO SCREEN WE PROJECT IMAGES TO THE PHOTO ARRAY SENSITIVE POLYMERS. SO BY SHINING A LIGHT, THESE POINTS, THESE PARTS WITH LIGHT WILL BE FORMING THE SOLID STRUCTURES. SO, IN TRADITIONAL 3D PRINTING PEOPLE USE A NOZZLE TO DELIVER THESE ONE BY ONE AND POINT BY POINTED AND LAYER BY LAYER. WE FOLLOW THE IDEA OF FILM PRODUCING -- FILM PLAYING. YOU SEE THIS SLIDE IS PROJECT WITH SCANNING XY AND ALSO IN Z DIRECTIONS DO WITH CONTINUOUS PRINTING OR CONTINUOUS IMAGING IN THIS CASE, IS PRINTING JUST LIKE PLAYING MOVIE WITHOUT STOPPING BETWEEN DIFFERENT LAYERS. THE SPEED IS EXTREMELY FAST. LET ME SHOW YOU HOW FAST THIS ONE IS. WE IN THIS CASE, I PRINTED A CONDUIT USED TO REPAIR SPINE DAMAGE. AND THE SPINAL CHORD HAS GRAY MATTER IN THE MIDDLE AND SO YOU CAN PRODUCE THESE LINEAR CHANNELS IN THIS CONDUIT TO HELP THIS NEURON TO GROW FROM BOTH SIDES SO HELP THEM TO CONNECT. SO, WE PRINTED ONE WHICH IS 3 MILLIMETER IN LENGTH AND ONE MILLIMETER IN DIAMETER AND THERE IS ABOUT 40 MICROCHANNELS, LINEAR CHANNELS IN THIS DIRECTION. YOU CAN SEE THAT IT IS EASY TO PRINT THIS REALLY IS GRAY MATTER IN THE MIDDLE AND ALL OF THESE CHANNELS IN THIS SCAFFOLD. AND LET ME TRY AGAIN. THIS MILLIMETER DEVICE TAKES UP JUST ONE SECOND. IF YOU USE A NOVEL BASED PRINTER IT MAY TAKE SEVERAL HOURS AND ALSO I THINK IT IS VERY HARD TO PRODUCE ALL THE WALLS BETWEEN THE CHANNELS BECAUSE THEY ARE SO THIN WITH THIS SOFT GEL. SO, MATERIAL WE HAVE BEEN PLAYING WITH INCLUDE POLEY GLYCOWHICH IS PECULIARAL PROPERTIES, NONTOXIC. PEOPLE USE FOR MEDICAL IMPLANTS. MANY OTHER DEVICES AND APPLICATIONS LIKE TISSUE ENGINEERING AND CULTURES AND PRINT GELATIN BASED MATERIALS AND THIS MATERIAL IS ALREADY CELL ADHESIVE. SO MANY BONDING SITES IN THAT STRUCTURE. ALSO THIS IS MORE FAMILIAR WITH YOU GUYS. YOU CAN PRINTED THIS IN NANOSECOND AND ALSO SEE THE CURBAATURE OF THIS ONE VERY SMOOTH TRADITIONALLY PRINTINGS INEL AND CREATED ART VISUAL INTERFACE BETWEEN LAYERS AND POINTS. HERE I DO CONTINUOUS PRINTING TO SEE THE SIDE WALL IS VERY SMOOTH. NO ARTIFICIAL LAYERS THERE. SO MECHANICAL INTEGRITY WILL BE MUCH BETTER CONTROLLED AND IT CAN PRINT ANY OTHER STRUCTURE AS LONG AS YOU HAVE -- DIGITAL IMAGE IN ONE SECOND. SO THIS IS LIKE VESSEL SYSTEM AND ALSO THIS IS PATTERNS. WHEN I SEE THIS SPINAL AREA, I THINK WHETHER WE CAN TRY TO PRINTED THAT ONE USING GEL TAN-BASED MATERIALS. WE CAN PRINT MECHANICAL PROPERTIES IN THE DEVICE THAT WE HAVE SO THIS IS A SO-CALLED KNEEINGATIVE POISON RATIO. SO NATURAL MATERIAL ALL BEHAVE LIKE THAT. WE PRINTED MATERIAL WHERE WE CAN STRETCH IT IT BECOMES LARGER. SO WE CALL IT NEGATIVE POISES ON RATIO MATERIAL. AND IT CAN PRINT MATERIAL JUST IN HYBRID FORMAT SELL ON ONE SIDE OF THE MATERIAL IS NATURAL AND SHRINKS WHEN YOU STRETCH AND THE RIGHT SIDE IS NEGATIVE POISES ON RATIO SO WHEN YOU STRETCH IT BECOMES LARGER. SO USING THIS KIND OF STRETCHING DEVICE TO UNDERSTAND DIFFERENT CELL BEHAVIOR, DIFFERENTIATION CAN BE DIFFERENT WHEN CELLS ON THIS SIDE HAS SHRINKING ENVIRONMENT AND OTHER SIDE YOU HAVE EXPANSION ENVIRONMENT. YOU CAN -- MECHANICAL PRINTING AND ADD FUNCTIONAL CHEMICALS INTO THE SYSTEM. SO IN THISIS CA, I PUT THIS DISECTION NANOPARTICLES INTO THE 3D HYDROGEN MATERIALS SO IT IS LIKE A SPONGE. AGAIN, THIS CAN SENSE AND CAPTURE TOXINS MOLECULES IN A SOLUTION. SO WE PRINTED THEM INTO LIVER MICKIC STRUCTURE. LIVER IS HEX CONIN NATURE FOR THE LOOK AT THE MICROARCHITECTURE. AND WE USE A MASK AND PLACE THEM IN DIFFERENT LOCATION SO YOU CAN GENERATE THIS SYSTEM IN 3 DIMENSIONAL FORMAT. SO MULTI-LEVEL STRUCTURES AND ONCE YOU PUT THIS IN THIS DEVICE, INTO THE MERITY CONTAINING SOLUTION, YOU CAN SEE THEY SUCK UP OUGHT OF THESE AND FICIENCY IS VERY, VERY HIGH WITH THIS KIND OF NANOPARTICLE ENHANCED HYDROGEL. AND ALSO EMBED MATERIALS IN THE SYSTEM. SO IN THIS CASE, WE PUT NANOPARTICLES INTO THE HYDROGEL SO NOW WE ARE MAKING A BIOCOMPATIBLE MATERIAL. SO USUALLY WHEN YOU TALK ABOUT PEG ELECTRIC, IT'S BASED ON PZT. AND IN THIS CASE, WE CHOOSE VERY HIGH EFFICIENCY IN TERMS OF GENERATING THIS ELECTRODES SIGNAL. SO, IT MEANS WHEN YOU PUSH THIS MATERIAL, WITH PRESSURE, WITH DISPLACEMENT, THEN YOU CAN GENERATE ELECTRICITY. SO IT IS A MEASURE FOR FORCE, FOR DISPLACEMENT, FOR MANY, AND VERY SENSITIVE. AND I'M THINKING OF THIS ALSO CAN GENERATE ACOUSTICS. SO CAN WE USE 3D PRINTING COMBINED WITH THIS KIND OF PEASO ELECTRIC MATERIAL TO GENERATE DESIGNER TYPE OF PROBES FOR MAXIMIZING THE SENSITIVITY OR POWER OF THIS PEASO ELECTRIC TRANSDUCERS. JUST ALATED. NOT SURE IT IS USEFUL. THIS COMES TO THE FISH PART. SO ADD MORE NANNIE PARTICLES BOTH ORGANIC INTO THE DEVICE THAT YOU'RE PRINTING SO WE HAVE THE NANNY ON PARTICLE IN THE TAIL AND MAGNETIC PARTICLE IN THE HEAD AND THEN YOU PRINT STEP-BY-STEP IN THIS CASE, AND IN THE MIDDLE WE PUT A TOXIN CAPTURED NANOPARTICLES PDA. SO AGAIN, YOU CAN PRINT SCHOOL OR FISH IF YOU WANT IN NANOSECONDS. YOU GET DIFFERENT TYPES OF FISH, SHARK ORMONDA RAY. THEN HE WERE --, MANTA RAY. AND THIS FISH DOES TURNING AROUND LIKE A DRUNKEN FISH. BUT IF YOU PUT A MAGNETIC NANOPARTICLE IN THE HEAD, SO WHEN THEY PUSH THE FISH FORWARD, THEY USE MAGNET TO GUIDE THEM AND THIS FISH CAN FOLLOW YOUR DESIGN. AGAIN HERE, YOU SEE THIS TOXIC REMOVING FISH IN THE SYSTEM. NOW I LIKE TO SHOW YOU WE CAN ALSO PRINTED BIOLOGICAL CELLS IN THE SYSTEM. THE PRINTING PROCESS BY TURNING THE SOLUTION INTO HYDROGEL. SO IN A SOLUTION, YOU CAN HAVE MANY THINGS. NANOPARTICLES LIKE I SHOW BEFORE AND IT CAN BE GROWTH FACTORS AND DRUG NANOPARTICLES OR CAN BE BIOLOGICAL CELLS. SO WE WERE FUNDED BY NIH FOR THIS LIVER ON A CHIP PROJECT AND IF YOU LOOK AT THE LIVER, YOU HAVE THIS HEXAGONAL ARCHITECTURE WITHIN THIS UNIT YOU HAVE ALL OF THESE CENTRAL VEINS AND ALL OF THESE BRANCHES. SO HOW CAN WE MIMIC THIS KIND OF DEVICE? USING A LIVE CELLS? SO YOU NEED SEVERAL THINGS. FIRST PATTERN? GEOMETRY ARCHITECTURE IS VERY IMPORTANT. CELL COMPOSITION HERE. YOU NEED TO HAVE DIFFERENTTINES OF CELLS IN THE SYSTEM. AND THE THIRD IS TO HAVE THE MATERIAL THAT CAN GIVE YOU THE CURES FOR CELL TO GROW. THAT'S WHAT WE DID. VERY RECENTLY IT WAS PUBLISHED IN FEBRUARY OF THIS YEAR. SO THE FIRST STEP INTO PRINT THE LIVER CELLS INTO THIS HEXAGON PATTERN AND THEN WE MIX THE LIVER. THIS IS HUMAN INDUCED CELLS DERIVED HEPATIC CELLS ALONG WITH GELATIN. GELATIN IS VERY -- PROVIDES VERY SIMILAR MECHANICAL STIFFNESS TO THE LIVER. THAT'S WHY WE USE THAT. AND WHEN YOU MIX THIS CELL TOGETHER AND YOU APPROXIMATE UT IT INTO THE PRINTER AND THEN SHINE THE LIGHT WITH THIS KIND OF PATTERN, AND WE CAN PRINT THIS LIVER TISSUE IN ONE SECOND. JUST VERY QUICK WITHOUT ANY SCALING OR ANY STOP IN PRINTING. SO THIS IS A STAIN, THESE ARE LIVER CELLS HERE DERIVED FROM IPCs. SO WE IN THIS CASE, WE LEAVE THIS HOST IN THE AREAS OPEN SO WE DO THE NEXT STEP BY PRINTING CELLS WITH AT I POSED DERIVED STEM CELLS MIXED WITH GEL TIP AND HIGHLYERONNIC ACID USEFUL FOR HELPING VASCULATURE GROWTH. AND THEN NEW CELL COMBINED WITH MONOMER SOLUTION AND THEN SECOND PART OF THE PATTERN TO GEL THIS YEAR'S. NOSE OPEN AREAS FROM PREVIOUS SUBSTRATE. AND ANOTHER SECOND WE PRINT THESE ENDOTHELIAL CELLS, STEM CELLS, ALONG THE SIDE OF THE NEUROCELLS. SO YOU CAN SEE THIS IS EMERGED IMAGE HERE AND IT IS 3 MILLIMETER BY 3 MILLIMETER. THE THICKNESS AT THIS MOMENT WE CONTROL ABOUT 250 MICRONS SO THEY HAVE ENOUGH DIFFUSION FOR SURVIVOR IN LONG TERM CULTURE. AND LOOK AT LONG TERM MAINTENANCE. DAY ONE AFTER YOU PRINT, YOU CAN SEE DIFFERENT PARTS OF THE LIVER TISSUE HERE. AND THEN EVEN AFTER 10 DAYS YOU SEE THE PATTERN IT SHOWS A VERY SIGNIFICANT EXPRESSION OF THESE GENES AND WE COMPARE THIS 3D TISSUE CULTURE WITH 2D MODERN LAYER AND ALSO 3D HEPATIC CELL ONLY WITH THE CELLS DIFFERENT TYPE OF MODELS FOR STUDY PURPOSE. WE ALSO LOOK AT LIVER FUNCTIONS LIKE ANABOLIC AND SHOWS THE 3D MODELING IS BETTER IN TERMS OF THESE FUNCTIONS. VERY IMPORTANT USING THIS KIND OF STRUCTURE IMVITRO MODEL BASED ON HUMAN CELLS TO DO DRUG TESTING. SO WE TAKE ANTIBIOTICS AND THEN LOOK AT THESE ENZYMES AND SHOW THE SIGNIFICANT INCREASE WHEN YOU DOSE THESE DRUGS INTO THE LIVER TISSUE. SO, WITH THAT, I LIKE TO SUMMARIZE MY TALK. I THINK SO-CALLED BLUE SKY TECHNOLOGY IS MANY THINGS ARE POSSIBLE AND THIS IS SPECIFIC FOR NANOBOTS, THEY CAN BE N. SELF PROPELLING, SENSING DETOXIFICATION, DRUG DELIVERY AND EVEN NANOSURGERY. BEHIND THIS DEVICE IS THE 3D PRINTING TECHNOLOGY. IT'S VERY POWERFUL FOR CREATING DEVICES WITH ANY SHAPE YOU WANT BECAUSE THAT IS REALLY THE BEST NATURE OF 3D PRINTING. SO FOR NIH THAT IS PATIENT SPECIFIC DEVICES AND IT CAN OFFER VERY UNIQUE MECHANICAL PROPERTIES LIKE STIFFNESS GRADIENT. IT CAN HAVE DESIGNER CHEMICAL COMPOSITIONS JUST ADD DIFFERENT THINGS AT DIFFERENT LOCATIONS AND ALSO BIOMETRIC CELLULAR ARCHITECTURES. AND I JUST WHEN I WAS SITTING THERE LISTENING TO THESE GREAT TALKS BEFORE ME, SOME IDEAS WE COULD TRY LIKE PLACENTA ON A CHIP. WE CAN TRY THOSE. PRINT THOSE TISSUES POSSIBLY ON TO A CHIP-TYPE OF SUBSTRATE AND STUDY THE INTERACTIONS AND WHETHER WE CAN ALSO 3D PRINT THOSE BIOMI METIC IN-VITRO MODELS BY PUTTING CELLS IN DIFFERENT LOCATIONS AND BY PRIVATING ARCHITECTURES. I LOOK AT THESE BEAUTIFUL DATA FOR THIS SPINAL ARTERY CELL THERE. REALLY NICE CELL BUT I THINK IT IS VERY EASY OR VERY DIFFICULT TO RE-CREATE THOSE. SO I'M THINKING 3D PRINTING CAN GENERATE WHATEVER SHAPE YOU WANT SO CAN WE TRY THAT? TALKING ABOUT DEVICES, AGAIN ACOUSTIC PROBES. CAN WE TRY THAT? AND DEFINITELY CREATE DIFFERENT TYPES OF PHANTOM TISSUES FOR IMAGING PURPOSES. THESE ARE ALL -- I CAN CONTROL THE STIFFNESS, AND THEN YOU CAN USE THAT KIND OF TISSUE MODEL TO CALIBRATE YOUR IMAGING SYSTEM. SO REALLY APPRECIATE THE SUPPORT FROM NIH AND NSF OVER THE YEARS. THAT'S ALL. THANK YOU VERY MUCH. [ APPLAUSE ] >> SO ANOTHER BEAUTIFUL TALK. AND I THOUGHT MAYBE WE COULD JUST TAKE JUST A SECOND TO THANK ALL OF THE SPEAKERS AGAIN FOR THEIR TALKS THIS MORNING. [ APPLAUSE ] OKAY. SO, IT IS LUNCH TIME AND WE ARE BEHIND. SO, I'M GOING TO DO LIKE I USED TO DO WHEN I RAN STUDY SECTION. WE ARE GOING TO DO WORKING LUNCHES. SO, 1:15 IS WHEN BREAKOUTS STARTED. SO YOU HAVE TIME. IT TAKES A WHILE. THERE ARE A LOT OF PEOPLE. UPSTAIRS IS CAFETERIA. I THINK THERE IS ANOTHER CAFETERIA THEY CAN POINT YOU TO AT THE FRONT LOBBY. GOAT YOUR LUNCH. BY 1:15 IF YOU COULD THEN MAKE YOUR WAY TO THE BREAKOUT SESSIONS, THAT WOULD BE SUPER. I THINK THAT THESE DISCUSSIONS ARE GOING TO BE GREAT. SO I HAVE TO TELL YOU, I FEEL LIKE I'M WALKING AROUND WITH THIS SORT OF DUMB GRIN ON MY FACE BECAUSE I THINK THAT THE TALKS WERE FANTASTIC AND THE BREAKOUT SESSIONS WERE AMAZING. I WALK AROUND TED AROUND TO EACH ONE OF THEM AND I HEARD A LOT OF GOOD DISCUSSION AND A LOT OF ENERGY, SO I HOPE YOU ENJOYED IT AS MUCH AS I DID, BECAUSE I JUST THOUGHT IT WAS FANTASTIC. I AM A LITTLE SAD, YOU KNOW, WE PUT UP THESE DREAM BOARDS THAT WE FIGURED PEOPLE WOULD PUT UP ALL THEIR CRAZY IDEAS, ALL THEIR CONCERNS ABOUT WHAT WE'RE NOT FOCUSING ON, AND THEY'RE LOOKING A LITTLE SPARSE, AND I HOPE THAT NOW THAT YOU'VE HEARD SOME TALKS AND YOU'VE WARMED UP, I HOPE WHEN YOU HEAD OFF TO THE POSTERS AND DEMOS AFTER THIS NEXT TALK, THAT YOU WILL THINK ABOUT THINGS THAT YOU MIGHT WANT TO ADD OR AT LEAST READ WHAT'S THERE AND SEE IF YOU ATBREE WIT AGREE WITH IT. SO I'M REALLY PLEASED THAT NOW WE'RE GOING TO HAVE A DISCUSSION FROM ONE OF OUR COLLEAGUES IN NEUROSIGSCIENCE, DR. ARTHUR TOGA IS GOING TO TALK ABOUT MANAGING AND VIEWING COMPLEX DATA, LABORATORY OF NEUROIMAGING, AND I'LL JUST SAY TH THE HUMAN PLACENTA PROJECT IS SORT OF AT AN EARLY STAGE, BUT ALREADY WE'RE RECOGNIZING IT AS WE GENERATE LARGE DATASETS, IMAGING DATA, GENETIC DATA, OMICS DATA, ALL THESE KINDS OF DATA, THAT WE'RE GOING TO HAVE TO THINK ABOUT HOW IT'S GOING TO BE MANAGED, OTHERWISE WE'LL HAVE LOTS OF SILOS WITH LITTLE BITS HERE AND THERE AND NO INTEGRATED WAY TO THINK ABOUT IT. SO ANYWAY, I'M DONE TALKING AND NOW I'LL INVITE DR. ARTHUR TOGA TO COME TO THE PODIUM. >> LET ME START OUT BY SAYING I KNOW ABSOLUTELY NOTHING ABOUT THE PLACENTA. SO WITH THAT PREMISE, I'D LIKE TO TELL YOU FOR THE NEXT -- WHAT DO I HAVE, 35, 40 MINUTES, 45 MINUTES? I'D LIKE TO TELL YOU IN MY ALLOTTED TIME HERE SOME OF THE EXPERIENCES THAT WE'VE HAD IN LOOKING AT BRAIN DATA OF ALL TYPES, AND THE WAYS IN WHICH WE'VE COLLECTED THEM, AGGREGATED THEM, UTILIZED THEM AND APPLIED THEM IN THE STUDY OF NEUROLOGICAL DISEASES AND PSYCHIATRIC DISORDERS AS WELL AS LIFESPAN CHANGES IN THE HUMAN BRAIN AND, IN FACT, ANOTHER SPECIES AS WELL. I THINK PERHAPS THE EXPERIENCES THAT WE'VE HAD ARE SIMILAR TO THE EXPERIENCES THAT YOU ARE HAVING AND WE'RE PROBABLY IN THE SAME BOAT IN MANY WAYS AND I WAS JUST TALKING TO TONY A MINUTE AGO AND I SAID TO HIM, IT'S NOT UNCOMMON FOR ORGAN SYSTEMS OR STUDIES OF A PARTICULAR ASPECT OF BIOLOGY TO BE SEPARATED FROM ITS NEIGHBOR. AND THAT'S JUST THE NATURE OF PERHAPS HOW WE FOCUS OUR ENERGIES OR WHERE WE SPEND OUR TIME. BUT I THINK OPPORTUNITIES LIKE THIS TO SHARE AND EXCHANGE IDEAS AND LEARN LESSONS FROM EACH OTHER IS SOMETHING PERHAPS WE SHOULD DO MORE OF. SO WITH THAT, LET ME BEGIN. SO THE STUDY OF HUMAN BRAIN IS PERHAPS LIKE THE STUDY OF THE HUMAN PLACENTA IN THAT IT CAN BE DONE ACROSS A VARIETY OF SPATIAL SCALES. THIS IS A SLIDE THAT ILLUSTRATES THE SPAN OF SPATIAL SCALES THAT CAN BE EXAMINES, LITERALLY FROM THE PROTEOMIC LEVEL UP TO THE WHOLE BRAIN LEVEL AND THAT'S DONE TYPICALLY IN THESE LARGE MULTISITE PROJECTS WHERE DATA ARE BEING COLLECTED USING A VARIETY OF METHODOLOGIES THEN HAVE TO BE COMBINED IN SOME WAY, INFORMATION FROM ONE CAN BE RELATED TO ANOTHER ACROSS THESE RATHER LARGE SCALES. GOING FROM NANOMETERS ALL THE WAY UM T UP TO CENTIMETERS REALLY PRESENTS SOME UNIQUE CHALLENGES BECAUSE FINDING SCALES AND COORDINATE SYSTEMS THAT ALLOW A RELATIONSHIP OF OBSERVATIONS TO BE MADE IS SOMETIMES VERY DIFFICULT BECAUSE EITHER THE METHODOLOGY IS A DESTRUCTIVE ONE OR THE TISSUE MUST BE TREATED IN SOME FASHION OR CHANGED OR MORPHED IN ONE WAY OR ANOTHER IN ORDER TO GET THE SIGNAL OUT OF IT. SO I THINK THIS IS ONE OF THE THINGS THAT'S QUITE SIMILAR BETWEEN OUR TWO TYPES OF STUDIES, AND WE WORK PRIMARILY FROM -- IN VARIOUS SPECIES FROM THE SYNAPSE LEVEL INTO THE BRAIN REGION LEVEL, BUT ALSO THERE ARE MEASUREMENTS WITHIN CELLS AND WITHIN REGIONS FROM THE GENOMIC LEVEL AND PROTEOMIC LEVEL. THE VERY SAME THING CAN BE SAID ABOUT FUNCTION. SO JUST AS IN THE PLACENTA, THE HUMAN BRAIN OBVIOUSLY PERFORMS A LOT OF DIFFERENT FUNCTIONS, AND THE TIME SCALE VARIES TREMENDOUSLY. IF ONE LOOKS AT THIS BRIEFLY, YOU CAN SEE LITERALLY FROM GOING MOLECULAR DYNAMICS ALL THE WAY UP TO BEHAVIOR AND MEMORY, THE NOTION THAT COGNITION, JUST US THINKING ABOUT THESE PROBLEMS, ARISES FROM INTERACTIONS AMONG MOLECULES, CELLS AND BRAIN REGIONS ACROSS TIME SCALES THAT ARE 18 ORDERS OF MAGNITUDE. 18 ORDERS OF MAGNITUDE. SO IF YOU'RE MAKING A MEASUREMENT OF THE MILLISECOND SCALE FOR EXAMPLE OR MINUTE SCALE AND TRYING TO RELATE THESE DIFFERENT THINGS, CLEARLY THE METHODOLOGY USED TO COLLECT THAT DATA IS QUITE DIFFERENT AND THE TYPE OF DATA THAT MAKES THOSE MEASUREMENTS IS ALSO ORGANIZED IN A VERY DIFFERENT WAY. SO IF YOU THINK ABOUT THESE TWO SCALES, TIME AND SPACE, THERE'S CLEARLY A BIG PROBLEM IN TERMS OF MANAGING DATA LIKE THIS. AND THERE ARE A NUMBER OF EFFORTS AROUND, AND I'LL SHOW YOU SOME EXAMPLES IN THE NEUROSCIENCE COMMUNITY WHERE PEOPLE HAVE DEVELOPED AN E SCIENCE TO TRY TO ASSIMILATE THESE DIFFERENT OBSERVATIONS ACROSS THESE DIFFERENT TYPES OF SCALES, AND IN ORDER TO DO THAT, ONE HAS TO CREATE DATABASES, TOOLS AND MODELS THAT ALLOW YOU TO MAKE COMPARISONS IN RELATIONSHIPS. OF COURSE YOU KNOW EVERYBODY WOULD SAY, WELL, NATURALLY YOU HAVE TO DO THAT, BUT THE WAY IN WHICH THAT'S DONE IN TERMS OF THE DEGREE TO WHICH IT'S EFFECTIVE IS REALLY IMPORTANT. I'LL SHOW YOU SOME EXAMPLES OF THAT AS WE GO ALONG AS WELL. BEFORE I DO THAT, LET ME SET THE STAGE ABOUT THE CHALLENGES THAT WE FACE, AND I MEAN ALL OF US, REGARDLESS OF THE ORGAN SYSTEM OR TISSUE YOU'RE LOOKING AT, AND ALSO THE SORT OF TECHNOLOGIES THAT MAY BE APPLIED TO SOME OF THESE THINGS. SO NEUROSCIENCE REALLY HAS BECOME A COMPUTATIONAL SCIENCE ALL THE WAY TO AN E-SCIENCE, SO MANIPULATING DATA IN A WAY TO MAKE THOSE COMPUTATIONS TRACTABLE. AND WE HAVE LOTS OF DATA AND IT'S INCREASING EVERY DAY, THE TECHNOLOGY IMPROVES ITS TEMPORAL SPATIAL RESOLUTION EVERY DAY, AMOUNT OF DATA THAT'S COLLECTED IN TERMS OF THE AMOUNT OF SUBJECT INCREASES EVERY DAY, THE NUMBER OF SITES THAT PARTICIPATE IN MULTISITE CONSORTIA GO UP, SO ALL OF THESE THINGS GENERATE VAST AMOUNTS OF DATA THAT REQUIRE REALLY NEW APPROACHES FOR US TO SOLVE THEM. AND I THINK THE MAIN PROBLEMS THAT WE FACE, THAT YOU ALSO FACE, ARE WHAT DO YOU DO WALL THWITHALL THE DATA, IT'S HUGE, HOW DO YOU MOVE IT AROUND, THE BANDWIDTH PROBLEMS ARE OBVIOUS WHEN YOU SIT HERE ON YOUR CELL PHONE TRYING TO CONNECT UP TO NIH'S WIRELESS. SORRY, WHOEVER RUNS THAT. THE DATA ANALYSIS ISSUES ARE PROBLEMATIC. THEY CAN BE EXPENSIVE, THEY ARE ALSO CHANGING AND GETTING MORE EXPENSIVE COMPUTATIONALLY THAN BEFORE, AND WE, LIKE YOU, HAVE PRIVACY CONCERNS, WHERE SOME OF THE DATA, WHETHER IT'S GENETICS OR EVEN A RECONSTRUCTION OF SOMEBODY'S FACE FROM AN MRI MACHINE PRESENTS SOME CHALLENGES IN TERMS OF PATIENT IDENTIFICATION ISSUES THAT HAVE TO BE RESOLVED, ESPECIALLY WHEN YOU'RE MOVING DATA ACROSS INSTITUTIONS OR EVEN COUNTRIES AND CONTINENTS, EACH OF WHICH HAVE THEIR OWN RULES ASSOCIATED WITH THAT. THIS IS JUST A SLIDE ALREADY QUITE A BIT OUT OF DATE, BUT OVER THE LAST 15 YEARS OR SO, WE SEE AN ORDER OF MAGNITUDE INCREASE IN A TYPICAL IMAGING STUDY. THAT'S NOT A CLINICAL STUDY BUT AN EXPERIMENTAL STUDY WHERE YOU'RE INVITED IN AS A SUBJECT OR PATIENT TO PARTICIPATE IN A PROTOCOL THAT MIGHT HAVE A BUNCH CH OF DIFFERENT IMAGE PULSE SEQUENCES DEFINED FOR THEM. THOUGH SEQUENCES GENERATE A NUMBER OF TYPE OF IMAGES THAT SCRIBE FUNCTION, WHITE MATTER, GRAY MATTER, YOU NAME IT. THAT HAS INCREASED, AS I SAID, ABOUT AN ORDER OF MAGNITUDE IN THE LAST 50 YEARS AND NOW THAT'S ACCELERATED EVEN FURTHER GIVING US A BETTER HANDLE ON SOME OF THE DATA AND SIGNALS THAT CAN BE DERIVED FROM IN VIVO BRAIN. NOT ONLY THAT, BUT THE DATA THAT'S ACQUIRED IS THEN PREPROCESSED, BECAUSE WHATEVER COMES OFF A MACHINE, AN MRI IN THIS KAI IS OFTEN DISTORTED OR HAS TO BE DISTORTED I PROCESSED IN A WAY - - SO THAT ALSO AUGMENTS THE SIZE OF DATA CONSIDERABLY WITH 22 MEGABYTES OF RAW DATA IN THE OLD DAYS GENERATING ABOUT 420 MEGABYTES OF DATA FOR ONE PARTICULAR SCAN. SO WE NOW GENERATE WELL OVER A GIGABYTE OF DATA PER ONE SUBJECT. WHEN ONE GETS INTO MANY THOUSANDS OF SUBJECTS, WHICH WE DO, IT PRESENTS SERIOUS PROBLEMS IN TERMS OF THOSE FOUR ISSUES THAT I MENTIONED EARLIER, HOW DO YOU COLLECT IT, MOVE IT, PROCESS IT. THIS IS A SLIDE WHICH I'M SURE YOU CAN READ EVERY SINGLE LETTER ON IT BUT I PUT IT UP THERE FOR A REASON. I PUT IT UP THERE TO ILLUSTRATE THE RATE AT WHICH THE TECHNOLOGY IS MOVING. THE LOWER BAR IS FROM 1990, I THINK, I CAN'T EVEN READ IT, FROM 1990 TO PRESENT, AND THESE ARE ALL SIGNIFICANT EVENTS IN TERMS OF DEVELOPMENT OF TECHNOLOGIES AND APPROACHES IN THE STUDY OF HUMAN BRAIN USING IMAGING. THEY'RE DRAMATIC. IT CONTINUES TO EVOLVE AT AN UNBELIEVABLE PACE AND IS EVEN AK SEACCELERATING. WHATEVER PLANS WE MAKE TODAY, WE HAVE TO FIND SOLUTIONS THAT ARE ADAPTIVE TO TOMORROW'S CHALLENGES. I THINK THAT'S PARTICULARLY TRUE IN E-SCIENCE AND THE WAY IN WHICH WE HAVE TO MANAGE, VISUALIZE AND PROCESS THE TYPES OF DATA BEING COLLECTED, WHETHER IT BE BRAIN OR PLACENTA. WE CANNOT SOLVE PROBLEMS FOR TODAY, WE HAVE TO SOLVE THE PROBLEMS THAT ARE COMING TOMORROW. AND THEY'RE REALLY QUITE CLEAR IN TERMS OF WHICH ONES ARE COMING. SO I'VE GIVEN YOU A COUPLE OF EXAMPLES ON IMAGING, AND I THINK THE SAME IS TRUE IN GENETICS. SO INCREASINGLY PEOPLE -- AND YOU'LL HEAR MORE ABOUT THAT TOMORROW -- INCREASINGLY PEOPLE ARE MAKING RELATIONSHIPS BETWEEN THE GENETIC OBSERVATIONS AND PROTEOMIC OBSERVATIONS WITH PHENOTYPES THAT CAN BE SEEN USING IMAGING. SO LITERALLY ABOUT SIX YEARS AGO, WE WERE COLLECTING GWAS DATA, WHICH IS SOMEWHERE AROUND 80 TO 90 MEGABYTES PER SAMPLE, AND THREE YEARS AGO, WE EMBARKED UPON A PROGRAM TO DO WHOLE GENOME SEQUENCING OF ALZHEIMER'S PATIENTS THAT WERE PART OF A BIG NATIONAL STUDY AND I'LL SHOW YOU SOME EXAMPLES OF THAT, WHICH GENERATED SOMEWHERE BETWEEN 250 AND 300 GIGABYTES PER, AND WE HAD A THOUSAND OF THEM. SO WE GENERATED SUCH MASSIVE DATA THAT THE COMPANY THAT DID THE SEQUENCING FOR US IN SAN DIEGO DELIVERED THE DATA TO US BY TRUCK, BY FEDEX, SO EVERY WEEK THEY WOULD SHOW UP WITH THESE DRIVES THAT WE WOULD UP LOAD, 200 TERABYTES BY THE TIME WE WERE DONE, AND PEOPLE STARTED ASKING FOR IT. THEY'D SAY WE WANT A COPY OF THE DATA BECAUSE WE'RE GOING TO DO SOME OF THE ANALYSES OURSELVES. YOU JUST CANNOT PUSH THAT ACROSS INTERNET, SO WE MAKE THEM SEND US A DISK ARRAY, WHICH THEY SEND BY FEDEX, WE COPY IT AND WE SEND IT BACK. WELL, CLEARLY THAT DOES NOT SCALE. THAT'S NOT SOMETHING THAT'S SUSTAINABLE. AND THAT'S' TODAY'S PROBLEM SO LET'S SEE WHAT HAPPENS TOMORROW, THERE ARE SOME BIG ISSUES TO FACE. SO CONSEQUENTLY, NIH IN ITS INFINITE WISDOM CAME UP WITH A PROGRAM CALLED BD2K, THAT STANDS FOR BIG DATA TO KNOWLEDGE. IT'S A VERY CLEVER PROGRAM BECAUSE IT WAS SPECIFICALLY DESIGNED TO ADDRESS THESE ISSUES. BIG DATA NOW IS A BIG CHALLENGE, AND HOW IS IT THAT WE CAN DEVELOP STRATEGIES THAT ALLOW US TO A ACCOMMODATE THESE BIG DATA. THERE WERE ABOUT 10 AWARDS MADE ACROSS THE COUNTRY, YOU IN THIS MEETING HERE ARE GOING TO GET SOME INFORMATION ON TWO OF THEM, ONE OF THEM IS CALLED BIG DATA FOR DISCOVERY SCIENCE AND THE OTHER ONE IS CALLED ENIGMA, WHICH PAUL THOMPSON WILL TELL YOU ABOUT TOMORROW. THESE TWO, I THINK ARE REPRESENTATIVE OF SOME OF THE ISSUES BUT BOTH OF THEM FOCUS ON NEUROSCIENCE. SO YOU'LL GET KIND OF A DIFFERENT PICTURE AND THE DIFFERENT WAYS ONE CAN HANDLE BIG DATA AS IT COMES IN NOT ONLY ACROSS THE SCALES THAT I MENTIONED EARLIER BUT FROM DIFFERENT SOURCES. THESE ARE CONSIDERABLE PROBLEMS AND MUST BE TREATED WITH RESPECT, THE DATA, AND I SAY THAT BECAUSE WITH BIG DATA COMES BIG RESPONSIBILITY. IF YOU HAVE BIG DATA, YOU CAN PROVE ANYTHING. ANYTHING. SO I PUT UP THIS SLIDE TO ILLUSTRATE THAT. YOU CAN'T READ THE AXES HERE BUT THIS IS A VERY HIGH CORRELATION. YOU CAN READ THAT. SO THIS IS A CORRELATION BETWEEN THE NATIONAL MARGARINE CONSUMPTION, MARGARINE THAT YOU PUT ON TOAST IN THE MORNING, AND THE DIVORCE RATE IN MAINE. [LAUGHTER] OKAY? SO THE LESSON HERE IS, IF YOU HAVE ENOUGH DATA, IT'S REALLY QUITE REMARKABLE ABOUT THE FINDINGS, AND THINK OF THE PUBLICATIONS YOU COULD COME UP WITH. BUT THIS IS AN IMPORTANT ILLUSTRATION BECAUSE I THINK BIG DATA REALLY DOESN'T ALWAYS GET TREATED IN THE RIGHT WAY BECAUSE WITH SUFFICIENT NUMBERS, RANDOM OCCURRENCES CAN -- EVEN RANDOM AKURNSES IN A PLOT LIKE THIS CAN PRODUCE SOME KIND OF FIND THATION ARE CLEARLY NONSENSE. AND I THINK THAT THE SCIENCE OF BIG DATA NEEDS ATTENTION BECAUSE OF THIS VERY REASON. SO LET ME START TO SHOW YOU SOME OF THE DATA THAT WE COLLECT, BECAUSE I THINK IT'S ILLUSTRATIVE OF THE ISSUES THAT WE FACE AND SHOWS YOU REAL WORLD EXAMPLES OF SOME OF THE THINGS WE HAVE TO DEAL WITH. IMAGING IS A CATCH ALL THESE DAYS, THERE'S MANY METHODS TO DO IT. IN BRAIN, PERHAPS THE TWO MOST COMMON TYPES OF TECHNIQUES THAT PEOPLE USE ARE POSITRON EMISSION AND MRI. I'M GOING TO USE THAT AS AN EXEMPLAR, WE USE BOTH QUITE FREQUENTLY. WE USE PET SCANNING WITH TRACERS THAT ALLOW US TO LOOK AT AMYLOID DEPOSITION IN THE BRAINS OF ALZHEIMER'S PATIENTS. THESE ARE NORMALS HERE. THESE ARE THOSE IN THE EARLY STAGES, WHICH WE CALL MILD COGNITIVE IMPAIRMENT. AND THESE IN THE LATER STAGES WITH A.D. ITSELF, ALZHEIMER'S DISEASE. AND AMYLOID HAS BEEN ASSOCIATED WITH TISSUE LOSS AND IS ONE OF THE PSEUDOBIOMARKER, NOT PARTICULARLY USEFUL, ASSOCIATED WITH ALZHEIMER'S DISEASE. IN FACT, A NUMBER OF DRUGS CAME OUT A FEW YEARS AGO AND LAST YEAR TRYING TO CLEAR AMYLOID AND DIDN'T REALLY WORK IN TERMS OF HELPING THE PATIENTS. THERE ARE OTHER TECHNIQUES TO LOOK AT ANOTHER MISFOLDED PROTEIN CALLED TAO, THESE ARE TAGGED WITH A VARIETY OF ISOTOPES AND CAN BE USED TO MAP THE DIFFERENTIAL ACCUMULATION OF THEM ACROSS THE BRAIN. AND OF COURSE IN THE HIPPOCAMPAL REGION HERE, YOU GET THE MOST ACCUMULATION OF THESE TRACERS. MRI CAN BE USED TO MEASURE ANATOMY. IN THIS PARTICULAR CASE, WE'RE MEASURING TISSUE LOSS. THE DISEASE CAUSES TISSUE LOSS DIFFERENTIALLY IN DIFFERENT PARTS OF THE BRAIN. THIS IS FRACTIONAL -- THIS IS CONNECTIVITY, SORT OF MEASURES THAT LOOK AT THE WIRING OF THE HUMAN BRAIN, THE WIRING DIAGRAM WHICH IS ILLUSTRATIVE IN TERMS OF PATHOLOGICAL CONSEQUENCES OF CELL DEATH AS A RESULT OF DISEASES, AND FINALLY, WE CAN LOOK AT FUNCTIONAL MEASURES, IN THIS PARTICULAR CASE, LOOKING AT FUNCTIONAL MEASURES OF THAT WIRING DIAGRAM. WHERE IN THOSE CIRCUITS IS THE BRAIN ACTIVE? SO THIS IS QUITE A DIVERSE ARRAY OF IMAGING TECHNIQUES, EACH WITH ITS OWN REQUIREMENTS, AND EACH WITH ITS OWN PROBLEMS. JUST AS THE SAME PROBLEM THAT YOU HAVE, WE HAVE A PROBLEM OF WHICH BRAIN DO WE MAKE A MAP OF. SO IF YOU'RE TRYING TO MAKE AN AT LAS OF THE HUMAN BRAIN, HOW DO WE ACCOMMODATE THE VARIABILITY? WHEN YOU'RE TRYING TO MAKE A MEASUREMENT IN THE PLACENTA, TO YOU DO YOU ACCOMMODATE THE VARIABILITY? YOU MUST COMPUTE -- SO YOU UNDERSTAND NORMAL RANGES IN TERMS OF THE MEASUREMENTS WHICH YOU'RE MAKING WHICH MAY, AS FAR AS I KNOW, BE GEOGRAPHICALLY DISTRIBUTED ACROSS THE PLACENTA, I DON'T EVEN KNOW, IN THE BRAIN, THAT'S THE CASE. THESE ARE FIVE PAIRS OF -- 10 IMAGES, MID SAGITTAL CUTS IN THE BRAIN. I'M SURE MOST OF YOU ARE PRETTY FAMILIAR WITH NEUROANATOMY, MAYBE LESS THAN YOU WERE WHEN YOU TRAINED, BUT NEVERTHELESS, THIS IS A MID SAGITTAL VIEW LOOKING AT THE CORPUS CALLOSUM. THESE ARE 10 DIFFERENT PEOPLE. IF YOU LOOK AT THIS SLIDE CAREFULLY, GIVEN THAT MANY OF YOU ARE CLINICIAN, I'M SURE YOU CAN APPRECIATE THE PATTERN. IF YOU CAN APPRECIATE THE PA TESH, PLEASE RAISE YOUR HAND. OH, WE HAVE PEOPLE THAT CAN. REALLY. ALL RIGHT. WELL, THAT'S GOOD. IF THE ANSWER IS CORRECT, THAT'S IMPRESSIVE. MOST PEOPLE CAN'T SEE IT. LOOK AT THE ROWS VERSUS THE COLUMNS. AND YOU'LL APPRECIATE THAT THE SHAPE AND FORM OF EACH OF THESE CORPUS CALLOSA IS MUCH MORE SIMILAR IN THE ROWS THAN IT IS IN THE COLUMNS. THE REASON FOR THAT IS, THESE ARE FIVE PAIRS OF MONO ZYGOTIC TWINS. NOW, TO ME, IT SAYS SOMETHING IMPORTANT. IT SAYS THAT GENETICS CLEARLY PLAYS A ROLE BUT IT'S NOT THE BE ALL AND END ALL. SPARE MENTION AND -- FACTORS CONTINUE TO INFLUENCE THE SHAPE OF THIS ANATOMIC FEATURE IN ADDITION TO THE GENETIC CONTRIBUTIONS. THAT'S THE PROBLEM THAT'S FACED WHEN ONE IS TRYING TO CREATE ATLASTS OF THE HUMAN BRAIN. NOT ONLY THAT, THE HUMAN BRAIN CHANGES OVER TIME MUCH AS THE PLACENTA PROBABLY DOES. WHEN ONE IS TRYING TO MAKE AN AT LAS, IT HAS TO BE FOUR-DIMENSIONAL, AT LEAST, IN TERMS OF SPATIAL COORDINATES, WE KNOW THE BRAIN LOSES CHANGES AND LOSES TISSUE THROUGHOUT LIFE, DURING DEVELOPMENT, PRUNING OF CONNECTIONS PRODUCING TISSUE LOSS SUCH AS IN THE SUPERIOR FRONTAL SULCUS AS YOU SEE HERE, BUT LATER IN LIFE, WE SEE IN THE HIPPOCAMPUS, THERE'S A TISSUE LOSS THAT'S A RESULT OF LOSS OF CELLS THAT REDUCES COGNITIVE FUNCTION. SO EVEN OLD AGE, NORMAL OLD AGE, PEOPLE HAVE SOME MEMORY LOSSES AND SOME COGNITIVE DECLINE, AND THAT ACCELERATES AS A RESULT OF A VARIETY OF AGE-RELATED DISEASES, IN PARTICULAR, THE DEMENTIAS. SO THIS KIND OF FOUR-DIMENSIONAL MAP REALLY MUST INCORPORATE OBSERVATIONS ACROSS POPULATIONS AND OVER TIME. AND HERE I'M JUST SHOWING YOU ONE TYPE OF IMAGE, WHEREAS IN THE PREVIOUS VIEW SLIDES, I SHOWED YOU MANY. SO WE HAVE TO TAKE THESE FOUR DIMENSIONAL MAPS AND LAYER UPON THEM ALL THE OTHER OBSERVATIONS ACROSS THE DIFFERENT SCALES. YOU CAN SEE HOW THE PROBLEM GETS INCREASINGLY PROBLEMATIC. IF WE JUST ACCELERATE THAT MAP OVER A PERIOD OF SECONDS, WE CAN SEE THE LIFESPAN CHANGES THAT CAN BE OBSERVED IN THESE BRAINS IS REALLY RATHER REMARKABLE, BOTH REGIONAL AND REALLY QUITE DYNAMIC. SO THIS IS A PROJECT THAT HAS SOME SIMILARITY WITH THE HUMAN PLACENTA PROJECT, ONLY BECAUSE, AGAIN, THIS WAS AN NIH IDEA TO CREATE UNIFIED MAPS OF THE WIRING DIAGRAM OF THE HUMAN BRAIN THAT COULD BE SHARED AND EXCHANGED AMONG SCIENTISTS WHO COULD THEN SUBSEQUENTLY ANALYZE THEM. ONE OF THE COP.I.s AND OTHER WAS AT MGH HARVARD, BRUCE ROSEN, AND IT WAS TO DEVELOP SOME NEW TECHNOLOGIES TO MAKE MAPS OF THE WIRING DIAGRAM USING A DIFFUSION-TYPE IMAGING WHICH IS ILLUSTRATED HERE. THIS IS A TECHNIQUE THAT TAKES ADVANTAGE OF THE DIFFUSION OF WATER MOLECULES THAT PREFERENTIALLY MOVE ALONG AN AXON AS OPPOSED TO ACROSS IT. NOW COLLECTING THAT DATA FROM AN MRI MACHINE NECESSITATES THAT ONE TREAT THESE DATA WITH ALL KINDS OF MATHEMATICS TO ULTIMATELY PRODUCE TRACTOGRAMS WHICH ARE BEING ILLUSTRATED HERE, SO THAT ONE CAN COMPUTE THE PREFERENTIAL DIRECTION OF BUNDLES OF AXONS AS THEY COURSE THROUGH THE BRAIN. NOW YOU'RE NOT LOOKING AT AXONS THEMSELVES. HERE YOU'RE LOOKING AT FASICLES AND BUNDLES OF THEM. WE DO NOT HAVE THE RESOLUTION TO LOOK AT INDIVIDUAL AXONS. BUT YOU CAN PRODUCE MAPS THAT LOOK LIKE THIS. WHICH ARE EXQUISITE TO LOOK AT BUT THEY ALSO PROVIDE YOU WITH A GREAT SORT OF SENSE OF FEELING ABOUT THOUSAND HO HOW THE BRAIN IS WIRED A ND CONNECTED AND ONE CAN MAKE COMPARISONS BETWEEN THIS NORMAL SUBJECT WITH GROUPS OF ABNORMAL SUBJECTS AND EXAMINE CONNECTOPATHYS THAT CAN BE THE RESULT OF A VARIETY OF DISEASES. SO THE TECHNOLOGY FOR DOING THIS CONTINUES TO EVOLVE. THIS IS LITERALLY FRESH OFF THE PRESS SO THEY'VE WORKED ON ALTERNATIVE STRATEGIES FOR MAKING THESE TRACTOGRAMS WHERE THEY CAN GET EVEN HIGHER FIDELITY IN TERMS OF THE SIZE OF THE BUNDLES OF THESE FIBERS AND LOOK AT THEM, AND HERE I THINK THIS IS JUST A GREAT MOVIE WHICH I LIKE, IT SHOWS YOU LITERALLY THE LEVEL OF DETAIL THAT CAN BE SEEN. THIS IS A TYPE OF IMAGING WE DIDN'T HAVE AVAILABLE TO US A LITTLE MORE THAN 10 YEARS AGO. NOW WE GET THESE EXQUISITE PICTURES THAT SHOW YOU WHERE FIBERS ARE CROSSING, WHERE BUNDLES OF FIBERS CROSS, HOW THEY'RE ORGANIZE AND HOW THEY COURSE THROUGH THE BRAIN IN A DETAIL THAT WAS ONLY AVAILABLE HISTOLOGICALLY UNTIL FAIRLY RECENTLY. SO WE'VE BEGUN TO LOOK AT THIS IN PATHOLOGICAL CONDITIONS. THERE'S A GROUP AT USC DOING RETINAL IMPLANTS ON PATIENTS THAT HAVE BEEN CONGENITALLY BLIND AND WE'RE TRYING TO SEE WHAT HAPPENS IN CENTRAL VISION AS A RESULT OF THAT. SO WE CAN TAKE THESE VERY SAME CONNECTOGRAMS AND LOOK AT REORGANIZATION OF VISUAL CORTEX AND OTHER FEATURES IN THE VISUAL CYST TIM USING THIS CA DIFFUSION TYPE SYSTEM AND -- IT HAS REAL CLINICAL VALUE IN TERMS OF UNDERSTANDING THE DEGREE TO WHICH THE BRAIN CAN BE REWIRED AT WHAT AGE AND HOW LONG THAT TAKES. WE'VE ALSO APPLIED THIS IN ALZHEIMER'S DISEASE. THIS IS HUMAN TISSUE, POSTMORTEM TISSUE FROM A PATIENT WHO DIED OF ALZHEIMER'S DISEASE AND WE'RE TAKING THIS TISSUE AND DOING HIGH FIELD IMAGING, CREATING THESE CONNECTOGRAMS AS YOU SEE HERE AND BECAUSE IT'S POSTMORTEM, WE'VE TAKEN THE SAME TISSUE SLICES AND DONE IN SITU HYBRIDIZATION ON THAT, AS WELL AS CELLULAR LIGHT FIELD MICROSCOPY, ALL THE WHILE KEEPING TRACK OF WHERE WE ARE. SO FOR THE FIRST TIME, WE GET VERY, VERY HIGH FIDELITY RELATIONSHIP BETWEEN THE GENOTYPE, THE GENES EXPRESSED IN THAT AREA, RELATIVE TO THE CONNECTOPATHY THAT'S ASSOCIATED WITH IT. SO WE'RE BEGINNING TO BE ABLE TO PUT TOGETHER THESE DIVERSE SETS OF IMAGING IN A UNIFORMED MAP. SO I PERSONALLY ALWAYS LIKE TO TAKE THE MODERN APPROACHES IN IMAGING AND RELATE THEM TO THE KINDS OF OBSERVATIONS THAT PEOPLE HAVE MADE HISTORICALLY. WHETHER IT'S EXAMINING HISTOLOGY AS I JUST ILLUSTRATED OR LOOKING AT EVEN A HISTORICAL EXAMPLE. I KNOW YOU'VE PROBABLY -- MOST OF YOU ARE NOT QUITE MY AGE BUT GETTING ON THERE, YOU MAY OR MAY NOT REMEMBER THIS FROM HIGH SCHOOL OR COLLEGE BIOLOGY BUT EVERYBODY REMEMBER FINNEAS GAUGE? HE WAS A WONDERFUL GUY. HE LIVED IN THE 1830s TO 1850s, AND HE WORKED ON A RAILROAD, AND HE WAS A FOREMAN, HIS JOB WAS -- IN NEW HAMPSHIRE, I THINK. HIS JOB WAS TO DRILL HOLES IN GRANITE, AND THEY WOULD POUR A CHARGE IN THE HOLE AND THEY WOULD TAMP IT DOWN WITH THIS BIG IRON BAR THEY CALLED IT, IT WASN'T A CROWBAR, IT WAS A STRAIGHT BAR, AND THEY WOULD TAMP IT DOWN AND LIGHT A FUSE AND SET OFF A CHARGE WHICH WOULD CRACK THE ROCKS AND THEY WERE DOING THIS SO THAT THE RAILROAD TRACKS WOULD BE FLAT AS OPPOSED TO GOING UP AND OVER THE HILLS. SO ONE DAY, POOR FINNEAS GAGE, THAT WAS HIS ACTUAL NAME, WAS DOING THIS WIS HIS TAMPING IRON AND HE FORGOT TO PUT THE WADDING IN, THE PERIOD BETWEEN THE GUN POWDER AND THE TAMPING IRON AND A SPARC FROM THE TAMPING IRON SETS THE CHARGE OFF. AND HE'S DOING THIS, AND HE'S GOT THIS IRON BAR THAT'S THIS TALL, WEIGHS ABOUT 15 POUNDS, ABOUT THAT BIG AROUND. IT'S AT HARVARD NOW, YOU CAN GO LOOK AT IT. AND THE THING FIRES UP AND GOES UP UNDER HIS ZYGOMA TICK ARCH, BEHIND HIS ORBIT, CROSSES THE MID SAGITTAL SUTURE AND EXITS THE TOC TOP OF HIS HEAD AND LANDS 30 FEET AWAY. SO THAT'S A HORRIFIC INJURY. SO HE SITS DOWN -- YOU CAN READ ABOUT THIS. HE SITS DOWN, KIND OF STUNNED, UNCONSCIOUS FOR LESS THAN A MINUTE, SITS UP, AND SAYS, I THINK I NEED TO SEE A DOCTOR. WELL, IT'S SORT OF FUNNY BUT IT'S REMARKABLY PRESH YENT. THE GUY WAS WITH IT. SO HE JUST HAD A FRONTAL LOBOTOMY, A PERFECT FRONTAL LOBOTOMY. SO WE WENT, AND WE WENT TO HARVARD, GOT THE IRON BAR, GOT HIS SKULL, WHICH IS AT HARVARD -- HE BECAME VERY FAMOUS BECAUSE THIS IS PRIOR TO THE CIVIL WAR. THE CIVIL WAR WAS ONE OF THE BEST OPPORTUNITIES TO LEARN BRAIN FUNCTION WE HAD AT THE TIME. SOW LEARN BRAIN FUNCTION BECAUSE PEOPLE WOULD HAVE THESE INJURIES AND YOU'D SAY, OKAY, THAT LEAGUES PRODUCED THIS DEFICIT. WE DIDN'T HAVE SO MUCH OF THAT BEFORE. THIS GUY, WHO HAD THIS INJURY BEFORE THE CIVIL WAR, BECAME VERY FAMOUS BECAUSE HE LIVED FOR QUITE SOME TIME. NORMALLY IN THOSE DAYS, YOU WOULD DIE, BUT HE LIVED AND PEOPLE WERE ABLE TO OBSERVE THE CHANGES IN HIS PERSONALITY. WE WENT AND GOT HIS SKULL, DIGITIZED THE SKULL AND THEN TOOK FROM OUR DATABASE ALL THE PEOPLE THAT MATCHED HIS AGE, HANDEDNESS AND SO FORTH, AND CREATED THE CONNECTOME FOR THOSE PEOPLE WHICH WOULD HAVE BEEN HIM AND THEN MAPPED WHERE THE INJURY WAS AND WHAT CONNECTIONS WERE DISRUPTED AS A RESULT OF THIS IRON BAR. SO THIS IS HIS INJURY HERE, SO YOU CAN SEE IT'S A SERIOUS INJURY, AND IT GOES THROUGH HIS HEAD LIKE THIS, AND WE ENDED UP MAPPING THE DISTURBED CONNECTIONS AND SOME OTHER SORT OF INTERPRETATIONS OF THE DEFICIT THAT HE ENCOUNTERED, AND JACK VAN HORN, WHO DID THIS WORK IN OUR GROUP, IT WAS REALLY A TOUR DEFORCE BECAUSE IT COMBINED NOT ONLY MODERN TECHNOLOGIES BUT SORT OF WENT BACK IN HISTORY AND LOOKED AT IT. I'M JUST FASCINATED BY THESE THINGS BECAUSE IT REALLY EXPLAINS A GREAT DEAL AND IT ALL FITS, IT ALL FITS. YOU CAN READ THIS PAPER, BUT THE INJURY ITSELF AS MAPPED USING THIS TECHNIQUE FITS EXACTLY WHAT THE OBSERVATIONS OF HIS DEFICIT. ANYWAY, SO WE CAN TAKE THESE CONNECT GRAMS AND BEGIN TO PUT THEM TOGETHER INTO POPULATION OBSERVATIONS AND THAT'S REALLY A DIFFICULT THING TO DO, BECAUSE REMEMBER THE RESOLUTION WE HAVE WITH THESE CONNECTOMES IS NOT PARTICULARLY HIGH AND THE VARIATION COULD BE CONSIDERABLE DUE TO THE ENVIRONMENTAL AND EXPERIENTIAL FACTORS, DEVELOPING STRATEGIES TO DO THAT AS ILLUSTRATED HERE. THERE'S STILL A LOT OF WORK TO DO THAT BECAUSE OF THE COMPLEXITY AND WE'VE DEVELOPED THESE TECHNIQUES TO TRY TO GET HANDLE ON THIS, ONE OF WHICH IS SORT OF A VISUALIZATION INTERFACE THAT YOU CAN ASK THE COMPUTER WHAT'S CONNECTED WITH WHAT, EITHER FOR A PARTICULAR POPULATION OR AN INDIVIDUAL USING THIS TYPE OF INTERFACE HERE, AND THIS CIRCLE IS DIVIDED UP BY HEMISPHERE, ONE ON ONE SIDE, ONE ON THE OTHER, AND EACH OF THESE SEGMENTS ARE DIFFERENT LOBES OF THE BRAIN SO ONE CAN CLICK ON ANY ONE OF THESE THINGS AND FIGURE OUT WHAT'S CONNECTED WITH WHAT AND ALSO RELATE IT TO OTHER OBSERVATIONS THAT WE MIGHT HAVE, WHETHER IT BE GRAY MATTER VOLUME, DEGREE OF AREA, CURVE TOUR, ALL KINDS OF OTHER STATISTICS. SO THESE ARE INTERFACE SYSTEMS THAT ALLOW US TO RELATE DIFFERENT TYPES OF OBSERVATIONS EVEN FROM DIFFERENT TYPES OF IMAGING ACROSS INDIVIDUALS AND POPULATIONS. AND I THINK THAT'S AN IMPORTANT ADVANCE BECAUSE THE COMPLEXITY OF THE DATA IS SO GREAT AND THE SIZE IS SO BIG, IT'S HARD TO DO ON YOUR OWN. WE'VE ALSO DEVELOPED A NUMBER OF TOOLS WHICH ARE GRAPHICALLY ENABLED SO THAT PEOPLE THAT DON'T HAVE THE WHEREWITHAL EXPERTISE TO DEVELOP ALGORITHMS THEMSELVES CAN USE THESE EITHER ON THEIR OWN SYSTEMS OR REMOTELY ON THE CLOUD OR OTHER TYPES OF BIG DATA SOLUTIONS THAT ARE IMPORTANT. THIS IS ONE SUCH TOOLSET THAT WE DEVELOPED IN OUR SHOP CALLED THE LONE PIPELINE, IT'S A FROM GRAPHICAL SYSTEM, YOU DRAG AND GROF AND RUN THE PROCESS THROUGH THESE THINGS AND IT CAN TALK WITH ANY COMPUTERS YOU WANT. IN THIS PARTICULAR CASE, IT'S AUTOMATICALLY SEGMENTING A PART OF THE BRAIN CALLED THE HIPPOCAMPUS WHICH WE LOOK AT QUITE FREQUENTLY IN A VARIETY OF DISEASES. HAPPENS TO BE SUSCEPTIBLE PERHAPS BECAUSE IT'S SO PLASTIC AND ADAPTIVE AS IT'S PART OF ITS NORMAL FUNCTION. YOU CAN ALSO USE THESE KINDS OF TECHNIQUES TO DO QUALITY CONTROL, AS I'M SURE YOU'RE AWARE, DEPENDING ON HOW THE DATA ARE COLLECTED, WHEN YOU'RE INVOLVED WITH A MULTISITE PROJECT, THE DATA CAN COME IN WITH DIFFERENT QUALITY. IT HAS TO BE HARMONIZED AND HO KNOWLEDGE NIEZED IN A WAY THAT MAKE THEM AGLAGATABLE, ONE OF THE MOST IMPORTANT ASPECTS OF IMAGING TO BE TRUE, PEOPLE SEND IMAGES WITH LOTS OF MOTION ARTIFACT, THEY DIDN'T FOLLOW THE PROTOCOL EXACTLY AND WE HAVE SYSTEMS THAT USE THAT USING THE VERY SAME GRAPHICAL APPROACH, SO IN THESE MULTISITE PROJECTS, WHICH I'M GOING TO SHOW YOU AN EXAMPLE OF IN A MINUTE, ALL THE DATA GOES THROUGH THESE SYSTEMS HERE AND THEN GETS THIS WHOLE BATTERY OF STATISTICS ASSOCIATED WITH IT, SO WHEN YOU'RE ANALYZING THE DATA, YOU CAN SAY, SHOW ME ONLY THE VERY BEST, SHOW ME THE MEDIAN, SHOW ME THE LOWEST, WORST, WHATEVER YOU WANT, AND THAT GIVES YOU A LOT OF UTILITY. DOING ALL THIS COMES WITH A COST, SO NIH DOESN'T LIKE TO BUY THIS STUFF. THIS IS REALLY EXPENSIVE WORK. THE COMPUTATIONAL HORSEPOWER BEHIND THIS IS CONSIDERABLE. WE RUN A VERY LARGE COMPUTATIONAL FACILITY. IT HAS TO BE POWER BEHIND THIS, CAN YOU RUN IT ON THE CLOUD, IT'S EXPENSIVE BUT YOU'VE GOT TO PUT DATA SOMEWHERE AND THESE ARE ISSUES THAT HAVE TO GET RESOLVE RESOLVED, AND I THINK YOU'RE GOING TO FACE THE VERY SAME PROBLEMS AS YOU MOVE FORWARD WITH YOUR PROJECT. THESE ARE SOME OF THE MULTISITE PROJECTS THAT WE RUN. THEY'RE INVOLVED WITH EXAMINING DIFFERENT DISEASES AS WELL AS NORMAL SUBJECTS, IT'S ALL BRAIN, OF COURSE. ALZHEIMER'S DISEASE, PARKINSON'S DISEASE. THESE ARE NORMALS. HUNTINGTON'S DISEASE. THESE ARE ALL PROJECTS WHERE THERE ARE DATA COMING FROM LITERALLY ALL OVER THE WORLD, AND THEN ASSIMILATED IN SOME FASHION TO BE EXAMINED BY OTHERS. THESE ARE SOME OF THE STATS THAT ARE IN OUR DATABASE SYSTEM, THIS IS WHAT'S CENTRALLY LOCATED. WE HAVE A FEDERATED SYSTEM AS WELL. NOW ALMOST 100,000 SUBJECTS ALL TOGETHER, WITH ABOUT A MILLION RAW SCANS ALL TOGETHER AND ABOUT HALF A MILLION OR SO PROCESS SCANS. SO THERE'S MASSIVE AMOUNTS OF DATA HERE AND IT ALLOWS ONE TO LITERALLY UNDERSTAND THE DISTRIBUTION AND RANGE OF TYPES OF OBSERVATIONS. THIS IS A FAMOUS STUDY, LESSONS HERE WITH IMPORTANT AND I'LL TELL YOU WHY IN A MINUTE. THIS WAS THE ALZHEIMER'S DISEASE NEUROIMAGING PROJECT, THERE ARE 58 DIFFERENT ACQUISITION SITES THAT WERE INVOLVED IN THIS. ALL MANNER OF DATA ARE COLLECTED IN SUBJECTS THAT ARE EITHER AT RISK FOR ALZHEIMER'S DISEASE, HAVE THE EARLY STAGES OR ARE IN ALZHEIMER'S DISEASE, AND IT INCLUDES EVERYTHING FROM CEREBRAL SPINAL FLUID TO GENETICS TO IMAGING, COGNITIVE MEASURE, ALL KINDS OF BIOMARKERS. IT IS A VERY COMPREHENSIVE STUDY. AND PERHAPS PRODUCED MORE PAPERS THAN ANY MULTISITE STUDY OF ALL TIME, THE ANNUAL MEETING IS IN VANCOUVER IN TWO DAYS AND WE WILL HAVE AT THAT POINT HAVE SOMEWHERE NEAR 1100 PAPERS STUDIED ON THIS ALONE. THE MAJORITY OF WHICH ARE PUBLISH BID PEOPLE NOT INVOLVED IN THE STUDY. ALL OF THE DATA ARE IMMEDIATELY MADE AVAILABLE ACQUISITION. AS SOON AS IT'S AT QC, IT COMES TO OUR SHOP AND WE'RE THE ONES THAT OPEN IT UP. THESE ARE THE DATA USE APPLICATION FOR THIS PROJECT SO IT'S A GREAT CURVE, IF YOU INVEST IN THE STOCK MARKET AND YOU HAVE A CURVE THAT LOOKS LIKE THAT, MY HATS OFF TO YOU. MINE DON'T. THIS IS A LITTLE OUT OF DATE NOW BUT JUST ABOUT 10,000 PEOPLE HAVE APPLIED TO USE THESE DATA. THE APPLICATION BASICALLY SCREENS OUT FOR SPAM AND IT'S BASICALLY GIVEN TO ANYBODY. THESE ARE THE KINDS OF IMAGE ARCHIVES OVER THE LAST 10 YEARS OR SO. YOU SEE IT GOES UP AND DOWN, SOME ARE RAW SCANS, SUBJECTS OVER TIME, THIS HAS TO DO WITH DIFFERENT PHASES OF THE PROJECT AS THE -- THESE ARE IMAGES DOWNLOADED OVER THE LAST PERIOD FROM 2008 TO 2015. RIGHT NOW THERE ARE TSH I BELIEVE WE'VE REACHED 10 MILLION FOR A BIOLOGICAL STUDY FUNDED BY NIH, THAT'S PRETTY REMARKABLE. THIS IS A SERIOUS PROJECT AND THIS IS LIKE THE HUMAN PLACENTA PROJECT. THIS IS THE LEVEL OF ACTIVITY THAT CAN BE DERIVED FROM A WELL RUN INFORMATICS PLATFORM. THESE ARE THE CLINICAL DATA THAT ARE DOWNLOADED SO THERE'S ALL KINDS OF THINGS YOU SEE LISTED ON THE BOTTOM FROM GENETIC IMAGING, MEDICAL HISTORY, YOU NAME IT, AND AGAIN, THESE PEAKS OFTEN HAVE DO WITH THE DEADLINES FOR PARTICULAR MEETINGS, SO WHEN A MEETING DEADLINE SHOWS UP, EVERYBODY JUMPS ON BOARD. HAVING AN INTERFACE THAT PEOPLE CAN UNDERSTAND IS IMPORTANT IN TERMS OF DEALING WITH DATA SUCH AS THIS. WE'VE ACTUALLY MOVED INTO MOBILE DEVICES SO THE SCIENTISTS DON'T EVENTUALLY COME TO WORK, THEY CAN SIT ON THE BEACH AND ACCESS THE SYSTEMS, ANALYZE THE DATA REMOTELY. I'M SORT OF MAKING A JOKE BUT NOT REALLY. I MEAN, I THINK HAVING ACCESS WHEN YOU'RE BORED IN A TALK OR SOMETHING, CHECKING ON THE PROCESSING OF OH YOUR DATA IS NOT UNREASONABLE. IT SHOULD BE HAPPENING ALL THE TIME. ALL THE RESOURCES SHOULD BE ACTIVE 100% OF THE TIME AND HAVING TOOLS TO DO THAT IS IMPORTANT. SO THESE ARE SORT OF SOME EXAMPLES OF WHAT ONE CAN DO, AND WE CAN LOOK AT A VARIETY OF FEATURES OF BRAIN THAT CAN BE ANALYZED IN A VARIETY OF WAY, RELATE THESE TO GENETICS, AND PAUL THOMPSON TOMORROW IS GOING TO TELL YOU ABOUT ENIGMA WHERE HE'S DONE A REMARKABLE JOB LOOKING AT THE RELATIONSHIP BETWEEN GENOTYPES, PARTICULAR SNPS, POLYMORPHISMS ASSOCIATED WITH THESE POPULATIONS. THAT'S A REMARKABLE ADVANCE BECAUSE IT REALLY BRINGS TOGETHER THE PHENOTYPE-GENOTYPE ASSOCIATION THAT'S IMPORTANT FOR UNDERSTANDING THE PATHOPHYSIOLOGY ASSOCIATED WITH THESE DISEASES. THERE'S SORT OF A SUMMARY OF THE KIND OF ACTIVITIES THAT CAN BE DONE DOING THESE THINGS. I STOLE THIS FROM PAUL, HE'S GOING TO TALK ABOUT THIS, I'M NOT GOING TO REALLY SPEND TIME ON IT, BUT JUST ONE SECOND, HE BASICALLY FINDS SOME PHENOTYPES AND THEN SEARCHES THE GENOME TO SEE WHAT SNPs ARE ASSOCIATED WITH THAT. THERE'S ANOTHER WAY ONE CAN DO IT. YOU CAN FLIP IT UP UPSIDE-DOWN AND LOOK THROUGH THE LITERATURE AND FIND SNPS IDENTIFIED TO HAVE BEEN ASSOCIATED WITH THE DISEASE OR SOME NEUROLOGICAL CONDITION. THIS IS STUFF WE'VE DONE. RATHER THAN CALL IT GWAS, WE CALLED IT PHWAS. WE FIND THE SNPs THAT HAVE ALREADY BEEN IDENTIFIED AND THEN WE LOOK AT PHENOTYPES. SO WE TAKE THOUSANDS OF SUBJECTS, WE DO ALL THESE TYPES OF ANALYSES, LITERALLY THOUSANDS OF THEM, PRODUCING 80,000 METRICS PER SUBJECT WITH 50,000 SUBJECTS SO YOU CAN SEE THE AMOUNT OF DATA THAT'S BEING PRODUCED HERE, OVER 3 TRILLION VARIABLES. THIS IS BIG DATA FOR SURE. AND THEN SAY DOES THIS SNP THAT HAS BEEN ASSOCIATED IN THE LITERATURE WITH THIS DISEASE OR THIS CONDITION, DOES WHAT PHENOTYPES ARE ASSOCIATED WITH IT? AND IN FACT, WE CAN FIND A NUMBER OF THINGS AT WORK. THIS IS ONE PARTICULAR COHORT HERE. I THINK I HAVE ANOTHER COHORT HERE. THIS IS A DIFFERENT COHORT. SO WITH THESE TWO COHORTS, THESE ARE ONLY HUNDREDS OF SUBJECTS, JUST UNDER A THOUSAND FOR BOTH OF THEM, BOTH ARE DEVELOPMENTAL BRAIN PROJECTS, ONE FINDS THE SAME RESULTS. SO WHEN YOU CAN REPLICATE THESE KIND OF FINDINGS IN COMPLETELY INDEPENDENT COHORTS, YOU BEGIN TO HAVE SOME CONFIDENCE IN THEM. THAT SORT OF ALLUDES BACK TO THE JOKE THAT I MADE ABOUT THE MARGARINE AND THE DIVORCE RATE OF MAINE BECAUSE WITH BIG DATA ONE HAS TO WORRY ABOUT DOING THE RIGHT STATISTICS TO MAKE SURE YOU DON'T JUST HAVE SPURIOUS INFORMATION THAT'S PREP R. REPETITIOUS. REPETITIOUS. SO THOSE WERE SOME EXAMPLES OF MULTISITE TRIALS WHERE THE DATA ARE CENTRALIZED, SO ALL THE DATA GOT CENTRALIZED IN ONE PLACE OR ANOTHER AND THEN PEOPLE GO AND DOWNLOAD IT. THE SOCIOLOGY OF DATA SHARING DOES NOT ALWAYS LEND ITSELF TO CENTRALIZATION. IF I WERE TO ASK EVERYBODY IN THE AUDIENCE, YOU KNOW, I'M THE EXPERT HERE, I WOULD LIKE ALL OF YOUR DATA, JUST SEND IT ALL TO ME AND I'LL TAKE CARE OF IT FOR YOU. MOST OF YOU, OR MANY OF YOU, WILL RESIST THAT WITH GOOD JUSTIFICATION. YOU PUT YOUR TIME AND YOUR EFFORT AND YOUR CAREER COLLECTING THESE DATA, YOUR WILLINGNESS TO GIVE IT AWAY WITHOUT SOME SORT OF STRINGS ATTACHED IS LIMITED. AND THAT'S FINE. THAT'S JUSTIFIED. SO CAN WE CREATE A SHAREABLE SYSTEM THAT ACCOMMODATES A COMMON NEED WITH SOME OWNERSHIP WITH IT? I THINK YOU CAN. WE DID THIS AGAIN IN ALZHEIMER'S DISEASE, THIS IS A PROJECT WHERE WE CREATED A FEDERATED SYSTEM. THE DATA LIVES IN THE ARCHIVES IN WHICH IT WAS ORIGINALLY PUT. INSTEAD, WE ONLY REPRESENT WHAT IS THERE, AND WE CONNECT IT UP, ALL OF THESE ARCHIVES, IN A NETWORK, SO THAT THE PORTAL OF THE NETWORK IS TALKING TO EACH ONE OF THESE ARCHIVES THAT'S AROUND THE WORLD, AND REPRESENTING THAT DATA FOR THE PERSON THAT'S SEARCHING IT. BUT THEY DON'T GET ACCESS TO IT UNLESS THE INDIVIDUAL ARCHIVE GIVES PERMISSION. SO IT'S A CATALOG, IF YOU WILL. THE OTHER POINT THAT I NEED TO MAKE HERE BEFORE I FORGET IS EACH OF THE OWNERS, THE ARCHIVES, HAS AN ON/OFF SWITCH. THEY CAN SWITCH IT OFF ANY TIME THEY WANT. SO THAT GIVES THEM TOTAL CONTROL. THEY CONTROL WHO GETS TO SEE THE DATA AND THEY CAN DISASSOCIATE THEMSELVES FROM THE NETWORK AT ANY TIME. SO THEY FEEL IN TOTAL CONTROL. AND, THEREFORE, WE GET PARTICIPATION. VERY WIDE PARTICIPATION FOR NO MONEY. WE'RE NOT PAYING THEM. THIS IS A DISTRIBUTION, THERE'S OVER 80-PLUS PARTNER, EACH OF WHICH MAY HAVE THOUSANDS OR TENS OF THOUSANDS OF SUBJECTS IN THEIR DATABASE, SOME AROUND THE WORLD, CONNECTED UP IN THIS NETWORK. BUT REMEMBER, I DON'T HAVE THEIR DATA. I HAVE THEIR META DATA. I KNOW WHAT THEY HAVE, AND I CAN DESCRIBE IT, BUT I DON'T ACTUALLY HAVE THEIR DATA. THIS IS SORT OF THE NUMBER OF SUBJECTS THAT ARE SEARCHABLE OVER THE COURSE OF ABOUT A YEAR AND HALF, THIS IS OUT OF DATE NOW WHERE I THINK ABOUT 370,000 COLLECTED IN HERE. SO YOU GET RAPID POWER IN TERMS OF BEING ABLE TO ASK QUESTIONS OF THESE DATA VERY RAPIDLY IF YOU'RE SENSITIVE TO THE SOCIOLOGICAL NEEDS OF MANY INVESTIGATORS AROUND THE WORLD. THIS IS WHAT ONE OF THE INTERFACES LOOKS LIKE, THERE ARE TWO OF THEM. YOU CAN GO TO THAT WEBSITE, SEARCH ON GAIN AND YOU'LL FIND IT, IT'S WIDE OPEN. THESE ARE THE PARTNER SITES. EACH PARTNER SITE'S WEBSITE IS SHOWN HERE SO THEY GET CREDIT. IN THIS PARTICULAR CASE, I'VE ASKED FOR ALL THE PROJECTS THAT HAVE GENDER, HIPPOCAMPAL VOLUME CALCULATED AND AGE, YOU SEE THIS PARTICULAR ONE DOESN'T HAVE IT, AGE AND GENDER NECESSARILY, WHICH IS ODD, BUT THEY DON'T, AND HERE'S SORT OF A HISTOGRAM THAT SHOWS IN ORDER THE NUMBER OF PROJECTS THAT SATISFY THIS PARTICULAR QUERY. YOU CAN ASK ANY QUERY, THERE ARE THOUSANDS OF VARIABLES IN THERE. SO HERE'S THE VARIABLES. YOU CLICK ON THESE LITTLE SWITCHES HERE, YOU GET SUBTREES AND YOU CAN BEGIN TO MAKE A QUERY THAT INCLUDES MANY, MANY DIFFERENT VARIABLES AND DO COHORT DISCOVERY AND SEE WHERE DO THE DATA LIVE IN ALL OF THESE PROJECTS THAT FIT MY PARTICULAR NEEDS. SO IT'S A GREAT WAY TO LINK UP TOTALLY INDEPENDENT PROJECTS, ALL THAT WAS NEEDED IS WE HAD TO HARMONIZE THE DATA DICTIONARIES, SO THAT WHEN YOU USE A TERM IN ONE PROJECT, IT MEANS THE SAME IN ANOTHER PROJECT. I SAY THAT WITH -- AS IF IT'S EASY. THAT PART'S REALLY HARD, BUT ONCE YOU HAVE DONE THAT, IT ALLOWS THE DATA TO BE LINKED TOGETHER. WE'VE ALSO PUT SOME TOOL SETS ON THIS DATABASE SO THAT YOU CAN WHILE YOU'RE TALKING TO THE DATABASE ITSELF, YOU CAN BEGIN TO ASK QUESTIONS. WHAT'S ASSOCIATED WITH WHAT? THIS PARTICULAR CASE, WE WERE LOOKING AT THE MINI MENTAL STATE EXAM WHICH IS A COGNITIVE BATTERY RELATIVE TO ALZHEIMER'S DISEASE AND I CAN'T QUITE READ IT BUT SOME OTHER STATISTICS, AND YOU GET HISTOGRAMS, PLOTS AND WHAT HAVE YOU. AS ALL THAT COMES DOWN TO YOU, YOU CAN THEN DOWNLOAD IT FROM THOSE SITES WITH WHICH YOU HAVE OBTAINED PERMISSION. SO I THINK THESE ARE THE KINDS OF THINGS THAT CAN FACILITATE MULTISITE EFFORTS WHEN THEY HAVE BEEN PUT TOGETHER IN AN INDEPENDENT WAY. THIS IS SORT OF THIS TOOL STACK THAT YOU SEE THAT I JUST MENTIONED. SO AS I SAID WHEN I BEGAN, WE'VE BEEN DOING THIS TOGETHER FOR ABOUT 20 SOME ODD YEARS, MANY 25 YEARS. SOME OF THE LESSONS WE'VE LEARNED, SOME OF THEM, WE'RE STILL LEARNING. I THINK A PROJECT SUCH AS YOURS IS ANOTHER EXAMPLE OF ONE WHERE WE MIGHT LEARN FROM YOU THE KINDS OF IMPEDIMENTS THAT YOU FIND, KINDS OF CHALLENGES THAT YOU MEET AND SUCCEED WITH. I THINK IT'S IMPORTANT THAT EACH OF THESE EFFORTS WORK TOGETHER TO INFORM ONE ANOTHER. SO I HAVE ONE FINAL SLIDE THAT I JUST WANTED TO GO OVER SOME OF THE ISSUES THAT WE'VE IDENTIFIED AS IMPORTANT FOR THE SUCCESS OF MULTISITE EFFORTS IN TERMS OF COMBINING DATA. FIRST THE DATA HAVE TO BE GOOD. IT'S REMARKABLE HOW MANY TIMES PEOPLE COLLECT DATA AND THEY SEND IT TO YOU AND THEY SAY, OH, WE'D LIKE TO BE PART OF YOUR CONSORTIA. AND IT'S -- PARDON THE EXPRESSION, IT'S CRAP. IT'S JUST AWFUL DATA. IT'S JUST NOT WELL COLLECTED, NOT WELL DESCRIBED, THEY CAN'T TELL YOU HOW WELL -- WHAT WAS DONE TO IT BEFOREHAND. IT DOESN'T DO YOU A LOT OF GOOD. SO THE DATA IS CRITICAL. THE DESIGN OF THE PROJECT IS ESSENTIAL. WHEN THEY'RE TOO DIFFUSE, THE DATA DOESN'T NECESSARILY MATCH THE QUESTIONS THAT YOU'RE GOING TO BE POASESSING. BE POSING. SO THE DESIGN IS IMPORTANT. THAT SAID, ONE SHOULD ALWAYS TRY TO ACCOMMODATE CHANGES IN DESIGN FOR THE FUTURE, BECAUSE THE QUESTIONS ALWAYS ARE NEW AND THEY'RE ALWAYS CHANGING. SAME WITH THE TECHNOLOGY AND TOOLS. STARTING OUT WITH THE BEST AT THE MOMENT YOU BEGIN IS ROWLY IMPORTANT, IN THE CASE OF MRI, THE TECHNOLOGY CHANGES EVERY MONTH, IT SEEMS, AND SO IT'S VERY IMPORTANT THAT WE KEEP UP WITH THAT, WHICH MEANS MRI IMAGING FROM 10 YEARS AGO IS NOT ANYWHERE NEAR AS GOOD AS IT IS TODAY, AND, THEREFORE, CONSIDERABLY LESS VALUABLE. THE SCIENTIFIC FOCUS SHOULD BE STATED UP FRONT. IF THE PROJECT DOESN'T HAVE ENOUGH FOCUS, THEN YOU DIDN'T COLLECT THE RIGHT DATA, PERHAPS, AND YOU DIDN'T COLLECT IT IN THE RIGHT WAY, PERHAPS. THE SIZE HAS TO BE SUFFICIENT. THE AMOUNT OF DATA THAT YOU COLLECT HAS TO BE APPROPRIATE. IF IT'S TOO BIG, YOU GET ALL KINDS OF CRAZY THINGS. IF IT'S TOO SMALL, YOU DON'T HAVE STATISTICAL POWER. WE ALL KNOW THAT BUT IT'S REMARKABLE HOW MANY PEOPLE IGNORE IT. THE DURATION, HOW LONG IS IT GOING TO GO FOR. I KNOW THERE'S SOME NIH PEOPLE IN THE AUDIENCE BUT IT'S NOT UNCOMMON FOR NIH TO START ONE OF THESE LARGE PROGRAMS THEAND SAY WE'RE GOING TO DECLARE VICTORY, IT'S OVER. SO YOU HAVE TO MAKE SURE UL PLAN IT IN A WAY WHERE YOU CAN GET THE FINDINGS AND THE OUTCOMES IN THE TIME FRAME THAT THE FUNDERS WILL ALLOW. AND THAT'S SOMETIMES DIFFICULT. THE MISSION SHOULD BE QUITE CLEAR. THE MISSION ISN'T CLEAR, JUST AS I STATED IN SOME OF THESE EARLIER POINTS, THEN PEOPLE DON'T KNOW WHAT TO DO. YOU MAY NOT GET IT DONE. YOU'VE GOT TO HAVE THE RIGHT PEOPLE. YOU NEED THE LEADERS, YOU NEED THE PEOPLE TO ORGANIZE THINGS, YOU NEED THE PEOPLE TO ACTUALLY CHASE EVERYTHING DOWN, YOU NEED THE PEOPLE THAT OTHERS WANT TO FOLLOW. IF YOU DON'T HAVE THAT, I DON'T THINK IT CAN BE A SUCCESS. TOTAL DEMOCRACIES IN THESE THINGS DON'T ALWAYS WORK. OR THEY'RE A LOT HARDER, ANYWAY. THE SOCIOLOGY, WHO GETS TO SEE WHAT AND WHEN? THE SHARING ASPECT OF IT HAS TO BE DECLIERED. DECLARED. IF YOU'RE FIGHTING ABOUT THAT ASK THE FACT, IT'S GOING TO MAKE A MESS OF THINGS. YOU HAVE TO HAVE THE RIGHT EXPERTISE. IT HAS TO CLUL INFORMATICS, BIG DATA, COMPUTATIONAL THINGS, AND THE LEADERSHIP HAS TO BE AGREEABLE. NOT ONLY DO YOU HAVE TO HAVE THE RIGHT EXPERTISE BUT EVERYBODY HAS TO AGREE THAT THAT IS THE LEADER, LIKE A CAPTAIN ON A SHIP, YOU HAVE TO AGREE. AND THE FUNDING HAS TO BE APPROPRIATE. IF YOU TRY TO MAKE A PROJECT THAT'S TOO BIG FOR THE FUNDING, THEN THE FUNDERS ARE UPSET, YOU FAILED, AND NOBODY'S HAPPY. SO THOSE ARE THE LESSONS THAT I'VE LEARNED. TAKE THEM WITH A GRAIN OF SALT, IT'S MY OWN BIAS, OF COURSE, AND I THINK THAT'S ALL I HAVE TO SAY. SO THANK YOU VERY MUCH. [APPLAUSE] >> THAT WAS A GREAT TALK. WE HAVE TIME FOR A FEW QUESTIONS IF PEOPLE HAVE ANY. >> SO I THOUGHT ESSENTIALLY THE VIRTUAL DATA BANK WAS A COOL IDEA WHERE THE META DATA IS THERE, PEOPLE CAN SEARCH AND CONTACT WHOEVER FOR THE DATA. IS THERE A PLAN FOR THE SUSTAINABILITY OF THAT INFRASTRUCTURE GOING FORWARD? >> YOU MEAN WHEN I GOT HIT BY A BUS? >> WELL, FUNDED BY THIS PART OF THE NIH INITIATIVE, IF THAT EVER GOES AWAY, HOW IS THAT SITE GOING TO BE MAINTAINED AND AVAILABLE TO PEOPLE TO USE? >> WELL, IT IS FEDERATED, SO THE IT'S ALL LIGHTWEIGHT, WHICH MEANS THAT THE RESOURCES AT ANY ONE SITE ARE EXTREMELY LIGHT. WE RUN THE PORTAL. THE HONEST TRUETT IS IT'S NOT TRUTH IS IT' S NOT FUNDED BY NIH RIGHT NOW, IT'S FUNDED BY PRIVATE FUNDERS. AND IT'S A PHILANTHROPY PRIMARILY, AND WE DO IT BECAUSE IT'S A GOOD IDEA. MY GUESS IS IT WILL HAVE ITS DAY IN THE SUN AND IT WILL EVOLVE TO SOMETHING ELSE. AND THE SOURCE CODE WE DEVELOP FOR M LM ALL O ALMOST ALL OF OUR PROJECTS IS GIVEN AWAY, SO ULTIMATELY SOMEONE WILL PICK IT UP AND TAKE IT AND RUN WITH IT. SO THE ANSWER IS IT'S NOT REALLY FUNDED NOW AND IT'S LIVING. EVENTUALLY IT WILL NOT BE USEFUL TO PEOPLE AND IT WILL BE SOMETHING BETTER AND SOMEBODY ELSE WILL RUN IT. THAT WILL BE MY GUESS. >> OKAY. [APPLAUSE] THANK YOU VERY MUCH. ALL RIGHT. SO NOW JUST A COUPLE OF ANNOUNCEMENTS. AFTER PREVIOUS MEETINGS, THE FEEDBACK I ALWAYS GOT WAS YOU DON'T GIVE US ENOUGH TIME TO MINGLE AND JUST HAVE CONVERSATIONS, YOU KNOW, YOU CAN GET US IN THE HARNESS AND THEN BOOM, BOOM, BOOM, BOOM, BOOM. SO WHAT WE'VE DONE IS WE'VE SET IT UP SO THAT THERE ARE SOME VERY GOOD POSTERS AND DEMONSTRATION TABLES SET UP UPSTAIRS, AND FOR THE NEXT UP TO HOUR AND A HALF OR SO, WE INVITE YOU TO GO UP AND MINGLE, TALK TO EACH OTHER, CHECK OUT THE POSTERS, AND TAKE ADVANTAGE OF THIS OPPORTUNITY. I WANTED TO SAY THAT THERE'S A COUPLE OF FLYERS OUT IN THE -- AT THE MAIN REGISTRATION TABLE THAT I'D ENCOURAGE YOU TO LOOK AT. ONE IS FROM COLAB, THE GLOBAL PREGNANCY COLLABORATION, AND ANOTHER ONE IS FOR IFBA, INTERNATIONAL FEDERATION OF PLACENTAL ASSOCIATIONS, I THINK I GOT THAT RIGHT. AND SO THERE'S SOME TAKEAWAYS ABOUT THAT MEETING. SORRY, I'M TIRED, IT'S BEEN A LONG DAY. AND THEN THE LAST THING IS I WANT TO TELL YOU THAT FOR TOMORROW, LUGGAGE IS ALWAYS A CONCERN, WE WILL HAVE A PLACE TO STORE YOUR LUGGAGE, SO DON'T WORRY ABOUT THAT, BRING IT HERE AND WE'LL KEEP IT SAFE. SO WITH THAT, I THANK YOU FOR MAKING THIS A GREAT FIRST DAY. UPSTAIRS, PLEASE ENJOY THE REST OF THE DAY AND YOUR EVENING AND I'LL SEE YOU TOMORROW MORNING. [APPLAUSE] >> WE'LL START AT 8:30.