PEOPLE FROM THE OUTSIDE TO PLEASE INTRODUCE YOURSELVES. YOU'RE HIDING IN THE BACK THERE. I SEE YOU, BUT NO ONE WANTS TO INTRODUCE THEMSELVES. >> GOOD MORNING. [INAUDIBLE] >> NIKI >> I THINK WE HAVE SOME PEOPLE WE'D LIKE TO INTRODUCE FROM OUR STAFF, SO START WITH DR. LILIAN -- >> GOOD MORNING. I'M DELIGHTED TO INTRODUCE MR. JOEL GUZMAN, WHO IS SITTING OVER THERE. HE'S OUR NEW PROGRAM ASSISTANT AND COORDINATOR. MR. GUZMAN RECEIVED HIS EDUCATION FROM MONTGOMERY COLLEGE WITH A FOCUS ON INFORMATION MANAGEMENT. HE SERVED IN VARIOUS CAPACITIES AS EXECUTIVE ASSISTANT, STAFF ASSISTANT, AND PROGRAM ASSISTANT, AND IN THE LAST FOUR YEARS, HE WAS WITH THE OFFICE OF DIRECTOR COORDINATING DAILY ADMINISTRATIVE ACTIVITIES WITH THE NATIONAL CENTER FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE. WITH US, HE WILL BE COORDINATING DIVISION WIDE ADMINISTRATIVE ACTIVITIES AND TASKS AND SERVING AS A LIAISON TO OTHER FUNCTIONAL COMPONENTS. PLEASE JOIN ME IN WELCOMING MR. GUZMAN. [APPLAUSE] >> DR. MARGO. >> GOOD MORNING. IN FEBRUARY, MR. DAHNTAY -- JOINED NIDCR AS A PROGRAM ASSISTANT IN THE OFFICE OF SCIENCE POLICY AND ANALYSIS. AND IN THE OFFICE OF COMMUNICATIONS AND HEALTH EDUCATION. BEFORE JOINING NIDCR, HE WAS PATHWAYS INTERN AT THE CENTERS FOR MEDICARE AND MEDICAID SERVICES, AND PRIOR TO THAT, HE SERVED MORE THAN NINE YEARS IN THE U.S. NAVY AS A PERSONNEL SPECIALIST. HE RECENTLY RECEIVED HIS B.A. DEGREE IN HEALTH ADMINISTRATION AND POLICY FROM THE UNIVERSITY OF M.D. BALTIMORE COUNTY. PLEASE JOIN ME ONCE AGAIN IN WELCOMING DANTE TO THE NIDCR. [APPLAUSE] >> [INAUDIBLE] >> GOOD MORNING. I'D LIKE TO INTRODUCE AND WELCOME MS. SUSAN LOWENTHAL TO MY LEFT, SHE'S JOINING AS A SENIOR GRANT SPECIALIST, STARTED WITH NIH ABOUT 12 YEARS AGO, MOVED ON TO NCRR WHICH BECAME NCATS. PLEASE JOIN ME IN WELCOMING SUSAN. [APPLAUSE] >> THE MINUTES. >> ALL RIGHT. I'LL ALSO WELCOME ALL OF OUR COUNCILMEMBERS AND GUESTS TODAY, AND REMEMBER WE WILL BE PROVIDE PROVIDING A WEBCAST OF THE PROCEEDINGS, SO IF YOU ARE SPEAKING, PLEASE TRY TO USE THE MICROPHONE SO THOSE OUT IN THE VIRTUAL WORLD WILL BE ABLE TO HEAR YOU. WE ALSO HAVE TWO OF OUR FABULOUS I.T. STAFF MEMBERS HERE TO HELP WITH ANY I.T. PROBLEMS. WE HAVE JOHN UP IN THE FRONT OF THE ROOM AND WARREN MADDOX OVER BY THE DOOR. THEY'D BE HAPPY TO HELP WITH ANYTHING HAVING TO DO WITH I.T. OKAY. FIRST ITEM OF BUSINESS IS APPROVAL OF MINUTES FROM THE PREVIOUS MEETING. THE MINUTES FROM THE JANUARY 2014 MEETING WERE MADE AVAILABLE OH IT THE COUNCIL MEMBERS FOR THEIR REVIEW, AND NOW I'LL ASK IF ANYONE HAS ANY COMMENTS OR CORRECTIONS FOR THE JANUARY COUNCIL MINUTES. IF NOT, WOULD A COUNCILMEMBER LIKE TO MAKE A MOTION TO APPROVE THE MINUTES? SECOND? A ALL IN FAVOR? ANY OPPOSE OKAY, THANK YOU. BACK TO MARTHA FOR THE REPORT OF THE DIRECTOR. >> THANK YOU. MY MICROPHONE IS ON AND EVERYTHING, SO AGAIN, WELCOME, EVERYBODY. I BELIEVE COUNCIL, YOU HAVE THE DIRECTOR'S REPORT IN FRONT OF YOU. I'M GOING TO BE MAYBE -- SOME OF THE THINGS THAT YOU HAVE THAT I MAY BE HIGHLIGHTING, BUT THERE'S SOME OTHER AREAS, SO AS I WAS GETTING READY FOR TODAY AND TRYING TO DECIDE SHOULD WE JUST MOVE ON BECAUSE WE HAVE A LOT OF EXCITING THINGS AND ACTUALLY I WANT TO MOVE ON BECAUSE I CAN'T WAIT TO HEAR FROM OUR GUESTS AND SOME OF OUR ANNOUNCEMENTS THIS MORNING. BUT I ALSO THOUGHT IT WAS VERY IMPORTANT TO UPDATE YOU ON SOME NIH ACTIVITIES AND SOME NIDCR-SPECIFIC ACTIVITIES AS WELL, AND WITH YOUR DIRECTOR'S REPORT, IF YOU HAVE ANY QUESTIONS ON THAT, I'D BE DELIGHTED OH T TO ANSWER, AND I'LL OPEN IT FOR QUESTIONS AFTER I TALK ABOUT IT. SO I'M GOING TO TALK ABOUT THE HEARINGS THAT HAVE BEEN ONGOING, MANY, SOME OF THE NIH INITIATIVES, MANY THAT YOU'VE HEARD IN THE NEWS AND MAYBE WE'LL GET SOME DISCUSSION GOING ON, THIS INTRAMURAL PROGRAM REVIEW, WHICH IS NOT QUITE A REVIEW BUT LOOKING FORWARD IN 10 YEARS FROM NOW OF WHAT WE SHOULD LOOK LIKE, AND I'LL EXPLAIN THAT IN THE FUTURE, AND THEN TO CLOSE THE LOOP A LITTLE BIT, LAST TIME I REPORTED ON THE NIDCR COMMITTEE ON DIVERSITY AND INKLUG, AND WE ARE MOVING FORWARD WITH THAT SO I WANT TO TALK TO YOU ABOUT SOME OF THE ACTIVITIES THERE THERE. SO THE FIRST IS THE NIH CONGRESSIONAL HEARINGS. THESE ARE ACTIVITIES THAT OUR DIRECTOR, DR. FRANCIS COLLINS, HAS BEEN ACTIVELY INVOLVED IN. THIS IS ALSO A TRIGGER FOR ME TO THANK ALL OF YOU, THE COUNCIL, AS WELL AS THE WONDERFUL STAFF AT NIDCR AND ALL OF YOU IN THE COMMUNITY ARE STAKEHOLDERS IN TERMS OF YOUR COMMITMENT AND PASSION FOR THE BIOMEDICAL RESEARCH ENTERPRISE, AND THAT A LOT OF TIMES WE DON'T THINK OUR VOICES MATTER. THEY MATTER AND YOU DON'T KNOW WHEN AND WHERE IT WILL REALLY HAVE THE IMPACT, SO THANK YOU, AND JUST KEEP GOING, NEVER STOP. AND I THINK I WOULD LIKE TO SAY THAT ABOUT OUR DIRECTOR, FRANCIS COLLINS. SO HERE IS JUST AN EXAMPLE OF SOME OF THE HEARINGS THAT HE'S BEEN INVOLVED WITH. HE'LL BRING SELECTIVE ICs BASED ON THE TOPICS THAT WERE REQUESTED TO BE DISCUSSED. AS YOU KNOW, HE'S ON NPR, HE'S ALSO BEEN IN TED TALKS, AND HE ALSO IS ON NIGHT SHOWS AND EVERYTHING ELSEWHERE IF I HAD MY GUITAR, I WOULD GO OUT AND SING WITH HIM BUT I DON'T, BUT IT'S JUST AN AMAZING THING THAT HE IS DOING FOR US, AND SIMILARLY WHAT YOU DO. THE TWO THAT I WANTED TO HIGHLIGHT WAS THE APRIL 29TH AND MAY 6TH. ON APRIL 29TH, THIS WAS UNIQUE BECAUSE IT WAS A FULL APPROPRIATIONS COMMITTEE. THE CHAIR, BARBARA MIKULSKI, PUT THIS TOGETHER, AND THE REASON SHE DID THIS WAS SHE SAID ALL THE SUBCOMMITTEES ARE INVOLVED, IT'S A BIPARTISAN ACTIVITY, AND HER CONCERN IS THAT WITH THE AUSTERE BUDGETS, AND YES A NEED TO CUT SOME THINGS, ARE WE DOING TOO MUCH DAMAGE, SO THAT WE'RE IN A WHAT SHE CALLS AN INNOVATION, HEADING TOWARD AN INNOVATION DEFICIT. SO SHE HAD A VARIETY OF PEOPLE, FRANCIS COLLINS WAS JOINED BY LEADERSHIP AT DOE AND DARPR, AS WELL AS NSF AND A RARE APPEARANCE OF JOHN HOLDREN FROM THE WHITE HOUSE, OFFICE OF SCIENCE AND TECHNOLOGY. THEY SAID IT WAS A LOVE FEST, AND THEY TALKED VARIOUS TYPES OF INNOVATIONS AND DIRECTIONS THEY NEEDED TO BE GOING. AMONG THINGS THAT FRANCIS COLLINS DISCUSSED INCLUDING TARGET VALIDATION, WHICH I'LL TALK ABOUT IN A MOMENT, AS WELL AS THE BRAIN INITIATIVE, AND CANCER IMMUNOTHERAPY. THE OTHER WAS NOT QUITE A HEARING BUT FRED UPTON AND RANKING MEMBER DIANA DEGETTE. THIS WAS VERY INTERESTING BECAUSE IT WAS THE FIRST OF MANY ROUNDTABLES, I HOPE, SOME THAT WILL BE IN DC AND OTHERS THAT WILL BE AROUND THE COUNTRY WITH THE GOAL THAT SOMEWHERE IN THE FALL, THEY WILL HAVE A REPORT OF SOME TYPE AND THE CHAIR, FRED UPTON, IS REALLY COMMITTED TO THIS. ATED LEGISLATORS WANT TO HEAR HOW TO ACCELERATE THE PACE OF CURES IN MEDICAL BREAK THROUGHS IN THE U.S., WHAT ARE THE OBSTACLES, WHAT DO THESE OPINION THOUGHT LEADERS SUCH AS FRANCIS COLLINS, FLAN THRO PHILANTHROPIC GROUPS AND OTHERS THINK NEED OH BE DONE IN ORDER TO MOVE FORWARD WITH THIS, AND A VERY COMMITTED GROUP OF INDIVIDUALS. STAY TUNED TO HEAR MORE ABOUT THESE ROUNDTABLES IN THE FUTURE. THEN I'M GOING TO TALK ABOUT A VARIETY OF DIFFERENT INITIATIVES AT NIH. AS I ALREADY MENTIONED, ONE OF THE AREAS OF CONCERN AND YOU HAVE PROBABLY HEARD IN THE NEWSPAPER RELATES TO THE TARGET VALIDATION AREA IN THAT THE MOLECULES THAT ARE BEING SELECTED FOR TARGETS ARE ALL FAILING FROM PRECLINICAL AS YOU MOVE TO PHASE 3, IN FACT, IT IT'S GETTING WORSE, NOT BETTER. AND SO WHAT DO WE DO ABOUT THIS? IT'S JUST IN ITS BEGINNING. BUT RIGHT NOW, THERE'S A STEERING COMMITTEE THAT IS A MIXTURE OF PEOPLE FROM INDUSTRY, AS WELL AS RESEARCHERS TO ADDRESS THIS ISSUE ON THE THREE AREAS THEY'VE SELECTED FOR NOW, INCLUDING ALZHEIMER'S DISEASE, TYPE 2 DIABETES, A AND SPECIFIC AUTOIMMUNE DISEASES SUCH AS LUPUS AND RHEUMATOID ARTHRITIS, AND THE MONEYS WILL BE SHARED BY BOTH GROUPS. IT'S PRETTY IMPRESSIVE, THE PARTNERSHIPS, A VARIETY OF DIFFERENT GROUP AS YOU CAN SEE, 10 BIOPHARMACEUTICAL COMPANIES, NIH AND FDA, AS WELL AS A VARIETY OF ADVOCACY GROUPS AND OTHER AREAS. AND THE GOAL IF IT DOES WORK, IT'S SOMETHING WE NEED TO DO IN OUR WHOLE COMMUNITY, IS TO SHARE THE -- DISCUSS IT AND TRY TO COME UP WITH INNOVA APPROACHES AND MOLECULES THAT WILL BE BETTER, AND THE ULTIMATE GOAL IS GETTING DIAGNOSTICS AND THERAPIES TO THE PATIENTS AND ALSO IN A MUCH MORE COST-EFFECTIVE AND RAPID METHOD THAN IN THE PAST. SO WE'LL SEE WHERE IT'S GOING WITH THE FIRST THREE DISEASES THAT THEY SELECTED, TWO RIGHT NOW THAT ARE MOVING FORWARD WITH THREE TO FIVE YEAR PILOT PROGRAMS. O THAT IS IN ALL OUR MINDS, WHERE WE ARE WITH THE FUNDING SIDE OF IT, AND WITH THAT OF COURSE, THE CONCERN ABOUT PEER REVIEW, AND IS PEER REVIEW BEING APROPRIATE AND SELECTIVE ENOUGH IN TERMS OF GETTING THINGS IN TERMS OF THE FUNDING OPPORTUNITIES THAT ARE AVAILABLE AND THE COMMUNITIES THAT WE SERVE AND THE RESEARCHERS WITH AN AVERAGE OF A 16% SUCCESS RATE. SO I THOUGHT IT WAS REALLY IMPORTANT FOR YOU TO TAKE A LOOK AT THIS, THAT IT'S NOT EASY. SO WE ISSUE OVER A THOUSAND FUNDING OPPORTUNITY ANNOUNCEMENTS A YEAR. 70,000, 80,000 APPLICATIONS A YEAR. 22,500 REVIEWERS WHERE WE URGE YOU TO PLEASE, PLEASE REVIEW IF CALLED UPON. HAD IS AN ISSU -- THIS IS AN ISSUE OF MAJOR CONCERN THAT A LOT OF PEOPLE THAT ARE VERY GOOD REVIEWERS ARE DECLINING, AND ABOUT 2,500 MEETINGS A YEAR. THIS IS AN INCREDIBLE AMOUNT THAT WE DO SUCH A GREAT JOB, BUT AS WE DO A GREAT JOB, WE COULD ALWAYS DO BETTER. AND I THINK THIS IS -- SO THIS IS AN IMPORTANT POINT THAT WE ARE CURRENTLY IN A PROCESS OF REVIEWING THE PEER REVIEW PROCESS, BUT THAT DOESN'T MEAN THAT IT'S NOT DONE ALL THE TIME. SO THERE ARE SURVEYS OUT THERE. SOLLIE ROCKY, THE DIRECTOR OF THE EXTRAMURAL RESEARCH PROGRAM, IS JUST WONDERFUL. I URGE YOU, YOUR COMMUNITIES, TO READ HER BLOGS. THEY'RE INCREDIBLY INFORMATIVE, BUT YOU KNOW SHE'S RESPONDING TO MANY THINGS, SO ONE OF THE AREAS THAT WAS HIGHLIGHTED RECENTLY IS EFFORT REPORTING. AND SHE'S COMMITTED WITHIN THE NEXT 12 MONTHS TO DO SOMETHING ABOUT THIS BECAUSE THIS IS A HUGE ADMINISTRATIVE BURDEN ON OUR RESEARCHERS. THE OTHER AREA THAT YOU KNOW ABOUT IS WHAT TO DO WITH THE RESUBMISSIONS AND THE A1s THAT SCORE WELL BUT BECAUSE OF THE SITUATION WITH THE BUDGETS, ARE NOT GETTING FUNDED, AND WITH THAT, YOU NOW KNOW THAT YOU CAN SUBMIT YOUR A1 THAT WAS NOT SUCCESSFULLY SCORED, YOU COULD NOW SUBMIT THAT, THE CONCEPT IN THAT AS A NEW GRANT. I THINK WE WILL SEE WHERE THIS GOES, BUT AT LEAST TRYING TO LISTEN, TRYING TO DO THINGS FOR THE COMMUNITIES. BEYOND THAT, OUR DIRECTOR, DR. FRANCIS COLLINS, HAS LOOKED AT SOME OTHER AREAS. ONE OF THE CONCERNS WITH THE DECLINE IN THE FUNDING IS THAT INNOVATION IS GOING OH G TO GO AWAY. BECAUSE THE BRIGHTEST OF THE BRIGHT HAVE WONDERFUL FORMULAS AND ALSO WONDERFUL GRANTSMANSHIP SKILLS, AND SO WITH THAT, WHERE IS THE INNOVATION? AND ARE THERE WAYS THAT WE CAN COULD MAKE SURE THAT THE INNOVATION IS STILL DRIVING US. VERY, VERY IMPORTANT. AND IT'S AT THE BASIC SCIENCE LEVEL, WE CAN'T LOSE THAT, AND THAT'S A BIG CONCERN THESE DAYS. ANOTHER AREA THAT HAS JUST BEEN CHARGED LAST WEEK BY DR. LARRY TABAK TO THE SCIENTIFIC MANAGEMENT REVIEW BOARD, WHICH I SERVE ON, IT'S ABOUT 50% FROM OUTSIDE, 50% FROM INSIDE, WAS RELATED TO THE BURDEN ON THE RESEARCHERS WHERE THEY ALMOST HAVE -- THEY SAY ABOUT 50% OF THEIR TIME IS SPENT ON ADMINISTRATIVE ISSUES. THIS IS A REAL PROBLEM, HOW CAN YOU GET YOUR RESEARCH DONE WHEN YOU'RE WORKING ON THE ADMINISTRATIVE SIDE. SO OUR SPECIFIC CHARGE IS HOW TO STREAMLINE THE GRANT-MAKING PROCESS AND SHORTEN THE TIME FROM THE BEGINNING OF THE APPLICATION TO ALLOCATION OF FUNDS. BOTH THE PROCESS IT SEL IT SELF AND ALSO WITHIN OUR INTRAM PROGRAMS AS WELL, CAN WE AT NIDCR, ONCE WE GET RECOGNITION, MOVE FASTER THAN WE DO. SO A LOT OF QUESTIONS ON THIS. SO YOU'LL HEAR MORE ABOUT THIS, THE CHARGE WAS JUST GIVEN TO US, I THINK, A WEEK AGO OR TWO WEEKS AGO. SO I'M GOING TO TALK ABOUT A FEW OTHER THINGS HA RELATE TO PEER REVIEW INDIRECTLY AND DIRECTLY. I THINK MANY OF YOU HAVE HEARD ABOUT THE REPRODUCIBILITY AND CONCERNS ABOUT INABILITY TO REPRODUCE RESULTS FROM ONE LAB TO ANOTHER, WHETHER IT'S AT THE PRECLINICAL STAGE OR DRUGS MANUFACTURED TO THE CLINIC AND THEN THE ANIMAL FINDINGS AREN'T REPRODUCED IN PATIENTS. OF VERY MUCH CONCERN AT ALL LEVELS. SO THERE ARE A LOT OF -- SO WE WERE REQUESTED AS INSTITUTES AND CENTERS TO COME UP WITH SOME CONCEPTS AND IDEAS AND TO PILOT THESE PROJECTS. ONE OF THE AREAS OF FOCUS IS THE TRAINING AREA, AND A LOT OF US FEEL THIS IS A REALLY IMPORTANT THING FOR THE NEXT GENERATION OF MAKING SURE THEY UNDERSTAND WHAT IT IS. THERE'S A LOT OF PRESSURE THESE DAYS, AND SOMETIMES, FOR EXAMPLE, IF A JOURNAL -- SO WE'RE GOING TO BE HAVING SOME MEETINGS WITH JOURNALS AS WELL. THE JOURNAL SAYS, OKAY, YOUR ARTICLE HAS BEEN ACCEPTED, NOW WE WANT YOU TO RESUBMIT IT IN ONE MONTH, AND BY THE WAY, YOU NEED TO TO DO THIS OTHER STUDY AGAIN. HOW CAN THEY RESUBMIT IT IN ONE MONTH AND DO THAT STUDY? SO I THINK THE JOURNALS -- I'M JUST GIVING YOU THAT AS ONE EXAMPLE. IT'S NOT JUST JOURNALS ALONE, THERE ARE MANY, MANY OTHER ISSUES IN TERMS OF THE TRAINING. THERE ARE ARE ALSO SOME PILOT CURRICULAR PROGRAMS BEING DEVELOPED AT NIH AND HOPEFULLY WITHIN YOUR SCHOOLS AS WELL. ONE OF THE AREAS THAT WE ARE WORKING O ISWORKWORKING ON IS THIS CHECKLI ST, THE WAKEUP CALL TO MAKE SURE YOU ARE LOOKING AT THE R RIGOR OF THE SCIENCE AND A VARIETY OF OTHER APPROACHES. AND I THINK JUST PAYING ATTENTION TO THIS, DISCUSSING IT, DISCUSSING IT WITH YOUR PREDOCS, POSTDOCS, NEXT GENERATION, I THINK IS A REALLY IMPORTANT THING. SO JUST HIGH 110ED AWARENESS, I THINK WILL MAKE A DIFFERENCE. SO THIS IS ONE THAT RECEIVED A LOT OF BUZZ. I WAS SURPRISED AT HOW MUCH BUZZ IT RECEIVED, RELATED TO THIS NATURE POLICY ARTICLE THAT CAME OUT. WHERE FRANCIS COLLINS, THE DIRECTOR OF NIH, AS WELL AS THE DIRECTOR OF THE OFFICE OF RESEARCH IN WOMEN'S HEALTH, THAT'S JENEANE CLAYTON, WERE DISCUSSING THE NIH TO BALANCE SEX IN CELLS. WAY BACK IN 1993, THERE WAS A RECOGNITION THAT WE WERE INAPPROPRIATELY WORKING AT THE CLINICAL LEVEL IN SOME OF THE CLINICAL TRIALS OF SELECTING MALES AND IGNORING FEMALES. AND WITH THIS NOW, ABOUT 50% OF THE CLINICAL TRIALS INCLUDE WOMEN. THERE'S STILL SOME ISSUES RELATED TO GENDER, ETHNICITY AND OTHER THINGS, AND WE COULD DO BETTER ON THIS AREA, BUT NOW THE RECOGNITION, SO AS SCIENCE KNOWLEDGE INCREASES, SO DO THE POLICIES THAT GOVERN THEM. AND SO THIS ARTICLE DISCUSSES HOW NIH IS ADDRESSING THESE ISSUES. SO SOME OF THE THINGS THAT WERE DISCUSSED, SO STARTING IN OCTOBER, YOU'RE GOING TO HAVE TO REPORT ON THE BALANCE OF MALE AND FEMALE CELLS AND ANIMALS, AND THEY'RE PREPARING SOME GUIDELINES OVER THE NEXT YEAR. SO THIS IS JUST THE BEGINNING. AGAIN, THE ABSOLUTE NEED FOR TRAINING, SO OUR GRANTEES UNDERSTAND EXACTLY WHAT IS REQUIRED. AND THEN THERE ARE SUPPLEMENTS TO EXISTING GRANTS ON THIS AREA, AND THE OFFICE OF RESEARCH AND WOMEN'S HEALTH OVER THE LAST TWO YEARS HAVE ACTUALLY BEEN SPONSORING THIS, AND WE'VE RECEIVED, OVER THE LAST FEW YEARS, TWO GRANTS AND MOST RECENTLY ONE THAT WILL JUST BE GETTING LAUNCHED, WHERE THEY FOUND IN MALE RATS, WHEN THEY HAD TRAUMA AND THEY RECEIVED MORPHINE IMMEDIATELY AFTER, THAT RATHER THAN HAVING A DIMINISHED PAIN RESPONSE, IT ACTUALLY ACCELERATED. AND NOW THEY'RE GOING TO USE FEMALE RATS. THEY ONLY USED MALE RATS IN THE INITIAL STUDY, AND THIS IS BEING FUNDED THROUGH THE OFFICE OF RESEARCH IN WOMEN'S HEALTH. AS YOU CAN SEE, THERE ARE OTHER ACTIVITIES THAT ARE GOING ON IN THIS AREA. THE OTHER THING THAT RELATES TO THIS INTRAMURAL PROGRAM REVIEW, THIS IS A CHARGE BY DR. FRANCIS COLLINS, AND IT'S LOOKING TEP 10 YEARS FROM NOW, WITH THE CONCERN HCONCERN, WITH DECLINING BUDGETS, MOST INSTITUTES ARE RUNNING ABOUT 25 TO 30% OF WHERE THEY WERE SEVERAL MONTHS AGO, AND EXPENSES ON THE PERSONNEL SIDE, APPROPRIATELY SO, BUT WHAT ABOUT BRINGING IN NEW INVESTIGATORS, WHAT ABOUT ADVANCES IN TOOLS AND TECHNOLOGIES THAT WE CAN'T KEEP UP WITH BECAUSE WE CAN'T AFFORD IT, SO WE REALLY DO NEED TO LOOK AT DOING BUSINESS DIFFERENTLY WITHIN OUR INTRAMURAL PROGRAMS. SO THIS WAS ON A RAPID PACE. THE CHARGE TO THE INSTITUTES AND CENTERS. THE MAIN QUESTION WAS WHAT SHOULD WE LOOK LIKE IN 10 YEARS, WHAT SHOULD THE INTRAMURAL PROGRAM ACROSS THE ICs AND SPECIFICALLY IN YOUR IC LOOK LIKE AND HOW CAN WE GET THERE. THIS WAS STARTED IN FEBRUARY WITH A REPORT TO THE ADVISORY DIRECTOR DUE IN DECEMBER. WE'RE GOING TO BE HAVING A FACE TO FACE MEETING THIS WEEKEND ON THIS. AND SO IT WAS SOMETHING WHERE IT'S SUPPOSED TO HAVE AT LEAST THREE MEETINGS, AND I'LL SHOW YOU IN A MOMENT THE COMMITTEE THAT WAS PUT TOGETHER, A SMALL COMMITTEE. BUT THINGS THAT WE NEED TO CONSIDER IS, ARE THERE ANY WONDERFUL SCIENTIFIC OPPORTUNITIES THAT EVERYBODY WOULD WISH THEY HAD THE CRYSTAL BALL AND WE KNEW IN 10 YEARS, WE WANT TO BE HERE, LIKE ON THE MOON, WHICH WE GOT TO, BUT BEYOND THAT, MAYBE SETTLING HOUSES ON THE MOON, OR WHAT ABOUT WITH OUR 10-YEAR PROGRAM, IS THERE SOMETHING THAT IS EXCITING THAT WE NEED TO BE THERE. AND THEN ARE THERE UNIQUENESSES. WE KEEP STRESSING THIS. THAT IN OUR INTRAMURAL PROGRAM, WE HAVE THE OPPORTUNITY TO TAKE HIGH RISK, HIGH REWARD-TYPE PROJECTS. AND WHAT SHOULD WE LOOK LIKE RELATIVE TO THE EXTRAMURAL COMMUNITY, WHAT'S INTRAMURAL, WHAT'S EXTRAMURAL. AND WITH OUR WONDERFUL RESOURCE IN THE CLINICAL RESEARCH CENTER, AND THE LARGEST CLINICAL RESEARCH CENTER IN THE NATION, ARE THERE THINGS THAT WE CAN BE DOING AND CAN NIDCR BE DOING SPECIFICALLY RELATED TO THE CLINICAL RESEARCH CENTER. OTHER THINGS ALSO WE ARE SUPPOSED TO COMMENT ON AND THEN DISCUSS THE BARRIERS. WE HAD A MEETING THIS LAST WEEK THAT WAS ABOUT FOUR-PLUS HOURS WITH MICHAEL GOTTESMAN, SEVERAL ICs AROUND THE TABLE, AS WELL AS THE SCIENTIFIC DIRECTORS AND MANY OTHER INDIVIDUALS JUST DISCUSSING THIS. IT'S TOUGH TO SEE WHERE IT'S GOING. NOURISBUT STAY TUNED, I THINK AT LEAST WE'LL COME UP WITH SOME INTERESTING THINGS FOR OUR INTRAMURAL PROGRAM AND PERHAPS PORFOR THE NIH. BUT THE COMMITTEE RIGHT NOW IS -- HE IS THE COMMITTEE HAD VERY SPECIFIC DIRECTORS. WE NEEDED OUR BOARD OF SCIENTIFIC COUNCIL ON HAD COMMITTEE, SUGGESTING IDEALLY THE BOARD OF SCIENTIFIC COUNCIL CHAIR SHOULD CO-DIRECT IT WITH ME, SO I DIDN'T SELECT TO BE ON THIS COMMITTEE, THEY TOLD ME I HAD TO BE. SO ON THE INTRAMURAL SIDE, WE HAD SEVERAL INVESTIGATORS THAT YOU CAN SEE HERE, AS WELL AS THE AD HOC GROUP, WHICH IS OUR EXTRAMURAL ACTIVITIES AND RESEARCH AREA THAT WILL BE IN THE FACE TO FACE BUT NOT IN THE OTHER, SO HEAR HERE THIS WEEKEND, HOW MUCH FUN. SO IN THE EXTRAMURAL, THE 22 PEOPLE ARE BRENDAN LEE AND JENNIFER GRANDIS, CHAIR AND COMING IN CHAIR. WE ALSO INVITED BILL MAIXNER BECAUSE HE HAS ACTIVITIES WITHIN OUR INTRAMURAL PROGRAM, HE UNDERSTANDS IT, AND HIS FOCUS IN THE AREA OF PAIN, WE THOUGHT WAS IMPORTANT TO HAVE SOMEBODY LIKE THIS ON BOARD. ALAN VERKMAN MAY BE FAMILIAR TO SOME OF YOU. HE'S A PROTEIN TRAFFICKING PERSON, VERY MUCH FOCUSED IN THE BASIC AREA ON UNDERSTANDING THE PROTEINS AND TARGETING AREAS FOR SIGNALING PATHWAYS AND SECRETION, BUT HE ALSO IS VERY MUCH A TRANSLATIONAL AND CLINICAL RESEARCHER AS WELL, SO HE'S BEEN INVOLVED, HE'S ON THE BOARD OF SCIENTIFIC COUNCIL FOR HEART, LUNG AND BLOOD, AND IS CURRENTLY FUNDED BY THREE OTHER INSTITUTES. SO WE'RE LOOKING FORWARD TO HIS JOINING US THIS WEEKEND AS WELL. SO THAT'S AN INTERESTING ACTIVITY. THE LAST IS THE NIDCR COMMITTEE ON DIVERSITY AND INCLUSION. AND THIS IS -- THE CHAIR OF THIS, AS YOU KNOW, IS DR. KATHY CARBONE. THIS IS ONE OF THOSE COMMITTEES WE STARTED ABOUT A YEAR AGO. THE TIMING COULD NOT HAVE BEEN BETTER. AS YOU KNOW, THE REPORT CAME OUT RELATED TO THESE ISSUES OF WORKFORCE AND THE CONCERNS ABOUT DIVERSITY AND INCLUSION AND THAT WE NEED TO DO A BETTER JOB, SORT OF A WAKE-UP CALL. ALSO WE JUST HAD ON BOARD, AND I THINK THIS IS IN YOUR DIRECTOR'S REPORT, DR. HANNA VALENTINE HAS JUST BEEN APPOINTED IN THE OFFICE OF -- I THINK IT'S CALLED THE OFFICE OF DIVERSITY. BUT SHE WAS MEETING WITH THE ICs, AND OF COURSE WE WENT RIGHT FIRST BECAUSE WE HAVE THIS REPORT, WE WERE ABLE TO TALK TO HER ABOUT IT. SHE'S INCREDIBLE, IF ANY OF YOU HAVE HEARD ANY OF HER CONVERSATIONS, SHE'S BEEN WORKING DAY ONE OR RUNNING DAY ONE WITH THIS AREA AND I'M SURE SHE'S GOING TO HAVE NEW ADVANCES AND WE'RE GOING TO BE ON PACE WITH HER OR IF NOT AHEAD. SO WITH THAT REPORT THAT WE SHARED WITH YOU LAST TIME, THERE WERE FOUR LARGE AREAS RELATED TO AREAS WE WANTED TO TACKLE. ONE WAS CULTURE AND INFRASTRUCTURE, DATA COLLECTION AND EVALUATION, HUGE FOR ALL OF US, NO MATTER WHAT AREA YOU'RE ADDRESSING, CAREER PREPARATION, MENTORING, RETENTION, AND OUTREACH AND COMMUNICATION. AT THIS POINT, WE HAVE SOME LIVELY GROUPS. WE HAVE A STAFF EDUCATION GROUP, AND YOU CAN SEE THE PEOPLE HEADING EACH ONE OF THESE, SO WE HAD A COMMITTEE, WE HAVE PEOPLE ON THE COMMITTEE, NOW WE HAVE THESE SUBCOMMITTEES WHERE OTHER PEOPLE AT NIDCR HAVE JOINED, AND THIS IS ONE OF THOSE AREAS WHERE WE HAVE HAD NO TROUBLE RECRUITING PEOPLE. PEOPLE ACTUALLY WANT TO JOIN AND BE A PART OF THESE COMMITTEES. SO THE STAFF EDUCATION DEMOGRAPHICS, EXTRAMURAL DPRANTS AND TRAINING RESOURCES, EDUCATION OF THE INTRAMURAL TRAINEES AND ALSO SO IMPORTANT IS THE COMMUNICATION SIDE. SO STAY TUNED FOR MORE UPDATES. THE COMMITTEES, THE SUBCOMMITTEES, I KNOW ARE MEETING, AND I KNOW YOU'LL LOOK FORWARD TO MORE PROGRESS IN THIS AREA FOR NIDCR AND ALSO FOR NIH. SO WITH THAT, I ALSO, IN CLOSING, WANTED TO SHOW YOU THE COVER. I KNOW YOU'RE ALL ANXIOUS AND WAITING FOR OUR STRATEGIC PLAN TO BE COMING OUT. WE HAVE SOME LAST-MINUTE PLANNING IN TERMS OF GETTING THE PICTURES TOGETHER AND IT'S NOT JUST GETTING THOSE BEAUTIFUL PICTURES TOGETHER WHICH ARE ARE VERY IMPORTANT FOR A STRATEGIC PLANNING MANUAL, BUT ALSO THE LEGAL SIDE OF IT. SO WE HAVE TO HAVE EVERY PICTURE LOOKED AT AND APPROVD AND OKAYED, AND SO IT'S AN INTERESTING PROCESS, BUT WE REALLY DO HOPE THAT YOU'LL SEE THIS IN JUNE. SO THAT'S OUR GOAL ON THAT. SO AGAIN, THANK YOU VERY MUCH FOR YOUR ATTENTION, AND I'D BE HAPPY TO ADDRESS ANY QUESTIONS. THANK YOU. [APPLAUSE] >> A QUESTION, TYPE~2 DIABETES IS ONE OF THE AREAS WHERE IT SEEMS LIKE GOVERNMENT AND INDUSTRY WERE GOING TO COME TOGETHER AND DO SOME ADDITIONAL WORK OR AT LEAST HAVE A TARGETED FOCUS. BUT I DIDN'T SEE DIET AND EXERCISE. AND SOME OTHER BIG DETERMINANTS OF THE RISK FACTOR FOR DIABET ITSELF. FOCUSED MORE TOWARDS A CURE RATHER THAN BEHAVIOR CHANGE? CAN YOU SAY A LITTLE BIT ABOUT THAT? >> SO AGAIN, THE PEOPLE THAT ARE ON THIS COMMITTEE CAN PROBABLY ADDRESS THAT MUCH BETTER THAN I CAN, BUT THERE ARE MANY DIFFERENT AREAS THAT ARE BEING STUDIED AND FOR SURE YOU'RE BRINGING UP AN EXCELLENT POINT. BUT THIS GOAL IS VALIDATION, SO THE FOCUS IS ON SOME OF THESE DRUGS INCLUDING IN TYPE~2 DIABETES RECENTLY WHERE THE REPORTS ON THE DRUGS IN THE CLINICAL -- WEREN'T AS THEY WERE HOPING. SO THIS IS AN IMPORTANT AREA, AND PERHAPS THEY CAN DEFINE BETTER DRUGS THAN THEY'VE HAD BEFORE. SO IT'S THE FOCUS, NOT TO ELIMINATE, I'M SURE, WHEN THE PHYSICIAN IS WITH THE PATIENT, THEY'RE GOING TO TALK ABOUT MANY, MANY OTHER THINGS. THAT'S NOT EXCLUSION OF OTHER THINGS. BUT THIS IS ON DRUG VALIDATION. ANY OTHER QUESTIONS, CLARIFICATIONS, PEER REVIEW? ALL RIGHT. SO THANK YOU VERY MUCH, AND WE'LL MOVE ON. [APPLAUSE] >> NEXT ON THE AGENDA, WE HAVE ONE CONCEPT CLEARANCE. WE ARE REQUIRED TO DOCUMENT THE CLEARANCE OF CONCEPTS FOR THE DEVELOPMENT OF GRANT AND CONTRACT OPPORTUNITIES BY PRESENTING THE PURPOSE, SCOPE AND OBJECTIVES IN A PUBLIC FORUM AND GIVING THE PUBLIC AN OPPORTUNITY TO COMMENT. TODAY, DR. NADYA LUMELSKY, PROGRAM DIRECTOR OF THE TISSUE ENGINEERING AND REGENERATIVE MEDICINE PROGRAM, WILL PRESENT A CONCEPT FOR THE DENTAL, ORAL AND CRANIOFACIAL TISSUE REGENERATION CONSORTIUM. >> GOOD MORNING. TODAY I WOULD LIKE TO PRESENT FOR YOUR CONSIDERATION OUR PLANS TO ESTABLISH DENTAL ORAL AND CRANIOFACIAL TISSUE REGENERATION CONSORTIUM, OR DOCTRC. SO THE GOAL OF THIS CONSORTIUM WILL BE TO DEVELOP EFFECTIVE CLINICALLY APPLICABLE TISSUE ENGINEERING AND REGENERATIVE MEDICINE STRATEGIES, AND I WILL REFER TO THEM AS TRM, FOR REGENERATION OF FUNCTIONAL TISSUES OF HUMAN DENTAL ORAL AND CRANIOFACIAL COMPLEX. WE ENVISION THAT OUT COME OF THE DOCTRC EFFORT WILL BE CLINICAL DEVELOPMENT OF COMBINATION PRODUCTS BASED ON CELLS, BIOLOGICS AND DEVICES, AND PROTOCOLS ASSOCIATED WITH THEM. WHICH WILL BE READY FOR INITIATION OF PHASE ONE CLINICAL TRIALS. NIDCR AT NIH OVER THE YEARS HAD MADE SIGNIFICANT INVESTMENT IN DEVELOPING TERM SCIENCE. THAT EFFORT PAID OFF TREMENDOUSLY. AS A RESULT, WE NOW HAVE A MULTITUDE OF VERY PROMISING TECHNOLOGIES AND TOOLS AS WELL AS EXCITING BASIC SCIENCE THAT IS RIPE TO BE TRANSLATED INTO DEVELOPING THERAPIES. BUT AS YOU KNOW, THE ROAD FROM LABORATORY BENCH TO THE HOSPITAL BED IS NEVER SIMPLE, ALMOST NEVER SIMPLE, AND SOMETIMES IT'S WINDING, AND WHAT WE'RE TRYING TO DO IS TO LEVERAGE NIDCR RESOURCES TO MAKE THIS ROAD AS SHORT AS POSSIBLE AND WITH MINIMAL NUMBER OF TERMS. RECOGNIZING THE CHALLENGES ASSOCIATED WITH THIS, WE HAVE DONE SOME PRELIMINARY WORK. WE WENT TO OUR EXTRAMURAL COMMUNITY FOR THEIR INPUT ON THE BEST WAY TO PROCEED, AND WE ALSO HAVE DONE A DETAILED ANALYSIS OF OUR OWN PORTFOLIO. AND I WANT TO MENTION SEVERAL POINTS THAT CAME OUT OF THIS ANALYSIS. FIRST, OUR EXTRAMURAL COLLEAGUES REITERATED TO US THAT FOR SUCCESSFUL TRANSLATION, WE NEED TO HAVE MULTIDISCIPLINARY TEAMS OF SCIENTISTS AND CLINICIANS WORKING ON THESE TASKS, AND CLINICIANS ACTUALLY SHOULD BE AT THE TOP OF THIS HIERARCHY, BECAUSE THESE ARE CLINICIANS WHO DETERMINE WHICH THERAPIES ARE NEEDED AT THE CLINIC, WHAT DO THEY ACTUALLY MEADE IN THE NEED IN THE CLINIC. THEN BIOLOGISTS, BIOENGINEER, MATERIAL SCIENTISTS AND OTHER SCIENCE PROFESSIONALS SHOULD TAKE THOSE IDEAS AND DEVELOP SPECIFIC STRATEGIES TO MEET THEM. ALSO PART OF THIS MIX SHOULD BE REGULATORY EXPERTS WHO KNOW HOW TO APPROACH FDA WITH -- BRINGING SPECIFIC PRODUCTS THROUGH THE TRANSLATIONAL PIPELINE. IN ADDITION, WE WERE AGAIN REMINDED, AND THAT CAME FROM, AS I SAID, FROM INTERACTIONS WITH THE COMMUNITY AND ALSO FROM THE ANALYSIS OF OUR OWN PORTFOLIO THAT DESPITE THE FACT THAT WE HAVE A LOT OF VERY INTERESTING SCIENCE, OFTEN WHAT IS NOT AS WELL DEVELOPED ARE WAYS TO COMPARE DIFFERENT TOOLS AND TECHNOLOGIES SIDE BY SIDE WITH EACH OTHER TO FIND OUT, TO VALIDATE THEM AND TO IDENTIFY THE MOST EFFICACIOUS METHODS. WE ALSO LACK GOOD LARGE ANIMAL MODELS THAT RECAPITULATE HUMAN DISEASE THAT WILL BE NEEDED FOR TESTING THOSE DIFFERENT TECHNOLOGIES SIDE BY SIDE. MOREOVER, WHEN IT COMES TO PRODUCTION, WE NEED GOOD MANUFACTURING PRACTICE TYPE OF PRODUCTION, METHODS FOR LARGE SCALE PRODUCTION OF PRODUCTS. SO ALL THESE THINGS NEED TO BE DEVELOPED FOR SUCCESSFUL TRANSLATION, SO WE WILL NEED SOME PREPARATORY WORK. SO ON THE BASIS O THESE CONSIDERATIONS, WE DEVELOPED A PLAN WHICH I WOULD LIKE TO PRESENT TO YOU TODAY. SO WE PROPOSE TO STRUCTURE DOCTRC IN THREE STAGES. THE FIRST STAGE WILL BE THE PLANNING STAGE. DURING THIS TIME, WE WOULD LIKE TO -- THE TEAMS WHO WILL BE SELECTED DURING THE COMPETITION TO COME TO US WITH SPECIFIC PLANS TO ESTABLISH CENTRALIZED RESOURCE CENTERS OVER ORCs AND PROVIDE US WITH EVIDENCE OF THE EXPERTISE IN REGULATING THROUGH PATHWAY. BY THE END OF PLANNING STAGE, WE WILL HAVE A COMPETITION FOR DEVELOPING, FOR ESTABLISHING THESE RESOURCE CENTERS. AND WHAT ARE RESOURCE CENTERS? FOR RESOURCE CENTERS, WE WILL SELECT SEVERAL OF THE MOST MERITORIOUS TEAMS THAT WILL EMERGE FROM THIS COMPETITION DURING PLANNING STAGE, AND THE RESOURCE CENTERS WILL BE DEALING WITH ESTABLISHING INFRASTRUCTURES TO CONDUCT THE TESTS THAT I JUST MENTIONED TO YOU, SIDE BY SIDE COMPARISONS OF DIFFERENT TECHNOLOGY, DEVELOPMENT AND IMPROVEMENT OF LARGE ANIMAL MODELS, LARGE SCALE PRODUCTIONS AND SO ON. SO THE RESOURCE CENTERS, WE WILL SELECT ONE OF SEVERAL GROUPS TO ESTABLISH THOSE CENTERS, AT THIS POINT WE DID NOT DETERMINE THE EXACT NUMBERS, IT WILL EMERGE FROM WHAT ACTUALLY WILL COME TO THE DOOR. BUT WHETHER IT'S ONE OR SEVERAL, IT WILL BE HIGHLY INTERACTIVE TEAMS THAT WILL EXCHANGE EXPERTISE AND WILL WORK IN CLOSE ASSOCIATION WITH THE FDA SO THAT THE TECHNOLOGIES THEY'RE DEVELOP DEVELOPING ARE ACTUALLY APPROPRIATE FOR FILING EVENTUALLY. SO THIS STAGE, THE SECOND STAGE, WILL BE FOLLOWED BY ACTUALLY THE THIRD STAGE, WHICH IS A CONSORTIUM STAGE. AT THIS TIME, THE FULL CONSORTIUM WILL BE ASSEMBLED, OKAY? SO I WANT TO MENTION THAT DURING THE LATER STAGES OF RC DEVELOPMENT, WE EXPECT TO IDENTIFY THE MOST LIKELY TO SUCCEED CLINICAL AREAS THAT WILL BE TAKEN TO THE THIRD STAGE. OKAY? WHAT I TOLD YOU ABOUT CLINICIANS BEING AN INTEGRAL PART OF THIS EFFORT WHERE THE EXPERTISE WILL COME VERY -- WILL BE VERY IMPORTANT. SO THESE CLINICIANS WILL TELL US WHICH AREAS ARE MOST LIKELY TO BE NEEDED, AND THE SCIENTISTS AND BUY OL OH GIST BIOLOGISTS AND BIOENGIN EERS, ON THE BASIS OF THAT, WILL DEVELOP SPECIFIC STRATEGIES. SO WE WILL BE LOOKING FOR THE INTERSECTION OF WHAT'S MOSTLY NEEDED IN THE CLINIC AND WHAT'S POSSIBLE TO DO. THAT'S WHERE OUR SWEET SPOT IS. SO WHEN WE TRANSITION INTO THE THIRD STAGE, WE WILL BE DEVELOPING THIS PARTICULAR AVENUE THAT WILL BE IDENTIFIED DURING THE SECOND STAGE, AND THE BACKBONE OF THE CONSORTIUM WILL BE INTERDISCIPLINARY TRANSLATIONAL PROJECTS. THOSE TEAMS WILL BE WORKING IN CLOSE ASSOCIATION WITH RSM Cs AND WITH THE FDA, AND ITPs WILL BE UTILIZING RESOURCES DEVELOPED BY THE RCs AND WORKING ON TAKING SPECIFIC PRODUCT TO FDA SO THAT THEY CAN CULMINATE IN THE INITIATION OF PHASE 1 CLINICAL TRIALS. I WANT TO SAY SEVERAL WORDS ABOUT THE TIMELINE OF THIS INITIATIVE. I WAS TALKING ABOUT ALL THE STAGES. SO THE PLAN IS TO NICHE THIS STAGE 1 IN FY15, AND THE SECOND STAGE, RC DEVELOPMENT, WILL FOLLOW CONSECUTIVELY. I MENTIONED TO YOU, BUT TOWARD THE END OF STAGE ONE, WE WILL HAVE A COMPETITION AND SELECT THE MOST MERITORIOUS TEAMS, SO WE ARE AIMING AT THE MINIMAL -- THIS TRANSITION WILL BE SMOOTH AND CON SEC TI CONSECUTIVE. THE TRANSITION FROM STAGE 2 TO STAGE III , WE ENVISION AS A GRADUAL TRANSITION. THE REASON FOR THAT IS THAT WE FEEL THAT IT IS IMPORTANT TO BEGIN TOGGLE TH TO GEL THE COLLABORATION BETWEEN THE RCs AND INDIVIDUAL ITPs BEFORE STAGE 2. IT'S A TIME WHERE WE'LL BEGIN TO IDENTIFY THE SPECIFIC PRODUCTS AND TECHNOLOGIES THAT WOULD GO FORWARD. WE WOULD LIKE THE ITPs TO COME IN AND BEGIN THEIR CONVERSATIONS AND THEIR INITIAL WORK WITH THE RCs. SO THE RCs WILL CONTINUE TO FUNCTION THROUGHOUT THE STAGE THREE. SO IN CLOSING, I WOULD LIKE TO SAY THAT WE HOPE THAT DOCTRC EFFORT WILL -- AND INPUT AND USEFULNESS WILL GO BEYOND THIS PARTICULAR INITIATIVE. WHAT WE'RE TRYING TO DO ACTUALLY IS TO ESTABLISH AN IMPORTANT PARADIGM FOR TAKING BASIC SCIENCE AND, YOU KNOW, EARLY STAGE DISCOVERY RESEARCH FROM THE LAB BENCH TO CLINIC, NOT ONLY FOR REGENERATION OF DOC TISSUES, BUT FOR REGENERATION OF MANY DIFFERENT TISSUES IN THE BODY, WHICH WILL BE USEFUL FOR THE WHOLE COMMUNITY OF SCIENTISTS, PRACTITIONERS AND PATIENTS ESPECIALLY. SO NOW I WOULD LIKE TO INVITE DR. MICHAEL LONGAKER AND DR. LESLIE WINSTON TO COMMENT ON THE INITIATIVE AND LEAD THE DISCUSSION. THANK YOU. >> THANK YOU, NADYA, THAT WAS WONDERFUL, AND I WANT TO APPLAUD YOU AND MEMBERS OF YOUR TEAM FR HOW YOU WENT ABOUT THIS. I HAD THE PLEASURE OF PARTICIPATING IN YOUR PLANNING PROCESS, WHICH I THOUGHT WAS THE EXACT WAY TO GO ABOUT THIS. JUST TO SET THE STAGE, I THINK CROSSING THE VALLEY OF DEATH FROM DISCOVERY INTO A NEW THERAPY IS VERY DIFFICULT. LIVING AND WORKING AT STANFORD AND SILICON VALLEY, IT'S SOMEWHAT EASIER TO DO THAT BECAUSE OF THE INFRASTRUCTURE ESTABLISHED THERE, SO IT'S NOT SURPRISING THAT CERTAIN POCKETS OF THE COUNTRY DO THAT MORE EFFICIENTLY THAN OTHERS. I THINK IT'S IMPORTANT TO LOOK AT THE CALIFORNIA INITIATIVE OVER 10 YEARS, BECAUSE AS YOU LOOK AT THE FIRST GRANTS, THEY'RE NOT DISSIMILAR TO YOUR ASSESSMENT OF YOUR PORTFOLIO. THEY WERE BASIC SCIENCE AWARDS, BASIC DISCOVERY GRANTS, THEN TRAINING GRANTS, AND THEN CAREER TRANSITION AWARDS AND NOW THERE'S EARLY TRANSLATION AWARDS AND DISEASE TEAMS. AND THE END PRODUCTS OF THOSE EARLY TRANSLATIONAL AWARDS AND DISEASE TEAMS IS AN IND FILING. SO THERE'S NO QUESTION THAT CAPITAL IS SCARCE, AND TRYING TO GET THE MOST OUT OF IT IS IMPORTANT, SO I APPLAUD YOUR PROCESS TO DO THAT. THE SECOND THING IS THE EXPERIENCE OF ESTABLISHING -- AND STEVE KNOWS THIS - THE HUB FOR FACE SPACE AND THEN HANGING PROJECTS OFF OF IT HAS BEEN VERY SUCCESSFUL AS IT'S BEING ROLLED OUT, SO AGAIN, THERE'S AN ANALOGY TO WHAT YOU'RE DOING. I THINK THE PHASE WHERE YOU'RE RECRUITING EXPERTISE FROM A REGULATORY STANDPOINT FROM A MANUFACTURING STANDPOINT IS NOT ALWAYS INTUITIVE FOR ACADEMIC MEDICAL CENTERS. BUT BY HAVING THE CLINICIAN AT THE TOP OF THE PYRAMID, SO TO SPEAK, THEN YOU HAVE A REALLY IMPORTANT LENS, IS IT AN UNMET NEED, THEN YOUR SECOND CUT THAT YOU INSISTED ON PUTTING IN THERE, IS IT REASONABLE AND PRACTICAL, IS IMPORTANT. THAT'S ONLY GOING TO COME ABOUT BECAUSE OF THAT PLANNING PROCESS, WHICH IS CRITICAL. SO I'M STRONGLY SUPPORTIVE, MORE THAN STRONGLY SUPPORTIVE OF THIS BECAUSE I THINK IT WILL MAKE A DIFFERENCE, AND I APPLAUD YOU FOR TAKING A BOLD STEP FROM A NIDCR STANDPOINT, BUT I THINK YOU'LL LEAD THE PACK, AND I THINK WE'LL LOOK BACK 10 YEARS F NOW AND SAY THE THINGS THAT CAME OUT OF THIS PROGRAM DID MAKE A DIFFERENCE IN THE PATIENT. SO I'M VERY SUPPORTIVE. THANK YOU. >> I JUST HAD A COUPLE MORE COMMENTS TO BUILD ON WHAT MICHAEL SHARED WITH THE GROUP. I THINK THIS WHOLE IDEA OF SORT OF MERGING AND FINDING THAT SWEET SPOT BETWEEN, YOU KNOW, WHAT'S NEEDED AND WHAT'S POSSIBLE IS REALLY KEY. AND IN MY OWN EXPERIENCE, IT'S A LITTLE BIT DIFFERENT SPECIFICS BUT WE FREQUENTLY USE THAT SORT OF VERNACULAR THAT THE APPROACH WE WANT TO TAKE WITH OUR INNOVATION PROGRAMS. NOW GRANTED, WE'RE THINKING MUCH MORE FOCUSED ON CONSUMERS WANT VERSUS WHAT CLINICIANS WANT, BUT I THINK THERE IS A LOT OF EVIDENCE, BOTH WITHIN NIH AND MORE BROADLY THAT THAT TYPE OF APPROACH TENDS TO LEAD TO MORE PRPRODUCTIVE TRANSLATION, SO I THINK CONCEPTUALLY, I THINK THE VISION IS GREAT. I THINK AS AN OUTSIDER, AND I USE THAT WORD NOT BECAUSE OF THE INDUSTRY PIECE BUT BECAUSE I'M NOT NECESSARILY -- HADN'T BEEN PART OF THE CONSULTATION THAT TOOK PLACE IN THE DEVELOPMENT OF THIS CONCEPT. I FOUND THE CONCEPT A LITTLE BIT CHALLENGING TO READ AND GRASP. WHEN I TALKED WITH NADYA AND MICHAEL, I GOT IT. I HAD EVEN SUGGESTED TO NADYA THAT ESPECIALLY SOME OF THE DIAGRAMS, I KNOW WE DON'T TYP PUT THOSE INTO ANNOUNCEMENTS, BUT IF YOU'RE REALLY TRYING TO BRING TOGETHER GROUPS MULTIFUNCTIONALLY AND MULTIDISCIPLINARY, I THINK THAT BECAUSE THIS ISN'T SOMETHING THAT PEOPLE TYPICALLY HAVE SEEN COMING FROM NIDCR, THAT IT MIGHT REALLY BE HELPFUL IN TRYING TO EXPLAI LITTLE BIT MORE CLEARLY, YOU KNOW, WHAT YOU'RE AFTER, BUT I 100% THINK IT'S THE WAY TO OH GO. THE OTHER AREAS THAT I BROUGHT UP IN OUR DISCUSSION WAS THAT PLANNING STAGE, AND AS MICHAEL SAID, VERY, VERY IMPORTANT. SO PART OF ME SAYS IS A YEARLONG ENOUGH, BECAUSE WITHOUT THAT DEFINITION OF REALLY, REALLY WHAT YOU WANT TO ACCOMPLISH, AND ESPECIALLY WHEN YOU WANT TO IDENTIFY THE REGULATORY COMPONENTS TO GO IN THERE, I THINK IT'S EASY TO COME UP WITH REGULATORY STRATEGIES. IT'S LESS EASY IN MY OPINION TO DEMONSTRATE THAT YOU HAVE THE EXPERTISE THAT'S REQUIRED TO TAKE YOU THROUGH THE REST OF THE PHASES. AND THE ONLY OTHER AREA I JUST WANT TO BRING UP, THIS I LITTLE BIT MORE SELF SERVING IS I THINK WHEN I READ THE NODE FROM THE CONSULTATION MEETING, IT HAD CALLED OUT THAT WE REALLY DIDN'T NECESSARILY WANT INDUSTRY INVOLVED IN THE PROJECT BECAUSE INDUSTRY IS TOO RISK-AVERSE TO GET IT. I THINK THE QUESTION MICHAEL AND I TALKED ABOUT THIS A LITTLE BIT IS WHO YOU GET THAT PERSPECTIVE FROM. BECAUSE IF YOU'RE TRYING TO ESTABLISH PRODUCT DEVELOPMENT CRITERIA, ESPECIALLY WHEN YOU GET INTO THINGS LIKE MANUFACTURING CAPABILITY AND SCALE-UP TECHNOLOGIES AND THOSE KINDS OF THINGS, I DO THINK THAT SOMEWHERE ALONG THE LINE, YOU PROBABLY DO NEED SOME INPUT, NOT NECESSARILY ARE YOU WILLING TO INVEST AND TAKE THIS TO THE MARKET KIND OF INPUT, BUT I DO THINK THAT THAT WILL BE VERY IMPORTANT TO THE SUCCESS OF THE PROGRAM. SO REALLY, REALLY LOOKING FORWARD TO SEEING HOW THIS COMES TOGETHER BECAUSE I THINK IT'S GREAT. THANKS FOR GIVING ME THE OPPORTUNITY TO COMMENT. >> ANY QUESTIONS? >> JEFF. >> THANK YOU VERY MUCH. I JUST HAD A COMMENT/SUGGESTION AND THEN A QUESTION. THE FIRST COMMENT IS PUTTING THE CLINICIANS AT THE TOP OF THE PYRAMID IS A GREAT THING, AND THE VAST MAJORITY OF THE TIME, THEY'RE THE ONES WHO UNDERSTAND THE UNMET NEEDS BEST BUT THE ULTIMATE CONSUMER IS THE PATIENT, I THINK ESPECIIN THE MIDDLE PARTS OF THE PROCESS, YOU MIGHT WANT SOME ADDITIONAL VALIDATION OF USEFULNESS OF THE PRODUCT FROM PATIENTS WITH A BROAD PERSPECTIVE IN LOOKING AT RELATIVE VALUE OF DIFFERENT PROJECTS. CERTAINLY INDUSTRY WOULD BRING THAT AS PART OF THEIR PROCESS IN THINKING ABOUT PRODUCT DEVELOPMENT. SO THAT'S JUST ONE SESSION. THE QUESTION I HAVE RELATES TO SAL VAIRSAL SALIVARY GLANDS, I BELIEVE THERE'S AN EXISTING PORTFOLIO OF SALIVARY GLAND REGENERATION. IS THAT VIEWED AS SEPARATE FROM THIS? ARE THERE LESSONS TO HAVE BEEN LEARNED FROM THAT PROCESS THAT MIGHT INFORM THIS? I JUST DIDN'T UNDERSTAND HOW THAT WORKS. >> AS YOU KNOW, WE RECENTLY HAD THE FOA ON SALIVARY GLAND REGENERATION AND THAT WORK IS GOING ON. AT THIS POINT, WE'RE NG THE AREA OPEN IN TERMS OF TISSUES, WE WOULD LIKE TO, YOU KNOW, INVEST INTO. THERE WILL BE PREPARATORY PROCESS AND WE DON'T EXCLUDE SALIVARY GLAND FROM THE LIST OF TISSUES WE'RE GOING TO ADDRESS. THEY ARE NOT EXCLUDED. WE WANT TO TAKE THOSE THAT ARE MOST LIKELY TO SUCCEED. THAT WILL BE OUR GOAL. IF WE HAVE A GREAT TECHNOLOGY AND, YOU KNOW, CLINICAL -- IMPORTANT CLINICAL NEEDS COMING FROM THAT AREA, WE WILL BE INTERESTED IN -- >> [INAUDIBLE] >> I THINK IT'S TOO EARLY. I THINK IT'S TOO EARLY AT THIS POINT. THAT'S MY OPINION -- TO MAKE ANY CONCLUSIONS. >> ANYONE ELSE, QUESTIONS, COMMENTS? >> NADYA, AS YOU KNOW, THERE WAS A WORLDWIDE EFFORT TO ESTABLISH STANDARDS IN DEALING WITH STEM CELLS, SO ANY PLANNING BEING SEEN WITH THIS EFFORT? >> ABSOLUTELY, YES. WHEN I SAID VALIDATION, STANDARDS I INCLUDED IN THERE. AND IT RELATES DEFINITELY TO CELL SOURCES, ABSOLUTELY. WE HAVE SOME DIFFERENT POTENTIALLY USEFUL CELL SOURCES. WE NEED TO PICK THE MOST LIKELY -- THE ONES MOST LIKELY TO SUCCEED, MOST PRACTICAL. THAT IS ALSO RELEVANT OBVIOUSLY TO MATERIAL SCAFFOLDS, ALL THIS TECHNOLOGY, ABSOLUTELY. THAT'S WHAT RCs WILL BE DOING. >> ANYONE ELSE? WOULD A COUNCILMEMBER LIKE TO MAKE A MOTION FOR APPROVAL OF THE CONCEPT? SECOND? ALL IN FAVOR? ANY OPPOSED? OKAY. THANK YOU. THANK YOU, NADYA. NEXT, WE ARE VERY EXCITED. WE HAVE A SPECIAL SESSION ON PERIODONTAL RESEARCH. DR. JANE ATKINSON, WHO'S DIRECTOR OF THE CLINICAL -- CENTER FOR CLINICAL RESEARCH IN OUR EXTRAMURAL PROGRAM WILL INTRODUCE THE SESSION ON PERIODONTAL DISEASE RESEARCH. >> GOOD MORNING. IT'S MIGRATE PLEASURE TO INTRODUCE TODAY'S SESSION. I'M GOING TO START WITH JUST A COUPLE OF SLIDES OVERVIEWING THE NIDCR SUPPORT FOR PERIODONTAL RESEARCH IN 2013, AND THEN WE'RE GOING TO HAVE A SHORT OVERVIEW OF PERIODONTAL DISEASE, FOLLOWED BY A BREAK, AND THEN WE WILL HAVE THREE IN DEPTH TALKS. SO PERIODONTAL RESEARCH R A LARGE PORTION OF THE NIDCR GRANT PORTFOLIO, AND APPROXIMATELY 95% OF THE DOLLARS THAT WE DEDICATE TO PERIODONTAL DISEASE RESEARCH IS AWARDED TO THE EXTRAMURAL COMMUNITY AND IN FY13, IT WAS ABOUT $41 MILLION. AND I THINK THIS IS A NICE REPRESENTATION OF THE DIVERSITY OF AREAS THAT WE SUPPORT. WE HAVE A CLEAR COMMITMENT TO THE BASIC SCIENCES, MICROBIOLOGY, MICROBIAL PATHOGENESIS, BUT WE ALSO HAVE A CLEAR COMMITMENT ALSO TO CLINICA RESEARCH, WHICH IS SHOWN IN THESE GREENS. AND ABOUT 90% OF THE EXTRAMURAL DOLLARS ARE AWARDED AS RESEARCH PROJECT GRANTS. SO NOW FOR TODAY'S TALK. WE'RE GOING TO START WITH A BRIEF OVERVIEW OF PERIODONTAL DISEASE, THEN WE WILL HAVE A BREAK, THEN WE'LL HAVE THREE IN DEPTH TALKS. WE BELIEVE THAT THESE REN PRESENTATIONS -- THESE TALKS WILL HIGHLIGHT BASIC CLINICAL AND TRANSLATIONAL RESEARCH. THE FIRST TALK WILL BE PRESENTED BY DR. GEORGE FROM ATHENS, GREECE. HE IS CURRENTLY A PROFESSOR OF MICROBIOLOGY, UNIVERSITY OF PENNSYLVANIA, SCHOOL OF DENTAL MEDICINE. AND HIS RESEARCH REALLY LIES AT THE INTERFACE OF MICROBIAL PATHOGENESIS AND IMMUNITY. HIS WORK IS ILLUMINATED NOVEL MECHANISMS OF MICROBIAL DISBIOSIS AND INFLAMMATION. HIS STUDIES HAVE BEEN PUBLISHED IN JOURNALS OF GENERAL SCIENTIFIC INTEREST, INCLUDING NATURE IMMUNOLOGY, SCIENCE TRANSLATIONAL MEDICINE, NATURE REVIEWS IMMUNOLOGY, AND NATURE REVIEWS MICROBIOLOGY. HE RECEIVED THE DISTINGUISHED SCIENTIST AWARD IN ORAL BIOLOGY FROM THE INTERNATIONAL ASSOCIATION OF DENTAL RESEARCH IN 2012, AND THE AADR IADR AWARD IN 2014. OUR SECOND PRESENTATION, UNDERSTANDING ORAL MUCOSAL IMMUNITY AND PERIODONTAL INFLAMMATION THROUGH THE STUDY OF PATIENTS WITH MONOGEMIC IMMUNE DEFECTS WILL BE PRESENTED BY DR. NIKI MOUTSOPOULOS. SHE RECEIVED HER PH.D. IN IMMUNOLOGY FROM THE UNIVERSITY OF M.D. IN CONJUNCTION WITH WORK THAT SHE DID IN THE INTRAMURAL PROGRAM AT NIDCR. SHE BECAME A RESEARCH FELLOW AT NIDCR IN 2006, AND IS CURRENTLY AN ASSISTANT CLINICAL INVESTIGATOR, DIVISION OF INTRAMURAL RESEARCH, NIDCR. DR. MOUTSOPOULOS' RESEARCH HAS FOCUSED ON INFLAMMATORY MECHANISMS LEADING TO IMMUNOPATHOLOGY IN THE ORAL CAVITY, A VERY EXCITING AREA OF RESEARCH. HER ONGOING CLINICAL STUDIES FOCUS ON ESTABLISHING THE ORAL CLINICAL PHENOTS OF THESE POPULATIONS. AND ALSO EXAMINING THE MICROBIOME AND THE IMMUNOLOGIC PROFILES OF PATIENTS WITH THESE MONOGENIC IMMUNE DEFECTS, MANY OF WHOM HAVE DISTINCT ORAL PHENOTYPES. HER GOAL IS TO DISSECT THE ROLES THAT PARTICULAR IMMUNE FACTORS PLAY IN MEDIATING IMMUNE HOMEOSTASIS OF THE ORAL MUCOSA A PERIOBONTIA. THE LAST PRESENTATION, BIOMARKERS OF PERIODONTAL DISEASE PROGRESSION, WILL BE PRESENTED BY DR. RICARDO TELES. HE RECEIVED HIS DOCTORATE FROM THE FEDERAL UNIVERSITY OF RIO DARIO, HE RETURNED TO BRAZIL TO TAKE A POSITION AS CHAIR IN RIO. DURING HIS TENURE AT THAT INSTITUTION, HE ALSO SERVED AS DEAN. IN 2003, HE RETURNED TO BOSTON TO TAKE A POSITION AT THE FORSYTH UNIVERSITY, WHERE HE'S CURRENTLY A SENIOR MEMBER OF THE STAFF. THE FOCUS OF HIS CURRENT RESEARCH IS TO EXAMINE THE IN VIVO INTERPLAY BETWEEN SUBGINGIVAL -- IMMUNOINFLAMMATORY HOST RESPONSE BY STUDYING 500 SUBJECTS WITH AND WITHOUT PERIODONTAL DISEASE, ENROLLED IN A LONGITUDINAL MULTICENTER TRIAL. SO OUR FIRST TALK WILL BE GIVEN BY DR. TELES. >> GOOD MORNING, LADIES AND GENTLEMEN. THANK YOU VERY MUCH FOR THE INVITATION TO BE HERE. IT'S A PLEASURE TO BE HERE AND TALKING TO THE COUNCIL. IT'S QUITE AN HONOR. AND I'LL TALK BASICALLY ABOUT A TOPIC THAT CONSUMES MY LIFE, WHICH IS PERIODONTAL DISEASES, AND HOPEFULLY GIVE A GOOD INTRODUCTION FOR THE TALKS THAT ARE ABOUT TO COME. IN VERY BROAD TERMS, ONE CAN DISTINGUISH THE TWO MAIN TYPES OF PERIODONTAL DISEASE IN GINGIVITIS, THE INFLAMMATION THAT OCCURS AROUND THE GUMS ONCE WE ALLOW PLAQUE TO ACCUMULATE, SUCH AS IN THIS SLIDE HERE. AND THAT IS TO BE DISTINGUISHED WHEN ONE STARTS LOSING THE ATTACHMENT BETWEEN THE SUPPORTING TISSUES THAT'S IN OUR -- KEEP OUR TEETS ATTACHE TEETH ATTACH ED TO OURSELVES AND START LOSING SUPPORTING STRUCTURES. GINGIVITIS, PRETTY MUCH EVERYONE WILL DEVELOP GINGIVITIS AT A CERTAIN POINT IN LIFE. IT'S INTERESTING AT TIMES ONE READS ABOUT - IT'S SOMETHING ACTUALLY EVERYBODY EXPERIENCES. ANYONE WHO HAS EVER FLOSSED AND SEEN SOME BLOOD COMING OUT, THAT'S GINGIVITIS. THERE'S DIAGNOSTIC PROCEDURES TO BASICALLY CLINICALLY DIAGNOSE THIS DISEASE AND CLASSIFY IT, GOES THROUGH SOME ASSESSMENT OF INFLAMMATION SO ONE CAN CHECK THE COLOR OF THE GINGIVA FOR REDNESS, BLEEDING, UPON GENTLE PROBING WITH A PERIODONTAL PROBE WHICH BASICALLY IS A YARDSTICK THAT WE USE TO MEASURE HOW ATTACHED OUR TEETH ARE TO OUR BODIES. MEASURE OF ACCUMULATION OF PLAQUE CAUSING PERIODONTAL DISEASE, BACTERIA ACCUMULATED ON OUR TEETH, AND ALSO ASSESSMENT OF DAMAGE THAT HAS TAKEN ALREADY PLACE. THAT GOES TO SOME MEASUREMENTS OF PERIODONTAL PROBING, SO AGAIN, USING THIS INSTRUMENT, WE BASICALLY INSERT IT BETWEEN THE GUMS AND THE TEETH AND GET A SENSE OF HOW DEEP IT GOES AND, THEREFORE, THAT ILLUSTRATES HOW MUCH ATTACHMENT HAS BEEN LOST AND ONE CAN ALSO ASSESS CLINICAL ATTACHMENT LOSS AND RADIOGRAPHS ALSO HELP US ASSESS HOW MUCH BONE LOSS HAS TAKEN PLACE WITH THIS DISEASE. HERE I'M TRY OG ILLUSTRATE A LITTLE MORE ABOUT THE CLINICAL NUANCES IN DIAGNOSING THIS CONDITION. SO ONCE YOU ARE TALKING ABOUT -- WE'RE TALKING ABOUT DISTANCE FROM THE GINGIVAL MARGIN AS FAR AS THE PROBE STOPS UPON GENTLE INSERTION. WHEN WE'RE TALKING ABOUT CLINICAL ATTACHMENT LEVEL, BECAUSE THIS GINGIVAL MARGIN TENDS TO FLUCTUATE WITH INFLAMMATION, AT TIMES UPWARDS AND AT TIMES DOWNWARDS IN RECESSION SUCH AS THOSE, WE TEND TO USE MORE STABLE LANDMARK CALLED THE CEJ, WHICH TENDS NOT TO CHANGE WITH THIS FLUCTUATION WITH INFLAMMATION AND ALLOWS US TO GET A MORE PRECISE ASSESSMENT OF HOW MUCH ATTACHMENT HAS BEEN LOST, AND THAT'S CLINICAL ATTACHMENT LOSS. SO HERE ONE WOULD HAVE A POCKET DEPTH OF 3 MILLIMETE BUT ONLY ATTACHMENT LOSS OF 3. HERE WE HAVE A POCKET DEPTH OF 6 BUT CLINICAL ATTACHMENT LOSS OF 9 BECAUSE THERE IS A LITTLE BIT OF RECESSION. TO MAKE MATTERS A LITTLE BIT MORE COMPLICATED, AT TIMES ONE LOSES ATTACHMENT BY REASONS THAT ARE NOT NECESSARILY RELATED TO THE INFLAMMATORY PROCESS THAT WE CALL PERIDONTITIS, DUE TO MECHANICAL TRAUMA CESSATION ASSOCIATED WITH TOOTHBRUSH ABRASION, FOR EXAMPLE, RESULTING IN RECESSION THAT IS NOT NECESSARILY THE RESULT OF THE INFLAMMATORY PROCESS HA WE CALL PERIODONTITIS. IN MEASURING THIS DISEASE, ASSESSMENT OF THE DISEASE IS QUITE A CHAL ECK BECAUSE WE USE THIS PROBE THAT HAS A PROBE TIP OF 5 MILLIMETERS, AND IF YOU QUANTIFY THIS AREA OF THE PERIO DONTIAN IN THE MOUTH, ONE CAN FIND WITH 1400 UNIQUE POINTS THAT ONE CAN PROBE WITH THAT TIP, WHICH IS -- SO INDICATED THE CHALLENGE OF REALLY MAPPING THE DISEASE. TYPICALLY ONE TENDS TO ASSESS 6 POINTS ON THE TOOTH, HOW TO PROPER DIAGNOSE AND MONITOR THE DISEASE. THERE'S ILLUSTRATED TYPE OF MAP THAT ONE GENERATES CLINICALLY, TRYING TO ASSESS AGAIN THE DIFFERENT POCKETS THAT WERE DEVELOPED AROUND THE TEETH, AND THE LOSS OF ATTACHMENT THAT ALSO HAPPENS. ONE ALSO TENDS TO RECORD BLEEDING ON PROBING TO HAVE A SENSE OF THE A OF INFLAMMATION. IN TERMS OF OVERALL CLASSIFICATION, THE AMERICAN ACADEMY RECOGNIZED TWO MAIN TYPES OF PERIDONTITIS, CHRONIC IS ASSOCIATED WITH VAST AMOUNTS OF PLAQUE AND CALCULUS ACCUMULATION AND ONE CAN SEE THE AMOUNT OF BONE LOSS THAT TENDS TO BE ASSOCIATED WITH THE PROGRESSION OF THE DISEASE. AND THAT IS IN CONTRAST WITH THE AGGRESSIVE TYPE OF PAIR DONE TIGHTS. IN THIS CASE, LOCALIZED TYPE OF AGGRESSIVE PERIDONE TIE TIS, WHICH ONE DOES NOT OBSERVE THE -- BUT RELATIVELY PRISTINE LOOKING GINGIVA, VERY NON-INFLAMED, THE PICTURE OF HEALTH PRETTY MUCH, BUT PROBING OR RADIOGRAPHICALLY, ONE CAN SEE A LOT OF ATTACHMENT HAS BEEN LOST IN LOCALIZED AREAS. THIS TENDS TO BE LOCALIZED TO FIRST MOLARS AND INCISORS. QUITE RECENTLY, THE EPIDEMIOLOGY OF PERIODONTAL DISEASE HAS BEEN SOMEWHAT OF DEBATE AGAIN. THE NEW DATA THAT CAME FROM THE FIRST TIME THAT A FULL MOUTH EXAM WAS DONE, SUGGESTED THAT PRETTY MUCH HALF THE POPULATION OF THE UNITED STATES HAS SOME FORM OF PERIDONTITIS. THIS HAS BEEN DISPUTED BY SOME EXPERTS ON AN OVERESTIMATION OF DISEASE DEPENDING ON THE CRITERIA THAT WAS USED TO DIAGNOSE PERIDONE TIGHTS, BUT THE TYPE OF PERIDONTITIC THAT PUTS AT RISK THE DENTITION. IT TENDS TO BE RATHER CONSIST ENT IT AND IT'S KIND OF THE EVIDENCE THAT SUGGESTS THERE IS A SUSCEPTIBLE POPULATION TO THIS INFECTION, THAT NOT EVERYBODY DEVELOPS PERIDONE TIGHTS BUT CERTAIN SUBJECTS ARE AT HIGHER RISK THAN OTHERS. ANOTHER CONCEPT IN UNDERSTANDING THE DISEASE IS THAT FOR A WHILE, IT WAS PROBABLY CONSIDERED, STILL IN THE EARLY EIGHTIES, IT WAS CONSIDERED THAT THE DISEASE WAS AT A CONTINUOUS MODE OF PROGRESSION. SO ONCE A SITE STARTED TO BREAK DOWN, IT CONTINUES THROUGHOUT LIFE. NO EXAMPLE OF A BIOLOGICAL PROCESS THAT ONCE IT STARTS, IT CONTINUES THROUGHOUT LIFE WITHOUT FLUCTUATIONS, AND PERIODS OF EXACERBATION, WHICH IS THE OPPOSING HYPOTHESIS, WHICH IS THE SO-CALLED RANDOM BURST MODEL, WHICH SUGGESTINGS THAT CERTAIN SITES WILL BREAK DOWN AT DIFFERENT TIME POINTS, SOME OF THEM WILL BREAK DOWN ONCE AND NEVER BREAK DOWN AGAIN, WHILE OTHERS MIGHT GO TO SEVERAL CYCLES OF BREAKING DOWN, THEREFORE LEADING POTENTIALLY TO LOSS. HERE WE'RE SORT OF SUMMARIZING OUR UNDERSTANDING OF THE PATHOGENESIS OF THIS DISEASE. IT'S UNDERSTOOD AS A POLYMICROBIAL INFECTION THAT TRIGGERS A WHOLE INFLAMMATORY RESPONSE. IT'S INTERPLAY THAT A LOT OF THE EVENTS ARE EVENTUALLY GOING TO LEAD TO CONNECTIVE TISSUE DESTRUCTION AND BONE LOSS TAKES PLACE. THIS ALL, OF COURSE, UNDER THE INFLUENCE OF SOME ENVIRONMENTAL AND ACQUIRED RISK FACTORS SUCH AS SMOKING, FOR EXAMPLE, AND OF COURSE THE GENETIC COMPOSITION OF THE SUBJECT PLAYS A ROLE. AND IT IS JUST TO ILLUSTRATE HOW WE GO HISTOLOGICALLY FROM A PRISTINE GINGIVA WITH VERY LITTLE INFLAMMATORY COMPONENT, BUT AS PLAQUE ACCUMULATES AND STAYS IN PLACE LONG ENOUGH, IN SOME SUBJECTS, IN CERTAIN SITES, THIS WILL PROGRESS INTO A LARGER LEAGUES THAT GOES INTO THE CONNECTIVE TISSUE, AND THAT GOES UNTIL BONE IS AFFECTED IN THE SUPPORTING STRUCTURES START TO BE COMPROMISED. THE PROCESS IS A RESULT NOT ONLY OF THE BACTER INFECTION BUT BY THIS INTERPLAY, ACTUALLY A LOT OF THE MECHANISMS THAT LEAD TO DESTRUCTION ARE ACTUALLY HOST-DERIVED, AND AT TIMES IN THE LITERATURE, ONE TRIES TO ASSIGN WHICH ONE HAS MORE WEIGHT, WHICH IN MY OPINION, IT'S A MOOT POINT BECAUSE BOTH ARE ESSENTIAL FOR DISEASE TO DEVELOP. WITHOUT THIS INTERPLAY BETWEEN THE HOST AND THE MICROBIAL CHALLENGE, THE DISEASE WILL NEVER TAKE PLACE, AND TO UNDERSTAND THIS PROCESS, WE SHOULD STRIVE TO UNDERSTAND BOTH PROBABLY AT THE SAME TIME. AND THERE'S A CASE THAT I LIKE TO USE JUST TO ILLUSTRATE HOW THERE'S STILL A LOT OF MYSTERY IN THIS DISEASE PROCESS. WE HAVE BEEN STUDYING PERIODONTAL DISEASE FOR DECADES AND THERE IS AT TIMES THE NOTION THAT WE ALREADY MOA EVERYTHING WE NEED TO MOA ABOUT THE DISEASE, AND THIS IS THE KIND OF CASE THEY ILLUSTRATE THAT'S ABSOLUTELY NOT THE CASE AT ALL. THERE'S A YOUNG GENTLEMAN IN HIS 30s, AND ONE CAN SEE THE A ATTACHMENT THAT IS ALREADY LOST, THAT HAS ALREADY TAKEN PLACE IN THE FORM PRIMARILY OF RECESSIONS, NOT THE TYPICAL EXPRESSION OF PERIODONTAL DISEASE, NEITHER CHRONIC NOR AGGRESSIVE. AND IF WE LOOK AT THE RADIOGRAPHS, ONE CAN SEE THAT AT SUCH A YOUNG AGE, THERE IS NOT THE AMOUNT OF BONE LOSS THAT ONE WOULD EXPECT IN THIS PATIENT. ONE DOES NOT SEE THE TYPICAL PATHOGENESIS ASSOCIATED WITH THIS DISEASE. ONE DOES NOT SEE A LOT OF INFLAMMATION ASSOCIATED WITH THIS CONDITION OF THIS PARTICULAR SUBJECT, ILLUSTRATING HOW OUR UNDERSTANDING OF PERIODONTAL DISEASE STILL HAS ROOM TO EXPAND, SEVERA OF THESE CASES HAVE ABSOLUTELY NO IDEA WHAT HAS TAKEN PLACE, AND THEREFORE, A LOT OF RESEARCH IS STILL NEEDED. THAT ACTUALLY CONCLUDES MY PRESENTATION OF PERIODONTAL DISEASE. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> ANY QUICK QUESTIONS BEFORE WE BREAK? OKAY. LET'S ALL BE BACK AT 10:00 FOR THE NEXT TALK. OKAY, WE'RE READY TO GO. DR. HAJISHENGALLIS WILL GIVE HIS PRESENTATION NEXT. >> WELL, GOOD MORNING AND THANKS FOR THE INVITATION. IT'S AN HONOR TO BE HERE AND PRESENT THE LATEST WORK FROM MY LABORATORY. I WILL TALK ABOUT MECHANISM OF PERIODONTAL PATHOGENESIS. CAN YOU HEAR ME? SO I SAID IT'S AN HONOR TO BE HERE. THANKS FOR THE INVITATION TO PRESENT OUR WORK. I WILL BE PRESENTING MECHANISM OF PERIODONTAL PATHOGENESIS IN TARGETED THERAPEUTIC INTERVENTIONS. DR. TELES GAVE AN EXCELLENT OVERVIEW OF PERIODONTITIS WHICH WILL MAKE MY JOB EASIER. PERIODONTAL HEALTH REPRESENTS BALANCED HOME STATIC RELATIONSHIP BETWEEN THE -- THE TISSUE. THE PROBLEMS BEGIN WHEN THIS BALANCE IS DISRURPTED, IN WHICH CASE THE MICROBE CAN YAL COMMUNITY BECOMES DYSBIOTIC, CAPCAPABLE OF INFLAMMATION. THERE ARE MANY FACTORS THAT CAN BREAK DOWN PERIODONTAL TISSUE, SOME ARE MICROBE RELATED AND SOME ARE HOST RELATED SUCH AS IN THE DEFICIENCY, SYSTEMIC DISEASE, SMOKING, STRESS, AGING. NOW THE DYSBIOTIC MICRO BIOTA -- INFLAMMATION HAS TWO MAJOR EFFECTS. ONE IS MORE -- LEADING TO BONE LOSS, AND THE OTHER ONE, WHICH IS SOMETIMES NEGLECTED, IS THAT THE TISSUE BREAKDOWN PRODUCT ARE MUTANTS FOR THE BACTERIA, AND THE BACTERIA INDUCE INFLAMMA NOT TO THE -- RELATED AND THEY DEPEND ON THE -- COLLAGEN, PEPTIDES, MANY OTHER BACTERIA, THEY USE -- CONTAINING COMPOUNDS TO GET -- YOU CAN SEE THAT THESE RELATIONSHIPS AR CREATE A VICIOUS CYCLE, INFLAMMATION INDUCES DYSBIOSIS AND SO ON. SO THIS IS WHAT I WILL TALK TODAY,LY PRESENT OUR WORK AS IT R TO NEW MECHANISMS OF PERIODONTAL TISSUE HOMEOSTASIS BREAKDOWN. ONE PART IS HOST RELATED, THE OTHER IS MICROBE RELATED, AN FINALLY I WILL CONCLUDE BY PRESENTING SOME THERAPEUTIC INTERVENTIONS TO COUNTERACT THESE PATHOGENIC MECHANISMS. FROM THE HOST POINT OF VIEW REGARDING -- BREAKDOWN, MY WORK HAS FOCUSED ON NEUTROPHILS. WE ARE INVESTIGATING -- RECRUITMENT AND WE HAVE SHOWN WITH OUR COLLABORATORS THAT BOTH UNRESTRAINED AND CONVERSELY IMPAIRED NEUTROPHIL RECRUITMENT HAS THE SAME END EFFECT. BOTH OF THESE CASES, BOTH OF THESE EXTREMES LEAD TO INFLAMMATION AND BONE LOSS, AND INFLAMMATION IS THEN DRIVING DIS BIOCYST WHICH MAKES THINGS EVEN WORSE. FROM -- IN WAY THAT TRANSFORMS -- INTO DYSBIOTIC ONE, WHICH IS INDUCING INFLAMMATORY BONE LOSS, THEN WE HAVE THIS VICIOUS CYCLE THAT I'M I JUST MENTIONED. THE DIFFERENCE BETWEEN THESE TWO MECHANISMS IS THAT HERE DISBIOSIS IS MORE OF A CONSEQUENCE RATHER THAN THE CAUSE OF THE DISEASE. SO I START WITH UNRESTRAINED NEUTROPHIL RECRUITMENT. A COUPLE YEARS AGO, WE HAVE IDENTIFIED REGULATORY MOLECULE THAT IS EXPRESSED BY ENDOTHELIAL CELLS CALLED DEL-1. THE MECHANISM BY WHICH -- THAT INHIBITS -- INTERACTIONS BETWEEN NEUTROPHILS AND ENDOTHELIAL CELLS -- TO FIRMLY APPEAR AND MATE, SO CANNOT -- IT DOES NOT MEAN THAT IT BLOCKS RECRUITMENT, IT JUST DOWNREGULATES IT. NOW WHAT WAS -- WHAT IS THE SIGNIFICANCE OF THIS MOLECULE IN PERIODONTITIS? WE HAVE SHOWN THAT DEL-1 DEFICIENCY CAUSES PERIODONTITIS. WE HAVE TWO MODELS. ONE IS THE GENETIC MOCKOUT, MICE THAT WERE GENETICALLY CONSTRUCTED TO LACK DEL-1 IN AGING MODEL BECAUSE OLD MICE LOSE DEL-1 EXPRESSION AS THEY GET VERY OLD, ABOUT TWO YEARS OF AGE, WHICH -- WE WOULD SAKE LIE 65 OR 70 YEARS OLD. WHEN DEL-1 IS -- THIS LEADS TO DESTRUCTIVE INFLAMMATION. WE DISCOVERED SOMETHING ELSE THAT WAS VERY INTERESTING FOR DEL-1. DEL-1 WAS DOING THE EXACT OPPOSITE OF WHAT THE CYTOKINE IL-17 HAS BEEN SHOWN BEFORE TO DO. IL-17 IS A CYTOKINE THAT ORCHESTRATES NEUTROPHIL RECRUITMENT AND -- PLAS TOEGENIC CYTOKINE, AND THAT INDUCES INFLAMMATORY BONE LOSS. DEL-1 NOT ONLY INHIBITS THESE FUNCTIONS BUT IT ALSO DOWNREGULATES THE EXPRESSION OF IL-18-17 -- IT'S A A YING-YANG RELATIONSHIP. ALTHOUGH IT'S ESTABLISHED IN MICE, IT'S NOT SOMETHING THAT CHARACTERIZES ONLY IN MICE BECAUSE WE HAVE SHOWN THIS ALSO WITH HUMAN GINGIVAL TISSUE. WE'VE SHOWN THAT DEL-1 EXPRESSION DOMINATES IN -- GINGIVAL TISSUE, AND IL-17 DOMINATES IN INFLAMED GINGIVAL TISSUE. NOW SINCE OUR PUBLICATION TWO OR THREE -- TWO YEARS AGO, OTHER GROUPS HAVE SHOWN THAT DEL-1 IS ALSO INVOLVED IN NOT JUST PERIODONTITIS BUT OTHER DISEASE MODELS. IT HAS BEEN SHOWN TO HAVE A ROLE -- A ROLE IN -- AND IN EXPERIMENTAL IMMUNE ENCEPHALITIS. MEANWHILE CLINICAL RESEARCH HAS SHOWN THAT THE DEL-1 GENE IS A DISEASE SUSCEPTIBILITY IN ALZHEIMER'S DISEASE, MULTIPLE SCLEROSIS, ANKYLOSING SPONDYLITIS AND CHILDHOOD OBESITY. NOW WHEN WE PUBLISHED THE FIRST PAPER, AND WE ALSO WANTED TO KNOW WHICH OTHER TISSUES EXPRESS DEL-1. SOME TISSUES LIKE LIVER, THEY DO NOT EXPRESS DEL-1. GIN VAGINGIVA EXPRESSES DEL-1. -- SO THAT'S SUGGESTED AND THIS IS THE DEL-1 EXPRESSION IN THE BRAIN OF THE MOUSE, THAT SUGGESTED THAT DEL-1 MAY HAVE MORE IMPLICATION THAN JUST PLAYING A ROLE IN PERIODONTITIS. OUR COLLABORATOR, THE UNIVERSITY OF DRESDEN, HAVE SHOWN THAT IN PEOPLE WITH MULTIPLE SKLARE OWE SIEVE, ACTIVE, SCLEROSIS, THEIR EXPRESSION OF DEL-1 IS DIMINISHED. WE STARTED A COLLABORATION AND WE HAVE SHOWN TOGETHER WITH DR. -- LAB, THIS IS UNPUBLISH BY THE WAY, IT WAS JUST SUBMITTED LAST MONTH, WE HAVE SHOWN THAT DEL-1 KNOCKOUT MICE ARE MORE SUSCEPTIBLE TO EXPERIMENTAL IMMUNE ENCEPHALITIS WHICH IS A MODEL FOR MULTIPLE SCLEROSIS. THE REASON I'M SHOWING THIS NON-PERIODONTAL RELATED RESEARCH IS TO MAKE A POINT HERE THAT PERIODONTITIS CAN ALSO PROVIDE NEW PARADIGMS FOR OTHER INFLAMMATORY DISEASES. THIS IS A PROJECT THAT WE DID TOGETHER WITH NIKI MOUTSOPOULOS, SHE WILL BE PRESENTING THE STUDY IN GREATER DETAIL. WHAT I WILL DO HERE IS JUST TO INTEGRATE THIS CONCEPT IN THE -- CONTEXT. SO -- CONDITIONS IN WHICH -- BECAUSE THESE PATIENTS LACK THE EXPRESSION OF -- THESE PATIENTS SUFFER FROM RECURRENT SYSTEMIC SKIN INFECTIONS AND DEVELOP SEVERE PERIODONTITIS. NOW THIS FORM OF PERIODONTITIS WAS HISTORICALLY ATTRIBUTED TO -- SURVEILLANCE OF THE PERIODONTAL INFECTION. THIS WAS SO COMMON SENSICAL -- IT MAKES SENSE TO SUGGEST THAT THIS ALLOWS UNCONTROLLED GROWTH OF THE BACTERIA. SO THIS HAD NEVER BEEN QUESTIONED FOR 20, 50 YEARS NOW. BUT WE HAVE PROVIDED AN ALTERNATIVE MECHANISM. THIS SUMMARIZES OUR FINDINGS. WE HAVE SHOWN THAT THE DB NEUTROPHIL LEADS TO DEREGULATION CONCERNING A CASCADE OF CYTOKINES THAT REGULATE -- THE PRODUCTION OF NEUTROPHILS. SO WHEN THERE ARE NO NEUTROPHILS AROUND, THERE IS OVEREXPRESSION OF L23, LEADING TO OTHER EXPRESSION OFISM L-17, AND FINALLY LEADING TO THE OTHER EXPRESSION OF G-CSF, THEIR MOBILIZATION FROM THE BONE MODEL TO THE CIRCULATION, BUT OF COURSE IN THIS CASE, THE NEUTROPHIL GETS STUCK -- CAN NOT TRANSMIGRATE. SO THE OTHER EXPRESSION OF G-CSF EXPLAIN NEUTROFEEL YA, BUT WHAT WE FOUND IS THAT THE IL-17 IS PRODUCED LOCALLY, BECAUSE LIKE I SAID BEFORE, IT'S BOTH FOR INFLAMMATORY AND -- THIS IS THE CYTOKINE THAT IS DRIVING THE DISTRACTION OF THE PERIODONTAL TISSUE IN THESE PATIENTS, AND THE PROOF THAT IL-17 IS THE CAUSE OF THIS DISEASE WAS ALSO SHOWN IN A MOUSE MODEL OF LAD, THE KNOCKOUT MICE FAIL TO RECRUIT NEUTROPHILS TO THE PAIR PERIODONTAL TISSUE, LEADING TO BONE LOSS IN EARLY LIFE, BUT WHEN WE TREATED THEM LOCALLY IN GINGIVAL TISSUE WITH IL-17 TO BLOCK THE CYTOKINE, THEY WERE PROTECTED FROM BONE LOSS. THE SAME HAPPENED WHEN WE TREATED THEM WITH -- IL-23 -- AND ALSO THE CYTOKINE -- INHIBITED PERIODONTAL INFLAMMATION AS -- BUT WHAT WAS REALLY STRIKING IS THAT -- ALSO HAD DIMINISHED PERIODONTAL BACTERIAL LOAD. SO THIS IS THE BACTERIAL LOAD OF AN UNTREATED LAD-1 KNOCKOUT MICE, BUT WHEN THEY WERE TREATED, THEIR NUMBERS WENT BACK TO BASELINE OF THE HEALTHY MICE. SO THIS SHOWS THAT THE BACTERIA WERE THERE BECAUSE OF THE INFLAMMATION, PROBABLY IF THAT WAS THE SOURCE OF GETTING THEIR FOOD, AND THEY WERE NOT ACTUALLY RESPONSIBLE FOR THIS FORM OF PERIODONTITIS, SO IN THIS CASE, THE DYSBIOSIS IS A CONSEQUENCE, NOT THE CAUSE OF PERIODONTITIS, THAT DOES NOT MEAN THAT ONCE YOU HAVE DYSBIOSIS, THINGS CANNOT GET WORSE, AND OF COURSE WE HAVE TO REMEMBER THAT BACTERIA ARE ALWAYS NECESSARY FOR INDUCTION OF PERIODONTITIS. NOW GOING TO THE MICROBICIDE OF THINGS TO SEE OTHER MECHANISMS BY WHICH HOMEOSTASIS -- IN THIS CASE A MICROBE IS DOING THE DIRTY JOB. SO THREE YEARS AGO, MY LAB AND THE LAB OF RICH DAVO IN SEE TILL HAVE INTROD THE KEYSTONE PATHOGEN CONCEPT. VERY SIMPLY WHAT THIS IS IS THAT -- HOST RESPONSE IN A WAY THAT ALLOWS THE OVERGROWTH OF THE DENTAL MICRO -- IN TERMS OF THE NUMBERS AND COMPOSITION CHANGES. WE CHARACTERIZED P. GINGIVA LIST -- -- CONFIRMED THAT GINGIVALIS MINORITY IN BACTERIAL PERIODONTAL LEAGUES, SO TWO CRITERIA. ONE IS LOW ABUNDANCE AND THE SECOND A COMMUNITY WIDE IMPACT. THIS TERM, OF COURSE, IS A METAPHOR AND ANALOGY TO THE REAL -- TO THE LITERAL KEYSTONE. THE KEYSTONE -- IS ONLY ONE OF MANY STONES, RIGHT? BUT IT'S VERY CRITICAL FOR THE OVERALL STRUCTURE. MORE RECENTLY, THE KEYSTONE PATHOGENS ARE CONSIDERED FOR THE EATOLOGY OF OTHER INFLAMMATORY DISEASES WHICH IS FROM A PUBLICATION -- AND HAD IS THE SECOND EXAMPLE THAT P CAN SET NEW PARADIGMS THAT CAN BE CONSIDERED IN OTHER INFLAMMATORY DISEASES. NOW MORE RECENTLY, THIS IS OUR LATEST -- WE ADDRESSED THIS QUESTION: HOW CAN PERIODONTITIS ASSOCIATED BACTERIA EVADE IMMUNITY WITHOUT BLOCKING INFLAMMATION? MANY OTHER PATHOGENS IN OTHER PARTS OF THE BODY, THEY SAVE THEIR LIVES BY CAUSING IMMUNOSUPPRESSION. BUT IF THIS WAS TO BE DONE BY PERIODONTAL BACTERIA, YES, IT WOULD HELP THEM TO ESCAPE KILLING BUT IT WOULD BLOCK FOOD. SO WE HIGH POTASSIUM SEIS HYPOTHESIZE TO H AVE A WAY TO ESCAPE KILLING WHILE PRESERVING OR PROMOTING INFLAMMATION. AND AS A MODEL, WE USE P. GINGIVAL NEUTROPHILS. THIS IS BECAUSE NEUTROPHILS MAKE UP THE OVERWHELMING MAJORITY OF -- BEING RECRUITED TO THE PERIODONTAL POCKETS. I WILL NOT HAVE TIME TO PRESENT THIS DATA, SO I HAVE THE SUMMARIZING FIGURE, BUT THIS WORK IS COMING UP NEXT MONTH IN JUNE ISSUE OF THE -- MICROBE. SO WHAT WE HAVE SHOWN IS THAT PG IS AN EFFECTIVE CROSS -- THIS CROSSTALK INACTIVATES A HOST PROTECTIVE PATHWAY DEPENDING ON THE -- SO THIS IS A PATHWA THAT COULD KILL P. JING VALS AND CLEAJING VALS ANDCLEAR OF INFECTION. PROBABLY BECAUSE OF THIS REASON, P. JING VALS IS ACTIVATING AN ALTERNATE PATHWAY, DEPENDING ON THESE KINASE PL3K -- INFLAMMATION. MORE OVER THE PI3K LEADS TO -- OF FA GOA CYTOCYST. THIS IS HOW EVERYBODY BENEFITS AS A COMMUNITY, THAT'S WHY WE CALL P. GINGIVALIS AS THE KEYSTONE PATHOGEN. WE HAVE AT LEAST THREE TARGETS HERE TO INHIBIT THIS EVASION STRATEGY. BECAUSE THIS IT IS CROSSTALK AND YOU CANNOT HAVE OTHER ACTIVATION O THIS KINASE, IF BE EVEN -- RECEPTORS IS MISSING, THAT WOULD MEAN THAT ANY OF THESE THREE TARGETS IS GOOD ENOUGH BY ITSELF TO PROVIDE PROTECTIVE EFFECTS. THIS IS WHAT WE SHOW HERE. THIS IS TREATMENT OF MICE ALREADY COLONIZED -- EXPERIENCING INFLAMMATION, AND IN THE END WE TREATED THEM LOCALLY. EITHER WITH AN INHIBITOR OF -- KINASE -- IN ALL THREE CASES, THESE TREATMENTS -- FROM THE PERIODONTAL TISSUE, SO THESE RESULTS HERE INDICATE ABOUT 90% OR MORE INHIBITION OF GINGIVALIS NUMBERS. AT THE SAME TIME, THE -- NUMBERS OF THE -- MICRO -- WENT DOWN BY 10 TIMES, AGAIN THIS IS A LOCK SCALE SO THIS IS 10 TIMES DIFFERENT, SO DIFFERENCE IS BETTER THAN WHAT IT SHOWS THERE. SO IN OTHER WORDS, TO SOME RISE THIS PART OF THSUMMARIZETHIS PART OF THE T ALK, PERIODONTAL BACTERIA -- WAYS NOT ONLY TO ENDURE INFLAMMATION BUT TO TAKE ADVANTAGE OF IT. VERY SIMPLY HERE, WE SHOW P. GINGIVALIS BLOCKING THE FA GOA CYTOCYST OF NEUTROPHILS AND OF COURSE EVERYBODY ELSE IN THE COMMUNITY BENEFITS, BUT AT THE SAME TIME, THE NEUTROPHILS HAVE PRESERVED INFLAMMATORY RESPONSES WHICH LIKE I SAID ALSO HELPS THE MICROBES TO -- AS A FOOD SOURCE. THE RECEPTOR I JUST SPOKE ABOUT IN THE COMPLEMENT SYSTEM -- INVOLVED IN INFLAMMATION AND IMMUNITY. MORE RECENTLY, WE FOCUSED OUR ATTENTION ON THE C3 COMPONENT, WHICH ACTS UPSTREAM OF THE -- RECEPTOR, AND THIS IS THE MOST CENTRAL MOLECULE OF THE COMPLEMENT CASCADE, THE POINT OF - FOR DISTINCT ACTIVATION MECHANISM, AND OUR LATEST WORK HAS SHOWN THAT -- IS REQUIRED FOR MAXIMUM PAI PERIODONTAL INFLAMMATION IN MOUSE MODEL AND ALSO FOR THE -- OF THE MICRO BIOTA. NOW THE COMPLEMENT DOES NOT ACT IN ISOLATION BUT IT CROSSTALKS WITH OTHER INFLAMMATORY PATHWAYS LIKE THE TOLL-LIKE RECEPTORS, SO BY BLOCKING C3, 1 IS NOT SIMPLY BLOCKING COMPLEMENT, BUT ALSO OTHER INFLAMMATORY PATHWAYS THAT ARE CROSSTALKING AND DEPEND ON COMPLEMENT ACTIVATION. SO WE CONSIDER C3 IS PROBABLY AN APPROPRIATE TARGET TO TREAT PERIODONTITIS. THROUGH THIS WORK, I COLLABORATED WITH -- FROM THE PENN SCHOOL OF MEDICINE, WHO HAVE DEVELOPED AN INHIBITOR AGAINST THE HUMAN C3. THIS INHIBITOR IS NOT ACTIVE IN MICE, SO WE HAD TO LEAVE THE MICE ALONE FOR THE TIME BEING AND GO TO AN ANIMAL MODEL, SO WE WENT TO NON-HUMAN PRIMATES. WE USED CYNOMOLGUS MONKEYS, ONE SITE WAS TREATED LOCALLY, THE OTHER WITH CP40, THE C C3 INHIBITORS. BY THE WAY, THE EXAMINATION WAS CLINICAL, AND ALSO WE WERE ALLOWED TO GET GINGIVAL -- FLUID AND SMALL PIECES OF GIN VA GINGIVAL AND BONE BIOPSIES. THEY WERE NOT USED -- THESE ANIMALS ARE DONATED FOR RESEARCH LIKE BEHAVIORAL RESEARCH OR GOING TO ZOOS, AND VERY BRIEFLY, I WILL SHOW SOME OF THE DATA. BESIDES THAT WERE TREATED WITH CP40 HAD LESS PROBE AND POCKET DEATH, LESS CLINICAL INFLAMMATION AT THE CLINICAL LEVEL. FROM THE BONE BIOPSY, WE COULD FIND OUT THERE WAS LESS -- IN THE TREATED SITE, AND WE ASSESS THE BONE LOSS RADIOGRAPHICALLY, AND THERE WAS STATISTICAL DIFFERENCE BETWEEN THE TREATED SITES AND THE CONTROL SITES. ALSO THIS DATA WAS CONSISTENT WITH WHAT WE'VE FOUND IN THE -- LESS PRODUCTION OF -- MAJOR OSTEOPATHIC FACTOR. YOU CAN SEE THE SAME RESULTS HERE -- LESS I. IL-17 -- THE DRUG TREATED SITES. NOW THE OPG IS A MOLECULE THAT IS A NATURAL INHIBITOR OF -- VERY INTERESTINGLY THOUGH THE OP GWAS DECLINING IN BOTH THE TREATED SITES AND THE -- SITES, THE OPG LEVELS WERE MAINTAINED AT HIGHER LEVELS IN THE TREATED SITES, SO BECAUSE IT'S ALSO KNOWN THAT THE HIGH -- RATIO PROMOTES BONE LOSS, WHEREAS THE LOW -- RANK L/OPG RATIO -- TREATMENT WITH THIS DRUG, HIGH AND LOW RANK L/OPG RATIO. EARLIER I TALKED ABOUT -- THIS NOVEL PROTEIN THAT REGULATES INFLAMMATORY NEUTROPHIL RECRUITMENT AND ALSO IT'S A MOLECULE THAT CAN RESTRAIN IL-17 -- THIS IS FROM AN UNPUBLISHED STUDY AND WE HAVE USED THE SAME NON-HUMAN PRIMATE MODEL OF PERIODONTITIS TO ASSESS DEL-1, THEN THOSE SITES THAT WERE TREATED WITH DEL-1, IN THIS CASE IT WAS -- WITH THE FC PART OF IGG TO IMPROVE THE HALF-LIFE, SO THE SITES THAT WERE TREATED WITH DEL-1 HAD LOWER CLINICAL INFLAMMATION. ALSO WE HAD LESS PRODUCTION OF INFLAMMATORY CYTOKINE -- LESS IL-17, LESS IL-8, LESS G-CSF AND LESS RANKL. ALSO THERE WAS LESS BONE LOSS IN THE SITES THAT WERE TREATED WITH DEL-1. HERE ARE THE BASELINE BONE HEIGHTS. SO THERE WAS NO DIFFERENCE BETWEEN THE LEFT AND RIGHT SIDES IN EACH ANIMAL, BUT THIS IS SIX WEEKS LATER, WHEN THE EXPERIMENT WAS CONCLUDED. AS YOU CAN SEE, THERE WAS MORE BONE LOSS IN THE -- TREATED SITES AND LESS ON THE -- TREATED SITES. THE STATISTICAL ANALYSIS OF THE RESULTS -- HERE YOU CAN SEE GOOD EXPRESSION OF IL AN 17 AND RANKL IN THE CONTROL TREATED SITES BUT MUCH LESS IN THE DELL-1 TREATED SITES. SO THIS CONCLUDES MY PRESENTATION, AND THE CONCLUSIONS: WE HAVE SHOWN TOGETHER WITH OUR COLLABORATORS THAT NEUTROPHIL HOMEOSTASIS IS KEY TO PERIODONTAL HEALTH. CONVERSELY, UNRESTRAINED NEUTROPHIL RECRUITMENT HAS THE SAME EFFECT THAT CAUSES INFLAMMATORY BONE LOSS. P. GINGIV EXPLOITS COMPLEMENT ASSOCIATED SIGNALING PATHWAYS TO MANIPULATE THE HOST RESPONSE LEADING TO DYSBIOSIS AND PERIODONTITIS. SO WE BELIEVE THAT PERIODONTITIS CAN BE -- HUMAN PERIODONTITIS PROBABLY CAN BE TREATED EITHER BY COMPLEMENT INHIBITORS OR USING DEL-1, AND OF COURSE FOR THE LAD FORM OF PERIODONTITIS, OUR FINDINGS SUGGEST THAT -- 17 MAY BE AN APPROPRIATE TREATMENT FOR THOSE PATIENTS. I WOULD LIKE, OF COURSE, TO THANK THE PEOPLE IN MY LAB THAT DID ALL THIS WORK, BOTH FORMER AND CURRENT MEMBERS FROM MY LAB. THE WORK THAT I PRESENTED MOSTLY WAS DONE BY TOMAKI AND TOSHIHARU, BUT EVERYBODY CONTRIBUTED, WITHOUT THEIR WORK, I WOULDN'T BE PRESENTING ANYTHING TODAY. ALSO TO THANK OUR COLLABORATORS, JOHN LAMBRIC, NIKI MOUTSOPOULOS, AND MORE RECENTLY WE ARE COLLABORATING WITH GRA BREEL NUSSBAUM TO UNDERSTAND INTERACTIONS WITH P. JING VALVESGINGIVALIS,AND OF COURSE THE WORK WO ULD NOT HAVE BEEN DONE AT ALL WITH THE NIDCR, AND I WILL ANSWER ANY QUESTIONS YOU HAVE. THANK YOU. [APPLAUSE] >> QUESTIONS? >> SO THE PEOPLE ON THE VIDEO CAN HEAR YOU. >> THANK YOU. >> I THOUGHT THAT WAS REALLY BEAUTIFUL WORK. VERY GOOD SCIENCE. I HAVE A QUESTION ABOUT YOUR COMPLEMENT INHI INHIBITING STRATEGY. I'M GETTING EXCITED BECAUSE I SPENT NINE YEARS WORKING ON THIS. C3 EXISTS IN VERY HIGH LEVELS IN THE BLOOD CIRCULATION. AND -- TISSUES. SO IN ORDER TO HAVE THE REALISTIC INHIBITOR INHIBITING STRATEGY, YO YOUR INHIBITOR MUST HAVE VERY HIGH INFINITI OR -- >> YES, YES, YES. >> SO WOULD JOHN LAMBRIE ALLOW YOU TO DIVULGE THE -- OF YOUR INHIBITOR? >> THIS IS THE LATEST VERSION OF COMP STUDY, AND ITS AFFINITY IS .5 NANOMOLAR. IT SATURATES C3 IN THE BLOOD, SO IT COMPLETELY INHIBITS C3 ACTIVATION IN THE BLOOD NOW FOR 12 HOURS. NOW, IMAGINE THAT THIS IS NOT SYSTEMIC TREATMENT, IT'S LOCAL, WHICH THINGS PROBABLY ARE EVEN BETTER, BUT THIS IS A GOOD VERY IMPORTANT INHIBITOR, AND WE ARE NOT USING IT ONLY FOR PERIODONTITIS. IT'S BEING USED ALSO FOR TNH AND SOME OTHER DISEASES THAT ARE SYSTEMIC. PNH IS -- >> HEMOGLOBIN -- >> YES, YES. SO IT'S A VERY POSITIVE INHIBITOR. >> SO WOULD YOU -- ALEXIAN FOR -- >> ALEXIAN BLOCKS AT THE RECEPTOR LEVEL BUT THAT LEAVES THE CPA -- WORKING UNINHIBITED AND THERE IS WORK TO SHOW THAT THERE IS DISEASE ALSO COMING FROM HAD THIS PATHWAY, SO BLOCKING AT THE C3 LEVEL, I THINK WOULD BE MORE EFFECTIVE THAN THE DRUG OF LEK SHOULD BE, LUCKTION B UT ELECTION BUT THIS IS MY PERSONAL OPINION. >> THANK YOU. >> YVONNE. >> BEAUTIFUL PRESENTATION. I WAS REALLY, REALLY ENGAGED, IT WAS WONDERFUL, THANK YOU FOR THAT LOVELY PRESENTATION. I JUST HAVE TWO SORT OF COMMENTS, MAYBE AN OBSERVATION TOO, SO SORT OF FOLLOWING UP ON THE QUESTION ON THE C3, SO I GUESS YOU INDICATED THAT IT'S LOCAL DELIVERY, AND THEN JUST THINKING FURTHER ABOUT IN THE OFF TARGET EFFECTS THAT YOU WOULD THEN HAVE FOR THIS INHIBITOR IF YOU WERE TO USE IT IN A CLINICAL SETTING. >> YES, THERE IS A LOT OF STUDIES BEING DONE BY OUR COLLABORATORS IN THE MEDICAL SCHOOL, AND THERE ARE NO ANY -- TARGETED EFFECTS THAT ARE KNOWN. THIS IS VERY SPECIFIC, DESIGNED TO BE SPECIFIC FOR C3. SO THIS DRUG HAS BEEN EVEN TESTED IN HUMANS AND SAFE, AND TO MY KNOWLEDGE, THERE IS NO SIDE EFFECTS OR ANY -- EFFECTS. >> WONDERFUL. THEN THE OTHER QUESTION HAD TO DO, I COULDN'T REALLY SEE THE GRAPHS CLEARLY, IN TERMS OF THE CLINICAL SIGNIFICANCE OF THE CLINICAL CHANGES YOU FOUND IN THE MONKEY MODEL, IF YOU COULD COMMENT ON THE CLINICAL RELEVANCE OF HOW THAT WOULD TRANSLATE MAYBE TO SORT OF IN THE HUMAN SCENARIO, I WASN'T SURE IF IT WAS LIKE MILLIMETER PROBING -- >> I CAN GO BACK. >> THAT'S OFTEN THE QUESTION THAT EMERGES IN TERMS OF THE CLINICAL RELEVANCE, HOW COST THADOESTHAT TRANSLATE. SO I'M SORRY, I CAN'T EVEN SEE FROM HERE EVEN WITH MY GLASSES. SO WHEN YOU HAD PROBING DEPTH CHANGES OR -- >> CLINICAL ATTACHMENT LEVEL, THE CONTROL TREATED SITES STARTED FROM 1 AND THEY WENT TO 2.7, SOMETHING LIKE THAT. IN THE OTHER ONE WENT UP TO PROBABLY 1.5. >> SO LIKE A MILLIMETER AND HALF MILLIMETER CHANGES? IS THAT -- AM I READING IT CORRECTLY? >> YES. >> SO AGAIN, I THINK FROM THE CLINICAL STANDPOINT, HOW DOES THAT TRANSLATE FROM A CLINICAL STANDPOINT? IS THAT A SIGNIFICANT -- >> I WOULD SAY THE MOST RELEVANT POINTS HERE IS THAT WE CAN INHIBIT THE GI GINGIVAL INFLAMMATION, BOTH AS WE CAN ASSESS IT BY MONITORING THE GINGIVAL -- FLUID ALSO IN THE TISSUE ITSELF, AND ALSO RADIOGRAPHICALLY, THERE WAS LESS BONE LOSS IN THE TREATED SITES. SO I THINK THAT THIS IS STRONG ENOUGH EVIDENCE TO GO TO HUMAN CLINICAL TRIALS AND THIS IS WHERE THE REAL TEST WILL BE. OF COURSE IT'S A LONG ROAD TO GO, BUT I THINK AT LEAST WE HAVE SCIENCE THAT CAN LEAD US THERE. >> ABSOLUTELY. VERY EXCITING. >> THANK YOU. >> THANK YOU. >> OKAY. ANYONE ELSE? THANK YOU AGAIN. >> THANK YOU VERY MUCH TOO. >> AND OUR NEXT SPEAKER IS NIKI MOUTSOPOULOS. >> WELL THANK YOU VERY MUCH. IT'S OBVIOUY AN HONOR TO BE PUT TOGETHER IN A LINEUP OF GURUS IN PERIODONTAL RESEARCH. SO WHAT I WOULD LIKE TO DO TODAY IS PUT A LITTLE BIT OF TIME TO PRESENT THE PROGRAM THAT I TRIED TO SET UP IN THE INTRAMURAL IACR WITH THE FOCUS OF TRYING TO UNDERSTAND ORAL MUCOSAL -- THROUGH STUDYING SPECIAL PATIENT POPULATIONS WITH AUTOIMMUNE DEFECTS. A YOU HEARD FROM RICARDO AND GEORGE, WE THINK OF PERIODONTAL DISEASE AS AN IMBALANCE BETWEEN THE MICROBIAL COMMUNITY AND A HOST THAT IS SUSCEPTIBLE, AND IN A SUSCEPTIBLE HOST, MICROBIAL TRIGGERS WILL LEAD TO INFLAMMATION THAT IS REALLY SEVERE, AND WILL TRIGGER BONE LOSS AND TISSUE DESTRUCTION, AND THIS IS A CLINICAL PICTURE OF PERIODONTITIS. WE KNOW THAT THE HOST IS VERY IMPORTANT, AS RICARDO MENTIONED, WE SEE POPULATION STUDIES WITH UNTREATED POPULATIONS GLOBALLY HAVING SUSCEPTIBILITY SIMILAR TO THE WESTERN WORLD. WE KNOW ALL OF OUR PATIENTS ARE NOT ALL SUSCEPTIBLE AND RESPOND IN THE SAME WAY. AS ALL HUMAN INFLAMMATORY DISEASES, IT'S VERY HARD TO DISSECT OUT WHAT FACTORS ARE MOST IMPORTANT TO PREDISPOSE TO THIS DISEASE. WE'VE HAD TREMENDOUS PROGRESS IN THE ANIMAL MODEL WORLD, BEING ABLE TO DISSECT FACTOR BY FACTOR OUT WHAT COULD REALLY BE IMPORTANT AND UNDERLYING HOST AFFECTABILITY AND WE'RE SLOWLY STARTING TO TRANSLATE THAT INTO THE HUMAN MODEL. ABOUT WHAT MY EFFORT HAS BEEN IN THE INTRAMURAL IS TRY TO NOT RE-CREATE THE EXTRAMURAL COMMUNITY THAT AS YOU'VE SEEN FROM JANE HAS A HUGE PORTFOLIO OF TRYING TO UNDERSTAND PERIODONTITIS. WE HAVE TO DO SOMETHING INTRAMURALLY THAT WOULD BE UNIQUE. AND AS WE MOVE FORWARD AND SEEING HOW OUR INTRAMURAL IS GOING TO LOOK, WE HAVE TO SEE WHAT WE CAN DO HERE THAT CAN COMPLIMENCOMPLEMENT THE SCIENCE -- LARGE POPULATION STUDIES. SO WHAT IS UNIQUE ABOUT THE NIH INTRAMURALLY, ONE OF THE UNIQUE FEATURES, IS A HOSPITAL OF RARE DISEASES. REALLY THE NIH HOSPITAL HAS A TREMENDOUS FOCUS IN HUMAN IMMUNOLOGY, SO BY SEEING AND OBSERVING AND ALSO STUDYING THESE PATIENTS, WE HAVE AN OPPORTUNITY TO BYPASS COMPLEX GENETICS THAT PLAGUE CLINICAL RESEARCH IN THE OUTSIDE WORLD, WE CAN STUDY ONE BY ONE SINGLE IMMUNE FACTORS AND HOW THEY WOULD AFFECT HEALTH OR DISEASE IN HUMANS, AND WITH A FOCUS OF PERIODONTAL DISEASE, WE CAN START TO UNDERSTAND THE ROLE OF SPECIFIC IMMUNE FACTORS IN SUSCEPTIBILITY AND PROGRESSION IN PERIODONTITIS. SO JUST TO SIMPLIFY THIS IN A CARTOON, WITH PATIENTS THAT HAVE -- GENE DISRUPTIONS, ONE GENE IS TREMENDOUSLY AFFECTED, IT'S USUALLY INHERITED IN A MENDELLIAN INHERITANCE PATTERN, AND PATIENTS THAT DO INHERIT THE DEFECTIVE GENE WILL HAVE 100% RISK OF HAVING DISEASE PHENOTYPE. AND THIS REALLY GIVES US AT LEAST TWO GREAT OPPORTUNITIES. WHEN A GENE IS IMPORTANT FOR A DISEASE PROCESS AND IT'S REALLY DRUPTED, THEN YOU WILL END UP WITH A SEVERE/EXTREME DISEASE PHENOTYPE AND IT'S AN OPPORTUNITY TO BE ABLE TO LOOK AT THE WORST-E SCENARIO OF DISEASE, WHAT THAT LOOKS LIKE AND WHAT THAT PROGRESSES LIKE. BUT ALSO FROM A BASIC SCIENCE STANDPOINT, AND FOR ME THIS IS ALSO VERY CLOSE TO MY HEART, YOU CAN DO BASIC HUMAN IMMUNOLOGY TO SEE WHAT IMMUNE MECHANISMS COULD BE REDUNDANT IN HUMANS, WHAT COMPENSATES, AND HOW MUCOSAL IMMUNITY IS REGULATED IN THE ORAL CAVITY. SO IN ORDER TO START THESE STUDIES, WE REALLY HAD TO CREATE AN INFRASTRUCTURE, AND THE INFRASTRUCTURE HAS COME THROUGH DEVELOPING OUR OWN CLINICAL PROGRAM AND WE PUT TOGETHER A CLINICAL PROTOCOL IN ORDER TO A BE ABLE TO RECRUIT THE DENTAL CLINIC AND SEE AND STUDY AND TREAT PATIENTS WITH PRIMARY IMMUNE DEFECT FROM THE DENTAL STANDPOINT, BUT ALSO RECRUIT OUR OWN HEALTHY VOLUNTEER CONTROL POPULATIONS WITH SEVERE PERIODONTITIS OR HEALTHY WITHOUT PERIODONTITIS AS CONTROL GROUP. THE FOCUS HERE IS TRY TO UNDERSTAND BOTH THE MICROBIAL SIDE AND STUDY THE ORAL MICROBE YUM BUT ALSO STUDY THE ORAL IMMUNE RESPONSE AND REALLY ONE OF THE BIG EFFORTS OF THE LAST COUPLE OF YEARS IS TRY TO ESTABLISH ASSAYS AND DO CUTTING EDGE -- USE CUTTING EDGE TECHNOLOGY THAT WE'RE NOW DEVELOPING TO BE ABLE TO STUDY MUCOSAL IMMUNI THE ORAL CAVITY. SO WHAT OUR INITIAL FOCUS FROM A DISEASE STANDPT HAS BEEN IN PATIENTS WITH NEUTROPHIL DEFECTS, AND YOU'VE HEARD A LITTLE BIT FROM GEORGE BUT I'LL TAKE YOU IN A MORE SLOW PATTERN THROUGH IT. WE WANTED TO LOOK AT PATIENTS WITH NEUTROPHIL DYSFUNCTIONS BECAUSE WE KNEW THAT WHEN PEOPLE DID NOT HAVE NEUTROPHILS AT ALL, EITHER BECAUSE THEY'RE NOT DIFFERENTIATED WELL OR BECAUSE THEY HAVE VERY REDUCED NUMBERS OR IN THE CASE OF LAD, THE NEUTROPHILS DON'T GET OH TISSUES, WE KNEW THAT THEY HAVE TREMENDOUS PERIODONTITIS. AND THIS IS REALLY CHARACTERIZED HISTORICALLY, IT'S PART OF THE CLASSIFICATION CRITERIA, AND WHEN YOU SEE THE PERIODONTITIS ASSOCIATED WITHIN A DISORDER, A LARGE NUMBER OF THE GENETIC DISORDERS HAVE TO DO WITH NEUTROPHIL NUMBERS AND NEUTROPHIL FUNCTION. SO THIS WAS A NATURAL PLACE FOR US TO START. WE HAD ACCESS TO THE LAD POPULATION. L A AD AS YOU HEARD -- THAT IS DUE TO THE MUTATION OF CD18. CD18 IS PARTNER IN ALL THE BETA 2 INTERGRONS, VERY IMPORTANT FOR NEUTROPHILS TO BE ABLE TO TRANSMIGRATE FROM THE BLOODSTREAM INTO THE TISSUE. SO THESE PATIENTS HAVE NORMAL NEUTROPHIL NUMBERS, ACTUALLY ELEVATING, BUT THEY NEVER MAKE IT INTO THE TISSUE. WHAT THEY DID IS GET IS LIFE-THREATENING SYSTEMIC INFECTION, PERIODONTITIS IS A HALLMARK OF THEIR DISEASE. I'M SHARING WITH YOU A PATIENT OF OURS, A 13-YEAR-OLD FEMALE THAT HAS THIS LEVEL OF BONE LOSS FOR THE NON-DENTISTS IN THE GROUP, THIS IS OBVIOUS THIS PATIENT HAS LOST PRETTY MUCH 100% OF THE BONE. IT'S IMPORTANT TO REALIZE AT THE AGE OF 13, THE PERMANENT DENTITION HAS ONLY BEEN IN THE MOUTH A FEW YEARS. WE THINK OF NEUTROPHILS AS INFECTION CONTROL, THIS PATIENT HAS BEEN ON SYSTEMIC ANTIBIOTICS AND ALL OF OUR PATIENTS HAVE BEEN ON SYSTEMIC ANTIBIOTICS PROPHYLACTICALLY SINCE PRETTY MUCH INFANCY, AND THESE ARE PAIRTS THAT ARE LOCAL THAT HAVE HAD ACCESS TO OUR DENTAL CLINIC FOR CARE BUT AT THE IJ OF 13 HAD TO GO INTO FULL MOUTH DENTURES, NOW THAT SHE'S 18, ARE ILL FITTING AND DYSFUNCTIONAL, THAT SHE ONLY WEARS FOR AESTHETIC PURPOSES AT SCHOOL. SO WHY STUDY THIS? WHAT CAN WE LEARN? WE CAN REALLY GET INSIGHTS INTO HUMAN IMMUNITY. WE CAN GAIN BASIC UNDERSTANDING OF THE IMPORTANCE OF TISSUE KNEW ROW FILLS FOR PERIODONTAL STABILITY, FROM A TANS LAITIONAL POINT, WE CAN IDENTIFY POSSIBLE TARGETS -- AND HOPEFULLY ALSO GAIN INSIGHTS INTO OTHER FORMS OF AGGRESSIVE PERIODONTAL DISEASE AND NOT JUST STUDY THESE COHORTS BUT REALLY USE THEM AS THE EXTREME CASE SCENARIO OF OUR DISEASE. SO I'LL TAKE YOU THROUGH OUR VENTURE OF SEEING THESE PATIENTS. FOR US A VERY IMPORTANT PART OF OUR PROGRAM IS CLINICALLY WELL PHENOTYPING THESE PATIENTS. YOU'LL SEE THIS AS A BONE LOSS, ATTACHMENT LOSS, THINK THESE NUMBERS ARE PRETTY LARGE. YOU CAN SEE THE MEAN ATTACHMENT LOSS OF THESE PATIENTS IS FIVE TO SIX MILLIMETERS THROUGHOUT THE MOUTH, WHICH IS HUGE. YOU ALSO SEE THAT THERE'S A SPECTRUM AND THE SPECTRUM REPRESENTS THE FACT THAT OUR PATIENTS THAT ARE ABLE TO LIVE WITHOUT TRANSPLANT HAVE A LEVEL O CT18 EXPRESSION LEFT. WHAT IS REALLY IMPRESSIVE IS THAT THE LEVEL OF CD18 THAT IS LEFT CORRELATES WITH HEALTH IN A WAY, SO THE MORE CD18 DEFICIENCY OR NEUTROPHIL YOU HAVE, THE MORE PERIODONTITIS, SO REALLY PERIODONTITIS IS A SURROGATE DISEASE MARKER FOR LAD SEVERITY. AS LORNLG MENTIONED TO YOU WHEN WE THINK NEUTROPHILS, WE THINK INFECTION, SO WE VEND A LITTLE TYPE LOOKING AT WHAT TREMENDOUS INFECTION COULD BE GOING ON HERE. SO THESE ARE EXTRACTED TEETH FROM ONE OF OUR PATIENTS. THIS IS A TOOTH, THIS IS A GRAM STAIN ON THE TOOTH SURFACE, YOU WILL SEE FORMATION OF AN INTENSE BIOFILM, BUT WITHIN THE TISSUES THEMSELVES, WE DID NOT SEE A TISSUE INVASIVE INFECTION. THAT WAS ALSO LOOKED AT BY FISH BUT ALSO GENETIC METHODOLOGIES AS WELL IN WHICH WE USE UNIVERSAL PRIMERS FOR RYE BOZO MALL RNA AND SEE THE LEVELS ARE COMPARABLE TO HEALTH. SO WHAT'S DRIVING THIS IS NOT A -- WHAT IS PROLIFERATE SOMETHING TREMENDOUS INFLAMMATION. YOU'LL SEE THE SOFT TISSUE IS ALL AROUND IT, WHICH MEANS THERE'S NO BONE LEFT, AND ALL OF THESE PACKED LITTLE DOTS ARE INFLAMMATORY CELLS THAT HAVE ENTERED THE TISSUE. WHEN WE WANT TO EXPLORE WHAT TYPE OF INFLAMMATION IS HERE, WE LOOK AT NEUTROPHILS, AND THERE'S NO NEUTROPHILS THERE WITHIN THE VESSELS. THIS IS A VESSEL BLOWN UP. NEUTROPHILS ARE STUCK. THEY WANT TO M COULD THROUGH BUT THEY CAN'T AND THIS IS REALLY THE -- IMAGE OF OUR DISEASE. BUT THERE'S T CELLS, B CELLS AND OTHER TYPES OF CELLS THAT I WON'T TIRE YOU THROUGH TODAY, BUT WE LOOKED AT WHEN IMMUNE FACTORS ARE PRESENT AND WE COMPARED OURS WITH THE MOST SEVERE WE COULD FIND AND WITH GINGIVITIS, WITH AND WITHOUT INFLAMMATION -- WAS THAT OF IL-17 AND FACTORS RELATED TO IH LN 17. WE WENT FURTHER AND LOOKED AT THE PRON PROTEIN LEVEL, THE BROWN STAINING CELLS ARE ALL IL-17 PRODUCING CELLS SO THERE'S TONS OF IT. AS I'VE MENTIONED TO YOU THAT WE'RE TRYING TO CREATE ON OUR OWN -- TO REALLY EVALUATE THE IMMUNE KIND OF RESPONSE AT A CUTTING EDGE LEVEL, WE NOW HAVE -- TO TAKE LITTLE PIECE OF TISSUES, GET IMMUNE CELLS OUT AND DO FUNCTIONAL ASSAYS THESE FUNCTIONAL ASSAYS CAN SHOW US THAT THE LAD PATIENTS HAVE A LOT MORE PRODUCTION OF IL-17. WE CAN ALSO, WITH MULTIPLE PANELS OF FLOW, BE ABLE TO CHARACTERIZE WHAT TYPE OF CELL COULD BE MAKING IT. SO WE WERE ABLE TO DO A DECENT LEVEL CHARACTERIZATION OF THE TYPE OF CELL MAKING IL17 HERE. WHY IS IL-17 HERE, WHY DO WE THINK IT'S HERE? MICROBIAL SENSORS, SENSING -- PRESENTING CELLS WILL LEAD TO PRODUCTION OF CYTOKINES THAT WILL STIMULATE IL-17 AND THE ROLE OF IL-17 NATURALLY IS TO RECRUIT NEUTROPHILS AND TO HELP THE DIFFERENTIATION OF NEUTROPHILS. SO IT WAS REALLY NATURAL OR MADE SENSE NOW THAT WE SAW IT, BUT IL-17 PRODUCTION CONTINUED TO BE HAPPENING IN A SETTING WHERE NEUTROPHILS NEVER COME BACK IN ORDER TO DO THEIR JOB. WE ALSO KNEW FROM ANIMAL MODELS THAT THE NEUTROPHILS, WHEN THEY'RE COMING BACK INTO THE TISSUE, COME AND GO AND THAT'S A SHUTTING DOWN MECHANISM FOR IL-17 AND 23 PRODUCTION. SO NOT ONLY DID WE NOT HAVE NEUTROPHILS COME BACK TO CONTROL ANY LEVEL OF INFECTION OR ANYTHING, BUT REALLY ALSO THEY WERE NOT ABLE TO DO THE REGULATORY FUNCTION. SO LOOK AT THE DOWNSTREAM EFFECTS OF IL-17, WE LOOKED AT THE PRESENCE OF -- AND -- FACTORS WP THE TISSUES AND THEY WERE ALL UPREGULATED IN OUR TISSUES, THEY WERE ALSO PRESENT IN THE BLOODSTREAM, AND THIS CORRELATED VERY WELL WITH THE HIGH NUMBERS OF NEUTROPHILS IN OUR PATIENTS SYSTEMICALLY. WHAT IS THE SUMMARY OF OUR HUMAN FINDINGS? WE SEE THAT THE PRESENCE OF NEUTROPHILS WITHIN THE TISSUE IS ESSENTIAL FOR PERIODONTAL STABILITY. WE KIND OF KNEW THAT FEE TYPICALLY. PHENOTYPICALLY, BUT WHAT WE THOUGHT WOULD BE HAPPENING WOULD BE A TREMENDOUS INVASIVE INFECTION, BUT ABSENCE OF NEUTROPHILS LEADS TO IL-17-DOMINATED IMMUNOPA WILLINGPATHOLOGY, BUT WE STILL CAN'T PROVE WITHOUT INHIBITING IL-17 THAT IL-17 IS DRIVING THE DAMAGE BECAUSE WE NEED TO KNOW THAT TO MAKE SURE THIS WILL BE A VIABLE THERAPEUTIC TARGET. SO CONCEPTUALLY -- WOULD BE A GREAT CANDIDATE, THAT'S WHY IL-19 HAS ALSO BEEN CANDIDATE IN -- IL-17 THE NOT ONLY ACTIVATES INFLAMMATORY CELLS TO AMPLIFY INFLAMMATION BUT IT ALSO HAS A DIRECT EFFECT ON OSTEO -- AND FIBROBLAST TO MAKE UP DEGRADING ENZYMES, SO IT REALLY HAS A DIRECT EFFECT ON TISSUE DEGRADATION, SO IT MAKES CONCEPT PLI GREACONCEPTUALLY GREAT SENSE AS MOLECULES TO INHIBIT, SO I WAS REALLY FORTUNATE TO TRACK GEORGE DOWN, I KNEW HE WAS REALLY A GOOD ONE IN MECHANISMS OF PERIODONTITIS, AND SO IT WAS -- THE RANDOM PART OF THIS WAS THAT GEORGE WAS ALREADY WORKING ON THE LFA MAP WHICH IS A MODEL ON PERIS AND HE ALREADY HAD -- MICE WITH DEFECTIVE NEUTROPHIL RECRUITMENT NATURALLY WITHOUT ANY INDUCTION MODEL HAVE PERIODONTITIS, SO THE MOUSE THAT HAS NEUTROPHIL RECRUITMENT ISSUES HAS THE SAME LEVEL OF BONE LOSS WITH AN AGING MOUTH, 18 MONTHS, AT THE TIME OF 18 WEEKS, AND ALSO THE CYTOKINE PATTERN IN HAD THIS MOUSE WAS SIMILAR TO HUMAN, SO THIS REALLY MAY SENSE AS AN ANIMAL MODEL TO USE PRECLINICALLY, SO WHEN INHIBITING IL-17 OR 23, AS YOU SAW BEFORE FROM GEORGE, BONE LOSS WAS INHIBITED IN THE MOUSE MODEL, GIVING US A GOOD PRECLINICAL BASIS TO GO FORWARD. DOES IT MAKE SENSE TO GO FORWARD AND THIS DISCUSSION HAS ALREADY BEEN BROUGHT UP, FROM A CLINICIAN STANDPOINT, THERE IS INTEREST MEN DUS CLINICAL NEED. SO THAT QUESTION IS REALLY ANSWERED. PATIENTS ARE NOT RESPONDING TO STANDARD PERIODONTAL PRACTICES, THEY DON'T RESPOND TO ANTIBIOTICS, THEY LOSE THEIR DENTITION EARLY IN LIFE AND THEY'RE NON-FUNCTIONAL. DRK TREATMENTS ARE ALSO IN USE FOR OTHER DISEASES, THEY HAVE A VERY GOOD SAFETY PROFILE, IN THE GENERAL POPULATION. THAT DOES NOT MEAN THE SAME IN IMMUNE DEFICIENCY PATIENTS, SO IT'S A BIG DISCUSSION, IT'S A DISCUSSION THAT WE CANNOT MAKE WITHOUT THE CLINICAL TEAM, AND REALLY WE ARE IN THE PROCESS OF THINKING THIS THROUGH AND PNG TOGETHER AN IDEA OF USING IL-17 INHIBITION FOR PATIENTS WITH LED PERIODONTITIS TOGETHER WITH A TEAM OF NIAID. AND WE HOPE THAT USING SUCH BIOLOGICS IN AN EXTREME CASE WILL START GIVING US INSIGHT IN USE OF BIOLOGICS FOR PERIODONTITIS OF OTHER FORMS AS WELL. SO JUST TO QI GIVE YOU THE PARADIGM OF HOW WE ARE WANTING TO TAKE HAD THROUGH, FROM A CLINICIAN-SCIENTIST STANDPOINT, WE WILL ALWAYS START FROM THE PATIENT AND THE QUESTIONS WILL ALWAYS BE FORMED FROM THE PATIENT SIDE. COMMITTED TO DETAILED AND RESPONSIBLE CLINICAL PHENOTYPING TO WELL CHARACTERIZED BY A SPECIMEN TO SERIOUS STUDIES IN THE LAB -- TO UNDERSTAND MECHANISM AND GO TO PRECLINICAL STUDY AND HOPEFULLY BE AT THIS POINT TO BE ABLE TO SLOWLY TURN THE CORNER AND GO BACK TO THE PATIENT, SO HOPEFULLY AI I'LL BE ABLE TO TURN THE CORNER AND REPORT BACK TO YOU LATER IN THE CURRENT YEAR. SO I HAVE TO ACKNOWLEDGE A HUGE EFFORT FROM MANY PEOPLE. THESE STUDIES DO NOT HAPPEN FROM ONE PERSON OR ONE LAB. I HAVE A SMALL LAB THAT HAS BEEN FORMED RECENTLY WITH VERY ENTHUSIASTIC SCIENTISTS. WE HAVE A CLINICAL TEAM THAT IS ALSO VERY COMMITTED TO SUPPORTING US. WE WORK VERY CLOSELY WITH A LABORATORY OF CLINICAL INFECTIOUS DISEASES IN NIAID AND WE REALLY CANNOT SURVIVOR ARE REALLY WITHOUT THEM, THEY'RE OUR FEEDING OF PATIENTS AND OF UNDERSTANDING OF CLINICAL IMMUNOLOGY. WE'VE RECRUITED HELP FROM VERY TALENTED BASIC SCIENTISTS TO HELP ESTABLISH ASSAYS SUCH AS JOANNE -- AND REALLY THE MOST REWARDING PARTNERSHIP HAS BEEN WITH GEORGE HAJISHENGALLIS AND HIS TEAM TO BE ABLE TO PERFORM FOR CLINICAL STUDIES, OBVIOUSLY I WOULD NOT BE HERE AND I'M VERY THANKFUL TO LEADERSHIP BOTH INTRAMURAL AND EXTRAMURAL, AND THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> QUESTIONS? ANN. >> I JUST HAVE A QUICK COMMENT. THE IDEA THAT YOU MIGHT BE ABLE TO ADDRESS SOME OF THESE GENERALLY HOPELESS PERIODONTAL DISEASES WITH -- IS ABSOLUTELY EXTRAORDINARY. IF COW D YOU COULD DO SOMETHING ABOUT THEM. >> LESLIE. >> SURE. I JUST HAD A QUESTION BASED ON OBVIOUSLY YOUR TARGET OR YOUR INTENT IS TO TREAT THESE SEVERE CASES. I'M CURIOUS IF YOU'RE LEARNING ANYTHING ALONG THE WAY THAT MIGHT BE MORE USEFUL IN A PREVENTION KIND OF CONTEXT OR ARE THERE ELEMENTS MAYBE NOT WITH THIS PARTICULAR PATIENT TYPE -- >> ONE THING ABOUT THESE PATIENTS IS THAT TREATMENT IS NOT AN OPTION AFTER IT'S HAPPENED. AND THAT'S A PROBLEM, PERIODONTAL DISEASE, YOU ONLY CAN ARREST -- UNLESS YOU START WORK GOING INTO REGENERATION. BUT THE IDEA WOULD BE TO USE THESE TYPES OF BIOLOGIC INHIBITORS EARLY ON, WITH AN INTENT TO PREVENT. I DON'T KNOW IF THAT ANSWERS YOUR QUESTION. >> ANYONE ELSE? JEFF. >> I MAY HAVE MISSED IT, BUT THE NIH FOCUS ON TARGET VALIDATION IS CLEARLY VERY HIGH. WHAT STEPS ARE YOU PLANNING TO VALIDATE IL-17 AS A TARGET? >> THIS IS GOING TO BE AN EFFORT WITH NIAID, IT'S NOT GOING TO BE A SOLE ATTEMPT. SO OUR NEXT -- YOU KNOW, THE CLINICAL STUDY, FIRST OF ALL IL-17 IS -- OR IL-23, AT LEAST, INHIBITION IS IN USE NOW AND AVAILABLE, SO THAT DOESN'T NEED VALIDATION. 17 SEEMS TO BE ON -- LICENSED IN EUROPE AND ON ITS WAY TO BE LICENSED HERE, SO AS TARGETS IN GENERAL, THESE ARE VALIDATED. FOR USE IN LAD, THAT'S A DIFFERENT SORRY AND THAT HAS TO HAPPEN WITH NIAID TOGETHER. IN THE SELECT CASES COHORT OF PATIENTS, WE'RE TRYING TO SELECT THE PATIENTS IT WOULD MAKE SENSE, THESE WOULD BE OUR MILDEST PATIENTS THAT HAVE THE LEAST INFECTION SUSCEPTIBILITY, BUT ALSO A LEVEL OF PERIODONTITIS THAT HAS SOMETHING TO SAVE. SO WE'RE DRAFTING A CLINICAL PROTOCOL AS A PILOT PROTOCOL TO ACTUALLY USE IT IN THIS COHORT OF PATIENTS IN THE NEAR FUTURE. >> I WAS GOING TO ASK ABOUT THE TARGET VALIDATION BUT I HAVE A FEW OTHER QUESTIONS, MAYBE CONCEPTUAL. THIS IS VERY BEAUTIFUL AND VERY EXCITING WORKING ON THE INFLAMMATORY SIDE, SO I ACTUALLY HAVE A QUESTION FOR YOU AND FOR DR. HAJ HAJISHENGALLIS IN RELATIONSHIP. WE NOW HAVE DEL-1, C3, IL-17, 23. HOW DO HE SE YOU SEE THEM SO THAT ONE IS THE WONDERFUL RARE DISEASE PROGRAM THAT ENABLES US TO GAIN INFORMATION ABOUT THESE TARGETS, NOT NECESSARILY FOR THOSE PATIENTS, BUT HOW DO YOU SEE ALL THESE MOLECULES WORKING TOGETHER AND THE INTERPLAY VERSUS JUST ONE TYPE OF TARGETED THERAPY? >> I DON'T WANT TO ANSWER FOR GEORGE SO I WILL GIVE MY SHORT ANSWER AND THEN I'LL HAND IT OVER TO GEORGE. BUT AT LEAST FOR DEL-1 AND IL-17, THE CONNECTION IN MY MIND IS OBVIOUS, AND BECAUSE THEY BOTH END UP WITH IL-17 OVERPRODUCTION. THERE'S DIFFERENT WAYS OF THEM BUT THEY BOTH FUNNEL INTO IL-17, SO THERE IL-17 AS A TARGET COULD COVER BOTH OF THE ABOVE. >> [INAUDIBLE] >> SO MUCH CROSSTALKING BETWEEN DIFFERENT INFLAMMATORY PATHWAYS THAT ONCE YOU KNOW THE RELATIONSHIPS, YOU CAN -- OF COURSE YOU CAN TEST IT BUT BY -- LET'S SAY BY BLOCKING C3, WE KNOW THAT DO WE ALSO INHIBIT A LOT OF TOLL-LIKE RECEPTOR ACTIVATION. IL-17 IS DOWNSTREAM OF THESE RECEPTORS, SO BLOCKING C3 WILL NOT ONLY BLOCK A COMPLEMENT -- BLOCK -- WILL AFFECT IL-17. THE PURPOSE HERE WAS NOT TO KILL INFLAMMATION, IT'S TO DOWN REGULATE IT TO BRING IT TO NORMAL LEVELS BECAUSE EVEN THE HEALTHIEST OF THE TISSUE, IT KEEPS A BALANCE. SO I THINK IF WE CAN REGULATE INFLAMMATION, NOT ONLY -- BUT THE REGENERATIVE MECHANISM WILL BE ABLE TO WORK. THAT DOES NOT MEAN WE MUST NOT KNOW MORE ABOUT REGENERATIVE MEDICINE AND DO MORE TARGETED APPROACHES, BUT I THINK THAT THE INHIBITION OF INFLAMMATION WILL HELP THE NATURAL REGENERATIVE MECHANISM. >> OKAY. THANK YOU. WE'LL MOVE ON TO DR. TELES. >> CAN YOU HEAR ME? IT'S WORKING? OKAY. SO NOW I'M GOING TO GO ON TO PRESENT SOME PRELIMINARY DATA ON THE STUDY THAT WAS FUNDED BY NIDCR IN 2010 TO EXPLORE THE PRESENCE OF BIOMARKERS OF PERIODONTAL DISEASE PROGRESSION OR THE FINDING OF BIOMARKERS OF PERIODONTAL DISEASE PROGRESSION. NIH DEFINES BIOMARKERSNORMAL BIOLOGICAL PROCESSES, PATHOGENIC PROCESSES O OR PHARMACOLOGICAL RESPONSES TO THERAPEUTIC INTERVENTION. THERE ARE SEVERAL ROLES THAT ONE CAN USE BIOMARKERS FOR OR DIFFERENT MOLECULES THAT MIGHT REFLECT A CERTAIN BIOLOGICAL PROCESS, NOT ONLY MOLECULES BUT EVEN CLINICAL MEASUREMENTS CAN BE UNDERSTOOD AS BIOMARKERS. BUT IN THE PARTICULARLY KEYS, WE ARE INTERESTED IN BIOMARKERS THAT ARE GOING TO ALLOW US TO MONITOR OR PROGRESSION OR RECURRENCE OF PERIODONTAL DISEASE. -- PROGRESSION FOR STARTERS. SO THE OVERALL OBJECTIVE OF THE STUDY IS TO IDENTIFY MARKERS OF PERIODONTAL DISEASE PROGRESSION -- WND HE STAWND PERIODONTAL DISEASE AS A CONSEQUENCE TO THIS INTERPLAY BETWEEN THE -- AND THE HOST RESPONSE. A COMBINATION OF BOTH WILL PROBABLY BE THE MOST POWERFUL -- SUCH BIOMARKERS, A COMBINATION WILL TELL US MORE ABOUT THE POSSIBILITY OF DEEDS PROGRESSION THAN LOOKING AT EITHER SIDE ALONE. SECONDARY OBJECTIVE, PATIENTS WILL RECEIVE TREATMENT, WE'LL WANT TO EFFECT THE TESTS OF TREATMENT ON THOSE BIOMARKERS. SO WHAT IS THE STUDY POPULATION? WE ARE RECRUITING 500 SUBJECTS, 375 PERIODONTITIS SUBJECTS, CHARACTERIZED ACCORDING TO MORE -- THAN ACTUAL SEVERITY. SO THOSE DESCRIB TORES DON'T REFER TO CLASSIC CLASSIFICATION SCHEMES FROM THE AMERICAN ACADEMY OF -- BASICALLY HAVE MORE TO DO WITH EXTENT OF DISEASE THAN WITH TRUE SEVERITY AT A LOCALIZED AREA. WE ALSO STUDIED 135 PERIODONTALLY HEALTH SUBJECTS AND FIVE CENTERS INVOLVED IN RECRUITING AND PROCESSING SAMPLES. FORSYTH, UNIVERSITY OF MICHIGAN, BLUESTONE AT NYU, SUNY AT BUFFALO AND SOUTHERN ILLINOIS UNIVERSITY. THIS IS TO ILLUSTRATE THE -- THAT WE ARE RECRUITING FOR THE STUDY. ONE CAN NOTICE SOME FEATURES OF PERIODONTAL DISEASE. I'M TRYING TO GO BACK. SUCH AS BONE LOSS AND CALCULUS ACCUMULATION, THE SPIKES THAT ONE CAN SEE HERE AND THERE. BUT WE ALSO ARE LOOKING FOR PATIENTS THAT HAVE OVERALL A FULL DENTITION THAT DON'T HAVE MANY OTHER DENTAL NEEDS, WE ARE TRYING TO UNDERSTAND THE NATURAL PROCESS OF THE DISEASE. WE ALSO ARE EXCLUDING PEOPLE THAT ARE HIGH RISK FOR PERIODONTAL DISEAS DUE TO SMOKING OR DIABETES BECAUSE WE WANT AGAIN TO UNDERSTAND THE PURE MECHANISM THAT LEADS PERIODONTAL DISEASE PROGRESSION, AND BIOMARKERS THAT CAN BE ASSOCIATED WITH THAT. SO IF ONE IS SEARCHING FOR A MOLECULE THAT ACTUALLY FOLLOWED THE DISEASE PROCESS, WE WANT BASICALLY TO FIND BIOMARKER LEVEL THAT INCREASES AS ONE MOVES FROM DIFFERENT STAGES OF THE DISEASE. AND IN ORDER TO IDENTIFY THOSE, THERE IS ONLY -- WAY OF GOING ABOUT CLINICALLY. SO THAT ONE CAN MEASURE THOSE BIOMARKERS. SO THE STUDY DESIGN ACTUALLY INVOLVES MONITORING PERIODONTITIS PATIENTS IN THE PERIODONTAL HEALTH OF PATIENTS FOR 12 MONTHS WITHOUT INTERVENTION. SO WE USE THE PERIODONTITIS PATIENTS HERE AS IN ESSENCE SUBJECTS THAT HAVE BEEN PRESELECTED FOR BEING SUSCEPTIBLE TO DISEASE PROGRESSION. THOSE DISEASES ARE CHRONIC AND PROGRESS VERY SLOWLY OVERMANY YEARS, SO DURING THIS ONE YEAR, WE KNEW THAT WE WOULD BE SEARCHING FOR AN ILL LOU SIEVE EVENT WHICH WOULD BE PERIODONTAL DISEASE PROGRESSION AND WITHOUT A SUSCEPTIBLE POPULATION, WE WOULD NEVER SEE IT T THE PERIODONTAL HEALTHY PATIENTS ALSO WITH THE HOPES THAT ONE CAN SEE MAYBE THE INITIAL LEAGUES, BUT THERE WAS -- VERY -- WILL SHOW SUCH CONVERSION TO DISEASE. SO THEY COME AFTER SCREENING EVERY TWO MONTHS WHERE WE COLLECT NOT ONLY THE CLINICAL MEASUREMENTS SO THAT WE CAN DETECT DISEASE PROGRESSION THROUGH CHANGES IN CLINICAL ATTACHMENT LEVEL, BUT WE ALSO COLLECT -- SAMPLES, GSF SAMPLES, PLAQUE SAMPLES, AND SERUM SAMPLES SO THAT WE CAN SEARCH FOR BIOMARKERS NOT ONLY AT THE LOCAL SITE BUT ALSO IN THIS FLUID SUCH AS SALIVA AND SERUM. AT THE END OF THIS ONE YEAR OF MONITORING OF INTENSE MONITORING, A HEALTHY POPULATION RECEIVES PROPHYLAXIS -- EXCUSE ON THIS STUDY, WHY THE PERIODONTITIS SUBJECTS RECEIVE -- MONITOR CLINICALLY FLEE MONTHS AFTER THAT WHETHER WE RECEIVE ALSO MAINTENANCE THERAPY AND AT SIX MONTHS, THEY RECEIVE THE FINAL EXAMINATION WHERE BIOLOGICAL SAMPLES ARE COLLECTED ALSO TO ASSESS THE EFFECTIVE TREATMENT ON THOSE BIOMARKERS. AGAIN THOSE ARE THE SAMPLES THAT -- SOME OF THEM WE ARE REFERRING TO AS PROXIMAL SAMPLES, NOT SENSE OF AN INTERPROXIMAL SPACE IN TERMS OF -- BUT IN A SENSE OF SAMPLES THAT ARE CLOSE TO THE SITE OF THE EVENT THAT WE'RE TRYING TO MONITOR. WE'RE TRYING TO MONITOR PERIODONTAL TISSUE DESTRUCTION, PERIODONTAL DISEASE PROGRESSION, SO THOSE SAMPLES ARE COLLECTED VERY CLOSE TO THE PAI PERIODONTAL EFFECT OF PERIODONTAL TISSUE AND THEREFORE THEY REPRESENT BIOMARKER JARGON PROXIMAL SAMPLES. CONTRAST TO SALIVA AND SERUM EVEN THOUGH SALIVA CAN BE PERCEIVED AS BEING VERY CLOSE TO THE SITE OF AN EVENT BUT BY COMPARISON TO GSF, IT'S CONSIDERED ADDITIONAL SAMPLE. AND -- RESULTS HAVE BEEN COLLECTED WITH HOPES THAT -- OF THOSE LOCAL BIOMARKERS. IN TERMS OF THE SITES THAT ARE BEING MONITORED, WE ELECTED BECAUSE UNFORTUNATELY WE COULDN'T MONITOR THE ENTIRE MOUTH, CLINICALLY 116 SITES, VIRTUALLY IMPOSSIBLE TO COLLECT SAMPLES FROM EVERY SINGLE ONE OF THOSE SITES. SO WE EECT ELECTED FOR -- BECAUSE OF A VERY FAINT SUGGESTION THAT THEY ARE MORE PRONE TO TO DISEASE PROGRESSION, THIS IS NOT VERY STRONG BUT WE FELT THAT THAT WOULD BE A WISE DECISION AT THE TIME AND WE COLLECT SAMPLES FROM BOTH MESIAL AND DISTAL FROM THE BUCCAL SIDES, SO EVEN THOUGH CLINICALLY -- 168 SITES, WE ARE COLLECTING SAMPLES FROM 32 SITES. THE PROXIMAL SITES WERE ALSO CHOSEN BECAUSE THE FREE SURFACE, THE FRONT AND THE BACK OF THE TEETH, ARE MORE SUSCEPTIBLE TO LOSS OF ATTACHMENTS -- AND WE'RE TRYING TO UNLD STAN UNDERSTAND THE EVENTS -- PROCESS OF PERIODONTITIS. THE DILEMMA IS WHICH PLATFORM YOU'RE GOING TO USE ON A SAMPLE BECAUSE FOR EVERY SINGLE SAMPLE THAT IS COLLECTED, THERE IS A MULTITUDE OF OPTIONS IN TERMS OF ONE CAN GO THROUGH TO COLLECTT POTENTIAL BIOMARKERS. POTENTIAL MOLECULES ASSOCIATED WITH THIS PROCESS. IN OUR CASE, WE ELECTED FOR USE THE MULTIPLEX IMMUNOASSAY, WHICH IS BASICALLY THE MIXTURE OF AN -- WITH A CELL SORTER, AND CAN TEASE OUT NOT ONLY A SINGLE ANOLYTE, SAME SAMPLE DURING THE SAME PROCESSING, AND THE IN THE MICRO BIOLOGICAL ASPECT SIDE OF THINGS, DR. BRUCE -- GOT FUNDED IN ASSOCIATION ALSO OF THE STUDY TO STUDY THE -- USING SEQUENCING OF THE SAMPLES WHILE ANOTHER INVESTIGATOR FORSYTH -- TO PROCESS TO A SMALLE SET OF SAMPLES BECAUSE THOSE ARE NOT AS HIGH THROUGHPUT AS -- SEQUENCING. THE ME -- AND THE -- OF THE MICROBIOME. SO WE ARE SEEKING TO UNDERSTAND NOT ONLY WHAT IS THE CHANGE IN THE COMPOSITION THAT MIGHT BE ASSOCIATED WITH THIS PROGRESSION BUT ALSO WHAT IS THE CHANGE IN THEIR BEHAVIOR THAT MIGHT BE ASSOCIATED WITH DISEASE PROGRESSION. WELL, NOW WE FOCUS A LITTLE BIT ON GCF BIOMARKERS. GCF IS BASICALLY A FLUID THAT CAN BE COLLECTED AT THE JING VALVE MARGIN AND CONSIDERED -- FIRST, WHEN YOU DEVELOP INFLAMMATION OF THE TISSUES IT BECOME AS TRUE EXUDATE AND IT HAS BEEN STUDIED OVER MANY DECADES SINCE THE 70s CONSISTENTLY, AS A POTENTIAL SOURCE OF MOLECULES, WHAT IS HAPPENING WITHIN THE TISSUES, AND MY LEAD IS AGAIN TO -- IMPROVEMENT IN THE DIAGNOSIS OF PERIODONTAL DISEASE AND THE PROGNOSIS. SO THE DREAM WOULD BE TO COME UP WITH MAGIC BULLET, A SILVER BULLET THAT WE WOULD BE DETECTING THERE, AND THAT WILL TELL US IF THE PATIENT IS AT RISK OR NOT FOR DISEASE PROGRESSION AND, THEREFORE, IF THE PATIENT SHOULD RECEIVE TREATMENT OR NOT. TALKING MORE ABOUT THE LUMINEX TECHNOLOGY, EVERY MICRO BEAD HAS A SPECTRAL SIGNATURE. SO THEY CAN BE DISTINGUISHED BY A READER. THEREFORE, BY TAGGING OR BY COKING EVERY SINGLE ONE WITH A DIFFERENT CAPTURE ANTIBODY, YOU CAN IN THE SAME ASSAY PROBE FOR DIFFERENT TARGETS SIMULTANEOUSLY. THE READER HAS ONE RED LASER THAT IDENTIFIES WHICH IS THE B, THEREFORE WHICH TARGET IS BEING MEASURED, AND ANOTHER LASER THAT ACTUALLY MEASURES THE FLUORESCENCE ASSOCIA WITH THE IMMUNOASSAY, GIVE YOU AN IDEA OF QUANTITY OF THE BIOMARKER PRESENT AT THAT SITE. AND THIS IS JUST AN ILLUSTRATION OF THE -- WELL, EVERYTHING IS FINE BUT STRUCTURALLY UNDERSTAND BIOMARKERS, ONE IS ASSOCIATED WITH AN EVENT. SO IF WE DON'T DEFINE WHAT IS OUR OUTCOME, WHAT IS DISEASE PROGRESSION QUITE WELL, ONE HAS A SERIOUS -- FINDING BIOMARKERS BECAUSE -- BIOMARKERS TO WHAT EXACTLY. AND THIS IS ILLUSTRATING THE MONITORING OF CLINICAL ATTACHMENT LEVEL OVER THE 12 MONTHS OF MONITORING IN A GIVEN PATIENT IN THE STUDY. THIS IS TRUE DATA. THEY WERE ALL ZEROED SO -- CHANGE IN CLINICAL ATTACHMENT LEVEL, WE DON'T KNOW EXACTLY HOW IT STARTED IN THIS PARTICULAR GRAPH. BUT THE TRADITIONAL WAY OF DETECTING DISEASE PROGRESSION IS -- ACROSS A CERTAIN THRESHOLD, AND TWO-MILLIMET AT TIMES IS CHOSEN IN THE LITERATURE -- INCREASED TO 3 MIL MILLIMETERS, DUE TO THE PROBLEMS WITH MEASUREMENT ERROR, SO IT'S VERY DIFFIC TO STANDARDIZE A MEASUREMENT OF CLINICAL ATTACHMENT LEVEL, POCKET DEPTH, THROUGH A VARIETY OF REASONS. ONE CAN SEE HERE THE DIFFICULTIES THAT ONE MIGHT ENCOUNTER. WE HAVE SEEN THE SAME SITE CROSSING THE 2-MILLIMETER THRESHOLD SEVERAL TIMES BACK AND FORTH. WHICH MAKES IT EXTREMELY DIFFICULT TO CHARACTERIZE THIS AS A TRUE PROGRESS IN SIGHT. KEEPING IN MIND THAT A LOT OF THE STUDY THAT EXISTS IN THE LITERATURE, A LOT OF OUR KNOWLEDGE ABOUT DISEASE PROGRESSION ARE BASED ON A PEER OF EXAMS AT BEST, AT TIEMENTS THREE EXAMS, AND IF ONE DOES THAT, ONE CAN SEE HOW WE CAN -- MAY BE MISTAKINGLY DIAGNOSED THIS SIDE IS PROGRESSING -- JUST TO CROSS IT BACK AGAIN DUE TO THIS VARIABILITY OF THE CLINICAL EXAMINATION. SO WHAT WE DETECT IS NOT TRUE PROGRESSION BUT IS A CHANGE IN CLINICAL MEASUREMENTS WHICH IS WAY MORE VARIABLE THAN TRUE PROGRESSION. ONE CAN SEE HOW THIS CAN GET COMPLEX AS YOU ADD MORE AND MORE SITES PROGRESSING THE SAME SUBJECT, MAKES IT DIFFICULT TO MAKE ANY SENSE OF THOSE PROFILES OF PROGRESSION. TRADITIONALLY AGAIN, THIS IS USING THE 2-MILLIMETER THRESHOLD, AGAIN IT TOUCHES IT EVERY TIME ALMOST, JUST TO BOUNCE BACK. WELL, AT TIMES THEL THE LITERATURE HAS ANSWERED THIS BY INCREASING THE THRESHOLD, IF WE INCREASE THE THRESHOLD WEE GOING TO COMPENSATE FOR THAT. YOU DO DECREASE -- INCREASE THE THRESHOLD, KEEPING THE ILLUSION, IF YOU WILL, OF A MORE SPECIFICITY. BUT THE TRUTH IS YOU CAN CROSS A 2-MILLIMETER THRESHOLD AT NO, -- WHICH IS MORE OF CROSSING THAT THRESHOLD AND STAYING HIGH OR SLOWLY BUT SURELY ALWAYS MOVING IN THAT DIRECTION OF REACHING A CERTAIN THRESHOLD OF CLINICAL ATTACHMENT CHANGE. SO BECAUSE OF THAT, AFTER WORKING EXTENSIVELY WITH THOSE PROFILES, WE CAME UP WITH A SET OF RULES THAT WE THINK GIVE US A BETTER DIAGNOSIS OF WHAT DISEASE PROGRESSION IS, BUT KEEP IN MIND THAT WE HAVE TO USE -- WE HAVE TO EXAMINE THE PATIENT SEVEN TIMES OVER ONE YEAR TO REALLY M PRECISELY DEFINE IN OUR MINDS AT LEAST AT THIS POINT WHAT THIS PROGRESSION WOULD BE. SO THEY'RE LOOKING FOR A TREND IN TERMS OF COEFFICIENT OF REGRESSION GREATER THAN .1, CROSS THE 2-MILLIMETER THRESHOLD COMPARED TO BASELINE, EXCLUDING SITES THAT ONLY REACH THE THRESHOLD ONCE TO AVOID THE ZIG-ZAG, AND WE ALSO DON'T WANT A LOT OF FLUCTUATION SO WE DON'T WANT IT THIS TO CROSS BACK TO THE PREVIOUS LEVEL. FOR THE -- IS THE SAME -- WE ALSO NEED A MORE STRINGENT CRITERIA, SO INSTEAD OF SIMPLY INCLUDING ANY SITE THAT HAS NOT CROSSED THE THRESHOLD OF 2 MILLIMETERS, THEY MIGHT STILL BE IN AN UPWARD TREND THAT HASN'T REACHED THAT THRESHOLD, WHICH IS ARBITRARY BY THE WAY, WE ARE ASKING FOR A VERY, VERY SMALL FLUCTUATION IN MEASUREMENT. SO AGAIN TRULY NON-PROGRESSING. THAT'S THE KIND OF PROFILE WE FIND WHEN WE APPLY THIS, SO THOSE APPEARS OF PROGRESSING IN THE CONTROL SITES TO THE SAME SUBJECT IN FOUR DIFFERENT SUBJECTS. ONE CAN SEE HOW WE'RE -- 4-MILLIMETER ATTACHMENT LEVEL CHANGING TO 6 BOUNCING BACK SLOWLY BUT SURELY GETTING UPWARDS. SO THAT KIND OF BEHAVIOR IS MORE COMPETITIVE WITH WHAT ONE WOULD EXPECT -- NO CHANGES FOR SEVERAL MONTHS, EVENTUALLY A JUMP, AND THEN STAYS AT THAT LEVEL. SO THAT KIND OF PROFILE GIVES A LITTLE BIT MORE CERTAINTY IN OUR MINDS THAT IT IS A TRUBY LOGICAL TRUE BUY LODGE KA EVENT OF DISEASE PROGRESSION. ILLUSTRATING FOR THOSE WHO ARE CLINICIANS HERE HOW YOU -- A SITE THAT HAD A VERY SHALLOW POCKET OF 2 MILLIMETERS PROGRESSING ALL THE WAY TO A 5-MILLIMETER POCKET, AND IN A WAY THAT IN OUR MIND IS VERY CONVINCING OF A TRUE PROGRESSION. YOU HAVE ANOTHER SITE HERE THAT ALSO STARTS WITH A 3-MILLIMETER POCKET THAT REGRESSED TO A LITTLE BIT OF RECESSION AND A DIPPING OF THE POCKET TOO, SO IT'S A COMBINATION OF RECESSION AND DEEPENING OF A POCKET. HERE WE HAVE A POCKET THAT WAS ALREADY DEEP TO START WITH AND EVENTUALLY PROGRESSED TO A MUCH DEEPER POCKET. WHEN WE ACTUALLY COMPILE ALL THE SITES NA WE'RE GOING TO USE IN OUR FIRST ASSESSMENT OF BIOMARKERS SO WE SELECTED 35 SUBJECTS WITH PAIRS OF PROGRESS AND -- IF WE MATCH THE PROGRESSIVE GOING TO ZERO, THOSE ARE THE -- LEADING TO IT BECAUSE THEY PROGRESS AT DIFFERENT TIMES SO WE HAD TO MATCH THIS PROGRESSIVE SITE TO COME UP WITH THOSE MEANS. AND ONE CAN SEE HOW THE CONTROL BEHAVES, THE PINK ONE, STRAIGHT LINE, WHILE THE BLUE EVENTUALLY HAS A JUMP WHEN IT GETS TO THE PROGRESS IN POINT. IF WE SEPARATE THEM ACCORDING TO THE ORIGINAL POCKET DEPTH, THE SAME TRENDS FOR THE TWO DIFFERENT TYPES OF SITES, THE ONES THAT HE STARTED DEEP AND PROC TO MUCH DEEPER SITE AND SHALLOW EVENTUALLY PROGRESS TO POCKETS. -- IN PERIODONTALLY DISEASED SUBJECTS ACTUALLY HEALTHY TO START WITH. WHICH IS AN IMPORTANT UNDERSTANDING THAT DISEASE DOES NOT ALREADY HAPPEN -- HAD ALREADY TAKEN PLACE. THIS IS JUST TO SHOW HOW CHANGING THIS CRITERIA FROM PROXIMAL 2-MILLIMETER THRESHOLD REDUCED OUR DIAGNOSIS OF PERCENTAGE OF PROGRESSING SUBJECTS FROM 68% TO NOW 39%. SO HOW WE ARE USING A MORE STRINGENT CRITERIA FOR DISEASE PROGRESSION IN HOPES THAT WE WILL FIND A BETTER DEFINITION OF BIOMARKERS. -- IT CAN MEASURE SEVERAL BIOMARKERS BUT THE IDEA IS THAT ONE CAN COULD ACTUALLY MEASURE ALL THE BIOMARKERS AT ONCE. THE MACHINE CAN ACTUALLY -- HAS THE CAPABILITY OF DISTINGUISHING ACTUALLY 100 DIFFERENT -- WHICH EQUATES TO 100 DIFFERENT ANOLYTES. WELL, NOT SO FAST. IMMUNE REACTIONS HAVE ALL SORTS OF COMPLICATIONS IN TERMS OF CROSS REACTIONS -- OF SOME OF THOSE TARGETS. T YOTHEREFORE YOU CANNOT -- SO THERE ARE DIFFERENT KITS WITH PROBE FOR DIFFERENT SETS OF TARGETS. AND WE WANT AGAIN TO TAKE AN AGNOSTIC APPROACH TO THIS AND WANT TO EXPLORE AS MANY POTENTIAL BIOMARKERS AS POSSIBLE. IN ORDER TO DO THAT, WE ACTUALLY USED -- SO WE WANTED TO -- IN THIS FIRST EXERCISE 80 ANALYTES WHICH WOULD REQUIRE SIX DIFFERENT KITS. THE PROBLEM WITH GCF IS THAT YOU COLLECT SUCH A SMALL VOLUME THAT YOU CANNOT SIMPLY SPLIT YOUR SAMPLE INTO AS MANY KITS AS ONE WANTS. IT'S NOT LIKE SALIVA OR SERUM THAT ONE CAN USE -- YOU'RE COLLECTING .5 TO ONE MICRO LITER AS BEST. SO WE'RE USING THESE ROBOTS, WHICH HAVE THE ABILITY OF FISHING OUT MAGNETIC BEATS. AS MAGNETIC, WHICH ALLOWS FOR THAT SEPARATION FROM THE SAMPLE. SO ONE CAN EXPOSE THE SAMPLE TO THE FIRST SET OF BEATS ALLOW FOR THE -- AND ONCE -- HAS TAKEN PLACE AND THE ANOLYTES HAVE BEEN CAPTURED BY THE BEADS -- YOUR FIRST KIT AND NOW YOU EXPOSE THE -- SAMPLE TO A SECOND KIT. AND CAN DO THIS SEQUENTIALLY, THEREFORE PROBING FOR SEVERAL OF THE KITS IN THE SAME SAMPLE. SO WE ACTUALLY WENT ON AND ACTUALLY SPLIT BECAUSE WE DIDN'T WANT TO DO SEQUENTIAL FOR TOO LONG BECAUSE THAT EXPOSED THE SAMPLE TO DEGRADATION BECAUSE WE HAVE TO KEEP THE SAMPLE -- YOU CANNOT FREEZE AND THAW MANY CYCLES. WE SPLIT IN TWO AFTER WE -- FROM THE STRIP -- AND WE -- TO COVER ALL THE 80 MARKERS. SO ONCE WE HAVE DONE THIS AND HAVE THE RESULTS -- WE WAN WANTED TO COME UP WITH WHAT WOULD BE THE BEST APPROACH AND SYSTEMS BIOLOGY TO FIND WHAT WOULD BE THE BEST COMBINATION OF THOSE BIOMARKERS THAT COULD TELL US WHICH ONE OF THE PROGRESSING VERSUS THE NON-PROGRESSION ONE, AND ACCORDING TO THE EXPERTS IN THE FIELDS, -- WHO WORK ON MY TEAM, THIS IS THE -- MODEL -- SO WHAT IT DOES IS BASICALLY IT ACCOUNTS FOR THE FACT THAT YOU HAVE LOTS OF VARIABLES AND VERY FEW OBSERVATIONS AND ALSO ACCOUNTS FOR TH FACT THAT A LOT OF THOSE ANALYTES -- THEY ARE CORRELATED. T MORE SORT OF PENALIZES THEM FOR THAT AND, THEREFORE, IT SORT OF ACCOUNTS FOR SOME OF THE LIMITATIONS OF THIS -- OF THE STANDARD LOGISTIC REGRESSION MODELS. THIS IS WHAT WE CAME UP WITH. SO IF WE COMPARE WHAT WAS THE CHANGE IN ANALYTES FROM BASELINE TO THE POINT OF PROGRESSION VERSUS THE CHANGE IN THE CON 16 TRAITION ICONCENTRATION -- COMBINATION OF EIGHT BIOMACKERS THAT CAN ACTUALLY QUITE NICE DIFFERENTIATE PROGRESSION FROM NON-PROGRESSION WITH AN ACCURACY OF 82%. NOT PERFECT BUT A VERY DISTANT START. AND HERE WE ARE JUST ILLUSTRATING THE CHANGE IN A LOCK SCALE OF THOSE EIGHT BIOMARKERS IN THE PROGRESSING SITES. SO ONE CAN SEE THAT HUMAN -- SOFTWARE -- FOR ANY REASON -- ACTUALLY INCREASED IN MOST OF THOSE PROGRESSING SITES AS WE'RE MOVING TOWARDS -- WHY WE COMPARE TO WHAT HAPPENED TO THE NON-PROGRESSING CONTROL, THERE WAS ACTUALLY A DECREASE IN THE LEVELS OF SOME OF THOSE BIOMARKERS WHILE KEROTENE AND -- -- IN THE PROGRESSING SITE. SO WE START TO GET A SENSE OF WHICH BIOMARKERS TEND TO BE ASSOCIATED WITH THIS PROCESS. SO IN CON KLUG, WE COULD COME UP WITH THE NOTION THAT PERIODONTAL DISEASE PROGRESSION CANNOT BE DEFINED BASED ON A SINGLE CHANGE IN CAL, LOGISTC MODEL 82% DISCRIMINATION ACCURACY, SEQUENTIAL LUMINEX POWERFUL FOR SYSTEMS BIOLOGY, AND ASSOCIATIONS AND PREDICTION MODEL MUST BE VALIDATED IN EXTRA SAMPLES. JACKIE ST. ARR TELLS ME THIS IS ALWAYS A MUST. SHE IS CORRECT BECAUSE BASKET MODELS HAVE LOTS OF PROBLEMS TOO, THERE'S NO MAGIC IN THE STATISTICS BEHIND THIS. THE TRUTH IS THAT WE ARE STILL TO PROCESS A LITTLE BIT OF BOOD BOOT SAMPLING -- TO COME UP WITH ACTUALLY ALL THE MODELS THAT WILL HAVE PROBABLY THE SAME LEVEL OF ACCURACY. SO THERE'S NOTHING MAGICAL ABOUT THOSE EIGHT BIOMARKERS, THEY DO MAKE SOME BIOLOGICAL SENSE, BUT THERE'S A POSSIBILITY THAT SEVERAL OF THE OTHER BIOMARKERS THAT WE MEASURE HERE WILL END UP IN OTHER MODELS ONCE WE DO THE FULL SIMULATIONS WITH THE DATASET WHICH ARE STILL TO DO. THIS IS TO BRING YOU AN UPDATE OF THE STATUS OF THE STUDY IN TERMS OF RECRUITMENT WE HAVE SCREEN OVER THE TELEPHONE OF 2,000 PATIENTS, OF THOSE -- QUALIFIED AND 470 HAVE ALREADY BASELINED. WE HAVE FINISHED THE -- 12 MONTH -- OF 193, AND 214 HAVE ALREADY GONE THROUGH THE PROPHYLAXIS PHASE. AND WE ARE KEEPING A RELATIVELY LOW ATTRITION FOR AN INTENSE STUDY OF THAT NATURE OF 10%. EVERY SINGLE VISIT THE PATIENT COMES, THEY STAY WITH US FOR 2 1/2 HOURS SO WE CAN CONDUCT THE ENTIRE EXAMINATION. THE CLINICAL EXAMINATION ACTUALLY REQUIRES TWO PASSES OF PROBING. WE HAVE A THIRD PASS OF CLARIFICATION IF THERE IS A DISCONNECT OF MORE THAN TWO-MILLIMETERS BETWEEN THE FIRST AND THE SECOND BEST. SO -- TO MAKE SURE WE'RE COLLECTING THE MOST ACCURATE MEASUREMENT POSSIBLE. THERE IS ALSO A MARRIAGE BETWEEN THE EXAMINER AND THE PATIENT, BECAUSE IF YOU CHANGE THE EXAMINER FOR THE NEXT VISIT, YOUR MEASUREMENTS ARE MEANINGLESS IN TERMS OF THE -- OF PROGRESSION, SO ONE GETS A SENSE OF THE MODEL THAT IS BEHIND THIS. JACKIE STAR -- WHO WORKED THE MAGIC WITH THE DATA ANALYSIS OF THIS AND PILOT STUDY. POSTDOC FROM CHINA WHO STAYED IN OUR LAB FOR 20 MONTHS AND PROCESSED ALL THE SAMPLES. AND OF COURSE EXTRA THANKS TO NIDCR FOR THE SUPPORT. THIS IS -- HAD I WAS TOL WHEN I WAS TOLD T HIS WOULD MOVE FROM AN RO1 TO U MECHANISM, I WAS TOLD BY MANY COLLEAGUES THAT IT WILL BE A NIGHTMARE IN MY LIFE, AND IT HAS NOT BEEN. IT HAS BEEN A LIFE SAVER. IT HAS BEEN A TRUE PARTNERSHIP, GIVEN ME EXACTLY WHAT I NEEDED TO MAKE THIS SUCCEED -- HAS BEEN A WONDERFUL COLLABORATION AND WOULD LIKE TO THANK JANE FOR BEING SUCH A GOOD PROGRAM OFFICER. THAT'S IT. I'M OPEN TO ANY QUESTIONS. [APPLAUSE] >> BRUCE. BRUCE WITH THE JOURNAL OF THE AMERICAN DENTAL ASSOCIATION. THIS IS SAY SHA VIEW ALL OVER AGAIN. A LOT OF US WENT THROUGH THIS IN THE 60s -- NOT 60s BUT IN THE 70s AND 80s, WE THOUGHT ABOUT IT IN THE 60s, I THINK, SOME PEOPLE. ONLY WITH BACTERIA. WE HAD HUNDREDS OF BACTERIA -- MONOCLONAL ANTIBODIES, PERIODONTAL MEASUREMENTS, ARGUMENTS FOREVER ABOUT HOW TO MEASURE PERIODONTAL DISEASE, AND THE INDUSTRY HAS ALL KINDS OF SOPHISTICATED WAYS USING CUMULATIVE METHODS AND EVERYTHING BUT IT EVEN GETS MORE COMPLEX AS YOU POINTED OUT. WE'VE GOT -- THE MEASUREMENTS ARE CORRELATED WITHIN PATIENTS. RECENTLY THERE'S DATA SHOWING THEIR SPATIAL LIQUOR LATED, BETWEEN POSTERIOR SITES AND BICUSPIDS, FOR EXAMPLE, ARE DIFFERENT WITH INSIGHTS WITH CORRELATIONS ACROSS THE MOUTH AND -- IT'S INCREDIBLY COMPLEX. THEN WE'VE GOT VARIATIONS AT LEAST WE HAD VARIATIONS, LOTS OF VARIATIONS IN OUR IMMUNOFLUORESCENT ASSAYS WITH THTHE BACTERIA, AND I ASSUME YOU'VE GOT THE SAME VARIATIONS WITH YOUR LABORATORY DATA. AND THOSE ARE CORRELATED. AND THOSE ARE MOST LIKELY CORRELATED WITHIN PATIENTS AS WELL. THEN WE'VE GOT 400 SPECIES OF BACTERIA THAT ARE ALSO PROBABLY CORRELATED WITHIN PATIENTS. SO YOU'RE RIGHT, IT'S A NIGHTMARE, AND IT'S WONDERFUL THAT YOU'RE TAKING IT ON. I THINK IT'S JUST TERRIFIC. YOU REALLY NEED SOME HEAVY-DUTY STATISTICAL ANALYSIS ON THIS BECAUSE IT'S -- THAT'S A MAJOR, MAJOR CHALLENGE. THAT'S ENOUGH SAID, BUT IT'S A WONDERFUL ATTEMPT AND IT'S DOABLE BUT IT'S -- WOW. CONGRATULATIONS FOR TAKING IT ON. >> THANK YOU. AGAIN IT'S A TEAM EFFORT, THERE ARE LOTS OF PEOPLE, PLENTY OF PEOPLE TO BLAME. [LAUGHTER] >> IF THINGS DON'T GO EXACTLY AS ONE EXPECTED. I APPRECIATE YOUR COMMENTS. WHEN I SUBMITTED THE GRANT, THE IDEA WAS EXACTLY THAT AND OTHERS HAVE SAID THERE'S NOTHING REALLY ORIGINAL ABOUT THIS. WHAT IS DIFFERT IS THE TECHNOLOGY THAT IS AVAILABLE FOR US TO PROCESS SAMPLES. THE AVAILABILITY OF BEING ABLE TO STORE SAMPLES AND PROCESS THEM LATER, WHICH MICRO BIOLOGICALLY WAS NOT POSSIBLE IN THE EIGHTIES WHEN SOME OF THOSE STUDIES WERE CARRIED OUT. AT THE TIME ONE HAD TO LIMIT FOR EXAMPLE TO EXTRACT THE SAMPLE WHEN THE SITE HAD PROGRESSED ALREADY AND -- TO THE LAB, ONE COULD NOT HAVE STORED SAMPLES AND THEN RETROACTIVELY CHOOSE THE ONES THAT PROGRESSED -- ALLOW US TO DO THE -- PLUS THE COMPUTATIONAL POWER THAT HAS EXTENDED IN THE PAST DECADE. SO THAT'S WHY WE ARE DARING TO UNDERTAKE THE CHALLENGE. HAVING SAID THAT, YOU ARE VERY CORRECT TO SAY THAT THERE ARE PLENTY OF CHALLENGES AHEAD OF US, BUT -- IT'S NOT BEEN EASY CAEASYWITH THE STUDY, BUT WE'RE HERE, SAMPLES HAVE BEEN STORED, TRACKED BEAUTIFULLY, AND SOON ENOUGH, WE SHOULD START GETTING ANSWERS. >> HI, MARY, UNIVERSITY OF PITTSBURGH. SO I JUST WANT TO THANK ALL THE SPEAKERS THIS MORNING FOR AN INCREDIBLY INFORMATIVE SESSION FOR ME AT LEAST, I HAD A COUPLE QUICK QUESTIONS, FIRST REALLY FOR BOTH RICARDO AND NIKI, ARE YOU OBTAINING MEASUREMENTS OF OTHER ORAL HEALTH INDICATORS LIKE -- OR DENTAL CARIES IN THESE STUDY SUBJECTS WHILE YOU HAVE THEM IN THE CHAIR, AND THEN SECOND, MORE FOR RICARDO, I GUESS, ARE YOU DOING ANALYSES OF THE SALIVA TO SEE THE CONCORDANCE BETWEEN THE RESULTS YOU GET IN SALIVA VERSUS THE GCF, I THINK THAT WOULD BE A REALLY VALUABLE CONTRIBUTION TO THE GENERAL FIELD IN TERMS OF RUNNING STUDIES LIKE THIS IN THE FUTURE, A LOT EASIER TO GET SALIVA THAN GCF, AND FINALLY, DON'T FORGET THE HUMAN GENOME, AND I'M WONDERING IF YOU ARE GETTING ANY HOST -- AT LEAST SAMPLES THAT COULD BE USED TO LOOK AT THE HOST GENOME WHILE YOU'RE DOG THESE STUDIES. >> WELL, YES, WE ARE COLLECTING SALIVA. THERE IS AN UPDATE OF THE -- STATUS, IF YOU WILL, SO THERE IS SOME MEASUREMENT OF THE CARIES STATE OF THOSE PATIENTS. WE ADDRESS EVERYTHING WE CAN BEFORE THEY ENROLL. WITBUT AT TIMES, THERE HAS NOT BEEN A DETERRENT OF RECRUITMENT IN THE SENSE THAT IF THE PATIENT HAS CARIES LESIONS, THEY'RE REFERRED TO TREATMENT BUT WE ARE NOT FORCING THEM INTO TREATMENT BEFORE WE ENROLL THEM. JUST NOT MAKE OUR LIVES IMPOSSIBLE. WE ARE COLLECTING SALIVA AND THERE IS OF COURSE A GREAT DEAL OF INTEREST IF THAT WOULD CORRELATE WITH GCF. AND IN MY PREVIOUS EXPERIENCE -- FOR BIOMARKERS IN BOTH IS THE DILUTION FACTOR, THAT REALLY DILUTES GCF GREATLY. HAVING SAID THAT, THERE ARE MORE AND MORE SENSITIVE METHODS -- SO I ONE FINDS SOMETHING THAT IS OF INTEREST IN GCF, AND -- IN SALIVA, IT MIGHT BE A -- SENSITIVITY AND GOING AFTER THAT SAME ANALYTE WITH A MORE SENSITIVE TECHNIQUE -- SO IT'S STILL WORTH PURSUING IT. THERE WAS ANOTHER POINT THAT YOU -- WE EXAMINE THEM FOR CARIES. WE ARE COLLECTING SALIVA. THERE WAS ANOTHER POINT. OH, DNA. OH, YES. THERE WAS ACTUALLY A DESIRE OF NIDCR THAT WE REQUEST THAT THE PATIENT PROVIDE US GENETIC MATERIAL. WHICH IS VOLUNTARY SO THAT IT DOESN'T CONFLICT WITH THE STUDY. SO THEY CAN PARTICIPATE IN THE STUDY AND NOT GIVE US THE GENETIC MATERIAL. WHICH IS BASICALLY BLOOD THAT WE EXTRACT DNA FROM BLOOD. HAVING SAID THAT, 80% OF PATIENTS HAVE AGREED TO GIVE US THE -- AT LEAST SO IT WILL BE A BIOBANK, IF YOU WILL. >> FROM OUR STANDPOINT AS WELL, WE COLLECT AND STUDY REALLY EVERYTHING THAT WE CAN IN THESE PATIENTS. OF COURSE WE LOOK AT PLAQUE MEASURES, BLEEDING ON PROBING, AND CARIS RATES. WE TAKE BLOOD FOR DNA BUT WE ALL HAVE TISSUES FROM PATIENTS AS WELL TO LOOK AT THE MUCOSAL SITE, FLOW CYTOMETRY, WE TRY TO DO AS MUCH AS WE CAN AND THE PATIENTS AT THE NIH ARE VERY GOOD PARTNERS BECAUSE THEY'RE VERY COMMITTED TO REALLY CONTRIBUTING TO RESEARCH AND TRYING TO UNDERSTAND WHEN THEY DO HAVE AN ORAL DISEASE BUT EVEN WHEN THEY DON'T HAVE A DISEASE PHENOTYPE, JUST WANTING TO CONTRIBUTE SO IT'S BEEN VERY -- IT'S BEEN V GOOD THAT WAY. BUT I ALSO WANT TO TAKE THE OPPORTUNITY TO ASK RICARDO SOMETHING, WHICH COMES BACK TO THE PROBING. SO WE ALL HAVE BEEN GROWING UP AS PERIODONTISTS VERY CONNECTED TO PROBES, AND STILL PROBES HAVE MANY PROBLEMS, THEY HAVE PROBLEMS OF WHO'S PROBING, WHAT ANGLE YOU'RE USING, WHAT SITE, SHOULD WE BE THINKING OF OTHER IMAGING MODALITIES THAT COULD SHOW YOU ALL AROUND THE TOOTH WHAT'S HAPPENING AND MONITOR MORE SPECIFICALLY THAN A PROBE? JUST GOING FORWARD? BECAUSE MANY OF US THAT FLAP TISSUES KNOW THAT WE OFTEN HAVE SURPRISES WHEN WE FLAP. >> THAT'S AN EXCELLENT POINT. THE LIMITATIONS OF THE YARDSTICK IN THE GUMS IS NOTORIOUS, AND IT IS A LIMITATION OF THE FIELD IN GENERAL. THE TECHNOLOGY THAT COMES TO MIND THAT EXACTLY THE MOST -- AND WE DISCUSSED A LITTLE BIT ABOUT CT SCANS, BUT I THINK THAT LIGHT, INFRARED LIGHT, IT'S PROBABLY AN APPROACH WITH THE INFRARED SPECTRA, BOUNCING BACK AND ALLOWING US TO MAYBE -- TISSUES IN THAT WAY, IT'S OF INTEREST TO ME. THE DIFFICULTY IS WHEN I THINK OF THE PROBLEM AND I ACT AS A CONSULTANT OF A COMPANY IN CALIFORNIA WHICH WANTED TO SUBMIT AN SBIR GRANT WHICH DIDN'T GET FUNDED, DIDN'T DESERVE IT SO IT'S OKAY, BUT IS THAT YOU STILL WOULD HAVE TO STANDARDIZE THE DISTANCE FROM THE SOURCE OF THE LIGHT TO WHATEVER THE RECEPTOR, SO IF ONE THINKS OF A FREE-STANDING SCAN IN YOUR HAND, IN MY MIND IT WOULDN'T WORK SO WELL, BECAUSE DEPENDING ON THE -- TO THE TISSUES, YOU MIGHT GET DIFFERENT RESPONSES. SO ONE CAN IMAGINE THE CHALLENGE OF -- SOMETHING THAT WOULD -- REALLY SCAN AROUND ALWAYS AT THE SAME DISTANCE FRO FROM TISSUES. BUT IN MY MIND THAT IS WHAT THE BEST BET IS IN THE HORIZON, COMING UP WITH A BETTER WAY OF MEASURING WHAT DISEASE IS IS CRUCIAL. PLEASE? >> ARE THERE ANY PLANS TO USE SOME KIND OF 3D IMAGING TECH NEEG? >TECHNIQUE? >> NOT IN THIS STUDY. WE DID COLLECT RADIOGRAPHS IN THE BEGINNING. THERTHERE ARE NO PLANS TO HAVE A SUBSEQUENT ONE BECAUSE OF THE SAME KIND OF LIMITATION THAT ONE WOULD FIND WITH RADIOGRAPHS. AND WE FELT THAT IT WAS ALREAD TRYING TO ASK TOO MUCH, TO ANSWER TOO MUCH WITH THE DESIGN AS IT WAS TO GO THROUGH STANDARDIZATION OF -- AND POSITIONING OF THE X-RAY SOURCE, SO UNFORTUNATELY THE ANSWER IS NO, WE DON'T HAVE ANY OF THAT CAPACITY IN THIS STUDY. >> NADYA. >> THANK YOU FOR A GREAT PRESENTATION. MY QUESTION IS RELATED TO THE PROBING, IN THOSE PATIENTS WHERE YOU SEE THE ZIG-ZAG, WHETHER THAT IS SIGNIFICANT, AND MAYBE IT'S JUST AN ISSUE OF IMPRECISE PROBING, BUT IF IT'S REAL THAT YOU'RE DEPTH GOES UP AND DOWN, IT GOES BACK TO THE ISSUES OF WHAT ARE THE ELEMENTS OF HOST HOMEOSTASIS THAT ALLOWS MAINTENANCE OF HEALTHY PERIODONTAL TISSUES, MAYBE WHAT YOU'RE SEEING IS A SIGN OF DEGENERATION REGENERATION, THAT THE BODY COMES BACK AND REGENERATES PERIODONTAL TISSUES, BUT ONCE IT GOES OUT OF CONTROL, THERE IS -- IT'S A POINT OF MO RETURN. NO RETURN. SO IN THIS REGARD, DOES -- DO YOU ALSO THINK THAT IT WOULD BE INTERESTING TO LOOK AT BIOMAR WHICH ARE DOWN REGULATED AS A TRANSITION FROM HEALTH TO DISEASE, NOT JUST THE BIOMARKERS THAT GO UP, BUT MAYBE, AGAIN, OF COURSE IT'S CLEAN, IT DOESN'T GIVE YOU THE MECHANISTIC UNDERSTANDING, BUT MAYBE AS A START OF ASKING A QUESTION WHAT IS IT -- HOMEOSTASIS, YOU CAN LOOK AT THE COUNCIDOWN REGULATION OF CERTAIN MARKERS. >> THAT'S A VERY EXCELLENT POINT. BY NO MEANS IN OUR ANALYSIS WE ARE FOCUSED ONLY ON THINGS THAT ARE UPREGULATED, SO THE DOWNREGULATION OF ANALYTES ARE BEING GIVEN THE SAME WEIGHT, IF YOU WILL, WITH THE MODEL. SO YES, THERE ARE THINGS THAT ACTUALLY OVEREXPRESS IN THE STABLE SITES IN COMPARISON TO THE PROGRESSING SITES AND THAT MIGHT BE A SIGN AGAIN OF A PROTECTIVE MECHANISM IF YOU WILL. WE ARE VERY MUCH INTERESTED IN THE FLUCTUATION. WE ARE NOT SIMPLY DISCARDING THOSE. BUT IN DRAFTING THE DRIVER QUESTION FOR THE GRANT, PROGRESSION VERSUS STABILITY, WE EXCLUDED THEM FOR THE TIME BEING. BUT THERE IS EVERY INTENT OF THROWING THEM IN THE MIXTURE TO GET A SENSE OF WHY IS THE FLUCTUATION OF BIOMARKERS OF THOSE SITES. I MEAN, I THINK WE HAVE FOR THE LONGEST WHILE ASSUME PROGRESSION TOOK ONLY ONE DIRECTION AND -- REVERSAL PHASE WHICH I THINK IT'S ALSO CLINICALLY WELL ESTABLISHED BY OTHER STUDIES. NOT ONLY FROM OUR -- SO WE'RE NOT ASSUMING -- BY NO STRETCH OF THE IMAGINATION. A TRUE FLUCTUATION WHICH MIGHT BE RELATED TO TRUE LOSS OF ATTACHMENT BUT JUST INFLAMMATION OF THE TISSUES, SORRY, REGROWTH OF COLLAGEN IN THE TISSUES GIVING A -- MO MORE RESISTANCE TO THE PROBE BACK AND FORTH AND IT'S TOTALLY WORTH EXPLORING. THOSE ARE ALSO VERY INTERESTING AS TO HOW CAN A SITE IMPROVE IN THE ABSENCE OF TREATMENT AND WHAT -- EVENTS -- SO WE'RE EXPLORING BOTH SIDES OF THE COIN. >> ANN? >> I GUESS I HAVE A QUESTION GOING FORWARD. YOU SCREENED -- YOU'VE SCREENED QUITE HEAVILY FOR THESE SUBJECTS TAKING OUT SMOKING AND DIABETES AND SO ON. DO YOU SEE GOING BACK TO THESE POPULATIONS LATER? I JUST THINK FOR MYSELF WHEN WE WERE ACTIVELY LOOKING TO FIND PEOPLE WITH PG AND TF AT ONE POINT, OUR BEST ENRICHMENT WAS TO GET THE SMOKERS, SO MAYBE SOME OF THESE THINGS WILL BE EXAGGERATION IN POPULATIONS AND YOU COULD PICK OUT WHICH ONES ARE MORE OR LESS MORE IMPORTANT. >> IT'S A GOOD POINT, AND THERE WAS A DISCUSSION WHEN INCLUSION/EXCLUSION WHICH IS A VERY HOT TOPIC AMONGST THE PIs FROM THE OTHER CENTERS AS TO WHY WE'RE EXCLUDING SMOKERS. THE IDEA COMES FROM THE WHOLE PIPELINE OF BIOMARKERS. ONE HAS TO START WITH A REALLY DEFINE POPPED LAITIODEFINE POPULATION. FOR SOMEONE WHO CONTINUES SMOKING SOLID FOR ONE YEAR CAN COME INTO THE STUDY, BUT THE IDEA IN EXCLUDING THEM WAS AGAIN WE'VE COME AWAY WITH THIS VERY HOMOGENEOUS POPULATION AS ONE CAN GET WITH PERIODONTAL DISEASE. THE NEXT STAGE IN BIOMARKER DISCOVERY OR IN BIOMARKER DEVELOPMENT FOR THIS KIND OF APP WOULD BE TO GO TO A NEW POPULATION AND NOW OPEN A LITTLE MORE OF THE CRITERIA FROM INCLUSION, STILL ADD VARIABILITY. SMOKING WAS PARTICULARLY A TOUGH ONE BECAUSE ONCE YOU ACCEPT THE SMOKERS, THEN YOU'RE GOING TO GRADES OF SMOKING. WHAT WOULD BE A TRUE SMOKE E HOW MUCH SMOKING WOULD BE A SMOKER, AND BECAUSE OF ALL OF THAT, OUR -- WOULD PROBABLY EXPLODE IF WE INCLUDED SMOKERS, SO THAT WAS THE APPROACH, IT WAS A TOUGH BATTLE, I MUST SAY. SO IF SOMETHING COMES OUT AND PEOPLE DON'T LIKE THE FACT THAT IT'S EXCLUDES SMOKERS, I'M THE ONE TO BLAME BECAUSE I WAS THE ONE WHO FOUGHT FOR IT. >> THANK YOU AGAIN ALL FOR THE WONDERFUL PRESENTATIONS TODAY. I REALLY APPRECIATE THE PERIO FORUM TODAY. I HAVE THREE LITTLE COMMENTS. ONE HAS TO DO WITH YOUR VALIDATION SO PERHAPS THAT MIGHT BE A REALLY OPPORTUNE TIME TO INCLUDE SOME OF THESE OTHER ADDITIONAL SUBJECTS, SMOKERS, MAYBE DIABETICS IN THE VALIDATION PHASE. THE OTHER COMMENT WAS TO DO WITH THE DIFFICULTY WHEN YOU'RE DOING THESE LONGITUDINAL STUDIES WE FACED A LITTLE BIT IN SOME OF THE SMALL STUDIES THAT WE'VE DONE ON THE ETHICAL THOUGHTS OF RESCUE THERAPY. SOME OF THESE PATIENTS PROGRESS, AND HOW COULD YO DO YOU ETHICALLY THEN SOR T OF COLLECT DATA FROM PATIENTS THAT ARE PROGRESSING AND NOT PROVIDE TREATMENT. >> THE WAY WE ADDRESS THIS IS IS THE UP A SET OF RULES FOR -- THERAPY. THE 2-MILLIMETER THRESHOLD BECAUSE OF THE REVERSAL PHASE WAS NOT SUFFICIENT TO TRIGGER -- BUT A 4-MILLIMETER CHANGE LOCAL -- THERAPY, SO SCIENCE IS EXCLUDED FROM MONITORING -- THE SITE RECEIVES TREATMENT, CONTINUES THE MONITO IF THE PATIENT PRESENRE THAN SIX SITES, ACCUMULATES MORE THAN SIX SITES THAT HAVE PROGRESSED AND ACCORDING TO THE LOWER THRESHOLD OF 2 MILLIMETERS, THEN WE MOVE THE PATIENT INTO THE TREATMENT PHASE. VERY FEW PATIENTS HAVE ACTUALLY UNDERGONE THIS. IN THE BEGINNING, WE HAD DIFFERENT CRITERIA TO MODIFY THAT BUT ONCE WE CAME UP WITH EXISTING CRITERIA OF HAVING TO HAVE AT LEAST FIVE SITES THAT PROGRESS TO MOVING TO TREATMENT, VERY, VERY FEW PATIENTS GO THAT ROUTE. SO FOR THE VAST MAJORITY -- SAFE PROTOC HAVE WE OBSERVED LOSS OF TEETH DUE TO PERIODONTAL DISEASE? YES, WE HAVE. I WAS ALWAYS INVOLVING -- THAT WERE NOT ADDRESSED WITHIN THE STUDY SO PATIENTS PURSUED TREATMENT ELSEWHERE EVEN THOUGH THEY WERE ADVISED TO SEEK TREATMENT WITH US FIRST. THEN THE DECISION WAS MADE TO EXTRACT THE TEETH. SO THAT WAS NOT DONE PRIMARILY UNDER THE STUDY. HAVING SAID THAT, THEY ESTIMATE THE NUMBER OF LOST TEETH IN THIS STUDY, IT'S MUS MUCH LESS THAN NUMBER OF TEETH LOST IF TREATMENT STUDIES. SO WE STILL FEEL WE ARE BEING QUITE SAFE AND QUITE CONSCIOUS OF THE RISKS AS OUR PATIENTS. >> WHO ELSE? MIKE? >> THANK YOU FOR THE PRESENTATIONS AS AN MD, I CERTAINLY LEARNED A LOT ABOUT PERIODONTAL DISEASE THIS MORNING, SO THE COMMENT I HAVE IS IT SEEMS LIKE THE HUMAN CAPITAL INVOLVED AND THE VOLATILITY OR VARIANCE IN YOUR MEASUREMENT IS A BIG DEAL. THIS SEEMS LIKE A DIAGNOSTIC CHALLENGE THAT'S BEGGING FOR TECHNOLOGY INNOVATION TO MAKE IT SIMPLER, AND I THINK THIS IS EXACTLY THE TYPE OF THING THAT NEW TECHNOLOGY CAN ADDRESS AS OPPOSED TO THE VARIATION AND PROBE. YOU SHOW PRETTY SIGNIFICANT VARIATIONS WITH THE SAME PERSON, BUT INTEROBSERVER, YOU HAVE TO GO BACK AND DO EVERYTHING ALL OVER. IT'S AN ENORMOUS UNDERTAKING, I APPLAUD YOU FOR DOING IT, BUT I THINK IT CAN BE SIMPLIFIED A LOT THROUGH A TECHNOLOGY THAT IS MORE REPRODUCIBLE AND SCALABLE. >> IT'S A VERY GOOD POINT THAT THE KEY ISSUES, THERE IS NO SUCH TECHNOLOGY. IT DOESN'T EXIST. I THINK A LOT OF THE FINDINGS OF THE STUDY REGARDING JUST THE CLINICAL DESCRIPTORS OF PROGRESSION WILL BE IN MY MIND VERY TELLING AND ALSO A GOOD PRIMER FOR THIS KIND OF PUSH FOR THOSE TECHNOLOGIES OF. -- WHEN EVERYB WAS DOING THIS KIND OF STUDY AND WE WERE CONFRONTED WITH THE LIMITATIONS OF PROBING, AND IF, IN FACT -- APPROACHES OR -- DESIGNS OF PROBES WERE INTRODUCED IN THE MARKET, NONE OF THEM REALLY TURNED OUT, ADDED A LOT OF REPRODUCIBILITY TO WHAT WE ARE DOING. THERE WAS A CLAIM OF HIGHER SENSITIVITY THAT WITHOUT REPRODUCIBILITY, MY MIND IS -- TO BE CONVINCING OF THAT. AND THEY'RE NOT PRACTICAL. THEY ARE VERY TOUGH TO USE. SOME OF THEM, AT LEAST. BUT I DEFINITELY SEE YOUR POINT AND I THINK THIS IS A VERY TELLING KIND OF OBSERVATION THAT WE HAVE SEEN HERE. IF WE LOOK AT THE PERCENTAGE OF SITES PROGRESSING IN OUR STUDY POPULATION COMPARED TO CLASSIC STUDIES, IT LOOKS LIKE WE ARE SEEING PROGRESSION IN TOO MANY PEOPLE. HOW COME YOU'RE SEEING 80% OF YOUR PATIENTS PROGRESSING? IT'S BECAUSE -- MOST PREVIOUS STUDIES MEASURE THEM TWICE. SO YOU HAD ONLY ONE OPPORTUNITY OF CHANGE CROSSING THAT THRESHOLD. THAT'S PART OF THE TRICK HERE. BUT HAVING THIS LONGITUDINAL MOB MONITORING ALLOWS US A MORE PRECISE HOPEFULLY DEFINITION OF WHAT IS PROGRESSION OR NOT. WE UNDERSTAND THERE ARE LIMITATIONS THAT WE'LL NEVER BE ABLE TO TELL FOR SURE IF A TRUE CLINICAL LOSS OF ATTACHMENT HAPPENED BECAUSE ONE WOULD NEED A HISTOLOGY FOR THAT, BUT HAVING SAID THAT, I THINK IT'S AS GOOD AS IT HAS COME THIS FAR, BUT YOU'RE CORRECT, IT'S A PROBLEM -- FOR TECHNOLOGY. >> ALEX. >> THANKS FOR THE PRESENTATION. I'M THINKING BACK TO THE FIRST SET OF SLIDES THAT YOU SHARED WITH US, THE MAP THAT HAD 48% OF THE POPULATION OF ADULTS WITH PERIODONTAL DISEASE. BUT WITHIN THAT NM BER, WE KNOW THAT THERE'S HUGE DISPARITIES, THAT MEN ARE MUCH MORE COMMON THAN WOMEN TO HAVE PERIODONTAL DISEASE, ABOUT TWO THIRDS OF PEOPLE THAT LIVE BELOW THE FEDERAL POVERTY LEVEL HAVE MODERATE TO SEVERE PERIODONTAL DISEASE AND ABOUT THE SAME NUMBER OF FOLKS WHO HAVE NEVER GRADUATED FROM HIGH SCHOOL. SO IF WE THINK -- THEN I THINK ABOUT THE NIDCR STRATEGIC PLAN, WHICH ADDRESSES HEALTH DISPARITIES AS ONE OF THE FOUR GOALS. ANY THOUGHTS ON HOW THOSE TWO CAN COMBINE, HOW THAT WE CAN LEVERAGE TO INCLUDE SOCIAL DETERMINANTS OF HEALTH? IT'S MORE THAN JUST AN ACCESS ISSUE, I WOULD THINK, BUT MAYBE NOT. ANY THOUGHTS ON THAT? >> WELL, I WISH I COULD SAY THAT WE HAD A COMPREHENSIVE QUESTIONNAIRE ASSESSING SOCIOECONOMIC -- BY THE SAME TOKEN, WE DO NOT HAVE A VERY GOOD NUTRITIONAL ASSESSMENT OF THOSE PATIENTS. AND OF THOSE -- MISSED OPPORTUNITIES AND THEY ARE, BUT AGAIN, THAT GOES FOR ANY CLINICAL TRIAL. THERE'S ONLY SO MUCH THAT WE CAN DO. HAVING SAID THAT, I THINK THAT WE ARE ON THE MARK IN ESTABLISHING THAT POVERTY IS PROBABLY ONE OF THE COMPOUNDING CAUSES OF PERIODONTAL DISEASE, AND IT IS. THERE'S DEFINITELY -- BIAS TOWARDS POOR PEOPLE TO HAVE MORE FOROF THE DISEASE, MORE SEVERE CONSEQUENCES AND NOT BEING ABLE TO REPLACE THEM. HAVING SAID THAT, I HAVE A GREAT DEAL OF FAITH IN SCIENCE AND GIVING US ALTERNATIVE APPROACHES. ONE THAT GOES MOST UNNOTICED TESE DAYS IS THE FACT IT TOOK US 40 YEARS TO COME UP WITH -- TO TREAT PERIODONTAL DISEASES. IT DOES WORK REALLY WELL VOR FOR A VAST MAJORITY OF PATIEN PARTIALLY WE UNDERSTAND WHY, BECAUSE OF THE CHANGES IT BRINGS TO THE MICRO BIOTO, WITHOUT A TOTAL UNDERSTANDING OF THE MICRO BIOTA WE HAVE, IT WOULD STILL BE A MYSTERY. AGAIN, IT'S NOT EVERY ANTIBIOTIC THAT WORKS THAT WAY. IT'S A COMBINATION, THERE'S SOMETHING SPECIAL ABOUT IT AND IT HAS BEEN SHOWN OVER AND OAF IN MANY COUNTRIES, IT BRINGS THE RISK OF RESIDUAL POCKETS OF VERY LOW NUMBER, IT DISCLOSES WE HAVE GOTTEN THIS FAR TO A SOLID CONTROL -- HAVING SAID THAT, IT'S ALSO TEMPORAL MEANING THAT EVENTUALLY MAINTENANCE WILL ALSO BE REQUIRED. BUT I THINK THAT IT'S A GOOD EXAMPLE OF HOW WE CAN ONLY APPRECIATE FULLY WHAT THIS NEW THERAPY BRINGS TO THE PATIENT BECAUSE OF CLINICAL STUDIES, BECAUSE OF CLINICAL TRIAL BECAUSE OF OUR UNDERSTANDING OF THE MICRO BIOTA, WITHOUT ANY OF THAT IN PLACE, THINGS COULD STILL BE SOMEWHAT OF A MYSTERY. SO I THINK WE'RE LEARNING MORE ABOUT THE DISEASE IS THE ONLY ALTERNATIVE. AS I'M GOING TO THINK ABOUT THIS QUESTION, WHAT THE -- KNOWLEDGE -- WHAT IS THE ALTERNATIVE? HOW ARE WE GOING TO COME UP WITH MORE KNOWLEDGE ABOUT HOW THE DISEASE BEHAVES? IT'S IMPOSSIBLE. SO I KEEP -- I BORROWED THIS FROM -- THE PAPER, THE ONLY PAPER THAT I WISH I COULD -- THE CAUSE AND CURE OF PERIODONTAL DISEASE. SO THIS IS LEARNING A LITTLE ABOUT THE CAUSE SO WE CAN MAYBE COME UP WITH BETTER TREATMENTS AND HOPEFULLY A CURE. BUT THAT'S THE IDEA. AND IF WE ERADICATED POVERTY, IT WOULD DO A GREAT JOB. >> ALL RIGHT. LET'S THANK ALL OF OUR SPEAKERS AGAIN. [APPLAUSE] WE HAVE A LITTLE BIT OF A DEPARTURE FROM OUR STANDARD SCHEDULE TODAY. NOW THE OPEN SESSION WILL ADJOURN. HOWEVER, COUNCIS SHOULD REMAIN AS WE'RE GOING TO GO RIGHT TO THE BSC REPORT, DR. BRENDAN LEE IS AVAILABLE NOW, WE GOT HIM ON THE PHONE A LITTLE BIT EARLY, AND WE'LL GO THROUGH THE BSC REPORT NOW. THEN WE'LL HAVE A 45-MINUTE LUNCH FOLLOWING THE BSC REPORT, AND READY TO RESUME CLOSED SESSION AT 1:30