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>> WELCOME TO THE THIRD SESSION

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OF THE 20th YEAR OF THE NIH

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COURSE ENTITLED DEMYSTIFYING

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MEDICINE.

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THE LOGO AS SHOWN ON THE SLIDE

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IS THE BROOKLYN BRIDGE.

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WE ARE LIKE THE INDIVIDUALS ON

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THE BRIDGE WHO ARE DISCUSSING OR

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LEARNING FROM ONE ANOTHER ABOUT

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IMPORTANT BIOMEDICAL AND

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ENGINEERING PROGRESS AS IT CAN

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INFLUENCE MEDICINE.

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THINGS ARE NEVER THE SAME AFTER

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A BRIDGE HAS BEEN SUCCESSFULLY

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BUILT AND IN COURT MAY BE

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THOUGHT OF AS YOU A COURSE IN

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BRIDGE BUILDING.

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TODAY'S TOPIC IS THE INTESTINAL

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MICROBIOME.

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I THINK THAT -- IN THE 17th

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CENTURY WAS THE FIRST TO EVER

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SEE THE MICROBIOME BY EXAMINING

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CONTENTS OF FECAL MATERIAL ON

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HIS MINIATURE MICROSCOPE.

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IN THE 19th CENTURY -- IS

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PROBABLY THE FIRST TO RELATE IT

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TO DISEASE.

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AND IN THAT SENSE TODAY WE WOULD

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CALL TOXIC SHOCK.

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BUT HE ALSO RELATED IT TO THE

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POSSIBILITY OF HEALTH AND THAT

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BY MODIFYING THE MICROBIOME

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THERE MAY BE INFLUENCES ON HUMAN

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HEALTH.

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BUT IT WASN'T UNTIL 1977 WHEN

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CARL WOESE INTRODUCED 16S

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SEQUENCING WHICH REVOLUTIONIZED

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MICROBIOLOGY 

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NOW THE DISCOVERY OF THESE

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METHODS LED TO THE

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QUANTIFICATION OF MICROBIOME

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SPECIES AND THEN THE STUDY OF

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THE COMPOSITION, REGULATION AND

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ROLE IN PHYSIOLOGY AND DISEASE.

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HOWEVER FOR MUCH OF THE WORK WE

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ARE IN A DESCRIPTIVE STAGE.

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THAT IS DESCRIBING THE

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MICROBIOME IN DIFFERENT AGES,

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SOCIOECONOMIC GROUPS AND

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COMPARISONS AND CONTROL PATIENTS

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AND THOSE WITH VARIOUS DIETS,

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WEIGHT AND DISEASE.

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THE HUGE CHALLENGE IS TO

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DETERMINE WHETHER THE OBSERVED

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MICROBIOME DIFFERENCES REPRESENT

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CAUSE OR EFFECT.

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NOW THE AVAILABILITY OF GERMFREE

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AND ANIMALS IS AIDED.

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HOWEVER THE QUESTIONS CONCERNING

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HUMANS IN WHOM CLINICAL STUDIES

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OF CAUSE AND EFFECT AND

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MECHANISM ARE DIFFICULT IF NOT

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AT TIMES SEEMINGLY IMPOSSIBLE TO

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PERFORM.

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AND THIS IS THE BRIDGE THAT WE

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WILL BE DISCUSSING TODAY.

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TODAY WE'RE VERY FORTUNATE TO

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HAVE TWO OUTSTANDING SCIENTIST

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DISCUSS THEIR EXCITING WORK IN

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BRIDGING THE MICROBIOME WITH TWO

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MAJOR CLINICAL PROBLEMS.

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MALNUTRITION AND CANCER.

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OUR FIRST SPEAKER WILL BE JEFFE

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GORDON.

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WHO GRADUATED FROM THE

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UNIVERSITY OF CHICAGO SCHOOL OF

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MEDICINE TRAINED IN MEDICINE AT

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WASHINGTON UNIVERSITY IN ST.

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LOUIS AND IN GASTROINTESTINAL.

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AND AT THE NATIONAL INSTITUTE OF

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HEALTH AND RETURNED TO

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WASHINGTON UNIVERSITY WHERE HE

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HAS SPENT HIS ENTIRE CAREER.

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HE STARTED TO USE GENOMIC

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SEQUENCES -- KNOW OBEY ON THEIC

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ANIMALS AND THEIR RESPONSE TO

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DIET IN PRECLINICAL AND CLINICAL

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STUDIES.

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* IN ONE OF HIS PAPERS HE SAID I

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WANT TO CONFESS I'M MORE

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MICROBIAL THAN I AM HUMAN

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BECAUSE THE CONTENTS OF THE

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MICROBIOME NUMBERING IN THE

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TRILLIONS FAR EXCEEDS THE SUM

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TOTAL AFTER ALL OF THE CELLS IN

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THE HUMAN BODY.

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JEFF IS A DISTINGUISHED

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UNIVERSITY PROFESSOR AT

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WASHINGTON UNIVERSITY.

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AND PROFESSOR OF PATHOLOGY AND

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IMMUNOLOGY ALSO OF DEVELOPMENTAL

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BIOLOGY AND OF MOLECULAR MICRO

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BIOLOGY.

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HE HAS RECEIVED AN EXTRAORDINARY

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NUMBER OF THE HIGHEST HONORS

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THAT CAN BE BESTOWED UPON EYE

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SCIENTISTS.

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HE IS * A MEMBER OF THE

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ASSOCIATION OF AMERICAN

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PHYSICIANS.

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A MEMBER OF THE NATIONAL ACADEMY

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OF SCIENCES, OF ARTS AND

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SCIENCES.

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THE NATIONAL INSTITUTE OF

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SCIENCE.

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THE INSTITUTE OF MEDICINE.

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THE AMERICAN PHILOSOPHICAL

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SOCIETY.

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AND HE HAS BEEN A RECIPIENT OF

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VIRTUALLY EVERY MAJOR PRIZE AND

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AWARD GIVEN FOR BIOMEDICAL

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RESEARCH.

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ONE OF THOSE AWARDS IN 2018 WAS

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FROM THE ROYAL SOCIETY WHICH

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BESTOWED ITS MEDAL WHICH IS THE

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OLDEST SCIENTIFIC PRIZE IN THE

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WORLD.

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AND I WOULD JUST READ AS PUT ON

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THE SLIDE THE REASONS FOR THAT

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AWARD.

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IT'S BECAUSE HIS WORK LED TO A

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FUNDAMENTAL SHIFT IN THE WAY

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SCIENTIST UNDERSTAND THE

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RELATIONSHIP BETWEEN MICROBES,

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HEALTH AND DISEASE AND HE LED TO

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DISCOVERIES WHICH SHED NEW LIGHT

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ON AMONG OTHER THINGS THE ORIGIN

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OF TWO PRESSING GLOBAL HEALTH

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PROBLEMS.

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OBESITY AND CHILDHOOD

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MALNUTRITION.

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TODAY DR. GORDON IS GOING TO

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SPEAK TO US ABOUT THE ROLE OF

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THE MICROBIOME IN MALNUTRITION.

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NEXT PLEASE.

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OUR SECOND SPEAKER IS TIM GRETEN

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WHO GRADUATED IN MEDICINE IN

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GERMANY.

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WAS A POSTDOCTORAL FELLOW IN

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JOHNS HOPKINS.

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RETURNED TO GERMANY AND IN 2010

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WAS RECRUITED TO THE NATIONAL

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CANCER INSTITUTE WHERE HE IS THE

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DEPUTY BRANCH CHIEF FOR THE

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THORACIC AND GI MA MALIGNANCY

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BRANCH.

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HE IS COCHAIR FOR THE CENTER OF

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EXCELLENCE OF IMMUNOLOGY.

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AND ALSO OF THE LARGE PROGRAM

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INTERDISCIPLINARY AT THE NIH

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DIRECTOR OFFED HEPATOCELLULAR

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CANCER.

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HE FOCUSES ON HEPATOCELLULAR

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CANCER AND DURING THIS WORK EVEN

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THE PAST SEVERAL YEARS HE HAS

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BECOME INVOLVED IN THE

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RELATIONSHIP BETWEEN LIVER

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TUMORS PARTICULARLY CANCERS AND

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THE GUT MICROBIOME.

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AND THE TOPIC OF TIM'S TALK IS

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HOW THE GUT MICROSOFT CONTROLS

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GROWTH OF LIVER TUMORS.

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NOW WE WILL CONSIDER QUESTIONS

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AND ANSWERS AND DISCUSSION AT

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THE CONCLUSION OF DR. GRETEN'S

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TALK BUT PLEASE SUBMIT YOUR

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QUESTIONS DURING THE ENTIRE

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PROGRAM AND THEY WILL BE

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PRESENTED AT THE END.

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SO NOW I WANT TO THANK BOTH OF

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OUR SPEAKERS FOR TAKING THE TIME

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AND INTEREST TO PARTICIPATE IN

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THIS PROGRAM.

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AND JEFF IF YOU WOULD PLEASE

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BEGIN.

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>> THANK YOU VERY MUCH.

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IT'S A PRIVILEGE AND PLEASURE TO

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BE ABLE TO PARTICIPATE IN THIS

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WONDERFUL PROGRAM.

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>> THIS IS ADVENTURE.

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TWO GROUPS OF INDIVIDUALS.

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ON THE LEFT YOU CAN SEE A GROUP

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OF VERY TALENTED STUDENTS AND

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POSTDOCTORAL FELLOWS IN THE LAB

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WHICH IS LOCATED AT THE CENTER

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FOR GENOME SCIENCES AT

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WASHINGTON UNIVERSITY IN ST.

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LOUIS.

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AND OUR LONG-STANDING

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COLLABORATORS -- AT THE

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INTERNATIONAL CENTER FOR

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RESEARCH.

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THIS IS FUNDED BUT THE BILL AND

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MELINDA FOUNDATION AT THE NIH.

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I HAVE NO CONFLICTS TO REPORT.

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IT'S WORK DIRECTED AT THE

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DEVELOPMENT OF COMPLIMENTARY

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FOOD FOR CHILDHOOD.

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THIS IS A GLOBAL HEALTH

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CHALLENGE MADE WORSE BY THE

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CURRENT PANDEMIC.

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IT'S THE LEADING CAUSE OF DEATH

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OF CHILDREN UNDER THE AGE OF

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FIVE.

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THERE HAVE BEEN MANY ESPECIALLY

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DEEM LOGICAL SKUD EASE THAT HAVE

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DEMONSTRATED THAT CHILD UNDER

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NUTRITION IS NOT DUE TO FOOD IN

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SECURITY ALONE.

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*.

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CURRENT THERAPIES HAVE EVOLVED

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TO REDUCE MORTALITY.

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BUT THEY'VE HAD VERY LIMITED

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UNFORTUNATELY SUCCESS IN

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OVERCOMING THE LONG-TERM

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CONSEQUENCES OF UNDER NUTRITION

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WHICH INCLUDES IMPAIRED LINEAR

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GROWTH.

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DEFECTS IN IMMUNE RESPONSES

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INCLUDING VACCINATION AND NEURAL

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DEVELOPMENTAL ABNORMALITIES.

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SO THERE IS SOMETHING ABOUT

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PATHOGENESIS THAT WE'RE MISSING

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AND WHAT IS THAT?

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WE'RE ALSO MISSING A

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COMPREHENSIVE DEFINITION OF THE

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BIOLOGICAL STATE OR STATES OF

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UNDER NUTRITION.

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THE TYPICAL WAY OF DEFINING

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UNDER NUTRITION IS THROUGH THE

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USE OF ANTHROPOMETRY.

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THE MEASUREMENT AND THE

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REFERENCING OF THOSE VALUES FOR

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AN INDIVIDUAL TO A MULTI-NATURAL

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BIRTH COHORT ASSEMBLED BY THE

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WORLD HEALTH ORGANIZATION.

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AND THE DEFINITION OF DEVIANTS

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FROM NORMAL BASED ON THE NUMBER

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OF NORMAL DEVIATIONS AN

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INDIVIDUAL IS FROM HEALTHY

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INDIVIDUALS IN THIS COHORT.

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SO WE CAN DEFINE STUNTING AS A

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LENGTH FOR AGE SCORE THAT IS A

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CERTAIN NUMBER OF STANDARD

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DEVIATIONS.

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MODERATE STUNTING TO THE

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DEVIATIONS BELOW THE MEDIAN FOR

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THIS HEALTHY COHORT.

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WASTING OR IMPAIRED GROWTH AS A

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DEVIATION FROM NORMAL OF WEIGHT

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FOR LENGTH OR HEIGHT.

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MODERATE WASTING TWO TO THREE

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STANDARD DEVIATIONS BELOW.

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SEVERE WASTING A WLZ SCORE THAT

265
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IS MORE THAN THREE STANDARD

266
00:12:24,200 --> 00:12:25,600
DEVIATIONS AWAY FROM NORMAL.

267
00:12:25,600 --> 00:12:28,400
BUT WHO WOULD DEFINE DISEASES

268
00:12:28,400 --> 00:12:32,000
LIKE CANCER OR CARDIOVASCULAR

269
00:12:32,000 --> 00:12:34,360
IMPAIRMENT AS MODERATOR SEVERE?

270
00:12:34,360 --> 00:12:36,800
WE NEED A MUCH MORE

271
00:12:36,800 --> 00:12:38,920
COMPREHENSIVE DEFINITION OF THIS

272
00:12:38,920 --> 00:12:40,520
STATE OF IMPAIRED GROWTH.

273
00:12:40,520 --> 00:12:42,600
AND YOU'LL SEE WHY THIS IS

274
00:12:42,600 --> 00:12:43,640
PARTICULARLY IMPORTANT WHEN IT

275
00:12:43,640 --> 00:12:46,200
COMES TO CONNECTING THE

276
00:12:46,200 --> 00:12:49,080
MICROBIOME TO THE DISEASE

277
00:12:49,080 --> 00:12:50,720
PATHOGENESIS.

278
00:12:50,720 --> 00:12:56,800
SO WHAT ARE THE HYPOTHESIS THAT

279
00:12:56,800 --> 00:13:02,000
OUR GROUP -- IS PURSUING?

280
00:13:02,000 --> 00:13:05,840
THE HYPOTHESIS IS THERE IS A

281
00:13:05,840 --> 00:13:07,680
DEFINAL NORMAL.

282
00:13:07,680 --> 00:13:12,320
IT HAS A CHARACTERISTIC PROGRAM

283
00:13:12,320 --> 00:13:14,040
OF ASSEMBLY THAT BEGINS AT

284
00:13:14,040 --> 00:13:16,000
BIRTH.

285
00:13:16,000 --> 00:13:18,320
AND THE DISRUPTION OF THIS

286
00:13:18,320 --> 00:13:20,560
DEVELOPMENTAL PROCESS AFFECTING

287
00:13:20,560 --> 00:13:24,080
AN ORGAN -- IS CAUSALLY RELATED

288
00:13:24,080 --> 00:13:25,560
TO UNDER NUTRITION.

289
00:13:25,560 --> 00:13:28,560
NOW A COROLLARY IS THAT HEALTHY

290
00:13:28,560 --> 00:13:30,640
GROWTH OF INFANTS AND CHILDREN

291
00:13:30,640 --> 00:13:32,840
IS LINKED TO HEALTHY DEVELOPMENT

292
00:13:32,840 --> 00:13:35,400
OF THE GUT MICROBIOME.

293
00:13:35,400 --> 00:13:38,920
THERE HAS TO BE A CO-DEVELOPMENT

294
00:13:38,920 --> 00:13:41,920
OF THIS COMMUNITY AND THE HOST.

295
00:13:41,920 --> 00:13:44,800
SO I'M GOING TO TAKE YOU ON A

296
00:13:44,800 --> 00:13:46,880
MULTI-STEP JOURNEY THAT

297
00:13:46,880 --> 00:13:51,200
DR. ARIAS HAS ELUDED TO IN HIS

298
00:13:51,200 --> 00:13:52,640
IN INTRODUCTORY COMMENTS.

299
00:13:52,640 --> 00:14:02,280
A JOURNEY THAT IS 'EM
EMBLEMATIC.

300
00:14:02,280 --> 00:14:04,840
THE FIRST IS TO DEFINE THE

301
00:14:04,840 --> 00:14:07,840
DEFINITION OF NORMAL.

302
00:14:07,840 --> 00:14:11,920
THE SECOND STEP IS DEVELOP A

303
00:14:11,920 --> 00:14:14,160
METRIC FOR QUANTIFYING

304
00:14:14,160 --> 00:14:15,720
DEVIATIONS FROM NORMAL AND

305
00:14:15,720 --> 00:14:17,720
DETERMINING WHETHER THOSE

306
00:14:17,720 --> 00:14:19,760
DEVIATIONS CORRELATE IN A

307
00:14:19,760 --> 00:14:20,640
STATISTICALLY SIGNIFICANT

308
00:14:20,640 --> 00:14:22,960
FASHION WITH DISEASE AND DISEASE

309
00:14:22,960 --> 00:14:26,600
SEVERITY.

310
00:14:26,600 --> 00:14:30,720
THE THIRD STEP IS TO DETERMINE

311
00:14:30,720 --> 00:14:33,240
IF DEVIATION FROM NORMAL DO

312
00:14:33,240 --> 00:14:36,440
CORRELATE WHETHER THEY ARE

313
00:14:36,440 --> 00:14:39,760
SIMPLY AN EFFECT OR PERHAPS A

314
00:14:39,760 --> 00:14:41,600
CAUSE OF DISEASE.

315
00:14:41,600 --> 00:14:44,680
THE NEXT STEP IS IDENTIFYING

316
00:14:44,680 --> 00:14:54,000
THERAPEUTIC TARGETS WITHIN A MY
-- A

317
00:14:54,000 --> 00:14:55,360
MICROBIAL COMMUNITY AND THEN

318
00:14:55,360 --> 00:14:56,800
DEVELOPING THERAPEUTIC

319
00:14:56,800 --> 00:14:58,840
INTERVENTIONS THAT ARE NOT

320
00:14:58,840 --> 00:15:01,720
ORIGINAL EFFICACIOUS IN A GIVEN

321
00:15:01,720 --> 00:15:05,160
POPULATION BUT THAT ARE SAFE,

322
00:15:05,160 --> 00:15:07,160
DURABLE AND GENERALIZABLE.

323
00:15:07,160 --> 00:15:09,960
AND CULTURALLY ACCEPTABLE AND

324
00:15:09,960 --> 00:15:10,520
AFFORDABLE.

325
00:15:10,520 --> 00:15:12,880
SO I'M GOING TO TAKE YOU ON THIS

326
00:15:12,880 --> 00:15:15,200
JOURNEY THAT WE HAVE BEEN

327
00:15:15,200 --> 00:15:19,760
PURSUING AND WE WILL BEGIN IN AN

328
00:15:19,760 --> 00:15:23,680
URBAN SLUM LOCATED IN THE

329
00:15:23,680 --> 00:15:26,400
CAPITAL OF BANGLADESH.

330
00:15:26,400 --> 00:15:29,920
THE POPULATION DENSITY IS

331
00:15:29,920 --> 00:15:30,520
REMARKABLE.

332
00:15:30,520 --> 00:15:33,400
A HALF A MILLION PEOPLE LIVING

333
00:15:33,400 --> 00:15:35,800
WITHIN TWO AND A HALF SQUARE

334
00:15:35,800 --> 00:15:36,880
MILE AREA.

335
00:15:36,880 --> 00:15:40,600
POPULATION DENSITY OF 77,000 PER

336
00:15:40,600 --> 00:15:42,760
SQUARE KILOMETER AND THE

337
00:15:42,760 --> 00:15:44,960
DEFINITION OF NORMAL WAS PURSUED

338
00:15:44,960 --> 00:15:47,960
IN A BIRTH COHORT WHERE

339
00:15:47,960 --> 00:15:50,400
INDIVIDUALS WERE ENROLLED AT

340
00:15:50,400 --> 00:15:52,800
BIRTH REFLECTING THE DEEP TRUST

341
00:15:52,800 --> 00:15:55,040
AND COMMITMENT OF MOTHERS AND

342
00:15:55,040 --> 00:15:57,840
FAMILIES FOR THE HEALTH OF THEIR

343
00:15:57,840 --> 00:16:01,720
OFFSPRING AS WELL AS THE DEEP

344
00:16:01,720 --> 00:16:03,480
TRUST AND RESPECT THAT THEY HAD

345
00:16:03,480 --> 00:16:06,160
FOR THE HEALTH CARE PROVIDERS

346
00:16:06,160 --> 00:16:08,920
THAT THEY'VE BEEN INTERACTING

347
00:16:08,920 --> 00:16:12,320
WITH SO THAT LONGITUDINAL

348
00:16:12,320 --> 00:16:14,320
STUDIES CAN BE PERFORMED.

349
00:16:14,320 --> 00:16:17,840
THEY'VE FORGED THAT LEVEL OF

350
00:16:17,840 --> 00:16:20,720
TRUST, RESPECT AND DEVOTION OVER

351
00:16:20,720 --> 00:16:22,600
THE COURSE OF THE LAST FOUR

352
00:16:22,600 --> 00:16:23,200
DECADES.

353
00:16:23,200 --> 00:16:25,640
MEMBERS OF THIS BIRTH COHORT

354
00:16:25,640 --> 00:16:27,320
WERE FOLLOWED MONTHLY INITIALLY

355
00:16:27,320 --> 00:16:30,800
FOR THE FIRST 24 MONTHS OF

356
00:16:30,800 --> 00:16:33,600
POSTNATAL LIFE AND THROUGH THE

357
00:16:33,600 --> 00:16:36,440
FIRST 60 MONTHS WITH MONTHLY

358
00:16:36,440 --> 00:16:43,600
SAMPLING OF THE FECAL MICRO

359
00:16:43,600 --> 00:16:44,400
BIOTA.

360
00:16:44,400 --> 00:16:48,600
DATA WAS ACCUMULATED AND THE

361
00:16:48,600 --> 00:16:51,480
INITIAL FOCUS WAS ON THE INFANTS

362
00:16:51,480 --> 00:16:58,360
AND CHILDREN THAT HAVE NORMAL

363
00:16:58,360 --> 00:16:59,680
SNTHROPOMY.

364
00:16:59,680 --> 00:17:03,600
* AND THEN THE APPLICATION OF

365
00:17:03,600 --> 00:17:06,440
CULTURE INDEPENDENT METHODS THAT

366
00:17:06,440 --> 00:17:08,200
DR. ARIAS HAD DESCRIBED USING

367
00:17:08,200 --> 00:17:15,120
THE BACTERIAL 16S GENE AS A BAR

368
00:17:15,120 --> 00:17:18,560
CODE OF LIFE OF BACTERIAL LIFE

369
00:17:18,560 --> 00:17:22,160
AND CLASSIFYING ORGANISM BASED

370
00:17:22,160 --> 00:17:25,280
ON THE 16S SEQUENCE.

371
00:17:25,280 --> 00:17:29,440
FROM HEALTHY MEMBERS LIVING IN

372
00:17:29,440 --> 00:17:35,000
THIS URBAN SLUM A MICROBIAL

373
00:17:35,000 --> 00:17:37,520
PICTURE OF NORMAL COMMUNITY

374
00:17:37,520 --> 00:17:39,760
DEVELOPMENT EMERGED AND IN ONE

375
00:17:39,760 --> 00:17:44,080
ITERATION OF THIS PICTURE SHOWN

376
00:17:44,080 --> 00:17:47,000
HERE YOU CAN SEE THE COLUMNS AS

377
00:17:47,000 --> 00:17:48,440
AGE BINS.

378
00:17:48,440 --> 00:17:52,560
THE ROWS AT DIFFERENT BACTERIAL

379
00:17:52,560 --> 00:17:55,320
-- AND THE COLORS INDICATING THE

380
00:17:55,320 --> 00:18:00,480
RELATIVE ABUNDANCES OF THESE AT

381
00:18:00,480 --> 00:18:03,040
A TIME AFTERBIRTH AND YOU CAN

382
00:18:03,040 --> 00:18:06,360
SEE IN THE LEFT LOWER QUADRANT

383
00:18:06,360 --> 00:18:09,560
AND GROUP OF ORGANISMS THAT ARE

384
00:18:09,560 --> 00:18:10,600
PROMINENTLY REPRESENTED IN THE

385
00:18:10,600 --> 00:18:13,320
FIRST SEVERAL MONTHS OF

386
00:18:13,320 --> 00:18:16,720
POSTNATAL LIFE AND THOSE THAT

387
00:18:16,720 --> 00:18:19,400
BECOME MORE PROMINENT LATER ON.

388
00:18:19,400 --> 00:18:21,200
THIS IS THE RESULT OF THE

389
00:18:21,200 --> 00:18:24,760
FIVE-YEAR ANALYSIS.

390
00:18:24,760 --> 00:18:27,160
AND THIS GIVES YOU AN IDEA OF

391
00:18:27,160 --> 00:18:28,720
WHAT PARTS OF THERE AND WHAT

392
00:18:28,720 --> 00:18:32,080
PARTS MIGHT BE SHARED BY MEMBERS

393
00:18:32,080 --> 00:18:36,600
OF THE MICROBIAL COMMUNITY.

394
00:18:36,600 --> 00:18:38,600
BUT THEY FAILED TO ADDRESS A

395
00:18:38,600 --> 00:18:40,360
FUNDAMENTAL ASPECT THAT WE NEED

396
00:18:40,360 --> 00:18:42,480
TO UNDERSTAND ABOUT THE GUT.

397
00:18:42,480 --> 00:18:45,360
AND THAT HAS TO DO WITH THE

398
00:18:45,360 --> 00:18:47,760
ORGANIZATION AND ITS DYNAMISM.

399
00:18:47,760 --> 00:18:51,800
WE NEED FOR GO BEYOND A SIMPLE

400
00:18:51,800 --> 00:19:06,000
LIST OF PARTS.

401
00:19:06,000 --> 00:19:11,400
-- SO WE NEED TO IDENTIFY A

402
00:19:11,400 --> 00:19:14,280
SMALLER NUMBER OF INTERACTING

403
00:19:14,280 --> 00:19:18,200
COMPONENTS THAT DESCRIBE NORMAL

404
00:19:18,200 --> 00:19:19,160
MICROBIAL COMMUNITY DEVELOPMENT

405
00:19:19,160 --> 00:19:21,040
IN HEALTHY INDIVIDUALS.

406
00:19:21,040 --> 00:19:22,080
WHY JEFF ARE YOU DESCRIBING 

407
00:19:22,080 --> 00:19:24,280
THIS NEED FOR LOOKING AT

408
00:19:24,280 --> 00:19:25,680
INTERACTIONS?

409
00:19:25,680 --> 00:19:27,720
I'LL TRY TO PAINT A PICTURE.

410
00:19:27,720 --> 00:19:31,000
BY GOING TO MACRO ECOSYSTEMS AND

411
00:19:31,000 --> 00:19:33,040
EVEN HUMAN BEHAVIORS.

412
00:19:33,040 --> 00:19:36,480
IMAGINE IF YOU ONLY FOCUSED ON

413
00:19:36,480 --> 00:19:38,400
INDIVIDUAL FISH AND DISCARDED

414
00:19:38,400 --> 00:19:40,280
ANY CONSIDERATION OF

415
00:19:40,280 --> 00:19:41,080
INTERACTIONS YOU WOULD NEVER

416
00:19:41,080 --> 00:19:43,400
APPRECIATE THE CONCEPT OF FISH

417
00:19:43,400 --> 00:19:45,120
SCHOOLING.

418
00:19:45,120 --> 00:19:46,360
SIMILARLY YOU WOULD NEVER BE

419
00:19:46,360 --> 00:19:51,640
ABLE TO APPRECIATE THE DYNAMISM

420
00:19:51,640 --> 00:19:55,960
OF BIRTH AND FLIGHTS OR ANTS

421
00:19:55,960 --> 00:19:56,560
FORAGING.

422
00:19:56,560 --> 00:19:58,960
SO HOW DO WE DO FEATURE

423
00:19:58,960 --> 00:20:01,840
SELECTION AND IDENTIFY A SMALLER

424
00:20:01,840 --> 00:20:05,480
NUMBER OF PARTS INTERACTING

425
00:20:05,480 --> 00:20:11,000
PARTS IN THE GUT MICRO BIOTA.

426
00:20:11,000 --> 00:20:13,800
NOR THAT PURPOSE WE TURN TO THE

427
00:20:13,800 --> 00:20:17,000
STOCK MARKET AND A FIELD KNOWN

428
00:20:17,000 --> 00:20:19,360
AS ECONO PHYSICS WHERE

429
00:20:19,360 --> 00:20:23,440
INDIVIDUALS STARTED TO USE

430
00:20:23,440 --> 00:20:25,800
STATISTICAL METHODS TO LOOK AT

431
00:20:25,800 --> 00:20:29,320
VARYING PRICES OF STOCKS TO

432
00:20:29,320 --> 00:20:31,480
UNDER THE DIFFERENT ECONOMIC

433
00:20:31,480 --> 00:20:33,600
SECTORS AND THE BEHAVIOR OF THE

434
00:20:33,600 --> 00:20:35,000
STOCK MARKET.

435
00:20:35,000 --> 00:20:38,520
AND A VERY TALENTED POSTDOC IN

436
00:20:38,520 --> 00:20:40,840
THE LAB APPLIED THE PRINCIPLES

437
00:20:40,840 --> 00:20:44,400
AND METHODS OF ECONO PHYSICS TO

438
00:20:44,400 --> 00:20:48,200
IDENTIFY A SMALL GROUP OF 15

439
00:20:48,200 --> 00:20:50,000
CO-VARYING GUT BACTERIAL STRAINS

440
00:20:50,000 --> 00:20:54,040
THAT DESCRIBED IN THIS HEALTHY

441
00:20:54,040 --> 00:20:56,240
COHORT OF INFANTS AND CHILDREN

442
00:20:56,240 --> 00:20:59,840
LIVING IN THE URBAN SLUM, NORMAL

443
00:20:59,840 --> 00:21:00,800
COMMUNITY DEVELOPMENT.

444
00:21:00,800 --> 00:21:04,400
AND THIS NETWORK OF CO-VARYING

445
00:21:04,400 --> 00:21:12,440
-- ARE DESCRIBED HERE IN THIS

446
00:21:12,440 --> 00:21:14,280
DIAGRAM HERE AND THE GREEN

447
00:21:14,280 --> 00:21:17,600
MEMBERS ARE COMPONENTS OF THIS

448
00:21:17,600 --> 00:21:19,600
NETWORK WHICH ARE TERMED AN ECO

449
00:21:19,600 --> 00:21:21,040
GROUP.

450
00:21:21,040 --> 00:21:23,280
FROM THIS ANALYSIS AS WELL AS

451
00:21:23,280 --> 00:21:26,600
FROM OTHER TYPES OF ANALYSIS WE

452
00:21:26,600 --> 00:21:28,440
WERE ABLE TO DETERMINE THIS

453
00:21:28,440 --> 00:21:30,600
PROGRAM OF COMMUNITY ASSEMBLY IN

454
00:21:30,600 --> 00:21:32,160
HEALTHY INDIVIDUALS IS LARGELY

455
00:21:32,160 --> 00:21:33,800
COMPLETE BY THE END OF THE

456
00:21:33,800 --> 00:21:35,960
SECOND POSTNATAL YEAR.

457
00:21:35,960 --> 00:21:41,440
WE ALSO DISCOVERED -- IN THE

458
00:21:41,440 --> 00:21:43,160
INITIAL ANALYSIS THAT THESE ARE

459
00:21:43,160 --> 00:21:45,680
ALSO REPRESENTED IN THE

460
00:21:45,680 --> 00:21:49,400
DEVELOPING GUT MY CREEPIAL

461
00:21:49,400 --> 00:21:52,760
COMMUNITIES OF BIRTH * COHORTS

462
00:21:52,760 --> 00:21:54,800
LIVING IN OTHER LOW-INCOME

463
00:21:54,800 --> 00:21:55,680
COUNTRIES.

464
00:21:55,680 --> 00:21:56,640
SO THERE IS SOMETHING ABOUT A

465
00:21:56,640 --> 00:21:58,040
SHARED FEATURE OF THIS

466
00:21:58,040 --> 00:22:08,920
DEFINITION OF NORMAL

467
00:22:08,920 --> 00:22:12,080
>> WE WERE ABLE TO DISCERN THAT

468
00:22:12,080 --> 00:22:13,520
CHILDREN HAD COMMUNITIES THAT

469
00:22:13,520 --> 00:22:15,400
LOOKED YOUNGER THAT THAN YOU

470
00:22:15,400 --> 00:22:17,400
WOULD EXPECT BASED ON THEIR

471
00:22:17,400 --> 00:22:19,480
CHRONOLOGICAL AGE.

472
00:22:19,480 --> 00:22:25,880
THIS CAN BE VIEWED AS MIKE CROW

473
00:22:25,880 --> 00:22:44,320
BIOTA IN MATURITY.

474
00:22:44,320 --> 00:22:49,160
AND CRITICALLY THIS IMMATURITY

475
00:22:49,160 --> 00:22:52,000
WAS NOT REPAIRED WITH CURRENT

476
00:22:52,000 --> 00:22:53,480
THERAPEUTIC FOODS.

477
00:22:53,480 --> 00:22:55,400
THAT IS THE RESULT OF SEVERAL

478
00:22:55,400 --> 00:23:00,280
HUMAN STUDIES DONE WITH OUR

479
00:23:00,280 --> 00:23:00,800
COLLEAGUES.

480
00:23:00,800 --> 00:23:03,240
BUT PERHAPS THIS IS NOT

481
00:23:03,240 --> 00:23:05,000
SURPRISING BECAUSE CURRENT FOOD

482
00:23:05,000 --> 00:23:08,880
BASED INTERVENTIONS FOR

483
00:23:08,880 --> 00:23:10,800
CHILDHOOD UNDER NUTRITION HAVE

484
00:23:10,800 --> 00:23:12,160
NOT BEEN DEVELOPED WITH

485
00:23:12,160 --> 00:23:13,600
KNOWLEDGE OF OR CONSIDERATION OF

486
00:23:13,600 --> 00:23:20,120
THE DEVELOPMENTAL BIOLOGY OF THE

487
00:23:20,120 --> 00:23:21,400
MICROBIOTA.

488
00:23:21,400 --> 00:23:26,960
THESE THEY WERE LEFT WITH AN

489
00:23:26,960 --> 00:23:27,440
ABNORMALITY.

490
00:23:27,440 --> 00:23:31,600
AND WE WONDERED WHETHER THERE IS

491
00:23:31,600 --> 00:23:33,560
SOMETHING THAT WE COULD DO ABOUT

492
00:23:33,560 --> 00:23:36,960
THIS BUT BEFORE WE PROCEEDED WE

493
00:23:36,960 --> 00:23:39,400
LISTENED TO THE WORDS OF

494
00:23:39,400 --> 00:23:41,080
DR. ARIAS AND TRIED TO CAPTURE

495
00:23:41,080 --> 00:23:46,000
THIS CONCEPT OF CAN WE PERFORM A

496
00:23:46,000 --> 00:23:52,400
TEST THAT DISTINGUISHES BETWEEN

497
00:23:52,400 --> 00:23:53,880
EFFECT OR CAUSE.

498
00:23:53,880 --> 00:23:56,960
THERE IS A STUDENT -- TOGETHER

499
00:23:56,960 --> 00:23:59,880
WITH MARIA CARLSON AND DAVE

500
00:23:59,880 --> 00:24:01,240
O'DONALD WHO ESTABLISHED OUR

501
00:24:01,240 --> 00:24:02,720
FACILITY HERE AT WASHINGTON

502
00:24:02,720 --> 00:24:05,520
UNIVERSITY IN 1996.

503
00:24:05,520 --> 00:24:10,440
DID A SERIES OF MICROBIOTA

504
00:24:10,440 --> 00:24:12,120
TRANSPLANT EXPERIMENTS.

505
00:24:12,120 --> 00:24:15,680
A GROUP OF HEALTHY INDIVIDUALS

506
00:24:15,680 --> 00:24:18,000
AND THOSE THAT HAD UNDER

507
00:24:18,000 --> 00:24:21,080
NUTRITION AS DEFINED PROVIDED

508
00:24:21,080 --> 00:24:22,400
FECAL SAMPLES.

509
00:24:22,400 --> 00:24:26,120
THOSE SAMPLES WERE PRESERVED

510
00:24:26,120 --> 00:24:28,200
IMMEDIATELY AFTER THEY WERE

511
00:24:28,200 --> 00:24:31,960
PROVIDED AND THEY REPRESENTED A

512
00:24:31,960 --> 00:24:39,200
SNAPSHOT OF THE MICROBIAL .

513
00:24:39,200 --> 00:24:42,360
THEY WERE INTRODUCED INTO THE

514
00:24:42,360 --> 00:24:43,960
INTESTINES OF YOUNG GERMFREE

515
00:24:43,960 --> 00:24:44,320
ANIMALS.

516
00:24:44,320 --> 00:24:48,800
SO BASICALLY SEVERAL ANIMALS

517
00:24:48,800 --> 00:24:56,960
RECEIVED MICR MICRO BUY ON MIKE
-- MICRO B
IOTA AND

518
00:24:56,960 --> 00:25:00,640
THE TEST CONSIST OF TAKING THE

519
00:25:00,640 --> 00:25:04,760
SNAPSHOT AND REPLICATING THE

520
00:25:04,760 --> 00:25:07,520
SNAPSHOT OF MICROBIAL LIFE AND

521
00:25:07,520 --> 00:25:11,400
CONVERTING IT TO A MOVIE SO WE

522
00:25:11,400 --> 00:25:14,680
COULD FOLLOW OVER TIME THE

523
00:25:14,680 --> 00:25:15,960
EFFECTS OF THE COMMUNITIES ON

524
00:25:15,960 --> 00:25:21,800
THE BIOLOGICAL PROPERTIES,

525
00:25:21,800 --> 00:25:24,080
PHYSIOLOGY, METABOLISM AND

526
00:25:24,080 --> 00:25:25,400
IMMUNE SYSTEM OF THE ANIMALS.

527
00:25:25,400 --> 00:25:28,000
THE ANIMALS WERE GIVEN DIETS

528
00:25:28,000 --> 00:25:29,280
THAT REPRESENTED THE DIETS OF

529
00:25:29,280 --> 00:25:30,640
THE HUMAN DONOR.

530
00:25:30,640 --> 00:25:35,000
IT WAS TYPICAL OF CHILDREN

531
00:25:35,000 --> 00:25:41,600
LIVING IN THE SLUM.

532
00:25:41,600 --> 00:25:49,680
SO WE COUL -- SO WE COULD ASK
THE

533
00:25:49,680 --> 00:25:50,160
QUESTION.

534
00:25:50,160 --> 00:25:53,040
HOW MANY OF THE PHENOTYPES COULD

535
00:25:53,040 --> 00:25:55,840
BE TRANSPLANT TO RECIPIENT

536
00:25:55,840 --> 00:25:58,800
ANIMALS AND THE ANSWER WAS MANY.

537
00:25:58,800 --> 00:26:01,800
SO USING QUANTITATIVE MAGNETIC

538
00:26:01,800 --> 00:26:05,000
RESONANCE TO DEFINE BODY

539
00:26:05,000 --> 00:26:06,800
COMPOSITION.

540
00:26:06,800 --> 00:26:12,120
USING MICRO COMPUTED TOPOGRAPHY,

541
00:26:12,120 --> 00:26:15,440
USING TARGETED MASS SPECTORMETRY

542
00:26:15,440 --> 00:26:18,080
AND USING A VARIETY OF

543
00:26:18,080 --> 00:26:20,000
APPROACHES INCLUDING FLOW TO

544
00:26:20,000 --> 00:26:21,360
CHARACTERIZE IMMUNE FUNCTION.

545
00:26:21,360 --> 00:26:23,840
IT WAS DETERMINED BY LAURA AND

546
00:26:23,840 --> 00:26:27,000
IN THIS FIRST SET OF EXPERIMENTS

547
00:26:27,000 --> 00:26:28,160
AND BY OF OTHERS IN THE

548
00:26:28,160 --> 00:26:29,800
LABORATORY THAT MANY FEATURES OF

549
00:26:29,800 --> 00:26:32,720
UNDER NUTRITION COULD BE

550
00:26:32,720 --> 00:26:37,400
TRANSPLANT TO THESE ANIMALS.

551
00:26:37,400 --> 00:26:41,680
LAURA TOOK ALL RECIPIENTS AND

552
00:26:41,680 --> 00:26:44,640
APPLIED MACHINE LEARNING

553
00:26:44,640 --> 00:26:48,280
ALGORITHMS TO IDENTIFY ORGANISMS

554
00:26:48,280 --> 00:26:50,200
WHO REPRESENTATION WAS

555
00:26:50,200 --> 00:26:51,520
SIGNIFICANTLY ASSOCIATED WITH

556
00:26:51,520 --> 00:26:54,440
DIFFERENT FACETS OF GROWTH SO

557
00:26:54,440 --> 00:26:56,920
SHE IDENTIFIED A SUBSET OF

558
00:26:56,920 --> 00:26:58,760
GROWTH DISCRIMINATORY STRAINS

559
00:26:58,760 --> 00:27:02,600
FROM THESE EXPERIMENTS AND THESE

560
00:27:02,600 --> 00:27:04,320
STRAINS INCLUDED STRAINS THAT

561
00:27:04,320 --> 00:27:06,600
WERE UNDER REPRESENTED AND UNDER

562
00:27:06,600 --> 00:27:11,760
PERFORMING IN MATURE MICRO BIOTA

563
00:27:11,760 --> 00:27:14,160
AND THEY BECAME OUR THERAPEUTIC

564
00:27:14,160 --> 00:27:15,960
TARGETS AND WE WERE FUNDED BY

565
00:27:15,960 --> 00:27:18,600
THE MELINDA AND BILL GATES

566
00:27:18,600 --> 00:27:20,080
FOUNDATION.

567
00:27:20,080 --> 00:27:23,400
USING THESE ANIMAL MODELS THAT

568
00:27:23,400 --> 00:27:25,400
PORTRAYED THE MICROBES OF THE

569
00:27:25,400 --> 00:27:27,480
VERY POPULATION THAT WE WANT TO

570
00:27:27,480 --> 00:27:29,160
CHEETAHS WELL AS THEIR DIETS BUT

571
00:27:29,160 --> 00:27:32,360
WE HAD TO DEVELOP AN

572
00:27:32,360 --> 00:27:34,760
INTERVENTION THAT WAS CULTURALLY

573
00:27:34,760 --> 00:27:36,560
ACCEPTABLE AND AFFORDABLE AND

574
00:27:36,560 --> 00:27:37,680
SCALABLE.

575
00:27:37,680 --> 00:27:40,360
SO WE SHALL NOT START BY

576
00:27:40,360 --> 00:27:43,200
BASICALLY CREATING A NEXT

577
00:27:43,200 --> 00:27:47,160
GENERATION CONSORTIUM OF AN A

578
00:27:47,160 --> 00:27:49,320
AEROBIC CULTURED BACTERIA WHICH

579
00:27:49,320 --> 00:27:51,160
WOULD BE DIFFICULT TO PRESERVE

580
00:27:51,160 --> 00:27:52,960
IN A COLD CHAIN AND THERE IS NOT

581
00:27:52,960 --> 00:27:56,600
A LOT OF TECHNOLOGY ABOUT HOW TO

582
00:27:56,600 --> 00:27:59,120
DO SO AND THIS WOULD BE

583
00:27:59,120 --> 00:28:01,640
EXTREMELY EXPENSIVE AS WELL AS

584
00:28:01,640 --> 00:28:04,080
FACING A VARIETY OF REGULATORY

585
00:28:04,080 --> 00:28:05,800
HURDLES THAT WOULD NOT BE FACED

586
00:28:05,800 --> 00:28:09,440
IF WE WERE TO TURN TO FOOD AS A

587
00:28:09,440 --> 00:28:12,200
PRINCIPLE AND FIRST CHOICE FOR

588
00:28:12,200 --> 00:28:14,840
REPAIRING THE GUT MICROBIAL

589
00:28:14,840 --> 00:28:17,200
COMMUNITIES OF THESE UNDER

590
00:28:17,200 --> 00:28:18,840
NOURISHED CHILDREN.

591
00:28:18,840 --> 00:28:22,240
SO A SECOND SERIES OF

592
00:28:22,240 --> 00:28:22,760
HYPOTHESIS.

593
00:28:22,760 --> 00:28:25,760
PERHAPS THE FOODS THAT ARE

594
00:28:25,760 --> 00:28:29,400
CONSUMED BETWEEN THE PERIOD OF

595
00:28:29,400 --> 00:28:33,520
EXCLUSIVE MILK CEASES AND THE

596
00:28:33,520 --> 00:28:34,800
CHILD IS FULLY WEANED.

597
00:28:34,800 --> 00:28:38,800
SOME OF THE FOODS MAY CONTAIN

598
00:28:38,800 --> 00:28:44,400
KEY NUTRIENTS THAT ARE COVETED

599
00:28:44,400 --> 00:28:46,080
BY THESE ORGANISMS.

600
00:28:46,080 --> 00:28:49,760
THESE FOODS BY DEFINITION ARE

601
00:28:49,760 --> 00:28:51,520
AVAILABLE AND CULTURALLY

602
00:28:51,520 --> 00:28:53,320
ACCEPTABLE BECAUSE THEY ARE THE

603
00:28:53,320 --> 00:28:54,640
FOODS THAT ARE GIVEN TO CHILDREN

604
00:28:54,640 --> 00:28:56,400
IN THIS AREA OF THE WORLD BUT

605
00:28:56,400 --> 00:29:00,560
THESE TYPES OF FOODS ALSO EMBODY

606
00:29:00,560 --> 00:29:02,200
THE CHOICE THAT EVERY FAMILY

607
00:29:02,200 --> 00:29:05,000
AROUND THE PLANET HAS TO MAKE.

608
00:29:05,000 --> 00:29:06,880
WHAT FOODS SHOULD I SELECT TO

609
00:29:06,880 --> 00:29:09,840
ENSURE THE HEALTHY GROWTH OF MY

610
00:29:09,840 --> 00:29:12,800
INFANT OR CHILD?

611
00:29:12,800 --> 00:29:19,240
SO IN APPROACHING THIS MINING

612
00:29:19,240 --> 00:29:20,720
EXPEDITION WE'RE APPROACHING

613
00:29:20,720 --> 00:29:22,720
THIS SET OF DECISIONS ABOUT HOW

614
00:29:22,720 --> 00:29:25,440
TO FEED OUR INFANTS AND

615
00:29:25,440 --> 00:29:26,560
CHILDREN.

616
00:29:26,560 --> 00:29:27,600
DECISIONS THAT ARE CURRENTLY

617
00:29:27,600 --> 00:29:29,840
BASED ON POLICIES THAT ARE NOT

618
00:29:29,840 --> 00:29:31,440
PREDICATED ON KNOWLEDGE OR

619
00:29:31,440 --> 00:29:32,240
CONSIDERATION OF THE

620
00:29:32,240 --> 00:29:37,720
DEVELOPMENTAL BIOLOGY OF THE

621
00:29:37,720 --> 00:29:40,400
MICROBIOTA.

622
00:29:40,400 --> 00:29:45,240
THE APPROACH IN CONCERT WITH A

623
00:29:45,240 --> 00:29:49,440
TALENTED POSTDOC A TALENTED

624
00:29:49,440 --> 00:29:51,640
PhD STUDENT, MIKE BARRETT A

625
00:29:51,640 --> 00:29:59,720
PERSON WHO OVERSAW OUR CLINICAL

626
00:29:59,720 --> 00:30:03,880
WORK HERE IN THE LABS AT

627
00:30:03,880 --> 00:30:04,880
WASHINGTON UNIVERSITY.

628
00:30:04,880 --> 00:30:07,720
-- CONDUCTED A SCREEN FOR THESE

629
00:30:07,720 --> 00:30:12,600
COMPLETE TREE FOOD INGREDIENTS.

630
00:30:12,600 --> 00:30:16,800
* AND TO INCORPORATE THESE INTO

631
00:30:16,800 --> 00:30:20,600
WHAT WE CALL PROTOTYPES THAT WE

632
00:30:20,600 --> 00:30:22,200
WOULD TEST.

633
00:30:22,200 --> 00:30:23,960
HERE IS OUR STRATEGY FOR

634
00:30:23,960 --> 00:30:25,000
TESTING.

635
00:30:25,000 --> 00:30:29,400
WE CULTURED ORGANISMS AND THE

636
00:30:29,400 --> 00:30:32,480
FECAL MICROBIOTA AND THESE WERE

637
00:30:32,480 --> 00:30:37,440
AGE AND GROWTH DISCRIMINATORY

638
00:30:37,440 --> 00:30:38,200
ORGANISMS.

639
00:30:38,200 --> 00:30:41,240
THEY WERE INTRODUCE INTO

640
00:30:41,240 --> 00:30:41,960
GERMFREE MICE.

641
00:30:41,960 --> 00:30:46,040
THEY WERE FED COMPLIMENTARY

642
00:30:46,040 --> 00:30:48,800
FOODS AVAILABLE TO CHILDREN

643
00:30:48,800 --> 00:30:50,800
LIVING THERE.

644
00:30:50,800 --> 00:30:53,080
AND THESE FOODS WERE TESTED

645
00:30:53,080 --> 00:30:55,040
INDIVIDUALLY AND IN VARIOUS

646
00:30:55,040 --> 00:30:56,600
COMBINATIONS TO IDENTIFY THOSE

647
00:30:56,600 --> 00:31:01,760
THAT WOULD INCREASE THE FITNESS

648
00:31:01,760 --> 00:31:04,680
OF OUR TARGET -- ORGANISMS.

649
00:31:04,680 --> 00:31:07,720
IF WE GOT A HIT WE WOULD

650
00:31:07,720 --> 00:31:10,280
PRIORITIZE THE HIT BASED ON THE

651
00:31:10,280 --> 00:31:14,000
SUSTAINABILITY, AFFORDABILITY

652
00:31:14,000 --> 00:31:18,560
AND THE TASTE AND TEXTURE AND

653
00:31:18,560 --> 00:31:26,800
SMELL.

654
00:31:26,800 --> 00:31:32,200
-- NOW AFTER THIS SCREEN WAS

655
00:31:32,200 --> 00:31:34,000
INITIATED AND THE LEADS WERE

656
00:31:34,000 --> 00:31:35,600
IDENTIFIED DEEPER ANALYSIS OF

657
00:31:35,600 --> 00:31:38,520
THE EFFECTS OF THE FORMULATIONS

658
00:31:38,520 --> 00:31:41,200
ON GENE EXPRESSION AMONG MEMBERS

659
00:31:41,200 --> 00:31:44,480
OF THE CONSORTIUM OF SEQUENCE

660
00:31:44,480 --> 00:31:50,080
GENOME SEQUENCE BACTERIA WAS

661
00:31:50,080 --> 00:31:53,560
AFFECTED.

662
00:31:53,560 --> 00:31:56,000
AND THEN PROMISING LEADS WERE

663
00:31:56,000 --> 00:31:58,720
ADVANCED TO A SECOND ROUND OF

664
00:31:58,720 --> 00:32:00,840
ANALYSIS AND THIS INVOLVED NOT A

665
00:32:00,840 --> 00:32:04,680
COLLECTION OF CULTURE SEQUENCE

666
00:32:04,680 --> 00:32:06,120
BACTERIAL STRAINS FROM THE

667
00:32:06,120 --> 00:32:09,560
CHILDREN BUT RATHER THE INTACT

668
00:32:09,560 --> 00:32:12,400
UNCULTURED BACTERIA OF CHILDREN

669
00:32:12,400 --> 00:32:14,400
WHO HAD BEEN TREATED WITHSTAND

670
00:32:14,400 --> 00:32:18,480
THERAPY BUT WHOSE MICRO BIOTA

671
00:32:18,480 --> 00:32:20,720
HAD NOT BEEN REPAIRED.

672
00:32:20,720 --> 00:32:24,680
SO COULD THESE REPAIR THE MICRO

673
00:32:24,680 --> 00:32:26,800
BIOTA THAT HAD BEEN INTRODUCED

674
00:32:26,800 --> 00:32:30,560
INTO THESE ANIMALS AND FOR THOSE

675
00:32:30,560 --> 00:32:33,640
COMBINATIONS THAT DID ADDITIONAL

676
00:32:33,640 --> 00:32:35,320
STUDIES WERE PERFORMED ABOUT HOW

677
00:32:35,320 --> 00:32:37,080
THE COMMUNITY RESPONDED AND HOW

678
00:32:37,080 --> 00:32:39,040
THE HOST RESPONDED AND A

679
00:32:39,040 --> 00:32:42,040
DECISION WAS MADE THAT I THINK

680
00:32:42,040 --> 00:32:43,520
EMBODIES SOME OF THE CHALLENGES

681
00:32:43,520 --> 00:32:44,400
IN THE FIELD.

682
00:32:44,400 --> 00:32:46,760
DO YOU DIRECTLY GO FROM MICE

683
00:32:46,760 --> 00:32:51,640
THAT EVEN THOUGH THEY PORTRAYAL

684
00:32:51,640 --> 00:32:55,080
THE MICROBES DON'T HAVE THE

685
00:32:55,080 --> 00:32:57,400
PROPERTIES THAT ARE AS CLOSE TO

686
00:32:57,400 --> 00:33:00,200
HUMANS AS CERTAIN OTHER ANIMALS.

687
00:33:00,200 --> 00:33:01,920
AND DO YOU CHOOSE A SECOND

688
00:33:01,920 --> 00:33:03,200
ANIMAL SPECIES AND THAT IS

689
00:33:03,200 --> 00:33:05,000
SOMETHING THAT WE DID.

690
00:33:05,000 --> 00:33:07,560
WE DEVELOPED METHODS FOR

691
00:33:07,560 --> 00:33:10,320
REDERIVING PIGS AT BIRTH AS

692
00:33:10,320 --> 00:33:12,880
GERMFREE AND MAINTAINING THEM IN

693
00:33:12,880 --> 00:33:15,840
A GERMFREE STATE AND INTRODUCED

694
00:33:15,840 --> 00:33:18,720
THESE CONSORTIA OF ORGANISMS AND

695
00:33:18,720 --> 00:33:20,800
LOOKED AT THE EFFECTS OF OUR

696
00:33:20,800 --> 00:33:22,200
LEADING CANDIDATES.

697
00:33:22,200 --> 00:33:24,520
SO THOSE CANDIDATES WERE THEN

698
00:33:24,520 --> 00:33:27,600
ADVANCED TO OUR FIRST PREPROOF

699
00:33:27,600 --> 00:33:29,560
OF CONCEPT STUDY.

700
00:33:29,560 --> 00:33:32,280
IT INVOLVED CHILDREN AGE 12-18

701
00:33:32,280 --> 00:33:36,560
MONTHS WITH WLZ SCORES OF MINUS

702
00:33:36,560 --> 00:33:38,120
2 TO MINUS 3.

703
00:33:38,120 --> 00:33:40,720
A SCORE ASSIGNED TO CHILDREN WHO

704
00:33:40,720 --> 00:33:43,600
HAVE MODERATOR ACUTE

705
00:33:43,600 --> 00:33:44,600
MALNUTRITION.

706
00:33:44,600 --> 00:33:46,200
THESE CHILDREN IN THIS SMALL

707
00:33:46,200 --> 00:33:49,480
STUDY OF 15 PER ARM RECEIVED ONE

708
00:33:49,480 --> 00:33:53,160
OF FOUR DIFFERENT FOODS.

709
00:33:53,160 --> 00:33:54,800
FOOD SUPPLEMENTS.

710
00:33:54,800 --> 00:33:58,440
A READY TO USE SUPPLEMENTAL

711
00:33:58,440 --> 00:34:02,440
FOOD, RICE AND LENTIL BASED.

712
00:34:02,440 --> 00:34:07,480
AND THEN WE HAD THE VARIOUS

713
00:34:07,480 --> 00:34:08,800
MBCF.

714
00:34:08,800 --> 00:34:10,600
ONE, TWO, AND THREE.

715
00:34:10,600 --> 00:34:14,800
THERE WAS A RUN IN PHASE FOR TWO

716
00:34:14,800 --> 00:34:17,000
WEEKS IN WHICH DATA WAS

717
00:34:17,000 --> 00:34:18,480
COLLECTED.

718
00:34:18,480 --> 00:34:22,800
FECAL SAMPLES WERE OBTAINED AND

719
00:34:22,800 --> 00:34:27,000
A BLOOD -- DRAW AT THE END OF

720
00:34:27,000 --> 00:34:28,800
THE SECOND WEEK.

721
00:34:28,800 --> 00:34:33,560
WE WANTED A MORE COMPREHENSIVE

722
00:34:33,560 --> 00:34:35,080
DEFINITION.

723
00:34:35,080 --> 00:34:38,680
AND WE COULD DO SO BECAUSE THERE

724
00:34:38,680 --> 00:34:42,120
IS A TECHNOLOGY WHICH ALLOWED

725
00:34:42,120 --> 00:34:44,640
MORE THAN 1300 DIFFERENT

726
00:34:44,640 --> 00:34:46,320
PROTEINS WHICH ARE BOTH

727
00:34:46,320 --> 00:34:50,280
BIOMARKERS AND MEDIATORS OF MANY

728
00:34:50,280 --> 00:34:53,960
ASPECTS OF HOST BIOLOGY TO BE

729
00:34:53,960 --> 00:34:56,440
QUANTIFIED.

730
00:34:56,440 --> 00:35:03,440
THE INTERVENTION -- EXCUSE ME.

731
00:35:03,440 --> 00:35:05,200
WE'RE ALMOST THERE.

732
00:35:05,200 --> 00:35:07,200
WE'RE GOING BACK IN TIME.

733
00:35:07,200 --> 00:35:11,320
THE INTERVENTION CONSIST OF TWO

734
00:35:11,320 --> 00:35:14,280
FEEDINGS EACH DAY UNDER

735
00:35:14,280 --> 00:35:16,960
SUPERVISION AND IN A UNIT

736
00:35:16,960 --> 00:35:18,840
ESTABLISHED BY OUR COLLEAGUES

737
00:35:18,840 --> 00:35:21,280
RIGHT IN THE MIDDLE OF THE URBAN

738
00:35:21,280 --> 00:35:23,000
SLUM AND THE DEVOTION TO THE

739
00:35:23,000 --> 00:35:25,280
MOTHERS OF THE CHILDREN IS

740
00:35:25,280 --> 00:35:27,200
EMBODIED BY THE FACT THAT THEY

741
00:35:27,200 --> 00:35:29,080
BROUGHT THE CHILDREN TWICE A DAY

742
00:35:29,080 --> 00:35:32,160
FOR THESE INTERVENTIONS.

743
00:35:32,160 --> 00:35:34,000
WHICH WERE PERFORMED UNDER

744
00:35:34,000 --> 00:35:36,000
SUPERVISION.

745
00:35:36,000 --> 00:35:39,440
THERE WAS A TWO WEEK FOLLOW-UP

746
00:35:39,440 --> 00:35:45,680
PERIOD OF OBSERVATION AFTER THE

747
00:35:45,680 --> 00:35:48,920
INTERVENTION AND THE OUTCOMES

748
00:35:48,920 --> 00:35:50,800
WERE WHAT ARE THE EFFECTS.

749
00:35:50,800 --> 00:35:53,160
WE DID NOT EXPECT GIVEN ONE

750
00:35:53,160 --> 00:35:54,400
MONTH AND SMALL NUMBER OF

751
00:35:54,400 --> 00:35:57,760
CHILDREN FOR US TO ACHIEVE A

752
00:35:57,760 --> 00:36:01,200
STATISTICALLY SIGNIFICANT EFFECT

753
00:36:01,200 --> 00:36:07,440
ON EITHER -- PONDERAL GROWTH OR

754
00:36:07,440 --> 00:36:08,560
LINEAR GROWTH.

755
00:36:08,560 --> 00:36:13,400
YOU CAN LOOK TO THE LOWER LEFT

756
00:36:13,400 --> 00:36:16,360
AND SEE THE DIFFERENT

757
00:36:16,360 --> 00:36:18,000
CONFIGURATIONS OF THE DIFFERENT

758
00:36:18,000 --> 00:36:19,040
GROUPS.

759
00:36:19,040 --> 00:36:22,800
AND THIS LOWER PORTION ARE

760
00:36:22,800 --> 00:36:25,640
CHILDREN WITH SEVERE ACUTE

761
00:36:25,640 --> 00:36:26,920
MALNUTRITION WHO ARE UNTREATED.

762
00:36:26,920 --> 00:36:30,040
THEY ARE 12-18 MONTHS OF AGE.

763
00:36:30,040 --> 00:36:33,480
HERE WE SEE FAR AWAY THE

764
00:36:33,480 --> 00:36:36,200
CONFIGURATION OF 12-18-MONTH-OLD

765
00:36:36,200 --> 00:36:37,600
HEALTHY CHILDREN.

766
00:36:37,600 --> 00:36:39,760
THESE CONFIGURATIONS ARE DEFINED

767
00:36:39,760 --> 00:36:41,640
BY THE REPRESENTATION OF THESE

768
00:36:41,640 --> 00:36:45,840
15 ECO GROUP TAXA THAT HAD BEEN

769
00:36:45,840 --> 00:36:48,040
IDENTIFIED AS CO-VARYING AND AS

770
00:36:48,040 --> 00:36:53,360
A WAY OF DEFINING THE MICRO

771
00:36:53,360 --> 00:36:54,800
BIOLOGY.

772
00:36:54,800 --> 00:36:56,960
THE CHILDREN THAT ARE UNTREATED

773
00:36:56,960 --> 00:36:59,360
ARE CLOSER TO HEALTHY THAN THOSE

774
00:36:59,360 --> 00:37:03,280
WHO HAD -- THAT WERE UNTREATED

775
00:37:03,280 --> 00:37:08,480
BUT OF ALL OF THE INTERVENTION

776
00:37:08,480 --> 00:37:11,360
-- THAT AFTER ONE MONTH THEIR

777
00:37:11,360 --> 00:37:12,920
EFFECTS ON THE CONFIGURATION

778
00:37:12,920 --> 00:37:14,800
WERE SIGNIFICANTLY LESS

779
00:37:14,800 --> 00:37:21,040
IMPRESSIVE THAN THE EFFECTS OF

780
00:37:21,040 --> 00:37:21,560
MCDF2.

781
00:37:21,560 --> 00:37:25,000
WHICH WAS THE BEST PERFORMING IN

782
00:37:25,000 --> 00:37:27,320
THE MOUSE AND THE PIGLET.

783
00:37:27,320 --> 00:37:30,680
NOT ONLY WAS THERE REPAIR BUT

784
00:37:30,680 --> 00:37:34,560
ALSO A DRAMATIC EFFECT ON THE

785
00:37:34,560 --> 00:37:36,480
PLASMA PROCEED YUM.

786
00:37:36,480 --> 00:37:37,080
*.

787
00:37:37,080 --> 00:37:39,840
YOU SEE A GROUP OF 50 PROTEINS

788
00:37:39,840 --> 00:37:43,040
THAT WERE IDENTIFIED FROM THIS

789
00:37:43,040 --> 00:37:46,800
-- ANALYSIS OF THE PLASMA --

790
00:37:46,800 --> 00:37:48,680
PROCEED YUM OF HEALTHY CHILDREN

791
00:37:48,680 --> 00:37:51,760
AND UNTREATED CHILDREN AS MOST

792
00:37:51,760 --> 00:37:53,200
DISCRIMINATORY FOR A HEALTHY

793
00:37:53,200 --> 00:37:55,320
STATE AND THE COLORS INDICATE

794
00:37:55,320 --> 00:37:56,720
THE CHANGE IN THE LEVELS OF THE

795
00:37:56,720 --> 00:37:59,120
PROTEIN AS A FUNCTION OF

796
00:37:59,120 --> 00:38:00,400
DIFFERENT TREATMENT.

797
00:38:00,400 --> 00:38:04,160
SO THE LEVELS, THE TREATMENT

798
00:38:04,160 --> 00:38:07,600
EFFECTS IS NORMALIZED AND

799
00:38:07,600 --> 00:38:09,400
MOVEMENT TOWARD RED INDICATES

800
00:38:09,400 --> 00:38:10,920
MOVEMENT TOWARDS A MORE HEALTHY

801
00:38:10,920 --> 00:38:13,400
LEVEL OF THIS PROTEIN.

802
00:38:13,400 --> 00:38:17,800
M DCF 2 ASSUMING YOU'RE NOT RED

803
00:38:17,800 --> 00:38:21,680
GREEN COLOR-BLIND IS ASSOCIATED

804
00:38:21,680 --> 00:38:24,520
WITH THIS DRAMATIC CHANGE.

805
00:38:24,520 --> 00:38:32,200
THAT HELTHATREPRESENT.

806
00:38:32,200 --> 00:38:34,760
THEY ARE MEDIATORS OF BONE

807
00:38:34,760 --> 00:38:37,400
GROWTH, METABOLISM, IMMUNE

808
00:38:37,400 --> 00:38:42,120
FUNCTION AND NEURO DEVELOPMENT.

809
00:38:42,120 --> 00:38:44,960
SO WITH THIS STUDY IN HAND A

810
00:38:44,960 --> 00:38:48,000
SECOND PROOF OF CONCEPT STUDY

811
00:38:48,000 --> 00:38:53,720
WAS PERFORMED WITH M DCF 2 AND

812
00:38:53,720 --> 00:38:54,040
RUSF.

813
00:38:54,040 --> 00:39:00,360
YOU CAN SEE THE COMPLIMENTARY

814
00:39:00,360 --> 00:39:12,000
FOODS -- AND YOU CAN ALSO SEE

815
00:39:12,000 --> 00:39:16,080
THAT THERE IS NUTRIENT

816
00:39:16,080 --> 00:39:18,280
MICRONUTRIENTS IN BOTH THAT THE

817
00:39:18,280 --> 00:39:19,720
PROTEIN ENERGY AND FAT ENERGY

818
00:39:19,720 --> 00:39:23,840
RATIO AND THE AMOUNT OF CORE BOW

819
00:39:23,840 --> 00:39:28,920
HYDRANTS ARE -- AND THE CALORIC

820
00:39:28,920 --> 00:39:32,280
DENSITY IS 15% LESS.

821
00:39:32,280 --> 00:39:36,280
SO AS IN THE * STUDY THE POC

822
00:39:36,280 --> 00:39:39,320
STUDY WAS PERFORMED WHERE UNDER

823
00:39:39,320 --> 00:39:41,320
SUPERVISION TWO SERVINGS

824
00:39:41,320 --> 00:39:47,280
25 GRAMS EACH WAS GIVEN PER DAY.

825
00:39:47,280 --> 00:39:49,000
NOW HERE IS THE DESIGN OF THE

826
00:39:49,000 --> 00:39:50,440
STUDY.

827
00:39:50,440 --> 00:39:51,800
A LONGER STUDY.

828
00:39:51,800 --> 00:39:53,400
THREE MONTHS.

829
00:39:53,400 --> 00:39:55,960
INITIALLY TWICE A DAY

830
00:39:55,960 --> 00:40:02,680
ADMINISTRATION OF EITHER M DCF 2

831
00:40:02,680 --> 00:40:06,080
OR RUSF.

832
00:40:06,080 --> 00:40:08,960
AND THE THIRD MONTH TWICE A DAY

833
00:40:08,960 --> 00:40:13,760
AT HOME UNDER SUPERVISION.

834
00:40:13,760 --> 00:40:15,680
12-18-MONTH-OLD CHILDREN WITH

835
00:40:15,680 --> 00:40:18,600
MODERATE ACUTE MALNUTRITION.

836
00:40:18,600 --> 00:40:20,960
THE OUTCOME MEASURES IS A CHANGE

837
00:40:20,960 --> 00:40:25,800
IN WLZ AND A SECOND OUTCOME

838
00:40:25,800 --> 00:40:28,000
MEASURE IS THE REPAIR OF THE

839
00:40:28,000 --> 00:40:31,760
MICRO BIOTA AND ALTERATIONS IN

840
00:40:31,760 --> 00:40:38,120
THE PLASMA -- AND WE'LL PRESENT

841
00:40:38,120 --> 00:40:43,600
THE RESULTS IN THE NEXT SLIDE.

842
00:40:43,600 --> 00:40:45,760
ROBERT CHEN ANALYZED THE

843
00:40:45,760 --> 00:40:50,880
RESULTS.

844
00:40:50,880 --> 00:40:55,080
AND YOU CAN SEE THAT M DCF 2

845
00:40:55,080 --> 00:40:58,800
PRODUCED A SIGNIFICANTLY GREATER

846
00:40:58,800 --> 00:41:02,200
RATE IN CHANGE IN WLZ SCORE.

847
00:41:02,200 --> 00:41:09,800
A GREAT RATE OF PONDERAL GROWTH.

848
00:41:09,800 --> 00:41:12,800
SO WE NOW SHOULD THINK ABOUT

849
00:41:12,800 --> 00:41:15,200
THERAPEUTIC FOODS NOT JUST BASED

850
00:41:15,200 --> 00:41:27,240
ON THEIR CALORIC CONSENT.

851
00:41:27,240 --> 00:41:31,080
WE DID AN ANALYSIS, ROBERT CHEN

852
00:41:31,080 --> 00:41:33,520
DID AN ANALYSIS WHERE HE TOOK

853
00:41:33,520 --> 00:41:36,280
THE DATASET FROM ALL

854
00:41:36,280 --> 00:41:38,840
PARTICIPANTS IN BOTH ARMS.

855
00:41:38,840 --> 00:41:42,800
AND THEN CORRELATED CHANGES IN

856
00:41:42,800 --> 00:41:45,800
WLZ WITH A CHANGE IN EACH OF

857
00:41:45,800 --> 00:41:49,000
5,000 DIFFERENT PLASMA PRO TEAMS

858
00:41:49,000 --> 00:41:51,160
WHOSE LEVELS WERE MEASURED PRIOR

859
00:41:51,160 --> 00:41:53,160
TO AND AT THE CONCLUSION OF THE

860
00:41:53,160 --> 00:41:54,520
INTERVENTION.

861
00:41:54,520 --> 00:41:56,840
SO SHOWN HERE IN THE LOWER LEFT

862
00:41:56,840 --> 00:41:59,200
IS AN EXAMPLE OF THE TYPES OF

863
00:41:59,200 --> 00:42:01,800
TESTS OF CORRELATION BETWEEN THE

864
00:42:01,800 --> 00:42:04,600
RATE OF CHANGE IN WLZ OVER TIME.

865
00:42:04,600 --> 00:42:08,880
AND THE RATE OF CHANGE OF A

866
00:42:08,880 --> 00:42:12,040
PARTICULAR PROTEIN IGF1 AND

867
00:42:12,040 --> 00:42:15,160
THOSE PLOTS ARE SHOWN AS DOTS

868
00:42:15,160 --> 00:42:18,040
AND FROM THIS ANALYSIS A GROUP

869
00:42:18,040 --> 00:42:20,720
OF 70WLZ CORRELATED PROTEINS

870
00:42:20,720 --> 00:42:22,920
WERE IDENTIFIED.

871
00:42:22,920 --> 00:42:25,600
THEY ARE INVOLVED IN MANY

872
00:42:25,600 --> 00:42:29,880
ASPECTS OF POSTNATAL GROWTH,

873
00:42:29,880 --> 00:42:32,400
MUSCULAR SKELETAL DEVELOPMENT

874
00:42:32,400 --> 00:42:35,800
AND CNS DEVELOPMENT.

875
00:42:35,800 --> 00:42:39,720
WE'RE LOOKING AT ON THE Y AXIS

876
00:42:39,720 --> 00:42:42,720
THE FULL CHANGE OF EACH OF THESE

877
00:42:42,720 --> 00:42:51,320
70 PROTEINS PRODUCED BY MCDF2

878
00:42:51,320 --> 00:42:54,960
COMPARED TO RUSF.

879
00:42:54,960 --> 00:42:58,800
SO NOW WE HAVE A GROUP OF 70

880
00:42:58,800 --> 00:43:02,800
PROTEINS THAT ARE IMPACTED MORE

881
00:43:02,800 --> 00:43:10,480
BY M DCF 2 THAN BY RUSF.

882
00:43:10,480 --> 00:43:12,800
SIMILARLY MATT HIBBERD LOOKED TO

883
00:43:12,800 --> 00:43:20,200
THE MICRO BIOTA TO IDENTIFY TAXA

884
00:43:20,200 --> 00:43:22,240
AND TO DETERMINE IF IT WAS MORE

885
00:43:22,240 --> 00:43:24,000
IMPACTED.

886
00:43:24,000 --> 00:43:26,200
AGAIN FOR EACH INDIVIDUAL TAKING

887
00:43:26,200 --> 00:43:29,080
THE DATA ABOUT THE CHANGE IN WLZ

888
00:43:29,080 --> 00:43:33,720
OVER TIME AND CORRELATE WITH THE

889
00:43:33,720 --> 00:43:39,760
CHANGE IN ABUNDANCE OF 700 --

890
00:43:39,760 --> 00:43:43,640
USING THESE MODELS.

891
00:43:43,640 --> 00:43:47,320
AND THOSE RESULTS SHOWN HERE

892
00:43:47,320 --> 00:43:51,280
DISCLOSED 23 DIFFERENT TAXA

893
00:43:51,280 --> 00:43:53,000
DEFINED AS STATISTICALLY

894
00:43:53,000 --> 00:43:54,800
SIGNIFICANT IN TERMS OF THEIR

895
00:43:54,800 --> 00:43:57,880
ASSOCIATIONS WITH WLZ.

896
00:43:57,880 --> 00:44:00,240
AND 21 OF THEM ARE POSSIBLY

897
00:44:00,240 --> 00:44:00,560
CORRELATED.

898
00:44:00,560 --> 00:44:04,400
TWO ARE NEGATIVELY CORRELATED.

899
00:44:04,400 --> 00:44:06,800
THIS ANALYSIS SHOWN IN THE LOWER

900
00:44:06,800 --> 00:44:12,400
PORTION LOWER HALF OF THE SLIDE

901
00:44:12,400 --> 00:44:15,200
DESCRIBES A COEFFICIENT BETA 1

902
00:44:15,200 --> 00:44:18,320
FROM THESE LINEAR MIXED MODELS

903
00:44:18,320 --> 00:44:22,600
THAT REPRESENTS THE CHANGE IN WL

904
00:44:22,600 --> 00:44:23,640
WLZ.

905
00:44:23,640 --> 00:44:27,560
THE TAXA ARE DESCRIBED BY

906
00:44:27,560 --> 00:44:30,600
AMPLIFIED SEQUENCE VARIANTS.

907
00:44:30,600 --> 00:44:35,000
AND YOU CAN SEE -- IT HAS

908
00:44:35,000 --> 00:44:38,240
GREATEST IMPACT ON WLZ FOR UNIT

909
00:44:38,240 --> 00:44:42,760
CHANGE IN IT'S BURNED ANNES BUT

910
00:44:42,760 --> 00:44:48,200
THERE ARE A * --

911
00:44:48,200 --> 00:44:49,000
[ INDISCERNIBLE ]

912
00:44:49,000 --> 00:44:51,240
BUT GOING BACK TO THE ORIGINAL

913
00:44:51,240 --> 00:44:51,600
QUESTION.

914
00:44:51,600 --> 00:44:55,160
IT HAS A SIGNIFICANTLY GREATER

915
00:44:55,160 --> 00:44:57,520
EFFECT PRODUCES SIGNIFICANTLY

916
00:44:57,520 --> 00:44:59,960
INCREASED AMOUNTS OF THESE

917
00:44:59,960 --> 00:45:03,040
POSSIBLY CORRELATED TAXA THAN

918
00:45:03,040 --> 00:45:06,040
DOES RUSF AND HAS THE GREATEST

919
00:45:06,040 --> 00:45:08,800
EFFECT ON REDUCING THE ABUNDANCE

920
00:45:08,800 --> 00:45:12,560
OF THE PRINCIPLE NEGATIVELY

921
00:45:12,560 --> 00:45:14,160
CORRELATED.

922
00:45:14,160 --> 00:45:17,360
SO THIS TYPE OF ANALYSIS STARTS

923
00:45:17,360 --> 00:45:19,920
TO CONNECT THE DOTS.

924
00:45:19,920 --> 00:45:25,200
OUR CHANGES IN PONDERAL GROWTH

925
00:45:25,200 --> 00:45:28,200
RELATED TO CHANGES IN AFFECTERS

926
00:45:28,200 --> 00:45:29,960
OF DIFFERENT ASPECTS OF GROWTH

927
00:45:29,960 --> 00:45:32,040
AS WELL AS CHANGES IN THE

928
00:45:32,040 --> 00:45:33,600
REPRESENTATION OF DIFFERENT

929
00:45:33,600 --> 00:45:37,480
COMPONENTS OF THE MICRO BIOTA.

930
00:45:37,480 --> 00:45:41,000
THE NEXT TASK OF COURSE IS TO

931
00:45:41,000 --> 00:45:43,160
GET DEEPER INTO THE MYSTERIES OF

932
00:45:43,160 --> 00:45:45,080
THE MICRO BIOTA AND TO

933
00:45:45,080 --> 00:45:47,640
UNDERSTAND HOW THESE DIFFERENT

934
00:45:47,640 --> 00:45:49,560
-- CHANGED THEIR PATTERNS OF

935
00:45:49,560 --> 00:45:51,560
GENE EXPRESSION SO HOW TO

936
00:45:51,560 --> 00:45:54,720
EXPRESS GENOMIC FEATURES

937
00:45:54,720 --> 00:45:57,640
CORRELATE WITH GROWTH RESPONSES?

938
00:45:57,640 --> 00:46:00,000
THAT QUESTION AND THE ANSWERS

939
00:46:00,000 --> 00:46:04,200
ARE CRITICAL FOR MORE DETAILED

940
00:46:04,200 --> 00:46:08,600
MECHANISTIC INSIGHTS ABOUT HOW

941
00:46:08,600 --> 00:46:10,000
MCDF2 AND OTHER INTERVENTIONS

942
00:46:10,000 --> 00:46:13,240
WOULD BE AFFECTING THE HOST

943
00:46:13,240 --> 00:46:13,760
GROWTH.

944
00:46:13,760 --> 00:46:18,520
KEY FOR DEVELOPING MCDF AS WELL

945
00:46:18,520 --> 00:46:23,320
AS THE DISCOVERY AND USE OF --

946
00:46:23,320 --> 00:46:25,760
COMBINATIONS OF PRO-BIOTICS.

947
00:46:25,760 --> 00:46:28,640
SO THE TASK ARE TO RECONSTRUCT

948
00:46:28,640 --> 00:46:31,480
THE GENOMES OF ASSOCIATED

949
00:46:31,480 --> 00:46:34,480
STRAINS PRESENT IN THE FECAL

950
00:46:34,480 --> 00:46:36,760
SAMPLES.

951
00:46:36,760 --> 00:46:40,280
IDENTIFY FUNCTION, FEATURES

952
00:46:40,280 --> 00:46:43,800
ENRICHED IN THESE ASSEMBLED

953
00:46:43,800 --> 00:46:44,360
GENOMES.

954
00:46:44,360 --> 00:46:47,000
AND THEN TO DETERMINE WHICH

955
00:46:47,000 --> 00:46:51,600
BACTERIAL PATHWAYS ARE IN THESE

956
00:46:51,600 --> 00:46:56,040
WLZ CORRELATED MAGS.

957
00:46:56,040 --> 00:46:58,880
AND TO CORRELATE THESE GENE

958
00:46:58,880 --> 00:47:02,200
EXPRESSION DATA WITH RUTS OF

959
00:47:02,200 --> 00:47:06,400
ANALYSIS OF THE COMPOSITION AND

960
00:47:06,400 --> 00:47:08,120
THE METABOLISM.

961
00:47:08,120 --> 00:47:14,040
SO IDENTIFYING THE BACTERIAL WLZ

962
00:47:14,040 --> 00:47:16,400
CORRELATED STRAINS ARE IMPORTANT

963
00:47:16,400 --> 00:47:17,400
TASKS AHEAD.

964
00:47:17,400 --> 00:47:19,280
THOSE TYPES OF QUESTIONS THOSE

965
00:47:19,280 --> 00:47:21,520
TYPES OF APPROACHES THE SEARCH

966
00:47:21,520 --> 00:47:23,200
FOR BAGS.

967
00:47:23,200 --> 00:47:26,640
AND THE USE AND TO GO BEYOND THE

968
00:47:26,640 --> 00:47:30,400
DNA BASED DESCRIPTION OF THE

969
00:47:30,400 --> 00:47:30,920
RESPONSE.

970
00:47:30,920 --> 00:47:35,360
ALSO OPENED A DOOR FOR A NEXT

971
00:47:35,360 --> 00:47:43,240
LEVEL OF MCDF DISCOVERY.

972
00:47:43,240 --> 00:47:45,400
AND LYNN IS PERFORMING THESE

973
00:47:45,400 --> 00:47:48,720
SORTS OF ANALYSIS WHERE

974
00:47:48,720 --> 00:47:50,800
DIFFERENT FOODS CONSUMED BY

975
00:47:50,800 --> 00:47:51,840
POPULATIONS IN DIFFERENT PARTS

976
00:47:51,840 --> 00:47:53,680
OF THE WORLD ARE SCREENED FOR

977
00:47:53,680 --> 00:47:59,400
THEIR EFFECTS ON MICROBIAL

978
00:47:59,400 --> 00:48:01,400
POPULATIONS WHERE THESE ARE

979
00:48:01,400 --> 00:48:06,040
CULTURALLY ACCEPTABLE AND HAVE

980
00:48:06,040 --> 00:48:07,320
SATISFACTORY PROPERTIES AND COME

981
00:48:07,320 --> 00:48:09,880
FROM SUSTAINABLE SOURCES.

982
00:48:09,880 --> 00:48:14,160
THIS IS A REVERSE TRANSLATION

983
00:48:14,160 --> 00:48:16,600
EXPERIMENT WHERE COMMUNITIES

984
00:48:16,600 --> 00:48:18,160
CAPTURED PRIOR TO DURING OR

985
00:48:18,160 --> 00:48:21,560
AFTER ONE OF THESE POC TRIALS

986
00:48:21,560 --> 00:48:23,800
CAN BE REENROLLED IN THE TRIAL

987
00:48:23,800 --> 00:48:27,400
IN THE FORM OF THEIR

988
00:48:27,400 --> 00:48:30,720
TRANSPLANTATION AND THE TRIAL

989
00:48:30,720 --> 00:48:32,800
CONDITIONS -- APPLY TO THE

990
00:48:32,800 --> 00:48:34,800
ANIMALS SO THAT WE CAN TAKE A

991
00:48:34,800 --> 00:48:37,000
MUCH DEEPER MORE REFINED VIEW OF

992
00:48:37,000 --> 00:48:41,200
THE SIGNALING PATHWAYS THAT

993
00:48:41,200 --> 00:48:43,360
CONNECT FOOD, FOOD METABOLISM

994
00:48:43,360 --> 00:48:45,680
AND THE RESPONSE OF DIFFERENT

995
00:48:45,680 --> 00:48:47,880
CELL LINEAGES AND DIFFERENT

996
00:48:47,880 --> 00:48:49,480
ORGANS OF THE ANIMAL.

997
00:48:49,480 --> 00:48:51,960
SO LET ME CONCLUDE.

998
00:48:51,960 --> 00:48:54,520
WHAT ARE THE IMPLICATIONS?

999
00:48:54,520 --> 00:48:56,200
I HOPE I PRESENTED SOME

1000
00:48:56,200 --> 00:48:57,720
INFORMATION THAT MIGHT PERSUADE

1001
00:48:57,720 --> 00:49:00,800
YOU TO THINK THAT HEALTHY GROWTH

1002
00:49:00,800 --> 00:49:04,120
MIGHT BE LINKED TO HEALTHY

1003
00:49:04,120 --> 00:49:06,000
GROWTH OF THE GUT.

1004
00:49:06,000 --> 00:49:08,440
ONE THAT INCLUDES A

1005
00:49:08,440 --> 00:49:10,880
CONSIDERATION OF THE ORGANISMS

1006
00:49:10,880 --> 00:49:12,240
IN GUT COMMUNITY.

1007
00:49:12,240 --> 00:49:16,200
THE MICRO BIOTA AND THE VAST

1008
00:49:16,200 --> 00:49:17,280
REPERTOIRE OF GENES.

1009
00:49:17,280 --> 00:49:18,080
THE MICROBIOME.

1010
00:49:18,080 --> 00:49:20,760
A POSSIBILITY OF A BETTER

1011
00:49:20,760 --> 00:49:22,880
DEFINITION OF WELLNESS FOR

1012
00:49:22,880 --> 00:49:23,800
INFANTS AND CHILDREN.

1013
00:49:23,800 --> 00:49:25,960
WE HAVE AT LEAST A TWO-YEAR

1014
00:49:25,960 --> 00:49:28,160
WINDOW IN POSTNATAL DEVELOPMENT

1015
00:49:28,160 --> 00:49:30,400
TO INTERVENE IF THERE IS

1016
00:49:30,400 --> 00:49:32,520
ALTERATION IN THE DEVELOPMENTAL

1017
00:49:32,520 --> 00:49:36,600
PROGRAM OF THIS MICROBIAL

1018
00:49:36,600 --> 00:49:39,320
COMMUNITY.

1019
00:49:39,320 --> 00:49:41,840
THE IMPLICATIONS ALSO OF HOW TO

1020
00:49:41,840 --> 00:49:43,440
FEED OUR INFANTS AND CHILDREN.

1021
00:49:43,440 --> 00:49:46,440
WHAT KIND OF COMPLIMENTARY FOODS

1022
00:49:46,440 --> 00:49:48,680
INFORMED BY KNOWLEDGE OF GUT

1023
00:49:48,680 --> 00:49:50,440
COMMUNITY DEVELOPMENT SO WE CAN

1024
00:49:50,440 --> 00:49:53,920
BE MUCH MORE EFFECTIVE STEWARDS.

1025
00:49:53,920 --> 00:49:56,920
AND THE NEED TO DETERMINE THE

1026
00:49:56,920 --> 00:50:00,120
EFFECTS OF INTERVENTIONS AT

1027
00:50:00,120 --> 00:50:01,800
DIFFERENT AGES, EARLIER.

1028
00:50:01,800 --> 00:50:03,520
THE DURATION OF THE

1029
00:50:03,520 --> 00:50:05,200
INTERVENTION.

1030
00:50:05,200 --> 00:50:07,200
THE DURABILITY OF THE EFFECTS OF

1031
00:50:07,200 --> 00:50:09,400
THE INTERVENTION ONCE IT IS

1032
00:50:09,400 --> 00:50:10,800
STOPPED.

1033
00:50:10,800 --> 00:50:13,880
SO GENERALIZABILITY, DURABILITY

1034
00:50:13,880 --> 00:50:17,120
AND SAFETY.

1035
00:50:17,120 --> 00:50:21,400
ALTERING HUMAN BIOLOGY BY TRYING

1036
00:50:21,400 --> 00:50:23,640
TO -- HAVE CATCH UP GROWTH AND

1037
00:50:23,640 --> 00:50:26,520
THIS IS SOMETHING THAT WE'RE

1038
00:50:26,520 --> 00:50:28,040
PURSUING AT SEVERAL DIFFERENT

1039
00:50:28,040 --> 00:50:30,280
SITES AROUND THE WORLD WHERE THE

1040
00:50:30,280 --> 00:50:31,960
BURDEN OF UNDER NUTRITION IS

1041
00:50:31,960 --> 00:50:33,640
GREAT SO I THANK YOU FOR YOUR

1042
00:50:33,640 --> 00:50:36,400
ATTENTION.

1043
00:50:36,400 --> 00:50:38,280
>> THANK YOU VERY MUCH JEFF FOR

1044
00:50:38,280 --> 00:50:41,040
THIS REALLY VERY EXCITING

1045
00:50:41,040 --> 00:50:44,760
PRESENTATION.

1046
00:50:44,760 --> 00:50:49,600
AND ILLUSTRATING VERY POWERFULLY

1047
00:50:49,600 --> 00:50:54,320
HOW THE PROBLEMS OF FINDING

1048
00:50:54,320 --> 00:50:58,680
CAUSE AND EFFECT BETWEEN A

1049
00:50:58,680 --> 00:51:02,640
CLINICAL PHENOMENA IN THIS CASE

1050
00:51:02,640 --> 00:51:06,400
MALNUTRITION AND THE MICROBIOME

1051
00:51:06,400 --> 00:51:12,320
IS A VERY DIFFICULT CHALLENGING

1052
00:51:12,320 --> 00:51:13,720
PROBLEM.

1053
00:51:13,720 --> 00:51:16,680
AND IS REALLY WHERE THE ACTION

1054
00:51:16,680 --> 00:51:19,200
IS AT AND IT'S VERY I THINK

1055
00:51:19,200 --> 00:51:21,120
AMAZING TO READ OF YOUR STUDIES

1056
00:51:21,120 --> 00:51:24,920
AND HEAR OF THEM.

1057
00:51:24,920 --> 00:51:29,280
AND REALIZE THAT IT'S MUCH MORE

1058
00:51:29,280 --> 00:51:30,960
COMPLICATED THAN JUST PRESENTING

1059
00:51:30,960 --> 00:51:33,160
A PATTERN OF DISTRIBUTION OF THE

1060
00:51:33,160 --> 00:51:37,560
MICROBIOME IN A GIVEN POPULATION

1061
00:51:37,560 --> 00:51:39,760
GROUP OR A GIVEN DISEASE GROUP

1062
00:51:39,760 --> 00:51:43,960
AND COMPARING IT.

1063
00:51:43,960 --> 00:51:46,720
THE MECHANICS, THE MECHANISMS

1064
00:51:46,720 --> 00:51:49,600
ARE CHALLENGING.

1065
00:51:49,600 --> 00:51:53,800
NOW WE'LL TURN TO TIM GRETEN AND

1066
00:51:53,800 --> 00:51:58,200
TIM, WOULD YOU PLEASE PROCEED.

1067
00:51:58,200 --> 00:52:03,280
>> THIS IS GOING TO BE VERY,

1068
00:52:03,280 --> 00:52:04,280
VERY DIFFICULT AFTER THIS

1069
00:52:04,280 --> 00:52:05,000
PRESENTATION.

1070
00:52:05,000 --> 00:52:06,040
BUT I WILL TRY MY BEST AND WE

1071
00:52:06,040 --> 00:52:07,200
ARE CHANGING GEARS QUITE

1072
00:52:07,200 --> 00:52:08,960
SIGNIFICANTLY.

1073
00:52:08,960 --> 00:52:10,280
WE'RE GOING TO TALK ABOUT HOW

1074
00:52:10,280 --> 00:52:12,720
THE GUT MICROBIOME CONTROLS

1075
00:52:12,720 --> 00:52:14,520
GROWTH OF LIVER TUMORS.

1076
00:52:14,520 --> 00:52:16,080
THESE ARE JUST A

1077
00:52:16,080 --> 00:52:17,360
DISCLOSURE.

1078
00:52:17,360 --> 00:52:19,560
I WANT TO SHOW YOU SOME CLINICAL

1079
00:52:19,560 --> 00:52:22,120
DATA IN THE BEGINNING HOW WE GOT

1080
00:52:22,120 --> 00:52:24,920
INVOLVED IN THIS.

1081
00:52:24,920 --> 00:52:28,920
SO AS A GENERAL INTRODUCTION YOU

1082
00:52:28,920 --> 00:52:32,360
HEARD ALREADY THE QUESTION IS

1083
00:52:32,360 --> 00:52:36,440
HOW DOES THE HUMAN CELLS AND THE

1084
00:52:36,440 --> 00:52:45,120
HUMAN GENOME INTERACT WITH THE

1085
00:52:45,120 --> 00:52:47,160
MICROBIAL CELLS AND GENES.

1086
00:52:47,160 --> 00:52:49,520
NOW WHAT WE'RE SPECIFICALLY

1087
00:52:49,520 --> 00:52:50,720
STUDYING HERE IS THE MICROBIOME

1088
00:52:50,720 --> 00:52:53,120
AND HUMAN CANCER.

1089
00:52:53,120 --> 00:52:54,480
AND THERE ARE CERTAIN ASPECTS.

1090
00:52:54,480 --> 00:52:57,600
WE KNOW THAT WE CAN USE THIS

1091
00:52:57,600 --> 00:52:59,600
ACTUALLY FOR DIAGNOSIS.

1092
00:52:59,600 --> 00:53:04,120
WE CAN IDENTIFY DNA IN BLOOD.

1093
00:53:04,120 --> 00:53:07,200
WE CAN USE AS A PROGNOSTIC

1094
00:53:07,200 --> 00:53:07,640
MARKER.

1095
00:53:07,640 --> 00:53:10,520
THERE ARE DIFFERENT WAYS HOW WE

1096
00:53:10,520 --> 00:53:15,680
CAN UTILIZE MICRO BIOTA

1097
00:53:15,680 --> 00:53:16,160
THERAPEUTICALLY.

1098
00:53:16,160 --> 00:53:19,560
AND HOW WE CAN USE THE

1099
00:53:19,560 --> 00:53:21,240
MICROBIOME TO UNDERSTAND

1100
00:53:21,240 --> 00:53:23,720
METASTASIS.

1101
00:53:23,720 --> 00:53:26,160
NOW WHAT I'M GOING TO TALK ABOUT

1102
00:53:26,160 --> 00:53:27,960
IS NOT CANCER IN GENERAL BUT I

1103
00:53:27,960 --> 00:53:31,360
WOULD LIKE TO FOCUS ON LIVER

1104
00:53:31,360 --> 00:53:34,680
TUMORS AND LIVER TUMORS CAN BE

1105
00:53:34,680 --> 00:53:39,760
DIVIDED INTO MAJORITY OF TUMORS

1106
00:53:39,760 --> 00:53:43,480
ARE LIVER METASTASISES AND

1107
00:53:43,480 --> 00:53:45,080
PRIMARY LIVER CANCER.

1108
00:53:45,080 --> 00:53:50,720
THE NUMBER ONE IS HELP WELL

1109
00:53:50,720 --> 00:54:13,560
EULAR AND CHOLANGIOCARCINOMA.

1110
00:54:13,560 --> 00:54:20,240
-- NOW WHY IS THERE THIS

1111
00:54:20,240 --> 00:54:22,000
INTEREST IN THE GUT MICROBIOME

1112
00:54:22,000 --> 00:54:23,320
AND THE LIVER?

1113
00:54:23,320 --> 00:54:24,880
THAT IS SIMPLE.

1114
00:54:24,880 --> 00:54:26,720
IT'S JUST ANATOMY.

1115
00:54:26,720 --> 00:54:29,120
YOU KNOW THAT THE MAJORITY OF

1116
00:54:29,120 --> 00:54:31,440
THE BLOOD THAT GOES INTO THE

1117
00:54:31,440 --> 00:54:35,320
LIVER AND FEEDS THE LIVER WITH

1118
00:54:35,320 --> 00:54:38,120
BLOOD SUPPLY IS ACTUALLY DRAINED

1119
00:54:38,120 --> 00:54:42,160
FRAT LARGE AND SMALL INTESTINE.

1120
00:54:42,160 --> 00:54:44,600
THAT DRAINS IN THE VEIN AND THEN

1121
00:54:44,600 --> 00:54:45,320
GOES INTO THE LIVER.

1122
00:54:45,320 --> 00:54:47,960
EVERYTHING THAT IS IN THE GUT

1123
00:54:47,960 --> 00:54:50,600
CAN POTENTIALLY MIGRATE HERE AND

1124
00:54:50,600 --> 00:54:52,960
BE DRAINED THROUGH THE DIFFERENT

1125
00:54:52,960 --> 00:54:54,720
BRANCHES INTO THE LIVER.

1126
00:54:54,720 --> 00:54:56,760
NOW LET ME GIVE YOU BECAUSE I

1127
00:54:56,760 --> 00:54:58,320
WANT TO TELL YOU A LITTLE BIT

1128
00:54:58,320 --> 00:55:02,160
ABOUT A SMALL CASE ABOUT BILL

1129
00:55:02,160 --> 00:55:03,680
ARI CANCER.

1130
00:55:03,680 --> 00:55:05,040
-- *.

1131
00:55:05,040 --> 00:55:08,000
THERE ARE LIMITED TREATMENT

1132
00:55:08,000 --> 00:55:08,400
OPTIONS.

1133
00:55:08,400 --> 00:55:11,040
AND WE DID A STUDY AND I'M NOT

1134
00:55:11,040 --> 00:55:13,080
GOING TO GO INTO THE DETAILS.

1135
00:55:13,080 --> 00:55:14,960
I WANT TO SHOW YOU WHAT DRIVES

1136
00:55:14,960 --> 00:55:15,760
OUR RESEARCH.

1137
00:55:15,760 --> 00:55:17,720
WE USED TREATMENT FOR PATIENTS

1138
00:55:17,720 --> 00:55:21,720
WITH DIFFERENT TYPES OF LIVER

1139
00:55:21,720 --> 00:55:23,120
CANCER.

1140
00:55:23,120 --> 00:55:25,960
WE TREATED THEM WITH INHIBITORS

1141
00:55:25,960 --> 00:55:27,560
THAT ACTIVATE THE IMMUNE

1142
00:55:27,560 --> 00:55:28,960
RESPONSE.

1143
00:55:28,960 --> 00:55:31,240
YOU CAN SEE THAT THE TREATMENT

1144
00:55:31,240 --> 00:55:32,600
WAS NOT EFFECTIVE.

1145
00:55:32,600 --> 00:55:34,800
THE MAJORITY OF PATIENTS WERE

1146
00:55:34,800 --> 00:55:37,600
ONLY TREATED FOR A SHORT PERIOD

1147
00:55:37,600 --> 00:55:39,000
OF TIME.

1148
00:55:39,000 --> 00:55:40,520
TUMORS GREW BUT THERE IS THIS

1149
00:55:40,520 --> 00:55:41,440
ONE OUTLIER.

1150
00:55:41,440 --> 00:55:43,240
YOU CAN SEE THIS PATIENTLY

1151
00:55:43,240 --> 00:55:45,120
SHOWED A CLEAR REDUCTION IN

1152
00:55:45,120 --> 00:55:46,960
TUMOR AND IT'S LONG LASTING.

1153
00:55:46,960 --> 00:55:48,720
SO IF YOU LOOK AT THIS

1154
00:55:48,720 --> 00:55:50,320
PARTICULAR CASE YOU CAN SEE HERE

1155
00:55:50,320 --> 00:55:52,320
NOW THE CLINICAL COURSE OF THE

1156
00:55:52,320 --> 00:55:53,040
PATIENT.

1157
00:55:53,040 --> 00:55:56,720
SO WE STARTED THE TREATMENT IN

1158
00:55:56,720 --> 00:55:58,880
2016 AND I CAN TELL YOU WE'VE

1159
00:55:58,880 --> 00:56:00,520
SEEN THIS PATIENT A COUPLE OF

1160
00:56:00,520 --> 00:56:02,080
WEEKS IN THE CLINIC AND SHE IS

1161
00:56:02,080 --> 00:56:03,920
STILL TUMOR FREE AND SHE WAS

1162
00:56:03,920 --> 00:56:06,040
TREATED WITH THE SAME TREATMENT

1163
00:56:06,040 --> 00:56:07,360
WITH THE REST OF THE POPULATION

1164
00:56:07,360 --> 00:56:09,720
THAT WE HAVE IN THIS TRIAL.

1165
00:56:09,720 --> 00:56:12,080
BUT SOMEHOW SOMETHING MUST HAD

1166
00:56:12,080 --> 00:56:13,600
BEEN VERY DIFFERENT.

1167
00:56:13,600 --> 00:56:15,720
THE PATIENT DEVELOPED AN

1168
00:56:15,720 --> 00:56:16,360
ABSCESS.

1169
00:56:16,360 --> 00:56:19,320
AND WE TREATED THE PATIENT WITH

1170
00:56:19,320 --> 00:56:20,480
ANTIBIOTICS.

1171
00:56:20,480 --> 00:56:22,800
THE PATIENT DEVELOPED COLITIS

1172
00:56:22,800 --> 00:56:24,280
AND WE PERFORMED A LOT OF

1173
00:56:24,280 --> 00:56:24,880
STUDIES.

1174
00:56:24,880 --> 00:56:30,280
WE LOOKED AT GENETIC -- AND WE

1175
00:56:30,280 --> 00:56:33,320
WERE NEVER SURE WHY THIS PATIENT

1176
00:56:33,320 --> 00:56:36,440
RESPONDED IN SUCH AN OUTLIER AND

1177
00:56:36,440 --> 00:56:38,040
I STILL DON'T KNOW THIS.

1178
00:56:38,040 --> 00:56:42,320
SO WHAT I WANT TO TELL YOU IS

1179
00:56:42,320 --> 00:56:45,200
IMMUNO THERAPY MAY ACTUALLY WORK

1180
00:56:45,200 --> 00:56:47,920
IN LIVER CANCERS.

1181
00:56:47,920 --> 00:56:50,520
BUT THERE ARE SO MANY UNANSWERED

1182
00:56:50,520 --> 00:56:52,120
QUESTIONS AND IN OUR INTEREST

1183
00:56:52,120 --> 00:56:57,600
HERE IS TO STUDY THE IMMUNE

1184
00:56:57,600 --> 00:57:02,800
MICRO ENVIRONMENT OF THE LEVE
LIVER

1185
00:57:02,800 --> 00:57:04,560
AND HOW THE GUT MICROBIOME CAN

1186
00:57:04,560 --> 00:57:07,160
CHANGE THIS AND HOW IT DOES IT

1187
00:57:07,160 --> 00:57:11,120
IN THE CONTEXT AND EFFECT IMMUNE

1188
00:57:11,120 --> 00:57:11,720
RESPONSES.

1189
00:57:11,720 --> 00:57:13,840
HOW DO WE DO THIS?

1190
00:57:13,840 --> 00:57:18,920
WE BASICALLY TOOK USE OF A VERY

1191
00:57:18,920 --> 00:57:23,360
SIMPLE MODEL.

1192
00:57:23,360 --> 00:57:26,120
WHERE WE CAN USE TUMORS IN THE

1193
00:57:26,120 --> 00:57:27,680
LIVERS OF THE MICE AND THEY

1194
00:57:27,680 --> 00:57:29,280
DEVELOP TUMORS OVER A PERIOD OF

1195
00:57:29,280 --> 00:57:31,360
TIME AND THEN A NUMBER OF YEARS

1196
00:57:31,360 --> 00:57:34,040
AGO THIS WAS ONE OF THE FIRST

1197
00:57:34,040 --> 00:57:37,520
STUDIES -- WHERE ANTIBIOTIC WAS

1198
00:57:37,520 --> 00:57:40,040
ADDED TO THEIR DRINKING WATER.

1199
00:57:40,040 --> 00:57:42,160
THEY DEVELOPED WAY FEWER TUMORS.

1200
00:57:42,160 --> 00:57:45,520
I TREAT A LOT OF PATIENTS WITH

1201
00:57:45,520 --> 00:57:45,720
CANCER.

1202
00:57:45,720 --> 00:57:47,400
THIS WAS VERY HARD FOR ME TO

1203
00:57:47,400 --> 00:57:49,400
BELIEVE THAT JUST ANTIBIOTIC

1204
00:57:49,400 --> 00:57:51,640
TREATMENT WOULD ACTUALLY REDUCE

1205
00:57:51,640 --> 00:57:52,920
TUMOR NOODLES.

1206
00:57:52,920 --> 00:57:56,400
WE REPEATED THIS EXPERIMENT AND

1207
00:57:56,400 --> 00:57:58,920
USED OTHER MICE MODELS.

1208
00:57:58,920 --> 00:58:01,600
THE RESULT WAS ALWAYS THE SAME.

1209
00:58:01,600 --> 00:58:03,840
SO WE DID WHAT WE USUALLY DO

1210
00:58:03,840 --> 00:58:07,480
WHEN WE GO INTO IMMUNO THERAPY

1211
00:58:07,480 --> 00:58:08,000
STUDIES.

1212
00:58:08,000 --> 00:58:11,800
WE LOOKED AT DIFFERENT IMMUNE

1213
00:58:11,800 --> 00:58:18,120
CELLS.

1214
00:58:18,120 --> 00:58:20,880
THERE IS ONE CELL POPULATION

1215
00:58:20,880 --> 00:58:23,120
WHERE WE NOTICED AN INCREASE IN

1216
00:58:23,120 --> 00:58:26,080
MICE THAT WERE TREATED WITH THE

1217
00:58:26,080 --> 00:58:28,080
ANTIBIOTICS AND WE OBSERVED THIS

1218
00:58:28,080 --> 00:58:32,840
ACCUMULATION OF MKT CELLS.

1219
00:58:32,840 --> 00:58:36,400
SO THEY SHARE THE PROPERTIES OF

1220
00:58:36,400 --> 00:58:39,600
T CELLS.

1221
00:58:39,600 --> 00:58:44,360
THEY REPS CD1 MOLECULE.

1222
00:58:44,360 --> 00:58:49,120
IT ACTUALLY RECOGNIZES FOREIGN

1223
00:58:49,120 --> 00:58:49,840
LIPIDS.

1224
00:58:49,840 --> 00:58:52,920
IT'S A RATHER ABUNDANT IN THE

1225
00:58:52,920 --> 00:58:53,720
MOUSE LIVER.

1226
00:58:53,720 --> 00:59:03,160
IT EXPRESSES CXCR6.  WE LOOKED

1227
00:59:03,160 --> 00:59:06,760
IN MORE DETAIL.

1228
00:59:06,760 --> 00:59:09,760
AND ANALYSIS WAS PERFORMED.

1229
00:59:09,760 --> 00:59:12,720
WE CAN IDENTIFY THEM AND IF WE

1230
00:59:12,720 --> 00:59:16,080
LOOK IN THE LIVER OF THE MICE WE

1231
00:59:16,080 --> 00:59:24,600
FIND MORE CXC6 POSITIVE CELLS.

1232
00:59:24,600 --> 00:59:26,600
THE IMPORTANT THING IS TO REALLY

1233
00:59:26,600 --> 00:59:30,240
LOOK AND REMEMBER THE LIVER

1234
00:59:30,240 --> 00:59:32,680
ANATOMY WITH THE PORTER VEIN

1235
00:59:32,680 --> 00:59:35,200
DRAINING THE BLOOD FROM THE GUT

1236
00:59:35,200 --> 00:59:37,480
BUT WHERE DOES THE BLOOD GO?

1237
00:59:37,480 --> 00:59:39,800
ONCE IT GOES INTO THE LIVER --

1238
00:59:39,800 --> 00:59:54,640
IT GOES INTO THE -- CENTRAL

1239
00:59:54,640 --> 00:59:55,480
VEIN.

1240
00:59:55,480 --> 01:00:04,720
THIS IS A MAGAZIN A --
MAGNIFICATION.

1241
01:00:04,720 --> 01:00:12,320
THEY ARE SO-CALLED LIVER SINUS

1242
01:00:12,320 --> 01:00:15,520
OIDAL AND ENDOTHELIAL CELLS.

1243
01:00:15,520 --> 01:00:18,360
HOW CAN THE GUT MICROBIOME

1244
01:00:18,360 --> 01:00:23,040
AFFECT MKT CELLS?

1245
01:00:23,040 --> 01:00:32,640
MKT CELLS EXPRESS CXC6.

1246
01:00:32,640 --> 01:00:41,640
AND IT TURNS OUT THAT INDEED --

1247
01:00:41,640 --> 01:00:43,120
MICE TREATED WITH ANTIBIOTICS

1248
01:00:43,120 --> 01:00:46,880
WERE THE MICE THAT HAD MORE NKT

1249
01:00:46,880 --> 01:00:51,240
CELLS AND FEWER TUMORS EXPRESSED

1250
01:00:51,240 --> 01:00:54,360
MORE CXCL16.

1251
01:00:54,360 --> 01:01:02,840
WE CONFIRMED THIS.

1252
01:01:02,840 --> 01:01:06,120
BASICALLY USING ANTIBIOTICS TO

1253
01:01:06,120 --> 01:01:08,320
DEPLETE THE MICROBIOME.

1254
01:01:08,320 --> 01:01:16,120
WE USED DIFFERENT MIKE -- MIKE

1255
01:01:16,120 --> 01:01:18,280
ANTIBIOTICS.

1256
01:01:18,280 --> 01:01:23,000
*

1257
01:01:27,920 --> 01:01:29,800
I DIDN'T SHOW YOU ALL OF THE

1258
01:01:29,800 --> 01:01:30,960
DETAILS.

1259
01:01:30,960 --> 01:01:34,520
THERE WERE MORE DETAILED STUDIES

1260
01:01:34,520 --> 01:01:34,760
STUDIES.

1261
01:01:34,760 --> 01:01:38,200
AND THE QUESTION IS AND REMAINS

1262
01:01:38,200 --> 01:01:43,240
HOW CAN THE GUT MICROBIOME

1263
01:01:43,240 --> 01:01:45,720
CONTROL -- EXPRESSION IN THE

1264
01:01:45,720 --> 01:01:48,720
LIVERMORE SPECIFICALLY IN THE

1265
01:01:48,720 --> 01:01:53,560
LIVER SINUS OUT AND ENDOTHELIAL

1266
01:01:53,560 --> 01:01:54,360
CELLS.

1267
01:01:54,360 --> 01:01:58,080
IT TURNED OUT THAT THE BILE

1268
01:01:58,080 --> 01:01:59,840
METABOLISM PLAYS A SIGNIFICANT

1269
01:01:59,840 --> 01:02:00,760
ROLE.

1270
01:02:00,760 --> 01:02:03,440
SO ONE OF THE -- IMPORTANT

1271
01:02:03,440 --> 01:02:06,720
FUNCTIONS OF THE LIVER IS TO

1272
01:02:06,720 --> 01:02:10,160
PRODUCE BIOSALTS WHICH ARE

1273
01:02:10,160 --> 01:02:18,680
RELEASED THROUGH THE COMMON DIAL

1274
01:02:18,680 --> 01:02:21,280
DUCT AND THE IMPORTANT THING TO

1275
01:02:21,280 --> 01:02:25,760
REMEMBER IS 95% ARE ACTUALLY

1276
01:02:25,760 --> 01:02:27,840
REABSORBED BY THE SMALL

1277
01:02:27,840 --> 01:02:29,760
INTESTINE AND GO BACK THROUGH

1278
01:02:29,760 --> 01:02:34,200
THE PORTER VEIN INTO THE LIVER.

1279
01:02:34,200 --> 01:02:37,640
NOW THE SECOND PART IS THAT THE

1280
01:02:37,640 --> 01:02:41,920
BIOSALTS ARE ACTUALLY

1281
01:02:41,920 --> 01:02:45,080
METABOLIZED BY BACTERIA.

1282
01:02:45,080 --> 01:02:52,640
CONGREGATED -- ARE RELEASED.

1283
01:02:52,640 --> 01:03:03,920
-- THEY ARE METABOLIZED BY A

1284
01:03:03,920 --> 01:03:04,920
SPECIFIC STEP.

1285
01:03:04,920 --> 01:03:14,440
AND THIS IS DONE BY CO BACTERIA.

1286
01:03:14,440 --> 01:03:17,720
THAT IS RESPONSIBLE FOR THIS

1287
01:03:17,720 --> 01:03:22,240
STEP OF METABOLIZING BILE ACIDS

1288
01:03:22,240 --> 01:03:30,600
TO SECONDARY BILE AS I -- BILE
ACIDS.

1289
01:03:30,600 --> 01:03:35,240
WE LOOKED IN THE LIVER AND THE

1290
01:03:35,240 --> 01:03:36,560
SECONDARY BILE ACIDS AND THERE

1291
01:03:36,560 --> 01:03:39,680
IS AN INCREASE OF PRIMARY BILE

1292
01:03:39,680 --> 01:03:43,120
ACIDS AND REDUCTION OF SECONDARY

1293
01:03:43,120 --> 01:03:44,440
BILE ACIDS.

1294
01:03:44,440 --> 01:03:47,120
SO WE TREATED MICE WITH BILE

1295
01:03:47,120 --> 01:03:50,120
ACIDS AND ASKED CAN WE USE BILE

1296
01:03:50,120 --> 01:03:52,400
ACIDS TO CONTROL TUMOR GROWTH?

1297
01:03:52,400 --> 01:03:54,680
YOU CAN SEE THE RESULT OF THIS

1298
01:03:54,680 --> 01:03:54,920
EXPERIMENT

1299
01:03:54,920 --> 01:03:56,160
THIS IS OUR CONTROL.

1300
01:03:56,160 --> 01:03:58,400
MOUSE TREATED WITH ANTIBIOTIC

1301
01:03:58,400 --> 01:04:00,840
HAS FEWER TUMORS AND THEN IF WE

1302
01:04:00,840 --> 01:04:04,360
BRING BACK THE SECONDARY BILE

1303
01:04:04,360 --> 01:04:07,120
ACIDS WE CAN BASICALLY RESCUE

1304
01:04:07,120 --> 01:04:09,760
THIS -- OR MICE WOULD DEVELOP

1305
01:04:09,760 --> 01:04:10,720
MORE TUMORS.

1306
01:04:10,720 --> 01:04:14,320
YOU CAN SEE THE CUMULATIVE DATA.

1307
01:04:14,320 --> 01:04:16,400
NOW THIS IS INTERESTING BUT THIS

1308
01:04:16,400 --> 01:04:19,560
ONLY TELLS YOU THAT BILE ACIDS

1309
01:04:19,560 --> 01:04:22,480
CAN CONTROL TUMOR GROWTH.

1310
01:04:22,480 --> 01:04:27,120
WHAT YOU'RE INTERESTED IN IS THE

1311
01:04:27,120 --> 01:04:27,520
BACTERIA.

1312
01:04:27,520 --> 01:04:29,400
A NUMBER HAVE STUDIES I'M GOING

1313
01:04:29,400 --> 01:04:31,520
TO SHOW YOU A FEW OF THEM WHERE

1314
01:04:31,520 --> 01:04:34,360
WE ACTUALLY LOOKED NOW AT THE

1315
01:04:34,360 --> 01:04:37,440
SPECIFIC BACTERIA IN THE MICE

1316
01:04:37,440 --> 01:04:41,120
AND I TOLD YOU THERE IS A

1317
01:04:41,120 --> 01:04:44,320
SPECIES -- THAT WAS KNOWN TO BE

1318
01:04:44,320 --> 01:04:48,000
ABLE TO METABOLIZE BILE ACIDS SO

1319
01:04:48,000 --> 01:04:50,320
WE SET UP A MODEL WHERE WE CAN

1320
01:04:50,320 --> 01:04:53,440
NOW TREAT MICE FIRST WITH

1321
01:04:53,440 --> 01:04:55,440
ANTIBIOTICS.

1322
01:04:55,440 --> 01:05:03,880
AND THEN BRING BACK THE

1323
01:05:03,880 --> 01:05:08,200
CLOSTRIDIUM IN AND LOOK AT NKT

1324
01:05:08,200 --> 01:05:11,280
CELLS AND YOU CAN SEE THEY

1325
01:05:11,280 --> 01:05:19,280
BASICALLY START TO METABOLIZE.

1326
01:05:19,280 --> 01:05:20,760
NOW THIS IS AGAIN INTERESTING.

1327
01:05:20,760 --> 01:05:24,720
WE CAN NOW SHOW THAT THESE

1328
01:05:24,720 --> 01:05:26,520
BACTERIA CAN CONTROL THE NUMBER

1329
01:05:26,520 --> 01:05:29,040
OF NKT CELLS IN THE LIVER BUT IT

1330
01:05:29,040 --> 01:05:32,600
DOES NOT ADDRESS IS IF BACTERIA

1331
01:05:32,600 --> 01:05:34,920
CAN CONTROL TUMOR GROWTH AND

1332
01:05:34,920 --> 01:05:36,400
THAT IS NOW SHOWN HERE.

1333
01:05:36,400 --> 01:05:38,040
YOU ALREADY KNOW THE MODEL SO WE

1334
01:05:38,040 --> 01:05:38,720
HAVE MICE.

1335
01:05:38,720 --> 01:05:41,160
WE TREAT THEM WITH ANTIBIOTICS.

1336
01:05:41,160 --> 01:05:43,360
WE CHALLENGE THEM WITH A TUMOR

1337
01:05:43,360 --> 01:05:46,400
THAT GROWS IN THE LIVER AND THEN

1338
01:05:46,400 --> 01:05:52,520
WE BRING BACK THE -- INTO THE

1339
01:05:52,520 --> 01:05:55,040
MICE AND LOOK FOR TUMOR GROWTH

1340
01:05:55,040 --> 01:05:57,240
AND YOU CAN SEE ANTIBIOTIC

1341
01:05:57,240 --> 01:06:00,040
TREATMENT LEADS TO FEWER TUMORS

1342
01:06:00,040 --> 01:06:05,200
BUT IF WE ACTUALLY INFECT THE

1343
01:06:05,200 --> 01:06:09,480
MUSIC SEE A HIGHER NUMBER OF

1344
01:06:09,480 --> 01:06:12,120
METASTASIS OR TUMORS AND WHAT I

1345
01:06:12,120 --> 01:06:15,320
DON'T SHOW YOU -- THIS IS ALSO

1346
01:06:15,320 --> 01:06:21,120
TO A CHANGE IN THE NKT CELLS.

1347
01:06:21,120 --> 01:06:24,560
THE NUMBER GOES DOWN AS WELL AS

1348
01:06:24,560 --> 01:06:25,600
THE METABOLISM.

1349
01:06:25,600 --> 01:06:28,400
SO I THINK HERE THIS IS

1350
01:06:28,400 --> 01:06:30,520
CLASSICAL AND ONE OF THE FIRST

1351
01:06:30,520 --> 01:06:33,120
EXAMPLES WHERE WE NOW CAN

1352
01:06:33,120 --> 01:06:36,760
ACTUALLY IN POINT AT LEAST IN A

1353
01:06:36,760 --> 01:06:40,840
MODEL SYSTEM IN MICE CHANGES TO

1354
01:06:40,840 --> 01:06:45,520
A SPECIFIC IMMUNE FUNCTION BY

1355
01:06:45,520 --> 01:06:47,400
COMMENSURATE BACTERIA.

1356
01:06:47,400 --> 01:06:50,440
WE KNOW UNDER NORMAL CONDITIONS

1357
01:06:50,440 --> 01:06:54,280
THEY ARE RELEASED AND THEN WE

1358
01:06:54,280 --> 01:07:00,120
HAVE THE -- IN THE FECAL POOL

1359
01:07:00,120 --> 01:07:02,040
AND WHAT TYPE DO WE HAVE?

1360
01:07:02,040 --> 01:07:05,320
ARE THEY ABLE TO METABOLIZE

1361
01:07:05,320 --> 01:07:09,520
PRIMARY ISOLATES INTO SECONDARY

1362
01:07:09,520 --> 01:07:14,240
BILE ACIDS AND IF NOT THIS

1363
01:07:14,240 --> 01:07:17,800
BALANCE ACTUALLY CAN CONTROL THE

1364
01:07:17,800 --> 01:07:25,000
RELEASE OF -- -- IN THE LIVER.

1365
01:07:25,000 --> 01:07:32,560
THESE BILING   BILE ACIDS GO
INTO THE

1366
01:07:32,560 --> 01:07:35,440
LIVER WHICH LEADS TO THE

1367
01:07:35,440 --> 01:07:40,520
ACCUMULATION OF CXCR6 POSITIVE

1368
01:07:40,520 --> 01:07:45,000
NKT CELLS AND THESE NKT CELLS

1369
01:07:45,000 --> 01:07:49,080
CAN CONTROL TUMOR GROWTH.

1370
01:07:49,080 --> 01:07:51,600
THIS IS AN IDEAL MOUSE MODEL

1371
01:07:51,600 --> 01:07:54,120
WHERE WE CAN STUDY THIS AND THE

1372
01:07:54,120 --> 01:07:56,680
QUESTION OBVIOUSLY NOW IS DOES

1373
01:07:56,680 --> 01:07:59,760
THIS APPLY TO HUMAN AND PATIENTS

1374
01:07:59,760 --> 01:08:01,040
WITH LIVER TUMORS.

1375
01:08:01,040 --> 01:08:02,200
WE DON'T KNOW YET.

1376
01:08:02,200 --> 01:08:04,120
WE'RE GOING TO STUDY THIS.

1377
01:08:04,120 --> 01:08:07,320
WE KNOW FROM LARGE PATIENT

1378
01:08:07,320 --> 01:08:08,800
COHORTS THAT THERE APPEARS TO BE

1379
01:08:08,800 --> 01:08:11,120
A CORRELATION BETWEEN THE BILE

1380
01:08:11,120 --> 01:08:14,440
ACIDS CONCENTRATION PRIMARY TO

1381
01:08:14,440 --> 01:08:18,240
SECONDARY -- AND THE EXPRESSION

1382
01:08:18,240 --> 01:08:23,720
OF THE CXCL16.

1383
01:08:23,720 --> 01:08:26,040
AND A STUDY HAS SHOWN THAT THE

1384
01:08:26,040 --> 01:08:28,560
SAME ANTIBIOTICS THAT WE USE IN

1385
01:08:28,560 --> 01:08:31,840
OUR MOUSE MODEL CAN ACTUALLY

1386
01:08:31,840 --> 01:08:36,720
ALSO CHANGE THE BILE ACID

1387
01:08:36,720 --> 01:08:39,720
COMPOSITION IN BLOOD FROM

1388
01:08:39,720 --> 01:08:41,920
PATIENTS THAT WERE ENROLLED IN A

1389
01:08:41,920 --> 01:08:43,520
SMALL CLINICAL TRIAL.

1390
01:08:43,520 --> 01:08:47,720
SO THERE IS CERTAINLY SOME DATA

1391
01:08:47,720 --> 01:08:49,840
SUGGESTING THAT THIS MECHANISM

1392
01:08:49,840 --> 01:08:52,200
MAY ALSO APPLY TO HUMAN.

1393
01:08:52,200 --> 01:08:55,600
SO WE'RE TESTING IT WHERE WE

1394
01:08:55,600 --> 01:09:00,000
TREAT PATIENTS TO TARGET THE

1395
01:09:00,000 --> 01:09:02,000
SPECIFIC -- SPECIES AND

1396
01:09:02,000 --> 01:09:04,520
HOPEFULLY IN A YEAR OR SO I WILL

1397
01:09:04,520 --> 01:09:08,880
BE ABLE TO SHOW YOU THIS DATA.

1398
01:09:08,880 --> 01:09:12,080
NOW I WOULD LIKE TO CHANGE GEARS

1399
01:09:12,080 --> 01:09:15,480
AGAIN AND GO AND TELL YOU ABOUT

1400
01:09:15,480 --> 01:09:24,560
BAILY CANCER.

1401
01:09:24,560 --> 01:09:28,040
A SECOND MECHANISM HOW GUT

1402
01:09:28,040 --> 01:09:32,320
BACTERIA CAN CONTROL BILIARY

1403
01:09:32,320 --> 01:09:32,840
CANCER.

1404
01:09:32,840 --> 01:09:35,640
IT IS RELATIVELY RARE.

1405
01:09:35,640 --> 01:09:38,520
PRIMARY CANCER OF THE LIVER --

1406
01:09:38,520 --> 01:09:40,240
BUT IT IS SOMEWHAT INTERESTING

1407
01:09:40,240 --> 01:09:42,360
BECAUSE THERE ARE CERTAIN RISK

1408
01:09:42,360 --> 01:09:43,880
FACTORS INCLUDING A DISEASE

1409
01:09:43,880 --> 01:09:48,560
WHICH IS CALLED PRIMARY -- AND

1410
01:09:48,560 --> 01:09:51,320
INFLAMMATORY BOWEL DISEASE WHICH

1411
01:09:51,320 --> 01:09:52,920
IS ASSOCIATED WITH BILIARY

1412
01:09:52,920 --> 01:09:54,600
CANCER.

1413
01:09:54,600 --> 01:09:58,240
NOW IT HAD ALREADY BEEN SHOWN

1414
01:09:58,240 --> 01:10:01,240
THAT THERE IS WHAT WE CALL

1415
01:10:01,240 --> 01:10:06,120
INTESTINAL -- IN PATIENTS.

1416
01:10:06,120 --> 01:10:09,520
YOU CAN SEE ON THIS ANALYSIS THE

1417
01:10:09,520 --> 01:10:11,640
HEALTHY CONTROLS AND THEN HERE

1418
01:10:11,640 --> 01:10:17,840
PATIENTS WITH PSC -- AND HERE

1419
01:10:17,840 --> 01:10:22,920
YOU CAN SEE THE MORE DETAILED

1420
01:10:22,920 --> 01:10:24,960
DESCRIPTION OF THE BACTERIA IN

1421
01:10:24,960 --> 01:10:26,320
THESE INDIVIDUALS.

1422
01:10:26,320 --> 01:10:28,680
THE IMPORTANT THING TO REMEMBER

1423
01:10:28,680 --> 01:10:32,600
IS THAT APPARENTLY A DISEASE IN

1424
01:10:32,600 --> 01:10:38,280
THE LIVER CAN CAUSE DISBIOS US

1425
01:10:38,280 --> 01:10:40,800
AND CHANGES IN THE COMPOSITION

1426
01:10:40,800 --> 01:10:53,360
OF THE GUT BACTERIA.

1427
01:10:53,360 --> 01:11:05,200
WE USED TWO DIFFERENT MODELS.

1428
01:11:05,200 --> 01:11:07,520
AND THE WAY WE DO THIS AND WAY

1429
01:11:07,520 --> 01:11:12,840
WE USE THIS IS BY A TECHNIQUE --

1430
01:11:12,840 --> 01:11:18,040
SO WE CAN ACTUALLY INJECT PLASMA

1431
01:11:18,040 --> 01:11:20,400
OF INTEREST INTO THE MICE AND

1432
01:11:20,400 --> 01:11:22,160
BECAUSE WE USE A RELATIVELY

1433
01:11:22,160 --> 01:11:26,720
LARGE AMOUNT OF VOLUME THAT WE

1434
01:11:26,720 --> 01:11:29,920
INJECT IN A SHORT AMOUNT OF TIME

1435
01:11:29,920 --> 01:11:31,440
WE CAN GET EFFICIENCY IN THE

1436
01:11:31,440 --> 01:11:33,480
LIVER AND THESE MICE WILL

1437
01:11:33,480 --> 01:11:39,440
EXPRESS THE GENE OF INTEREST.

1438
01:11:39,440 --> 01:11:43,040
WE COMBINE THESE MODELS WITH

1439
01:11:43,040 --> 01:11:46,280
DIFFERENT PSC MODELS WHICH ONE

1440
01:11:46,280 --> 01:11:48,640
IS A GENETIC MODEL.

1441
01:11:48,640 --> 01:11:49,680
KNOCKOUT MODEL.

1442
01:11:49,680 --> 01:11:53,000
YOU CAN SEE HOW THE MICE DEVELOP

1443
01:11:53,000 --> 01:11:55,640
THE INFLAMMATION AND SCARS

1444
01:11:55,640 --> 01:11:58,280
AROUND THE BILE DUCTS AND THE

1445
01:11:58,280 --> 01:12:02,160
MODEL ON THE RIGHT IS WHERE WE

1446
01:12:02,160 --> 01:12:05,120
CONDUCT BILE -- IN THESE MICE.

1447
01:12:05,120 --> 01:12:11,480
SO IF WE INDUCE PSC IN THESE

1448
01:12:11,480 --> 01:12:14,160
MICE AND YOU CAN SEE HERE THE

1449
01:12:14,160 --> 01:12:17,160
RESULT WHERE WE INDUCE THE PSC

1450
01:12:17,160 --> 01:12:20,880
AND THE SAME APPLIES WITH MICE

1451
01:12:20,880 --> 01:12:22,840
-- THE KNOCKOUT MICE.

1452
01:12:22,840 --> 01:12:25,680
IT WAS INTERESTING TO SEE IF WE

1453
01:12:25,680 --> 01:12:30,680
LOOK AT THE -- THERE ARE CLEAR

1454
01:12:30,680 --> 01:12:35,640
SIGNS OF COLITIS.

1455
01:12:35,640 --> 01:12:36,880
YOU DON'T HAVE THE NICE

1456
01:12:36,880 --> 01:12:39,640
STRUCTURE AND THE MICE AFTER

1457
01:12:39,640 --> 01:12:42,240
BILE DUCT LOCATION AND IF YOU

1458
01:12:42,240 --> 01:12:45,080
LOOK AT PROTEINS IN THIS CASE --

1459
01:12:45,080 --> 01:12:47,080
YOU CAN SEE THAT THEY ARE

1460
01:12:47,080 --> 01:12:52,520
REDUCED IN MICE THAT HAVE

1461
01:12:52,520 --> 01:12:54,160
UNDERGONE BILE .

1462
01:12:54,160 --> 01:13:01,160
WE LOOKED AT THE NUMBER OF --

1463
01:13:01,160 --> 01:13:02,360
[ INDISCERNIBLE ]

1464
01:13:02,360 --> 01:13:06,720
WE LOOKED AT THE PORTER VEIN OF

1465
01:13:06,720 --> 01:13:13,760
THESE MICE AND WE CAN IDENTIFY

1466
01:13:13,760 --> 01:13:15,240
16SRNA.

1467
01:13:15,240 --> 01:13:17,000
WHICH A FUNCTIONAL EXAMPLE

1468
01:13:17,000 --> 01:13:23,720
PEOPLE--EXPERIMENT.

1469
01:13:23,720 --> 01:13:25,240
AND THEN WE CAN FIND THIS AND

1470
01:13:25,240 --> 01:13:28,840
YOU CAN SEE AN INCREASED UP TAKE

1471
01:13:28,840 --> 01:13:32,160
IN MICE AS A READ OUT FOR LEAKY

1472
01:13:32,160 --> 01:13:33,680
GUT AND COLITIS.

1473
01:13:33,680 --> 01:13:36,760
AND IF WE LOOK AT PATIENT

1474
01:13:36,760 --> 01:13:39,920
SAMPLES WE CAN FIND SIGNS OF A

1475
01:13:39,920 --> 01:13:42,120
BACTERIA IN LPS.

1476
01:13:42,120 --> 01:13:47,160
NOW IF YOU FYWE LOOK AT THE --

1477
01:13:47,160 --> 01:13:51,280
MICE IN WHICH WE INDUCE PSC WE

1478
01:13:51,280 --> 01:13:54,800
NOTICE AN ACCUMULATION OF

1479
01:13:54,800 --> 01:13:58,480
MYELOID OR DEpReS OR CELLS.

1480
01:13:58,480 --> 01:14:02,280
WHICH WE HAVE STUDIED * AND THEY

1481
01:14:02,280 --> 01:14:04,520
ARE VERY IMPORTANT IMMUNE

1482
01:14:04,520 --> 01:14:05,120
SUPPRESSORS.

1483
01:14:05,120 --> 01:14:10,400
YOU CAN SEE AN INCREASE OF THIS

1484
01:14:10,400 --> 01:14:13,080
CELL IN MICE WITH PSC.

1485
01:14:13,080 --> 01:14:16,120
WE CAN FURTHER SUBDIVIDE AND I'M

1486
01:14:16,120 --> 01:14:19,240
NOT GOING TO GO INTO THE DETAILS

1487
01:14:19,240 --> 01:14:26,280
-- ---THIS DOESN'T ONLY APPLY TO

1488
01:14:26,280 --> 01:14:28,000
ONE MODEL BUT WE CAN FIND THIS

1489
01:14:28,000 --> 01:14:29,840
IN THE SECOND MODEL.

1490
01:14:29,840 --> 01:14:34,040
NOW IF WE TREAT THESE MILES

1491
01:14:34,040 --> 01:14:37,640
SPECIFICALLY WITH NEOMYCIN YOU

1492
01:14:37,640 --> 01:14:41,760
CAN SEE THE ACCUMULATION -- THE

1493
01:14:41,760 --> 01:14:43,800
CELLS ARE NO LONGER PRESENT AND

1494
01:14:43,800 --> 01:14:47,320
IF WE PERFORM FMT STUDIES.

1495
01:14:47,320 --> 01:14:49,720
STUDIES WHERE WE TAKE REGULAR

1496
01:14:49,720 --> 01:14:52,400
MICE KEPT UNDER SPF CONDITIONS

1497
01:14:52,400 --> 01:14:58,360
AND WE TREAT THEM -- TO TARGET

1498
01:14:58,360 --> 01:15:02,880
GRAM POSITIVE OR GRAM NEGATIVE

1499
01:15:02,880 --> 01:15:04,280
BACTERIA.

1500
01:15:04,280 --> 01:15:06,800
HARVEST STOOL SAMPLES AND THEN

1501
01:15:06,800 --> 01:15:08,720
TRANSFER THESE INTO GERMFREE

1502
01:15:08,720 --> 01:15:11,200
MUSIC SEE THIS HAS A SIGNIFICANT

1503
01:15:11,200 --> 01:15:15,080
IMPACT ON THE NUMBER OF CELLS

1504
01:15:15,080 --> 01:15:16,960
AND YOU CAN SEE ON THE LOWER

1505
01:15:16,960 --> 01:15:20,480
RIGHT CORNER IF WE TREAT THESE

1506
01:15:20,480 --> 01:15:26,320
MICE WITH STOOL -- THERE IS A

1507
01:15:26,320 --> 01:15:35,240
SIGNIFICANT INCREASE.

1508
01:15:35,240 --> 01:15:38,760
DOES THIS ALSO LEAD TO AN

1509
01:15:38,760 --> 01:15:40,080
ACCUMULATION AS SHOWN ON THIS

1510
01:15:40,080 --> 01:15:40,920
SLIDE.

1511
01:15:40,920 --> 01:15:46,080
THE WHOLE MECHANISM -- ---

1512
01:15:46,080 --> 01:15:48,840
---APPEARS TO BE DEPENDENT ON

1513
01:15:48,840 --> 01:15:56,640
AGAIN A MECHANISM OR TLR4 AND

1514
01:15:56,640 --> 01:15:59,440
CXCL1.

1515
01:15:59,440 --> 01:16:05,280
MICE TREATED WITH -- TO INDUCE

1516
01:16:05,280 --> 01:16:09,080
COLITIS HAVE INCREASED NUMBERS.

1517
01:16:09,080 --> 01:16:15,400
WE CAN CLOCK OR OVER EXPRESS IT

1518
01:16:15,400 --> 01:16:17,800
AND THIS IS DEPENDENT ON

1519
01:16:17,800 --> 01:16:20,520
EXPRESSION OF TLR4.

1520
01:16:20,520 --> 01:16:23,920
YOU CAN SEE IN MICE WHERE THE

1521
01:16:23,920 --> 01:16:26,240
RECEPTOR IS KNOCKED OUT AND WE

1522
01:16:26,240 --> 01:16:27,600
DON'T FIND THESE CELLS.

1523
01:16:27,600 --> 01:16:31,800
SO WHAT I'VE SHOWN YOU IN THE

1524
01:16:31,800 --> 01:16:34,040
CONTEXT OF LIVER -- MICE THAT

1525
01:16:34,040 --> 01:16:36,480
DEVELOP A LEAKY GUT.

1526
01:16:36,480 --> 01:16:43,600
IT PLAYS A SIGNIFICANT ROLE.

1527
01:16:50,840 --> 01:16:55,920
AND THIS MECHANISM APPEARS TO BE

1528
01:16:55,920 --> 01:16:58,240
DEPENDENT TO GRAM NEGATIVE

1529
01:16:58,240 --> 01:17:06,080
BACTERIA.

1530
01:17:06,080 --> 01:17:07,320
NOW I HAVE NOT SHOWN YOU

1531
01:17:07,320 --> 01:17:09,200
ANYTHING ABOUT TUMORS AT THIS

1532
01:17:09,200 --> 01:17:09,600
POINT.

1533
01:17:09,600 --> 01:17:12,520
THIS IS ONLY LIVER CIRRHOSIS.

1534
01:17:12,520 --> 01:17:16,680
LEAKY GUT.

1535
01:17:16,680 --> 01:17:18,320
SO WHAT I WOULD LIKE TO SHOW YOU

1536
01:17:18,320 --> 01:17:21,080
NOW IS IF WE COMBINE THE MODELS

1537
01:17:21,080 --> 01:17:23,880
WHERE WE INDUCE TUMORS BY

1538
01:17:23,880 --> 01:17:29,280
INJECTION OF -- AND IN THIS CASE

1539
01:17:29,280 --> 01:17:31,800
-- WE SEE THAT THESE MICE

1540
01:17:31,800 --> 01:17:34,280
DEVELOP MORE AND LARGER TUMORS.

1541
01:17:34,280 --> 01:17:36,880
THE SAME APPLIES TO A SECOND

1542
01:17:36,880 --> 01:17:41,680
MODEL WHERE WE USE MDR2.

1543
01:17:41,680 --> 01:17:44,440
OR IF WE INDUCE COLITIS.

1544
01:17:44,440 --> 01:17:46,560
BUT ANYTHING THAT I'VE SHOWN YOU

1545
01:17:46,560 --> 01:17:52,920
SO FAR THAT LOCALS CONTROLS THE

1546
01:17:52,920 --> 01:17:55,160
MDSCS IT CONTROLS TUMORS.

1547
01:17:55,160 --> 01:17:57,920
IF WE OVER EXPRESS IN THE LIST

1548
01:17:57,920 --> 01:18:09,960
WE FIND MORE TUMORS.

1549
01:18:09,960 --> 01:18:12,400
WE CAN CONTROL AGAIN TUMOR

1550
01:18:12,400 --> 01:18:15,080
GROWTH IN THE MICE DEPENDENT ON

1551
01:18:15,080 --> 01:18:18,800
WHETHER WE COLONIZE MICE WITH

1552
01:18:18,800 --> 01:18:22,680
STOOL FROM THE INITIAL MICE

1553
01:18:22,680 --> 01:18:24,920
TREATED WITH NEO MICE SIN.

1554
01:18:24,920 --> 01:18:29,640
AND THE * THE MECHANISM IS

1555
01:18:29,640 --> 01:18:32,640
DEPENDENT ON THE RECEPTOR.

1556
01:18:32,640 --> 01:18:37,920
YOU CAN SEE THE BACTERIA OR THE

1557
01:18:37,920 --> 01:18:41,120
LPS DERIVED FROM A THE MICE WITH

1558
01:18:41,120 --> 01:18:43,760
COLITIS GO INTO THE LIVER AND

1559
01:18:43,760 --> 01:18:46,720
THEY DO NOT EXPRESS THE

1560
01:18:46,720 --> 01:18:47,320
RECEPTOR.

1561
01:18:47,320 --> 01:18:49,760
WE HAVE FEWER TUMORS AND WE CAN

1562
01:18:49,760 --> 01:18:51,240
OVERCOME THIS AGAIN BY OVER

1563
01:18:51,240 --> 01:19:19,120
EXPRESSION.

1564
01:19:19,120 --> 01:19:23,240
THERE IS SHOWN HERE UNDER NORMAL

1565
01:19:23,240 --> 01:19:24,360
CONDITIONS.

1566
01:19:24,360 --> 01:19:32,080
A NORMA NORM --

1567
01:19:34,840 --> 01:19:38,720
THIS WOULD BASICALLY CHANGE BILE

1568
01:19:38,720 --> 01:19:39,880
ACIDS AND CAUSE OTHER CHANGES

1569
01:19:39,880 --> 01:19:44,160
THAT WILL LEAD TO DISPIES ON US

1570
01:19:44,160 --> 01:19:50,040
AND A CHANGE * IN THE

1571
01:19:50,040 --> 01:20:03,960
COMPOSITION.

1572
01:20:03,960 --> 01:20:06,520
AND THEN WHAT I'VE SHOWN YOU

1573
01:20:06,520 --> 01:20:16,080
HERE THAT THROUGH A TLR4 -- THEY

1574
01:20:16,080 --> 01:20:38,720
EXPRESS CXCL1.

1575
01:20:38,720 --> 01:20:41,080
SO I BELIEVE I'VE SHOWN YOU HERE

1576
01:20:41,080 --> 01:20:44,160
TWO DIFFERENT MODELS HOW THE

1577
01:20:44,160 --> 01:20:46,720
MICROBIOME CAN CONTRIBUTOR

1578
01:20:46,720 --> 01:20:49,920
CHANGE THE TUMOR MICRO

1579
01:20:49,920 --> 01:20:51,040
ENVIRONMENT.

1580
01:20:51,040 --> 01:20:54,400
I'VE SHOWN YOU HOW THE LEAKY GUT

1581
01:20:54,400 --> 01:20:59,440
CAN LEAD TO AN ACCUMULATION OF

1582
01:20:59,440 --> 01:21:03,080
-- ---WHICH CAN CAUSE

1583
01:21:03,080 --> 01:21:04,960
INFLAMMATION BUT THERE IS OTHER

1584
01:21:04,960 --> 01:21:06,240
MECHANISMS THAT I DIDN'T SHOW

1585
01:21:06,240 --> 01:21:08,760
YOU OUT OF TIME BECAUSE I WANTED

1586
01:21:08,760 --> 01:21:11,280
TO SPECIFICALLY FOCUS ON IMMUNE

1587
01:21:11,280 --> 01:21:11,920
RESPONSES.

1588
01:21:11,920 --> 01:21:14,040
WE KNOW THERE ARE ALSO EFFECTS

1589
01:21:14,040 --> 01:21:20,160
THAT ARE MEDIATED BY STELATE

1590
01:21:20,160 --> 01:21:20,760
CELLS.

1591
01:21:20,760 --> 01:21:24,840
WE KNOW THAT THE -- THAT ARE

1592
01:21:24,840 --> 01:21:28,280
AFFECTED IN THE SYSTEM CAN ALSO

1593
01:21:28,280 --> 01:21:35,720
HAVE DIRECT EFFECT ON

1594
01:21:35,720 --> 01:21:40,520
HEPATOCYTES.

1595
01:21:40,520 --> 01:21:42,400
WHICH HAVE BEEN DESCRIBED TO

1596
01:21:42,400 --> 01:21:45,280
CONTROLLED TUMOR GROWTH.

1597
01:21:45,280 --> 01:21:47,200
SO WHAT I WOULD LIKE TO

1598
01:21:47,200 --> 01:21:52,480
SUMMARIZE AND LEAVE YOU WITH IS

1599
01:21:52,480 --> 01:21:56,200
THERE ARE MICRO BIOTA DEPENDENT

1600
01:21:56,200 --> 01:21:58,840
OF REGULATION OF CANCER

1601
01:21:58,840 --> 01:21:59,840
DEVELOPMENT AND PROGRESSION AND

1602
01:21:59,840 --> 01:22:00,320
TREATMENT.

1603
01:22:00,320 --> 01:22:05,040
IN THIS TALK I TOLD YOU ABOUT

1604
01:22:05,040 --> 01:22:07,720
THE MICRO BIOTA IN THE GUT AND

1605
01:22:07,720 --> 01:22:09,800
HOW THEY TALK TO THE LIVER.

1606
01:22:09,800 --> 01:22:13,040
WE KNOW THAT THESE MICRO BIOTA

1607
01:22:13,040 --> 01:22:15,560
CAN BE CHANGED TO A DIFFERENT

1608
01:22:15,560 --> 01:22:17,520
MECHANISM AS YOU HEARD IN THE

1609
01:22:17,520 --> 01:22:21,920
FIRST TALK HOW DIET CAN CHANGE

1610
01:22:21,920 --> 01:22:29,080
THIS.

1611
01:22:29,080 --> 01:22:31,760
WE CAN POTENTIALLY CHANGE THIS

1612
01:22:31,760 --> 01:22:37,120
BY ANTIBIOTICS.

1613
01:22:37,120 --> 01:22:43,920
WE CAN PERFORM FEELINGAL TRANS

1614
01:22:43,920 --> 01:22:45,040
TRANSPLANTATION.

1615
01:22:45,040 --> 01:22:47,200
THIS HAS AN EFFECT ON DIFFERENT

1616
01:22:47,200 --> 01:22:48,760
IMMUNE CELLS IN DIFFERENT PARTS

1617
01:22:48,760 --> 01:22:51,120
OF THE BODY.

1618
01:22:51,120 --> 01:22:53,720
I SPECIFICALLY FOCUSED ON THE

1619
01:22:53,720 --> 01:22:55,120
IMMUNE CELLS IN THE SPECIFIC

1620
01:22:55,120 --> 01:22:56,280
ENVIRONMENT OF THE LIVER AND I

1621
01:22:56,280 --> 01:22:59,240
SHOWED YOU IN THE FIRST PART

1622
01:22:59,240 --> 01:23:04,240
CHANGES ON NKT CELLS AND HOW IT

1623
01:23:04,240 --> 01:23:07,160
EFFECTS MYELOID CELLS AND THEN

1624
01:23:07,160 --> 01:23:10,600
THIS WILL LEAD TO CHANGES IN

1625
01:23:10,600 --> 01:23:12,800
CANCER INITIATION AND

1626
01:23:12,800 --> 01:23:13,200
PROGRESSION.

1627
01:23:13,200 --> 01:23:16,600
BUT THERE ARE ALSO VERY GOOD AND

1628
01:23:16,600 --> 01:23:19,120
INTERESTING DATA HOW THE GUT

1629
01:23:19,120 --> 01:23:22,400
MICROBIOME CAN ACTUALLY

1630
01:23:22,400 --> 01:23:25,440
POTENTIALLY ENHANCE THE EFFICACY

1631
01:23:25,440 --> 01:23:30,600
OR IMPAIR THE EFFICACY OF TYPES

1632
01:23:30,600 --> 01:23:32,720
OF CANCER TREATMENTS AND THERE

1633
01:23:32,720 --> 01:23:37,080
IS ACCUMULATING DATA ON

1634
01:23:37,080 --> 01:23:40,120
COMORBIDITY AND POTENTIAL SIDE

1635
01:23:40,120 --> 01:23:42,040
EFFECTS AND WITH THIS I WOULD

1636
01:23:42,040 --> 01:23:45,320
LIKE TO CLOSE AND THANK THE

1637
01:23:45,320 --> 01:23:46,520
PEOPLE IN MY LAB.

1638
01:23:46,520 --> 01:23:49,280
THE FIRST STUDY WAS LED BY THE

1639
01:23:49,280 --> 01:23:49,920
GROUP.

1640
01:23:49,920 --> 01:23:56,120
THE SECOND ONE BY -- AND NONE OF

1641
01:23:56,120 --> 01:23:58,680
THIS WORK WOULD BE POSSIBLE

1642
01:23:58,680 --> 01:24:00,520
WITHOUT COLLABORATORS IN THE

1643
01:24:00,520 --> 01:24:04,080
NIH.

1644
01:24:11,800 --> 01:24:15,480
WITH THIS I WOULD LIKE TO CLOSE

1645
01:24:15,480 --> 01:24:17,400
AND I'M HAPPY TO TAKE ANY

1646
01:24:17,400 --> 01:24:18,360
QUESTIONS.

1647
01:24:18,360 --> 01:24:19,880
>> THANK YOU.

1648
01:24:19,880 --> 01:24:23,040
THANK YOU VERY MUCH, TIM.

1649
01:24:23,040 --> 01:24:25,240
NOW WE HAVE A WHOLE SERIES OF

1650
01:24:25,240 --> 01:24:27,560
QUESTIONS AND I'VE TRIED TO PUT

1651
01:24:27,560 --> 01:24:32,520
SOME OF THEM TOGETHER SO THAT

1652
01:24:32,520 --> 01:24:34,720
FOLKS WHO -- NOT EVERYONE WHO

1653
01:24:34,720 --> 01:24:40,680
HAS SUBMITTED A QUESTION -- WILL

1654
01:24:40,680 --> 01:24:43,120
BE ABLE TO PRESENT.

1655
01:24:43,120 --> 01:24:50,960
LET ME POSE A FEW OF THEM HERE.

1656
01:24:50,960 --> 01:24:54,400
SO JEFF THE INTESTINAL

1657
01:24:54,400 --> 01:24:57,160
MICROBIOME CONSIST OF MORE THAN

1658
01:24:57,160 --> 01:24:58,760
JUST BACTERIA.

1659
01:24:58,760 --> 01:25:01,760
AND THERE IS AN INTERESTING

1660
01:25:01,760 --> 01:25:04,720
QUESTION ABOUT THE POSSIBLE ROLE

1661
01:25:04,720 --> 01:25:07,080
OR IF WE KNOW ANYTHING ABOUT THE

1662
01:25:07,080 --> 01:25:13,960
ROLE OF FACH AS THE MAJOR VIRUS

1663
01:25:13,960 --> 01:25:20,920
PRESENT IN THE INTESTINAL

1664
01:25:20,920 --> 01:25:22,960
MICROBIOME.

1665
01:25:22,960 --> 01:25:26,680
IS VIRUS LIKELY TO BE THE NEXT

1666
01:25:26,680 --> 01:25:29,720
AREA OF CONCERN IN TERMS OF ITS

1667
01:25:29,720 --> 01:25:35,080
INFLUENCING MICROBIOME ACTIVITY

1668
01:25:35,080 --> 01:25:36,920
OR WOULD YOU COMMENT ABOUT THAT?

1669
01:25:36,920 --> 01:25:39,920
IT'S AN INTERESTING QUESTION.

1670
01:25:39,920 --> 01:25:44,600
>> WELL, I THINK THAT IS A VERY

1671
01:25:44,600 --> 01:25:48,440
APPROPRIATE QUESTION TO ASK

1672
01:25:48,440 --> 01:25:54,160
CONSIDERING THAT FACH INFLUENCE

1673
01:25:54,160 --> 01:26:01,000
-- THAT MANY BACTERIA HAVE PRO

1674
01:26:01,000 --> 01:26:03,240
FAGUE WITHIN THEIR GENOME.

1675
01:26:03,240 --> 01:26:08,960
THE PARTS OF THE MICROBIOTA ARE

1676
01:26:08,960 --> 01:26:09,520
INTERCONNECTED.

1677
01:26:09,520 --> 01:26:11,040
THERE IS ROBUSTNESS.

1678
01:26:11,040 --> 01:26:13,240
AND THE ABILITY TO EXPRESS

1679
01:26:13,240 --> 01:26:14,920
CRITICAL FUNCTIONS DESPITE A

1680
01:26:14,920 --> 01:26:17,960
NUMBER OF PROTO BASES AND THE

1681
01:26:17,960 --> 01:26:19,800
ABILITY TO RECOVER.

1682
01:26:19,800 --> 01:26:21,320
*.

1683
01:26:21,320 --> 01:26:23,720
THERE IS A LITTLE QUESTION THAT

1684
01:26:23,720 --> 01:26:25,920
IT'S PLAYING ITSELF OUT WITHIN

1685
01:26:25,920 --> 01:26:29,720
THE GUT MICRO BIOTA BUT IT'S A

1686
01:26:29,720 --> 01:26:32,520
DIFFICULT SYSTEM TO DISSECT.

1687
01:26:32,520 --> 01:26:34,840
SO THERE IS AN EFFORT TO

1688
01:26:34,840 --> 01:26:39,000
CHARACTERIZE THE FHAGE THAT ARE

1689
01:26:39,000 --> 01:26:42,280
REPRESENTED IN MICROBIAL

1690
01:26:42,280 --> 01:26:43,360
COMMUNITIES.

1691
01:26:43,360 --> 01:26:48,320
MANY OF THE GENES IN BACTERIA

1692
01:26:48,320 --> 01:26:50,320
PHAGE -- WE HAVE LITTLE

1693
01:26:50,320 --> 01:26:51,520
UNDERSTANDING OF THEIR FUNCTION

1694
01:26:51,520 --> 01:26:56,400
WHICH LIMITS OUR ABILITY TO

1695
01:26:56,400 --> 01:26:57,320
GREATLY APPRECIATE THEIR

1696
01:26:57,320 --> 01:27:00,360
INFLUENCE ON THEIR HOST BACTERIA

1697
01:27:00,360 --> 01:27:01,120
CELLS.

1698
01:27:01,120 --> 01:27:03,240
THEY'VE BEEN VIEWED FOR SOME

1699
01:27:03,240 --> 01:27:06,800
TIME AS THERAPEUTIC AGENTS SO

1700
01:27:06,800 --> 01:27:10,440
ONE COULD DELIBERATELY STAGE AN

1701
01:27:10,440 --> 01:27:13,200
ATTACK OR TARGET PARTICULAR

1702
01:27:13,200 --> 01:27:13,600
ORGANISMS.

1703
01:27:13,600 --> 01:27:15,800
I WOULD ASK THE PERSON WHO POSED

1704
01:27:15,800 --> 01:27:18,560
THE QUESTION TO CONSIDER THE

1705
01:27:18,560 --> 01:27:24,440
FACT THAT PHAGE ARE A COMPONENT

1706
01:27:24,440 --> 01:27:31,440
ARE INSTRUMENTAL IN PROPELLING

1707
01:27:31,440 --> 01:27:33,320
THE DYNAMISM BUT WE HAVE A LOT

1708
01:27:33,320 --> 01:27:35,360
TO LEARN.

1709
01:27:35,360 --> 01:27:39,000
ONE SCHOOL COULD BE THE VERY

1710
01:27:39,000 --> 01:27:45,720
MODELS WE TALKED B. DEFINED

1711
01:27:45,720 --> 01:27:47,160
COMMUNITIES CAN BE INTRODUCED

1712
01:27:47,160 --> 01:27:49,280
INTO THE ENTRUSTMENTS OF THE

1713
01:27:49,280 --> 01:27:51,200
ANIMALS.

1714
01:27:51,200 --> 01:27:53,160
DEFINED COMMUNITIES CREATED AND

1715
01:27:53,160 --> 01:27:56,920
DELIBERATE ATTACKS BY PHAGE.

1716
01:27:56,920 --> 01:28:07,000
RECOVERED FROM HEALTHY OR

1717
01:28:07,000 --> 01:28:11,320
DISEASED INDIVIDUALS.

1718
01:28:11,320 --> 01:28:13,640
BUT THE DEVELOPMENT OF

1719
01:28:13,640 --> 01:28:16,400
RESISTANCE -- IS A FORM OF

1720
01:28:16,400 --> 01:28:18,040
BACTERIAL IMMUNITY.

1721
01:28:18,040 --> 01:28:21,560
WHETHER THE PHAGE DYNAMIC IS

1722
01:28:21,560 --> 01:28:41,960
MORE TELL RAT -- TELL RANT OR
NOT.

1723
01:28:41,960 --> 01:28:43,880
>> ANOTHER QUESTION IS IN SOME

1724
01:28:43,880 --> 01:28:47,200
OF YOUR EARLIEST WORK I RECALL

1725
01:28:47,200 --> 01:28:48,760
THAT YOU WERE INTERESTED IN THE

1726
01:28:48,760 --> 01:28:53,320
QUESTION OF HOW THE INTESTINE

1727
01:28:53,320 --> 01:28:54,560
ACTUALLY DEVELOPS?

1728
01:28:54,560 --> 01:28:56,040
HOW THE INDIVIDUAL CELLS

1729
01:28:56,040 --> 01:28:57,680
CARRYING OUT DIFFERENT FUNCTIONS

1730
01:28:57,680 --> 01:29:00,760
ALONG THE LENGTH OF THE

1731
01:29:00,760 --> 01:29:03,320
INTESTINE COMPARTMENTALIZE THOSE

1732
01:29:03,320 --> 01:29:07,160
AREAS OF THE GUT.

1733
01:29:07,160 --> 01:29:10,040
SO THERE IS A QUESTION AS TO

1734
01:29:10,040 --> 01:29:15,400
WHAT DETERMINES -- WELL IT'S A

1735
01:29:15,400 --> 01:29:16,120
DOUBLE QUESTION.

1736
01:29:16,120 --> 01:29:20,160
WHAT DETERMINES THE MICROBIOME

1737
01:29:20,160 --> 01:29:21,320
DEVELOPMENT WITH AGE?

1738
01:29:21,320 --> 01:29:26,280
AND THE OTHER SIDE OF IT IS DOES

1739
01:29:26,280 --> 01:29:31,240
THE MICROBIOME IN THE NEWBORN

1740
01:29:31,240 --> 01:29:35,680
PLAY A ROLE IN THIS DEVELOPMENT

1741
01:29:35,680 --> 01:29:40,400
OF THE INTESTINE AND ITS VARIOUS

1742
01:29:40,400 --> 01:29:43,520
SEGMENT TALL FUNCTIONS AND

1743
01:29:43,520 --> 01:29:43,880
DISTRIBUTIONS.

1744
01:29:43,880 --> 01:29:48,600
*.

1745
01:29:48,600 --> 01:29:49,480
>> BIOGEOGRAPHY, THE FACT THAT

1746
01:29:49,480 --> 01:29:52,280
WE HAVE TO LOOK AT THE INTESTINE

1747
01:29:52,280 --> 01:29:54,920
AS CHANGING NOT ONLY WITH AGE

1748
01:29:54,920 --> 01:29:56,360
DURING THE FIRST SEVERAL YEARS

1749
01:29:56,360 --> 01:29:58,400
OF LIFE BUT ALSO THE FACT THAT

1750
01:29:58,400 --> 01:30:00,920
THERE ARE DIFFERENT COMMUNITY

1751
01:30:00,920 --> 01:30:02,240
CONFIGURATIONS ALONG THE LENGTH

1752
01:30:02,240 --> 01:30:03,640
OF THE GUT.

1753
01:30:03,640 --> 01:30:07,720
THAT THE SMALL INTESTINAL MICRO

1754
01:30:07,720 --> 01:30:11,120
BIOTA HAS BEEN A -- IN DOING

1755
01:30:11,120 --> 01:30:14,080
NITA BECAUSE OF THE DIFFICULTY

1756
01:30:14,080 --> 01:30:15,040
OF SAMPLING.

1757
01:30:15,040 --> 01:30:18,280
WE HAVE TO THINK ABOUT THE AGE

1758
01:30:18,280 --> 01:30:20,440
OF THE HOST.

1759
01:30:20,440 --> 01:30:22,240
THE CO-DEVELOPMENT AND WHAT

1760
01:30:22,240 --> 01:30:24,480
REGIONS OF THE INTESTINE WE WANT

1761
01:30:24,480 --> 01:30:27,920
TO SEEK TO REPAIR.

1762
01:30:27,920 --> 01:30:29,760
AND I'LL JUST SAY TO THE PERSON

1763
01:30:29,760 --> 01:30:32,320
WHO ASKED THE QUESTION.

1764
01:30:32,320 --> 01:30:34,920
NUMBER ONE, THERE IS AN ONGOING

1765
01:30:34,920 --> 01:30:36,720
EFFORT TO DETERMINE THE DEGREE

1766
01:30:36,720 --> 01:30:44,840
TO WHICH THE SMALL ENTRUS IN --

1767
01:30:44,840 --> 01:30:46,720
INTESTINE IS CONTRIBUTING TO THE

1768
01:30:46,720 --> 01:30:47,320
DISORDER.

1769
01:30:47,320 --> 01:30:49,880
IT WAS FIRST IDENTIFIED IN PEACE

1770
01:30:49,880 --> 01:30:51,800
CORPS WORKERS RETURNING TO THE

1771
01:30:51,800 --> 01:30:53,440
UNITED STATES AFTER LIVING FOR

1772
01:30:53,440 --> 01:30:56,200
SEVERAL YEARS IN AREAS OF POOR

1773
01:30:56,200 --> 01:30:57,320
SANITATION.

1774
01:30:57,320 --> 01:31:01,000
WHERE THEY HAD DEVELOPED MALL

1775
01:31:01,000 --> 01:31:03,760
ABSORBS, WEIGHT LOSS, DIARRHEA

1776
01:31:03,760 --> 01:31:05,880
AND THEY WERE ENDOSCOPED AND

1777
01:31:05,880 --> 01:31:08,640
WHAT WAS SEEN WAS THE SMALL

1778
01:31:08,640 --> 01:31:11,240
INTESTINAL VILLA HAD COLLAPSED.

1779
01:31:11,240 --> 01:31:15,320
THE SURFACE AREA HAD BEEN

1780
01:31:15,320 --> 01:31:15,920
REDUCED.

1781
01:31:15,920 --> 01:31:18,120
THE BARRIER DISRUPTED.

1782
01:31:18,120 --> 01:31:20,240
THERE WAS INFLAMMATORY DISORDER

1783
01:31:20,240 --> 01:31:23,720
IN THE SMALL INTESTINE.

1784
01:31:23,720 --> 01:31:26,480
THE BILL AND MELINDA GATES

1785
01:31:26,480 --> 01:31:28,240
FOUNDATION HAS BEEN WONDERING

1786
01:31:28,240 --> 01:31:32,000
WHETHER THE SMALL INTESTINAL

1787
01:31:32,000 --> 01:31:36,160
MICROBIOTA IS -- IN UNDER

1788
01:31:36,160 --> 01:31:37,680
NOURISHED CHILDREN.

1789
01:31:37,680 --> 01:31:40,760
OF CHILDREN WHO FAILED STANDARD

1790
01:31:40,760 --> 01:31:42,080
INTERVENTIONS AND WHERE IN

1791
01:31:42,080 --> 01:31:44,760
HIGHLY SPECIALIZED CENTERS WITH

1792
01:31:44,760 --> 01:31:48,280
ETHICAL APPROVAL THESE CHILDREN

1793
01:31:48,280 --> 01:31:51,720
UNDERWENT IN DO IS CO-PEOPLE TO

1794
01:31:51,720 --> 01:31:54,840
DETERMINE IF THEIR SMALL

1795
01:31:54,840 --> 01:32:09,840
INTESTINES -- --

1796
01:32:09,840 --> 01:32:11,720
AS WE MOVE FORWARD TO LOOK AT

1797
01:32:11,720 --> 01:32:14,640
THE DEVELOPMENTAL BIOLOGY AND

1798
01:32:14,640 --> 01:32:16,600
REPAIR AND STATES OF DISEASE

1799
01:32:16,600 --> 01:32:19,000
THAT WE'RE GOING TO HAVE TO HAVE

1800
01:32:19,000 --> 01:32:22,080
A POSITIONAL PERSPECTIVE.

1801
01:32:22,080 --> 01:32:23,800
ONE LAST COMMENT.

1802
01:32:23,800 --> 01:32:26,920
THE PERSON WHO QUESTIONED OR

1803
01:32:26,920 --> 01:32:28,360
RAISEDDED  THIS QUESTION MUST

1804
01:32:28,360 --> 01:32:33,880
HAVE SPENT SOME TIME IN THE LAB

1805
01:32:33,880 --> 01:32:38,280
UNDER STEALTH TECHNOLOGY.

1806
01:32:38,280 --> 01:32:41,760
IS THE REPAIR OF THE MICRO BUY

1807
01:32:41,760 --> 01:32:44,040
AT ON ASSOCIATED WITH THE

1808
01:32:44,040 --> 01:32:48,760
EFFECTS ON EPITHELIAL BIOLOGY *.

1809
01:32:48,760 --> 01:32:50,920
CAN ONE CONNECT THE DOTS TO SEE

1810
01:32:50,920 --> 01:32:54,040
HOW REPAIR OF THE MICRO BIOTA

1811
01:32:54,040 --> 01:32:57,480
READS OUT IN TERMS OF THE

1812
01:32:57,480 --> 01:33:00,480
EXPRESSION OF GENES IN DIFFERENT

1813
01:33:00,480 --> 01:33:08,560
EPITHELIAL LINEAGES AS THEY

1814
01:33:08,560 --> 01:33:12,560
DIFFERENTIATE -- -- -- AND THERE

1815
01:33:12,560 --> 01:33:14,920
IS A LOT OF REASON TO BELIEVE

1816
01:33:14,920 --> 01:33:18,480
THAT IS ONE MANIFESTATION OF THE

1817
01:33:18,480 --> 01:33:21,560
IMPACT OF THE MICRO BIOTA JUST

1818
01:33:21,560 --> 01:33:24,960
LIKE WE BELIEVE THAT THE SHAPES

1819
01:33:24,960 --> 01:33:27,640
IN HEALTHY INDIVIDUALS THE

1820
01:33:27,640 --> 01:33:35,800
DEVELOPMENT OF EPITHELIUM -- --

1821
01:33:35,800 --> 01:33:38,280
-- --

1822
01:33:40,520 --> 01:33:43,160
>> IT'S BEEN ASKED IF THERE IS A

1823
01:33:43,160 --> 01:33:45,800
CORRELATION BETWEEN THE GUT

1824
01:33:45,800 --> 01:33:49,000
MICROBIOME AND THE SKIN

1825
01:33:49,000 --> 01:33:53,720
MICROBIOME IN TERMS OF CHANGES

1826
01:33:53,720 --> 01:33:54,720
PERHAPS DURING DEVELOPMENT I

1827
01:33:54,720 --> 01:33:56,880
GUESS IS WHAT THE QUESTION THAT

1828
01:33:56,880 --> 01:34:00,320
HAS BEEN ASKED IN THE NEWBORN.

1829
01:34:00,320 --> 01:34:05,160
AND IF SO AND STUDIES OF THE

1830
01:34:05,160 --> 01:34:06,360
SKIN MICROBIOME PROVIDE CLUES AS

1831
01:34:06,360 --> 01:34:09,800
TO WHAT IS GOING ON IN THE

1832
01:34:09,800 --> 01:34:11,040
INTESTINE.

1833
01:34:11,040 --> 01:34:13,040
AND MAYBE MAKE THINGS EASIER IN

1834
01:34:13,040 --> 01:34:14,840
TERMS OF ASSESSING SOME OF THE

1835
01:34:14,840 --> 01:34:19,600
CLINICAL STUDIES.

1836
01:34:19,600 --> 01:34:20,920
>> WELL I THINK THAT THE

1837
01:34:20,920 --> 01:34:23,840
STATEMENT IS A VERY GOOD ONE.

1838
01:34:23,840 --> 01:34:27,360
THERE IS MATERNAL TRANSFER OF

1839
01:34:27,360 --> 01:34:29,640
MICROBES TO NEONATE.

1840
01:34:29,640 --> 01:34:32,640
SOME OF THAT TRANSFER INVOLVES

1841
01:34:32,640 --> 01:34:34,320
ORGANISMS ASSOCIATED WITH SKIN.

1842
01:34:34,320 --> 01:34:40,280
THE SKIN IS A VERY

1843
01:34:40,280 --> 01:34:42,720
BIOGEOGRAPHICALLY COMPLEX ORGAN

1844
01:34:42,720 --> 01:34:47,680
WITH MANY DIFFERENT AND VARIED

1845
01:34:47,680 --> 01:34:49,480
METABOLIC FEATURES.

1846
01:34:49,480 --> 01:34:52,000
AND THAT IS REFLECTED BY

1847
01:34:52,000 --> 01:34:53,560
DIFFERENCES IN COMMUNITY

1848
01:34:53,560 --> 01:34:58,400
COMPOSITION AND FUNCTION.

1849
01:34:58,400 --> 01:35:01,720
THE OFTEN CITED EXAMPLE OF THE

1850
01:35:01,720 --> 01:35:05,560
ROLE OF THE SKIN IN MATERNAL

1851
01:35:05,560 --> 01:35:08,480
TRANSFER OF MICROBES TO THE

1852
01:35:08,480 --> 01:35:11,240
INFANT IS THE DIFFERENCES IN THE

1853
01:35:11,240 --> 01:35:13,760
INITIAL GUT COMMUNITY IN

1854
01:35:13,760 --> 01:35:15,440
VAGINALLY DELIVERED INFANTS

1855
01:35:15,440 --> 01:35:17,760
VERSUS C-SECTION.

1856
01:35:17,760 --> 01:35:25,200
I THINK THAT THE PRECISE ROLE OF

1857
01:35:25,200 --> 01:35:30,200
THE SKIN MICRO BIOTA IN DEFINING

1858
01:35:30,200 --> 01:35:33,720
THE LATER TRAJECTORY IS NOT AS

1859
01:35:33,720 --> 01:35:36,200
WELL UNDERSTOOD.

1860
01:35:36,200 --> 01:35:41,600
BUT TO THE EXTENT THAT THERE IS

1861
01:35:41,600 --> 01:35:44,080
CO-DEVELOPMENT OF MICROBIAL IN

1862
01:35:44,080 --> 01:35:46,800
THE IMMUNE SYSTEM AND SINCE THE

1863
01:35:46,800 --> 01:35:50,680
IMMUNE SYSTEM IS IMPORTANT AS A

1864
01:35:50,680 --> 01:35:52,640
FACTOR AS A DETERMINANT OF

1865
01:35:52,640 --> 01:35:54,560
COMMUNITY CONFIGURATION ONE

1866
01:35:54,560 --> 01:35:56,600
COULD IMAGINE THAT THERE ARE

1867
01:35:56,600 --> 01:35:58,320
MANY WAYS IN WHICH THESE

1868
01:35:58,320 --> 01:36:01,120
COMMUNITIES MIGHT BE CONNECTED.

1869
01:36:01,120 --> 01:36:02,560
>> SEVERAL PEOPLE ASKED WHAT ARE

1870
01:36:02,560 --> 01:36:09,160
THE PLANS FOR FOLLOWING UP THE

1871
01:36:09,160 --> 01:36:12,120
PARTICIPANTS IN THE BANGLADESH

1872
01:36:12,120 --> 01:36:16,520
STUDY IN TERMS OF FOLLOWING THEM

1873
01:36:16,520 --> 01:36:19,120
THROUGH MANY YEARS TO FIND OUT

1874
01:36:19,120 --> 01:36:22,360
WHETHER THERE ARE THINGS IN

1875
01:36:22,360 --> 01:36:24,680
THEIR COGNITIVE ABILITY OR ANY

1876
01:36:24,680 --> 01:36:26,040
OTHER MEASURABLE EVENT.

1877
01:36:26,040 --> 01:36:29,280
IS THAT PART OF YOUR PLAN?

1878
01:36:29,280 --> 01:36:31,720
>> WELL I LOVE THE QUESTION FOR

1879
01:36:31,720 --> 01:36:33,600
MANY REASONS BECAUSE IT

1880
01:36:33,600 --> 01:36:35,360
EMPHASIZES THE IMPORTANCE OF

1881
01:36:35,360 --> 01:36:36,920
LONGITUDINAL STUDIES AND

1882
01:36:36,920 --> 01:36:39,120
UNDERSTANDING HOW THE MICRO

1883
01:36:39,120 --> 01:36:41,920
BIOTA AFFECTS HOST BIOLOGY

1884
01:36:41,920 --> 01:36:43,520
RATHER THAN CROSS SECTIONAL

1885
01:36:43,520 --> 01:36:45,080
STUDIES.

1886
01:36:45,080 --> 01:36:47,320
I LOVE THE QUESTION BECAUSE IT

1887
01:36:47,320 --> 01:36:49,960
SPEAKS TO THE POINT OF WHAT ARE

1888
01:36:49,960 --> 01:36:53,360
THE EFFECTS OF REPAIR OF A

1889
01:36:53,360 --> 01:36:54,720
MICROBIAL COMMUNITY ON HOST

1890
01:36:54,720 --> 01:36:56,320
SYSTEMS BIOLOGY.

1891
01:36:56,320 --> 01:37:02,040
AND HOW LONG IS THE REPAIR?

1892
01:37:02,040 --> 01:37:08,080
EVIDENCEVIDENT IN TERMS OF
CELLULAR AND

1893
01:37:08,080 --> 01:37:09,400
MOLECULAR AND WHETHER THE

1894
01:37:09,400 --> 01:37:12,920
EFFECTS ON DIFFERENT ORGANISMS

1895
01:37:12,920 --> 01:37:14,560
ARE ALSO DURABLE.

1896
01:37:14,560 --> 01:37:16,680
WE FEEL IT'S CRITICAL TO DO

1897
01:37:16,680 --> 01:37:18,400
FOLLOW-UP STUDIES IN POPULATIONS

1898
01:37:18,400 --> 01:37:23,000
WHERE THE LEVEL OF TRUST AND

1899
01:37:23,000 --> 01:37:24,480
DEVOTION BETWEEN THE HEALTH CARE

1900
01:37:24,480 --> 01:37:27,560
PROVIDERS AND THE FAMILIES IS

1901
01:37:27,560 --> 01:37:29,280
ENORMOUS AND THAT IS ONE OF THE

1902
01:37:29,280 --> 01:37:32,680
REASONS WHY WE'RE SO FORTUNATE

1903
01:37:32,680 --> 01:37:35,640
TO BE ABLE TO INTERACT WITH OUR

1904
01:37:35,640 --> 01:37:37,040
COLLEAGUES AND THE PROOF OF

1905
01:37:37,040 --> 01:37:41,160
CONCEPT STUDY OF CHILDREN WITH

1906
01:37:41,160 --> 01:37:44,480
PRIMARY MAM IS BEING EXTENDED

1907
01:37:44,480 --> 01:37:47,080
FOR FOUR YEARS WE EVERY SIX

1908
01:37:47,080 --> 01:37:48,160
MONTH SAMPLING.

1909
01:37:48,160 --> 01:37:50,400
EVEN THOUGH IT'S A THREE MONTH

1910
01:37:50,400 --> 01:37:52,200
INTERVENTION WE FEEL THAT THOSE

1911
01:37:52,200 --> 01:37:58,520
SORTS OF ANALYSIS -- ARE

1912
01:37:58,520 --> 01:37:59,040
CRITICAL.

1913
01:37:59,040 --> 01:38:01,000
WE WOULD LOVE TO LOOK AT MUCH

1914
01:38:01,000 --> 01:38:03,800
MORE DETAILED PHENOTYPING

1915
01:38:03,800 --> 01:38:05,240
INCLUDING AS THE PERSON ASKED

1916
01:38:05,240 --> 01:38:08,800
THE QUESTION -- IMPLIED.

1917
01:38:08,800 --> 01:38:10,720
NEURO DEVELOPMENT, LONG-TERM

1918
01:38:10,720 --> 01:38:14,760
EFFECTS ON BODY COMPOSITION ON

1919
01:38:14,760 --> 01:38:15,400
IMMUNITY.

1920
01:38:15,400 --> 01:38:21,080
THOSE TYPES OF STUDIES ARE VERY

1921
01:38:21,080 --> 01:38:22,520
DIFFICULT TO ACTUALLY EXECUTE

1922
01:38:22,520 --> 01:38:24,600
AND ARE QUITE COSTLY.

1923
01:38:24,600 --> 01:38:26,760
WE FEEL THEY ARE CRITICAL AND

1924
01:38:26,760 --> 01:38:28,200
THEY HAVE TO BE SUFFICIENTLY

1925
01:38:28,200 --> 01:38:28,920
POWERED.

1926
01:38:28,920 --> 01:38:33,520
ONE OTHER THING -- THE

1927
01:38:33,520 --> 01:38:35,240
IMPORTANCE OF DETERMINING

1928
01:38:35,240 --> 01:38:37,760
WHETHER A MORE EXTENDED PERIOD

1929
01:38:37,760 --> 01:38:39,720
OF INTERVENTION IS NECESSARY TO

1930
01:38:39,720 --> 01:38:41,480
HAVE A MORE DURABLE EFFECT AND

1931
01:38:41,480 --> 01:38:46,400
WHAT THE EFFECTS OF INTERVENTION

1932
01:38:46,400 --> 01:38:47,080
INTERVENTIONS ARE.

1933
01:38:47,080 --> 01:38:49,440
WOULD AN INTERVENTION FOR THREE

1934
01:38:49,440 --> 01:38:51,880
MONTHS IN A CHILD WHO'S SIX

1935
01:38:51,880 --> 01:38:57,520
MONTHS OLD HAVE A GREATER IMPACT

1936
01:38:57,520 --> 01:38:59,400
THAN LATER ON.

1937
01:38:59,400 --> 01:39:02,640
ON THE OTHER HAND YOU CAN SAY

1938
01:39:02,640 --> 01:39:05,720
THE MICRO BIOTA HAS MANY

1939
01:39:05,720 --> 01:39:06,760
DIFFERENT FUNCTIONAL STATES AND

1940
01:39:06,760 --> 01:39:10,040
THERE ARE MANY DIFFERENT

1941
01:39:10,040 --> 01:39:12,840
BIOLOGICAL STATES TO BEING UNDER

1942
01:39:12,840 --> 01:39:14,480
NOURISHED AND ONE OF THE

1943
01:39:14,480 --> 01:39:16,760
IMPORTANT LESSONS THAT WE WANT

1944
01:39:16,760 --> 01:39:20,080
TO LEARN IS HOW REPAIR OF THE

1945
01:39:20,080 --> 01:39:29,640
MICRO BIOTA IS LINKED TO THE

1946
01:39:29,640 --> 01:39:33,120
RESPONSES OF DIFFERENT ORGAN

1947
01:39:33,120 --> 01:39:33,920
SYSTEMS.

1948
01:39:33,920 --> 01:39:36,640
I THINK THOSE SORTS OF

1949
01:39:36,640 --> 01:39:40,800
CONNECTIONS WILL GIVE US DEEPER

1950
01:39:40,800 --> 01:39:44,520
INSIGHTS INTO THE PATHOGENESIS

1951
01:39:44,520 --> 01:39:49,640
OF UNDER NUTRITION.

1952
01:39:49,640 --> 01:39:52,720
BECAUSE WE WILL DEFINE DISREPAIR

1953
01:39:52,720 --> 01:39:57,760
MUCH MORE CO-GENTLY.

1954
01:39:57,760 --> 01:40:07,720
*.

1955
01:40:07,720 --> 01:40:09,000
INCLUDING THEIR AGE AS ONE

1956
01:40:09,000 --> 01:40:14,080
FACTOR.

1957
01:40:14,080 --> 01:40:19,400
>> YOUR STUDIES ARE IN

1958
01:40:19,400 --> 01:40:20,200
MALNOURISHED VERY YOUNG

1959
01:40:20,200 --> 01:40:22,240
CHILDREN.

1960
01:40:22,240 --> 01:40:26,240
DO YOU THINK THAT A SIMILAR

1961
01:40:26,240 --> 01:40:31,040
MECHANISM MAY BE A FOOT IN MUCH

1962
01:40:31,040 --> 01:40:34,280
OLDER INDIVIDUALS WHO HAVE

1963
01:40:34,280 --> 01:40:39,160
DISEASES WHICH ARE CHARACTERIZED

1964
01:40:39,160 --> 01:40:46,920
BY WEIGHT LOSS AND MAYBE EVEN

1965
01:40:46,920 --> 01:40:49,680
MAINTAINING A DIET BUT THEY ARE

1966
01:40:49,680 --> 01:40:51,280
STILL LOSING WEIGHT.

1967
01:40:51,280 --> 01:40:53,600
I'M THINKING OF PATIENTS WITH

1968
01:40:53,600 --> 01:40:55,520
LIVER DISEASE IN PARTICULAR BUT

1969
01:40:55,520 --> 01:40:59,840
TO TRY TO BRING IN -- PERHAPS

1970
01:40:59,840 --> 01:41:01,720
TIM WOULD WANT TO COMMENT.

1971
01:41:01,720 --> 01:41:04,480
IS IT POSSIBLE THAT ONE OF THE

1972
01:41:04,480 --> 01:41:07,040
-- WHAT YOU HAVE OBSERVED JEFF

1973
01:41:07,040 --> 01:41:10,240
IN YOUNG CHILDREN IS ALSO

1974
01:41:10,240 --> 01:41:13,720
OCCURRING IN MUCH OLDER

1975
01:41:13,720 --> 01:41:15,320
INDIVIDUALS PERHAPS EVEN IN

1976
01:41:15,320 --> 01:41:18,920
AGING LET ALONE WITH -- MAJOR

1977
01:41:18,920 --> 01:41:19,920
ORGAN DISEASE.

1978
01:41:19,920 --> 01:41:24,520
WHAT DO YOU THINK OF THAT?

1979
01:41:24,520 --> 01:41:26,920
>> DO YOU WANT TIM TO ANSWER OR

1980
01:41:26,920 --> 01:41:28,520
ME TO ANSWER.

1981
01:41:28,520 --> 01:41:30,720
>> MAYBE YOU BOTH CAN ANSWER IF

1982
01:41:30,720 --> 01:41:32,920
THERE IS AN ANSWER.

1983
01:41:32,920 --> 01:41:36,920
TIM, WHAT IS YOUR VIEW?

1984
01:41:36,920 --> 01:41:41,200
>> SO OBVIOUSLY THERE MAY BE

1985
01:41:41,200 --> 01:41:41,520
SIMILARITIES.

1986
01:41:41,520 --> 01:41:46,960
I'M SURE THERE ARE SIMILARITIES.

1987
01:41:46,960 --> 01:41:50,640
BUT IT'S VERY DIFFICULT TO

1988
01:41:50,640 --> 01:41:52,400
PREDICT THIS WITHOUT DOING THE

1989
01:41:52,400 --> 01:41:56,800
STUDY BUT I HAVE A QUESTION AND

1990
01:41:56,800 --> 01:41:58,840
JEFF WILL GIVE HIS ANSWER WHICH

1991
01:41:58,840 --> 01:42:00,480
IS IN THE SAME DIRECTION THAT

1992
01:42:00,480 --> 01:42:02,360
WAS JUST ASKED ABOUT THE

1993
01:42:02,360 --> 01:42:03,680
LONG-TERM FOLLOW-UP.

1994
01:42:03,680 --> 01:42:12,240
WE KNOW THAT ANY -- OF THE BIOME

1995
01:42:12,240 --> 01:42:15,200
IS VERY RAPID BUT USUALLY NOT

1996
01:42:15,200 --> 01:42:15,920
LONG LASTING.

1997
01:42:15,920 --> 01:42:19,160
AND I SAW IT ON YOUR SLIDES THAT

1998
01:42:19,160 --> 01:42:23,720
YOU ACTUALLY FOLLOW THE CHILDREN

1999
01:42:23,720 --> 01:42:25,520
FOR I BELIEVE IT WAS ONE OR

2000
01:42:25,520 --> 01:42:27,520
THREE MONTHS AFTER YOU STOPPED

2001
01:42:27,520 --> 01:42:31,960
THE INTERVENTION.

2002
01:42:31,960 --> 01:42:34,600
SO DO YOU THINK YOU'RE GOING TO

2003
01:42:34,600 --> 01:42:37,080
HAVE LONG LASTING EFFECTS IN THE

2004
01:42:37,080 --> 01:42:38,720
CHILDREN?

2005
01:42:38,720 --> 01:42:41,920
>> ONE OF THE REASONS THAT WE

2006
01:42:41,920 --> 01:42:44,320
WANTED TO BEGIN THESE TYPE OF

2007
01:42:44,320 --> 01:42:48,320
STUDIES IN THE DEVELOPING PHASE

2008
01:42:48,320 --> 01:42:53,200
IS THAT YOU BELIEVE IN THE

2009
01:42:53,200 --> 01:42:55,360
HYPOTHESIS -- IT HAS A PROFOUND

2010
01:42:55,360 --> 01:42:59,840
EFFECT ON SETTING PHYSIOLOGICAL

2011
01:42:59,840 --> 01:43:03,000
TRAJECTORY IS IT'S POSSIBLE THAT

2012
01:43:03,000 --> 01:43:09,040
AS THESE MECHANISMS EXIST ARE

2013
01:43:09,040 --> 01:43:10,720
FIRST ESTABLISHED -- THAT YOU

2014
01:43:10,720 --> 01:43:13,520
COULD HAVE A DURABLE EFFECT.

2015
01:43:13,520 --> 01:43:17,520
SO I DO THINK THAT IT WILL BE --

2016
01:43:17,520 --> 01:43:19,880
INTERESTING TO SEE THAT THE

2017
01:43:19,880 --> 01:43:22,720
DURATION OF AN EFFECT OF MICRO

2018
01:43:22,720 --> 01:43:24,720
BIOTA REPAIR DURING ITS

2019
01:43:24,720 --> 01:43:27,520
FORMATION AS OPPOSED TO THE

2020
01:43:27,520 --> 01:43:29,840
EFFECTS OF REPAIR ONCE THE ORGAN

2021
01:43:29,840 --> 01:43:32,280
SYSTEM AND THE HOST HAS FULLY

2022
01:43:32,280 --> 01:43:33,960
MATURED AND DEVELOPED.

2023
01:43:33,960 --> 01:43:35,400
WHAT IS THE EFFECT OF THE REPAIR

2024
01:43:35,400 --> 01:43:39,040
TO THE MICRO BIOTA IN A

2025
01:43:39,040 --> 01:43:42,240
60-YEAR-OLD AS OPPOSED TO A

2026
01:43:42,240 --> 01:43:42,600
SIX-MONTH-OLD?

2027
01:43:42,600 --> 01:43:44,560
>> IF THAT IS THE CASE THE

2028
01:43:44,560 --> 01:43:45,480
ANSWER TO THE QUESTION IF YOU

2029
01:43:45,480 --> 01:43:47,720
WILL SEE THE SAME EFFECT IN AN

2030
01:43:47,720 --> 01:43:51,080
ADULT THAT YOU SEE IN THE SMALL

2031
01:43:51,080 --> 01:43:54,440
CHILDREN IS PROBABLY NO.

2032
01:43:54,440 --> 01:43:56,120
>> MAYBE YES OR MAYBE NO.

2033
01:43:56,120 --> 01:43:59,360
IF ONE GOES BEYOND THE TYPES OF

2034
01:43:59,360 --> 01:44:02,080
STUDIES I JUST DESCRIBED.

2035
01:44:02,080 --> 01:44:07,120
TO A DEEP AND INSPIRING BUT

2036
01:44:07,120 --> 01:44:11,120
NONETHELESS DIFFICULT TASK OF

2037
01:44:11,120 --> 01:44:13,520
IDENTIFYING SIGNALING PATHWAYS

2038
01:44:13,520 --> 01:44:17,360
BY WHICH DIFFERENT COMPONENT

2039
01:44:17,360 --> 01:44:18,520
INFLUENCE HOST BIOLOGY.

2040
01:44:18,520 --> 01:44:22,240
SO IF YOU'RE ABLE AS A DURABLE

2041
01:44:22,240 --> 01:44:27,080
LEGACY TO ULTIMATELY BE ABLE TO

2042
01:44:27,080 --> 01:44:29,400
IDENTIFY THESE SIGNALING

2043
01:44:29,400 --> 01:44:31,760
PATHWAYS THEY BECOME YOUR

2044
01:44:31,760 --> 01:44:34,440
THERAPEUTIC TARGETS AND THERE IS

2045
01:44:34,440 --> 01:44:38,320
REASON TO CONJECTURE THAT THOSE

2046
01:44:38,320 --> 01:44:40,520
PATHWAYS STILL OPERATE DURING

2047
01:44:40,520 --> 01:44:42,200
THE INDIVIDUAL'S LIFE-SPAN.

2048
01:44:42,200 --> 01:44:46,320
SO I THINK THESE ARE I THINK ONE

2049
01:44:46,320 --> 01:44:49,520
OF THE AGENDA ITEMS IF WE'RE

2050
01:44:49,520 --> 01:44:53,160
FORTUNATE ENOUGH TO BE ABLE TO

2051
01:44:53,160 --> 01:44:56,040
SUPPORTED IN THESE TYPES OF

2052
01:44:56,040 --> 01:44:57,840
TRANSLATIONAL STUDIES AND

2053
01:44:57,840 --> 01:44:59,520
REVERSE TRANSLATIONAL STUDIES TO

2054
01:44:59,520 --> 01:45:02,040
BE ABLE TO DISCERN THE SIGNALING

2055
01:45:02,040 --> 01:45:03,760
PATHWAYS AND THEIR COMPONENTS.

2056
01:45:03,760 --> 01:45:06,520
THAT IS MY HOPE AND EXPECTATION.

2057
01:45:06,520 --> 01:45:09,880
BUT I ALSO AGREE WITH YOU

2058
01:45:09,880 --> 01:45:11,040
SOBRIETY IS VERY IMPORTANT IN

2059
01:45:11,040 --> 01:45:15,720
THE FIELD AND TO TEST THE

2060
01:45:15,720 --> 01:45:16,720
GENERALIZABILITY OF AN

2061
01:45:16,720 --> 01:45:17,520
INTERVENTION.

2062
01:45:17,520 --> 01:45:20,120
CHILDREN OF A PARTICULAR AGE

2063
01:45:20,120 --> 01:45:23,240
LIVING IN DIFFERENT REGIONS OF

2064
01:45:23,240 --> 01:45:24,400
THE WORLD.

2065
01:45:24,400 --> 01:45:26,960
TO BE ABLE TO DETERMINE THE

2066
01:45:26,960 --> 01:45:28,640
DURABILITY OF THE EFFECTS.

2067
01:45:28,640 --> 01:45:31,760
THAT IS ABSOLUTELY CRITICAL.

2068
01:45:31,760 --> 01:45:36,320
AND I HOPE THAT IS DONE IN A

2069
01:45:36,320 --> 01:45:38,040
VERY CAUTIOUS AND METHODICAL

2070
01:45:38,040 --> 01:45:38,920
KAY.

2071
01:45:38,920 --> 01:45:42,120
>> TIM, THERE IS AN INTERESTING

2072
01:45:42,120 --> 01:45:44,560
QUESTION WHERE SOMEONE HAS

2073
01:45:44,560 --> 01:45:46,880
POINTED OUT THAT THE VAST

2074
01:45:46,880 --> 01:45:52,680
MAJORITY OF PATIENTS WITH

2075
01:45:52,680 --> 01:45:54,920
HEPATOCELLULAR CANCER HAVE SOME

2076
01:45:54,920 --> 01:45:56,680
UNDERLYING CHRONIC LIVER DISEASE

2077
01:45:56,680 --> 01:46:02,080
ASSOCIATED WITH A LOT OF

2078
01:46:02,080 --> 01:46:04,520
REGENERATION, CIRRHOSIS AND ALL

2079
01:46:04,520 --> 01:46:07,240
SORTS OF THINGS.

2080
01:46:07,240 --> 01:46:15,040
THE QUESTION IS DOES DISBIOUS

2081
01:46:15,040 --> 01:46:20,320
AND THE INTESTINE -- * IS A

2082
01:46:20,320 --> 01:46:25,520
MAJOR ROUTE LEADING TO FIBROSIS

2083
01:46:25,520 --> 01:46:29,840
THE ALTERED HEPATOCELLULAR

2084
01:46:29,840 --> 01:46:32,520
REGENERATION AND NOT DIRECTLY TO

2085
01:46:32,520 --> 01:46:33,440
CANCER ITSELF?

2086
01:46:33,440 --> 01:46:37,320
CAN YOU VISUALIZE A WAY IN WHICH

2087
01:46:37,320 --> 01:46:40,280
ONE CAN DIFFERENTIATE THESE

2088
01:46:40,280 --> 01:46:41,520
VARIOUS ASSOCIATED EVENTS WITH

2089
01:46:41,520 --> 01:46:44,480
THE FACT THAT THE CANCER IS

2090
01:46:44,480 --> 01:46:47,800
OCCURRING IN PATIENTS WITH

2091
01:46:47,800 --> 01:46:51,000
CHRONIC ACTIVE FORMS OF LIVER

2092
01:46:51,000 --> 01:46:53,680
DISEASE, FIBROSIS AND A LOT ELSE

2093
01:46:53,680 --> 01:46:58,480
GOING ON

2094
01:46:58,480 --> 01:46:59,760
>> OBVIOUSLY THAT'S AN VERY

2095
01:46:59,760 --> 01:47:03,120
INTERESTING QUESTION.

2096
01:47:03,120 --> 01:47:05,040
AND THERE ARE MODELS WHERE WE

2097
01:47:05,040 --> 01:47:05,680
CAN DO THIS.

2098
01:47:05,680 --> 01:47:10,640
WE HAVE WAYS TO INDUCE DYSB

2099
01:47:10,640 --> 01:47:12,800
IOS IS.

2100
01:47:12,800 --> 01:47:15,440
THE MICE WITH LIVER DISEASE BUT

2101
01:47:15,440 --> 01:47:17,840
THERE ARE MANY WAYS.

2102
01:47:17,840 --> 01:47:19,760
SIMPLE ANTIBIOTIC TREATMENT IS

2103
01:47:19,760 --> 01:47:21,360
ONE.

2104
01:47:21,360 --> 01:47:23,880
AND IF YOU GO INTO THE ANIMAL

2105
01:47:23,880 --> 01:47:27,360
SYSTEM THAT ALLOWS YOU TO DO FMT

2106
01:47:27,360 --> 01:47:31,320
STUDIES YOU CAN INDUCE THE FMT

2107
01:47:31,320 --> 01:47:34,080
IN GERMFREE MICE AND THEN LOOK

2108
01:47:34,080 --> 01:47:38,080
AT THE EFFECT ON MECHANISMS THAT

2109
01:47:38,080 --> 01:47:41,120
WILL AUTOMATICALLY LEAD TO

2110
01:47:41,120 --> 01:47:48,280
FIBROID BROSIU AND CIRRHOSIS IN
MICE.

2111
01:47:48,280 --> 01:47:50,840
IT IS NOT AS STRAIGHTFORWARD AS

2112
01:47:50,840 --> 01:47:53,040
ONE WOULD THINK BECAUSE GERMFREE

2113
01:47:53,040 --> 01:47:56,320
MICE ACTUALLY HAVE SIGNIFICANT

2114
01:47:56,320 --> 01:47:58,800
CHANGES IN THEIR GI TRACT BY

2115
01:47:58,800 --> 01:47:59,280
ITSELF.

2116
01:47:59,280 --> 01:48:03,280
SO JUST THE ABSENCE OF BACTERIAS

2117
01:48:03,280 --> 01:48:05,520
CAUSING SIGNIFICANT CHANGES BUT

2118
01:48:05,520 --> 01:48:12,080
YES WE DO KNOW THAT DYSB iOS

2119
01:48:12,080 --> 01:48:18,000
IS HAS SIGNIFICANT CHANGES.

2120
01:48:18,000 --> 01:48:20,680
* THAT CAN UP INTRODUCE OR

2121
01:48:20,680 --> 01:48:22,720
AMPLIFY CHANGES IN THE LIVER AND

2122
01:48:22,720 --> 01:48:24,680
NOT ONLY IN THE CONTEXT OF VIRAL

2123
01:48:24,680 --> 01:48:25,320
INFECTION.

2124
01:48:25,320 --> 01:48:28,520
WE KNOW THAT COMING BACK TO THE

2125
01:48:28,520 --> 01:48:30,840
IDEA OF NUTRITION THAT OBVIOUSLY

2126
01:48:30,840 --> 01:48:33,840
NOT ONLY WITH MALNUTRITION BUT

2127
01:48:33,840 --> 01:48:37,280
ALSO WITH OBESITY THERE IS

2128
01:48:37,280 --> 01:48:40,240
SIGNIFICANT CHANGES AND THE GUT

2129
01:48:40,240 --> 01:48:41,480
MICROBIOME IS SIGNIFICANTLY

2130
01:48:41,480 --> 01:48:42,320
DIFFERENT.

2131
01:48:42,320 --> 01:48:46,600
SO THE IDEA THAT THE GUT

2132
01:48:46,600 --> 01:48:48,360
MICROBIOME PLAYS A SIGNIFICANT

2133
01:48:48,360 --> 01:48:49,720
ROLE HERE IS CLEAR.

2134
01:48:49,720 --> 01:48:51,600
AND THEN LAST BUT NOT LEAST

2135
01:48:51,600 --> 01:48:53,960
THERE IS VERY GOOD DATA THAT THE

2136
01:48:53,960 --> 01:48:58,040
GUT MICROBIOME CAN ACTUALLY

2137
01:48:58,040 --> 01:49:01,160
CONTROL ALCOHOLIC LIVER DISEASE.

2138
01:49:01,160 --> 01:49:05,760
THIS IS DONE WITH WORK FROM OUR

2139
01:49:05,760 --> 01:49:07,760
COLLABORATOR WHO HAS DONE THIS

2140
01:49:07,760 --> 01:49:08,200
WORK.

2141
01:49:08,200 --> 01:49:10,520
AND THE REASON WHY I MENTIONED

2142
01:49:10,520 --> 01:49:13,080
THIS IS BECAUSE YOU TALKED ABOUT

2143
01:49:13,080 --> 01:49:16,320
THE PHAGES.

2144
01:49:16,320 --> 01:49:21,080
YOU CAN USE THIS TO DISRUPT

2145
01:49:21,080 --> 01:49:25,080
MECHANISMS AND THEREBY TREAT

2146
01:49:25,080 --> 01:49:26,560
ALCOHOLIC LIVER DISEASE.

2147
01:49:26,560 --> 01:49:30,520
IT'S A LONG ANSWER BUT BASICALLY

2148
01:49:30,520 --> 01:49:32,320
THEY ARE ALL INTERCONNECTED WITH

2149
01:49:32,320 --> 01:49:33,680
EACH OTHER AND IT'S VERY

2150
01:49:33,680 --> 01:49:34,800
DIFFICULT TO SAY IN THE END

2151
01:49:34,800 --> 01:49:39,440
WHICH IS THE --

2152
01:49:39,440 --> 01:49:40,800
[ INDISCERNIBLE ]

2153
01:49:40,800 --> 01:49:45,440
>> DO WE UNDERSTAND HOW ANY

2154
01:49:45,440 --> 01:49:55,920
INTESTINAL MICROBE YET A --

2155
01:49:55,920 --> 01:50:09,800
DYSBIOSIS US CAUSES.

2156
01:50:09,800 --> 01:50:12,600
>> IF YOU KILL ONE ANOTHER ONE

2157
01:50:12,600 --> 01:50:13,320
WILL GROW OUT.

2158
01:50:13,320 --> 01:50:16,080
THAT WOULD BE MY SIMPLISTIC

2159
01:50:16,080 --> 01:50:16,280
ANSWER

2160
01:50:16,280 --> 01:50:19,600
>> ONE OF THE LESSONS IS HOW

2161
01:50:19,600 --> 01:50:21,840
ELABORATE THE INTERACTION OF

2162
01:50:21,840 --> 01:50:23,320
MICROBES ARE AND THEY DON'T

2163
01:50:23,320 --> 01:50:24,840
FUNCTION IN ISOLATION AND THERE

2164
01:50:24,840 --> 01:50:28,200
HAS BEEN A LOT OF WORK SPEAKING

2165
01:50:28,200 --> 01:50:32,280
OF -- METABOLISM -- WITH -- AND

2166
01:50:32,280 --> 01:50:35,280
HAVE COMPLEX METABOLIC

2167
01:50:35,280 --> 01:50:41,080
INTERACTIONS THAT OCCUR THAT

2168
01:50:41,080 --> 01:50:45,720
CAUSES SEVERE -- WE CAN THINK

2169
01:50:45,720 --> 01:50:48,280
ABOUT MICROBIAL ACTIVITIES AS

2170
01:50:48,280 --> 01:50:51,920
HEALTH PROMOTING OR DISEASE

2171
01:50:51,920 --> 01:50:54,720
PROMOTING DEPENDING ON -- WHICH

2172
01:50:54,720 --> 01:50:56,480
THEY EXIST.

2173
01:50:56,480 --> 01:50:58,920
JUST LIKE THE NUTRITIONAL VALUE

2174
01:50:58,920 --> 01:51:02,240
OF FOOD MAY BE INFLUENCED TO A

2175
01:51:02,240 --> 01:51:07,040
SIGNIFICANT DEGREE BY THE

2176
01:51:07,040 --> 01:51:08,480
CHEMICAL COMPOSITION OF FOOD.

2177
01:51:08,480 --> 01:51:11,440
THE MICROBES DON'T SEE FOOD AS

2178
01:51:11,440 --> 01:51:12,080
BROCCOLI.

2179
01:51:12,080 --> 01:51:15,360
THEY SEE IT AS A COMPLEX -- OF

2180
01:51:15,360 --> 01:51:17,480
STRUCTURES.

2181
01:51:17,480 --> 01:51:20,760
AND DIFFERENT ORGANISMS ARE

2182
01:51:20,760 --> 01:51:23,320
CAPABLE OF HAVING DIFFERENT

2183
01:51:23,320 --> 01:51:25,040
ROLES IN THE PROCESSING OF THESE

2184
01:51:25,040 --> 01:51:25,760
THINGS.

2185
01:51:25,760 --> 01:51:27,200
ALTHOUGH IN GENERAL THESE

2186
01:51:27,200 --> 01:51:31,560
COMMUNITIES HAVE A LOT OF

2187
01:51:31,560 --> 01:51:33,280
DIVERSITY AND REDUNDANCY THAT

2188
01:51:33,280 --> 01:51:37,960
ALLOWS THEM TO WITHSTAND.

2189
01:51:37,960 --> 01:51:40,160
THE NUMBER OF GENES IN THE

2190
01:51:40,160 --> 01:51:41,960
MICROBIOME VASTLY EXCEED THE

2191
01:51:41,960 --> 01:51:43,720
NUMBER OF GAMES IN THE HUMAN

2192
01:51:43,720 --> 01:51:45,400
GENOME BECAUSE THEY ARE ABLE TO

2193
01:51:45,400 --> 01:51:48,360
PROVIDE US WITH BIOCHEMICAL

2194
01:51:48,360 --> 01:51:49,640
CAPABILITIES THAT WE HAVE NOT

2195
01:51:49,640 --> 01:51:50,680
EVOLVED ON OUR OWN.

2196
01:51:50,680 --> 01:51:55,600
THAT IS ONE OF THE WAYS THAT WE

2197
01:51:55,600 --> 01:51:57,600
CONSTRUE THIS.

2198
01:51:57,600 --> 01:51:59,520
BRINGING TOGETHER DIFFERENT

2199
01:51:59,520 --> 01:52:01,080
ORGANISMS THAT HAVE DIFFERENT

2200
01:52:01,080 --> 01:52:04,720
JOBS SO THE ENTIRE -- BIOME IS

2201
01:52:04,720 --> 01:52:05,280
FITTER.

2202
01:52:05,280 --> 01:52:07,000
>> THAT IS THE MIRACLE.

2203
01:52:07,000 --> 01:52:09,680
HOW DO THESE SYSTEMS ASSEMBLE?

2204
01:52:09,680 --> 01:52:14,160
HOW ARE THEY MAINTAINED AS WE

2205
01:52:14,160 --> 01:52:15,000
PERTURB THEM.

2206
01:52:15,000 --> 01:52:16,600
HOW DO THEY RECOVER?

2207
01:52:16,600 --> 01:52:17,600
IT'S STUNNING.

2208
01:52:17,600 --> 01:52:19,240
AND INSPIRING.

2209
01:52:19,240 --> 01:52:21,240
BUT TRYING TO FIGURE OUT THE

2210
01:52:21,240 --> 01:52:23,320
UNDERLYING MECHANISMS REALLY

2211
01:52:23,320 --> 01:52:27,200
REQUIRES A LOT OF TOOLS AND

2212
01:52:27,200 --> 01:52:29,880
LUCKILY WE LIVE IN AN ERA WHERE

2213
01:52:29,880 --> 01:52:34,360
WE HAVE THE CAPACITY TO DO DEEP

2214
01:52:34,360 --> 01:52:39,120
SEQUENCING NOT ONLY OF DNA BUT

2215
01:52:39,120 --> 01:52:46,040
RNA AND DO A LOT OF METABALOMICS

2216
01:52:46,040 --> 01:52:49,240
TO START LEARNING BASIC

2217
01:52:49,240 --> 01:52:50,920
PRINCIPLES THAT GLUE ORGANISMS

2218
01:52:50,920 --> 01:52:52,240
TOGETHER AND CONNECT THEM WITH

2219
01:52:52,240 --> 01:52:53,040
OURSELVES.

2220
01:52:53,040 --> 01:52:55,000
THAT IS THE HOPE.

2221
01:52:55,000 --> 01:52:58,960
BUT HUMILITY GIVEN THE FACE OF

2222
01:52:58,960 --> 01:53:02,040
THIS AND LACK OF HOW ABOUT ROUSE

2223
01:53:02,040 --> 01:53:03,920
AND SOBRIETY IS * IS REALLY

2224
01:53:03,920 --> 01:53:04,880
IMPORTANT.

2225
01:53:04,880 --> 01:53:05,880
>> THANK YOU.

2226
01:53:05,880 --> 01:53:07,960
TIM YOU MENTIONED THAT IN

2227
01:53:07,960 --> 01:53:10,080
GERMFREE ANIMALS THE INTESTINE

2228
01:53:10,080 --> 01:53:16,520
IS NOT LIKE IT IS IN INFECTED OR

2229
01:53:16,520 --> 01:53:17,040
NORMAL.

2230
01:53:17,040 --> 01:53:19,440
DO YOU WANT TO COMMENT BRIEFLY

2231
01:53:19,440 --> 01:53:20,280
ABOUT THAT?

2232
01:53:20,280 --> 01:53:23,480
WHAT ARE THE DIFFERENCES?

2233
01:53:23,480 --> 01:53:25,280
>> ANY POSTDOC OR GRADUATE

2234
01:53:25,280 --> 01:53:26,920
STUDENT AT THE LAB WHO'S WORKING

2235
01:53:26,920 --> 01:53:31,200
ON THIS ONLY HAS TO OPEN THE

2236
01:53:31,200 --> 01:53:33,240
ABDOMINAL CAVITY OF A MOUSE AND

2237
01:53:33,240 --> 01:53:37,400
YOU WOULD IMMEDIATELY SEE GROSS

2238
01:53:37,400 --> 01:53:37,880
CHANGES.

2239
01:53:37,880 --> 01:53:43,680
YOU WILL SEE A LARGE -- AND THE

2240
01:53:43,680 --> 01:53:44,680
GALLBLADDER IS DIFFERENT.

2241
01:53:44,680 --> 01:53:49,560
YOU CAN SEE THIS WITH YOUR BARE

2242
01:53:49,560 --> 01:53:50,320
EYE.

2243
01:53:50,320 --> 01:53:52,280
ONCE YOU START LOOKING CLOSER

2244
01:53:52,280 --> 01:53:54,560
YOU'LL SEE MORE CHANGES BUT IT'S

2245
01:53:54,560 --> 01:53:55,840
VERY OBVIOUS AND STUNNING WHEN

2246
01:53:55,840 --> 01:54:00,320
YOU SEE IT FOR THE FIRST TIME.

2247
01:54:00,320 --> 01:54:05,200
>> VERY EXCITING.

2248
01:54:05,200 --> 01:54:07,760
WELL WE'RE OUT OF TIME AND I'M

2249
01:54:07,760 --> 01:54:10,320
SURE ON BEHALF OF THE MANY, MANY

2250
01:54:10,320 --> 01:54:12,680
PEOPLE AROUND THE WORLD WHO HAVE

2251
01:54:12,680 --> 01:54:17,240
BEEN TAKING PART IN THIS, THEY

2252
01:54:17,240 --> 01:54:19,760
WOULD JOIN ME IN THANKING BOTH

2253
01:54:19,760 --> 01:54:23,200
OF YOU FOR TAKING THE TIME, THE

2254
01:54:23,200 --> 01:54:24,880
INTEREST AND PRESENTING SUCH

2255
01:54:24,880 --> 01:54:28,160
REALLY PROVOCATIVE AND

2256
01:54:28,160 --> 01:54:29,280
CHALLENGING, EXCITING

2257
01:54:29,280 --> 01:54:31,880
OPPORTUNITIES TO BUILD BRIDGES

2258
01:54:31,880 --> 01:54:34,600
AND IT SEEMS AS IF THERE ARE

2259
01:54:34,600 --> 01:54:37,280
GREAT OPPORTUNITIES IN THESE

2260
01:54:37,280 --> 01:54:38,640
FIELDS FOR BRIGHT YOUNG PEOPLE

2261
01:54:38,640 --> 01:54:43,480
WHO ARE LOOKING FOR NEW WORLDS

2262
01:54:43,480 --> 01:54:45,920
TO CONQUER.

2263
01:54:45,920 --> 01:54:47,640
THANK YOU VERY MUCH AND GOOD

2264
01:54:47,640 --> 01:54:47,800
LUCK

2265
01:54:47,800 --> 01:55:20,480
>> THANK YOU VERY MUCH.