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>> GOOD AFTERNOON, GOOD
DAY FOR

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THOSE IN WHOM IT'S NOT THE

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AFTERNOON.

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I AM WIN ARIAS, I AM A SENIOR

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SCIENTIST EMERITUS AT THE

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NATIONAL INSTITUTES OF HEALTH IN

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BETHESDA, MARYLAND.

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IT'S A PLEASURE TO WELCOME YOU

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TO THE NEXT TO THE LAST SESSION

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00:00:26,944 --> 00:00:30,714
OF THE 23rd YEAR OF A COURSE

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CALLED DEMYSTIFYING MEDICINE

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WHICH IS HELD HERE AT THE NIH.

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THIS IS A COURSE IN BRIDGE

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BUILDING. 

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IT IS DESIGNED TO TAKE THE VERY

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CONCENTRATED INFORMATION THAT

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PEOPLE KNOW IN DIFFERENT DOMAINS

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OF BIOLOGY, ENGINEERING AND

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COMPUTER SCIENCE AND IN

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MEDICINE, SORT OF IN THE FORM OF

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SILOS, BUT QUITE SEPARATED FROM

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1 ANOTHER.

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SO THE GOAL OF THIS COURSE HAS

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BEEN TO BRIDGE THE EXCITING

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DEVELOPMENTS THAT GO ON AT A

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SEEMINGLY EVER-INCREASING RATE

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IN BIOLOGY, ENGINEERING AND

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00:01:11,088 --> 00:01:12,823
COMPUTER SCIENCE AND BRIDGE THEM

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00:01:12,823 --> 00:01:15,926
WITH OUR UNDERSTANDING OF HUMAN

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DISEASE AND IDENTIFY THE MAJOR

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CHALLENGES.

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AND THE LOGO FOR THIS COURSE FOR

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23 YEARS IS THE PHOTOGRAPH OF

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THE BROOKLYN BRIDGE DURING ITS

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CONSTRUCTION.

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AND HERE YOU SEE 2 INDIVIDUALS

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ON THE CAT WALK AND IN EFFECT,

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THEY ARE AS WE ARE TODAY

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REPRESENTED 2 INDIVIDUALS EACH

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HAVING SPECIAL EXPERTISE IN A

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VERY TIGHT AREA OF SCIENCE AND

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EACH HAS A DIFFERENT 1 AND THEY

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IN EFFECT HAVE COLLECTIVELY

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UNITED THEIR KNOWLEDGE AND

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ADVANCED SUBSTANTIALLY HUMAN

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MEDICINE IN THIS AREA WE WILL

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DISCUSS TODAY AND ALSO IN THE

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00:02:03,607 --> 00:02:07,411
BROADER AREA OF CELL BIOLOGY.

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WELL, DEMYSTIFYING MEDICINE

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MEETS ON TUESDAYS FROM 3-5

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EASTERN STANDARD TIME FROM

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JANUARY TO THE END OF MAY.

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YOU CAN WATCH IT USING THE LINK

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SHOWN ON THE SLIDE AND YOU DON'T

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HAVE TO BE HERE TODAY TO

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ACTUALLY HEAR IT IN ATTENDANCE,

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BECAUSE IT'S VIRTUAL, YOU CAN

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ACCESS IT AND ANY OF THE

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PROGRAMS FOR THE PAST 23 YEARS

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00:02:34,104 --> 00:02:35,072
USING THE LINK SHOWN FURTHER

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DOWN ON THE SLIDE. 

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FOR THOSE WHO SEEK CME CREDIT,

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00:02:43,480 --> 00:02:48,319
IT'S AVAILABLE AND THE CODE FOR

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00:02:48,319 --> 00:02:49,486
TODAY IS 58799.

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NOW, WE ENCOURAGE YOU TO SUBMIT

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QUESTIONS DURING TODAY'S

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PRESENTATIONS AND YOU CAN DO

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THAT BY CLICKING ON THE SEND

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LIVE FEEDBACK ON YOUR VIDEOCAST

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00:03:04,168 --> 00:03:05,669
DISPLAY.

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00:03:05,669 --> 00:03:07,304
AND THESE QUESTIONS WILL INFORM

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THE BASIS OF WHAT IS A VERY

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EXCITING DETAILED NOT JUST

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QUESTION AND ANSWER BUT

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DISCUSSION PERIOD FOLLOWING THE

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PRESENTATIONS. 

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IF YOU HAVE ANY DESIRE FOR

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ADDITIONAL INFORMATION, YOU CAN

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SEND US A MESSAGE AT

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DEMYSTIFYING MEDICINE AT NIH.GOV

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AS WELL AS SUGGESTIONS PERHAPS

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FOR NEXT YEAR'S TOPICS AND

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SPEAKERS. 

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NEXT SLIDE, PLEASE. 

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NEXT SLIDE.

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NOW, TODAY WE'RE GOING TO

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DISCUSS NONINFECTIOUS NEONATAL

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DIARRHEA.

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NOW GLOBALLY THIS PROBLEM

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INFECTIOUS DIARRHEA IS OFFENSE

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FATAL AND IT CERTAINLY IS A HUGE

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GLOBAL PROBLEM AND IT'S

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PRIMARILY DUE TO INFECTION DUE

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TO BACTERIA, VIRUSES SOMETIMES,

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FUNGUS, PARASITES AND THAT'S

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AIDED AND ABETTED BY

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MALNUTRITION  EMPLOY SO GLOBAL

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DIARRHEA IS A VERY SERIOUS

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PROBLEM.

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HOWEVER, WITHIN THIS LARGE

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GROUP, THERE ARE RARE

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INHERITABLE CASES WHICH HAVE

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00:04:26,283 --> 00:04:30,354
BEEN IDENTIFIED AND THEY HAVE

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BEEN CHARACTERIZED AND THIS

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00:04:31,822 --> 00:04:33,257
THEIR CHARACTERIZATION, THEY

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00:04:33,257 --> 00:04:36,593
HAVE PROVEN INVALUABLE IN

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DISSECTING THE MOLECULAR

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00:04:38,595 --> 00:04:39,430
MECHANISMS RESPONSIBLE FOR

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00:04:39,430 --> 00:04:40,464
OBLIGATIONS SORPTION AND

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SECRETION IN THE INTESTINE,

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LIVER, AND PERHAPS OTHER ORGANS.

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SO DISCOVERY OF THESE RARE

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INHERITABLE CAUSES OF

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NONINFECTIOUS NEONATAL DIARRHEA

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00:04:56,413 --> 00:04:59,083
HAS NOT ONLY RESULTED IN LIFE

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SAVING TREATMENT WHICH AT THE

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MOMENT IS USUALLY SURGERY BUT IT

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ALSO -- IT HAS RAISED CHALLENGES

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TO UNDERSTAND BETTER THE COMPLEX

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PROCESSES INVOLVED AND HOW

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THEY'RE REGULATED.

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AND AS THAT ACTIVITY IN CELL

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BIOLOGY IS PRECEDED, THE DOOR

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HAS BEEN OPEN TO BETTER

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DIAGNOSIS AND IT POINTS IN THE

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DIRECTION OF LESS INVASIVE BUT

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EFFECTIVE TREATMENTS.

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NOW IT'S ALSO INTERESTING THAT

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EACH OF THE INHERITABLE

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DISEASES, RESPONSIBLE FOR

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NONINFECTIOUS NEONATAL DIARRHEA

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EACH HAS A REMARKABLE HISTORY OF

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DISCOVERY.

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DISCOVERY BY ASTUTE PHYSICIANS

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WHICH THEN, WHO THEN QUESTION

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WHAT'S GOING ON HERE AND

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BRIDGED, THAT MEANS TALKED WITH,

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MET WITH, DRANK COFFEE WITH,

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BASIC SCIENTISTS AND

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COLLECTIVELY TO UNDERSTAND

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BETTER MECHANISMS AND THOSE

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MECHANISMS INCLUDE CLINICAL

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DETECTION OF INHERITABLE

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DISEASES AND ALSO BETTER

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UNDERSTANDING OF THE NORMAL

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PROCESSES OF ABSORPTION AND

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SECRETION AND EVEN POINTING TO

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HOW WHEN THEY ARE DEFECTIVE IN

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INFECTIOUS DIARRHEA SO IT OPENS

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A LARGE AREA OF CELL BIOLOGY.

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BASED UPON A CLINICAL SERIES OF

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OBSERVATIONS.

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THAT'S BRIDGING AT ITS HIGHEST

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LEVEL IF YOU'RE A PHYSICIAN

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SCIENTIST.

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NEXT SLIDE, PLEASE.

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SO OUR 2 SPEAKERS TODAY, NEXT

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SLID, OUR FIRST SPEAKER IS

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MITCHELL CHO, MITCHELL GRADUATED

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FROM MOTHER EASTERN, GOT HIS

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MEDICAL DEGREE AT THE UNIVERSITY

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OF VERMONT, DID A RESIDENCY IN

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PEDIATRIC AT DUKE, AND THEN A

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FELLOWSHIP AT PEDIATRIC

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GHASTROLOGY AND PEDIATRIC

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NUTRITION AT THE HARVARD IN

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CAMBRIDGE, SINCE 1986 HE'S BEEN

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AT THE PHOENIX CHILDREN'S

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HOSPITAL WHERE HE IN 2012 BECAME

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PROFESSOR AND ALSO HAS MANY

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ACTIVITIES INCLUDING BEING

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EXECUTIVE CHAIR OF THE

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DEPARTMENT OF CHILD HEALTH AND

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PEDIATRIC GASTRONEUROLOGY.

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MITCHELL HAS RECEIVED MANY, MANY

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HONORS AND RECOGNITION

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THROUGHOUT A LONG AND

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DISTINGUISHED CAREER.

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HE'S CONSISTENTLY RATED AS 1 OF

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AMERICA'S TOP PHYSICIANS,

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GASTRONEUROLOGYIST AND EVEN ONCE

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PHYSICIAN OF THE YEAR, I

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BELIEVE, AT ANY RATE, HE IS

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KNOWN AS A AN OUTSTANDING

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COMMENCEMENT SPEAKER AND ALSO

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EXTREMELY ACTIVE IN

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INSTITUTIONAL AND NATIONAL

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COMMITTEES.

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HE'S RECEIVED MANY, MANY AWARDS

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FOR TEACHING, SERVICE AND

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SCIENCE.

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NOW IN ADDITION TO THESE

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CLINICAL AND HIGH LEVEL

194
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RESPONSIBILITIES, HE HAS

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CONDUCTED RESEARCH THROUGHOUT

196
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HIS CAREER, HAS RECEIVED

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NUMEROUS NIH GRANTS FOR BASIC

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AND ALSO TRANSLATIONAL RESEARCH

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AND INHERITABLE AND ACQUIRED

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GASTROINTESTINAL DISEASES, AND

201
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IN THE COURSE OF THIS, THIS IS A

202
00:08:39,303 --> 00:08:41,738
SUPERB EXAMPLE OF A BRIDGE

203
00:08:41,738 --> 00:08:43,507
BUILDING ENGINEER BECAUSE OF

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EXTENSIVE COLLABORATIONS WITH

205
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COLLEAGUES FROM THE BASIC

206
00:08:50,280 --> 00:08:51,248
SCIENCE COMMUNITIES.

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NOW OUR SECOND SPEAKER, NEXT

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00:08:53,617 --> 00:08:56,954
SLIDE, PLEASE IS JIM GOLDENRING,

209
00:08:56,954 --> 00:08:58,822
WHO GRADUATED FROM HARVARD AND

210
00:08:58,822 --> 00:09:01,592
GOT HIS M. D. AND Ph.D. AT

211
00:09:01,592 --> 00:09:01,825
YALE.

212
00:09:01,825 --> 00:09:05,295
NOW JIM IS TRAINED AS A SURGEON

213
00:09:05,295 --> 00:09:08,665
AND DID A SURGICAL RESIDENCY AT

214
00:09:08,665 --> 00:09:11,668
YALE AND I BELIEVE STILL

215
00:09:11,668 --> 00:09:13,370
CONTINUES TO DO GASTROINTESTINAL

216
00:09:13,370 --> 00:09:14,037
SURGERY.

217
00:09:14,037 --> 00:09:16,573
HE'S HAD SEVERAL POST DOCTORAL

218
00:09:16,573 --> 00:09:18,308
FELLOWSHIPS AND SURGICAL

219
00:09:18,308 --> 00:09:20,777
RESEARCH AND INCREASINGLY IN

220
00:09:20,777 --> 00:09:25,349
CELL BIOLOGY AND HAS SWITCHED TO

221
00:09:25,349 --> 00:09:31,588
CELL BIOLOGY, THOUGH NOT A 

222
00:09:31,588 --> 00:09:35,759
COMPLETE 1, IT WAS LINKED TO HIS

223
00:09:35,759 --> 00:09:37,494
TRAINING AND RESEARCH

224
00:09:37,494 --> 00:09:38,862
PARTICULARLY REGARDING THE

225
00:09:38,862 --> 00:09:39,830
GASTROINTESTINAL TRACT.

226
00:09:39,830 --> 00:09:42,032
PRESENTLY HE'S THE PAUL SANGER

227
00:09:42,032 --> 00:09:43,133
PROFESSOR OF SURGERY AND

228
00:09:43,133 --> 00:09:47,204
PROCESSOR OF CELL AND

229
00:09:47,204 --> 00:09:48,338
DEVELOPMENTAL BIOLOGY BOTHAD

230
00:09:48,338 --> 00:09:50,874
VANDERBILT UNIVERSITY SCHOOL OF

231
00:09:50,874 --> 00:09:51,274
MEDICINE.

232
00:09:51,274 --> 00:09:53,443
NOW JIM HAS RECEIVED ALL KINDS

233
00:09:53,443 --> 00:09:56,146
OF HONORS, HE'S A MEMBER OF THE

234
00:09:56,146 --> 00:09:58,615
AMERICAN SOCIETY OF CLINICAL

235
00:09:58,615 --> 00:10:00,550
INVESTIGATION, THE ASSOCIATION

236
00:10:00,550 --> 00:10:01,618
FOR ACADEMIC PHYSICIANS, A

237
00:10:01,618 --> 00:10:06,857
FELLOW OF THE AMERICAN

238
00:10:06,857 --> 00:10:07,391
GASTROENTHUSIASMEROLOGICAL

239
00:10:07,391 --> 00:10:09,126
ASSOCIATION, A MEMBER OF THE

240
00:10:09,126 --> 00:10:15,198
INSTITUTE COUNCIL FOR CELLULAR

241
00:10:15,198 --> 00:10:17,668
AND MOLECULAR GASTROENTEROLOGY.

242
00:10:17,668 --> 00:10:19,403
HE'S RECEIVED AWARDS FOR

243
00:10:19,403 --> 00:10:20,704
OUTSTANDING MENTORSHIP AND

244
00:10:20,704 --> 00:10:21,338
DISTINGUISHED ACHIEVEMENT AND

245
00:10:21,338 --> 00:10:22,606
FOR THE AMERICAN ASSOCIATION FOR

246
00:10:22,606 --> 00:10:25,142
THE ADVANCEMENT OF SCIENCE,

247
00:10:25,142 --> 00:10:26,410
ELECTED MEMBER, AND ALSO

248
00:10:26,410 --> 00:10:27,911
RECIPIENT OF A DISTINGUISHED

249
00:10:27,911 --> 00:10:31,081
RESEARCH AWARD FROM THE AMERICAN

250
00:10:31,081 --> 00:10:32,149
PHYSIOLOGICAL SOCIETY.

251
00:10:32,149 --> 00:10:35,318
THIS AMONGST MANY OTHER

252
00:10:35,318 --> 00:10:35,919
ACTIVITIES.

253
00:10:35,919 --> 00:10:38,789
NOW AS HIS RESEARCH SPANS

254
00:10:38,789 --> 00:10:41,758
MULTIPLE AREAS OF EPITHELIAL

255
00:10:41,758 --> 00:10:46,997
BIOLOGY, IN PARTICULARLY, THE

256
00:10:46,997 --> 00:10:51,268
ROLE OF RAB SMALL GTPACES IN

257
00:10:51,268 --> 00:10:52,469
REGULATING VESICLE TRAFFICKING

258
00:10:52,469 --> 00:10:58,975
AND MEMBRANE RECYCLING IN

259
00:10:58,975 --> 00:11:01,745
POLARIZED CELLS, HE ALSO DID

260
00:11:01,745 --> 00:11:04,781
OUTSTANDING WORK IN THE LARGE

261
00:11:04,781 --> 00:11:09,453
MULTIPLE SPLICE GENE CODING FOR

262
00:11:09,453 --> 00:11:11,988
THE A53 SCAFFOLDING PROTEINS AND

263
00:11:11,988 --> 00:11:14,458
HIS RESEARCH HAS EXTENDED IN

264
00:11:14,458 --> 00:11:17,260
CONSIDERABLE DEPTH ALSO INTO THE

265
00:11:17,260 --> 00:11:20,997
MECHANISMS OF METAPLACIA AND

266
00:11:20,997 --> 00:11:23,033
GASTRIC CANCER.

267
00:11:23,033 --> 00:11:25,736
JIM'S A RENAISSANCE MAN, A

268
00:11:25,736 --> 00:11:29,306
SURGEON, SCIENTIST, EDUCATOR, A

269
00:11:29,306 --> 00:11:30,307
TRAINER, MENTOR, OUTSTANDING

270
00:11:30,307 --> 00:11:32,375
FENCER AT 1 TIME IN HIS CAREER,

271
00:11:32,375 --> 00:11:35,712
I GUESS, AND EXCELLENT WRITER

272
00:11:35,712 --> 00:11:42,085
AND HE AND HIS COLLEAGUE

273
00:11:42,085 --> 00:11:43,720
MITCHELL ARE TRUE BRIDGE

274
00:11:43,720 --> 00:11:44,988
BUILDERS.

275
00:11:44,988 --> 00:11:47,424
SO WE'RE DELIGHTED HAVE BOTH OF

276
00:11:47,424 --> 00:11:47,958
YOU HERE TODAY.

277
00:11:47,958 --> 00:11:52,195
APPRECIATE VERY MUCH YOUR

278
00:11:52,195 --> 00:11:53,096
PARTICIPATION IN DEMYSTIFYING

279
00:11:53,096 --> 00:11:54,564
MEDICINE AND MITCHELL PERHAPS

280
00:11:54,564 --> 00:11:55,932
YOU WILL BEGIN. 

281
00:11:55,932 --> 00:12:06,109
THANK YOU.

282
00:12:11,715 --> 00:12:13,016
>> THANK YOU.

283
00:12:13,016 --> 00:12:21,057
IS THAT SEEABLE BY EVERYONE?

284
00:12:21,057 --> 00:12:22,392
>> YES, PERFECT.

285
00:12:22,392 --> 00:12:22,759
>> THANK YOU.

286
00:12:22,759 --> 00:12:25,695
WELL I WOULD LIKE TO THANK THE

287
00:12:25,695 --> 00:12:29,366
NIH IN BRINGING ME AND

288
00:12:29,366 --> 00:12:30,467
DR. GOLDENRING TO SPEAK TODAY.

289
00:12:30,467 --> 00:12:32,636
THE TOPIC WE WILL REVIEW TODAY

290
00:12:32,636 --> 00:12:42,579
IS A RARE CONGENITAL DIARRHEA

291
00:12:42,579 --> 00:12:43,280
DISEASE.

292
00:12:43,280 --> 00:12:44,648
I'VE HAD THE UNIQUE OPPORTUNITY

293
00:12:44,648 --> 00:12:47,250
TO CHAIR FOR A LARGE NUMBER OF

294
00:12:47,250 --> 00:12:48,618
CHILDREN WITH THIS DISEASE

295
00:12:48,618 --> 00:12:50,453
BECAUSE OF THE INCREASED

296
00:12:50,453 --> 00:12:52,522
INCIDENCE IN THE NAVAHO

297
00:12:52,522 --> 00:12:55,025
POPULATION OF WHICH WE PROVIDE

298
00:12:55,025 --> 00:12:56,860
TERTIARY CARE AND BECAUSE OF

299
00:12:56,860 --> 00:13:00,297
THAT, IS HOW I GOT INVOLVED WITH

300
00:13:00,297 --> 00:13:02,165
THIS AND THEN LATER JOINED WITH

301
00:13:02,165 --> 00:13:04,234
JIM WHO REAL LEGAL HAS TAKEN THE

302
00:13:04,234 --> 00:13:08,205
SCIENCE TO THE NEXT LEVEL.

303
00:13:08,205 --> 00:13:18,748
I HAVE NO CONFLICTS OF INTEREST

304
00:13:28,024 --> 00:13:28,391
OR DISCLOSURES.

305
00:13:28,391 --> 00:13:30,660
SO THIS DISEASE IS PART OF A

306
00:13:30,660 --> 00:13:35,465
BROADER CATEGORY OF WHAT WE CALL

307
00:13:35,465 --> 00:13:36,399
NEONATAL DIARRHEA AND

308
00:13:36,399 --> 00:13:36,700
NEUROPATHY.

309
00:13:36,700 --> 00:13:39,469
THESE ARE RARE AND CHAL ENKING

310
00:13:39,469 --> 00:13:42,172
TO TREAT, EXACT PREVALENCE OF

311
00:13:42,172 --> 00:13:43,940
QUALITIES AND CONDITIONS IS

312
00:13:43,940 --> 00:13:45,976
UNKNOWN, FREQUENT DELAY OR

313
00:13:45,976 --> 00:13:49,145
MISDIAGNOSES THAT CAN LEAD TO

314
00:13:49,145 --> 00:13:52,449
INAPPROPRIATE TREATMENT OR WORSE

315
00:13:52,449 --> 00:13:54,150
DEMISE, THESE CONDITIONS ARE

316
00:13:54,150 --> 00:13:55,785
OFTEN ASSOCIATED WITH

317
00:13:55,785 --> 00:13:56,653
SUBSTANTIAL MORBIDITY AND

318
00:13:56,653 --> 00:14:01,791
MORTALITY AND ARE WANTING BETTER

319
00:14:01,791 --> 00:14:04,761
TREATMENTS.

320
00:14:04,761 --> 00:14:11,868
OUR PATIENTS WITH MVID, CAN'T

321
00:14:11,868 --> 00:14:15,338
ABSORB ANYTHING INTERNALLY, OR

322
00:14:15,338 --> 00:14:16,706
BOWEL TRANSPLANT, PROMPT

323
00:14:16,706 --> 00:14:19,643
DIAGNOSE IS REQUIRED TO PROVIDE

324
00:14:19,643 --> 00:14:20,911
CORRECT TREATMENT AND EVEN

325
00:14:20,911 --> 00:14:23,446
THOUGH MANY OF THE GENE

326
00:14:23,446 --> 00:14:24,414
ABNORMALITIES HAVE BEEN

327
00:14:24,414 --> 00:14:25,248
DESCRIBED, THERE ARE MANY OTHERS

328
00:14:25,248 --> 00:14:35,759
THAT ARE YET TO BE ELUCIDATED.

329
00:14:37,060 --> 00:14:38,628
NOW THESENYONATAL CONGENITAL

330
00:14:38,628 --> 00:14:42,832
DIARRHEAS FIT INTO 5 CATEGORIES.

331
00:14:42,832 --> 00:14:48,271
THE EPITHELIAL TRAFFICKING AND

332
00:14:48,271 --> 00:14:50,240
POLARITY ABNORMALITIES IS THE

333
00:14:50,240 --> 00:14:51,641
MICRO INCLUSION THAT THE DISEASE

334
00:14:51,641 --> 00:14:54,678
FITS WITH OTHER CATEGORIES THAT

335
00:14:54,678 --> 00:14:58,782
INCLUDES THINGS LIKE EPITHOOLIAL

336
00:14:58,782 --> 00:15:01,318
ELECTROLYTE TRANSPORT OR

337
00:15:01,318 --> 00:15:03,386
CONGENITAL DIARRHEA, EPITHELIAL

338
00:15:03,386 --> 00:15:04,688
ENZYME AND METABOLISM DISORDERS,

339
00:15:04,688 --> 00:15:07,657
SOME CHILDREN ARE BORN WITH THE

340
00:15:07,657 --> 00:15:10,226
ABILITY TO ABNORMALITIES SORP

341
00:15:10,226 --> 00:15:11,861
CERTAIN CARBOHYDRATES THAT CAN

342
00:15:11,861 --> 00:15:17,801
LEAD TO PROFUSE DIARHEA, AND

343
00:15:17,801 --> 00:15:19,736
ENTERO ENDOCRINE DISORDERS, SO

344
00:15:19,736 --> 00:15:22,339
PLACES LIKE NEOBLASTOMA CAN

345
00:15:22,339 --> 00:15:24,674
CAUSE TERRIBLE SECRET ORY

346
00:15:24,674 --> 00:15:27,477
DIARRHEA, AND AUTOIMMUNE DISEASE

347
00:15:27,477 --> 00:15:30,246
OF THE GASTROINTESTINAL TRACT.

348
00:15:30,246 --> 00:15:31,982
NOW MVID SO FAR AS BEEN

349
00:15:31,982 --> 00:15:35,885
IEE, AUDIENCE DENTIFIED AS CAUSE

350
00:15:35,885 --> 00:15:38,288
BY MUTATIONS 5 F4 GENES.

351
00:15:38,288 --> 00:15:43,426
MY O 5 B WHICH APPEARS TO BE

352
00:15:43,426 --> 00:15:45,962
MOST PREVALENT, STX3, STXBP2,

353
00:15:45,962 --> 00:15:47,864
AND UNC45 E HAVE ALL BEEN

354
00:15:47,864 --> 00:15:50,033
DESCROIBED WITH MUTATIONS

355
00:15:50,033 --> 00:15:50,900
CAUSING MICRODOSE INCLUSION.

356
00:15:50,900 --> 00:15:55,672
THIS LEADS TO A DEFECTIVE

357
00:15:55,672 --> 00:15:57,674
MEMBRANE RECYCLING AND

358
00:15:57,674 --> 00:16:00,410
INTESTINAL EPITHELIAL CELLS THAT

359
00:16:00,410 --> 00:16:01,678
DR. GOLDENRING WILL SPEAK TO IN

360
00:16:01,678 --> 00:16:04,447
HIS LECTURE IN GREAT DETAIL.

361
00:16:04,447 --> 00:16:09,252
THIS PATIENTS HAVE INTRACTABLE

362
00:16:09,252 --> 00:16:10,387
SECRETATTORY DIARRHEA THAT

363
00:16:10,387 --> 00:16:11,321
BEGINS WITHIN THE FIRST FEW DAYS

364
00:16:11,321 --> 00:16:13,723
OF LIFE AND ASSOCIATED WITH

365
00:16:13,723 --> 00:16:15,825
HISTOLOGIC CHANGES OF THE

366
00:16:15,825 --> 00:16:17,260
INTESTINAL LINING WHERE THE

367
00:16:17,260 --> 00:16:19,129
VILLI THAT ARE NORMALLY PRESENT

368
00:16:19,129 --> 00:16:21,364
OR FINGER LIKE STRUCTURES THAT

369
00:16:21,364 --> 00:16:24,034
HELP WITH ABSORPTION AND

370
00:16:24,034 --> 00:16:26,102
INCREASED SURFACE AREA OF THE

371
00:16:26,102 --> 00:16:26,803
SMALL INTEST IEP, THEY'RE

372
00:16:26,803 --> 00:16:35,078
ATROPHIED AND ON THE SURFACE OF

373
00:16:35,078 --> 00:16:37,113
THE ENTERO-SITES, SHOULD BE

374
00:16:37,113 --> 00:16:39,582
ABSENT RENDERING IT UNABLE TO

375
00:16:39,582 --> 00:16:40,950
ABSORB AND INTERACT WITH THE

376
00:16:40,950 --> 00:16:43,319
ENVIRONMENT IN AN APPROPRIATION

377
00:16:43,319 --> 00:16:43,553
FASHION.

378
00:16:43,553 --> 00:16:44,821
AND A UNIQUE ASPECT OF THIS

379
00:16:44,821 --> 00:16:53,029
DISEASE THAT LED TO THE NAMING

380
00:16:53,029 --> 00:16:54,531
WAS MICROVILLUS INCLUSIONS AND

381
00:16:54,531 --> 00:16:56,533
WHAT I HAVE HERE AND JIM WILL

382
00:16:56,533 --> 00:16:59,702
SHOW FURTHER SLIDES, ON THE LEFT

383
00:16:59,702 --> 00:17:02,372
IS A SCANNING ELECTRON

384
00:17:02,372 --> 00:17:08,878
MICROSCOPY VIEW OF THE SURFACE

385
00:17:08,878 --> 00:17:09,579
OF INTESTINAL ENTERO-SITES AND

386
00:17:09,579 --> 00:17:12,215
YOU CAN SEE THERE ARE ALL THESE

387
00:17:12,215 --> 00:17:13,283
FILAMENT LIKE STRUCTURES THAT

388
00:17:13,283 --> 00:17:14,717
COAT THE SURFACE AND THAT'S

389
00:17:14,717 --> 00:17:15,618
NORMAL, THAT'S WHAT SHOULD BE

390
00:17:15,618 --> 00:17:19,756
THERE AND THOSE ARE KNOWN AS

391
00:17:19,756 --> 00:17:20,056
MICROVILLI.

392
00:17:20,056 --> 00:17:24,160
NOW ON THE RIGHT IS A BIOPSY

393
00:17:24,160 --> 00:17:30,900
UNDER ELECTRON MICROSCOPY OF A

394
00:17:30,900 --> 00:17:32,836
PATIENT WITH DISEASE, THE BLACK

395
00:17:32,836 --> 00:17:34,838
ARROW POINTS TO THE SURFACE AND

396
00:17:34,838 --> 00:17:36,573
THERE'S NO MICROVILLI ON THE

397
00:17:36,573 --> 00:17:39,409
SURFACE AND THE RED ARROWS ARE

398
00:17:39,409 --> 00:17:40,577
SURROUNDING A VESICLE THAT

399
00:17:40,577 --> 00:17:42,512
CONTAIN ALL THESE FORMED

400
00:17:42,512 --> 00:17:44,547
MICROVILLI THAT JUST CAN'T GET

401
00:17:44,547 --> 00:17:45,281
TO THE SURFACE.

402
00:17:45,281 --> 00:17:47,350
AND THAT'S WHERE THE DISEASE

403
00:17:47,350 --> 00:17:53,356
NAME WAS COINED BY A DOCTOR IN

404
00:17:53,356 --> 00:17:55,425
TORONTO FOR SICK CHILDREN BACK

405
00:17:55,425 --> 00:17:57,494
IN THE LATE 1970S.

406
00:17:57,494 --> 00:17:59,429
NOW MICRODOSE INCLUSION DISEASE

407
00:17:59,429 --> 00:18:01,898
IN THE NAVAHO IS TUE TO A RATHER

408
00:18:01,898 --> 00:18:04,467
UNIQUE SITUATION THAT I THINK IS

409
00:18:04,467 --> 00:18:05,635
IMPORTANT FOR THE AUDIENCE TO

410
00:18:05,635 --> 00:18:08,238
UNDERSTAND, IN FACT THERE ARE 6

411
00:18:08,238 --> 00:18:09,973
RARE GENETIC CONDITIONS THAT CAN

412
00:18:09,973 --> 00:18:14,077
BE FOUND IN THE NOX FAMILY

413
00:18:14,077 --> 00:18:17,680
ACTIVATORRA  -- NAA HOE AND THIS

414
00:18:17,680 --> 00:18:21,784
WAS FOUND BY GENETIC BOTTLENECK,

415
00:18:21,784 --> 00:18:23,520
IN THE 1860S, MOST OF THEM WERE

416
00:18:23,520 --> 00:18:27,290
ROUNDED UP BY THE GOVERNMENT AND

417
00:18:27,290 --> 00:18:28,324
MARCHED TO AN INTER MENTORSHIP

418
00:18:28,324 --> 00:18:29,926
SKILL CAMP HUNDREDS OF MAILS

419
00:18:29,926 --> 00:18:32,662
FROM WHERE THEIR NATIVE LAND WAS

420
00:18:32,662 --> 00:18:34,164
IN EASTERN NEW MEXICO BUT ABOUT

421
00:18:34,164 --> 00:18:35,265
A THOUSAND INDIVIDUALS WERE

422
00:18:35,265 --> 00:18:38,568
NEVER ABLE TO BE CAPTURED AND

423
00:18:38,568 --> 00:18:40,236
IT'S THOUGHT THAT THE ENTIRE

424
00:18:40,236 --> 00:18:42,739
GENETIC POOL OF THE WESTERN HALF

425
00:18:42,739 --> 00:18:44,841
OF THE POPULATION CAME FROM

426
00:18:44,841 --> 00:18:47,410
THOSE THOUSAND INDIVIDUALS.

427
00:18:47,410 --> 00:18:57,954
SO IN ORDER TO CREATE A FOUNDER

428
00:19:02,258 --> 00:19:05,128
EFFECT -- YOU KNOW IT'S VERY

429
00:19:05,128 --> 00:19:06,796
ISOLATED AND VERY UNIQUE

430
00:19:06,796 --> 00:19:10,300
TOPOGRAPHY AND THEN FOLLOWED BY

431
00:19:10,300 --> 00:19:11,467
A TREMENDOUS GROWTH IN

432
00:19:11,467 --> 00:19:14,103
POPULATION, SO WE KNOW THAT IN

433
00:19:14,103 --> 00:19:17,006
THE LATE 1860S, THE ENTIRE

434
00:19:17,006 --> 00:19:19,242
NAVAJO POPULATION WAS REDUCED TO

435
00:19:19,242 --> 00:19:22,545
6 OR 7000 INDIVIDUALS AND NOW

436
00:19:22,545 --> 00:19:23,279
THERE'S GREATER THAN 400,000

437
00:19:23,279 --> 00:19:23,680
NAVAJO.

438
00:19:23,680 --> 00:19:26,883
SO AS A RESULT OF THIS, THEY HAD

439
00:19:26,883 --> 00:19:30,620
CERTAIN GENE MUTATIONS THAT WERE

440
00:19:30,620 --> 00:19:32,755
JUST RETAKENNED IN THAT THOUSAND

441
00:19:32,755 --> 00:19:36,326
PEOPLE POOL THAT ENDED UP BEING

442
00:19:36,326 --> 00:19:44,867
PROMULGATED IN THE POPULATION

443
00:19:44,867 --> 00:19:50,006
WITH SUBSEQUENT -- LET'S SEE.

444
00:19:50,006 --> 00:19:52,809
LET ME GET BACK TO WHERE I WAS.

445
00:19:52,809 --> 00:19:54,777
THERE WE GO.

446
00:19:54,777 --> 00:19:56,746
ALL RIGHT.

447
00:19:56,746 --> 00:20:00,216
SO, WHEN WE FIRST STARTED

448
00:20:00,216 --> 00:20:02,852
GETTING PATIENTS WITH THIS RARE

449
00:20:02,852 --> 00:20:04,721
DIAGNOSIS BY THE FOURTH 1, WE

450
00:20:04,721 --> 00:20:07,991
SAID, YOU KNOW THIS IS REALLY

451
00:20:07,991 --> 00:20:08,224
UNUSUAL.

452
00:20:08,224 --> 00:20:10,960
IT'S NOT COMMON TO SEE SO MANY

453
00:20:10,960 --> 00:20:16,032
PATIENTS WITH THIS CONDITION, SO

454
00:20:16,032 --> 00:20:20,003
I JOINED FORCES WITH A RESEARCH

455
00:20:20,003 --> 00:20:22,205
GENETICIST IN TUCSON, A FELLA BY

456
00:20:22,205 --> 00:20:24,407
THE NAME OF DR. ERIC ROBINSON

457
00:20:24,407 --> 00:20:27,176
WHO HAD DONE A LOT OF RESEARCH

458
00:20:27,176 --> 00:20:29,345
IN NAVAJO RARE DISORDERS AND

459
00:20:29,345 --> 00:20:30,880
SAID, YOU KNOW I THINK THIS IS

460
00:20:30,880 --> 00:20:32,048
ANOTHER 1.

461
00:20:32,048 --> 00:20:34,717
SO UNDER IRB APPROVAL AND WITH

462
00:20:34,717 --> 00:20:40,089
FAMILIES CONSENT, WE WERE ABLE

463
00:20:40,089 --> 00:20:42,025
TO RETAIN BLOOD FROM THEIR

464
00:20:42,025 --> 00:20:45,261
PATIENTS AND THEIR PARENTS AND

465
00:20:45,261 --> 00:20:49,699
IN 2008, THE GENE MUTATION WAS

466
00:20:49,699 --> 00:20:54,337
DISCOVERED IN MY O 5 B, IT WAS A

467
00:20:54,337 --> 00:20:56,139
HOMOZYGOUS MISENSEL MUTATION

468
00:20:56,139 --> 00:20:59,642
THAT WE CALL P660 L, AND THIS

469
00:20:59,642 --> 00:21:03,446
RESULTED IN AN APICAL MEMBRANE,

470
00:21:03,446 --> 00:21:05,615
DEFECTIVE APICAL MEMBRANE

471
00:21:05,615 --> 00:21:07,583
RECYCLING PATHWAY AND

472
00:21:07,583 --> 00:21:09,052
DR. GOLDENRING WILL DISCUSS THAT

473
00:21:09,052 --> 00:21:09,786
IN GREATER DETAIL.

474
00:21:09,786 --> 00:21:11,487
AS A RESULT OF THIS DEFECT,

475
00:21:11,487 --> 00:21:13,623
THESE PATIENTS WITHIN THE FIRST

476
00:21:13,623 --> 00:21:18,961
FEW DAYS OF LIFE HAVE SEVERE

477
00:21:18,961 --> 00:21:21,230
DIARRHE APROFUSE, WATERY RESULTS

478
00:21:21,230 --> 00:21:26,269
IN ACIDOSEIS AND DEHYDRATION AND

479
00:21:26,269 --> 00:21:27,070
ELECTROLYTE ABNORMALITIES.

480
00:21:27,070 --> 00:21:29,706
THEY REQUIRE PRETTY RAPID

481
00:21:29,706 --> 00:21:32,108
RECOGNITION TO PREVENT THEM FROM

482
00:21:32,108 --> 00:21:35,178
SUCCUMBING TO THIS DISEASE AND

483
00:21:35,178 --> 00:21:38,614
THEY NEED AGGRESSIVE FOOD AND

484
00:21:38,614 --> 00:21:40,083
ELECTROLYTE RESUSCITATION, THEY

485
00:21:40,083 --> 00:21:41,818
HAVE A LIFE LONG INABILITY TO

486
00:21:41,818 --> 00:21:43,553
TOLERATE ANY FORM OF FEEDS

487
00:21:43,553 --> 00:21:46,556
INCLUDING THE MOST ELEMENTAL

488
00:21:46,556 --> 00:21:47,890
FORMULAS, AND THEY REQUIRE

489
00:21:47,890 --> 00:21:51,961
LONG-TERM TREATMENT WITH EITHER

490
00:21:51,961 --> 00:21:59,602
TPN OR BOWEL TRANSPLANT.

491
00:21:59,602 --> 00:22:02,705
NOW TPN AND LIFE SAVING FOR

492
00:22:02,705 --> 00:22:04,440
THESE PATIENTS, IT INVOLVES

493
00:22:04,440 --> 00:22:07,577
PLACING A CENTRAL VENUS LINE AND

494
00:22:07,577 --> 00:22:08,544
SURGEONS DO THAT AND THEN

495
00:22:08,544 --> 00:22:10,380
THROUGH THAT LINE WE HAVE ACCESS

496
00:22:10,380 --> 00:22:13,149
TO BE ABLE TO PROVOID THEM

497
00:22:13,149 --> 00:22:15,485
FLUIDS, ELECTROLYTES AND

498
00:22:15,485 --> 00:22:15,852
NUTRITION.

499
00:22:15,852 --> 00:22:16,586
UNFORTUNATELY, LONG-TERM PTN AND

500
00:22:16,586 --> 00:22:21,023
ASSOCIATED WITH THE NUMBER OF

501
00:22:21,023 --> 00:22:23,693
COMPLICATIONS INCLUDING SEPSIS,

502
00:22:23,693 --> 00:22:27,663
FLUID ELECTROLYTE IMBALANCE IS A

503
00:22:27,663 --> 00:22:29,866
CONSTANT PROBLEM, 1 NEEDS TO

504
00:22:29,866 --> 00:22:32,235
MONITOR THESE PATIENTS CLOSELY

505
00:22:32,235 --> 00:22:34,237
AND MAKE ADJUSTMENT THEMENTS TO

506
00:22:34,237 --> 00:22:38,474
THE FLUID AND ELECTROLYTES TO

507
00:22:38,474 --> 00:22:40,443
THE TPN, AND THROMBOSIS OF THE

508
00:22:40,443 --> 00:22:42,111
VESSELS, AND OVER TIME YOU CAN

509
00:22:42,111 --> 00:22:44,046
USE UP VESSELS TO THE POINT

510
00:22:44,046 --> 00:22:46,916
WHERE THERE'S NO VENUS ACCESS TO

511
00:22:46,916 --> 00:22:49,685
PROVIDE CENTRAL VENUS NUTRITION.

512
00:22:49,685 --> 00:22:55,024
TPN IS ALSO ASSOCIATED WITH

513
00:22:55,024 --> 00:22:56,325
LIVER DISEASE AND IN OUR

514
00:22:56,325 --> 00:22:59,061
POPULATION WE THINK THAT LIVER

515
00:22:59,061 --> 00:23:01,798
DISEASE IS AGGRAVATED BY

516
00:23:01,798 --> 00:23:09,906
EFFECTIVE TARGETING OF BIOSALT

517
00:23:09,906 --> 00:23:13,609
PUMPS TO THE BIOCANALICULI, AND

518
00:23:13,609 --> 00:23:19,682
PEOPLE ARE NOW CALLING THIS FORM

519
00:23:19,682 --> 00:23:21,684
OF PFIC 6, BUT IT SEEMS TO

520
00:23:21,684 --> 00:23:23,719
ACCELERATE THE LIVER DISEASE SO

521
00:23:23,719 --> 00:23:25,488
THAT THESE PATIENTS GET SEVERE

522
00:23:25,488 --> 00:23:27,723
AND PROFOUND LIVER DISEASE MUCH

523
00:23:27,723 --> 00:23:31,294
EARLIER THAN JUST TPN ALONE WILL

524
00:23:31,294 --> 00:23:31,527
COST.

525
00:23:31,527 --> 00:23:34,163
OTHER COMPLICATIONS OF LONG-TERM

526
00:23:34,163 --> 00:23:35,865
TPN INCLUDE METABOLIC BONE

527
00:23:35,865 --> 00:23:39,001
DISEASE AND VARIOUS TRACE

528
00:23:39,001 --> 00:23:40,636
ELEMENTS DISORDERS THAT 1 NEEDS

529
00:23:40,636 --> 00:23:42,672
TO MONITOR.

530
00:23:42,672 --> 00:23:45,241
NOW LONG-TERM SURVIVAL ON TPN,

531
00:23:45,241 --> 00:23:49,912
IN OUR HANDS, THE LONGEST

532
00:23:49,912 --> 00:23:51,848
SURVIVOR LIVED TO 15 YEARS OF

533
00:23:51,848 --> 00:23:53,616
AGE WHICH IS PRETTY IMPRESSIVE

534
00:23:53,616 --> 00:23:57,253
AND THESE PATIENTS WERE BEFORE

535
00:23:57,253 --> 00:24:00,456
THE ADVENT OF BOWEL TRANSPLANTS.

536
00:24:00,456 --> 00:24:02,525
SINCE THEN, WE'VE SENT OUR

537
00:24:02,525 --> 00:24:04,827
PATIENTS FOR EVALUATION FOR

538
00:24:04,827 --> 00:24:06,696
TRANSPLANT BUT EVEN WITH ALL OF

539
00:24:06,696 --> 00:24:09,966
THESE EFFORTS, MANY OF OUR

540
00:24:09,966 --> 00:24:11,167
PATIENTS DIE WITHIN THE FIRST 2

541
00:24:11,167 --> 00:24:18,074
YEARS OF LIFE BECAUSE OF THE

542
00:24:18,074 --> 00:24:28,551
COMPLICATIONS LISTED ABOVE.

543
00:24:30,887 --> 00:24:31,721
NOW MULTIVISCERAL TRANSPLANTS

544
00:24:31,721 --> 00:24:33,856
ARE CURRENTLY THE WAY TO GO.

545
00:24:33,856 --> 00:24:37,393
IF SUCCESSFUL THEY ALLOW THE

546
00:24:37,393 --> 00:24:38,928
PATIENTS TO ABSORB ENTERO

547
00:24:38,928 --> 00:24:41,831
FEEDINGS AND GO OFF TPN WHICH IS

548
00:24:41,831 --> 00:24:43,766
FANTASTIC HOWEVER, THERE'S

549
00:24:43,766 --> 00:24:45,902
NUMEROUS COMPLICATIONS

550
00:24:45,902 --> 00:24:46,969
ASSOCIATED WITH THIS

551
00:24:46,969 --> 00:24:47,637
INTERVENTION, FIRST AND FOREMOST

552
00:24:47,637 --> 00:24:49,672
A LOT OF PATIENTS DIE IN THE

553
00:24:49,672 --> 00:24:52,842
WAITING LIST WAITING FOR THEIR

554
00:24:52,842 --> 00:24:53,643
TRANSPLANT.

555
00:24:53,643 --> 00:24:55,278
ONCE THEY'RE TRANSPLANTED, THEY

556
00:24:55,278 --> 00:25:03,352
HAVE COMPLICATIONS OF REJECTION,

557
00:25:03,352 --> 00:25:04,453
INFECTION, LYMPHOPROLIFERATIVE

558
00:25:04,453 --> 00:25:06,188
DISORDER, GRAFT VERSUS HOST

559
00:25:06,188 --> 00:25:08,958
DISEASE, ALL SEVERE LIFE

560
00:25:08,958 --> 00:25:09,458
THREATENING CONDITIONS.

561
00:25:09,458 --> 00:25:11,127
AND IN THE MOST RECENT

562
00:25:11,127 --> 00:25:12,161
PUBLICATION, 10 YEAR SURVIVAL

563
00:25:12,161 --> 00:25:17,366
RATES OF ALL COMERS WITH BOWEL

564
00:25:17,366 --> 00:25:20,236
TRANSPLANTS IS IN THE 40-75%

565
00:25:20,236 --> 00:25:26,242
RANGE. 

566
00:25:26,242 --> 00:25:26,809
SO NOT IDEAL.

567
00:25:26,809 --> 00:25:29,812
BEFORE I TURN THIS OVER TO

568
00:25:29,812 --> 00:25:31,447
DR. GOLDEN RING, I WOULD LIKE TO

569
00:25:31,447 --> 00:25:33,416
PRESENT YOU OF A REAL CASE OF A

570
00:25:33,416 --> 00:25:40,256
PEASHT I WAS CONSULTED ON WITH

571
00:25:40,256 --> 00:25:42,058
MICROVILLUS INCLUSION TO GIVE

572
00:25:42,058 --> 00:25:43,593
YOU A VISION OF HOW THEY

573
00:25:43,593 --> 00:25:43,826
PRESENT.

574
00:25:43,826 --> 00:25:47,763
SO THIS WAS A 2 WEEK OLD NAVAJO

575
00:25:47,763 --> 00:25:49,365
TRANSFORTED FROM THE HOSPITAL TO

576
00:25:49,365 --> 00:25:52,602
THE NICU AT OUR FACILITY AND HAD

577
00:25:52,602 --> 00:25:57,907
PROGRESSIVE WEIGHT LOSS DESPITE

578
00:25:57,907 --> 00:26:00,176
ELEMENTAL FORMULA FEEDINGS AND

579
00:26:00,176 --> 00:26:06,682
HAD REPEATED BOUTS OF SEVERE

580
00:26:06,682 --> 00:26:12,088
DEHYDRATION, ACIDOSEIS AND

581
00:26:12,088 --> 00:26:16,125
HYPONATREMIA, EVERY TIME THEY

582
00:26:16,125 --> 00:26:20,129
WITHDREW THE SUPPORT.

583
00:26:20,129 --> 00:26:21,964
INTERESTINGLY, THE PATIENTS HAVE

584
00:26:21,964 --> 00:26:24,600
DIARRHEA IT'S SO WATERY THAT IT

585
00:26:24,600 --> 00:26:26,302
SOAKS RIGHT INTO THE DIAPER AND

586
00:26:26,302 --> 00:26:33,209
IT LOOKS LIKE URINE, SO THEY HAD

587
00:26:33,209 --> 00:26:34,610
CONSULTED ENDOCRINOLOGISTS,

588
00:26:34,610 --> 00:26:38,080
METABOLIC SPECIALISTS AND

589
00:26:38,080 --> 00:26:40,783
NEPHROLOGY IV THERAPYS AND

590
00:26:40,783 --> 00:26:41,884
FINALLY 1 SENIOR PERSON WHO WAS

591
00:26:41,884 --> 00:26:45,454
INVOLVED IN A LOT OF NAVAJO

592
00:26:45,454 --> 00:26:46,288
DISEASE ABNORMALITIES SAID, YOU

593
00:26:46,288 --> 00:26:48,457
KNOW THIS COULD BE SOMETHING

594
00:26:48,457 --> 00:26:50,993
THAT THE WAY MICROVILLUS

595
00:26:50,993 --> 00:26:52,728
INCLUSION DISEASE PRESENTS, HE

596
00:26:52,728 --> 00:26:55,064
CALLED ME, CAME DOWN, CONSULTED

597
00:26:55,064 --> 00:26:57,066
AND SAID, YEAH THIS IS A CLASSIC

598
00:26:57,066 --> 00:26:58,534
PRESENTATION FOR IT, AND THE

599
00:26:58,534 --> 00:27:00,436
FIRST THING I WAS ABLE DO WAS

600
00:27:00,436 --> 00:27:01,470
COLLECT STOOL FROM THE PATIENT,

601
00:27:01,470 --> 00:27:02,772
NOT AN EASY THING TO DO BUT WE

602
00:27:02,772 --> 00:27:04,140
WERE ABLE TO GET IT DONE AND

603
00:27:04,140 --> 00:27:09,111
WHAT WE FOUND WAS THAT PATIENT'S

604
00:27:09,111 --> 00:27:11,814
STOOL HAD A SECRETATTORY

605
00:27:11,814 --> 00:27:14,016
DIARRHEA PATTERN, THE SODIUM AND

606
00:27:14,016 --> 00:27:16,752
CHLORIDE CONTENT OF THE TOOL ARE

607
00:27:16,752 --> 00:27:18,621
MUCH HIGHER, NORMAL STOOL SODIUM

608
00:27:18,621 --> 00:27:25,327
IS IN THE 20-30 RAINCHL AND THIS

609
00:27:25,327 --> 00:27:28,397
PATIENT HAD 110 MMOL PER LITER

610
00:27:28,397 --> 00:27:28,864
OF SODIUM.

611
00:27:28,864 --> 00:27:31,200
AND IN THE FLIP SITUATION, THE

612
00:27:31,200 --> 00:27:34,537
CONTENT OF POTASSIUM WAS REALLY

613
00:27:34,537 --> 00:27:36,672
LOW, NORMAL POTASSIUM IS 55'VE

614
00:27:36,672 --> 00:27:39,141
65, SO THESE TOOL ELECTROLYTES

615
00:27:39,141 --> 00:27:41,210
WERE MUCH SIMILAR TO SERUM THAN

616
00:27:41,210 --> 00:27:44,046
TO STOOL AND THAT'S CLASSIC FOR

617
00:27:44,046 --> 00:27:49,485
WHAT 1 SEES IN A SECRETTATORY

618
00:27:49,485 --> 00:27:55,758
DIARRHEA LIKE 1 WOULD GET WITH

619
00:27:55,758 --> 00:27:55,991
CHOLERA.

620
00:27:55,991 --> 00:27:59,829
THIS PATIENT WAS PUTTING ON

621
00:27:59,829 --> 00:28:01,097
200-MILLILITERS PER KILOGRAM PER

622
00:28:01,097 --> 00:28:03,332
DAY WHICH IS 10 TIMES THE NORMAL

623
00:28:03,332 --> 00:28:05,935
AMOUNT OF STOOL OUTPUT AND WHEN

624
00:28:05,935 --> 00:28:09,004
FED WAS UP TO 250-MILLILITERS

625
00:28:09,004 --> 00:28:13,309
PER DAY, BUT TO PUT IT IN MORE

626
00:28:13,309 --> 00:28:15,745
RELATABLE TERMS IN A 3 KILOGRAM

627
00:28:15,745 --> 00:28:17,913
INFANT, THIS CHILD WAS PUTTING

628
00:28:17,913 --> 00:28:19,248
OUT A QUARTY OF THEIR THEIR BODY

629
00:28:19,248 --> 00:28:20,282
WEIGHT IN STOOL EVERY DAY AND

630
00:28:20,282 --> 00:28:22,718
IT'S NOT HARD TO IMAGINE HOW

631
00:28:22,718 --> 00:28:26,489
THESE PATIENTS RAPIDLY

632
00:28:26,489 --> 00:28:27,490
DETERIORATE.

633
00:28:27,490 --> 00:28:28,891
WE NEEDED TO RESUSCITATE THIS

634
00:28:28,891 --> 00:28:31,093
PATIENT WITH TWICE THE NORMAL

635
00:28:31,093 --> 00:28:32,895
FLUID VOLUME THAT WOULD BE

636
00:28:32,895 --> 00:28:34,230
CONSIDERED MAINTENANCE.

637
00:28:34,230 --> 00:28:37,466
WE GAVE 200 MILL LET LITERS PER

638
00:28:37,466 --> 00:28:38,834
KILOGRAM PER DAY.

639
00:28:38,834 --> 00:28:41,103
ONCE WE STABILIZED THE PATIENT A

640
00:28:41,103 --> 00:28:42,438
CENTRAL VENUS LINE WAS PLACED BY

641
00:28:42,438 --> 00:28:45,975
THE SURGEON SO THAT WE COULD

642
00:28:45,975 --> 00:28:48,677
PROVIDE NUTRITION AND THEN, WE

643
00:28:48,677 --> 00:28:53,516
SET ABOUT THE TASK OF CONFIRMING

644
00:28:53,516 --> 00:28:56,418
A DIAGNOSIS.

645
00:28:56,418 --> 00:28:58,821
WE DIDENDOSCOPY UNDER ANESTHESIA

646
00:28:58,821 --> 00:29:02,758
AND DID BIOS COPY UNDER ELECTRON

647
00:29:02,758 --> 00:29:04,160
MICROSCOPY, REVEALED MICRODOSE

648
00:29:04,160 --> 00:29:05,694
INCLUSIONS, AND SEND THEM OFF

649
00:29:05,694 --> 00:29:08,230
GENETIC TESTING THAT CONFIRMED

650
00:29:08,230 --> 00:29:08,564
THE DIAGNOSIS.

651
00:29:08,564 --> 00:29:11,467
THIS PATIENT WAS SUBSEQUENTLY

652
00:29:11,467 --> 00:29:14,003
EVALUATED FOR MULTIORGAN BOWEL,

653
00:29:14,003 --> 00:29:15,504
LIVER AND PANCREAS TRANSPLANT

654
00:29:15,504 --> 00:29:16,806
AND UNFORTUNATELY THIS PATIENT

655
00:29:16,806 --> 00:29:18,641
SUCCUMBED A LITTLE OVER A YEAR

656
00:29:18,641 --> 00:29:20,476
OF AGE FROM A SEPTIC EPISODE

657
00:29:20,476 --> 00:29:24,713
THAT WE JUST COULDN'T GET ON TOP

658
00:29:24,713 --> 00:29:25,181
OF.

659
00:29:25,181 --> 00:29:28,284
SO WITH THAT, LET ME TURN IT

660
00:29:28,284 --> 00:29:32,855
OVER TO DR. GOLDENRING SO THAT

661
00:29:32,855 --> 00:29:37,126
HE CAN PROVIDE TO US A PICTURE

662
00:29:37,126 --> 00:29:42,231
OF THE BASIC SCIENCE BEHIND THIS

663
00:29:42,231 --> 00:29:42,498
CONDITION.

664
00:29:42,498 --> 00:29:45,000
LET ME JUST SEE IF I CAN GET OUT

665
00:29:45,000 --> 00:29:53,509
OF THIS AND THEN STOP SHARING.

666
00:29:53,509 --> 00:29:57,746
AND THEN I WILL PUT MY CAMERA

667
00:29:57,746 --> 00:30:00,015
ON. 

668
00:30:00,015 --> 00:30:00,816
DR. GOLDENRING?

669
00:30:00,816 --> 00:30:05,955
>> OKAY, THANK YOU DR.
SHUB.

670
00:30:05,955 --> 00:30:12,194
AND I WOULD LIKE TO THANK WIN

671
00:30:12,194 --> 00:30:12,995
ARIAS FOR INVITINGITOUS THIS

672
00:30:12,995 --> 00:30:14,563
FORUM AND I WANT TO TAKE YOU ON

673
00:30:14,563 --> 00:30:16,065
A LITTLE JOURNEY AND MY JOURNEY

674
00:30:16,065 --> 00:30:18,467
OBVIOUSLY HAS BEEN WITH MITCH,

675
00:30:18,467 --> 00:30:20,135
BUT IT'S A JOURNEY FROM BEDSIDE

676
00:30:20,135 --> 00:30:24,106
TO BENCH AND BACK AGAIN, AND I

677
00:30:24,106 --> 00:30:25,641
HOPE THAT THIS WILL BE OF

678
00:30:25,641 --> 00:30:26,575
INTEREST TO PEOPLE.

679
00:30:26,575 --> 00:30:30,613
SO I WANT TO START BY REMINDING

680
00:30:30,613 --> 00:30:33,048
YOU JUST AS MITCH HAD TALKED

681
00:30:33,048 --> 00:30:35,017
ABOUT THAT THE INTESTINE IS AN

682
00:30:35,017 --> 00:30:39,288
AMAZING ORGAN THAT IS REALLY --

683
00:30:39,288 --> 00:30:42,291
IT'S HUGE AND IT'S MASSIVELY

684
00:30:42,291 --> 00:30:43,225
EXPANSIVE.

685
00:30:43,225 --> 00:30:44,960
SO YOU HAVE AT THREEOF THE

686
00:30:44,960 --> 00:30:46,328
23 FEET OF GUT RIGHT IN YOU

687
00:30:46,328 --> 00:30:50,132
RIGHT NOW, AND THAT SURFACE AREA

688
00:30:50,132 --> 00:30:53,669
IS MAXIMALLY AMPLIFIED AND THE

689
00:30:53,669 --> 00:30:54,970
AMPLIFICATION COMES PARTIALLY

690
00:30:54,970 --> 00:30:56,906
FROM THESE LARGE VILLUS

691
00:30:56,906 --> 00:31:01,243
PROJECTIONS INTO THE LUMEN AND

692
00:31:01,243 --> 00:31:04,580
THESE VILLUS PROJECTIONS COME

693
00:31:04,580 --> 00:31:07,716
OUT OF THE MUCOSAL SURFACE OF

694
00:31:07,716 --> 00:31:09,385
THE INTESTINE FROM CRIP REGIONS

695
00:31:09,385 --> 00:31:11,787
WHERE CELLS ARE BORN AND CELLS

696
00:31:11,787 --> 00:31:16,058
MOVE UP TO THE TIPS AND THIS

697
00:31:16,058 --> 00:31:17,993
WHOLE VILLUS STRUCTURE IS

698
00:31:17,993 --> 00:31:21,597
RENEWED EVERY 4-5 DAYS.

699
00:31:21,597 --> 00:31:26,769
AND ON TOP OF THAT ALL THESE

700
00:31:26,769 --> 00:31:27,670
ABSORBAATIVE ENTER-SITES THAT

701
00:31:27,670 --> 00:31:32,808
YOU NEED TO PULL WATER IN, THEY

702
00:31:32,808 --> 00:31:35,144
ARE HAVING AT THEIR TIPS THIS

703
00:31:35,144 --> 00:31:37,713
EWILL BEERATION OF MICROVILLI

704
00:31:37,713 --> 00:31:38,781
THAT MASSIVELY EXPANDS THE

705
00:31:38,781 --> 00:31:41,750
SURFACE AREA OF THE GUT AND THAT

706
00:31:41,750 --> 00:31:43,052
SURFACE AREA OF THE GUT IS

707
00:31:43,052 --> 00:31:45,721
REALLY THERE TO DO 1 MAJOR THING

708
00:31:45,721 --> 00:31:46,689
AND THAT'S ABSORB WATER.

709
00:31:46,689 --> 00:31:49,858
AND IF YOU DON'T ABSORB WATER

710
00:31:49,858 --> 00:31:51,293
YOU'RE GOING TO HAVE -- YOU'RE

711
00:31:51,293 --> 00:31:55,564
GOING TO HAVE DIARRHEA.

712
00:31:55,564 --> 00:31:58,734
NOW, MITCH HAS GONE OVER MICRO

713
00:31:58,734 --> 00:32:00,369
VILLUS INCLUSION DISEASE AND I

714
00:32:00,369 --> 00:32:05,441
WILL FOCUS MOSTLY IN MY TALK

715
00:32:05,441 --> 00:32:06,709
ABOUT THE CELL BIOLOGY AND

716
00:32:06,709 --> 00:32:07,543
PHYSIOLOGY THAT WE'VE LEARNED

717
00:32:07,543 --> 00:32:10,646
ABOUT THE DISEASE IN THE

718
00:32:10,646 --> 00:32:11,981
INTESTINE AND UNFORTUNATELY

719
00:32:11,981 --> 00:32:14,650
WIN'S GOING TO BE UPSET WITH ME,

720
00:32:14,650 --> 00:32:16,218
I WILL NOT TALK ABOUT THE LIVER,

721
00:32:16,218 --> 00:32:18,454
BUT I AM HAPPY TO TALK ABOUT IT

722
00:32:18,454 --> 00:32:19,154
IN THE QUESTIONS.

723
00:32:19,154 --> 00:32:24,193
SO AS MITCH DESCRIBED THE

724
00:32:24,193 --> 00:32:25,094
DISEASE WAS INITIALLY FOUND

725
00:32:25,094 --> 00:32:33,702
FIRST BY DIFIDZON AND THEN

726
00:32:33,702 --> 00:32:35,204
MICROVILLUS INCLUSION BY KROITS,

727
00:32:35,204 --> 00:32:40,709
BUT THESE ARE OBSERVE INDEED A

728
00:32:40,709 --> 00:32:41,410
MINORITY OF ENTER-SITES IN

729
00:32:41,410 --> 00:32:43,212
PATIENTS BUT THAT THE KEY THING

730
00:32:43,212 --> 00:32:49,118
THAT WAS THE DORPHY OF THE

731
00:32:49,118 --> 00:32:51,653
GENETIC MUTATIONS IN MYO5 B, AT

732
00:32:51,653 --> 00:32:53,622
THE SAME TIME BY POSITIONAL

733
00:32:53,622 --> 00:32:56,892
CLONING AS MITCH DESCRIBED IN

734
00:32:56,892 --> 00:32:58,660
THE NAVAJO WITH ROBERT ERICKSON

735
00:32:58,660 --> 00:33:02,898
AND MITCH, AND THEN, MULLERS

736
00:33:02,898 --> 00:33:08,070
GERMANY LOOKING AT MULTIPLE

737
00:33:08,070 --> 00:33:09,471
MUTATIONS IN MYOSIN 5 B.

738
00:33:09,471 --> 00:33:12,808
SO WHAT IS MYOSIN 5 B?

739
00:33:12,808 --> 00:33:16,011
ON SO MYOSIN 5 B IS A DOUBLE

740
00:33:16,011 --> 00:33:18,313
HEADED MOTOR.

741
00:33:18,313 --> 00:33:20,849
IT HAS THESE HEAD DOMAINS WHERE

742
00:33:20,849 --> 00:33:24,086
THE MOTOR IS, THE NECK DOMAINS

743
00:33:24,086 --> 00:33:26,155
ARE STIFFENED BY 6 CAL MODUE

744
00:33:26,155 --> 00:33:27,222
LYNN RESIDUES AND THEN AT THE

745
00:33:27,222 --> 00:33:30,259
BASE OF THIS, IN THE DISTAL AREA

746
00:33:30,259 --> 00:33:31,960
IS THIS CARBOBINDING DOMAIN THAT

747
00:33:31,960 --> 00:33:38,367
LINKS THE MOTOR TO VARIOUS

748
00:33:38,367 --> 00:33:43,906
MEMBRANES AND THIS LINK TO

749
00:33:43,906 --> 00:33:46,675
VARIOUS RAB SMALL GTP A SES, IS

750
00:33:46,675 --> 00:33:49,278
WHERE I STARTED MY WORK

751
00:33:49,278 --> 00:33:51,713
INITIALLY THROUGH STUDYING

752
00:33:51,713 --> 00:33:54,583
GASTRIC ACIDS SECRETING PARIETAL

753
00:33:54,583 --> 00:33:55,884
CELL, WE ORIGINALLY CLONED MICE

754
00:33:55,884 --> 00:33:57,853
IN 5 B AS AN ISHT ACTOR WITH

755
00:33:57,853 --> 00:34:02,624
THIS FAMILY OF RABS, SMALL GTP A

756
00:34:02,624 --> 00:34:04,960
SES, AND THEN LATER SHOWED THAT

757
00:34:04,960 --> 00:34:06,728
OTHER RABS WERE ALSO INTERACTING

758
00:34:06,728 --> 00:34:10,232
IN DIFFERENT PARTS OF THIS CARGO

759
00:34:10,232 --> 00:34:10,466
BINDING.

760
00:34:10,466 --> 00:34:15,504
AND IN PARTICULAR IT WAS LUCAS

761
00:34:15,504 --> 00:34:19,842
HOOFERS POST DOC WHO SAW A LATE

762
00:34:19,842 --> 00:34:25,314
BREAKING POSTER AT THE AMERICAN

763
00:34:25,314 --> 00:34:26,548
CELL BIOLOGY MEETING IN 2007

764
00:34:26,548 --> 00:34:29,785
WHERE WE SHOWED THAT MYOSIN 5 B

765
00:34:29,785 --> 00:34:33,222
WAS INTERACTING WITH RAB 8-A AND

766
00:34:33,222 --> 00:34:36,091
HE WENT HOME TO LUCAS, TOLD

767
00:34:36,091 --> 00:34:38,093
LUCAS ABOUT THAT BECAUSE THEY

768
00:34:38,093 --> 00:34:41,797
HAD BEEN SEQUENCING RAB 8 FOR

769
00:34:41,797 --> 00:34:43,198
MUTATIONS AND MICROVILLUS

770
00:34:43,198 --> 00:34:46,135
INCLUSION DISEASE, SO THEY THEN

771
00:34:46,135 --> 00:34:48,837
WENT AND SEQUENCED MYOSIN 5 B

772
00:34:48,837 --> 00:34:49,905
AND THAT'S HOW THEY FOUND.

773
00:34:49,905 --> 00:34:55,444
SO THIS WAS DEFINITELY THE BASIC

774
00:34:55,444 --> 00:34:58,247
SCIENCE LEADING THE CLINICAL

775
00:34:58,247 --> 00:34:58,580
INSIGHT.

776
00:34:58,580 --> 00:35:01,450
SO WHAT ARE RAB PROTEINS?

777
00:35:01,450 --> 00:35:05,687
SO THIS IS SORT OF A SIMPLIFIED

778
00:35:05,687 --> 00:35:08,290
VERSION OF SOME OF THE RABS,

779
00:35:08,290 --> 00:35:10,659
THEY ARE NOW 43 DIFFERENT RABS,

780
00:35:10,659 --> 00:35:12,327
I BELIEVE, BUT RAB PROTEINS CAN

781
00:35:12,327 --> 00:35:16,932
BE THOUGHT OF AS MOLECULAR ZIP

782
00:35:16,932 --> 00:35:20,569
CODES FOR VARIOUS VESICLE

783
00:35:20,569 --> 00:35:22,504
POPULATIONS SO CERTAIN

784
00:35:22,504 --> 00:35:24,740
POPULATIONS OF MEMBRANES INSIDE

785
00:35:24,740 --> 00:35:28,177
THE CELL WILL BE ENRICHED FOR

786
00:35:28,177 --> 00:35:30,145
RAB PROTEINS AND THE CLASS --

787
00:35:30,145 --> 00:35:34,683
THE FIRST 1S THAT WERE FOUND

788
00:35:34,683 --> 00:35:38,353
WERE RAB 1 AND RAB 2 IN THE ER

789
00:35:38,353 --> 00:35:39,321
AND ER-GOLGI DEPARTMENT AND THE

790
00:35:39,321 --> 00:35:41,523
1S YOU WILL HEAR ME TALK ABOUT

791
00:35:41,523 --> 00:35:46,261
TODAY ARE RAB 11 A WHICH IS ON

792
00:35:46,261 --> 00:35:48,130
RECYCLING MEMBRANES IN POLARIZED

793
00:35:48,130 --> 00:35:55,837
CELLS AND RAB  8A, WHICH APPEARS

794
00:35:55,837 --> 00:35:58,340
TO BE INVOLVED IN THESE GOLGI

795
00:35:58,340 --> 00:35:58,740
VESICLES.

796
00:35:58,740 --> 00:36:00,742
BOTH OF THESE ARE SIGNIFICANT

797
00:36:00,742 --> 00:36:06,648
BINDERS WITH THE MY O SIGN 5 B

798
00:36:06,648 --> 00:36:06,848
MOTOR.

799
00:36:06,848 --> 00:36:09,685
NOW, THE END POINT OF ALL THIS

800
00:36:09,685 --> 00:36:17,125
WORK IS TO KNOW THAT MOST OF THE

801
00:36:17,125 --> 00:36:19,761
ABNORMALITIES SORPAATIVE AND

802
00:36:19,761 --> 00:36:20,429
SECRETORY FUNCTION ALONG THE

803
00:36:20,429 --> 00:36:23,665
LINE OF THE SMALL INTESTINE IS

804
00:36:23,665 --> 00:36:25,767
REALLY REGULATED BY 3

805
00:36:25,767 --> 00:36:26,101
TRANSPORTERS.

806
00:36:26,101 --> 00:36:28,337
YOU HAVE SODIUM HYDRATE

807
00:36:28,337 --> 00:36:30,405
EXCHANGER AND SGLT 1 WHICH ARE

808
00:36:30,405 --> 00:36:37,212
RESPONSIBLE FOR A PULLING IN, SO

809
00:36:37,212 --> 00:36:40,515
IT'S SODIUM AND THEREFORE WATER

810
00:36:40,515 --> 00:36:46,421
FROM THE LUMEN, SGLT1 IS KNOWN

811
00:36:46,421 --> 00:36:48,824
MOST AS THE REASON WE HAVE

812
00:36:48,824 --> 00:36:49,091
GATORADE.

813
00:36:49,091 --> 00:36:51,393
BECAUSE YOU HAVE TO HAVE SUGAR

814
00:36:51,393 --> 00:36:53,895
TO PULL THE SODIUM IN.

815
00:36:53,895 --> 00:36:59,801
AND THEN CFTR, THE

816
00:36:59,801 --> 00:37:00,402
CYSTIC FIBROSIS TRANSMEMBRANE

817
00:37:00,402 --> 00:37:04,606
REGULATOR IS A CHLORIDE AND

818
00:37:04,606 --> 00:37:06,408
ASSOCIATED WITH SOWBS DISEASES

819
00:37:06,408 --> 00:37:07,242
LIKE CHOLERA.

820
00:37:07,242 --> 00:37:09,378
SO IT'S A BALANCE OF THESE MAJOR

821
00:37:09,378 --> 00:37:10,412
TRANSPORTERS THAT THE MAJOR

822
00:37:10,412 --> 00:37:12,247
DRIVING FORCE FOR BRINGING WATER

823
00:37:12,247 --> 00:37:16,985
IN OR SENDING WATER OUT.

824
00:37:16,985 --> 00:37:19,521
NOW, IF YOU LOOK AT THE

825
00:37:19,521 --> 00:37:26,328
INTESTINAL MUCOSA, AND THESE ARE

826
00:37:26,328 --> 00:37:28,630
ALL DUO DEANAL BIOPSIES FROM

827
00:37:28,630 --> 00:37:38,974
PATIENTS IN THE HEALTHY DUE

828
00:37:38,974 --> 00:37:41,343
DUODENUM, HAVE MICE VILLI WHICH

829
00:37:41,343 --> 00:37:45,113
HAVE SGLT1 ON THE SURFACE AS

830
00:37:45,113 --> 00:37:46,948
WELL AS SODIUM BUT IN THESE

831
00:37:46,948 --> 00:37:50,218
SAMPLES, I THINK IT'S PRETTY

832
00:37:50,218 --> 00:37:51,887
CLEAR, YOU'VE LOST THOSE

833
00:37:51,887 --> 00:37:53,789
TRANSPORTERS AT THE APICK WILL

834
00:37:53,789 --> 00:37:54,990
MEMBRANE, SO IT'S NOT SURPRISING

835
00:37:54,990 --> 00:37:57,893
THEN THAT THESE PATIENTS WOULD

836
00:37:57,893 --> 00:37:58,960
HAVE DIARRHEA BECAUSE THEY DON'T

837
00:37:58,960 --> 00:38:04,032
HAVE THE ABILITY TO PULL IN

838
00:38:04,032 --> 00:38:04,266
SODIUM.

839
00:38:04,266 --> 00:38:06,468
AT THE SAME TIME, THIS WORK IS

840
00:38:06,468 --> 00:38:10,539
FROM NADELLIA MEANS GROUP, WHERE

841
00:38:10,539 --> 00:38:13,175
THEY SHOWED AGAIN, IN SAMPLES

842
00:38:13,175 --> 00:38:15,110
FROM MVID PATIENTS THAT WHILE

843
00:38:15,110 --> 00:38:18,046
THE SODIUM AND TRANSFERS WERE

844
00:38:18,046 --> 00:38:21,383
GONE, CFTR WAS STILL AT THE

845
00:38:21,383 --> 00:38:23,852
APICAL MEMBRANES IN THESE

846
00:38:23,852 --> 00:38:24,186
CHILDREN.

847
00:38:24,186 --> 00:38:28,724
SO WHAT YOU HAVE HERE THEN IS A

848
00:38:28,724 --> 00:38:30,959
BIG BAD PROBLEM BECAUSE WITH THE

849
00:38:30,959 --> 00:38:33,462
MY O 5 B MUTATION, YOU LOSE YOUR

850
00:38:33,462 --> 00:38:35,831
PATHWAYS TO PULL WATER IN AND

851
00:38:35,831 --> 00:38:39,201
YOU STILL HAVE CFTR SECRETING

852
00:38:39,201 --> 00:38:40,402
FLUID OUT.

853
00:38:40,402 --> 00:38:42,137
SO THESE PATIENTS ARE BETWEEN

854
00:38:42,137 --> 00:38:50,412
THE DEVIL AND THE DEEP BLUE SEA.

855
00:38:50,412 --> 00:38:51,980
SO HOW DO WE DEAL WITH THIS AND

856
00:38:51,980 --> 00:38:54,216
I WILL REALLY FOCUS ON HOW

857
00:38:54,216 --> 00:38:56,118
ANIMAL MODELS ACTUALLY HAVE

858
00:38:56,118 --> 00:38:58,220
HELPED US UNDERSTAND WHAT'S

859
00:38:58,220 --> 00:39:00,021
REALLY HAPPENING IN THIS

860
00:39:00,021 --> 00:39:00,255
DISEASE.

861
00:39:00,255 --> 00:39:01,957
AND I THINK IT'S NOT SURPRISING

862
00:39:01,957 --> 00:39:06,094
THAT IF YOU BUILD AN ANIMAL

863
00:39:06,094 --> 00:39:09,664
MODEL, YOU HAVE TO SHOW THAT THE

864
00:39:09,664 --> 00:39:11,233
ANIMAL MODEL RECAPITULATES THE

865
00:39:11,233 --> 00:39:12,534
PATHOPHYSIOLOGY OF THE DISEASE

866
00:39:12,534 --> 00:39:16,204
AND OVER THE LAST DECADE, WE'VE

867
00:39:16,204 --> 00:39:18,140
SPENT A LOT OF TIME BUILDING A

868
00:39:18,140 --> 00:39:20,008
LARGE NUMBER OF ANIMAL MODELS,

869
00:39:20,008 --> 00:39:22,811
THEY ARE LISTED HERE AND THEY

870
00:39:22,811 --> 00:39:24,780
INCLUDE ANIMAL MODELS FOR GERM

871
00:39:24,780 --> 00:39:28,116
LINE AND INDUCIBLE TARGETING

872
00:39:28,116 --> 00:39:33,755
LOSS OF MYOSIN 5 B IN THE

873
00:39:33,755 --> 00:39:35,490
INTESTINE, A POINT -- INDUCIBLE

874
00:39:35,490 --> 00:39:38,427
POINT MUTATION OF MYOSIN 5 B

875
00:39:38,427 --> 00:39:40,862
BASED ON A PATIENT SEEN HERE AT

876
00:39:40,862 --> 00:39:41,897
VANDERBILT AND WE EVEN HAVE THIS

877
00:39:41,897 --> 00:39:45,667
DONE AND I WILL NOT DISCUSS

878
00:39:45,667 --> 00:39:48,537
EXTENSIVELY, A YEEN -- A GENE

879
00:39:48,537 --> 00:39:54,376
TARGETING IN PIGS TO CREATE A

880
00:39:54,376 --> 00:39:57,446
PIG MODEL OF THE PATHWAY GIVES

881
00:39:57,446 --> 00:40:02,918
RALGOUS MUTATION IN THE NAVAJO

882
00:40:02,918 --> 00:40:05,620
WHICH IS PSS3 L AND MYOSIN 5 B

883
00:40:05,620 --> 00:40:06,288
FROM PIG.

884
00:40:06,288 --> 00:40:08,390
SO ALL THESE MODELS HAVE REALLY

885
00:40:08,390 --> 00:40:09,324
ABOUT THE SAME PHENOTYPE.

886
00:40:09,324 --> 00:40:11,993
SO IF YOU LOOK IN MYOSIN 5 B

887
00:40:11,993 --> 00:40:15,363
KNOCKOUT MICE OR ANY OF THESE

888
00:40:15,363 --> 00:40:16,631
OTHER MODELS I JUST LISTED

889
00:40:16,631 --> 00:40:19,701
THERE, YOU SEE THE DEFICIT YOU

890
00:40:19,701 --> 00:40:20,068
WOULD EXPECT.

891
00:40:20,068 --> 00:40:24,539
SO HERE IS THE NORMAL INTESTINAL

892
00:40:24,539 --> 00:40:28,944
MUCOSA, YOU SEE A NICE BRUSH

893
00:40:28,944 --> 00:40:34,015
BOARD  BORD -- BORDER LACED WITH

894
00:40:34,015 --> 00:40:35,550
FOSTER NURSED FOCUSED ON

895
00:40:35,550 --> 00:40:38,053
STAINING BUT WITH MYOSIN 5 B

896
00:40:38,053 --> 00:40:40,889
KNOCK OUT YOU SUBSTANTIALLY LOSE

897
00:40:40,889 --> 00:40:42,491
THAT BRUSH BORDER AND NOW YOU

898
00:40:42,491 --> 00:40:46,261
SEE ALL THESE VERY LARGE

899
00:40:46,261 --> 00:40:47,496
MICROVILLUS INCLUSIONS LABELED

900
00:40:47,496 --> 00:40:51,900
WITH FOSTER NURSED FOCUSED ON

901
00:40:51,900 --> 00:40:53,268
EZRIN, USUALLY THERE'S 1

902
00:40:53,268 --> 00:40:54,669
INCLUSION PER CELL AND YOU CAN

903
00:40:54,669 --> 00:40:57,973
SEE HERE, THESE ARE VERY LARGE,

904
00:40:57,973 --> 00:40:59,608
SO 5-8-MICRONS IN DIAMETER.

905
00:40:59,608 --> 00:41:05,580
THESE ARE REALLY VERY BIG

906
00:41:05,580 --> 00:41:05,914
ORGANELLES.

907
00:41:05,914 --> 00:41:09,017
THE OTHER THING YOU CAN SEE IN

908
00:41:09,017 --> 00:41:10,852
THESE MICE, IS WHEREAS THE BRUSH

909
00:41:10,852 --> 00:41:15,657
BORDER IS VERY TALL IN A NORMAL

910
00:41:15,657 --> 00:41:20,128
MOUSE, IN A MY O 5 B KNOCK OUT

911
00:41:20,128 --> 00:41:22,631
MOUSE, THE MICROVILLI ARE MUCH,

912
00:41:22,631 --> 00:41:23,265
MUCH, SHORTER.

913
00:41:23,265 --> 00:41:25,500
THERE ARE ALSO BROADENED AND YOU

914
00:41:25,500 --> 00:41:26,902
CAN SEE THESE MICROVILLUS IN

915
00:41:26,902 --> 00:41:31,506
CONCLUSIONS HERE AND HERE.

916
00:41:31,506 --> 00:41:35,343
SO LIKE THE PATIENTS, THESE MICE

917
00:41:35,343 --> 00:41:37,112
GET MICRO VILLUS INCLUSIONS AND

918
00:41:37,112 --> 00:41:38,813
ACTUALLY THEY GET FAR MORE THAN

919
00:41:38,813 --> 00:41:40,949
YOU EVER SEE IN MOST HUMANS.

920
00:41:40,949 --> 00:41:45,153
BUT THE MOST IMPORTANT THING IS,

921
00:41:45,153 --> 00:41:46,655
THAT THE DEFICITS IN

922
00:41:46,655 --> 00:41:47,889
TRANSPORTERS ARE ALSO SEEN IN

923
00:41:47,889 --> 00:41:51,960
THESE MICE. 

924
00:41:51,960 --> 00:41:54,629
SO FOR BOTH NH3 T AND SGL1 WHICH

925
00:41:54,629 --> 00:41:59,467
ARE USUALLY SEEN VERY NICELY ON

926
00:41:59,467 --> 00:42:00,802
THE BRUSH BORDER, IN THE

927
00:42:00,802 --> 00:42:03,171
KNOCKOUT MICE, YOU GET ALMOST A

928
00:42:03,171 --> 00:42:09,177
COMPLETE LOSS OF BOTH NHG3 AND

929
00:42:09,177 --> 00:42:09,411
SGLT1.

930
00:42:09,411 --> 00:42:11,346
THEIR LOST SIMILAR TO WHAT WE

931
00:42:11,346 --> 00:42:15,650
SEE IN THE PATIENTS.

932
00:42:15,650 --> 00:42:20,622
HOWEVER, IF YOU LOOK AT CFTR,

933
00:42:20,622 --> 00:42:23,558
CFTR IS STILL THERE. 

934
00:42:23,558 --> 00:42:26,127
AND IN FACT, CFTR IS IN A LOT OF

935
00:42:26,127 --> 00:42:27,095
THE INCLUSIONS AND YOU CAN SEE

936
00:42:27,095 --> 00:42:30,365
THAT AT THE BOTTOM OF THE SLIDE

937
00:42:30,365 --> 00:42:31,433
IN THE CFTR STAINING.

938
00:42:31,433 --> 00:42:37,405
YOU CAN SEE ALL THESE

939
00:42:37,405 --> 00:42:38,673
MICROVILLUS INCLUSIONS.

940
00:42:38,673 --> 00:42:41,376
SO SODIUM TRANSPORTERS ARE LOST,

941
00:42:41,376 --> 00:42:45,914
CFTR IS MAINTAINED, AND THIS IS

942
00:42:45,914 --> 00:42:48,416
THE BIG PATHOPHYSIOLOGY

943
00:42:48,416 --> 00:42:56,324
OBVIOUSLY IN THIS DIARRHEAL

944
00:42:56,324 --> 00:42:57,993
DISEASE, SO THIS SINCE WE DIDN'T

945
00:42:57,993 --> 00:43:00,095
KNOW BEFORE WAS THERE MUST BE

946
00:43:00,095 --> 00:43:03,198
MULTIPLE PATHWAYS FOR THE ACHE

947
00:43:03,198 --> 00:43:09,371
PICKAL MEMBRANE TRANSPORTERS

948
00:43:09,371 --> 00:43:11,072
BECAUSE SODIUM, ARE ALL BEING

949
00:43:11,072 --> 00:43:16,077
AFFECTED BY THE LOSS BUT CFTR IS

950
00:43:16,077 --> 00:43:16,244
NOT.

951
00:43:16,244 --> 00:43:18,146
NOW WE'VE ALSO LOOKEDDA THE A

952
00:43:18,146 --> 00:43:19,114
POINT MUTATION, SO EVERYTHING I

953
00:43:19,114 --> 00:43:20,982
SHOWED YOU BEFORE WAS A KNOCK

954
00:43:20,982 --> 00:43:23,952
OUT, WE'VE ALSO LOOKEDDA THE A

955
00:43:23,952 --> 00:43:26,254
POINT MUTATION, THIS IS MY O

956
00:43:26,254 --> 00:43:28,023
SIGN 5G 519 R, THIS WAS A LITTLE

957
00:43:28,023 --> 00:43:33,595
IMIRL SEEN HERE AT VANDERBILT

958
00:43:33,595 --> 00:43:36,765
AND AGAIN, SHE WITH THIS POINT

959
00:43:36,765 --> 00:43:39,801
MUTATION, I SHOULD SAY, SHE WAS

960
00:43:39,801 --> 00:43:41,603
A POINT MUTANT ON 1 ALLELE THAT

961
00:43:41,603 --> 00:43:46,174
CAME FROM HER MOTHER, AND SHE

962
00:43:46,174 --> 00:43:49,577
HAD A DE NOVO TRUNCATION

963
00:43:49,577 --> 00:43:51,112
MUTATION IN THE FIRST HUNDRED

964
00:43:51,112 --> 00:43:53,314
AMINO ACIDS ON THE SECOND

965
00:43:53,314 --> 00:43:53,715
ALATELY.

966
00:43:53,715 --> 00:43:57,052
SO SHE WAS VERY UNFORTUNATE.

967
00:43:57,052 --> 00:44:02,190
AND HER MOTHER HAS NO PROBLEM AS

968
00:44:02,190 --> 00:44:02,557
A HETEROZYGOTE.

969
00:44:02,557 --> 00:44:05,160
AND WHAT YOU SEE IN THIS AGAIN

970
00:44:05,160 --> 00:44:14,035
IS LOSS OF SGLT1, LOSS OF NHE3,

971
00:44:14,035 --> 00:44:15,904
WE ARE STILL WORKING ON IT

972
00:44:15,904 --> 00:44:17,739
BECAUSE SHE DOESN'T LOSE MYOSIN

973
00:44:17,739 --> 00:44:19,874
5 B, IT SEEMS TO BE STUCK IN

974
00:44:19,874 --> 00:44:22,210
VESICLES THAT ARE MISLOCALLIZED

975
00:44:22,210 --> 00:44:23,244
WITH RAB 11A.

976
00:44:23,244 --> 00:44:25,380
BUT THIS SHOWS YOU THAT THE

977
00:44:25,380 --> 00:44:26,815
POINT MUTATIONS IN THE KNOCK OUT

978
00:44:26,815 --> 00:44:29,751
ALL END UP WITH THE SAME THING

979
00:44:29,751 --> 00:44:37,759
WHICH IS THE LOSS OF THESE

980
00:44:37,759 --> 00:44:38,993
APICAL TRANSPORTERS.

981
00:44:38,993 --> 00:44:42,297
NOW, 1 THING I WANT TO TALK

982
00:44:42,297 --> 00:44:45,567
ABOUT FOR MICE, IS MICE GAVE YOU

983
00:44:45,567 --> 00:44:48,737
THE CHANCE TO LOOK AT THINGS IN

984
00:44:48,737 --> 00:44:49,838
TIME, AND SO WHAT WE'VE

985
00:44:49,838 --> 00:44:56,211
DEVELOPED IS A NUMBER OF MICE

986
00:44:56,211 --> 00:44:57,278
THAT HAD INDUCIBLE KNOCK OUT AND

987
00:44:57,278 --> 00:45:01,182
IN THE CASE OF THIS G519 R

988
00:45:01,182 --> 00:45:02,250
MUTATION, WE BASICALLY MADE THE

989
00:45:02,250 --> 00:45:04,419
MICE TO FIT THE CHILD.

990
00:45:04,419 --> 00:45:08,823
SO WE MADE A MOUSE THAT'S

991
00:45:08,823 --> 00:45:12,193
DIRECTED -- WHERE, KNOCK OUT IS

992
00:45:12,193 --> 00:45:16,798
DIRECTED BY THIS CREE DRIVER

993
00:45:16,798 --> 00:45:19,400
FROM VILLIN WHICH IS AN

994
00:45:19,400 --> 00:45:22,370
INTESTINAL SPECIFIC DRIVER AND

995
00:45:22,370 --> 00:45:24,706
WITH A G519 MUTATION ON 1 ALLELE

996
00:45:24,706 --> 00:45:26,441
AND A FLOCKS ALLELED ON THE

997
00:45:26,441 --> 00:45:29,611
OTHER IF YOU GIVE THIS MOUSE

998
00:45:29,611 --> 00:45:31,212
TAMOXIFEN NOW, YOU WILL HAVE A

999
00:45:31,212 --> 00:45:35,416
MOUSE THAT ONLY HAS THIS

1000
00:45:35,416 --> 00:45:36,785
PATHOGENIC 519 R MUTATION.

1001
00:45:36,785 --> 00:45:40,155
AND WHAT YOU SEE IS THAT IF YOU

1002
00:45:40,155 --> 00:45:42,891
GIVE 1 DOSE OF TAMOXIFEN EITHER

1003
00:45:42,891 --> 00:45:48,463
IN THE MY O 5 B KNOCK OUT, OR

1004
00:45:48,463 --> 00:45:51,900
THE INDUCIBLE 519 R, BY 4 DAYS,

1005
00:45:51,900 --> 00:45:55,103
YOU HAVE ALMOST A 20% DECREASE

1006
00:45:55,103 --> 00:45:56,204
IN BODY WEIGHT.

1007
00:45:56,204 --> 00:45:59,641
YOU CAN ALMOST SET YOUR WATCH ON

1008
00:45:59,641 --> 00:45:59,841
THIS.

1009
00:45:59,841 --> 00:46:05,547
THESE MICE ARE GOING TO BE MORE

1010
00:46:05,547 --> 00:46:07,315
THAN THAT BY THE FIFTH MORNING

1011
00:46:07,315 --> 00:46:08,683
AFTER THE TAMOXIFEN DOSE.

1012
00:46:08,683 --> 00:46:11,853
AND JUST AS MITCH SAID, YOU SEE

1013
00:46:11,853 --> 00:46:16,291
IN THE CHILDREN, THEIR

1014
00:46:16,291 --> 00:46:17,225
INTESTINAL LUMEN IS BASICALLY

1015
00:46:17,225 --> 00:46:20,995
FILLED WITH CLEAR FLUID.

1016
00:46:20,995 --> 00:46:25,800
IT IS ABSOLUTELY DEAD CLEAR.

1017
00:46:25,800 --> 00:46:27,569
NOW THE GREAT THING ABOUT

1018
00:46:27,569 --> 00:46:28,770
INDUCIBLE MODEL SINCE THIS IS

1019
00:46:28,770 --> 00:46:30,572
INDUCED IN THE ADULT, WE CAN USE

1020
00:46:30,572 --> 00:46:31,472
THIS FOR INTERVENTION AND THAT'S

1021
00:46:31,472 --> 00:46:38,279
WHAT I WILL TALK ABOUT IN A FEW

1022
00:46:38,279 --> 00:46:38,513
SLIDES.

1023
00:46:38,513 --> 00:46:39,981
ACTUALLY I'M JUST GOING TO SKIP

1024
00:46:39,981 --> 00:46:40,348
THAT.

1025
00:46:40,348 --> 00:46:44,118
NOW WE HAVE ALSO MODELED THIS

1026
00:46:44,118 --> 00:46:46,955
WITH ANOTHER POINT MUTANT, AS I

1027
00:46:46,955 --> 00:46:49,891
SAID THE EQUIVALENT OF THE

1028
00:46:49,891 --> 00:46:51,092
NAVAJO MUTATION IN PIG AND WE

1029
00:46:51,092 --> 00:46:54,362
SAW THE XCT SAME THING OF A --

1030
00:46:54,362 --> 00:46:57,265
EXACT SAME THING OF THE LOSS OF

1031
00:46:57,265 --> 00:46:57,832
THESE 2 TRANSPORTERS, NATIVE

1032
00:46:57,832 --> 00:46:59,434
AMERICANS IN THE NORTHERNINENCE

1033
00:46:59,434 --> 00:47:02,737
OF CFTR, I WISH THIS MODEL HAD

1034
00:47:02,737 --> 00:47:04,639
GONE BETTER FOR US.

1035
00:47:04,639 --> 00:47:07,675
THESE PIGS TURNED OUT TO COST US

1036
00:47:07,675 --> 00:47:11,479
ALMOST 30,000 THERE IS A PIGLET

1037
00:47:11,479 --> 00:47:16,651
TO MAKE SO THIS IS NOT EXACTLY

1038
00:47:16,651 --> 00:47:19,854
THE GREATEST MODEL FOR FINANCIAL

1039
00:47:19,854 --> 00:47:22,824
STABILITY IN YOUR LABORATORY.

1040
00:47:22,824 --> 00:47:28,863
OKAY, SO WHAT I TOLD YOU IS THAT

1041
00:47:28,863 --> 00:47:31,099
ANIMAL MODELS CAN REPRODUCE THE

1042
00:47:31,099 --> 00:47:33,401
PATHOLOGY SEEN IN CHILDREN WITH

1043
00:47:33,401 --> 00:47:37,272
NBID, THAT IS LOSS OF

1044
00:47:37,272 --> 00:47:40,942
IEE, AUDIENCE PICKAL SODIUM

1045
00:47:40,942 --> 00:47:42,944
TRANSPORTERS, MAINTENANCE OF

1046
00:47:42,944 --> 00:47:43,611
SODIUM CHLORIDE TRANSPORT

1047
00:47:43,611 --> 00:47:43,945
THROUGH CFTR.

1048
00:47:43,945 --> 00:47:45,713
NOW YOU CAN THINK OF THIS IN A

1049
00:47:45,713 --> 00:47:46,781
COUPLE WAYS AND 1 WAY I WILL

1050
00:47:46,781 --> 00:47:48,149
SUGGIEST TO YOU THAT WILL BE

1051
00:47:48,149 --> 00:47:50,685
IMPORTANT LATE OR IS TO THINK

1052
00:47:50,685 --> 00:47:54,188
ABOUT THIS CELL, IN THE NORMAL

1053
00:47:54,188 --> 00:47:56,691
IS A MATURE ENTHUSIASMER O CITE

1054
00:47:56,691 --> 00:47:58,226
THAT YOU WOULD EXPECT TO FIND AT

1055
00:47:58,226 --> 00:47:59,894
THE TIP OF THE VILLI.

1056
00:47:59,894 --> 00:48:02,263
THIS CELL SEEMS TO BE A BIT

1057
00:48:02,263 --> 00:48:07,068
STUCK IN THE IMMATURE CRIP CELL

1058
00:48:07,068 --> 00:48:09,237
SO IT HAS CFTR WHICH EXISTS IN

1059
00:48:09,237 --> 00:48:13,841
THE CRIP BUT IT HASN'T EXACTLY

1060
00:48:13,841 --> 00:48:14,709
UPREGULATED THESE SODIUM

1061
00:48:14,709 --> 00:48:22,016
TRANSPORTERS IT NEEDS TO DO THE

1062
00:48:22,016 --> 00:48:22,583
ABSORPTION OF WATER.

1063
00:48:22,583 --> 00:48:25,286
SO NOW AS AN ASIDE BECAUSE

1064
00:48:25,286 --> 00:48:26,554
EVERYBODY ASKS ME, I WILL ASK

1065
00:48:26,554 --> 00:48:28,423
THE QUESTION HOW ARE MICROVILLUS

1066
00:48:28,423 --> 00:48:30,258
INCLUSIONS MADE AND WHAT IS THE

1067
00:48:30,258 --> 00:48:32,794
RELATIONSHIP TO THE DISEASE?

1068
00:48:32,794 --> 00:48:36,564
AND THIS IS WRORK BY AMY ANG

1069
00:48:36,564 --> 00:48:38,199
OVIC WHEN SHE WAS IN MY LAB AND

1070
00:48:38,199 --> 00:48:40,902
SHE NOW HAS HER OWN LAB AT

1071
00:48:40,902 --> 00:48:42,603
MEDICAL UNIVERSITY OF SOUTH

1072
00:48:42,603 --> 00:48:42,870
CAROLINA.

1073
00:48:42,870 --> 00:48:47,709
AND SO WHAT AMY DID WAS SHE

1074
00:48:47,709 --> 00:48:51,646
LOOKED AT HOW THESE INGCLIEWGZS

1075
00:48:51,646 --> 00:48:53,948
WERE FORMED IN THE MY O 5 B

1076
00:48:53,948 --> 00:48:57,085
KNOCK OUTS AND SHE FOUND THAT

1077
00:48:57,085 --> 00:49:00,822
THE ENCLIEWGZS WERE AGAIN, 1 PER

1078
00:49:00,822 --> 00:49:05,226
CELL AND THEY WERE ASSOCIATED

1079
00:49:05,226 --> 00:49:06,995
WITH SUBAPICAL VESICLES THAT

1080
00:49:06,995 --> 00:49:10,164
WERE POSITIVE FOR THIS PROTEIN

1081
00:49:10,164 --> 00:49:11,199
CALLED ENDOTUBEIN WHICH IS

1082
00:49:11,199 --> 00:49:15,503
THOUGHT TO BE AN INDO SOMAL

1083
00:49:15,503 --> 00:49:15,970
FACTOR.

1084
00:49:15,970 --> 00:49:20,141
BUT YOU NEVER SAW ENDOTUBEIN IN

1085
00:49:20,141 --> 00:49:20,508
THE INCLUSIONS.

1086
00:49:20,508 --> 00:49:26,848
INCLUSIONS ARE SEEN HERE IN

1087
00:49:26,848 --> 00:49:27,048
GREEN.

1088
00:49:27,048 --> 00:49:28,950
NOW FROM TIME TO TIME AS YOU'RE

1089
00:49:28,950 --> 00:49:33,221
LOOKING AT THESE, YOU SAW THIS

1090
00:49:33,221 --> 00:49:36,190
PICTURE AND THIS PICTURE WAS A

1091
00:49:36,190 --> 00:49:37,992
FORMING INCLUSION FROM THE

1092
00:49:37,992 --> 00:49:39,861
APICKA MEMBRANE IS HERE, THE

1093
00:49:39,861 --> 00:49:40,828
INTERNAL IS HERE AND WHAT YOU

1094
00:49:40,828 --> 00:49:43,998
WOULD SEE IS YOU WOULD SEE THESE

1095
00:49:43,998 --> 00:49:46,100
INCLUSIONS PINCHING OFF AND

1096
00:49:46,100 --> 00:49:47,502
PUSHING THE ENDOTUBEIN BACK INTO

1097
00:49:47,502 --> 00:49:51,205
THE CELL AND THIS IS HOW WE

1098
00:49:51,205 --> 00:49:51,939
REALIZED THAT DESPITE THE FACT

1099
00:49:51,939 --> 00:49:54,075
THAT A NUMBER OF PEOPLE HAD

1100
00:49:54,075 --> 00:49:56,444
THOUGHT THE INCLUSIONS WERE A

1101
00:49:56,444 --> 00:50:00,214
FAILURE TO DELIVER MEMBRANE,

1102
00:50:00,214 --> 00:50:04,385
ACTUALLY IT TURNS OUT IT'S A

1103
00:50:04,385 --> 00:50:07,955
LARGE ENDOSOMMAL PROCESS THAT WE

1104
00:50:07,955 --> 00:50:09,123
CALL APICKA BULK ENDOCYTOSIS.

1105
00:50:09,123 --> 00:50:11,459
SO I WILL SHOW YOU THIS, IN THIS

1106
00:50:11,459 --> 00:50:13,161
MOVIE WHICH I HOPE WILL PLAY AND

1107
00:50:13,161 --> 00:50:15,563
IF YOU LOOK RIGHT ABOUT HERE, I

1108
00:50:15,563 --> 00:50:21,502
THINK YOU WILL SEE THIS

1109
00:50:21,502 --> 00:50:25,006
INCLUSION COMING IN AND THIS

1110
00:50:25,006 --> 00:50:27,341
PROCESS HAPPENS NOT OVER A FEW

1111
00:50:27,341 --> 00:50:30,378
MINUTES, THIS TAKES 2-3 HOURS.

1112
00:50:30,378 --> 00:50:33,414
SO AMY HAD TO SIT THERE ON A

1113
00:50:33,414 --> 00:50:34,282
MICROSCOPE LOOKING FOR THESE

1114
00:50:34,282 --> 00:50:41,022
EVENTS FOR A LONG, LONG TIME TO

1115
00:50:41,022 --> 00:50:42,457
CAPTURE THESE LANCH ENDOSIGNIFY

1116
00:50:42,457 --> 00:50:42,890
TO THETIC EVENTS.

1117
00:50:42,890 --> 00:50:46,527
SO LET ME  PLAY THIS FOR YOU 1

1118
00:50:46,527 --> 00:50:48,062
MORE TIME FOR PEOPLE.

1119
00:50:48,062 --> 00:50:51,132
YOU CAN SEE THE INCLUSION

1120
00:50:51,132 --> 00:50:55,503
FORMING FROM THE APICAL MEMBRANE

1121
00:50:55,503 --> 00:50:56,170
AND GOING IN.

1122
00:50:56,170 --> 00:50:57,105
OKAY, SO THE OTHER THING YOU CAN

1123
00:50:57,105 --> 00:51:00,575
SEE IS YOU CAN JUST TAKE A PIECE

1124
00:51:00,575 --> 00:51:03,411
OF TISSUE LIKE JERRY USED TO DO

1125
00:51:03,411 --> 00:51:06,080
AND YOU PUT 70 KILODALTON FITC

1126
00:51:06,080 --> 00:51:07,682
DEXTRAN ON THE OUTSIDE OF A

1127
00:51:07,682 --> 00:51:10,251
PIECE OF TISSUE AND LET IT

1128
00:51:10,251 --> 00:51:14,055
INCUBATE AND WHAT YOU CAN FIND

1129
00:51:14,055 --> 00:51:17,058
AND YOU GET DEXTRAN COMING INTO

1130
00:51:17,058 --> 00:51:18,659
THE THESE INCLUSIONS SO THIS

1131
00:51:18,659 --> 00:51:21,329
REALLY SAID THAT THIS WAS

1132
00:51:21,329 --> 00:51:24,966
ENDOSIGNIFY TO THETIC EVENT, NOT

1133
00:51:24,966 --> 00:51:27,668
AN  EXOSIGNIFY TO THETIC EVENT

1134
00:51:27,668 --> 00:51:30,538
AND INDEED SOME ALSO SEE A BIT

1135
00:51:30,538 --> 00:51:32,039
OF DISCIPLINARY AMILLIOIN WHICH

1136
00:51:32,039 --> 00:51:38,045
IS A PROTEIN THAT IS INVOLVED IN

1137
00:51:38,045 --> 00:51:39,881
BREAKING OFF ENDOSOMES FOLLOWING

1138
00:51:39,881 --> 00:51:40,848
INTERNALIZATION, YOU CAN SEE A

1139
00:51:40,848 --> 00:51:42,416
LITTLE BIT OF IT SITTING AT THE

1140
00:51:42,416 --> 00:51:49,757
NECK OF THESE INTERNALIZATIONS

1141
00:51:49,757 --> 00:51:52,693
AND EVEN WHEN A BUT OFF THAT

1142
00:51:52,693 --> 00:51:55,897
LITTLE BIT OF DIAMIN SITTING ON

1143
00:51:55,897 --> 00:51:57,431
THE MICROVILLUS INCLUSION AND

1144
00:51:57,431 --> 00:52:02,270
YOU USUALLY SEE 1 LITTLE SPOT OF

1145
00:52:02,270 --> 00:52:04,405
DIAMIN STUCKOT ENCLIEWGZ.

1146
00:52:04,405 --> 00:52:10,678
THEN THERE ARE INHIBITORS OF

1147
00:52:10,678 --> 00:52:11,846
DYNAMIN, IF YOU THROW THOSE IN

1148
00:52:11,846 --> 00:52:13,548
THERE, YOU GET A LARGE NUMBER OF

1149
00:52:13,548 --> 00:52:16,417
THESE OMEGAS AND YOU CAN SEE A

1150
00:52:16,417 --> 00:52:19,487
TON OF THEM SOMETIMES IN AN

1151
00:52:19,487 --> 00:52:19,754
ORGANOID.

1152
00:52:19,754 --> 00:52:22,156
WE CAN DO THIS IN AN ORGANOID.

1153
00:52:22,156 --> 00:52:27,128
SO THESE ARE LITTLE MINIGUTS

1154
00:52:27,128 --> 00:52:30,131
GROWN IN CULTURE AND THEN YOU

1155
00:52:30,131 --> 00:52:35,102
CAN INCUBATE THEM WITH THE

1156
00:52:35,102 --> 00:52:36,671
DYNAMIN INHIBITOR WHICH IS DYNG

1157
00:52:36,671 --> 00:52:39,240
O, AND YOU SEE AN INCREASE IN

1158
00:52:39,240 --> 00:52:47,682
THESE INTERNALIZATIONS THAT GET

1159
00:52:47,682 --> 00:52:47,915
STUCK.

1160
00:52:47,915 --> 00:52:50,184
SO HOW DOES THIS FIT WITH THE

1161
00:52:50,184 --> 00:52:51,786
DISEASE AND THE IMPORTANT THING

1162
00:52:51,786 --> 00:52:57,191
IS WE REALIZE THERE WAS A

1163
00:52:57,191 --> 00:52:57,692
PROTEIN CALLED SIN DATA

1164
00:52:57,692 --> 00:52:58,893
PROTECTIONIN 2, SOME PEOPLE CALL

1165
00:52:58,893 --> 00:53:01,362
IT SIM P A XATOXIN 2 NOW THAT

1166
00:53:01,362 --> 00:53:02,964
WAS PRESENTOT MEMBRANE ANDS THE

1167
00:53:02,964 --> 00:53:06,867
INCLUSIONS AND SO WE CROSS THE

1168
00:53:06,867 --> 00:53:10,404
MYO5 B KNOCK OUTS ON TO SYNDAPIN

1169
00:53:10,404 --> 00:53:11,772
2 KNOCK OUTS AND WHAT HAPPENS

1170
00:53:11,772 --> 00:53:14,475
IS, I HOPE YOU CAN SEE THAT

1171
00:53:14,475 --> 00:53:16,210
WHILE THE REGULAR KNOCK OUT HAS

1172
00:53:16,210 --> 00:53:20,114
TONS OF THESE LITTLE ENCLIEWGZS

1173
00:53:20,114 --> 00:53:27,788
ALL OVER THE PLACE, THE SYNDAPIN

1174
00:53:27,788 --> 00:53:29,857
2 DOUBLE KNOCK OUT HAS NO

1175
00:53:29,857 --> 00:53:30,157
INCLUSIONS.

1176
00:53:30,157 --> 00:53:31,525
WELL, HERE'S THE PROBLEM.

1177
00:53:31,525 --> 00:53:35,129
THE MICE STILL ARE DYING FROM

1178
00:53:35,129 --> 00:53:35,396
DIARRHEA.

1179
00:53:35,396 --> 00:53:38,232
AND THEY STILL DON'T HAVE THEIR

1180
00:53:38,232 --> 00:53:39,634
TRANSPORTERS UP, IT TURNS OUT

1181
00:53:39,634 --> 00:53:41,535
AND YOU CAN SEE 1 OF THESE

1182
00:53:41,535 --> 00:53:44,171
EXAMPLES, THIS IS NOT A

1183
00:53:44,171 --> 00:53:46,807
TRANSPORTER, THIS AN APICAL

1184
00:53:46,807 --> 00:53:49,043
ENZYME DTP4 AND IT'S STILL NOT

1185
00:53:49,043 --> 00:53:52,913
GETTING TO THE APICAL MEMBRANE

1186
00:53:52,913 --> 00:53:53,814
LIKE THE CONTROL.

1187
00:53:53,814 --> 00:53:58,786
SO THE INCLUSIONS ARE A REALLY

1188
00:53:58,786 --> 00:53:59,820
INTERESTING EPIPHENOMENON,

1189
00:53:59,820 --> 00:54:00,421
ADJUST QUANTITATED HERE SO I

1190
00:54:00,421 --> 00:54:01,956
WILL JUST KEEP GOING.

1191
00:54:01,956 --> 00:54:06,093
SO THE INCLUSIONS ARE REALLY

1192
00:54:06,093 --> 00:54:07,094
INTERESTING EPIPHENOMENON THAT

1193
00:54:07,094 --> 00:54:10,264
HAS BEEN UNCOVERED BY THIS LOSS

1194
00:54:10,264 --> 00:54:11,232
OF MYOSIN 5 B.

1195
00:54:11,232 --> 00:54:17,004
IT'S A PROCESS WE CALL APICAL

1196
00:54:17,004 --> 00:54:19,907
BULK ENDOCYTOSIS AND IT MAY BE

1197
00:54:19,907 --> 00:54:22,043
INVOLVED ESPEBLLY IN THENYONATAL

1198
00:54:22,043 --> 00:54:23,711
PERIOD AND WE COULD TALK ABOUT

1199
00:54:23,711 --> 00:54:25,846
WHAT IT COULD BE DOING BUT 1

1200
00:54:25,846 --> 00:54:27,014
THING THAT'S CLEAR HERE IS THE

1201
00:54:27,014 --> 00:54:30,985
FORMATION OF THESE INCLUSIONS IS

1202
00:54:30,985 --> 00:54:33,454
NOT THE DISEASE, IT'S THE

1203
00:54:33,454 --> 00:54:34,655
TARGETING OF THE TRANSPORTERS

1204
00:54:34,655 --> 00:54:42,330
THAT IS THE DISEASE.

1205
00:54:42,330 --> 00:54:43,898
SO, WELL, IF THAT'S TRUE, WHAT

1206
00:54:43,898 --> 00:54:50,037
DO WE DO IN TERMS OF THE

1207
00:54:50,037 --> 00:54:50,471
DISEASE.

1208
00:54:50,471 --> 00:54:54,675
SO THERE ARE A NUMBER OF

1209
00:54:54,675 --> 00:54:56,711
APPROACHES YOU CAN IMAGINE FOR

1210
00:54:56,711 --> 00:54:58,446
TREATING THESE CHILDREN, MITCH

1211
00:54:58,446 --> 00:55:00,314
HAS TALKED ABOUT ORGAN

1212
00:55:00,314 --> 00:55:04,418
TRANSPLANTATION WHICH CAN BE

1213
00:55:04,418 --> 00:55:04,719
SUCCESSFUL.

1214
00:55:04,719 --> 00:55:07,755
SOME HAVE SUGGESTED TO

1215
00:55:07,755 --> 00:55:09,156
REPOPULATE, LIKE HANZ CLAIFER

1216
00:55:09,156 --> 00:55:12,460
SUGGESTED THIS IN A MEETING

1217
00:55:12,460 --> 00:55:14,662
REPOPULATE THE INTESTAL

1218
00:55:14,662 --> 00:55:16,397
NUCLEOTIDESICOSA WITH WILD-TYPE

1219
00:55:16,397 --> 00:55:16,931
ORGANOIDS.

1220
00:55:16,931 --> 00:55:19,300
HANZ IS A HEMEATOLOGYIST, THERE,

1221
00:55:19,300 --> 00:55:24,238
IT'S REALLY HARD TO DO THIS WITH

1222
00:55:24,238 --> 00:55:26,173
23 FEET OF INTESTINE.

1223
00:55:26,173 --> 00:55:30,911
SOME PEOPLE HAVE SUGGESTED A

1224
00:55:30,911 --> 00:55:32,880
GENE THERAPY APPROACH AND WE'VE

1225
00:55:32,880 --> 00:55:34,682
LOOKED INTO THIS FOR OURSELVES,

1226
00:55:34,682 --> 00:55:38,085
RIGHT NOW THERE REALLY ISN'T A

1227
00:55:38,085 --> 00:55:42,390
WAY TO TARGET GENE THERAPY TO

1228
00:55:42,390 --> 00:55:43,391
INTESTINAL CELLS SO THIS HAS

1229
00:55:43,391 --> 00:55:44,392
BEEN A PROBLEM.

1230
00:55:44,392 --> 00:55:46,327
SO WE'VE SPENT A LOT OF TIME ON

1231
00:55:46,327 --> 00:55:47,995
THE POSSIBILITY OF

1232
00:55:47,995 --> 00:55:50,798
PHARMAICOLOGICALLY BYPASSING THE

1233
00:55:50,798 --> 00:55:53,267
TRAFFICKING BLOCKADE TO PROMOTE

1234
00:55:53,267 --> 00:55:54,668
MATURATION OF ENTER O CITES.

1235
00:55:54,668 --> 00:55:58,172
SO WHAT DOES THIS LOOK LIKE IN

1236
00:55:58,172 --> 00:55:59,940
SO THIS WORK WAS REALLY FOUNDED

1237
00:55:59,940 --> 00:56:03,711
AND IS CONTINUING TO BE DONE BY

1238
00:56:03,711 --> 00:56:04,845
ESWRIEWMY COGY WHICH WAS A

1239
00:56:04,845 --> 00:56:06,847
MEMBER OF MY LAB FOR A COUPLE OF

1240
00:56:06,847 --> 00:56:13,187
YEARS AND HOW HAS HER OWN LAB AT

1241
00:56:13,187 --> 00:56:13,587
VANDERBILT.

1242
00:56:13,587 --> 00:56:16,257
IZUMI IS UNIQUE IN THAT SHE HAS

1243
00:56:16,257 --> 00:56:17,992
A BACKGROUND IN NUTRITION, SO

1244
00:56:17,992 --> 00:56:20,528
SHE STARTED OUT AS A

1245
00:56:20,528 --> 00:56:21,829
NUTRITIONIST BEFORE SHE DID HER

1246
00:56:21,829 --> 00:56:25,699
Ph.D. IN PHYSIOLOGY AND SHE

1247
00:56:25,699 --> 00:56:27,334
RECOGNIZE THAD LPA, LYSOIFY O

1248
00:56:27,334 --> 00:56:29,170
SITTIC ACID WAS AN IMPORTANT

1249
00:56:29,170 --> 00:56:31,338
REGULATOR OF THE FUNCTION OF

1250
00:56:31,338 --> 00:56:34,341
EPITHELIAL CELLS AND NORMALLY IT

1251
00:56:34,341 --> 00:56:37,211
CAN INHIBIT CFTR ASK ACTIVATE

1252
00:56:37,211 --> 00:56:40,347
THE SODIUM HYDROIEN EXCHANGER.

1253
00:56:40,347 --> 00:56:41,882
SO SHE WAS SMART ENOUGH TO SAY,

1254
00:56:41,882 --> 00:56:45,152
COULD THIS AFFECT THE MICE.

1255
00:56:45,152 --> 00:56:48,856
SO WHAT SHE DID WAS SHE TREATED

1256
00:56:48,856 --> 00:56:55,463
MICE SHOWN HERE IN THE UPPER

1257
00:56:55,463 --> 00:56:59,633
RIGHT, WITH TAMOXIFEN TO INDUCE

1258
00:56:59,633 --> 00:57:02,169
THE KNOCK OUT OF MYO5 B AND THEN

1259
00:57:02,169 --> 00:57:10,744
TREAT IT OVER THE 53 DAYS WITH

1260
00:57:10,744 --> 00:57:12,546
LPA EITHER ORALLY OR IV.

1261
00:57:12,546 --> 00:57:14,548
SO HERE'S THE LONG INTESTINE,

1262
00:57:14,548 --> 00:57:16,417
HAVE YOU LONG VILLI, HAVE YOU

1263
00:57:16,417 --> 00:57:19,286
CRIPS, HERE'S THE NORMAL 4 DAYS

1264
00:57:19,286 --> 00:57:22,690
OF WHAT YOU SEE IN A MYOSIN 5 B

1265
00:57:22,690 --> 00:57:23,357
KNOCK OUT MOUSE.

1266
00:57:23,357 --> 00:57:27,895
HAVE YOU LONG CRIPS AND BLUNTED

1267
00:57:27,895 --> 00:57:31,098
VILLI. 

1268
00:57:31,098 --> 00:57:36,670
IF YOU GIVE EITHER ORAL OR

1269
00:57:36,670 --> 00:57:38,272
IV LPA, YOU GET EXTENSION OF THE

1270
00:57:38,272 --> 00:57:44,311
VILLI ALTHOUGH YOU STILL HAVE

1271
00:57:44,311 --> 00:57:45,446
VERY LONG CRIPS.

1272
00:57:45,446 --> 00:57:47,982
BUT MOST IMPORTANTLY WHEN SHE

1273
00:57:47,982 --> 00:57:51,685
LOOKED AT SGLT1 AND HE3, HERE'S

1274
00:57:51,685 --> 00:57:56,390
THE VEHICLE AND YOU SEE SGLT1 IS

1275
00:57:56,390 --> 00:58:00,561
INTERNAL OR NOT THERE, AND HE3

1276
00:58:00,561 --> 00:58:03,397
IN THESE MICE WAS INTERNAL BUT

1277
00:58:03,397 --> 00:58:04,765
NOT AT THE APICAL MEMBRANE AS

1278
00:58:04,765 --> 00:58:08,302
YOU SEE IN THE CONTROL BUT NOW

1279
00:58:08,302 --> 00:58:13,707
IS AFTER LPA TREATMENT, YOU SEE

1280
00:58:13,707 --> 00:58:24,184
SGLT1 AND NHE3 ON THE APICAL

1281
00:58:25,419 --> 00:58:25,553
VILLI.

1282
00:58:25,553 --> 00:58:28,255
AND IMPORTANTLY YOU SEE A BIG

1283
00:58:28,255 --> 00:58:29,390
CHANGE IN THE BORDER.

1284
00:58:29,390 --> 00:58:32,927
SO THESE HAVE A STUNTED

1285
00:58:32,927 --> 00:58:35,029
MICROVILLI AND NOW AFTER LPA,

1286
00:58:35,029 --> 00:58:36,430
THEY STARTED MAKING REAL BRUSH

1287
00:58:36,430 --> 00:58:38,899
BORDERS IN MANY PLACES ALTHOUGH

1288
00:58:38,899 --> 00:58:42,069
THERE ARE STILL STUNTED 1S IN

1289
00:58:42,069 --> 00:58:44,138
SOME OF THE ENTER O CITES AND

1290
00:58:44,138 --> 00:58:45,639
NOTICE AS YOU MIGHT EXPECT

1291
00:58:45,639 --> 00:58:50,611
THERE'S NO CHANGE IN THE

1292
00:58:50,611 --> 00:58:51,278
MICROVILLUS INCLUSIONS, BETWEEN

1293
00:58:51,278 --> 00:58:57,484
THE VEHICLE AND THE LPA TREE.

1294
00:58:57,484 --> 00:59:02,356
OKAY, SO JUST RECENTLY IZUMI HAS

1295
00:59:02,356 --> 00:59:04,425
ALSO MOVED ON AND SHE'S GONE TO

1296
00:59:04,425 --> 00:59:11,832
A MORE SPECIFIC LPA 5 -- THAT'S

1297
00:59:11,832 --> 00:59:15,035
A MISTYPO, THIS SHOULD BE LP A

1298
00:59:15,035 --> 00:59:19,340
R5, AGONIST, NOT INHIBITION.

1299
00:59:19,340 --> 00:59:23,043
SO THE PROBLEM WITH LPA IS ITS

1300
00:59:23,043 --> 00:59:25,746
OILY, IT'SICKY, IT'S HARD TO

1301
00:59:25,746 --> 00:59:26,480
DELIVER, THIS COMPOUND HERE

1302
00:59:26,480 --> 00:59:33,153
WHICH IS A SPECIFIC LP A R 5

1303
00:59:33,153 --> 00:59:34,722
AGONIST IS WATER SOLUBLE AND

1304
00:59:34,722 --> 00:59:36,924
WHEN SHE GAVE THIS IN THE SAME

1305
00:59:36,924 --> 00:59:39,860
PATTERN, SORRY ABOUT THE LOSS OF

1306
00:59:39,860 --> 00:59:45,666
RESOLUTION HERE WHAT SHE AGAIN

1307
00:59:45,666 --> 00:59:53,574
SAW WAS A RETURN OF NORMAL LELGT

1308
00:59:53,574 --> 00:59:59,346
VILLI.

1309
00:59:59,346 --> 01:00:00,948
MORE IMPORTANT THAL LPR AGONIST

1310
01:00:00,948 --> 01:00:02,916
WHICH HAD AN AMAZING NAME OF

1311
01:00:02,916 --> 01:00:04,718
COMPOUND 1, WE HAVE TO GET A

1312
01:00:04,718 --> 01:00:05,619
BETTER NAME, SOMEBODY COME UP

1313
01:00:05,619 --> 01:00:09,056
WITH IT FOR US, PLEASE, THIS

1314
01:00:09,056 --> 01:00:12,826
COMPOUND 1 CAUSED THE RETURN OF

1315
01:00:12,826 --> 01:00:14,895
SGLT1 TO THE APICAL MEMBRANE

1316
01:00:14,895 --> 01:00:19,433
MUCH BETTER FRANKLY THAN JUST L

1317
01:00:19,433 --> 01:00:21,902
PA AND THE OTHER THING IT DID

1318
01:00:21,902 --> 01:00:30,244
WAS THAT IT IMPROVED THE

1319
01:00:30,244 --> 01:00:31,512
MYOCHONDRIAL FUNCTION IN THE

1320
01:00:31,512 --> 01:00:34,248
ENTER O CITES AND SO THIS IS

1321
01:00:34,248 --> 01:00:44,692
SEEN -- SO YOU SEE ACTIVE

1322
01:00:51,331 --> 01:00:53,267
EE ACTIVE MITOCHONDRIA

1323
01:00:53,267 --> 01:00:55,035
THROUGHOUT MOST -- YOU TEND TO

1324
01:00:55,035 --> 01:00:56,370
LOOSE THESE ESPECIALLY AT THE

1325
01:00:56,370 --> 01:00:59,506
APICAL POLE OF THE CELLS BUT

1326
01:00:59,506 --> 01:01:02,643
WHEN YOU GAVE COMPOUND 1, YOU

1327
01:01:02,643 --> 01:01:04,044
AGAIN BROUGHT ACTIVITY IN

1328
01:01:04,044 --> 01:01:09,283
MITOCHONDRIA BACK TO NEAR NORMAL

1329
01:01:09,283 --> 01:01:15,889
LEVELS IN MOST OF THE 

1330
01:01:15,889 --> 01:01:17,658
ENTHUSIASMER O CITES, SO THIS

1331
01:01:17,658 --> 01:01:19,359
AGAIN, SAYS WE'RE PUSHING NORMAL

1332
01:01:19,359 --> 01:01:21,361
DIFFERENT WHEN WE GIVE COMPOUND

1333
01:01:21,361 --> 01:01:21,895
1.

1334
01:01:21,895 --> 01:01:23,630
NOW MOST EXCITINGLY, I HAVE

1335
01:01:23,630 --> 01:01:27,301
PREVIOUSLY SHOWN YOU THIS MICE

1336
01:01:27,301 --> 01:01:29,336
LOSE ABOUT 20% OF THE THEIR BODY

1337
01:01:29,336 --> 01:01:31,672
WEIGHT WITHIN 4 DAYS OF GETTING

1338
01:01:31,672 --> 01:01:33,574
LOSS OF MYOSIN 5 B AND THAT'S

1339
01:01:33,574 --> 01:01:35,075
EXACTLY THE AMOUNT OF TIME IT

1340
01:01:35,075 --> 01:01:36,877
TAKES TO GO FROM THE CRYPT TO

1341
01:01:36,877 --> 01:01:40,848
THE TIP OF THE VILLUS.

1342
01:01:40,848 --> 01:01:42,750
AND THAT'S USUALLY WHAT WE SEE.

1343
01:01:42,750 --> 01:01:44,384
IF YOU FOCUS YOUR ATTENTION HERE

1344
01:01:44,384 --> 01:01:50,524
ON THE MALES FOR INSTANCE, YOU

1345
01:01:50,524 --> 01:01:52,726
SEE ABOUT A 20-25% LOSS OF BODY

1346
01:01:52,726 --> 01:01:54,428
WEIGHT BUT WHEN YOU GIVE

1347
01:01:54,428 --> 01:01:58,866
COMPOUND 1 IN THE MALES, YOU GET

1348
01:01:58,866 --> 01:02:00,567
A MARKED IMPROVEMENT IN BODY

1349
01:02:00,567 --> 01:02:02,302
WEIGHT CHANGE AND THESE MICE DO

1350
01:02:02,302 --> 01:02:05,405
NOT HAVE AS MUCH DIARRHEA AND

1351
01:02:05,405 --> 01:02:07,941
THEY DON'T GET AS MUCH

1352
01:02:07,941 --> 01:02:08,242
DEHYDRATION.

1353
01:02:08,242 --> 01:02:10,377
INTERESTINGLY FOR REASONS THAT I

1354
01:02:10,377 --> 01:02:13,647
STILL DON'T KNOW, COMPOUND 1 IS

1355
01:02:13,647 --> 01:02:14,915
NOT THAT SUCCESSFUL IN THE

1356
01:02:14,915 --> 01:02:18,919
FEMALE MICE AND THIS IS

1357
01:02:18,919 --> 01:02:20,187
SOMETHING THAT IZUMI IS WORKING

1358
01:02:20,187 --> 01:02:21,054
ON A LOT NOW.

1359
01:02:21,054 --> 01:02:24,024
BUT AT LEAST THIS IS SAYING THAT

1360
01:02:24,024 --> 01:02:29,797
COMPOUND 1 MAY WORK.

1361
01:02:29,797 --> 01:02:31,532
SO IN TERMS OF LPA TREATMENT,

1362
01:02:31,532 --> 01:02:33,066
THIS IS WHAT WE LEARNED AND THIS

1363
01:02:33,066 --> 01:02:35,736
IS I THINK STILL SURPRISING.

1364
01:02:35,736 --> 01:02:38,205
THERE ARE TREATMENTS THAT CAN BE

1365
01:02:38,205 --> 01:02:45,379
GIVEN THAT CAN AMELIORIATE THE

1366
01:02:45,379 --> 01:02:47,214
BLOCKATE SEEMINGLY WITH MYO5 B

1367
01:02:47,214 --> 01:02:50,884
LOSS, SO THERE'S HOPE TO GET

1368
01:02:50,884 --> 01:02:51,718
AROUND THE PATHOPHYSIOLOGY, BUT

1369
01:02:51,718 --> 01:02:52,886
THERE'S A LOT OF THINGS THAT

1370
01:02:52,886 --> 01:02:55,189
HAVE TO WORK IN OUR FAVOR, THE

1371
01:02:55,189 --> 01:02:56,857
DRUGS HAVE TO BE DELIVERED

1372
01:02:56,857 --> 01:02:58,659
EFFECTIVELY TO THE MUCOSA AND

1373
01:02:58,659 --> 01:03:06,300
THIS IS A PROBLEM OF SOLUBLITY

1374
01:03:06,300 --> 01:03:07,334
OF THE DRUG.

1375
01:03:07,334 --> 01:03:08,468
THE COMPOUND 1 SEEMS TO BE

1376
01:03:08,468 --> 01:03:11,872
BETTER BUT IT STILL NEEDS

1377
01:03:11,872 --> 01:03:12,239
OPTIMAL DOSING.

1378
01:03:12,239 --> 01:03:13,574
THERE MAY BE LITTLER DRUGS OUT

1379
01:03:13,574 --> 01:03:17,911
THERE, BUT AT LEAST THIS IS

1380
01:03:17,911 --> 01:03:21,181
SAYING OKAY, WE CAN HAVE AN

1381
01:03:21,181 --> 01:03:24,384
EFFECT ON THIS PATHOPHYSIOLOGY.

1382
01:03:24,384 --> 01:03:27,054
NOW I'M GOING TO GIVE 1 MORE

1383
01:03:27,054 --> 01:03:33,227
SCENARIO THAT MAY LEAD US TO AN

1384
01:03:33,227 --> 01:03:35,262
UNDERSTANDING OF THE PROCESS AND

1385
01:03:35,262 --> 01:03:36,663
MAYBE NEW THERAPIES AND THAT'S

1386
01:03:36,663 --> 01:03:39,633
TO GO BACK TO THIS IDEA THAT

1387
01:03:39,633 --> 01:03:43,070
WHEN YOU HAVE MBID, THE CELLS

1388
01:03:43,070 --> 01:03:50,611
NEVER -- WHEN THEY LEAVE THE

1389
01:03:50,611 --> 01:03:52,179
VILLUS, THEY DON'T REALLY LEAVE

1390
01:03:52,179 --> 01:03:54,681
SO THEY DON'T MAINTAIN THEIR

1391
01:03:54,681 --> 01:03:55,716
CRYPT LIKE DIFFERENTIATION, SO

1392
01:03:55,716 --> 01:03:58,952
THIS IS AGAIN WHAT BRINGS UP

1393
01:03:58,952 --> 01:04:02,256
THIS IDEA OF AND THE MVID

1394
01:04:02,256 --> 01:04:04,424
PEASHTS HAVE A CRIP VILLUS

1395
01:04:04,424 --> 01:04:10,330
THAT'S FILLED WITH CRYPT LIKE

1396
01:04:10,330 --> 01:04:10,731
CELLS.

1397
01:04:10,731 --> 01:04:13,400
SO THIS MAKES SENSE BECAUSE THE

1398
01:04:13,400 --> 01:04:17,971
CRYPT LENGTH IS EXPANDED.

1399
01:04:17,971 --> 01:04:19,373
THERE'S LOSS OF TOUGH CELLS

1400
01:04:19,373 --> 01:04:22,609
WHICH ARE A SENSING CELLS,

1401
01:04:22,609 --> 01:04:23,777
THERE'S AN EXPANSION OF PANNA

1402
01:04:23,777 --> 01:04:27,114
CELLS AT THE BASE OF CRYPTS AND

1403
01:04:27,114 --> 01:04:28,715
ALMOST MORE IMPORTANTLY THERE'S

1404
01:04:28,715 --> 01:04:31,451
ALMOST A COMPLETE LOSS OF LIGAND

1405
01:04:31,451 --> 01:04:32,519
EXPRESSION WITH A MAINTENANCE OF

1406
01:04:32,519 --> 01:04:36,456
NOTCH SIGNALING SO THIS BALANCE

1407
01:04:36,456 --> 01:04:40,661
IS -- THIS IS AN IMBALANCE OF

1408
01:04:40,661 --> 01:04:42,062
THE NORMAL SYSTEM OF PUSH ME,

1409
01:04:42,062 --> 01:04:43,797
PULL YOU THAT YOU SEE IN A CRYPT

1410
01:04:43,797 --> 01:04:50,671
THAT LEADS TO DIFFERENTIATION.

1411
01:04:50,671 --> 01:04:55,242
SO COULD WE USE THIS AS A

1412
01:04:55,242 --> 01:04:57,077
THERAPEUTIC APPROACH AND TO LOOK

1413
01:04:57,077 --> 01:04:59,813
AT THIS, WHAT IZUMI DID AGAIN,

1414
01:04:59,813 --> 01:05:06,019
WAS SHE TOOK THOSE SAME

1415
01:05:06,019 --> 01:05:07,621
INDUCIBLE KNOCKOUT MICE AND

1416
01:05:07,621 --> 01:05:09,356
INDUCED KNOCK OUT WITH TAMOXIFEN

1417
01:05:09,356 --> 01:05:17,831
AND THEN ON DAY 1 GAVE 1 DOSE OF

1418
01:05:17,831 --> 01:05:20,467
DVC, AN INHIBITOR OF NOTCH AND

1419
01:05:20,467 --> 01:05:21,969
GAMMA SECRET ACE, AND WHAT SHE

1420
01:05:21,969 --> 01:05:24,604
SAW WAS THE VILLUS CRYPT RATIO

1421
01:05:24,604 --> 01:05:29,776
IMPROVE AND AGAIN, SHE GOT A

1422
01:05:29,776 --> 01:05:35,215
RETURN OF NHE3 AND SGLT1 TO THE

1423
01:05:35,215 --> 01:05:40,287
APICAL SURFACE IN THESE MICE.

1424
01:05:40,287 --> 01:05:42,422
NOW, HONESTLY, THIS IS NOT A

1425
01:05:42,422 --> 01:05:43,824
PRACTICAL SOLUTION BECAUSE THESE

1426
01:05:43,824 --> 01:05:46,526
DRUG -- THIS DRUG IS VERY TOXIC

1427
01:05:46,526 --> 01:05:51,365
SO WE'RE NOT GOING TO GIVE THIS

1428
01:05:51,365 --> 01:05:51,631
TO KIDS.

1429
01:05:51,631 --> 01:05:55,902
BUT IT SAYS, YOU KNOW ALL THIS

1430
01:05:55,902 --> 01:05:58,538
STUFF SAYS, THAT SOMEWHAT

1431
01:05:58,538 --> 01:06:03,343
SURPRISINGLY, WE CAN RESET SOME

1432
01:06:03,343 --> 01:06:06,480
OF THE ABERRANT BLOCKADE OF

1433
01:06:06,480 --> 01:06:08,181
PROGENITOR -- STEM PROGENITOR

1434
01:06:08,181 --> 01:06:10,751
CELLS GIVING RISE TO ACTIVE

1435
01:06:10,751 --> 01:06:12,719
ABSORBAATIVE CELLS BY EITHER LP

1436
01:06:12,719 --> 01:06:20,327
A R 5 ACTIVATION, OR REBALANCING

1437
01:06:20,327 --> 01:06:20,761
OF NOTCH SIGNALING.

1438
01:06:20,761 --> 01:06:22,062
AND THIS I THINK IS WHERE WE

1439
01:06:22,062 --> 01:06:25,899
HAVE TO GO TO FIND A PRACTICAL

1440
01:06:25,899 --> 01:06:27,534
TREATMENT FOR THESE CHILDREN

1441
01:06:27,534 --> 01:06:33,073
THAT CAN BE ADMINISTERED SAFELY.

1442
01:06:33,073 --> 01:06:38,278
I WILL END WITH A LITTLE BIT OF

1443
01:06:38,278 --> 01:06:43,016
BANGING THE DRUM FOR REALLY ALSO

1444
01:06:43,016 --> 01:06:45,052
DERIVING PATIENT SAMPLES FOR

1445
01:06:45,052 --> 01:06:46,620
PATIENT DIRECTED DISEASE AND SO,

1446
01:06:46,620 --> 01:06:48,822
OVER THE LAST SEVERAL YEARS,

1447
01:06:48,822 --> 01:06:54,995
WE'VE BEEN ABLE TO MAKE

1448
01:06:54,995 --> 01:06:56,830
INTESTINAL ENTHUSIASMERROID SAYS

1449
01:06:56,830 --> 01:06:58,365
FROM MVID PATIENTS WITH VARIOUS

1450
01:06:58,365 --> 01:06:59,566
MUTATIONS.

1451
01:06:59,566 --> 01:07:04,104
HERE I'M SHOWING YOU AIR LIQUID

1452
01:07:04,104 --> 01:07:09,676
INTERFACE MONOLAYER CULTURES OF

1453
01:07:09,676 --> 01:07:13,013
HEALTHY DUODENUM, ENTERROIDS AND

1454
01:07:13,013 --> 01:07:14,081
STAINED WITH F-ACTIN SO YOU CAN

1455
01:07:14,081 --> 01:07:17,084
SEE THEY HAVE A VERY NICE BRUSH

1456
01:07:17,084 --> 01:07:17,951
BORDER.

1457
01:07:17,951 --> 01:07:24,524
AND THIS IS THE CULTURE OF AN

1458
01:07:24,524 --> 01:07:28,361
MVID PATIENT WITH WITH A

1459
01:07:28,361 --> 01:07:30,730
MUTATION, 1 OF MITCH SHUB'S

1460
01:07:30,730 --> 01:07:32,532
PATIENTS ACTUALLY, AND YOU CAN

1461
01:07:32,532 --> 01:07:37,671
SEE VERY LITTLE OR DISCIPLINARY

1462
01:07:37,671 --> 01:07:39,573
MINUTIVE IF ANY STAINING ON THE

1463
01:07:39,573 --> 01:07:40,507
BORDER.

1464
01:07:40,507 --> 01:07:42,008
NOW WHAT IZUMI HAS DONE RECENTLY

1465
01:07:42,008 --> 01:07:44,211
WITH JAY AT HARVARD, IS THEY

1466
01:07:44,211 --> 01:07:49,816
WENT AND THEY LOOKED AT TREATING

1467
01:07:49,816 --> 01:07:53,720
THOSE MONOLAYERS WITH ANOTHER

1468
01:07:53,720 --> 01:07:56,323
NOTCH INHIBITOR EAPT WHICH IS A

1469
01:07:56,323 --> 01:07:57,924
GAMMA SECRET ACE INHIBITOR AND

1470
01:07:57,924 --> 01:08:01,561
THEY WERE AGAIN ABLE TO BRING

1471
01:08:01,561 --> 01:08:11,071
BACK NHE3 TO THE APICAL MEMBRANE

1472
01:08:11,071 --> 01:08:12,372
OF THOSE NAVAJO ENTER O SIGHTS

1473
01:08:12,372 --> 01:08:15,809
AND THEY WERE ALSO ABLE TO SEE

1474
01:08:15,809 --> 01:08:16,643
NHE3 ACTIVITY AFTER TREATMENT

1475
01:08:16,643 --> 01:08:20,380
WITH THE NOTCH INHIBITOR.

1476
01:08:20,380 --> 01:08:23,984
SO, THESE -- WE REALLY FEEL THAT

1477
01:08:23,984 --> 01:08:25,886
GET THESE ENTERROIDS FROM

1478
01:08:25,886 --> 01:08:27,954
PATIENTS GIVES US A REALLY

1479
01:08:27,954 --> 01:08:30,457
PRACTICAL MODEL FOR DOING

1480
01:08:30,457 --> 01:08:34,394
FURTHER DRUG SCREENING AND

1481
01:08:34,394 --> 01:08:35,295
DEVELOPING NEW TREATMENTS THAT

1482
01:08:35,295 --> 01:08:42,035
MAY BE MORE PRACTICAL FOR THESE

1483
01:08:42,035 --> 01:08:43,870
PATIENTS.

1484
01:08:43,870 --> 01:08:45,639
SO WHAT IS MVID TAUGHT US SO

1485
01:08:45,639 --> 01:08:46,173
FAR?

1486
01:08:46,173 --> 01:08:47,807
AS I SAID IT'S TAUGHT US

1487
01:08:47,807 --> 01:08:48,842
SOMETHING ABOUT HOW THERE ARE

1488
01:08:48,842 --> 01:08:50,277
MULTIPLE WAYS TO GET TO THE

1489
01:08:50,277 --> 01:08:52,078
IEE, AUDIENCE PICKA MEMBRANE,

1490
01:08:52,078 --> 01:08:53,980
NOT JUST 1, NOT JUST A BIG ARROW

1491
01:08:53,980 --> 01:09:00,820
GOING THROUGH THE GOLGI.

1492
01:09:00,820 --> 01:09:04,157
YES, LOSS OF MY O SIGN 5 B

1493
01:09:04,157 --> 01:09:07,294
REVEALS A NOVEL APICAL BULK

1494
01:09:07,294 --> 01:09:08,328
ENDOCYTOSIS PATHWAY, AND IT

1495
01:09:08,328 --> 01:09:11,665
REMAINS TO BE SEEN WHAT IT'S

1496
01:09:11,665 --> 01:09:15,068
THERE FOR BUT IT'S NOT THE MVID

1497
01:09:15,068 --> 01:09:16,503
DISEASE ITSELF, AND IT'S ABLE TO

1498
01:09:16,503 --> 01:09:18,271
SHOW THAT IT IS POSSIBLE TO

1499
01:09:18,271 --> 01:09:20,373
CHANGE THE DYNAMICS OF APICAL

1500
01:09:20,373 --> 01:09:21,975
TRAFFICKING OF TRANSPORTERS THAT

1501
01:09:21,975 --> 01:09:24,711
CAN BYPASS OR WHAT YOU THINK WAS

1502
01:09:24,711 --> 01:09:30,550
A REALLY SIGNIFICANT BLOCKADE

1503
01:09:30,550 --> 01:09:32,586
AND PERHAPS AMELIORATE PATIENTS.

1504
01:09:32,586 --> 01:09:35,121
NOW, I THINK VERY IMPORTANT

1505
01:09:35,121 --> 01:09:36,256
CLINICAL IMPLICATIONS OF THIS

1506
01:09:36,256 --> 01:09:41,461
WHOLE PIECE OF WORK AND ALSO FOR

1507
01:09:41,461 --> 01:09:42,062
CONGENITAL DIARRHEAL SYNDROMES

1508
01:09:42,062 --> 01:09:47,234
IN GENERAL AND THIS IS THE FOCUS

1509
01:09:47,234 --> 01:09:50,036
OF THE PEDIATRIC CONGENITAL

1510
01:09:50,036 --> 01:09:51,338
DIARRHEA ENTER OPEN MEETINGATHY

1511
01:09:51,338 --> 01:09:54,007
CONSORTIUM THAT WE'RE PART OF

1512
01:09:54,007 --> 01:09:55,175
WITH HARVARD, UCLA AND SICK KIDS

1513
01:09:55,175 --> 01:09:57,844
AND THAT IS THE FOLLOWING:  IT'S

1514
01:09:57,844 --> 01:10:00,714
PRETTY CLEAR THAT IN TAKING CARE

1515
01:10:00,714 --> 01:10:03,016
OF THESE PATIENTS AS MITCH

1516
01:10:03,016 --> 01:10:05,619
REALLY EMPHASIZED, IT'S REALLY

1517
01:10:05,619 --> 01:10:09,522
IMPORTANT TO DETERMINE EARLY ON

1518
01:10:09,522 --> 01:10:14,427
THAT THERE'S A PROBLEM AND GET

1519
01:10:14,427 --> 01:10:15,829
THESE PATIENTS INTO A NEW

1520
01:10:15,829 --> 01:10:17,864
PIPELINE AND THAT NEW PIPELINE

1521
01:10:17,864 --> 01:10:23,103
IN THIS DAY AND AGE, IS EARLY

1522
01:10:23,103 --> 01:10:24,471
GENOMICS SEQUENCING OF THE PRO

1523
01:10:24,471 --> 01:10:28,141
BAND AND THE PARENTS THAT CAN

1524
01:10:28,141 --> 01:10:30,210
LEAD TO A DEFINITIVE DIAGNOSIS

1525
01:10:30,210 --> 01:10:38,285
FOR THESE CONGENITAL DISEASE.

1526
01:10:38,285 --> 01:10:40,787
THERE ARE A NUMBER OF THESE NOW.

1527
01:10:40,787 --> 01:10:42,289
I ALSO WANT TO EMPHASIZE AND

1528
01:10:42,289 --> 01:10:44,624
THIS IS THE HARDER THING TO DO,

1529
01:10:44,624 --> 01:10:48,628
IS TO GET AT THE TIME

1530
01:10:48,628 --> 01:10:51,464
OFENDOSCOPY, WE REALLY NEED TO

1531
01:10:51,464 --> 01:10:53,099
BE RETRIEVING INTESTINAL SAMPLES

1532
01:10:53,099 --> 01:10:54,934
TO MAKE ENTERROIDS SO THAT WE

1533
01:10:54,934 --> 01:10:57,604
CAN MODEL OF PATIENT'S DISEASES,

1534
01:10:57,604 --> 01:10:59,606
SEXER SPECIALLY IF THEY HAVE A

1535
01:10:59,606 --> 01:11:00,607
NEW MUTATION.

1536
01:11:00,607 --> 01:11:02,175
SO INCREASINGLY WE'RE TRYING,

1537
01:11:02,175 --> 01:11:03,877
SPECIALLY AT OUR INSTITUTIONS TO

1538
01:11:03,877 --> 01:11:05,278
MAKE THIS PART OF THE STANDARD

1539
01:11:05,278 --> 01:11:08,348
OF CARE IF YOU'RE GOING IN, TO

1540
01:11:08,348 --> 01:11:10,850
SCOPE THESE PATIENTS, PLEASE,

1541
01:11:10,850 --> 01:11:13,486
PLEASE, PLEASE, GET BYOPSYS AND

1542
01:11:13,486 --> 01:11:16,656
SEND THEM OFF TO PREPARE

1543
01:11:16,656 --> 01:11:17,924
ENTERROIDS, AND INTB CAN SEND

1544
01:11:17,924 --> 01:11:20,460
THEM TO THE PDCODE CONSORTIUM

1545
01:11:20,460 --> 01:11:21,995
AND IT'S REALLY SIMPLE, YOU JUST

1546
01:11:21,995 --> 01:11:25,865
SEND THEM TO US OVERNIGHT IN SAY

1547
01:11:25,865 --> 01:11:27,600
LEAN OR OPTIMALLY WISCONSIN

1548
01:11:27,600 --> 01:11:29,502
SOLUTION AND WE WILL BE ABLE TO

1549
01:11:29,502 --> 01:11:30,437
MAKE ENTERROIDS ALMOST ALL THE

1550
01:11:30,437 --> 01:11:30,670
TIME.

1551
01:11:30,670 --> 01:11:33,840
SO I THINK THIS IS REALLY

1552
01:11:33,840 --> 01:11:35,875
CHANGING HOW WE WILL DEAL WITH

1553
01:11:35,875 --> 01:11:37,677
THESE KIDS WHO ARE REALLY VERY

1554
01:11:37,677 --> 01:11:40,280
SICK IN THE FIRST COUPLE OF

1555
01:11:40,280 --> 01:11:41,281
WEEKS OF LIFE.

1556
01:11:41,281 --> 01:11:43,817
SO, WITH THAT I WILL JUST THANK

1557
01:11:43,817 --> 01:11:45,685
A NUMBER OF PEOPLE IN MY LAB,

1558
01:11:45,685 --> 01:11:47,087
WHO HAVE WORKED ON THIS AND ARE

1559
01:11:47,087 --> 01:11:52,125
CONTINUING TO WORK ON THIS AND

1560
01:11:52,125 --> 01:11:54,661
ALSO, THANK MY COLLABORATORS,

1561
01:11:54,661 --> 01:12:04,938
MITCH OF COURSE, AND THE

1562
01:12:04,938 --> 01:12:05,572
PEDIATRIC DIARRHEA CONSORTIUM

1563
01:12:05,572 --> 01:12:06,873
AND WITH THAT I WILL STOP AND I

1564
01:12:06,873 --> 01:12:17,450
GUESS WE CAN TAKE ANY QUESTIONS 

1565
01:12:25,992 --> 01:12:26,426
>> OKAY.

1566
01:12:26,426 --> 01:12:27,961
WELL, THANK YOU BOTH FOR

1567
01:12:27,961 --> 01:12:29,362
EXTREMELY EXCITING AND IMPORTANT

1568
01:12:29,362 --> 01:12:29,696
PRESENTATIONS.

1569
01:12:29,696 --> 01:12:32,932
WE HAVE SEVERAL QUESTIONS THAT

1570
01:12:32,932 --> 01:12:36,469
HAVE COME IN. 

1571
01:12:36,469 --> 01:12:37,871
PEOPLE HAVE ASKED ABOUT LIVER

1572
01:12:37,871 --> 01:12:41,975
DEC, I KNEW WE WOULD GET THERE.

1573
01:12:41,975 --> 01:12:42,242
[LAUGHTER]

1574
01:12:42,242 --> 01:12:43,676
WELL, MAYBE BOTH OF YOU WOULD

1575
01:12:43,676 --> 01:12:54,120
DISCUSS THIS A LITTLE BIT.

1576
01:12:54,587 --> 01:12:58,057
IT SOME PATIENTS, THE LIVER

1577
01:12:58,057 --> 01:13:01,394
DISEASE SEEMS TO BE EXTREMELY

1578
01:13:01,394 --> 01:13:03,096
SERIOUS SITUATION AND MAYBE YOU

1579
01:13:03,096 --> 01:13:04,397
WOULD LIKE TO ELABORATE A LITTLE

1580
01:13:04,397 --> 01:13:10,236
BIT MORE ABOUT WHAT THE

1581
01:13:10,236 --> 01:13:11,905
POSSIBILITIES ARE NOW, EITHER 1

1582
01:13:11,905 --> 01:13:13,139
OF YOU, MITCHELL YOU DISCUSSED

1583
01:13:13,139 --> 01:13:15,074
THIS A LITTLE BIT, DO YOU WANT

1584
01:13:15,074 --> 01:13:18,611
TO ADD TO THAT CONSIDERATION?

1585
01:13:18,611 --> 01:13:19,579
WHAT'S YOUR THINKING?

1586
01:13:19,579 --> 01:13:21,481
>> I WILL LET JIM TAKE
OVER WITH

1587
01:13:21,481 --> 01:13:23,850
THE SELECT PROCESS, BUT THE ONLY

1588
01:13:23,850 --> 01:13:25,919
THING THAT STRUCK US EARLY ON

1589
01:13:25,919 --> 01:13:28,588
WAS THAT NORMALLY WITH TPN

1590
01:13:28,588 --> 01:13:32,425
RELATED COAL O STASIS, WE SEE

1591
01:13:32,425 --> 01:13:33,726
ALL THE GGT, GAMMA TBLIEWTA

1592
01:13:33,726 --> 01:13:36,863
TRANSFER ACE, AND IN OUR

1593
01:13:36,863 --> 01:13:38,932
PATIENTS WITH MVID, IT WAS A BIG

1594
01:13:38,932 --> 01:13:40,099
PUZZLE WE DIDN'T UNDERSTAND WHAT

1595
01:13:40,099 --> 01:13:44,404
IT MEANT BUT ALL OF THEM HAD

1596
01:13:44,404 --> 01:13:45,738
NORMAL GGT LEVELS.

1597
01:13:45,738 --> 01:13:47,140
AND IT MADE ME WONDER THAT IT

1598
01:13:47,140 --> 01:13:49,642
WAS SOMETHING DIFFERENT THAN

1599
01:13:49,642 --> 01:13:51,811
JUST TPN ALONE THAT WAS DOING

1600
01:13:51,811 --> 01:13:52,278
THIS.

1601
01:13:52,278 --> 01:13:55,014
SO FROM A CLINICAL SIDE, I CAN

1602
01:13:55,014 --> 01:13:59,252
SAY AND WE'VE BEEN TAUGHT BY

1603
01:13:59,252 --> 01:14:02,522
OTHERS, THAT LOW GGT COLO-STASIS

1604
01:14:02,522 --> 01:14:06,159
IS ONLY DUE TO 2 ENTITIES, 1

1605
01:14:06,159 --> 01:14:09,028
BEING INBORN AS A BIOMETABOLISM

1606
01:14:09,028 --> 01:14:13,166
AND OTHER IS FORMS OF PFIC, SO

1607
01:14:13,166 --> 01:14:16,436
BASED ON THAT CLINICALLY, IT

1608
01:14:16,436 --> 01:14:19,572
JUST DIDN'T FIT WITH TTN ALONE

1609
01:14:19,572 --> 01:14:20,540
AS DRIVING LIVER DEC.

1610
01:14:20,540 --> 01:14:21,608
NOW I WILL TURN IT OVER TO I

1611
01:14:21,608 --> 01:14:23,176
DIDN'T MEAN WHO I KNOW HAS

1612
01:14:23,176 --> 01:14:24,577
THOUGHT A LOT ABOUT THIS NYEAH,

1613
01:14:24,577 --> 01:14:26,112
YOU KNOW WHEN I FIRST GOT INTO

1614
01:14:26,112 --> 01:14:30,116
THIS AND TALKING TO MITCH, I

1615
01:14:30,116 --> 01:14:32,886
ASSUMED THE LIVER DISEASE WAS

1616
01:14:32,886 --> 01:14:33,920
TOTALLY FROM TPN.

1617
01:14:33,920 --> 01:14:40,293
AND WHEN WE DID THE INITIAL MY

1618
01:14:40,293 --> 01:14:43,463
MYOCIDE GERM LINE KNOCK OUT IN

1619
01:14:43,463 --> 01:14:47,033
MOUSE, WE WERE NOT REALLY SURE

1620
01:14:47,033 --> 01:14:47,600
ABOUT THE LESIONS.

1621
01:14:47,600 --> 01:14:49,569
AND I MEAN BECAUSE THOSE MICE --

1622
01:14:49,569 --> 01:14:51,271
THOSE MICE I SHOULD HAVE SAID,

1623
01:14:51,271 --> 01:14:55,008
THEY DIE IN THE FIRST 40 DAYS OF

1624
01:14:55,008 --> 01:14:55,208
LIFE.

1625
01:14:55,208 --> 01:15:00,613
BUT WHEN WE DID THE PIG WHERE

1626
01:15:00,613 --> 01:15:08,488
THE PIGLETS WERE BORN, WE FOUND

1627
01:15:08,488 --> 01:15:09,989
THAT THEY HAD TRAFFICKING

1628
01:15:09,989 --> 01:15:10,223
DEFECTS.

1629
01:15:10,223 --> 01:15:11,691
SO THEY WERE BORN AND ON THEIR

1630
01:15:11,691 --> 01:15:14,294
FIRST DAY, IF WE SACRIFICED THE

1631
01:15:14,294 --> 01:15:16,596
MOUSE -- THE PIG ON ITS FIRST

1632
01:15:16,596 --> 01:15:22,368
DAY OF LIFE, THERE WERE LIVER

1633
01:15:22,368 --> 01:15:25,805
DEFECTS.

1634
01:15:25,805 --> 01:15:27,707
NOW SUBSEQUENTLY, AMY HAS GONE

1635
01:15:27,707 --> 01:15:34,147
FORWARD AND DONE A LIVER

1636
01:15:34,147 --> 01:15:36,449
SPECIFIC KNOCK OUT AND OVER

1637
01:15:36,449 --> 01:15:38,284
ABOUT 6 MONTHS THOSE MICE DO

1638
01:15:38,284 --> 01:15:46,259
SEEM TO DEVELOP A PFIC SCENARIO 

1639
01:15:46,259 --> 01:15:46,859
IT TURNS OUT.

1640
01:15:46,859 --> 01:15:48,361
AND THEP THERE'S THE REAL

1641
01:15:48,361 --> 01:15:49,829
PUZZLING QUESTION WHICH IS THERE

1642
01:15:49,829 --> 01:15:58,237
ARE KIDS WHO JUST HAVE PFIC 6,

1643
01:15:58,237 --> 01:16:00,740
WHO HAVE MOYSIN 5 B MUTATIONS.

1644
01:16:00,740 --> 01:16:02,609
I THOUGHT THIS IS INSANE, IT

1645
01:16:02,609 --> 01:16:03,910
CAN'T BE TRUE BUT WE ACTUALLY

1646
01:16:03,910 --> 01:16:07,480
MADE 1 OF THESE KNOCK OUTS IN

1647
01:16:07,480 --> 01:16:09,716
MICE, C26 XR AND LOW AND BEHOLD

1648
01:16:09,716 --> 01:16:11,317
AMY STUDIED THIS MOUSE QUITE A

1649
01:16:11,317 --> 01:16:13,419
LOT AND IS ABOUT TO PUT A PAPER

1650
01:16:13,419 --> 01:16:17,624
OUT ON IT, THE MOUSE OVER 6 +

1651
01:16:17,624 --> 01:16:20,493
MONTHS GETS PFIC AND THE

1652
01:16:20,493 --> 01:16:26,065
INTESTINE IS ESSENTIALLY NORMAL.

1653
01:16:26,065 --> 01:16:27,000
NOW WHY IS THAT?

1654
01:16:27,000 --> 01:16:30,737
I HAVE NO IDEA.

1655
01:16:30,737 --> 01:16:34,273
WE'VE ACTUALLY LOOKED AT THE

1656
01:16:34,273 --> 01:16:36,342
AMERICA YO5 B, C266 R MUTATION

1657
01:16:36,342 --> 01:16:39,812
AND REALLY THE MOTOR IS PRETTY

1658
01:16:39,812 --> 01:16:40,480
NORMAL.

1659
01:16:40,480 --> 01:16:45,752
SO AT THIS MOMENT, I STILL CAN'T

1660
01:16:45,752 --> 01:16:47,587
FIGURE OUT WHY SOME OF THESE

1661
01:16:47,587 --> 01:16:50,857
MUTATIONS GIVE ONLY LIVER 

1662
01:16:50,857 --> 01:16:53,192
DISEASE AND I THINK THAT'S A

1663
01:16:53,192 --> 01:16:56,295
REALLY INTERESTING PROBLEM.

1664
01:16:56,295 --> 01:16:59,766
>> SO HAD THERE BEEN
PATIENTS

1665
01:16:59,766 --> 01:17:01,601
THAT REQUIRE BOTH MIXED

1666
01:17:01,601 --> 01:17:05,905
TRANSPLANT OF THE LIVER AND

1667
01:17:05,905 --> 01:17:06,706
INTESTINE FOR SURVIVAL?

1668
01:17:06,706 --> 01:17:09,542
>> I THINK PRETTY MUCH
NOW,

1669
01:17:09,542 --> 01:17:13,713
ANYBODY BEING TRANSPLANTED WILL

1670
01:17:13,713 --> 01:17:15,415
HAVE COMBINED TRANSPLANT BECAUSE

1671
01:17:15,415 --> 01:17:17,150
-- WHAT DO YOU THINK MITCH --

1672
01:17:17,150 --> 01:17:18,284
I'VE HEARD PEOPLE ARGUE SOMEWHAT

1673
01:17:18,284 --> 01:17:20,186
BACK AND FORTH ON THIS,

1674
01:17:20,186 --> 01:17:21,387
OBVIOUSLY THERE'S A NUMBER OF

1675
01:17:21,387 --> 01:17:22,922
MUTATIONS BUT IT SEEMS TO ME

1676
01:17:22,922 --> 01:17:26,859
THAT MOST OF THE PATIENTS, I

1677
01:17:26,859 --> 01:17:29,362
JUST HAVE BEEN CONSULTED OR

1678
01:17:29,362 --> 01:17:31,531
HEARD ABOUT EVENTUALLY IF THEY

1679
01:17:31,531 --> 01:17:34,267
HAVE INTESTINAL DISEASE

1680
01:17:34,267 --> 01:17:35,334
EVENTUALLY THEY GET LIVER

1681
01:17:35,334 --> 01:17:35,668
DISEASE?

1682
01:17:35,668 --> 01:17:38,304
DO YOU THINK THAT'S TRUE MITCH?

1683
01:17:38,304 --> 01:17:40,473
>> I DO, OBVIOUSLY WE'VE
SEEN A

1684
01:17:40,473 --> 01:17:43,009
NARROWER BAND OF MUTATIONS, WE

1685
01:17:43,009 --> 01:17:46,746
HAVE CARED FOR 2 SIBLINGS THAT

1686
01:17:46,746 --> 01:17:49,282
WERE HISPANIC THAT I'M ASSUMING

1687
01:17:49,282 --> 01:17:52,318
HAD A DIFFERENT MUTATION AND

1688
01:17:52,318 --> 01:17:53,953
THEY DEVELOP LIVER DISEASE AND

1689
01:17:53,953 --> 01:17:56,723
THE ONLY THING I CAN SAY, I KNOW

1690
01:17:56,723 --> 01:18:00,626
IN THE NAVAJO, WE HAVE LOTS OF

1691
01:18:00,626 --> 01:18:02,595
SHORP BALB PATIENTS THAT ARE ON

1692
01:18:02,595 --> 01:18:04,864
TPN FROM THE WORD GO AND FOR A

1693
01:18:04,864 --> 01:18:05,598
LONG TIME.

1694
01:18:05,598 --> 01:18:08,735
AND THE RATE AT WHICH THEY

1695
01:18:08,735 --> 01:18:09,969
DEVELOP LIVER DISEASE DOESN'T

1696
01:18:09,969 --> 01:18:13,706
APPEAR TO BE AS FAST AS THE RATE

1697
01:18:13,706 --> 01:18:16,843
AT WHICH THE NAVAJO MICRODOSE SO

1698
01:18:16,843 --> 01:18:18,377
I ALWAYS THOUGHT AND COUPLED

1699
01:18:18,377 --> 01:18:22,014
WITH THE NORMAL GGT, IT JUST

1700
01:18:22,014 --> 01:18:23,282
SAID TO ME, THAT THERE WAS

1701
01:18:23,282 --> 01:18:24,951
SOMETHING ELSE GOING ON IN THE

1702
01:18:24,951 --> 01:18:33,559
LIVER THAT IS OVER AND ABOVE

1703
01:18:33,559 --> 01:18:33,826
JUST TPN.

1704
01:18:33,826 --> 01:18:35,528
>> SO WHEN YOU ARE TALKING
ABOUT

1705
01:18:35,528 --> 01:18:36,629
LIVER DISEASE, BOTH OF YOU ARE

1706
01:18:36,629 --> 01:18:40,800
TALKING ABOUT A FORM OFA

1707
01:18:40,800 --> 01:18:42,168
PROGRESSIVE FAMILIAL INTERO

1708
01:18:42,168 --> 01:18:44,804
PATTIC COAL O STASIS, IS THAT

1709
01:18:44,804 --> 01:18:50,810
THE UNIFORM PATHOLOGY THAT YOU

1710
01:18:50,810 --> 01:18:51,210
SEE?

1711
01:18:51,210 --> 01:18:54,914
OR IS THAT BASED UPON THE FACT

1712
01:18:54,914 --> 01:18:57,250
THAT YOU SHOW AND COMPARE TO

1713
01:18:57,250 --> 01:18:59,685
TRAFFICKING OF AN ABC

1714
01:18:59,685 --> 01:19:00,553
TRANSPORTERS?

1715
01:19:00,553 --> 01:19:06,659
WHAT IS IT THE ACTUAL PATHOLOGY?

1716
01:19:06,659 --> 01:19:09,395
>> YOU KNOW THE PATHOLOGY
IS

1717
01:19:09,395 --> 01:19:10,429
JUST PROGRESSIVE CIRRHOSIS AND

1718
01:19:10,429 --> 01:19:11,831
LIVER DISEASE AND I DON'T KNOW

1719
01:19:11,831 --> 01:19:15,768
IF WE WOULD BE ABLE TO

1720
01:19:15,768 --> 01:19:17,436
DISTINGUISH WHICH TYPE TO BE

1721
01:19:17,436 --> 01:19:18,004
HONEST WITH YOU.

1722
01:19:18,004 --> 01:19:20,306
I DON'T KNOW THAT PFIC -- MAYBE

1723
01:19:20,306 --> 01:19:26,245
YOU KNOW THIS BETTER THAN I DO,

1724
01:19:26,245 --> 01:19:29,382
BUT I'M NOT AWARE PFICs GIVE A

1725
01:19:29,382 --> 01:19:30,983
UNIQUE HISTOLOGY TYPE THAT WOULD

1726
01:19:30,983 --> 01:19:32,985
DISTINGUISH IT FROM OTHER FORMS

1727
01:19:32,985 --> 01:19:39,025
OF NEONATAL LIVER DISEASE.

1728
01:19:39,025 --> 01:19:41,761
JIM DO YOU HAVE A COMMENT?

1729
01:19:41,761 --> 01:19:42,829
>> YEAH, I'M NOT GOING TO
TALK

1730
01:19:42,829 --> 01:19:48,534
ABOUT LIVER IN FRONT OF YOU.

1731
01:19:48,534 --> 01:19:48,801
[LAUGHTER]

1732
01:19:48,801 --> 01:19:52,104
NO, BUT AT LEAST, SO I WAS JUST

1733
01:19:52,104 --> 01:19:55,508
AT A MEETING WITH AMY AND WHAT

1734
01:19:55,508 --> 01:19:59,645
SHE SHOWED ME WAS THE MICE SORT

1735
01:19:59,645 --> 01:20:02,248
OF LIKE WHAT WE SAW IN THE PIG

1736
01:20:02,248 --> 01:20:03,950
BUT ACTUALLY IT'S MORE CLEAR IN

1737
01:20:03,950 --> 01:20:05,785
THE MICE NOW THAT HE'S GOT IT,

1738
01:20:05,785 --> 01:20:08,788
THEY DON'T REALLY GET A SERIES

1739
01:20:08,788 --> 01:20:10,923
POINTSOTTIC PICTURE, THEY GET A

1740
01:20:10,923 --> 01:20:20,633
COAL O STASIS PICTURE MORE.

1741
01:20:20,633 --> 01:20:23,870
SO I THINK IT IS PROGRESSIVE, IT

1742
01:20:23,870 --> 01:20:25,571
IS THAT PROGRESSIVE ENDOLYNN

1743
01:20:25,571 --> 01:20:27,306
COAL O STASIS THAT KICKS IN XI

1744
01:20:27,306 --> 01:20:28,708
WOULD MAWG THAT BECAUSE THE

1745
01:20:28,708 --> 01:20:30,910
PROCESS IS ONGOING THAT AGAIN,

1746
01:20:30,910 --> 01:20:36,682
AS MITCH SAID, TPN'S GOT TO MAKE

1747
01:20:36,682 --> 01:20:38,050
THIS WORSE.

1748
01:20:38,050 --> 01:20:39,552
>> THERE'S NO PFIC
LONG-TERM

1749
01:20:39,552 --> 01:20:41,754
ENDS UP WITH PROGRESSIVE LIVER

1750
01:20:41,754 --> 01:20:45,091
DEC, IT'S NOT -- SO I THINK THE

1751
01:20:45,091 --> 01:20:46,025
LIVER GERONTOLOGYSTSS DAMAGED AS

1752
01:20:46,025 --> 01:20:49,929
A RESULT OF THE BIOSALTS NOT

1753
01:20:49,929 --> 01:20:51,197
BEING EXCRETED PROPER LOW AND

1754
01:20:51,197 --> 01:20:53,165
PROBABLY OTHER TOXINS THAT NEED

1755
01:20:53,165 --> 01:20:55,001
TO BE EXCRETED AND I THINK IT

1756
01:20:55,001 --> 01:21:01,741
ENDS UP DAMAGING THE HEPATITIS

1757
01:21:01,741 --> 01:21:02,041
HEPATOCYTES.

1758
01:21:02,041 --> 01:21:05,144
>> I WOULD VENTURE THERE'S
ALSO

1759
01:21:05,144 --> 01:21:07,780
PROBABLY A SERIOUS PROBLEM IN

1760
01:21:07,780 --> 01:21:11,751
THE ENERGETICS WITHIN THE CELL.

1761
01:21:11,751 --> 01:21:14,720
IN OUR MODEL WHICH IS NOT --

1762
01:21:14,720 --> 01:21:16,689
WHICH IS -- YOU KNOW WE STUDIED

1763
01:21:16,689 --> 01:21:20,660
IN NORMAL LIVER CELLS WHERE WE

1764
01:21:20,660 --> 01:21:25,131
SORT OF REMOVE MYOSIN 5 B, OR

1765
01:21:25,131 --> 01:21:28,801
INHIBITED RAB 11A AND SO FORTH,

1766
01:21:28,801 --> 01:21:34,240
THERE WHAT HAPPENS IS THAT YOU

1767
01:21:34,240 --> 01:21:37,243
GET A REAL YEVENTUAL

1768
01:21:37,243 --> 01:21:40,346
MITOCHONDRIA INJURY IN THE SENSE

1769
01:21:40,346 --> 01:21:45,051
THAT ENERGY PRODUCTION, ATP

1770
01:21:45,051 --> 01:21:49,889
LEVELS FALL, THE OKB1 MK-PATHWAY

1771
01:21:49,889 --> 01:21:53,159
KICKS IN AND FOR A WHILE

1772
01:21:53,159 --> 01:21:54,927
POLARITY IS MAINTAINED BUT

1773
01:21:54,927 --> 01:21:58,264
EVENTUALLY THOSE CELLS BECOME

1774
01:21:58,264 --> 01:22:00,099
POLARIZED AND THE BIO ACIDS

1775
01:22:00,099 --> 01:22:01,400
ACCUMULATE AND RAISE HELL AND

1776
01:22:01,400 --> 01:22:08,307
THE CELL DIES, AND SO I WONDER

1777
01:22:08,307 --> 01:22:11,610
WHETHER IN THESE ORDERS OF

1778
01:22:11,610 --> 01:22:15,247
TRAFFICKING, WHETHER THE ENERN

1779
01:22:15,247 --> 01:22:16,449
GETTICS OF THE CELL BE IT IN THE

1780
01:22:16,449 --> 01:22:21,020
GUT OR IN THE LIVER, ARE

1781
01:22:21,020 --> 01:22:22,788
PROFOUNDLY AFFECTED AND HAVE

1782
01:22:22,788 --> 01:22:23,589
SECONDARY EEIVETS THAT

1783
01:22:23,589 --> 01:22:26,125
ULTIMATELY SAY LEAD TO CIRRHOSIS

1784
01:22:26,125 --> 01:22:29,462
IN THE LIVER AND FURTHER DAMAGE

1785
01:22:29,462 --> 01:22:30,429
IN THE GUT.

1786
01:22:30,429 --> 01:22:31,630
IS THERE ANY OTHER --

1787
01:22:31,630 --> 01:22:36,469
>> I THINK YOU'RE RIGHT.

1788
01:22:36,469 --> 01:22:38,904
YOU KNOW, IZUMI SHOWN IN THE

1789
01:22:38,904 --> 01:22:39,705
INTESTINE VERY NICELY IS WHEN

1790
01:22:39,705 --> 01:22:42,575
YOU LOOK AT THE MITOCHONDRIA IN

1791
01:22:42,575 --> 01:22:44,076
THE CRYPT PROGENITORS, WHAT YOU

1792
01:22:44,076 --> 01:22:46,612
SEE IS THEY LOOK REALLY BAD.

1793
01:22:46,612 --> 01:22:50,583
THEY HAVE -- THEY LOOK TERRIBLE.

1794
01:22:50,583 --> 01:22:52,518
INTERESTINGLY, THE PAN OF CELLS

1795
01:22:52,518 --> 01:22:55,321
RIGHT NEXT DOOR TO THE

1796
01:22:55,321 --> 01:22:57,390
PROGENITORS, THEIR MITOCHONDRIA

1797
01:22:57,390 --> 01:22:57,690
ARE FINE.

1798
01:22:57,690 --> 01:23:01,127
SO THERE IS A STEM CELL THING,

1799
01:23:01,127 --> 01:23:03,929
AND AMY SHOWED ME A COUPLE OF

1800
01:23:03,929 --> 01:23:05,998
INITIAL EMs, WHERE I THINK

1801
01:23:05,998 --> 01:23:07,299
SHE'S SEEING PROBABLY THE SAME

1802
01:23:07,299 --> 01:23:07,700
PATTERN.

1803
01:23:07,700 --> 01:23:10,536
SO I THINK YOU'RE TOTALLY RIGHT.

1804
01:23:10,536 --> 01:23:12,938
I ENERGETICS ARE MESSED UP IN

1805
01:23:12,938 --> 01:23:14,640
THESE CELLS AND MAYBE IT'S

1806
01:23:14,640 --> 01:23:18,010
BECAUSE THE LIVER CELLS DON'T

1807
01:23:18,010 --> 01:23:20,413
TURNOVER AS MUCH THAT IT IS THAT

1808
01:23:20,413 --> 01:23:22,081
IT TAKES LONGER FOR REALLY TO

1809
01:23:22,081 --> 01:23:30,289
IMPACT BUT IT GETS THERE

1810
01:23:30,289 --> 01:23:30,589
EVENTUALLY.

1811
01:23:30,589 --> 01:23:36,962
>> WELL, IT HAS A LONG
LIFE

1812
01:23:36,962 --> 01:23:37,897
SPAN.

1813
01:23:37,897 --> 01:23:38,531
>> DENDRITIC CELLROCYTES

1814
01:23:38,531 --> 01:23:43,669
TURNOVER OVER 5 DAYS,

1815
01:23:43,669 --> 01:23:44,637
EVERYTHING'S CRANKING.

1816
01:23:44,637 --> 01:23:45,838
>> LET ME ASK BOTH OF YOU
A

1817
01:23:45,838 --> 01:23:47,573
QUESTION, DO YOU THINK BECAUSE

1818
01:23:47,573 --> 01:23:52,311
OF THE ABNORMAL SURFACE OF THE

1819
01:23:52,311 --> 01:23:53,145
INTESTINAL LINING, DO YOU THINK

1820
01:23:53,145 --> 01:23:58,350
THAT MIGHT ALLOW FOR ENTER O

1821
01:23:58,350 --> 01:24:00,553
TOXINS AND OTHER THINGS TO CROSS

1822
01:24:00,553 --> 01:24:04,190
THE BARRIER MORE EASILY AND

1823
01:24:04,190 --> 01:24:05,324
UNFORTUNATELY LIVERS ARE THE

1824
01:24:05,324 --> 01:24:07,226
FIRST POINT OF CONTACT TYPICALLY

1825
01:24:07,226 --> 01:24:10,930
IF THOSE ENTER A TOXINS CROSS.

1826
01:24:10,930 --> 01:24:13,732
-- ENTER O TOXINS CROSS.

1827
01:24:13,732 --> 01:24:14,667
>> WELL, GHEE, I GUESS
IT'S A

1828
01:24:14,667 --> 01:24:16,368
POSSIBILITY AND THE OTHER

1829
01:24:16,368 --> 01:24:18,604
QUESTION, YOU KNOW, WHAT'S THE

1830
01:24:18,604 --> 01:24:24,777
IMPACT ON, YOU KNOW,

1831
01:24:24,777 --> 01:24:26,112
BIORECYCLING THROUGH THE ENTER O

1832
01:24:26,112 --> 01:24:27,279
HEPATIC CIRCULATION AND I DON'T

1833
01:24:27,279 --> 01:24:35,454
THINK WE KNOW THAT EITHER AND 1

1834
01:24:35,454 --> 01:24:36,989
THING WE DO KNOW IS THAT THE

1835
01:24:36,989 --> 01:24:38,958
MUCOSA IS NOT LEAKY.

1836
01:24:38,958 --> 01:24:42,261
IN FACT, IT ACTUALLY HAS

1837
01:24:42,261 --> 01:24:42,828
SLIGHTLY HIGHER RESISTANCE.

1838
01:24:42,828 --> 01:24:46,899
THIS IS NOT A LEAKY THING, LIKE

1839
01:24:46,899 --> 01:24:51,470
YOU SEE, SAY IN DGDAMUTATIONS.

1840
01:24:51,470 --> 01:24:54,340
BUT I ACTUALLY, YOU KNOW IT'S

1841
01:24:54,340 --> 01:24:55,241
CERTAINLY POSSIBLE, THE OTHER

1842
01:24:55,241 --> 01:24:58,878
THING IS BECAUSE WE DON'T HAVE

1843
01:24:58,878 --> 01:25:02,748
ALL THIS CORRECT APICAL

1844
01:25:02,748 --> 01:25:04,316
TRAFFICKING, WE'RE PROBABLY ARE

1845
01:25:04,316 --> 01:25:06,852
SETTING IT UP FOR THAT, EXACTLY

1846
01:25:06,852 --> 01:25:10,723
THOSE MECHANISMS SO THERE'S LESS

1847
01:25:10,723 --> 01:25:14,226
ALCO LINE PHOSPHOR TAISS--SYNTH

1848
01:25:14,226 --> 01:25:18,631
THERE, THEY DON'T PRESENT

1849
01:25:18,631 --> 01:25:19,765
PHOSPHOR LIESATE 2 FOR INSTANCE

1850
01:25:19,765 --> 01:25:22,601
WHICH IS NECESSARY FOR

1851
01:25:22,601 --> 01:25:27,139
CONVERTING PHOSPHO LYTIC ACID TO

1852
01:25:27,139 --> 01:25:31,877
FOSTER NURSED O LYTIC ACE, YOU

1853
01:25:31,877 --> 01:25:33,979
CAN'T JUST GIVE THE KID PHOSPHO

1854
01:25:33,979 --> 01:25:35,614
LYTIC ACID, LIKE THE BODY

1855
01:25:35,614 --> 01:25:37,616
BUILDERS USE BUT BECAUSE THEY

1856
01:25:37,616 --> 01:25:38,584
DON'T TRAFFIC FOSTER NURSED

1857
01:25:38,584 --> 01:25:40,953
FOCUSED ON LIPASE A2, IN THE

1858
01:25:40,953 --> 01:25:42,721
ACHE PECULIARAL MEMBRANE THEY

1859
01:25:42,721 --> 01:25:47,159
CAN'T CONVERT THE ACID TO THE

1860
01:25:47,159 --> 01:25:48,394
LYSOFOSTER NURSED FOCUSED ON

1861
01:25:48,394 --> 01:25:49,094
SITTIC ACID.

1862
01:25:49,094 --> 01:25:50,596
SO I THINK YOU'RE RIGHT, THEY

1863
01:25:50,596 --> 01:25:52,131
ALSO WILL BE SET UP AND MAYBE

1864
01:25:52,131 --> 01:25:54,667
THAT SETS THEM UP FOR THE SEPSIS

1865
01:25:54,667 --> 01:25:54,934
PARTIALLY.

1866
01:25:54,934 --> 01:25:57,102
YOU KNOW WE LIKE TO BLAME IT ON

1867
01:25:57,102 --> 01:26:01,173
THE CATHETERS BUT IT MAY NOT BE

1868
01:26:01,173 --> 01:26:01,473
COMPLETELY.

1869
01:26:01,473 --> 01:26:05,678
>> WHAT ABOUT THE KIDNEY?

1870
01:26:05,678 --> 01:26:08,280
IN SOME OF THE REPORTS THESE

1871
01:26:08,280 --> 01:26:14,420
PATIENTS HAVE A NEFF ROTTIC LIKE

1872
01:26:14,420 --> 01:26:15,821
SYNDROME AND OTHER DEFECTS WE

1873
01:26:15,821 --> 01:26:18,958
DON'T HEAR MUCH ABOUT THE KIDNEY

1874
01:26:18,958 --> 01:26:19,625
IN THESE DISORDERS?

1875
01:26:19,625 --> 01:26:20,726
IS THIS A PROBLEM IN THE

1876
01:26:20,726 --> 01:26:31,270
PATIENTS THAT EITHER OF YOU HAVE

1877
01:26:35,274 --> 01:26:35,808
DEALT WITH?

1878
01:26:35,808 --> 01:26:37,943
STRKS WE HAD PATIENTS DEVELOP

1879
01:26:37,943 --> 01:26:39,878
NEPHROTIC SYNDROME AND WE WERE

1880
01:26:39,878 --> 01:26:41,847
SURE -- WE LET JIM LOOK AT THOSE

1881
01:26:41,847 --> 01:26:46,085
AND WE JUST WEREN'T ABLE TO

1882
01:26:46,085 --> 01:26:46,885
IDENTIFY A REASON.

1883
01:26:46,885 --> 01:26:47,152
>> YEAH.

1884
01:26:47,152 --> 01:26:49,288
>> NOT FOR A LOCK OF
TRYING.

1885
01:26:49,288 --> 01:26:51,056
HOWEVER, I CAN TELL YOU THE

1886
01:26:51,056 --> 01:26:56,962
PANCREAS, WE HAD A PATIENT THAT

1887
01:26:56,962 --> 01:27:00,599
DEVELOPED DIABETES TYPE PICTURE

1888
01:27:00,599 --> 01:27:04,536
AND WE HAD SENT JIM SAMPLES OF

1889
01:27:04,536 --> 01:27:07,673
PANCREAS FROM A PATIENT THAT

1890
01:27:07,673 --> 01:27:09,508
RECEIVED A MULTIORGAN TRANSPLANT

1891
01:27:09,508 --> 01:27:12,344
AND THE PANCREAS DID NOT LOOK

1892
01:27:12,344 --> 01:27:14,246
NORMAL IN THAT PATIENT WHICH IS

1893
01:27:14,246 --> 01:27:15,814
ANOTHER REASON THAT I THINK IF

1894
01:27:15,814 --> 01:27:18,117
THESE PATIENTS ARE GOING TO BE

1895
01:27:18,117 --> 01:27:20,519
TRANSPLANTED, YOU BETTER THINK

1896
01:27:20,519 --> 01:27:22,354
ABOUT WHAT OTHER ORGANS MIGHT

1897
01:27:22,354 --> 01:27:25,090
LOOK LIKE, THE LIVER, THE

1898
01:27:25,090 --> 01:27:26,392
PANCREAS, THE TOMAC, THEY MAY

1899
01:27:26,392 --> 01:27:29,962
NOT BE NORMAL EITHER.

1900
01:27:29,962 --> 01:27:31,497
>> YEAH, SO 1 THING I DO
KNOW,

1901
01:27:31,497 --> 01:27:33,932
SO 1 THING WE SHOULD HAVE SAID

1902
01:27:33,932 --> 01:27:37,636
IS WHY IS IT SO PROMINENT IN THE

1903
01:27:37,636 --> 01:27:41,573
INTESTINE, AND IT TURNS OUT, THE

1904
01:27:41,573 --> 01:27:46,245
INTESTINE AND ALSO THE LIVER,

1905
01:27:46,245 --> 01:27:48,180
THERE ARE 2 -- THERE ARE 2

1906
01:27:48,180 --> 01:27:49,948
FAMILY MEMBERS VERY CLOSE TO

1907
01:27:49,948 --> 01:27:53,052
EACH OTHER, MY O SIGN 5 A AND MY

1908
01:27:53,052 --> 01:27:55,888
O SIGN 5 B, FOR REASONS THAT

1909
01:27:55,888 --> 01:27:57,923
MAKE NO SENSE EVOLUTIONARY, THE

1910
01:27:57,923 --> 01:28:01,694
GUT HAVE NO MICE O SIN 5A, AND

1911
01:28:01,694 --> 01:28:04,430
IT DOESN'T UPREGULATE IT AND

1912
01:28:04,430 --> 01:28:06,665
LIVER ALMOST HAS NO MY O SIGN

1913
01:28:06,665 --> 01:28:09,168
5A, SO WHERE AS THE KIDNEY HAS

1914
01:28:09,168 --> 01:28:11,804
MORE 5 A THAN 5 ABOUT ISSUES THE

1915
01:28:11,804 --> 01:28:18,610
BRAIN MORE 5A THAN  5 B, SO I

1916
01:28:18,610 --> 01:28:20,579
THINK THESE OTHER ORGANS MIGHT

1917
01:28:20,579 --> 01:28:23,949
BE PROTECTED BECAUSE THEY CAN

1918
01:28:23,949 --> 01:28:25,984
SUBIN 5A TO DO WHAT 5 B DOES,

1919
01:28:25,984 --> 01:28:26,852
HOWEVER I'M FASCINATED BY THIS,

1920
01:28:26,852 --> 01:28:28,921
SO I HAVE TO TELL YOU, I HAVE A

1921
01:28:28,921 --> 01:28:31,457
MOUSE BREEDING RIGHT NOW, I'M

1922
01:28:31,457 --> 01:28:41,033
TARGETING MY O 5 B KNOCK OUT IN

1923
01:28:41,033 --> 01:28:41,533
THE MALTUBULES.

1924
01:28:41,533 --> 01:28:42,901
>> SO GIVE ME A FEW MONTHS
AND

1925
01:28:42,901 --> 01:28:44,136
I'LL TELL YOU ABOUT IT.

1926
01:28:44,136 --> 01:28:45,204
>> SO WHAT ABOUT THE
BRAIN.

1927
01:28:45,204 --> 01:28:46,605
IS THERE A DIFFERENCE IN THE

1928
01:28:46,605 --> 01:28:49,341
EXPRESSION OF 5 A OR 5 B IN

1929
01:28:49,341 --> 01:28:51,577
MIEWRONS OR IN GLUE MARIOUSA IN

1930
01:28:51,577 --> 01:28:56,415
-- OR  IN GLIA?

1931
01:28:56,415 --> 01:28:58,617
>> SO I'VE ONLY DO A
LITTLE BIT

1932
01:28:58,617 --> 01:29:00,052
ON THIS, AND I REALLY WANT TO

1933
01:29:00,052 --> 01:29:01,453
GET BACK TO IT BECAUSE I STARTED

1934
01:29:01,453 --> 01:29:05,157
LIFE AS A NEUROSCIENTIST, BUT I

1935
01:29:05,157 --> 01:29:06,925
HAVEN'T -- I HAVEN'T DONE A

1936
01:29:06,925 --> 01:29:09,261
DIRECT TARGETING INTO THE BRAIN

1937
01:29:09,261 --> 01:29:10,295
BUT I REALLY WANT TO DO IT.

1938
01:29:10,295 --> 01:29:14,533
I THINK WE HAVE TO TRY IT,

1939
01:29:14,533 --> 01:29:15,367
MOSTLY FOR IMPLICATIONS BUT YOU

1940
01:29:15,367 --> 01:29:16,802
KNOW SOME OF THESE KIDS ARE

1941
01:29:16,802 --> 01:29:21,640
LIVING A LONG TIME ON TPN OR

1942
01:29:21,640 --> 01:29:24,710
TRANSPLANT, I THINK THE HARVARD

1943
01:29:24,710 --> 01:29:26,578
GUYS WHO ARE JUST LIKE THE

1944
01:29:26,578 --> 01:29:28,313
BOSTON CHILDREN GUYS SEEM TO BE

1945
01:29:28,313 --> 01:29:31,250
THE GURUS OF TPN.

1946
01:29:31,250 --> 01:29:33,018
SOME OF THOSE KIDS THEY'VE BEEN

1947
01:29:33,018 --> 01:29:37,689
TAKING CARE OF ARE GOING TO

1948
01:29:37,689 --> 01:29:38,257
COLLEGE, WITH TPN.

1949
01:29:38,257 --> 01:29:41,193
SO I DON'T KNOW ABOUT, YOU KNOW

1950
01:29:41,193 --> 01:29:44,062
-- I HAVEN'T HEARD ABOUT

1951
01:29:44,062 --> 01:29:46,098
SEEREBERAL DEFEBTS ALTHOUGH WHEN

1952
01:29:46,098 --> 01:29:49,067
YOU'VE BEEN THIS SICK, USUALLY

1953
01:29:49,067 --> 01:29:52,838
OFTEN HAVE DEVELOPMENTAL DELAYS,

1954
01:29:52,838 --> 01:29:53,038
RIGHT?

1955
01:29:53,038 --> 01:29:55,774
>> YEAH, A LOT OF OUR KIDS
SEEM

1956
01:29:55,774 --> 01:29:57,209
TO BE DEVELOPMENTALLY DELAYED

1957
01:29:57,209 --> 01:29:58,544
COMPARED TO SIBLINGS BUT WE

1958
01:29:58,544 --> 01:30:01,246
ATTRIBUTE IT TO CHRONIC ILLNESS

1959
01:30:01,246 --> 01:30:02,981
AND MAYBE FACTORS THAT WE WERE

1960
01:30:02,981 --> 01:30:05,684
BT REPLACING IN THE TPN, ET

1961
01:30:05,684 --> 01:30:06,084
CETERA.

1962
01:30:06,084 --> 01:30:07,219
>> YEAH, SO THAT'S GOING
TO BE

1963
01:30:07,219 --> 01:30:09,087
HARD, BUT I THINK WE NEED TO --

1964
01:30:09,087 --> 01:30:10,222
JUST LIKE I SAID I'M GOING TO

1965
01:30:10,222 --> 01:30:13,025
LOOK AT THE KIDNEY, I THINK

1966
01:30:13,025 --> 01:30:14,092
EVENTUALLY, I GOTTA SEND IT TO

1967
01:30:14,092 --> 01:30:20,098
THE BRAIN AND FIND OUT.

1968
01:30:20,098 --> 01:30:22,601
SO WHAT'S THE ROLE OF THE

1969
01:30:22,601 --> 01:30:27,239
ADAPTER PROTEINS THAT YOU

1970
01:30:27,239 --> 01:30:29,208
DESCRIBED RAB 11A ADAPTER AND SO

1971
01:30:29,208 --> 01:30:33,779
FORTH, ARE THEY PLANNING A

1972
01:30:33,779 --> 01:30:40,219
FUNCTIONAL ROLE IN RAB 11A

1973
01:30:40,219 --> 01:30:41,220
ACTIVITY?

1974
01:30:41,220 --> 01:30:45,257
>> SO IT'S THOUGHT THAT
IT'S THE

1975
01:30:45,257 --> 01:30:48,760
RAB PROTEIN THAT YOU KNOW BINDS

1976
01:30:48,760 --> 01:30:54,199
THE MYOSIN 5 TO THE VESICLE.

1977
01:30:54,199 --> 01:30:57,603
OR RAB ETA THAT BINDS THE MYOSIN

1978
01:30:57,603 --> 01:31:01,940
5 TO ANOTHER VESICLE POPULATION.

1979
01:31:01,940 --> 01:31:04,977
SO, AS FAR AS WE KNOW THE RABS

1980
01:31:04,977 --> 01:31:08,413
DON'T AFFECT THE MOTOR ACTIVITY

1981
01:31:08,413 --> 01:31:16,822
ITSELF, BUT CERTAINLY AFFECTS

1982
01:31:16,822 --> 01:31:17,322
LOCALIZATION.

1983
01:31:17,322 --> 01:31:25,697
BUT WHAT MICE O SIN 5 B IS

1984
01:31:25,697 --> 01:31:26,632
FUNCTIONALLY DOING IN THESE

1985
01:31:26,632 --> 01:31:26,832
CELLS.

1986
01:31:26,832 --> 01:31:28,967
YOU KNOW WE LIKE TO THINK OF

1987
01:31:28,967 --> 01:31:30,269
MYOSINS AS A MOTOR BUT IF YOU

1988
01:31:30,269 --> 01:31:32,304
ACTUAL LYE LOOK AT THE BEHAVIOR

1989
01:31:32,304 --> 01:31:35,741
OF MYOSIN 5 ABOUT, IT LOOKS LIKE

1990
01:31:35,741 --> 01:31:37,109
A MICROTUBULE ASSOCIATED

1991
01:31:37,109 --> 01:31:37,976
PROTEIN, SO THE IDEA WE'VE

1992
01:31:37,976 --> 01:31:41,113
ACTUALLY COME UP WITH, WHICH IS

1993
01:31:41,113 --> 01:31:44,550
A CONSTRUCT AND MAY BE FANCIFUL

1994
01:31:44,550 --> 01:31:48,287
IS THAT THE MYOSIN 5 B REALLY IS

1995
01:31:48,287 --> 01:31:50,222
NOT FUNCTIONING SO MUCH IN THE

1996
01:31:50,222 --> 01:31:52,224
MOVEMENT OF THE VESICLE TO THE

1997
01:31:52,224 --> 01:31:53,992
APICAL MEMBRANE, BUT AT THE

1998
01:31:53,992 --> 01:31:56,395
APICAL MEMBRANE AND BELOW IT IS

1999
01:31:56,395 --> 01:31:59,031
THIS REALLY DENSE EFFECT AND

2000
01:31:59,031 --> 01:32:01,300
STRUCTURE, THE TERMINAL WEB AND

2001
01:32:01,300 --> 01:32:02,768
WHAT WE'VE COME UP WITH THIS

2002
01:32:02,768 --> 01:32:04,836
IDEA THAT MAYBE, WHAT THE MYOSIN

2003
01:32:04,836 --> 01:32:10,342
5 B IS, RATHER THAN A  

2004
01:32:10,342 --> 01:32:12,377
PERASSESSESSIVE MOTOR, IT'S

2005
01:32:12,377 --> 01:32:13,812
ACTUALLY A   PERASSESSESSIVE

2006
01:32:13,812 --> 01:32:15,180
ANCHOR AND THE VISUAL THAT I USE

2007
01:32:15,180 --> 01:32:20,519
IS WHAT I CALL THE CRAZY

2008
01:32:20,519 --> 01:32:20,786
ORANGUTAN.

2009
01:32:20,786 --> 01:32:24,156
WHERE IF YOU HAVE A BUNCH OF BAR

2010
01:32:24,156 --> 01:32:26,224
HOLDS LIKE YOUR KIDS USED TO

2011
01:32:26,224 --> 01:32:29,962
CLIMB ON AND IT'S MOVING, THEN

2012
01:32:29,962 --> 01:32:33,932
THE MOTOR WILL STAND IN PLACE

2013
01:32:33,932 --> 01:32:35,567
WHILE JUST GRABBING LIKE THIS,

2014
01:32:35,567 --> 01:32:35,867
UP AND DOWN.

2015
01:32:35,867 --> 01:32:38,804
AND THAT MIGHT HOLD THE VESICLES

2016
01:32:38,804 --> 01:32:43,909
IN PLACE UNDERNEATH THE APICAL

2017
01:32:43,909 --> 01:32:45,043
MEMBRANE DIFFUSE, WHAT'S IN

2018
01:32:45,043 --> 01:32:45,544
FAVOR OF THAT?

2019
01:32:45,544 --> 01:32:48,447
WHEN YOU LOOK AT RAB 11 IN MICE

2020
01:32:48,447 --> 01:32:52,117
O SIGN 5 B, IT'S CONCENTRATED

2021
01:32:52,117 --> 01:32:55,053
RIGHT UNDER THE -- RIGHT UNDER

2022
01:32:55,053 --> 01:32:58,123
THE APICKA MEL BRAIN IN

2023
01:32:58,123 --> 01:32:59,758
ANDROGENROCYTES BUT THIS IS, YOU

2024
01:32:59,758 --> 01:33:04,529
KNOW SOMETHING THAT NEEDS

2025
01:33:04,529 --> 01:33:06,665
FURTHER INVESTIGATION.

2026
01:33:06,665 --> 01:33:11,336
>> THERE'S SOME QUESTIONS
ABOUT

2027
01:33:11,336 --> 01:33:12,504
RAB 8.

2028
01:33:12,504 --> 01:33:16,341
WHICH YOU BOTH COMMENTED ABOUT.

2029
01:33:16,341 --> 01:33:19,945
IS THERE A FORM OF MICROVILLAR

2030
01:33:19,945 --> 01:33:23,915
INCLUSION BODY DISEASE IN HUMANS

2031
01:33:23,915 --> 01:33:27,686
THAT IS SPECIFICALLY DUE TO

2032
01:33:27,686 --> 01:33:29,287
MUTATIONS IN RAB 8?

2033
01:33:29,287 --> 01:33:34,026
>> SO AS FAR AS I KNOW, NO
1 HAS

2034
01:33:34,026 --> 01:33:35,527
EVER SEEN A PATHOLOGICAL

2035
01:33:35,527 --> 01:33:37,763
MUTATION IN 8 A OR 11A.

2036
01:33:37,763 --> 01:33:38,330
AM I RIGHT?

2037
01:33:38,330 --> 01:33:41,166
MITCH, DO YOU KNOW OF ANYBODY?

2038
01:33:41,166 --> 01:33:42,234
>> NO, NO.

2039
01:33:42,234 --> 01:33:42,567
>> NO?

2040
01:33:42,567 --> 01:33:46,238
SO WHAT WAS DONE?

2041
01:33:46,238 --> 01:33:51,510
SO WAS THAT INITIALLY A GROUP IN

2042
01:33:51,510 --> 01:33:56,415
JAPAN DID THE RAB ETA KNOCK OUT

2043
01:33:56,415 --> 01:33:57,249
AND THEY SAW LARGE LIES STUDIES

2044
01:33:57,249 --> 01:33:59,851
OF MULTIPLE ENDOCRINES AND A FEW

2045
01:33:59,851 --> 01:34:00,819
MICROVILLUS INCLUSIONS IN THOSE

2046
01:34:00,819 --> 01:34:01,053
MICE.

2047
01:34:01,053 --> 01:34:03,922
AND THE MICE DIDN'T REALLY HAVE

2048
01:34:03,922 --> 01:34:14,399
HUGE AMOUNTS OF DIARRHEA, N

2049
01:34:14,733 --> 01:34:16,068
AN GOUH DID KNOCK OUTS OF 11A

2050
01:34:16,068 --> 01:34:17,969
AND HE SAW A FEW MORE INCLUSIONS

2051
01:34:17,969 --> 01:34:21,039
AND GOT A LITTLE BIT WORSE

2052
01:34:21,039 --> 01:34:24,209
DIARRHEA THEN HE KNOCKED THEM

2053
01:34:24,209 --> 01:34:30,849
BOTH OUT TOGETHER AND HE GOT A

2054
01:34:30,849 --> 01:34:32,017
MORE PROMINENT EFFECT BUT

2055
01:34:32,017 --> 01:34:36,254
ACTUALLY WHAT THEY SAW WAS MORE

2056
01:34:36,254 --> 01:34:38,523
MISSED TRAFFICKING.

2057
01:34:38,523 --> 01:34:40,292
SO INSTEAD OF HAVING MICROVILLI

2058
01:34:40,292 --> 01:34:42,194
ON THE APICAL MEMBRANE, YOU

2059
01:34:42,194 --> 01:34:48,734
WOULD HAVE MICROVILLI ON THE

2060
01:34:48,734 --> 01:34:49,901
LATERAL MEMBRANE, AND ACTUALLY

2061
01:34:49,901 --> 01:34:53,071
YOU CAN SEE THAT IN SOME MICRO

2062
01:34:53,071 --> 01:34:54,339
VILLUS INCLUSIONS WITH THESE

2063
01:34:54,339 --> 01:34:57,008
KIDS, SOME OF THEM DO GET

2064
01:34:57,008 --> 01:34:57,676
LATERAL MICROVILLI.

2065
01:34:57,676 --> 01:35:01,046
BUT AS FAR AS I KNOW, NO 1 HAS

2066
01:35:01,046 --> 01:35:02,848
EVER SEEN AND IT MAY JUST BE

2067
01:35:02,848 --> 01:35:06,518
BECAUSE IF YOU CREW UP RAB 11A

2068
01:35:06,518 --> 01:35:08,053
AND RAB ETA, IT WILL PROBABLY

2069
01:35:08,053 --> 01:35:13,492
GIVE YOU A DEVELOPMENTAL LETHAL.

2070
01:35:13,492 --> 01:35:18,630
BOTH OF THOSE WERE DONE WITH

2071
01:35:18,630 --> 01:35:22,534
TARGETED ALLELES NOT GERM LINE.

2072
01:35:22,534 --> 01:35:26,271
SO, SO THAT MAY BE WHY WE DON'T

2073
01:35:26,271 --> 01:35:28,273
EVER SEE IT IN KIDS. 

2074
01:35:28,273 --> 01:35:32,277
>> THAT'S VERY
INTERESTING.

2075
01:35:32,277 --> 01:35:34,546
SO WE HAVE A QUESTION HERE,

2076
01:35:34,546 --> 01:35:37,415
SEVERAL WHERE PEOPLE ARE

2077
01:35:37,415 --> 01:35:39,751
INTERESTED IN HEARING FOR THE

2078
01:35:39,751 --> 01:35:45,357
FIRST TIME THAT THE NAVAJO HAVE

2079
01:35:45,357 --> 01:35:51,129
THIS SUBSTANTIAL NUMBER OF RARE

2080
01:35:51,129 --> 01:35:52,097
INHERITABLE DISEASES.

2081
01:35:52,097 --> 01:35:54,132
SO MITCHELL WOULD YOU ELABORATE

2082
01:35:54,132 --> 01:35:56,868
A LITTLE BIT ON SOME OF THE

2083
01:35:56,868 --> 01:35:59,571
OTHER DISEASES JUST SO FOLKS

2084
01:35:59,571 --> 01:36:03,074
HAVE A GLIMPSE OF THIS

2085
01:36:03,074 --> 01:36:05,043
EXTRAORDINARY DEVELOPMENT IN

2086
01:36:05,043 --> 01:36:06,778
THIS POPULATION?

2087
01:36:06,778 --> 01:36:07,512
>> YEAH.

2088
01:36:07,512 --> 01:36:08,446
THERE ARE SEVERAL.

2089
01:36:08,446 --> 01:36:14,252
ONE OF THEM IS A MITT O

2090
01:36:14,252 --> 01:36:15,787
CHONDRIAL DEPLETION DISORDER IN

2091
01:36:15,787 --> 01:36:16,188
PB17.

2092
01:36:16,188 --> 01:36:18,623
WE USED TO CALL NAVAJO

2093
01:36:18,623 --> 01:36:23,929
NEUROPATHY BUT NOW HAS EVOLVED

2094
01:36:23,929 --> 01:36:25,130
TO MPV17, DESCRIBED IN OTHER

2095
01:36:25,130 --> 01:36:27,866
POPULATIONS BUT THEY HAVE A

2096
01:36:27,866 --> 01:36:30,268
SPECIFIC MUTATION IN THE MVP 17

2097
01:36:30,268 --> 01:36:34,105
AND THERE'S ANOTHER CONDITION

2098
01:36:34,105 --> 01:36:37,142
CALLED OCCUE TAINIOUS ALBANNISM

2099
01:36:37,142 --> 01:36:39,177
TYPE 2 THAT INCREASE INCIDENCE

2100
01:36:39,177 --> 01:36:41,646
IN NAVAJO, THERE'S A FORM OF

2101
01:36:41,646 --> 01:36:43,281
BRAIN STEM DISGENESIS THAT USED

2102
01:36:43,281 --> 01:36:46,218
TO BE CALLED ABNORMAL GLUCOSE

2103
01:36:46,218 --> 01:36:47,719
TOLERANCA BASKIN BRAIN STEM

2104
01:36:47,719 --> 01:36:51,990
GENESIS BUT NOW REFERRED TO AS

2105
01:36:51,990 --> 01:36:52,924
BRAIN STEM DISGENESIS, AND THEY

2106
01:36:52,924 --> 01:36:56,361
HAVE A FORM OF SEVERE COMBINED

2107
01:36:56,361 --> 01:36:57,696
IMMUNO DEFICIENCY.

2108
01:36:57,696 --> 01:36:59,731
ALL OF WHICH IS CONSERVED

2109
01:36:59,731 --> 01:37:02,634
MUTATIONS, THE MUTATIONS ARE

2110
01:37:02,634 --> 01:37:04,102
KNOWN, AND EVERY PATIENT WITH

2111
01:37:04,102 --> 01:37:06,238
THAT CONDITION IN THE NAVAJO HAS

2112
01:37:06,238 --> 01:37:11,843
THE EXACT SAME MUTATION.

2113
01:37:11,843 --> 01:37:22,287
SO 1 OF THOSE IS THE GDIAC

2114
01:37:23,154 --> 01:37:25,757
HIGASHI, A LIES STUDIES OF

2115
01:37:25,757 --> 01:37:26,358
MULTIPLE ENDOCRINAL DISORDER?

2116
01:37:26,358 --> 01:37:27,959
>> YOU MAY BE CORRECT.

2117
01:37:27,959 --> 01:37:29,494
I MAY HAVE MISSED 1, I WAS

2118
01:37:29,494 --> 01:37:30,762
TRYING TO REMEMBER ALL THE 1S I

2119
01:37:30,762 --> 01:37:32,697
COULD THINK OF BUT THAT MAY BE

2120
01:37:32,697 --> 01:37:34,833
ANOTHER 1.

2121
01:37:34,833 --> 01:37:37,035
>> SO GIVEN THE RATHER

2122
01:37:37,035 --> 01:37:40,538
DISTINCTIVE HISTORY OF MANY OF

2123
01:37:40,538 --> 01:37:42,040
THE NATIVE AMERICAN TRIBES FROM

2124
01:37:42,040 --> 01:37:44,609
THE POINT OF THEIR ORIGINS OR

2125
01:37:44,609 --> 01:37:48,613
WHERE THEY FINALLY WOUND UP, DO

2126
01:37:48,613 --> 01:37:52,817
YOU FIND WITHIN OTHER SOMEWHAT

2127
01:37:52,817 --> 01:37:55,487
ISOLATED POPULATIONS OF NATIVE

2128
01:37:55,487 --> 01:37:56,521
AMERICANS, THESE DISORDERS

2129
01:37:56,521 --> 01:38:01,226
APPEARING OR IS THIS TRULY IN

2130
01:38:01,226 --> 01:38:05,196
THAT POPULATION UNIQUE FOR THE

2131
01:38:05,196 --> 01:38:05,430
NAVAJO?

2132
01:38:05,430 --> 01:38:08,033
>> YEAH, I THINK THE
NAVAJO SEEM

2133
01:38:08,033 --> 01:38:13,271
TO HAVE THE LARGEST NUMBER.

2134
01:38:13,271 --> 01:38:16,141
I'VE NOT RECENTLY READ BUT I

2135
01:38:16,141 --> 01:38:17,309
THINK IN THE ESKIMO POPULATION

2136
01:38:17,309 --> 01:38:18,376
THERE ARE SOME UNIQUE CONDITIONS

2137
01:38:18,376 --> 01:38:21,913
THAT OCCUR IN THE ESKIMO, SO I

2138
01:38:21,913 --> 01:38:25,050
THINK THERE ARE PROBABLY ARE THE

2139
01:38:25,050 --> 01:38:25,517
OTHER NATIVE AMERICAN

2140
01:38:25,517 --> 01:38:27,085
POPULATIONS THAT COULD HAVE COME

2141
01:38:27,085 --> 01:38:30,555
UNDER THE SAME CONSTRAINTS OF

2142
01:38:30,555 --> 01:38:34,826
ISOLATED POPULATIONS AND LIMITED

2143
01:38:34,826 --> 01:38:36,227
NUMBERS THAT RETAIN WHATEVER

2144
01:38:36,227 --> 01:38:37,896
GENE MUTATIONS WERE FOUND AT THE

2145
01:38:37,896 --> 01:38:40,231
TIME, AT THAT POINT IN TIME IN

2146
01:38:40,231 --> 01:38:43,768
THAT POPULATION THAT THEN WERE

2147
01:38:43,768 --> 01:38:46,304
CARRIED BUT BY FAR AND AWAY, I

2148
01:38:46,304 --> 01:38:48,473
THINK THE NAVAJO SEEM TO HAVE

2149
01:38:48,473 --> 01:38:50,141
THE MOST NUMBER AND I THINK IT'S

2150
01:38:50,141 --> 01:38:51,876
-- IT'S DUE TO ALL FACTORS THAT

2151
01:38:51,876 --> 01:38:54,412
I LAID OUT, IT WAS VERY SMALL

2152
01:38:54,412 --> 01:39:01,686
GENE POOL AND THEN RAPID GROWTH.

2153
01:39:01,686 --> 01:39:04,522
SO 

2154
01:39:04,522 --> 01:39:04,789
--

2155
01:39:04,789 --> 01:39:07,459
>> SO WE ALSO HAVE AN
INQUIRY OF

2156
01:39:07,459 --> 01:39:09,194
THE EFFECT OF ENVIRONMENTAL

2157
01:39:09,194 --> 01:39:14,032
FACTORS IN THE NAVAJO AS MAYBE

2158
01:39:14,032 --> 01:39:15,867
EXACERBATING OR AGGRAVATING OR

2159
01:39:15,867 --> 01:39:17,502
DOING SOMETHING, THINGS LIKE

2160
01:39:17,502 --> 01:39:21,239
EVERYTHING FROM HEAVY METALS TO

2161
01:39:21,239 --> 01:39:23,074
URANIUM AND COAL AND ALL THAT

2162
01:39:23,074 --> 01:39:24,709
SORT OF STUFF, THEY'VE REALLY

2163
01:39:24,709 --> 01:39:29,447
BEEN EXPOSED TO A GREAT VARIETY

2164
01:39:29,447 --> 01:39:31,483
OF INSULTS, SO IS THERE ANY

2165
01:39:31,483 --> 01:39:36,988
EVIDENT THAT THEY PLAY A ROLE IN

2166
01:39:36,988 --> 01:39:42,660
EITHER PHENOTYPE OR ANY FEATURE

2167
01:39:42,660 --> 01:39:43,028
OF THE DISEASE?

2168
01:39:43,028 --> 01:39:44,162
>> TO MY KNOWLEDGE THE
ANSWER TO

2169
01:39:44,162 --> 01:39:48,800
THAT IS NO, BUT PEOPLE HAVE

2170
01:39:48,800 --> 01:39:52,737
LOOKED EXTENSIVELY AT THAT AND

2171
01:39:52,737 --> 01:39:54,105
I'LL NOT REMEMBERING AND JIM

2172
01:39:54,105 --> 01:39:55,640
CORRECT ME IF I'M WRONG BUT I'VE

2173
01:39:55,640 --> 01:39:59,377
NOT READ ANY PAPERS THAT HAVE

2174
01:39:59,377 --> 01:40:00,945
SCIENTIFICALLY SUPPORTED THAT AS

2175
01:40:00,945 --> 01:40:02,080
A NOTION.

2176
01:40:02,080 --> 01:40:04,049
I COULD UNDERSTAND WHY THERE ARE

2177
01:40:04,049 --> 01:40:07,152
CONCERNS AND ACTUALLY IT IS A

2178
01:40:07,152 --> 01:40:08,486
VERY LEGITIMATE CONCERN, BUT SO

2179
01:40:08,486 --> 01:40:10,622
FAR, I'VE NOT SEEN ANYTHING TO

2180
01:40:10,622 --> 01:40:14,259
CONVINCE ME OF THAT, WHEREAS I

2181
01:40:14,259 --> 01:40:18,696
SUSPECT WHAT WE'RE DEALING WITH

2182
01:40:18,696 --> 01:40:20,198
WITH MICROVILLUS AND SOME OF THE

2183
01:40:20,198 --> 01:40:22,267
OTHERS WE KNOW, I THINK THOSE

2184
01:40:22,267 --> 01:40:23,701
WERE GENETIC MUTATIONS THAT WERE

2185
01:40:23,701 --> 01:40:25,370
RETAINED IN THE POPULATION AND

2186
01:40:25,370 --> 01:40:31,076
THEN WERE BROUGHT FORTH OVER

2187
01:40:31,076 --> 01:40:31,476
SEVERAL DECADES.

2188
01:40:31,476 --> 01:40:33,912
AND YOU KNOW IN THE 40S AND 50S

2189
01:40:33,912 --> 01:40:37,248
IF A KID WAS BONE WITH MVID ON

2190
01:40:37,248 --> 01:40:39,751
THE RESERVATION, THEY JUST DIED.

2191
01:40:39,751 --> 01:40:42,287
YOU WOULD NEVER HAVE KNOWN IN

2192
01:40:42,287 --> 01:40:43,988
THE FIRST FEW WEEKS OF LIFE AND

2193
01:40:43,988 --> 01:40:47,025
IT WOULD HAVE BEEN ATTRIBUTED TO

2194
01:40:47,025 --> 01:40:48,426
JUST NEONATAL DIARRHEA, JUST AS

2195
01:40:48,426 --> 01:40:53,832
YOU SUGGESTED IN THE THIRD

2196
01:40:53,832 --> 01:40:54,466
WORLD.

2197
01:40:54,466 --> 01:40:58,570
AND THESE PATIENTS PUT OUT SO

2198
01:40:58,570 --> 01:41:00,004
MUCH POO, WITHIN A WEEK THEY

2199
01:41:00,004 --> 01:41:00,772
WOULD BE GONE.

2200
01:41:00,772 --> 01:41:03,074
SOPHISTICATED I THINK THE SIGNAL

2201
01:41:03,074 --> 01:41:04,542
MAY HAVE BEEN THERE EARLIER BUT

2202
01:41:04,542 --> 01:41:08,913
IT WOULDN'T HAVE BEEN RECOGNIZED

2203
01:41:08,913 --> 01:41:11,249
AT LEAST FOR MID.

2204
01:41:11,249 --> 01:41:12,717
>> YOU COULD ARGUE THAT'S
TRUE

2205
01:41:12,717 --> 01:41:16,988
FOR A LARGE AMOUNT OF PEDIATRIC

2206
01:41:16,988 --> 01:41:17,388
DIAREALA DISEASE.

2207
01:41:17,388 --> 01:41:19,657
MANY KIDS BORN WITH THE

2208
01:41:19,657 --> 01:41:20,358
TERRIBLIBLE DISEASES, THE SYSTEM

2209
01:41:20,358 --> 01:41:22,760
WAS NOT SET UP TO RESPOND MOST

2210
01:41:22,760 --> 01:41:26,097
OF THESE KIDS DIED BECAUSE JUST,

2211
01:41:26,097 --> 01:41:27,966
YOU BE KNOW IT WASN'T RECOGNIZED

2212
01:41:27,966 --> 01:41:32,704
SOON ENOUGH AND YOU KNOW WHEN

2213
01:41:32,704 --> 01:41:34,572
YOU SEE HOW WHEN YOU SEE HOW

2214
01:41:34,572 --> 01:41:36,207
MUCH FLUID THEY WERE PUTTING

2215
01:41:36,207 --> 01:41:44,048
OUT, IT'S STAGGERING TO ME.

2216
01:41:44,048 --> 01:41:45,717
AND IN THIS, IT CAN BE MISSED SO

2217
01:41:45,717 --> 01:41:47,585
EASILY BECAUSE IT LOOKS LIKE

2218
01:41:47,585 --> 01:41:47,919
URINE.

2219
01:41:47,919 --> 01:41:50,355
YOU KNOW THE MOTHERS ARE SAYING,

2220
01:41:50,355 --> 01:41:52,590
IN FACT, WE ALWAYS ASK THE

2221
01:41:52,590 --> 01:41:54,893
PASHTS, ARE THEY HAVING GOOD

2222
01:41:54,893 --> 01:41:57,195
URINE OUTPUT WHEN IT'S A

2223
01:41:57,195 --> 01:41:59,164
DIARRHEA SITUATION AND NORMALLY

2224
01:41:59,164 --> 01:42:01,332
THE ANSWER IS NO, THEY HAVEN'T

2225
01:42:01,332 --> 01:42:03,635
PEED FOR DAYS, AND INSTEAD THEY

2226
01:42:03,635 --> 01:42:05,170
SAY NO, THEIR DIAPERS ARE

2227
01:42:05,170 --> 01:42:07,138
SOAKING WET AND IT WAS STOOL

2228
01:42:07,138 --> 01:42:17,682
THAT WAS SOAK, IT WASN'T URINE.

2229
01:42:21,019 --> 01:42:24,556
>> IT WAS INTERESTING THAT

2230
01:42:24,556 --> 01:42:28,092
JENNIFER WHO WAS IN DEMYSTIFYING

2231
01:42:28,092 --> 01:42:30,595
MEDICINE LAST YEAR, SHE STUDIES

2232
01:42:30,595 --> 01:42:32,564
SKID IN CHILDREN, WHICH IS

2233
01:42:32,564 --> 01:42:34,299
APPARENTLY VERY COMMON AMONGST

2234
01:42:34,299 --> 01:42:39,170
THE NAVAJO AND THEY ACTUALLY --

2235
01:42:39,170 --> 01:42:40,238
IT'S OBLIGATIONS BLIGATTORY SHE

2236
01:42:40,238 --> 01:42:42,340
TELLS ME THAT ALL NEWBORNS ARE

2237
01:42:42,340 --> 01:42:51,516
SCREENED FOR SKID ON DAY 1.

2238
01:42:51,516 --> 01:42:53,117
IF YOU SCREEN MICROVILLI

2239
01:42:53,117 --> 01:42:55,520
INCLUSION BY DISEASE, IT MAY BE

2240
01:42:55,520 --> 01:42:57,922
OF THE SAME FREQUENCY OF SKID IN

2241
01:42:57,922 --> 01:42:59,657
THAT GROUP BUT DO YOU THINK THAT

2242
01:42:59,657 --> 01:43:01,492
NEW BORN CHILDREN ON THE NAVAJO

2243
01:43:01,492 --> 01:43:02,160
SHOULD BE SCREEN OFFICE OF

2244
01:43:02,160 --> 01:43:04,696
DIVERSITY DAY 1 AND IF SO WOULD

2245
01:43:04,696 --> 01:43:10,335
THAT PROVIDE A HEAD START SO

2246
01:43:10,335 --> 01:43:12,503
PERSONALLY I BELIEVE THEY

2247
01:43:12,503 --> 01:43:14,038
SHOULD, I'M NOT ABLE TO MAKE

2248
01:43:14,038 --> 01:43:18,243
MUCH HEAD WAY WITH THAT.

2249
01:43:18,243 --> 01:43:19,344
I'VE SPOKEN WITH MY COLLEAGUES

2250
01:43:19,344 --> 01:43:20,945
ON THAT RESERVATION AND I DON'T

2251
01:43:20,945 --> 01:43:24,682
KNOW ALL THE BARRIERS TO IT, BUT

2252
01:43:24,682 --> 01:43:26,584
IT WOULD SEEM THAT EACH OF THESE

2253
01:43:26,584 --> 01:43:28,987
CONDITIONS HAD THE POTENTIAL OF

2254
01:43:28,987 --> 01:43:34,259
A NEW BORN SCREEN TO BE PICKED

2255
01:43:34,259 --> 01:43:34,759
UP VERY RAPIDLY.

2256
01:43:34,759 --> 01:43:37,395
AND SO, I WOULD STRONGLY

2257
01:43:37,395 --> 01:43:39,931
ADVOCATE FOR THAT, BUT MY VOICE

2258
01:43:39,931 --> 01:43:42,533
HASN'T CARRIED ENOUGH WEIGHT.

2259
01:43:42,533 --> 01:43:46,537
I JUST I FEEL LIKE DON

2260
01:43:46,537 --> 01:43:48,006
QUESTIONNAIRES HOATY.

2261
01:43:48,006 --> 01:43:50,275
>> MITCH, THE INCIDENCE OF
THE

2262
01:43:50,275 --> 01:43:52,110
NAVAJOS FOR MVID IS 1 IN 12,000

2263
01:43:52,110 --> 01:43:53,311
OR SOMETHING LIKE THAT, WHAT

2264
01:43:53,311 --> 01:43:54,812
ABOUT FOR SKID AND THESE OTHERS

2265
01:43:54,812 --> 01:43:57,248
1S ARE THEY ALSO AT THAT LEVEL?

2266
01:43:57,248 --> 01:43:58,349
>> THEY'RE IN THAT
BALLPARK,

2267
01:43:58,349 --> 01:44:02,553
JIM, I WOULD HAVE TO GO AND LOOK

2268
01:44:02,553 --> 01:44:04,822
IT UP, YOU ABOUT YOU KNOW WE

2269
01:44:04,822 --> 01:44:07,625
SCREEN FOR THING IN THE NEW BORN

2270
01:44:07,625 --> 01:44:09,927
SCREENS THAT ARE MUCH RARER.

2271
01:44:09,927 --> 01:44:12,897
>> THAT'S WHERE I'M GOING
WITH

2272
01:44:12,897 --> 01:44:13,097
THIS.

2273
01:44:13,097 --> 01:44:13,464
>> ABSOLUTELY.

2274
01:44:13,464 --> 01:44:15,867
>> IT SEEMS LIKE IN THE
NORTHEST

2275
01:44:15,867 --> 01:44:18,670
EVERYBODY GETS SCREENED FOR THAT

2276
01:44:18,670 --> 01:44:21,539
WILLSEMIA, YOU KNOW?

2277
01:44:21,539 --> 01:44:24,442
>> THE OTHER QUESTION THAT
COULD

2278
01:44:24,442 --> 01:44:29,414
BE ASKED IS LIKE IN TASTE DECKS

2279
01:44:29,414 --> 01:44:31,849
WE COULD SCREEN FOR PERSPECTIVE

2280
01:44:31,849 --> 01:44:35,453
PARENTS SO THAT THEY WERE AWARE

2281
01:44:35,453 --> 01:44:38,389
THAT THEY CARRY OUR GENETIC

2282
01:44:38,389 --> 01:44:39,891
ABNORMALITY BUT I DON'T KNOW

2283
01:44:39,891 --> 01:44:43,194
WHERE THAT SITS NOW, CULTURALLY,

2284
01:44:43,194 --> 01:44:47,765
BUT I CAN TELL YOU THAT EARLIER

2285
01:44:47,765 --> 01:44:53,037
IN MY INTERACTIONS, THAT WAS NOT

2286
01:44:53,037 --> 01:44:54,806
EVEN A POSSIBILITY THAT THESE

2287
01:44:54,806 --> 01:44:56,708
THINGS WERE ORDAINED FOR

2288
01:44:56,708 --> 01:44:59,310
DIFFERENT REASONS AND SO, BUT

2289
01:44:59,310 --> 01:45:02,780
YES, THE ABILITY IS THERE TO BE

2290
01:45:02,780 --> 01:45:05,850
-- ACTUALLY, ONCE HAD A

2291
01:45:05,850 --> 01:45:07,785
GRANDMOTHER WHO WAS PRETTY SAVVY

2292
01:45:07,785 --> 01:45:13,291
WHO HAD SEVERAL CHILDREN WITH

2293
01:45:13,291 --> 01:45:14,892
MPV17 AND THEN HAD HER FIRST

2294
01:45:14,892 --> 01:45:16,527
GRAND CHILD WITH IT.

2295
01:45:16,527 --> 01:45:19,731
AND SHE PULLED ME ASIDE AND SHE

2296
01:45:19,731 --> 01:45:21,866
SAID, YOU MEAN TO TELL ME WE

2297
01:45:21,866 --> 01:45:23,634
CAN'T SCREEN FOR THIS?

2298
01:45:23,634 --> 01:45:25,837
THAT THERE'S NO WAY TO PREVENT

2299
01:45:25,837 --> 01:45:26,471
THIS TRAGEDY?

2300
01:45:26,471 --> 01:45:28,373
AND I EXPLAINED TO HER WHAT THE

2301
01:45:28,373 --> 01:45:32,810
ISSUES WERE AND SHE JUST SAID

2302
01:45:32,810 --> 01:45:36,381
HMM, AND WALKED AWAY.

2303
01:45:36,381 --> 01:45:38,649
SHE WAS RIGHT, SHE WAS ON TO

2304
01:45:38,649 --> 01:45:44,389
SOMETHING BUT IT'S BIGGER THAN

2305
01:45:44,389 --> 01:45:45,823
THAT, BUT IT WOULD HAVE TO BE

2306
01:45:45,823 --> 01:45:47,558
MORE OF A CULTURAL ACCEPTANCE

2307
01:45:47,558 --> 01:45:51,429
BUT YES, THE  ABILITY IS THERE.

2308
01:45:51,429 --> 01:45:52,063
>> HAVING DONE SOME WORK

2309
01:45:52,063 --> 01:45:55,099
OURSELVES WITH THE WESTERN

2310
01:45:55,099 --> 01:45:58,469
NAVAJO, I HAVE SOME APPRECIATION

2311
01:45:58,469 --> 01:46:03,307
OF THEIR CULTURE AND THEIR

2312
01:46:03,307 --> 01:46:05,209
REQUIREMENTS, IT'S NOT LIKE

2313
01:46:05,209 --> 01:46:06,844
DOING RESEARCH IN ANY PATIENT

2314
01:46:06,844 --> 01:46:08,346
POPULATION I WAS EVER INVOLVED

2315
01:46:08,346 --> 01:46:10,415
IN BUT MAYBE MITCH WOULD YOU

2316
01:46:10,415 --> 01:46:17,722
ELABORATE A LITTLE BIT MORE ON

2317
01:46:17,722 --> 01:46:18,990
WHAT ARE THE DIFFERENCES IN

2318
01:46:18,990 --> 01:46:21,192
DOING THIS TYPE OF RESEARCH IN

2319
01:46:21,192 --> 01:46:22,693
THE NAVAJO COMPARED TO THE

2320
01:46:22,693 --> 01:46:23,628
GENTLEMEN POPULATION, WHAT SORT

2321
01:46:23,628 --> 01:46:29,333
OF ISSUES ON DO YOU CONFRONT?

2322
01:46:29,333 --> 01:46:36,674
>> WELL WHEN WE FIRST
STARTED

2323
01:46:36,674 --> 01:46:40,678
DOING THIS WORK WE CONTACTED THE

2324
01:46:40,678 --> 01:46:42,947
NAVAJO TRIBE FROM THE IRB, AND

2325
01:46:42,947 --> 01:46:44,882
THEY ASSURED ME THAT IF I WANTED

2326
01:46:44,882 --> 01:46:46,984
TO RECRUIT FROM THE RESERVATION,

2327
01:46:46,984 --> 01:46:48,286
THE IRB WOULD NOT REVIEW THE

2328
01:46:48,286 --> 01:46:49,821
STUDY BECAUSE THEY DID NOT

2329
01:46:49,821 --> 01:46:52,957
APPROVE OF ANY GENETIC RESEARCH

2330
01:46:52,957 --> 01:46:54,258
IN THE NAVAJO SOPHISTICATED WHAT

2331
01:46:54,258 --> 01:46:55,426
WE ESTABLISHED WAS THAT OF

2332
01:46:55,426 --> 01:46:56,861
COURSE WE WEREN'T RECRUITING

2333
01:46:56,861 --> 01:46:58,262
FROM THE RESERVATION, THESE WERE

2334
01:46:58,262 --> 01:47:02,400
PATIENTS THAT CAME TO US BECAUSE

2335
01:47:02,400 --> 01:47:03,935
OF DIRE CONSEQUENCES AND OWZ OF

2336
01:47:03,935 --> 01:47:09,307
THE RESERVATION, WE WERE ABLE TO

2337
01:47:09,307 --> 01:47:10,741
GET CONSENT THROUGH OUR IRB, BUT

2338
01:47:10,741 --> 01:47:14,612
WHAT I WILL SAY, IS THAT EVERY

2339
01:47:14,612 --> 01:47:17,148
PUBLICATION WE'VE EVER DONE I

2340
01:47:17,148 --> 01:47:20,284
SENT TO THE NAVAJO IRB AND TO

2341
01:47:20,284 --> 01:47:22,520
THE NAVAJO TRIBE BECAUSE I

2342
01:47:22,520 --> 01:47:25,690
WANTED THEM TO BE REASSURED THAT

2343
01:47:25,690 --> 01:47:27,825
NOTHING IN THE PUBLICATIONS CAST

2344
01:47:27,825 --> 01:47:29,427
ANY NEGATIVE LIGHT OR VIEWS

2345
01:47:29,427 --> 01:47:34,165
AGAINST THE NAVAJO AND I THINK

2346
01:47:34,165 --> 01:47:37,168
UNDERSTANDABLY SO, THERE'S BEEN

2347
01:47:37,168 --> 01:47:39,070
SOME MISCUES IN RESEARCH AND

2348
01:47:39,070 --> 01:47:40,738
NATIVE AMERICANS THE 1 THAT

2349
01:47:40,738 --> 01:47:44,442
COMES IT MIND IS RESEARCH THAT

2350
01:47:44,442 --> 01:47:48,813
WAS DONE ON THE HAVI SUP A I

2351
01:47:48,813 --> 01:47:50,414
INDIANS AND THEY WERE STUDYING

2352
01:47:50,414 --> 01:47:51,849
DIABETES AND THEY ENDED UP

2353
01:47:51,849 --> 01:47:53,818
SHARING SOME OF THE SAMPLES THEY

2354
01:47:53,818 --> 01:47:54,986
HAD RETRIEVED FOR A DIFFERENT

2355
01:47:54,986 --> 01:47:58,322
LINE OF RESEARCH WITHOUT

2356
01:47:58,322 --> 01:47:59,991
INFORMING THE HAVI SUP A I AND

2357
01:47:59,991 --> 01:48:03,261
THAT PUBLICATION CAME OUT AND

2358
01:48:03,261 --> 01:48:05,663
BOY THAT WAS NOT THE RIGHT THING

2359
01:48:05,663 --> 01:48:07,698
TO DO.

2360
01:48:07,698 --> 01:48:08,866
SO THERE'S TREMENDOUS

2361
01:48:08,866 --> 01:48:10,301
SENSITIVITY AND MISTRUST, AND I

2362
01:48:10,301 --> 01:48:11,636
GET IT.

2363
01:48:11,636 --> 01:48:12,103
I GET IT.

2364
01:48:12,103 --> 01:48:15,339
I THINK THE BETTER WAY TO GO IS

2365
01:48:15,339 --> 01:48:19,710
TO BE VERY UPFRONT, OPEN AND

2366
01:48:19,710 --> 01:48:22,713
HONEST AND IF WE HAVE TO DO IT

2367
01:48:22,713 --> 01:48:24,482
ON THE RESERVATION, WE PROBABLY

2368
01:48:24,482 --> 01:48:26,250
WOULDN'T HAVE BEEN ABLE TO DO

2369
01:48:26,250 --> 01:48:26,584
THE RESEARCH.

2370
01:48:26,584 --> 01:48:29,186
>> WAS THERE ANY DIFFICULT

2371
01:48:29,186 --> 01:48:31,622
NEUROECTODERMAL NAVAJO ACCEPTING

2372
01:48:31,622 --> 01:48:35,293
SURGERIES SUCH AS MASSIVE ORGAN

2373
01:48:35,293 --> 01:48:38,329
TRANSPLANT OR EVEN SINGLE ORGAN

2374
01:48:38,329 --> 01:48:40,331
TRANSPLANT?

2375
01:48:40,331 --> 01:48:41,032
>> NO, BRILLIANT QUESTION.

2376
01:48:41,032 --> 01:48:45,937
THAT SEEMS TO HAVE MODIFIED OVER

2377
01:48:45,937 --> 01:48:46,137
TIME.

2378
01:48:46,137 --> 01:48:47,905
ONE OF THE ISSUES WE RAN INTO

2379
01:48:47,905 --> 01:48:49,473
WITH WE FIRST OFFERED A

2380
01:48:49,473 --> 01:48:51,075
TRANSPLANT IS THEY WANTED YOU

2381
01:48:51,075 --> 01:48:53,311
KNOW IF IT COULD BE DONE FROM

2382
01:48:53,311 --> 01:48:56,314
THE NAVAJO, THEY WANTED ANOTHER

2383
01:48:56,314 --> 01:49:00,151
NAVAJO TO DONATE AND YOU CAN

2384
01:49:00,151 --> 01:49:04,722
IMAGINE THE IMPOSSIBILITIES OF

2385
01:49:04,722 --> 01:49:06,357
THAT PLAYING OUT AND SO THAT DID

2386
01:49:06,357 --> 01:49:08,225
HOLD UP, BUT NOW DAYS IT SEEMS

2387
01:49:08,225 --> 01:49:09,827
THEY'VE BEEN MORE ACCEPTING OF

2388
01:49:09,827 --> 01:49:13,197
THIS AS A THERAPEUTIC MEASURE

2389
01:49:13,197 --> 01:49:16,167
AND HAVE NOT STOOD IN THE WAY

2390
01:49:16,167 --> 01:49:18,002
BECAUSE WE'VE HAD SEVERAL THAT

2391
01:49:18,002 --> 01:49:19,804
WERE TRANSPLANTED BUT THAT

2392
01:49:19,804 --> 01:49:21,505
WASN'T -- EARLY ON THAT WAS

2393
01:49:21,505 --> 01:49:23,474
DEFINITELY A BARRIER.

2394
01:49:23,474 --> 01:49:25,776
>> IT SOUNDS VERY SIMILAR
TO

2395
01:49:25,776 --> 01:49:29,347
WHAT JENNIFER TELLS ME ABOUT THE

2396
01:49:29,347 --> 01:49:31,816
SKID ISSUE BUT EVENTUALLY THEY

2397
01:49:31,816 --> 01:49:34,418
OVERCAME IT, AND FAMILIES WOULD

2398
01:49:34,418 --> 01:49:36,554
BE TRANSPORTED FROM THEIR

2399
01:49:36,554 --> 01:49:45,396
RESERVATION TO SAN FRANCISCO

2400
01:49:45,396 --> 01:49:46,330
WHERE THE TRANSPLANTATION WAS

2401
01:49:46,330 --> 01:49:47,999
WAS CARRIED OUT AND THE OUTCOME

2402
01:49:47,999 --> 01:49:54,572
HAS REALLY BEEN SUCCESSFUL AND

2403
01:49:54,572 --> 01:49:55,773
IT WAS MY UNDERSTANDING IS

2404
01:49:55,773 --> 01:49:57,341
BECAUSE OF THE EXPERIENCE WITH

2405
01:49:57,341 --> 01:49:59,744
THE NAVAJO, IT BECAME POSSIBLE

2406
01:49:59,744 --> 01:50:03,381
TO INTRODUCE IN THE STATE OF

2407
01:50:03,381 --> 01:50:08,152
CALIFORNIA, FOR THE WHOLE STATE

2408
01:50:08,152 --> 01:50:08,986
PRENATAL SCREENING FOR SKID

2409
01:50:08,986 --> 01:50:10,821
WHICH WAS THERE BEFORE BUT WAS

2410
01:50:10,821 --> 01:50:12,490
SORT OF, YOU KNOW DISAPPEARED,

2411
01:50:12,490 --> 01:50:16,594
NOBODY COULD DO MUCH ABOUT IT.

2412
01:50:16,594 --> 01:50:17,495
>> ABSOLUTELY.

2413
01:50:17,495 --> 01:50:20,131
AND IT AFFECTED ARIZONA AS WELL,

2414
01:50:20,131 --> 01:50:20,965
THANK GOODNESS.

2415
01:50:20,965 --> 01:50:21,232
>> YEAH.

2416
01:50:21,232 --> 01:50:24,268
>> WE'VE DONE A NUMBER OF
MARROW

2417
01:50:24,268 --> 01:50:25,870
TRANSPLANTS AT PHOENIX CHILDRENS

2418
01:50:25,870 --> 01:50:32,610
ON THIS POPULATION AS WELL FOR

2419
01:50:32,610 --> 01:50:32,810
SKIDS.

2420
01:50:32,810 --> 01:50:34,311
>> SO JIM IF YOU HAD 2 OR
3

2421
01:50:34,311 --> 01:50:38,182
QUESTIONS THAT YOU WOULD REALLY

2422
01:50:38,182 --> 01:50:40,518
LOVE TO SEE THE ANSWER TO

2423
01:50:40,518 --> 01:50:42,586
BEFORE, IF THE DAY EVER COMES

2424
01:50:42,586 --> 01:50:47,625
THAT YOU PUT YOUR SABER AWAY,

2425
01:50:47,625 --> 01:50:49,660
YOU'RE MY INSPIRATION, WIN, I'M

2426
01:50:49,660 --> 01:50:55,066
NEVER GOING TO RETIRE.

2427
01:50:55,066 --> 01:50:55,433
[LAUGHTER]

2428
01:50:55,433 --> 01:50:57,735
>> I TELL YOU WHAT, AGAIN,

2429
01:50:57,735 --> 01:50:59,603
YOU'RE DEALING WITH RARE

2430
01:50:59,603 --> 01:51:01,338
DISEASES AND NOW, WE'RE FACING

2431
01:51:01,338 --> 01:51:07,411
HOW DO WE TAKE THIS SO WE HAVE

2432
01:51:07,411 --> 01:51:10,514
THIS LP A 5 RECEPTOR AGONIST,

2433
01:51:10,514 --> 01:51:16,620
IT'S A DAUNTING THING TO GET A

2434
01:51:16,620 --> 01:51:17,688
DRUG BROUGHT TO MARKET

2435
01:51:17,688 --> 01:51:20,725
ESPECIALLY IN THE RARE DISEASE

2436
01:51:20,725 --> 01:51:21,959
SPACE.

2437
01:51:21,959 --> 01:51:25,596
WHAT WE'RE FACING IS WE NEED

2438
01:51:25,596 --> 01:51:28,499
MONEY FOR TOXICITY TESTING, DOZE

2439
01:51:28,499 --> 01:51:30,534
FINDINGS, ALL THIS STUFF, AND OF

2440
01:51:30,534 --> 01:51:34,238
COURSE, WE'RE GOING INTO VERY

2441
01:51:34,238 --> 01:51:37,341
VULNERABLE, VERY SICK CHILDREN.

2442
01:51:37,341 --> 01:51:39,443
ALBEIT THEY MIGHT BE STABILIZED

2443
01:51:39,443 --> 01:51:42,513
ON TPN, BUT THAT'S 1 THING I

2444
01:51:42,513 --> 01:51:47,918
WOULD LIKE TO SEE, AND YOU KNOW,

2445
01:51:47,918 --> 01:51:55,259
IT'S NOT -- WE DON'T HAVE A GOOD

2446
01:51:55,259 --> 01:51:58,496
SUPPORT SYSTEM THROUGH

2447
01:51:58,496 --> 01:51:59,063
PHARMACEUTICAL COMPANIES OR

2448
01:51:59,063 --> 01:52:00,831
ELSEWHERE TO BRING THESE RARE

2449
01:52:00,831 --> 01:52:01,632
DISEASE TREATMENTS FORWARD VERY

2450
01:52:01,632 --> 01:52:03,534
MUCH AND THAT'S UNFORTUNATE, SO

2451
01:52:03,534 --> 01:52:08,105
I WOULD REALLY LOVE TO SEE AN

2452
01:52:08,105 --> 01:52:08,906
OPTIMIZED PATHWAY.

2453
01:52:08,906 --> 01:52:11,041
I ALSO -- YOU KNOW THE BIG

2454
01:52:11,041 --> 01:52:12,343
QUESTION I STILL -- I HAVE TO

2455
01:52:12,343 --> 01:52:20,284
FIGURE OUT BECAUSE IT DRIVES ME

2456
01:52:20,284 --> 01:52:22,920
CRAZY IS THAT P-FIX, 6, AT HEART

2457
01:52:22,920 --> 01:52:24,121
I'M STILL A CHEMIST SO I STILL

2458
01:52:24,121 --> 01:52:25,990
WANT TO KNOW WHAT IS THE PROTEIN

2459
01:52:25,990 --> 01:52:28,058
BASIS FOR THESE MUTATIONS HAVING

2460
01:52:28,058 --> 01:52:30,361
SUCH A SPECIFIC AND DIFFERENT

2461
01:52:30,361 --> 01:52:32,530
YOU KNOW IMPACT, SO, I WOULD

2462
01:52:32,530 --> 01:52:37,268
REALLY LOVE TO FIGURE THAT 1 OUT

2463
01:52:37,268 --> 01:52:37,635
SOMEHOW.

2464
01:52:37,635 --> 01:52:39,503
AND WE'RE DOING BY O ID WORK TO

2465
01:52:39,503 --> 01:52:44,375
TRY TO TAKE A  LOOK AT IT, BUT

2466
01:52:44,375 --> 01:52:54,819
YOU KNOW THAT'S OUT THERE.

2467
01:52:55,920 --> 01:52:56,520
>> MICROVILLI INCLUSION
BODY

2468
01:52:56,520 --> 01:53:00,491
DISEASE SOMETIMES I GUESS VERY

2469
01:53:00,491 --> 01:53:05,763
OFTEN APPEARS SPORADICALLY, YOU

2470
01:53:05,763 --> 01:53:08,599
KNOW, 1 CHILD, OR YOU KNOW, SO

2471
01:53:08,599 --> 01:53:10,401
IT'S NOT NECESSARILY THE

2472
01:53:10,401 --> 01:53:12,002
BEAUTIFUL FAMILY TREE WITH

2473
01:53:12,002 --> 01:53:13,771
EVERYBODY AND YOU CAN SORT OF

2474
01:53:13,771 --> 01:53:15,406
FIGURE OUT SOMETHING ABOUT THE

2475
01:53:15,406 --> 01:53:17,374
-- ABOUT THE GENETICS.

2476
01:53:17,374 --> 01:53:20,010
SO THAT MEANS WITHIN THE

2477
01:53:20,010 --> 01:53:24,048
PEDIATRIC POPULATION AROUND THE

2478
01:53:24,048 --> 01:53:29,086
WORLD, MOST PEDIATRICIANS

2479
01:53:29,086 --> 01:53:30,287
RECOGNIZE THIS ENTITY, I DON'T

2480
01:53:30,287 --> 01:53:34,491
THINK SO, I'M THE SON OF A

2481
01:53:34,491 --> 01:53:35,893
CANONICLE PEDIATRICIAN, MY

2482
01:53:35,893 --> 01:53:37,394
FATHER WAS THE FIRST

2483
01:53:37,394 --> 01:53:38,028
PEDIATRICIANOT CONNECTICUT SHORE

2484
01:53:38,028 --> 01:53:40,598
LINE AND I DON'T REMEMBER HIM

2485
01:53:40,598 --> 01:53:42,032
TELLING ME ANY OF THIS AND HE

2486
01:53:42,032 --> 01:53:44,535
WAS HEAD OF THE NEW BORN NURSERY

2487
01:53:44,535 --> 01:53:46,971
FOR 10 YEARS AFTER HE RETIRED,

2488
01:53:46,971 --> 01:53:48,272
IT I DON'T REMEMBER --

2489
01:53:48,272 --> 01:53:50,441
>> I REMEMBER WHEN WE WERE
IN

2490
01:53:50,441 --> 01:53:52,509
TRAINING WE USED TO CALL THESE

2491
01:53:52,509 --> 01:53:53,477
CONDITIONS, WE DIDN'T RECOGNIZE

2492
01:53:53,477 --> 01:53:56,614
THERE WERE SO MANY, INTRACTABLE

2493
01:53:56,614 --> 01:53:59,450
DIARRHEA OF INFANCY AND PHIL

2494
01:53:59,450 --> 01:54:02,319
SUNSHINE WROTE 1 OF THE FIRST

2495
01:54:02,319 --> 01:54:03,053
PAPERS ON THAT.

2496
01:54:03,053 --> 01:54:04,855
HE JUST RECEIPTLY PASSED AWAY ON

2497
01:54:04,855 --> 01:54:09,126
THAT UNFORTUNATELY BUT IT WAS SO

2498
01:54:09,126 --> 01:54:13,163
VAGUE AND UNKNOWN THEN, THAT

2499
01:54:13,163 --> 01:54:15,132
IT'S BEEN JIM, IN MY LIFETIME

2500
01:54:15,132 --> 01:54:17,468
THAT WE'VE WATCHED THEM IDENTIFY

2501
01:54:17,468 --> 01:54:21,338
1 AFTER ANOTHER OF THESE

2502
01:54:21,338 --> 01:54:22,740
CONDITIONS TO A POINT WHERE WE

2503
01:54:22,740 --> 01:54:24,108
CAN MANAGE THEM.

2504
01:54:24,108 --> 01:54:27,077
AS A PGI WHERE WE HAVE A BROAD

2505
01:54:27,077 --> 01:54:28,145
REFERRAL POPULATION, OVER THE

2506
01:54:28,145 --> 01:54:31,348
YEARS I'VE CARED FOR ALMOST ALL

2507
01:54:31,348 --> 01:54:37,254
OF THEM BUT IT'S USUALLY 1

2508
01:54:37,254 --> 01:54:37,721
PATIENT, MAYBE 2.

2509
01:54:37,721 --> 01:54:42,826
IF I WAS IN BOSTON IF THEY HAD 1

2510
01:54:42,826 --> 01:54:44,128
MVID EVERYONE HEARD ABOUT IT AND

2511
01:54:44,128 --> 01:54:45,596
WENT TO SEE IT BECAUSE YOU

2512
01:54:45,596 --> 01:54:47,264
WOULDN'T SEE THEM BUT ONCE EVERY

2513
01:54:47,264 --> 01:54:51,135
NOW AND THEN, SO IT WAS, THE

2514
01:54:51,135 --> 01:54:52,436
PATHOLOGIST FROM TORONTO THAT

2515
01:54:52,436 --> 01:54:55,539
CALLED ME, WHEN I SENT HIM THE

2516
01:54:55,539 --> 01:54:57,241
FOURTH BIOPSY SPECIMEN OF A

2517
01:54:57,241 --> 01:54:58,275
FOURTH DIFFERENT PATIENT AND HE

2518
01:54:58,275 --> 01:55:01,045
SAID WHAT IS GOING ON?

2519
01:55:01,045 --> 01:55:03,881
HE SAID I'VE NEVER SEEN SO MANY

2520
01:55:03,881 --> 01:55:04,882
PATIENTS FROM 1 CENTER?

2521
01:55:04,882 --> 01:55:12,723
I SAID YEAH, WE'RE GOING TO

2522
01:55:12,723 --> 01:55:13,657
REPORT THIS, YEAH, I'VE NEVER

2523
01:55:13,657 --> 01:55:16,827
SEEN SO MANY BUT I CAN TELL YOU

2524
01:55:16,827 --> 01:55:17,995
THAT MOST PLACES IT'S

2525
01:55:17,995 --> 01:55:20,064
INDIVIDUAL, MAYBE 1 PATIENT OR 2

2526
01:55:20,064 --> 01:55:21,131
PATIENT, JIM HOW MANY AT

2527
01:55:21,131 --> 01:55:25,336
VANDERBILT DO YOU SEE AND HOW

2528
01:55:25,336 --> 01:55:25,669
OFTEN?

2529
01:55:25,669 --> 01:55:29,340
>> YOU KNOW KIDS WITH
THESE

2530
01:55:29,340 --> 01:55:30,507
GENETIC DIARRHEAS PROBABLY HERE

2531
01:55:30,507 --> 01:55:33,877
2-3 MAX A YEAR.

2532
01:55:33,877 --> 01:55:35,646
AND I THINK THE BIGGEST CHANGE

2533
01:55:35,646 --> 01:55:38,082
IS REALLY GETTING PEOPLE USED --

2534
01:55:38,082 --> 01:55:40,784
NOT -- TO NOT FEAR THE GENETIC

2535
01:55:40,784 --> 01:55:41,018
DATA.

2536
01:55:41,018 --> 01:55:43,587
SO IT'S REALLY THE PHYSICIANS I

2537
01:55:43,587 --> 01:55:45,990
THINK ABOUT 10 YEARS AGO,

2538
01:55:45,990 --> 01:55:47,257
ESPECIALLY WERE FEARING GENETIC

2539
01:55:47,257 --> 01:55:47,491
DATA.

2540
01:55:47,491 --> 01:55:51,195
THEY SAID WHERE DON'T YOU GET

2541
01:55:51,195 --> 01:55:53,030
GENETIC ANALYSIS, WELL, THE

2542
01:55:53,030 --> 01:55:53,630
INSURANCE COMPANIES WON'T PAY

2543
01:55:53,630 --> 01:55:55,933
FOR IT AND I DON'T KNOW HOW TO

2544
01:55:55,933 --> 01:55:57,001
UNDERSTAND IT SO THEY JUST

2545
01:55:57,001 --> 01:55:59,236
WOULDN'T GET IT SO I GUESS IT

2546
01:55:59,236 --> 01:56:05,442
WAS ABOUT 12 YEARS AGO,  KID WAS

2547
01:56:05,442 --> 01:56:08,445
IN HERE WHO HAD INTRACTABLE

2548
01:56:08,445 --> 01:56:09,513
DIARRHEA, FAILURE TO DRIVE, AND

2549
01:56:09,513 --> 01:56:11,048
THEY WERE DOING ALL KINDS OF

2550
01:56:11,048 --> 01:56:13,650
STUFF AND I SAID WHY DON'T WE

2551
01:56:13,650 --> 01:56:14,952
JUST SEQUENCE THEM, THEY SAID

2552
01:56:14,952 --> 01:56:17,354
HOW DO WE GET THE MONEY.

2553
01:56:17,354 --> 01:56:18,922
SO I THROUGH $6000 INTO THE TILL

2554
01:56:18,922 --> 01:56:21,291
TO SEQUENCE HIM AND HIS MOTHER,

2555
01:56:21,291 --> 01:56:27,398
AND THAT WAS THE SECOND CASE OF

2556
01:56:27,398 --> 01:56:28,499
DGAT 1 MUTATION.

2557
01:56:28,499 --> 01:56:29,700
AND THAT LITTLE KID ALL YOU HAVE

2558
01:56:29,700 --> 01:56:32,569
TO DO IS STOP HIM FROM EATING

2559
01:56:32,569 --> 01:56:32,903
FAT.

2560
01:56:32,903 --> 01:56:35,439
HE'S ALIVE AND HE'S A BRUISER

2561
01:56:35,439 --> 01:56:35,873
NOW.

2562
01:56:35,873 --> 01:56:39,009
HE'S GOT THE MOST AWFUL DIET

2563
01:56:39,009 --> 01:56:40,677
BECAUSE HE CAN'T EAT FAT BUT WE

2564
01:56:40,677 --> 01:56:45,616
JUST FIGURED OUT THAT THESE KIDS

2565
01:56:45,616 --> 01:56:48,786
CAN EAT YOU KNOW CERTAIN LIPIDS

2566
01:56:48,786 --> 01:56:50,521
LIKE PALMAITATE, THEY CAN EAT

2567
01:56:50,521 --> 01:56:51,722
PALMAITATE AND THEY WON'T GET

2568
01:56:51,722 --> 01:56:53,791
SICK, SO THAT'S GOING TO HELP

2569
01:56:53,791 --> 01:56:55,993
HIS DIET, BUT THE KEY IS TO GET

2570
01:56:55,993 --> 01:56:57,861
PEOPLE TO ACTUALLY NOT FEAR

2571
01:56:57,861 --> 01:57:00,931
DOING THE GENETIC ANALYSIS.

2572
01:57:00,931 --> 01:57:03,600
AND MY OWN FEELING IS, YOU DON'T

2573
01:57:03,600 --> 01:57:04,635
DO THESE EXPENSIVE PANELS THAT

2574
01:57:04,635 --> 01:57:07,604
COMPANIES ARE TRYING TO SELL, MY

2575
01:57:07,604 --> 01:57:10,174
FEELING IS, IF THE KID'S GOT A

2576
01:57:10,174 --> 01:57:12,810
PROBLEM, YOU DO WHOLE EXOHM

2577
01:57:12,810 --> 01:57:14,445
SEQUENCING, IT'S CHEAPER THAN

2578
01:57:14,445 --> 01:57:16,080
THE PANELS IN THIS DAY AND AGE,

2579
01:57:16,080 --> 01:57:18,816
IT'S HARD TO BELIEVE, BUT YOU

2580
01:57:18,816 --> 01:57:22,886
CAN DO A WHOLE EXOHM SEQUENCING

2581
01:57:22,886 --> 01:57:26,290
FOR UNDER $300.

2582
01:57:26,290 --> 01:57:34,264
IT'S AMAZING.

2583
01:57:34,264 --> 01:57:37,201
>> SO I GUESS, HAS THIS
VIEW

2584
01:57:37,201 --> 01:57:38,836
THAT YOU'VE JUST PRESENTED BEEN

2585
01:57:38,836 --> 01:57:44,007
A SORT OF PRETTY WIDELY ACCEPTED

2586
01:57:44,007 --> 01:57:50,280
WITHIN GENERAL PEDIATRICS OR

2587
01:57:50,280 --> 01:57:51,181
PEDIATRIC GASTROINTROLOGYISTS?

2588
01:57:51,181 --> 01:57:54,651
>> I HAVE TO SAY NO
BECAUSE OUR

2589
01:57:54,651 --> 01:57:56,620
CHIEF OF PH CI IS TRYING TO PUSH

2590
01:57:56,620 --> 01:57:57,888
PEOPLE TO BED THIS.

2591
01:57:57,888 --> 01:57:59,189
SO THERE IS STILL FEAR OUT

2592
01:57:59,189 --> 01:57:59,389
THERE.

2593
01:57:59,389 --> 01:58:00,524
IS THAT TRUE MITCH?

2594
01:58:00,524 --> 01:58:02,593
>> YEAH, I THINK SO.

2595
01:58:02,593 --> 01:58:04,194
I THINK SO.

2596
01:58:04,194 --> 01:58:06,029
IN PSGI, I THINK WE'VE COME

2597
01:58:06,029 --> 01:58:06,597
AROUND.

2598
01:58:06,597 --> 01:58:08,565
I THINK THE DATA IS SO

2599
01:58:08,565 --> 01:58:10,968
CONVINCING THAT WE'RE PUSHING

2600
01:58:10,968 --> 01:58:14,671
FORWARD AND WE NOW HAVE

2601
01:58:14,671 --> 01:58:17,174
INTERESTING AVENUES THAT HAVE

2602
01:58:17,174 --> 01:58:18,775
COME UP ABOUT, WHERE FOR PRETTY

2603
01:58:18,775 --> 01:58:21,478
CHEAP WE CAN GET THESE SCREENS

2604
01:58:21,478 --> 01:58:21,678
DONE.

2605
01:58:21,678 --> 01:58:26,550
FOR INSTANCE WE CAN DO THE MPB17

2606
01:58:26,550 --> 01:58:28,185
GENETIC SCREEN THROUGH A

2607
01:58:28,185 --> 01:58:30,888
SCREENING THING THAT'S ON

2608
01:58:30,888 --> 01:58:33,090
ANYONATAL COLO STASIS PANEL THAT

2609
01:58:33,090 --> 01:58:36,193
SCREENS FOR LIKE 40 THINGS, 1 OF

2610
01:58:36,193 --> 01:58:37,661
WHICH IS MPV 17, AND SO WE'VE

2611
01:58:37,661 --> 01:58:40,030
BEEN ABLE TO MAKE DIAGNOSIS AND

2612
01:58:40,030 --> 01:58:45,869
IT'S LIKE 300 OR $350.

2613
01:58:45,869 --> 01:58:46,837
>> YEAH, YEAH.

2614
01:58:46,837 --> 01:58:47,538
>> BRAVE NEW WORLD.

2615
01:58:47,538 --> 01:58:48,372
>> IT IS!

2616
01:58:48,372 --> 01:58:48,672
>> IT IS.

2617
01:58:48,672 --> 01:58:52,843
>> IT IS A BRAVE NEW
WORLD.

2618
01:58:52,843 --> 01:58:54,912
[LAUGHTER]

2619
01:58:54,912 --> 01:58:57,114
>> SO, HAVE PEOPLE LIKE --
YOU

2620
01:58:57,114 --> 01:59:00,417
KNOW THE WORK OF DAVID RIKE AT

2621
01:59:00,417 --> 01:59:03,654
HARVARD, I THINK IT'S DAVID, HIS

2622
01:59:03,654 --> 01:59:06,790
BROTHER'S AT NIH, THEY DO THESE

2623
01:59:06,790 --> 01:59:10,928
REALLY EXTRAORDINARY STUDIES

2624
01:59:10,928 --> 01:59:15,165
BASED UPON EXTENSIVE GENETICS OF

2625
01:59:15,165 --> 01:59:17,134
THE ORIGIN OF HOMOSAIPIANS AND

2626
01:59:17,134 --> 01:59:18,335
HERE'S THE FELLOW WHO DISCOVERED

2627
01:59:18,335 --> 01:59:26,643
THAT AT 4% OF OUR GENES ARE

2628
01:59:26,643 --> 01:59:28,145
NEANDERTHAL SO THEY STUDY THESE

2629
01:59:28,145 --> 01:59:34,585
POPULATIONS IN REMOTE AREAS

2630
01:59:34,585 --> 01:59:35,619
WHICH ANTHROPOETIC LOGICALLY ARE

2631
01:59:35,619 --> 01:59:37,888
PART OF A MIGRATION PATTERN SO

2632
01:59:37,888 --> 01:59:38,689
I'M SORT OF CURIOUS WHETHER THE

2633
01:59:38,689 --> 01:59:40,857
NOX FAMILY ACTIVATOR ON HOE LIKE

2634
01:59:40,857 --> 01:59:43,060
MOST OF THE NATIVE AMERICAN

2635
01:59:43,060 --> 01:59:47,698
POPULATION ARE SUPPOSEDLY, CROSS

2636
01:59:47,698 --> 01:59:53,670
THE A LIEWTIANS FROM EAST OTHER

2637
01:59:53,670 --> 01:59:55,939
THAN PART OF EASTERN RUSSIA AND

2638
01:59:55,939 --> 01:59:57,608
WHAT NOT, DO ANY OF THESE APPEAR

2639
01:59:57,608 --> 02:00:01,311
IN ANY OF THOSE POPULATIONS? 

2640
02:00:01,311 --> 02:00:01,845
DOES ANYBODY KNOW?

2641
02:00:01,845 --> 02:00:05,282
>> I DON'T KNOW EMPLOY.

2642
02:00:05,282 --> 02:00:07,584
I MEAN I FIND THIS WHOLE THING

2643
02:00:07,584 --> 02:00:11,488
OF GENETIC EVOLUTION REALLY

2644
02:00:11,488 --> 02:00:11,788
FASCINATING.

2645
02:00:11,788 --> 02:00:13,724
BUT YOU KNOW GOING BACK TO THAT

2646
02:00:13,724 --> 02:00:17,294
CHILD WE HAD WITH DGAT1

2647
02:00:17,294 --> 02:00:21,665
MUTATION, SO, ALMOST WITHIN THE

2648
02:00:21,665 --> 02:00:24,334
SAME YEAR, THE FOLKS UP AT

2649
02:00:24,334 --> 02:00:27,471
HARVARD REPORTED A PAIR OF

2650
02:00:27,471 --> 02:00:29,106
JEWISH KIDDINGS WHO HAD THE

2651
02:00:29,106 --> 02:00:30,707
EXACT SAME MUTATION AS OUR

2652
02:00:30,707 --> 02:00:37,414
PATIENT WHO WAS HISPANIC.

2653
02:00:37,414 --> 02:00:38,348
THEN WE ACTUALLY FOUND A COULD

2654
02:00:38,348 --> 02:00:42,152
YOU SAYIN OF THIS GUY, ALSO

2655
02:00:42,152 --> 02:00:43,353
HISPANIC SAME EXACT MUTATION SO

2656
02:00:43,353 --> 02:00:45,756
IT MAKES ME FEEL LIKE GOING BACK

2657
02:00:45,756 --> 02:00:48,325
TO THE 15th CENTURY IN SPAIN,

2658
02:00:48,325 --> 02:00:50,193
SOMEBODY MAYBE HAD A FOUNDER

2659
02:00:50,193 --> 02:00:53,797
MUTATION BACK THEN.

2660
02:00:53,797 --> 02:00:56,967
>> IT'S POSSIBLE.

2661
02:00:56,967 --> 02:00:58,502
MPV17 DR. ARIAS CORRECT ME IF

2662
02:00:58,502 --> 02:01:00,871
I'M WRONG BUT I THOUGHT IT WAS

2663
02:01:00,871 --> 02:01:07,611
IN A EUROPEAN OR MAYBE IT WAS A

2664
02:01:07,611 --> 02:01:09,846
TURKISH PATIENT THAT WAS A

2665
02:01:09,846 --> 02:01:11,281
SIMILAR THAT THEY IDENTIFIED IT

2666
02:01:11,281 --> 02:01:14,785
AND THEY WENT BACKWARDS AND

2667
02:01:14,785 --> 02:01:16,987
CHECKED TO SEE IF THE NAVAJO

2668
02:01:16,987 --> 02:01:21,091
MIGHT HAVE THIS KIND OF MUTATION

2669
02:01:21,091 --> 02:01:25,295
AND IT DID SO COMPLETELY

2670
02:01:25,295 --> 02:01:27,564
DESPARRATE POPULATION SO IT'S

2671
02:01:27,564 --> 02:01:32,302
MORE COMPLEX AND THERE'S SO MANY

2672
02:01:32,302 --> 02:01:33,136
MUTATIONS.

2673
02:01:33,136 --> 02:01:35,739
MY GOD FOR MVID DEC, HOW MANY

2674
02:01:35,739 --> 02:01:37,607
ARE THERE NOW, SEIVET, 80.

2675
02:01:37,607 --> 02:01:40,243
>> I MEAN IT'S A BIG
PROTEIN BUT

2676
02:01:40,243 --> 02:01:43,413
THAT'S STILL A LOT OF MUTATIONS.

2677
02:01:43,413 --> 02:01:45,782
NRIGHT, RIGHT.

2678
02:01:45,782 --> 02:01:48,618
>> WELL, WE NEED -- I
WOULD

2679
02:01:48,618 --> 02:01:53,290
REMIND YOU AT 1 POINT THE

2680
02:01:53,290 --> 02:01:55,459
SPANISH SEFARDIN AND THE

2681
02:01:55,459 --> 02:01:58,762
EUROPEAN, AT LEAST THE MALE

2682
02:01:58,762 --> 02:01:59,796
POPULATIONS ALL LIVED TOGETHER

2683
02:01:59,796 --> 02:02:03,834
IN THE KINGDOM OF JUDEA, SO YOU

2684
02:02:03,834 --> 02:02:04,034
KNOW?

2685
02:02:04,034 --> 02:02:08,972
>> YEAH, IT'S LIKE TAKE IT
BACK.

2686
02:02:08,972 --> 02:02:09,239
I MEAN ...

2687
02:02:09,239 --> 02:02:10,774
>> WELL, I THINK WE HAVE
REACHED

2688
02:02:10,774 --> 02:02:13,977
THE END OF OUR TIME AND I TRULY

2689
02:02:13,977 --> 02:02:18,715
WANT TO THANK YOU BOTH VERY

2690
02:02:18,715 --> 02:02:19,015
MUCH.

2691
02:02:19,015 --> 02:02:21,918
THIS HAS BEEN A VERY EXCITING

2692
02:02:21,918 --> 02:02:24,988
PRESENTATION AND THEN FURTHER,

2693
02:02:24,988 --> 02:02:26,156
YOU KNOW ILLUSTRATES THE

2694
02:02:26,156 --> 02:02:30,794
NECESSITY TO BUILD BRIDGES

2695
02:02:30,794 --> 02:02:32,662
ACROSS DISCIPLINES AND THEY

2696
02:02:32,662 --> 02:02:34,965
COVER MAJOR CLINICAL PROBLEMS

2697
02:02:34,965 --> 02:02:37,100
AND CHALLENGING BASIC PROBLEMS

2698
02:02:37,100 --> 02:02:38,902
AND IT'S REALLY THROUGH

2699
02:02:38,902 --> 02:02:41,505
EXPERIENCES LIKE THIS, THAT YOU

2700
02:02:41,505 --> 02:02:42,973
SEE PROGRESS BEING MADE.

2701
02:02:42,973 --> 02:02:47,811
PROGRESS ISN'T ALWAYS SOLUTIONS,

2702
02:02:47,811 --> 02:02:48,779
SOMETIMES MORE QUESTIONS AND WE

2703
02:02:48,779 --> 02:02:50,981
HOPE THAT WE WILL BE ABLE TO

2704
02:02:50,981 --> 02:02:52,682
CONTINUE TO EXPLORE THOSE

2705
02:02:52,682 --> 02:02:54,651
QUESTIONS BECAUSE, THEY

2706
02:02:54,651 --> 02:02:58,555
ULTIMATELY LEAD TO GOOD THINGS

2707
02:02:58,555 --> 02:02:59,156
FOR THE PATIENTS.

2708
02:02:59,156 --> 02:03:01,892
SO THANK YOU BOTH VERY, VERY

2709
02:03:01,892 --> 02:03:03,627
MUCH AND WE WILL KEEP YOU

2710
02:03:03,627 --> 02:03:04,895
INFORMED ABOUT ANY OTHER

2711
02:03:04,895 --> 02:03:08,632
QUESTIONS THAT COME IN.

2712
02:03:08,632 --> 02:03:11,568
>> WE THANK YOU FOR
INVITING US

2713
02:03:11,568 --> 02:03:13,236
WIN EMPLOY.

2714
02:03:13,236 --> 02:03:13,603
>> THANK YOU.

2715
02:03:13,603 --> 02:03:15,338
>> GREAT FUN.

2716
02:03:15,338 --> 02:03:15,839
>> THANKS.

2717
02:03:15,839 --> 02:03:17,207
>> THANKS FOR INVITING US.

2718
02:03:17,207 --> 02:03:20,210
>> THANKS SO MUCH.

2719
02:03:20,210 --> 02:03:20,510
>> OKAY.

2720
02:03:20,510 --> 02:03:30,787
AND WE ARE OFF.