>> GOOD AFTERNOON, GOOD DAY FOR
THOSE IN WHOM IT'S NOT THE
AFTERNOON.
I AM WIN ARIAS, I AM A SENIOR
SCIENTIST EMERITUS AT THE
NATIONAL INSTITUTES OF HEALTH IN
BETHESDA, MARYLAND.
IT'S A PLEASURE TO WELCOME YOU
TO THE NEXT TO THE LAST SESSION
OF THE 23rd YEAR OF A COURSE
CALLED DEMYSTIFYING MEDICINE
WHICH IS HELD HERE AT THE NIH.
THIS IS A COURSE IN BRIDGE
BUILDING.
IT IS DESIGNED TO TAKE THE VERY
CONCENTRATED INFORMATION THAT
PEOPLE KNOW IN DIFFERENT DOMAINS
OF BIOLOGY, ENGINEERING AND
COMPUTER SCIENCE AND IN
MEDICINE, SORT OF IN THE FORM OF
SILOS, BUT QUITE SEPARATED FROM
1 ANOTHER.
SO THE GOAL OF THIS COURSE HAS
BEEN TO BRIDGE THE EXCITING
DEVELOPMENTS THAT GO ON AT A
SEEMINGLY EVER-INCREASING RATE
IN BIOLOGY, ENGINEERING AND
COMPUTER SCIENCE AND BRIDGE THEM
WITH OUR UNDERSTANDING OF HUMAN
DISEASE AND IDENTIFY THE MAJOR
CHALLENGES.
AND THE LOGO FOR THIS COURSE FOR
23 YEARS IS THE PHOTOGRAPH OF
THE BROOKLYN BRIDGE DURING ITS
CONSTRUCTION.
AND HERE YOU SEE 2 INDIVIDUALS
ON THE CAT WALK AND IN EFFECT,
THEY ARE AS WE ARE TODAY
REPRESENTED 2 INDIVIDUALS EACH
HAVING SPECIAL EXPERTISE IN A
VERY TIGHT AREA OF SCIENCE AND
EACH HAS A DIFFERENT 1 AND THEY
IN EFFECT HAVE COLLECTIVELY
UNITED THEIR KNOWLEDGE AND
ADVANCED SUBSTANTIALLY HUMAN
MEDICINE IN THIS AREA WE WILL
DISCUSS TODAY AND ALSO IN THE
BROADER AREA OF CELL BIOLOGY.
WELL, DEMYSTIFYING MEDICINE
MEETS ON TUESDAYS FROM 3-5
EASTERN STANDARD TIME FROM
JANUARY TO THE END OF MAY.
YOU CAN WATCH IT USING THE LINK
SHOWN ON THE SLIDE AND YOU DON'T
HAVE TO BE HERE TODAY TO
ACTUALLY HEAR IT IN ATTENDANCE,
BECAUSE IT'S VIRTUAL, YOU CAN
ACCESS IT AND ANY OF THE
PROGRAMS FOR THE PAST 23 YEARS
USING THE LINK SHOWN FURTHER
DOWN ON THE SLIDE.
FOR THOSE WHO SEEK CME CREDIT,
IT'S AVAILABLE AND THE CODE FOR
TODAY IS 58799.
NOW, WE ENCOURAGE YOU TO SUBMIT
QUESTIONS DURING TODAY'S
PRESENTATIONS AND YOU CAN DO
THAT BY CLICKING ON THE SEND
LIVE FEEDBACK ON YOUR VIDEOCAST
DISPLAY.
AND THESE QUESTIONS WILL INFORM
THE BASIS OF WHAT IS A VERY
EXCITING DETAILED NOT JUST
QUESTION AND ANSWER BUT
DISCUSSION PERIOD FOLLOWING THE
PRESENTATIONS.
IF YOU HAVE ANY DESIRE FOR
ADDITIONAL INFORMATION, YOU CAN
SEND US A MESSAGE AT
DEMYSTIFYING MEDICINE AT NIH.GOV
AS WELL AS SUGGESTIONS PERHAPS
FOR NEXT YEAR'S TOPICS AND
SPEAKERS.
NEXT SLIDE, PLEASE.
NEXT SLIDE.
NOW, TODAY WE'RE GOING TO
DISCUSS NONINFECTIOUS NEONATAL
DIARRHEA.
NOW GLOBALLY THIS PROBLEM
INFECTIOUS DIARRHEA IS OFFENSE
FATAL AND IT CERTAINLY IS A HUGE
GLOBAL PROBLEM AND IT'S
PRIMARILY DUE TO INFECTION DUE
TO BACTERIA, VIRUSES SOMETIMES,
FUNGUS, PARASITES AND THAT'S
AIDED AND ABETTED BY
MALNUTRITION EMPLOY SO GLOBAL
DIARRHEA IS A VERY SERIOUS
PROBLEM.
HOWEVER, WITHIN THIS LARGE
GROUP, THERE ARE RARE
INHERITABLE CASES WHICH HAVE
BEEN IDENTIFIED AND THEY HAVE
BEEN CHARACTERIZED AND THIS
THEIR CHARACTERIZATION, THEY
HAVE PROVEN INVALUABLE IN
DISSECTING THE MOLECULAR
MECHANISMS RESPONSIBLE FOR
OBLIGATIONS SORPTION AND
SECRETION IN THE INTESTINE,
LIVER, AND PERHAPS OTHER ORGANS.
SO DISCOVERY OF THESE RARE
INHERITABLE CAUSES OF
NONINFECTIOUS NEONATAL DIARRHEA
HAS NOT ONLY RESULTED IN LIFE
SAVING TREATMENT WHICH AT THE
MOMENT IS USUALLY SURGERY BUT IT
ALSO -- IT HAS RAISED CHALLENGES
TO UNDERSTAND BETTER THE COMPLEX
PROCESSES INVOLVED AND HOW
THEY'RE REGULATED.
AND AS THAT ACTIVITY IN CELL
BIOLOGY IS PRECEDED, THE DOOR
HAS BEEN OPEN TO BETTER
DIAGNOSIS AND IT POINTS IN THE
DIRECTION OF LESS INVASIVE BUT
EFFECTIVE TREATMENTS.
NOW IT'S ALSO INTERESTING THAT
EACH OF THE INHERITABLE
DISEASES, RESPONSIBLE FOR
NONINFECTIOUS NEONATAL DIARRHEA
EACH HAS A REMARKABLE HISTORY OF
DISCOVERY.
DISCOVERY BY ASTUTE PHYSICIANS
WHICH THEN, WHO THEN QUESTION
WHAT'S GOING ON HERE AND
BRIDGED, THAT MEANS TALKED WITH,
MET WITH, DRANK COFFEE WITH,
BASIC SCIENTISTS AND
COLLECTIVELY TO UNDERSTAND
BETTER MECHANISMS AND THOSE
MECHANISMS INCLUDE CLINICAL
DETECTION OF INHERITABLE
DISEASES AND ALSO BETTER
UNDERSTANDING OF THE NORMAL
PROCESSES OF ABSORPTION AND
SECRETION AND EVEN POINTING TO
HOW WHEN THEY ARE DEFECTIVE IN
INFECTIOUS DIARRHEA SO IT OPENS
A LARGE AREA OF CELL BIOLOGY.
BASED UPON A CLINICAL SERIES OF
OBSERVATIONS.
THAT'S BRIDGING AT ITS HIGHEST
LEVEL IF YOU'RE A PHYSICIAN
SCIENTIST.
NEXT SLIDE, PLEASE.
SO OUR 2 SPEAKERS TODAY, NEXT
SLID, OUR FIRST SPEAKER IS
MITCHELL CHO, MITCHELL GRADUATED
FROM MOTHER EASTERN, GOT HIS
MEDICAL DEGREE AT THE UNIVERSITY
OF VERMONT, DID A RESIDENCY IN
PEDIATRIC AT DUKE, AND THEN A
FELLOWSHIP AT PEDIATRIC
GHASTROLOGY AND PEDIATRIC
NUTRITION AT THE HARVARD IN
CAMBRIDGE, SINCE 1986 HE'S BEEN
AT THE PHOENIX CHILDREN'S
HOSPITAL WHERE HE IN 2012 BECAME
PROFESSOR AND ALSO HAS MANY
ACTIVITIES INCLUDING BEING
EXECUTIVE CHAIR OF THE
DEPARTMENT OF CHILD HEALTH AND
PEDIATRIC GASTRONEUROLOGY.
MITCHELL HAS RECEIVED MANY, MANY
HONORS AND RECOGNITION
THROUGHOUT A LONG AND
DISTINGUISHED CAREER.
HE'S CONSISTENTLY RATED AS 1 OF
AMERICA'S TOP PHYSICIANS,
GASTRONEUROLOGYIST AND EVEN ONCE
PHYSICIAN OF THE YEAR, I
BELIEVE, AT ANY RATE, HE IS
KNOWN AS A AN OUTSTANDING
COMMENCEMENT SPEAKER AND ALSO
EXTREMELY ACTIVE IN
INSTITUTIONAL AND NATIONAL
COMMITTEES.
HE'S RECEIVED MANY, MANY AWARDS
FOR TEACHING, SERVICE AND
SCIENCE.
NOW IN ADDITION TO THESE
CLINICAL AND HIGH LEVEL
RESPONSIBILITIES, HE HAS
CONDUCTED RESEARCH THROUGHOUT
HIS CAREER, HAS RECEIVED
NUMEROUS NIH GRANTS FOR BASIC
AND ALSO TRANSLATIONAL RESEARCH
AND INHERITABLE AND ACQUIRED
GASTROINTESTINAL DISEASES, AND
IN THE COURSE OF THIS, THIS IS A
SUPERB EXAMPLE OF A BRIDGE
BUILDING ENGINEER BECAUSE OF
EXTENSIVE COLLABORATIONS WITH
COLLEAGUES FROM THE BASIC
SCIENCE COMMUNITIES.
NOW OUR SECOND SPEAKER, NEXT
SLIDE, PLEASE IS JIM GOLDENRING,
WHO GRADUATED FROM HARVARD AND
GOT HIS M. D. AND Ph.D. AT
YALE.
NOW JIM IS TRAINED AS A SURGEON
AND DID A SURGICAL RESIDENCY AT
YALE AND I BELIEVE STILL
CONTINUES TO DO GASTROINTESTINAL
SURGERY.
HE'S HAD SEVERAL POST DOCTORAL
FELLOWSHIPS AND SURGICAL
RESEARCH AND INCREASINGLY IN
CELL BIOLOGY AND HAS SWITCHED TO
CELL BIOLOGY, THOUGH NOT A
COMPLETE 1, IT WAS LINKED TO HIS
TRAINING AND RESEARCH
PARTICULARLY REGARDING THE
GASTROINTESTINAL TRACT.
PRESENTLY HE'S THE PAUL SANGER
PROFESSOR OF SURGERY AND
PROCESSOR OF CELL AND
DEVELOPMENTAL BIOLOGY BOTHAD
VANDERBILT UNIVERSITY SCHOOL OF
MEDICINE.
NOW JIM HAS RECEIVED ALL KINDS
OF HONORS, HE'S A MEMBER OF THE
AMERICAN SOCIETY OF CLINICAL
INVESTIGATION, THE ASSOCIATION
FOR ACADEMIC PHYSICIANS, A
FELLOW OF THE AMERICAN
GASTROENTHUSIASMEROLOGICAL
ASSOCIATION, A MEMBER OF THE
INSTITUTE COUNCIL FOR CELLULAR
AND MOLECULAR GASTROENTEROLOGY.
HE'S RECEIVED AWARDS FOR
OUTSTANDING MENTORSHIP AND
DISTINGUISHED ACHIEVEMENT AND
FOR THE AMERICAN ASSOCIATION FOR
THE ADVANCEMENT OF SCIENCE,
ELECTED MEMBER, AND ALSO
RECIPIENT OF A DISTINGUISHED
RESEARCH AWARD FROM THE AMERICAN
PHYSIOLOGICAL SOCIETY.
THIS AMONGST MANY OTHER
ACTIVITIES.
NOW AS HIS RESEARCH SPANS
MULTIPLE AREAS OF EPITHELIAL
BIOLOGY, IN PARTICULARLY, THE
ROLE OF RAB SMALL GTPACES IN
REGULATING VESICLE TRAFFICKING
AND MEMBRANE RECYCLING IN
POLARIZED CELLS, HE ALSO DID
OUTSTANDING WORK IN THE LARGE
MULTIPLE SPLICE GENE CODING FOR
THE A53 SCAFFOLDING PROTEINS AND
HIS RESEARCH HAS EXTENDED IN
CONSIDERABLE DEPTH ALSO INTO THE
MECHANISMS OF METAPLACIA AND
GASTRIC CANCER.
JIM'S A RENAISSANCE MAN, A
SURGEON, SCIENTIST, EDUCATOR, A
TRAINER, MENTOR, OUTSTANDING
FENCER AT 1 TIME IN HIS CAREER,
I GUESS, AND EXCELLENT WRITER
AND HE AND HIS COLLEAGUE
MITCHELL ARE TRUE BRIDGE
BUILDERS.
SO WE'RE DELIGHTED HAVE BOTH OF
YOU HERE TODAY.
APPRECIATE VERY MUCH YOUR
PARTICIPATION IN DEMYSTIFYING
MEDICINE AND MITCHELL PERHAPS
YOU WILL BEGIN.
THANK YOU.
>> THANK YOU.
IS THAT SEEABLE BY EVERYONE?
>> YES, PERFECT.
>> THANK YOU.
WELL I WOULD LIKE TO THANK THE
NIH IN BRINGING ME AND
DR. GOLDENRING TO SPEAK TODAY.
THE TOPIC WE WILL REVIEW TODAY
IS A RARE CONGENITAL DIARRHEA
DISEASE.
I'VE HAD THE UNIQUE OPPORTUNITY
TO CHAIR FOR A LARGE NUMBER OF
CHILDREN WITH THIS DISEASE
BECAUSE OF THE INCREASED
INCIDENCE IN THE NAVAHO
POPULATION OF WHICH WE PROVIDE
TERTIARY CARE AND BECAUSE OF
THAT, IS HOW I GOT INVOLVED WITH
THIS AND THEN LATER JOINED WITH
JIM WHO REAL LEGAL HAS TAKEN THE
SCIENCE TO THE NEXT LEVEL.
I HAVE NO CONFLICTS OF INTEREST
OR DISCLOSURES.
SO THIS DISEASE IS PART OF A
BROADER CATEGORY OF WHAT WE CALL
NEONATAL DIARRHEA AND
NEUROPATHY.
THESE ARE RARE AND CHAL ENKING
TO TREAT, EXACT PREVALENCE OF
QUALITIES AND CONDITIONS IS
UNKNOWN, FREQUENT DELAY OR
MISDIAGNOSES THAT CAN LEAD TO
INAPPROPRIATE TREATMENT OR WORSE
DEMISE, THESE CONDITIONS ARE
OFTEN ASSOCIATED WITH
SUBSTANTIAL MORBIDITY AND
MORTALITY AND ARE WANTING BETTER
TREATMENTS.
OUR PATIENTS WITH MVID, CAN'T
ABSORB ANYTHING INTERNALLY, OR
BOWEL TRANSPLANT, PROMPT
DIAGNOSE IS REQUIRED TO PROVIDE
CORRECT TREATMENT AND EVEN
THOUGH MANY OF THE GENE
ABNORMALITIES HAVE BEEN
DESCRIBED, THERE ARE MANY OTHERS
THAT ARE YET TO BE ELUCIDATED.
NOW THESENYONATAL CONGENITAL
DIARRHEAS FIT INTO 5 CATEGORIES.
THE EPITHELIAL TRAFFICKING AND
POLARITY ABNORMALITIES IS THE
MICRO INCLUSION THAT THE DISEASE
FITS WITH OTHER CATEGORIES THAT
INCLUDES THINGS LIKE EPITHOOLIAL
ELECTROLYTE TRANSPORT OR
CONGENITAL DIARRHEA, EPITHELIAL
ENZYME AND METABOLISM DISORDERS,
SOME CHILDREN ARE BORN WITH THE
ABILITY TO ABNORMALITIES SORP
CERTAIN CARBOHYDRATES THAT CAN
LEAD TO PROFUSE DIARHEA, AND
ENTERO ENDOCRINE DISORDERS, SO
PLACES LIKE NEOBLASTOMA CAN
CAUSE TERRIBLE SECRET ORY
DIARRHEA, AND AUTOIMMUNE DISEASE
OF THE GASTROINTESTINAL TRACT.
NOW MVID SO FAR AS BEEN
IEE, AUDIENCE DENTIFIED AS CAUSE
BY MUTATIONS 5 F4 GENES.
MY O 5 B WHICH APPEARS TO BE
MOST PREVALENT, STX3, STXBP2,
AND UNC45 E HAVE ALL BEEN
DESCROIBED WITH MUTATIONS
CAUSING MICRODOSE INCLUSION.
THIS LEADS TO A DEFECTIVE
MEMBRANE RECYCLING AND
INTESTINAL EPITHELIAL CELLS THAT
DR. GOLDENRING WILL SPEAK TO IN
HIS LECTURE IN GREAT DETAIL.
THIS PATIENTS HAVE INTRACTABLE
SECRETATTORY DIARRHEA THAT
BEGINS WITHIN THE FIRST FEW DAYS
OF LIFE AND ASSOCIATED WITH
HISTOLOGIC CHANGES OF THE
INTESTINAL LINING WHERE THE
VILLI THAT ARE NORMALLY PRESENT
OR FINGER LIKE STRUCTURES THAT
HELP WITH ABSORPTION AND
INCREASED SURFACE AREA OF THE
SMALL INTEST IEP, THEY'RE
ATROPHIED AND ON THE SURFACE OF
THE ENTERO-SITES, SHOULD BE
ABSENT RENDERING IT UNABLE TO
ABSORB AND INTERACT WITH THE
ENVIRONMENT IN AN APPROPRIATION
FASHION.
AND A UNIQUE ASPECT OF THIS
DISEASE THAT LED TO THE NAMING
WAS MICROVILLUS INCLUSIONS AND
WHAT I HAVE HERE AND JIM WILL
SHOW FURTHER SLIDES, ON THE LEFT
IS A SCANNING ELECTRON
MICROSCOPY VIEW OF THE SURFACE
OF INTESTINAL ENTERO-SITES AND
YOU CAN SEE THERE ARE ALL THESE
FILAMENT LIKE STRUCTURES THAT
COAT THE SURFACE AND THAT'S
NORMAL, THAT'S WHAT SHOULD BE
THERE AND THOSE ARE KNOWN AS
MICROVILLI.
NOW ON THE RIGHT IS A BIOPSY
UNDER ELECTRON MICROSCOPY OF A
PATIENT WITH DISEASE, THE BLACK
ARROW POINTS TO THE SURFACE AND
THERE'S NO MICROVILLI ON THE
SURFACE AND THE RED ARROWS ARE
SURROUNDING A VESICLE THAT
CONTAIN ALL THESE FORMED
MICROVILLI THAT JUST CAN'T GET
TO THE SURFACE.
AND THAT'S WHERE THE DISEASE
NAME WAS COINED BY A DOCTOR IN
TORONTO FOR SICK CHILDREN BACK
IN THE LATE 1970S.
NOW MICRODOSE INCLUSION DISEASE
IN THE NAVAHO IS TUE TO A RATHER
UNIQUE SITUATION THAT I THINK IS
IMPORTANT FOR THE AUDIENCE TO
UNDERSTAND, IN FACT THERE ARE 6
RARE GENETIC CONDITIONS THAT CAN
BE FOUND IN THE NOX FAMILY
ACTIVATORRA -- NAA HOE AND THIS
WAS FOUND BY GENETIC BOTTLENECK,
IN THE 1860S, MOST OF THEM WERE
ROUNDED UP BY THE GOVERNMENT AND
MARCHED TO AN INTER MENTORSHIP
SKILL CAMP HUNDREDS OF MAILS
FROM WHERE THEIR NATIVE LAND WAS
IN EASTERN NEW MEXICO BUT ABOUT
A THOUSAND INDIVIDUALS WERE
NEVER ABLE TO BE CAPTURED AND
IT'S THOUGHT THAT THE ENTIRE
GENETIC POOL OF THE WESTERN HALF
OF THE POPULATION CAME FROM
THOSE THOUSAND INDIVIDUALS.
SO IN ORDER TO CREATE A FOUNDER
EFFECT -- YOU KNOW IT'S VERY
ISOLATED AND VERY UNIQUE
TOPOGRAPHY AND THEN FOLLOWED BY
A TREMENDOUS GROWTH IN
POPULATION, SO WE KNOW THAT IN
THE LATE 1860S, THE ENTIRE
NAVAJO POPULATION WAS REDUCED TO
6 OR 7000 INDIVIDUALS AND NOW
THERE'S GREATER THAN 400,000
NAVAJO.
SO AS A RESULT OF THIS, THEY HAD
CERTAIN GENE MUTATIONS THAT WERE
JUST RETAKENNED IN THAT THOUSAND
PEOPLE POOL THAT ENDED UP BEING
PROMULGATED IN THE POPULATION
WITH SUBSEQUENT -- LET'S SEE.
LET ME GET BACK TO WHERE I WAS.
THERE WE GO.
ALL RIGHT.
SO, WHEN WE FIRST STARTED
GETTING PATIENTS WITH THIS RARE
DIAGNOSIS BY THE FOURTH 1, WE
SAID, YOU KNOW THIS IS REALLY
UNUSUAL.
IT'S NOT COMMON TO SEE SO MANY
PATIENTS WITH THIS CONDITION, SO
I JOINED FORCES WITH A RESEARCH
GENETICIST IN TUCSON, A FELLA BY
THE NAME OF DR. ERIC ROBINSON
WHO HAD DONE A LOT OF RESEARCH
IN NAVAJO RARE DISORDERS AND
SAID, YOU KNOW I THINK THIS IS
ANOTHER 1.
SO UNDER IRB APPROVAL AND WITH
FAMILIES CONSENT, WE WERE ABLE
TO RETAIN BLOOD FROM THEIR
PATIENTS AND THEIR PARENTS AND
IN 2008, THE GENE MUTATION WAS
DISCOVERED IN MY O 5 B, IT WAS A
HOMOZYGOUS MISENSEL MUTATION
THAT WE CALL P660 L, AND THIS
RESULTED IN AN APICAL MEMBRANE,
DEFECTIVE APICAL MEMBRANE
RECYCLING PATHWAY AND
DR. GOLDENRING WILL DISCUSS THAT
IN GREATER DETAIL.
AS A RESULT OF THIS DEFECT,
THESE PATIENTS WITHIN THE FIRST
FEW DAYS OF LIFE HAVE SEVERE
DIARRHE APROFUSE, WATERY RESULTS
IN ACIDOSEIS AND DEHYDRATION AND
ELECTROLYTE ABNORMALITIES.
THEY REQUIRE PRETTY RAPID
RECOGNITION TO PREVENT THEM FROM
SUCCUMBING TO THIS DISEASE AND
THEY NEED AGGRESSIVE FOOD AND
ELECTROLYTE RESUSCITATION, THEY
HAVE A LIFE LONG INABILITY TO
TOLERATE ANY FORM OF FEEDS
INCLUDING THE MOST ELEMENTAL
FORMULAS, AND THEY REQUIRE
LONG-TERM TREATMENT WITH EITHER
TPN OR BOWEL TRANSPLANT.
NOW TPN AND LIFE SAVING FOR
THESE PATIENTS, IT INVOLVES
PLACING A CENTRAL VENUS LINE AND
SURGEONS DO THAT AND THEN
THROUGH THAT LINE WE HAVE ACCESS
TO BE ABLE TO PROVOID THEM
FLUIDS, ELECTROLYTES AND
NUTRITION.
UNFORTUNATELY, LONG-TERM PTN AND
ASSOCIATED WITH THE NUMBER OF
COMPLICATIONS INCLUDING SEPSIS,
FLUID ELECTROLYTE IMBALANCE IS A
CONSTANT PROBLEM, 1 NEEDS TO
MONITOR THESE PATIENTS CLOSELY
AND MAKE ADJUSTMENT THEMENTS TO
THE FLUID AND ELECTROLYTES TO
THE TPN, AND THROMBOSIS OF THE
VESSELS, AND OVER TIME YOU CAN
USE UP VESSELS TO THE POINT
WHERE THERE'S NO VENUS ACCESS TO
PROVIDE CENTRAL VENUS NUTRITION.
TPN IS ALSO ASSOCIATED WITH
LIVER DISEASE AND IN OUR
POPULATION WE THINK THAT LIVER
DISEASE IS AGGRAVATED BY
EFFECTIVE TARGETING OF BIOSALT
PUMPS TO THE BIOCANALICULI, AND
PEOPLE ARE NOW CALLING THIS FORM
OF PFIC 6, BUT IT SEEMS TO
ACCELERATE THE LIVER DISEASE SO
THAT THESE PATIENTS GET SEVERE
AND PROFOUND LIVER DISEASE MUCH
EARLIER THAN JUST TPN ALONE WILL
COST.
OTHER COMPLICATIONS OF LONG-TERM
TPN INCLUDE METABOLIC BONE
DISEASE AND VARIOUS TRACE
ELEMENTS DISORDERS THAT 1 NEEDS
TO MONITOR.
NOW LONG-TERM SURVIVAL ON TPN,
IN OUR HANDS, THE LONGEST
SURVIVOR LIVED TO 15 YEARS OF
AGE WHICH IS PRETTY IMPRESSIVE
AND THESE PATIENTS WERE BEFORE
THE ADVENT OF BOWEL TRANSPLANTS.
SINCE THEN, WE'VE SENT OUR
PATIENTS FOR EVALUATION FOR
TRANSPLANT BUT EVEN WITH ALL OF
THESE EFFORTS, MANY OF OUR
PATIENTS DIE WITHIN THE FIRST 2
YEARS OF LIFE BECAUSE OF THE
COMPLICATIONS LISTED ABOVE.
NOW MULTIVISCERAL TRANSPLANTS
ARE CURRENTLY THE WAY TO GO.
IF SUCCESSFUL THEY ALLOW THE
PATIENTS TO ABSORB ENTERO
FEEDINGS AND GO OFF TPN WHICH IS
FANTASTIC HOWEVER, THERE'S
NUMEROUS COMPLICATIONS
ASSOCIATED WITH THIS
INTERVENTION, FIRST AND FOREMOST
A LOT OF PATIENTS DIE IN THE
WAITING LIST WAITING FOR THEIR
TRANSPLANT.
ONCE THEY'RE TRANSPLANTED, THEY
HAVE COMPLICATIONS OF REJECTION,
INFECTION, LYMPHOPROLIFERATIVE
DISORDER, GRAFT VERSUS HOST
DISEASE, ALL SEVERE LIFE
THREATENING CONDITIONS.
AND IN THE MOST RECENT
PUBLICATION, 10 YEAR SURVIVAL
RATES OF ALL COMERS WITH BOWEL
TRANSPLANTS IS IN THE 40-75%
RANGE.
SO NOT IDEAL.
BEFORE I TURN THIS OVER TO
DR. GOLDEN RING, I WOULD LIKE TO
PRESENT YOU OF A REAL CASE OF A
PEASHT I WAS CONSULTED ON WITH
MICROVILLUS INCLUSION TO GIVE
YOU A VISION OF HOW THEY
PRESENT.
SO THIS WAS A 2 WEEK OLD NAVAJO
TRANSFORTED FROM THE HOSPITAL TO
THE NICU AT OUR FACILITY AND HAD
PROGRESSIVE WEIGHT LOSS DESPITE
ELEMENTAL FORMULA FEEDINGS AND
HAD REPEATED BOUTS OF SEVERE
DEHYDRATION, ACIDOSEIS AND
HYPONATREMIA, EVERY TIME THEY
WITHDREW THE SUPPORT.
INTERESTINGLY, THE PATIENTS HAVE
DIARRHEA IT'S SO WATERY THAT IT
SOAKS RIGHT INTO THE DIAPER AND
IT LOOKS LIKE URINE, SO THEY HAD
CONSULTED ENDOCRINOLOGISTS,
METABOLIC SPECIALISTS AND
NEPHROLOGY IV THERAPYS AND
FINALLY 1 SENIOR PERSON WHO WAS
INVOLVED IN A LOT OF NAVAJO
DISEASE ABNORMALITIES SAID, YOU
KNOW THIS COULD BE SOMETHING
THAT THE WAY MICROVILLUS
INCLUSION DISEASE PRESENTS, HE
CALLED ME, CAME DOWN, CONSULTED
AND SAID, YEAH THIS IS A CLASSIC
PRESENTATION FOR IT, AND THE
FIRST THING I WAS ABLE DO WAS
COLLECT STOOL FROM THE PATIENT,
NOT AN EASY THING TO DO BUT WE
WERE ABLE TO GET IT DONE AND
WHAT WE FOUND WAS THAT PATIENT'S
STOOL HAD A SECRETATTORY
DIARRHEA PATTERN, THE SODIUM AND
CHLORIDE CONTENT OF THE TOOL ARE
MUCH HIGHER, NORMAL STOOL SODIUM
IS IN THE 20-30 RAINCHL AND THIS
PATIENT HAD 110 MMOL PER LITER
OF SODIUM.
AND IN THE FLIP SITUATION, THE
CONTENT OF POTASSIUM WAS REALLY
LOW, NORMAL POTASSIUM IS 55'VE
65, SO THESE TOOL ELECTROLYTES
WERE MUCH SIMILAR TO SERUM THAN
TO STOOL AND THAT'S CLASSIC FOR
WHAT 1 SEES IN A SECRETTATORY
DIARRHEA LIKE 1 WOULD GET WITH
CHOLERA.
THIS PATIENT WAS PUTTING ON
200-MILLILITERS PER KILOGRAM PER
DAY WHICH IS 10 TIMES THE NORMAL
AMOUNT OF STOOL OUTPUT AND WHEN
FED WAS UP TO 250-MILLILITERS
PER DAY, BUT TO PUT IT IN MORE
RELATABLE TERMS IN A 3 KILOGRAM
INFANT, THIS CHILD WAS PUTTING
OUT A QUARTY OF THEIR THEIR BODY
WEIGHT IN STOOL EVERY DAY AND
IT'S NOT HARD TO IMAGINE HOW
THESE PATIENTS RAPIDLY
DETERIORATE.
WE NEEDED TO RESUSCITATE THIS
PATIENT WITH TWICE THE NORMAL
FLUID VOLUME THAT WOULD BE
CONSIDERED MAINTENANCE.
WE GAVE 200 MILL LET LITERS PER
KILOGRAM PER DAY.
ONCE WE STABILIZED THE PATIENT A
CENTRAL VENUS LINE WAS PLACED BY
THE SURGEON SO THAT WE COULD
PROVIDE NUTRITION AND THEN, WE
SET ABOUT THE TASK OF CONFIRMING
A DIAGNOSIS.
WE DIDENDOSCOPY UNDER ANESTHESIA
AND DID BIOS COPY UNDER ELECTRON
MICROSCOPY, REVEALED MICRODOSE
INCLUSIONS, AND SEND THEM OFF
GENETIC TESTING THAT CONFIRMED
THE DIAGNOSIS.
THIS PATIENT WAS SUBSEQUENTLY
EVALUATED FOR MULTIORGAN BOWEL,
LIVER AND PANCREAS TRANSPLANT
AND UNFORTUNATELY THIS PATIENT
SUCCUMBED A LITTLE OVER A YEAR
OF AGE FROM A SEPTIC EPISODE
THAT WE JUST COULDN'T GET ON TOP
OF.
SO WITH THAT, LET ME TURN IT
OVER TO DR. GOLDENRING SO THAT
HE CAN PROVIDE TO US A PICTURE
OF THE BASIC SCIENCE BEHIND THIS
CONDITION.
LET ME JUST SEE IF I CAN GET OUT
OF THIS AND THEN STOP SHARING.
AND THEN I WILL PUT MY CAMERA
ON.
DR. GOLDENRING?
>> OKAY, THANK YOU DR. SHUB.
AND I WOULD LIKE TO THANK WIN
ARIAS FOR INVITINGITOUS THIS
FORUM AND I WANT TO TAKE YOU ON
A LITTLE JOURNEY AND MY JOURNEY
OBVIOUSLY HAS BEEN WITH MITCH,
BUT IT'S A JOURNEY FROM BEDSIDE
TO BENCH AND BACK AGAIN, AND I
HOPE THAT THIS WILL BE OF
INTEREST TO PEOPLE.
SO I WANT TO START BY REMINDING
YOU JUST AS MITCH HAD TALKED
ABOUT THAT THE INTESTINE IS AN
AMAZING ORGAN THAT IS REALLY --
IT'S HUGE AND IT'S MASSIVELY
EXPANSIVE.
SO YOU HAVE AT THREEOF THE
23 FEET OF GUT RIGHT IN YOU
RIGHT NOW, AND THAT SURFACE AREA
IS MAXIMALLY AMPLIFIED AND THE
AMPLIFICATION COMES PARTIALLY
FROM THESE LARGE VILLUS
PROJECTIONS INTO THE LUMEN AND
THESE VILLUS PROJECTIONS COME
OUT OF THE MUCOSAL SURFACE OF
THE INTESTINE FROM CRIP REGIONS
WHERE CELLS ARE BORN AND CELLS
MOVE UP TO THE TIPS AND THIS
WHOLE VILLUS STRUCTURE IS
RENEWED EVERY 4-5 DAYS.
AND ON TOP OF THAT ALL THESE
ABSORBAATIVE ENTER-SITES THAT
YOU NEED TO PULL WATER IN, THEY
ARE HAVING AT THEIR TIPS THIS
EWILL BEERATION OF MICROVILLI
THAT MASSIVELY EXPANDS THE
SURFACE AREA OF THE GUT AND THAT
SURFACE AREA OF THE GUT IS
REALLY THERE TO DO 1 MAJOR THING
AND THAT'S ABSORB WATER.
AND IF YOU DON'T ABSORB WATER
YOU'RE GOING TO HAVE -- YOU'RE
GOING TO HAVE DIARRHEA.
NOW, MITCH HAS GONE OVER MICRO
VILLUS INCLUSION DISEASE AND I
WILL FOCUS MOSTLY IN MY TALK
ABOUT THE CELL BIOLOGY AND
PHYSIOLOGY THAT WE'VE LEARNED
ABOUT THE DISEASE IN THE
INTESTINE AND UNFORTUNATELY
WIN'S GOING TO BE UPSET WITH ME,
I WILL NOT TALK ABOUT THE LIVER,
BUT I AM HAPPY TO TALK ABOUT IT
IN THE QUESTIONS.
SO AS MITCH DESCRIBED THE
DISEASE WAS INITIALLY FOUND
FIRST BY DIFIDZON AND THEN
MICROVILLUS INCLUSION BY KROITS,
BUT THESE ARE OBSERVE INDEED A
MINORITY OF ENTER-SITES IN
PATIENTS BUT THAT THE KEY THING
THAT WAS THE DORPHY OF THE
GENETIC MUTATIONS IN MYO5 B, AT
THE SAME TIME BY POSITIONAL
CLONING AS MITCH DESCRIBED IN
THE NAVAJO WITH ROBERT ERICKSON
AND MITCH, AND THEN, MULLERS
GERMANY LOOKING AT MULTIPLE
MUTATIONS IN MYOSIN 5 B.
SO WHAT IS MYOSIN 5 B?
ON SO MYOSIN 5 B IS A DOUBLE
HEADED MOTOR.
IT HAS THESE HEAD DOMAINS WHERE
THE MOTOR IS, THE NECK DOMAINS
ARE STIFFENED BY 6 CAL MODUE
LYNN RESIDUES AND THEN AT THE
BASE OF THIS, IN THE DISTAL AREA
IS THIS CARBOBINDING DOMAIN THAT
LINKS THE MOTOR TO VARIOUS
MEMBRANES AND THIS LINK TO
VARIOUS RAB SMALL GTP A SES, IS
WHERE I STARTED MY WORK
INITIALLY THROUGH STUDYING
GASTRIC ACIDS SECRETING PARIETAL
CELL, WE ORIGINALLY CLONED MICE
IN 5 B AS AN ISHT ACTOR WITH
THIS FAMILY OF RABS, SMALL GTP A
SES, AND THEN LATER SHOWED THAT
OTHER RABS WERE ALSO INTERACTING
IN DIFFERENT PARTS OF THIS CARGO
BINDING.
AND IN PARTICULAR IT WAS LUCAS
HOOFERS POST DOC WHO SAW A LATE
BREAKING POSTER AT THE AMERICAN
CELL BIOLOGY MEETING IN 2007
WHERE WE SHOWED THAT MYOSIN 5 B
WAS INTERACTING WITH RAB 8-A AND
HE WENT HOME TO LUCAS, TOLD
LUCAS ABOUT THAT BECAUSE THEY
HAD BEEN SEQUENCING RAB 8 FOR
MUTATIONS AND MICROVILLUS
INCLUSION DISEASE, SO THEY THEN
WENT AND SEQUENCED MYOSIN 5 B
AND THAT'S HOW THEY FOUND.
SO THIS WAS DEFINITELY THE BASIC
SCIENCE LEADING THE CLINICAL
INSIGHT.
SO WHAT ARE RAB PROTEINS?
SO THIS IS SORT OF A SIMPLIFIED
VERSION OF SOME OF THE RABS,
THEY ARE NOW 43 DIFFERENT RABS,
I BELIEVE, BUT RAB PROTEINS CAN
BE THOUGHT OF AS MOLECULAR ZIP
CODES FOR VARIOUS VESICLE
POPULATIONS SO CERTAIN
POPULATIONS OF MEMBRANES INSIDE
THE CELL WILL BE ENRICHED FOR
RAB PROTEINS AND THE CLASS --
THE FIRST 1S THAT WERE FOUND
WERE RAB 1 AND RAB 2 IN THE ER
AND ER-GOLGI DEPARTMENT AND THE
1S YOU WILL HEAR ME TALK ABOUT
TODAY ARE RAB 11 A WHICH IS ON
RECYCLING MEMBRANES IN POLARIZED
CELLS AND RAB 8A, WHICH APPEARS
TO BE INVOLVED IN THESE GOLGI
VESICLES.
BOTH OF THESE ARE SIGNIFICANT
BINDERS WITH THE MY O SIGN 5 B
MOTOR.
NOW, THE END POINT OF ALL THIS
WORK IS TO KNOW THAT MOST OF THE
ABNORMALITIES SORPAATIVE AND
SECRETORY FUNCTION ALONG THE
LINE OF THE SMALL INTESTINE IS
REALLY REGULATED BY 3
TRANSPORTERS.
YOU HAVE SODIUM HYDRATE
EXCHANGER AND SGLT 1 WHICH ARE
RESPONSIBLE FOR A PULLING IN, SO
IT'S SODIUM AND THEREFORE WATER
FROM THE LUMEN, SGLT1 IS KNOWN
MOST AS THE REASON WE HAVE
GATORADE.
BECAUSE YOU HAVE TO HAVE SUGAR
TO PULL THE SODIUM IN.
AND THEN CFTR, THE
CYSTIC FIBROSIS TRANSMEMBRANE
REGULATOR IS A CHLORIDE AND
ASSOCIATED WITH SOWBS DISEASES
LIKE CHOLERA.
SO IT'S A BALANCE OF THESE MAJOR
TRANSPORTERS THAT THE MAJOR
DRIVING FORCE FOR BRINGING WATER
IN OR SENDING WATER OUT.
NOW, IF YOU LOOK AT THE
INTESTINAL MUCOSA, AND THESE ARE
ALL DUO DEANAL BIOPSIES FROM
PATIENTS IN THE HEALTHY DUE
DUODENUM, HAVE MICE VILLI WHICH
HAVE SGLT1 ON THE SURFACE AS
WELL AS SODIUM BUT IN THESE
SAMPLES, I THINK IT'S PRETTY
CLEAR, YOU'VE LOST THOSE
TRANSPORTERS AT THE APICK WILL
MEMBRANE, SO IT'S NOT SURPRISING
THEN THAT THESE PATIENTS WOULD
HAVE DIARRHEA BECAUSE THEY DON'T
HAVE THE ABILITY TO PULL IN
SODIUM.
AT THE SAME TIME, THIS WORK IS
FROM NADELLIA MEANS GROUP, WHERE
THEY SHOWED AGAIN, IN SAMPLES
FROM MVID PATIENTS THAT WHILE
THE SODIUM AND TRANSFERS WERE
GONE, CFTR WAS STILL AT THE
APICAL MEMBRANES IN THESE
CHILDREN.
SO WHAT YOU HAVE HERE THEN IS A
BIG BAD PROBLEM BECAUSE WITH THE
MY O 5 B MUTATION, YOU LOSE YOUR
PATHWAYS TO PULL WATER IN AND
YOU STILL HAVE CFTR SECRETING
FLUID OUT.
SO THESE PATIENTS ARE BETWEEN
THE DEVIL AND THE DEEP BLUE SEA.
SO HOW DO WE DEAL WITH THIS AND
I WILL REALLY FOCUS ON HOW
ANIMAL MODELS ACTUALLY HAVE
HELPED US UNDERSTAND WHAT'S
REALLY HAPPENING IN THIS
DISEASE.
AND I THINK IT'S NOT SURPRISING
THAT IF YOU BUILD AN ANIMAL
MODEL, YOU HAVE TO SHOW THAT THE
ANIMAL MODEL RECAPITULATES THE
PATHOPHYSIOLOGY OF THE DISEASE
AND OVER THE LAST DECADE, WE'VE
SPENT A LOT OF TIME BUILDING A
LARGE NUMBER OF ANIMAL MODELS,
THEY ARE LISTED HERE AND THEY
INCLUDE ANIMAL MODELS FOR GERM
LINE AND INDUCIBLE TARGETING
LOSS OF MYOSIN 5 B IN THE
INTESTINE, A POINT -- INDUCIBLE
POINT MUTATION OF MYOSIN 5 B
BASED ON A PATIENT SEEN HERE AT
VANDERBILT AND WE EVEN HAVE THIS
DONE AND I WILL NOT DISCUSS
EXTENSIVELY, A YEEN -- A GENE
TARGETING IN PIGS TO CREATE A
PIG MODEL OF THE PATHWAY GIVES
RALGOUS MUTATION IN THE NAVAJO
WHICH IS PSS3 L AND MYOSIN 5 B
FROM PIG.
SO ALL THESE MODELS HAVE REALLY
ABOUT THE SAME PHENOTYPE.
SO IF YOU LOOK IN MYOSIN 5 B
KNOCKOUT MICE OR ANY OF THESE
OTHER MODELS I JUST LISTED
THERE, YOU SEE THE DEFICIT YOU
WOULD EXPECT.
SO HERE IS THE NORMAL INTESTINAL
MUCOSA, YOU SEE A NICE BRUSH
BOARD BORD -- BORDER LACED WITH
FOSTER NURSED FOCUSED ON
STAINING BUT WITH MYOSIN 5 B
KNOCK OUT YOU SUBSTANTIALLY LOSE
THAT BRUSH BORDER AND NOW YOU
SEE ALL THESE VERY LARGE
MICROVILLUS INCLUSIONS LABELED
WITH FOSTER NURSED FOCUSED ON
EZRIN, USUALLY THERE'S 1
INCLUSION PER CELL AND YOU CAN
SEE HERE, THESE ARE VERY LARGE,
SO 5-8-MICRONS IN DIAMETER.
THESE ARE REALLY VERY BIG
ORGANELLES.
THE OTHER THING YOU CAN SEE IN
THESE MICE, IS WHEREAS THE BRUSH
BORDER IS VERY TALL IN A NORMAL
MOUSE, IN A MY O 5 B KNOCK OUT
MOUSE, THE MICROVILLI ARE MUCH,
MUCH, SHORTER.
THERE ARE ALSO BROADENED AND YOU
CAN SEE THESE MICROVILLUS IN
CONCLUSIONS HERE AND HERE.
SO LIKE THE PATIENTS, THESE MICE
GET MICRO VILLUS INCLUSIONS AND
ACTUALLY THEY GET FAR MORE THAN
YOU EVER SEE IN MOST HUMANS.
BUT THE MOST IMPORTANT THING IS,
THAT THE DEFICITS IN
TRANSPORTERS ARE ALSO SEEN IN
THESE MICE.
SO FOR BOTH NH3 T AND SGL1 WHICH
ARE USUALLY SEEN VERY NICELY ON
THE BRUSH BORDER, IN THE
KNOCKOUT MICE, YOU GET ALMOST A
COMPLETE LOSS OF BOTH NHG3 AND
SGLT1.
THEIR LOST SIMILAR TO WHAT WE
SEE IN THE PATIENTS.
HOWEVER, IF YOU LOOK AT CFTR,
CFTR IS STILL THERE.
AND IN FACT, CFTR IS IN A LOT OF
THE INCLUSIONS AND YOU CAN SEE
THAT AT THE BOTTOM OF THE SLIDE
IN THE CFTR STAINING.
YOU CAN SEE ALL THESE
MICROVILLUS INCLUSIONS.
SO SODIUM TRANSPORTERS ARE LOST,
CFTR IS MAINTAINED, AND THIS IS
THE BIG PATHOPHYSIOLOGY
OBVIOUSLY IN THIS DIARRHEAL
DISEASE, SO THIS SINCE WE DIDN'T
KNOW BEFORE WAS THERE MUST BE
MULTIPLE PATHWAYS FOR THE ACHE
PICKAL MEMBRANE TRANSPORTERS
BECAUSE SODIUM, ARE ALL BEING
AFFECTED BY THE LOSS BUT CFTR IS
NOT.
NOW WE'VE ALSO LOOKEDDA THE A
POINT MUTATION, SO EVERYTHING I
SHOWED YOU BEFORE WAS A KNOCK
OUT, WE'VE ALSO LOOKEDDA THE A
POINT MUTATION, THIS IS MY O
SIGN 5G 519 R, THIS WAS A LITTLE
IMIRL SEEN HERE AT VANDERBILT
AND AGAIN, SHE WITH THIS POINT
MUTATION, I SHOULD SAY, SHE WAS
A POINT MUTANT ON 1 ALLELE THAT
CAME FROM HER MOTHER, AND SHE
HAD A DE NOVO TRUNCATION
MUTATION IN THE FIRST HUNDRED
AMINO ACIDS ON THE SECOND
ALATELY.
SO SHE WAS VERY UNFORTUNATE.
AND HER MOTHER HAS NO PROBLEM AS
A HETEROZYGOTE.
AND WHAT YOU SEE IN THIS AGAIN
IS LOSS OF SGLT1, LOSS OF NHE3,
WE ARE STILL WORKING ON IT
BECAUSE SHE DOESN'T LOSE MYOSIN
5 B, IT SEEMS TO BE STUCK IN
VESICLES THAT ARE MISLOCALLIZED
WITH RAB 11A.
BUT THIS SHOWS YOU THAT THE
POINT MUTATIONS IN THE KNOCK OUT
ALL END UP WITH THE SAME THING
WHICH IS THE LOSS OF THESE
APICAL TRANSPORTERS.
NOW, 1 THING I WANT TO TALK
ABOUT FOR MICE, IS MICE GAVE YOU
THE CHANCE TO LOOK AT THINGS IN
TIME, AND SO WHAT WE'VE
DEVELOPED IS A NUMBER OF MICE
THAT HAD INDUCIBLE KNOCK OUT AND
IN THE CASE OF THIS G519 R
MUTATION, WE BASICALLY MADE THE
MICE TO FIT THE CHILD.
SO WE MADE A MOUSE THAT'S
DIRECTED -- WHERE, KNOCK OUT IS
DIRECTED BY THIS CREE DRIVER
FROM VILLIN WHICH IS AN
INTESTINAL SPECIFIC DRIVER AND
WITH A G519 MUTATION ON 1 ALLELE
AND A FLOCKS ALLELED ON THE
OTHER IF YOU GIVE THIS MOUSE
TAMOXIFEN NOW, YOU WILL HAVE A
MOUSE THAT ONLY HAS THIS
PATHOGENIC 519 R MUTATION.
AND WHAT YOU SEE IS THAT IF YOU
GIVE 1 DOSE OF TAMOXIFEN EITHER
IN THE MY O 5 B KNOCK OUT, OR
THE INDUCIBLE 519 R, BY 4 DAYS,
YOU HAVE ALMOST A 20% DECREASE
IN BODY WEIGHT.
YOU CAN ALMOST SET YOUR WATCH ON
THIS.
THESE MICE ARE GOING TO BE MORE
THAN THAT BY THE FIFTH MORNING
AFTER THE TAMOXIFEN DOSE.
AND JUST AS MITCH SAID, YOU SEE
IN THE CHILDREN, THEIR
INTESTINAL LUMEN IS BASICALLY
FILLED WITH CLEAR FLUID.
IT IS ABSOLUTELY DEAD CLEAR.
NOW THE GREAT THING ABOUT
INDUCIBLE MODEL SINCE THIS IS
INDUCED IN THE ADULT, WE CAN USE
THIS FOR INTERVENTION AND THAT'S
WHAT I WILL TALK ABOUT IN A FEW
SLIDES.
ACTUALLY I'M JUST GOING TO SKIP
THAT.
NOW WE HAVE ALSO MODELED THIS
WITH ANOTHER POINT MUTANT, AS I
SAID THE EQUIVALENT OF THE
NAVAJO MUTATION IN PIG AND WE
SAW THE XCT SAME THING OF A --
EXACT SAME THING OF THE LOSS OF
THESE 2 TRANSPORTERS, NATIVE
AMERICANS IN THE NORTHERNINENCE
OF CFTR, I WISH THIS MODEL HAD
GONE BETTER FOR US.
THESE PIGS TURNED OUT TO COST US
ALMOST 30,000 THERE IS A PIGLET
TO MAKE SO THIS IS NOT EXACTLY
THE GREATEST MODEL FOR FINANCIAL
STABILITY IN YOUR LABORATORY.
OKAY, SO WHAT I TOLD YOU IS THAT
ANIMAL MODELS CAN REPRODUCE THE
PATHOLOGY SEEN IN CHILDREN WITH
NBID, THAT IS LOSS OF
IEE, AUDIENCE PICKAL SODIUM
TRANSPORTERS, MAINTENANCE OF
SODIUM CHLORIDE TRANSPORT
THROUGH CFTR.
NOW YOU CAN THINK OF THIS IN A
COUPLE WAYS AND 1 WAY I WILL
SUGGIEST TO YOU THAT WILL BE
IMPORTANT LATE OR IS TO THINK
ABOUT THIS CELL, IN THE NORMAL
IS A MATURE ENTHUSIASMER O CITE
THAT YOU WOULD EXPECT TO FIND AT
THE TIP OF THE VILLI.
THIS CELL SEEMS TO BE A BIT
STUCK IN THE IMMATURE CRIP CELL
SO IT HAS CFTR WHICH EXISTS IN
THE CRIP BUT IT HASN'T EXACTLY
UPREGULATED THESE SODIUM
TRANSPORTERS IT NEEDS TO DO THE
ABSORPTION OF WATER.
SO NOW AS AN ASIDE BECAUSE
EVERYBODY ASKS ME, I WILL ASK
THE QUESTION HOW ARE MICROVILLUS
INCLUSIONS MADE AND WHAT IS THE
RELATIONSHIP TO THE DISEASE?
AND THIS IS WRORK BY AMY ANG
OVIC WHEN SHE WAS IN MY LAB AND
SHE NOW HAS HER OWN LAB AT
MEDICAL UNIVERSITY OF SOUTH
CAROLINA.
AND SO WHAT AMY DID WAS SHE
LOOKED AT HOW THESE INGCLIEWGZS
WERE FORMED IN THE MY O 5 B
KNOCK OUTS AND SHE FOUND THAT
THE ENCLIEWGZS WERE AGAIN, 1 PER
CELL AND THEY WERE ASSOCIATED
WITH SUBAPICAL VESICLES THAT
WERE POSITIVE FOR THIS PROTEIN
CALLED ENDOTUBEIN WHICH IS
THOUGHT TO BE AN INDO SOMAL
FACTOR.
BUT YOU NEVER SAW ENDOTUBEIN IN
THE INCLUSIONS.
INCLUSIONS ARE SEEN HERE IN
GREEN.
NOW FROM TIME TO TIME AS YOU'RE
LOOKING AT THESE, YOU SAW THIS
PICTURE AND THIS PICTURE WAS A
FORMING INCLUSION FROM THE
APICKA MEMBRANE IS HERE, THE
INTERNAL IS HERE AND WHAT YOU
WOULD SEE IS YOU WOULD SEE THESE
INCLUSIONS PINCHING OFF AND
PUSHING THE ENDOTUBEIN BACK INTO
THE CELL AND THIS IS HOW WE
REALIZED THAT DESPITE THE FACT
THAT A NUMBER OF PEOPLE HAD
THOUGHT THE INCLUSIONS WERE A
FAILURE TO DELIVER MEMBRANE,
ACTUALLY IT TURNS OUT IT'S A
LARGE ENDOSOMMAL PROCESS THAT WE
CALL APICKA BULK ENDOCYTOSIS.
SO I WILL SHOW YOU THIS, IN THIS
MOVIE WHICH I HOPE WILL PLAY AND
IF YOU LOOK RIGHT ABOUT HERE, I
THINK YOU WILL SEE THIS
INCLUSION COMING IN AND THIS
PROCESS HAPPENS NOT OVER A FEW
MINUTES, THIS TAKES 2-3 HOURS.
SO AMY HAD TO SIT THERE ON A
MICROSCOPE LOOKING FOR THESE
EVENTS FOR A LONG, LONG TIME TO
CAPTURE THESE LANCH ENDOSIGNIFY
TO THETIC EVENTS.
SO LET ME PLAY THIS FOR YOU 1
MORE TIME FOR PEOPLE.
YOU CAN SEE THE INCLUSION
FORMING FROM THE APICAL MEMBRANE
AND GOING IN.
OKAY, SO THE OTHER THING YOU CAN
SEE IS YOU CAN JUST TAKE A PIECE
OF TISSUE LIKE JERRY USED TO DO
AND YOU PUT 70 KILODALTON FITC
DEXTRAN ON THE OUTSIDE OF A
PIECE OF TISSUE AND LET IT
INCUBATE AND WHAT YOU CAN FIND
AND YOU GET DEXTRAN COMING INTO
THE THESE INCLUSIONS SO THIS
REALLY SAID THAT THIS WAS
ENDOSIGNIFY TO THETIC EVENT, NOT
AN EXOSIGNIFY TO THETIC EVENT
AND INDEED SOME ALSO SEE A BIT
OF DISCIPLINARY AMILLIOIN WHICH
IS A PROTEIN THAT IS INVOLVED IN
BREAKING OFF ENDOSOMES FOLLOWING
INTERNALIZATION, YOU CAN SEE A
LITTLE BIT OF IT SITTING AT THE
NECK OF THESE INTERNALIZATIONS
AND EVEN WHEN A BUT OFF THAT
LITTLE BIT OF DIAMIN SITTING ON
THE MICROVILLUS INCLUSION AND
YOU USUALLY SEE 1 LITTLE SPOT OF
DIAMIN STUCKOT ENCLIEWGZ.
THEN THERE ARE INHIBITORS OF
DYNAMIN, IF YOU THROW THOSE IN
THERE, YOU GET A LARGE NUMBER OF
THESE OMEGAS AND YOU CAN SEE A
TON OF THEM SOMETIMES IN AN
ORGANOID.
WE CAN DO THIS IN AN ORGANOID.
SO THESE ARE LITTLE MINIGUTS
GROWN IN CULTURE AND THEN YOU
CAN INCUBATE THEM WITH THE
DYNAMIN INHIBITOR WHICH IS DYNG
O, AND YOU SEE AN INCREASE IN
THESE INTERNALIZATIONS THAT GET
STUCK.
SO HOW DOES THIS FIT WITH THE
DISEASE AND THE IMPORTANT THING
IS WE REALIZE THERE WAS A
PROTEIN CALLED SIN DATA
PROTECTIONIN 2, SOME PEOPLE CALL
IT SIM P A XATOXIN 2 NOW THAT
WAS PRESENTOT MEMBRANE ANDS THE
INCLUSIONS AND SO WE CROSS THE
MYO5 B KNOCK OUTS ON TO SYNDAPIN
2 KNOCK OUTS AND WHAT HAPPENS
IS, I HOPE YOU CAN SEE THAT
WHILE THE REGULAR KNOCK OUT HAS
TONS OF THESE LITTLE ENCLIEWGZS
ALL OVER THE PLACE, THE SYNDAPIN
2 DOUBLE KNOCK OUT HAS NO
INCLUSIONS.
WELL, HERE'S THE PROBLEM.
THE MICE STILL ARE DYING FROM
DIARRHEA.
AND THEY STILL DON'T HAVE THEIR
TRANSPORTERS UP, IT TURNS OUT
AND YOU CAN SEE 1 OF THESE
EXAMPLES, THIS IS NOT A
TRANSPORTER, THIS AN APICAL
ENZYME DTP4 AND IT'S STILL NOT
GETTING TO THE APICAL MEMBRANE
LIKE THE CONTROL.
SO THE INCLUSIONS ARE A REALLY
INTERESTING EPIPHENOMENON,
ADJUST QUANTITATED HERE SO I
WILL JUST KEEP GOING.
SO THE INCLUSIONS ARE REALLY
INTERESTING EPIPHENOMENON THAT
HAS BEEN UNCOVERED BY THIS LOSS
OF MYOSIN 5 B.
IT'S A PROCESS WE CALL APICAL
BULK ENDOCYTOSIS AND IT MAY BE
INVOLVED ESPEBLLY IN THENYONATAL
PERIOD AND WE COULD TALK ABOUT
WHAT IT COULD BE DOING BUT 1
THING THAT'S CLEAR HERE IS THE
FORMATION OF THESE INCLUSIONS IS
NOT THE DISEASE, IT'S THE
TARGETING OF THE TRANSPORTERS
THAT IS THE DISEASE.
SO, WELL, IF THAT'S TRUE, WHAT
DO WE DO IN TERMS OF THE
DISEASE.
SO THERE ARE A NUMBER OF
APPROACHES YOU CAN IMAGINE FOR
TREATING THESE CHILDREN, MITCH
HAS TALKED ABOUT ORGAN
TRANSPLANTATION WHICH CAN BE
SUCCESSFUL.
SOME HAVE SUGGESTED TO
REPOPULATE, LIKE HANZ CLAIFER
SUGGESTED THIS IN A MEETING
REPOPULATE THE INTESTAL
NUCLEOTIDESICOSA WITH WILD-TYPE
ORGANOIDS.
HANZ IS A HEMEATOLOGYIST, THERE,
IT'S REALLY HARD TO DO THIS WITH
23 FEET OF INTESTINE.
SOME PEOPLE HAVE SUGGESTED A
GENE THERAPY APPROACH AND WE'VE
LOOKED INTO THIS FOR OURSELVES,
RIGHT NOW THERE REALLY ISN'T A
WAY TO TARGET GENE THERAPY TO
INTESTINAL CELLS SO THIS HAS
BEEN A PROBLEM.
SO WE'VE SPENT A LOT OF TIME ON
THE POSSIBILITY OF
PHARMAICOLOGICALLY BYPASSING THE
TRAFFICKING BLOCKADE TO PROMOTE
MATURATION OF ENTER O CITES.
SO WHAT DOES THIS LOOK LIKE IN
SO THIS WORK WAS REALLY FOUNDED
AND IS CONTINUING TO BE DONE BY
ESWRIEWMY COGY WHICH WAS A
MEMBER OF MY LAB FOR A COUPLE OF
YEARS AND HOW HAS HER OWN LAB AT
VANDERBILT.
IZUMI IS UNIQUE IN THAT SHE HAS
A BACKGROUND IN NUTRITION, SO
SHE STARTED OUT AS A
NUTRITIONIST BEFORE SHE DID HER
Ph.D. IN PHYSIOLOGY AND SHE
RECOGNIZE THAD LPA, LYSOIFY O
SITTIC ACID WAS AN IMPORTANT
REGULATOR OF THE FUNCTION OF
EPITHELIAL CELLS AND NORMALLY IT
CAN INHIBIT CFTR ASK ACTIVATE
THE SODIUM HYDROIEN EXCHANGER.
SO SHE WAS SMART ENOUGH TO SAY,
COULD THIS AFFECT THE MICE.
SO WHAT SHE DID WAS SHE TREATED
MICE SHOWN HERE IN THE UPPER
RIGHT, WITH TAMOXIFEN TO INDUCE
THE KNOCK OUT OF MYO5 B AND THEN
TREAT IT OVER THE 53 DAYS WITH
LPA EITHER ORALLY OR IV.
SO HERE'S THE LONG INTESTINE,
HAVE YOU LONG VILLI, HAVE YOU
CRIPS, HERE'S THE NORMAL 4 DAYS
OF WHAT YOU SEE IN A MYOSIN 5 B
KNOCK OUT MOUSE.
HAVE YOU LONG CRIPS AND BLUNTED
VILLI.
IF YOU GIVE EITHER ORAL OR
IV LPA, YOU GET EXTENSION OF THE
VILLI ALTHOUGH YOU STILL HAVE
VERY LONG CRIPS.
BUT MOST IMPORTANTLY WHEN SHE
LOOKED AT SGLT1 AND HE3, HERE'S
THE VEHICLE AND YOU SEE SGLT1 IS
INTERNAL OR NOT THERE, AND HE3
IN THESE MICE WAS INTERNAL BUT
NOT AT THE APICAL MEMBRANE AS
YOU SEE IN THE CONTROL BUT NOW
IS AFTER LPA TREATMENT, YOU SEE
SGLT1 AND NHE3 ON THE APICAL
VILLI.
AND IMPORTANTLY YOU SEE A BIG
CHANGE IN THE BORDER.
SO THESE HAVE A STUNTED
MICROVILLI AND NOW AFTER LPA,
THEY STARTED MAKING REAL BRUSH
BORDERS IN MANY PLACES ALTHOUGH
THERE ARE STILL STUNTED 1S IN
SOME OF THE ENTER O CITES AND
NOTICE AS YOU MIGHT EXPECT
THERE'S NO CHANGE IN THE
MICROVILLUS INCLUSIONS, BETWEEN
THE VEHICLE AND THE LPA TREE.
OKAY, SO JUST RECENTLY IZUMI HAS
ALSO MOVED ON AND SHE'S GONE TO
A MORE SPECIFIC LPA 5 -- THAT'S
A MISTYPO, THIS SHOULD BE LP A
R5, AGONIST, NOT INHIBITION.
SO THE PROBLEM WITH LPA IS ITS
OILY, IT'SICKY, IT'S HARD TO
DELIVER, THIS COMPOUND HERE
WHICH IS A SPECIFIC LP A R 5
AGONIST IS WATER SOLUBLE AND
WHEN SHE GAVE THIS IN THE SAME
PATTERN, SORRY ABOUT THE LOSS OF
RESOLUTION HERE WHAT SHE AGAIN
SAW WAS A RETURN OF NORMAL LELGT
VILLI.
MORE IMPORTANT THAL LPR AGONIST
WHICH HAD AN AMAZING NAME OF
COMPOUND 1, WE HAVE TO GET A
BETTER NAME, SOMEBODY COME UP
WITH IT FOR US, PLEASE, THIS
COMPOUND 1 CAUSED THE RETURN OF
SGLT1 TO THE APICAL MEMBRANE
MUCH BETTER FRANKLY THAN JUST L
PA AND THE OTHER THING IT DID
WAS THAT IT IMPROVED THE
MYOCHONDRIAL FUNCTION IN THE
ENTER O CITES AND SO THIS IS
SEEN -- SO YOU SEE ACTIVE
EE ACTIVE MITOCHONDRIA
THROUGHOUT MOST -- YOU TEND TO
LOOSE THESE ESPECIALLY AT THE
APICAL POLE OF THE CELLS BUT
WHEN YOU GAVE COMPOUND 1, YOU
AGAIN BROUGHT ACTIVITY IN
MITOCHONDRIA BACK TO NEAR NORMAL
LEVELS IN MOST OF THE
ENTHUSIASMER O CITES, SO THIS
AGAIN, SAYS WE'RE PUSHING NORMAL
DIFFERENT WHEN WE GIVE COMPOUND
1.
NOW MOST EXCITINGLY, I HAVE
PREVIOUSLY SHOWN YOU THIS MICE
LOSE ABOUT 20% OF THE THEIR BODY
WEIGHT WITHIN 4 DAYS OF GETTING
LOSS OF MYOSIN 5 B AND THAT'S
EXACTLY THE AMOUNT OF TIME IT
TAKES TO GO FROM THE CRYPT TO
THE TIP OF THE VILLUS.
AND THAT'S USUALLY WHAT WE SEE.
IF YOU FOCUS YOUR ATTENTION HERE
ON THE MALES FOR INSTANCE, YOU
SEE ABOUT A 20-25% LOSS OF BODY
WEIGHT BUT WHEN YOU GIVE
COMPOUND 1 IN THE MALES, YOU GET
A MARKED IMPROVEMENT IN BODY
WEIGHT CHANGE AND THESE MICE DO
NOT HAVE AS MUCH DIARRHEA AND
THEY DON'T GET AS MUCH
DEHYDRATION.
INTERESTINGLY FOR REASONS THAT I
STILL DON'T KNOW, COMPOUND 1 IS
NOT THAT SUCCESSFUL IN THE
FEMALE MICE AND THIS IS
SOMETHING THAT IZUMI IS WORKING
ON A LOT NOW.
BUT AT LEAST THIS IS SAYING THAT
COMPOUND 1 MAY WORK.
SO IN TERMS OF LPA TREATMENT,
THIS IS WHAT WE LEARNED AND THIS
IS I THINK STILL SURPRISING.
THERE ARE TREATMENTS THAT CAN BE
GIVEN THAT CAN AMELIORIATE THE
BLOCKATE SEEMINGLY WITH MYO5 B
LOSS, SO THERE'S HOPE TO GET
AROUND THE PATHOPHYSIOLOGY, BUT
THERE'S A LOT OF THINGS THAT
HAVE TO WORK IN OUR FAVOR, THE
DRUGS HAVE TO BE DELIVERED
EFFECTIVELY TO THE MUCOSA AND
THIS IS A PROBLEM OF SOLUBLITY
OF THE DRUG.
THE COMPOUND 1 SEEMS TO BE
BETTER BUT IT STILL NEEDS
OPTIMAL DOSING.
THERE MAY BE LITTLER DRUGS OUT
THERE, BUT AT LEAST THIS IS
SAYING OKAY, WE CAN HAVE AN
EFFECT ON THIS PATHOPHYSIOLOGY.
NOW I'M GOING TO GIVE 1 MORE
SCENARIO THAT MAY LEAD US TO AN
UNDERSTANDING OF THE PROCESS AND
MAYBE NEW THERAPIES AND THAT'S
TO GO BACK TO THIS IDEA THAT
WHEN YOU HAVE MBID, THE CELLS
NEVER -- WHEN THEY LEAVE THE
VILLUS, THEY DON'T REALLY LEAVE
SO THEY DON'T MAINTAIN THEIR
CRYPT LIKE DIFFERENTIATION, SO
THIS IS AGAIN WHAT BRINGS UP
THIS IDEA OF AND THE MVID
PEASHTS HAVE A CRIP VILLUS
THAT'S FILLED WITH CRYPT LIKE
CELLS.
SO THIS MAKES SENSE BECAUSE THE
CRYPT LENGTH IS EXPANDED.
THERE'S LOSS OF TOUGH CELLS
WHICH ARE A SENSING CELLS,
THERE'S AN EXPANSION OF PANNA
CELLS AT THE BASE OF CRYPTS AND
ALMOST MORE IMPORTANTLY THERE'S
ALMOST A COMPLETE LOSS OF LIGAND
EXPRESSION WITH A MAINTENANCE OF
NOTCH SIGNALING SO THIS BALANCE
IS -- THIS IS AN IMBALANCE OF
THE NORMAL SYSTEM OF PUSH ME,
PULL YOU THAT YOU SEE IN A CRYPT
THAT LEADS TO DIFFERENTIATION.
SO COULD WE USE THIS AS A
THERAPEUTIC APPROACH AND TO LOOK
AT THIS, WHAT IZUMI DID AGAIN,
WAS SHE TOOK THOSE SAME
INDUCIBLE KNOCKOUT MICE AND
INDUCED KNOCK OUT WITH TAMOXIFEN
AND THEN ON DAY 1 GAVE 1 DOSE OF
DVC, AN INHIBITOR OF NOTCH AND
GAMMA SECRET ACE, AND WHAT SHE
SAW WAS THE VILLUS CRYPT RATIO
IMPROVE AND AGAIN, SHE GOT A
RETURN OF NHE3 AND SGLT1 TO THE
APICAL SURFACE IN THESE MICE.
NOW, HONESTLY, THIS IS NOT A
PRACTICAL SOLUTION BECAUSE THESE
DRUG -- THIS DRUG IS VERY TOXIC
SO WE'RE NOT GOING TO GIVE THIS
TO KIDS.
BUT IT SAYS, YOU KNOW ALL THIS
STUFF SAYS, THAT SOMEWHAT
SURPRISINGLY, WE CAN RESET SOME
OF THE ABERRANT BLOCKADE OF
PROGENITOR -- STEM PROGENITOR
CELLS GIVING RISE TO ACTIVE
ABSORBAATIVE CELLS BY EITHER LP
A R 5 ACTIVATION, OR REBALANCING
OF NOTCH SIGNALING.
AND THIS I THINK IS WHERE WE
HAVE TO GO TO FIND A PRACTICAL
TREATMENT FOR THESE CHILDREN
THAT CAN BE ADMINISTERED SAFELY.
I WILL END WITH A LITTLE BIT OF
BANGING THE DRUM FOR REALLY ALSO
DERIVING PATIENT SAMPLES FOR
PATIENT DIRECTED DISEASE AND SO,
OVER THE LAST SEVERAL YEARS,
WE'VE BEEN ABLE TO MAKE
INTESTINAL ENTHUSIASMERROID SAYS
FROM MVID PATIENTS WITH VARIOUS
MUTATIONS.
HERE I'M SHOWING YOU AIR LIQUID
INTERFACE MONOLAYER CULTURES OF
HEALTHY DUODENUM, ENTERROIDS AND
STAINED WITH F-ACTIN SO YOU CAN
SEE THEY HAVE A VERY NICE BRUSH
BORDER.
AND THIS IS THE CULTURE OF AN
MVID PATIENT WITH WITH A
MUTATION, 1 OF MITCH SHUB'S
PATIENTS ACTUALLY, AND YOU CAN
SEE VERY LITTLE OR DISCIPLINARY
MINUTIVE IF ANY STAINING ON THE
BORDER.
NOW WHAT IZUMI HAS DONE RECENTLY
WITH JAY AT HARVARD, IS THEY
WENT AND THEY LOOKED AT TREATING
THOSE MONOLAYERS WITH ANOTHER
NOTCH INHIBITOR EAPT WHICH IS A
GAMMA SECRET ACE INHIBITOR AND
THEY WERE AGAIN ABLE TO BRING
BACK NHE3 TO THE APICAL MEMBRANE
OF THOSE NAVAJO ENTER O SIGHTS
AND THEY WERE ALSO ABLE TO SEE
NHE3 ACTIVITY AFTER TREATMENT
WITH THE NOTCH INHIBITOR.
SO, THESE -- WE REALLY FEEL THAT
GET THESE ENTERROIDS FROM
PATIENTS GIVES US A REALLY
PRACTICAL MODEL FOR DOING
FURTHER DRUG SCREENING AND
DEVELOPING NEW TREATMENTS THAT
MAY BE MORE PRACTICAL FOR THESE
PATIENTS.
SO WHAT IS MVID TAUGHT US SO
FAR?
AS I SAID IT'S TAUGHT US
SOMETHING ABOUT HOW THERE ARE
MULTIPLE WAYS TO GET TO THE
IEE, AUDIENCE PICKA MEMBRANE,
NOT JUST 1, NOT JUST A BIG ARROW
GOING THROUGH THE GOLGI.
YES, LOSS OF MY O SIGN 5 B
REVEALS A NOVEL APICAL BULK
ENDOCYTOSIS PATHWAY, AND IT
REMAINS TO BE SEEN WHAT IT'S
THERE FOR BUT IT'S NOT THE MVID
DISEASE ITSELF, AND IT'S ABLE TO
SHOW THAT IT IS POSSIBLE TO
CHANGE THE DYNAMICS OF APICAL
TRAFFICKING OF TRANSPORTERS THAT
CAN BYPASS OR WHAT YOU THINK WAS
A REALLY SIGNIFICANT BLOCKADE
AND PERHAPS AMELIORATE PATIENTS.
NOW, I THINK VERY IMPORTANT
CLINICAL IMPLICATIONS OF THIS
WHOLE PIECE OF WORK AND ALSO FOR
CONGENITAL DIARRHEAL SYNDROMES
IN GENERAL AND THIS IS THE FOCUS
OF THE PEDIATRIC CONGENITAL
DIARRHEA ENTER OPEN MEETINGATHY
CONSORTIUM THAT WE'RE PART OF
WITH HARVARD, UCLA AND SICK KIDS
AND THAT IS THE FOLLOWING: IT'S
PRETTY CLEAR THAT IN TAKING CARE
OF THESE PATIENTS AS MITCH
REALLY EMPHASIZED, IT'S REALLY
IMPORTANT TO DETERMINE EARLY ON
THAT THERE'S A PROBLEM AND GET
THESE PATIENTS INTO A NEW
PIPELINE AND THAT NEW PIPELINE
IN THIS DAY AND AGE, IS EARLY
GENOMICS SEQUENCING OF THE PRO
BAND AND THE PARENTS THAT CAN
LEAD TO A DEFINITIVE DIAGNOSIS
FOR THESE CONGENITAL DISEASE.
THERE ARE A NUMBER OF THESE NOW.
I ALSO WANT TO EMPHASIZE AND
THIS IS THE HARDER THING TO DO,
IS TO GET AT THE TIME
OFENDOSCOPY, WE REALLY NEED TO
BE RETRIEVING INTESTINAL SAMPLES
TO MAKE ENTERROIDS SO THAT WE
CAN MODEL OF PATIENT'S DISEASES,
SEXER SPECIALLY IF THEY HAVE A
NEW MUTATION.
SO INCREASINGLY WE'RE TRYING,
SPECIALLY AT OUR INSTITUTIONS TO
MAKE THIS PART OF THE STANDARD
OF CARE IF YOU'RE GOING IN, TO
SCOPE THESE PATIENTS, PLEASE,
PLEASE, PLEASE, GET BYOPSYS AND
SEND THEM OFF TO PREPARE
ENTERROIDS, AND INTB CAN SEND
THEM TO THE PDCODE CONSORTIUM
AND IT'S REALLY SIMPLE, YOU JUST
SEND THEM TO US OVERNIGHT IN SAY
LEAN OR OPTIMALLY WISCONSIN
SOLUTION AND WE WILL BE ABLE TO
MAKE ENTERROIDS ALMOST ALL THE
TIME.
SO I THINK THIS IS REALLY
CHANGING HOW WE WILL DEAL WITH
THESE KIDS WHO ARE REALLY VERY
SICK IN THE FIRST COUPLE OF
WEEKS OF LIFE.
SO, WITH THAT I WILL JUST THANK
A NUMBER OF PEOPLE IN MY LAB,
WHO HAVE WORKED ON THIS AND ARE
CONTINUING TO WORK ON THIS AND
ALSO, THANK MY COLLABORATORS,
MITCH OF COURSE, AND THE
PEDIATRIC DIARRHEA CONSORTIUM
AND WITH THAT I WILL STOP AND I
GUESS WE CAN TAKE ANY QUESTIONS
>> OKAY.
WELL, THANK YOU BOTH FOR
EXTREMELY EXCITING AND IMPORTANT
PRESENTATIONS.
WE HAVE SEVERAL QUESTIONS THAT
HAVE COME IN.
PEOPLE HAVE ASKED ABOUT LIVER
DEC, I KNEW WE WOULD GET THERE.
[LAUGHTER]
WELL, MAYBE BOTH OF YOU WOULD
DISCUSS THIS A LITTLE BIT.
IT SOME PATIENTS, THE LIVER
DISEASE SEEMS TO BE EXTREMELY
SERIOUS SITUATION AND MAYBE YOU
WOULD LIKE TO ELABORATE A LITTLE
BIT MORE ABOUT WHAT THE
POSSIBILITIES ARE NOW, EITHER 1
OF YOU, MITCHELL YOU DISCUSSED
THIS A LITTLE BIT, DO YOU WANT
TO ADD TO THAT CONSIDERATION?
WHAT'S YOUR THINKING?
>> I WILL LET JIM TAKE OVER WITH
THE SELECT PROCESS, BUT THE ONLY
THING THAT STRUCK US EARLY ON
WAS THAT NORMALLY WITH TPN
RELATED COAL O STASIS, WE SEE
ALL THE GGT, GAMMA TBLIEWTA
TRANSFER ACE, AND IN OUR
PATIENTS WITH MVID, IT WAS A BIG
PUZZLE WE DIDN'T UNDERSTAND WHAT
IT MEANT BUT ALL OF THEM HAD
NORMAL GGT LEVELS.
AND IT MADE ME WONDER THAT IT
WAS SOMETHING DIFFERENT THAN
JUST TPN ALONE THAT WAS DOING
THIS.
SO FROM A CLINICAL SIDE, I CAN
SAY AND WE'VE BEEN TAUGHT BY
OTHERS, THAT LOW GGT COLO-STASIS
IS ONLY DUE TO 2 ENTITIES, 1
BEING INBORN AS A BIOMETABOLISM
AND OTHER IS FORMS OF PFIC, SO
BASED ON THAT CLINICALLY, IT
JUST DIDN'T FIT WITH TTN ALONE
AS DRIVING LIVER DEC.
NOW I WILL TURN IT OVER TO I
DIDN'T MEAN WHO I KNOW HAS
THOUGHT A LOT ABOUT THIS NYEAH,
YOU KNOW WHEN I FIRST GOT INTO
THIS AND TALKING TO MITCH, I
ASSUMED THE LIVER DISEASE WAS
TOTALLY FROM TPN.
AND WHEN WE DID THE INITIAL MY
MYOCIDE GERM LINE KNOCK OUT IN
MOUSE, WE WERE NOT REALLY SURE
ABOUT THE LESIONS.
AND I MEAN BECAUSE THOSE MICE --
THOSE MICE I SHOULD HAVE SAID,
THEY DIE IN THE FIRST 40 DAYS OF
LIFE.
BUT WHEN WE DID THE PIG WHERE
THE PIGLETS WERE BORN, WE FOUND
THAT THEY HAD TRAFFICKING
DEFECTS.
SO THEY WERE BORN AND ON THEIR
FIRST DAY, IF WE SACRIFICED THE
MOUSE -- THE PIG ON ITS FIRST
DAY OF LIFE, THERE WERE LIVER
DEFECTS.
NOW SUBSEQUENTLY, AMY HAS GONE
FORWARD AND DONE A LIVER
SPECIFIC KNOCK OUT AND OVER
ABOUT 6 MONTHS THOSE MICE DO
SEEM TO DEVELOP A PFIC SCENARIO
IT TURNS OUT.
AND THEP THERE'S THE REAL
PUZZLING QUESTION WHICH IS THERE
ARE KIDS WHO JUST HAVE PFIC 6,
WHO HAVE MOYSIN 5 B MUTATIONS.
I THOUGHT THIS IS INSANE, IT
CAN'T BE TRUE BUT WE ACTUALLY
MADE 1 OF THESE KNOCK OUTS IN
MICE, C26 XR AND LOW AND BEHOLD
AMY STUDIED THIS MOUSE QUITE A
LOT AND IS ABOUT TO PUT A PAPER
OUT ON IT, THE MOUSE OVER 6 +
MONTHS GETS PFIC AND THE
INTESTINE IS ESSENTIALLY NORMAL.
NOW WHY IS THAT?
I HAVE NO IDEA.
WE'VE ACTUALLY LOOKED AT THE
AMERICA YO5 B, C266 R MUTATION
AND REALLY THE MOTOR IS PRETTY
NORMAL.
SO AT THIS MOMENT, I STILL CAN'T
FIGURE OUT WHY SOME OF THESE
MUTATIONS GIVE ONLY LIVER
DISEASE AND I THINK THAT'S A
REALLY INTERESTING PROBLEM.
>> SO HAD THERE BEEN PATIENTS
THAT REQUIRE BOTH MIXED
TRANSPLANT OF THE LIVER AND
INTESTINE FOR SURVIVAL?
>> I THINK PRETTY MUCH NOW,
ANYBODY BEING TRANSPLANTED WILL
HAVE COMBINED TRANSPLANT BECAUSE
-- WHAT DO YOU THINK MITCH --
I'VE HEARD PEOPLE ARGUE SOMEWHAT
BACK AND FORTH ON THIS,
OBVIOUSLY THERE'S A NUMBER OF
MUTATIONS BUT IT SEEMS TO ME
THAT MOST OF THE PATIENTS, I
JUST HAVE BEEN CONSULTED OR
HEARD ABOUT EVENTUALLY IF THEY
HAVE INTESTINAL DISEASE
EVENTUALLY THEY GET LIVER
DISEASE?
DO YOU THINK THAT'S TRUE MITCH?
>> I DO, OBVIOUSLY WE'VE SEEN A
NARROWER BAND OF MUTATIONS, WE
HAVE CARED FOR 2 SIBLINGS THAT
WERE HISPANIC THAT I'M ASSUMING
HAD A DIFFERENT MUTATION AND
THEY DEVELOP LIVER DISEASE AND
THE ONLY THING I CAN SAY, I KNOW
IN THE NAVAJO, WE HAVE LOTS OF
SHORP BALB PATIENTS THAT ARE ON
TPN FROM THE WORD GO AND FOR A
LONG TIME.
AND THE RATE AT WHICH THEY
DEVELOP LIVER DISEASE DOESN'T
APPEAR TO BE AS FAST AS THE RATE
AT WHICH THE NAVAJO MICRODOSE SO
I ALWAYS THOUGHT AND COUPLED
WITH THE NORMAL GGT, IT JUST
SAID TO ME, THAT THERE WAS
SOMETHING ELSE GOING ON IN THE
LIVER THAT IS OVER AND ABOVE
JUST TPN.
>> SO WHEN YOU ARE TALKING ABOUT
LIVER DISEASE, BOTH OF YOU ARE
TALKING ABOUT A FORM OFA
PROGRESSIVE FAMILIAL INTERO
PATTIC COAL O STASIS, IS THAT
THE UNIFORM PATHOLOGY THAT YOU
SEE?
OR IS THAT BASED UPON THE FACT
THAT YOU SHOW AND COMPARE TO
TRAFFICKING OF AN ABC
TRANSPORTERS?
WHAT IS IT THE ACTUAL PATHOLOGY?
>> YOU KNOW THE PATHOLOGY IS
JUST PROGRESSIVE CIRRHOSIS AND
LIVER DISEASE AND I DON'T KNOW
IF WE WOULD BE ABLE TO
DISTINGUISH WHICH TYPE TO BE
HONEST WITH YOU.
I DON'T KNOW THAT PFIC -- MAYBE
YOU KNOW THIS BETTER THAN I DO,
BUT I'M NOT AWARE PFICs GIVE A
UNIQUE HISTOLOGY TYPE THAT WOULD
DISTINGUISH IT FROM OTHER FORMS
OF NEONATAL LIVER DISEASE.
JIM DO YOU HAVE A COMMENT?
>> YEAH, I'M NOT GOING TO TALK
ABOUT LIVER IN FRONT OF YOU.
[LAUGHTER]
NO, BUT AT LEAST, SO I WAS JUST
AT A MEETING WITH AMY AND WHAT
SHE SHOWED ME WAS THE MICE SORT
OF LIKE WHAT WE SAW IN THE PIG
BUT ACTUALLY IT'S MORE CLEAR IN
THE MICE NOW THAT HE'S GOT IT,
THEY DON'T REALLY GET A SERIES
POINTSOTTIC PICTURE, THEY GET A
COAL O STASIS PICTURE MORE.
SO I THINK IT IS PROGRESSIVE, IT
IS THAT PROGRESSIVE ENDOLYNN
COAL O STASIS THAT KICKS IN XI
WOULD MAWG THAT BECAUSE THE
PROCESS IS ONGOING THAT AGAIN,
AS MITCH SAID, TPN'S GOT TO MAKE
THIS WORSE.
>> THERE'S NO PFIC LONG-TERM
ENDS UP WITH PROGRESSIVE LIVER
DEC, IT'S NOT -- SO I THINK THE
LIVER GERONTOLOGYSTSS DAMAGED AS
A RESULT OF THE BIOSALTS NOT
BEING EXCRETED PROPER LOW AND
PROBABLY OTHER TOXINS THAT NEED
TO BE EXCRETED AND I THINK IT
ENDS UP DAMAGING THE HEPATITIS
HEPATOCYTES.
>> I WOULD VENTURE THERE'S ALSO
PROBABLY A SERIOUS PROBLEM IN
THE ENERGETICS WITHIN THE CELL.
IN OUR MODEL WHICH IS NOT --
WHICH IS -- YOU KNOW WE STUDIED
IN NORMAL LIVER CELLS WHERE WE
SORT OF REMOVE MYOSIN 5 B, OR
INHIBITED RAB 11A AND SO FORTH,
THERE WHAT HAPPENS IS THAT YOU
GET A REAL YEVENTUAL
MITOCHONDRIA INJURY IN THE SENSE
THAT ENERGY PRODUCTION, ATP
LEVELS FALL, THE OKB1 MK-PATHWAY
KICKS IN AND FOR A WHILE
POLARITY IS MAINTAINED BUT
EVENTUALLY THOSE CELLS BECOME
POLARIZED AND THE BIO ACIDS
ACCUMULATE AND RAISE HELL AND
THE CELL DIES, AND SO I WONDER
WHETHER IN THESE ORDERS OF
TRAFFICKING, WHETHER THE ENERN
GETTICS OF THE CELL BE IT IN THE
GUT OR IN THE LIVER, ARE
PROFOUNDLY AFFECTED AND HAVE
SECONDARY EEIVETS THAT
ULTIMATELY SAY LEAD TO CIRRHOSIS
IN THE LIVER AND FURTHER DAMAGE
IN THE GUT.
IS THERE ANY OTHER --
>> I THINK YOU'RE RIGHT.
YOU KNOW, IZUMI SHOWN IN THE
INTESTINE VERY NICELY IS WHEN
YOU LOOK AT THE MITOCHONDRIA IN
THE CRYPT PROGENITORS, WHAT YOU
SEE IS THEY LOOK REALLY BAD.
THEY HAVE -- THEY LOOK TERRIBLE.
INTERESTINGLY, THE PAN OF CELLS
RIGHT NEXT DOOR TO THE
PROGENITORS, THEIR MITOCHONDRIA
ARE FINE.
SO THERE IS A STEM CELL THING,
AND AMY SHOWED ME A COUPLE OF
INITIAL EMs, WHERE I THINK
SHE'S SEEING PROBABLY THE SAME
PATTERN.
SO I THINK YOU'RE TOTALLY RIGHT.
I ENERGETICS ARE MESSED UP IN
THESE CELLS AND MAYBE IT'S
BECAUSE THE LIVER CELLS DON'T
TURNOVER AS MUCH THAT IT IS THAT
IT TAKES LONGER FOR REALLY TO
IMPACT BUT IT GETS THERE
EVENTUALLY.
>> WELL, IT HAS A LONG LIFE
SPAN.
>> DENDRITIC CELLROCYTES
TURNOVER OVER 5 DAYS,
EVERYTHING'S CRANKING.
>> LET ME ASK BOTH OF YOU A
QUESTION, DO YOU THINK BECAUSE
OF THE ABNORMAL SURFACE OF THE
INTESTINAL LINING, DO YOU THINK
THAT MIGHT ALLOW FOR ENTER O
TOXINS AND OTHER THINGS TO CROSS
THE BARRIER MORE EASILY AND
UNFORTUNATELY LIVERS ARE THE
FIRST POINT OF CONTACT TYPICALLY
IF THOSE ENTER A TOXINS CROSS.
-- ENTER O TOXINS CROSS.
>> WELL, GHEE, I GUESS IT'S A
POSSIBILITY AND THE OTHER
QUESTION, YOU KNOW, WHAT'S THE
IMPACT ON, YOU KNOW,
BIORECYCLING THROUGH THE ENTER O
HEPATIC CIRCULATION AND I DON'T
THINK WE KNOW THAT EITHER AND 1
THING WE DO KNOW IS THAT THE
MUCOSA IS NOT LEAKY.
IN FACT, IT ACTUALLY HAS
SLIGHTLY HIGHER RESISTANCE.
THIS IS NOT A LEAKY THING, LIKE
YOU SEE, SAY IN DGDAMUTATIONS.
BUT I ACTUALLY, YOU KNOW IT'S
CERTAINLY POSSIBLE, THE OTHER
THING IS BECAUSE WE DON'T HAVE
ALL THIS CORRECT APICAL
TRAFFICKING, WE'RE PROBABLY ARE
SETTING IT UP FOR THAT, EXACTLY
THOSE MECHANISMS SO THERE'S LESS
ALCO LINE PHOSPHOR TAISS--SYNTH
THERE, THEY DON'T PRESENT
PHOSPHOR LIESATE 2 FOR INSTANCE
WHICH IS NECESSARY FOR
CONVERTING PHOSPHO LYTIC ACID TO
FOSTER NURSED O LYTIC ACE, YOU
CAN'T JUST GIVE THE KID PHOSPHO
LYTIC ACID, LIKE THE BODY
BUILDERS USE BUT BECAUSE THEY
DON'T TRAFFIC FOSTER NURSED
FOCUSED ON LIPASE A2, IN THE
ACHE PECULIARAL MEMBRANE THEY
CAN'T CONVERT THE ACID TO THE
LYSOFOSTER NURSED FOCUSED ON
SITTIC ACID.
SO I THINK YOU'RE RIGHT, THEY
ALSO WILL BE SET UP AND MAYBE
THAT SETS THEM UP FOR THE SEPSIS
PARTIALLY.
YOU KNOW WE LIKE TO BLAME IT ON
THE CATHETERS BUT IT MAY NOT BE
COMPLETELY.
>> WHAT ABOUT THE KIDNEY?
IN SOME OF THE REPORTS THESE
PATIENTS HAVE A NEFF ROTTIC LIKE
SYNDROME AND OTHER DEFECTS WE
DON'T HEAR MUCH ABOUT THE KIDNEY
IN THESE DISORDERS?
IS THIS A PROBLEM IN THE
PATIENTS THAT EITHER OF YOU HAVE
DEALT WITH?
STRKS WE HAD PATIENTS DEVELOP
NEPHROTIC SYNDROME AND WE WERE
SURE -- WE LET JIM LOOK AT THOSE
AND WE JUST WEREN'T ABLE TO
IDENTIFY A REASON.
>> YEAH.
>> NOT FOR A LOCK OF TRYING.
HOWEVER, I CAN TELL YOU THE
PANCREAS, WE HAD A PATIENT THAT
DEVELOPED DIABETES TYPE PICTURE
AND WE HAD SENT JIM SAMPLES OF
PANCREAS FROM A PATIENT THAT
RECEIVED A MULTIORGAN TRANSPLANT
AND THE PANCREAS DID NOT LOOK
NORMAL IN THAT PATIENT WHICH IS
ANOTHER REASON THAT I THINK IF
THESE PATIENTS ARE GOING TO BE
TRANSPLANTED, YOU BETTER THINK
ABOUT WHAT OTHER ORGANS MIGHT
LOOK LIKE, THE LIVER, THE
PANCREAS, THE TOMAC, THEY MAY
NOT BE NORMAL EITHER.
>> YEAH, SO 1 THING I DO KNOW,
SO 1 THING WE SHOULD HAVE SAID
IS WHY IS IT SO PROMINENT IN THE
INTESTINE, AND IT TURNS OUT, THE
INTESTINE AND ALSO THE LIVER,
THERE ARE 2 -- THERE ARE 2
FAMILY MEMBERS VERY CLOSE TO
EACH OTHER, MY O SIGN 5 A AND MY
O SIGN 5 B, FOR REASONS THAT
MAKE NO SENSE EVOLUTIONARY, THE
GUT HAVE NO MICE O SIN 5A, AND
IT DOESN'T UPREGULATE IT AND
LIVER ALMOST HAS NO MY O SIGN
5A, SO WHERE AS THE KIDNEY HAS
MORE 5 A THAN 5 ABOUT ISSUES THE
BRAIN MORE 5A THAN 5 B, SO I
THINK THESE OTHER ORGANS MIGHT
BE PROTECTED BECAUSE THEY CAN
SUBIN 5A TO DO WHAT 5 B DOES,
HOWEVER I'M FASCINATED BY THIS,
SO I HAVE TO TELL YOU, I HAVE A
MOUSE BREEDING RIGHT NOW, I'M
TARGETING MY O 5 B KNOCK OUT IN
THE MALTUBULES.
>> SO GIVE ME A FEW MONTHS AND
I'LL TELL YOU ABOUT IT.
>> SO WHAT ABOUT THE BRAIN.
IS THERE A DIFFERENCE IN THE
EXPRESSION OF 5 A OR 5 B IN
MIEWRONS OR IN GLUE MARIOUSA IN
-- OR IN GLIA?
>> SO I'VE ONLY DO A LITTLE BIT
ON THIS, AND I REALLY WANT TO
GET BACK TO IT BECAUSE I STARTED
LIFE AS A NEUROSCIENTIST, BUT I
HAVEN'T -- I HAVEN'T DONE A
DIRECT TARGETING INTO THE BRAIN
BUT I REALLY WANT TO DO IT.
I THINK WE HAVE TO TRY IT,
MOSTLY FOR IMPLICATIONS BUT YOU
KNOW SOME OF THESE KIDS ARE
LIVING A LONG TIME ON TPN OR
TRANSPLANT, I THINK THE HARVARD
GUYS WHO ARE JUST LIKE THE
BOSTON CHILDREN GUYS SEEM TO BE
THE GURUS OF TPN.
SOME OF THOSE KIDS THEY'VE BEEN
TAKING CARE OF ARE GOING TO
COLLEGE, WITH TPN.
SO I DON'T KNOW ABOUT, YOU KNOW
-- I HAVEN'T HEARD ABOUT
SEEREBERAL DEFEBTS ALTHOUGH WHEN
YOU'VE BEEN THIS SICK, USUALLY
OFTEN HAVE DEVELOPMENTAL DELAYS,
RIGHT?
>> YEAH, A LOT OF OUR KIDS SEEM
TO BE DEVELOPMENTALLY DELAYED
COMPARED TO SIBLINGS BUT WE
ATTRIBUTE IT TO CHRONIC ILLNESS
AND MAYBE FACTORS THAT WE WERE
BT REPLACING IN THE TPN, ET
CETERA.
>> YEAH, SO THAT'S GOING TO BE
HARD, BUT I THINK WE NEED TO --
JUST LIKE I SAID I'M GOING TO
LOOK AT THE KIDNEY, I THINK
EVENTUALLY, I GOTTA SEND IT TO
THE BRAIN AND FIND OUT.
SO WHAT'S THE ROLE OF THE
ADAPTER PROTEINS THAT YOU
DESCRIBED RAB 11A ADAPTER AND SO
FORTH, ARE THEY PLANNING A
FUNCTIONAL ROLE IN RAB 11A
ACTIVITY?
>> SO IT'S THOUGHT THAT IT'S THE
RAB PROTEIN THAT YOU KNOW BINDS
THE MYOSIN 5 TO THE VESICLE.
OR RAB ETA THAT BINDS THE MYOSIN
5 TO ANOTHER VESICLE POPULATION.
SO, AS FAR AS WE KNOW THE RABS
DON'T AFFECT THE MOTOR ACTIVITY
ITSELF, BUT CERTAINLY AFFECTS
LOCALIZATION.
BUT WHAT MICE O SIN 5 B IS
FUNCTIONALLY DOING IN THESE
CELLS.
YOU KNOW WE LIKE TO THINK OF
MYOSINS AS A MOTOR BUT IF YOU
ACTUAL LYE LOOK AT THE BEHAVIOR
OF MYOSIN 5 ABOUT, IT LOOKS LIKE
A MICROTUBULE ASSOCIATED
PROTEIN, SO THE IDEA WE'VE
ACTUALLY COME UP WITH, WHICH IS
A CONSTRUCT AND MAY BE FANCIFUL
IS THAT THE MYOSIN 5 B REALLY IS
NOT FUNCTIONING SO MUCH IN THE
MOVEMENT OF THE VESICLE TO THE
APICAL MEMBRANE, BUT AT THE
APICAL MEMBRANE AND BELOW IT IS
THIS REALLY DENSE EFFECT AND
STRUCTURE, THE TERMINAL WEB AND
WHAT WE'VE COME UP WITH THIS
IDEA THAT MAYBE, WHAT THE MYOSIN
5 B IS, RATHER THAN A
PERASSESSESSIVE MOTOR, IT'S
ACTUALLY A PERASSESSESSIVE
ANCHOR AND THE VISUAL THAT I USE
IS WHAT I CALL THE CRAZY
ORANGUTAN.
WHERE IF YOU HAVE A BUNCH OF BAR
HOLDS LIKE YOUR KIDS USED TO
CLIMB ON AND IT'S MOVING, THEN
THE MOTOR WILL STAND IN PLACE
WHILE JUST GRABBING LIKE THIS,
UP AND DOWN.
AND THAT MIGHT HOLD THE VESICLES
IN PLACE UNDERNEATH THE APICAL
MEMBRANE DIFFUSE, WHAT'S IN
FAVOR OF THAT?
WHEN YOU LOOK AT RAB 11 IN MICE
O SIGN 5 B, IT'S CONCENTRATED
RIGHT UNDER THE -- RIGHT UNDER
THE APICKA MEL BRAIN IN
ANDROGENROCYTES BUT THIS IS, YOU
KNOW SOMETHING THAT NEEDS
FURTHER INVESTIGATION.
>> THERE'S SOME QUESTIONS ABOUT
RAB 8.
WHICH YOU BOTH COMMENTED ABOUT.
IS THERE A FORM OF MICROVILLAR
INCLUSION BODY DISEASE IN HUMANS
THAT IS SPECIFICALLY DUE TO
MUTATIONS IN RAB 8?
>> SO AS FAR AS I KNOW, NO 1 HAS
EVER SEEN A PATHOLOGICAL
MUTATION IN 8 A OR 11A.
AM I RIGHT?
MITCH, DO YOU KNOW OF ANYBODY?
>> NO, NO.
>> NO?
SO WHAT WAS DONE?
SO WAS THAT INITIALLY A GROUP IN
JAPAN DID THE RAB ETA KNOCK OUT
AND THEY SAW LARGE LIES STUDIES
OF MULTIPLE ENDOCRINES AND A FEW
MICROVILLUS INCLUSIONS IN THOSE
MICE.
AND THE MICE DIDN'T REALLY HAVE
HUGE AMOUNTS OF DIARRHEA, N
AN GOUH DID KNOCK OUTS OF 11A
AND HE SAW A FEW MORE INCLUSIONS
AND GOT A LITTLE BIT WORSE
DIARRHEA THEN HE KNOCKED THEM
BOTH OUT TOGETHER AND HE GOT A
MORE PROMINENT EFFECT BUT
ACTUALLY WHAT THEY SAW WAS MORE
MISSED TRAFFICKING.
SO INSTEAD OF HAVING MICROVILLI
ON THE APICAL MEMBRANE, YOU
WOULD HAVE MICROVILLI ON THE
LATERAL MEMBRANE, AND ACTUALLY
YOU CAN SEE THAT IN SOME MICRO
VILLUS INCLUSIONS WITH THESE
KIDS, SOME OF THEM DO GET
LATERAL MICROVILLI.
BUT AS FAR AS I KNOW, NO 1 HAS
EVER SEEN AND IT MAY JUST BE
BECAUSE IF YOU CREW UP RAB 11A
AND RAB ETA, IT WILL PROBABLY
GIVE YOU A DEVELOPMENTAL LETHAL.
BOTH OF THOSE WERE DONE WITH
TARGETED ALLELES NOT GERM LINE.
SO, SO THAT MAY BE WHY WE DON'T
EVER SEE IT IN KIDS.
>> THAT'S VERY INTERESTING.
SO WE HAVE A QUESTION HERE,
SEVERAL WHERE PEOPLE ARE
INTERESTED IN HEARING FOR THE
FIRST TIME THAT THE NAVAJO HAVE
THIS SUBSTANTIAL NUMBER OF RARE
INHERITABLE DISEASES.
SO MITCHELL WOULD YOU ELABORATE
A LITTLE BIT ON SOME OF THE
OTHER DISEASES JUST SO FOLKS
HAVE A GLIMPSE OF THIS
EXTRAORDINARY DEVELOPMENT IN
THIS POPULATION?
>> YEAH.
THERE ARE SEVERAL.
ONE OF THEM IS A MITT O
CHONDRIAL DEPLETION DISORDER IN
PB17.
WE USED TO CALL NAVAJO
NEUROPATHY BUT NOW HAS EVOLVED
TO MPV17, DESCRIBED IN OTHER
POPULATIONS BUT THEY HAVE A
SPECIFIC MUTATION IN THE MVP 17
AND THERE'S ANOTHER CONDITION
CALLED OCCUE TAINIOUS ALBANNISM
TYPE 2 THAT INCREASE INCIDENCE
IN NAVAJO, THERE'S A FORM OF
BRAIN STEM DISGENESIS THAT USED
TO BE CALLED ABNORMAL GLUCOSE
TOLERANCA BASKIN BRAIN STEM
GENESIS BUT NOW REFERRED TO AS
BRAIN STEM DISGENESIS, AND THEY
HAVE A FORM OF SEVERE COMBINED
IMMUNO DEFICIENCY.
ALL OF WHICH IS CONSERVED
MUTATIONS, THE MUTATIONS ARE
KNOWN, AND EVERY PATIENT WITH
THAT CONDITION IN THE NAVAJO HAS
THE EXACT SAME MUTATION.
SO 1 OF THOSE IS THE GDIAC
HIGASHI, A LIES STUDIES OF
MULTIPLE ENDOCRINAL DISORDER?
>> YOU MAY BE CORRECT.
I MAY HAVE MISSED 1, I WAS
TRYING TO REMEMBER ALL THE 1S I
COULD THINK OF BUT THAT MAY BE
ANOTHER 1.
>> SO GIVEN THE RATHER
DISTINCTIVE HISTORY OF MANY OF
THE NATIVE AMERICAN TRIBES FROM
THE POINT OF THEIR ORIGINS OR
WHERE THEY FINALLY WOUND UP, DO
YOU FIND WITHIN OTHER SOMEWHAT
ISOLATED POPULATIONS OF NATIVE
AMERICANS, THESE DISORDERS
APPEARING OR IS THIS TRULY IN
THAT POPULATION UNIQUE FOR THE
NAVAJO?
>> YEAH, I THINK THE NAVAJO SEEM
TO HAVE THE LARGEST NUMBER.
I'VE NOT RECENTLY READ BUT I
THINK IN THE ESKIMO POPULATION
THERE ARE SOME UNIQUE CONDITIONS
THAT OCCUR IN THE ESKIMO, SO I
THINK THERE ARE PROBABLY ARE THE
OTHER NATIVE AMERICAN
POPULATIONS THAT COULD HAVE COME
UNDER THE SAME CONSTRAINTS OF
ISOLATED POPULATIONS AND LIMITED
NUMBERS THAT RETAIN WHATEVER
GENE MUTATIONS WERE FOUND AT THE
TIME, AT THAT POINT IN TIME IN
THAT POPULATION THAT THEN WERE
CARRIED BUT BY FAR AND AWAY, I
THINK THE NAVAJO SEEM TO HAVE
THE MOST NUMBER AND I THINK IT'S
-- IT'S DUE TO ALL FACTORS THAT
I LAID OUT, IT WAS VERY SMALL
GENE POOL AND THEN RAPID GROWTH.
SO
--
>> SO WE ALSO HAVE AN INQUIRY OF
THE EFFECT OF ENVIRONMENTAL
FACTORS IN THE NAVAJO AS MAYBE
EXACERBATING OR AGGRAVATING OR
DOING SOMETHING, THINGS LIKE
EVERYTHING FROM HEAVY METALS TO
URANIUM AND COAL AND ALL THAT
SORT OF STUFF, THEY'VE REALLY
BEEN EXPOSED TO A GREAT VARIETY
OF INSULTS, SO IS THERE ANY
EVIDENT THAT THEY PLAY A ROLE IN
EITHER PHENOTYPE OR ANY FEATURE
OF THE DISEASE?
>> TO MY KNOWLEDGE THE ANSWER TO
THAT IS NO, BUT PEOPLE HAVE
LOOKED EXTENSIVELY AT THAT AND
I'LL NOT REMEMBERING AND JIM
CORRECT ME IF I'M WRONG BUT I'VE
NOT READ ANY PAPERS THAT HAVE
SCIENTIFICALLY SUPPORTED THAT AS
A NOTION.
I COULD UNDERSTAND WHY THERE ARE
CONCERNS AND ACTUALLY IT IS A
VERY LEGITIMATE CONCERN, BUT SO
FAR, I'VE NOT SEEN ANYTHING TO
CONVINCE ME OF THAT, WHEREAS I
SUSPECT WHAT WE'RE DEALING WITH
WITH MICROVILLUS AND SOME OF THE
OTHERS WE KNOW, I THINK THOSE
WERE GENETIC MUTATIONS THAT WERE
RETAINED IN THE POPULATION AND
THEN WERE BROUGHT FORTH OVER
SEVERAL DECADES.
AND YOU KNOW IN THE 40S AND 50S
IF A KID WAS BONE WITH MVID ON
THE RESERVATION, THEY JUST DIED.
YOU WOULD NEVER HAVE KNOWN IN
THE FIRST FEW WEEKS OF LIFE AND
IT WOULD HAVE BEEN ATTRIBUTED TO
JUST NEONATAL DIARRHEA, JUST AS
YOU SUGGESTED IN THE THIRD
WORLD.
AND THESE PATIENTS PUT OUT SO
MUCH POO, WITHIN A WEEK THEY
WOULD BE GONE.
SOPHISTICATED I THINK THE SIGNAL
MAY HAVE BEEN THERE EARLIER BUT
IT WOULDN'T HAVE BEEN RECOGNIZED
AT LEAST FOR MID.
>> YOU COULD ARGUE THAT'S TRUE
FOR A LARGE AMOUNT OF PEDIATRIC
DIAREALA DISEASE.
MANY KIDS BORN WITH THE
TERRIBLIBLE DISEASES, THE SYSTEM
WAS NOT SET UP TO RESPOND MOST
OF THESE KIDS DIED BECAUSE JUST,
YOU BE KNOW IT WASN'T RECOGNIZED
SOON ENOUGH AND YOU KNOW WHEN
YOU SEE HOW WHEN YOU SEE HOW
MUCH FLUID THEY WERE PUTTING
OUT, IT'S STAGGERING TO ME.
AND IN THIS, IT CAN BE MISSED SO
EASILY BECAUSE IT LOOKS LIKE
URINE.
YOU KNOW THE MOTHERS ARE SAYING,
IN FACT, WE ALWAYS ASK THE
PASHTS, ARE THEY HAVING GOOD
URINE OUTPUT WHEN IT'S A
DIARRHEA SITUATION AND NORMALLY
THE ANSWER IS NO, THEY HAVEN'T
PEED FOR DAYS, AND INSTEAD THEY
SAY NO, THEIR DIAPERS ARE
SOAKING WET AND IT WAS STOOL
THAT WAS SOAK, IT WASN'T URINE.
>> IT WAS INTERESTING THAT
JENNIFER WHO WAS IN DEMYSTIFYING
MEDICINE LAST YEAR, SHE STUDIES
SKID IN CHILDREN, WHICH IS
APPARENTLY VERY COMMON AMONGST
THE NAVAJO AND THEY ACTUALLY --
IT'S OBLIGATIONS BLIGATTORY SHE
TELLS ME THAT ALL NEWBORNS ARE
SCREENED FOR SKID ON DAY 1.
IF YOU SCREEN MICROVILLI
INCLUSION BY DISEASE, IT MAY BE
OF THE SAME FREQUENCY OF SKID IN
THAT GROUP BUT DO YOU THINK THAT
NEW BORN CHILDREN ON THE NAVAJO
SHOULD BE SCREEN OFFICE OF
DIVERSITY DAY 1 AND IF SO WOULD
THAT PROVIDE A HEAD START SO
PERSONALLY I BELIEVE THEY
SHOULD, I'M NOT ABLE TO MAKE
MUCH HEAD WAY WITH THAT.
I'VE SPOKEN WITH MY COLLEAGUES
ON THAT RESERVATION AND I DON'T
KNOW ALL THE BARRIERS TO IT, BUT
IT WOULD SEEM THAT EACH OF THESE
CONDITIONS HAD THE POTENTIAL OF
A NEW BORN SCREEN TO BE PICKED
UP VERY RAPIDLY.
AND SO, I WOULD STRONGLY
ADVOCATE FOR THAT, BUT MY VOICE
HASN'T CARRIED ENOUGH WEIGHT.
I JUST I FEEL LIKE DON
QUESTIONNAIRES HOATY.
>> MITCH, THE INCIDENCE OF THE
NAVAJOS FOR MVID IS 1 IN 12,000
OR SOMETHING LIKE THAT, WHAT
ABOUT FOR SKID AND THESE OTHERS
1S ARE THEY ALSO AT THAT LEVEL?
>> THEY'RE IN THAT BALLPARK,
JIM, I WOULD HAVE TO GO AND LOOK
IT UP, YOU ABOUT YOU KNOW WE
SCREEN FOR THING IN THE NEW BORN
SCREENS THAT ARE MUCH RARER.
>> THAT'S WHERE I'M GOING WITH
THIS.
>> ABSOLUTELY.
>> IT SEEMS LIKE IN THE NORTHEST
EVERYBODY GETS SCREENED FOR THAT
WILLSEMIA, YOU KNOW?
>> THE OTHER QUESTION THAT COULD
BE ASKED IS LIKE IN TASTE DECKS
WE COULD SCREEN FOR PERSPECTIVE
PARENTS SO THAT THEY WERE AWARE
THAT THEY CARRY OUR GENETIC
ABNORMALITY BUT I DON'T KNOW
WHERE THAT SITS NOW, CULTURALLY,
BUT I CAN TELL YOU THAT EARLIER
IN MY INTERACTIONS, THAT WAS NOT
EVEN A POSSIBILITY THAT THESE
THINGS WERE ORDAINED FOR
DIFFERENT REASONS AND SO, BUT
YES, THE ABILITY IS THERE TO BE
-- ACTUALLY, ONCE HAD A
GRANDMOTHER WHO WAS PRETTY SAVVY
WHO HAD SEVERAL CHILDREN WITH
MPV17 AND THEN HAD HER FIRST
GRAND CHILD WITH IT.
AND SHE PULLED ME ASIDE AND SHE
SAID, YOU MEAN TO TELL ME WE
CAN'T SCREEN FOR THIS?
THAT THERE'S NO WAY TO PREVENT
THIS TRAGEDY?
AND I EXPLAINED TO HER WHAT THE
ISSUES WERE AND SHE JUST SAID
HMM, AND WALKED AWAY.
SHE WAS RIGHT, SHE WAS ON TO
SOMETHING BUT IT'S BIGGER THAN
THAT, BUT IT WOULD HAVE TO BE
MORE OF A CULTURAL ACCEPTANCE
BUT YES, THE ABILITY IS THERE.
>> HAVING DONE SOME WORK
OURSELVES WITH THE WESTERN
NAVAJO, I HAVE SOME APPRECIATION
OF THEIR CULTURE AND THEIR
REQUIREMENTS, IT'S NOT LIKE
DOING RESEARCH IN ANY PATIENT
POPULATION I WAS EVER INVOLVED
IN BUT MAYBE MITCH WOULD YOU
ELABORATE A LITTLE BIT MORE ON
WHAT ARE THE DIFFERENCES IN
DOING THIS TYPE OF RESEARCH IN
THE NAVAJO COMPARED TO THE
GENTLEMEN POPULATION, WHAT SORT
OF ISSUES ON DO YOU CONFRONT?
>> WELL WHEN WE FIRST STARTED
DOING THIS WORK WE CONTACTED THE
NAVAJO TRIBE FROM THE IRB, AND
THEY ASSURED ME THAT IF I WANTED
TO RECRUIT FROM THE RESERVATION,
THE IRB WOULD NOT REVIEW THE
STUDY BECAUSE THEY DID NOT
APPROVE OF ANY GENETIC RESEARCH
IN THE NAVAJO SOPHISTICATED WHAT
WE ESTABLISHED WAS THAT OF
COURSE WE WEREN'T RECRUITING
FROM THE RESERVATION, THESE WERE
PATIENTS THAT CAME TO US BECAUSE
OF DIRE CONSEQUENCES AND OWZ OF
THE RESERVATION, WE WERE ABLE TO
GET CONSENT THROUGH OUR IRB, BUT
WHAT I WILL SAY, IS THAT EVERY
PUBLICATION WE'VE EVER DONE I
SENT TO THE NAVAJO IRB AND TO
THE NAVAJO TRIBE BECAUSE I
WANTED THEM TO BE REASSURED THAT
NOTHING IN THE PUBLICATIONS CAST
ANY NEGATIVE LIGHT OR VIEWS
AGAINST THE NAVAJO AND I THINK
UNDERSTANDABLY SO, THERE'S BEEN
SOME MISCUES IN RESEARCH AND
NATIVE AMERICANS THE 1 THAT
COMES IT MIND IS RESEARCH THAT
WAS DONE ON THE HAVI SUP A I
INDIANS AND THEY WERE STUDYING
DIABETES AND THEY ENDED UP
SHARING SOME OF THE SAMPLES THEY
HAD RETRIEVED FOR A DIFFERENT
LINE OF RESEARCH WITHOUT
INFORMING THE HAVI SUP A I AND
THAT PUBLICATION CAME OUT AND
BOY THAT WAS NOT THE RIGHT THING
TO DO.
SO THERE'S TREMENDOUS
SENSITIVITY AND MISTRUST, AND I
GET IT.
I GET IT.
I THINK THE BETTER WAY TO GO IS
TO BE VERY UPFRONT, OPEN AND
HONEST AND IF WE HAVE TO DO IT
ON THE RESERVATION, WE PROBABLY
WOULDN'T HAVE BEEN ABLE TO DO
THE RESEARCH.
>> WAS THERE ANY DIFFICULT
NEUROECTODERMAL NAVAJO ACCEPTING
SURGERIES SUCH AS MASSIVE ORGAN
TRANSPLANT OR EVEN SINGLE ORGAN
TRANSPLANT?
>> NO, BRILLIANT QUESTION.
THAT SEEMS TO HAVE MODIFIED OVER
TIME.
ONE OF THE ISSUES WE RAN INTO
WITH WE FIRST OFFERED A
TRANSPLANT IS THEY WANTED YOU
KNOW IF IT COULD BE DONE FROM
THE NAVAJO, THEY WANTED ANOTHER
NAVAJO TO DONATE AND YOU CAN
IMAGINE THE IMPOSSIBILITIES OF
THAT PLAYING OUT AND SO THAT DID
HOLD UP, BUT NOW DAYS IT SEEMS
THEY'VE BEEN MORE ACCEPTING OF
THIS AS A THERAPEUTIC MEASURE
AND HAVE NOT STOOD IN THE WAY
BECAUSE WE'VE HAD SEVERAL THAT
WERE TRANSPLANTED BUT THAT
WASN'T -- EARLY ON THAT WAS
DEFINITELY A BARRIER.
>> IT SOUNDS VERY SIMILAR TO
WHAT JENNIFER TELLS ME ABOUT THE
SKID ISSUE BUT EVENTUALLY THEY
OVERCAME IT, AND FAMILIES WOULD
BE TRANSPORTED FROM THEIR
RESERVATION TO SAN FRANCISCO
WHERE THE TRANSPLANTATION WAS
WAS CARRIED OUT AND THE OUTCOME
HAS REALLY BEEN SUCCESSFUL AND
IT WAS MY UNDERSTANDING IS
BECAUSE OF THE EXPERIENCE WITH
THE NAVAJO, IT BECAME POSSIBLE
TO INTRODUCE IN THE STATE OF
CALIFORNIA, FOR THE WHOLE STATE
PRENATAL SCREENING FOR SKID
WHICH WAS THERE BEFORE BUT WAS
SORT OF, YOU KNOW DISAPPEARED,
NOBODY COULD DO MUCH ABOUT IT.
>> ABSOLUTELY.
AND IT AFFECTED ARIZONA AS WELL,
THANK GOODNESS.
>> YEAH.
>> WE'VE DONE A NUMBER OF MARROW
TRANSPLANTS AT PHOENIX CHILDRENS
ON THIS POPULATION AS WELL FOR
SKIDS.
>> SO JIM IF YOU HAD 2 OR 3
QUESTIONS THAT YOU WOULD REALLY
LOVE TO SEE THE ANSWER TO
BEFORE, IF THE DAY EVER COMES
THAT YOU PUT YOUR SABER AWAY,
YOU'RE MY INSPIRATION, WIN, I'M
NEVER GOING TO RETIRE.
[LAUGHTER]
>> I TELL YOU WHAT, AGAIN,
YOU'RE DEALING WITH RARE
DISEASES AND NOW, WE'RE FACING
HOW DO WE TAKE THIS SO WE HAVE
THIS LP A 5 RECEPTOR AGONIST,
IT'S A DAUNTING THING TO GET A
DRUG BROUGHT TO MARKET
ESPECIALLY IN THE RARE DISEASE
SPACE.
WHAT WE'RE FACING IS WE NEED
MONEY FOR TOXICITY TESTING, DOZE
FINDINGS, ALL THIS STUFF, AND OF
COURSE, WE'RE GOING INTO VERY
VULNERABLE, VERY SICK CHILDREN.
ALBEIT THEY MIGHT BE STABILIZED
ON TPN, BUT THAT'S 1 THING I
WOULD LIKE TO SEE, AND YOU KNOW,
IT'S NOT -- WE DON'T HAVE A GOOD
SUPPORT SYSTEM THROUGH
PHARMACEUTICAL COMPANIES OR
ELSEWHERE TO BRING THESE RARE
DISEASE TREATMENTS FORWARD VERY
MUCH AND THAT'S UNFORTUNATE, SO
I WOULD REALLY LOVE TO SEE AN
OPTIMIZED PATHWAY.
I ALSO -- YOU KNOW THE BIG
QUESTION I STILL -- I HAVE TO
FIGURE OUT BECAUSE IT DRIVES ME
CRAZY IS THAT P-FIX, 6, AT HEART
I'M STILL A CHEMIST SO I STILL
WANT TO KNOW WHAT IS THE PROTEIN
BASIS FOR THESE MUTATIONS HAVING
SUCH A SPECIFIC AND DIFFERENT
YOU KNOW IMPACT, SO, I WOULD
REALLY LOVE TO FIGURE THAT 1 OUT
SOMEHOW.
AND WE'RE DOING BY O ID WORK TO
TRY TO TAKE A LOOK AT IT, BUT
YOU KNOW THAT'S OUT THERE.
>> MICROVILLI INCLUSION BODY
DISEASE SOMETIMES I GUESS VERY
OFTEN APPEARS SPORADICALLY, YOU
KNOW, 1 CHILD, OR YOU KNOW, SO
IT'S NOT NECESSARILY THE
BEAUTIFUL FAMILY TREE WITH
EVERYBODY AND YOU CAN SORT OF
FIGURE OUT SOMETHING ABOUT THE
-- ABOUT THE GENETICS.
SO THAT MEANS WITHIN THE
PEDIATRIC POPULATION AROUND THE
WORLD, MOST PEDIATRICIANS
RECOGNIZE THIS ENTITY, I DON'T
THINK SO, I'M THE SON OF A
CANONICLE PEDIATRICIAN, MY
FATHER WAS THE FIRST
PEDIATRICIANOT CONNECTICUT SHORE
LINE AND I DON'T REMEMBER HIM
TELLING ME ANY OF THIS AND HE
WAS HEAD OF THE NEW BORN NURSERY
FOR 10 YEARS AFTER HE RETIRED,
IT I DON'T REMEMBER --
>> I REMEMBER WHEN WE WERE IN
TRAINING WE USED TO CALL THESE
CONDITIONS, WE DIDN'T RECOGNIZE
THERE WERE SO MANY, INTRACTABLE
DIARRHEA OF INFANCY AND PHIL
SUNSHINE WROTE 1 OF THE FIRST
PAPERS ON THAT.
HE JUST RECEIPTLY PASSED AWAY ON
THAT UNFORTUNATELY BUT IT WAS SO
VAGUE AND UNKNOWN THEN, THAT
IT'S BEEN JIM, IN MY LIFETIME
THAT WE'VE WATCHED THEM IDENTIFY
1 AFTER ANOTHER OF THESE
CONDITIONS TO A POINT WHERE WE
CAN MANAGE THEM.
AS A PGI WHERE WE HAVE A BROAD
REFERRAL POPULATION, OVER THE
YEARS I'VE CARED FOR ALMOST ALL
OF THEM BUT IT'S USUALLY 1
PATIENT, MAYBE 2.
IF I WAS IN BOSTON IF THEY HAD 1
MVID EVERYONE HEARD ABOUT IT AND
WENT TO SEE IT BECAUSE YOU
WOULDN'T SEE THEM BUT ONCE EVERY
NOW AND THEN, SO IT WAS, THE
PATHOLOGIST FROM TORONTO THAT
CALLED ME, WHEN I SENT HIM THE
FOURTH BIOPSY SPECIMEN OF A
FOURTH DIFFERENT PATIENT AND HE
SAID WHAT IS GOING ON?
HE SAID I'VE NEVER SEEN SO MANY
PATIENTS FROM 1 CENTER?
I SAID YEAH, WE'RE GOING TO
REPORT THIS, YEAH, I'VE NEVER
SEEN SO MANY BUT I CAN TELL YOU
THAT MOST PLACES IT'S
INDIVIDUAL, MAYBE 1 PATIENT OR 2
PATIENT, JIM HOW MANY AT
VANDERBILT DO YOU SEE AND HOW
OFTEN?
>> YOU KNOW KIDS WITH THESE
GENETIC DIARRHEAS PROBABLY HERE
2-3 MAX A YEAR.
AND I THINK THE BIGGEST CHANGE
IS REALLY GETTING PEOPLE USED --
NOT -- TO NOT FEAR THE GENETIC
DATA.
SO IT'S REALLY THE PHYSICIANS I
THINK ABOUT 10 YEARS AGO,
ESPECIALLY WERE FEARING GENETIC
DATA.
THEY SAID WHERE DON'T YOU GET
GENETIC ANALYSIS, WELL, THE
INSURANCE COMPANIES WON'T PAY
FOR IT AND I DON'T KNOW HOW TO
UNDERSTAND IT SO THEY JUST
WOULDN'T GET IT SO I GUESS IT
WAS ABOUT 12 YEARS AGO, KID WAS
IN HERE WHO HAD INTRACTABLE
DIARRHEA, FAILURE TO DRIVE, AND
THEY WERE DOING ALL KINDS OF
STUFF AND I SAID WHY DON'T WE
JUST SEQUENCE THEM, THEY SAID
HOW DO WE GET THE MONEY.
SO I THROUGH $6000 INTO THE TILL
TO SEQUENCE HIM AND HIS MOTHER,
AND THAT WAS THE SECOND CASE OF
DGAT 1 MUTATION.
AND THAT LITTLE KID ALL YOU HAVE
TO DO IS STOP HIM FROM EATING
FAT.
HE'S ALIVE AND HE'S A BRUISER
NOW.
HE'S GOT THE MOST AWFUL DIET
BECAUSE HE CAN'T EAT FAT BUT WE
JUST FIGURED OUT THAT THESE KIDS
CAN EAT YOU KNOW CERTAIN LIPIDS
LIKE PALMAITATE, THEY CAN EAT
PALMAITATE AND THEY WON'T GET
SICK, SO THAT'S GOING TO HELP
HIS DIET, BUT THE KEY IS TO GET
PEOPLE TO ACTUALLY NOT FEAR
DOING THE GENETIC ANALYSIS.
AND MY OWN FEELING IS, YOU DON'T
DO THESE EXPENSIVE PANELS THAT
COMPANIES ARE TRYING TO SELL, MY
FEELING IS, IF THE KID'S GOT A
PROBLEM, YOU DO WHOLE EXOHM
SEQUENCING, IT'S CHEAPER THAN
THE PANELS IN THIS DAY AND AGE,
IT'S HARD TO BELIEVE, BUT YOU
CAN DO A WHOLE EXOHM SEQUENCING
FOR UNDER $300.
IT'S AMAZING.
>> SO I GUESS, HAS THIS VIEW
THAT YOU'VE JUST PRESENTED BEEN
A SORT OF PRETTY WIDELY ACCEPTED
WITHIN GENERAL PEDIATRICS OR
PEDIATRIC GASTROINTROLOGYISTS?
>> I HAVE TO SAY NO BECAUSE OUR
CHIEF OF PH CI IS TRYING TO PUSH
PEOPLE TO BED THIS.
SO THERE IS STILL FEAR OUT
THERE.
IS THAT TRUE MITCH?
>> YEAH, I THINK SO.
I THINK SO.
IN PSGI, I THINK WE'VE COME
AROUND.
I THINK THE DATA IS SO
CONVINCING THAT WE'RE PUSHING
FORWARD AND WE NOW HAVE
INTERESTING AVENUES THAT HAVE
COME UP ABOUT, WHERE FOR PRETTY
CHEAP WE CAN GET THESE SCREENS
DONE.
FOR INSTANCE WE CAN DO THE MPB17
GENETIC SCREEN THROUGH A
SCREENING THING THAT'S ON
ANYONATAL COLO STASIS PANEL THAT
SCREENS FOR LIKE 40 THINGS, 1 OF
WHICH IS MPV 17, AND SO WE'VE
BEEN ABLE TO MAKE DIAGNOSIS AND
IT'S LIKE 300 OR $350.
>> YEAH, YEAH.
>> BRAVE NEW WORLD.
>> IT IS!
>> IT IS.
>> IT IS A BRAVE NEW WORLD.
[LAUGHTER]
>> SO, HAVE PEOPLE LIKE -- YOU
KNOW THE WORK OF DAVID RIKE AT
HARVARD, I THINK IT'S DAVID, HIS
BROTHER'S AT NIH, THEY DO THESE
REALLY EXTRAORDINARY STUDIES
BASED UPON EXTENSIVE GENETICS OF
THE ORIGIN OF HOMOSAIPIANS AND
HERE'S THE FELLOW WHO DISCOVERED
THAT AT 4% OF OUR GENES ARE
NEANDERTHAL SO THEY STUDY THESE
POPULATIONS IN REMOTE AREAS
WHICH ANTHROPOETIC LOGICALLY ARE
PART OF A MIGRATION PATTERN SO
I'M SORT OF CURIOUS WHETHER THE
NOX FAMILY ACTIVATOR ON HOE LIKE
MOST OF THE NATIVE AMERICAN
POPULATION ARE SUPPOSEDLY, CROSS
THE A LIEWTIANS FROM EAST OTHER
THAN PART OF EASTERN RUSSIA AND
WHAT NOT, DO ANY OF THESE APPEAR
IN ANY OF THOSE POPULATIONS?
DOES ANYBODY KNOW?
>> I DON'T KNOW EMPLOY.
I MEAN I FIND THIS WHOLE THING
OF GENETIC EVOLUTION REALLY
FASCINATING.
BUT YOU KNOW GOING BACK TO THAT
CHILD WE HAD WITH DGAT1
MUTATION, SO, ALMOST WITHIN THE
SAME YEAR, THE FOLKS UP AT
HARVARD REPORTED A PAIR OF
JEWISH KIDDINGS WHO HAD THE
EXACT SAME MUTATION AS OUR
PATIENT WHO WAS HISPANIC.
THEN WE ACTUALLY FOUND A COULD
YOU SAYIN OF THIS GUY, ALSO
HISPANIC SAME EXACT MUTATION SO
IT MAKES ME FEEL LIKE GOING BACK
TO THE 15th CENTURY IN SPAIN,
SOMEBODY MAYBE HAD A FOUNDER
MUTATION BACK THEN.
>> IT'S POSSIBLE.
MPV17 DR. ARIAS CORRECT ME IF
I'M WRONG BUT I THOUGHT IT WAS
IN A EUROPEAN OR MAYBE IT WAS A
TURKISH PATIENT THAT WAS A
SIMILAR THAT THEY IDENTIFIED IT
AND THEY WENT BACKWARDS AND
CHECKED TO SEE IF THE NAVAJO
MIGHT HAVE THIS KIND OF MUTATION
AND IT DID SO COMPLETELY
DESPARRATE POPULATION SO IT'S
MORE COMPLEX AND THERE'S SO MANY
MUTATIONS.
MY GOD FOR MVID DEC, HOW MANY
ARE THERE NOW, SEIVET, 80.
>> I MEAN IT'S A BIG PROTEIN BUT
THAT'S STILL A LOT OF MUTATIONS.
NRIGHT, RIGHT.
>> WELL, WE NEED -- I WOULD
REMIND YOU AT 1 POINT THE
SPANISH SEFARDIN AND THE
EUROPEAN, AT LEAST THE MALE
POPULATIONS ALL LIVED TOGETHER
IN THE KINGDOM OF JUDEA, SO YOU
KNOW?
>> YEAH, IT'S LIKE TAKE IT BACK.
I MEAN ...
>> WELL, I THINK WE HAVE REACHED
THE END OF OUR TIME AND I TRULY
WANT TO THANK YOU BOTH VERY
MUCH.
THIS HAS BEEN A VERY EXCITING
PRESENTATION AND THEN FURTHER,
YOU KNOW ILLUSTRATES THE
NECESSITY TO BUILD BRIDGES
ACROSS DISCIPLINES AND THEY
COVER MAJOR CLINICAL PROBLEMS
AND CHALLENGING BASIC PROBLEMS
AND IT'S REALLY THROUGH
EXPERIENCES LIKE THIS, THAT YOU
SEE PROGRESS BEING MADE.
PROGRESS ISN'T ALWAYS SOLUTIONS,
SOMETIMES MORE QUESTIONS AND WE
HOPE THAT WE WILL BE ABLE TO
CONTINUE TO EXPLORE THOSE
QUESTIONS BECAUSE, THEY
ULTIMATELY LEAD TO GOOD THINGS
FOR THE PATIENTS.
SO THANK YOU BOTH VERY, VERY
MUCH AND WE WILL KEEP YOU
INFORMED ABOUT ANY OTHER
QUESTIONS THAT COME IN.
>> WE THANK YOU FOR INVITING US
WIN EMPLOY.
>> THANK YOU.
>> GREAT FUN.
>> THANKS.
>> THANKS FOR INVITING US.
>> THANKS SO MUCH.
>> OKAY.
AND WE ARE OFF.