Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
The NIH Clinical Center is the world's largest hospital totally
dedicated to investigational research and leads the global
effort in training today's investigators and discovering
tomorrow's cures.
Learn more by visiting us online at http://clinicalcenter.nih.gov
TODAY'S LECTURE IS PART OF OUR
CLINICAL GRAND ROUNDINGS GREAT
TEACHER SERIES TODAY WE HONOR
THE LEGACY OF DR. JOHN DECKER,
WHO SERVED FROM 1983-1990.
DURING HADIS TENURE AS DIRECTOR
ADVANCES AT THE CLINICAL CENTER
INCLUDED DEVELOPMENT OF THE
POSITRON EMISSION TOMOGRAPHY
PROGRAM, INITIATION OF THE USE
OF MAGNETIC IMAGES AND
MARSHALING OF SUPPORT AGE
RESEARCH.
I'M ESPEBLLY HONORED AND PLEASED
TO WELCOME THE DECKER FAMILY WHO
ARE JOINING US TODAY VIRTUALLY.
NOW, I WOULD LIKE TO TURN THE
PODIUM OVER TO MISS SANDRA HOYE
ADVANCE ASSOCIATE FOR THE
FOUNDATION FOR THE NATIONAL
INSTITUTES OF HEALTH FOR
REMARCOS BEHALF OF THE FNIH.
>> THANK YOU DR. BURKLOW.
GOOD AFTERNOON AND WELCOME, MY
NAME IS KACCT SANDRA HOCE AND
I'M AN ADVANCE ASSOCIATE FOR THE
FOUNDATION FOR THE NIH.
I AM DELIGHTED TO WELCOME YOU TO
THE 18th ANNUAL JOHN LAWS
DECKER MEMORIAL LECTURE
FEATURING THE 2022 DISTINGUISHED
CLINICAL TEACHER AWARD RECIPIENT
DR. JONATHAN M. HERNÁNDEZ.
DR. HERNÁNDEZ WE LOOK FORWARD TO
YOUR PRESENTATION.
THE FNIH IS PROUD TO HAVE BEEN A
PARTNER OF THE IMPORTANT LECTURE
SINCE 2003 WHEN THE NIH BEGAN
RECOGNIZING THE LATE NIH
CLINICAL DIRECTOR ANNUALLY
THROUGH THE CLINICAL CENTER
GRAND ROUNDS LECTURE SERIES.
AT THIS TIME, FRIENDS AND FAMILY
OF DR. DECKER WORKED WITH THE
FNIH TO ESTABLISH THE MEMORIAL
FUND IN HONOR OF THEIR LATE
FATHER.
DURING HIS LIFETIME DR. DECKER
WAS AN OUTSTANDING TEACHER WHO
THRIVED TO CONNECT TO SCIENTIFIC
COMMUNICATIONS AROUND THE WORLD
TO ACCELERATE IMPORTANT
RESEARCH.
THIS IS THEIR AND OUR WAY OF
EXTENDING HIS LEGACY.
I WANT TO THANK THE DECKER
FAMILY FOR THEIR GENEROSITY AND
INSPIRED VISION IN ESTABLISHING
THE DECKER MEMORIAL FUND.
THE FNIH IS PROUD OF OUR LONG
LASTING COLLABORATION WITH YOU
AND THE CLINICAL CENTER TO
RECOGNIZE INNOVATIVE
ACCOMPLISHMENTS IN CLINICAL
RESEARCH AND THEIR LASTING
IMPACT ON TRAINING THE NEXT
GROUP OF GREAT SCIENTISTS.
WE INVITE TO YOU EXPLORE THE
MANY PARTNERSHIPS FORMED AND THE
INNOVATIVE SCIENTIFIC THINKING
THAT IS SUPPORTED THROUGH OUR
PROGRAMS ON THE FNIH WEBSITE,
FNIH.ORG.
I WILL NOW TURN THINGS BACK TO
DR. BURKLOW TO INTRODUCE THE NIH
CLINICAL FELLOWS COMMITTEE.
THANK YOU FOR JOINING US FOR
THIS EVENT AND PLEASE ENJOY THE
18th ANNUAL JOHN LAWS DECKER
MEMORIAL LECTURE.
>> THANK YOU MISS HOYE FOR YOUR
KIND REMARKS AND ESPECIALLY TO
THE DECKER FAMILY FOR YOUR
CONTINUED GENERATEDDOUS SUPPORT,
IT IS MUCH APPRECIATED.
EACH YEAR, NIH CLINICAL FELLOWS
SEEK OUT A HIGHLY REGARDED
TEACHER TO RECEIVE THE CLINICAL
TEACHER AWARD.
DR. DECKER WAS AN INSPIRING
LEADER AND MENTOR SO IT'S VERY
IMPORTANT THAT THE DISTINGUISHED
CLINICAL TEACHER AWARDEE
DELIVERED ANNUAL DECKER MEMORIAL
LECTURE.
BEFORE INTRODUCING TODAY'S
SPEAKER AND THE 2022
DISTINGUISHED CLINICAL TEACHER
AWORRIEDEE, I WOULD LIKE TO TURN
THE VIRTUAL PLATFORM OVER TO
DR. MARJA BROLINSON WHO CO
CHAIRS THE COMMITTEE TO,A NOUNS
THE WINNER OF THE 2023 CLINICAL
TEACHER AWARD.
>> MY NAME IS MARJA BROLINSON
AND I AM THE CLINICAL FELLOWS
COMMITTEE CO CHAIR, I WOULD LIKE
TO THANK DR. BURKLOW FOR HIS
ONGOING SUPPORT AND THE NIH
CLINICAL FELLOWS AND FOR A
STRONG COMMITMENT TO THE
IMPORTANCE OF MENTORING AT NIH.
I AM HOONORRED TO,A NOUNS THE
WINNER FOR THE 2023
DISTINGUISHED CLINICAL TEACHER
AWARD.
A MENTOR GUIDES PROFESSIONAL
GROWTH BY HELPING TRAINEES
IDENTIFY AND DEVELOP SKILLS AND
TALENT, SET AND ACHIEVE GOALS,
ANTICIPATE ROAD BLOCKS AND
OVERCOME OBSTACLES.
A CLINICAL MENTOR ALSO 'EM
BODIES THE CHARACTERISTICS OF AN
ETHICAL AND PASSIONAL PHYSICIAN.
ALL OF THE INDIVIDUALS NOMINATED
FOR THIS YEAR'S AWARD AND
RECOGNITION AS OUTSTANDING
CLINICAL MENTORS.
I WOULD LIKE TO THANK ALL OF THE
NOMINEES FOR THEIR COMMITMENT TO
TRAINING CLINICAL INVESTIGATORS
AT THE NIH AND THEIR OVERALL
CONTRIBUTION TO MEDICAL
EDUCATION.
EACH YEAR, THE DISTINGUISHED
CLINICAL TEACHER AWARD IS
DECIDED BY A VOTE OF THE
CLINICAL FELLOWS AND PRESENTED
TO AN INDIVIDUAL WHO EXEMPLIFIES
THE IDEA OF A MENTOR TEACHER AND
CLINICIAN AND RESEARCHER.
HERE ARE A FEW WORDS EXPRESSED
ABOUT THIS YEAR'S AWARDEE.
WITH THE UTMOST PATIENCE AND
SINCERITY HE ALWAYS GOES ABOVE
AND BEYOND TO TEACH THE FELLOWS
HOWEVER MANY TIME ITS TAKES TO
SOLIDIFY OUR KNOWLEDGE MAKING
DIFFICULT CONCEPTS EASIER AND
FORMING US INTO BETTER
CLINICIANS.
YOU CAN ALWAYS FIND HIM WITH A
CUP OF COFFEE IN HAND, A JOKE IN
HIS BACK POCKET AND A SMILE
TWINKLING THROUGH HIS EYES
BEHIND HIS MASK AS HE JUMPS
BETWEEN FELLOWS TO HELP THEM GET
THROUGH DIFFICULT PATIENTS.
IF YOU LOOK CLOSE ENOUGH, YOU
CAN FIND EXTREMELY HELPFUL
CLINICAL PEARLS IN HIS MANY
PUBLICATIONS.
ONE PUBLISHED EXAMPLE IS
HYPOCYSTITESIS AN UPPERDATEOT
DISORDERS DIAGNOSE AND
MANAGEMENT OF PITUITARYY
INFLAMMATION, PLEASE JOIN ME IN
WELCOMING OUR CLINICAL AWARD
WINNER DR. SRIRAM, GUBBI, IN THE
NATIONAL INSTITUTE OF DIABETES
AND DIGESTIVE AND KIDNEY
DISEASES.
I WOULD NOW LIKE TO TURN THE MIC
OVER TO DR. BURKLOW TO INTRODUCE
TODAY'S SPEAKER AND OUR 2022
DCTA AWARD WINNER.
THANK YOU.
>> THANK YOU DR. BROLINSON AND
MANY CONGRATULATIONS TO
DR. GUBBI.
I'M NOW HONORED TO INTRODUCE
TODAY'S SPEAKER THE A RESENT OF
THE 2022 DISTINGUISHED TEACHER
AWARD, DR. JONATHAN M.
HERNÁNDEZ.
HE IS THE CHIEF OF THE SURGAL
ONCOLOGY SECTION, HEAD OF THE
METASTASIS BIOLOGY SECTION AT
THE CENTER FOR CANCER RESEARCH
AND THE NATIONAL CANCER
EN--STRATEGIESITUTE AND
ASSOCIATE PROFESSOR OF SURGERY
FOR UNIFORM SERVICES, UNIVERSITY
OF HEALTH SCIENCES.
DR. HERNÁNDEZ EARNED HIS MEDICAL
DEGREE FROM THE UNIVERSITY OF
FLORIDA IN 2005 AND COMPLETEDT
GENERAL SURGERY
UNIVERSITY OF SOUTH FLORIDA.
DURING HIS HESIDENCY
DR. HERNÁNDEZ SPENT 2 YEARS AT
THE MOFET CANCER RESEARCH CENTER
AND INSTITUTE, FOR LIVER,
METASTASIS, AND METASTATIC
SPREAD TO SUPPORT THE NIH
FUNDING.
FOLLOWING HIS RESIDENCY HE
COMPLETED SURGERY AND PSYCHOLOGY
AT THE MEMORY RESPONSOR SLOAN
KETTERRING CANCER CENTER.
DURING FELLOWSHIP TRAINING
DR. HERNÁNDEZ SPENT AN
ADDITIONAL 2 YEARS IN DEDICATED
BASIC RESEARCH STUDYING
METASTATIC COLONIZATION WHILE A
SCHOLAR IN THE CELL BIOLOGY
PROGRAM OF THE SLOAN KETTERRING
INSTITUTE AND A VISITING
INVESTIGATOR AT THE WILD MEDICAL
COLLEGE OF CORNELL UNIVERSITY.
DR. HERNÁNDEZ JOINED THE
SURGICAL ONCOLOGY PROGRAM IN
2016 AS A TENURED TRACK
INVESTIGATOR.
CLINICALLY HE SPECIALIZED IN THE
TREATMENT OF METASTATIC AND
TUMOR AND BILE DUCTS AND
PANCREAS AND SURGICAL MANAGEMENT
OF COMPLEX ABDOMINAL TUMORS,
DR. HERNÁNDEZ FOCUSED ON THE
IMELEMENTATION OF AN EXVIEF O
TUMOR SYSTEMS THAT ALLOW HIS
LABORATORY TO FULLY CHARACTERIZE
THESE IN THE OPERATING ROOM AND
EVALUATE THERAPIES, AND THEY
ALLOW THESE TO BUILD COMBINATION
THERAPIES FOR TUMORS AND
DELINEATE AND TARGET
UNCHARACTERRIZED SINGLE AXIS FOR
GAIN IN PATIENTS WITH COLANGIAL
CARCINOMA AND ELUCIDATE
MECHANISMS FOR WHICH TUMOR CELLS
MARK THE ENVIRONMENT OF THIS
ORGAN TO FORM LIFE THREATENING
METASTASIS.
DR.ENER NANOG IT DES IS BOARD
CERT TIE INDEED GENERAL SURGERY
AND COMPLEX GENERAL SURGICAL
ONCOLOGY BY THE AMERICAN BOARD
OF DIRECTORS OF SURGERY.
MEMBER OF THE AMERICAN
ASSOCIATION FOR CANCER WERE,
ASSOCIATE FOR SURGICAL ONCOLOGY,
AMERICA'S PAN KRE TINSAT OLDER
PEOPLE ASSOCIATION, SOCIETY OF
UNIVERSITY SURGEONS AND AMERICAN
COLLEGE OF OF SURGEONS,
DR. HERNÁNDEZ HAS AUTHORED OVER
100 PEER PUBLICATIONS AND
NUMEROUS BOOK CHAPTERS AND
AUTHORITATIVE TEXTBOOKS.
HIS TALK TODAY IS ENTITLED THE
DEVELOPMENT AND IMPLEMENTATION
OF EXVIVO HUMAN TUMOR SYSTEMS
FOR TRANSLATIONAL SCIENCE.
PLEASE WELCOME OUR SPEAKER
DR. JONATHAN HERNÁNDEZ.
THANK YOU SO MUCH, TOM THANK YOU
FOR THE INTRODUCTION, MARJA,
THANK YOU ABOUT THE KIND WORDS
ABOUT MENTORING AND TEACHING AND
THE TIELT OF MY TALK IS AGAIN IS
THE DEVELOPMENT AND
IMPLEMENTATION OF EXVIVO HUMAN
TUMOR SYSTEMS FOR TRANSLATIONAL
SCIENCE.
I WANT TO START WITH A FEW
COMMENTS, THIS IS A HUMBLING
AWARD TO BE HONOR WIDE, I DON'T
NECESSARILY SEE MYSELF AS A
MENTORSHIP SKILL OR OR A
TEACHER, INSTEADY I SORT OF
THINK ABOUT THE PEOPLE WHO WORK
WITH ME AND WORKED WITH ME
THROUGH THE YEARS AS SORT OF
PARTNERS AND THIS HAS BEEN A
MUTUALLY BENEFICIAL RELATIONSHIP
AND SO I--INSTEAD OF SORT OF
TALKING ABOUT A GIVEN TOPIC,
WHAT I WANT TO DO IS HIGHLIGHT
THE ACHIEVEMENTS OF MY PARTNERS,
MY CLINICAL FELLOW PARTNERS OVER
THE LAST SEVERAL YEARS, SO
THAT'S WHAT I WANT TO SPEND THE
NEXT 40 MINUTES AND SO I WILL DO
THAT IN THE CONTEXT OF SORT OF 3
AREAS, BUT FIRST I WILL TALK
ABOUT EXVIVO LIVER SYSTEM AND
SECONDLY I WILL TALK ABOUT THE
SMART SYSTEM AND TELL WHAT YOU
THAT IS AND LAST I WILL TALK
ABOUT USING THE TOOLS SO THOSE
WILL BE 2 SEPARATE ROUTES THAT I
SHOW HOW WE UTILIZE THESE TUMOR
SYSTEMS AND THAT'S HOW WE WILL
DO THIS.
SO I THINK ABOUT HUMAN TUMOR
SETS SORT OF VERY COOL, VERY
UNIQUE THINGS THAT HAPPEN
UNFORTUNATELY TO PEOPLE.
IT'S VERY HARD TO REPLICATE AND
YOU THINK ABOUT IT WHERE WOULD
YOU EVEN GO TO GET TUMORS, YOU
VALID TO GO TO PATIENT WHO IS
DEVELOP THESE, THEY'RE VERY
COMPLICATED AND I HAD THIS IDEA
THAT ALL THESE PRECLINICAL
MODELS ARE AVAILABLE TO US, THEY
DON'T--THEY DON'T REPLICATE WHAT
WE ACTUALLY SEE AND FEEL IN
PEOPLE WHEN WE OPERATE ON THEM
EVERY DAY.
DISP SO I HAD THIS IDEA THAT WE
SHOULD INSTEAD MAYBE UTILIZE THE
TUMORS THAT WE'RE TAKING OUT OF
PEOPLE IN A DIFFERENT WAY, DON'T
PUT THEM IN A FREEZER, DON'T
JUST SEQUENCE THEM, BUT ACTUALLY
USE THEM SO I HAD THIS IDEA THAT
WE WOULD DO THE FOLLOWING, SO
I'M A LIVER SURGEON, I SPEND A
FAIR AMOUNT OF TIME DOING LIVER
SURGERY, INSTEAD OF TAKING OFF A
THIRD OR A QUARTER OF SOMEBODY'S
LIVER SO I CAN TAKE OFF THE
TUMOR, I WOULD INSTEADY TAKE
THIS DOWN THE HALLWAY TO A
PROFUSION MACHINE AND
KAN--KANAUE LATE IT AND KEEP THE
THING VIABLE AND IF I COULD DO
THAT, THAT WOULD THEN BE AS REAL
AS THINGS WOULD EVER BE AND
WHATEVER QUESTIONS WE ASKED
WOULD BE TRANSLATIONALLY
RELEVANT AND THEN WE COULD START
DOING REALLY COOL EXPERIMENTS
LIKE THE FOLLOWING, WE COULD
GIVE VARIOUS DRUGS DEPENDING ON
WHAT WE ALREADY KNEW ABOUT THE
TUMOR BEFORE WE OPERATED ON THE
PASHT AND THAT COULD BE BASED ON
MUTATIONAL STATUS OR SOME SORT
OF TRANSCRIPT THAT THE TUMOR WAS
EXPRESSING, OF COURSE, NOW, A
LOT OF THINGS ARE FOCUSED ON
IMMUNOTHERAPY AND ACTIVATING THE
IMMUNE SYSTEM IN THE TUMOR, AND
IT'S CERTAINLY FOCUSED DRUGS ON
THESE EFFORTS.
THESE ARE VERY HARD TO
RECAPITULATE OUTSIDE OF
PATIENTS, AND IT WILL GIVE CELL
THERAPY INTO OUR SYSTEM AND NONE
OF THIS WOULD HARM ANY CAUSE OF
HARM TO THE PATIENT BECAUSE
EVERYTHING WOULD BE OUTSIDE THE
PATIENT AND SO THIS WAS A
CONCEPT I SORT OF CAME WITH.
SO I--YOU KNOW I GOT HERE IN
FALL OF 2016 AND I AGREED TO
TAKE SEVERAL FELLOWS IN THE LAB,
JULY OF 2017, I TOOK 3 AGAINST
THE ADVICE OF MANY PEOPLE.
I COULDN'T TALK THEM OUT OF IT,
THEY SIMPLY WOULDN'T LISTEN AND
SO WE STARTED A PARTNERSHIP AND
WE SAID OKAY, LET'S SEE IF WE
CAN MAKE THIS COME TO FRUITIONS
AND WE CONVINCED THE POWERS THAT
BE AT NCI THAT WE NEED A
TRANSPLANT TRANSFUSION MACHINE,
AT THE TIME NONE OF THIS WAS
APPROVED IN THE FDA, WE BOUGHT
IT WITH FROM A COMPANY IN
EUROPE, WE DEVELOPED A BACK
TABLE SET UP AND PLANNED
EVERYTHING, WITH THE APPROVAL OF
THE NCI AND PLANNED IT
APPROPRIATELY AND SAM AND 2 OF
THE FELLOWS THAT REALLY WORKED
DAY AND NIGHT ON THIS ARE SAM
ROUGH AND MIKE [INDISCERNIBLE].
THEY WOULD SORT OF WALK THE
LIVER DOWN THE HALL AND REALLY
SPEND THE NIGHT NEXT TO THE
MACHINE, THEY HAD A BET IN THE
LAB AND THEY WOULD SPEPPED THE
NIGHT NEXT TO THE MACHINE AND WE
DID THIS SEVERAL TIMES SO THIS
WAS THE FIRST PATIENT WE DID.
YOU CAN SEE A LESION THERE, THIS
IS A CO LANCHIAL CARCINOMA.
WE CANNULATED THE VASCULARRURE
AND PUT IT ON THE MACHINE AND
FOR OUR FIRST HUMAN RUN DIDN'T
GO POORLY BUT CERTAINLY NOT WHAT
WE INTENDED, THIS ONLY LASTED 11
HOURS, OUR GOAL WAS ABOUT A WEEK
SO WE COULD PERFORM ALL SORTS OF
REALLY COOL EXPERIMENTS, WE DID
THIS AGAIN ON A PATIENT, THIS
WAS A COLORECTAL LIVER
METASTASIS, WE GOT BETTER AT IT
AND AT THE TIME WE WERE ABLE TO
KEEP THIS THING VIABLE AND
DIDN'T REALLY GET BETTER BUT WE
WERE A BIT SLICKENER DOING THIS,
I THINK AN IMPORTANT POINT I
LEARNED EARLY WAS WAS THAT EVEN
THOUGH THE LIVER WAS NOT HAPPY
ON OUR MACHINE EARLY ON, THE
TUMOR REMAINED VERY HAPPY AND
THAT'S SORT OF THE PROBLEM,
RIGHT?
TUMORS DON'T DIE.
AND SO THIS WAS AT LEAST
CONCEPTUALLY, WE WERE
ENTHUSIASTIC BY THE CONCEPT THAT
THE TUMOR REALLY REMAINED OKAY.
NOW, SAM AND MIKE CONVINCED ME
WE SHOULD GO TO GONIGAN, IN THE
NETHERLANDS WHERE THE PEOPLE
MADE THIS MACHINE BECAUSE THEY
ALLOWED US TO GET PIG LIVERS
OVER AND OVER AND OVER THERE
WITHOUT HAVING TO BURN THROUGH
OUR LABORATORY BUDGET ON
DISPOSABLES, SO I TELL THEM WE
TOOK A VACATION TO THE
NETHERLANDS, BUT THE TRUTH IS IT
WAS NOT A VACATION BUT THEY TOOK
TURNS SPENDING THE NIGHT IN THE
WAREHOUSE PROFUSING LIVERS, NOW
WE GOT BETTER AT IT BUT WE GET
BETTER, I WILL SHOW YOU DATA
FROM THE THIRD PERSON WE DSO
THIS TUMOR WAS ANOTHER
COLORECTAL LIVER METASTASIS, WE
CANNULATED EVERYTHING, WE GOT
BETTER AT THIS, YOU CAN SEE THE
ARTERIAL AND VENOUS LINES, THE
VENUS LINE WAS EXTRACTING OX
GENERATED.
IT MADE BILE, THE BILLIARY
COMPOSITION LOOKED REASONABLE,
BUT WHAT YOU CAN SEE AT ABOUT 24
HOURS IS THE LEVELS BEGIN TO
CLIMB AND BY 48 HOURS BY ABOUT 2
DAYS THE LIVER LOOKED BASICALLY
NONVIABLE.
THE TUMOR HOWEVER, AGAIN AT THE
END OF THE RUN, AGAIN THE
PROBLEM WITH TUMORS THEY DON'T
DIE, THE TUMOR STAYED QUITE
VIABLE AND QUITE HAPPY AND I
EVEN CONVINCED THEM FROM
DR. ROSENBERG'S LAB TO COME
DOWN, TAKE A PIECE OF THE LIVER
AND DO THEIR TILL HARVEST FROM
THIS AND THAT SEEMED TO WORK
VERY WELL IN MY MIND SO THE TOMB
ARE WAS HAPPY, THE TUMOR IMMUNE
MICROENVIRONMENT WAS HAPPY, WE
JUST WEREN'T VERY GOOD YET AT
PROFUSING ORGANS.
SORT OF WHAT WAS DEJECTED A
LITTLE BIT AND THE TEAM SORT
OF--WE HAD TO RECENTER OUR
THINKING AND SO AS TIME WENT BY,
I HAD NEW FELLOWS JOIN THE LAB,
NOW PARTNERS IN ALL OF THIS AND
WE HAD A NEW IDEA NAWE NEEDED TO
COMPLETELY GET RID OF THE OLD
MACHINE AND THIS WAS LED BY ALEX
AND A POST BACKTHAT HE WANTED IN
THE LAB VERY MUCH, ALAN LUNA AND
WE NAMED THE SYSTEM AFTER ALAN
AND SO A LOT OF PEOPLE HAVE
CONTRIBUTED TO THIS, JACOB
LANDEN CARRY RYAN, STEPHANIE AND
LAILA, AND A LOT OF PEOPLE
CONTRIBUTE TO THIS, BUT WE
REDESIGNED THE SYSTEM IN
ENTIRETYY AND SO WE'VE BASICALLY
DECIDE THAD WE WOULD HAVE TO
BUILD EACH OF THE ORGAN SYSTEMS
AROUND THE LIVER IN ORDER TO
KEEP THIS THING VIABLE AND HAPPY
FOR A PROLONGED PERIOD OF TIME
AND THAT INVOLVED THE ADRENAL
GLAND, PANCREAS, HEART AND
LUNGS, WE HAD THAT BEFORE BUT WE
NEED TODAY TO OPTIMIZE THAT, WE
HAD TO ADD IN A DIALYSIS
CIRCUIT, WE WOULD ADD IN THE GUT
SO WE WOULD ADD IN BIOSALT AND
NUTRIENTS TO SORT OF GIVE YOU A
TASTE OF WHAT THIS LOOKS LIKE
YOU KNOW WE DESIGNED A
SEMIAUTOMATED SYSTEM FROM THE
DAYS WHEN SAM AND MIKE WERE
SLEEPING NEXT TO THIS THING,
MASSAGING THE LIVER EVERY COUPLE
OF HOURS TO SORT OF TRY AND GET
RID OF THE EDEMA, OLYMPIC
EXPECTATIONS AND THE TEAM
DECIDED THAT WE SHOULD HAVE A
CENTRAL NERVOUS SYSTEM SUCH THAT
ANY PARAMETERS THAT WERE
BREECHED, WE WOULD AUTOMATICALLY
INFUSE VARIOUS BASAL ACTIVE
SUBSTANCES, NOW THIS DIDN'T
OBVIATE THE NEED TO SLEEP NEXT
TO THIS, I DON'T WANT TO DOWN
GRADE THIS SORT OF LEVEL OF
COMMITMENT THAT THE FELLOWS HAVE
HAD OVER THE TIME, BUT WE
DEVELOPED A CENTRAL NERVOUS
SYSTEM TO SEMIAUTOMATE THINGS.
WE HAD ISSUES WITH HOMOLYSIS AND
SO, THE TEAM HACKED INTO A
ROTOFLOW PUMP SUCH THAT WE COULD
CONTROL THIS PUMP
SEMIAUTOMATICALLY AND THIS WAS
ASSOCIATED WITH FAR LESS
HOMOLYSIS, THE DIALYSIS WAS A
PROBLEM FOR US BECAUSE WE HAD TO
CONTROL THE DISCIPLINARIAL SAIT
VOLUMES AND CONTROL THINGS SO
THE TEAM CIRCUMVENTED THESE
PROBLEMS BY USING 2 SEPARATE
PROMPTS 1 BEFORE AND AFTER THE
DIALYSIS FILTER AND WE COULD
CONTROL THE SPEED AND DETERMINE
IF WE WANT TO PUT FLUID INTO THE
DIALYSIS OF THE SYSTEM OR TAKE
OFF AND YOU CAN SEE THAT THE
URINE LOOKS LIKE URAIN BASICALLY
SO WE EALZ REALIZED THAT
OVERTIME AS I'M SIGHTING HERE
TALKING TO YOU AND BREEGING MY
DIAPHRAGM IS MOVING UP AND DOWN
AND I'M COMPRESSING MY LIVER AND
SO WE FELT LIKE THAT WOULD BE AN
IMPORTANT COMPONENT OF THIS AS
WELL, SO, WE DESIGNED AND
IMPLEMENTED A DIAPHRAGM IF YOU
WILL AND THIS WAS CONTROLLED BY
A PORTABLE VENTILATURE SUCH THAT
THE GRIEVING DYNAMICS WERE
SIMILAR TO THAT OF A PERSON AND
FINALLY, YOU KNOW THE TEAM
DEVELOPED THIS GLUCOSE SENSOR
WHICH WOULD BE THE SAME SENSOR A
DIABETIC PATIENT WOULD HAVE
EMBEDDED IN THEIR SKIN, WE HAD
TO ENGINEER AN ADAPTER SUCH THAT
WE COULD GET CONSTANT GLUCOSE
FEEDBACKS SO WE WOULD KNOW
WHETHER THE SYSTEM NEEDED
INSULIN OR GLUE CODON, I WANT TO
HIGHLIGHT THE COMPLEXITY BEFORE
I SHOW IT TO BECAUSE IT'S TOO
COMPLICATED TO GO THROUGH IT IN
THE PICTURE BUT SUFFICE IT TO
SAY THAT THIS IS YEARS OF WORK
AND THIS IS A WORKABLE SYSTEM
UNLIKE THE 1 WE PURCHASED.
THIS WAS OF OUR OWN DESIGN AND
OF OUR OWN MAKING AND I REALLY
WANT TO CREDIT THE FELLOWS
INVOLVED OVER THE PERIODS OF
TIME WHO REALLY MADE THIS HAPPEN
AND THEY MADE THIS COME TO
FRUITION AND THEY DID THIS BY
MANY, MANY SLEEPLESS NIGHTS.
AND SO, I WANT TO GO THROUGH HOW
WE OPTIMIZE IT SO WE DESIGNED IT
AND THEN, OF COURSE, HOW ARE WE
GOING TO OPTIMIZE THIS SO WE
DECIDED THAT WE WOULD--SOME OF
THE FELLOWS IN THE LAB FOUND A
SLAUGHTER HOUSE AND SO, I HAVE
NOT BEEN.
THEY DON'T INVITE ME BUT THEY GO
TO A SLAUGHTER HOUSE AND THEY GO
UP THERE AS BEST I CAN TELL THEY
HAVE A GREAT TIME AND THEY GO TO
MOWPT AIRY AND GET PIGGINGS FROM
THE LIVERS FROM THE SLAUGHTER
HOUSE, THEY GET BLOOD AND
SOMETIMES THEY WILL BRING BACK
TREATS, THEY DON'T SHARE WITH ME
NECESSARILY, BUT, AND SO THEY
BRING BACK TREATS AND THEY COME
BACK TO THE NIH WITH THE ORGANS
AND WE OPTIMIZE THAT WAY.
I'M NOT GOING TO SHOW YOU ANY
DATA ABOUT PIG LIVERS BUT THIS
IS A PATIENTS IN THE CLINIC
UPPER OF ME ASSISTING
DR. LAMBEDDEN, HE WAS TAKING OUT
THIS LIVER AND THIS IS STEPHAN
EXPE JACOB AND THEY'RE
CANNULATING ON THE BACK TABLE
AND LONG AND SHORT IS, ALL OF
THE HARD WORK PAID OFF. THIS IS
A VERY RECENT PICTURE OF US AND
WITH A PATIENT WHO THIS IS THE
PATIENT, HER LIVER'S BACK BEHIND
HER, THIS IS POST OPERATIVE DAY
NUMBER--6 DAYS AFTER WE PUT HER
LIVER ON THE SYSTEM.
THIS IS ALAN, STEPHANIE 2 VERY
BRIGHT POST BACKSTUDENTS AND
JACOB, YOU SAY JACOB TAKING OUT
THE PATIENT'S LIVER WITH ME,A
CYSTING AND HERE'S THE PATIENT
SO ALL OF OUR STRUGGLES AND ALL
OF OUR EFFORTS STARTED BY SAM
AND MIKE AND REALLY SORT OF CAME
TO FRUITION BY A TEAM LED BY
ALEX, JACOB AND OTHERS, REALLY
IT WORKED AND THE LIVER LOOKED
GOOD AND IMPORTANTLY THE TUMOR
LOOKED GOOD AND THIS IS A
NEUROENDOCRINE TUMOR AND I THINK
THIS IS IMPORTANT BECAUSE AS YOU
THINK ABOUT NEUROENDOCRINE
TUMORS THEY ARE NOT GOOD IF ANY
PRECLINICAL MODEL OF VALUE SO
HAVING A SYSTEM LIKE THIS FOR
VAR TUMORS WHERE YOU DON'T HAVE
A MOUSE MODEL, YOU DON'T HAVE,
YOU KNOW PATIENT DERIVED EXTEN O
GRAPHS TO UTILIZE, THESE ARE
TRUE OF NEUROENDOCRINE TUMORS,
THIS BECOMES A REALLY VALUABLE
TOOL AND BASED WHERE THERE
AREN'T ANY OTHER OPTIONS.
SO AGAIN, THE TEAM WE MIGHT HAVE
HAD A BOTTLE OR 2 OF CHAMPAGNE
TO CELEBRATE THIS 1 AND I WOULD
SAY THAT I AM VERY HAPPY WITH
THE WAY THE TEAM CAME TOGETHER
AND REALLY OVERCAME A LOT OF
OBSTACLES.
OKAY, I DIDN'T REALLY EXPANDOT
AMOUNT OF FRUSTRATIONS WE SAW IN
THAT SYSTEM TO MAKE IT WORK.
IN THE MIDDLE OF THAT I DECIDED
WE SHOULD PIVOT AND WE HAD AN
IDEA THAT MAYBE, YOU KNOW IF YOU
THINK OF THE LIVER AS THE
CADILLAC, IT'S THE TRUEST
PRECLINICAL MODEL YOU COULD EVER
HAVE, IT HAS THE CIRCULATORY
SYSTEM, HAS ALL THE COMPONENTS
BUT WHAT IF WE COULD DO THIS ON
A SMALLER SCALE.
AND SO THIS ALSO WAS A VERY LONG
TIME IN THE MAKING AND
ULTIMATELY CULMINATED IN THIS
SORT OF IDEAL WAS SOMETHING THE
FELLAS MADE SYSTEM CALLED SMART
SYSTEM, THIS STANDS FOR
SURGICALLY RESECTED MESOTHELIUM
CONTAINING UNAFFAIRS TEAM
LEADERRERRED TUMOR
MICROENVIRONMENT.
I WON'T SHOW YOU WHAT IT LOOKED
LIKE EARLY ON BECAUSE IT'S
LAUGHABLE TO BE HONEST BUT UNDER
ALEX, JAMES AND STRAYA, GUPTA
AND EMILY WITH THE HAD BEEN OF
NEWER MEMBERS, CARRY AND RON AND
STEPHANIE, THEY BROUGHT THIS TO
FRUITION, AND SO WHAT THIS IS IS
THIS LOOKS LIKE WHEN A PATIENT
HAS METASTASIS ON THE LINING OF
THEIR ABDOMINAL CAVITY THIS, IS
POETIC THE PERO TONEM,
DIAGNOSTICALLY OR
THERAPEUTICALLY IT'S INDICATED
WE WOULD REMOVE THIS LINING AND
WE WOULD THEN PUT THIS ON TO
PLATFORMS ALMOST LIKE A MODIFIED
CHAMBER, WE DRAW THE PATIENT'S
BLOOD BEFORE HAND AND WE COLLECT
THEIR PLASMA, SUCH THAT THESE
PROFUSION CHAMBERS ARE BATHED
INOX GENERATED 8ED PLASMA FROM
THE SAME PATIENT AND WE USED
POINT OF CARE INSTRUMENTS TO
MAKE SURE NORMAL PHYSIOLOGY IS
MAINTAINED AS BEST WE CAN.
AND THEN WE CAN CERTAINLY
CONCEIVE OF ADDING DRUGS INTO
THIS CIRCUIT SUCH THAT IT WOULD
MIMIC THE PATIENT'S PLASMA
LEVELS OF THE DRUG AND THEN WE
CONCEIVED AFRONS AN IMPLEMENT
THE MULTIPLE IMAGING, MULTIPLE
INTERROGATION PILLARS, PILLARS
OF INTERROGATION, SOME OF THESE
ARE ADVANCED IMAGING, FLOW
CYTOMETRY, ALL OF THE OMICs
YOU CAN THINK OF AND THEN WE
LOOK AT THE PROFUSATE IN THE
PLATMA AS A WAY TO IDENTIFY
BIOMARKERS OF RESPONSE OR NOT.
SO THIS WAS A WAY--THIS IS TD
WAY WE DO THIS.
SO WE PUT A SCOPE IN SOMEBODY'S
ABDOMEN AND WE'RE LOOKING FOR
THESE METASTASIS AND HERE CAN
YOU SEE WE'RE REMOVING THIS VERY
THIN LAYER BLUNTLY AND DOING
THIS VERY GENERALLY, ALTHOUGH I
GUESS IT MAY NOT LOOK THAT WAY
TO SOME BUT THEN WE'RE ABLE TO
SORT OF CUT THIS AREA OFF AND
TAKE THAT OUT OF THE PATIENT AND
THEN ON THE BACK TABLE, AGAIN WE
USE THAT SAME BACK TABLE SET UP,
THE FELLOWS HAVE SORT OF
DESIGNED THIS REALLY COOL WAY TO
HOLD EVERYTHING STILL, AND THEY
TIE AS WE DO IN SURGERY, TIE
KNOTS DOWN AND MAKE SURE IT
STAYS AFFIXED TO THE PLATFORM
AND THEN WE HAVE A RUNNER THAT
RUNS DOWN TO THE LAB AND BRINGS
THIS INTO THEOX GENERATEDDATED
PROFUSION CIRCUIT, THIS IS WHAT
IT LOOKS LIKE ON THE RIGHT, CAN
YOU SEE THERE'S AN OBVIOUS
NODULE OR METASTASIS SURROUNDED
BY WHAT OTHERWISE WOULD BE
NORMAL PEROTONEUM, OKAY.
AND SO THE MAINTENANCE OF THIS
SYSTEM TOOK US A LONG TIME TO
FIGURE OUT.
BY US I DON'T MEAN ME, I MEAN IT
TOOK THE FELLOWS, THE PARTNERS,
MY PARTNERS A LONG TIME TO
FIGURE THIS OUT AND SO, WHAT WE
REALIZED EARLY ON WAS THAT WE
WOULD NEED A SMALL CHAMBER, WE
COULDN'T HAVE SOMETHING HUGE
BECAUSE THE PLASMA VOLUME WAS
TOO MUCH.
WE WERE DRAWING TOO MUCH BLOOD
FROM PEOPLE AND THAT'S NOT FAIR
AND WE WEREN'T GOING TO DO THAT
SOY REALIZED WE NEEDED TO SHRINK
EVERYTHING DOWN AND THEN WE
NEEDED TO HAVE THE PERSTALTIC
PUMP BUT WE NEEDED A WAI TO
CONTROL THE Ph ANDOX
GENERATEDDATION, AND YOU CAN BE
THE JUST RUN PURE OXIEN AND SO
WE ENDED UP COMING WITH A GAS
MIXER AND WE ENDED UP BUYING
MULTIPLE GAS MIXERS WHICH
ALLOWED US TO HAVE THE OX
GENERATED--OXYGEN LEVELS, AND
THEY REALIZED THERE WERE
ELECTROLYTE ABNORMALITIES AS
RESULT OF THE LOSSES SO JAIMINGS
HOOKED UP A SYRINGE PUMP TO THE
SYSTEM THAT SLOWLY DREVERS WATER
AT THE RATE OF BASICALLY TO
REPLACE EVABBARATIVE WATER AND
TO MAINTAIN ELECTROLYTE LEVELS
AS THEY WOULD BE IN THE PERSON
ISSUES IN THE PATIENT.
SO OUR FIRST QUESTION WAS OKAY,
THIS IS COOL, BUT DOES IT
ACTUALLY REFLECT WHAT COMES OUT
OF THE PERSON?
SECONDLY, CAN WE DO THIS ON ANY
TUMOR TYPE?
AGAIN I THINK THE IMPORTANCE
HERE, PARTICULARLY CONSIDERING
WHERE WE WORK IS THREEZ RARE
TUMORS THAT DON'T HAVE A LOT OF
GOOD ANSWERS AND DON'T HAVE A
LOT OF OR ANY PRECLINICAL MODEL,
THIS WOULD BE THE CASE FOR
GASTROINTESTINAL STROMAL FOR
EXAMPLE AND WHAT I'M SHOWING YOU
HERE IS THAT WE'RE ABLE TO
MAINTAIN HISTOLOGY, AND WE'RE
ABLE TO MAINTAIN CELL NUMBERS,
T-CELLS MACROPHAGES,
PROLIFERATION, CONTINUES DURING
OUR 4 DAY TIME POINT.
WHEN YOU LOOK AT THE TUMOR
TRANSCRIPT ORDER OF
MICRONSICALLY WHICH IS OF COURSE
COMMON NOW DAYS YOU SEE IS WE DO
SEE ELEVATIONS IN HYPOXIA, AND
YOU KNOW WE DON'T HAVE ANY RED
CELLS IN THE SYSTEM, SO WE
RAISED THE OXYGEN LEVELS AS HIGH
AS WE CAN, WE DON'T ACCEPT ANY
THICK TUMORS BECAUSE WE'RE
RELYING ON OXYGEN DIFFUSION BUT
OTHER THAN THAT THE TUMORS STAY
REALLY QUITE AS THEY DID WHEN
THEY CAME OUT OF THE PERSON'S
BODY AS BEST WE CAN TELL.
NOW, WITH THE SYSTEM SORT OF
OPTIMIZED THAT 1 OF THE FELLOWS
[INDISCERNIBLE] CAME TO US AND
SAID, YOU KNOW YOU MIGHT AS
WELL--YOU'RE NOT REALLY LOOKING
AT THIS IN A WAY THAT YOU COULD.
YOU SHOULD LEVERAGE THE
ADVANTAGE HERE OTHERWISE YOU'RE
SORT OF BEHAVING LIKE THOO CAVE
PEOPLE AND ARI BA HAD THIS IDEA
THAT WE COULD TAKE THAT PLATFORM
OUT OF THAT PROFUSION CIRCUIT
AND ARIBA IN CONJUNCTION WITH
ENGINEERS REDESIGNED A WAY TO
IMAGE THE TUMOR ON AN INVERTED
WHITE LIGHT LASER CONFOCAL
SCOPE.
THIS FIRST DONE ON A MULTIPHOTON
SCOPE AND FOW WE DO IT ON A
WHITE LIGHT LASER SCOPE AND IT'S
A SCREW TYPE MECHANISM SO WE CAN
CONTROL THE DEPTH AND THEN ARIBA
AND THE TEAM DOES IS THEY
INCUBATE WITH ANTIBODIES TO
HIGHLIGHT VARIOUS CELL FRACTIONS
AND THEN THIS SITS JUST LIKE
THIS, AND THEY'VE DESIGNED A
STAGE INCUBATOR TO MAINTAIN
NIZIO LOGIC PARAMETERS DURING
THE ACTUAL VISUALIZATION, SO
IT'S ALMOST LIKE WE'RE PUTTING A
WINDOW INTO THE TUMORS SO WE CAN
THEN REALIZE WHAT'S GOING ON IN
REALTIME.
TO THE BEST OF MY KNOWLEDGE THIS
HAS BEEN DONE WITH ANIMALS BUT I
DON'T KNOW IT'S EVER REALLY BEEN
DONE WITH HUMANS ON A SCALE LIKE
THIS, SO LET ME SHOW YOU THE
SORT OF INFORMATION YOU GET AND
SO HAD IS A GASTRIC CARCINOMA TO
THE PEROTONEUM AND YOU CAN SEE
WHAT WE'VE DONE HERE IS LABELED
TUMOR CELLS WITH A GREEN CD44
AND WE'VE LABELED IMMUNE CELLS
WITH A CD45.
COLLAGEN IS BLUE UP HERE IN THE
TOP AND YOU CAN SEE THE ACTIVITY
OF THESE IMMUNE CELLS NOT
NECESSARILY KILLING ANY TUMOR
CELLS BUT YOU CAN SEE, THE
ACTIVITY AND I CAN TELL YOU NOT
ALL TUMORS LOOK LIKE THIS.
HERE'S ANOTHER EXAMPLE OF A
MESOTHELIOMA ON THE LEFT HERE
AND WHAT CAN YOU SEE IS THE
TUMORS OVER HERE AND THE ACTIVE
IMMUNE CELLS OVER HERE AND THE
IMMUNE CELLS ARE IN RED, THIS
WOULD BE DESCRIBED AS A COLD
NODULE, YOU DON'T SEE MANY
IMMUNE CELLS MIXED IN WITH THE
TUMOR CELLS.
NOW ON OCCASION WHAT WE SEE IS
THIS IS A REALLY COOL VIDEO,
OVER HERE ON THE RIGHT, I WILL
DRAW YOUR ATTENTION TO THE GREEN
AGAIN, A CD44 TUMOR CELL AND THE
RED IS AN IMMUNE CELL AND YOU
CAN SEE THIS IS AN ENDOGENOUS NO
DRUGS ADDED AND THERE'S AN
IMMUNE CELL THAT RUINS RIGHT UP
AGAINST THESE TUMOR CELLS AND
DOCKS TZ ON THIS TUMOR CELL AND
BEGINS KILLING IT.
AND SO THIS SORT OF STUFF, YOU
WOULDN'T OTHERWISE KNOW THAT
THIS SORT OF HAPPENS WITHOUT
DRUGS ON A SORT OF CONTINUAL
BASIS BUT IT APPEARS TO IN
CERTAIN TUMORS AND NOT IN
OTHERS.
AND THIS WAS REALLY AN
ENLIGHTENING PIECE OF
INFORMATION AND THERE'S A LOT OF
CONSTERNATION ABOUT WHO'S GOING
TO RESPOND TO IMMUNOTHERAPY AND
WHO SUBJECT AND HOW ARE WE GOING
TO DECIDE WHO TO GIVE THIS TO
AND NOT, AND THERE ISN'T A
PERFECT WAY LONG AND SHORT.
I DON'T REALLY SRO THE TIME TO
GO THROUGH ALL THE LITERATURE
BUT WE'RE ABLE TO ADD ANOTHER
PARAMETER.
NOW WHETHER IT WILL BE USEFUL OR
NOT, I DON'T KNOW BUT WE'RE
CLEARLY ABLE TO ADD A DYNAMIC
METRIC, ARIBA HAS THAT
PREVIOUSLY HAS NOT BEEN
ACCOUNTED FOR.
AND I THINK THAT POINT IS MADE
BEST BY EXAMINING THESE 2 MOVIES
SIDE BY SIDE.
YOU CAN SEE THE 1 ON THE LEFT
METASTATIC COLORECTAL ADEN O
CARCINOMA, VERY ACTIVE IPT
GREATERUNE CELLS, THOSE CELLS
RUNNING,A ROUND IN RED, LOOK
LIKE ANTS RUNNING AROUND OR
SOMETHING LIKE THAT, VERY ACTIVE
IMMUNE SYSTEM IN THIS TUMOR
WHEREAS THIS GASTROINTESTINAL
STROMAL TUMOR VERY QUIESCENT,
DON'T SEE A LOST MOVEMENT, MAYBE
A LITTLE BIT BUT REALLY NOT A
LOT.
NOW THE TASK IS ON US TO
DETERMINE WHETHER THIS MEANS
ANYTHING BUT I THINK IT WILL BE
A VALUABLE METRIC MOVING
FORWARD.
ARIBA THEN ASKED THE QUESTION,
THAT'S PRETTY INTERESTING, HOW
LONG CAN WE DO THIS?
HOW LONG CAN WE PUT OUR CAMERA
INTO THIS TUMOR AND REALLY TAKE
A LOOK?
THE ANSWER IS WITHOUT DETRIMENT
TO THE IMMUNE CELLS AND WE'VE
DETERMINED DETRIMENT IN THIS
EXPERIMENT BY LOSS OF MOVEMENT
AND WE CAN DO IT FOR UP TO 8
HOURS AND THAT'S REALLY COOL
BECAUSE THAT SUGGESTS CAN YOU
PUT A DRUG INTO THE SYSTEM AND
REALLY WATCH BEFORE AND AFTER
DEPENDING ON THE DRUG AND
DEPENDING ON WHAT YOU THINK THE
KINETICS ARE, BUT THIS ALLOWS
YOU YOU TO LOOK BEFORE AND AFTER
AND THAT'S REALLY QUITE COOL.
NEXT ARIBA AND THE TEAM ASKED A
DIFFERENT QUESTION, WHAT IF YOU
DO THIS NOT NECESSARILY FOR A
VERY LONG PERIOD OF TIME BUT
WHAT IF YOU DID THIS OVER
CONSECUTIVE DAYS SUCH THAT YOU
COULD TAKE THE SNAPSHOTS IN A
DIFFERENT WAY RATHER THAN 1 LONG
CONTINUOUS MOVIE COULD YOU DO
THIS ON VARIOUS DAYS AND THE
ANSWER IS YES, YOU CAN, CAN YOU
DO IT FOR 2 DAYS AND YOU CAN SEE
WITHOUT--CAN YOU SEE THE CELLS
STILL REMAIN HAPPY AND STILL
MOVE.
AGAIN RED MARKS THE IMMUNE CELLS
WITH THE CD45 MARKER SO WHAT WE
BEGIN TO REALIZE IS WE'VE GOT A
VERY COOL TOOL TO BEGIN TO
EVALUATE HUMAN TUMORS IN A WAY
THAT IS SORT OF HARD TO DO IN A
PERSON, HARD TO DO IN A MOUSE, I
CAN TELL YOU BECAUSE I'VE TRIED
AND HARD TO DO IN AND PROBABLY
IMPOSSIBLE TO DO IN ANY OTHER
MEANINGFUL WAY.
SO, NEXT, YOU KNOW ARIBA AND THE
TEAM SAID WELL, OKAY, WE CAN
ONLY DO A COUPLE PARAMETERS
LIVE, BUT WHAT IF WE THEN BEGIN
TO MULTIPLEX ON TOP OF THAT
USING VARIOUS TECHNIQUES AND
THAT'S EXACTLY WHAT WAS DONE
HERE.
SO YOU CAN--YOU KNOW USE THE RED
AND GREEN LIVE, BUT AFTER THAT
WE COULD FIX IT, SECTION IT SUCH
THAT WE COULD ORIENT OURSELVES
BACK TO WHERE THE LIVE IMAGING
WAS AND THEN REALLY GAIN A LOT
OF INFORMATION AND IF--IF WE DID
THAT I WILL SKIP FORWARD, IF WE
DID THAT WE COULD REALLY BEGIN
TO UNDERSTAND THE WHOLE 3
DIMENSIONAL PICTURE, REMEMBER,
YOU CAN ONLY SEE WHAT RIEWR
LOOKING FOR BUT IN THIS
SCENARIO, YOU WE CAN SEE LIVE
ELEMENTS AND THEN WE CAN BEGIN
TO UNDERSTAND THE REAL
COMPLEXITY OF TUMORS, AFTER
WE'VE ACQUIRED THE DYNAMIC PARTS
OF THE IMAGING.
NOW MARTHA CAME TO THE LAB AND
SAID, WELL, HAVE YOU A COOL
SYSTEM, THAT'S TRUE, NO 1 CAN
DENY THIS BUT YOU HAVE A
LIMITATION AND THAT LIMITATION
IS, YOU CERTAINLY HAVE AN INTACT
TUMOR MICROENVIRONMENT, AND,
THAT'S COOL BUT HOW DO YOU MODEL
ANY NEW CELLS WHEN YOU COME INTO
THE TUMOR, AND SO EXAMPLE WOULD
BE HOW DO YOU MODEL, IMMUNE CELL
RECRUITMENT AND YOU DON'T HAVE A
WAY OF DOING THAT AND SO WHAT
MARTHA DID, MARTHA REELZED WE
WERE DRAWING A BUNCH OF BLOOD,
BLOOD FROM PATIENTS AND THEN WE
WERE SIMPLY THROWING AWAY THE
BUFFING OR THE BPMCs, AND
MARTHA CLICKED THEM INSTEAD OF
THROWING THEM AWAY AND BEGAN TO
LABEL THEM WITH A TRACKING DIE.
AND SHE DEVELOPED WITH A TEAM OF
ENGINEERS A WAY OF INJECTING
THESE LABELED CELLS, NOT INTO
THE TUMOR, THAT WOULD BE SORT
OF--I DON'T KNOW IF THAT WOULD
BE REALISTIC BUT MARTHA
DEVELOPED A WAY TO INJECT THOSE
CELLS INTO THE P
EROTONEUM AJAIZENT OR AWAY FROM
THE TUMOR, IT'S A FANCY SET UP
AND A VERY FANCY GONIOMETER WITH
A SENSITIVE INJECTOR AND SO
MARTHA DEVELOPED THIS TECHNIQUE
AND I'M GOING TO SHOW YOU WHAT
THIS LOOKS LIKE, IF THE SLIDES
WILL ADVANCE.
HERE WE GO SO WHEN MARTHA
INJECTS THOSE CELLS, SHE SEES
THEM AS SORT OF ROUND IN THE
BEGINNING BUT OVER A PERIOD OF
ABOUT 3-4 HOURS, THEY BEGIN TO
ELONGATE AND THEY ACTUALLY MOVE
ALONG FIBERS OF THE NORMAL
MESOTHELIUM WHICH IS REALLY COOL
AND THE QUESTION BECOMES, IS
THIS PURPOSEFUL MOVEMENT OR IS
IT JUST SORT OF MOVEMENT?
AND THE QUESTION BECOMES DOES IT
GET INTO THE TUMOR AND IN FACT,
WHAT WE'VE BEEN ABLE TO TO SHOW,
WHAT MARTHA'S BEEN ABLE TO SHOW
ALONG WITH ARIBA AND THE REST OF
THE TEAM, THAT THOSE OVER A
PERIOD OF A COUPLE OF DAYS,
THOSE INJECTED PBMC'S LABELED
FEAR IN GREEN, THEY ALSO ARE
IMMUNE CELLS OF COURSE SO THEY
HAVE A RED, GREEN, AND RED
LABEL.
THOSE ARE FOUND INSIDE THE TUMOR
AT THE END OF A 2 DAY RUN AND
THEY INTERACT WITH AN EVEN KILL
TUMOR CELL AND I WILL SHOW YOU
THAT HERE.
WHAT YOU CAN SEE HERE IS 1 OF
THOSE GREEN AND RED CELLS, HERE
IS A CYAN WHICH MARKETS A TUMOR
CELL AND YOU CAN TRACK THIS OVER
TIME, I'VE TAKEN IT OUT OF A
MOVIE FORMAT JUST TO MAKE IT
EASIER TO SEE AND WHAT YOU CAN
SEE IS THIS CELL IS NOW
INTIMATELY ASSOCIATE WIDE THAT
TUMOR CELL.
AND THAT WILL ULTIMATELY RESULT
IN THAT TUMOR CELL DYING.
OKAY, I'VE SHOWED YOU THE FACT
THAT MY PARTNERS OVER THE LAST
SEVERAL 4 OR 5 YEARS, HAVE
DEVELOPED THESE REALLY COOL
TOOLS TO BE ABLE TO INVESTIGATE
DRUGS IN AN OTHERWISE UNFETTERED
FLAT FORM AND NOW I WILL SHOW
YOU HOW WE WILL USE THESE TOOLS,
OKAY?
SO, EMILY [INDISCERNIBLE] WAS
HEAVILY INVOLVED IN THE SMART
SYSTEM AND OPTIMIZING IT BUT SHE
STARTED THESE EXPERIMENTS BY
ADDING THE TRIED AND TRUE
ILTWORKS THE OLD NIH IL2 AND
HERE WE GO, AND WHAT 'EM
ILLEGALS SHOWED THAT WAS THAT
AFTER BEING IN THE SYSTEM FOR 4
DAYS, YOU CAN DUMP INTERLEUKIN 2
ON TO THE SYSTEM AND YOU CAN SEE
THE IMMUNE CELLS IN THE SYSTEM
RESPOND BY MOVING AND INCREASING
THEIR VELOCITY AND THAT'S
ACTUALLY MAPPED OUT HERE.
AND SO THIS WAS OUR FIRST SORT
OF REAL DATA THAT YOU CAN ADD
DRUGS INTO THE SYSTEM AND THE
IMMUNE CELLS WILL RESPOND TO IT,
NOW EMILY, WAS INTERESTED IN
IMMUNOTHERAPY AND SO WE WANTED
TO GET A DRUG THAT WAS BEING
USED CLINICALLY AT THE CLINICAL
CENTER SO EMILY CONVINCED SOME
OF OUR FRIENDS FROM THE NOW
CENTER FOR IMMUNO ONCOLOGY TO
LET US TRY M7824, NOW THIS IS A
PBL 1 BI FUNCTIONAL TGF BETA
TRAPPED MOLECULE.
OKAY, AND WHAT WE ULTIMATELY SAW
WAS WHEN WE GAVE THE DRUG WE
COULD IN CERTAIN PATIENTS SEE, I
WON'T GO THROUGH THIS IN
ENTIRETY BUT WE COULD SEE CELL
KILLING, WE COULD SEE CLUSTERING
OF CD8 CELLS SEQUESTERED TO
CERTAIN AREAS, THESE ARE AREAS
THAT CO INSIDED WITH CELL
KILLING BY TUNNEL STAIN WHICH
WAS REALLY COOL FOR US.
NOW EMILY DID SIGNED, AND
THOUGHT ABOUT AND DESIGNED THIS
EXPERIMENT AND SO, WE TOOK
SEVERAL PATIENTS WHO ACTUALLY
RECEIVED THE DRUG ON A STUDY AND
WE ENDED UP OPERATING ON THEM.
AND WE USED THEIR TUMOR IN THE
SMART SYSTEM AND THEN WE LOOKED
AT WHAT HAPPENED TO THEIR TUMOR
BECAUSE WE ALREADY KNEW WHAT
HAPPENED TO THEM IN REAL LIFE.
AND THEN WE TOOK A SEPARATE
SMART COHORT, THESE ARE PATIENTS
WHO NEVER SAW THE DRUG, AND WE
GAVE THEM THE DRUG IN THE SMART
SYSTEM AND THEN WE LOOKED TO SEE
WHAT HAPPENED, JUST SO SHOW THE
CLINICAL RESPONDERS AND
NONRESPONDERS.
SO THE CLINICAL RESPONDERS IS AN
INTERESTING STORY.
HOW WOULD YOU GET A TUMOR THAT
RESPONDED TO A DRUG AND AT THE
END OF THE TIME WOULDN'T IT JUST
BE RESIDUAL CELLS, THAT WOULD BE
TRUE BUT AS IT TURNS OUT THAT
PATIENT RECEIVED TOXICITY FROM
THE DRUG AND SHE WOULD COME OFF
THE DRUG AND THE TUMOR WOULD
GROW AND THEN SHE WOULD DP BACK
ON THE DRUG AND THE TUMOR WOULD
SHRINK AND THEN SHE WOULD GET
THE DRUG AGAIN AND SO ON AND SO
FORTH AND I ENDED UP OPERATING
ON HER SO SHE WAS SOMEBODY WHO
HAD TUMOR WE KNEW WOULD BE
RESPONSIVE TO THE DRUG, SHE WAS
OUR TRUE POSITIVE AND THEN THERE
WERE PEOPLE WHO GOT THE DRUG AND
NOTHING APPARENTLY OSTENSIBLY
HAPPENED TO THE TUMOR ON RADIO
GRAPHS WHICH IS OUR GOLD
STANDARD AND WE LOOKEDDA THE
SINGLE PATIENT WHO RESPONDED
VERY WELL, IS THAT PATIENT THAT
INCLUDED DAY 0 HERE AND THIS IS
A 2 DAY EXPERIENCE, I INCLUDED
DAY 0 JUST TO SHOW YOU NOTHING
REALLY HAPPENED BETWEEN THE
CONTROL IN DAY ANSWER BUT WHAT
WE SEE IS ACTIVATED NATURAL
KILLER CELLS, WE SEE ACTIVATED
CD8 CELLS, WE SEE PROLIFERATING
CD45 POSITIVE IMMUNE CELLS,
INCREASED CASPACE 3, SO CELLS
ARE DYING, WE SEE DECREASED PDL
1 STAINING MEMBER BECAUSE THIS
DRUG BINDS TO PDL MASKING THE
EPITOPE WE WOULD GUESS SO THIS
IS WHAT IT LOOKS LIKE WHEN
SOMEBODY RESPONDS TO THE DRUG.
AND SO, I WILL SHOW YOU THE
NATURAL KILLER CELL ACTIVATION
AND WHEN WE LOOK AT EMILY'S TEST
COHORT, SOME OF THESE PATIENTS
LOOK VERY SIMILAR TO WHAT
HAPPENED TO THE PERSON WHO
ACTUALLY GOT THE DRUG AND
RESPONDED TO IT AND HERE'S THE
CD8 POSITIVE, AGAIN, WE SEE THAT
RELATIONSHIP WITH 1 OR MAYBE 2
OF THE PATIENTS WHERE THEY LOOK
LIKE THE PERSON WHO RESPONDED TO
THE DRUG.
HERE'S THE DATA FOR KI67.
SAME THING IS TRUE HERE, HERE'S
THE DAILY BASIS THEA FROM PDL 1
AND THE CULMINATION OF THIS
EXPERIMENT IS NOT TO SAY THAT,
YOU KNOW THIS PERSON RESPONDED
TO THE DRUG.
EMILY WOULD TELL YOU THAT THIS
PERSON--WE OUTTO THINK ABOUT
T-REGGAGING THIS PATIENT TO
THORS STUDY SHOULD THE DISEASE
COME BACK AFTER WE OPERATED ON
THEM.
AND MUCH TO MY DISPLAY MOST OF
THE TIME, PATIENTS WITH VERY
AGGRESSIVE DISEASE END UP HAVING
RECURRENCE OF DISEASE SO I THINK
OF THIS EXPERIMENT AS A VERY
GOOD DEMONSTRATION THAT THIS CAN
BE USED AS A TRIAGE TOOL TO
VARIOUS STUDIES IN THE CLINICAL
CENTER.
OKAY, WE'RE MOVING ALONG WIGHT A
BIT HERE WE'RE OKAY ON TIME BUT
I'M RUNNING SHORT SO I WILL SHOW
THIS DATA.
NOW WHEN I WAS A FELLOW--I WILL
SHOW THIS DATA BECAUSE I WANT TO
HIGHLIGHT THE CONTRIBUTIONS OF 2
PEOPLE WHO WORKED REALLY HARD ON
A SEPARATE PART OF THE LAB.
AND THEN ULTIMATELY UTILIZE THE
SYSTEM TO REALLY--FOR REALLY A
BENCH TO BEDSIDE EFFORT.
SO WHEN I WAS A FELLOW AT SLOAN
KETTERRING, 1 THING I DID WAS A
COLLECTED, WELL WAS THERE WAS A
BANK OF BILE ON PATIENTS AND WE
COLLECTED EXOSTUDIES OF MULTIPLE
ENDOCRINES FROM THIS BILE AND 1
OF THE THOUGHTS WAS MAYBE WE
COULD LEARN SOMETHING ABOUT CO
LANCHIAL CARCINOMA CANCER OF THE
BILE DUCTS AND WE LOOK AT THE
EXOSTUDIES OF MULTIPLE
ENDOCRINES AND THE PROTEIN IN
THE EXOSTUDIES OF MULTIPLE
ENDOCRINES KIND OF HARD TO DO
SINGLE CELL MASS SPECT TROMETRY
OR PROTEOMICS SPECIAL SO 1 THING
WE REALIZED WAS THERE A HIGH
LEVEL OF SOMETHING CALLED EXPORT
AND 7, I CAME TO THE NIH WITH
THIS DATA, I AWLTZ KNEW IT WAS
VERY INTERESTING--ALWAYS KNEW IT
WAS VERY INTERESTING, IT WASN'T
ALL PATIENTS, IT WAS MOST, ABOUT
A FRACTION, ABOUT A THIRD OF
THEM BUT WHEN IT WAS--WHEN XPO7,
WHEN WE LOOK AT THE STAINING
THIS WAS DONE AGAIN BEFORE I
LEFT AND BEFORE I CAME HERE,
WHAT WE SAW WAS THAT WAS THERE
CYTOPLASMIC STAIN NOTHING THE
CANCER CELLS WHICH WAS SORT OF
WEIRD AND AGAIN WHEN I TOLD YOU
BEFORE THAT SAM AND MIKE JOINED
THE LAB, MY FIRST YEAR HERE IN
JULY OF 2017 AND I ACTUALLY TOOK
3 THAT YEAR AND [INDISCERNIBLE]
AND I SAT THE 3 OF THEM DOWN, I
DON'T KNOW IF I CAN TAKE 3 OF
YOU, AND THEY CAME BACK TO ME
LATER IN THE DAY, THEY SAID NO,
WE WANT TO DO THIS AND I SAID,
WELL WHO AM I TO TALK YOU OUT OF
IT SO REED WORKED INCREDIBLY
HARD ON THIS AND THE FIRST THING
REED DID WAS HE GOT A TISSUE
MICROARRAY FROM STEVE YOU HADET
HERE AND STEVE STAINED THE
TISSUE MICROARRAY AND WE
VALIDATED THIS ON AN INDEPENDENT
COHORT, THAT THERE'S A FRACTION
OF THESE PATIENTS WITH CO
LANCHIAL CARCINOMA THAT HAVE
THIS EXVIVO STAIN NOTHING THE
CYTOPLASM AND LOW AND BEHOLD IT
RESULTS IN WORSE SURVIVAL AND
THAT IS TRUE ON A MULTIVALID AND
RELIABLE YABT ANALYSIS SO
WHATEVER THIS IS, IT'S A MARKER
OF AGGRESSIVE DISEASE.
NOW REED DID A LOT OF
EXPERIMENTS BUT HE FIGURED OUT
WAS FROM USING TUMOR
ORGANIZATIONS RANNOIDS WHAT HE
FIGURED OUT WAS THAT WHEN YOU
DID A NEW CLE O PLASMIC
SEPARATION AND AN EXPERIMENT
FROM THE CYTOPLASM HE PULLED
DOWN SOMETHING CALLED SLK, HE
THEN DID THE OPPOSITE EXPERIMENT
WHERE HE PULLED DOWN SLK AND HE
GOT XPO7.
AND WHEN YOU DO THIS
COMPUTATIONALLY THESE 2
MOLECULES FIT TOGETHER VERY
WELL, SO HMM, A KINASE, THAT'S
INTERESTING AND YOU CAN INHIBIT
KINASES SO WE DID THIS WITH
SHORT HAIR PINS IN THE BEGINNING
AND WE REALIZED THAT IN AN
ORTHOTOPIC TUMOR INJECTION MODEL
THAT YOU ACTUALLY INHIBIT TUMOR
FORMATION AND IT FORMS BUT IT'S
SMALL BUT REALLY COOL IS IT
LOOKS WAY DIFFERENT THAN A
FORMAL TUMOR, IT'S NOT JUST A
SMALL TUMOR, IT HAS A CYSTIC
APPEARANCE, THERE'S A LOT OF
DEGENERATING CELLS, THERE WASN'T
A LOT OF TUMOR INVADING INTO THE
SORT EVER NORMAL LIVER
ARCHITECTURE THAT WE ALWAYS SEE
WITH THIS DISEASE.
AND THEN TOSSIN JOINED THE LAB
SEVERAL YEARS AGO AND TOSSIN HAD
EXPERIENCE WITH SIGNALING AND HE
SAID, WELL, YOU CERTAINLY CAN'T
GIVE PEOPLE SHORT HAIR PINS BUT
CAN YOU DO IS GIVE PEOPLE KINASE
INHIBITORS.
WELL, THERE IS NO KINASE
INHIBITOR TO SLK SO TOSSEN
WORKED WITH OUR FRIENDS AT CAPER
AND HE CAME UP WITH SEVERAL
DRUGS HE THOUGHT MAYBE COULD
WORK AND AND HE RAN THIS EARLY
EXPERIMENT WHERE HE SHOWED THAT
1 OF THESE DRUGS, RESULT IN
SUBSTANTIAL TUMOR REGRESSION,
NOT JUST PREVENTATIVE TUMOR FROM
GROWING, HE LET THEM GROW AND
TREATED THEM AND HERE'S THE
WATER FALL PLOT AND HE SAW
SHRINKAGE OF THESE TUMORS.
NOW TOSSIN DID A TON OF WORK,
IT'S OUTSIDE THE SCOPE OF THIS
TALK BUT TOSSIN REALLY PROVED
THAT THAT DRUG TIVOZANIB BINDS
AND PUSHING UP THE REGION AND
BLOCKING THE KINASE FUNCTION.
HE DID THIS, I'M SHOWING YOU
HERE BECAUSE IT LOOKS THE
COOLEST BUT HE DID THIS--USING
AND CRYSTALLIZING SLK WITH
[INDISCERNIBLE] DRUGS AND
CRYSTALLIZED UNDER HIS WATCH, HE
ALSO DID A NUMBER OF
EXPERIMENTS, KINASE DEAD
CONSTRUCTS HE HAS DRUG RESIST
ABT CONSTRUCTS AND THE DRUG
COMBINED, SO HE DID A LOT OF
WORK TO PROVE THIS IS IN FACT,
HAPPENING THEN HE SAID OKAY, WE
NEED TO GET AHOLD OF PDXs AND
WE DIDN'T HAVE PDXs, THE NIH
DOESN'T HAVE ANY PDXs BUT WE
BOUGHT THEM FROM A VENDOR AND WE
CHECKED THISEM AND LOW AND
BEHOLD THEY ALL HAD EXPRESSION
IN THE CYTOPLASM AND WHEN WE
TREAT WITH THE SINGLE DRUG
TIVOZANIB, WE SEE QUICKLY THAT
IT DOESN'T GROW AT ALL, IT STAYS
AND SHRINKS AND THIS PDX GREW
QUICKER AND IT EXPERIMENT IS
TILL ONGOING, THEY BOTH ARE
REALLY, BUT THIS DRUG LOOKS LIKE
IT WORKS VERY WELL'RE XPO7
EXPRESSING FILLAGEIO CARCINOMA
NOW TOSSIN WANTED TO TAKE THIS A
STEP FURTHER.
I WILL TAKE IT BACK FULL CIRCLE
AND SHOW THAT TOSSEN THEN USED
THIS DATA AND TREATED 2 PATIENTS
IN THE SMART SYSTEM, FIRST
PATIENT WAS ON THE LEFT HERE
THIS, IS PATIENT LABELED A, THIS
IS AN XPO7 NEGATIVE CO LANCHIAL
CARCINOMA, WHEN YOU GIVE THE
DRUG INTO THE SYSTEM, IT'S A 4
DAY EXPERIMENT WHAT YOU SEE IS
NOT A WHOLE LOT TO BE FOUND
TOTALLY HONEST WE DON'T SEE A
MUCH INCREASE IN CASPACE 3,
TUNNEL STAINING DEPECTED
GRAPHICALLY HERE, CONTRAST THAT
TO THE PATIENT WHO HAD XPO7 AND
THE CYTOPLASM AS SHOWN BY THE
GROUND STAIN HERE AND WHAT
HAPPENED WHEN WE GAVE TIVOZANIB
FOR 4 DAYS YOU CAN SEE TUMOR
DEATH BY DAY 3 AND TUNNEL
STAINING AND YOU CAN SEE THAT
QUANTIFIED HERE AND YOU CAN SEE
A HUGE AMOUNT OF CELL DEATH
ASSOCIATED WITH THIS DRUG.
NOW, TOSSEN AND I THEN SAT AND
WE WERE VERY IMPRESSED BY ALL
THIS DATA.
WE APPROACHED THIS COMPANY AND
SAID WE WANT THIS DRUG TO RUN IN
PATIENT SAYS, THIS WOULD BE A
FIRST EVER CO LANCHIAL CARCINOMA
ANDY WOO WE WROTE THIS TRIAL
TOGETHER AND I'M PROUD TO SAY WE
HAVE NOW TREATED OUR SECOND
PATIENT ON STUDY, WE DON'T ARE
RESULTS YET, THEY ARE BEING
TREATED WE HAVEN'T DONE ANY
EVALUATION YET BUT WE'VE TREATED
2 PATIENTS ON STUDY, AND THIS IS
A TRUE BENCH TO BEDSIDE MISSION,
MISSION ACCOMPLISHED, NOW OF
COURSE IT HAS TO WORK OTHERWISE
IT DOESN'T MATTER BUT WE'RE HOPE
EMPLOY.
OKAY, I WANT TO END WITH AGAIN A
THANK YOU.
I MEANT TO HIGHLIGHT EVERYBODY'S
CONTRIBUTIONS AND I DIDN'T GET A
CHANCE TO GO THROUGH ALL OF THE
NEWER FELLOWS IN THE LAB BUT
CARRY RYAN'S DOING SOMETHING
COOL, SHE FIGURED OUT A WEB
CONNECTED AND THEY'RE GOING TO
FIGURE THAT OUT, LAILA IS,
WOOING ON SOMETHING NEAR AND
DAILY BASISSER TO MY HEART WHICH
IS IDENTIFYING CELLS THAT YOU
CANNOT OTHERWISE SEE IN
MICROMETASTASIS AND LARGE PIECES
OF LIVER, STEPHANIE GREGORY WILL
IS WORKING WITH ANDREW BLAKELY
AND WE'RE LOOKING TO SEE IF WE
CAN AND DECIDE WHICH DRUGS WE
SHOULD GIVE PATIENTS RIGHT NOW
IT'S A GUESS, STEPHANIE STANDS
TO MAKE A BIG CONTRIBUTION
THERE, I JUST WANT TO BE
EVERYBODY SORT OF CAME TOGETHER
AND EVERYBODY CONTRIBUTED AND IT
HAS TRULY BEEN MY PLEASURE OVER
THESE LAST 5 OR 6 YEARS TO WORK
WITH ALL OF THESE PARTNERS THAT
I'VE HAD.
--WORKED REALLY, REALLY HARD TO
DEVELOP THESE COOL IMAGING
THINGS YOU JUST SAW, ANDREW
BLAKELY AND JEREMY DAVIS ARE MY
SURGERY PARTNERS AND OPERATE ON
THESE PATIENTS WITH ME.
AND WE WOULDN'T--NONE OF THIS
WOULD BE POSSIBLE IF WE DIDN'T
DO A VERY GOOD JOB FOR PATIENTS
AND I'M VERY PROUD OF THE WAY WE
TREAT PATIENTS AND HOW WE TAKE
CARE OF THEM.
AND VERY PROUD OF EVERYBODY IN
THE OPERATING RADIO AM AND
EVERYBODY DOES WHAT THEY CAN AND
THEY TAKE CARE OF THE PATIENTS
AND THEY MAKE THINGS HAPPEN.
DR. CLIENER WE WOULD BE LOST
WITHOUT HIM, HE REVIEWS ALL
THESE SORT OF HISTOLOGY FOR US
ON ALL OF THESE RUNS, AND I
WOULD SAY PROBABLY THE PERSON I
DIDN'T MENTION YOU GO PROBABLY
DESERVES NOR CREDIT THAN I DO
FOR SURE AND TOM AND HIS GROUP.
THEY ARE THE ENGINEERS THAT HAVE
WORKED BEHIND THE SCENES REALLY
CREATE ALL OF THESE THINGS, SO
OUR IDEAS CAME TO FRUITION BY
TOM, JOHN, MARCI, RANDY, THE
GUYS OVER THERE AND THEY REALLY
HAVE DONE AN EXCELLENT JOB AND
CO INVEBTORS ON ALL THE PATENTS.
SO WITH THAT, I WOULD LIKE TO
END AND TAKE ANY QUESTIONS.
>> DR. HERNÁNDEZ, OKAY, SO IMIE
FIRST OF ALL I WANT TO THANK YOU
FOR SHARING YOUR ABSOLUTELY
FASCINATING WORK AND
CONGRATULATIONS ON ALL YOUR
PROGRESS.
WE LOOK FORWARD TO SEEING WHAT
YOU WILL ACCOMPLISH IN THE
FUTURE, I THINK WHAT'S MOST
IMPORTANT AND STANDS OUT TO ME
IS YOU WERE SELECTED AS OUR
DISTINGUISHED CLINICAL TEACHER
AT EVERY STEP IN THE PROGRESS OF
YOUR RESEARCH, YOU GIVE SO MUCH
CREDIT TO YOUR FELLOWS WHO WOULD
BRING LIGHT AND INSIGHTS INTO
PROBLEMS THAT WERE ENCOUNTERED
WHILE YOU MENTORED THEIR
SOLUTIONS THAT THEY SUGGESTED
BUT, YOU KNOW IT'S NOT LOST ON
US THAT IT IS YOUR OWN INSIGHTS
AND THAT HAVE GUIDED TOWARD
THESE SOLUTIONS.
YOU'RE OBVIOUSLY A VERY HIGHLY
RESPECTED METROPOLITANNOR AND
LAUNCHED MANY CAREERS HERE FOR
NEW PHYSICIAN SCIENTISTS
SPECIFICALLY SURGEON SCIENTISTS
AND AGAIN CONGRATULATIONS ON
YOUR WELL-DESERVING OF THE
CLINICAL TEACHER AWARD AND SO
CONGRATULATIONS FOR THAT AND
THIS WONDERFUL TALK.
SO WE HAVE TIME FOR--THERE'S A
COUPLE QUESTIONS HERE.
LET'S SEE HERE, TO START, SO
YOUR SYSTEM LOOKEDDA THE VARIOUS
TUMORS IS THERE A TYPE OF
TUMORROR THAT APPEARS TO BE A
BEST CANDAD FOR BEING STUDIED IN
YOUR ALAN SYSTEM SPECIFICALLY?
>> YEAH, SO THEA WILL AN SYSTEM
IS 1 THAT PROABT DOESN'T MATTER
AS MUCH I THINK THAT WE HAVEN'T
DONE IT ENOUGH TO ANSWER THAT
QUESTION, BUT I THINK I WILL
ANSWER THAT USING THE SMART
SYSTEM, SO, THAT SYSTEM THE MORE
AGGRESSIVE THE TUMOR, THE EASIER
IT IS.
AND SO, TUMORS THAT SORT OF ARE
SORT OF SOFT AND HAVE A LOT OF
NECROSIS IN THE MIDDLE, THOSE
TEND TO BE MORE DIFFICULT FOR
US--BUT THE PATIENT HAS
DEVELOPED AND KNEW IT WOULD BE
FAIRLY AGGRESSIVE AND ONCE THAT
HAPPENS THE TUMORS STAY FAIRLY
VIABLE, THE ADVANTAGE OF THE
ALLEN SYSTEM IS WE DON'T GO
ANYWHERE NEAR THE TUMOR, I USE
THE INFLOW AND OUTFLOW KNOWLEDGE
OF THE LIVER AND INFLOW AND
OUTFLOW VESSELS AND THAT
TENDINGS TO STAY FAIRLY HAPPY
AND YOU WOULD MENTION THE MOST
DIFFICULT PART OF THAT SYSTEM IS
KEEPING THE LIVER HAPPY, THE
LIVER'S NORMAL TISSUE, THE
NORMAL TISSUE NOT REALLY MEANT
TO BE LIVING LIKE THIS.
BUT A TOMB OAR TENDS TO DO JUST
FINE.
SO I THINK, YOU KNOW THAT THE
ALAN SYSTEM IS GOING TO BE--IT'S
GOING TO WORK FOR ANYBODY WHO
HAS THE METASTASIS IN THE RIGHT
PLACE OR IS UNDERGOING A
THERAPEUTIC METRICS TAFTSECTOMY
AND THAT'S NOT EVERYBODY I
OPERATE ON, IT'S A FRACTION BUT
TUMOR HAS TO BE IN THE RIGHT LO
XAIGZ AND I HAVE TO FEEL LIKE
IT'S THE RIGHT THING TO DO FOR
THE PATIENT BUT I DON'T THINK
THE TYPE OF TUMOR IS GOING TO--I
THINK IT'S ALL GOING TO WORK OUT
OKAY.
I DON'T THINK THAT'S GOING TO BE
DETRIMENTAL DEPENDING ON ACROSS
VARIOUS TUMOR TYPES, OBVIOUSLY
WE HAVE TO PROVE THAT BUT THAT'S
MY FEELING.
>> THANK YOU.
OKAY, LET'S SEE HERE 1 OTHER
QUESTION.
IT'S EXCITING HOW THE SMART
SYSTEM ALLOWS FOR DIRECT
EVALUATION TOZINIB IN THE EFFECT
OF PATIENTS WHO INSIGHTS HAS
YOUR SYSTEM REVEALED TO TUMOR
BIOLOGY THAT MAY OFFER THAT
OTHER NEXT GREAT STEPS IN
THERAPEUTICS?
>> SO WHAT I THINK, YOU KNOW, I
WOULD SAY, I WILL ANSWER THAT IN
THE FOLLOWING WAY, SO, WHEN YOU
LOOK AT WHAT HAPPENS WHEN YOU
GIVE A DRUG THAT KILLS A LOT OF
TUMOR CELLS, THEY DON'T ALL DIE,
AND THAT'S SORT OF WHAT WE
OTHERWISE KNOW TO BE TRUE IN
PATIENTS.
YOU DON'T SEE THESE DRUGS MELT
AWAY ALL THE TUMOR AND SO, THE
HETEROGENERATED AITY IS REALLY,
REALLY CAPTURED HERE SO THIS
ISN'T AN ISOLATED CELL
POPULATION LIKE AN ORGANOID
POPULATION WHERE THEY'RE
PROBABLY ALL LIKELY TO RESPOND
OR NOT, THIS CAPTURES ALL THE
HETEROGENERATED AITY AND SO
THAT'S A VERY ENLIGHTENING THING
THAT YOU REALIZE THERE ARE
POCKETS OF TUMOR CELLS THAT
APPEAR TO NOT RESPOND AT ALL,
THE OTHER THING THAT'S SUPER
INSIGHTFUL THAT WE COME TO
REALIZE IS YOU SEE AREAS WHERE
IMMUNE CELLS ARE KILLING TUMOR
CELLS AND THAT IMMUNE SYSTEMUNE
CELL COULD HAVE WALKED RIGHT BY
10 TUMOR CELLS AND BE TOTALLY
UNBOTHERRED BY THEIR PRESENCE,
SO WE'RE ABLE TO VISUALIZE THESE
PROCESSES, NOW WE NEED TO
UNDERSTAND THEM AND SO WE'RE
WORKING ON THAT, BUT THESE SORT
OF THINGS THAT THIS CONCEPT THAT
SOMETHING WORKS OR DOESN'T,
BLACK AND WHITE IT'S NOT
REALITY.
REALITY IS THAT SOME OF THE
TUMOR IS ULTIMATELY KILLED BY
THESE DRUGS THAT WORK OR NOT AND
SOME ISN'T.
AND REMEMBER, THERE'S A
DISCREPANCY BETWEEN CLINICALLY
WORKING AND NOT, STUFF'S GOT TO
SHRINK, NORMAL TISSUE HAS TO
GROW IN AND IT HAS TO BE
MEASURABLE BUT WHAT'S HAPPENING
BELOW THAT IS A VERY COMPLICATED
THING AND I THINK IT'S SUPER
ENLIGHTENING TO WATCH THESE
THINGS.
>> WE'RE UP ON THE HOUR AND
THAT'S ALL THE QUESTIONS WE SEE.
IF I GET ANY MORE QUESTIONS I
WILL CERTAINLY REPORT THEM TO
YOU FOR ANSWERINGMENT BUT AGAIN
I WANT TO SAY THANK YOU FOR THIS
ENLIGHTENING AND SUCK SETIONFUL
TALK AND CONGRATULATIONS AGAIN
FOR BEING NAMED THE
DISTINGUISHED CLINICAL TEACHER
AWARDEE, CLEARLY, A HIGHLY
QUALIFIED APPLICANT AND I THINK
OF ANYONE WHO'S MORE DESERVING
AND FINALLY I WANT TO THANK THE
DECKER FAMILY FOR SUPPORTING
THIS LECTURE AND FOR THE
GENEROUS SUPPORT THAT YOU'VE
GIVEN US AS WELL AS FNIH, THANK
YOU VERY MUCH AND EVERYBODY HAVE
A WONDERFUL AFTERNOON.