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>> WELCOME EVERYONE TO THE

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WEDNESDAY AFTERNOON LECTURE

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SERIES, I'M DR. KELLY, I AM A

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CCR DEPUTY DIRECTOR AND I AM

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VERY EXCITED TO INTRODUCE

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TODAY'S SPEAKER DR. HANS CLEVERS

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WHO HAS PIONEERED THE FIELD OF

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ORGANOIDS

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OUR SPEAKER TODAY TRULY IS

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WELL KNOWN TO MOST OF YOU, HANS

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CLEVERS HAS LONG HELD THE

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POSITION OF PROFESSOR OF

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DEVELOPMENTAL BIOLOGY, IN

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MARCH 2022 HE ACCEPTED THE

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POSITION OF HEAD OF ROCHE PHARMA

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RESEARCH AND EARLY DEVELOPMENT

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INDEED, HE'S GIVING HIS LECTURE

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TODAY FROM BOSUL WHERE IT IS NOW

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9 P.M.  SO DR. CLEVERS OBTAINED

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HIS MD DEGREE IN 1984 AND

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Ph.D. IN 1985 FROM HUBRECHT,

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UNIVERSITY, AND HIS POST

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DOCTORAL WORK IN 86-89 WAS DONE

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AT THE DANA FARBER CANCER

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INSTITUTE AND HARVARD,

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UNIVERSITY.

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THROUGHOUT HIS CAREER, HE HAS

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WORKED ON THE ROLE OF SIGNALING

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AND STEM CELLS IN CANCER AND HIS

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DISCOVERIES INCLUDE TCF AS THE

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NUCLEAR WINTER WEATHER EFFECTOR,

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THE LOCAL OF WINTER WEATHER IN

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STEM CELL BIOLOGY AND OF WITN

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COLAN CANCER AND LGR IS A MARKER

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OF NOVEL TYPES AND THE AMPLIFIED

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ARE OUR RESPONDENTS AND NEW

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METHODS TO GROW EVERYEXPANDING

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ORGANOIDS DERIVE FRIDAY A RANGE

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OF HEALTHY AND DISEASED HUMAN IS

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SHE.

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THIS WORK LED TO 750

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PUBLICATIONS AT LEAST AND 90,000

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CITATIONS.

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DR. CLEVERS IS A MEMBER OF THE

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ROYAL ACADEMY OF ARTS AND

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SCIENCES, AMERICAN ACADEMY OF

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THE ARTS AND SCIENCES U.S.

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AMERICAN ACADEMY OF ARTS AND

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SCIENCES AND FRENCH ACADEMY OF

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TOMORROWS AND HE IS A RECIPIENT

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OF AND ORGANOIDS TO MODEL HUMAN

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DISEASE, HAN SWELCOME TO THE NIH

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AND THANK YOU SO MUCH FOR BEING

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HERE AND WE LOOK FORWARD TO YOUR

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TALK.

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>> THANK YOU VERY MUCH VERY MUCH

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KELLY, FOR THE INTRODUCTION AND

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SPEAK

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WHAT I WILL TRY TO DO IS GIVE

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A BIT OF BACKGROUND AS TO HOW WE

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MORE OR LESS BY CHANCE

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DISCOVERED THIS TECHNOLOGY TO

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GROW HUMAN ORGANOIDS FOR HUMAN

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AND DISEASE AND TAKE IT BACK 25

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YEARS OR SO AGO, WHEN MY LAB

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JUST DISCOVERED THAT THE TCF

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TRANSCRIPTION FACTORS ARE THE

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EFFECTORS OF THE PATHWAY AND AT

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THE SAME TIME WE NOTE THAD WHEN

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WE KNOCK OUT 1 OF THOSE TCF 4,

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THAT THE PROCESS YOU'RE LOOKING

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AT COMES TO AN ABRUPT HALT AND

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THIS IS TO SEE THE STEM CELLS IN

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ACTION AND WE ALSO THEN SHOWED

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THAT IN COLOON CANCER IN

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PARTICULAR, ACTIVATING THE

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MUTATIONS ACTIVATE THE STEM

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CELLS, LEADING TO ADENOMA

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PROLIFERATION.

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HERE YOU SEE VILLUS IN THE HUMAN

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BEING AND THESE ARE ABOUT 6-10

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AND THIS IS WHERE IT WAS WELL

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KNOWN THAT STEM CELLS AND THE

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PROCESS SO CELLS ARE BORNE NEAR

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THE BASE OF THE CRYPT FROM THESE

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ELUSIVE STEM CELLS, THE DAUGHTER

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CELLS ONLY TAKE 2 DAYS WHILE

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THEY PROLIFERATE TO XIPT THE

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CRYPTS, THEN THEY TAKE IT

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RAPIDLY 1 OF 10 DIFFERENT CELL

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TYPES AND CELL FETES, CELLS ARE

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LIKELY TO SETTLE AT THE BASE,

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YOU SEE THESE LARGE CELLS HERE,

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ALL OF THE CELL TYPES KEEP ON

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MOVING UP AND WHEN THEY'RE ABOUT

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5-6 DAYS OLD IN THE MOUSE, THEY

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REACH THE TIPS OF THE VILLI AND

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THE APOPTOSIS AND A MOUSE IN THE

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TISSUE CELLS EVERY WEEK OR SO IN

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HUMANS IT MIGHT BE CLOSER TO 2

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WEEKS, PROBABLY THE FASTEST AS I

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SAID, CELL RENEWING TISSUE.

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SO WE HAVE FOUND THAT IN CANCER

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AND IN PHYSIOLOGY OF CRYPTS,

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THIS IS THE DRIVING FORCE, IT

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TOOK US A WHILE TO FIND OUT THE

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TARGETS PROGRAM, WE HAD TO WAIT

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UNTIL MICROARRAY WAS INVENTED IN

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THE EARLY 2000S.

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NOW YOU WOULD PROBABLY DO THAT

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WITH RNA SEEK, THIS ALLOWED US

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IN COLON CANCER CELL LINES,

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ABOUT  200,000 GENES THAT WERE

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UNDER THE CONTROL OF THE THIS

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WEN PATHWAY AND WE FOUND THAT

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THIS IS ACTIVE IN CRYPTS AND

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THEN WE THOUGHT POSSIBLY AS NICK

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BARKER A BRITISH POST DOC FOUND

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IT HIDDEN IN 200 TARGET GENES

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AND MOST OF THEM ACTUALLY

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EXPRESSED IN THE ENTIRE CRYPTS

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AS THEY WERE EXPRESSED IN THE

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ENTIRE ADENOMA CARCINOMAS OF THE

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GUT AND THAT HIDDEN IN THERE,

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THAT MAYBE 1 OR MORE THAT WOULD

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MARK THE STEM CELLS AT THE BASE,

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AND YOU SEE A GENE THAT PICKED

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AFTER SEVERAL EXERCISES EARLIER

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ON, AND THIS IS A KNOCK OUT AND

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GFP BUT ALSO A RECOMBINATION EFR

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AND I WILL SHOW THIS IN THE NEXT

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SLIDE.

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THIS LIGHTS UP TINY CELLS, THIS

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IS 1 CELL ON THE LIGHT, THE

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LARGER CELLS ARE THE BANNER

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CELLS, POST MITOTIC CELLS, FULLY

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DIFFERENTIATED, ACTIVE IN

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KEEPING IN OUT OF THE CRYPTS AND

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THESE CELLS WE THEN THOUGHT THEY

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MIGHT BE GOOD CANDIDATES TO BE

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STEM CELLS.

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THEY'RE AT THE BASE OF THE

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CRYPT, THEY'RE PROLIFERATIVE AND

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INDEED WHEN WE NOW PERFORM A SO

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CALLED LINEAGE TRACING

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EXPERIMENTS, HERE WE CROSS THIS

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MOUTH WITH A GOOD REPORTER

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AND--I WON'T GIVE YOU TOO MUCH

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DETAIL HERE BUT WE CAN NOW TERM

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1 OF THESE CANDIDATE STEM CELLS

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PERMANENTLY PLURIBU AND WHEN THE

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CELL DIVIDES THE DAUGHTER CELLS

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WILL BE BLUE AND YOU SEE HERE

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SUMMARIZING THE EXPERIMENTS OF

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MYC, THE FIRST FEW DAYS YOU SAW

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BLUE DAUGHTER SALES ARISING FROM

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THIS MARKED STEM CELL IN ADULT

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MOUSE, AFTER 2 OR 3 DAYS THEY

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XIPT THE CRYPTS, THEY

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DIFFERENTIATE OUT INTO 1 OR MORE

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OF THESE CELL TYPES, GOBLETS,

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ENTHUSIASMER O CITES AND DAY 3

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OR 4 OR 5 OF THE EXPERIMENT AS

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HOPED FOR, WE SAW THIS BLUE

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RIBBON SLOWLY CREEPS UP THE

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FRANKS AND THEN BY DAY 5 OR 6 OF

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THE EXPERIMENT, THE FIRST BLUE

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CELLS ARRIVE AT THE TIPS OF THE

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VILLI AND THEY UNDERGO

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APOPTOSIS.

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NOW IF YOU DON'T TERMINATE

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EXPERIMENT HERE BUT WE LEAVE THE

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MICE FOR ANOTHER 2 YEARS THAT

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BLUE RIBBON IS STILL THERE, SO

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THE CELL WE MARKED AT THE START

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OF EXPERIMENT IS LONG LIVED

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EVERY DAY IT KEEPS ON CRANKING

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OUT THESE BLUE DAUGHTER CELLS,

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2IERS LONG, 3 YEARS LONG, AND

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WHEN WE DO THE EXPERIMENT WELL

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AND WE ONLY MARK HERE AND THERE

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A SINGLE CELL AND PRODUCE THESE

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RIBBONS WE CAN HAVE READ OUT IN

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THE RIBBONS WHAT KIND OF CELL

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TYPES CAN BE PRODUCED BY THIS

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CELL AND WHAT WE FOUND, WHAT

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NICK FOUND WAS THAT ALL THE

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OTHER CELL TYPES, THAT YOU SEE

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IN THE EPITHELIUM, ARE PRESENT

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IN 1 OF THESE COLONIAL RIBBONS

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AND IMPLAYING FITTER THAT THE

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CELL MARKER IS LONG LIVED UNLIKE

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A LOT OF CELL TYPES OR THAT

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SECOND THAT ACTUALLY IS

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MULTIPOTENT STATANT BECAUSE IT

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MAKES ALL CELLS ON THIS TISSUE.

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NOW WE TRY TO PUBLISH THAT THESE

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CELLS ARE THE CELLS IN THE GUT

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AND IT'S A LOT OF RESISTANCE

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BECAUSE IT'S GENERALLY ASSUME

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THAD THESE CELLS DIVIDE VERY

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RARELY AND CHARACTERISTIC OR

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DEFINING CHARACTERISTIC OF AN

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ADULT STEM CELL WOULD BE THE

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FACT THAT IF YOU LABELED ITS DNA

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THAT CELL WOULD HAVE RETAINED

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THE DNA LABEL FOR LONG PERIODS

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OF TIME BECAUSE IT WOULD NOT

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DIVIDE FOR A LONG PERIOD, THAT

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WAS QUITE A REASONABLE

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HYPOTHESIS, BECAUSE, NO, WHEN

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YOU DIVIDE, YOU HAVE TO COPY DNA

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AND MAKE MISTAKES SO STEM CELLS

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MIGHT NOT WANT TO DO THAT,

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HOWEVER, THE GUT STEM CELL, YOU

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KNOW NOW KNOW THE STOMACH STEM

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CELL, GO THROUGH MANY, MANY CELL

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CYCLES IN A MOUSE WE THINK THESE

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CELLS GO ABOUT THROUGH ABOUT A

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THOUSAND CELL CYCLES IN A

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LIFETIME OF MOUSE, CONSECUTIVE

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MICE WITH 20,000, BUT MUST BE

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ENORMOUS BUT SOMEHOW THESE CELLS

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MANAGE.

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NOW BASED ON THIS, ANOTHER POST

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DOC IN THE LAB, YOU SEE HIM

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HERE, THEY SAT DOWN AND WE ASKED

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CAN WE POSSIBLY CREATE AN

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ENVIRONMENT IN A PLAOF THE IRK

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DISH, IN A PET RI DISH THAT

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MIMICS THE ENVIRONMENT AND THE

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INTENTION WAS NOT WHAT YOU SEE

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HERE, THE INTENTION WAS TO SAKE

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A SINGLE STEM CELL, TOP LEFT AND

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THE GROWTH FACTORS WE KNOW THAT

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WIND WAS KEY, WE KNEW ALSO THAT

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OUR RESPONDENT IS AN AMPLIFIER

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THE SIGNALS WE DIDN'T KNOW IT

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WAS THE LIGAND OF OUR LGFR

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RECEPTOR BUT ACTUALLY THAT WE

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FOWBD OUT MUCH LATER AND

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EXPLAINS WHAT WE WERE SEEING, SO

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WE HAD OUR [INDISCERNIBLE] IN

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OUR COCKTAIL AND ACTIVATOR OF

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THE KINASE RECEPTOR AND THEN

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FROM AN OLD TRANSGENIC MOUSE

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EXPERIMENT, WE KNEW WE HAD TO

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BLOCK BMP SIGNALS, IF YOU

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EXPRESSION NOGGIN IN THE GUT OF

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A MOUSE, YOU WILL SEE MANY, MANY

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MORE CRYPTS SO IT WILL BE

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INHIBITION SOMEHOW CREATES A

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CRYPT FROM THIS ENVIRONMENT.

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NOW THE COMBINATION OF THESE

255
00:09:38,680 --> 00:09:41,800
GROWTH FACTORS, NO SERUM, BUT WE

256
00:09:41,800 --> 00:09:44,160
DO THIS IN MATE RIGEL AS

257
00:09:44,160 --> 00:09:46,280
PIONEERED BY [INDISCERNIBLE]

258
00:09:46,280 --> 00:09:50,680
OVER THE PAST 30 OR 40 YEARS,

259
00:09:50,680 --> 00:09:56,560
WAS A MIX OF LLAMA NIN,

260
00:09:56,560 --> 00:09:57,960
MATRIGEL, AND IT WAS TO CREATE

261
00:09:57,960 --> 00:09:59,440
MANY STEM CELLS FROM A SINGLE

262
00:09:59,440 --> 00:10:01,320
STEM CELL LIKE PEOPLE ARE

263
00:10:01,320 --> 00:10:03,640
GROWING ES AND IPS CELLSA THE

264
00:10:03,640 --> 00:10:05,200
TIME BUT WE GOT SOMETHING VERY

265
00:10:05,200 --> 00:10:05,720
DIFFERENT.

266
00:10:05,720 --> 00:10:11,480
WE GOT EPITHELIAL STRUCTURES AND

267
00:10:11,480 --> 00:10:12,680
KD--SALLY TOSHIRO, STARTED

268
00:10:12,680 --> 00:10:14,120
LOOKING QUICKLY AND THERE WOULD

269
00:10:14,120 --> 00:10:16,040
BE MULTIPLE STEM CELLS AT THE

270
00:10:16,040 --> 00:10:18,880
BASE, AND OTHER CELLS THAT ARE

271
00:10:18,880 --> 00:10:20,800
THERE, THE OTHER CELLS IN THIS

272
00:10:20,800 --> 00:10:23,680
WILL BE RAPIDLY DEFINING, AND A

273
00:10:23,680 --> 00:10:25,320
CENTRAL LUMEN WAS LINED BY ALL

274
00:10:25,320 --> 00:10:27,960
THE OTHER 9 OR 10 CELL TYPES

275
00:10:27,960 --> 00:10:30,360
THAT WE REMOVE FROM THE PRIMARY

276
00:10:30,360 --> 00:10:32,200
EPITHELIUM AND A NUMBER OF YEARS

277
00:10:32,200 --> 00:10:33,560
LATER BY SEQUENCING WE

278
00:10:33,560 --> 00:10:36,000
DISCOVERED 2 NOVEL CELL TYPES

279
00:10:36,000 --> 00:10:39,880
THAT WE HAVE NOT SEEN EARLIER IN

280
00:10:39,880 --> 00:10:40,560
ORGANOIDS, WE THEN WENT BACK TO

281
00:10:40,560 --> 00:10:43,160
A REAL GUT AND WE FOUND THAT

282
00:10:43,160 --> 00:10:43,600
THEY REALLY EXISTED.

283
00:10:43,600 --> 00:10:45,960
SO IT'S REALLY REMARKABLE THAT A

284
00:10:45,960 --> 00:10:48,480
SINGLE STEM CELL, 3 GROWTH

285
00:10:48,480 --> 00:10:51,120
FACTORS, MATE RIGEL AND OTHERS

286
00:10:51,120 --> 00:10:53,360
APPARENTLY REMEMBERS HOW TO

287
00:10:53,360 --> 00:10:55,600
BUILD A COMPLETE VERSION OF THE

288
00:10:55,600 --> 00:10:58,920
TISSUE THAT EMERGES FROM.

289
00:10:58,920 --> 00:11:00,680
AND TOSHIRO CALLED THESE MANY

290
00:11:00,680 --> 00:11:02,440
STRUCTURES AND TODAY THEY WOULD

291
00:11:02,440 --> 00:11:04,320
BE CALLED DECIMAL ORGANOIDS.

292
00:11:04,320 --> 00:11:05,760
SO THEY GROW FOR VERY LONG

293
00:11:05,760 --> 00:11:07,640
PERIODS OF TIME AND 10 YEARS AND

294
00:11:07,640 --> 00:11:10,600
MOUSE LIVES ONLY 3 YEARS AS YOU

295
00:11:10,600 --> 00:11:12,200
PROBABLY KNOW, TELOMERES STAY

296
00:11:12,200 --> 00:11:14,800
LONG, WE'VE NEVER SEEN

297
00:11:14,800 --> 00:11:17,080
SENESCENSEL BY SEQUENCING, WE'VE

298
00:11:17,080 --> 00:11:19,240
NEVER SEEN ONCOGENIC MUTATIONS

299
00:11:19,240 --> 00:11:20,120
AND PHENOTYPICALLY THEY STAY

300
00:11:20,120 --> 00:11:21,400
STABLE OVER TIME AND THE

301
00:11:21,400 --> 00:11:22,880
ULTIMATE EXPERIENCE TO SEE IF

302
00:11:22,880 --> 00:11:24,240
THEY REALLY STAYED NORMAL WOULD

303
00:11:24,240 --> 00:11:25,600
BE A TRANSPLANTATION, AND THIS

304
00:11:25,600 --> 00:11:28,720
WAS DONE BY TOSHI IN MY LAB AND

305
00:11:28,720 --> 00:11:32,960
[INDISCERNIBLE] AND THE PEOPLE

306
00:11:32,960 --> 00:11:34,760
TOKYO, SO TOSHI, TOOK A SINGLE

307
00:11:34,760 --> 00:11:35,880
STEM CELL FROM THE MICE WHERE IT

308
00:11:35,880 --> 00:11:39,080
WAS GREEN BUT THE ENTIRE MOUSE

309
00:11:39,080 --> 00:11:41,840
WAS RFP POSITIVE SO IT WAS RAT

310
00:11:41,840 --> 00:11:42,880
FLUORESCENCE, AND IT ALLOWED US

311
00:11:42,880 --> 00:11:43,840
TO KEEP TRACK OF THE TISSUE

312
00:11:43,840 --> 00:11:47,440
WE'RE GROWING SO FROM A DUTCH

313
00:11:47,440 --> 00:11:49,440
MOUSE ISOLATED TO SINGLE CELL,

314
00:11:49,440 --> 00:11:51,280
UP TO ABOUT A HUNDRED MILLION

315
00:11:51,280 --> 00:11:54,280
CELLS IN THE FORM OF THIS MANY

316
00:11:54,280 --> 00:11:57,720
AND THERE AND THE PEOPLE HAD TO

317
00:11:57,720 --> 00:11:59,160
TREATED SEVERAL DOZEN MICE WITH

318
00:11:59,160 --> 00:12:01,720
DSS, WHICH IS A CHEMICAL THAT

319
00:12:01,720 --> 00:12:02,920
INDUCES INFLAMMATORY BOWEL LIKE

320
00:12:02,920 --> 00:12:04,520
SYNDROME IN THESE MICE.

321
00:12:04,520 --> 00:12:06,680
THEY INFUSE THESE RED

322
00:12:06,680 --> 00:12:09,800
FLUORESCENT DUTCH ORGANOIDS

323
00:12:09,800 --> 00:12:11,600
THROUGH THE ANUSES OF THESE

324
00:12:11,600 --> 00:12:13,480
SEVERAL DOSEN MICE AND OVER THE

325
00:12:13,480 --> 00:12:16,280
NEXT HOUR THIS MOVIE SUMMARIZES

326
00:12:16,280 --> 00:12:18,160
THE FLOAT AROUND, ALWAYS THE

327
00:12:18,160 --> 00:12:19,440
BASAL SIDE, SO THE INTERNATIONAL

328
00:12:19,440 --> 00:12:20,840
CLASSIFICATION GRENS ARE ON THE

329
00:12:20,840 --> 00:12:23,720
OUTSIDE AND THE MOMENT THEY SEE

330
00:12:23,720 --> 00:12:25,360
THESE OPEN LESIONS, OF

331
00:12:25,360 --> 00:12:26,680
COLLAGENS, FIBER NECT

332
00:12:26,680 --> 00:12:28,000
EPIGENETICS THEY WILL ATTACH AND

333
00:12:28,000 --> 00:12:30,320
OPEN UP, LIKE A LIVING BAND 8,

334
00:12:30,320 --> 00:12:31,680
ORGANOIDS AND I EXPRESSED THEY

335
00:12:31,680 --> 00:12:34,240
GROW FROM A SINGLE STEM CELL, A

336
00:12:34,240 --> 00:12:35,640
FEW MONTHS EARLIER, THESE WILL

337
00:12:35,640 --> 00:12:38,000
SEAL THESE LESIONS AND THIS IS

338
00:12:38,000 --> 00:12:39,160
THE REAL EXPERIMENT, WITH THESE

339
00:12:39,160 --> 00:12:41,120
MICE, WHAT IS BLACK IS THE

340
00:12:41,120 --> 00:12:43,480
JAPANESE TISSUE, HERE YOU SEE

341
00:12:43,480 --> 00:12:47,520
THE DUTCH TRANSPLANTED TISSUE, I

342
00:12:47,520 --> 00:12:49,760
STRESS AGAIN GROWN FROM A SINGLE

343
00:12:49,760 --> 00:12:51,200
TRAN PLANT CELL USED TO GROW

344
00:12:51,200 --> 00:12:53,640
MAYBE 40 MICE AND YOU SEE THE

345
00:12:53,640 --> 00:12:54,920
LARGE PATCHES OF RED FLUORESCENT

346
00:12:54,920 --> 00:12:56,880
TISSUE SO THE OFFSPRING OF A

347
00:12:56,880 --> 00:12:58,840
STEM CELL THAT WAS ISOLATED AND

348
00:12:58,840 --> 00:12:59,480
GROWN, FULLY INTEGRATED IN THE

349
00:12:59,480 --> 00:13:01,320
TISSUE AND THE ONLY WAY YOU CAN

350
00:13:01,320 --> 00:13:04,200
FIND IT IS WITH A CONFOCAL

351
00:13:04,200 --> 00:13:05,400
MICROSCOPE AND ANY MARKER

352
00:13:05,400 --> 00:13:07,760
ANALYSIS WE DO IS NORMAL TISSUE.

353
00:13:07,760 --> 00:13:09,560
NOW 1 PREDICTION WOULD BE THAT

354
00:13:09,560 --> 00:13:11,000
THE STEM CELL SHOULD BE AN

355
00:13:11,000 --> 00:13:13,040
EXHAUSTED BY NOW BECAUSE IT'S

356
00:13:13,040 --> 00:13:15,040
EXPANDED SO DRAMATICALLY

357
00:13:15,040 --> 00:13:17,080
OVERTIME IN THE LAB.

358
00:13:17,080 --> 00:13:18,640
SO WE LOSE THESE PATCHES, THAT

359
00:13:18,640 --> 00:13:20,280
IS NOT WHAT'S HAPPENING, OTHER

360
00:13:20,280 --> 00:13:21,640
PREDICTION WOULD BE FROM PEOPLE

361
00:13:21,640 --> 00:13:23,400
WHO BELIEVE THE STEM CELL SHOULD

362
00:13:23,400 --> 00:13:25,080
REALLY BE QUIESCENT IS THAT

363
00:13:25,080 --> 00:13:27,200
THESE CELLS PROBABLY NOT ARE

364
00:13:27,200 --> 00:13:30,360
SOMEHOW TRANSFORMED SO IT MIGHT

365
00:13:30,360 --> 00:13:32,280
SEE NEOPLASMS, ALSO WE NEVER SAW

366
00:13:32,280 --> 00:13:33,640
THESE THINGS HAPPENING.

367
00:13:33,640 --> 00:13:35,680
AND BASED ON THIS, IT HAS GONE

368
00:13:35,680 --> 00:13:38,960
ON TO DO THIS WITH HUMAN

369
00:13:38,960 --> 00:13:40,360
ORGANOIDS TO IMMUNO DEFICIENT

370
00:13:40,360 --> 00:13:42,080
MICE, THEY ALSO INTEGRATE NICELY

371
00:13:42,080 --> 00:13:45,920
AND CURRENTLY PERFORMING A FIRST

372
00:13:45,920 --> 00:13:47,680
IN MAN TRIAL TREAT INFLAMMATORY

373
00:13:47,680 --> 00:13:50,080
BOWEL DISEASE WITH PATES FOR

374
00:13:50,080 --> 00:13:51,560
THERAPY RESISTANT FORM OF IBS

375
00:13:51,560 --> 00:13:53,960
AND IT TREATS THEM WITH

376
00:13:53,960 --> 00:13:55,120
ORGANOIDS GROWN FROM HEALTHY

377
00:13:55,120 --> 00:13:57,680
PARTS OF THEIR OWN COLON SO THIS

378
00:13:57,680 --> 00:13:59,160
WOULD BE AN AHATOLOGIOUS

379
00:13:59,160 --> 00:14:02,480
TRANSPLANT AND OF COURSE, WE ARE

380
00:14:02,480 --> 00:14:04,360
CURIOUS TO SEE IF THIS WILL WORK

381
00:14:04,360 --> 00:14:04,760
OUT.

382
00:14:04,760 --> 00:14:08,480
THIS IS PROBABLY ALL

383
00:14:08,480 --> 00:14:10,040
EXPERIMENTAL IS ABOUT 10 YEARS

384
00:14:10,040 --> 00:14:11,200
OLD, BUT WE FIRST THOUGHT THAT

385
00:14:11,200 --> 00:14:12,480
WAS UNIQUE TO THE GUT STEM

386
00:14:12,480 --> 00:14:13,200
CELLS, BECAUSE THEY'RE

387
00:14:13,200 --> 00:14:14,320
INCREDIBLE LOAMACYY ACTIVE AND

388
00:14:14,320 --> 00:14:16,400
THEN THIS SHOWED THIS COULD BE

389
00:14:16,400 --> 00:14:19,080
DONE FOR PANCREAS AND IT'S NOT

390
00:14:19,080 --> 00:14:20,160
ONLY PROLIFERATIVE TISSUE, UNDER

391
00:14:20,160 --> 00:14:22,200
NORMAL CONDITIONS BUT YOU SEE

392
00:14:22,200 --> 00:14:23,840
THERE NOW A LONG LIST OF

393
00:14:23,840 --> 00:14:24,720
PROTOCOLS AVAILABLE IN HUMAN AND

394
00:14:24,720 --> 00:14:26,480
MOUSE, WHERE YOU CAN START WITH

395
00:14:26,480 --> 00:14:28,480
A TINY BIT OF TISSUE FROM A

396
00:14:28,480 --> 00:14:29,200
BIOPSY FOR INSTANCE, CAN YOU

397
00:14:29,200 --> 00:14:30,200
SEND THEM AROUND THE WORLD AS

398
00:14:30,200 --> 00:14:35,080
LONG AS YOU KEEP IT ON ICE, ON

399
00:14:35,080 --> 00:14:36,560
0-DEGREES IN A COMPLETE MEDIUM,

400
00:14:36,560 --> 00:14:38,040
CAN YOU SEND THEM AROUND FOR 2

401
00:14:38,040 --> 00:14:41,160
OR 3 DAYS BEFORE YOU PUT THEM IN

402
00:14:41,160 --> 00:14:41,400
CULTURE.

403
00:14:41,400 --> 00:14:43,720
THEY WILL NEED AN ACTIVATOR ON

404
00:14:43,720 --> 00:14:46,680
THE WIN PATHWAY, OVER THE KINASE

405
00:14:46,680 --> 00:14:49,720
RECEPTOR AND THEY TYPICALLY NEED

406
00:14:49,720 --> 00:14:51,920
INHIBITORS OF TGF BETA AND

407
00:14:51,920 --> 00:14:53,120
B-SIGNALING IN ADDITION TO THE

408
00:14:53,120 --> 00:14:54,640
MEMORY LIKE ESTROUGH ATOM GENS,

409
00:14:54,640 --> 00:14:56,640
PROSTATE, HERE IT IS LIKE

410
00:14:56,640 --> 00:14:58,640
TESTOSTERONE, SO THERE ARE

411
00:14:58,640 --> 00:14:59,800
ADDITIONAL COMPONENTS.

412
00:14:59,800 --> 00:15:01,360
MANY OF THESE CULTURE CONDITIONS

413
00:15:01,360 --> 00:15:02,800
HAVE BEEN PUBLISHED, AND THEN WE

414
00:15:02,800 --> 00:15:04,920
CAN DO BASICALLY GET YOUR

415
00:15:04,920 --> 00:15:06,680
TISSUE, GRIND IT UP IN SMALL

416
00:15:06,680 --> 00:15:11,920
PIECES, STICK IT IN, PUT IN THIS

417
00:15:11,920 --> 00:15:16,280
MATE RIJELL AND AND YOU SEE THAT

418
00:15:16,280 --> 00:15:17,680
VERY RAPIDLY CLOSE ENOUGH AND

419
00:15:17,680 --> 00:15:21,520
THE STRUCTURE AND THEN THEY GOT

420
00:15:21,520 --> 00:15:23,520
IT GROWING IN HERE AS WELL AND

421
00:15:23,520 --> 00:15:24,720
DEPENDING ON THE CONDITION, YOU

422
00:15:24,720 --> 00:15:32,200
WILL SEE STEM CELLS THAT ALL THE

423
00:15:32,200 --> 00:15:32,880
DIFFERENTIATION, AND ALL SORTS

424
00:15:32,880 --> 00:15:35,560
OF BASIC SCIENCE QUESTIONS OR

425
00:15:35,560 --> 00:15:43,240
USING KNOCK OUT MICE OR MAYBE AT

426
00:15:43,240 --> 00:15:45,520
LEAST CELL LINES, AND ALSO CAN

427
00:15:45,520 --> 00:15:47,760
BE GROWN DIRECTLY FROM IN HERE

428
00:15:47,760 --> 00:15:51,680
AND CANCERS WE'VE DONE A LOT ON

429
00:15:51,680 --> 00:15:53,080
CYSTIC FIBROSIS AS WELL, SO YOU

430
00:15:53,080 --> 00:15:59,200
CAN REALLY MEASURE AS WELL, THE

431
00:15:59,200 --> 00:16:01,240
DRUG RESPONSE, AND AND RESPONSE

432
00:16:01,240 --> 00:16:02,640
TO THE DRUG, ALSO THE

433
00:16:02,640 --> 00:16:17,320
INTERACTION OF THE DRUGS, ALSO,

434
00:16:17,320 --> 00:16:18,480
GIVE SOME EXAMPLES FOR

435
00:16:18,480 --> 00:16:24,880
INFECTIOUS DISEASES QUITE WELL,

436
00:16:24,880 --> 00:16:26,040
THEY ARE THE HEPATOCYTES FROM

437
00:16:26,040 --> 00:16:27,880
THE HUMAN LIVER AND AS YOU

438
00:16:27,880 --> 00:16:29,080
PROBABLY REALIZE, THESE ARE VERY

439
00:16:29,080 --> 00:16:31,240
IMPORTANT CELLS IN DRUG

440
00:16:31,240 --> 00:16:32,160
DEVELOPMENT PROCESS, BUT ALSO IN

441
00:16:32,160 --> 00:16:33,720
THE STANDS TO CONTROL METABOLISM

442
00:16:33,720 --> 00:16:36,840
AND THE SIPGHT SIS OF MANY SERUM

443
00:16:36,840 --> 00:16:38,080
PROTEINS, ET CETERA, ET CETERA,

444
00:16:38,080 --> 00:16:40,200
THEY WILL DELIVER ESSENTIALLY

445
00:16:40,200 --> 00:16:42,640
ONLY HAS 2 REAL LIVER CELL

446
00:16:42,640 --> 00:16:44,720
SITES, THAT BUILD THE BILE DUCTS

447
00:16:44,720 --> 00:16:47,120
AND ALL THE OTHER CELLS THAT SEE

448
00:16:47,120 --> 00:16:49,760
THE COOPER CELLS,

449
00:16:49,760 --> 00:16:50,920
[INDISCERNIBLE] CELLS ARE

450
00:16:50,920 --> 00:16:52,320
MIGRATING INTO THE LIVE WHEN

451
00:16:52,320 --> 00:16:58,000
IT'S FORMING BUT THE IT'S THE

452
00:16:58,000 --> 00:16:59,280
[INDISCERNIBLE] THAT BUILD THE

453
00:16:59,280 --> 00:17:01,280
LIVER, THE LIVER IS PROBABLY THE

454
00:17:01,280 --> 00:17:02,280
MOST REGENRATIVE ORGAN OF THE

455
00:17:02,280 --> 00:17:03,920
HUMAN BODY AND THERE'S 2 WAYS BY

456
00:17:03,920 --> 00:17:06,280
WHICH IT CAN REPAIR THE CELLS

457
00:17:06,280 --> 00:17:08,320
BUT ALL HEPATOCYTES ARE SICK FOR

458
00:17:08,320 --> 00:17:09,680
AN INFECTION OR INTOXICATION,

459
00:17:09,680 --> 00:17:12,200
THE BILE DUCT CELLS CAN BE

460
00:17:12,200 --> 00:17:15,800
DIFFERENTIATED TO OVAL CELLS,

461
00:17:15,800 --> 00:17:19,800
PROLIFERATE AND THEN RECREATE

462
00:17:19,800 --> 00:17:22,520
BILED CELLS AS WELL AS

463
00:17:22,520 --> 00:17:26,360
HEPATOCYTES AND THEN METASTASIS

464
00:17:26,360 --> 00:17:27,320
FROM COLAN CANCER, IF YOU LIVE

465
00:17:27,320 --> 00:17:29,080
THE LIVER IN PLACE ISSUES THE

466
00:17:29,080 --> 00:17:29,920
LIVER WILL RAPIDLY GROW BACK AND

467
00:17:29,920 --> 00:17:33,760
THEN THIS IS DONE BY HEPATOCYTES

468
00:17:33,760 --> 00:17:34,920
BECAUSE REMAINING HEPATOCYTES

469
00:17:34,920 --> 00:17:35,800
ARE HEALTHY, CAN YOU DIVIDE

470
00:17:35,800 --> 00:17:37,240
THOSE SO YOU WOULD NEVER CALL

471
00:17:37,240 --> 00:17:39,760
THE REAL STEM CELLS, YOU HAVE TO

472
00:17:39,760 --> 00:17:43,080
CREATE A LOST TISSUE AND THEN IN

473
00:17:43,080 --> 00:17:44,960
THE RESTORING LIVER, YOU WILL

474
00:17:44,960 --> 00:17:46,520
SEE HEPATOCYTES, YOU WILL SEE

475
00:17:46,520 --> 00:17:47,960
THE BILE DUCT FORMED AS WELL

476
00:17:47,960 --> 00:17:51,960
FROM THIS, AND YOU WILL SEE THE

477
00:17:51,960 --> 00:17:52,440
OUTER CELLS MIGRATING.

478
00:17:52,440 --> 00:18:01,440
SO HERE YOU CAN SEE THAT THE

479
00:18:01,440 --> 00:18:05,440
COLINGIOO CITES THEY'RE FULLY

480
00:18:05,440 --> 00:18:06,120
DIFIENTIATED GLANDIO CITES AND

481
00:18:06,120 --> 00:18:08,160
PUT IN THE RIGHT COCKTAIL GROWTH

482
00:18:08,160 --> 00:18:09,400
FACTOR, MAYBE FROM MOUSE A BIT

483
00:18:09,400 --> 00:18:10,720
EARLIER ABOUT YOU THIS IS HUMAN

484
00:18:10,720 --> 00:18:18,360
HERE WHAT YOU SEE, ALMOST EVERY

485
00:18:18,360 --> 00:18:21,680
COLANGIO CITE ORGANOID, THESE

486
00:18:21,680 --> 00:18:23,960
WILL HAVE EARLY COLANGIOCITE

487
00:18:23,960 --> 00:18:25,880
MARKERS IN VITROW, WE CAN

488
00:18:25,880 --> 00:18:27,480
DIFFERENTIATE TOWARDS IT BUT IT

489
00:18:27,480 --> 00:18:29,920
NEVER GET VERY ADULT LIKE, THEY

490
00:18:29,920 --> 00:18:31,560
REALLY ARE IMMATURE, AND YOU

491
00:18:31,560 --> 00:18:34,040
HAVE TO TRAN PLANT TO SEE THEY

492
00:18:34,040 --> 00:18:35,680
CAN MAKE HEPATOCYTES AND HERE

493
00:18:35,680 --> 00:18:36,720
ARE LARGE CELLS, BEAUTIFUL

494
00:18:36,720 --> 00:18:38,840
CELLS, YOU CAN BUY THEM, THERE

495
00:18:38,840 --> 00:18:41,400
ARE OFTEN USED IN THE DRUG

496
00:18:41,400 --> 00:18:43,720
DEVELOPMENT INDUSTRY, BUT IT'S

497
00:18:43,720 --> 00:18:46,480
BEEN ALMOST IMPOSSIBLE TO KEEP

498
00:18:46,480 --> 00:18:48,120
THESE HEPATITIS EAT O CITES IN

499
00:18:48,120 --> 00:18:49,160
THEIR HEALTHY STAGE FOR MORE

500
00:18:49,160 --> 00:18:50,720
THAN A FEW DAYS OR A WEEK.

501
00:18:50,720 --> 00:18:52,080
THERE'S REALLY A CELL TYPE TO

502
00:18:52,080 --> 00:18:56,520
CANCER CELL LINES THAT MANY LABS

503
00:18:56,520 --> 00:19:01,160
USE ARE CARCINOMAS, OF LIVER

504
00:19:01,160 --> 00:19:02,760
CANCER, AND THEY--THEY EXPRESS

505
00:19:02,760 --> 00:19:04,720
THE LIVER [INDISCERNIBLE] WILL

506
00:19:04,720 --> 00:19:06,200
TYPICALLY BE A HUNDRED OR

507
00:19:06,200 --> 00:19:07,360
THOUSAND FOLD LOWER THAN A REAL

508
00:19:07,360 --> 00:19:09,320
HEPATITIS EAT O CITE, THE GROWTH

509
00:19:09,320 --> 00:19:10,440
WOULD BE THE SAME.

510
00:19:10,440 --> 00:19:12,960
SO WE WORKED VERY HARD FOR

511
00:19:12,960 --> 00:19:15,520
MULTILE YEARS UP UNTIL THE

512
00:19:15,520 --> 00:19:16,560
CHINESE POSTDOC OUR OWN LAB BACK

513
00:19:16,560 --> 00:19:21,600
IN CHINA CAME UP WITH A

514
00:19:21,600 --> 00:19:22,680
COMPLICATED COCKTAIL WITH ABOUT

515
00:19:22,680 --> 00:19:24,240
10 GROWTH MOLECULES AND, ALLOWED

516
00:19:24,240 --> 00:19:26,880
US TO TAKE A SINGLE HEPATITIS

517
00:19:26,880 --> 00:19:29,640
EAT O CITE AND CONVINCE THESE TO

518
00:19:29,640 --> 00:19:30,080
START DIVIDING.

519
00:19:30,080 --> 00:19:31,520
SO THEY'RE SLOWER THAN THE GUT

520
00:19:31,520 --> 00:19:33,440
ORGANOIDS BUT YOU CAN SEE THE

521
00:19:33,440 --> 00:19:33,720
GROWTH WELL.

522
00:19:33,720 --> 00:19:36,520
THIS IS MOUSE MARKED IN ALBUT

523
00:19:36,520 --> 00:19:38,160
MEN EXPRESSION, WE THEN COULD

524
00:19:38,160 --> 00:19:41,120
ALSO DO SOMETHING SIMILAR FOR

525
00:19:41,120 --> 00:19:42,880
HUMAN LIVER WHERE THE YOUNGER

526
00:19:42,880 --> 00:19:45,160
THE DONOR OF THIS WORKS AND THE

527
00:19:45,160 --> 00:19:48,040
USE NOW ROUTINELY FETAL HUMAN

528
00:19:48,040 --> 00:19:49,160
LIVER PROBABLY A LOT HARDER TO

529
00:19:49,160 --> 00:19:52,360
WORK WITH IN THE U.S. BUT THEY

530
00:19:52,360 --> 00:19:53,920
LOOK AT WHAT WE GROW, LOOKS

531
00:19:53,920 --> 00:19:56,480
SIMILAR TO,A DULT LIVERS, THE

532
00:19:56,480 --> 00:19:58,160
ONLY THING THEY ACTUALLY SEEM TO

533
00:19:58,160 --> 00:20:00,520
BE GROW FOREVER AS ADULT LIVER

534
00:20:00,520 --> 00:20:03,480
STOP AFTER 4, 6, 7, 8 MONTHS AND

535
00:20:03,480 --> 00:20:05,720
WE APPRECIATE THESE LARGE CELLS,

536
00:20:05,720 --> 00:20:08,200
IN THERE BUT LARGE NUCLEI, AND

537
00:20:08,200 --> 00:20:10,560
BIG LIST, THE HNF 4 ALPHA

538
00:20:10,560 --> 00:20:12,080
TRANSCRIPTION FACTOR MARKING

539
00:20:12,080 --> 00:20:13,680
WITH THE HEPATOCYTES CLEARLY

540
00:20:13,680 --> 00:20:16,280
EXPRESSED, YOU EVEN SEE A

541
00:20:16,280 --> 00:20:17,480
DIVIDING HEPATOCYTE HERE BUT THE

542
00:20:17,480 --> 00:20:19,360
PROTEIN WE STAYED FOR, COULD BE

543
00:20:19,360 --> 00:20:21,000
ALBUMIN BUT THIS IS THE

544
00:20:21,000 --> 00:20:22,320
TRANSCRIPTION ABUNKED AN

545
00:20:22,320 --> 00:20:24,120
EXPRESSION, YOU DO SINGLE CELL

546
00:20:24,120 --> 00:20:27,120
SEQUENCING, THESE CELLS ARE

547
00:20:27,120 --> 00:20:28,120
INDISTINGUISHABLE FROM REAL

548
00:20:28,120 --> 00:20:28,600
HEPATOCYTES FROM THE 1

549
00:20:28,600 --> 00:20:30,640
DIFFERENCE YOU SEE A LOT OF CELL

550
00:20:30,640 --> 00:20:31,520
CYCLE MARKERS EXPRESSED IN MANY

551
00:20:31,520 --> 00:20:37,960
OF THE CELLS BECAUSE THEY'RE

552
00:20:37,960 --> 00:20:38,280
PROLIFERATIVE.

553
00:20:38,280 --> 00:20:39,800
EVEN BETTER THEY CREATE A SUPER

554
00:20:39,800 --> 00:20:40,680
CELLULAR STRUCTURES AND MAYBE

555
00:20:40,680 --> 00:20:42,720
THE NEXT SLIDE IS BETTER, YEAH,

556
00:20:42,720 --> 00:20:45,320
HERE YOU SEE AGAIN, THESE LARGE

557
00:20:45,320 --> 00:20:46,520
HEPATOCYTES, THESE THIS IS NOW

558
00:20:46,520 --> 00:20:51,280
STAINED FOR A BILE DUCT, BIOACID

559
00:20:51,280 --> 00:20:53,320
TRANSPORTER AND NRP2 AND THIS IS

560
00:20:53,320 --> 00:20:55,000
EXPRESSED IN BILE

561
00:20:55,000 --> 00:20:56,160
[INDISCERNIBLE] SMALL CHANNELS

562
00:20:56,160 --> 00:20:58,560
THAT ARE FORMED BAYOUS FUSING

563
00:20:58,560 --> 00:21:00,480
THE APICKAL DOMAINS OF THE 2

564
00:21:00,480 --> 00:21:01,480
NEIGHBORS HEPATITIS EAT O CITES

565
00:21:01,480 --> 00:21:03,040
TOGETHER AND THIS CREATING A

566
00:21:03,040 --> 00:21:07,080
LITTLE CHAN AND HE WILL THE

567
00:21:07,080 --> 00:21:07,560
HEPATOCYTES WILL SECRETE

568
00:21:07,560 --> 00:21:10,080
BIOASSAYS THEY MAKE IN THESE

569
00:21:10,080 --> 00:21:10,800
CULTURES, VERY ABUNDANTLY AND

570
00:21:10,800 --> 00:21:13,200
THEY FEED INTO A CENTRAL SPACE,

571
00:21:13,200 --> 00:21:15,720
WHICH NORMALLY WE THINK WOULD BE

572
00:21:15,720 --> 00:21:17,640
DISPLACED BY ANOTHER BILE DUCT

573
00:21:17,640 --> 00:21:20,240
TO CONNECT UP CREATED BY THE

574
00:21:20,240 --> 00:21:21,480
OTHER CELL HEPATITIS EAT O CITES

575
00:21:21,480 --> 00:21:23,920
TO TAKE IT OUT OF THE LIVER AND

576
00:21:23,920 --> 00:21:25,680
YOU SEE THESE PATIENTS SWELL UP

577
00:21:25,680 --> 00:21:28,720
AND BURST AND THAT'S HOW THEY

578
00:21:28,720 --> 00:21:30,200
RELEASE THEIR BIOASSAY, AND YOU

579
00:21:30,200 --> 00:21:32,240
MIGHT ALSO SEE EVERY HEPATITIS

580
00:21:32,240 --> 00:21:34,520
EAT O CITE HAS MANAGED TO CREATE

581
00:21:34,520 --> 00:21:35,480
A [INDISCERNIBLE] WITH ITS

582
00:21:35,480 --> 00:21:35,760
NEIGHBOR.

583
00:21:35,760 --> 00:21:39,960
WE HAVE NICE MOVIES WHERE WE SEE

584
00:21:39,960 --> 00:21:41,680
HOW THIS PROCESS PROGRESS.

585
00:21:41,680 --> 00:21:43,240
YOU CAN TRANSPLANT THESE AGAIN,

586
00:21:43,240 --> 00:21:44,760
LIKE WHAT I SHOWED EARLIER FOR

587
00:21:44,760 --> 00:21:46,040
THE GUT HERE AND THIS WAS

588
00:21:46,040 --> 00:21:47,480
NOTHING BUT YOU COULD GO ON

589
00:21:47,480 --> 00:21:50,680
NEW YORK AND MY LAB, AND THE

590
00:21:50,680 --> 00:21:53,000
ORGANOIDS, THIS IS HUMAN

591
00:21:53,000 --> 00:21:55,400
ALBUMIN, STAINING A LARGE

592
00:21:55,400 --> 00:21:59,800
TRANSPLANTED HUMAN HEPATITIS EAT

593
00:21:59,800 --> 00:22:01,440
O CITE, ORGANOIDS AND YOU SEE

594
00:22:01,440 --> 00:22:04,360
THESE STAINING, THIS IS ABOUT 23

595
00:22:04,360 --> 00:22:05,000
MONTHS AFTER TRANSPLANTATION,

596
00:22:05,000 --> 00:22:06,600
CAN YOU SEE THE HUMANOID IS

597
00:22:06,600 --> 00:22:08,560
STILL GROWING AND THIS IS DONE

598
00:22:08,560 --> 00:22:11,960
IN THE BACKGROUND FOR THE MUSEUM

599
00:22:11,960 --> 00:22:16,280
STANT MICE WHICH NORMAL CHAO,

600
00:22:16,280 --> 00:22:16,880
SLOWLY LOSE ITS OWN HEPATITIS

601
00:22:16,880 --> 00:22:18,640
EAT O CITE AND ACREATES SPACE

602
00:22:18,640 --> 00:22:20,200
AND ALLOWS THESE TO GROW AND

603
00:22:20,200 --> 00:22:22,480
SLOWLY FILL UP THE ENTIRE MOUSE

604
00:22:22,480 --> 00:22:24,400
LIVER, AGAIN, SHOWING THAT WHAT

605
00:22:24,400 --> 00:22:25,920
WE ARE GROWING HERE FROM THE

606
00:22:25,920 --> 00:22:29,120
VERY FEW WITH MAYBE PROBABLY

607
00:22:29,120 --> 00:22:31,480
ONLY 1 CELL, REMAINS ENTIRELY

608
00:22:31,480 --> 00:22:33,720
NORMAL DESPITE THE PACT THAT WE

609
00:22:33,720 --> 00:22:35,880
CAN EXPAND VERY DRAMENTIC

610
00:22:35,880 --> 00:22:36,280
LOAMACYY OVERTIME.

611
00:22:36,280 --> 00:22:37,320
CURRENTLY THIS IS UNPUBLISHED

612
00:22:37,320 --> 00:22:39,160
BUT WE ARE TRYING TO NOW SEE IF

613
00:22:39,160 --> 00:22:43,240
WE CAN USE THESE ORGANOIDS FOR

614
00:22:43,240 --> 00:22:45,560
VARIOUS DISEASE MODELING HERE.

615
00:22:45,560 --> 00:22:47,880
WE MIMIC CHRONIC HBV, HEPATITIS

616
00:22:47,880 --> 00:22:50,080
B INFECTION WHICH IS HUGE

617
00:22:50,080 --> 00:22:53,200
CHALLENGE IN AFRICA AND ASIA AND

618
00:22:53,200 --> 00:22:53,640
CHINA.

619
00:22:53,640 --> 00:22:58,440
AND BECAUSE  HEPATOCYTES CAN NOT

620
00:22:58,440 --> 00:23:00,640
BE MAINTAINED IN CULTURE, DAYS,

621
00:23:00,640 --> 00:23:02,640
MAYBE WEEK, YOU CAN NOT STUDY

622
00:23:02,640 --> 00:23:03,800
CHRONIC INFECTIONS SO WE PLAYED

623
00:23:03,800 --> 00:23:05,240
THEM OUT IN 2 D AFTER WE GROW

624
00:23:05,240 --> 00:23:10,040
THEM AND KEEP THEM IN 2 D, AND

625
00:23:10,040 --> 00:23:11,680
[INDISCERNIBLE] 1 CHINESE POST

626
00:23:11,680 --> 00:23:14,840
DOC CURRENTLY IN THE LAB, HE IS

627
00:23:14,840 --> 00:23:17,200
MANAGED TO MAINTAIN HPV

628
00:23:17,200 --> 00:23:21,120
INFECTION FOR 2 MONTHS IN THESE

629
00:23:21,120 --> 00:23:24,360
CULTURES AND FOR THE INSIDE, THE

630
00:23:24,360 --> 00:23:26,360
CCDNA, SORT OF LATENT FORM OF

631
00:23:26,360 --> 00:23:28,920
THE HEPATITIS B VIRUS, GENOME,

632
00:23:28,920 --> 00:23:30,840
IS ABUNDANTLY PRESENT IN

633
00:23:30,840 --> 00:23:32,880
THESE--IN THESE CELLS AND KEEPS

634
00:23:32,880 --> 00:23:35,160
ON CRANKING OUT THE HBS ANTIGEN

635
00:23:35,160 --> 00:23:36,680
SO CAN YOU MEASURE IT OUTSIDE TO

636
00:23:36,680 --> 00:23:42,040
CELLS BUT AS YOU SEE ALSO

637
00:23:42,040 --> 00:23:43,480
VIRAL--INFECTIOUS VIRAL PARTING

638
00:23:43,480 --> 00:23:44,520
ARE PRODUCED IN THESE CULTURES

639
00:23:44,520 --> 00:23:47,600
SO WE THINK THIS MIGHT BE A NICE

640
00:23:47,600 --> 00:23:49,600
PLATFORM TO STUDY CHRONIC HPV

641
00:23:49,600 --> 00:23:51,840
INFECTIONS AND POSSIBLY DEVELOP

642
00:23:51,840 --> 00:23:53,640
THERAPYINGS FOR THESE CHRONIC

643
00:23:53,640 --> 00:23:55,880
HPV INFECTIONS AND ANOTHER MODEL

644
00:23:55,880 --> 00:23:57,560
WE CURRENTLY, JUST SUBMIT AID

645
00:23:57,560 --> 00:24:00,920
PAPER BUT THE NAME HERE, WHO'S

646
00:24:00,920 --> 00:24:02,000
BEEN TRYING TO MODEL

647
00:24:02,000 --> 00:24:04,960
[INDISCERNIBLE] THE FIRST STAGE

648
00:24:04,960 --> 00:24:07,120
OF NONALCOHOLIC FATTY LIVER

649
00:24:07,120 --> 00:24:09,880
DISEASE, SEE THE NAMES HERE AND

650
00:24:09,880 --> 00:24:12,080
1 WAY OF CREATING THESE MODELS

651
00:24:12,080 --> 00:24:14,320
IS BY KNOCKING OUT GENES THAT

652
00:24:14,320 --> 00:24:18,520
ARE AT THE END OF THE LIPID

653
00:24:18,520 --> 00:24:20,880
SECRETION PATHWAY, TO APO-B AS A

654
00:24:20,880 --> 00:24:23,880
CENTRAL ELEMENT OF THE LDL

655
00:24:23,880 --> 00:24:26,240
PARTICLES AND THE HEPATOCYTES

656
00:24:26,240 --> 00:24:28,520
NEEDED TO SECRETE DE NOVO

657
00:24:28,520 --> 00:24:30,520
SYNTHESIZED LIPITS IF YOU KNOCK

658
00:24:30,520 --> 00:24:33,960
IT OUT, THERE'S ALSO HER HER

659
00:24:33,960 --> 00:24:34,640
EDUCATIONALITARY SYNDROME,

660
00:24:34,640 --> 00:24:37,080
THERE'S LARGE DROPLETS OF LIPIDS

661
00:24:37,080 --> 00:24:38,000
SYNTHESIZED BY THE HEPATOCYTES

662
00:24:38,000 --> 00:24:40,480
BUT THEY'RE NOT ABLE TO SECRETE

663
00:24:40,480 --> 00:24:40,680
IT.

664
00:24:40,680 --> 00:24:42,880
SO SURPRISINGLY EVEN DESPITE THE

665
00:24:42,880 --> 00:24:44,200
SO HEAVILY LIPID, IT WILL

666
00:24:44,200 --> 00:24:45,400
CONTINUE TO GROW, BUT I DON'T

667
00:24:45,400 --> 00:24:47,600
SHOW HERE WE CAN DO THE SAME

668
00:24:47,600 --> 00:24:48,400
THING WITH WILD TYPE ORGANOIDS

669
00:24:48,400 --> 00:24:50,120
IF YOU GROW THEM IN HIGH

670
00:24:50,120 --> 00:24:51,640
CONCENTRATIONS OF FATTY ACIDS,

671
00:24:51,640 --> 00:24:55,920
THEY ALSO SHOWED THE SAME LIPID

672
00:24:55,920 --> 00:24:58,040
DROPLETS, THERE'S NO REGISTERED

673
00:24:58,040 --> 00:25:00,240
DRUGS AT THE MOMENT EVEN THOUGH

674
00:25:00,240 --> 00:25:02,800
IT'S ESTIMATED ABOUT 20% OF ALL

675
00:25:02,800 --> 00:25:04,480
ADULT AMERICANS HAVE A FATTY

676
00:25:04,480 --> 00:25:07,080
LIVER WHICH MIGHT DEVELOP INTO

677
00:25:07,080 --> 00:25:09,560
CIRRHOSIS AND FIBROSIS AND

678
00:25:09,560 --> 00:25:11,200
EVENTUALLY INTO LIVER CANCER.

679
00:25:11,200 --> 00:25:13,600
THERE'S A LARGE NUMBER OF

680
00:25:13,600 --> 00:25:14,320
COMPOUNDS IN DEVELOPMENT.

681
00:25:14,320 --> 00:25:15,440
WE TESTED A WHOLE SERIES OF THEM

682
00:25:15,440 --> 00:25:16,880
AND WE SEE A FEW THAT ACTUALLY

683
00:25:16,880 --> 00:25:19,200
IN A MATTER OF 1 OR 2 DAYS WILL

684
00:25:19,200 --> 00:25:22,680
TOTALLY LEAD TO THE REMOVAL OF

685
00:25:22,680 --> 00:25:23,680
THESE LIPID PARTICLES SO

686
00:25:23,680 --> 00:25:25,440
BASICALLY RESTORE IN A NORMAL

687
00:25:25,440 --> 00:25:26,600
SITUATION, SO WE THINK THIS

688
00:25:26,600 --> 00:25:30,880
WOULD BE A NICE MODEL TO STUDY

689
00:25:30,880 --> 00:25:31,560
HOW HEPATOCYTES, OR LIPIDS WHAT

690
00:25:31,560 --> 00:25:34,680
YOU CAN DO ABOUT THIS.

691
00:25:34,680 --> 00:25:36,120
>> OTHER HAPPENLICATIONS THIS IS

692
00:25:36,120 --> 00:25:37,120
INFECTIOUS DISEASES, I JUST

693
00:25:37,120 --> 00:25:38,800
SHOWED BECAUSE THE ANIMATION IS

694
00:25:38,800 --> 00:25:40,680
THERE, THAT THE ALBUMIN MAKES

695
00:25:40,680 --> 00:25:42,240
AND THEN THE ANIMATION IS VERY

696
00:25:42,240 --> 00:25:47,560
NICE, BUT HERE WE WORK WITH ROB

697
00:25:47,560 --> 00:25:48,520
O'CONNOR IN BOSTON AND TRY TO

698
00:25:48,520 --> 00:25:50,480
SEE IF WE COULD GROW MICROBES

699
00:25:50,480 --> 00:25:52,600
THAT COULD NOT BE GROWN IN THE

700
00:25:52,600 --> 00:25:57,120
LAB ON NORMAL CELL LINES AND 1

701
00:25:57,120 --> 00:26:05,960
OF THEM IS SPOREDUCATIONALIUM,

702
00:26:05,960 --> 00:26:07,040
AND HERE YOU SEE THE

703
00:26:07,040 --> 00:26:09,280
EXPERIMENTS, SO WHAT WE WANTED

704
00:26:09,280 --> 00:26:11,160
TO DO IS ASSUMING THAT IT'S A

705
00:26:11,160 --> 00:26:13,520
GUT INFECTION THAT THEY CAUSE

706
00:26:13,520 --> 00:26:14,760
CHRONIC GUT INFECTIONS

707
00:26:14,760 --> 00:26:15,640
PARTICULARLY IN THE THIRD WORLD

708
00:26:15,640 --> 00:26:18,200
COUNTRIES SO WE ARE GOING TO

709
00:26:18,200 --> 00:26:20,080
REJECT SO CALLED OCYST WHICH IS

710
00:26:20,080 --> 00:26:24,360
THE INFECTIOUS STAGE LIKE AN EGG

711
00:26:24,360 --> 00:26:25,640
WITH SPOROZITE INSIDE AND HOPING

712
00:26:25,640 --> 00:26:26,760
THAT IN OUR ORGANIZATIONSONNOID

713
00:26:26,760 --> 00:26:28,960
WE HAVE THE CELL TYPE THAT WOULD

714
00:26:28,960 --> 00:26:31,040
BE REFERRED SITE FOR THESE

715
00:26:31,040 --> 00:26:32,880
PARASITES TO PROLIFERATE.

716
00:26:32,880 --> 00:26:35,360
YOU SEE THE OSIS LANDING INSIDE

717
00:26:35,360 --> 00:26:37,200
A HUMAN SMALL INTESTINAL

718
00:26:37,200 --> 00:26:37,840
ORGANIZATIONSONNOID, MOST OF

719
00:26:37,840 --> 00:26:40,280
THEM IN CELL TYPE IN NEEZ

720
00:26:40,280 --> 00:26:41,240
ORGANIZATIONSONNOIDS IN THESE

721
00:26:41,240 --> 00:26:45,480
SIGHTS, THESE ARE THE CELLS ON

722
00:26:45,480 --> 00:26:47,680
THE VILLI THAT ABSORB THIS

723
00:26:47,680 --> 00:26:48,280
ACTIVITY OF THE GUT.

724
00:26:48,280 --> 00:26:51,880
YOU SEE THIS COMING OUT OF THE

725
00:26:51,880 --> 00:26:53,840
OCYST, WE FIND THIS IN THE REAL

726
00:26:53,840 --> 00:26:55,680
EXPERIMENTS THAT THEY PREFER THE

727
00:26:55,680 --> 00:26:57,640
ENTHUSIASMER O SIGHTS, SO THE

728
00:26:57,640 --> 00:27:00,280
ABUNDANT CELL TYPE, YOU SEE THE

729
00:27:00,280 --> 00:27:01,600
MICROVILLI HERE AND ONCE THEY DO

730
00:27:01,600 --> 00:27:04,480
THIS THEY TALK ABOUT INSIDE THE

731
00:27:04,480 --> 00:27:06,000
MIRON AND THEY MULTIPLY TO ABOUT

732
00:27:06,000 --> 00:27:09,480
8 OF THESE, SO ESSENTIALLY, THIS

733
00:27:09,480 --> 00:27:12,120
STEP, AFTER ABOUT A DAY OR SO,

734
00:27:12,120 --> 00:27:13,600
THIS STAGE COMES OUT OF THE

735
00:27:13,600 --> 00:27:16,960
STRUCTURE AND NOW EFFECTS A

736
00:27:16,960 --> 00:27:18,960
SECONDARY ENTHUSIASMER O CITE,

737
00:27:18,960 --> 00:27:22,400
SIMILARLY AGAIN FORMS A MIRO, SO

738
00:27:22,400 --> 00:27:24,360
IT'S TYPE 2 MERONT, SO IT'S

739
00:27:24,360 --> 00:27:26,240
READY TO GO INTO SEXUAL STAGES

740
00:27:26,240 --> 00:27:28,040
ABOUT 2 DAYS INTO THE INFECTION

741
00:27:28,040 --> 00:27:28,680
CYCLE.

742
00:27:28,680 --> 00:27:30,280
NOW WE GET 2 WITH TYPES OF

743
00:27:30,280 --> 00:27:32,720
STRUCTURES IN FRONT, WE SEE A

744
00:27:32,720 --> 00:27:35,280
MIL STRUCTURE, WE SAY A FEMALE

745
00:27:35,280 --> 00:27:37,960
STRUCTURE AND THEY THE MALE

746
00:27:37,960 --> 00:27:40,480
STRUCTURE HAS THE MICROGAM EATS,

747
00:27:40,480 --> 00:27:42,680
THE MICROGAMMONS, LIKE THE SPERM

748
00:27:42,680 --> 00:27:44,880
EQUIVALENCE, WHEN THEY LEAVE THE

749
00:27:44,880 --> 00:27:46,200
MICROGAMMON THEY CAN FERTILIZE,

750
00:27:46,200 --> 00:27:49,560
THIS IS THE FERTILIZE THE

751
00:27:49,560 --> 00:27:50,440
MACROGAMMONS AND NOW WE'RE

752
00:27:50,440 --> 00:27:54,840
ACTUALLY BACK AT STAGE 1 WHERE

753
00:27:54,840 --> 00:27:56,200
AN OCYST IS FORMED AND IT'S THEN

754
00:27:56,200 --> 00:27:58,080
RELEASED AND NOW CAN LEAVE THE

755
00:27:58,080 --> 00:28:00,880
BODY OF THE INFECTED ANIMAL, CAN

756
00:28:00,880 --> 00:28:03,680
BE [INDISCERNIBLE] FOR HUMAN

757
00:28:03,680 --> 00:28:05,680
BEINGS AND THEN TO BE AFFECTING

758
00:28:05,680 --> 00:28:06,440
THE NEXT PARASITE.

759
00:28:06,440 --> 00:28:07,680
NOW IT WORKS VERY WELL, AS CAN

760
00:28:07,680 --> 00:28:09,520
YOU SEE HERE BY EM, I WON'T

761
00:28:09,520 --> 00:28:12,280
SPEND TOO MUCH TIME ON THIS BUT

762
00:28:12,280 --> 00:28:13,680
INDEED, THE REASON PROBABLY THAT

763
00:28:13,680 --> 00:28:14,680
THIS PARAICIDE COULD NEVER BE

764
00:28:14,680 --> 00:28:17,840
GROWN IN THE LAB WAS BECAUSE,

765
00:28:17,840 --> 00:28:19,320
CANCER CELL LINES, AT LEAST THAT

766
00:28:19,320 --> 00:28:21,600
WE KNOW ARE TRANSFORMED CELLS,

767
00:28:21,600 --> 00:28:24,680
YOU DO NOT HAVE THESE FULLY

768
00:28:24,680 --> 00:28:25,280
DIFFERENTIATED [INDISCERNIBLE]

769
00:28:25,280 --> 00:28:27,440
AND THEREFORE THEY CANNOT

770
00:28:27,440 --> 00:28:27,960
PROPAGATE THIS PARTICULAR

771
00:28:27,960 --> 00:28:29,160
MICROBE BUT THEY ASKED US

772
00:28:29,160 --> 00:28:31,080
EARLIER SHOWED THAT THE SAME

773
00:28:31,080 --> 00:28:32,520
THING FOR NORO VIRUS CHRKS IS A

774
00:28:32,520 --> 00:28:33,280
VIRUS THAT COULD NEVER BE

775
00:28:33,280 --> 00:28:35,600
CULTURE INDEED THE LAB.

776
00:28:35,600 --> 00:28:37,480
IT ALSO PREFERS ENTHUSIASMER O

777
00:28:37,480 --> 00:28:39,480
SIGHTS AND ACTUALLY, WE TRIED,

778
00:28:39,480 --> 00:28:45,120
THIS NEVER WORKS FOR US BUT MARY

779
00:28:45,120 --> 00:28:46,200
REASONED THAT POSSIBLY BIOASSETS

780
00:28:46,200 --> 00:28:46,960
COULD BE IMPORTANT AND THAT WAS

781
00:28:46,960 --> 00:28:49,280
THE KEY TO GET THIS WORKING SO

782
00:28:49,280 --> 00:28:52,680
SHE COULD SHOW THAT YOU COULD

783
00:28:52,680 --> 00:28:54,120
PROPAGATE NORO-VIRUS IN THE LAB

784
00:28:54,120 --> 00:28:55,880
USING THE ORGANOIDS WITH THE

785
00:28:55,880 --> 00:28:56,360
DIFFERENTIATED CELLS.

786
00:28:56,360 --> 00:28:58,040
I THINK IT WAS VERY PRODUCTIVE

787
00:28:58,040 --> 00:29:00,320
TO USE THIS TECHNOLOGY FOR

788
00:29:00,320 --> 00:29:02,080
CANCER RESEARCH, WE AND MANY

789
00:29:02,080 --> 00:29:05,360
OTHER LABS PUBLISHED EXTENSIVELY

790
00:29:05,360 --> 00:29:07,720
ON GENERATING ORGANOIDS FROM ALL

791
00:29:07,720 --> 00:29:10,680
SORTS OF CARCINOMAS, GUT, LUNG,

792
00:29:10,680 --> 00:29:11,320
PROSTATE, BREAST, TYPICALLY,

793
00:29:11,320 --> 00:29:14,160
WHEN YOU USE THE BASIC PROCESSES

794
00:29:14,160 --> 00:29:15,680
PROT COL, SOMETHING WILL GROW

795
00:29:15,680 --> 00:29:16,280
AND IMPROVE.

796
00:29:16,280 --> 00:29:18,240
ALSO SIDE BY SIDE, CAN YOU GROW

797
00:29:18,240 --> 00:29:19,000
HEALTHY TISSUE AND CANCER TISSUE

798
00:29:19,000 --> 00:29:21,520
FROM THE SAME PATIENT, WITH

799
00:29:21,520 --> 00:29:23,480
CRISPR, CAN YOU TAKE HEALTHY

800
00:29:23,480 --> 00:29:26,320
TISSUE AND TURN IT INTO 4 OR 5

801
00:29:26,320 --> 00:29:27,680
MUTATIONS FROM CANCER FROM

802
00:29:27,680 --> 00:29:29,560
CRISPR, CAN YOU REMOVE THEM AND

803
00:29:29,560 --> 00:29:30,520
SEE WHAT THAT MUTATION

804
00:29:30,520 --> 00:29:32,160
CONTRIBUTED TO AS THE PHENOTYPE.

805
00:29:32,160 --> 00:29:34,000
SO THAT'S ALL DESCRIBED, YOU CAN

806
00:29:34,000 --> 00:29:35,520
USE IT FOR PERSONALIZED MEDICINE

807
00:29:35,520 --> 00:29:39,120
AND LARGE NUMBER OF STUDIES NOW

808
00:29:39,120 --> 00:29:41,680
SORT OF VALIDATING ORGANOIDS AS

809
00:29:41,680 --> 00:29:43,880
AN AVATAR OF PATIENTS SO TEST

810
00:29:43,880 --> 00:29:44,880
DRUGS ON ORGANIZATIONSONNOIDS

811
00:29:44,880 --> 00:29:47,880
MIGHT PREDICT WHAT WOULD BE GOOD

812
00:29:47,880 --> 00:29:49,520
DRUG COMBINATION TO TREAT

813
00:29:49,520 --> 00:29:50,200
PATIENTS.

814
00:29:50,200 --> 00:29:51,720
THIS IS A RECENT STUDY, VERY

815
00:29:51,720 --> 00:29:54,600
DIFFERENT FROM WHAT I JUST

816
00:29:54,600 --> 00:29:56,040
DESCRIBED, PUBLISHED LAST YEAR

817
00:29:56,040 --> 00:29:57,840
AND ACTUALLY THESE 3 PIECE,

818
00:29:57,840 --> 00:30:00,840
[INDISCERNIBLE] AND MY LAB AND

819
00:30:00,840 --> 00:30:02,080
[INDISCERNIBLE] RUBEN'S LAB CAME

820
00:30:02,080 --> 00:30:03,680
UP WITH THIS EXPERIMENT AND THEY

821
00:30:03,680 --> 00:30:05,880
SHOWED THE RESULTS BEFORE RUBEN

822
00:30:05,880 --> 00:30:07,400
OR I RENEWED THIS PROJECT.

823
00:30:07,400 --> 00:30:09,920
THEY STARTED READING ABOUT A

824
00:30:09,920 --> 00:30:13,640
VERSION OF E.COLI, SO A VERY

825
00:30:13,640 --> 00:30:15,040
COMMON MICROBIOME COMPONENT AND

826
00:30:15,040 --> 00:30:16,440
THESE PARTICULAR E.COLI HAVE AN

827
00:30:16,440 --> 00:30:20,960
EXTRA BIT OF DNA ABOUT 60 DILL O

828
00:30:20,960 --> 00:30:22,920
BASES CALLED POLYKETIDE

829
00:30:22,920 --> 00:30:24,440
SYNTHESIS, PKAS POSITIVE,

830
00:30:24,440 --> 00:30:27,400
CONTAINING 10 GENES MOSTLY

831
00:30:27,400 --> 00:30:29,160
ENZYMES TOGETHER CONITUTE A

832
00:30:29,160 --> 00:30:37,200
SYNTHESIS PATHWAY, AND THIS

833
00:30:37,200 --> 00:30:38,720
PARTICULAR POLYKETO VECTOR

834
00:30:38,720 --> 00:30:39,760
GENOMEIN, THESE HAVE BEEN KNOWN

835
00:30:39,760 --> 00:30:41,720
FOR ABOUT 30 YEARS TO BE

836
00:30:41,720 --> 00:30:43,680
PHONOTOXIC SO WHEN YOU CULTURE

837
00:30:43,680 --> 00:30:46,480
THE EON COAL I WITH THAT EXTRA

838
00:30:46,480 --> 00:30:47,560
PENE OF THE CHROMOSOME, YOU CALL

839
00:30:47,560 --> 00:30:49,720
TO THEM ON TOP OF HUMAN CELL

840
00:30:49,720 --> 00:30:51,000
LINES YOU RAPIDLY SEE DOUBLE

841
00:30:51,000 --> 00:30:53,120
STRAND BREAKS THAT,'S WHY

842
00:30:53,120 --> 00:30:56,800
THEY'RE CALLED GENO TOXIC AND

843
00:30:56,800 --> 00:30:58,680
THE QUESTION THAT THE 3

844
00:30:58,680 --> 00:31:06,240
PHYSICIANS ASKED IS ESSENTIALLY

845
00:31:06,240 --> 00:31:07,640
CAN SECRETE THIS AND EXPOSURE TO

846
00:31:07,640 --> 00:31:09,280
THIS LEAD TO MUTATIONS AND THE

847
00:31:09,280 --> 00:31:11,040
PARTICULAR CAN LEAD TO CANCER

848
00:31:11,040 --> 00:31:12,800
MUTATIONS, SO NOT ONLY CAUSING

849
00:31:12,800 --> 00:31:14,440
DOUBLE STRAND BREAKS AND ALSO IN

850
00:31:14,440 --> 00:31:15,880
THE RESOLUTION OF THESE DOUBLE

851
00:31:15,880 --> 00:31:17,000
STRAND BREAKS RESULT IN

852
00:31:17,000 --> 00:31:18,080
MUTATIONS THAT WOULD THEN

853
00:31:18,080 --> 00:31:23,680
ULTIMATELY LEAD TO CANCER, BUT

854
00:31:23,680 --> 00:31:25,480
THIS IS COLI BACTERIAIN, AND

855
00:31:25,480 --> 00:31:37,360
WHILE WE WERE DOING THIS IN THIS

856
00:31:37,360 --> 00:31:40,000
PAPER ARE BIND TO SPECIFICALLY

857
00:31:40,000 --> 00:31:56,160
TO A-RESIDUES AND DNA AND

858
00:31:56,160 --> 00:31:58,640
MODELED HERE, CROSS LINK THIS IS

859
00:31:58,640 --> 00:32:02,560
NOT COMPATIBLE WITH THE LIFE OF

860
00:32:02,560 --> 00:32:04,360
THE CELL APPARENTLY IN THIS

861
00:32:04,360 --> 00:32:06,080
PROCESS, THE CELL CAN UNDERGO

862
00:32:06,080 --> 00:32:07,680
DOUBLE TRAND BREAKS AND THAT

863
00:32:07,680 --> 00:32:09,440
WOULD MOST LIKELY LEAD TO THE

864
00:32:09,440 --> 00:32:18,480
DEATH OF THE CELL, SO THAT'S WHY

865
00:32:18,480 --> 00:32:34,440
IN THE RESOLUTION OF DOING THE

866
00:32:34,440 --> 00:32:35,760
E.COLI, THE MUTANT, DERIVED FROM

867
00:32:35,760 --> 00:32:37,600
THIS, ON THE LEFT, WE SEE IT ON

868
00:32:37,600 --> 00:32:40,080
THE RIGHT, WHICH LACKS 1 OF

869
00:32:40,080 --> 00:32:42,200
THESE GENES AND SO THIS IS THE

870
00:32:42,200 --> 00:32:44,240
BAD GUY ON THE RIGHT, HAVE YOU

871
00:32:44,240 --> 00:32:45,480
THE CONTROL FOR THAT GUY, AND

872
00:32:45,480 --> 00:32:47,840
THE OTHER WOULD BE THAT NOW WE

873
00:32:47,840 --> 00:32:50,560
GROW THEM ON OUTER PLATES WE ARE

874
00:32:50,560 --> 00:32:52,760
NOT MICROBIOLOGIST BUT THAT'S

875
00:32:52,760 --> 00:32:55,400
EASY, WE THEN PICKED THEM UP AND

876
00:32:55,400 --> 00:32:58,040
THEY HAVE GLASS NEEDLES WE USE

877
00:32:58,040 --> 00:32:58,840
THESE INJECTORS FOR THIS AND

878
00:32:58,840 --> 00:33:01,360
THEN WE WOULD INJECT INDIVIDUAL

879
00:33:01,360 --> 00:33:03,000
ORGANOIDS WITH THESE BACTERIA,

880
00:33:03,000 --> 00:33:06,280
LEAVE THEM IN FOR 1 OR 2 DAYS

881
00:33:06,280 --> 00:33:10,000
AND THEN ASK AND SEE WHAT WAS

882
00:33:10,000 --> 00:33:12,440
PUBLISHED PREVIOUSLY IN THE

883
00:33:12,440 --> 00:33:13,080
DOUBLE STRAND BREAKS.

884
00:33:13,080 --> 00:33:14,440
AND THEN OF COURSE ON THE LEFT

885
00:33:14,440 --> 00:33:16,040
WE SEE THEM AND ON THE RIGHT

886
00:33:16,040 --> 00:33:17,680
THERE WOULD BE NEGATIVE CONTROL.

887
00:33:17,680 --> 00:33:20,880
AND ON THE LEFT ABOUT MAYBE 40

888
00:33:20,880 --> 00:33:22,640
OR 50 ORGANIZATIONSONNOIDS, 1 BY

889
00:33:22,640 --> 00:33:25,200
1 INJECTED BY [INDISCERNIBLE]

890
00:33:25,200 --> 00:33:26,880
WITH THE PKS BACTERIA AND INDEED

891
00:33:26,880 --> 00:33:29,600
ON THE GLOW, 1 OF THESE SEE MANY

892
00:33:29,600 --> 00:33:33,280
OF THESE RED DOTS, WHICH

893
00:33:33,280 --> 00:33:35,640
ESSENTIALLY ARE GAMMA H2 X FOCI

894
00:33:35,640 --> 00:33:37,280
WHICH REVEAL THE PRESENCE OF A

895
00:33:37,280 --> 00:33:37,720
DOUBLE STRAND BREAK.

896
00:33:37,720 --> 00:33:38,960
SO INDEED IN THE CONTROL WE

897
00:33:38,960 --> 00:34:19,480
DON'T SEE IT, SO WE ASK,

898
00:34:19,480 --> 00:34:20,680
YES,--IT WILL OVERGROW THE

899
00:34:20,680 --> 00:34:21,560
CULTURE AND THE END OF THE

900
00:34:21,560 --> 00:34:23,760
EXPERIMENT SO IT IS FOR ABOUT 3

901
00:34:23,760 --> 00:34:31,680
MONTHS AND REALLY MIMICKING

902
00:34:31,680 --> 00:34:34,040
CHRONIC EXPOSURE TO PKS E.COLI

903
00:34:34,040 --> 00:34:37,080
THAN THE CONTROLS ON THE RIGHT

904
00:34:37,080 --> 00:34:37,920
YOU WOULD PROBABLY STILL HAVE

905
00:34:37,920 --> 00:34:42,040
THE HATTER TIME WITH THE

906
00:34:42,040 --> 00:34:42,680
MUTATIONS BECAUSE EVERY CELL

907
00:34:42,680 --> 00:34:44,840
MIGHT HAVE A DIFFERENT

908
00:34:44,840 --> 00:34:46,680
COMPLEMENT OF THESE SMALL

909
00:34:46,680 --> 00:34:48,960
LESIONS AND INSERTIONS, SO THEN

910
00:34:48,960 --> 00:34:51,400
WE DID THE SUBCLONES AFTER 3

911
00:34:51,400 --> 00:34:53,720
MONTH EXPOSURE, THESE CELLS GREW

912
00:34:53,720 --> 00:34:55,640
THEM UP, ESSENTIALLY TO AMPRIFY

913
00:34:55,640 --> 00:34:57,040
THE GENOMES OF THESE SINGLE

914
00:34:57,040 --> 00:35:01,400
CELLS, TO AN AMOUNT WHERE WE

915
00:35:01,400 --> 00:35:02,240
COULD SEEQUENCE THESE ORGANOIDS

916
00:35:02,240 --> 00:35:06,680
AND IN ESSENCE READ OUT THE

917
00:35:06,680 --> 00:35:10,440
GENOME OF THE CELL THATULENT TO

918
00:35:10,440 --> 00:35:12,640
THE SUBCOLON, AND THIS ALLOWED

919
00:35:12,640 --> 00:35:14,480
US TO COUNT MUTATIONS AND

920
00:35:14,480 --> 00:35:16,200
INDEEDOT LEFT, THE MUTATIONS

921
00:35:16,200 --> 00:35:18,040
THAN ARE ON THE RIGHT BUT MORE

922
00:35:18,040 --> 00:35:20,440
IMPORTANTLY AND THIS WAS USING

923
00:35:20,440 --> 00:35:24,400
MIKE STRATEGIC PLANON'S WAY OF

924
00:35:24,400 --> 00:35:26,520
USING DNA SIGNATURES OR LOOKING

925
00:35:26,520 --> 00:35:28,240
FOR WHAT KINDS OF MUTATIONS YOU

926
00:35:28,240 --> 00:35:29,400
CAN INDUCE AND I WILL SHOW THIS

927
00:35:29,400 --> 00:35:31,280
BETTER IN THE NEXT SLIDE, BUT WE

928
00:35:31,280 --> 00:35:33,120
FOUND OUT THAT INDEED THIS WOULD

929
00:35:33,120 --> 00:35:35,320
BE THE NORMAL MUTATIONS YOU SEE

930
00:35:35,320 --> 00:35:37,520
IN CELL CULTURE, SO CELLS IN

931
00:35:37,520 --> 00:35:41,680
CULTURE SUSTAIN RANDOM MUTATIONS

932
00:35:41,680 --> 00:35:43,840
OF SOME LEVEL, ASK PARTICULARLY

933
00:35:43,840 --> 00:35:47,080
WHEN YOU SCORE FOR T TO C OR

934
00:35:47,080 --> 00:35:49,080
CHANGES OR T-G, AND WE SEE PEEKS

935
00:35:49,080 --> 00:35:52,720
WE MED NOT SEE IN THE CONTROLS.

936
00:35:52,720 --> 00:35:54,960
IMH WE VERY CAREFULLY MET THE

937
00:35:54,960 --> 00:35:56,320
SINGLE BASE CHANGES OR DELETIONS

938
00:35:56,320 --> 00:35:59,200
IN THE EXPOSED ORGANOIDS AND

939
00:35:59,200 --> 00:36:01,240
MAKE A STRIKING DISCOVERY.

940
00:36:01,240 --> 00:36:03,720
SO THIS GOES FOR A VERY UNIQUE

941
00:36:03,720 --> 00:36:05,000
MOTIF, ALMOST LIKE A RESTRICTION

942
00:36:05,000 --> 00:36:07,680
ENZYME OR A TRANSCRIPTION

943
00:36:07,680 --> 00:36:10,200
FACTOR, SO YOU SEE, A T 8 THERE

944
00:36:10,200 --> 00:36:13,480
IS EITHER DELETED OR MUTATED BUT

945
00:36:13,480 --> 00:36:17,280
IS DONE IN A CONTEXT OF AT RICH

946
00:36:17,280 --> 00:36:19,240
DOMAIN AND A ON THE MINUS 3

947
00:36:19,240 --> 00:36:19,800
POSITION.

948
00:36:19,800 --> 00:36:21,040
AND IF YOU MODEL THIS AGAIN THE

949
00:36:21,040 --> 00:36:22,840
WAY I SHOWED YOU EARLIER, WE

950
00:36:22,840 --> 00:36:25,480
BELIEVE WHAT'S HAPPENING IS THAT

951
00:36:25,480 --> 00:36:27,280
THIS BINDS TO THE POSITIVE

952
00:36:27,280 --> 00:36:29,360
STRAND SO THIS WOULD BE THIS A

953
00:36:29,360 --> 00:36:31,720
AND THIS BINDS COVALENTLY TO AN

954
00:36:31,720 --> 00:36:34,720
A ON THE NEGATIVE STRAND, AND

955
00:36:34,720 --> 00:36:36,280
THE OPPOSITE THE T OF HERE, AND

956
00:36:36,280 --> 00:36:39,280
NOW THE CELL AS A PROBLEM, IT

957
00:36:39,280 --> 00:36:40,640
HAS TO RID OF THIS ADDUCT AND

958
00:36:40,640 --> 00:36:43,720
WHILE IT GETS RID OF IT, IT

959
00:36:43,720 --> 00:36:47,360
APPARENTLY CHANGES HERE INTO ANY

960
00:36:47,360 --> 00:36:49,480
OTHER BASE OR IT DELETES THIS,

961
00:36:49,480 --> 00:36:51,720
NOW IF THIS HAPPENS IN A READING

962
00:36:51,720 --> 00:36:53,680
FRAME, CHANGING IT IN ANY OTHER

963
00:36:53,680 --> 00:36:55,400
BASE COULD CAUSE A MISSED SENSE

964
00:36:55,400 --> 00:36:57,920
MUTATION AND DELETING THIS

965
00:36:57,920 --> 00:37:00,200
SINGLE BASE PAIR WOULD LEAD TO A

966
00:37:00,200 --> 00:37:01,360
FRAME SHIFT IN BOTH CASES OF

967
00:37:01,360 --> 00:37:09,600
COURSE CAN CONTRIBUTE TO CANCER.

968
00:37:09,600 --> 00:37:11,480
NOW THESE MUTATIONS OCCUR

969
00:37:11,480 --> 00:37:14,000
RARELY, BUT IN THIS ASSIGNMENT

970
00:37:14,000 --> 00:37:15,280
WE SEQUENCED THE ENTIRE GENOME

971
00:37:15,280 --> 00:37:17,080
AND WE SEE WHERE IT HITS THE

972
00:37:17,080 --> 00:37:18,880
GENOME AND WE DON'T THINK IT HAS

973
00:37:18,880 --> 00:37:23,760
PREFERENCE FOR A GENE TJUST GOES

974
00:37:23,760 --> 00:37:27,800
FOR AT RICH SEQUENCES AND IT

975
00:37:27,800 --> 00:37:28,800
WILL CHANGEERER REMOVE THIS

976
00:37:28,800 --> 00:37:29,520
THERE.

977
00:37:29,520 --> 00:37:30,480
SO VERY ARTIFICIAL, WE THEN

978
00:37:30,480 --> 00:37:35,360
ASKED DOES IT HAPPEN IN REAL

979
00:37:35,360 --> 00:37:36,920
LIFE THEY WERE VERY UNUSUAL,

980
00:37:36,920 --> 00:37:38,560
THEY HAVE NEVER BEEN SEEN BEFORE

981
00:37:38,560 --> 00:37:40,280
WE WERE LUCKY TO HAVE ACCESS TO

982
00:37:40,280 --> 00:37:40,960
THE MEDICAL FOUNDATION

983
00:37:40,960 --> 00:37:43,560
COLLECTION AND SO THEY'VE BEEN

984
00:37:43,560 --> 00:37:44,080
SEQUENCING WHOLE GENOME,

985
00:37:44,080 --> 00:37:45,600
METASTASIS FOR A LARGE VARIETY

986
00:37:45,600 --> 00:37:48,080
OF DIFFERENT HUMAN CANCERS WE

987
00:37:48,080 --> 00:37:50,560
ASK WHICH OF THESE CANCERS DO WE

988
00:37:50,560 --> 00:37:53,600
SEE SIGNS OF THIS PARTICULAR

989
00:37:53,600 --> 00:37:55,320
MUTATIONAL PROCESS, AND LOW AND

990
00:37:55,320 --> 00:37:57,080
BEHOLD WE DO SEE THAT MAYBE WE

991
00:37:57,080 --> 00:38:03,680
DO THINK ABOUT 15% OF ALL COLON

992
00:38:03,680 --> 00:38:05,160
CANCERS SHOW CLEAR SIGNS OF

993
00:38:05,160 --> 00:38:06,760
THESE MUTATIONS SO THIS SCORES

994
00:38:06,760 --> 00:38:08,480
HOW MANY MUTATIONS FIT WHAT I

995
00:38:08,480 --> 00:38:10,360
JUST SHOWED YOU FOR THE

996
00:38:10,360 --> 00:38:11,240
SIGNATURE, BY COMPARISON, THERE

997
00:38:11,240 --> 00:38:13,320
ARE QUITE A FEW BREAST CANCER

998
00:38:13,320 --> 00:38:14,280
CASES IN THIS COLLECTION, THERE

999
00:38:14,280 --> 00:38:15,720
WAS NOT A SINGLE BREAST CANCER

1000
00:38:15,720 --> 00:38:16,760
CASE WHERE WE SAW ANY EVIDENCE

1001
00:38:16,760 --> 00:38:18,680
OF THIS TYPE OF MUTATIONS, YOU

1002
00:38:18,680 --> 00:38:21,040
GET THE ON OCCASIONAL HEAD AND

1003
00:38:21,040 --> 00:38:23,000
NECK CANCER WE'VE SEEN A FEW

1004
00:38:23,000 --> 00:38:23,880
MORE, OCCASIONALLY BLADDER

1005
00:38:23,880 --> 00:38:26,280
CANCERS HERE, AND THOSE ARE

1006
00:38:26,280 --> 00:38:28,080
SIGNS WHERE E.COLI CAN LIVE, SO

1007
00:38:28,080 --> 00:38:31,760
POSSIBLY THESE ARE ALSO CAUSED

1008
00:38:31,760 --> 00:38:32,120
BY PKS E.COLI.

1009
00:38:32,120 --> 00:38:34,600
AND THEN IN THE SECOND COHORT,

1010
00:38:34,600 --> 00:38:36,400
THIS IS COLORECTAL CANCERS,

1011
00:38:36,400 --> 00:38:38,640
AGAIN, THE SAME PREVALENCE WAS

1012
00:38:38,640 --> 00:38:40,720
FOUND WITH MAYBE 5 TO 10% OF THE

1013
00:38:40,720 --> 00:38:43,080
COLON CANCER PATIENTS HAD THIS

1014
00:38:43,080 --> 00:38:44,480
PARTICULAR SIGNATURE AND HAVE

1015
00:38:44,480 --> 00:38:46,680
IMPROVED ALGORITHM AND THE

1016
00:38:46,680 --> 00:38:49,600
RIBBON, WHOSE LAB IS PURSUING

1017
00:38:49,600 --> 00:38:52,160
BIO-INFORMATICS OF THIS,

1018
00:38:52,160 --> 00:38:55,680
BELIEVES THAT 15% OF COLOON

1019
00:38:55,680 --> 00:38:58,200
CANCERS HAVE LARGE NUMBERS OR

1020
00:38:58,200 --> 00:38:59,680
FEWER NUMBERS WITH CLEAR

1021
00:38:59,680 --> 00:39:00,680
EVIDENCE OF THIS MUTATIONAL

1022
00:39:00,680 --> 00:39:01,280
PROCESS.

1023
00:39:01,280 --> 00:39:07,680
WE THEN ASKED, SO IT'S--SO FAR

1024
00:39:07,680 --> 00:39:10,680
BEFORE WE LOOKED AT DO WE HIT

1025
00:39:10,680 --> 00:39:11,680
CANCER GENES, NO, THE KRASE

1026
00:39:11,680 --> 00:39:16,880
MODEL ARE QUITE COLON IN COLON

1027
00:39:16,880 --> 00:39:18,400
CANCER, THIS CANNOT BE CREATED

1028
00:39:18,400 --> 00:39:20,120
BY THIS MUTATIONAL PROCESS

1029
00:39:20,120 --> 00:39:21,840
BECAUSE THE MUTATIONAL FOOTPRINT

1030
00:39:21,840 --> 00:39:24,200
IS NOT THERE, THE RICH SEQUENCE,

1031
00:39:24,200 --> 00:39:27,520
APC, WHICH IS THE MOST COMMON

1032
00:39:27,520 --> 00:39:29,160
TUMOR SUPPRESSOR IN COLON CANCER

1033
00:39:29,160 --> 00:39:39,000
MUTATED UP TO 90% OF OF THE

1034
00:39:39,000 --> 00:39:45,920
RELIEF TO CARRY OUT AND THESE

1035
00:39:45,920 --> 00:40:01,320
CANCER CASES WE FIND.

1036
00:40:01,320 --> 00:40:10,680
THE WITH THE APC, SO E.COLI IS

1037
00:40:10,680 --> 00:40:16,160
REDUCING MUTATIONS AND SEE

1038
00:40:16,160 --> 00:40:17,640
SPECIFICALLY KNOW FROM

1039
00:40:17,640 --> 00:40:21,040
LITERATURE THAT ABOUT 10% OF THE

1040
00:40:21,040 --> 00:40:22,240
POPULATION CARRIES BACTERIA AT

1041
00:40:22,240 --> 00:40:23,560
ANY GIVEN TIME, OF COURSE

1042
00:40:23,560 --> 00:40:24,960
BACTERIA DON'T HAVE TO BE

1043
00:40:24,960 --> 00:40:27,240
PRESENT IN E.COLI CANCER

1044
00:40:27,240 --> 00:40:29,080
PATIENT, WHEN CANCER EMERGES, IT

1045
00:40:29,080 --> 00:40:32,000
MIGHT HAVE HAPPENED MUCH EARLIER

1046
00:40:32,000 --> 00:40:41,320
IN LIFE, BUT BASED ON THIS, IT

1047
00:40:41,320 --> 00:40:45,400
IS CONFIRMED, COLO VECTOR IS THE

1048
00:40:45,400 --> 00:40:46,320
ECOLI THAT PROVES CAUSING CANCER

1049
00:40:46,320 --> 00:40:47,360
DIRECTLY IN UH ATHLETICS HANS

1050
00:40:47,360 --> 00:40:48,960
AND THIS MIGHT EVENTUALLY LEAD

1051
00:40:48,960 --> 00:40:51,360
TO MAYBE FIND OUT WHO CARRIES

1052
00:40:51,360 --> 00:40:53,360
THESE BACTERIA TO QUITE EASILY

1053
00:40:53,360 --> 00:40:54,080
REMOVE THEM WITH ANTIBIOTICS AND

1054
00:40:54,080 --> 00:40:56,640
THAT COULD LEAD TO A SITUATION

1055
00:40:56,640 --> 00:40:59,520
WHERE YOU PREVENT COLAN CANCER

1056
00:40:59,520 --> 00:41:00,920
PARTICULARLY WE THINK ABOUT HIGH

1057
00:41:00,920 --> 00:41:02,680
RISK PATIENTS LIKE HER

1058
00:41:02,680 --> 00:41:05,360
EDUCATIONALITARY COLON CANCER,

1059
00:41:05,360 --> 00:41:06,680
PATIENTS OR PATIENTS WITH

1060
00:41:06,680 --> 00:41:07,880
CHRONIC INFLAMMATORY DISEASE

1061
00:41:07,880 --> 00:41:13,280
WHERE YOU DON'T WANT ANOTHER

1062
00:41:13,280 --> 00:41:14,920
EVENT AND THEN A FINAL STORY, I

1063
00:41:14,920 --> 00:41:17,600
THINK I HAVE TIME FOR THIS, OR

1064
00:41:17,600 --> 00:41:19,800
WHEN COVID BROKE OUT 2 YEARS

1065
00:41:19,800 --> 00:41:21,400
AGO, WE, LIKE MANY COUNTRIES

1066
00:41:21,400 --> 00:41:24,680
WENT INTO LOCK DOWN AND WE ARE

1067
00:41:24,680 --> 00:41:27,040
ONLY ALLOWED TO DO THE MOST

1068
00:41:27,040 --> 00:41:28,440
ESSENTIAL EXPERIMENTS BUT WE ARE

1069
00:41:28,440 --> 00:41:29,600
ENCOURAGED TO DO COVID

1070
00:41:29,600 --> 00:41:31,760
EXPERIMENTS SO WE TEAMED UP WITH

1071
00:41:31,760 --> 00:41:39,120
A CORONA LAB IN ROTTER DAM LED

1072
00:41:39,120 --> 00:41:39,560
BY [INDISCERNIBLE],

1073
00:41:39,560 --> 00:41:40,440
COLLABORATORS THERE, AND THE

1074
00:41:40,440 --> 00:41:41,480
QUESTION WAS QUITE SIMPLE THAT

1075
00:41:41,480 --> 00:41:43,400
WE ASKED, SO WE ASK, IS THE GUT

1076
00:41:43,400 --> 00:41:46,000
AND THIS IS MARCH 2020, SO IS

1077
00:41:46,000 --> 00:41:47,880
THE GUT ALSO A TARGET FOR THIS

1078
00:41:47,880 --> 00:41:50,080
VIRUS, AND THEN WE KNOW A FEW

1079
00:41:50,080 --> 00:41:51,880
THINGS THEN, ACE 2, TO BE

1080
00:41:51,880 --> 00:41:53,280
XREAMLY HIGHLY EXPRESSED IN THE

1081
00:41:53,280 --> 00:41:56,080
GUT, MUCH HIGHER THAN IN THE AIR

1082
00:41:56,080 --> 00:41:58,360
WAYS AND ACE 2 WAS DONE ALREADY

1083
00:41:58,360 --> 00:42:00,080
AND RECOGNIZES RECEPTOR FOR

1084
00:42:00,080 --> 00:42:01,080
SARS-COV-2, AND WAS RAPIDLY

1085
00:42:01,080 --> 00:42:02,520
FOUND BECAUSE THERE WAS ALSO A

1086
00:42:02,520 --> 00:42:04,480
RECEPTOR FOR THE ORIGINAL SARS

1087
00:42:04,480 --> 00:42:06,800
VIRUS 20 YEARS AGO, WE ALSO

1088
00:42:06,800 --> 00:42:08,560
NOTED THAT QUITE SIGNIFICANT

1089
00:42:08,560 --> 00:42:11,680
PERCENTAGE OF COVID-19 PATIENTS,

1090
00:42:11,680 --> 00:42:16,120
SHOW UP WITH THE GI SYMPTOMS, SO

1091
00:42:16,120 --> 00:42:18,000
NAUSEA, TOMAC ACHES AND SOME THE

1092
00:42:18,000 --> 00:42:19,280
FIRST PC R TESTS WERE BECOMING

1093
00:42:19,280 --> 00:42:21,000
AVAILABLE BASED ON THE GENOME OF

1094
00:42:21,000 --> 00:42:24,080
THE VIRUS, AND PEOPLE HAD SHOWN

1095
00:42:24,080 --> 00:42:25,280
THE VIRAL RNA DETECTABLE IN

1096
00:42:25,280 --> 00:42:26,560
STOOL, SO IT CAME OUT OF THE

1097
00:42:26,560 --> 00:42:28,640
LUNGS AND ENDED UP IN STOOL

1098
00:42:28,640 --> 00:42:30,240
POSSIBLY IT WAS PRODUCED BY

1099
00:42:30,240 --> 00:42:34,840
INFECTED CELLS IN THE GUT, SO WE

1100
00:42:34,840 --> 00:42:36,720
ASKED VERY SIMPLY EVERY ORGANOID

1101
00:42:36,720 --> 00:42:39,200
CAN BE IN FACT ORGANOIDS, WORKED

1102
00:42:39,200 --> 00:42:41,160
BUT THE GOOD ORGANOIDS ARE MUCH

1103
00:42:41,160 --> 00:42:43,680
EASIER TO INFECT AND THEY

1104
00:42:43,680 --> 00:42:46,120
PRODUCE MUCH LARGER VIRAL

1105
00:42:46,120 --> 00:42:47,800
NUMBERS, VIRAL PARTICLES UV

1106
00:42:47,800 --> 00:42:49,440
SCORE FOR A LIFE VIRUS AND ONLY

1107
00:42:49,440 --> 00:42:52,680
2 AND HALF DAYS WE GET AN

1108
00:42:52,680 --> 00:42:55,000
INCREASE IN VIRAL PARTICLES,

1109
00:42:55,000 --> 00:42:56,640
QUITE SURPRISINGLY THESE CELLS

1110
00:42:56,640 --> 00:42:58,080
KEEP ON LOOKING FOR HEALTHY,

1111
00:42:58,080 --> 00:43:01,080
THEY KEEP ON GROWING FOR RNA

1112
00:43:01,080 --> 00:43:20,480
SAME THING AND THEY ONLY HAVE

1113
00:43:20,480 --> 00:43:21,520
AND PORNLLY EXPLAINING WHY

1114
00:43:21,520 --> 00:43:23,080
INDIVIDUALS COULD PRODUCE SO

1115
00:43:23,080 --> 00:43:24,960
MUCH VIRUS IN THE BEGINNING OF

1116
00:43:24,960 --> 00:43:27,200
THEIR DISEASE AND THAT WAY BEING

1117
00:43:27,200 --> 00:43:29,680
FANTASTIC SPREADERS OF THE VIRAL

1118
00:43:29,680 --> 00:43:31,440
INFECTIONS, SO YOU SEE A SINGLE

1119
00:43:31,440 --> 00:43:33,840
INFECTED CELL BY EN, WE SULLY

1120
00:43:33,840 --> 00:43:35,240
SEE THAT THE RIEROUS WILL ATTACH

1121
00:43:35,240 --> 00:43:36,680
TO THE APEX OF THE CELLS SO THIS

1122
00:43:36,680 --> 00:43:38,800
IS WHERE THE ACE 2 SITS AND SO

1123
00:43:38,800 --> 00:43:41,240
THE INFECTION COME FROM THE

1124
00:43:41,240 --> 00:43:45,080
LUMEN, MUCH LIKE THEY ENTER THE

1125
00:43:45,080 --> 00:43:46,080
PATIENT, NO INTESTINAL FACTOR IN

1126
00:43:46,080 --> 00:43:48,160
THE LUNGS, THAT'S HERE, SITS ON

1127
00:43:48,160 --> 00:43:49,680
THE BASAL SIDE, STAIN FOR

1128
00:43:49,680 --> 00:43:51,800
NUCLEAR PROTEIN HERE AND WIDE,

1129
00:43:51,800 --> 00:43:53,640
YOU ALSO HAVE THE VIRUS IS

1130
00:43:53,640 --> 00:43:54,880
SECRETED AGAIN TO THE LUMINAL

1131
00:43:54,880 --> 00:43:56,640
SIDE OF THE CELL AND INDEED

1132
00:43:56,640 --> 00:43:58,680
AFTER 60 HOURS YOU CAN SEE THAT

1133
00:43:58,680 --> 00:44:00,480
IN THE INFECTED ORGANOID, MANY

1134
00:44:00,480 --> 00:44:02,800
CELLS GET INFECTED BUT

1135
00:44:02,800 --> 00:44:04,560
NEIGHBORING ORGANOIDS ARE NOT

1136
00:44:04,560 --> 00:44:05,200
PRIMARILY INFECTED DON'T APPEAR

1137
00:44:05,200 --> 00:44:07,280
TO BE SENSITIVE TO THE VIRUS, SO

1138
00:44:07,280 --> 00:44:08,840
THEY HAVE TO ENTER THROUGH THE

1139
00:44:08,840 --> 00:44:10,920
APEX AND LEADS THE CELL AGAIN SO

1140
00:44:10,920 --> 00:44:12,600
THE ACHE PICKA MEMBRANE AND THEN

1141
00:44:12,600 --> 00:44:14,680
BECOMES A LITTLE BIT IMPORTANT

1142
00:44:14,680 --> 00:44:18,560
IN THE LAST BIT OF THE TALK.

1143
00:44:18,560 --> 00:44:21,720
SO IT WAS PUBLISHED RAPIDLY AND

1144
00:44:21,720 --> 00:44:23,000
REVIEWED OVERNIGHT THE JOURNAL

1145
00:44:23,000 --> 00:44:24,440
IS PUBLISHED OVERNIGHT AND

1146
00:44:24,440 --> 00:44:28,080
ACTUALLY SEVERAL OTHER PAPERS

1147
00:44:28,080 --> 00:44:29,280
SHOWING SOMETHING SIMILAR AND

1148
00:44:29,280 --> 00:44:31,760
VERY NICE NATURE MEDICINE FROM

1149
00:44:31,760 --> 00:44:34,120
JANE IN HONG KONG, SHE SHOWED

1150
00:44:34,120 --> 00:44:38,600
YOU CAN QUITE EASILY GROW BAT

1151
00:44:38,600 --> 00:44:42,520
ORGANOIDS FROM THE GUTS OF BATS

1152
00:44:42,520 --> 00:44:46,400
AND THEY ARE ACCUSTOMED TO MANY

1153
00:44:46,400 --> 00:44:47,920
CORONAVIRUSS IN HUMANS SO IT'S

1154
00:44:47,920 --> 00:44:49,600
SEQUENCES THAT ARE NEVER GROWN,

1155
00:44:49,600 --> 00:44:52,880
THEY COME FROM BATS AND WE

1156
00:44:52,880 --> 00:44:54,160
PROPOSE THESE BATS ORGANOIDS

1157
00:44:54,160 --> 00:44:57,320
WILL BE GREAT TO TBROA THESE

1158
00:44:57,320 --> 00:44:58,240
CORONAVIRUSS, BUT YES,

1159
00:44:58,240 --> 00:44:59,040
REGULATORY AUTHORITIES ARE VERY

1160
00:44:59,040 --> 00:45:01,640
MUCH AFRAID OF GREEN CELLING

1161
00:45:01,640 --> 00:45:02,840
ADDITIONAL SPECIES OF COROWN A

1162
00:45:02,840 --> 00:45:03,920
VIRUS IN THE LAB SO I DON'T

1163
00:45:03,920 --> 00:45:09,160
THINK THAT HAS BEEN FOLLOWED BY

1164
00:45:09,160 --> 00:45:09,880
[INDISCERNIBLE].

1165
00:45:09,880 --> 00:45:11,280
THIS STUDY HAS NOT BEEN

1166
00:45:11,280 --> 00:45:12,360
PUBLISHED BUT HERE WE ASK WHAT

1167
00:45:12,360 --> 00:45:16,440
ARE THE HOST GENES THAT ARE USED

1168
00:45:16,440 --> 00:45:17,200
BY THESE VIRUSES?

1169
00:45:17,200 --> 00:45:19,000
AND THERE WERE THEN ALREADY A

1170
00:45:19,000 --> 00:45:23,400
FEW PAPERS MOSTLY IN CELL WHERE

1171
00:45:23,400 --> 00:45:25,400
GENOME WIDE CRSPR HAD BEEN DONE,

1172
00:45:25,400 --> 00:45:28,080
THE LINES THAT HAD BEEN DONE,

1173
00:45:28,080 --> 00:45:30,640
AND MAYBE 50, 60 Gs HAVE BEEN

1174
00:45:30,640 --> 00:45:33,080
PROPOSED FOR THE VIRAL

1175
00:45:33,080 --> 00:45:34,160
INFECTIOUS CYCLE, ACE 2 I

1176
00:45:34,160 --> 00:45:35,520
MENTIONED IT, THE RECEPTOR THIS

1177
00:45:35,520 --> 00:45:37,760
WAS A CONTROL HERE SO WHAT WE DO

1178
00:45:37,760 --> 00:45:41,360
HERE AND WE DON'T DO BAR CODE,

1179
00:45:41,360 --> 00:45:44,400
TRANSFECTIONS WE BASICALLY GO

1180
00:45:44,400 --> 00:45:46,240
CLONE BY CLONE AND CANDIDATE

1181
00:45:46,240 --> 00:45:48,360
GENES SO THIS IS WITH A NUMBER

1182
00:45:48,360 --> 00:45:51,000
OF MUTANTS WE SEQUENCE THEM AND

1183
00:45:51,000 --> 00:45:52,680
CONFIRM THEY ARE NULLS AND WE

1184
00:45:52,680 --> 00:45:54,320
USE THEM AND THEN WIEWS WE USE

1185
00:45:54,320 --> 00:45:56,160
THEM AND AS YOU CAN SEE HERE,

1186
00:45:56,160 --> 00:45:58,840
COMPARED TO WILD TYPE, THEY CAN

1187
00:45:58,840 --> 00:46:01,280
NOT BE EFFECTED BY SARS 2, AND

1188
00:46:01,280 --> 00:46:03,480
THEY CANNOT BE INFECTED BY THE

1189
00:46:03,480 --> 00:46:05,200
ORIGINAL SARS VIRUS ABOUT THEY

1190
00:46:05,200 --> 00:46:09,360
ARE INFECTED BY A THIRD SPECIES

1191
00:46:09,360 --> 00:46:12,160
HERE RELATED TO SPECIES FIRST

1192
00:46:12,160 --> 00:46:14,680
AND CORONAVIRUS HAS BEEN AROUND

1193
00:46:14,680 --> 00:46:15,680
IN OTHER COUNTRIES AND APPEARS

1194
00:46:15,680 --> 00:46:18,280
TO BE JUMPING FROM CAMELS AND

1195
00:46:18,280 --> 00:46:22,080
HUMANS AND VERY FEW REPORT OF

1196
00:46:22,080 --> 00:46:23,680
THIS VIRUS JUMPS FROM HUMANS TO

1197
00:46:23,680 --> 00:46:24,400
HUMANS.

1198
00:46:24,400 --> 00:46:25,760
ONE THING WITH SARS-COV-2 IS

1199
00:46:25,760 --> 00:46:28,400
PEOPLE GET VERY SICK RIGHT AWAY

1200
00:46:28,400 --> 00:46:30,360
AND HIGH LEATH ALGORITHMSITY,

1201
00:46:30,360 --> 00:46:31,920
50% OR SO, BUT WE ALSO SEE THAT

1202
00:46:31,920 --> 00:46:33,640
THE CULTURE IS ESSENTIALLY THAT

1203
00:46:33,640 --> 00:46:36,880
IN 2 OR 3 DAYS, SO THE MOMENT

1204
00:46:36,880 --> 00:46:38,480
THE VIRUS STARTS PROPAGATING

1205
00:46:38,480 --> 00:46:41,600
ITSELF, IT KILLS THE CELLS AND

1206
00:46:41,600 --> 00:46:44,880
THAT'S MAYBE WHY MRS HAS NOT

1207
00:46:44,880 --> 00:46:46,560
SPREAD SO FAR COMPARED TO

1208
00:46:46,560 --> 00:46:48,840
SARS-COV-2.

1209
00:46:48,840 --> 00:46:50,280
SO THAT'S POSITIVE CONTROL.

1210
00:46:50,280 --> 00:46:51,360
ANOTHER CONTROL HERE IS KNOWN TO

1211
00:46:51,360 --> 00:46:53,680
BE THE RECEPTOR OF MERS, HAS

1212
00:46:53,680 --> 00:46:56,800
BEEN PROPOSED TO BE A RECEPTOR

1213
00:46:56,800 --> 00:46:58,800
FOR SARS-COV-2, HOWEVER WHEN WE

1214
00:46:58,800 --> 00:47:00,480
KNOCK OUT DP 4, THIS AFFECTS

1215
00:47:00,480 --> 00:47:01,920
HERE IN RED COMPARED TO GREEN

1216
00:47:01,920 --> 00:47:07,600
THE CONTROL, BUT NOW MERS, VIRUS

1217
00:47:07,600 --> 00:47:10,680
IS CONTROL AND THESE ARE PP4

1218
00:47:10,680 --> 00:47:12,520
CONTROL MUTANTS SO THIS CONNIRMS

1219
00:47:12,520 --> 00:47:15,440
CAN YOU READ OUT IN THESE MUTANT

1220
00:47:15,440 --> 00:47:19,480
ORGANOIDS WHAT THE VIRUS NEEDS

1221
00:47:19,480 --> 00:47:23,080
TO PROPAGATE AND STRESS THIS

1222
00:47:23,080 --> 00:47:23,880
PRIMARYY EPITHELIUM AND FIBRO

1223
00:47:23,880 --> 00:47:25,720
BLAST LIKE CELL LINE AND WE THEN

1224
00:47:25,720 --> 00:47:28,400
WENT THROUGH A LONG LIST OF

1225
00:47:28,400 --> 00:47:30,080
THESE PUBLISHED GENES AND MUCH

1226
00:47:30,080 --> 00:47:31,400
TO OUR SURPRISE NONE OF THESE

1227
00:47:31,400 --> 00:47:33,040
GAVE US A PHENOTYPE SO WE COULD

1228
00:47:33,040 --> 00:47:34,600
KNOCK OUT QUITE A FEW WITHOUT

1229
00:47:34,600 --> 00:47:40,600
ANY EFFECT OF A SINGLE GENE,

1230
00:47:40,600 --> 00:47:43,640
REALLY WELL STUDIED, TEMPRESS 2

1231
00:47:43,640 --> 00:47:45,480
IS A PROTEASE DOMAIN ON THE

1232
00:47:45,480 --> 00:47:46,720
OUTSIDE ON THE APICKAL SIDE OF

1233
00:47:46,720 --> 00:47:48,360
THE CELL, THIS IS KNOWN TO

1234
00:47:48,360 --> 00:47:50,360
CLEAVE THE SPIKE PROTEIN OF THE

1235
00:47:50,360 --> 00:47:52,520
VIRUS AND THEN ALLOWS FUSION OF

1236
00:47:52,520 --> 00:47:54,680
THE VIRAL MEMBRANE AND VIRAL

1237
00:47:54,680 --> 00:47:56,280
ENVELOPE WITH THE HOST CELL.

1238
00:47:56,280 --> 00:47:58,760
SO VIRUS KNOCK OUT, IT CANNOT

1239
00:47:58,760 --> 00:48:00,680
EFFECT, THIS IS THE RULE LINES

1240
00:48:00,680 --> 00:48:02,320
HERE, KNOCKED OUT OF THE

1241
00:48:02,320 --> 00:48:03,240
EXPRESSION OF EPITHELIAL

1242
00:48:03,240 --> 00:48:05,600
TISSUES, THEY HAVE NO EFFECT SO

1243
00:48:05,600 --> 00:48:08,600
WE WOULD CONCLUDE THAT TMPRSS2

1244
00:48:08,600 --> 00:48:12,120
WOULD BE A GREAT DRUG TARGET.

1245
00:48:12,120 --> 00:48:13,880
TMPRSS2 ARE 9 AS PUBLISHED SO IT

1246
00:48:13,880 --> 00:48:15,200
SHOULD BE SAFE AND JUST LAST

1247
00:48:15,200 --> 00:48:16,920
WEEK I THINK IS A PARTNERSHIP

1248
00:48:16,920 --> 00:48:18,160
THAT APPEAR INDEED BIOARCHIVES

1249
00:48:18,160 --> 00:48:22,040
WITH AN INHIBITOR OF THE TMPRS

1250
00:48:22,040 --> 00:48:24,160
PROTEASE BUT IT WILL NOT MUTATE

1251
00:48:24,160 --> 00:48:25,640
WHERE THE VIRUS STARTS TOGETHER

1252
00:48:25,640 --> 00:48:27,960
AROUND THE DRUG AND IT WAS SHOWN

1253
00:48:27,960 --> 00:48:29,760
TO BE EFFECTIVE BLOCKER OF VIRAL

1254
00:48:29,760 --> 00:48:32,080
INFECTION AND THIS WILL NOT ONLY

1255
00:48:32,080 --> 00:48:33,280
WORK FOR SARS-COV-2 BUT

1256
00:48:33,280 --> 00:48:35,760
HOPEFULLY IT WILL WORK FOR MANY

1257
00:48:35,760 --> 00:48:38,440
OTHER CORONAVIRUSS AND WE THINK

1258
00:48:38,440 --> 00:48:40,400
IT'S A FANTASTIC DRUG TARGET.

1259
00:48:40,400 --> 00:48:41,680
NONE OF THESE OTHERS REALLY

1260
00:48:41,680 --> 00:48:46,280
WORKED I DRAW YOUR TENSION TO

1261
00:48:46,280 --> 00:48:48,760
CTSL HERE IN PURPLE HERE, IT'S

1262
00:48:48,760 --> 00:48:50,400
THE PATHWAY THAT CAME UP IN MOST

1263
00:48:50,400 --> 00:48:52,480
OF THE SCREENS AND IT ENHANCES

1264
00:48:52,480 --> 00:48:53,480
ACTIVITY BILET VIRUS SO IT

1265
00:48:53,480 --> 00:48:56,280
DOESN'T BLOCK IT AT ALL.

1266
00:48:56,280 --> 00:48:59,200
QUITE SURPRISING AND THEN WE

1267
00:48:59,200 --> 00:49:00,880
REPEATED EXPERIMENTS FOR

1268
00:49:00,880 --> 00:49:03,720
LITERATURE, CHLOR O QUINN,

1269
00:49:03,720 --> 00:49:05,520
HYDROXYCHLOROQUINE WHEN USED ON

1270
00:49:05,520 --> 00:49:07,400
VOE 6 CELLS, WE USE THESE CELLS

1271
00:49:07,400 --> 00:49:11,760
IN THE SCREENS, AT LEAST IN MOST

1272
00:49:11,760 --> 00:49:13,440
OF THESE AND FANTASTIC INHIBITOR

1273
00:49:13,440 --> 00:49:15,720
OF VIRAL REP REPLICATION AND 1

1274
00:49:15,720 --> 00:49:17,520
MICROMOLAR WE REACHED IT AT 10

1275
00:49:17,520 --> 00:49:19,720
MICROMOLAR THERE ARE NO VIRAL

1276
00:49:19,720 --> 00:49:21,360
PROPAGATION IN THESE VERY 6

1277
00:49:21,360 --> 00:49:23,480
CELLS, LET ME KNOW, TAKE 10

1278
00:49:23,480 --> 00:49:25,160
MICROMOLAR IN THE PRIMEAR

1279
00:49:25,160 --> 00:49:26,840
EPITHELIAL STRUCTURE AS

1280
00:49:26,840 --> 00:49:28,400
ORGANIZATIONSONNOIDS HERE IN

1281
00:49:28,400 --> 00:49:29,120
BLUE AND DOES NOTHING.

1282
00:49:29,120 --> 00:49:30,920
NOW HOW DO WE PUT ALL THIS

1283
00:49:30,920 --> 00:49:32,320
TOGETHER, AND INTO A SINGLE

1284
00:49:32,320 --> 00:49:33,960
STORY, I SHOULD STRESS AGAIN WE

1285
00:49:33,960 --> 00:49:37,440
AREN'T THE ONLY 1S THAT POSE

1286
00:49:37,440 --> 00:49:39,320
THIS OR PAPERS THAT STAIM TIME

1287
00:49:39,320 --> 00:49:41,120
AS WE PROPOSE THIS SO WHAT

1288
00:49:41,120 --> 00:49:43,680
HAPPENS IN THESE WORK HORSE CELL

1289
00:49:43,680 --> 00:49:44,480
LINES, AS TYPICALLY MORE FIBRO

1290
00:49:44,480 --> 00:49:47,000
BLAST LIKE THE WAY THEY GROW,

1291
00:49:47,000 --> 00:49:49,360
THEY ARE DEFINITELY NOT LIKE

1292
00:49:49,360 --> 00:49:50,800
EPITHELIA, AND THEY DON'T

1293
00:49:50,800 --> 00:49:52,280
EXPRESS ACE 2 SO YOU NEED TO

1294
00:49:52,280 --> 00:49:54,520
TRANSFECT ACE 2 TO MAKE THEM

1295
00:49:54,520 --> 00:49:56,600
SENSITIVE TO THE VIRUS, THEY CAN

1296
00:49:56,600 --> 00:49:58,480
THEN BIND THE ENDOSIGNIFYITOSE

1297
00:49:58,480 --> 00:49:59,720
AND THIS ENDOSIGNIFYITOSEIS STEP

1298
00:49:59,720 --> 00:50:02,840
IS ARE READILY BLOCKABLE BY

1299
00:50:02,840 --> 00:50:03,760
HYDROXYCHLOROQUINE, THAT'S ALSO

1300
00:50:03,760 --> 00:50:05,520
HOW IT WORKS ALSO IN MALARIA AND

1301
00:50:05,520 --> 00:50:06,960
THEN TO RELEASE THE VIRUS FROM

1302
00:50:06,960 --> 00:50:07,560
THE ENDOSTUDIES OF MULTIPLE

1303
00:50:07,560 --> 00:50:09,520
ENDOCRINE THIS IS WHERE THEY'RE

1304
00:50:09,520 --> 00:50:12,080
CALLED IN SO IT'S NO WONDER THAT

1305
00:50:12,080 --> 00:50:14,040
THIS IS LIKE CONCEPTIONS CAME UP

1306
00:50:14,040 --> 00:50:17,200
IN THE WIDE SCREENS, WHAT

1307
00:50:17,200 --> 00:50:17,880
HAPPENS IN PRIMARY EPITHELIA,

1308
00:50:17,880 --> 00:50:19,800
THIS WOULD BE THE ACHE PICKA

1309
00:50:19,800 --> 00:50:23,160
SIDE OF EPITHELIUM, ACE 2 IS

1310
00:50:23,160 --> 00:50:24,520
NATURALLY EXPRESSED, TMPRSS2 IS

1311
00:50:24,520 --> 00:50:25,640
EXPRESSED ON THE APICKA

1312
00:50:25,640 --> 00:50:29,280
MEMBRANE, THE VIRUS BINDS TO ACE

1313
00:50:29,280 --> 00:50:31,440
2, TMPRSS2 ACTIVATES BY PROTEASE

1314
00:50:31,440 --> 00:50:33,080
CLEAVAGE DESPITE THAT SITS ON

1315
00:50:33,080 --> 00:50:34,560
THE OUTSIDE OF THE CORONAVIRUS

1316
00:50:34,560 --> 00:50:37,280
AND NOW, THE VIRUS DIRECTLY

1317
00:50:37,280 --> 00:50:38,680
FUSES IT'S ENVELOPE WITH THE

1318
00:50:38,680 --> 00:50:40,160
HOST CELL MEMBRANE AND CAN

1319
00:50:40,160 --> 00:50:41,600
INJECT THE RNA MOLECULES

1320
00:50:41,600 --> 00:50:42,480
STRAIGHT INTO THE CYTOPLASM OF

1321
00:50:42,480 --> 00:50:43,920
THE CELL.

1322
00:50:43,920 --> 00:50:45,480
THIS DOES NOT INVOLVE

1323
00:50:45,480 --> 00:50:47,200
ENDOSIGNIFYITOSEIS SO THERE IS

1324
00:50:47,200 --> 00:50:48,480
NO SENSITIVITY TO HYDROXY LORA

1325
00:50:48,480 --> 00:50:51,000
RODRIGUEZ CLOA QUINN AND NO

1326
00:50:51,000 --> 00:50:51,480
REASON WHY TRANSLATIONAL

1327
00:50:51,480 --> 00:50:53,400
RESEARCH TRANSITION SHOULD BE

1328
00:50:53,400 --> 00:50:54,440
INVOLVED IN THIS STEP.

1329
00:50:54,440 --> 00:50:55,240
THAT'S WAY FIND.

1330
00:50:55,240 --> 00:50:55,680
THEY ARE NOT THERE.

1331
00:50:55,680 --> 00:50:57,760
SO FROM THIS WE WERE ABLE TO

1332
00:50:57,760 --> 00:51:00,080
DEDUCE THAT IT'S PROBABLY A GOOD

1333
00:51:00,080 --> 00:51:02,520
IDEA IF 1 DOES NO SCREENS,

1334
00:51:02,520 --> 00:51:05,560
HITHROUGH PUT SCREENS, IN EASY

1335
00:51:05,560 --> 00:51:07,320
CELL LINES, EASY TO WORK WITH,

1336
00:51:07,320 --> 00:51:09,080
THE HITS MAYBE WOULD BE GOOD TO

1337
00:51:09,080 --> 00:51:13,080
ALSO CONFIRM IN TISSUES THAT ARE

1338
00:51:13,080 --> 00:51:14,280
MORE CLOSE TO PRIMARY EPITHELIUM

1339
00:51:14,280 --> 00:51:19,080
IN THIS CASE, SUCH AS AIR WAY OR

1340
00:51:19,080 --> 00:51:20,480
GUT ORGANOIDS AND AGAIN, VIRUSES

1341
00:51:20,480 --> 00:51:23,520
THAT ENTER THE AIR WAYS OR

1342
00:51:23,520 --> 00:51:24,280
INTESTINAL TRACT, IT WILL ALWAYS

1343
00:51:24,280 --> 00:51:26,080
COME IN THROUGH THE APICKA SIDE,

1344
00:51:26,080 --> 00:51:27,880
SO THERE WE BELIEVE THE THESE

1345
00:51:27,880 --> 00:51:30,200
ARE SUITED BECAUSE CAN YOU

1346
00:51:30,200 --> 00:51:31,560
INJECT YOUR, WHATEVER AGENT INTO

1347
00:51:31,560 --> 00:51:33,200
THE LUMENS OF THE ORGANIZATIONS

1348
00:51:33,200 --> 00:51:34,280
KNOWOIDS IT WOULD BE HERE AND

1349
00:51:34,280 --> 00:51:36,280
YOU CAN GROW THEM WHEN THEY'RE

1350
00:51:36,280 --> 00:51:37,520
EXPAND INDEED 2 D IF YOU KEEP

1351
00:51:37,520 --> 00:51:38,960
THEM FOR A FEW WEEKS AND THEN

1352
00:51:38,960 --> 00:51:42,120
JUST ADD WHATEVER YOU WANT TO

1353
00:51:42,120 --> 00:51:43,880
ADD ON THE TOP SIDE OF THE

1354
00:51:43,880 --> 00:51:46,360
CULTURE ON THE APICKA SIDE AND

1355
00:51:46,360 --> 00:51:47,720
ANS WELL, FLIPPING AROUND FOR

1356
00:51:47,720 --> 00:51:50,080
THE BASAL SIDE OF THE EPITHELIUM

1357
00:51:50,080 --> 00:51:51,880
AND WITH THAT I REACH THE END OF

1358
00:51:51,880 --> 00:51:52,240
MY TALK.

1359
00:51:52,240 --> 00:51:54,520
I BELIEVE MENTIONED ALL OUR

1360
00:51:54,520 --> 00:51:55,600
COLLABORATORS DURING THE TALK SO

1361
00:51:55,600 --> 00:51:59,280
I WILL STOP SHARE AND I HOPE I

1362
00:51:59,280 --> 00:52:11,760
LEFT TIME FOR Q ANDA.

1363
00:52:11,760 --> 00:52:13,960
>> GREAT, THANKS, HANS, THAT WAS

1364
00:52:13,960 --> 00:52:15,800
GREAT PRESENTATION TO TALK ABOUT

1365
00:52:15,800 --> 00:52:17,640
ORGANOIDS TO MIMIC HUMAN TISSUE

1366
00:52:17,640 --> 00:52:18,680
TO STUDY HUMAN DISEASE.

1367
00:52:18,680 --> 00:52:22,160
VERY INTERESTING, THERE ARE A

1368
00:52:22,160 --> 00:52:24,000
FEW QUESTIONS AND MAYBE I WILL

1369
00:52:24,000 --> 00:52:24,880
TAKE THE FIRST.

1370
00:52:24,880 --> 00:52:28,480
IF I UNDERSTOOD CORRECTLY, I

1371
00:52:28,480 --> 00:52:31,720
THINK THAT YOUR CULTURE OF FETAL

1372
00:52:31,720 --> 00:52:33,640
VERSUS ADULT LIVER, ARE REALLY

1373
00:52:33,640 --> 00:52:38,360
MIMICKING THE AGING PROCESS,

1374
00:52:38,360 --> 00:52:41,240
SO--SO HAVE YOU AN INVITRO

1375
00:52:41,240 --> 00:52:42,320
[INDISCERNIBLE] THERE THAT

1376
00:52:42,320 --> 00:52:43,720
HOPEFULLY IS ACCURATE AND I'M

1377
00:52:43,720 --> 00:52:46,520
WONDER FIGURE YOU ANALYZED IT,

1378
00:52:46,520 --> 00:52:49,520
IS IT TELOMERE EROSION,

1379
00:52:49,520 --> 00:52:50,040
EPIGENETIC DIFFERENCES?

1380
00:52:50,040 --> 00:52:52,080
DO YOU KNOW WHAT'S GOING ON?

1381
00:52:52,080 --> 00:52:53,880
>> YEAH, SO, ACTUALLY WE DID A

1382
00:52:53,880 --> 00:52:56,960
LOT OF--ALL SORTS OF GENOMICS

1383
00:52:56,960 --> 00:52:58,640
BUT THE PRINCIPLE OBSERVATION

1384
00:52:58,640 --> 00:52:59,640
THAT THE THALAMUS WERE WORKING

1385
00:52:59,640 --> 00:53:01,320
AND WE DON'T SEE THAT IN MOST

1386
00:53:01,320 --> 00:53:03,080
OTHER CULTURE SO FOR INSTANCE

1387
00:53:03,080 --> 00:53:04,400
DIRT IS HIGHLY EXPRESSED IN OUR

1388
00:53:04,400 --> 00:53:05,280
GUT ORGANIZATIONSONNOIDS BUT IN

1389
00:53:05,280 --> 00:53:07,240
THE LIVER IT'S LIMITING THING,

1390
00:53:07,240 --> 00:53:10,600
ALSO IN LIVER CANCERS, IT'S

1391
00:53:10,600 --> 00:53:11,360
ACTIVATING MUTATIONS ARE QUITE

1392
00:53:11,360 --> 00:53:13,240
COMMON, SO IT LOOKS LIKE IN THE

1393
00:53:13,240 --> 00:53:14,880
LIVER, IF YOU WANT TO

1394
00:53:14,880 --> 00:53:17,680
PROLIFERATE, YOU NEED TO DO

1395
00:53:17,680 --> 00:53:18,560
SOMETHING ABOUT YOUR

1396
00:53:18,560 --> 00:53:20,120
[INDISCERNIBLE], WE CAN OVER

1397
00:53:20,120 --> 00:53:24,800
COME IT NOTEB ENTIRELY BUT BY

1398
00:53:24,800 --> 00:53:26,240
DERT, EXPRESSION AND BY

1399
00:53:26,240 --> 00:53:28,680
TRANSVEKS OF DERT, AND YOU SEE

1400
00:53:28,680 --> 00:53:30,280
THE TYPICAL SENESCENSEL AND THEN

1401
00:53:30,280 --> 00:53:32,120
P16 COME UP AND IT LOOKS LIKE

1402
00:53:32,120 --> 00:53:33,000
CLASSIC SEN ILLEGALSEN CESS

1403
00:53:33,000 --> 00:53:36,400
ENSEL WHICH WE NEVER SEE IN

1404
00:53:36,400 --> 00:53:37,120
OTHER, STILL WE DON'T KNOW

1405
00:53:37,120 --> 00:53:39,200
WHETHER IT'S LACK OF 1 GROWTH

1406
00:53:39,200 --> 00:53:40,800
FACTOR THAT WOULD SOLVE THIS OR

1407
00:53:40,800 --> 00:53:45,400
WHETHER IT'S SORT OF BAKED IN

1408
00:53:45,400 --> 00:53:45,800
THE LIVER.

1409
00:53:45,800 --> 00:53:47,560
BUT THE FETAL LIVER INDEED, BUT

1410
00:53:47,560 --> 00:53:48,800
MANY SAMPLES WE CAN GROW FOR

1411
00:53:48,800 --> 00:53:51,160
YEARS THEY LOOK IF THEY DO RNA

1412
00:53:51,160 --> 00:53:55,160
SEQ, THEY ARE ALMOST IDENTICAL

1413
00:53:55,160 --> 00:53:56,920
TO THE ADULT LIVERS, SOME

1414
00:53:56,920 --> 00:53:59,520
CYTOCHROMES MAY NOT BE AT THE

1415
00:53:59,520 --> 00:54:01,480
ADULT LEVEL, YOU PLAY AROUND

1416
00:54:01,480 --> 00:54:03,280
WITH GROWTH FACTOR CONDITIONS

1417
00:54:03,280 --> 00:54:04,400
AND THERE'S 1 BIG DIFFERENCE

1418
00:54:04,400 --> 00:54:06,560
WHERE THEY WILL GROW FOREVER AND

1419
00:54:06,560 --> 00:54:06,960
THE ADULLS DON'T.

1420
00:54:06,960 --> 00:54:09,560
>> YEAH, THAT'S REALLY

1421
00:54:09,560 --> 00:54:12,640
INTERESTING, PROSTATE ACTUALLY

1422
00:54:12,640 --> 00:54:20,000
SENESCS AS WELL, SO THERE ARE A

1423
00:54:20,000 --> 00:54:20,720
FEW QUESTIONS HERE,

1424
00:54:20,720 --> 00:54:23,480
[INDISCERNIBLE] HAD A QUESTION

1425
00:54:23,480 --> 00:54:24,680
ABOUT THE BOWEL REPAIR

1426
00:54:24,680 --> 00:54:26,360
EXPERIMENTS AND SHE'S WONDERING

1427
00:54:26,360 --> 00:54:27,920
ABOUT THE PLASTICITY OF THE STEM

1428
00:54:27,920 --> 00:54:29,080
CELLS IN THE GUT SO IF YOU WERE

1429
00:54:29,080 --> 00:54:31,680
TO USE STEM CELLS FROM

1430
00:54:31,680 --> 00:54:33,800
ESOPHAGUS, GASTRIC, SMALL,

1431
00:54:33,800 --> 00:54:35,920
LARGE, BOWEL, WHAT WOULD YOU

1432
00:54:35,920 --> 00:54:36,360
EXPECT?

1433
00:54:36,360 --> 00:54:38,200
>> THAT'S A VERY GOOD QUESTION.

1434
00:54:38,200 --> 00:54:40,400
ACTUALLY, SO THERE ARE MY FORMER

1435
00:54:40,400 --> 00:54:42,600
POST DOC WHO ESSENTIALLY

1436
00:54:42,600 --> 00:54:43,480
DEVELOPED ORGANIZATIONSONNOID

1437
00:54:43,480 --> 00:54:45,240
TECHNOLOGY IN MY LAB, IN HIS OWN

1438
00:54:45,240 --> 00:54:47,120
LAB HAS DONE A LOT OF

1439
00:54:47,120 --> 00:54:50,840
TRANSPLANTS AND WHAT HE FINDS IN

1440
00:54:50,840 --> 00:54:52,280
ESSENCE IS THAT SO ONCE THE

1441
00:54:52,280 --> 00:54:54,320
TISSUES ARE ESTABLISHED, SO IF

1442
00:54:54,320 --> 00:54:55,720
YOU TAKE SAMPLES LATE FETAL OR

1443
00:54:55,720 --> 00:54:57,080
ADULT, THEY KNOW WHAT THEY ARE

1444
00:54:57,080 --> 00:54:58,880
AND YOU CANNOT CHANGE THAT FATE.

1445
00:54:58,880 --> 00:55:01,680
SO THEY CAN ACTUALLY--STEM CELLS

1446
00:55:01,680 --> 00:55:02,400
CAN [INDISCERNIBLE] AND THAT I

1447
00:55:02,400 --> 00:55:04,000
CAN MOVE BACK AND FORTH SO

1448
00:55:04,000 --> 00:55:05,040
THERE'S PLASTICITY IN THE

1449
00:55:05,040 --> 00:55:10,600
LINEAGE BUT IF YOU TRANSPLANT A

1450
00:55:10,600 --> 00:55:13,800
SMALL--I SHOULD SAY, YEAH, A

1451
00:55:13,800 --> 00:55:15,440
SMALL INTESTINAL ORGANOID TO

1452
00:55:15,440 --> 00:55:16,800
COLON IT DOESN'T HAVE VILLI, IT

1453
00:55:16,800 --> 00:55:18,640
DOESN'T HAVE THE CELLS YOU WILL

1454
00:55:18,640 --> 00:55:21,880
GET THE COLON WITH VILLI AND

1455
00:55:21,880 --> 00:55:23,280
CELLS, THERE'S A BEAUTIFUL

1456
00:55:23,280 --> 00:55:26,080
NATURE RECENTLY WHERE IT SHOWS

1457
00:55:26,080 --> 00:55:28,400
SORT BOWEL DISEASE WHICH IS A

1458
00:55:28,400 --> 00:55:29,520
TERRIBLEIN SYNDROME OF INFANTS

1459
00:55:29,520 --> 00:55:31,600
WHEN THEY LOSE A LARGE PART OF

1460
00:55:31,600 --> 00:55:33,000
THE SMALL INTESTINE, THE COLON

1461
00:55:33,000 --> 00:55:34,840
IS FINE BAH IT DOESN'T HELP BUT

1462
00:55:34,840 --> 00:55:36,440
THE SMALL INTESTINE IS WHERE YOU

1463
00:55:36,440 --> 00:55:37,720
ABSORB THE NUCLEOTIDES T-REGENTS

1464
00:55:37,720 --> 00:55:40,800
AND IT IN IT CASE IT ONLY

1465
00:55:40,800 --> 00:55:42,240
ABSORBS WATER, SO HE CONVERTED

1466
00:55:42,240 --> 00:55:43,680
COLON INTO SMALL INTESTINE AND

1467
00:55:43,680 --> 00:55:45,560
THIS WAS DONE IN ANIMALS AND WE

1468
00:55:45,560 --> 00:55:46,880
HOPE TO DO THIS IN THE BABIES

1469
00:55:46,880 --> 00:55:49,520
AND YOU TAKE PART OF THE COLON,

1470
00:55:49,520 --> 00:55:52,080
STRIP THE EPITHELIUM OFF, SEED

1471
00:55:52,080 --> 00:55:54,400
IT WITH SMALL INTESTINAL

1472
00:55:54,400 --> 00:55:55,280
ORGANOIDS AND BEING BE GROWN

1473
00:55:55,280 --> 00:55:59,760
FROM THE PATIENT YOU ARE

1474
00:55:59,760 --> 00:56:00,320
TRANSPLANTING INVITRO AND

1475
00:56:00,320 --> 00:56:00,960
THOUGH--SO FIRST HE CREATES A

1476
00:56:00,960 --> 00:56:02,200
LOOP WITH 2 ENDS ON THE OUTSIDE

1477
00:56:02,200 --> 00:56:04,680
THROUGH THE SKIN AND THEN YOU

1478
00:56:04,680 --> 00:56:06,360
HAVE MANIPULATE THE COLON SO

1479
00:56:06,360 --> 00:56:08,320
THEN IT'S SEEDED WITH THE SMALL

1480
00:56:08,320 --> 00:56:09,240
INTESTINAL EPITHELIUM, HE TAKES

1481
00:56:09,240 --> 00:56:12,160
THAT LOOP AND PLACES IT IN THE

1482
00:56:12,160 --> 00:56:16,280
SMALL INTESTINAL TRACT AND THEN

1483
00:56:16,280 --> 00:56:17,920
IT WORKS.

1484
00:56:17,920 --> 00:56:18,240
>> WOW.

1485
00:56:18,240 --> 00:56:20,360
>> SO DEVELOPMENTAL BIOLOGY

1486
00:56:20,360 --> 00:56:23,560
EXPERIMENTS WHERE IT'S THE

1487
00:56:23,560 --> 00:56:24,160
SUBEPITHELIAL STRUCTURES, BUT

1488
00:56:24,160 --> 00:56:26,440
APPARENTLY LATER IN LIFE, SO

1489
00:56:26,440 --> 00:56:29,240
ONCE THEY HAVE THEIR FATE, YOU

1490
00:56:29,240 --> 00:56:30,120
CANNOT MOVE THEM.

1491
00:56:30,120 --> 00:56:32,480
YOU CAN NOT TURN STOMACH INTO

1492
00:56:32,480 --> 00:56:34,160
NAWL INTESTINE AND THE LENGTH OF

1493
00:56:34,160 --> 00:56:35,160
THE SMALL INTESTINES THERE ARE

1494
00:56:35,160 --> 00:56:35,960
REGIONS THAT ARE QUITE DIFFERENT

1495
00:56:35,960 --> 00:56:37,920
IN WHAT THEY TAKE UP, THEY KNOW

1496
00:56:37,920 --> 00:56:40,560
WHAT THEY ARE, AND EVEN AFTER

1497
00:56:40,560 --> 00:56:44,280
HERE IN CULTURE, THEY ARE STILL

1498
00:56:44,280 --> 00:56:45,840
ILIUM OR JUJUNUM, OR TRANSPLANT

1499
00:56:45,840 --> 00:56:47,000
THEM, THAT'S WHAT THEY MAKE.

1500
00:56:47,000 --> 00:56:52,000
>> WELL IN SOME WAYS THAT MAKES

1501
00:56:52,000 --> 00:56:53,000
THE SYSTEM, GIVES YOU CONFIDENCE

1502
00:56:53,000 --> 00:56:55,280
THAT YOU'RE LOOKING AT THE RIGHT

1503
00:56:55,280 --> 00:56:56,920
THING WHEN YOU DEVELOP THESE

1504
00:56:56,920 --> 00:56:59,560
ORGANOIDS TO MIMIC THE TISSUE,

1505
00:56:59,560 --> 00:57:01,480
IT'S VERY DIFFERENT FROM IPS

1506
00:57:01,480 --> 00:57:03,560
CELLS WHERE YOU PUSH THEM IN ANY

1507
00:57:03,560 --> 00:57:05,920
DIRECTION AND THE IPS GUT

1508
00:57:05,920 --> 00:57:09,120
ORGANOIDS TEND TO BE A MIX OF

1509
00:57:09,120 --> 00:57:11,080
THE DIFFERENT AREAS.

1510
00:57:11,080 --> 00:57:12,160
>> YEAH, ABSOLUTELY.

1511
00:57:12,160 --> 00:57:13,800
YEAH, OKAY, THERE IS A QUESTION

1512
00:57:13,800 --> 00:57:15,840
FROM JIM FLEET, HE SAYS, OTHERS

1513
00:57:15,840 --> 00:57:18,000
HAVE NOW SHOWN THAT TRADITIONAL

1514
00:57:18,000 --> 00:57:18,920
CULTURING OF INTESTINAL

1515
00:57:18,920 --> 00:57:22,400
ORGANOIDS LEADS TO MANY MORE

1516
00:57:22,400 --> 00:57:23,360
MUTATIONS FROMOXIDATIVE STRESS

1517
00:57:23,360 --> 00:57:25,360
THAN WHAT 1 SEES INVIVO.

1518
00:57:25,360 --> 00:57:29,200
HAVE YOU CULTURED ORGANOIDS IN A

1519
00:57:29,200 --> 00:57:30,760
RELATIVE HIGHWAY POXIC--IN

1520
00:57:30,760 --> 00:57:34,160
RELATIVE HIPOXIC ENVIRONMENT TO

1521
00:57:34,160 --> 00:57:34,880
MIMIC NORMAL PHYSIOLOGY.

1522
00:57:34,880 --> 00:57:38,360
>> THIS WAS SHOWN BY OUR

1523
00:57:38,360 --> 00:57:39,360
COLLABORATORS, AND SOME OTHER

1524
00:57:39,360 --> 00:57:40,520
LABS SHOWING THIS, THE

1525
00:57:40,520 --> 00:57:43,760
MUTATIONAL RATE IS 4 OR TIMES

1526
00:57:43,760 --> 00:57:44,480
HYPER AND INVIVO, INVIVO

1527
00:57:44,480 --> 00:57:46,760
ACTUALLY COULD USE THIS

1528
00:57:46,760 --> 00:57:49,280
TECHNOLOGY TO SHOW THAT A GUT

1529
00:57:49,280 --> 00:57:51,880
STEM CELL IN HUMANS SUSTAINED

1530
00:57:51,880 --> 00:57:53,160
ABOUT 40 SINGLE BASE CHANGES PER

1531
00:57:53,160 --> 00:57:56,760
YEAR OF LIFE SO 1 PER WEEK.

1532
00:57:56,760 --> 00:57:59,160
AND IT'S LINEAR THROUGHOUT LIFE.

1533
00:57:59,160 --> 00:58:00,480
LIVER THE SAME THING ALTHOUGH

1534
00:58:00,480 --> 00:58:01,800
THE CELLS DON'T DIVIDE MUCH,

1535
00:58:01,800 --> 00:58:03,520
ALSO ABOUT 1 PER WEEK, IT'S

1536
00:58:03,520 --> 00:58:06,120
SIGNIFICANTLY HIGHER IN CULTURE,

1537
00:58:06,120 --> 00:58:09,120
YEAH, WE'VE WORKED WITH OXYGEN

1538
00:58:09,120 --> 00:58:11,600
SCAVENGERS SO LOW OXYGEN AND SO

1539
00:58:11,600 --> 00:58:14,040
LOW EXGEN IS MUTATIONS BUT ALSO

1540
00:58:14,040 --> 00:58:15,080
GROWS SLOWER SO PEOPLE THAT

1541
00:58:15,080 --> 00:58:19,800
BELIEVE THAT STEM CELLS LIKE

1542
00:58:19,800 --> 00:58:20,560
HIPOXIC CONDITIONS AND IT IS

1543
00:58:20,560 --> 00:58:21,680
TRUE THAT SUSTAINED FOR THE

1544
00:58:21,680 --> 00:58:24,520
MUTATIONS BUT ALSO IF THEY

1545
00:58:24,520 --> 00:58:26,080
UNDERGO, IF YOU CALCULATE, YOU

1546
00:58:26,080 --> 00:58:27,920
DON'T WIN, BECAUSE THEY GROWTH

1547
00:58:27,920 --> 00:58:29,000
FACTOR SLOWER AND THEY HAVE TO

1548
00:58:29,000 --> 00:58:30,960
GROW LONGER AND THEY HAVE THOSE

1549
00:58:30,960 --> 00:58:33,280
MUTATIONS BUT IT'S CLEAR THAT

1550
00:58:33,280 --> 00:58:34,160
OUR--THE CULTURAL ENVIRONMENT IS

1551
00:58:34,160 --> 00:58:36,520
MORE MORPH O GENIC THAN WHAT

1552
00:58:36,520 --> 00:58:39,920
THEY SUSTAIN AND REAL LIFE,

1553
00:58:39,920 --> 00:58:40,200
YEAH.

1554
00:58:40,200 --> 00:58:41,440
>> GOOD AND THEN THERE ARE

1555
00:58:41,440 --> 00:58:43,720
MULTIPLE MESSAGES ABOUT WHAT A

1556
00:58:43,720 --> 00:58:44,960
WONDERFUL AND INFORMATIVE TALK

1557
00:58:44,960 --> 00:58:46,760
IT WAS AND SIGNIFICANT AND THANK

1558
00:58:46,760 --> 00:58:49,400
YOU, THANK YOU, THANK YOU, SO I

1559
00:58:49,400 --> 00:58:52,080
YOU WILL PROBABLY BE ABLE TO SEE

1560
00:58:52,080 --> 00:58:52,400
THOSE.

1561
00:58:52,400 --> 00:58:54,160
SO I--YOU KNOW I KNOW IT'S

1562
00:58:54,160 --> 00:58:55,120
10:00 P.M., THERE, I FEEL LIKE

1563
00:58:55,120 --> 00:58:57,720
WE SHOULD LET YOU GO, BUT I

1564
00:58:57,720 --> 00:58:58,840
WOULD JUST LIKE TO THANK YOU

1565
00:58:58,840 --> 00:58:59,760
AGAIN.

1566
00:58:59,760 --> 00:59:01,760
IT WAS A WONDERFUL PRESENTATION.

1567
00:59:01,760 --> 00:59:02,160
>> OKAY.

1568
00:59:02,160 --> 00:59:04,160
>> WE ALL LEARNED A LOT.

1569
00:59:04,160 --> 00:59:07,760
>> WELL, THANKS TO ALL FOR

1570
00:59:07,760 --> 00:59:08,040
LISTENING.

1571
00:59:08,040 --> 00:00:00,000
AND GOOD REST OF THE DAY DAY.