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WELCOME, EVERYBODY.

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I'M DAN GALLAHAN THE DIRECTOR OF

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THE DIVISION OF CANCER BIOLOGY.

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ONE OF THE FOUR MAJOR EXTRAMURAL

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DIVISIONS WITHIN THE NCI.

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ON BEHALF OF MYSELF, OUR 

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DIRECTOR, MONICA BERTAGNOLLI WHO

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WILL REMAIN OUR DIRECTOR FOR A 

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WHILE AND THANK YOU FOR 

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ATTENDING HERE AND VIRTUALLY.

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I THINK THIS IS AN EXCITING 

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MEETING.

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I'M GLAD YOU CAN MAKE IT AND 

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GIVE THESE OPENING REMARKS.

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I WASN'T SO SURE.

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IT WASN'T THE FACT THAT I WAS IN

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IRELAND YESTERDAY.

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IT WAS THE FACT I WAS ON 270 FOR

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THOSE LOCAL THIS MORNING AND 

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THERE WAS A LOT OF TRAFFIC BUT 

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PERSEVERED.

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SO ANYWAY, I WANT TO AND I'LL 

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THANK ANDY FEINBERG FOR SETTING 

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THE FIELD FOR THIS AND ALLOWING 

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US TO COME TOGETHER IN THE 

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MEETING AND THE ORGANIZATION OF 

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THAT.

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WHAT I'D LIKE TO DO I ALREADY 

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WELCOMED EVERYBODY AND THANK YOU

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FOR ATTENDING.

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I THINK IN AN AREA THAT I THINK 

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HAS HAD GREAT IMPACT ALREADY AND

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I THINK IS GOING TO REMAIN TO 

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HAVE IMPACT AND I THINK THE MORE

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MEETINGS LIKE THIS WILL BRING IT

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MORE FROM UNDERSTANDING OF 

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EPIGENETICS AND EPIGENETICS TO 

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TRANSLATIONAL DRUGS.

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A YEAR AGO WE FINISHED A 50 YEAR

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ANNIVERSARY FOR THE NCI.

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THAT MARK WHERE WE ACHIEVED A 

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LOT BUT AN A LOT WELL STILL TO 

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BE DONE.

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AT THAT TIME I REMEMBER IN TERMS

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OF WHERE WE WERE AT AND I WAS 

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THERE AND LET US IN THE 

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MOLECULAR AGE COME WOULD CALL IT

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WHERE WE ARE STUDYING NOW AND 

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IDENTIFY GENES.

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AND ABLE TO HAVE DISCOVERY OF ON

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CA GENES AND TUMOR SUPPRESSER 

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GENES LEADING TO PERSONALIZED 

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MEDICINE WHERE THERE WAS A 

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COMMON DOGMA AT THE TIME FOR 

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CANCER WHERE WE HAD ONE GENE 

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ABERRATION, ONE CELL TRANSFORMED

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AND THAT WAS CANCER AND IF WE 

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COULD CURE THAT, IF WE COULD 

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TREAT THAT OR ANY OTHER WAY 

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TREAT THAT MUTATION AND THAT 

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CELL WE COULD CURE CANCER.

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AND OBVIOUSLY IT WASN'T THAT 

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SIMPLE.

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WE LEARNED THERE'S THE TUMOR 

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ENVIRONMENT GROWING FROM ONE 

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CELL TO A SYSTEM AND THE MODERN 

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ERA BROUGHT IN NEW TECHNOLOGIES 

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AND ALSO GAVE US NEW INSIGHT AND

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ALONG THIS PATH WE UNDERSTOOD 

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THAT IT WASN'T JUST SOMATIC AND 

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GERM LINE MUTATIONS BUT 

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EPIGENETICS AND OTHER 

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CONTROLLING EVENTS AND GENES WE 

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HAD TO PAY ATTENTION TO AS WE 

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WENT ALONG.

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AT THE START OF THIS AND THIS 

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COINCIDES WITH THE 40 YEARS AND 

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ANDY FEINBERG OBSERVED THERE WAS

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IN CERTAIN TUMORS THEY SAW A 

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CASE OF HYPOMETHYLATION AND 

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THERE WERE FOUR PAPERS 

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ASSOCIATION PAPERS IN 1983 HERE.

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THERE WAS ANOTHER PAPER THEY 

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REFERENCED IN THAT PAPER THAT 

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SPOKE TO HYPOMETHYLATION -- I 

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THINK SOMEONE'S SUPPOSED TO BE 

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MUTING.

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ANYWAY, SO ANYWAY, THIS SORT OF 

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BROUGHT EVERYONE'S ATTENTION TO 

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THE FACT THAT A FIELD OF 

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EPIGENETICS IN CANCER WOULD BE 

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FOREVER WEDDED TOGETHER 

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OBVIOUSLY, THAT SLIDE EVERYONE 

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SEES AND WE SEE IN PUB MED, I 

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DON'T KNOW, I CUT OFF THE Y 

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AXIS.

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THERE WERE A LOT OF PUBLICATIONS

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THAT EMANATED FROM THIS FIELD 

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DURING THIS PERIOD WHERE THE 

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STUDY OF HERITABLE CHANGES AND 

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GENE EXPRESSION OCCURRED 

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INDEPENDENT OF THE PRIMARY DNA 

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CONSEQUENCE AND STOOD IN THE 

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FACE OF CENTRAL DOGMA AND MADE 

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IT MORE COMPLICATED BUT AS 

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BIOLOGY IS COMPLICATED THERE'S 

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ALWAYS -- THE WAY I LOOK AT IT 

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THERE'S NEW OPPORTUNITIES FOR 

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NOT ONLY UNDERSTANDING BUT 

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TREATING THE DISEASE.

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THIS IS FROM A REVIEW SHOWING 

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GENETIC MUTATIONS AND MODIFIERS 

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IN CANCER AND SPECIFIC GENES ARE

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AFFECTING -- CAN AFFECT CERTAIN 

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PROCESSES CRITICAL IN CANCER.

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EACH ONE OF THESE.

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I HAD ANOTHER VERSION OF THE 

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SLIDE AND HALLMARKS OF CANCER IN

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THE MIDDLE OF THIS BECAUSE I 

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THINK IT CAN AFFECT ALL THOSE 

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THINGS.

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THE VERSION DIDN'T MAKE IT OUT 

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OF IRELAND.

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SO ANYWAY, I THINK AS WE GO 

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FORWARD WE'RE INTO THE PHRASE 

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AND WE ALWAYS HAVE BEEN TO A 

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CERTAIN EXTENT OF TRANSLATIONAL 

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EFFORTS FROM EARLY USE OF DNA 

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METHYLATION AND LOOKING AT THE 

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HVAV INHIBITORS.

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THIS LED US TO NOT ONLY DIRECTLY

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BUT NOW AS A WAY USING THE 

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ADVANTAGE OF EPIGENETIC CONTROL 

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TO TRY TO DRUG WHAT WE 

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CONSIDERED AT THE TIME 

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UNDRUGGABLE PRODUCT AND HAVE 

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EPIGENETIC THERAPIES AND IT'S AN

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AREA WE PUT GREAT HOPE IN IN 

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TERMS OF WHAT WE'LL BE ABLE TO 

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DO IN THE FUTURE AS WE 

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UNDERSTAND MORE OF THE PROCESSES

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INVOLVED.

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IN IRELAND I MENTIONED ABOUT 

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SYSTEMS BIOLOGY IN CANCER.

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THE HTAN PROGRAM IS LOOKING AT 

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SPATIAL AWARENESS AMONG THE 

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ATLAS AND UNDERSTANDING THE 

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RELATIONSHIP BETWEEN CHANGES IN 

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CANCER AND HOW IT WILL BE 

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CRITICAL IN OUR UNDERSTANDING 

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LEADS TO CANCER TREATMENTS AS WE

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GO FORWARD.

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SO I THINK THIS HAS BEEN A WELL 

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DESIGN MEETING WITH ALL THE 

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IMPORTANT TOPICS.

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MY CREDIT TO THE ORGANIZERS AND 

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ALL AND I THINK OF THE MAJOR 

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ISSUES AND THIS IS IN THE 

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MEETING AND THEMES AND GENETIC 

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LAND SCAPES AND TRANSLATIONAL 

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GENETICS AND WHERE ELSE ARE THEY

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AFFECTED AND THE NEW FRONTIER.

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I'M EXCITED ABOUT THIS MEETING.

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I THINK IT'S SORT OF AMAZING AND

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MY HATS OFF TO ANDY AND THE 

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OTHERS TO GET THE CALIBER OF 

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SPEAKERS WE HAVE IN THIS 

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ENCOURAGING AND GROWING FIELD OF

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CANCER EPIGENETICS.

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I ALREADY THANKED MONICA.

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I'D LIKE TO THANK DENA SINGER 

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DEPUTY DIRECTOR AT THE NCI.

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ANDY WORKED ON WITH DENA AND INE

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 -- IAN AND MY DEPUTY AND 

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ADMINISTRATIVELY AS WITH ALL OUR

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MEETINGS THANK TIFFANY AND 

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TOMIKA FROM DCB FOR THIS.

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PART OF MY JOB IS TO MAKE SURE 

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WE STAY ON TIME AND STEFON 

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DIDN'T TIME ME BUT THAT'S OKAY.

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AND SO WITH THAT, I THINK OUR 

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FIRST SPEAKER IS ANDY FEINBERG.

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>> THANK YOU VERY MUCH.

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I APPRECIATE THIS AND ALSO THANK

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NORM WHO SITTING -- SUGGESTED 

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THIS AND DENA AND I'M HUMBLED 

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THIS IS HAPPENING BUT GREAT TO 

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SEE COLLEAGUES FROM THE OLD DAYS

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AND THE YOUNG PEOPLE DOING 

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AMAZING THINGS.

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I'LL START WITH CANCER AS A 

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DISEASE OF EPIGENETIC PLASTICITY

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AND GIVE AN EXAMPLE.

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SO THIS IS WHAT WE LOOKED AT 

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BACK THEN AND INSIDE OF OUR 

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BRAINS -- I'M ONLY GOING TO 

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SPEAK FOR MYSELF BUT WHAT I 

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THINK WE STILL LOOK LIKE UNTIL 

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YOU LOOK IN THE MIRROR.

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AND I WANTED TO SAY, I WANT TO 

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START BY THANKING HIM AND HOW 

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MUCH I VALUE HIM.

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I WENT TO HIM TO DO A SECOND 

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POSTDOC AND WORKED IN 

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DEVELOPMENT BIOLOGY BEFORE AND 

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WANTED TO DO THIS EPIGENETIC AND

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TAUGHT ME ABOUT MOLECULAR 

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BIOLOGY AND THE SECOND THING IS 

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I LOVE BURT AND OUR FAMILIES ARE

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INCREDIBLY CLOSE.

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I CAN'T IMAGINE A WORLD I WENT 

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THROUGH WITHOUT HIM THERE AND 

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EILEEN AND HIS KIDS, ONE OF WHOM

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IS A COLLEAGUE OF MINE NOW, 

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JOSH, AND THIRD IS THIS IS A BIT

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OF JEWISH HUMOR BUT I'M GRATEFUL

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HE DIDN'T THINK WHAT I WORK ON 

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IS PARTICULARLY IMPORTANT.

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WHAT I MEAN IS HE'S NOT BEEN ALL

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THAT INTERESTED IN PURSUING THE 

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KIND OF EPIGENETIC HYPOTHESIS I 

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HAVE WHICH IS GREAT BECAUSE HE'S

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SO GOOD AND THEN HAVE TO COMPETE

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WITH HIM AS I WAS GOING ON MY 

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OWN WAY.

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SO I WANT TO JUST SHOW A SLIDE 

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FROM A REVIEW I WROTE SEVERAL 

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YEARS AGO ON THE CLONAL GENETIC 

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MODEL OF CANCER.

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SO THE EXTERNAL HYPOTHESIS WHICH

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WAS THE REIGNING THING AND 

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THERE'S A SERIES OF GENETIC 

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MUTATIONS FROM A NORMAL CELL TO 

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BENIGN TUMOR AND BURT IS THE 

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CHAMPION OF THE MODEL AND 

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PROBABLY MADE THE LEADING 

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CONTRIBUTION TO INDIVIDUALIZED 

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THERAPY, TO MOST THE MEDICINES.

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YOU MENTION THE EPIGENETIC 

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MEDICINES AND I HAVE A LOT OF 

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HOPE FOR THEM.

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SOME ARE PRETTY USEFUL BUT IF 

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YOU THINK OF TARGETED MUTATION 

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DRUGS IT'S AMAZING AND BURT HAS 

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LED THE WAY THROUGH THIS.

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WHAT I'VE BEEN INTERESTED IN 

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SINCE THE BEGINNING IS SOMEWHAT 

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DIFFERENT IDEA THAT CANCER IS A 

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DISEASE OF EPIGENETIC 

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PLASTICITY.

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I USED TO GET ASKED ALL THE TIME

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WHY DON'T YOU THINK GENETICS IS 

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IMPORTANT.

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YOU HEARD ME NOT SAY THIS.

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THIS IS ONE OF THE THING YOU 

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HAVE TO THINK AND INTEGRATING 

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THE TWO IS VERY IMPORTANT.

258
00:12:45,320 --> 00:12:46,421
THERE ARE A COUPLE OTHER THINGS 

259
00:12:46,421 --> 00:12:48,490
I THINK ARE IMPORTANT I 

260
00:12:48,490 --> 00:12:49,591
SUGGESTED IN THIS PAPER.

261
00:12:49,591 --> 00:12:52,694
ONE IS THAT THERE MIGHT BE GENES

262
00:12:52,694 --> 00:12:54,362
THAT ARE PROGENITOR GENES FOR 

263
00:12:54,362 --> 00:12:54,796
CANCER.

264
00:12:54,796 --> 00:12:57,899
THEY AREN'T MUTATED THAT ARE 

265
00:12:57,899 --> 00:13:00,902
ALTERED EPIGENETICALLY IN THE 

266
00:13:00,902 --> 00:13:04,239
NORMAL--MAYBE IN RESPONSE TO 

267
00:13:04,239 --> 00:13:06,975
INFLAMMATION OR INJURY AND SET 

268
00:13:06,975 --> 00:13:08,743
THE STAGE FOR CANCER TO EMERGE 

269
00:13:08,743 --> 00:13:11,946
LATER WHEN MUTATIONS TAKE PLACE.

270
00:13:11,946 --> 00:13:18,319
BUT THAT CAN LEAD TO AN EXPANDED

271
00:13:18,319 --> 00:13:22,257
EPIGENETIC PROGENITOR CELL AND 

272
00:13:22,257 --> 00:13:27,495
CAME FROM A DOUBLE DOSE OF IGF2 

273
00:13:27,495 --> 00:13:32,033
THE CAUSE OF CERTAIN LUMPS TUMOR

274
00:13:32,033 --> 00:13:33,968
ASSOCIATED WITH KIDNEY 

275
00:13:33,968 --> 00:13:36,037
OVERGROWTH IN THE SYNDROME AND 

276
00:13:36,037 --> 00:13:38,840
YOU HAVE ONCA GENES AND TUMOR 

277
00:13:38,840 --> 00:13:40,642
SUPPRESSER GENES BUT IN LATER 

278
00:13:40,642 --> 00:13:42,577
STAGES THEY MAY REAR THEIR UGLY 

279
00:13:42,577 --> 00:13:45,213
HEADS GOOD-BYE AND LEAD TO 

280
00:13:45,213 --> 00:13:45,880
EPIGENETIC PLASTICITY AROUND HOW

281
00:13:45,880 --> 00:13:47,682
DO YOU GET RESISTANCE TO 

282
00:13:47,682 --> 00:13:50,151
SOMETHING AND THEN YOU USE 

283
00:13:50,151 --> 00:13:51,519
ANOTHER DRUG AND GET RESISTANCE 

284
00:13:51,519 --> 00:13:54,422
TO THAT AND THEN YOU HAVE 

285
00:13:54,422 --> 00:13:57,525
SENSITIVITY AGAIN WITH THE FIRST

286
00:13:57,525 --> 00:13:57,726
DRUG?

287
00:13:57,726 --> 00:14:02,797
THERE'S AN EXAMPLE IN PANCREATIC

288
00:14:02,797 --> 00:14:09,370
CANCER AND GET RESISTANCE.

289
00:14:09,370 --> 00:14:14,743
THERE'S A SEQUEL PAPER WITH A 

290
00:14:14,743 --> 00:14:17,579
COLLEAGUE WHERE I SUGGESTED THE 

291
00:14:17,579 --> 00:14:19,981
CLASSIFICATION SCHEME YOU HAVE 

292
00:14:19,981 --> 00:14:22,016
EPIGENETIC MODULATORS THINGS 

293
00:14:22,016 --> 00:14:23,685
FROM THE ENVIRONMENT THAT AFFECT

294
00:14:23,685 --> 00:14:25,286
THE GENES THAT CODE FOR THE 

295
00:14:25,286 --> 00:14:27,722
GENOME RELATED TO AGING AND 

296
00:14:27,722 --> 00:14:28,990
ENVIRONMENTAL FACTORS AND THEN 

297
00:14:28,990 --> 00:14:29,357
THE MODIFIERS.

298
00:14:29,357 --> 00:14:31,459
THAT'S A NICE REVIEW.

299
00:14:31,459 --> 00:14:33,228
THERE ARE MUTATIONS THAT OCCUR 

300
00:14:33,228 --> 00:14:35,697
IN MODIFIERS AND THE MOST COMMON

301
00:14:35,697 --> 00:14:40,301
MUTATIONS IN CANCER FROM THE 

302
00:14:40,301 --> 00:14:41,970
CANCER GENOME ATLAS.

303
00:14:41,970 --> 00:14:43,371
THEY MODIFY THE MODULATORS.

304
00:14:43,371 --> 00:14:49,577
THEY DEFINE WHAT YOU CALL THE 

305
00:14:49,577 --> 00:14:53,581
EPIGENETIC LANDSCAPE AND DEFINE 

306
00:14:53,581 --> 00:14:59,387
THE PLURIPOTENCY MODIFIERS AND 

307
00:14:59,387 --> 00:15:03,725
THINGS LIKE DNTs AND THEY 

308
00:15:03,725 --> 00:15:05,226
DETERMINE THE LANDSCAPE AND THE 

309
00:15:05,226 --> 00:15:09,597
MEDIATORS ARE THINGS THAT I 

310
00:15:09,597 --> 00:15:11,099
SUGGESTED TUMOR PROGENITOR GENES

311
00:15:11,099 --> 00:15:15,970
BUT ALSO THE PLURIPOTENT GENES 

312
00:15:15,970 --> 00:15:19,707
AND THE YAMIAKA FACTORS AND 

313
00:15:19,707 --> 00:15:20,508
FACTORS OF DIFFERENTIATION.

314
00:15:20,508 --> 00:15:21,609
I GOT THIS IDEA.

315
00:15:21,609 --> 00:15:23,545
THIS IS WHAT I'LL TALK ABOUT 

316
00:15:23,545 --> 00:15:23,778
MOSTLY.

317
00:15:23,778 --> 00:15:28,983
I GOT THIS IDEA ABOUT YEARS AGO.

318
00:15:28,983 --> 00:15:30,985
I WAS ACTUALLY -- WE JUST 

319
00:15:30,985 --> 00:15:34,122
PUBLISHED A PAPER ON THE FIRST 

320
00:15:34,122 --> 00:15:37,225
COMPREHENSIVE LOOK AT THE 

321
00:15:37,225 --> 00:15:37,492
EPIGENOME.

322
00:15:37,492 --> 00:15:40,595
THERE WASN'T A WAY TO REALLY 

323
00:15:40,595 --> 00:15:42,530
MEASURE METHYLATION ACROSS THE 

324
00:15:42,530 --> 00:15:45,600
WHOLE GENOME EXCEPT FOR LIBRARY 

325
00:15:45,600 --> 00:15:48,736
OF CPGI LUNGS AND WE INVENTED 

326
00:15:48,736 --> 00:15:51,806
THIS RAY-BASED METHOD AND THIS 

327
00:15:51,806 --> 00:15:53,808
COMPARES NORMAL COLON TO COLON 

328
00:15:53,808 --> 00:15:54,943
CANCER AND I CAN'T POINT BECAUSE

329
00:15:54,943 --> 00:15:57,078
I DON'T THINK PEOPLE ON TV CAN 

330
00:15:57,078 --> 00:15:58,413
SEE IT BUT ON THE LEFT HAND 

331
00:15:58,413 --> 00:16:01,583
PANEL THE LEFT SIDE HAVE THE 

332
00:16:01,583 --> 00:16:03,785
NORMAL COLONS AND THE RIGHT SIDE

333
00:16:03,785 --> 00:16:05,687
ARE COLON CANCERS.

334
00:16:05,687 --> 00:16:09,090
THERE'S GENES DOWN THE LEFT AND 

335
00:16:09,090 --> 00:16:11,259
THE SAMPLES ON THE X AXIS AND 

336
00:16:11,259 --> 00:16:13,394
BESIDES THE DIFFERENCES THERE'S 

337
00:16:13,394 --> 00:16:15,463
A HUGE DEGREE OF HETEROGENEITY 

338
00:16:15,463 --> 00:16:16,798
OR VARIABILITY IN THE CANCERS.

339
00:16:16,798 --> 00:16:19,834
MAYBE THAT'S RELATED TO TUMOR 

340
00:16:19,834 --> 00:16:20,602
HETEROGENEITY.

341
00:16:20,602 --> 00:16:23,905
WHAT'S AMAZING IS IF YOU DO WITH

342
00:16:23,905 --> 00:16:28,209
THE TOP DIFFERENTIALLY METHYL 

343
00:16:28,209 --> 00:16:33,581
EIGHTED REGIONS AND DO TISSUES 

344
00:16:33,581 --> 00:16:35,984
OF SPLEEN, LIVER AND COLON THEY 

345
00:16:35,984 --> 00:16:37,652
DISCRIMINATE FROM EACH OTHER 

346
00:16:37,652 --> 00:16:39,821
WHICH MEANS IT'S SORT OF 

347
00:16:39,821 --> 00:16:42,957
SHOCKING THE VERY EPIGENETIC 

348
00:16:42,957 --> 00:16:45,927
CHANGES THAT TELL COLON CANCER 

349
00:16:45,927 --> 00:16:51,032
IT'S NOT NORMAL ARE THE SAME 

350
00:16:51,032 --> 00:16:55,870
GENES AND THE CANCER DMRs AND IN

351
00:16:55,870 --> 00:16:57,505
WORK WITH GEORGE DAILY THEY'RE 

352
00:16:57,505 --> 00:17:00,942
THE SAME IN PROGRAMMING.

353
00:17:00,942 --> 00:17:03,645
THE DIFFERENCES IN THE TISSUES 

354
00:17:03,645 --> 00:17:05,046
AND WITH CANCER INVOLVE KIND OF 

355
00:17:05,046 --> 00:17:06,114
THE SAME GENES IT'S JUST THE 

356
00:17:06,114 --> 00:17:09,250
QUESTION OF WHICH ONES AND WHICH

357
00:17:09,250 --> 00:17:10,485
ONES TO DISTURB AND SO FORTH.

358
00:17:10,485 --> 00:17:14,622
WHEN WE DID THIS WORK WE WERE 

359
00:17:14,622 --> 00:17:15,957
ASKED TO PROVE THERE'S INHERENT 

360
00:17:15,957 --> 00:17:18,393
VARIABILITY BY REVIEWERS AND 

361
00:17:18,393 --> 00:17:20,561
WENT BACK TO -- I SHOULD SAY, 

362
00:17:20,561 --> 00:17:24,532
YOU COULD SEE THIS IN THE NORMAL

363
00:17:24,532 --> 00:17:30,338
TISSUE AS WELL THE VARIABILITY.

364
00:17:30,338 --> 00:17:34,776
THIS IS UNSUPERVISED TISSUES OF 

365
00:17:34,776 --> 00:17:36,778
MICE FROM THE SAME LITTER AND 

366
00:17:36,778 --> 00:17:39,047
IDENTICAL GENOMES AND THE 

367
00:17:39,047 --> 00:17:40,315
TISSUES SEGREGATE COMPLETELY.

368
00:17:40,315 --> 00:17:43,184
NOT THE SPECIES THOUGH WE'RE 50 

369
00:17:43,184 --> 00:17:45,720
MILLION YEARS A PART.

370
00:17:45,720 --> 00:17:51,826
IF YOU LOOK THERE AT THE ONES 

371
00:17:51,826 --> 00:17:54,128
LABELLED THE MOUSE, THERE'S 

372
00:17:54,128 --> 00:17:54,762
ENORMOUS VARIABILITY IN THE 

373
00:17:54,762 --> 00:17:56,531
GENES DETERMINING THE 

374
00:17:56,531 --> 00:17:58,466
DIFFERENCES FROM ONE TISSUE FROM

375
00:17:58,466 --> 00:18:02,637
ONE MOUSE TO ANOTHER THAT'S ISO 

376
00:18:02,637 --> 00:18:03,137
GENIC.

377
00:18:03,137 --> 00:18:05,139
 IN OTHER WORDS THEY HAVE 

378
00:18:05,139 --> 00:18:09,210
INHERENT VARIABILITY AND WE CALL

379
00:18:09,210 --> 00:18:14,148
THEM VMRs, VARIABLY METH LATED 

380
00:18:14,148 --> 00:18:17,085
REGIONS AND IS THERE A CONSERVED

381
00:18:17,085 --> 00:18:18,286
DRUG FOR EPIGENETIC VARIABILITY 

382
00:18:18,286 --> 00:18:20,088
AND THE REASON WE WERE ABLE TO 

383
00:18:20,088 --> 00:18:22,657
DO THE NEW ASSAYS WE GOT A GRANT

384
00:18:22,657 --> 00:18:26,894
FROM THE NIH WHICH I SHOULD SAY 

385
00:18:26,894 --> 00:18:29,597
WE HAVE ALL THESE THANKS FOR 

386
00:18:29,597 --> 00:18:30,631
CONTRIBUTIONS FROM PEOPLE AND 

387
00:18:30,631 --> 00:18:31,833
THE VALUE OF NIH AND ALLOWING US

388
00:18:31,833 --> 00:18:35,136
TO DO WHAT WE DO IS SO DEEP AND 

389
00:18:35,136 --> 00:18:38,239
I'M SO GRATEFUL.

390
00:18:38,239 --> 00:18:39,707
WE HAD THIS GENOME CENTER TO 

391
00:18:39,707 --> 00:18:41,242
DEVELOP THESE TECHNIQUES AND THE

392
00:18:41,242 --> 00:18:44,912
PURPOSE OF THE GENOME CENTER WAS

393
00:18:44,912 --> 00:18:46,714
TO EXPLORE, HOW'S EPIGENETICS 

394
00:18:46,714 --> 00:18:50,184
INVOLVED IN COMMON DISEASES.

395
00:18:50,184 --> 00:18:52,086
THE COMMON VARIANCE THAT WE'RE 

396
00:18:52,086 --> 00:18:57,125
HYPOTHESIZED TO CONTROL HUMAN 

397
00:18:57,125 --> 00:19:00,328
DISEASE OCCUR RELATIVELY 

398
00:19:00,328 --> 00:19:01,529
COMMONLY BUT CONTRIBUTE 

399
00:19:01,529 --> 00:19:04,232
RELATIVELY LITTLE TO THE OVER 

400
00:19:04,232 --> 00:19:07,135
ALL EXPLAIN VARIANTS OF COMMON 

401
00:19:07,135 --> 00:19:07,535
DISEASE.

402
00:19:07,535 --> 00:19:10,938
EVEN NOW AFTER ALL THE WORK DONE

403
00:19:10,938 --> 00:19:13,174
MY FAVORITE IS THIS ONE FROM 

404
00:19:13,174 --> 00:19:15,810
BURT AND JOSH, HIS SON, SHOWED 

405
00:19:15,810 --> 00:19:17,945
THAT BASED ON TWIN STUDIES THAT 

406
00:19:17,945 --> 00:19:21,049
EVEN IF YOU KNEW EVERYTHING 

407
00:19:21,049 --> 00:19:21,616
ABOUT BIOLOGY AND HAD THE 

408
00:19:21,616 --> 00:19:23,985
COMPLETE SEQUENCE OF A PERSON 

409
00:19:23,985 --> 00:19:25,586
YOU CAN ONLY PREDICT 20% OF THE 

410
00:19:25,586 --> 00:19:35,863
RISK OF DISEASE.

411
00:19:38,866 --> 00:19:40,201
AND THE ENVIRONMENT INDUCES A 

412
00:19:40,201 --> 00:19:41,102
CHANGE.

413
00:19:41,102 --> 00:19:42,403
INDUCES A CHANGE THAT'S GOING TO

414
00:19:42,403 --> 00:19:45,073
GIVE YOU A SELECTIVE ADVANTAGE 

415
00:19:45,073 --> 00:19:48,376
THAT'S GOING TO BE TRANSMITTED 

416
00:19:48,376 --> 00:19:49,310
EPIGENETICALLY FROM GENERATION 

417
00:19:49,310 --> 00:19:53,014
TO GENERATION AND SHOULD BE 

418
00:19:53,014 --> 00:19:56,117
SPORADIC AND RESPONSE TO STRESS.

419
00:19:56,117 --> 00:19:59,587
WHILE THERE'S VARIANTS ACROSS 

420
00:19:59,587 --> 00:20:00,855
GENERATIONS THEY'RE DELETERIOUS 

421
00:20:00,855 --> 00:20:06,060
AND THAT MAKES FUN OF LAMAR 

422
00:20:06,060 --> 00:20:08,062
BECAUSE HE SAID THE FOREST 

423
00:20:08,062 --> 00:20:09,397
TURNED INTO A GIRAFFE BECAUSE HE

424
00:20:09,397 --> 00:20:11,065
HAD TO STRETCH TO GET THE LEAVES

425
00:20:11,065 --> 00:20:12,266
OR SOMETHING LIKE THAT.

426
00:20:12,266 --> 00:20:16,437
IF THAT'S NOT THE EXPLANATION 

427
00:20:16,437 --> 00:20:18,673
AND STILL DARWINIAN MAYBE WE 

428
00:20:18,673 --> 00:20:20,541
SHOULD THINK OF WHAT ELSE CAUSES

429
00:20:20,541 --> 00:20:20,775
DISEASE.

430
00:20:20,775 --> 00:20:26,280
SHE ENVIRONMENT LIKE SMOKING AND

431
00:20:26,280 --> 00:20:29,550
THE SUN AND EATING CHEESE 

432
00:20:29,550 --> 00:20:32,787
BURGERS AND DRINKING ALCOHOL AND

433
00:20:32,787 --> 00:20:34,188
THIS MAKES YOU WANT TO GO TO THE

434
00:20:34,188 --> 00:20:36,591
BEACH BUT DON'T HAVE A CIGARETTE

435
00:20:36,591 --> 00:20:37,925
WHEN YOU DO IT.

436
00:20:37,925 --> 00:20:44,732
HOW IS THAT SOMEHOW DARWINIAN 

437
00:20:44,732 --> 00:20:46,767
AND I WOULD HAVE EPISODES OF 

438
00:20:46,767 --> 00:20:48,903
READING AT NIGHT AND STUFF LIKE 

439
00:20:48,903 --> 00:20:50,271
THAT SO I HAPPEN TO BE CHASING 

440
00:20:50,271 --> 00:20:51,806
DOWN SAMPLES I WANTED TO GET 

441
00:20:51,806 --> 00:20:55,943
FROM SOMEONE IN HOLLAND LIKE 

442
00:20:55,943 --> 00:20:56,344
TWINS.

443
00:20:56,344 --> 00:20:59,080
THAT WAS UNSUCCESSFUL AND I FLEW

444
00:20:59,080 --> 00:21:02,550
THERE THROUGH LONDON AND MY SON,

445
00:21:02,550 --> 00:21:05,453
JASON, WHO I PUBLISHED WITH TOO 

446
00:21:05,453 --> 00:21:09,023
AND I'M HAPPY ABOUT, HE WAS 

447
00:21:09,023 --> 00:21:11,692
WORKING IN SPAIN AND HADN'T SEEN

448
00:21:11,692 --> 00:21:14,162
LONDON SO WE SPENT A WEEKEND 

449
00:21:14,162 --> 00:21:16,464
THERE AS I WAS FLYING BACK FROM 

450
00:21:16,464 --> 00:21:17,665
HOLLAND ON MY UNSUCCESSFUL 

451
00:21:17,665 --> 00:21:19,267
MISSION AND WE LIKE TO GO TO 

452
00:21:19,267 --> 00:21:21,736
TALL PLACES AND GET A VIEW SO WE

453
00:21:21,736 --> 00:21:23,571
WENT ON THE LONDON EYE AND WE 

454
00:21:23,571 --> 00:21:25,540
SAW BIG BEN AND SAID WE WANT TO 

455
00:21:25,540 --> 00:21:27,742
GO SEE THAT SO WE WALKED ACROSS 

456
00:21:27,742 --> 00:21:29,877
WESTMINSTER BRIDGE AND THERE'S A

457
00:21:29,877 --> 00:21:34,215
SIGN AT BIG BEN AND THE BRITISH 

458
00:21:34,215 --> 00:21:36,817
ARE INSULTING IN A POLITE WAY 

459
00:21:36,817 --> 00:21:40,354
AND IT'S AN ART FORM AND IT SAYS

460
00:21:40,354 --> 00:21:42,223
YOU'RE NOT WELCOME UNLESS YOU'RE

461
00:21:42,223 --> 00:21:44,659
ONE OF SO AND IF SO GO AWAY.

462
00:21:44,659 --> 00:21:47,261
NEXT DOOR IS WESTMINSTER ABBY 

463
00:21:47,261 --> 00:21:49,830
AND THIS IS NOVEMBER 2009 SAYING

464
00:21:49,830 --> 00:21:51,732
THE 150th ANNIVERSARY OF ORIGIN 

465
00:21:51,732 --> 00:21:53,401
SPECIES COME IN AND SEE DARWIN 

466
00:21:53,401 --> 00:21:54,035
HE'S HERE.

467
00:21:54,035 --> 00:21:56,871
SO WE WENT IN THERE INSTEAD AND 

468
00:21:56,871 --> 00:21:58,272
FOUND OURSELVES STANDING ON 

469
00:21:58,272 --> 00:22:00,107
DARWIN'S GRAVE AND NEXT TO 

470
00:22:00,107 --> 00:22:02,009
DARWIN'S GRAVE IS NEWTON'S 

471
00:22:02,009 --> 00:22:02,677
GRAVE.

472
00:22:02,677 --> 00:22:05,479
NOW, THERE'S A VELVET ROPE SAME 

473
00:22:05,479 --> 00:22:07,114
KIND THAT WAS OUTSIDE OF BIG BEN

474
00:22:07,114 --> 00:22:09,083
AND SAYS YOU MAY NOT CROSS BUT 

475
00:22:09,083 --> 00:22:12,220
YOU CAN PUT YOUR FILTHY FEET ON 

476
00:22:12,220 --> 00:22:14,889
DARWIN'S GRAVE, THAT'S FINE.

477
00:22:14,889 --> 00:22:17,458
AND BEHIND NEWTON'S GRAVE 

478
00:22:17,458 --> 00:22:20,094
THERE'S THE CHERUBS AND BIG ARCH

479
00:22:20,094 --> 00:22:24,632
AND NOTHING LIKE THAT FOR DARWIN

480
00:22:24,632 --> 00:22:32,006
AND ON TOP OF NEWTON AND IT'S BY

481
00:22:32,006 --> 00:22:35,209
THE FOUNDER OF A QUANTUM THEORY 

482
00:22:35,209 --> 00:22:36,577
AND A THOUGHT WHAT IS THERE AN 

483
00:22:36,577 --> 00:22:40,348
URN IN THERE OR BURIED STANDING 

484
00:22:40,348 --> 00:22:41,382
UP.

485
00:22:41,382 --> 00:22:47,888
HE'S BURIED SOMEWHERE ELSE AND 

486
00:22:47,888 --> 00:22:49,156
NO DISRESPECT TO THE CHURCH BUT 

487
00:22:49,156 --> 00:22:51,759
IT'S A FUNNY THING TO SAY AND 

488
00:22:51,759 --> 00:22:56,931
THE EPIPHANY WAS WELL WE DON'T 

489
00:22:56,931 --> 00:23:00,001
HAVE SOMETHING LIKE THAT IN 

490
00:23:00,001 --> 00:23:00,234
BIOLOGY.

491
00:23:00,234 --> 00:23:02,203
THE FOUNDER THIS WAS FLUID IN MY

492
00:23:02,203 --> 00:23:07,208
HEAD OUT OF BODY EXPERIENCE AND 

493
00:23:07,208 --> 00:23:12,246
I WALKED WITH JASON A PUB NEXT 

494
00:23:12,246 --> 00:23:14,649
TO THE TOWER OF LONDON WHERE 

495
00:23:14,649 --> 00:23:20,655
THEY WOULD EXECUTE PEOPLE AND I 

496
00:23:20,655 --> 00:23:24,125
WROTE A PAPER BUT THE IDEA IS 

497
00:23:24,125 --> 00:23:26,294
THE GENETIC VARIATION SAY 

498
00:23:26,294 --> 00:23:29,063
DRIVING FORCE OF DEVELOPMENT OF 

499
00:23:29,063 --> 00:23:30,965
ADAPTATION AND IDEA THAT WOULD 

500
00:23:30,965 --> 00:23:36,971
FIT THE EVOLUTION OF COMPLEX 

501
00:23:36,971 --> 00:23:37,204
SPECIES.

502
00:23:37,204 --> 00:23:47,615
STOCHASTIC VARIATION IS 

503
00:23:48,816 --> 00:23:49,583
EPIGENETICALLY BUT THE CONTROL 

504
00:23:49,583 --> 00:23:55,323
OF DEGREE -- CONTROLLED BY GENE 

505
00:23:55,323 --> 00:23:57,591
SEQUENCES AND GENETIC VARIANCES 

506
00:23:57,591 --> 00:23:59,894
THAT INDUCE PLASTICITY OVER 

507
00:23:59,894 --> 00:24:01,429
REVOLUTION FOR TRACE AFFECTED BY

508
00:24:01,429 --> 00:24:05,566
A FLUCTUATING ENVIRONMENT.

509
00:24:05,566 --> 00:24:07,968
IF YOU HAVE A LITTLE LESS 

510
00:24:07,968 --> 00:24:10,037
ROBUSTNESS BUT HAVE OFFSPRING 

511
00:24:10,037 --> 00:24:12,273
OPPOSITE TO THE TRAIT YOU HAVE 

512
00:24:12,273 --> 00:24:13,974
IT WON'T BE PASSED ALONG BUT IF 

513
00:24:13,974 --> 00:24:15,776
THE ENVIRONMENT SUDDENLY CHANGES

514
00:24:15,776 --> 00:24:17,111
OVER ALL YOU'LL HAVE A SELECTIVE

515
00:24:17,111 --> 00:24:18,746
ADVANTAGE AND WE PROVED THIS 

516
00:24:18,746 --> 00:24:20,681
RIGOROUSLY AND MATHEMATICALLY.

517
00:24:20,681 --> 00:24:24,485
IT COULD BE IMPORTANT IN CANCER 

518
00:24:24,485 --> 00:24:25,586
PROGRESSION.

519
00:24:25,586 --> 00:24:29,790
HERE ARE THE VARIABLY METHYLATED

520
00:24:29,790 --> 00:24:31,459
REGIONS AND SEE THE HIGH DEGREE 

521
00:24:31,459 --> 00:24:32,693
OF VARIATION IN A PARTICULAR 

522
00:24:32,693 --> 00:24:33,794
REGION.

523
00:24:33,794 --> 00:24:35,062
IF YOU ASK WHERE THEY ARE 

524
00:24:35,062 --> 00:24:39,266
THEY'RE EVERYTHING RELATED TO 

525
00:24:39,266 --> 00:24:39,700
DEVELOPMENT.

526
00:24:39,700 --> 00:24:42,269
GUT, MORPH GENESIS AND THAT 

527
00:24:42,269 --> 00:24:45,005
MAKES SENSE WITH WHAT I SHOWED 

528
00:24:45,005 --> 00:24:47,808
YOU EARLIER FROM THE ARRAY BASED

529
00:24:47,808 --> 00:24:50,344
PLOT AND A FRIEND OF MINE AT 

530
00:24:50,344 --> 00:24:52,780
UCSD PROVED THEY'RE TRANSMITTED 

531
00:24:52,780 --> 00:24:54,348
THROUGH MULTIPLE GENERATIONS SO 

532
00:24:54,348 --> 00:24:55,616
THEY DO EXIST.

533
00:24:55,616 --> 00:24:58,519
A LOT OF PEOPLE STUDIED THEM 

534
00:24:58,519 --> 00:25:01,589
NOW.

535
00:25:01,589 --> 00:25:03,324
WHILE THAT MIGHT BE IMPORTANT IN

536
00:25:03,324 --> 00:25:05,593
CANCER AND ONE OF THE BIG THINGS

537
00:25:05,593 --> 00:25:08,829
IS CYCLES OF INJURY AND REPAIR, 

538
00:25:08,829 --> 00:25:11,465
EXPOSURE, HEALING, EXPOSURE.

539
00:25:11,465 --> 00:25:13,601
YOU CAN IMAGINE SELECTIVE 

540
00:25:13,601 --> 00:25:16,370
ENVIRONMENTAL PRESSURES AND THEN

541
00:25:16,370 --> 00:25:20,408
THAT WILL SELECT SAY FOR 

542
00:25:20,408 --> 00:25:22,877
MUTATIONS OR NATIVE EPIGENETIC 

543
00:25:22,877 --> 00:25:24,812
CHANGES HAVING INHERENT 

544
00:25:24,812 --> 00:25:25,579
VARIABILITY AND WE DISCOVERED 

545
00:25:25,579 --> 00:25:30,785
THE MECHANISM FOR THIS.

546
00:25:30,785 --> 00:25:34,755
SO WE DID THE FIRST SEQUENCING 

547
00:25:34,755 --> 00:25:35,990
OF PAIRED NORMAL AND CANCER FOR 

548
00:25:35,990 --> 00:25:39,226
COLON AND ONE THING WE SAW RIGHT

549
00:25:39,226 --> 00:25:41,095
AWAY HAVE THE BLOCKS WHERE THE 

550
00:25:41,095 --> 00:25:46,267
NORMAL'S IN BLUE AND CANCER'S IN

551
00:25:46,267 --> 00:25:47,501
RED AND LOOK HOW VARIABLE THE 

552
00:25:47,501 --> 00:25:48,135
CANCERS ARE.

553
00:25:48,135 --> 00:25:49,036
THEY'RE NOT JUST BIG.

554
00:25:49,036 --> 00:25:52,440
THAT'S WHAT WE SAW IN THE PAPER.

555
00:25:52,440 --> 00:25:58,646
SOME ARE AS SMALL AS FIVE KB OR 

556
00:25:58,646 --> 00:26:00,414
THREE OR FOUR KB.

557
00:26:00,414 --> 00:26:02,383
WITHIN THE REGIONS THERE'S 

558
00:26:02,383 --> 00:26:03,517
ISLANDS.

559
00:26:03,517 --> 00:26:09,056
THEY TEND TO BE HYPERMETHYLATED 

560
00:26:09,056 --> 00:26:11,459
AND THIS IS A BAR CODE GENE 

561
00:26:11,459 --> 00:26:13,461
EXPRESSION PAIR SET.

562
00:26:13,461 --> 00:26:15,229
THE MORE HIGHLY VARIABLY 

563
00:26:15,229 --> 00:26:16,564
EXPRESSED GENES IN THE GENOME 

564
00:26:16,564 --> 00:26:20,034
AND INVOLVED IN CANCER 

565
00:26:20,034 --> 00:26:21,836
PROGRESSION.

566
00:26:21,836 --> 00:26:23,571
THE ENVIRONMENT ALSO CAN HAVE A 

567
00:26:23,571 --> 00:26:26,474
MAJOR AFFECT ON THE GENERATION 

568
00:26:26,474 --> 00:26:36,984
OF THESE REGIONS OF VARIABLE 

569
00:26:37,685 --> 00:26:39,487
METHYLATION WE LOOKED AT PEOPLE 

570
00:26:39,487 --> 00:26:41,922
OLDER OR SUN EXPOSED OR BOTH.

571
00:26:41,922 --> 00:26:44,091
LIKE IN MEN THE LEFT ARM AND 

572
00:26:44,091 --> 00:26:46,727
WOMEN THE RIGHT ARM JUST BECAUSE

573
00:26:46,727 --> 00:26:48,796
OF THE HABITS OF PEOPLE DRIVING.

574
00:26:48,796 --> 00:26:50,664
IF YOU LOOK AT SPECIMENS YOU SEE

575
00:26:50,664 --> 00:26:52,700
THE SAME THING ENVIRONMENTALLY 

576
00:26:52,700 --> 00:26:53,100
INDUCED.

577
00:26:53,100 --> 00:26:57,204
THE AREAS OF HYPERVARIABILITY 

578
00:26:57,204 --> 00:26:59,840
THAT HAVE CHANGES IN ISLANDS AND

579
00:26:59,840 --> 00:27:01,742
SHORES AND THE LONG REGIONS.

580
00:27:01,742 --> 00:27:03,978
THAT'S A DISTRIBUTION OF 

581
00:27:03,978 --> 00:27:05,279
METHYLATION ON THE LEFT WITHIN 

582
00:27:05,279 --> 00:27:07,481
WHAT WE CALL THE PHOTO AGING 

583
00:27:07,481 --> 00:27:10,084
BLOCKS AND THE PINK IS THE 

584
00:27:10,084 --> 00:27:10,317
CANCERS.

585
00:27:10,317 --> 00:27:12,720
THE EPIGENETIC CHANGES IN THE 

586
00:27:12,720 --> 00:27:15,256
CANCERS ARE AN ACCELERATED 

587
00:27:15,256 --> 00:27:15,923
VERSION OF WHAT HAPPENS AFTER 

588
00:27:15,923 --> 00:27:17,291
THE EXPOSURE AND OUTSIDE THE 

589
00:27:17,291 --> 00:27:17,892
BLOCKS YOU DON'T SEE THE SAME 

590
00:27:17,892 --> 00:27:19,426
THING.

591
00:27:19,426 --> 00:27:25,032
HOW DO WE THEN MEASURE THIS 

592
00:27:25,032 --> 00:27:25,366
STOCHASTICITY.

593
00:27:25,366 --> 00:27:30,404
I WENT BACK TO SCHOOL AND GOT A 

594
00:27:30,404 --> 00:27:34,241
PIONEER AWARDS AND THE FIRST 

595
00:27:34,241 --> 00:27:41,048
YEAR I SPENT MY 50% ON 

596
00:27:41,048 --> 00:27:42,816
STOCHASTIC MARK-UP PROCESSES AND

597
00:27:42,816 --> 00:27:48,022
I DEVELOPED THIS MODEL WITH A 

598
00:27:48,022 --> 00:27:54,995
FRIEND IN THE COURSE AND YOU CAN

599
00:27:54,995 --> 00:27:57,398
GENERATE TRUE STOCHASTIC MODELS 

600
00:27:57,398 --> 00:27:59,233
OF LANDSCAPES WHERE YOU CAN FOR 

601
00:27:59,233 --> 00:28:01,569
EXAMPLE SEE THE DIFFERENCE 

602
00:28:01,569 --> 00:28:04,838
BETWEEN MONOSTABLE METHYLATION 

603
00:28:04,838 --> 00:28:06,106
OR BISTABLE METHYLATION.

604
00:28:06,106 --> 00:28:07,741
THERE'S THE SAME MEAN VALUE BUT 

605
00:28:07,741 --> 00:28:09,443
THERE'S A DIFFERENCE AND YOU 

606
00:28:09,443 --> 00:28:10,711
COULD NOT DETECT THAT USING 

607
00:28:10,711 --> 00:28:11,845
OTHER METHODS.

608
00:28:11,845 --> 00:28:14,048
YOU CAN SEE AN EXAMPLE OF A 

609
00:28:14,048 --> 00:28:16,750
LANDSCAPE OF COLON NORMAL VERSUS

610
00:28:16,750 --> 00:28:19,019
COLON CANCER AT THE ONE GENE AND

611
00:28:19,019 --> 00:28:22,856
LOOK HOW FLAT THE LANDSCAPE IS 

612
00:28:22,856 --> 00:28:29,363
IN THE CANCER SHOWED ENTROPY AND

613
00:28:29,363 --> 00:28:30,931
STEM CELL ON THE LEFT AND 

614
00:28:30,931 --> 00:28:34,868
STOCHASTIC AND IN BRAIN 

615
00:28:34,868 --> 00:28:36,670
DEVELOPMENT HAS BECOME MUCH LESS

616
00:28:36,670 --> 00:28:38,839
RANDOM AND MEASURE OF ENTROPY.

617
00:28:38,839 --> 00:28:40,074
I WANT TO SHOW HOW USEFUL THIS 

618
00:28:40,074 --> 00:28:47,948
IS FOR UNDERSTANDING CANCER.

619
00:28:47,948 --> 00:28:52,252
THIS LOOKED AT ACUTE 

620
00:28:52,252 --> 00:28:54,655
LYMPHOBLASTIC LEUKEMIA AND HIGH 

621
00:28:54,655 --> 00:28:56,824
ENTROPY THROUGHOUT THE GENOME 

622
00:28:56,824 --> 00:28:58,392
DEPENDING ON DIFFERENT GENETIC 

623
00:28:58,392 --> 00:28:59,493
BACKGROUNDS BECAUSE THEY HAVE 

624
00:28:59,493 --> 00:29:01,161
VARIOUS KINDS OF CHROMOSOMAL 

625
00:29:01,161 --> 00:29:03,931
LOCATIONS LEADING TO ALL.

626
00:29:03,931 --> 00:29:06,634
IF YOU LOOK AT ALL THE GENETIC 

627
00:29:06,634 --> 00:29:10,671
TYPES THEY CONVERGE ON A SET OF 

628
00:29:10,671 --> 00:29:13,574
GENES THAT ARE ENTROPIC AND 

629
00:29:13,574 --> 00:29:14,675
COMMON ACROSS THE GROUP.

630
00:29:14,675 --> 00:29:17,845
AND IF YOU THEN LOOK AT THE 

631
00:29:17,845 --> 00:29:19,847
GENES AS SINGLE CELL GENE 

632
00:29:19,847 --> 00:29:22,249
EXPRESSION AND METHODS OF 

633
00:29:22,249 --> 00:29:25,019
MEASURING ENTROPY OPPOSED TO 

634
00:29:25,019 --> 00:29:28,222
MEAN EXPRESSION THEY FORM IN A 

635
00:29:28,222 --> 00:29:31,158
PARALLEL UNIVERSE SORT OF.

636
00:29:31,158 --> 00:29:32,660
ENTROPY GENE EXPRESSION NETWORK 

637
00:29:32,660 --> 00:29:34,862
CONVENING ON A GENE NOT 

638
00:29:34,862 --> 00:29:36,196
DESCRIBED MUCH IN CANCER.

639
00:29:36,196 --> 00:29:38,766
IT'S INVOLVED UP PROSTATE CANCER

640
00:29:38,766 --> 00:29:45,673
BUT NOT OTHERS CALLED UFGR1 

641
00:29:45,673 --> 00:29:48,242
BETWEEN CHROMATIN AND WE'RE 

642
00:29:48,242 --> 00:29:50,711
FINDING A SIMILAR EXAMPLE IN AML

643
00:29:50,711 --> 00:29:53,180
AND IT'S ANOTHER WAY WE CAN SEE 

644
00:29:53,180 --> 00:29:58,252
THIS HIDDEN EPIGENOME LOOK AT 

645
00:29:58,252 --> 00:30:02,356
STOCHASTICITY AND ANOTHER STUDY 

646
00:30:02,356 --> 00:30:05,392
I DID GENERATING XENO GRAPHS 

647
00:30:05,392 --> 00:30:10,864
FROM PATIENTS WITH PANCREATIC 

648
00:30:10,864 --> 00:30:16,336
CANCER AND THAT'D METASTASES 

649
00:30:16,336 --> 00:30:18,072
AFTER THE PATIENT PASSED AND YOU

650
00:30:18,072 --> 00:30:20,107
CAN SEE WHAT GAVE RISE TO THIS 

651
00:30:20,107 --> 00:30:21,809
VERSUS THOSE THAT SHOWED LOCAL 

652
00:30:21,809 --> 00:30:23,444
SPREAD.

653
00:30:23,444 --> 00:30:25,479
ON THE RIGHT IT SHOWS THERE'S 

654
00:30:25,479 --> 00:30:28,015
BLOG LIKE REGIONS OF VARIABLE 

655
00:30:28,015 --> 00:30:28,315
SIZE.

656
00:30:28,315 --> 00:30:30,484
SOME SMALL AND SOME LARGE AND 

657
00:30:30,484 --> 00:30:33,353
YOU SEE THIS DISORDER CHROMATIN 

658
00:30:33,353 --> 00:30:34,054
AND METHYLATION.

659
00:30:34,054 --> 00:30:37,891
THOSE ARE THE REGIONS THAT GIVE 

660
00:30:37,891 --> 00:30:41,161
RISE TO THE DISTANT METASTASES.

661
00:30:41,161 --> 00:30:46,200
THERE'S A MECHANISM WE THINK 

662
00:30:46,200 --> 00:30:47,701
MIGHT BE DRIVING THESE BUT THESE

663
00:30:47,701 --> 00:30:49,436
DON'T HAVE ADDITIONAL MUTATIONS 

664
00:30:49,436 --> 00:30:52,139
DRIVING THE METASTASES SO WE'RE 

665
00:30:52,139 --> 00:30:54,041
RIGHT ABOUT THIS IN SOME CASES 

666
00:30:54,041 --> 00:30:56,643
NOT BEING DRIVEN BY ADDITIONAL 

667
00:30:56,643 --> 00:30:59,113
MUTATIONS BUT BEING DRIVEN BY 

668
00:30:59,113 --> 00:31:01,482
EPIGENETIC CHANGE AND AROUND THE

669
00:31:01,482 --> 00:31:03,717
EDGES OF THESE BLOCK LIKE 

670
00:31:03,717 --> 00:31:05,385
REGIONS THIS CAME OUT IN CANCER 

671
00:31:05,385 --> 00:31:10,224
RESEARCH FROM MY STUDENT AT THE 

672
00:31:10,224 --> 00:31:12,559
BOUNDARIES OF THESE THERE'S 

673
00:31:12,559 --> 00:31:16,964
TRANSCRIPTION FOR BINDER SITES 

674
00:31:16,964 --> 00:31:19,600
AND DOWN BELOW ARE THE GENES 

675
00:31:19,600 --> 00:31:23,403
THAT ARE MEDIATORS AND TUMOR 

676
00:31:23,403 --> 00:31:24,104
PROGENITOR GENES.

677
00:31:24,104 --> 00:31:29,543
I'LL BE DONE IN A MINUTE.

678
00:31:29,543 --> 00:31:30,911
THEY'RE THE THINGS THAT DRIVE 

679
00:31:30,911 --> 00:31:33,747
THE VMRs IN NORMAL DEVELOPMENT 

680
00:31:33,747 --> 00:31:35,182
AND IN CANCER AND IN ANOTHER 

681
00:31:35,182 --> 00:31:37,518
PAPER THEY CAME OUT THIS YEAR, 

682
00:31:37,518 --> 00:31:43,190
OUR COLLEAGUES IN BIO 

683
00:31:43,190 --> 00:31:44,591
STATISTICS, USING A 

684
00:31:44,591 --> 00:31:47,561
COMPUTATIONAL METHOD ON DATA 

685
00:31:47,561 --> 00:31:49,429
SETS LOOKED AT THE DNA 

686
00:31:49,429 --> 00:31:51,532
RESPONSIBLE FOR METHYLATION IN 

687
00:31:51,532 --> 00:31:52,800
THE FIRST PLACE WHICH HADN'T 

688
00:31:52,800 --> 00:31:54,768
BEEN ANSWERED AND SEQUENCE 

689
00:31:54,768 --> 00:31:56,503
VARIANTS IN THE BINDING SITES OF

690
00:31:56,503 --> 00:31:58,539
TRANSCRIPTION FACTORS.

691
00:31:58,539 --> 00:32:01,675
SO IT LOOKS LIKE THIS IS RELATED

692
00:32:01,675 --> 00:32:04,044
TO TRANSCRIPTION REGULATORY 

693
00:32:04,044 --> 00:32:05,846
NETWORKS AND SUBTLE NETWORKS AND

694
00:32:05,846 --> 00:32:07,414
HOW THEY BIND ACROSS THE GENOME 

695
00:32:07,414 --> 00:32:10,317
IN MANY SITES AND PARTICULARLY 

696
00:32:10,317 --> 00:32:13,921
IF THE BOUNDARIES BE REGULATING 

697
00:32:13,921 --> 00:32:14,922
NOT JUST INDIVIDUAL GENES BUT 

698
00:32:14,922 --> 00:32:16,657
BLOCKS OF GENES AND GLAD YOU 

699
00:32:16,657 --> 00:32:17,057
MENTIONED THERAPY.

700
00:32:17,057 --> 00:32:18,692
I THINK IT'S RELEVANT.

701
00:32:18,692 --> 00:32:20,894
SOME DRUGS BEING USED MAY BE 

702
00:32:20,894 --> 00:32:22,229
AFFECTING THE REGIONS MORE 

703
00:32:22,229 --> 00:32:22,996
BROADLY RATHER THAN SAY A 

704
00:32:22,996 --> 00:32:24,131
SPECIFIC GENE AND THERE'S 

705
00:32:24,131 --> 00:32:25,766
REASONS WE THINK THAT MIGHT BE 

706
00:32:25,766 --> 00:32:28,235
THE CASE.

707
00:32:28,235 --> 00:32:32,139
JUST WORTH LOOKING AT.

708
00:32:32,139 --> 00:32:36,977
AND SAME REGIONS CONFIRM GROWTH 

709
00:32:36,977 --> 00:32:38,745
ADVANTAGE AND RESISTANCE AND 

710
00:32:38,745 --> 00:32:40,881
MEDIATED BY THESE REGIONS.

711
00:32:40,881 --> 00:32:43,684
THERE'S TRICKS YOU CAN USE TO 

712
00:32:43,684 --> 00:32:46,887
REVERSE THEM AND THAT GOES AWAY.

713
00:32:46,887 --> 00:32:50,257
IT SEEMS TO UNDER LIE ENT 

714
00:32:50,257 --> 00:32:50,557
TRANSITION.

715
00:32:50,557 --> 00:32:56,263
THE MODEL I WOULD HAVE AND I'M 

716
00:32:56,263 --> 00:33:01,101
GLAD YOU MENTIONED THE HALLMARKS

717
00:33:01,101 --> 00:33:01,501
PAPER.

718
00:33:01,501 --> 00:33:03,670
THE ORIGINAL DIDN'T MENTION 

719
00:33:03,670 --> 00:33:04,504
EPIGENETICS AND THE 10 YEAR 

720
00:33:04,504 --> 00:33:07,374
ANNIVERSARY MENTIONED IT TWICE 

721
00:33:07,374 --> 00:33:08,208
AND SAID WE DON'T THINK 

722
00:33:08,208 --> 00:33:09,476
EPIGENETICS IS PARTICULARLY 

723
00:33:09,476 --> 00:33:11,044
IMPORTANT AND SAID IT TWICE.

724
00:33:11,044 --> 00:33:13,747
I THINK IT'S AT THE CENTER, 

725
00:33:13,747 --> 00:33:15,249
ACTUALLY, OF THE HALLMARKS.

726
00:33:15,249 --> 00:33:18,619
I THINK WHAT HAPPENS IN THE 

727
00:33:18,619 --> 00:33:21,622
REVIEW I DID IS THAT THE 

728
00:33:21,622 --> 00:33:23,390
EPIGENETIC PLASTICITY AND I 

729
00:33:23,390 --> 00:33:25,692
GUESS MATHEMATICALLY ENTROPY 

730
00:33:25,692 --> 00:33:28,262
ALLOWS FOR SELECTION OF THESE 

731
00:33:28,262 --> 00:33:29,596
INDIVIDUAL TRAITS THAT ARE 

732
00:33:29,596 --> 00:33:31,098
CONSIDERED THE HALLMARKS NOT 

733
00:33:31,098 --> 00:33:32,699
THAT MUTATIONS CAN'T DO THAT 

734
00:33:32,699 --> 00:33:34,534
INDEPENDENTLY BUT IN TERMS OF 

735
00:33:34,534 --> 00:33:38,171
TUMOR PROGRESSION METASTASES THE

736
00:33:38,171 --> 00:33:39,740
SELECTION FOR THESE TRAITS AND 

737
00:33:39,740 --> 00:33:41,141
CONTINUED SELECTION AS THE 

738
00:33:41,141 --> 00:33:44,544
ENVIRONMENT CHANGES AS THE CELL 

739
00:33:44,544 --> 00:33:45,145
METASTASESES DRIVES CANCER 

740
00:33:45,145 --> 00:33:47,881
PLASTICITY AND THE KEY THING WE 

741
00:33:47,881 --> 00:33:49,483
NEED TO ADDRESS WE HAVEN'T MET.

742
00:33:49,483 --> 00:33:54,121
THE KEY THING I WANT TO SHOW IS 

743
00:33:54,121 --> 00:33:55,989
WHEN THAT MODEL CAME OUT I 

744
00:33:55,989 --> 00:33:58,992
SUGGESTED AN ART THING.

745
00:33:58,992 --> 00:34:02,195
I MADE THIS AND MY MOM WAS AN 

746
00:34:02,195 --> 00:34:02,763
ARTIST.

747
00:34:02,763 --> 00:34:05,399
A COUPLE COVERS I'VE HAD AND 

748
00:34:05,399 --> 00:34:07,467
ONLY THING I EVER DID SHE 

749
00:34:07,467 --> 00:34:09,102
UNDERSTOOD WERE THESE THINGS.

750
00:34:09,102 --> 00:34:10,637
THIS IS FROM SOME FAMOUS PICTURE

751
00:34:10,637 --> 00:34:14,408
AND HAVE PICTURES OF STOCHASTIC 

752
00:34:14,408 --> 00:34:19,746
THINGS AND MADE THIS OUT OF THIS

753
00:34:19,746 --> 00:34:22,015
AND I SNUCK SOMETHING IN THERE.

754
00:34:22,015 --> 00:34:23,050
IF YOU LOOK AT THE JOURNAL 

755
00:34:23,050 --> 00:34:24,851
YOURSELF YOU FIND IT AND YOU GO,

756
00:34:24,851 --> 00:34:26,920
JUST THE LOWER LEFT OF THE 

757
00:34:26,920 --> 00:34:30,457
SECOND E THERE'S A PICTURE OF MY

758
00:34:30,457 --> 00:34:35,662
WIFE PLAYING MAJONG WITH HER 

759
00:34:35,662 --> 00:34:36,330
FRIENDS AND THANK YOU VERY MUCH.

760
00:34:36,330 --> 00:34:36,697
I APPRECIATE IT.

761
00:34:36,697 --> 00:34:37,531
 

762
00:34:42,102 --> 00:34:42,636
>> THANK YOU.

763
00:34:42,636 --> 00:34:44,905
WE HAVE TIME FOR ONE QUESTION.

764
00:34:44,905 --> 00:34:48,775
>> I'M LIKE THE MODERATOR
SO I 

765
00:34:48,775 --> 00:34:50,811
COULDN'T TELL MYSELF TO SHUT UP 

766
00:34:50,811 --> 00:34:53,513
WHICH IS KIND OF UNIQUE.

767
00:34:53,513 --> 00:34:55,983
JUST USE THE MIC.

768
00:34:55,983 --> 00:34:58,185
>> THE DOUBLE CHANGES.

769
00:34:58,185 --> 00:34:59,252
>> FOR PEOPLE ONLINE --
I'M 

770
00:34:59,252 --> 00:35:00,754
GOING TO DISAPPEAR FROM THE 

771
00:35:00,754 --> 00:35:01,989
SCREEN BECAUSE I'M GOING TO GO 

772
00:35:01,989 --> 00:35:03,357
OUT AND SHARE THE MIC WITH THE 

773
00:35:03,357 --> 00:35:04,725
PERSON SO I CAN HEAR THEM 

774
00:35:04,725 --> 00:35:06,693
BECAUSE THE ECHO IS SO MUCH IN 

775
00:35:06,693 --> 00:35:06,960
THE ROOM.

776
00:35:06,960 --> 00:35:09,596
I'M COMING DOWN TO WHERE YOU 

777
00:35:09,596 --> 00:35:19,673
ARE.

778
00:35:25,545 --> 00:35:27,614
>> YOU TALKED ABOUT CANCER
HAS 

779
00:35:27,614 --> 00:35:30,617
ANYBODY LOOKED AT IS ANY PART OF

780
00:35:30,617 --> 00:35:33,587
THAT EXPLAINED BY NON-CANCER 

781
00:35:33,587 --> 00:35:35,322
CELLS IN THE TUMOR 

782
00:35:35,322 --> 00:35:37,524
MICROENVIRONMENT OR 100% 

783
00:35:37,524 --> 00:35:38,558
CONTRIBUTED BY -- 

784
00:35:38,558 --> 00:35:39,426
>> THAT'S A GOOD QUESTION.

785
00:35:39,426 --> 00:35:43,997
I DON'T KNOW.

786
00:35:43,997 --> 00:35:45,932
I THINK THERE'S BEEN PAPERS FROM

787
00:35:45,932 --> 00:35:49,603
SUE CLARK ON THIS FOR EXAMPLE ON

788
00:35:49,603 --> 00:35:50,604
FIBROBLAST AND WE'RE DOING PAPER

789
00:35:50,604 --> 00:35:54,341
ON PANCREAS TO LOOK AT THIS IN 

790
00:35:54,341 --> 00:35:55,842
DETAIL AND MAYBE THE EXTRA 

791
00:35:55,842 --> 00:35:57,177
CELLULAR NOT THE CELLS BUT WE 

792
00:35:57,177 --> 00:36:04,384
HAVE DATA AND SOME CAME OUT IN A

793
00:36:04,384 --> 00:36:07,521
RECENT PAPER THE EXTRA CELLULAR 

794
00:36:07,521 --> 00:36:08,221
ENVIRONMENT CAN CHANGE THE 

795
00:36:08,221 --> 00:36:11,391
EPIGENOME VISCOSITY.

796
00:36:11,391 --> 00:36:12,659
WE'RE DOING OTHER WORK RELATED 

797
00:36:12,659 --> 00:36:14,294
TO THAT AND I THINK THE ANSWER 

798
00:36:14,294 --> 00:36:16,029
IS CLEARLY YES BUT HASN'T BEEN 

799
00:36:16,029 --> 00:36:16,763
PAID ENOUGH ATTENTION TO AND 

800
00:36:16,763 --> 00:36:17,230
IT'S A GREAT QUESTION.

801
00:36:17,230 --> 00:36:27,407
THANK YOU.

802
00:36:57,137 --> 00:36:59,172
 SHOULD TALK TO THIS GUY ABOUT 

803
00:36:59,172 --> 00:36:59,906
WORKING YOUR SLIDES.

804
00:36:59,906 --> 00:37:10,317
I'M REALLY BAD AT THAT.

805
00:37:25,765 --> 00:37:28,201
>> THANK YOU, ANDY FOR THE

806
00:37:28,201 --> 00:37:30,137
INTRODUCTION AND THANKS IAN AND 

807
00:37:30,137 --> 00:37:31,671
DAN FOR GIVING ME THIS 

808
00:37:31,671 --> 00:37:31,972
OPPORTUNITY.

809
00:37:31,972 --> 00:37:35,342
I'M HONORED AND HUMBLED TO BE IN

810
00:37:35,342 --> 00:37:37,511
THIS ROOM WITH PIONEERS IN THE 

811
00:37:37,511 --> 00:37:40,080
FIELD OF EPIGENETICS IN CANCER 

812
00:37:40,080 --> 00:37:40,347
RESEARCH.

813
00:37:40,347 --> 00:37:43,617
SO WHAT I'M GOING TO SHARE WITH 

814
00:37:43,617 --> 00:37:46,786
YOU TODAY IS LARGELY TECHNOLOGY 

815
00:37:46,786 --> 00:37:48,155
RESEARCH IN MY LABORATORY.

816
00:37:48,155 --> 00:37:52,092
THIS IS MY DISCLAIMER.

817
00:37:52,092 --> 00:37:56,296
I WOULD LIKE TO EMPHASIZE MY 

818
00:37:56,296 --> 00:37:57,631
VERY EARLY MOMENT OF BIOMEDICAL 

819
00:37:57,631 --> 00:38:02,202
RESEARCH IN MY CAREER WHEN I 

820
00:38:02,202 --> 00:38:04,871
SWITCHED MY CAREER FROM ENERGY 

821
00:38:04,871 --> 00:38:08,708
SCIENCE AND PHYSICAL FUNDAMENTAL

822
00:38:08,708 --> 00:38:10,243
PHYSICS TO BIOMEDICAL RESEARCH.

823
00:38:10,243 --> 00:38:14,014
I WAS INSPIRED BY THE CANCER 

824
00:38:14,014 --> 00:38:15,815
BIOLOGY IN PARTICULAR TUMOR 

825
00:38:15,815 --> 00:38:17,217
MICRO ENVIRONMENT.

826
00:38:17,217 --> 00:38:20,954
WHEN I READ THE ARTICLE IN 2006 

827
00:38:20,954 --> 00:38:25,025
REGARDING A COMPLEX OF TUMOR 

828
00:38:25,025 --> 00:38:28,528
MICRO ENVIRONMENT I REALIZED WE 

829
00:38:28,528 --> 00:38:32,232
NEEDED NEW TOOLS TO RESOLVE THE 

830
00:38:32,232 --> 00:38:35,969
MICROENVIRONMENT IN A SINGLE 

831
00:38:35,969 --> 00:38:37,170
RESOLUTION FOR THE CELLS.

832
00:38:37,170 --> 00:38:38,305
AND IF YOU CAN'T MAP OUT THE 

833
00:38:38,305 --> 00:38:40,273
CELLS AND WHAT A THAT DO IN THE 

834
00:38:40,273 --> 00:38:42,209
TISSUE CONTEXT THAT WOULD BE A 

835
00:38:42,209 --> 00:38:42,842
HOME RUN.

836
00:38:42,842 --> 00:38:46,746
LET'S DO THIS STEP BY STEP.

837
00:38:46,746 --> 00:38:47,948
I DEVELOPED THE TECHNOLOGY WHILE

838
00:38:47,948 --> 00:38:49,816
PROTEINS IS PRODUCED BY 

839
00:38:49,816 --> 00:38:52,919
DIFFERENT CELLS AND HOW THEY 

840
00:38:52,919 --> 00:38:55,088
INTERACT IN A TUMOR MICRO 

841
00:38:55,088 --> 00:38:55,388
ENVIRONMENT.

842
00:38:55,388 --> 00:39:01,394
THAT WAS MY EARLY RESEARCH IN 

843
00:39:01,394 --> 00:39:05,298
THE IMMUNOINTERACTION AND IN THE

844
00:39:05,298 --> 00:39:08,902
CONTEXT OF EME AND WE CONTINUED 

845
00:39:08,902 --> 00:39:12,405
TO DEVELOP NEW TOOLS AND ADAPT 

846
00:39:12,405 --> 00:39:14,841
NEW TOOLS IN A SPACE OF SINGLE 

847
00:39:14,841 --> 00:39:17,577
CELL BIOLOGY TO LOOK AT CANCER, 

848
00:39:17,577 --> 00:39:19,079
IMMUNOTHERAPY AND THE ONCOLOGY.

849
00:39:19,079 --> 00:39:20,981
WE'RE STILL WORKING ON THAT.

850
00:39:20,981 --> 00:39:22,882
YOU SEE THE NUMBER OF 

851
00:39:22,882 --> 00:39:24,117
PUBLICATIONS BUT NOW THOSE WILL 

852
00:39:24,117 --> 00:39:29,623
ADDRESS MY SECOND QUESTION, CAN 

853
00:39:29,623 --> 00:39:33,493
WE LOOK TO AT THE INTERACTION IN

854
00:39:33,493 --> 00:39:35,295
THE CONTEXT OF THE 

855
00:39:35,295 --> 00:39:35,729
NATIVE--ENVIRONMENT.

856
00:39:35,729 --> 00:39:38,698
SO PEOPLE REALIZE THAT CHALLENGE

857
00:39:38,698 --> 00:39:42,836
ABOUT 10 YEARS AND DEVELOPED NEW

858
00:39:42,836 --> 00:39:45,005
TECHNOLOGIES TO ADDRESS THIS 

859
00:39:45,005 --> 00:39:46,806
SPATIAL BIOLOGY OR SPATIAL 

860
00:39:46,806 --> 00:39:47,741
CANCER BIOLOGY.

861
00:39:47,741 --> 00:39:52,912
SO BROADLY SPEAKING THERE'S TWO 

862
00:39:52,912 --> 00:39:54,948
DIRECTIONS TO DO THOSE.

863
00:39:54,948 --> 00:39:56,983
MICROSCOPY IS PUSHING THE 

864
00:39:56,983 --> 00:40:02,255
BOUNDARY TO A LEVEL UNBELIEVABLE

865
00:40:02,255 --> 00:40:04,291
AND IN THE PAST IF YOU IMAGED 

866
00:40:04,291 --> 00:40:07,160
TWO OR THREE PROTEIN MARKERS AND

867
00:40:07,160 --> 00:40:12,899
MAYBE TWO OR THREE TO LOOK AT 

868
00:40:12,899 --> 00:40:14,734
DIFFERENT GENES YOU ARE ADVANCED

869
00:40:14,734 --> 00:40:20,907
AND PEOPLE ARELIO JEALOUS YOU'RN

870
00:40:20,907 --> 00:40:23,710
EXPECT AND YOU CAN IMAGE GENES 

871
00:40:23,710 --> 00:40:29,382
AND TO LOOK AT THE PROTEINS YOU 

872
00:40:29,382 --> 00:40:34,287
CAN EITHER USE 

873
00:40:34,287 --> 00:40:37,357
IMMUNOFLUORESCENCE AND A PAPER 

874
00:40:37,357 --> 00:40:39,659
IN GENE BIO TECHNOLOGY FROM A 

875
00:40:39,659 --> 00:40:41,161
GRUP IN AUSTRALIA THAT 

876
00:40:41,161 --> 00:40:43,663
DEMONSTRATE THEY CAN IMAGE UP TO

877
00:40:43,663 --> 00:40:49,035
101 DIFFERENT PROTEIN MARKERS 

878
00:40:49,035 --> 00:40:50,770
SETTING A NEW WORLD RECORD IN 

879
00:40:50,770 --> 00:40:51,204
IMAGING.

880
00:40:51,204 --> 00:40:53,373
WHAT I'M GOING TO TALK ABOUT IS 

881
00:40:53,373 --> 00:40:55,141
A DIFFERENT DIRECTION TO DO 

882
00:40:55,141 --> 00:41:00,413
SPATIAL OMICS BASED ON HIGH 

883
00:41:00,413 --> 00:41:01,247
THROUGHPUT SEQUENCING.

884
00:41:01,247 --> 00:41:05,285
AND IN THE LANDMARK PAPER THAT 

885
00:41:05,285 --> 00:41:09,689
CAME OUT 2006 FROM A LAB IN 

886
00:41:09,689 --> 00:41:12,525
STOCKHOLM USING THE DNA MICROWAY

887
00:41:12,525 --> 00:41:14,861
TO CAPTURE THE TISSUE SECTION 

888
00:41:14,861 --> 00:41:18,565
AND IF YOU LOOK AT THE TISSUE 

889
00:41:18,565 --> 00:41:21,101
SECTION YOU PLACE THE TISSUE 

890
00:41:21,101 --> 00:41:24,104
SECTION TO ABUT TRANSCRIPTS TO 

891
00:41:24,104 --> 00:41:27,707
BE RELEASED AND THEN CAPTURE THE

892
00:41:27,707 --> 00:41:30,944
PLOTS AND EACH HAS A UNIQUE 

893
00:41:30,944 --> 00:41:34,614
SPATIAL ADDRESS CODE AND YOU DO 

894
00:41:34,614 --> 00:41:36,449
SYNTHESIS AND YOU'LL INCORPORATE

895
00:41:36,449 --> 00:41:41,755
THE ADDRESS CODES AND WHEN YOU 

896
00:41:41,755 --> 00:41:44,758
WILL DECODE WHERE THE DIFFERENT 

897
00:41:44,758 --> 00:41:50,130
TRANSCRIPTS ARE COMING FROM IN 

898
00:41:50,130 --> 00:41:57,470
THE SPATIAL DEFINED MANNER AND 

899
00:41:57,470 --> 00:41:59,773
THE COMMERCIALIZED LABORATORIES 

900
00:41:59,773 --> 00:42:01,341
PUSHING THE BOUNDARIES TO PUSH 

901
00:42:01,341 --> 00:42:04,911
IT FROM THE BEGINNING IN A LAB 

902
00:42:04,911 --> 00:42:13,586
THAT WAS LIKE 100 MICRONS AND 

903
00:42:13,586 --> 00:42:19,926
THEY ALL FOLLOW THE SAME 

904
00:42:19,926 --> 00:42:22,228
FUNDAMENTAL AND LOOK AT SURFACES

905
00:42:22,228 --> 00:42:25,598
FOR CAPTURE IN THE SPATIAL 

906
00:42:25,598 --> 00:42:25,965
TRANSCRIPTOMICS.

907
00:42:25,965 --> 00:42:28,268
ONE OF MY LABORATORY CAME UP 

908
00:42:28,268 --> 00:42:35,642
WITH OPPOSITE.

909
00:42:35,642 --> 00:42:39,946
AND THERE'S DIFFERENT WAYS BUT 

910
00:42:39,946 --> 00:42:41,848
WE'RE GOOD AT MICRO FLUID 

911
00:42:41,848 --> 00:42:47,220
DELIVERY AND LOOSE THE FLUIDIC 

912
00:42:47,220 --> 00:42:49,589
SYSTEMS TO DO BAR CODING AND 

913
00:42:49,589 --> 00:42:49,989
IT'S VERSATILE.

914
00:42:49,989 --> 00:42:55,328
YOU CAN BAR CODE NOT JUST THE 

915
00:42:55,328 --> 00:42:57,096
TRANSCRIPT AND POTENTIALLY BAR 

916
00:42:57,096 --> 00:42:58,164
CODE EPIGENETICS.

917
00:42:58,164 --> 00:42:59,199
THAT'S WHY I'M HERE TODAY.

918
00:42:59,199 --> 00:43:05,004
WHEN WE PUBLISHED THAT PAPER IT 

919
00:43:05,004 --> 00:43:07,707
TENDED TO SHOW THE BAR CODING TO

920
00:43:07,707 --> 00:43:11,878
LOOK AT WHOLE TRANSCRIPTOME AND 

921
00:43:11,878 --> 00:43:12,512
PROTEIN SETTINGS AND A LOT OF 

922
00:43:12,512 --> 00:43:13,780
RESEARCH GROUPS AROUND THE WORLD

923
00:43:13,780 --> 00:43:15,114
WERE ABLE TO ADOPT THE 

924
00:43:15,114 --> 00:43:17,016
TECHNOLOGY AND SOME ARE ACTUALLY

925
00:43:17,016 --> 00:43:20,954
EVEN DOING BETTER JOB MAKING 

926
00:43:20,954 --> 00:43:21,855
THIS MUCH HIGHER THROUGHPUT.

927
00:43:21,855 --> 00:43:23,790
FOR EXAMPLE THE GROUP FROM 

928
00:43:23,790 --> 00:43:27,527
GERMANY IN MUNICH WERE ABLE TO 

929
00:43:27,527 --> 00:43:29,295
MAP OUT NINE DIFFERENT TISSUES 

930
00:43:29,295 --> 00:43:33,600
IN A SINGLE EXPERIMENT AND TAKE 

931
00:43:33,600 --> 00:43:37,570
ON THE MICROFLUIDIC TO CREATE 

932
00:43:37,570 --> 00:43:41,474
YOUR OWN MARK ARRAY FOR SPATIAL 

933
00:43:41,474 --> 00:43:41,741
ANALYSIS.

934
00:43:41,741 --> 00:43:43,543
HOW THE TECHNOLOGY WORKS TO KEEP

935
00:43:43,543 --> 00:43:46,813
IT BRIEF YOU USE THE MICROFLUID 

936
00:43:46,813 --> 00:43:49,082
DEVICE TO DELIVER DNA BAR CODES 

937
00:43:49,082 --> 00:43:51,417
ONE DIRECTION BUT IT DOES NOT 

938
00:43:51,417 --> 00:43:53,453
GIVE THE 2-D SPATIAL ADDRESS 

939
00:43:53,453 --> 00:43:55,255
CODE SO YOU USE ANOTHER 

940
00:43:55,255 --> 00:43:57,590
MICROFLUID ADVICE TO DELIVER IN 

941
00:43:57,590 --> 00:44:02,629
A HORIZONTAL DIRECTION AND BEAD 

942
00:44:02,629 --> 00:44:05,565
TOGETHER TO CREATE THE PIXEL 

943
00:44:05,565 --> 00:44:07,934
WITH THE COMBINATION AND THAT'S 

944
00:44:07,934 --> 00:44:10,370
HIGH LEVEL IDEA TO DO IN TISSUE 

945
00:44:10,370 --> 00:44:12,272
BAR CODING AND NOW IT DEPENDS ON

946
00:44:12,272 --> 00:44:14,974
WHAT THEY'RE TRYING TO BAR CODE,

947
00:44:14,974 --> 00:44:15,608
TRANSCRIPT PROTEINS OR SOMETHING

948
00:44:15,608 --> 00:44:18,711
ELSE.

949
00:44:18,711 --> 00:44:20,813
AND SO AFTER WE PUBLISHED THAT 

950
00:44:20,813 --> 00:44:24,117
PAPER I THINK A COUPLE MONTHS 

951
00:44:24,117 --> 00:44:26,386
LATER, SPATIAL TRANSCRIPTOMICS 

952
00:44:26,386 --> 00:44:28,955
WAS CHOSEN AND EVERYONE WAS SO 

953
00:44:28,955 --> 00:44:32,125
EXCITED ABOUT IT AND ALSO IN THE

954
00:44:32,125 --> 00:44:34,294
SAME ISSUE OF PAPER AND METHODS 

955
00:44:34,294 --> 00:44:38,298
OUR PAPER WAS HIGHLIGHTED WITH 

956
00:44:38,298 --> 00:44:38,998
MULTIOMIC SPATIAL NOW.

957
00:44:38,998 --> 00:44:42,368
I HAD TO CONFESS, THAT WAS BACK 

958
00:44:42,368 --> 00:44:46,272
TO THAT TIME WE WERE ABLE TO 

959
00:44:46,272 --> 00:44:48,474
DETECT PROTEINS IN CONJUNCTION 

960
00:44:48,474 --> 00:44:50,577
WITH TRANSCRIPTOME TO MY 

961
00:44:50,577 --> 00:44:52,879
STANDARD I WOULD NOT CALL THAT 

962
00:44:52,879 --> 00:44:56,549
PROTEOME AND WHETHER OR NOT YOU 

963
00:44:56,549 --> 00:44:58,985
CAN LOOK AT HUNDREDS OF PROTEINS

964
00:44:58,985 --> 00:45:03,222
OR EVEN THOUSANDS OF PROTEINS IN

965
00:45:03,222 --> 00:45:06,259
CONJUNCTION WITH 

966
00:45:06,259 --> 00:45:07,860
PROTRANSCRIPTOME AND TO 

967
00:45:07,860 --> 00:45:09,829
DEMONSTRATE HOW IT WORKS AND WE 

968
00:45:09,829 --> 00:45:15,735
WERE ABLE TO MAP 300 PROTEINS 

969
00:45:15,735 --> 00:45:23,810
FROM HUMAN TISSUES AND PIXEL BY 

970
00:45:23,810 --> 00:45:26,879
PIXEL COMPARING TISSUE SECTIONS 

971
00:45:26,879 --> 00:45:29,582
INCLUDING I THINK SOME NORM JULY

972
00:45:29,582 --> 00:45:34,621
AND MALIGNANT TISSUE SAMPLES IN 

973
00:45:34,621 --> 00:45:35,955
HUMAN TUMORS.

974
00:45:35,955 --> 00:45:37,290
HOWEVER, WHAT I WANT TO SHARE 

975
00:45:37,290 --> 00:45:41,060
WITH YOU IS WHAT WE BELIEVE THE 

976
00:45:41,060 --> 00:45:45,999
REAL POTENTIAL IS WAY BEYOND THE

977
00:45:45,999 --> 00:45:47,767
SPATIAL GENE EXPRESSION ANALYSIS

978
00:45:47,767 --> 00:45:55,775
TO SOME DEGREE IS STILL -- SO 

979
00:45:55,775 --> 00:45:56,809
MAJORITY OF THE WORK IN THE 

980
00:45:56,809 --> 00:45:58,077
SPACE MOST SPATIAL TECHNOLOGIES 

981
00:45:58,077 --> 00:46:00,313
IS TO MAPPING THE SPATIAL 

982
00:46:00,313 --> 00:46:01,414
AGAINST AND PROTEINS.

983
00:46:01,414 --> 00:46:05,585
WE'RE VERY EXCITED HOW THE 

984
00:46:05,585 --> 00:46:09,122
EXPRESSION OF PROTEINS WAS 

985
00:46:09,122 --> 00:46:12,325
REGULATED IN AN EPIGENETIC LEVEL

986
00:46:12,325 --> 00:46:14,193
AND THERE'S MANY REGULATIONS 

987
00:46:14,193 --> 00:46:17,330
FROM THE ENLIGHTENING TALK FROM 

988
00:46:17,330 --> 00:46:19,932
ANDY ABOUT THE MECHANISMS AND 

989
00:46:19,932 --> 00:46:21,601
HOW THEY'RE RELATED TO CANCER 

990
00:46:21,601 --> 00:46:24,871
AND DECIDED TO START WITH THIS 

991
00:46:24,871 --> 00:46:27,040
CHROMATIN ACCESSIBILITY AND 

992
00:46:27,040 --> 00:46:28,408
HISTO MODIFICATIONS AND WE 

993
00:46:28,408 --> 00:46:31,177
BELIEVE OUR APPROACH CAN BE 

994
00:46:31,177 --> 00:46:35,882
ADAPTED AND FURTHER MODIFIED TO 

995
00:46:35,882 --> 00:46:39,318
MAP SPATIAL METHYLOME AND 3-D 

996
00:46:39,318 --> 00:46:41,587
GENOME AND THERE'S ONGOING WORK 

997
00:46:41,587 --> 00:46:48,895
IN MY LABORATORY AND MY TRAINEES

998
00:46:48,895 --> 00:46:57,570
LABORATORIES AND SO WE USED A 

999
00:46:57,570 --> 00:47:02,775
TAXIC DEVELOPED BY ELEGANT 

1000
00:47:02,775 --> 00:47:08,214
CHEMISTRY TREATING THE ISOLATED 

1001
00:47:08,214 --> 00:47:15,755
NUCLEI AND TRANS POSE THIS WITH 

1002
00:47:15,755 --> 00:47:17,890
THE SEQUENCE AND IT WILL BE 

1003
00:47:17,890 --> 00:47:23,896
INSERTED INTO GENOMIC DNA AND 

1004
00:47:23,896 --> 00:47:25,765
CLAMP IT IN THE SEQUENCE AND 

1005
00:47:25,765 --> 00:47:27,100
YOU'LL MAP WHERE THE RATINGS ARE

1006
00:47:27,100 --> 00:47:30,036
LOCATED IN THE GENOME.

1007
00:47:30,036 --> 00:47:33,606
BUT IF YOU DO THIS EXPERIMENT 

1008
00:47:33,606 --> 00:47:35,608
PEOPLE ALWAYS ADVISE ALL RIGHT, 

1009
00:47:35,608 --> 00:47:40,246
FIRST STEP IS THE NUCLEI BUT WE 

1010
00:47:40,246 --> 00:47:42,915
FOUND IF YOU HAVE THIN TISSUE 

1011
00:47:42,915 --> 00:47:45,585
SECTION YOU CAN GO IN THE 

1012
00:47:45,585 --> 00:47:52,625
PROCESS WITH TRANSPOSES.

1013
00:47:52,625 --> 00:47:57,396
WITH OUR EXPERIMENT TO TREAT 

1014
00:47:57,396 --> 00:47:59,899
THE--TISSUE SECTIONS AND WE USE 

1015
00:47:59,899 --> 00:48:01,601
THE MICROFLUID DEVICE FOR BAR 

1016
00:48:01,601 --> 00:48:06,105
CODE A AND B AND HAVE NO SPATIAL

1017
00:48:06,105 --> 00:48:11,310
RESULT ATAXIC DATA PIXEL BY 

1018
00:48:11,310 --> 00:48:16,282
PIXEL AND IN ONE EXPERIMENT YOU 

1019
00:48:16,282 --> 00:48:21,854
DO THOUSANDS OF EXPERIMENTS AT 

1020
00:48:21,854 --> 00:48:24,123
THE SAME TIME AND EACH RESPONDS 

1021
00:48:24,123 --> 00:48:27,693
TO A TINY TISSUE AND NOW WHERE 

1022
00:48:27,693 --> 00:48:29,262
THEY ARE IN THE SECTION.

1023
00:48:29,262 --> 00:48:32,064
SO FROM THE PIXELS, FOR EXAMPLE,

1024
00:48:32,064 --> 00:48:39,305
ASSOCIATED WITH THE EMBRYONIC 

1025
00:48:39,305 --> 00:48:43,042
LEVER YOU SEE THE DATA TRACE YOU

1026
00:48:43,042 --> 00:48:44,377
CAN ALSO AGGREGATE ALL THE 

1027
00:48:44,377 --> 00:48:49,582
PIXELS FROM LEVER TO PRODUCE 

1028
00:48:49,582 --> 00:48:54,620
THIS CONCORDANCE WITH A 

1029
00:48:54,620 --> 00:48:55,955
REFERENCE DATA.

1030
00:48:55,955 --> 00:48:57,723
WHEN YOU LOOK AT PIXELS YOU CAN 

1031
00:48:57,723 --> 00:49:02,862
LOOK AT THE CLUSTER ANALYSIS USE

1032
00:49:02,862 --> 00:49:06,799
ROUTINE LEVEL ATAXIC TO KIND OF 

1033
00:49:06,799 --> 00:49:07,733
AGGREGATE DIFFERENT CAST 

1034
00:49:07,733 --> 00:49:12,939
DIFFERENT PIXELS INTO DIFFERENT 

1035
00:49:12,939 --> 00:49:13,206
CLUSTERS.

1036
00:49:13,206 --> 00:49:14,841
AND HERE YOU CAN FIGURE OUT 

1037
00:49:14,841 --> 00:49:16,843
WHERE THE PIXELS ARE IN THE 

1038
00:49:16,843 --> 00:49:22,081
CLUSTERS ARE LOCATED IN THE 

1039
00:49:22,081 --> 00:49:24,784
TISSUE AND CLUSTERS IDENTIFIED 

1040
00:49:24,784 --> 00:49:26,252
IN THE UMAB IN THE FIGURE B 

1041
00:49:26,252 --> 00:49:29,956
HERE.

1042
00:49:29,956 --> 00:49:33,593
YOU'LL SEE WHERE THEY ARE AND 

1043
00:49:33,593 --> 00:49:36,229
THE CLUSTER IS INDEED FROM THE 

1044
00:49:36,229 --> 00:49:39,765
ANALYSIS AND YOU CAN DO YOUR OWN

1045
00:49:39,765 --> 00:49:41,500
ANNOTATION AND THAT'S THE LIVER 

1046
00:49:41,500 --> 00:49:45,571
AND SPINE AND YOU CAN PROJECT 

1047
00:49:45,571 --> 00:49:50,376
ALL THE TISSUE PIXELS AND ALSO 

1048
00:49:50,376 --> 00:49:51,777
VISUALIZE INDIVIDUAL GENES BY 

1049
00:49:51,777 --> 00:49:52,979
KEEPING IN MIND WHAT YOU'RE 

1050
00:49:52,979 --> 00:49:56,315
SEEING IS NOT GENE EXPRESSION 

1051
00:49:56,315 --> 00:49:57,783
BUT IT'S ASSOCIATED WITH THE 

1052
00:49:57,783 --> 00:49:57,984
GENES.

1053
00:49:57,984 --> 00:50:00,920
NOW YOUR ABLE TO DIRECTLY 

1054
00:50:00,920 --> 00:50:01,954
VISUALIZE THE DATA IN THE TISSUE

1055
00:50:01,954 --> 00:50:04,290
THAT HAS NEVER BEEN POSSIBLE IN 

1056
00:50:04,290 --> 00:50:08,127
THE PAST.

1057
00:50:08,127 --> 00:50:13,599
WHAT'S INTERESTING IN MY LAB 

1058
00:50:13,599 --> 00:50:15,601
NOWADAYS AND THE IMMUNOLOGY WE 

1059
00:50:15,601 --> 00:50:19,372
CONTINUE TO LOOK AT THE IMMUNE 

1060
00:50:19,372 --> 00:50:22,208
SYSTEM AND IN PARTICULAR HOW THE

1061
00:50:22,208 --> 00:50:24,410
IMMUNOSENESCENCE IS CONNECTED TO

1062
00:50:24,410 --> 00:50:26,312
THE DIFFERENT DISEASE INCLUDING 

1063
00:50:26,312 --> 00:50:26,545
CANCER.

1064
00:50:26,545 --> 00:50:32,318
YOU CAN LOOK AT THE IMMUNOCELL 

1065
00:50:32,318 --> 00:50:34,787
HALLMARKS AND SOME REASON WE'RE 

1066
00:50:34,787 --> 00:50:39,725
LOOKING TO EPIGENETICS DATA FOR 

1067
00:50:39,725 --> 00:50:40,793
IMMUNOSENESCENCE AN THIS IS 

1068
00:50:40,793 --> 00:50:46,632
BASED ON THE ATAXIC DATA AND THE

1069
00:50:46,632 --> 00:50:52,104
HALLMARKS AND MARKERS OF THE 

1070
00:50:52,104 --> 00:50:59,345
ZONES YOU CAN'T IDENTIFY THE 

1071
00:50:59,345 --> 00:51:08,587
MARKER GENES AND WE CAN IDENTIFY

1072
00:51:08,587 --> 00:51:11,757
THE MARKERS AND THEY DON'T 

1073
00:51:11,757 --> 00:51:14,060
ALWAYS OVERLAP FURTHER 

1074
00:51:14,060 --> 00:51:14,593
EMPHASIZE.

1075
00:51:14,593 --> 00:51:19,131
EVEN SENESCENT CELLS FROM THE 

1076
00:51:19,131 --> 00:51:22,568
SAME CELL TYPES ARE HETEROGENOUS

1077
00:51:22,568 --> 00:51:28,274
FROM THE DISEASE STATE AND 

1078
00:51:28,274 --> 00:51:34,080
CHANGE IN THE LOCAL TISSUE 

1079
00:51:34,080 --> 00:51:36,682
ENVIRONMENT AND OTHER CELLS NEED

1080
00:51:36,682 --> 00:51:37,083
TO BE ELUCIDATED.

1081
00:51:37,083 --> 00:51:47,493
WE NEED TO LOOK TO THE 

1082
00:51:49,662 --> 00:51:56,535
MODIFICATIONS AND THERE'S A 

1083
00:51:56,535 --> 00:52:05,144
SIMILAR CHEMISTRY BUT USE 

1084
00:52:05,144 --> 00:52:08,681
PROTEIN A TO LOOK AT THE SITES 

1085
00:52:08,681 --> 00:52:10,082
WITH THE SPECIFIC MODIFICATIONS.

1086
00:52:10,082 --> 00:52:16,288
WE DEMONSTRATED THIS IN MOUSE 

1087
00:52:16,288 --> 00:52:19,291
EMBRYO AND USING DIFFERENT MARKS

1088
00:52:19,291 --> 00:52:28,267
AND EVEN WITHOUT DOING THEO  

1089
00:52:28,267 --> 00:52:32,571
HISTO MODIFICATIONS YOU CAN SEE 

1090
00:52:32,571 --> 00:52:35,641
HOW THEY CONTROL TISSUE TYPES AT

1091
00:52:35,641 --> 00:52:38,744
THIS STAGE OF MOUSE EMBRYONIC 

1092
00:52:38,744 --> 00:52:39,045
DEVELOPMENT.

1093
00:52:39,045 --> 00:52:42,848
WHEN YOU CLUSTER ALL THE PIXELS 

1094
00:52:42,848 --> 00:52:43,682
TOGETHER AND COMPARE AGAINST THE

1095
00:52:43,682 --> 00:52:48,421
REFERENCE DATA YOU DO SEE OVER 

1096
00:52:48,421 --> 00:52:50,022
ALL CONCORDANCE BETWEEN OUR DATA

1097
00:52:50,022 --> 00:52:51,057
AND REFERENCE DATA.

1098
00:52:51,057 --> 00:52:54,460
OUR DATA GIVES YOU MORE GRANULAR

1099
00:52:54,460 --> 00:52:56,328
INFORMATION BECAUSE WE HAVE 

1100
00:52:56,328 --> 00:52:59,698
PIXEL BY PIXEL AND HAVE THE SAME

1101
00:52:59,698 --> 00:53:01,534
LEVER I THINK DIFFERENT WITHIN 

1102
00:53:01,534 --> 00:53:09,575
THE LEVER YOU SHOULD BE ABLE TO 

1103
00:53:09,575 --> 00:53:11,644
SEE EPIGENETICS AS WELL.

1104
00:53:11,644 --> 00:53:16,115
SO AND IN THE INTRODUCTION SLIDE

1105
00:53:16,115 --> 00:53:18,117
WE WERE ABLE TO FURTHER COMBINE 

1106
00:53:18,117 --> 00:53:19,819
EPIGENETIC TRANSCRIPTOME IN THE 

1107
00:53:19,819 --> 00:53:23,522
SAME CELL PIXEL BY PIXEL ACROSS 

1108
00:53:23,522 --> 00:53:24,757
THE ENTIRE TISSUE AND WHAT 

1109
00:53:24,757 --> 00:53:25,925
YOU'RE SEEING IS THREE DIFFERENT

1110
00:53:25,925 --> 00:53:30,429
HISTO MARKED FROM EVERY SINGLE 

1111
00:53:30,429 --> 00:53:32,932
HISTO MARK EXPERIMENT WE'RE ABLE

1112
00:53:32,932 --> 00:53:35,901
TO PERFORM WHOLE TRANSCRIPTOME 

1113
00:53:35,901 --> 00:53:38,704
SPATIAL SEQUENCING.

1114
00:53:38,704 --> 00:53:40,406
YOU CAN THINK IN THE EPIGENETIC 

1115
00:53:40,406 --> 00:53:42,441
MECHANISM TO THE OUTCOME IN THE 

1116
00:53:42,441 --> 00:53:45,578
GENE EXPRESSION.

1117
00:53:45,578 --> 00:53:49,148
I DID SHOW YOU ONE EXAMPLE WITH 

1118
00:53:49,148 --> 00:53:50,950
THE EMBRYONIC MOUSE DEVELOPMENT 

1119
00:53:50,950 --> 00:53:51,617
PARTICULARLY IN THE BRAIN FROM 

1120
00:53:51,617 --> 00:53:59,925
EITHER ATAXIC OR RNA.

1121
00:53:59,925 --> 00:54:02,561
YOU'RE ABLE TO CLUSTER THE 

1122
00:54:02,561 --> 00:54:03,762
PIXELS INTO DIFFERENT TISSUE 

1123
00:54:03,762 --> 00:54:03,963
TYPES.

1124
00:54:03,963 --> 00:54:05,865
EITHER ONE WORKED OUT VERY WELL.

1125
00:54:05,865 --> 00:54:11,537
YOU CAN ALSO FURTHER INTEGRATE 

1126
00:54:11,537 --> 00:54:17,977
YOUR DATA WITH SINGLE CELL 

1127
00:54:17,977 --> 00:54:20,246
ANNOTATION TO SPATIAL AND WE'RE 

1128
00:54:20,246 --> 00:54:23,182
IN A DIFFERENT CELLS ARE AND 

1129
00:54:23,182 --> 00:54:25,851
HERE'S A FEW EXAMPLE FOR EXAMPLE

1130
00:54:25,851 --> 00:54:29,588
THE INHIBITORY INTERNEURONS AND 

1131
00:54:29,588 --> 00:54:33,592
PROGENITOR NEURONS LIKE THE 

1132
00:54:33,592 --> 00:54:37,596
RADIAL GLIA AND IT'S LOCALIZED 

1133
00:54:37,596 --> 00:54:42,401
IN THE VENTRICLE IS WHAT I 

1134
00:54:42,401 --> 00:54:43,769
ANTICIPATED AND NOW WHERE THE 

1135
00:54:43,769 --> 00:54:45,237
MECHANISM CONTROL THE 

1136
00:54:45,237 --> 00:54:47,039
DEVELOPMENT OF THE PARTICULAR 

1137
00:54:47,039 --> 00:54:50,109
CELL OR MECHANISM OF THE CELL 

1138
00:54:50,109 --> 00:54:50,309
FATE.

1139
00:54:50,309 --> 00:54:53,913
WITH THE TUMOR DATA YOU CAN LOOK

1140
00:54:53,913 --> 00:54:57,049
AT THE GENE REGULATORY NETWORK.

1141
00:54:57,049 --> 00:55:00,553
ANOTHER EXAMPLE SHOWING THE 

1142
00:55:00,553 --> 00:55:02,888
POWER TO HAVE THE SAME CELL 

1143
00:55:02,888 --> 00:55:08,093
ACROSS THE WHOLE TISSUE IS WE 

1144
00:55:08,093 --> 00:55:13,599
CAN LOOK AT THE PROCESS FOR THE 

1145
00:55:13,599 --> 00:55:16,302
PLASTICITY AND THE CANCER CELL 

1146
00:55:16,302 --> 00:55:19,638
SO TRANSITION FOR EXAMPLE IN 

1147
00:55:19,638 --> 00:55:19,805
EMT.

1148
00:55:19,805 --> 00:55:25,844
WHAT I'M SHOWING IS RADIAL GLIA 

1149
00:55:25,844 --> 00:55:27,980
DIFFERENTIATION NEURONS AND THE 

1150
00:55:27,980 --> 00:55:31,917
GENERAL HYPOTHESIS OPENING UP 

1151
00:55:31,917 --> 00:55:33,052
FIRST AND LATER IN THE GENE 

1152
00:55:33,052 --> 00:55:38,691
EXPRESSED YOU SEE IT'S TRUE IN 

1153
00:55:38,691 --> 00:55:45,231
MOST THE CASES BUT YOU'LL SEE 

1154
00:55:45,231 --> 00:55:50,970
CHROMATIN OPENED UP AND THIS IS 

1155
00:55:50,970 --> 00:55:53,305
THE GROUP OF GENES.

1156
00:55:53,305 --> 00:55:56,108
AND REMAINS OPEN BUT IN THE RNA 

1157
00:55:56,108 --> 00:55:58,277
QUICKLY DIMINISH AND WE FOUND 

1158
00:55:58,277 --> 00:56:02,881
THOSE GENES ARE NOT FOR NEURONS 

1159
00:56:02,881 --> 00:56:05,117
NEURONAL CELLS COMMITTED TO 

1160
00:56:05,117 --> 00:56:05,618
LINEAGES.

1161
00:56:05,618 --> 00:56:12,858
THOSE GENES ARE STRONGLY 

1162
00:56:12,858 --> 00:56:13,559
ASSOCIATED WITH OLIGO DENDRO 

1163
00:56:13,559 --> 00:56:14,893
LINEAGE AND THE CELLS DECIDED TO

1164
00:56:14,893 --> 00:56:19,365
BE BECOME NEURONS BUT STILL 

1165
00:56:19,365 --> 00:56:24,303
THEIR POTENTIAL TO BECOME OLIGO 

1166
00:56:24,303 --> 00:56:27,806
DENDROCYTES IS INTRIGUING SO ANY

1167
00:56:27,806 --> 00:56:29,575
ENVIRONMENTAL STIMULATION THAT 

1168
00:56:29,575 --> 00:56:31,076
MAY TRIGGER THE TRANS 

1169
00:56:31,076 --> 00:56:36,048
DIFFERENTIATION THOSE CELLS DO 

1170
00:56:36,048 --> 00:56:39,285
HAVE THE POTENTIAL TO BECOME 

1171
00:56:39,285 --> 00:56:43,622
OLIGO DENDROCELL LINEAGE AND 

1172
00:56:43,622 --> 00:56:47,159
THEY HAVE THE POTENTIAL AND 

1173
00:56:47,159 --> 00:56:52,564
COMMITTED TO THE OLIGO 

1174
00:56:52,564 --> 00:56:54,433
DENDROLINEAGE AND THE TWO 

1175
00:56:54,433 --> 00:56:56,635
PATHWAYS THEY MIGHT TAKE AND YOU

1176
00:56:56,635 --> 00:56:57,336
CAN VISUALIZE WHERE THEY ARE IN 

1177
00:56:57,336 --> 00:57:05,711
THE SPATIAL CONTEXT.

1178
00:57:05,711 --> 00:57:07,579
I WANTED TO SHOW OUR ONGOING 

1179
00:57:07,579 --> 00:57:10,316
WORK IN THE CANCER RESEARCH 

1180
00:57:10,316 --> 00:57:12,785
SPACE.

1181
00:57:12,785 --> 00:57:16,288
WE MAPPED OUT THE SPATIAL 

1182
00:57:16,288 --> 00:57:23,896
PROFILE THE HUMAN GLI AL BLASTOA

1183
00:57:23,896 --> 00:57:26,165
AND YOU SEE THE SECOND ROW AND 

1184
00:57:26,165 --> 00:57:29,601
THIRD AND FOURTH ARE FROM 

1185
00:57:29,601 --> 00:57:33,505
ANOTHER TUMOR SAMPLE AND RNA AND

1186
00:57:33,505 --> 00:57:35,507
PROTEIN AND CHROMATIN ACCESS.

1187
00:57:35,507 --> 00:57:35,941
I'LL WRAP UP.

1188
00:57:35,941 --> 00:57:38,811
ONE LAST SLIDE.

1189
00:57:38,811 --> 00:57:41,747
I CAN DIRECTLY VISUALIZE THE 

1190
00:57:41,747 --> 00:57:45,384
EPIGENETIC PLASTICITY OF HUMAN 

1191
00:57:45,384 --> 00:57:47,786
BLASTOMA AND BASED ON THE 

1192
00:57:47,786 --> 00:57:51,824
SIGNATURES IDENTIFIED FOR MPC, 

1193
00:57:51,824 --> 00:57:57,196
OPC THROUGH ASTROCYTE.

1194
00:57:57,196 --> 00:57:59,732
YOU PERFORM THE TIME TO LOOK AT 

1195
00:57:59,732 --> 00:58:04,803
THE CELLS AND YOU CAN DIRECTLY 

1196
00:58:04,803 --> 00:58:06,472
VISUALIZE THE CELL CAPSULE WITH 

1197
00:58:06,472 --> 00:58:12,144
THE DIFFERENTIATION OR THE 

1198
00:58:12,144 --> 00:58:13,612
PLASTIC TRANSITION IN THE SPACE 

1199
00:58:13,612 --> 00:58:17,316
IN THE BOUNDARY OF THE TUMOR 

1200
00:58:17,316 --> 00:58:18,417
SUBTYPES IN THE TUMOR.

1201
00:58:18,417 --> 00:58:22,888
JUST TO WRAP UP HERE, ANOTHER 

1202
00:58:22,888 --> 00:58:27,826
GAM IS NEUROENDOCRY TUMOR IN THE

1203
00:58:27,826 --> 00:58:38,370
HUMAN PANCREAS AND I'LL WRAP UP 

1204
00:58:41,407 --> 00:58:43,208
BY THANKING MY OWN GROUP MEMBERS

1205
00:58:43,208 --> 00:58:50,249
AND MY AMAZING COLLABORATORS AND

1206
00:58:50,249 --> 00:58:55,721
SUPPORT FROM NCI.

1207
00:58:55,721 --> 00:59:00,426
THANK YOU FOR YOUR ATTENTION.

1208
00:59:00,426 --> 00:59:02,094
>> THANK YOU SO MUCH.

1209
00:59:02,094 --> 00:59:05,497
IT'S AMAZING WORK.

1210
00:59:05,497 --> 00:59:06,098
INCREDIBLY POWERFUL.

1211
00:59:06,098 --> 00:59:07,933
I THINK BECAUSE OF THE TIME 

1212
00:59:07,933 --> 00:59:09,168
WE'LL TAKE ONE QUESTION IF 

1213
00:59:09,168 --> 00:59:10,569
THAT'S OKAY IF THERE'S A 

1214
00:59:10,569 --> 00:59:10,836
QUESTION.

1215
00:59:10,836 --> 00:59:11,270
GO AHEAD.

1216
00:59:11,270 --> 00:59:15,374
I'LL GO DOWN TO MAKE SURE -- 

1217
00:59:15,374 --> 00:59:16,275
>> QUICK QUESTION.

1218
00:59:16,275 --> 00:59:17,142
GREAT TALK.

1219
00:59:17,142 --> 00:59:19,711
I WAS WONDERING IN THE 

1220
00:59:19,711 --> 00:59:21,079
SENESCENCE MARKERS YOU WERE 

1221
00:59:21,079 --> 00:59:30,756
SHOWING THE HETEROGENEITY OF 

1222
00:59:30,756 --> 00:59:32,424
CDKN WHERE OTHER MARKERS LIKE 

1223
00:59:32,424 --> 00:59:35,694
IL6 AND SO ON DO YOU SEE A 

1224
00:59:35,694 --> 00:59:38,931
DIFFERENCE IN DEGRADATION IN 

1225
00:59:38,931 --> 00:59:39,164
MARKERS?

1226
00:59:39,164 --> 00:59:45,604
MY NAME IS HARI ISHWAN FROM 

1227
00:59:45,604 --> 00:59:51,543
JOHNS HOPKINS UNIVERSITY.

1228
00:59:51,543 --> 00:59:53,545
>> THAT'S THE MESSAGE I
WANT TO 

1229
00:59:53,545 --> 00:59:55,681
CONVEY IF I DIDN'T MAKE THAT 

1230
00:59:55,681 --> 00:59:56,014
CLEAR.

1231
00:59:56,014 --> 00:59:58,217
IT'S STILL TOO EARLY TO DRAW ANY

1232
00:59:58,217 --> 01:00:01,453
CONCLUSION BUT WE OBSERVED THE 

1233
01:00:01,453 --> 01:00:03,989
HETEROGENEITY BETWEEN THE 

1234
01:00:03,989 --> 01:00:11,029
MARKERS P16 AND MGB1 AND NOT 

1235
01:00:11,029 --> 01:00:12,731
ALWAYS THERE'S SENESCENCE 

1236
01:00:12,731 --> 01:00:14,633
MARKERS AND ONCE YOU SEE IT 

1237
01:00:14,633 --> 01:00:16,068
POSITIVE FOR P16 BUT NOT 

1238
01:00:16,068 --> 01:00:17,603
POSITIVE FOR OTHERS.

1239
01:00:17,603 --> 01:00:21,340
SOMETIMES WE SEE THERE'S 

1240
01:00:21,340 --> 01:00:22,174
MUTUALLY EXCLUSIVE.

1241
01:00:22,174 --> 01:00:24,810
WE STILL DON'T HAVE CLEAR ANSWER

1242
01:00:24,810 --> 01:00:28,614
BUT THE GENERAL OBSERVATION SO 

1243
01:00:28,614 --> 01:00:31,617
FAR ACROSS SEVERAL TISSUE TYPES 

1244
01:00:31,617 --> 01:00:32,851
IF THEY BECOME CELLS DRIVING 

1245
01:00:32,851 --> 01:00:35,821
DISEASE OR DRIVING AGING AND YOU

1246
01:00:35,821 --> 01:00:38,023
SEE THOSE MARKERS REGULARLY 

1247
01:00:38,023 --> 01:00:39,925
CONVERGE BUT EARLY STAGE YOU SEE

1248
01:00:39,925 --> 01:00:46,398
THE SENESCENCE OR SENESCENT LAG 

1249
01:00:46,398 --> 01:00:48,333
CELLS THEY DEVELOP THROUGH 

1250
01:00:48,333 --> 01:00:49,868
DIFFERENT BIOLOGICAL PATHWAYS.

1251
01:00:49,868 --> 01:00:54,873
AND WE CHOOSE THE MARKERS 

1252
01:00:54,873 --> 01:00:56,341
BECAUSE THEY REPRESENT PROCESSES

1253
01:00:56,341 --> 01:00:58,944
TO BECOME SENESCENT AND YOU SEE 

1254
01:00:58,944 --> 01:01:04,249
IT COME FROM DIFFERENT PATH AND 

1255
01:01:04,249 --> 01:01:06,685
IF THEY CONVERGE THEY'RE MAKING 

1256
01:01:06,685 --> 01:01:09,588
TROUBLE.

1257
01:01:09,588 --> 01:01:10,455
BUT I THINK IT'S EARLY 

1258
01:01:10,455 --> 01:01:12,224
PHILOSOPHICAL THINK.

1259
01:01:12,224 --> 01:01:16,194
I THINK WE NEED MORE DATA TO 

1260
01:01:16,194 --> 01:01:16,595
DRAW CONCLUSIONS.

1261
01:01:16,595 --> 01:01:26,939
THANK YOU VERY MUCH.

1262
01:01:28,907 --> 01:01:32,244
>> THE NEXT SPEAKER IS
STEVE 

1263
01:01:32,244 --> 01:01:35,714
BAYLIN FROM JOHNS HOPKINS 

1264
01:01:35,714 --> 01:01:37,583
TALKING ABOUT EPIGENETIC STATES 

1265
01:01:37,583 --> 01:01:39,918
OF TUMOR PARENT CELLS AND HOW 

1266
01:01:39,918 --> 01:01:41,153
EPIGENETIC ABNORMALITIES CAN 

1267
01:01:41,153 --> 01:01:42,287
DRIVE PRE-MALIGNANT TUMOR 

1268
01:01:42,287 --> 01:01:45,457
PROGRESSION.

1269
01:01:45,457 --> 01:01:45,857
>> THANK YOU.

1270
01:01:45,857 --> 01:01:50,128
I WANT TO THANK THE ORGANIZERS.

1271
01:01:50,128 --> 01:01:58,604
I'M HONORED TO BE PART OF THIS 

1272
01:01:58,604 --> 01:01:59,471
ANNIVERSARY AND CONTRIBUTE SOME.

1273
01:01:59,471 --> 01:02:10,015
THE FIRST ACKNOWLEDGEMENT IS A 

1274
01:02:12,884 --> 01:02:13,885
WHIMSICAL ONES AND UNDERSTANDING

1275
01:02:13,885 --> 01:02:19,925
HOW EMBRYOS FORM ALL THE WAY 

1276
01:02:19,925 --> 01:02:27,265
THROUGH WE HAVE TRANSPOSE 

1277
01:02:27,265 --> 01:02:27,499
ELEMENT.

1278
01:02:27,499 --> 01:02:29,034
EPIGENETICS WRIT LARGE IS A 

1279
01:02:29,034 --> 01:02:30,135
BUILDING FIELD AND HERE HAVE YOU

1280
01:02:30,135 --> 01:02:33,071
CANCER PIONEERS AND STEVEN JONES

1281
01:02:33,071 --> 01:02:39,711
AND ANDY FINEBERG DOWN HERE AND 

1282
01:02:39,711 --> 01:02:43,415
IT'S QUITE A HISTORY OF 

1283
01:02:43,415 --> 01:02:44,416
CONTRIBUTIONS FROM THE SHOULDERS

1284
01:02:44,416 --> 01:02:45,450
WE STAND ON.

1285
01:02:45,450 --> 01:02:46,818
THE ONLY REASON I'M HERE IS I 

1286
01:02:46,818 --> 01:02:49,221
STAND ON ALL THESE SHOULDERS AND

1287
01:02:49,221 --> 01:02:50,822
THESE ARE SOME OF A GROUP OF 

1288
01:02:50,822 --> 01:02:52,924
PEOPLE THAT TRAINED WITH ME AND 

1289
01:02:52,924 --> 01:02:54,026
CONTRIBUTED TO THE FIELD AND 

1290
01:02:54,026 --> 01:02:55,327
SOME IN THE AUDIENCE.

1291
01:02:55,327 --> 01:03:00,832
I'LL ONLY INTRODUCE A FEW DURING

1292
01:03:00,832 --> 01:03:05,837
THE TALK BUT THEY'VE TAKEN THE 

1293
01:03:05,837 --> 01:03:08,774
FIELD INTO FIELD I NEVER WOULD 

1294
01:03:08,774 --> 01:03:10,375
HAVE IMAGINED AND AREAS I NEVER 

1295
01:03:10,375 --> 01:03:13,078
WOULD HAVE IMAGINED.

1296
01:03:13,078 --> 01:03:17,816
HERE'S WHAT I'LL TALK ABOUT 

1297
01:03:17,816 --> 01:03:18,016
TODAY.

1298
01:03:18,016 --> 01:03:20,652
I HAVE REMARKS ANDY MADE AND 

1299
01:03:20,652 --> 01:03:22,721
TALK ABOUT THE EVOLUTION OF 

1300
01:03:22,721 --> 01:03:26,792
CANCER FROM THE CELLS OF ORIGIN 

1301
01:03:26,792 --> 01:03:29,594
AND THEY'RE EPIGENETIC STATE 

1302
01:03:29,594 --> 01:03:32,898
SETS THE STAGE AND THEY CAN 

1303
01:03:32,898 --> 01:03:35,333
DEPEND ON PROGRESSION OF 

1304
01:03:35,333 --> 01:03:38,704
ABNORMALITIES DURING THE PRE 

1305
01:03:38,704 --> 01:03:40,205
MALIGNANT PHASE AND BRING THEM 

1306
01:03:40,205 --> 01:03:41,973
TO A POINT THAT ALLOW THE CELL 

1307
01:03:41,973 --> 01:03:45,010
WHEN IT SEES THE MUTATION TO 

1308
01:03:45,010 --> 01:03:46,611
FORM CANCER AND HAVE CANCER 

1309
01:03:46,611 --> 01:03:46,912
INITIATION.

1310
01:03:46,912 --> 01:03:49,581
AT THE END I'LL TALK ABOUT VERY 

1311
01:03:49,581 --> 01:03:50,882
BRIEFLY SOME DRUG DEVELOPMENT 

1312
01:03:50,882 --> 01:03:52,317
FOR NEW TARGETS THAT HAVE COME 

1313
01:03:52,317 --> 01:03:55,387
OUT OF SOME OF THE THINGS THAT 

1314
01:03:55,387 --> 01:03:55,887
I'LL TALK TO YOU ABOUT.

1315
01:03:55,887 --> 01:03:58,290
SO THIS IS A SLIDE FROM PETER 

1316
01:03:58,290 --> 01:03:58,790
JONES.

1317
01:03:58,790 --> 01:04:01,426
A GOOD ONE THE THREE DIMENSIONAL

1318
01:04:01,426 --> 01:04:03,528
STRUCTURE OF THE EPIGENOME WE'VE

1319
01:04:03,528 --> 01:04:07,265
BEEN HEARING ABOUT AND HOW THE 

1320
01:04:07,265 --> 01:04:09,701
MICROCOSM STARTED IN THE MID 

1321
01:04:09,701 --> 01:04:11,770
'80s AND A GRANT GAVE US A 

1322
01:04:11,770 --> 01:04:14,072
CHANCE TO START PLAYING THIS OUT

1323
01:04:14,072 --> 01:04:16,475
WHERE YOU HAVE DURING TUMOR 

1324
01:04:16,475 --> 01:04:21,079
PROGRESSION AT SOME POINT A 

1325
01:04:21,079 --> 01:04:26,518
TRANSITION WHERE DNA METHYLATION

1326
01:04:26,518 --> 01:04:28,086
CREEPS INTO GENES THAT DON'T 

1327
01:04:28,086 --> 01:04:32,157
HAVE THIS CHANGE FOR THE MOST 

1328
01:04:32,157 --> 01:04:32,557
PART.

1329
01:04:32,557 --> 01:04:43,068
THEY REMAIN UNMETHYLATED AND 

1330
01:04:45,670 --> 01:04:47,439
MANY GENES THAT MAKE THE CHANGE 

1331
01:04:47,439 --> 01:04:51,543
ARE CONTROLLED DURING NORMAL 

1332
01:04:51,543 --> 01:04:53,011
DEVELOPMENT WITHOUT DNA 

1333
01:04:53,011 --> 01:04:56,014
METHYLATION AND BY THE 

1334
01:04:56,014 --> 01:04:58,116
PLASTICITY OF THE REPRESSER 

1335
01:04:58,116 --> 01:04:58,316
UNIT.

1336
01:04:58,316 --> 01:05:02,420
I WANT TO ALSO POINT OUT THIS 

1337
01:05:02,420 --> 01:05:03,421
SAY PROGRESSIVE CHANGE.

1338
01:05:03,421 --> 01:05:09,060
THIS IS A REVIEW PETER AND I 

1339
01:05:09,060 --> 01:05:12,564
WROTE BACK IN 2002 IF YOU HAVE 

1340
01:05:12,564 --> 01:05:14,099
THIS YOU GENERALLY HAVE ONE AND 

1341
01:05:14,099 --> 01:05:16,234
YOU KNOCK THE PROTEIN OUT.

1342
01:05:16,234 --> 01:05:19,471
THE PROGRESSIVE CHANGES IN CPGI 

1343
01:05:19,471 --> 01:05:21,373
LINK WHERE IT GETS DENSER AND 

1344
01:05:21,373 --> 01:05:28,313
DENSER AND BEGINS TO SILENCE THE

1345
01:05:28,313 --> 01:05:38,790
GENE IS A HAPLO FLUORESCENT 

1346
01:05:39,357 --> 01:05:39,858
STATE AND INTERFERE IN THE 

1347
01:05:39,858 --> 01:05:50,001
PATHWAY.

1348
01:05:53,805 --> 01:05:56,842
BACK IN 2012 HARI HAD A PAPER 

1349
01:05:56,842 --> 01:06:01,580
WHERE HE SHOWED HOW THE 

1350
01:06:01,580 --> 01:06:03,048
PROGRESSION TO THE DNA 

1351
01:06:03,048 --> 01:06:04,916
METHYLATION CORRELATED WITH THE 

1352
01:06:04,916 --> 01:06:08,086
RELATIVE LOCKING IN OF THE STEM 

1353
01:06:08,086 --> 01:06:08,887
CELL LIKE PHENOTYPE.

1354
01:06:08,887 --> 01:06:10,822
AND THROUGH THE WORK IN THIS 

1355
01:06:10,822 --> 01:06:13,158
PAPER CAME UP WITH THE 

1356
01:06:13,158 --> 01:06:14,459
HYPOTHESIS WHICH I'M GOING TO 

1357
01:06:14,459 --> 01:06:16,061
SHOW YOU ONE PROBABLY PLAYING 

1358
01:06:16,061 --> 01:06:19,264
OUT IN THE DATA THAT THAT STEM 

1359
01:06:19,264 --> 01:06:21,166
CELL STATE THEN BECAME SENSITIVE

1360
01:06:21,166 --> 01:06:26,805
TO THE ONCA GENIC AFFECTS OF 

1361
01:06:26,805 --> 01:06:29,241
EXPRESSION OR ONCA GENE AND SET 

1362
01:06:29,241 --> 01:06:32,244
UP THE STAGE FOR CANCER 

1363
01:06:32,244 --> 01:06:32,544
INITIATION.

1364
01:06:32,544 --> 01:06:40,986
AGAIN THE GROUP OF GENES 

1365
01:06:40,986 --> 01:06:42,821
SUSCEPTIBLE TO THIS CHANGE AND 

1366
01:06:42,821 --> 01:06:47,092
FOLLOW THIS THROUGH TO CANCER 

1367
01:06:47,092 --> 01:06:48,593
PROGRESS AND SOME OF THE PAPERS 

1368
01:06:48,593 --> 01:06:51,296
THAT HAVE COME OUT ON IT DON'T 

1369
01:06:51,296 --> 01:06:53,231
SAY THE WORD EPIGENETICS.

1370
01:06:53,231 --> 01:06:55,233
THAT'S TAKING THE STATE OF THAT 

1371
01:06:55,233 --> 01:06:58,670
PARENT CELL AND FOLLOWING IT 

1372
01:06:58,670 --> 01:07:00,238
THROUGH LIKE IN THE COLON CANCER

1373
01:07:00,238 --> 01:07:02,874
TO PREINVASIVE CHANGES AND 

1374
01:07:02,874 --> 01:07:04,242
CANCER AND NOTING THE CHANGE OF 

1375
01:07:04,242 --> 01:07:07,646
THE ENVIRONMENT ANDY AND THE 

1376
01:07:07,646 --> 01:07:08,246
PREVIOUS SPEAKER POINTED OUT 

1377
01:07:08,246 --> 01:07:13,285
THAT CAN IMPOSE ON THIS PARENT 

1378
01:07:13,285 --> 01:07:14,819
CELL THE START OF A CHRONIC 

1379
01:07:14,819 --> 01:07:16,288
INFLAMMATION CHANGE THAT STOKES 

1380
01:07:16,288 --> 01:07:17,455
THIS PROGRESSION ALONG THE 

1381
01:07:17,455 --> 01:07:18,089
COURSE THAT WE'RE GOING TO TALK 

1382
01:07:18,089 --> 01:07:28,199
ABOUT.

1383
01:07:34,506 --> 01:07:36,841
I WANT TO POINT OUT A PAPER FROM

1384
01:07:36,841 --> 01:07:38,476
JOHNS HOPKINS AND THE POINT I'M 

1385
01:07:38,476 --> 01:07:42,380
GOING TO MAKE IS THE CHANGES 

1386
01:07:42,380 --> 01:07:43,148
AGAIN STARTING FOR CANCER.

1387
01:07:43,148 --> 01:07:48,620
WHAT THEY HAVE DEFINED IN THIS 

1388
01:07:48,620 --> 01:07:55,460
PAPER WHICH YOU CAN READ IS THIS

1389
01:07:55,460 --> 01:07:59,064
FOR THE CPGI METHYLATION 

1390
01:07:59,064 --> 01:08:02,534
PHENOTYPE AND A QUANTITATIVE 

1391
01:08:02,534 --> 01:08:05,603
MEASURE AND THE YELLOW ACROSS 

1392
01:08:05,603 --> 01:08:06,571
THE ARRAY IS THE DENSE DNA 

1393
01:08:06,571 --> 01:08:08,907
METHYLATION THE NORMAL IS IN 

1394
01:08:08,907 --> 01:08:09,107
BLUE.

1395
01:08:09,107 --> 01:08:11,109
WHAT THEY HAVE CLEVERLY DONE IN 

1396
01:08:11,109 --> 01:08:13,044
THE PCGA HERE MOST THE PURPOSE 

1397
01:08:13,044 --> 01:08:15,747
IN THE BAR ARE CANCERS BUT 

1398
01:08:15,747 --> 01:08:18,650
THEY'VE WOVEN IN AND HARD TO SEE

1399
01:08:18,650 --> 01:08:21,619
POLYPS AND IT POINTS OUT YOU'VE 

1400
01:08:21,619 --> 01:08:25,357
GOT POLYPS THAT HAVE ALREADY 

1401
01:08:25,357 --> 01:08:28,326
DEVELOPED IN THE DENSE CHANGE IN

1402
01:08:28,326 --> 01:08:30,295
THE PHASE AND WHAT THEY 

1403
01:08:30,295 --> 01:08:31,529
RECOGNIZE A LOW EXPRESSION OF 

1404
01:08:31,529 --> 01:08:36,701
TRANSCRIPTION FACTORS MANY OF 

1405
01:08:36,701 --> 01:08:38,870
THEM THE POLY COMB TRANSCRIPTION

1406
01:08:38,870 --> 01:08:41,339
FACTORS WHEN THEY WERE LOW, THIS

1407
01:08:41,339 --> 01:08:49,114
CORRELATED WITH THE EMERGENCE OF

1408
01:08:49,114 --> 01:08:52,317
THIS PHENOTYPE BY SEWING THE 

1409
01:08:52,317 --> 01:08:54,019
COGNATE BINDING SITES IN THE 

1410
01:08:54,019 --> 01:08:55,854
ENHANCERS OF GENES AND COGNATE 

1411
01:08:55,854 --> 01:08:58,256
SITES IN THE PROMOTERS WERE 

1412
01:08:58,256 --> 01:09:01,893
LINKED TO THIS SUCH THAT YOU HAD

1413
01:09:01,893 --> 01:09:06,931
IN THE ONLY CEMP BUT GAINED DNA 

1414
01:09:06,931 --> 01:09:10,435
METHYLATION IN THE ENHANCERS AND

1415
01:09:10,435 --> 01:09:12,937
THE IMPORTANT THING IS LOOK HOW 

1416
01:09:12,937 --> 01:09:14,672
IT MIMICS THE POLYPS AGAIN ARE 

1417
01:09:14,672 --> 01:09:15,507
FACTORS IN HERE.

1418
01:09:15,507 --> 01:09:16,341
THERE'S LOW EXPRESSION.

1419
01:09:16,341 --> 01:09:20,545
THE CHANGES IN THE ENHANCERS 

1420
01:09:20,545 --> 01:09:21,546
ALMOST VIRTUALLY PARALLEL THE 

1421
01:09:21,546 --> 01:09:23,381
DEVELOPMENT OF THOSE PROMOTER 

1422
01:09:23,381 --> 01:09:32,857
CHANGES IN CEMP.

1423
01:09:32,857 --> 01:09:34,292
A PLASIA ARISING.

1424
01:09:34,292 --> 01:09:35,093
I DON'T KNOW WHAT THEY'RE 

1425
01:09:35,093 --> 01:09:42,967
REQUESTING OF ME.

1426
01:09:42,967 --> 01:09:45,970
HERE'S THE MODEL I WANT TO POINT

1427
01:09:45,970 --> 01:09:47,372
OUT WE'VE BEEN USING.

1428
01:09:47,372 --> 01:09:49,207
HARI MYSELF AND PEOPLE I'LL TELL

1429
01:09:49,207 --> 01:09:49,741
YOU ABOUT.

1430
01:09:49,741 --> 01:09:52,343
THIS IS A MODEL TAKING PARENT 

1431
01:09:52,343 --> 01:10:02,887
CELLS OF ORIGIN IN THE ELEGANS 

1432
01:10:13,398 --> 01:10:17,202
REGIONS AND DURING PREMALIGNANCY

1433
01:10:17,202 --> 01:10:20,004
YOU DEVELOP CEMP AND WHEN THAT 

1434
01:10:20,004 --> 01:10:23,341
ARISES THE ORIGINAL MUTATION ONE

1435
01:10:23,341 --> 01:10:26,344
STEP RIGHT SIDE IN COLON CANCERS

1436
01:10:26,344 --> 01:10:27,479
IN THE MODEL.

1437
01:10:27,479 --> 01:10:32,383
THE OTHER MODEL IS TO IMPOSE THE

1438
01:10:32,383 --> 01:10:33,251
CHRONIC INFLAMMATION 

1439
01:10:33,251 --> 01:10:35,854
ENVIRONMENTAL CHANGE AND THEN 

1440
01:10:35,854 --> 01:10:38,456
INDUCING MUTATION AT THAT POINT 

1441
01:10:38,456 --> 01:10:43,461
AND YOU GET ONE STEP ON THIS.

1442
01:10:43,461 --> 01:10:49,701
THIS PUBLICATION FROM 

1443
01:10:49,701 --> 01:10:53,371
HARIISHWAN'S LAB WAS THE FIRST 

1444
01:10:53,371 --> 01:10:54,906
IN THE COLON CANCER MODEL AND 

1445
01:10:54,906 --> 01:10:57,275
YOU HAVE THIS IN THE MOUSE AND 

1446
01:10:57,275 --> 01:10:59,177
INDUCE IT IN THE ORGANOIDS.

1447
01:10:59,177 --> 01:11:02,981
IT TAKES FIVE MONTHS TO GET 

1448
01:11:02,981 --> 01:11:10,788
AROUND CELL DEATH AND OXYGEN 

1449
01:11:10,788 --> 01:11:21,299
SPECIES AND DAMAGE -- SO FIVE 

1450
01:11:28,740 --> 01:11:31,509
MONTHS AT THE MUTATION THAT AT 

1451
01:11:31,509 --> 01:11:33,311
THAT TIME CAUSES COLON CANCER 

1452
01:11:33,311 --> 01:11:35,613
BUT IF YOU LET THE ORGANOIDS AGE

1453
01:11:35,613 --> 01:11:38,183
THEY DEVELOP AND IF YOU INDUCE 

1454
01:11:38,183 --> 01:11:40,785
THE MUTATION NOT FIVE MONTHS IT 

1455
01:11:40,785 --> 01:11:48,026
ONLY TAKES WEEKS AND TO SHOW THE

1456
01:11:48,026 --> 01:11:53,598
REQUISITE CONTRIBUTION, A 

1457
01:11:53,598 --> 01:11:56,768
STUDENT CRISPRED GENETICALLY 

1458
01:11:56,768 --> 01:11:58,770
SILENCED THE GENES SILENCED HERE

1459
01:11:58,770 --> 01:12:01,072
AND SET UP THE MUTATION AND ONLY

1460
01:12:01,072 --> 01:12:01,806
TAKES WEEKS.

1461
01:12:01,806 --> 01:12:06,277
THE GENES THAT WERE SILENCED 

1462
01:12:06,277 --> 01:12:08,012
REQUISITE IN THE MODEL TO SET UP

1463
01:12:08,012 --> 01:12:09,581
THE CANCER INITIATION RESPONSE 

1464
01:12:09,581 --> 01:12:13,351
TO THE MUTATION.

1465
01:12:13,351 --> 01:12:16,321
LET'S TAKE THIS FORWARD ONE 

1466
01:12:16,321 --> 01:12:16,754
STEP.

1467
01:12:16,754 --> 01:12:22,093
THE MICE CAME FROM INDUCIBLE B 

1468
01:12:22,093 --> 01:12:23,494
RAP IN THE MOUSE AND WHEN IT'S 

1469
01:12:23,494 --> 01:12:28,333
DONE IN THE MOUSE YOU GET RIGHT 

1470
01:12:28,333 --> 01:12:30,268
SIDED COLON CANCER THE RIGHT 

1471
01:12:30,268 --> 01:12:31,769
SIDE OF THE GUT IS DIFFERENT 

1472
01:12:31,769 --> 01:12:33,037
THAN THE LEFT SIDE.

1473
01:12:33,037 --> 01:12:40,345
AND WHEN YOU INDUCE THIS IN THE 

1474
01:12:40,345 --> 01:12:50,855
MICE -- I HAVE TO BOOGIE HERE 

1475
01:12:57,328 --> 01:13:07,505
WITH THE TIME.

1476
01:13:08,506 --> 01:13:09,641
WHAT I'LL SHOW YOU NEXT I'LL 

1477
01:13:09,641 --> 01:13:11,709
TELL YOU WHAT IT IS.

1478
01:13:11,709 --> 01:13:15,380
THIS TIME THE MUTATION WAS 

1479
01:13:15,380 --> 01:13:17,582
INDUCED IN THE MOUSE STARTING IN

1480
01:13:17,582 --> 01:13:20,618
OUR LAB AND WORKING WITH OTHERS 

1481
01:13:20,618 --> 01:13:21,853
AND WHEN THEY INDUCED THIS IN 

1482
01:13:21,853 --> 01:13:24,756
THE MOUSE AND THEN CHALLENGED 

1483
01:13:24,756 --> 01:13:28,326
THAT MOUSE WITH THE 

1484
01:13:28,326 --> 01:13:31,195
MICROBIOME

1485
01:13:31,195 --> 01:13:34,866
MICROBIOMEDICAL  -- 

1486
01:13:34,866 --> 01:13:36,301
MICROENVIRONMENT THEY SAW 

1487
01:13:36,301 --> 01:13:38,469
CHANGES THEY'VE NEVER SEEN AND 

1488
01:13:38,469 --> 01:13:41,572
THIS TIME THEY SAW HYPERPLASIA 

1489
01:13:41,572 --> 01:13:45,576
ON THE RIGHT SIDE OF THE 

1490
01:13:45,576 --> 01:13:48,913
PRECURSOR CELLS AND THE MUTATION

1491
01:13:48,913 --> 01:13:50,481
PICKED ON PARENT CELLS FOR THE 

1492
01:13:50,481 --> 01:13:52,350
SENSITIVITY ON THE RIGHT SIDE OF

1493
01:13:52,350 --> 01:14:02,827
THE COLON TO INDUCE THAT TUMORO 

1494
01:14:02,827 --> 01:14:03,394
GENIC CHANGE.

1495
01:14:03,394 --> 01:14:06,297
SO WHAT WHERE I'LL TAKE YOU NEXT

1496
01:14:06,297 --> 01:14:09,067
IS THE MODEL AND TELL YOU ABOUT 

1497
01:14:09,067 --> 01:14:11,469
THE WORK OF A YOUNG 

1498
01:14:11,469 --> 01:14:12,603
INVESTIGATOR, MICHELLE VAS AT 

1499
01:14:12,603 --> 01:14:16,341
HOPKINS WHO STARTED HER WORK AS 

1500
01:14:16,341 --> 01:14:20,645
A POSTDOC IN OUR LAB.

1501
01:14:20,645 --> 01:14:23,047
A TALENTED POST DOCK WITH HER 

1502
01:14:23,047 --> 01:14:28,353
AND TAKE IT TO LONG ORGANOIDS 

1503
01:14:28,353 --> 01:14:32,056
THE ELEGANS MODEL AND START WITH

1504
01:14:32,056 --> 01:14:36,794
NORMAL AIRWAY CELLS IN THE LUNG 

1505
01:14:36,794 --> 01:14:37,895
AND I'LL SHOW YOU WHAT HAPPENS 

1506
01:14:37,895 --> 01:14:40,732
THERE IS THE SAME PROGRESSION TO

1507
01:14:40,732 --> 01:14:43,468
CEMP IN A WAY AT THAT TIME THAT 

1508
01:14:43,468 --> 01:14:46,437
SOME OF THE GENES THAT GET 

1509
01:14:46,437 --> 01:14:52,076
SILENCED WOULD OTHERWISE HAVE 

1510
01:14:52,076 --> 01:14:52,410
VE

1511
01:14:52,410 --> 01:14:55,146
PREVENTED THE K RAS PATHWAY FROM

1512
01:14:55,146 --> 01:14:55,713
COMING UP.

1513
01:14:55,713 --> 01:14:57,415
AT THAT POINT IF YOU INTRODUCE 

1514
01:14:57,415 --> 01:15:02,553
THE K RAS MUTATION YOU GET ONE 

1515
01:15:02,553 --> 01:15:05,022
STEP LUNG ADENO CARCINOMA AND A 

1516
01:15:05,022 --> 01:15:08,693
WANT TO SLOW YOU IF I CAN THE 

1517
01:15:08,693 --> 01:15:10,395
BEAUTIFUL MODEL AND PICTURES OF 

1518
01:15:10,395 --> 01:15:13,598
HOW THEY MARK THESE STEM CELLS 

1519
01:15:13,598 --> 01:15:23,708
AND FOLLOW THEM THROUGH AND -- I

1520
01:15:23,708 --> 01:15:24,242
DON'T KNOW.

1521
01:15:24,242 --> 01:15:28,346
IS THERE ANY WAY I CAN GET THEM?

1522
01:15:28,346 --> 01:15:33,651
I'LL BOOGIE TO THAT SLIDE 

1523
01:15:33,651 --> 01:15:37,855
BECAUSE -- THERE WE GO.

1524
01:15:37,855 --> 01:15:40,224
THAT'S THE RIGHT SIDED MODEL AND

1525
01:15:40,224 --> 01:15:42,560
THE ROS MODEL I'LL COME BACK TO 

1526
01:15:42,560 --> 01:15:43,161
THE WAY WE THINK ABOUT THESE 

1527
01:15:43,161 --> 01:15:52,336
CHANGES.

1528
01:15:52,336 --> 01:15:58,342
THE LUNG IS A PSEUDO STRATIFIED 

1529
01:15:58,342 --> 01:16:00,311
EPITHELIUM WITH AIRWAY CELLS IN 

1530
01:16:00,311 --> 01:16:04,182
THE PROXIMAL REGION WITH STEM 

1531
01:16:04,182 --> 01:16:06,884
CELLS AND THE CARCINOMA COMES 

1532
01:16:06,884 --> 01:16:08,386
ALONG AND THIS MODEL FOR THE 

1533
01:16:08,386 --> 01:16:10,321
MOUSE YOU CAN GET ALL THE WAY 

1534
01:16:10,321 --> 01:16:14,292
DOWN TO THE STEM CELLS AND THE 

1535
01:16:14,292 --> 01:16:20,531
ATC AND ATP CELLS IN THE ALVEOLI

1536
01:16:20,531 --> 01:16:24,068
AND YOU CAN MARK THE CELLS AS 

1537
01:16:24,068 --> 01:16:26,604
I'LL SHOW IN THE ORGANOID MODEL 

1538
01:16:26,604 --> 01:16:27,305
WITH DIFFERENTIATION AND I'LL 

1539
01:16:27,305 --> 01:16:28,339
SHOW YOU A COUPLE CHANGES IN 

1540
01:16:28,339 --> 01:16:37,849
EXAMPLE.

1541
01:16:37,849 --> 01:16:39,250
IN THE UPPER AIRWAYS IN THE 

1542
01:16:39,250 --> 01:16:40,685
HUMAN AND MOUSE CAPTURE THIS 

1543
01:16:40,685 --> 01:16:44,755
STRUCTURE WITH THE AIRWAY IN THE

1544
01:16:44,755 --> 01:16:47,992
MIDDLE AND BASAL CELL STEM CELLS

1545
01:16:47,992 --> 01:16:50,628
AROUND THE EDGE BUT THE AIRWAY 

1546
01:16:50,628 --> 01:16:53,464
IS SURROUNDED BY GRAPE LIKE 

1547
01:16:53,464 --> 01:16:53,764
STRUCTURES.

1548
01:16:53,764 --> 01:16:55,867
THESE ARE STEM CELLS.

1549
01:16:55,867 --> 01:16:57,768
SO KEEP YOU'RE EYE ON THE STEM 

1550
01:16:57,768 --> 01:16:57,969
CELLS.

1551
01:16:57,969 --> 01:17:03,708
WHAT THE MODEL DOES IS THIS.

1552
01:17:03,708 --> 01:17:05,676
YOU'VE EXPOSED THEM TO TWO 

1553
01:17:05,676 --> 01:17:08,479
DOSES, CIGARETTE SMOKE EXTRACT.

1554
01:17:08,479 --> 01:17:09,580
THIS IS THE ENVIRONMENTAL 

1555
01:17:09,580 --> 01:17:10,715
INFLAMMATORY CHALLENGE IN THIS 

1556
01:17:10,715 --> 01:17:10,915
MODEL.

1557
01:17:10,915 --> 01:17:15,653
AND WHEN THIS HAPPENS, ONE 

1558
01:17:15,653 --> 01:17:18,122
MONTH, THREE MONTHS, SIX MONTHS.

1559
01:17:18,122 --> 01:17:19,757
THE ORGANOIDS AFTER CELL DEATH 

1560
01:17:19,757 --> 01:17:21,092
BEGIN TO GROW.

1561
01:17:21,092 --> 01:17:23,160
RAPIDLY.

1562
01:17:23,160 --> 01:17:23,895
YOU'LL NOTICE THEY GET DENSER 

1563
01:17:23,895 --> 01:17:32,303
AND DENSER.

1564
01:17:32,303 --> 01:17:34,105
AND STRUCTURES AROUND THE 

1565
01:17:34,105 --> 01:17:36,140
ORGANOID WHICH ARE THE STEM 

1566
01:17:36,140 --> 01:17:36,340
CELLS.

1567
01:17:36,340 --> 01:17:38,509
YOU CAN MARK THESE STEM CELLS.

1568
01:17:38,509 --> 01:17:39,810
THERE'S BEAUTIFUL ARTWORK.

1569
01:17:39,810 --> 01:17:46,050
ONE OF THE CHANGES THAT OCCURS.

1570
01:17:46,050 --> 01:17:52,323
THERE'S MARKERS OF 

1571
01:17:52,323 --> 01:17:55,259
DIFFERENTIATION BUT THERE'S AN 

1572
01:17:55,259 --> 01:17:57,361
IMAGE HERE, WHAT YOU SEE OVER 

1573
01:17:57,361 --> 01:17:58,729
SIX MONTHS OF THE TWO EXPOSURES 

1574
01:17:58,729 --> 01:18:04,168
TO THE CIGARETTE EXTRACT IS THE 

1575
01:18:04,168 --> 01:18:04,835
DIFFERENTIATED ONE STAYS AROUND 

1576
01:18:04,835 --> 01:18:12,276
AND LOOK AT THE IMAGE IN THE 

1577
01:18:12,276 --> 01:18:17,682
SIGN OF STEMIS IN THE LUNG AND 

1578
01:18:17,682 --> 01:18:20,518
YOU SEE THIS WAY AND THIS WAY 

1579
01:18:20,518 --> 01:18:22,687
THERE'S VIRTUALLY NO KRT14 IN 

1580
01:18:22,687 --> 01:18:27,325
THE CONTROL BUT AS YOU EXPOSE 

1581
01:18:27,325 --> 01:18:29,594
THE CIGARETTE SMOKE YOU CAN 

1582
01:18:29,594 --> 01:18:32,964
TRACK THIS.

1583
01:18:32,964 --> 01:18:35,066
MOREOVER, IF YOU FOLLOW THESE 

1584
01:18:35,066 --> 01:18:38,069
CELLS YOU NOTICE THE CONTROL YOU

1585
01:18:38,069 --> 01:18:43,574
SEE THIS NICE MARKER FROM CELLS 

1586
01:18:43,574 --> 01:18:45,910
DOWN IN THE AIRWAYS IN THE DITCH

1587
01:18:45,910 --> 01:18:46,777
STATION MARK.

1588
01:18:46,777 --> 01:18:52,149
YOU LOSE DIFFERENTIATION AND 

1589
01:18:52,149 --> 01:18:53,784
GETTING THIS IN THE MODEL WITH 

1590
01:18:53,784 --> 01:18:55,753
THE CIGARETTES.

1591
01:18:55,753 --> 01:19:01,158
SO THIS IS AN INCREASE IN 

1592
01:19:01,158 --> 01:19:03,394
PROLIFERATION THAT OCCURS MAKING

1593
01:19:03,394 --> 01:19:07,264
IT IMMUNOEXPRESSIVE.

1594
01:19:07,264 --> 01:19:11,135
AND THESE GENES TEND TO BE 

1595
01:19:11,135 --> 01:19:13,571
EFFECTED AND HERE'S THE DNA 

1596
01:19:13,571 --> 01:19:19,310
METHYLATION PROFILE FOR THE 

1597
01:19:19,310 --> 01:19:29,854
GENOMES AND THE HYPERMETH LATE 

1598
01:19:33,124 --> 01:19:36,160
HYPERMETHYLATED GENES AND YOU 

1599
01:19:36,160 --> 01:19:39,997
SEE EVIDENCE FOR PRE MALIGNANT 

1600
01:19:39,997 --> 01:19:41,065
IMMUNE EVICTION AND THE RESPONSE

1601
01:19:41,065 --> 01:19:43,267
IS EXPRESSED AND THE INTERFERON 

1602
01:19:43,267 --> 01:19:44,201
ALPHA AND BETA ARE SUPPRESSED 

1603
01:19:44,201 --> 01:19:45,603
AND THESE ARE MARKERS THAT IF 

1604
01:19:45,603 --> 01:19:51,742
THEY'RE UP WOULD BE PART OF THE 

1605
01:19:51,742 --> 01:19:53,577
TUMOR CELL INFLAMMATORY SIGNAL 

1606
01:19:53,577 --> 01:19:54,845
GETTING EXPRESSED PRE MALIGNANT 

1607
01:19:54,845 --> 01:19:55,680
IN THE MODEL.

1608
01:19:55,680 --> 01:19:57,548
AT THE SAME TIME YOU CAN 

1609
01:19:57,548 --> 01:20:03,921
ENGINEER THESE ORGANOIDS FOR THE

1610
01:20:03,921 --> 01:20:06,891
MICROENVIRONMENT AND THE PURIFY 

1611
01:20:06,891 --> 01:20:12,530
MACROPHAGES AND AT THE START THE

1612
01:20:12,530 --> 01:20:16,333
MORE COMBINANT AND OVER SIX 

1613
01:20:16,333 --> 01:20:26,844
MONTHS A MORE PROTUMORO GENIC 

1614
01:20:27,678 --> 01:20:27,812
PHASE.

1615
01:20:27,812 --> 01:20:30,347
AND THE KEY IS WHAT ABOUT TUMOR 

1616
01:20:30,347 --> 01:20:30,614
GENICITY?

1617
01:20:30,614 --> 01:20:33,050
WHAT YOU CAN DO WITH THE 

1618
01:20:33,050 --> 01:20:34,585
ORGANOID MODELS DONE IN THE 

1619
01:20:34,585 --> 01:20:40,324
COLON ONES TOO TAKE THE CLEAVER 

1620
01:20:40,324 --> 01:20:42,159
FACTORS OUT THAT SUPPORT THE 

1621
01:20:42,159 --> 01:20:46,964
NORMAL ORGANOIDS AND THEIR 

1622
01:20:46,964 --> 01:20:47,898
ABILITY TO GROW SHOWS IT'S A 

1623
01:20:47,898 --> 01:20:49,033
SIGN OF INITIATION.

1624
01:20:49,033 --> 01:20:53,370
AND WHEN YOU EXPOSE THEM THEY 

1625
01:20:53,370 --> 01:20:55,106
GET BIGGER AND GROW RAPIDLY.

1626
01:20:55,106 --> 01:20:56,073
INDEPENDENCE OF THE SUPPORT 

1627
01:20:56,073 --> 01:21:00,411
FACTORS FOR NORMAL, AT THAT 

1628
01:21:00,411 --> 01:21:02,346
POINT YOU CAN PUT IN A GENE 

1629
01:21:02,346 --> 01:21:03,380
MUTATION.

1630
01:21:03,380 --> 01:21:09,120
IF YOU PUT THE KRAS IN YOU GET 

1631
01:21:09,120 --> 01:21:11,522
AN AGGRESSIVE METASTATIC LUNG 

1632
01:21:11,522 --> 01:21:12,623
CARCINOMA.

1633
01:21:12,623 --> 01:21:15,292
IF YOU TAKE OUT THE EXPRESSER 

1634
01:21:15,292 --> 01:21:20,364
GENE YOU GET A CARCINOMA AND ONE

1635
01:21:20,364 --> 01:21:25,603
STEP INITIATION PRE EXISTENT 

1636
01:21:25,603 --> 01:21:36,113
EPIGENETIC CHANGES FROM THERE.

1637
01:21:36,747 --> 01:21:37,715
I WANT TO COME BACK A QUICK 

1638
01:21:37,715 --> 01:21:38,048
STORY.

1639
01:21:38,048 --> 01:21:40,351
THE SLIDE I DIDN'T GET TO SHOW 

1640
01:21:40,351 --> 01:21:45,589
YOU BEFORE SHOWING HYDROGEN 

1641
01:21:45,589 --> 01:21:51,462
PEROXIDE IS A GREAT MODEL AND 

1642
01:21:51,462 --> 01:21:53,497
THIS SYSTEM WAS STARTED WAY BACK

1643
01:21:53,497 --> 01:21:55,533
HERE AND THE COLLABORATION WITH 

1644
01:21:55,533 --> 01:21:57,601
MY WIFE OVER THE PAST DECADE AND

1645
01:21:57,601 --> 01:21:59,003
THIS TALENTED INVESTIGATOR 

1646
01:21:59,003 --> 01:22:01,872
VISITING SCIENTIST AT THE TIME 

1647
01:22:01,872 --> 01:22:09,013
FROM CHINA AND HER GROUP IN BIG 

1648
01:22:09,013 --> 01:22:12,616
LUNG CANCER COHORTS WE CAN STUDY

1649
01:22:12,616 --> 01:22:17,621
AND THAT TRIGGERS THE OGG1 AND 

1650
01:22:17,621 --> 01:22:22,793
WHEN IT SEES THAT IT REPRESS THE

1651
01:22:22,793 --> 01:22:24,829
COMPLEX TO C-G MODEL AND WITHIN 

1652
01:22:24,829 --> 01:22:30,501
SIX HOURS IT CAN START TO 

1653
01:22:30,501 --> 01:22:33,604
INSIGHT THE METHYLATION AND IF 

1654
01:22:33,604 --> 01:22:40,211
YOU INHIBIT THESE AND NOT YOU 

1655
01:22:40,211 --> 01:22:42,279
CAN REVERSE REEXPRESS THE 

1656
01:22:42,279 --> 01:22:49,820
SILENCE GENES AND TUMOROGENIC 

1657
01:22:49,820 --> 01:22:50,821
PROPERTIES.

1658
01:22:50,821 --> 01:22:54,892
AND IT TIGHTLY BINDS MANY OF THE

1659
01:22:54,892 --> 01:22:58,562
PROTEINS THE TRANSFERASES 

1660
01:22:58,562 --> 01:23:08,839
AND BINDS UHFR1.

1661
01:23:20,818 --> 01:23:28,325
AND THEY COMPLETED THIS SO THIS 

1662
01:23:28,325 --> 01:23:33,264
A FASCINATING PROTEIN.

1663
01:23:33,264 --> 01:23:43,841
AND THIS RECOGNIZES METHYLATED 

1664
01:23:51,649 --> 01:24:02,092
CELLS AND IT TRACKS WITH AND 

1665
01:24:04,161 --> 01:24:06,330
MAPS ACROSS THE BIG COHORTS.

1666
01:24:06,330 --> 01:24:09,600
SO MY FINAL SLIDES I'M GOING TO 

1667
01:24:09,600 --> 01:24:15,172
SHOW YOU THERE'S A NATURAL 

1668
01:24:15,172 --> 01:24:18,075
INHIBITOR OF THE PROTEINS DPPA1 

1669
01:24:18,075 --> 01:24:23,380
IT WORKS IN THE HOUSE TO GO GET 

1670
01:24:23,380 --> 01:24:26,483
UHFR1 AND TAKE IT OFF THE 

1671
01:24:26,483 --> 01:24:28,452
CHROMATIN, TRANSPORT IT AND KEEP

1672
01:24:28,452 --> 01:24:30,621
IT OUT IN THE CYTOPLASM.

1673
01:24:30,621 --> 01:24:34,658
IN THIS WORK WE DECIDED TO OVER 

1674
01:24:34,658 --> 01:24:36,226
EXPRESS AND GOT A REMARKABLE 

1675
01:24:36,226 --> 01:24:38,662
SERIES OF CHANGES.

1676
01:24:38,662 --> 01:24:40,898
WHEN WE TOOK COLON CANCER CELLS 

1677
01:24:40,898 --> 01:24:43,634
AND PUT THIS IN THE MOUSE ONLY 

1678
01:24:43,634 --> 01:24:48,772
THE MOUSE WOULD REPLICATE TAKING

1679
01:24:48,772 --> 01:24:52,343
UHFR1 OUT OF THE NUCLEUS AND 

1680
01:24:52,343 --> 01:24:54,678
TRANSFERRING IT TO THE 

1681
01:24:54,678 --> 01:24:55,346
CYTOPLASM.

1682
01:24:55,346 --> 01:24:56,880
NOT THE HUMAN.

1683
01:24:56,880 --> 01:24:58,716
HERE'S WHY.

1684
01:24:58,716 --> 01:25:02,086
ONLY 31% AMINO ACID IDENTITY 

1685
01:25:02,086 --> 01:25:09,593
BETWEEN THE MOUSE UHFR IS AND 

1686
01:25:09,593 --> 01:25:11,562
HUMANS AND1 IS AND 

1687
01:25:11,562 --> 01:25:15,766
HUMANS AND HERE'S THE AFFECT.S  

1688
01:25:15,766 --> 01:25:16,433
HUMANS AND HERE'S THE AFFECT. A 

1689
01:25:16,433 --> 01:25:26,944
HUMANS AND HERE'S THE AFFECT.

1690
01:25:39,390 --> 01:25:49,833
AND IT'S ALL DUE TO AN LYSINE 

1691
01:25:51,268 --> 01:25:52,036
PULLS THEM TOGETHER IN THIS 

1692
01:25:52,036 --> 01:25:53,604
DIRECTION WHERE THE HUMAN WILL 

1693
01:25:53,604 --> 01:25:55,539
NOT DO THAT AND REMAINS FURTHER 

1694
01:25:55,539 --> 01:26:02,212
APART AND LINEAR.

1695
01:26:02,212 --> 01:26:05,582
WE PINNED THIS DOWN TO A SMALL 

1696
01:26:05,582 --> 01:26:09,520
REGION HEMOLOGY.

1697
01:26:09,520 --> 01:26:13,590
A SMALL REGION OF 85 TO ABOUT 

1698
01:26:13,590 --> 01:26:16,326
115 AMINO ACIDS.

1699
01:26:16,326 --> 01:26:17,795
THEY'VE BEEN ABLE TO DELIVER 

1700
01:26:17,795 --> 01:26:19,930
THIS IN HIS WORK IN CHINA WITH 

1701
01:26:19,930 --> 01:26:23,200
THE NANO PARTICLE IN CELLS AND 

1702
01:26:23,200 --> 01:26:26,236
IN VIVO AND MIMIC THE INHIBITION

1703
01:26:26,236 --> 01:26:28,038
OF THE BLOCK OF THE DNA 

1704
01:26:28,038 --> 01:26:28,338
METHYLATION.

1705
01:26:28,338 --> 01:26:30,874
SO WE ARE HOPEFUL WE HAVE A DRUG

1706
01:26:30,874 --> 01:26:32,076
DELIVERY HERE AND IT'S AN 

1707
01:26:32,076 --> 01:26:35,345
EXAMPLE OF THE NEWER DRUG THAT 

1708
01:26:35,345 --> 01:26:37,648
COMES OUT UNDERSTANDING THE 

1709
01:26:37,648 --> 01:26:38,348
REPRESSIVE COMPLEXES.

1710
01:26:38,348 --> 01:26:43,420
I'M SORRY FOR THE LAX  -- LACK 

1711
01:26:43,420 --> 01:26:44,555
OF MECHANICS AND THANK YOU FOR 

1712
01:26:44,555 --> 01:26:54,765
INVITING ME.

1713
01:27:12,883 --> 01:27:13,150
ANY QUESTIONS?

1714
01:27:13,150 --> 01:27:22,059
>> THANK YOU.

1715
01:27:22,059 --> 01:27:23,927
SO THE LAST TALK OF THE 

1716
01:27:23,927 --> 01:27:24,228
SESSION -- 

1717
01:27:24,228 --> 01:27:26,396
>> SOMEBODY HAS A
QUESTION.

1718
01:27:26,396 --> 01:27:30,334
GO AHEAD.

1719
01:27:30,334 --> 01:27:31,702
>> WHERE ARE THEY?

1720
01:27:31,702 --> 01:27:33,137
GO AHEAD, PLEASE.

1721
01:27:33,137 --> 01:27:35,706
>> INTRIGUING TALK.

1722
01:27:35,706 --> 01:27:39,743
I WAS WONDERING IN THE MODEL -- 

1723
01:27:39,743 --> 01:27:40,744
>> YOU HAVE TO BEND OVER.

1724
01:27:40,744 --> 01:27:42,312
YOU'RE A TALL GUY.

1725
01:27:42,312 --> 01:27:45,582
>> THE LUNG CANCER
ORGANOID 

1726
01:27:45,582 --> 01:27:48,352
EXPERIMENT US LOOKED AT DNA 

1727
01:27:48,352 --> 01:27:49,153
METHYLATION CHANGES AFTER 

1728
01:27:49,153 --> 01:27:49,486
TREATMENT.

1729
01:27:49,486 --> 01:27:50,888
HAVE YOU LOOKED AT OTHER 

1730
01:27:50,888 --> 01:27:52,789
CHROMATIN FEATURES OF HISTO 

1731
01:27:52,789 --> 01:27:56,059
MODIFICATIONS AND SEE IF ANY OF 

1732
01:27:56,059 --> 01:27:58,228
THESE ALSO ASSOCIATED WITH GENE 

1733
01:27:58,228 --> 01:27:59,329
EXPRESSION CHANGES?

1734
01:27:59,329 --> 01:28:04,635
>> IN THE PAPER THEY
INDEED DID.

1735
01:28:04,635 --> 01:28:10,340
THEY'VE DONE IN THE HUMAN TAC 

1736
01:28:10,340 --> 01:28:12,576
SEQ AND WITH THE REVERSION TO 

1737
01:28:12,576 --> 01:28:15,546
THE BLOCK THE DNA METHYLATION IS

1738
01:28:15,546 --> 01:28:20,684
GIVEN YOU SEE INCREASING 

1739
01:28:20,684 --> 01:28:26,089
REPRESSIVE METHYLATION AND ALLOW

1740
01:28:26,089 --> 01:28:28,358
THE DNA METHYLATION TO OBSERVE 

1741
01:28:28,358 --> 01:28:30,093
THE REPRESSIVE EFFECTS AND THEY 

1742
01:28:30,093 --> 01:28:31,895
SHOULD BE SUBMITTING THIS SOON.

1743
01:28:31,895 --> 01:28:34,097
IT'S A DEEP PAPER ON GOING 

1744
01:28:34,097 --> 01:28:35,933
THROUGH THE CHROMATIN AS WELL AS

1745
01:28:35,933 --> 01:28:37,301
GOING THROUGH SOME METHYLATION 

1746
01:28:37,301 --> 01:28:37,734
CHANGES THEY SHOULD.

1747
01:28:37,734 --> 01:28:43,941
>> THANK YOU.

1748
01:28:43,941 --> 01:28:46,610
>> THE LAST SPEAKER OF THE

1749
01:28:46,610 --> 01:28:50,147
SESSION IS CHERYL ARROWSMITH 

1750
01:28:50,147 --> 01:28:52,216
FROM THE PRINCESS MARGARET 

1751
01:28:52,216 --> 01:28:57,454
CANCER CENTER UNIVERSITY OF 

1752
01:28:57,454 --> 01:28:59,056
TORONTO TALKING ABOUT 

1753
01:28:59,056 --> 01:29:00,390
THERAPEUTIC EPIGENETICS.

1754
01:29:00,390 --> 01:29:01,258
>> THANK YOU, IT'S A
PLEASURE TO

1755
01:29:01,258 --> 01:29:11,635
BE AT THE CELEBRATION.

1756
01:29:11,635 --> 01:29:13,937
40 YEARS OF EPIGENETICS.

1757
01:29:13,937 --> 01:29:17,674
MY STORY IS IN 1980s WHEN I WAS 

1758
01:29:17,674 --> 01:29:21,945
A STUDENT I READ SOMEWHERE 

1759
01:29:21,945 --> 01:29:22,846
METHYLATION HAD SOMETHING TO DO 

1760
01:29:22,846 --> 01:29:25,048
WITH CANCER.

1761
01:29:25,048 --> 01:29:26,383
I WAS A CHEMISTRY STUDENT AND 

1762
01:29:26,383 --> 01:29:29,086
DIDN'T KNOW WHAT A METHYL GROUP 

1763
01:29:29,086 --> 01:29:29,286
WAS.

1764
01:29:29,286 --> 01:29:31,421
I FOUND TA EXCITING.

1765
01:29:31,421 --> 01:29:32,923
I DID KNOW WHAT CANCER WAS 

1766
01:29:32,923 --> 01:29:35,559
BECAUSE WE HAVE IT IN OUR 

1767
01:29:35,559 --> 01:29:35,826
FAMILY.

1768
01:29:35,826 --> 01:29:39,963
LONG CIRCUITOUS ROUTE BUT BY THE

1769
01:29:39,963 --> 01:29:42,432
EARLY 2000s IN THE MEANTIME I'D 

1770
01:29:42,432 --> 01:29:45,302
BEEN WORKING ON TRANSCRIPTION 

1771
01:29:45,302 --> 01:29:49,673
FACTORS AND THE RISE OF MANY OF 

1772
01:29:49,673 --> 01:29:53,076
THE GIANTS ON WHOM SHOULDERS WE 

1773
01:29:53,076 --> 01:29:54,978
STAND HAD DONE MUCH OF THE 

1774
01:29:54,978 --> 01:29:56,380
WORK -- SOME OF THE WORK YOU 

1775
01:29:56,380 --> 01:29:59,182
HEARD ABOUT AND IT WAS BECOMING 

1776
01:29:59,182 --> 01:30:01,118
CLEAR EPIGENETICS WAS AN 

1777
01:30:01,118 --> 01:30:03,320
IMPORTANT DRIVER OF CANCER AND I

1778
01:30:03,320 --> 01:30:05,255
KNEW MORE ABOUT THE BIOLOGY BY 

1779
01:30:05,255 --> 01:30:06,123
THAT TIME.

1780
01:30:06,123 --> 01:30:08,458
SO OUR WORK IS I'M VERY MUCH 

1781
01:30:08,458 --> 01:30:11,895
INTERESTED IN METHYLATION 

1782
01:30:11,895 --> 01:30:17,834
SIGNALLING PARTICULARLY IN 

1783
01:30:17,834 --> 01:30:28,378
METHYLATION OF PROTEIN HISTONES.

1784
01:30:33,884 --> 01:30:36,486
WE CALL THEM CHEMICAL PROBES.

1785
01:30:36,486 --> 01:30:39,056
IT'S A TOOL COMPOUND POTENT FOR 

1786
01:30:39,056 --> 01:30:41,858
ITS TARGET IN CELLS SELECTIVE 

1787
01:30:41,858 --> 01:30:44,428
ESPECIALLY WITH RESPECT TO OTHER

1788
01:30:44,428 --> 01:30:46,330
MEMBERS OF THE PROTEIN FAMILY 

1789
01:30:46,330 --> 01:30:48,632
AND METHYL TRANSFERASES MEANT TO

1790
01:30:48,632 --> 01:30:50,233
BE USED AS A TOOL TO UNDERSTAND 

1791
01:30:50,233 --> 01:30:52,669
THE FUNCTION IN THE CELL OF THE 

1792
01:30:52,669 --> 01:30:56,139
PROTEIN OF INTEREST BY 

1793
01:30:56,139 --> 01:30:56,907
INHIBITING IT.

1794
01:30:56,907 --> 01:30:59,109
COMPLIMENTARY GENETIC METHODS.

1795
01:30:59,109 --> 01:31:01,611
WE DO IT IN COLLABORATION WITH 

1796
01:31:01,611 --> 01:31:04,047
INDUSTRY AND ACADEMIC CHEMISTS 

1797
01:31:04,047 --> 01:31:07,884
AND THESE TOOLS ARE ALL PUBLICLY

1798
01:31:07,884 --> 01:31:11,421
AVAILABLE, UNINCUMBERED AND WE 

1799
01:31:11,421 --> 01:31:14,424
HOPE BY USING THESE THE BIOLOGY 

1800
01:31:14,424 --> 01:31:16,860
THAT'S DISCOVERED WILL INSPIRE 

1801
01:31:16,860 --> 01:31:17,794
AND IDENTIFY THERAPEUTIC TARGETS

1802
01:31:17,794 --> 01:31:20,464
AND THE MOLECULES COULD BE 

1803
01:31:20,464 --> 01:31:23,667
FURTHER DEVELOPED OR THE TARGET 

1804
01:31:23,667 --> 01:31:25,569
IS IDENTIFIED FOR THERAPEUTIC 

1805
01:31:25,569 --> 01:31:35,245
DEVELOPMENT.

1806
01:31:35,245 --> 01:31:38,915
ONE ON TOOL SET AND BRODDER 

1807
01:31:38,915 --> 01:31:40,550
DOMAINS AND WE'VE WORKED ON 

1808
01:31:40,550 --> 01:31:45,956
METHYL READER DOMAINS AND 

1809
01:31:45,956 --> 01:31:49,226
DEMETHYLASE ENZYMES.

1810
01:31:49,226 --> 01:31:51,695
ONE THING WE WANT TO DO WITH 

1811
01:31:51,695 --> 01:31:54,264
THESE IS USE THEM TO IDENTIFY 

1812
01:31:54,264 --> 01:32:00,003
VULNERABILITIES IN CANCER CELLS 

1813
01:32:00,003 --> 01:32:01,972
AND CANCER ORGANOIDS.

1814
01:32:01,972 --> 01:32:03,540
THIS SUMMARIZES THE CONCEPT OF 

1815
01:32:03,540 --> 01:32:05,609
THE WORK WE'VE BEEN DOING IN MY 

1816
01:32:05,609 --> 01:32:08,845
LAB THOUGH AN OLD SLIDE.

1817
01:32:08,845 --> 01:32:14,317
ON THE Y AXIS YOU CAN SEE THE 

1818
01:32:14,317 --> 01:32:19,189
CHEMICAL PROBES WE'VE USED AND 

1819
01:32:19,189 --> 01:32:20,957
ACROSS THE SLIDE ARE DIFFERENT 

1820
01:32:20,957 --> 01:32:22,092
TUMOR MODELS.

1821
01:32:22,092 --> 01:32:28,231
IN MANY CASES, CERTAIN CASES 

1822
01:32:28,231 --> 01:32:32,002
SUCH AS THE BROMA DOMAIN 

1823
01:32:32,002 --> 01:32:33,737
INHIBITORS ALMOST ALL FAST 

1824
01:32:33,737 --> 01:32:35,205
GROWING CANCER CELLS ARE 

1825
01:32:35,205 --> 01:32:40,110
SENSITIVE TO THESE INHIBITORS 

1826
01:32:40,110 --> 01:32:43,713
AND OTHERS LIKE THE TRANSFERASE 

1827
01:32:43,713 --> 01:32:48,518
INHIBITORS THE CELLS ARE ONLY 

1828
01:32:48,518 --> 01:32:52,055
SENSITIVE TO THEM IN CERTAIN SUB

1829
01:32:52,055 --> 01:32:55,792
TYPES OF TUMOR TYPE AND WHAT WE 

1830
01:32:55,792 --> 01:32:57,394
SET OUT TO UNDERSTAND IN A 

1831
01:32:57,394 --> 01:32:59,129
NUMBER OF PAPERS.

1832
01:32:59,129 --> 01:33:01,097
WE'VE DONE THESE TYPES OF 

1833
01:33:01,097 --> 01:33:04,334
SCREENS AND THEN INVESTIGATED 

1834
01:33:04,334 --> 01:33:06,036
FURTHER WHAT MAKES THE CELL 

1835
01:33:06,036 --> 01:33:08,538
SUSCEPTIBLE AND WHAT'S THE 

1836
01:33:08,538 --> 01:33:09,873
MOLECULAR SIGNALLING INTERNALLY 

1837
01:33:09,873 --> 01:33:15,212
GOING ON WITH INHIBITION OF 

1838
01:33:15,212 --> 01:33:18,448
USUALLY METHYLATION SOMETIMES 

1839
01:33:18,448 --> 01:33:23,420
OTHER CHEMICAL BIOLOGY AND HAVE 

1840
01:33:23,420 --> 01:33:31,661
IDENTIFIED CASES OF OVERCOMING 

1841
01:33:31,661 --> 01:33:34,331
STEMNESS AND TRIGGERING 

1842
01:33:34,331 --> 01:33:38,468
DIFFERENTIATION.

1843
01:33:38,468 --> 01:33:46,543
A NUMBER OF CASES AND STRESS 

1844
01:33:46,543 --> 01:33:48,845
RESPONSE AND THIS IS A 

1845
01:33:48,845 --> 01:33:49,913
METABOLOMICS STORY.

1846
01:33:49,913 --> 01:33:56,286
I'LL TELL YOU ABOUT A RECENTLY 

1847
01:33:56,286 --> 01:33:58,021
PUBLISHED PAPER WHERE WE 

1848
01:33:58,021 --> 01:34:03,293
IDENTIFIED SUBSETS OF CELLS 

1849
01:34:03,293 --> 01:34:03,827
WHOSE TRANSCRIPTAL STATE 

1850
01:34:03,827 --> 01:34:06,696
DETERMINES THE SENSITIVITY TO 

1851
01:34:06,696 --> 01:34:08,365
ONE OF THE INHIBITORS AND TALK 

1852
01:34:08,365 --> 01:34:19,175
ABOUT UNMILITIPUBLISHED WORK.

1853
01:34:22,412 --> 01:34:29,019
THIS WAS WORK WAS LED BY A 

1854
01:34:29,019 --> 01:34:32,556
TALENTED POSTDOC WITH HER OWN 

1855
01:34:32,556 --> 01:34:35,025
LAB NOW IN CHINA AND THEY 

1856
01:34:35,025 --> 01:34:35,725
SCREENED AGAINST THE CHEMICAL 

1857
01:34:35,725 --> 01:34:36,893
PROBE LIBRARY.

1858
01:34:36,893 --> 01:34:41,498
WE'RE LOOKING AT CELL 

1859
01:34:41,498 --> 01:34:44,401
PROLIFERATION AND VIABILITY AND 

1860
01:34:44,401 --> 01:34:49,573
IDENTIFIED A TYPE 1 PROTEIN 

1861
01:34:49,573 --> 01:34:52,976
ARGININE TRANSFERASE INHIBITOR 

1862
01:34:52,976 --> 01:34:55,912
IN SUBSET OF THE CELLS ROBUSTLY 

1863
01:34:55,912 --> 01:34:57,581
STOPS CELL GROWTH.

1864
01:34:57,581 --> 01:34:59,716
THE INACTIVE CONTROL COMPOUND 

1865
01:34:59,716 --> 01:35:07,724
NOT ACTIVE ON THE ENZYME DID NOT

1866
01:35:07,724 --> 01:35:11,828
EXPRESS GROWTH.

1867
01:35:11,828 --> 01:35:20,070
WHAT THE INHIBITORS INHIBIT THE 

1868
01:35:20,070 --> 01:35:23,773
ARGININE ON HISTONES AND THEN 

1869
01:35:23,773 --> 01:35:26,309
IT'S OFTEN GROUPED WITH 

1870
01:35:26,309 --> 01:35:30,714
EPIGENETIC REGULATORS.

1871
01:35:30,714 --> 01:35:33,149
PROBABLY THE MORE SIGNIFICANT 

1872
01:35:33,149 --> 01:35:34,784
SUBSTRATE ARE RNA BINDING 

1873
01:35:34,784 --> 01:35:37,587
PROTEINS PARTICULARLY THE 

1874
01:35:37,587 --> 01:35:38,421
SPLICING MACHINERY AND I'LL COME

1875
01:35:38,421 --> 01:35:41,057
BACK TO THAT IN A MOMENT.

1876
01:35:41,057 --> 01:35:43,059
HERE WE HAVE A SET OF CELL LINES

1877
01:35:43,059 --> 01:35:45,729
THAT ALL HAVE INHIBITION OF THE 

1878
01:35:45,729 --> 01:35:46,429
ENZYME.

1879
01:35:46,429 --> 01:35:49,666
YOU CAN TELL THAT BECAUSE THE 

1880
01:35:49,666 --> 01:35:51,134
ASYMMETRIC MARK IS INHIBITED 

1881
01:35:51,134 --> 01:35:52,302
WITH THE ENZYME.

1882
01:35:52,302 --> 01:35:56,039
THEY RESPOND IN A DIFFERENT WAY.

1883
01:35:56,039 --> 01:36:01,578
THE ONES IN RED ARE SENSITIVE TO

1884
01:36:01,578 --> 01:36:04,614
THEY DON'T GROW ANY MORE IN THE 

1885
01:36:04,614 --> 01:36:06,016
PRESENCE OF THE INHIBITORS AND 

1886
01:36:06,016 --> 01:36:07,150
OTHERS ARE SENSITIVE.

1887
01:36:07,150 --> 01:36:09,719
I WON'T GO INTO DETAILS BUT LONG

1888
01:36:09,719 --> 01:36:13,023
STORY SHORT IT'S MOST LIKELY 

1889
01:36:13,023 --> 01:36:19,262
PRNT1 MOSTLY AFFECTED BY THIS 

1890
01:36:19,262 --> 01:36:22,098
INHIBITOR AND IT'S AN ESSENTIAL 

1891
01:36:22,098 --> 01:36:27,937
GENE TRIPLE NEGATIVE BREAST 

1892
01:36:27,937 --> 01:36:32,442
CANCER IF YOU LOOK IN THE TCGA.

1893
01:36:32,442 --> 01:36:37,080
AND THIS JUST SHOWS THAT YOU CAN

1894
01:36:37,080 --> 01:36:41,584
PHENOCOPY THIS IN MOUSE MODELS 

1895
01:36:41,584 --> 01:36:43,319
WITH KNOCK DOWN OF THIS AND YOU 

1896
01:36:43,319 --> 01:36:46,122
CAN SEE THIS AFFECT IN THE 

1897
01:36:46,122 --> 01:36:46,389
ORGANOIDS.

1898
01:36:46,389 --> 01:36:48,658
WHAT IS IT ABOUT THE SENSITIVE 

1899
01:36:48,658 --> 01:36:51,528
CELL LINES THAT MAKES THEM 

1900
01:36:51,528 --> 01:36:55,198
SENSITIVE TO TYPE 1 INHIBITION?

1901
01:36:55,198 --> 01:36:57,600
WE FOUND THROUGH USING RNA SEQ 

1902
01:36:57,600 --> 01:37:00,670
THE SENSITIVE CELL LINES HAVE A 

1903
01:37:00,670 --> 01:37:03,273
HIGHER LEVEL OF SIGNALLING 

1904
01:37:03,273 --> 01:37:05,575
PRETREATMENT OF THE INHIBITOR 

1905
01:37:05,575 --> 01:37:09,579
AND HAVE HIGH INTERFERON 

1906
01:37:09,579 --> 01:37:10,346
SIGNALLING FEATURE IN THE CELL 

1907
01:37:10,346 --> 01:37:14,884
LINES AND TUMOR ORGANOIDS.

1908
01:37:14,884 --> 01:37:17,887
IF WE TREAT THOSE CELLS WITH THE

1909
01:37:17,887 --> 01:37:21,524
INHIBITOR YOU GET A FURTHER 

1910
01:37:21,524 --> 01:37:22,258
INDUCTION OF INFLAMMATORY SIGNAL

1911
01:37:22,258 --> 01:37:25,895
AS SHOWN HERE.

1912
01:37:25,895 --> 01:37:27,530
SO CHANGE IN GENE EXPRESSION.

1913
01:37:27,530 --> 01:37:29,699
SOME OF THE GENES MODULATED ARE 

1914
01:37:29,699 --> 01:37:35,371
SHOWN IN THE MIDDLE PANEL HERE 

1915
01:37:35,371 --> 01:37:37,273
AND VALIDATED WITH PCR ON THE 

1916
01:37:37,273 --> 01:37:37,474
RIGHT.

1917
01:37:37,474 --> 01:37:38,942
WHAT IS IT ABOUT THE 

1918
01:37:38,942 --> 01:37:43,813
INFLAMMATORY SIGNAL AND WHERE'S 

1919
01:37:43,813 --> 01:37:46,583
IT COMING FROM?

1920
01:37:46,583 --> 01:37:50,487
INSPIRED BY MY COLLEAGUE DANIEL 

1921
01:37:50,487 --> 01:37:53,256
DI CARDELO HE SAID WHAT IS 

1922
01:37:53,256 --> 01:37:55,458
HAPPENING TO THE GENES THAT ARE 

1923
01:37:55,458 --> 01:37:59,763
BEING EXPRESSED HERE?

1924
01:37:59,763 --> 01:38:04,701
BECAUSE WE KNOW THAT PRNT 

1925
01:38:04,701 --> 01:38:08,505
INHIBITERS SPLICE BINDING 

1926
01:38:08,505 --> 01:38:09,572
PROTEINS AND METHYLATION OF 

1927
01:38:09,572 --> 01:38:11,641
SPLICING FACTORS IS IMPORTANT 

1928
01:38:11,641 --> 01:38:13,209
FOR PROPER SPLICING.

1929
01:38:13,209 --> 01:38:15,044
WE LOOKED AT THE RNA SEQ WE 

1930
01:38:15,044 --> 01:38:17,413
LOOKED INTO THE SPLICING EFFECTS

1931
01:38:17,413 --> 01:38:20,517
AND THERE ARE LOTS OF 

1932
01:38:20,517 --> 01:38:21,651
DISRUPTIONS OF SPLICING 

1933
01:38:21,651 --> 01:38:24,420
PARTICULARLY RETENTIONS TO 

1934
01:38:24,420 --> 01:38:27,290
IDENTIFY 152 OF THESE.

1935
01:38:27,290 --> 01:38:31,027
IF WE LOOKED AT THESE RETAINED 

1936
01:38:31,027 --> 01:38:35,498
ENTRONS ALMOST -- A VERY LARGE 

1937
01:38:35,498 --> 01:38:37,400
PROPORTION OF THEM HAVE THIS 

1938
01:38:37,400 --> 01:38:40,503
POTENTIAL FOR PERFORMING 

1939
01:38:40,503 --> 01:38:41,938
DOUBLE-STRANDED RNA ANDALO 

1940
01:38:41,938 --> 01:38:45,275
SEQUENCES THAT HAVE INVERTED 

1941
01:38:45,275 --> 01:38:47,977
REPEATS NORMALLY NOT EXPRESSED 

1942
01:38:47,977 --> 01:38:52,582
IN THE CELLS BUT IN THE PRESENCE

1943
01:38:52,582 --> 01:38:54,584
OF INHIBITORS AND YOU CAN DETECT

1944
01:38:54,584 --> 01:38:58,822
THE DOUBLE-STRANDED RNA WITH 

1945
01:38:58,822 --> 01:39:01,191
THIS ANTIBODY AND WE CAN ALSO 

1946
01:39:01,191 --> 01:39:10,466
MIMIC THIS WITH PRNT1 KNOCK DOWN

1947
01:39:10,466 --> 01:39:17,273
AND TRIGGERING AN INNATE 

1948
01:39:17,273 --> 01:39:18,641
RESPONSE WE BELIEVE IT'S 

1949
01:39:18,641 --> 01:39:21,611
RETAINED WITH THE INVERTED 

1950
01:39:21,611 --> 01:39:22,078
RETREATS.

1951
01:39:22,078 --> 01:39:24,447
IN SUMMARY FOR THIS PROJECT WE 

1952
01:39:24,447 --> 01:39:26,950
HAVE TWO STATES OF CELLS.

1953
01:39:26,950 --> 01:39:33,656
ON THE LEFT WE ARE THE 

1954
01:39:33,656 --> 01:39:37,594
INSENSITIVE CELLS THAT HAVE WHO 

1955
01:39:37,594 --> 01:39:41,631
STILL GET RETAINED INTRONS IN 

1956
01:39:41,631 --> 01:39:47,070
THE RNA SEQ DATA UPON MSO23 

1957
01:39:47,070 --> 01:39:47,971
TREATMENT AND THE EXPRESSION 

1958
01:39:47,971 --> 01:39:50,206
PROGRAM DOESN'T HAVE THE 

1959
01:39:50,206 --> 01:39:52,742
CAPABILITY TO PERFORM INVERTED 

1960
01:39:52,742 --> 01:39:54,143
REPEATS.

1961
01:39:54,143 --> 01:39:56,446
SO YOU DON'T GET THE INTERFERON 

1962
01:39:56,446 --> 01:39:57,080
SIGNALLING.

1963
01:39:57,080 --> 01:40:01,551
THE SENSITIVE CELLS ARE 

1964
01:40:01,551 --> 01:40:02,418
EXPRESSING TRANSCRIPTS WHO'S 

1965
01:40:02,418 --> 01:40:08,091
INTRONS WHO NOW GET RETAINED 

1966
01:40:08,091 --> 01:40:14,597
HAVE THE PROPENSITY TO PERFORM 

1967
01:40:14,597 --> 01:40:21,738
REPEATS AND THIS SIGNALS CELL 

1968
01:40:21,738 --> 01:40:25,575
DEATH AND CONTEMPORANEOUS WITH 

1969
01:40:25,575 --> 01:40:29,412
THIS GROUP AND BOEING ET AL. HAD

1970
01:40:29,412 --> 01:40:33,583
SIMILAR RESULTS USING SPLICING 

1971
01:40:33,583 --> 01:40:38,054
KINASES AND A SIMILAR AFFECT.

1972
01:40:38,054 --> 01:40:40,890
WE THINK REMEMBER THE SENSITIVE 

1973
01:40:40,890 --> 01:40:49,098
CELLS ALSO HAD THIS UNDERLYING 

1974
01:40:49,098 --> 01:40:52,368
LOW-LEVEL INTERFERON FROM THE 

1975
01:40:52,368 --> 01:41:01,144
RNA SEQ AND HAD MUTATIONS 

1976
01:41:01,144 --> 01:41:02,445
ASSOCIATED WITH DNA DAMAGE.

1977
01:41:02,445 --> 01:41:06,382
MAYBE THAT WAS LEADING TO THE 

1978
01:41:06,382 --> 01:41:07,383
UNDERLYING SIGNAL AND NOW YOU 

1979
01:41:07,383 --> 01:41:10,920
COME IN AND YOU INCREASE IT EVEN

1980
01:41:10,920 --> 01:41:13,489
MORE PERHAPS ABOVE A CERTAIN 

1981
01:41:13,489 --> 01:41:14,023
THRESHOLD THE CELL COULD 

1982
01:41:14,023 --> 01:41:24,200
TOLERATE.

1983
01:41:25,868 --> 01:41:27,804
EPIGENETICS DRUGS HAVE BEEN 

1984
01:41:27,804 --> 01:41:33,176
SHOWN TO STIMULATE MIMICRY AND 

1985
01:41:33,176 --> 01:41:36,112
THIS IS MECHANISMS OF GROWTH 

1986
01:41:36,112 --> 01:41:38,147
EXPRESSION AND HIS OPENS UP 

1987
01:41:38,147 --> 01:41:40,383
EXCITING AVENUES FOR FURTHER 

1988
01:41:40,383 --> 01:41:42,652
INVESTIGATION.

1989
01:41:42,652 --> 01:41:44,787
SO THE NEXT QUICK LAST STOREY I 

1990
01:41:44,787 --> 01:41:47,957
WANT TO SHOW MUCH OF IT IS 

1991
01:41:47,957 --> 01:41:48,257
UNPUBLISHED.

1992
01:41:48,257 --> 01:41:51,861
SO WE HAVE THIS COLLECTION OF 

1993
01:41:51,861 --> 01:41:55,331
COMPOUNDS THAT MODULATE 

1994
01:41:55,331 --> 01:42:04,874
METHYLATION ON THE HISTONES, 

1995
01:42:04,874 --> 01:42:09,245
ARGININE AND LYSINE.

1996
01:42:09,245 --> 01:42:13,216
WE'VE NOT BEEN ABLE TO IDENTIFY 

1997
01:42:13,216 --> 01:42:19,956
AN INHIBITOR OF NSD2 OR THE NSD 

1998
01:42:19,956 --> 01:42:21,357
PROTEINS THAT METHYLATE LYSINE 

1999
01:42:21,357 --> 01:42:27,430
36.

2000
01:42:27,430 --> 01:42:33,069
NOW, WE HAVE BEEN ABLE TO HAVE 

2001
01:42:33,069 --> 01:42:35,338
ANTAGONIST OF THE READER DOMAINS

2002
01:42:35,338 --> 01:42:37,173
OF NST2 AND 3.

2003
01:42:37,173 --> 01:42:41,444
WE NOW LAUNCHED INTO USING THESE

2004
01:42:41,444 --> 01:42:44,580
AS HANDLES ON THE NST2 PROTEIN 

2005
01:42:44,580 --> 01:42:49,452
IT CREATE TARGETED DEGRADER 

2006
01:42:49,452 --> 01:42:49,719
COMPOUNDS.

2007
01:42:49,719 --> 01:42:53,523
LET ME FIRST EXPLAIN THE 

2008
01:42:53,523 --> 01:42:56,092
RATIONALE FOR WHY WE DO THIS AND

2009
01:42:56,092 --> 01:43:00,963
THE POLY COMB PROTEINS ARE 

2010
01:43:00,963 --> 01:43:02,632
DRIVERS OF EPIGENETIC PLASTICITY

2011
01:43:02,632 --> 01:43:08,271
AND COORDINATED WITH THIS IS THE

2012
01:43:08,271 --> 01:43:13,142
CHANGES IN THE HDK36 METHYLATION

2013
01:43:13,142 --> 01:43:13,810
DOMAINS BOTH OCCURRING IN SPREAD

2014
01:43:13,810 --> 01:43:16,412
OUT DOMAINS OVER THE EPIGENOME 

2015
01:43:16,412 --> 01:43:18,881
AND THEY'RE ANTAGONISTIC.

2016
01:43:18,881 --> 01:43:21,818
AND NST2 IS SHOWN HERE ON THE 

2017
01:43:21,818 --> 01:43:28,224
LOWER RIGHT WHERE MUTATIONS 

2018
01:43:28,224 --> 01:43:29,125
WHERE ACTIVATING MUTATIONS CAN 

2019
01:43:29,125 --> 01:43:32,228
OCCUR.

2020
01:43:32,228 --> 01:43:37,533
AND WE ALSO KNOW ABOUT ONCO

2021
01:43:37,533 --> 01:43:41,003
ONCOHISTONES THAT CAN AFFECT THE

2022
01:43:41,003 --> 01:43:41,270
PATHWAYS.

2023
01:43:41,270 --> 01:43:43,906
THE MUTATIONS AND TRANS 

2024
01:43:43,906 --> 01:43:47,343
LOCATIONS IN NTS2 OR ACTIVATING 

2025
01:43:47,343 --> 01:43:50,313
MUTATIONS CAN LEAD TO 

2026
01:43:50,313 --> 01:43:55,451
ONCO-GENESIS IN MULTIPLE MYELOMA

2027
01:43:55,451 --> 01:44:02,225
AND ACUTE LYMPHOBLASTIC LEUKEMIA

2028
01:44:02,225 --> 01:44:07,864
AND CAUSE POOR PROGNOSIS AND 

2029
01:44:07,864 --> 01:44:08,231
OUTCOME.

2030
01:44:08,231 --> 01:44:12,168
AND THE DOMAIN WE IDENTIFIED A 

2031
01:44:12,168 --> 01:44:15,538
COMPOUND THAT DISRUPTS ITS 

2032
01:44:15,538 --> 01:44:19,675
INTERACTION WITH METHYL LYSINE 

2033
01:44:19,675 --> 01:44:22,311
IN THE NUCLEOSOMAL CONTEXT AND 

2034
01:44:22,311 --> 01:44:23,746
THE COMPOUND OVER HERE.

2035
01:44:23,746 --> 01:44:27,049
IT DOESN'T HAVE -- IT'S NOT 

2036
01:44:27,049 --> 01:44:29,819
ENOUGH TO KNOCK NST2 OFF 

2037
01:44:29,819 --> 01:44:31,354
CHROMATIN BECAUSE IT HAS ALL 

2038
01:44:31,354 --> 01:44:32,522
THESE OTHER READER DOMAINS SHOWN

2039
01:44:32,522 --> 01:44:34,457
HERE AND SO WE DIDN'T SEE MUCH 

2040
01:44:34,457 --> 01:44:36,359
OF A PHENOTYPE IN THE ONCOLOGY 

2041
01:44:36,359 --> 01:44:37,226
SETTING WITH THIS.

2042
01:44:37,226 --> 01:44:39,295
SO WE THOUGHT WHAT IF WE CAN 

2043
01:44:39,295 --> 01:44:41,464
JUST GET RID OF THE ENTIRE 

2044
01:44:41,464 --> 01:44:42,031
PROTEIN.

2045
01:44:42,031 --> 01:44:48,905
SO WE'RE USING THE NEW MODALITY 

2046
01:44:48,905 --> 01:44:50,239
CALLED TARGETED PROTEIN 

2047
01:44:50,239 --> 01:44:52,108
DEGRADATION OR PROTAX AND YOU 

2048
01:44:52,108 --> 01:44:58,181
CAN BRING IT TOGETHER WITH AN E3

2049
01:44:58,181 --> 01:45:03,553
LIGASE TO CALL DEGRADATION AND 

2050
01:45:03,553 --> 01:45:05,755
THIS IS THE WORK OF MY TALENTED 

2051
01:45:05,755 --> 01:45:07,190
STUDENT IN COLLABORATION WITH 

2052
01:45:07,190 --> 01:45:12,028
LINDSEY JAMES AT THE UNIVERSITY 

2053
01:45:12,028 --> 01:45:15,097
OF NORTH CAROLINA AND THIS IS 

2054
01:45:15,097 --> 01:45:17,600
PUBLISHED EARLIER THIS YEAR.

2055
01:45:17,600 --> 01:45:21,704
THIS MOLECULE WHICH CAN REDUCE 

2056
01:45:21,704 --> 01:45:25,441
OR TODAY GRADES NST2 IN CELLS 

2057
01:45:25,441 --> 01:45:28,744
AND REDUCE METHYLATION MARK 

2058
01:45:28,744 --> 01:45:37,453
SHOWN HERE OF K36 DIMYETHYL AND 

2059
01:45:37,453 --> 01:45:42,825
THIS IS THE INHIBITION OR THE 

2060
01:45:42,825 --> 01:45:43,893
DEGRADATION CURVE SHOWN HERE IN 

2061
01:45:43,893 --> 01:45:45,661
A DOSE DEPENDENT MANNER.

2062
01:45:45,661 --> 01:45:49,365
WE DIDN'T KNOW WHAT THE E3 

2063
01:45:49,365 --> 01:45:50,900
LIGASE WAS AT THE TIME BECAUSE 

2064
01:45:50,900 --> 01:45:55,605
IT'S A NOVEL COMPOUND USUALLY 

2065
01:45:55,605 --> 01:45:59,475
ONE TRIES -- THEY RECRUIT THE 

2066
01:45:59,475 --> 01:46:02,778
LIGASE AND THIS IS NOT -- THIS 

2067
01:46:02,778 --> 01:46:04,513
LIGAND DOES NOT RECRUIT EITHER 

2068
01:46:04,513 --> 01:46:08,050
OF THOSE SO WE HAD TO FIGURE IT 

2069
01:46:08,050 --> 01:46:09,318
OUT WHAT THE COMPOUND WAS I'LL 

2070
01:46:09,318 --> 01:46:11,621
SHOW IN A MOMENT AND HAS A MILD 

2071
01:46:11,621 --> 01:46:15,625
GROWTH EXPRESSIVE ACTIVITY IN A 

2072
01:46:15,625 --> 01:46:17,994
MULTIPLE MYELOMA CELL LINE SHOWN

2073
01:46:17,994 --> 01:46:22,632
HERE BUT SIGNIFICANT AFFECTS ON 

2074
01:46:22,632 --> 01:46:24,700
ADHESION IN KMS11 CELL LINES.

2075
01:46:24,700 --> 01:46:26,102
WE WERE ENCOURAGED TO GO ON AND 

2076
01:46:26,102 --> 01:46:29,538
TRY TO DEVELOP THIS FURTHER.

2077
01:46:29,538 --> 01:46:33,309
WE NOW HAVE A SECOND GENERATION 

2078
01:46:33,309 --> 01:46:36,712
DEGRADER WHICH HAS SIMILAR CHEMO

2079
01:46:36,712 --> 01:46:36,912
TYPE.

2080
01:46:36,912 --> 01:46:43,919
IT'S JUST RANGED BY THIS AND AN 

2081
01:46:43,919 --> 01:46:47,957
UNUSUAL WAR HEAD COMPOUND AND 

2082
01:46:47,957 --> 01:46:54,397
HAS AN ORDER OF MAGNITUDE DC50 

2083
01:46:54,397 --> 01:46:57,566
WHERE IT'S 50% DEGRADED USING 

2084
01:46:57,566 --> 01:47:04,407
BIO I.D. PROTEOMICS WITH THE F 

2085
01:47:04,407 --> 01:47:10,446
OX COLUMN 1FCS COMPLEX AND CAN 

2086
01:47:10,446 --> 01:47:13,215
SHOW THE COMPOUND BRINGS NST2 

2087
01:47:13,215 --> 01:47:14,083
TOGETHER IN CELLS.

2088
01:47:14,083 --> 01:47:18,888
I WANT TO END GOING BACK TO THIS

2089
01:47:18,888 --> 01:47:24,226
ANTAGONISTIC AND PLASTICITY 

2090
01:47:24,226 --> 01:47:28,431
ASPECT OF THE POLY COMB MARKS.

2091
01:47:28,431 --> 01:47:29,865
THIS IS A TIME SCALE OF 

2092
01:47:29,865 --> 01:47:32,435
TREATMENT AND MEASURING THE 

2093
01:47:32,435 --> 01:47:35,237
GLOBAL LEVELS IN A CELL THE K36 

2094
01:47:35,237 --> 01:47:37,006
AND K27 MARK.

2095
01:47:37,006 --> 01:47:40,409
THERE'S A SLOW -- WE DEGRADE 

2096
01:47:40,409 --> 01:47:42,511
NST2 ALMOST VERY QUICKLY IN A 

2097
01:47:42,511 --> 01:47:53,055
MATTER OF FOUR HOURS IT'S GONE.

2098
01:47:54,557 --> 01:47:56,359
IT TAKES DAYS FOR THE MARKS TO 

2099
01:47:56,359 --> 01:47:58,027
START TO CHANGE AND IT'S OVER IN

2100
01:47:58,027 --> 01:48:04,066
WEEKS FOR THE MARK TO GO AWAY 

2101
01:48:04,066 --> 01:48:09,305
AND YOU START TO SEE THE KH27 

2102
01:48:09,305 --> 01:48:11,140
BIMETHYL MARK INCREASING.

2103
01:48:11,140 --> 01:48:13,676
AND ONE IS ASSOCIATED WITH 

2104
01:48:13,676 --> 01:48:17,580
TRANSCRIPTION ACTIVATION AND ONE

2105
01:48:17,580 --> 01:48:21,517
WITH TRANSCRIPTIONAL REPRESSION.

2106
01:48:21,517 --> 01:48:23,652
AND THEN FURTHER ONCE THE MARK'S

2107
01:48:23,652 --> 01:48:26,355
ON THE CHROMATIN CHANGE THERE'S 

2108
01:48:26,355 --> 01:48:28,557
LIKELY A REPROGRAMMING AND 

2109
01:48:28,557 --> 01:48:29,325
CHANGE IN GENE EXPRESSION 

2110
01:48:29,325 --> 01:48:33,596
PROGRAM THAT CAN HAPPEN OVER 

2111
01:48:33,596 --> 01:48:38,134
FURTHER TIME.

2112
01:48:38,134 --> 01:48:44,106
VERY INVESTIGATED THIS AND 

2113
01:48:44,106 --> 01:48:47,443
IDENTIFIED AND GENERATED A NICE 

2114
01:48:47,443 --> 01:48:49,078
ISO GENIC PAIR OF CELL LINE AND 

2115
01:48:49,078 --> 01:48:54,116
HAVE THE ACTIVATING MUTATION AND

2116
01:48:54,116 --> 01:48:56,152
THE CELLS ARE SOMEWHAT DEPENDENT

2117
01:48:56,152 --> 01:49:01,590
ON THE HIGH EXPRESSION OR HIGH 

2118
01:49:01,590 --> 01:49:05,995
ACTIVITY OF NST2.

2119
01:49:05,995 --> 01:49:12,034
WHEN I THE INHIBITOR WE INHIBIT 

2120
01:49:12,034 --> 01:49:22,578
EXPRESSION AND IT INCREASES WITH

2121
01:49:27,616 --> 01:49:30,820
TIME AND GOING FROM 12 DAYS, 15,

2122
01:49:30,820 --> 01:49:34,790
18, 21 YOU SEE A REMARKABLE 

2123
01:49:34,790 --> 01:49:35,624
DECREASE IN CELL VIABILITY AND 

2124
01:49:35,624 --> 01:49:39,161
THESE ARE THE CELLS THAT HAVE --

2125
01:49:39,161 --> 01:49:40,596
ACTIVATING THE MUTATION.

2126
01:49:40,596 --> 01:49:46,168
THE RED.

2127
01:49:46,168 --> 01:49:50,840
AND THE ACTIVE COMPOUND AND THE 

2128
01:49:50,840 --> 01:49:55,277
RED YOU WANT TO FOCUS ON AND 

2129
01:49:55,277 --> 01:49:57,246
THEN IF WE TEST IN COMBINATION 

2130
01:49:57,246 --> 01:50:07,723
WITH DEXOMETHOSONE AND THE 

2131
01:50:11,627 --> 01:50:12,094
REOCCURRENCE IS MET WITH 

2132
01:50:12,094 --> 01:50:14,864
RESISTANCE TO THIS AND SO IS THE

2133
01:50:14,864 --> 01:50:17,867
MUTATION WITH NSD2 AND WE SEE A 

2134
01:50:17,867 --> 01:50:22,471
SIGNIFICANT INCREASE IN RECOVERY

2135
01:50:22,471 --> 01:50:27,409
OF THE DEXOMETHOSONE RESISTANCE.

2136
01:50:27,409 --> 01:50:30,746
SO LET ME SUMMARIZE BY SAYING 

2137
01:50:30,746 --> 01:50:33,582
THE CHEMICAL PROBES AND CHEMICAL

2138
01:50:33,582 --> 01:50:35,684
BIOLOGY ARE AMONG THE MOST 

2139
01:50:35,684 --> 01:50:37,653
USEFUL TOOLS IN DRUG BIOLOGY AND

2140
01:50:37,653 --> 01:50:40,422
DRUG DISCOVERY.

2141
01:50:40,422 --> 01:50:42,591
EPIGENETIC CHEMICAL PROBES 

2142
01:50:42,591 --> 01:50:43,359
IDENTIFIED MULTIPLE SUB TYPE AND

2143
01:50:43,359 --> 01:50:45,294
WE'VE GIVEN OUR COLLECTION TO 

2144
01:50:45,294 --> 01:50:49,465
MANY OF YOU IN THE AUDIENCE AND 

2145
01:50:49,465 --> 01:50:52,835
ALSO MANY OTHERS AND IT IS 

2146
01:50:52,835 --> 01:50:53,702
INSPIRING NOVEL THERAPEUTIC 

2147
01:50:53,702 --> 01:50:55,204
HYPOTHESES AND PROCESSES.

2148
01:50:55,204 --> 01:50:57,339
GOOD CHEMICAL PROBES ARE VERY 

2149
01:50:57,339 --> 01:51:00,776
IMPORTANT TO THE BIOLOGY AND OUR

2150
01:51:00,776 --> 01:51:04,079
ORGANIZATION HAS INITIATED A 

2151
01:51:04,079 --> 01:51:06,882
NUMBER OF INITIATIVES TO PROMOTE

2152
01:51:06,882 --> 01:51:10,119
BEST PRACTICES IN USING CHEMICAL

2153
01:51:10,119 --> 01:51:10,352
PROBES.

2154
01:51:10,352 --> 01:51:12,321
THE CHEMICAL PROBES PORTAL HELPS

2155
01:51:12,321 --> 01:51:21,130
YOU DETERMINE THE BEST PROBE AND

2156
01:51:21,130 --> 01:51:23,866
HELP DRUG DISCOVERY GO FASTER IN

2157
01:51:23,866 --> 01:51:24,433
THE FUTURE.

2158
01:51:24,433 --> 01:51:28,003
I WANT TO THANK ALL THE GIANTS 

2159
01:51:28,003 --> 01:51:31,073
ON WHOSE SHOULDERS I STAND AND 

2160
01:51:31,073 --> 01:51:34,076
IN MY LAB AND MANY COLLABORATORS

2161
01:51:34,076 --> 01:51:35,911
PARTICULARLY FOR THE STORIES I 

2162
01:51:35,911 --> 01:51:38,147
TALKED ABOUT AND LINDSEY JAMES' 

2163
01:51:38,147 --> 01:51:39,348
LAB AT THE UNIVERSITY OF NORTH 

2164
01:51:39,348 --> 01:51:40,683
CAROLINA AND MY COLLEAGUES AT 

2165
01:51:40,683 --> 01:51:43,686
PRINCESS MARGARET.

2166
01:51:43,686 --> 01:51:49,291
THE SGC SITE IN TORONTO I LEAD 

2167
01:51:49,291 --> 01:51:51,794
AND CHEMISTS WHO MAKE THEIR 

2168
01:51:51,794 --> 01:51:52,628
CHEMICAL PROBES AVAILABLE FOR 

2169
01:51:52,628 --> 01:51:54,096
EVERYONE TO USE.

2170
01:51:54,096 --> 01:51:56,465
OUR FUNDING FROM THE SGC AND 

2171
01:51:56,465 --> 01:51:57,866
I'LL END WITH A QUICK PLUG FOR 

2172
01:51:57,866 --> 01:52:08,010
TORONTO.

2173
01:52:08,677 --> 01:52:10,879
>> THIS IS INCREDIBLY
VALUABLE.

2174
01:52:10,879 --> 01:52:12,181
WE HAVE TIME FOR MAYBE A COUPLE 

2175
01:52:12,181 --> 01:52:14,116
QUICK QUESTIONS BUT THEY HAVE TO

2176
01:52:14,116 --> 01:52:15,150
BE QUICK QUESTIONS.

2177
01:52:15,150 --> 01:52:15,384
THANKS.

2178
01:52:15,384 --> 01:52:19,221
>> HI, THANK YOU FOR A
GREAT 

2179
01:52:19,221 --> 01:52:19,755
TALK.

2180
01:52:19,755 --> 01:52:20,623
I'M FROM GEORGE WASHINGTON 

2181
01:52:20,623 --> 01:52:20,923
UNIVERSITY.

2182
01:52:20,923 --> 01:52:25,160
IN YOUR FIRST STORY ABOUT THE 

2183
01:52:25,160 --> 01:52:27,663
PRMT ONE INHIBITION, DID YOU 

2184
01:52:27,663 --> 01:52:29,198
LOOK AT WHAT CHARACTERIZED THE 

2185
01:52:29,198 --> 01:52:32,401
SENSITIVE CELL LINES IN TERMS OF

2186
01:52:32,401 --> 01:52:35,004
MORE OF THE ALOS THAT WERE IN 

2187
01:52:35,004 --> 01:52:39,375
THE SPLICING VARIANTS?

2188
01:52:39,375 --> 01:52:44,346
WAS THERE A DIFFERENT IN THE 

2189
01:52:44,346 --> 01:52:46,415
BASELINE LIKE OTHER EPIGENETIC 

2190
01:52:46,415 --> 01:52:46,749
MODIFICATIONS?

2191
01:52:46,749 --> 01:52:51,387
>> DID WE CHARACTERIZE THE
GENES

2192
01:52:51,387 --> 01:52:55,724
THAT CONTAINED THE ALOES.

2193
01:52:55,724 --> 01:52:59,428
>> YOU NOTICE THE THE
SENSITIVE 

2194
01:52:59,428 --> 01:53:04,867
ONES HAD THE MORE ALLO IRs.

2195
01:53:04,867 --> 01:53:09,038
I WAS CURIOUS ABOUT WHY.

2196
01:53:09,038 --> 01:53:12,875
>> THEY HAD THEY BOTH HAD
THEM 

2197
01:53:12,875 --> 01:53:15,144
INADVERTENTLY EXPRESSED.

2198
01:53:15,144 --> 01:53:17,980
THE SENSITIVE ONES THOSE HAD THE

2199
01:53:17,980 --> 01:53:20,616
INVERTED REPEATS IN THEM WHERE 

2200
01:53:20,616 --> 01:53:21,216
THE OTHER SENSITIVE LINES DID 

2201
01:53:21,216 --> 01:53:29,158
NOT.

2202
01:53:29,158 --> 01:53:30,693
>> I'M IN EPIGENETICS.

2203
01:53:30,693 --> 01:53:31,393
GREAT TALK.

2204
01:53:31,393 --> 01:53:33,429
I HAD A MORE GENERAL QUESTION 

2205
01:53:33,429 --> 01:53:36,298
ABOUT THE PROBE COLLECTION WHICH

2206
01:53:36,298 --> 01:53:39,168
OBVIOUSLY HASN'T BEEN ENRICHED 

2207
01:53:39,168 --> 01:53:40,135
WITH INHIBITERS AND HASN'T GROWN

2208
01:53:40,135 --> 01:53:45,374
TO INCLUDE THE DE GRID  

2209
01:53:45,374 --> 01:53:48,811
GRADERS -- DEGRADERS AND WITH 

2210
01:53:48,811 --> 01:53:50,646
BREAKTHROUGHS IN THE FIELD WHERE

2211
01:53:50,646 --> 01:53:52,781
DO THEY STAND?

2212
01:53:52,781 --> 01:53:57,686
>> A NUMBER OF OUR
CHEMICAL 

2213
01:53:57,686 --> 01:53:59,288
PROBES AND OUR READERS AND 

2214
01:53:59,288 --> 01:54:01,423
METHYL TRANSFERASES HAVE BEEN 

2215
01:54:01,423 --> 01:54:02,925
TURNED INTO TARGETED DEGRADERS.

2216
01:54:02,925 --> 01:54:08,263
SOME ARE INCLUDED IN OUR 

2217
01:54:08,263 --> 01:54:14,203
COLLECTION LIST.

2218
01:54:14,203 --> 01:54:19,341
AND WE HAVE SOME OF THESE IN 

2219
01:54:19,341 --> 01:54:21,510
FRANKFURT AND THEY'RE ALL IN 

2220
01:54:21,510 --> 01:54:22,511
ENCUMBERED COMPOUNDS.

2221
01:54:22,511 --> 01:54:23,779
WE ENCOURAGE ANYBODY WHO WANTS 

2222
01:54:23,779 --> 01:54:26,648
TO TO MAKE DEGRADERS OUT OF THEM

2223
01:54:26,648 --> 01:54:28,851
BUT THEY'RE COMING.

2224
01:54:28,851 --> 01:54:30,419
IT'S FAST AND FURIOUS NEW 

2225
01:54:30,419 --> 01:54:31,754
DEGRADERS COMING FOR A LOT OF 

2226
01:54:31,754 --> 01:54:31,954
THESE.

2227
01:54:31,954 --> 01:54:32,888
>> THANK YOU VERY MUCH.

2228
01:54:32,888 --> 01:54:34,289
I APPRECIATE IT.

2229
01:54:34,289 --> 01:54:38,658
AND SO WE'RE GOING TO HAVE THE
FIRST BREAK.

2230
01:54:38,658 --> 01:54:44,497
>> THANK YOU.

2231
01:54:44,497 --> 01:54:46,399
IT'S MY PLEASURE TO INTRODUCE 

2232
01:54:46,399 --> 01:54:47,801
OWE NEXT SPEAKER AND WE'RE IN 

2233
01:54:47,801 --> 01:54:52,639
FOR A REAL TREAT TO HERE HIS 

2234
01:54:52,639 --> 01:54:58,011
STORY ABOUT 5 AZACYTIDINE FROM 

2235
01:54:58,011 --> 01:55:01,981
MYOGENESIS TO MDS.

2236
01:55:01,981 --> 01:55:03,850
HE WAS IN SOUTH AFRICA BEFORE 

2237
01:55:03,850 --> 01:55:04,884
COMING A CHIEF SCIENTIFIC 

2238
01:55:04,884 --> 01:55:09,722
OFFICER IN GRAND RAPIDS IN 

2239
01:55:09,722 --> 01:55:09,989
MICHIGAN.

2240
01:55:09,989 --> 01:55:12,058
HE'S FROM SOUTHERN CALIFORNIA 

2241
01:55:12,058 --> 01:55:17,130
AND BECOMING A DISTINGUISHED 

2242
01:55:17,130 --> 01:55:18,665
PROFESSOR AND DIRECTOR.

2243
01:55:18,665 --> 01:55:28,775
THANK YOU.

2244
01:55:28,775 --> 01:55:30,777
>> THANK YOU.

2245
01:55:30,777 --> 01:55:32,612
IT'S REALLY GREAT TO BE HERE.

2246
01:55:32,612 --> 01:55:33,513
THANK YOU FOR PUTTING TOGETHER 

2247
01:55:33,513 --> 01:55:35,048
THIS SYMPOSIUM.

2248
01:55:35,048 --> 01:55:40,320
I'M GOING TO TALK ABOUT 5 

2249
01:55:40,320 --> 01:55:42,355
AZACYTIDINE AND DESCRIBE MY 

2250
01:55:42,355 --> 01:55:44,724
STORY HOW I GOT INTO EPIGENETICS

2251
01:55:44,724 --> 01:55:48,962
AND HOPEFULLY BRING YOU UP TO 

2252
01:55:48,962 --> 01:55:51,631
SPEED WITH THE COMPOUND.

2253
01:55:51,631 --> 01:55:56,903
MY STORY STARTS WITH THIS 5 

2254
01:55:56,903 --> 01:55:57,570
AZACYTIDINE DEVELOPED IN PRAGUE 

2255
01:55:57,570 --> 01:56:01,574
IN THE '60 AS A CHEMO 

2256
01:56:01,574 --> 01:56:03,309
THERAPEUTIC AGENT AND DID A FEW 

2257
01:56:03,309 --> 01:56:04,344
CLINICAL TRIALS IN EUROPE AND 

2258
01:56:04,344 --> 01:56:08,448
THEN SENT THE DRUG TO THE 

2259
01:56:08,448 --> 01:56:10,950
U.S. WHERE IT UNDERWENT CLINICAL

2260
01:56:10,950 --> 01:56:14,354
TESTING AND THIS PAPER WAS A 

2261
01:56:14,354 --> 01:56:16,422
REVIEW PAPER ON 5 AZACYTIDINE 

2262
01:56:16,422 --> 01:56:20,426
FROM 1976 AND YOU'LL NOTICE THE 

2263
01:56:20,426 --> 01:56:24,564
ADDRESS IS BETHESDA, MARYLAND 

2264
01:56:24,564 --> 01:56:26,566
WHERE WE ARE.

2265
01:56:26,566 --> 01:56:28,101
THIS CARRIED OUT CLINICAL 

2266
01:56:28,101 --> 01:56:29,836
STUDIES DONE HERE AT THE 

2267
01:56:29,836 --> 01:56:30,637
NATIONAL CANCER INSTITUTE.

2268
01:56:30,637 --> 01:56:33,907
THIS DRUG WAS FOUND TO BE NOT 

2269
01:56:33,907 --> 01:56:36,109
THAT EFFECTIVE IN TUMORS AND HAD

2270
01:56:36,109 --> 01:56:46,119
SOME PROMISE WITH AML.

2271
01:56:46,119 --> 01:56:48,922
WHEN WE PUT THESE ON MOUSE CELLS

2272
01:56:48,922 --> 01:56:50,990
WE WERE SHOCKED TO SEE THE 

2273
01:56:50,990 --> 01:56:58,164
DEVELOPMENT OF FUNCTIONAL 

2274
01:56:58,164 --> 01:56:59,465
CONTRACTILE MUSCLE CELLS SEVERAL

2275
01:56:59,465 --> 01:57:00,433
DAYS OR WEEKS AFTER EXPOSURE.

2276
01:57:00,433 --> 01:57:03,536
THIS PAPER WAS PUBLISHED IN 

2277
01:57:03,536 --> 01:57:13,813
NATURE IN 1977.

2278
01:57:19,752 --> 01:57:21,154
YOU COULD TREAT FOR THE DRUG FOR

2279
01:57:21,154 --> 01:57:23,289
24 HOURS, REMOVE THE DRUGS AND 

2280
01:57:23,289 --> 01:57:28,561
THE CELLS WOULD THEN GROW AND AT

2281
01:57:28,561 --> 01:57:35,268
THE TIME WE SAW THE DEVELOPMENT 

2282
01:57:35,268 --> 01:57:37,503
WITHOUT PLANT OR MUSCLE AND ONE 

2283
01:57:37,503 --> 01:57:38,972
OF THE FIRST EXAMPLES OF 

2284
01:57:38,972 --> 01:57:41,007
CELLULAR REPROGRAMMING AND 

2285
01:57:41,007 --> 01:57:43,009
PROGRAMMING WITH A SMALL 

2286
01:57:43,009 --> 01:57:44,210
MOLECULE.

2287
01:57:44,210 --> 01:57:44,877
NATURALLY I WAS VERY INTERESTED 

2288
01:57:44,877 --> 01:57:48,848
IN THAT.

2289
01:57:48,848 --> 01:57:50,950
I'VE NEVER HEARD OF DNA 

2290
01:57:50,950 --> 01:57:51,250
METHYLATION.

2291
01:57:51,250 --> 01:57:53,486
NEVER HEARD OF EPIGENETICS.

2292
01:57:53,486 --> 01:57:54,620
SOMEBODY MENTIONED TO ME MAYBE 

2293
01:57:54,620 --> 01:57:56,923
WE SHOULD THINK WITH THE FACT 

2294
01:57:56,923 --> 01:58:01,661
THIS IS ROBERT STALWAGGIN IT MAY

2295
01:58:01,661 --> 01:58:03,563
BE INHIBITOR OF DNA METHYLATION 

2296
01:58:03,563 --> 01:58:05,531
AND SO WE TESTED THAT AND FOUND 

2297
01:58:05,531 --> 01:58:07,934
OUT VERY QUICKLY -- IN FACT IT 

2298
01:58:07,934 --> 01:58:10,670
WAS A VERY POWERFUL INHIBITOR OF

2299
01:58:10,670 --> 01:58:12,472
DNA METHYLATION AND NOT ONLY 

2300
01:58:12,472 --> 01:58:22,949
THAT COULD INDUCE CELLULAR 

2301
01:58:29,155 --> 01:58:36,396
DIFFERENCES AND THIS STIMULATED 

2302
01:58:36,396 --> 01:58:37,030
ARTHUR RIGS WAS ONE OF THE FIRST

2303
01:58:37,030 --> 01:58:38,131
PEOPLE TO SUGGEST DNA 

2304
01:58:38,131 --> 01:58:39,532
METHYLATION WAS AN IMPORTANT 

2305
01:58:39,532 --> 01:58:44,704
PROCESS IN CELLS AND MIGHT BE 

2306
01:58:44,704 --> 01:58:49,342
INVOLVED IN EPIGENETICS.

2307
01:58:49,342 --> 01:58:55,882
HE WAS IN DUARTE, CALIFORNIA AND

2308
01:58:55,882 --> 01:58:56,616
I ESTABLISHED A LONG-TERM 

2309
01:58:56,616 --> 01:59:06,993
INTERACTION WITH ART.

2310
01:59:08,494 --> 01:59:10,663
 WE MEASURED THE AFFECT ON DNA 

2311
01:59:10,663 --> 01:59:14,667
METHYLATION AND INDUCING MUSCLE 

2312
01:59:14,667 --> 01:59:16,302
FORMATION.

2313
01:59:16,302 --> 01:59:20,540
YOU CAN SEE YOU CAN INHIBIT DNA 

2314
01:59:20,540 --> 01:59:23,676
METHYLATION BY A LARGE AMOUNT 

2315
01:59:23,676 --> 01:59:26,579
MORE THAN 50% AND THE INCREASING

2316
01:59:26,579 --> 01:59:29,182
DOSES DIDN'T HAVE MUCH MORE OF 

2317
01:59:29,182 --> 01:59:31,951
AN AFFECT AND ONCE YOU INHIBIT 

2318
01:59:31,951 --> 01:59:33,052
YOU CAN'T INHIBIT FURTHER 

2319
01:59:33,052 --> 01:59:35,388
BECAUSE YOU REMOVE THE 

2320
01:59:35,388 --> 01:59:39,525
TRANSFERASE FROM THE CELL AND 

2321
01:59:39,525 --> 01:59:44,197
THE RESPONSE CURVE WITH RESPECT 

2322
01:59:44,197 --> 01:59:46,899
TO DIFFERENTIATION YOU INCREASE 

2323
01:59:46,899 --> 01:59:47,500
THE DOSE AND THE AFFECT GOES 

2324
01:59:47,500 --> 01:59:49,602
DOWN.

2325
01:59:49,602 --> 01:59:51,571
THIS ACTUALLY, I BELIEVE, HELD 

2326
01:59:51,571 --> 01:59:53,606
UP THE CLINICAL DEVELOPMENT OF 

2327
01:59:53,606 --> 01:59:57,543
THIS DRUG FOR MANY MANY YEARS 

2328
01:59:57,543 --> 02:00:04,917
BECAUSE MANY STUDIES SHOULD FOR 

2329
02:00:04,917 --> 02:00:10,523
THE MAXIMUM TOLERATE DOSE AND 

2330
02:00:10,523 --> 02:00:13,059
THIS DOESN'T AND WHEN IT WAS 

2331
02:00:13,059 --> 02:00:14,327
PEARED BACK THE VALIDITY BECAME 

2332
02:00:14,327 --> 02:00:18,197
APPARENT.

2333
02:00:18,197 --> 02:00:21,601
WE FIGURED OUT HOW THE DRUG 

2334
02:00:21,601 --> 02:00:27,974
WORKS TO SOME EXTENT.

2335
02:00:27,974 --> 02:00:29,475
IT REQUIRES THE INCORPORATION OF

2336
02:00:29,475 --> 02:00:32,645
DNA AND WE DIDN'T KNOW ABOUT THE

2337
02:00:32,645 --> 02:00:34,213
DIFFERENT DNA TRANSFERASES AT 

2338
02:00:34,213 --> 02:00:38,351
THE TIME AND FORM A BOND WITH 

2339
02:00:38,351 --> 02:00:42,455
THE TRANSFERASE AND CAUSES AN 

2340
02:00:42,455 --> 02:00:44,357
IMMEDIATE REDUCTION IN THE LEVEL

2341
02:00:44,357 --> 02:00:45,958
OF PROTEIN IN THE CELL.

2342
02:00:45,958 --> 02:00:49,795
SO IT'S A MECHANISM BASED 

2343
02:00:49,795 --> 02:00:51,864
INHIBITION WHICH LEADS TO THE 

2344
02:00:51,864 --> 02:00:53,366
DEGRADATION OF THE ENZYME.

2345
02:00:53,366 --> 02:00:55,835
IT ALSO CAUSES DNA BREAKS WHICH 

2346
02:00:55,835 --> 02:00:56,335
COMPLICATE SOME OF THE 

2347
02:00:56,335 --> 02:01:04,043
INTERPRETATION.

2348
02:01:04,043 --> 02:01:05,011
HOW'S IT WORK?

2349
02:01:05,011 --> 02:01:08,481
WHAT CAUSE THE CHANGES?

2350
02:01:08,481 --> 02:01:09,682
WE SPENT A LOT OF TIME TRYING TO

2351
02:01:09,682 --> 02:01:11,284
FIGURE THIS OUT.

2352
02:01:11,284 --> 02:01:13,786
WHEN YOU TAKE MOUSE EMBRYO CELLS

2353
02:01:13,786 --> 02:01:16,589
THE CELLS GROW IN THE CULTURE 

2354
02:01:16,589 --> 02:01:19,192
DISH AND WHEN THEY BECOME 

2355
02:01:19,192 --> 02:01:20,860
IMMORTAL THEY KNOW THEIR 

2356
02:01:20,860 --> 02:01:22,929
METHYLATION RESULTS IN THE 

2357
02:01:22,929 --> 02:01:26,566
FORMATION OF IMMORTAL CELLS AND 

2358
02:01:26,566 --> 02:01:28,601
WHEN THEY'RE TREATED THEY'RE 

2359
02:01:28,601 --> 02:01:31,437
TURNED BACK TO STEM CELLS AND 

2360
02:01:31,437 --> 02:01:33,306
CAN DIFFERENTIATE INTO THE THREE

2361
02:01:33,306 --> 02:01:43,015
LINEAGES AND HERALD WINETRAUL 

2362
02:01:43,015 --> 02:01:45,985
LOOKED AT THE DETERMINATION 

2363
02:01:45,985 --> 02:01:50,656
FACTOR CALLED MYODE1.

2364
02:01:50,656 --> 02:01:54,227
AND MY FIRST Ph.D. STUDENT AND I

2365
02:01:54,227 --> 02:01:54,660
CELEBRATED THE WORK.

2366
02:01:54,660 --> 02:01:57,964
THIS WAS TAKEN PROBABLY IN '83 

2367
02:01:57,964 --> 02:01:59,165
OR SO.

2368
02:01:59,165 --> 02:02:01,701
YOU CAN SEE I HAVE UNDER GONE 

2369
02:02:01,701 --> 02:02:04,203
EPIGENETIC AGING AS ANDY 

2370
02:02:04,203 --> 02:02:06,706
FEINBERG POINTED OUT EARLIER ON 

2371
02:02:06,706 --> 02:02:07,006
AS WELL.

2372
02:02:07,006 --> 02:02:09,508
BUT THIS WAS AN EXCITING TIME 

2373
02:02:09,508 --> 02:02:11,944
AND WE WERE HOOKED ON 

2374
02:02:11,944 --> 02:02:14,847
EPIGENETICS AND I'VE NEVER 

2375
02:02:14,847 --> 02:02:16,682
WAVERED FROM EPIGENETICS EVER 

2376
02:02:16,682 --> 02:02:18,017
SINCE.

2377
02:02:18,017 --> 02:02:21,187
NOW, I'M ACTUALLY A CANCER GUY.

2378
02:02:21,187 --> 02:02:23,055
I'M NOT A DEVELOPMENT BIOLOGIST 

2379
02:02:23,055 --> 02:02:25,891
BUT I NOTICED AT THAT TIME THERE

2380
02:02:25,891 --> 02:02:30,529
WAS INTEREST IN DNA METHYLATION.

2381
02:02:30,529 --> 02:02:35,468
MELANIE ORNIK AND FRED BECKER AT

2382
02:02:35,468 --> 02:02:37,970
THE INDIANA CANCER CENTER, 

2383
02:02:37,970 --> 02:02:39,205
PEOPLE STARTED MEASURING DNA 

2384
02:02:39,205 --> 02:02:40,740
METHYLATION IN DIFFERENT TUMORS.

2385
02:02:40,740 --> 02:02:42,408
I DON'T THINK THIS WENT VERY FAR

2386
02:02:42,408 --> 02:02:43,843
BECAUSE NO ONE WAS INTERESTED IN

2387
02:02:43,843 --> 02:02:47,380
IT AND NOT ONLY WAS THERE NO 

2388
02:02:47,380 --> 02:02:47,980
SPECIFICITY.

2389
02:02:47,980 --> 02:02:50,483
CANCER CELLS HAVE LOTS OF 

2390
02:02:50,483 --> 02:02:52,852
DIFFERENT CHANGES BUT THEY WROTE

2391
02:02:52,852 --> 02:02:54,920
A REVIEW AND I HAVEN'T LOOKED AT

2392
02:02:54,920 --> 02:02:57,323
IT FOR 40 YEARS SINCE I WROTE IT

2393
02:02:57,323 --> 02:02:58,524
WITH HIM AND A WAS STUNNED 

2394
02:02:58,524 --> 02:03:00,960
BECAUSE THERE'S A FIGURE IN 

2395
02:03:00,960 --> 02:03:02,662
THERE AND I THINK ONE OF THE 

2396
02:03:02,662 --> 02:03:05,698
VERY FIRST REVIEWS EVER OF DNA 

2397
02:03:05,698 --> 02:03:09,735
METHYLATION AND CANCER IN 1983 

2398
02:03:09,735 --> 02:03:13,839
IN WHICH WE PROPOSED THE 

2399
02:03:13,839 --> 02:03:14,674
METHYLATION THAT CAUSED INSULT 

2400
02:03:14,674 --> 02:03:17,576
AND YOU CAN GET MUTATIONS AN 

2401
02:03:17,576 --> 02:03:19,845
DECREASED METHYLATION BASED ON 

2402
02:03:19,845 --> 02:03:21,781
ALL THIS STUFF AND OF COURSE 

2403
02:03:21,781 --> 02:03:23,783
THESE COULD BECOME MORE 

2404
02:03:23,783 --> 02:03:24,717
PROGRESSIVE.

2405
02:03:24,717 --> 02:03:27,987
I THINK WE SORT OF HAD THE RIGHT

2406
02:03:27,987 --> 02:03:32,058
IDEA BY GUESSWORK AND OF COURSE 

2407
02:03:32,058 --> 02:03:34,260
WE DID MANAGE -- WHEN ANDY'S 

2408
02:03:34,260 --> 02:03:37,296
PAPER CAME OUT WE ACTUALLY 

2409
02:03:37,296 --> 02:03:39,031
REALLY FELT, WELL, THIS REALLY 

2410
02:03:39,031 --> 02:03:41,000
HAS LEGS BECAUSE ANDY TOOK IT 

2411
02:03:41,000 --> 02:03:43,035
FROM A GENERAL MODEL TO SHOWING 

2412
02:03:43,035 --> 02:03:44,937
SPECIFICALLY IN HUMAN TUMORS 

2413
02:03:44,937 --> 02:03:47,606
WHICH ARE UNCULTURED YOU COULD 

2414
02:03:47,606 --> 02:03:50,710
SEE CHANGES IN DNA METHYLATION 

2415
02:03:50,710 --> 02:03:53,846
AT THE GENE LEVEL.

2416
02:03:53,846 --> 02:03:56,782
SO WE ALL KNOW METHYLATION LOOKS

2417
02:03:56,782 --> 02:03:57,350
LIKE THIS.

2418
02:03:57,350 --> 02:04:00,820
AND DURING THE FORMATION OF 

2419
02:04:00,820 --> 02:04:02,288
CANCER YOU GET THESE CHANGES.

2420
02:04:02,288 --> 02:04:06,025
OF COURSE ANDY AND STEVE BAYLIN 

2421
02:04:06,025 --> 02:04:06,625
PLAYED MAJOR ROLES IN 

2422
02:04:06,625 --> 02:04:07,126
UNDERSTANDING THESE TWO 

2423
02:04:07,126 --> 02:04:10,396
PROCESSES.

2424
02:04:10,396 --> 02:04:12,965
SO THE QUESTION IS THEN IS HOW 

2425
02:04:12,965 --> 02:04:15,568
DOES THIS HAPPEN.

2426
02:04:15,568 --> 02:04:18,270
WHY DO CELLS CHANGE DNA 

2427
02:04:18,270 --> 02:04:19,839
METHYLATION PATTERNS?

2428
02:04:19,839 --> 02:04:22,675
WELL, EARLY ON, FRED BECKER 

2429
02:04:22,675 --> 02:04:24,577
ACTUALLY LOOKED TO SEE WHETHER 

2430
02:04:24,577 --> 02:04:26,545
THE DNA METHYL TRANSFERASE WAS 

2431
02:04:26,545 --> 02:04:29,715
TO BLAME AND WE DID THIS AND 

2432
02:04:29,715 --> 02:04:32,518
FOUND THAT IN FACT THOUGH THE 

2433
02:04:32,518 --> 02:04:34,353
DNA WAS HYPERMETHYLATE THE LEVEL

2434
02:04:34,353 --> 02:04:36,555
OF ENZYME WAS INCREASED.

2435
02:04:36,555 --> 02:04:38,124
THAT DIDN'T MAKE MUCH SENSE SO 

2436
02:04:38,124 --> 02:04:40,192
WHY WAS THAT?

2437
02:04:40,192 --> 02:04:41,694
AGAIN, BECAUSE HISTORICAL 

2438
02:04:41,694 --> 02:04:43,028
SYMPOSIUM WE DIDN'T KNOW AT THAT

2439
02:04:43,028 --> 02:04:46,465
TIME ABOUT THE EXISTENCE OF 

2440
02:04:46,465 --> 02:04:50,703
MULTIPLE DNA METHYL TRANSFERASE 

2441
02:04:50,703 --> 02:05:00,212
THE DI -- DE NOVO TRANSFERASES 

2442
02:05:00,212 --> 02:05:03,916
AND THE ENZYMES CAN DO A 

2443
02:05:03,916 --> 02:05:05,251
BEAUTIFUL JOB WITH NAKED DNA AND

2444
02:05:05,251 --> 02:05:11,090
NOT SO GOOD WHEN IT COMES TO DNA

2445
02:05:11,090 --> 02:05:15,428
IN THE NUCLEOSOME AND EVERYBODY 

2446
02:05:15,428 --> 02:05:25,137
KNOWS ABOUT EHRF1 AND THE 

2447
02:05:25,137 --> 02:05:26,439
ACCESSORY PROTEIN EXPRESSED 

2448
02:05:26,439 --> 02:05:30,576
EXCLUSIVELY IN EMBRYONIC STEM 

2449
02:05:30,576 --> 02:05:34,246
CELLS AND A SPLICING WHICH IS 

2450
02:05:34,246 --> 02:05:36,715
ALSO AN ACCESSORY PROTEIN THORR 

2451
02:05:36,715 --> 02:05:37,349
NOT REALLY ACKNOWLEDGED IN THE 

2452
02:05:37,349 --> 02:05:42,588
FIELD.

2453
02:05:42,588 --> 02:05:46,158
-- I'M NOT GOING TO TALK ABOUT 

2454
02:05:46,158 --> 02:05:48,394
DNA T1 BECAUSE WE HEARD 

2455
02:05:48,394 --> 02:05:51,664
SOMETHING ABOUT THAT ALREADY BUT

2456
02:05:51,664 --> 02:05:57,303
DNA 302 HAS A SHORT VERSION WITH

2457
02:05:57,303 --> 02:06:02,241
A PROMOTER AND A VARIANT OF 

2458
02:06:02,241 --> 02:06:07,046
SPLICE 3D1 A CATALYTICALLY 

2459
02:06:07,046 --> 02:06:12,751
ACTIVE  DOMAIN AND IT ALLOWS IT 

2460
02:06:12,751 --> 02:06:23,262
TO BIND TO A CELL AND HERE IN 

2461
02:06:26,398 --> 02:06:28,767
NORMAL TISSUES THE KEY GUY IS 

2462
02:06:28,767 --> 02:06:32,771
THE 3A1 AND IN CANCERS THESE ARE

2463
02:06:32,771 --> 02:06:35,274
ALL DIFFERENT CANCERS YOU CAN 

2464
02:06:35,274 --> 02:06:41,714
SEE 3A2 THE SHORT VERSION COMES 

2465
02:06:41,714 --> 02:06:44,049
UP THE SAME TIME AS THE 

2466
02:06:44,049 --> 02:06:49,188
ACCESSORY PROTEIN.

2467
02:06:49,188 --> 02:06:52,024
THESE ARE SEQ EXPERIMENTS AND 

2468
02:06:52,024 --> 02:06:54,560
WHAT IS IMPORTANT IS TO REALIZE 

2469
02:06:54,560 --> 02:07:04,336
IS THEY WORK AS A HETRO DIMER.

2470
02:07:04,336 --> 02:07:14,880
WE SOLVED THE STRUCTURE OF THE 

2471
02:07:15,848 --> 02:07:16,181
HET

2472
02:07:16,181 --> 02:07:18,417
HETROTETROMIN AND THE SO-CALLED 

2473
02:07:18,417 --> 02:07:21,387
ACIDIC PATCH AND IT ANCHORS THE 

2474
02:07:21,387 --> 02:07:23,589
COMPLEX IN THE ACIDIC PATCH AND 

2475
02:07:23,589 --> 02:07:26,258
HAVE YOU TWO ACTIVE ENZYMES HERE

2476
02:07:26,258 --> 02:07:36,635
AND ANOTHER 3B3 THERE.

2477
02:08:04,196 --> 02:08:06,665
THERE'S A CONSISTENT FINDING AND

2478
02:08:06,665 --> 02:08:08,500
THIS SEEMS TO BE A PRETTY 

2479
02:08:08,500 --> 02:08:09,168
UNIVERSAL AS TO WHAT'S GOING ON 

2480
02:08:09,168 --> 02:08:14,940
HERE.

2481
02:08:14,940 --> 02:08:17,209
THE UPREGULATE THE SHORT TERM 

2482
02:08:17,209 --> 02:08:19,311
EXPRESSED IN THE EMBRYO AND DOWN

2483
02:08:19,311 --> 02:08:20,613
REGULATE THE 3B3.

2484
02:08:20,613 --> 02:08:22,548
WE THINK MAYBE THE RATIO BETWEEN

2485
02:08:22,548 --> 02:08:27,519
THE ENZYME AND THE ACCESSORY 

2486
02:08:27,519 --> 02:08:28,354
PROTEIN CHANGES AND MAYBE THIS 

2487
02:08:28,354 --> 02:08:30,522
CONTRIBUTES TO THE FORMATION OF 

2488
02:08:30,522 --> 02:08:31,724
THE DIFFERENT METHYLATION 

2489
02:08:31,724 --> 02:08:31,991
PATTERNS.

2490
02:08:31,991 --> 02:08:35,794
WE DON'T KNOW THAT YET BUT WE'RE

2491
02:08:35,794 --> 02:08:37,496
CERTAINLY TRYING TO FIGURE OUT 

2492
02:08:37,496 --> 02:08:43,936
WHETHER THAT'S REALLY THE CASE.

2493
02:08:43,936 --> 02:08:46,505
WE'VE GONE FROM MEASURING CRUDE 

2494
02:08:46,505 --> 02:08:48,707
EXTRACTS IN CELLS TO LOOKING AT 

2495
02:08:48,707 --> 02:08:50,709
THE CRYO EM STRUCTURE AND HOW 

2496
02:08:50,709 --> 02:08:51,510
THE RATIO CHANGES IN THE 

2497
02:08:51,510 --> 02:09:01,954
FORMATION OF HUMAN CANCER.

2498
02:09:08,494 --> 02:09:13,632
AND IT TOOK 40 YEARS TO GET 

2499
02:09:13,632 --> 02:09:15,567
TESTED WITH THE SYNDROME AND 

2500
02:09:15,567 --> 02:09:21,140
THERE WAS A PIVOTAL STUDY 

2501
02:09:21,140 --> 02:09:24,009
PUBLISHED IN 2009 SHOWING 5 

2502
02:09:24,009 --> 02:09:25,177
AZACYTIDINE COMBINED WITH 

2503
02:09:25,177 --> 02:09:29,348
CONVENTIONAL CARE IN A TREATMENT

2504
02:09:29,348 --> 02:09:31,250
OF HIGH RISK MDS WAS AN 

2505
02:09:31,250 --> 02:09:32,584
EFFECTIVE TREATMENT.

2506
02:09:32,584 --> 02:09:39,391
AND THE MDS IS A PRE-LEUKEMIC 

2507
02:09:39,391 --> 02:09:40,359
CONDITION.

2508
02:09:40,359 --> 02:09:41,727
MOST PEOPLE DON'T GET CURED.

2509
02:09:41,727 --> 02:09:43,796
MOST PEOPLE HAVE AN EXTENDED 

2510
02:09:43,796 --> 02:09:45,297
LIFE SPAN AND ALSO HAVE AN 

2511
02:09:45,297 --> 02:09:55,741
EXTENDED QUALITY OF LIFE.

2512
02:10:02,715 --> 02:10:04,316
AND SHE RECOGNIZED MY LICENSE 

2513
02:10:04,316 --> 02:10:06,652
PLATE AND SHE CAME UP TO ME AND 

2514
02:10:06,652 --> 02:10:09,288
SAID THANK YOU, DOCTOR.

2515
02:10:09,288 --> 02:10:10,823
I'M NOT REALLY A DOCTOR BUT 

2516
02:10:10,823 --> 02:10:12,591
EVERY YEAR I GET A CHRISTMAS 

2517
02:10:12,591 --> 02:10:13,058
CARD FROM HER.

2518
02:10:13,058 --> 02:10:15,694
SHE WAS GOING TO GET A BONE 

2519
02:10:15,694 --> 02:10:18,464
MARROW TRANSPLANT AND COULDN'T 

2520
02:10:18,464 --> 02:10:21,700
DO IT BUT SHE GOT ON 5 

2521
02:10:21,700 --> 02:10:23,235
AZACYTIDINE AND IS STILL ALIVE.

2522
02:10:23,235 --> 02:10:24,737
IF ONLY WE COULD DO THAT FOR 

2523
02:10:24,737 --> 02:10:32,778
EVERY PATIENT.

2524
02:10:32,778 --> 02:10:34,847
WHY DO PATIENTS RESPOND TO THESE

2525
02:10:34,847 --> 02:10:35,114
THERAPIES.

2526
02:10:35,114 --> 02:10:37,883
THIS IS FROM A REVIEW STEVE AND 

2527
02:10:37,883 --> 02:10:38,350
I WROTE.

2528
02:10:38,350 --> 02:10:39,485
ONE MORE THING I THINK IS 

2529
02:10:39,485 --> 02:10:43,122
INTERESTING IS IT THE IDEA OF 

2530
02:10:43,122 --> 02:10:53,599
VIRAL MIMICRY WHICH I KNOW 

2531
02:10:57,636 --> 02:11:00,806
POSTDOCS CAME UP WITH THIS 

2532
02:11:00,806 --> 02:11:01,940
BEAUTIFUL IDEA THAT MAYBE ONE 

2533
02:11:01,940 --> 02:11:05,010
WAY THEY WORK IS BY INDUCING THE

2534
02:11:05,010 --> 02:11:15,287
STATE OF VIRAL MIMICRY COULD 

2535
02:11:15,287 --> 02:11:18,757
TRIGGER THE IMMUNE RESPONSE.

2536
02:11:18,757 --> 02:11:20,392
THAT IS A COMMON THOUGHT MAYBE 

2537
02:11:20,392 --> 02:11:22,094
THAT'S SOME OF THE WAY THE 

2538
02:11:22,094 --> 02:11:23,829
EPIGENETIC DRUGS WORK AND YOU 

2539
02:11:23,829 --> 02:11:25,864
HEARD TALK ABOUT THAT TODAY AS 

2540
02:11:25,864 --> 02:11:26,064
WELL.

2541
02:11:26,064 --> 02:11:26,899
SO VERY EXCITING.

2542
02:11:26,899 --> 02:11:30,669
MAYBE WE CAN NOW FIND OUT HOW 

2543
02:11:30,669 --> 02:11:31,236
THESE DRUGS WORK.

2544
02:11:31,236 --> 02:11:33,238
NOW, WE'RE PUSHING THE ENVELOPE 

2545
02:11:33,238 --> 02:11:36,542
WITH OUR STAND UP TO CANCER 

2546
02:11:36,542 --> 02:11:39,478
EPIGENETICS DREAM TEAM TO TAKE 

2547
02:11:39,478 --> 02:11:40,312
THIS TO THE NEXT LEVEL.

2548
02:11:40,312 --> 02:11:41,980
I WANT TO TELL YOU ABOUT AN 

2549
02:11:41,980 --> 02:11:44,383
EXCITING TRIAL WE JUST 

2550
02:11:44,383 --> 02:11:44,650
COMPLETED.

2551
02:11:44,650 --> 02:11:45,818
THESE ARE THE TWO PHYSICIANS 

2552
02:11:45,818 --> 02:11:47,152
THAT REALLY COMPLETED IT.

2553
02:11:47,152 --> 02:11:53,525
WE TOOK PATIENTS WHO FAILED 5 

2554
02:11:53,525 --> 02:11:54,493
AZACYTIDINE TREATMENT AND 

2555
02:11:54,493 --> 02:12:00,532
TREATED THEM WITH A NEW 

2556
02:12:00,532 --> 02:12:02,234
EPIGENETIC DRUG DNA METHYLATION 

2557
02:12:02,234 --> 02:12:03,368
INHIBITOR TO SEE WHETHER WE 

2558
02:12:03,368 --> 02:12:06,672
COULD CHANGE THE PATIENTS AND 

2559
02:12:06,672 --> 02:12:09,608
MAKE THEM SENSITIVE TO THE 

2560
02:12:09,608 --> 02:12:09,875
THERAPIES.

2561
02:12:09,875 --> 02:12:11,577
AGAIN THE RESULTS ARE ACTUALLY 

2562
02:12:11,577 --> 02:12:12,544
VERY INTERESTING.

2563
02:12:12,544 --> 02:12:14,680
IT'S A VERY SMALL TRIAL AND SO 

2564
02:12:14,680 --> 02:12:16,515
THE NUMBERS OF PATIENTS ARE VERY

2565
02:12:16,515 --> 02:12:20,018
SMALL BUT THESE ARE THE SURVIVAL

2566
02:12:20,018 --> 02:12:21,119
PATIENTS IN THE TRIAL AND YOU 

2567
02:12:21,119 --> 02:12:22,654
CAN SEE THERE'S ONE GROUP OF 

2568
02:12:22,654 --> 02:12:27,059
THEM THAT DID REALLY WELL, FIVE 

2569
02:12:27,059 --> 02:12:29,361
OF THEM, WHEREAS THE OTHER ONES 

2570
02:12:29,361 --> 02:12:31,997
DID NOT DO SO WELL.

2571
02:12:31,997 --> 02:12:33,265
THE INTERESTING THING WAS THOSE 

2572
02:12:33,265 --> 02:12:40,639
PATIENTS THAT HAD MUTATIONS IN 

2573
02:12:40,639 --> 02:12:45,477
AL601 IN ONE OF CHERYL AS A 

2574
02:12:45,477 --> 02:12:47,446
SLIDE WAS INTERESTING TO THINK 

2575
02:12:47,446 --> 02:12:47,646
ABOUT.

2576
02:12:47,646 --> 02:12:50,649
THEY HAVE A MUTATION IN THE T 

2577
02:12:50,649 --> 02:12:53,685
CELL, IT MAKES THAT PATIENT HAVE

2578
02:12:53,685 --> 02:12:59,291
A BETTER SURVIVAL AT LEAST IN 

2579
02:12:59,291 --> 02:13:00,626
THE SMALL CLINICAL TRIAL AND 

2580
02:13:00,626 --> 02:13:01,960
ONLY FIVE PATIENTS BUT THEY ALL 

2581
02:13:01,960 --> 02:13:02,828
DID REALLY WELL.

2582
02:13:02,828 --> 02:13:06,231
SO WHAT WE THINK IS HAPPENING IS

2583
02:13:06,231 --> 02:13:10,035
THE MUTATION MAY BE INCREASING 

2584
02:13:10,035 --> 02:13:13,071
THE LIFE SPAN OF THE T CELLS.

2585
02:13:13,071 --> 02:13:15,807
AND IN CONTEXT OF THIS 

2586
02:13:15,807 --> 02:13:16,241
IMMUNOTHERAPY.

2587
02:13:16,241 --> 02:13:19,745
SO WE ARE SEEING THIS ACTIVELY 

2588
02:13:19,745 --> 02:13:20,646
AND I FIND IT INTERESTING 

2589
02:13:20,646 --> 02:13:23,749
BECAUSE WE THINK MUTATIONS FOCUS

2590
02:13:23,749 --> 02:13:26,084
ON MUTATIONS IN THE MALIGNANT 

2591
02:13:26,084 --> 02:13:28,220
CLONE AND FORGET ABOUT THOSE 

2592
02:13:28,220 --> 02:13:30,656
MUTATIONS THAT MIGHT OCCUR IN 

2593
02:13:30,656 --> 02:13:31,323
THE IMMUNE CELLS AS IN THIS 

2594
02:13:31,323 --> 02:13:36,161
PARTICULAR TRIAL.

2595
02:13:36,161 --> 02:13:38,363
SO WHERE ARE WE WITH THE 

2596
02:13:38,363 --> 02:13:42,968
DEVELOPMENT OF DNA METHYLATION 

2597
02:13:42,968 --> 02:13:43,268
INHIBITORS?

2598
02:13:43,268 --> 02:13:45,871
THIS GOES BACK TO 1977.

2599
02:13:45,871 --> 02:13:49,841
WE TRIED OTHER DRUGS WHICH 

2600
02:13:49,841 --> 02:13:52,244
DIDN'T MAKE IT.

2601
02:13:52,244 --> 02:13:54,813
I TALKED ABOUT THE NEW DRUG AND 

2602
02:13:54,813 --> 02:13:56,848
BUT NOT BETTER THAN 5 

2603
02:13:56,848 --> 02:13:57,149
AZACYTIDINE.

2604
02:13:57,149 --> 02:13:59,751
ONE OF THE EXCITING DEVELOPMENTS

2605
02:13:59,751 --> 02:14:04,990
BEEN THE DEVELOPMENT OF THIS GSK

2606
02:14:04,990 --> 02:14:09,528
DRUG WHICH ACTUALLY -- SHOULDN'T

2607
02:14:09,528 --> 02:14:12,097
BE 2003.

2608
02:14:12,097 --> 02:14:13,865
THERE'S SOMETHING WRONG WITH THE

2609
02:14:13,865 --> 02:14:14,132
DRUG.

2610
02:14:14,132 --> 02:14:16,068
IT DOESN'T HAVE TO GET IN THE 

2611
02:14:16,068 --> 02:14:20,739
DNA TO INHIBIT METHYLATION AND' 

2612
02:14:20,739 --> 02:14:26,178
SPECIFIC INHIBITOR OF DNA 1 AND 

2613
02:14:26,178 --> 02:14:27,479
THERE'S A TRIALIVE SICKLE CELL 

2614
02:14:27,479 --> 02:14:30,082
ANEMIA PATIENTS WITH THE HOPE OF

2615
02:14:30,082 --> 02:14:40,625
USING THE EPIGENETIC APPROVE  --

2616
02:14:41,526 --> 02:14:45,297
APPROACH TO TURN ON THE GENES 

2617
02:14:45,297 --> 02:14:47,632
AND ONE WAS DONE TO TEST WHETHER

2618
02:14:47,632 --> 02:14:50,535
THE DRUG COULD IN FACT TURN ON 

2619
02:14:50,535 --> 02:14:51,603
THE FETAL GLOBIN PATIENT GENE IN

2620
02:14:51,603 --> 02:14:55,207
PATIENTS.

2621
02:14:55,207 --> 02:14:57,676
SO THINKING BEYOND MALIGNANCY 

2622
02:14:57,676 --> 02:15:01,179
THESE DRUGS HAVE TREMENDOUS 

2623
02:15:01,179 --> 02:15:01,446
POTENTIAL.

2624
02:15:01,446 --> 02:15:02,647
SICKLE CELL DISEASE IS NOT A 

2625
02:15:02,647 --> 02:15:03,949
NICE DISEASE.

2626
02:15:03,949 --> 02:15:04,950
INCREDIBLY PAINFUL.

2627
02:15:04,950 --> 02:15:06,051
I REALLY HOPE THIS PARTICULAR 

2628
02:15:06,051 --> 02:15:13,925
DRUG WILL WORK.

2629
02:15:13,925 --> 02:15:15,660
WHAT'S INTERESTING NOW IS ALL 

2630
02:15:15,660 --> 02:15:18,363
THE BIG GUNS IN THE TRIALS AND 

2631
02:15:18,363 --> 02:15:20,766
NOW CAN SEE IN FACT ALL THE BIG 

2632
02:15:20,766 --> 02:15:22,667
ONES ARE IN AND THE THERAPIES 

2633
02:15:22,667 --> 02:15:26,872
ARE NOW MORPHING INTO THE USE OF

2634
02:15:26,872 --> 02:15:28,340
COMBINATIONS AND AVAILABLE DRUG.

2635
02:15:28,340 --> 02:15:33,812
WHAT IS INHIBITED THE 

2636
02:15:33,812 --> 02:15:35,347
DEVELOPMENT OF THESE DRUGS TO 

2637
02:15:35,347 --> 02:15:36,048
SOME EXTENT.

2638
02:15:36,048 --> 02:15:38,316
-- I GOT A YELLOW.

2639
02:15:38,316 --> 02:15:41,453
I DIDN'T EVEN GET A YELLOW IN 

2640
02:15:41,453 --> 02:15:43,155
WHAT ARE YOU DOING TO ME?

2641
02:15:43,155 --> 02:15:46,158
I DON'T HAVE TO GO THROUGH BUT 

2642
02:15:46,158 --> 02:15:47,726
WE'RE AT A VERY EXCITING AGE.

2643
02:15:47,726 --> 02:15:49,127
I SHARED SOME OF THE PEOPLE AT 

2644
02:15:49,127 --> 02:15:51,630
THE BEGINNING OF THIS JOURNEY 

2645
02:15:51,630 --> 02:15:57,035
WHICH IS GOING ON FOR ACTUALLY 

2646
02:15:57,035 --> 02:15:59,071
MORE THAN 40 YEARS.

2647
02:15:59,071 --> 02:16:01,573
THIS IS MY CURRENT LAB BUT I 

2648
02:16:01,573 --> 02:16:02,674
WANT TO END WITH A VERY 

2649
02:16:02,674 --> 02:16:06,812
IMPORTANT THANK YOU.

2650
02:16:06,812 --> 02:16:09,081
I WANT TO THANK THE NATIONAL 

2651
02:16:09,081 --> 02:16:10,715
CANCER INSTITUTE FOR 43 YEARS OF

2652
02:16:10,715 --> 02:16:11,950
CONTINUOUS SUPPORT.

2653
02:16:11,950 --> 02:16:14,219
I'VE BEEN SUPPORTED BY THE NCI 

2654
02:16:14,219 --> 02:16:17,155
FOR 40 YEARS AND HAVE ANOTHER 7 

2655
02:16:17,155 --> 02:16:21,526
YEARS TO GO, BY THE WAY.

2656
02:16:21,526 --> 02:16:23,462
I'M EXCITED ABOUT THAT AND A 

2657
02:16:23,462 --> 02:16:26,665
SHOUT OUT TO PAUL O'CONNOR MY 

2658
02:16:26,665 --> 02:16:27,766
PROGRAM OFFICER.

2659
02:16:27,766 --> 02:16:29,401
PAUL HAS BEEN WITH ME NOT 

2660
02:16:29,401 --> 02:16:31,303
THROUGH THE WHOLE JOURNEY FOR 

2661
02:16:31,303 --> 02:16:32,804
MOST OF IT AND SOMETIMES I THINK

2662
02:16:32,804 --> 02:16:35,307
HE HAS MORE CONFIDENCE IN ME 

2663
02:16:35,307 --> 02:16:36,541
THAN I HAVE AND WITHOUT HIM 

2664
02:16:36,541 --> 02:16:38,410
PUSHING ME I DON'T KNOW I WOULD 

2665
02:16:38,410 --> 02:16:40,946
BE HERE TODAY TALKING TO YOU.

2666
02:16:40,946 --> 02:16:42,414
I WANT TO THANK YOU AND THE 

2667
02:16:42,414 --> 02:16:42,681
WHOLE NCI.

2668
02:16:42,681 --> 02:16:52,858
THANK YOU.

2669
02:17:11,977 --> 02:17:15,814
>> FOR THE THERAPY WITH
PATIENTS

2670
02:17:15,814 --> 02:17:19,918
IN CLINICAL AND CAN YOU EXPLAIN 

2671
02:17:19,918 --> 02:17:25,824
WHY THOSE CELLS SURVIVE LONGER 

2672
02:17:25,824 --> 02:17:27,292
WITH THE TREATMENT WITH THE 

2673
02:17:27,292 --> 02:17:29,861
INHI

2674
02:17:29,861 --> 02:17:30,128
INHIBITER.

2675
02:17:30,128 --> 02:17:34,032
>> I THINK IT'S PREVENTING

2676
02:17:34,032 --> 02:17:34,332
EXHAUSTION.

2677
02:17:34,332 --> 02:17:36,635
PROPER T CELL BIOLOGY REQUIRES T

2678
02:17:36,635 --> 02:17:38,069
CELLS TO BECOME EXHAUSTED AND 

2679
02:17:38,069 --> 02:17:41,072
STOP CONTINUOUSLY EXPANDING AND 

2680
02:17:41,072 --> 02:17:42,874
THAT'S REGULATED AND PEOPLE 

2681
02:17:42,874 --> 02:17:48,680
CONCENTRATED ON DNA METHYLATION 

2682
02:17:48,680 --> 02:17:53,051
AND DE NOVO DNA METHYLATION IS 

2683
02:17:53,051 --> 02:17:54,753
PART OF EXHAUSTING CELLS.

2684
02:17:54,753 --> 02:17:57,055
I'M NOT AN IMMUNOLOGIST BUT I 

2685
02:17:57,055 --> 02:18:01,493
THINK WHAT'S HAPPENING IS AL6L1 

2686
02:18:01,493 --> 02:18:04,763
IS ALLOWING THE T CELLS TO AVOID

2687
02:18:04,763 --> 02:18:05,163
BECOMING EXHAUST.

2688
02:18:05,163 --> 02:18:15,540
THAT'S THE HYPOTHESIS.

2689
02:18:16,208 --> 02:18:23,148
>> WOULD YOU COMMENT ON
THE FULL

2690
02:18:23,148 --> 02:18:25,383
GENETIC DRUGS ON RESISTANCE AND 

2691
02:18:25,383 --> 02:18:25,684
RECURRENCE.

2692
02:18:25,684 --> 02:18:26,818
>> THE QUESTION IS ABOUT 

2693
02:18:26,818 --> 02:18:28,019
RESISTANCE AND RECURRENCE.

2694
02:18:28,019 --> 02:18:34,125
I GUESS THAT HAPPENS WITH ALL 

2695
02:18:34,125 --> 02:18:34,993
DRUGS, RIGHT.

2696
02:18:34,993 --> 02:18:42,667
I THINK WITH THE EPIGENETIC 

2697
02:18:42,667 --> 02:18:43,969
DRUGS MAYBE THE RESISTANCE IS 

2698
02:18:43,969 --> 02:18:47,339
DUE TO, FOR EXAMPLE, NOT 

2699
02:18:47,339 --> 02:18:50,508
PHOSPHORYLATING THE DRUG TO 

2700
02:18:50,508 --> 02:18:55,113
INCORPORATE DNA OR ENHANCED 

2701
02:18:55,113 --> 02:18:57,215
DE-AMINATION BECAUSE WE DON'T 

2702
02:18:57,215 --> 02:18:57,816
KNOW.

2703
02:18:57,816 --> 02:18:59,818
SO USING ADDITIONAL THERAPIES, 

2704
02:18:59,818 --> 02:19:02,654
FOR EXAMPLE, AS I'VE SHOWED YOU 

2705
02:19:02,654 --> 02:19:03,588
WITH IMMUNOTHERAPY MIGHT BE 

2706
02:19:03,588 --> 02:19:12,364
HELPFUL.

2707
02:19:12,364 --> 02:19:15,767
>> I'M WITH NCI.

2708
02:19:15,767 --> 02:19:20,105
SO HEMATOLOGY MALIGNANCIES THE 

2709
02:19:20,105 --> 02:19:27,545
TUMOR CELLS ALSO CARRY A 6L1 

2710
02:19:27,545 --> 02:19:32,183
MUTATION DID YOU LOOK

2711
02:19:32,183 --> 02:19:36,421
 IN COMPARISON TO THE T-CELLS.

2712
02:19:36,421 --> 02:19:40,058
>>  WE HAVEN'T GONE THAT
FAR, 

2713
02:19:40,058 --> 02:19:44,729
BUT AL6L1 IS A -- IN OTHER 

2714
02:19:44,729 --> 02:19:46,331
WORDS, AL6L1 IS VERY OFTEN 

2715
02:19:46,331 --> 02:19:47,165
ASSOCIATED WITH THE DEVELOPMENT 

2716
02:19:47,165 --> 02:19:51,836
OF MDS AND AML.

2717
02:19:51,836 --> 02:19:55,273
I THINK WHAT'S HAPPENING IS IN 

2718
02:19:55,273 --> 02:19:56,207
THESE PARTICULAR PATIENTS THE 

2719
02:19:56,207 --> 02:19:57,609
MUTATION HAS OCCURRED AT A VERY 

2720
02:19:57,609 --> 02:20:00,111
EARLY STEM CELL, AND AS THE 

2721
02:20:00,111 --> 02:20:02,847
CELLS ARE BRANCHED INTO THE 

2722
02:20:02,847 --> 02:20:04,749
MYOLOID AND T-CELL LINEAGE, MOST

2723
02:20:04,749 --> 02:20:06,951
OF THE TIME YOU DON'T GET AL6L1 

2724
02:20:06,951 --> 02:20:09,487
MUTATION IN THE T-CELLS, BUT 

2725
02:20:09,487 --> 02:20:12,190
WHEN THEY ARE PRESENT IN THE 

2726
02:20:12,190 --> 02:20:14,926
CONTEXT OF IMMUNOTHERAPY -- 

2727
02:20:14,926 --> 02:20:15,460
BECAUSE, REMEMBER, THESE 

2728
02:20:15,460 --> 02:20:16,428
PATIENTS DIDN'T RESPOND BEFORE 

2729
02:20:16,428 --> 02:20:17,028
OR STOPPED RESPONDING.

2730
02:20:17,028 --> 02:20:20,165
I THINK IT'S IN THE CONTEXT OF 

2731
02:20:20,165 --> 02:20:20,899
IMMUNOTHERAPY WHERE YOU ARE 

2732
02:20:20,899 --> 02:20:23,535
CHANGING THE BIOLOGY OF THE 

2733
02:20:23,535 --> 02:20:25,370
T-CELLS, WHICH MAYBE IS HAVING 

2734
02:20:25,370 --> 02:20:25,870
THIS IMPACT.

2735
02:20:25,870 --> 02:20:31,309
I HOPE THAT ANSWERS THE 

2736
02:20:31,309 --> 02:20:35,547
QUESTION.

2737
02:20:35,547 --> 02:20:37,015
THANK YOU.

2738
02:20:37,015 --> 02:20:39,250
>>  SO OUR NEXT SPEAKER
COULDN'T

2739
02:20:39,250 --> 02:20:43,655
BE HERE BECAUSE OF THE TRAGEDY 

2740
02:20:43,655 --> 02:20:44,255
THAT HAPPENED.

2741
02:20:44,255 --> 02:20:45,590
SHE'S FROM WEIZMANN INSTITUTE, 

2742
02:20:45,590 --> 02:20:48,560
AND SHE'S GOING TO TALK ABOUT 

2743
02:20:48,560 --> 02:20:49,961
USING HER VERY INNOVATIVE 

2744
02:20:49,961 --> 02:20:52,931
TECHNOLOGY FOR DECODING THE 

2745
02:20:52,931 --> 02:20:54,632
CANCER EPIGENOME FOR RESEARCH 

2746
02:20:54,632 --> 02:20:56,735
AND DIAGNOSIS, AND SHE'S GOING 

2747
02:20:56,735 --> 02:21:02,374
TO LISTEN IN, BUT SHE'S ABLE TO 

2748
02:21:02,374 --> 02:21:12,851
ANSWER QUESTIONS AFTERWARD.

2749
02:21:27,632 --> 02:21:30,001
>>  I WOULD LIKE TO START
BY 

2750
02:21:30,001 --> 02:21:33,238
THANKING THE ORGANIZERS FOR 

2751
02:21:33,238 --> 02:21:34,506
INVITING ME TO PRESENT MY LATEST

2752
02:21:34,506 --> 02:21:35,073
WORKS IN THIS MEETING.

2753
02:21:35,073 --> 02:21:37,509
I WILL SAY THAT I'M SURE ALL OF 

2754
02:21:37,509 --> 02:21:38,910
YOU ARE AWARE THAT THESE ARE 

2755
02:21:38,910 --> 02:21:42,680
ESPECIALLY DIFFICULT TIMES IN 

2756
02:21:42,680 --> 02:21:42,947
ISRAEL.

2757
02:21:42,947 --> 02:21:49,053
MY HEART IS BROKEN FOR ALL THE 

2758
02:21:49,053 --> 02:21:50,054
FRIENDS AND FAMILIES THAT HAVE 

2759
02:21:50,054 --> 02:21:51,189
LOST LOVED ONES IN THE TERROR 

2760
02:21:51,189 --> 02:21:52,257
ATTACKS THAT WE HAVE SUFFERED, 

2761
02:21:52,257 --> 02:21:57,395
AND I THANK ALL OF YOU FOR YOUR 

2762
02:21:57,395 --> 02:21:57,629
SUPPORT.

2763
02:21:57,629 --> 02:21:59,697
TO THE SCIENTIFIC PART, I WILL 

2764
02:21:59,697 --> 02:22:00,799
TELL YOU ABOUT MY LIFE'S WORK ON

2765
02:22:00,799 --> 02:22:03,168
DECODING THE EPIGENOME FOR 

2766
02:22:03,168 --> 02:22:08,006
CANCER IN RESEARCH AND 

2767
02:22:08,006 --> 02:22:08,306
DIAGNOSTICS.

2768
02:22:08,306 --> 02:22:09,174
OBVIOUSLY I DON'T NEED TO 

2769
02:22:09,174 --> 02:22:13,077
INTRODUCE YOU TO THE OBVIOUS 

2770
02:22:13,077 --> 02:22:14,479
WHERE EPIGENETICS IS IMPORTANT, 

2771
02:22:14,479 --> 02:22:18,016
AND WE KNOW WE HAVE THE T-CELLS 

2772
02:22:18,016 --> 02:22:22,654
THAT RECRUIT FROM THE GLOBAL 

2773
02:22:22,654 --> 02:22:24,389
NUCLEOZOME AND SPECIFICATIONS.

2774
02:22:24,389 --> 02:22:26,491
IT IS THOUGHT THAT THESE 

2775
02:22:26,491 --> 02:22:28,560
SPECIFICATIONS AND PATTERNS ARE 

2776
02:22:28,560 --> 02:22:29,861
ESSENTIAL FOR REGULATING 

2777
02:22:29,861 --> 02:22:35,533
ESSENTIALLY EVERY DNA TEMPLATE 

2778
02:22:35,533 --> 02:22:36,534
PROCESS IN THE CELL.

2779
02:22:36,534 --> 02:22:39,437
THIS NETWORK OF MODIFICATIONS IS

2780
02:22:39,437 --> 02:22:40,772
HOW THEY CAN CREATE SO MANY 

2781
02:22:40,772 --> 02:22:42,774
TYPES, AND IT'S OFTEN 

2782
02:22:42,774 --> 02:22:43,341
DEREGULATED IN CANCER.

2783
02:22:43,341 --> 02:22:46,678
WE KNOW THAT MORE THAN 50% OF 

2784
02:22:46,678 --> 02:22:51,316
HUMAN CANCER IS MUTATIONS AND 

2785
02:22:51,316 --> 02:22:51,850
COMMUNOREGULATORS.

2786
02:22:51,850 --> 02:22:56,454
MY LAB IS DEDICATED TO NEW 

2787
02:22:56,454 --> 02:22:59,791
TECHNOLOGIES TO DECODE GENOMES 

2788
02:22:59,791 --> 02:23:01,426
IN EPI REGULATION.

2789
02:23:01,426 --> 02:23:02,961
ABOUT TWO OF THESE TECHNOLOGIES 

2790
02:23:02,961 --> 02:23:04,095
THAT ARE VERY DIFFERENT.

2791
02:23:04,095 --> 02:23:06,664
THE FIRST ONE IS SINGLE MOLECULE

2792
02:23:06,664 --> 02:23:09,200
BAITSED ASSAY THAT ALLOWS YOU TO

2793
02:23:09,200 --> 02:23:14,372
CAPTURE NUCLEOZOMES AND DECODE 

2794
02:23:14,372 --> 02:23:15,907
THEIR PATTERNS OF NOTIFICATIONS.

2795
02:23:15,907 --> 02:23:19,110
WHILE THE OTHER TECHNOLOGY, A 

2796
02:23:19,110 --> 02:23:20,512
SINGLE-CELL-BASED ASSAY THAT 

2797
02:23:20,512 --> 02:23:21,613
ALLOWS YOU TO ADDRESS QUESTIONS,

2798
02:23:21,613 --> 02:23:27,118
SUCH AS EPIGENETIC HYPERGENEITY 

2799
02:23:27,118 --> 02:23:28,253
IN CANCER, WHICH IS SOMETHING 

2800
02:23:28,253 --> 02:23:32,390
WE'RE VERY PASSIONATE ABOUT.

2801
02:23:32,390 --> 02:23:35,360
SINGLE CELL MOLECULE TECHNOLOGY,

2802
02:23:35,360 --> 02:23:38,530
WE TAKE INDIVIDUAL NUCLEOZOMES, 

2803
02:23:38,530 --> 02:23:41,866
AND WE FRAGMENT THE MICRONUCLEUS

2804
02:23:41,866 --> 02:23:43,635
FROM PLASMA, AND I'LL TELL YOU 

2805
02:23:43,635 --> 02:23:47,171
MORE ABOUT IT IN A BIT.

2806
02:23:47,171 --> 02:23:51,142
WE TAKE THESE NUCLEOZOMES AND 

2807
02:23:51,142 --> 02:23:57,615
ADD IT TO THE DNA END AND ALSO 

2808
02:23:57,615 --> 02:24:03,054
TELL THEM DID, THIS ENTIRE 

2809
02:24:03,054 --> 02:24:06,591
TECHNOLOGY IS BUILT ON INTERNAL 

2810
02:24:06,591 --> 02:24:07,191
REFLECTION MICROSCOPY.

2811
02:24:07,191 --> 02:24:12,764
ALL YOU NEED TO KNOW ABOUT IT IS

2812
02:24:12,764 --> 02:24:13,998
THAT ESSENTIALLY ALL THE LIGHT 

2813
02:24:13,998 --> 02:24:16,534
ON THE SURFACE IS REFLECTED BACK

2814
02:24:16,534 --> 02:24:18,236
INTO A NARROW OBJECTIONIZATION 

2815
02:24:18,236 --> 02:24:18,469
WEIGHT.

2816
02:24:18,469 --> 02:24:21,940
ALL THE MOLECULES ARE ABOUT 1 

2817
02:24:21,940 --> 02:24:22,607
HNK NANOMETERS ARE EXCITED, AND 

2818
02:24:22,607 --> 02:24:25,476
THIS IS HOW YOU DON'T HAVE ANY 

2819
02:24:25,476 --> 02:24:26,477
BACK FROM THE SOLUTION, AND IT 

2820
02:24:26,477 --> 02:24:28,546
ALLOWS YOU TO IMAGE INDIVIDUAL 

2821
02:24:28,546 --> 02:24:28,913
FLOOR FOR US.

2822
02:24:28,913 --> 02:24:32,784
YOU SEE THERE ON THE IMAGE EVERY

2823
02:24:32,784 --> 02:24:35,853
SPOT IS A SINGLE NUCLOESOME THAT

2824
02:24:35,853 --> 02:24:37,755
WAS AT THE SURFACE, AND WE ARE 

2825
02:24:37,755 --> 02:24:43,595
IMAGING MILLIONS OF THESE.

2826
02:24:43,595 --> 02:24:54,839
MILLIONS OF NUKE SYNDCLEONUCLEO.

2827
02:24:59,110 --> 02:25:02,347
WE DON'T ACTUALLY THINK ABOUT IT

2828
02:25:02,347 --> 02:25:04,449
OFTEN, BUT ANTI-BODIES OFTEN WE 

2829
02:25:04,449 --> 02:25:05,617
WANT TO KNOW FOR EVERY 

2830
02:25:05,617 --> 02:25:06,884
NUCLEOSOME HOW IT IS MODIFIED.

2831
02:25:06,884 --> 02:25:09,988
SO ESSENTIALLY THIS IS WHERE WE 

2832
02:25:09,988 --> 02:25:10,288
LEVERAGE.

2833
02:25:10,288 --> 02:25:13,825
WE JUST TAKE SEVERAL IMAGES OVER

2834
02:25:13,825 --> 02:25:16,828
TIME, SO WE CAN THEN SUM ALL 

2835
02:25:16,828 --> 02:25:21,432
THESE EVENTS AND COLLOQUELIZE 

2836
02:25:21,432 --> 02:25:23,234
THEM TO WHERE THE NUCLEOSOMES 

2837
02:25:23,234 --> 02:25:23,668
ARE.

2838
02:25:23,668 --> 02:25:25,536
NOW WE CAN KNOW HOW MANY 

2839
02:25:25,536 --> 02:25:27,071
NUCLEOSOMES HAVE THIS 

2840
02:25:27,071 --> 02:25:28,373
MODIFICATION OR ANOTHER, OR IT 

2841
02:25:28,373 --> 02:25:32,510
CAN BE EFFECTIVE FOR BOTH OF 

2842
02:25:32,510 --> 02:25:34,245
THESE MODIFICATIONS.

2843
02:25:34,245 --> 02:25:34,912
THIS IS REALLY CRITICAL BECAUSE 

2844
02:25:34,912 --> 02:25:37,215
NOW THAT WE HAVE ALL THE 

2845
02:25:37,215 --> 02:25:38,650
INFORMATION, WE CAN ALSO WASH 

2846
02:25:38,650 --> 02:25:40,852
THESE ANTIBODIES AND ADD NEW 

2847
02:25:40,852 --> 02:25:42,587
ONES AND ACTUALLY GENERATE 

2848
02:25:42,587 --> 02:25:44,856
HIGHER ORDER COMBINATIONS OF 

2849
02:25:44,856 --> 02:25:48,126
THESE SYSTEM MODIFICATIONS ON 

2850
02:25:48,126 --> 02:25:49,627
INDIVIDUAL NUCLEOSOMES.

2851
02:25:49,627 --> 02:25:52,196
SO AFTER WE DO THAT, NOW WE WANT

2852
02:25:52,196 --> 02:25:57,101
TO KNOW, OF COURSE, WHAT IS THE 

2853
02:25:57,101 --> 02:26:00,571
SEQUENCE ASSOCIATED WITH THIS 

2854
02:26:00,571 --> 02:26:01,606
NUCLEOSOME.

2855
02:26:01,606 --> 02:26:04,609
THIS IS STILL VERY EXCITING SORT

2856
02:26:04,609 --> 02:26:07,879
OF, LIKE, JUST A MASS DATA OF 

2857
02:26:07,879 --> 02:26:10,181
HOW NUCLEOSOMES MODIFY, BUT WE 

2858
02:26:10,181 --> 02:26:12,583
ALSO WANT TO IDENTIFY THE 

2859
02:26:12,583 --> 02:26:15,887
ASSOCIATED SEQUENCE, AND WE DO.

2860
02:26:15,887 --> 02:26:18,289
WE JUST TAKE THE PROTEINS FROM 

2861
02:26:18,289 --> 02:26:18,589
THE SURFACE.

2862
02:26:18,589 --> 02:26:21,092
WE DON'T DO ANY FIXATION, AND 

2863
02:26:21,092 --> 02:26:22,460
THEN WE FOLLOW UP WITH SINGLE 

2864
02:26:22,460 --> 02:26:24,629
MOLECULE DNA SEQUENCING, WHICH 

2865
02:26:24,629 --> 02:26:27,598
IN TERM OF CHEMISTRY, IS VERY 

2866
02:26:27,598 --> 02:26:30,334
SIMILAR TO GENOME SEQUENCING.

2867
02:26:30,334 --> 02:26:32,437
WE JUST ADD ONE OF THE 

2868
02:26:32,437 --> 02:26:34,172
NUCLEOTYPES AND IMAGE WHERE IT'S

2869
02:26:34,172 --> 02:26:36,708
INCORPORATED WITH THE MIXTURE.

2870
02:26:36,708 --> 02:26:38,076
YOU CLEAN THE FLOOR UNTIL THE 

2871
02:26:38,076 --> 02:26:39,877
NEXT ONE UNTIL YOU BUILD A 

2872
02:26:39,877 --> 02:26:40,778
SEQUENCE, WHICH IS LARGE ENOUGH 

2873
02:26:40,778 --> 02:26:44,115
AND LONG ENOUGH SO YOU CAN ALIGN

2874
02:26:44,115 --> 02:26:46,350
TO THE GENOME.

2875
02:26:46,350 --> 02:26:47,852
THIS TECHNOLOGY WE USE IN THE 

2876
02:26:47,852 --> 02:26:50,688
BODY A LOT TO ADDRESS BASIC 

2877
02:26:50,688 --> 02:26:54,525
QUESTIONS OF EPIGENETIC 

2878
02:26:54,525 --> 02:26:55,426
VARIATIONS IN CANCER.

2879
02:26:55,426 --> 02:26:58,529
TODAY WE'LL TALK ABOUT ONLY ONE,

2880
02:26:58,529 --> 02:27:00,865
AND IT'S QUITE DIFFERENT, WHICH 

2881
02:27:00,865 --> 02:27:05,336
IS HOW WE'RE USING IT FOR LIQUID

2882
02:27:05,336 --> 02:27:07,138
BIOSIS FOR A CHANCE OF 

2883
02:27:07,138 --> 02:27:07,438
DIAGNOSIS.

2884
02:27:07,438 --> 02:27:08,172
JUST AS AN INTRODUCTION TO THIS 

2885
02:27:08,172 --> 02:27:10,308
FIELD, PROBABLY ALL OF YOU KNOW 

2886
02:27:10,308 --> 02:27:12,977
THAT IF I JUST TAKE AN EXAMPLE 

2887
02:27:12,977 --> 02:27:15,580
FROM ANY OF YOU, BLOOD EXAMPLE, 

2888
02:27:15,580 --> 02:27:21,319
YOU WILL HAVE SELF-GENIOATED IN 

2889
02:27:21,319 --> 02:27:21,919
YOUR BLOODSTREAM.

2890
02:27:21,919 --> 02:27:23,154
IF YOU ARE HEALTHY THIS ALSO 

2891
02:27:23,154 --> 02:27:24,155
COMES FROM BLOOD CELLS THAT DIED

2892
02:27:24,155 --> 02:27:28,126
AND DUMPED THEIR CONTENT INTO 

2893
02:27:28,126 --> 02:27:29,494
THE BLOODSTREAM.

2894
02:27:29,494 --> 02:27:31,362
SOMEONE, FOR EXAMPLE, THAT HAS 

2895
02:27:31,362 --> 02:27:32,196
COLORECTAL CANCER, THEN SOME OF 

2896
02:27:32,196 --> 02:27:34,665
THE DNA WOULD COME FROM COLON 

2897
02:27:34,665 --> 02:27:43,040
CELLS THAT DIED AS PART OF THE 

2898
02:27:43,040 --> 02:27:43,474
HEMOROGENIS PROCESS.

2899
02:27:43,474 --> 02:27:48,713
MAYBE THE DNA HAS SOME 

2900
02:27:48,713 --> 02:27:50,681
MUTATIONS, BUT TRYING TO 

2901
02:27:50,681 --> 02:27:52,383
IDENTIFY THESE MUTATIONS ARE A 

2902
02:27:52,383 --> 02:27:53,351
WAY TO IDENTIFY CANCER THAT HAVE

2903
02:27:53,351 --> 02:27:55,286
FAILED TO A LARGE EXTENT BECAUSE

2904
02:27:55,286 --> 02:27:56,788
ALL OF THE MUTATION, WHETHER WE 

2905
02:27:56,788 --> 02:27:59,991
HAVE CANCER OR NOT, BUT THEN, 

2906
02:27:59,991 --> 02:28:01,192
YOU KNOW, PEOPLE REALIZE IF WE 

2907
02:28:01,192 --> 02:28:03,060
CAN SAY WHERE THE DNA IS COMING 

2908
02:28:03,060 --> 02:28:09,600
FROM, THEN WE MIGHT BE ABLE TO 

2909
02:28:09,600 --> 02:28:11,369
DETECT WHETHER THERE IS DEATH 

2910
02:28:11,369 --> 02:28:13,037
ASSOCIATED WITH CANCER IN THE 

2911
02:28:13,037 --> 02:28:13,437
SPECIFIC TISSUE.

2912
02:28:13,437 --> 02:28:16,874
AND I THINK THAT, YOU KNOW, ONE 

2913
02:28:16,874 --> 02:28:18,676
OF THE GREAT INFLUENCES IN THE 

2914
02:28:18,676 --> 02:28:19,744
FIELD CAME WITH THE 

2915
02:28:19,744 --> 02:28:21,112
UNDERSTANDING THAT THIS DNA, 

2916
02:28:21,112 --> 02:28:24,015
IT'S NOT JUST NAKED DNA, BUT 

2917
02:28:24,015 --> 02:28:26,384
IT'S ACTUALLY STILL WRAPPED 

2918
02:28:26,384 --> 02:28:30,655
AROUND THE PROTEINS IN THE 

2919
02:28:30,655 --> 02:28:31,455
NUCLEOSOME FORM.

2920
02:28:31,455 --> 02:28:33,858
OBVIOUSLY THIS NUCLEUS WILL 

2921
02:28:33,858 --> 02:28:36,494
STILL HAVE THEIR EPI GENETIC 

2922
02:28:36,494 --> 02:28:38,563
MODIFICATIONS AND ARE TYPICAL OF

2923
02:28:38,563 --> 02:28:39,263
THEIR ORIGIN.

2924
02:28:39,263 --> 02:28:44,468
EVERY TISSUE IN OUR BODY HAS ITS

2925
02:28:44,468 --> 02:28:44,869
OWN FOOTPRINTING.

2926
02:28:44,869 --> 02:28:46,437
IF WE CAN DETECT THE 

2927
02:28:46,437 --> 02:28:47,872
MODIFICATIONS, THEN WE KNOW 

2928
02:28:47,872 --> 02:28:49,740
WHERE THE NUCLEOSOMES ARE COMING

2929
02:28:49,740 --> 02:28:50,141
FROM.

2930
02:28:50,141 --> 02:28:55,012
SO WE DEVELOPED A TECHNOLOGY WE 

2931
02:28:55,012 --> 02:28:56,781
CALLED FOR -- IT'S ESSENTIALLY 

2932
02:28:56,781 --> 02:28:58,749
BASED ON A SINGLE MOLECULE 

2933
02:28:58,749 --> 02:29:03,187
IMAGING BECAUSE WE REALIZED THAT

2934
02:29:03,187 --> 02:29:04,388
ONE OF THE MAJOR CHALLENGES IS 

2935
02:29:04,388 --> 02:29:06,023
THAT THE PLASMA IS FULL OF 

2936
02:29:06,023 --> 02:29:06,557
PROTEINS.

2937
02:29:06,557 --> 02:29:11,829
NUCLEOSOMES ARE JUST A TINY 

2938
02:29:11,829 --> 02:29:12,396
FRACTION, BUT WE ARE USING 

2939
02:29:12,396 --> 02:29:13,731
SINGLE MOLECULE IMAGING.

2940
02:29:13,731 --> 02:29:14,665
ESSENTIALLY WE NEED ALMOST 

2941
02:29:14,665 --> 02:29:16,033
NOTHING IN TERMS OF MATERIAL.

2942
02:29:16,033 --> 02:29:18,636
IF WE CAN CAPTURE THIS 

2943
02:29:18,636 --> 02:29:20,438
NUCLEOSOMES ON THE SURFACE FROM 

2944
02:29:20,438 --> 02:29:22,673
THE PLASMA, THEN WE'LL BE ABLE 

2945
02:29:22,673 --> 02:29:26,644
TO GET A LOT OF INFORMATION AND 

2946
02:29:26,644 --> 02:29:30,281
DETECT MANY MODIFICATIONS IN THE

2947
02:29:30,281 --> 02:29:31,015
COMMUNITORIAL PATTERNS.

2948
02:29:31,015 --> 02:29:32,250
THAT IS WHAT I'M GOING TO SHOW 

2949
02:29:32,250 --> 02:29:32,550
YOU TODAY.

2950
02:29:32,550 --> 02:29:34,552
THIS IS EXACTLY WHAT WE SET UP 

2951
02:29:34,552 --> 02:29:35,486
TO DO.

2952
02:29:35,486 --> 02:29:38,322
OF COURSE, OUR FIRST CHALLENGE 

2953
02:29:38,322 --> 02:29:39,523
WAS PROVING THAT WE CAN ACTUALLY

2954
02:29:39,523 --> 02:29:42,360
CAPTURE THE NUCLEOSOMES FROM THE

2955
02:29:42,360 --> 02:29:42,593
PLASMA.

2956
02:29:42,593 --> 02:29:45,529
WHAT WE DID IS WE WANTED TO MAKE

2957
02:29:45,529 --> 02:29:47,365
SURE THAT WE HAVE SPECIFIC 

2958
02:29:47,365 --> 02:29:48,699
BINDING, SO AS A CONTROL -- SO 

2959
02:29:48,699 --> 02:29:52,937
WE EITHER DID THESE POLYATELLING

2960
02:29:52,937 --> 02:29:57,008
OR TELL THE NUCLEOSOMES WITH 

2961
02:29:57,008 --> 02:29:58,576
DTB, AND OBVIOUSLY THEY GENERATE

2962
02:29:58,576 --> 02:30:02,346
A POLYT-CELL, THEY CAN'T ANCHOR 

2963
02:30:02,346 --> 02:30:03,214
TO THE SURFACE.

2964
02:30:03,214 --> 02:30:05,616
INDEED, YOU CAN SEE HERE THAT 

2965
02:30:05,616 --> 02:30:10,054
ONLY WHEN YOU HAVE THE ATLE, 

2966
02:30:10,054 --> 02:30:11,022
THEN YOU REALLY GET THESE 

2967
02:30:11,022 --> 02:30:12,823
SPECIFIC SPOTS ON THE SURFACE 

2968
02:30:12,823 --> 02:30:13,557
CORRESPONDING TO THE NUCLEOSOMES

2969
02:30:13,557 --> 02:30:15,626
ON THE PLASMA, AND THEN ONLY 

2970
02:30:15,626 --> 02:30:17,328
WHEN YOU HAVE NUCLEOSOMES, YOU 

2971
02:30:17,328 --> 02:30:19,363
ACTUALLY GET SIGNALS FROM THE 

2972
02:30:19,363 --> 02:30:20,765
ANTIBODIES.

2973
02:30:20,765 --> 02:30:23,901
IN THIS CASE I'M SHOWING YOU IN 

2974
02:30:23,901 --> 02:30:26,237
THESE PICTURES A FORM, WHICH IS 

2975
02:30:26,237 --> 02:30:27,738
A MARK OF ACTIVE TRANSCRIPTION 

2976
02:30:27,738 --> 02:30:31,442
AND K-27, WHICH IS A MARK OF 

2977
02:30:31,442 --> 02:30:32,476
REPRESSIVE TRANSCRIPTION, BUT 

2978
02:30:32,476 --> 02:30:34,111
WE'VE ACTUALLY MEASURED ALL 60 

2979
02:30:34,111 --> 02:30:36,080
MODIFICATIONS THAT ARE LISTED 

2980
02:30:36,080 --> 02:30:40,851
HERE, AND ALL OF THAT FROM A FEW

2981
02:30:40,851 --> 02:30:42,920
HUNDRED MICROLITERS OF PLASMA.

2982
02:30:42,920 --> 02:30:46,457
IT'S LESS THAN 1 ML, WHICH IS 

2983
02:30:46,457 --> 02:30:49,260
ESSENTIALLY ALMOST NOTHING.

2984
02:30:49,260 --> 02:30:50,695
JUST TO SHOW YOU HOW THE DATA 

2985
02:30:50,695 --> 02:30:52,396
LOOKS LIKE.

2986
02:30:52,396 --> 02:30:55,232
SO, FOR EXAMPLE, NOW WE CAN TELL

2987
02:30:55,232 --> 02:30:59,537
YOU EXACTLY WHAT IS A PERCENTAGE

2988
02:30:59,537 --> 02:31:01,405
OF K27 NUCLEOSOMES IN A PERSON'S

2989
02:31:01,405 --> 02:31:01,605
BLOOD.

2990
02:31:01,605 --> 02:31:04,909
HERE IS JUST AN EXAMPLE OF ONE 

2991
02:31:04,909 --> 02:31:07,645
COLORECTAL CANCER PATIENT AND 

2992
02:31:07,645 --> 02:31:09,313
ONE HEALTHY INDIVIDUAL.

2993
02:31:09,313 --> 02:31:11,549
WE CAN SPECIFICALLY COUNT HOW 

2994
02:31:11,549 --> 02:31:14,485
MANY K27MEL NUCLEOSOMES ARE 

2995
02:31:14,485 --> 02:31:14,685
THERE?

2996
02:31:14,685 --> 02:31:16,620
IT'S LIKE A DIGITAL ASSAY.

2997
02:31:16,620 --> 02:31:18,656
THERE ARE SO MANY THINGS WE'RE 

2998
02:31:18,656 --> 02:31:18,956
MEASURING.

2999
02:31:18,956 --> 02:31:22,660
WE CAN ALSO ASK NOW WHAT IS THE 

3000
02:31:22,660 --> 02:31:25,796
RATIO BETWEEN K4 AND K27 

3001
02:31:25,796 --> 02:31:28,566
REPRESSIVE NUCLEOSOMES?

3002
02:31:28,566 --> 02:31:32,436
IS IT AFFECTED WHEN SOMEONE HAS 

3003
02:31:32,436 --> 02:31:32,670
CANCER?

3004
02:31:32,670 --> 02:31:33,337
MAYBE THE MOST IMPORTANT PART, 

3005
02:31:33,337 --> 02:31:37,942
WE CAN LOOK AT COMBINATIONS.

3006
02:31:37,942 --> 02:31:38,909
HOW MANY NUCLEOSOMES AT THESE 

3007
02:31:38,909 --> 02:31:41,345
PEOPLE'S BLOOD HAD BOTH K4ME3 

3008
02:31:41,345 --> 02:31:48,252
AND K27ME3, SO FROM THOSE OF YOU

3009
02:31:48,252 --> 02:31:48,919
FROM THE EPIGENETIC FIELD, THIS 

3010
02:31:48,919 --> 02:31:50,087
IS THE COMBINATION THAT YOU 

3011
02:31:50,087 --> 02:31:51,355
OFTEN FIND IN STEM CELLS, BUT 

3012
02:31:51,355 --> 02:31:54,258
IT'S ALSO DEREGULATED IN CANCER.

3013
02:31:54,258 --> 02:31:57,895
THIS IS ESSENTIALLY THE ONLY 

3014
02:31:57,895 --> 02:31:59,463
TECHNOLOGY THAT CAN QUANTIFY 

3015
02:31:59,463 --> 02:32:01,265
VERY ACCURATELY AND SENSITIVELY 

3016
02:32:01,265 --> 02:32:02,867
ALL THESE DIFFERENT 

3017
02:32:02,867 --> 02:32:03,200
COMBINATIONS.

3018
02:32:03,200 --> 02:32:05,336
HERE I JUST SHOWED YOU AN 

3019
02:32:05,336 --> 02:32:08,773
EXAMPLE, BUT WHAT WE DID IS WE 

3020
02:32:08,773 --> 02:32:12,543
ACTUALLY LOOK AT, AGAIN, THE 60 

3021
02:32:12,543 --> 02:32:13,344
MODIFICATIONS OR COMBINATIONS 

3022
02:32:13,344 --> 02:32:14,211
AND RATIOS.

3023
02:32:14,211 --> 02:32:16,814
I DO NOT HAVE TIME TO GO INTO IT

3024
02:32:16,814 --> 02:32:19,483
TODAY, BUT WE ARE ALSO MEASURING

3025
02:32:19,483 --> 02:32:23,921
AT SINGLE MOLECULE LEVEL DNA 

3026
02:32:23,921 --> 02:32:24,488
DEREGULATION, AND MEASURING 

3027
02:32:24,488 --> 02:32:25,990
PROTEIN BIOMARKERS WITH VERY 

3028
02:32:25,990 --> 02:32:27,024
HIGH SENSITIVITY.

3029
02:32:27,024 --> 02:32:29,560
I'M SKIPPING THAT, BUT IT'S ALL 

3030
02:32:29,560 --> 02:32:30,027
IN THE PAPER.

3031
02:32:30,027 --> 02:32:32,730
AT THE END OF THE DAY WE ARE 

3032
02:32:32,730 --> 02:32:34,465
GETTING A LOT OF DATA FROM EACH 

3033
02:32:34,465 --> 02:32:35,499
PLASMA SAMPLE, AND THIS IS JUST 

3034
02:32:35,499 --> 02:32:37,635
TO SHOW YOU, YOU KNOW, SOME OF 

3035
02:32:37,635 --> 02:32:40,371
THE EPIGENETIC PARAMETERS THAT 

3036
02:32:40,371 --> 02:32:42,606
ARE SIGNIFICANTLY DIFFERENT 

3037
02:32:42,606 --> 02:32:44,241
BETWEEN COLORECTAL CANCER AND 

3038
02:32:44,241 --> 02:32:44,475
HEALTHY.

3039
02:32:44,475 --> 02:32:46,110
HERE WE ARE TALKING ABOUT A 

3040
02:32:46,110 --> 02:32:49,513
COHORT OF 60 COLORECTAL CANCER 

3041
02:32:49,513 --> 02:32:51,082
PATIENTS VERSUS ABOUT 40 HEALTHY

3042
02:32:51,082 --> 02:32:52,583
INDIVIDUALS, AND YOU CAN SEE THE

3043
02:32:52,583 --> 02:32:54,652
SIGNIFICANT CHANGES, BUT AT THE 

3044
02:32:54,652 --> 02:32:57,655
END OF THE DAY NO SINGLE 

3045
02:32:57,655 --> 02:32:59,523
PARAMETER WOULD BE ENOUGH TO 

3046
02:32:59,523 --> 02:33:00,891
ACTUALLY BE ABLE TO DIAGNOSE 

3047
02:33:00,891 --> 02:33:01,492
CANCER.

3048
02:33:01,492 --> 02:33:04,428
I THINK THIS IS REALLY WHERE THE

3049
02:33:04,428 --> 02:33:05,963
POWER OF OUR TECHNOLOGY IS OUR 

3050
02:33:05,963 --> 02:33:08,399
ABILITY TO MEASURE MANY, MANY 

3051
02:33:08,399 --> 02:33:10,634
THINGS, AND AT THE END OF THE 

3052
02:33:10,634 --> 02:33:15,673
DAY YOU CAN SEE THAT EVEN JUST 

3053
02:33:15,673 --> 02:33:17,875
USING ALL OF THE INFORMATION IN 

3054
02:33:17,875 --> 02:33:21,011
THE PTA PLOT, YOU CAN SEE THE 

3055
02:33:21,011 --> 02:33:21,645
COLORECTAL CANCER PATIENTS IN 

3056
02:33:21,645 --> 02:33:24,081
THE RED HERE ARE CLUSTERED 

3057
02:33:24,081 --> 02:33:25,116
SEPARATELY FROM THE HEALTHY 

3058
02:33:25,116 --> 02:33:25,416
INDIVIDUALS.

3059
02:33:25,416 --> 02:33:27,384
WHAT I THINK IS MORE STRIKING --

3060
02:33:27,384 --> 02:33:30,254
SO WITHIN THE REVISIONS FOR THIS

3061
02:33:30,254 --> 02:33:32,389
PAPER, THE REVIEWERS ASKED US TO

3062
02:33:32,389 --> 02:33:34,125
TRY TO LOOK AT AT LEAST ONE 

3063
02:33:34,125 --> 02:33:36,894
OTHER CANCER, SO WE'VE ANALYZED 

3064
02:33:36,894 --> 02:33:37,795
TEN SAMPLES OF PANCREATIC 

3065
02:33:37,795 --> 02:33:39,864
CANCER, AND YOU CAN SEE THAT 

3066
02:33:39,864 --> 02:33:41,565
THESE SAMPLES ACTUALLY CLUSTER 

3067
02:33:41,565 --> 02:33:44,068
ALSO SEPARATELY FROM THE 

3068
02:33:44,068 --> 02:33:47,938
COLORECTAL ON THIS BCA PLOT.

3069
02:33:47,938 --> 02:33:49,240
THE REASON WHY THE FINDINGS ARE 

3070
02:33:49,240 --> 02:33:51,742
AMAZING IS CONSIDER THE FACT 

3071
02:33:51,742 --> 02:33:53,744
THAT UNTIL NOW WE HAVEN'T 

3072
02:33:53,744 --> 02:33:55,579
SEQUENCED A SINGLE MOLECULE.

3073
02:33:55,579 --> 02:33:57,681
SO ESSENTIALLY THIS IS ALL JUST 

3074
02:33:57,681 --> 02:34:01,685
BASED ON VERY QUANTITATIVE 

3075
02:34:01,685 --> 02:34:02,186
INFORMATION ABOUT THE 

3076
02:34:02,186 --> 02:34:03,487
SIGNIFICANT FICTIONS AND THE 

3077
02:34:03,487 --> 02:34:05,022
COMBINATIONS AND RATIOS, BUT 

3078
02:34:05,022 --> 02:34:07,725
THERE IS NO SET SEQUENCING.

3079
02:34:07,725 --> 02:34:10,661
THE REASON WHY IT'S IMPORTANT IN

3080
02:34:10,661 --> 02:34:14,031
THE BIOIS THIS RENDERS THIS 

3081
02:34:14,031 --> 02:34:15,833
TECHNOLOGY VERY, VERY CHEAP.

3082
02:34:15,833 --> 02:34:18,502
WE CAN DO THIS ENTIRE ANALYSIS 

3083
02:34:18,502 --> 02:34:20,437
WITHIN A COUPLE OF HOURS, SO 

3084
02:34:20,437 --> 02:34:23,140
IT'S VERY CHEAP AND SIMPLE TO 

3085
02:34:23,140 --> 02:34:23,707
DO.

3086
02:34:23,707 --> 02:34:27,678
ESSENTIALLY, WHEN WE FEED ALL 

3087
02:34:27,678 --> 02:34:29,213
THE PARAMETERS TO THE 

3088
02:34:29,213 --> 02:34:31,348
CLASSIFIER, AGAIN, WITHOUT 

3089
02:34:31,348 --> 02:34:36,220
SEQUENCING, WE CAN ALREADY VERY 

3090
02:34:36,220 --> 02:34:36,887
ACCURATELY SEPARATE THE HEALTHY 

3091
02:34:36,887 --> 02:34:40,457
VERSUS THE COLORECTAL CANCER 

3092
02:34:40,457 --> 02:34:43,928
PATIENTS, BUT OF COURSE, WHILE 

3093
02:34:43,928 --> 02:34:48,566
WE CAN SEPARATE, WE DID WANT TO 

3094
02:34:48,566 --> 02:34:49,800
BE ABLE TO SAY THESE ARE COMING 

3095
02:34:49,800 --> 02:34:50,201
FROM COLON.

3096
02:34:50,201 --> 02:34:52,536
FOR THAT WE DID A SEQUENCE, AND 

3097
02:34:52,536 --> 02:34:53,103
THERE ARE THREE DIFFERENT 

3098
02:34:53,103 --> 02:34:53,370
PATIENTS.

3099
02:34:53,370 --> 02:34:56,307
THE COLORECTAL CANCER AND YOU 

3100
02:34:56,307 --> 02:34:58,909
CAN SEE HERE THAT ONCE WE ARE 

3101
02:34:58,909 --> 02:35:00,911
SEQUENCING, THEN WE CAN CLEARLY 

3102
02:35:00,911 --> 02:35:02,313
SEE THAT THESE NUCLEOSOMES ARE 

3103
02:35:02,313 --> 02:35:05,616
COMING FROM COLON, AND 

3104
02:35:05,616 --> 02:35:08,752
SPECIFICALLY THIS RED AND ORANGE

3105
02:35:08,752 --> 02:35:11,956
PATIENTS, THEY ALSO HAD 

3106
02:35:11,956 --> 02:35:14,491
METASTASIS, WHICH WE CAN DETECT 

3107
02:35:14,491 --> 02:35:16,460
AS WELL USING THIS TECHNOLOGY.

3108
02:35:16,460 --> 02:35:20,864
I HOPE I'VE BEEN ABLE TO 

3109
02:35:20,864 --> 02:35:23,100
CONVINCE YOU THAT THIS 

3110
02:35:23,100 --> 02:35:26,103
EPIGENETIC TECHNOLOGIES ALLOWS 

3111
02:35:26,103 --> 02:35:27,104
YOU TO LOOK AT MANY 

3112
02:35:27,104 --> 02:35:27,771
MODIFICATIONS AND THEIR 

3113
02:35:27,771 --> 02:35:30,007
COMBINATIONS AND RATIOS WITH 

3114
02:35:30,007 --> 02:35:32,409
SINGLE MOLECULE IMAGING, SO IT'S

3115
02:35:32,409 --> 02:35:35,012
VERY HIGH RESOLUTION AND VERY 

3116
02:35:35,012 --> 02:35:36,013
QUANTITATIVE INFORMATION, SO 

3117
02:35:36,013 --> 02:35:37,781
IT'S REALLY UNIQUE IN ITS 

3118
02:35:37,781 --> 02:35:41,652
CAPACITY TO GENERATE THIS 

3119
02:35:41,652 --> 02:35:42,353
MULTI-LAYERED INFORMATION FROM 

3120
02:35:42,353 --> 02:35:45,289
VERY LIMITED BIO MATERIAL, AND 

3121
02:35:45,289 --> 02:35:48,292
IT REVEALS SIGNIFICANT 

3122
02:35:48,292 --> 02:35:48,892
DIFFERENCES BETWEEN HEALTHY 

3123
02:35:48,892 --> 02:35:50,995
INDIVIDUALS VERSUS COLORECTAL 

3124
02:35:50,995 --> 02:35:53,063
CANCER PATIENTS.

3125
02:35:53,063 --> 02:35:54,431
COMBINING WITH SINGLE MOLECULE 

3126
02:35:54,431 --> 02:35:57,167
SEQUENCING, SO WE CALL IT 

3127
02:35:57,167 --> 02:35:58,936
EPINOSIC, ALLOWS THE POTENTIAL 

3128
02:35:58,936 --> 02:35:59,803
OF THE SPECIFIC ORIGIN.

3129
02:35:59,803 --> 02:36:01,805
I'LL SHOW YOU FOR COLORECTAL, 

3130
02:36:01,805 --> 02:36:05,175
BUT WE'VE ACTUALLY DONE THAT 

3131
02:36:05,175 --> 02:36:06,677
ALSO FOR BREAST CANCER, 

3132
02:36:06,677 --> 02:36:07,845
PANCREATIC CANCER, AND LUNG 

3133
02:36:07,845 --> 02:36:09,680
CANCER AND SO ON.

3134
02:36:09,680 --> 02:36:12,383
WE CAN VERY EASILY DETECT WHERE 

3135
02:36:12,383 --> 02:36:14,051
THESE NUCLEOSOMES ARE COMING 

3136
02:36:14,051 --> 02:36:15,953
FROM ONCE WE ARE SEQUENCING.

3137
02:36:15,953 --> 02:36:17,655
I HAVEN'T MENTION IT, BUT WE'RE 

3138
02:36:17,655 --> 02:36:20,224
TAKING OUR SEQUENCING DATA, AND 

3139
02:36:20,224 --> 02:36:23,093
WE OVERLAID THE CHIEF DATA WHICH

3140
02:36:23,093 --> 02:36:25,296
HAS ALL THE DIFFERENT TISSUES, 

3141
02:36:25,296 --> 02:36:30,267
AND THAT'S HOW WE CAN DEDUCE THE

3142
02:36:30,267 --> 02:36:31,802
TISSUE OF ORIGIN.

3143
02:36:31,802 --> 02:36:34,004
I'M SHIFTING GEARS NOW BECAUSE I

3144
02:36:34,004 --> 02:36:38,142
DO WANT TO USE THE LAST FEW 

3145
02:36:38,142 --> 02:36:43,380
MINUTES OF THE TALK TO TELL YOU 

3146
02:36:43,380 --> 02:36:52,289
ABOUT THE OTHER TECHNOLOGY.

3147
02:36:52,289 --> 02:36:54,658
THE SINGLE MOLECULE TECHNOLOGY 

3148
02:36:54,658 --> 02:36:57,227
REALLY IS GREAT IN GIVING YOU 

3149
02:36:57,227 --> 02:36:59,697
THE HIGH RESOLUTION OF HOW 

3150
02:36:59,697 --> 02:37:01,198
INDIVIDUAL NUCLEOSOMES ARE 

3151
02:37:01,198 --> 02:37:06,337
MODIFIED, BUT IT'S NOT SINGLE 

3152
02:37:06,337 --> 02:37:07,938
CELL.

3153
02:37:07,938 --> 02:37:11,275
I WAS ALWAYS INTRIGUED BY THE 

3154
02:37:11,275 --> 02:37:12,109
QUESTION IN CANCER.

3155
02:37:12,109 --> 02:37:14,645
MOREOVER, IN THE SINGLE MOLECULE

3156
02:37:14,645 --> 02:37:16,280
ASSAY, WE'RE FOCUSED ON THE 

3157
02:37:16,280 --> 02:37:17,548
GENOME MODIFICATIONS THAT 

3158
02:37:17,548 --> 02:37:18,649
BASICALLY EVERYONE ELSE IS 

3159
02:37:18,649 --> 02:37:19,983
STUDYING BECAUSE THEY'RE KNOWN 

3160
02:37:19,983 --> 02:37:21,518
TO HAVE REGULATORY ROLES, BUT 

3161
02:37:21,518 --> 02:37:23,253
WHAT ABOUT ALL THE OTHER 

3162
02:37:23,253 --> 02:37:23,587
MODIFICATIONS?

3163
02:37:23,587 --> 02:37:25,155
HOW DO WE KNOW THAT THESE ARE 

3164
02:37:25,155 --> 02:37:27,624
NOT IMPORTANT AS WELL?

3165
02:37:27,624 --> 02:37:30,661
IF YOU LOOK AT THE RECENT YEARS 

3166
02:37:30,661 --> 02:37:32,096
IN THE EPIGENETIC COMMUNITY, YOU

3167
02:37:32,096 --> 02:37:34,365
YOU WOULD SEE THAT IT'S VERY 

3168
02:37:34,365 --> 02:37:37,601
MUCH BIASED TO STUDY THE SAME 

3169
02:37:37,601 --> 02:37:38,168
MODIFICATIONS, AND THIS IS 

3170
02:37:38,168 --> 02:37:41,472
SOMETHING THAT WE REALLY WANTED 

3171
02:37:41,472 --> 02:37:43,574
TO ADDRESS USING THESE NEW 

3172
02:37:43,574 --> 02:37:46,510
ASSAYS, SO WE DID.

3173
02:37:46,510 --> 02:37:49,279
WE TOOK -- I'M SURE MANY OF YOU 

3174
02:37:49,279 --> 02:37:51,148
AT LEAST IF YOU'RE FROM 

3175
02:37:51,148 --> 02:37:52,449
IMMUNOLOGY BACKGROUND, YOU'RE 

3176
02:37:52,449 --> 02:37:53,517
FAMILIAR WITH THAT.

3177
02:37:53,517 --> 02:37:57,287
YOU TAKE A PANEL OF ANTIBODIES, 

3178
02:37:57,287 --> 02:37:58,856
AND YOU CONJUGATE THEM.

3179
02:37:58,856 --> 02:38:00,657
IT'S ABOUT 40 ANTIBODIES.

3180
02:38:00,657 --> 02:38:02,693
YOU CAN CONJU GATE TLEM TO 

3181
02:38:02,693 --> 02:38:04,762
DIFFERENT METALS.

3182
02:38:04,762 --> 02:38:07,531
WHEN YOU STAIN YOUR ANTIBODIES 

3183
02:38:07,531 --> 02:38:10,267
AND WHEN A CELL GOES INTO THE 

3184
02:38:10,267 --> 02:38:11,235
CYTO MACHINE IT GETS BLOWN OFF, 

3185
02:38:11,235 --> 02:38:18,142
AND ALL THE METALS ARE DETECTED.

3186
02:38:18,142 --> 02:38:18,776
YOU GET QUANTITATIVE INFORMATION

3187
02:38:18,776 --> 02:38:20,210
FOR EACH CELL, FOR THE 40 

3188
02:38:20,210 --> 02:38:21,278
ANTIBODIES THAT YOU MEASURED.

3189
02:38:21,278 --> 02:38:23,647
WHEN YOU LOOK AT COMMERCIAL 

3190
02:38:23,647 --> 02:38:27,117
ANTIBODIES, ALMOST ALL OF THEM 

3191
02:38:27,117 --> 02:38:28,986
START WITH SOMETHING, SO IT'S 

3192
02:38:28,986 --> 02:38:29,787
VERY MUCH IMMUNOLOGY.

3193
02:38:29,787 --> 02:38:33,690
WHAT WE DECIDED TO DO IS TRY TO 

3194
02:38:33,690 --> 02:38:42,833
DO A CUSTOM-MADE EPIGENETIC 

3195
02:38:42,833 --> 02:38:43,033
BIOME.

3196
02:38:43,033 --> 02:38:46,303
WE GENERATE THIS EPIGENETIC 

3197
02:38:46,303 --> 02:38:47,971
CUSTOM TO BE ABLE TO LOOK AT 

3198
02:38:47,971 --> 02:38:50,340
MANY OF THESE MODIFICATIONS AT 

3199
02:38:50,340 --> 02:38:51,108
LOW RESOLUTION, SO YOU ONLY GET 

3200
02:38:51,108 --> 02:38:53,977
THE LOWER LEVELS OF THESE 

3201
02:38:53,977 --> 02:38:56,013
MODIFICATIONS PER CELL, BUT YOU 

3202
02:38:56,013 --> 02:38:57,347
CAN ACTUALLY GET INFORMATION 

3203
02:38:57,347 --> 02:39:00,150
ABOUT THOUSANDS OF CELLS IN EACH

3204
02:39:00,150 --> 02:39:00,584
EXPERIMENT.

3205
02:39:00,584 --> 02:39:03,053
SO THIS IS WHAT WE SET UP TO DO,

3206
02:39:03,053 --> 02:39:05,355
AND THE FIRST IMPLEMENTATION OF 

3207
02:39:05,355 --> 02:39:08,425
THAT WAS WE DID IT FOR PEDIATRIC

3208
02:39:08,425 --> 02:39:10,360
GLIOMAS, AND IT WAS FEATURED ON 

3209
02:39:10,360 --> 02:39:12,262
THE COVER OF MOLECULAR CELL, AND

3210
02:39:12,262 --> 02:39:13,464
WHAT WE'RE TRYING TO ILLUSTRATE 

3211
02:39:13,464 --> 02:39:16,033
IS HOW WHEN YOU TAKE A STEP 

3212
02:39:16,033 --> 02:39:18,469
BACK, YOU CAN MAYBE SEE THESE 

3213
02:39:18,469 --> 02:39:20,771
PATTERNS THAT YOU WOULDN'T HAVE 

3214
02:39:20,771 --> 02:39:21,138
SEEN OTHERWISE.

3215
02:39:21,138 --> 02:39:23,607
SORT OF LIKE A BIRD'S VIEW.

3216
02:39:23,607 --> 02:39:26,677
SO THE FIRST IMPLEMENTATION WAS 

3217
02:39:26,677 --> 02:39:31,048
FOR PEDIATRIC GLIOMAS, AND 

3218
02:39:31,048 --> 02:39:33,217
SPECIFICALLY THE MIDLINE 

3219
02:39:33,217 --> 02:39:34,017
GLIOMAS.

3220
02:39:34,017 --> 02:39:36,653
THEY ARE AGGRESSIVE TUMORS OF 

3221
02:39:36,653 --> 02:39:36,920
CHILDREN.

3222
02:39:36,920 --> 02:39:39,056
MAYBE SOME OF YOU ARE FAMILIAR 

3223
02:39:39,056 --> 02:39:40,691
WITH THEM BECAUSE ONE OF THE 

3224
02:39:40,691 --> 02:39:44,328
MAJOR CHARACTERISTICS OF THESE 

3225
02:39:44,328 --> 02:39:50,567
TUMORS IS THAT THEY HAVE THE 

3226
02:39:50,567 --> 02:39:52,936
MUTATION OF THYAZINE.

3227
02:39:52,936 --> 02:39:54,805
THE AK327M MUTATION.

3228
02:39:54,805 --> 02:39:57,975
THIS MUTATION, YOU KNOW, DESPITE

3229
02:39:57,975 --> 02:40:00,043
BEING JUST MINOR OF THE 

3230
02:40:00,043 --> 02:40:00,911
NUCLEOSOMES BECAUSE THERE ARE 

3231
02:40:00,911 --> 02:40:04,781
MANY GENES IN ENCODING THE WILD 

3232
02:40:04,781 --> 02:40:05,983
IP ZONES, IT'S COMPLETELY MESSED

3233
02:40:05,983 --> 02:40:08,185
UP WITH THE EPIGENETIC 

3234
02:40:08,185 --> 02:40:11,355
REGULATION OF THESE CELLS AND 

3235
02:40:11,355 --> 02:40:12,756
LEADING TO THE CANCER.

3236
02:40:12,756 --> 02:40:16,527
WHAT WE DID IS WE TOOK -- WE HAD

3237
02:40:16,527 --> 02:40:20,330
A PRIMARY CELL LINE FROM ONE OF 

3238
02:40:20,330 --> 02:40:22,666
THESE PATIENTS, AND WE HAVE 

3239
02:40:22,666 --> 02:40:23,700
ANALYZED THIS.

3240
02:40:23,700 --> 02:40:24,968
THIS IS ONE OF THE FIRST 

3241
02:40:24,968 --> 02:40:25,936
EXPERIMENTS THAT WE DID, AND 

3242
02:40:25,936 --> 02:40:30,107
WHAT WE SAW IS THAT WE ACTUALLY 

3243
02:40:30,107 --> 02:40:31,341
GET TWO EPIGENETIC 

3244
02:40:31,341 --> 02:40:36,313
SUBREGULATIONS IN THESE CELLS.

3245
02:40:36,313 --> 02:40:40,617
THIS IS JUST ALL THE EPIGENETICS

3246
02:40:40,617 --> 02:40:41,818
THAT WE HAVE MEASURED.

3247
02:40:41,818 --> 02:40:44,988
THE REASON WHY THIS WASN'T IN 

3248
02:40:44,988 --> 02:40:46,456
THIS TEST IS JUST CONSIDER THE 

3249
02:40:46,456 --> 02:40:48,825
FACT THAT THESE CELLS HAVE BEEN 

3250
02:40:48,825 --> 02:40:50,394
EXTENTIVELY STUDIED IN THE 

3251
02:40:50,394 --> 02:40:51,595
EPIGENETIC CONTEXT.

3252
02:40:51,595 --> 02:40:52,896
PEOPLE ALWAYS ANALYZE THIS, AND 

3253
02:40:52,896 --> 02:40:55,232
WHAT YOU CAN SEE HERE IS THAT 

3254
02:40:55,232 --> 02:40:56,533
YOU HAVE TWO SUBREGULATIONS THAT

3255
02:40:56,533 --> 02:41:00,304
ARE VERY DISTINCT, AND THEY HAVE

3256
02:41:00,304 --> 02:41:02,873
DIFFERENT PATTERNS AND 

3257
02:41:02,873 --> 02:41:03,206
MODIFICATIONS.

3258
02:41:03,206 --> 02:41:04,942
WE THINK THAT WE GENERATE THIS 

3259
02:41:04,942 --> 02:41:07,678
TO SUBPOPULATIONS.

3260
02:41:07,678 --> 02:41:09,246
THEY HAVE HIGHER AND LOWER 

3261
02:41:09,246 --> 02:41:11,348
LEVELS OF THIS MUTE ANT T-CELLS,

3262
02:41:11,348 --> 02:41:14,585
WHICH PUSHES DIFFERENT 

3263
02:41:14,585 --> 02:41:18,088
EPIGENETIC FATES, AND THIS -- 

3264
02:41:18,088 --> 02:41:20,657
FIRST WE THOUGHT THAT THIS COULD

3265
02:41:20,657 --> 02:41:21,692
BE MAYBE SOMETHING THIS IS JUST 

3266
02:41:21,692 --> 02:41:24,795
WEIRD ABOUT THESE SPECIFIC CELL 

3267
02:41:24,795 --> 02:41:27,631
LINES, BUT WHAT WE FOUND IS THAT

3268
02:41:27,631 --> 02:41:28,765
IN EVERY PATIENT WE ARE TELLING 

3269
02:41:28,765 --> 02:41:31,435
THAT WE HAVE ANALYZED, WE'VE 

3270
02:41:31,435 --> 02:41:35,639
ACTUALLY SEEN THIS TO EPIGENETIC

3271
02:41:35,639 --> 02:41:36,006
SUBREGULATIONS.

3272
02:41:36,006 --> 02:41:39,676
IT'S THE SAME SUBREGULATIONS IN 

3273
02:41:39,676 --> 02:41:40,410
EVERY PATIENT.

3274
02:41:40,410 --> 02:41:45,482
WE HAVE THIS INTERTUMOR 

3275
02:41:45,482 --> 02:41:45,816
HEPEAGENEITY.

3276
02:41:45,816 --> 02:41:47,384
IT MEANS THAT THIS IS SOMETHING 

3277
02:41:47,384 --> 02:41:49,319
THAT YOU COULD POTENTIALLY 

3278
02:41:49,319 --> 02:41:50,821
TARGET, WHICH WE THINK IS A VERY

3279
02:41:50,821 --> 02:41:53,490
CRITICAL ASPECT OF IT.

3280
02:41:53,490 --> 02:41:55,726
I WILL NOT HAVE TIME TO GO INTO 

3281
02:41:55,726 --> 02:41:58,395
THE DETAILS, BUT I WILL TELL YOU

3282
02:41:58,395 --> 02:42:00,998
THAT WE VERIFIED THIS H EPA 

3283
02:42:00,998 --> 02:42:02,833
GENEITY IN A MOUSE MODEL, AND 

3284
02:42:02,833 --> 02:42:06,670
YOU CAN ACTUALLY INJECT PATIENT 

3285
02:42:06,670 --> 02:42:09,606
CELLS TO THE KINDS OF MOUSE TO 

3286
02:42:09,606 --> 02:42:10,974
GENERATE THE TUMORS.

3287
02:42:10,974 --> 02:42:14,611
IT'S A COMPLICATED MOUSE MODEL, 

3288
02:42:14,611 --> 02:42:20,717
BUT WE'VE SEEN THIS HEPAGENEITY 

3289
02:42:20,717 --> 02:42:23,687
IN HUMAN BIOPSIES FROM CHILDREN.

3290
02:42:23,687 --> 02:42:24,988
AGAIN, I DON'T HAVE ENOUGH TIME 

3291
02:42:24,988 --> 02:42:27,724
TO TELL YOU ABOUT ALL OF THAT, 

3292
02:42:27,724 --> 02:42:30,661
BUT THESE TWO SUBREGULATIONS 

3293
02:42:30,661 --> 02:42:33,864
ACTUALLY HAVE DISTINCT FEATURES 

3294
02:42:33,864 --> 02:42:38,669
BOTH IN TERMS OF PROLIFERATION 

3295
02:42:38,669 --> 02:42:40,637
CAPACITY AND STEM CELL FEATURES,

3296
02:42:40,637 --> 02:42:43,674
AND WE SOMEHOW -- THE TUMOR -- 

3297
02:42:43,674 --> 02:42:45,342
AND I DON'T KNOW -- I DON'T HAVE

3298
02:42:45,342 --> 02:42:47,711
AN EXPLANATION FOR THAT, BUT 

3299
02:42:47,711 --> 02:42:50,681
SOME OF THE TUMORS SEEM TO 

3300
02:42:50,681 --> 02:42:57,587
BENEFIT FROM MAINTAINING THIS 

3301
02:42:57,587 --> 02:42:57,888
HEPAGENEITY.

3302
02:42:57,888 --> 02:42:59,623
WE'RE NOW DOING FOLLOW-UP 

3303
02:42:59,623 --> 02:43:05,095
STUDIES TO TRY TO UNDERSTAND IT 

3304
02:43:05,095 --> 02:43:05,328
BETTER.

3305
02:43:05,328 --> 02:43:08,665
JUST IN CONTEXT OF THE GLIOMAS 

3306
02:43:08,665 --> 02:43:11,435
AND THEN ALSO CONNECTED TO THE 

3307
02:43:11,435 --> 02:43:15,739
BIOPSY, SO NOW WHAT WE DO IS WE 

3308
02:43:15,739 --> 02:43:21,745
ARE ALSO COLLABORATING WITH 

3309
02:43:21,745 --> 02:43:24,681
DOCTORS AND RESEARCHERS IN THE 

3310
02:43:24,681 --> 02:43:25,549
HOSPITAL OF MICHIGAN, AND WHAT 

3311
02:43:25,549 --> 02:43:27,484
WE ARE DOING IS USING THE SINGLE

3312
02:43:27,484 --> 02:43:29,553
MOLECULE IMAGING.

3313
02:43:29,553 --> 02:43:33,690
WE CAN ACTUALLY CAPTURE 

3314
02:43:33,690 --> 02:43:36,393
NUCLEOSOMES, MUTANT NUCLEOSOMES 

3315
02:43:36,393 --> 02:43:39,062
FROM THE CHILDREN'S BLOOD AND 

3316
02:43:39,062 --> 02:43:40,363
SEE WHETHER THEIR RESPONSE TO 

3317
02:43:40,363 --> 02:43:42,265
TREATMENT AND SO ON.

3318
02:43:42,265 --> 02:43:43,700
THIS IS PRETTY CRITICAL IN ALL 

3319
02:43:43,700 --> 02:43:44,768
OF THESE KIDS BECAUSE THIS IS 

3320
02:43:44,768 --> 02:43:48,205
SUCH A DEADLY DISEASE.

3321
02:43:48,205 --> 02:43:49,005
THERE ARE MULTIPLE CLINICAL 

3322
02:43:49,005 --> 02:43:50,340
TRIALS, BUT HOW DO YOU EVEN 

3323
02:43:50,340 --> 02:43:51,842
MEASURE WHETHER A CHILD IS 

3324
02:43:51,842 --> 02:43:52,776
RESPONDING TO THE TREATMENT?

3325
02:43:52,776 --> 02:43:57,514
SO YOU COULD DO AN MRI, BUT THIS

3326
02:43:57,514 --> 02:43:59,516
IS USUALLY DIAGNOSED AT EARLY 

3327
02:43:59,516 --> 02:44:02,486
AGES, SO IT'S NOT SO EASY TO PUT

3328
02:44:02,486 --> 02:44:05,756
A 5-YEAR-OLD IN AN MRI MACHINE 

3329
02:44:05,756 --> 02:44:07,324
EVERY TWO OR THREE MONTHS, OR 

3330
02:44:07,324 --> 02:44:08,759
YOU CAN TAKE SPINAL FLUID, BUT 

3331
02:44:08,759 --> 02:44:11,228
THIS IS AN INVASIVE OF 

3332
02:44:11,228 --> 02:44:11,495
PROCEDURE.

3333
02:44:11,495 --> 02:44:12,929
WHAT WE CAN SHOW IS THAT THE 

3334
02:44:12,929 --> 02:44:15,699
SINGLE MOLECULE TECHNOLOGY IS SO

3335
02:44:15,699 --> 02:44:17,901
SENSITIVE THAT YOU CAN ACTUALLY 

3336
02:44:17,901 --> 02:44:21,671
CAPTURE THIS MUTANT, THIS K27 

3337
02:44:21,671 --> 02:44:22,272
MUTANT NUCLEOSOMES FROM THE 

3338
02:44:22,272 --> 02:44:26,676
BLOOD AND ANALYZE IT WITH A 

3339
02:44:26,676 --> 02:44:28,578
LIQUID BIOPSY TECHNOLOGY.

3340
02:44:28,578 --> 02:44:31,915
JUST TO SUMMARIZE, THE SINGLE 

3341
02:44:31,915 --> 02:44:35,285
CELL ASSAY WE ADAPTED TO 

3342
02:44:35,285 --> 02:44:37,788
IDENTIFY THE -- AND IDENTIFY 

3343
02:44:37,788 --> 02:44:40,557
THESE TWO EPIGENTLY DISTINCT 

3344
02:44:40,557 --> 02:44:40,957
POPULATIONS.

3345
02:44:40,957 --> 02:44:42,826
I DIDN'T HAVE TIME TO GO INTO 

3346
02:44:42,826 --> 02:44:44,361
IT, BUT THE SINGLE CELL DATA CAN

3347
02:44:44,361 --> 02:44:46,696
ACTUALLY REVEAL MANY CONNECTIONS

3348
02:44:46,696 --> 02:44:48,932
BETWEEN THESE TWO MODIFICATIONS.

3349
02:44:48,932 --> 02:44:50,200
WE'VE SEEN THIS NETWORK, AND 

3350
02:44:50,200 --> 02:44:50,867
IT'S SOMETHING THAT WE'RE REALLY

3351
02:44:50,867 --> 02:44:51,735
INTERESTED IN.

3352
02:44:51,735 --> 02:44:55,705
I JUST WANT TO CONCLUDE BY 

3353
02:44:55,705 --> 02:44:56,373
THANKING MY LAB.

3354
02:44:56,373 --> 02:45:02,078
WE'VE DONE THIS WORK, AND FROM 

3355
02:45:02,078 --> 02:45:02,646
ESPECIALLY NOW MANY OF MY 

3356
02:45:02,646 --> 02:45:04,648
STUDENTS ARE ACTUALLY DRAFTED TO

3357
02:45:04,648 --> 02:45:09,052
THE ARMY, AND I'M REALLY PROUD 

3358
02:45:09,052 --> 02:45:11,354
OF THEM AND I WOULD LIKE TO 

3359
02:45:11,354 --> 02:45:13,190
THANK I DON'T FEEL THE DOCTORS 

3360
02:45:13,190 --> 02:45:14,991
AND THE PATIENTS FOR CONJUGATING

3361
02:45:14,991 --> 02:45:16,459
TO THIS WORK AND ALSO THE 

3362
02:45:16,459 --> 02:45:16,726
FUNDING.

3363
02:45:16,726 --> 02:45:27,270
THANK YOU SO MUCH FOR LISTENING.

3364
02:46:08,879 --> 02:46:11,081
>>  EFRAT, ARE YOU THERE?

3365
02:46:11,081 --> 02:46:12,015
>> CAN YOU HEAR ME?

3366
02:46:12,015 --> 02:46:12,949
>>  THANK YOU FOR YOUR
WONDERFUL

3367
02:46:12,949 --> 02:46:14,217
PRESENTATION, AND I HOPE YOU AND

3368
02:46:14,217 --> 02:46:19,623
YOUR LOVED ONES ARE DOING WELL.

3369
02:46:19,623 --> 02:46:21,458
DO YOU MIND FOR QUESTION AND 

3370
02:46:21,458 --> 02:46:21,691
ANSWERS?

3371
02:46:21,691 --> 02:46:26,763
>> YES, OF COURSE.

3372
02:46:26,763 --> 02:46:31,868
>> ANY QUESTIONS?

3373
02:46:31,868 --> 02:46:35,639
IF I MAY ASK YOU TO TALK ABOUT, 

3374
02:46:35,639 --> 02:46:38,975
I WONDER WITH YOUR LIQUID 

3375
02:46:38,975 --> 02:46:42,078
BIOPSY, HAVE YOU EVER TRIED 

3376
02:46:42,078 --> 02:46:44,547
URINE SAMPLES?

3377
02:46:44,547 --> 02:46:45,916
>>  THAT'S A GOOD
QUESTION.

3378
02:46:45,916 --> 02:46:48,285
I THINK THAT IN CONTEXT OF 

3379
02:46:48,285 --> 02:46:50,654
SEVERAL CANCERS IT COULD 

3380
02:46:50,654 --> 02:46:52,322
ACTUALLY BE VERY BENEFICIAL TO 

3381
02:46:52,322 --> 02:46:53,723
LOOK AT URINE SAMPLES.

3382
02:46:53,723 --> 02:46:55,926
WE HAVEN'T ACTUALLY TRIED THIS 

3383
02:46:55,926 --> 02:47:01,498
IN THE LAB, BUT I DON'T SEE ANY 

3384
02:47:01,498 --> 02:47:02,532
REASON WHY IT SHOULDN'T WORK.

3385
02:47:02,532 --> 02:47:04,334
RIGHT NOW WE ARE FOCUSING ON LAB

3386
02:47:04,334 --> 02:47:07,804
SAMPLES, BOTH FOR DIAGNOSTICS, 

3387
02:47:07,804 --> 02:47:10,440
BUT ALSO FOR TREATMENT 

3388
02:47:10,440 --> 02:47:14,678
MONITORING AND IDENTIFYING 

3389
02:47:14,678 --> 02:47:25,155
RESIDUAL DISEASE AND SO ON.

3390
02:47:29,693 --> 02:47:33,730
>>  EFRAT, WE MET IN
GERMANY A 

3391
02:47:33,730 --> 02:47:37,334
COUPLE OF MONTHS AGO.

3392
02:47:37,334 --> 02:47:38,668
I HOPE EVERYTHING GOES WELL WITH

3393
02:47:38,668 --> 02:47:41,071
YOUR FAMILY.

3394
02:47:41,071 --> 02:47:42,672
MAYBE YOU CAN TALK ABOUT THE 

3395
02:47:42,672 --> 02:47:44,541
SINGLE MOLECULE IMAGING.

3396
02:47:44,541 --> 02:47:49,646
YOU WERE ABLE TO LOOK AT 

3397
02:47:49,646 --> 02:47:54,651
SPECIFIC MODIFICATIONS IF YOU 

3398
02:47:54,651 --> 02:47:56,519
ARE ABLE TO LOOK AT 

3399
02:47:56,519 --> 02:48:01,658
MULTIAVAILABILITY AND ALSO 

3400
02:48:01,658 --> 02:48:12,135
COMBINED WITH THE ISSUES --

3401
02:48:19,042 --> 02:48:20,810
>>  THAT'S A GREAT
QUESTION, AND

3402
02:48:20,810 --> 02:48:21,444
WE ARE IN THE PROCESS OF DOING 

3403
02:48:21,444 --> 02:48:21,644
THAT.

3404
02:48:21,644 --> 02:48:23,680
FIRST OF ALL, FOR DNA 

3405
02:48:23,680 --> 02:48:25,749
MANIPULATION, THE WAY WE ARE 

3406
02:48:25,749 --> 02:48:27,984
EXACTING IT WITH SINGLE 

3407
02:48:27,984 --> 02:48:28,952
MOLECULE, WE DIDN'T HAVE TIME TO

3408
02:48:28,952 --> 02:48:30,653
GET INTO IT, BUT WHAT WE ARE 

3409
02:48:30,653 --> 02:48:35,125
DOING IS REUSING THE MBD2 DOMAIN

3410
02:48:35,125 --> 02:48:36,626
WHICH BINDS SPECIFICALLY TO MAP 

3411
02:48:36,626 --> 02:48:38,028
THE DNA.

3412
02:48:38,028 --> 02:48:39,796
WE CONJUGATE THE FLOOR, SO WE 

3413
02:48:39,796 --> 02:48:45,535
ARE USING IT SORT OF LIKE AN 

3414
02:48:45,535 --> 02:48:47,937
ANTI-BODY, AND IT BINDS 

3415
02:48:47,937 --> 02:48:48,972
UNMETHYLATED DNA, AND WE ARE 

3416
02:48:48,972 --> 02:48:51,007
FOLLOWING THE BINDING OF THE TWO

3417
02:48:51,007 --> 02:48:55,445
DOMAINS TO THE MOLECULES ON THE 

3418
02:48:55,445 --> 02:49:00,683
SURFACE TO TRY TO USE THE DNA 

3419
02:49:00,683 --> 02:49:01,184
MANIPULATION PATTERNS.

3420
02:49:01,184 --> 02:49:02,652
OBVIOUSLY THE RESOLUTION THAT WE

3421
02:49:02,652 --> 02:49:05,955
HAVE IS NOT A BASE RESOLUTION 

3422
02:49:05,955 --> 02:49:07,991
LIKE YOU HAVE BY SEQUENCING, BUT

3423
02:49:07,991 --> 02:49:11,561
IT'S MORE THE ENTIRE PIECE OF 

3424
02:49:11,561 --> 02:49:14,164
115 BASE OF DNA THAT YOU HAVE ON

3425
02:49:14,164 --> 02:49:18,268
THE SURFACE, BUT WE DEFINITELY 

3426
02:49:18,268 --> 02:49:20,904
SEE VERY INTERESTING PATTERNS OF

3427
02:49:20,904 --> 02:49:25,542
THESE COMBINATIONS BETWEEN 

3428
02:49:25,542 --> 02:49:28,044
KEYSTONE MODIFICATIONS AND DNA 

3429
02:49:28,044 --> 02:49:30,413
MANIPULATIONS, AND WHICH 

3430
02:49:30,413 --> 02:49:34,484
COMBINATIONS SEEM TO BE ENRICHED

3431
02:49:34,484 --> 02:49:35,452
OR DEPLETED.

3432
02:49:35,452 --> 02:49:38,855
>>  THANK YOU.

3433
02:49:38,855 --> 02:49:40,356
>>  THANK YOU.

3434
02:49:40,356 --> 02:49:41,124
>>  THANK YOU, AGAIN.

3435
02:49:41,124 --> 02:49:44,027
HOPE YOU ARE SAFE.

3436
02:49:44,027 --> 02:49:44,461
BE WELL.

3437
02:49:44,461 --> 02:49:46,429
THANK YOU.

3438
02:49:46,429 --> 02:49:52,569
OUR NEXT SPEAKER OR GONZANI, HE 

3439
02:49:52,569 --> 02:49:53,269
CAME DOWN WITH ACUTE DISEASE.

3440
02:49:53,269 --> 02:49:54,838
HE CAN'T BE HERE, AND I HOPE HE 

3441
02:49:54,838 --> 02:49:56,372
IS DOING WELL.

3442
02:49:56,372 --> 02:49:59,109
SO OUR NEXT SPEAKER WILL BE 

3443
02:49:59,109 --> 02:50:01,678
DENNIS LO.

3444
02:50:01,678 --> 02:50:05,715
HE'S RECORDED FROM HONG KONG.

3445
02:50:05,715 --> 02:50:09,219
GAINING INSIGHTS INTO CANCER 

3446
02:50:09,219 --> 02:50:19,662
EPIGENOMICS THROUGH CFDNA.

3447
02:50:35,345 --> 02:50:36,946
>>  I WOULD LIKE TO THANK
THE 

3448
02:50:36,946 --> 02:50:42,652
ORGANIZERS FOR INVITING ME TO 

3449
02:50:42,652 --> 02:50:52,862
PARTICI

3450
02:50:57,000 --> 02:51:00,970
PARTICIPATE IN THIS CONFERENCE 

3451
02:51:00,970 --> 02:51:02,839
CELEBRATING 40 YEARS OF CANCER 

3452
02:51:02,839 --> 02:51:03,139
EPIGENETICS.

3453
02:51:03,139 --> 02:51:06,976
I WOULD LIKE TO TALK ABOUT SOME 

3454
02:51:06,976 --> 02:51:07,477
WORK.

3455
02:51:07,477 --> 02:51:10,380
THE TOPIC OF MY TALK IS GAINING 

3456
02:51:10,380 --> 02:51:14,717
INSIGHTS INTO CANCER EPIGENOMICS

3457
02:51:14,717 --> 02:51:24,093
THROUGH CFDNA FRAGMENTOMICS.

3458
02:51:24,093 --> 02:51:24,928
OUR GROUP HAS BEEN WORKING IN 

3459
02:51:24,928 --> 02:51:25,695
TWO OF THESE AREAS.

3460
02:51:25,695 --> 02:51:31,901
FIRST, IT'S THE DETECTION OF 

3461
02:51:31,901 --> 02:51:33,303
PHYTO-DNA IN PREGNANT WOMAN, AND

3462
02:51:33,303 --> 02:51:37,507
THE DETECTION OF THE PLASMA OF 

3463
02:51:37,507 --> 02:51:37,874
CANCER PATIENTS.

3464
02:51:37,874 --> 02:51:40,577
THESE TWO AREAS HAVE MANY 

3465
02:51:40,577 --> 02:51:51,087
SIMILARITIES, AND SO THEY'RE 

3466
02:51:53,156 --> 02:51:54,457
SINS

3467
02:51:54,457 --> 02:51:56,326
SYNERGINISTC IN WORKING 

3468
02:51:56,326 --> 02:51:56,593
TOGETHER.

3469
02:51:56,593 --> 02:51:59,162
SO WE ACHIEVED THIS BACK IN 2013

3470
02:51:59,162 --> 02:52:02,332
IN WHICH WE DESCRIBE A GENOME 

3471
02:52:02,332 --> 02:52:03,800
APPROACH TO DETECT MULTIPLE 

3472
02:52:03,800 --> 02:52:07,403
TYPES OF CANCER, BUT BY USING 

3473
02:52:07,403 --> 02:52:08,104
ONE BLOOD TEST.

3474
02:52:08,104 --> 02:52:10,106
THEN BY 2015 WE DEVELOPED A 

3475
02:52:10,106 --> 02:52:11,708
TECHNOLOGY CALLED PLASMA DNA 

3476
02:52:11,708 --> 02:52:14,644
TISSUE MAPPING IN WHICH WE USED 

3477
02:52:14,644 --> 02:52:19,349
TISSUE MANIPULATION PROFILES TO 

3478
02:52:19,349 --> 02:52:21,784
LOCALIZE THE ORIGIN OF 

3479
02:52:21,784 --> 02:52:22,652
PARTICULAR CANCERS.

3480
02:52:22,652 --> 02:52:25,054
THIS INVENTION IS NOW PART OF 

3481
02:52:25,054 --> 02:52:29,492
THE COMPONENTS OF THE GALLERY 

3482
02:52:29,492 --> 02:52:29,692
TESTS.

3483
02:52:29,692 --> 02:52:31,194
FOR THIS SORT OF TEST AND MANY 

3484
02:52:31,194 --> 02:52:34,964
OF THE OTHERS WHICH ARE BASED IN

3485
02:52:34,964 --> 02:52:39,269
EPIGENETICS BECAUSE THE DNA 

3486
02:52:39,269 --> 02:52:40,503
TECHNOLOGY IS NORMALLY DESIGNED 

3487
02:52:40,503 --> 02:52:42,572
TO ANALYZE GENETICS RATHER 

3488
02:52:42,572 --> 02:52:43,706
EPIGENETICS PHENOMENON.

3489
02:52:43,706 --> 02:52:45,808
SO USUALLY WE WILL REQUIRE SOME 

3490
02:52:45,808 --> 02:52:50,146
SORT OF CONVERSION PROCESS, SUCH

3491
02:52:50,146 --> 02:52:55,918
AS -- IN THE CASE OF THE 

3492
02:52:55,918 --> 02:52:57,220
EPISUFFIC CONVERSION THIS COULD 

3493
02:52:57,220 --> 02:52:59,122
BE DESTRUCTIVE ON THE DNA.

3494
02:52:59,122 --> 02:53:00,990
FOR THIS REASON IN THE LAST FEW 

3495
02:53:00,990 --> 02:53:02,692
YEARS WE'VE BEEN INTERESTED TO 

3496
02:53:02,692 --> 02:53:05,461
EXPLORE METHODS WHICH DO NOT 

3497
02:53:05,461 --> 02:53:06,229
REQUIRE SUCH CONVERSION.

3498
02:53:06,229 --> 02:53:07,864
IN ONE AREA THAT WE ARE WORKING 

3499
02:53:07,864 --> 02:53:12,602
ON IT'S IN THE FRAGMENTATION OF 

3500
02:53:12,602 --> 02:53:12,835
DNA.

3501
02:53:12,835 --> 02:53:14,570
SO BASICALLY IF WE ARE LOOKING 

3502
02:53:14,570 --> 02:53:16,406
AT DNA INSIDE THE CELL, IT'S 

3503
02:53:16,406 --> 02:53:18,508
VERY LONG MOLECULES.

3504
02:53:18,508 --> 02:53:19,909
IT COULD BE UP TO 2 METERS LONG 

3505
02:53:19,909 --> 02:53:22,979
IF YOU EXTEND A WHOLE GENOME 

3506
02:53:22,979 --> 02:53:23,379
TOGETHER.

3507
02:53:23,379 --> 02:53:27,784
HOWEVER, THE PLASMA, THE DNA, IS

3508
02:53:27,784 --> 02:53:29,319
GENERALLY FRAGMENTS OF DNA.

3509
02:53:29,319 --> 02:53:30,920
BY LOOKING AT, FOR EXAMPLE, THE 

3510
02:53:30,920 --> 02:53:33,456
FRAGMENT SIZE, WE CAN 

3511
02:53:33,456 --> 02:53:34,123
DIFFERENTIATE CANCER AND 

3512
02:53:34,123 --> 02:53:37,060
NONCANCER BECAUSE CANCER DNA IS 

3513
02:53:37,060 --> 02:53:38,661
GENERALLY SHORTER THAN NONCANCER

3514
02:53:38,661 --> 02:53:39,362
DNA.

3515
02:53:39,362 --> 02:53:43,700
YOU CAN ALSO LOOK AT THE END 

3516
02:53:43,700 --> 02:53:45,268
MOTIF, THE SUBSTRETCH OF 

3517
02:53:45,268 --> 02:53:47,136
SEQUENCES OF THE END OF THE 

3518
02:53:47,136 --> 02:53:48,171
MOLECULES, AND THIS CAN 

3519
02:53:48,171 --> 02:53:48,738
DIFFERENTIATE CANCER AND 

3520
02:53:48,738 --> 02:53:50,707
NONCANCER DNA.

3521
02:53:50,707 --> 02:53:52,742
YOU CAN ALSO LOOK AT THE END OF 

3522
02:53:52,742 --> 02:53:54,644
THE FRAGMENT SINGLE STRANDED OR 

3523
02:53:54,644 --> 02:53:58,548
DOUBLE STRANDED, SO THESE 

3524
02:53:58,548 --> 02:54:00,783
COMBINATIONS ARE NOW REFERRED TO

3525
02:54:00,783 --> 02:54:03,286
AS FRAGMENTOMICS THAT ARE THE 

3526
02:54:03,286 --> 02:54:06,656
FRAGMENTATION PATTERNS IN BODILY

3527
02:54:06,656 --> 02:54:06,989
FLUID.

3528
02:54:06,989 --> 02:54:09,659
ONE VERY POWERFUL METHOD TO LOOK

3529
02:54:09,659 --> 02:54:12,795
AT THIS FRAGMENTOMICS IS BY THE 

3530
02:54:12,795 --> 02:54:15,798
USE OF OUR MODEL IN WHICH THE 

3531
02:54:15,798 --> 02:54:20,803
SELECTED NUCLEOIC GENES IN MICE,

3532
02:54:20,803 --> 02:54:23,573
AND THEN WE CAN LOOK AT THE DNA 

3533
02:54:23,573 --> 02:54:24,006
PROFILE.

3534
02:54:24,006 --> 02:54:26,175
FOR EXAMPLE HERE IN THIS 

3535
02:54:26,175 --> 02:54:28,010
EXPERIMENT WE LOOK AT WILD TYPE 

3536
02:54:28,010 --> 02:54:29,612
MICE, AND THEN WE ACTUALLY DO 

3537
02:54:29,612 --> 02:54:31,581
THE SEQUENCING ON THE PLASMA, 

3538
02:54:31,581 --> 02:54:34,183
AND THEN WE MEASURE THE 

3539
02:54:34,183 --> 02:54:35,518
MANIPULATION PROFILE.

3540
02:54:35,518 --> 02:54:38,755
THEN IF YOU KNOCK OUT IN NUCLEUS

3541
02:54:38,755 --> 02:54:40,123
GENE LIKE DNA1 GENE, AND THEN 

3542
02:54:40,123 --> 02:54:42,759
YOU SEE THE METHYLATION PROFILE 

3543
02:54:42,759 --> 02:54:43,826
REMAINS UNCHANGED.

3544
02:54:43,826 --> 02:54:45,828
IF YOU CONTINUE, YOU COME ACROSS

3545
02:54:45,828 --> 02:54:50,166
THE STRAIN OF DNA, WHICH SOME 

3546
02:54:50,166 --> 02:54:51,834
PEOPLE REFER AS DNA SCAM, WHICH 

3547
02:54:51,834 --> 02:54:57,173
IS BASICALLY DNA WHICH CUT 

3548
02:54:57,173 --> 02:55:01,677
CHROMATON, AND IT'S CIRCLING IN 

3549
02:55:01,677 --> 02:55:01,944
CHROMATON.

3550
02:55:01,944 --> 02:55:03,813
YOU CAN SEE THE MANIPULATION 

3551
02:55:03,813 --> 02:55:06,449
PROFILE IN CREATION OF A LOT OF 

3552
02:55:06,449 --> 02:55:08,351
THOSE HYPER METHYLATED FRAGMENTS

3553
02:55:08,351 --> 02:55:09,619
IN PLASMA.

3554
02:55:09,619 --> 02:55:13,423
WHEN WE LOOK AT THE DATA LIKE 

3555
02:55:13,423 --> 02:55:14,657
THIS, THERE ARE DIFFERENT 

3556
02:55:14,657 --> 02:55:15,591
POTENTIAL EXPLANATIONS, AND ONE 

3557
02:55:15,591 --> 02:55:16,993
OF THE QUESTIONS THAT WE 

3558
02:55:16,993 --> 02:55:21,097
INITIALLY ASKED IS WHETHER 

3559
02:55:21,097 --> 02:55:24,233
KNOCKING OUT THE DNA GENE WOULD 

3560
02:55:24,233 --> 02:55:25,735
SOMEHOW CHANGE THE 

3561
02:55:25,735 --> 02:55:27,170
CONSTITUTIONAL METHYLOMIC 

3562
02:55:27,170 --> 02:55:29,806
PROFILE OF CELLS, AND THEN WE 

3563
02:55:29,806 --> 02:55:31,207
SHOW THAT THAT IT DOESN'T HAPPEN

3564
02:55:31,207 --> 02:55:33,810
BECAUSE HERE YOU CAN SEE WILD 

3565
02:55:33,810 --> 02:55:37,480
TYPE DNA KNOCK OUT AND DNA1 

3566
02:55:37,480 --> 02:55:38,648
KNOCKOUT, AND BASICALLY THERE'S 

3567
02:55:38,648 --> 02:55:42,418
NO CHANGE IN THE CELLULAR 

3568
02:55:42,418 --> 02:55:43,286
METHYLOMIC PROFILE.

3569
02:55:43,286 --> 02:55:44,720
HOWEVER, CAN YOU LOOK AT PLASMA,

3570
02:55:44,720 --> 02:55:45,621
AND THIS IS WHERE THAT CHANGE 

3571
02:55:45,621 --> 02:55:45,855
OCCURS.

3572
02:55:45,855 --> 02:55:49,525
WHEN YOU SEE THAT KNOCKING OF 

3573
02:55:49,525 --> 02:55:51,828
DNA1 LIVE 3 GENE WILL BASICALLY 

3574
02:55:51,828 --> 02:55:56,432
RESULT IN HYPER METHYLATION IN 

3575
02:55:56,432 --> 02:55:56,666
PLASMA.

3576
02:55:56,666 --> 02:55:58,668
THIS WORK HAS RESULTED IN THIS 

3577
02:55:58,668 --> 02:56:00,503
PUBLICATION IN WHICH WE CONCLUDE

3578
02:56:00,503 --> 02:56:01,504
THAT NUCLEUS DEFICIENCY WILL 

3579
02:56:01,504 --> 02:56:06,442
AFFECT THE PLASMA DNA 

3580
02:56:06,442 --> 02:56:06,909
METHYLATION PROFILES.

3581
02:56:06,909 --> 02:56:08,144
THE QUESTION IS WHAT ARE THE 

3582
02:56:08,144 --> 02:56:10,480
IMPLICATIONS OF THIS WORK?

3583
02:56:10,480 --> 02:56:11,914
SO THAT TIME WE HAVE THOUGHT 

3584
02:56:11,914 --> 02:56:15,084
LONG AND HARD FOR THAT, AND ONE 

3585
02:56:15,084 --> 02:56:16,219
POTENTIAL IMPLICATION IS THEN, 

3586
02:56:16,219 --> 02:56:21,824
WELL, INDIVIDUALS WITH DNA1 LIVE

3587
02:56:21,824 --> 02:56:23,626
FREE DEFICIENCY MAY GIVE FALSE 

3588
02:56:23,626 --> 02:56:25,528
POSITIVE RESULTS IN LIQUID 

3589
02:56:25,528 --> 02:56:27,830
BIOPSY TESTS.

3590
02:56:27,830 --> 02:56:29,098
WHILE THIS PARTICULAR RESULT 

3591
02:56:29,098 --> 02:56:31,601
IS -- THIS CONCLUSION IS VALID, 

3592
02:56:31,601 --> 02:56:33,870
BUT THEN THE BROADNESS OF THE 

3593
02:56:33,870 --> 02:56:35,805
BREADTH OF THIS IMPLICATION 

3594
02:56:35,805 --> 02:56:37,707
COULD BE RATHER NARROW BECAUSE 

3595
02:56:37,707 --> 02:56:43,012
INDIVIDUALS WITH DNA1L FREE 

3596
02:56:43,012 --> 02:56:43,946
DEFICIENCY COULD FEEL.

3597
02:56:43,946 --> 02:56:46,782
WE THOUGHT ABOUT THIS FOR A 

3598
02:56:46,782 --> 02:56:48,518
WHILE, AND THEN WE FINALLY 

3599
02:56:48,518 --> 02:56:50,386
ARRIVE AT A CONCLUSION THAT A 

3600
02:56:50,386 --> 02:56:52,255
GOOD WAY TO ACTUALLY THINK ABOUT

3601
02:56:52,255 --> 02:56:54,657
THIS PROBLEM IS TO ACTUALLY ASK 

3602
02:56:54,657 --> 02:56:57,793
THE OPPOSITE QUESTION, AND THAT 

3603
02:56:57,793 --> 02:57:00,162
IS CAN FRAGMENTOMICS PROFILE BE 

3604
02:57:00,162 --> 02:57:03,165
USED TO DEDUCE THE MANIPULATION 

3605
02:57:03,165 --> 02:57:04,901
STATUS OF CELL-FREE DNA?

3606
02:57:04,901 --> 02:57:07,603
TO DO THIS WE HAVE TO ACTUALLY 

3607
02:57:07,603 --> 02:57:09,839
LOOK AT FRAGMENTOMIC PROFILE IN 

3608
02:57:09,839 --> 02:57:11,607
RELATION TO THE METHYLATION 

3609
02:57:11,607 --> 02:57:12,108
STATUS IN DETAIL.

3610
02:57:12,108 --> 02:57:15,745
SO THIS GRAPH HERE ON THE X AXIS

3611
02:57:15,745 --> 02:57:17,713
BASICALLY IS GENOMIC COORDINATES

3612
02:57:17,713 --> 02:57:21,751
IN WHICH WE PUT THE C ON A CG 

3613
02:57:21,751 --> 02:57:23,352
SITE AND PUTS IT AT ZERO.

3614
02:57:23,352 --> 02:57:24,820
G WOULD BE NUMBER ONE.

3615
02:57:24,820 --> 02:57:26,489
THEN THE RED LINE HERE IS WHEN 

3616
02:57:26,489 --> 02:57:30,226
WE LOOK AT METHYLATED DNA IN 

3617
02:57:30,226 --> 02:57:30,626
PLASMA.

3618
02:57:30,626 --> 02:57:33,462
CAN YOU SEE THAT METHYLATED DNA,

3619
02:57:33,462 --> 02:57:34,363
THAT THERE IS A HIGH 

3620
02:57:34,363 --> 02:57:37,433
PREPONDERANCE OF THE DNA BEING 

3621
02:57:37,433 --> 02:57:38,134
CLEAVED EXACTLY AT THIS POSITION

3622
02:57:38,134 --> 02:57:40,169
ZERO WHERE THE C IS.

3623
02:57:40,169 --> 02:57:42,538
WHEN YOU LOOK AT THIS 

3624
02:57:42,538 --> 02:57:45,908
MANIPULATION, THEN THIS 

3625
02:57:45,908 --> 02:57:49,412
PROBABILITY REDUCES GREATLY.

3626
02:57:49,412 --> 02:57:53,416
IF YOU LOOK AT THE HYPER 

3627
02:57:53,416 --> 02:57:54,617
METHYLATED CELL FREE DNA, THEN 

3628
02:57:54,617 --> 02:57:56,385
THE PATTERN IS VERY DIFFERENT.

3629
02:57:56,385 --> 02:57:58,654
YOU CAN SEE THAT ACTUALLY THIS 

3630
02:57:58,654 --> 02:57:59,021
AT ZERO.

3631
02:57:59,021 --> 02:58:00,890
THERE'S NO PREPONDERANCE, AND 

3632
02:58:00,890 --> 02:58:03,192
THEN IT'S NOT A LOT OF 

3633
02:58:03,192 --> 02:58:06,028
DIFFERENCE IN THIS DISPOSITION 

3634
02:58:06,028 --> 02:58:06,862
AND THE MINUS ONE POSITION.

3635
02:58:06,862 --> 02:58:09,899
WHEN WE THINK ABOUT THIS, THEN 

3636
02:58:09,899 --> 02:58:12,602
OUR THOUGHT ABOUT THIS CONCEPT 

3637
02:58:12,602 --> 02:58:15,671
CALLED FRAGMENT WHICH IS 

3638
02:58:15,671 --> 02:58:16,906
FRAGMENTOMICS-BASED ANALYSIS, SO

3639
02:58:16,906 --> 02:58:18,941
IN WHICH YOU HAVE METHYLATED DNA

3640
02:58:18,941 --> 02:58:20,476
ON THE LEFT-HAND SIDE, AND 

3641
02:58:20,476 --> 02:58:23,312
METHYLATED DNA ON THE RIGHT-HAND

3642
02:58:23,312 --> 02:58:23,512
SIDE.

3643
02:58:23,512 --> 02:58:29,051
YOU CAN ACTUALLY LOOK AT THIS 

3644
02:58:29,051 --> 02:58:34,290
FREE NUCLEO TYPE CGN.

3645
02:58:34,290 --> 02:58:36,759
IF YOU LOOK AT THE FRAGMENT 

3646
02:58:36,759 --> 02:58:42,665
ENDING IN CGN VERSUS THOSE 

3647
02:58:42,665 --> 02:58:48,471
ENDING IN HAD CGD IT'S MANY 

3648
02:58:48,471 --> 02:58:49,038
METHYLATED, IT WILL BE HIGH.

3649
02:58:49,038 --> 02:58:51,741
ON THE RIGHT-HAND SIDE IF IT'S 

3650
02:58:51,741 --> 02:58:52,875
UNMETHYLATED, THE CGN WOULD BE 

3651
02:58:52,875 --> 02:58:55,845
LOW, AND THE NCG WOULD BE HIGH.

3652
02:58:55,845 --> 02:58:57,346
FOR EXAMPLE, YOU SCAN ACROSS A 

3653
02:58:57,346 --> 02:59:00,583
WHOLE GENOME AND FIND THAT THE 

3654
02:59:00,583 --> 02:59:05,755
CGN AND NCG RATIO FOR METHYLATED

3655
02:59:05,755 --> 02:59:09,592
FRAGMENTS ARE BASICALLY ABOUT 

3656
02:59:09,592 --> 02:59:11,060
4.5 OR SO, BUT ON THE OTHER HAND

3657
02:59:11,060 --> 02:59:15,398
IF IT IS HYPERMETHYLATED, IT'S 

3658
02:59:15,398 --> 02:59:15,765
JUST ABOVE ONE.

3659
02:59:15,765 --> 02:59:17,566
HERE WHEN WE COMPARE THE DATA 

3660
02:59:17,566 --> 02:59:19,402
WITH GOAL STANDARD SEQUENCING, 

3661
02:59:19,402 --> 02:59:21,470
FOR EXAMPLE, ACROSS THE WHOLE 

3662
02:59:21,470 --> 02:59:23,773
GENOME IN OTHER REGIONS AND IN 

3663
02:59:23,773 --> 02:59:25,708
CVG ISLANDS, THEN YOU HAVE A 

3664
02:59:25,708 --> 02:59:27,009
NUMBER OF DIFFERENT METHYLATION 

3665
02:59:27,009 --> 02:59:27,309
DENSITIES.

3666
02:59:27,309 --> 02:59:29,111
ON THE RIGHT-HAND SIDE HERE, 

3667
02:59:29,111 --> 02:59:34,350
WHEN YOU GO TO FRAGMENT DATA, 

3668
02:59:34,350 --> 02:59:36,752
FRAGMENT WILL MIRROR THE 

3669
02:59:36,752 --> 02:59:37,820
SEQUENCING RESULT.

3670
02:59:37,820 --> 02:59:38,688
IN OTHER WORDS, YOU DON'T HAVE 

3671
02:59:38,688 --> 02:59:39,755
TO DO THE CONVERSION.

3672
02:59:39,755 --> 02:59:42,391
ANOTHER WAY IN WHICH WE CAN 

3673
02:59:42,391 --> 02:59:47,463
DEMONSTRATE THE FRAGMENT WORKS 

3674
02:59:47,463 --> 02:59:51,734
IS A LOOK AT -- FOR EXAMPLE, WE 

3675
02:59:51,734 --> 02:59:55,805
LOOK AT THE GNA AT LOCUSTS IN 

3676
02:59:55,805 --> 02:59:56,439
THIS PARTICULAR INDIVIDUAL.

3677
02:59:56,439 --> 02:59:58,674
THIS ALU HERE IS METHYLATED AS 

3678
02:59:58,674 --> 03:00:02,678
INDICATED BY THE BLACK DOTS.

3679
03:00:02,678 --> 03:00:03,913
THE GL IS HYPERMETHYLATED, AS 

3680
03:00:03,913 --> 03:00:04,814
INDICATED BY THE WHITE DOTS.

3681
03:00:04,814 --> 03:00:07,149
ON THE RIGHT-HAND SIDE HERE YOU 

3682
03:00:07,149 --> 03:00:16,392
BASICALLY LOOK AT THE CGN TO NCG

3683
03:00:16,392 --> 03:00:16,592
RATIO.

3684
03:00:16,592 --> 03:00:19,595
YOU FOR G ON THE RIGHT-HAND 

3685
03:00:19,595 --> 03:00:22,431
SIDE, THE CGN IS LOW, AND THE 

3686
03:00:22,431 --> 03:00:23,265
NCG IS HIGH.

3687
03:00:23,265 --> 03:00:26,669
THAT DEMONSTRATES THE FRAGMENT 

3688
03:00:26,669 --> 03:00:29,905
CONCEPT WORKS FOR IMPRINTING.

3689
03:00:29,905 --> 03:00:33,442
AS WE MENTIONED ABOUT THE 

3690
03:00:33,442 --> 03:00:35,177
FRAGMENT CONCEPT IS INTIMATELY 

3691
03:00:35,177 --> 03:00:38,848
RELATED TO THE ACTIVITY OF DNA1 

3692
03:00:38,848 --> 03:00:39,448
LIVE FREE.

3693
03:00:39,448 --> 03:00:41,617
WE ACTUALLY LOOK AT THE 

3694
03:00:41,617 --> 03:00:42,651
INDIVIDUALS WITH INDIVIDUALS 

3695
03:00:42,651 --> 03:00:46,088
WITH DNA 1 LIVE FREE 

3696
03:00:46,088 --> 03:00:48,290
INDIVIDUALS, AND WE LOOK AT THE 

3697
03:00:48,290 --> 03:00:48,891
FRAGMENT PHENOMENON DOESN'T 

3698
03:00:48,891 --> 03:00:49,091
EXIST.

3699
03:00:49,091 --> 03:00:50,226
YOU CAN SEE THERE'S NO 

3700
03:00:50,226 --> 03:00:51,961
DIFFERENCE BETWEEN THE 

3701
03:00:51,961 --> 03:00:54,563
METHYLATED AND UNMETHYLATED 

3702
03:00:54,563 --> 03:00:59,368
FRAGMENTS IN TERMS OF THIS M 

3703
03:00:59,368 --> 03:01:00,336
MODE OF RATIOS.

3704
03:01:00,336 --> 03:01:02,605
WITH NORMAL INDIVIDUALS WITH THE

3705
03:01:02,605 --> 03:01:05,875
FULL XLIM OF THE NUCLEUS GENES, 

3706
03:01:05,875 --> 03:01:08,878
YOU CAN SEE WE CAN DIFFERENTIATE

3707
03:01:08,878 --> 03:01:10,513
THE TWO TYPES OF SEQUENCES.

3708
03:01:10,513 --> 03:01:12,615
THEN WE WONDER WHERE CAN WE USE 

3709
03:01:12,615 --> 03:01:13,716
FRAGMENTS IN TERMS OF DETECTION?

3710
03:01:13,716 --> 03:01:22,491
WE DECIDED TO USE IT FOR HEPA 

3711
03:01:22,491 --> 03:01:22,725
CANCER.

3712
03:01:22,725 --> 03:01:26,128
WE USE COPY NUMBER PRAYINGS AS A

3713
03:01:26,128 --> 03:01:28,831
MARKER FOR TUMOR DNA, AND Y AXIS

3714
03:01:28,831 --> 03:01:35,004
IS THE FRAGMENT RATIO.

3715
03:01:35,004 --> 03:01:36,238
CAN YOU SEE THERE'S A 

3716
03:01:36,238 --> 03:01:37,139
CORRELATION BETWEEN WHAT WE 

3717
03:01:37,139 --> 03:01:44,346
MEASURE AND THE CNA IN THE 

3718
03:01:44,346 --> 03:01:44,580
PLASMA.

3719
03:01:44,580 --> 03:01:46,248
AS YOU LOOK AT THE DIFFERENT 

3720
03:01:46,248 --> 03:01:49,385
STAGE OF XCC, WE USE THE 

3721
03:01:49,385 --> 03:01:54,023
STAGING, AND WE LOOK AT THE 

3722
03:01:54,023 --> 03:01:54,990
PERILILE STAGE AND IN THE 

3723
03:01:54,990 --> 03:01:55,357
ADVANCED STAGE.

3724
03:01:55,357 --> 03:01:59,128
YOU CAN SEE HERE THAT BASICALLY 

3725
03:01:59,128 --> 03:02:01,530
AS THE STAGING CHANGES, THE 

3726
03:02:01,530 --> 03:02:03,999
FRAGMENT RATIOS ALSO 

3727
03:02:03,999 --> 03:02:05,901
PROGRESSIVELY CHANGE.

3728
03:02:05,901 --> 03:02:09,805
THEN WE CAN ALSO USE A SUPPORT 

3729
03:02:09,805 --> 03:02:12,842
VECTOR MACHINE MODEL TO FURTHER 

3730
03:02:12,842 --> 03:02:13,175
DIFFERENTIATE.

3731
03:02:13,175 --> 03:02:16,579
IN THIS MODEL WE LOOK AT THE 

3732
03:02:16,579 --> 03:02:18,314
FREE MOTIVE AT THE END OF THE 

3733
03:02:18,314 --> 03:02:20,182
FRAGMENTS, WHICH CONTAIN THE CG.

3734
03:02:20,182 --> 03:02:24,386
NOW WE CAN HAVE CG, THE FIRST 

3735
03:02:24,386 --> 03:02:28,057
TWO POSITIONS, AND THEN WITH ATC

3736
03:02:28,057 --> 03:02:29,825
OR G IN THE FIRST POSITION OR WE

3737
03:02:29,825 --> 03:02:32,361
CAN HAVE CG IN THE SECOND OR 

3738
03:02:32,361 --> 03:02:32,728
THIRD POSITION.

3739
03:02:32,728 --> 03:02:35,197
THEN CHANGE THE FIRST POSITION 

3740
03:02:35,197 --> 03:02:36,966
FROM A, T, C, AND G, AND PUT ALL

3741
03:02:36,966 --> 03:02:39,935
THE FRAGMENTS WITH ALL OF THOSE 

3742
03:02:39,935 --> 03:02:42,872
MOTIFS INTO THIS SBM MODEL.

3743
03:02:42,872 --> 03:02:44,773
WE CAN SEE HERE IN THE GRAPH 

3744
03:02:44,773 --> 03:02:46,909
THAT BASICALLY WE HAVE TO 

3745
03:02:46,909 --> 03:02:50,145
DIFFERENTIATE THE LIVER CANCER 

3746
03:02:50,145 --> 03:02:54,483
GROUP, WHICH IS THE THREE PLOTS 

3747
03:02:54,483 --> 03:02:55,251
HERE VERSUS CONTROLS, AN 

3748
03:02:55,251 --> 03:02:59,321
INDIVIDUAL WHO H EPA TIZED B.

3749
03:02:59,321 --> 03:03:04,026
THE POLICY CURVE IS 0.98.

3750
03:03:04,026 --> 03:03:05,794
THAT IS SUPERIOR TO ANOTHER 

3751
03:03:05,794 --> 03:03:06,528
MOTIVE MEASUREMENT METHOD THAT 

3752
03:03:06,528 --> 03:03:08,397
WE PREVIOUSLY PUBLISHED IN 2020 

3753
03:03:08,397 --> 03:03:12,968
CALLED THE MOTIF DIVERSITY SCORE

3754
03:03:12,968 --> 03:03:17,006
IN WHICH THE ERROR CURVE IS 

3755
03:03:17,006 --> 03:03:17,206
0.86.

3756
03:03:17,206 --> 03:03:20,876
SO BASICALLY I THINK THAT THE 

3757
03:03:20,876 --> 03:03:21,510
FRAGMENT IS, THEREFORE, A LOW 

3758
03:03:21,510 --> 03:03:24,546
COST WAY IN WHICH WE CAN UNLOCK 

3759
03:03:24,546 --> 03:03:26,849
THE POWER OF THE PLASMA 

3760
03:03:26,849 --> 03:03:28,350
METHOMES.

3761
03:03:28,350 --> 03:03:30,152
BASICALLY ALL WE NEED IS CELL 

3762
03:03:30,152 --> 03:03:32,254
FREE DNA SEQUENCING RESULTS, AND

3763
03:03:32,254 --> 03:03:35,124
THEN FROM THAT WE CAN ALREADY 

3764
03:03:35,124 --> 03:03:38,327
DEDUCE THE METHYLOMIC STATUS OF 

3765
03:03:38,327 --> 03:03:38,727
THE SAMPLE.

3766
03:03:38,727 --> 03:03:42,097
I THINK THIS HAS MANY 

3767
03:03:42,097 --> 03:03:43,399
APPLICATIONS BOTH IN CANCER AND 

3768
03:03:43,399 --> 03:03:48,637
IN OTHER AREAS IN WHICH LIQUID 

3769
03:03:48,637 --> 03:03:49,738
BIOPSY HAS BEEN APPLIED.

3770
03:03:49,738 --> 03:03:54,576
SO UP UNTIL NOW WE'VE 

3771
03:03:54,576 --> 03:03:55,210
DEMONSTRATED SOME APPLICATIONS 

3772
03:03:55,210 --> 03:03:56,779
OF CELL FREE DNA GENOMICS, AND 

3773
03:03:56,779 --> 03:03:59,648
AS WE TALK ABOUT THE DNA ONE 

3774
03:03:59,648 --> 03:04:02,651
LIVE FREE, THE ROLE IT PLAYS IN 

3775
03:04:02,651 --> 03:04:03,085
THIS FRAGMENTATION.

3776
03:04:03,085 --> 03:04:05,721
WE'RE NOT VERY INTERESTED TO SEE

3777
03:04:05,721 --> 03:04:08,791
IF WE CAN ACTUALLY DEVELOP A 

3778
03:04:08,791 --> 03:04:11,694
GENERIC METHOD IN WHICH WE CAN 

3779
03:04:11,694 --> 03:04:12,461
EXPAND THE KNOWLEDGE OF CELL 

3780
03:04:12,461 --> 03:04:14,330
FREE DNA GENOMICS.

3781
03:04:14,330 --> 03:04:17,633
FOR EXAMPLE, HOW CAN WE DISCOVER

3782
03:04:17,633 --> 03:04:21,303
PREVIOUSLY A NON-FRAGMENTOMICS 

3783
03:04:21,303 --> 03:04:21,537
METHOD?

3784
03:04:21,537 --> 03:04:22,604
ONE METHOD THAT WE'VE BEEN 

3785
03:04:22,604 --> 03:04:23,839
INVESTIGATING RECENTLY IS THIS 

3786
03:04:23,839 --> 03:04:25,808
APPROACH BASED ON NON-NEGATIVE 

3787
03:04:25,808 --> 03:04:29,611
MATE RICKS VECTORIZATION.

3788
03:04:29,611 --> 03:04:31,213
BASICALLY IT'S AN APPROACH IN 

3789
03:04:31,213 --> 03:04:34,049
WHICH WE MATHEMATICALLY TRY TO 

3790
03:04:34,049 --> 03:04:37,987
DEDUCE COMPONENTS OF A 

3791
03:04:37,987 --> 03:04:38,554
PARTICULAR SYSTEM.

3792
03:04:38,554 --> 03:04:39,455
FOR EXAMPLE, WHICH HAS BEEN 

3793
03:04:39,455 --> 03:04:43,759
USED, FOR EXAMPLE, IN AUDIO 

3794
03:04:43,759 --> 03:04:44,059
ENGINEERING.

3795
03:04:44,059 --> 03:04:44,760
BASICALLY HERE WE HAVE THE 

3796
03:04:44,760 --> 03:04:47,830
SYSTEM IN WHICH WE LIKE TO FIND 

3797
03:04:47,830 --> 03:04:48,931
VARIOUS COMPONENTS AND THEN 

3798
03:04:48,931 --> 03:04:51,000
THROUGH THE NMF PROCESS WE CAN 

3799
03:04:51,000 --> 03:04:54,370
SPLIT THEM INTO THE COMPONENTS.

3800
03:04:54,370 --> 03:04:56,305
ONE ANALYSIS OF THIS WOULD BE, 

3801
03:04:56,305 --> 03:04:57,439
LIKE, YOU HAVE COLOR LIGHT, AND 

3802
03:04:57,439 --> 03:04:59,608
WHEN YOU PASS A LIGHT THROUGH A 

3803
03:04:59,608 --> 03:05:00,776
PRISM, THE PRISM WOULD THEN 

3804
03:05:00,776 --> 03:05:04,013
SPLIT IT INTO THE COMPONENT 

3805
03:05:04,013 --> 03:05:04,279
COLORS.

3806
03:05:04,279 --> 03:05:08,083
WHAT WE WOULD LIKE TO KNOW IS 

3807
03:05:08,083 --> 03:05:10,019
ABOUT WHERE WE CAN USE NMF TO 

3808
03:05:10,019 --> 03:05:11,553
LOOK AT THE DIFFERENT COMPONENTS

3809
03:05:11,553 --> 03:05:15,724
OF THE FRAGMENTATION PROFILES OF

3810
03:05:15,724 --> 03:05:17,426
CELL FREE DNA.

3811
03:05:17,426 --> 03:05:20,829
WE START THIS WITH MIRROR IN 

3812
03:05:20,829 --> 03:05:22,664
PLASMA IN WHICH WE HAVE WILD 

3813
03:05:22,664 --> 03:05:23,999
TYPE MICE AND MICE WITH 

3814
03:05:23,999 --> 03:05:27,436
DIFFERENT NUCLEUS KNOCK-OUT.

3815
03:05:27,436 --> 03:05:28,604
THEN BECAUSE WE ACTUALLY WANT 

3816
03:05:28,604 --> 03:05:35,044
THE SYSTEM TO HAVE A BIT MORE 

3817
03:05:35,044 --> 03:05:35,944
RESOLUTION, SO WE LOOK AT THREE,

3818
03:05:35,944 --> 03:05:38,747
BUT WE LOOK AT FOUR FOUR.

3819
03:05:38,747 --> 03:05:40,115
WE HAVE FOUR POSSIBILITIES, 

3820
03:05:40,115 --> 03:05:45,120
WHICH IS 256 DIFFERENT MOTIFS.

3821
03:05:45,120 --> 03:05:48,123
WHEN WE PASS THIS NMF APPROACH 

3822
03:05:48,123 --> 03:05:53,729
WE FIND ACTUALLY THAT THERE ARE 

3823
03:05:53,729 --> 03:05:55,397
SIX MOTIF PROGRAMS.

3824
03:05:55,397 --> 03:05:57,966
WE CALL THEM F PROGRAMS.

3825
03:05:57,966 --> 03:05:59,968
FOR THIS THE X AXIS IS THE 

3826
03:05:59,968 --> 03:06:02,571
DIFFERENT FORM OF MOTIF IN WHICH

3827
03:06:02,571 --> 03:06:05,040
WE ARRANGE FOR THEM IN DIFFERENT

3828
03:06:05,040 --> 03:06:05,274
ORDERS.

3829
03:06:05,274 --> 03:06:05,841
SO IN F ORDER.

3830
03:06:05,841 --> 03:06:08,077
AN A GROUP HERE, THE C GROUP 

3831
03:06:08,077 --> 03:06:14,483
HERE, AND G AND T.

3832
03:06:14,483 --> 03:06:15,884
THEN Y AXIS IS THE FREQUENCY OF 

3833
03:06:15,884 --> 03:06:16,285
DIFFERENT MOTIFS.

3834
03:06:16,285 --> 03:06:18,287
THIS IS PROFILE ONE, TWO, THREE,

3835
03:06:18,287 --> 03:06:20,889
AND THEN FOUR, FIVE, AND SIX.

3836
03:06:20,889 --> 03:06:22,658
YOU CAN SEE THAT THE BASIC ISSUE

3837
03:06:22,658 --> 03:06:25,394
OF THOSE PROFILES HAS RELATIVE 

3838
03:06:25,394 --> 03:06:29,765
DIFFERENT RELATIVE WEIGHTINGS OF

3839
03:06:29,765 --> 03:06:30,232
THE DIFFERENT COLORS.

3840
03:06:30,232 --> 03:06:33,135
FOR EXAMPLE, WE SEE PROFILE ONE.

3841
03:06:33,135 --> 03:06:37,606
IT IS PREPONDERANCE OF THIS 

3842
03:06:37,606 --> 03:06:38,240
WHICH IS CELL FREE FRAGMENTS 

3843
03:06:38,240 --> 03:06:39,274
WITH CN.

3844
03:06:39,274 --> 03:06:42,311
YOU CAN SEE HERE, FOR EXAMPLE, 

3845
03:06:42,311 --> 03:06:44,646
IN VIAL TWO THAT YOU HAVE A BIT 

3846
03:06:44,646 --> 03:06:46,582
MORE TN.

3847
03:06:46,582 --> 03:06:49,518
EACH PROFILE HAS A 

3848
03:06:49,518 --> 03:06:50,018
CHARACTERISTIC FEATURE.

3849
03:06:50,018 --> 03:06:51,687
THEN WE CAN ACTUALLY USE THIS 

3850
03:06:51,687 --> 03:06:53,355
APPROACH IN PLASMA, WHICH IS ON 

3851
03:06:53,355 --> 03:06:55,757
THE LEFT-HAND SIDE, AND THEN 

3852
03:06:55,757 --> 03:06:57,392
URINE ON THE RIGHT-HAND SIDE.

3853
03:06:57,392 --> 03:07:00,095
THEN DIFFERENT COLORS HERE ONCE 

3854
03:07:00,095 --> 03:07:01,563
AGAIN INDICATE THE DIFFERENT 

3855
03:07:01,563 --> 03:07:02,531
PROFILES, WHICH IS INDICATED IN 

3856
03:07:02,531 --> 03:07:04,299
THIS KEY.

3857
03:07:04,299 --> 03:07:04,800
SO ONE THROUGH SIX.

3858
03:07:04,800 --> 03:07:06,401
ONE THING WE CAN SEE, FOR 

3859
03:07:06,401 --> 03:07:08,770
EXAMPLE, IS THAT IF YOU LOOK AT 

3860
03:07:08,770 --> 03:07:12,307
THE WILD TYPE MICE, YOU LOOK AT 

3861
03:07:12,307 --> 03:07:13,509
PLASMA VERSUS URINE, IT'S THAT 

3862
03:07:13,509 --> 03:07:15,744
YOU CAN SEE THAT IN PLASMA 

3863
03:07:15,744 --> 03:07:17,813
THERE'S A LOT OF THIS RED 

3864
03:07:17,813 --> 03:07:19,548
SIGNAL, WHICH IN URINE IS 

3865
03:07:19,548 --> 03:07:19,848
SUPPRESSED.

3866
03:07:19,848 --> 03:07:22,151
BUT THEN IN REPLACEMENT, THEN WE

3867
03:07:22,151 --> 03:07:23,819
HAVE A LOT OF THIS YELLOW 

3868
03:07:23,819 --> 03:07:26,288
SIGNAL, WHICH IS PROFILE TWO.

3869
03:07:26,288 --> 03:07:29,224
BUT THEN INTERESTING WHEN YOU 

3870
03:07:29,224 --> 03:07:31,126
LOOK AT THE URINE, YOU CAN FIND 

3871
03:07:31,126 --> 03:07:34,129
IF WE KNOCK OUT THE DNA1 GENE, 

3872
03:07:34,129 --> 03:07:35,397
THEN THIS YELLOW SIGNAL 

3873
03:07:35,397 --> 03:07:36,498
DIMINISHES A LOT.

3874
03:07:36,498 --> 03:07:39,735
SO FROM THIS WORK THAT WE CAN 

3875
03:07:39,735 --> 03:07:40,836
CONCLUDE THAT ACTUALLY THIS 

3876
03:07:40,836 --> 03:07:44,573
PROFILE TOO IS RELATED TO DNA'S 

3877
03:07:44,573 --> 03:07:44,873
1 ACTIVITY.

3878
03:07:44,873 --> 03:07:46,141
NOW LOOK BACK TO THE LEFT-HAND 

3879
03:07:46,141 --> 03:07:48,243
SIDE IN THE PLASMA.

3880
03:07:48,243 --> 03:07:50,646
AGAIN, SEE THAT THE RED SIGNAL 

3881
03:07:50,646 --> 03:07:52,414
PREPONDERANCE IN WILD TYPE 

3882
03:07:52,414 --> 03:07:55,150
PLASMA, BUT WHEN WE KNOCK OUT 

3883
03:07:55,150 --> 03:07:57,586
DNA1 LIVE FREE GENE, IT'S RESTED

3884
03:07:57,586 --> 03:07:57,953
GREATLY.

3885
03:07:57,953 --> 03:08:01,023
BY DOING THIS, THEN WE CAN 

3886
03:08:01,023 --> 03:08:03,525
ACTUALLY ENTER THIS PROFILE 1 TO

3887
03:08:03,525 --> 03:08:06,728
DNA'S 1 LIVE FREE.

3888
03:08:06,728 --> 03:08:08,297
NOW WE'LL LOOK AT MORE DETAIL 

3889
03:08:08,297 --> 03:08:08,730
HERE.

3890
03:08:08,730 --> 03:08:10,132
YOU CAN SEE THIS PROFILE 1 WITH 

3891
03:08:10,132 --> 03:08:12,801
A LOT OF THE RED SIGNAL.

3892
03:08:12,801 --> 03:08:14,336
NORMALLY IF YOU LOOK AT WILD 

3893
03:08:14,336 --> 03:08:19,575
TYPE MICE, THIS RED SIGNAL 

3894
03:08:19,575 --> 03:08:21,610
REPRESENTS ABOUT 35% OF THE 

3895
03:08:21,610 --> 03:08:22,644
PLASMA DNA.

3896
03:08:22,644 --> 03:08:25,781
THEN IF WE KNOCK OUT THE 1 LIVE 

3897
03:08:25,781 --> 03:08:27,449
DNA GENE, THIS IS GOES TO LESS 

3898
03:08:27,449 --> 03:08:29,484
THAN 5%.

3899
03:08:29,484 --> 03:08:32,321
SO BY USING THIS APPROACH, THEN 

3900
03:08:32,321 --> 03:08:34,189
WE ACTUALLY CAN ENTER PROFILE 1 

3901
03:08:34,189 --> 03:08:36,091
INTO DNA1 LIVE FREE.

3902
03:08:36,091 --> 03:08:39,428
PROFILE 2 TO DNA1, AND PREFILE 3

3903
03:08:39,428 --> 03:08:40,862
TO THE NUCLEUS CALLED THE FFB, 

3904
03:08:40,862 --> 03:08:44,833
WHICH IS DNA'S FRAGMENTATION 

3905
03:08:44,833 --> 03:08:45,234
FACTOR BETA.

3906
03:08:45,234 --> 03:08:49,037
BUT CURRENTLY WE HAVE NO IDEA 

3907
03:08:49,037 --> 03:08:51,139
WHAT DOES 4, 5, AND 6 DO JUST 

3908
03:08:51,139 --> 03:08:53,375
YET, BUT WE ARE PROCEEDING WITH 

3909
03:08:53,375 --> 03:08:55,611
THE WORK TO ILLUCIDATE THEM.

3910
03:08:55,611 --> 03:09:00,616
THAT SAID, EVEN WITH OUR FULL 

3911
03:09:00,616 --> 03:09:01,316
CHARACTERIZATION OF THE 

3912
03:09:01,316 --> 03:09:03,785
GENERATING 4, 5, AND 6, WE CAN 

3913
03:09:03,785 --> 03:09:06,255
ACTUALLY STILL USE THIS VARIOUS 

3914
03:09:06,255 --> 03:09:07,356
PROFILE AS POTENTIAL TO MARKERS.

3915
03:09:07,356 --> 03:09:09,491
FOR EXAMPLE, YOU CAN LOOK AT THE

3916
03:09:09,491 --> 03:09:11,994
RELATIVE AMOUNT OF THOSE 

3917
03:09:11,994 --> 03:09:13,362
PROFILES IN RELATION TO, FOR 

3918
03:09:13,362 --> 03:09:23,905
EXAMPLE, DETECTING HEPA ITCYLUS 

3919
03:09:24,873 --> 03:09:25,073
CANCER.

3920
03:09:25,073 --> 03:09:28,210
INTERESTING ACTIVE PROFILE 6 

3921
03:09:28,210 --> 03:09:29,778
LOOKS REMARKABLY GOOD WITH THIS 

3922
03:09:29,778 --> 03:09:33,982
PINK LINE HERE WITH THE AREA AT 

3923
03:09:33,982 --> 03:09:34,316
0.97.

3924
03:09:34,316 --> 03:09:37,486
SO NOW WHEN YOU LOOK AT CONTROL 

3925
03:09:37,486 --> 03:09:39,187
INDIVIDUALS, PEOPLE WITH CHRONIC

3926
03:09:39,187 --> 03:09:45,527
HEPATITIS AND PEOPLE WITH HEPATO

3927
03:09:45,527 --> 03:09:47,162
CANCER, CAN YOU SEE THE DEGREE 

3928
03:09:47,162 --> 03:09:49,898
IN THE REPRESENTATION OF PROFILE

3929
03:09:49,898 --> 03:09:50,032
6.

3930
03:09:50,032 --> 03:09:52,601
APART FROM HEPA CANCER WE 

3931
03:09:52,601 --> 03:09:54,102
DECIDED TO LOOK AT COLORECTAL 

3932
03:09:54,102 --> 03:09:54,369
CANCER.

3933
03:09:54,369 --> 03:09:56,371
YOU CAN SEE THAT THERE'S A 

3934
03:09:56,371 --> 03:09:58,674
CONTROL AND COLORECTAL CANCER 

3935
03:09:58,674 --> 03:09:59,875
PATIENTS WITHOUT LIVER 

3936
03:09:59,875 --> 03:10:03,312
METASTASIS TO COLORECTAL CANCER 

3937
03:10:03,312 --> 03:10:06,648
PATIENTS WITH LIVER METASTASIS 

3938
03:10:06,648 --> 03:10:09,284
THERE'S A GRADUAL -- 

3939
03:10:09,284 --> 03:10:10,352
WE DECIDED TO TAKE A LOOK IN 

3940
03:10:10,352 --> 03:10:12,387
MORE DETAIL IN PROFILE 6, AND 

3941
03:10:12,387 --> 03:10:18,193
YOU CAN SEE THAT PROFILE 6 HAS 

3942
03:10:18,193 --> 03:10:21,463
THIS RATHER INTERESTING 

3943
03:10:21,463 --> 03:10:23,832
PHENOMENON IN WHICH THERE IS A, 

3944
03:10:23,832 --> 03:10:27,135
E, C, G, N, T.

3945
03:10:27,135 --> 03:10:37,679
IT WORKS IN KNOCKING OUT THE -- 

3946
03:10:43,719 --> 03:10:45,120
THIS ONE GOES WITH T.

3947
03:10:45,120 --> 03:10:46,421
INTERESTING FOR PROFILE 6 WE 

3948
03:10:46,421 --> 03:10:47,923
DON'T HAVE THAT PREFERENCE.

3949
03:10:47,923 --> 03:10:50,359
SO WE STARTED TO WONDER, IS IT 

3950
03:10:50,359 --> 03:10:52,861
POSSIBLE THERE IS ACTUALLY A 

3951
03:10:52,861 --> 03:10:54,129
NONENZYMATIC PROCESS?

3952
03:10:54,129 --> 03:10:57,632
WE WONDER WHETHER IT COULD BE 

3953
03:10:57,632 --> 03:10:59,301
RELATED TO SOME PHYSICAL 

3954
03:10:59,301 --> 03:11:01,737
MECHANISMS, WHICH BREAK UP THE 

3955
03:11:01,737 --> 03:11:05,907
DNA, FOR EXAMPLE, LIKE RADIATION

3956
03:11:05,907 --> 03:11:08,110
OR REACTIVE SPECIES.

3957
03:11:08,110 --> 03:11:10,278
IN ORDER TO TEST THAT HYPOTHESIS

3958
03:11:10,278 --> 03:11:12,414
WE WILL LOOK AT CANCER PATIENTS 

3959
03:11:12,414 --> 03:11:14,082
UNDERGOING CHEMO RADIOTHERAPY 

3960
03:11:14,082 --> 03:11:15,917
AND YOU CAN SEE THAT, FOR 

3961
03:11:15,917 --> 03:11:18,487
EXAMPLE, BEFORE AND AFTER 

3962
03:11:18,487 --> 03:11:18,954
THERE'S AN INCREASING 

3963
03:11:18,954 --> 03:11:21,656
CONTRIBUTION TO PROFILE 6.

3964
03:11:21,656 --> 03:11:23,558
BASICALLY BEFORE CHEMO 

3965
03:11:23,558 --> 03:11:24,493
RADIOTHERAPY PROFILE 6 

3966
03:11:24,493 --> 03:11:26,027
REPRESENTS ABOUT 6% OF THE 

3967
03:11:26,027 --> 03:11:30,866
PLASMA DNA PROFILE, WHICH GOES 

3968
03:11:30,866 --> 03:11:32,801
TO 10% AFTER THIS PROCESS.

3969
03:11:32,801 --> 03:11:37,572
I THINK THAT WE SHOULD LOOK AT 

3970
03:11:37,572 --> 03:11:38,673
MORE CLINICAL SITUATIONS IN 

3971
03:11:38,673 --> 03:11:41,910
WHICH THERE'S AN INCREASE IN 

3972
03:11:41,910 --> 03:11:44,279
THOSE PHYSICAL PHENOMENON OF THE

3973
03:11:44,279 --> 03:11:46,314
SPECIES WITH RADIATION DAMAGE TO

3974
03:11:46,314 --> 03:11:49,751
FULL CONSOLIDATE THIS WORK.

3975
03:11:49,751 --> 03:11:51,920
SO IN SUMMARY, WE HAVE BEEN 

3976
03:11:51,920 --> 03:11:53,688
INTERESTED IN LOOKING AT THE 

3977
03:11:53,688 --> 03:11:56,458
RELATIONSHIP BETWEEN CELL FREE 

3978
03:11:56,458 --> 03:11:58,059
DNA AND FRAGMENTOMICS.

3979
03:11:58,059 --> 03:12:00,095
WE FIND THERE IS DEFINITELY A 

3980
03:12:00,095 --> 03:12:00,762
LINK, AND THROUGH THAT LINK WE 

3981
03:12:00,762 --> 03:12:02,664
HAVE ACTUALLY INVENTED THIS 

3982
03:12:02,664 --> 03:12:05,500
FRAGMENT CONCEPT, WHICH IS A 

3983
03:12:05,500 --> 03:12:06,701
RELATIVELY LOW COST WAY TO 

3984
03:12:06,701 --> 03:12:09,704
ACTUALLY LOOK AT CELL FREE DNA 

3985
03:12:09,704 --> 03:12:10,038
ANALYSIS.

3986
03:12:10,038 --> 03:12:14,443
BASICALLY OPENING THE POWER OF 

3987
03:12:14,443 --> 03:12:16,278
THE LEVEL TO DO ANY DNA 

3988
03:12:16,278 --> 03:12:17,279
SEQUENCING HERE.

3989
03:12:17,279 --> 03:12:25,220
THEN WE ALSO EXPLORE THE USE OF 

3990
03:12:25,220 --> 03:12:28,323
THE CONVOLUNTARTION OF OTHERS U 

3991
03:12:28,323 --> 03:12:30,659
THE FRAGMENTATION THAT WE'LL 

3992
03:12:30,659 --> 03:12:31,460
PURSUE IN THE COMING YEARS.

3993
03:12:31,460 --> 03:12:32,627
FINALLY, I WOULD LIKE TO THANK 

3994
03:12:32,627 --> 03:12:34,095
OUR GROUP FOR GENERATING THE 

3995
03:12:34,095 --> 03:12:35,764
DATA WHICH I PRESENTED TO YOU 

3996
03:12:35,764 --> 03:12:38,667
TODAY.

3997
03:12:38,667 --> 03:12:40,735
THANK YOU VERY MUCH FOR YOUR 

3998
03:12:40,735 --> 03:12:49,377
TIM

3999
03:12:49,377 --> 03:12:49,578
TIME.

4000
03:12:49,578 --> 03:12:50,345
>>  THAT CONCLUDES THIS
SESSION.

4001
03:12:50,345 --> 03:12:53,849
I WANT TO THANK ALL THE 

4002
03:12:53,849 --> 03:12:54,916
SPEAKERS, INCLUDING PETER.

4003
03:12:54,916 --> 03:12:57,252
I THINK IT'S GOING TO BE LUNCH 

4004
03:12:57,252 --> 03:13:04,091
BREAK.

4005
03:13:04,091 --> 03:13:06,093
I HOPE YOU ALL HAD A NICE 

4006
03:13:06,093 --> 03:13:06,293
LUNCH.

4007
03:13:06,293 --> 03:13:09,596
THE NEXT SESSION WILL BE ON 

4008
03:13:09,596 --> 03:13:20,341
SYSTEMIC IMPACTS OF HHEPAGENICS.

4009
03:13:25,746 --> 03:13:30,584
OUR FIRST SPEAKER IS EVA 

4010
03:13:30,584 --> 03:13:30,951
HERNANDO-MONGE.

4011
03:13:30,951 --> 03:13:33,754
>>  IT'S A PLEASURE TO BE
HERE 

4012
03:13:33,754 --> 03:13:38,892
WITH ALL THE PIONEERS IN THIS 

4013
03:13:38,892 --> 03:13:39,960
FIELD.

4014
03:13:39,960 --> 03:13:41,762
I'M VERY GRATEFUL TO BE HERE.

4015
03:13:41,762 --> 03:13:43,297
I'M GOING TO PRESENT THE 

4016
03:13:43,297 --> 03:13:48,168
STUDY -- LET'S SEE HOW I DO 

4017
03:13:48,168 --> 03:13:48,369
THIS.

4018
03:13:48,369 --> 03:13:49,636
THIS IS THE STUDY THAT IS ARE 

4019
03:13:49,636 --> 03:13:56,176
UNPUBLISHED AND IS THE WORK OF 

4020
03:13:56,176 --> 03:13:56,910
MY LAB.

4021
03:13:56,910 --> 03:13:58,145
IT'S, IN PART, A COLLABORATION 

4022
03:13:58,145 --> 03:13:59,580
WITH A PROFESSOR IN MY 

4023
03:13:59,580 --> 03:14:01,181
DEPARTMENT AND A LONG-TERM 

4024
03:14:01,181 --> 03:14:05,619
COLLABORATOR AND FRIEND, JAMES 

4025
03:14:05,619 --> 03:14:06,854
COOK, AND ASSISTANT PROFESSOR 

4026
03:14:06,854 --> 03:14:07,154
K

4027
03:14:07,154 --> 03:14:08,088
KATHLEEN DOLE IN HER LAB.

4028
03:14:08,088 --> 03:14:10,557
WE WERE ASKED IN PREPARING THIS 

4029
03:14:10,557 --> 03:14:12,326
TALK TO PRESENT ON HOW THE FIELD

4030
03:14:12,326 --> 03:14:15,028
OF CANCER GENETICS HAS AFFECTED 

4031
03:14:15,028 --> 03:14:18,365
OUR PARTICULAR PROGRAMS AND OUR 

4032
03:14:18,365 --> 03:14:19,199
PARTICULAR QUESTIONS.

4033
03:14:19,199 --> 03:14:22,102
I THOUGHT OF THE COVER OF THE 

4034
03:14:22,102 --> 03:14:22,936
MAGAZINE "TIME" AND THE TITLE 

4035
03:14:22,936 --> 03:14:27,641
WAS "WHY YOUR DNA ISN'T YOUR 

4036
03:14:27,641 --> 03:14:28,442
DESTINY."  

4037
03:14:28,442 --> 03:14:30,411
I THINK THIS REFLECTS EXACTLY 

4038
03:14:30,411 --> 03:14:33,747
WHAT IS THE CASE FOR OUR 

4039
03:14:33,747 --> 03:14:34,848
STUDIES, WHICH ARE FOCUSED ON --

4040
03:14:34,848 --> 03:14:36,450
OR MY PARTICULAR FIELD, WHICH IS

4041
03:14:36,450 --> 03:14:40,654
THE FIELD OF CANCER METASTASIS.

4042
03:14:40,654 --> 03:14:45,759
WE USED THE GENOMA AS A MODEL OF

4043
03:14:45,759 --> 03:14:46,994
METASTASIS BECAUSE THESE TUMORS 

4044
03:14:46,994 --> 03:14:50,531
CAN GO ON AND METASTASIZE IN 

4045
03:14:50,531 --> 03:14:51,331
DIFFERENT ORGANS.

4046
03:14:51,331 --> 03:14:53,600
WHAT IS REALLY INTERESTING ABOUT

4047
03:14:53,600 --> 03:14:55,002
THESE TUMORS IS THAT TWO 

4048
03:14:55,002 --> 03:14:56,437
PATIENTS THAT CARRIED TUMORS 

4049
03:14:56,437 --> 03:14:58,405
THAT HAVE THE SAME CLINICAL 

4050
03:14:58,405 --> 03:15:01,842
BIOLOGICAL CHARACTERISTICS AND 

4051
03:15:01,842 --> 03:15:05,913
EVEN THE SAME GENETIC MAKEUP CAN

4052
03:15:05,913 --> 03:15:06,480
HAVE COMPLETELY DIFFERENT 

4053
03:15:06,480 --> 03:15:08,449
OUTCOMES WITH A PATIENT THAT CAN

4054
03:15:08,449 --> 03:15:10,484
BE CURED AFTER RECESSION.

4055
03:15:10,484 --> 03:15:13,387
IN ANOTHER PATIENT THAT WILL 

4056
03:15:13,387 --> 03:15:17,057
HAVE RECURRENCE IN METASTASIS 

4057
03:15:17,057 --> 03:15:17,991
POST-RESECTION.

4058
03:15:17,991 --> 03:15:19,460
AGAIN, THE GENETIC ALTERATIONS 

4059
03:15:19,460 --> 03:15:22,696
OR COMBIN AINGS OF GENETIC 

4060
03:15:22,696 --> 03:15:24,531
CHARACTERIST HEICS OF THE 

4061
03:15:24,531 --> 03:15:26,033
TUMORS, WHICH HAVE BEEN 

4062
03:15:26,033 --> 03:15:27,568
EXTENSIVELY CHARACTERIZED IN THE

4063
03:15:27,568 --> 03:15:31,371
CASE OF MELANOMA CANNOT PREDICT 

4064
03:15:31,371 --> 03:15:33,340
WHICH PATIENTS WILL REOCCUR AND 

4065
03:15:33,340 --> 03:15:34,174
METASTASIZE.

4066
03:15:34,174 --> 03:15:36,443
MY LAB HAS TURNED INTO EXAMINING

4067
03:15:36,443 --> 03:15:39,112
NON-GENETIC MECHANISMS AS 

4068
03:15:39,112 --> 03:15:42,082
POTENTIAL DRIVERS OF METASTATIC 

4069
03:15:42,082 --> 03:15:42,449
BEHAVIOR.

4070
03:15:42,449 --> 03:15:44,718
IN PARTICULAR, OVER THE PAST FEW

4071
03:15:44,718 --> 03:15:48,555
YEARS OUR LAB AND OTHERS HAVE 

4072
03:15:48,555 --> 03:15:49,189
FOCUSED ATTENTION OF THESE 

4073
03:15:49,189 --> 03:15:52,893
INTERESTING FINDINGS, WHICH IS 

4074
03:15:52,893 --> 03:15:56,930
THE PRESENCE OF INTERTUMOR 

4075
03:15:56,930 --> 03:15:57,297
HETEROGENEITY.

4076
03:15:57,297 --> 03:15:58,999
OUR SIMILAR STATES PRODUCE 

4077
03:15:58,999 --> 03:16:00,634
CANCER CELLS WITH A LOT OF 

4078
03:16:00,634 --> 03:16:01,368
ADVANTAGES.

4079
03:16:01,368 --> 03:16:03,036
STILL, HOWEVER, IT ISN'T CLEAR 

4080
03:16:03,036 --> 03:16:09,076
HOW THIS INTERTUMOR 

4081
03:16:09,076 --> 03:16:11,678
HETEROGENEITY IS CURED.

4082
03:16:11,678 --> 03:16:13,180
TO REMIND YOU ALL WE MUST 

4083
03:16:13,180 --> 03:16:15,616
ORIGINATE FROM THE PIGMENTED 

4084
03:16:15,616 --> 03:16:17,484
CELLS IN THE SKIN AS A 

4085
03:16:17,484 --> 03:16:21,421
CONSEQUENCE OF UV RADIATION, AND

4086
03:16:21,421 --> 03:16:22,589
IMMEDIATELY AT THOSE VERY AREAS 

4087
03:16:22,589 --> 03:16:25,058
TUMOR REGENESIS, ONE CAN 

4088
03:16:25,058 --> 03:16:26,159
APPRECIATE ALREADY THE PRESENCE 

4089
03:16:26,159 --> 03:16:29,763
OF THESE INTERTUMOR 

4090
03:16:29,763 --> 03:16:30,998
HETEROGENEITY AND 

4091
03:16:30,998 --> 03:16:32,866
CHARACTERISTICS MORE PIGMENTED 

4092
03:16:32,866 --> 03:16:35,903
AND DIFFERENTIATED AND ALSO SOME

4093
03:16:35,903 --> 03:16:40,607
OTHER POPULATIONS THAT, FOR 

4094
03:16:40,607 --> 03:16:41,875
EXAMPLE, ARE MORE -- 

4095
03:16:41,875 --> 03:16:42,175
POPULATIONS.

4096
03:16:42,175 --> 03:16:43,410
ONE CAN BE MORE GRANULAR AND 

4097
03:16:43,410 --> 03:16:45,913
IDENTIFY IN OTHER STATES, BUT 

4098
03:16:45,913 --> 03:16:46,880
FOR THE PURPOSE OF THIS TALK, I 

4099
03:16:46,880 --> 03:16:48,248
WILL BE TALKING ABOUT THESE TWO 

4100
03:16:48,248 --> 03:16:53,120
EXTREMES, THE MELANOCYTIC OR H 

4101
03:16:53,120 --> 03:16:57,190
EPA STATIC POPULATION.

4102
03:16:57,190 --> 03:16:58,058
THERE'S A POPULATION THAT WE 

4103
03:16:58,058 --> 03:17:01,228
CONSIDER INTERMEDIATE.

4104
03:17:01,228 --> 03:17:02,796
THESE CELLULAR STATES HAVE BEEN 

4105
03:17:02,796 --> 03:17:05,265
SEEN TO BE EXTREMELY PLASTIC.

4106
03:17:05,265 --> 03:17:06,867
CELLS CAN NAVIGATE OR CAN GO 

4107
03:17:06,867 --> 03:17:08,569
BACK AND FORTH FROM THESE 

4108
03:17:08,569 --> 03:17:10,304
DIFFERENT CELLULAR STATES.

4109
03:17:10,304 --> 03:17:11,071
TWO TRANSCRIPTION FACTORS HAVE 

4110
03:17:11,071 --> 03:17:13,574
BEEN SHOWN TO PLAY A VERY 

4111
03:17:13,574 --> 03:17:14,141
IMPORTANT ROLE IN THE 

4112
03:17:14,141 --> 03:17:16,343
PREPARATION FROM ONE STATE TO 

4113
03:17:16,343 --> 03:17:16,610
ANOTHER.

4114
03:17:16,610 --> 03:17:17,844
ONE IS THE SAME IDEA, WHICH IS 

4115
03:17:17,844 --> 03:17:22,382
THE MASTER REGULATOR OF 

4116
03:17:22,382 --> 03:17:23,517
MELANOMACYTE REGULATION, AND THE

4117
03:17:23,517 --> 03:17:26,987
OTHER ONE WHICH ARE IN CONTROL 

4118
03:17:26,987 --> 03:17:29,389
OF THE BASIC PHENOTYPE.

4119
03:17:29,389 --> 03:17:30,991
THE INTERCONVERSION BETWEEN THE 

4120
03:17:30,991 --> 03:17:32,292
CELLULAR STATES, WHICH IS VERY 

4121
03:17:32,292 --> 03:17:33,460
PLASTIC, VERY DYNAMIC, IS 

4122
03:17:33,460 --> 03:17:34,828
CONTROLLED BY INTERACTIONS 

4123
03:17:34,828 --> 03:17:38,198
BETWEEN THE TUMOR CELLS AND THE 

4124
03:17:38,198 --> 03:17:38,599
MICROENVIRONMENTS.

4125
03:17:38,599 --> 03:17:40,100
ONE OF THE CUE CENTERS FOR THE 

4126
03:17:40,100 --> 03:17:41,234
STIMULI FOR THESE CONVERSIONS 

4127
03:17:41,234 --> 03:17:43,737
CAN FROM THE INTERACTIONS 

4128
03:17:43,737 --> 03:17:46,306
BETWEEN THE CANCER CELLS AND THE

4129
03:17:46,306 --> 03:17:47,140
STROMA AS WELL AS THE 

4130
03:17:47,140 --> 03:17:49,810
INTERABBINGS WITH THE 

4131
03:17:49,810 --> 03:17:50,911
IMMUNO-CELLS, AND IN SOME CASES 

4132
03:17:50,911 --> 03:17:52,479
THERAPY CAN BE A STRONG 

4133
03:17:52,479 --> 03:17:56,917
REGULATOR OF THESE TRANSITIONS.

4134
03:17:56,917 --> 03:17:57,884
WE ARE ASKING HOW IS THIS 

4135
03:17:57,884 --> 03:18:01,822
INTERTUMOR HETERGENEITY 

4136
03:18:01,822 --> 03:18:02,089
PUBLISHED.

4137
03:18:02,089 --> 03:18:06,994
IN PARTICULAR, TODAY'S TALK I'M 

4138
03:18:06,994 --> 03:18:08,428
GOING TO FOCUS ON THE 

4139
03:18:08,428 --> 03:18:10,263
TRANSCRIPTIONAL PROGRAMS 

4140
03:18:10,263 --> 03:18:14,301
DOWNSTREAM OF THESE CHANGES IN 

4141
03:18:14,301 --> 03:18:14,735
CONFIRMATION.

4142
03:18:14,735 --> 03:18:18,472
WITH THE STUDY WE DECIDED TO 

4143
03:18:18,472 --> 03:18:20,741
CHARACTERIZE BY THE THREE 

4144
03:18:20,741 --> 03:18:23,010
CHROMATIC CONFIRMATION OF THREE 

4145
03:18:23,010 --> 03:18:25,512
TYPES OF MELANOMA CELL LINES.

4146
03:18:25,512 --> 03:18:28,382
ALTHOUGH I TOLD YOU THAT TUMORS 

4147
03:18:28,382 --> 03:18:32,152
ARE VERY HETEROGENEROUS, AND 

4148
03:18:32,152 --> 03:18:32,753
THEY HAVE DIFFERENT STATES.

4149
03:18:32,753 --> 03:18:33,920
WHEN CELL LINES ARE ESTABLISHED 

4150
03:18:33,920 --> 03:18:35,522
FROM THESE TUMORS, THEY ACQUIRE 

4151
03:18:35,522 --> 03:18:36,990
VERY OFTEN FEATURES OF THE 

4152
03:18:36,990 --> 03:18:37,391
DIFFERENT STATES.

4153
03:18:37,391 --> 03:18:41,161
SO THERE ARE CELL LINES THAT ARE

4154
03:18:41,161 --> 03:18:44,531
MORE REPRESENTATIVE OF THE 

4155
03:18:44,531 --> 03:18:45,666
MELANOCYTIC STATE.

4156
03:18:45,666 --> 03:18:49,302
WE CHARACTERIZE THREE OF THESE 

4157
03:18:49,302 --> 03:18:52,606
TYPES, OR STATES, BUT WE ALSO 

4158
03:18:52,606 --> 03:18:56,476
TOOK THE 501 CELL, WHICH IS A 

4159
03:18:56,476 --> 03:18:57,310
MELANOCYTIC CELL LINE AND THE 

4160
03:18:57,310 --> 03:18:59,079
TRANSCRIPTION FACTOR IN ITF IN 

4161
03:18:59,079 --> 03:19:00,981
ORDER TO SEE WHAT WOULD BE THE 

4162
03:19:00,981 --> 03:19:02,883
IMPACT OF TARGETING OR SILENCING

4163
03:19:02,883 --> 03:19:06,620
THESE MASTER REGULATOR OF THE 

4164
03:19:06,620 --> 03:19:08,488
DIFFERENTIATED IMMUNOCYTIC 

4165
03:19:08,488 --> 03:19:08,755
PHENOTYPE.

4166
03:19:08,755 --> 03:19:09,656
WOULD IT BE POSSIBLE THAT A CELL

4167
03:19:09,656 --> 03:19:15,062
THAT IS MORE MELANOCYTIC WOULD 

4168
03:19:15,062 --> 03:19:18,398
BE MORE FROM THE PERSPECTIVE OF 

4169
03:19:18,398 --> 03:19:21,601
THE CHROMATINE.

4170
03:19:21,601 --> 03:19:27,007
THE FIRST ANALYSIS AT THE VERY 

4171
03:19:27,007 --> 03:19:28,341
HIGH -- AT THE VERY HIGH PART 

4172
03:19:28,341 --> 03:19:30,210
THAT I MENTIONED SHOWS THAT IN 

4173
03:19:30,210 --> 03:19:32,012
THE CONVERSION BETWEEN 

4174
03:19:32,012 --> 03:19:35,215
INTERMEDIATE TO MELANOCYTIC, ONE

4175
03:19:35,215 --> 03:19:38,618
CAN SEE THAT THERE IS AN 

4176
03:19:38,618 --> 03:19:40,387
INCREASE IN THE NUMBER OF 

4177
03:19:40,387 --> 03:19:40,954
INTERACTIONS.

4178
03:19:40,954 --> 03:19:43,824
THIS IS PERCEIVED HERE WITH THIS

4179
03:19:43,824 --> 03:19:45,826
RED SIGNAL.

4180
03:19:45,826 --> 03:19:48,228
IN THE TRANSITION BETWEEN 

4181
03:19:48,228 --> 03:19:52,099
INTERMEDIATE TUMORS ONE CAN SEE 

4182
03:19:52,099 --> 03:19:53,400
THAT THERE ARE NOW MORE INTACT 

4183
03:19:53,400 --> 03:19:53,734
INTERACTIONS.

4184
03:19:53,734 --> 03:19:54,534
THIS IS DEPICTED IN THIS CARTOON

4185
03:19:54,534 --> 03:19:58,038
WHERE YOU CAN SEE THAT, AGAIN, 

4186
03:19:58,038 --> 03:19:59,806
THERE ARE AN INCREASE INITIALLY 

4187
03:19:59,806 --> 03:20:02,275
OF THE INTRUKS AND THEN 

4188
03:20:02,275 --> 03:20:03,543
INCREASED OF THESE MORE 

4189
03:20:03,543 --> 03:20:05,846
LONG-RANGING INTERABBINGS.

4190
03:20:05,846 --> 03:20:08,081
WE ARE STARTING TO WONDER WHAT 

4191
03:20:08,081 --> 03:20:11,351
IS THE IMPACT OF THIS EFFECT?

4192
03:20:11,351 --> 03:20:13,720
FIRST OF ALL, WE SEE THAT THE 

4193
03:20:13,720 --> 03:20:17,791
MISSING KYMA CELLS HAVE AN 

4194
03:20:17,791 --> 03:20:18,592
ADVANTAGE WHICH IS CONSISTENT 

4195
03:20:18,592 --> 03:20:22,329
WITH INTERTARGETED INTERACTION, 

4196
03:20:22,329 --> 03:20:22,963
WHEREAS THERE'S NO CHANGE WHEN 

4197
03:20:22,963 --> 03:20:23,630
WE COMPARED THE INTERMEDIATE TO 

4198
03:20:23,630 --> 03:20:25,966
THE MELANOCYTIC.

4199
03:20:25,966 --> 03:20:29,936
IF WE ZOOM IN IN THIS PARTICULAR

4200
03:20:29,936 --> 03:20:33,140
CASE, ONE CAN SEE THAT INITIALLY

4201
03:20:33,140 --> 03:20:38,812
IN THE GENOCYTIC, ONE CAN SEE 

4202
03:20:38,812 --> 03:20:39,379
THAT THERE ARE SHORT LOOPS.

4203
03:20:39,379 --> 03:20:43,049
IT'S CHARACTERISTIC OF THIS, AND

4204
03:20:43,049 --> 03:20:46,553
THEY LOCALIZE.

4205
03:20:46,553 --> 03:20:50,490
THEN AS YOU MOVE TO THE CHYME 

4206
03:20:50,490 --> 03:20:52,859
STATE, ONE CAN SEE HOW THIS 

4207
03:20:52,859 --> 03:20:54,127
DISAPPEARS AND STARTS TO FADE.

4208
03:20:54,127 --> 03:20:57,197
ONE CAN SEE NOW THE INCREASE OF 

4209
03:20:57,197 --> 03:21:01,968
THIS MORE LONG-RANGE 

4210
03:21:01,968 --> 03:21:02,302
INTERACTIONS.

4211
03:21:02,302 --> 03:21:05,305
NOW, IF WE ANALYZE THE 

4212
03:21:05,305 --> 03:21:07,007
COMPARTMENTS AND, AGAIN, TO 

4213
03:21:07,007 --> 03:21:08,375
REMIND US ALL COMPARTMENT A IS 

4214
03:21:08,375 --> 03:21:10,343
THE ONE THAT HAS MORE ACTIVE 

4215
03:21:10,343 --> 03:21:15,448
TRANSCRIPTION AND IT HAS MORE 

4216
03:21:15,448 --> 03:21:18,552
PRESENCE OF ACYTL, WHICH 

4217
03:21:18,552 --> 03:21:19,786
COMPARTMENT B IS ONE THAT IS 

4218
03:21:19,786 --> 03:21:20,053
INACTIVE.

4219
03:21:20,053 --> 03:21:23,290
ONE CAN SEE WHEN WE COMPARE THE 

4220
03:21:23,290 --> 03:21:25,325
DIFFERENT STATES, THERE ARE 

4221
03:21:25,325 --> 03:21:25,926
SIGNIFICANT CHANGES IN THIS 

4222
03:21:25,926 --> 03:21:26,226
COMPARTMENT.

4223
03:21:26,226 --> 03:21:29,296
FOR INSTANCE, I WANT TO CALL 

4224
03:21:29,296 --> 03:21:33,200
YOUR ATTENTION TO THE COMPARISON

4225
03:21:33,200 --> 03:21:35,001
BETWEEN THE -- ONE CAN SEE THAT 

4226
03:21:35,001 --> 03:21:40,106
THERE IS A REGION HERE THAT IS 

4227
03:21:40,106 --> 03:21:41,808
COMPLETELY COMPARTMENT E HERE ON

4228
03:21:41,808 --> 03:21:45,478
THE UPPER PART THAT BECOMES NOW 

4229
03:21:45,478 --> 03:21:47,714
LESS REPRESSED OR MORE ACTIVE IN

4230
03:21:47,714 --> 03:21:49,816
THE MISSING CHYMAL CELLS.

4231
03:21:49,816 --> 03:21:51,518
THIS IS CHROMOSOME ONE.

4232
03:21:51,518 --> 03:21:53,854
ONE CAN GO CHROMOSOME BY 

4233
03:21:53,854 --> 03:21:54,721
CHROMOSOME IDENTIFYING CHANGES 

4234
03:21:54,721 --> 03:21:56,690
IN CHARACTERISTICS IN THE 

4235
03:21:56,690 --> 03:21:58,592
CHARACTERIST OF THE TRANSITION 

4236
03:21:58,592 --> 03:22:03,964
OF THE DIFFERENT CELLULAR 

4237
03:22:03,964 --> 03:22:07,467
STATES.

4238
03:22:07,467 --> 03:22:09,569
SO, AGAIN, FOR INSTANCE IN THE 

4239
03:22:09,569 --> 03:22:12,205
OTHER EXAMPLE IN CHROMOSOME 12 

4240
03:22:12,205 --> 03:22:15,609
AND CHROMOSOME 2, ONE CAN SEE 

4241
03:22:15,609 --> 03:22:16,710
ANOTHER AREA THAT HAS 

4242
03:22:16,710 --> 03:22:19,112
COMPARTMENT A AND B INTEGRATED 

4243
03:22:19,112 --> 03:22:21,181
TOGETHER, WHEREAS IT BECOMES 

4244
03:22:21,181 --> 03:22:23,884
COMPLETELY ACTIVE IN COMPARTMENT

4245
03:22:23,884 --> 03:22:31,758
A IN THE MISSING CELL LINES.

4246
03:22:31,758 --> 03:22:33,994
WHAT TRIGGERS THIS MAJOR 

4247
03:22:33,994 --> 03:22:34,327
CONFIRMATION?

4248
03:22:34,327 --> 03:22:38,965
WE SEE THAT CELLS AS WE MOVE 

4249
03:22:38,965 --> 03:22:40,967
BETWEEN THESE DIFFERENT STATES 

4250
03:22:40,967 --> 03:22:41,968
HAVE CHROMATIC CHANGES, BUT WHAT

4251
03:22:41,968 --> 03:22:43,470
ARE THE FACTORS RESPONSIBLE FOR 

4252
03:22:43,470 --> 03:22:44,104
THESE CHANGES?

4253
03:22:44,104 --> 03:22:45,972
ARE THERE MECHANICAL FACTORS, 

4254
03:22:45,972 --> 03:22:48,375
SUCH AS PREPARATION AS THE CELLS

4255
03:22:48,375 --> 03:22:50,577
MOVE THROUGH THE MATRIX OR THE 

4256
03:22:50,577 --> 03:22:53,480
SHEER STRESS AS THEY ENCOUNTER 

4257
03:22:53,480 --> 03:22:53,780
CIRCULATION?

4258
03:22:53,780 --> 03:22:58,051
IS IT THE ABILITY OR HYPOXIA 

4259
03:22:58,051 --> 03:22:58,652
INFLUENCING THESE CHANGES?

4260
03:22:58,652 --> 03:22:59,586
WHAT IS THE ROLE, FOR INSTANCE, 

4261
03:22:59,586 --> 03:23:02,989
IN THERAPY OF ALL OF THIS?

4262
03:23:02,989 --> 03:23:07,460
NOW, WE ALSO WONDER HOW THESE 

4263
03:23:07,460 --> 03:23:10,630
CHROMATINE CHANGES AND 

4264
03:23:10,630 --> 03:23:11,665
TOPOLOGICAL CHANGES ARE 

4265
03:23:11,665 --> 03:23:13,566
EXPRESSED DOWNSTREAM, AND HOW 

4266
03:23:13,566 --> 03:23:14,834
THIS RESULTS IN THE ADAPTATIONS 

4267
03:23:14,834 --> 03:23:20,006
THAT WE MENTIONED?

4268
03:23:20,006 --> 03:23:21,074
FIRST OF ALL, WE WONDER THE 

4269
03:23:21,074 --> 03:23:23,276
TRANSCRIPTION PATHS THAT CAN 

4270
03:23:23,276 --> 03:23:23,877
ORCHESTRATE THE EXPRESSION 

4271
03:23:23,877 --> 03:23:26,947
CHANGES DOWNSTREAM OF THESE 

4272
03:23:26,947 --> 03:23:27,580
CONFIRMATIONAL CHANGES.

4273
03:23:27,580 --> 03:23:30,750
WE MENTIONED MITF AND AP1 AS THE

4274
03:23:30,750 --> 03:23:32,719
TRANSCRIPTION FACTORS THAT SEEM 

4275
03:23:32,719 --> 03:23:34,988
TO BE CRITICAL FOR THE 

4276
03:23:34,988 --> 03:23:39,993
CONVERSION BETWEEN THE 

4277
03:23:39,993 --> 03:23:42,295
METASPECIFIC AND METASTATIC 

4278
03:23:42,295 --> 03:23:42,595
TYPES.

4279
03:23:42,595 --> 03:23:46,132
AS WE LOOK AT THE ANALYSIS, YOU 

4280
03:23:46,132 --> 03:23:50,437
CAN SEE THAT THREE ARE ABLE TO 

4281
03:23:50,437 --> 03:23:55,008
CLASSIFY THE CELLS SPEW THE 

4282
03:23:55,008 --> 03:23:56,476
DIFFERENT PHENOTYPES OR 

4283
03:23:56,476 --> 03:23:56,876
DIFFERENT STATES.

4284
03:23:56,876 --> 03:23:58,778
HERE IN GREEN YOU CAN SEE THE 

4285
03:23:58,778 --> 03:23:59,245
CELL LINES.

4286
03:23:59,245 --> 03:24:00,480
IN BLUE, THE INTERMEDIATE.

4287
03:24:00,480 --> 03:24:04,517
IN GREEN, YOU CAN SEE THE MORE 

4288
03:24:04,517 --> 03:24:05,919
INVASIVE WITH ONE CELL LINE IT 

4289
03:24:05,919 --> 03:24:09,422
SEEMS TO BE NOT WELL-CLASSIFIED 

4290
03:24:09,422 --> 03:24:12,492
FOR REASONS THAT WE CAN'T 

4291
03:24:12,492 --> 03:24:12,792
UNDERSTAND.

4292
03:24:12,792 --> 03:24:14,094
IF NOW WE ZOOM INTO THE CELL 

4293
03:24:14,094 --> 03:24:15,729
LINES, ONE CAN SEE THAT THE 

4294
03:24:15,729 --> 03:24:18,631
SILENCING OF MITF DID NOT HAVE A

4295
03:24:18,631 --> 03:24:22,802
MAJOR AFFECT IN CHROMATING 

4296
03:24:22,802 --> 03:24:23,136
CONFIRMATION.

4297
03:24:23,136 --> 03:24:26,773
IF WE ZOOM INTO THIS REGION, ONE

4298
03:24:26,773 --> 03:24:31,011
CAN SEE MITF IS ONLY ABLE TO 

4299
03:24:31,011 --> 03:24:32,245
PARTIALLY MOVE THE CELLS TOWARDS

4300
03:24:32,245 --> 03:24:37,517
THE RIGHT, AND THEY SEEM TO NOW 

4301
03:24:37,517 --> 03:24:39,319
MIMIC MORE THE BEHAVIOR OF THE 

4302
03:24:39,319 --> 03:24:41,421
INTERMEDIATE CELL LINES, BUT 

4303
03:24:41,421 --> 03:24:43,256
STILL, IT'S INCOMPLETE TO FULLY 

4304
03:24:43,256 --> 03:24:46,860
TRIGGER A CONVERSION, A 

4305
03:24:46,860 --> 03:24:47,627
CHROMATINE CONFIRMATION CHANGE 

4306
03:24:47,627 --> 03:24:48,428
CHARACTERISTIC OF THE 

4307
03:24:48,428 --> 03:24:50,030
INTERMEDIATE AND INVASIVE CELL 

4308
03:24:50,030 --> 03:24:52,499
LINES.

4309
03:24:52,499 --> 03:24:55,235
IF WE LOOK AT THE PROFILES, 

4310
03:24:55,235 --> 03:24:56,803
SIMILARLY ONE CAN SEE THAT THESE

4311
03:24:56,803 --> 03:24:58,371
PROFILES CAN CLUSTER THE CELLS 

4312
03:24:58,371 --> 03:25:01,941
INTO THE INVASIVE, INTERMEDIATE,

4313
03:25:01,941 --> 03:25:04,944
AND ACIDIC, BUT IF WE LOOK AT 

4314
03:25:04,944 --> 03:25:06,513
THE PROFILES IN THESE CLUSTERS 

4315
03:25:06,513 --> 03:25:07,447
AND PARTICULARLY AT THE TOP, ONE

4316
03:25:07,447 --> 03:25:09,282
CAN SEE THAT THE SILENCING OF 

4317
03:25:09,282 --> 03:25:13,153
MITF IN THE MELANOCYTIC CELL 

4318
03:25:13,153 --> 03:25:15,922
LINES HAD SOME IMPACT ON THE 

4319
03:25:15,922 --> 03:25:18,725
CLUSTERS SO YOU CAN SEE HOW SOME

4320
03:25:18,725 --> 03:25:20,593
OF THESE CLUSTERS AND SOME OF 

4321
03:25:20,593 --> 03:25:23,196
THESE THINGS NOW ARE STARTING TO

4322
03:25:23,196 --> 03:25:25,465
CLOSE OR THEY'RE NOT ACTIVE 

4323
03:25:25,465 --> 03:25:27,767
ANYMORE, BUT THIS SCIENCE IS 

4324
03:25:27,767 --> 03:25:31,004
ENABLING THE OPENING OF THE 

4325
03:25:31,004 --> 03:25:36,676
CLUSTERS CHARACTERISTIC OF THE 

4326
03:25:36,676 --> 03:25:40,380
INTERMEDIAL OR CHYMAL CELL 

4327
03:25:40,380 --> 03:25:40,680
LINES.

4328
03:25:40,680 --> 03:25:42,215
THE MASTER OF THE 

4329
03:25:42,215 --> 03:25:44,417
DIFFERENTIATION IS STILL UNABLE 

4330
03:25:44,417 --> 03:25:46,986
TO TRIGGER THE CONVERSION AND 

4331
03:25:46,986 --> 03:25:50,857
THE ACTIVATION OF ENHANCERS IN 

4332
03:25:50,857 --> 03:25:52,659
ACTIVE MEDIANSISTIC OF THE 

4333
03:25:52,659 --> 03:25:55,462
INTERMEDIATE AND INVASIVE CELLS.

4334
03:25:55,462 --> 03:25:57,330
IF WE LOOK AT CTCF, FOR 

4335
03:25:57,330 --> 03:26:01,301
INSTANCE, ONE CAN SEE, AGAIN, 

4336
03:26:01,301 --> 03:26:02,469
THE SAME PHENOTYPE.

4337
03:26:02,469 --> 03:26:04,871
PRESENTLY ONE CAN SEE THAT CTCF 

4338
03:26:04,871 --> 03:26:07,540
IS ABLE TO CLASSIFY THE CELL 

4339
03:26:07,540 --> 03:26:09,309
LINES BASED ON THE OPENING OR 

4340
03:26:09,309 --> 03:26:13,379
THE REGIONS THAT ARE ACCESSIBLE 

4341
03:26:13,379 --> 03:26:15,715
TO CTCF.

4342
03:26:15,715 --> 03:26:19,119
AGAIN, WE SEE THAT THE 

4343
03:26:19,119 --> 03:26:22,922
INACTIVATION OF MITF CONVERTS 

4344
03:26:22,922 --> 03:26:26,459
THE ACIDIC, BUT NEVER ABLE TO 

4345
03:26:26,459 --> 03:26:32,632
CHANGE THEM TO BECOME MORE  

4346
03:26:32,632 --> 03:26:35,568
>> CONTRIBUTING TO THESE 

4347
03:26:35,568 --> 03:26:35,802
CHANGES.

4348
03:26:35,802 --> 03:26:41,574
AND FOR THAT, WE WILL LOOK AT 

4349
03:26:41,574 --> 03:26:44,377
ESTABLISHED SET OF MELANOMAS AND

4350
03:26:44,377 --> 03:26:49,215
HE LOOK AT EXPRESSION OF THE 

4351
03:26:49,215 --> 03:26:49,949
TRANSCRIPTION FACTORS OF MORE 

4352
03:26:49,949 --> 03:26:53,153
THAN 1,000 TRANSCRIPTION 

4353
03:26:53,153 --> 03:26:53,386
FACTORS.

4354
03:26:53,386 --> 03:26:55,722
AND YOU CAN SEE THAT MORE THAN 

4355
03:26:55,722 --> 03:26:58,291
280 WERE FOUND ARTICULATE IN A 

4356
03:26:58,291 --> 03:26:58,558
MELANOMA.

4357
03:26:58,558 --> 03:27:01,928
AND MORE SPECIFICALLY, HE FOUND 

4358
03:27:01,928 --> 03:27:03,863
THAT A SUBSET OF THEM, A SUBSET 

4359
03:27:03,863 --> 03:27:06,766
OF TRANSCRIPTIONAL FACTORS SEEM 

4360
03:27:06,766 --> 03:27:08,568
TO BE ENRICHED IN MELANOMA 

4361
03:27:08,568 --> 03:27:11,604
COMPARED TO ANY OTHER CANCER 

4362
03:27:11,604 --> 03:27:11,804
TYPE.

4363
03:27:11,804 --> 03:27:12,839
THESE ARE INDICATED ON THE 

4364
03:27:12,839 --> 03:27:13,907
RIGHT.

4365
03:27:13,907 --> 03:27:16,176
I LX6.

4366
03:27:16,176 --> 03:27:18,711
FOR THIS TALK I WILL CONTINUE 

4367
03:27:18,711 --> 03:27:20,813
NOW TALKING ABOUT EN TWO.

4368
03:27:20,813 --> 03:27:22,182
WE FOUND THIS A TRANSCRIPTIONAL 

4369
03:27:22,182 --> 03:27:23,950
FACTOR THAT A MELANOMA AS YOU 

4370
03:27:23,950 --> 03:27:27,020
COMPARE TO ANY OTHER CALIFORNIA 

4371
03:27:27,020 --> 03:27:30,156
CANCER TYPE.

4372
03:27:30,156 --> 03:27:33,626
NOT ONLY WE CONFIRM IN BUT ALSO 

4373
03:27:33,626 --> 03:27:36,796
IN METASTATIC COMPARED TO 

4374
03:27:36,796 --> 03:27:37,964
PRIMARY MELANOMA.

4375
03:27:37,964 --> 03:27:40,166
EXPRESSION OF EN CORRELATES WITH

4376
03:27:40,166 --> 03:27:41,501
OUTCOME, HIGHER LEVELS OF 

4377
03:27:41,501 --> 03:27:44,137
ASSOCIATED WITH SHORTER 

4378
03:27:44,137 --> 03:27:44,704
SURVIVAL.

4379
03:27:44,704 --> 03:27:47,373
SO WHAT EN2.

4380
03:27:47,373 --> 03:27:49,142
EN TWO A HOW MOJ JANE OUTS 

4381
03:27:49,142 --> 03:27:53,546
FAMILY OF TRANSCRIPTIONAL 

4382
03:27:53,546 --> 03:27:54,214
FACTORS WHICH ARE INVOLVED IN A 

4383
03:27:54,214 --> 03:27:55,215
PROCESS AND A FOR PARTICULAR 

4384
03:27:55,215 --> 03:27:55,515
DEVELOPMENT.

4385
03:27:55,515 --> 03:27:58,251
YOU CAN SEE ON THE RIGHT.

4386
03:27:58,251 --> 03:28:05,692
EN HAS AN ATROPHIC SET OF, AND.

4387
03:28:05,692 --> 03:28:09,829
AND ALSO IMPORTANT FOR EM2 TO BE

4388
03:28:09,829 --> 03:28:11,331
ASSOCIATED WITH AUTISM.

4389
03:28:11,331 --> 03:28:18,538
SO EN2, IT HAS ALSO BEEN FOUND 

4390
03:28:18,538 --> 03:28:19,272
IN OVARIAN CANCER AND ASSOCIATED

4391
03:28:19,272 --> 03:28:21,641
WITH A POOR PROGNOSIS.

4392
03:28:21,641 --> 03:28:25,278
WE FOUND THAT EN2 ALTHOUGH COS 

4393
03:28:25,278 --> 03:28:31,851
HAS ENHANCER EXCLUSIVE OF 

4394
03:28:31,851 --> 03:28:32,118
MELANOMA.

4395
03:28:32,118 --> 03:28:32,752
NOT FOUND IN MELANOCYTIC OR OR 

4396
03:28:32,752 --> 03:28:33,186
CELL LINES.

4397
03:28:33,186 --> 03:28:38,891
LEVERAGING THE ESGA DATA ONE CAN

4398
03:28:38,891 --> 03:28:39,592
SEE IT A VERY GOOD CORRELATION 

4399
03:28:39,592 --> 03:28:43,029
BETWEEN EXPRESSION OF EN2 AND 

4400
03:28:43,029 --> 03:28:44,264
ACTIVATION OF THE CENTERS YOU 

4401
03:28:44,264 --> 03:28:45,531
CAN SEE ON THE RIGHT THE 

4402
03:28:45,531 --> 03:28:47,667
ACTIVITY OF THESE INCIDENCE 

4403
03:28:47,667 --> 03:28:49,602
HANSERS SEEM TO BE PARTICULARLY 

4404
03:28:49,602 --> 03:28:54,540
ACTIVE IN MELANOMA SAMPLES.

4405
03:28:54,540 --> 03:28:56,476
NOW IF WE LOOK AT CELL LINES AND

4406
03:28:56,476 --> 03:28:58,311
WE COMPARE CELL LINES THAT HAVE 

4407
03:28:58,311 --> 03:29:01,414
HIGH LEVELS OF EN2, WITH 

4408
03:29:01,414 --> 03:29:03,383
INTERMEDIATE AND LOW ONE CAN SEE

4409
03:29:03,383 --> 03:29:06,853
THAT THOSE THAT HAVE HIGH LEVELS

4410
03:29:06,853 --> 03:29:10,490
OF EN2 ARE USUALLY THE ONE THAT 

4411
03:29:10,490 --> 03:29:13,393
MITF HIGH EN2 LOW HAVE HIGH 

4412
03:29:13,393 --> 03:29:15,361
WHICH HAVE MORE INVASIVE.

4413
03:29:15,361 --> 03:29:19,999
THE CELL OF EN2 HAS NO EFFECT IN

4414
03:29:19,999 --> 03:29:23,770
PRO LIVE REEGS IN VITRO.

4415
03:29:23,770 --> 03:29:25,138
INVIVO IT REDUCED THE ABILITY OF

4416
03:29:25,138 --> 03:29:26,873
CELLS TO GROW INVIVO.

4417
03:29:26,873 --> 03:29:29,809
WHEN WE DID TRANSCRIPTION OF 

4418
03:29:29,809 --> 03:29:32,412
THESE CELLS WE LOOK AT THE CELLS

4419
03:29:32,412 --> 03:29:38,318
SCIENCE E N2, THEY THE CELLS 

4420
03:29:38,318 --> 03:29:40,053
THAT WERE MORE SIGNIFICANTLY UP 

4421
03:29:40,053 --> 03:29:45,458
REGULATED, WHEN WE EN2 IS ON 

4422
03:29:45,458 --> 03:29:48,361
CONTRARY ON THE UPPOP SID SIDE  

4423
03:29:48,361 --> 03:29:51,464
THEY ARE DOWN REGULATED 

4424
03:29:51,464 --> 03:29:54,167
ASSOCIATED TO MORE TILT.

4425
03:29:54,167 --> 03:29:56,302
EN2 SEEMS TO BE PARTICULARLY 

4426
03:29:56,302 --> 03:30:00,173
ACTIVE IN CELLS MISSING CHYMAL 

4427
03:30:00,173 --> 03:30:00,473
AND.

4428
03:30:00,473 --> 03:30:02,241
AND IT SEEMS THAT THEY 

4429
03:30:02,241 --> 03:30:07,847
EXPRESSION OF EM2 NEGATIVELY 

4430
03:30:07,847 --> 03:30:08,414
ASSOCIATES WITH RESPONSE TO 

4431
03:30:08,414 --> 03:30:09,082
THERAPY, MEANING THAT THOSE HAVE

4432
03:30:09,082 --> 03:30:14,487
HIGHER LEVELS EN2 USUAL NOT 

4433
03:30:14,487 --> 03:30:14,787
RESPONDERS.

4434
03:30:14,787 --> 03:30:15,421
THE SAME EFFECT CAN BE SEEN IF 

4435
03:30:15,421 --> 03:30:19,292
WE PATIENTS, INTO HIGH AND LOW.

4436
03:30:19,292 --> 03:30:19,992
EN2 LEVELS.

4437
03:30:19,992 --> 03:30:24,297
THOUGH WITH EN2 LOW HAVE A MORE 

4438
03:30:24,297 --> 03:30:26,699
ACTIVITY OF PATHWAYS.

4439
03:30:26,699 --> 03:30:31,003
AND AGAIN, HIGHER LEVEL EN2 

4440
03:30:31,003 --> 03:30:31,637
ASSOCIATED WITH LOWER LEVELS OF 

4441
03:30:31,637 --> 03:30:33,806
THE SIGNATURE THAT PREVIOUS 

4442
03:30:33,806 --> 03:30:36,542
ASSOCIATED WITH POOR RESPONSE IN

4443
03:30:36,542 --> 03:30:40,880
WITH NOT GOOD PROGNOSIS 

4444
03:30:40,880 --> 03:30:41,147
MELANOMA.

4445
03:30:41,147 --> 03:30:44,016
ALL OF THESE INDICATE THE 

4446
03:30:44,016 --> 03:30:45,118
POSSIBILITY EN2 PLAY AS ROLE IN 

4447
03:30:45,118 --> 03:30:48,988
ANTI TUMOR IMMUNE RESPONSE.

4448
03:30:48,988 --> 03:30:53,760
SO WE TOOK THE CELLS ENGINIC 

4449
03:30:53,760 --> 03:30:56,496
CELL LINE AND TRANS FUSED IT 

4450
03:30:56,496 --> 03:30:58,431
WITH EN2.

4451
03:30:58,431 --> 03:31:01,100
AS YOU CAN SEE ON THE LEFT, THEY

4452
03:31:01,100 --> 03:31:03,770
OVER EXPRESSION OF EN2 HAD 

4453
03:31:03,770 --> 03:31:05,138
MINIMAL EFFECT ON THE GROWTH OF 

4454
03:31:05,138 --> 03:31:07,540
THE EN CELLS WHEN THEY ARE 

4455
03:31:07,540 --> 03:31:12,745
INJECTED ANY IMMUNE DEFICIENT 

4456
03:31:12,745 --> 03:31:14,414
MICE.

4457
03:31:14,414 --> 03:31:16,949
IF YOU SIMULTANEOUS IN AN IMMUNE

4458
03:31:16,949 --> 03:31:18,885
COMPROMISED MOUSE ONE CAN SEE A 

4459
03:31:18,885 --> 03:31:22,088
VERY SIGNIFICANT ENHANCEMENT OF 

4460
03:31:22,088 --> 03:31:24,690
GROWTH.

4461
03:31:24,690 --> 03:31:25,191
THIS ASSOCIATES WITH A 

4462
03:31:25,191 --> 03:31:26,259
PRACTICALLY TOTAL EXCLUSION OF 

4463
03:31:26,259 --> 03:31:31,130
BOTH CDA AND CD4 POSITIVE T 

4464
03:31:31,130 --> 03:31:31,431
CELLS.

4465
03:31:31,431 --> 03:31:34,100
SAME RESULTS WERE AN IN ANOTHER 

4466
03:31:34,100 --> 03:31:35,168
INDEPENDENT CELL LINE WITH 

4467
03:31:35,168 --> 03:31:38,471
EXPRESSION OF EN2 ALSO ENHANCES 

4468
03:31:38,471 --> 03:31:39,972
GROWTH.

4469
03:31:39,972 --> 03:31:43,042
AND SUPPRESSES INFILTRATION.

4470
03:31:43,042 --> 03:31:49,182
HOW EN2 AFFECTING ALL AND FOUND 

4471
03:31:49,182 --> 03:31:51,517
EN2 BINDS IN GENIC REGIONS AND 

4472
03:31:51,517 --> 03:31:54,454
IS A PARTICULARLY OR A MORE 

4473
03:31:54,454 --> 03:31:57,890
FOUND IN ENHANCERS ARE OH 

4474
03:31:57,890 --> 03:32:00,893
IPRODUCTION MALENHANCERS WITH 

4475
03:32:00,893 --> 03:32:03,196
CO-LOCALIZING PROBLEMS WITH 

4476
03:32:03,196 --> 03:32:03,496
CONVERSION.

4477
03:32:03,496 --> 03:32:06,966
BUT IT REALLY COLOCALIZES WITH 

4478
03:32:06,966 --> 03:32:12,171
AS WELL AS ATAXIC OPENING.

4479
03:32:12,171 --> 03:32:14,073
BUT WHAT IS STRANGE TO US IS 

4480
03:32:14,073 --> 03:32:20,413
THAT THE NUMBER OF PEAKS IS 

4481
03:32:20,413 --> 03:32:22,014
LIKELY LOW.

4482
03:32:22,014 --> 03:32:23,382
DOESN'T SEEM TO ECONOMIC 

4483
03:32:23,382 --> 03:32:24,750
ACTUALLY BIND.

4484
03:32:24,750 --> 03:32:26,819
SO WHAT WE FOUND IS THAT EN2 IS 

4485
03:32:26,819 --> 03:32:29,956
ABLE TO ORCHESTRATE LONGER 

4486
03:32:29,956 --> 03:32:30,289
INTERACTIONS.

4487
03:32:30,289 --> 03:32:33,359
SO ONE CAN FIND A LOCATION OF A 

4488
03:32:33,359 --> 03:32:35,595
27 DISABILITY THAT STUDIES LONG 

4489
03:32:35,595 --> 03:32:40,666
RANGE INTERACTIONS BASED ON 

4490
03:32:40,666 --> 03:32:40,967
DATA.

4491
03:32:40,967 --> 03:32:43,002
AND THE THESE INTERACTIONS ARE 

4492
03:32:43,002 --> 03:32:45,605
OUT THERE WHEN WE SILENCE EN2.

4493
03:32:45,605 --> 03:32:48,708
SO THIS OPENS POSSIBILITY THAT 

4494
03:32:48,708 --> 03:32:51,310
EN2 IS CONTROLLING A LONG RANGES

4495
03:32:51,310 --> 03:32:53,646
INTERACTIONS IN ESTABLISHING 

4496
03:32:53,646 --> 03:32:54,447
TRANSCRIP

4497
03:32:54,447 --> 03:32:55,348
TRANSCRIPT

4498
03:32:55,348 --> 03:32:56,415
TRANSCRIPTIONAL HALVES TO 

4499
03:32:56,415 --> 03:32:57,783
FARTHER INVESTIGATE THIS 

4500
03:32:57,783 --> 03:33:01,420
POSSIBILITY, WE LOOK AT FIRST 

4501
03:33:01,420 --> 03:33:03,823
LOCATION OF THE NECHLT 2 BY 

4502
03:33:03,823 --> 03:33:05,124
DOING AFRACTION NATION.

4503
03:33:05,124 --> 03:33:09,695
WE FOUND THAT EN2 IS AS EXPECTED

4504
03:33:09,695 --> 03:33:12,932
IN NUCLEUS BUT MATURITY OF EN2 

4505
03:33:12,932 --> 03:33:15,701
ISN'T NOUN SOLUBLE FORM MEANING 

4506
03:33:15,701 --> 03:33:18,738
NOT BOUNDED TO CHROMATIN.

4507
03:33:18,738 --> 03:33:21,707
ONLY ONE FRACTION ATTACHED TO 

4508
03:33:21,707 --> 03:33:21,974
CHROMATIN.

4509
03:33:21,974 --> 03:33:24,410
IT MAY BE SCHULTZING IN AND OUT 

4510
03:33:24,410 --> 03:33:26,846
OF CHROMATIN.

4511
03:33:26,846 --> 03:33:27,079
AND IN.

4512
03:33:27,079 --> 03:33:31,117
E.  2 FOR MASS SPECK TOMORROW 

4513
03:33:31,117 --> 03:33:31,317
TREE.

4514
03:33:31,317 --> 03:33:33,819
EN2 INTERACT WITH A COMPONENTS, 

4515
03:33:33,819 --> 03:33:34,387
COMPLEX.

4516
03:33:34,387 --> 03:33:40,259
THAT IS AND IS A SUPPRESSIVE 

4517
03:33:40,259 --> 03:33:41,794
COMPLEX THAT DOESN'T BIND.

4518
03:33:41,794 --> 03:33:44,363
SO WE FOUND WE CONFIRMED THIS 

4519
03:33:44,363 --> 03:33:48,968
INTERACTION BY CHROMATIN.

4520
03:33:48,968 --> 03:33:52,104
THIS OPENS THE POSSIBILITY THAT 

4521
03:33:52,104 --> 03:33:53,372
EN2 INTERACTS WITH IN CHROMATIN 

4522
03:33:53,372 --> 03:33:56,909
OR THAT THE THERE IS A 

4523
03:33:56,909 --> 03:34:00,446
COMPETITION BETWEEN EN2 AND 

4524
03:34:00,446 --> 03:34:01,047
OTHER TRANSCRIPTIONAL FACTORS 

4525
03:34:01,047 --> 03:34:03,950
FOR BINDING AND ACCESS TO 

4526
03:34:03,950 --> 03:34:04,750
CHROMATIN.

4527
03:34:04,750 --> 03:34:07,019
TO FINALIZE, THIS IS OUR MODEL.

4528
03:34:07,019 --> 03:34:11,490
MELANOMA CELLS INITIALLY ARE A 

4529
03:34:11,490 --> 03:34:14,393
RECOGNIZED BY T CELLS IN THE 

4530
03:34:14,393 --> 03:34:17,229
INITIAL STEPS OF BUT WHEN EN2 

4531
03:34:17,229 --> 03:34:20,099
LEVELS GO THESE MELANOMA CELLS 

4532
03:34:20,099 --> 03:34:21,867
START TRANSCRIPT FACTORS THAT 

4533
03:34:21,867 --> 03:34:24,303
MAKE THEM NOW MORE, MORE IMMUNE 

4534
03:34:24,303 --> 03:34:29,208
OR MORE ANAL TO AN EVADE IMMUNE 

4535
03:34:29,208 --> 03:34:29,475
RESPONSE.

4536
03:34:29,475 --> 03:34:31,110
AND THIS IS DUE TO THE ABILITY 

4537
03:34:31,110 --> 03:34:35,481
OF EN2 TO FROM SORRY FROM 

4538
03:34:35,481 --> 03:34:37,116
CYTOPLASM INTO NUCLEUS.

4539
03:34:37,116 --> 03:34:44,156
WE NO FROM DATA THAT I HADN'T 

4540
03:34:44,156 --> 03:34:44,790
HAD A CHANCE TO PRESENT IN THIS 

4541
03:34:44,790 --> 03:34:47,193
UP UP REGULATED WHEN, THEY 

4542
03:34:47,193 --> 03:34:49,128
SUPPRESS GENES.

4543
03:34:49,128 --> 03:34:51,597
AT THE SAME TIME EN2 CAN BE AN 

4544
03:34:51,597 --> 03:34:54,834
ACTIVE REGULATOR OF EN WENT 2 

4545
03:34:54,834 --> 03:34:55,868
INNOVATION GENES.

4546
03:34:55,868 --> 03:34:58,170
I WILL NOT READ THE BECAUSE I'M 

4547
03:34:58,170 --> 03:34:59,238
RUNNING OUT OF TIME.

4548
03:34:59,238 --> 03:35:01,307
BUT JUST TO PUT TOGETHER THE TWO

4549
03:35:01,307 --> 03:35:07,013
PARTS THE PRESENTATION AS I 

4550
03:35:07,013 --> 03:35:09,281
MENTIONED ABLE TO DIFFERENT 

4551
03:35:09,281 --> 03:35:16,722
STATES AND WE ARE HYPOTHESIZING 

4552
03:35:16,722 --> 03:35:17,390
DOWN STREAM OF THESE MAY ACCEPT 

4553
03:35:17,390 --> 03:35:19,291
MAYR YOUR CHANGES IN 

4554
03:35:19,291 --> 03:35:20,660
TRANSCRIPTIONAL HALVES AND 

4555
03:35:20,660 --> 03:35:22,662
ORCHESTRATE SOME OF THIS 

4556
03:35:22,662 --> 03:35:24,397
TRANSCRIPTIONAL CHANGES THAT 

4557
03:35:24,397 --> 03:35:26,832
CONFIRM MELANOMA CELLS WITH 

4558
03:35:26,832 --> 03:35:28,534
ADAPTATION AND ABILITY TO ME TAZ

4559
03:35:28,534 --> 03:35:30,970
SIZE AND EVADE IMMUNE SYSTEM.

4560
03:35:30,970 --> 03:35:32,805
AGAIN I WANT TO THANK THE 

4561
03:35:32,805 --> 03:35:35,975
MEMBERS OF MY LAB WHO WORK WITH 

4562
03:35:35,975 --> 03:35:41,514
US ON THE THIS PROJECT.

4563
03:35:41,514 --> 03:35:44,383
AND I WILL STOP HERE.

4564
03:35:44,383 --> 03:35:47,653
I APPRECIATE YOUR TIME AND STOP 

4565
03:35:47,653 --> 03:35:48,988
HERE AND TAKE QUESTIONS, THANK 

4566
03:35:48,988 --> 03:35:59,065
YOU.

4567
03:35:59,932 --> 03:36:00,900
 [ APPLAUSE ] 

4568
03:36:00,900 --> 03:36:03,436
>> A BEAUTIFUL TALK.

4569
03:36:03,436 --> 03:36:05,004
THERE WE GO.

4570
03:36:05,004 --> 03:36:09,775
OKAY.

4571
03:36:09,775 --> 03:36:11,811
I HAVE A QUESTION ABOUT I THINK 

4572
03:36:11,811 --> 03:36:13,546
YOU MENTIONED EN2 WAS INVOLVED 

4573
03:36:13,546 --> 03:36:15,014
IN BRAIN DEVELOPMENT.

4574
03:36:15,014 --> 03:36:16,982
I WONDERED IF THERE IS ANY 

4575
03:36:16,982 --> 03:36:20,352
SPECIFIC RELATIONSHIP TO METS IN

4576
03:36:20,352 --> 03:36:24,924
THE PLAIN TBRAIN THERE 

4577
03:36:24,924 --> 03:36:26,926
>> AS YOU KNOW WE HAVE
DON'T NOT

4578
03:36:26,926 --> 03:36:29,528
HAVE A TRANSCRIPTION UP DATA AS 

4579
03:36:29,528 --> 03:36:34,467
WE HAVE FOR SITE OF ME TAZ CIS.

4580
03:36:34,467 --> 03:36:36,669
PRIMARILY ANALYSIS OF A 

4581
03:36:36,669 --> 03:36:39,138
COMPUTATION, PREMA TAZ SEES 

4582
03:36:39,138 --> 03:36:40,473
DOESN'T SHOW A DIFFERENCE OF 

4583
03:36:40,473 --> 03:36:42,041
EXPRESSION IN EN2.

4584
03:36:42,041 --> 03:36:45,044
WE DIDN'T SEE THAT THERE IS 

4585
03:36:45,044 --> 03:36:45,511
INCREASED EXPRESSION.

4586
03:36:45,511 --> 03:36:46,712
BUT I THINK THAT'S A VERY 

4587
03:36:46,712 --> 03:36:48,047
IMPORTANT QUESTION.

4588
03:36:48,047 --> 03:36:50,649
WE UNDERSTAND IN WHETHER 

4589
03:36:50,649 --> 03:36:52,118
TRANSCRIPTIONAL PROGRAM THATTASE

4590
03:36:52,118 --> 03:36:53,052
ESTABLISHING IN BRAIN.

4591
03:36:53,052 --> 03:36:55,221
SO WE DEFINITELY LOOKING INTO 

4592
03:36:55,221 --> 03:36:55,654
IT.

4593
03:36:55,654 --> 03:36:57,790
AND I HOPE I WILL PROVIDE 

4594
03:36:57,790 --> 03:37:08,134
UPDATES, THANK YOU.

4595
03:37:09,034 --> 03:37:15,775
>> NEXT SPEAKER IS
CHRISTINA 

4596
03:37:15,775 --> 03:37:16,008
LESLIE.

4597
03:37:16,008 --> 03:37:20,446
CANCER EPIGENETICS IN 3D.

4598
03:37:20,446 --> 03:37:22,581
SHE WILL GIVE IT VIRTUALLY.

4599
03:37:22,581 --> 03:37:28,454
>> OKAY.

4600
03:37:28,454 --> 03:37:29,121
>> OKAY.

4601
03:37:29,121 --> 03:37:30,856
I HOPE YOU CAN SEMI SLIDES.

4602
03:37:30,856 --> 03:37:32,491
THANKS SO MUCH FOR THE 

4603
03:37:32,491 --> 03:37:33,793
ORGANIZERS FOR INVITING ME.

4604
03:37:33,793 --> 03:37:35,261
I'M VERY SORRY THAT I COULDN'T 

4605
03:37:35,261 --> 03:37:38,197
BE THERE IN PERSON.

4606
03:37:38,197 --> 03:37:38,831
I AM CURRENTLY GROUNDED IN NEW 

4607
03:37:38,831 --> 03:37:40,466
YORK WITH COVID.

4608
03:37:40,466 --> 03:37:44,503
SO I WANT TO START WITH A 

4609
03:37:44,503 --> 03:37:50,843
VIGNETTE TO REMIND EVERYONE THAT

4610
03:37:50,843 --> 03:37:52,845
SOMATIC ALTERATIONS IN EPIGENTIC

4611
03:37:52,845 --> 03:37:55,681
REGULATORS CAN A CAUSE GLOBAL 

4612
03:37:55,681 --> 03:37:59,084
CHANGES AND SHORT VIGNETTE IN 

4613
03:37:59,084 --> 03:38:00,119
COLLABORATION WITH AN EMILY 

4614
03:38:00,119 --> 03:38:01,620
CHANG THAT DID ALL THE 

4615
03:38:01,620 --> 03:38:03,556
EXPERIMENTS WORK AND WE DID 

4616
03:38:03,556 --> 03:38:04,557
COMPUTATIONAL ANALYSIS.

4617
03:38:04,557 --> 03:38:06,759
SO THIS WAS A STUDY OF A LOSS OF

4618
03:38:06,759 --> 03:38:12,464
FUNCTION MUTATION IN RENAL CELL 

4619
03:38:12,464 --> 03:38:12,998
CARCINOMA.

4620
03:38:12,998 --> 03:38:20,739
SO IT IS THE NONREDONE DANTS 

4621
03:38:20,739 --> 03:38:21,340
HISTONE METHYL TRANSFER RACE 

4622
03:38:21,340 --> 03:38:22,341
THAT CO-TRANSCRIPTIONALLY 

4623
03:38:22,341 --> 03:38:27,580
DEPOSITS A33 K TRY METHYL.

4624
03:38:27,580 --> 03:38:28,714
EVEN THOUGH IT IS ASSOCIATED 

4625
03:38:28,714 --> 03:38:30,916
WITH ACTIVELY TRANSCRIBED GENES,

4626
03:38:30,916 --> 03:38:33,686
IT IS A REPRESSIVE MARK.

4627
03:38:33,686 --> 03:38:36,755
IT'S SUPPRESS CRIPPIC INITIATION

4628
03:38:36,755 --> 03:38:38,691
OF TRANSCRIPTION.

4629
03:38:38,691 --> 03:38:44,096
IT IS MUTATED IN 13 PERCENT OF 

4630
03:38:44,096 --> 03:38:45,998
CLEAR CELL REENLT CELL CARCINOMA

4631
03:38:45,998 --> 03:38:47,266
ASSOCIATED WITH PROGRESSION AND 

4632
03:38:47,266 --> 03:38:49,435
ME TAZ CIS.

4633
03:38:49,435 --> 03:38:49,635
EMILY.

4634
03:38:49,635 --> 03:38:51,637
AND AN EMILY CHANG HAS NIGHT 

4635
03:38:51,637 --> 03:38:53,839
PATIENT MODEL WITH A MUTANT IN 

4636
03:38:53,839 --> 03:38:57,276
THE XENOGRAPH YOU CAN 

4637
03:38:57,276 --> 03:39:00,312
RECAPITULATE THIS METASTASIS TO 

4638
03:39:00,312 --> 03:39:02,047
A BRAIN, LUNG AND LIVER.

4639
03:39:02,047 --> 03:39:05,017
AND, THEN SHE CAN ENGINEER THE 

4640
03:39:05,017 --> 03:39:08,320
CELLS TO RESTORE ACTIVITY OF AND

4641
03:39:08,320 --> 03:39:12,157
THAT REDUCES THE METASTASIS.

4642
03:39:12,157 --> 03:39:13,459
OKAY.

4643
03:39:13,459 --> 03:39:15,394
SO WHAT WE DID IN THIS PAPER AND

4644
03:39:15,394 --> 03:39:20,032
AGAIN JUST VERY QUICKLY, WE 

4645
03:39:20,032 --> 03:39:21,200
TRIED TO UNDERSTAND E

4646
03:39:21,200 --> 03:39:23,135
EPIGENOMECALLY WHAT IS HAPPENING

4647
03:39:23,135 --> 03:39:24,703
WITH A FUNCTION.

4648
03:39:24,703 --> 03:39:26,071
AND THE FIRST THING WE COULD SEE

4649
03:39:26,071 --> 03:39:28,941
IS THAT YOU HAVE MASSIVE CHANGES

4650
03:39:28,941 --> 03:39:32,111
IN CHROMATIN ACCESSIBILITY.

4651
03:39:32,111 --> 03:39:39,485
SO OVER HERE THIS IS YOU CAN SEE

4652
03:39:39,485 --> 03:39:41,720
A YOU GET OPENING OF MANY PEAKS.

4653
03:39:41,720 --> 03:39:45,991
AND FROM THE TORNADO PLOTS HERE 

4654
03:39:45,991 --> 03:39:48,661
YOU CAN SEE BOTH ERNT GENIC 

4655
03:39:48,661 --> 03:39:56,268
REGIONS YOU, WHEN YOU LOSS H3 K 

4656
03:39:56,268 --> 03:39:59,038
36 TRY METHYL, LOSS THE 

4657
03:39:59,038 --> 03:40:02,541
ACTIVITY, YOU GET OPENING OF 

4658
03:40:02,541 --> 03:40:04,109
PEAKS AND IT'S ALSO ASSOCIATED 

4659
03:40:04,109 --> 03:40:09,915
WITH ACTIVE HISTONE MARKS.

4660
03:40:09,915 --> 03:40:12,885
AND THAT MEANS THAT GENETIC 

4661
03:40:12,885 --> 03:40:15,321
PROGRAMS ARE AMPLIFIED.

4662
03:40:15,321 --> 03:40:17,323
SO FOR EXAMPLE THIS IS A PRO 

4663
03:40:17,323 --> 03:40:18,424
METASTASIS GENE.

4664
03:40:18,424 --> 03:40:22,328
AND YOU CAN SEE WITH LOSS OF 

4665
03:40:22,328 --> 03:40:25,564
ACTIVITY OF 2 INCREASE IN 

4666
03:40:25,564 --> 03:40:27,833
ACCESSIBILITY OF ENHANCERS AND 

4667
03:40:27,833 --> 03:40:29,535
INCREASE OF EXPRESSION.

4668
03:40:29,535 --> 03:40:30,369
OKAY.

4669
03:40:30,369 --> 03:40:32,471
THERE'S MORE ON THE PAPER.

4670
03:40:32,471 --> 03:40:35,441
THERE'S ALSO INTERESTING 

4671
03:40:35,441 --> 03:40:37,643
DEPENDENCIES IN THESE CELLS WHEN

4672
03:40:37,643 --> 03:40:42,247
YOU LOSE H K 36 YOU HAVE GREATER

4673
03:40:42,247 --> 03:40:43,482
HISTONE TURN OVER.

4674
03:40:43,482 --> 03:40:46,652
AND IT SENSITIZES THE CELLS TO 

4675
03:40:46,652 --> 03:40:48,954
INHIBITERS OF HISTONE CHAPERONES

4676
03:40:48,954 --> 03:40:52,157
AND TRANSCRIPTION ELONGATION.

4677
03:40:52,157 --> 03:40:52,358
OKAY.

4678
03:40:52,358 --> 03:40:53,792
SO THAT IS MY OPEN VIGNETTE.

4679
03:40:53,792 --> 03:40:55,694
BUT WHAT I REALLY WANT TO TALK 

4680
03:40:55,694 --> 03:40:59,865
TO YOU TODAY IS THE IDEA THAT 

4681
03:40:59,865 --> 03:41:01,266
SOMATIC ALTERATIONS CAN ALSO 

4682
03:41:01,266 --> 03:41:04,069
LEAD TO GLOBAL CHANGES IN 3D 

4683
03:41:04,069 --> 03:41:04,403
ORGANIZATION.

4684
03:41:04,403 --> 03:41:04,937
OKAY.

4685
03:41:04,937 --> 03:41:07,272
I'M GOING TO START WITH SOME 

4686
03:41:07,272 --> 03:41:11,176
PRELIMINARIES ON HI C 

4687
03:41:11,176 --> 03:41:12,478
ANALYSISIKE DO THAT BECAUSE HIGH

4688
03:41:12,478 --> 03:41:14,947
C WAS INTRODUCED IN THE PREVIOUS

4689
03:41:14,947 --> 03:41:15,547
TALK.

4690
03:41:15,547 --> 03:41:16,982
I'M GOING TO VERY BRIEFLY 

4691
03:41:16,982 --> 03:41:20,119
MENTION SOME OF THE WORK WE DO 

4692
03:41:20,119 --> 03:41:22,221
AS COMPUTATIONAL BIEGS 

4693
03:41:22,221 --> 03:41:23,522
BIOLOGISTS DEVELOPING MACHINE 

4694
03:41:23,522 --> 03:41:26,992
LEARNING MODELS TO PREDICT 3D 

4695
03:41:26,992 --> 03:41:30,329
THE CONTACT MATRIX FROM ONE D 

4696
03:41:30,329 --> 03:41:34,033
ESPECIALLY GENOMIC TRACKS.

4697
03:41:34,033 --> 03:41:34,633
THEN I WILL TELL YOU A STORY 

4698
03:41:34,633 --> 03:41:39,171
THAT UNPUBLISHED IN 

4699
03:41:39,171 --> 03:41:44,510
COLLABORATION WITH IN MELANOMA 

4700
03:41:44,510 --> 03:41:44,810
V

4701
03:41:44,810 --> 03:41:47,513
VIA DEFICIENCY THAT A DRIVES 3D 

4702
03:41:47,513 --> 03:41:52,217
CHANGES AND A -- SO THAT'S THE 

4703
03:41:52,217 --> 03:41:52,518
PLAN.

4704
03:41:52,518 --> 03:41:53,118
ALL RIGHT.

4705
03:41:53,118 --> 03:41:56,555
SO, UM, VERY QUICKLY, SINCE 

4706
03:41:56,555 --> 03:41:59,658
WE'VE ALREADY SEEN HIGH C IN THE

4707
03:41:59,658 --> 03:42:04,863
PREVIOUS TALK, THIS IS AN ASSAY 

4708
03:42:04,863 --> 03:42:11,070
THAT IS BASED ON CROSSLINKING 

4709
03:42:11,070 --> 03:42:12,638
DNA N C 2 IN THE NUCLEUS AND 

4710
03:42:12,638 --> 03:42:15,741
RESTRICTION ENZYME DYE TEST 

4711
03:42:15,741 --> 03:42:17,910
PROXIMITY LIGATION PULL DOWN.

4712
03:42:17,910 --> 03:42:20,712
IN THE END WE HAVE THEE CHI 

4713
03:42:20,712 --> 03:42:21,013
MERIC READS.

4714
03:42:21,013 --> 03:42:23,115
WE SEQUENCE ANCHORS THE ANCHORS 

4715
03:42:23,115 --> 03:42:25,384
SOMETIMES COME FROM REGION THAT 

4716
03:42:25,384 --> 03:42:28,120
IS VERY FAR IN THE 1 D GENOME 

4717
03:42:28,120 --> 03:42:30,189
BUT MUST HAVE BEEN CLOSE IN 

4718
03:42:30,189 --> 03:42:33,859
CONTACT IN SOME CELLS IN THE 

4719
03:42:33,859 --> 03:42:34,193
INPUT.

4720
03:42:34,193 --> 03:42:36,662
SO WE CALL THESE CONTACTS.

4721
03:42:36,662 --> 03:42:40,466
AND WE BUILD A CONTACT MATRIX SO

4722
03:42:40,466 --> 03:42:42,868
A MATRIX WHERE WE'RE JUST 

4723
03:42:42,868 --> 03:42:48,740
COUNTING THE NUMBER OF PARADIGM 

4724
03:42:48,740 --> 03:42:50,342
READS WITH ANCHORS AOKAY.

4725
03:42:50,342 --> 03:42:51,844
AND IT HAS ALREADY BEEN 

4726
03:42:51,844 --> 03:42:53,879
DISCUSSED THAT YOU CAN YOU CAN 

4727
03:42:53,879 --> 03:42:56,381
LOOK AT CONTACT MATRIX AT 

4728
03:42:56,381 --> 03:42:58,484
DIFFERENT LEVELS.

4729
03:42:58,484 --> 03:43:01,720
IT IS VERY INTERESTING AND 

4730
03:43:01,720 --> 03:43:02,654
COMPLEX DATA EVEN THOUGH YOU'RE 

4731
03:43:02,654 --> 03:43:06,525
ONLY CAPTURING CONTACTS THAT ARE

4732
03:43:06,525 --> 03:43:07,826
CLOSE, IT IS GIVING INFORMATION 

4733
03:43:07,826 --> 03:43:11,430
ON MORE GLOBAL AND HIERARCHICAL 

4734
03:43:11,430 --> 03:43:12,498
3D STRUCTURE.

4735
03:43:12,498 --> 03:43:14,867
BUT WE'RE GOING TO FOCUS MORE AT

4736
03:43:14,867 --> 03:43:19,805
THIS LEVEL OF TABS THAT TOX 

4737
03:43:19,805 --> 03:43:20,739
LOGICALLY ASSOCIATING DOMAINS 

4738
03:43:20,739 --> 03:43:23,542
THAT WE'VE ALREADY TALKED ABOUT,

4739
03:43:23,542 --> 03:43:25,244
THE IDEA THAT YOU HAVE REGIONS 

4740
03:43:25,244 --> 03:43:27,112
MEGA BASE AND LENGTHS THAT ARE 

4741
03:43:27,112 --> 03:43:29,515
MORE SELF INTERACTING THAN 

4742
03:43:29,515 --> 03:43:32,985
INTERACTING WITH ANOTHER JAVENT 

4743
03:43:32,985 --> 03:43:33,152
TAB.

4744
03:43:33,152 --> 03:43:33,952
AND YOU CAN ALSO SOMETIMES BY 

4745
03:43:33,952 --> 03:43:37,489
EYE SEE THESE STRONGS LOOPS THAT

4746
03:43:37,489 --> 03:43:43,629
ARE MEDIATED .

4747
03:43:43,629 --> 03:43:47,799
SO ONE THING I JUST WANT TO 

4748
03:43:47,799 --> 03:43:50,869
POINT OUT IS THAT IN THE FIELD 

4749
03:43:50,869 --> 03:44:01,313
MANY AGAIN, VERY QUICKLY.

4750
03:45:48,253 --> 03:45:54,159
THIS IS LOT OF INTEREST IN MANY 

4751
03:45:54,159 --> 03:45:56,194
LEARNING FOR GENOMIC COMMUNITY 

4752
03:45:56,194 --> 03:45:57,062
IN PREDICTING MATRIX FROM DNA 

4753
03:45:57,062 --> 03:45:57,329
SEQUENCE.

4754
03:45:57,329 --> 03:45:58,764
WE WERE INTERESTED IN DEVELOPING

4755
03:45:58,764 --> 03:46:04,836
A MODEL THAT COULD PREDICT FROM 

4756
03:46:04,836 --> 03:46:05,804
ESPECI

4757
03:46:05,804 --> 03:46:06,104
E

4758
03:46:06,104 --> 03:46:07,139
EPIGENOMIC MARKS.

4759
03:46:07,139 --> 03:46:10,809
BECAUSE THEN, YOU COULD IMAGINE 

4760
03:46:10,809 --> 03:46:15,647
THE MODEL GENERALIZING TO NEW 

4761
03:46:15,647 --> 03:46:16,114
CELL TYPES.

4762
03:46:16,114 --> 03:46:25,324
AND THIS MODEL CALLED EPIPHANY, 

4763
03:46:25,324 --> 03:46:29,027
IS LOCATIONAL CONTACT MATRIX 

4764
03:46:29,027 --> 03:46:31,163
FROM A SET OF HISTONE MARKS WAS 

4765
03:46:31,163 --> 03:46:33,231
JUST PUBLISHED THIS YEAR.

4766
03:46:33,231 --> 03:46:37,903
AND AN IDEA 

4767
03:46:37,903 --> 03:46:39,538
WHERE WE'RE GOING WITH THIS AND 

4768
03:46:39,538 --> 03:46:42,474
CONNECTING WITH AT STORY, WE 

4769
03:46:42,474 --> 03:46:46,945
ALSO HAVE A HI C IN OUR R C C 

4770
03:46:46,945 --> 03:46:51,350
CLEAR CELL CARCINOMA MODEL WITH 

4771
03:46:51,350 --> 03:46:55,220
LOSS OF FUNCTION OF SET D2 AND 

4772
03:46:55,220 --> 03:46:56,188
SET D 2 RESTORED.

4773
03:46:56,188 --> 03:46:58,590
SO YOU SEE FOR EXAMPLE, THIS IS 

4774
03:46:58,590 --> 03:47:03,595
H3 K 36 TRY METHYL THESE DOMAINS

4775
03:47:03,595 --> 03:47:04,963
ONCE ACTIVITY IS RESTORED.

4776
03:47:04,963 --> 03:47:06,998
LOST IN THE MUTANT.

4777
03:47:06,998 --> 03:47:10,602
HD F IS ONE GENES THAT MOST 

4778
03:47:10,602 --> 03:47:13,905
HIGHLY UPREGULATED IN THE SET D 

4779
03:47:13,905 --> 03:47:14,973
2 MUTANT.

4780
03:47:14,973 --> 03:47:17,376
THERE ARE SUBTLE BUT 

4781
03:47:17,376 --> 03:47:20,278
REPRODUCIBLE DIFFERENCES IN HI 

4782
03:47:20,278 --> 03:47:20,879
C.

4783
03:47:20,879 --> 03:47:22,414
IF YOU LOOK AT THE A LAB CHANGES

4784
03:47:22,414 --> 03:47:26,685
IT LOOKS QUITE COMPLICATED.

4785
03:47:26,685 --> 03:47:27,285
IF YOU SEPARATE THE POSITIVE 

4786
03:47:27,285 --> 03:47:28,720
FROM NEGATIVE LOG FULL CHANGES 

4787
03:47:28,720 --> 03:47:30,922
YOU START TO SEE THAT THERE ARE 

4788
03:47:30,922 --> 03:47:31,523
STRUCT

4789
03:47:31,523 --> 03:47:34,793
STRUCTURES ASSOCIATED WITH SET D

4790
03:47:34,793 --> 03:47:36,962
2 ACTIVITY VERSE SET D2 LOSS.

4791
03:47:36,962 --> 03:47:40,132
AND WE CAN PREDICT THESE 

4792
03:47:40,132 --> 03:47:43,502
POSITIVE AND NEGATIVE CHANGES 

4793
03:47:43,502 --> 03:47:45,537
FROM HISTONE MARKS.

4794
03:47:45,537 --> 03:47:49,374
SO USING THIS MODEL BUILT ON 

4795
03:47:49,374 --> 03:47:49,641
EPIPHANY.

4796
03:47:49,641 --> 03:47:53,478
SO WE'RE GOING FORWARD TRYING TO

4797
03:47:53,478 --> 03:47:56,548
USE THE FACT THAT WE CAN PREDICT

4798
03:47:56,548 --> 03:47:58,483
THE CONTACT MATRIX AND THESE 

4799
03:47:58,483 --> 03:48:01,887
CHANGES FROM HISTONE MARKS TO 

4800
03:48:01,887 --> 03:48:03,822
TRY TO UNDERSTAND THE CHANGES 

4801
03:48:03,822 --> 03:48:06,792
THAT WE'RE SEEING.

4802
03:48:06,792 --> 03:48:06,992
OKAY.

4803
03:48:06,992 --> 03:48:10,929
I'M GOING SWITCH GEARS AND TALK 

4804
03:48:10,929 --> 03:48:12,230
ABOUT AT SECOND STORY.

4805
03:48:12,230 --> 03:48:17,803
NI PBL HAPPEN ALTHOUGH DIVISION 

4806
03:48:17,803 --> 03:48:17,969
INC.

4807
03:48:17,969 --> 03:48:19,738
THIS IS A COLLABORATION.

4808
03:48:19,738 --> 03:48:22,808
AND IT IS STARTED WITH ONE GENE.

4809
03:48:22,808 --> 03:48:25,644
IT STARTED WITH AN ALKAGENE 

4810
03:48:25,644 --> 03:48:28,413
CALLED AT LKATI.

4811
03:48:28,413 --> 03:48:32,050
AND PING DESCRIBED THAT THROUGH 

4812
03:48:32,050 --> 03:48:34,019
ALTERNATIVE TRANSCRIPTION 

4813
03:48:34,019 --> 03:48:39,691
INITIATION IN THE LOCUS OF THE 

4814
03:48:39,691 --> 03:48:45,931
ALK YOU LOSE THESE EXTRA 

4815
03:48:45,931 --> 03:48:48,867
CELLULAR MEMBRANE DOMAINS.

4816
03:48:48,867 --> 03:48:52,103
YOU ARE LEFT WITH CHI MACE 

4817
03:48:52,103 --> 03:48:56,241
DOMAIN AND IT IS AN ALKAGENE.

4818
03:48:56,241 --> 03:48:56,875
IF YOU LOOK AT THE A LOCUS AND 

4819
03:48:56,875 --> 03:49:00,345
YOU ZOOM IN AND SEE WHERE THIS 

4820
03:49:00,345 --> 03:49:01,913
INITIATION, WHERE THIS 

4821
03:49:01,913 --> 03:49:04,616
ALTERNATIVE TRANSCRIPTION 

4822
03:49:04,616 --> 03:49:06,184
INITIATION HAPPENS, IT ACTUALLY 

4823
03:49:06,184 --> 03:49:06,685
HAPP

4824
03:49:06,685 --> 03:49:08,119
HAPPENS, OKAY, SO THIS IN, THIS 

4825
03:49:08,119 --> 03:49:12,390
IS HI C IN A CELL LINE WHERE ALK

4826
03:49:12,390 --> 03:49:13,458
IS NOT EXPRESSED.

4827
03:49:13,458 --> 03:49:16,895
IT IS INSIDE SUBTEXT.

4828
03:49:16,895 --> 03:49:24,903
SO JUST WITHIN THE BOUNDARY OF A

4829
03:49:24,903 --> 03:49:26,371
SUBTAT.

4830
03:49:26,371 --> 03:49:27,005
AND YOU CAN ALSO SEE IF YOU DO 4

4831
03:49:27,005 --> 03:49:30,242
C WHICH IS WHICH A VERY POINT 

4832
03:49:30,242 --> 03:49:30,942
CHROMOSOME CAPTURE.

4833
03:49:30,942 --> 03:49:33,044
I'M SHOWING HERE IN THE MELANOMA

4834
03:49:33,044 --> 03:49:35,814
CELL LINES WHERE ALKATI IS 

4835
03:49:35,814 --> 03:49:38,783
EXPRESSED VERSUS NOT EXPRESSED, 

4836
03:49:38,783 --> 03:49:41,453
THIS ALTERNATIVE TRANSCRIPTION 

4837
03:49:41,453 --> 03:49:42,787
INITIATION, TRANSCRIPTION START 

4838
03:49:42,787 --> 03:49:50,028
SITE IS MAKING CONTACT WITH DOWN

4839
03:49:50,028 --> 03:49:55,066
-- UPSTREAM AND DOWN STREAM 

4840
03:49:55,066 --> 03:49:58,937
REGIONS AND YOU DON'T SEE THOSE 

4841
03:49:58,937 --> 03:49:59,371
KAK

4842
03:49:59,371 --> 03:50:02,607
CONTACTS WHEN ALKATI IS NOT 

4843
03:50:02,607 --> 03:50:02,908
EXPRESSED.

4844
03:50:02,908 --> 03:50:05,110
SO SOME INTERESTING ORGANIZATION

4845
03:50:05,110 --> 03:50:10,849
OF ALKATI BEING JUST WITHIN A 

4846
03:50:10,849 --> 03:50:15,153
SUBTAT IS IT ASSOCIATED WITH 

4847
03:50:15,153 --> 03:50:17,022
COHESS INDYSREGULATION.

4848
03:50:17,022 --> 03:50:19,524
AND WHAT ONE COULD SEE, WE KIND 

4849
03:50:19,524 --> 03:50:29,534
OF OR PING CHI ZOOMED IN ON IT 

4850
03:50:29,534 --> 03:50:32,237
IS TCOHESIN LOADER AND IS 

4851
03:50:32,237 --> 03:50:34,372
IMPORTANT FOR SORT OF INITIATING

4852
03:50:34,372 --> 03:50:38,710
THIS PROCESS OF LOADING COHESIN 

4853
03:50:38,710 --> 03:50:40,111
AND GETTING LOOP EXTRUSION WHICH

4854
03:50:40,111 --> 03:50:41,546
AS ASSOCIATED WITH TATS.

4855
03:50:41,546 --> 03:50:43,448
AND WHAT YOU CAN SEE IS THAT IN 

4856
03:50:43,448 --> 03:50:46,284
MELANOMA LINES THAT DON'T 

4857
03:50:46,284 --> 03:50:50,789
EXPRESS ALKATI, IT IS HIGHER 

4858
03:50:50,789 --> 03:50:51,056
EXPRESSED.

4859
03:50:51,056 --> 03:50:53,191
AND ALK EXPRESSION IS ASSOCIATED

4860
03:50:53,191 --> 03:50:57,128
WITH LOWER IPPBL.

4861
03:50:57,128 --> 03:50:58,496
AND THIS OVER HERE AT THE A 

4862
03:50:58,496 --> 03:50:59,764
BOTTOM I'M JUST SHOWING TRACKS 

4863
03:50:59,764 --> 03:51:02,300
WHERE YOU CAN SEE THIS ALKATI 

4864
03:51:02,300 --> 03:51:07,572
EXPRESSION IN SOME CELL LINES, 

4865
03:51:07,572 --> 03:51:07,872
NOT OTHERS.

4866
03:51:07,872 --> 03:51:11,242
ALSO LOOKING A DATA -- 

4867
03:51:11,242 --> 03:51:15,680
EXPRESSION OF ALKATI IS 

4868
03:51:15,680 --> 03:51:21,186
ASSOCIATED WITH NICHLT IPBL OR 

4869
03:51:21,186 --> 03:51:23,588
MORE DELETERIOUS MUTATIONS.

4870
03:51:23,588 --> 03:51:26,324
SO PERHAPS THIS IS A LINK 

4871
03:51:26,324 --> 03:51:31,162
BETWEEN NIPBL AND EXPRESSION OF 

4872
03:51:31,162 --> 03:51:31,396
ALKATI.

4873
03:51:31,396 --> 03:51:35,533
ALL RIGHT THE NEXT THING PING'S 

4874
03:51:35,533 --> 03:51:42,874
LAB DID WAS KNOCK DOWN AN NIPBL.

4875
03:51:42,874 --> 03:51:45,844
THERE IS TWO SRRNA WHICH IS 

4876
03:51:45,844 --> 03:51:47,278
STRONGER ONE IS STRONGER.

4877
03:51:47,278 --> 03:51:51,349
SHE DID BOTH RNA SEEK AND K H 

4878
03:51:51,349 --> 03:51:54,786
SEEK WHICH ALLOWS YOU TO MAP 

4879
03:51:54,786 --> 03:51:57,155
DIFFERENTIAL USAGE OF START 

4880
03:51:57,155 --> 03:51:57,455
SITES.

4881
03:51:57,455 --> 03:51:58,690
WHAT YOU CAN SEE IS THAT THERE 

4882
03:51:58,690 --> 03:52:03,294
ARE WHEN YOU KNOCK DOWN NIPBL 

4883
03:52:03,294 --> 03:52:07,198
THERE ARE MANY EVENTS, MANY 

4884
03:52:07,198 --> 03:52:10,969
CHANGES IN EXPRESSION INCLUDING 

4885
03:52:10,969 --> 03:52:13,872
ALKATI AND MANY ALTERNATIVE 

4886
03:52:13,872 --> 03:52:20,011
TRANSCRIPTION SITES BY ALK, ALK4

4887
03:52:20,011 --> 03:52:20,912
AND OTHERS.

4888
03:52:20,912 --> 03:52:22,414
IN PARTICULAR THERE THIS KNOCK 

4889
03:52:22,414 --> 03:52:32,957
DOWN INDUCES THIS ALKAT UING ON 

4890
03:52:40,732 --> 03:52:40,832
JEN.

4891
03:52:40,832 --> 03:52:41,166
OK

4892
03:52:41,166 --> 03:52:41,599
AWN

4893
03:52:41,599 --> 03:52:41,733
.

4894
03:52:41,733 --> 03:52:45,136
>> IF YOU LOOK CLUSTER IN
KRAN 

4895
03:52:45,136 --> 03:52:46,838
DESCRIPTION SATURDAY S

4896
03:52:46,838 --> 03:52:47,172
START SITES.

4897
03:52:47,172 --> 03:52:50,508
IN ALK, IN NORMAL CIRCUMSTANCES 

4898
03:52:50,508 --> 03:52:52,544
MOST OF THEM ARE ASSOCIATED WITH

4899
03:52:52,544 --> 03:52:52,877
PROMOTERS.

4900
03:52:52,877 --> 03:52:57,382
WHEN YOU KNOCK DOWN NIPBL YOU 

4901
03:52:57,382 --> 03:53:03,521
GET AN EXPANSION SO NEW 

4902
03:53:03,521 --> 03:53:05,323
INITIATION OF TRANSCRIPTION.

4903
03:53:05,323 --> 03:53:05,957
NEW TRANSCRIPTION START SITES AT

4904
03:53:05,957 --> 03:53:08,493
DISTAL INTERGENIC REGIONS.

4905
03:53:08,493 --> 03:53:10,562
WITH BOTH.

4906
03:53:10,562 --> 03:53:10,862
OKAY.

4907
03:53:10,862 --> 03:53:21,406
SO YOU ARE GETTING THIS GLOBAL 

4908
03:53:22,373 --> 03:53:22,941
ALTERNATIVE PROMOTER USAGE WITH 

4909
03:53:22,941 --> 03:53:23,374
KNOCKDOWN OF NIPBL.

4910
03:53:23,374 --> 03:53:23,575
OKAY.

4911
03:53:23,575 --> 03:53:25,910
A NEW OBSERVATION.

4912
03:53:25,910 --> 03:53:26,878
WHEN YOU START LOOKING AT SOME 

4913
03:53:26,878 --> 03:53:29,781
OF THESE EVENTS, OKAY YOU BEING 

4914
03:53:29,781 --> 03:53:34,853
WITH K H SEEK THIS ALKATI EVENT 

4915
03:53:34,853 --> 03:53:38,189
AND INITIATION OF TRANSCRIPTION.

4916
03:53:38,189 --> 03:53:39,657
YOU CAN SEE RNA SEQ.

4917
03:53:39,657 --> 03:53:42,460
AND THERE IS AN TRANSCRIPT BUT 

4918
03:53:42,460 --> 03:53:45,630
YOU CAN ALSO LOOK AT REPEAT 

4919
03:53:45,630 --> 03:53:45,897
ELEMENTS.

4920
03:53:45,897 --> 03:53:46,731
AND YOU CAN SEE THAT THERE THIS 

4921
03:53:46,731 --> 03:53:53,705
EVENT OVERLAPS WITH AN LTR 

4922
03:53:53,705 --> 03:53:53,938
REPEAT.

4923
03:53:53,938 --> 03:53:54,139
OKAY.

4924
03:53:54,139 --> 03:53:58,009
AND IN FACT, WE SAW THAT IN 

4925
03:53:58,009 --> 03:53:58,977
MULTIPLE CASES THAT YOU SAW 

4926
03:53:58,977 --> 03:54:02,180
ASSOCIATION WITH ALTERNATIVE 

4927
03:54:02,180 --> 03:54:05,984
TRANSCRIPTION INITIATION UNDER 

4928
03:54:05,984 --> 03:54:09,888
NICHLT IPBL KNOCKDOWN WITH PRESS

4929
03:54:09,888 --> 03:54:12,757
ENOF AN LTR REPEAT.

4930
03:54:12,757 --> 03:54:14,726
OKAY.

4931
03:54:14,726 --> 03:54:16,828
LTRS OCCUPY 8 PERCENT OF THE 

4932
03:54:16,828 --> 03:54:17,162
GENOME.

4933
03:54:17,162 --> 03:54:21,266
AND THEY HARBOR REGULATORY 

4934
03:54:21,266 --> 03:54:22,133
ELEMENTS.

4935
03:54:22,133 --> 03:54:24,602
THEY HAD HARBOR TRANSCRIPTION 

4936
03:54:24,602 --> 03:54:25,837
AND BINDING SITES.

4937
03:54:25,837 --> 03:54:30,308
IT IS KNOWN THAT SUBSET OF LTRS 

4938
03:54:30,308 --> 03:54:32,777
ACTUALLY ACT AS PRIMARY 

4939
03:54:32,777 --> 03:54:34,813
ALTERNATIVE PROMOTERS.

4940
03:54:34,813 --> 03:54:35,180
OKAY.

4941
03:54:35,180 --> 03:54:39,284
AND WHAT YOU CAN SEE HERE WHEN 

4942
03:54:39,284 --> 03:54:42,821
WE LOOK AT ENELECTRONIC AND 

4943
03:54:42,821 --> 03:54:46,057
DISTALLY, EVEN PROMOTER REGIONS 

4944
03:54:46,057 --> 03:54:50,895
AND WE LOOK AT THE ALTERNATIVE 

4945
03:54:50,895 --> 03:54:53,631
TRANSCRIPTION INITIATION SITES 

4946
03:54:53,631 --> 03:54:56,534
YOU SEE AN ENRICHMENT OF SITES 

4947
03:54:56,534 --> 03:55:01,005
THAT OVERLAP WITH LTR REPEATS.

4948
03:55:01,005 --> 03:55:05,510
EVEN IN THE PROMOTER CASE.

4949
03:55:05,510 --> 03:55:08,813
OKAY.

4950
03:55:08,813 --> 03:55:11,683
SO LTRS CARRY REGULATORY 

4951
03:55:11,683 --> 03:55:13,117
ELEMENTS, ONE OF THEM THAT HAS 

4952
03:55:13,117 --> 03:55:15,954
BEEN REPORTED BEFORE IS MITF 

4953
03:55:15,954 --> 03:55:17,522
WHICH IS ALSO DISCUSSED IN 

4954
03:55:17,522 --> 03:55:24,662
PREVIOUS TALKS.

4955
03:55:24,662 --> 03:55:27,599
AND INDEED WHEN YOU KNOCK DOWN 

4956
03:55:27,599 --> 03:55:30,668
NIPBL YOU SEE INCREASED 

4957
03:55:30,668 --> 03:55:34,005
OCCUPANCY OF MITF.

4958
03:55:34,005 --> 03:55:37,642
FOR EXAMPLE AT THE ALKTI LOCUS 

4959
03:55:37,642 --> 03:55:42,347
AND OTHER SPOTS.

4960
03:55:42,347 --> 03:55:45,450
OKAY.

4961
03:55:45,450 --> 03:55:50,722
SO NEXT WE LOOKED AT OVERALL 

4962
03:55:50,722 --> 03:55:52,223
CHROMATIN ORGANIZATION.

4963
03:55:52,223 --> 03:55:57,428
AND WHAT YOU CAN SEE PERHAPS, IS

4964
03:55:57,428 --> 03:56:05,069
THAT SOME OF THE STRONG TAD 

4965
03:56:05,069 --> 03:56:05,670
STRUCT

4966
03:56:05,670 --> 03:56:08,139
STRUCTURES ARE BREAKING DOWN.

4967
03:56:08,139 --> 03:56:08,740
AND THIS IS PERHAPS WHAT YOU 

4968
03:56:08,740 --> 03:56:10,875
WOULD EXPECT IF YOU REDUCED 

4969
03:56:10,875 --> 03:56:14,145
EXPRESSION OF THE COHES 

4970
03:56:14,145 --> 03:56:15,013
INLOADER.

4971
03:56:15,013 --> 03:56:16,614
SO QUANTIFY THIS WE USED A 

4972
03:56:16,614 --> 03:56:19,517
METHOD CALLED ON TAD.

4973
03:56:19,517 --> 03:56:22,353
IT A HIERARCHICAL TAD.

4974
03:56:22,353 --> 03:56:26,391
HAS IF XU STATES A METHOD WHERE 

4975
03:56:26,391 --> 03:56:28,793
IS CALLING TAD AND A SUBTAD AND 

4976
03:56:28,793 --> 03:56:31,429
GIVING AN ANNOTATION.

4977
03:56:31,429 --> 03:56:34,599
SO THINK ELTON IS JUST SO A TAD 

4978
03:56:34,599 --> 03:56:37,168
HAS NO SUBTADS FOR NESTED TADS 

4979
03:56:37,168 --> 03:56:39,604
YOU HAVE LEVEL 1, LEVEL 2, LEVEL

4980
03:56:39,604 --> 03:56:39,737
3.

4981
03:56:39,737 --> 03:56:45,009
WHAT YOU CAN SEE UNDER LOSS OF 

4982
03:56:45,009 --> 03:56:48,446
OR REDUCED NIPBL EXPRESSION 

4983
03:56:48,446 --> 03:56:50,014
YOU'RE ALSO REDUCING THE LEVEL 

4984
03:56:50,014 --> 03:56:51,983
OF HIESHG AROUND KEY OF TADS.

4985
03:56:51,983 --> 03:56:56,788
SO YOU HAVE SINGLETON AND AMONG 

4986
03:56:56,788 --> 03:57:00,491
NESTED TADS THEY HAVE REDUCED 

4987
03:57:00,491 --> 03:57:03,828
LEVELS.

4988
03:57:03,828 --> 03:57:04,963
OKAY.

4989
03:57:04,963 --> 03:57:10,101
AND THAT'S TRUE AT ALKATI AND 

4990
03:57:10,101 --> 03:57:11,903
MANY OTHER LOCI.

4991
03:57:11,903 --> 03:57:15,239
SO LET'S LOOK AT THE HI C.

4992
03:57:15,239 --> 03:57:19,444
THIS IS NIPBL INSUFFICIENT CELLS

4993
03:57:19,444 --> 03:57:23,414
AND IN THE KNOCKDOWN.

4994
03:57:23,414 --> 03:57:24,048
WHAUK ASEE RIGHT AT THIS LOCUS 

4995
03:57:24,048 --> 03:57:28,319
AND THESE ARE PART OF ON TAD 

4996
03:57:28,319 --> 03:57:32,423
RESULTS, AND VISUALIZATION HERE,

4997
03:57:32,423 --> 03:57:35,727
ALKATI IS INSIDE THE SUBTAD.

4998
03:57:35,727 --> 03:57:37,562
AND UNDER LOSS OF EXPRESSION AS 

4999
03:57:37,562 --> 03:57:41,366
OF NIPBL YOU HAVE DYSAGGREGATION

5000
03:57:41,366 --> 03:57:44,936
OF THE TAD AND A SUDDENLY ALKATI

5001
03:57:44,936 --> 03:57:46,671
IS NEAR THE BOUNDARY OF A TOP 

5002
03:57:46,671 --> 03:57:50,108
LEVEL TAD.

5003
03:57:50,108 --> 03:57:51,709
IN GENERAL WHAT WE SEE, AND I I 

5004
03:57:51,709 --> 03:57:53,011
DON'T SHOW THE QUANTIFICATION 

5005
03:57:53,011 --> 03:57:54,379
HERE BUT JUST THE CARTOON.

5006
03:57:54,379 --> 03:57:57,615
YOU HAVE DYSAGGREGATION OF TADS.

5007
03:57:57,615 --> 03:58:01,452
THIS LOSS OF HIERARCHICAL 

5008
03:58:01,452 --> 03:58:01,753
STRUCTURE.

5009
03:58:01,753 --> 03:58:04,222
AND NEW ALTERNATIVE 

5010
03:58:04,222 --> 03:58:05,223
TRANSCRIPTION SITES THAT ARE 

5011
03:58:05,223 --> 03:58:07,525
USED TEND TO BE NEAR THE 

5012
03:58:07,525 --> 03:58:10,695
BOUNDARIES OF WHAT USED TO BE 

5013
03:58:10,695 --> 03:58:12,930
SUBTADS AND ARE NOW TAD 

5014
03:58:12,930 --> 03:58:15,533
BOUNDARIES.

5015
03:58:15,533 --> 03:58:17,068
OKAY.

5016
03:58:17,068 --> 03:58:19,137
FINAL POINTS.

5017
03:58:19,137 --> 03:58:25,209
WHAT WE CAN ALSO SEE IS THAT 

5018
03:58:25,209 --> 03:58:28,813
THROUGH THIS LOSS OF 

5019
03:58:28,813 --> 03:58:34,018
HIERARCHICAL TAD STRUCTURE 

5020
03:58:34,018 --> 03:58:36,387
ALKATI WHICH IS AT THE BOUNDARY 

5021
03:58:36,387 --> 03:58:39,190
OF WHAT WAS SUBTAD IS ALSO 

5022
03:58:39,190 --> 03:58:40,892
GAINING INTERACTIONS WITH 

5023
03:58:40,892 --> 03:58:42,593
UPSTREAM AND DOWN STREAM 

5024
03:58:42,593 --> 03:58:42,927
ENHANCERS.

5025
03:58:42,927 --> 03:58:46,531
SO AGAIN, THIS IS FOR C.

5026
03:58:46,531 --> 03:58:48,800
IN BLACK IS THE CONTROL.

5027
03:58:48,800 --> 03:58:51,469
AND GREEN IS THE KNOCKDOWN.

5028
03:58:51,469 --> 03:58:57,508
AND YOU CAN SEE THE SPECIFIC 

5029
03:58:57,508 --> 03:58:57,775
INCREASES.

5030
03:58:57,775 --> 03:59:02,580
SO AND HERE IS THE DATA WHERE 

5031
03:59:02,580 --> 03:59:07,985
YOU LOOK AT EXPRESSION OF ALKRNA

5032
03:59:07,985 --> 03:59:13,524
AND YOU DO CRISPR.

5033
03:59:13,524 --> 03:59:16,027
A SPECIFIC ENHANCER.

5034
03:59:16,027 --> 03:59:19,097
ALK GAINS SHORT RANGE 

5035
03:59:19,097 --> 03:59:21,566
INTERACTION ACTIONS WITH ACTIVE 

5036
03:59:21,566 --> 03:59:21,999
ENHANCERS.

5037
03:59:21,999 --> 03:59:29,273
ALSO LOSES INTERACTIONS WITH UP 

5038
03:59:29,273 --> 03:59:34,479
TRY METHYL DOMAIN.

5039
03:59:34,479 --> 03:59:35,113
THAT IS MAIN THING I WANTED TO 

5040
03:59:35,113 --> 03:59:35,780
TELL YOU AND I'M ALMOST OUT OF 

5041
03:59:35,780 --> 03:59:36,747
THE TIME.

5042
03:59:36,747 --> 03:59:37,782
THIS IS THE MODEL.

5043
03:59:37,782 --> 03:59:38,082
OKAY.

5044
03:59:38,082 --> 03:59:41,719
SO THAT IN LOSS OF NIPBL THIS 

5045
03:59:41,719 --> 03:59:51,762
TYPE OF ASSOCIATED COHESIN OP 

5046
03:59:51,762 --> 03:59:52,797
THEE.

5047
03:59:52,797 --> 03:59:55,566
YOU GET INITIATION TRANSCRIPTION

5048
03:59:55,566 --> 03:59:57,201
START SITES NEAR BOUNDARY 

5049
03:59:57,201 --> 03:59:57,535
ELEMENTS.

5050
03:59:57,535 --> 04:00:00,138
THEY ARE ALSO ASSOCIATED WITH 

5051
04:00:00,138 --> 04:00:00,938
LTR REPEATS.

5052
04:00:00,938 --> 04:00:04,442
YOU CAN ALSO THINK IN 

5053
04:00:04,442 --> 04:00:05,943
PHYSIOLOGICAL CONTEXT MAYBE THIS

5054
04:00:05,943 --> 04:00:07,011
TAD STRUCTURE.

5055
04:00:07,011 --> 04:00:10,815
THIS HIERARCHICAL TAD STRUCTURE 

5056
04:00:10,815 --> 04:00:13,151
IS PART OF GENOME ORGANIZATION 

5057
04:00:13,151 --> 04:00:17,722
THAT PREVENTS EXPRESSION OF 

5058
04:00:17,722 --> 04:00:18,022
LTRS.

5059
04:00:18,022 --> 04:00:18,322
OKAY.

5060
04:00:18,322 --> 04:00:20,925
I WILL JUST END BY THANK 

5061
04:00:20,925 --> 04:00:22,793
EVERYONE WHO DID THE WORK.

5062
04:00:22,793 --> 04:00:25,429
ALISSA LONG IN THE LAB DID ALL 

5063
04:00:25,429 --> 04:00:34,338
THE EXPERIMENTAL WORK.

5064
04:00:34,338 --> 04:00:38,209
THANK YOU TO ALL THAT DID WORK 

5065
04:00:38,209 --> 04:00:39,877
ON THIS PROJECT.

5066
04:00:39,877 --> 04:00:41,646
AND I WILL JUST STOP SHARING AND

5067
04:00:41,646 --> 04:00:47,084
TAKE ANY QUESTIONS.

5068
04:00:47,084 --> 04:00:49,387
>> THANK YOU SO MUCH,
CHRISTINA.

5069
04:00:49,387 --> 04:00:54,158
WE HAVE TIME FOR ONE QUESTION.

5070
04:00:54,158 --> 04:00:56,060
>> THANK YOU FOR YOUR
TALK.

5071
04:00:56,060 --> 04:01:00,364
SO I WONDER WHAT ARE BIOLOGICAL 

5072
04:01:00,364 --> 04:01:03,434
CONSEQUENCE OF NI PBL.

5073
04:01:03,434 --> 04:01:07,338
YOU MAY IMAGINE THIS IS GOING TO

5074
04:01:07,338 --> 04:01:09,440
INDID YOU GOS EXPRESSION OF NEW 

5075
04:01:09,440 --> 04:01:09,807
ANTIGENS.

5076
04:01:09,807 --> 04:01:15,479
THAT IS HAPPENING, DO YOU HAVE A

5077
04:01:15,479 --> 04:01:15,746
RESPONSE?

5078
04:01:15,746 --> 04:01:23,354
>> SO THIS SOMETHING THAT,

5079
04:01:23,354 --> 04:01:25,523
ANOTHER PROJECTS SHE'S DEFINITE 

5080
04:01:25,523 --> 04:01:27,725
LT IN IMMUNE RESPONSE.

5081
04:01:27,725 --> 04:01:30,294
WE WERE MAINLY LOOKING AT THAT 

5082
04:01:30,294 --> 04:01:37,835
THE ALKATTI GENE AND OTHER 

5083
04:01:37,835 --> 04:01:38,069
EVENTS.

5084
04:01:38,069 --> 04:01:40,838
BUT IT ALSO TRUE THAT THIS KIND 

5085
04:01:40,838 --> 04:01:42,173
OF MORE PERMISSIVE TRANSCRIPTION

5086
04:01:42,173 --> 04:01:47,778
COULD HAVE COULD HAVE ADDITIONAL

5087
04:01:47,778 --> 04:01:48,112
CONSEQUENCES.

5088
04:01:48,112 --> 04:01:50,214
>> THANK YOU SO MUCH.

5089
04:01:50,214 --> 04:01:53,017
NEXT SPEAKER IS JASON LOCASALE 

5090
04:01:53,017 --> 04:01:55,486
WHO WILL TALK TO US ABOUT 

5091
04:01:55,486 --> 04:02:05,963
INTERFACE OF METABOLISM AND 

5092
04:02:46,237 --> 04:02:46,804
EPIGEN

5093
04:02:46,804 --> 04:02:49,173
EPIGENETICS.

5094
04:02:49,173 --> 04:02:57,948
 >> OKAY.

5095
04:02:57,948 --> 04:03:00,718
THANK YOU ORGANIZERS FOR PUTTING

5096
04:03:00,718 --> 04:03:03,587
TOGETHER WHAT HAS BEEN A REALLY 

5097
04:03:03,587 --> 04:03:05,056
GREAT MEETING.

5098
04:03:05,056 --> 04:03:06,324
I CERTAINLY LEARNED A LOT.

5099
04:03:06,324 --> 04:03:08,192
I MEAN IT WAS ESPECIALLY NICE TO

5100
04:03:08,192 --> 04:03:10,328
SEE ALL THE HISTORY AND TO 

5101
04:03:10,328 --> 04:03:12,096
REVISIT A LOT OF THAT AND LEARN 

5102
04:03:12,096 --> 04:03:13,864
ABOUT IT.

5103
04:03:13,864 --> 04:03:16,667
AND SEE ALL OF THESE DIVERSE 

5104
04:03:16,667 --> 04:03:19,070
AREAS OF EPIGENTICS COME IN AND 

5105
04:03:19,070 --> 04:03:21,238
SEE ALL THE NEW DEVELOPMENTS.

5106
04:03:21,238 --> 04:03:22,440
IS IT REALLY A. REALLY GREAT 

5107
04:03:22,440 --> 04:03:23,774
MEETING I'M REALLY LEARNING A 

5108
04:03:23,774 --> 04:03:24,308
LOT.

5109
04:03:24,308 --> 04:03:26,610
ESPECIALLY HAVING BEEN FOCUSED 

5110
04:03:26,610 --> 04:03:28,312
MAINLY IN THE METABOLISM FIELD 

5111
04:03:28,312 --> 04:03:31,282
OVER THE YEARS.

5112
04:03:31,282 --> 04:03:31,982
OKAY.

5113
04:03:31,982 --> 04:03:36,187
SO THIS IS FIRST TIME I'M 

5114
04:03:36,187 --> 04:03:38,422
TALKING TO MANY OF YOU.

5115
04:03:38,422 --> 04:03:41,425
I'LL JUST INTRODUCE OUR RESEARCH

5116
04:03:41,425 --> 04:03:45,196
AND THE PROGRAM OF DEVELOPING 

5117
04:03:45,196 --> 04:03:48,532
OVER THE YEARS FIRST AND I'LL DO

5118
04:03:48,532 --> 04:03:51,068
THAT VERY BRIEFLY.

5119
04:03:51,068 --> 04:03:54,171
NEXT I'LL, YOU KNOW I WANT TO 

5120
04:03:54,171 --> 04:03:54,672
KIND

5121
04:03:54,672 --> 04:03:56,374
KIND OF EMPHASIZE SOME OF THE 

5122
04:03:56,374 --> 04:04:00,177
CONCEPTS RELATED TO THE STUDY OF

5123
04:04:00,177 --> 04:04:03,214
EPIGENTICS, PARTICULARLY AS IT 

5124
04:04:03,214 --> 04:04:04,515
RELATES TO METABOLISM AND NOW 

5125
04:04:04,515 --> 04:04:07,451
METABOLISM INTERSECTS, CONNECTS 

5126
04:04:07,451 --> 04:04:09,687
SOMETIMES, INFLUENCES, YOU KNOW 

5127
04:04:09,687 --> 04:04:13,124
THE ASPECTS OF ALL THE THINGS 

5128
04:04:13,124 --> 04:04:14,392
WE'VE BEEN LEARNING ABOUT TODAY.

5129
04:04:14,392 --> 04:04:17,027
AND THEN, FINALLY, FOR THE 

5130
04:04:17,027 --> 04:04:19,096
LATTER PART OF THE TALK, I'LL 

5131
04:04:19,096 --> 04:04:22,867
TALK ABOUT AT DEFINING 

5132
04:04:22,867 --> 04:04:26,404
METABOLISM AND A METABOLISMIC 

5133
04:04:26,404 --> 04:04:27,037
NETWORK THAT WE'VE WORKING ON 

5134
04:04:27,037 --> 04:04:29,573
AND I'LL TALK ABOUT HOW THAT IS 

5135
04:04:29,573 --> 04:04:30,975
INFLUENCED BY DIET AND HOW THAT 

5136
04:04:30,975 --> 04:04:35,546
COMES INTO THE CONCEPTS AROUND 

5137
04:04:35,546 --> 04:04:35,846
EPIGENTICS.

5138
04:04:35,846 --> 04:04:36,480
>> OKAY.

5139
04:04:36,480 --> 04:04:38,883
SO OUR RESEARCH GENERALLY 

5140
04:04:38,883 --> 04:04:41,552
SPEAKING IS IN YOU KNOW THREE 

5141
04:04:41,552 --> 04:04:42,420
BASIC AREAS.

5142
04:04:42,420 --> 04:04:47,558
I MEAN WE'RE -- I ORIGINALLY 

5143
04:04:47,558 --> 04:04:50,995
TRAINED IN CHEMISTRY AND 

5144
04:04:50,995 --> 04:04:51,228
PHYSICS.

5145
04:04:51,228 --> 04:04:52,830
WHEN I WAS LOOKING FOR A POST 

5146
04:04:52,830 --> 04:04:54,498
DOC I WANTED TO THINK ABOUT 

5147
04:04:54,498 --> 04:04:56,867
AREAS OF STUDY WHERE I COULD 

5148
04:04:56,867 --> 04:04:59,303
APPLY SOME OF THE SKILLS AND 

5149
04:04:59,303 --> 04:05:01,505
SOME OF THE TECHNIQUES THAT I'VE

5150
04:05:01,505 --> 04:05:04,408
AND WAYS OF THINKING THAT 

5151
04:05:04,408 --> 04:05:06,177
ACCUMULATED SINCE THAT TIME.

5152
04:05:06,177 --> 04:05:09,280
AND WANTED TO WORK IN AN AREA OF

5153
04:05:09,280 --> 04:05:10,147
BIOMEDICAL RESEARCH.

5154
04:05:10,147 --> 04:05:13,751
SO I EVENTUALLY DID A POST DOC A

5155
04:05:13,751 --> 04:05:20,858
CANCER HOSPITAL AT BETH IS RAY 

5156
04:05:20,858 --> 04:05:21,492
HE WILL.

5157
04:05:21,492 --> 04:05:24,061
AND WILL YOU WAS A HIGHLY 

5158
04:05:24,061 --> 04:05:27,832
ESTABLISHED IN GROWTH FACTORS 

5159
04:05:27,832 --> 04:05:28,232
SIGNALLING FIELD.

5160
04:05:28,232 --> 04:05:30,668
HE REALLY MADE A LOT OF 

5161
04:05:30,668 --> 04:05:32,069
CONTRIBUTIONS AND GETTING INTO 

5162
04:05:32,069 --> 04:05:34,271
HOW SIGNAL PATHWAYS WERE 

5163
04:05:34,271 --> 04:05:36,474
INTERACTING WITH METABOLISM.

5164
04:05:36,474 --> 04:05:38,509
IT WAS A PERFECT FIT.

5165
04:05:38,509 --> 04:05:41,545
IT ENABLED ME TO BRING IN A LOT 

5166
04:05:41,545 --> 04:05:42,880
OF EXPERTISE THAT I HAD BOTH IN 

5167
04:05:42,880 --> 04:05:44,982
CHEMISTRY AND ALSO IN PHYSICAL 

5168
04:05:44,982 --> 04:05:45,216
SCIENCE.

5169
04:05:45,216 --> 04:05:49,320
SO MY RESEARCH OVER THE YEARS IS

5170
04:05:49,320 --> 04:05:53,057
FOCUSED A LOT ON METABOLISM, AND

5171
04:05:53,057 --> 04:05:54,024
A WAYS TO MEASURE METABOLISM.

5172
04:05:54,024 --> 04:05:57,461
COMPUTATIONAL APPROACH AND 

5173
04:05:57,461 --> 04:05:58,095
ANALYZING STRUCTURE AND FUNCTION

5174
04:05:58,095 --> 04:05:58,429
OF METABOLISM.

5175
04:05:58,429 --> 04:06:03,000
THAT LEAD TO THINGS OF ABOUT 

5176
04:06:03,000 --> 04:06:03,634
THINKING LIKE THERAPEUTIC AND 

5177
04:06:03,634 --> 04:06:05,402
MORE RECENT DIET IN CANCER AND 

5178
04:06:05,402 --> 04:06:07,872
ALSO WAYS THESE NETWORK OF 

5179
04:06:07,872 --> 04:06:11,742
METABOLISM CONFER BIOLOGICAL 

5180
04:06:11,742 --> 04:06:12,343
FUNCTION AND THAT ESSENTIALLY 

5181
04:06:12,343 --> 04:06:14,078
GOT US THINKING TO THINKING 

5182
04:06:14,078 --> 04:06:16,447
ABOUT EPIGENTICS AND I'LL 

5183
04:06:16,447 --> 04:06:17,515
INTRODUCE THAT IN A BIT.

5184
04:06:17,515 --> 04:06:19,283
SO GENERALLY SPEAKING A STRONG 

5185
04:06:19,283 --> 04:06:20,451
INTEREST IN TECHNOLOGY 

5186
04:06:20,451 --> 04:06:23,521
DEVELOPMENT TO STUDY METABOLISM.

5187
04:06:23,521 --> 04:06:25,623
BOTH IN THE AREA OF ANALYTICAL 

5188
04:06:25,623 --> 04:06:26,857
CHEMISTRY AND ALSO IN THE AREA 

5189
04:06:26,857 --> 04:06:31,829
OF DEVELOPING MATHEMATICAL TO

5190
04:06:31,829 --> 04:06:32,496
TOOLS.

5191
04:06:32,496 --> 04:06:34,932
BOTH IN PHYSIC AND AI AND 

5192
04:06:34,932 --> 04:06:36,300
MACHINE LEARNING.

5193
04:06:36,300 --> 04:06:38,235
THESE ARE JUST SOME OF THE KIND 

5194
04:06:38,235 --> 04:06:40,638
OF EXAMPLES OF THINGS WE'VE 

5195
04:06:40,638 --> 04:06:41,505
LOOKING AT OVER THE YEARS IN 

5196
04:06:41,505 --> 04:06:44,174
THIS AREA.

5197
04:06:44,174 --> 04:06:44,708
LIKE ONE, WHETHER IT IS 

5198
04:06:44,708 --> 04:06:47,011
DEVELOPING TRACING TOOLS AND 

5199
04:06:47,011 --> 04:06:48,012
QUANTITATIVE ANALYSIS TO 

5200
04:06:48,012 --> 04:06:50,881
UNDERSTAND THE STRUCTURE OF 

5201
04:06:50,881 --> 04:06:51,982
METABOLISM.

5202
04:06:51,982 --> 04:06:54,084
THOUGHT ABOUT SINGLE CELL 

5203
04:06:54,084 --> 04:06:56,253
ANALYSIS OF METABOLISM.

5204
04:06:56,253 --> 04:06:57,855
AND WAYS TO USE MACHINE LEARNING

5205
04:06:57,855 --> 04:07:01,392
TO UNDERSTAND NUTRITION AND DIET

5206
04:07:01,392 --> 04:07:03,994
AND HOW IT INTERACTS WITH 

5207
04:07:03,994 --> 04:07:04,828
METABOLISM.

5208
04:07:04,828 --> 04:07:06,597
THESE ARE ALL THINGS THIS WE'VE 

5209
04:07:06,597 --> 04:07:08,399
BEEN WORKING ON.

5210
04:07:08,399 --> 04:07:10,334
BUT THIS IS THE TOPIC OF WHAT I 

5211
04:07:10,334 --> 04:07:13,003
WANTED TO TALK TO IN THE SPIRIT 

5212
04:07:13,003 --> 04:07:16,740
OF THIS MEETING.

5213
04:07:16,740 --> 04:07:17,274
BASICALLY HOW METABOLISM 

5214
04:07:17,274 --> 04:07:18,275
INTERACTS WITH ALL OF THE THINGS

5215
04:07:18,275 --> 04:07:19,777
WE'VE THINKING ABOUT AND ALL THE

5216
04:07:19,777 --> 04:07:21,512
CONCEPTS THAT HAVE BEEN 

5217
04:07:21,512 --> 04:07:23,280
DEVELOPED AT THIS MEETING AND 

5218
04:07:23,280 --> 04:07:28,352
OVER THE LAST 40 YEARS.

5219
04:07:28,352 --> 04:07:28,919
SO BASIC IDEA IS YOU'VE GOT 

5220
04:07:28,919 --> 04:07:33,157
THESE METABOLIC NETWORKS THAT 

5221
04:07:33,157 --> 04:07:34,959
ARE NODES WITHIN THESE METABOLIC

5222
04:07:34,959 --> 04:07:37,361
NED WORKS THAT INVOLVE SMALL 

5223
04:07:37,361 --> 04:07:38,696
MOLECULES ACTIVE NODES, AND 

5224
04:07:38,696 --> 04:07:43,567
THESE MOLECULES SERVE AS 

5225
04:07:43,567 --> 04:07:44,234
CO-FACTORS, AS BINDING PARTNERS 

5226
04:07:44,234 --> 04:07:48,639
A WELL SUBSTRATES AND PRODUCTS 

5227
04:07:48,639 --> 04:07:49,673
OF ENZYMES THAT THAT WITHDREW 

5228
04:07:49,673 --> 04:07:53,477
THINK ABOUT TO BE INVOLVED IN 

5229
04:07:53,477 --> 04:07:54,078
CHROMA

5230
04:07:54,078 --> 04:07:55,713
CHROMATIN, DNA METHYLATION AND 

5231
04:07:55,713 --> 04:07:59,116
THE GENERAL CONCEPT OF 

5232
04:07:59,116 --> 04:07:59,416
EPIGENTICS.

5233
04:07:59,416 --> 04:08:02,286
AND THOSE ARE THE MOST COMMONLY 

5234
04:08:02,286 --> 04:08:05,255
THOUGHT OF ALPHA, A SUBSTRATE 

5235
04:08:05,255 --> 04:08:09,526
FOR METH LACES.

5236
04:08:09,526 --> 04:08:14,098
USED IN HI STONE.

5237
04:08:14,098 --> 04:08:18,869
ONE I'LL TALK ABOUT TODAY IS -- 

5238
04:08:18,869 --> 04:08:22,239
AND THAT IS OR SAND IS THE 

5239
04:08:22,239 --> 04:08:24,775
METHYL DONOR THAT ARE USED IN 

5240
04:08:24,775 --> 04:08:27,878
THE REACTION TIME SHOWN ON THE 

5241
04:08:27,878 --> 04:08:28,545
RIGHT HERE.

5242
04:08:28,545 --> 04:08:33,183
THESE ARE JUST SOME EXAMPLES.

5243
04:08:33,183 --> 04:08:35,619
POTENTIALLY LINKED TO DIET TO 

5244
04:08:35,619 --> 04:08:38,555
THINGS LIKE EPIGENTICS VIA 

5245
04:08:38,555 --> 04:08:39,823
INTERACTIONS WITH CHROMATIN AND 

5246
04:08:39,823 --> 04:08:41,859
AS WELL A DNA.

5247
04:08:41,859 --> 04:08:44,862
YOU CAN THINK OF A NUMBER OF 

5248
04:08:44,862 --> 04:08:46,930
DIETARY FACTORS AS WELLS 

5249
04:08:46,930 --> 04:08:47,865
ENVIRONMENTAL INFLUENCES THAT 

5250
04:08:47,865 --> 04:08:49,833
INFLUENCE THESE MOLECULE THAT I 

5251
04:08:49,833 --> 04:08:51,935
JUST TALKED ABOUT.

5252
04:08:51,935 --> 04:08:54,071
RANGING FROM HI POX SEE YA, 

5253
04:08:54,071 --> 04:08:56,640
CALORIE RESTRICTION, EXERCISE, 

5254
04:08:56,640 --> 04:08:59,176
TO MORE SPECIFIC THINGS LIKE 

5255
04:08:59,176 --> 04:09:00,577
ALCOHOL INTAKE.

5256
04:09:00,577 --> 04:09:02,680
DIETARY FIBER, FAT INTAKE, 

5257
04:09:02,680 --> 04:09:11,021
SOMETHING TALK A LOT MORE ABOUT 

5258
04:09:11,021 --> 04:09:11,655
IN A BIT DEFINE LEARNING MORE 

5259
04:09:11,655 --> 04:09:13,824
RECENTLY BEING A POTENTIALLY 

5260
04:09:13,824 --> 04:09:15,726
MAJOR MODIFIER PS BASICALLY 

5261
04:09:15,726 --> 04:09:16,827
THINKING THIS ONE WAY IN WHICH 

5262
04:09:16,827 --> 04:09:18,395
THE ENVIRONMENT POTENTIALLY 

5263
04:09:18,395 --> 04:09:20,097
INTERACTS WITH THE KIND OF 

5264
04:09:20,097 --> 04:09:21,165
THINGS THAT WE'VE TALKING ABOUT 

5265
04:09:21,165 --> 04:09:24,635
DURING THIS MEETINGS.

5266
04:09:24,635 --> 04:09:26,203
JUST DIFFERENT WAYS TO 

5267
04:09:26,203 --> 04:09:26,870
CONCEPTUALIZE THIS.

5268
04:09:26,870 --> 04:09:28,839
THIS IS ONE KIND OF WAY OF 

5269
04:09:28,839 --> 04:09:31,175
THINKING ABOUT IT IN TERMS OF 

5270
04:09:31,175 --> 04:09:31,442
GENETICS.

5271
04:09:31,442 --> 04:09:32,843
AND I'LL TALK MORE ABOUT 

5272
04:09:32,843 --> 04:09:33,877
EPIGENTICS IN A BIT.

5273
04:09:33,877 --> 04:09:36,513
BUT JUST THINKING ABOUT GENETICS

5274
04:09:36,513 --> 04:09:38,215
ONE WAY WE THINK ABOUT CANCER 

5275
04:09:38,215 --> 04:09:40,884
AND CONTEXT OF GENETICS I KNOW 

5276
04:09:40,884 --> 04:09:42,853
CANCER EPIGENTIC DISEASE BUT 

5277
04:09:42,853 --> 04:09:46,123
THINKING ABOUT GENETICS FOR A 

5278
04:09:46,123 --> 04:09:46,356
SECOND.

5279
04:09:46,356 --> 04:09:47,991
GENERALLY THINKING YOU THINK OF 

5280
04:09:47,991 --> 04:09:50,494
CELLS REQUIRE MUTATION THAT COOP

5281
04:09:50,494 --> 04:09:52,362
NORMAL PHYSIOLOGY WHETHER THAT 

5282
04:09:52,362 --> 04:09:55,232
WOUND HEALING OR INFLAMMATION OR

5283
04:09:55,232 --> 04:09:57,067
GROWTH FACTOR SIGNALLING.

5284
04:09:57,067 --> 04:10:00,003
BASICALLY CELLS ACQUIRE MUTATION

5285
04:10:00,003 --> 04:10:03,140
THAT IS ALLOW THEM TO COOP THESE

5286
04:10:03,140 --> 04:10:03,807
PATHWAYS.

5287
04:10:03,807 --> 04:10:05,476
THINKING ABOUT A CANCER 

5288
04:10:05,476 --> 04:10:07,444
METABOLISM, GENERALLY SPEAKING 

5289
04:10:07,444 --> 04:10:09,179
THE CRITICISM ESPECIALLY FROM 

5290
04:10:09,179 --> 04:10:12,583
JET NETTIC IS ALWAYS RECEIVED AS

5291
04:10:12,583 --> 04:10:16,019
NOT MANY MUTATIONS IN METABOLIC 

5292
04:10:16,019 --> 04:10:16,420
NETWORKS.

5293
04:10:16,420 --> 04:10:18,756
AND THE WAY I KIND OF GRAPPLED 

5294
04:10:18,756 --> 04:10:20,057
WITH THIS AND TRIED TO THINK 

5295
04:10:20,057 --> 04:10:21,725
ABOUT WHERE METABOLISM MIGHT BE 

5296
04:10:21,725 --> 04:10:23,460
INVOLVED IN ACTUALLY DRIVING 

5297
04:10:23,460 --> 04:10:25,963
DEVELOPMENT IS IT ACTUALLY VERY 

5298
04:10:25,963 --> 04:10:26,830
CLOSELY CONNECTED TO YOU KNOW 

5299
04:10:26,830 --> 04:10:28,966
CLASSES OF ENZYME THAT IS 

5300
04:10:28,966 --> 04:10:31,502
COMMONLY MUTATED.

5301
04:10:31,502 --> 04:10:35,706
IN FACT, THESE ARE ONE WAY TO 

5302
04:10:35,706 --> 04:10:36,306
THINK ABOUT METABOLISM IN THE 

5303
04:10:36,306 --> 04:10:37,674
CONTEXT OF CANCER IS BASICALLY 

5304
04:10:37,674 --> 04:10:39,877
IMPLODER, PART OF THE PROCESS OF

5305
04:10:39,877 --> 04:10:42,179
ACTUALLY MODIFYING THINGS LIKE 

5306
04:10:42,179 --> 04:10:47,017
CHROMATIN AND DNA.

5307
04:10:47,017 --> 04:10:50,888
THE BIOCHEMICAL BASIS OF THIS IS

5308
04:10:50,888 --> 04:10:53,524
FAIRLY SIMPLE.

5309
04:10:53,524 --> 04:10:55,726
SO GENERALLY SPEAKING POST 

5310
04:10:55,726 --> 04:10:56,760
TRANSLATIONAL MODIFICATIONS 

5311
04:10:56,760 --> 04:10:58,829
THINGS LIKE PHOSPHORYLATION, 

5312
04:10:58,829 --> 04:11:01,532
ASEAT LAGS, METHYLATION, 

5313
04:11:01,532 --> 04:11:02,866
GENERALLY THEY HAVE AN ENZYME 

5314
04:11:02,866 --> 04:11:06,069
AND SUBSTRATE AND CO-FACTORS.

5315
04:11:06,069 --> 04:11:09,072
THE MOST COMMONLY STUDIED ONE 

5316
04:11:09,072 --> 04:11:10,674
ARGUABLY PROTEIN CAN I NIECES.

5317
04:11:10,674 --> 04:11:14,344
THOSE ARE ALL KINDS OF CELLULAR 

5318
04:11:14,344 --> 04:11:14,678
PHYSIOLOGY.

5319
04:11:14,678 --> 04:11:20,017
BUT THESE KINASES USE METABOLIC 

5320
04:11:20,017 --> 04:11:21,385
SUBSTRATE ATP.

5321
04:11:21,385 --> 04:11:24,221
FOR THE CASE OF KINASES THE 

5322
04:11:24,221 --> 04:11:26,590
CONSTANT IS GENERALLY ON THE 

5323
04:11:26,590 --> 04:11:27,791
MICRO MOLAR.

5324
04:11:27,791 --> 04:11:30,594
ATP IS ON AN ORDER OF MINI 

5325
04:11:30,594 --> 04:11:31,161
MOLAR.

5326
04:11:31,161 --> 04:11:34,131
KINASES NEVER SEE SITUATIONS IN 

5327
04:11:34,131 --> 04:11:37,601
CELLS WHERE THEY ARE LIMITED BY 

5328
04:11:37,601 --> 04:11:37,768
ATP.

5329
04:11:37,768 --> 04:11:40,437
THAT'S IN CONTRAST TO THE ENZYME

5330
04:11:40,437 --> 04:11:47,444
IS LIKE HI STONES, ET CETERA 

5331
04:11:47,444 --> 04:11:48,011
WHERE THOSE, THOSE HAVE A 

5332
04:11:48,011 --> 04:11:50,047
SUBSTRATE KM OS N OUT ORDER OF 

5333
04:11:50,047 --> 04:11:50,814
MICRO HAULER.

5334
04:11:50,814 --> 04:11:53,283
AND SUBSTRATE RANGES 

5335
04:11:53,283 --> 04:11:55,786
CONCENTRATION RANGES ARE ALSO 

5336
04:11:55,786 --> 04:11:56,453
MICRO.

5337
04:11:56,453 --> 04:12:01,859
SUGGESTING THAT CHANGES IN THE 

5338
04:12:01,859 --> 04:12:02,492
CONCENTRATION OF THINGS LIKE SAM

5339
04:12:02,492 --> 04:12:05,529
OR ACTUALLY CHANGE THE RATE RATE

5340
04:12:05,529 --> 04:12:06,330
OF ENZYME.

5341
04:12:06,330 --> 04:12:09,833
THE ACTIVITY OF THE ENZYME.

5342
04:12:09,833 --> 04:12:11,068
AND WHAT I'LL SHOW LATER ON IN 

5343
04:12:11,068 --> 04:12:12,903
THE TALK IN MANY CASES THEY CAN 

5344
04:12:12,903 --> 04:12:16,473
BE JUST AS STRONG AS EPIGENETIC 

5345
04:12:16,473 --> 04:12:18,575
MODIFYING FACTOR AS SOME OF 

5346
04:12:18,575 --> 04:12:20,477
THESE ENZYMES I'M JUST LIMITING 

5347
04:12:20,477 --> 04:12:23,080
THE SUBSTRATE AVAILABILITY.

5348
04:12:23,080 --> 04:12:24,915
THIS IS HIGHLIGHTED IN A REVIEW 

5349
04:12:24,915 --> 04:12:28,385
THAT WE WROTE MANY YEARS AGO.

5350
04:12:28,385 --> 04:12:29,987
WHICH JUST BASIC COLLECTS A LOT 

5351
04:12:29,987 --> 04:12:32,656
OF PRIMERS AND UNFORTUNATELY THE

5352
04:12:32,656 --> 04:12:34,925
GROUPS LIKE HAVE DONE A LOT OF 

5353
04:12:34,925 --> 04:12:36,360
CHARACTERIZATION ON THE 

5354
04:12:36,360 --> 04:12:41,498
ENTOMOLOGY AND DEFINING KINETIC 

5355
04:12:41,498 --> 04:12:41,999
PARAMETER AND A LOT OF 

5356
04:12:41,999 --> 04:12:44,001
INFORMATION ESPECIALLY AS IT 

5357
04:12:44,001 --> 04:12:45,168
RELATES TO A DRUG DEVELOPMENT 

5358
04:12:45,168 --> 04:12:46,536
AND COMPOUNDS.

5359
04:12:46,536 --> 04:12:47,738
THERASE LOT OF INFORMATION AND 

5360
04:12:47,738 --> 04:12:50,507
THIS IS JUST AN EXAMPLE OF ALL 

5361
04:12:50,507 --> 04:12:53,610
THE DIFFERENT KINETIC PARAMETER 

5362
04:12:53,610 --> 04:12:54,211
AND HOW THEY ARE WITHIN THE 

5363
04:12:54,211 --> 04:12:56,847
RANGE OF METABOLISM 

5364
04:12:56,847 --> 04:12:57,214
CONCENTRATIONS.

5365
04:12:57,214 --> 04:12:58,282
IN TERMS OF THINKING ABOUT THIS 

5366
04:12:58,282 --> 04:13:00,183
IN TERMS OF EPIGENTICS.

5367
04:13:00,183 --> 04:13:03,053
I REALLY WAS INSPIRED BY, 

5368
04:13:03,053 --> 04:13:04,521
ESPECIALLY BY ANDY'S WORK OVER 

5369
04:13:04,521 --> 04:13:06,156
THE YEARS.

5370
04:13:06,156 --> 04:13:08,592
AS HE TALKED ABOUT EARLIER, AND 

5371
04:13:08,592 --> 04:13:11,962
BASICALLY BRINGING THE WADDING 

5372
04:13:11,962 --> 04:13:17,234
TON LAND SKSCAPE INTO THEORY OFW

5373
04:13:17,234 --> 04:13:20,070
EPIGENTICS MIGHT WORK AND.

5374
04:13:20,070 --> 04:13:22,873
SOME POINT BUT, GENERALLY 

5375
04:13:22,873 --> 04:13:23,907
SPEAKING, YOU KNOW THERE IS 

5376
04:13:23,907 --> 04:13:25,409
STILL KIND OF DEVELOPING THIS, 

5377
04:13:25,409 --> 04:13:28,512
BUT THERE TWO WAYS IN WHICH 

5378
04:13:28,512 --> 04:13:32,115
METABOLISM MIGHT INTERACT WITH 

5379
04:13:32,115 --> 04:13:32,983
EPIGENTICS.

5380
04:13:32,983 --> 04:13:35,552
ONE IS A POTENTIALLY ALLOWS 

5381
04:13:35,552 --> 04:13:36,820
MOVEMENT ALONG THE LANDSCAPE.

5382
04:13:36,820 --> 04:13:39,056
IT IS EITHER AN ENVIRONMENTAL 

5383
04:13:39,056 --> 04:13:40,590
DRIVER OR A CONTRIBUTES 

5384
04:13:40,590 --> 04:13:42,125
SOMETHING TO THE PROCESS.

5385
04:13:42,125 --> 04:13:43,627
OR THE OTHER IS JUST THAT IT 

5386
04:13:43,627 --> 04:13:45,362
ACTUALLY IS PART OF THE 

5387
04:13:45,362 --> 04:13:47,965
LANDSCAPE JUST AS ENZYMES AND 

5388
04:13:47,965 --> 04:13:51,601
OTHER ASPECTS OF EPIGENTICS ARE.

5389
04:13:51,601 --> 04:13:53,003
IN THAT CASE IT WOULD ACTUALLY 

5390
04:13:53,003 --> 04:13:54,338
BE CHANGING THE ACTUAL STRUCTURE

5391
04:13:54,338 --> 04:13:56,640
OF THE LANDSCAPE.

5392
04:13:56,640 --> 04:13:57,941
BUT BOTH OF THESE KIND OF THINGS

5393
04:13:57,941 --> 04:13:59,309
MIGHT BE IN PLAY IN DIFFERENT 

5394
04:13:59,309 --> 04:14:01,678
SITUATIONS.

5395
04:14:01,678 --> 04:14:02,312
AND THEN STILL A LOT OF WORK TO 

5396
04:14:02,312 --> 04:14:03,447
DO IN TERMS OF CHARACTERIZING 

5397
04:14:03,447 --> 04:14:03,647
THIS.

5398
04:14:03,647 --> 04:14:07,551
BUT THIS IS JUST BASICALLY A 

5399
04:14:07,551 --> 04:14:08,485
FRAMEWORK OF THINKING ABOUT HOW 

5400
04:14:08,485 --> 04:14:10,988
METABOLISM MIGHT BE INVOLVED IN 

5401
04:14:10,988 --> 04:14:14,057
EPIGENTICS.

5402
04:14:14,057 --> 04:14:14,257
OKAY.

5403
04:14:14,257 --> 04:14:18,495
SO THE PATHWAY OR NETWORK WE'VE 

5404
04:14:18,495 --> 04:14:23,266
WORKING ON OVER YEAR IS THIS ONE

5405
04:14:23,266 --> 04:14:23,667
CARBON METABOLISM.

5406
04:14:23,667 --> 04:14:25,635
IT BEGAN AS I WAS POST DOC IN 

5407
04:14:25,635 --> 04:14:28,939
LOUIE'S LAB I WAS A WAR BIRD OR 

5408
04:14:28,939 --> 04:14:30,974
ALTERED GLUCOSE METABOLISM AT 

5409
04:14:30,974 --> 04:14:32,209
THAT TIME I MADE OBSERVATION 

5410
04:14:32,209 --> 04:14:34,544
THAT CERTAIN CANCER CELLS WERE 

5411
04:14:34,544 --> 04:14:36,480
DIVERTING THEIR GLUCOSE INTO 

5412
04:14:36,480 --> 04:14:39,683
AMINO ACID SYNTHESIS.

5413
04:14:39,683 --> 04:14:44,254
VIA OXIDATION AND A TRANS AM 

5414
04:14:44,254 --> 04:14:44,921
NATION REACTION AND INTERMEDIATE

5415
04:14:44,921 --> 04:14:46,123
ALT GLYCOLYSIS.

5416
04:14:46,123 --> 04:14:47,391
BUT GENERALLY SPEAKING THAT KIND

5417
04:14:47,391 --> 04:14:52,896
OF OPENED THE DOOR TO ME AND TO 

5418
04:14:52,896 --> 04:14:54,197
MANY OTHERS AROUND THAT TIME IN 

5419
04:14:54,197 --> 04:14:55,732
THINKING ABOUT WHAT THIS PATHWAY

5420
04:14:55,732 --> 04:14:57,334
ACTUALLY DOES AND HOW IT IS 

5421
04:14:57,334 --> 04:14:59,970
CONNECTED TO CANCER.

5422
04:14:59,970 --> 04:15:02,539
CANCER BIOLOGY AND ONE WAY TO 

5423
04:15:02,539 --> 04:15:04,041
THINK ABOUT THIS PATHWAY IT IS 

5424
04:15:04,041 --> 04:15:06,510
BASICALLY AN INTEGRATION HUB OR 

5425
04:15:06,510 --> 04:15:07,411
NUTRIENTS COME IN.

5426
04:15:07,411 --> 04:15:09,346
IT IS CALLED ONE CARBON 

5427
04:15:09,346 --> 04:15:10,347
METABOLISM WITHOUT GETTING INTO 

5428
04:15:10,347 --> 04:15:11,415
ALL BIOCHEMISTRY.

5429
04:15:11,415 --> 04:15:13,817
BUT THE MOVEMENT OF A CARBON 

5430
04:15:13,817 --> 04:15:15,786
UNIT AROUND A COUPLE OF 

5431
04:15:15,786 --> 04:15:17,954
DIFFERENT METABOLIC CYCLES.

5432
04:15:17,954 --> 04:15:27,898
AND FOR THE PURPOSES OF THIS 

5433
04:15:27,898 --> 04:15:28,532
SYMPOSIUM, THAT CARBON UNIT IS 

5434
04:15:28,532 --> 04:15:29,166
ALSO THE METHYL WOULD WORD THAT 

5435
04:15:29,166 --> 04:15:31,301
A USE USED FOR HI STONES AND 

5436
04:15:31,301 --> 04:15:31,468
DNA.

5437
04:15:31,468 --> 04:15:33,403
THERE ALSO A LOT OF OTHER 

5438
04:15:33,403 --> 04:15:36,740
FUNCTIONS, RANGING FROM ANABOLIC

5439
04:15:36,740 --> 04:15:40,744
METABOLISM, REDUCTION 

5440
04:15:40,744 --> 04:15:44,314
METABOLISM, ET CETERA.

5441
04:15:44,314 --> 04:15:45,315
IN STUDYING THIS WE WERE 

5442
04:15:45,315 --> 04:15:47,317
BASICALLY PROFILING 

5443
04:15:47,317 --> 04:15:49,719
CONCENTRATIONS OF, WE WERE USING

5444
04:15:49,719 --> 04:15:51,988
METABOLISM TO A PROFILE WILL 

5445
04:15:51,988 --> 04:15:53,590
CONCENTRATION IRNLT MEDIATES IN 

5446
04:15:53,590 --> 04:15:56,393
A PATHWAYS IN HEALTHY HUMAN 

5447
04:15:56,393 --> 04:15:56,660
SUBJECTS.

5448
04:15:56,660 --> 04:16:05,836
AND WHAT WE FOUND WAS TMETHIONI 

5449
04:16:05,836 --> 04:16:08,138
A MOST DYNAMIC.

5450
04:16:08,138 --> 04:16:09,706
I SHOULD MENTION THIS WILL 

5451
04:16:09,706 --> 04:16:11,108
BECOME RELEVANT IN A MOMENT.

5452
04:16:11,108 --> 04:16:14,010
BUT THE TYPICAL TISSUE CULTURE 

5453
04:16:14,010 --> 04:16:16,046
CONCENTRATION IS AROUND 100 

5454
04:16:16,046 --> 04:16:17,047
MICRO MOLAR.

5455
04:16:17,047 --> 04:16:19,683
RANGE WE SAW IN HUMANS WAS ABOUT

5456
04:16:19,683 --> 04:16:22,719
THREE TO 35, THREE OF 35 MICRO 

5457
04:16:22,719 --> 04:16:22,986
MOLAR.

5458
04:16:22,986 --> 04:16:24,554
IT TURNS OUT THAT THERE IS A 

5459
04:16:24,554 --> 04:16:35,031
LONG STANDING HISTORY OF ME 

5460
04:16:35,799 --> 04:16:36,700
THYM 

5461
04:16:36,700 --> 04:16:37,033
ME

5462
04:16:37,033 --> 04:16:37,434
MEME 

5463
04:16:37,434 --> 04:16:38,268
THIO NEEN.

5464
04:16:38,268 --> 04:16:40,837
IT HAS OFFICIALLY SUBSTANTIAL 

5465
04:16:40,837 --> 04:16:44,541
EFFECTS ON HEALTH IN ANIMALS.

5466
04:16:44,541 --> 04:16:45,709
IT A CONCERTED FACTOR INVOLVED 

5467
04:16:45,709 --> 04:16:48,845
IN AGING ALL THE WAY DOWN TO 

5468
04:16:48,845 --> 04:16:49,246
YEAST.

5469
04:16:49,246 --> 04:16:52,549
DIET INDUCED AN OBESITY CAN OH 

5470
04:16:52,549 --> 04:16:57,721
BELATED WITH ME THYMINE 

5471
04:16:57,721 --> 04:16:58,021
RESTRICTION.

5472
04:16:58,021 --> 04:16:59,556
AND SOMETHING IT HAS A LOT OF 

5473
04:16:59,556 --> 04:17:02,826
INTERESTING ANTI CANCER EFFECTS.

5474
04:17:02,826 --> 04:17:05,996
PARTICULARLY AS IT COUPLES TO 

5475
04:17:05,996 --> 04:17:06,630
THERAPIES THAT ARE ALSO INVOLVED

5476
04:17:06,630 --> 04:17:08,732
IN ONE CARBON.

5477
04:17:08,732 --> 04:17:10,467
RADIATION WHICH AFFECTS 

5478
04:17:10,467 --> 04:17:12,669
NUCLEOTIDE SYNTHESIS, ET CETERA.

5479
04:17:12,669 --> 04:17:13,770
SO THERE ARE A LOT OF 

5480
04:17:13,770 --> 04:17:19,643
INTERESTING THINGS ABOUT DIETARY

5481
04:17:19,643 --> 04:17:20,243
ME TIE

5482
04:17:20,243 --> 04:17:20,911
ME THIO NEEN.

5483
04:17:20,911 --> 04:17:22,612
WHEN WE LOOK AT HUMAN FOOD.

5484
04:17:22,612 --> 04:17:24,548
I WAS BRIEFLY MENTIONING 

5485
04:17:24,548 --> 04:17:27,350
EARLIER, IS THAT YOU KNOW, THERE

5486
04:17:27,350 --> 04:17:28,885
IS WIDE RANGES OF CONTENT IN 

5487
04:17:28,885 --> 04:17:29,519
HUMAN FOOD.

5488
04:17:29,519 --> 04:17:32,289
YOU CAN WE CATEGORIZE IT IN THE 

5489
04:17:32,289 --> 04:17:35,025
CONTEXT OF TYPICAL HUMAN DIETS 

5490
04:17:35,025 --> 04:17:35,859
ON THE LEFT.

5491
04:17:35,859 --> 04:17:37,794
YOU CAN SEE WESTERN DIET YOU GO 

5492
04:17:37,794 --> 04:17:39,729
FROM A WESTERN TO A, YOU KNOW TO

5493
04:17:39,729 --> 04:17:44,668
A VEGAN OR A JAPANESE KIND OF 

5494
04:17:44,668 --> 04:17:48,138
SPACED DIET YOU CAN GET 3 FOLD, 

5495
04:17:48,138 --> 04:17:50,173
FOR FOLD CHANGES IN CONTENT THAT

5496
04:17:50,173 --> 04:17:50,941
ONE EATS.

5497
04:17:50,941 --> 04:17:53,410
IF YOU LOOK ALONG DIFFERENT FOOD

5498
04:17:53,410 --> 04:17:56,346
GROUPS, GENERALLY SPEAKING ON 

5499
04:17:56,346 --> 04:18:00,150
PER PROTEIN BASIS, THINGS LIKE 

5500
04:18:00,150 --> 04:18:01,952
LEGUMES AND VEGETABLE BASED 

5501
04:18:01,952 --> 04:18:05,689
PROTEIN ARE LOW IN ME THIO NEEN.

5502
04:18:05,689 --> 04:18:08,258
AND THINGS LIKE MUSCLE BASE 

5503
04:18:08,258 --> 04:18:10,594
PROTEIN LIKE MEAT ARE HIGHEST IN

5504
04:18:10,594 --> 04:18:11,861
ME THIO NEEN.

5505
04:18:11,861 --> 04:18:14,030
WITH EGGS BEING THE HIGHEST.

5506
04:18:14,030 --> 04:18:16,499
SO YOU GET A VERY DYNAMIC RANGE 

5507
04:18:16,499 --> 04:18:17,834
BASED ON FOOD.

5508
04:18:17,834 --> 04:18:19,436
AND WE WORK WITH NUTRITION 

5509
04:18:19,436 --> 04:18:22,005
GROUPS TO SEE AND THERE'S BEEN 

5510
04:18:22,005 --> 04:18:24,241
SOME CLINICAL TRIALS IN THE LAST

5511
04:18:24,241 --> 04:18:28,311
FEW YEARS SHOWING THAT DIETARY 

5512
04:18:28,311 --> 04:18:32,682
CONTENT OF ME THIO NEEN CAN 

5513
04:18:32,682 --> 04:18:33,250
INFLUENCE PLASMA IN A VERY 

5514
04:18:33,250 --> 04:18:35,385
DYNAMIC ACUTE.

5515
04:18:35,385 --> 04:18:37,254
SO I MENTION ONE CARBON.

5516
04:18:37,254 --> 04:18:40,590
IT HAS LOT OF FUNCTIONS.

5517
04:18:40,590 --> 04:18:41,891
ONE I WILL TALK ABOUT AND FOR 

5518
04:18:41,891 --> 04:18:48,098
THE REST OF THIS MEETING IS THIS

5519
04:18:48,098 --> 04:18:48,665
POTENTIAL INTERACTION WITH 

5520
04:18:48,665 --> 04:18:48,965
EPIGENTICS.

5521
04:18:48,965 --> 04:18:51,501
SO THE KEY KIND OF FINDINGS THAT

5522
04:18:51,501 --> 04:19:00,010
WE MADE MADE OVER THE YEARS WAS 

5523
04:19:00,010 --> 04:19:02,746
THIS BASIC CONCEPT THAT TYPICAL 

5524
04:19:02,746 --> 04:19:05,482
TISSUE CULTURE CONCENTRATIONS OF

5525
04:19:05,482 --> 04:19:08,351
ME THIO NEEN IN TISSUE CULTURE 

5526
04:19:08,351 --> 04:19:12,222
MEDIUM 100 MICRO MOLAR.

5527
04:19:12,222 --> 04:19:12,822
WE BRING IT DOWN TO THE LOWER 

5528
04:19:12,822 --> 04:19:14,524
LIMIT OF WHAT HAS BEEN OBSERVED 

5529
04:19:14,524 --> 04:19:17,093
IN HUMANS WHICH ABOUT THREE PRY 

5530
04:19:17,093 --> 04:19:20,096
CHROMO LAR YOU CAN SEE DYNAMICS 

5531
04:19:20,096 --> 04:19:21,898
HI STONE MODIFICATIONS.

5532
04:19:21,898 --> 04:19:24,401
THEY ARE ACUTE, REVERSIBLE AND A

5533
04:19:24,401 --> 04:19:26,970
SUFFICIENT TO ALTER DEPOSITION 

5534
04:19:26,970 --> 04:19:30,607
OF MARKS ACROSS THE GENOME.

5535
04:19:30,607 --> 04:19:32,475
THERE IS A LOT OF WORK WE'VE 

5536
04:19:32,475 --> 04:19:34,944
DONE ON THIS OVER THE YEARS.

5537
04:19:34,944 --> 04:19:37,981
I MEAN STILL A LOT OF OPEN 

5538
04:19:37,981 --> 04:19:38,515
QUEST

5539
04:19:38,515 --> 04:19:39,015
QUESTIONS.

5540
04:19:39,015 --> 04:19:40,550
ONE IS JUST, YOU KNOW HOW THIS 

5541
04:19:40,550 --> 04:19:43,653
POTENTIALLY INTERACTS WITH GENE 

5542
04:19:43,653 --> 04:19:45,922
REGULATION, GENE EXPRESSION.

5543
04:19:45,922 --> 04:19:48,291
WHETHER THIS HAS ANYTHING TO DO 

5544
04:19:48,291 --> 04:19:51,828
WITH EPIGENTIC WHICH INVOLVED 

5545
04:19:51,828 --> 04:19:54,097
STABLE PHENO TYPES.

5546
04:19:54,097 --> 04:19:56,299
AND INHERITABLE.

5547
04:19:56,299 --> 04:19:58,968
AND A GENERALITY OR SPECIFICITY.

5548
04:19:58,968 --> 04:19:59,969
SOME OF THE ORIGINAL STUDIES WE 

5549
04:19:59,969 --> 04:20:02,205
FOUND CERTAIN MARKS WERE VERY 

5550
04:20:02,205 --> 04:20:04,107
DYNAMIC AND OTHER ONES WEREN'T.

5551
04:20:04,107 --> 04:20:06,042
I'LL TRY TO BRIEFLY TOUCH UPON A

5552
04:20:06,042 --> 04:20:09,679
COUPLE OF THESE QUESTIONS.

5553
04:20:09,679 --> 04:20:12,215
OKAY TO DO THIS WE HAVE DOING A 

5554
04:20:12,215 --> 04:20:13,049
CLASSIC DIFFERENTIATION ASSAY 

5555
04:20:13,049 --> 04:20:13,249
HERE.

5556
04:20:13,249 --> 04:20:19,989
THIS A MYO-GENESIS ASSAY.

5557
04:20:19,989 --> 04:20:22,425
I BELIEVE PETER WEATHERS 

5558
04:20:22,425 --> 04:20:26,629
DISCUSSED THIS ONE PREVIOUSLY.

5559
04:20:26,629 --> 04:20:26,930
A

5560
04:20:26,930 --> 04:20:29,566
AND BASICALLY, LONG STORY SHORT 

5561
04:20:29,566 --> 04:20:31,668
IS THAT THESE DATA ARE SHOWING 

5562
04:20:31,668 --> 04:20:34,971
THAT ME THIO NEEN.

5563
04:20:34,971 --> 04:20:35,605
THERE IS A DEPENDENCE ON THE 

5564
04:20:35,605 --> 04:20:37,841
DIFFERENTIATION IT IS DOSE 

5565
04:20:37,841 --> 04:20:38,108
DEPENDENT.

5566
04:20:38,108 --> 04:20:41,378
AND BASICALLY, YOU KNOW, IT IS 

5567
04:20:41,378 --> 04:20:41,878
REQU

5568
04:20:41,878 --> 04:20:42,612
REQUIRED.

5569
04:20:42,612 --> 04:20:43,680
DIFFERENTIATION, BUT NOT CELL 

5570
04:20:43,680 --> 04:20:46,082
VIABILITY AND NOT PROLIFERATION 

5571
04:20:46,082 --> 04:20:51,321
AT THE HIGHER DOSES IS REQUIRED,

5572
04:20:51,321 --> 04:20:55,959
REQUIRES ME THIO NEEN.

5573
04:20:56,259 --> 04:20:58,628
 HI STONE, OR DYNAMICALLY 

5574
04:20:58,628 --> 04:21:00,363
ARTICLED IN THESE THESE 

5575
04:21:00,363 --> 04:21:00,663
SETTINGS.

5576
04:21:00,663 --> 04:21:03,433
WE BASICALLY PRO FILED A BUNCH 

5577
04:21:03,433 --> 04:21:10,340
OF COMMONLY STUDY HIS STONE 

5578
04:21:10,340 --> 04:21:10,940
MODIFICATIONS.

5579
04:21:10,940 --> 04:21:13,910
0 ON K 36, THAT WAS HIGHLY 

5580
04:21:13,910 --> 04:21:17,313
DYNAMIC ONE IN THIS SETTING.

5581
04:21:17,313 --> 04:21:23,820
THAT IS AIDED BY SET D2.

5582
04:21:23,820 --> 04:21:26,923
IN THIS CASE YOU KNOCK OUT SET D

5583
04:21:26,923 --> 04:21:28,458
2 OR LOWER IT YOU GET SIMILAR 

5584
04:21:28,458 --> 04:21:30,760
TYPES OF PHENOTYPE WITH RESPECT 

5585
04:21:30,760 --> 04:21:32,061
TO DIFFERENTIATION AND YOU CAN 

5586
04:21:32,061 --> 04:21:34,330
ACTUALLY RESCUE SOME 

5587
04:21:34,330 --> 04:21:35,365
DIFFERENTIATION BY EXPRESSIONS 

5588
04:21:35,365 --> 04:21:39,302
SECHLT D 2 ON TOP OF KNOCKDOWN 

5589
04:21:39,302 --> 04:21:41,304
AND THAT WILL CHANGE WHETHER THE

5590
04:21:41,304 --> 04:21:44,607
CELLS RESPOND TO METHIONINE OR 

5591
04:21:44,607 --> 04:21:44,874
NOT.

5592
04:21:44,874 --> 04:21:47,744
IF WE LOOK AT GENE ACTIVITY 

5593
04:21:47,744 --> 04:21:50,413
ASSOCIATED WITH K 36, DURING THE

5594
04:21:50,413 --> 04:21:52,182
DIFFERENTIATION PROCESS AS WELL 

5595
04:21:52,182 --> 04:21:55,752
AS IN RESPONSE TO METHIONINE.

5596
04:21:55,752 --> 04:21:59,422
WE HE ENRICHMENTS IN A MYO.

5597
04:21:59,422 --> 04:22:01,458
THAT IS IMPACTING GENES INVOLVED

5598
04:22:01,458 --> 04:22:05,929
IN THE IDENTITY OF THESE CELLS.

5599
04:22:05,929 --> 04:22:08,531
AND IF WE LOOK AT CHROMATIN 

5600
04:22:08,531 --> 04:22:11,601
DYNAMICS, YOU KNOW, USING ATK, 

5601
04:22:11,601 --> 04:22:14,204
DOING THAT EITHER WITH 

5602
04:22:14,204 --> 04:22:14,838
METHIO

5603
04:22:14,838 --> 04:22:18,208
METHIONINE.

5604
04:22:18,208 --> 04:22:21,878
SET D TWOMENT 2 DO.  KNOCK OUT .

5605
04:22:21,878 --> 04:22:26,583
IF EITHER METHIONINE RESTRICTED 

5606
04:22:26,583 --> 04:22:27,851
CELLS OR WE KNOCK OUT THE ACTUAL

5607
04:22:27,851 --> 04:22:32,555
ENZYME THAT PUTS ON THE 

5608
04:22:32,555 --> 04:22:32,956
METHYLATION GROUP.

5609
04:22:32,956 --> 04:22:33,156
OKAY.

5610
04:22:33,156 --> 04:22:34,691
SO THIS IS AT LEAST JUST SHOWING

5611
04:22:34,691 --> 04:22:36,593
THAT AT LEAST IN SOME BASIC 

5612
04:22:36,593 --> 04:22:40,196
SIMPLE MODELS LIKE JUST A MYO-2 

5613
04:22:40,196 --> 04:22:41,798
DIFFERENTIATION MODEL THAT THE 

5614
04:22:41,798 --> 04:22:44,968
METHIONINE CAN ACTUALLY BE 

5615
04:22:44,968 --> 04:22:46,836
INVOLVED IN THESE KINDS OF 

5616
04:22:46,836 --> 04:22:49,172
EPIGENETIC PROCESS TO A SIMILAR 

5617
04:22:49,172 --> 04:22:51,875
EXTENT IF NOT AT SAME EXTENT 

5618
04:22:51,875 --> 04:22:56,646
THAT A KEY EPIGENETIC ENZYME IN 

5619
04:22:56,646 --> 04:22:57,981
THIS CASE IS DOING.

5620
04:22:57,981 --> 04:22:58,281
OKAY.

5621
04:22:58,281 --> 04:22:59,916
AND SO NOW TO THINK ABOUT HOW 

5622
04:22:59,916 --> 04:23:02,919
THIS MIGHT BE THOUGHT ABOUT IN 

5623
04:23:02,919 --> 04:23:04,854
THE CONTEXT OF AN ORGANISM.

5624
04:23:04,854 --> 04:23:06,556
TO THAT WE'VE USING OUR CLASSIC 

5625
04:23:06,556 --> 04:23:11,394
MODEL FOR DIFFERENTIATION AND 

5626
04:23:11,394 --> 04:23:12,929
EPIGENETIC TRANSMISSION.

5627
04:23:12,929 --> 04:23:14,664
THE REASON WHY WE LIKE THIS 

5628
04:23:14,664 --> 04:23:15,098
MODEL SO MUCH.

5629
04:23:15,098 --> 04:23:17,033
IT WAS A VERY PANDEMIC FRIENDLY 

5630
04:23:17,033 --> 04:23:17,534
MODEL.

5631
04:23:17,534 --> 04:23:20,470
THE ENTIRETY OF THIS IS A CHEAP 

5632
04:23:20,470 --> 04:23:20,670
MODEL.

5633
04:23:20,670 --> 04:23:23,773
THE ENTIRETY OF THESE DATA COST 

5634
04:23:23,773 --> 04:23:25,275
ABOUT $200 TO COLLECT.

5635
04:23:25,275 --> 04:23:27,877
THIS IS QUITE IN CONTRAST TO THE

5636
04:23:27,877 --> 04:23:31,447
MICE AT LEAST I'M WORKING WITH.

5637
04:23:31,447 --> 04:23:35,718
BUT THE REASON WE WERE, BUT THE 

5638
04:23:35,718 --> 04:23:36,352
KEY REASON WE WERE SO INTERESTED

5639
04:23:36,352 --> 04:23:36,986
IN THIS PERSPECTIVE OF 

5640
04:23:36,986 --> 04:23:39,022
METABOLISM IS THAT YOU KNOW, 

5641
04:23:39,022 --> 04:23:41,124
THAT THERE'S A HISTORY OF 

5642
04:23:41,124 --> 04:23:42,992
CHEMICALLY DEFINED DIETS BEING 

5643
04:23:42,992 --> 04:23:45,094
ABLE TO YOU KNOW SUPPORT THE 

5644
04:23:45,094 --> 04:23:48,498
LIFE OF A FRUIT FLY.

5645
04:23:48,498 --> 04:23:51,801
A TYPICAL FRUIT FLY IT'S AGAR, 

5646
04:23:51,801 --> 04:23:53,836
SOI, CORN MEAL, MOLASSES, YEAST 

5647
04:23:53,836 --> 04:23:54,704
FOR PROTEIN.

5648
04:23:54,704 --> 04:23:56,239
BASICALLY YOU CAN COME UP WITH A

5649
04:23:56,239 --> 04:24:00,009
COCKTAIL FROM THE SIGMA CATALOG 

5650
04:24:00,009 --> 04:24:04,180
AND DEFINE CHEMICAL CONSTITUENTS

5651
04:24:04,180 --> 04:24:08,585
BASICALLY RECREATE THE FRUIT FLY

5652
04:24:08,585 --> 04:24:11,421
DEVELOPMENT AND PROPAGATE ITS 

5653
04:24:11,421 --> 04:24:14,791
LIFE AND ITS LIFE HISTORY.

5654
04:24:14,791 --> 04:24:17,460
AND SO WITH SELECTED DIET YOU 

5655
04:24:17,460 --> 04:24:22,031
CAN DO VERY PRECISE CONTROLLABLE

5656
04:24:22,031 --> 04:24:22,565
FEATURES.

5657
04:24:22,565 --> 04:24:24,100
YOU HAVE VERY PREADVICE 

5658
04:24:24,100 --> 04:24:25,368
CONTROLLABLE FEATURES ASSOCIATED

5659
04:24:25,368 --> 04:24:28,504
WITH THE DIET OF THE FRUIT FLY.

5660
04:24:28,504 --> 04:24:33,843
SO SOMETHING LIKE METHIONINE CAN

5661
04:24:33,843 --> 04:24:34,210
EASILY STUDIED.

5662
04:24:34,210 --> 04:24:35,278
THIS IS JUST TO SHOW THAT THAT 

5663
04:24:35,278 --> 04:24:37,814
THESE CHEMICAL DIETS CAN 

5664
04:24:37,814 --> 04:24:41,551
ACTUALLY, ACTUALLY REPRODUCE 

5665
04:24:41,551 --> 04:24:41,985
FRUIT MY PHYSIOLOGY.

5666
04:24:41,985 --> 04:24:44,020
YOU CAN GET SIMILAR LIFE-SPANS 

5667
04:24:44,020 --> 04:24:45,955
SIMILAR BODY WEIGHT AND A 

5668
04:24:45,955 --> 04:24:47,323
DEVELOPMENT TIME AND FERTILITY, 

5669
04:24:47,323 --> 04:24:48,524
ET CETERA.

5670
04:24:48,524 --> 04:24:50,326
BASICALLY YOU CAN CREATE ALL THE

5671
04:24:50,326 --> 04:24:51,794
PROPERTIES OF A FRUIT FLY WITH 

5672
04:24:51,794 --> 04:24:53,096
THESE CHEMICAL DIETS.

5673
04:24:53,096 --> 04:24:55,131
AND SO WE WANTED TO LOOK AT THIS

5674
04:24:55,131 --> 04:24:57,934
IN CONTEXT OF SOME OF THE OLD 

5675
04:24:57,934 --> 04:25:00,236
SCHOOL EPIGENETIC ASSAYS.

5676
04:25:00,236 --> 04:25:03,973
AND THIS IS AN OLD MODEL CALLED 

5677
04:25:03,973 --> 04:25:10,313
POSITION EFFECT LOCUS.

5678
04:25:10,313 --> 04:25:11,147
LONG STORY SHORT.

5679
04:25:11,147 --> 04:25:13,750
THERE IS A GENE THAT SITS AT THE

5680
04:25:13,750 --> 04:25:15,151
BOUNDARY OF YOU KNOW HETEROAND 

5681
04:25:15,151 --> 04:25:20,690
OPEN CHROMATIN.

5682
04:25:20,690 --> 04:25:21,691
AND DYNAMICS AND THIS GENE 

5683
04:25:21,691 --> 04:25:23,726
DETERMINES EYE COLOR AND DYNAMIC

5684
04:25:23,726 --> 04:25:24,994
ASSOCIATE WITH THIS GENE IF THEY

5685
04:25:24,994 --> 04:25:27,730
ARE ALTERED POTENTIALLY BY WHAT 

5686
04:25:27,730 --> 04:25:30,933
THE FRUIT FLY HAS CLASSICALLY 

5687
04:25:30,933 --> 04:25:33,703
STUDIED FOR IS THE GENETICS, 

5688
04:25:33,703 --> 04:25:35,438
THAT YOU KNOW IT TURNS OUT A LOT

5689
04:25:35,438 --> 04:25:38,508
OF THESE CHROMATIN MODIFYING 

5690
04:25:38,508 --> 04:25:39,909
ENZYMES WERE CLONED IN THE 

5691
04:25:39,909 --> 04:25:41,944
CONTEXT OF A GENES THAT GAVE 

5692
04:25:41,944 --> 04:25:43,579
PHENOTYPES IN THIS KIND OF ASSAY

5693
04:25:43,579 --> 04:25:46,416
WHETHER THEY CHANGE THE COLOR OF

5694
04:25:46,416 --> 04:25:49,986
THE FLIY'S EYE.

5695
04:25:49,986 --> 04:25:51,921
JUST HIGHLIGHTING SOME DATA FROM

5696
04:25:51,921 --> 04:25:52,288
THAT.

5697
04:25:52,288 --> 04:25:56,693
IF YOU ACTUALLY PUT THE FLIES ON

5698
04:25:56,693 --> 04:26:01,130
METHIONINE, AND WE CAN DO TRANS 

5699
04:26:01,130 --> 04:26:01,497
GENERATIONALLY, 

5700
04:26:01,497 --> 04:26:02,598
INTERGENERATI

5701
04:26:02,598 --> 04:26:03,700
INTERGENERATI

5702
04:26:03,700 --> 04:26:04,133
INTERGENERATIONALLY.

5703
04:26:04,133 --> 04:26:04,434
ET CETERA.

5704
04:26:04,434 --> 04:26:05,134
BUT THE BASIC IDEA IS THAT YOU 

5705
04:26:05,134 --> 04:26:06,736
PUT THE FLY ON THE THIS DIET AND

5706
04:26:06,736 --> 04:26:10,707
YOU INTRODUCES A STABLE EYE 

5707
04:26:10,707 --> 04:26:16,312
COLOR PHENOTYPE IN THIS MODEL.

5708
04:26:16,312 --> 04:26:17,714
OKAY.

5709
04:26:17,714 --> 04:26:21,017
SO JUST TO SUMMARIZE, I JUST 

5710
04:26:21,017 --> 04:26:22,418
KIND OF HIGHLIGHTED OR 

5711
04:26:22,418 --> 04:26:25,254
INTRODUCED A LOT OF ASPECTS OF 

5712
04:26:25,254 --> 04:26:28,591
METABOLISM EPIGENETIC AND TALKED

5713
04:26:28,591 --> 04:26:29,192
ABOUT FINDING IN CELL STATE 

5714
04:26:29,192 --> 04:26:32,895
TRANSITIONS AND WELL ORGANISMAL 

5715
04:26:32,895 --> 04:26:34,230
PHENOTYPE AND PROPAGATION.

5716
04:26:34,230 --> 04:26:36,132
AND WITH THAT I JUST WANT TO 

5717
04:26:36,132 --> 04:26:38,201
BRIEFLY THANK A FEW OF THE LAB 

5718
04:26:38,201 --> 04:26:40,169
MEMBERS WHO WERE INSTRUMENTAL IN

5719
04:26:40,169 --> 04:26:41,404
THIS WORK.

5720
04:26:41,404 --> 04:26:45,241
MIKE REED A POST DOC ON THE 

5721
04:26:45,241 --> 04:26:48,177
FRUIT FLY STUFF AND CONTINUED 

5722
04:26:48,177 --> 04:26:50,813
AND MIKE IS STILL WORKING WITH 

5723
04:26:50,813 --> 04:26:51,614
ME.

5724
04:26:51,614 --> 04:26:54,283
MIKE IS SENIOR SCIENTIST APPEAR.

5725
04:26:54,283 --> 04:26:57,286
AND A GRAD STUDENT AWAY 

5726
04:26:57,286 --> 04:26:58,955
COMPUTATIONAL BIOLOGIES.

5727
04:26:58,955 --> 04:27:00,857
SHE HAS HER ON LAB NOW.

5728
04:27:00,857 --> 04:27:03,226
WITH THAT HAPPY TO TAKE ANY 

5729
04:27:03,226 --> 04:27:03,960
QUESTIONS.

5730
04:27:03,960 --> 04:27:14,337
THANKS FOR YOUR TIME.

5731
04:27:48,805 --> 04:27:49,705
 [ APPLAUSE ] 

5732
04:27:49,705 --> 04:27:51,641
>> THE BINDING RESTRICTION
ARE 

5733
04:27:51,641 --> 04:27:55,144
SOME EXTENT OF THE METHIONINE 

5734
04:27:55,144 --> 04:27:57,947
RESTRICTION IS, LARGELY IN THE 

5735
04:27:57,947 --> 04:28:06,722
PROTEIN CONTENT OF THE DIET.

5736
04:28:06,722 --> 04:28:07,256
LIKE 

5737
04:28:07,256 --> 04:28:08,324
 THERE AROUND MANY OTHER GROUPS 

5738
04:28:08,324 --> 04:28:10,059
HAVE, AS WELL.

5739
04:28:10,059 --> 04:28:12,628
IN THE CLINICAL NUTRITION FIELD 

5740
04:28:12,628 --> 04:28:15,331
IS THAT GENERALLY SPEAKING 

5741
04:28:15,331 --> 04:28:17,733
PLANTED BASED DIETS AND/OR LOW 

5742
04:28:17,733 --> 04:28:21,704
IN METHIONINE.

5743
04:28:21,704 --> 04:28:24,941
MEAT-BASED DIETS OR FAIRLY 

5744
04:28:24,941 --> 04:28:26,542
SUBSTANTIAL DYNAMICS HOW THAT 

5745
04:28:26,542 --> 04:28:28,744
PROPAGATES TO EPIGENETICS THAT I

5746
04:28:28,744 --> 04:28:31,347
THINK WAS, I THINK AT THE VERY 

5747
04:28:31,347 --> 04:28:35,751
LEAST IT IS INTERESTING.

5748
04:28:35,751 --> 04:28:38,054
IN SOME CASES, WE DON'T SEE A 

5749
04:28:38,054 --> 04:28:39,222
LOT OF CHANGES.

5750
04:28:39,222 --> 04:28:47,697
BUT IN SPECIFIC LABORATORY 

5751
04:28:47,697 --> 04:28:50,499
SETTING LIKE WHETHER CLASSIC 

5752
04:28:50,499 --> 04:28:51,100
DIFFER REPUBLICAN SHAGS SELL 

5753
04:28:51,100 --> 04:28:51,367
STRAIGHT.

5754
04:28:51,367 --> 04:28:51,968
LIKE MYOGENESIS OR FRUIT FLY 

5755
04:28:51,968 --> 04:28:52,768
TRANSMITTING EYE COLOR.

5756
04:28:52,768 --> 04:28:54,036
WE'RE SEEING SOME PRETTY 

5757
04:28:54,036 --> 04:28:57,106
INTERESTING EFFECTS.

5758
04:28:57,106 --> 04:28:58,808
EVENTUALLY FIGURING OUT HOW MUCH

5759
04:28:58,808 --> 04:29:01,077
THIS ACTUALLY PROPAGATES INTO 

5760
04:29:01,077 --> 04:29:03,312
HUMANS IS, IT REMAINS TO BE 

5761
04:29:03,312 --> 04:29:04,280
DETERMINED WHETHER YOU CAN 

5762
04:29:04,280 --> 04:29:05,114
INTERFERE WITH THIS.

5763
04:29:05,114 --> 04:29:08,851
AND THERE SOME LITH ON 

5764
04:29:08,851 --> 04:29:10,486
INTERRUPTING MINTERR

5765
04:29:10,486 --> 04:29:12,288
INTERRUPTING METHIONINE 

5766
04:29:12,288 --> 04:29:14,090
METABOLISMS LIKE SOME PEDIATRIC 

5767
04:29:14,090 --> 04:29:14,490
ONES.

5768
04:29:14,490 --> 04:29:17,093
ESPECIALLY THE K 27 FOR 

5769
04:29:17,093 --> 04:29:17,426
INSTANCE.

5770
04:29:17,426 --> 04:29:19,629
AND THAT, THAT IS PRETTY 

5771
04:29:19,629 --> 04:29:19,929
INTERESTING.

5772
04:29:19,929 --> 04:29:22,331
THERE IS ANOTHER ASPECT OF THIS 

5773
04:29:22,331 --> 04:29:25,001
WHICH IS ACTUALLY SUPPLEMENT 

5774
04:29:25,001 --> 04:29:25,434
LIKE YOU MENTIONED.

5775
04:29:25,434 --> 04:29:27,236
THERE THERE NUTRIENT SUPPLEMENTS

5776
04:29:27,236 --> 04:29:29,472
THAT CAN INTERFERE WITH A 

5777
04:29:29,472 --> 04:29:31,540
METABOLISM AND METHIONINE 

5778
04:29:31,540 --> 04:29:32,541
METABOLISM PROCESSING LIKE THE 

5779
04:29:32,541 --> 04:29:34,477
ONE THAT WAS ON THE NEWS 

5780
04:29:34,477 --> 04:29:34,744
RECENTLY.

5781
04:29:34,744 --> 04:29:37,079
I ACTUALLY HAD AN ENERGY DRINK 

5782
04:29:37,079 --> 04:29:40,116
ABOUT AN HOUR AGO.

5783
04:29:40,116 --> 04:29:43,386
AND IT LACK OF COFFEE BREAKS.

5784
04:29:43,386 --> 04:29:44,654
SO THAT ENERGY DRINK ACTUALLY 

5785
04:29:44,654 --> 04:29:47,523
HAS HIGH CONCENTRATION OF TORE 

5786
04:29:47,523 --> 04:29:50,626
REASON IN IT.

5787
04:29:50,626 --> 04:29:52,895
IT DROWN STREAM OF METHIONINE 

5788
04:29:52,895 --> 04:29:55,431
METABOLISM AND POTENTIALLY 

5789
04:29:55,431 --> 04:30:01,971
DISRUPT THE PROCESS OF 

5790
04:30:01,971 --> 04:30:02,271
METABOLISM.

5791
04:30:02,271 --> 04:30:02,905
HOW MUCH OF HAPPENING IN HUMANS 

5792
04:30:02,905 --> 04:30:03,472
ON DAY-TO-DAY BASIS ON AN 

5793
04:30:03,472 --> 04:30:04,006
INTERGENERATIONAL BASIS.

5794
04:30:04,006 --> 04:30:05,574
WHEN I USED TO TEACH UNDERGRAD, 

5795
04:30:05,574 --> 04:30:07,443
AND LIKE I CAN REMEMBER I USED 

5796
04:30:07,443 --> 04:30:10,546
TO TEACH A COUPLE LECTURES ON 

5797
04:30:10,546 --> 04:30:13,316
EPIGENETIC AND UNDERGRADS AND 

5798
04:30:13,316 --> 04:30:14,684
DUKE, I MENTIONED THAT.

5799
04:30:14,684 --> 04:30:16,919
AND THEY, YOU KNOW, WAS JUST 

5800
04:30:16,919 --> 04:30:20,022
KIND OF AN INTERESTING CONCEPT 

5801
04:30:20,022 --> 04:30:21,524
THAT LIKE WHAT YOUR PARENTS ARE 

5802
04:30:21,524 --> 04:30:21,824
E

5803
04:30:21,824 --> 04:30:23,359
EATING, LIKE THAT COULD AFFECT 

5804
04:30:23,359 --> 04:30:24,760
YOUR TRAITS.

5805
04:30:24,760 --> 04:30:35,204
AND LIKE IN EPIGENETICS 

5806
04:30:35,604 --> 04:30:36,872
COMMUNITY THERE IS A HUNGER FA 

5807
04:30:36,872 --> 04:30:37,173
M

5808
04:30:37,173 --> 04:30:37,907
FA MIN.

5809
04:30:37,907 --> 04:30:39,475
THERE AROUND THOUGHT TO BE SOME 

5810
04:30:39,475 --> 04:30:41,711
SORT OF A TRANS MISSABLE 

5811
04:30:41,711 --> 04:30:42,311
PHENOTYPE.

5812
04:30:42,311 --> 04:30:46,649
BUT WHETHER IT IS OBSERVED IN 

5813
04:30:46,649 --> 04:30:47,316
DAY-TO-DAY, LIKE IF YOU HAVE, I 

5814
04:30:47,316 --> 04:30:55,291
MEAN LIKELY LIKE PLANT BASED SRI

5815
04:30:55,291 --> 04:30:55,691
BEG

5816
04:30:55,691 --> 04:30:57,526
VEGAN IS MORE POPULAR.

5817
04:30:57,526 --> 04:30:59,595
A THERE IN PARTICULAR AREAS.

5818
04:30:59,595 --> 04:31:00,796
GENERALLY THOUGHT TO BE INVOLVED

5819
04:31:00,796 --> 04:31:03,032
IN THINGS LIKE HEALTH SPAN AND 

5820
04:31:03,032 --> 04:31:08,304
ANTI CANCER, ET CETERA WHETHER 

5821
04:31:08,304 --> 04:31:10,239
NEW UF THOSE EFFECTS ARE 

5822
04:31:10,239 --> 04:31:12,141
OCCURRING THROUGH ANY OF THESE 

5823
04:31:12,141 --> 04:31:13,009
PROCESSES DEFINITELY SOMETHING 

5824
04:31:13,009 --> 04:31:16,312
YOU WANT TO WRITE ON.

5825
04:31:16,312 --> 04:31:26,288
>> OKAY.

5826
04:31:26,288 --> 04:31:27,656
>> THANK YOU SO MUCH.

5827
04:31:27,656 --> 04:31:29,759
WE'VE COME TO THE END OF THE 

5828
04:31:29,759 --> 04:31:30,393
SESSION.

5829
04:31:30,393 --> 04:31:39,402
WE WILL HAVE ABOUT FIVE OR 10 

5830
04:31:39,402 --> 04:31:46,175
MINUTES AND WE WILL RECONVENE AT

5831
04:31:46,175 --> 04:31:47,943
3:25.

5832
04:31:53,352 --> 04:32:01,794
ALSO BACK.

5833
04:32:01,794 --> 04:32:07,066
WE'LL HAVE YVONNE 

5834
04:32:07,066 --> 04:32:09,936
FONDUFE-MITTENDORF TO TALK ABOUT

5835
04:32:09,936 --> 04:32:13,139
3-D CHROMATIN STRUCTURE AT THE 

5836
04:32:13,139 --> 04:32:15,908
INTERSECTION OF TOXICOLOGY AND 

5837
04:32:15,908 --> 04:32:18,444
DISEASE.

5838
04:32:18,444 --> 04:32:21,113
>> I'D LIKE TO THANK THE 

5839
04:32:21,113 --> 04:32:26,452
ORGANIZERS FOR INVITING ME ABOUT

5840
04:32:26,452 --> 04:32:36,796
THE WORK IN OUR LAB.

5841
04:32:37,997 --> 04:32:40,766
AND THE WORK WE DO IN THE LAB IS

5842
04:32:40,766 --> 04:32:43,903
ON ARSENIC AND LOW-DOSE CHRONIC 

5843
04:32:43,903 --> 04:32:45,638
EXPOSURE TO ARSENIC HAS BEEN 

5844
04:32:45,638 --> 04:32:49,709
ASSOCIATED WITH SEVERAL DISEASES

5845
04:32:49,709 --> 04:32:50,510
INCLUDING DIABETES AND CANCER 

5846
04:32:50,510 --> 04:32:55,047
AND YOU'RE WONDERING WHERE WE 

5847
04:32:55,047 --> 04:32:57,450
GET ARSENIC FROM AND WE GET IT 

5848
04:32:57,450 --> 04:33:03,789
FROM DRINKING CONTAMINATED WATER

5849
04:33:03,789 --> 04:33:06,292
AND FOOD SOURCES AND FOR THOSE 

5850
04:33:06,292 --> 04:33:09,128
WHO LIVE IN THE AREA AND ARSENIC

5851
04:33:09,128 --> 04:33:10,463
SEEPS IN THE SOIL AND GETS IN 

5852
04:33:10,463 --> 04:33:12,098
THE DRINKING WATER AND WE GET 

5853
04:33:12,098 --> 04:33:14,233
EXPOSED THAT WAY.

5854
04:33:14,233 --> 04:33:16,702
MAKING IT MORE COMPLICATED THE 

5855
04:33:16,702 --> 04:33:22,275
NEW YORK TIMES PUBLISHED EARLY 

5856
04:33:22,275 --> 04:33:30,383
LAST YEAR THAT DUE TO CLIMATE 

5857
04:33:30,383 --> 04:33:33,986
CHANGE WHEN THE WATER BED DRIES 

5858
04:33:33,986 --> 04:33:38,124
UP THE DUST CAN EXPOSE PEOPLE.

5859
04:33:38,124 --> 04:33:40,893
YOU HAVE HIGH LEVELS OF ARSENIC 

5860
04:33:40,893 --> 04:33:42,228
AND HAVING THE CONTAMINATION 

5861
04:33:42,228 --> 04:33:43,029
THROUGH AIR AND DUST YOU COULD 

5862
04:33:43,029 --> 04:33:53,439
HAVE EXPOSURE THAT WAY.

5863
04:33:54,407 --> 04:33:56,776
EXPOSURE CORRELATES TO HIGH 

5864
04:33:56,776 --> 04:33:59,979
INCIDENCE OF CANCER.

5865
04:33:59,979 --> 04:34:06,452
ARSENIC DOES NOT DIRECTLY  DNA 

5866
04:34:06,452 --> 04:34:08,854
AND WE HYPOTHESIZE IT'S CHANGING

5867
04:34:08,854 --> 04:34:15,895
THE CHROMATIN STRUCTURE ORRIAN 

5868
04:34:15,895 --> 04:34:16,796
DIRECTLY CHANGING THE EXPOSURE 

5869
04:34:16,796 --> 04:34:20,533
LEADING TO GENE EXPRESSION.

5870
04:34:20,533 --> 04:34:22,368
-- INDIRECTLY CHANGING THE 

5871
04:34:22,368 --> 04:34:23,369
EXPOSURE LEADING TO THE GENE 

5872
04:34:23,369 --> 04:34:24,203
EXPRESSION.

5873
04:34:24,203 --> 04:34:25,471
WE DECIDED TO BUILD A MODEL 

5874
04:34:25,471 --> 04:34:26,439
UNDERSTANDING CANCER IS A 

5875
04:34:26,439 --> 04:34:29,709
PROCESS AND NOT ALL OR NOTHING.

5876
04:34:29,709 --> 04:34:34,447
SO WHAT WE DID WAS WE TREATED 

5877
04:34:34,447 --> 04:34:37,016
CELLS WITH MICROMOLAR OF ARSENIC

5878
04:34:37,016 --> 04:34:40,886
AND WATCHED THE PROGRESSION AND 

5879
04:34:40,886 --> 04:34:44,357
THE CELLS BECOME MORE MIGRATORY 

5880
04:34:44,357 --> 04:34:46,926
AND AFTER SEVERAL WEEKS OF 

5881
04:34:46,926 --> 04:34:50,029
TREATMENT THE CELLS BECOME LESS 

5882
04:34:50,029 --> 04:34:52,765
MIGRATORY AND YOU CAN SEE THEM 

5883
04:34:52,765 --> 04:34:59,005
FORMING COLONIES AND WHEN YOU IN

5884
04:34:59,005 --> 04:35:03,376
MICE AND WE SEE EPITHELIAL TO 

5885
04:35:03,376 --> 04:35:06,679
WEEK 16 AND REVERTS TO 

5886
04:35:06,679 --> 04:35:07,446
EPITHELIAL.

5887
04:35:07,446 --> 04:35:17,023
EMT BACK TO MET.

5888
04:35:17,023 --> 04:35:22,395
WE FOUND A TARGET FOR ARSENIC IS

5889
04:35:22,395 --> 04:35:25,531
CTC WHICH WE HEARD ABOUT AND 

5890
04:35:25,531 --> 04:35:30,469
IT'S BEEN SHOWN PERSONS WOULD 

5891
04:35:30,469 --> 04:35:36,042
HAVE THESE ARSENIC CAN INSERT 

5892
04:35:36,042 --> 04:35:38,477
ITSELF INTO THE LOCATION IN 

5893
04:35:38,477 --> 04:35:42,381
PLACE OF THE ZINC AND THAT WILL 

5894
04:35:42,381 --> 04:35:45,718
NOT BE ABLE TO BIND AND THERE'S 

5895
04:35:45,718 --> 04:35:48,087
11 ZINC FINGERS.

5896
04:35:48,087 --> 04:35:50,723
10 ARE TARGETED OF ARSENIC AND 

5897
04:35:50,723 --> 04:35:55,428
THE 11th FINGER IS C3H1.

5898
04:35:55,428 --> 04:36:00,900
AND PROMOTERS THAT HAVE ONE 

5899
04:36:00,900 --> 04:36:04,570
BINDING SITE WHICH IS A WEAK 

5900
04:36:04,570 --> 04:36:06,472
BINDING SITE THAT PROMOTER IS 

5901
04:36:06,472 --> 04:36:09,809
BOUND BY CTCF AND WE HAVE GENE 

5902
04:36:09,809 --> 04:36:10,443
EXPRESSION.

5903
04:36:10,443 --> 04:36:13,412
HOWEVER, NOW IN ARSENIC 

5904
04:36:13,412 --> 04:36:14,447
TRANSFORM CELLS OR EXPOSE CELLS 

5905
04:36:14,447 --> 04:36:19,552
AT THE BINDING SO IING SITE IS R

5906
04:36:19,552 --> 04:36:21,287
BOUND AND WE THINK IT DOESN'T 

5907
04:36:21,287 --> 04:36:24,156
LIKE TO BIND SO YOU NOW HAVE THE

5908
04:36:24,156 --> 04:36:26,525
11 ZINC FINGERS MODULATED BY 

5909
04:36:26,525 --> 04:36:29,128
ARSENIC OR INHIBITED BY ARSENIC 

5910
04:36:29,128 --> 04:36:31,330
AND CTCF IS NO LONGER ABLE TO 

5911
04:36:31,330 --> 04:36:34,233
BIND AND WE'RE SEEING CHANGES IN

5912
04:36:34,233 --> 04:36:42,742
GENE EXPRESSION.

5913
04:36:42,742 --> 04:36:45,344
WE SEE A WEAK CTCF BINDING SITE 

5914
04:36:45,344 --> 04:36:48,681
OR PROMOTER AND A STRONG CTCF 

5915
04:36:48,681 --> 04:36:51,584
BINDING SITE AT THE ENHANCER.

5916
04:36:51,584 --> 04:36:57,189
WE THINK CTCF INTERACTION WOULD 

5917
04:36:57,189 --> 04:37:00,159
BE CLOSE TO THE PROMOTER AND 

5918
04:37:00,159 --> 04:37:01,160
DRIVE GENE EXPRESSION AND IF YOU

5919
04:37:01,160 --> 04:37:04,697
EXPOSE CELLS TO ARSENIC THE CTCF

5920
04:37:04,697 --> 04:37:06,732
SITE WE DON'T SEE BINDING BUT 

5921
04:37:06,732 --> 04:37:10,469
SEE AN ENHANCE THE CTCF AT THE 

5922
04:37:10,469 --> 04:37:11,370
ENHANCER SITE AND THINK BECAUSE 

5923
04:37:11,370 --> 04:37:12,838
OF THAT IT'S LOOKING BACK OVER 

5924
04:37:12,838 --> 04:37:14,473
TO THE PROMOTER TO DRIVE GENE 

5925
04:37:14,473 --> 04:37:19,211
EXPRESSION.

5926
04:37:19,211 --> 04:37:25,050
IS IT TRUE ARSENIC IS TARGETING?

5927
04:37:25,050 --> 04:37:32,424
WE TRIED TO LABEL IT AND WHEN WE

5928
04:37:32,424 --> 04:37:34,960
PERFORMED GEL SHEET ASSAYS WE 

5929
04:37:34,960 --> 04:37:37,696
SEE IT BINDS TO THE STRONG SITE 

5930
04:37:37,696 --> 04:37:43,302
AND CAUSE A GEL SHIFT AND A WEAK

5931
04:37:43,302 --> 04:37:48,808
SITE CAUSES A LOT OF GEL SHIFT.

5932
04:37:48,808 --> 04:37:52,978
IF WE PLACE IT WITH THE ARSENIC 

5933
04:37:52,978 --> 04:37:55,214
SEE THE REDUCTION OF CTCF 

5934
04:37:55,214 --> 04:37:56,749
BINDING REEN TO THE STRONG 

5935
04:37:56,749 --> 04:37:59,685
BINDING SITE BUT TO THE WEAK 

5936
04:37:59,685 --> 04:38:03,155
SITE IT SEEMED TO HAVE ABOLISHED

5937
04:38:03,155 --> 04:38:03,989
CTCF BINDING.

5938
04:38:03,989 --> 04:38:10,830
WE MUTATED THE 11 ZINC FINGER TO

5939
04:38:10,830 --> 04:38:12,965
SEE IT AND SHOULDN'T SEE AFFECT 

5940
04:38:12,965 --> 04:38:15,734
OF ARSENIC TO THE BINDING.

5941
04:38:15,734 --> 04:38:17,403
THAT'S WHAT WE SEE PERFORMING 

5942
04:38:17,403 --> 04:38:20,239
THE SAME EXPERIMENT CTCF BINDS 

5943
04:38:20,239 --> 04:38:20,472
NICELY.

5944
04:38:20,472 --> 04:38:22,575
THE STRONG CTCF BINDING SITE IN 

5945
04:38:22,575 --> 04:38:24,577
THE ABSENCE AND PRESENCE OF 

5946
04:38:24,577 --> 04:38:25,110
ARSENIC.

5947
04:38:25,110 --> 04:38:30,182
THE WEAK CTCF BINDING SITE IS A 

5948
04:38:30,182 --> 04:38:32,818
BETTER BINDER IN THE ABSENCE OF 

5949
04:38:32,818 --> 04:38:36,488
THE CTCF AND I SUMMARIZED THIS 

5950
04:38:36,488 --> 04:38:40,259
IN THE TABLE WHERE WE SHOW WILD 

5951
04:38:40,259 --> 04:38:44,430
TYPE CTCF REQUIRED 91 NANO MOLAR

5952
04:38:44,430 --> 04:38:49,602
FOR THE VALUES AND THE WEAK CTCF

5953
04:38:49,602 --> 04:38:53,973
BINDING SITE REQUIRES 110 AND IF

5954
04:38:53,973 --> 04:38:59,645
WE DALIZE WE GET THE BINDING AND

5955
04:38:59,645 --> 04:39:02,081
IT REQUIRES A LOT TO BIND TO THE

5956
04:39:02,081 --> 04:39:03,916
WEAK CTCF BINDING SITE.

5957
04:39:03,916 --> 04:39:06,352
WHEN WE PERFORM THAT IT DIDN'T 

5958
04:39:06,352 --> 04:39:08,354
MATTER WHETHER YOU HAD ARSENIC 

5959
04:39:08,354 --> 04:39:10,990
IN THERE OR NO ARSENIC.

5960
04:39:10,990 --> 04:39:12,358
WE SEE THE STRONG CTCF BINDING 

5961
04:39:12,358 --> 04:39:14,393
SITE IS STILL BINDING TO THE 

5962
04:39:14,393 --> 04:39:16,061
WEAK CTCF BINDING SITE IT SEEMS 

5963
04:39:16,061 --> 04:39:19,465
IT MAKE IT A BETTER BINDER.

5964
04:39:19,465 --> 04:39:22,301
SO WE HEARD FROM TALKS THIS 

5965
04:39:22,301 --> 04:39:29,008
MORNING WHAT DOES CTCF DO?

5966
04:39:29,008 --> 04:39:33,712
IT CREATES THE DOMAIN AND YOU 

5967
04:39:33,712 --> 04:39:36,582
HAVE A PROMOTER TO DRIVE GENE 

5968
04:39:36,582 --> 04:39:38,450
EXPRESSION AND BLOCKS THE 

5969
04:39:38,450 --> 04:39:42,454
ENHANCER FROM ECTOPICALLY 

5970
04:39:42,454 --> 04:39:46,859
ENHANCIE IING  THIS FROM THE 

5971
04:39:46,859 --> 04:39:52,097
PROMOTER AND IF YOU DISRUPT THIS

5972
04:39:52,097 --> 04:39:54,466
YOU CAN DISRUPT AND THIS COULD 

5973
04:39:54,466 --> 04:39:56,769
DRIVE CARCINOGENESIS THAT WAY.

5974
04:39:56,769 --> 04:39:58,404
WE STARTED DOING HIGH SPEED DATA

5975
04:39:58,404 --> 04:40:00,306
AND ANALYZING THAT BUT I SHOW AN

5976
04:40:00,306 --> 04:40:03,609
EXAMPLE WHERE WE'RE LOOKING AT 

5977
04:40:03,609 --> 04:40:06,445
INTERACTION BETWEEN THE A 

5978
04:40:06,445 --> 04:40:07,746
COMPARTMENT AND AS WE GO THROUGH

5979
04:40:07,746 --> 04:40:09,915
THE MEDIATED TRANSFORMATION WE 

5980
04:40:09,915 --> 04:40:11,984
START WITH THE INTERACTION AND 

5981
04:40:11,984 --> 04:40:15,387
GO DOWN TO AN INTERACTION 

5982
04:40:15,387 --> 04:40:16,822
STRENGTH ABOUT 3.

5983
04:40:16,822 --> 04:40:18,457
B AND B INTERACTION WE START 

5984
04:40:18,457 --> 04:40:22,061
WITH  8 AND WE COME TO AN 

5985
04:40:22,061 --> 04:40:24,396
INTERACTION STRENGTH OF ABOUT 

5986
04:40:24,396 --> 04:40:26,465
4.3.

5987
04:40:26,465 --> 04:40:28,100
SUGGESTING POSSIBLY ARSENIC 

5988
04:40:28,100 --> 04:40:30,035
DISRUPTING CTCF BINDING TO THE 

5989
04:40:30,035 --> 04:40:32,671
WEAK CTCF BINDING SITE MAY BE 

5990
04:40:32,671 --> 04:40:34,073
DISRUPTING THE INTERACTION 

5991
04:40:34,073 --> 04:40:44,483
STRENGTH WE'RE GETTING.

5992
04:40:54,727 --> 04:40:58,998
AND WE'RE LOOKING THE AT NON 

5993
04:40:58,998 --> 04:41:01,900
EXPOSED CELLS AT THE BASELINE.

5994
04:41:01,900 --> 04:41:02,835
THE WILD TYPE YOU SEE AS YOU 

5995
04:41:02,835 --> 04:41:04,603
EXPOSE THE CELLS THROUGH THE 

5996
04:41:04,603 --> 04:41:06,705
WEEKLY EXPOSURE OF ARSENIC.

5997
04:41:06,705 --> 04:41:09,641
WE SEE THE CELLS BECOME MORE 

5998
04:41:09,641 --> 04:41:12,644
MIGRATORY AS EXPECTED DUE TO THE

5999
04:41:12,644 --> 04:41:13,612
TRANSFORMATION POTENTIAL.

6000
04:41:13,612 --> 04:41:16,315
HOWEVER, IF WE TAKE THE CELL 

6001
04:41:16,315 --> 04:41:21,920
LINE OUT MUTATED TO C2H2 WE SEE 

6002
04:41:21,920 --> 04:41:26,458
AN INHIBITION TO THE MIGRATION 

6003
04:41:26,458 --> 04:41:30,429
POTENTIAL OF THOSE CELLS.

6004
04:41:30,429 --> 04:41:32,531
THE QUESTION IS ARE THERE OTHERS

6005
04:41:32,531 --> 04:41:34,066
TARGETED THAT MIGHT BE TARGETED 

6006
04:41:34,066 --> 04:41:37,002
BY ARSENIC BECAUSE IF YOU'RE 

6007
04:41:37,002 --> 04:41:38,404
SEEING ZINC IS THE ISSUE MORE 

6008
04:41:38,404 --> 04:41:39,438
SHOULD BE TARGETED.

6009
04:41:39,438 --> 04:41:42,474
SO WHAT WE DID WAS AS WE EXPOSED

6010
04:41:42,474 --> 04:41:47,579
THE CELLS TO ARSENIC, WE NOW ADD

6011
04:41:47,579 --> 04:41:49,948
A TENFOLD AMOUNT CONCENTRATION 

6012
04:41:49,948 --> 04:41:52,918
OF ZINC TO THE CELLS AND AGAIN 

6013
04:41:52,918 --> 04:41:54,920
MEASURED THE MIGRATORY 

6014
04:41:54,920 --> 04:41:55,287
POTENTIAL.

6015
04:41:55,287 --> 04:41:57,956
IF WE TREAT THE CELLS THROUGH 

6016
04:41:57,956 --> 04:41:59,124
WEEK THREE AND ADD ZINC AS WE 

6017
04:41:59,124 --> 04:42:01,460
CONTINUE THE CELLS WITH ARSENIC 

6018
04:42:01,460 --> 04:42:02,628
WE SEE A DECREASE IN THE 

6019
04:42:02,628 --> 04:42:04,063
MIGRATION POTENTIAL AND SEEMS TO

6020
04:42:04,063 --> 04:42:05,731
US THE EARLIER YOU DO THAT THE 

6021
04:42:05,731 --> 04:42:10,069
BETTER FOR THE CELLS BECAUSE WE 

6022
04:42:10,069 --> 04:42:13,305
SEE IF WE HAD TREATMENT AT WEEK 

6023
04:42:13,305 --> 04:42:15,774
8 AS NOT AS DECREASED AS IF YOU 

6024
04:42:15,774 --> 04:42:18,077
START EARLY SUGGESTING POSSIBLY 

6025
04:42:18,077 --> 04:42:18,911
EARLIER TREATMENT WITH ZINC MAY 

6026
04:42:18,911 --> 04:42:22,081
BE MORE BENEFICIAL FOR THE 

6027
04:42:22,081 --> 04:42:30,923
CELLS.

6028
04:42:30,923 --> 04:42:35,194
WE THINK IT'S GIVEN A STRONGER 

6029
04:42:35,194 --> 04:42:35,961
POTENTIAL COMPARED TO THE ZINC 

6030
04:42:35,961 --> 04:42:39,164
AND THE ZINC IS STRONGER.

6031
04:42:39,164 --> 04:42:42,468
SO WHAT WE'RE DOING WITH THE 

6032
04:42:42,468 --> 04:42:45,838
STORY IS WE THINK TOXICOLOGISTS 

6033
04:42:45,838 --> 04:42:48,607
ALLOWED TO UNDERSTAND THE IMPACT

6034
04:42:48,607 --> 04:42:52,077
OF CTCF IN THE 3-D CHROMATIN 

6035
04:42:52,077 --> 04:42:54,646
ARCHITECTURE BECAUSE PEOPLE HAVE

6036
04:42:54,646 --> 04:42:56,582
ARGUED IF YOU KNOCK DOWN CTCF 

6037
04:42:56,582 --> 04:43:02,121
YOU SEE CHANGES BUT NOT MASSIVE 

6038
04:43:02,121 --> 04:43:03,822
ENOUGH -- THEY'VE NOT SEEN 

6039
04:43:03,822 --> 04:43:05,157
CHANGES IN GENE EXPRESSION 

6040
04:43:05,157 --> 04:43:06,458
ASSOCIATED WITH THE MASSIVE 

6041
04:43:06,458 --> 04:43:11,763
IMPACT OF CTCF BUT WE THINK IN 

6042
04:43:11,763 --> 04:43:22,307
THE ONLY KNOCK DOWN AND MAY BE 

6043
04:43:22,774 --> 04:43:24,209
ABLE TO EXPLAIN IT IN THE 

6044
04:43:24,209 --> 04:43:25,978
EXPRESSION AND DOMAINS WE'RE 

6045
04:43:25,978 --> 04:43:26,178
FIND.

6046
04:43:26,178 --> 04:43:28,780
WE'RE DOING EXPERIMENTS ON THE 

6047
04:43:28,780 --> 04:43:31,083
C2H2 MUTANT TO SEE THE 

6048
04:43:31,083 --> 04:43:31,750
DIFFERENCES IN THE GENE 

6049
04:43:31,750 --> 04:43:34,086
EXPRESSION PATTERNS AND WHERE 

6050
04:43:34,086 --> 04:43:37,122
IT'S BOUND AND WHERE YOU LOST 

6051
04:43:37,122 --> 04:43:38,323
AND GAINED SITES OF CTCF BINDING

6052
04:43:38,323 --> 04:43:39,558
IN BOTH CELL TYPES.

6053
04:43:39,558 --> 04:43:42,127
AGAIN, BECAUSE OF THAT PEOPLE 

6054
04:43:42,127 --> 04:43:44,296
HAVE ARGUED THAT POSSIBLY IT'S 

6055
04:43:44,296 --> 04:43:47,432
BETTER TO HAVE A CELL TYPE 

6056
04:43:47,432 --> 04:43:49,868
SPECIFIC 3-D GENOME REWIRER.

6057
04:43:49,868 --> 04:43:51,537
AND WE ALSO WENT OUT LOOKING FOR

6058
04:43:51,537 --> 04:43:54,406
THAT AND THE ONE WE THOUGHT WAS 

6059
04:43:54,406 --> 04:43:56,441
INTERESTING TO US WHICH WE 

6060
04:43:56,441 --> 04:43:58,477
THOUGHT WAS HIGHLY EXPRESSED IN 

6061
04:43:58,477 --> 04:44:04,016
ARSENIC TRANSFORMED CELLS IS 

6062
04:44:04,016 --> 04:44:07,386
HERE YOU START WITH YOUR 

6063
04:44:07,386 --> 04:44:11,723
CHROMATIN AND IT PLAYS A ROLE 

6064
04:44:11,723 --> 04:44:14,459
AND B COMPARTMENTS.

6065
04:44:14,459 --> 04:44:14,826
AND WHAT 

6066
04:44:14,826 --> 04:44:18,697
 B2 DOES IS BRINGS THE DNA TO 

6067
04:44:18,697 --> 04:44:21,733
THE FAMILY TRAIT AND IT USES TO 

6068
04:44:21,733 --> 04:44:23,902
BIND TO THE MATRIX AND ALSO HAS 

6069
04:44:23,902 --> 04:44:25,837
THE DNA BINDING DOMAIN WHICH IT 

6070
04:44:25,837 --> 04:44:30,309
USES TO BIND TO DNA AND YOU CAN 

6071
04:44:30,309 --> 04:44:31,310
IMAGINE IT CAN BRING SEVERAL 

6072
04:44:31,310 --> 04:44:34,346
REGIONS OF THE DNA TO THE MATRIX

6073
04:44:34,346 --> 04:44:38,483
THAT WAY AND BY BRINGING 

6074
04:44:38,483 --> 04:44:43,989
CELLULAR REGIONS IT CAN BRING AN

6075
04:44:43,989 --> 04:44:49,127
ENHANCER AND BRING THE REWIRER.

6076
04:44:49,127 --> 04:44:54,967
AND WE HAVE A STORY WE THINK 

6077
04:44:54,967 --> 04:44:56,835
CTCF MIGHT DIRECTLY BE 

6078
04:44:56,835 --> 04:44:58,070
IMPLICATED IN CHROMATIN CHANGES 

6079
04:44:58,070 --> 04:45:00,038
WHICH WOULD LEAD IT CHANGES IN 

6080
04:45:00,038 --> 04:45:01,073
GENE EXPRESSION.

6081
04:45:01,073 --> 04:45:04,076
PEOPLE LOOK AT GENE EXPRESSION 

6082
04:45:04,076 --> 04:45:12,818
AS TRANSCRIPT ABUNDANCE AND THE 

6083
04:45:12,818 --> 04:45:16,455
ROLE OF A CIRCULAR RNA THAT 

6084
04:45:16,455 --> 04:45:19,391
COMES THIS CAN GO BACK AND PLI A

6085
04:45:19,391 --> 04:45:21,426
ROLE IN ROW MATTIN MEDIATED 

6086
04:45:21,426 --> 04:45:23,662
CHANGE CAN LEAD TO CANCER.

6087
04:45:23,662 --> 04:45:25,631
WHAT IS BACK SPLICING?

6088
04:45:25,631 --> 04:45:31,870
THIS IS TYPICALLY YOUR PRE mRNA 

6089
04:45:31,870 --> 04:45:34,473
AND MATURE RNA LOOKS LIKE THIS 

6090
04:45:34,473 --> 04:45:39,244
AND BACK SLICING YOU HAVE EXON 4

6091
04:45:39,244 --> 04:45:41,079
BACK SPLICING TO EXON 3 AND THE 

6092
04:45:41,079 --> 04:45:43,782
ONLY WAY YOU CAN DIFFERENTIATE 

6093
04:45:43,782 --> 04:45:49,087
THAT IS THIS BACKSPLICE JUNCTION

6094
04:45:49,087 --> 04:45:49,988
UNIQUE TO THIS mRNA.

6095
04:45:49,988 --> 04:45:51,923
PEOPLE HAVE LOOKED AT THIS FOR 

6096
04:45:51,923 --> 04:45:53,859
YEARS AND ACTUALLY WOULD 

6097
04:45:53,859 --> 04:45:57,095
DISCOUNT THEM AS JUNK RNA.

6098
04:45:57,095 --> 04:45:59,831
RECENT PAPERS HAVE SHOWN THEIR 

6099
04:45:59,831 --> 04:46:01,400
FUNCTIONAL AND COULD PLAY IF 

6100
04:46:01,400 --> 04:46:02,801
FOUND IN THE NUCLEUS CAN PLAYING

6101
04:46:02,801 --> 04:46:06,004
A ROLE IN REGULATING 

6102
04:46:06,004 --> 04:46:08,507
TRANSCRIPTION AND COULD ACT AS 

6103
04:46:08,507 --> 04:46:14,613
MICRO RNA SPONGES OR DEKOIZ -- 

6104
04:46:14,613 --> 04:46:16,815
DOUGH  

6105
04:46:18,984 --> 04:46:20,152
DECOYS AND I'LL SHOW AN EXAMPLE.

6106
04:46:20,152 --> 04:46:22,254
LIKE EVERYTHING WE DO IN OUR LAB

6107
04:46:22,254 --> 04:46:24,289
WE START WITH PROFILING AND WHAT

6108
04:46:24,289 --> 04:46:26,825
ARE THE CIRCULAR RNA'S EXPRESSED

6109
04:46:26,825 --> 04:46:28,427
IN ARSENIC TRANSFORMED CELLS?

6110
04:46:28,427 --> 04:46:31,630
WHEN WE DID THAT WE SAW 

6111
04:46:31,630 --> 04:46:32,998
DYSREGULATED CIRCULAR RNAs AND 

6112
04:46:32,998 --> 04:46:35,967
THE QUESTION FOR US WAS THAT THE

6113
04:46:35,967 --> 04:46:38,470
ONLY TRANSCRIPT FROM THE GENE OR

6114
04:46:38,470 --> 04:46:41,406
WAS THE mRNA  ALSO DYSREGULATED.

6115
04:46:41,406 --> 04:46:43,475
WE PERFORMED A NANO STRING 

6116
04:46:43,475 --> 04:46:45,110
ANALYSIS AND TOOK THE TOP 

6117
04:46:45,110 --> 04:46:46,545
CIRCULAR RNAs AND COMPARED THEIR

6118
04:46:46,545 --> 04:46:50,449
EXPRESSION TO THE EXPRESSION OF 

6119
04:46:50,449 --> 04:46:56,421
THE LINEAR mRNA.

6120
04:46:56,421 --> 04:46:58,457
AND THE mRNA  WAS UPREGULATED 

6121
04:46:58,457 --> 04:47:03,095
AND THE CIRCULAR RNA FROM THIS 

6122
04:47:03,095 --> 04:47:04,096
WAS ALSO DYSREGULATED.

6123
04:47:04,096 --> 04:47:08,133
AND THIS WAS EXCITING BECAUSE 

6124
04:47:08,133 --> 04:47:10,001
RECENT PAPERS HAD SHOWN THE 

6125
04:47:10,001 --> 04:47:12,704
EXPRESSION PLAYS A ROLE IN 

6126
04:47:12,704 --> 04:47:14,973
INDEPENDENT GROWTH AND CELL 

6127
04:47:14,973 --> 04:47:17,909
MIGRATION AND FOR IT TO BE 

6128
04:47:17,909 --> 04:47:20,712
EXPRESSED AND MICRORNA THAT 

6129
04:47:20,712 --> 04:47:22,180
NEEDS TO BE DOWN REGULATED TO BE

6130
04:47:22,180 --> 04:47:24,583
EXPRESSED AND LASTLY THERE'S A 

6131
04:47:24,583 --> 04:47:26,985
PAPER THAT SHOWED RECENTLY 

6132
04:47:26,985 --> 04:47:28,153
THERE'S A CIRCULAR RNA DIFFERENT

6133
04:47:28,153 --> 04:47:32,224
FROM THE ONE WE FOUND 8928 AND 

6134
04:47:32,224 --> 04:47:34,860
IT SHOWED IT PROMOTES 

6135
04:47:34,860 --> 04:47:38,897
PROGRESSION OF NON-SMALL LUNG 

6136
04:47:38,897 --> 04:47:41,566
CANCER AND WE ASKED THE QUESTION

6137
04:47:41,566 --> 04:47:45,604
HOW IS THIS CIRCULAR RNA 

6138
04:47:45,604 --> 04:47:45,871
EXPRESSED?

6139
04:47:45,871 --> 04:47:48,774
BECAUSE OF TRANSFORMATION OR 

6140
04:47:48,774 --> 04:47:49,841
ARSENIC EXPOSURE?

6141
04:47:49,841 --> 04:47:51,443
WE PERFORMED ACUTE EXPOSURE OF 

6142
04:47:51,443 --> 04:47:54,279
THE CELLS TO ARSENIC.

6143
04:47:54,279 --> 04:47:56,748
YOU SEE THE CONCENTRATION 

6144
04:47:56,748 --> 04:48:00,318
INCREASED AND SAW THE EXPRESSION

6145
04:48:00,318 --> 04:48:01,353
OF THIS AS WELL AS THE CIRCULAR 

6146
04:48:01,353 --> 04:48:02,254
RNA EXPRESSION.

6147
04:48:02,254 --> 04:48:05,857
WE THEN LOOKED AT IT IN A 

6148
04:48:05,857 --> 04:48:08,293
TRANSFORMATION MODEL AND SEE THE

6149
04:48:08,293 --> 04:48:11,930
WEEKLY EXPOSURE OF ARSENIC AS IT

6150
04:48:11,930 --> 04:48:14,466
GETS EXPRESSED LIKEWISE THE 

6151
04:48:14,466 --> 04:48:18,270
CIRCU

6152
04:48:18,270 --> 04:48:19,538
CIRCULAR RNA GETS EXPRESSED.

6153
04:48:19,538 --> 04:48:22,474
IS IT WE'RE MEASURING THE SAME 

6154
04:48:22,474 --> 04:48:24,776
TRANSCRIPT OR MEASURING TWO 

6155
04:48:24,776 --> 04:48:25,243
DIFFERENT TRANSCRIPTS.

6156
04:48:25,243 --> 04:48:28,480
I THINK WE'RE MEASURING TWO 

6157
04:48:28,480 --> 04:48:31,950
TRANSCRIPTS AS SHOWN HERE.

6158
04:48:31,950 --> 04:48:35,520
IF WE KNOCK DOWN SAT B2 WE DON'T

6159
04:48:35,520 --> 04:48:37,622
SEE AN DECREASE IN THE CIRCULAR 

6160
04:48:37,622 --> 04:48:39,991
RNA EXPRESSION BUT IF WE KNOCK 

6161
04:48:39,991 --> 04:48:43,395
DOWN THE CIRCULAR RNA THE SAT B2

6162
04:48:43,395 --> 04:48:45,130
mRNA  GOES DOWN.

6163
04:48:45,130 --> 04:48:47,566
SUGGESTING COULD IT BE THE 

6164
04:48:47,566 --> 04:48:50,869
CIRCULAR RNA COMES IN TO PROTECT

6165
04:48:50,869 --> 04:48:52,037
AT LINEAR mRNA ?

6166
04:48:52,037 --> 04:48:54,139
WE THINK THAT'S TRUE BECAUSE IF 

6167
04:48:54,139 --> 04:48:55,941
WE JUST OVER EXPRESS THE 

6168
04:48:55,941 --> 04:48:59,344
CIRCULAR RNA BY ITSELF WE DON'T 

6169
04:48:59,344 --> 04:49:01,880
SEE CHANGES IN SAT B2 BUT ONCE 

6170
04:49:01,880 --> 04:49:04,082
WE EVERY EXPRESS WE SEE THE 

6171
04:49:04,082 --> 04:49:09,221
CIRCULAR RNA COMING UP.

6172
04:49:09,221 --> 04:49:14,159
WE'VE SEWN DOWN OF THE CIRCULAR 

6173
04:49:14,159 --> 04:49:16,495
RNA CAUSE CELL MIGRATION AND 

6174
04:49:16,495 --> 04:49:18,964
PROLIFERATION AND LIKEWISE IF WE

6175
04:49:18,964 --> 04:49:21,333
EXPRESS SAT B2 IN NON-TREATED 

6176
04:49:21,333 --> 04:49:24,069
CELLS WE SEE INCREASE IN CELL 

6177
04:49:24,069 --> 04:49:24,603
PROLIFERATION AS WELL AS 

6178
04:49:24,603 --> 04:49:25,737
INCREASE IN CELL MIGRATION.

6179
04:49:25,737 --> 04:49:28,006
WE WENT BACK AND ASKED THE 

6180
04:49:28,006 --> 04:49:30,141
QUESTION WHAT ARE THE PATHWAYS 

6181
04:49:30,141 --> 04:49:33,812
THAT ARE SIMILAR ONCOGENIC 

6182
04:49:33,812 --> 04:49:39,050
PATHWAYS SIMILAR BETWEEN ARSENIC

6183
04:49:39,050 --> 04:49:42,654
TRANSFORMED CELLS AND SAT B2 AND

6184
04:49:42,654 --> 04:49:44,456
WE HAVE THE K RAS ONCOGENIC 

6185
04:49:44,456 --> 04:49:45,891
PATHWAYS AND THIS WAS AMAZING TO

6186
04:49:45,891 --> 04:49:48,059
SEE BECAUSE IF YOU LOOK AT 

6187
04:49:48,059 --> 04:49:51,897
ARSENIC TRANSFORMED CELLS AND 

6188
04:49:51,897 --> 04:49:54,165
THIS IS ONCOGENIC PATHWAY WITH A

6189
04:49:54,165 --> 04:49:56,668
NUMBER OF GENES WE SEE FOR 

6190
04:49:56,668 --> 04:49:58,703
ARSENIC EXPOSED CELLS WE SEE 

6191
04:49:58,703 --> 04:50:01,806
WHEN THE GENES ARE EXPRESSED IN 

6192
04:50:01,806 --> 04:50:06,044
ARSENIC TRANSFORMED CELLS AND 

6193
04:50:06,044 --> 04:50:11,583
SEE SAT B2 CELLS EXPRESSED 

6194
04:50:11,583 --> 04:50:11,783
CELLS.

6195
04:50:11,783 --> 04:50:15,020
HERE'S 600 WE SEE ARSENIC 

6196
04:50:15,020 --> 04:50:17,255
TRANSFORMED CELLS AS WELL AS THE

6197
04:50:17,255 --> 04:50:21,793
SAT B2 CELLS AND THE K RAS 

6198
04:50:21,793 --> 04:50:22,427
ONCOGENIC SIGNATURE GENES.

6199
04:50:22,427 --> 04:50:24,262
IF SOME OF THOSE GENES IN THE K 

6200
04:50:24,262 --> 04:50:26,464
RAS PATHWAYS THAT WERE DOWN 

6201
04:50:26,464 --> 04:50:28,099
REGULATED FOR ARSENIC 

6202
04:50:28,099 --> 04:50:32,404
TRANSFORMED CELLS IN SAT B2 

6203
04:50:32,404 --> 04:50:34,973
CELLS THEY WERE DOWN REGULATED 

6204
04:50:34,973 --> 04:50:36,174
SUGGESTING IT'S POSSIBLE ARSENIC

6205
04:50:36,174 --> 04:50:43,014
IS TARGETING SAT B2 TO DRIVE THE

6206
04:50:43,014 --> 04:50:48,987
K RAS PATHWAY IN ARSENIC 

6207
04:50:48,987 --> 04:50:50,622
TRANSFORMATION CELLS AND THE SAT

6208
04:50:50,622 --> 04:50:53,792
B2 CELLS WHERE YOU HAVE THE 

6209
04:50:53,792 --> 04:50:55,994
PATHWAY UPREGULATED.

6210
04:50:55,994 --> 04:50:59,831
THOSE GENES WERE UPREGULATED AND

6211
04:50:59,831 --> 04:51:02,200
SAT B2 CELLS ALL REGULATED WITH 

6212
04:51:02,200 --> 04:51:04,102
SIMILAR AND WHEN WE KNOCKED DOWN

6213
04:51:04,102 --> 04:51:08,873
SAT B2 OR THE CIRCULAR RNA WE 

6214
04:51:08,873 --> 04:51:10,575
SEE A REVERSAL OF THE 

6215
04:51:10,575 --> 04:51:12,210
UPREGULATION WENT DOWN AND FOR 

6216
04:51:12,210 --> 04:51:14,279
THOSE AGAINST UP REGULATED WHEN 

6217
04:51:14,279 --> 04:51:18,116
WE KNOCK DOWN SAT B2 OR CIRCULAR

6218
04:51:18,116 --> 04:51:19,584
RNA WE SEE THAT GOING BACK UP 

6219
04:51:19,584 --> 04:51:20,986
SUGGESTING AGAIN THAT POSSIBLY 

6220
04:51:20,986 --> 04:51:26,458
THIS IS THE PATHWAY THAT ARSENIC

6221
04:51:26,458 --> 04:51:32,163
IS TARGETING FOR DRIVING 

6222
04:51:32,163 --> 04:51:33,164
CARCINOGENESIS AND THE CIRCULAR 

6223
04:51:33,164 --> 04:51:36,568
RNA COMES UP AND MAYBE IT'S 

6224
04:51:36,568 --> 04:51:39,404
PROTECTING SAT B2 TRANSSCRIPT 

6225
04:51:39,404 --> 04:51:43,441
FOR DEGRADATION BY EXPUNGING THE

6226
04:51:43,441 --> 04:51:46,011
MICRORNA AND WE THINK IT TARGETS

6227
04:51:46,011 --> 04:51:50,448
SIMILAR K RAS PATHWAYS AS IN 

6228
04:51:50,448 --> 04:51:53,018
ARSENIC TRANSFORMATION.

6229
04:51:53,018 --> 04:51:57,522
AND LASTLY WE SAW WHEN WE MAKE 

6230
04:51:57,522 --> 04:52:00,959
THIS CIRCULAR RNA IT FORMS AN 

6231
04:52:00,959 --> 04:52:02,460
ATG SITE SO COULD IT BE 

6232
04:52:02,460 --> 04:52:03,995
TRANSLATED AND IF IT'S 

6233
04:52:03,995 --> 04:52:06,464
TRANSLATED YOU IMAGINE IT WILL 

6234
04:52:06,464 --> 04:52:07,799
FORM A PEPTIDE THAT LOOKS 

6235
04:52:07,799 --> 04:52:09,934
DIFFERENT FROM SAT B2 BECAUSE 

6236
04:52:09,934 --> 04:52:11,670
YOU WILL NOT HAVE THE DNA 

6237
04:52:11,670 --> 04:52:12,671
BINDING DOMAIN.

6238
04:52:12,671 --> 04:52:17,108
INDEED WE'RE ABLE TO SHOW IT'S 

6239
04:52:17,108 --> 04:52:18,410
TRANSLATED BECAUSE WE USE THIS 

6240
04:52:18,410 --> 04:52:19,911
AND THE ONLY WAY IT'S EXPRESSED 

6241
04:52:19,911 --> 04:52:21,312
OR TRANSLATED AND WE'RE ABLE TO 

6242
04:52:21,312 --> 04:52:24,983
SEE THAT IS IF THE CIRCLE GOES 

6243
04:52:24,983 --> 04:52:28,219
AROUND AND TRANSLATES THIS BUT 

6244
04:52:28,219 --> 04:52:30,155
IF YOU TREAT THE CELLS TO TARGET

6245
04:52:30,155 --> 04:52:32,190
AND TREAT IT WITH A SUBSTRATE 

6246
04:52:32,190 --> 04:52:37,962
YOU'LL BE ABLE TO READ IT WITH 

6247
04:52:37,962 --> 04:52:39,064
LUMINESCENCE AND MAKE THE 

6248
04:52:39,064 --> 04:52:41,866
PEPTIDE AND WE ALSO SHOW THAT 

6249
04:52:41,866 --> 04:52:45,603
IT'S ACTUALLY A NUCLIDE 

6250
04:52:45,603 --> 04:52:47,672
CO-LOCALIZED AND LASTLY WE'RE 

6251
04:52:47,672 --> 04:52:50,442
ABLE TO SHOW THAT IT ASSOCIATES 

6252
04:52:50,442 --> 04:52:53,645
WITH POLY SOMES AND WE DID 

6253
04:52:53,645 --> 04:52:57,782
PROFILING AND mRNA  ASSOCIATED 

6254
04:52:57,782 --> 04:53:03,288
WITH HEAVY LIGHT AND VERY LITTLE

6255
04:53:03,288 --> 04:53:08,259
mRNA  AND LITTLE ORGANOID FREE 

6256
04:53:08,259 --> 04:53:10,495
AND THIS IS NOT TRANSLATED SEEN 

6257
04:53:10,495 --> 04:53:12,630
WITH FREE.

6258
04:53:12,630 --> 04:53:22,006
IF WE THEN TREAT IT WITH EDT 

6259
04:53:22,006 --> 04:53:26,311
WHICH SHOULD DISASSOCIATE AND 

6260
04:53:26,311 --> 04:53:26,611
TRANSLATED.

6261
04:53:26,611 --> 04:53:29,981
SO THIS IS WHAT WE THINK IS 

6262
04:53:29,981 --> 04:53:30,248
HAPPENING.

6263
04:53:30,248 --> 04:53:34,052
YOU HAVE SAT B2 WHICH IS THEN 

6264
04:53:34,052 --> 04:53:44,662
MADE AND YOU CAN ACTUALLY OLI

6265
04:53:45,096 --> 04:53:46,798
OLIGOMERIZE AND IF IT INTERACTS 

6266
04:53:46,798 --> 04:53:48,900
IT WOULD NOT BRING IT TO THE 

6267
04:53:48,900 --> 04:53:49,834
MATRIX.

6268
04:53:49,834 --> 04:53:54,239
IN THAT CASE IT COULD ACT AS A 

6269
04:53:54,239 --> 04:53:58,109
DOMINANT NEGATIVE SAT B2 

6270
04:53:58,109 --> 04:53:58,943
FUNCTION AND WE HAVE PRELIMINARY

6271
04:53:58,943 --> 04:54:03,915
DATA THAT MAY BE TRUE AND IT 

6272
04:54:03,915 --> 04:54:06,451
BINDS TO THE MATRIX ASSOCIATED 

6273
04:54:06,451 --> 04:54:08,453
DOMAINS OF DNA AND BRING DOWN 

6274
04:54:08,453 --> 04:54:10,121
ONE WHICH BINDS TO THE INNER 

6275
04:54:10,121 --> 04:54:14,692
NUCLEAR MATRIX AND BRING OUT 

6276
04:54:14,692 --> 04:54:18,463
HISTONES AND BRING DOWN SPLICING

6277
04:54:18,463 --> 04:54:20,698
FACTORS BUT SAT B2 BE PLAYING A 

6278
04:54:20,698 --> 04:54:22,734
ROLE IN ALTERNATIVE SPLICING.

6279
04:54:22,734 --> 04:54:24,836
IT BRINGS UP ANOTHER AREA IN THE

6280
04:54:24,836 --> 04:54:25,637
LAB.

6281
04:54:25,637 --> 04:54:28,840
IF WE PULL DOWN WITH THE 

6282
04:54:28,840 --> 04:54:31,009
CIRCULAR RNA WE LOSE WHAT BINDS 

6283
04:54:31,009 --> 04:54:35,213
TO DNA AND LOSE SOME OF THE 

6284
04:54:35,213 --> 04:54:38,449
MARKS AND WE RETAIN AND ARE ABLE

6285
04:54:38,449 --> 04:54:41,486
TO RETAIN DOWN 1 AND SEE SAT B2 

6286
04:54:41,486 --> 04:54:45,156
COMING UP AGAIN SUGGESTING MOST 

6287
04:54:45,156 --> 04:54:46,357
LIKELY THE CIRCULAR RNA COULD BE

6288
04:54:46,357 --> 04:54:50,461
BINDING AND WOULD BE ACTING AS A

6289
04:54:50,461 --> 04:54:52,897
DOMINANT NEGATIVE.

6290
04:54:52,897 --> 04:54:59,370
SO WE HAVE A POSSIBLE MODEL 

6291
04:54:59,370 --> 04:55:02,040
WHERE WE HAVE SEEN THE CELLS ARE

6292
04:55:02,040 --> 04:55:03,842
EXPOSED TO ARSENIC THROUGH THE 

6293
04:55:03,842 --> 04:55:06,444
PROCESS OF ARSENIC 

6294
04:55:06,444 --> 04:55:08,179
TRANSFORMATION WEEKEND SEE THE 

6295
04:55:08,179 --> 04:55:14,452
CIRCULAR RNA COME UP LIKEWISE 

6296
04:55:14,452 --> 04:55:17,889
LINEAR mRNA  AND THINK IT MY BE 

6297
04:55:17,889 --> 04:55:20,391
DECOYING OR EXPUNGING THE 

6298
04:55:20,391 --> 04:55:20,658
MICRO-RNA.

6299
04:55:20,658 --> 04:55:22,460
WHAT WE DON'T KNOW YET IS WHEN 

6300
04:55:22,460 --> 04:55:24,195
DOES IT MOVE FROM NON CODING 

6301
04:55:24,195 --> 04:55:25,964
FUNCTION TO A CODING FUNCTION.

6302
04:55:25,964 --> 04:55:32,604
WE HAVE A HYPOTHESIS THROUGH Y 

6303
04:55:32,604 --> 04:55:34,138
JIO

6304
04:55:34,138 --> 04:55:39,410
-- MYOGENESIS AND CLEAVES SAT B2

6305
04:55:39,410 --> 04:55:42,447
AND THAT'S A SIGNAL TO DRIVE THE

6306
04:55:42,447 --> 04:55:44,482
CELLS TOWARDS MYOGENESIS.

6307
04:55:44,482 --> 04:55:47,218
WE HYPOTHESIZE MAYBE SOMETHING 

6308
04:55:47,218 --> 04:55:53,725
LIKE THAT IS HAPPENS BECAUSE WE 

6309
04:55:53,725 --> 04:55:58,663
SEE BANDS AND CLEAVED AND SEE 

6310
04:55:58,663 --> 04:56:03,801
MORE OF SAT B2 AND LESS CIRCULAR

6311
04:56:03,801 --> 04:56:04,002
mRNA.

6312
04:56:04,002 --> 04:56:05,637
WE THINK THE CELL ONCE IT'S 

6313
04:56:05,637 --> 04:56:07,505
DEGRADED IT WANTS TO MAKE SOME 

6314
04:56:07,505 --> 04:56:12,377
FORM OF SAT B2 AND CONVERTS THAT

6315
04:56:12,377 --> 04:56:15,647
FROM A NON-CODING TO A CODING 

6316
04:56:15,647 --> 04:56:15,914
FUNCTION.

6317
04:56:15,914 --> 04:56:17,282
IF THAT'S TRUE MAYBE WHAT'S 

6318
04:56:17,282 --> 04:56:19,250
HAPPENING IS IT MIGHT CHANGE THE

6319
04:56:19,250 --> 04:56:22,353
3-D GENOME ARCHITECTURE THERE BE

6320
04:56:22,353 --> 04:56:25,356
DRIVING ONCOGENESIS THAT WAY.

6321
04:56:25,356 --> 04:56:28,226
AGAIN, I'M SO HAPPY I DO 

6322
04:56:28,226 --> 04:56:28,526
TOXICOLOGY.

6323
04:56:28,526 --> 04:56:32,931
I WAS NEVER A TOXICOLOGIST BUT 

6324
04:56:32,931 --> 04:56:33,631
ALLOWED US TO DISCOVER 

6325
04:56:33,631 --> 04:56:35,700
REGULATORS AND THEIR FUNCTIONS I

6326
04:56:35,700 --> 04:56:38,469
WOULD NOT HAVE FOUND IF I WAS 

6327
04:56:38,469 --> 04:56:39,370
DOING NORMAL GROWTH IN CELLS.

6328
04:56:39,370 --> 04:56:41,806
I'D LIKE TO THANK ALL THE 

6329
04:56:41,806 --> 04:56:44,809
MEMBERS OF MY LABS, VIA FOR 

6330
04:56:44,809 --> 04:56:47,145
THEIR SUPPORT AND COLLABORATORS 

6331
04:56:47,145 --> 04:56:47,445
AND FUNDING.

6332
04:56:47,445 --> 04:56:57,622
THANK YOU.

6333
04:57:06,164 --> 04:57:08,166
>> MY BRAIN IS ON A FRIDAY

6334
04:57:08,166 --> 04:57:09,133
AFTERNOON SCHEDULE SO FORGIVE 

6335
04:57:09,133 --> 04:57:09,300
ME.

6336
04:57:09,300 --> 04:57:10,635
I WANT TO MAKE SURE I'M 

6337
04:57:10,635 --> 04:57:12,770
FOLLOWING ALL THE DIFFERENT WAYS

6338
04:57:12,770 --> 04:57:16,674
IT SEEMS LIKE SAT B2 IS 

6339
04:57:16,674 --> 04:57:18,076
REGULATING ITSELF.

6340
04:57:18,076 --> 04:57:21,179
SO THE CIRCULAR RNA PLAY ACT AS 

6341
04:57:21,179 --> 04:57:23,381
A SPONGE TO PROTECT THE FULL 

6342
04:57:23,381 --> 04:57:25,350
LENGTH RNA AND ALSO BEING 

6343
04:57:25,350 --> 04:57:29,020
TRANSLATE INTO A PEPTIDE AS ACTS

6344
04:57:29,020 --> 04:57:34,025
AS A DOMINANT NEGATIVE OF THE 

6345
04:57:34,025 --> 04:57:34,258
PROTEIN.

6346
04:57:34,258 --> 04:57:36,327
IS THAT WHAT YOU SAID?

6347
04:57:36,327 --> 04:57:37,362
>> YES, BECAUSE IT DOESN'T
HAVE 

6348
04:57:37,362 --> 04:57:40,098
THE ABILITY TO BIND TO DNA AND 

6349
04:57:40,098 --> 04:57:43,534
DIDN'T FUNCTION AS SAT B2 WOULD 

6350
04:57:43,534 --> 04:57:45,403
FUNCTION.

6351
04:57:45,403 --> 04:57:49,173
NOT BRINGING THE DNA TO THE 

6352
04:57:49,173 --> 04:57:50,174
MATRIX FOR TRANSCRIPTION.

6353
04:57:50,174 --> 04:57:51,743
WE'RE WORKING ON TESTING THAT.

6354
04:57:51,743 --> 04:57:54,879
>> THE DUAL LAYER OF
REGULATION 

6355
04:57:54,879 --> 04:57:58,649
OF THAT PROTEIN ITSELF MUST MEAN

6356
04:57:58,649 --> 04:58:01,786
IT'S VERY IMPORTANT.

6357
04:58:01,786 --> 04:58:02,420
>> EXACTLY.

6358
04:58:02,420 --> 04:58:03,588
WHAT WE'RE EXCITED ABOUT IS 

6359
04:58:03,588 --> 04:58:05,189
MAYBE THIS IS THE SAME THING 

6360
04:58:05,189 --> 04:58:07,625
HAPPENING IN MYOGENESIS BUT WE 

6361
04:58:07,625 --> 04:58:09,227
WANT TO LOOK AT THE RNA WHICH 

6362
04:58:09,227 --> 04:58:10,361
COULD BE TRANSLATED.

6363
04:58:10,361 --> 04:58:14,465
NOW WE'RE SEEING THIS HERE MAYBE

6364
04:58:14,465 --> 04:58:17,201
ACT THE SAME WAY IN OTHER AREAS 

6365
04:58:17,201 --> 04:58:18,936
THAT NO ONE HAD LOOKED AT IT.

6366
04:58:18,936 --> 04:58:20,605
IT'S OPENED UP A LOT.

6367
04:58:20,605 --> 04:58:23,274
>> QUICK QUESTION FOR YOU.

6368
04:58:23,274 --> 04:58:29,781
IN THE ARSENIC WHEN YOU SEE ALL 

6369
04:58:29,781 --> 04:58:31,983
THESE CHANGES AND DRIVING UP RAS

6370
04:58:31,983 --> 04:58:36,921
SIGNALLING YOU SEEING IT IN 

6371
04:58:36,921 --> 04:58:39,257
TYPICAL WITHOUT MUTATIONS IN RAS

6372
04:58:39,257 --> 04:58:41,225
ARE THERE OTHER MUTATIONS.

6373
04:58:41,225 --> 04:58:42,860
>> THAT'S A GOOD QUESTION
AND I 

6374
04:58:42,860 --> 04:58:43,494
EXPECTED THAT.

6375
04:58:43,494 --> 04:58:46,397
WEN WHEN HE SAW THIS WE THOUGHT 

6376
04:58:46,397 --> 04:58:48,099
MAYBE THERE'S A MUTATION BUT THE

6377
04:58:48,099 --> 04:58:50,468
FACT THAT WE'RE ABLE TO KNOCK 

6378
04:58:50,468 --> 04:58:57,742
DOWN SAT B2 AND mRNA  AND 

6379
04:58:57,742 --> 04:58:58,810
REVERSE MAYBE IT'S NOT A 

6380
04:58:58,810 --> 04:58:59,944
MUTATION AND THAT'S WHERE WE'RE 

6381
04:58:59,944 --> 04:59:00,311
GOING FROM HERE.

6382
04:59:00,311 --> 04:59:02,847
>> THANK YOU.

6383
04:59:02,847 --> 04:59:06,617
>> OUR NEXT TALK IS FROM
SEAN LI

6384
04:59:06,617 --> 04:59:11,756
FROM CEDAR-SINAI AND INTERESTED 

6385
04:59:11,756 --> 04:59:18,463
IN THE EPIGENETIC SEX IN BLADDER

6386
04:59:18,463 --> 04:59:20,031
TUMORIGENESIS.

6387
04:59:20,031 --> 04:59:22,233
>> I'M VERY HONORED TO BE 

6388
04:59:22,233 --> 04:59:22,467
INVITED.

6389
04:59:22,467 --> 04:59:24,268
THANK YOU AGAIN FOR THE 

6390
04:59:24,268 --> 04:59:31,309
INVITATION AND HUMBLED.

6391
04:59:31,309 --> 04:59:34,245
TO SHARE THE STAGE WITH TRUE 

6392
04:59:34,245 --> 04:59:34,512
PIONEERS.

6393
04:59:34,512 --> 04:59:37,582
THANK YOU ALL.

6394
04:59:37,582 --> 04:59:38,683
I'LL TALK ABOUT SEX BUT 

6395
04:59:38,683 --> 04:59:39,383
E-GENETIC SEX.

6396
04:59:41,085 --> 04:59:51,295
EPIGENETIC SEX.

6397
05:00:06,144 --> 05:00:08,446
THIS IS KNOWN FOR AUTO IMMUNE 

6398
05:00:08,446 --> 05:00:11,249
DISEASE MORE FEMALE DOMINANT 

6399
05:00:11,249 --> 05:00:21,792
DISEASE FOR AUTO IMMUNE DISEASE.

6400
05:00:29,433 --> 05:00:34,172
WE'RE INTERESTED IN FEMALES FOUR

6401
05:00:34,172 --> 05:00:35,840
TO FIVE TIMES MORE.

6402
05:00:35,840 --> 05:00:40,845
TAKING ABOUT BLADDER AND IT 

6403
05:00:40,845 --> 05:00:46,150
HAPPENS IN MAMMALS AND THEY ARE 

6404
05:00:46,150 --> 05:00:48,452
WATER SEX IN TURTLES AND FROGS 

6405
05:00:48,452 --> 05:00:52,657
AND THOSE ARE NOT EQUIVALENT IN 

6406
05:00:52,657 --> 05:00:56,127
BLADDER BECAUSE THEY USE IT AS A

6407
05:00:56,127 --> 05:00:57,995
WATER REVERSE BECAUSE THEY CAN 

6408
05:00:57,995 --> 05:01:01,199
COME BACK AND REABSORB WATER AND

6409
05:01:01,199 --> 05:01:04,168
WE HUMANS DON'T ABSORB WATER 

6410
05:01:04,168 --> 05:01:09,807
FROM BLADDER.

6411
05:01:09,807 --> 05:01:14,045
WHAT'S INTERESTING ABOUT THE 

6412
05:01:14,045 --> 05:01:17,582
BLADDER CELLS IT IS QUITE AN 

6413
05:01:17,582 --> 05:01:19,850
EFFECTIVE BARRIER MUCH BETTER 

6414
05:01:19,850 --> 05:01:20,952
BARRIER THAN THE BLOOD BRAIN 

6415
05:01:20,952 --> 05:01:21,285
BARRIER.

6416
05:01:21,285 --> 05:01:23,688
IT'S MAKING SENSE BECAUSE THEY 

6417
05:01:23,688 --> 05:01:25,990
WANT TO KEEP URINE AWAY FROM THE

6418
05:01:25,990 --> 05:01:30,461
TISSUE AND BLOOD.

6419
05:01:30,461 --> 05:01:41,005
IN ADDITION, BLADDER UROTHELIUM 

6420
05:01:41,372 --> 05:01:46,143
CYCLE AND IT'S A VERY QUIESCENT 

6421
05:01:46,143 --> 05:01:52,917
STRUCTURE.

6422
05:01:52,917 --> 05:01:56,320
IT'S AN EPITHELIAL STRUCTURE AND

6423
05:01:56,320 --> 05:02:04,061
UNLIKE GUT EPITHELIUM CONSTANTLY

6424
05:02:04,061 --> 05:02:05,429
AND BLADDER UROTHELIUM IS UNIQUE

6425
05:02:05,429 --> 05:02:10,468
IN A WAY THAT IT REGENERATES SO 

6426
05:02:10,468 --> 05:02:16,207
UNDER A URINARY TRACT INFECTION 

6427
05:02:16,207 --> 05:02:18,809
OR SUBJECT TO CHEMICAL INJURIES 

6428
05:02:18,809 --> 05:02:21,646
IT REGENERATES VERY QUICKLY.

6429
05:02:21,646 --> 05:02:25,683
BECAUSE OF THIS RAPID 

6430
05:02:25,683 --> 05:02:28,152
REGENERATIVE POTENTIAL OR 

6431
05:02:28,152 --> 05:02:29,754
KINETICS BLADDER CANCER IS 

6432
05:02:29,754 --> 05:02:31,289
RELATIVELY HIGH.

6433
05:02:31,289 --> 05:02:31,889
THIS IS PARTICULARLY TRUE FOR 

6434
05:02:31,889 --> 05:02:37,061
MALE.

6435
05:02:37,061 --> 05:02:39,263
SO IT'S A NUMBER FOUR FOR MALES 

6436
05:02:39,263 --> 05:02:46,137
AND THIS IS NOT THE CASE FOR 

6437
05:02:46,137 --> 05:02:46,370
FEMALES.

6438
05:02:46,370 --> 05:02:53,577
IT'S QUITE SURPRISING.

6439
05:02:53,577 --> 05:02:56,447
WHAT'S INTERESTED IN TERMS OF 

6440
05:02:56,447 --> 05:02:58,716
CLINICAL TRIAL PUBLISHED A FEW 

6441
05:02:58,716 --> 05:03:00,051
YEARS BACK IN NEW ENGLAND 

6442
05:03:00,051 --> 05:03:02,687
JOURNAL SO AS YOU CAN SEE HERE 

6443
05:03:02,687 --> 05:03:09,360
THIS IS A TARGETED CHEMOTHERAPY 

6444
05:03:09,360 --> 05:03:09,660
DRUG.

6445
05:03:09,660 --> 05:03:20,204
FOR MALES AND FOR BLADDER CANCER

6446
05:03:28,212 --> 05:03:33,317
A FEW FEMALES HAVE BLADDER 

6447
05:03:33,317 --> 05:03:34,452
CANCER SO THERE'S OTHER 

6448
05:03:34,452 --> 05:03:36,387
INDICATIONS IN TERMS OF 

6449
05:03:36,387 --> 05:03:39,623
THERAPEUTIC RESPONSES INCLUDING 

6450
05:03:39,623 --> 05:03:40,491
IMMUNOTHERAPY RESPONSES BETWEEN 

6451
05:03:40,491 --> 05:03:45,162
MALE AND FEMALE.

6452
05:03:45,162 --> 05:03:46,163
SO WHAT'S ALSO INTERESTING ABOUT

6453
05:03:46,163 --> 05:03:49,767
THE GENDER DISPARITY IS YOU CAN 

6454
05:03:49,767 --> 05:03:52,737
RECAPITULATE THIS IN RODENT 

6455
05:03:52,737 --> 05:03:56,006
MODELS USING CARCINOGENESIS 

6456
05:03:56,006 --> 05:04:01,145
MODEL WHICH WE USE IN THE MODEL 

6457
05:04:01,145 --> 05:04:05,149
THIS FEEDS BBN IN THE WATER AND 

6458
05:04:05,149 --> 05:04:06,550
MOUSE DRINK IT AND DEVELOP 

6459
05:04:06,550 --> 05:04:09,553
BADDER CANCER AND MALES DEVELOP 

6460
05:04:09,553 --> 05:04:11,288
AND DIE FROM BLADDER CANCER 

6461
05:04:11,288 --> 05:04:12,523
SOONER THAN FEMALE.

6462
05:04:12,523 --> 05:04:22,032
YOU CAN ALSO RECAPITULATE THIS 

6463
05:04:22,032 --> 05:04:22,800
USING GENETICALLY ENGINEERED 

6464
05:04:22,800 --> 05:04:27,872
MOUSE MODELS AND IT'S NOT JUST A

6465
05:04:27,872 --> 05:04:32,009
BLADDER CANCER BUT MELANOMA YOU 

6466
05:04:32,009 --> 05:04:34,145
CAN MODEL IN RODENTS.

6467
05:04:34,145 --> 05:04:40,117
IT SUGGESTED TO US IT'S NOT JUST

6468
05:04:40,117 --> 05:04:40,451
ENVIRONMENTAL.

6469
05:04:40,451 --> 05:04:41,152
ENVIRONMENTAL IS OBVIOUSLY 

6470
05:04:41,152 --> 05:04:43,220
IMPORTANT AS YOU HEARD AND THE 

6471
05:04:43,220 --> 05:04:45,055
GENETIC OF BIOLOGICAL BASIS FOR 

6472
05:04:45,055 --> 05:04:47,324
GENDER DISPARITIES IN CANCER.

6473
05:04:47,324 --> 05:04:50,394
SO WE ARE INTERESTED IN THIS 

6474
05:04:50,394 --> 05:04:52,563
QUESTION QUITE A FEW YEARS BACK 

6475
05:04:52,563 --> 05:04:55,699
TRYING TO FIGURE OUT OR TRYING 

6476
05:04:55,699 --> 05:04:58,135
TO UNDERSTAND WHY THERE'S A MALE

6477
05:04:58,135 --> 05:04:58,736
DOMINANCE IN CANCERS.

6478
05:04:58,736 --> 05:05:03,674
SO ONE OF THE FIRST THINGS 

6479
05:05:03,674 --> 05:05:07,445
PEOPLE LOOKED IS DURING THE 

6480
05:05:07,445 --> 05:05:09,713
EPIDEMIOLOGICAL STUDY DO SEE IF 

6481
05:05:09,713 --> 05:05:10,714
IS THE REASON FOR SEX DIFFERENCE

6482
05:05:10,714 --> 05:05:13,017
AND THAT TURNS OUT TO BE NOT 

6483
05:05:13,017 --> 05:05:13,951
TRUE.

6484
05:05:13,951 --> 05:05:15,953
SMOKING IS IMPORTANT BUT SMOKING

6485
05:05:15,953 --> 05:05:20,224
IS NOT THE REASON MALE HAS A 

6486
05:05:20,224 --> 05:05:21,692
HIGHER INCIDENTS OF BLADDER 

6487
05:05:21,692 --> 05:05:23,794
CANCER.

6488
05:05:23,794 --> 05:05:24,428
NEXT THING PEOPLE LOOKED IS SEX 

6489
05:05:24,428 --> 05:05:34,605
HORMONES.

6490
05:05:42,513 --> 05:05:46,050
SO ANDROGEN IS A MAJOR DRIVER 

6491
05:05:46,050 --> 05:05:49,587
AND CAN EXPOSE TO ANDROGEN AND 

6492
05:05:49,587 --> 05:05:54,391
IT'S CLEARLY A MAJOR DRIVER AND 

6493
05:05:54,391 --> 05:05:56,093
ESTROGEN DEPENDING ON THE 

6494
05:05:56,093 --> 05:05:59,296
RECEPTORS I THINK WOULD BE 

6495
05:05:59,296 --> 05:06:03,100
PROTECTIVE OR PROMOTING BLADDER 

6496
05:06:03,100 --> 05:06:05,135
CANCER BUT THE EFFECT SIZE IS 

6497
05:06:05,135 --> 05:06:05,736
SMALLER THAN ANDROGEN 

6498
05:06:05,736 --> 05:06:12,176
SIGNALLING.

6499
05:06:12,176 --> 05:06:16,847
WE REPORTED LAST YEAR ANDROGEN 

6500
05:06:16,847 --> 05:06:21,552
NOT ONLY FUNCTION IN UROTHELIUM 

6501
05:06:21,552 --> 05:06:24,955
CELLS AND SIGNALLING THROUGH THE

6502
05:06:24,955 --> 05:06:30,461
IMMUNE MICRO ENVIRONMENT AND IT 

6503
05:06:30,461 --> 05:06:37,768
INDUCES PREMATURE CD 8 T CELL 

6504
05:06:37,768 --> 05:06:39,236
EXHAUSTION AND THIS WAS 

6505
05:06:39,236 --> 05:06:42,239
PUBLISHED WITH CLOSE 

6506
05:06:42,239 --> 05:06:43,674
COLLABORATION WITH MY COLLEAGUE 

6507
05:06:43,674 --> 05:06:49,313
DR. LEE AT OSU.

6508
05:06:49,313 --> 05:06:54,585
ANOTHER REPORT ON SEX CHROM

6509
05:06:54,585 --> 05:06:54,885
CHROMOSOMES.

6510
05:06:54,885 --> 05:07:00,558
FOR PATIENTS WHICH LOST X 

6511
05:07:00,558 --> 05:07:02,359
CHROMOSOME AND THEY HAVE 

6512
05:07:02,359 --> 05:07:05,563
INCREASED BLADDER CANCER RISK 

6513
05:07:05,563 --> 05:07:07,565
SUGGESTING THAT SEX HORMONE 

6514
05:07:07,565 --> 05:07:09,400
IMPACT IS ALSO IMPORTANT 

6515
05:07:09,400 --> 05:07:11,435
HOWEVER, THIS STUDY IS 

6516
05:07:11,435 --> 05:07:13,837
CONFOUNDED WITH OTHER CLINICAL 

6517
05:07:13,837 --> 05:07:16,540
OBSERVATIONS IN TERMS OF OTHER 

6518
05:07:16,540 --> 05:07:16,874
COMORBIDITIES.

6519
05:07:16,874 --> 05:07:21,478
SO ONE CANNOT FOR CERTAIN FROM 

6520
05:07:21,478 --> 05:07:22,179
OTHER COMORBIDITIES OR BECAUSE 

6521
05:07:22,179 --> 05:07:26,150
OF SEX CHROMOSOME.

6522
05:07:26,150 --> 05:07:29,320
SO WE DECIDED I WANT TO MENTION 

6523
05:07:29,320 --> 05:07:33,390
MY COLLEAGUES LY SOME MAY OR MAY

6524
05:07:33,390 --> 05:07:36,327
NOT KNOW THAT Y CHROMOSOME, 

6525
05:07:36,327 --> 05:07:39,029
MALES HAVE Y CHROMOSOME AND IT'S

6526
05:07:39,029 --> 05:07:43,434
OFTEN LOST DURING AGING OR 

6527
05:07:43,434 --> 05:07:45,536
ENVIRONMENTAL EXPOSURE AND ALSO 

6528
05:07:45,536 --> 05:07:51,342
Y CHROMOSOME TRIGGERS ADAPTIVE 

6529
05:07:51,342 --> 05:07:53,077
IMMUNITY DYSFUNCTIONING.

6530
05:07:53,077 --> 05:07:55,980
THAT'S NOT THE REASON MALE HAS 

6531
05:07:55,980 --> 05:07:56,347
HIGHER RISK.

6532
05:07:56,347 --> 05:08:01,785
SO WE DECIDE TO LOOK AT THIS 

6533
05:08:01,785 --> 05:08:04,755
QUIT A FEW YEARS BACK USING THE 

6534
05:08:04,755 --> 05:08:04,955
MODEL.

6535
05:08:04,955 --> 05:08:06,457
THERE'S FOUR SEX TYPES RATHER 

6536
05:08:06,457 --> 05:08:06,924
THAN TWO.

6537
05:08:06,924 --> 05:08:13,764
WE HAVE A NORMAL XX FEMALE, XX 

6538
05:08:13,764 --> 05:08:16,867
CHROMOSOME OVARY, NORMAL OVARY 

6539
05:08:16,867 --> 05:08:22,039
AND XX MALE.

6540
05:08:22,039 --> 05:08:24,742
XX SEX CHROMOSOME COMPLIMENT FOR

6541
05:08:24,742 --> 05:08:29,480
THE TESTES AND THIS IS LOSS OF 

6542
05:08:29,480 --> 05:08:34,551
THE Y GONAD DEVELOPED TO IN THIS

6543
05:08:34,551 --> 05:08:37,321
CASE TRANSGENIC AND 

6544
05:08:37,321 --> 05:08:40,157
OVEREXPRESSION OF XYL VIA 

6545
05:08:40,157 --> 05:08:41,425
AUTOSOME AND THE GONAD DEVELOPED

6546
05:08:41,425 --> 05:08:44,962
TO TEST THIS INSTEAD OF OVARY.

6547
05:08:44,962 --> 05:08:50,901
AND CONVERSELY WE HAVE THE XLY 

6548
05:08:50,901 --> 05:08:53,037
CHROMOSOME BUT LOSS OF XLY AND 

6549
05:08:53,037 --> 05:08:58,475
THEY DEVELOP AN OAF  OVARY 

6550
05:08:58,475 --> 05:09:01,211
INSTEAD OF TESTES AND USING THE 

6551
05:09:01,211 --> 05:09:03,847
MODEL ENABLES US TO SEGREGATE 

6552
05:09:03,847 --> 05:09:06,583
THE EFFECT OF SEX CHROMOSOMES 

6553
05:09:06,583 --> 05:09:12,723
VERSUS SEX HORMONE.

6554
05:09:12,723 --> 05:09:14,458
GONADO EFFECT VERSUS CHROMOSOMAL

6555
05:09:14,458 --> 05:09:16,326
ACT AND WE CAN LOOK AT THE 

6556
05:09:16,326 --> 05:09:16,994
INTERSECT WHETHER THEY FUNCTION 

6557
05:09:16,994 --> 05:09:18,462
TOGETHER OR NOT.

6558
05:09:18,462 --> 05:09:21,699
THIS IS A QUICK RESULT.

6559
05:09:21,699 --> 05:09:24,501
YOU CAN SEE XX IN THE MIDDLE IS 

6560
05:09:24,501 --> 05:09:28,138
IS THE SURVIVAL CURVE.

6561
05:09:28,138 --> 05:09:30,474
XX CHROMOSOME WITH FEMALE 

6562
05:09:30,474 --> 05:09:32,710
PHENOTYPE CAN DEVELOP AND DIE 

6563
05:09:32,710 --> 05:09:33,911
FROM BLADDER CANCER MUCH MUCH 

6564
05:09:33,911 --> 05:09:38,315
LATER AND IF YOU COMPARE XX 

6565
05:09:38,315 --> 05:09:42,119
FEMALE VERSUS XX MALE THEY HAVE 

6566
05:09:42,119 --> 05:09:46,156
THE SAME CHROMOSOMAL COMPLIMENT 

6567
05:09:46,156 --> 05:09:49,393
BUT DIFFERENT GONADOCYTES AND 

6568
05:09:49,393 --> 05:09:51,161
HAVE TESTES INCREASES THE CANCER

6569
05:09:51,161 --> 05:09:53,864
RISK AND ANDROGEN IS A RISK 

6570
05:09:53,864 --> 05:09:54,098
FACTOR.

6571
05:09:54,098 --> 05:09:58,168
WHAT IS INTERESTING IF YOU 

6572
05:09:58,168 --> 05:10:01,105
COMPARE XX FEMALE VERSUS XY 

6573
05:10:01,105 --> 05:10:03,273
FEMALE THEY AN ALL HAVE ANDROGEN

6574
05:10:03,273 --> 05:10:07,311
AND OVARIES BUT THE ONLY 

6575
05:10:07,311 --> 05:10:11,448
DIFFERENCE IS XX VERSUS XY.

6576
05:10:11,448 --> 05:10:17,521
IT INCREASES BLADDER CANCER 

6577
05:10:17,521 --> 05:10:17,721
RISK.

6578
05:10:17,721 --> 05:10:24,294
WHAT IS INTERESTING IS IF YOU 

6579
05:10:24,294 --> 05:10:28,165
LOOK IF THEY'RE INTERACTIVE AND 

6580
05:10:28,165 --> 05:10:32,236
ANALYSIS AND HAVING XLY IS OVER 

6581
05:10:32,236 --> 05:10:36,974
2.5 TIMES MORE HIGHER RISK.

6582
05:10:36,974 --> 05:10:41,245
AND HAVING TESTES IS 4.7 TIMES 

6583
05:10:41,245 --> 05:10:41,812
MORE.

6584
05:10:41,812 --> 05:10:43,480
AND IF THERE'S A COMBINATION XLY

6585
05:10:43,480 --> 05:10:46,150
AND TESTES IT'S A 12.4 TIMES 

6586
05:10:46,150 --> 05:10:49,253
MORE LIKELY TO DEVELOP BLADDER 

6587
05:10:49,253 --> 05:10:51,822
CANCER IN THIS RODENT MODELS.

6588
05:10:51,822 --> 05:10:57,261
THIS CLEARLY SUGGESTS THERE'S 

6589
05:10:57,261 --> 05:10:59,129
SOME INTERACTION BETWEEN 

6590
05:10:59,129 --> 05:11:00,898
CHROMOSOMAL AND GONADAL AFFECT 

6591
05:11:00,898 --> 05:11:02,900
AND WE'RE INTERESTED IN THE 

6592
05:11:02,900 --> 05:11:03,467
INTERACTIVE MECHANISM.

6593
05:11:03,467 --> 05:11:05,869
ALL THIS INTERACTION LEADS TO AN

6594
05:11:05,869 --> 05:11:08,739
INCREASED CANCER RISK IF WE KNOW

6595
05:11:08,739 --> 05:11:14,444
THE MECHANISM, CAN WE TARGET IT 

6596
05:11:14,444 --> 05:11:20,584
TO REDUCE CANCER RISK?

6597
05:11:20,584 --> 05:11:22,252
WE'RE INTERESTING TO LOOK AT THE

6598
05:11:22,252 --> 05:11:24,588
CHROME SOME FOR BLADDER CANCER 

6599
05:11:24,588 --> 05:11:31,829
RISK AND HAVING A Y CHROMOSOME 

6600
05:11:31,829 --> 05:11:34,198
IS EFFECTIVE AND LOOKING AT TWO 

6601
05:11:34,198 --> 05:11:37,534
CHROMOSOME WHETHER IT'S BETTER 

6602
05:11:37,534 --> 05:11:38,068
PROTECTED.

6603
05:11:38,068 --> 05:11:41,004
WE DID A QUICK RNA SEQ ANALYSIS 

6604
05:11:41,004 --> 05:11:44,341
AND LOOKED AT THE TYPES AND 

6605
05:11:44,341 --> 05:11:48,946
IDENTIFIED THE DIFFERENTIALLY 

6606
05:11:48,946 --> 05:11:54,918
EXPRESSED AND KDM68 IS LINKED 

6607
05:11:54,918 --> 05:12:05,362
AND ESCAPES IN ACTIVATION.

6608
05:12:11,935 --> 05:12:16,039
AND IT'S X CHROMOSOME LINK AND 

6609
05:12:16,039 --> 05:12:18,675
MUTATED IN BLADDER CANCER ABOUT 

6610
05:12:18,675 --> 05:12:29,219
24% IT'S INVOLVED IN REGULATING 

6611
05:12:30,520 --> 05:12:31,521
POLY CHROME BECAUSE OF THE 

6612
05:12:31,521 --> 05:12:37,794
METHYLATION AND PART OF THE 

6613
05:12:37,794 --> 05:12:44,468
COMPLEX INVOLVED IN METH IN K4 

6614
05:12:44,468 --> 05:12:46,036
MONOLATION.

6615
05:12:46,036 --> 05:12:49,706
AND ACTIVATION AND FUNGTION INTO

6616
05:12:49,706 --> 05:12:53,977
TWO MAJOR EPIGENETIC COMPLEXES 

6617
05:12:53,977 --> 05:12:54,745
AND POTENT REGULATOR.

6618
05:12:54,745 --> 05:12:59,416
I'M GOING TO TALK BRIEFLY ABOUT 

6619
05:12:59,416 --> 05:13:01,051
BLADDER CANCER MOLECULAR SUB 

6620
05:13:01,051 --> 05:13:02,386
TYPE AND PATHOLOGY.

6621
05:13:02,386 --> 05:13:09,426
THE KEY IS BLADDER CANCER ARISE 

6622
05:13:09,426 --> 05:13:12,663
PREDOMINANTLY FROM THE 

6623
05:13:12,663 --> 05:13:13,931
UROTHELIUM STRUCTURE IN MOUSE IS

6624
05:13:13,931 --> 05:13:17,868
ONLY THREE LAYERS.

6625
05:13:17,868 --> 05:13:18,602
IN HUMAN MAYBE SEVEN TO NINE 

6626
05:13:18,602 --> 05:13:28,745
LAYERS.

6627
05:15:03,473 --> 05:15:06,443
AND THEY CAN ENHANCE OR 

6628
05:15:06,443 --> 05:15:10,447
COMPLIMENT EACH OTHER AND APPLY 

6629
05:15:10,447 --> 05:15:11,848
SEX DIFFERENCES IN CANCER.

6630
05:15:11,848 --> 05:15:12,783
SO THAT LEADS TO WHAT WE WANT TO

6631
05:15:12,783 --> 05:15:23,093
DO IN THE FUTURE.

6632
05:15:31,101 --> 05:15:33,303
AND ESTABLISHED EPIGENETIC SEX 

6633
05:15:33,303 --> 05:15:36,573
AND WHETHER THERE'S CONSENSUS 

6634
05:15:36,573 --> 05:15:38,575
FROM TISSUE TO TISSUE, FROM 

6635
05:15:38,575 --> 05:15:40,143
STAGE TO STAGE OR FROM SPECIES 

6636
05:15:40,143 --> 05:15:43,046
TO SPECIES.

6637
05:15:43,046 --> 05:15:44,214
AND WE ARE ALSO VERY MUCH 

6638
05:15:44,214 --> 05:15:46,883
INTERESTED TO KNOW THE POTENTIAL

6639
05:15:46,883 --> 05:15:50,887
IMPACT OF EPIGENETIC SEX, 

6640
05:15:50,887 --> 05:15:52,456
HETEROGENEITY OR PLASTICITY AND 

6641
05:15:52,456 --> 05:15:56,460
PLASTICITY MAYBE OF CANCERS.

6642
05:15:56,460 --> 05:16:00,831
AND WE WOULD LIKE TO KNOW 

6643
05:16:00,831 --> 05:16:03,600
WHETHER IT'S USEFUL OR NOT OR 

6644
05:16:03,600 --> 05:16:05,869
MAYBE IT'S USEFUL IN THE COMPLEX

6645
05:16:05,869 --> 05:16:07,170
OF EPIGENETIC SEX IN CANCER 

6646
05:16:07,170 --> 05:16:09,406
RISK.

6647
05:16:09,406 --> 05:16:14,444
SO TO GIVE YOU A VERY BRIEF WE 

6648
05:16:14,444 --> 05:16:17,047
DID LOTS OF EPIGENETIC HISTO 

6649
05:16:17,047 --> 05:16:17,714
MODIFICATIONS FOR THE FIRST 

6650
05:16:17,714 --> 05:16:18,982
ROUND.

6651
05:16:18,982 --> 05:16:23,720
YOU CAN SEE IF YOU PERFORM 

6652
05:16:23,720 --> 05:16:26,389
ANALYSIS AND LOOK AT THE 

6653
05:16:26,389 --> 05:16:29,926
ACETYLATION AND THIS IS A 

6654
05:16:29,926 --> 05:16:31,761
POSITIVE CONTROL FOLLOWING X 

6655
05:16:31,761 --> 05:16:35,799
CHROMATIN GENES AND YOU CAN SEE 

6656
05:16:35,799 --> 05:16:38,869
HIGHER IN FEE FEMALES AND AS THE

6657
05:16:38,869 --> 05:16:41,705
NOT ALLELE SPECIFIC BECAUSE IT'S

6658
05:16:41,705 --> 05:16:42,873
A HIGHER SIGNAL.

6659
05:16:42,873 --> 05:16:47,110
IT'S AS EXPECTED AND YOU CAN SEE

6660
05:16:47,110 --> 05:16:48,545
THIS IS BINDING TO Y IN MALES 

6661
05:16:48,545 --> 05:16:50,347
NOT IN FEMALES.

6662
05:16:50,347 --> 05:16:52,149
THIS IS OUR INTERNAL CONTROL 

6663
05:16:52,149 --> 05:17:02,459
WHICH IS PERFECT.

6664
05:17:06,163 --> 05:17:10,767
WE SEE MALE PEAKS ARE HIGHER 

6665
05:17:10,767 --> 05:17:12,369
CONSISTENTLY AND THE TWO PEAKS 

6666
05:17:12,369 --> 05:17:13,904
APPEAR TO BE HIGHER IN MALES 

6667
05:17:13,904 --> 05:17:14,437
THAN IN FEMALES.

6668
05:17:14,437 --> 05:17:18,308
SO WHAT WE WANT TO DO IS REALLY 

6669
05:17:18,308 --> 05:17:20,043
TAKE AN DIAGNOSTIC APPROACH TO 

6670
05:17:20,043 --> 05:17:24,414
LOOK NOT ONLY BASED ON THE GENE 

6671
05:17:24,414 --> 05:17:25,515
JUST LOOK AT EPIGENETIC 

6672
05:17:25,515 --> 05:17:30,220
MODIFICATION PATTERN.

6673
05:17:30,220 --> 05:17:33,456
CAN WE ESTABLISH EPIGENETIC 

6674
05:17:33,456 --> 05:17:42,465
SITES HISTONE ASSCETYLATION AND 

6675
05:17:42,465 --> 05:17:44,534
USING THAT CONSENSUS CAN WE 

6676
05:17:44,534 --> 05:17:46,169
BUILD OUT THE IDEA OF EPIGENETIC

6677
05:17:46,169 --> 05:17:49,806
SEX.

6678
05:17:49,806 --> 05:17:52,142
WITH THEY WANT TO SAY SEX IS A 

6679
05:17:52,142 --> 05:17:54,177
BIOLOGICAL VARIABLE IN CANCERS.

6680
05:17:54,177 --> 05:17:55,579
I THINK IT'S AN IMPORTANT 

6681
05:17:55,579 --> 05:17:57,480
CONSIDERATION NOT ONLY WE HAVE 

6682
05:17:57,480 --> 05:18:03,153
TO DO IT IN APPLICATIONS BUT WE 

6683
05:18:03,153 --> 05:18:05,121
ARE DOING IT IN THE LAB AND IN 

6684
05:18:05,121 --> 05:18:06,990
TALKING TO IAN WE HAVE TO USE 

6685
05:18:06,990 --> 05:18:07,591
FOUR DIFFERENT SEX TYPES NOT 

6686
05:18:07,591 --> 05:18:12,696
TWO.

6687
05:18:12,696 --> 05:18:14,664
WITH THAT I WANT TO THANK THE 

6688
05:18:14,664 --> 05:18:16,166
PEOPLE IN THE LAB AND I'M 

6689
05:18:16,166 --> 05:18:18,535
GRATEFUL FOR THE SUPPORT FROM 

6690
05:18:18,535 --> 05:18:20,270
THE NIH AND NIDDK AND VERY MUCH 

6691
05:18:20,270 --> 05:18:30,413
TO NCI.

6692
05:18:32,749 --> 05:18:35,285
>> WE HAVE TIME FOR A
COUPLE 

6693
05:18:35,285 --> 05:18:35,552
QUESTIONS.

6694
05:18:35,552 --> 05:18:38,088
>> INTERESTING TALK, SEAN.

6695
05:18:38,088 --> 05:18:42,058
I THINK ALSO VERY INTERESTING 

6696
05:18:42,058 --> 05:18:43,593
POPULATION OF PATIENTS AT RISK 

6697
05:18:43,593 --> 05:18:46,162
KIND OF EXCITED ABOUT 

6698
05:18:46,162 --> 05:18:53,570
TRANSGENDER POPULATION.

6699
05:18:53,570 --> 05:18:58,174
ARE YOU AWARE IN HIGHER OR LOWER

6700
05:18:58,174 --> 05:18:59,809
RISK IN DEVELOPING BLADDER 

6701
05:18:59,809 --> 05:19:01,144
CANCER IN THIS POPULATION YOU 

6702
05:19:01,144 --> 05:19:06,583
PROBABLY HAVE A BETTER CHANCE TO

6703
05:19:06,583 --> 05:19:08,885
DECOUPLE THE EPIGENETIC AND 

6704
05:19:08,885 --> 05:19:10,520
OTHER AFFECTS CAN BE MODULATED 

6705
05:19:10,520 --> 05:19:17,460
AS WELL.

6706
05:19:17,460 --> 05:19:19,596
>> I THINK THAT THE JURY
IS 

6707
05:19:19,596 --> 05:19:20,497
STILL OUT IN TERMS OF 

6708
05:19:20,497 --> 05:19:27,737
TRANSGENDER POPULATION.

6709
05:19:27,737 --> 05:19:30,440
WE TRY HARD TO GET IN TOUCH WITH

6710
05:19:30,440 --> 05:19:34,177
THIS POPULATION TO STUDY AND IN 

6711
05:19:34,177 --> 05:19:41,785
TERMS OF WHAT IS ALREADY KNOWN 

6712
05:19:41,785 --> 05:19:44,788
PROSTATE CANCER IS BETTER KNOWN 

6713
05:19:44,788 --> 05:19:50,460
FOR TRANS GENDER FEMALES AND IS 

6714
05:19:50,460 --> 05:19:53,029
LOWER AND HAVE INNER CANCER MY 

6715
05:19:53,029 --> 05:19:57,667
COLLEAGUE PUBLISHED A PAPER IN 

6716
05:19:57,667 --> 05:20:00,770
JAMA IN CERTAIN POPULATIONS AN 

6717
05:20:00,770 --> 05:20:01,805
ANOTHER PUBLICATION THIS WAS 

6718
05:20:01,805 --> 05:20:09,212
LAST YEAR OR EARLY THIS YEAR 

6719
05:20:09,212 --> 05:20:10,347
TALKING ABOUT BREAST TISSUE AND 

6720
05:20:10,347 --> 05:20:15,118
GENDER CONFIRMATION IN THERAPY.

6721
05:20:15,118 --> 05:20:20,590
WHEN MALES ARE EXPOSED TO 

6722
05:20:20,590 --> 05:20:21,858
ESTROGEN OR FEMALES EXPOSED TO 

6723
05:20:21,858 --> 05:20:32,535
ANDROGEN AND IT REALLY CHANGES 

6724
05:20:35,872 --> 05:20:40,543
THE GENE EXPRESSION AND THIS IS 

6725
05:20:40,543 --> 05:20:41,745
STILL YOUNG TO LOOK AT I THINK.

6726
05:20:41,745 --> 05:20:52,122
THAT'S A GREAT QUESTION.

6727
05:20:52,122 --> 05:20:53,390
>> OTHERS.

6728
05:20:53,390 --> 05:20:55,558
>> YOU TALKED ABOUT
BLANDER 

6729
05:20:55,558 --> 05:20:57,927
CANCER, WHAT OTHER SEX BIASES OF

6730
05:20:57,927 --> 05:21:00,630
TUMOR TYPES ARE THERE OR 

6731
05:21:00,630 --> 05:21:02,298
INVOLVED MAYBE 6A AND ANYTHING 

6732
05:21:02,298 --> 05:21:05,635
LIKE THIS YOU CAN TALK ABOUT?

6733
05:21:05,635 --> 05:21:10,440
>> FOR BLADDER CANCER, THE
PLEK 

6734
05:21:10,440 --> 05:21:13,309
SUB TYPE OR PATHOLOGICAL SUB 

6735
05:21:13,309 --> 05:21:18,715
TYPE IT'S REALLY NOT CLEAR CUT.

6736
05:21:18,715 --> 05:21:24,654
THEY ARE INDICATIONS IT MAY BE 

6737
05:21:24,654 --> 05:21:31,494
DITCH BUT IN THE DATA AND ONE 

6738
05:21:31,494 --> 05:21:36,132
THING IS CLEAR OR SEMI CLEAR FOR

6739
05:21:36,132 --> 05:21:40,970
FEMALES IT APPEARS TO ACCELERATE

6740
05:21:40,970 --> 05:21:45,108
MUCH FASTER IN FEMALE DEVELOP 

6741
05:21:45,108 --> 05:21:47,844
BLADDER CANCER IN TUMOR AND GET 

6742
05:21:47,844 --> 05:21:53,683
POORER OUTCOME BUT THE QUESTION 

6743
05:21:53,683 --> 05:21:58,188
IS IT WAS CONSIDERED TO BE FOR 

6744
05:21:58,188 --> 05:22:01,357
LATER DIAGNOSIS RATHER THAN 

6745
05:22:01,357 --> 05:22:03,726
BECAUSE FEMALES DON'T SEE 

6746
05:22:03,726 --> 05:22:06,429
UROLOGIST AND FOR GUYS YOU GO TO

6747
05:22:06,429 --> 05:22:07,597
THE UROLOGIST AND GET A CHECK 

6748
05:22:07,597 --> 05:22:11,634
UP.

6749
05:22:11,634 --> 05:22:13,236
WHEN YOU DO A SPECIFIC 

6750
05:22:13,236 --> 05:22:14,437
COMPARISON IT APPEARS TO HAVE 

6751
05:22:14,437 --> 05:22:16,206
FEMALES THAT HAVE A WORSE 

6752
05:22:16,206 --> 05:22:23,713
OUTCOME.

6753
05:22:23,713 --> 05:22:30,453
OUR NEXT TALK IS BY TERESA 

6754
05:22:30,453 --> 05:22:35,859
VINCENT FROM NEW YORK UNIVERSITY

6755
05:22:35,859 --> 05:22:40,196
mRNA  POLYMERASE FUELLING TUMOR 

6756
05:22:40,196 --> 05:22:50,473
CELL PLASTICITY.

6757
05:23:01,784 --> 05:23:02,986
>> THANK YOU FOR INVITING
ME TO 

6758
05:23:02,986 --> 05:23:04,354
THIS AMAZING DAY.

6759
05:23:04,354 --> 05:23:08,925
I FEEL VERY HONORED TO TALK IN 

6760
05:23:08,925 --> 05:23:09,993
THIS SECTION.

6761
05:23:09,993 --> 05:23:12,862
I'LL SPEAK TO YOU A LITTLE BIT 

6762
05:23:12,862 --> 05:23:16,466
ABOUT mRNA  POLYMERASE 1 AND WA 

6763
05:23:16,466 --> 05:23:17,867
WE BELIEVE IS AN UNDER STUDIED 

6764
05:23:17,867 --> 05:23:18,968
AMONG THE THREE.

6765
05:23:18,968 --> 05:23:23,740
THERE'S A MEETING EVERY THIRD 

6766
05:23:23,740 --> 05:23:28,545
YEAR WHICH BASICALLY STRUCTURE 

6767
05:23:28,545 --> 05:23:32,048
LOOK AT POLYMER AS A 1 AND 3 AND

6768
05:23:32,048 --> 05:23:36,519
DECIDED TO MAKE A BREAKOUT 

6769
05:23:36,519 --> 05:23:37,220
MEETING.

6770
05:23:37,220 --> 05:23:40,189
I HOPE I'LL GET YOU MORE EXCITED

6771
05:23:40,189 --> 05:23:44,193
ABOUT mRNA  POLYMERASE 1 THAT 

6772
05:23:44,193 --> 05:23:45,962
MAKES THE BIGGEST COMPONENT OF 

6773
05:23:45,962 --> 05:23:51,000
THE RIBOSOME THE mRNA.

6774
05:23:51,000 --> 05:23:53,303
AND WE BELIEVE EVERYTHING mRNA  

6775
05:23:53,303 --> 05:23:55,538
POLYMERASE FOR THE BIO GENESIS 

6776
05:23:55,538 --> 05:23:58,207
OR RIBOSOME COULD BE A NEW 

6777
05:23:58,207 --> 05:23:59,609
THERAPEUTIC TARGET FOR TREATING 

6778
05:23:59,609 --> 05:24:01,144
CANCER.

6779
05:24:01,144 --> 05:24:02,579
MOSTLY I'VE BEEN STUDYING BREAST

6780
05:24:02,579 --> 05:24:09,319
AND I'M GRATEFUL TO THE NCI THAT

6781
05:24:09,319 --> 05:24:16,192
SUPPORT THE RESEARCH.

6782
05:24:16,192 --> 05:24:17,694
SO THIS IS ONE OF THE WORSE 

6783
05:24:17,694 --> 05:24:21,164
BRAIN TUMORS THAT EXIST AND MOST

6784
05:24:21,164 --> 05:24:24,467
COMMON MALIGNANT BRAIN TUMOR.

6785
05:24:24,467 --> 05:24:29,372
80% OF CASE DBM AND POOR 

6786
05:24:29,372 --> 05:24:30,440
SURVIVAL, 14 1/2 MONTHS AND THE 

6787
05:24:30,440 --> 05:24:33,643
QUALITY OF LIFE IS POOR BECAUSE 

6788
05:24:33,643 --> 05:24:42,452
OF THE INFILTRATIVE NATURE OF 

6789
05:24:42,452 --> 05:24:46,189
THE TUMORS AND THOUGH IT 

6790
05:24:46,189 --> 05:24:48,524
INCLUDES SURGERY AND RADIATION 

6791
05:24:48,524 --> 05:24:49,826
HASN'T IMPROVED LONG-TERM 

6792
05:24:49,826 --> 05:24:50,760
SURVIVAL WITH THESE TUMORS.

6793
05:24:50,760 --> 05:24:52,462
THERE'S A GREAT NEED TO LOOK AT 

6794
05:24:52,462 --> 05:24:53,796
OTHER THERAPEUTICS AND HOW TO 

6795
05:24:53,796 --> 05:24:55,798
TARGET THE TUMORS WHICH IS NOT 

6796
05:24:55,798 --> 05:24:56,332
SOLELY FOCUSSED ON TUMOR 

6797
05:24:56,332 --> 05:25:04,807
PROLIFERATION.

6798
05:25:04,807 --> 05:25:12,081
SO GBM SUB TYPES HAVE BEEN 

6799
05:25:12,081 --> 05:25:13,049
STUDIED AND SIGNIFICANTLY 

6800
05:25:13,049 --> 05:25:17,086
THERE'S BEEN GENERATED USING RNA

6801
05:25:17,086 --> 05:25:18,988
SEQ AND NEW SINGLE SEQUENCING.

6802
05:25:18,988 --> 05:25:21,491
PEOPLE HAVE COME UP WITH 

6803
05:25:21,491 --> 05:25:23,292
CONSENSUS OF THREE DIFFERENT SUB

6804
05:25:23,292 --> 05:25:27,597
TYPES CAN WHICH IS SIGNIFIED BY 

6805
05:25:27,597 --> 05:25:29,632
ONLY TWO EXPRESSION THE 1 

6806
05:25:29,632 --> 05:25:30,967
MUTATION AND PROLIFERATIVE IN 

6807
05:25:30,967 --> 05:25:31,868
THEIR NATURE.

6808
05:25:31,868 --> 05:25:35,738
THESE TUMORS ARE EASIER TO TREAT

6809
05:25:35,738 --> 05:25:39,208
OR EASIER BUT NOT AS RESISTANCE 

6810
05:25:39,208 --> 05:25:49,552
AS THE MESSENCHYMAL.

6811
05:26:03,066 --> 05:26:04,400
AND THEY TRANSITION IN THE TUMOR

6812
05:26:04,400 --> 05:26:05,334
BETWEEN THE CELL TYPE.

6813
05:26:05,334 --> 05:26:08,671
THIS IS MEDIATED BY DIFFERENT 

6814
05:26:08,671 --> 05:26:11,541
PROGRAMS THAT ARE DRIVEN BY THE 

6815
05:26:11,541 --> 05:26:13,810
MICROENVIRONMENT THAT WAS BY THE

6816
05:26:13,810 --> 05:26:14,210
TREATMENT ITSELF.

6817
05:26:14,210 --> 05:26:16,179
BECAUSE RADIATION HAS BEEN SHOWN

6818
05:26:16,179 --> 05:26:20,783
TO INDUCE PLASTICITY AND INDUCE 

6819
05:26:20,783 --> 05:26:31,227
A MER MIGRATORY PHENOTYPE.

6820
05:26:34,931 --> 05:26:39,769
I'LL TALK ABOUT THE MESENCHYMAL 

6821
05:26:39,769 --> 05:26:42,672
POSITION FROM THE SUB TYPE.

6822
05:26:42,672 --> 05:26:48,177
HOW WE DECIDED TO DO THIS WAS TO

6823
05:26:48,177 --> 05:26:50,747
DO A VERY OVER ALL GENOMIC 

6824
05:26:50,747 --> 05:26:51,247
STUDY.

6825
05:26:51,247 --> 05:26:55,051
SO WE BASICALLY HAD HUMAN PDX 

6826
05:26:55,051 --> 05:26:58,988
LINES U1313 FROM THE HGG 

6827
05:26:58,988 --> 05:27:02,959
DATABASE GENERATED WHERE I WAS 

6828
05:27:02,959 --> 05:27:06,062
PREVIOUSLY AFFILIATED WITH THE 

6829
05:27:06,062 --> 05:27:06,729
VSHS AND GROW THESE FOR 24 HOURS

6830
05:27:06,729 --> 05:27:08,831
WHICH IS KNOWN TO INDUCE A KIND 

6831
05:27:08,831 --> 05:27:12,702
OF INVASIVE STEM LIKE PHENOTYPE.

6832
05:27:12,702 --> 05:27:20,176
AND WE DO RNA SEQUENCING AND 

6833
05:27:20,176 --> 05:27:26,682
MASS SPECTOMETRY AND WANTED TO 

6834
05:27:26,682 --> 05:27:28,117
LOOK AT THE DRIVERS AND THE CELL

6835
05:27:28,117 --> 05:27:38,661
STARTS TO BECOME MORE INVASIVE.

6836
05:27:51,040 --> 05:27:57,580
AND WE LOOKED AT THE MESENCHYMAL

6837
05:27:57,580 --> 05:27:59,348
GENE MADE IT COMFORTABLE AND 

6838
05:27:59,348 --> 05:28:04,720
SAFE AND THE BETA CAN INDUCE 

6839
05:28:04,720 --> 05:28:06,455
CHANGES SO IT'S IMPORTANT TO 

6840
05:28:06,455 --> 05:28:10,359
LOOK AT THE TUMOR CELL 

6841
05:28:10,359 --> 05:28:10,660
SPECIFICITY.

6842
05:28:10,660 --> 05:28:14,797
AND WHEN WE OVERLAID THE 

6843
05:28:14,797 --> 05:28:17,800
PROTEOMICS AND 65% OF ALL THE 

6844
05:28:17,800 --> 05:28:19,969
GENES DETECTED WERE NOT 

6845
05:28:19,969 --> 05:28:21,771
SIGNIFICANTLY CHANGED WITH THE 

6846
05:28:21,771 --> 05:28:24,340
mRNA.

6847
05:28:24,340 --> 05:28:30,146
AND THOSE WERE ACTUALLY INVOLVED

6848
05:28:30,146 --> 05:28:32,748
WITH ADHESION AND THERE WAS A 

6849
05:28:32,748 --> 05:28:36,819
LOT OF CHANGES IN RNA PROCESSING

6850
05:28:36,819 --> 05:28:40,089
AND RIBOSOME GENESIS AND IF WE 

6851
05:28:40,089 --> 05:28:42,124
DIDN'T LOOK AT THE PROTEOME WE 

6852
05:28:42,124 --> 05:28:43,993
WOULD HAVE MISSED THOSE CHANGES.

6853
05:28:43,993 --> 05:28:49,565
SO THEN WHAT IS RIBOSOME RIBO 

6854
05:28:49,565 --> 05:28:51,300
GENESIS AND THIS IS THIS 

6855
05:28:51,300 --> 05:28:52,635
BEAUTIFUL MACHINE DISCOVERED BY 

6856
05:28:52,635 --> 05:28:56,439
GEORGE PALADAY IN 1955 MADE IN 

6857
05:28:56,439 --> 05:28:57,974
THE CELL AND IT'S BASICALLY 

6858
05:28:57,974 --> 05:29:00,476
COMPOSED OF IF YOU WOULD BE 

6859
05:29:00,476 --> 05:29:04,881
INSIDE A CELL YOU WOULD 

6860
05:29:04,881 --> 05:29:05,882
ENCOUNTER RIBOSOME IN THE 

6861
05:29:05,882 --> 05:29:08,184
NUCLEUS BUT THOSE WOULD BE 

6862
05:29:08,184 --> 05:29:09,886
IMMATURE RIBOSOME AND GOING BACK

6863
05:29:09,886 --> 05:29:12,021
TO THE THREE POLYMERASES AND 

6864
05:29:12,021 --> 05:29:15,057
WHAT I BELONGED TO POLYMERASE 1 

6865
05:29:15,057 --> 05:29:19,762
AND 3 IS BASICALLY MAKING THE 

6866
05:29:19,762 --> 05:29:20,263
RRNA.

6867
05:29:20,263 --> 05:29:24,867
AND ONE MAKES THE 47S.

6868
05:29:24,867 --> 05:29:27,603
AND 3 MAKES THE 5S.

6869
05:29:27,603 --> 05:29:34,176
YOU HAVE 2 HELPING OUT BUT WITH 

6870
05:29:34,176 --> 05:29:37,113
mRNA  TRANSLATION THEY'RE MAKING

6871
05:29:37,113 --> 05:29:40,149
THE SNOW RNAs AND IT'S HELPING 

6872
05:29:40,149 --> 05:29:43,085
IN THE MODIFYING THE FIRST LONG 

6873
05:29:43,085 --> 05:29:49,091
TRANS AND CUTTING IT AND 

6874
05:29:49,091 --> 05:29:52,194
MODIFYING IT AND THE RIBOSOME 

6875
05:29:52,194 --> 05:29:54,597
MAKES THE IMMATURE RIBOSOME AND 

6876
05:29:54,597 --> 05:30:02,705
IT'S NOT UNTIL YOU HIT THE SI 

6877
05:30:02,705 --> 05:30:03,906
CYTOPLASM AND IT RELEASES 

6878
05:30:03,906 --> 05:30:04,740
CERTAIN FACTORS.

6879
05:30:04,740 --> 05:30:07,944
THE RIBOSOME IS COMPLEX BOTH HOW

6880
05:30:07,944 --> 05:30:10,446
IT'S MADE AND BEFORE IT'S ACTIVE

6881
05:30:10,446 --> 05:30:14,951
AND COMPETENT FOR CELLS.

6882
05:30:14,951 --> 05:30:18,688
SO HOW IS RIBOSOME MADE IN 

6883
05:30:18,688 --> 05:30:18,988
CELLS?

6884
05:30:18,988 --> 05:30:21,424
IT'S BEEN SHOWN CLEARLY IN 

6885
05:30:21,424 --> 05:30:24,193
PROLIFERATING CELLS ALL THREE 

6886
05:30:24,193 --> 05:30:25,695
POLYMERASES NEED TO BE 

6887
05:30:25,695 --> 05:30:27,663
COORDINATED DURING THE PROCESS.

6888
05:30:27,663 --> 05:30:30,399
SO THERE'S A TRANSCRIPTION 

6889
05:30:30,399 --> 05:30:32,935
FACTOR AND POLYMERASE REGULATED 

6890
05:30:32,935 --> 05:30:35,237
BECAUSE IT COORDINATES ALL THE 

6891
05:30:35,237 --> 05:30:39,442
THREE POLYMERASES.

6892
05:30:39,442 --> 05:30:43,679
YOU HAVE ENOUGH mRNA  AND GET 

6893
05:30:43,679 --> 05:30:44,613
ENOUGH RIBOSOME EXPRESSED TO 

6894
05:30:44,613 --> 05:30:50,453
MAKE THE RIBOSOME.

6895
05:30:50,453 --> 05:30:53,389
AND WHEN CELLS ARE CYCLED OFF 

6896
05:30:53,389 --> 05:30:54,857
BECAUSE WHEN YOU ADD THE BETA TO

6897
05:30:54,857 --> 05:30:57,860
THE CELLS THEY'RE NO LONGER 

6898
05:30:57,860 --> 05:30:58,194
PROLIFERATING.

6899
05:30:58,194 --> 05:30:59,562
THEY HAVE A CHANGE IN THEIR CELL

6900
05:30:59,562 --> 05:31:09,572
IDENTITY.

6901
05:31:09,572 --> 05:31:14,343
THIS IS WHAT WE DISCOVERED AND 

6902
05:31:14,343 --> 05:31:16,512
TUMOR CELL PLASTICITY AND WHEN I

6903
05:31:16,512 --> 05:31:20,216
START MIDED MY LAB WE WERE ASKI 

6904
05:31:20,216 --> 05:31:22,451
ABOUT THE CELL CYCLE ARRESTED IN

6905
05:31:22,451 --> 05:31:25,788
CELLS STARTING TO MIGRATE AND 

6906
05:31:25,788 --> 05:31:28,190
STOP PROLIFERATING OR ARE THEY 

6907
05:31:28,190 --> 05:31:36,665
MAKING RIBOSOMES?

6908
05:31:36,665 --> 05:31:38,467
STRANGELY ENOUGH IT HADN'T BEEN 

6909
05:31:38,467 --> 05:31:45,508
STUDIED AND WHAT WE SEE HERE 

6910
05:31:45,508 --> 05:31:56,018
THAT WE SAW THEY WERE MAKING 

6911
05:32:01,157 --> 05:32:01,957
RIBOSO

6912
05:32:01,957 --> 05:32:03,125
RIBOSO

6913
05:32:03,125 --> 05:32:06,429
RIBOSOMES WE SAW THIS IN 

6914
05:32:06,429 --> 05:32:09,498
DIFFERENT STIMULI AND SAW IF 

6915
05:32:09,498 --> 05:32:10,666
IT'S TRUE IT'S A RECREATION 

6916
05:32:10,666 --> 05:32:13,069
DURING THE DEVELOPMENT.

6917
05:32:13,069 --> 05:32:14,870
WE DID THE EXACT SAME EXPERIMENT

6918
05:32:14,870 --> 05:32:20,142
IN MICE AND CHICKEN AND INDEBTED

6919
05:32:20,142 --> 05:32:23,546
EDU AND EU AND STAINED AND LOOK 

6920
05:32:23,546 --> 05:32:28,184
FOR WHETHER THE CELLS CHANGED IN

6921
05:32:28,184 --> 05:32:38,727
THE CELL IDENTIFY MARK HERE AND 

6922
05:32:41,530 --> 05:32:51,941
THOSE CELLS AND WE SEE OUT 

6923
05:32:58,247 --> 05:33:02,451
CREATE THE TISSUES WE HAVE AN 

6924
05:33:02,451 --> 05:33:03,652
ENRICHMENT AND THIS mRNA  

6925
05:33:03,652 --> 05:33:07,857
SYNTHESIS IS NOT BEING DRIVEN BY

6926
05:33:07,857 --> 05:33:10,459
MIC ACTING IN THE PROLIFERATING 

6927
05:33:10,459 --> 05:33:13,429
CELLS BUT DRIVEN BY SNAIL ONE OF

6928
05:33:13,429 --> 05:33:18,400
THE MOST IMPORTANT TRANSCRIPTION

6929
05:33:18,400 --> 05:33:24,507
FACTORS AND ALSO SHOWED WHEN WE 

6930
05:33:24,507 --> 05:33:28,177
TURN ON SNAIL WE TURN ON mRNA  

6931
05:33:28,177 --> 05:33:28,511
TRANSCRIPTION.

6932
05:33:28,511 --> 05:33:30,446
WE WERE THINKING CAN THIS BE A 

6933
05:33:30,446 --> 05:33:31,680
GENERAL FEATURE OF PLASTICITY 

6934
05:33:31,680 --> 05:33:36,986
PROGRAMS NOT JUST INDUCED BY TGF

6935
05:33:36,986 --> 05:33:38,287
BETA BUT LINKED AT THE CELLS 

6936
05:33:38,287 --> 05:33:40,456
WHEN THEY CHANGE THEIR IDENTITY 

6937
05:33:40,456 --> 05:33:44,193
THEY NEED TO MAKE OTHER TYPES OF

6938
05:33:44,193 --> 05:33:45,594
RIBOSOMES AND OTHER TYPES IN 

6939
05:33:45,594 --> 05:33:48,130
ORDER TO CHANGE THE CELL 

6940
05:33:48,130 --> 05:33:51,700
IDENTITY FROM THE PROLIFERATIVE 

6941
05:33:51,700 --> 05:33:53,636
CELLS TO THE MIGRATORY CELLS.

6942
05:33:53,636 --> 05:34:02,444
WE LOOKED AT 47S THE FIRST 

6943
05:34:02,444 --> 05:34:08,684
TRANSCRIPT AND COULD SEE AND WE 

6944
05:34:08,684 --> 05:34:14,690
SEE AN INDUCTION AND WE HAVE 

6945
05:34:14,690 --> 05:34:22,998
CLONES FROM ONE PATIENT AND FIND

6946
05:34:22,998 --> 05:34:26,468
CLONES OF PRONEURAL AND 

6947
05:34:26,468 --> 05:34:27,903
MESENCHYMAL AND IT'S IMPORTANT 

6948
05:34:27,903 --> 05:34:31,373
TO NOTICE HERE THAT MESENCHYMAL 

6949
05:34:31,373 --> 05:34:33,075
CELLS DON'T ALWAYS PROLIFERATE.

6950
05:34:33,075 --> 05:34:39,548
THIS IS NOT JUST DUE TO THE 

6951
05:34:39,548 --> 05:34:43,953
PROLIFERATION.

6952
05:34:43,953 --> 05:34:46,422
AND HOW IS THIS mRNA  

6953
05:34:46,422 --> 05:34:47,690
TRANSCRIPTION REGULATED IN THE 

6954
05:34:47,690 --> 05:34:47,957
CELL?

6955
05:34:47,957 --> 05:34:50,492
IT'S PRETTY COMPLICATED BECAUSE 

6956
05:34:50,492 --> 05:34:54,430
mRNA  IS DIFFERENTLY LOCATED IN 

6957
05:34:54,430 --> 05:34:56,298
DIFFERENT CHROMOSOMES.

6958
05:34:56,298 --> 05:34:58,200
AND WE KNOW THEY'RE DIFFERENT 

6959
05:34:58,200 --> 05:34:59,735
FROM DIFFERENT PEOPLE.

6960
05:34:59,735 --> 05:35:01,103
AND SOME OF US PERHAPS SITTING 

6961
05:35:01,103 --> 05:35:03,672
UP THIS ROOM HAVE 500 COPIES AND

6962
05:35:03,672 --> 05:35:06,442
OTHERS CAN HAVE 1500 COPIES AND 

6963
05:35:06,442 --> 05:35:08,077
IT'S THE SAME IF YOU COMPARE 

6964
05:35:08,077 --> 05:35:09,311
DIFFERENT MICE STRAINS AND WE 

6965
05:35:09,311 --> 05:35:12,414
DON'T KNOW WHY THAT IS THE CASE.

6966
05:35:12,414 --> 05:35:14,283
WHY WOULD SOME PEOPLE HAVE MORE 

6967
05:35:14,283 --> 05:35:18,287
AND ONE OF THE PROBLEMS WITH 

6968
05:35:18,287 --> 05:35:20,589
THIS RESEARCH AREA IS IS OUR DNA

6969
05:35:20,589 --> 05:35:22,591
GENES ARE REFERRED TO AS THE 

6970
05:35:22,591 --> 05:35:23,659
DARK GENOME.

6971
05:35:23,659 --> 05:35:28,197
BECAUSE IT'S COMPLICATED AND 

6972
05:35:28,197 --> 05:35:28,964
BASICALLY REPETITIVE GENES.

6973
05:35:28,964 --> 05:35:31,567
THEY'RE VERY SIMILAR AND WHEN 

6974
05:35:31,567 --> 05:35:34,837
YOU DO THE BIO INFORM ATTIC 

6975
05:35:34,837 --> 05:35:37,072
ANALYSIS IT'S MORE TO ASSEMBLE.

6976
05:35:37,072 --> 05:35:38,941
OF COURSE THERE'S HOT SPOTS FOR 

6977
05:35:38,941 --> 05:35:41,310
CANCER IF THEY'RE REPETITIVE IN 

6978
05:35:41,310 --> 05:35:41,710
SEQUENCING.

6979
05:35:41,710 --> 05:35:45,614
SO THE MAJORITY WILL WALK AROUND

6980
05:35:45,614 --> 05:35:46,282
HAD MOST ASSIGNED BY THE 

6981
05:35:46,282 --> 05:35:49,718
COMPLEX.

6982
05:35:49,718 --> 05:35:51,153
THEN THEY WERE THINKING PERHAPS 

6983
05:35:51,153 --> 05:35:55,190
IT COULD BE THE CASE THAT DURING

6984
05:35:55,190 --> 05:35:57,693
PNT THAT BECAUSE THERE HAS NOT 

6985
05:35:57,693 --> 05:36:00,229
BEEN STUDIES HOW RNA SYNTHESIS 

6986
05:36:00,229 --> 05:36:03,666
IS REGULATED SO WE THEN LOOKED 

6987
05:36:03,666 --> 05:36:05,501
IS IT THAT HAVE YOU MORE OPEN 

6988
05:36:05,501 --> 05:36:07,202
CHROMATIN IN THE CELLS.

6989
05:36:07,202 --> 05:36:11,440
THEY'RE OPENING MORE AND WHAT WE

6990
05:36:11,440 --> 05:36:14,810
COULD SEE IS WE HAVE ALMOST A 50

6991
05:36:14,810 --> 05:36:19,048
PATIENCE REDUCTION MEANING MORE 

6992
05:36:19,048 --> 05:36:25,120
R DNA CHROMATIN AND MORE 

6993
05:36:25,120 --> 05:36:29,825
RECRUITMENT AND SNAIL IS BEING 

6994
05:36:29,825 --> 05:36:31,493
RECRUITED IN ORDER TO DRIVE THE 

6995
05:36:31,493 --> 05:36:34,063
RNA TRANSCRIPTION.

6996
05:36:34,063 --> 05:36:36,899
WE WANTED TO DEMONSTRATE THE 

6997
05:36:36,899 --> 05:36:39,034
NON-CYCLING CELLS ARE MAKE mRNA 

6998
05:36:39,034 --> 05:36:43,839
IN RIBOSOMES BUT WE'RE FOLLOWING

6999
05:36:43,839 --> 05:36:50,446
UP WITH NCI IS TO DETERMINE WHY 

7000
05:36:50,446 --> 05:36:58,520
ARE THERE AND THEY'RE INCREASING

7001
05:36:58,520 --> 05:36:59,755
THE SIZE BUT NOT DIVIDING.

7002
05:36:59,755 --> 05:37:05,260
WE STARTED THINKING ABOUT 

7003
05:37:05,260 --> 05:37:10,432
RIBOSOME AND SINCE IT WAS 

7004
05:37:10,432 --> 05:37:18,874
DISCOVERED IN 1975 FOR THE NOBEL

7005
05:37:18,874 --> 05:37:22,945
PRIZE IN FOR THE HYPE THE FACT 

7006
05:37:22,945 --> 05:37:24,079
THE BEAUTIFUL CRYSTAL STRUCTURES

7007
05:37:24,079 --> 05:37:26,281
OF THE RIBOSOMES AND AN OLD 

7008
05:37:26,281 --> 05:37:28,217
QUESTION WAS ALWAYS ARE THERE 

7009
05:37:28,217 --> 05:37:30,452
DIFFERENT RIBOSOMES IN DIFFERENT

7010
05:37:30,452 --> 05:37:32,821
CELLS THAT ARE SPECIFICALLY 

7011
05:37:32,821 --> 05:37:34,890
DESIGNATED TO TRANSLATE CERTAIN 

7012
05:37:34,890 --> 05:37:36,925
mRNA s?

7013
05:37:36,925 --> 05:37:38,460
A FIELD THAT'S BEEN IN 

7014
05:37:38,460 --> 05:37:42,364
DEVELOPMENT HAS BEEN STUDIED AND

7015
05:37:42,364 --> 05:37:43,565
VERY CONTROVERSIAL SOME PEOPLE 

7016
05:37:43,565 --> 05:37:45,768
REALLY DON'T BELIEVE IN 

7017
05:37:45,768 --> 05:37:47,903
HETEROGENEITY WITH RIBOSOMES 

7018
05:37:47,903 --> 05:37:50,038
BECAUSE THEY'RE SAYING THEY'RE 

7019
05:37:50,038 --> 05:37:52,441
TOO EVOLUTIONARY AND DOESN'T 

7020
05:37:52,441 --> 05:37:53,976
MAKE SENSE BECAUSE OF THE 

7021
05:37:53,976 --> 05:37:55,644
PRODUCTION MACHINERY TO MAKE 

7022
05:37:55,644 --> 05:38:01,383
SPECIAL RIBOSOMES SENSE FROM A 

7023
05:38:01,383 --> 05:38:02,084
METABOLIC POINT OF VIEW.

7024
05:38:02,084 --> 05:38:04,052
HOWEVER, WHAT'S SUGGEST THE IN 

7025
05:38:04,052 --> 05:38:07,856
THE LITERATURE AFBD WHAT'S BEEN 

7026
05:38:07,856 --> 05:38:09,091
DISCOVERED AND PROJECT IS 

7027
05:38:09,091 --> 05:38:11,193
THEY'RE PAIR PARALOGS IN 

7028
05:38:11,193 --> 05:38:14,963
DIFFERENT TISSUES AND DISEASES.

7029
05:38:14,963 --> 05:38:18,467
THERE'S MOST TRANSLATION 

7030
05:38:18,467 --> 05:38:23,539
MODIFICATION AND THERE'S 

7031
05:38:23,539 --> 05:38:26,442
PHOSPHORYLATION A COMMON 

7032
05:38:26,442 --> 05:38:33,182
MARKETER FOR SIGNALLING AND 10 

7033
05:38:33,182 --> 05:38:34,550
YEARS AGO IT WAS SHOWED NORD FOR

7034
05:38:34,550 --> 05:38:36,919
THIS TOCK ACTIVATED IN THE CELL 

7035
05:38:36,919 --> 05:38:40,456
AND HAVE THE KINASE ACTIVATED IT

7036
05:38:40,456 --> 05:38:41,657
BINDS TO RIBOSOME.

7037
05:38:41,657 --> 05:38:44,726
FOR THEM TO BIND IT GETS 

7038
05:38:44,726 --> 05:38:45,260
ACTIVATED.

7039
05:38:45,260 --> 05:38:47,663
AND WE DON'T NEED THAT MANY MORE

7040
05:38:47,663 --> 05:38:51,366
RIBOSOMES IN A CELL ONLY A FEW 

7041
05:38:51,366 --> 05:38:53,769
THAT HAVE THE CAPACITY TO BIND 

7042
05:38:53,769 --> 05:38:55,838
THE RIBOSOME TO PROPAGATE THE 

7043
05:38:55,838 --> 05:38:58,373
SIGNAL IF RIBOSOMES ARE ALSO 

7044
05:38:58,373 --> 05:39:02,277
SIGNALLING.

7045
05:39:02,277 --> 05:39:05,681
YOU ALSO HAVE mRNA  VARIATION 

7046
05:39:05,681 --> 05:39:08,917
BUT WE'RE VERY INTERESTED IN 

7047
05:39:08,917 --> 05:39:12,721
THIS AREA WHICH IS CALLED RRNA 

7048
05:39:12,721 --> 05:39:13,088
MODIFICATION.

7049
05:39:13,088 --> 05:39:20,229
AND RRNA MODIFICATION NEEDS TO 

7050
05:39:20,229 --> 05:39:22,030
OCCUR WHILE THE mRNA  IS BEING 

7051
05:39:22,030 --> 05:39:26,201
TRANSCRIBED IT CAN'T COME AFTER 

7052
05:39:26,201 --> 05:39:27,970
BECAUSE THE IMPORTANT SITES ARE 

7053
05:39:27,970 --> 05:39:38,447
HIDDEN IN SIDE THE RIBOSOME.

7054
05:39:38,780 --> 05:39:43,952
AND IT OCCURS ON ALL MRNs AND 

7055
05:39:43,952 --> 05:39:46,588
SHOWN TO PLAY A ROLE IN 

7056
05:39:46,588 --> 05:39:48,123
EMBRYONIC DEVELOPMENT AND 

7057
05:39:48,123 --> 05:39:48,757
PROGRAMMING.

7058
05:39:48,757 --> 05:39:52,227
IT'S ALSO BEEN SHOWN TO BE 

7059
05:39:52,227 --> 05:40:01,670
IMPORTANT FOR MESENCHYMAL TYPES 

7060
05:40:01,670 --> 05:40:12,214
AND THERE'S TWO AND THE MAJORITY

7061
05:40:30,299 --> 05:40:35,070
ARE RRNA AND WE USED THE HDC BIO

7062
05:40:35,070 --> 05:40:39,508
BANK AND LOOKED AT THE 

7063
05:40:39,508 --> 05:40:45,080
EXPRESSION OF THE TWO AND ONLY 

7064
05:40:45,080 --> 05:40:52,254
35 WAS  -- 5 WAS CHANGED AND YOU

7065
05:40:52,254 --> 05:40:53,555
CAN FIND AP32.

7066
05:40:53,555 --> 05:40:56,892
IT'S INSIDE THE RIBOSOME IN THE 

7067
05:40:56,892 --> 05:40:58,226
DECODING CENTER WHICH IS 

7068
05:40:58,226 --> 05:41:00,162
IMPORTANT FOR mRNA  TRANSLATION 

7069
05:41:00,162 --> 05:41:02,464
WHERE IT COMES IN AND LEADS TO 

7070
05:41:02,464 --> 05:41:03,398
DOWN mRNA.

7071
05:41:03,398 --> 05:41:06,034
WE FOUND THAT INTERESTING AND 

7072
05:41:06,034 --> 05:41:09,071
BASICALLY LOOKED AT GBM AND SAW 

7073
05:41:09,071 --> 05:41:12,174
IT WAS STRONGLY EXPRESSED AND 

7074
05:41:12,174 --> 05:41:15,243
ALSO EXPRESSED [INDISCERNIBLE].

7075
05:41:15,243 --> 05:41:17,779
THEN WE WERE WONDERING WOULD 

7076
05:41:17,779 --> 05:41:20,816
THIS BE THE SPECIFIC TRANSFERASE

7077
05:41:20,816 --> 05:41:23,018
IS COMING AND A MODIFYING THE 

7078
05:41:23,018 --> 05:41:23,218
mRNA.

7079
05:41:23,218 --> 05:41:29,758
THAT'S WHY WE SEE MORE BEING 

7080
05:41:29,758 --> 05:41:31,593
MADE.

7081
05:41:31,593 --> 05:41:38,500
AND WE DO SEE THE COMPLEX AND 

7082
05:41:38,500 --> 05:41:43,372
ALMOST THE LOW ASSOCIATED 

7083
05:41:43,372 --> 05:41:48,210
[INDISCERNIBLE] AND WHEN WE 

7084
05:41:48,210 --> 05:41:52,047
LOOKED FOR THE SPECIFIC SELECT 

7085
05:41:52,047 --> 05:41:54,750
OME ONE SITE WHERE WE'RE LOOKING

7086
05:41:54,750 --> 05:41:57,719
AT AND WE CAN SEE TWO DIFFERENT 

7087
05:41:57,719 --> 05:41:59,554
CELL LINES WE CAN SEE AN UP 

7088
05:41:59,554 --> 05:42:01,957
REGULATION AND HAVE MORE IN THE 

7089
05:42:01,957 --> 05:42:03,058
MESENCHYMAL.

7090
05:42:03,058 --> 05:42:05,460
THEN WE WERE THINKING OKAY LET'S

7091
05:42:05,460 --> 05:42:06,361
SILENCE THIS AND LOOK WHAT 

7092
05:42:06,361 --> 05:42:06,762
HAPPENS.

7093
05:42:06,762 --> 05:42:10,165
AS EXPECTED WHEN YOU SILENCE 5 

7094
05:42:10,165 --> 05:42:18,440
YOU HAVE LESS OF THE SITE AND 

7095
05:42:18,440 --> 05:42:20,909
WHEN WE DO THE PROTEOMIC 

7096
05:42:20,909 --> 05:42:22,210
ANALYSIS WE ALMOST SEE A 

7097
05:42:22,210 --> 05:42:26,448
COMPLETE STOP IN THE HALT SO 

7098
05:42:26,448 --> 05:42:34,456
CELLS AND GENES UPREGULATED ARE 

7099
05:42:34,456 --> 05:42:37,826
SILENCE AND ONE NUCLEOTIDE IS 

7100
05:42:37,826 --> 05:42:40,128
HAVING THIS MASSIVE AFFECT ON 

7101
05:42:40,128 --> 05:42:42,330
THE PROGRAM AND IT INDUCES 

7102
05:42:42,330 --> 05:42:46,668
INVASION WHEN YOU SILENCE THIS.

7103
05:42:46,668 --> 05:42:48,804
THEN WE'RE THINKING THIS IS A 

7104
05:42:48,804 --> 05:42:50,439
BEAUTIFUL SITUATION AND NICE 

7105
05:42:50,439 --> 05:42:55,410
TARGET FOR SMALL MOLECULE 

7106
05:42:55,410 --> 05:43:00,816
BECAUSE METTL3 HAS IT AND METTL5

7107
05:43:00,816 --> 05:43:01,950
THERE'S NO SMALL MOLECULE 

7108
05:43:01,950 --> 05:43:03,885
INHIBITORS OUT THERE.

7109
05:43:03,885 --> 05:43:07,322
WE THOUGHT IF IT'S CODE 

7110
05:43:07,322 --> 05:43:10,225
TRANSCRIPTIONALLY IF WE INHIBIT 

7111
05:43:10,225 --> 05:43:13,762
THE mRNA  TRANSCRIPTION WILL WE 

7112
05:43:13,762 --> 05:43:15,263
INHIBIT SOME OF THE 

7113
05:43:15,263 --> 05:43:16,198
MODIFICATION.

7114
05:43:16,198 --> 05:43:24,840
WE USED TWO DIFFERENT DRUGS AND 

7115
05:43:24,840 --> 05:43:29,745
CX5461 WE DON'T UNDERSTAND HOW 

7116
05:43:29,745 --> 05:43:36,952
TO GIVE PATIENTS AN RNA POLYMER 

7117
05:43:36,952 --> 05:43:38,887
AS AN INHIBITOR WITH NO EFFECTS 

7118
05:43:38,887 --> 05:43:41,656
AND THERE'S GREAT TOOLS AND 

7119
05:43:41,656 --> 05:43:44,159
SINCE THEY'RE WELL TOLERATED IN 

7120
05:43:44,159 --> 05:43:47,529
THE CLINIC WE STILL NOY KNOW TOO

7121
05:43:47,529 --> 05:43:50,465
LITTLE HOW'S IT'S REGULATED IN 

7122
05:43:50,465 --> 05:43:53,869
DIFFERENT CELLULAR SPACE.

7123
05:43:53,869 --> 05:44:02,110
AND NPMR PASSES THE BLOOD BRAIN 

7124
05:44:02,110 --> 05:44:03,879
BARRIER AND USED FOR GBM.

7125
05:44:03,879 --> 05:44:09,184
WE SAW THE DRUGS WORKED.

7126
05:44:09,184 --> 05:44:13,822
AND THEY REDUCED SYNTHESIS, BOTH

7127
05:44:13,822 --> 05:44:18,994
OF THEM AND POL 1 IS NO LONGER 

7128
05:44:18,994 --> 05:44:20,162
RECRUITED AND LOST AMONG THE 

7129
05:44:20,162 --> 05:44:21,730
TREME AND WE ALSO SEE SNAIL IS 

7130
05:44:21,730 --> 05:44:24,332
NO LONGER RECRUTED MEANING WE 

7131
05:44:24,332 --> 05:44:28,203
BELIEVE SNAIL IS ALSO DRIVING IN

7132
05:44:28,203 --> 05:44:33,375
THIS CONTEXT RRNA TRANSCRIPTION 

7133
05:44:33,375 --> 05:44:36,511
AND COULD IT BE THAT BECAUSE 

7134
05:44:36,511 --> 05:44:39,114
METTL5 NEEDS TO BE 

7135
05:44:39,114 --> 05:44:39,748
CO-TRANSCRIPTIONALLY REGULATED 

7136
05:44:39,748 --> 05:44:41,583
AND FOUND A NICHE HOW THE DRUGS 

7137
05:44:41,583 --> 05:44:43,752
ARE WORKED AND LOOKED AT 

7138
05:44:43,752 --> 05:44:46,855
RECRUITMENT OF METTL5 AND ADDING

7139
05:44:46,855 --> 05:44:49,024
THE DRUGS WE DON'T SEE AN 

7140
05:44:49,024 --> 05:44:54,462
RECRUITMENT OF METTL5 AND SEE 

7141
05:44:54,462 --> 05:45:02,204
SIMILAR TO WHEN WE ARE SILENCING

7142
05:45:02,204 --> 05:45:05,807
METTL5 WE REDUCE AND IN THIS 

7143
05:45:05,807 --> 05:45:08,476
CASE THESE BOTH SILENCING OF 

7144
05:45:08,476 --> 05:45:10,779
METTL5 AND REDUCING THE CAPACITY

7145
05:45:10,779 --> 05:45:12,747
OF THE CELLS.

7146
05:45:12,747 --> 05:45:16,218
WE LOOKED AT THE PHENOTYPE FOR 

7147
05:45:16,218 --> 05:45:21,089
THE MECHANISM AND SAW THE REAR 

7148
05:45:21,089 --> 05:45:26,661
ORGANIZATION OF THE CYTOSKELETON

7149
05:45:26,661 --> 05:45:30,465
WAS REDUCED AND UNDERSTAND FROM 

7150
05:45:30,465 --> 05:45:31,900
AN UNBIASSED POINT OF VIEW HOW 

7151
05:45:31,900 --> 05:45:33,735
THE DRUG ARE WORKING.

7152
05:45:33,735 --> 05:45:36,605
THESE ARE NOT INHIBITERS.

7153
05:45:36,605 --> 05:45:38,473
THEY HAD LITTLE AFFECT IN mRNA  

7154
05:45:38,473 --> 05:45:48,717
TRANSCRIPTION.

7155
05:46:00,562 --> 05:46:01,930
AND THEY'VE DEVELOPED SMALL 

7156
05:46:01,930 --> 05:46:04,232
MOLECULE INHIBITORS AND ITS WAS 

7157
05:46:04,232 --> 05:46:08,637
NICE FOR US TO IS SEE THE 

7158
05:46:08,637 --> 05:46:10,972
LITERATURE BECAUSE IT'S BEEN 

7159
05:46:10,972 --> 05:46:12,641
PROVEN IT'S IMPORTANT.

7160
05:46:12,641 --> 05:46:14,075
IT HAS BEEN SHOWN FOR OTHER 

7161
05:46:14,075 --> 05:46:16,244
CANCERS TOO OTHERWISE ALL THE 

7162
05:46:16,244 --> 05:46:16,912
BEAUTIFUL DRUGS BEING DEVELOPED 

7163
05:46:16,912 --> 05:46:19,814
AND WHAT WAS INTERESTING TO US 

7164
05:46:19,814 --> 05:46:26,454
IT WAS PUBLISHED A TRANSLATIONAL

7165
05:46:26,454 --> 05:46:33,795
COMPONENT MEANING WE'RE STUCK IN

7166
05:46:33,795 --> 05:46:37,766
MAKING THE NEW MODIFIED mRNA  

7167
05:46:37,766 --> 05:46:39,200
MICROSOMES AND WE DECIDE IT HAD 

7168
05:46:39,200 --> 05:46:40,535
LOOK AT TRANSLATION.

7169
05:46:40,535 --> 05:46:45,874
SO WE JUST FIRST CONFIRMED THERE

7170
05:46:45,874 --> 05:46:49,711
WAS NO AFFECT ON mRNA  

7171
05:46:49,711 --> 05:46:51,446
TRANSCRIPTION FROM THE DRUGS 

7172
05:46:51,446 --> 05:46:53,548
HOWEVER, WE SAW BIG EFFECT AND 

7173
05:46:53,548 --> 05:46:55,750
THEN WE DID POLY SOME ANALYSIS 

7174
05:46:55,750 --> 05:47:00,255
AND WE BASICALLY ISOLATED THE 

7175
05:47:00,255 --> 05:47:02,223
ACTIVELY TRANSLATING RIBOSOMES 

7176
05:47:02,223 --> 05:47:05,593
AND THEN DID PCR AND IN LINE 

7177
05:47:05,593 --> 05:47:08,997
WITH WHAT OUR HYPOTHESIS WAS WE 

7178
05:47:08,997 --> 05:47:12,534
HAD MORE mRNA  KINASE TRANSLATED

7179
05:47:12,534 --> 05:47:14,069
IN THE POLY SOME IN THE BETA AND

7180
05:47:14,069 --> 05:47:16,538
WHEN WE STOPPED THE RIBOSOMES 

7181
05:47:16,538 --> 05:47:19,274
FROM BEING MADE WE'RE NO LONGER 

7182
05:47:19,274 --> 05:47:20,508
TRANSLATING THE KINASE.

7183
05:47:20,508 --> 05:47:24,713
THEN COMING TO MY LAST SLIDE WE 

7184
05:47:24,713 --> 05:47:26,614
WERE LOOKING IS THIS 

7185
05:47:26,614 --> 05:47:26,915
THERAPEUTIC.

7186
05:47:26,915 --> 05:47:28,083
IT'S IN CLINICAL TRIAL AND SO 

7187
05:47:28,083 --> 05:47:29,884
FAR IN ADVERSE EFFECT AND WOULD 

7188
05:47:29,884 --> 05:47:32,020
LIKE TO DEVELOP THIS TOGETHER 

7189
05:47:32,020 --> 05:47:36,157
WITH NCU PERHAPS FOR A FUTURE 

7190
05:47:36,157 --> 05:47:39,027
CLINICAL TRIAL.

7191
05:47:39,027 --> 05:47:40,228
WE W

7192
05:47:40,228 --> 05:47:42,964
WE WERE LOOKING AT TWO ASSAY ONE

7193
05:47:42,964 --> 05:47:52,807
EXO -- IN VIVO AND EX VIVO AND 

7194
05:47:52,807 --> 05:47:56,945
WE LOOKED AT MIGRATION.

7195
05:47:56,945 --> 05:48:02,450
WE SAW THE INHIBITORS REDUCED 

7196
05:48:02,450 --> 05:48:05,754
THE MIGRATION OF BOTH THE GBM 

7197
05:48:05,754 --> 05:48:06,087
CELLS.

7198
05:48:06,087 --> 05:48:07,956
THEN WE DID A MOUSE EXPERIMENT 

7199
05:48:07,956 --> 05:48:10,225
WHERE WE BASICALLY DOSED THEM 

7200
05:48:10,225 --> 05:48:11,226
TWICE A WEEK.

7201
05:48:11,226 --> 05:48:15,764
WE TRANSPLANTED THE F3030 CELLS 

7202
05:48:15,764 --> 05:48:17,065
AND LET THEM GROW FOR TWO WEEKS 

7203
05:48:17,065 --> 05:48:22,937
AND TREAT THEM FOR THREE WEEKS 

7204
05:48:22,937 --> 05:48:26,441
AND THEN WE ISOLATED THE TUMORS 

7205
05:48:26,441 --> 05:48:30,845
AND WE CHECKED AND WE ALSO REARE

7206
05:48:30,845 --> 05:48:34,449
REDUCING THE ONE SITE ON THE 

7207
05:48:34,449 --> 05:48:36,017
RRNA AND WE SAW WHEN WE 

7208
05:48:36,017 --> 05:48:37,419
SACRIFICED ANIMALS WE CAN SEE 

7209
05:48:37,419 --> 05:48:40,422
THE CELLS ARE STARTING TO CREATE

7210
05:48:40,422 --> 05:48:43,258
A MORE ROUND SHAPE AND YOU CAN 

7211
05:48:43,258 --> 05:48:45,860
SEE THESE SPIKY TUMORS.

7212
05:48:45,860 --> 05:48:52,100
THESE GBM TUMORS DON'T FORM THEY

7213
05:48:52,100 --> 05:48:54,035
BECOME HARD TO TREAT AND WE 

7214
05:48:54,035 --> 05:48:57,972
COULD SEE LESS OF THE SPIKING IN

7215
05:48:57,972 --> 05:48:58,573
THE PHENOTYPE IN THE TREATED 

7216
05:48:58,573 --> 05:49:02,777
TUMORS.

7217
05:49:02,777 --> 05:49:06,448
SO TODAY I HOPE I'VE BEEN ABLE 

7218
05:49:06,448 --> 05:49:14,189
TO CONVINCE YOU THAT RRNA POLIO 

7219
05:49:14,189 --> 05:49:20,995
 -- POLYMERASE  1 IS IMPORTANT 

7220
05:49:20,995 --> 05:49:23,064
AND THERE'S DIFFERENT COMPLEXES 

7221
05:49:23,064 --> 05:49:24,199
FORMED IN DIFFERENT CELLAR STATE

7222
05:49:24,199 --> 05:49:26,067
WHETHER IT'S GBM OR BREAST 

7223
05:49:26,067 --> 05:49:26,301
CANCER.

7224
05:49:26,301 --> 05:49:30,171
SO BASICALLY WHAT WE SUGGEST IS 

7225
05:49:30,171 --> 05:49:36,144
THAT HAVE A BETA SIGNAL, OUR 

7226
05:49:36,144 --> 05:49:38,913
COMPASS WILL BE OPENED OR CLOSED

7227
05:49:38,913 --> 05:49:39,547
DEPENDING ON THE SIGNAL.

7228
05:49:39,547 --> 05:49:41,716
DIFFERENT MODIFIERS CAN COME AND

7229
05:49:41,716 --> 05:49:46,688
MODIFY THE RRNA.

7230
05:49:46,688 --> 05:49:53,862
-- SORRY.

7231
05:49:53,862 --> 05:49:59,067
SO THE SUMMARY THEN IS BASICALLY

7232
05:49:59,067 --> 05:50:01,369
POL 1 IS AS IMPORTANT AN POL 2 

7233
05:50:01,369 --> 05:50:04,339
BY RECRUITING DIFFERENT 

7234
05:50:04,339 --> 05:50:06,074
TRANSCRIPTION FACTORS AN CAN 

7235
05:50:06,074 --> 05:50:09,010
HAVE THE MODIFIERS THAT CAN 

7236
05:50:09,010 --> 05:50:10,912
GENERATE THE SPECIFIC RIBOSOME 

7237
05:50:10,912 --> 05:50:13,648
AND YOU HAVE POL 2 WORKING IN 

7238
05:50:13,648 --> 05:50:15,850
CONJUNCTION WITH THIS AND THOSE 

7239
05:50:15,850 --> 05:50:18,219
TWO TOGETHER WOULD THEN 

7240
05:50:18,219 --> 05:50:23,992
BASICALLY FORM A SELECTIVE 

7241
05:50:23,992 --> 05:50:26,895
TRANSLATION PROGRAM SUCH AS THIS

7242
05:50:26,895 --> 05:50:32,066
KINASE AND TRANSLATE THE mRNA s 

7243
05:50:32,066 --> 05:50:34,202
TO PROMOTE TUMOR PLASTICITY AND 

7244
05:50:34,202 --> 05:50:36,371
BELIEVE WE HAVE NEW DRUGS IF WE 

7245
05:50:36,371 --> 05:50:40,608
CAN TARGET THESE PATHWAYS WE CAN

7246
05:50:40,608 --> 05:50:42,544
HAVE NEW THERAPEUTICS NOT 

7247
05:50:42,544 --> 05:50:46,347
DEPENDENT ON DNA REPLICATION.

7248
05:50:46,347 --> 05:50:51,085
THANK YOU SO MUCH.

7249
05:50:51,085 --> 05:50:52,921
THIS IS MY LAB.

7250
05:50:52,921 --> 05:51:02,130
AND THANKS AGAIN.

7251
05:51:02,130 --> 05:51:08,336
>> A FEW MINUTES FOR
QUESTIONS.

7252
05:51:08,336 --> 05:51:08,870
>> ANDY.

7253
05:51:08,870 --> 05:51:09,771
THIS IS INTERESTING.

7254
05:51:09,771 --> 05:51:12,340
I WANT TO ASK ABOUT PAPERS FROM 

7255
05:51:12,340 --> 05:51:14,676
A WHILE AGO.

7256
05:51:14,676 --> 05:51:17,812
HE HAD THESE PAPERS ONE WAS IN 

7257
05:51:17,812 --> 05:51:18,379
MOLECULAR CELL THAT I KNOW 

7258
05:51:18,379 --> 05:51:23,818
ABOUT.

7259
05:51:23,818 --> 05:51:26,454
IT'S INTERESTING BECAUSE HE 

7260
05:51:26,454 --> 05:51:27,956
TALKS ABOUT TRANS LOCATION OF 

7261
05:51:27,956 --> 05:51:31,759
LAMIN TYPE PROTEINS BETWEEN THE 

7262
05:51:31,759 --> 05:51:33,027
NUCLEAR MEMBRANE AT THE NUCLEUS.

7263
05:51:33,027 --> 05:51:36,497
IT DOESN'T HAVE A MEMBRANE OF 

7264
05:51:36,497 --> 05:51:36,731
COURSE.

7265
05:51:36,731 --> 05:51:39,801
BUT THE VERY FIRST TIME ANYBODY 

7266
05:51:39,801 --> 05:51:42,537
EVER LOOKED AT CTCF IN THE CELL 

7267
05:51:42,537 --> 05:51:45,306
WAS AN IMMUNOLOCALIZATION 

7268
05:51:45,306 --> 05:51:46,941
EXPERIMENT AT THE NUCLEUS AND 

7269
05:51:46,941 --> 05:51:52,180
NOT JUST THAT BUT DATA IN THE 

7270
05:51:52,180 --> 05:51:53,047
PAPER THAT SHOWED THE LOOPS 

7271
05:51:53,047 --> 05:51:55,250
EITHER THE PROMOTER NEXT TO THIS

7272
05:51:55,250 --> 05:51:58,219
OR THAT ENHANCER.

7273
05:51:58,219 --> 05:52:04,192
THE QUESTION IS HAVE YOU THOUGHT

7274
05:52:04,192 --> 05:52:05,927
ABOUT HOW THE HIGH ORDER 

7275
05:52:05,927 --> 05:52:06,561
STRUCTURE ISN'T JUST SOMETHING 

7276
05:52:06,561 --> 05:52:09,063
OUT THERE ON THE NUCLEAR EDGE OR

7277
05:52:09,063 --> 05:52:10,732
WHATEVER OR EVEN IN THE INTERIOR

7278
05:52:10,732 --> 05:52:12,200
BUT COMES DOWN TO THIS REGION 

7279
05:52:12,200 --> 05:52:14,836
WHICH IS THIS REALLY IMPORTANT 

7280
05:52:14,836 --> 05:52:18,539
REGION INVOLVING 

7281
05:52:18,539 --> 05:52:21,276
HETEROCHROMATINS SO THE 

7282
05:52:21,276 --> 05:52:24,012
RIBOSOMAL GENES HAVE TO BE SHUT 

7283
05:52:24,012 --> 05:52:27,048
DOWN EXCEPT FOR ONE AND WHAT ARE

7284
05:52:27,048 --> 05:52:32,053
YOUR THOUGHTS BECAUSE IT'S A 

7285
05:52:32,053 --> 05:52:34,222
CONNECTION BETWEEN YOUR TALK AND

7286
05:52:34,222 --> 05:52:34,455
OTHERS.

7287
05:52:34,455 --> 05:52:37,091
>> HAVING ALL THE
CHROMATIN IN 

7288
05:52:37,091 --> 05:52:40,428
ONE PLACE AND HAVING THEM OPEN 

7289
05:52:40,428 --> 05:52:45,500
VERSUS DOWN IS A BIG QUESTION 

7290
05:52:45,500 --> 05:52:46,434
HOW THAT AFFECTS THE 

7291
05:52:46,434 --> 05:52:49,637
TRANSCRIPTION IN GENERAL.

7292
05:52:49,637 --> 05:52:52,774
I ALSO THINK PERHAPS I 

7293
05:52:52,774 --> 05:52:53,641
MISUNDERSTOOD THE QUESTION A 

7294
05:52:53,641 --> 05:52:55,977
LITTLE BIT BUT IN GENERAL WE 

7295
05:52:55,977 --> 05:53:00,615
THOUGHT OF mRNA  POLYMERASE AS A

7296
05:53:00,615 --> 05:53:02,183
PASSIVE PLAYER.

7297
05:53:02,183 --> 05:53:05,920
IT'S HARD TO KNOW EXACTLY KNOW 

7298
05:53:05,920 --> 05:53:07,522
HOW ALL THESE THINGS ARE 

7299
05:53:07,522 --> 05:53:10,458
INTERLINKED BUT GIVEN THAT SO 

7300
05:53:10,458 --> 05:53:13,361
MUCH ENERGY GOES -- 80% OF THE 

7301
05:53:13,361 --> 05:53:16,097
CELLS ENERGY GOES TO MAKE 

7302
05:53:16,097 --> 05:53:18,099
RIBOSOMES IS A FASCINATING THING

7303
05:53:18,099 --> 05:53:20,234
HOW THE CELL IS PARTICIPATING IN

7304
05:53:20,234 --> 05:53:21,769
THIS ENERGY AND ALSO WHEN IT 

7305
05:53:21,769 --> 05:53:25,740
COMES TO THE SIZE OF THE NUCLEUS

7306
05:53:25,740 --> 05:53:27,709
WHICH HAS BEEN A CANCER 

7307
05:53:27,709 --> 05:53:32,613
DIAGNOSTIC FOR A LONG TIME 

7308
05:53:32,613 --> 05:53:42,990
PEOPLE HAVE LOOKED AT.

7309
05:53:51,132 --> 05:53:57,004
WE DON'T  KNOW WHICH ONE OF 

7310
05:53:57,004 --> 05:53:58,873
THESE RNA COPIES ARE OPEN OR 

7311
05:53:58,873 --> 05:54:01,776
CLOSED IN DIFFERENT SETTINGS SO 

7312
05:54:01,776 --> 05:54:03,111
WE STILL PROBE THE ONE RNA 

7313
05:54:03,111 --> 05:54:04,879
SEQUENCE OVER AND OVER AGAIN FOR

7314
05:54:04,879 --> 05:54:06,080
OUR EXPERIMENTS.

7315
05:54:06,080 --> 05:54:09,917
YES, IF ANYONE WOULD LIKE TO 

7316
05:54:09,917 --> 05:54:14,122
HELP I'M VERY OPEN FOR 

7317
05:54:14,122 --> 05:54:15,256
COLLABORATION AND HELP.

7318
05:54:15,256 --> 05:54:18,126
>> LET ME ASK YOU A QUICK
ONE, A

7319
05:54:18,126 --> 05:54:19,093
TRANSLATIONAL ONE.

7320
05:54:19,093 --> 05:54:22,296
ALL THESE INHIBITORS COULD COME 

7321
05:54:22,296 --> 05:54:23,765
DOWN TO COMBINATIONS.

7322
05:54:23,765 --> 05:54:25,733
AND YOU HAVE THE LAST SUMMARY 

7323
05:54:25,733 --> 05:54:28,369
SLIDE AND GOING THROUGH A SERIES

7324
05:54:28,369 --> 05:54:36,110
OF PGF BETA.

7325
05:54:36,110 --> 05:54:44,652
THANK YOU THOUGHT OF COMBINATOR 

7326
05:54:44,952 --> 05:54:45,486
IAL STUDIES.

7327
05:54:45,486 --> 05:54:49,190
>> YES, WE'RE COMBINING
WITH 

7328
05:54:49,190 --> 05:54:53,494
RADIATION WE'RE COMBINING IT 

7329
05:54:53,494 --> 05:55:03,971
WITH AND WE'RE TREATING THE 

7330
05:55:04,472 --> 05:55:05,406
TUMORS.

7331
05:55:05,406 --> 05:55:05,940
[INDISCERNIBLE] AND WE'RE 

7332
05:55:05,940 --> 05:55:10,478
CONTINUING THE TREATMENT.

7333
05:55:10,478 --> 05:55:20,822
WE HOPE FOR LONGER.

7334
05:55:23,658 --> 05:55:34,168
>> LAST IS CHIA LIN WEI.

7335
05:55:49,517 --> 05:55:55,723
TALKING ABOUT EXTRA CHROMOSOMAL 

7336
05:55:55,723 --> 05:55:59,327
DNA TRANSCRIPTION.

7337
05:55:59,327 --> 05:56:03,097
>> IT WAS BELIEVED FOR THE

7338
05:56:03,097 --> 05:56:06,467
TRANSCRIPTION IS THROUGH A 

7339
05:56:06,467 --> 05:56:14,475
HIGHLY ORGANIZED SUBNUCLEUS 

7340
05:56:14,475 --> 05:56:25,019
STRUCTURE THROUGH THE ORGANELLE.

7341
05:56:37,732 --> 05:56:41,969
SO I THINK THERE'S 3-D 

7342
05:56:41,969 --> 05:56:46,107
CONFIRMATION THAT ACTUALLY MOVE 

7343
05:56:46,107 --> 05:56:48,476
THOSE RIBOSOMAL DNA LOCATION 

7344
05:56:48,476 --> 05:56:51,479
INTO A VERY SPECIALIZED REGION 

7345
05:56:51,479 --> 05:57:01,789
FOR TRANSCRIPTION.

7346
05:57:02,023 --> 05:57:06,394
I THINK BUT I THINK IN GBM THESE

7347
05:57:06,394 --> 05:57:08,362
ARE PROBABLY HIGHLY TRANSCRIBED 

7348
05:57:08,362 --> 05:57:11,933
AS I UNDERSTOOD.

7349
05:57:11,933 --> 05:57:18,506
SO WHILE THIS IS BEING SET UP, 

7350
05:57:18,506 --> 05:57:20,274
MY NAME IS CHIN LIN WEI.

7351
05:57:20,274 --> 05:57:22,443
SOME IN THE AUDIENCE I KNEW FROM

7352
05:57:22,443 --> 05:57:28,149
JACKSON LABORATORY OVER A MONTH 

7353
05:57:28,149 --> 05:57:29,483
AGO.

7354
05:57:29,483 --> 05:57:31,852
AND I'M LEADING THE NORTHWEST 

7355
05:57:31,852 --> 05:57:33,187
GENO CENTER.

7356
05:57:33,187 --> 05:57:39,260
TODAY TARGETS WORK BEING DONE IN

7357
05:57:39,260 --> 05:57:41,228
JAX BUT IAN CHARGED ME FOR THE 

7358
05:57:41,228 --> 05:57:51,472
NEW FRONTIER.

7359
05:58:06,520 --> 05:58:08,222
I STARTED THE FIRST JUNIOR 

7360
05:58:08,222 --> 05:58:12,326
FACULTY POSITION IN SINGAPORE IN

7361
05:58:12,326 --> 05:58:15,129
EARLY 2000s.

7362
05:58:15,129 --> 05:58:19,500
THE WORKED WITH ACB MEMBERS AND 

7363
05:58:19,500 --> 05:58:22,503
THE FIRST SO-CALLED SENIOR 

7364
05:58:22,503 --> 05:58:28,142
CORRESPONDING PAPER WE USING 

7365
05:58:28,142 --> 05:58:34,081
SINGER SEQUENCE TO SEQUENCE IP 

7366
05:58:34,081 --> 05:58:42,189
DNA AND SECOND WHEN ILUMINA GA 

7367
05:58:42,189 --> 05:58:46,227
STARTED.

7368
05:58:46,227 --> 05:58:56,637
IT'S NOT REALLY MOVING.

7369
05:59:45,419 --> 05:59:51,192
AND WE ARE USING GA2 TO 

7370
05:59:51,192 --> 06:00:01,736
SEQUENCING BY DNA ACROSS HUMAN 

7371
06:00:04,305 --> 06:00:08,242
EMBRYONIC STEM CELL 

7372
06:00:08,242 --> 06:00:09,643
DIFFERENTIATION AND OUR PAPER 

7373
06:00:09,643 --> 06:00:11,645
GETS PUBLISHED A FEW MONTHS 

7374
06:00:11,645 --> 06:00:15,950
LATER BUT NEVERTHELESS PAVED ME 

7375
06:00:15,950 --> 06:00:18,052
TO THE SUBSEQUENT FOUNDATION OF 

7376
06:00:18,052 --> 06:00:28,596
MY LAB WANTING TO STUDY -- SO MY

7377
06:00:52,887 --> 06:00:58,225
LAB IS STUDYING THE 

7378
06:00:58,225 --> 06:01:08,769
REGULATION -- AND LOOKING AT HOW

7379
06:01:59,386 --> 06:02:00,921
GENETIC S AFFECT TRANSCRIPTION 

7380
06:02:00,921 --> 06:02:06,126
AND IN FACT THE CHROMATIN 

7381
06:02:06,126 --> 06:02:07,561
ORGANIZING STRUCTURE.

7382
06:02:07,561 --> 06:02:08,996
WE KNOW THE WHOLE DNA SEQUENCE 

7383
06:02:08,996 --> 06:02:11,265
ADDING TOGETHER IS ABOUT TWO 

7384
06:02:11,265 --> 06:02:13,634
METERS AND THE SIZE OF LeBRON 

7385
06:02:13,634 --> 06:02:13,901
JAMES.

7386
06:02:13,901 --> 06:02:18,706
HOW IT GETS CODED INTO A 10 

7387
06:02:18,706 --> 06:02:25,145
NUCLEI AND EXACTLY PRECISELY 

7388
06:02:25,145 --> 06:02:25,913
EXECUTED TRANSCRIPTION 

7389
06:02:25,913 --> 06:02:28,382
REGULATIONS AND HOW IT HAS TO BE

7390
06:02:28,382 --> 06:02:30,384
PERTURBED IN CANCER GENOME THAT 

7391
06:02:30,384 --> 06:02:33,220
AFFECT THE TUMOR HETEROGENEITY 

7392
06:02:33,220 --> 06:02:35,522
AND HOW TUMOR PROGRESSION IN THE

7393
06:02:35,522 --> 06:02:38,492
DRUG RESISTANCE.

7394
06:02:38,492 --> 06:02:40,594
AND KNOWING THAT EXPERIENCE OF 

7395
06:02:40,594 --> 06:02:46,233
USING POWERFUL NEXT GENOMIC 

7396
06:02:46,233 --> 06:02:56,777
TECHNOLOGIES --  AND FACILITATE 

7397
06:03:00,514 --> 06:03:01,315
THAT UNDERSTANDING HAS BEEN THE 

7398
06:03:01,315 --> 06:03:11,725
CENTRAL FOCUS OF MY LAB.

7399
06:03:16,830 --> 06:03:19,199
AND THE SEQUENCING IS SIMILAR TO

7400
06:03:19,199 --> 06:03:19,867
HI C.

7401
06:03:19,867 --> 06:03:22,469
YOU START WITH THE CROSS LINK 

7402
06:03:22,469 --> 06:03:28,642
CHROMATINS TO SNAP FROZEN THE 

7403
06:03:28,642 --> 06:03:30,444
ELEMENTS AND DIFFERENT FROM HI C

7404
06:03:30,444 --> 06:03:32,446
WE INTERROGATE THESE 

7405
06:03:32,446 --> 06:03:40,220
INTERACTIONS WITH A FUNCTION AL 

7406
06:03:40,220 --> 06:03:45,392
INTERACTION OF THE PROTEIN OF 

7407
06:03:45,392 --> 06:03:55,202
INTEREST BY ANTIBODY.

7408
06:03:55,202 --> 06:03:57,504
ANG SIMILAR TO THE HIGH C OF THE

7409
06:03:57,504 --> 06:03:59,640
HEAT MAP IN THE MEASURE.

7410
06:03:59,640 --> 06:04:03,944
SECOND, BECAUSE WE USE CHROMATIN

7411
06:04:03,944 --> 06:04:09,116
PRECIPITATION WE CAN DETERMINE 

7412
06:04:09,116 --> 06:04:13,053
PRECISE PROTEIN OR BINDING 

7413
06:04:13,053 --> 06:04:16,190
LOCATION LIKE CHIP SEQ.

7414
06:04:16,190 --> 06:04:18,325
THIRDLY BECAUSE WE PULL DOWN THE

7415
06:04:18,325 --> 06:04:20,728
INTERACTING FRAGMENT USING THE 

7416
06:04:20,728 --> 06:04:24,932
PROTEIN OF INTEREST WE CAN 

7417
06:04:24,932 --> 06:04:27,935
GENERATE PRECISE RESOLUTION OF 

7418
06:04:27,935 --> 06:04:30,838
LOOP INFORMATION INDICATING WHAT

7419
06:04:30,838 --> 06:04:32,940
POSITION THE TWO STILL 

7420
06:04:32,940 --> 06:04:33,941
REGULATORY ELEMENTS COME 

7421
06:04:33,941 --> 06:04:35,909
TOGETHER TO FORM INTERACTIONS.

7422
06:04:35,909 --> 06:04:38,312
SO THREE LEVELS OF INFORMATION 

7423
06:04:38,312 --> 06:04:40,781
FROM DATA SETS AND BINDING 

7424
06:04:40,781 --> 06:04:42,883
SITES, PROXIMITY AND 

7425
06:04:42,883 --> 06:04:45,085
MEASUREMENTS AND THE GLOBAL GENE

7426
06:04:45,085 --> 06:04:45,886
I'M WIDE LEVEL AND SPECIFIC 

7427
06:04:45,886 --> 06:04:56,230
INTERACTION REGIONS.

7428
06:04:57,164 --> 06:05:00,100
AND EXPAND UTILITY OF HI C TO 

7429
06:05:00,100 --> 06:05:04,405
LOOK FOR NOT ONLY THE PROXIMITY 

7430
06:05:04,405 --> 06:05:07,374
DISTAL REGULATOR INTERACTION AND

7431
06:05:07,374 --> 06:05:09,209
INFER STRUCTURE VARIATION.

7432
06:05:09,209 --> 06:05:11,278
FOR EXAMPLE THE THREE HERE TRANS

7433
06:05:11,278 --> 06:05:11,779
LOCATION, DELETIONS AND 

7434
06:05:11,779 --> 06:05:14,081
APPLICATIONS.

7435
06:05:14,081 --> 06:05:16,216
SO THIS HAS BEEN DEMONSTRATED 

7436
06:05:16,216 --> 06:05:22,456
THE UTILITY IN THE CANCER GENOME

7437
06:05:22,456 --> 06:05:23,991
INTERROGATION UNDERSTANDING THE 

7438
06:05:23,991 --> 06:05:25,125
CHROMATIN INTERACTION AS WELL AS

7439
06:05:25,125 --> 06:05:33,467
THE PRIMARY STRUCTURE IN IMPACT 

7440
06:05:33,467 --> 06:05:34,001
TRANSCRIPTION REGULATION.

7441
06:05:34,001 --> 06:05:44,545
SO AND WITH THE CANCER BIOLOGY 

7442
06:05:48,348 --> 06:05:50,417
INVESTI

7443
06:05:50,417 --> 06:05:51,552
INVESTIGATOR IS IN GLIAL 

7444
06:05:51,552 --> 06:05:52,886
BLASTOMA RESEARCH AND INTRODUCED

7445
06:05:52,886 --> 06:05:57,024
ME TO THE OBSERVATION HE MADE IN

7446
06:05:57,024 --> 06:06:07,568
THE GBM IS HIGH FREQUENCY OF THE

7447
06:06:08,435 --> 06:06:10,237
EXTRACHROMOSOMAL DNA FROM THE 

7448
06:06:10,237 --> 06:06:14,041
FIELD IS A CHROMATINIZED 

7449
06:06:14,041 --> 06:06:17,377
CIRCULAR DNA OFTEN FOUND IN THE 

7450
06:06:17,377 --> 06:06:20,647
CANCER CELLS AND USUALLY KNOWN 

7451
06:06:20,647 --> 06:06:26,453
TO CARRY HIGH COPY NUMBER FOR 

7452
06:06:26,453 --> 06:06:32,559
FOCAL APPLICATION OF ONCOGENES 

7453
06:06:32,559 --> 06:06:35,362
AND IT WAS BELIEVED TO BRING 

7454
06:06:35,362 --> 06:06:39,099
HIGH COPY OF ONO GENE EXPRESSION

7455
06:06:39,099 --> 06:06:41,401
THUS GIVING THE CELLS A HIGH 

7456
06:06:41,401 --> 06:06:46,073
LEVEL OF ONCOGENE EXPRESSION AN 

7457
06:06:46,073 --> 06:06:47,374
AN ADVANTAGE THEREFORE GIVING 

7458
06:06:47,374 --> 06:06:50,444
THE CANCER CELLS VERY HIGH 

7459
06:06:50,444 --> 06:06:51,211
SO-CALLED ADVANTAGE IN TERM OF 

7460
06:06:51,211 --> 06:06:55,516
GROWTH FITNESS.

7461
06:06:55,516 --> 06:06:59,486
IT WAS RECENTLY IN THE LAST FEW 

7462
06:06:59,486 --> 06:07:05,159
YEARS IT WAS THE FREQUENCY OF EC

7463
06:07:05,159 --> 06:07:07,828
DNA FOUND BETWEEN THE METASTASIS

7464
06:07:07,828 --> 06:07:09,963
VERSUS THE PRIMARY TISSUE AND 

7465
06:07:09,963 --> 06:07:12,499
BETWEEN THE AGGRESSIVE CANCER 

7466
06:07:12,499 --> 06:07:15,169
TYPE VERSUS NON INDICATING THE 

7467
06:07:15,169 --> 06:07:18,105
SIGNIFICANCE OF CC DNA IS VERY 

7468
06:07:18,105 --> 06:07:21,074
IMPORTANT FOR US TO UNDERSTAND 

7469
06:07:21,074 --> 06:07:24,945
THE TUMOR METASTASIS DRUG 

7470
06:07:24,945 --> 06:07:27,681
RESISTANCE AN AGGRESSIVE TUMOR 

7471
06:07:27,681 --> 06:07:28,015
PHENOTYPES.

7472
06:07:28,015 --> 06:07:31,885
AS A GENOME BIOLOGIST IT'S BEEN 

7473
06:07:31,885 --> 06:07:35,022
VERY INTERESTING TO ME BECAUSE 

7474
06:07:35,022 --> 06:07:37,891
EC DNA IS EXTRACHROMOSOMAL DNA 

7475
06:07:37,891 --> 06:07:42,329
AND COULD ACTUALLY EVADE ALL THE

7476
06:07:42,329 --> 06:07:46,233
CHROMATIN FOLDING PRINCIPLE THE 

7477
06:07:46,233 --> 06:07:49,736
TERRITORIES OF SO-CALLED DISTAL 

7478
06:07:49,736 --> 06:07:53,173
REGULATION HAPPENS BETWEEN ON 

7479
06:07:53,173 --> 06:07:54,575
THE CHROMOSOMES.

7480
06:07:54,575 --> 06:07:56,577
IT'S A QUESTION OF HOW IT'S A 

7481
06:07:56,577 --> 06:07:57,644
CHROMATIN STATE.

7482
06:07:57,644 --> 06:08:02,049
DOES IT PERSIST WITH A UNIQUE 

7483
06:08:02,049 --> 06:08:07,554
EPIGENETIC STATE AND CHROMATIN 

7484
06:08:07,554 --> 06:08:09,823
GENERATION AND IMPORTANT FOR THE

7485
06:08:09,823 --> 06:08:12,092
FUNCTION BEYOND JUST THE VESICLE

7486
06:08:12,092 --> 06:08:16,230
OR VEHICLE CARRYING HIGH COPIES 

7487
06:08:16,230 --> 06:08:26,473
OF ONCOGENES.

7488
06:08:40,287 --> 06:08:45,959
WE MEASURED THE GENOME WIDE 

7489
06:08:45,959 --> 06:08:56,503
INTERACTIONS HERE SHOWING THAT 

7490
06:08:59,539 --> 06:09:03,677
AND THERE'S HIGH CHROMATIN 

7491
06:09:03,677 --> 06:09:07,414
INTERACTIONS AND SUGGESTING EC 

7492
06:09:07,414 --> 06:09:10,150
DNA BEING SMALL, BEING CIRCULAR 

7493
06:09:10,150 --> 06:09:13,954
AND FREELY MOVE AROUND THE 

7494
06:09:13,954 --> 06:09:16,056
NUCLEUS MAKING A LOT OF 

7495
06:09:16,056 --> 06:09:19,893
CHROMATIN CONTACT WITH THE 

7496
06:09:19,893 --> 06:09:20,260
CHROMOSOMES.

7497
06:09:20,260 --> 06:09:24,164
AND THE FREQUENCY IS NORMALIZED 

7498
06:09:24,164 --> 06:09:27,034
BY NUMBER AND SPIKING THE 

7499
06:09:27,034 --> 06:09:29,569
CONTACT NOT BECAUSE THERE'S NOT 

7500
06:09:29,569 --> 06:09:32,172
HIGH COPY NATIONAL BUT 

7501
06:09:32,172 --> 06:09:34,174
SUGGESTING THE MOVING AROUND IN 

7502
06:09:34,174 --> 06:09:36,043
THE NUCLEUS MAKING THE CONTACT.

7503
06:09:36,043 --> 06:09:46,219
NEXT, WE ASKED IF THAT CONTEXT 

7504
06:09:46,219 --> 06:09:56,763
MEANING AND SPECIFIC REGIONS IS 

7505
06:10:08,375 --> 06:10:13,480
IN CONTACT WITH A LOT OF 

7506
06:10:13,480 --> 06:10:21,722
CHROMOSOMES AND THAT CARRIES 

7507
06:10:21,722 --> 06:10:24,758
BROAD RANGE OF ESCALATION AND 

7508
06:10:24,758 --> 06:10:27,661
IT'S BEING INDICATING ENHANCER 

7509
06:10:27,661 --> 06:10:31,298
SIGNATURES AND THE HIGH LEVEL 

7510
06:10:31,298 --> 06:10:35,369
K27 ACTIVITY AND BROAD SPAN OF 

7511
06:10:35,369 --> 06:10:38,438
K27 ACTIVITY INDICATING A SUPER 

7512
06:10:38,438 --> 06:10:40,240
ENHANCER TYPE OF SIGNATURE AS WE

7513
06:10:40,240 --> 06:10:45,545
HAVE SHOWN IS THE IMMUNOSTAINING

7514
06:10:45,545 --> 06:10:50,350
OF THE K27 STAINING AS THE STAIN

7515
06:10:50,350 --> 06:10:52,252
ON THE EXTRACHROMOSOMAL 

7516
06:10:52,252 --> 06:10:54,321
SUGGESTING EXTRACHROMOSOMAL DNA 

7517
06:10:54,321 --> 06:10:59,760
HARBOR A LOT OF ENHANCER 

7518
06:10:59,760 --> 06:11:00,060
SIGNATURES.

7519
06:11:00,060 --> 06:11:02,896
AND THE ENHANCER SIGNATURE IT TO

7520
06:11:02,896 --> 06:11:06,466
MAKE SPECIFIC CONTACT WITH THE 

7521
06:11:06,466 --> 06:11:10,737
CHROMOSOME ACTIVATING CHROMOSOME

7522
06:11:10,737 --> 06:11:20,981
INTERACTIONS.

7523
06:11:22,282 --> 06:11:24,050
ONE THING WE ARE TRYING TO PROVE

7524
06:11:24,050 --> 06:11:28,188
IS WHETHER THE SUPER ENHANCER AS

7525
06:11:28,188 --> 06:11:32,325
A HUB FOR THE TRANSCRIPTION HIGH

7526
06:11:32,325 --> 06:11:33,160
LEVEL TRANSCRIPTION FACTORIES 

7527
06:11:33,160 --> 06:11:35,328
AND IT ALLOWED US TO MAKE THIS 

7528
06:11:35,328 --> 06:11:38,865
AS A MOBILE ENHANCER.

7529
06:11:38,865 --> 06:11:41,968
SO ONE THING WE FIRST ASKED 

7530
06:11:41,968 --> 06:11:45,005
WHETHER THIS TRANSCRIPTION 

7531
06:11:45,005 --> 06:11:50,477
FACTORY CO-LOCALIZED WITH 

7532
06:11:50,477 --> 06:11:53,480
TRANSCRIPTION ACTIVATE 1 AND 

7533
06:11:53,480 --> 06:11:57,217
WHEN WE DID THE CHIP SEQ THE EC 

7534
06:11:57,217 --> 06:11:59,753
CONTACT SHOWN AS A BLUE IS 

7535
06:11:59,753 --> 06:12:00,921
HIGHLY OVERLAPPED AND SUPER 

7536
06:12:00,921 --> 06:12:03,990
IMPOSED WITH THE BINDING AND THE

7537
06:12:03,990 --> 06:12:05,559
K27 SIGNATURES SUGGESTING THAT 

7538
06:12:05,559 --> 06:12:10,230
THIS IS SUPER ENHANCER HUBS ARE 

7539
06:12:10,230 --> 06:12:13,733
ACTUALLY CO-LOCALIZED WITH MET 1

7540
06:12:13,733 --> 06:12:15,135
AND NOT ONLY IN THE SPECIFIC 

7541
06:12:15,135 --> 06:12:15,802
CELL LINE.

7542
06:12:15,802 --> 06:12:17,637
WE'RE SHOWING ACROSS MANY 

7543
06:12:17,637 --> 06:12:21,508
DIFFERENT CELL LINE THIS 

7544
06:12:21,508 --> 06:12:27,547
COLOCALIZATION IS CROSSING CELL 

7545
06:12:27,547 --> 06:12:29,683
TYPE AND HAVING THE INTRINSIC 

7546
06:12:29,683 --> 06:12:33,954
DOMAIN REGIONS IS KNOWN TO FORM 

7547
06:12:33,954 --> 06:12:38,291
LIPIDS SEPARATED AND WHEN WE 

7548
06:12:38,291 --> 06:12:41,127
LOOKED IS TO SEE WHETHER THIS IS

7549
06:12:41,127 --> 06:12:46,233
REALLY A PART OF LIQUID-LIQUID 

7550
06:12:46,233 --> 06:12:50,670
CONDENSATE SO THE 

7551
06:12:50,670 --> 06:12:51,204
EXTRACHROMOSOMAL STAINING 

7552
06:12:51,204 --> 06:12:53,006
SHOWING THEY'RE HIGHLY 

7553
06:12:53,006 --> 06:12:55,375
SIGNIFICANTLY CO-LOCALIZED AND 

7554
06:12:55,375 --> 06:12:59,679
ALSO THE LIVE IMAGING STAINING 

7555
06:12:59,679 --> 06:13:04,451
OF EC DNA SHOWS THE CONDENSATE 

7556
06:13:04,451 --> 06:13:08,288
MORPHOLOGIES SUGGESTING THIS IS 

7557
06:13:08,288 --> 06:13:10,257
REALLY A WAY OF EC DNA FUNCTION 

7558
06:13:10,257 --> 06:13:14,261
TO FORM HIGHLY CLUSTERED 

7559
06:13:14,261 --> 06:13:16,663
AGGREGATE IN THE PHASE SEPARATED

7560
06:13:16,663 --> 06:13:20,367
CONDENSATE FORMAT CARRYING 

7561
06:13:20,367 --> 06:13:24,871
TRANS

7562
06:13:24,871 --> 06:13:27,774
TRANSACT -- TRANS ACTIVATOR AND 

7563
06:13:27,774 --> 06:13:29,809
SEE IF THERE'S SPECIFICITY WHERE

7564
06:13:29,809 --> 06:13:31,745
THEY MAKE THE CHROMOSOME CAN BE 

7565
06:13:31,745 --> 06:13:31,945
TACT.

7566
06:13:31,945 --> 06:13:36,583
WE USED A SINGLE MOLECULE, 

7567
06:13:36,583 --> 06:13:39,352
CHROMATIN INTERACTION ANALYSIS 

7568
06:13:39,352 --> 06:13:40,787
BY LEVERAGING 10X DROP LET 

7569
06:13:40,787 --> 06:13:47,661
SYSTEM USING THE CHROMATIN 

7570
06:13:47,661 --> 06:13:51,831
FORMALDEHYDE COMPLEXES, DILUTED 

7571
06:13:51,831 --> 06:13:55,235
LOADING TO THE 10X AND THE 

7572
06:13:55,235 --> 06:13:58,238
CHROMATIN FRAGMENTS CARRIED THE 

7573
06:13:58,238 --> 06:14:01,641
SAME 10X BAR CODE SIGNATURE SO 

7574
06:14:01,641 --> 06:14:03,543
THEY'RE SUGGESTING FORMING THE 

7575
06:14:03,543 --> 06:14:07,614
SAME SINGLE MOLECULE COMPLEX.

7576
06:14:07,614 --> 06:14:11,718
WE CAN DECIPHER -- ECDNA 

7577
06:14:11,718 --> 06:14:14,454
CHROMATIN INTERACTION REPERTOIRE

7578
06:14:14,454 --> 06:14:16,556
AND LOOKING HOW THE SIGNATURES 

7579
06:14:16,556 --> 06:14:18,925
GENE OVEREXPRESSION AND THEIR 

7580
06:14:18,925 --> 06:14:21,161
FUNCTION AND SHOWING THEY'RE 

7581
06:14:21,161 --> 06:14:26,466
ENRICHED IN ONCOGENE 

7582
06:14:26,466 --> 06:14:28,234
PROLIFERATION AND GENE INVOLVED 

7583
06:14:28,234 --> 06:14:31,371
IN HIGH LEVEL CELL PROLIFERATION

7584
06:14:31,371 --> 06:14:33,773
ACTIVITY AND USE THE FISH TO 

7585
06:14:33,773 --> 06:14:36,476
CONFIRM THE INTERACTION 

7586
06:14:36,476 --> 06:14:42,282
REPERTOIRES BY SHOWING THE 

7587
06:14:42,282 --> 06:14:42,649
CO-LOCALIZATION.

7588
06:14:42,649 --> 06:14:47,821
SO HERE WE HAVE VALIDATED 

7589
06:14:47,821 --> 06:14:49,422
CONCEPT OF HIGH CHROMATIN 

7590
06:14:49,422 --> 06:14:53,159
INTERACTIONS ON THE SUPER 

7591
06:14:53,159 --> 06:14:54,794
ENHANCER SHOWING IN THE CONTEXT 

7592
06:14:54,794 --> 06:14:56,963
FREQUENCY MAP SUPER ENHANCER 

7593
06:14:56,963 --> 06:15:00,367
SHOWING IN BLACK AND THE MET 1 

7594
06:15:00,367 --> 06:15:02,035
BINDING ARE SUPER IMPOSED AND 

7595
06:15:02,035 --> 06:15:04,604
THE HIGH CONTACT FREQUENCY NOT 

7596
06:15:04,604 --> 06:15:07,273
ON ONCOGENE BUT ACTUALLY ON THE 

7597
06:15:07,273 --> 06:15:08,508
SUPER ENHANCER REGIONS.

7598
06:15:08,508 --> 06:15:11,845
AND THE NEXT IS IF THIS IS 

7599
06:15:11,845 --> 06:15:17,183
INDEED A SEPARATED CONDENSATE OF

7600
06:15:17,183 --> 06:15:19,853
EC DNA USING TRANSACTING GENE 

7601
06:15:19,853 --> 06:15:21,187
EXPRESSION IS ACTUALLY GOING 

7602
06:15:21,187 --> 06:15:25,759
BEYOND JUST THE ONCOGENE 

7603
06:15:25,759 --> 06:15:27,694
ACTIVATION AND A STRUCTURE BASED

7604
06:15:27,694 --> 06:15:29,396
WAY TO MODULATE CANCER CELL GENE

7605
06:15:29,396 --> 06:15:29,696
EXPRESSION.

7606
06:15:29,696 --> 06:15:33,033
THIS IS A STRUCTURE BASED 

7607
06:15:33,033 --> 06:15:37,370
MECHANISM CAN IT BE EXPLOITED TO

7608
06:15:37,370 --> 06:15:41,541
USE AS A CANCER THERAPEUTIC 

7609
06:15:41,541 --> 06:15:45,145
MEANING TO MODULATE CANCER CELL 

7610
06:15:45,145 --> 06:15:46,246
PROLIFERATION.

7611
06:15:46,246 --> 06:15:49,149
USING A WELL KNOWN CHEMICAL THAT

7612
06:15:49,149 --> 06:15:51,084
CAN PERTURB THE CONDENSATE WE 

7613
06:15:51,084 --> 06:15:54,788
WANT TO TEST THE IDEA CAN WE USE

7614
06:15:54,788 --> 06:15:58,024
THE STRUCTURE BASED PERTURBATION

7615
06:15:58,024 --> 06:16:01,261
TO PERTURB THE FUNCTION AND THIS

7616
06:16:01,261 --> 06:16:08,401
IS SHOWING THAT USING THE AGENT 

7617
06:16:08,401 --> 06:16:11,204
TO PERTURB SEPARATIONS WE CAN 

7618
06:16:11,204 --> 06:16:20,914
EASILY SEE THE EC DARN -- DNA 

7619
06:16:20,914 --> 06:16:26,453
DIMINI

7620
06:16:26,453 --> 06:16:32,726
DIMINISHED AGGREGATION TREATED 

7621
06:16:32,726 --> 06:16:43,236
IN THE CELL COLORECTAL AND IT 

7622
06:16:44,671 --> 06:16:46,706
WORKED ACROSS MULTIPLE CANCER 

7623
06:16:46,706 --> 06:16:52,278
TYPES AND MULTIPLE EC DNA 

7624
06:16:52,278 --> 06:16:54,714
ONCOGENES AND HERE'S THE GMDDM 

7625
06:16:54,714 --> 06:16:58,451
AND COULD BE A WAY TO MODULATE 

7626
06:16:58,451 --> 06:17:00,453
SO-CALLED UNDRUGGABLE ONCOGENE 

7627
06:17:00,453 --> 06:17:02,455
EXPRESSION AND WE ALSO 

7628
06:17:02,455 --> 06:17:07,227
DEMONSTRATE THE AGGREGATION DOES

7629
06:17:07,227 --> 06:17:10,864
FOT CHANGE THE COPY NUMBER BUT 

7630
06:17:10,864 --> 06:17:14,467
BY JUST PERTURB THEIR 

7631
06:17:14,467 --> 06:17:19,305
AGGREGATION WE CAN MODULATE ON 

7632
06:17:19,305 --> 06:17:19,806
COGENE EXPRESSION.

7633
06:17:19,806 --> 06:17:21,808
-- ONCOGENE EXPRESSION.

7634
06:17:21,808 --> 06:17:26,112
WE DEMONSTRATED BY USING THIS 

7635
06:17:26,112 --> 06:17:27,547
PERTURBATION CONDENSATE WE CAN 

7636
06:17:27,547 --> 06:17:29,983
CHANGE THE MET 1 BINDING, 

7637
06:17:29,983 --> 06:17:33,453
PERTURB THE GENE EXPRESSION AND 

7638
06:17:33,453 --> 06:17:38,491
SUPER ENHANCE ACTIVITIES AND 

7639
06:17:38,491 --> 06:17:47,367
MODULATE THE EXPRESSION.

7640
06:17:47,367 --> 06:17:49,335
SO THIS IS DEMONSTRATING WHEN WE

7641
06:17:49,335 --> 06:17:51,404
LOOK AT THE LOOP INTERACTIONS 

7642
06:17:51,404 --> 06:17:57,177
THE ECDM MEDIA LOOPS ARE 

7643
06:17:57,177 --> 06:17:58,678
SELECTIVELY DOWNREGULATED IN 

7644
06:17:58,678 --> 06:18:03,817
16HD SUGGESTING THE MECHANISM 

7645
06:18:03,817 --> 06:18:04,751
MODULATED MAKES EXPRESSION AND 

7646
06:18:04,751 --> 06:18:05,952
AGGREGATION THROUGH THE 

7647
06:18:05,952 --> 06:18:09,422
INTERACTION AND CAN SHOW THAT 

7648
06:18:09,422 --> 06:18:12,225
NEXT THE PERTURBATION AFFECT IS 

7649
06:18:12,225 --> 06:18:22,235
GETTING MORE SENSITIVE IN THE 

7650
06:18:22,235 --> 06:18:26,206
APOPTOSIS ASSAYS WITHOUT DOUBLE 

7651
06:18:26,206 --> 06:18:28,341
MINUTE AND THESE ARE MORE 

7652
06:18:28,341 --> 06:18:30,844
SENSITIVE TO THE TREAT AND 

7653
06:18:30,844 --> 06:18:32,946
HIGHER APOPTOSIS SIGNIFICANTLY 

7654
06:18:32,946 --> 06:18:37,350
AND THE STREAM DOES NOT HARM -- 

7655
06:18:37,350 --> 06:18:40,220
HARBOR DOUBLE MINUTE AND THIS 

7656
06:18:40,220 --> 06:18:44,991
PHENOMENA CANNOT ONLY BE DEA

7657
06:18:44,991 --> 06:18:46,593
DEMONSTRATED IN ONE TYPE BUT GBM

7658
06:18:46,593 --> 06:18:51,264
AND PROSTATE AND COLORECTAL 

7659
06:18:51,264 --> 06:18:52,732
DEMONSTRATING THE MECHANISM IS 

7660
06:18:52,732 --> 06:18:54,500
NOT BASED ON SPECIFIC ONCOGENES 

7661
06:18:54,500 --> 06:18:57,237
BUT A STRUCTURE BASED 

7662
06:18:57,237 --> 06:18:58,238
PERTURBATION THAT AFFECT THE 

7663
06:18:58,238 --> 06:19:01,574
FUNCTION.

7664
06:19:01,574 --> 06:19:04,244
OF COURSE YOU CAN ALWAYS ARGUE 

7665
06:19:04,244 --> 06:19:05,678
THIS IS JUST A CORRELATION 

7666
06:19:05,678 --> 06:19:08,047
BECAUSE IT'S NOT SPECIFIC AND 

7667
06:19:08,047 --> 06:19:09,182
YOU MAY AFFECT OTHER THINGS THAT

7668
06:19:09,182 --> 06:19:10,583
YOU'RE NOT AWARE OF.

7669
06:19:10,583 --> 06:19:15,788
WE CARRY OUT CRISPR EPIGENETIC 

7670
06:19:15,788 --> 06:19:19,626
EDITING OF THE SUPER ENHANCER 

7671
06:19:19,626 --> 06:19:22,061
REGION WITH THE MOST 

7672
06:19:22,061 --> 06:19:22,395
INTERACTIONS.

7673
06:19:22,395 --> 06:19:25,164
WE COMPARE THAT PERTURBATION AT 

7674
06:19:25,164 --> 06:19:29,435
THE SUPER ENHANCER AND THE 

7675
06:19:29,435 --> 06:19:32,171
PROMOTER SHOWING THAT BY 

7676
06:19:32,171 --> 06:19:35,341
PERTURBED SUPER ENHANCER NOT 

7677
06:19:35,341 --> 06:19:38,211
MAKING THE PBT1 PROMOTER HAS THE

7678
06:19:38,211 --> 06:19:40,513
MOST SIGNIFICANT AFFECT OF GENE 

7679
06:19:40,513 --> 06:19:43,583
EXPRESSION SHOWING WE CAN BOTH 

7680
06:19:43,583 --> 06:19:50,523
DOWN REGULATE MIK AND PBT1 AND 

7681
06:19:50,523 --> 06:19:54,527
DEMONSTRATE EC DNA PRECIPITATED 

7682
06:19:54,527 --> 06:19:59,332
AND THE EC HARBORING CELL HAS 

7683
06:19:59,332 --> 06:19:59,866
LOST THE PROLIFERATION 

7684
06:19:59,866 --> 06:20:03,803
ACTIVITIES.

7685
06:20:03,803 --> 06:20:13,046
HERE'S WHAT I REALLY WANTED 

7686
06:20:13,046 --> 06:20:19,786
TO -- THE THINGS WE SEE IN A 

7687
06:20:19,786 --> 06:20:24,357
CANCER CELL THE DNA HOW IS IT A 

7688
06:20:24,357 --> 06:20:26,459
FIREBALL ACTIVATED WITH THE 

7689
06:20:26,459 --> 06:20:28,227
CHROMOSOMAL INTERACTION AS THE 

7690
06:20:28,227 --> 06:20:32,598
MOBILE ACTIVITIES.

7691
06:20:32,598 --> 06:20:35,168
IS THAT NEW?

7692
06:20:35,168 --> 06:20:37,470
AND LOOK AT THE RECEPTOR 

7693
06:20:37,470 --> 06:20:39,939
REGULATED NOT INTRERCHLGED BY 

7694
06:20:39,939 --> 06:20:42,809
ENHANCE R  -- 

7695
06:20:46,312 --> 06:20:48,381
INTERCHANGED WORKING IN THE 

7696
06:20:48,381 --> 06:20:50,450
EPISOME LOADING THE WHOLE CELLS 

7697
06:20:50,450 --> 06:20:52,986
AND TRANS LOCATED AND IN CASES 

7698
06:20:52,986 --> 06:20:55,288
IT SUGGESTS IT'S NOT JUST A 

7699
06:20:55,288 --> 06:21:01,461
UNIQUE PHENOMENA CARRIED BY A 

7700
06:21:01,461 --> 06:21:06,466
CANCER CELL IT HAS ENHANCED A

7701
06:21:06,466 --> 06:21:11,771
ACTIVATIONS CAN BE A MECHANISM 

7702
06:21:11,771 --> 06:21:12,772
THAT PROVIDE CELL WITH 

7703
06:21:12,772 --> 06:21:15,475
ADDITIONAL LEVEL OF 

7704
06:21:15,475 --> 06:21:17,744
HETEROGENEITY OR IN ANDY'S WORD,

7705
06:21:17,744 --> 06:21:28,221
STOCHASTIC REGULATION THERE.

7706
06:21:30,656 --> 06:21:34,227
THIS IS ALSO FOR THE AUDIENCE 

7707
06:21:34,227 --> 06:21:37,397
AND STARTING AS A GRADUATE 

7708
06:21:37,397 --> 06:21:39,699
STUDENT LOOKING FOR ALL THE 

7709
06:21:39,699 --> 06:21:40,733
REGULATORY REGIONS CLOSE TO 

7710
06:21:40,733 --> 06:21:44,437
PROMOTER AND WHEN I STARTED TO 

7711
06:21:44,437 --> 06:21:46,706
STUDY 3-D CHROMATIN INTERACTIONS

7712
06:21:46,706 --> 06:21:51,344
LOOKING AT REGIONS AT HUNDREDS 

7713
06:21:51,344 --> 06:21:54,447
OF KBs AWAY FROM THE PROMOTER ON

7714
06:21:54,447 --> 06:21:56,682
THE SAME CHROMOSOMES AND LIKE 

7715
06:21:56,682 --> 06:21:58,751
THE MOLECULE IN THE CANCER CELL 

7716
06:21:58,751 --> 06:22:03,022
OR EVEN SOMATIC CELLS ALLOWS US 

7717
06:22:03,022 --> 06:22:04,157
TO UNDERSTAND MAYBE THERE'S 

7718
06:22:04,157 --> 06:22:04,690
ADDITIONAL LAYER OF 

7719
06:22:04,690 --> 06:22:06,626
TRANSCRIPTION REGULATIONS THAT 

7720
06:22:06,626 --> 06:22:08,528
LOOK AT THIS OUTSIDE THE 

7721
06:22:08,528 --> 06:22:11,931
CHROMOSOME AND OFFER ADDITIONAL 

7722
06:22:11,931 --> 06:22:14,700
LAYER OF PLASTICITY, AVOID AND 

7723
06:22:14,700 --> 06:22:18,838
ALLOW THE CELL TO GENERATE MORE 

7724
06:22:18,838 --> 06:22:19,472
HETEROGENEITY AND MORE DIVERSITY

7725
06:22:19,472 --> 06:22:28,214
THERE.

7726
06:22:28,214 --> 06:22:31,050
SINCE I'M THE LAST ONE TO TALK I

7727
06:22:31,050 --> 06:22:33,820
FEEL I'M OBLIGED TO LOOP BACK TO

7728
06:22:33,820 --> 06:22:42,261
THE FIRST TALK WE HEARD HOW THE 

7729
06:22:42,261 --> 06:22:43,696
CHROMOSOMAL DNA VARIATION USE 

7730
06:22:43,696 --> 06:22:48,401
THE MOBILE ENHANCER CONCEPT OF 

7731
06:22:48,401 --> 06:22:52,004
CELLS INCLUDING CANCER CELLS AND

7732
06:22:52,004 --> 06:22:53,773
LOOKING AT EPIGENETIC 

7733
06:22:53,773 --> 06:22:55,942
STOCHASTICITY AND LOOKING AT THE

7734
06:22:55,942 --> 06:22:59,645
HETEROGENEITY AND STRUCTURE 

7735
06:22:59,645 --> 06:23:01,214
HETEROGENEITY AND GENE 

7736
06:23:01,214 --> 06:23:01,914
EXPRESSION HETEROGENEITY AND 

7737
06:23:01,914 --> 06:23:04,050
TOGETHER IT OFFERS SOME WAY TO 

7738
06:23:04,050 --> 06:23:04,717
PROMOTE TUMOR EVOLUTION.

7739
06:23:04,717 --> 06:23:08,087
THAT'S THE CONCEPT I WANT TO 

7740
06:23:08,087 --> 06:23:11,491
REALLY USE TO STIMULATE LOOKING 

7741
06:23:11,491 --> 06:23:13,226
FORWARD IN THE NEXT I DON'T 

7742
06:23:13,226 --> 06:23:14,861
KNOW, 10 YEARS, 20 YEARS 

7743
06:23:14,861 --> 06:23:16,829
HOPEFULLY COME BACK HERE AGAIN 

7744
06:23:16,829 --> 06:23:19,565
TO UNDERSTAND HOW THIS CANCER 

7745
06:23:19,565 --> 06:23:24,170
EPIGENETICS EVOLVED USING THE 

7746
06:23:24,170 --> 06:23:24,770
TECHNOLOGIES, GENOMIC 

7747
06:23:24,770 --> 06:23:25,304
TECHNOLOGIES IN THE NEXT 

7748
06:23:25,304 --> 06:23:31,144
GENERATION WE CAN LEARN.

7749
06:23:31,144 --> 06:23:34,247
I ALSO WANT TO THANK NCI BUT MY 

7750
06:23:34,247 --> 06:23:37,116
OTHER GRANT IS NOT FUNDED BY NCI

7751
06:23:37,116 --> 06:23:41,787
SO I HOPE NCI WILL FUND MORE 

7752
06:23:41,787 --> 06:23:42,455
EXTRACHROMOSOMAL RESEARCH IN THE

7753
06:23:42,455 --> 06:23:42,722
FUTURE.

7754
06:23:42,722 --> 06:23:43,089
THAT'S A PLEAD.

7755
06:23:43,089 --> 06:23:50,730
THANK YOU VERY MUCH.

7756
06:23:50,730 --> 06:23:52,231
SORRY ABOUT THE TECHNICAL 

7757
06:23:52,231 --> 06:23:52,565
COORDINATION.

7758
06:23:52,565 --> 06:23:55,801
>> DON'T WORRY, I'VE BEEN
THERE.

7759
06:23:55,801 --> 06:23:59,539
SO HAVE TIME FOR QUESTIONS 

7760
06:23:59,539 --> 06:24:00,540
BEFORE WE HEAR CLOSING REMARKS 

7761
06:24:00,540 --> 06:24:03,776
FROM THE AUDIENCE, PLEASE.

7762
06:24:03,776 --> 06:24:06,045
I'LL ASK YOU ONE.

7763
06:24:06,045 --> 06:24:08,381
I WAS TRYING TO GET A SENSE OF 

7764
06:24:08,381 --> 06:24:08,748
BALANCE.

7765
06:24:08,748 --> 06:24:14,453
YOU HAVE A BIG DRIVEN TUMOR AND 

7766
06:24:14,453 --> 06:24:16,155
HAVE THESE EXTRACHROMOSOMAL 

7767
06:24:16,155 --> 06:24:18,457
ENHANCERS DRIVING MIC AND OTHER 

7768
06:24:18,457 --> 06:24:20,560
CELLULAR STRUCTURES DRIVING MIK 

7769
06:24:20,560 --> 06:24:22,929
WHAT'S THE PERCENTAGE OF HOW 

7770
06:24:22,929 --> 06:24:26,465
MUCH DRIVE YOU GET THE 

7771
06:24:26,465 --> 06:24:28,401
EXTRACHROMOSOMAL MATTERS THAN 

7772
06:24:28,401 --> 06:24:30,436
OTHERS TO SPECIFICALLY BLOCK?

7773
06:24:30,436 --> 06:24:32,238
>> RIGHT.

7774
06:24:32,238 --> 06:24:38,144
IN OUR CRISPR CAS EXPERIMENTS 

7775
06:24:38,144 --> 06:24:41,547
THIS IS VERY INTERESTING WHEN WE

7776
06:24:41,547 --> 06:24:47,086
BLOCK THE SUPER ENHANCER ON 

7777
06:24:47,086 --> 06:24:48,087
EXTRACHROMOSOMAL DNA AND THE 

7778
06:24:48,087 --> 06:24:49,055
EXPRESSION IS REDUCED 

7779
06:24:49,055 --> 06:24:52,391
DRASTICALLY WE SEE ALL THE 

7780
06:24:52,391 --> 06:24:54,760
ENHANCER SIGNATURES MOVING TO 

7781
06:24:54,760 --> 06:24:59,732
THE CHROMOSOME.

7782
06:24:59,732 --> 06:25:05,771
THERE'S A MOBILITY OR DYNAMICS 

7783
06:25:05,771 --> 06:25:08,507
AND WE SEE NUMBER OF GENE 

7784
06:25:08,507 --> 06:25:14,447
ACTIVATIONS WHEN WE BLOCK THE 

7785
06:25:14,447 --> 06:25:16,582
ENHANCER ON THE EXTRACHROMOSOMAL

7786
06:25:16,582 --> 06:25:19,151
DNA.

7787
06:25:19,151 --> 06:25:22,822
>> IS IT IN VARIOUS
SWITCHES?

7788
06:25:22,822 --> 06:25:26,192
>> RIBOSOMAL DNA.

7789
06:25:26,192 --> 06:25:27,927
>> THAT CLOSES OUT AND
CLOSING 

7790
06:25:27,927 --> 06:25:29,629
REMARKS AND I WANT TO THANK ALL 

7791
06:25:29,629 --> 06:25:30,263
THE SPEAKERS FOR THE SESSION AS 

7792
06:25:30,263 --> 06:25:40,373
WELL.

7793
06:25:43,743 --> 06:25:45,978
>> SO THAT PRETTY MUCH
WRAPS UP 

7794
06:25:45,978 --> 06:25:49,582
I THINK A PRETTY INCREDIBLE DAY.

7795
06:25:49,582 --> 06:25:53,386
REFLECTION ON 40 YEARS ON CANCER

7796
06:25:53,386 --> 06:25:54,754
EPIGENETICS AND FANTASTIC TALKS.

7797
06:25:54,754 --> 06:25:56,389
WE WENT FULL CIRCLE FROM THE 

7798
06:25:56,389 --> 06:26:00,426
HISTORY TO WHAT'S UP AND COMING.

7799
06:26:00,426 --> 06:26:04,196
I REALLY WANT TO EXTEND MY 

7800
06:26:04,196 --> 06:26:04,864
PROFOUND GRATITUDE FOR EVERYONE 

7801
06:26:04,864 --> 06:26:06,899
THAT CAME TODAY ESPECIALLY THOSE

7802
06:26:06,899 --> 06:26:07,867
THAT CAME IN PERSON.

7803
06:26:07,867 --> 06:26:10,436
I WANT TO THANK ALL THE SPEAKERS

7804
06:26:10,436 --> 06:26:13,939
WHO MADE THE TREK TO NIH AND FOR

7805
06:26:13,939 --> 06:26:16,275
THEIR GREAT PRESENTATIONS AND 

7806
06:26:16,275 --> 06:26:18,944
AGAIN WE REALLY VALUE THE IN 

7807
06:26:18,944 --> 06:26:19,845
PERSON PARTICIPATION AND EVEN 

7808
06:26:19,845 --> 06:26:21,781
THOUGH IT MAY LOOK SPARSE AT 

7809
06:26:21,781 --> 06:26:26,452
THIS TIME OF DAY, WE DID HAVE 

7810
06:26:26,452 --> 06:26:28,287
SIGNIFICANT PARTICIPATION 

7811
06:26:28,287 --> 06:26:31,223
THROUGH VIRTUAL PLATFORMS WITH 

7812
06:26:31,223 --> 06:26:33,859
AT TIMES CLOSE TO 200 PEOPLE 

7813
06:26:33,859 --> 06:26:36,529
WATCHING SO I'D BE ENCOURAGED 

7814
06:26:36,529 --> 06:26:38,064
THERE'S A LOT OF INTEREST IN OUR

7815
06:26:38,064 --> 06:26:38,964
SYMPOSIUM TODAY AND WITH THAT 

7816
06:26:38,964 --> 06:26:42,001
I'D ALSO LIKE TO THANK ALL THE 

7817
06:26:42,001 --> 06:26:43,436
NIH STAFF THAT HELPED MAKE THIS 

7818
06:26:43,436 --> 06:26:45,338
POSSIBLE AND OUR CONTRACTOR AND 

7819
06:26:45,338 --> 06:26:46,439
THANKS ONCE AGAIN FOR COMING AND

7820
06:26:46,439 --> 06:26:47,573
HOPE YOU ALL HAVE A SAFE TRIP 

7821
06:26:47,573 --> 06:26:57,683
HOME.