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>> ALL RIGHT, GOOD MORNING

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EVERYONE, ONLINE AND HERE, THANK

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YOU FOR BEING HERE, THIS IS THE

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FINAL SEMINAR ORGANIZED BY THE

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PROTEOMICS INTEREST GROUP IN

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THIS SEASON, AND FOR OUR SPEAKER

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WE HAVE DR. DAVID SCHWEPPE, HE

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BEGAN HIS RESEARCH CAREER

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WORKING FOR A DOCTOR AT WILLIAMS

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COLLEGE AND THEN PURSUED

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DOCTORAL WORK AT MEDICAL SCHOOL.

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THEN HE DID POST DOCS AT THE

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UNIVERSITY OF WASHINGTON AND

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HARVARD MEDICAL SCHOOL. 

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IN 2020, DEVIN ESTABLISHED HIS

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RESEARCH GROUP IN THE DEPARTMENT

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OF GENOME SCIENCES AND HIS FOCUS

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IS ON THE INFORMATION 

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PROTEOMICS, AND THEY QUANTIFY

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PROTEINS AS A READ OUT  SPANNING

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MICROBIAL STUDIES.

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THE RESEARCH BUILDS ON THE

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STUDYING DISCOVERY AND

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PROTEOMICS PLATFORMS.

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ALONG WITH TECHNOLOGY

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DEVELOPMENT FOCUS THE WORK GROUP

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TO BUILD APPLICATIONS AND

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RESOURCES TO DISSEMINATE

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PROTEOMICS DATA SETS TO THE

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RESEARCH COMMUNITY AND THIS

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EFFORTS INCLUDE WORK WITH THE

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CROSS THINKING MAZ SPECTROMETRY

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AND EXVIVO DATABASE AND BIOFLEX

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HUMAN PROTEIN COMPLEX YOLKS

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STUDY.

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HIS TALK TODAY IS MOLECULAR

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PHENOTYPING OF THERAPEUTIC

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RESPONSES AND MAMMALIAN AGING

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WITH QUAWPTITATIVE PROTEOMICS

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AND I HAVE TO MENTION THAT HE'S

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TRAVELED AND VISIT IS MADE

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POSSIBLE GENERAL SPONSORSHIP.

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>> THANK YOU FOR THAT
GENEROUS

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INTRODUCTION.

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I DID A LOT OF WORK FOR

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INTELLIGENT DATA ACQUISITION AND

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I'M NOT GOING TO TALK ABOUT ANY

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OF THAT BUT YOU CAN BELIEVE WE

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USED IT TO DO MOST OF THE WORK

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THAT I'M GOING TO SHOW YOU

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TODAY.

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SO WHAT I WILL HOPEFULLY

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CONVINCE YOU OF TODAY IS THAT MY

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LAB STUDIES A REALLY SIMPLE

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QUESTION, RIGHT?

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WHAT HAPPENS TO CELLS WHEN WE

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PERTURB THEM AND THE MANNER WITH

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WHICH I STUDY THIS, I WOULD NOT

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BE HERE IF NOT, IS HOW DO CELLS

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REMODEL THEMSELVES AND

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PARTICULARLY THEIR BIOLOGICAL

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BIOCHEMICAL MACHINERY UPON THAT

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PROTURBATION.

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AND WE CPS ABOUT THIS IN THE

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SIMPLEST POSSIBLE CASE AND 1 WE

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THINK OF PRETTY CONSISTENTLY IN

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NIGH LAB, WHICH IS WHAT HAPPENS

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TO PROTEOME WHEN WE ADD A DRUG

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TO CELLS OR TO LIAISON

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SUITABILITY ZONESS?

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RELATIVELY SIMPLE QUESTION,

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RIGHT?

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THIS SMALL MOLECULE IS TARGETED

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AND SHOULD HIT 1 PROTEIN, MAYBE

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A SMALL FAMILY OF PROTEINS AT

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BEST, AND WE CAN THINK IF THIS

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IS REALRY TRUE IN THE MENTALITY

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RIGHT HERE WHERE WE HAVE A BUNCH

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OF STUFF BASICALLY HAPPENS, AND

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REALLY WE'RE GOING TO FOCUS ON 2

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THINGS FOR THE MOST PART, AN

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INITIAL SET OF INTERACTIONS AND

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SOME DOWN STREAM SET OF EFFECTS

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AND THE BENEFIT AND UTILITY OF

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USING PROTEOMICS IS ACTUALLY

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THAT IF WE DO THIS RIGHT AND IF

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WE DO THIS A LOT WITH MANY

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SAMPLES AND MANY DRUGS, WE CAN

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ACTUALLY BUILD UP LARGE SCALE

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NETWORKS AND BEGIN TO UNDERSTAND

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MORE METHODS OF ACTION AND

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THOROUGHLY UNDERSTAND THE

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PROCESS BETWEEN INITIAL

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INTERACTION BETWEEN SMALL

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MOLECULES AND PROTEIN AND

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EVERYTHING THAT HAPPENS AFTER

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THAT.

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ALL RIGHT, SO THAT'S HARD,

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RIGHT, OF COURSE, EVERYONE KNOWS

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PROTURBATIONS CAN DRIVE

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THOUSANDS OF PROTEIN CHANGES.

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ONE OF MY FAVORITE SET SUGGESTS

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ON ARE SMALL MOLECULE INHIBITORS

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BECAUSE THEY REALLY JUST MUCK UP

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CELLS.

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YOU TREAT -- MOST CANCER CELLS

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PICK JUST ABOUT ANY TISSUE, ANY

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SUBTYPE AND YOU CAN CHANGE

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ALMOST EVERYTHING GOING ON WITH

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IT BY MESSING WITH THE

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EPIGENOME.

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SO IN THIS CASE, IF WE MESS WITH

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HISTONE ACETYLATION, INCREASE

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HISTONE ACETYLATION, WE GET

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CLARNLG SCALE CHANGES ON THE ORD

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EVALUATION PROCESS OF THOUSANDS

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OF PROTEINS THAT CHANGE, RIGHT?

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THAT'S NOT THE MOST HELPFUL

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THING RIGHT BECAUSE WHAT DO YOU

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TELL A COLLABORATOR, WE WERE

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JUST TALKING THIS MORNING, WHAT

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DO YOU TELL A COLLABORATOR WHEN

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YOU GIVE THEM A LIST OF 2000

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THINGS THAT HAVE CHANGED?

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WHAT ARE WE GOING TO FOCUS ON?

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WHAT ARE THEY GOING TO FOCUS ON?

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WHAT WILL SOMEONE BUILD THEIR

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THESIS ON?

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AND THE QUESTION BECOMES TO NOW

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WHAT, 2 GENERAL STORIES CUSTOMER

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PROTECTION THE FIRST LOOKING AT

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DRUG MECHANISMS OF ACTION AND SO

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DIGGING DEEPER TO TRY TO

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UNDERSTAND ON-TARGET

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INTERACTIONS WE KNOW SHOULD BE

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HAPPENING AND OFF-TARGET

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INTERACTION WE BELIEVE ARE

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HAPPENING AND THE CAUSE OF

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ADVERSE EFFECTS AND

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SECONDULARLY, I WILL TALK ABOUT

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HOW PROTERBATIONS AFFECT CELLS

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IN LETTING US STUDY THEM IN

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DEVELOPMENT FEATURE, AND WE WILL

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START WITH THE SIMPLEST CASE,

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AND DRUG PROTERBATION AND

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LOOKING AT A DRUG SPECIFIC

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RESPONSE, WE TREAT CELLS,

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PROTEOME RESPONSES IN A SPECIFIC

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WAY TO THAT DRUG, CERTAIN SET OF

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PROTEINS HERE CHANGE IN

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MEANINGFUL WAYS, VIOLA, WE CAN

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DRIVE UNDERSTANDING FROM THAT.

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WE CAN ALSO GO THE OTHER WAY IF

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WE WANT TO DO A LOT OF

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EXPERIMENTS RIGHT, ESSENTIALLY A

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PROTEIN SPECIFIC RESPONSE SO

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INSTEAD OF LOOKINGAL EVERYTHING

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THAT HAPPENS THAT YOU TREAT WITH

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THE DRUG, WHAT HAPPENS TO 1

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PROTEIN WHEN YOU TREAT WITH LOTS

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OF DRUGS.

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SO 1 BIG QUESTION THAT WAS BEING

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ASKED 

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ASKED BY DYLAN MITCHELL WAS WHAT

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IF YOU JUST COMBINE THESE?

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SO WHAT YOU DO PROTEOMICS ON A

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LARGE NUMBER OF SMALL MOLECULE

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DRUG TREATMENTS AND LOOK FOR

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PROTEIN SPECIFIC EFFECTS ACROSS

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THESE?

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SO THAT LED TO THE DEEP COVER

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MOA PROJECT AND I'M NOT GOING TO

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GET FULLY INTO THAT, I WILL

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MENTION MORE ABOUT THE SPECIFICS

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IN 1-SECOND, BUT 1 OF THE BIG

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THINGS I WANT TO HIGHLIGHT ABOUT

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THIS PROGEC, WAS THAT SOMETHING

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THAT DYLAN PULLED OUT OF THIS IS

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THIS IDEA THAT EVEN THOUGH IF

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YOU LOOK AT THIS LIST OF

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PROTEINS THAT ARE RESPONDING TO

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POLO LIKE KINASE 1, IT'S NOT

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CHANGING SIGNIFICANTLY, BUT WE

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SEE A LOT OF OTHER PROTEINS

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CHANGING AND CHANGING

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CONSISTENTLY WITH 1 OR 2

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STRUCTURALLY INHIBITED

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INHIBITORS SO THE PROTEOME

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CHANGES, WE NOT SEEING THE

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DIRECT MECHANISM TO BE THE DREK

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MECHANISM BUT WE CAN USE THAT TO

192
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BUILD UP NETWORKS OF COORDINATED

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PROTILES AND THAL CASE ARE NODES

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IN THIS CASE OR DRUGS, AND EDGES

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BETWEEN THOSE NODES THEN, ARE

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THE LEVEL OF CORRELATION,

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BETWEEN PROTEOME RESPONSES TO

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THESE INDIVIDUAL DRUGS, AND THEN

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WE CAN SEE, RIGHT, SO WE KNOW

200
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VOLASERTIB, AND PLK 1 ARE

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INHIBITORS THEY HAVE A BIG

202
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PURPLE EDGE BETWEEN THEM.

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WE CAN SEE THE BRD INHIBITORS

204
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HAVE NICE HIGHLY COORDINATED

205
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EDGES BETWEEN THEM AND WE KNOW

206
00:07:49,535 --> 00:07:53,606
THAT BRD 1 AND PLK1 INHIBITORS

207
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HAVE ESSENTIALLY OFF TARGET

208
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EFFECTS WITH EACH OTHER AND SO

209
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WE SEE CORRELATED PROFILES WITH

210
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THESE 2, SO THE INTERESTING

211
00:07:59,411 --> 00:08:00,779
THING ABOUT THE DATA SET IS THE

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00:08:00,779 --> 00:08:03,549
IDEA THAT IF YOU HAVE SOME NEW

213
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COMPOUNDS, YOU HAVE NO IDEA WHAT

214
00:08:04,650 --> 00:08:07,086
IT HITS OR WHAT IT DOES, IF YOU

215
00:08:07,086 --> 00:08:09,955
TREAT CELLS, AND YOU SEE A

216
00:08:09,955 --> 00:08:10,956
CORRELATIVE RESPONSE, IN THIS

217
00:08:10,956 --> 00:08:16,061
CASE, SAY TO BOTH OF THESE PLK 1

218
00:08:16,061 --> 00:08:17,529
ENHIB THORSITTORS, THAT'S A GO

219
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CHANCE THAT A NEW INHIBITOR.

220
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IF YOU'RE NEW COMPOUND IS IN

221
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ACCORD ASBESTOS WITH THE PLK1,

222
00:08:27,673 --> 00:08:30,209
IT'S A CHANCE IT'S A GOOD

223
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COMBINATION OF THE PLK1, AND

224
00:08:32,778 --> 00:08:33,946
BRD4 INHIBITOR.

225
00:08:33,946 --> 00:08:35,814
SO WE COO MAKE A CORRELATION

226
00:08:35,814 --> 00:08:36,715
LOOKING AT HOW THEY RESPOND.

227
00:08:36,715 --> 00:08:39,418
WE CAN DO RELATIVELY SIMPLE

228
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WORK, EVERYONE HERE HAS DONE

229
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PROTEOMICS LIKELY RIGHT, BUT IF

230
00:08:42,288 --> 00:08:45,057
WE DO ENOUGH OF IT, WE USE THESE

231
00:08:45,057 --> 00:08:46,225
PROFILES AND THE INHERENT

232
00:08:46,225 --> 00:08:47,826
INFORMATION, WE CAN GAIN USEFUL

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00:08:47,826 --> 00:08:49,528
MECHANISMS OF ACTION DATA FOR

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00:08:49,528 --> 00:08:50,829
NEW COMPOUNDS, SO THE REQUESTY

235
00:08:50,829 --> 00:08:53,232
IS THEN, HOW DO WE BEGIN TO

236
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UNDERSTAND THESE OFF TARGET

237
00:08:55,868 --> 00:08:57,369
INTERACTIONS, AND THE EFFECTS

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THAT THEY HAVE, SO 1 TIDBIT, SO

239
00:08:59,238 --> 00:09:02,107
THIS IS A SUMMARY FROM DYLAN'S

240
00:09:02,107 --> 00:09:04,443
PAPER, OF DEEP COVER MOA PAPER

241
00:09:04,443 --> 00:09:07,646
THAT CAME OUT OF THE LAB, RIGHT,

242
00:09:07,646 --> 00:09:09,949
AND THE EAGLE EYED WILL SEE

243
00:09:09,949 --> 00:09:11,383
THAT'S THE INTELLIGENT DATA

244
00:09:11,383 --> 00:09:12,117
ACQUISITION PLATFORM THAT I SAID

245
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I WILL NOT TALK ABOUT BUT WILL

246
00:09:15,754 --> 00:09:20,960
BE IN THERE, RIGHT?

247
00:09:20,960 --> 00:09:24,363
875 COMPOUNDS TREAT OFFICE OF

248
00:09:24,363 --> 00:09:26,732
DIVERSITY CELLS AT 10

249
00:09:26,732 --> 00:09:29,034
MICROMOLAR, HUGE STUDY, A LOT OF

250
00:09:29,034 --> 00:09:29,301
PROFILES.

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00:09:29,301 --> 00:09:32,371
A SIMILAR 1 CAME OUT OF A

252
00:09:32,371 --> 00:09:33,505
COLLEAGUE'S LAB, THE EXPRESSION

253
00:09:33,505 --> 00:09:36,375
BASED ANALYSIS FOR THE EQUIPPED

254
00:09:36,375 --> 00:09:38,010
GENERAL PLATFORM, FOR THE 144

255
00:09:38,010 --> 00:09:41,080
DRUGS FOR A VARIETY OF DIFFERENT

256
00:09:41,080 --> 00:09:42,348
CONCENTRATIONS OF SMALL

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00:09:42,348 --> 00:09:43,816
MOLECULE, PROTEOME TREATMENT AND

258
00:09:43,816 --> 00:09:44,116
READ OUT.

259
00:09:44,116 --> 00:09:48,320
AND THESE WERE FANTASTIC STUDIES

260
00:09:48,320 --> 00:09:49,722
BUT 1 CAVEAT TO BOTH OF THESE IS

261
00:09:49,722 --> 00:09:52,624
THAT EACH 1 IS DONE IN A SINGLE

262
00:09:52,624 --> 00:09:54,093
CELL LINE, RIGHT?

263
00:09:54,093 --> 00:09:54,960
SO THERE'S OBVIOUS TURNOVERS

264
00:09:54,960 --> 00:09:56,662
ABOUT IF YOU LOOK FOR A PROTEOME

265
00:09:56,662 --> 00:09:58,364
RESPONSE AND YOU MAKE ASERKZS

266
00:09:58,364 --> 00:09:59,798
ABOUT MECHANISMS OF ACTION BUT

267
00:09:59,798 --> 00:10:01,967
YOU'RE CONSIDERING A SINGLE

268
00:10:01,967 --> 00:10:04,536
ISOGENIC BACKGROUND, WHAT ARE WE

269
00:10:04,536 --> 00:10:05,704
MISSING WITH THAT IN OUR

270
00:10:05,704 --> 00:10:07,606
UNDERSTANDING, SO I WILL MAKE

271
00:10:07,606 --> 00:10:09,541
THE CASE TO YOU, THERE'S A LEVEL

272
00:10:09,541 --> 00:10:11,143
OF UNDERSTANDING WE NEED TO

273
00:10:11,143 --> 00:10:13,345
GLEAN ABOUT CELLULAR STATE, AND

274
00:10:13,345 --> 00:10:14,513
THE IMPORTANCE OF DIFFERENT

275
00:10:14,513 --> 00:10:16,482
FACTORS IN CELL STATE, THEY

276
00:10:16,482 --> 00:10:17,383
COULD BE METABOLIC,

277
00:10:17,383 --> 00:10:20,386
ENVIRONMENTAL, WE WILL FOCUS ON

278
00:10:20,386 --> 00:10:21,620
ESSENTIALLY THE BACKGROUNDS, AS

279
00:10:21,620 --> 00:10:24,623
A MAIN VARIANT AND ALSO, THE

280
00:10:24,623 --> 00:10:26,592
CASE THAT WHILE WE'RE STILL

281
00:10:26,592 --> 00:10:28,160
MISSING FROM THOSE MECHANISMS OF

282
00:10:28,160 --> 00:10:29,862
ACTION STUDY, IS THE IDEA OF

283
00:10:29,862 --> 00:10:31,463
WHAT'S ACTUALLY HAPPENING, WHAT

284
00:10:31,463 --> 00:10:32,965
ARE THE SMALL MOLECULES,

285
00:10:32,965 --> 00:10:34,600
INTERACTING WITH, ARE THEY

286
00:10:34,600 --> 00:10:38,303
ACTUALLY ISHT ACTING WITH THEIR

287
00:10:38,303 --> 00:10:38,704
INTENDED TARGETS.

288
00:10:38,704 --> 00:10:40,572
SO WE WILL DIVE INTO THE FIRST

289
00:10:40,572 --> 00:10:42,841
CELL STATE BASED ANALYSIS

290
00:10:42,841 --> 00:10:46,912
FITTER, SO, CHELSEA IN THE LAB,

291
00:10:46,912 --> 00:10:47,946
ORIGINALLY PUT OUT A PREPRINT IN

292
00:10:47,946 --> 00:10:50,716
THE FIRST PRINT OF THESE STUDIES

293
00:10:50,716 --> 00:10:56,655
WHERE ESSENTIALLY SHE'S BUILT AN

294
00:10:56,655 --> 00:11:01,060
QUANTITATIVE PLATFORM FOR DRUG

295
00:11:01,060 --> 00:11:01,727
PROTERBATION, AND DATA

296
00:11:01,727 --> 00:11:03,362
ACQUISITION TO PULL OUT THE

297
00:11:03,362 --> 00:11:04,830
RESPONSES ON THE PROTEOMIC

298
00:11:04,830 --> 00:11:06,799
LEVEL, SHE ALSO DOES PHOSPHO

299
00:11:06,799 --> 00:11:12,438
PROTEOMICS BUT I WON'T GET INTO

300
00:11:12,438 --> 00:11:15,074
TOO MUCH TODAY.

301
00:11:15,074 --> 00:11:16,308
SHE ESTABLISHED CANCER CELL

302
00:11:16,308 --> 00:11:22,081
LINES, 1 IS LUNG CELL AND 1 IS

303
00:11:22,081 --> 00:11:23,482
HTT116 AND HDT116 WE INCLUDED

304
00:11:23,482 --> 00:11:26,051
BECAUSE IT WAS IN DEEP COVER MOA

305
00:11:26,051 --> 00:11:28,020
ANY IT GIVES US A REFERENCE TO

306
00:11:28,020 --> 00:11:29,354
SEE IF THE CORRELATED PROFILES

307
00:11:29,354 --> 00:11:31,990
WE WILL PULL OUT MATCH TO

308
00:11:31,990 --> 00:11:35,594
CORRELATED PROFILES WITH A STOCK

309
00:11:35,594 --> 00:11:37,262
OF HTCC116 IS IN A DIFFERENT LAB

310
00:11:37,262 --> 00:11:38,564
4 YEARS LATER SO THAT SHOULD BE

311
00:11:38,564 --> 00:11:40,566
A GOOD CONTROL FOR US.

312
00:11:40,566 --> 00:11:42,434
SHE THEN COMPARED THESE

313
00:11:42,434 --> 00:11:44,770
ESSENTIALLY BY TREATING WITH A

314
00:11:44,770 --> 00:11:50,509
SERIES OF IN THIS CASE, HDAC, OR

315
00:11:50,509 --> 00:11:53,278
HISTONE DEACETYLASE, AND 1 EGFR

316
00:11:53,278 --> 00:11:55,681
AND 1 INHIBITOR TO SEE HOW

317
00:11:55,681 --> 00:11:57,683
PROTURBATIONS OF EPIGENETIC

318
00:11:57,683 --> 00:12:02,621
REGULATION  WILL AFFECT

319
00:12:02,621 --> 00:12:03,889
ESSENTIALLY THE PROTEOME.

320
00:12:03,889 --> 00:12:07,092
AND WE HAVE 1 GROUP HERE WITH

321
00:12:07,092 --> 00:12:11,163
THE INHIBITOR AND SHE MADE SURE

322
00:12:11,163 --> 00:12:12,531
TO SHOW WHERE EACH 1 IS

323
00:12:12,531 --> 00:12:13,031
ASSOCIATED.

324
00:12:13,031 --> 00:12:14,199
SHE PUT TOGETHER THE LARGE DATA

325
00:12:14,199 --> 00:12:15,601
SET, THE CELL LINE'S SPECIFIC

326
00:12:15,601 --> 00:12:18,537
DRUG EFFECTS TO SEE IF WE'RE

327
00:12:18,537 --> 00:12:19,138
SEEING DIFFERENTIAL RESPONSES

328
00:12:19,138 --> 00:12:23,275
AND OF COURSE WE WERE OR ELSE WE

329
00:12:23,275 --> 00:12:23,876
PROBABLY WOULDN'T PRESENT ON

330
00:12:23,876 --> 00:12:26,979
THIS AND TRY TO PUBLISH IT, JUST

331
00:12:26,979 --> 00:12:27,379
IN VIABILITY DATA.

332
00:12:27,379 --> 00:12:28,914
SO YOU TREAT ALL OF THESE CELL

333
00:12:28,914 --> 00:12:32,084
LINES WITH THE EXACT SAME

334
00:12:32,084 --> 00:12:32,751
CONCENTRATION FOR THE EXACT SAME

335
00:12:32,751 --> 00:12:36,088
TIME RECOLLECT AND THE VIABILITY

336
00:12:36,088 --> 00:12:37,122
AND SMALL MOLECULES VARIES

337
00:12:37,122 --> 00:12:38,690
MARKEDLY AND IN THIS CASE, SOME

338
00:12:38,690 --> 00:12:40,025
OF THEM HAVE VIABILITY, SO THE

339
00:12:40,025 --> 00:12:43,095
ARELATIVE LEVEL OF THIS, SHOULD

340
00:12:43,095 --> 00:12:44,029
BE VIABILITY PRETREATMENT AND

341
00:12:44,029 --> 00:12:46,632
POST TREATMENT SHOULD BE A 1 TO

342
00:12:46,632 --> 00:12:47,666
1 RATIO, ALL THESE NUMBERS

343
00:12:47,666 --> 00:12:48,834
SHOULD BE 1 IF THERE'S NO

344
00:12:48,834 --> 00:12:51,737
EFFECT, WE CAN SEE IN THIS CASE,

345
00:12:51,737 --> 00:12:56,875
RIGHT, FOR PC 9 CELLS EXPOSED TO

346
00:12:56,875 --> 00:12:59,211
CDC101, THEY LOSE 70% OF THEIR

347
00:12:59,211 --> 00:12:59,444
BIODATA.

348
00:12:59,444 --> 00:13:01,346
BUT NONE OF THE OTHER, RIGHT,

349
00:13:01,346 --> 00:13:04,216
CELL LINES HAVE SUCH A DRAMATIC

350
00:13:04,216 --> 00:13:04,449
EFFECT.

351
00:13:04,449 --> 00:13:06,585
WE SEE SIMILAR EFFECTS ACROSS

352
00:13:06,585 --> 00:13:07,886
BASICALLY PC 9 SO THERE'S

353
00:13:07,886 --> 00:13:09,755
CLEARLY A CELL TYPE SPECIFIC

354
00:13:09,755 --> 00:13:10,789
EFFECT BUT THERE'S INTERESTING

355
00:13:10,789 --> 00:13:13,325
FACTORS HERE WHERE THERE'S A

356
00:13:13,325 --> 00:13:17,062
LARGE EFFECT ON 8549S, ONLY 1

357
00:13:17,062 --> 00:13:22,367
HDAC INHIBITOR, IN THIS CASE,

358
00:13:22,367 --> 00:13:23,502
POLINSTAB, AND WE CAN SEE THAT

359
00:13:23,502 --> 00:13:26,305
MORE IN THE PROTEOME SPECIFIC

360
00:13:26,305 --> 00:13:26,939
LEVEL, SO ESSENTIALLY EACH ROW

361
00:13:26,939 --> 00:13:28,440
I'M SHOWING YOU AND THE DATA IS

362
00:13:28,440 --> 00:13:31,143
THE PROTEOME AND THE PROTEOME

363
00:13:31,143 --> 00:13:32,544
RESPONSE COMPARED TO DMSO

364
00:13:32,544 --> 00:13:34,146
CONTROLS, THE LOG 2 PULL CHAINS,

365
00:13:34,146 --> 00:13:36,148
PLURIBU IS HIGHER, RED IS LOWER,

366
00:13:36,148 --> 00:13:37,649
WE SHOULD PROBABLY SWITCH THOSE,

367
00:13:37,649 --> 00:13:39,451
BUT IN THIS CASE, WHAT HOPEFULLY

368
00:13:39,451 --> 00:13:41,687
YOU CAN GREEN FROM THE HEAT MAP

369
00:13:41,687 --> 00:13:44,957
RIGHT IS THAT THE RESPONSES SEEM

370
00:13:44,957 --> 00:13:47,693
TO VARY IN THESE TRAWNCHS GOING

371
00:13:47,693 --> 00:13:50,462
ACROSS BUT WE CAN NICELY SEE IS

372
00:13:50,462 --> 00:13:51,496
THAT THOSE ESSENTIALLY ARE

373
00:13:51,496 --> 00:13:52,931
CONSIST WENT JUST THE CELL

374
00:13:52,931 --> 00:13:55,234
LINES, SO THESE CELL LINES ARE

375
00:13:55,234 --> 00:13:59,404
RESPONDING CONSISTENTLY TO THE

376
00:13:59,404 --> 00:14:01,406
DEACETYLASE INHIBITORS ALMOST OF

377
00:14:01,406 --> 00:14:03,809
WHAT, REALLY ROBUST WAYS, WITH

378
00:14:03,809 --> 00:14:06,111
SPECIFIC CLEVES OR PROTEINS THAT

379
00:14:06,111 --> 00:14:07,479
ARE AFFECTED, IN 1 CELL LINE AND

380
00:14:07,479 --> 00:14:08,814
NOT AFFECTED IN BASICALLY ANY

381
00:14:08,814 --> 00:14:10,148
OTHER CELL LINE.

382
00:14:10,148 --> 00:14:10,949
THAT'S FUNCTIONALLY INTERESTING,

383
00:14:10,949 --> 00:14:12,517
WHAT'S DRIVING THAT EFFECT?

384
00:14:12,517 --> 00:14:15,787
LOOKING BACK THEN TO THE DEEP

385
00:14:15,787 --> 00:14:17,723
COVER MOA STUDY, AND DOING

386
00:14:17,723 --> 00:14:20,492
EVERYTHING IN THE 116S WE CAN

387
00:14:20,492 --> 00:14:22,027
SEE THAT THE HCT 116 RESPONSE IS

388
00:14:22,027 --> 00:14:24,663
QUITE DEFINITE THAN THE 85449

389
00:14:24,663 --> 00:14:25,397
RESPONSE AND INTERESTING CAVEAT

390
00:14:25,397 --> 00:14:27,699
HERE IS BOTH OF THESE ARE DRIVEN

391
00:14:27,699 --> 00:14:28,467
BY KRACE MUTATIONS.

392
00:14:28,467 --> 00:14:30,435
THE SAME DRIVER MUTATION AND

393
00:14:30,435 --> 00:14:31,637
MARKETEDLY DIFFERENT RESPONSES

394
00:14:31,637 --> 00:14:41,046
TO SMALL MOLECULE INHIBITORS,

395
00:14:41,046 --> 00:14:42,180
YEAH, YEAH.

396
00:14:42,180 --> 00:14:52,024
>> [INAUDIBLE QUESTION
FROM

397
00:14:52,024 --> 00:14:54,559
AUDIENCE ]

398
00:14:54,559 --> 00:14:55,861
>> YEAH, NORMALLY I TRY TO
USE

399
00:14:55,861 --> 00:14:57,729
THE SAME NUMBER OF LIVING CELLS

400
00:14:57,729 --> 00:15:03,669
AND BASICALLY WASH OFF THE DEAD

401
00:15:03,669 --> 00:15:05,704
KIND OF LEVY APOPTOTIC CELLS,

402
00:15:05,704 --> 00:15:08,240
SAME TOTAL PROTEIN INPUT THAT

403
00:15:08,240 --> 00:15:10,609
GOES INTO EACH AFTER GETTING RID

404
00:15:10,609 --> 00:15:15,013
OF THE HOPEFULLY DEAD CELLS.

405
00:15:15,013 --> 00:15:16,014
YEAH.

406
00:15:16,014 --> 00:15:19,151
FREIGHT  -- GREAT QUESTION AND A

407
00:15:19,151 --> 00:15:20,686
LEAD IN FOR 2 CLICKS AWAY.

408
00:15:20,686 --> 00:15:21,853
ONE THING BEFORE WE GET

409
00:15:21,853 --> 00:15:23,255
TRUSTEES, WE CAN SEE SOME OF THE

410
00:15:23,255 --> 00:15:26,024
RESPONSES IN THE HEAT MAP, YOU

411
00:15:26,024 --> 00:15:27,526
CAN SEE THESE AFFECTS IN SMALL

412
00:15:27,526 --> 00:15:29,461
CLEVES OF THESE PROEN TOOS WHERE

413
00:15:29,461 --> 00:15:30,896
THERE SEEM TO BE DRUG SPECIFIC

414
00:15:30,896 --> 00:15:31,930
EFFECTS WITHIN THE CELL LINES,

415
00:15:31,930 --> 00:15:34,566
SO WE CAN SEE THIS LINE RIGHT

416
00:15:34,566 --> 00:15:38,970
HERE, OF BLUE AND PC 9s, THAT

417
00:15:38,970 --> 00:15:41,039
IS CONSISTENT WITH PC 1s AND

418
00:15:41,039 --> 00:15:44,810
H292, SO THERE IS SOME

419
00:15:44,810 --> 00:15:46,311
CONSISTENCY ACROSS, THAT IS

420
00:15:46,311 --> 00:15:47,879
LIKELY MORE CLICKS THAN I WILL

421
00:15:47,879 --> 00:15:49,014
JUST SHOW YOU NOW BECAUSE YOU

422
00:15:49,014 --> 00:15:50,949
ASKED, ALL OF THAT, RIGHT THERE

423
00:15:50,949 --> 00:15:55,087
IS ACTUALLY THE P38 KINASE

424
00:15:55,087 --> 00:15:55,354
INHIBITOR.

425
00:15:55,354 --> 00:15:58,190
SO THAT'S A STRIKING THING,

426
00:15:58,190 --> 00:15:58,790
RIGHT?

427
00:15:58,790 --> 00:16:01,226
SO HDAC INHIBITORS ARE ALL OVER

428
00:16:01,226 --> 00:16:03,962
THE PLACE, P38 KINASE INHIBITORS

429
00:16:03,962 --> 00:16:07,933
RESPOND THE SAME, ALL THESE CELL

430
00:16:07,933 --> 00:16:11,737
TYPES RESPOND EXACTLY SAME TO

431
00:16:11,737 --> 00:16:13,472
THE P-KINASE INHIBITION.

432
00:16:13,472 --> 00:16:15,874
SO STEPPING BACK, WE DO SEE SOME

433
00:16:15,874 --> 00:16:17,943
UCIBOLITTOUS RESPONSES NO MATTER

434
00:16:17,943 --> 00:16:19,811
WHAT WHICH WERE ENCOURAGING SO

435
00:16:19,811 --> 00:16:22,180
AGAIN, ON THE LEFT-HAND SIDE

436
00:16:22,180 --> 00:16:25,784
HERE, THIS IS P38 KINASE

437
00:16:25,784 --> 00:16:27,119
INHIBITOR, ESSENTIALLY NO

438
00:16:27,119 --> 00:16:27,853
CONSISTENT CHANGE, THE CLAYED

439
00:16:27,853 --> 00:16:32,290
HERE IS ALL THE CELL LINES

440
00:16:32,290 --> 00:16:33,158
RESPONDING TO RELAMATIN INCREASE

441
00:16:33,158 --> 00:16:34,426
IN BODY, AND EVERYTHING ELSE

442
00:16:34,426 --> 00:16:37,162
HERE IS RESPONSES TO HDAC

443
00:16:37,162 --> 00:16:38,330
INHIBITORS, SO ALL THESE

444
00:16:38,330 --> 00:16:40,699
PROTEINS IN EVERY CELL LINE

445
00:16:40,699 --> 00:16:42,567
CHANGE, THERE'S NICE 1S SHOULD

446
00:16:42,567 --> 00:16:44,302
BE RELATED LIKE THE PSYCHE LYNN,

447
00:16:44,302 --> 00:16:48,874
D3 AND SO THAT WAS ENCOURAGING

448
00:16:48,874 --> 00:16:49,441
TO SEE.

449
00:16:49,441 --> 00:16:50,909
WHAT WAS INTERESTING THOUGH,

450
00:16:50,909 --> 00:16:54,379
RIGHT, WAS THE NOT SO UBIQUITOUS

451
00:16:54,379 --> 00:16:57,716
CHANGES SO DES ACETYLASES DON'T

452
00:16:57,716 --> 00:16:59,684
RESPOND TO THE INHIBITION.

453
00:16:59,684 --> 00:17:03,622
HDAC 7 WAS BY FAR THE MOST

454
00:17:03,622 --> 00:17:04,256
RESPONSIVE GENERALLY, GENERALLY

455
00:17:04,256 --> 00:17:07,025
WENT DOWN IN THIS CASE.

456
00:17:07,025 --> 00:17:10,128
BUT THE OTHERS DON'T SHOW WHAT I

457
00:17:10,128 --> 00:17:11,296
WOULD CALL A CONSISTENT

458
00:17:11,296 --> 00:17:13,265
RESPONSE, YOU SEE MAYBE AN

459
00:17:13,265 --> 00:17:14,866
EFFECT ON HDAC 5, BUT NOTHING WE

460
00:17:14,866 --> 00:17:18,236
CAN POINT TO AND SAY, THIS IS

461
00:17:18,236 --> 00:17:26,178
PROBABLY WHY THERE'S AN EFFECT. 

462
00:17:26,178 --> 00:17:27,045
AGAIN, THE RELAMATINIB, YOU CAN

463
00:17:27,045 --> 00:17:29,014
ALSO SEE THESE IN PC SPACE, SO

464
00:17:29,014 --> 00:17:31,850
EVERY 1 OF THESE CLUSTERS OF

465
00:17:31,850 --> 00:17:33,685
POINTS HERE ARE CELL LINES

466
00:17:33,685 --> 00:17:34,352
RESPONDING TO SMALL MOLECULES

467
00:17:34,352 --> 00:17:36,521
AND YOU CAN SEE THE COLORS ARE

468
00:17:36,521 --> 00:17:37,389
ALL THE DIFFERENT SMALL

469
00:17:37,389 --> 00:17:40,692
MOLECULES AND THE SHAPE IS THE

470
00:17:40,692 --> 00:17:42,093
CELL LINES, BASICALLY THE

471
00:17:42,093 --> 00:17:43,094
SHAPE'S ALL CLUSTERED TOGETHER

472
00:17:43,094 --> 00:17:48,033
WITH THE EXCEPTION OF

473
00:17:48,033 --> 00:17:48,600
RELAMATINIB, WHICH RESPONDS

474
00:17:48,600 --> 00:17:48,934
UBIQUITOUSLY.

475
00:17:48,934 --> 00:17:50,435
SO WE CAN SEE DRUG AND CELL

476
00:17:50,435 --> 00:17:51,269
SPECIFIC EFFECTS, THIS AGAIN

477
00:17:51,269 --> 00:17:52,471
COMES BACK TO THE IDEA OF

478
00:17:52,471 --> 00:17:53,805
BUILDING NETWORKS ON THIS TYPE

479
00:17:53,805 --> 00:17:55,707
OF DAT AIT WILL BE PERTINENT TO

480
00:17:55,707 --> 00:17:57,042
THINK ABOUT THE CELL LINE YOU'RE

481
00:17:57,042 --> 00:17:57,843
USING, WE'VE SEEN THE EFFECT

482
00:17:57,843 --> 00:18:00,078
WHERE YOU TRY TO COMPARE IN THE

483
00:18:00,078 --> 00:18:03,348
DEEP COVER MOA STUDY TO THE

484
00:18:03,348 --> 00:18:07,085
DECRYPT E-STUDY, THE CORRELATION

485
00:18:07,085 --> 00:18:07,919
ABOUT .4-.6 FI REMEMBER

486
00:18:07,919 --> 00:18:08,220
CORRECTLY.

487
00:18:08,220 --> 00:18:13,692
SO YOU HAVE TO BE CAREFUL THERE.

488
00:18:13,692 --> 00:18:15,427
OKAY, SO, CHELSEA WAS NOT 1 TO

489
00:18:15,427 --> 00:18:17,028
SIT ON HER HANDS ONCE SHE HAD A

490
00:18:17,028 --> 00:18:19,197
BIG DATA SET AND SO SHE WENT FOR

491
00:18:19,197 --> 00:18:20,065
INCREASING BOTH THE NUMBER OF

492
00:18:20,065 --> 00:18:25,036
CELL LINES AND THE DRUGS USED

493
00:18:25,036 --> 00:18:25,937
FOR TREATMENT, ESSENTIALLY,

494
00:18:25,937 --> 00:18:27,405
ADDED A LOT MORE TO EACH.

495
00:18:27,405 --> 00:18:29,574
SO WHATLY ACTUALLY DID WAS

496
00:18:29,574 --> 00:18:31,209
INCREASE THE NUMBER OF CELL

497
00:18:31,209 --> 00:18:32,744
LINES FROM 5-24.

498
00:18:32,744 --> 00:18:38,517
THEY  ENCOMPASS LARGE

499
00:18:38,517 --> 00:18:40,819
HETEROGENEOUS GENETIC POPULATION

500
00:18:40,819 --> 00:18:42,120
OF EUROPEAN, AFRICAN, ASIAN,

501
00:18:42,120 --> 00:18:44,022
MALE AND FEMALE CELL LINES WITH

502
00:18:44,022 --> 00:18:46,224
DIFFERENT DRIVER MUTATIONS EGFR,

503
00:18:46,224 --> 00:18:47,559
KRASE MODEL, P53 AND TREATED

504
00:18:47,559 --> 00:18:50,195
THESE WITH A SERIES OF SMALL

505
00:18:50,195 --> 00:18:51,897
MOLECULE INHIBITORS, TO THINGS

506
00:18:51,897 --> 00:18:55,433
LIKE ORAL KINASE B, P38 KINASE

507
00:18:55,433 --> 00:18:56,902
INHIBITOR, AND SO EXPANDING THE

508
00:18:56,902 --> 00:18:59,037
REPERER TWOAR OF PROTURBATIONS.

509
00:18:59,037 --> 00:19:01,172
AND BUILT UP A NETWORK IN THIS

510
00:19:01,172 --> 00:19:02,941
CASE, TAKING THE TOP HALF OF

511
00:19:02,941 --> 00:19:03,808
THAT HEAT MAP, MAKING IT

512
00:19:03,808 --> 00:19:04,809
CIRCULAR SO CAN YOU SEE

513
00:19:04,809 --> 00:19:06,211
EVERYTHING AT ONCE ON 1 SLIDE,

514
00:19:06,211 --> 00:19:10,181
AND WE CAN SEE THE CORRELATION

515
00:19:10,181 --> 00:19:13,418
ESSENTIALLY, OF THE RESPONSES.

516
00:19:13,418 --> 00:19:15,387
HOPEFULLY WHAT YOU CAN GLEAN BY

517
00:19:15,387 --> 00:19:17,989
LOOKING AT IT ARE CONSISTENT

518
00:19:17,989 --> 00:19:20,025
RESPONSES, THE CELLS CLUSTER,

519
00:19:20,025 --> 00:19:22,127
RTK INHIBITORS AND HDAC

520
00:19:22,127 --> 00:19:24,029
INHIBITORS TOGETHER, THAT'S

521
00:19:24,029 --> 00:19:25,397
INTERESTING, THERE'S A DIVERSITY

522
00:19:25,397 --> 00:19:27,232
OF RESPONSES BUT THESE LARGELY

523
00:19:27,232 --> 00:19:28,433
SEEM TO CLUSTER TOGETHER OR AT

524
00:19:28,433 --> 00:19:31,403
LEAST AWAY FROM THE OTHER

525
00:19:31,403 --> 00:19:32,704
INHIBITORS, SO, THAT IS

526
00:19:32,704 --> 00:19:33,638
INTERESTING TO SEE, AND 1 THING

527
00:19:33,638 --> 00:19:34,940
WE WERE ALSO EXCITED ABOUT FOR

528
00:19:34,940 --> 00:19:36,474
THIS LARGER SET OF DATA AND I

529
00:19:36,474 --> 00:19:38,643
WON'T GO INTO TOO MUCH DETAIL,

530
00:19:38,643 --> 00:19:40,178
CHELSEA WILL BE PRESENTING ABOUT

531
00:19:40,178 --> 00:19:42,480
THIS IN THE ASMS ON THURSDAY,

532
00:19:42,480 --> 00:19:43,882
THIS IDEA THAT ONCE WE HAVE MORE

533
00:19:43,882 --> 00:19:46,217
CELL LINES WE CAN BEGIN TO DO

534
00:19:46,217 --> 00:19:48,787
COMPARISONS AND MOAR MORE

535
00:19:48,787 --> 00:19:50,255
PROTEIN COMPLEXIO GENOMIC LAND

536
00:19:50,255 --> 00:19:52,524
SCAPE, YOU BEE WE DO SEE EFFECTS

537
00:19:52,524 --> 00:19:54,159
DRIVEN BY THE DRIVER MUTATION

538
00:19:54,159 --> 00:19:55,160
BEING PRESENT OR ABNORMALITIES

539
00:19:55,160 --> 00:19:55,360
SEBT.

540
00:19:55,360 --> 00:19:59,397
SO IN THIS CASE, LOOKING AT THE

541
00:19:59,397 --> 00:20:03,501
RESPONSE OF CELLS TO GEFITINIB,

542
00:20:03,501 --> 00:20:04,436
APPARENTLY THAT'S LOW BATTERY,

543
00:20:04,436 --> 00:20:05,937
ALL RIGHT, WITH OR WITHOUT THE

544
00:20:05,937 --> 00:20:13,144
MUTATION, SO WE CAN SEE DCBL,

545
00:20:13,144 --> 00:20:16,314
FD2, ESSENTIALLY IF THERE'S NO

546
00:20:16,314 --> 00:20:22,120
MUTANTS JUST WILD-TYPE EGFR,

547
00:20:22,120 --> 00:20:23,288
GEFITINIB PRODUCES NO EFFECTS,

548
00:20:23,288 --> 00:20:25,490
BUT IF IT HAS A MUSEUM TABT

549
00:20:25,490 --> 00:20:27,325
EFFECT THERE'S A DIG 95 CANT

550
00:20:27,325 --> 00:20:29,260
COUNSEL REGULATION OF THIS

551
00:20:29,260 --> 00:20:29,828
PROTEIN.

552
00:20:29,828 --> 00:20:31,229
IF WE LOOKEDDA THIS, THERE WERE

553
00:20:31,229 --> 00:20:33,031
A SERIES OF INTERESTING PATHWAYS

554
00:20:33,031 --> 00:20:35,634
WITH THE EFFECTS OF EGFR AND WE

555
00:20:35,634 --> 00:20:37,636
HAVE MORE CANDIDATES FOR THIS

556
00:20:37,636 --> 00:20:40,205
BUT THINGS LIKE THE UPICK WITTEN

557
00:20:40,205 --> 00:20:41,940
LIGASE ACTIVITY THAT WE'RE

558
00:20:41,940 --> 00:20:43,441
INTERESTED IN PLAYING IN.

559
00:20:43,441 --> 00:20:44,709
ONE FURTHER STEP SHE WENT AND

560
00:20:44,709 --> 00:20:46,211
LOOKED AT SHE HAS VIABILITY DATA

561
00:20:46,211 --> 00:20:48,079
FOR ALL OF THESE AND IN ADDITION

562
00:20:48,079 --> 00:20:51,449
AND SHE BEGAN TO LOOK AT WHAT

563
00:20:51,449 --> 00:20:52,951
THE EFFECT IS OR THE LIKELY

564
00:20:52,951 --> 00:20:56,755
EFFECT IS OF MUTATIONS ON

565
00:20:56,755 --> 00:20:59,924
VIABILITY, THESE DAT AAND THE

566
00:20:59,924 --> 00:21:01,559
EFFECTS, THAT'S DRIVEN BY SMALL

567
00:21:01,559 --> 00:21:05,964
MOLECULE TREATMENT AND IN THIS

568
00:21:05,964 --> 00:21:08,767
CASE, TREATMENT, AND THE TOP

569
00:21:08,767 --> 00:21:10,502
CANDIDATE HERE, THIS IS JUST THE

570
00:21:10,502 --> 00:21:14,873
LOG 2 VIABILITY RATIO, PRE- AND

571
00:21:14,873 --> 00:21:16,841
POST TREATMENT, THEY ARE

572
00:21:16,841 --> 00:21:21,746
SLIGHTLY MORE VIABLE ODDLY AFTER

573
00:21:21,746 --> 00:21:23,214
GEFITINIB TREATMENT, ON THE SPOT

574
00:21:23,214 --> 00:21:25,483
AND THEN WHAT'S SHOWING UP OVER

575
00:21:25,483 --> 00:21:27,585
HERE ARE EACH 1 OF THESE DOTS IS

576
00:21:27,585 --> 00:21:30,355
A CELL LINE AND WHETHER OR NOT

577
00:21:30,355 --> 00:21:35,326
IT'S MUTATIONAL STATUS IS EGFR,

578
00:21:35,326 --> 00:21:37,696
MUTANT, KITHROORKS CA MUTANT, ET

579
00:21:37,696 --> 00:21:39,164
CETERA, ET CETERA, AND THEN EACH

580
00:21:39,164 --> 00:21:43,668
OF THESE POINTS WOULD BE 3 EGFR

581
00:21:43,668 --> 00:21:44,903
MUTANTS, EGFR MUTATION IS

582
00:21:44,903 --> 00:21:47,305
SEPARATING AWAY FROM THE PACK

583
00:21:47,305 --> 00:21:51,076
OVER HERE IN TERMS OF THE IMPACT

584
00:21:51,076 --> 00:21:52,644
OF THE GEFITINIB, SO IF YOU HAVE

585
00:21:52,644 --> 00:21:57,549
THE MUTANT YOU ARE LIKELY TO

586
00:21:57,549 --> 00:21:58,783
HAVE THE GEFITINIB, IT'S

587
00:21:58,783 --> 00:22:00,985
SLIGHTLY PROTECTIVE IN THIS CASE

588
00:22:00,985 --> 00:22:03,655
AND FEN2 SEEMS TO BE SLIGHTLY

589
00:22:03,655 --> 00:22:04,456
EFFECTIVE AT LEADING THE

590
00:22:04,456 --> 00:22:05,557
GEFITINIB RESPONSE, SO THERE'S

591
00:22:05,557 --> 00:22:07,025
THINGS TO PULL OUT IN THE

592
00:22:07,025 --> 00:22:09,894
LANDSCAPE OF THIS BUT OVERALL I

593
00:22:09,894 --> 00:22:11,362
JUST WANT TO POINT OUT WITH THIS

594
00:22:11,362 --> 00:22:14,899
INITIAL STEP, WE HAD TO DEEP

595
00:22:14,899 --> 00:22:19,804
COVER MOA, YOU HAVE DECRYPT-E,

596
00:22:19,804 --> 00:22:21,039
AND WE'RE MISSING THE KEY OF

597
00:22:21,039 --> 00:22:22,507
WHAT ARE THE CELL LINES SPECIFIC

598
00:22:22,507 --> 00:22:24,709
RESPONSES AND HOW CONSISTENT ARE

599
00:22:24,709 --> 00:22:25,777
THOSE OVERALL?

600
00:22:25,777 --> 00:22:28,246
OKAY, SO THERE'S ANOTHER STEP

601
00:22:28,246 --> 00:22:29,681
HERE, THE FIRST I MENTIONED WAS

602
00:22:29,681 --> 00:22:31,416
THIS IDEA THAT WE WANTED TO LOOK

603
00:22:31,416 --> 00:22:34,185
AT WHAT ARE ESSENTIALLY THE CELL

604
00:22:34,185 --> 00:22:35,720
STATE FACTORS THAT MIGHT IMPINGE

605
00:22:35,720 --> 00:22:37,288
ON WHAT WE'RE LOOKING AT, AND

606
00:22:37,288 --> 00:22:38,423
THE OTHER THING THAT WE'RE

607
00:22:38,423 --> 00:22:40,091
REALLY INTERESTED IN TRYING TO

608
00:22:40,091 --> 00:22:41,459
ASKER TAIN ARE WHAT ARE THE

609
00:22:41,459 --> 00:22:44,162
ACTUAL MECHANISMS OF ACTION, WE

610
00:22:44,162 --> 00:22:45,730
GET AN IDEA OF PUTATIVE

611
00:22:45,730 --> 00:22:47,966
MECHANISMS OF ACTION WHEN WE DO

612
00:22:47,966 --> 00:22:48,833
THE PROTEOME RESPONSIVE DATA,

613
00:22:48,833 --> 00:22:50,401
BUT WE WOULD LIKE TO DIG A

614
00:22:50,401 --> 00:22:52,670
LITTLE BIT FURTHER THAN THAT AND

615
00:22:52,670 --> 00:22:54,472
WE CAN THINK, WE TREAT WITH

616
00:22:54,472 --> 00:22:55,774
DRUGS, SOME STUFF HAPPENS AND

617
00:22:55,774 --> 00:22:57,442
THEN THE PROTEOME SHIFTS, ALL

618
00:22:57,442 --> 00:22:57,642
RIGHT.

619
00:22:57,642 --> 00:23:00,345
WE CAN LOOK AT THIS IN SINGLE

620
00:23:00,345 --> 00:23:02,914
CELL SEQUENCING LAND FOR SOME

621
00:23:02,914 --> 00:23:06,718
FOLKS OUT AT U-W, AND MISSIONARY

622
00:23:06,718 --> 00:23:08,353
AND OTHER LABS WHERE THEY DID

623
00:23:08,353 --> 00:23:10,655
SIMILAR WORK AND SHARE THAD

624
00:23:10,655 --> 00:23:12,624
THERE'S HETEROGENEOUS SINGLE

625
00:23:12,624 --> 00:23:13,391
CELL RESPONSES IN

626
00:23:13,391 --> 00:23:14,225
TRANSCRIPTOMICS AND AGAIN THIS

627
00:23:14,225 --> 00:23:15,960
IS JUST RESPONSES AND SO WE'RE

628
00:23:15,960 --> 00:23:17,996
STILL REALLY INTERESTED IN THIS,

629
00:23:17,996 --> 00:23:23,368
SOME STUFF HAPPENS SO WE OF

630
00:23:23,368 --> 00:23:26,104
COURSE TURNED TO COLLEAGUES' LAB

631
00:23:26,104 --> 00:23:28,039
AND TTP PROTOCOLLINGS AND A

632
00:23:28,039 --> 00:23:31,643
FAVOR OF THEM THAT CAME OUT OF

633
00:23:31,643 --> 00:23:34,946
THE LAB WAS PISA, SO THIS IS THE

634
00:23:34,946 --> 00:23:36,314
IDEA WE'RE TREATING WITH

635
00:23:36,314 --> 00:23:39,317
DENATURING WITH VEHICLE

636
00:23:39,317 --> 00:23:41,119
CONTROLS, PROTEINS WILL DENATURE

637
00:23:41,119 --> 00:23:43,421
AND HAVE SOME SPACE MELTING

638
00:23:43,421 --> 00:23:46,257
TEMPERATURE, YOU ADD DRUG IT'LL

639
00:23:46,257 --> 00:23:50,628
CHANGE THE MELTING TEMPERATURE,

640
00:23:50,628 --> 00:23:51,362
CHANGE THE MELTING TEMPERATURE

641
00:23:51,362 --> 00:23:52,730
IN THE CHANGE IN ABUNDANCE AND

642
00:23:52,730 --> 00:23:54,399
OUR IDEA IS TO INTEGRATE ALL

643
00:23:54,399 --> 00:23:59,003
DATA SETS WE NOW HAVE PROTEOMICS

644
00:23:59,003 --> 00:23:59,604
SINGLE CELL TRANSCRIPTOMICS,

645
00:23:59,604 --> 00:24:01,105
TRANSCRIPTOMICS ON SOME OF THESE

646
00:24:01,105 --> 00:24:02,640
AND ASSESS DRUG SPECIFIC

647
00:24:02,640 --> 00:24:04,676
ENGAGEMENT AND PROTEIN SPECIFIC

648
00:24:04,676 --> 00:24:07,045
ENGAGEMENT AND THIS MULTIOMIC

649
00:24:07,045 --> 00:24:07,345
COMPARISON.

650
00:24:07,345 --> 00:24:09,180
SO WE'VE BEEN ABLE TO DO THIS

651
00:24:09,180 --> 00:24:12,383
RIGHT, AND THE PISA IDEA IS

652
00:24:12,383 --> 00:24:13,551
INSTEAD OF GETTING MELTING

653
00:24:13,551 --> 00:24:15,486
TURNLS YOU GET RELATIVE

654
00:24:15,486 --> 00:24:16,487
COMPARISON TO DMSO CONTROLS AND

655
00:24:16,487 --> 00:24:21,092
SO IN THIS CASE, WHAT THIS MEANS

656
00:24:21,092 --> 00:24:22,894
IS OUR LOG 2 RATIO SPACE, THINGS

657
00:24:22,894 --> 00:24:25,630
THAT ARE ON THE LEFT SIDE HERE,

658
00:24:25,630 --> 00:24:27,565
WOULD BE DESTABILIZED WHEN YOU

659
00:24:27,565 --> 00:24:29,334
ADD INHIBITORS AND THINGS ON THE

660
00:24:29,334 --> 00:24:31,870
RIGHT SIDE THERE, HAD TO BE

661
00:24:31,870 --> 00:24:34,038
STABILIZED AND EITHER WAY,

662
00:24:34,038 --> 00:24:34,706
STABILIZED OR DESTABILIZED IS

663
00:24:34,706 --> 00:24:36,841
INTERESTING TO US BECAUSE IT

664
00:24:36,841 --> 00:24:37,942
MEANINGS SOME CHANGE IN THE

665
00:24:37,942 --> 00:24:39,177
THERMAL STABILITY OF THOSE

666
00:24:39,177 --> 00:24:39,444
PROTEINS.

667
00:24:39,444 --> 00:24:42,347
IT WAS NICE TO SEE HISTONE

668
00:24:42,347 --> 00:24:47,085
DEACETYLASE INHIBITOR AND TREAT.

669
00:24:47,085 --> 00:24:48,519
ALL RIGHT, GREAT, THE ASSAY

670
00:24:48,519 --> 00:24:53,024
WORKS, WE ALSO SEE SOME

671
00:24:53,024 --> 00:24:55,693
DISCRIMINATION RATE, HDAC, 1, 2,

672
00:24:55,693 --> 00:24:59,497
6 ARE ALTERED BUT 3, 4, 7, AITD,

673
00:24:59,497 --> 00:25:00,632
HAVE NO STABILITY CHANGES AT

674
00:25:00,632 --> 00:25:02,734
LEAST IN THE ASSAY THAT WE USED.

675
00:25:02,734 --> 00:25:04,502
AND EVEN IF YOU JUST LOOK AT ALL

676
00:25:04,502 --> 00:25:06,437
THE OTHER POINTS THAT ARE

677
00:25:06,437 --> 00:25:08,306
SIGNIFICANT, TO FIND THE

678
00:25:08,306 --> 00:25:09,807
SIGNIFICANT IN THIS VOLCANO

679
00:25:09,807 --> 00:25:11,643
PLOT, WE SEE SIGNIFICANT CHANGE

680
00:25:11,643 --> 00:25:12,977
FROM ABOUT 40-50 PROTEINS THAT

681
00:25:12,977 --> 00:25:15,146
WE NOW CONSIDER FOR MECHANISM OF

682
00:25:15,146 --> 00:25:16,014
ACTION VERSUS THE 2200 PROTEINS

683
00:25:16,014 --> 00:25:19,851
WE HAD TO ESSENTIA WILY

684
00:25:19,851 --> 00:25:21,552
CONSIDER, SO WE CAN THINK SOME

685
00:25:21,552 --> 00:25:22,820
OF THESE WILL BE ON TARGETS WE

686
00:25:22,820 --> 00:25:24,756
KNOW AND ALL OF THE REST ARE OFF

687
00:25:24,756 --> 00:25:26,190
TARGETS THAT ARE INTERESTING FOR

688
00:25:26,190 --> 00:25:29,193
THE ADVERSE EFFECTS OF THESE.

689
00:25:29,193 --> 00:25:31,863
OKAY, SO, CELL TYPE SPECIFIC

690
00:25:31,863 --> 00:25:32,697
RESPONSES, RIGHT, WE CAN

691
00:25:32,697 --> 00:25:34,966
ACTUALLY GO IN AND USE THESE

692
00:25:34,966 --> 00:25:36,367
ASSAYS, BOTH IN CELLS AND

693
00:25:36,367 --> 00:25:37,602
LIAISON SUITABILITY ZONESS, AND

694
00:25:37,602 --> 00:25:39,337
1 INTERESTING HIT THAT WE PICKED

695
00:25:39,337 --> 00:25:41,706
OUT, THIS IS ANOTHER SMALL

696
00:25:41,706 --> 00:25:43,908
MOLECULE INHIBITOR OF HISTONE

697
00:25:43,908 --> 00:25:45,777
DEACETYLASES, SO AGAIN IN TERMAL

698
00:25:45,777 --> 00:25:46,711
STABILITY LAND, WE SEE

699
00:25:46,711 --> 00:25:48,846
STABILIZATION OF OUR HISTONE

700
00:25:48,846 --> 00:25:49,914
DEACETYLASES, THAT'S GREAT, AND

701
00:25:49,914 --> 00:25:52,450
WE ALSO SAW THIS INTERESTING OFF

702
00:25:52,450 --> 00:25:54,485
TARGET HIT, AND THE ANALYSIS WE

703
00:25:54,485 --> 00:25:55,219
SAW THESE CONSISTENTLY WHETHER

704
00:25:55,219 --> 00:25:57,622
OR NOT WE DID THIS INTACT CELLS

705
00:25:57,622 --> 00:25:59,290
OR IN LIAISON SUITABILITY

706
00:25:59,290 --> 00:26:09,701
ZONESS, AND WE ALSO SEE

707
00:26:13,338 --> 00:26:14,672
PARTICULARLY IN 8549 WHICH WE

708
00:26:14,672 --> 00:26:15,974
DID THIS THERMAL STABILITY ASSAY

709
00:26:15,974 --> 00:26:18,876
AND THEY ARE PARTICULARLY

710
00:26:18,876 --> 00:26:21,879
SUSCEPTIBLE AS I MENTIONED

711
00:26:21,879 --> 00:26:22,113
BEFORE.

712
00:26:22,113 --> 00:26:23,448
SO 1 THING THAT WAS INTERESTING

713
00:26:23,448 --> 00:26:27,552
THERE IS THAT IF WE GO LOOK AT

714
00:26:27,552 --> 00:26:31,222
DEEP COVER MOA, BUT IF WE GO

715
00:26:31,222 --> 00:26:35,159
LOOK IN DEPTH MAP FOR THE

716
00:26:35,159 --> 00:26:39,430
RELATIVE ABUNDANCE OF 8549, AND

717
00:26:39,430 --> 00:26:44,936
H202, IN OUR ANALYSIS, 8549 HAS

718
00:26:44,936 --> 00:26:49,640
THE LOWEST, MEANING THEY'RE

719
00:26:49,640 --> 00:26:50,708
PARTICULARLY SUSCEPTIBLE TO

720
00:26:50,708 --> 00:26:51,009
INHIBITION.

721
00:26:51,009 --> 00:26:56,080
WE CAN ALSO GO FURTHER AND DO

722
00:26:56,080 --> 00:26:58,516
STUDIES ON THE KINASE B, AND

723
00:26:58,516 --> 00:27:03,254
MODELED IN THE CENTER IS THE

724
00:27:03,254 --> 00:27:08,826
INHIBITOR, BX680, AND IF WE PUT

725
00:27:08,826 --> 00:27:10,528
BELINOSTAT IN THERE, IT HAS A

726
00:27:10,528 --> 00:27:14,098
NEAR PERFECT OVERLAP, AND THE

727
00:27:14,098 --> 00:27:15,533
INHIBITOR WILL BE 880 AND WE'RE

728
00:27:15,533 --> 00:27:18,936
TRYING TO FOLLOW THIS UP TO

729
00:27:18,936 --> 00:27:19,170
VERIFY.

730
00:27:19,170 --> 00:27:22,006
SO IF WE CAN DO 1 THERMAL

731
00:27:22,006 --> 00:27:23,074
ANALYSIS, WE CAN DO A HUNDRED

732
00:27:23,074 --> 00:27:25,343
FWE CAN DO A HUNDRED, WE CAN DO

733
00:27:25,343 --> 00:27:28,413
200, SO THAT'S WHAT MEGAN AND

734
00:27:28,413 --> 00:27:30,448
JOHN DID.

735
00:27:30,448 --> 00:27:32,784
RAN THIS LARGE SCALE SMALL

736
00:27:32,784 --> 00:27:36,087
MOLECULE PANEL, FOCUSING ON THE

737
00:27:36,087 --> 00:27:37,522
KINASE INHIBITORS, A FEW

738
00:27:37,522 --> 00:27:39,123
SMATTERING OF OTHERS IN THERE, 

739
00:27:39,123 --> 00:27:41,159
SO WE FOCUSED ON CYTOKINASE

740
00:27:41,159 --> 00:27:42,927
INHIBITORS AND DID THIS ON 96

741
00:27:42,927 --> 00:27:45,563
TOTAL, 70 OF THESE ARE KINASE

742
00:27:45,563 --> 00:27:47,065
INHIBITORS, GOT RELATIVELY

743
00:27:47,065 --> 00:27:48,599
MASSIVE DATA SET, WITH THERMAL

744
00:27:48,599 --> 00:27:49,500
STABILITY AND MEASUREMENTS FOR

745
00:27:49,500 --> 00:27:53,905
ALL OF THESE TREATMENTS, RIGHT?

746
00:27:53,905 --> 00:27:56,374
AND NOW, WE HAVE A LARGE SCALE

747
00:27:56,374 --> 00:27:59,744
DATA SET TO TRY AND USE OR

748
00:27:59,744 --> 00:28:03,347
UNDERSTAND NECKANISMS OF ACTION

749
00:28:03,347 --> 00:28:04,248
FOR SMALL MOLECULES.

750
00:28:04,248 --> 00:28:05,716
LARGE SCALE DATA ANALYSIS WE

751
00:28:05,716 --> 00:28:07,985
HAVE LOSS AND LOTS OF POINTS FOR

752
00:28:07,985 --> 00:28:08,786
THE THERMAL STABILITY CHANGES

753
00:28:08,786 --> 00:28:10,388
ABOUT YOU WHAT WAS STRIKING AND

754
00:28:10,388 --> 00:28:12,490
INTERESTING TO US IS THAT WE CAN

755
00:28:12,490 --> 00:28:14,325
USE THE SCALE OF THIS TO

756
00:28:14,325 --> 00:28:16,861
INTERPRET ON AND OFF TARGET

757
00:28:16,861 --> 00:28:17,495
EFFECTS.

758
00:28:17,495 --> 00:28:20,064
AND SO WHAT I'M SHOWING YOU

759
00:28:20,064 --> 00:28:22,366
HERE, AGAIN, ARE THERMAL

760
00:28:22,366 --> 00:28:23,468
STABILITY MEASUREMENTS AND THE

761
00:28:23,468 --> 00:28:27,772
FULL CHANGE THAT WAS THE NEXT

762
00:28:27,772 --> 00:28:30,208
ACCESSOT PLOTS, AND FOCUSING ON

763
00:28:30,208 --> 00:28:31,442
THE K526 CELLS AND OTHER CANCER

764
00:28:31,442 --> 00:28:35,346
CELLS IN THE LINE, LOOKING AT

765
00:28:35,346 --> 00:28:38,282
RIP KINASE 1 STABILITY TREATING

766
00:28:38,282 --> 00:28:41,319
WITH ORAL KINASE INHIBITORS O

767
00:28:41,319 --> 00:28:42,086
CDK9 INHIB THORS IDENTITY ARES

768
00:28:42,086 --> 00:28:43,855
ON AND YOU SEE THAT ACROSS ALL

769
00:28:43,855 --> 00:28:46,090
TREATMENTS THE YELLOW 1S ARE

770
00:28:46,090 --> 00:28:48,025
DMSO, THE OTHERS ARE GRAY SMALL

771
00:28:48,025 --> 00:28:49,393
MOLECULE DRUGS, THERE'S

772
00:28:49,393 --> 00:28:50,428
RELATIVELY LITTLE EFFECT EXCEPT

773
00:28:50,428 --> 00:28:52,730
FOR THESE 4 WHICH HAVE

774
00:28:52,730 --> 00:28:53,798
SIGNIFICANTLY ALTERED AND

775
00:28:53,798 --> 00:28:57,235
INCREASED STABILITY, SO WE CAN

776
00:28:57,235 --> 00:28:58,336
ACTUALLY SEE THESE INHIBITORS

777
00:28:58,336 --> 00:29:01,606
ARE KNOWN TO HAVE THIS AS AN OFF

778
00:29:01,606 --> 00:29:02,440
TARGET EFFECT, RECENTLY, IT WAS

779
00:29:02,440 --> 00:29:05,076
FOUND TO HAVE THIS AND WE HAVE

780
00:29:05,076 --> 00:29:07,678
THIS NEW POTENTIAL CANDIDATE FOR

781
00:29:07,678 --> 00:29:12,049
A RIP KINASE 1 INTERACTIONS WITH

782
00:29:12,049 --> 00:29:12,250
THIS.

783
00:29:12,250 --> 00:29:13,184
AGAINY WE GO BACK TO THE

784
00:29:13,184 --> 00:29:14,752
CORRELATION AND WE LOOK AT

785
00:29:14,752 --> 00:29:15,987
CORRELATION OF THERMAL STABILITY

786
00:29:15,987 --> 00:29:20,424
PROFILES FOR THIS, SO HERE,

787
00:29:20,424 --> 00:29:22,860
WE'RE SHING AGAIN, I SHOWED THE

788
00:29:22,860 --> 00:29:23,761
PROTEOME SCALE PREVIOUSLY, AND

789
00:29:23,761 --> 00:29:26,030
IN THIS CASE, IT'S THE THERMAL

790
00:29:26,030 --> 00:29:28,232
ABILITY SCALE, WE CAN SEE THAT

791
00:29:28,232 --> 00:29:29,734
ESSENTIALLY THE DATA INDICATE

792
00:29:29,734 --> 00:29:31,869
THAT BRD 4 AND 3, AND IF YOU

793
00:29:31,869 --> 00:29:34,805
LOOK REALLY CLOSELY BEHIND THAT,

794
00:29:34,805 --> 00:29:37,408
THERE'S BRD2, AND PLK1 HAVE

795
00:29:37,408 --> 00:29:38,376
SIGNIFICANTLY ALTERED THERMAL

796
00:29:38,376 --> 00:29:38,976
STABILITY, WITH TREATMENT OF

797
00:29:38,976 --> 00:29:42,079
THESE THINGS THAT SHOULD TARGET

798
00:29:42,079 --> 00:29:42,580
THEM.

799
00:29:42,580 --> 00:29:42,780
GREAT.

800
00:29:42,780 --> 00:29:45,850
HOWEVER WHAT IT SAYS TO US IS

801
00:29:45,850 --> 00:29:48,553
THAT INTERESTINGLY STRUCTURAL

802
00:29:48,553 --> 00:29:50,154
THINGS ARE INDUCING THERMAL

803
00:29:50,154 --> 00:29:50,988
ABILITY CHANGES WHICH IS USEFUL

804
00:29:50,988 --> 00:29:53,191
BECAUSE WE CAN LOOK AT SMALL

805
00:29:53,191 --> 00:29:54,959
MOLECULES THAT ARE STRUCTURALLY

806
00:29:54,959 --> 00:29:56,494
SIMILAR AND SEE IF THEY ARE

807
00:29:56,494 --> 00:29:58,095
PRODUCING EFFECTS THAT MIGHT BE

808
00:29:58,095 --> 00:30:00,064
OF INTEREST, IN THIS CASE, I

809
00:30:00,064 --> 00:30:03,034
WILL SHOWING THAT THE BI13536,

810
00:30:03,034 --> 00:30:06,337
AND THE MVP, AND WE CAN LOOK AT

811
00:30:06,337 --> 00:30:08,472
ESSENTIALLY, TITRATIONS OF

812
00:30:08,472 --> 00:30:10,074
THESE, AGAIN, WE'RE STAYING IN

813
00:30:10,074 --> 00:30:12,810
LOG 2 FULL CHAINS BEING THERMAL

814
00:30:12,810 --> 00:30:14,745
STABILITY BASE ANALYSIS AND WE

815
00:30:14,745 --> 00:30:17,215
CAN SEE FOR CDK4 AND 6, WHICH

816
00:30:17,215 --> 00:30:20,685
ARE THE TARGET, AS YOU INCREASE

817
00:30:20,685 --> 00:30:21,619
CONCENTRATION, YOU INCREASE IN

818
00:30:21,619 --> 00:30:24,388
THIS CASE, THE EFFECTIVE CHANGE

819
00:30:24,388 --> 00:30:26,557
IN THERMAL STABILITY, YOU HAVE A

820
00:30:26,557 --> 00:30:28,292
DOSE DEPEBDENT BINDING, WE

821
00:30:28,292 --> 00:30:30,895
CONFIRMED WHAT EVERYONE ALREADY

822
00:30:30,895 --> 00:30:31,162
KNEW.

823
00:30:31,162 --> 00:30:33,097
WHAT WAS MORE FUN IS WE CAN

824
00:30:33,097 --> 00:30:34,565
THINK AND DO THE EXACT SAME

825
00:30:34,565 --> 00:30:37,868
THING AND FIND THIS KNOWN OFF

826
00:30:37,868 --> 00:30:39,770
TARGET INTERACTION WITH PROTEINS

827
00:30:39,770 --> 00:30:42,006
SO BRD4 IN THIS CASE, AND WE

828
00:30:42,006 --> 00:30:44,809
ACTUALLY FOUND STRIKING WAS THAT

829
00:30:44,809 --> 00:30:47,945
BOTH ARE EQUIPPED HERE IN THE

830
00:30:47,945 --> 00:30:49,714
BROWNISH COLORS AND BI2536,

831
00:30:49,714 --> 00:30:51,916
WHICH IS A KNOWN PLK INHIBITOR

832
00:30:51,916 --> 00:30:55,786
SEEMED TO BE ENGAGING PLK 1.

833
00:30:55,786 --> 00:30:57,088
SO THAT'S INTERESTING RIGHT

834
00:30:57,088 --> 00:30:59,857
BECAUSE IT SUGGESTS TO US THAT

835
00:30:59,857 --> 00:31:06,197
PLK1 IS AN OFF TARGET FOR P A

836
00:31:06,197 --> 00:31:10,468
LBOCICLIB, AND IF WE LOOK AT A

837
00:31:10,468 --> 00:31:15,039
MARKER FOR PLK1 IN THESE CELLS,

838
00:31:15,039 --> 00:31:16,641
PHOSPHORYLATION OF CTP, WE CAN

839
00:31:16,641 --> 00:31:18,009
SEE HIGHER CONCENTRATIONS, YOU

840
00:31:18,009 --> 00:31:19,910
CAN INHIB THORS INCREASE IN BODY

841
00:31:19,910 --> 00:31:22,013
THE ACTIVITY OF PLK 1, SO IT'S

842
00:31:22,013 --> 00:31:23,714
NOT ONLY BINDING BUT AFFECTING

843
00:31:23,714 --> 00:31:26,484
THE ACTIVITY OF THIS MITOTIC

844
00:31:26,484 --> 00:31:27,652
REGULATOR, WE CAN DO MY FAVORITE

845
00:31:27,652 --> 00:31:30,421
THING WHICH IS GO SIT IN PIMAL

846
00:31:30,421 --> 00:31:33,491
FOR HOURS AND DO DOCKING AND WE

847
00:31:33,491 --> 00:31:36,961
CAN SEE THAT WHERE PI3526, THE

848
00:31:36,961 --> 00:31:37,695
KINASE ININCREASE IN BODYITOR

849
00:31:37,695 --> 00:31:40,431
CAN'T REALLY BIND TO THIS, AT

850
00:31:40,431 --> 00:31:43,200
THE TOP AND BENEFICIAL OF THE

851
00:31:43,200 --> 00:31:44,835
BINDING POCKET, THE PLK 1

852
00:31:44,835 --> 00:31:46,304
BINDING SITE IS MUCH MORE  

853
00:31:46,304 --> 00:31:49,040
PERMISSIVE AND SO, THEREFORE, WE

854
00:31:49,040 --> 00:31:58,783
THINK THAT'S WHY IT CAN DIRECTLY

855
00:31:58,783 --> 00:31:59,417
INHIBIT THE PLK1.

856
00:31:59,417 --> 00:32:01,485
SO GENERATED, I AM A REPETITIVE

857
00:32:01,485 --> 00:32:02,887
PERSON, SO IF I DO SOMETHING

858
00:32:02,887 --> 00:32:04,322
ONCE, I WILL PROBABLY END UP

859
00:32:04,322 --> 00:32:07,091
DOING IT AGAIN, IN THIS CASE WE

860
00:32:07,091 --> 00:32:08,826
LIKE CORRELATION A LOT SO WE

861
00:32:08,826 --> 00:32:10,561
WERE LIKE IT WORKED ON THE

862
00:32:10,561 --> 00:32:12,063
PROTEOME SCALE, LET'S KEEP IT

863
00:32:12,063 --> 00:32:13,431
GOING FOR THE THERMAL STABILITY

864
00:32:13,431 --> 00:32:14,999
SCALE AND WE FOUND IT WAS A BIT

865
00:32:14,999 --> 00:32:17,034
SURPRISING AT THE TIME IS IF YOU

866
00:32:17,034 --> 00:32:18,536
DO ENOUGH OF THESE ANALYSIS AND

867
00:32:18,536 --> 00:32:20,438
LOOK ACROSS ENOUGH TREATMENTS

868
00:32:20,438 --> 00:32:22,673
WITH ENOUGH DRUGS, WE CAN SEE

869
00:32:22,673 --> 00:32:25,609
VERY CONSISTENT RESPONSES, THE

870
00:32:25,609 --> 00:32:26,977
SMALL MOLECULES, WERE

871
00:32:26,977 --> 00:32:28,145
STRUCTURALLY AND COMPLEX RELATED

872
00:32:28,145 --> 00:32:30,548
PROTEINS, SO IN THIS CASE,

873
00:32:30,548 --> 00:32:33,417
LOOKING AT P38 ALPHA AND MAP

874
00:32:33,417 --> 00:32:34,251
KINASE APK2 AND 3.

875
00:32:34,251 --> 00:32:37,621
WE CAN SEE THAT THERE IS A

876
00:32:37,621 --> 00:32:39,090
SIGNIFICANT CORRELATION OF THE

877
00:32:39,090 --> 00:32:40,725
THERMAL STABILITY RESPONSES OF

878
00:32:40,725 --> 00:32:41,392
THESE SMALL MOLECULES.

879
00:32:41,392 --> 00:32:42,326
WHAT WAS GREAT ABOUT THAT IS

880
00:32:42,326 --> 00:32:46,397
THAT WE KNOW THAT THERE'S DIRECT

881
00:32:46,397 --> 00:32:48,165
OR AT LEAST DIRECT PROTEIN

882
00:32:48,165 --> 00:32:50,801
INTERACTIONS BETWEEN THESE

883
00:32:50,801 --> 00:32:52,336
PROTEINS, SO EITHER WE'RE

884
00:32:52,336 --> 00:32:53,804
PULLING DOWN SECONDARY EFFECTS

885
00:32:53,804 --> 00:32:56,340
HERE OR WE'RE SEEING ESSENTIALLY

886
00:32:56,340 --> 00:32:58,376
BINDING TO RELATED COMPLEXES AND

887
00:32:58,376 --> 00:32:59,710
RELATED PROTEINS, BECAUSE THAT

888
00:32:59,710 --> 00:33:01,612
WAS INTERESTING, SO THAT HINTED

889
00:33:01,612 --> 00:33:03,047
THAT THIS CORRELATION OF

890
00:33:03,047 --> 00:33:05,082
CIVILIAN PROFILES MIGHT BE

891
00:33:05,082 --> 00:33:07,084
USEFUL MORE DPLOABALLY SO WE DID

892
00:33:07,084 --> 00:33:09,153
IT MORE GLOBALLY AND WE LOOKED

893
00:33:09,153 --> 00:33:13,891
AT CORRELATION PROFILES OF ALL

894
00:33:13,891 --> 00:33:16,494
PROTEINS AND WE THOSE IT WAS TO

895
00:33:16,494 --> 00:33:19,029
OWNEROUS, SO WE LOOKED AT THE

896
00:33:19,029 --> 00:33:22,166
COMPLETE SET OF KINOAM, WITHIN

897
00:33:22,166 --> 00:33:23,868
THE K5626 CELLS AND YOU CAN SEE

898
00:33:23,868 --> 00:33:26,237
HERE WE HAVE THESE WONDERFUL

899
00:33:26,237 --> 00:33:28,372
CORRELATION PLOTS, SIGNIFICANCE

900
00:33:28,372 --> 00:33:31,208
IS LOW ENOUGH THAT R-HAS TROUBLE

901
00:33:31,208 --> 00:33:34,645
GIVING YOU A REAL ANSWER BECAUSE

902
00:33:34,645 --> 00:33:38,616
THAT'S A GOOD SIGN, WE CAN SEE

903
00:33:38,616 --> 00:33:42,086
THESE KINASES, REALLY STRONGLY

904
00:33:42,086 --> 00:33:42,920
CORRELATED RESPONSES, WE DO THIS

905
00:33:42,920 --> 00:33:45,890
AT LARGE SO THE ENTIRETY OF KINE

906
00:33:45,890 --> 00:33:48,025
OHM, WE CAN BUILD UP A

907
00:33:48,025 --> 00:33:49,693
CORRELATION NETWORK, FOR HOW

908
00:33:49,693 --> 00:33:51,328
CORRELATIVE THE THERMAL CIVILIT

909
00:33:51,328 --> 00:33:52,229
RESPONSES ARE, SO WITHIN THIS,

910
00:33:52,229 --> 00:33:55,199
WE CAN SEE HERE, HERE'S THESE

911
00:33:55,199 --> 00:33:57,234
RPS ON THE PAGE, WE CAN SEE DOWN

912
00:33:57,234 --> 00:34:00,538
HERE ON THE LEFT ARE THE MAP

913
00:34:00,538 --> 00:34:01,839
KINASE 14, AND RELATED AND THOSE

914
00:34:01,839 --> 00:34:04,074
ARE PART OF THIS CORRELATION

915
00:34:04,074 --> 00:34:05,776
NETWORK BUT WE SEE A WHOLE HOST

916
00:34:05,776 --> 00:34:07,077
OF OTHER PROTEIN INTERACTIONS

917
00:34:07,077 --> 00:34:07,378
WITHIN IT.

918
00:34:07,378 --> 00:34:09,513
SO THAT WAS EXCITING AND SO WE

919
00:34:09,513 --> 00:34:11,882
WANTED TO BUILD ON THAT A LITTLE

920
00:34:11,882 --> 00:34:17,121
BIT MORE, BECAUSE WITHIN THAT,

921
00:34:17,121 --> 00:34:18,823
AN ASTUTE OBSERVER MIGHT SEE WE

922
00:34:18,823 --> 00:34:20,057
HAVE KINASE GROUPS UP HERE ON

923
00:34:20,057 --> 00:34:22,359
THE TOP, A BUNCH OF POINTS THAT

924
00:34:22,359 --> 00:34:23,961
ARE NOT CALLING THE WHITE,

925
00:34:23,961 --> 00:34:26,464
THEY'RE NOT COLORED BECAUSE

926
00:34:26,464 --> 00:34:27,698
THEY'RE NOT PROTEIN KINASES,

927
00:34:27,698 --> 00:34:29,300
THEY'RE KINASES, THEY'RE IN THE

928
00:34:29,300 --> 00:34:31,869
KINE OHM, BUT THEY'RE NOT

929
00:34:31,869 --> 00:34:33,037
PROTEIN KINASES.

930
00:34:33,037 --> 00:34:35,573
WE SAW A WHOLE HOST OF THESE

931
00:34:35,573 --> 00:34:37,441
RESPONDING TO SMALL MOLECULES

932
00:34:37,441 --> 00:34:39,844
SPECIFICALLY, CHANGING TO

933
00:34:39,844 --> 00:34:40,444
KINASES CHANGING THERMAL

934
00:34:40,444 --> 00:34:40,945
STABILITY.

935
00:34:40,945 --> 00:34:42,880
WE CAN PULL THOSE OUT, AND WE

936
00:34:42,880 --> 00:34:47,985
CAN THINK ABOUT IN THIS CASE,

937
00:34:47,985 --> 00:34:53,524
PICAIN ICE, AND CHANGING THE

938
00:34:53,524 --> 00:34:56,794
THERMAL PIP-KINASE, AND WITHIN

939
00:34:56,794 --> 00:35:00,998
THE NONKINASES IS A STRONG

940
00:35:00,998 --> 00:35:01,966
CORRELATED PROFILE, THESE SEEM

941
00:35:01,966 --> 00:35:04,101
TO BE HAVING DIRECT ENGAGEMENTS

942
00:35:04,101 --> 00:35:07,171
WITH SMALL MOLECULES AND LARGELY

943
00:35:07,171 --> 00:35:10,374
ARREST THAT IS LARGELY UNBIVED

944
00:35:10,374 --> 00:35:17,948
FROM THESE STUDIES LAST TIDBIT

945
00:35:17,948 --> 00:35:20,217
HERE IS ABOUT THE CONTEXT OF

946
00:35:20,217 --> 00:35:30,127
CELLS AND IT MATTERS SOMETIMES.

947
00:35:30,127 --> 00:35:31,529
WE ACTUALLY SEE THE OPPOSITE

948
00:35:31,529 --> 00:35:34,798
EFFECT FOR SOME KINASES LIKE

949
00:35:34,798 --> 00:35:37,301
BRAF, WHICH AFFECT LIAISON

950
00:35:37,301 --> 00:35:38,903
SUITABILITY ZONESS, THIS IS THE

951
00:35:38,903 --> 00:35:41,705
CONTEXT OF THEM SEMESTERS, THAT

952
00:35:41,705 --> 00:35:43,741
CAN BE IMPORTANT MOVING FORWARD.

953
00:35:43,741 --> 00:35:46,644
OVERALL METHOD OF ACTION WE CAN

954
00:35:46,644 --> 00:35:48,646
INFER THIS FROM THIS, AND WE CAN

955
00:35:48,646 --> 00:35:50,581
WITH POINT CORRELATION AND LARGE

956
00:35:50,581 --> 00:35:51,549
SCALE ANALYSIS AND COMPLEX

957
00:35:51,549 --> 00:35:52,182
INTERACTIONS AND SECONDARY

958
00:35:52,182 --> 00:35:54,351
EFFECTS SO WE SEE HERE, 1 ASPECT

959
00:35:54,351 --> 00:35:56,186
OF THIS AGAIN, JUST SO I DON'T

960
00:35:56,186 --> 00:35:59,557
GO, TOO, TOO, LONG IS THE WHYED

961
00:35:59,557 --> 00:36:00,624
THAT WE'RE INHIBITING KINASES,

962
00:36:00,624 --> 00:36:02,226
KINASES AFFECT OTHER PROTEINS

963
00:36:02,226 --> 00:36:03,127
THROUGH PHOSPHORYLATION WHICH

964
00:36:03,127 --> 00:36:04,662
CAN AFFECT THE THERMAL

965
00:36:04,662 --> 00:36:04,929
STABILITY.

966
00:36:04,929 --> 00:36:07,598
WE CAN ACTUALLY SEE IN THESE

967
00:36:07,598 --> 00:36:08,832
ASSAYS, THAT PHOSPHORYLATION

968
00:36:08,832 --> 00:36:10,801
EFFECT ON THERMAL STABILITY AS A

969
00:36:10,801 --> 00:36:12,703
SECONDARY EFFECT WHICH CAN BE

970
00:36:12,703 --> 00:36:14,238
USEFUL FOR PICKING UP MECHANISM

971
00:36:14,238 --> 00:36:14,838
OF ACTION TOOL.

972
00:36:14,838 --> 00:36:17,207
AND AGAIN THE AFFECT OF CELLULAR

973
00:36:17,207 --> 00:36:21,412
CONTEXT ESPECIALLY ON CHROMATIN

974
00:36:21,412 --> 00:36:23,047
AND COMPLEX BOUNDARIES.

975
00:36:23,047 --> 00:36:25,849
SO WE HAVE PROTEIN COMPLEX TEEN

976
00:36:25,849 --> 00:36:27,585
WIDE DRUG INTERACTIONS AND 1

977
00:36:27,585 --> 00:36:29,720
LAST TIDBIT OF A STORY THAT I

978
00:36:29,720 --> 00:36:31,522
WILL HINT AT IS WE HAVE A HOST

979
00:36:31,522 --> 00:36:34,158
OF THESE SMALL MOLECULES, BIND

980
00:36:34,158 --> 00:36:37,027
PROTEIN ANDS THESE PROTEINS, AND

981
00:36:37,027 --> 00:36:37,628
SMALL MOLECULES AREN'T ALONE,

982
00:36:37,628 --> 00:36:39,330
AND SO WE CAN THINK ABOUT THE

983
00:36:39,330 --> 00:36:44,401
EXAMPLE OF PROTEIN KINASE C, AND

984
00:36:44,401 --> 00:36:46,303
SOME OF THOSE THERE, WHICH IF

985
00:36:46,303 --> 00:36:52,409
YOU TREAT PROTEIN, OR TREAT

986
00:36:52,409 --> 00:36:55,012
CELLS, RIGHT, WHICH INHIBITS

987
00:36:55,012 --> 00:36:56,413
PRCA, AND BINDS, THAT'S ITS

988
00:36:56,413 --> 00:36:57,681
TARGET BUT IF YOU DO THAT IN

989
00:36:57,681 --> 00:36:58,849
LIAISON SUITABILITY ZONESS YOU

990
00:36:58,849 --> 00:37:00,317
GET A STRANG INCREASE IN

991
00:37:00,317 --> 00:37:01,318
STABILITY, IF YOU DO THAT IN

992
00:37:01,318 --> 00:37:03,087
CELLS WITH THE CELLULAR CONTEXT

993
00:37:03,087 --> 00:37:05,823
YOU GET A STRONG DECREASE IN

994
00:37:05,823 --> 00:37:06,824
STABILITY, THERE'S SOMETHING

995
00:37:06,824 --> 00:37:08,025
ABOUT THE CELLULAR CONTEXT THAT

996
00:37:08,025 --> 00:37:10,094
IS CHANGING THE RESPONSE TO THE

997
00:37:10,094 --> 00:37:11,595
SMALL MOLECULE, SO WE WERE

998
00:37:11,595 --> 00:37:13,764
CURIOUS ABOUT THAT AND CURIOUS

999
00:37:13,764 --> 00:37:16,867
OF THINKING ABOUT HOW NATIVE

1000
00:37:16,867 --> 00:37:21,739
LIGANDS CHANGE THE PROTEOME, TIM

1001
00:37:21,739 --> 00:37:26,176
AND ROSE, AT U-W, AND ROSE WHO

1002
00:37:26,176 --> 00:37:28,245
IS NOW GOING TO NORTHWESTERN DID

1003
00:37:28,245 --> 00:37:30,047
THIS BY LOOKING AT MUSE LIVER

1004
00:37:30,047 --> 00:37:30,814
MITOCHONDRIA, AND HUMAN CELLS

1005
00:37:30,814 --> 00:37:35,152
AND YEAST FOR PROTEINS THAT BIND

1006
00:37:35,152 --> 00:37:37,755
THE CALCIUM, THE PRKCA EXAMPLE,

1007
00:37:37,755 --> 00:37:39,556
WE WERE ABLE TO TEASE OUT A

1008
00:37:39,556 --> 00:37:41,859
LARGE NUMBER OF THESE CALCIUM

1009
00:37:41,859 --> 00:37:43,861
BINDING PROTEINS THIS WAY USING

1010
00:37:43,861 --> 00:37:46,597
THERMAL PROTEOME, AND THERMAL

1011
00:37:46,597 --> 00:37:47,631
STABILITY ASSAYS, WHERE WE CAN

1012
00:37:47,631 --> 00:37:50,534
SEE THAT SOME OF THESE PROTEINS

1013
00:37:50,534 --> 00:37:52,603
ARE DESTABILIZED BY CALCIUM CAN

1014
00:37:52,603 --> 00:37:55,072
OR DESTABILIZED BY MAGNESIUM,

1015
00:37:55,072 --> 00:37:56,306
AND THE SPECIFIC RESPONSES AND

1016
00:37:56,306 --> 00:37:58,709
THAT WAS FUN, AND THEN WE BEGIN

1017
00:37:58,709 --> 00:38:01,578
TO SEE PAPERS CONFIRMING, THESE

1018
00:38:01,578 --> 00:38:04,682
THINGS THAT WE SPECULATED ON

1019
00:38:04,682 --> 00:38:05,482
WERE CALCIUM BINDERS AND WE

1020
00:38:05,482 --> 00:38:07,918
THINK YOU HAVE A PREPPER TWOAR

1021
00:38:07,918 --> 00:38:11,321
OF NATIVE LIGANDS THERE AND OUR

1022
00:38:11,321 --> 00:38:12,356
SMALL MOLECULE NATIVE LIAISON

1023
00:38:12,356 --> 00:38:13,724
GAPPEDS WE FOUND THIS

1024
00:38:13,724 --> 00:38:20,864
INTERESTING ASPECT OF CAT 

1025
00:38:20,864 --> 00:38:22,800
IENGAGEMENT WHERE THE SUBSTREAM

1026
00:38:22,800 --> 00:38:24,201
EFFECTS CALCIUM BINDING, SO THIS

1027
00:38:24,201 --> 00:38:27,104
IS A STRUCTURE OF WE CAN SEE

1028
00:38:27,104 --> 00:38:28,706
NADP H THAT SHOULD BIND HERE AND

1029
00:38:28,706 --> 00:38:30,374
RIGHT HERE IS THE BINDING POCKET

1030
00:38:30,374 --> 00:38:35,879
FOR CALCIUM SO IF YOU HAVE A

1031
00:38:35,879 --> 00:38:38,549
NATURAL SUBSTRATE FOR DECR1, YOU

1032
00:38:38,549 --> 00:38:41,351
HAVE A KD, OVER HERE IN THE LOW

1033
00:38:41,351 --> 00:38:42,186
MICROMOLAR AND ABOUT 10 TOLD

1034
00:38:42,186 --> 00:38:46,824
HIGHER AND YOU DON'T HAVE THAT

1035
00:38:46,824 --> 00:38:47,925
LIAISON GABBED THERE.

1036
00:38:47,925 --> 00:38:51,095
SO WE'RE ABLE TO ACTUALLY USE

1037
00:38:51,095 --> 00:38:52,362
THESE PROTEOME PROFILES AND THE

1038
00:38:52,362 --> 00:38:52,930
ASSAY TREATMENT OF SUBSTANCE

1039
00:38:52,930 --> 00:38:54,498
ABUSE TEASE THESE OUT, SO WE'RE

1040
00:38:54,498 --> 00:38:55,432
INTERESTED IN COMBINING THE

1041
00:38:55,432 --> 00:39:00,104
NATIVE LIAISON GABBED AND

1042
00:39:00,104 --> 00:39:00,871
PROTEIN DRUG INTERACTION.

1043
00:39:00,871 --> 00:39:02,139
I COULD TALK MORE ABOUT THE

1044
00:39:02,139 --> 00:39:04,475
AGING STUDY, I WILL LEAVE IT

1045
00:39:04,475 --> 00:39:06,043
HERE IF SOMEBODY WANTS TO TALK

1046
00:39:06,043 --> 00:39:07,611
ABOUT IT, I PUT TOO MUCH IN

1047
00:39:07,611 --> 00:39:10,614
THIS, BUT I LEAVE YOU WITH THE

1048
00:39:10,614 --> 00:39:12,349
LAST BIG THING WE'RE INTERESTED

1049
00:39:12,349 --> 00:39:15,052
IN IS SMALL MOLECULE

1050
00:39:15,052 --> 00:39:16,386
PROTERBATIONS DON'T JUST DRIVE

1051
00:39:16,386 --> 00:39:17,321
PROTEOME SHIFTS BUTEE CAN USE

1052
00:39:17,321 --> 00:39:19,523
THEM TO CHANGE HOW CELLS BEHAVE

1053
00:39:19,523 --> 00:39:21,625
IN A MUCH LARGER CONTEXT, THIS

1054
00:39:21,625 --> 00:39:24,428
IN CASE, SMALL MOLECULE

1055
00:39:24,428 --> 00:39:28,065
INHIBITION WITH CHI RON WITH

1056
00:39:28,065 --> 00:39:29,399
INHIBITS GSK3A AND RETINAL

1057
00:39:29,399 --> 00:39:31,468
LOCATION NONAPOPTOTICKIC ACID

1058
00:39:31,468 --> 00:39:32,503
WHICH INDUCES NEUROMESODERM

1059
00:39:32,503 --> 00:39:32,770
FORMATION.

1060
00:39:32,770 --> 00:39:34,972
IF WE DO THESE THINGS IN STEM

1061
00:39:34,972 --> 00:39:36,673
CELLS, WE CAN ACTUALLY DRIVE THE

1062
00:39:36,673 --> 00:39:38,075
FORMATION OF THESE ORGANOIDS AND

1063
00:39:38,075 --> 00:39:39,143
THESE REALLY BEAUTIFUL WAYS AND

1064
00:39:39,143 --> 00:39:45,582
THEN USE THESE SYSTEMS TO

1065
00:39:45,582 --> 00:39:46,550
UNDERSTAND THE PROTERBATIONS

1066
00:39:46,550 --> 00:39:47,851
EFFECTS ARE CHANGE NOTHING

1067
00:39:47,851 --> 00:39:49,086
DEVELOPMENT AGING AND I AM HAPPY

1068
00:39:49,086 --> 00:39:50,287
TO CHAT MORE ABOUT THAT BUT JUST

1069
00:39:50,287 --> 00:39:53,457
IN THE INTEREST OF TIME I WILL

1070
00:39:53,457 --> 00:39:55,159
BLAZE THROUGH ALL OF THIS JUST

1071
00:39:55,159 --> 00:39:57,294
TO MAKE SURE I CAN THANK PEOPLE

1072
00:39:57,294 --> 00:40:01,532
AND ANSWER ANY QUESTIONS.

1073
00:40:01,532 --> 00:40:02,733
JUST TEASE YOU WITH ALL THE DATA

1074
00:40:02,733 --> 00:40:05,002
THAT WAS THERE.

1075
00:40:05,002 --> 00:40:06,770
CORRELATION COMES BACK UP, I

1076
00:40:06,770 --> 00:40:08,172
PROMISE IT'S EVERYWHERE, THAT'S

1077
00:40:08,172 --> 00:40:09,573
PROBABLY, THE OTHER THING JUST

1078
00:40:09,573 --> 00:40:12,576
FOR NATHAN WHEN I TALK TO HIM,

1079
00:40:12,576 --> 00:40:16,446
SO SHE HAVE A REFERENCE POINT IN

1080
00:40:16,446 --> 00:40:21,819
TERMS OF THE SLIDE, SO LED THE

1081
00:40:21,819 --> 00:40:25,322
DEVELOPMENT OF THE PROFILING,

1082
00:40:25,322 --> 00:40:27,224
CATARINNA IS LEADING THE AGING

1083
00:40:27,224 --> 00:40:28,592
PROTEOMES AND WE'RE EVENTUALLY

1084
00:40:28,592 --> 00:40:30,894
HOPING TO MARRY THESE 2 WHERE

1085
00:40:30,894 --> 00:40:35,165
IT'S LIKE GASTROLLOYDS AND SMALL

1086
00:40:35,165 --> 00:40:36,567
ORGANOID BASED PROFILING,

1087
00:40:36,567 --> 00:40:38,368
UNDERSTANDING HOW AGING HAPPENS

1088
00:40:38,368 --> 00:40:40,737
AND THE CLOSER WE GET THESE THE

1089
00:40:40,737 --> 00:40:43,273
MORE COMPREHENSIVE ANALYSIS OF

1090
00:40:43,273 --> 00:40:43,807
MORE AGING THERE.

1091
00:40:43,807 --> 00:40:45,475
THESE ARE THE FOLKS WHO DID THE

1092
00:40:45,475 --> 00:40:48,612
WORK, I HAVE A GREAT LAB, FOLKS

1093
00:40:48,612 --> 00:40:51,849
THAT I FEATURED IN THIS WERE

1094
00:40:51,849 --> 00:40:54,451
CATARENA, KATHRYN AND CATARINNA

1095
00:40:54,451 --> 00:40:56,854
ARE LEADING THE THERMAL

1096
00:40:56,854 --> 00:40:58,121
STABILITY WORK, CATARINNA IS

1097
00:40:58,121 --> 00:41:00,324
LEADING THE MOUSE AGING WORK AND

1098
00:41:00,324 --> 00:41:00,657
COLLABORATORS.

1099
00:41:00,657 --> 00:41:04,828
SO I GUESS I WOULD BE REMISS TO

1100
00:41:04,828 --> 00:41:06,463
NOT THANK ASMS FOR LETTING MOOY

1101
00:41:06,463 --> 00:41:08,098
COME OUT HERE AND PAYING THE

1102
00:41:08,098 --> 00:41:08,966
WAY. 

1103
00:41:08,966 --> 00:41:12,903
THANK YOU ASMS. 

1104
00:41:12,903 --> 00:41:21,678
APPRECIATE IT.

1105
00:41:21,678 --> 00:41:24,581
YEAH. 

1106
00:41:24,581 --> 00:41:25,015
>> THAT WAS GREAT.

1107
00:41:25,015 --> 00:41:27,818
OKAY, SO I HAVE A FEW QUESTIONS,

1108
00:41:27,818 --> 00:41:32,289
ACTUALLY, FIRST OF ALL -- SO THE

1109
00:41:32,289 --> 00:41:36,460
CELL LINES AND THE DRUGS AND

1110
00:41:36,460 --> 00:41:38,929
SEEING THINGS AND SEEING THINGS

1111
00:41:38,929 --> 00:41:40,097
THAT CHANGE DIFFERENTLY THAT'S A

1112
00:41:40,097 --> 00:41:41,598
VERY NICE DATA SET, I WONDER

1113
00:41:41,598 --> 00:41:43,967
FIRST OF ALL IF YOU INCREASE THE

1114
00:41:43,967 --> 00:41:46,136
AMOUNT OF THESE DRUGS, WHAT

1115
00:41:46,136 --> 00:41:48,872
WOULD BE THE EFFECT ON THE

1116
00:41:48,872 --> 00:41:49,973
DIFFERENCES BETWEEN DRUGS AND

1117
00:41:49,973 --> 00:41:52,242
BETWEEN -- I MEAN IF YOU REALLY

1118
00:41:52,242 --> 00:41:54,244
SLAMMED THE CELLS, WOULD THEY

1119
00:41:54,244 --> 00:41:55,579
SORT OF LINE UP WHAT COULD SOME

1120
00:41:55,579 --> 00:41:57,814
OF THE DIFFERENCES HAVE BEEN

1121
00:41:57,814 --> 00:42:00,350
BECAUSE SOME OF THE, YOU KNOW

1122
00:42:00,350 --> 00:42:05,255
PROTEINS WERE MAYBE PARTIALLY

1123
00:42:05,255 --> 00:42:05,522
INHIBITED.

1124
00:42:05,522 --> 00:42:07,257
>> YEAH, SO IT'S A FUN
QUESTION

1125
00:42:07,257 --> 00:42:09,259
AND HONESTLY THE REVIEW CRITIQUE

1126
00:42:09,259 --> 00:42:10,661
WE GET IS THE OPPOSITE BECAUSE

1127
00:42:10,661 --> 00:42:13,030
WE HIT THEM HARD, SO IT'S LIKE

1128
00:42:13,030 --> 00:42:14,765
10 MICROMOLAR FOR 24 HOURS.

1129
00:42:14,765 --> 00:42:18,435
IF WE HIT THEM MUCH HARDER

1130
00:42:18,435 --> 00:42:21,204
THEY'RE BASICALLY ALL DEAD.

1131
00:42:21,204 --> 00:42:23,707
SO WE'RE TRYING TO HIT THEM AS

1132
00:42:23,707 --> 00:42:26,810
HARD AS WE CAN TO SEE IF WE CAN

1133
00:42:26,810 --> 00:42:28,745
INDUCE A SIMILAR RESPONSE AND

1134
00:42:28,745 --> 00:42:28,979
DON'T.

1135
00:42:28,979 --> 00:42:30,447
AND THERE'S MORE SUBTLE RESPONSE

1136
00:42:30,447 --> 00:42:33,350
FIST YOU TUNE DOWN LIKE A

1137
00:42:33,350 --> 00:42:35,485
HUNDRED NANO MOLAR, WHAT THE

1138
00:42:35,485 --> 00:42:37,354
RESPONSE IS OR PARTIAL RESPONSE

1139
00:42:37,354 --> 00:42:37,587
TO IT.

1140
00:42:37,587 --> 00:42:38,388
>> SO YOU TOUCH OFFICE OF

1141
00:42:38,388 --> 00:42:40,157
DIVERSITY THIS, BUT I WONDER --

1142
00:42:40,157 --> 00:42:42,626
SO YOU KNOW YOU SEE CHANGES, YOU

1143
00:42:42,626 --> 00:42:43,827
SEE SOME PROTEINS DO THIS AND

1144
00:42:43,827 --> 00:42:46,863
SOME CELLS, DO THIS, BUT MAYBE

1145
00:42:46,863 --> 00:42:49,199
THESE PROTEINS ARE A LITTLE

1146
00:42:49,199 --> 00:42:51,234
DEFINITE BETWEEN CELLS AND DRUGS

1147
00:42:51,234 --> 00:42:52,102
BUT SOMETIMES RELATED DRUGS AND

1148
00:42:52,102 --> 00:42:54,738
I WONDER IF THEY HAD SIMILAR

1149
00:42:54,738 --> 00:42:56,807
GENIAN OITATIONS LIKE SIMILAR

1150
00:42:56,807 --> 00:42:58,909
DOMAINS OR THEY'RE BOTH PART OF

1151
00:42:58,909 --> 00:43:00,510
THE SAME BIOLOGICAL PATHWAYS AND

1152
00:43:00,510 --> 00:43:02,112
YOU WOULD SEE OVERLAP THERE,

1153
00:43:02,112 --> 00:43:04,715
HAVE YOU DONE LIKE GENE

1154
00:43:04,715 --> 00:43:06,717
ANNOTATION AND THEN, LOOKEDDA

1155
00:43:06,717 --> 00:43:07,751
THE IT THAT WAY?

1156
00:43:07,751 --> 00:43:08,952
>> YEAH, SOPHISTICATEDY WE

1157
00:43:08,952 --> 00:43:12,422
GENERALLY DO -- LIKE GO GSCA, TO

1158
00:43:12,422 --> 00:43:13,757
SEE WHAT THE GENERAL THE

1159
00:43:13,757 --> 00:43:16,293
PROFILES ARE, I THINK WE CAN GET

1160
00:43:16,293 --> 00:43:16,994
SOME, ADDITIONAL INFORMATION, I

1161
00:43:16,994 --> 00:43:18,929
GUESS, 1 THING THAT I'M REALLY

1162
00:43:18,929 --> 00:43:20,464
CURIOUS ABOUT MOVING FORWARD IS

1163
00:43:20,464 --> 00:43:22,366
WE'VE DONE LIMITED AMOUNTS OF

1164
00:43:22,366 --> 00:43:25,035
DOMAIN COMPARISONS TO UNDERSTAND

1165
00:43:25,035 --> 00:43:26,770
BINARY ASPECTINGS OF THE

1166
00:43:26,770 --> 00:43:29,606
INTERACTION, AND THERE'S ALSO 1

1167
00:43:29,606 --> 00:43:31,341
THAT WE GOT TUNED INTO FOR A

1168
00:43:31,341 --> 00:43:33,677
RECENT MEETING AND JUST TRY TO

1169
00:43:33,677 --> 00:43:34,745
THINK OF ESPECIALLY WORKING DOWN

1170
00:43:34,745 --> 00:43:36,580
THE HALL FROM MIKE IS THINKING

1171
00:43:36,580 --> 00:43:38,315
ABOUT HOW ISOFORMS ARE

1172
00:43:38,315 --> 00:43:39,549
DIFFERENT, PROTEIN COMPLEXIO

1173
00:43:39,549 --> 00:43:40,784
FORM VARIANTS AND THESE MIGHT BE

1174
00:43:40,784 --> 00:43:42,452
AFFECTING AND TUNING RESPONSES

1175
00:43:42,452 --> 00:43:45,689
SO PARTICULARLY FOR THE BRD FOR

1176
00:43:45,689 --> 00:43:47,357
EXAMPLE, IT HAS 2 ISOFORMS THAT

1177
00:43:47,357 --> 00:43:48,859
ARE KNOWN TO CAUSE DIFFERENT

1178
00:43:48,859 --> 00:43:52,696
EFFECTS AND YOU CAN INHIBIT THEM

1179
00:43:52,696 --> 00:43:53,196
POTENTIALLY SLIGHTLY

1180
00:43:53,196 --> 00:43:53,497
DIFFERENTLY.

1181
00:43:53,497 --> 00:43:56,333
SO THERE MIGHT BE DOMAIN AND

1182
00:43:56,333 --> 00:43:58,368
ISOFORM SPECIFIC EFFECTS THAT

1183
00:43:58,368 --> 00:44:03,173
UNDERLIE EVEN THE GENOME

1184
00:44:03,173 --> 00:44:03,473
ANNOTATIONS.

1185
00:44:03,473 --> 00:44:05,409
>> AND FINALLY, I KNOW YOU
DID

1186
00:44:05,409 --> 00:44:07,878
LIKE CELL TO CELL LINE

1187
00:44:07,878 --> 00:44:09,079
DIFFERENCES BUT I WONDER,

1188
00:44:09,079 --> 00:44:10,480
ESPECIALLY IF YOU DID PRIMARY

1189
00:44:10,480 --> 00:44:12,983
CELLS OF SOME SORT, IF YOU ARE

1190
00:44:12,983 --> 00:44:15,085
THINKING ABOUT SINGLE CELL

1191
00:44:15,085 --> 00:44:15,385
PROTEOMICS.

1192
00:44:15,385 --> 00:44:19,489
>> YEAH, I LOVE IT, SO WE
HAVE

1193
00:44:19,489 --> 00:44:21,691
-- I THINK WE'RE TRYING FOR NOW

1194
00:44:21,691 --> 00:44:23,326
A TWIST ON SINGLE CELL

1195
00:44:23,326 --> 00:44:24,528
PROTEOMICS WHICH IS TRYING TO DO

1196
00:44:24,528 --> 00:44:26,863
THINGS IN TISSUES AND LOOK HOW

1197
00:44:26,863 --> 00:44:27,297
CELL TYPES RESPOND.

1198
00:44:27,297 --> 00:44:29,232
AND SEE IF THAT'S CONSISTENT

1199
00:44:29,232 --> 00:44:36,006
ESPECIALLY IN THE CONTEXT OF

1200
00:44:36,006 --> 00:44:39,409
TISSUES OR ORGANOIDS, THE SINGLE

1201
00:44:39,409 --> 00:44:40,544
CELL ANGLE IS CHALLENGING I

1202
00:44:40,544 --> 00:44:41,912
THINK AS WE ALL KNOW, SO I THINK

1203
00:44:41,912 --> 00:44:43,580
IT WOULD BE AWESOME TO DO, MY

1204
00:44:43,580 --> 00:44:46,083
WORRY IS THAT WE HAVE ENOUGH

1205
00:44:46,083 --> 00:44:50,387
CELLS SO IF WE LOOK AT 1 PCA

1206
00:44:50,387 --> 00:44:55,358
PLOT FROM THAT SHOWED SINGLE

1207
00:44:55,358 --> 00:44:56,993
CELL TRANSCRIPTOMIC RESPONSES TO

1208
00:44:56,993 --> 00:45:02,132
HDAC INHIBITION WHICH SHOULD

1209
00:45:02,132 --> 00:45:04,101
MASSIVELY REMODEL THE TRANSCRIPT

1210
00:45:04,101 --> 00:45:06,536
ORDER OF MICRONS AND THEY STILL

1211
00:45:06,536 --> 00:45:08,505
SEE RESPONSES OF POCKETS CELLS

1212
00:45:08,505 --> 00:45:10,040
AND A LARGE NUMBER OF CELLS SO

1213
00:45:10,040 --> 00:45:11,775
MY WORRY WOULD BE WE HAVE TO DO

1214
00:45:11,775 --> 00:45:13,243
SUCH A DEEP DIVE IN SINGLE CELL

1215
00:45:13,243 --> 00:45:15,512
LAND TO BE ABLE TO TEASE THAT

1216
00:45:15,512 --> 00:45:19,483
OUT THAT THEY WOULD LIKE LIKE

1217
00:45:19,483 --> 00:45:20,083
COMPETING WITH PARALENS LENS

1218
00:45:20,083 --> 00:45:22,285
LENS LENS TO GET TO 19 OR 50,000

1219
00:45:22,285 --> 00:45:23,854
CELLS AND WE DON'T HAVE AS MUCH

1220
00:45:23,854 --> 00:45:34,164
MONEY AS THEY DO.

1221
00:45:36,366 --> 00:45:38,168
>> SO YOU'RE LOOKING FOR
MANY OF

1222
00:45:38,168 --> 00:45:39,603
THE SIMILAR CHANGES THAT OCCUR

1223
00:45:39,603 --> 00:45:41,805
AND SOME DISCORD ON CHANGES, I

1224
00:45:41,805 --> 00:45:43,306
WOULD BE INTERESTED TO SEE IF

1225
00:45:43,306 --> 00:45:45,642
YOU SAW 2 DRUGS THAT MAY BE HAD

1226
00:45:45,642 --> 00:45:47,344
A SIMILAR CHANGE ON SOMEONE

1227
00:45:47,344 --> 00:45:49,312
WOULD SAY EXPECTED TARGET BUT

1228
00:45:49,312 --> 00:45:50,814
DISCORDANT CHANGES ON OFF TARGET

1229
00:45:50,814 --> 00:45:51,848
EFFECTS AND POTENTIALLY IF YOU

1230
00:45:51,848 --> 00:45:54,151
WERE TO TREAT WITH BOTH DRUGS

1231
00:45:54,151 --> 00:45:55,752
MAYBE THOSE OFF AGER AT THE TIME

1232
00:45:55,752 --> 00:45:57,020
EFFECTS WOULD CANCEL OUT IN THIS

1233
00:45:57,020 --> 00:45:58,622
WAY, I DON'T KNOW IF THAT'S AN

1234
00:45:58,622 --> 00:45:59,923
ANGLE YOU LOOKED FOR BUT IT'S

1235
00:45:59,923 --> 00:46:02,259
SORT OF LIKE LOOKING ON THE

1236
00:46:02,259 --> 00:46:03,860
PERIPHERY OF THINGS THAT MIGHT

1237
00:46:03,860 --> 00:46:05,662
HELP LET'S SAY CERTAIN DRUGS

1238
00:46:05,662 --> 00:46:05,996
WORK TOGETHER.

1239
00:46:05,996 --> 00:46:10,100
>> YEAH, I MEAN THE IDEA
OF

1240
00:46:10,100 --> 00:46:12,536
DOING KIND OF THESE MULTIDRUG

1241
00:46:12,536 --> 00:46:14,037
TREATMENTS COCKTAIL TREATMENTS,

1242
00:46:14,037 --> 00:46:15,705
THAT'S SUPER APPEALING,

1243
00:46:15,705 --> 00:46:17,407
HONESTLY, MITIGATE THE EFFECTS,

1244
00:46:17,407 --> 00:46:20,544
NEGATIVE EFFECTS OF 1 BY HAVING

1245
00:46:20,544 --> 00:46:22,112
ANOTHER, SO I WILL GET CLOSE TO

1246
00:46:22,112 --> 00:46:25,015
THAT IDEA, I MEAN, LET ME KNOW

1247
00:46:25,015 --> 00:46:26,816
IF IT ANSWERS, ESSENTIALLY,

1248
00:46:26,816 --> 00:46:28,818
THERE'S A EFFECT THAT CHELSEA

1249
00:46:28,818 --> 00:46:34,824
SAW IN HER INITIAL DATA ON THE

1250
00:46:34,824 --> 00:46:36,259
APOPTOTIC PROTEIN, BUT DIDN'T

1251
00:46:36,259 --> 00:46:38,161
SHOW YOU THE PROTEOMICS DATA

1252
00:46:38,161 --> 00:46:39,863
THAT WENT ALONG WITH DATA BUT

1253
00:46:39,863 --> 00:46:41,865
THERE ARE CELL TYPE SPECIFIC

1254
00:46:41,865 --> 00:46:43,934
CHANGES AND BAD PHOSPHORYLATION

1255
00:46:43,934 --> 00:46:45,835
WHICH SEEMS TO PARTIALLY

1256
00:46:45,835 --> 00:46:46,770
CORRELATE OR POTENTIALLY BE

1257
00:46:46,770 --> 00:46:50,106
RELATED TO THE VIABILITY THAT

1258
00:46:50,106 --> 00:46:52,442
YOU SEE, BUT WE'RE TREATING

1259
00:46:52,442 --> 00:46:55,478
HISTONE DE, SET LACE INHIBITOR

1260
00:46:55,478 --> 00:46:55,912
THAT'S CLEARLY NOT

1261
00:46:55,912 --> 00:46:57,781
PHOSPHORYLATING BAD, AND IF

1262
00:46:57,781 --> 00:47:00,550
THAT'S LEADING THESE CELLS

1263
00:47:00,550 --> 00:47:02,686
SURVIVE, HDAC INHIBITION BECAUSE

1264
00:47:02,686 --> 00:47:04,754
IT'S BAD, WE TREAT WITH

1265
00:47:04,754 --> 00:47:06,122
SOMETHING THAT'S INCONSISTENTLY

1266
00:47:06,122 --> 00:47:08,024
EXPRESSED THERE, AND SO, THE

1267
00:47:08,024 --> 00:47:10,060
IDEA IS ESSENTIALLY WE FOUND A

1268
00:47:10,060 --> 00:47:12,562
MOTIF, IT'S A BASIC MOTIF AND

1269
00:47:12,562 --> 00:47:14,097
THERE'S 2 MANY BASED ON THE

1270
00:47:14,097 --> 00:47:15,599
KINASES BUT THERE'S ENOUGH THAT

1271
00:47:15,599 --> 00:47:20,270
WE HAVE PRETTY DESCENT SMALL

1272
00:47:20,270 --> 00:47:21,004
MOLECULE INHIBITORS FOR AKT, AND

1273
00:47:21,004 --> 00:47:23,039
SO THE IDEA IS ESSENTIALLY, CAN

1274
00:47:23,039 --> 00:47:25,976
WE CHANGE THE VIABILITY OR

1275
00:47:25,976 --> 00:47:27,777
CHANGE THE SENSITIVITY, TO HDAC

1276
00:47:27,777 --> 00:47:31,081
ININCREASE IN BODY HIGZ BY

1277
00:47:31,081 --> 00:47:32,849
PROHIBITING THESE GENERAL

1278
00:47:32,849 --> 00:47:34,050
MITOTIC SIGNALS WHICH WOULD BE

1279
00:47:34,050 --> 00:47:36,353
REALLY FUN, WE CAN PROVE THAT

1280
00:47:36,353 --> 00:47:37,621
AFTER IT HAPPENS.

1281
00:47:37,621 --> 00:47:39,155
>> AND MY SECOND QUESTION
IS

1282
00:47:39,155 --> 00:47:40,390
ABOUT YOUR CORRELATION NETWORK,

1283
00:47:40,390 --> 00:47:42,859
SO HOW DO YOU -- HOW DO YOU DO

1284
00:47:42,859 --> 00:47:44,361
LIKE QUALITY CONTROL TO ASSIST

1285
00:47:44,361 --> 00:47:46,663
OR ASSESS WHETHER OR NOT THESE

1286
00:47:46,663 --> 00:47:47,931
CORRELATION EDGES ARE ROBUST

1287
00:47:47,931 --> 00:47:50,433
ENOUGH. 

1288
00:47:50,433 --> 00:47:52,369
>> YEAH, SO THERE'S -- I
DON'T

1289
00:47:52,369 --> 00:47:53,803
HAVE IT FOR THE SMALL MOLECULE,

1290
00:47:53,803 --> 00:47:58,074
I JUST DIDN'T PUT IT IN THERE,

1291
00:47:58,074 --> 00:48:00,677
BUT WE DO THESE PERMIAITATION

1292
00:48:00,677 --> 00:48:03,113
TESTS TO MAKE SURE -- SO HERE'S

1293
00:48:03,113 --> 00:48:05,849
AN EXAMPLE FOR THIS ORGANOID

1294
00:48:05,849 --> 00:48:07,617
BASED STUDY SO WE CAN   PERMUTE

1295
00:48:07,617 --> 00:48:08,818
ALL POSSIBLE COMBINATIONS AND

1296
00:48:08,818 --> 00:48:10,820
SEE ESSENTIALLY WHAT IS THE

1297
00:48:10,820 --> 00:48:12,789
BACKGROUND CORRELATION, AND SEE

1298
00:48:12,789 --> 00:48:14,991
IF IS WHAT WE'RE SEEING

1299
00:48:14,991 --> 00:48:16,192
SIGNIFICANTLY DIFFERENT FROM

1300
00:48:16,192 --> 00:48:20,630
WHAT'S THERE, WHERE WE KIND OF

1301
00:48:20,630 --> 00:48:28,138
BACK TO ASK DEMONSTRATED AT 0 WE

1302
00:48:28,138 --> 00:48:29,973
GENERALLY DON'T SEE THAT OUTLIER

1303
00:48:29,973 --> 00:48:32,876
AND WE WITH CAN AGAIN TO USE

1304
00:48:32,876 --> 00:48:37,747
THAT AND USE SIMILAR CONCEPTS

1305
00:48:37,747 --> 00:48:40,617
WHICH CAN WITHIN SETS OF DATA,

1306
00:48:40,617 --> 00:48:42,886
GETTING THE IDEA OF ANNOTATIONS

1307
00:48:42,886 --> 00:48:44,821
IF WE ANNOTATE NICELY SO IF WE

1308
00:48:44,821 --> 00:48:47,524
LOOK AT PROTEIN COMPLEXES, SO A

1309
00:48:47,524 --> 00:48:49,159
PROTURBATION LIKE IN THE MAP K

1310
00:48:49,159 --> 00:48:51,461
14 EXAMPLE, WE EXPECTED PROBABLY

1311
00:48:51,461 --> 00:48:54,964
TO EFFECT THINGS IN A COMPLEX

1312
00:48:54,964 --> 00:48:57,133
WITH 814 AND LET SEEEE IF IT'S

1313
00:48:57,133 --> 00:48:58,335
HIGHLY CORRELATED RESPONSE TO

1314
00:48:58,335 --> 00:49:03,840
THAT, AND IT VALIDATE THAT WE

1315
00:49:03,840 --> 00:49:06,042
ALSO APPLY PRETTY STRONG FILTERS

1316
00:49:06,042 --> 00:49:09,045
TO USE TO OFFSET, OR GET AN IDEA

1317
00:49:09,045 --> 00:49:11,114
OF THE SAWLS DISCOVERY RATE FOR

1318
00:49:11,114 --> 00:49:15,085
KIND OF THIS RANDOM PROFILE,

1319
00:49:15,085 --> 00:49:16,052
THAT GENERALLY DOES A PRETTY

1320
00:49:16,052 --> 00:49:26,363
GOOD JOB OF THAT. 

1321
00:49:26,863 --> 00:49:29,132
>> THANK YOU.

1322
00:49:29,132 --> 00:49:30,567
>> SO, YEAH, VERY NICE
TALK.

1323
00:49:30,567 --> 00:49:35,105
SO I WAS WONDERING, WHEN YOU

1324
00:49:35,105 --> 00:49:36,840
TREAT THE CELLS WITH MULTIPLE

1325
00:49:36,840 --> 00:49:41,010
DRUG ANDS IN RESPONSE TO THAT,

1326
00:49:41,010 --> 00:49:44,848
DID YOU LOOK AT LIKE SOME PTMs

1327
00:49:44,848 --> 00:49:45,882
ALONG WITH LIKE PHOSPHORYLATION,

1328
00:49:45,882 --> 00:49:51,654
AND DID YOU TRY TO QUANTIFY?

1329
00:49:51,654 --> 00:49:53,323
>> SO THE ONLY AISLE GIVE
YOU

1330
00:49:53,323 --> 00:49:55,225
THE TECHNICAL ANSWER AFTER THAT,

1331
00:49:55,225 --> 00:50:00,497
NOT GENERALLY, SO WE DIDN'T DO

1332
00:50:00,497 --> 00:50:02,532
GENERAL ACETYL PROFILING, BUT

1333
00:50:02,532 --> 00:50:05,068
THE 1 CAVEAT TO THAT IS WE LOOK

1334
00:50:05,068 --> 00:50:07,537
FOR HISTONE METHYLATION

1335
00:50:07,537 --> 00:50:09,005
ACETYLATION TO TRY TO VERIFY IF

1336
00:50:09,005 --> 00:50:12,409
THE EFFECTS WE WERE SEEING WERE

1337
00:50:12,409 --> 00:50:13,443
DIRECTLY AFFECTING HISTONE

1338
00:50:13,443 --> 00:50:17,046
MODIFICATIONS, AND WE SAW A

1339
00:50:17,046 --> 00:50:18,481
GENERALLY DEACETYLASE INHIBITOR,

1340
00:50:18,481 --> 00:50:19,649
THE METHYLATION GOES ON AND

1341
00:50:19,649 --> 00:50:25,755
DOWN, AND EXPECT TO BE BUFFERED.

1342
00:50:25,755 --> 00:50:26,156
>> THANK YOU.

1343
00:50:26,156 --> 00:50:32,996
>> I HAVE A COUPLE OF
SMALL

1344
00:50:32,996 --> 00:50:33,463
QUESTIONS.

1345
00:50:33,463 --> 00:50:36,633
ONE IS YOU USE IN YOUR PANEL OF

1346
00:50:36,633 --> 00:50:38,435
DIFFERENT CELLS YOU USE ONLY

1347
00:50:38,435 --> 00:50:41,571
CELL LINES NO PRIMARY CELLS, NO?

1348
00:50:41,571 --> 00:50:43,373
>> NO PRIMARY CELLS YET.

1349
00:50:43,373 --> 00:50:45,675
>> YEAH BECAUSE IT WOULD
BE NICE

1350
00:50:45,675 --> 00:50:47,444
TO HAVE PRIMARY CELLS FROM THIS

1351
00:50:47,444 --> 00:50:49,312
TYPE OF LINEAGE, THIS IS WHAT IS

1352
00:50:49,312 --> 00:50:50,580
MOST RELEVANT, RIGHT, AND THE

1353
00:50:50,580 --> 00:50:53,783
SAME TYPE OF RELEVANCE, QUESTION

1354
00:50:53,783 --> 00:50:58,588
IS ABOUT YOUR COMPAREISON OF

1355
00:50:58,588 --> 00:51:00,924
LISATE, OFF OF CELLS SO TREATING

1356
00:51:00,924 --> 00:51:03,760
LISATE WITH A DRUG IS KIND OF

1357
00:51:03,760 --> 00:51:08,998
INTERESTING BUT THE CELLS ARE

1358
00:51:08,998 --> 00:51:11,267
WHAT IS REAL EXISTING

1359
00:51:11,267 --> 00:51:13,069
ORGANELLES, SO, YEAH, JUST MAYBE

1360
00:51:13,069 --> 00:51:14,671
MORE COMMENT THAN QUESTION.

1361
00:51:14,671 --> 00:51:16,339
, YEAH, YEAH, I GUESS YOUR FIRST

1362
00:51:16,339 --> 00:51:18,808
POINT IS THAT OUR GOAL IS WE

1363
00:51:18,808 --> 00:51:20,176
WOULD LOVE TO DO PRIMARY CELLS

1364
00:51:20,176 --> 00:51:23,079
BUT 1 THING WE REALLY LOVE TO DO

1365
00:51:23,079 --> 00:51:25,715
IS LOOK ACROSS KIND OF

1366
00:51:25,715 --> 00:51:26,483
DEVELOPMENTAL TRAJECTORIES SO

1367
00:51:26,483 --> 00:51:28,284
CELLS WITH VERY DIFFERENT

1368
00:51:28,284 --> 00:51:29,219
CELLITATES TO TRY TO UNDERSTAND

1369
00:51:29,219 --> 00:51:30,787
THE EFFECT THERE AND THEN

1370
00:51:30,787 --> 00:51:31,754
OBVIOUSLY IT WOULD BE REALLY FUN

1371
00:51:31,754 --> 00:51:38,127
TO BE ABLE TO DO THAT, IN

1372
00:51:38,127 --> 00:51:38,695
TESTING.

1373
00:51:38,695 --> 00:51:39,329
>> YEAH, ORGANIZATIONS
CANCER

1374
00:51:39,329 --> 00:51:42,799
CENTERIE, SO KEEP A STEP GOING

1375
00:51:42,799 --> 00:51:43,700
OVER PRIMARY CELLS.

1376
00:51:43,700 --> 00:51:46,236
>> FOR FOR THE CELL FIRST

1377
00:51:46,236 --> 00:51:47,203
LYSATE, YEAH, WE STARTED OFF

1378
00:51:47,203 --> 00:51:49,305
WITH THE IDEA THAT THE LISATE

1379
00:51:49,305 --> 00:51:52,208
WOULD BE GREAT BECAUSE YOU WILL

1380
00:51:52,208 --> 00:51:55,311
GET LIKE REALLY SPECIFIC

1381
00:51:55,311 --> 00:51:56,746
INTERACTIONS, RIGHT, AH, GET RID

1382
00:51:56,746 --> 00:51:58,448
OF THE MILIEU, ALL THE STUFF

1383
00:51:58,448 --> 00:52:00,183
THAT MIGHT INTERFERE WITH

1384
00:52:00,183 --> 00:52:02,151
INTERACTIONS, JUST LOOK FOR HARD

1385
00:52:02,151 --> 00:52:03,086
CORE BIOCHEMICAL INTERACTIONS

1386
00:52:03,086 --> 00:52:04,954
AND LIKE CONTROLLED BUFFERS, WE

1387
00:52:04,954 --> 00:52:08,925
WILL GET IT OUT, AND FOR SOME OF

1388
00:52:08,925 --> 00:52:09,526
THEM, WORKED BRILLIANTLY, AND

1389
00:52:09,526 --> 00:52:11,928
THEN FOR A LOT OF THEM,

1390
00:52:11,928 --> 00:52:13,129
ESPECIALLY EPIGENETIC RELATED

1391
00:52:13,129 --> 00:52:14,063
PROTEINS WHICH WE'RE MOST

1392
00:52:14,063 --> 00:52:17,600
INTERESTED FOR LIKE THE HDAC,

1393
00:52:17,600 --> 00:52:18,835
STUFF, WE NEEDED CELLULAR

1394
00:52:18,835 --> 00:52:22,772
CONTACTS AND SO, YEAH, WE FOUND

1395
00:52:22,772 --> 00:52:24,007
THAT THEY WERE MORE

1396
00:52:24,007 --> 00:52:25,241
COMPLIMENTARY I THINK THAN WE

1397
00:52:25,241 --> 00:52:31,915
WOULD HAVE EXPECTED TO BEGIN

1398
00:52:31,915 --> 00:52:32,215
WITH.

1399
00:52:32,215 --> 00:52:34,050
>> SO FOLLOWING UP ON
THAT, SO

1400
00:52:34,050 --> 00:52:35,852
DID YOU THINK OF GOING THE OTHER

1401
00:52:35,852 --> 00:52:38,888
DIRECTION AND DO A SUBCELLULAR

1402
00:52:38,888 --> 00:52:41,791
FRACTIONATION AND LOOK AT

1403
00:52:41,791 --> 00:52:42,425
DEFINITE SUBCELLULAR COMPONENTS

1404
00:52:42,425 --> 00:52:44,694
TO SEE WHERE THE CHANGES ARE

1405
00:52:44,694 --> 00:52:47,664
COMING FROM, SO WE DIDN'T DO IT

1406
00:52:47,664 --> 00:52:50,500
FOR THE DRUGS BUT FOR THE

1407
00:52:50,500 --> 00:52:54,604
CALCIUM BINDING, THE LAB

1408
00:52:54,604 --> 00:52:56,005
SPECIFICALLY IS INTERESTED

1409
00:52:56,005 --> 00:52:56,906
MITOCHONDRIA RELATIONSHIP TO

1410
00:52:56,906 --> 00:52:58,675
CALCIUM SIGNALING SO WE DID IT

1411
00:52:58,675 --> 00:53:01,110
IN THAT CASE AND IT WORKED

1412
00:53:01,110 --> 00:53:03,646
REMARKABLY WELL, SO THAT WAS IN

1413
00:53:03,646 --> 00:53:05,882
WHOLE LIVE RESPIRING

1414
00:53:05,882 --> 00:53:07,183
MITOCHONDRIA, ISOLATED FROM MICE

1415
00:53:07,183 --> 00:53:10,320
AND YOU CAN STILL DO PSET MAP

1416
00:53:10,320 --> 00:53:12,589
AND GET THERMAL STABILITY

1417
00:53:12,589 --> 00:53:13,423
MEASUREMENTS SO THE THING I

1418
00:53:13,423 --> 00:53:15,792
WOULD LOVE TO DO WHICH I AM

1419
00:53:15,792 --> 00:53:17,193
TRYING TO CONVINCE THE GRADUATE

1420
00:53:17,193 --> 00:53:20,263
STUDENTS TO DO THIS IS TAKE

1421
00:53:20,263 --> 00:53:23,232
THIS, AND TAKE SUBCELLULAR

1422
00:53:23,232 --> 00:53:25,602
ENVIRONMENTS AND SEE IF THERE'S

1423
00:53:25,602 --> 00:53:26,369
CROSSES BETWEEN THEM.

1424
00:53:26,369 --> 00:53:28,204
>> ALL RIGHT, IF THAT'S
ALL THE

1425
00:53:28,204 --> 00:53:31,107
QUESTIONS, THANKS AGAIN, THIS

1426
00:53:31,107 --> 00:53:34,944
WAS A FANTASTIC TALK.

1427
00:53:34,944 --> 00:53:45,221
>> THANK YOU.