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Mitochondria as Signaling Hubs
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0:06
MY NAME IS MICHAEL GRAHAM ESPEY PROGRAM DIRECTOR NCI DIVISION OF CANCER BIOLOGY. IT'S A PLEASURE TO INTRODUCE WALS LECTURE SPEAKER NAVDEEP CHANDEL. NAV HIS FRIENDS CALL HIM HE RECEIVED HIS Ph.D. AND POST DOCTORAL TRAINING AT UNIVERSITY OF CHICAGO IN CELLULAR PHYSIOLOGY, WITH PAUL SHOEMAKER AND CRAIG THOMPSON. HE'S CURRENTLY THE DAVID DISTINGUISHED PROFESSOR OF MEDICINE AT NORTHWESTERN UNIVERSITY AND IS NCI OUTSTANDING INVESTIGATOR AWARDEE. NAV BEGAN STUDIES ON MOLECULAR
0:45
CELLULAR BASIS OF OXYGEN SENSING WHICH NATURALLY LED HIS CURIOSITY TO AN EVER DEEPENING UNDERSTANDING OF MITOCHONDRIAL METABOLISM IN DIVERSE CELL TYPES. BEGINNING MOST 20 YEARS AGO TO THE PRESENT DAY, NAV DEVELOPED THE CONCEPT OF MITOCHONDRIA SERVING BEYOND THE MORE TRADITIONAL VIEWPOINT OF BIOSYNTHETIC AND BIOENERGETIC ORGANELLES TO INCLUDE A THIRD DISTINCT ROLE AS SIGNALING HUBS WHEREBY PHYSIOLOGIC RELEASE OF REACTIVE OXYGEN SPECIES AND METABOLITES REGULATE TRANSCRIPTION FACTORS
1:22
EPIGENETICS AND TO CONTROL DIVERSE CELLULAR FUNCTIONS. HIS RECENT WORK FOCUSED ON THE SENSUALITY OF MITOCHONDRIA METABOLIC AND RA S AGONALLING TO CONTROL STEM CELL -- INVOLVING CONTROL OF CANCER CELL PHENOTYPE AND ADAPTIVE IMMUNITY AS YOU WILL SEE IN THE PRESENTATION TODAY. IN ADDITION TO BEING A CHAMPION OF BASIC SCIENCE, NAV RECENTLY LEVERAGED HIS TRANSDISCIPLINARY UNDERSTANDING OF THE MITOCHONDRIA TOWARDS A MORE TRANSLATIONAL REPURPOSING OF THE ANTI-DIABETES DRUG METAPHORMAN
1:57
AS POTENTIAL CANCER THERAPEUTIC SO WITHOUT FURTHER ADIEU I WOULD LIKE TO INVITE OUR FRIEND NAV CHANDEL UP TO GIVE TODAY'S WALS LECTURE. [APPLAUSE] THANKS AGAIN, MICHAEL AND THE FOLKS AT THE NCI AS WELL AS THE NIH HERE FOR THIS REAL HONOR TO GIVE A WALS LECTURE. AS YOU CAN SEE FROM MY TITLE, IT'S -- GOING TO TALK MITOCHONDRIA AND HOW WE THINK ARE ESSENTIAL PLAYERS IN NORMAL PHYSIOLOGY AND CONTROL OF HOMEOSTASIS AS WELL AS HOW MITOCHONDRIA CAN BE CO-OPTED IN DIFFERENT PATHOLOGIES.
2:41
MUCH WHAT I'M GOING TO TALK TO YOU ABOUT IS THE TITLE SAYS BEYOND ATP. HOPEFULLY YOU'LL SEE WHY I THINK THAT. THE MOST IMPORTANT SLIDE IS THIS ONE BECAUSE THE WORK THAT I'M GOING TO PRESENT IS AN UNPUBLISHED STORY FROM SAM WINEBERG, AN M.D. Ph.D. STUDENT IN MY LABORATORY AND HE'S HELPED BY TWO OTHERS IN THE LABORATORY ELIZABETH STANDARD AND -- WE TALKED PREVIOUS DATA FROM GREAT COLLABORATOR IT IS OVER THE YEARS AND CURRENT AS WELL BEN SINGER PAUL SHOEMAKER AND CARLOS MARTINEZ WHO IS
3:22
HELPING US DO SOME OF OUR RNA SEQUENCING AND LARRY TURKA WHO IS WELL KNOWN FOR HIS WORK IN T-CELLS HAS BEEN GIVING US FRIENDLY ADVICE AND TUTORING ABOUT T-CELL BIOLOGY. SO WE HAVE A VERY SIMPLE QUESTION IN THE HAS BEENTORY. WHICH IS WHY ANY -- LABORATORY WHICH IS WHY ANY MAMMALIAN ASPIRES. S. IT'S ALMOST AN OBVIOUS QUESTION, YOU HAVE A MITOCHONDRIA, IT USES OXYGEN, GENERATES ARCTP AND YOU ASSUME THAT'S THE ONLY REASON WHY WE HAVE MITOCHONDRIA. HERE ARE CELLS WHICH ARE FOUND IN THE GENERAL TUMOR
4:00
MICROENVIRONMENT THAT WE'RE INTERESTED IN. WE STARTED MUCH OF OUR WORK IN TUMOR CELLS, BUT IT OCCURRED TO US THAT THE TUMORS HAVE T-CELLS AROUND MACROPHAGES ENDOTHELIAL CELLS, AND THEN ALSO WE STARTED TO THINK WHAT ABOUT OTHER PROLIFERATING CELLS, THE STEM CELLS. WHAT IS THE METABOLISM OF NORMAL CELLS. THIS IS SORT OF A QUESTION THAT WE HAVE BEEN INTERESTED IN. JUST TO GET YOU ALL CAUGHT UP ON THE SIMPLE BIOCHEMISTRY OF MITOCHONDRIA, AS MANY OF YOU KNOW THERE'S RESPIRATORY CHAIN,
4:32
THE RESPIRATORY CHAIN ELECTRONS TO MOLECULAR OXYGEN, THIS IS COUPLED TO A PROTON MOTOR FORCE WHICH GENERATES ARCTP. EVERYBODY IS COMFORTABLE WITH THIS IDEA, IT'S TRUE, IT STILL HOLDS TRUE, LOTS OF CELLS DO THIS. THE SECOND THING WHICH WAS ACTUALLY THE ORIGINAL FUNCTION OF MITOCHONDRIA, WELL BEFORE OXIDATIVE PHOSPHORYLATION, WAS WORKED OUT, IS THAT THE TCA CYCLE METABOLITES, AND THE TCA CYCLE IS COUPLED TO THE RESPIRATORY CHAIN BECAUSE THE TCA CYCLE USES NAD AND FAD AND
5:05
BECOME FADH AND NADH AND THE ELECTRON TRANSPORT RESPIRATORY CHAIN WILL MAKE IT BACK THE NAD TO KEEP THE CYCLE GOING. THESE METABOLITES ARE THE TCA CYCLE ARE IMPORTANTTOR MACRO MOLECULE SYNTHESIS. IF YOU GO BACK TO GREAT BIOCHEMISTRY BOOKS LIKE LENINGER AND OTHER BOOKS FOLLOW THE CARBONS, HOW DO YOU GET TO A NUCLEOTIDE, HOW YOU GET THE A LIPID, HOW GET TO PROTEINS, AMINO ACIDS MUCH BACKBONES COME IN PART FROM THE CYCLE. HISTORICALLY THESE ARE THE TWO FUNCTIONS THAT HAVE BEEN
5:38
ASCRIBED TO MITOCHONDRIA, THERE TO PROVIDE YOU ENERGY, AND TO GIVE YOU METABOLITES FOR GROWTH. HOWEVER, WE ARGUED THERE'S A THIRD FUNCTION, IT SEEMS OBVIOUS TODAY BUT WHEN WE FIRST THOUGHT ABOUT THIS MORE THAN 20 YEARS AGO WE HAD A LITTLE BIT OF A PUSH BACK, AND THE REASON WAS THE WAY MANY OF US WERE TAUGHT BIOLOGY AND WHERE MITOCHONDRIA SITS WITHIN A CELL IS THE FOLLOWING. IF YOU HAVE A PHYSIOLOGIC SIGNAL, IF FOR EXAMPLE A T-CELL RESPONDS TO ANTIGEN OR GROWTH FACTORS THERE'S TO PROLIFERATE
6:11
OR CELLULAR DIFFERENTIATION, ANY PHYSIOLOGICAL PROCESSES AT THE CELLULAR MOLECULAR LEVEL, WE'RE HARD WIRED TO THINK THOSE SIGNALS ARE INTEGRATED BUSYINGNAL TRANSDUCTION MECHANISMS, FUNNELING TO G TRANSCRIPTIONAL NETWORKS AS WELL AS REMODELING THE CHROMATIN, THAT CELL WILL DO WHATEVER IT'S SUPPOSED TO DO WHETHER PROLIFERATE DIFFERENTIATE MAKE CYTOKINES, ET CETERA. THAT MODEL, ONCE ALL OF THIS ACTION IS HAPPENING AT THE SIGNALING LEVEL AND THE GENE TRANSCRIPTION CHROMATIN
6:45
REMODELING THEN IT JUST FEEDS BACK TO MITOCHONDRIA AND SAYS I'M GOING TO DOUBLE MYSELF PROLIFERATE OR DIFFERENTIATE OR MAKE THESE CYTOKINES, GIVE ME WHATEVER ENERGY OR BIOSYNTHESIS CAPACITY I NEED. THIS IS ALMOST IN A WAY A PASSIVE PLAYER IN THIS PROCESS JUST RESPONDING TO DOWNSTREAM SIGNALING, GENE EXPRESSION OF CHROMATIN REMODELING. FOR US IT DIDN'T MAKE SENSE BECAUSE THIS WOULD BE LIKE GETTING IN YOUR CAR EVERY MORNING AND NOT KNOWING HOW MUCH FUEL YOU HAVE. SO ONE SIMPLE THING WE THOUGHT
7:20
OF, PERHAPS MITOCHONDRIA NOT SO PASSIVE BUT ACTUALLY PART OF THE ACTIVE DECISION MAKING PROCESS, THAT TO DETERMINE CELL FATE AND CELL FUNCTION. OPPORTUNISTIC WAY OF THINKING ABOUT THIS, IF YOU HAVE THE SIGNALS, YES THEY ACTIVATE MANY SIGNAL TRANSDUCTION PATHWAYS AND TRY TO REMODEL CHROMATIN IN GENES BUT THEY HAVE TO GO THROUGH OBLIGATORY STEP WHICH IS TO ASSESS MITOCHONDRIAL FITNESS. SIGNALS HAVE TO COMMUNICATE FROM THE MITOCHONDRIA ON TO THE NUCLEUS. AND WHAT WOULD THESE SIGNALS BE?
7:53
WE GOT INSPIRED BY TWO FINDINGS, WHEN WE REPORTED THIS PAPER ON HYPOXIA, CONTROL OF THE HIPS, WHICH IS A DOMINANT TRANSCRIPTION FACTOR HYPOXIA WHAT THE SIGNAL COULD BE SO WHEN THE COLLEAGUES FOUND CYTOCHROME C RELEASE, THAT HAPPENED UNDER CELL DEATH WE START TO THINK MITOCHONDRIA MUST BE RELEASING THINGS. THAT SIGNAL WAS A DEATH SIGNAL AND WE THOUGHT MITOCHONDRIA OBVIOUSLY ARE SO SELECTIVE FOR A POSITIVE SIGNAL BENEFICIAL SIGNAL, ONE OBVIOUS WAS REACTIVE OXYGEN SPECIES AND LUCKILY HERE
8:26
FROM KOREA, ONE OF THE PIONEERS WHO PROPOSE THAT EARLY WORK SHOWING REACTIVE OXYGEN SPECIES COULD BE A SIGNALING MOLECULE AND I THINK THAT BIOLOGY CONTINUES TO EXPAND AND OTHER WORKING ON THIS PROPOSE NAD,PH OXIDASE BEING A CRITICAL GENERATOR OF ROS. WE THOUGHT MAYBE THE MITOCHONDRIA COULD BE THAT GENERATOR OF ROS. PEOPLE DIDN'T LIKE THAT IDEA BECAUSE THEIR SIMPLISTIC NOTION MITOCHONDRIA ONLY GENERATED ROS WHEN DAMAGED. THIS EXPLAIN NEURODEGENERATION, MAYBE THIS EXPLAIN HEART FAILURE
9:02
FREE RADICAL THEORY OF AGING AND THIS IDEA THAT MITOCHONDRIA ARE BAD ACTORS. AND SO ONE OF THE THINGS WE CONTINUE TO SHOW OVER THE YEARS WAS THAT'S NOT QUITE TRUE. MANY INSTANCES WE THINK MITOCHONDRIA RELEASE REACTIVE OXYGEN SPECIES UNDER PHYSIOLOGICAL STIMULI TO CONTROL A VARIETY OF IMPORTANT TRANSCRIPTIONAL NODES INCLUDING NOTCH SIGNALING NF KAPPA B. SO THE RESPIRATORY CHAIN ISN'T PERFECT AND ELECTRONS CAN LEAK TO MAKE SUPER OXIDE AND HYDROGEN PEROXIDE TO MAKE MITOCHONDRIAL
9:35
REACTIVE OXYGEN SPECIES RELEASED UNDER VARIETY OF STIMULUSES, TO CONTROL THESE IMPORTANT TRANSCRIPTIONAL NETWORKS. THE OTHER THING, MORE THAN A 15, 20 YEARS AGO WE -- EPIGENETIC AND CHROMATIN FIELDS WERE DISCOVERING ENZYME OVER THE PAST TWO DECADE LIKE HISTONE ACETYLASES THAT CONTROL CHROMATIN REMODELING. ONE THING THAT WAS OBVIOUS TO SOMEONE WHO WORKS ON MITOCHONDRIA, ISN'T IT INTERESTING THEY USE TCA CYCLE METABOLITES TO WORK. WHERE DOES YOUR ACETYL COA COME FROM TO MAKE DEMETHYLASES WORK
10:16
AN THINGS LIKE SUCCINATE ARE POWERFUL INHIBITORS OF THESE DEMETHYLASES. I HAVE QUITE A WONDERFUL COLLEAGUE AT NORTHWESTERN INCLUDING BIOCHEMISTRY CHAIR ALI, MANY OF YOU KNOW HIS WORK IN THE CHROMATIN FIELD, HE'S LOOKING AT OUTPUT OF MITOCHONDRIA WHEN HE STUDIES EPIGENETICS BECAUSE THESE THINGS WE HAVE BEEN ABLE TO TCA CYCLE METABOLITES, CONTROLLING THE HISTONE ACETYLATIONS. IF WE RESTRICT GENERATION OF CITRATE HERE WE CAN IMPACT HISTONE ACETYLATIONS AND WE PUBLISHED THIS BEFORE.
10:51
IN THINKING ABOUT WHAT FUNCTIONAL LIVE MITOCHONDRIA DO, WE CAN MANY OF US ARE COMFORTABLE MITOCHONDRIA MIGHT BE IMPORTANT FOR SURVIVAL BY KEEPING THE ATP ADP RATIO HIGH TO DRIVE MANY CELLULAR REACTIONS. GLYCOLYSIS CAN COMPENSATE BECAUSE THEY GENERATE ATP. THE OTHER, IT'S IMPORTANT FOR LIPIDS NUCLEOTIDES, MANY MACRO MOLECULE SYNTHESIS COMES FROM MITOCHONDRIA SO IT'S THIRD FUNCTION MY LAB IS REALLY WORKED A LOT ON IS THIS IDEA THERE'S THINGS RELEASED FROM MITOCHONDRIA METABOLITES
11:35
REACTIVE OX GENERAL SPECIES WHICH CONTROL TRANSCRIPTION THROUGH CHROMATIN REMODELING DIRECTLY BY ACTIVATING TRANSCRIPTION FACTORS. PLAYS OUT DIFFERENTLY IN DIFFERENT CELL TYPES IN VIVO. SEEMS LIKE CANCER CELLS USE MITOCHONDRIAL METABOLISM NOR GROWTH AND SURVIVAL. WHERE STEM CELLS IN PARTICULAR HEMATOPOIETIC STEM CELLS DON'T CARE ABOUT ABILITY TO PROLIFERATE. IF WE KNOCK OUT THE SAME RESPIRATORY CHAIN GENES AND CANCER CELLS AND STEM CELLS, THEY CONTINUE TO PROLIFERATE, THE FETAL STEM CELLS,
12:22
HEMATOPOIETIC PROLIFERATE BUT NOT DIFFERENTIATE INTO PROGENITORS. ADULTS WHICH TEND TO BE QUIESCENT LOSE ITS AND UNDERGO HYPERPROLIFERATION AND STEM CELL EXHAUSTION SHUN. COMPLETELY DIFFERENT IN THE CANCER. WHY THAT IS, WE'RE STILL TRYING TO FIGURE OUT AND FINALLY T-CELLS, SEEMS TO BE ALL ABOUT THEIR ABILITY TO FUNCTION SO IF IT'S A REGULATED T CELLS, IT DOESN'T SUPPRESS. I'LL SHOW YOU WHAT I MEAN. I CAN'T GO INTO ALL THE MODEL SYSTEMS BUT SIMPLE COMPARE AND CONTRAST IN VIVO I'LL FOCUS ON
12:54
CANCER AND ON REGULATORY T-CELLS TO SHOW AN EXAMPLE. WE GOT INTO THE CANCER METABOLISM FIELD, MORE THAN 12, 13 YEARS AGO, AS YOU KNOW CANCER METABOLISM FIELD IS REVIVED IN PART BY OLD OBSERVATION MADE BY OTTO WARBERG ALMOST 90 YEARS AGO WHICH SHE OBSERVED A CANCER TISSUE UNDER NORMAL OXYGEN CONDITIONS RIGHT ON THE LABORATORY BENCH WOULD MAKE LOTS OF LACTATE. THIS IS CALLED THE AEROBIC GLYCOLYSIS OR THE WARBERG EFFECT. CLINICIANS KNOW THAT USING PET IMAGERY YOU CAN SEE WITH A
13:30
GLUCOSE TRACER PET POSITIVE. SO YES, TUMORS O GLYCOLYTIC. THERE'S A LOT OF HYPE AROUND THAT TO THE POINT PEOPLE THINK THE MITOCHONDRIA DISPENSABLE IN CANCER. SO WE SAID DOESN'T MAKE SENSE BASED ON SIMPLE BIOCHEMISTRY KNOWLEDGE AND WE INVESTED EARLY ON IN MAKING MOUSE MODELS USING MOUSE MODELS OF CANCER LIKE TYLER JACKS AND OTHERS PIONEERED BUT ALSO MAKING SOME MODELS WE CAN USE IN VIVO TO TEST NECESSITY OF THE RESPIRATORY CHAIN SO ONE WE MADE WAS TFAM. SO TFAF ENCODES, IS A NUCLEAR
14:08
PROTEIN NECESSARY FOR MITOCHONDRIA DNA REPLICATION AND TRANSCRIPTION SO REMEMBER THE MITOCHONDRIA HAS ITS OWN GENOME AND IT ENCODES FOR CERTAIN KEY SUBUNITS OF RESPIRATORY CHAIN. IF YOU -- WE GENERATE A PHLOX MOUSE, WHEREVER YOU KNOCKED OUT MITOCHONDRIAL DNA IS GONE. MITOCHONDRIAL DNA IS GONE, A VARIETY OF THE CRITICAL SUBUNITS OF THE RESPIRATORY CHAIN ARE GONE. YOU DON'T HAVE MITOCHONDRIA THAT ASPIRES. FUNCTIONALLY IN CELL BIOLOGY EVEL IF YOU LOOK BY ELECTRON MICROSCOPY THE MITE CON TRIA
14:41
THERE THAT DON'T RESPIRE. SO WE ASKED WHAT HAPPENS IN ONE OF THESE MOUSE MODELS THAT THE FIELD USES AND THE ONE WE USE IS THE LOCK STOP LOCKS KRAS ONCOGENIC KRAS DRIVEN LUNG CANCER MODEL WE DUMP ADENOVIRUS, CRE AND THE LOCK STOP LOX ALLELE IS GONE ACTIVATES ONCOGENIC KRAS AND YOU SEE INCREASE IN IN TUMOR BURDEN. TO THE E TENT YOU KNOCK OUT TFAM AND EXCISE THE TFAN GENE WE NOTICE LESS TUMORS. SO REMEMBER BY KNOCKING OUT TFAN WE HAVE MADE THE TUMORS COMPLETELY DEPENDENT ON GLYCOLYSIS.
15:20
THE ULTIMATE WARBERG CELLS AS I CALL THEM BUT LESS TUMORS THIS SIMPLE EXPERIMENT TOLD US WITH NECESSITY OF THE RESPIRATORY CHAIN UNDER THESE MOUSE MODELS, FOR TUMORIGENESIS. ONE THING WEES ARE GOT INTO WAS METAPHOR MAN BECAUSE EPIDEMIOLOGISTS NOTICED THAT PEOPLE WHO HAD TAKEN METFORMAN FOR DIABETES HAS LOWER CANCER ACROSS SOME CANCERS THIS LED TO CLINICAL TRIALS INCLUDING LARGE SCALE HAPPENING IN CANADA IN BREAST CANCER. AND THE RESULTS WILL BE OUT NEXT YEAR. BUT SOMETIMES WHEN A DRUG IS
15:58
REALLY CHEAP AND EASILY REPURPOSED AND OBVIOUSLY UNFORTUNATELY PATIENTS SUFFERING FROM THE TERRIBLE DISEASE OF CANCER YOU RUSH TO DO THE CLINICAL TRIALS. AND I'M NOT COMPLETELY CONVINCED WE HAVE BEEN VERY I SHOULD SAY VERY THOUGHTFUL ABOUT SOME OF THESE TRIALS, BECAUSE IT'S NOT CLEAR WHETHER THE ANTI-DIABETIC DOSE SHOULD BE THE DOSE FOR ANTI-CANCER. IN FACT, OUR STUDIES MIGHT SUGGEST YOU NEED ALMOST A MAXIMAL TOLERATED DOSE OF METFORMAN TO HAVE EFFICACY. NOT EVERY TUMOR RESPONDS BECAUSE
16:30
IN ORDER FOR IT TO GET INTHE A TUMOR CELL IT NEED ORGANIC CATION TRANSPORTERS. IN THE ABSENCE OF THAT TRANSPORTER YOU CAN THROW BUCKETS MILLIMOLAR AMOUNTS AND NOTHING HAPPENS. OTHER QUESTION IS WHAT'S THE TARGET? IN 2000 THERE WAS TWO REPORTS IN JBC THAT SUGGESTED GIVE ISOLATED MITOCHONDRIA METFORMAN YOU CAN INHIBIT COMPLEX 1. THERE'S 45 SUBUNITS IN COMPLEX 1. THE BEST WAY TO SHOW WHAT A DRUG DOES, THE GOLD STANDARD IS FIND IT WHERE IT BINDS IN PARTICULAR COMPLEX OR PROTEIN SO IT DOESN'T
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CHANGE THE CATALYSIS OF THAT PROTEIN BUT MAKES IT REFRACTORY TO BINDING, THAT'S THE GOLD STANDARD. I'M NOT A STRUCTURAL BIOLOGIST WE DIDN'T DO ELEGANT EXPERIMENT LIKE THAT. IT'S A 45 SUBUNIT COMPLEX. PRETTY BIG BUT WE DID SOMETHING CLEVER, WE SAID LET METAPHORMAN INHIBIT MITOCHONDRIAL COMPLEX 1 AND IF NECESSARY FOR ANTITUMOR EFFECTS LET'S RESCUE IT BY PUTTING IN THE CANCER CELLS A PROTEIN CALLED NDI 1, FOUNDING EAST. SACK CROW MYSISTER SRIS YEAH. NAD, THE ONLY THING IT DOESN'T
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DO IS PUMP HYDROGEN. AND BY PUMPING -- DOING NADH TO NAD DONATE ELECTRONSES TO COQ AND DOWN TO MOLECULAR OXYGEN. SO FUNCTIONAL RESCUE. WE DID THIS IN A COLON CANCER MODEL AND LUNG CANCER MODEL. AS YOU CAN SEE WE LET THE TUMORS GROW, IF WE GIVE METAPHORMAN IN THE DRINKING WATER WE CAN INHIBIT TUMORIGENESIS, IF THERE ARE NDI 1 THERE THEY'RE REFRACTORY, ALL CONTROL EXCEPT PLUS OR MINUS NDI 1 OR METAPHORMAN. WHAT'S NICE IS THAT ONCE WE PUBLISHED THIS COUPLE OF YEARS AGO, A BUNCH OF OTHER PHYSICIAN
18:29
SCIENTISTS AND CLINICIAN SCIENTISTS HAVE NOW GONE AND GIVEN METFORMAN TO PATIENT COHORTS AND TAKEN BIOPSIES TO DO METABALOMICS AND WE KNOW A SIGNATURE WHEN MITOCHONDRIAL RESPIRATORY CHAIN INHIBITED WE KNOW A METABOLIC SIGNATURE CONSISTENT WITH THAT AND NOW GIVING METAPHORMAN TO PATIENTS YOU CAN SEE THAT SIGNATURE IMPLYING METFORMAN IN HUMAN PATIENTS CAN GET INTO THEIR CANCER CELL MITOCHONDRIA AND PERTURB METABOLISM. SO ONE OF THE THINGS WE HAVE BEEN TRYING TO FIGURE OUT WHAT
19:04
ASPECTS OF THE RESPIRATORY CHAIN ARE CRITICAL. DO YOU NEED ATP COMING, NOR IS IT JUST ABOUT THE METABOLITES. ONE WAY WE THOUGHT ABOUT DOING THIS IS WE KNOCKED OUT MITOCHONDRIA COMPLEX 3, KNOCK OUT COMPLEX 3 IN THE MIDDLE THESE ELECTRONS AREN'T GOING TO FLOW AND YOU WON'T PROTON PUMP, TCA CYCLE WON'T WORK OR CANONICALLY LIKE IT SHOULD AND THEN MAYBE YOU WANT TO GROW. SO IF YOU KNOCK OUT COMPLEX 3 CONSISTENT WITH WHAT EVERYTHING ELSE I HAVE SHOWN YOU, AGAIN, YOU GET VERY LITTLE TUMORS GROWING OUT.
19:41
NOW AGAIN, WE HAVE GOT INTO GIVING ANCIENT ENZYMES TO COMPLIMENT MUTATIONS. HERE IS ANOTHER ONE WE AGAIN TAKE THE COMPLEX 3 KNOCK OUTS, ALL GONE, HERE WE PUT A PROTEIN CALLED THE ALTERNATIVE OXIDASE FOUND IN PLANTS, FOUND IN SEA AND LOWER ORGANIZE IMS, IT CAN TAKE ELECTRONS FROM Q AND AGAIN, TRANSFORM TO MOLECULAR OXYGEN. SIMILAR TO CYTOCHROME C OXIDASE BUT WILL ALLOW THE TCA CYCLE TO OCCUR BECAUSE COMPLEX 1 AND 2 ACTIVITY IS REGAINED BECAUSE IT CAN DONATE ALL THIS ELECTRONS SO
20:17
WHEN YOU DO THAT, COMPARED TO THE CONTROL, COMPLEX 3 KNOCK OUTS THAT DON'T GROW PEER BY PUTTING BACK AOX WE CAN RECOVER TUMORIGENESIS. THIS SIMPLE EXPERIMENT STARTS TO POINT ONE OF THE KEY FUNCTIONS OF MITOCHONDRIA WE THINK IS TO GENERATE THOSE TCA CYCLE METABOLITES. IT'S FOR GROWTH AND A MODEL THAT'S EMERGED FROM MY LAB AND PEOPLE AT RALPH DENNIS WHO HAD DONE NICE WORK IN HUMAN PATIENTS WITH GLUCOSE TRACERS, AS WELL AS WORK OF ALEX KIMMELMAN AND OTHERS, HAS COME TO -- THIS IS
20:54
IS A BIRD'S EYE VIEW THAT IN THE LAND OF PLENTY WHEN NUTRIENTS ARE AVAILABLE THE MITOCHONDRIA IS BIOSYNTHETIC BIOENERGETIC HUB ALIGNED FOR RAPID CELL PROLIFERATION. IT CAN GIVE YOU ALL THE LIPIDS, HELP MAKE NUCLEOTIDES, GIVE YOU THE ENERGY, BUT MANY OF YOU KNOW, TUMORS SIT IN HARSH ENVIRONMENTS AND THERE MANY WAYS CANCER METABOLISM COMMUNITIES DISCOVERED, WE HAVEN'T CONTRIBUTED MUCH TO THIS, WHICH IS THINGS LIKE CYTOSIS OR AUTOPHAGY OR BRANCHING AMINO ASITS OR FATTY ACID OXIDATION,
21:30
ALL THESE SURVIVAL PATHWAYS ONE OF THEIR JOBS IS TO CATABOLIZE WHATEVER THEY CAN IN A CELL TO FEED THIS MITOCHONDRIA MAKE ENOUGH ENERGY TO AT LEAST SURVIVE UNTIL YOU GET NEW VASCULARIZATION AND GO BACK TO THE LAND OF PLENTY, TO GROW. SO UNDER BOTH CONDITIONS, NUTRIENT REPLETE CONDITION IS ANN BOLLIC MACHINERY AND NUTRIENT DEPLETED IS A CAT BOLLIC MACHINERY TO GENERATE ATP FOR SURVIVAL. THIS IS A MODEL WE CONTINUE TO TEST AND OBVIOUSLY WE'RE LOOKING FOR NODES THAT WE CAN INTERFERE
22:08
WITH FOR CANCER THERAPY. SO REALLY THE TAKE HOME HERE IS THAT WE THINK IN VIVO ROLE OF THE RESPIRATORY CHAIN, IS CONTROL PROLIFERATION SURVIVAL, I WON'T HAVE TIME TO SHOW YOU THE STEM CELL DATA BUT WE CAN DO SIMILAR GENETIC TRICKS KNOCKING OUT COMPLEX 3 OR OTHER WAYS TO KNOCK OUT THE RESPIRATORY CHAIN AS I ALLUDED TO, STEM CELLS THEMSELVES ARE THERE, THEY'RE PHENOTYPICALLY LOOK LIKE STEM CELLS BUT DON'T DO WHEY THERE SUPPOSED TO WHICH IS GENERATE PROGENITORS. SO THEY DON'T HAVE A
22:39
PROLIFERATIVE DEFECT LIKE CANCER CELLS IN VIVO BUT THEY HAVE A DIFFERENTIATION DEFECT. AND THE T-CELLS I'M GOING TO SHOW YOU, IT'S ABOUT THEIR FUNCTION. SO WE GOT INTO THIS SEVEN OR EIGHT YEARS AGO, TALENTED M.D. Ph.D., WE WERE WATCHING THE FIELD OF IMMUNOMETABOLISM THAT CONTINUES TO GROW AND EVOLVE AND AGAIN, THERE HISTORIC BIAS HAS ALWAYS BEEN THEY'RE GLYCOLYTIC. IN FACT RAPIDLY PROPROLIFERATING CELLS SHOW PROBUST GLYCOLYSIS BUT IT SHOULDN'T BE MISINTERPRETED THEIR MITOCHONDRIA ARE NOT EQUALLY
23:18
IMPORTANT. SO AGAIN, WE DO VERY SIMPLE EXPERIMENTS, WE ASK THE QUESTION IS THE RESPIRATORY CHAIN NECESSARY FOR PROLIFERATION OR T-CELL ACTIVATION? AND COULD WE USE SOME OF OUR NEWER MOUSE MODELS? ONE OF THE ONES WE HAVE BEEN USING IS KNOCKING OUT CATALYTIC SUBUNIT OF COMPLEX 3, IT HAS 11 SUBUNITS, THE RISKY IRON SULFUR PROTEIN IS ENCODED BY NUCLEI EIUS SO WE CAN PHLOX THESE ALLELES KNOCK OUT COMPLEX 3 CROSS IT TO CD4 CRE AND THE RESPIRATORY CHAIN WON'T WORK. IF IT DOESN'T WORK YOU DON'T
23:53
MAKE ATP OBVIOUSLY. SO B CELLS BECOME PURELY GLYCOLYTIC. GROWTH MAYBE COMPROMISED BECAUSE YOU MAY NOT MAKE ENOUGH CYCLE METABOLITES. THE ROSS GENERATED BY COMPLEX 3 FOR SIGNALING MIGHT BE AFFECTED. METABOLITES FOR HISTONE ACETYLATIONS MIGHT BE AFFECTED SO MULTIPLE EFFECTS AND IT GETS DIFFICULT TO DISCERN ALL THE REASONS WHY. BUT LAURA INITIALLY DID THIS ON THE SIMPLE EXPERIMENTS ONE OF THEM IS YOU CAN TAKE A RAG DEFICIENT MOUSE, LYMPHOPENIC MOUSE AND ADOPTIVELY TRANSFER
24:26
WILD TYPE OR RISK KNOCK OUT THIS IS THIS HOMEOSTATIC EXPANSION OF T-CELLS, VERY BREAD AND BUTTER ASSAY OF COMMUNITY. SHE NOTICED NO PHENOTYPE, THE WILD TYPE CELLS, IF YOU WILD TYPE T-CELLS PUT THEM IN THIS RAG DEFICIENT MOUSE, IT PROLIFERATES FINE, AS OTHERS HAVE SHOWN. AND SO DO OUR COMPLEX 3 KNOCK OUTS. WE SUGGESTED THAT THERE'S NO GROWTH DEFECT. I DID REMIND LAURA THAT T-CELLS ARE THERE TO RESPOND, SHE SHOULD TRY THE VARIETY OF ANTIGENS WHEN SHE DID THAT THEY GOT THE
25:03
OPPOSITE RESPONSE SO THEY HAVE THE ABILITY TO GROW UNDER HOMEOSTATIC CONDITIONS AND JUST DON'T DO IT WHEN THEY HAVE TO RESPOND TO AN ANTIGEN. THAT THAT STARTED TO SMELL LIKE SIGNALING BECAUSE THEY CAN FIND A WAY TO GROW AND SURVIVE UNDER ONE CONDITION BUT NOT THE OTHER. WITH THAT GOING THROUGH A LOT OF MECHANISTIC DETAILS AS THIS WAS PUBLISHED A WHILE BACK, I WANT TO SHOW YOU MORE RECENT UNPUBLISHED DATA, BUT THIS IS SORT OF WAS A NICE EXPERIMENT. SO REMEMBER THE COMPLEX 3 KNOCK
25:30
OUTS ARE GLYCOLYTIC SO YOU CAN ARGUE THE FACT THEY'RE TOO GLYCOLYTIC OR SOMETHING ABOUT ENERGY, THAT WAS A PROBLEM. BUT WE LIKE SIGNALING PARADIGM, ONE OF THE WAYS WE THINK SIGNALING IS GENERATING MITOCHONDRIAL ROS SO LOOK AT IL 2 PRODUCTION THIS IS IN CELL CULTURE THE WILD TYPE CELLS WHEN STIMULATED MAKE IL 2, THE CLASSICAL SITESKINE OF T-CELLS BEINGS ACTIVATED. THE COMPLEX 3 KNOCK OUT RISK KNOCK OUT MARKED REDUCTION. AND ALL WE DO IS WE TITRATE IN NANOMOLAR AMOUNTS OF GALACTOSE
26:04
OF H 2 O2 BY GIVING GALACTOSE OXIDASE. IT'S A SUBSTRATE FOR GALACTOSE OXIDASE AND WE CAN TITRATE THE SUBTRAIT AND THE -- SUBSTRATE AND THE ENZYME CONCENTRATION AND TO WHATEVER LEVEL WE WANT, WE CAN GENERATE NANOMOLAR, MICROMOLAR MILLIMOLAR TO CONTINUOUSLY AND BY FLOODING THE SYSTEM WITH NANOMOLAR AMOUNTS WE ASKED WHETHER IN THE RISK KNOCK OUT WE CAN BRING BACK THE IL 2. AND WE CAN. THE BLACK BARS ARE THE RISK KNOCK OUT SO VERY LITTLE IL 2 WHEN STIMULATED AS LONG AS WE PROVIDE ONE THING BACK.
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H 2 O2 WE CAN BRING BACK IL 2 LEVELS. THAT SUGGESTED THAT ONE OF THE THINGS THAT WAS IMPORTANT IN ABSENCE OF COMPLEX 3 WAS PERHAPS ROS PRODUCTION FROM COMPLEXIN. WE SHOWED THAT USING DYES AND OTHER METHODS BUT THE SIMPLE MECHANISM THAT WE OUTLINED WAS THAT THE EARLY SIGNAL ONCE YOU ACTIVATE THE T-CELL BY T-CELL RECEPTOR ENGAGEMENT IS INFLUX OF CALCIUM, ONE OF THE EARLIEST YOU CAN DETECT AND LARGE PART THAT SIGNAL WAS INTACT. IN OUR KNOCK OUTS. WHAT WASN'T INTACT WAS THE
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GENERATION OF HYDROGEN PEROXIDE IN OUR KNOCK OUTS AND THAT WAS NECESSARY FOR TRANSLOCATION INTO THE NUCLEUS FOR IL 2 PRODUCTION AS MANY OF YOU KNOW N FAT IS ONE OF THE KEY TRANS SUBSCRIPTION FACTORS NECESSARY FOR IL 2, NF KAPPA B AND AP 1 ARE THE OTHER TWO. THEY WERE NOT IN EFFECTED SO THERE WAS SOME SPECIFICITY TO THIS PATHWAY. AND SO THE IDEA WE HAVE IS THAT THE CALCIUM WOULD ENTER MITOCHONDRIA TO ACTIVATE THE DEHYDROGENASES, TO PUMP UP AND REV UP RESPIRATORY CHAIN
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ACTIVITY AND BY-PRODUCT IS H 2O 2 WHICH THEN ALLOW FOR THIS INFAT DEPENDING IL 2 PRODUCTION. WHEN SAM WINEBERG TALENTED Ph.D. GRADUATING NEXT MONTH, WANTED TO FOLLOW-UP AND START TO ASK BEYOND ACTIVATION WHAT ARE THE DIFFERENT SUBSETS? WHAT IS ROLE OFs RESPIRATORY CHAIN IN MEMORY CELL OR EFFECTOR CELL OR IN A REGULATORY T-CELL AND WE LIKE THE REGULATORY T-CELLS BECAUSE THERE'S NICE LITERATURE IN REGULATORY T-CELL, ALSO MUCH OF HOW THE TREG T-CELL LITERATURE, THERE'S EPIGENETIC
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CONTROL OF TREG FUNCTION WHICH TO US LIKE I SAID, WE LIKE TO THINK OF CHROMATIN REMODELING AND EPIGENETIC LANDSCAPE BECAUSE IT'S -- WE CAN SEE HOW IT NICELY TIES INTO MITOCHONDRIA FUNCTION BECAUSE MANY TCA CYCLE METABOLITES CONTROL THOSE ENZYMES. SO AGAIN, VERY SIMILAR APPROACH. WE TAKE THE FOX P 3 CRE AN THESE MICE HAVE YFP SO YOU CAN TAG THEM IF CRE IS ACTIVE AND CROSS TO THE COMPLEX 3. THE RISK OF PHLOX MICE SO YOU HAVE COMPLEX 3 GONE AGAIN AND WHAT HAPPENS? AND WE GOT A COMPLETELY
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ASOUNDING RESULT, HE T GO A MOUSE THAT LOOKS LIKE A FOX P 3 NULL MOUSE. SO FOX P 3 IS THE LINEAR SPECIFIC TRANSCRIPTION FACTOR NECESSARY FOR REGULATORY T-CELL FUNCTION. YOU LOOSE FOX P 3 IN A MOUSE YOU GET THE MOUSE AND THREE WEEKS THE MOUSE DIES THERE'S AUTO-IMMUNITY IMMUNE DISREGULATION EVERYWHERE, HYPERINFLAMMATION AND PATIENTS THAT HAVE MUTATIONS IN FOX P 3 ALSO HAVE THIS HYPERINFLAMMATION IMMUNE DISREGULATION. WE GOT THE ONLY MOUSE, I KNOW ALMOST ALL PHENO COPIES. I COULDN'T BELIEVE IT.
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GENETICS DON'T LIE SOMETIMES THEY DO, WE MADE SURE THAT'S TRUE, WE SHOULD TAKE ANOTHER SUBUNIT OF COMPLEX 3. THAT'S 11 SUBUNITS ONE ENCODED BY MITOCHONDRIAL DNA, THE OTHER TEN ARE NUCLEAR ENCODED AND ALL OF THOSE TEN ARE ALL NECESSARY FOR THE COMPLEX. IF YOU LOSE ANY ONE, THE COMPLEX DOESN'T WORK WELL. THIS IS THE QPC PROTEIN, WE GOT IDENTICAL PHENOTYPE SO ALL THE DATA I SHOW YOU, WE SORT OF PHENO COPIED WITH EACH OTHER MOUSE. THAT WAS GOOD. THOUGH WE WERE QUITE EXCITED BY
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THIS FINDING THERE WAS ONE SIMPLE EXPERIMENT SAM HAD TO DO FOR ME TO GET EXCITED. LISTEN, IF YOU SHOW THIS TO ANYBODY THEY'LL SAY YOU HAVE A DEAD MOUSE BECAUSE YOU HAD NO TREGS, YOU GOT A MOUSE TREGS NEEDED FOR SURVIVAL TELL ME WHAT THE TREG NUMBERS ARE. IF THEY'RE COMPLETELY GONE, REALLY LOW, IT'S A COOL FINDING BUT IT AIN'T THAT COOL. YOU NEED ATP. WHAT HE FOUND WAS THE OPPOSITE. THE NUMBER OF FOX P 3 POSITIVE CELLS, WERE IDENTICAL BETWEEN -- IN FACT LITTLE BIT MORE IN THE COMPLEX KNOCK OUT.
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AND YOU CAN SEE IF YOU TAKE OUT THESE NUMBERS OUT AND PUT KI 67 OR CD4 4 WHICH IS ACTIVATION MARKER, PHENOTYPICALLY WE HAVE GOT PLENTY OF FOX P 3 POSITIVE SO CALLED TREGS THAT PROLIFERATE, THAT LOOK LIKE THEY'RE ACTIVATED, THEY'RE SURVIVING PROLIFERATING. SO WE'RE DOWN TO THE LAST FUNCTION. ARE THEY SUPPRESSIVE? AND HERE I'M SHOWING YOU WE HAVE DONE IN VITRO SUPPRESSION AWE SAYS THEY DON'T SUPPRESS WELL. HERE IS IN VIVO. THIS IS WHERE AGAIN WE GO BACK INTO RAG MICE WHERE WE GIVE WILD
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TYPE EFFECTOR CELLS AND YOU CAN SEE THESE MICE DEVELOP COLITIS AND IMMUNE DISREGULATION AND DIE. IF YOU GIVE WILD TYPE EFFECTORS WITH THE WILD TYPE TREGS, THAT SHOULD SUPPRESS VECTOR CELLS, CLASSIC SUPPRESSION ASSAY, THE MICE SURVIVE. BUT NOW REDO THE EXPERIMENT WITH WILD TYPE EFFECTORS WITH THE KNOCK OUT TREG, AND LOOKS LIKE THEY NEVER GOT ANY REGULATORY T-CELLS. THIS TELLS US WE HAVE T-CELLS THAT ARE THERE, PROLIFERATE AND SURVIVE BASED ON MARKERS THAT WOULD BE CALLED ESSENTIAL FOR
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TREGS, MANY H ARE THERE INCLUDING CTLA 4, FOX P 3 BUT THEY DON'T SUPPRESS. ANOTHER EXPERIMENT WE CAN DO NOW WE GO TO INDUCIBLE SYSTEM. INSTEAD OF USING FOX P 3 IN DEVELOPMENT THIS IS TO MAX FEN INDUCIBLE CRE SO WE LET THEM GET TO ADULT AND NOW WE ADD A B 16 MELANOMA, THE CLASSIC IN MY LAB WE DON'T TRY TO REINVENT TOO MANY TECHNIQUES OTHER THAN OUR MITOCHONDRIAL STUFF AND YOU GET A NICE TUMOR THAT GROWS OUT AND NOW WE'RE ADDING TO MOCKS FEN. IT -- TAMOXIFEN, IT ONLY ACTIVATES CRE IN FOX P 3 TREG
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CELLS, BY KNOCKING OUT COMPLEX 3 INDUCEBLY IN THE REGULATORY T-CELLS, OBVIOUSLY WE HAVE ALLOWED THESE DREGS TO STOP SUPPRESSING AND UNLEASH IMMUNITY AND MAKE VERY SMALL TUMORS THAT GET CLEARED OUT. SO THAT TELLS US THAT COMPLEX 3 IS NECESSARY FOR TREG FUNCTION. THE QUESTION IS WHY. SO HERE, WHAT WE HAVE DONE IS TAKEN THE TREG OUT AND SHOT THROUGH RNA SEQ ANALYSIS TO GIVE IDEA WHAT'S UP, WHAT'S DOWN. THE NUMBER ONE PATHWAY WE CONSISTENTLY SEE IN VIVO WHEN MITOCHONDRIA ARE -- RESPIRATORY
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CHAIN IS IMPAIRED IN OUR STEM CELLS AND K CELLS SO FAR IS MIC. IT TENDS TO BE UP AND SO DOES MTOR 1, THOSE PATHWAYS TEND TO BE UP. AND IT'S ALMOST AS IF THE SYSTEM WAS SENT SOME THINGS WRONG AND TRYING TO COMPENSATE BY ACTIVATING. REMEMBER MIC AND M TOR 1 ARE TWO OF THE PATHWAYS THAT CONTROL METABOLISM. REGULATES ALMOST EVERY METABOLIC GENE PHOSPHORYL HATING SUBSTRATES IN THE LIPO GENESIS AND NUCLEOTIDE SYNTHESIS PATHWAY SO THIS IS A FEEDBACK ON THE SYSTEM. BUT THE OTHER THING, WHAT'S DOWN
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REGULATED? WE THINK THAT IT MUST BE DOWN REGULATING SUPPRESSIVE GENES. IT'S TWO OBVIOUS ONES WERE FOX P 3 AND CTLA 4. BUT THEN WE STARTED TO LOOK INTO THIS A LITTLE BIT MORE HERE ARE GENES THAT HAVE BEEN ASSOCIATED TO SUPPRESS SHY REGULATORY T-CELL FUNCTION. IF YOU LOSE THESE GENES IN REGULATORY T-CELLS YOU EVENTUALLY DEVELOP AUTOIMMUNE DISORDER. SOME OF THESE NEUROPILL LYNN 1 TAKES MORE THAN A YEAR, SOME LESS, BUT REMEMBER WE'RE HAVING A WHOLE HOST OF THESE GENES ALL
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COORDINATEDLY DOWN REGULATED IT'S ALMOST LIKE WE MADE MULTIPLE KNOCK OUTS ALL IN ONE. SO HOW DO YOU COORDINATE WIDESPREAD SUPPRESSIVE GENOME DOWN REGULATION? WHAT ARE SOME OF THESE -- HOW DO YOU GET ALL THESE GENES PERHAPS TO DOWN REGULATE? WE TURN TO DNA METHYLATION AND HISTONE METHYLATION. THAT'S A LARGE FAMILY OF ENZYMES CALLED ALPHA GLUTE RATE HYDROGENASES. MY FRIEND BILL GAVE THE WALS A COUPLE OF WEEK AGO, PRO OWE HYDROXYLACE. SO THESE ARE REGULATORS OF HIF. THEY CONTROL HYDROXYLATION OF
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HIF AND THEIR ALPHA KETOGLUTE RATE DEPENDENT. AND SOME OF THE OTHER ONES ARE THE GEMONGI DOMAIN, TEP ENZYMES THAT ARE PARTICIPATING IN DE METHYLATION. SO THE HISTONE LYSINE DEMETHYLATION, THE DNA DEMETHYLATION, ALL THESE REACTIONS ARE DRIVEN BY ALPHA KETOGLUTE RATE. THEY USE OXYGEN, MAKE CO 2 AND MAKE IRON AND THE BY-PRODUCT IS SUCCINATE. GO TO PUBMED, ALPHA' KETOGLUTE RATE IS MITOCHONDRIA, IRON IS CONTROLLED BY MITOCHONDRIA, OXYGEN CONTROLLED BY MITOCHONDRIA. SUCCINATE IS GENERATEDDED IN THE
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MITOCHONDRIA. YOU CAN SEE EARLY EVOLUTION ONE WAY MITOCHONDRIA MIGHT HAVE COMMUNICATED TO THE NUCLEUS OR TO THE CYTOPLASM IS THANK YOU THESE ENZYMES BECAUSE IT CAN POTENTIALLY CONTROL THE ACTIVITY, BY ALL A VARIETY OF WAYS. ONE THING THAT'S COME OUT OF PEOPLE WHO STUDIED THESE ENZYMES IS THE MOST POTENT REGULATOR IS TWO HYDROXY GLUTE RATE. SUCCINATE WILL ALSO INHIBIT ENZYME NOT AS EFFECTIVE AS 2 HYDROXY GLUTE RATE. 2 AG AND ALPHA GLUTE RATE IS THE SAME AND ONE IS OXIDIZED REDUCED VERSIONS OF IT.
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THE CANCER PEOPLE KNOW ABOUT ALPHA KETOGLUTE RATE. THEY'RE FOUND IN GLIOMAS AND AML MAKE 2 HYDROXY GLUTE RATE. MUCH UNDERSTANDING OF IT FUNNELING INTO ENZYMES COMES FROM THAT LITERATURE. NOW, THE TYPE OF 2 HYDROXY GLUTARATE THE IDEATIONS MAKE IS THE R FORMTOR THE D FORM. SO REMEMBER THIS PLURALITY. THERE'S ANOTHER VERSION CALLED THE L FORM OR THE S FORM THAT EVERY PERSON IN THIS ROOM CAN MAKE WITHOUT IDH MUTATION. PLANTS MAKE IT. IT'S BEEN CONSERVED THROUGHOUT EVOLUTION. I WANT TO TALK ABOUT
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HOW DO YOU MAKE NOT THE IDH MUTATION VERSION OF 2 AG BUT THE L. I THINK THE IMPLICATION OF THIS IS MUCH BROADER AND I WILL TELL YOU WHY IN A SECOND. SO THE WAY YOU MAKE L 2HE, OR THE S 2AG, IS YOU ONLY MAKE IT WHEN NADH LEVELS ARE HIGH. NADH LEVELS ARE HIGH IF RESPIRATORY CHAIN IS INHIBITED OR IMPAIRED. COMPLEX ONE'S JOB IS TAKE NADH MAKE NAD SO MOVES US HAVE A LOT MORE NAD THAN NADH IN MITOCHONDRIA. BUT IF WE'RE SEVERELY HYPOXIC OR IF WE FAKE A POISON INHIBITS OUR RESPIRATORY CHAIN OR AS MANY
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ALLUDED DISEASES LIKE PARKINSON'S OR NATURAL AGING YOU SEE A DOWN REGULATION OF RESPIRATORY CHIN AND YOU START TO SEE A BUILD UP OF NADH COMPARED TO NAD, THERE'S A WHOLE LITERATURE ABOUT GIVING NKD SUPPLEMENTS NOW. I HAVE ASKED PEOPLE WHAT DOES NAD DO? THIS IS ONE EXPLANATION. WHEN THE NADH LEVELS INCREASE COMPARED TO NAD, MARKSAL DEHYDROGENASES, IT TAKES CONVERTS TOM ACETATE. IT'S NATURALLY PREFERRED SUBSTRATE BUT IT WILL PROMISCUOUSLY UTILIZE ALPHA KETOGLUTER RATE AND IF THERE'S A
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LOT OF NADH AROUND THE MAL DEHYDROGENASE WILL CONVERT TO 2 HYDROXY GLUTERATE. YOU NEED THE NADH TO DRIVE THE REACTION. THERE'S AN ENZYME CALLED 2 HYDROXY DEHYDROGENASE THAT WILL GIVE RID OF THE BUILD UP. THE BRAIN HAS THE HIGHEST LEVELS DEHYDROGENASE, PATIENTS WHICH HAVE MUTATION IN THAT ENZYME WILL ACCUMULATE 2 AG AND GET ALL SORTS OF NEURAL DEVELOPMENTAL AND NEURAL DEGENERATED PHENOTYPES. SO WE CAN SEE HOW 2 AG MIGHT BE LINKED TO NEURODEGENERATION. ONE THING IS THIS ENZYME IS
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COMPLETELY DEPENDENT ON DUMPING ELECTRONS TO COMPLEX 3. SO WHEN WE KNOCK OUT COMPLEX 3, AND WE FIRST DID IT IN OUR STEM CELLS IN VIVO, WE SAW A LOT OF 2 AG ACCUMULATING, UP TO A MILLIMOLAR. AND IS BEING DRIVEN BUZZ NADH BUILDS UP IN OUR COMPLEX 3 KNOCK OUTS AND YOU CAN'T GET RID OF IT. THE OTHER PLACE IS LDH, WITH ACIDIC PH CAN ALSO GENERATE 2 HG SO GLYCOLYTIC CELLS. YOU NEED NADH TO DRIVE THAT. WE HAVE NOW HAVE MANY WAYS TO RECONSTITUTE WITH ENZYMES AND REPLENISH THE NAD POOL IN OUR
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COMPLEX 3 KNOCK OUTS AND WE CAN BRING DOWN 2 AG SO WE'RE CONFIDENT THIS IS THE MECHANISM BY WHICH YOU GENERATE THE 2 AG. NAD MALI DEHYDROGENASE SYSTEM. SO THE KEY IS WHETHER THE 2 HYDROXY GLOOM EAT RATE ACCUMULATES IN THE TREGS. AND WILD TYPES HAVE 50 TO 100 MICROMOLAR, ACCUMULATES UP TO SOMEWHERE BETWEEN 3 TO 400 MICROMOLAR BUT THE KEY IS HOW TO TRANSLATE TO ALPHA 2AG, IT HA Z TO OUTCOMPETE AND WE START TO SEE, DOING METABALOMICS OUT OF THE MOUSE, IF A MOUSE DEES THREE
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WEEKS BEFORE AND TAKE IT OUT AND SHOOT THROUGH MASS SPEC. THE SUCCINATE RATIO TO ALPHA KG ALSO GOES UP AND SO THE QUESTION IS, DOES THIS CORRELATE WITH ANYTHING TO DO WITH DNA METHYLATION. TEN ENZYMES PARTICIPATE IN DNA METHYLATION AND THEY HAVE BEEN SHOWN IN VITROTOR SENSITIVE BOTH TO ALPHA KG AND THE SUCCINATE. THEY ARE ALPHA KG DEPENDENT IN -- IF YOU PUT IT 2 AG OR SUCCINATE YOU YOU CAN SEE HYPERMETHYLATION OF DNA. WE WENT BACK TO RAB SEQ AND SAID LET'S LOOK AT THE -- RNA SEQ AND
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LOOK AT 200 GENES DOWN REGULATED AND DO BISULFITE DNA METHYLATION SEQUENCING AND NOW AT THE TOP DOWN REGULATING GENES, LOOK AT THE CPG ISLANDS AS YOU SEE HYPERMETHYLATION COMPARED TO THE WILD TYPE. SO THERE'S A CORRELATION BETWEEN THE LOSS OF COMPLEX 3, LOSS OF SUPPRESSIVE FUNCTION, DOWN REGULATION OF KEY SUPPRESSIVE GENES, HYPERMETHYLATION O DNA, AND INCREASE IN THINGS LIKE 2 HYDROXY GLUTERATE AND SUCCINATE. ALL CORRELATIVE. THE REASON I KEEP ON SAYING, I'M VERY CAREFUL ABOUT THIS, ONE OF
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MY ORIGINAL DEGREE WAS IN MATH, ONE THING YOU LEARN OVER AND OVER IS CAUSALITY. UNFORTUNATELY I DON'T HAVE A GOOD CAUSAL EMPERIMENT. THE CAUSAL EXPERIMENT WOULD BE TO TAKE OUR COMPLEX 3 KNOCK OUTS, AND FIND WAY TO GET RID OF 2 HYDROXY GLUTE RATE AND FIX THE PHENOTYPE. IF THAT'S THE DRIVER. BEST WAY WOULD BE TO OVEREXPRESS ENZYME. WE CAN'T AND TRIED, THE PROBLEM IS COMPLEX THREE KNOCK OUTS IF WE HAVE ONE MAKE 2 HYDROXY DILUTE RATE WE CAN HAVE THAT SYSTEM OVEREXPRESS HYDROXY GLUTE
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RATE BECAUSE COMPLEX 3 IS INTACT WHEN COMPLEX 1 IS KNOCKED OUT. SO WE'RE GOING BACK TO DO THIS EXPERIMENT, ONE EXPERIMENT WE CAN DO IS IN VITRO SUFFICIENCY, WE CAN TAKE FOX P 3 NULL, WILD TYPE RIGHT OUT OF A MOUSE, GIVE IT ALL THE CYTOKINES KEEP THEM HAPPY, GET THEM TO PROLIFERATE, AND GIVE IT 50 MICROMOLAR 2 HYDROXY GLUTE RATE. 50 MICROMOLAR GIVES YOU 400 MICROMOLAR IN THE CELL. IF YOU PUT 50 MICROMOLAR IN CELL CULTURE AND BY METABALOMICS ASK HOW MUCH THE CONCENTRATION IS
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ENRICHED, IT'S ALMOST TENFOLD. IT'S ABOUT WHAT WE SEE IN OUR KNOCK OUTS. SO WE'RE ON PAR, SO IN OTHER WORDS YOU CAN ALWAYS THIS IS ONE OF MIKE'S FAVORITE THINGS, YOU CAN DUMP IN AS MUCH METABOLITE OR TOXIN TO SEE EFFECT. WE WERE CAREFUL TO PUT BACK THE MONOHYDROXY GLUTERATE IN THE WILD TYPE CELL WHETHER GIVING THAT 2 AG IS SUFFICIENT TO DRIVE DOWN REGULATION OF SOME KEY GENES INCLUDING NEUROFILL LYNN AND -- THE GENES THAT WE OBSERVE WERE DOWN REGULATED BY CONTRAST FOX P 3 NOT DOWN REGULATED,
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REMAINS UNCHANGED SO THIS SORT OF KEEPS US GOING DOWN THIS 2 HYDROXY GROUT RATE PATHWAY GOING FORWARD. BUT REALLY THE SIMPLE TAKE HOME MESSAGE IS WHEN WE THINK ABOUT WHY IN THIS CASE WHY ANY MAMMALIAN CELL MISFIRES, TREGS CAN SURVIVE WITHOUT HAVING FUNCTIONAL RESPIRATORY CHAIN OR FUNCTIONAL COMPLEX 3 DEFINE WAY TO PROLIFERATE AND GROW, I FIND FASCINATING, HOW ARE THEY IN VIVO GETTING THEIR NUTRIENTS FOR GROWTH. BUT WHAT THEIR REALLY USING THE RESPIRATORY CHAIN IS TO CONTROL
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THEIR SUPPRESSIVE FUNCTION. IN THE ABSENCE OF FUNCTIONAL RESPIRATORY CHAIN, THEY DON'T SUPPRESS PROPERLY. THIS IS CONTINUES TO ADD TO THIS IDEA THAT MITOCHONDRIA COMMUNICATE WITH THE NUCLEUS. WE WORKED ON THE IDEA THAT IT RELEASE H 2O 2 TO FUNNEL TO TRANSCRIPTIONAL NODES. ONE OF THE CHALLENGES FOR THE FIELD, THE THAT CONTINUES TO HAPPEN IS EXACTLY HOW THE H 2 O2 SIGNAL TRANSDUCTION RELAY HAPPENS IN THE PIONEERING PROPOSING SOME ELEGANT MODELS HOW THIS WORKS. WE HAVE BEEN INTERESTED IN
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TAKING THE HIF SYSTEM AND FITTING WHAT 15 RESIDUES THAT PEROXIDE WOULD OXIDIZE IN THE HIF PATHWAY OR THE PROTEOHYDROXYLACES THAT ACCOUNT FOR THE BIOLOGY. THE OTHER THING WE'RE EXCITED ABOUT IS THIS IDEA THAT THE TCA CYCLE METABOLITES COULD BUILD UP TO CAUSE HAVOC. SO IN OUR WORLD H 2 O2 IS GENERALLY BENEFICIAL, SELECTED UNDER PHYSIOLOGICAL CONDITIONS, AND WHERE MITOCHONDRIAL METABOLITES MIGHT BE TOXIC IS WHEN YOU HAVE RESPIRATORY IMPAIRMENT OR DOWN REGULATION OF RESPIRATION OR SOMEHOW YOU HAVE
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THE NAD NADH RATIO OF NOD BALANCE AND TOO MUCH NAD THAT MIGHT TRIGGER SOMETHING LIKE 2 HYDROXY GLUTERATE WHICH CAUSE DNA METHYLATION HYPERMETHYLATION BUT REMEMBER 2 HYDROXY GLUTERATE BASED ON PATIENT DATA CAUSES NEURODEGENERATION. SO THAT'S SORT OF LEAVES US TO THINK MANY OF THE NAD DEPENDENT DECREASE IN NAD WHICH IS BEING LINK TO PATHOLOGY, ONE OR TWO HYDROXY GLUTERATE IS ONE ASPECT OF THAT MISSING LINK. AND IT IS A NEUROTOXIC MOLECULE THAT CAUSES HAVOC. BUT THE OTHER THING IS, WHETHER
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NATURE ALSO ORIGINALLY SELECTED THIS AS A PHYSIOLOGICAL SIGNAL DURING THE DEVELOPMENT BUT ONLY WHEN YOU ACCUMULATE HIGH LEVELS IT BECOMES A PATHOLOGIC MOLECULE JUST LIKE ROS CAN. AGAIN, WE HAVE TO DEVELOP NEWER MOUSE MODELS, TO PERTURB NAD NADH RATIO THE TRIHYDROXY GLUTERATE, MORE WAYS TO SLOP UP COMPLEX 3, OTHER SOURCES TO INVOKE BIOLOGY. ANYWAYS, THANKS AGAIN, MIKE AND TO THE INSTITUTE AND THANK YOU FOR YOUR PATIENTS. I THINK I HAVE GOT ABOUT TEN OR TWELVE MINUTES TO ANSWER SOME QUESTIONS.
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[APPLAUSE] >> GREAT JOB. THANK YOU VERY MUCH, FOR QUESTIONS PLEASE COME UP TO THE MICROPHONE. YES PLEASE. >> VERY NICE STORY PARTICULARLY ABOUT THE EPIGENETICS PART BUT I'M A LITTLE CONFUSED ABOUT YOUR ASSERTIONS AND H 2 O2. YOU HAVE SO MUCH SUPEROXIDE AND CATALASE IN THE MITOCHONDRIA, HOW DO YOU ACCOUNT FOR THIS? >> EXCELLENT QUESTION. HOW DOES SUPEROXIDE OR HYDROGEN PEROXIDE EVER ESCAPE BECAUSE AS WE KNOW THE MITOCHONDRIAL MATRIX IS SUPER WELL BUFFERED WITH ANTIOXIDANTS CORRECT? >> YEAH.
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>> SO ONE OF THE REASONS WE REALLY LIKE COMPLEX 3 AS A MAJOR SITE FOR THE RELEASE OF SUPEROXIDE, BECAUSE IT'S THE ONLY COMPLEX OR THE ONLY SYSTEM WITHIN THE MITOCHONDRIA THAT GENERATES SUPER OXIDE THAT DUMPS INTO THE MEMBRANE SPACE WHERE IT LEAKS OUT AND THERE'S SOD 1 IN THE MEMBRANE SPACE, WE CAN CONVERT PEROXIDE AND BOOM YOU GET IT RIGHT OUT OF THE MITOCHONDRIA OR THAT SUPER OXIDE GOES THROUGH VDAC CHANNELS. WE HAVE SEEN THAT. SO THAT'S ONE OF THE REASONS WE LIKE COMPLEX 3 AS MAJOR SITE OF
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THE SUPER OXIDE AND OBVIOUSLY BY DUMPING IN MEMBRANE SPACE YOU HAVE ACCESSIBILITY TO THE OUTER MEMBRANE QUICKLY, WHERE WE WOULD ARGUE THINGS LIKE HYDROXYLACES ARE THE DIRECT TARGETS OF THE MITOCHONDRIA WOULD HAVE TO BE. ONE OF THE THINGS THAT SUPPORTS THIS IDEA IS UNDER HYPOXIA,, THIS IS THE WORK OF MARK GILLESPIE, HE SHOWED WITH SENSORS AND EVERYTHING SOON AS HE MADE CELLS HYPOXIC. YOU HAVE DIFFUSE MITOCHONDRIAL STAINING PATTERN, THEY ALL WENT PERINUCLEAR. AND HE COULD SHOW THAT THE
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MITOCHONDRIA WERE THEN DUMPING HYDROGEN PEROXIDE IN THAT VICINITY. THAT WAS ALL DUE TO COMPLEX 3. >> DID YOU LOOK AT THE GLUTATHIONE AND OTHER LABELS IN THESE CELLS? >> YEAH. >> A LOT OF GLUTE TATHIONE AND EVERYTHING ELSE. JUST WONDERING IF THERE IS -- THERE'S SO MUCH OUT THERE. >> YEAH. SO THIS IS A MORE -- BEYOND MITOCHONDRIA, AND AGAIN I SHOULD DEFER TO -- AND HIS WORK ON THIS, ONE OF THE QUESTIONS IS, OKAY WE PROVIDE A SIMPLE EXPLANATION HOW COMPLEX 3 RELEASE ROS IN THE RIGHT
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COMPARTMENT IS THAT IS DUMPING IT AND THE NEXT QUESTION, HOW DOES THAT H 2 O2 RELAY ITS SIGNAL TO EVENTUALLY CAUSE CYSTEINE MODIFICATION WHICH ALER PROTEINS. THERE'S A VARIETY OF MODELS THAT HAVE BEEN PROPOSED INCLUDING THE PROXY THEMSELVES RELAYING, ANOTHER MODEL CALLED THE FLOOD GATE MODEL THAT AGAIN THIS IS A WORK OF SUBARY AND COLLEAGUES. SO THESE THINGS CONTINUE TO BE TRIGGERED OUT AND THOSE ARE STILL PERTINENT QUESTIONS. >> >> ONE MORE QUICK QUESTION. THAT IS DID YOU LOOK AT PHOTO
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RECEPTORS IN YOUR NICE? BECAUSE PHOTO RECEPTORS USE MAXIMUM AMOUNT OF OXYGEN FOR ANY POST -- CELL. >> NO. IF YOU'RE INTERESTED WE'RE HAPPY TO SEND YOU THE MICE. GREAT. CROSS IT TO A CRE AND SEE WHAT YOU GET. >> THANK YOU VERY MUCH. I'M GLAD AFTER TWO DECADES OF STRUGGLING TO INTRODUCE THE ROLE OF IMMUNITY IN CANCER PEOPLE ARE TALKING ABOUT THESE FANTASTIC TOPICS IN CANCER DEVELOPMENT. I THINK WHAT YOU WERE MENTIONING ABOUT MITOCHONDRIA GOING OFF AND ON AND BEING IN WAY TO CANCER,
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WE HAVE DETAILED THIS WHAT HAPPENS WHEN YOU INDUCE GROWTH PROMOTING ROLE OF TUMOR GENIC PROPERTY OF ACUTE INFLAMMATION YOU SHUT DOWN THE MITOCHONDRIA. SO THAT THE MITOCHONDRIA HAS CHANGED TO REGENERATE SUCCINATE AND ALL THOSE OTHER MEDIATORS THAT YOU MENTION. IN THIS PROCESS THE SHUTTLE TO MITOCHONDRIA ALSO IS AFFECTED. MY QUESTION IS, WHEN YOU WERE TALKING ABOUT ALPHA KETOGLUTERATE OR LDH, HAVE YOU LOOKED AT SOME MULTI-METABOLISM OF THE MACRO MOLECULES THAT ARE ALSO NEEDED, THE ENERGY FOR
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METABOLIZING ESSENTIAL AMINO ACIDS ISOLEUCINE. >> >> RIGHT. >> HAVE YOU LOOKED AT THOSE? AND ALSO MANY OTHER COMPONENTS, THIS IS VERY INTERESTING TOPIC. >> THANK YOU FOR BRINGING UP. WE HAVE NOT BUT THE COMMUNITIES ARE VERY INTERESTED IN BRANCHING APPLY KNOW ACIDS -- AMINO ACIDS. ONE OF THE PLACES THEY LIKE TO DUMP THE CARBONSES IS ONE TO ACETYL COA LEUCINE AND OTHER ONE VALINE UNDER SUCCINIL COA, THIS CAN FULFILL THE TCA CYCLE. THERE'S A SIMPLISTIC VIEW THAT EVERYTHING IS ABOUT GLUCOSE TO
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ACETYL COA TO ALPHA KETOGLUTERATE BUT ONE OF THE ONES WHICH CAN DO IT WE FIND AT LEAST IN CELL CULTURE THAT CAN SUBSTITUTES VERY WELL IS BRANCHING AMINO ACIDS. BRANCHING AMINO ACIDS ARE ELEVATED EARLY LIKE PANCREATIC CANCER SO I ARGUED THAT THERE'S GOOD REASONS TO THINK ABOUT BRANCHING AMINO ACID METABOLISM AS SORT OF AN ANOPOROTIC FULFILLING THE TCA CYCLE METABOLITES. BUT WE HAVEN'T OURSELVES MANIPULATED THIS SYSTEM. I KNOW THERE ARE OTHERS INTERESTED IN DOING THAT. >> IT'S A FASCINATING TOPIC.
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I HAVE PUBLISHED IT RECENTLY, IF YOU'RE INTERESTED WE CAN DISCUSS. >> >> THAT WOULD BE GREAT. THANK YOU. >> THANK YOU, ON OUR LEFT. >> SO IN THE TREG SETUP OR BACK GROUND, HAVE YOU TRIED EXPRESSING THE ALTERNATIVE OXIDASE? BECAUSE IN THAT CASE 2 HYDROXY GLUTERATE LEVELS GO DOWN BECAUSE YOU -- THE ALTERNATIVE DOESN'T GENERATE ROS LIKE -- SO WHAT HAPPENS? >> EXCELLENT. SO LET ME JUST -- SO AS I SHOWED YOU THE WAY WE RESCUE THE TUMORIGENITICITY IN THE CANCER WAS WE KNOCKED OUT COMPLEX 3,
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THE TUMORS DIDN'T GROW, WE PUT THIS ANCIENT ENZYME ALTERNATIVE OXIDASE WHICH ALLOW COMPLEX 1 AND 2 TO WORK IN ABSENCE OF 3 AND IT RESCUED THE TUMORS, ALLOW IT IS METABOLITES TO COME BACK AND THE 2 AG DOES GO DOWN IN THAT SETTING. WE HAVE DONE THOSE EXPERIMENTS. WE SHOULD BE ABLE TO USE THE SAME STRATEGY, IN OUR TREG SO WE GENERATE AD CONDITIONAL LOCK STOP LOX AND THE LOCUST OF THE AOX AND WE'RE NOW CROSSING THAT TO OUR COMPLEX 3. THAT'S EXACTLY -- WOULD BE ONE OF THE WAYS.
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AND WHAT'S NICE AS YOU POINTED OUT, IT DOESN'T RESCUE THE ROS. ALL IT RESCUES THE METABOLITES. >> THANKS. >> ON OUR RIGHT. >> VERY NICE. SO THE ONCOGENESIS MODEL YOU CHOSE THE RAS DRIVEN MODEL RAS DRIVEN ONCOGENESIS HAS BEEN SHOWN TO DEPEND IN SOME PART ON NF KAPPA B TO PREVENT RAS INDUCED SENESCENCE. SO DID YOU LOOK TO SEE WHETHER THIS MIGHT BE DEPENDENT ON NF KAPPA B AND ALSO IF YOU USE NON-RAS DRIVEN MODEL DO YOU SEE A SIMILAR DEPENDENCE IN TUMOR JOE AT THIS IN THISTY?
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>> WE HAVE NOT NF KAPPA B. I THINK WE HAVE BEEN LITTLE NAIVE IN SOME EXPERIMENTS, A LITTLE OBSESSED BY SHOWING THE NECESSITY OF THE RESPIRATORY CHAIN AND COMPLIMENTING WITH ALL THESE ANCIENT ENZYMES TO FIGURE EXACTLY WHAT ASPECT OF THE RESPIRATORY CHAIN BUT AS WE GET CLOSER NO U THE NEXT STEP, OKAY, THEN WHAT? THAT'S FOR US BOTH NF KAPPA B AN HIF CONTINUE TO BE THE ONES WE'RE MOST INTRIGUED BY. YOUR SECOND QUESTION WAS ABOUT -- >> JUST WHETHER -- >> WHETHER OTHER MODELS. >> A NON-RAS MODEL --
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>> RIGHT. SO WE HAVE DONE A MIG MODEL, OSTEOSARCOMA INDUCIBLE MIG MODEL THAT DEAN FILCHER'S LAB MADE SEVERAL YEARS AGO AND THE RESULTS HOLD UP IN THOSE MODELS. I THINK MORE AND MORE THERE'S PEOPLE USED A VARIETY OF GENETIC AND PHARMACOLOGICAL WAYS OF SUPPRESSING THE RESPIRATORY CHAIN AND THEIR FINDING SIMILAR THINGS. PROBABLY THE ONE THAT I'M MOST EXCITED ABOUT IS THAT CELLS THAT EMERGE, THAT ARE RESISTANT TO A PARTICULAR THERAPY, ANTI-ANGIOGENIC THERAPY, CHEMOTHERAPY, BRAF OR SOME
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TARGETED THERAPIES, THE CELLS THAT PERSIST FOR A WHILE, AND THEY'RE SLOW GROWING AND MIGHT HAVE SO CALLED TUMOR INITIATING STEM LIKE -- THOSE CELLS ALL TAUGHT ARE MUCH MORE SENSITIVE TO MITOCHONDRIAL RESPIRATORY CHAIN INHIBITORS THAN THE ORIGINAL TUMORS. I THINK THAT'S QUITE EXCITING. AVENUE TO PURSUE. >> EMERGING AREA. SO WE'RE GOING TO HAVE A RECEPTION IN THE NIH LIBRARY AFTER THIS LECTURE BUT LET'S THANK NAV AGAIN FOR GIVING US A GREAT PRESENTATION. [APPLAUSE]
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