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OKAY, I THINK WE CAN GET

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STARTED.

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WELCOME TO TODAY'S WEDNESDAY

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AFTERNOON LECTURE TALK.

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I'M DR. STORTs AND IT'S REALLY

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MY GREAT PLEASURE TO BRUCE

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TODAY'S SPEAKER ON BEHALF OF THE

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LAMBDA LUNCH SCIENTIFIC INTEREST

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GROUP.

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SO, LIKE I SAID IT'S A GREAT

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PLEASURE TO INTRODUCE

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DR. HERAN DARWIN BUT I NEED ON

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DO SOME LOGISTICAL THINGS.

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SO WE'RE LIVE HERE IN 

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LIPSETT HERE IN THE AMPHITHEATRE

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BUT THOSE WATCHING REMOTELY, YOU

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CAN STILL SUBMIT QUESTIONS TO

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THE SPEAKER EMPLOY BUT YOU SAYS

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SIMPLY CLICK THE BUTTON THAT

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SAYS ACCEPTED LIVE FEEDBACK,

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CORRECT?

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>> YEAH EMPLOY.

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>> WHICH IS DELOW YOUR
VIDEOCAST

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WINDOW AND THEN TYPE IN YOUR

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MESSAGE, CHRIS WILL MONITOR THEM

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AND HE WILL REPLAY THEM TO THE

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SPEAKER.

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FOR EVERYBODY, THE CME CODE IS

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50092.

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SO YOU CAN ALSO READ THAT HERE,

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BUT MOST IMPORTANTLY NOW, LET ME

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INTRODUCE DR. DARWIN.

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SHE IS A PROFESSOR OF

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MICROBIOLOGY AT NYU UNIVERSITY.

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SHE EARNED HER Ph.D. TODAYING

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SALMONELLA PATHOGENESIS, WITH

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DR. VIRGINIA MILLER WHO WAS

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FIRST AT THE UNIVERSITY OF

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CALIFORNIA LOS ANGELES AND THEN

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WENT TO WASHINGTON UNIVERSITY.

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SO THEN AFTER THAT, SHE WENT TO

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NEW YORK WHERE SHE CARRIED OUT

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POST DOCTORAL WORK WITH DR. KARL

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NATHAN AT WILD MEDICAL COLLEGE.

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AND THAT'S WHERE SHE FIRST

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STARTED WORKING ON TB AND I

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THINK SHE BECAME REALLY

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INTERESTED IN TB BECAUSE IT'S

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SUCH AN IMPORTANT BUG, SO THE

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CAUSATIVE AGENT, I SHOULD SAY OF

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TB, DID YOU BERKULOSEIS CAN BE

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CONSIDERED 1 OF THE MOST

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SUCCESSFUL PATHOGENS ON EITHER

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AND I PULLED THIS FROM

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DR. DARWIN'S WEBSITE THAT

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ONE-THIRD OF WORLD'S POPULATION

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IS INFECTED BY THIS, IS THAT

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CORRECT?

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DID YOU THE LONG CO EXISTENCE OF

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MICROBACTERIUM NTB WITH HUMANS

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HAS LIKELY RESULTED IN THE

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SELECTION OF HOST AND PATHOGEN

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POPULATIONS THAT PREVENT EACH

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OTHER'S EXTINCTION AND THAT'S

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SORT OF A THEME OF TODAY'S TALK

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AND SURPRISINGLY, RECENTLY

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DR. DARWIN'S GROUP FOUND THAT

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REACTIVE ALDEHYDES ARE EXPLOITED

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IN THIS UNEASY TRUCE BETWEEN

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HUMANS AND MTB.

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AND INTERESTINGLY A COMMON HUMAN

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MUTATION WAS SELECTED FOR BY

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BACTERIAL INFECTION.

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SO DR. DARWIN WAS NAMED FRONTIER

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SCIENCE AND FELLOW OF THE

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NATIONAL ACADEMY OF SCIENCES IN

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2012 AND BECAME A FELLOW OF THE

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AMERICAN ARK CAD ME OF

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MICROBIOLOGY IN 2016.

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SHE ALSO CURRENTLY SERVES ON THE

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BOARD OF DIRECTORS, OF THE VIERK

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LCHECK FOUNDATION WHICH I GUESS

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IS AN INTERESTING EXPERIENCE,

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ALSO IT HAS BEEN A TERRIFIC

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MENTOR TO MANY DIFFERENT

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STUDENTS AND FELLOWS.

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SO PLEASE JOIN ME IN WELCOMING

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DR. DARWIN.

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THANK YOU VERY MUCH FOR COMING

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TO VISIT US.

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[ APPLAUSE ]

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>> CAN YOU HEAR ME?

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THANK YOU.

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SO FIRST OF ALL THANK YOU SO

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MUCH TO SUSAN AND GI GI AND

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EVERYBODY ELSE FOR THIS

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WONDERFUL INVITATION, I HAD TO

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READ THE INVITATION TWICE, SO

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THANK YOU FOR BEING HERE CAN AS

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WELL AS VIRTUALLY.

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I'VE BEEN HAVING A DPRIT DAY AND

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I'M LOOKING IF ORDER TO TALKING

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TO EVERYONE OVER THE NEXT COUPLE

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DAYS.

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SO TODAY'S TALK HALF OF IT IS

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PUBLISHED BUT IT'S COMPLICATED

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AND IT REALLY LED TO THE STORY I

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WILL TALK ABOUT IN THE SECOND

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HALF WHICH IS ALL COMPLETELY

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UNPUBLISHED RIGHT NOW BUT IT IS

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UP ON BIOARCHIVE IF YOU CONSIDER

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THAT BEING PUB LESHED, AND OKAY,

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FOR THOSE WHO ARE COMING TO

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LAMBDA LUNCH, IT'S A COMLITELY

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DIFFERENT TOPIC AND ONLY

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IN-PERSON.

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SO THE ORGANIZATIONS INFORM I

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WORK ON IS CALLED MICROBACTERIUM

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TO BURKE CUEULOSEIS, IT IS THE

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STRIET COLONY THING, NOT AS

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PRETTY AS E.COLI, IT TAKES 2-3

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WEEKS TO FORM THESE COLONIES ON

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THE PLATE, IT'S A HUMAN

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EXCLUSIVE PATHOGEN SO THERE ARE

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ANIMAL MODELS OF INFECTION BUT

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IN THE REAL WORLD IT OHM INFECS

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HUMAN ANDS IT'S INCREDIBLY

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INFECTIOUS TAWZ IT ONLY TAKES A

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FEW TO INFECT A HUGH MAN, OKAY,

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IT IS THE LEADING CAUSE OF

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DEATH, GLOBALLY BY AN INFECTIOUS

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AGENT.

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SO IT WAS ONLY BEAT OUT BY SARS

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COV-2 IN THE LAST COUPLE YEARS

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BUT OVERALL IT KILLS AN

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ESTIMATED 1 AND HALF TO

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2 MILLION PEOPLE EVERY YEAR AND

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THIS HAS BEEN HAPPENING FOR

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THOUSANDS OF YORES, SO IT IS AN

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IMPORTANT PATHOGEN.

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AND THEREFORE, THERE'S A LOT OF

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MORTALITY AND A BIG PROBLEM AND

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I KNOW THERE ARE A LOT OF PEOPLE

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WHO WORK AT THE NIH, WHO WERE

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VERY CONCERNED AND MOTIVATED TO

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IDENTIFYING NEW DRUGS AND NIGH

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WAYS TO TREAT TB BECAUSE DRUG

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RESISTANCE IS A HIEWNL PROBLEM,

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SO CLIFF BARRY'S LAB HAS BEEN

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INCREDIBLY PIONEERING IN THEIR

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ABILITY TO IDENTIFY NEW DRUGS

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AND NEW WAYS TO AND ALSO USE OLD

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DRUGS TO TREAT TUBERCULOSEIS.

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SO EYE BIG PROBLEM IS THAT TB

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LIKES TO LIVE IN MACROPHAGES AND

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MACROPHAGES ARE SUPPOSED TO

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PROTECT YOU AGAINST INFEC,

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RIGHT?

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SO, THIS IS REALLY BEEN A

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PROBLEM FOR US AS SCIENTISTS

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BECAUSE MACROPHAGES ARE YOUR

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FIRST LINE OF DEFENSE AND YET

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IT'S NOT REALLY UNDERSTOOD HOW

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MACROPHAGES CONTROL BACTERIA,

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AND THIS IS NOT JUST TB SO THEY

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MAKE A LOT OF DIFFERENT

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MOLECULES FROM REACTIVE OXIEN

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AND NITROGEN SPECIES AS WELL AS

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ANTIMICROBIAL PEPTIDES SO

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UNDERSTANDING HOW MACROPHAGES

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KILL TB HAS BEEN A BIG GOAL OF

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MY LAB AS WELLsA THE LAB OF

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OTHERS.

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ONE THING WE DO KNOW ABOUT

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MACROPHAGES AND CAT, I'M SORRY

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BUT HAD IS MY MACROPHAGE, IS

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THAT WHEN YOU HAVE AN INFECTION,

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INTERFERON-GAMMA GETS INVOKED

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AND YOU STIMULATE A

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TRANSCRIPTIONAL RESPONSE.

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AND MANY, MANY THINGS HAPPEN,

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AND 1 OF THEM IS THE PRODUCTION

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OF NITRIC OXIDE BY THE ENZYME

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INDUCIBLE NITRIC OXIDE SYNTHASE

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AND IT DID APPEAR SO NO CAN

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DEFINITELY KILL BACTERIA INVITIO

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AND THERE'S EVIDENCE THAT

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MACROPHAGES USE IT TO KILL

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BACTERIA IN A CELL INTRINSIC

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MANNER IN VIVO.

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THE PROBLEM IS WE DON'T HAVE

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INOS DEFEBTIVE HUMANS OUT THERE

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SO IT'S HARD TO PROVE THIS IN

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HUMANS WE THERE'S A WHOLE DEBATE

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ABOUT THAT THAT WE CAN GET INTO

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IN THE QUESTIONS SESSION IF YOU

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WISH BUT I WILL FOCUS ON WHAT WE

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KNOW ABOUT IN MICE.

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00:07:35,571 --> 00:07:38,374
SO THE KIND OF MOST COMPELLING

200
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EVIDENCE TO SUPPORT THAT INOS

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00:07:40,943 --> 00:07:42,311
WAS IMPORTANT WAS DONE IN THE

202
00:07:42,311 --> 00:07:45,981
LAB MANY WREERS AGO NOW AND THIS

203
00:07:45,981 --> 00:07:48,617
IS WHEN JOHN MACK MICKING WAS A

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STUDENT IN THE LACK, AND THEY

205
00:07:50,186 --> 00:07:51,821
KNOCKED OUT THE SYNTHASE

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EXPRESSED IN MACROPHAGES AND

207
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FOUND THESE MICE ARE

208
00:07:55,124 --> 00:07:55,925
RIDICULOUSLY SUSCEPTIBLE TO TB

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AS WELL AS OTHER  INFECTION.

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SO THIS IS JUST A SURVIVAL

211
00:08:02,098 --> 00:08:04,066
CURVE, THIS IS A NUMBER OF MICE

212
00:08:04,066 --> 00:08:05,868
ALIVE OVER TIME AND DAYS POST

213
00:08:05,868 --> 00:08:06,635
INFECTION, NOT MINUTES AND WHAT

214
00:08:06,635 --> 00:08:11,040
YOU WILL SEE IS THAT C57 BLACK 6

215
00:08:11,040 --> 00:08:12,441
OR ILWILD-TYPE MICE WILL LIVE A

216
00:08:12,441 --> 00:08:15,244
VERY LONG TIME WITH A LOW TO

217
00:08:15,244 --> 00:08:16,312
MEDIUM DOSED AEROSOL INFECTION

218
00:08:16,312 --> 00:08:21,083
OF TB, SO THIS IS H37, RB AND IN

219
00:08:21,083 --> 00:08:24,053
A YEAR AND HALF ALL MICE WILL

220
00:08:24,053 --> 00:08:26,489
EVENTUALLY DIE EMPLOY NOW WE

221
00:08:26,489 --> 00:08:27,656
KNOW iNOS IS IMPORTANT BECAUSE

222
00:08:27,656 --> 00:08:31,093
IF YOU ACTIVATE IT, THESE MYSELF

223
00:08:31,093 --> 00:08:31,927
ARE RIDICULOUSLY SUSCEPTIBLE TO

224
00:08:31,927 --> 00:08:33,262
INFECTION, BUT THE THING THAT'S

225
00:08:33,262 --> 00:08:34,964
REMARKABLE TO ME IS WHEN YOU

226
00:08:34,964 --> 00:08:36,365
LOOK AT THIS CURVE AT THE END OF

227
00:08:36,365 --> 00:08:38,067
THE DAY, EACH THE WILD-TYPE MICE

228
00:08:38,067 --> 00:08:41,237
ALL DIE OF TB, IT JUST TAKES A

229
00:08:41,237 --> 00:08:42,671
REALLY LONG TIME AND THIS IS

230
00:08:42,671 --> 00:08:43,739
KIND OF DOSE DEPENDENT.

231
00:08:43,739 --> 00:08:45,975
IF YOU GIVE THEM MORE BACTERIA,

232
00:08:45,975 --> 00:08:47,743
THEY WILL DIE FASTER.

233
00:08:47,743 --> 00:08:50,412
SO THE QUESTION WE HAD WAS HOW

234
00:08:50,412 --> 00:08:52,748
DOES THE BACTERIA PERSIST IN THE

235
00:08:52,748 --> 00:08:54,116
FACE OF NITRIC OXIDE STRESS, AND

236
00:08:54,116 --> 00:08:56,719
SO THIS IS WHAT I--THIS IS THE

237
00:08:56,719 --> 00:08:59,121
QUESTION I ASKED AS A POST DOCK

238
00:08:59,121 --> 00:09:00,422
IN THE NATHAN LAB ALMOST 20

239
00:09:00,422 --> 00:09:03,526
YEARS AGO AND I DID A BIG

240
00:09:03,526 --> 00:09:05,394
GENETIC SCREEN LOOKING FOR

241
00:09:05,394 --> 00:09:07,563
MUSEUM AT THAT POINTS WITH

242
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NITRIC OXIDE HOPING THEY WILL BE

243
00:09:09,832 --> 00:09:10,666
ATTENUATE IN VIVO.

244
00:09:10,666 --> 00:09:12,968
WE SUCCEEDED AND WE FOUND THAT

245
00:09:12,968 --> 00:09:15,771
THE PROTEOSOME WAS REQUIRED FOR

246
00:09:15,771 --> 00:09:17,173
THIS PHENOTYPE.

247
00:09:17,173 --> 00:09:19,608
SO THE PROTEOSOME, OKAY, SO IF

248
00:09:19,608 --> 00:09:20,776
YOU'RE A MICROBIOLOGIST LIKE

249
00:09:20,776 --> 00:09:23,112
YOURS TRULY, YOU DON'T REALLY

250
00:09:23,112 --> 00:09:25,347
THINK ABOUT PROTEOSOMES BECAUSE

251
00:09:25,347 --> 00:09:26,315
MOST NORMAL BACTERIA DON'T HAVE

252
00:09:26,315 --> 00:09:27,283
THEM.

253
00:09:27,283 --> 00:09:30,319
WE HAVE THINGS LIKE CLIP P AND

254
00:09:30,319 --> 00:09:31,453
OTHER PROTEASES BUT THEIR

255
00:09:31,453 --> 00:09:33,122
BACTERIA, WHICH IS A BIG CLASS

256
00:09:33,122 --> 00:09:35,124
OF BACTERIA, THEY DO ENCODE

257
00:09:35,124 --> 00:09:37,092
PROTEOSOMES WITH MAYBE A FEW

258
00:09:37,092 --> 00:09:39,161
MINOR EXCEPTIONS AND THESE

259
00:09:39,161 --> 00:09:40,996
PROTEOSOMES ARE BARRELL SHAPED

260
00:09:40,996 --> 00:09:43,399
PROTEASES THAT ARE ENCLOSED,

261
00:09:43,399 --> 00:09:44,900
THEY ARE BIOCHEMICALLY AND

262
00:09:44,900 --> 00:09:46,735
GENETICALLY HIGHLY SIMILAR TO

263
00:09:46,735 --> 00:09:49,538
THOSE FOUND IN EUKARYOTES.

264
00:09:49,538 --> 00:09:51,040
THERE'S AN ATPA CHAPERON LIKE

265
00:09:51,040 --> 00:09:54,009
CLIP X, IT'S A HEXAMERAND IT

266
00:09:54,009 --> 00:09:55,411
HELPS UNFOLD PROTEINS FOR

267
00:09:55,411 --> 00:09:57,079
DEGRADATION DPRAIDATION.

268
00:09:57,079 --> 00:09:58,647
THE WAY PROTEINS ARE TARGETED TO

269
00:09:58,647 --> 00:10:01,016
THE SYSTEM OR THE PROTEOSOME

270
00:10:01,016 --> 00:10:04,253
SYSTEM IS FOR A SMALL 64 AMINO

271
00:10:04,253 --> 00:10:05,054
PROTEIN THAT IS MOSTLY

272
00:10:05,054 --> 00:10:08,657
DISORDERED BUT AS KYLEY WALT

273
00:10:08,657 --> 00:10:10,392
WALTERS HELPED US SHOW YEARS AGO

274
00:10:10,392 --> 00:10:13,262
THAT IT IS IRPT ACTING WITH THE

275
00:10:13,262 --> 00:10:20,636
ATP ACE, SO THIS PROTEIN FIRST

276
00:10:20,636 --> 00:10:27,076
HAS A GLUTAMINE BY AN ENZYME

277
00:10:27,076 --> 00:10:28,410
DISCOVERED BY WEBB'S LAB.

278
00:10:28,410 --> 00:10:29,645
THEN THIS BECOMES AMENABLE BY

279
00:10:29,645 --> 00:10:33,949
PATH A WHICH IS THE ONLY KNOWN

280
00:10:33,949 --> 00:10:36,719
POP LIGASE, AND IT

281
00:10:36,719 --> 00:10:37,987
PHOSPHORYLATES THE GLUTAMATE

282
00:10:37,987 --> 00:10:40,856
THAT MAKE ITS ATTACK BY A BI

283
00:10:40,856 --> 00:10:43,092
SEEN THATNY NEEDS TO GET

284
00:10:43,092 --> 00:10:43,459
DEGREATED AND.

285
00:10:43,459 --> 00:10:47,329
IT'S TO GET THE TARGETED TO THE

286
00:10:47,329 --> 00:10:48,931
PROTEOSOME FOR DEGRADATION, I

287
00:10:48,931 --> 00:10:53,369
CALL THIS THE PROTEOSOME OR PPS,

288
00:10:53,369 --> 00:10:54,503
IT'S REQUIRED FOR NITRIC OXIDE

289
00:10:54,503 --> 00:10:56,438
RESISTANCE AND MORE BROADLY

290
00:10:56,438 --> 00:10:58,540
NEEDED FOR ROBUST VIRULENCE IN

291
00:10:58,540 --> 00:10:59,642
AN ANIMAL INFECTION MODEL.

292
00:10:59,642 --> 00:11:03,379
OKAY, SO HOW DOES THE PROTEIN

293
00:11:03,379 --> 00:11:04,613
PROTECT AGAINST NITRIC OXIDE

294
00:11:04,613 --> 00:11:05,648
TOXICITY, SO THIS WAS THE

295
00:11:05,648 --> 00:11:07,116
QUESTION THAT TOOK A LONG TIME

296
00:11:07,116 --> 00:11:08,684
TO ANSWER BECAUSE IT WASN'T

297
00:11:08,684 --> 00:11:10,953
SUPER EASY AND I ALSO HAD TO

298
00:11:10,953 --> 00:11:12,187
FIND A VERY INTREPID PERSON TO

299
00:11:12,187 --> 00:11:14,990
TAKE IT ON AND THIS WAS DONE BY

300
00:11:14,990 --> 00:11:16,325
A FORMER POST DOC,

301
00:11:16,325 --> 00:11:17,993
[INDISCERNIBLE] WHO RUNS OUR

302
00:11:17,993 --> 00:11:19,061
VACCINE CENTER AT NYU AND

303
00:11:19,061 --> 00:11:22,264
LAWEDDER --WHAT SHE

304
00:11:22,264 --> 00:11:24,400
DID WAS SHE WANTED TO TEST

305
00:11:24,400 --> 00:11:25,067
HYPOTHESIS, SO THE FIRST

306
00:11:25,067 --> 00:11:27,136
HYPOTHESIS WAS THAT THE

307
00:11:27,136 --> 00:11:29,471
ACCUMULATION OF MANY DAMAGED

308
00:11:29,471 --> 00:11:31,774
PROTEINS FROM LIKE NITROSALATION

309
00:11:31,774 --> 00:11:33,242
OR NITRATION, LEADS TO CELL

310
00:11:33,242 --> 00:11:35,244
DEATH, RIGHT, SO PROTEIN IMAWLT

311
00:11:35,244 --> 00:11:36,779
CONTROLS IS VERY IMPORTANT THIS

312
00:11:36,779 --> 00:11:38,781
ALL FORMS OF LIFE AS WE KNOW AND

313
00:11:38,781 --> 00:11:44,520
WE QUICKLY RULED OUT THIS

314
00:11:44,520 --> 00:11:45,220
HYPOTHESIS MAINLY BECAUSE,

315
00:11:45,220 --> 00:11:48,524
NITRIC OXIDE STRESS, THE

316
00:11:48,524 --> 00:11:49,758
SENSITIVITY OF PROTEOSOME SEEMS

317
00:11:49,758 --> 00:11:51,193
SPECIFIC SO IF YOU THRESHOLD

318
00:11:51,193 --> 00:11:52,594
OTHER TRESESS AT THE MUSEUM

319
00:11:52,594 --> 00:11:56,365
TABTS THEY DID PERFECTLY FINE.

320
00:11:56,365 --> 00:11:56,799
OKAY.

321
00:11:56,799 --> 00:11:57,366
THE SECOND HYPOTHESIS THAT

322
00:11:57,366 --> 00:11:58,967
TURNED ON UTR TO BE CORRECT OR

323
00:11:58,967 --> 00:12:00,069
ELSE I WOULDN'T BE TELLING YOU

324
00:12:00,069 --> 00:12:03,072
ABOUT THIS IS MAYBE THERE WAS 1

325
00:12:03,072 --> 00:12:06,709
PROTEOSOME SUBTRAIT THAT WHEN

326
00:12:06,709 --> 00:12:08,077
ACCUMULATED LED TO NO

327
00:12:08,077 --> 00:12:08,444
SENSITIVITY.

328
00:12:08,444 --> 00:12:10,746
SO THE WAY IT LOOKED IS IN THE

329
00:12:10,746 --> 00:12:12,247
ABSENCE OF THE PROTEOSOME, HAVE

330
00:12:12,247 --> 00:12:14,249
YOU THE ACCUMULATION OF A

331
00:12:14,249 --> 00:12:16,485
MYTHICAL SUBSTRATE AND IN THE

332
00:12:16,485 --> 00:12:19,455
PRESENCE OF NITRIC OXIDE THE,

333
00:12:19,455 --> 00:12:20,122
BACTERIA ARE KILLED.

334
00:12:20,122 --> 00:12:21,590
IN MY LAB WE DO GENETICS

335
00:12:21,590 --> 00:12:22,558
SOPHISTICATEDY WOO DID A

336
00:12:22,558 --> 00:12:24,093
SUPPRESSOR KREEN AND WE LOOKED

337
00:12:24,093 --> 00:12:29,598
FOR MUTATIONS THAT WOULD MAKE A

338
00:12:29,598 --> 00:12:30,766
PROTEOSOME MUTANT RESISTANT TO

339
00:12:30,766 --> 00:12:32,801
NITRIC OXIDE, SO YOU GET RID OF

340
00:12:32,801 --> 00:12:35,070
SUBSTRATE THEN YOU GET RID OF NO

341
00:12:35,070 --> 00:12:35,371
SENSITIVITY.

342
00:12:35,371 --> 00:12:37,306
SO I WILL SUMMARIZE WHAT WAS A

343
00:12:37,306 --> 00:12:38,440
VERY EPIC SUPPRESSOR KREEN THAT

344
00:12:38,440 --> 00:12:41,443
WAS DONE BY MARIE.

345
00:12:41,443 --> 00:12:44,713
SO FIRSTLY, SHE FOUND THAT--SHE

346
00:12:44,713 --> 00:12:46,682
FOUND 2 INDEPENDENT MUTATIONS

347
00:12:46,682 --> 00:12:49,518
THAT KILLED AN EPIZYME CALLED

348
00:12:49,518 --> 00:12:52,955
LONELY GUY OR LOG, AND THIS SHE

349
00:12:52,955 --> 00:12:57,793
DISCOVERED WAS A POP IELTED

350
00:12:57,793 --> 00:13:07,936
SUBSTRATE, IT CATALYZES THE

351
00:13:07,936 --> 00:13:09,338
SYNTHESIS, AND CYTOKINEINS ARE

352
00:13:09,338 --> 00:13:11,673
USED FOR SIGNALING IN PLANTS,

353
00:13:11,673 --> 00:13:13,442
THEY HAVE 9 COPIES AND IF YOU

354
00:13:13,442 --> 00:13:17,613
MUTATE 1 YOU DISRUPT GROWTH

355
00:13:17,613 --> 00:13:17,980
BASICALLY.

356
00:13:17,980 --> 00:13:21,183
SO TURNS OUT TB ACTUALLY MAKES

357
00:13:21,183 --> 00:13:23,519
CYTOKININES AND AND IF YOU HAVE

358
00:13:23,519 --> 00:13:26,422
A PROTEOSOME, THEY HYPER SECRETE

359
00:13:26,422 --> 00:13:27,089
CYTOKININES, SO THAT WAS

360
00:13:27,089 --> 00:13:29,091
INTERESTING AND WE WANTED TO

361
00:13:29,091 --> 00:13:31,994
KNOW, OKAY, ARE THE CYTOKININES

362
00:13:31,994 --> 00:13:33,896
INDUCING IMPORTANT FOR THE

363
00:13:33,896 --> 00:13:35,297
EXPRESSION OF SOMETHING THAT HAS

364
00:13:35,297 --> 00:13:37,499
TO DO WITH NITRIC OXIDE

365
00:13:37,499 --> 00:13:40,436
SENSITIVITY SO WE DID AN RNA SEQ

366
00:13:40,436 --> 00:13:42,838
EXPERIMENT AND FOUND THIS 1 GENE

367
00:13:42,838 --> 00:13:47,109
CALLED LOW A OR RV0077 C WAS

368
00:13:47,109 --> 00:13:53,382
HIGHLY INDUCED IN THE PRESENCE

369
00:13:53,382 --> 00:13:54,383
OF CYTOKININE.

370
00:13:54,383 --> 00:13:55,717
AND WHAT MARIE FIGURED OUT IS

371
00:13:55,717 --> 00:13:59,388
THEY LOSE A LOSS IN STAINING.

372
00:13:59,388 --> 00:14:02,391
SO MICROBACTERIA ARE NOT

373
00:14:02,391 --> 00:14:04,026
GRANPOSITIVES, IT JUST GRINDS MY

374
00:14:04,026 --> 00:14:05,694
EARS WHEN I HEAR PEOPLE SAY

375
00:14:05,694 --> 00:14:07,930
THAT, THEY ARE NOT, THEY ARE

376
00:14:07,930 --> 00:14:10,365
ACID FAST BACTERIA BECAUSE THEY

377
00:14:10,365 --> 00:14:11,433
DON'T STAIN WITH GRAHAM STAIN,

378
00:14:11,433 --> 00:14:13,001
AND IF YOU STAIN THEM THEY'RE

379
00:14:13,001 --> 00:14:16,071
HOT PINK, RIGHT IN BUT WHEN

380
00:14:16,071 --> 00:14:17,272
MARIE ADDED CYTOKININE AND TRIED

381
00:14:17,272 --> 00:14:19,141
TO STAIN THEM, SHE HAD A HARD

382
00:14:19,141 --> 00:14:22,478
TIME SEEING THE BACTERIA.

383
00:14:22,478 --> 00:14:24,112
IF YOU KNOCK OUT THE GENE THAT

384
00:14:24,112 --> 00:14:25,814
IS STRONGLY INDUCED BY

385
00:14:25,814 --> 00:14:26,849
CYTOKININE, YOU LOSE THIS

386
00:14:26,849 --> 00:14:28,250
ABILITY TO GHOST, RIGHT?

387
00:14:28,250 --> 00:14:29,751
SO THEY JUST KIND OF STAY PINK

388
00:14:29,751 --> 00:14:31,753
AND I DO THINK THEY LOOK

389
00:14:31,753 --> 00:14:33,121
DIFFERENT FOR REASONS WE DON'T

390
00:14:33,121 --> 00:14:34,656
UNDERSTAND, YOU CAN COMPLEMENT

391
00:14:34,656 --> 00:14:35,824
THIS MUTATION IN SINGLE COPY BUT

392
00:14:35,824 --> 00:14:38,927
WHAT WAS FUN IS WE OOH DENTIFIED

393
00:14:38,927 --> 00:14:40,262
THE TRANSCRIPTIONAL REPRESSOR OF

394
00:14:40,262 --> 00:14:42,364
LOWER A THAT'S RESPONDING TO THE

395
00:14:42,364 --> 00:14:44,132
CYTOKINE IIN, IF YOU KNOCK THAT

396
00:14:44,132 --> 00:14:46,535
OUT YOU HAVE CONSTITTATIVE

397
00:14:46,535 --> 00:14:48,904
EXPRESSION OF LOWERA, AND AS A

398
00:14:48,904 --> 00:14:52,741
CONSEQUENCE YOU HAVE IMOAOF

399
00:14:52,741 --> 00:14:53,742
THING IRRESPECTIVE OF

400
00:14:53,742 --> 00:14:54,042
CYTOKININE.

401
00:14:54,042 --> 00:14:55,210
THIS WAS REALLY COOL, HOWEVER

402
00:14:55,210 --> 00:14:56,979
THIS HAS NOTHING TO DO WITH

403
00:14:56,979 --> 00:14:58,847
NITRIC OXIDE AND IN FACT, ANY OF

404
00:14:58,847 --> 00:15:00,282
THOSE MUTANTS THERE WAS NO

405
00:15:00,282 --> 00:15:02,885
EFFECT ON VIRULENCE, SO WE HAVE

406
00:15:02,885 --> 00:15:05,787
NO IDEA OF WHAT THE ROLE OF

407
00:15:05,787 --> 00:15:06,855
GHOSTING IS, MAYBE IT'S SPECIFIC

408
00:15:06,855 --> 00:15:09,024
TO HOST MODEL OF INFECTION OR

409
00:15:09,024 --> 00:15:11,460
MAYBE IT'S SPECIFIC TO HUMANS OF

410
00:15:11,460 --> 00:15:13,595
COURSE WHICH WE CAN'T REALLY

411
00:15:13,595 --> 00:15:14,463
TEST, MAYBE DIFFERENT MOUSE

412
00:15:14,463 --> 00:15:16,698
MODELS WILL GIVE YOU A DIFFERENT

413
00:15:16,698 --> 00:15:17,566
PHENOTYPE BUT NONETHELESS, WOE

414
00:15:17,566 --> 00:15:19,334
MOVED ON BECAUSE IT HAD NOTHING

415
00:15:19,334 --> 00:15:23,605
TO DO WITH NITRIC OXIDE SO WE

416
00:15:23,605 --> 00:15:26,508
THOUGHT, SO HOW ARE THEY LINKED

417
00:15:26,508 --> 00:15:28,310
TO NITRIC OXIDE SENSITIVITY.

418
00:15:28,310 --> 00:15:30,112
SO MARIE, SO YOU KNOW, IT'S

419
00:15:30,112 --> 00:15:31,280
REALLY IMPORTANT, I THINK FOR

420
00:15:31,280 --> 00:15:32,681
TRAINEES TO KNOW AN HOUR IN THE

421
00:15:32,681 --> 00:15:34,850
LIBRARY CAN SAVE YOU WEEKSA THE

422
00:15:34,850 --> 00:15:36,485
BENCH AND THAT IS CERTAINLY

423
00:15:36,485 --> 00:15:37,786
STILL TRUE AND MARIE WAS DOING

424
00:15:37,786 --> 00:15:38,620
READING AND I REMEMBER WALKING

425
00:15:38,620 --> 00:15:39,821
INTO THE LAB AND SHE'S LIKE, I

426
00:15:39,821 --> 00:15:41,456
THINK I HAVE IT, APPROXIMATE SHE

427
00:15:41,456 --> 00:15:44,059
SAID YOU KNOW WHAT, CYTOKINEINS

428
00:15:44,059 --> 00:15:49,665
ALWAYS ARE BROKEN DOWN INTO

429
00:15:49,665 --> 00:15:50,933
ALDEHYDES AND ADENINE, SO I

430
00:15:50,933 --> 00:15:52,768
EVAPORATE SHOWN YOU A KITE O

431
00:15:52,768 --> 00:15:56,071
KINE YET, BUT THIS IS CALLED I.

432
00:15:56,071 --> 00:15:59,274
PERFORM SO THERE'S THE ADENINE,

433
00:15:59,274 --> 00:16:03,211
CAN YOU ALSO HAVE ACTUALLY A

434
00:16:03,211 --> 00:16:05,347
METHYL THIOS, AND THEN HAVE YOU

435
00:16:05,347 --> 00:16:08,817
THE NITROIEN 6 MODIFICATION AND

436
00:16:08,817 --> 00:16:11,520
IN PLANTS WHEN THAT'S REMOVED

437
00:16:11,520 --> 00:16:14,256
YOU GET AN ALDEHYDE, SO THESE

438
00:16:14,256 --> 00:16:15,090
ALDEHYDES ARE INCREDIBLE

439
00:16:15,090 --> 00:16:16,758
LOAMACYY REACTIVE AND THIS

440
00:16:16,758 --> 00:16:22,731
PARTICULAR ALDEHYDE WOULD BE 3

441
00:16:22,731 --> 00:16:24,833
METHUE BEAUT NOLL.

442
00:16:24,833 --> 00:16:27,369
HOWEVER, MARIE DETECTED THIS

443
00:16:27,369 --> 00:16:29,137
ALDEHYDE QUITE ABUNDANTLY IN

444
00:16:29,137 --> 00:16:29,972
PROTEOSOME DEFECTIVE STRAINS AND

445
00:16:29,972 --> 00:16:33,709
SHE WAS BT UNDERSTANDING WHY IS

446
00:16:33,709 --> 00:16:35,010
IT MAKING PARAHYDROXY BENZ

447
00:16:35,010 --> 00:16:36,645
ALDEHYDE AND SHE REALIZED

448
00:16:36,645 --> 00:16:39,982
THERE'S THIS KIND OF WEIRD

449
00:16:39,982 --> 00:16:41,149
CYTOKINEIN CALLED PARATOPOLYNN

450
00:16:41,149 --> 00:16:43,518
AND WE COULD DETECT IT IN T. B.,

451
00:16:43,518 --> 00:16:45,053
I DON'T KNOW IF WE REPORTED IT

452
00:16:45,053 --> 00:16:47,623
BECAUSE IT WAS SO LOW, BUT IF

453
00:16:47,623 --> 00:16:51,159
YOU REMOVE THIS IN 6 GROUP, YOU

454
00:16:51,159 --> 00:16:53,128
GET PARAHIDE BROXIE BENZ

455
00:16:53,128 --> 00:16:53,528
ALDEHYDE.

456
00:16:53,528 --> 00:16:55,297
SO THIS TESTS THE WHYED THAT

457
00:16:55,297 --> 00:16:58,200
MAYBE THE ALDEHYDES WERE SOMEHOW

458
00:16:58,200 --> 00:16:59,901
SENSITIZING THE BACTERIA IN

459
00:16:59,901 --> 00:17:01,870
NITRIC OXIDE, O TO TEST THE

460
00:17:01,870 --> 00:17:05,007
HYPOTHESIS WAS VERY EASE, WE

461
00:17:05,007 --> 00:17:07,009
TOOK ALDEHYDE AND ADDED IT TO

462
00:17:07,009 --> 00:17:08,577
WILD-TYPE TB IN THE PRESENCE OF

463
00:17:08,577 --> 00:17:09,711
NITRIC OXIDE AND TECHNOLOGY

464
00:17:09,711 --> 00:17:11,413
ORGANIZATION THIS TO SEE IF IT

465
00:17:11,413 --> 00:17:13,515
WOULD MAKE THEM MORE SENSITIVE

466
00:17:13,515 --> 00:17:16,985
TO NL, I THINK HAD IS THE FIRST

467
00:17:16,985 --> 00:17:18,220
SENSITIVITY I'M SHOWING YOU,

468
00:17:18,220 --> 00:17:21,390
WON'T BE THE LAST, SPOILER.

469
00:17:21,390 --> 00:17:22,691
HERE'SOT Y-AXIS IS A LOG SCALE

470
00:17:22,691 --> 00:17:24,926
OF THE NUMBER OF COLONY FORMING

471
00:17:24,926 --> 00:17:26,361
UNITS OF BACTERIA THAT WE TARTED

472
00:17:26,361 --> 00:17:28,330
WITH THE INPUT AND IMRAI IS

473
00:17:28,330 --> 00:17:30,232
ACIDIFIED MEDIA WHICH WE USE TO

474
00:17:30,232 --> 00:17:33,068
GENERATE N. O. AND THEY SIT IN

475
00:17:33,068 --> 00:17:35,871
THIS FOR 6 DAYS, SO THEY GROW A

476
00:17:35,871 --> 00:17:39,141
LITTLE OR AT A STATIC AND THEN

477
00:17:39,141 --> 00:17:41,243
YOU ADD SODIUM NITRITE.

478
00:17:41,243 --> 00:17:42,878
SO WILD-TYPE TB DIES A LITTLE

479
00:17:42,878 --> 00:17:46,415
BIT AND HERE IS THE MPA, OR

480
00:17:46,415 --> 00:17:47,549
CHAPERON MUTANT OF THE THE

481
00:17:47,549 --> 00:17:49,351
PROTEOSOME AND YOU CAN SEE IT

482
00:17:49,351 --> 00:17:52,354
DIES MORE, AND SPECIFIC TO N. O.

483
00:17:52,354 --> 00:17:58,093
SO IF MARIE ADDED PH BA, YOU CAN

484
00:17:58,093 --> 00:18:00,429
SEE YOU GET A DOSE DEPENDENT

485
00:18:00,429 --> 00:18:03,231
KILLS OF THE BACTERIA AND SHE

486
00:18:03,231 --> 00:18:04,066
GOT STERILIZATION OF THE CULTURE

487
00:18:04,066 --> 00:18:07,569
AND THIS WAS SPECIFIC TO MEDIA,

488
00:18:07,569 --> 00:18:09,805
IF YOU USE SODIUM NITRATE WHICH

489
00:18:09,805 --> 00:18:10,706
DOESN'T GENERATE N. O. WE

490
00:18:10,706 --> 00:18:15,844
WOULDN'T GET ANY  KILLING.

491
00:18:15,844 --> 00:18:19,281
NOW THE CYTOKINEIN WE MOSTLY LIE

492
00:18:19,281 --> 00:18:22,050
DETECTED IN CULTURES WAS

493
00:18:22,050 --> 00:18:22,918
ISOPENTINE REGIMEN ILLEGALS ALDA

494
00:18:22,918 --> 00:18:25,020
HIDES 19 AND THAT IS INEDIBLY

495
00:18:25,020 --> 00:18:26,388
VOLATILE AND SHE SAW THE SAME

496
00:18:26,388 --> 00:18:27,789
RESULT WHICH IS IF YOU ADD IT,

497
00:18:27,789 --> 00:18:30,058
YOU GET A DOSE DEPENDENT KILLING

498
00:18:30,058 --> 00:18:31,460
OF THE BACTERIAIA AND THIS AGAIN

499
00:18:31,460 --> 00:18:34,162
WAS IN THE MICROMOLAR RANGE.

500
00:18:34,162 --> 00:18:35,864
OKAY, SO THIS IS ALL PUBLISHED

501
00:18:35,864 --> 00:18:38,200
DATA AND JUST TO KIND OF

502
00:18:38,200 --> 00:18:42,003
SUMMARIZE ALL THIS, THE MODEL OF

503
00:18:42,003 --> 00:18:43,038
THE PROTEOSOME DEPENDENCE IS

504
00:18:43,038 --> 00:18:44,573
THAT LONELY GUY NEEDS TO AT A

505
00:18:44,573 --> 00:18:46,641
LONELY, RIGHT IN THE ABSENCE OF

506
00:18:46,641 --> 00:18:48,577
PROTEOSOMES YOU GET AN

507
00:18:48,577 --> 00:18:50,078
ACCUMULATION OF LONELY GUY, YOU

508
00:18:50,078 --> 00:18:52,080
GET AN ACCUMULATION OF

509
00:18:52,080 --> 00:18:54,249
CYTOKINEINS WE CAN DEFECT AND

510
00:18:54,249 --> 00:18:56,017
GET AN ACCUMULATION OF ALDEHYDES

511
00:18:56,017 --> 00:18:58,587
AND WE DETECT 1 ALDEHYDE.

512
00:18:58,587 --> 00:18:59,921
UNDER NORMAL CONDITIONS, THE

513
00:18:59,921 --> 00:19:01,490
ALDEHYDES ARE FINE, THEY'RE

514
00:19:01,490 --> 00:19:02,691
TOLERATED BY THE BACTERIA, IF WE

515
00:19:02,691 --> 00:19:05,827
ARE JUST GROWING THESE IN BROTH

516
00:19:05,827 --> 00:19:08,363
THEY'RE FINE, BUT IN THE

517
00:19:08,363 --> 00:19:09,698
PRESENCE OF NITRIC OXIDE, THE

518
00:19:09,698 --> 00:19:12,100
BACTERIA ARE VERY UNHAPPY AND

519
00:19:12,100 --> 00:19:13,702
ATTENUATE IN ANIMALS.

520
00:19:13,702 --> 00:19:20,942
OKAY, SO THAT'S KIND OF THE

521
00:19:20,942 --> 00:19:24,412
COMPLICATED WAY OF HOW THE

522
00:19:24,412 --> 00:19:25,480
PROTEOSOME PROTECTS THE NITRIC

523
00:19:25,480 --> 00:19:25,814
OXIDE.

524
00:19:25,814 --> 00:19:27,149
AND THIS IS WHERE I GET INTO THE

525
00:19:27,149 --> 00:19:30,352
MORE AND CRAZY STUFF AND THAT IS

526
00:19:30,352 --> 00:19:32,888
THAT ALDEHYDE SENSITIZES TB TO

527
00:19:32,888 --> 00:19:33,221
NITRIC OXIDE.

528
00:19:33,221 --> 00:19:34,689
MORE RECENTLY THIS YEAR WE

529
00:19:34,689 --> 00:19:37,893
PUBLISHED A STORY SHOWING THAT

530
00:19:37,893 --> 00:19:38,760
ALDEHYDES ALSO SENSITIZE TB TO

531
00:19:38,760 --> 00:19:41,363
COPPER AND THIS SEEPS TO BE, WE

532
00:19:41,363 --> 00:19:42,831
KIND OF WORKED OUT THE MECHANISM

533
00:19:42,831 --> 00:19:45,200
OF THIS, WE THINK THE ALDEHYDES

534
00:19:45,200 --> 00:19:47,202
MESS WITH CYSTINES IN COPPER

535
00:19:47,202 --> 00:19:49,538
SENSING PROTEIN ANDS THAT

536
00:19:49,538 --> 00:19:53,975
DISRUPTS RESISTANCE TO THE

537
00:19:53,975 --> 00:19:54,209
COPPER.

538
00:19:54,209 --> 00:19:55,811
SO SOMETHING THAT SEEMED

539
00:19:55,811 --> 00:19:56,778
VERY--JUMPED OUT TO ME WHEN WE

540
00:19:56,778 --> 00:19:58,680
WERE DOING THIS IS THAT ALDEHYDE

541
00:19:58,680 --> 00:20:01,249
SEEMED TO BE AN ARK CHILLIES

542
00:20:01,249 --> 00:20:03,552
HE'LL FOR TB, IT DOESN'T LIKE

543
00:20:03,552 --> 00:20:04,820
THE ACCUMULATION OF ALDEHYDES,

544
00:20:04,820 --> 00:20:07,088
IT DOESN'T LIKE TO SEE

545
00:20:07,088 --> 00:20:09,424
ALDEHYDES, EVERY, WHEN I

546
00:20:09,424 --> 00:20:10,692
LOOKEDDA THE LITERATURE, I

547
00:20:10,692 --> 00:20:12,761
WONDERED IF THERE WAS SOMETHING

548
00:20:12,761 --> 00:20:13,061
BIGGER HERE.

549
00:20:13,061 --> 00:20:13,995
THE CONCEPTUAL LEAP I WANT YOU

550
00:20:13,995 --> 00:20:15,397
TO BELIEVE BY THE END OF THE

551
00:20:15,397 --> 00:20:17,632
TORSETHAT WE HAVE EVOLVED TO

552
00:20:17,632 --> 00:20:19,367
PRODUS OR DIVERSE ALDEHYDES THAT

553
00:20:19,367 --> 00:20:21,837
WE PRODUCE TO HELP CONTROL

554
00:20:21,837 --> 00:20:22,804
BACTERIAL INFECTIONS NOT JUST TB

555
00:20:22,804 --> 00:20:33,315
AND THIS IS SOMETHING WE CALL

556
00:20:39,754 --> 00:20:41,323
ALDEHYDE HYPOTHESIS THAT YOU ARK

557
00:20:41,323 --> 00:20:42,958
KIEWMULATE LONELY GUY, YOU

558
00:20:42,958 --> 00:20:44,926
ACCUMULATE ALDEHYDE ANDS YOU

559
00:20:44,926 --> 00:20:45,727
BECOME SENSITIVE TO INFORM O.

560
00:20:45,727 --> 00:20:47,462
AND COPPER AND YOU DIE.

561
00:20:47,462 --> 00:20:49,998
BUT IT TURNS OUT THAT IF YOU

562
00:20:49,998 --> 00:20:52,334
LOOK AT THE LITERATURE, YOU

563
00:20:52,334 --> 00:20:54,236
FIEBD OUT THAT TB IS HIGHLY

564
00:20:54,236 --> 00:20:57,239
SENSITIVE TO MUSEUM TAIGS--I AM

565
00:20:57,239 --> 00:21:01,042
GOING TO TAKE OFF MY CARDIGAN

566
00:21:01,042 --> 00:21:03,144
BECAUSE I'M BOILING.

567
00:21:03,144 --> 00:21:07,115
OKAY, SO, TB IS HIGHLY SENSITIVE

568
00:21:07,115 --> 00:21:10,085
TO MUTATIONS THAT PERTURB

569
00:21:10,085 --> 00:21:11,720
CENTRAL METABOLISM, AND IN SOME

570
00:21:11,720 --> 00:21:12,988
CASES IT'S BECAUSE THEY

571
00:21:12,988 --> 00:21:14,589
ACCUMULATE 1 OR MORE ALDEHYDE,

572
00:21:14,589 --> 00:21:19,127
AND THE LAB AT CORNELL HAD MADE

573
00:21:19,127 --> 00:21:20,295
THIS OBSERVATION, WHAT'S REALLY

574
00:21:20,295 --> 00:21:22,130
REMARKABLE AND INTERESTING I

575
00:21:22,130 --> 00:21:24,866
THINK IN THE RECENT MAYBE 4

576
00:21:24,866 --> 00:21:29,004
YEARS, CLINICALLY, SEVERAL LABS

577
00:21:29,004 --> 00:21:29,905
HAVE INDEPENDENTLY NOTICED THAT

578
00:21:29,905 --> 00:21:32,040
TB SEEMS TO GET THESE LOSS OF

579
00:21:32,040 --> 00:21:34,276
FUNCTION MUTATIONS IN A GENE

580
00:21:34,276 --> 00:21:36,411
CALLED GLYCEROL KINASE OR GLPK,

581
00:21:36,411 --> 00:21:38,980
AND PROD UBIQUITINNATIONS DOWN

582
00:21:38,980 --> 00:21:40,315
STREAM OF GLPK INCLUDE ALDEHYDE,

583
00:21:40,315 --> 00:21:45,954
THIS IS WORK DONE BY THE TODAY

584
00:21:45,954 --> 00:21:46,154
LABS.

585
00:21:46,154 --> 00:21:51,026
WE, OR I SHOULD SAY MARIE FOUND

586
00:21:51,026 --> 00:22:01,169
AN INSERTION IN GLPK THAT

587
00:22:01,169 --> 00:22:02,537
SUGGESTED THAT,--I'LL GET TO WHY

588
00:22:02,537 --> 00:22:05,040
THIS IS INTERESTING BUT GLPK IS

589
00:22:05,040 --> 00:22:07,208
UPSTREAM OF A COUPLE DIFFERENT

590
00:22:07,208 --> 00:22:07,776
ALDEHYDES, RIGHT?

591
00:22:07,776 --> 00:22:11,346
OKAY, SO IN MAMMALS, SARAH'S LAB

592
00:22:11,346 --> 00:22:13,848
HAD REPORTED THAT WHEN YOU

593
00:22:13,848 --> 00:22:15,917
INFECT MACROPHAGES EATER MOUSE

594
00:22:15,917 --> 00:22:18,753
OR HUMAN THAT TB AND ISHT FERON

595
00:22:18,753 --> 00:22:20,722
IMAMMA INDUCED AEROBIC FLI

596
00:22:20,722 --> 00:22:22,357
COLSIS ALSO KNOWN AS WAR BERG,

597
00:22:22,357 --> 00:22:24,326
OR WAR BERG LIKE EFFECT.

598
00:22:24,326 --> 00:22:25,794
AND 1 OF THE THINGS THAT'S KIND

599
00:22:25,794 --> 00:22:29,864
OF FUNNY ABOUT THIS IS FLI

600
00:22:29,864 --> 00:22:31,199
COLSIS IS CONSERVED IN

601
00:22:31,199 --> 00:22:33,668
EVERYTHING, IT'S WHY IT'S CALLED

602
00:22:33,668 --> 00:22:36,304
CENTRAL METABOLISM.

603
00:22:36,304 --> 00:22:37,939
SO AS [INDISCERNIBLE] SAID, WHAT

604
00:22:37,939 --> 00:22:41,176
IS TRUE OF THE ELEPHANT IS TRUE

605
00:22:41,176 --> 00:22:41,743
OF E.COLI.

606
00:22:41,743 --> 00:22:43,445
I THINK WE HAVE TO REMEMBER THAT

607
00:22:43,445 --> 00:22:44,980
BECAUSE EVEN PEOPLE IN MY LAB

608
00:22:44,980 --> 00:22:46,014
FORGET ABOUT THIS BUT IF YOU

609
00:22:46,014 --> 00:22:51,786
LOOK AT THIS PATHWAY WITH

610
00:22:51,786 --> 00:22:59,527
GLUCOMETABOLISM, THESE ARE ALL

611
00:22:59,527 --> 00:23:01,830
ALDEHYDES, SO METHITG GLUE

612
00:23:01,830 --> 00:23:03,298
MARIOUS COLOSSAL IS AN ALDEHYDE,

613
00:23:03,298 --> 00:23:07,836
SO WHEN YOU INFECT THESE MOUSE

614
00:23:07,836 --> 00:23:12,407
MACROPHAGES THEY SECRETE BUCKETS

615
00:23:12,407 --> 00:23:14,309
OF METHYL TBLIS ON ILLEGALS, SO

616
00:23:14,309 --> 00:23:16,311
MAYBE WHAT'S BEING INDUCED TO

617
00:23:16,311 --> 00:23:18,713
HELP CLEAR THE INFECTION, OKAY?

618
00:23:18,713 --> 00:23:21,049
SO THIS IS WHY GLPK COULD PLAY

619
00:23:21,049 --> 00:23:25,053
IN, SO IF THIS WAS INSIDE THE

620
00:23:25,053 --> 00:23:27,622
BACTERIUM, IF GLYCEROL KINASE

621
00:23:27,622 --> 00:23:29,624
WILL PHOSPHORYLATE IT AND THEN A

622
00:23:29,624 --> 00:23:35,663
COUPLE STEPS DOWN WILL MAKE

623
00:23:35,663 --> 00:23:40,668
GLYCEROL, SO IF YOU LOWURE YOUR

624
00:23:40,668 --> 00:23:43,004
GLPK, YOU MIGHT LOWER YOUR

625
00:23:43,004 --> 00:23:45,640
GLYCEROL IN THE BACTERIA.

626
00:23:45,640 --> 00:23:47,776
SO SO THIS INDUCES

627
00:23:47,776 --> 00:23:50,145
ARE--ADMINISTRATIVE OWNIC MRI

628
00:23:50,145 --> 00:23:51,880
COLSIS AND SO WE ACCIDENT WANTED

629
00:23:51,880 --> 00:23:54,849
TO ASK IS IT POSSIBLE THAT THESE

630
00:23:54,849 --> 00:23:58,820
HOST DERIVED ALDEHYDES CAN KILL

631
00:23:58,820 --> 00:24:00,655
OR CONTROL TB.

632
00:24:00,655 --> 00:24:01,790
SO, THIS WAS AN EXPERIMENT MARIE

633
00:24:01,790 --> 00:24:04,192
HAD SET UP BEFORE SHE LEFT AND I

634
00:24:04,192 --> 00:24:04,993
REPEATED MORE RECENTLY AND THEN

635
00:24:04,993 --> 00:24:06,361
LET ME TELL YOU IT IS VERY

636
00:24:06,361 --> 00:24:07,562
SATISFYING WHEN YOU'RE THE PI

637
00:24:07,562 --> 00:24:10,565
AND YOU CAN REPEAT WHAT YOUR

638
00:24:10,565 --> 00:24:11,366
POST DOC DID.

639
00:24:11,366 --> 00:24:13,935
THEY'RE LAUGHING BUT IT'S TRUE,

640
00:24:13,935 --> 00:24:15,270
SO HERE'S FLI COLSIS COLSIS

641
00:24:15,270 --> 00:24:18,106
AGAIN AND WHAT I DID WAS I DID A

642
00:24:18,106 --> 00:24:19,741
NITRIC OXIDE ASSAY SO IN THIS

643
00:24:19,741 --> 00:24:21,376
CASE, I'M LOOKING FOR SYNERGY

644
00:24:21,376 --> 00:24:24,679
WITH NO, SO HERE IS THE CALLING

645
00:24:24,679 --> 00:24:25,880
FORMING UNITS LONG SCALE AND

646
00:24:25,880 --> 00:24:26,614
LOOK AT THE BLACK, SO YOU CAN

647
00:24:26,614 --> 00:24:33,154
SEE WITH THE ARK DITION OF

648
00:24:33,154 --> 00:24:37,525
MICROMOLAR CONCENTRATIONS OF

649
00:24:37,525 --> 00:24:41,029
GLYCOLYTIC ALDEHYDES, YOU WILL

650
00:24:41,029 --> 00:24:42,497
KILL THE BACTERIA WITH NO WHICH

651
00:24:42,497 --> 00:24:43,231
IS IMPORTANT.

652
00:24:43,231 --> 00:24:50,071
MY FAVORITE ALDEHYDE IS METHYL

653
00:24:50,071 --> 00:24:52,140
GLYXOL, AND IT KILLS BACTERIA

654
00:24:52,140 --> 00:24:54,375
BUT BY ITSELF AT THESE

655
00:24:54,375 --> 00:24:55,009
CONCENTRATIONS AGAIN MICROMOLAR

656
00:24:55,009 --> 00:24:56,277
YOU DON'T GET A LOT OF KILLS BUT

657
00:24:56,277 --> 00:25:00,014
IF YOU GO HIGHER YOU TART TO

658
00:25:00,014 --> 00:25:01,216
KILL THE BACTERIA.

659
00:25:01,216 --> 00:25:02,784
OKAY, SO, THE OTHER THINGS THAT

660
00:25:02,784 --> 00:25:04,752
HAPPEN DURING INFLAMMATION IS

661
00:25:04,752 --> 00:25:07,288
YOU GET REACTIVE OX GENERATED

662
00:25:07,288 --> 00:25:09,958
SPECIES RIGHT, SO WHAT ARE THE

663
00:25:09,958 --> 00:25:11,826
ROSS DOING, SO ROSS ARE

664
00:25:11,826 --> 00:25:13,128
IMPORTANT FOR GENERATING LIPID

665
00:25:13,128 --> 00:25:15,063
ALDEHYDES AND THESE ARE

666
00:25:15,063 --> 00:25:16,498
GENERATED BY LIPID PEROXIDATION

667
00:25:16,498 --> 00:25:20,502
SO YOU GET THINGS LIKE 4 HYDROXY

668
00:25:20,502 --> 00:25:21,769
AND DISCIPLINARY ALDEHYDE, AND

669
00:25:21,769 --> 00:25:26,374
SO, OF COURSE, THEN, WE WENT

670
00:25:26,374 --> 00:25:36,050
AHEAD AND TESTED THESE. 

671
00:25:36,050 --> 00:25:38,553
AND FHNE AND THEY WORK TOGETHER

672
00:25:38,553 --> 00:25:40,488
WELL TO KILL BACTERIAIA.

673
00:25:40,488 --> 00:25:44,626
SO, THAT WAS ALL VERY COOL AND

674
00:25:44,626 --> 00:25:45,827
LIKE INSPIRING, I THOUGHT BUT I

675
00:25:45,827 --> 00:25:47,328
THINK WHAT WAS REALLY REMARKABLE

676
00:25:47,328 --> 00:25:51,466
WAS THIS IDEA THAT MAYBE HUMANS

677
00:25:51,466 --> 00:25:55,503
HAVE EVOLVED AN ANTITB ROLE.

678
00:25:55,503 --> 00:25:58,239
BY USING THEIR OWN ALDEHYDES.

679
00:25:58,239 --> 00:26:01,643
SO THE MOST COMMON HUMAN GENETIC

680
00:26:01,643 --> 00:26:03,978
MUTATION ON IS AN ALD H2, I WILL

681
00:26:03,978 --> 00:26:07,148
ASK HOW MANY IN THIS AUDIENCE

682
00:26:07,148 --> 00:26:08,283
CANNOT DRINK ALCOHOL BECAUSE

683
00:26:08,283 --> 00:26:11,586
THEY GET RED?

684
00:26:11,586 --> 00:26:13,354
I KNEW ABOUT PONG, HE CAN'T BE

685
00:26:13,354 --> 00:26:15,990
THE ONLY 1 EMPLOY OKAY, WELL

686
00:26:15,990 --> 00:26:18,993
IT'S NOT ME, I'M WILD-TYPE BUT

687
00:26:18,993 --> 00:26:20,762
ANYWAY, THIS MUTATION AND SUPER

688
00:26:20,762 --> 00:26:22,830
COMMON AND IT'S IN A ABOUT A

689
00:26:22,830 --> 00:26:24,465
HALF BILLION PEOPLE, MOSTLY OF

690
00:26:24,465 --> 00:26:26,568
EAST ASIAN DESCENT AND IT'S A

691
00:26:26,568 --> 00:26:29,971
LOSS OF FUNCTION MUTATION, IT'S

692
00:26:29,971 --> 00:26:31,940
AN AMINO ACID,LY CONSERVED IN

693
00:26:31,940 --> 00:26:35,043
ALL THESE PEOPLE, THERE'S NOT 10

694
00:26:35,043 --> 00:26:38,046
SNPs, AND MAYBE A FEW GUYS AND

695
00:26:38,046 --> 00:26:40,081
HETEROZYGOUS DOMINANT SO THE

696
00:26:40,081 --> 00:26:41,349
ENZYME IS A TETRAMER, IF YOU

697
00:26:41,349 --> 00:26:47,388
HAVE 1 BAD COPY YOU WILL MAKE A

698
00:26:47,388 --> 00:26:48,356
FAILED ENZYME.

699
00:26:48,356 --> 00:26:50,792
AND IT TURNS OUT A GROUP IN

700
00:26:50,792 --> 00:26:52,527
KOREA WANTED TO KNOW WHY THEY

701
00:26:52,527 --> 00:26:54,329
HAD THIS MUTATION AND IF IT WAS

702
00:26:54,329 --> 00:26:55,897
LINKED TO ANYTHING APPROXIMATE

703
00:26:55,897 --> 00:26:57,498
AND WHAT THEY FOUND THAT WAS

704
00:26:57,498 --> 00:26:59,634
REMARKABLE IS PEOPLE WHO HAD

705
00:26:59,634 --> 00:27:02,637
THIS MUTATION WERE LESS LIKELY

706
00:27:02,637 --> 00:27:04,339
TO HAVE TUBERC CUEULOSEIS, AND

707
00:27:04,339 --> 00:27:07,275
THEY'RE LIKE FEBRUARY YOU LIVE A

708
00:27:07,275 --> 00:27:09,377
HELTIER LIVE STYLE, YOU'RE LESS

709
00:27:09,377 --> 00:27:11,412
LIKELY TO GET TB, I DON'T THINK

710
00:27:11,412 --> 00:27:12,347
THAT'S IT.

711
00:27:12,347 --> 00:27:14,415
SO WE DID META-ANALYSIS WITH

712
00:27:14,415 --> 00:27:15,550
SARAH AND HER COLLEAGUES LOOKING

713
00:27:15,550 --> 00:27:18,386
AT 2 OTHER COHORTS INCLUDING

714
00:27:18,386 --> 00:27:19,554
VIETNAM AND SINGAPORE AND WE

715
00:27:19,554 --> 00:27:21,189
FOUND THAT BASICALLY THE

716
00:27:21,189 --> 00:27:22,924
ASSOCIATION OF MUTATION WITH TB

717
00:27:22,924 --> 00:27:24,525
WAS EVEN STRONGER, RIGHT, THAN

718
00:27:24,525 --> 00:27:27,195
WHAT THEY FOUND IN THIS ORIGINAL

719
00:27:27,195 --> 00:27:30,798
PAPER AND AGAIN IT WAS ASSOCIATE

720
00:27:30,798 --> 00:27:32,200
WIDE PROTECTION AGAINST

721
00:27:32,200 --> 00:27:32,634
TUBERCULOSIS.

722
00:27:32,634 --> 00:27:34,402
SO COULD DISRUPTION OF THIS GENE

723
00:27:34,402 --> 00:27:36,904
RESULT IN RESISTANCE TO

724
00:27:36,904 --> 00:27:37,572
BACTERIALIN INFECTIONS, RIGHT IN

725
00:27:37,572 --> 00:27:38,673
HARD TO TEST THAT IN MUSEUM MANS

726
00:27:38,673 --> 00:27:40,742
BUT WE CAN TEST IT IN MICE, SO

727
00:27:40,742 --> 00:27:42,677
IN COLLABORATION WITH RUSSELL

728
00:27:42,677 --> 00:27:53,221
VANCE'S LAB, HIS POST DOC, MADE

729
00:27:53,621 --> 00:27:55,890
THE KNOCKING THE WHOLE THING OUT

730
00:27:55,890 --> 00:27:58,893
SO WE HAVE TO DO THIS WITH

731
00:27:58,893 --> 00:28:00,728
HOMOZYGOTES AND IN COLLABORATION

732
00:28:00,728 --> 00:28:02,764
WITH CHRIS CHAIN'S LAB, THEY HAD

733
00:28:02,764 --> 00:28:04,966
MADE THESE FORM ALDEHYDE SENSORS

734
00:28:04,966 --> 00:28:06,501
SO THESE ALDEHYDE SENSORS THAT

735
00:28:06,501 --> 00:28:07,468
COULD LOOK IN MACROPHAGES AND

736
00:28:07,468 --> 00:28:09,003
COULD NOT GET INTO THE DETAILS

737
00:28:09,003 --> 00:28:10,271
OF THE DIFFERENT 1S THAT THEY

738
00:28:10,271 --> 00:28:12,540
MADE BUT WHAT THEY FOUND WAS IN

739
00:28:12,540 --> 00:28:13,708
A BLACK 6 MOUSE BACKGROUND,

740
00:28:13,708 --> 00:28:15,677
OKAY, SO THIS IS JUST WILD-TYPE

741
00:28:15,677 --> 00:28:18,313
MICE, IF YOU INDUCE IT WITH

742
00:28:18,313 --> 00:28:19,580
INTERFERON-GAMMA AND A TLR

743
00:28:19,580 --> 00:28:23,818
AGONIST, YOU GET AN INDUCTION OF

744
00:28:23,818 --> 00:28:24,652
ALDEHYDE PRODUCTION, RIGHT?

745
00:28:24,652 --> 00:28:27,355
BUT IN THE LDH2 MICE, THEY'RE

746
00:28:27,355 --> 00:28:29,824
HIGH FOR ALDEHYDE, THAT WAS KIND

747
00:28:29,824 --> 00:28:30,558
OF COOL.

748
00:28:30,558 --> 00:28:33,127
BUT WHAT WAS REALLY NICE WAS THE

749
00:28:33,127 --> 00:28:35,029
INFECTION EXPERIMENT.

750
00:28:35,029 --> 00:28:39,200
SO STAN BARRY WHO'S A POST DOC

751
00:28:39,200 --> 00:28:44,739
IN SARAH STANLEY'S LAB, SO THIS

752
00:28:44,739 --> 00:28:46,974
IS EACH DOT IS A MOUSE AND EACH

753
00:28:46,974 --> 00:28:48,109
LINE IS A LUNG PAIR,

754
00:28:48,109 --> 00:28:49,877
SOPHISTICATEDY THIS A

755
00:28:49,877 --> 00:28:50,611
GENETICALLY SUSCEPTIBLE MOUSE,

756
00:28:50,611 --> 00:28:52,680
IT HAS AN INTERFERON, HAS TOO

757
00:28:52,680 --> 00:28:55,216
MUCH TYPE 1 INTERFERON AND THEY

758
00:28:55,216 --> 00:28:59,187
DIE VERY EARLY EMPLOY SO IF YOU

759
00:28:59,187 --> 00:29:01,656
PUT THE LDH MUTATION IN THE

760
00:29:01,656 --> 00:29:04,058
BACKGROUND IT GIVES THEM SOME

761
00:29:04,058 --> 00:29:05,827
LEVEL OF PROTECTION, RIGHT IN SO

762
00:29:05,827 --> 00:29:07,328
FEWER CFURKSs IF YOU LAY

763
00:29:07,328 --> 00:29:08,563
AROUND THIS MUTATION, AND WE DID

764
00:29:08,563 --> 00:29:10,765
IT IN THE B6 BACKGROUND.

765
00:29:10,765 --> 00:29:12,333
WE DIDN'T REALLY EXPECT TO SEE

766
00:29:12,333 --> 00:29:16,771
AN EFFECT WITH THE HEADS WHICH

767
00:29:16,771 --> 00:29:20,908
WE DON'T BUT THE ALD H2 KNOCK

768
00:29:20,908 --> 00:29:23,778
OUTS HAVE THIS IN THEIR LUNGS,

769
00:29:23,778 --> 00:29:25,980
THIS A COMPLETELY DIFFERENT GRAM

770
00:29:25,980 --> 00:29:28,316
NEGATIVE PATHOGEN, DONE ABOUT A

771
00:29:28,316 --> 00:29:30,251
OPPORTUNITY IN SARAH'S LAB,

772
00:29:30,251 --> 00:29:32,019
SANCHEZ, AND THERE ARE PAY FEWER

773
00:29:32,019 --> 00:29:34,389
BACTERIAER RAW DATA IN THE ALD

774
00:29:34,389 --> 00:29:35,957
H2 MICE.

775
00:29:35,957 --> 00:29:38,025
THEY COULD ACTUALLY, SO INVITRO

776
00:29:38,025 --> 00:29:39,961
MACROPHAGE SPRMS IT'S HARD TO DO

777
00:29:39,961 --> 00:29:41,796
THAT WITH TB BECAUSE TB IS SLOW,

778
00:29:41,796 --> 00:29:44,999
SO IN THE MACROPHAGES DON'T LIVE

779
00:29:44,999 --> 00:29:46,567
LONG, BUT, ANDRIEA COULD SHOW

780
00:29:46,567 --> 00:29:49,871
THIS WAS EFFECTIVE INVITRO, SO

781
00:29:49,871 --> 00:29:51,606
THERE WAS A CELL INTRINSIC

782
00:29:51,606 --> 00:29:54,409
EFFECT OF THE ALDEHYDES ON

783
00:29:54,409 --> 00:29:55,143
BACTERIAL GROWTH.

784
00:29:55,143 --> 00:29:56,577
SO WHAT I'M HOPING TO LEAVE YOU

785
00:29:56,577 --> 00:29:58,479
WITH AND THERE WILL BE PLENTY OF

786
00:29:58,479 --> 00:30:01,849
TIME FOR DISCUSSION IS THAT I

787
00:30:01,849 --> 00:30:04,952
THINK ALDEHYDES ARE NEWEL

788
00:30:04,952 --> 00:30:05,620
APPRECIATED ANTIMICROBIAL FACTOR

789
00:30:05,620 --> 00:30:07,188
SO I DIDN'T GET A CHANCE TO TALK

790
00:30:07,188 --> 00:30:08,689
ABOUT COPPER BUT THIS IS MANAGE

791
00:30:08,689 --> 00:30:11,459
MY LAB WORKED ON BUT WE THINK

792
00:30:11,459 --> 00:30:13,127
THAT ALDEHYDES HELP PROTENTIATE

793
00:30:13,127 --> 00:30:16,297
THE THINGS LIKE NO AND COPPER

794
00:30:16,297 --> 00:30:17,532
AND OTHER ANTIMICROBIAL

795
00:30:17,532 --> 00:30:18,633
MOLECULES THAT MACROPHAGES ARE

796
00:30:18,633 --> 00:30:19,734
MAKING AND CERTAINLY THE

797
00:30:19,734 --> 00:30:22,069
ALDEHYDES THEMSELVES ARE VERY

798
00:30:22,069 --> 00:30:26,841
GOOD AT ENACTIVATING BACTERIA

799
00:30:26,841 --> 00:30:28,609
AND PARASITES, WE DON'T KNOW

800
00:30:28,609 --> 00:30:29,811
THAT YET.

801
00:30:29,811 --> 00:30:31,179
WE PUBLISHED THIS HYPOTHESIS

802
00:30:31,179 --> 00:30:33,514
YEARS AGO BUT NOW THE PAPER

803
00:30:33,514 --> 00:30:35,583
THAT'S UNDERREVIEW IS KINE OF

804
00:30:35,583 --> 00:30:36,984
FINALLY TESTED THE HYPOTHESIS,

805
00:30:36,984 --> 00:30:38,085
IT'S LOOKY PRETTY GOOD.

806
00:30:38,085 --> 00:30:39,420
SO WHERE DO WE GO FROM THERE, I

807
00:30:39,420 --> 00:30:43,724
AM IS RISE AND TELL YOU WHAT

808
00:30:43,724 --> 00:30:44,826
WE'RE DOING NEXT.

809
00:30:44,826 --> 00:30:45,660
SO PHYSIOLOGIC ALDEHYDES

810
00:30:45,660 --> 00:30:46,961
PRODUCED DURING INFECTIONS ARE

811
00:30:46,961 --> 00:30:50,665
TOXIC TO TB, AND A COMMON HUMAN

812
00:30:50,665 --> 00:30:52,900
LOSS OF FUNCTION LOSS OF

813
00:30:52,900 --> 00:30:54,302
MUTATION IN ALDEHYDE

814
00:30:54,302 --> 00:30:55,303
DETOXIFICATION IS PROTECTIVE

815
00:30:55,303 --> 00:30:58,105
AGAINST MTB AND IT'S A PHENOTYPE

816
00:30:58,105 --> 00:31:00,107
THAT WE CAPILATULATED IN MICE.

817
00:31:00,107 --> 00:31:01,676
AND I THINK WHAT'S REALLY

818
00:31:01,676 --> 00:31:03,277
REMARKABLE, I AM NOT AN

819
00:31:03,277 --> 00:31:06,447
IMMUNOLOGIST, I AM JUST A HUMBLE

820
00:31:06,447 --> 00:31:09,450
MICROBIOLOGIST AND SOMEHOW BY

821
00:31:09,450 --> 00:31:12,987
STUDYING VERY FUNDAMENTAL

822
00:31:12,987 --> 00:31:13,754
BACTERIAL PHYSIOLOGY WE REVEALED

823
00:31:13,754 --> 00:31:14,956
AN IMPORTANT WEAKNESS IN THIS

824
00:31:14,956 --> 00:31:16,457
PATHOGEN AND I THINK THIS

825
00:31:16,457 --> 00:31:17,925
COLLABORATION WITH SARAH STANLEY

826
00:31:17,925 --> 00:31:19,293
HAS BEEN PHENOMENAL AND WE'RE

827
00:31:19,293 --> 00:31:21,028
REAL LEKS SIGHED ABOUT MOVING

828
00:31:21,028 --> 00:31:21,395
THINGS FORWARD.

829
00:31:21,395 --> 00:31:23,164
SO WHAT ARE WE DOING NOW?

830
00:31:23,164 --> 00:31:23,865
RIGHT?

831
00:31:23,865 --> 00:31:25,466
YOU GOT EVERYTHING, SO WHAT'S

832
00:31:25,466 --> 00:31:26,901
INTERESTING IS, THIS MUTATION

833
00:31:26,901 --> 00:31:28,836
WAS BELIEVED TO HAVE AROSE IN

834
00:31:28,836 --> 00:31:30,371
CHINA SEVERAL THOUSAND YEARS AGO

835
00:31:30,371 --> 00:31:32,039
AND IT OBVIOUSLY SPREAD LIKE

836
00:31:32,039 --> 00:31:36,410
WILDFIRE PROBABLY BECAUSE IT WAS

837
00:31:36,410 --> 00:31:40,314
GIVING SOME SORT OF FITNESS

838
00:31:40,314 --> 00:31:42,149
ADVANTAGE, SO IN 1995 A NEW

839
00:31:42,149 --> 00:31:45,553
LINEAGE OF TB WAS RECOGNIZED AS

840
00:31:45,553 --> 00:31:47,722
THE L2 OR BEIJING LINEAGE AND

841
00:31:47,722 --> 00:31:49,657
IT'S NAMED BEIJING WHERE IT WAS

842
00:31:49,657 --> 00:31:51,592
DOMINATING IN CHINA AND EMERGED

843
00:31:51,592 --> 00:31:52,793
SEVERAL THOUSAND YEARS AGO, SO

844
00:31:52,793 --> 00:31:55,129
BACK IN 1995 WHEN GENOMICS WERE

845
00:31:55,129 --> 00:31:56,430
COMING OUT AND PEOPLE WERE

846
00:31:56,430 --> 00:31:58,032
SAYING WE HAVE THESE DIFFERENT

847
00:31:58,032 --> 00:32:00,034
LINEAGES OF TB, PEOPLE THOUGHT,

848
00:32:00,034 --> 00:32:02,370
WELL MAYBE IN EMERGED FROM

849
00:32:02,370 --> 00:32:05,072
ANTIBIOTIC USAGE IN ASIA,

850
00:32:05,072 --> 00:32:06,807
VACCINATION IN ASIA, BUT WITH

851
00:32:06,807 --> 00:32:08,876
DEEPER ANALYSIS, IT'S NOW CLEAR

852
00:32:08,876 --> 00:32:11,145
THAT THE BEIJING LINEAGE EMERGED

853
00:32:11,145 --> 00:32:13,314
SEVERAL THOUSAND YEARS AGO SO IT

854
00:32:13,314 --> 00:32:14,715
COULDN'T HAVE BEEN DRIVEN BY

855
00:32:14,715 --> 00:32:17,518
THESE HUMAN FACTORS SO WHAT IF

856
00:32:17,518 --> 00:32:19,287
THIS WAS BASICALLY THIS LINEAGE

857
00:32:19,287 --> 00:32:21,122
EMERGED TO COUNTER THE FITNESS

858
00:32:21,122 --> 00:32:22,990
ADVABTAGE OF A POPULATION THAT

859
00:32:22,990 --> 00:32:24,091
HAD BECOME MORE RESISTANT, RIGHT

860
00:32:24,091 --> 00:32:26,561
IN O WHAT WE'RE DOING NOW IS

861
00:32:26,561 --> 00:32:29,630
TRYING TO UNDERSTAND WHAT ARE

862
00:32:29,630 --> 00:32:30,398
THE REAL ROBUST PHENOTYPES

863
00:32:30,398 --> 00:32:32,133
ASSOCIATED WITH THE DIFFERENCE

864
00:32:32,133 --> 00:32:33,634
BETWEEN A LABORATORY LINEAGE

865
00:32:33,634 --> 00:32:35,503
LIKE L4 AND MAYBE LAURA CAN HELP

866
00:32:35,503 --> 00:32:37,705
ME WITH THIS, VERSUS L2, THERE'S

867
00:32:37,705 --> 00:32:39,740
A LOT OF LITERATURE OUT THERE

868
00:32:39,740 --> 00:32:41,809
BUT WHAT HAPPENS WHEN YOU READ

869
00:32:41,809 --> 00:32:43,945
IS HOW CONFUSING A LOT OF IT IS,

870
00:32:43,945 --> 00:32:45,980
HOW UNCLEAR A LOT OF IT IS AND

871
00:32:45,980 --> 00:32:47,181
MAYBE IT NEEDS TO GET

872
00:32:47,181 --> 00:32:49,584
STRAIGHTENED OUT OF IT.

873
00:32:49,584 --> 00:32:50,618
BUT 1 THING THAT'S BEEN SORT OF

874
00:32:50,618 --> 00:32:52,086
NOTICED IN THE PAST AND WE

875
00:32:52,086 --> 00:32:53,955
REALLY WANTED TO KIND OF GET A

876
00:32:53,955 --> 00:32:54,922
BETTER HANDLE ON WAS THE

877
00:32:54,922 --> 00:32:58,392
PRODUCTION OF THESE LIPID BODIES

878
00:32:58,392 --> 00:33:01,996
CALLED ILIs.

879
00:33:01,996 --> 00:33:06,200
AND SO, HERE IS OUR LAB STRAIN,

880
00:33:06,200 --> 00:33:10,137
AND HERE IS A BEGINNING STRAIN,

881
00:33:10,137 --> 00:33:12,840
AND THIS IN THIS PARTICULAR

882
00:33:12,840 --> 00:33:16,377
STRAIN MAKES THESE ROBUST LIPID

883
00:33:16,377 --> 00:33:16,744
BODIES.

884
00:33:16,744 --> 00:33:19,580
THIS PHENOTYPE ISN'T A HUNDRED%

885
00:33:19,580 --> 00:33:20,982
CONSISTENT ACROSS L2 LINEAGE BUT

886
00:33:20,982 --> 00:33:22,049
IT'S SUPER CONSIST WENT THIS

887
00:33:22,049 --> 00:33:23,284
PARTICULAR 1 SO WE THINK THAT

888
00:33:23,284 --> 00:33:24,185
MAYBE UNDERSTANDING WHY THESE

889
00:33:24,185 --> 00:33:26,487
ARE MADE OR HOW THEY'RE MADE

890
00:33:26,487 --> 00:33:28,022
MIGHT GIVE US SOME INSIGHT INTO

891
00:33:28,022 --> 00:33:30,057
HOW THEY DEAL WITH BEING IN A

892
00:33:30,057 --> 00:33:32,860
MORE RESISTANT HUMAN POPULATION

893
00:33:32,860 --> 00:33:38,799
AND SO WHAT DAISY IS DOING IS

894
00:33:38,799 --> 00:33:40,901
SHE'S ORDERING AN ENTIRE LIBRARY

895
00:33:40,901 --> 00:33:41,435
AND ENCODING THE 7

896
00:33:41,435 --> 00:33:42,236
HGERONTOLOGYSTS MEMORY CLONE

897
00:33:42,236 --> 00:33:44,271
ANDEE IF SHE CAN TRANSFORM THIS

898
00:33:44,271 --> 00:33:49,810
INTO AN L4 TRAIN AND

899
00:33:49,810 --> 00:33:50,811
[INDISCERNIBLE] PHENOTYPES.

900
00:33:50,811 --> 00:33:53,080
IT'S HARD BUT DAISY'S A BEAST.

901
00:33:53,080 --> 00:33:55,282
THE OTHER THING WE'RE HOPING TO

902
00:33:55,282 --> 00:33:56,117
DO AND I'VE APPLIED FOR FUNDING

903
00:33:56,117 --> 00:33:58,586
BA UNITED STATES WE'RE NOT

904
00:33:58,586 --> 00:34:04,058
TECHNICALLY FUNDED TO DO THIS IS

905
00:34:04,058 --> 00:34:07,194
DB1, AND MULTIOMICS ANALYSIS,

906
00:34:07,194 --> 00:34:09,397
CAN WE DO TRANSCRIPT OMICS,

907
00:34:09,397 --> 00:34:11,432
METRICS TAB O OHMICS IN THE SAME

908
00:34:11,432 --> 00:34:13,401
LAB, WITH SAME BATCHES OF MEDIA

909
00:34:13,401 --> 00:34:14,301
WITH DRUG SENSITIVE STRAINS TO

910
00:34:14,301 --> 00:34:16,003
SEE WHAT ARE THE KEY

911
00:34:16,003 --> 00:34:16,437
DIFFERENCES.

912
00:34:16,437 --> 00:34:17,471
IT'S A PRETTY SIMPLE EXPERIENCE

913
00:34:17,471 --> 00:34:20,408
BUT I THINK IT REQUIRES PEOPLE

914
00:34:20,408 --> 00:34:21,642
BEING ORGANIZED, SOMEONE TRIED

915
00:34:21,642 --> 00:34:27,848
TO DO WITH BUT WITH WITH DRUG

916
00:34:27,848 --> 00:34:30,885
RESISTANCE STRAINS AND SINCE

917
00:34:30,885 --> 00:34:34,055
IT'S CATEGORIZED BY

918
00:34:34,055 --> 00:34:35,156
[INDISCERNIBLE], YOU WANT TO

919
00:34:35,156 --> 00:34:36,524
START WITH TRAINS THAT ARE ALL

920
00:34:36,524 --> 00:34:38,259
DRUG SENSITIVE AND THEN USE SAME

921
00:34:38,259 --> 00:34:39,627
BATCHES IN MEDIA AND HOPEFULLY

922
00:34:39,627 --> 00:34:42,897
WE CAN GET ANSWERS.

923
00:34:42,897 --> 00:34:46,200
THE OTHER THING WE'RE ASKING IS

924
00:34:46,200 --> 00:34:47,935
DOES TB HAVE RESIST ALDEHYDES

925
00:34:47,935 --> 00:34:50,571
AND 1 HAS DONE A MASSIVE GENETIC

926
00:34:50,571 --> 00:34:51,906
KREENS LOOKING FOR MUSEUM TABTS,

927
00:34:51,906 --> 00:34:53,207
SHE'S FOUND THEM AND NOW WE'RE

928
00:34:53,207 --> 00:34:57,344
TRYING TO FIGURE OUT HOW THEY

929
00:34:57,344 --> 00:34:59,080
CONFER SENSITIVITY, OR HOW THOSE

930
00:34:59,080 --> 00:35:06,854
GENES CONFER RESIST APT TO

931
00:35:06,854 --> 00:35:07,421
METHYL GLYOXYL.

932
00:35:07,421 --> 00:35:09,757
SO JUST WATCH THE SPACE AND I

933
00:35:09,757 --> 00:35:11,192
NOW HAVE TO THANK THE PEOPLE WHO

934
00:35:11,192 --> 00:35:12,727
HAVE DONE THIS WORK OVER THE

935
00:35:12,727 --> 00:35:15,396
YEARS SO MARIE, MY FORMER POST

936
00:35:15,396 --> 00:35:17,364
DOC HAS JUST--SHE WAS JUST

937
00:35:17,364 --> 00:35:20,601
INCREDIBLE, SHE'S THE 1 WHO DID

938
00:35:20,601 --> 00:35:22,703
ALL THE CYTOKINEIN NNO

939
00:35:22,703 --> 00:35:24,538
SUSCEPTIBILITY WORK AND MY 2

940
00:35:24,538 --> 00:35:25,673
POST DOCS DACEY APPROXIMATE FONG

941
00:35:25,673 --> 00:35:27,041
WHO ARE CARRYING ON THAT

942
00:35:27,041 --> 00:35:30,578
RESEARCH .

943
00:35:30,578 --> 00:35:32,613
I COULDN'T HAVE DONE THIS

944
00:35:32,613 --> 00:35:36,350
WITHOUT AMAZING COLLABORATORS AT

945
00:35:36,350 --> 00:35:37,017
BERKELEY, MELBOURNE, VIETNAM, A

946
00:35:37,017 --> 00:35:39,086
LOT OF PEOPLE AT BERKELEY AND

947
00:35:39,086 --> 00:35:41,188
FUNDING FROM THE NIH AND I AM

948
00:35:41,188 --> 00:35:42,456
HAPPY TO TAKE QUESTIONS AND I

949
00:35:42,456 --> 00:35:43,591
REALLY THANK YOU SO MUCH FOR

950
00:35:43,591 --> 00:35:48,395
BEING HERE.

951
00:35:48,395 --> 00:35:48,896
WHOO.

952
00:35:48,896 --> 00:35:54,668
[ APPLAUSE ]

953
00:35:54,668 --> 00:35:57,138
>> BIA ALL MEANS USE THE
MICs

954
00:35:57,138 --> 00:35:59,006
NTHANK YOU FOR SUCH A COMPELLING

955
00:35:59,006 --> 00:35:59,774
AND EXCITING TALK THAT WAS

956
00:35:59,774 --> 00:36:01,742
BEAUTIFUL AND I WANT TO

957
00:36:01,742 --> 00:36:04,745
REITERATE THAT THERE WILL BE

958
00:36:04,745 --> 00:36:08,082
PART 2 A DIFFERENT TALK TOMORROW

959
00:36:08,082 --> 00:36:09,950
AT LAMDA LUNCH THAT ARE IN

960
00:36:09,950 --> 00:36:12,453
PERSON BUT I SEE WE HAVE PEOPLE

961
00:36:12,453 --> 00:36:14,789
AT THE MICs AND ON ONLINE BUT

962
00:36:14,789 --> 00:36:16,590
PART 1.5 IS THE RECEPTION AFTER

963
00:36:16,590 --> 00:36:16,791
THIS.

964
00:36:16,791 --> 00:36:21,295
SO LOTS OF OPPORTUNITIES TO ASK

965
00:36:21,295 --> 00:36:21,562
QUESTIONS.

966
00:36:21,562 --> 00:36:22,663
>> YEAH, SO JUST A
VERY--THAT

967
00:36:22,663 --> 00:36:25,933
WAS A GREAT TALK, JUST A VERY

968
00:36:25,933 --> 00:36:27,234
FUNDAMENTAL QUESTION, HOW DO YOU

969
00:36:27,234 --> 00:36:31,405
THINK A WIDE ARRAY OF ALDEHYDES

970
00:36:31,405 --> 00:36:34,108
KILLS A WIDE VARIETY OF

971
00:36:34,108 --> 00:36:37,044
PATHOGENS, IS IT ALL BY

972
00:36:37,044 --> 00:36:42,049
ACTIVATING NITRIC OXIDE, OTHER

973
00:36:42,049 --> 00:36:42,416
MECHANISMS?

974
00:36:42,416 --> 00:36:44,351
SO RIGHT, THE QUESTION IS SO

975
00:36:44,351 --> 00:36:46,420
MANY DIFFERENT ALDEHYDES SO MANY

976
00:36:46,420 --> 00:36:47,454
DIFFERENT PATHOGENS IS IT 1

977
00:36:47,454 --> 00:36:51,559
MECHANISM, I WILL SAY WE'VE

978
00:36:51,559 --> 00:36:52,560
ONLY--THE FIRST QUESTION IS

979
00:36:52,560 --> 00:36:54,395
ALDEHYDES SO I DO THINK THAT

980
00:36:54,395 --> 00:36:55,396
DIFFERENT ALDEHYDES HAVE

981
00:36:55,396 --> 00:36:56,530
DIFFERENT LEVELS OF TOXICITY AND

982
00:36:56,530 --> 00:36:58,065
WE DON'T KNOW FOR CERTAIN ARE

983
00:36:58,065 --> 00:37:00,868
WHICH 1S ARE ACTUALLY HAVING AN

984
00:37:00,868 --> 00:37:04,805
EFFECT IN VIVO, SO LDH2 IS

985
00:37:04,805 --> 00:37:06,407
MOSTLY THERE TO DETOXIFY THE

986
00:37:06,407 --> 00:37:13,514
LIPID ALDEHYDES IN OUR LIVER AND

987
00:37:13,514 --> 00:37:15,249
FROM INFLATION, BUT, IT'S KIND

988
00:37:15,249 --> 00:37:25,459
OF PROPHOSPHORYLATED CUE USE, IT

989
00:37:25,459 --> 00:37:27,595
COULD COME FROM DETOXIFICATION

990
00:37:27,595 --> 00:37:29,663
FROM GLOW 1, THOSE MOUSE ARE NOW

991
00:37:29,663 --> 00:37:31,632
BREED NOTHING OUR FACILITY BUT

992
00:37:31,632 --> 00:37:33,968
AT LEAST WITH TB GLOW 1 DOESN'T

993
00:37:33,968 --> 00:37:34,835
SEEM TO HAVE A BILGE CENTER FOR

994
00:37:34,835 --> 00:37:36,437
EXCELLENCE ON AGING ON THE

995
00:37:36,437 --> 00:37:37,271
WILD-TYPE MICE, SO WE DON'T KNOW

996
00:37:37,271 --> 00:37:38,739
IN TERMS OF HOW THE ALDEHYDES

997
00:37:38,739 --> 00:37:39,974
WORK, I HAVE A FEELING IT'S

998
00:37:39,974 --> 00:37:42,910
GOING TO BE ORGANISM SPECIFIC.

999
00:37:42,910 --> 00:37:45,179
SO IN TB WE KNOW THAT ALDEHYDES

1000
00:37:45,179 --> 00:37:48,249
REACT WITH CYSTINES AND SEEM TO

1001
00:37:48,249 --> 00:37:50,050
DISARM METAL, TRANSPORTERS WE

1002
00:37:50,050 --> 00:37:50,751
DON'T UNDERSTAND THE NITRIC

1003
00:37:50,751 --> 00:37:53,087
OXIDE LINK AT ALL.

1004
00:37:53,087 --> 00:37:54,088
STAFF AURUOUS, I DIDN'T TALK

1005
00:37:54,088 --> 00:37:56,390
ABOUT IT AT ALL CRAZY RESISTANT

1006
00:37:56,390 --> 00:37:58,158
TO ALDEHYDE, SO MAYBE WE DON'T

1007
00:37:58,158 --> 00:38:02,229
WANT TO TALK ABOUT STAPH

1008
00:38:02,229 --> 00:38:03,964
AUREOUS, I HAVE NO IDEA BUT THIS

1009
00:38:03,964 --> 00:38:05,666
IS STUFF THAT SARAH'S LAB WILL

1010
00:38:05,666 --> 00:38:08,502
WORK ON AND WE'RE CONTINUING TO

1011
00:38:08,502 --> 00:38:09,737
WORK ON EMPLOY IT'S A GREAT

1012
00:38:09,737 --> 00:38:13,540
QUESTION, WE DON'T HAVE ALL THE

1013
00:38:13,540 --> 00:38:14,141
ANSWERS YET.

1014
00:38:14,141 --> 00:38:14,475
>> THANKS.

1015
00:38:14,475 --> 00:38:17,678
>> SO SOMEBODY WHO GETS
BACTERIA

1016
00:38:17,678 --> 00:38:20,848
INFECS ALLOT, DID IS IT WORK THE

1017
00:38:20,848 --> 00:38:24,985
OTHER WAY AROUND IN IS MY

1018
00:38:24,985 --> 00:38:26,787
ALDEHYDE DEHYDROGENASE TOO GOOD

1019
00:38:26,787 --> 00:38:27,488
IN CONVERTING ALDEHYDES, HAVE

1020
00:38:27,488 --> 00:38:29,857
YOU THOUGHT ABOUT THOSE LINES OR

1021
00:38:29,857 --> 00:38:31,025
ANY OTHER MORE COMMON VARIANTS

1022
00:38:31,025 --> 00:38:35,129
IN THE ALDEHYDES THAT COULD MAKE

1023
00:38:35,129 --> 00:38:35,729
THE ENZYME BETTER?

1024
00:38:35,729 --> 00:38:37,598
>> NOT THEY KNOW OF AND
THERE

1025
00:38:37,598 --> 00:38:39,500
ARE OTHER MUTANT ALLELES BUT

1026
00:38:39,500 --> 00:38:41,902
THEY'RE VERY RARE AND I DON'T

1027
00:38:41,902 --> 00:38:43,570
THINK--NOBODY KNOWS WHETHER OR

1028
00:38:43,570 --> 00:38:45,506
NOT THEY CONFER PROTECTION

1029
00:38:45,506 --> 00:38:46,974
BETTER OR WORSE.

1030
00:38:46,974 --> 00:38:50,711
YEAH, I DON'T KNOW.

1031
00:38:50,711 --> 00:38:51,679
YEAH, SORRY.

1032
00:38:51,679 --> 00:38:52,813
NNO WORRIES.

1033
00:38:52,813 --> 00:38:54,548
NCAN I USE THE PREROGATIVE, HAVE

1034
00:38:54,548 --> 00:38:58,719
YOU LOOKED AT SORT OF THE

1035
00:38:58,719 --> 00:39:01,922
OVERLAY OF TB INFECTION AND AND

1036
00:39:01,922 --> 00:39:04,525
MUSEUM TAIGS ON A FLOABAL LEVEL

1037
00:39:04,525 --> 00:39:08,162
SO WHY ARE THERE IN POPULATIONS,

1038
00:39:08,162 --> 00:39:10,030
WHERE THERE SEEM TO HAVE BEEN A

1039
00:39:10,030 --> 00:39:11,498
STRONGER SELECTION, DOES IT MAKE

1040
00:39:11,498 --> 00:39:12,032
SENSE?

1041
00:39:12,032 --> 00:39:14,168
NSO LIKE THE 1 QUESTION I GET A

1042
00:39:14,168 --> 00:39:16,770
LOT, THE GREAT QUESTION, IS HOW

1043
00:39:16,770 --> 00:39:18,639
COME THAT LDH2 MUTATION HASN'T

1044
00:39:18,639 --> 00:39:19,740
HAPPENED IN OTHER POPULATIONS SO

1045
00:39:19,740 --> 00:39:21,642
I THINK THAT PERSON IN CHINA

1046
00:39:21,642 --> 00:39:23,243
THOUSANDS OF YEARS AGO JUST WON

1047
00:39:23,243 --> 00:39:25,079
THE GENETIC LOTTERY, THEY GOT

1048
00:39:25,079 --> 00:39:28,215
THIS VERY RARE, IT'S LIKE LYSINE

1049
00:39:28,215 --> 00:39:29,616
TO A PARTATE OR DPLIEWTA MATE

1050
00:39:29,616 --> 00:39:33,354
MUTATION AND IT MAKES A STABLE

1051
00:39:33,354 --> 00:39:34,922
PROTEIN, IT STILL CAN INTERACT

1052
00:39:34,922 --> 00:39:37,591
WITH THE WILD-TYPE COPIES YET IT

1053
00:39:37,591 --> 00:39:38,359
COMPLETELY KILLS ITS FUNCTION

1054
00:39:38,359 --> 00:39:40,160
EMPLOY SO MY FEELING WAS IT

1055
00:39:40,160 --> 00:39:41,595
REALLY WAS LUCK IN MANY WAYS,

1056
00:39:41,595 --> 00:39:43,330
BECAUSE IF YOU GET A COMPLETE

1057
00:39:43,330 --> 00:39:44,231
LOSS OF FUNCTION, THEN YOU NEED

1058
00:39:44,231 --> 00:39:46,934
TO BE A HYM O ZYGOTE FOR IT AND

1059
00:39:46,934 --> 00:39:49,570
I THINK THOSE PEOPLE, SO LET'S

1060
00:39:49,570 --> 00:39:52,806
SAY SOMEONE GOT AN LDHWOKNOCK

1061
00:39:52,806 --> 00:39:54,908
OUT, MAYBE IF THEY MATED WITH

1062
00:39:54,908 --> 00:39:55,909
SOMEONE WHO'S WILD-TYPE, THEN

1063
00:39:55,909 --> 00:40:00,481
THEIR OFFSPRING WILL NOT BE ANY

1064
00:40:00,481 --> 00:40:01,115
BETTER PROTECTED, RIGHT?

1065
00:40:01,115 --> 00:40:03,784
SO I THINK IT WAS JUST FREAKISH

1066
00:40:03,784 --> 00:40:05,652
THING OF NATURE, IT'S KIND OF

1067
00:40:05,652 --> 00:40:06,854
LIKE SICKLE CELL, IT HAPPEN

1068
00:40:06,854 --> 00:40:08,322
INDEED AN AREA WHERE SOMETHING

1069
00:40:08,322 --> 00:40:09,923
WAS VERY INDEMMIC AND THE ONLY

1070
00:40:09,923 --> 00:40:12,092
WAY THE POPULATION WOULD MAKE IT

1071
00:40:12,092 --> 00:40:14,228
IF THEY GET THIS DEVELOPMENTAL

1072
00:40:14,228 --> 00:40:15,796
ENDOCRINOLOGYITATING DISEASE

1073
00:40:15,796 --> 00:40:17,464
EMPLOY LDH2, IT'S NOT TERRIBLE,

1074
00:40:17,464 --> 00:40:19,733
YOU KNOW, YOU'RE GOING TO HAVE

1075
00:40:19,733 --> 00:40:20,267
CHILDREN RIGHT?

1076
00:40:20,267 --> 00:40:22,169
SO YOU HAVE PLENTY OF TIME TO

1077
00:40:22,169 --> 00:40:23,570
HAVE KIDS AND PROKRE TINSATE BUT

1078
00:40:23,570 --> 00:40:26,106
I DO THINK THERE WAS SOME--MAYBE

1079
00:40:26,106 --> 00:40:27,641
IT WASN'T TB NECESSARILY COULD

1080
00:40:27,641 --> 00:40:29,043
HAVE BEEN SOME OTHER INFECT

1081
00:40:29,043 --> 00:40:29,843
YOURCANDIDATES DEC THAT IT

1082
00:40:29,843 --> 00:40:32,246
PROTEBTED AGAINST BUT IT'S VERY

1083
00:40:32,246 --> 00:40:33,080
SATISFYING BECAUSE SO MANY

1084
00:40:33,080 --> 00:40:36,150
PEOPLE HAVE THE MUTATIONS TO GO

1085
00:40:36,150 --> 00:40:40,487
OH, THIS IS WHY .

1086
00:40:40,487 --> 00:40:42,689
THERE ARE FITNESS CAUSE, IT JUST

1087
00:40:42,689 --> 00:40:44,058
TAKESSA I LONG TIME FOR THEM TO

1088
00:40:44,058 --> 00:40:46,126
HAPPEN NSO DO YOU THINK THERE'S

1089
00:40:46,126 --> 00:40:47,828
A ROLE FOR DISCIPLINARY SULFUR

1090
00:40:47,828 --> 00:40:50,764
AN IN THE TREATMENT OF TB?

1091
00:40:50,764 --> 00:40:52,800
>> THANK YOU FOR ASKING
THE

1092
00:40:52,800 --> 00:40:53,534
QUESTION.

1093
00:40:53,534 --> 00:40:57,871
IT'S KNOWN AS EABT ABUSE, SO IT

1094
00:40:57,871 --> 00:40:58,939
TREATS ALCOHOLISM, IT INHIBITS

1095
00:40:58,939 --> 00:41:00,941
LDH2 SO YOU THROW UP WHEN YOU

1096
00:41:00,941 --> 00:41:01,942
DRINK ALCOHOL, THE PROBLEM IS

1097
00:41:01,942 --> 00:41:04,511
YOU CAN TOP TAKING IT, RIGHT IN

1098
00:41:04,511 --> 00:41:06,647
SO SEVERAL YEARS AGO, A GROUP,

1099
00:41:06,647 --> 00:41:11,652
IN YAP AN DID A STUDY LOOKING

1100
00:41:11,652 --> 00:41:13,353
FOR THINGS THAT TRYING TO

1101
00:41:13,353 --> 00:41:15,989
REPURPOSE EXISTING DRUGS TO

1102
00:41:15,989 --> 00:41:26,467
TREAT TB AND THEY FOUND THAT

1103
00:41:31,438 --> 00:41:33,173
DISULPHURE AN, SO THAT DOESN'T

1104
00:41:33,173 --> 00:41:35,142
MAKE SENSE, THAT COPY MIGHT BE

1105
00:41:35,142 --> 00:41:35,576
AN INVITROART FACT.

1106
00:41:35,576 --> 00:41:37,444
SO 1 OF THE THINGS SARAH'S TRIED

1107
00:41:37,444 --> 00:41:41,281
TO DO IS TO TREAT MICE WITH

1108
00:41:41,281 --> 00:41:42,416
DISCIPLINARY SULFUR AN AFTER TB

1109
00:41:42,416 --> 00:41:43,684
INFECTION, THE PROBLEM IS, SO

1110
00:41:43,684 --> 00:41:45,018
SOMEONE DID THAT AND THEY SAID

1111
00:41:45,018 --> 00:41:46,353
IT WORKED GREAT, SO THEY'RE LIKE

1112
00:41:46,353 --> 00:41:48,222
OKAY, WE'RE GOING TO REPEAT THIS

1113
00:41:48,222 --> 00:41:51,291
EXPERIMENT BUT IT WAS VERY TOXIC

1114
00:41:51,291 --> 00:41:52,626
RIGHT SO DISCIPLINARY SULFUR AN

1115
00:41:52,626 --> 00:41:54,394
WAS TOXIC TO THE MICE, BUT

1116
00:41:54,394 --> 00:41:56,396
MAYBE, YOU CAN MAKE A BETTER

1117
00:41:56,396 --> 00:41:58,799
VERSION OR USE LESS, MAYBE YOU

1118
00:41:58,799 --> 00:42:00,300
COULD SINNER UTILIZE WITH

1119
00:42:00,300 --> 00:42:01,635
EXISTING DRUGS, WE JUST--I WOULD

1120
00:42:01,635 --> 00:42:03,670
LOVE FOR SOMEONE TO TRY

1121
00:42:03,670 --> 00:42:05,005
DISCIPLINARY SULFUR AN BUT

1122
00:42:05,005 --> 00:42:07,608
EVERYBODY'S TELLING ME IT'S TOO

1123
00:42:07,608 --> 00:42:09,443
TOXIC BUT YET IT'S USED TO TREAT

1124
00:42:09,443 --> 00:42:09,743
ALCOHOLISM.

1125
00:42:09,743 --> 00:42:11,411
SO I DON'T KNOW WHAT TO DO WITH

1126
00:42:11,411 --> 00:42:11,912
THAT.

1127
00:42:11,912 --> 00:42:14,014
I'VE BEEN TRYING TO CONVINCE TB

1128
00:42:14,014 --> 00:42:18,819
ALLIANCE AND THEY'RE NOT REALLY

1129
00:42:18,819 --> 00:42:20,120
LISTENING.

1130
00:42:20,120 --> 00:42:20,320
JULIE?

1131
00:42:20,320 --> 00:42:22,122
>> HI, I HAD A QUESTION
THAT'S

1132
00:42:22,122 --> 00:42:24,091
MORE ROOTED IN YOU KNOW MY

1133
00:42:24,091 --> 00:42:25,826
KNOWLEDGE WHICH IS BASIC OF

1134
00:42:25,826 --> 00:42:27,461
OTHER BACTERIA, WHERE YOU'RE

1135
00:42:27,461 --> 00:42:29,196
TALKING ABOUT CENTRAL

1136
00:42:29,196 --> 00:42:30,831
METABOLISM, AND THEN I'M

1137
00:42:30,831 --> 00:42:32,666
WONDERING DO THE BACTERIA

1138
00:42:32,666 --> 00:42:35,402
ACTUALLY HAVE ALTERNATIVE

1139
00:42:35,402 --> 00:42:37,337
PATHWAYS TO GO THROUGH THAT OR

1140
00:42:37,337 --> 00:42:39,106
CAN THEY MAYBE BREAK DOWN SOME

1141
00:42:39,106 --> 00:42:42,109
OF THE SECONDARY METABOLITES

1142
00:42:42,109 --> 00:42:42,676
THAT WOULD ACCUMULATE.

1143
00:42:42,676 --> 00:42:44,444
I'M KIND OF TRYING TO UNDERSTAND

1144
00:42:44,444 --> 00:42:46,113
IT ALSO FROM THE PERSPECTIVE OF

1145
00:42:46,113 --> 00:42:50,918
COULD THERE BE ANY ADVANTAGE TO

1146
00:42:50,918 --> 00:42:52,152
THE TUBERCULOSIS IN INFECTION

1147
00:42:52,152 --> 00:42:58,458
THAT MAYBE YOU WOULD BE TAKING

1148
00:42:58,458 --> 00:43:03,197
CARE OF OTHERWISE METABOLITE,

1149
00:43:03,197 --> 00:43:03,864
SECONDARY METABOLITES THAT LIGHT

1150
00:43:03,864 --> 00:43:05,432
ACCUMULATE OR ARE THE BACTERIA

1151
00:43:05,432 --> 00:43:07,467
IN THE HUMAN PATHWAYS REALLY

1152
00:43:07,467 --> 00:43:08,902
IDENTICAL NI DON'T THINK THEY'RE

1153
00:43:08,902 --> 00:43:10,404
IDENTICAL SO I DON'T WANT

1154
00:43:10,404 --> 00:43:12,072
TO--THEY'RE VERY CLOSE, SO IN

1155
00:43:12,072 --> 00:43:13,640
TERMS OF--MAYBE YOU'RE IMETTING

1156
00:43:13,640 --> 00:43:16,043
AT LIKE--PEOPLE WHO MADE THOUGH

1157
00:43:16,043 --> 00:43:17,945
CENTRAL METABOLISM MUTATIONS

1158
00:43:17,945 --> 00:43:19,279
NWAIT, REMEMBER, I AM ASKING A

1159
00:43:19,279 --> 00:43:22,282
VERY BASIC QUESTION, LIKE, YOU

1160
00:43:22,282 --> 00:43:23,116
KNOW PROPRINCIPAL DEPUTIATE

1161
00:43:23,116 --> 00:43:25,953
SUCKS IN PATHWAYS, WE HAVE THEIR

1162
00:43:25,953 --> 00:43:27,921
BACTERIUM BECAUSE THEY HAVE

1163
00:43:27,921 --> 00:43:29,790
ALTERNATIVE AREAS FOR THE KREBS

1164
00:43:29,790 --> 00:43:31,391
CYCLE SO I'M REALLY ASKING LIKE

1165
00:43:31,391 --> 00:43:32,826
THAT I THINK THERE MAY BE SOME

1166
00:43:32,826 --> 00:43:35,862
WAYS IN WHICH BACTERIA AND

1167
00:43:35,862 --> 00:43:38,332
HUMANS, LIKE BACTERIA ACTUALLY

1168
00:43:38,332 --> 00:43:40,901
PROVIDE, MAYBE TB AS A POGHT O

1169
00:43:40,901 --> 00:43:42,869
GEN DOESN'T DO THIS BUT THERE

1170
00:43:42,869 --> 00:43:44,338
ARE SOME BACTERIA THAT PROVIDE A

1171
00:43:44,338 --> 00:43:46,406
BENEFIT TO HUMANS BECAUSE THEY

1172
00:43:46,406 --> 00:43:48,642
HAVE ALTERNATIVE WAYS OF GOING

1173
00:43:48,642 --> 00:43:57,117
THROUGH THESE CENTRAL METABOLISM

1174
00:43:57,117 --> 00:43:59,086
PATHWAYS IN DEVELOPING THE

1175
00:43:59,086 --> 00:43:59,653
SYMBIOTIC RELATIONSHIP, AND

1176
00:43:59,653 --> 00:44:00,654
THINK BEING THAT IS THERE SOME

1177
00:44:00,654 --> 00:44:03,590
WAY IN WHICH THE HUMAN DOES HAVE

1178
00:44:03,590 --> 00:44:05,359
AN ADVANTAGE AT BEING AFFECTED

1179
00:44:05,359 --> 00:44:13,767
THAT MTB HAS TRIED TO TAILOR ITS

1180
00:44:13,767 --> 00:44:15,402
SYMBIOTIC RELATIONSHIP IN NSO

1181
00:44:15,402 --> 00:44:16,403
CERTAINLY I DON'T HAVE AN

1182
00:44:16,403 --> 00:44:18,372
ANSWER, I THINK TB IS SUPER WELL

1183
00:44:18,372 --> 00:44:20,140
ADAPTED TO BE IN HUMANS BECAUSE

1184
00:44:20,140 --> 00:44:22,042
IT DID HAVE WEIRD METABOLISM BUT

1185
00:44:22,042 --> 00:44:25,779
INTERESTINGLY A LOT OF THEM DO

1186
00:44:25,779 --> 00:44:26,980
GENERATE ALDEHYDES SO--BUT I

1187
00:44:26,980 --> 00:44:28,949
THINK THAT'S WHY IF THEY'RE NOT

1188
00:44:28,949 --> 00:44:30,617
CONSTANTLY BEING MOVED FORWARD,

1189
00:44:30,617 --> 00:44:31,785
SO LIPID METABOLISM FOR EXAMPLE,

1190
00:44:31,785 --> 00:44:37,591
IS LIKE A HUGE THING FOR TB TO

1191
00:44:37,591 --> 00:44:40,661
STAY ALIVE IN HUMANS, BUT, YEAH,

1192
00:44:40,661 --> 00:44:43,096
I THINK YOUR QUESTION'S TOO BIG

1193
00:44:43,096 --> 00:44:45,132
FOR ME.

1194
00:44:45,132 --> 00:44:48,135
[LAUGHTER]

1195
00:44:48,135 --> 00:44:48,635
YEAH.

1196
00:44:48,635 --> 00:44:51,004
>> OKAY SO OUR COLLEAGUE
ASKS

1197
00:44:51,004 --> 00:44:52,939
ALD H2, STAR 2, IS SOCKED WITH

1198
00:44:52,939 --> 00:44:55,275
THE DEPRIVATIONMENT OF SEVERAL

1199
00:44:55,275 --> 00:44:55,942
TYPES OF CANCER

1200
00:44:55,942 --> 00:44:57,477
CERTAINLY--CERTAINLY SPECIALLY

1201
00:44:57,477 --> 00:44:59,012
IN THE GASTROINTESTINAL TRACT

1202
00:44:59,012 --> 00:44:59,880
EVEN WITHOUT ALCOHOL

1203
00:44:59,880 --> 00:45:01,715
COMSUMPTION, DO YOU THINK THAT

1204
00:45:01,715 --> 00:45:03,116
INCREASED ALDEHYDES IN THE GI

1205
00:45:03,116 --> 00:45:07,187
TRACT CAN LEAD TO THE DEATH OF

1206
00:45:07,187 --> 00:45:10,390
BENEFICIAL BACTERIA AND AFFECT

1207
00:45:10,390 --> 00:45:13,360
CARCINOGEN SIS ?

1208
00:45:13,360 --> 00:45:14,194
>> YEAH, SURE.

1209
00:45:14,194 --> 00:45:14,995
I DON'T KNOW WHY NOT.

1210
00:45:14,995 --> 00:45:17,564
A LOT OF PEOPLE ARE TRYING TO

1211
00:45:17,564 --> 00:45:21,401
UNDERSTAND THE CONQUENCES OF THE

1212
00:45:21,401 --> 00:45:23,770
LDHTAR 2 MUTATION BECAUSE IT IS

1213
00:45:23,770 --> 00:45:25,906
LINKED WITH ESOPHAGEAL CANCER,

1214
00:45:25,906 --> 00:45:27,174
CARDIO VASCULARY ISSUES,

1215
00:45:27,174 --> 00:45:29,209
PROBABLY GI ISSUES TOO AND THOSE

1216
00:45:29,209 --> 00:45:30,277
ALDEHYDES ARE NOT--SO THERE'S 2

1217
00:45:30,277 --> 00:45:32,979
THINGS I WANT TO POINT OUT, 1 IS

1218
00:45:32,979 --> 00:45:35,248
LDH2 FUNCTION IS NOT ALCOHOL

1219
00:45:35,248 --> 00:45:37,117
METABOLISM, IT'S JUST 1 OF THE

1220
00:45:37,117 --> 00:45:37,517
BENEFITS.

1221
00:45:37,517 --> 00:45:39,619
TWO, YOU DO NOT WANT TO DRINK

1222
00:45:39,619 --> 00:45:41,488
ALCOHOL TO TREAT YOUR TB.

1223
00:45:41,488 --> 00:45:45,225
AND IN FACT, I HAVE TESTED, SO

1224
00:45:45,225 --> 00:45:46,793
THE ETHANOLE DERIVED ALDEHYDE IS

1225
00:45:46,793 --> 00:45:49,496
ACID ALDEHYDE IT DOES NOT DO

1226
00:45:49,496 --> 00:45:51,865
SQUAT TO TB, IT DOES NOTHING, SO

1227
00:45:51,865 --> 00:45:54,401
DON'T DRINK ALCOHOLISM AND TB

1228
00:45:54,401 --> 00:45:55,302
THEY'RE LIKE CO-MORBIDITIES SO

1229
00:45:55,302 --> 00:45:58,405
DON'T DO IT BUT I DO THINK THESE

1230
00:45:58,405 --> 00:45:59,940
INCREASES IN CARCINOMAS AND

1231
00:45:59,940 --> 00:46:01,742
THINGS, IT'S BECAUSE ALDEHYDES

1232
00:46:01,742 --> 00:46:06,580
DAMAGE DNA SO I THINK THAT'S A

1233
00:46:06,580 --> 00:46:08,382
BIG PROBLEM.

1234
00:46:08,382 --> 00:46:09,349
>> GREAT TALK.

1235
00:46:09,349 --> 00:46:11,218
MAB I JUST MISSED THIS BUT IN

1236
00:46:11,218 --> 00:46:13,186
TERMS OF TESTING THE LINEAGE

1237
00:46:13,186 --> 00:46:15,222
HYPOTHESIS OF LYNN LINEAGE 2

1238
00:46:15,222 --> 00:46:18,392
VERSUS LINEAGE 4, HAVE YOU

1239
00:46:18,392 --> 00:46:21,928
TESTED THE INVITRO ALDEHYDE

1240
00:46:21,928 --> 00:46:23,230
SENSITIVITY OF [INDISCERNIBLE]

1241
00:46:23,230 --> 00:46:24,297
>> YES, YES, YOU
DEPARTMENT MESS

1242
00:46:24,297 --> 00:46:26,266
IT, I TESTED THIS PERSONALLY O

1243
00:46:26,266 --> 00:46:29,269
OUR LINEAGE 2 MORE RESISTANT TO

1244
00:46:29,269 --> 00:46:29,669
ALDEHYDES INVITRO?

1245
00:46:29,669 --> 00:46:33,206
SHORT ANSWER IS NO, IF ANYTHING

1246
00:46:33,206 --> 00:46:34,107
THEY'RE MORE SENSITIVE, SO WHAT

1247
00:46:34,107 --> 00:46:36,810
IS MAKING US START TO THINK IS

1248
00:46:36,810 --> 00:46:38,745
MAYBE THE BACTERIA DO SOMETHING

1249
00:46:38,745 --> 00:46:39,646
DIFFERENT IMMUNOLOGICALLY TO THE

1250
00:46:39,646 --> 00:46:42,949
HOST SO MAYBE THEY STIMULATE

1251
00:46:42,949 --> 00:46:43,650
LESS INTERFERON, OR

1252
00:46:43,650 --> 00:46:44,584
INTERFERON-GAMMA SO MAYBE

1253
00:46:44,584 --> 00:46:45,419
THERE'S SOMETHING GOING THERE

1254
00:46:45,419 --> 00:46:46,887
BUT THAT'S SOMETHING WE NEED TO

1255
00:46:46,887 --> 00:46:49,456
START LOOKING AT MORE CLOSELY,

1256
00:46:49,456 --> 00:46:50,257
YEAH, GOOD QUESTION.

1257
00:46:50,257 --> 00:46:52,726
>> AND THEN MAYBE JUST A
QUICK

1258
00:46:52,726 --> 00:46:56,029
FOLLOW UP, THAT ORIGINAL iNOS

1259
00:46:56,029 --> 00:46:58,365
DATA IS WITH LIGAN 4, IS THERE A

1260
00:46:58,365 --> 00:47:00,901
DIFFERENCE BETWEEN LINEAGE 4 AND

1261
00:47:00,901 --> 00:47:01,601
2 FOR SIZE?

1262
00:47:01,601 --> 00:47:03,503
>> THAT'S A GOOD QUESTION.

1263
00:47:03,503 --> 00:47:06,273
WE'VE NEVER LOOKED AT iNOS SO

1264
00:47:06,273 --> 00:47:06,907
1 TECHNOLOGY TRANSFER THAT'S

1265
00:47:06,907 --> 00:47:10,410
BEEN HARD TO FIGURE OUT AND SO

1266
00:47:10,410 --> 00:47:12,913
ACTUALLY IN VIVO, THE IN VIVO

1267
00:47:12,913 --> 00:47:13,447
PHENOTYPES ASSOCIATED WITH

1268
00:47:13,447 --> 00:47:15,081
LINEAGE 2 AND 4 ARE NOT VERY

1269
00:47:15,081 --> 00:47:16,917
CLEAR, SO THERE'S A VERY OLD

1270
00:47:16,917 --> 00:47:21,521
PAPER FROM I THINK CLAUDIA

1271
00:47:21,521 --> 00:47:23,156
MONKA, THERE'S MORE INIAGE MADE

1272
00:47:23,156 --> 00:47:24,958
BY THE INFECTED CELLS SO THAT IS

1273
00:47:24,958 --> 00:47:28,795
A HARD THING, WE KNOW TYPE 1

1274
00:47:28,795 --> 00:47:30,397
INTERFERON CAT IS BAD FOR TB

1275
00:47:30,397 --> 00:47:32,065
INFECTION, SO WHAT WE DON'T KNOW

1276
00:47:32,065 --> 00:47:33,633
IS, IS THAT STILL REALLY A

1277
00:47:33,633 --> 00:47:33,867
THING.

1278
00:47:33,867 --> 00:47:35,936
IT'S NOT SOMETHING WE CAN

1279
00:47:35,936 --> 00:47:37,904
QUANTIFY IN VIVO, MAYBE SOME OF

1280
00:47:37,904 --> 00:47:39,239
THE BEST IN VIVO DATA THAT I

1281
00:47:39,239 --> 00:47:43,243
NEED TO TALK TO AMY BARZAK ABOUT

1282
00:47:43,243 --> 00:47:44,711
WHEN SHE WAS IN CLIFF'S LAB, IF

1283
00:47:44,711 --> 00:47:48,381
YOU DO A MIXED INFECTION, AN L2

1284
00:47:48,381 --> 00:47:49,983
STRAIN WILL OUTCOMPETE THE L4

1285
00:47:49,983 --> 00:47:50,417
STRAIN.

1286
00:47:50,417 --> 00:47:52,018
SO IF THAT HOLDS UP IN OUR

1287
00:47:52,018 --> 00:47:53,220
HANDS, I THINK THAT'S GOING TO

1288
00:47:53,220 --> 00:47:54,254
BE SOMETHING WE CAN AT LEAST

1289
00:47:54,254 --> 00:47:56,122
TART TO WORK WITH IN TERMS OF

1290
00:47:56,122 --> 00:48:00,560
TRYING TO DISSECT WHAT'S GOING

1291
00:48:00,560 --> 00:48:02,996
ON BETWEEN THE 2 DIFFERENT

1292
00:48:02,996 --> 00:48:03,797
LINEAGES.

1293
00:48:03,797 --> 00:48:06,032
NGOOD QUESTION, THANKS.

1294
00:48:06,032 --> 00:48:07,000
NCAT, GREAT TALK.

1295
00:48:07,000 --> 00:48:08,101
AND SOMEWHAT RELATED TO HIS

1296
00:48:08,101 --> 00:48:10,003
QUESTION TOO BUT SOMETHING ABOUT

1297
00:48:10,003 --> 00:48:15,108
THAT YOU MENTIONED THAT STAPH

1298
00:48:15,108 --> 00:48:17,077
AURREUS, IS SUPER,--I'M NOT A

1299
00:48:17,077 --> 00:48:19,846
MICROBIOLOGIST BUT I CAT GO

1300
00:48:19,846 --> 00:48:27,487
ARIZED FROM EXTRA CELLULAR VERSE

1301
00:48:27,487 --> 00:48:28,788
INTRACELLULAR, COULD IT BE THAT

1302
00:48:28,788 --> 00:48:30,190
THERE'S A HOST CELL FOR THE

1303
00:48:30,190 --> 00:48:32,592
ALDEHYDES TO WORK IF AND IF A

1304
00:48:32,592 --> 00:48:34,561
PATHOGEN IS OFTEN JUST

1305
00:48:34,561 --> 00:48:35,996
INTRACELLULAR AND THAT COULD

1306
00:48:35,996 --> 00:48:37,163
ALSO EXPLAIN POTENTIAL DRVESS

1307
00:48:37,163 --> 00:48:39,966
BETWEEN THE L2 AND L4 IN THERE

1308
00:48:39,966 --> 00:48:41,902
RIGHT, IF THERE'S A DIFFERENT

1309
00:48:41,902 --> 00:48:44,471
ENGAGEMENT IN THE MACROPHAGE BUT

1310
00:48:44,471 --> 00:48:45,238
EXCUSE THE ALDEHYDE SENSITIVITY

1311
00:48:45,238 --> 00:48:46,640
AND THE HOST CELL IS CRITICAL.

1312
00:48:46,640 --> 00:48:48,408
I KNOW THAT ENVITRO IF YOU JUST

1313
00:48:48,408 --> 00:48:50,810
PUT THE ALDEHYDE ON IT, BUT IF

1314
00:48:50,810 --> 00:48:54,581
YOU DO THE--SO, RIGHT, SO I'VE

1315
00:48:54,581 --> 00:48:55,849
GOTTEN THIS QUESTION BEFORE.

1316
00:48:55,849 --> 00:48:58,818
IS THIS SOMETHING SPECIFIC TO

1317
00:48:58,818 --> 00:48:59,719
INTRACELLULAR PATHOGENS OR

1318
00:48:59,719 --> 00:49:01,087
BACTERIA.

1319
00:49:01,087 --> 00:49:01,588
I DON'T KNOW.

1320
00:49:01,588 --> 00:49:02,556
I LIKE THAT IDEA.

1321
00:49:02,556 --> 00:49:04,424
THE OTHER THING I KIND OF LIKE

1322
00:49:04,424 --> 00:49:05,692
IS THE IDEA THAT MAYBE THE

1323
00:49:05,692 --> 00:49:07,160
ALDEHYDES ARE LIKE, THEY LIKE TO

1324
00:49:07,160 --> 00:49:09,663
WORK WITH A SLOW BURN PATHOGEN,

1325
00:49:09,663 --> 00:49:12,666
SO TB IS VERY PERSISTENT SO

1326
00:49:12,666 --> 00:49:14,367
SALMONELLA, STAFF, THOSE ARE

1327
00:49:14,367 --> 00:49:14,968
ACUTE INFECS, RIGHT?

1328
00:49:14,968 --> 00:49:17,437
THOSE ARE GOING TO GROW SO FAST,

1329
00:49:17,437 --> 00:49:18,705
THE ALDEHYDES CAN'T DO QUAT AND

1330
00:49:18,705 --> 00:49:21,308
MAYBE THEY WILL KILL YOU ON OR

1331
00:49:21,308 --> 00:49:22,609
MAKE YOU SICK BEFORE THE

1332
00:49:22,609 --> 00:49:26,212
ALDEHYDES CAN DO ANYTHING.

1333
00:49:26,212 --> 00:49:28,782
I THINK WITH TB BECAUSE IT'S

1334
00:49:28,782 --> 00:49:29,516
SLOW, IT'S ACCUMULATION OF

1335
00:49:29,516 --> 00:49:31,985
DAMAGE BY THE ALDEHYDES.

1336
00:49:31,985 --> 00:49:33,820
SO WE DON'T KNOW YET AND THIS IS

1337
00:49:33,820 --> 00:49:35,589
SOMETHING THAT SARAH AND I--I

1338
00:49:35,589 --> 00:49:37,624
THINK SHE'S GOING TO EXPLORE

1339
00:49:37,624 --> 00:49:38,058
THAT MORE.

1340
00:49:38,058 --> 00:49:40,460
I FEEL LIKE THEY MAY HAVE TRIED

1341
00:49:40,460 --> 00:49:42,429
STAPH, AND I KNOW THEY TRIED

1342
00:49:42,429 --> 00:49:43,930
LISTERIA, BUT I CAN'T REMEMBER.

1343
00:49:43,930 --> 00:49:46,566
>> YOU GUYS ARE TOTALLY ON
TO

1344
00:49:46,566 --> 00:49:49,603
SOMETHING, I'M CONVINCED.

1345
00:49:49,603 --> 00:49:54,374
>> AWWELCOMER, THANK YOU.

1346
00:49:54,374 --> 00:49:54,574
PONG?

1347
00:49:54,574 --> 00:49:55,642
>> FOLLOWING UP FROM THOSE

1348
00:49:55,642 --> 00:49:57,243
QUESTIONS IT SEEMED LIKE YOU

1349
00:49:57,243 --> 00:49:58,912
COULD TAKE MONOCYTES FROM PEOPLE

1350
00:49:58,912 --> 00:50:02,115
LIKE ME, THAT HAVE THE MUTATION,

1351
00:50:02,115 --> 00:50:03,316
COMPARED TO WILD-TYPES AND BE

1352
00:50:03,316 --> 00:50:08,254
ABLE TO TEASE OUT THE

1353
00:50:08,254 --> 00:50:11,191
SENSITIVITY OF OF MACROPHAGES

1354
00:50:11,191 --> 00:50:14,828
FROM DIFFERENT LINEAGES TO

1355
00:50:14,828 --> 00:50:16,129
SENSITIVITY FROM DIFFERENT--FROM

1356
00:50:16,129 --> 00:50:18,398
THE DIFFERENT LINEAGE 2 VERSUS

1357
00:50:18,398 --> 00:50:18,898
LINEAGE 4.

1358
00:50:18,898 --> 00:50:22,802
NTHE PROBLEM WITH TB IS THAT I

1359
00:50:22,802 --> 00:50:24,037
HATE THE INVITRO MACROPHAGE

1360
00:50:24,037 --> 00:50:25,238
MODEL, BECAUSE THE ISSUE IS IT'S

1361
00:50:25,238 --> 00:50:28,141
A 6 DAY INFECTION AND IT JUST

1362
00:50:28,141 --> 00:50:29,576
DOESN'T REALLY CAPTURE WHAT'S

1363
00:50:29,576 --> 00:50:31,211
IMPORTANT IN TERMS OF--RIGHT IN

1364
00:50:31,211 --> 00:50:33,213
AND LIKE I SAID SLOW BURN, IT

1365
00:50:33,213 --> 00:50:35,482
MIGHT TACK A LONG TIME AND

1366
00:50:35,482 --> 00:50:40,453
INVITRO IF YOU XOK OUT ALD H2 OR

1367
00:50:40,453 --> 00:50:44,557
DPRKS LO1, IT DOESN'T DO

1368
00:50:44,557 --> 00:50:45,525
ANYTHING DIFFERENTLY HOWEVER,

1369
00:50:45,525 --> 00:50:47,160
[INDISCERNIBLE] FOR SURE, IT

1370
00:50:47,160 --> 00:50:50,330
MIGHT DEPEND ON THE PATHOGEN.

1371
00:50:50,330 --> 00:50:52,632
YEAH, THERE'S A LOT.

1372
00:50:52,632 --> 00:50:55,035
NNO NOTHING ELSE ONLINE JUST

1373
00:50:55,035 --> 00:50:56,403
YET.

1374
00:50:56,403 --> 00:50:57,137
>> I'M PROBABLY GOING TO
PROVE

1375
00:50:57,137 --> 00:50:59,939
IN FRONT OF EVERYBODY THAT I'M

1376
00:50:59,939 --> 00:51:05,612
NEITHER A MICROBIOLOGIST NOR AN

1377
00:51:05,612 --> 00:51:07,380
IMMUNOLOGIST BUT I'M JUST

1378
00:51:07,380 --> 00:51:09,783
WONDERING LISTENING TO THIS AND

1379
00:51:09,783 --> 00:51:12,252
THE RELATIVE LACK OF SPECIFICITY

1380
00:51:12,252 --> 00:51:13,353
OF WHICH ALDEHYDE IT IS WHAT THE

1381
00:51:13,353 --> 00:51:15,555
EFFECT IS OUT THE OTHER END, ARE

1382
00:51:15,555 --> 00:51:17,490
WE WRONG IN MAKING THE

1383
00:51:17,490 --> 00:51:19,492
ASSUMPTION THAT THE ALDEHYDE

1384
00:51:19,492 --> 00:51:22,062
ITSELF IS THE ACTOR BECAUSE

1385
00:51:22,062 --> 00:51:23,596
ALDEHYDES FORM SHIFT BASES WITH

1386
00:51:23,596 --> 00:51:26,733
ALL THE PROTEINS IN THIS THE

1387
00:51:26,733 --> 00:51:29,269
MACROPHAGE AND WHATEVER, MAYBE

1388
00:51:29,269 --> 00:51:32,639
IT'S DOWN STREAM OF THE ALDEHYDE

1389
00:51:32,639 --> 00:51:35,408
RELATED TO SOME COMMON PROPERTY

1390
00:51:35,408 --> 00:51:38,912
CHEMICALLY OF THE ALDEHYDES THAT

1391
00:51:38,912 --> 00:51:39,412
ARE--

1392
00:51:39,412 --> 00:51:41,514
>> I DON'T THINK THAT'S
NAIVE AT

1393
00:51:41,514 --> 00:51:42,549
ALL.

1394
00:51:42,549 --> 00:51:43,083
IT'S ABSOLUTELY POSSIBLE.

1395
00:51:43,083 --> 00:51:46,319
ONE OF THE DEBITS WE HAVE IS ARE

1396
00:51:46,319 --> 00:51:48,922
THE ALDEHYDES DIRECTLY HAVING AN

1397
00:51:48,922 --> 00:51:51,157
EFFECT ON THE BACTERIA OR IS

1398
00:51:51,157 --> 00:51:53,793
THERE SOMETHING ALDEHYDE IS

1399
00:51:53,793 --> 00:51:56,996
DOING TO THE HOST CELL EVEN TO

1400
00:51:56,996 --> 00:51:57,764
CHANGE TRANSCRIPTION OR

1401
00:51:57,764 --> 00:51:58,698
SOMETHING, SO 1 OF THE WAYS WE

1402
00:51:58,698 --> 00:52:01,634
ARE TRYING TO GET IT ADDED AS

1403
00:52:01,634 --> 00:52:02,902
MICROBIOLOGIST IS WE'RE MAKING

1404
00:52:02,902 --> 00:52:04,571
MUTANTS THAT ARE MORE SENSITIVE

1405
00:52:04,571 --> 00:52:06,005
TO ALDEHYDES BECAUSE THAT WILL

1406
00:52:06,005 --> 00:52:07,774
TEST, IF THEY'RE MORE SENSITIVE,

1407
00:52:07,774 --> 00:52:09,743
THEN THEY SHOULD BE VERY

1408
00:52:09,743 --> 00:52:12,712
ATTENUATE INDEED A GLO1 MOUSE

1409
00:52:12,712 --> 00:52:16,683
WHICH WILL ACCUMULATE METHYL FLI

1410
00:52:16,683 --> 00:52:18,384
COLSIS GLYOXOL SPECIFICALLY

1411
00:52:18,384 --> 00:52:18,685
SUPPOSEDLY.

1412
00:52:18,685 --> 00:52:20,620
IS IT A HUNDRED%, I DON'T KNOW

1413
00:52:20,620 --> 00:52:24,290
BUT IT'S ABSOLUTELY A FAIR

1414
00:52:24,290 --> 00:52:24,724
COMMENT.

1415
00:52:24,724 --> 00:52:25,024
DEFINITELY.

1416
00:52:25,024 --> 00:52:26,326
IT'S A LOT.

1417
00:52:26,326 --> 00:52:34,400
THERE'S A LOT WE STILL NEED TO

1418
00:52:34,400 --> 00:52:35,034
FIGURE OUT.

1419
00:52:35,034 --> 00:52:37,036
>> DOES IT MATTER THE
LOCATION

1420
00:52:37,036 --> 00:52:38,171
OF THE BACTERIUM.

1421
00:52:38,171 --> 00:52:45,979
SO DO THEY STILL NEED TO BE IN

1422
00:52:45,979 --> 00:52:48,448
THE FAIG OSOME OR COULD THEY

1423
00:52:48,448 --> 00:52:49,315
HAVE ESCAPED INTO THE CYTOPLASM

1424
00:52:49,315 --> 00:52:52,318
SO YOU HAVE TRIED IT WITH ESX6

1425
00:52:52,318 --> 00:52:54,120
OR WHATEVER IT IS MUTATION.

1426
00:52:54,120 --> 00:52:56,589
>> OH MIRROR IMAGE
GOODNESS.

1427
00:52:56,589 --> 00:52:58,358
>> SO SEE IF THEY'RE
SENSITIVE

1428
00:52:58,358 --> 00:53:00,460
IN BOTH SITUATIONS IN THE FAG O

1429
00:53:00,460 --> 00:53:05,431
STUDIES OF MULTIPLE ENDOCRINE

1430
00:53:05,431 --> 00:53:06,800
AND THE AND CYTOPLASM.

1431
00:53:06,800 --> 00:53:08,268
>> WE HAVEN'T GOT THERE,

1432
00:53:08,268 --> 00:53:11,504
DEPENDING ON WHICH PATHWAY, IT

1433
00:53:11,504 --> 00:53:13,640
WILL BE MITOCHONDRIA OR

1434
00:53:13,640 --> 00:53:13,940
CYTOPLASMIC.

1435
00:53:13,940 --> 00:53:14,974
NOW 1 THING I DIDN'T SHOW IS

1436
00:53:14,974 --> 00:53:17,811
THAT IT TURNS OUT THE ALDEHYDE

1437
00:53:17,811 --> 00:53:20,346
SENSOR CHRIS CHANG MADE IS

1438
00:53:20,346 --> 00:53:22,248
PACIFIC TO ALDEHYDE, NOT ALWAYS

1439
00:53:22,248 --> 00:53:24,250
A HUNDRED% BUT THEY HAD 1 THAT

1440
00:53:24,250 --> 00:53:26,386
WAS SPECIFIC TO THE WHOLE CELL

1441
00:53:26,386 --> 00:53:28,788
ENCLOUDING EVERYTHING IS JUST

1442
00:53:28,788 --> 00:53:29,122
MITOCHONDRIA.

1443
00:53:29,122 --> 00:53:32,325
WHAT WAS VERY OBVIOUS IS IT IT

1444
00:53:32,325 --> 00:53:33,059
WAS THE MITOCHONDRIAIAL THAT

1445
00:53:33,059 --> 00:53:34,594
GOES UP A LOT.

1446
00:53:34,594 --> 00:53:36,663
SO IT I WAS STUNNED AT THE IDEA

1447
00:53:36,663 --> 00:53:38,298
THAT WE'RE MAKING FORM ALDEHYDE

1448
00:53:38,298 --> 00:53:39,499
GIVEN THAT IN THE LAB YOU'RE

1449
00:53:39,499 --> 00:53:41,701
SUPPOSED TO BE AVOIDING IT AT

1450
00:53:41,701 --> 00:53:45,371
ALL COSTS MUCH BUT THE GUY AT

1451
00:53:45,371 --> 00:53:47,774
CAME BRIDGE NAMED KJ P A TELL,

1452
00:53:47,774 --> 00:53:50,643
AND HE DORPHED OR IS POSING THAT

1453
00:53:50,643 --> 00:53:54,113
WE ARE CONITANTLY MAKING

1454
00:53:54,113 --> 00:53:55,114
FORMALDEHYDE FROM VARIOUS

1455
00:53:55,114 --> 00:53:56,850
METABOLIC PROCESSES AND IT'S

1456
00:53:56,850 --> 00:53:57,817
RECYCLED FOR AMINO ASIGNIFY ANDS

1457
00:53:57,817 --> 00:53:58,685
TECHNOLOGY TRANSFERS LIKE THAT.

1458
00:53:58,685 --> 00:54:01,254
SO I DON'T KNOW BUT MY, I'M VERY

1459
00:54:01,254 --> 00:54:02,555
NAIVE WHEN IT COMES TO

1460
00:54:02,555 --> 00:54:04,657
IMMUNOLOGY AND I THINK OKAY, THE

1461
00:54:04,657 --> 00:54:06,960
CELL BLOWS UP AND THERE'S STUFF,

1462
00:54:06,960 --> 00:54:09,362
AND YOU HAVE LIKE NO, HAVE YOU

1463
00:54:09,362 --> 00:54:10,763
ALDEHYDES, YOU HAVE MAYBE, MAYBE

1464
00:54:10,763 --> 00:54:14,100
IT DOESN'T NEED TO BE

1465
00:54:14,100 --> 00:54:14,467
INCAPSULATED.

1466
00:54:14,467 --> 00:54:16,836
I DON'T KNOW I THINK IT'S JUST A

1467
00:54:16,836 --> 00:54:18,938
COMLITELY BLACK BOX AND

1468
00:54:18,938 --> 00:54:19,539
HOPEFULLY WE WILL FIGURE THAT

1469
00:54:19,539 --> 00:54:24,477
OUT IN THE FIXTURE FEW YEARS.

1470
00:54:24,477 --> 00:54:27,647
>> WHACKY QUESTION, DO YOU
THINK

1471
00:54:27,647 --> 00:54:29,616
THAT THE ABILITY OF ALDEHYDES TO

1472
00:54:29,616 --> 00:54:31,451
TALK TO FOR BACTERIA COULD BE

1473
00:54:31,451 --> 00:54:33,386
THE REASON FOR THE WAR BERG

1474
00:54:33,386 --> 00:54:33,653
EFFECT IN.

1475
00:54:33,653 --> 00:54:36,656
>> WAIT A MINUTE WHAT?

1476
00:54:36,656 --> 00:54:37,657
>> ASK IT AGAIN.

1477
00:54:37,657 --> 00:54:39,659
>> SINCE ALDEHYDES ARE
TOXIC TO

1478
00:54:39,659 --> 00:54:41,261
BACTERIA, TIMES, DO YOU THINK

1479
00:54:41,261 --> 00:54:43,429
THAT COULD BE LIKE THE REASON

1480
00:54:43,429 --> 00:54:46,599
FOR THE WAR BERG EFFECT IN.

1481
00:54:46,599 --> 00:54:46,966
>> OH EYEAH.

1482
00:54:46,966 --> 00:54:49,702
SO MAYBE I DIDN'T MAKE

1483
00:54:49,702 --> 00:54:50,670
THAT--YEAH, ACTUALLY I DO.

1484
00:54:50,670 --> 00:54:54,674
IT'S NOT THAT WHACKY.

1485
00:54:54,674 --> 00:54:55,508
SO, OBVIOUSLY THE WAR BERG

1486
00:54:55,508 --> 00:54:57,176
EFFECT IS IMPORTANT FOR BIOLOGY

1487
00:54:57,176 --> 00:54:58,811
FOR MANY DIFFERENT REASONS AND

1488
00:54:58,811 --> 00:54:59,746
IT'S VERY HIGHLY STUDIED IN

1489
00:54:59,746 --> 00:55:01,247
CANCER BIOLOGY BECAUSE IT SEEMS

1490
00:55:01,247 --> 00:55:04,684
TO BE REQUISITE FOR TUMOR

1491
00:55:04,684 --> 00:55:05,451
DEVELOPMENT, RIGHT?

1492
00:55:05,451 --> 00:55:07,153
AND INFECTION BIOLOGY IN THE

1493
00:55:07,153 --> 00:55:08,621
LAST FEW YEARS, SEVERAL GROUPS

1494
00:55:08,621 --> 00:55:12,425
HAVE NOTICED THAT IF YOU INFECT

1495
00:55:12,425 --> 00:55:14,460
TB OR OTHER INTRACELLULAR YOU

1496
00:55:14,460 --> 00:55:16,396
GET INCREASED FLI COLSIS COLSIS,

1497
00:55:16,396 --> 00:55:18,932
I DON'T REMEMBER WHAT ASSPECS

1498
00:55:18,932 --> 00:55:20,700
ARE NOT EXACTLY LIKE WAR BERG

1499
00:55:20,700 --> 00:55:22,168
AND PEOPLE HAVE NOTICED IN AND

1500
00:55:22,168 --> 00:55:24,003
NO 1 BEDS WHY, SO SOME PEOPLE

1501
00:55:24,003 --> 00:55:26,039
THINK WELL, MAYBE IT'S MAKING

1502
00:55:26,039 --> 00:55:27,640
AMINO ACIDS FOR SOMETHING, YOU

1503
00:55:27,640 --> 00:55:28,775
KNOW I DON'T REALLY GET IT XI

1504
00:55:28,775 --> 00:55:30,276
THINK SOME PEOPLE THINK IT'S

1505
00:55:30,276 --> 00:55:32,345
BENEFICIAL FOR THE BACTERIA BUT

1506
00:55:32,345 --> 00:55:35,048
I'M LIKE, MAYBE THAT'S TRUE BUT

1507
00:55:35,048 --> 00:55:36,416
I DON'T SEE WHY WE WOULD WANT TO

1508
00:55:36,416 --> 00:55:38,618
DO THAT SO I DO THINK THAT

1509
00:55:38,618 --> 00:55:40,219
MAYBE, IT'S INDUCIBLE BY GAMMA,

1510
00:55:40,219 --> 00:55:44,891
SO I THINK SOMEHOW WE EVOLVED,

1511
00:55:44,891 --> 00:55:45,858
FOR AEROBIC GLYCOLYSIS TO GET

1512
00:55:45,858 --> 00:55:47,527
HARD WIRED INTO THE

1513
00:55:47,527 --> 00:55:48,728
INTERFERON-GAMMA PATHWAY SO WE

1514
00:55:48,728 --> 00:55:50,563
CAN MAKE MORE ADHIDES TO HELP

1515
00:55:50,563 --> 00:55:52,732
CONTROL INFECS THAT'S MY CRAZY

1516
00:55:52,732 --> 00:55:57,070
PROPOSAL AND I HOPE IT'S TRUE.

1517
00:55:57,070 --> 00:55:58,738
BUT YEAH, TOTALLY, NOT WHACKY.

1518
00:55:58,738 --> 00:56:02,775
>> ON THAT CRAZY NOTE, I
WANT TO

1519
00:56:02,775 --> 00:56:05,578
THANK DR. DARWIN AGAIN FOR SUCH

1520
00:56:05,578 --> 00:56:06,980
A STIMULATING TALK AND IT'S

1521
00:56:06,980 --> 00:56:08,281
REALLY GREAT DISCUSSION, I THINK

1522
00:56:08,281 --> 00:56:10,283
THAT'S ALWAYS THE MOST FUN AND

1523
00:56:10,283 --> 00:56:13,453
SO I WOULD ENCOURAGE PEOPLE TO

1524
00:56:13,453 --> 00:56:15,621
AT A AND GO TO THE RECEPTION TO

1525
00:56:15,621 --> 00:56:19,459
CONTINUE THIS DISCUSSION AND I

1526
00:56:19,459 --> 00:56:22,829
WANT TO ESPECIALLY ENCOURAGE

1527
00:56:22,829 --> 00:56:26,766
FELLOWS THAT ASK DR. DARWIN

1528
00:56:26,766 --> 00:56:27,166
QUESTIONS.

1529
00:56:27,166 --> 00:56:37,166
YEAH, SO CONTINUE THE DISCUSSION