OKAY, I THINK WE CAN GET
STARTED.
WELCOME TO TODAY'S WEDNESDAY
AFTERNOON LECTURE TALK.
I'M DR. STORTs AND IT'S REALLY
MY GREAT PLEASURE TO BRUCE
TODAY'S SPEAKER ON BEHALF OF THE
LAMBDA LUNCH SCIENTIFIC INTEREST
GROUP.
SO, LIKE I SAID IT'S A GREAT
PLEASURE TO INTRODUCE
DR. HERAN DARWIN BUT I NEED ON
DO SOME LOGISTICAL THINGS.
SO WE'RE LIVE HERE IN
LIPSETT HERE IN THE AMPHITHEATRE
BUT THOSE WATCHING REMOTELY, YOU
CAN STILL SUBMIT QUESTIONS TO
THE SPEAKER EMPLOY BUT YOU SAYS
SIMPLY CLICK THE BUTTON THAT
SAYS ACCEPTED LIVE FEEDBACK,
CORRECT?
>> YEAH EMPLOY.
>> WHICH IS DELOW YOUR VIDEOCAST
WINDOW AND THEN TYPE IN YOUR
MESSAGE, CHRIS WILL MONITOR THEM
AND HE WILL REPLAY THEM TO THE
SPEAKER.
FOR EVERYBODY, THE CME CODE IS
50092.
SO YOU CAN ALSO READ THAT HERE,
BUT MOST IMPORTANTLY NOW, LET ME
INTRODUCE DR. DARWIN.
SHE IS A PROFESSOR OF
MICROBIOLOGY AT NYU UNIVERSITY.
SHE EARNED HER Ph.D. TODAYING
SALMONELLA PATHOGENESIS, WITH
DR. VIRGINIA MILLER WHO WAS
FIRST AT THE UNIVERSITY OF
CALIFORNIA LOS ANGELES AND THEN
WENT TO WASHINGTON UNIVERSITY.
SO THEN AFTER THAT, SHE WENT TO
NEW YORK WHERE SHE CARRIED OUT
POST DOCTORAL WORK WITH DR. KARL
NATHAN AT WILD MEDICAL COLLEGE.
AND THAT'S WHERE SHE FIRST
STARTED WORKING ON TB AND I
THINK SHE BECAME REALLY
INTERESTED IN TB BECAUSE IT'S
SUCH AN IMPORTANT BUG, SO THE
CAUSATIVE AGENT, I SHOULD SAY OF
TB, DID YOU BERKULOSEIS CAN BE
CONSIDERED 1 OF THE MOST
SUCCESSFUL PATHOGENS ON EITHER
AND I PULLED THIS FROM
DR. DARWIN'S WEBSITE THAT
ONE-THIRD OF WORLD'S POPULATION
IS INFECTED BY THIS, IS THAT
CORRECT?
DID YOU THE LONG CO EXISTENCE OF
MICROBACTERIUM NTB WITH HUMANS
HAS LIKELY RESULTED IN THE
SELECTION OF HOST AND PATHOGEN
POPULATIONS THAT PREVENT EACH
OTHER'S EXTINCTION AND THAT'S
SORT OF A THEME OF TODAY'S TALK
AND SURPRISINGLY, RECENTLY
DR. DARWIN'S GROUP FOUND THAT
REACTIVE ALDEHYDES ARE EXPLOITED
IN THIS UNEASY TRUCE BETWEEN
HUMANS AND MTB.
AND INTERESTINGLY A COMMON HUMAN
MUTATION WAS SELECTED FOR BY
BACTERIAL INFECTION.
SO DR. DARWIN WAS NAMED FRONTIER
SCIENCE AND FELLOW OF THE
NATIONAL ACADEMY OF SCIENCES IN
2012 AND BECAME A FELLOW OF THE
AMERICAN ARK CAD ME OF
MICROBIOLOGY IN 2016.
SHE ALSO CURRENTLY SERVES ON THE
BOARD OF DIRECTORS, OF THE VIERK
LCHECK FOUNDATION WHICH I GUESS
IS AN INTERESTING EXPERIENCE,
ALSO IT HAS BEEN A TERRIFIC
MENTOR TO MANY DIFFERENT
STUDENTS AND FELLOWS.
SO PLEASE JOIN ME IN WELCOMING
DR. DARWIN.
THANK YOU VERY MUCH FOR COMING
TO VISIT US.
[ APPLAUSE ]
>> CAN YOU HEAR ME?
THANK YOU.
SO FIRST OF ALL THANK YOU SO
MUCH TO SUSAN AND GI GI AND
EVERYBODY ELSE FOR THIS
WONDERFUL INVITATION, I HAD TO
READ THE INVITATION TWICE, SO
THANK YOU FOR BEING HERE CAN AS
WELL AS VIRTUALLY.
I'VE BEEN HAVING A DPRIT DAY AND
I'M LOOKING IF ORDER TO TALKING
TO EVERYONE OVER THE NEXT COUPLE
DAYS.
SO TODAY'S TALK HALF OF IT IS
PUBLISHED BUT IT'S COMPLICATED
AND IT REALLY LED TO THE STORY I
WILL TALK ABOUT IN THE SECOND
HALF WHICH IS ALL COMPLETELY
UNPUBLISHED RIGHT NOW BUT IT IS
UP ON BIOARCHIVE IF YOU CONSIDER
THAT BEING PUB LESHED, AND OKAY,
FOR THOSE WHO ARE COMING TO
LAMBDA LUNCH, IT'S A COMLITELY
DIFFERENT TOPIC AND ONLY
IN-PERSON.
SO THE ORGANIZATIONS INFORM I
WORK ON IS CALLED MICROBACTERIUM
TO BURKE CUEULOSEIS, IT IS THE
STRIET COLONY THING, NOT AS
PRETTY AS E.COLI, IT TAKES 2-3
WEEKS TO FORM THESE COLONIES ON
THE PLATE, IT'S A HUMAN
EXCLUSIVE PATHOGEN SO THERE ARE
ANIMAL MODELS OF INFECTION BUT
IN THE REAL WORLD IT OHM INFECS
HUMAN ANDS IT'S INCREDIBLY
INFECTIOUS TAWZ IT ONLY TAKES A
FEW TO INFECT A HUGH MAN, OKAY,
IT IS THE LEADING CAUSE OF
DEATH, GLOBALLY BY AN INFECTIOUS
AGENT.
SO IT WAS ONLY BEAT OUT BY SARS
COV-2 IN THE LAST COUPLE YEARS
BUT OVERALL IT KILLS AN
ESTIMATED 1 AND HALF TO
2 MILLION PEOPLE EVERY YEAR AND
THIS HAS BEEN HAPPENING FOR
THOUSANDS OF YORES, SO IT IS AN
IMPORTANT PATHOGEN.
AND THEREFORE, THERE'S A LOT OF
MORTALITY AND A BIG PROBLEM AND
I KNOW THERE ARE A LOT OF PEOPLE
WHO WORK AT THE NIH, WHO WERE
VERY CONCERNED AND MOTIVATED TO
IDENTIFYING NEW DRUGS AND NIGH
WAYS TO TREAT TB BECAUSE DRUG
RESISTANCE IS A HIEWNL PROBLEM,
SO CLIFF BARRY'S LAB HAS BEEN
INCREDIBLY PIONEERING IN THEIR
ABILITY TO IDENTIFY NEW DRUGS
AND NEW WAYS TO AND ALSO USE OLD
DRUGS TO TREAT TUBERCULOSEIS.
SO EYE BIG PROBLEM IS THAT TB
LIKES TO LIVE IN MACROPHAGES AND
MACROPHAGES ARE SUPPOSED TO
PROTECT YOU AGAINST INFEC,
RIGHT?
SO, THIS IS REALLY BEEN A
PROBLEM FOR US AS SCIENTISTS
BECAUSE MACROPHAGES ARE YOUR
FIRST LINE OF DEFENSE AND YET
IT'S NOT REALLY UNDERSTOOD HOW
MACROPHAGES CONTROL BACTERIA,
AND THIS IS NOT JUST TB SO THEY
MAKE A LOT OF DIFFERENT
MOLECULES FROM REACTIVE OXIEN
AND NITROGEN SPECIES AS WELL AS
ANTIMICROBIAL PEPTIDES SO
UNDERSTANDING HOW MACROPHAGES
KILL TB HAS BEEN A BIG GOAL OF
MY LAB AS WELLsA THE LAB OF
OTHERS.
ONE THING WE DO KNOW ABOUT
MACROPHAGES AND CAT, I'M SORRY
BUT HAD IS MY MACROPHAGE, IS
THAT WHEN YOU HAVE AN INFECTION,
INTERFERON-GAMMA GETS INVOKED
AND YOU STIMULATE A
TRANSCRIPTIONAL RESPONSE.
AND MANY, MANY THINGS HAPPEN,
AND 1 OF THEM IS THE PRODUCTION
OF NITRIC OXIDE BY THE ENZYME
INDUCIBLE NITRIC OXIDE SYNTHASE
AND IT DID APPEAR SO NO CAN
DEFINITELY KILL BACTERIA INVITIO
AND THERE'S EVIDENCE THAT
MACROPHAGES USE IT TO KILL
BACTERIA IN A CELL INTRINSIC
MANNER IN VIVO.
THE PROBLEM IS WE DON'T HAVE
INOS DEFEBTIVE HUMANS OUT THERE
SO IT'S HARD TO PROVE THIS IN
HUMANS WE THERE'S A WHOLE DEBATE
ABOUT THAT THAT WE CAN GET INTO
IN THE QUESTIONS SESSION IF YOU
WISH BUT I WILL FOCUS ON WHAT WE
KNOW ABOUT IN MICE.
SO THE KIND OF MOST COMPELLING
EVIDENCE TO SUPPORT THAT INOS
WAS IMPORTANT WAS DONE IN THE
LAB MANY WREERS AGO NOW AND THIS
IS WHEN JOHN MACK MICKING WAS A
STUDENT IN THE LACK, AND THEY
KNOCKED OUT THE SYNTHASE
EXPRESSED IN MACROPHAGES AND
FOUND THESE MICE ARE
RIDICULOUSLY SUSCEPTIBLE TO TB
AS WELL AS OTHER INFECTION.
SO THIS IS JUST A SURVIVAL
CURVE, THIS IS A NUMBER OF MICE
ALIVE OVER TIME AND DAYS POST
INFECTION, NOT MINUTES AND WHAT
YOU WILL SEE IS THAT C57 BLACK 6
OR ILWILD-TYPE MICE WILL LIVE A
VERY LONG TIME WITH A LOW TO
MEDIUM DOSED AEROSOL INFECTION
OF TB, SO THIS IS H37, RB AND IN
A YEAR AND HALF ALL MICE WILL
EVENTUALLY DIE EMPLOY NOW WE
KNOW iNOS IS IMPORTANT BECAUSE
IF YOU ACTIVATE IT, THESE MYSELF
ARE RIDICULOUSLY SUSCEPTIBLE TO
INFECTION, BUT THE THING THAT'S
REMARKABLE TO ME IS WHEN YOU
LOOK AT THIS CURVE AT THE END OF
THE DAY, EACH THE WILD-TYPE MICE
ALL DIE OF TB, IT JUST TAKES A
REALLY LONG TIME AND THIS IS
KIND OF DOSE DEPENDENT.
IF YOU GIVE THEM MORE BACTERIA,
THEY WILL DIE FASTER.
SO THE QUESTION WE HAD WAS HOW
DOES THE BACTERIA PERSIST IN THE
FACE OF NITRIC OXIDE STRESS, AND
SO THIS IS WHAT I--THIS IS THE
QUESTION I ASKED AS A POST DOCK
IN THE NATHAN LAB ALMOST 20
YEARS AGO AND I DID A BIG
GENETIC SCREEN LOOKING FOR
MUSEUM AT THAT POINTS WITH
NITRIC OXIDE HOPING THEY WILL BE
ATTENUATE IN VIVO.
WE SUCCEEDED AND WE FOUND THAT
THE PROTEOSOME WAS REQUIRED FOR
THIS PHENOTYPE.
SO THE PROTEOSOME, OKAY, SO IF
YOU'RE A MICROBIOLOGIST LIKE
YOURS TRULY, YOU DON'T REALLY
THINK ABOUT PROTEOSOMES BECAUSE
MOST NORMAL BACTERIA DON'T HAVE
THEM.
WE HAVE THINGS LIKE CLIP P AND
OTHER PROTEASES BUT THEIR
BACTERIA, WHICH IS A BIG CLASS
OF BACTERIA, THEY DO ENCODE
PROTEOSOMES WITH MAYBE A FEW
MINOR EXCEPTIONS AND THESE
PROTEOSOMES ARE BARRELL SHAPED
PROTEASES THAT ARE ENCLOSED,
THEY ARE BIOCHEMICALLY AND
GENETICALLY HIGHLY SIMILAR TO
THOSE FOUND IN EUKARYOTES.
THERE'S AN ATPA CHAPERON LIKE
CLIP X, IT'S A HEXAMERAND IT
HELPS UNFOLD PROTEINS FOR
DEGRADATION DPRAIDATION.
THE WAY PROTEINS ARE TARGETED TO
THE SYSTEM OR THE PROTEOSOME
SYSTEM IS FOR A SMALL 64 AMINO
PROTEIN THAT IS MOSTLY
DISORDERED BUT AS KYLEY WALT
WALTERS HELPED US SHOW YEARS AGO
THAT IT IS IRPT ACTING WITH THE
ATP ACE, SO THIS PROTEIN FIRST
HAS A GLUTAMINE BY AN ENZYME
DISCOVERED BY WEBB'S LAB.
THEN THIS BECOMES AMENABLE BY
PATH A WHICH IS THE ONLY KNOWN
POP LIGASE, AND IT
PHOSPHORYLATES THE GLUTAMATE
THAT MAKE ITS ATTACK BY A BI
SEEN THATNY NEEDS TO GET
DEGREATED AND.
IT'S TO GET THE TARGETED TO THE
PROTEOSOME FOR DEGRADATION, I
CALL THIS THE PROTEOSOME OR PPS,
IT'S REQUIRED FOR NITRIC OXIDE
RESISTANCE AND MORE BROADLY
NEEDED FOR ROBUST VIRULENCE IN
AN ANIMAL INFECTION MODEL.
OKAY, SO HOW DOES THE PROTEIN
PROTECT AGAINST NITRIC OXIDE
TOXICITY, SO THIS WAS THE
QUESTION THAT TOOK A LONG TIME
TO ANSWER BECAUSE IT WASN'T
SUPER EASY AND I ALSO HAD TO
FIND A VERY INTREPID PERSON TO
TAKE IT ON AND THIS WAS DONE BY
A FORMER POST DOC,
[INDISCERNIBLE] WHO RUNS OUR
VACCINE CENTER AT NYU AND
LAWEDDER --WHAT SHE
DID WAS SHE WANTED TO TEST
HYPOTHESIS, SO THE FIRST
HYPOTHESIS WAS THAT THE
ACCUMULATION OF MANY DAMAGED
PROTEINS FROM LIKE NITROSALATION
OR NITRATION, LEADS TO CELL
DEATH, RIGHT, SO PROTEIN IMAWLT
CONTROLS IS VERY IMPORTANT THIS
ALL FORMS OF LIFE AS WE KNOW AND
WE QUICKLY RULED OUT THIS
HYPOTHESIS MAINLY BECAUSE,
NITRIC OXIDE STRESS, THE
SENSITIVITY OF PROTEOSOME SEEMS
SPECIFIC SO IF YOU THRESHOLD
OTHER TRESESS AT THE MUSEUM
TABTS THEY DID PERFECTLY FINE.
OKAY.
THE SECOND HYPOTHESIS THAT
TURNED ON UTR TO BE CORRECT OR
ELSE I WOULDN'T BE TELLING YOU
ABOUT THIS IS MAYBE THERE WAS 1
PROTEOSOME SUBTRAIT THAT WHEN
ACCUMULATED LED TO NO
SENSITIVITY.
SO THE WAY IT LOOKED IS IN THE
ABSENCE OF THE PROTEOSOME, HAVE
YOU THE ACCUMULATION OF A
MYTHICAL SUBSTRATE AND IN THE
PRESENCE OF NITRIC OXIDE THE,
BACTERIA ARE KILLED.
IN MY LAB WE DO GENETICS
SOPHISTICATEDY WOO DID A
SUPPRESSOR KREEN AND WE LOOKED
FOR MUTATIONS THAT WOULD MAKE A
PROTEOSOME MUTANT RESISTANT TO
NITRIC OXIDE, SO YOU GET RID OF
SUBSTRATE THEN YOU GET RID OF NO
SENSITIVITY.
SO I WILL SUMMARIZE WHAT WAS A
VERY EPIC SUPPRESSOR KREEN THAT
WAS DONE BY MARIE.
SO FIRSTLY, SHE FOUND THAT--SHE
FOUND 2 INDEPENDENT MUTATIONS
THAT KILLED AN EPIZYME CALLED
LONELY GUY OR LOG, AND THIS SHE
DISCOVERED WAS A POP IELTED
SUBSTRATE, IT CATALYZES THE
SYNTHESIS, AND CYTOKINEINS ARE
USED FOR SIGNALING IN PLANTS,
THEY HAVE 9 COPIES AND IF YOU
MUTATE 1 YOU DISRUPT GROWTH
BASICALLY.
SO TURNS OUT TB ACTUALLY MAKES
CYTOKININES AND AND IF YOU HAVE
A PROTEOSOME, THEY HYPER SECRETE
CYTOKININES, SO THAT WAS
INTERESTING AND WE WANTED TO
KNOW, OKAY, ARE THE CYTOKININES
INDUCING IMPORTANT FOR THE
EXPRESSION OF SOMETHING THAT HAS
TO DO WITH NITRIC OXIDE
SENSITIVITY SO WE DID AN RNA SEQ
EXPERIMENT AND FOUND THIS 1 GENE
CALLED LOW A OR RV0077 C WAS
HIGHLY INDUCED IN THE PRESENCE
OF CYTOKININE.
AND WHAT MARIE FIGURED OUT IS
THEY LOSE A LOSS IN STAINING.
SO MICROBACTERIA ARE NOT
GRANPOSITIVES, IT JUST GRINDS MY
EARS WHEN I HEAR PEOPLE SAY
THAT, THEY ARE NOT, THEY ARE
ACID FAST BACTERIA BECAUSE THEY
DON'T STAIN WITH GRAHAM STAIN,
AND IF YOU STAIN THEM THEY'RE
HOT PINK, RIGHT IN BUT WHEN
MARIE ADDED CYTOKININE AND TRIED
TO STAIN THEM, SHE HAD A HARD
TIME SEEING THE BACTERIA.
IF YOU KNOCK OUT THE GENE THAT
IS STRONGLY INDUCED BY
CYTOKININE, YOU LOSE THIS
ABILITY TO GHOST, RIGHT?
SO THEY JUST KIND OF STAY PINK
AND I DO THINK THEY LOOK
DIFFERENT FOR REASONS WE DON'T
UNDERSTAND, YOU CAN COMPLEMENT
THIS MUTATION IN SINGLE COPY BUT
WHAT WAS FUN IS WE OOH DENTIFIED
THE TRANSCRIPTIONAL REPRESSOR OF
LOWER A THAT'S RESPONDING TO THE
CYTOKINE IIN, IF YOU KNOCK THAT
OUT YOU HAVE CONSTITTATIVE
EXPRESSION OF LOWERA, AND AS A
CONSEQUENCE YOU HAVE IMOAOF
THING IRRESPECTIVE OF
CYTOKININE.
THIS WAS REALLY COOL, HOWEVER
THIS HAS NOTHING TO DO WITH
NITRIC OXIDE AND IN FACT, ANY OF
THOSE MUTANTS THERE WAS NO
EFFECT ON VIRULENCE, SO WE HAVE
NO IDEA OF WHAT THE ROLE OF
GHOSTING IS, MAYBE IT'S SPECIFIC
TO HOST MODEL OF INFECTION OR
MAYBE IT'S SPECIFIC TO HUMANS OF
COURSE WHICH WE CAN'T REALLY
TEST, MAYBE DIFFERENT MOUSE
MODELS WILL GIVE YOU A DIFFERENT
PHENOTYPE BUT NONETHELESS, WOE
MOVED ON BECAUSE IT HAD NOTHING
TO DO WITH NITRIC OXIDE SO WE
THOUGHT, SO HOW ARE THEY LINKED
TO NITRIC OXIDE SENSITIVITY.
SO MARIE, SO YOU KNOW, IT'S
REALLY IMPORTANT, I THINK FOR
TRAINEES TO KNOW AN HOUR IN THE
LIBRARY CAN SAVE YOU WEEKSA THE
BENCH AND THAT IS CERTAINLY
STILL TRUE AND MARIE WAS DOING
READING AND I REMEMBER WALKING
INTO THE LAB AND SHE'S LIKE, I
THINK I HAVE IT, APPROXIMATE SHE
SAID YOU KNOW WHAT, CYTOKINEINS
ALWAYS ARE BROKEN DOWN INTO
ALDEHYDES AND ADENINE, SO I
EVAPORATE SHOWN YOU A KITE O
KINE YET, BUT THIS IS CALLED I.
PERFORM SO THERE'S THE ADENINE,
CAN YOU ALSO HAVE ACTUALLY A
METHYL THIOS, AND THEN HAVE YOU
THE NITROIEN 6 MODIFICATION AND
IN PLANTS WHEN THAT'S REMOVED
YOU GET AN ALDEHYDE, SO THESE
ALDEHYDES ARE INCREDIBLE
LOAMACYY REACTIVE AND THIS
PARTICULAR ALDEHYDE WOULD BE 3
METHUE BEAUT NOLL.
HOWEVER, MARIE DETECTED THIS
ALDEHYDE QUITE ABUNDANTLY IN
PROTEOSOME DEFECTIVE STRAINS AND
SHE WAS BT UNDERSTANDING WHY IS
IT MAKING PARAHYDROXY BENZ
ALDEHYDE AND SHE REALIZED
THERE'S THIS KIND OF WEIRD
CYTOKINEIN CALLED PARATOPOLYNN
AND WE COULD DETECT IT IN T. B.,
I DON'T KNOW IF WE REPORTED IT
BECAUSE IT WAS SO LOW, BUT IF
YOU REMOVE THIS IN 6 GROUP, YOU
GET PARAHIDE BROXIE BENZ
ALDEHYDE.
SO THIS TESTS THE WHYED THAT
MAYBE THE ALDEHYDES WERE SOMEHOW
SENSITIZING THE BACTERIA IN
NITRIC OXIDE, O TO TEST THE
HYPOTHESIS WAS VERY EASE, WE
TOOK ALDEHYDE AND ADDED IT TO
WILD-TYPE TB IN THE PRESENCE OF
NITRIC OXIDE AND TECHNOLOGY
ORGANIZATION THIS TO SEE IF IT
WOULD MAKE THEM MORE SENSITIVE
TO NL, I THINK HAD IS THE FIRST
SENSITIVITY I'M SHOWING YOU,
WON'T BE THE LAST, SPOILER.
HERE'SOT Y-AXIS IS A LOG SCALE
OF THE NUMBER OF COLONY FORMING
UNITS OF BACTERIA THAT WE TARTED
WITH THE INPUT AND IMRAI IS
ACIDIFIED MEDIA WHICH WE USE TO
GENERATE N. O. AND THEY SIT IN
THIS FOR 6 DAYS, SO THEY GROW A
LITTLE OR AT A STATIC AND THEN
YOU ADD SODIUM NITRITE.
SO WILD-TYPE TB DIES A LITTLE
BIT AND HERE IS THE MPA, OR
CHAPERON MUTANT OF THE THE
PROTEOSOME AND YOU CAN SEE IT
DIES MORE, AND SPECIFIC TO N. O.
SO IF MARIE ADDED PH BA, YOU CAN
SEE YOU GET A DOSE DEPENDENT
KILLS OF THE BACTERIA AND SHE
GOT STERILIZATION OF THE CULTURE
AND THIS WAS SPECIFIC TO MEDIA,
IF YOU USE SODIUM NITRATE WHICH
DOESN'T GENERATE N. O. WE
WOULDN'T GET ANY KILLING.
NOW THE CYTOKINEIN WE MOSTLY LIE
DETECTED IN CULTURES WAS
ISOPENTINE REGIMEN ILLEGALS ALDA
HIDES 19 AND THAT IS INEDIBLY
VOLATILE AND SHE SAW THE SAME
RESULT WHICH IS IF YOU ADD IT,
YOU GET A DOSE DEPENDENT KILLING
OF THE BACTERIAIA AND THIS AGAIN
WAS IN THE MICROMOLAR RANGE.
OKAY, SO THIS IS ALL PUBLISHED
DATA AND JUST TO KIND OF
SUMMARIZE ALL THIS, THE MODEL OF
THE PROTEOSOME DEPENDENCE IS
THAT LONELY GUY NEEDS TO AT A
LONELY, RIGHT IN THE ABSENCE OF
PROTEOSOMES YOU GET AN
ACCUMULATION OF LONELY GUY, YOU
GET AN ACCUMULATION OF
CYTOKINEINS WE CAN DEFECT AND
GET AN ACCUMULATION OF ALDEHYDES
AND WE DETECT 1 ALDEHYDE.
UNDER NORMAL CONDITIONS, THE
ALDEHYDES ARE FINE, THEY'RE
TOLERATED BY THE BACTERIA, IF WE
ARE JUST GROWING THESE IN BROTH
THEY'RE FINE, BUT IN THE
PRESENCE OF NITRIC OXIDE, THE
BACTERIA ARE VERY UNHAPPY AND
ATTENUATE IN ANIMALS.
OKAY, SO THAT'S KIND OF THE
COMPLICATED WAY OF HOW THE
PROTEOSOME PROTECTS THE NITRIC
OXIDE.
AND THIS IS WHERE I GET INTO THE
MORE AND CRAZY STUFF AND THAT IS
THAT ALDEHYDE SENSITIZES TB TO
NITRIC OXIDE.
MORE RECENTLY THIS YEAR WE
PUBLISHED A STORY SHOWING THAT
ALDEHYDES ALSO SENSITIZE TB TO
COPPER AND THIS SEEPS TO BE, WE
KIND OF WORKED OUT THE MECHANISM
OF THIS, WE THINK THE ALDEHYDES
MESS WITH CYSTINES IN COPPER
SENSING PROTEIN ANDS THAT
DISRUPTS RESISTANCE TO THE
COPPER.
SO SOMETHING THAT SEEMED
VERY--JUMPED OUT TO ME WHEN WE
WERE DOING THIS IS THAT ALDEHYDE
SEEMED TO BE AN ARK CHILLIES
HE'LL FOR TB, IT DOESN'T LIKE
THE ACCUMULATION OF ALDEHYDES,
IT DOESN'T LIKE TO SEE
ALDEHYDES, EVERY, WHEN I
LOOKEDDA THE LITERATURE, I
WONDERED IF THERE WAS SOMETHING
BIGGER HERE.
THE CONCEPTUAL LEAP I WANT YOU
TO BELIEVE BY THE END OF THE
TORSETHAT WE HAVE EVOLVED TO
PRODUS OR DIVERSE ALDEHYDES THAT
WE PRODUCE TO HELP CONTROL
BACTERIAL INFECTIONS NOT JUST TB
AND THIS IS SOMETHING WE CALL
ALDEHYDE HYPOTHESIS THAT YOU ARK
KIEWMULATE LONELY GUY, YOU
ACCUMULATE ALDEHYDE ANDS YOU
BECOME SENSITIVE TO INFORM O.
AND COPPER AND YOU DIE.
BUT IT TURNS OUT THAT IF YOU
LOOK AT THE LITERATURE, YOU
FIEBD OUT THAT TB IS HIGHLY
SENSITIVE TO MUSEUM TAIGS--I AM
GOING TO TAKE OFF MY CARDIGAN
BECAUSE I'M BOILING.
OKAY, SO, TB IS HIGHLY SENSITIVE
TO MUTATIONS THAT PERTURB
CENTRAL METABOLISM, AND IN SOME
CASES IT'S BECAUSE THEY
ACCUMULATE 1 OR MORE ALDEHYDE,
AND THE LAB AT CORNELL HAD MADE
THIS OBSERVATION, WHAT'S REALLY
REMARKABLE AND INTERESTING I
THINK IN THE RECENT MAYBE 4
YEARS, CLINICALLY, SEVERAL LABS
HAVE INDEPENDENTLY NOTICED THAT
TB SEEMS TO GET THESE LOSS OF
FUNCTION MUTATIONS IN A GENE
CALLED GLYCEROL KINASE OR GLPK,
AND PROD UBIQUITINNATIONS DOWN
STREAM OF GLPK INCLUDE ALDEHYDE,
THIS IS WORK DONE BY THE TODAY
LABS.
WE, OR I SHOULD SAY MARIE FOUND
AN INSERTION IN GLPK THAT
SUGGESTED THAT,--I'LL GET TO WHY
THIS IS INTERESTING BUT GLPK IS
UPSTREAM OF A COUPLE DIFFERENT
ALDEHYDES, RIGHT?
OKAY, SO IN MAMMALS, SARAH'S LAB
HAD REPORTED THAT WHEN YOU
INFECT MACROPHAGES EATER MOUSE
OR HUMAN THAT TB AND ISHT FERON
IMAMMA INDUCED AEROBIC FLI
COLSIS ALSO KNOWN AS WAR BERG,
OR WAR BERG LIKE EFFECT.
AND 1 OF THE THINGS THAT'S KIND
OF FUNNY ABOUT THIS IS FLI
COLSIS IS CONSERVED IN
EVERYTHING, IT'S WHY IT'S CALLED
CENTRAL METABOLISM.
SO AS [INDISCERNIBLE] SAID, WHAT
IS TRUE OF THE ELEPHANT IS TRUE
OF E.COLI.
I THINK WE HAVE TO REMEMBER THAT
BECAUSE EVEN PEOPLE IN MY LAB
FORGET ABOUT THIS BUT IF YOU
LOOK AT THIS PATHWAY WITH
GLUCOMETABOLISM, THESE ARE ALL
ALDEHYDES, SO METHITG GLUE
MARIOUS COLOSSAL IS AN ALDEHYDE,
SO WHEN YOU INFECT THESE MOUSE
MACROPHAGES THEY SECRETE BUCKETS
OF METHYL TBLIS ON ILLEGALS, SO
MAYBE WHAT'S BEING INDUCED TO
HELP CLEAR THE INFECTION, OKAY?
SO THIS IS WHY GLPK COULD PLAY
IN, SO IF THIS WAS INSIDE THE
BACTERIUM, IF GLYCEROL KINASE
WILL PHOSPHORYLATE IT AND THEN A
COUPLE STEPS DOWN WILL MAKE
GLYCEROL, SO IF YOU LOWURE YOUR
GLPK, YOU MIGHT LOWER YOUR
GLYCEROL IN THE BACTERIA.
SO SO THIS INDUCES
ARE--ADMINISTRATIVE OWNIC MRI
COLSIS AND SO WE ACCIDENT WANTED
TO ASK IS IT POSSIBLE THAT THESE
HOST DERIVED ALDEHYDES CAN KILL
OR CONTROL TB.
SO, THIS WAS AN EXPERIMENT MARIE
HAD SET UP BEFORE SHE LEFT AND I
REPEATED MORE RECENTLY AND THEN
LET ME TELL YOU IT IS VERY
SATISFYING WHEN YOU'RE THE PI
AND YOU CAN REPEAT WHAT YOUR
POST DOC DID.
THEY'RE LAUGHING BUT IT'S TRUE,
SO HERE'S FLI COLSIS COLSIS
AGAIN AND WHAT I DID WAS I DID A
NITRIC OXIDE ASSAY SO IN THIS
CASE, I'M LOOKING FOR SYNERGY
WITH NO, SO HERE IS THE CALLING
FORMING UNITS LONG SCALE AND
LOOK AT THE BLACK, SO YOU CAN
SEE WITH THE ARK DITION OF
MICROMOLAR CONCENTRATIONS OF
GLYCOLYTIC ALDEHYDES, YOU WILL
KILL THE BACTERIA WITH NO WHICH
IS IMPORTANT.
MY FAVORITE ALDEHYDE IS METHYL
GLYXOL, AND IT KILLS BACTERIA
BUT BY ITSELF AT THESE
CONCENTRATIONS AGAIN MICROMOLAR
YOU DON'T GET A LOT OF KILLS BUT
IF YOU GO HIGHER YOU TART TO
KILL THE BACTERIA.
OKAY, SO, THE OTHER THINGS THAT
HAPPEN DURING INFLAMMATION IS
YOU GET REACTIVE OX GENERATED
SPECIES RIGHT, SO WHAT ARE THE
ROSS DOING, SO ROSS ARE
IMPORTANT FOR GENERATING LIPID
ALDEHYDES AND THESE ARE
GENERATED BY LIPID PEROXIDATION
SO YOU GET THINGS LIKE 4 HYDROXY
AND DISCIPLINARY ALDEHYDE, AND
SO, OF COURSE, THEN, WE WENT
AHEAD AND TESTED THESE.
AND FHNE AND THEY WORK TOGETHER
WELL TO KILL BACTERIAIA.
SO, THAT WAS ALL VERY COOL AND
LIKE INSPIRING, I THOUGHT BUT I
THINK WHAT WAS REALLY REMARKABLE
WAS THIS IDEA THAT MAYBE HUMANS
HAVE EVOLVED AN ANTITB ROLE.
BY USING THEIR OWN ALDEHYDES.
SO THE MOST COMMON HUMAN GENETIC
MUTATION ON IS AN ALD H2, I WILL
ASK HOW MANY IN THIS AUDIENCE
CANNOT DRINK ALCOHOL BECAUSE
THEY GET RED?
I KNEW ABOUT PONG, HE CAN'T BE
THE ONLY 1 EMPLOY OKAY, WELL
IT'S NOT ME, I'M WILD-TYPE BUT
ANYWAY, THIS MUTATION AND SUPER
COMMON AND IT'S IN A ABOUT A
HALF BILLION PEOPLE, MOSTLY OF
EAST ASIAN DESCENT AND IT'S A
LOSS OF FUNCTION MUTATION, IT'S
AN AMINO ACID,LY CONSERVED IN
ALL THESE PEOPLE, THERE'S NOT 10
SNPs, AND MAYBE A FEW GUYS AND
HETEROZYGOUS DOMINANT SO THE
ENZYME IS A TETRAMER, IF YOU
HAVE 1 BAD COPY YOU WILL MAKE A
FAILED ENZYME.
AND IT TURNS OUT A GROUP IN
KOREA WANTED TO KNOW WHY THEY
HAD THIS MUTATION AND IF IT WAS
LINKED TO ANYTHING APPROXIMATE
AND WHAT THEY FOUND THAT WAS
REMARKABLE IS PEOPLE WHO HAD
THIS MUTATION WERE LESS LIKELY
TO HAVE TUBERC CUEULOSEIS, AND
THEY'RE LIKE FEBRUARY YOU LIVE A
HELTIER LIVE STYLE, YOU'RE LESS
LIKELY TO GET TB, I DON'T THINK
THAT'S IT.
SO WE DID META-ANALYSIS WITH
SARAH AND HER COLLEAGUES LOOKING
AT 2 OTHER COHORTS INCLUDING
VIETNAM AND SINGAPORE AND WE
FOUND THAT BASICALLY THE
ASSOCIATION OF MUTATION WITH TB
WAS EVEN STRONGER, RIGHT, THAN
WHAT THEY FOUND IN THIS ORIGINAL
PAPER AND AGAIN IT WAS ASSOCIATE
WIDE PROTECTION AGAINST
TUBERCULOSIS.
SO COULD DISRUPTION OF THIS GENE
RESULT IN RESISTANCE TO
BACTERIALIN INFECTIONS, RIGHT IN
HARD TO TEST THAT IN MUSEUM MANS
BUT WE CAN TEST IT IN MICE, SO
IN COLLABORATION WITH RUSSELL
VANCE'S LAB, HIS POST DOC, MADE
THE KNOCKING THE WHOLE THING OUT
SO WE HAVE TO DO THIS WITH
HOMOZYGOTES AND IN COLLABORATION
WITH CHRIS CHAIN'S LAB, THEY HAD
MADE THESE FORM ALDEHYDE SENSORS
SO THESE ALDEHYDE SENSORS THAT
COULD LOOK IN MACROPHAGES AND
COULD NOT GET INTO THE DETAILS
OF THE DIFFERENT 1S THAT THEY
MADE BUT WHAT THEY FOUND WAS IN
A BLACK 6 MOUSE BACKGROUND,
OKAY, SO THIS IS JUST WILD-TYPE
MICE, IF YOU INDUCE IT WITH
INTERFERON-GAMMA AND A TLR
AGONIST, YOU GET AN INDUCTION OF
ALDEHYDE PRODUCTION, RIGHT?
BUT IN THE LDH2 MICE, THEY'RE
HIGH FOR ALDEHYDE, THAT WAS KIND
OF COOL.
BUT WHAT WAS REALLY NICE WAS THE
INFECTION EXPERIMENT.
SO STAN BARRY WHO'S A POST DOC
IN SARAH STANLEY'S LAB, SO THIS
IS EACH DOT IS A MOUSE AND EACH
LINE IS A LUNG PAIR,
SOPHISTICATEDY THIS A
GENETICALLY SUSCEPTIBLE MOUSE,
IT HAS AN INTERFERON, HAS TOO
MUCH TYPE 1 INTERFERON AND THEY
DIE VERY EARLY EMPLOY SO IF YOU
PUT THE LDH MUTATION IN THE
BACKGROUND IT GIVES THEM SOME
LEVEL OF PROTECTION, RIGHT IN SO
FEWER CFURKSs IF YOU LAY
AROUND THIS MUTATION, AND WE DID
IT IN THE B6 BACKGROUND.
WE DIDN'T REALLY EXPECT TO SEE
AN EFFECT WITH THE HEADS WHICH
WE DON'T BUT THE ALD H2 KNOCK
OUTS HAVE THIS IN THEIR LUNGS,
THIS A COMPLETELY DIFFERENT GRAM
NEGATIVE PATHOGEN, DONE ABOUT A
OPPORTUNITY IN SARAH'S LAB,
SANCHEZ, AND THERE ARE PAY FEWER
BACTERIAER RAW DATA IN THE ALD
H2 MICE.
THEY COULD ACTUALLY, SO INVITRO
MACROPHAGE SPRMS IT'S HARD TO DO
THAT WITH TB BECAUSE TB IS SLOW,
SO IN THE MACROPHAGES DON'T LIVE
LONG, BUT, ANDRIEA COULD SHOW
THIS WAS EFFECTIVE INVITRO, SO
THERE WAS A CELL INTRINSIC
EFFECT OF THE ALDEHYDES ON
BACTERIAL GROWTH.
SO WHAT I'M HOPING TO LEAVE YOU
WITH AND THERE WILL BE PLENTY OF
TIME FOR DISCUSSION IS THAT I
THINK ALDEHYDES ARE NEWEL
APPRECIATED ANTIMICROBIAL FACTOR
SO I DIDN'T GET A CHANCE TO TALK
ABOUT COPPER BUT THIS IS MANAGE
MY LAB WORKED ON BUT WE THINK
THAT ALDEHYDES HELP PROTENTIATE
THE THINGS LIKE NO AND COPPER
AND OTHER ANTIMICROBIAL
MOLECULES THAT MACROPHAGES ARE
MAKING AND CERTAINLY THE
ALDEHYDES THEMSELVES ARE VERY
GOOD AT ENACTIVATING BACTERIA
AND PARASITES, WE DON'T KNOW
THAT YET.
WE PUBLISHED THIS HYPOTHESIS
YEARS AGO BUT NOW THE PAPER
THAT'S UNDERREVIEW IS KINE OF
FINALLY TESTED THE HYPOTHESIS,
IT'S LOOKY PRETTY GOOD.
SO WHERE DO WE GO FROM THERE, I
AM IS RISE AND TELL YOU WHAT
WE'RE DOING NEXT.
SO PHYSIOLOGIC ALDEHYDES
PRODUCED DURING INFECTIONS ARE
TOXIC TO TB, AND A COMMON HUMAN
LOSS OF FUNCTION LOSS OF
MUTATION IN ALDEHYDE
DETOXIFICATION IS PROTECTIVE
AGAINST MTB AND IT'S A PHENOTYPE
THAT WE CAPILATULATED IN MICE.
AND I THINK WHAT'S REALLY
REMARKABLE, I AM NOT AN
IMMUNOLOGIST, I AM JUST A HUMBLE
MICROBIOLOGIST AND SOMEHOW BY
STUDYING VERY FUNDAMENTAL
BACTERIAL PHYSIOLOGY WE REVEALED
AN IMPORTANT WEAKNESS IN THIS
PATHOGEN AND I THINK THIS
COLLABORATION WITH SARAH STANLEY
HAS BEEN PHENOMENAL AND WE'RE
REAL LEKS SIGHED ABOUT MOVING
THINGS FORWARD.
SO WHAT ARE WE DOING NOW?
RIGHT?
YOU GOT EVERYTHING, SO WHAT'S
INTERESTING IS, THIS MUTATION
WAS BELIEVED TO HAVE AROSE IN
CHINA SEVERAL THOUSAND YEARS AGO
AND IT OBVIOUSLY SPREAD LIKE
WILDFIRE PROBABLY BECAUSE IT WAS
GIVING SOME SORT OF FITNESS
ADVANTAGE, SO IN 1995 A NEW
LINEAGE OF TB WAS RECOGNIZED AS
THE L2 OR BEIJING LINEAGE AND
IT'S NAMED BEIJING WHERE IT WAS
DOMINATING IN CHINA AND EMERGED
SEVERAL THOUSAND YEARS AGO, SO
BACK IN 1995 WHEN GENOMICS WERE
COMING OUT AND PEOPLE WERE
SAYING WE HAVE THESE DIFFERENT
LINEAGES OF TB, PEOPLE THOUGHT,
WELL MAYBE IN EMERGED FROM
ANTIBIOTIC USAGE IN ASIA,
VACCINATION IN ASIA, BUT WITH
DEEPER ANALYSIS, IT'S NOW CLEAR
THAT THE BEIJING LINEAGE EMERGED
SEVERAL THOUSAND YEARS AGO SO IT
COULDN'T HAVE BEEN DRIVEN BY
THESE HUMAN FACTORS SO WHAT IF
THIS WAS BASICALLY THIS LINEAGE
EMERGED TO COUNTER THE FITNESS
ADVABTAGE OF A POPULATION THAT
HAD BECOME MORE RESISTANT, RIGHT
IN O WHAT WE'RE DOING NOW IS
TRYING TO UNDERSTAND WHAT ARE
THE REAL ROBUST PHENOTYPES
ASSOCIATED WITH THE DIFFERENCE
BETWEEN A LABORATORY LINEAGE
LIKE L4 AND MAYBE LAURA CAN HELP
ME WITH THIS, VERSUS L2, THERE'S
A LOT OF LITERATURE OUT THERE
BUT WHAT HAPPENS WHEN YOU READ
IS HOW CONFUSING A LOT OF IT IS,
HOW UNCLEAR A LOT OF IT IS AND
MAYBE IT NEEDS TO GET
STRAIGHTENED OUT OF IT.
BUT 1 THING THAT'S BEEN SORT OF
NOTICED IN THE PAST AND WE
REALLY WANTED TO KIND OF GET A
BETTER HANDLE ON WAS THE
PRODUCTION OF THESE LIPID BODIES
CALLED ILIs.
AND SO, HERE IS OUR LAB STRAIN,
AND HERE IS A BEGINNING STRAIN,
AND THIS IN THIS PARTICULAR
STRAIN MAKES THESE ROBUST LIPID
BODIES.
THIS PHENOTYPE ISN'T A HUNDRED%
CONSISTENT ACROSS L2 LINEAGE BUT
IT'S SUPER CONSIST WENT THIS
PARTICULAR 1 SO WE THINK THAT
MAYBE UNDERSTANDING WHY THESE
ARE MADE OR HOW THEY'RE MADE
MIGHT GIVE US SOME INSIGHT INTO
HOW THEY DEAL WITH BEING IN A
MORE RESISTANT HUMAN POPULATION
AND SO WHAT DAISY IS DOING IS
SHE'S ORDERING AN ENTIRE LIBRARY
AND ENCODING THE 7
HGERONTOLOGYSTS MEMORY CLONE
ANDEE IF SHE CAN TRANSFORM THIS
INTO AN L4 TRAIN AND
[INDISCERNIBLE] PHENOTYPES.
IT'S HARD BUT DAISY'S A BEAST.
THE OTHER THING WE'RE HOPING TO
DO AND I'VE APPLIED FOR FUNDING
BA UNITED STATES WE'RE NOT
TECHNICALLY FUNDED TO DO THIS IS
DB1, AND MULTIOMICS ANALYSIS,
CAN WE DO TRANSCRIPT OMICS,
METRICS TAB O OHMICS IN THE SAME
LAB, WITH SAME BATCHES OF MEDIA
WITH DRUG SENSITIVE STRAINS TO
SEE WHAT ARE THE KEY
DIFFERENCES.
IT'S A PRETTY SIMPLE EXPERIENCE
BUT I THINK IT REQUIRES PEOPLE
BEING ORGANIZED, SOMEONE TRIED
TO DO WITH BUT WITH WITH DRUG
RESISTANCE STRAINS AND SINCE
IT'S CATEGORIZED BY
[INDISCERNIBLE], YOU WANT TO
START WITH TRAINS THAT ARE ALL
DRUG SENSITIVE AND THEN USE SAME
BATCHES IN MEDIA AND HOPEFULLY
WE CAN GET ANSWERS.
THE OTHER THING WE'RE ASKING IS
DOES TB HAVE RESIST ALDEHYDES
AND 1 HAS DONE A MASSIVE GENETIC
KREENS LOOKING FOR MUSEUM TABTS,
SHE'S FOUND THEM AND NOW WE'RE
TRYING TO FIGURE OUT HOW THEY
CONFER SENSITIVITY, OR HOW THOSE
GENES CONFER RESIST APT TO
METHYL GLYOXYL.
SO JUST WATCH THE SPACE AND I
NOW HAVE TO THANK THE PEOPLE WHO
HAVE DONE THIS WORK OVER THE
YEARS SO MARIE, MY FORMER POST
DOC HAS JUST--SHE WAS JUST
INCREDIBLE, SHE'S THE 1 WHO DID
ALL THE CYTOKINEIN NNO
SUSCEPTIBILITY WORK AND MY 2
POST DOCS DACEY APPROXIMATE FONG
WHO ARE CARRYING ON THAT
RESEARCH .
I COULDN'T HAVE DONE THIS
WITHOUT AMAZING COLLABORATORS AT
BERKELEY, MELBOURNE, VIETNAM, A
LOT OF PEOPLE AT BERKELEY AND
FUNDING FROM THE NIH AND I AM
HAPPY TO TAKE QUESTIONS AND I
REALLY THANK YOU SO MUCH FOR
BEING HERE.
WHOO.
[ APPLAUSE ]
>> BIA ALL MEANS USE THE MICs
NTHANK YOU FOR SUCH A COMPELLING
AND EXCITING TALK THAT WAS
BEAUTIFUL AND I WANT TO
REITERATE THAT THERE WILL BE
PART 2 A DIFFERENT TALK TOMORROW
AT LAMDA LUNCH THAT ARE IN
PERSON BUT I SEE WE HAVE PEOPLE
AT THE MICs AND ON ONLINE BUT
PART 1.5 IS THE RECEPTION AFTER
THIS.
SO LOTS OF OPPORTUNITIES TO ASK
QUESTIONS.
>> YEAH, SO JUST A VERY--THAT
WAS A GREAT TALK, JUST A VERY
FUNDAMENTAL QUESTION, HOW DO YOU
THINK A WIDE ARRAY OF ALDEHYDES
KILLS A WIDE VARIETY OF
PATHOGENS, IS IT ALL BY
ACTIVATING NITRIC OXIDE, OTHER
MECHANISMS?
SO RIGHT, THE QUESTION IS SO
MANY DIFFERENT ALDEHYDES SO MANY
DIFFERENT PATHOGENS IS IT 1
MECHANISM, I WILL SAY WE'VE
ONLY--THE FIRST QUESTION IS
ALDEHYDES SO I DO THINK THAT
DIFFERENT ALDEHYDES HAVE
DIFFERENT LEVELS OF TOXICITY AND
WE DON'T KNOW FOR CERTAIN ARE
WHICH 1S ARE ACTUALLY HAVING AN
EFFECT IN VIVO, SO LDH2 IS
MOSTLY THERE TO DETOXIFY THE
LIPID ALDEHYDES IN OUR LIVER AND
FROM INFLATION, BUT, IT'S KIND
OF PROPHOSPHORYLATED CUE USE, IT
COULD COME FROM DETOXIFICATION
FROM GLOW 1, THOSE MOUSE ARE NOW
BREED NOTHING OUR FACILITY BUT
AT LEAST WITH TB GLOW 1 DOESN'T
SEEM TO HAVE A BILGE CENTER FOR
EXCELLENCE ON AGING ON THE
WILD-TYPE MICE, SO WE DON'T KNOW
IN TERMS OF HOW THE ALDEHYDES
WORK, I HAVE A FEELING IT'S
GOING TO BE ORGANISM SPECIFIC.
SO IN TB WE KNOW THAT ALDEHYDES
REACT WITH CYSTINES AND SEEM TO
DISARM METAL, TRANSPORTERS WE
DON'T UNDERSTAND THE NITRIC
OXIDE LINK AT ALL.
STAFF AURUOUS, I DIDN'T TALK
ABOUT IT AT ALL CRAZY RESISTANT
TO ALDEHYDE, SO MAYBE WE DON'T
WANT TO TALK ABOUT STAPH
AUREOUS, I HAVE NO IDEA BUT THIS
IS STUFF THAT SARAH'S LAB WILL
WORK ON AND WE'RE CONTINUING TO
WORK ON EMPLOY IT'S A GREAT
QUESTION, WE DON'T HAVE ALL THE
ANSWERS YET.
>> THANKS.
>> SO SOMEBODY WHO GETS BACTERIA
INFECS ALLOT, DID IS IT WORK THE
OTHER WAY AROUND IN IS MY
ALDEHYDE DEHYDROGENASE TOO GOOD
IN CONVERTING ALDEHYDES, HAVE
YOU THOUGHT ABOUT THOSE LINES OR
ANY OTHER MORE COMMON VARIANTS
IN THE ALDEHYDES THAT COULD MAKE
THE ENZYME BETTER?
>> NOT THEY KNOW OF AND THERE
ARE OTHER MUTANT ALLELES BUT
THEY'RE VERY RARE AND I DON'T
THINK--NOBODY KNOWS WHETHER OR
NOT THEY CONFER PROTECTION
BETTER OR WORSE.
YEAH, I DON'T KNOW.
YEAH, SORRY.
NNO WORRIES.
NCAN I USE THE PREROGATIVE, HAVE
YOU LOOKED AT SORT OF THE
OVERLAY OF TB INFECTION AND AND
MUSEUM TAIGS ON A FLOABAL LEVEL
SO WHY ARE THERE IN POPULATIONS,
WHERE THERE SEEM TO HAVE BEEN A
STRONGER SELECTION, DOES IT MAKE
SENSE?
NSO LIKE THE 1 QUESTION I GET A
LOT, THE GREAT QUESTION, IS HOW
COME THAT LDH2 MUTATION HASN'T
HAPPENED IN OTHER POPULATIONS SO
I THINK THAT PERSON IN CHINA
THOUSANDS OF YEARS AGO JUST WON
THE GENETIC LOTTERY, THEY GOT
THIS VERY RARE, IT'S LIKE LYSINE
TO A PARTATE OR DPLIEWTA MATE
MUTATION AND IT MAKES A STABLE
PROTEIN, IT STILL CAN INTERACT
WITH THE WILD-TYPE COPIES YET IT
COMPLETELY KILLS ITS FUNCTION
EMPLOY SO MY FEELING WAS IT
REALLY WAS LUCK IN MANY WAYS,
BECAUSE IF YOU GET A COMPLETE
LOSS OF FUNCTION, THEN YOU NEED
TO BE A HYM O ZYGOTE FOR IT AND
I THINK THOSE PEOPLE, SO LET'S
SAY SOMEONE GOT AN LDHWOKNOCK
OUT, MAYBE IF THEY MATED WITH
SOMEONE WHO'S WILD-TYPE, THEN
THEIR OFFSPRING WILL NOT BE ANY
BETTER PROTECTED, RIGHT?
SO I THINK IT WAS JUST FREAKISH
THING OF NATURE, IT'S KIND OF
LIKE SICKLE CELL, IT HAPPEN
INDEED AN AREA WHERE SOMETHING
WAS VERY INDEMMIC AND THE ONLY
WAY THE POPULATION WOULD MAKE IT
IF THEY GET THIS DEVELOPMENTAL
ENDOCRINOLOGYITATING DISEASE
EMPLOY LDH2, IT'S NOT TERRIBLE,
YOU KNOW, YOU'RE GOING TO HAVE
CHILDREN RIGHT?
SO YOU HAVE PLENTY OF TIME TO
HAVE KIDS AND PROKRE TINSATE BUT
I DO THINK THERE WAS SOME--MAYBE
IT WASN'T TB NECESSARILY COULD
HAVE BEEN SOME OTHER INFECT
YOURCANDIDATES DEC THAT IT
PROTEBTED AGAINST BUT IT'S VERY
SATISFYING BECAUSE SO MANY
PEOPLE HAVE THE MUTATIONS TO GO
OH, THIS IS WHY .
THERE ARE FITNESS CAUSE, IT JUST
TAKESSA I LONG TIME FOR THEM TO
HAPPEN NSO DO YOU THINK THERE'S
A ROLE FOR DISCIPLINARY SULFUR
AN IN THE TREATMENT OF TB?
>> THANK YOU FOR ASKING THE
QUESTION.
IT'S KNOWN AS EABT ABUSE, SO IT
TREATS ALCOHOLISM, IT INHIBITS
LDH2 SO YOU THROW UP WHEN YOU
DRINK ALCOHOL, THE PROBLEM IS
YOU CAN TOP TAKING IT, RIGHT IN
SO SEVERAL YEARS AGO, A GROUP,
IN YAP AN DID A STUDY LOOKING
FOR THINGS THAT TRYING TO
REPURPOSE EXISTING DRUGS TO
TREAT TB AND THEY FOUND THAT
DISULPHURE AN, SO THAT DOESN'T
MAKE SENSE, THAT COPY MIGHT BE
AN INVITROART FACT.
SO 1 OF THE THINGS SARAH'S TRIED
TO DO IS TO TREAT MICE WITH
DISCIPLINARY SULFUR AN AFTER TB
INFECTION, THE PROBLEM IS, SO
SOMEONE DID THAT AND THEY SAID
IT WORKED GREAT, SO THEY'RE LIKE
OKAY, WE'RE GOING TO REPEAT THIS
EXPERIMENT BUT IT WAS VERY TOXIC
RIGHT SO DISCIPLINARY SULFUR AN
WAS TOXIC TO THE MICE, BUT
MAYBE, YOU CAN MAKE A BETTER
VERSION OR USE LESS, MAYBE YOU
COULD SINNER UTILIZE WITH
EXISTING DRUGS, WE JUST--I WOULD
LOVE FOR SOMEONE TO TRY
DISCIPLINARY SULFUR AN BUT
EVERYBODY'S TELLING ME IT'S TOO
TOXIC BUT YET IT'S USED TO TREAT
ALCOHOLISM.
SO I DON'T KNOW WHAT TO DO WITH
THAT.
I'VE BEEN TRYING TO CONVINCE TB
ALLIANCE AND THEY'RE NOT REALLY
LISTENING.
JULIE?
>> HI, I HAD A QUESTION THAT'S
MORE ROOTED IN YOU KNOW MY
KNOWLEDGE WHICH IS BASIC OF
OTHER BACTERIA, WHERE YOU'RE
TALKING ABOUT CENTRAL
METABOLISM, AND THEN I'M
WONDERING DO THE BACTERIA
ACTUALLY HAVE ALTERNATIVE
PATHWAYS TO GO THROUGH THAT OR
CAN THEY MAYBE BREAK DOWN SOME
OF THE SECONDARY METABOLITES
THAT WOULD ACCUMULATE.
I'M KIND OF TRYING TO UNDERSTAND
IT ALSO FROM THE PERSPECTIVE OF
COULD THERE BE ANY ADVANTAGE TO
THE TUBERCULOSIS IN INFECTION
THAT MAYBE YOU WOULD BE TAKING
CARE OF OTHERWISE METABOLITE,
SECONDARY METABOLITES THAT LIGHT
ACCUMULATE OR ARE THE BACTERIA
IN THE HUMAN PATHWAYS REALLY
IDENTICAL NI DON'T THINK THEY'RE
IDENTICAL SO I DON'T WANT
TO--THEY'RE VERY CLOSE, SO IN
TERMS OF--MAYBE YOU'RE IMETTING
AT LIKE--PEOPLE WHO MADE THOUGH
CENTRAL METABOLISM MUTATIONS
NWAIT, REMEMBER, I AM ASKING A
VERY BASIC QUESTION, LIKE, YOU
KNOW PROPRINCIPAL DEPUTIATE
SUCKS IN PATHWAYS, WE HAVE THEIR
BACTERIUM BECAUSE THEY HAVE
ALTERNATIVE AREAS FOR THE KREBS
CYCLE SO I'M REALLY ASKING LIKE
THAT I THINK THERE MAY BE SOME
WAYS IN WHICH BACTERIA AND
HUMANS, LIKE BACTERIA ACTUALLY
PROVIDE, MAYBE TB AS A POGHT O
GEN DOESN'T DO THIS BUT THERE
ARE SOME BACTERIA THAT PROVIDE A
BENEFIT TO HUMANS BECAUSE THEY
HAVE ALTERNATIVE WAYS OF GOING
THROUGH THESE CENTRAL METABOLISM
PATHWAYS IN DEVELOPING THE
SYMBIOTIC RELATIONSHIP, AND
THINK BEING THAT IS THERE SOME
WAY IN WHICH THE HUMAN DOES HAVE
AN ADVANTAGE AT BEING AFFECTED
THAT MTB HAS TRIED TO TAILOR ITS
SYMBIOTIC RELATIONSHIP IN NSO
CERTAINLY I DON'T HAVE AN
ANSWER, I THINK TB IS SUPER WELL
ADAPTED TO BE IN HUMANS BECAUSE
IT DID HAVE WEIRD METABOLISM BUT
INTERESTINGLY A LOT OF THEM DO
GENERATE ALDEHYDES SO--BUT I
THINK THAT'S WHY IF THEY'RE NOT
CONSTANTLY BEING MOVED FORWARD,
SO LIPID METABOLISM FOR EXAMPLE,
IS LIKE A HUGE THING FOR TB TO
STAY ALIVE IN HUMANS, BUT, YEAH,
I THINK YOUR QUESTION'S TOO BIG
FOR ME.
[LAUGHTER]
YEAH.
>> OKAY SO OUR COLLEAGUE ASKS
ALD H2, STAR 2, IS SOCKED WITH
THE DEPRIVATIONMENT OF SEVERAL
TYPES OF CANCER
CERTAINLY--CERTAINLY SPECIALLY
IN THE GASTROINTESTINAL TRACT
EVEN WITHOUT ALCOHOL
COMSUMPTION, DO YOU THINK THAT
INCREASED ALDEHYDES IN THE GI
TRACT CAN LEAD TO THE DEATH OF
BENEFICIAL BACTERIA AND AFFECT
CARCINOGEN SIS ?
>> YEAH, SURE.
I DON'T KNOW WHY NOT.
A LOT OF PEOPLE ARE TRYING TO
UNDERSTAND THE CONQUENCES OF THE
LDHTAR 2 MUTATION BECAUSE IT IS
LINKED WITH ESOPHAGEAL CANCER,
CARDIO VASCULARY ISSUES,
PROBABLY GI ISSUES TOO AND THOSE
ALDEHYDES ARE NOT--SO THERE'S 2
THINGS I WANT TO POINT OUT, 1 IS
LDH2 FUNCTION IS NOT ALCOHOL
METABOLISM, IT'S JUST 1 OF THE
BENEFITS.
TWO, YOU DO NOT WANT TO DRINK
ALCOHOL TO TREAT YOUR TB.
AND IN FACT, I HAVE TESTED, SO
THE ETHANOLE DERIVED ALDEHYDE IS
ACID ALDEHYDE IT DOES NOT DO
SQUAT TO TB, IT DOES NOTHING, SO
DON'T DRINK ALCOHOLISM AND TB
THEY'RE LIKE CO-MORBIDITIES SO
DON'T DO IT BUT I DO THINK THESE
INCREASES IN CARCINOMAS AND
THINGS, IT'S BECAUSE ALDEHYDES
DAMAGE DNA SO I THINK THAT'S A
BIG PROBLEM.
>> GREAT TALK.
MAB I JUST MISSED THIS BUT IN
TERMS OF TESTING THE LINEAGE
HYPOTHESIS OF LYNN LINEAGE 2
VERSUS LINEAGE 4, HAVE YOU
TESTED THE INVITRO ALDEHYDE
SENSITIVITY OF [INDISCERNIBLE]
>> YES, YES, YOU DEPARTMENT MESS
IT, I TESTED THIS PERSONALLY O
OUR LINEAGE 2 MORE RESISTANT TO
ALDEHYDES INVITRO?
SHORT ANSWER IS NO, IF ANYTHING
THEY'RE MORE SENSITIVE, SO WHAT
IS MAKING US START TO THINK IS
MAYBE THE BACTERIA DO SOMETHING
DIFFERENT IMMUNOLOGICALLY TO THE
HOST SO MAYBE THEY STIMULATE
LESS INTERFERON, OR
INTERFERON-GAMMA SO MAYBE
THERE'S SOMETHING GOING THERE
BUT THAT'S SOMETHING WE NEED TO
START LOOKING AT MORE CLOSELY,
YEAH, GOOD QUESTION.
>> AND THEN MAYBE JUST A QUICK
FOLLOW UP, THAT ORIGINAL iNOS
DATA IS WITH LIGAN 4, IS THERE A
DIFFERENCE BETWEEN LINEAGE 4 AND
2 FOR SIZE?
>> THAT'S A GOOD QUESTION.
WE'VE NEVER LOOKED AT iNOS SO
1 TECHNOLOGY TRANSFER THAT'S
BEEN HARD TO FIGURE OUT AND SO
ACTUALLY IN VIVO, THE IN VIVO
PHENOTYPES ASSOCIATED WITH
LINEAGE 2 AND 4 ARE NOT VERY
CLEAR, SO THERE'S A VERY OLD
PAPER FROM I THINK CLAUDIA
MONKA, THERE'S MORE INIAGE MADE
BY THE INFECTED CELLS SO THAT IS
A HARD THING, WE KNOW TYPE 1
INTERFERON CAT IS BAD FOR TB
INFECTION, SO WHAT WE DON'T KNOW
IS, IS THAT STILL REALLY A
THING.
IT'S NOT SOMETHING WE CAN
QUANTIFY IN VIVO, MAYBE SOME OF
THE BEST IN VIVO DATA THAT I
NEED TO TALK TO AMY BARZAK ABOUT
WHEN SHE WAS IN CLIFF'S LAB, IF
YOU DO A MIXED INFECTION, AN L2
STRAIN WILL OUTCOMPETE THE L4
STRAIN.
SO IF THAT HOLDS UP IN OUR
HANDS, I THINK THAT'S GOING TO
BE SOMETHING WE CAN AT LEAST
TART TO WORK WITH IN TERMS OF
TRYING TO DISSECT WHAT'S GOING
ON BETWEEN THE 2 DIFFERENT
LINEAGES.
NGOOD QUESTION, THANKS.
NCAT, GREAT TALK.
AND SOMEWHAT RELATED TO HIS
QUESTION TOO BUT SOMETHING ABOUT
THAT YOU MENTIONED THAT STAPH
AURREUS, IS SUPER,--I'M NOT A
MICROBIOLOGIST BUT I CAT GO
ARIZED FROM EXTRA CELLULAR VERSE
INTRACELLULAR, COULD IT BE THAT
THERE'S A HOST CELL FOR THE
ALDEHYDES TO WORK IF AND IF A
PATHOGEN IS OFTEN JUST
INTRACELLULAR AND THAT COULD
ALSO EXPLAIN POTENTIAL DRVESS
BETWEEN THE L2 AND L4 IN THERE
RIGHT, IF THERE'S A DIFFERENT
ENGAGEMENT IN THE MACROPHAGE BUT
EXCUSE THE ALDEHYDE SENSITIVITY
AND THE HOST CELL IS CRITICAL.
I KNOW THAT ENVITRO IF YOU JUST
PUT THE ALDEHYDE ON IT, BUT IF
YOU DO THE--SO, RIGHT, SO I'VE
GOTTEN THIS QUESTION BEFORE.
IS THIS SOMETHING SPECIFIC TO
INTRACELLULAR PATHOGENS OR
BACTERIA.
I DON'T KNOW.
I LIKE THAT IDEA.
THE OTHER THING I KIND OF LIKE
IS THE IDEA THAT MAYBE THE
ALDEHYDES ARE LIKE, THEY LIKE TO
WORK WITH A SLOW BURN PATHOGEN,
SO TB IS VERY PERSISTENT SO
SALMONELLA, STAFF, THOSE ARE
ACUTE INFECS, RIGHT?
THOSE ARE GOING TO GROW SO FAST,
THE ALDEHYDES CAN'T DO QUAT AND
MAYBE THEY WILL KILL YOU ON OR
MAKE YOU SICK BEFORE THE
ALDEHYDES CAN DO ANYTHING.
I THINK WITH TB BECAUSE IT'S
SLOW, IT'S ACCUMULATION OF
DAMAGE BY THE ALDEHYDES.
SO WE DON'T KNOW YET AND THIS IS
SOMETHING THAT SARAH AND I--I
THINK SHE'S GOING TO EXPLORE
THAT MORE.
I FEEL LIKE THEY MAY HAVE TRIED
STAPH, AND I KNOW THEY TRIED
LISTERIA, BUT I CAN'T REMEMBER.
>> YOU GUYS ARE TOTALLY ON TO
SOMETHING, I'M CONVINCED.
>> AWWELCOMER, THANK YOU.
PONG?
>> FOLLOWING UP FROM THOSE
QUESTIONS IT SEEMED LIKE YOU
COULD TAKE MONOCYTES FROM PEOPLE
LIKE ME, THAT HAVE THE MUTATION,
COMPARED TO WILD-TYPES AND BE
ABLE TO TEASE OUT THE
SENSITIVITY OF OF MACROPHAGES
FROM DIFFERENT LINEAGES TO
SENSITIVITY FROM DIFFERENT--FROM
THE DIFFERENT LINEAGE 2 VERSUS
LINEAGE 4.
NTHE PROBLEM WITH TB IS THAT I
HATE THE INVITRO MACROPHAGE
MODEL, BECAUSE THE ISSUE IS IT'S
A 6 DAY INFECTION AND IT JUST
DOESN'T REALLY CAPTURE WHAT'S
IMPORTANT IN TERMS OF--RIGHT IN
AND LIKE I SAID SLOW BURN, IT
MIGHT TACK A LONG TIME AND
INVITRO IF YOU XOK OUT ALD H2 OR
DPRKS LO1, IT DOESN'T DO
ANYTHING DIFFERENTLY HOWEVER,
[INDISCERNIBLE] FOR SURE, IT
MIGHT DEPEND ON THE PATHOGEN.
YEAH, THERE'S A LOT.
NNO NOTHING ELSE ONLINE JUST
YET.
>> I'M PROBABLY GOING TO PROVE
IN FRONT OF EVERYBODY THAT I'M
NEITHER A MICROBIOLOGIST NOR AN
IMMUNOLOGIST BUT I'M JUST
WONDERING LISTENING TO THIS AND
THE RELATIVE LACK OF SPECIFICITY
OF WHICH ALDEHYDE IT IS WHAT THE
EFFECT IS OUT THE OTHER END, ARE
WE WRONG IN MAKING THE
ASSUMPTION THAT THE ALDEHYDE
ITSELF IS THE ACTOR BECAUSE
ALDEHYDES FORM SHIFT BASES WITH
ALL THE PROTEINS IN THIS THE
MACROPHAGE AND WHATEVER, MAYBE
IT'S DOWN STREAM OF THE ALDEHYDE
RELATED TO SOME COMMON PROPERTY
CHEMICALLY OF THE ALDEHYDES THAT
ARE--
>> I DON'T THINK THAT'S NAIVE AT
ALL.
IT'S ABSOLUTELY POSSIBLE.
ONE OF THE DEBITS WE HAVE IS ARE
THE ALDEHYDES DIRECTLY HAVING AN
EFFECT ON THE BACTERIA OR IS
THERE SOMETHING ALDEHYDE IS
DOING TO THE HOST CELL EVEN TO
CHANGE TRANSCRIPTION OR
SOMETHING, SO 1 OF THE WAYS WE
ARE TRYING TO GET IT ADDED AS
MICROBIOLOGIST IS WE'RE MAKING
MUTANTS THAT ARE MORE SENSITIVE
TO ALDEHYDES BECAUSE THAT WILL
TEST, IF THEY'RE MORE SENSITIVE,
THEN THEY SHOULD BE VERY
ATTENUATE INDEED A GLO1 MOUSE
WHICH WILL ACCUMULATE METHYL FLI
COLSIS GLYOXOL SPECIFICALLY
SUPPOSEDLY.
IS IT A HUNDRED%, I DON'T KNOW
BUT IT'S ABSOLUTELY A FAIR
COMMENT.
DEFINITELY.
IT'S A LOT.
THERE'S A LOT WE STILL NEED TO
FIGURE OUT.
>> DOES IT MATTER THE LOCATION
OF THE BACTERIUM.
SO DO THEY STILL NEED TO BE IN
THE FAIG OSOME OR COULD THEY
HAVE ESCAPED INTO THE CYTOPLASM
SO YOU HAVE TRIED IT WITH ESX6
OR WHATEVER IT IS MUTATION.
>> OH MIRROR IMAGE GOODNESS.
>> SO SEE IF THEY'RE SENSITIVE
IN BOTH SITUATIONS IN THE FAG O
STUDIES OF MULTIPLE ENDOCRINE
AND THE AND CYTOPLASM.
>> WE HAVEN'T GOT THERE,
DEPENDING ON WHICH PATHWAY, IT
WILL BE MITOCHONDRIA OR
CYTOPLASMIC.
NOW 1 THING I DIDN'T SHOW IS
THAT IT TURNS OUT THE ALDEHYDE
SENSOR CHRIS CHANG MADE IS
PACIFIC TO ALDEHYDE, NOT ALWAYS
A HUNDRED% BUT THEY HAD 1 THAT
WAS SPECIFIC TO THE WHOLE CELL
ENCLOUDING EVERYTHING IS JUST
MITOCHONDRIA.
WHAT WAS VERY OBVIOUS IS IT IT
WAS THE MITOCHONDRIAIAL THAT
GOES UP A LOT.
SO IT I WAS STUNNED AT THE IDEA
THAT WE'RE MAKING FORM ALDEHYDE
GIVEN THAT IN THE LAB YOU'RE
SUPPOSED TO BE AVOIDING IT AT
ALL COSTS MUCH BUT THE GUY AT
CAME BRIDGE NAMED KJ P A TELL,
AND HE DORPHED OR IS POSING THAT
WE ARE CONITANTLY MAKING
FORMALDEHYDE FROM VARIOUS
METABOLIC PROCESSES AND IT'S
RECYCLED FOR AMINO ASIGNIFY ANDS
TECHNOLOGY TRANSFERS LIKE THAT.
SO I DON'T KNOW BUT MY, I'M VERY
NAIVE WHEN IT COMES TO
IMMUNOLOGY AND I THINK OKAY, THE
CELL BLOWS UP AND THERE'S STUFF,
AND YOU HAVE LIKE NO, HAVE YOU
ALDEHYDES, YOU HAVE MAYBE, MAYBE
IT DOESN'T NEED TO BE
INCAPSULATED.
I DON'T KNOW I THINK IT'S JUST A
COMLITELY BLACK BOX AND
HOPEFULLY WE WILL FIGURE THAT
OUT IN THE FIXTURE FEW YEARS.
>> WHACKY QUESTION, DO YOU THINK
THAT THE ABILITY OF ALDEHYDES TO
TALK TO FOR BACTERIA COULD BE
THE REASON FOR THE WAR BERG
EFFECT IN.
>> WAIT A MINUTE WHAT?
>> ASK IT AGAIN.
>> SINCE ALDEHYDES ARE TOXIC TO
BACTERIA, TIMES, DO YOU THINK
THAT COULD BE LIKE THE REASON
FOR THE WAR BERG EFFECT IN.
>> OH EYEAH.
SO MAYBE I DIDN'T MAKE
THAT--YEAH, ACTUALLY I DO.
IT'S NOT THAT WHACKY.
SO, OBVIOUSLY THE WAR BERG
EFFECT IS IMPORTANT FOR BIOLOGY
FOR MANY DIFFERENT REASONS AND
IT'S VERY HIGHLY STUDIED IN
CANCER BIOLOGY BECAUSE IT SEEMS
TO BE REQUISITE FOR TUMOR
DEVELOPMENT, RIGHT?
AND INFECTION BIOLOGY IN THE
LAST FEW YEARS, SEVERAL GROUPS
HAVE NOTICED THAT IF YOU INFECT
TB OR OTHER INTRACELLULAR YOU
GET INCREASED FLI COLSIS COLSIS,
I DON'T REMEMBER WHAT ASSPECS
ARE NOT EXACTLY LIKE WAR BERG
AND PEOPLE HAVE NOTICED IN AND
NO 1 BEDS WHY, SO SOME PEOPLE
THINK WELL, MAYBE IT'S MAKING
AMINO ACIDS FOR SOMETHING, YOU
KNOW I DON'T REALLY GET IT XI
THINK SOME PEOPLE THINK IT'S
BENEFICIAL FOR THE BACTERIA BUT
I'M LIKE, MAYBE THAT'S TRUE BUT
I DON'T SEE WHY WE WOULD WANT TO
DO THAT SO I DO THINK THAT
MAYBE, IT'S INDUCIBLE BY GAMMA,
SO I THINK SOMEHOW WE EVOLVED,
FOR AEROBIC GLYCOLYSIS TO GET
HARD WIRED INTO THE
INTERFERON-GAMMA PATHWAY SO WE
CAN MAKE MORE ADHIDES TO HELP
CONTROL INFECS THAT'S MY CRAZY
PROPOSAL AND I HOPE IT'S TRUE.
BUT YEAH, TOTALLY, NOT WHACKY.
>> ON THAT CRAZY NOTE, I WANT TO
THANK DR. DARWIN AGAIN FOR SUCH
A STIMULATING TALK AND IT'S
REALLY GREAT DISCUSSION, I THINK
THAT'S ALWAYS THE MOST FUN AND
SO I WOULD ENCOURAGE PEOPLE TO
AT A AND GO TO THE RECEPTION TO
CONTINUE THIS DISCUSSION AND I
WANT TO ESPECIALLY ENCOURAGE
FELLOWS THAT ASK DR. DARWIN
QUESTIONS.
YEAH, SO CONTINUE THE DISCUSSION