All language subtitles for islpd060322

I WORK WITH ALAN FOR 12 YEARS.

FIRST AS POSTDOC AND THEN STAFF

SCIENTIST, SO, THIS MORNING'S

SESSION IS REALLY DEDICATED,

CELEBRATING ALAN'S LEADERSHIP IN

THE COLLABORATION AND NIAID

IMMUNOLOGY PROGRAM.

AS SOME OF YOU KNOW, ALAN HAS

LONGSTANDING INTEREST IN MICRO

BACTERIA RESEARCH AND I THINK HE

STARTED WITH MICRO BACTERIA

AVIAN WITH MARK DOUGHERTY AND

2000, ALAN DECIDED TO REALLY

MOVE INTO USE REAL BUGS AND MBT

AND THEN HE HIRED MYSELF TO

REALLY KICK-START THE PROGRAM

AND ALAN USED TO CALL US THREE

MUSKETEERS AND WE REALLY WORKED

FROM SCRATCH AT THE TIME AND I

REMEMBER THAT TIME WHEN YOU EVEN

DON'T HAVE A FUNCTION OF PIECE

OF THREAD SO WE HAVE TO BOR'

SPACE.

I HAD TO WORK WITH KAREN AND

DAMIAN AND CHUCK HAS TO DRIVE TO

TIM BROOKE TO USE TIMBER''S PC3

AND I REMEMBER WE ALWAYS TALK

ABOUT HOW WE CAN MAKE A

CONTRIBUTION TO THE TB RESEARCH

AND HOW TO MARK OUR TERRITORY AS

A NEW KID ON THE BLOCK.

DON'T GET BULLIED BY OTHERS.

SO, ANYWAY, SO THAT IS THE LONG

TIME AGO SO I THINK UNDER ALAN'S

LEADERSHIP, AS YOU CAN SEE NOW,

NIAID PROVIDES THE BEST EQUIPPED

AND LEADER IN THE TB IMMUNOLOGY

IN THE WORLD.

SO THAT IS REALLY REFLECTION OF

ALAN'S LEADERSHIP AND THIS

PROGRAM HAS TRAINED 15 FELLOWS

AND POSTDOCS AND ALL OF US HAVE

GONE TO ESTABLISH OUR OWN

RESEARCH PROGRAMS.

SO I THINK THAT IS TREMENDOUS

CAREER AND GREAT CAREER FOR

ALAN.

WE ALL APPRECIATE IT.

THANK YOU, VERY MUCH, ALAN.

IT'S A GREAT HONOR TO BE PART OF

THIS PROGRAM AND IN YOUR

MENTORSHIP.

IT'S GREAT FUN.

I HAD A GOOD TIME AND WE HAD A

FUN TIME.

SO, BEFORE INTRODUCING AND

INVITING OUR FELLOW FORMER

TRAINEES TO PRESENT THEIR RECENT

WORK, I JUST WANT TO INVITE BOB,

BOB COFFMAN, TO HAVE SEVERAL

WORDS AND OPENING REMARKS FOR

ALAN.

ROBERT COFFMAN HAS BEEN A STRONG

SUPPORTER OF IMMUNO BIOLOGY

SECTION.

[APPLAUSE]

ALL RIGHT.

SO, IT SORT OF FOR THOUSANDS OF

YEARS NOW, I'M SURE, WHEN THE

ELDERS OF ANY TRIBE GOT TOGETHER

AS WE'RE DOING HERE, THEY WOULD

SIT AROUND THE CAMPFIRE OR WHAT

HAVE YOU AND TELL ORIGIN STORIES

TO PASS THEM ON ORALLY TO THE

NEXT GENERATION, I SUPPOSE WAS

THE PURPOSE OF THAT SO THAT'S

WHAT I'LL TRY TO DO IN THE NEXT

FEW MINUTES IS TELL A COUPLE OF

ORIGIN STORIES.

AND PROBABLY IT'S GOOD TO FALL

TO ME SINCE I MAY HAVE KNOWN

ALAN LONGER THAN ANYONE HERE,

HAVING MET HIM ORIGINALLY HERE

AT THE VERY BEGINNING OF 1970.

SO PLAS TA STEEN SO STONE

ARCHITECT TIRE AND IT'S A SOCK

INSTITUTE.

I WAS COMING IN AS A WET BEHIND

THE EARS AND BEGINNING GRADUATE

STUDENT TRYING TO LEARN WHAT

ANTIBODIES WERE.

ALAN WAS ON THE OTHER SIDE OF

TBENCH.

ALAN WAS TRYING TO CRAFT

SOMETHING LIKE A PRESENTABLE

THESIS AND GET OUT AT THE TIME.

WE OVERLAPPED FOR ABOUT 18

MONTHS ACROSS THE BENCH.

I CAN'T SAY I KNEW ALAN

PARTICULARLY WELL.

HE WORKED VERY HARD AND HE

WORKED LATE AND HE WAS VERY

SERIOUS.

CHRIST, HE DIDN'T EVEN SURF SO

WE HAD NO SHARED VALUES AT THAT

POINT.

BUT HE WAS A NICE GUY AND I

ENJOYED TIME.

HE IS LOOKING VERY DAPPER THIS

IS FROM 1967.

EVEN THEN TRYING TO SMILE.

SO, OUR MENTOR WAS ON THE RIGHT,

VERY PROMINENT IMMUNOLOGY AT THE

TIME, VERY BRILLIANT MAN AND HAD

A LOT OF INFLUENCE IN

FORMULATING THE QUESTIONS AND

CELLULAR AND MOLECULAR

IMMUNOLOGY AND THERE IS JOHN

WITH HIS WIFE SUZANNE AND A VERY

YOUNG LOOKING GUS ON THE LEFT.

MEL HAD GROWN UP AND DONE HIS

FORMATIVE TRAINING FOR MANY

YEARS IN PARIS AND STUDYING THE

PIONEERS STUDIES OF BACTERIAL

GENE REGULATION SO HE WAS,

ALTHOUGH INTERESTED IN

IMMUNOLOGY AT THIS POINT, A

REALLY COMMITTED REDUCTIONIST IN

TERMS OF HIS APPROACH TO SCIENCE

AND A VERY MUCH COMMITTED TO

USING SIMPLE SYSTEMS AND MODEL

ORGANISMS AND THE IDEA OF

ACTUALLY SIACTUALSTUDYING THE IE

JUST SENT CHILLS DOWN HIS SPINE.

AT THE SAME TIME, THERE WERE NEW

WINDS BLOWING AROUND EVERYWHERE

IN THE EARLY 70s AND THE ERA

OF VIETNAM WAR PROTEST AND SO

FOURTH AND SO ON AND ALONG WITH

THAT A NEW SENSE OF SOCIAL

RESPONSIBILITY THAT TOOK HOLD IN

A LOT OF THE STUDENTS AND

POSTDOCS AT SOCK INSTITUTE.

I REMEMBER THIS VERY CLEARLY

BECAUSE THIS IS WHAT WAS ALL

FERMENTING OVER MY FIRST YEAR OR

TWO THERE.

I THINK IT INFLUENCED ALAN,

BECAUSE HE MUCH TO THE DISGRACE

OF THE LAB HE DECIDED TO BECOME

A PARA SATOLOGIST WHEN HE LEFT

THE LAB AND TRAINED THERE.

AT THIS POINT, ALAN AND I, OUR

PATHS DIVERGED A LOT.

I WENT AHEAD AND FINISHED

GRADUATE WORK AND DID POSTDOC AT

STANFORD AND GOT INVOLVED IN

STARTING A VERY INTERESTING

RESEARCH INSTITUTE CALLED DEAN

ACTS IN PALO ALTO WHICH SOME OF

THE OLDTIMERS KNOW.

AND I PROBABLY DIDN'T SEE ALAN

FOR 12 OR 13 YEARS AT LEAST.

IN THE MEANTIME, TIM AND I HAD

DONE SOME OF THE WORK THAT WE'VE

BEEN DOING IN OUR RESPECTIVE

LABS ON TRYING TO DEFINE T-CELL

CYTOKINES AND SOME OF THEIR

FUNCTIONS.

AND CAME OUT WITH SOMETHING THAT

LOOKS FAMILIAR NOW AND I WON'T

BELABOR HERE.

WE'RE PROPOSING THAT BASICALLY

THE CD4 T-CELL RESPONSE TO

ANTIGENS COULD REALLY SORT

ITSELF OUT AS TWO MAJOR T-CELL

SUBSETS AND NAMED TH1 AND TH2.

THESE DELIVERED BY THEIR

PATTERNS OF CYTOKINE EXPRESSION

BUT ALSO BY THE DIFFERENCES IN

FUNCTIONS THAT ARE MEDIATED BY

THOSE DIFFERENT EVERY SHALL

CYTOKINE PATTERNS AND IN

ADDITION IT'S SHOWN IN THE BLUE

ARROWS, THERE WERE A NUMBER OF

RECIPROCAL INHIBITORY

INTERACTION THAT'S ALLOWED FOR

INTERESTING POSSIBILITIES FOR

THEIR UNDERSTANDING IMMUNO

REGULATION.

DURING THE BEGINNINGS OF THIS WE

WERE CONVINCED THIS WAS RELEVANT

TO ALLERGIC DISEASES BUT WE'RE

JUST, TIM AND I WERE TRYING TO

FIGURE OUT DOES IT HAVE

RELEVANCE BEYOND THAT?

WHAT ABOUT REAL INFECTIONS AND

CONTROLLING INFECTIONS?

SO BY CHANCE, I WAS ON THE NIH

CAMPUS AND I THINK WE WERE

REALLY JUST RANDOMLY BUMPED INTO

ALLEN WE GOT TO TALKING AND I

TOLD HIM ABOUT THAT AND HE GOT

EXCITED AND SAID THIS MAY BE THE

ANSWER TO ALL OF THE UNANSWERED

PHENOMENON IN SOME OF THE

PARASITE IMMUNOLOGY SYSTEMS I

STUDIFUL LET'S TRY TO DO SOME

THINGS TOGETHER AND WE DID AND A

NUMBER OF YEARS OF LOVELY AND

VERY FRUITFUL COLLABORATIONS AND

THE FIRST OF THEM I THINK IS

VERY IMPORTANT.

PHIL SCOTT ALLUDED TO IT

YESTERDAY BUT LET ME SHOW YOU

THE BOTTOM LINE.

THIS IS THE FIRST OUTCOME OF THE

WORK WETOGETHER AND THIS IS WITH

PHIL AND PEARCE AND AT THE TIME,

THAT ALAN AND I MET UP THEY WERE

DEVELOPING A T-CELL LINES AND

WE'RE NOT FORMALLY CLONES BUT

CLOSE, T-CELL LINES TO ANTIGENS

THAT HAD INTERESTING PROPERTIES

WHEN YOU TRANSFERRED THEM IN

NORMAL MICE AND INFECTED AND

THIS IS A GOOD EXAMPLE.

THIS IS LYNN ONE ACTUALLY DID

SOMETHING QUITE REMARKABLE WHICH

IT MADE THE FOOT PADS SWELLING

AND THE DISEASE WORSE THAN IF

YOU JUST PUT IN NORMAL T CELLS

OR NO T CELLS AT ALL WHERE

OTHERS SUCHS A THE LINE NINE

GAVE COMPLETE PROTECTION WHEN

YOU CHALLENGED.

THE DIFFERENCES CORRELATED

PRETTY ACCURATELY WITH THE

DISTINCTIONS THAT TIM AND I HAD

PROPOSED AND NOT SHOWN HERE IS

INTERFERON GAMMA BUT ALIGN NINE

AND IN ADDITION TO MAKING IL2

BUT NOT IL4 AND 5 MADE GAMMA AND

LINE ONE DID NOT.

THESE WERE CLASSIC PHENOTYPES

BUT THIS WAS THE FIRST PAPER TO

REALLY SHOW THAT THEY WERE

LEADING TO REALLY DRAMATICALLY

DIFFERENT OUTCOMES IN AN

INFECTIOUS DISEASE SYSTEM.

EVERYTHING ELSE BEING COST IN

THIS FIELD.

IT WAS A LANDMARK TIME.

SO THIS WAS A REAL I AM FLECKION

POINT FOR ALAN AND I.

ALAN BECAME A T-CELL AND

IMMUNOLOGIST HERE AND I BECAME A

LEASH MANIAC AND STARTED FROM

ALAN AND THEY LET ME SET UP A

LEISHMANIA SYSTEM IN MY LAB AND

WE DID STUDIES USE PARTICULAR AS

A COOL FOR STUDYING IMMUNE

REGULATION AND I'LL JUST SHOW

YOU ONE OF THE FAVORITE PAPER

BECAUSE IT'S A GREAT EXAMPLE OF

A YOU DON'T ALWAYS GET WHAT YOU

WANT BUT SOMETIMES YOU GET WHAT

YOU NEED PHENOMENON TO PHOTO

MICK JAGGER AND SO A PAPER WITH

TWO VERY RIGHT PEOPLE, RODRIGO

FROM ALAN'S LAB AND FIONA AND

BASICALLY THEY WERE TRYING TO

CHASE UP WHAT WE AND OTHERS WAS

THE FACT THAT IN MICE THAT DON'T

HEAL AND DEVELOP A THC RESPONSE

WHEN THEY'RE INFECTED WITH LEASH

MANIA THAT THERE'S ALWAYS

EVIDENCE OF SOME LEASH MANIA

SPECIFIC INTERFERON GAM AND

WHETHER IT'S TH1 CELLS AND WHY

IN THEY THERE AND IT WAS REVERSD

BY ANTI-IL4 BUT AN INTERESTING

THING IS THE INTERFERON RESPONSE

WAS AMONG THE PHENOTYPE WHICH

WAS ASSOCIATED WITH NAIVE T

CELLS AND THE RBIT CELLS AND

THEY WERE TRANSFERRED HEALING

TH1 RESPONSE TO THIS ANIMAL AND

THAT WAS ALL VERY INTERESTING

EXCEPT THE MICE THAT HEALED

WEREN'T REALLY OUT OF T WOODS BE

IN SIX OR EIGHT WEEKS THEY

STARTED SUFFERING FROM A SEVERE

INFLAMMATION OF THE COLON, SO

FIONA DID THE OBVIOUS CELL AND

SASS IF THIS HAPPENS IF WE TAKE

LEISHMANIA OUT OF THE EQUATION,

WE DO ISOLATE THE CELLS FROM

LEISHMANIA INFECTED MICE AND WE

JUST DID NORMAL CELLS AND

FRACTION EIGHT THEM AND TRANSFER

THEM INTO SKID MICE NO

LEISHMANIA INFECTION TO THAT AND

YOU GET THE SAME PHENOMENON MANY

OF NORMAL MOUSE COLONS AND IT'S

TYPICAL SECTIONS AND

TRANSFERRING THE CELLS LED TO

GREAT ENLARGEMENT OF THE COLON,

SEVERE DISRUPTION OF THE

ARCHITECTURE AND CELL TYPES AND

LOSS OF T CELLS IN THERE BUT

INTERESTINGLY ENOUGH, IF YOU MIX

BACK IN AND CO TRANSFERRED AN

PRE PRE AT NUMBER OF THE CD45RB

LOW CELLS WITH THOSE, NONE OF

THIS HAPPENS AND THEY WERE

NORMAL AND YOU CAN LET THEM DIE

OF OLD AGE AND SEE ANYTHING.

SO, THIS TURNED OUT AFTER

ANOTHER SERIES OF VERY ELEGANT

EXPERIMENTS FROM GERMAN BUY

FIONA TO BE ONE OF THE THREE OR

OUR DIFFERENT LINES THAT LED TO

OUR CURRENT SYNTHESIS OF

REGULATORY T CELLS THE STORY

BEING THEY'RE LOW POPULATION

CONTAINED A POPULATION OF T

CELLS AND LEISHMANIA THAT WERE

REGULATORY.

NOW, SO, THE LAST BIT OF ORIGIN

AND SET US OFF TO SOME

INTERESTING THING PEOPLE LIKE

ALAN AND STEPHANIE IN PARTICULAR

AND KEEP LOOKING AT OUR DIE A

TRAMS AND LOOKED AT IL5 WHICH WE

KNEW WAS STRONG STIMULATING

FACTS OR AND BUT IT WAS NOT

UNTIL WITH THE ASSISTANCE FROM

TIM'S LAB WE MADE THE FIRST MONO

CLONE ANTIBODY AND ASKED THE

QUESTION, INITIALLY IN A SIMPLE

SYSTEM WHICH WE HAD RUNNING IN

OUR LAB AND SUBSEQUENTLY WITH

ALAN AND IN A MUCH MORE

COMPLICATED, RELEVANT SYSTEM

WHICH IS HERE.

AND WHAT ROLE WAS ID5 AND THE

WISDOM OF THE TIME SMITH IT

WOULD BE A MULTI FACTORIAL

RESPONSE TO REALLY GET THE

DRAMATIC YOU SEE IN A COMPLEX

SIS SEES SUCH AS INFECTION.

AND ANSWER TRYING TO BE SIMPLE

AND ANTI-IL5 BLOCKS AN EFFECTER

AND REDUCED THE BLOOD LEVELS TO

ALMOST ZERO AS YOU SEE HERE.

ANTI-IL4 AS NO EFFECT ON EITHER

OF THESE MODELS AND I'M SHOWING

YOU THE DATA AND RESIP I CANNILY

IT HAS NO EFFECT ON IT BLOCKS

IGE PRODUCTION SO REALLY NAILED

DOWN THE DIFFERENCE BETWEEN

THESE DIFFERENT FUNCTIONS AND

LED TO THE DEVELOPMENT OF

SEVERAL ANTI-IL5 TREATMENTED

WHICH ARE NOW COMMONLY USED IN A

NUMBER OF ALLERGIC DISEASES.

SO ABOUT THIS TIME, 1990s,

ALAN SAID A LOT OF PEOPLE ARE

LOOKING AT THE INFLUENCE OF

CYTOKINES AND T-CELL CYTOKINES

AND T-CELL SUBSETS IN A WIDE

RANGE OF DISEASES.

A LOT OF PEOPLE WORKED A

WORORGANIZED AWORKSHOP SO WITH Y

TAPPING ALL THE PEOPLE, PRESSING

STEPHEN COFFMAN AND I COULD

RAISE MONEY, HE PUT TOGETHER A

WONDERFUL CONFERENCE AND IT WAS

1992, HERE ON THE NIH CAMPUS

THAT I THINK WAS REALLY A

SEMINOLE JUNCTURE OF T-CELL

IMMUNOLOGY BECAUSE IT BROUGHT

TOGETHER WHOLE GROUPS OF PEOPLE

FROM DIFFERENT FIELDS BASIC

IMMUNOLOGY, AUTOIMMUNE DISEASE

O FOURTH THAT REALLY DIDN'T

TALK TO EACH OTHER BUT NEVER GO

TO THE SAME MEETINGS AND WE GOT

TOGETHER FOR SEVERAL DAYS AND IT

WAS REALLY A FORMATIVE TIME.

THERE'S ACTUALLY THE CONFERENCE

PICTURE THERE.

YOU SEE OUR FEAR LESS LEADER

HERE LOCKING VERY GO AHEAD.

YES, THAT'S ME WITH A WOMAN ON

MY LAP.

HERE IN THAT AND I REALIZED THAT

WOULD NEVER FLY THESE DAYS.

I GUARANTEE YOU.

IT WAS POLY PATSINGER.

IT'S A LOT OF THINGS HAVE

CHANGED AROUND HERE AND NOT THE

LEAST OF WHICH THAT WOULD NEVER

BE ALLOWED ON THE NIH CAMPUS.

I'LL FINISH BY SAYING ONE THING

AROUND NIH THAT HASN'T CHANGED

AT ALL SINCE THAT TIME, IS ALAN

AND ALAN'S LOVE OF SCIENTISTS

AND HIS ENORMOUS AFFECTION FOR

THE PEOPLE THAT DO SCIENCE,

WHICH COMES OUT AND IT'S COMING

OUT OBVIOUSLY IN SO MANY TALKS

WE'VE HEARD TODAY.

ALAN'S INFECTIOUS ENTHUSIASM AND

HIS LEGENDARY GENEROSITY NOT

MUCH MORE I CAN SAY ON THAT.

THAT HASN'T ALREADY BEEN SAID.

I WANT TO THANK ALAN FOR HAVING

SUCH A STRONG INFLUENCE ON THE

DIRECTION OF MY CAREER TOOK EVER

SINCE AND MANY OF THE PEOPLE IN

MY LAB.

THANK YOU.

[APPLAUSE]

>> THANK YOU, BOB.

SO OUR NEXT SPEAKER IS ALSO A

VERY STRONG SUPPORTER OF IMMUNO

BIOLOGY SECTION AND ANNE O'GARRA

FROM THE CRICK AND ANNE, PLEASE.

ANNE REALLY INTRODUCED SYSTEM

BIOLOGY'S INTO TB FIELD AND MAKE

A --

>> HOW DO I DO THIS?

>> TECHNOLOGY IS THE MOST

CHALLENGING BUT IT ALL WORKS

HERE, WHICH IS GREAT.

>> SO, IT'S MY HONOR AND
MY

PLEASURE TO REALLY BE HERE TO

CELEBRATE ALAN'S CAREER.

WHICH THINK IS GOING TO CONTINUE

FOR A LOT LONGER ANYWAY.

AND THAT I'VE BEEN SELECTED TO

ALSO GIVE A SCIENCE TALK AS WELL

AS MY MEMORIES OF ALL THE

INTERACTIONS WE'VE HAD.

WE KEEP HAVING AND WE'RE GOING

TO KEEP HAVING.

SO, BEFORE I GO ONTO THE WORK

THAT WE'VE BEEN DOING IN

TUBERCULOSIS, I JUST WANT TO SAY

A FEW WORDS ABOUT ALAN SHER.

AND LOOKING AT IT FROM THE POINT

OF VIEW OF ALAN, A PEOPLE

PERSON, COMPLETELY CURIOUS ABOUT

SCIENCE, EXCITED, FINDING NEW

AREAS TO WORK ON AS HIS YOUNG

POSTDOCS GO ON TAKING PROJECTS

AND DEVELOPING THEIR OWN LABS

AND FULLY SUPPORTIVE AND MEETING

WHEN PROJECTS AND DIFFERENT LABS

COME TOGETHER COLLABORATING,

HAVING FUN, AND REALLY BEING

INSPIRED.

SO WITH A SMILE, I'VE BEEN

INSPIRED THROUGH ALL MY

INTERACTIONS WITH ALAN.

I'M GOING TO RECAP JUST A FEW

THINGS THAT'S BEEN SAID BUT JUST

TO SAY HOW WHEN I FIRST METAL

AN, SO, YOU'VE HEARD FROM RON

AND OTHERS THAT ALAN DID A

POSTDOC AT THE NIMR AT MEL HILL

THAT LOVELY OLD BUILDING WITH A

GUY CALLED RON SMITHERS.

I KNEW RON SMITHERS BUT I WASN'T

THERE BETWEEN 70 AND '74 BUT

ALSO HEARD FROM DAVID SACKS WITH

HIS FAMILY TREE THAT HE WAS A

POSTDOC AFTER ALAN IN '77 TO '7S

BECAUSE THEY CAPTURE THE ERA.

SO LOOK AT DAVID SACKS AND THIS

GUY JERRY WAS ACTUALLY THEN

BECAME MY SUPERVISOR SO ED

PEARCE WHO THEN DID HIS PH.D

ALSO AT NIMR IN RON SMITHERS

DIVISION ON SCHISTO SO I WAS

ACQUAINTED WITH PATHOLOGY AND

ALAN SHER AND DAVID SACKS, THE

WORK THERE ALTHOUGH I WAS A

MICROBIOLOGIST LOOKING AT

BACTERIAL ADHESION AND I DID A

POSTDOC ON IMMUNOLOGY AND I HAD

THE LUCK TO BE INTRODUCED TO BOB

COFFMAN AND I CAME AS A POSTDOC

TO DEAN X AND S DNAX.

ALAN IS NOT THERE YET BUT YOU

WILL SEE SOME PICTURES.

SO, IT WAS THAT PAPER THAT BOB

HAS JUST TOLD YOU ABOUT THAT

REALLY STARTED THAT

COLLABORATION WITH BOB AND DNAX

AND I WAS A POSTDOC AT XNAX AND

I WAS LUCKY TO PROGRESS AND GET

A JOB THERE AND INSTEAD OF

SAYING TWO YEARS I STAYED 15

YEARS AND BOB I HAD JOINT LAB

MEETINGS TOGETHER AND WE SAW

ALAN AND ALL HIS LAB MEMBERS,

PHIL SCOTT, EDMONTON PEARCE AND

THROUGH THE YEARS, WE BECAME

FRIENDS.

I DIDN'T COLLABORATE SO MUCH,

ALTHOUGH ON SOME PAPERS I DID ON

THIS ERA.

WE HAVE A COLLABORATION, ALAN

BUT FROM THE BOB COFFMAN DNAX TO

TIM MONTHSMANNIL-10 THIS IS THE

FIRST THINGTHEFIRST PAPER YOU PH

ED PEARCE AND THIS WAS IN

SCHISTO AND SO THAT IS WHEN I

WAS LUCKY TO REALLY NOT HAVE

JUST JOINED DNAX AND INTERACT

WITH BOB AND TIM AND MEET ALAN,

PHIL, DAVID, ED AND I ALREADY

KNEW EACH OTHER.

SO, SPIN FORWARD A LONG WAY

BECAUSE I'LL GET TO THE SCIENCE

BUT I REALLY WANT TO REALLY

EMPHASIS THAT ALAN, YOU KNOW,

I'VE HAD REASONS TO LOOK AT

ALAN, I WON'T GO INTO THEM.

IT'S EASIER THAN LOOKING AT

PUBMED BY I NOTICED LOTS OF

PEOPLE LEAVING HIS LAB TAKE THE

PROGRAMS AND THEN PHIL LEFT TOOK

THE PROGRAM AND THEN TOXO AND

THEN ALL THESE MODELS WE'VE

HEARD OF AND ALAN'S GENEROSITY

AND ALSO CREATIVITY AND

IMAGINATION IN LOOKING FOR OTHER

MODELS EXPERIMENTAL MODELS TO

TELL US ABOUT IMMUNO REGULATION

AND HE HAS BEEN THE KING ON

THIS.

NOW, TB IS WHAT, AS CARL THANKS

FOR THAT INTRODUCTION BECAUSE I

COULDN'T INTRODUCE ALL THE

SEMINOLE PAPERS THAT HAVE BEEN

PUBLISHED FROM ALAN'S LAB I

THINK IT WAS SINCE 2000 THAT YOU

GUYS STARTED WORKING ON TB.

I SUFFER WITH YOU BECAUSE WE

STARTED IN 2003 AND IT WAS HARD

AND IT WAS HARD FOR MANY YEARS

THAT WE'LL DISCUSS IN A BAR OVER

WINE, NOT JUST CONTAINMENT 3 BUT

LOTS OF DIFFERENCE.

SO ALAN'S CONTRIBUTIONS ARE

RECOGNIZED ALL OVER THE WORLD IN

PATHOLOGY AND ALSO IN TB AND

BASICALLY THIS IS EX EMPTIED OF

THIS TWITTER OF FEED WHICH IS A

RESEARCH REBOOT OF TUBERCULOSIS

AT THE SYMPOSIUM 50th

ANNIVERSARY WHICH ALAN IS LED

ORGANIZERS AN AND IT WILL HAPPEN

FROM JANUARY AND THE FACT THAT

ALAN IS LEADING THIS MEETING IS

PRETTY IMPORTANT BECAUSE YOU

KNOW, THE TB FIELD HAS BEEN KIND

OF TRACTION AND HARD AND HERE WE

HAVE CAT AND DAN WHO ARE

CONTINUING THE LEGACY OF WORKING

IN TB AT THE NIH.

SO, WITHOUT FURTHER ADIEU, I

WANT TO SHOW YOU A BIT MORE OF

THE HUMAN ASPECT OF ALAN THAT

LOOK AT HIM SMILING.

AND BOB AND THIS IS A KEYSTONE

WHICH ALAN WAS INSTRUMENTAL

ACTUALLY IN MY BECOMING INVOLVED

AND BOB AND ALAN THERE AND I HAD

SUCH WONDERFUL TIMES AND YOU SEE

US WITH DRINKS AND THIS IS THE

LAKE BY KEYSTONE AND THAT IS THE

PATH MUCH WE WOULD GO FOR A WALK

AND YOU KNOW, ALAN MENTORS IN A

WAY IT DOESN'T COME ACROSS AS

MENTORING BECAUSE HE IS CHATTING

BUT HE IS GIVING YOU WISDOM AND

GEMS OF HOW TO THINK ABOUT THE

WAY FORWARD IN RESEARCH PROGRAMS

AND RUNNING A LAB, THE PEOPLE,

THE DIFFICULTIES, THE HARDSHIPS,

THE JOYS AND SO THAT GIVES ME

SUCH PLEASURE WHEN I LOOK AT

THOSE PHOTOS AND I'LL BE HAPPY

TO SEND YOU SOME OF THESE AS OUR

MEMORIES.

THANK YOU FOR YOUR GENEROSITY

AND HELPING ME COME INTO THE TB

FIELD BECAUSE IT WASN'T EASY.

I STARTED BECAUSE IT SEEMED

IMPORTANT THAT I WORK ON A

DISEASE THAT ACTUALLY KILLED

PEOPLE AND HAVING COME FROM DNAX

AND I WAS SUPPOSED TO INTERFACE

IMMUNE OLE GOUGH AND INFECTION

SO I'LL COME AND IT WILL

INTERFACE WITH ALAN AND CAT

MAINLY THROUGH THE WORK AND SO,

I'LL TALK TO YOU ABOUT HOW THEY

HELPED US AND TO GIVE YOU

BACKGROUND OF WHAT WE KNEW IN

2003 ABOUT THE IMMUNE RESPONSE

AND MTB AND MTB AND IT WOULDN'T

GO INTO BUT COULD INFECT KNEW

TRA FILLS AND WE FOUND

MACROPHAGES AND THEY MIGRATE TO

THE LYNCH NODE AND THE RIGHT T

CELLS WERE ACTIVATED AND THEY

WOULD ACTIVATE AND THAT COULD

PROTECT AND IT WAS FUNDAMENTAL

IN EXPERIMENTAL MODEL BY ANDREW

COOPER AND JOANNE FLYNN AND

ALAN'S LAB ADVANCED A LOT OF

THAT AND TNF WAS FUNDAMENTAL AND

WHAT WAS REALLY AMAZING IS THESE

FACTORS WERE ALSO SHOWN TO BE

IMPORTANT IN HUMAN DISEASE AND

THE TH1 ACCESS AND SUSCEPTIBLE

DISEASES AND ANTI-TNF HAVE BEEN

SHOWN TO ACTIVATE TD IN

INDIVIDUALS WHO HAD BEEN EXPOSED

BUT THAT WAS IT.

THAT WAS THE TIP OF THE ICEBERG.

I CAME FROM DNAX AND WORKED

COLLABORATE BEING WITH TIM AND

BOB FOR MANY YEARS AND SO, I

THOUGHT OK, LET'S HAVE A LOOK TO

SEE WHAT IL-10 DOES AND STOPS

DEVELOPMENT MUST HAVE A ROLE AND

I'M NOT GOING TO SHOW YOU THE

DATA THIS WAS ALREADY PUBLISHED

AND IN DEED IT DID HAVE A ROLE

AND IN THESE RESIST APARTMENT

MICE THERE WAS A SLIGHT ROLE BUT

IT WASN'T PROFOUND SO THIS WAS A

TIP OF THE ICEBERG.

SO HOW ELSE TO GO AND THIS

BRINGS INTO MIND THE

COLLABORATIVE NATURE OF THIS

FAMILY FOR PEOPLE LIKE ALAN,

BOB, AND JACK WHO RAN THE

INSTITUTE THAT WAS PARALLEL BUT

MOVED TO DAMN AS AND WHERE I

THEN WAS THERE FOR MEETING AND I

SAID TO ALAN, TO TUBERCULOSIS IS

A PROBLEM AND I'M STARTING TO

WORK ON IT AND IT'S DIFFICULT.

THOSE WHO DON'T WORK ON TB

1.5 MILLION DEATHS DIAGNOSIS IS

DIFFICULT AND NOT GOING TO GO

INTO THIS FOR THE SCOPE OF THIS

TALK AND THE FASCINATING POINT

OF IMMUNOLOGIST IS THAT A THIRD

OF THE WORLD ESTIMATED A QUARTER

OF WORLD TO BE LATENT AND THOSE

WILL PROGRESS TO TB AND YOU CAN

SAY BY DEFINED BY IMMUNE

REACTIVITY BUT YOU CAN'T SAY WHO

WILL GO.

I'LL COME BACK TO THAT AT THE

END OF THE MY TALK.

TO GET TO THE QUESTION WE ASKED

AND HOW THE HELP FROM OUR

FRIENDS AND THIS WAS DAMIAN WHO

IS HERE WHO REALLY HELPED THIS

SO THE LINE LINE WAS I WILL HELP

YOU CONQUER TB AND THOSE WHO

KNOW YOU AND OUR QUESTION WAS

MOUSE MODELS AND THEY WEREN'T

AND THEY TOLD US ABOUT RESISTANT

BUT WHY DO INDIVIDUALS REMAIN

LATE ANT AND HEALTHY AND OTHERS

GO ON TO GET TB WHAT FACTORS OF

THE IMMUNE RESPONSE CONTRIBUTE

TO TB AND THAT WAS THE QUESTION

THAT CAME AFTER I LOOKED AT

VIRGINIA PASQUAL'S COMPUTER AND

SEEING THE IMMUNE SIGNATURES SHE

DEFINED IN AUTOIMMUNITY SO

TOGETHER WE ASKED THE QUESTION,

CAN HUMAN BLOOD TRANSCRIPTIONAL

SIGNATURES DISTINGUISH

INDIVIDUALS WITH LATENT AND

ACTIVE TB AND THIS IS PUBLISHED

SO I'M GOING TO GO THROUGH IT

QUICKLY, BUT TO SAY WE DEFINED

AN INTERFERON BLOOD

TRANSCRIPTIONAL SIGNATURES THAT

WAS MISSING IN LAT ENTER AND

HEALTHY INDIVIDUALS AND I'M

GOING TO SHOW YOU A LITTLE BIT

OF THESE DATA AND SHOW THE

CONTRIBUTION THAT THEY HELPED US

TO DECIPHER THIS TOGETHER WITH

VIRGINIA.

SO THIS SIGNATURE OF ACTIVE TB

WAS DOMINATED BY AUGUST

REGULATED GOWNS IN DOWN

REGULATED SCENES IN ACTIVE TB

BUT NOT IN LATENT AND THIS WAS

IN LONDON AND WE REKA PIT RATED

THAT IN SOUTH AFRICA AND THERE

EVERYBODY WAS POSITIVE AND THE

INTERFERON GAMMA AND ANTIGENS

BUT STILL, THEY DIDN'T HAVE THE

SIGNATURE BUT THE ACTIVE TB

PATIENTS DID AND I'LL COME BACK

TO THE HETEROGENEITY LATER.

NOW, HOW DO YOU GET ALL THESE

GENES AND DAMIAN HAD COME UP

WITH A MODULAR APPROACH AND HE

SHOWED IT COULD PUT INTO MODEL

AND THEY COULD BE ANNOTATED

LOOKING THEM AT THEM SO THEY HAD

A APPROACH THAT WE USED IN

TESTING AND OUR TB TRAINING SET

IN LONDON AND OUR SOUTH AFRICA

VALIDATION ZENDAYA SET AND YOU

CAN SEE THIS IS SUPER IMPOSE

ABLE THREE DIFFERENT YEARS AND

THIS WAS GENES AND I TOLD YOU

GAMMA INTER FEWER ON CAME UP IN

TB PROTECTIVE SO COULD BE SEEN

SO I THOUGHT IT'S GAMMA

INTERFERON BUT THIS IS WHY

TOOKING TO COLLABORATORS SAID

NO, NO, IT'S NOT GAMMA

INTERFERON BUT WAS IMPORTANT

THAT S THESE CONFOUNDING DISEASE

OF GROUP A STREP AND STAFF, DID

NOT HAVE THE SIGNATURE BUT THIS

OTHER BLOB WHICH IS A PLASMA

GENE SIGNATURE SO YOU CAN

DISTINGUISH TB FROM OTHER

DISEASES AND WE'VE DONE A LOT

MORE ON OUR WORK SHOW BUT

VIRGINIA'S POINT AND THAT HAS TO

BE TYPE ONE BECAUSE IT'S TYPE

ONE INTERFERON AND I SAID NO,

NO, IT HAS TO BE GAMMA, AND WHEN

THE PHYSICIAN LOOKED AT THIS 393

SIGNATURE IN DETAIL HE FOUND

THAT IT WAS GENESM D AND

INTERFERON ALPHABET TA UP

REGULATED YOU COULDN'T SEE

CYTOKINES THEMSELVES SO THEY

HAVE TO INDUCE THE GOWNS THAT

GIVE THEM THE SIGNATURE AND ON

PURCHASEIFICATION OF CELLS FROM

THE BLOOD WHICH HAD A SIGNATURE,

CHRIS GRAHAM IN THE LAB SHOWED

THAT IT WAS NEWT TRA FILL AND

MONOCYTES THAT EXPRESS THIS

INTERFERON INDUCE ABLE

SIGNATURE.

NOW WHY WERE WE SURPRISED ABOUT

TYPE ONE INTERFERON BECAUSE

NOTHING WAS REALLY TALKED ABOUT

IN TB IN TYPE ONE INTERFERON AND

TB AS YOU KNOW TYPE ONE WAS

FAMOUS FOR PROTECTING AGAINST

VIRUSES AND CANCER AND IT'S

CERTAINLY MODELS LIKE LISTERIA

IT COULD EXACERBATE INFECTION SO

WHAT WAS GOING ON SO THIS MADE

US DIG DOPE INTO THE LITERATURE

AND THERE WERE TWO PAPERS BY

KAPLAN THAT SHOWED THAT TYPE ONE

INTERFERON CORRELATED WITH

SHORTER SURVIVAL TIMES IN MICE

AND THE BLOCKADE COULD GIVE

LONGER SURVIVAL TIMES OF THE

TYPE 1 INTERFERON IF NOT

SIGNALING.

WHAT WAS DIFFERENT?

RE RACKED OUR BRAINS SO WE

WEREN'T -- SHE WASN'T USING THE

H37 LAB STRAIN OF TB SHE WAS

USING A CLINICAL ISOLATE AND SHE

WAS USING F-1 INTRA BRED MICE OF

GOD KNOWS WHAT GENETIC

BACKGROUND THEY WERE AND SO

PROBABLY GENETIC BACKGROUND

STARTED TO BE IMPORTANT.

WHAT STARTED TO COME OUT AS WELL

IN PARALLEL, IS THE INCREASING

LEVELS OF TYPE 1 INTERFERON

DURING TB INFECTION BY OTHER

MEANS COULD EXACERBATE TB SO

ALAN, DOING THE TREATMENT TO

PROTECT AGAINST TB AND LOW AND

BOW HOLD IT LED TO TWO LOG FOLD

INCREASE IN THE LUNG TB LOAD BUT

NOT IN THE RECEPTOR KNOCK OUT

MICE SO TYPE 1 INTERFERON IS

BAD.

IN OUR LAB WE HAD TO EXACERBATE

AND THAT WAS A COLLABORATION

WITH ALAN AND ANDRE AS WHERE WE

FOUND THE INFLUENZA VIRUS A WILL

IMPAIR THE PROTECTION AGAINST

MTB AGAIN THROUGH A TYPE ONE

INTERFERON PATHWAY AND A GENETIC

APPROACH GETTING RID OF THIS

TPL2 PATHWAY IN MICE AND WE

FOUND IT WAS ELEVATED AND FIN

MACK NAB SHOW THIS COINCIDED AND

DEPENDED ON TYPE ONE INTERFERON

SIGNALING SO THIS WAS MEANS THAT

YOU HAVE TO USE TO PUT THIS TYPE

ONE INTERFERON UP AND THE MICE

SUCCUMB SO TO SUMMARIZE A LOT OF

WORK PUBLISHED BY A LOT OF

PEOPLE, TYPE 1 INTERFERON COULD

AT EARLY STAGES, MAYBE BE

PROTECTIVE AND THERE'S STILL A

LOT TO LEARN BUT WHEN IT WAS

LATE SUSTAINED HIGH DOSES IN THE

SYSTEMS IT COULD BLOCK IL-12 AND

TNF AND INDUCE IL10 AND MY

PROGRAM HAS A WHOLE PROGRAM ON

IL-10 AND TYPE ONE INTERFERON

COULD ALSO BLOCK ACTIVATION OF

MACROPHAGE BY FAMILIAR A

INTERFERON TO KILL BACTERIA AND

ALSO PRO THESE PROTECTIVE

CYTOKINES.

SO, THAT WAS USING THESE METHODS

TO TURN IT ON.

I WANT TO REMIND YOU THOUGH OF

OF SOME DATA THAT THEN CAT AND

ALAN REALLY LED TO THEIR NEXT

SEM SEMINOLE FINDINGS IS ALAN

HAD FINDINGS IN HIS LAB THAT MY

D88 MICE DEFICIENT MICE DISPLAY

A PROFOUND LOSS IN RESISTANCE TO

MTA AND CAT CAME IN VERY

TENACIOUS AND LIKE HANGING ON

AND I'VE GOT TO WORK THIS OUT

AND I'LL NEVER FORGET SAYING

ANNE, WHAT DO YOU THINK IS GOING

ON?

IT WAS TOUGH TO FIGURE OUT WHY

IL-1 PROTECTION WAS REQUIRED

DOWN TREATMENT MYD88 AND I'LL

TOUCH ON THIS SEMINOLE PAPER

THAT FOLLOWED AFTER A LOT OF

THINKING AND DISCUSSION OF ALAN

AND KAT AND KAT GOING TO CHINA

AND REALLY PUSHING UNTIL THIS

STAGE WHERE SHE'S ABOUT TO HAVE

A BABY AND SHE'S FOUND OUT THE Y

AND THE HOW AND LOOK THEY'RE

SMILING AND CAT, THIS IS A

MIRACLE, SHE WAS SUBMITTING THIS

PAPER AND GOING FOR AN AWARD AND

JUST REALLY PREGNANT.

SO, THIS IS FOR ALL YOUNG PEOPLE

TO KNOW ABOUT.

KAT AND ALAN AND COLLABORATE

HOST DIRECTIVE OF TUBERCULOSIS

WAS BASED ON R1 AND TYPE 1

INTERFERON CROSS TALK AND SO THE

THE KNOCK OUTS DIED YET WHEN YOU

CROSS THEM TO THE KNOCK OUT THEY

GOT BETTER SO THIS CROSS

REGULATION THAT BOB HAD BEEN

TALKING ABOUT WITH GAMMA AND L4

THEN THERE'S BEEN IL-10 AND

GAMMA NOW IT WAS TYPE 1 AND L1

AND THERE'S A HUGE AMOUNT TO BE

DONE AND A LOT OF THINKING HAS

BEEN GOING ON DURING THESE TYPES

AND KAT AND ALAN TOGETHER WITH

ANDRE HE IS, MARK AND MY LAB

MEMBERS WE'VE WRITTEN REVIEWS ON

TYPE 1 FOR INFECTIONION DISEASE

AND TB AND OCCASIONALLY FRIEND

THAT WAS LUCIA WITH KAT AND ALAN

AND THIS IS BEEN SO MANY GREAT

DISCUSSIONS OF WHERE THIS IS

GOING AND TYPE 1 INTERFERON IS

TOUGH AND TB IS TOUGH AND WE

KNOW THAT KAT AND DAN FOLLOWING

ON FROM ALAN WHO WILL BE THERE

TO GIVE TIPS AND WHATEVER, WE

WERE TRYING TO FIND A MODEL

WHERE WE DIDN'T HAVE TO KNOCK

OUT A GENE SO WE LOOKED FOR

MOLDS AND THERE WAS A MOUSE

WHICH HAD BEEN HAVE LUNG

RESEMBLING HUMAN CASES GRANULOM

A AND COULD IT BE THE STRAIN

BASED ON THIS PAST THINKING AND

ALL OUR DISCUSSION.

WHAT WE DID WAS WE FOLLOWED ON

THE BLOOD SIGNATURES OF HUMAN TB

AND I'M TAKING YOU THROUGH A LOT

OF DATA.

THIS IS WHOLE BLOOD OF HUMAN

FROM LONDON, SOUTH AFRICA LESTER

AND I SHOWED YOU BEFORE WITH A

DIFFERENT APPROACH WHERE WE SEE

A NEW TRA FILL SIGNATURE AND

ANOTHER INDUCE ABLE SIGNATURE IN

THE HUMAN.

WE USED LOW AND HIGH DOSE OF THE

BUG AND EACH BUG TOGETHER WITH

EACH STRAIN AND YOU HAVE TO LOOK

ON THE RIGHT-HAND SIDE AND SEE

WHEN IT'S HIT WITH THIS CLINICAL

ISOLATE REALLY STARTS TO LOOK

LIKE HUMAN DISEASE.

AND SO, ALL OF A SUDDEN WE HAD A

MODEL AND SO GOING IN AND

LOOKING AT THIS MODEL, IN FACT

YOU COULD SEE THAT THE B6 WHEN

YOU GAVE IT A HIGH DOSE OF H78

HIGH DOSE, ALSO COULD RESEMBLE A

HUMAN DISEASE SO HIGH DOSE,

DIFFERENT STRAINS, ALL OF THIS

MAKES A DIFFERENCE AND MAKES A

DIFFERENCE IN HUMANS AND SURE

ENOUGH, LOW DOSE IN THE MICE IF

NO KNOCK OUTS HAVE NO EFFECT

HIGH DOSE, YOU CAN SEE THE

BACTERIAL LOAD BUT YOU CAN SEE

THAT IN THE MOUSE ACTUAL LOW

THIS IS EVEN A LOW DOSE YOU SEE

THE ANTI-IF NOT ANTIBODIES SINCE

IT'S THE WRONG BACKGROUND FOR

THE KNOCK OUT CAN HAVE A AN

AMELIORATING EFFECT.

>> THIS WAS AN INTERACTION
WITH

CAT AND ALAN HELPING US AND

CONTRIBUTING, PARTICULARLY WHEN

OUR MOUSE CL3 WAS DOWN AND ALSO

ON THE THINKING SO LUCIA SHOWED

THE MICE REDUCTION OF LESION

BURDEN AND CFU AND PRODUCTION OF

KNEW TRA FILL TRAP FORMATION AND

SHOWN BY H3 AND YOU SEE THAT THE

MPO STAINING IS REDUCED BUT

STILL THERE AND IN THAT NOT ALL

THE KNEW TRA FILLS WERE GONE BUT

THE NETS WERE GONE.

THE GREN IS FOR THE B CELLS AND

THE RED YOU SEE THE T CELLS AND

JUST GOING RESISTANCE AND

SUSCEPTIBLE LAB STRAIN CLINICAL

ISOLATE AND YOU CAN SEE AS SOON

AS YOU START GETTING THE

PATHOGENESIS, THE B AND THE T

CELLS DIMINISH AND WE NEED TO

KNOW CHICKEN AND EGG AND WHAT'S

GOING ON SO THERE'S A LOT MORE

TO EXPLORE THAT WE'LL BRANCH IT

AND CONTINUING THE LAB BUT THIS

IS FROM ACTUALLY, THIS IS THE

EARLY FIGURE REMEMBER ALAN IN

THE REVIEW WE'VE JUST WRITTEN

WITH ALAN AND ANDRES AND IT'S

MUCH CHANGED THAT IT ACTIVATES

NEUTROPHIL FOR MICE AND WE STILL

ARE NOT SURE WHERE THE TYPE ONE

INTER FOUR ON DRIVES RECRUITMENT

MONOCYTES AND NEUTROPHIL FROM

THE BONE MARROW TO THE LUNG.

KAT WILL FOLLOW ON THE IL1 AND

HOW THE TYPE ONE INTERFERON

CONTINUES AND WHEN YOU GET

CONTROL VERSUS DEATH AND

SUSCEPTIBLE AND WORE STILL

ASKING THIS QUESTION DOES TYPE

ONE INTERFERON AT A LOW LEVEL

EARLY HELP ON THESE BNT

RESISTANT MICE.

SO THERE'S STILL A LOT TO ANSWER

IN THE EXPERIMENTAL MODELS BUT I

STARTED WORK ONG THE HUMAN TB TO

TRY AND UNDERSTAND WHAT WAS

GOING ON.

AS AN IMMUNOLOGIST, I SAID, WHAT

REALLY WAS FASCINATING IS THE

PROBLEM OF LATENT SEE, A QUARTER

OF THE WORLD ESTIMATED TO BE

INFECTED BUT ALL YOU CAN SAY IS

THAT THEY'RE POSITIVE FOR THIS

INTERFERON GAMMA RELEASE ASSAY

AND YOU JUST DON'T KNOW WHO IS

GOING TO GO AND IN ALL THE

TEXTBOOKS IT SAID, THESE LATER

INDIVIDUALS CAN PROGRESS TO

ACTIVE DUTY AT ANY TIME DURING

THEIR LIFETIME AND THIS

SOMETHING THAT I'D LUKE TO

REVISIT HERE AND SUGGEST THAT

IT'S A SHORTER WINDOW WHEN

PEOPLE CAN PROGRESS TO TB AND

AFTER THAT, IT'S POTENTIALLY

REINFECTION AND SO HOW DID WE

GET AT THIS?

SO THE QUESTION WAS, OF THESE

LATENT INDIVIDUALS, THEY COULD

BE FIVE TO 10% PROGRESSIVE AND

CLEARED THE INFECTION AND IT

COULD BE CONTROLLED OR

PERSISTENT AND SUB CLINICAL

DISEASE AND ALL YOU CAN SAY IS

THAT THEY'RE POSITIVE FOR THE

TEST WHICH SHOWS THAT THEY

REACTED AND LOOKING BACK AT OUR

OLD DATA, WHAT I DIDN'T POINT

OUT IS THAT THESE LATENT

INDIVIDUALS WHERE HETERO GONE

YUS THAT THEY LOOKED LIKE THE

ACTIVE TBN AND IF YOU JUST LOOK,

THESE ARE LATENT BUT THEY HAVE A

SIGNATURE OF ACTIVE TB SO THIS

IS STATIC.

IF YOU LOCK AT A MODULAR LEVEL

YOU CAN SEE THAT YOU TAKEAWAY

THE ACTIVE TB OUT LIES, THESE

THAT WERE THE HETEROGENEOUS ONES

AND LOOK AT THE ACTIVE TB BLOOD

SIGNATURE AND YOU SEE THE

INTERFERON AND THE OUTLIERS AND

THE OTHER LATE ENTERS, NO

SIGNATURE.

THIS IS STATIC.

CAN TRANSCRIPTOMIC TELL US ABOUT

PROGRESSION TO TB SO TO DO THAT

IS QUITE TOUGH AND WE'RE VERY

LUCKY TO HAVE COLLABORATORS IN

LESTER WHO ARE THIS MINIMIZES

REINFECTION OF MTB WITH ANOTHER

STRAIN AND SO WE DID A

LONGITUDINAL STUDY WITH THEM

THAT WE PUBLISHED IN 2018 SO I'M

SUMMARIZING IN A CARTOON HERE

AND LED IN LESTER AND IN MY LAB

LOOKING AT THE ANALYSIS AND THE

BOTTOM LINE OF THESE 53 ACTIVE

TB PATIENTS, THESE CONTEXT, 108

CONTEXT WERE FOLLOWED SOME WERE

NEGATIVE AND 49 WERE POSITIVE

BUT STAYED HEALTHY AND THEY'RE

STILL HEALTHY FIVE YEARS LATER.

THE NEGATIVE WENT POSITIVE WENT

ON TO DEVELOP TB AND THIS WAS

10% AND THEY WERE CHARACTERIZED

BY A PERSISTENT HIGH BLOOD

SIGNATURE IN MOST OF THEM.

SO WE WANTED TO LOOK FORWARD AND

WE INCREASED THE NUMBERS AND DID

A QUITE A DETAIL STUDY WHERE

THEY WERE FUNDAMENTAL AND WE

LEARNED A LOT AND LINKING

CLINICAL PHENOTYPES WITH GENOME

DATA SO THE BUG WAS SEQUENCED IN

THE ACTIVE TB PATIENTS AND THEN

IN THE CONTEXT WHEN THEY

PROGRESS TO TB SO WE GOT THE

INDEX CASE AND THEY HAD THE SAME

SEQUENCE WHICH IS NOT BEEN DONE

IN OTHER STUDIES, WE COULD DO

IT.

SO, THIS IS THE DESIGN OF THE

STUDY THAT WE'VE JUST PUBLISHED

IN THE JOURNAL OF EXPERIMENTAL

MEDICINE AND IT WAS HARD AND IT

CAN TAKE MONTHS TO DETERMINE

THAT SOMEONE HAS TB BUT, THE

ONES WHO HAVE TB ARE RECRUITED

TO THE STUDY AND THEN OF 365 IF

I CAN FIND MY POINTER.

THESE WERE MONITORED OVER THREE

YEARS AND IT'S NOW FIVE YEARS

AND MEETING WITH HE KNOWS ME

NONE OF THE OTHER DEVELOP MOST

OF THEM ONE TIGER WOODS AND TWO

AND A FEW OF THREE YEARS AND

THOSE THAT THEY WERE DEFINITELY

CONTEXT OF THOSE TB AND NOW,

FROM THE CLINIC, THE PROGRESSIVE

TL IT COULD BE PEOPLE WHO HAVE

NO SYMPTOMS AND THEY'RE POSITIVE

AND NOW CLINICAL AND NO

RADIOLOGICAL ABNORMALITIES AND

NO EVIDENCE OF ACTIVITY TB AND

WE FOUND THAT THESE TOOK BETWEEN

41, 125 AND SOME 200 TO 300 DAYS

TO PROGRESS TO T AND THE SUB

CLINICAL ARE ONES THAT EITHER

HAVE NO CLINICAL SYMPTOMS.

THEY REALLY ARE FINE AND THEY'VE

BEEN TAKEN BECAUSE THEY WERE

CONTACTS OR FOR SOME OF THE

REASONS THEY LOOKED AT THEIR

LUNG AND THESE MAY HAVE A CHANGE

IN THEIR LUNG X-RAY BUT THIS

COULD BE ANOTHER LUNG DISEASE,

IT COULD BE CANCER, PNEUMONIA OR

THEY COULD HAVE GROWN A BUG FROM

THESE PATIENTS BUT THEY HAVE NO

SYMPTOMS AND NO LUNG SYMPTOMS

AND THAT COULD BE CROSS

CONTAMINATION OR AN OLD

SCARRING.

AND THESE ONES WE FOUND

DEVELOPED TB WITHIN 20 TO 40

DAYS AND THEN THEY HAD

RADIOLOGICAL FEATURES AND

EVIDENCE OF ACTIVE AND

PARTICULARLY FOLLOWING THESE

CONTEXT THE NEW SCENARIO AND SO,

WE LOGGED AT THE GONE SIGNATURE

AND I'M ONLY SHOWING YOU PART OF

WHAT IS IN THE PAPER AND YOU CAN

SEE CERTAIN GENES ARE STARTING

TO GO UP AND THEN BY SUB

CLINICAL, THEY'RE GETTING HIGHER

AND THEN AT CLINICAL TB THEY'RE

HIGHER AND THESE ARE THE CONTEXT

BUT THEY'RE NOT EVEN NEARLY AS

HIGH OF WHEN YOU HAVE HIGH FULLY

BLOWN ACTIVE TB AND WE HAD A LOT

OF THINKING ON THIS AND ANALYZED

ALL THE DATA AND THERE ARE A

COMMON PATHWAYS ENRICHED IN UP

REGULATED GOWNS IN ALL THROW OF

THE CLINICAL GROUPS THAT ARE

TYPE ONE INTERFERON TIM YOU

LATED GOWNS AND HIGHLY ENRICHED

SO EARLY ON BEFORE ANYBODY HAS

ANY SYMPTOMS, THESE TYPE 1 ARE

COMING UP AND THE GLAD SIGNATURE

IS MORE AND MORE PRONOUNCED AS

THEY PROGRESS.

YOU CAN'T -- IT ALSO DEALS US A

LOT ABOUT THE POTENTIAL

PATHOGENESIS AND WITH THE

EXPERIMENTAL MODELS.

USING THE MODELS AGAIN WE COULD

TEASE OUT A LITTLE BIT MORE AND

ACTUALLY WHAT WE CAN SEE HERE IS

THAT IN DEED IN THE SUB CLINICAL

YOU CAN SEE THE INTERFERON

SIGNATURE AND THE SECOND

INTERFERON SIGNATURE WHICH USING

WGCNA WE TEASE OUT MORE.

WE SEE THOSE T-CELL GOWNS ARE

STARTING TO GO DOWN IN THIS

ACTIVE, IN THIS PROGRESSION FROM

NO SYMPTOMS TO THEN HIGH

SYMPTOMS AND THIS IS WHAT NEEDS

TO BE TEASED OUT MORE BUT OF

COURSE, THE BLOOD WE WERE LUCKY

TO SEE A SIGNATURE AT ALL IN THE

BLOOD OF TB PATIENTS NEVER MIND

PROGRESSES SO OUR FUTURE STUDIES

IS WHAT I'M GOING TO LEAVE YOU

WITH, I'M NOT SHOWING ANY DATA.

THIS IS WHAT WE'RE IN THE MIDDLE

OF.

CONTINUING OUR STUDIES WITH POUR

COLLABORATORS ON PATIENTS WITH

ACTIVE TB WHERE SAMPLING 30

EXPOSURE GET THE RECENT CONTEXT

IN AND WHEN THEY'RE POSITIVE WE

WILL BASICALLY TAKE AN AIRWAY

SAMPLE AT ONE VISIT THAT WE CAN

DISCUSS SO DEEPLY WITH AND

REALLY GET TO THE BOTTOM OF IT

ALL AND THIS IS JUST TAKING US

THROUGH THE JOURNEY WITH MATTHEW

BERRY THE FIRST CLINICIANS AND

LOTS OF CLINICIANS FOLLOWING.

WE STARTED IN LONDON AND WE HAD

TO LEAVE THERE BECAUSE THE

CLINICIAN, THE TB PROFESSOR

DIDN'T WANT TO SHARE SAMPLES SO

THEN WE WANT TO LESTER AND IN

LESTER THEY HAVE SUCH A

FANTASTIC SET UP FOR GETTING TB

PATIENTS CONTACTS IN EARLY TO

THE CLINIC AND OF COURSE NO RISK

OF REINFECTION AS YOU GET IN

AFRICA WHEN PEOPLE ARE SUGGEST

THAT YOU ARE REACTIVATING TB AND

ROB WILKINSON IS A LONG-TERM

COLLABORATOR AND THE BEGINNING

WAS IN THE HUMAN STUDY WAS

REALLY JAQUES AND VIRGINIA WHO

GAVE US THE STRENGTH AND THE

KNOW HOW TO GO FORWARD AND ALL

MY LAB MEMBERS USED TO GO THERE

AND GET TRAINED NOW WE'RE VERY

HAPPY WE DO THE BIO FORMAT TICKS

OURSELVES WITH OUR OWN LAB AND

THESE ARE ALL THE PEOPLE

CONTRIBUTING TO THE MOUSE WORK

AND THROUGH THE YEARS I

HIGHLIGHTED FIN SAY LONG-TERM

MEMBER OF MY LAB WHO IS STILL

WITH US DURING THE MTB MOUSE

STUDIES WHICH ARE HARD.

WE HAD TO GO TO LONDON SCHOOL

AND TAKE A TAXI AT THE BEGINNING

OF OUR TB STUDY SO WE EMPATHIZE

AND WE'RE LUCKY WITH OUR SCIENCE

TECHNOLOGY PLATFORMS AND ANDRES

IS A FRIEND AND KAT AND ALAN, I

HAVE TO SINGLE OUT THIS IS BEEN

SUCH A REWARDING INTERACTION ON

WHAT WE ALL AGREE IS A DAMN

DIFFICULT DISEASE TO WORK ON AT

ALL LEVELS.

WE CAN DRINK TO THAT FOR THE

FUTURE.

GOOD LUCK TO ALL OF YOU ALUMNI

OF ALAN'S AND ALL THE TRAINEES

WHO HAVE NOW GONE OUT TO THE

WORLD TO CURE TB.

[APPLAUSE]

>> DO I HAVE ANY
QUESTIONS?

IT'S TOO ARTICLE IN THE MORNING

I THINK.

>> I WOULDN'T TO
CONTRIBUTION

[OFF MIC]

>> ALAN SAID HE IS GOOD I
THINK

HE WOULD BE PERFECT BUT HE SITS

AT HIS DESK A LOT.

[LAUGHTER]

YOU LED THE WAY.

AND YOU KNOW WHAT, I THINK IT'S

WORTH, THANKS FOR HIGHLIGHTING

THAT BECAUSE DAMIAN IS BACK IN

NEW YORK SINCE FEBRUARY AND

WE'RE ALL DELIGHTED THAT WE CAN

INTERACT.

NEW YORK IS A HOP FROM LONDON

AND IT WAS GREAT TO SEE HIS KID

AND SEE THAT IT'S ALL SETTLING

AND ANOTHER ALUMNI OF ALAN'S.

HIM SITTING AT HIS DESK WAS

USEFUL.

[LAUGHTER]

>> THANK YOU FOR THAT

FASCINATING TALK.

HAVE YOU LOCKED AT EXTRA PULL

PULMONARY TB VERSUS DISSEMINATED

OR.

>> WE PUBLISHED A PAPER
THAT WAS

SIMON BLACKLY'S WORK WHICH I

COULDN'T GO INTO EVERYTHING AND

EXTRA PULMONARY TB HAS AN

IDENTICAL SIGNATURE AND WE

THOUGHT IT WAS WEAKER AND

ACTUALLY WHEN WE STUDIED IT, IT

WAS MORE SIM POM RELATED.

SO, WE PUBLISHED IN OUR FIRST

PAPER AND THEN SUBSEQUENTLY THAT

THE EXTENT OF LUNG RADIO GRAPHIC

DISEASE IN PULMONARY TB

CORRELATES WITH THE SIGNATURE

AND EXTRA PULMONARY TB WE

THOUGHT IT WAS HAVING A WEAKER

SIGNATURE BUT WHEN WE SEPARATED

THE SYMPTOMS, WE FOUND AGAIN

STRONG SIGNATURES WHEN THEY HAVE

BAD DISEASE AND WEAKER.

IT'S VERY, VERY SIMILAR AND SO

THIS IS A QUESTION WE'VE ASKED

FOR MANY YEARS AND THE

DISSEMINATION AND WHY DOES IT

HAPPEN AND IT'S SOMETHING WE'RE

NOT FOLLOWING AND IT'S OBVIOUS

LOW A HARD ONE BECAUSE IT'S

DIFFICULT TO DIAGNOSE.

THERE HERE ARE FOLLOWING TO TRY

AND GET A SUPPORT FOR DIAGNOSIS

OF TB IN THE SIGNATURE TO

SUPPORT OTHER ASPECTS LIKE EXTRA

PULL MINPULMONARY.

>> THANK YOU.

ALL RIGHT.

THANK YOU.

[APPLAUSE]

OUR NEXT SPEAKER IS TRAINEE FROM

ALAN'S LAB AND ANTONIO

ROTHCHS.

>> THESE PODIUMS IN THE
U.S.

MADE FOR MUCH SHORTER PEOPLE

THAN THE SWEDISH ONES.

I REALLY APPRECIATE THAT.

SO, WHERE IS DRAGANA BY THE WAY.

I HAVE TO START BY SAYING

DRAGANA FOR ORGANIZING THIS

FAMILY ROW UNION WHICH HAS BEEN

AMAZING SO THANK YOU FOR

ORGANIZING THIS AND IT'S A

TREMENDOUS HONOR FOR ME TO BE

HERE AND TO PRESENT.

WE'VE SEEN A LOT OF PICTURES OF

ALAN SO I THOUGHT I WOULD BREAK

THAT TREND AND I START WITH A

PICTURE OF ME SO FOR THOSE OF

YOU WHO DO KNOW ME, I'M TONY

ROTHFUCHS AND THIS IS WHAT I

LOOKED LIKE BACK IN THE DAY SO

WHEN I WAS A POSTDOC IN ALAN'S

LAB I WAS IN BUILDING 50 AND I

ACTUALLY SAT WHERE DAMIAN SAT

BUT I DIDN'T SIT MUCH ON THAT

SEAT.

I WAS MOSTLY SACKING MICE AND

ONE OF THE THINGS THAT I DID WAS

TO DO MICRO BACTERIAL GRAN YOU

LOMA WHICH WAS A COLLABORATION

WITH RON'S LAB.

WHEN I WAS INVITE TODAY AND AND

SPEAK.

I HAVET BEEN BACK SINCE 2009.

I THOUGHT ABOUT THE EXPERIENCES

AND HOW THIS HAS SHAPED MY

CAREER AND HOW THIS HAS HELPED

ME SET UP SHOP BACK IN AND I'VE

FOR THIS SHORT TALK, I TRIED TO

CHANNEL THIS TO THREE BASIC

COMPONENTS THAT CAN GO THROUGH

IN THE ENTIRE TALK.

SO, NUMBER ONE, IT'S HERE WERE

IN ALAN'S LAB WHERE I LEARNED TO

DO MICRO BACTERIAL WORK AND THIS

IS SOMETHING THAT MY LAB IN

STOCKHOLM DOES ON INFECTION X I

LEARNED BSL3 WORK AND THIS IS

IMPORTANT TO LAND A KEY

COMMISSIONS OF TRUST AT

KAROLINSKA WHICH BASICALLY

HELPED BRING HOME THE BACON SO

TO SAY.

AND THE THIRD POINT IS THAT IT'S

REALLY -- SO, ONE KEY THING THAT

I LEARNED WAS LIKE BE TO BE

AFRAID TO JUMP INTO THE DEEP END

OF THE POOL SO TO SAY.

SO TO TRY NEW THING, SET UP NEW

METHODS, A REPLY NEW TECHNOLOGY

AND ADDRESS IMPORTANT QUESTIONS.

AND I AM NOT DOING SO MUCH

IMMUNOLOGY ANYMORE SO I AM IN

THE FIELD OF TB ARROW BIOLOGY SO

THAT IS REALLY IN THE DEEP END

FOR IMMUNOLOGY SO I THOUGHT I

WOULD START A LITTLE BIT BY

INTRODUCING THIS FIELD WHICH IS

REALLY A VERY OLD FIELD IN TB

AND YET IT'S STILL AT THE SAME

TIME A REEMERGING FIELD SO THIS

TB ARROW BIOLOGY WAS KICKED OFF

BY CARL IN GERMANY AND AND HE

GUINEA PIG TRANSMIT

COUGHING.

THIS KICKED OFF THE AEROBIOLOGY

FIELD.

SO TODAY, WE'VE PRETTY MUCH

REPLACED FLUGGE'S GUINEA PIGS

WITH AIR SAMPLERS TO DO THE SAME

THING.

SO, THROUGH AIR SAMPLING, IT'S

SO IMPORTANT FOR THIS BECAUSE IT

A US TO COLLECT THE ARROW SOLE

AND DETECT AND ANALYZE THE

PATHOGEN COMPONENT.

WE'RE STUDYING IMPORTANT GAPS IN

TB ARROW BIOLOGY AND

TRANSMISSION SO I WILL TOUCH SO

YOU CAN IDENTIFY HOTSPOTS OF

COMMUNITY TRANSMISSION.

WHERE IS TRANSMISSION TAKING

PLACE IN A CERTAIN COMMUNITY BY

SAMPLING THE AIR.

YOU CAN USE IT TO IDENTIFY NEW

CASES OF TB BASED ON THE

INFECTIOUS AEROSOLS OF THE

GENERATED BY PATIENTS AND THIS

IS WORK THAT KEVIN FENLY HERE AT

NIH HAS REALLY BEEN PIONEERING.

AND THE THIRD POINT WHICH IS

REALLY EASIER SAID THAN DONE, IS

THAT THROUGH AIR SAMPLING WE CAN

STUDY THE BUG IN ITS

TRANSMISSIBLE FORM AND BY THE

WAY THE WORD "BUG" IN CONNECTION

TO PATHOGENS I JUST REALIZE IS

SOMETHING I PICKED UP FROM YOU,

ALAN.

PROBLEM THE VERY FIRST THING I

PICKED UP FROM YOU AND I HAVEN'T

DROPPED IT AND IT DOESN'T

TRANSLATE WELL IN SWEDISH.

IT SOUNDS LIKE A BUG BUT I USE

IT.

I JUST REALIZED THAT NOW.

SO ANYWAY, SO, WE'RE DEVELOPING

AIR SAMPLERS TO ADDRESS THESE

POINTS.

SO, WE'VE DEVELOPED SOMETHING

CALLED A TB HOTSPOT DETECT ERROR

4 AND I CAME UP WITH THE NAME

THOR.

WORE IN SWEDEN AND WE HAVE TO A

COOL NAME SO THOR IS A PORTABLE

AIR SAMPLER AND IT'S COMPACT AND

EASY TO USE AND YOU CAN SEE IT'S

HAND PORTABLE AND IT DOESN'T

REQUIRE POWER AND THE PARTS ARE

CHEAP AND YOU CAN REPLACE THEM.

THE WAY IT WORKS FROM THESE

HEADS THERE'S A CORONA DISCHARGE

AND IT CHARGES PART ALS IN THE

CARE AND THEY GET COLLECTED

THROUGH A ON TO THIS COLLECT OR

PEACE AND WE REMOVE THIS PIECE

AND WE CAN PERFORM ANALYSIS.

THIS IS WHAT IT LOOKS LIKE WHEN

YOUR SUBPOENA POLL SMOKE.

THEY ACCELERATE TOWARDS THE

COLLECT OR PEACE AND IT'S

CHANGING COLOR AND GETTING A

LAYER OF SMOKE AND LET'S WATCH

THAT AGAIN.

SEE IT'S SHINY AND ON AND THEN

THERE IT GOES.

THE SMOKE GETS COLLECTED.

SO, YOU KNOW, HOW DO WE IDENTIFY

NEW INFECTION?

SO, A COUPLE OF EXPERIMENTS SO

WE STARTED THIS OUT WITH

EXPERIMENTS IN BSL2 USING BCG SO

THE LIVE VACCINE AND SO THE SET

UP THAT WE DEVELOPED THAT WAS

FUNDED BY THE GATES FOUNDATION

WAS WE SET UP A HUGE PLASTIC CAN

PEE IN WHICH WE AR SOLLIZED BCG

AND PERFORMED EXPERIMENTS WITH

OUR DEVISE AND THIS WE STARTED A

COLLABORATION FOR THOSE THAT ARE

NOT FAMILIAR WITH GONE EXPERT

THIS IS YOU BASICALLY A

AUTOMATED PCR SYSTEM USED FOR

MOLECULAR DETECTION.

IT'S A CARTRIDGE AND YOU PUT IT

IN AND IT GOES INTO A LITTLE

MACHINE AND IT GIVES YOU A

RESULT BACK AND WE MANAGED TO

GET CT VALUES FOR THAT BECAUSE

NORMALLY WE GET HIGH, LOW,

MEDIUM DETECTION AND SO WE

PERFORMED THIS EXPERIMENT AND

BCG ACROSS VARIOUS

CONCENTRATIONS AND WITH THE

DEVICE TURNED ON AND TURNED OFF,

AND WE WERE ABLE TO EXTRACT THE

CT VALUES AS WELL AND SO IT

TURNS OUT THAT THE COMBINATION

OF THOR AND GENE EXPERT IS AWE

SHOULD SO IT GIVES YOU QUITE A

SENSITIVE DETECTION AND ABOUT .5

COPIES OF BCG PER LITER OF AIR

SO THIS IS KIND OF A -- WHEN THE

DEVIS IS TURNED ON, THAT'S WHEN

YOU GET THE SENSITIVE DETECTION

SO IT IT IS ACTIVE COLLECTION

REQUIRED FOR THIS AND SO THIS IS

WE THOUGHT OK, THIS SOUNDS GOOD

AND BECAUSE WE HAVE NO IDEA OF

TRUE CONCENTRATION OF TB IN THE

AIR SO IT'S GUESSWORK IN THE

AEROBIOLOGY AND WE THOUGHT OK,

THIS IS LOW ENOUGH SO LET'S TRY

TO DO THIS WITH PATIENTS SO WE

TURNED TO COLLEAGUES AT

KAROLINSKA UNIVERSITY HOSPITAL

AND THIS WAS A SURPRISE TO ME

AND THERE'S NEVER GOING TO BE

ABLE TO DO THIS IN AND JUST FOR

A TRY AND IT TURNS OUT THAT YES,

WE HAVE TB IN SWEDEN AND UNFORT

LOW THERE'S NOT ENOUGH SWEDES IN

THE AUDIENCE HERE FOR ME TO MAKE

THAT AS A SUCCESSFUL PITCH THAT

YES, WE DO HAVE TUBERCULOSIS

EVEN IN SWEDEN AND AT ANY GIVEN

DAY OF THE WEEK, AND KAROLINSKA

UNIVERSITY HOSPITAL YOU WILL

HAVE FOUR PEOPLE WITH TB IN THE

WARD, AT LEAST.

TODAY WE HAVE MORE TB CASES THAN

COVID CASES ACTUALLY.

AND WE PERFORMED GENE EXPERT ON

THIS AND SO, WE, THIS IS REALLY

PRELIMINARY SO WE WERE ABLE TO

TRY FOUR PEOPLE AND WHERE DOING

THIS AND SO IF YOU LOOK HERE FOR

EXAMPLE, SO, YOU SEE THIS.

WE TRIED TO SAMPLE PEOPLE FOR

SIX DAYS SO WE FIND THIS

TRIANGLE, THIS INDIVIDUAL WAS

POSITIVE BY COUGH TWICE AND THE

ROOM AIR WAS ALSO POSITIVE AT

THE SAME TIME, AT THE SAME EVENT

OF COUGH SAMPLING AND THIS WAS

THE CASE FOR ALL OF THESE

INDIVIDUALS.

THEY'RE POSITIVE, MOST OF THE

TIME THEY'RE POSITIVE TWICE OUT

OF FOUR OR FIVE SAMPLE OCCASIONS

AND WHICH IS REALLY COOL THAT WE

ARE ABLE TO MAKE A POSITIVE

MOLECULAR DETECTION JUST BY

HAVING A PERSON COUGH ONTO THE

DEVICE.

BUT THIS IS, I MEAN, THIS IS

EARLY DAYS AND NEVERTHELESS, THE

CONCEPT, WHERE AND HOW COULD WE

USE THIS?

SO, IN THE ONE END WOULD BE TO

USE A POINT OF CARE SO YOU GO

OUT AND THIS DEVICE AND YOU ARE

ASKING YOU HAVE THIS AND YOU CAN

DO IT ANYWHERE.

THE OTHER APPROACH AN YOU CAN

SAMPLE THE AIR.

FOR EXAMPLE, HERE WOULD BE A

GOOD EXAMPLE TO SEE IF WE CAN

MAKE POSITIVE DOUGH TEXT AND SO

THAT WOULD BE MORE MONITORING OR

AN ENVIRONMENTAL SURVEILLANCE

FOR TB AND EVEN IN THIS SETTING,

YOU COULD FOLLOW ON WITH THE

POINT OF CARE SETTING TO

IDENTIFY INFECTIOUS INDIVIDUALS

IN THAT SETTING.

IT'S ON GOING HERE AND WE'RE

FOCUSING MORE ON THE POINT OF

CARE ASPECT AND IN COLLABORATION

WITH PARTNERS AT STELLEN BUSH

AND IN MOZAMBIQUE AS WELL AND

WORE TRYING TO FIGURE OUT WHAT

DOES IT MEAN TO BE PCR POSITIVE

IN THIS DETECTION METHOD.

WHAT IS THE DIAGNOSTIC

PERFORMANCE AND HOW LONG DO YOU

HAVE TO SAMPLE AN INDIVIDUAL AND

WHAT'S THE PROTOCOL TO MAKE

THIS.

AND THEN LATER ON IT WOULD BE TO

SEE IF ONE IS ABLE TO ASSOCIATE

WITH ACTIVE TB IN THE HOUSEHOLD

BECAUSE IF IT WORKS, IT WOULD BE

A VERY SIMPLE WAY THAT YOU COULD

JUST, ANYONE COULD MANAGE A

THOR.

AND THE PROOF OF THAT IS THAT

WE'VE DONE THIS PRELIMINARY IN A

BRAZILIAN PRISON WHERE WE HANDED

OVER THE DEVICE TO INMATES AND

THEY WERE ABLE TO SAMPLE

THEMSELVES.

SO IF IT WORKS IN A BRAZILIAN

PRISON, IT WILL WORK ANYMORE AND

IT'S KIND OF THE RATIONALE BUT

IT'S EARLY DAYS SO THIS IS WHAT

IS ON GOING.

SO, WHAT ABOUT AIR SAMPLING TO

STUDY THE INFECTION BIOLOGY SO

THIS IS VERY TRICKY AND AND IN

LET'S SAY THE INFECTION

TRANSMISSION AND WE KNOW THAT TB

IS AN AIRBORN DISEASE AND WE

KNOW VERY LITTLE ABOUT THIS PART

AND SO YOU CAN FIND OF SPLIT

THIS UP.

I MEAN, YOU CAN SPLIT IT UP INTO

HOW DOES THE DOUG SURVIVE IN THE

AEROSOL AND THAT IS IMPORTANT

FOR INFECTION PREVENTION AND HOW

LONG IF I COUGH AND I HAVE TB

AND I LEAVE THIS ALMOST FOR HOW

LONG IS THAT BUG GOING TO BE

REMAINING IN THE AIR AND BE A

RISK FOR TRANSMISSION SO IT'S A

KEY QUESTION.

ALSO, YOU KNOW, IN WHAT DOES IT

MEAN?

THAT AGING IN THE AEROSOL, HOW

DOES IT IMPACT THE INFECTION

EVENT IN THE TARGET CELLS AND

THE MACROPHAGE AND OF COURSE

IMMUNE RESPONSE, I AM AN

IMMUNOLOGIST AND I WOULD LIKE TO

SEE HOW THE ARROW S AEROSOL PROG

AND THERE ARE QUESTIONS WITH THE

AEROSOL AND WHAT'S THE PARTICLE

SIZE BECAUSE IF YOU JUST DOUBLED

THE DIAMETER OF THE PARTICLE YOU

HAVE INCREASED THE HAVE 10 TIMES

SO THAT CAN HAVE A MAJOR IMPACT

ON MAKING IT MORE COMFY FOR THE

BUG AND TO TRAVEL IN THE AIR AND

IT CAN ALSO MEAN A MUCH HIGHER

PATHOGEN PAY LOAD AND THAT WOULD

IMPACT ON THE ABILITY TO INFECT.

AND SO TO TRY TO INVESTIGATE

THIS REQUIRES MORE THAN JUST AIR

SAMPLING THERE AND IT'S MORE

LIKE AIR SAMPLING IS A COMPONENT

OF A WHOLE SET OF TOOLS AND

GADGETS THAT WE'VE JUST SET UP

IN OUR BSL3 AT KAROLINSKA SO

WE -- IT'S CRAZY JUST LOOKING AT

THE PICTURE.

IT'S AN AIRTIGHT GLOVE BOX

INSIDE AN AIR FIGHT FLEXIBLE

CANOPY AND WE CAN GAS THE HELL

OUT OF EVERYTHING AND DISINFECT

AND HELP A FILTER IT ALL-OUT SO

MAKE SURE THAT NOTHING GETS OUT

AND IN THIS GLOVE BOX HERE WE'RE

USING THE NEGOTIAT NUMBER YOU LT

HAS A

IT HAS LIVE BASIL EYE SO WE'RE

USING A TAKE IT IN THIS BOX AND

THEN WE CAN AGE THE AEROSOL IN

THE BOX AND WE COLLECT THEM ON

SOMETHING CALLED CORYOLIS SO

THIS IS A COMMERCIAL HIGH-VOLUME

AIR SAMPLER AND WOVE MADE SOME

MODIFICATIONS TO MAKE IT BIO

SAFE FOR USE IN BSL3 AND THE WAY

THAT IT WORKS IS IT SUCKS

PARTICLES INTO THIS HEADPIECE

THROUGH A CORY OWE LIS EFFECT

AND THEY GET STUCK IN THAT

CHAMPAGNE CONE AND IT'S LIQUID

AND YOU CAN ANALYZE THE

PARTICLES SO IT'S A NICE

EXTRACTION PROCESS.

WE'VE USED THE SET UP AND IN

PRELIMINARY EXPERIMENTS I'M

GOING TO SHOW YOU USING BCG, WE

HAVE AR SOLLIZED BCG AND

COLLECTED THEM ON THE CORY OWE

LIS AND

THIS SPRAY FACTOR IT'S NOT

REALLY IMPORTANT IT'S JUST

REALLY -- IT'S A MATHEMATICAL

KIND OF DATA CRUNCHING FOR YOU

TO REPORT THE AMOUNT OF CFUs

THAT YOU'VE EXTRACTED FROM THE

AIR RELATIVE TO THE AMOUNT THAT

WAS IN THE COLUMN SO IT'S DATA

CRUNCHING BUT IT'S A MEASUREMENT

OF VIABLE BUGS, THE VIABLE

FRACTIONION AND OVER TIME THE

SPRAY FACTOR IS GOING DOWN AND

IT MEANS THE C RECOVERY GOES DO.

IF YOU TAKE THE BUGS THAT WERE

AT THIS EIGHT-MINUTE AGING,

EARLY, AND YOU COMPARE THEM TO

BUGS THAT COME STRAIGHT OUT OF

BROTH AND YOU CAN ADD THEM TO

BONE MARROW MAX, IT SEEMS THAT

THE BUGS THAT ARE COMING FROM

THE AIR ARE HAVING A HARD TIME

ESTABLISHING THE INFECTION IN

THE MACROPHAGE AND THIS IS EARLY

DAYS.

AND SO WE'RE IN THE PROCESS OF

REPEATING THIS WITH TB NOW AND

THEN SO WE HAVE A COLLABORATION

WITH CHAD ROY AT TO YOU LANE

UNIVERSITY AND HE IS LIKE THE

KING.

HE USED THE COLD BERG DRUM THAT

KEEPS AEROSOLS, BUGS IN THE

AEROSOLS STATE FOR AS LONG AS

YOU WANT PRETTY MUCH WHAT HE HAS

DONE HERE IS COMPARED IT SEEMS

THAT THE BUGS GOING DOWN IN RISK

IN TWO AND ONE THEY SEEM TO

SURVIVE LESS WELL IN AEROSOL

COMPARED TO TB AND IN THIS CASE

THE CDC 1551 WHICH IS A

REPRESENTATIVE OUTBREAKS STRAINS

AND THAT IS COMMERCIALLY

AVAILABLE AND SO, WHAT WE WANT

TO DO NOW IS TOGETHER WITH CHAD

AND TOGETHER WITH OUR COLLEAGUE

AT STELLEN BASH, WE WANTED TO

INVESTIGATE WHAT THIS MEANS WITH

IS THERE THE ABILITY OF A STRAIN

THAT IS SUCCESSFUL WITHIN A

GIVEN COMMUNITY AND A GIVEN

ENVIRONMENT BECAUSE IT'S MORE

FIT AND IT'S ADAPTED TO THE

AEROSOL TRANSPORT PROCESS AND

YOU CAN ADD THIS TO MACROPHAGES

AFTER AEROSOL AGING AND SEE WHAT

WE GET OUT IN THE END.

AND THAT IS WHAT I WANTED TO

SHARE WITH YOU GUYS TODAY SO

THIS IS US AT OUR NEW BUILDING

AND WE'RE IN THE NINTH FLOOR AND

I'M AFRAID OF HEIGHTS BUT WE

HAVE TO BE ON THE TOP BECAUSE

WHERE THE BSL3 SO IT'S NICE I

HAVE A BSL3 BY MY OFFICE AND ALL

THE COMPLAINTS FROM ALL THE

USERS IS NOT SO NICE AND I TAKE

THAT AS PART OF A JOB BECAUSE

THERE'S TREMENDOUS OPPORTUNITIES

AND THE WORK I SHOWED YOU IS

DONE BY IN THE LAB BY NUNO

RUFINO DE SOUSA, A STUDENT FROM

PORTUGAL.

THANK YOU, VERY MUCH.

[APPLAUSE]

THAT WAS WONDERFUL.

I DON'T HAVE MUCH OF A QUESTION

BUT MORE LIKE A COMMENT SO I

HAVE COLLEAGUES BACK AT RUTGERS

AND THEY'VE BEEN LOOKING AT HIGH

TRANSMISSION AND LOW

TRANSMISSION HOUSEHOLDS ISOLATES

AND IT SEEMS LIKE I'M NOT SURE

IF THEY FIGURED OUT WHETHER

THEY'RE AGAIGONEOWE TYPICALLY DT

SEEMS LIKE IT'S INTERESTING AND

THE HIGH TRANSMISSION STRAINS

SEEM TO INDUCE ACTUALLY LOWER

BUG COUNTS IN THE LONG AND THE

G -- SOTHEN THERE'S THIS PROPULF

THESE BASILII WHERE THE LOW

TRANSMISSION STRAINS THEY'RE

HIGHER IN THE LUNG BUT THEY'RE

ENCASED IN MORE LIKE A TH1

GRANULOMA SO I THOUGHT IT WOULD

BE SO COOL, RIGHT, IF YOU CAN

AGAIN --IF THEY FIGURE OUT A CN

IF YOU COULD SAMPLE RIGHT FROM

THE AND FROM THE AIR AIR

SAMPLING OF WHICH TYPES OF BASIL

EYE ARE GETTING HIGHLY

TRANSMITTED,.

>> IT'S A GREAT POINT.

SO, THE COOL THING ABOUT THIS

STELLEN BASH STRAINS WE ARE

BASICALLY PICKING IN GRANT

FREEZERS THEY'VE BEEN SEQUENCES

AND THEY FOLLOWED UP THESE TWO

COMMUNITIES IN THE WESTERN CAPE

THIS IS ROB WARRENS STUFF AND SO

THEY'VE BEEN SEQUENCED SO WE

WILL HAVE THAT INFORMATION AND

THERE'S MANY ASPECT THAT'S

YOU'VE POINTED AT THERE THAT I

MEAN THERE'S DIFFERENT WAYS TO

LOOK AT THIS.

OTHER THING THE FIELD IS

INVESTIGATING VERY MUCH IS WE

HAVEN'T PULLED DOWN ENOUGH BUGS

TO BE ABLE TO DO GENE EXPRESSION

ANALYSIS BECAUSE IT'S VERY FEW

BUGS HERE SO THAT WOULD BE A WAY

TO ADDRESS THAT FURTHER AND.

>> WONDERING ABOUT TWO
SORT OF

RELATED USE WITH THAT THOR SAM

PLEASURE YOU SHOWED A NICE

PICTURE OF IT PULLING SMOKE IN

SO, I ALSO THE RELATIONSHIP

BETWEEN HOW FAR AWAY YOU CAN

PULL PARTICLES AND THE PARTICLE

SIZE SO DO YOU SAMPLE DIFFERENT

SIZE PARTICLES AND DIFFERENT

DEFICIENCIES.

>> YEAH, SO THIS IS THE
PART OF

THE TRY TO UNDERSTAND THE

SPECIFICATIONS OF THE DEVOICE

VOICE SO BECAUSE IT'S AN OPEN

DEVICE SO WE CAN'T MEASURE THE

FLOW RATE WHICH SAY MEASUREMENT

OF MANY OF THESE AIR SAMPLERS SO

CONSIDER SOMETIMES LIKE A BIG

VACUUM CLEANER AND IT WOULD

SOMETIMES YOU CAN ADAPT THE

FILTER TO THE VACUUM CLEANER AND

YOU TURN IT ON AND YOU KNOW IT'S

GOING TO -- THE FLOW RATE OF THE

VACUUM CLEANER IS 2,000-LITER

AND THE VOLUME OF THE ROOM SO

YOU HAVE AN IDEA HOW LONG DO I

NEED TO SAMPLE IT'S AN OPEN

DEVICE SO WE WE KNOW THERE'S NO

AIR FILTRATION AND THERE'S NO

AIR FLOW OTHER THAN THAT

GENERATE BID THE DEVICE AND IT

COMES TO YOUR OTHER POINT OF HOW

FAR AWAY YOU CAN BE SO THE

DEVICE ITSELF, THE SAMPLING

PROCESS DOES GENERATE AN AIR

FLOW OF SEVERAL LITERS PER

MINUTE SO IT'S THAN IT WILL ONLY

SAMPLE MATERIALS WHICH IS

PRESENT BUT IF YOU ARE COUGHING

IT WILL BE MUCH HIGHER THAN YOU

PICK UP FROM SOMEONE FURTHER

AWAY BUT WE'LL HAVE TO DETERMINE

THAT BY SEQUENCING THE PATIENT'S

BUG IF WE GET IT FROM THE COUGH.

CERTAINLY HOW MANY THORS WOULD

YOU NEED TO SAMPLE THIS ROOM?

IS THE QUESTION.

WE KNOW ONE THOR FOR

10,000 LITERS IS OUR ROUGH

ESTIMATE.

ANOTHER CAVEAT IS THAT IT'S A

GOOD CAVEAT BUT BAD FOR THE

SCIENCES THE ELECTROSTATIC

SAMPLING KILLS TB AS PART OF THE

COLLECTION PROCESS SO IT'S ALSO

A FILTRATION DEVICE STERILIZING

DEVICE AT THE SAME TIME AS IT

COLLECTS WHICH IS GOOD.

>> IT'S GOOD FOR
COMPLIANCE.

>> IT'S VERY GOOD.

BECAUSE OTHERWISE YOU ARE

CONCENTRATING TB INTO THIS

TINY -- IT WOULD BE DANGEROUS.

WE KNOW IT'S STERILIZING AND SO

YEAH WHERE WAS I.

>> IT SOUNDS LIKE THE
VOLUME

ISSUE IS IT'S A GREAT SAMPLE FOR

A HOUSEHOLD.

YOU ARE NOT GOING FOR A FOOTBALL

STADIUM.

>> WE'RE NOT GOING FOR
THAT, NO.

IT WILL BE SOMETHING YOU CAN

TAKE WITH YOU, RIGHT SO YOU CAN

HAVE MANY OF THESE SO IT CAN BE

THE SMOKE DEVICE TYPE OF THING

IN A PRISON CELL WHERE THE

INMATE DOES THE SAMPLING AND

HANDS OFF THE BULLET OR IT COULD

BE WHAT YOU GO INTO THE VILLAGE

AND ASK PEOPLE TO COUGH ON TO

THIS AND THEY CAN EITHER SHIP

THE BULLET OR YOU WASH THE

BULLET AT HOME SO IT'S THAT TYPE

OF -- YEAH.

[OFF MIC] [OFF MIC]

YES, SO I HAVE TOLD MANY PEOPLE

HERE AND THE PANDEMIC HAS REALLY

BEEN HORRIBLE AND ESPECIALLY IN

SWEDEN BUT THERE'S THE POSITIVE

SIDE OF THE HORRIBLE SITUATION

THAT IS IT HAS BEEN VERY GOOD

FOR INFECTIOUS DISEASE RESEARCH

AND WHAT SPILLS OVER IN TB SO

YES WE'VE DONE A LOT OF WORK

WITH COVID AND ACTUALLY WE'RE

USING THOR TO SAMPLE COVID AND

THIS WAS DONE IN (INAUDIBLE) SO

WE DIDN'T HAVE ETHICAL TO GET

PEM TO COUGH ON TO THE DEVICE

BUT WE SAMPLED THE ROOM AND ROOM

AIR OF PATIENTS AND WE TOOK

SURFACE SWABS AND WE ACTUALLY SO

WE'RE THE FIRST GROUP TO TO

RECOVER PFUs FROM AIR, COVID

PFUs FROM AIR SO THERE'S A LOT

OF RNA DETECTION OF AIR FROM

COVID AND PATIENT WARDS AND ALSO

ON THIS WALLS AND SURFACES AND

IN SURFACES THAT CAN'T BE

TOUCHED WHICH SUGGEST THAT THEY

MUST HAVE FLOWN, TRAVELED

THROUGH AIR STREAMS THERE AND SO

WE ACTUALLY USING THOR WHICH IS

SURPRISING BECAUSE I JUST SAID

IT STERILIZES BUT IN THIS CASE

WE WERE ABLE TO ACTUALLY REGROW

PFUs IN CELLS SO IF YOU

ACTUALLY DO THE EXPERIMENT INVET

ROW AND YOU PUT VIRUS ON TO THE

VICE.

THE AIR FILTRATION WAS VERY LOW

SO IT WAS 2.4 AIR CHANGES PER

HOUR SO VERY, VERY LOW AND SO I

WILL NOT ANSWER -- FELIX WILL

ANSWER A BUT I WON'T ANSWER A

QUESTION ABOUT FACE MASKS

BECAUSE I IF THERE WAS ANYONE

WITH A FACE MASK QUESTION I

WON'T ANSWER THAT BUT I WILL SAY

SO AIR FILTRATION IS THE KEY

THING FOR PREVENTING AIRBORN

TRANSMISSION.

SARS IN THE I WON'T MAKE A

STATEMENT ABOUT FACE MASKS BUT I

WILL SAY AIR FILTRATION IS

IMPORTANT.

I CAN HAVE ONE MADE FOR YOU NO

PROBLEM.

>> THAT'S REALLY GREAT.

THAT'S FUN.

IT'S A SUGGESTION RATHER THAN A

QUESTION.

THEY TAKE TIME AND IT'S A SLOW

PROCESS IF YOU MOVE ON TO

MOLECULAR SENSORS, DETECTION OF

TB IT WOULD BE GOLDEN THAT'S

WONDERFUL.

>> THANK YOU.

ALL RIGHT.

[APPLAUSE]

SO OUR NEXT SPEAKER IS CHUCK

SCANGA FROM UNIVERSITY OF

PITTSBURG SO HE IS ONE OF THE

THREE MUSKETEERS.

>> THANK YOU, CARL.

THANK YOU ESPECIALLY TO DRAGANA

FOR BOG THE OPPORTUNITY TO SPEAK

TODAY AND ALSO FOR ORGANIZING

THIS ENTIRE SYMPOSIUM.

AS CARL MENTIONED I'M ONE OF THE

ORIGINAL TB MUSKETEERS, CARL,

DAMIAN AND I SPENT A LOT OF TIME

SETTING UP THE BSL3 AND IT

ALLOWED ME TO DO WORK IN KNOCK

OUT MICE AND THE WORK THAT FEE

LEX MENTIONED YESTERDAY AND

AFTER OUR BSL3 GOT UP AND

RUNNING I PICKED UP A STUDY THAT

HAD BEEN STARTED IN THE LAB BY

MARCO SHEET OWE USING HIV

TRANSGENIC MICE TO LOOK AT CO

INFECTION AND I EXTENDED THAT

WORK INTO MTB AND THAT'S A --

THAT CO INFECTION WORK IS

SOMETHING THIS CONTINUES IN MY

OWN LAB TODAY SO FOR THIS

AUDIENAUDIENCE IDON'T NEED TO GL

HEALTH THREAT AND NEEDLESS TO

SAY IT'S I USE IT COMING FROM

RUSSIA AND THIS IS A STUDY THAT

STARTED WITH A COLLABORATION

WITH SHELBY OWE GONER ABOUT

EIGHT YEARS AGO AND WE USED

THESE MACAQUES THEY'VE BEEN USED

TO STUDY HIV USING SIV AS A

GARROW GET AND THEY HAVEN'T BEEN

USED MUCH TO STUDY TB AND SALLY

SHARP PUBLISHED THE FIRST PAPER

IN 2017 JUST AS WE WERE GETTING

STARTED AND THE REASON WE USED

THEM IS THE MACAQUES COME FROM

THIS TINY ISOLATED ISLAND OF

MAURITIAS AND THEY STARTED WITH

A FOUNDER POPULATION OF JUST 12

ANIMALS AND THIS IS GENETIC

BOTTLENECK RESULTED IN A LIMITED

NUMBER OF MHC HAB LOW TYPES AND

IT'S TH HAPPEN LOW TYPES.

WHEN YOU LOOK AT THE PROGRESSION

OF TB IN THESE TWO SPECIES, YOU

CAN SEE THERE'S FIRST THERE'S A

SPECTRUM OF SUSCEPTIBLE WITHIN

EACH OF THE SPECIES BUT IN

GENERAL, THE CHINESE MACAQUES

TEND TO BE MORE RESISTANT AND

THEY EXHIBIT LESS PATHOLOGY THAN

DO THE RECESS AND THEY HAVE

LOWER BACK TER Y'ALL ROADS

COMPARED TO THE RHESUS AND WE

USE PET IMAGING AND REUSE FDG AS

A PROBE FOR A NON SPECIFIC PROBE

FOR IN FROM MISSION AND IT

LIGHTSFOR --THEY ARE MUCH CLOSES

AND SO SHELBY AND I STARTED THIS

PROJECT QUITE A FEW YEARS AGO

AND THE FIRST QUESTION WE ASKED

IS DOES PREEXISTING SIV

INFECTION AFFECT TB PROGRESSION

AND TO DO THIS STUDY WE INFECTED

SOME ANIMALS WITH

3,000TDI50 AND WE EFFECT THEM

INTER RECTAL' AND SIX MONTHS

LATER, WE CO EFFECT THESE

ANIMALS WITH LOW DOSE OF

TUBERCULOSIS ANDE USE THE

STRAIN AND WE DELIVER IT BY

DELIVERY AND WE FOLLOWED THOSE

ANIMALS AND WE COMPARED THE TB

PROGRESSION IN THOSE CO EFFECTED

ANIMALS TO ANIMALS INFECTED WITH

MTB ALONE AND THE CO EFFECTED

ANIMALS EXHIBITED A LOSS OF CD4

CELLS AS A RESULT OF THE SIV

INFECTION AND THEY INTENDED TO

HAVE MORE TB DISEASE AND HIGHER

BACTERIAL BURDEN.

AND GIVEN THAT TB IS RESPONSIBLE

FOR SO MANY DEATHS IN PEOPLE

LIVING WITH HIV AND IT REALLY

BEGS TO QUESTION IS THERE A WAY

THAT WE CAN PROJECT THESE HIV

POSITIVE INDIVIDUALS FROM TB?

OF COURSE, THE SIMPLEST WAY IS

WITH A VACCINE AND IN DEED

THERE'S A VACCINE FOR

TUBERCULOSIS WHICH IS A LIFE

ATTENUATED STRAIN BCG IS ONE OF

THE MOST WIDELY USED VACCINES IN

THE WORLD AND ONE OF THE LEAST

EFFECTIVE AND IT IS BEEN AROUND

FOR 100 YEARS WHEN IT WAS FIRST

DEVELOPED BY CALMETTE-GUERIN AND

IT'S GIVEN SHORTLY AFTERBIRTH

AND THE DOSE IS FIVE TIMES 10 TO

THE FIFTH CFU AND IT'S GIVEN

INTRA BERMALLY AND IT DOES

PROTECT AGAINST CHILDHOOD TB AND

AS THEY GROW UP IT IS POOR

PROTECTION AGAINST ADULT

PULMONARY TB.

WE SEE THIS IN MACAQUES.

THIS IS WORK WE DID HERE AT THE

VACCINE RESEARCH CENTER AND YOU

CAN SEE IN THE SUSCEPTIBLE MA

CONTACT MODEL IT GIVES YOU ONE

LOG OF PROTECTION IN TERMS OF

CFU AND MACAQUES BY CHANGING THE

DOSE OR ROUTE WE COULD GET

BETTER PROTECTION.

AND IN THIS STUDY, HE INCREASED

BY 100 FOLD THE INTRA DETERMINAL

DOSE OF BCG IN MACAQUES AND

DELIVERED HIGH DOSE BCG

INTRAVENOUSLY AND HE DID

INCLUDED ANIMALS VACCINATED BY

THE AEROSOL ROUTE AND BOB AND

HIS TEAM FOLLOWED THE

DEVELOPMENT AND THE AIRWAY

RESPONSES USING ABL AND FLOW

CYTOMETRY TO LOOK AT CELLS AND

REALLY IT WAS ONLY THE

INTRAVENOUS ROUTE THAT WAS AWAY

FROM THE TYPICAL LVO OR

MACROPHAGES THAT ARE MOST

PREVALENT IN BAL TO THIS T-CELL

PROMINENT PHENOTYPE AND THAT IS

MAINTAINED FOR MANY, MANY WEEKS

AND MONTHS AFTER VACCINATION.

ONLY IN THE INTRAVENOUSLY

VACCINATED ANIMALS AND THEY SENT

THOSE ANIMALS TO RTB GROUP AT

PIT LED BY JOANNE FLYNN AND WE

CHALLENGED THOSE ANIMALS AND YOU

CAN SEE THAT THE ANIMALS

VACCINATED INTRAVENOUSLY 90%

WERE PROTECTED FROM M

TUBERCULOSIS.

IN FACT, SIX OUT OF THE 10

ANIMALS IN THIS GROUP EXHIBITED

STERILIZING IMMUNITY AND IN

OTHER WORDS, WE COULD NOT

CULTURAL ANY MICRO BACTERIAL

FROM THOSE ANIMALS AT THE TIME

OF NECROPSY SO THIS WAS REALLY

DRAMATIC PROTECTION.

IT'S CHALLENGES WITH NTB AND

NECROPSY 12 WEEKS LATER.

THE SECOND GROUP OF ANIMALS,

THESE ARE SIV NAIVE ANIMALS

VACCINATED WITH HIGH DOSE

INTRAVENOUS BCG AND SEVERAL

MONTHS LATER CHALLENGED AGAIN

WITH M TUBERCULOSIS.

AND ONE GROUP OF ANIMALS WAS

INFECTED WITH SIV AGAIN, WE USED

THE MACK 239 STRAIN GIVEN

ININTEREST RECTAL' AND FOLLOWED

THESE ANIMALS AND FOLLOWED VIRAL

LOADS IN THESE ANIMALS AND FIVES

LATER WE VACCINATED THEM WITH A

HIGH DOSE OF BCG INTRAVENOUSLY

AND THEN CHALLENGES THEM SEVERAL

MONTHS LATER WITH M

TUBERCULOSIS.

NOW MY BIG FEAR WAS IN THESE

IMMUNO DEFICIENT ANIMALS SIV

POSITIVE ANIMALS, THIS HIGH DOSE

LIVE BCG INJECTIO INJECTED INTOD

STREAM AND KILL THESE MONKEYS

AND THAT WAS MY BIGGEST FEAR AND

BECAUSE OF THAT I DECIDED TO

TREAT THE ANIMALS WITH TO KILL

THE BCG THROW TO FOUR WEEKS

AFTER VACCINATION.

AND JUST TO KEEP THAT CONSTANT

AND ALL THE GROUPS, ALL THE

ANIMALS REGARDLESS OF WHETHER

THEY'RE VACCINATED, RECEIVED

THIS SAME HRA REGIMENT WHICH WE

STOPPED ONE MONTH BEFORE

CHALLENGE SO THAT THE DRUGS WERE

NOT PRESENT WHEN WE ACTUALLY DID

THE CHALLENGE.

THE FIRST QUESTION IS IT SAFE?

THEY WERE NEGATIVE IN THE BLOOD

CULTURE AND WE CAN'T GO OUT BCG

TWO WEEKS AFTER VACCINATION AND

THEY DIDN'T EXHIBIT ANY CLINICAL

SCIENCE OF BCG DISEASE AND THEY

HAD NO NORMAL ESRs SO JUST

BASED ON THOSE KIND OF CURSORY

FINDINGS, IVBCG DOES APPEAR TO

BE SAFE IN SIV AND THE CAVEAT

THOUGH IS THAT AT LEAST WHEN

THEY WERE TREATED WITH ANTI BCG

DRUGS, STARTING THREE TO FOUR

WEEKS AFTER VACCINATION.

SO THE NEXT QUESTION BECAME WHAT

EFFECT DOES THAT BCG HAVE ON SIV

SO AGAIN WE UPON INFECTION, YOU

SEE ALL THE ANIMALS EXHIBIT THIS

SPIKE IN VI REEMIA THAT IS THEN

THEY HAVE A SPIKE IN VIREMIA AND

BACK UNDER CONTROL AND ALL OF

THESE ANIMALS REESTABLISHED

THEIR ORIGINAL VIRAL BASE LINES.

WHAT ABOUT IMMUNO.

JUST LIKE THE MACAQUES WE SAW IN

SIV NAIVE MACAQUES IV BCG HAD A

SHIFT FROM MACROPHAGE DOMINATED

BAL CELLS TO ONE DOMINATED BY T

CELLS AND THAT WAS MAINTAINED

FOR MANY WEEKS AFTER

VACCINATION.

AND QUITE SURPRISINGLY TO ME WE

SAW THAT SAME AFFECT HERE IN THE

SIV POSITIVE ANIMALS AND AGAIN,

EVEN IN ANIMALS INFECTED WITH

SIV, IVBCG STILL ILLICITTED THIS

DRAMATIC INCREASE IN THE

PREPORTION OF T CELLS IN THE

BAL.

IT WAS T CONTROLS SHOWN IN THE

BAL AND THIS IS BUSY LIED BUT

THE THIN LINES AND WHETHER OR

NOT THEY HAD PREEXISTING SIV

INFECTION YOU SEE THE INCREASE

IN THE LUNG AND THESE T CELLS

THAT COME INTO THE LUNG WERE

ACTUALLY PRIME TO MICRO BACTERIA

AN THROW AGAINST SO YOU SEE THIS

SHOWING CD4 MEMORY CELLS THAT

ARE RESPONDING BY MAKING

CYTOKINES IN RESPONSE TO PPD

RESTIMULATION.

YOU CAN SEE WHETHER THEY HAVE

SERVE OR NOT FOLLOWING MTB

CHALLENGE.

IN THE SIV AND VACCINATIONED AND

WE SAW COMPLETE PROTECTION FROM

DISEASE IN ALL OF THE ANIMALS.

WE SAW THAT IVBCG ELICITED

STRIKING PROTECTION IN THE

MAJORITY OF ANIMALS THIS SEVEN

OUT OF THE 10 ANIMALS THEY

REALLY HAD NO DISEASE VISIBLE BY

PET CT AND ONE ANIMAL WAS

PARTIALLY PROTECT AND TWO

ANIMALS THAT WERE VACCINE AND WE

CAN QUANTIFY THIS PROTECTION BY

MEASURING THE TOTAL FDG

ACCUMULATION AND YOU CAN SEE

THAT IDBCG ANIMALS, WHETHER

THEY'RE INFECTED AND WHETHER

THEY'RE INFECTED OR NOT AND AND

THEY HAVE STERILIZING IMMUNITY

TO A MTB CHALLENGE AND SEVEN OUT

OF THE 10 ANIMALS SIV POSITIVE

ANIMALS WERE SIMILARLY STERILE

AFTER CHALLENGE.

AND ONE ANIMAL IS PARTIALLY

PROTECTED AND TWO ANIMALS WERE

NOT.

AND I THINK ONE OF THE MOST

DRAMATIC FINDINGS FROM THIS

STUDY WHEN WE DID PBMC ALLEY

SPOTS, AFTER INFECTION AND

RESTIMULATED THE CELLS WITH

MTB-SPECIFIC ANTIGENS SO WHICH

ARE PRESENT ONLY IN MTB NOT

PRESENT IN BCG AND AS EXPECTED

BEFORE MTB CHALLENGE AND YOU

DON'T SEE ANY RESPONSES IN ANY

OF THE ANIMALS AND IN THE

UNVACCINATED ANIMALS, AFTER MTB

CHALLENGE, YOU SEE THE NICE

INTERFERON GAMMA RESPONSES IN

THE PBMCs IN RESPONSE TO THESE

MTB-SPECIFIC ANTIGENS AND QUITE

STRIKINGLY IN THE VACCINATED

ANIMALS, EVEN AFTER MTV AND YOU

DID SEE RESPONSE AND IT SUGGESTS

THAT THE VACCINATED ANIMALS AND

ELIMINATING CLEARING THE

BACTERIA BEFORE AND ADAPTIVE AND

IS EVEN GENERATED AND THAT IS

QUITE INTRIGUING AND AMAZING SO

THE CONCLUSION 0 CON IT PROTECTV

NAIVE AND CONFERRED PROTECTION

IN 80% OF THE SIV POSITIVE AND

SO THOSE STUDIES CHRONICALLY

EFFECTED WITH SIV AND IT REALLY

OPENS UP SOME EXCITING POTENTIAL

FOR EFFECTIVE VACCINES IN THIS

REALLY SIS SUSCEPTIBLE

POPULATION.

SO WITH THAT LET ME ACKNOWLEDGE

LOB, TRISHA, WITHIN THE TB

RESEARCH GROUP AT PIT LED BY

JOANNE FLYNN WHO I KNOW MANY OF

YOU KNOW WELL AND THIS.

>> WE MIGHT BE ABLE TO USE

MUTANT OR SOMETHING LIKE THAT TO

BE A MUCH SAFER VACCINE BECAUSE

GIVING HIGH DOSE IVBCD IN HIV

POSITIVE PEOPLE PROBABLY IS HIGH

BAR TO CLEAR BUT THESE DATA

CERTAINLY SUGGEST THAT WE COULD

USE A SAFER VARIANT OF BCG.

>> DEAD BUGS DOESN'T GET
SAFER.

>> DEAD BUGS SOMETHING
LIKE THAT

AND DEFINITELY THINGS THAT WE'RE

LOOKING AT.

>> COOL.

>> CONGRATULATIONS ON THAT

REALLY IMPORTANT RESULT.

WHY DO THE CELLS GO TO THE LUNG

IF THE VACCINATION?

WHAT'S THE IMMUNO PHENOTYPE AND

FUNCTIONALITY OF THE T CELLS

LONG BEFORE INFECTION AND CAN

YOU GIVE BCG INTRAVENOUSLY TO

TREAT ESTABLISHED TB INFECTION?

>> ALL GOOD QUESTIONS,
WE'VE NOT

DONE THE USE OF BCGIVBCG AS A

THERAPEUTIC AND CERTAINLY THAT'S

SOMETHING THAT COULD BE

INVESTIGATED AND WHY ARE THE

CELLS TO THE LUNG AND WHAT ARE

THEY DOING WHEN THEY GET THERE

IS A QUESTION THAT WE'RE

ACTIVELY LOOKING AT NOW AND

WE'RE USING A LOT OF SINGLE CELL

RNC SEEK TO MORE FULLY

CHARACTERIZE THE CELL

POPULATIONS SO I HOPE TO HAVE

SOME BETTER ANSWERS FOR YOU

WITHIN THE NEXT YEAR.

>> I WAS VERY STRIKING AT
THE

END WHEN YOU SUGGESTED THAT YOU

COULDN'T FIND THE SPECIFIC T

CELLS IN THE BLOOD BECAUSE I

THINK WE WERE ALL THINKING

THAT'S WHAT YOU WERE GOING TO

FIND.

WHAT IS THE MECHANISM?

WHAT DO YOU THINK IS GOING ON?

>> THE MECHANISM IS A
REALLY,

REALLY IMPORTANT QUESTION AND SO

WE'RE TRYING IDENTIFY THE

MECHANISM AND LOOK FOR COR

IMMUNITY.

I KNOW STUDIES WITH BOB SEEDER

AND JOANNE FLYNN HAS SHOWN AN

NIH NAIVE ANIMALS AND PRETEXT IS

ASSOCIATED WITH IGM AND IT'S

ASSOCIATED WITH AN INFLUX OF T

RESIDENT MEMBER RE CELLS AND

THESE ARE ALL ASSOCIATIONS WHERE

CURRENTLY DOING STUDIES TO KIND

OF MORE FIRMLY HAVE MECHANISM

PROTECTION.

>> YOU ARE NOT ARGUING
IT'S NOT

T CELLS YOU ARE ARGUING THEY

MIGHT NOT BE IN THE BLOOD.

>> THAT'S RIGHT.

>> THEY MIGHT BE IN THE
LUNG.

>> ABSOLUTELY.

>> IS IT ETHICALLY
FEASIBLE TO

SPLIN HE CAN TOM EYES THESE NON

PRAIRIE HUMAN IT'S A.

PRACTICE.

>> DO YOU AT THIS NOTICE
THE

SPLEEN.

>> THEY DEVELOP A
SPLEENAMOGLIA

AND I THINK IT'S THE IDEA.

PRIOR TO INFECTION.

>> THANK YOU.

>> WAS THAT RELATED IN THE

MACAQUES?

>> YEAH, THE ANIMALS THIS

UNPROTECTED BY IVBCG HAD ONE

THING IN COMMON, THEY WERE POOR

VIRAL CONTROLLER NUMBER ONE AND

NUMBER TWO, THEY INTENDED TO

HAVE FEWER -- A MORE DRAMATIC

CD4 DEPLETION.

WE KNOW THAT WITH ART THERAPY

THOSE THINGS ARE CORRECTED SO I

THINK CERTAINLY IN HIV CONTEXT

ART WOULD BE A REALLY IMPORTANT

COMPONENT OF THIS.

[OFF MIC]

THE

[OFF MIC]

>> ABSOLUTELY, IT'S A
REALLY

GOOD QUESTION, IT'S TRUE THAT

THE AEROSOL DELIVERED BCG JUST

DOESN'T PROTECT WELL.

OF COURSE IT'S GET TO GO THE

LUNG BY A DIFFERENT MECHANISM,

RIGHT, IT'S COMING IN FROM THE

AIRWAYS RATHER THAN SOME PLACE

ELSE AND THE IMMUNE CELLS ARE

ENTERING THE LUNG PRANK FROM THE

VAAS CUE LATOUR.

IF WE CAN TEASE OUT THE

DIFFERENCES BETWEEN THOSE TWO

ROUTES I THINK IT WOULD BE

REALLY CONSTRUCTIVE.

[OFF MIC]

>> I WAS REALLY HAPPY TO

RECAPITULATE THE FINDINGS

BETWEEN JOB AND JOANNE IN A

MODEL RATHER THAN REHSUS VERY

GOOD.

>> THANK YOU, ALL.

[APPLAUSE]

>> WE'RE GOING TO CHANGE
THE

TOPIC NOW SO OUR NEXT SPEAKER IS

DIEGO COSTA FROM UNIVERSITY OF

SAO PAULO.

>> I WOULD LIKE TO SAY
IT'S A

HUGE HONOR TO BE HERE PRESENTING

MY WORK AND ALSO TO THANK

DRAGANA AND DAN FOR MAKING THIS

BOTH ABLE SO I'M GOING TO SHOW

YOU THE DEVELOPMENT OF THE WORK

I'VE DONE AS A TIME AS A TRAINEE

FOR ESTABLISHING THE RESEARCH

PROGRAM THAT I'M START TO GO

DEVELOP IN BRAZIL RIGHT NOW.

I HAVE WORKED WITH ALAN AND I

CONTINUE TO DO THAT AND I'M

GOING TO SHOW YOU DATA FOR TB

AND TARGETING HOMEOSTASIS AND

LUNG INFLAMMATION SO IT WAS

INTRODUCED HERE A MAJOR

PUBLIC-HEALTH PROBLEM AROUND THE

WORLD AND SO JUST LAST YEAR,

AROUND 10 MILLION PEOPLE HAD

BEEN INFECTED AND HALF MILLION

OF THOSE PEOPLE WITH DRUG

RESISTANT BAGS AND 1.5 MILLION

PEOPLE DIED FROM THE DISEASE AND

SO WHY DID WE CONTINUE TO BE

SUCH A MAJOR PROBLEM IF THERE'S

A VACCINE FOR IT AND A TREATMENT

AND THE VACCINE IS NOT THAT

EFFECTIVE IN CONTAINING

PREVENTING TUBERCULOSIS AND THE

TREATMENT, THE REGULAR

TREATMENT, THE DIRECT TREATMENT

SHORT COURSE LASTS FOR SIX

MONTHS WHERE FOUR DIFFERENT

DRUGS ARE ADMINISTERED SO THE

PATIENTS PRESENT SEVERAL SIDE

EFFECTS AND A LOT OF THEM DO NOT

COMPLY WITH THE FULL TREATMENT

IN THAT FAVORS THE RELAPSE FOR

THE DISEASE AND SELECTION OF

DRUG ROW RESISTANT TREATMENT SOS

AN URGENT NEED THAT ELIMINATED

THE TREATMENT FOR RAPIDLY AND

ALSO THEY DO NOT RELY ON

ANTIBIOTICS AND IN THAT SENSE,

WE COME TO THE THERAPY AS A

STRATEGY BECAUSE THEY TARGET

HOST BIOLOGICAL FACTORS THAT CAN

FAVOR THE DISEASE DEVELOPMENT

AND AND HOW DOES HOST IMMUNITY

AND WORK AND IT'S A BACTERIAL

THAT IS TRANCE MUTED THROUGH THE

AIR SO IT EFFECTS MAINLY THE

LUNGS AND IN THE LUNGS, IT'S

FIRST ENCOUNTERING THEY ARE THE

MAIN CELLS BY TB AND TB HAS

DELAND THEYARE PART ANT CYTOKINE

HOST COULD CONTAIN THE DISEASE

AND THESE MACROPHAGES WILL PHAGO

SIGHT THOSE BACTERIA AND PHAGO

SOME WILL OCCUR AND THE FUSION

AND THIS CAN LEAD TO THE

BACTERIA AND IF THEY'RE NOT

KILLED AND LATER ON AND TH1

IMMUNITY WILL KICK IN WITH THE

PREDICTION AND IT'S IMPORTANT

FOR ACTIVATING THE EXPRESSION OF

INOS AND OX SA DAZING MACROPHAGE

AND THEY'RE HARMFUL BUT EVEN SO,

ALL ALONG THE EVOLUTION, THE CO

EVOLUTION WITH THE HUMAN SPECIES

AND THERE ARE WAYS TO SUBVERT

THIS IMMUNO RESPONSE AND IT CAN

SURVIVE THIS STRETCH FROM THE

MACROPHAGE ONE OF THE THINGS IS

THEY CAN TRIGGER A MASSIVE

PRODUCTION, ESCAPE THIS TRIGGERS

A MASSIVE PREDICTION AND WHEN A

CHRONIC DEVELOP WE CAN HAVE A

PROTECTIVE CYTOKINES AND LEAD TO

GO A MASSIVE PREDICTION AND THIS

WILL END UP TRIGGERING CELL

DEATH OF THE MACROPHAGES BECAUSE

THEY WILL TRIGGER TISSUE DAMAGE

AND THE BACTERIA AND SO THE THEY

SHOW DESTRUCTION IS WELL

CHARACTERIZED IN THE GRANULOMA

SO THEY HAVE A MASSIVE CASE OF

NECROSIS WHICH WILL LEAD TO THE

FORMATION OF THIS CAVITIES AND

THIS CAN HELP TO SPREAD BACTERIA

TO TRANSMIT THE BACTERIA SO

CONSIDERING THAT THE IMMUNE

RESPONSE IS IMPORTANT TO CONTAIN

THE BACTERIA AND ALSO TRIGGER

TISSUE DESTRUCTION THE MAIN

STRATEGIES FOR DEVELOPMENT OF

HOST DISTRICTED THERAPIST FOR TB

RELY ON INCREASING THIS IMMUNITY

SO WE CAN GET RID OF THE

BACTERIA MORE EASILY OR USE

ANTIINFLAMMATORY STRATEGIES SO

WE CAN CALM DOWN THIS

INFLAMMATORY RESPONSE PRESERVING

TISSUE AND DISRUPT GRANULOMA SO

THEY PENETRATE INTO THE CORE

WHERE THE EFFECTED CELLS ARE.

SO, WHEN I WAS IN THE LAB, WE

WERE TRYING TO TARGET FOR HOST

DIRECTED THERAPIES SO HO1 IS

ANEN TIME THAT CATALYZES THE

DEROGATION AND RELEASING AMOUNTS

OF CARBON MONOXIDE AND BILLY VER

DIN AND IT WAS A STUDY THAT WAS

DEVELOPED BY BRUNO WHEN HE WAS

IN THE LAB.

THIS IS HUMANS SUCCESSFUL

TREATMENT CURSE THERE'S A

EXPRESSION OF HO-1.

IT'S A GOOD BIOMARKER BUT WE

WERE INTERESTED IN THE ROLE OF

IT AND WE USED THESE INHIBITOR

OF HO-1 THAT IS ALSO CALLED

LIPIDS YOU CAN SEE HERE IT'S AN

MOLECULE OF HEME AND INSTEAD OF

RAILRRIN FROM THE SO WHEN WE IND

THE MICE WITH A LOW DOSE OF TB

AND WAITED FOR THE INFECTION TO

ROW ESTAREESTABLISH AND ONLY TWS

OF TREATMENT LED TO A MASSIVE

REDUCTION OF THE BACTERIAL LOAD

IN THE LUNGS AND NOT JUST THAT

WHEN YOU COMBINE THIS WITH THE

REAGAN ANTIBIOTICS AND WE FOLLOE

MICE IN THE LONG-TERM YOU CAN

SEE IN THE GROWN L GREEN LINE AS

COMPARED TO THE RED LINE THAT

ANTIBIOTICS ALONE SO IN FOUR

MONTHS IT COULD CLEAR THE

BACTERIA FROM THE LUNGS AND

TREATED ONLY WITH ANTIBIOTICS IT

SAKES SIX MONTHS SO WE SAVE TWO

MONTHS OF TREATMENT.

ONE INTERESTING THING THAT WE

FOUND WHEN WE STARTED TO TREAT

THESE MICE FROM DAY ZERO IS THAT

DURING THIS FIRST THREE WEEKS,

WE HAD NO CHANGE IN BACTERIAL

LOAD.

YOU COULD ONLY WORK LATER ON SO

THEM IF WE HAVE SIX WEEKS POST

INFECTION WE COULD FIND THE

BACTERIA LOAD REDUCTION AND ONE

THING THAT IS VERY CLAR TERRIZED

ALREADY IN TB IS IN THE THIRD

WEEK OF INFECTION, IT'S WHEN THE

T-CELL RESPONSE KICKS IN SO HERE

WE HAVE THIS MASSIVE INCREASE IN

PRODUCTION AND WE CAN SEE THE

EXPRESSION SO WE WANTED TO KNOW

IF THESE EFFECT WOULD BE THE T

CELLS SO AND THEY'RE KNOCK OFF

MICE AND TREATED THEM AND WE CAN

SEE HERE A NICE REDUCTION AND WE

HAVE NO REDUCTION IN GAMMA AND

SO THIS SHOWS THAT THE BACTERIAL

LOAD RESULTING FROM THE HO-1 IS

THE IMMUNE RESPONSE AND MORE

SPECIFICALLY IN THE REDEX OF

EXPRESSION OF IONS SO WE ALSO

MADE A NICE CHARACTERIZATION OF

WHICH CELLS EXPRESSED HO1 IN THE

LONG INFECTED MICE AND I'M NOT

SHOWING THE DATA HERE BECAUSE OF

LACK OF TIME BUT BASICALLY WE

FOUND THAT THIS CELLS WHERE WE

HAD THE LARGEST INCREASE IN HO1

EXPRESSION WERE INFLAMMATORY

MACROPHAGES THAT WERE RECRUITED

FOR MONOCYTES AND THE LUNGS SO,

WE USED AN IN VITRO MODEL OF THE

MACROPHAGES TO ANALYZE WHAT WERE

THE MECHANISMS BEHIND THIS

INQUIZ ITS EFFECT WE WERE SERVE

WHAT IS WE BROUGHT THE AND AS

EXPECTED, WE SEE JUST MEASURING

THE EXPRESSION AND IT'S TREATED

WITH GAMMA IN THE PRESENCE OR

ABSENCE OF THE INHIBITOR, BLOCK

H1 WE HAVE AN INCREASED

EXPRESSION OF FOLLOWED BY THE

INCREASED PRODUCTION AND SO IN

THE BLOCK HO-1 THEY HAVE

ENHANCED EXPRESSION IN RESPONSE

TO GAMMA ACTIVATION AND SO SINCE

HO-1, WORKS BY DEGRADING HIM,

RELEASING CARBON MONOXIDE IN WE

WERE INTERESTED IN SEEING WHICH

OF THESE PRODUCTS WOULD BE SO WE

REPEATED THE SAME APPROACH AS WE

CAN SEE HERE WE HAVE GAMMA AND

THE EFFECT WITH GAMMA PLUS

INHIBITOR AND WE GAVE BACK

CARBON MONOXIDE OR IRON AND AS

YOU CAN SEE HERE, CARBON

MONOXIDE MAY BE THAT RESULT IN

ANY CHANGE AND BILIVERDIN AND WE

REVERSED THE EFFECT AND SO THEY

WERE ACTIVATED WITH GAMMA IN THE

PRESENCE AND THE INHIBITOR AS

YOU CAN SEE HERE, THIS INCREASE

THE EXPRESSION IN THE PRESENCE

OF H-01 INHIBITOR IS REVERTED IF

WE HAD IRON BACK TO THE CELLS

AND WHEN WE DO THE OPPOSITE

APPROACH WE WILL INCUBATE THE

CELLS AND WE HAVE A MASSIVE

INCREASE IN THE EXPRESSION OF

THE VIRUS SO THIS SHOWS US THAT

THE IRON THAT IS BEING RELEASED

BY ACTIVITY ACTUALLY IMPAIRS

THAT EXPRESSION RESULTING FROM

IS THE EFFECTIVE TEE OF THE

EFFECTED MACROPHAGES AND SO WITH

THESE WE WANTED TO FINALLY PROVE

THAT IN FACT THE TREATMENT WITH

H-O1 THE IRON LEVELS OF THE CELL

SO WE DID WITH DEBATED CELLS

RESULTING A REDUCTION IN THE

INTER CELL LEVELS AND IN VIVO AS

WELL WE ISOLATED LUNGS FROM

TREATED MICE OR SMMP TREATED

MICE WE CAN SEE HERE THIS BROWN

SPOTS WHERE SUSTAINED AND SO WE

SEE A LOT OF IRON IN THE LUNG OF

ANIMALS INFECTED WITH TB BUT NOT

TREAT SOD THERE'S IRON

COMBINATION IN CELLS AND WE HAVE

A DECREASING AND INFECTED ITSELF

AND WE SET UP THE IDEA OF HOW

THE MODULATION OF HOMEOSTASIS

CAN BE MAUD LATING THE RESPONSE

OF MACROPHAGES AND CAN THIS BE

TARGETED FOR THE DEVELOPMENT OF

NEW THERAPY SO WITH THAT, I

WROTE A GRANT APPLICATION FOR IN

BRAZIL AND SO I GOT THIS CALLED

YOUNG INVESTIGATOR GRANT AND I

WAS ABLE TO MOVE BACK TO BRAZIL

MORE SPECIFICALLY I WENT BACK TO

SAO PAULO AND MORE SPECIFICALLY

I WENT BACK TO WHERE I DID MY

PH.D IN UNIVERSITY OF SAO PAULO

SO HERE IS A PICTURE.

HERE IS A PICTURE OF THE MEDICAL

SCHOOL IN THE UNIVERSITY OF SAO

PAULO AND THIS IS A BEAUTIFUL

PICTURE OF THIS BUILDING HERE

THAT IS WHERE THE BASIC SIGNS

LABS ARE LOCATED BECAUSE HERE IS

THE HOSPITAL.

OUR LAB IS IN THIS BUILDING AND

THERE ARE JOINED ABOUT THE GROUP

AND MY GROUP WITH THEY WERE

PATIO OF THAT BUILDING AND WE

HAVE A NICE CAFETERIA HERE SO

SHE HELPED ME TO SET UP THIS

PROGRAM THERE AND HER HELP WAS

CRITICAL FOR ME TO BE ABLE TO

DEVELOP IT THERE AND ACTUALLY

I'M START TO GO DEVELOP IT AND

HERE I HAVE A PICTURE OF MY OWN

GROUP SO THOSE ARE MY STUDENTS

WITH ME AND THE INTEREST O

ENTRANCE OF THAT BUILDING AND AS

I MENTIONED TO YOU I'M

INTERESTED IN HOW IRON CAN BE

MODULATING THIS I'M UNION

RESPONSE TO TB SO PARTICULARLY

IN MACROPHAGES, WHICH ARE THE

CELLS AFFECTED BY TB WE WANT TO

ADDRESS HOW IRON METABOLISM IS

WORKING IN TB INFECTION SO

MACROPHAGES CAN AK PAIR IRON

THROUGH MULTIPLE WAYS SO

ESPECIALLY BY RED BLOOD CELLS

AND THEY CAN ALSO DEGRADE HEMO

PROTEINS AND GET HEMOGLOBIN FROM

THE CIRCULATION AND THIS IRON

AND ALSO ACQUIRE IRON DIRECT

LIEU THROUGH OTHER TRANSMITTERS

BUT THEY CAN ONLY GET RID OF

IRON BY THESE TRANSPORTERS HERE

THAT IS FERRO FOR TIN.

WE GOT INTERESTED IN THE

MODULATION BECAUSE THE

REGULATION OF THE EXPRESSION OF

FER OWE FOR TIN.

THE PRODUCED BY IRON AND THE SER

OWN BUT IT CAN BE PRODUCED BY

MACROPHAGES IN RESPONSE TO

INFLAMMATORY SUCH AS IL-11, IL-6

AND RECEPTORS 4 SO THESE HAVE

PRODUCTION WE WILL FERROPORTIN

AND ON THE OTHER SIDE TRYING

ORING OF RECEPTORS 2 CAN LEAD TO

DOWN REGULATION OF FERROPORTIN

TRANSLATION SO THESE ARE ALL

ACTIVATED AND WE ARE INTERESTING

KNOW THE ROLE OF FERROPORTIN

DURING THE TB INFECTION AND HOW

DOES IT WORK IN THE MODULATION

OF HOMEOSTASIS AND MODULATION IN

IMMUNE RESPONSE SO THIS IS A

WORK IN PROGRESS AND I'M GOING

TO SHOW YOU SOME VERY

PRELIMINARY DETAILS THAT I'M

START TO GO GET IN THE LAB WITH

MY STUDENTS.

MY MASTER STUDENT IS WORKING ON

THIS PROJECT SO SHE JUST

MEASURED H-01 EXPRESSION AND AS

YOU CAN SEE HERE WHY H-01 GOES

UP AND FERROPORTIN GOES DOWN SO

THIS IS FLAVORING THE LUNGS SO

INTERESTINGLY, THIS IS THE

EXPRESSION OF HELP SEW DIN AND

IT GOES DOWN SO THE DOWN

REGULATION OF FERROPORTIN IN THE

CELLS MAY NOT BE RELATED TO

HEPSODINE ITSELF BUT AS WELL AS

TALL 1 AND 6 ARE BEING WITH ON

GOING INFECTION SO WE BELIEVE

THAT MAYBE THIS DOWN REGULATION

IS MEDIATED BY REACC RETO BE ANE

DID MODEL OF INFECTION IN

MACROPHAGES SO WE ASKED THE

COMPANY TO SYNTHESIZE AND TEST

IT IF IT WAS REALLY WORKING TO

DOWN REGULATE FARRO PORTIN

THERE'S A DOWN REGULATION IN THE

FIRST OF THIS BONE MARROW DRIVE

AND WHEN I SEE EFFECTED THOSE

CELLS WITH TB AND TREATED THEM

WITH GAMMA OR HEPCIDIN IT DID

ARE NOT HAVE A CHANGE IN THED

CELLS AND INTER FUR AN GAMMA WE

SEE A NICE REDUCTION BUT PUT

HELP SEDIN HERE AND IT WILL DOWN

REGULATE IT AND IT'S A WORK IN

PROGRESS AND WE HAVE ESTABLISHED

A COLLABORATION WITH DAVID

FRASIER FROM AUSTRALIA AND GET

THIS IN MICE AND WORE BREEDING

THEM WITH SOME PRETTY EXPRESSING

STRAINS TO KNOCK OUT IT

SPECIFICALLY IN THE MIO LLOYD

CELLS AND WEREN'T ABLE BECAUSE

WE FOUND THAT THESE ONES WERE

NOT VIABLE IF WE CROSSED THEM

WITH CSFR1 AND LET'S SEE WHAT

HAPPENS SO MA PRONE A IS DOING

HER FIRST INFECTION THIS WEEK.

LET'S SEE WHAT WE HAVE FROM

THAT.

AND ALSO, WE'RE INTERESTED IN

SEEING HOW IS IT MODULATING

THESE AND IN PARTICULAR, WE ARE

INTERESTED IN SEEING YOU HOW

THEY CAN MODULATE THE EXPRESSION

OF HIGH POX AND HI F-1 AND HI

F-2 AND WHY IS THAT?

AND DEGRADING THE HIF OF THE

MOLECULES AND IT TURNS OUT THAT

IT ALSO UTILIZES IRON TO THIS

AND FO HIF-1 WHEN IRON DEPLETION

OCCURS IT CAN MIGRATE TO THE

NUCLEUS AND INDUCE THE SUB

DESCRIPTION OF SEVERAL GENES

ASSOCIATED WITH METABOLISM OF

GLUCOSE AND A LOT OF CYTOKINES

THAT ARE IMPORTANT FOR IT AND ON

THE OTHER HAND, THE MODULATION

OF IRON WORKS ON THE OPPOSITE

DIRECTION AND THAT WORKS BECAUSE

THAT HAPPENS LIKE THIS BECAUSE

OF THIS IRON RESPONSIVE ELEMENT

AND THIS IS A MOTIVE PRESENT ON

THE MANAGERRER RNA MOLECULE SO

WHEN WE HAVE THE INTERACTION OF

THESE PROTEINS THAT THE IRON

REGULATORY PROTEIN WITH THESE

IRON RESPONSIVE ELEMENTS AND

WHEN THE IRON CONCENTRATION OF

THE CELLS AND LOW THEY HAVE A

CONFIRMATION, THEY HAVE A HIGH

AFFINITY FOR THE IRON SO THEY'RE

GOING TO MIND AND THROUGH THE

PRESENT IN HIF-2 AND BLOCK ITS

TRANSLATION AND WHEN IRON

ACCUMULATES INSIDE THE CELLS,

IT'S GOING TO BIND TO THIS IRP

AND ALTERS ITS CONFIRMATION AND

LOSES ITS AFFINITY AND RELEASES

THE MRNA AND THEN WE HAVE AN

INCREASE IN THE EXPRESSION OF

HIF-2 SO WHEN IRON IS HIGH

INSIDE CELLS WE HAVE A DEM

INAUGURATION OF HIF-1 ALPHA AND

HIF-2 ALPHA AND WHAT HAPPENS IS

HIF-1 ALPHA IS ASSOCIATED WITH

M1 MACROPHAGES WHERE WE HAVE

INFECTION OF EFFECT AND BETA

PRODUCTION AND ALL IMPORTANT FOR

CONTAINING TB REPLICATION AND

THEY ASSOCIATED WITH MACROPHAGES

AND IT'S AN IMPORTANT INDUCER OF

RGNA1 WHICH FACILITATES

REPLICATION AND MACROPHAGES SO

WE'RE INTERESTED IN ESPECIALLY

IN ASSESSING WHAT IS THE ROLE OF

THIS ALPHA PATHWAY IN INFECTION

AND ESPECIALLY FIGURING OUT HOW

THE MODULATION OF THESE IRON

LEVELS INSIDE THE CELLS CAN BE

REGULATING THESE PATHWAYS SO

THIS IS OUR WORK THAT IS BEING

DEVELOPED BY A PH.D STUDENT IN

MY LAB AND SO THIS IS ALSO SOME

VERY PRELIMINARY DATA USING BONE

MARROW MACROPHAGES TREATED WITH

ANY INHIBITOR WE DO SEE A

REDUCTION AND WHEN WE TRICK THEM

WITH GAMMA HERE IS THE REDUCTION

AND WE PUT GAMMA PLUS THE

INHIBITOR WE HAVE THIS OF THE

ACTIVITIES OF THIS MACROPHAGES

AND WE ALSO USE THIS H37RVN TO

BE EXPRESSING SO WE COULD SEE IF

INVIVO THE INFECTION WOULD

TRIGGER THE INFECTION SO WE

COMPARED TO THE NON EFFECTED

CELLS SO WITH THAT, WE WANTED TO

START A SESSION THE ROLE DURING

MTB INFECTION AND WE USE IT

MODEL OF A LOW DOSE AND TREATED

WITH AN INHIBITOR OF HIF-2 ALPHA

AND THE MOUSE HAVE A LOWER

BACTERIAL LOAD IN THE LUNGS SO

WE GOT THIS AND WHAT WE GOT IS N

EFFECT THE MICE WERE CONDITIONED

KNOCK OUT MICE WITH LOW OR HIGH

DOSE OF BOTH OF THEM AND WE HAVE

A LOWER BACTERIAL LOAD WITH MORE

EVIDENCE IN HIGH DOSE SO

EVERYTHING POINTS OUT TO THE

FACT THAT HIF-2 ALPHA IS

DETRIMENTAL FOR THE CONTROL OF

BACTERIAL INFECTION AND WE

BELIEVE THIS IS BEING MODULATED

BY THE CHANGES IN IRON LEVELS

INSIDE THE CELLS AND IN RESPONSE

TO OTHER INFLAMMATORY SO, THAT

IS ONE PROJECT AND THIS IS

ANOTHER PROJECT THAT WE ARE

CARRYING ON IN OUR LABORATORY

AND THIS IS IMPORTANT FOR ME TO

SAY THAT IT'S BEING DEVELOPED IN

COLLABORATION WITH Dr. CARLA

ROTH LYNN AND HERE AGAIN CAN BE

PRESENT BECAUSE I REMEMBER FIRST

OF ALL, CARLA IS AN EXPERT IN

THE FIELD OF RECEPTORS RIGHT SO

THESE RECEPTORS THEY RECOGNIZE

IN THE MEMBRANES OF CELLS AND

THEY BRIDGE WITH THESE LIE GANTZ

TO PRO MOT THE CELLS AND PHAGO

TIE SEW SIS IS CALLED OF CELLS

AND ALSO I SAID THIS PATHWAY

MUST BE VERY IMPORTANT FOR THE

REGULATION OF IMMUNE RESPONSES

IN TB AND WE MAY HAVE NICE

TARGETS HERE TO TRY TO DEVELOP

NEW STRETCHES, YOU KNOW, WE

SHOULD GET MICE WITH HER AND SEE

AND SHE SAID TOTALLY, LET'S TALK

WITH HER, SHE'S A VERY NICE

PERSON AND ALAN INTRODUCED ME TO

CARLA SO I KNEW HER AND GOT TO

KNOW HER AND ACTUALLY SHE SENT

THE MICE TO ME AND WE ARE

DEVELOPING THIS PROJECT RIGHT

NOW AND SO THIS IS SOME RESULTS

THAT I'M GOING TO SHOW YOU TOO,

THESE ARE VERY PRELIMINARY AND

BEING DEVELOPED BY THIS STUDENT

OF MINE ANDREA, HE IS A MASTERS

STUDENT AND HE IS SHOWN THAT THE

EXPRESSION OF AXL IN MACROPHAGES

IN RESPONSE TO INFECTION THIS IS

24 AND 48 HOURS AS YOU CAN SEE

HERE AND HE ALSO FOUND THAT IN

VIVO, IN MICE INFECTED WITH A

HIGH DOSE, WE STARTED WITH A

HIGH DOSE BECAUSE WE WANTED TO

SEE HOW IT COMMODE YOU LATE THE

LESIONS IN THIS MICE AND THE

SIGNIFICANT INCREASE IN IF YOU

ARE MACROPHAGES BUT IF YOU ARE

MACROPHAGES ARE ALREADY

EXPRESSING A LOT OF AXL SINCE

THE BEGINNING AND IT'S LITTLE TO

DECREASE BUZZ IN PARTICULARLY IN

THIS CD11B POSITIVE CELLS AS YOU

CAN SEE IT'S REDISTRICTED AND

IT'S POSITIVE EVENTS AND WE HAVE

A MAJOR INCREASE IN THE

EXPRESSION OF AXL THAT AT THE

SAME TIME IN THE LONG OF THESE

ANIMALS WE HAVE A MAJOR INCREASE

IN THE PREDICTION OF THE LAG ANT

SO WE HAVE TWO OPTIONS, FIRST,

IF WE AXL CAN BE DOWN MODULATING

AND IF YOU COULD BLOCK IT WE CAN

MAKE IT BETTER OR ON THE OTHER

SIDE, IT'S THERE TO MODULATE IT

AND IF YOU BLOCK IT IT WILL BE

BAD.

TO START ADDRESSING THESE WE

EFFECTED MICE WITH A HIGH DOSE

OF TB AND TREATED THEM WITH A

CONTROL OR AN INHIBITOR AND THIS

IS A DRUG THAT HAS BEEN USED IN

CLINICAL TRIALS FOR CANCER SO

THE GOOD THINGS HERE IS IT CAN

BE REPRE POSED.

AND WHAT I FOUND IS THAT WE HAD

TO SPEED OUR EXPERIMENT BECAUSE

BY DAY 25 THE MICE TREATED WITH

THE AXL INHIBITOR WERE STARTING

TO DIE.

AND WHEN WE EUTHANIZED THESE

MICERS THERE WAS NO CHANGE IN

THE LUNGS OF THE MICE AND THE

MICE TREATED WITH THE INHIBITORY

THEY HAD MILE OWE CELLS AND IN

PARTICULAR, NEUTROPHILS SO WE

HAD THE KNOCK OUT MICE IN THE

LAB AND AGAIN, NO CHANGE IN WHEE

HAVE THEM THREE WEEKS POST

INFECTION BUT THEY HAVE WAY MORE

SPECIALTY IN THE LUNGS AND WHEN

WE MEASURED THE CD4 AND CD8 BY

ACTIVATING THE CD4 CELLS WITH

PEPTIDES AND SPECIFIC PEPTIDES

WE SEE HERE THAT CD4s

EXPRESSWAY MORE GAMMA AND TNF

ALPHA AND THIS IS THE KNOCK OUTS

MICE AND CD8 CELLS WHEN

ACTIVATED WITH SPECIFIC PEPTIDES

AS WELL THEY ARE HIGHER AND THE

MAJOR PHENOTYPE IS THAT HUGE

INCREASING IN THE LUNGS OF THESE

MICE SO YOU CAN SEE HERE.

ASSOCIATED WITH THAT, IT'S KNOWN

TO BE DID HE TELL INTEREST

DETRIMENTAL AND YOU CANSEE BY TD

THERE'S MORE KNOCK OUT MICE AS

WELL AS MORE KNOW TOE SIS AND AS

YOU CAN SEE BY THE GRAPH SO

WE'RE CONTINUING TO WORK ON THAT

TO ACTUALLY ASSESS WHICH ARE THE

MECHANISMS INVOLVED IN THIS

HIGHER INFLAMMATION AND IF NETS

ARE REALLY CONTRIBUTING TO THE

DAMAGE TO THE LUNGS OF THESE

MICE AND WITH THAT WE EXPECT TO

PINPOINT SPECIFIC MEDIATORS WE

CAN TARGET TO DEVELOP NEW STRAT

GOES FOR TREATING THESE MICE

WITH THAT, THESE ARE VERY

PRELIMINARY DATA THAT I'M

SHOWING HERE THAT I'M STILL

START TO GO DEVELOP IN BRAZIL.

I WOULD LIKE TO THANK ALL THE

LAB MEMBERS AND MY LAB MEMBERS

FOR THEIR SUPPORT AND WITHOUT

WHICH I WOULD NOT START THIS AND

ALAN SHER AND THE LAB MEMBERS

AND BRUNO AND THEY HAVE ALWAYS

PARTICIPATED A LOT IN THE

DEVELOPMENT IN THIS PROJECT AND

ALAN AS EVERYBODY HERE ALREADY

MENTIONED HIS SUPPORT WAS

CRITICAL FOR ME AND IT SEEMS

LIKE I CAME TO THE NIH UNTIL I

LEFT IT WAS CRITICAL FOR ME TO

CHANGE MY WAY OF THINKING

SCIENCE AND ALAN IS VERY

CRITICAL ATTENTION OF MAKING YOU

LEARN STUFF AND ESPECIALLY

TEACHING YOU HOW TO WRITE.

SO ALONG THE HOT SEATS I HAD TO

WRITE PAPERS OR EVERYTHING, I

THINK MY ENGLISH SKILLS AND

WRITING SKILLS IMPROVED

EXPONENTIALLY SO AS I SAID,

ALAN'S TOUCH TO FACILITATE OUR

COLLABORATIONS WITH OTHER PEOPLE

IN THE FIELD AS WELL AND THEY

HAVE BEEN VERY IMPORTANT AND HIS

COLLABORATION HAS BEEN AND

CONTINUES TO BE VERY IMPORTANT

FOR THE DEVELOPMENT OF THIS WORK

AND I EXPECT THAT YOU CONTINUE

TO HAVE YOUR SUPPORT AND BE ABLE

TO CHAT WITH HIM WITH THE

RESULTS HAVING HIS INPUT AND

EVERYTHING BECAUSE I KNOW THAT'S

"REAL LIFE" CCRITICAL FORT DEVEE

WORK.

THANK YOU, EVERYBODY.

[APPLAUSE]

>> SO MANY FASCINATING

OBSERVATIONS.

I GUESS I'LL START FROM THE LAST

SECTION.

SO IN THE ACTION I WILL KNOCK

OUT MICE, DO YOU HAVE A DEFECT

IN NITRIC OXIDE WE ALSO TRIED TO

SEE IF THERE'S A DIFFERENCE IN

THE AXLE POSITIVE AND NEGATIVE

CELLS REGARDING THE INS

EXPRESSION AND WE FOUND THAT

POSITIVE CELLS ARE DOING AND

SPECIFICALLY THAT IS HAPPENING

AND OR IF IT'S JUST MORE AND

MORE CYTOKINES OR IF THERE'S A

ROW FOR AXL IN MODULATE

SOMETHING KIND OF SPECIFIC

NECROSIS TYPE OF DEATH OR SO

WE'RE STARTING TO INVESTIGATE

THAT NOW BUT I THINK THE MOST

LOGICAL THING TO THINK BY NOW IS

THAT IT'S A FAILURE TO CLEAR

CELLS.

DO YOU KNOW IF IT'S CELL

AUTONOMOUS?

>> MEANING YOU KNOW, IF
YOU MADE

A CHIMER IT ONLY OCCURS?

>> SO I DON'T REALLY KNOW
MANY

OF THAT'S ANOTHER THING WE'RE

TRYING TO SEE.

WE ACTUALLY GOT THE AXL FLUXED

MICE THAT WE'RE BREEDING WITH

SOME LINES SO WE WILL TROY TO

DELETE CELLS AND THE MAIN WOULD

BE THE MACROPHAGES.

>> I AM ASSUMING THAT THE
TRYING

TO PROTECT THIS CELL FROM THE

RIGHT INDUCTION AND SO -- IT'S

HANIN ZOABI HYOU CAN COMPLETE T.

>> YES.

DEFINITELY.

THANK YOU FOR THE EXCELLENT

TALK.

BOTH THE MACROPHAGE AND THE BUG

NEED IRON AND I COULDN'T QUITE

TELL WHETHER YOU DISTINGUISHED

BETWEEN THE REQUIREMENT OF

EITHER OF THE BUG FOR IRON IN

YOUR SYSTEM?

>> RIGHT.

YEAH, SO, THAT'S THE PROBLEM OF

MISSING WITH IRON METABOLISM AS

A WHOLE, RIGHT.

SO IRON IS CRITICAL FOR PART OF

GROWTH AND BUT TB SPECIFICALLY

IS A LITTLE BIT MORE RESISTANCE

TO IRON DEPRIVATION THAN OTHER

SPECIES OF MICRO BACTERIA FOR

EXAMPLE AND MICRO BACTERIA IS

VERY, VERY SUSCEPTIBLE AND IF

YOU EFFECT MICE LA LACK IT WILL

PUT IRON INSIDE THE PHAGO SOME,

THE MICE PROSECUTE GOING TO BE

RESISTANT TO AVIAN BUT NOT TO

MTV FOR EXAMPLE.

AND DEFINITELY IT'S A TWO-HEADED

SWORD.

IF I LIMIT IRON I'LL BE STARVING

THE BUGS AND I MAY BE I'M ALSO

GOING TO BE MAKING THE

MACROPHAGES WORK BETTER SO THEN

THERE'S ANOTHER POINT SO IN

STUDYING THE EYE OWN HOMEOSTASIS

ITSELF, IT'S TRICKY FOR US TO

DEAL, THIS IS GOING TO CAUSE

OTHERS PROBLEMS, RIGHT.

THIS IS GOING TO CAUSE ANEMIA

AND SEVERAL OTHER STUFF OR LET'S

INDUCE A LOT OF -- IT WILL MESS

UP WITH THE WHOLE BODY OUR

HOMEOSTASIS SYSTEM AND THE POINT

YOU ARE USED TO ACTUALLY FIND

WHICH ARE THE MODULATING THIS

AND STRETCH THE TARGET THEN AND

FOR EXAMPLE, IF TOO OFTEN IT'S A

GO AHEAD ONE, BECAUSE ALSO WE

HAVE THESE THAT HAVE BEEN USED

ALREADY IN CANCER TREATMENT AND

IT CAN BE EASILY REPO POSED FOR

TB SO WE'RE TRYING TO THINK AND

IDENTIFY THAT CAN BE TARGETED.

IF YOU REAL WITH IRON ALONE,

IT'S GOING TO BE A MESS, I

GUESS.

>> SO IT SOUNDS LIKE YOU
ARE NOT

ENTHUSIASTIC ABOUT DEVELOPING

SNPP9 AS A CLINICAL AGENT.

>> WE HAVE COLLABORATION
THAT

PEOPLE HAVE BEEN TRYING TO --

OUR INHIBITORS OF H-O01 AND THEY

CAN'T USE IT FOR A LONG TIME AND

IT HAS TO BE SHORT TERM.

>> ONE LAST QUESTION,
THERE'S

IRON DEFICIENCY IN THE THIRD

WORLD, IS THERE ANY DATA

ASSOCIATING BETTER OUTCOMES IN

TB PATIENTS THAT ARE IRON

DEFICIENT?

>> YES, SO IT VARIES A
LOT.

THERE ARE SOME VERY OLD PAPERS

THAT ALREADY SHOW IN THE 1800S

THAT PATIENTS THAT HAVE BEEN

SUPPLEMENTED WITH IRON WOULD

HAVE A WORSENING OF THE HE HAVE

EFFECTS OR IT WOULD FAVOR THE

DISSEMINATION BECAUSE MAINLY YOU

HAVE THESE RETENTION OF IRON IN

THE LIVER AND IN THE SPLEEN, SO

IT FAVORS THE DISSEMINATION OF

BACTERIA.

THERE ARE NOT SO MANY NEW

STUDIES ON THIS CASE THEY'RE

MAJORLY OLD STUDIES.

>> I AM BUILDING ON PHIL'S

QUESTIONS ABOUT IRON REGULATION.

IT'S ALSO THOUGHT TO PLAY A ROLE

IN THE OBESITY EPIDEMIC IN NASH

WITH HELP SIDE AND I THINK

LEVELS DECROWS CREASING AND LEAO

HIGH GROW SIS SO I'M CURIOUS

WHAT IS THE CORRELATION SORRY

CONNECTION BETWEEN OBESITY AND

NASH AND SEVERITY OF TB?

>> IS THAT KNOWN?

>> I KNOW LIKE THERE ARE
SOME

DATA SHOWING THAT OBESITY IS A

RISK FACTOR FOR TB, RIGHT.

SO ACTUALLY WE JUST SUBMIT AID

PAPER IN AN EXPERIMENTAL MODEL

WHERE WE FEED HIGH-FAT DIE ITS

FOR THESE HIGHS IT'S NOT SO BAD

FOR BACK ROLE AND IT TRIGGERED

BECAUSE OF THESE LIP ITS AND

THERE'S GOING TO TRIGGER INFLAM

OWE SOMEONE'S AND IT MAKES IT

WORSE SO FOR OBESITY IT'S BA%

úFOR TB BUT MAINLY BECAUSE OF

THESE HIGH INFLAMMATION THAT IS

GENERATED.

>> COOL.

NICE WORK.

>> THANK YOU.

>>

[APPLAUSE]

[OFF MIC]

>> IT'S ALWAYS TREATED BY

ANTIBIOTICS.

>> THANK YOU.

>> ALL RIGHT.

SO NEXT SPEAKER IS NICOLAS

RITEAU HE IS FROM FRANCE AND

PLEASE.

>> THANK YOU, VERY MUCH.

FIRST I'D LIKE TO THANK DRAGANA,

LIKE ALL THE OTHERS, FOR

ORGANIZING THIS REALLY NICE

SYMPOSIUM SO I WAS A POSTDOC IN

ALAN'S LAB FROM 2012 TO 2017 AND

SOME OF THE PEOPLE I KNEW IN THE

LAB AND IT'S A GREAT OCCASION

AND IN ANY CASE TO MEET A LOT OF

PEOPLE AND IN FRANCE SO ONCE

AGAIN THANK YOU VERY MUCH.

SO, DURING MY TIME AT ALAN'S LAB

I WORK MAINLY ON CONTEXT OF

VACCINES AND NOW WHAT I'M GOING

TO PRESENT TO YOU IS MORE

STEROID INFLAMMATION AND MODEL

IN THE CONTEXT OF THE ROLE OF

STING IN THIS DAY SO I'M SENIOR

SCIENTIST IN FRANCE AND SO IN

ADDITION TO THE CLASSICAL MODEL

OF INNATE IMMUNITY, AND FIRST

DESCRIBED BY JANEWAY WE HAVE

PATHOGEN RECOGNITION AND

RECEPTORS AND THAT ARE GOING TO

DRIVE IMMUNO ACTIVATION AND

REGULATION AND MATT SINGER IN

ABOUT 28 YEARS AGO SAID.

>> AND ATP AND THROUGH
RECEPTIVE

2X7 BUT WE'RE NOW IN LINE WITH

THE RECENTLY WE TRIED TO SENSING

AND AND ESPECIALLY THE STING

PATHWAY SO THIS IS BRIEFLY

MENTIONED YESTERDAY BY JASMINE

AND THIS STING WAS FIRST

DESCRIBED IN 2008 AND THE

CONTEXT OF INFECTION AND SO THIS

BINDS TO FORMED THEY GO THE IN

THTHTHE CYTOPLASM AND.

>> SO YOU CAN OTHER AND OR
AND

DEPENDING ON HOW LONG AND YOU

ENVIRONMENT AND SIGNAL AND WHERE

YOU WANT TO TREAT AND.

>> YOU CAN SEE THERE ARE
MANY

CELLS EXPRESSING STING AND IT IS

EXPOSED BY MANY DIFFERENT CELL

TYPES AND SO AT FIRST WE SAW

THAT IF WE WOULD REMOVE STING,

WE WOULD HAVE LESS PATHOLOGY AND

IT'S WHAT WE HAVE SEEN WHEN WE

REMOVED INNATE MEDIATORS AND

PROTEINS THAT ARE IN PATHWAYS

SUCH AS THE INFLAMOSOME AND WE

HAD A DECREASED PATHOLOGY AND

EVERYTHING IS BY HOST IF YOU

REMOVED ONE OF THE PATHWAYS YOU

HAVE LESS INFLAMMATORY AND

FIBROSIS AND WE GOT REALLY

EXCITED WHEN WE REMOVED STINGS

AND WE USED STING KNOCK OUT

ANIMALS WE HAD AN INCREASE IN

THE CLINICAL SCORE OF THE

ANIMALS AND INCREASED WEIGHT

LOSS AND THE AND AND IN THE LUND

THEY'RE FREQUENT AND THEIR

PHENOTYPE IS ALTERED AND SO WE

LOOK AT DIFFERENT MARKERS AND WE

WERE ABLE TO SHOW THAT THE IMAGE

CLASS 2 EXPRESSION OF

NEUTROPHILS IS DECREASED

COMPARED TO THE WILD TYPE

NEUTROPHILS SO WE DO KNOW

EXACTLY WHAT IT MEANS BUT WE CAN

SOMEHOW BE RELATED WITHOUT IT AW

AN INCREASE THIS TYPE OF

EXPRESSION IN COMPARED TO THE

WILD TYPES AND THIS CAN BE

LINKED MAYBE TO INCREASED

EXPRESSION AND THEY'RE PAPERS

SHOWINTHAT THEY'RE CONNECTIONS

BETWEEN WHERE THE INDUCTION OF

TYPE ONE INTER NEURONS AND A FEW

PAPERS SHOWED IT'S HAPPENING IN

OTHER COULD BE TEXT THAT IT'S

REALLY IMPORTANT ALSO BECAUSE

TH17 CELLS AND I17 IS A DRIVER

OF THIS MODEL AND IT'S A PAPER

THAT TOM WYNN PUBLISHED ABOUT 10

YEARS AGO SHOWING THAT IL-17 IS

IMPORTANT TO DRIVE PATHOLOGY BUT

HERE WE DIDN'T SEE ANY

DIFFERENCE COMPARING WILD TYPE

MICE AND KNOCK OUT ANIMALS AND

TREATED WITH ROW HIGH SINCE SO

IT'S REPRESENTATIVE AND CD4

POSITIVE T CELLS IN THE LUNGS OF

SALINE CONTRA MICE SO ALMOST NO

IL-17 AND AFTER THERE'S AN

INDUCTION OF IL-17 PROGRESS

CELLS BUT NO DIFFERENCE

COMPARING WILD TYPE AND STING

KNOCK OUT ANIMALS AS QUANTIFY

HERE BY IL-17 POSITIVE CELLS OR

THE TOTAL NUMBERS OF THESE CELLS

AND SO THEN WE MOVED AND WE ARE

NOW REALLY INTERESTED IN TYPE 3

INTER NEURONS OR IL28 AND 29 AND

THEY ARE AT LEAST NOW MORE THAN

THAT FIVE OR SIX MORE PAPERS

SHOWING YOU CAN HAVE TYPE 3

INDUCTION DOWNSTREAM OF STING SO

IT'S LESS KNOWN THAT THEY ARE

DISCOVERED IN 2003 AND THEY ARE

FOUR INTERFERON IN HUMANS ONLY

TWO IN MICE AND THEY ARE REALLY

ABUNDANT AND IN TRACT AND THEY

SHARE A UNIQUE RECEPTORS AND

WITH ONE CHAIN OF THE I L-10

RECEPTORS AND THIS SIGNALING

DOWNSTREAM IS VERY SIMILAR TO

THAT OF TYPE 1 NEURONS AND THEY

CANNOT INDUCE THE SAME ISGs SO

IT SOUNDS EXPRESSING AND THE

EVERYTHING AROUND REALLY THE

ACTUAL DEFERS AND IT'S BEEN MANY

STUDY AND IDEA IS WHEN YOU HAVE

AND BY MOSTLY THE CELLS AND THEN

IF IT'S EFFECTIVE, YOU WOULD

HAVE LESS TYPE 1 INDUCTION AND

PATHOLOGY SO THESE ARE THE

PRELIMINARY DATA BUT WE WERE

ABLE TO SHOW THAT THERE IS AN

INDUCTION OF I28 IN THE LONG OF

WILD TYPE MICE TREATED WITH A

PARTIAL REDUCTION WHEN WE LOOKED

IN ANIMALS AND THE CASE IN THE

TYPE 1 KNOCK OUT ANIMALS AND

IT'S SHOWN HERE BY WESTERN BLOCK

AND THERE'S LESS EXPRESSION IN

THE KNOCK OUT AS COMPARED TO THE

WILD TYPES.

SO THAT'S OUR WORK HYPOTHESIS AT

LEAST IN LINE WITH TYPE 3

INTERFERON WHICH DOWNSTREAM OF

STING THIS WITH BIND TO

SELECTIVELY EXPRESS RECEPTORS ON

THE CELLS ON NEUTRAL AND THIS

CAN SOMEHOW RETURN AND AND EVENT

LOW THE FIBROSIS AND WE ALSO

KNOW WE ARE INTERESTED IN LOOK

AT A SO I DIDN'T SHOW YOU

DOWNSTREAM BUT IT'S INVOLVED IN

MANY DIFFERENT PROCESSES

DEPENDING ON THE CELL TYPES AND

CONTEXT AND I HAVE THREE

ACTIVATION AND MENTIONED BUT

ALSO MORE CELL DEATH ESPECIALLY

IN AUTO PATH GEE AND ALSO, WE DD

THE EXPRESSION LEVEL AND AND

IT'S REALLY HARD AND PATHWAY AND

WHAT WE SEE HERE IS WE HAVE

INDUCTION OF THIS AUTOPHAGY IN

THE WILD TYPE MICE TREATED WITH

NOT THE CASE IN SING ANIMALS BUT

WE ALSO HAVE A STRONG INDUCTION

OF P62 IN WILD TYPE MICE THAT

WOULD INDICATE MORE LIKE

DECREASED OR LIKE A BLOCKED SO

IT'S NOT COMPLETELY CLEAR HOW

THIS HAPPENS BUT IMPORTANTLY

THIS IS ALSO CRITICALLY

DECREASING IN ANIMALS SO THERE'S

SOMETHING THAT WE WOULD LIKE TO

PURSUE AND SEE WHETHER THIS

PATHWAY CAN BE WHAT IS DRIVING

THE PROTECTION OF DOWNSTREAM OF

STING AND THIS IS RELEVANT IN

THE TEAM IT'S BEEN SLOAN THAT IT

PROTEINS ARE DECREASED IN

PATIENTS AND THAT FEARS AND

DEROGATION IN MOUSE AND SURVIVAL

AND WHEN IT'S LINK THE TO CELL

SIGNIFICANCE AND EFFICIENT MICE

AND THEN PEOPLE HAVE SHOWED THAT

THIS MICE DID I PLAY INCREASED

FIBROSIS AND SO, THIS AND MY

LAST DATA SLIDE AND WE ARE NOW

ALSO TRYING TO SEE WHETHER WE

CAN ACT RATE IS STING SO WE'RE

USING THIS REALLY STRONG

IMPORTANT AND IN THIS PARTICULAR

EXPERIMENT, ONE SINGLE

ADMINISTRATION OF DIABZ7 WAS

ENOUGH TO REDUCE FIBROSIS WITH

THE SCORE AND ALSO, THE COLOGIN

CONTENT SO IT'S SOMETHING THAT

WE ARE REALLY INTERESTED IN AND

WE'RE GOING TO PURSUE SO THE

GENERAL IDEA IS THAT IT'S KNOWN

TO CREATE A LOT OF CELL THERE'S

NOT IN DNA DAMAGE AND DNA

RELEASE AND SO THIS WOULD NEED

TO AN INCREASE OF MIGHT TOE AND

IN THE PLUS UM ACTIVATING AND

THE OTHER SENSORS AND THE

INDUCTION THAT COULD BE

BENEFICIAL AND ALSO STING CAN BE

PART OF THIS PROCESS AND WE HAVE

A COUPLE OF QUESTIONS THAT WE

ARE TRYING TO ADDRESS AT THE

MOMENT AND THE TYPE OF ACID AND

AND MAYBE SOME OF THEM ARE

INTERESTING TO LOOK AT AND ALSO

I WOULD GAIN ACCESS TO THE SITE

AND IT'S SOMETHING REALLY

IMPORTANT IN THE FIELD BECAUSE

YOU HAVE CELLS AND DNA FLOATING

AROUND, HOW CAN IT COME TO THE

SO IT'S NOT SOMETHING THAT WELL

ASK THERE'S A BIG BLACK BOX HERE

AND AND ALSO, IF WE CAN ACTIVATE

STING AND SEE IF CAN BE

BENEFICIAL OF THE FIBROSIS AS

WELL AS THE EFFECT OF TYPE 3

INTERFERON AND THE AUTO IF GEE

AND SO THESE ARE THE PEOPLE IN

MY LAB THAT ARE LED BY ISABEL

AND THE DIRECTORS OF I KNOW ALAN

KNOW THEM REALLY WELL AND I USED

TO WORK WITH TB FOR MANY YEARS

AND HOW I GOT TO KNOW ALAN AT

FIRST AND I'D LIKE TO SHARE A

FEW PICTURES SO I TOOK WHEN I

WAS A POSTDOC AND LIKE MANY

OTHERS, I THINK IT HOTSEAT IS

SOMETHING THAT SOME WOULD CALL

IT PAINFUL AND YOU TOOK MANY

TIME AT EVERY OCCASION IT WAS

LIKE A 15-LINE ABSTRACT IT WOULD

TAKE ONE AFTERNOON TO GO SO I

WAS ABLE TO SPEAK TO HIM A

COUPLE OF TIMES DURING THE

HOTSEAT SO I DON'T HAVE ALL OF

THE PEOPLE THAT WERE AROUND BUT

I GOT MANY OF THEM SO KEN AND

TOSH, PH.D STUDENT IN THE LAB

AND I ALREADY SHOWED THIS

PICTURE SO THIS WAS THE NATURE

PAPER AND IN PROGRESS TOO AND

DRAG AN SA, NO EXCEPTION.

HOTSEAT IS NOT ONLY FOR FELLOWS

IT'S EVERYBODY HAD TO GO THERE

SO THIS IS WHEN IN DRAGANA SAME

SO YOU CAN -- YEAH.

JACKIE.

YEAH.

IT'S THE ONLY ONE WHERE HE IS

SITTING AND WRITING SO I DON'T

KNOW WHAT WAS GOING ON HERE BUT

SEE THE KIND OF SURPRISE BECAUSE

IT WAS NOT UP ANDIST LEAVING.

WHAT ARE WE DOING?

I'M HAPPY I DID IT AND IT'S THE

ONE I TOOK IN (INAUDIBLE).

A FEW YEARS AGO AND SO ALTHOUGH

I'M FRENCH I'M NOT BRAZILIAN, MY

WIFE IS BRAZILIAN AND IT WAS MY

GREAT PLEASURE TO BE SURROUNDED

BY SO MANY BRAZILIAN PEOPLE AND

BE ADOPTED BY THEM SO I'M REALLY

GRATEFUL THAT I'VE BEEN IN THIS

ENVIRONMENT AND OF COURSE, MANY

OTHER PEOPLE ALYSE, THAT WE'RE

PART OF THE COMMUNITY AND THE

CHILDREN OF ALAN AT THE TIME I

WAS THERE AND WE ALSO REALLY

GRATEFUL THAT WE HAVE BEEN

INVITED AND WONDERFUL BARBECUES

AND ALSO THANKSGIVING PARTIES

WITH ALAN AND STEPHANIE AND I'VE

ALSO KNOWN IN FACT WITH MANY

GOOD FRIENDS IN DIFFERENT LABS

SO THAT IS ALAN AND YOU KNOW HIM

SO LIKE YESTERDAY, THERE WERE

TWO OTHER FRENCH PEOPLE IN THIS

ROOM, AT LEAST TWO AND ALAN

WANTED TO MACK SURE THAT I WOULD

INTERACT AND GET TO KNOW THEM SO

OH YOU DON'T KNOW, COME!

SO NOW I KNOW ISABEL AND DANIEL

BUT IT'S SOMETHING THAT ALAN

WOULD DO WITH EVERYBODY.

IT'S NOTHING SPECIAL.

IT IS A PICTURE, A BLURRY ONE,

FROM THE TYPE INTERFERON

KEYSTONE MEETING AND JUST TO SAY

IN ADDITION TO BE A GREAT

MENTOR, AND TO BE AND I'M

GRATEFUL HE HIRED ME HE IS A

GREAT HUMAN BEING AND I'M HAPPY

TO BE HERE TODAY.

THANK YOU, VERY MUCH.

[APPLAUSE]

>> DO YOU WANT TO ASK A

QUESTION?

>> SO, OK.

>> SO NUR ANALYSIS OF THE

INCREASE DISEASE IN THE ABSENCE

OF STING THE NEWT TRA FILL

RESPONSE WAS DRAMATIC AND

SUSTAINED SO I'M CURIOUS ABOUT

HOW YOU ARE FOLLOWING UP ON THAT

AND THAT THE INCREASE CURE ARE

YOU CERTAIN THAT WAS SAT A SOL I

CAN OR MIG MIGHT OW -- THERE'S W

APPRECIATION IT'S INCREASE NORTH

VARIOUS CELL TYPES SO A CHANGE

IN THE METABOLIC CHANGE OF THE

CELLS AND IT'S INTERESTING

BECAUSE SYNTHESIZES SUBSTRATES

THAT CAN INCREASE FIBERROSIS.

>> THAT'S A GOOD POINT.

WE DID IT BY FLOW.

SO I DON'T KNOW WHETHER IT WAS

FROM THE MITO IS IT'S SOMETHING.

>> IT WOULD BE INTERESTING
TO DO

A WHOLE MORE SINGLE CELL

ANALYSIS OF THAT BECAUSE THERE

IS A LOT OF INTEREST TO THE CD9

POSITIVE SCAR ASSOCIATED MAX AND

THEY'RE THOUGHT TO BE PROFANE

ROT TICK SO THERE'S A NEWT TRA

FILL PART OF THAT.

>> YEAH, YEAH.

>> IT'S SOMETHING THAT WE
ARE

REALLY SURPRISED WITH AND REALLY

INTERESTED BUT I DON'T KNOW

WHETHER IT'S THEY'RE JUST IF

IT'S ALSO LIKE COMING OF THE

PERSIST AND HOW MUCH IT'S

RELATED TO OTHER THINGS THAT ARE

GOING ON AND THAT LEAD TO THIS

PERSISTENCE OR REALLY THEY'RE

PARTICIPATING IN THE DISEASE SO

IT'S SOMETHING THAT I DON'T

KNOW.

>> AND YOUR SNAPSHOT OF
IL-17

DID YOU LOOK A SINGLE TIME

POINT.

>> I DID TWO TIME POINTS
SO IT'S

THE 8 AND I ALSO HAVE A LATER

TIME POINT AND IT WAS NO

DIFFERENCE.

>> THANK YOU.

>> I'LL ASK THE LAST
REQUEST

QUESTION.

SO HOW DO YOU THINK THE ROLE OF

TYPE 3 INTERFERON REGULATING

NEUTROPHIL RESPONSE IN THIS

MODEL?

>> IN THIS MODEL I DON'T
KNOW

BUT IT'S BEEN SHOWN IN TWO OTHER

MODELS AND ONE PAPER SHOWED THAT

IL-28 CAN LIMIT THE NEUTRAL

MIGRATION SO THE SKIN AND THE

OTHER ONE SAID THAT IN THE GUT

IT'S NOT THE CASE AT ALL.

IT DOESN'T CHANGE BUT IT'S

EFFECTIVE FUNCTION OF NEWT TREE

FILLS THAT ARE EFFECTED WITH

LESS WHEN YOU HAVE IL-28 SO IT'S

NOT SURE WHAT IT'S DOING.

I THINK IT HAS MULTIPLE ROLES.

>> ALL RIGHT.

THANK YOU.

>> THANK YOU.

>[OFF MIC]>> IN THE
MOUSE YOU HS

PATHOLOGY.

WITH THE GR1 AT LEAST.

[APPLAUSE]

>> SO, LAST SPEAKER AND
KEVIN

SCHENDEROV.

DRAGON A, THANK YOU FOR IN

INVITING ME TO SPEAK.

IT'S REALLY A GREAT HONOR TO BE

HERE WITH SO MANY LUMINARIES

FROM WITHIN LPD OUTSIDE LPD

STANDING AT THIS PODIUM IT'S

INCREDIBLE TO BE HERE AND SO

GRATEFUL TO BE INVITED.

YOU KNOW, TONY PUT THIS AS A

FAMILY REUNION AND I ACTUALLY,

YESTERDAY AND THIS MORNING I WAS

THINKING THE EX ACTS SAME

PHRASING THIS REALLY DOES FEEL

LIKE COMING HOME TO A FAMILY TO

BE AMONG AWFUL YOU AND IT'S SO

GRATEFUL TO SEE EVERYONE HORNING

ALAN AND USUALLY ALAN IS NOT THE

CENTER OF ATTENTION BECAUSE AS

ALAN'S TRAINEE, I HAVE FELT AND

I KNOW SO MANY OTHERS HAVE SAID

THE SAME THING THAT HE ALWAYS

PUT US FRONT AND CENTER AND THAT

HE WAS ALWAYS SUPPORTING US AND

HELPING US AND INTERROG INTRODUO

OTHERS EVEN YESTERDAY AT

RECEPTION, ALAN'S HONOR, HE WAS

INTRODUCING US TO OTHER PEOPLE

SO I KNOW THAT THIS IS PROBABLY

COUNTER TO YOUR NATURAL AN BUT

I'M GLAD WE'RE TAKING THE TIME

TO REALLY TALK ABOUT EVERYTHING

THAT YOU'VE DONE FOR ALL OF US

AND THIS IS OF COURSE FROM LAST

NIGHT AND AS CARL MENTIONED, I

WAS A GRAD STUDENT WITH ALAN

FROM '07 TO 2012 I CAME TO HIM

BEING INTERESTED IN WORKING ON

TH17 CELLS AND HE GRACIOUSLY

TOOK ME ON AND EVEN THOUGH HE

WAS BASICALLY WITH PTDOCS OR

MUCH MORE EXPERIENCED THAN I WAS

AT THE TIME IN THE LAB AND HE

WAS WILLING TO HUMOR ME AND

TRAIN ME AND TEACH ME SO MUCH

ABOUT SCIENCE AND HOW TO CRAFT

EXPERIMENT AND HOW TO WRITE

PAPERS AND EVEN AFTER I LEFT THE

LAB, HE HAS BEEN SO SUPPORTIVE I

WENT TO HOP TINS FOR MEDICINE

SCHOOL, ALAN CAME TO MY

GRADUATION AND SINCE THEN I'M

BACK IN THE RESEARCH WORLD AS

SAY FELLOW AND PULL LYNN ARY

CRITICAL AIR AND I'M APPLYING

FOR A GRANT AND RECENTLY AND

VERY HELPFULLY SUGGESTED THAT I

SPEAK TO EDMONTON PEARCE WHEN

EDMONTON PEARCE CAME AND MY

CURRENT MENTOR IS LEAVING

HOPKINS AND ED IS GRACIOUSLY

TAKING ME ON SO ALAN HAS BEEN

HELPING ME EVERYWHERE ALONG THE

WAY WHEN I WAS IN HIS LAB TO

CURRENTLY AND MY WIFE AND I HAD

A SON 16 MONTHS AGO NOW AND ALAN

ALSO IS THERE AT HIS PANDEMIC

ZOOM BIRTHDAY PARTY AND

GRACIOUSLY PUTTING UP WITH THE

BIBBY SHARK VIDEO THAT WE WERE

WATCHING AND SO ALAN HAS BEEN SO

MUCH MORE THAN JUST A COLLEAGUE

AND A MENTOR AND YOU HAVE BEEN

REALLY A FRIEND TO US AND THANK

YOU SO MUCH, ALAN.

GETTING TO THE SCIENTIFIC PART

I'M GOING TO TALK ABOUT WORK

RELATED TO ACUTE RESPIRATORY

DISTRESS SYSTEM SO I'M DOING

TRAINING SO I SPENT IN THE

ICUs AND THIS IS A CONDITION

WE TREAT REGULARLY AND

ESPECIALLY RECENTLY WITH THE

COVID PANDEMIC AND SO ARDS IS

DISEASES CALLED IN L AS AN

ACRONYM WAS FIRST DESCRIBED IN

1967 IN THE STUDY IN THE LAND

SET IN A DOZEN PATIENTS WITH

RESPIRATORY FAILURE FOR VARIOUS

REASONS AND SINCE THEN WE'VE

REALIZED THAT AIRDS CAN OCCUR

DUE TO DIRECTOR INDIRECT LUNG

INJURY FOR ANY NUMBER OF CAUSES

THAT EFFECT ABOUT 200,000

INDIVIDUALS IN THE U.S. AND A

FEW MILLION WORLDWIDE EACH YEAR

AND UNFORTUNATELY WE'RE TERRIBLE

AT TREATING IT.

WE REALLY HAVE VERY HIGH

MORTALITY DESPITE BEST ICU CARE

30% TO 40% OF ERS DIE OF MULTI

ORGAN FAILURE PRIMARILY AND JUST

TO GIVE AN IDEA OF WHAT IT LOOKS

LIKE, THIS IS A NORMAL X-RAY.

THE LUNGS LOOK DARK AND YOU DO

HAVE TO BE A PULL MINUTOLOGIST

TO SEE THE LUNGS LOOK WHITE AND

SO REALLY DIFFUSED LUNG INJURY

AND I ALLUDED TO MANY DIFFERENT

CLAUSES BUT JUST TO SPECIFY A

FEW OF THEM IN TERMS OF DIRECT

LUNG ENTRY AND PNEUMONIA AND

SEVERE COVID-19 LEADING TO

PNEUMONIA AND AS SIRRATION AND

TRAUMA TO THE CHEST AND NEAR

DROWNING AND ALSO INDIRECT LUNG

INJURY AND NON NA MOAN KA CAN

CAUSE ARDS IN ADDITION TO NA

KNOWNIA AND THEY CAN CAUSE ARDS

AND REALLY ARE CARE FOR ARDS IS

SUPPORTIVE SO PEOPLE HAVE

SIGNIFICANT HIGH POXEMIA, LOW

LEVELS OF OXYGEN SO WE PUT THEM

ON VENTILATORS AND BREATHING

MACHINES TO HELP SUPPORT AND WE

HAVE LEARNED THAT YOU HAVE TO

USE A VENTILATOR IN A SPECIFIC

WAY.

WE CALL IT LUNG PROTECTIVE

VENTILATION AND LOW TITLE

VOLUMES TO REDUCE TRAUMA FROM

PRESSURE AND OVER DIS TENSION OF

THE LUNGS AND WE'VE ALSO FOUND

THAT CERTAIN PATIENTS BENEFIT

FROM PRONING, TURNING THEM ON

THEIR BELLY NOW THAT I HAVE A

KID I CALL IT TUMMY TIME AND WE

LEARNED YOU HAVE TO BE CAREFUL

OF THE A FLUID YOU GIVE THESE

PATIENTS BUT THERE'S NO

PHARMACOLOGICAL THERAPY FOR

ARDS.

WE DO KNOW PATH OWE

PHYSIOLOGICALLY THAT ARDS IS

HIGHLY INFLAMMATORY SO THIS IS A

FIGURE SUMMARIZING WHAT WE KNOW

BUT IN THE INITIAL PHASE OF

ARDS, YOU GET ACTIVATION OF A

LOT OF THE INNATE IMMUNE CELLS

THAT WE ALL KNOW AND LOVE AND

THEY USE LOTS OF LOAN CYTOKINES,

REACTIVE OXYGEN PEE SEIZE AND

YOU GET LOTS OF BARRIER INJURY

TO THE BARRIERS AND MORE CELLS

COME IN FLUID COMES IN AND THE

VLI ARE FLOODED THAT WHY THE

LUNG IS WHITE AS I SHOWED YOU ON

THAT X-RAY.

IF MANY PATIENTS, IF YOU SUPPORT

THEM, THEN OVER TIME THEY WILL

HEAL AND THIS WILL ROW SOLVE

THERE'S A SHIFT IN THE

PHENOTYPES OF THE MACROPHAGES IN

THE LUNG AND THEY BECOME MORE

PRO RESOLUTION RATHER THAN PRO

INFLAMMATORY AND YOU HAVE A DROP

IN THE PRODUCTION OF CYTOKINES

AND BASICALLY THESE PRONE

INFLAMMATORY STIMULI RESOLVE AND

THERE'S HEALING AND

UNFORTUNATELY AS I SAID, 30% TO

40% OF PATIENTS DOES NOT HAPPEN

AND EVEN IN PEOPLE WHO DO HEAL A

LOT OF THEM HEAL IN A

DIS-REGULATED FIE BROTT TICK WAY

AND HAVE ARDS, EVEN IF PATIENTS

SURVIVE THEY CAN HAVE MORBIDITY

LATER ON.

PEOPLE HAVE TRIED KNOWING THIS

PATH OF PHYSIOLOGY VARIOUS

INFLAMMATORY THERAPIES AND

UNFORTUNATELY, THEY HAVE LARGELY

BEEN FAILURES SO STEROIDS

HAVEN'T WORKED OUTSIDE OF

COVID-19 AND ANTI-GMCSF, ALL OF

THESE HAVE BEEN FAILED CLINICAL

TRIALS AND SO THE THOUGHT BEHIND

THE WORK THAT I DID, I STARTED

THIS WITH JOHNATHAN POWELL AND

MAUREEN HORTON AT HOPKINS AND

WE'LL CONTINUE ED PEARCE IS

MAYBE WE'RE NOT TARGETING

INFLAMMATION THE RIGHT WAY SO

WE'RE INTERESTED IN IMMUNO

METABOLISM AND PEOPLE HAVE

REALIZED THAT THERE ARE PROFOUND

METABOLIC SHIFTS GOING ON IN

IMMUNE CELLS THAT'S AIR

ACTIVATED DEPENDING ON HOW YOU

ACTIVATE THEM AND THOSE

METABOLIC CHANGES ARE VERY

IMPORTANT FOR THEIR FUNCTION.

SO, WE HYPOTHESIZED THAT MAYBE

BY UNDERSTANDING SOME OF THE

METABOLIC CHANGES HAPPENING IN

ARDS, WE CAN FIND SOME

DIS-REGULATED METABOLIC PATHWAYS

SO THAT MAYBE WE CAN TARGET TO

TROY TO PROMOTE BETTER RECOVER

ROW FROM LUNG INJURY AND REDUCED

DETRIMENTAL INFLAMMATION SO OUR

APPROACH WAS TO SET UP MODELS OF

LUNG INJURY BECAUSE WE WANTED TO

FIND PATHWAYS THAT OCCURRED IN

MORE THAN ONE MODEL AND WE

DIDN'T WANT TO JUST FIND ONE

MODEL SPECIFIC PATHWAY AND SO WE

SET UP A FEW DIFFERENT MODELS

AND USING METABALOMICS, WE

MEASURED LEVELS OF A FEW HUNDRED

METABOLITES IN THE LUNGS OF

INJURED VERSUS UNINJURED MICE

AND SO JUST TO QUICKLY TELL YOU

THE MODELS WE USED, ONE IS A

BACTERIA MA KNOWNIA AND AND

EARLY ON AND.

>> TO MA LAB LOAM I CAN
AND IN

RED AND THESE AND DIFFERENT

BETWEEN THE DAMAGE LUNGS VERSUS

THE NAIVE MICE SO THIS IS IN THE

MODEL AND SO YOU CAN SEE MANY

METABOLITES ARE CHANGING AND IF

YOU DO A PRINCIPLE COMPONENT

ANALYSIS WE CAN SEE THE MICE

REALLY DO CLUSTER BASED ON THEIR

STATUS SO THESE ARE THE NAIVE

MICE AND THE INFECTED MICE AT

DIFFERENT TIME POINTS AND THE

MICE AR RESOLVING THE RESOLUTIOO

THEY GO BACK TO THE NAIVE MICE.

THIS IS A HEAT MAP SHOWING IS

THAT MANY OF THE METABOLITES WE

LOOK AT START OFF HIGH IN THE

NAIVE MICE SO EACH A IS A MOUSE

AND THE RED ARE NAIVE SO THEY

START OFF HIGH AND NAIVE AND

DROVE DURING INJURY AND START TO

RECOVER DURING LATER TIME POINTS

AND THEN ALSO, SOME METABOLITES

START LOW AND GO UP DURING LUNG

INJURY AND THEN START TO COME

BACK DOWN SO, THERE ARE BOTH

PATTERNS THAT WE SEE AND OF

COURSE, IT'S HARD LOOKING AT

LISTS OF THESE SO ONE THING WE

DID WAS LOOK AT PATHWAY ANALYSIS

AND YOU CAN SEE VARIOUS

METABOLICS PATHWAYS THAT ARE

CHANGING DURING LUNG INJURY WITH

STREP NOW MANY OWE AND YOU SEE

NUCLEOTIDE METABOLISM, AMINO

ACID, TCA CYCLE, ET CETERA.

WE BECAME INTERESTED IN TWO

SPECIFIC METABOLITES, MIO AND WE

SAW THAT ACROSS THE THREE LUNG

INJURY MODELS THEY HAD SIMILAR

CONNETICS SO IN ALL THREE

MODELS, BOTH WOULD DROP DURING

ACUTE LUNG INJURY AND THEN AS

YOU LOOK LATER THEY START TO

COME BACK UP.

SO, MANY OF YOU MAY KNOW

GLUTATHIONE IS A TRY PEP SIDE

AND REACTS WITH FRO RADICALS AND

THOSE CHANGE IT FROM A REDUCED

FORM TO SAY OXIDIZED FORM AND

INTERESTINGLY FOR A LONG TIME

ACTUALLY, PEOPLE HAD SHOWN THAT

THE LEVELS OF GLUTE A THIGH ON O

IT'S A LITTLE CHALLENGING TO

ACTUALLY USE THIS AS A TREATMENT

THOUGH BECAUSE IT'S NOT

INEFFICIENT WAY TO INCREASE SO

PEOPLE HAVE TRIED ALTERNATIVES

AND SO THERE WAS ACTUALLY A

COUPLE OF TRIALS IN PEOPLE USING

SISTINE KNACK WHICH IS PROVIDING

SISTINE IT'S AN AMINO ACID SO

IT'S THOUGHT IT WILL HELP

INCREASE IN OTHER COMPOUND WE

WERE INTERESTED IN IS IT'S A HAS

BETTER BIO AVAILABILITY AND CELL

PERMEABILITY AND ACTUALLY CAN

GET INTO CELLS AND IS CONVERTED

INTO REDUCED GLUTATHIONE AND THE

OTHER IS A SUGAR ALCOHOL THAT IS

A PRECURSOR USED IN INTRA

CELLULAR SIGNALING LIKE THE KAI

A NAS PATHWAY SO IT'S A PRE

CURSER OF A COMPONENT AND SUR

FALK TIN IS IMPORTANT FOR THE

LUNG AND TO REDUCE SURFACE

FUNCTION AND IT HAS A REGULATORY

ROLE AND IT'S BEEN SHOWN TO HELP

WITH INSULIN RESISTANCE AND ALSO

MOST RELEVANT TO WHAT WE SAW

WITH GLUTATHIONE IT HAS A ROLE

IN REDOX BALANCE.

IT CAN HELP WITH THE PHOSPHATE

PATHWAY SO WE ASKED A RELATIVELY

SIMPLE QUESTION SINCE THE MIO

INOS OWE TOLL AND LEVELS ARE LOW

IN THE MICE WITH ACUTE LUNG

INJURY,

WE TREATED MICE WITH EITHER JUST

CONTROL WATER OR MIO MONTHS

INTOLL OR KNACK AND IT DIDN'T

WORK IN THE HUMAN TRIALS AND

DAILY BY PUT THESE COMPOUNDS IN

THEIR DRINKING WATER SO THEY

WERE EXPOSED TO THEM

CONTINUOUSLY DURING THAT TIME AS

WELL AND WE WERE EXCITED TO SEE

THAT WE DID SEE A REDUCTION IN

MORTALITY FROM STREP NUMO AND

INTERESTINGLY DIDN'T SEE ANY

REDUCTION MORTALITY WITH KNACK

SO THIS WE HAVE TO SEE WHETHER

THIS HAS ANY RELEVANCE TO ANY

MODELS OF LUNG INJURY BUT WE

WERE EXCITED TO SEE THIS AT

LEAST IN ONE MODEL.

AND WE'RE WORKING ON

MECHANISTICALLY SEEING WHAT IS

GOING ON BUT ONE THING WE HAVE

SEEN IS REDUCED BACTERIAL LOADS

SO FASTER BACTERIAL CLEAR NOT IN

ANCE IN THEBAL AND IN DAY FIVE R

INFECTION SO IT SEEMS THAT

TREATING THE MICE WITH THESE

COMPOUNDS DOES SPEED UP

BACTERIAL CLEARANCE SO OF

COURSE, WE'RE WONDERING WHETHER

THIS IS AN ALL RELEVANT TO

PEOPLE SO THIS MIGHT JUST BE A

PHENOMENON OF MICE SO TO GET AT

THIS, WE'VE DONE SOME

METABOLOMICS IN HUMANS SO IN OUR

ICUs OF COURSE, ESPECIALLY

EARLY IN THE PANDEMIC WE HAD A

LOT OF COVID-19 PATIENTS AND

SOME OF THEIR FAMILIES CONSENTED

FOR US TO DO NON LAVAGE WHERE WE

PUT A SUCTION CATHETER DOWN IN

THE TRACK Y'ALL TUBES AND PULLED

IT BACK AND WITH OUR

COLLABORATORS WE'VE DONE --

COMPARED TO PATIENTS UNDER

ANESTHESIAIA FOR ELECTIVE

SURGERY AND AGREED TO LET US DO

THE SAME PROCEDURE, COMPARED TO

THESE HEALTHY CONTROLS, THE

COVID PATIENTS WITH ARDS HAVE

LOWER LEVELS OF MIO INOS TOLL

AND OF COURSE WAS EXCITING SINCE

THAT CORRELATED WITH WHAT WE SAW

IN THE MOUSE MODELS.

SO, TO CONCLUDE, WE'VE SEEN THAT

THERE ARE SOME METABOLICS SHARED

BETWEEN VARIOUS LUNG INJURY

MODELS AND BOTH DIRECT AND

INDIRECT LUNG INJURY AND IT

SEEMS THAT THEY ARE INDEPENDENT

OF THE EXACT MECHANISM OF INJURY

AND SO WE'RE HOPING THAT THIS

ACTUALLY IS RELEVANT TO HUMAN

ARDS AND LOOKING AT OTHER LUNG

INJURY MODEL AND MODEL THAT NICO

SHOWED LOOKING MORE AT MECHANISM

AND WHAT THEY'RE DOING AND ALSO

ALL THE DATA I'VE SHOWN YOU IS

LOOKING AT WHOLE LUNG AND WE'RE

INTERESTED IN UNDERSTANDING

WHETHER THESE METABOLICS CHANGES

ARE HAPPENING IN THE IMMUNE OR

NON IMMUNE AND AND METABOLOMICS

ON THOSE SO INTERESTED IN

LOOKING AT REGULATION OF GONE

EXPRESSION METABOLIC ENZYMES AND

SEEING IF THEY'RE CHANGING

WHETHER IT UNDERLIES THE

METABOLITE CHANGES WE'RE SEEING

AND LOOKING AT METABOLIC FLUX

THROUGH THESE PATHWAYS AND

LOOKING AT NON COVID-19 ARDS

PATIENTS TO SEE WHETHER THIS IS

RELEVANT TO DISEASES OTHER THAN

COVID-19 SO A LOT OF WORK TO DO

SO WE HAVE SO FAR SO, I WANT TO

THANK MY ADVISERS AND AS I

MENTIONED I STARTED THIS WORK

WITH MAUREEN AND JOHNATHAN AND

ED IS GOING TO TAKE ME ON AS

JOHNATHAN AND MAUREEN HAVE LEFT

AND WE HAVE A LOT OF HELP FROM

PEOPLE AT MAUREEN'S LAB AND LEON

AND ED IS REALLY THE KEY

METABOLOMICS COLLABORATOR AND WE

HAD A LOT OF HELP AND SO THANK

YOU GUYS SO MUCH FOR YOUR

ATTENTION AND LOVE TO TAKE ANY

QUESTIONS.

[APPLAUSE]

>> TERRIFIC TALK.

THANK YOU.

YOU KNOW, MORE OF A COMMENT THAN

ANYTHING ELSE.

GIVEN THE HUGE AMOUNT OF

LITERATURE ON OXIDATE TIVE

STRESS, AND THE FACT THAT

CLINICAL TRIALS BASICALLY HE

HAVE ALWAYS FAILED,

, IF YOU LOCK AT THAT LITERATURE

THE THING THAT IS MOST A PARENT

IS AS PEOPLE MOVE

TRANSLATIONALLY COMPLETE LACK OF

ATTENTION TO PKPD RELATIONSHIPS

AND SO AS YOU F. THIS GOES

FORWARD AS YOU DO THIS I THINK

IT'S THE CRITICAL THING WHEN YOU

START THINKING TRANSLATIONALLY

AND BECAUSE THAT LITERATURE IS

JUST RIFE WITH DISAPPOINTMENT

AND RIFE WITH POOR TRANSLATION.

>> THAT'S A GREAT POINT,
THANK

YOU.

>>LET'S START WHERE WHERE

STOPPED BEFORE LUNCH SO WE'LL

JUST FINISH THE LAST SECTION AND

WE MENTION SEVERAL TIMES IN THIS

MEETING, ALAN'S LAB ALWAYS HAS A

LOT OF BRAZILIANS SO I THINK

THIS IS INGREDIENT FOR BRAZILIAN

SCIENTISTS EVEN ENRICHED IN THE

TV PROGRAMS OR FIVE OR SIX

BRAZILIANS AND SIX OR SEVEN OR

10 YEARS AND SHE SPENT SIX YEARS

AND IN TUCSON AND ALL RIGHT -- I

HOPE EVERYBODY IS WELL FED.

SO, I WANT TODAY REALLY EXPRESS

MY GRATEFULNESS TO BE HERE AND

I'M REALLY GRATEFUL, NOT ONLY TO

BE HERE NOW BUT GRATEFUL BY ALL

THE TIME THAT I SPENT IN THE

IMMUNO BIOLOGY SECTION.

NOW I'M BACK IN BRAZIL AND I SET

UP MY SHOP SOUTH OF BRAZIL

ALTHOUGH AS A BIT COLD SO ALAN

VISITS THERE BUT TAKES A WHILE

BECAUSE HE REALLY, REALLY LIKES

THE NORTHEAST PART OF BRAZIL AND

THAT IS HIS FAVORITE AND LOOK AT

THAT.

THAT WAS NATAL AND SO LOOK AT

HIS FACE AND HIS SMILE.

HE IS RELAXED THERE.

HE IS ALWAYS LIKE THAT WHEN HE

IS IN NORTHEAST, I CAN TELL YOU.

I AM GOING TO READ SOMETHING

THAT I WROTE SO I DON'T -- I

DON'T MISS ANYTHING THAT I WANT

TO SAY.

ALAN, FIRST EVER ALL, I LOVE

YOU.

I LOVE YOU GATO, A LOT.

SERIOUSLY, 22 YEARS AGO, HOW CAN

I NOT LOVE THIS GUY.

22 YEARS AGO, ALAN TAKES A RIDE

WITH ME BECAUSE MY FORMER

PROFESSORS GINA BA HAW ASKED ME

TO TAKE ALAN, STEPHANIE AND BOB

COFFMAN TO SHOW THEM A GOOD

TIME.

OF COURSE, THAT'S WHAT I DID.

SO, WE WENT TO PILLOW RIO AND

ALISON AND LAURA WAS ALSO THERE

SO WE WENT AND DID A LOT OF

DANCING AND SALVADOR IF YOU ARE

NOT FAMILIAR WITH THE AREA.

A LOT OF CYPERONIAS.

IT WAS AN OLD CAR AND I FELT

REALLY RESPONSIBLE FOR THESE

GUYS, I BECAUSE NOTHING COULD

HAPPEN LIKE AN ACCIDENT OR

ANYTHING SO IT WAS KIND OF A

VERY BIG RESPONSIBILITY.

SO, I DID MY JOB, I DELIVERED

THEM VERY HAPPY TO THE HOTEL.

SO THE NEXT DAY, ALAN ASKED ME

WHAT I WANT TO DO AFTER MEDICAL

SCHOOL AND I SAID, I WANT TO DO

RESEARCH AND HE SAID, I LIKED

YOU.

I WANT TO WORK ON A MECHANISM

FOR YOU TO COME TO THE IMMUNO

BIOLOGY SE SECTION AND WORK WITS

SO IT WAS MY DREAMT AND I FELT

REALLY, REALLY HAPPY ABOUT IT.

SO I GUESS ALAN SAW SOMETHING IN

ME THAT I WAS NOT EVEN SEEING

BACK THEN.

SO I ARRIVED HERE IN 2001 AND IT

WAS A VERY COLD WINTER BUT

COMING FROM BRAZIL BUT I WAS

STAYING AT CHIEFERS PLACE, REST

IN PEACE, AND HE INTRODUCED ME

TO A LOT OF THE THINGS, EVEN THE

CHIEFERENI WHICH IS A WAY TO

MAKE HYPER INIA.

I LOVE THIS RIGHT AWAY.

I MET THESE GUYS ARE THE THREE

MUSKETEERS AND I REMEMBER THEM

IN IT TOOK ME LIKE IN THE HAND

AND GAVE ME A TOUR AT THE NIH,

WE CAME TO FAS BACK THEN WE HAD

TO SHOW THE IAP66 FORM BUT NOW

THEY CHANGED TO HOLD THE NUMBERS

SO IT WAS REALLY FUN.

AND THAT WAS --

[LAUGHTER]

SO I HAVE LEARNED ANYTHING FOR

YOU.

CHOW CHUCK, DAMIAN AND ALSO I

WORKED A LITTLE BIT AND I

LEARNED A LOT EVEN THOUGH I

DON'T THINK I'M A TOXO PERSON

BUT I LEARNED A LOT FROM THE

MEETINGS AND WITH DRAGANA,

ROMINA AND JULIO BACK THEN.

AFTERWARDS, I WORKED WITH TWO

CRUISE IN THE LAB AND HOW TO PAG

STUDENT AND HE CAME SO HE WORKED

HARD EARL ON.

SO HERE, I DID SOME PADDING AND

I DID A LOT OF THE BARBECUE FOR

ALAN AND I DID A LOT OF LAB

ENTERTAINMENT.

AND I CAN TELL YOU FROM MY

HEART, I LIKED THAT EACH ONE OF

YOU CAN FEEL MY LOVE AND MY HUG

FOR THE SPECIAL TREATMENT I

RECEIVED TO HEAR AND ACTUALLY,

IT WAS VERY IMPORTANT FOR ME NOT

ONLY AS A SCIENTIST BUT AS A

SCIENTIST BUT AS A HUMAN BEING.

ALAN, I NEVER TOLD YOU GUYS I

WON THE LOTTERY HERE BUT

SOMETHING WAY, WAY BETTER THAN

MONEY, NEW SISTERS AND BROTHERS

CAME INTO MY LIFE WHICH I STILL

HAVE TODAY SO MY STUDENTS,

FORMER STUDENTS IN THE LAB, THEY

CAME TO CHUCK'S LAB AND THEY

EVEN WENT TO AUSTRALIA AND

ACROSS GROUP AND THEY DID A LOT

OF COURSES WITH BIO FORMAT TICKS

SO I'M TRYING TO GIVE BACK TO

THE PLANET WHAT YOU TAUGHT ME.

AND THANK YOU VERY MUCH FOR THE

OPPORTUNITY.

SO, JUST THAT'S ALAN I WAS A

VISITING PROFESSOR IN 2017 AND I

ALWAYS COME HERE AND ALAN WOULD

ALWAYS TAKE ME AND DRAGANA AND

EVERYBODY WAS, I WAS VERY HAPPY

AND I FELT REALLY AT HOME AND

THAT DRAGANA, MAYBE I CAN DO

THIS ALL ON HERE.

THERE'S A SOUND THERE WE CANNOT

HEAR SO HE IS MAKING A COFFEE

AND HE IS LIKE, OH, I GOT TO DIG

UP THIS OLD PICTURE OF ME ON MY

SURF BOARD BECAUSE I WAS DOING

SUFFERING BACK THEN SO, I DON'T

THINK THAT'S THE PICTURE BECAUSE

THE SKIN COLOR DOESN'T MATCH BUT

IT COULD BE YOU I STILL WAIT ON

THAT PICTURE.

OF COURSE, THE ONE TO ONE

HOTSEAT WRITING THE PAPER AND I

HAD MY CURLY BIG HAIR DURING MY

SA BAD CAL.

I CAME HERE AND WORKED ON THE

HOTSEAT.

I TOOK OUT THE ADDRESS BUT I

KNOW YOU ARE INVITING PEOPLE SO

YOU CAN REMOVE IT AND PEOPLE CAN

SEE THE ADDRESS OVER HERE.

SO, AND THAT IS ALAN'S

INVITATION.

HE LIKED THE LITTLE WORD DOCK

GUYS AND I THINK THAT WAS BEFORE

THE PANDEMIC SO YOU SEE ALSO

DIEGO HERE, EDUARDO, THAT IS

PEDRO AND THAT IS -- WHAT'S HIS

NAME.

AND THAT IS ALSO -- WHAT'S HIS

NAME?

SO, I DIDN'T BRING ANY DATA.

I WANT TO SHOW YOU WHAT I HELPED

PEOPLE AT MY UNIVERSITY.

SO WE WORKED ON THIS NEW HERE

AND THAT IS MY RIDE I USED TO DO

EVERYDAY DURING THE PANDEMIC AND

HERE THAT'S OUR IF STYLE THAT

I'M GOING TO BE RESPONSIBLE IN

THAT INSTITUTION NOW.

DEDICATING TO OUR BRAZIL VERSION

OF THE LAB OF IMMUNO BIOLOGY

THAT'S NOT OF COURSE STOPPING

HERE AND IT'S DAVID SACKS PUT IT

REALLY NICELY BEFORE.

SO, IN THIS 13 AND 14 YEARS A

LOT OF PEOPLE STUDENT HE'D IN

THE LABS ABLE TO CREATE THREE

P.I.s AND EVERYTHING THAT ALAN

CAUGHT ME AND AS I PROMISED,

THAT'S ISABELLA MY DAUGHTER AND

WE USED TO GO SURFING TOGETHER

AND OVER HERE AND SHE WAS LITTLE

SHE STARTED PAINTING AND NOW

SHE'S GRILL AND SHE'S BECOMING

AN ARTIST WITH THE WATER

PAINTING THAT SHE'S DOING A LOT

NOW AND ALAN IS ALWAYS ASKING

HOW IS SHE.

SHE'S NOW 14-YEARS-OLD SO NOW

THAT SHE'S GOT HER MOTHER'S

LOOKS, I GUESS, BEAUTIFUL.

AND THAT IT.

THANK YOU, VERY MUCH.

[APPLAUSE]

I FORGOT TO TELL YOU GUYS, I WAS

GOING TO DID A GEORGE YO PLAY SO

HE INVITED YOU TO GO TO HIS

HOUSE IN ITALY.

THAT'S NOT AS BEAUTIFUL AS ITALY

HOUSE BUT YOU CAN COME TO MY

HOUSE.

IT'S AVAILABLE TO YOU TOO.

THANK YOU.

[APPLAUSE]

>> GOOD AFTERNOON,
EVERYONE, I'M

FROM THE NATIONAL CANCER

INSTITUTE AND TOGETHER WITH

NIKKI AT NIDCR I'M CHAIRING THE

NIH FDA CYTOKINE CENTER GROUP

AND.

>> IT'S AN 800-MEMBER
STRONG

COMMUNITY OF SCIENTISTS AT NIH

AND FDA INTERESTED IN SIGN

CYTOKINE BIOLOGY AND WE DO TWO

OR THREE MINI SYMPOSIUMS ON

CYTOKINE RESEARCH EVERY YEAR AND

WE WATER ANNUAL BEST PAPER IN

SIGHT OWEICYTOKINE AND WE HAVE R

WINNER FROM MIKE AND THE REASON

WHY WE ARE HERE ACTUALLY IS

BECAUSE NIH CIG HAS FINISHED

TELEVISION 1992 AND HAS BEEN CO

FOUNDED, IT'S ACTUALLY A

BRAINCHILD OF ALAN, WHO

ORGANIZED AT IT AT THAT TIME AND

HAS BEEN STILL RUNNING IT ON TO

THIS TIME TOGETHER WITH US AND

SO IN 2017 THE CIG CELEBRATED

ITS 25th ANNIVERSARY AND I

REMEMBER IT WAS A COMMITTEE IN

GEORGE YO'S LAB AT BUILDING 37

AND WE WERE THINKING ABOUT HOW

TO ORGANIZE IT AND MAKE A POSTER

FOR IT AND ALAN SAID I

THINK WE SHOULD HAVE A BALLOON?

I SAID YOU WANT A BALLOON FOR A

POSTER.

I WANT A BALLOON WITH THIS ONE

HERE AND I SAID, YOU WANT A

CONGRATULATIONS BALLOON, NO, I

WANT MANY BALLOONS.

SO, I WAS ASKING ALAN S. THAT

ENOUGH?

YEAH BUT THEN IT NEEDS TO BE

CONNECTED TO THE NIH AND I

REALLY HAD NO IDEA WHAT IS GOING

ABOUT AND LISTENING TO ALL THE

TALKS, ALAN HAS AN ALREADY AND

HE LIKES TO DRAG IT OUT AND THEN

AFTER TALKING WITH ALAN, I

FINALLY FOUND OUT WHAT HE

WANTED.

AND HE WANTED, HE GOT

INSPIRATION FROM HIS FAVORITE

MOVIE WHICH IS THIS -- AND WHAT

HE WANTED IS HAVING A LOT OF

BALLOONS AND LIFTING UP A HOUSE

WHICH IS THE NIH.

SO, WE ENDED UP WITH THIS

POSTER.

AND AS WE CAN SEE, IT'S THE

BALLOON AND ALAN WAS HAPPY AND

HE WAS LIFTING THE NIH THAT WAS

ALSO GOOD AND THEN HE SAYS NOW

LET'S ALL DECIDE TO TEST COVERED

BY NIH INVESTIGATORS WHO ARE AT

THE NIH.

SO IT WAS GREAT.

I THINK IN HINDSIGHT WE WERE

WRONG BECAUSE THE SCIENCE AT NIH

IS LIFTED BY THE PEOPLE WHO DO

THE SCIENCE AND IN HAD I THINK

THERE'S A BIG BALLOON WHICH IS

MISSING WHICH IS ALAN AND THIS

IS JUST CELEBRATING THAT HE

REALLY HAS WON THIS ALL TOGETHER

TO CYTOKINE FOR THE LAST 30

YEARS AND AS YOU CAN REMEMBER,

THIS YEAR IT'S GOING TO BE A

30th ANNIVERSARY OF THE THE

NIH FDA CYTOKINE INTEREST GROUP

AND ALAN HAS A LOT OF FREE TIME

NOW --

[LAUGHTER]

>> I HOPE IT'S GOING TO
HELP US

TO ORGANIZE AND I'M NOT SURE

WHAT MOVIES HE IS WATCHING BUT

AT LEAST WE'LL HAVE DECIDE ABOUT

WHAT THE POSTER LOOKS LIKE SO

WITH THAT, I'LL GIVE IT TO

KAREN.

[APPLAUSE]

THANK YOU SO I'M KAREN I'M FROM

THE CENTER FOR BUY LOGICS OF THE

FD A AND CONTINUING THE THEME OF

INTEREST GROUPS REPRESENTATION

I'M HAPPEN TO BE THE CURRENT

CHAIR OF THE IMMUNOLOGY INTEREST

GROUP OF WHICH ALAN HAS BEEN A

SUPPORTER EVERY MANY, MANY

YEARS.

I HAVE TO DIVERT AND BLOW

DRAGANA FIVE MINUTES TO ALSO

ACKNOWLEDGE THAT I THINK I'M A

REPRESENTATIVE OF ONE OF THE'

NUMEROUS ABLE PEOPLE OUT THERE

BEYOND THE IMMEDIATE TRAINEES WR

I WAS YOUNGER AND STUPIDER THAN

I AM NOW, ALAN WENT OUT OF HIS

WAY TO TAKE AN INTEREST IN ME

AND MY CAREER AND MY SCIENCE AND

FOR MANY YEARS, HE HAS BEEN A

SOUNDING BOARD, A SOURCE OF

WONDERFUL IN A SCIENTIFIC

INSPIRATION, PERSONAL SUPPORT

AND ADVISE, I AM STANDING IN MY

CURRENT JOB ALMOST ENTIRELY

BECAUSE OF A PIECE OF SAGE

ADVICE HE GAVE ME WHEN I WAS

CONSIDERING THIS RELATIVELY NEW

POSITION FOR ME AND WHICH I

CANNOT REMEET A PUBLIC MEETING.

THANK YOU SO MUCH FOR IN

CONCLUDING ME AND MY LAB AND

EVERYTHING THAT IS HAPPENED OVER

THE LAST MANY, MANY YEARS.

YOU KNOW, WE HAVE ALL TALKED

THROUGHOUT THE LAST TWO DAYS

ABOUT ALAN'S BUILDING OF

COMMUNITIES EVERYWHERE WITHIN

THE LPD, OF COURSE BUT THROUGH

OUT THE SCIENCE WORLD AND SO THE

REST OF MY TASK IS TO RECOGNIZE

HIS ROLE IN FORMAL COMMUNITY

BUILDING AND HYUN TOLD US ABOUT

THTHTHE SIGH COC SIGH CO -- HE D

THE KNIT BRITS AND THAT

COMMUNITY TOO IS DRAWING

TOGETHER PEOPLE WITH COMMON

INTERESTS IN TUBERCULOSIS AND IT

IS GOING STRONG.

ON BEHALF OF ALL OF THOSE NORMAL

GROUPS THAT YOU HAVE GONE OUT OF

YOUR WAY TO CREATE AND NURTURE,

AND TO MOVE ALONG TO THE NEXT

GENERATION OF PEOPLE, WE HAVE A

VERY SMALL TOKEN OF APPRECIATION

WHICH THIS CAN GO TO THE

BATHROOM AND MOVE DAVID'S MUCH

BETTER POSTER UP.

[APPLAUSE]

[APPLAUSE]

>> THANK YOU.

>> HELLO, I'M CATHY ZOON
I'M THE

FORMER SD OF NIAID AND I HAVE A

DIVISION OF INTRAMURAL RESEARCH

AND SO I WOULD LIKE TO FIRST OF

ALL THANK THE ORGANIZERS.

>> GENEROSITY IN SO MANY
WAYS

AND I'LL ELABORATE ON TWO THINGS

THAT HAVE GOTTEN SOME ATTENTION

ALREADY.

HOPEFULLY WE'LL ADD A FEW MORE

TIDBITS TO ALAN'S REMARKS OVER

THE PAST TWO DAYS.

I'D LIKE TO TALK A LITTLE BIT

ABOUT ALAN'S LEADERSHIP SKILLS

AND THEN ALSO HIS MENTORING

SKILLS AND YOU KNOW, AS A LEADER

IN ANY ORGANIZATION YOU CAN ONLY

DO SO MUCH WITHOUT THE SUPPORT

OF OTHER LEADERS IN YOUR

ORGANIZATION AND ALAN HAS ALWAYS

BEEN ONE OF THE FOLKS WHEN I WAS

SCIENTIFIC DIRECTOR I COULD

COUNT ON.

HE WAS ALWAYS THERE AND ASKING

WHAT HE COULD DO TO HELP.

SOMETIMES IT WASN'T HELP BUT --

ME WAS THERE AND YOU KNOW, I

HAVE TO SAY ALAN, AND THIS IS

PARTICULARLY INTERESTING BECAUSE

ALAN DOES ALWAYS SMILE, ALWAYS

SMILES.

BUT ALAN ALSO WORRIES ALL THE

TIME.

AND YOU KNOW, NO ONE BROUGHT

THAT UP.

ALAN, YOU WOULD COME INTO MY

OFFICE AND YOU WOULD HAVE A

SMILE AND YOU WOULD SAY WELL,

I'M CONCERNED ABOUT THIS AND I'M

CONCERNED ABOUT THAT AND WE

WOULD TALK FOR ANOTHER HOUR AND

FINALLY WE WOULD GET TO THE

NITTY GRITTY OF THE PROBLEM AND

I APPRECIATED THAT BECAUSE YOU

EXPANDED MY HORIZONS AND WHAT TO

THINK ABOUT AS WELL AS MAKE SURE

I DIDN'T OVERLOOK ANYTHING AND

WE ALL RECOGNIZE ALAN'S GREAT

SCIENTIFIC ACHIEVEMENTS AND I

HAVE TO SAY, SINKEL BSE THE

LABORATORY HAD OUTSTANDING

REVIEW AND PROBABLY THAT I

SHOULDN'T SAY THAT BECAUSE IT'S

PROBABLY CONFIDENTIAL

INFORMATION BUT TOO BAD AND HE

DID A MARVEL US JOB PREPARING

HIS FOLKS FOR THE BSCs, ALWAYS

OUTSTANDING PRESENTATIONS AND HE

WENT OVER EACH AND EVERY ONE OF

YOUR SLIDES AND MADE SURE IT WAS

ALL PERFECT AND I BELIEVE IT HAD

A GREAT CONTRIBUTION TO THE

SUCCESS OF LPD AND WHEN WE HAD

NEW INITIATIVES AND I COULD SAY

FOR SURE, THERE WAS A TIME AT

NIH WHEN ACTUALLY WE DIDN'T HAVE

AN INCREASE IN OUR BUDGET WE

ACTUALLY HAD A RELATIVE DECREASE

IN OUR BUDGET AND IT WAS GOING

TO BE PRETTY TRAUMATIC FOR THE

INTRAMURAL RESEARCH DIVISION SO

WE GOT TOGETHER TO COME UP WITH

SOME IDEAS AND ONE OF THEM WAS

TO MAKE SURE THAT WE PRESERVED

THE RESOURCES FOR OUR TENURE

TRACKS AND ALAN WAS A BIG

SUPPORTER OF THAT TO REALLY MAKE

SURE OUR YOUNG PEOPLE COULD DO

THEIR RESEARCH AND BE ABLE TO

MOVE ON.

SOME OF THE OLDER FOLKS WERE NOT

ENAMOR WITH THAT BUT THEY

UNDERSTAND THE IMPORTANCE OF ITG

TO ALL OF THAT.

I ALSO WANT TO SAY THAT YOU

KNOW, TOM WYNN IS HERE BUT WHEN

I LEFT NIH I WENT TO BE ON THE

BOARD OF THE INTERNATIONAL

BIOMEDICAL RESEARCH ALLIANCE AND

THAT IS A NON-PROFIT

ORGANIZATION WHICH HELPS SUPPORT

THE NIH OXFORD, CAMBRIDGE

SCHOLARS PROGRAM AND TOM, WHO

WAS LEADING THE PRO VERSE

MICHAEL LENARD OWE AND TOM WYNN

AND TOM HAD AN OFFER HE COULDN'T

REFUSE TO GO TO PFIZER SO ALAN

STEPPED IN TAKING ON THE

LEADERSHIP ROLE THERE AND I HAVE

TO SAY ALAN, WITH THE HELP OF

CHRISTIE PORTER, WHO IS NOW YOUR

RIGHT HAND PERSON, YOU'VE DONE

AN OUTSTANDING JOB IN HELPING

THIS PROGRAM TO GROW AND

CONTINUE TO BENEFIT ALL OUR

GRADUATE STUDENTS WHO ARE

INVOLVED IN THAT PROGRAM SO,

THANK YOU AND I HAVE EVERY

CONFIDENCE THAT YOU ARE GOING TO

BE CONTINUING TO HAVE A ROLE IN

THAT PROGRAM AND HELPING MENTOR

THOSE STUDENTS BECAUSE THEY

REALLY LOCK FORWARD TO ALL YOUR

SAGE ADVICE.

WELL WITH MENTORING, SO MANY

PEOPLE HAVE TALKED ABOUT ALAN

AND HIS MENTORING SKILLS.

HE EVEN MEN FORWARD TO ME SO

THANK YOU, ALAN.

FOR PEOPLE WHO DON'T KNOW, ALAN

IS SO GENEROUS WITH HIS TIME AND

WE HAVE COMMUNITY AND

PREPARATION FOR THEIR TENURE AS

WELL AS FOR THEIR BSCs AND HE

WAS ALWAYS THERE GIVING THEM ADD

VOICE FOR ALL THE COMMITTEES HE

WAS ON SO ALAN, YOU'VE DONE SUCH

A GREAT SERVICE TO ALL.

AND JUST A NOTE.

WHEN I RETIRED, IT WAS ALWAYS A

PUSH-PULL.

YOU NEVER KNOW WHAT THE RIGHT

TIME IS IT TO -- NOT EVEN RETIRE

RETIRE BUT EVEN TO STEP AWAY

FROM THE BENCH I WOULD SAY AND

SO ALAN, I KNOW YOU HAVE COME TO

THE FORK IN THE ROAD AND AS YOGI

BAR A SAYS, TAKE IT.

AND I THINK TAKE SOME TIME NOW

TO DO THE THINGS YOU LOVE AND

BEING WITH YOUR FAMILY AND BEING

WITH VISITING THE CHILDREN AND

GRANDCHILDREN AND TRAVEL AND

DOING THE THINGS YOU LOVE AND I

WILL BE HERE TO MENTOR HERE ON

HOW TO RETIRE.

[LAUGHTER]

AND SO, YOU ARE DEVOTED AND WILL

WANT SCIENTIFICALLY BECAUSE IT'S

INAND I CAN NEVER GUARANTEE SO I

WANT TO CLOSE IN SAY IN THE

WORDS OF ALBERT EINSTEIN.

KEEP YOUR BALANCE ON A BICYCLE

YOU MUST KEEP MOVING AND ALAN,

I'LL BE THERE FOR YOU AND IT'S

BEEN WONDERFUL WORKING WITH YOU

AND WARM REGARDS ON YOUR NEXT

STEPS IN YO YO JOURNEY.

THANK YOU.

>> THANK YOU, VERY MUCH.

THANK YOU FOR STICKING AROUND

FOR THE LAST SCIENTIFIC SESSION

OF THE AFTERNOON AND BEFORE I

START, I'LL JUST MAKE A COUPLE

OF QUICK COMMENTS.

I THINK OVERWHELMING MAJORITY OF

THE PEOPLE IN THE ROOM ARE

ALAN'S SCIENTIFIC GRANDCHILDREN

AND CHILDREN AND I FALL IN THE

CATEGORY OF NEPHEW OR FIRST

COUSIN ONCE REMOVED AND I SAY

THAT BECAUSE IT TURNS OUT

THATTAL ANNE AND CRITICAL ROLE

TO PLAY AND IF AND HAD ANY

RESEARCH JOB WITH WITH A

COLLEAGUE OFFALLANCE WHO SORT OF

ALLUDED TO BY AND THERE WERE

THREE PH.D STUDENTS AT THE IN

SAN DIEGO AND ALL TOGETHER AND

MADE A DECISION TO DITCH BASIC

IMMUNOLOGY AND MOVE TO NEGLEC

NEGLECTED.

>> WHILE I WAS THERE I
WENT TO

HARVARD WHERE ALAN AND ANTHONY

BUTTERWORTH WERE SHARING A

CUBICAL AND AND I MET HIM AND I

WAS ABLE TO PARLAY THAT

INTERACTION AND INTO A AFTER THE

FIRST YEARS OF MEDICAL SCHOOL

AND KENYA AND IT WAS THAT

EXPERIENCE THAT FIELD WORK AND

DISEASE AND WANTED TO DO AND SO

FOR THAT, INDIRECTLY, ALAN

REALLY WAS ALREADY AN INFLUENCE

AND FOR THE PROGRAM AND AND IN

1982 AND PRIVILEGE TO WORK

ALONGSIDE AND AND CAREER AND WE

WERE COMBATING ARMS AND FIGHTING

OFF THE ONSLAUGHT AND OF MALARIA

AND MAKING BEGINNING FOR AND

RESEARCH AND FOR THE PAST 20 SO

YEARS AS SORT OF A PARTNER IN

AND HELPING TO OVERSEE THE

OPPORTUNITY AND I VALUE EVERY

MINUTE AND ALAN WAS AND SO THANK

YOU.

[APPLAUSE]

WE'RE GOING TO THE PROGRAM AND

IT'S ED PEARCE, IS THAT --

>> THANK YOU FOR GIVING ME
AN

OPPORTUNITY TO SAY A FEW WORDS

ABOUT ALAN.

I THINK AS YOU GET OLDER, I HAVE

REALIZED THE IMPORTANCE THESE

EVENTS AND SUE GET TO SAY THINGS

THAT YOU MIGHT NOT SAY TO OTHER

PEOPLE AND YOU SAY THEM PUBLICLY

AND I DON'T KNOW WHY THAT'S

EASIER BUT PERHAPS IT IS.

ANYWAY, I'M -- I WAS GOING TO

SAY EXACTLY WHAT TOM SAID ABOUT

ALAN BEING ONE OF THROW THREE

MUSKETEERS WHO WERE BASIC

IMMUNOLOGISTS WHO TURNED TO

WORKING -- WHO DECIDED

IDEALISTICKLY TO WORK ON

NEGLECTED TROPICAL DISEASES AND

THAT USE MADE AN IMPRESSION ON

ME AND I GOT TO MEAT PAUL AND

DONATO THE OTHER TWO GUYS THAT

WERE ALAN'S FRIENDS AND THEY

MADE AN IMPRESSION ON ME AS

WELL.

SO, THE THING THAT ALAN LOVES

SCIENCE AND HE IS INTERESTED IN

EVERY SCIENTIFIC QUESTION AND

ONE OF THE FANTASTIC THINGS

ABOUT ALAN IS HIS ENTHUSIASM AND

AS A TRAINEE IN HIS LAB, YOU

COME UP WITH AN IDEA AND HE

WOULD ALWAYS PUT A POSITIVE SPIN

ON IT AND TRY AND MAKE IT GO

FORWARD AND SEE THE GOOD SIDE OF

IT AND YOU KNOW, BE SUPPORTIVE

AS YOU TRIED TO MAKE SOMETHING

COME OF THAT IDEA THAT YOU'VE

HAD AND THAT WAS AND INVALUABLE

AND SUCCEED AS WELL AS ALAN DID

AND THAT IS SOMETHING THAT WAS

REALLY AND WHEN I WAS IN HIS LAB

AND IT'S SOMETHING THAT I REALLY

APPRECIATE.

SO A POINT THAT WAS MADE, MAYBE

IT WAS IT'S SOMETHING WE'LL ALL

AWARE OF HOW PROLIFIC AND IT'S

PUBLISHED AND OVER 500 PAPERS

AND IT'S A TESTAMENT TO HIS WORK

OATH I CAN AND ALAN WORKS

REALLY, REALLY HARD AND IT'S

SOMETHING I RECOGNIZED AS WELL

AND YOU KNOW THAT IS AN AMAZING

ROLE MODEL IN THAT RECORD.

SO, WHEN I THINK ABOUT MY TIME

IN ALAN'S LAB IT CERTAINLY IS

THE TIME WHEN I LEARNED TO BE A

SCIENTIST.

ALAN TAUGHT ME HOW TO BE A

SCIENTIST AND THROUGH HIS

ENTHUSIASM AND THROUGH TAKING

THE TIME TO SIT DOWN AND TALK TO

ME AND THE EXPERIMENTS I WAS

DOING AND HOW I SHOULD INTERPRET

THE DATA AND WHAT WE SHOULD SEE

IN IT.

HE TAUGHT ME HOW TO WRITE.

THE STORY THAT EVERYBODY HAS HAD

ABOUT BEING IN THE HOTSEAT, I

WAS IN THE HOTSEAT MANY, MANY

TIMES AND IT'S AMAZING WE WERE

DOING IT IN A LONGHAND ON A

YELLOW PAD AND HE WOULD WE

REWRITE IT AND IT'S HARD TO

THINK THAT'S THE WAY WE DID IT.

THAT'S HOW I LEARNED TO WRITE

AND IT'S INVALUABLE.

AS A SCIENTIST, IF YOU CAN'T

WRITE YOU ARE DONE.

SO, HE NOT ONLY TAUGHT ME HOW TO

BE A SCIENTIST AND HOW TO WRITE

BUT HE TAUGHT ME OTHER THING.

HE TOOK ME SAILING ONCE AND

TRIED TO TEACH ME HOW TO SAIL.

>> THAT SPEAKS TO ALAN'S

CONNECTIONS AND HE IS CONNECTED

TO SO MANY PEOPLE AND OBVIOUSLY

THE EMPHASIS TODAY IS ON

IMMUNOLOGISTS AND HE IS WIDELY

RESPECTED AND CONNECTED IN THE

IMMUNOLOGY FIELD AND HE IS AND

HE IS CONNECTED TO HARDCORE

PATHTOLOGISTS AND THAT'S ANOTHER

THING AND HE IS MEETING THESE

FANTASTIC WHO COME THROUGH AND

VISIT AND ALL SORTS OF PEOPLE

WERE COMING THROUGH AND VISITING

IN THE LAB ALL THE TIME AND HE

WOULD GO OUT OF HIS TO INTRODUCE

US AND I GOT TO KNOW PAUL

ENGLAND AND JOHN HOPKINS WHO WAS

ONE OF THE PEOPLE THAT WORKED

OUT HOW GPI ANCHORS ARE

CONSTRUCTED AND INSIDE A CELL

AND I GOT TO MEET A OCC WANG

FROM UCSF WHO DISCOVE INEVER MEC

TIN AND ALAN IS THE CENTER OF

THIS SCIENTIST OF PEOPLE THAT

I'M A PART OF AND THIS IS

FANTASTIC BECAUSE IT OPENS THE

DOOR TO US ALL GOING TO EACH

OTHER AND I FEEL LIKE AND THAT'S

BECAUSE OF ALAN AND THAT AND THE

WAY HE CAN BEHAVE AS A

CHEERLEADER AND TO BE HONEST

WITH YOU, IT'S PRETTY

INTOXICATING WHEN HE IS WORKING

WITH YOU TO GET THAT PAPER

TOGETHER AND AND IT WAS BETTER

WHEN HE WAS THINKING ABOUT MY

WORLD TO WORK HARD AND HE DID

THAT IN A GREAT WAY AND AND THE

WAY HE TALKED ABOUT MICHAEL AND

MICHAEL GOOD WAS MANY OF YOU MAY

KNOW AND HE ENDED UP AND BEING

CURE IMR AND HE REALLY IS A GOOD

SCIENTIST AND WHEN ALAN WERE

TALK TO US ABOUT MICHAEL GOOD HE

WAS A PARADIGM OF VIRTUE AND

THIS IS HOW YOU GET AND MICHAEL.

GOOD.

MICHAEL EXCELLENCE AND SO I JUST

THINK ABOUT IT AND I NEVER THINK

OF MICHAEL GOOD WITHOUT THINKING

ABOUT HIM AS MICHAEL EXCELLENT.

THANK YOU, ALAN, IT'S BEEN MY

PRIVILEGE TO BE HERE TODAY.

THANK YOU.

AND SO MOVING ON FROM THERE, I

HAVE THE PRIVILEGE ALSO OF

INTRODUCE PAUL BRINDLEY, MY OLD

COM PADRES FROM ALAN'S LAB AND

WE SPENT A LOT OF TIME TOGETHER

AND I'M LOOKING FORWARD TO

HEARING WHAT YOU HAVE TO SAY,

PAUL.

[APPLAUSE]

>> THANK YOU, ED.

AND THANK YOU TO DRAGANA AND THE

OTHER FOLKS WHO INVITED ME INTO

PUTTING ON THIS WONDERFUL

SYMPOSIUM.

OK.

SO, DRAGANA ASKED ME OR I SAID I

COULD TALK ABOUT SOMETHING TO DO

WITH GENOMES AND RELATED FLUKES

SO I WANT TO MAKE A FEW SIMILAR

REMARKS TO THAT PROFESSOR PEARCE

AND OTHERS WHO HAVE MADE TODAY

BECAUSE I ALSO WAS A POSTDOC IN

ALAN'S LAB AND SO I'M GOING TO

TALK ABOUT THE SCIENTIFIC

ASPECTS A LITTLE BIT FURTHER ON

AND I'M GOING TO CONSUME TOO

MUCH TIME AND I'VE BEEN OFFERED

LESS BUT I WANT TO MAKE A COUPLE

OF PERSONAL REMARKS.

SO, THAT IS THE INTERVAL WHEN I

WAS IN ALAN'S LAB IN 1985 TO

1991 AND WHERE AS ALAN MIGHT

HAVE KNOWN Dr. MICHAEL

EXCELLENT HE DIDN'T KNOW ME AND

EVEN THOUGH MICHAEL AND I KNEW

EACH OTHER AND WE WERE BOTH FROM

AUSTRALIA I WANT TO TELL YOU HOW

I CAME TO A ARRIVE HERE SO, I

JUST FINISHED MY PH.D DEGREE AT

AN INSTITUTE ALAN NEVER HEARD OF

AND THE DOCTOR GOOD WAS ALSO A

GRADUATE AND SO I WROTE A LETTER

AND PUT IT A LETTER IN A BOTTLE

THAT I TOSSED INTO THE PACIFIC

OCEAN AND I FORGOT ABOUT IT AND

I HAD WRITTEN THIS LETTER TO THE

DIRECTOR OF NIAID WHICH I TAKE

IT OUT WAS PART OF THE NIH AND

SOMETIMES LATER, I RECEIVED A

LETTER BACK IN THE MAIL AND AND

I SAVED AND HOW LONG AND AND I

OPENED IT UP AND IT JUST ALLUDE

TODAY AND AND SEVERAL PAGES OF

THE CURSE TOMORROW EXPLAINED WHO

HE WAS AND THAT MY LETTER HAD

BEEN RECEIVED BY THE NIAID AND

IT MOVED Dr. GALAN'S OFFICE

AND HE TALKED TO Dr. FRANKLIN

THE CHIEF OF THE LPD AND SOMEHOW

Dr. NEVER DECIDED THAT I MIGHT

BE A PERSON WHO COULD HELP HIM

OUT BECAUSE THIS GUY BRINDLEY

CLAIMED HE KNEW SOMETHING ABOUT

WORMS IN HIS DOCTORATE AND Dr.

NEVER HAD AN INTEREST IN WORMS

BUT HE TALKED TO ALLEN AND SAID,

YOU'VE BEEN BADGERING ME FOR A

POSTDOC BUDGET SALARY AND HE

SAID I'VE GOT AN INTEREST IN

THIS LETTER THAT Dr. GALLON

HAS PASSED ON TO ME AND WE

BETTER DO SOMETHING ABOUT IT BUT

I WILL TAKE HIM ON IF YOU WILL

TAKE HIM ON TOO.

I THINK IT'S HOW THE STORY WENT

AND SO ALAN EXPLAINED TO ME IN

THIS LETTER ON THE YELLOW NOTE

PAD THAT YES, THAT I'M

INTERESTED IN HIRING ME BUT I

WOULD HAVE TO WORK PRETTY HARD,

12 HOURS FOR Dr. NEVER EACH

DAY AND 12 HOURS FOR Dr. SHER.

THE UP REPO SHORT OF THAT, SO A

LITTLE WHILE LATER, AFTER IF I

SAT IN THE HOTSEAT WITH ALAN WE

MANAGED TO PUBLISH THIS PAPER

AND THIS PAPER DEALT WITH

EXPOSURE OF MICE TO THE

ANTI- PARASITIC DRUG AND

OTHERWISE MY SURFACE THAT Dr.

HALL BY OTHER ANTIGENS WERE

EXPOSED TO SERUM ANTIBODIES AND

SOON THE MICE WERE EXPELLED SO

THE LINKAGE WAS THERE THAT

EFFICACY OF THIS DRUG HAD AN

IMMUNE DEPENDEN SEE COMPONENT

AND THE OTHER THING I WOULD LIKE

TO SAY ABOUT THIS PAPER AS PROUD

OF IT I WAS, THE DAY THE LETTER

FROM THE JOURNAL OF IMMUNOLOGY

SAID IT WAS ACCEPTED WE WERE

FEELING CHUFFED AND ANOTHER

LETTER APPEARED ON MY DESK AND

THIS LETTER EXPLAINED THAT THEY

MADE A TERRIBLE MISTAKE.

AND THAT THERE WAS A CLERICAL

ERROR AND ACTUALLY THE PAPER

HADN'T BEEN ACCEPTED AND THEY

WERE WITH DRUG THEIR OFFER OF

ACCEPTANCE AND YOU WOULD HAVE TO

TROY SOMEWHERE ELSE BUT Dr.

CHIEFER WAS RESPONSIBLE FOR

THAT.

THAT WAS MY THE LAB IN IMMUNO

BIOLOGY AND IMMUNE SERUM AND

ALAN PROBABLY PRESENTLY DECIDED

THAT THIS GUY BRIND LIKE UNLIKE

Dr. EXCELLENT, KNEW NOTHING

ABOUT IMMUNOLOGY AND THAT'S THE

LAST I WORKED ON ANYTHING IMMUNE

LOGICAL SO ALAN SUGGESTED I WORK

ON THE WORM THEMSELVES OR THEIR

GENOMES, I'M GOING TO SHOW THE

WORK I DID TO ALAN'S ADVICE TO

STICK TO THE PARASITE.

SOME FOLKS MENTION Dr. GEORGE

YAP INDICATED THAT IF YOU HAD A

FORK IN THE ROAD AND Dr. SHER

SAID YOU CAN WORK ON TOXO YOU

WOULD SOON BELIEVE YOUR CAREER

WAS DEAD ENDED IF YOU WORK ON

SISTER SO YOU BETTER WORK ON

TOXOPLASMOSIS AND HE DIDN'T

OFFER ME THAT ADVICE, I DIDN'T

GET THE OFFER SEW SAID YOU WORK

ON SHISTER SEEMS.

SO ANYWAY, THE PROBLEM WITH S

THEY'RE GENETICALLY NOT VERY

ATTRACT ABLE AND THEY'RE WORK TO

WORK ON AND THEY'RE UNLIKE

SINGLE CELL PATHOGENS THEY HAVE

A COMPLEX GENOME AND THEY SEX

I'LLLY REPRODUCE AND THEY HAVE A

COMPLEX LIFE CYCLE AND SOME OF

THEM ARE MORE COMPLEX AND THEY

HAVE A SMELL INVOLVED.

SO IN SUBSEQUENT YEARS, YOU

KNOW, IN A PARTICULAR SINCE THE

CRISPR REVOLUTION AND THE NOBEL

PRIZE TO RELATED TO THAT, PEOPLE

NOW HAVE ADAPTED CRISPR GENE

NOAM ETIQUETTING AND WE'VE BEEN

INVOLVED IN THAT OURSELVES AND

I'LL MENTION THAT AND WHAT WE

REALLY WOULD LIKE TO DO IS IT'S

A CHARGE BUT IT'S WHAT WE DO IN

SOME RELATED WORMS NOWADAYS.

TO GET INTO CRISPR EDITING, A

COUPLE OF YEARS A. I CAME BECOME

TO SEE ALAN AND DRAGANA JUST

BEFORE THE COVID AND I WAS A

WAIVER THEIR PAPER FROM THE

MIDDLE, WELL ABOUT 2009 AND I

QUICK WILL HE CHECKED PUBMED

TODAY AND AMONG THOSE 500 PAPERS

THAT ALAN PUBLISHED THIS WAS THE

LAST ONE THAT HAD THE NAME OF

SHER AND SCHISTOME IN THE SEARCH

THAT I PICKED UP.

I WAS AWARE THAT THE EGG OF THE

SCHISTOSOME WAS RESPONSIBLE FOR

THE DISEASE AND SO WE DECIDED IN

MY LAB, PARTICULARLY WITH

HOTSHOT YOUNG ASSISTANT

PROFESSOR WHO WORKED WITH ME

THAT WE WOULD EDIT SOMETHING AND

GET A PHENOTYPE AND WE KNEW THE

EGGS HAD A PHENOTYPE OF THE

GRANULOMA AND THE TH2 SHIFT AND

SO WHAT COULD WE EDIT IN A EGG

AND THERE WAS THIS PEOPLE AND

THEY PUBLISHED SIMILAR PAPERS

THAT THE EGG SECRETS A OMEGA 1

PROBABLY NAMED DISCOVERED LONG

BEFORE BY DAVID DUNN AS WELL.

THE OMEGA STANDARD FOR THE

FRACTION FROM THE CROW MATGRAM

SO WE'RE ABLE TO LOOK AT THE

GENOME.

THE GENOME IS IN GOOD SHAPE

NOWADAYS BUT NOT TOTALLY

COMPLETE.

UNFORTUNATELY THIS PARTICULAR

ENZYME HAS THREE GENES BUT

THEY'RE ALL SIMILAR AND I WANT

TO POINT OUT WHAT IS SOMETHING

ON THE BOTTOM OF THE PANEL

THERE.

DON'T WORRY ABOUT THE GENE

STRUCTURE.

THAT PARTICULAR ENZYME HAS A

VERY SPECIFIC DEVELOPMENTAL

EXPRESSION AND IT'S ONLY

EXPRESSED IN THE EXPRESSION

LEVELS OF THE TRANSCRIPT AT

VARIOUS STAGES OF THE LIFE CYCLE

OF THE THREE DIFFERENT GENES.

ONLY SEEN WITHIN THE EGG AND THE

EGG PROBABLY TAKES SEVEN DAYS TO

DEVELOP WHEN THE FEMALE LAYS IT

UNTIL IT COULD REACH THE BELL

AND ONLY EXPRESSED?

THE LAST THREE OUR FOUR DAYS OF

THAT SO IN THE MATURE EGG SO WE

DECIDED TO TRY AND EDIT THAT

THIS THE UP SHOT OF WHAT WE SAW

THAT ON THE LEFT HAND PANEL WE

CAN GET A REDUCTION THAT WE CAN

MEASURE IF WE TOOK RNA FROM THE

EGGS AND WE DELIVERED IT AND WE

ALSO CAN DELIVER BY THE VIRUS

AND IT'S INFECTIOUS THOUGH OR

OTHER RETRO AND SO AND I DON'T

WANT TO SHOW YOU THE EDITING PAD

ENTER AND A SMALL PERCENTAGE OF

THE GENOMES SO WE TAKE 10,000

EGGS AND EDIT THEM AND RECOVER

THE FEW DAYS AND, I WANT TO TALK

ABOUT JUST AS I FINISH UP ON

THIS RUN RIGHT NOW.

BUT THOSE MANIPULATED EGGS IF WE

PUT THEM INTO LUNG GRANULOMA

WHEN YOU LOOK AT THESE 10 DAYS

LATER IN THE MOUSE, THAT IS THE

VOLUME OF THE GRANULOMA

SURROUNDING THE EGG.

THE EGG IS RIGHT THERE.

THE GENOME EGGS IS JUST

GOBSMACKEDDINGLY ABSENT AND THE

SIZE OF THE GRANULOMA AND ROB

THOMPSON WHO WORKED FOR TOM WYNN

HELPED US SCAN THOSE AND HE LET

US USE BUT THIS IS JUST THE

VOLUME AND THE AMOUNT OF VOLUME

TO AND THAT IS THE EDITING CAN

DO ON THIS PARTICULAR ENZYME AND

IT WAS CURIOUS WHEN WE SAW THAT

BECAUSE WE GOT THIS 100%

REDUCTION IN TRANSCRIPT LEVEL

AND AT LEAST 50% REDUCTION IN

THE RNA ACTIVITY AND AT THE

GENOME LEVEL A SMALL PERCENTAGE

WERE EDITED AND WHY IS THAT

BECAUSE THIS IS THE STAGE, THE

EGG STAGE IS WHAT WE EDITED AND

THIS IS NOT OUR WORK THIS IS

FROM THE LITERATURE AND THE EGG

ITSELF WHEN IT'S DEVELOPED AND

YOU CAN SEE THE SILLIA ON THE

OUTSIDE OF THIS WITHIN THE EGG

SHELL IN THE MOUSE LIVER, THIS

EXAMPLE.

AND THERE'S ACTUALLY SOME TISSUE

JUST INSIDE THE INNER COAT OF

THE EGG AND IN AN ENVELOPE WHICH

IS ANOTHER THING WHEN TISSUE

GROWS OUT AS THE EGG DEVELOPS DD

IT'S THE ONLY PLACE IN THIS

ORGANISM WHERE OMEGA IS

EXPRESSED AND WHEN WE INTRODUCE

THOSE EGGS IN CRISPR IN THOSE

EGGS CLEARLY JUST PHYSICAL LIE

WE ONLY REACH THAT TISSUE SO

VERY WE KNOCKED OUT THIS

VACCINES OF PHENOTYPE AND WE

CHOSE AN INTEREST GENE TO SO IT

HAPPENED THERE.

I MENTIONED THAT THE SISTER

SEEMS ARE DIFFERENTLY AND TO

MANIPULATE SO YOU CAN WELL

MARRIAGE OTHER PEOPLE ARE

INTERESTED IN THIS GERM LINE

EDITING AND THAT WAS AN EXAMPLE

OF TISSUE EDITING DONE NOW FOR

THE TREATMENT OF HUMAN

HEMOGLOBIN FOR INSTANCE.

AND WE WOULD LIKE TO GERM LINE

AND CHANGE THE ORGANISM AND TURN

IT BLUE OR GROWN TO MAKE THE

COVER EVER A MAGAZINE OR

SOMETHING BUT TO GET IT TO GERM

LINE AND THE GERM LINE IS A

VALUABLE IN A NUMBER OF WINDOWS

IN THE DEVELOPMENTAL CYCLE BUT

IT'S AVAILABLE AS SOON AS THE

EGGS LAY BECAUSE THEY'RE THAT IS

WHAT HAPPENS IN THE LIVER WHERE

THEY'RE TRAPPED SO WE WANTED TO

LAY CRISPR MATER MATERIAL AND TS

OUR PLAN SO WE DECIDE THAT

BEFORE CRISPR BY VIRAL INFECTION

OF EGGS AND MAKE GERM LINE WORMS

AND WE PUBLISHED THIS A FEW

YEARS AGO AND I WENT GO THROUGH

THE PATENT BUT THESE THE GENE

HERE WE CAN FIND IT IN THE F-1

AND THE DIFFICULTY IS THAT THAT

IS A SINGLE SEX.

IT'S HOW THE MALE OR FEMALE AND

THAT'S WHAT WE GOT AND WE MADE A

NUMBER OF AND WE CAN TRANSIT AND

GOWN THE GENERATIONS AND AND THE

REPORTED SOON WAS SOONLY

ACTIVATED WHEN USED RETRO VIRUS

AND THIS INVOLVED AND THEY'RE

OFTEN DEPENDING ON THE LAND AND

NONE THE LESS I WANT TO TRY TO

TELL YOU THAT WE CAN MAKE AND WE

CROSS THEM AND IT WILL BE IN

CONTAIN THE TRANCE GENE AT THIS

LOCUS AND THEN IT WILL BE PASSED

DOWN THE LINE AND IN VERY RECENT

TIMES THESE DATA ARE UNPUBLISHED

AND WE ACTUALLY IDENTIFIED WHAT

WE CONSIDERED GENOME SAFE

HARBORS IN THE GENOME SAYING TO

THE ROSE 26 SIDE AND OTHERS THAT

ARE USED IN HUMAN GENE THERAPY

OR MOUSE MODELS OF HUMAN GENE

THERAPY AND SO WITH A NUMBER OF

MANIPULATIONS AND GRUNT WE CAN

DELIVER CRISPR REPORTED TRANCE

AGAINST WE WANT TO PUNE NA TIVE

SAFE HARBOR SO IF WE LOCK TO THE

EGG IT WAS FLORES ANTS WE CAN GO

70% OF THE EGGS WILL BE DARPHA

CONTACTED US AND CALLED ABOUT

THE BIO SYSTEM AND I WON'T GO

INTO THIS AND I WILL PROBABLY BE

BREAKING SOME CONFIDENCE WITHIN

AND I'LL BE ARRESTED BUT,

THEY'RE INTERESTED IN CHANGING

THE MICROBE OF SOLDIERS AND

MEDICAL FIRST RESPONDERS BY A

NUMBER OF WAYS THEY SAID COULD A

MACRO BUY OT I CAN ORGANISM LIKE

A SCHISTOSOMES OR A HOOK WORM BE

SOLVED AND AND IT'S MUCH MORE

GENETICALLY ATTRACT ABLE.

AND IT'S DIFFICULT PROJECTS AND

SOUTHEAST ASIA IN THE RIVER

DELTA AND THEY'RE A CURSE AND.

>> THE FISH THE LARVA AND
AND

ARRIVES IN THE UPPER SMALL

INTESTINE AND LIVES IN THE TRACT

AND IT'S A HUMAN AND RELATIVELY

RESEARCH IN MEDICAL SCHOOL IN

NORTHEAST THAILAND AND YOU CAN

SEE A COUPLE OF THE FLUKES ARE

JUST POPPED OUT AND SEVERED WILD

AND THIS TISSUE WAS SECTION BY

THE PATHOLOGIST IN THE LAB OF A

COLLEAGUE OF MINE AND THE TUMOR

THE SURGEON WAS ADDRESS WHAT IS

THIS SECTION IS UP IN THE TOP

CORNER AND IT'S A DIRE DISMAL

PROGNOSIS AND MOST OF THE PEOPLE

WOULD BE AND DEAD AFTER THE

DIAGNOSIS.

THE WORMS LIVE IN THE BILE DUCT

AND LONG LIST LIKE SCHIS.

>> Toni-Marie: AND THEY
EAT IN

THE BIO DUCT IN THIS TISSUE HERE

AND THIS IS EXPERIMENT FROM OUR

GROUP WHERE WE JUST CULTURE

HUMAN CHOLANGIOCYTES AND YOU CAN

SEE THE VEHICLES ARE UPTAKEN BY

THE CHOLANGIOCYTES AND WE GEE

OWN EDIT THIS FLUTE AND AFTER WE

MA LIP NATURED THE LAVA

INFECTING THE HAMSTERS AND YOU

LOCK AT EXPERIMENTALLY INFECTED

WITH A FLU AND RIGHT THERE THIS

ALREADY HYPO PLASIC LINING IS

SEVERAL CELLS THICK IN NATURE

IT'S ONE CELL THICK HOWEVER, THE

PLACE WE HAD THIS GENOME IN

CODES OF GROWTH FACTOR KNOWN AS

GRAN YOU LYNN AND IN THE ABSENCE

OF GRANYOU, LYNN THERE'S NO

PROLIFERATION OF THE TRACT AND

THAT IS THE CELL THAT IS SELL OF

ORIGIN OF THIS LIVER CANCER AND

WE HAD BEEN PLAYING AROUND WITH

A GROWTH FACTOR AND I DON'T HAVE

TIME TO TELL YOU ABOUT IT.

WE COULD GET RID OF SOME OF THE

DISEASE AND SO, CHANGE TRACK A

LITTLE BIT, THIS IS NOT MY WORK

BUT WORK BY CONCORD UNIVERSITY.

THE GEE OWN SEQUENCED CARCINOMA

FROM HUMANS AND IN THAT PART OF

THE WORLD SO LIVER FLUKE IT'S A

GREAT ON CARCINOGEN AND WHEN

THEY PROFILED THE GENETIC

CHANGES, ON THE FEWTATION THAT'S

PROGRESSIVE IN VERSUS NON LIVER

FLUKE AND IT MIGHT TURN BORING I

WANT TO POINT OUT THAT TP5 3 IS

SEEN AND THIS IS A CHRONIC

INFECTION SO WE'RE IN A GENERAL

WAY THIS IS A CHRONIC INFECTION

ASSOCIATED MALIGNANCY AND SO

BACK TO MY STORY.

SO WOAD LIKE TO MODEL THAT.

IF WE INFECT A HAMSTER IN THE

LAB AND THESE WORMS ARE WILD

ANIMALS AND THESE ARE NOT

MAINTAINED IN THE LAB.

THE COLLEAGUES HAVE TO GO TO THE

MARKET OR HAVE SOMEONE FISH TO

FIND THESE SO WE ONLY GET THE

WORMS FROM THE WILD.

AND THEN YOU INFECT THE LAB

RODENTS OR WHATEVER HAMSTER AND

YOU DO AROUND EXPERIMENT IN THE

LIFE OF A HAMSTER IN THE LABS A

YEAR OR SO, THE TUMOR DOESN'T

DEVELOP AND IT DOESN'T DEVELOP

UNTIL THE MID DECADES OF LIFE IN

PEOPLE BUT IT WAS WELL-KNOWN FOR

30 OR 40 YEARS, PARTICULARLY

FROM PEOPLE AT THE UNIVERSITY IN

BANGKOK, THAT THEY COULD INDUCE

A MODEL OF COL ANGIE OWE C CARCA

BY ADDING IT RELEVANT BECAUSE

THE DIET OF THE PEOPLE IN

NORTHEAST THAILAND IS RICH CAN

YOU INDUCE IN A FEW MONTHS SO

DURING COVID WE TRIED TO DID

THAT EXPERIMENT AND WE HAD TO

GUESS WHICH OF THESE LEVELS SO

WE ACTUALLY DIALED RIGHT UP AND

WE USED 100 NUCKS AND 12.5 PARTS

PER MILLION AND WE INFECTED A

NUMBER OF HAMSTERS AND VERY

BRIEFLY TO FINISH UP, WHEN WE

DID THAT, AND I ONLY JUST PLEASE

LOOK AT THE TWO LEFT HAND BARS

THERE, THE PUNCH LINE IS THIS

AND THIS IS UNDER REVIEW AT

PRESENT PEER ROW VIEW BUT IT'S

IN YOU WANT TO LOOK AT IT AND

ALL THE HAMSTERS GOT CARCINOMA

BUT THERE WAS SIGNIFICANTLY LESS

DISEASE AND LESS MARKET DISEASE

WHEN WE KNOCKED OUT GRANULE LAR

AND INFECTED LIVER FLOCKS SO FL.

IT'S OVER LEVEL FLEW BUT WE

LOOKED AT MANY OF THE KIND OF

HALLMARKS OF CANCER THINGS,

CANCER EXPERTS LOOK AT INCLUDING

PROLIFERATION AND THERE'S A LOT

MORE PROLIFERATION OF THE SITES

AND IN THE CONTROLS VERSUS THE

ONES THAT WHERE IT'S KNOCKED OUT

OR KNOCKED DOWN AND I THINK LET

ME SEE, YEAH, AND P53 THIS IS

LESS OF MUTANT P53 THAN IN THE

CONTROLS SO, I THINK I'M

FINISHING UP NOW IS CRISPR

EDITING IS ACTION TIVE IN LIVER

FLOCKS AS SOME OF THE THINGS YOU

CAN DO WITH IT SUCH AS REPAIR

AND IN TERMS OF THE TWO EXAMPLES

OF SHOWED YOU, WE IN

SCHISTOSOMES WE KNOCKED OUT THE

MEGA RESPONSIBLE FOR THE TH2 AS

AN EXAMPLE AND WE'RE TRYING TO

DERIVE A LINE BUT IT MAY BE A

LETHAL MUTATION AND I SHOWED YOU

THAT WE CAN GET SIMILAR THINGS

TO WORK IN LIVER FLUKES SO WE

THINK FUNCTIONAL GENOMICS IS

ACCESSIBLE FOR PARA SID I CAN

ELEMENTS FOR THE MAJOR AND HOPEY

IT'S LOWER.

THESE ARE THE FOLKS I'VE

COLLABORATED.

JUST TOO MANY PEOPLE TO GO INTO.

I WILL MENTION MY COLLEAGUES IN

CON CANE UNIVERSITY AND JAMES

COOK UNIVERSITY.

I WANT TO FINISH UP WITH THIS

SLIDE BECAUSE BLACK AND WHITE,

ALL WE COULD AFFORD IN THE PAPER

WAS A BLACK AND WHITE

PHOTOGRAPH.

I NOW HAVE A COLOR CAMERA AND I

STILL COME DOWNTOWN HERE AND

TAKE ELLEN'S SAGE ADVICE ABOUT

OMEGA AND OTHER THINGS AND IT'S

USUALLY IN AN IRISH BAR SO THANK

YOU, VERY MUCH, ALAN.

[APPLAUSE]

[OFF MIC]

WE KNOCKED OUT A SECOND GENE

ENCODING A BAN ON THE WORMS

DIDN'T SURVIVE.

THE GRANULAR WORMS ARE

RECOVERABLE AT THE END OF THE

SIX MONTH EXPERIMENT AND WE

DON'T THINK THERE'S FIT BUT IT'S

TRACT ABLE TO DO THAT KIND OF

MALIGNANCY ASSOCIATED RODENT

EXPERIMENT.

WE CAN LOOK AT MARKERS BUT

DEFINITELY FIT ENOUGH TO DO THIS

KIND OF EXPERIMENT.

WHAT I WOULD SAY ABOUT LIVER

FLUKE THOUGH, WE DON'T HAVE ANY

PRE TENSION THAT'S WE COULD MAKE

A GERM LINE TRANSGENIC ANY TIME

SOON BUT WE CAN DEFINITELY DO

THAT WITH (INAUDIBLE) NOW.

[OFF MIC]

>> OH, BECAUSE THE --

NO, THE BLOCK IS, WELL, THE

BLOCK IS HUMAN GET AROUND ABLE

WITH MY POOR EXAMPLE OF ENGLISH.

IF YOU DON'T HAVE OMEGA, YOU

WON'T GET A GRANULOMA AND THE

GRANULOMA IS NEEDED FOR THE

TRANSIT ACROSS THE BALL WALL.

WE PRESUME WE WOULD RECOVER EGGS

FROM THE LIVER, THERE WOULDN'T

BE A GRANULOMA AND THEY VERY

WELL MAY HATCH.

THANK YOU.

>> THE NEXT SPEAKER IS Dr.

P'NG LOKE.

NIAID WAS LUCKY ENOUGH TO

RECRUIT HIM RECENTLY AND WHO IS

TALK TO TALK ABOUT HETEROGENEITY

MACROPHAGES.

>> WELL, FIRST OF ALL IT'S

REALLY SUCH A PLEASURE AND HONOR

TO BE SPEAKING AT ALAN AND IT IS

DRAG AM A FOR PUTTING TOGETHER

THIS AMAMAZING EVENT.

LONG BIFF METAL AN I WAS READING

HIS PAPER SO I AM ABOUT THE

CELLS THAT WOULD HAVE MAJOR

EFFECTS ON THE WAY THAT I

THOUGHT ABOUT PARASITE IMMUNE

RESPONSES SO AND I USE IT A LOT

IN MY PRESENTATION AND IT WAS

ALREADY THERE IN THIS ORIGINAL

REVIEW ARTICLE.

AND YOU KNOW, DURING THE COST OF

THE LAST FEW DAYS, WE'VE HEARD A

LOT ABOUT THE TCH AND HE PASSED

AND TALKING ABOUT THE ASPECTS OF

IMMUNE RESPONSE AND THE

CONTRIBUTION AND I DON'T HAVE

ALAN AND UNDERSTANDING AND AND

LONG BEFORE HE WORKED ON THE TB

GRANULOMA AND IT WAS A KEY COM

PHONE AROUND OF THE PARK IN

SOMEONE THEY GET STUCK IN THE

LIVER AND CAUSE THESE GRANULOMA

TO FORM AND IN DEED THE

GRANULOMA IS THE PASSAGE FOR THE

INTESTINE AND THIS CAME OUT

YESTERDAY THAT I OFTEN THINK OF

THIS AS BEING A GOOD MODEL FOR

TUMOR METASTASIS AND TUMORS HAVE

GRANULOMA STRUCTURE THAT MIGRATE

THROUGH DIFFERENT TISSUE WALLS

AND AS WE HEARD FROM BOB COFFMAN

EARLIER THERE WAS A REMARKABLE

PERIOD OF WORK FROM ED PEARCE

AND TOM AND ALAN TO REALLY

DESCRIBE THE FUNCTION OF AND IL4

AND IL5 AND IL-12 INTERFERON

GAMMA AND THE ROLE OF ALL THESE

CYTOKINES AND FUNCTION OF THESE

CYTO TO INITIATE THIS ENTIRE

CASCADE AND I THINK THE WORK

THAT ALAN'S GROUP HAS DONE ON

ALL THESE CYTOKINES ARE

INCREASINGLY IMPORTANT IN OUR

UNDERSTANDING OF THE ROLE OF THE

TYPE 2 IMMUNE RESPONSE AND

MAINTAINING TISSUE HOMEOSTASIS

AND IT BECOMES MORE AND MORE

CLEAR THAT OVER THE LAST, FROM

WORK OVER THE LAST FEW YEARS

THAT THIS TYPE 2 RESPONSE IS

VERY IMPORTANT FOR THE PROCESSES

OF WOUND REPAIR AND WOUND

HEALING AND TISSUE REPAIR AND

ALSO, ADD A POST TISSUE AND

METABOLISM AND I USED TO BE IN

THE CAMP THAT BELIEVED THE TYPE

2 IMMUNE RESPONSE EVOLVED TO

PROTECT US FROM HELL MINUTE

INFECTIONS TO MAINTAIN AND WAS

CO OPTED BY THE IMMUNE SYSTEM

AND THE SAME PROCESS OF WOUND

HEALING AND TISSUE REPAIR AND

VERY IMPORTANT ALSO IN

RESISTANCE AND TOLERANCE

MECHANISMS TO HELMINTH

INFECTIONS SO FOR ME PERSONALLY

AND I THINK MY INTEREST START

TODAY OVER HAL THAT WAS DONE AND

DEACTIVATED AND MAKE ROW PAGES

AND THIS CONCEPT I THINK THAT

AND AND THE TEEN SIGHT AND HE

DIFFERENT PHONY TYPE AND

ACTIVATION AND NOW WELL

SEPTEMBER AND BY EVERYONE AND

IT'S CLEAR THAT THE THESE

ALTERNATIVE MACROPHAGES AND WITH

HIGH CONCENTRATIONS O THEY'RE NT

REPRESENTATIVE PERHAPS OF WHAT

IS FOUND IN THE TISSUE AND IT'S

CLEAR SEEK EXPERIMENTS AND

MACROPHAGES IN THE TISSUE AND

FALL MORE DIFFERENT ACTIVATIONS

STATES OF WHICH AND THE OTHER IS

THESE ARE ACTIVATION STATES SO

MACROPHAGES ARE MUCH MORE

PLASTIC CELL TYPES AND THE

TRANSCRIPTION FACTORS ARE MORE

SNAPS DEPEND AND LINEAGE

DEPENDING AND THAT YOU CAN GET

WITH T CELLS.

MY INTEREST IN THESE

ALTERNATIVELY ACTIVATED

MACROPHAGES STARTED WHEN I WAS A

PH.D STUDENT AND AND IT'S

ANOTHER FAVORITE ORGANISM OF THE

LPD AND ALTHOUGH I THINK TOM

THOUGHT THESE EXPERIMENTS WHERE

WE IMPLANTED THESE PARASITES

INTO THE PERITONEAL CAVITY WAS

NOT PHYSIOLOGICAL BUT NONE THE

LESS, WHILE I WAS PH.D STUDENT

IN JUDY ALLEN'S LAB, WE FOUND

THAT THEY INDUCE ACCUMULATIONS

AND THEY HAD A DISTINCT

PHENOTYPE OF BEING ABLE TO

SUPPRESS T-CELL PROLIFERATION

AND EXPRESS THESE GENES THAT AT

A TIME THE FUNCTION OF WHICH WAS

VERY MUCH UNCHARACTERIZED AND

HAS BECOME REALLY USEFUL MARKERS

FORT PRESENCE OF IL-4 ACTIVATED

MACROPHAGES OVER THE LAST FOUR

YEARS AND WE KNOW FROM THE WORK

OF TOM WYNN THAT JUDY ALLEN'S

LAB HAS CONTINUED TO WORK ON THE

CHITON ACE LIKE MOLECULES AND

ANOTHER TRAINEE IN JUDY ALAN'S

LAB HAS CONTINUED TO WORK ON ALL

OF THESE MOLECULES PLAY VERY

IMPORTANT ROLES IN IMMUNE

REGULATION AND IMMUNE REGULATION

IS A VERY IMPORTANT FUNCTION OF

THESE ALTERNATIVE ACTIVATED

MACROPHAGES AND NOW, I WENT AND

DID MY POSTDOC TO BAL WORK IN

JIM WALL SON'S LAB AT BERKELEY

SO I SEARCHED AWAY AND STARTED

TO WORK ON MOLECULES AND ONE OF

THE THINGS I FOUND AT THE TIME

WAS IF YOU PAR TENILLEAL

MACROPHAGES IF YOU HAVE IL-4 OR

TH-2 CELLS THEY WOULD UP

REGULATE SPECIFICALLY THE PDL2

SO THE TH1 CELLS AND THE TH2

CELLS UP REGULATED PDL2 BUT THE

THING THAT BOTHERED ME ABOUT THE

WORK THAT WE DID AT THE TIME WAS

NO HARD I LOOKED THEY WERE

INDUCED NEVER UP REGULATED PDL2

AND THIS IS SOMETHING THAT

REALLY BOTHERED ME AT A TIME AND

DIDN'T MAKE IT INTO THE

MANUSCRIPT OR THE PAPER, AND IT

WAS REALLY ONLY MANY, MANY YEARS

LATER THAT I UNDERSTAND WHY THIS

WAS THE CASE AND IT COMES BACK

TO SOME OF THE SUBJECT THAT

FELIX WAS TALKING ABOUT THAT WE

KNOW NOW THAT TISSUE MACROPHAGES

COMES FROM DIFFERENT ORIGINS AND

YOU HAVE INFLAMMATORY

MACROPHAGES THAT ARE DERIVED

FROM MONOCYTES AND YOU ALSO HAVE

TISSUE RESIDENT MACROPHAGES

DERIVED FROM EMBRYONIC PRE

CURSERS THAT CAN PROLIFERATE AND

SELF-RENEW WITHIN THE TISSUES

AND IT TURNS OUT THAT DEPENDING

ON THE TYPE OF PARASITE, HELMET

PARASITE YOU ARE LOOKING AT YOU

CAN GET ACCUMULATION OF

ALTERNATIVELY ACTIVATED

MACROPHAGES THAT COME FROM

DIFFERENT ORIGINS AND SO I HAD

THIS FUN VISIT TO EDINBURGH AIR

STARTED MY LAB AT NY YOU AND

JUDY AND RICK INVITED ME BACK TO

GIVE A SEMINAR AND I WAS

CHATTING WITH JUDY AND I WAS

SAYING, OH, I KNOW WHERE THESE

ALTERNATIVE MACRO RATE ISED COME

FROM MAN OWE SIGHTS AND JUDY

ALAN WAS LIKE NO, NO, NO, THESE

COME FROM PROLIFERATING TISSUE

AND MACROPHAGES AND WHAT IT

TURNED OUT AND SO WE AND

ALONGSIDE, WE KNOW THAT IT

INDUCES THE ACCUMULATION OF

TISSUE RESIDENT ALTERNATIVELY

ACTIVATED MACROPHAGES THAT ARE

DERIVED FROM FETAL PRE CURSERS

WHEREAS, IN OUR LAB, AT THE

TIME, WE WERE STUDYING THE SHIR

SOMA AND THE MACROPHAGES YOU GET

AROUND THE ARE DERIVED FROM

MONOCYTES AND PHENOTYPICALLY

THEY CAN ALTERNATIVE MACROPHAGES

DO NOT EXPRESS AND THEY CANNOT

UP REGULATE PDL2 AND THEY

EXPRESS HIGH LEVELS OF F-4 08

AND UNCOUPLING PROTEIN UCP1 AND

THE FUNCTION OF WHICH WE STILL

DON'T FULLY UNDERSTAND AND SO

THIS ENDS UP BEING A VERY NICE

MODEL BECAUSE DEPENDING ON WHICH

LINEAGE OF MACROPHAGES YOU ARE

INTERESTED IN STUDYING, YOU CAN

USE DIFFERENT HELMET PARASITES

FOR THE DEVELOPMENTAL BIOLOGY

AND ONE OF THE REASONS I HAD

READ UP ON ALL OF THE WORK IN

AND THE CELLS WERE INVITE RALLYE

GRANULOMA AND THE PRODUCTION OF

IL-4 AND IT ALSO BECAME CLEAR TE

IL-4 WERE ACTING ON THE

MACROPHAGES IN ORDER TO HAVE THE

PROPER GRANULOMA AND SO THEY

WERE ESSENTIAL FOR HOST SURVIVAL

AND WERE INCORPORATED INTO THESE

GRANULOMA INDUCED BY THE TYPE 2

CYTOKINE.

WHEN WE STARTED THIS EXPERIMENT,

THERE WAS A QUESTION OF WHETHER

THESE MACROPHAGES WERE DERIVED

FROM LY60 HIGH OR HIGH MONOCYTES

AND IT WAS CLEAR FROM A POSTDOC

IN MY LAB, ESPECIALLY TRUE

MONOCYTE TRANSFER EXPERIMENTS IT

WAS THE LY60 HIGH MONOCYTES THAT

WERE THE SOURCE OF THESE

GRANULOMA MACROPHAGES AND THIS

WAS AROUND THE SAME TIME I WORK

FROM ED PEARCE'S LAB AND ALSO

PAUL CUBES' LAB AND IT ALL

POINTED TO THE DIRECTION OF THE

LY6C HIGH MONOCYTES AS BEING THE

PRIMARY SOURCE OF THE

ALTERNATIVELY ACTIVATED

MACROPHAGES AND WHAT WAS

INTERESTING THOUGH IS THAT AS

THE LY60 HIGH MONOCYTES

ENCOUNTER THIS INFLAMED TISSUE

THEY WOULD DOWN REGULATE

EXPRESSION OF AND ADOPT PET

TROLLING BEHAVIOR THAT WAS

REMINISCENT OF THE LOW MONOCYTE

POPULATION BEFORE UP REGULATING

EXPRESSIONS OF PDL2 AND WE

HYPOTHESIZED THIS IS A IMPORTANT

PART OF ROW MODELING PROCESS TO

REMOVE THE EGGS OUT OF THE BLOOD

VESSELS.

OF COURSE, BEING IMMUNOLOGY,

THINGS GET MORE AND MORE

COMPLICATED AND ONE OF THE

THINGS THAT TASHA IN THE LAB AT

THE TIME WAS THINKING AND WHAT

TASHA REALIZED WAS THAT THIS

INFLAMMATORY MACROPHAGES, WHEN

THEY SPENT ENOUGH TIME IN THE

TISSUES, BEGIN TO ADOPT THE

PROPERTIES OF THE TISSUE

RESIDENT MACROPHAGES AND IN THE

GRANULOMA, ONE COULD SEE THAT AS

THE GRANULOMA MATURE, THE

MACROPHAGES AROUND THE FOR FRINS

ADOPT PROPERTIES OF THE TISSUE

RESIDENT AND AND AT THE SAME

TIME, WAS STUDY THE

VITAMIN A ON THE THERE WAS A

FAILURE FOR THESE INFLAMMATORY

MACROPHAGES TO CONVERT INTO THIS

TISSUE RESIDENT PHENOTYPE.

AND IN DEED, IN VITAMIN A MICE

THEY CONDUCT SOPPED T -- LEADINC

PHONY TYPES TO ONE OF THE AND IS

THAT AND AT NYU ONE OF MY

COLLEAGUES AND DARWIN AND

POINTED OUT TO ME SOME WORK AND

WHAT WAS REMARKABLE ABOUT THIS

EPIDEMIOLOGICAL STUDY WAS THAT

THEY FOUND THAT BASELINE VITAMIN

A DEFICIENCY WAS ACTUALLY

ASSOCIATED WITH A 10 FOLD

INCREASE RISK OF TUBERCULOSIS

DISEASE AND SO IT'S POSSIBLE

THAT THIS CONVERSION PROCESS TO

TISSUE RESIDENT MACROPHAGES HEY

BE IMPORTANT FOR A WIDE RANGE OF

INFECTIOUS DISEASES AND

ESPECIALLY SITUATIONS WHERE YOU

GET FORMATION OF GRANULOMA.

NOW, BEING IMMUNOLOGY, THINGS

GET EVEN MORE COMPLICATED.

BECAUSE AS WE SHOWN WHAT WE

REALIZE AND LATER EVENT AND

SUBSEQUENT THAT IN ADDITION

VITAMIN A DEFICIENCY AND

REGULATE THIS CONVERSION AND

MACROPHAGES PHENOTYPE IN

DIFFERENT INBRED STRAINS OF MICE

AND THE RATE OF A CONVERSION TO

A TISSUE RESIDENT MACROPHAGES IS

DIFFERENT AND EVEN BETWEEN

DIFFERENT SEXES OF MICE AND IS

THIS REALLY THE WORK

FROM JUDY AND AND THEY STRUGGLE

THAT MALE MICE MORE RAPIDLY

CONVERTED BON MARROW MACROPHAGES

INTO TISSUE RESIDENT MACROPHAGES

THAN FEMALE MICE SO IN THE CASEF

JUDY ALAN'S LAB I WANTED TO SHOW

YOU THIS PARTICULAR PIECE OF

DATA FROM THEIR LAB WHERE THEY

SHOWED THAT THERE IS A BIG

DIFFERENCE BETWEEN THE BLACK SIX

MOUSE AND THE C MICE WHERE AND

THE EXPANSION OF THE TISSUE

MACROPHAGES DURING THE INFECTION

PRIMARILY THESE LARGE PARROT

TENILLE MACROPHAGES AND THERE'S

SOME EXPANSIONS OF THE MONOCYTE

DERIVED MACROPHAGES BUT IN THE C

MICE, THERE'S MUCH LESS

ACCUMULATION OF THE TISSUE

RESIDENT AND MACROPHAGES AND

THEY HAVE NOW DONE EXPERIMENTS

TO INDICATE THAT INFLAMMATORY

MACROPHAGES GET STUCK IN THE

MICE INTO A TISSUE RESIDENT

MACROPHAGES AND THIS IS

INTERESTING IN THE CONTEXT OF

INFECTION AND JUDY THINKS THIS

MIGHT BE RELATED TO THE

DIFFERENCE IN SUSCEPTIBLE

BECAUSE UNLIKE THE INTESTINAL

AND AND COMING BACK AND IN ABOVE

SEA MICE AND THERE'S LESS

CONVERSION OF THE MONOCYTE DRIVE

MACROPHAGES INTO THE TISSUE AND

YOU ALSO ZIZI GREATER

ACCUMULATION OF PDL2 POSITIVE

MACROPHAGES WHICH PREVIOUSLY NOT

SEEN IN THIS C57 BLACK SIX MICE

SO THIS MADE UP BEGIN TO REALIZE

AND AND BIOLOGY AND

DIFFERENTIATION IS BASED ON WORK

AND ALL THE LINEAGE TRACKING

SYSTEMS AND ALL THE LABS HAVE

UTILIZED BASED ON THE BLACK SIX

SYSTEM, SO NOT ONLY IS

DEVELOPMENTAL BIOLOGY

POTENTIALLY EFFECTED AND BY THE

GENETIC BACKGROUND OF THE MICE

AND CHRIS GLASS HAS DONE AND

THEY MADE BONE MARROW

MACROPHAGES FROM FIVE DIFFERENT

STRAINS OF MICE AND STIMULATED

THEM WITH IL-4 TO LOOK AT HOW

THESE GENETIC BACKGROUND OF THE

BONE MARROW MACROPHAGES AND IN

VITRO SETTING AND IT WOULD

EFFECT THE TRANSCRIPTIONAL

RESPONSE TO IL4 AND ONLY 27

GENES AND MACROPHAGES AND SO

THERE'S A HIGHLY STRAIN SPECIFIC

TRANSCRIPTIONAL RESPONSE TO IL-4

AND MEDIATED SIGNALING AND SO I

COME FROM A SELL EYE LAR

IMMUNOLOGY BACKGROUND AND IT WAS

REALLY A POSTDOC IN THE LAB

MAYSON TANG WHO KIND OF BROUGHT

US DOWN BIT ROAD OF

TRANSCRIPTIONAL REGULATIONS AND

I'M SURE THAT ALAN AND ALL THE

OTHER PEOPLE HERE HAVE

APPRECIATED WHEN THEY HAD A

TRAINEES THAT TAKEN DOWN A AND

BROUGHT THE IDEAS OF

TRANSCRIPTIONAL REGULATION TO A

LAB AND ONE OF THE THINGS THAT

SHE FOUND WAS THAT IN DEED, YOU

KNOW, IN THE PAR TA KNEAL CAVITY

THAT WAS CONSISTENT WITH THE

WORK THAT JUDY AND WE HAVE THIS

VERY LARGE THOSE STRINGS AND AND

ACTIVATION AND THIS WORK IS

BEING CONTINUED IN OUR LAB HERE

AT NYU, AT NIH.

[LAUGHTER]

I SAID THAT, I'VE BEEN USING NYU

FOR SO MANY WORDS IT'S HARD TO

TRANSITION.

AND SO THIS IS A VERY SIMPLE SIL

AND THE COMPLICATED HELM AND THE

MACROPHAGES FOR IN THIS CASE

RNA-SEQ AND WHAT IS REALLY

INTERESTING HERE IS THAT THE IS

THE STRAIN OF MICE IS ACTUAL

WILL HE EXPLAINS 61% OF THE

VARIANTS WHEREAS THE EFFECTS OF

IL-4 IS 34% OF THE VARIANTS

INDICATING THAT THE STRING

SPECIFIC EFFECTS ARE GREATER

THAN THE EFFECTS OF THIS

STIMULATION ITSELF AND WHAT

WE'VE ALSO BEEN REALLY

INTERESTED IN IS THAT DESPITE

THE FACT THAT WE THINK OF C MICE

AS BEG MORE TH-2 BOY AS WHEN IT

COMES TO THE MACROPHAGES

TRANSCRIPTIONAL RESPONSES TO

THIS IL-4IP TREATMENT, IT IS THE

BLACK SIX MACROPHAGES THAT ARE

MORE RESPONSIVE IN TERMS OF

TRANSCRIPTIONAL CHANGES IN

RESPONSE TO IL-4 AND JUST AS WAS

SHOWN IN CHRIS GOSSE'S WORK

THAT'S ACTUALLY QUITE A SMALL

OVERLAP IN TERMS OF THE GENES

THAT ARE INDUCED IN BOTH OF THE

BLACK 6 AND C MICE SO SHE'S BEEN

USING THESE DIFFERENT DENOAM I

CAN APPROACHES TO UNDERSTAND THE

DIFFERENCE THIS IS THIS

TRANSCRIPTIONAL REGULATION

RESPONSE TO IL4 IN THE BLACK SIX

MACROPHAGES.

SO I JUST WANT TO SUMMARIZE SOME

OF THE OBSERVATIONS SHE'S MADE

THAT ESSENTIALLY AS I SAID THE

BLACK SIX MACROPHAGES ARE MORE

RESPONSIVE TO IL-4 STIMULATION

AND IT DOES SEEM TO BE

ENRICHMENT FOR THE ACTIVITIES OF

THE PU1 AND NF FACTORS WHEREAS

IN THE MICE WE SEE MORE

ENRICHMENT IN THE AP1 FAMILY OF

TRANSCRIPTION FACTORS AND FOR

THE BLACK SIX GENES, THERE ARE

INDUCED BY IL4 THEY'RE

ASSOCIATED WITH SUPER ENHANCERS

WHICH MIGHT EXPLAIN WHY THEY ARE

MORE RESPONSIVE TO I L-4

STIMULATION AND THE SEA MICE IN

THE SINGLE CELL RNA-SEQ THOSE

HETEROGENEITY AND HOW IT MIGHT

APPEAR TO BE LESS

TRANSCRIPTIONALLY RESPONSIVE AND

HOWEVER WHAT WE WERE HOPING TO

DO IS MAP THE

DIFFERENCES IN THE CHROMATIN

DIFFERENCES WITH SPECIFIC

SEQUENCE IN THOSE SITES AND IN

THIS ESSENCE WE WOULD LIKE TO GO

IN AND DID CRISPR REGIONS RIGHT

AND WE WOULD FIND WE WOULD FIND

THE REGION IN THE GATA6 LOCUS

THAT WOULD THE LEVEL THAT

DIFFERENTER BETWEEN THE NOT

ASSOCIATED WITH DIFFERENCES IN

SEQUENCE IN THOSE PARTICULAR

REGIONS AND SO THERE IS

CERTAINLY STILL A LOT MORE WE

DON'T UNDERSTAND ABOUT WHY YOU

HAVE THESE STRAIN-SPECIFIC

DIFFERENCES IN EPIGENETIC AND AS

WELL AS TRANSCRIPTIONAL

RESPONSES TO IL-4 AND BUT WE

COULD GOING BACK TO THE MODEL

AND I CONTINUE TO HAVING

BRAZILIAN POSTDOCS IN THE LAB

AND A NEW POSTDOC FROM BRAZIL IN

THE LAB AND SHE HAS DONE

EXPERIMENTS WHERE WE ARE LOOKING

AT GOING BACK TO IN BRED STRAINS

OF MICE AND THIS IS THE GOING

BACK TO THE ROOTS OF PARASITE

IMMUNOLOGY AND THE BLACK 6 MICE

AND DIFFERENCES IN THE RESPONSES

AND WHAT CAMILLA HAS FOUND IS

THAT IN SOME OF THIS IS

REPEATING WORK THAT HAD BEEN

DONE IN THE 1980s AND 1990s

THAT THE DIFFERENCES IN

SUSCEPTIBLITY BETWEEN DIFFERENT

INBRED STRAINS OF MICE SO SCHISO

INFECTION AND WHAT IS

INTERESTING IS THAT SP LE

NOMEGALY THAT IS POORLY

UNDERSTAND IN THE CONTEXT OF

SCHISTO INFECTION AND AN

INDICATION OF EXTRA (INAUDIBLE)

IS MUCH GREATER IN THE STRAINS

OF MICE AND PARASITE INFECTION

AND IN DEED THIS IS NOT ACTUALLY

REFLECTED IN NECESSARILY IN THE

LIVER AND IN THE LIVER SHOWN BY

MIGGAL GROUP SUFFERED MUCH

GREATER AND SOMEHOW THEY

SURVIVED AND SEA MICE AND IT

REPRESENTS THE WORK I'VE BEEN

TRYING TO PURSUE AND IT REFLECTS

HOW HOW INFECTIONS DELIVER IN

TERMS OF PATHOGENESIS BECAUSE

PEOPLE AND IN AN ENDEMIC

SITUATION, MOST PEOPLE ARE

ASYMPTOMATIC FROM THE HELMINTH

INFECTION AND PEOPLE THAT

DEVELOP PATHOLOGY FALL ON THE

EXTREMES AND EITHER THEY ARE

SUPER INFECTED OR THEY SUFFER

FROM IMMUNO PATHOLOGY AND THIS

KIND OF DISTRIBUTION IS COMMON

AMONG ALL AND THIS KIND OF ENTER

INDIVIDUAL VARIATION IN IMMUNE

RESPONSES BETWEEN PEOPLE AND

SOMETHING THAT I THINK AND THEY

HAVE TAKEN REDUCTIONIST

APPROACHES OVER THE LAST FEW

DECADES TO TRY AND UNDERSTAND

SPECIFIC CELLULAR AND MOLECULAR

MECHANISMS BUT WHEN WE WANT TO

TRY AND UNDERSTAND VARIATIONS IN

IMMUNE RESPONSES WE MIGHT HAVE

TO TURN TOWARDS TOOLS THAT

ECOLOGISTS AND COMPUTATIONAL

BIOLOGIST USE TO MEASURE THE

EFFECT SIZES AND OF THE

DIFFERENT COMPONENTS AND OF

COURSE, IT'S GOING TO BE A

COMBINATION OF GENETIC AND

ENVIRONMENTAL FACTORS THAT

DETERMINE THIS INTER INDIVIDUAL

VARIATION BUT HOW THIS GENETIC

AND IT'S A KEY THAT FAULT IN THE

GENOME IN OFTEN FOUND THAT WILL

BE THE LARGEST CONTRIBUTORS TO

THE INDIVIDUAL VARIATION AND IN

SOME WAYS THE MICE ACTUALLY A

GOOD MODEL FOR THAT BECAUSE ONE

CAN TRACK, ONE CAN ESSENTIALLY

AND AS FORM YOU MUTATION ALANAL

SIS AND TO STUDY SEQUENCE

VARIANTS THAT FALL INTO THESE

NON CODING REGIONS.

SO, I FEEL -- SO THIS WORK OF

COURSE HAS BEEN DONE BY -- THIS

IS THE FIRST COHORT OF PEOPLE IN

THE LAB AND OF THIS COHORT,

TASHA, MICHAEL AND THAT IS AN

PLAYED CRITICAL ROLES IN OUR

STUDY ON MACROPHAGES BIOLOGY

THAT WAS ALWAYS BEEN A CLOSE

COLLABORATION WITH JUDY ALLEN

AND HER GROUP BECAUSE NOW IN THE

UNIVERSITY OF MANCHESTER AND

THIS WAS THE SECOND COHORT OF

PEOPLE IN MY LAB AND IT WAS AN

NYU JUST BECAUSE WE JOINED THE

NIH AND I'M REALLY EXTREMELY

EXCITED TO BE HERE AND WE NOW

HAVE A GREAT DEAL OF PEOPLE AND

I WANT TO REALLY THANK ALAN FOR

EVEN I THINK SEVERAL YEARS

BEFORE THE POSITION WAS

OFFICIALLY OPENED, IT WAS

ALREAENCOURAGING ME TO THINK ABT

THE POSSIBILITY OF AND THIS AND

AND MUCH LATER AND MOST OF YOU

BECAUSE HE WAS HE WAS A LEGEND

AND WHEN I MET HIM IN-PERSON AND

HE REALLY DIDN'T FIT WITH MY

INITIAL CONCEPTIONS OF THIS

LEGEND OF THE FIELD AND AND I

THINK THAT THE THING THAT HASN'T

BEEN MENTIONED BECAUSE

EVERYTHING HAS ALMOST EVERYTHING

HAS ALREADY BEEN SAID, I HAD THE

PRIVILEGE OF ORGANIZING THE

IMMUNOLOGY MODULE FOR THE PARA

SITTISM COURSE AND AND THIS IS A

LONG HISTORY AND WE INVITED ALAN

TO GIVE THE PRODUCTION TO

IMMUNOLOGY COSTS AND I WOULD SAY

80% OF STUDENTS ON THIS CAUSE

ARE BASIC AND YOU CAN SEE THE

EYES LIGHT UP AS HE EXPLAINS TO

THEM EXPANSION AND THEY'VE NEVER

THOUGHT ABOUT THAT WHOLE PROCESS

BEFORE AND SO ALAN IN ADDITION

TO ALL THE THE THINGS THAT YOU

GUYS HAVE SAID IS ALSO A

REMARKABLE TEACHER AND OF OF NEW

COMMERCE TO IMMUNOLOGY AND I

THINK IT'S REALLY A PRIVILEGE TO

NOW HAVE YOU AS A COLLEAGUE AND

OF COURSE HE IS DONE ALL THE

THINGS YOU HAVE SAID AND HE HAS

INTRODUCED ME TO EVERYONE IN THE

NIH, AND CONNECTED ME TO BASED

ON THE SCIENCE, YOU KNOW I THINK

THAT'S THE AMAZING FEATURE OF

ALAN IS HE IS ABLE TO IDENTIFY

THE RIGHT FIT OF PEOPLE BASED ON

THE WORK THAT THEY'RE DOING SO

KIND OF BRING THEM TOGETHER AND

SO WITH THAT, THANK YOU, ALAN

FOR ADOPTING ME INTO THE KIND OF

LPD/NIH FAMILY.

[APPLAUSE]

>> SO, THANK YOU AND VERY

INTERESTING.

I WANTED TO ASK ABOUT TWO OTHER

GENETIC DIFFERENCES BETWEEN

VALVE C AND 6 THAT MIGHT PLAY A

ROLE.

ONE IS THAT B6 EXPRESSES HIGHER

LEVELS OF ONE CHAIN OF THE IL-12

RECEPTORS WHICH MAKES B6 MORE

RESPONSIVE TO IL12 OF COURSE

LEADING TO INTERFERING GAMMA

PRODUCTION.

AND THE OTHER IS DIFFERENCES IN

THE NK LOCUS THAT WAYNE HAS

STUDIED EXTENSIVELY BETWEEN THE

TWO STRAINS WITH REKUM BENT

STRAINS THAT ARE PART OF ONE

STRAIN AND PART OF THE LOCUS

FROM ANOTHER STRAIN AND THAT

INFECT THINGS LIKE THE MCMV

INFECTION AND OF COURSE NK CELLS

MAKE ANOTHER GAMMA INTERFERON

CELLS SO THAT'S A LOT OF COM

ANALITY AND YOU FOCUSED ON IL-4

BUT I WONDER IF THOSE GENETIC

DIFFERENCES MIGHT PLAY A ROLE

HERE?

>> I THINK IT'S VERY
IMPORTANT

POINT THAT HAS BEEN POINTED OUT

TO ME BY DRAGANA AND DAVID SACKS

IS THAT THE DIFFICULTY IN

SEPARATING THE ENVIRONMENT FROM

THE CELL INTRINSIC EFFECTS OF

THE MACROPHAGES THEMSELVES SO WE

PLAN TO TRY AND ADDRESS THIS

QUESTION AND WHETHER THE

ENVIRONMENT AND THE TISSUE

ENVIRONMENT AND AND THE

COMPETITION OF THE IMMUNE CELLS

AND ALTHOUGH I GUESS, THE CASE

AND ADDRESS THAT AND TRUE USING,

DOING A.

>> GREAT TALK.

SO M. WHAT RELATED TO THE

COMMENTS (INAUDIBLE) DUE TO

OTHER CELLS AND THE VARIATION

CAUSED THE BEHAVIOR OF OTHER

CELLS AND I THINK DIRECTLY THE

MACROPHAGES BUT WHEN YOU THINK

ABOUT IT ALL THOSE PROBABLY

WOULD BE SOMEWHAT MARKETED GREN

ET TICK LEVEL SO HAVE YOU

ACTUALLY TRIED TO LOOK AT BEFORE

OURS AND THERE'S AND IT'S THAT

WERE PRONE THEM TO BE MORE AND

AS I SAID BEFORE AND STIMULATION

AND AND IT'S SOME OF THE WORK

THAT MING HAS BEEN DOING AND WE

LOOKED AT.

EXIST EXAMINING DIFFERENCES AND

EPI GENETIC LEVEL AND WHAT IS

INTERESTING AND THE RESPONSE TO

I-L4 BETWEEN TWO DIFFERENT

STRAINS OF MICE AND INDUCED CROW

A TIN CHANGES AND AND WHAT IS

AND THE REGENTS THAT ARE AND

STATUS AND THOSE TEND TO FALL IN

THE NON CODING REGIONS AND THE

NAIVE SO THE NAIVE CON AND AND

PROMOTE REGIONS AND SO THERE IS

LESS OF THOSE DIFFERENCES BUT

THEY'RE INDUCED CHANGES TEND TO

BE AND AND IN BETWEEN THE

STRAINS AND SO --

>> IS IT FAIR TO SAY THAT
THOSE

FUNCTIONING MOSTLY IMPORTANTLY

THE GENES AND ACTUALLY VERY

CONSERVED WHERE LESS IMPORTANT

GONE MAY REPRESENTING AND

INDUCING MAY NOT BE FUNCTIONING

AND CAN YOU ACTUALLY A GOOD

EXAMPLE THAT DEMONSTRATES AND

FUNCTIONALITY.

>> THAT'S A GREAT POINT
AND IN

FACT, I WAS TALKING TO JUDY

ALLEN ABOUT THAT AND I WAS

SPECULATING SO THAT HUMANS, THE

LONG BEEN KNOWN THAT

ALTERNATIVELY ACTIVATED GENES IN

MICE ARE NOT REFLECTIVE IN

HUMANS, RIGHT AND SO ONE OF THE

HYPOTHESIS WAS MAYBE IT'S

BECAUSE WE'RE STARTING BLACK SIX

MICE AND MAYBE WE NEED TO LOOK

AT THE CONSERVED GENES THAT ARE

CONSERVED AND ALTHOUGH AND THEY

PHASE AND THOSE ARE HIGHLY

CONSERVATIVE OF BEING INDUCED

AND WHERE THOSE ARE THE ONES

THAT ACTUALLY AND AND IT MIGHT

BE SPECIFIC CORE KIND OF EFFECTS

THAT ARE PULLING.

>> THAT'S BEAUTIFUL AS
ALWAYS.

A REMARE DIFFERENCE IS

BETWEEN NAIVE BOB C AND B6

MACROPHAGES BEGGING TO QUESTION

IF YOU AND AND MACROPHAGES AND

STRAINED CROSS TO CHAIN

DEFICIENT MICE AND TO ELIMINATE

THE FACTS OF INNATELY AND T

CELLS PRIMING IN IDEALLY EVEN

DERIVED TO GERM FREE ENVIRONMENT

WHAT DO YOU THINK WOULD BE THE

DIFFERENCES?

WOULD IT BE REDUCED?

>> I MEAN, YEAH, THAT'S
AGAIN A

GREAT IDEA TO TRY AND REMOVE AS

MUCH AS POSSIBLE THE

CONTRIBUTIONS OF THE OTHER CELL

TYPES AND INTO THE SYSTEM.

THE GROUP HAS LOOKED AT THAT

FROM THE PERSPECTIVE OF BONE

MARROW MACROPHAGES AND WE KNOW

THAT TISSUE AND MACROPHAGES ARE

NOT THE SAME AS BONE MARROW

MACROPHAGES SO THAT'S A GREAT

IDEA.

>> BONE MARROW MACROPHAGES
THE

HEAVY INFLUENCES AND JASMINE

SHOWED BEAUTIFULLY AND IT'S A

WAY TO START.

>> YEAH.

YEAH.

>> GOOD.

>> THANK YOU.

[APPLAUSE]

>> WE'RE GOING TO TURN
THIS OVER

TO TOM WYNN WHO IS GOING TO HAVE

TO PENT ULTIMATE REMARKS.

>> I SEE THE BIG BOSS IS
HERE,

HI, STEVE.

SO I PROBABLY DON'T HAVE AS MUCH

TIME AS I THINK OF THE THANK YOU

FOR ORGANIZING IT'S BEEN A

REALLY FUN TWO DAYS AND MY

CAREER AT NIH STARTED 31 YEARS

AGO AND I SPENT 26 YEARS HERE

BEFORE DECIDING TO LEAVE ABOUT

FIVE YEARS AGO AND IT WAS A VERY

HARD DECISION.

IT WAS A JOY TO WORK WITH ALAN

FOR SO MANY YEARS.

AND IT WAS A GREAT CHOICE TO

COME HERE AND I WAS DECIDING

BETWEEN HIS LABORATORY AND

ROBERT MAUD LYNN WHO WORKED ON

HELP RA SEE AND TB AND THE TH2

AND RICHARD AND THERE'S A LOT OF

FUNNY STORIES I WANT TO SHARE.

AND IT'S GREAT TO SEE LPD AND

AND INFECTION MORE THAN I STILL

HAVEN'T FOUND IT AND I KNOW IT'S

OUT THERE SOMEWHERE.

DAVID SACKS FOR LETTING ME SIT

IN HIS LAB WHEN I FIRST CAME.

ALAN'S LAB WAS OVERFLOWING WITH

PEOPLE NOT SURPRISINGLY AND

DAVID LET ME SIT IN HIS

LABORATORY AND I SAT IN THE AREA

WHERE THEY KILLED THE MICE AND

THAT WAS AN INTERESTING

EXPERIENCE AND SO I WAS SITTING

RIGHT BEHIND HIS REALLY AWFUL

OFFICE AND I STILL HAVE AND SO

THANK YOU AND THANK YOU.

WE HAD A LOT OF THIS AND A LOT

OF PEOPLE TOUCHED ON THE AMAZING

EDUCATION AND CAREER AND I'M

GOING BACK FURTHER BACK TO

COLLEGE AND THIS IS MY FIRST

CONNECTION FOR ALLEN AND AND

ALAN WOULDN'T TO OBSERVER LAND

AND FANCY AND ELITE LIBERAL ARTS

COLLEGE AND BEAUTIFUL COLLEGE

AND NEAR CLEVELAND AND SOME OF

YOU DO REALIZE AND CORRECT ME IF

I'M WRONG BUT YOU WERE AN

ENGLISH MAJOR.

>> WHAT IS IT?

>> CLASSICS.

BUT OK CLASSICS.

HE IS A GOOD WRITER BECAUSE OF

HIS EDUCATION AT THE SCHOOL I

THINK.

THERE WAS A REAL FOCUS ON

WRITING.

AND WE'VE ALL TALKED ABOUT THAT

TODAY HOWEN INFLUENTIAL THAT'S

BEEN AND AS WE MOW WE MOVED ONTO

THE MILL HILL, ASSIST APARTMENT

PROFESSOR AT HARVARD AND THE NIH

AND THIS IS WHAT WE'RE LEFT

WITH.

ALAN WAS ALWAYS A LOT OF FUN AND

HE WAS NOT ONLY A GREAT MENTOR

BUT HE WAS A REALLY FUN MENTOR

TO WORK WITH AND WE'VE GONE

THROUGH ALL OF THIS AND THE

HISTORY AND I THOUGHT I WOULD

TURN IT BACK ON ALL OF YOU

BECAUSE THIS IS WHAT ALAN CARES

ABOUT THE MOST.

I'M GLAD WE'RE ABLE TO DO THIS

NOW BEFORE YOU ARE 100-YEARS-OLD

AND WE'RE CELEBRATING YOUR

100th BIRTHDAY SO YOU STILL

REMEMBER WHO WE ARE.

AND SO IT'S GREAT YOU CAN BE

HERE AND CELEBRATE AND PUBLISH

SEMINOLE PAPERS AND WE'VE TALKED

ABOUT THE EARLY WORK WITH PHIL

SCOTT AND MOB MAUDELYNN AND IT'S

AN AMAZING AND AND ALAN AGAIN, A

LOT OF AND I THINK THIS IS ALAN,

ROB THOMPSON SENT ME THESE

PHOTOGRAPHS AND I THINK THAT'S

ALAN ON THE LEFT.

HE REALLY LIKED HALLOWEEN AND HE

LIKED TO I COULD NOT FIND A

PHOTO OF THAT AND AND BENEFITED

FROM AMMAN WORKING ON TOXO SO IT

FREED THAT AREA UP FOR THEM TO

EXCEL AND BE RECOGNIZED FOR

THEIR OWN SEMINOLE RESEARCH.

HE MOVED ON TO TALK AND I'M SURE

THE HIV EPIDEMIC HAD A LOT TO DO

WITH THAT PARTICULAR INTEREST

AND IT'S AN AMAZING GROUP OF

COLLEAGUES THAT WORKED WITH HIM

OVER THE YEARS AND SOME OF THE

NICE PAPERS THAT GROUP PUBLISHED

AND SOME OF THE MOST CITED

PAPERS ARE SHOWN HERE AND ONE

THAT WAS PERSONALLY INSPIRING

FOR ME AND TO A DIFFERENT WAY

AND AND IT'S CRITICAL AND I

THOUGHT THAT WAY IN MY OWN

RESEARCH FOR MANY YEARS AND IT

GUIDES THE RESEARCH THAT I DO.

HE ALSO MOVED ON ANOTHER MAJOR

AREA AND I HAVE TO SAY A PET

AREA OF RESEARCH IDENTIFYING THE

PERSON PARASITE FACTORS THAT

WERE DRIVING AND WHAT WERE THE

FACTORS WHAT WERE THE RESPONSE

AND AND THAT WAS A PROJECT THAT

ALAN ENJOYED HERE AND HE IS

STANCING AFTER THE DISCOVERY OF

PRO FILL AND INTERACTING WITH

RECEPTORS 11 AND THEN DRAGANA'S

BEAUTIFUL WORK ON THE OMEGA 1

THAT WE HEARD ABOUT EARLIER.

AND A BIG MOVE AGAIN THIS CAME

AROUND THE TIME WHERE I WAS

BECOMING A 10-YEAR TRACK

INVESTIGATOR AND ACTUALLY

ANOTHER FUNNY STORY IS THAT I

NEVER REALLY WORKED IN ALAN'S

LAB WHEN I FIRST CAME.

I SAT IN DAVID'S LAB AND WE

ACQUIRED SPACE IN THE SUB

BASEMENT WHERE THERE ARE NO

WINDOWS AND BUILDING 4 AND I WAS

TOWN THERE WITH LENA AND DRAGANA

AND OUR OWN LITTLE TRIO AND NO

WINDOWS AND WE WOULD BE THERE

UNTIL 8:00 AT NIGHT BECAUSE WE

HAD NO IDEA WHAT TIME IT WAS BUT

IT WAS A GOOD THING AND IT WAS A

FUN TIME AND I REMEMBER ONE

STORY THAT RICARDO COMING DOWN.

IT WAS A PLACE WHERE WE KILLED

MICE AND COLLECTED PARASITE

MATERIALS AND RICARDO COMES DOWN

COLLECTING MOUSE BRAINS TO GET

TOXO AND HE IS SITTING RIGHT

NEXT TO ME.

I WAS A MOLECULAR BIOLOGIST

DOING PCR AND RICARDO IS RIGHT

NEXT TO ME, LAB COAST, GLOVES,

MASK, EYE FIELD, AND I SAT HERE

WITH NOTHING AND NOTHING AND

RICARDO, DO I NEED TO BE WORRIED

ABOUT THIS.

TOM, TOM, NO!

YOU DON'T HAVE TO WORRY.

SURE ENOUGH, WHEN WE WENT TO THE

COURSE LATER THAT YEAR ONE OF

THE STUDIES THAT WE DID WAS TO

DO A SERUM AS SAY FOR EXPOSURE

TO AND I WAS THE POSITIVE

CONTROL AND I WAS SCREAMING AND

THANK YOU, RICARDO.

BUT THIS WAS AN AMAZING RESEARCH

AND I LIKE THE PAPER AND AND BY

ANNE REALLY AND BEAUTIFUL WORK

AND THE TV WORK IS CONTINUING IN

GREAT HANDS HERE AT THE NIH WITH

CAT AND BEGAN SO T DAN SO IT'S T

OF CHARACTERS THAT PLAYED A KEY

ROLE IN THE WORK AND I CAME INTO

ALAN'S LAB IS A PAPER LOOKING AT

THE THI AND TH2 DICHOTOMY TO

JUST TO SOME INFECTION AND IT

WAS LIKE SO I JUST THOUGHT I WAS

GOING TO FREE ASSOCIATE WHAT

WERE THE WORDS I ASSOCIATE WITH

THAT AND BE RELENTLESS AND ALAN

WAS RELENTLESS WHEN I DECIDED TO

COME TO HIS LAB.

AND IN FACT, WHEN I WAS DECIDING

BETWEEN BOB AND RICH, HE

LITERALLY AND HE CALLED AND SHE

SAID IT'S YOUR NEW BOSS ON THE

PHONE AND SO HE WAS REALLY

RELENTLESS ABOUT ME DECIDE TO GO

COME TO HIS LAB AND I ALWAYS

APPRECIATED THAT BECAUSE I KNEW

THAT HE WANTED ME TO COME AND

THAT MEANT A LOT TO ME AND I

THINK ABOUT THAT A LOT WHEN I

WOULD HIRE PEOPLE THAT MAKE IT

CLEAR THAT YOU ARE REALLY

WANTING THEM.

BE SEEN AND WOVE HEARD A LOT

ABOUT THAT AND GO TO MEETINGS

AND BRAG ABOUT YOUR WORK AND YOU

ARE THE CHEERLEADER AND I HAVE

THAT BELOW.

ALAN WAS AN AMAZING CHEERLEADER

AND ED USED THAT WORD AND ALAN

IS A CHEERLEADER.

I REMEMBER THE FIRST YEAR IN THE

LAB, NO ONE KNEW WHICH WAS AND .

PEOPLE WERE COMING UP TO ME

SAYING WOW WE LIKE YOUR WORK AND

I WAS LIKE HOW DO YOU KNOW.

I HAVE NOT PUBLISHED ANYTHING

AND ALAN WAS OUT THERE BEING MY

CHEERLEADER AND BE A STORY

TELLER AND A FANTASTIC AND

STRIVING FOR EXCELLENCE AND

WE'VE HEARD ABOUT TEAMWORK AND

THANK GOD FOR SARAH HEINE'Y AND

PAT CASPER SO WE CAN EXCEL AT

OUR WORK AND OF COURSE

COLLABORATION BOB COFFMAN AND

GORGIO AND HE HAD A GREAT

COLLABORATORS AND THAT ALSO

ELEVATED THE KIND OF WORK THAT

HE DID AND HE WAS ALWAYS

GRACIOUS AND THANKED US AND

PATIENTS AND NOT SO MUCH.

AND HE WOULD I'VE LEARNED TO BE

PATIENT IN MY OWN LIFE.

HE WAS COURAGEOUS AND LET'S TRY

WITH THEM AND LET'S SAY AND

SITTING IN THAT AWFUL SEAT AND

WE ALL LEARNED A LOT AND HE

ALWAYS CELEBRATED OUR

ACCOMPLISHMENTS AND THERE WAS A

BOTTLE OF CHAMPAGNE AND LOVED

THAT AND MADE YOU FEEL SPECIAL

AND LOVED TO PARTY AND ALWAYS

HAD GREAT PARTIES ALAN CHIEFER

WAS A PESSIMIST AND WHAT A GREAT

SITUATION.

ALAN SAID EVERYTHING IS EXCITING

AND YOU CAN DO THAT AND I COULD

TELL ALAN AND SAID YOU CAN DO

THAT FIVE YEARS AGO HE WOULD GO

TO HIS COMPLEX FILE SYSTEM AND

PULL THE PAPER OUT AND SHOW ME

BUT THERE'S ALWAYS A NEW ANGLE

ON IT AND SO I HAD TWO GREAT

MENTORS HERE AND HE WAS A GREAT

COOK AND I HAD INDIAN DINNERS

AND HE WAS VERY GOOD AT LAMB AND

THAT WAS HIS CONTRIBUTION AND

THE HOTSEAT, THIS IS LIZ WHO

COULDN'T BE HERE AND SO SHE

WOULD HAVE LOVED TO HAVE BEEN

HERE AND WE ALL HATED THIS

HOTSEAT AND I LEARNED A LOT

ABOUT WRITING AND I ALSO LEARNED

A LOT ABOUT WHAT FAVORITE WORDS

ALAN HAD AND YOU CAN THROW OUT

HIS FAVORITE WORDS AND I

REMEMBER NEVERTHELESS.

HE WAS SO HAPPY IF HE USED IT.

>> SO WILL YOU, ALAN.

I IT'S AN IMPACT AND THIS IS A

REVIEW ABOUT COLLEAGUES ABOUT

TH1 AND T H2 PARADIGM WHICH

NEVER DIES AND HOPEFULLY THIS

WILL ILLUSTRATE WHY IT'S

IMPORTANT AND ALAN WORKED ON ALL

OF THESE AND THE FLIP SIDE AND

TH-2 RESPONSE AND WHEN YOU THINK

ABOUT OTHER DISEASES THAT ARE

IMPACTED BY THIS PARADIGM,

DISEASES THAT I NOW WORK ON,

PSORIASIS, ARTHRITIS, CROWNS,

RA, ALL DRIVEN BY WHAT LOOKS

LIKE A TYPE ONE INFLAMMATORY

RESPONSE AND THEN ON THE OTHER

SIDE, THESE DISEASES, FOOD

ALLERGY, ASTHMA AND DRIVEN BY

THAT TH2 SIGNATURE AND THERE'S

SOME DISEASES THAT DON'T FALL

NEATLY INTO THESE CATEGORIES

THAT HAVE A MIXED INFLAMMATORY

RESPONSE AND WHAT IS TRULY

AMAZING IS THE NUMBER OF NEW

MEDS THAT ARE BEING MADE AND

BASED OFF OF THE SITE OWE KEEN

WORK THAT A LOT OF YOU HAVE DONE

IN THIS ROOM AND HUMARA IS A

OTHER BILLION DOLLAR A YEAR

INDUSTRY CREATING MANY DIFFERENT

DISEASES, ANTI-IL-6 AND IL-1 AND

WE THINK ABOUT IL-17, IL-23,

P-19, IL-12.

AND MULTI BILLION DOLLARS DRUGS

AND EVERY YEAR AND TREATING

THESE DISEASES AND ON THE FLIP

SIDE, THE TH2 RESPONSE AND

ANTIBODY IL4 RECEPTORS AND IL5,

MORE RECENTLY TSLP ARE START TO

GO TREAT THESE TH2 DISEASE AND

THE OVER ALL IMPACTS IS IT'S A

$1 BILLION A YEAR INDUSTRY SO A

LOT OF THAT CAN COME BACK TO YOU

AND THE TRAINEES YOU'VE TRAINED

OVER THE YEARS, I'LL STOP THERE.

THANK YOU.

[APPLAUSE]

>> WE'RE COMING TO THE END
SO

I'M GOING TO TURN IT

>> THE SCIENTIFIC DIRECTOR
OF

THE DIVISION OF INTRAMURAL

RESEARCH RIGHT HERE.

>> ALL RIGHT, ALLAN.

ALAN.

TOM, I WAS VERY HAPPY TO HEAR

YOU TALK ABOUT $100 BILLION

COMING BACK TO ALAN.

I WILL HAVE MY PEOPLE TALK TO

YOUR PEOPLE.

THANK YOU.

ALAN, HAVE YOU HAD A CHANCE TO

STAND UP AND LOOK AT EVERYBODY

HERE?

STAND UP.

JUST STAND UP.

TAKE A TURN AROUND.

THIS IS REALLY REMARKABLE.

[APPLAUSE]

I MET ALAN ABOUT 33 YEARS AGO IN

THE BASEMENT OF BUILDING 4, AND

I SAW THAT PIPETTE TIP.

I THINK IT WAS THE SAME ONE FOR

SEVERAL YEARS.

HE WAS AN ENERGETIC OMNIPRESENT

GUY, ABSOLUTELY NEVER AT REST.

THAT POISE THAT YOU CAUGHT

DANCING, IT HAD TO BE A FREEZE

FRAME BECAUSE IT DIDN'T HAPPEN

ANY OTHER TIME.

SO I HAD A CHANCE OVER THE YEARS

TO COLLABORATE WITH ALAN TO

LEARN A LOT FROM HIM, BOTH AS A

YOUNG PRE-TENURED TRACK, TENURED

TRACK, AND THEN A MORE USELESS

INVESTIGATOR.

AND ALAN HAS ALWAYS BEEN REALLY

EXTRAORDINARY IN TERMS OF THE

ABILITY TO GIVE ADVICE, TO GIVE

ENCOURAGEMENT, AND JUST TO GIVE

WISDOM.

ALAN IS A REALLY REMARKABLE GUY.

AND THIS MORNING, AS I WAS

THINKING ABOUT THIS, I HAD

REMEMBERED THAT ALAN HAD GIVEN

AN ORAL HISTORY.

I DON'T KNOW IF ANY OF YOU HAVE

READ HIS OR ANY OF THE ORAL

HISTORYS THAT HAVE BEEN DONE

HERE AT THE NIH FOR

INVESTIGATORS.

THEY'RE REALLY REMARKABLE.

AND ALAN'S HISTORY WAS

WONDERFUL.

I HAD A GREAT TIME READING THAT.

I WANTED TO SHARE A COUPLE OF

QUOTES FROM IT.

I'M NOT ORIGINAL ENOUGH TO COME

UP WITH MY OWN, AND THESE, I

PROMISE, ARE VERBATIM.

A GOOD LEADER FINDS OUT WHAT

PEOPLE ARE GOOD AT, AND THEN

LETS THEM DO THAT THING.

SEEMS PRETTY STRAIGHTFORWARD.

NOT MANY PEOPLE ARE ABLE TO DO

THAT.

I HEARD ABOUT THE HOT SEAT.

I READ ABOUT THAT TOO.

BUT IT IS THAT ABILITY TO TRY

AND FIGURE OUT, WELL, WHAT IS

SOMEBODY GOOD AT?

AND THEN MAKE SURE THAT THEY GET

A CHANCE TO DO THAT AND PROVIDE

THAT OPPORTUNITY.

AS PUN GWAS POINTING OUT, IT'S

SORT OF BEING CAUGHT IN A

SPIDER'S WEB BUT RATHER THAN

THAT SPIDER THAT SUCKS ALL THE

JUICE OUT, IT'S THE OPPOSITE.

YOU GET CAUGHT AND THEN HE'S

LIKE, HERE, COME ON, DO THIS, DO

THAT, WHAT ARE YOU DOING, DO

THIS, DO THIS.

ALAN IS A SPECIAL INVIGORATING

ENLIVENING SOURCE.

HE ALSO SAID AS YOU POINTED OUT,

MY PHILOSOPHY IS SIMPLE.

I'M A CHEERLEADER.

AND THERE'S NO QUESTION THAT

THAT IS -- YOU KNOW, THERE ARE A

LOT OF PEOPLE WHO ARE CHEER

LEERS.

THERE AREN'T A LOT OF PEOPLE WHO

ARE OUTSTANDING CHEER LEERS.

LEERED --

CHEERLEADERS.

ALAN REALLY HAS BEEN THAT

THROUGHOUT THE 33 YEARS THAT

I'VE KNOWN HIM.

IN THE LAST FEW YEARS, WE AS AN

INSTITUTION HAVE BEEN ENORMOUSLY

BLESSED TO HAVE HIM LEADING THE

PROGRAM, HELPING TO TAKE YOUNG

PEOPLE AND PERVERT THEM TO OUR

WAY OF LIFE.

[LAUGHTER]

AND ALAN DIDN'T COME TO THIS BY

ACCIDENT.

AND ONE OF THE THINGS THAT YOU

ALSO LEARN IS THAT ALAN, AS YOU

ALL KNOW, HE'S BRAVE, HE'S

INDEPENDENT, ICONICLASTIC, WISE,

AND THAT WAS SHOWN WHEN HE LEFT

BASIC IMMUNOLOGY TO GO AFTER,

EWW, PARASITES.

TOM, I KNOW WHERE YOUR FOOT IS,

DON'T WORRY.

TO GO LOOK AT PARASITOLOGY, AND

THEN WHEN HE MADE THAT HORRIBLE,

HORRIBLE BLUNDER TO LEAVE

HARVARD AND COME HERE.

MY GOD, WHAT A BACKWATER, YOU

KNOW?

WHO GOES THERE EXCEPT TO DIE?

BUT ALAN KNEW THAT THIS WAS

SMART, HE KNEW IT WAS TIME TO GO

INTO SOMETHING NEW, LIKE

PARASITOLOGY.

THE IMPACT HE'S HAD ON THESE

FIELDS AND OUR LIFE AND WORLD IN

WHICH WE LIVE HAS BEEN

EXTRAORDINARY.

SO I JUST WANTED TO CONCLUDE BY

THANKING ALAN FOR COMMITTING

THIS EXPERIMENT IN LEAVING THE

BEATEN PATH AND IN COMING HERE

AND CARVING OUT NEW AREAS AND

NEW PARADIGMS, SHARING THEM WITH

US AND SHARING THEM WITH THE

WORLD.

YOU HAVE DONE AN EXTRAORDINARY

JOB, AND MADE US RICHER AND

BETTER FOR IT.

AND I JUST WANT TO EXTEND MY

PERSONAL AND PROFESSIONAL

GRATITUDE FOR YOUR SERVICE HERE.

THANK YOU.

[APPLAUSE]

>>SO WITH THIS, THIS
CONCLUDES

THIS INCREDIBLE TWO-DAY

SYMPOSIUM IN ALAN'S HONOR.

ONE MORE CHEER FOR REALLY

PUTTING THIS TOGETHER.

[APPLAUSE]

IT WAS ABSOLUTELY -- IT COULD

NOT HAVE HAPPENED.

AND I KNOW THIS WON'T BE THE

LAST TIME WE'RE ALL TOGETHER.

SO ANYWAY, ENJOY THE REST OF THE

FESTIVITIES.