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]
>> 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.