Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
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effort in training today's investigators and discovering
tomorrow's cures.
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>>TODAY WE ARE HONORED TO HAVE
DR. STEVEN HOLLAND
NIH DISTINGUISHED INVESTIGATOR,
SCIENTIFIC INVESTOR FOR ALLERGY
AND INFECTIOUS DISEASES.
DR. HOLLAND EARNED HIS MEDICAL
DEGREE FROM JOHNS HOPKINS
UNIVERSITY WHERE HE REMAINED FOR
INTERNAL MEDICINE RESIDENCY,
CHIEF RESIDENCY AND FELLOWSHIP
IN INFECTIOUS DISEASE.
HE CAME TO NIAD FROM A
LABORATORY OF MOLECULAR BIOLOGY
WORKING ON TRANSCRIPTIONAL
REVELATION OF HIV.
HE SHIFTED HIS RESEARCH TO THE
HOST SIDE WITH A FOCUS ON
PHAGOCYTE DEFECTS AND ASSOCIATED
INFECTIONS.
THE FOCUS OF THIS RESEARCH IN
THE IMMUNOPATHOGENESIS SECTION
IS A FULLY INTEGRATED APPROACH
TO INFECTIOUS DISEASE,
INCORPORATED THE MOLECULAR
GENETICS OF THE HOET AND THE
PATHOGEN AS WELL AS MECHANISMS
OF THE PATHOGENESIS.
TO GAIN NEW INSIGHTS INTO
MECHANISMS OF ACTION AND AVENUES
OF THERAPY.
THE INTEGRATED BENCH TO BEDSIDE
MODEL IS INTRINSIC TO HIS
SECTIONS APPROACH AND IS
REFLECTED IN THE CLOSE
INVOLVEMENT OF M.D. AND PH.D.
TRAININGS IN LABORATORY WORK AND
IN HIS CLINICAL APPRECIATION OF
DISEASE, WHICH TOGETHER ADD NEW
INSIGHT INTO AMERICA NICHLS OF
ACTION AND AVENUES OF THERAPY.
DR. HOLLAND IS A RECIPIENT OF
NUMEROUS AWARDS, THE NIH
DIRECTOR'S AWARD FOR DISCOVERY
OF JOB AND CO-DISCOVERY OF -- IN
2010.
HE RECEIVED THE AMERICAN COLLEGE
OF PHYSICIANS AWARD FOR SCIENCE,
BOYLE FROM THE IMMUNE DEFICIENCY
FOUNDATION AND AMERICAN SOCIETY
FOR MICROBIOLOGY AWARD.
AND THE NIH DISTINGUISHED
CLINICAL TEACHER AWARD AMONG
OTHER HONOR.
HE IS RECOGNIZED GLOBALLY FOR
HIS SCIENTIFIC EXPERTISE AND HIS
TRUE ROLE AS A ROLE MODEL OF A
CARING, COMPASSIONATE CLINICIAN
TO ALL OF HIS PATIENTS.
THE TITLE OF DR. HOLLAND'S
PRESENTATION IS DISEASE
DISCOVERY AT THE NIH CLINICAL
CENTER: TRANSLATIONAL APPROACHES
TO RARE DISEASES.
PLEASE JOIN ME IN WELCOMING OUR
SPEAKER.
[ APPLAUSE ]
>>OKAY.
THANK YOU, JOYCE.
IT REALLY IS A BLAST TO BE BACK
HERE.
IT IS GREAT TO SEE MORE THAN
FIVE PEOPLE IN THE AUDIENCE.
I COULD GET USED TO THIS AGAIN.
I HOPE THAT WE ALL GET USED TO
IT AND CAN KEEP IT GOING.
SO I BELIEVE THAT TODAY IS
REALLY MOSTLY FOR THE INCOMING
FELLOWS.
AND I CAN TELL YOU THAT'S WHAT
I'M REALLY GOING TO BE FOCUSING
ON.
FOR THOSE OF YOU WHO ARE NEITHER
INCOMING NOR FELLOWS NOR MAYBE
EVEN NOT NEW, THIS IS A GREAT
OPPORTUNITY FOR A NAP AND THE
CHAIRS ARE WELL UPHOLSTERED AND
HAVE BEEN RENOVATED DURING THE
PERIOD OF THE PANDEMIC.
SO PLEASE FEEL FREE TO RELAX.
I'M GOING TO START OUT BY
REMINDING US ALL THE FIRST
HIPPOCRATIC APHORISM POINTS OUT
LIFE IS SHORT, THE ART IS LONG,
OPPORTUNITY FLEETING, EXPERIENCE
MISLEADING AND JUDGMENT
DIFFICULT.
AND, YOU KNOW, I WOULD LOVE TO
BE ABLE TO SAY I MEMORIZED THIS
IN ALL THE DIFFERENT LANGUAGES.
THAT AIN'T TRUE.
BUT IT IS TRUE NO MATTER WHAT
LANGUAGE YOU ARE DEALING WITH.
EACH ONE OF THOSE ASPECTS OF THE
FIRST HIPPOCRATIC APHORISM TURNS
OUT TO BE IMPORTANT.
THE OTHERS GET A WHOLE LOT LESS
INTERESTING, BUT AT LEAST THEY
FRONT LOADED IT FOR THE GOOD
STUFF.
I'M GOING TO TRY TO ILLUSTRATE
BETWEEN NOW AND 3:00 SOME OF THE
ASPECTS.
FOR THOSE OF YOU WHO ARE NEW,
SOME FROM THIS REGION, SOME NOT,
I WANT TO TRY TO MAKE THIS AS
CLEAR AS POSSIBLE.
WE ARE RIGHT THERE IN
WASHINGTON, D.C.
IN FACT, WE ARE RIGHT HERE IN AN
AREA CARVED OUT IN THE STATES OF
MARYLAND AND VIRGINIA AND WE ARE
IN THIS LOCATION KNOWN AS
BETHESDA.
AND WE ARE SMACK HERE BETWEEN
TWO OF THE MAJOR ARTERIES IN
BETHESDA, OLD GEORGETOWN AND
WISCONSIN.
AND WE ARE NOW IN THIS BUILDING,
BUILDING 10, THE CLINICAL
CENTER.
IF YOU ARE NOT FROM HERE OR
DON'T HAPPEN TO HAVE A REALLY
COOL DRONE, THIS IS THE NORTH
FACE OF THE BUILDING WHERE WE
CURRENTLY HAVE THE ENTRANCE THAT
TAKES YOU RIGHT INTO THE ATRIUM
WHERE AT LEAST ONE OF THE
CRITICAL COFFEE BARS IS LOCATED.
AND IF YOU HAPPEN TO HAVE A
DIFFERENT DRONE FROM A DIFFERENT
LOCATION, THIS IS THE SOUTH SIDE
OF THE BUILDING THAT USED TO BE
THE FRONT ENTRANCE AND HAS BEEN
REORIENTING.
REORIENTING IS A CRITICAL PART
OF WHAT EDUCATION IS SUPPOSED TO
DO.
TAKING YOU FROM WHERE YOU
STARTED TO WHERE YOU END.
THE ARROW POINTS OUT WHERE THE
LIPSETT AUDITORIUM SORT OF IS,
ALTHOUGH IT DOESN'T HAVE THAT
DIRECT POINTER THERE, BUT IT IS
HOW WE UNDERSTAND WHERE WE ARE.
I POINT ALL THIS OUT BECAUSE,
YOU KNOW, AS YOU KNOW, IF YOU
CAME IN HERE TODAY, UNLESS YOU
HAVE BEEN SEQUESTERED HERE FOR
QUITE A WHILE, YOU CAME IN
THROUGH THE GATES.
YOU KNOW WE NOW HAVE A FENCE
AROUND IT.
THAT IS A REMINDER, ALBEIT TOO
STARK THAT INTRAMURAL MEANS
INSIDE THE WALL, EXTRA MURAL
OUTSIDE THE WALL.
THE EXTRAMURAL COMMUNITY WHERE
EVERY SINGLE ONE OF US CAME FROM
IS COMPOSED OF HOSPITALS,
UNIVERSITIES, RESEARCH
INSTITUTIONS AND MEDICAL SCHOOLS
AS WELL AS FACILITIES ALL AROUND
THE WORLD AND THAT IS WHERE
ABOUT 90% OF OUR TREASURE GOES
TO SUPPORTING AND FOSTERING THAT
ACTIVITY.
AND THAT IS IMPORTANT.
BUT INSIDE THE WALL, WHERE YOU
ARE NOW, AND IF YOU ARE A NEW
FELLOW, WHERE YOU WILL BE FOR AT
LEAST THE NEXT SEVERAL YEARS,
THE INTRAMURAL COMMUNITY IS
COMPOSED OF NOT ONLY WHAT IS
HERE INSIDE THESE WALLS BUT
SEVERAL OTHER AREAS AS WELL.
WE IN NIAD HAPPEN TO HAVE A
CAMPUS IN MONTANA, AT HAMILTON,
MONTANA, WHERE WE DO A LOT OF
OUR BSL4 WORK.
I STRONGLY ENCOURAGE YOU TO
THINK ABOUT TRAVELING OUT THERE.
IF YOU WANT TO GO OUT THERE,
THESE TALK TO ME ABOUT IT.
I THINK IT IS A CRITICAL PART OF
THE INTRAMURAL PROGRAM AND I
DON'T WANT ANYMORE TO NOT
EXPERIENCE IT BECAUSE OF
LIMITATIONS OF DISTANCE AND
COST.
I'M NOT TALKING ABOUT SKI
SEASON.
I'M TALKING ABOUT I'M GETTING
OUT THERE BECAUSE THERE IS
REALLY SPECTACULAR SCIENCE.
THERE ARE CAMPUSES IN ARIZONA,
NORTH CAROLINA, MASSACHUSETTS,
MICHIGAN AND OTHER PLACES AS
WELL AS FACILITIES THAT ARE AN
INTEGRAL PART OF THE INTRAMURAL
PROGRAM IN COUNTRIES AROUND THE
WORLD, IN PARTICULAR AFRICA AND
ASIA AND I KNOW OTHER INSTITUTES
DO AS WELL.
THE INTRAMURAL PROGRAM GETS
ABOUT 10% OF THE FUNDING OF THE
NIH AS A WHOLE.
BUT WHAT IS IT THAT MAKES THE
INTRAMURAL PROGRAM DIFFERENT?
I WANT TO JUST TAKE A MOMENT TO
EMPHASIZE THIS BECAUSE IT IS WHY
SOME OF US STAY.
IT IS WHY SOME GO.
AND ONE OF THE THINGS THAT MAKES
IT DIFFERENT IN THE INTRAMURAL
PROGRAM IS RETROSPECTIVE REVIEW.
SPEAKING NOW TO YOU NEW
TRAINEES, THE THREE MOST
DANGEROUS LETTERS IN THE ENGLISH
LANGUAGE ARE BSC.
THAT IS WHAT HAPPENS EVERY FOUR
YEARS WHEN YOUR PI GETS
REVIEWED.
IT IS A RETROPEKTIVE REVIEW.
THE PARABLE OF THE 10 TALENTS.
YOU ARE GIVEN THE 10 TALENTS AND
SOMEBODY COMES BACK AND SAYS
WHAT DID YOU DO.
AT THE END OF THE FOUR YEARS YOU
BETTER BE ABLE TO SAY WHAT YOU
DID.
IN THE OUTSIDE WORLD IT IS
PROSPECTIVE REVIEW, YOU SUBMIT A
GRANT, IT GETS EVALUATED, HERE
IT IS NOT THAT WAY.
SO RETROSPECTIVE REVIEW MAKES US
DIFFERENT AND WE REVEL IN THAT
DIFFERENCE.
WE HAVE TABLE RESOURCES THAT
CONTINUE FOR THE MOST PART FROM
YEAR TO YEAR.
THAT STABILITY ALLOWS YOU TO
FOCUS ON LONG-TERM RESEARCH
PROJECTS THAT CAN BE COMPLEX AND
ARE HIGHLY SUSCEPTIBLE TO
FAILURE.
DON'T BE AFRAID OF THE FAILURES.
YOU WILL LEARN MORE FROM THEM
THAN THE SUCCESSES.
I MEAN, YOU WANT TO HAVE
SUCCESSES.
DON'T GET ME WRONG.
IT IS OKAY TO HAVE THINGS GO
WRONG AS LONG AS YOU WRITE IT
UP.
FINALLY, WHAT MAKES THE PROGRAM
HERE VERY DISTINCT AND THE
STRUCTURE OF THE BUILDINGS
DISTINCT IS THE HOSPITAL AND
LABORATORIES ARE FULLY
INTEGRATED.
IN FACT, IT IS SO INTEGRATED YOU
CAN PUT AN ORDER IN THAT SAYS
PLEASE DELIVER BLOOD TO MY LAB.
THAT IS EXTRAORDINARY.
THAT MEANS WE ARE COMMITTED AT
EVERY FASICAL OF THE BEING OF
THE ORGANIZATION TO MAKE SURE
INTEGRATION OF PATIENT CARE AND
RESEARCH IS COMPLETE AND
CONSTANT.
AN HOUR, AGAIN, FOR THE CLINICAL
FELLOWS, THIS MAY HAVE BEEN GONE
OVER, IN WHICH CASE JUST SNOOZE.
YOU WILL DO CLINICAL TRAINING
AND THEN YOU CHOOSE A
LABORATORY, IT CAN BE A DRY LAB
OR A WET LAB, BUT YOU WILL SPEND
A FEW YEARS THERE.
AFTER THAT YOU HAVE TO DECIDE
WHAT TO DO.
YOU CAN STAY IN THAT LAB, BECOME
A STAFF CLINICIAN, AN ASSOCIATE,
AN ASSISTANT CLINICAL
INVESTIGATOR OR YOU CAN GO OFF
AND DO OTHER THINGS.
THE PATHWAYS OUTLINED HERE FROM
THESE DIFFERENT CATEGORIES YOU
CAN TURN INTO OTHER SORT OF
THINGS.
THE METAMORPHASIS CAN TAKE TIME.
BUT THIS IS THE STRUCTURE OF
INTRAMURAL PROGRESS MIGHT LOOK
LIKE.
THE ASSISTANT CLINICAL
INVESTIGATOR, A PRETENURE TRACT
PROGRAM.
ALLOWS YOU THREE TO FIVE YEARS
TO DEVELOP YOUR OWN PORTFOLIO OF
RESEARCH SO YOU CAN GO BACK AND
CREATE SOMETHING TO APPLY FOR A
TENURE TRACK POSITION.
THERE IS THE NIH LASKER PROGRAM
THAT ALLOWS YOU TO APPLY FOR A
POSITION THAT WILL GIVE YOU FIVE
YEARS OF INTRAMURAL TIME AND IF
YOU WANT YOU CAN GO OUT TO THE
EXTRAMURAL COMMUNITY AFTER THAT.
AND FINALLY, THERE IS THE
STATMAN SCHOLARS PROGRAM, WHICH
ALLOWS YOU TO TAKE A MORE BASIC
SCIENCE ORIENTED APPROACH THAT
ALLOWS FOR A SIX TO SEVEN-YEAR
CLOCK TOWARD TENURE.
ALL OF THESE ARE AVAILABLE
TOWARD THE END OF YOUR
FELLOWSHIP OR AFTER YOUR
FELLOWSHIP, IF THAT IS WHEN IT
IS MOST APPROPRIATE FOR YOU.
I ALSO WANT TO MAKE SURE TO
EMPHASIZE THERE ARE WAYS TO
PARTICIPATE IN PH.D. TRAINING,
IF THAT IS SOMETHING YOU AS AN
M.D. HAVE NOT DONE ALREADY.
THE OXCAM PROGRAM IS A GREAT
OPPORTUNITY.
I STRONGLY URGE YOU TO SPECIOUS
IT.
THESE PEOPLE WHO RUN THE PROGRAM
ARE AVAILABLE AND KEEN TO TELL
YOU ABOUT IT.
BY THE TIME YOU ARE DONE WITH
YOUR FELLOWSHIP, YOU HAVE OTHER
OPTIONS AS WELL.
YOU HAVE OPTIONS OUTSIDE THE
INTRAMURAL WORLD.
I HAVE BEEN HERE SO LONG, I
DON'T KNOW ABOUT THEM EXCEPT
HERE SAY AND TIKTOK VIDEOS.
THE THING THAT IS REFERRED TO
LOVINGLY BY SOME, WITH FEAR BY
OTHERS AS THE REAL WORLD.
YOU CAN GO TO ANY OF THOSE AND
I'M ACCOUNT YOUR TRAINING HERE
WILL GET YOU PREPARED FOR THEM.
SO IN SUMMARY, LIKE ALL OF GALL
MY TALK ENDS HERE.
YOU ARE THE INSIDE.
YOU WILL GET A LOT OF CLINICAL
LABORATORY RESEARCH.
YOU ARE GOING TO HAVE A LOT OF
OPTIONS.
I ENCOURAGE YOU TO TAKE
ADVANTAGE OF THOSE.
YOU WILL GET A LOT OF SUPPORT
WHEN YOU ARE HERE.
WHEN I CAME HERE, ONE OF MY
SENIOR MENTORS GARY HOFFMANN
TURNED TO ME AND SAID, STEVE, IF
YOU CAN'T MAKE IT AT THE NIH,
YOU CAN'T MAKE IT ANYWHERE ELSE.
NO PLACE ELSE IS GOING TO WORK
AS HARD ON YOUR BEHALF.
I HAVE FOUND THAT TO BE
ABSOLUTELY RIGHT.
TAKE ADVANTAGE OF WHAT YOU HAVE.
NOW I'M DONE WITH THE
PROSELYT
PROSELYTIZEDD .
WHY DO WE STUDY RARE DISEASES?
THE TRUTH IS WE STUDY THE RARE
THINGS IN ORDER TO UNDERSTAND
THE COMMON THINGS.
ONE OF THE REAL MISCONCEPTIONS
THAT PEOPLE HAVE IS THAT WHEN
YOU SEE A RARE INFECTION AND YOU
SAY, OH, THAT PERSON MUST HAVE
IMMUNODEFICIENCY BECAUSE THEY
HAVE PNEUMOSISTIS.
THEY ARE SICK.
EVERYBODY IS EXPOSED.
IT IS PRECISELY THE FACTS THAT
THOSE PEOPLE WHO GOT SICK DIDN'T
CONTROL IT THAT TELLS YOU THEY
MIGHT BE SICK.
WHAT WE ARE REALLY STUDYING ARE
COMMON INFECTIONS THAT ARE NOT
WELL CONTROLLED.
SO OUR INTEREST IS IN THE
INFECTIONS THAT ARE CAUSED BY
COMMON ORGANISMS AND OUR
HYPOTHESIS, WHICH SO FAR I HAVE
SEEN TO BE QUITE CORRECT, IS YOU
ONLY GET THREE CHOICES IN
INFECTIOUS DISEASES, THAT IS WHY
I WIND UP, BAD BUG, THINK OF
ANTHRAX OR SMALLPOX, IT IS A BAD
EXPOS
EXPOSURE, SOMEBODY GOT INJECTED
OR IT IS A HOST PROBLEM.
AND FRANKLY, OUR ASSUMPTION IS
THAT NO MATTER WHICH OF THOSE IT
IS, WE CAN FIGURE IT OUT.
AND IF WE WORK HARD ENOUGH, WE
SHOULD BE ABLE TO DISSECT THOSE
THINGS OUT.
A WORD ABOUT HOW I WOUND UP
HERE.
I DID MY TRAINING IN BATTLE AS
JOYCE SAID.
I CAME DOWN HERE IN 1989 IN
ORDER TO LEARN A LITTLE MORE
MOLECULAR BIOLOGY.
I WAS IN THE LAB OF MEL MARTIN,
AND AS I WAS WORKING THERE THIS
FRIEND OF MINE NAPED SKIP
FRANCIS, WHO IS NOW ONE OF THE
FINER GOALIES OF THE THE BEER
LEAGUE IN WHICH WE PLAY ICE
HOCKEY, SKIP CAME BY AND SAID,
THERE IS THIS GUY OVER IN
BUILDING 10 WHO'S GOT AN OPENING
THAT YOU SHOULD REALLY GO AND
LOOK AT.
THIS GUY'S NAME IS JOHN GALLIN.
I SAID, YEAH, YEAH, YEAH I'M
WORKING ON HIV.
I'M DOING SOMETHING IMPORTANT.
SKIP SAID, YEAH, YEAH.
HE CAME BACK A FEW WEEKS LATER
AND SAID, DID YOU TALK TO JOHN?
I SAID, NO, SKIP, I'M DOING
REALLY IMPORTANT THINGS HERE.
HE SAID, UH-HUH, UH-HUH, YOU
HAVE TO GO DO.
THANK GOD HE DID THAT BECAUSE IT
CHANGED MY TRAJECTORY ENTIRELY.
I WENT TO MEET THIS GUY JOHN
GALLIN, THE SCIENTIFIC DIRECTOR
OF THE INSTITUTE.
HE SAID YOU CAN COME OVER HERE
AND WORK ON ANYTHING YOU WANT AS
LONG AS IT IS NEUTROPHILS.
I SAID THAT IS A TOUGH OFFER.
HE SAID, LOOK, THE WARD IS 50
YARDS AWAY FROM YOUR LAB.
YOU CAN GO BACK AND FORTH ALL
DAY LONG, ALL NIGHT LONG IF YOU
WANT AND TAKE CARE OF PATIENTS
AND STUDY THEM IN THE
LABORATORY.
I SAID THAT IS AN EXTRAORDINARY
OPPORTUNITY.
THEN HE SAID, AFTER YOU DO ALL
THAT, AFTER YOU TAKE CARE OF ALL
THE PATIENTS I HAVE BEEN
STUDYING THE LAST NUMBER OF
YEARS, THEN YOU CAN GO OFF AND
FIND YOUR OWN DISEASES AND
THAT'S YOUR PROBLEM.
I SAID, THAT SOUNDS RIDICULOUS.
WHO GOES AROUND FINDING
DISEASES.
IT IS NOT LIKE THEY GROW ON
TREES.
I DIDN'T KNOW ABOUT WHAT THE
INTRAMURAL PROGRAM WAS LIKE.
THIS IS WHERE THE TREES ARE
PLANTED.
SO I CAME INTO JOHN'S LAB AND I
PICKED UP THE PHONE ON AN
AFTERNOON, I'M SURE IT WAS A
FRIDAY AFTERNOON, THESE THINGS
ALWAYS ARE.
IT WAS A PEDIATRICIAN FROM
FLORIDA CALLING ME FROM HIS CELL
PHONE.
THIS IS WHAT A CELL PHONE LOOKED
LIKE IN 1992.
THIS PROBABLY WASN'T 1992, THIS
WAS PROBABLY 1994.
I HAD NEVER BEEN CALLED ON A
CELL PHONE FROM A CAR BEFORE.
IT WAS PRETTY COOL.
HE TOLD ME ABOUT THIS FAMILY IN
WHICH A 5-YEAR-OLD BOY WAS SO
SICK HE WAS ON PARENTERAL
NUTRITION AND HE WAS GROWING
AVIUM FROM HIS BOWEL.
HE HAD TWO UNCLES WITH THE SAME
THING.
JOHN ESTABLISHED THE CHRONIC
GRANULOMATOUS DISEASE.
THESE GUYS SAID I WONDER IF THEY
HAVE CHRONIC GRANULOMATOUS
DISEASE?
COULD THAT BE WHAT IS GOING ON
AND WOULD YOU BE WILLING TO SEE
THEM.
M AVIUM COMPLEX IS IN THE FAMILY
OF MICROBACTERIA.
WHEN THE CAUSE OF TB WAS
DISCOVERED, HE INVITED EVERYONE
TO SEE HIS DISCOVERY.
HE HAD IT IN HIS HOUSE IN HIS
KITCHEN UNDER THE MIB SCOPE.
HE SAID, LOOK, LOOK WHAT I
FOUND.
NO YOU DIDN'T.
THAT COUNT BE THE SKAUZ OF
TUBERCULOSIS.
HE DEVELOPED OVER YEARS COX
POSTULATES TO PROVE WHAT YOU
THOUGHT WAS PORNTS IS IMPORTANT.
HE LOST THE OPPORTUNITY TO HAVE
ANYBODY OVER FOR DINNER EVER
AGAIN.
THAT WAS 141 YEARS AGO.
IN THE IMPORTANT DISCOVERY THERE
ARE 150 SPECIES OUT THERE.
TUBERCULOSIS IS A BAD ACTOR AND
CAUSES DISEASE IN LOTS OF PEOPLE
AND RESPONSIBLE FOR HUMAN TO
HUMAN SPREAD.
THESE OTHER MICROBACTERIA DOWN
HERE, THE NONTUBERCULOUS
BACTERIA ARE ACQUIRED THROUGH
AIR, THROUGH WATER, THROUGH
SOIL.
THEY ARE NOT AVOIDABLE.
AND SO, YOU KNOW, WE THOUGHT
EARLY ON THE WE UNDERSTOOD ABOUT
NONTUBERCULOUS ORGANISMS WE
WOULD LEARN MORE ABOUT
TUBERCULOSIS.
MAVIUM WHEN THERE WAS NO DRUG
FOR HIV TREATMENT, IT WAS WITH
THIS ORGANIZE HERE CALLED MAC.
THIS GUY SAID I THINK IT IS
CHRONIC MACROLOMA DISEASE.
HE SAID, CDG DOESN'T GET
DISSEMINATED MAC.
I THOUGHT THREE MALES CONNECTED
BY AN ASYMPTOMATIC FEMALE, THE
MOTHER OF MY PATIENT SAYS A IT
IS GENETIC, B IT IS PROBABLY ON
THE X CHROMOSOME AND IF IT IS
ANY OF THOSE THINGS WE SHOULD BE
ABLE TO DISCOVER IT.
I'M NOT SURE WHAT TO SAY HERE,
BUT WHY DON'T YOU SEND US THAT
PATIENT HERE TO THE NIH.
AND THE WHOLE FAMILY.
WE'LL TAKE THEM ALL.
THAT REALLY IS WHY WE HAVE A
HOSPITAL ATTACHED TO A
LABORATORY.
THERE IS NO OTHER GOOD REASON
FOR THAT.
THE WORLD DOESN'T NEED MORE
HOSPITALS.
THE WORLD HAS PLENTY OF
LABORATORIES.
WHAT WE HAVE IS UNIQUE IN
PUTTING THOSE TWO TOGETHER.
SO WHAT WE WERE THINKING ABOUT
IS THE FACT IN THE 1990s WE KNEW
MICROBACTERIA INFECT
MACROPHAGES, AND THE INTERFERE
RON GAMMA ACTIVATES A RECEPTOR
AND THAT WAS LINKED IN BEING IN
CONTROL OF MICROBACTERIA.
MYCO BACTERIA.
THIS WAS 1991 TO 1992.
INTERFERON GAMMA, THE FIRST
CYTOKINE CLONED WAS USED AND IT
WAS CLEAR IT MADE THE DISEASE
HAVE LESS INFECTIONS.
SO WE SAID, OKAY, WHAT DOES THAT
DO?
AND BY THE EARLY 1990s IT WAS
CLEAR WHAT INTERFERON GAMMA
ACTIVATED THE RECEPTOR, IT
BINDS, AGGREGATED THE RECEPTOR,
BRINGS THESE COMPONENTS
TOGETHER, LEADS TO THE
PHOPORILATION AND ACTIVATED
INTERFERON GAMMA IN THE NUCLEUS.
IT PRUSZS MORE SUPEROXIDE, NI
NIGHT -- AS WELL AS PRODUCTION
OF OTHER CYTOKINES.
WE KNEW THAT FROM BASIC STUDIES
BEFORE WE MET THESE PATIENTS AND
SAID, OKAY, LET'S BRING THEM UP.
THEY ARE GETTING
ANTI-MICROBIALS.
THAT IS NOT ENOUGH.
IT IS A GENETIC PROBLEM.
HOW ARE WE GOING TO TREAT THEM.
REGARDLESS OF THE PROTOCOL YOU
ARE FOLLOWING YOU HAVE TO BE
THINKING, HOW AM I GOING TO
TREAT THIS PATIENT.
PATIENTS ARE RELUCTANT TO HEAR
WHY THEY ARE SO SICK.
THEY WANT TO HEAR WHY THEY ARE
SICK AND HOW YOU ARE GOING TO
MAKE THEM BETTER.
LET'S TREAT THESE PATIENTS WITH
INTERDOCTORS FERON GAMMA.
IF WE COULD ACTIVATE MACROPHAGES
IT WOULD WORK.
WE WERE VERY LUCKY THE FIRST
PATIENTS WE CHOSE IN WHOM TO DO
THIS WORKED.
THIS IS A 5-YEAR-OLD BOY.
HIS GROWTH HAD BEEN STYMIED FOR
QUITE A WHILE AT AGE 4 TO 5.
HIS HEIGHT AND SERUM ALBUMEN IS
INDICATION OF NUTRITION.
HE GREW AND CAME UP TO HIS
NORMAL SIZE AND WITH TREATMENT
WE WERE ABLE TO GET HIS ALBUMEN
OFF, TAKE HIM OFF HIS PARENTAL
NUTRITION AND GET BACK TO ORAL
TREATMENT AND HE WENT BACK TO
HAVING A NORMAL LIFE.
THIS GUY AT THE BOTTOM HAD
SEVERE DISEASE.
HE KEPT ON ACCUMULATING ACYTES.
EVERY WEEK WE HAD TO TAKE FOUR
TO FIVE LITERS OF ACYTES OUT OF
HIS BELLY.
EVERY WEEK.
THIS IS THE VOLUME WE REMOVED
EACH MONTH.
WITH INTERFERON HE HAS NO CYTES.
WE THOUGHT WE STRUCK GOLD.
WE PUBLISHED THAT PAPER AND
PEOPLE WENT, WOW, THAT IS GREAT.
LET'S SEND YOU THE REFRACTORY
MICROBACTERIA WE'VE GOT.
SO THEY DID.
THE NEXT YEAR WE WERE SENT AN
18-MONTH-OLD BOY PAKISTANI WHO
LIVED IN NEW YORK.
THEY READ OUR PAPER, STARTS HIM
ON INTERFERON GAMMA AND HE
DIDN'T GET BETTER.
THEY CALLED AND SAID WHAT IS THE
PROBLEM?
IS I SAID LORD IF I KNOW.
WHY DON'T YOU REFER US THE
PATIENT.
WE WOULD BE HAPPY TO TAKE A
LOOK.
HERE IS AN EXAMPLE OF THE
PROBLEM.
WHEN YOU EXPOSE CELLS TO
ENDSOTOXIN, THEY MAKE --.
WHEN YOU ADD INTERS THERE FERON
GAMMA TO THE ENDOTOXIN, THEY
MAKE BOAT LOADS MORE.
AND THE PATIENT DIDN'T.
THAT SUGGESTED HIS PROBLEM WAS
HANDLING INTERFERON GAMMA WHICH
IS WHY IT DIDN'T WORK WHEN THEY
TREATED HIM WITH IT.
HE HAD A MUTATION IN THE
INTERFERON RECEPTOR MAKING IT
IMPOSSIBLE TO UPLOAD THE FACTOR.
THE NEXT PATIENT WE GOT CALLED
ABOUT HAS PERFECTLY LEVELS OF
INTERFERON GAMMA 1, BUT DIDN'T
RESPOND TO STIMULATION.
A 2-YEAR-OLD BOY WHOSE PARENTS
WERE MIXED ENGLISH AND
PORTUGUESE BACKGROUND WHO ALSO
WAS BEING TREATED WITH
INTERFERON GAMMA AND NOT GETTING
BETTER.
YOU CAN SEE THE PRODUCTION OF
TNF IN RESPONSE TO ENDOTOXIN WAS
NORMAL.
THEIR PARENTS UPREGULATED, HE
DID NOT.
ONE WAS NORMAL.
WHERE IS HIS PROBLEM?
IN INTERFERON GAMMA RECEPTOR 2.
THIS HELPED US BEGIN TO SAY,
OKAY, WHAT ELSE IS GOING ON IN
THIS PATHWAY.
WE KNOW WE CAN TREAT THESE
INFECTIONS IF PEOPLE HAVE AN
INTACT PATHWAY, BUT IF THEY
DON'T, WHAT DO WE NEED TO DO?
THE OVER THE YEARS, LOTS MORE
GENES HAVE BEEN IDENTIFIED IN
THE PATHWAY THAT IS RESPONSIBLE
FOR THE CONTROL OF MYCO BACTERIA
DISEASE.
IT IS MENDELLIAN SUSCEPTIBILITY.
IT IS A CATCHY NAME, ROLLS RIGHT
OFF THE TONGUE.
IT IS NICE BUT MISSES THE FACT
THIS PATHWAY CONTROLLING
SUSCEPTIBILITY TO ORGANISMS THAT
LIKE TO LIVE IN THE MACROPHAGE.
MOST OF THESE THINGS, AS I HAVE
ALREADY TRIED TO SHOW, PRESENT
IN CHILDHOOD.
AND SO OUR NEXT DILEMMA CAME
WHEN WE STARTED TO GET MORE
PEOPLE REFERRED.
NOW, AGAIN, WHO WEREN'T
RESPONDING TO INTERFERON GAMMA
BUT NOW WEREN'T CHILDREN.
THIS PATIENT A 60-YEAR-OLD WOMAN
FROM VIETNAM, SURVIVED THE WAR,
CAME OUT ON A BOAT LIFT, WHO
CLEARLY HAD BEEN THROUGH A LOT
OF EXPOSURES IN HER LIFE WAS
FINE UNTIL SHE WAS IN HER LATE
50s, BEGAN TO LOSE WEIGHT AND
DESPITE GETTING PERFECTLY GOOD
TREATMENT HAD PLENTY PERSISTENT
DISEASE.
THESE LESIONS WERE COMING FROM
OSTEOMYOLITIS LEADING TO
FRACTURES IN HER CLAVICLE.
SO WE HAVE SEEN A LOT OF GENETIC
SUSCEPTIBILITY.
WE KNOW THOSE GENETIC CONDITIONS
ARE PRESENT FROM CONCEPTION.
WHAT IS GOING ON HERE THAT SHE
COULD HAVE GOTTEN THROUGH SO
MUCH?
IT LOOKS LIKE A GENETIC DISEASE,
ACTS LIKE A GENETIC DISEASE, IT
COMES ON LATER IN LIFE.
I'M NOT SAYING 60 IS OLD, BUT IT
IS NOT CHILDHOOD.
SO WE HAVE TO THINK FURTHER
OUTSIDE THE BOX.
SO WE LOOKED AT ALL OF THE -- WE
ROUNDED UP THE USUAL SUSPECTS,
AS THEY SAY, AND DIDN'T FIND
ANYBODY WE RECOGNIZED HERE.
SO WHERE IS THE LESION?
WELL, WE DECIDED IN ORDER TO
STUDY THIS CAREFULLY, WE WOULD
NEED TO TWO TO THE SOURCE.
THIS WOMAN WAS FROM VIETNAM.
WE HAD A COLLABORATOR IN
THAILAND WHERE THEY HAD MANY
OPPORTUNISTIC INFECTIONS IN
ADULTS WHO HAD NOT HAD ANYTHING
IN CHILDHOOD.
AND WHAT DID THESE PATIENTS LOOK
LIKE.
THIS MAN HAS DISSEMINATED
TALAROMYCES, A FUNGUS.
THIS WOMAN HAS A SALMONELLA
LYMPHADENITIS.
WHEN WE WENT TO THAILAND, WE
IDENTIFIED THESE PATIENTS HAD
AUTOANTIBODIES.
WE LOOKED AT PEOPLE RESPONDING
TO INTERFERON GAMMA, PEOPLE WHO
FAILED TO RESPOND AND NOW
STARTING TO ACCUMULATE PEOPLE
WHO IN ADULTHOOD FAIL TO RESPOND
TO INTERFERON GAMMA.
THIS IS SOMETHING WE CONTINUE TO
STUDY IN SOME DETAIL.
PEOPLE ARE NOT KEEN TO BE TOLD
AT LEAST WE UNDERSTAND WHY YOU
ARE GOING TO DIE.
THEY TOLERATE IT.
THAT IS NOT WHERE WE WANT TO BE.
WE WANT TO SAY WE UNDERSTAND WHY
YOU ARE SICK AND WE ARE GOING TO
FIX IT.
AN ANTIBODY PROBLEM PRODUCED BY
ABRANT B CELLS THAT ARE NO
LONGER REGULATED, YOU CAN GO
AFTER THOSE B CELLS AND TRY TO
ATTACK THEM.
THE DRUG RETUXEMAB CAN BE QUITE
EFFECTIVE.
WHEN WE TREATED THESE PATIENTS,
THIS IS THEIR STARTING THE
TIGHTER, WHEN WE STOPPED GIVING
HER THE DRUG, HE LEVELS CAME
BACK UP, WE GAVE IT TO HER
AGAIN, THEY CAME BACK DOWN.
ALL OF THESE PATIENTS THAT
RESPONDED TO THERAPY CLEARED
THEIR INFECTIONS AND HAVE GONE
BACK TO NORMAL LIVES.
NOW, JUST I'LL POINT OUT IN
PASSES THAT THIS IS JUST THE TIP
OF THE ICEBERG.
WE'VE ALL HEARD ABOUT
AUTOANTIBODIES.
THEY ARE INVOLVED IN LUPUS, ITP
AND NEPHOTIC.
THEY BIND DIRECTLY TO CYTOKINES
AND INHIBIT THEM TO SIGNAL AND
ARE RESPONSIBLE FOR INFECTIONS.
YOU MIGHT THINK THAT IS A
PROBLEM FOR JUST US IN THE
INFECTIOUS DISEASE WORLD, BUT,
NO, IT IS PROBLEM IN NEUROLOGY,
WHERE IT CAUSES NEUROMYOLITIS
OPTS THERE ICA AND OTHER
CONDITIONS.
THESE ARE GENERALIZED PROBLEMS
AND IF YOU ARE NOT STOPPING TO
THINK ABOUT THEM, YOU ARE I
PROMISE MISSING A WHOLE LIMB OF
DEFECTS.
I SAY THAT AS SOMEBODY WHO
MISSED THAT LIMB FOR DECADES.
DON'T FOLLOW MY EXAMPLE.
THESE ARE EXAMPLES HERE OF SOME
OF THE AUTOANTIBODIES THAT ARE
CURRENTLY WELL RECOGNIZED AND
CLEARLY PATHOLOGIC.
TO SUMMARIZE THIS PART OF MY
TALK, JUST ANSWER THE PHONE.
OKAY.
ANSWER THE DAMN PHONE.
IT IS NOT THAT HARD.
IT IS NOT THAT PAINFUL.
IT IS OKAY IF IT GOES TO
VOICEMAIL.
BUT TALK TO PEOPLE.
AND IF YOU ANSWER THE PHONE
ESPECIALLY FROM PEOPLE CALLING
YOU UP BECAUSE THEY'VE GOT A
PROBLEM, YOU'LL BE AMAZED WHAT
THEY HAVE TO SAY TO YOU.
THEY CALL YOU BECAUSE THEY HAVE
A PROBLEM.
SOMETIMES IT IS A PATIENT.
SOMETIMES IT IS A DOCTOR.
SOMETIMES IT'S SOMEBODY WHO IS
LOOKING TO REFER THEM OUT.
IT REALLY CAN BE TRANSFORMATIVE.
COMPLETELY CHANGED MY LIFE.
AND I WOULD ENCOURAGE YOU TO
EMBRACE THE UNEXPECTED.
THAT IS WHERE THE NOVELTY IS.
THINGS THAT WORK OUT THE WAY YOU
EXPECT, OKAY, FINE.
THINGS THAT WORK OUT THE WAY YOU
DON'T EXPECT, THAT IS WHERE THE
FUN IS, THAT IS WHAT I HOPE WILL
KEEP YOU UP AT NIGHT AND MAKE
YOU GET INTERESTED IN DOING
MORE.
I CAN'T EMPHASIZE ENOUGH HOW
IMPORTANT IT IS TO ADMIT TO THE
HOSPITAL AND CARE FOR THE
PATIENTS.
I KNOW THERE IS A GENERAL
FEELING THAT WE HAVE MOVED INTO
A PHASE WHERE EVERYTHING CAN BE
DONE OUTPATIENT.
HIPS CAN BE REPLACED.
KNEES CAN BE REPLACED.
HEARTS CAN BE FIXED
PREDOMINANTLY OUTPATIENT.
IT IS AN EXTRAORDINARY WORLD.
I GET THAT.
IT IS ALSO A WORLD IN WHICH
HOSPITALS ARE OVERWHELMED WITH
SICK INPATIENTS.
WE HAVE A HOSPITAL THAT CAN DO
THAT AND WITHOUT REGARD FOR
INSURANCE, FOR MONEY, FOR
ETHNICITY, FOR LEGALITY OF
RESIDE
RESIDENCE.
THIS IS AN OPPORTUNITY THAT YOU
SHOULD TAKE ADVANTAGE OF.
AND FINALLY, PLEASE BE
SKEPTICAL.
NOT OF ME, BUT PLEASE BE
SKEPTICAL OF WHAT EXPLANATIONS
PEOPLE GIVE YOU.
WE ALL HAVE EXPLANATIONS THAT WE
USE TO GET THROUGH ROUNDS, TO
GET THROUGH THE AFTERNOON.
MANY OF WHICH, SEE, EVEN HARRY
POTTER KNOWS, MANY OF WHICH DO
NOT HAPPEN TO BE CORRECT.
AND WE HAVE A CHANCE HERE TO
LEARN WHAT IS TRUE.
OKAY.
THE LAST COMPONENT I'M GOING TO
TALK ABOUT IS A LITTLE BIT ABOUT
WHAT NEUTRPHIS DO.
THIS IS MY HOMAGE TO JOHN
GALLIN.
THEY HAVE A COMPLEX JOB.
THEY HAVE TO ROLL ALONG THE
ENDOTHELIUM WHERE THEY ARE
CONSTANTLY WAITING FOR SOMEONE
TO SAY, DINNER.
WHEN THE NEUTROPHIL HEARS THAT
CALL, IT PRODUCES SBEGRINS AND
BINDS TO I CAMS AND GOES OUT
INTO THE TISSUE.
IF THE NUTROPHIL CAN'T STICK, IT
CAN'T GET OUT AND IF IT CAN'T
GET OUT, ALL HELL BREAKS LOOSE.
THIS IS LEUKOCYTE DEFICIENDEFIC.
WE HAVE A BIG INTEREST GOING
BACK 40 YEARS.
THIS IS LOOKING AT THE ABILITY
OF A NUTROPHIL TO STICK TO A
GLASS SLIDE.
THIS IS WHAT IT DOES, I LOVE
GLASS.
THE PEOPLE WITH THE DEFICIENCY,
THEY CAN'T DO THAT.
THIS IS WHY GLASS SLIDES ARE
SUCH AN ENDANGERED SPECIES.
WHAT DOES THAT MEAN IN THE
HUMAN?
WHAT DOES THAT MEAN HERE?
SO NUTROPHILS ARE REQUIRED FOR A
WHOLE PILE OF THINGS.
NOT ONLY TO MAKE THE UM BELL CAL
CORD DETACH AFTER DELIVERY.
IF THEY ARE NOT FUNCTIONING, YOU
CAN'T GET THE UMBILICAL CORD TO
DROP OFF SO IT STAYS ON EXTRA
LONG.
THAT IS TO REMIND YOU THAT
NUTROPHIS ARE RESPONSIBLE FOR
REMODELING TISSUE WITH SCABBING.
THIS SCAB HAD BEEN ON HIS LEG
FOR MONTHS.
WE HAD TO GET A SURGEON TO TAKE
IT OFF.
ON THE OCCASION WHEN THE WOUNDS
DO HEAL ON THEIR OWN, THEY GET A
CHARACTERISTIC DYSMORPHIC.
THIS IS REFERRED TO AS CIGARETTE
PAPER SCARRING, WHICH MIGHT MEAN
MORE TO CHILDREN OF THE 60s THAN
YOU.
THIS IS TYPICAL.
IT IS SORT OF EMBODIED IN THIS
PICK CHUR HERE FROM THE COLON OF
A YOUNG MAN HAVING ACTIVE
COLITIS.
THESE ARE COLONIC GLANDS.
HERE IS THE INTERSTIUM.
THIS IS IN THE VASCULAR SPACE
BUT NONE ARE GETTING OUT IN THE
TISSUE.
THIS IS THE FUNDAMENTAL PROBLEM.
THEY KNOW THERE IS A PROBLEM,
BUT THEY CAN'T GET THERE TO DEAL
WITH IT.
AND ONE OF THE CONSEQUENCES OF
THIS DISEASE THAT REALLY LED ME,
IT CHANGED THE WAY I THOUGHT
ABOUT DISEASE IS THEIR TEETH.
SO TYPICALLY THE GINGIVA IS
WHERE LOTS OF THE INSIDE WORLD
MEETS THE OUTSIDE WORLD.
I DON'T MEAN JUST FLOSS.
BACTERIA AND CELLS AND ALL SORTS
OF THINGS COMING TOGETHER AND
USUALLY PATIENTS WITH LEUKOCYTE
DEFICIENCY DISEASE LOSE ALL
THEIR TEETH IN LATE ADOLESCENTS.
THIS WOMAN AGE 18 HER TEETH WERE
SO UNCOMFORTABLE AND LOOSE, YOU
CAN SEE THEY ARE BARELY BEING
HELD IN.
SHE HAD TROUBLE EATING BECAUSE
HER TEETH WAS SO LOOSE AND
PAINFUL.
AFTER THIS PICTURE WAS TAKEN HER
TEETH WERE REMOVED AND SHE WAS
MORE COMFORTABLE AND WAS ABLE TO
DO MUCH BETTER.
OKAY.
THAT IS THE BACKGROUND.
WHAT WE THOUGHT WE KNEW ABOUT
THIS DISEASE IS NUTROPHILS ARE
ABUNDANT.
THEY ARE GETTING PLENTY OF
SIGNALS TO MAKE MORE, BUT CAN'T
GET IN THE TISSUE.
THEY SENSE THE SIGNALS BUT CAN'T
GET OUT.
PATIENTS HAVE TISSUE NUTROPENIA.
THAT LEADS TO RECURRING
INFECTIONS AND GINGIVITIS IN
PARTICULAR.
I RAN INTO SOMEBODY WHO WAS KIND
ENOUGH TO TELL ME WHY I WAS SO
MISGUIDED.
IF YOU CAN'T TRUST YOUR FRIENDS
AND COLLEAGUES TO TELL YOU WHEN
YOU GET IT WRONG, WHO ARE YOU
GOING TO TRUST?
TIKTOK?
NO.
THIS IS IMPORTANT THAT SOMEBODY
THINKS IT IS WORTH THEIR TIME TO
TRY TO EDUCATE YOU.
A TENURED INVESTIGATOR IN THE
DENTAL INSTITUTE SAID I THINK
YOU NEED TO REASSESS WHAT IS
GOING ON IN ORAL DISEASE.
IT CULMINATED IN THIS.
WE DIDN'T TEACH MICE HOW TO
BRUSH.
THEY ALREADY KNEW HOW.
EXPERIMENTS YOU DO IN MICE HAVE
TO BE DONE IN HUMANS IN ORDER TO
MAKE SURE THEY MAKE SENSE.
WHAT NIKI WORKED OUT BEFORE WE
GOT TO THE PATIENT GOES LIKE
THIS.
NEUTROPHILS ARE IN THE BLOOD
VES
VESSEL.
MACROPHAGES ARE IN THE TISSUE
CONSTANTLY SAYING I WANT TO EAT
A NEUTROPHIL.
THEY PRODUCE A CYTOKINE THAT
ACTS ON T-CELLS TO PRODUCE AISLE
17 THAT LEADS TO GCSF, WHICH
DRIVES UP THE PRODUCTION OF
NEUTROPHILS.
IT HAPPENS TO LEAD TO BONE LOSS
AND INFLAMMATION.
SO WHEN MACROPHAGES ARE BEING
SATISFIED, BY GETTING A
NEUTROPHIL OUT IN THE TISSUE,
THEY STOP MAKING IL23.
THEY STOP MAKING IL17 AND
INFLAMMATION SHUTS OFF AND THE
DRIVING FORCE TO PRODUCE MORE
NEUTROPHILS GETS SHUT OFF.
WHY DO I TELL YOU?
IN LEUKOCYTE DEFICIENT, THEY
CAN'T GET OUT.
SO A MACROPHAGE IS HANGRY.
I WANT MINUTE -- I WANT MY
NEUTROPHIL.
IT GENERATES IL27, TO GENERATE
MORE IL17 AND LEADS TO MORE
INFLAMMATION AND IN THE SETTING
OF THE TEETH MORE BONE LOSS.
SO WHY AM I TELLS YOU THIS
STORY?
I WAS AT A MEETING IN ITALY AND
I WAS SORT OF APPROACHED BY A
YOUNG MAN AND HIS PARENTS.
AND THIS YOUNG MAN SAID I HAVE
LEUKOCYTE DEFICIENCY.
MY DENTIST SAID I SHOULD HAVE
ALL MY TEETH EXTRACTED.
HE LOOKED AT ME VERY SINCERELY
AND SAID, DO YOU KNOW HOW HARD
IT IS TO DATE WITH NO TEETH?
THAT IS WHAT HAD HIM WORRIED.
I SAID, I CAN IDENTIFY WITH
THAT.
AND THAT WAS REALLY ALL HE
WORRIED ABOUT.
AND SO OVER THE COURSE OF
SEVERAL MONTHS WE CORRESPONDED.
THIS IS WHAT HIS TEETH LOOKED
LIKE.
THIS PANOREX, YOU CAN SEE THE
BLUE LINE IS WHERE HIS BONE
OUGHT TO BE TO HOLD HIS TEETH IN
PLACE IN HIS JAW.
THE WHITE LINE IS WHERE THE BONE
ACTUALLY IS.
HERE ON THESE BITE WING SHOTS
THAT YOU SEE HERE YOU CAN SEE
HOW THE BONE IS COMPLETELY
RESORBED AND THE TEETH IS HELD
BY THE GUM SO WHEN HE CHEWS, IT
IS HARD.
SO WE EVENTUALLY THOUGHT THAT WE
HAD ENOUGH DATA TO REALLY BRING
HIM OVER HERE AND TO TRY TO WORK
ON GETTING HIS TEETH FIXED UP.
AND WHEN HE CAME, THIS IS WHAT
HIS TEETH LOOKED LIKE.
WHAT YOU SEE IS THE GUMS ARE
INFLAMED AND VERY RED.
YOU CAN SEE SOME RECESSION WITH
A FAIR AMOUNT OF PLAQUE BUILDUP.
WHEN NIKI GOT SAMPLES FROM HIS
GUMS, THIS IS WHAT SHE FOUND.
THAT JUST AS WE WOULD HAVE
PREDICTED, HIS LEVELS OF IL23
AND IL17 IN THE TISSUE WERE
ELEVATED, EXACTLY WHAT WE WOULD
PREDICT FOR LAD1.
HE HAS AN INFLAMMATORY REACTION
IN RESPONSE TO THE INABILITY OF
HIS NEUTROPHILS TO GET OUT IN
THE TISSUE AND THAT IS DRIVING A
LOT OF THE INFLAMMATION.
OKAY.
THAT SEEMED STRAIGHT FORWARD.
WHAT WE DIDN'T EXPECT WAS THAT
WHEN WE ACTUALLY WENT TO EXAMINE
THE PATIENT, WHAT HE DIDN'T EVEN
TELL US ABOUT WAS THAT FOR TWO
YEARS HE HAD THIS WOUND ON HIS
SACRUM.
HE SAID HE GOT IT WHILE RIDING A
MOTORBIKE.
IT WAS GETTING WORSE.
HE HAD SEVERAL SURGERIES AND HE
WAS ON ANTIBIOTICS.
HE DIDN'T MENTION THAT.
THAT DIDN'T WORRY HIM BECAUSE HE
THOUGHT HE COULD HANDLE THAT.
WE WERE A LITTLE SURPRISED, JUST
TO BE HONEST, HE HAD NOT THOUGHT
THIS WAS WORTH MENTIONS.
ALL HE WANTED TO TALK ABOUT WAS
HIS ORAL HEALTH PROBLEMS.
SO WE STARTED TO SAY, OKAY, NOW
WE HAVE A BIGGER PROBLEM THAN WE
THOUGHT.
AND WE REASONED THAT IF THIS
MECHANISM ABOUT NEUTROPHIL
INABILITY TO SATISFY THE
MACROPHAGE WAS A PROBLEM, WE HAD
OVERPRODUCTION OF IL23 AND THAT
WAS LEADING TO INFLAMMATION AND
THE WAY WE ARE GOING TO ADDRESS
THIS IS TO BLOCK IL23
SIGNALLING.
SO THE ANTIBODY USTEKINUMAB IS
USED FOR PSOARIASIS AND WE USED
THAT TO TREAT HIS INFLAMMATION.
IN THE COURSE OF 10 MONTHS, HIS
TEETH IMPROVED.
YOU CAN SEE THE REDUCTION IN
PLAQUE AND IMPROVEMENT IN GUM
HEALTH.
THIS IS THE AMOUNT OF BLEEDING
THAT HAPPENED WHEN PEOPLE WOULD
PROBE THE GUM TO SEE HOW
INFLAMED IT WAS.
REALLY DRAMATIC IMPROVEMENT.
OF COURSE, WHAT WE WERE MORE
INTERESTED IN WAS WHAT WAS GOING
ON ON HIS BACKSIDE.
AFTER 16 MONTHS, HIS WOUND
HEALED UP ENTIRELY AND HE WAS
ABLE TO GO BACK AND FINISH NOW
HIS GRADUATE DEGREE.
SO WE WERE ABLE TO PUBLISH THIS
AS A SINGLE CASE REPORT BECAUSE
IT ILLUSTRATED ELEMENTS OF
MECHANISM, PATHOPHYSIOLOGY AND
TREATMENT.
THAT HAS LED US GO ON TO DEVELOP
A PROSPECTIVE TRIAL IN WHICH WE
HAVE TREATED SIX PATIENTS.
IT IS A VERY RARE DISEASE, BUT
IT TAUGHT US A LOT IN TERMS OF
ORAL INFLAMMATION AND ORAL
HEALTH.
PART 3 AND I'M ALMOST DONE HERE.
WHEN ALL ELSE FAILS, AS THE
ADDAGE GOES, EXAMINE THE
PATIENT.
IT IS AMAZING WHAT YOU CAN FIND.
AT LEAST WHAT I FIND WITH MANY
TRAINEES, THEY FORGET THAT THERE
IS ACTUALLY, OF COURSE, AND IT
IS EASY WHEN EVERYONE IS WEARING
A MASK.
THERE IS AN ORAL CAVITY.
IT IS WORTH TAKING A LOOK IN
THERE.
IT HAS FASCINATING THINGS IN
THERE.
TEETH, TONSILS, TONGUE, THE
WHOLE AREA BELOW THE NAVEL THAT
NO ONE WANTS TO EXPLORE, BUT IT
IS ALSO WHERE PEOPLE HIDE
EMBARRASSMENT.
THIS IS WHAT HAPPENED IN THIS
YOUNG MAN'S CASE.
HE DIDN'T WANT TO TELL PEOPLE
WHAT WAS GOING ON BECAUSE HE WAS
EMBARRASSED ABOUT IT.
ONLY BECAUSE WE WERE ABLE TO
DEAL WITH THAT WERE WE ABLE TO
HELP HIM.
I ENCOURAGE YOU TO DARE TO
RETHINK THE PROBLEM.
IF A PROBLEM PERSISTS FOR A LONG
TIME IT COULD SIMPLY BE YOU HAVE
THE WRONG HYPOTHESIS.
MAN, I HAVE HAD SO MANY WRONG
HIYPOTH
HYPOTH
HYPOTHESIS.
F IF YOU DON'T SAY COULD I
EXPLORE THOSE BETTER, YOU WON'T
HAVE THE OPPORTUNITY TO DO IT.
FINALLY, I URGE YOU TO GET
COMFORTABLE WITH ERROR.
YOU ARE HERE BECAUSE YOU ARE
UNSATISFIED WITH THE MAY
MEDICINE IS TODAY.
IF YOU ARE NOT UNSATISFIED, YOU
ARE NOT PAYING ATTENTION.
THERE IS PLENTY THAT AIN'T GOING
GOOD.
YOUR JOB IS TO MAKE SURE THE
STUPID THINGS I TOLD YOU GET
UNTOLD.
THE SMART THINGS YOU HAVE TO BE
NICE ABOUT.
PAY ATTENTION.
WE HAVE A LOT WRONG AND YOU ARE
HERE TO GET IT RIGHT.
DON'T LET THE FEAR OF BEING
WRONG GET IN THE WAY.
SOMETIMES YOU JUST ARE WRONG.
AND SOMETIMES YOU HAVE TO SAY
THAT, TO YOURSELF, YOUR
COLLEAGUES AND SOMETIMES TO YOUR
PATIENTS.
THOSE ARE HARD CONVERSATIONS AND
YET IF YOU DON'T GO IN TO SAY
THAT WHEN IT HAPPENS, TO SAY,
YOU KNOW, THAT WAS A MISTAKE.
WE HAD THE WRONG IDEA.
WE HAVE TO DO SOMETHING
DIFFERENT.
IT IS MUCH EASIER TO MAKE SURE
THEY ARE ON YOUR SIDE WHEN YOU
ARE ON THEIR SIDE AND THEY KNOW
YOU ARE WILLING TO MAKE THAT
SACRIFICE.
OKAY.
SO I'M GOING TO STOP HERE AND
JUST SAY CLINICAL MEDICINE
REALLY IS A TEAM SPORT AND I
CERTAINLY DON'T TO GET TO DO ANY
OF THIS ON MY OWN.
THERE ARE A LOT OF EXTRAORDINARY
INDIVIDUALS WHO HAVE MADE THE
CLINICAL CARE THE BASIC
OBSERVATIONS, THE SCIENCE
POSSIBLE.
AND I REALLY COULD NOT DO IT
WITHOUT THIS TEAM.
I HAVE TRIED TO ACKNOWLEDGE SOME
OF THEM AS WE HAVE GONE ALONG
AND I WANT TO MAKE SURE I SHOW
YOU WHO THEY ARE.
BECAUSE I KNOW YOU ARE GOING TO
SEE THEM.
NOW THEY ARE NOT WEARING MASKS
AND NEITHER ARE YOU, YOU MIGHT
EVEN RECOGNIZE THEM.
I'M GOING TO CONCLUDE BY SAYING,
YOU KNOW, IN MY CAREER I HAVE
LEARNED A LOT FROM MY MISTAKES.
AND I'M SURE I WILL MAKE MANY
MORE.
AND I REALLY DO HOPE THAT YOU
HAVE THE CHANCE TO AS WELL.
AND THAT YOU GET THE OPPORTUNITY
TO RECOGNIZE THE THINGS YOU DID
RIGHT AND THE THINGS YOU DID
WRONG.
BECAUSE THAT'S REALLY WHERE THE
OPPORTUNITIES FOR GROWTH AND FOR
DEVELOPMENT ARE.
AND THERE WILL BE PLENTY OF
PEOPLE WHO WANT TO POINT THEM
OUT TO YOU.
IT IS NOT SO VALUABLE WHEN
SOMEONE ELSE POINTS IT OUT.
IT IS REALLY VALUABLE TO FIGURE
IT OUT ON YOUR OWN.
I HOPE YOU HAVE THE OPPORTUNITY
TO DO THAT.
I WELCOME YOU TO THE NIH.
I LOOK FORWARD TO INTERACTING
WITH YOU ON THE WARDS, THE UNITS
AND LABORATORIES FOR YEARS TO
COME.
THANK YOU.
[ APPLAUSE ]
>>THANK YOU SO MUCH FOR
YOUR TALK.
IT WAS VERY INTERESTING.
MY QUESTION WAS ABOUT THE
SECOND -- YOUR SECOND PART WITH
THE OLDER PATIENTS WHO HAD
AUTOANTIBODIES.
WERE YOU ABLE TO LOOK AT KIND OF
HOMOLOGOUS STRUCTURES AND THE
EPITOPES THESE ANTIBODIES WERE
TARGETING WITH OTHER PATHOGENS
TO SEE WHAT PATHOGEN MAY HAVE
BEEN INFECTED WITH TO PROVOKE?
>>GREAT QUESTION.
THIS IS A DISEASE THAT IS FOR
THE INTERFERON GAMMA ANTIBODIES,
THIS IS A DISEASE THAT IS ALMOST
EXCLUSIVE TO PEOPLE IN SOUTHEAST
ASIA.
SOUTHERN CHINA, VIETNAM,
CAMBODIA, LAOS AND SO ON.
AS YOU MIGHT EXPECT, WHEN YOU
GET INTO REGIONS YOU GET INTO
CERTAIN GENETIC CLUSTERS.
THIS IS AN HLA.
THERE ARE TWO PARTICULAR HLA
ALLELES.
THE ARGUMENT RUNS THE LAST 10
AMINO ACIDS ARE IDENTICAL TO
AMINO ACIDS IN A GENE -- SO
THEIR ARGUMENT, WHICH I THINK IS
A GOOD ARGUMENT, PEOPLE ARE
GETTING EXPOSED TO THE NOCT-2
GENE AND ARE DEVELOPING
ANTIBODIES AGAINST NOC-2.
THAT CROSS REACTS WITH
INTERFERON GAMMA AND IS LEADING
TO NEUTRALIZATION.
I THINK THAT IS A GOOD ARGUMENT.
SOME OF THE FLAWS OR THE
FASCINATING THINGS, IT IS ALMOST
EXCLUSIVELY SOUTHEAST ASIANS.
OKAY.
IN SOUTHEAST ASIA THE RATE OF
MALES AND FEMALES IS ABOUT
EQUAL.
ONCE PEOPLE LEAVE SOUTHEAST
ASIA, IT IS ALMOST EXCLUSIVELY
WOMEN.
THAT IS A LITTLE FUNNY.
AND PEOPLE OF THE SAME ETHNICITY
BORN IN OTHER COUNTRIES DON'T
SEEM TO GET IT.
SO THAT SUGGESTS THAT THERE IS A
GENETIC COMPONENT, A GEOGRAPHIC
COMPONENT, COULD BE AN EXPOSURE.
AND THEN THERE IS A GENDER
COMPONENT.
I DON'T UNDERSTAND IT, BUT THAT
IS THE ARGUMENT AROUND WHAT IS
REALLY GOING ON IN TERMS OF THE
MIMICRY.
>>VERY COOL.
THANK YOU.
>>SURE.
>>HI DR. HOLLAND.
THANK YOU SO MUCH FOR THE TALK.
THIS IS MORE OF A GENERAL
QUESTION, BUT IN YOUR EXPERIENCE
AS A CLINICIAN SCIENTIST, IS
THERE A TENSION BETWEEN TREATING
PATIENTS IN A TIMELY MANNER AND
TAKING CARE OF RESEARCH.
HOW DO YOU STRIKE A BALANCE
BETWEEN THE TWO FACTORS IF THERE
IS.
>>I CAN'T THINK ABOUT ANYTHING
IN LIFE THAT INVOLVES TIME THAT
DOESN'T INVOLVE TENSION.
WHETHER IF IT IS TIME FOR
DINNER, TIME FOR SLEEP, TIME FOR
ANYTHING ELSE.
IF YOU ARE ASKING ME DOES TIME
MAGICALLY APPEAR WHEN YOU WANT
TO DO RESEARCH OR PATIENT CARE?
NO.
IT DOES NOT.
THERE IS ALWAYS A TENSION WHEN
YOU HAVE TWO THINGS YOU WANT TO
DO AT THE SAME TIME.
AND, YOU KNOW, GOOD LUCK WITH
THAT.
BUT I DON'T THINK THAT JUST
BECAUSE THERE IS TENSION DOESN'T
MEAN IT IS NOT SOLUBLE.
AND, OF COURSE, THERE IS A
TENSION BETWEEN TRYING TO GET
THROUGH ALL OF THE THINGS YOU
WANT TO GET THROUGH IN ANY DAY.
I DON'T KNOW IF YOU MAKE LISTS
FOR YOUR DAY, YOU KNOW, MOST OF
US MAKE LISTS THAT DON'T ALWAYS
GET COMPLETED.
AND HOW TO STRUCTURE YOUR
ACTIVITIES SO THAT YOU CAN MAKE
SURE THAT PATIENTS GET PROVIDED
THE CARE THEY NEED AND THAT YOU
CAN DO THE RESEARCH, I WOULD
JUST SAY ONE MORE THING.
THAT IS TRYING TO CREATE THIS
DICHOTOMY IN WHICH RESEARCH AND
PATIENT CARE ARE OPPOSED TO EACH
OTHER OR NOT OVERLAPPING WITH
EACH OTHER, I THINK MISSES THE
POINT OF WHAT WE CAN DO HERE.
AND I FIND IT VERY DIFFICULT
WHEN THERE IS A HARD DISTINCTION
BETWEEN RESEARCH AND CARE.
WE DO RESEARCH IN ORDER TO MAKE
THE CARE BETTER.
WE DO CARE IN ORDER TO MAKE THE
RESEARCH RELEVANT.
I WOULD URGE YOU TO TRY AND FIND
WAYS TO MAKE THOSE OVERLAP AS
MUCH AS POSSIBLE.
AND WHAT I FOUND HERE THAT IS
DIFFERENT THAN WHAT I FOUND ON
THE OUTSIDE IS THAT I CAN ADMIT
ONLY THE PATIENTS THAT I'M GOING
TO BE STUDYING AND STUDY ONLY
THE PATIENTS THAT I ADMIT.
THAT IS WHY WE DON'T HAVE AN
EMERGENCY ROOM.
NOT BECAUSE WE DON'T THINK
EMERGENCY DISEASE IS IRRELEVANT.
BECAUSE IT IS VERY HARD TO MAKE
SURE WE CAN DO THE RESEARCH AT
THE SAME TIME.
I'M SURE I HAVE EVADED YOUR
QUESTION VERY CAREFULLY, BUT
THERE IS PLENTY OF TENSION IN
LIFE AND THANK GOD FOR THAT.
>>THANK YOU SO MUCH.
>>GREAT.
WONDERFUL TALK.
I'M WONDERING IF YOU CAN THINK
ABOUT ONE EXAMPLE FROM YOUR
EARLY FELLOWSHIP THAT FAILURES
TAUGHT YOU MORE THAN SUCCESSES.
SOMETHING THAT HELPED YOU GROW
AND HOW YOU TRANSFORMED THAT
INTO A SUCCESS.
>>I THOUGHT THAT IT WAS OKAY TO
GO AHEAD AND STOP HIS
INTRAVENOUS ANTIBIOTICS.
I THOUGHT WE ACHIEVED ADEQUATE
CONTROL.
I THOUGHT HE WAS OKAY.
I TURNED OUT TO BE TRAGICALLY
WRONG.
I DON'T KNOW IF I CONTINUED
THEM, I WOULD HAVE COME UP WITH
A DIFFERENT OUTCOME.
I DO KNOW THAT AFTER I STOPPED,
THINGS GOT MUCH WORSE.
YOU KNOW, YOU HAVE TO
DIFFERENTIATE BETWEEN TRYING TO
TREAT YOUR LAST ERROR AND TRYING
TO MOVE FORWARD.
AND I'VE TRIED TO INCORPORATE
WHAT I UNDERSTOOD FROM THAT,
THAT IS DON'T STOP EVEN WHEN YOU
THINK YOU ARE OKAY, YOU MIGHT
NOT BE.
USE AS MANY DIFFERENT TECHNIQUES
AS POSSIBLE TO FIGURE THAT OUT.
IT TAUGHT ME A LOT ABOUT WHAT
YOU CAN DO IN THE SETTING OF
IMMUNE DEFICIENCY WITH SEVERE
DISEASE.
I KNOW WE ARE AT TIME.
THANK YOU VERY MUCH.
[ APPLAUSE ]
>>IT IS WONDERFUL TO SEE THE
BIG CROWD.
I WANT TO SAY OUR GRAND ROUNDS
PROGRAM ARE GOING TO CONCLUDE
WITH THIS PRESENTATION UNTIL
SEPTEMBER.
WONDERFUL TO SEE YOU.
PLEASE COME BACK IN THE FALL.
IT IS GREAT TO SEE A CROWD AND
THE SPEAKERS REALLY APPRECIATE
IT.
THANK YOU SO MUCH.