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.
The NIH Clinical Center is the world's largest hospital totally
dedicated to investigational research and leads the global
effort in training today's investigators and discovering
tomorrow's cures.
Learn more by visiting us online at http://clinicalcenter.nih.gov
OUR SPEAKER TODAY IS Dr.
MICHAEL M. GOTTESMAN THE
NATIONAL INSTITUTE OF HEALTH OR
NIH DEPUTY DIRECTOR FOR
INTERMURAL RESEARCH SINCE 1993.
Dr. GOTTESMAN IS A SENIOR
INVESTIGATORS AND CHIEF OF THE
LABORATORY OF CELL BIOLOGY AND
HEAD OF THE MULTI-DRUG RESISTANT
SECTION AT THE NATIONAL CANCER
INSTITUTE OR NCI.
Dr. GOTTESMAN EARNED HIS
MEDICAL DEGREE FROM HARVARD
UNIVERSITY MEDICAL SCHOOL AND
COMPLETED HIS INTERNSHIP AND
RESIDENCY IN MEDICINE AT THE
PETER BENT BRIGHAM HOSPITAL IN
BOSTON, MASSACHUSETTS.
HE RECEIVED HIS POSTDOC TO BAL
RESEARCH TRAIN NORTH MOLECULAR
GENETICS AT THE NIH.
HE RETURNED TO HARVARD MEDICAL
SCHOOL AS AN ASSISTANT PROFESSOR
IN THE DEPARTMENT OF AN A MAT .
HE WAS THE CHIEF OF LABORATORY
OF CELL BIOLOGY AND NCI AND IN
1990 AND FROM 1992, TO 1993, HE
WAS THE ACTING DIRECTOR FOR THE
NATIONAL CENTER FOR HUMAN GENOME
RESEARCH OR NHGRI.
HE SERVED AS THE ACTING
SCIENTIFIC DIRECTOR FOR NHGRI IN
1993 BEFORE HE BECAME THE NIH
DEPUTY DIRECTOR FOR INTERMURAL
RESEARCH.
WITH OVER 550 PEER REVIEWED
SCIENTIFIC PUBLICATIONS, Dr.
GOTTESMAN RESEARCH INTEREST HAS
RANGED FROM HOW DNA IS
REPLICATED IN BACTERIA TO HOW
CANCER CELLS ELUDE CHEMOTHERAPY.
HIS LABORATORY IDENTIFIED THE
HUMAN GENE THAT CAUSES CANCER
CELLS TO RESIST ANTICANCER
DRUGS, AND HAS USED THIS
INFORMATION TO CREATE GENE
TRANSFER VECTORS TO CIRCUMVENT
DRUG RESISTANCE IN CAN SEPTEMBE.
HIS WORK HAS DETERMINED THE
CLINICAL RELEVANCE OF THESE
MECHANISMS.
IN HIS ROLL-OVER SEEING THE
INTRAMURAL RESEARCH PROGRAM AT
THE NIH, Dr. GOTTESMAN HAS
INITIATED SEVERAL TRAINING AND
MENTORING PROGRAMS FOR HIGH
SCHOOL, COLLEGE, POSTBAC
LAUREATE, MEDICAL AND GREAT WAD
STUDENTS.
THIS INCLUDES TRAINING PROGRAMS
FOR STUDENTS FROM DISADVANTAGED
POPULATIONS, PROGRAMS TO ADVANCE
CAT REOF WOMEN SCIENTISTS AND
LOAN REPAYMENT PROGRAMS AND THE
TENURE TRACK FACULTY DEDICATED
TO BUILDING A MORE DIVERSE AND
INCLUSIVE SCIENTIFIC COMMUNITY
AND FOR BOTH CLINICAL AND
LABORATORY BASED INVESTIGATORS
AND THE TRANS NIH TENURE TRACK
RECRUIT MANY PROGRAM AND THE
LASKERS PROGRAM.
HE OVERSEES THE REVIEW PROCESS
AND FOR 1100 PRINCIPLE
INVESTIGATORS AND IS THE
INSTITUTION OFFICIAL FOR HUMAN
SUBJECTS RESEARCH AND ANIMAL
CARE AND USE AND TECHNOLOGY
TRANSFER AT THE NIH AND THE
AMERICAN SEWIZATION OF
PHYSICIANS AND THE AMERICAN
SOCIETY FOR PHARMACOLOGY AND
EXPERIMENTAL THERAPEUTICS AND
BEEN A ELECTED MEMBER OF THE
NATIONAL ACADEMY OF MEDICINE
SINCE 2003 AND THE ACADEMY OF
ARTS AND SCIENCES SINCE 2008,
AND THE NATIONAL ACADEMY OF
SCIENCES SINCE 2018.
THE TITLE OF Dr. GOTTESMAN'S
PRESENTATION TODAY IS
"CONDUCTING AN OVERSEEING
RESEARCH, LESSONS LEARNED"
PLEASE JOINED ME IN EXTENDING A
WARM WELCOME TO TODAY'S GREAT
SPEAKER/TEACHER, Dr. MICHAEL
GOTTESMAN.
>>THANK YOU SO MUCH FOR THAT
VERY GENEROUS INTRODUCTION.
IT'S NOT SURPRISING THAT I'M
EXHAUSTED.
[LAUGHTER]
SO, TOM BERKLOW THE DIRECTOR OF
THIS SERIES ASKED IF I WOULD
GIVE A LECTURE ABOUT MY
EXPERIENCE BOTH AS A SCIENTIST
AT THE NIH AND AS THE
ADMINISTRATOR WHO IS RESPONSIBLE
FOR OVERSEEING THE INTRAMURAL
RESEARCH PROGRAM.
I THOUGHT QUITE A LOT ABOUT HOW
TO DO THIS.
I'VE GIVEN SIMILAR TALKS BEFORE.
I THOUGHT IT WOULD BE NICE TO
TELL YOU WHAT I'VE LEARNED
DURING MY EXPERIENCE HERE,
ALMOST 50 YEARS AT THE NIH, IN
TERMS OF THE WAY SCIENCE CAN BE
CONDUCTED AND THE BEST WAY TO
OVERSEE SCIENCE AND I DISCOVERED
SOME COMMONALITIES AND I'D LIKE
TO FOCUS ON THOSE COMMONALITIES
AS I TALK TODAY TO YOU.
I HAVE NO FINANCIAL CONFLICTS OF
INTEREST TO REPORT AND THERE
WILL BE NO UNAPPROVED OR
OFF-LABEL DRUGS IN MY
PRESENTATION.
SO, AGAIN, MY OBJECTIVES ARE TO
SUMMARIZE THE CHALLENGES
ASSOCIATED WITH PURSUING A MAJOR
RESEARCH PROGRAM AS WELL AS
OVERSEEING RESEARCH AT THE NIH.
HOPEFULLY ACQUAINT YOU WITH BEST
PRACTICES MOVING FORWARD.
LET ME START WITH A MAJOR MENTOR
AND ADD V ADVOCATES, RUTH
KIRSCHSTTEIN.
SHE HAS THE NRSA AWARDS ARE
NAMED AFTER HER IN HER HONOR.
SHE WAS FOR SEVEN YEARS, WHEN I
FIRST BEGAN AS DEPUTY DIRECTOR
FOR INTRAMURAL RESEARCH SHE WAS
THE PRINCE PAP DEPUTY DIRECTOR
AND ACTING NIH DIRECTOR AND RUTH
USED TO SAY AND THE QUOTE IS
HERE BUT NOT PRECISE, SHE SAID
IN MY EXPERIENCE, PROBLEMS
ACCOUNTED IN MANAGING SCIENCE
MAY BE MORE DIFFICULT THAN THOSE
ENCOUNTERED IN THE RESEARCH
LABORATORY AND I THINK I SHARE
THAT BELIEF THE LAB IS GREAT
FUND AND A GREAT CHALLENGE BUT
MANAGING MANY PEOPLE WHO ARE
DOING SCIENCE CAN BE EVEN MORE
CHALLENGING AND THERE ARE MANY
OPPORTUNITIES, BOTH TO DO GOOD
AND ALSO TO MAKE MISTAKES.
SO, I'M GOING TO CARRY THROUGH A
CERTAIN NUMBER OF LESSONS THAT
I'VE LEARNED AND LESSON NUMBER
ONE IS YOU HAVE TO FOCUS ON AN
IMPORTANT PROBLEM AND THAT'S IN
ADMINISTRATIVE AND SCIENTIFIC
WORK.
MY SCIENTIFIC WORK, AS DAN
MENTIONED, HAS BEEN FOCUSED ON
WHAT IS THE MOLECULAR BASIS FOR
MULTI-DRUG RESISTANCE IN CANCER.
THE PROBLEM OF COURSE IS THAT
WE'RE VERY SUCCESSFUL IN
TREATING CANCER THAT IS SPREAD
WITH CHEMOTHERAPY.
MANY PATIENTS REALLY HAVE
PROFOUND LOSS OF SYMPTOMS OF
CANCER.
VERY FREQUENTLY AND FOR SOLID
TUMORS THE CANCER RECURES AND
THE TUMORS ARE RESISTANT TO
THERAPY AND THE PATIENTS DIE
UNFORTUNATELY.
WE WERE INTERESTED IN FIGURING
OUT WHAT WE COULD LEARN ABOUT
MULTI DRUG RESISTANCE THAT WOULD
IMPROVE THE TREATMENT OF CANCER.
WITH RESPECT TO THE SCIENCE
MANAGEMENT ISSUE, WHAT IS THE
MISSION OF THE INTRAMURAL
RESEARCH PROGRAM?
WELL, IT'S RELAT REALLY AN IMPOT
MISSION FOR HIGH-IMPACT
LABORATORY CLINICAL AND
POPULATION-BASED RESEARCH TO
FACILITATE NEW APPROACHES TO
IMPROVE HEALTH THROUGH
PREVENTION, DIAGNOSIS, TREATMENT
AND RESPOND TO PUBLIC-HEALTH
EMERGENCIES AND TO TRAIN THE
NEXT GENERATION OF BIOMEDICAL
RESEARCHERS.
CLEARLY ALL IMPORTANT PROBLEMS.
SO, TO GO BACK TO MY RESEARCH,
YOU NEED TO SET ACHIEVABLE GOALS
AND I ACTUALLY RECENTLY CAME
UPON A STRATEGIC PLAN I WROTE
WHEN WE FIRST STARTED WORKING ON
MULTI-DRUG RESISTANCE AND I SHOW
HERE SOME PICTURES OF THE PEOPLE
WHO MADE THIS POSSIBLE AND
ANOTHER THEME THAT'S GOING TO BE
RECURRENT IS THAT THE PEOPLE YOU
WORK WITH ARE REALLY CRITICAL IN
HELPING YOU SOLVE PROBLEMS.
OUR FIRST GOAL WAS TO SELECT
CELLS AND WE WANTED HUMAN LINES
BECAUSE WE WANTED REAGENTS, GENE
PROBES AND ANTIBODIES AND SO ON,
THAT COULD BE USED FOR HUMAN
STUDIES.
AND SO THAT WORK BEGAN WITH
SHIN-ICHI AKIYAMA AND WE NEEDED
TO CLONES THE GENES RESPONSIBLE
FOR RESISTANCE AND I WAS AT A
GORDON CONFERENCE PRESENTING OUR
WORK ON THESE HIGHLY DRUG
RESISTANT CELL LINES AND I HAD A
POSTER NEXT TO IGOR ROBINSON A
POSTDOC TO BAL FELLOW AT MIT AND
IGOR, A BRILLIANT MOLECULAR
BIOLOGIST FIGURED OUT HOW TO
CLONE GENES THAT WERE MANY NOT .
WE DIDN'T HAVE EASY WAY TO CLONE
GENES, IT WAS THE 197 '50‘S.
HE CLONED AMPLIFIED GENES AND WE
GOT TOGETHER AND WE CLONED THE
GENES AMPLIFIED IN OUR DRUG
RESIST APARTMENT CELLS AND IT
TURNED OUT THAT WHEN OE A DA
CAME TO A LAB AND THAT WE COULD
CON FUR A PHENOTYPE OF MULTI
DRUG RESISTANCE, CROSS
RESISTANCE TO MULTIPLE DIFFERENT
DRUGS, JUST BY PUTTING IN ONE
PARTICULAR GENE.
AND THAT GENE TURNED OUT TO BE
GENE THAT VICTOR LING CALLED P
LACK PROTEIN WE CALLED IT MDR
ONE AND THE OFFICIAL NAME IS
ABCB1 AND IT'S A MEMBER OF A
FAMILY OF ATP DID HE PENDANT
TRANSPORTERS AND I'LL SAY MORE
ABOUT THAT.
SO, AS WE BEGAN TO STUDY DRUG
RESISTANCE, WE REALIZED THAT IT
WAS REALLY A MULTI FACTORIAL
PROCESS.
THERE WERE MANY WAYS, AT LEAST
AT THE CELLULAR LEVELS THAT
CELLS CAN BE RESISTANT AND AT
THE LEVEL THEY'RE EVEN MORE
MECHANISMS AND IN GENERAL,
THEY'RE CHARACTERIZED AS SHOWN
IN THIS SCHEMATIC.
DRUGS CAN FAIL TO BE TAKEN UP.
THERE ARE 386 UPTAKE
TRANSPORTERS IN THE CELLS AND
THOSE CAN BE ALTERED OR MISSING.
AND SO DRUGS THAT REQUIRE UPTAKE
TRANSPORTERS DON'T GET INTO
CELLS WHEN THOSE ARE ALTERED.
THERE ARE ALSO WHAT ARE CALLED
EFFLUX TRANSPORTERS AND WE
DISCOVERED THESE WHEN WE FIRST
BEGAN TO STUDY MULTI DRUG
RESISTANCE IN OUR CULTURE CELLS.
THESE ARE ENERGY DEPENDENT AND
THERE ARE 48 KNOWN SYSTEMS OF
WHICH THREE ARE INVOLVED IN
MULTI-DRUG RESISTANCE AND CANCER
AND I'LL SAY MORE ABOUT THOSE IN
A MOMENT.
OF COURSE NOT ALL CELLS
DEMONSTRATE DECREASED UPTAKE OR
INCREASED EFFLUX BUT THEY CAN BE
RESISTANT IN THE WAY SHOWN IN
THIS SLIDE WITH ALTERATIONS AT
PEE TOE SIS AND CHECKPOINTS AND
GROWTH PATHWAYS AND METABOLISM
AND MANY WAYS THROUGH RESISTANCE
TO OCCUR.
SO TO GET BACK TO THESE' FLUX
PUMPS, THROW CONFIRM MULTI DRUG
RESISTANCE AND WE HAVE
STRUCTURES FOR THESE THREE ABC
DEPEND ANT TRANSPORTERS AND
THEY LOOK THE SAME BUT THEY'RE
DIFFERENT.
IN THE S THE SITE OWE PLAS MICKD
THE TRANS MEMBRANE PARTS THERE
ARE DOMAINS WHICH AS YOU WILL
HEAR, SEEM TO BE THE REGIONS IN
WHICH THE DRUGS ARE TRANSPORTER.
THEY EACH PROGRESS DOZENS OR
HUNDREDS OF DIFFERENT DRUGS.
SOME SUBSTRATES ARE IN COMMON IN
THOSE TEND TO BE THE ONES
INVOLVED IN DRUG RESISTANCE IN
CANCER AND THEY'RE SHOWN HERE
AND OTHERS MAY HAVE MORE
SPECIFIC METABOLICS FUNCTIONS IN
CELLS.
IT'S IMPORTANT TO REALIZE IF YOU
STUDY ANY PARTICULAR CANCER,
THAT THE EXPRESSION OF ONE OR
MORE OF THESE TRANSPORTERS CAN
CONTRIBUTE TO DRUG RESISTANCE.
THEY PLAY IMPORTANT ROLES,
PHYSIOLOGICAL ROLES IN THE HUMAN
BODY AND IN ALL ORGANISMS
BASICALLY AND MY VERSION OF THE
HUMAN BODY SHOWN ON THE LEFT AND
IT'S TOTALLY ROUND WHICH IS
PROBABLY A SIGN OF THE WAY
EVOLUTION IS GOING AND THESE
TRANSPORTERS, PARTICULARLY PLA
PROTEIN OR MDR1 ARE AT BARRIER
SITES IN THE BODY AND THEY'RE AT
BLOOD PLACENTAL BARRIER AND THE
BRAIN BLOOD BARRIER AND THEY
HAVE FUNCTION IN THE KIDNEY,
LUNG, LIVER AND INTESTINE.
AND SO, THE PHARMA CO DYNAMICS
OF MANY, MANY DRUGS ARE AFFECTED
NORMALLY BY EXPRESSION OF THESE
TRANSPORTERS AND SOME OF THOSE
DRUGS ARE SHOWN TO THE RIGHT.
EACH ONE OF THEM IS KIND OF AN
INTERESTING STORY.
SINCE YOU'VE HEARD ABO IVORMECT,
IT IS NOT TOXIC TO HUMANS TO THE
CENTRAL NERVOUS SYSTEM AND IT
CAN'T GET INTO THE BRAIN IT'S A
SUBSTRATE FOR THIS TRANSPORT
SYSTEM.
VETERINARIAN KNOW WHEN THEY
DEWORM ANIMALS, THEY CAN'T GIVE
IVORMECTINS BECAUSE COLLIES DO
NOT HAVE AN ACTIVE PROTEIN AT
THEIR DRUG BRAIN BARRIER AND THE
DRUG GETS IN AND THEY DEVELOP
NEUROLOGICAL SYMPTOMS AND THEY
DIE.
A ARTICLE ABOUT A FRENCH PATIENT
WHO WAS GIVEN IT TO TREAT
SCABIES INDICATED THE PATIENT
DEVELOPED SEIZURES AND THE DRUG
WAS STOPPED, THE PATIENT
SURVIVED AND THEY THOUGHT TO
SEQUENCE PROTEIN IN THIS PATIENT
AND THE PATIENT WAS A COMPOUND
HETERO SYGAT AND THEY WERE
EFFETIVE.THERE'S NOT A LOT OF HN
BEINGS WALKING AROUND WITH A LOT
OF P OF PROTEIN AND THERE'S
TREATING RIVER BLINDNESS IN
AFRICA DONE WITH IVERMECTIN BUT
NO ONE HAS PERSUADE THAT.
I WOULD EXPECT WITH THE CURRENT
INTEREST IN THE DRUG AS A
TREATMENT POTENTIAL TREATMENT
FOR COVID-19, AND A LOT OF
PEOPLE TAKING IT WITHOUT ANY
GOOD INDICATION, BUT WE'RE
TALKING ABOUT FEWER THAN
1/100,000 PEOPLE WOULD BE SO
EFFECTIVE AND THERE ARE OTHER
STORIES AMONGST THIS LIST.
ANTIHISTAMINES AND DRUGS SUCH AS
LOPERMIDE, USED TO TREAT
DIARREAH, ARE POTENT BUT THEY'RE
NOT INTOXICATING BECAUSE THEY
CAN'T CROSS THE DRUG-BRAIN
BARRIER.
AND ON AND ON AND ON.
A LOT OF WAYS THE FUNCTION OF
PGP AFFECTED IMPORTANT
PHARMACOLOGICAL RESPONSES.
NOW, FOR THE INTRAMURAL RESEARCH
PROGRAM, ACHIEVABLE GOALS ARE
EVEN HARDER TO ACHIEVE.
AND THE WAY THAT WE GO ABOUT
MAKING SIGNIFICANT CHANGE, AND
YOU HEARD ABOUT A LOT OF
DIFFERENT THINGS THAT HAPPENED
DURING MY TIME AS DDIR, IS WE
TEND TO USE OUTSIDE EXTERNAL
REVIEW AND WE ASK EXPERTS TO
COME IN AND WE DO THIS TO REVIEW
OUR SCIENCE BUT WE DO IT ALSO TO
REVIEW OUR INTRAMURAL RESEARCH
PROGRAMS IN GENERAL.
AND THOSE REVIEWS ARE SHOWN HERE
SOME OF THOSE REVIEWS AND THEY
AVERAGE ABOUT ONE EVERY 10
YEARS.
THEY'RE MAJOR ACTIVITIES, HALF
OF THE NIH BY OUTSIDE VERY
SENIOR ADVISERS.
AND EACH ONE OF THEM HAVE LED TO
SOME OF THESE CHANGES THAT
YOU'VE HEARD ABOUT.
FOR EXAMPLE, THE IOM REPORT IN
1988 RECOMMENDED THAT WE HAVE A
FOUNDATION FOR THE NIH, WHICH
OCCURRED.
RECOMMENDED THAT THE DIRECTOR
HAVE A DISCRETIONARY FUND, WHICH
OCCURRED AND RECOMMENDED THAT WE
DEVELOP A TENURE PROGRAM AT THE
NIH, WHICH OCCURRED.
AND THE MAJOR REVIEW THAT HAS
AFFECTED MY ACTIVITIES AS DDIR,
WAS THE SO-CALLED MARKS CASTLE
REVIEW IN 1994 WHICH WAS
CONGRESSIONAL LEHMAN DATED TO
LOOK AT THE INTRAMURAL PROGRAM
AND LED TO WHAT WE CONSIDER A
RIGOROUS PROCESS OF A REVIEWS
AND CENTRAL TENURE COMMITTEE AND
AND THIS IS BEEN A BLUE PRINT TO
ENABLE US TO MAKE IMPORTANT
CHANGES IN THE INTRAMURAL
PROGRAM.
THERE WAS ANOTHER REPORT IN
2003.
AND THEN THERE WAS A BLUE RIBBON
REPORT ON CLINICAL RESEARCH IN
2004 WHICH CREATED WHAT WAS THEN
THE AD ADVISORY BOARD ON CLINICL
RESEARCH AND CLINICALLY ORIENTED
ENHANCEMENT THIS IS OUR PROGRAM.
THE ASSISTANT CLINICAL
INVESTIGATORS, THE CLINICAL
SCHOLARS PROGRAM AND THE MOST
RECENT REVIEW WAS IN 2014 AND
MADE SOME IMPORTANT
RECOMMENDATIONS TO IMPROVE
DIVERSITY AT THE NIH INCLUDING
THE DISTINGUISH SCHOLARS
PROGRAMS AND THE RESEARCH
SCHOLARS PROGRAM AND GENERAL
IMPROVED REVIEW OF OUR CLINICAL
RESEARCH THROUGH THE DEVELOPMENT
OF A CENTRALIZED IRB SO, THESE
GIVE YOU SOME EXAMPLES AND THE
CHANGES THAT YOU ARE HAVE TO
DEAL WITH ON A REGULAR BASIS
DON'T COME OUT OF THE BLUE.
THEY USUALLY ARE HIGHLY
CONSIDERED AND RECOMMENDED BY
OUTSIDE EXPERTS.
SO, THE THIRD THING AND I
REFERRED TO THIS AS THE
IMPORTANCE OF BUILDING DIVERSE
TEAMS TO ACCOMPLISH THESE GOALS
AND THIS IS MY LAB AT NIH.
PICTURE TAKEN, NO MASKS, SO
TAKEN RIGHT BEFORE THE PANDEMIC.
AND WE'VE REALLY MADE AN EFFORT
TO BRING IN PEOPLE WITH MANY
TALENTS, MANY SKILLS, MANY
DIFFERENT BECOME GROUNDS TO MAKE
SURE THAT WE GET THE BEST
POSSIBLE SCIENTISTS TO WORK ON
OUR PROJECTS.
AND IN MY OFFICE OF ININTEREST
MURAL RESEARCH, I HAVE EIGHT
SORT OF PERMANENT MEMBERS OF THE
OFFICE WHO ARE ON THE PAYROLL
AND THEY'RE SHOWN HERE AS WELL
AS SEVEN OR EIGHT VOLUNTEERS WHO
COME AND MEET WITH US RUGLY WHO
BRINGER PECK TEASE FROM THE
INSTITUTES AND GIVES US A GOOD
FEEDBACK AND OFFERS HELP FREE OF
CHARGE TO THE ACTIVITIES YOU
GROW TO KNOW AND LOVE THAT WE
TAKE CARE OF.
NOW THE LESSON FLOOR HAS TO DO
WITH COLLABORATION AND I WANT TO
SAY SOMETHING HERE ABOUT AND IRA
WHO I HAVE COLLABORATED FOR
MANY, MANY YEARS AND IRA HAS
MADE CONTRIBUTIONS IN MANY
DIFFERENT FIELDS AND HE
RECRUITED ME AND MY WIFE, ZOOS
ARRSUSAN,IN 1985 TO COME BACK AE
POSITIONS.
WE HAD DISCUSSIONS ABOUT
IMPORTANT PROJECTS THE LAB AS A
WHOLE COULD UNDER TAKE.
AND WE DECIDED TO GO AHEAD WITH
THIS PROJECT TO UNDERSTAND THE
BASIS OF MULTI-DRUG RESISTANCE
AND IT'S REALLY BEEN A WONDERFUL
EXPERIENCE AND IT'S BEEN MANY
YEARS SINCE WE COLLABORATED
DIRECTLY BUT WE STILL ARE IN
CONTACT WITH EACH OTHER AND
STILL SHARE IDEAS ABOUT
EXPERIMENTS.
I MENTIONED ALREADY THAT WE
WOULD NOT HAVE BEEN ABLE TO
CLONE THIS PROTEIN GONE THE
FIRST MEMBER OF THE ABC FAMILY
OF TRANSPORTERS WITHOUT THE HELP
OF EGGIGOR ROBINSON.
THIS IS ONE REASON WHY IT'S
IMPORTANT TO GET BACK TO
IN-PERSON MEETINGS.
THESE CONVERSATIONS ARE HARD TO
HAVE OVER REMOTE MECHANISMS.
WE'VE WORKED PEOPLE TO
UNDERSTAND THE BIOLOGY,
BIOCHEMISTRY OF PLAC PROTEIN AND
HOW IT WORKS AND I WANT TO SAY
MORE ABOUT MECHANISM OF ACTION.
ONE IDEA THAT CAME OUT OF A
COLLABORATION WITH BOB
BLOOMENTHAL WHO WAS INTERESTED
IN FLIP AND FLOP ACES AND
MEMBRANE PRE TEENS AND HOW TO
MEASURE THE EXISTENCE AND THE
ACTIVITIES OF MEMBRANE PROTEINS,
HE HAD A PROBE WHICH WAS VERY
HYDRO PHOBIC, ONLY EXISTED IN
MEMBRANES AND WE SHOWED THAT YOU
COULD TRANSFER ENERGY AND IODINE
TO DOXORUBICIN TO THIS P-GP IN
THE MEMBRANES AND THE
TRANSPORTERS WAS RECOGNIZING
THESE CANCER DRUGS WITHIN THE
BUY LAYER.
AND WE CAME UP WITH THIS IDEA
THAT WAS THE PUMP WAS A HIGHDRO
PHOBIC VACUUM CLEANER SHOWN ON
THE LEFT.
DRUGS ENTERED THE CELL, THEY GET
TRAPPED IN THE INTER MEMBRANE.
THEY'RE RECOGNIZED BY A DOMAIN
IN THE TRANCE MEMBRANE REGION OF
THE TRANSPORTER AND UNDER THE
INFLUENCE OF ATP, WHICH IS HYDRO
LIESED.
THEY'RE EXCLUDED FROM THE CELL.
ON THE RIGHT IS AN ALTERNATIVE
MODEL.
WHICH IS THAT PGP IS LIKE A
LIPID FLIPASE AND THEY'RE
FLIPPED WHERE THEY CAN
DIFFUSE OUT OF THE CELL AND
BOUND TO PROTEIN AND THERE'S END
IT'S AN IMPORTANT PART OF THE
TRANSPORT PROCESS OUT OF CELLS.
THIS MODEL, WHICH WE REALLY, I
THINK, CAME UP WITH 25 YEARS
AGO, IS ACTUALLY WITHSTOOD THE
TEST OF TIME AND A GOING MODEL
FOR HOW THESE MULTI-DRUG
TRANSPORTERS CAN RECOGNIZE SO
MANY DRUGS.
THESE ARE HYDRO PHOBIC
INTERACTIONS MOSTLY AND THEIR
RULES ARE DIFFERENT FROM NORMAL
SUBSTRATES SPECIFICITY.
HOW DOES THIS WORK?
AND AGAIN, WE HAVE PRETTY HIGH
RESOLUTION CRYSTAL GRAPHIC
STUDIES FROM DEE SHAW A MEMBER
OF MY LABORATORY OF CELL BIOLOGY
SHOWING THAT THE CRYSTAL GRAPHIC
FORM MOST COMMON FORM OF P-GP IS
SHOWN ON THE LEFT IN WHAT IS
CALLED INWARD OPEN CONFIRMATION
AND THE ATP SITES ARE FAR APART.
IT BRINGS THE TWO SITES TOGETHER
WHEN IT BOUNDS AND JU CHEN AT
ROCKEFELLER HAS BEAUTIFUL CRYO
EM AND HE GAVE A WALLS TALK LAST
YEAR ABOUT THIS.
SHE HAS BEAUTIFUL CRYO EM
STUDIES SHOWING THE STRUCTURES
THAT ARE SHOWN ON THE RIGHT.
WHEN THE TWO SITES COME TOGETHER
THEY CHANGE THEIR AFFINITY AND
THE DRUGS CAN BE EXCRETED.
THIS IS THE OVER ALL MECHANISM.
BECAUSE THE STRUCTURES ARE
SOMEWHAT DIFFERENT, THE
MECHANISMS MAY BE SOMEWHAT
DIFFERENT FROM ABC TRANSPORTER
TO ABC TRANSPORTERS.
AND ANOTHER THING WE'VE BEEN
INTERESTED IN IS HOW ARE THE
VARIOUS SUBSTRATES BOUND AND
OTHER SENIOR MEMBER OF MY LAB
HAS BEEN STUDYING THIS FOR MANY
YEARS.
AMONG OTHER THINGS, HE HAS MADE
A MUTATIONS IN THE SITES THAT
APPEAR TO BE THE SUBSTRATE
BINDING SITES.
AND THE STRIKING FINDING IS YOU
CAN CHANGE 13 OR 14 OF OF WHAT
APPEAR.
IF YOU CHANGE ENOUGH OF THESE,
THE TRANSPORTER, WHICH NORMALLY
WOULD EXCRETE DRUGS FROM THE
CELL PUMPS DRUGS INTO THE CELL.
SO THE MISSION TER MYSTERY LIESE
AFFINITY OF THE DRUGS FOR THE
TRANCE MEMBRANE REGIONS AND MORE
STRUCTURE AND MORE WORK NEEDS TO
BE DONE TO SUPPORT AND EXPAND
THIS HIGH POTH SIS.
AND FINALLY, THIS IS ANOTHER
OBSERVATION MADE SEVERAL YEARS
AGO.
BY A SENIOR SCIENTIST AT THE
FDA.
SO, WE HAD NOTICED THAT THE
TRANSPORTER WE HAD WHICH WAS
ORIGINALLY CLONED FROM HEILO
CELLS FROM HENRIETTA LAX, AN
AFRICAN AMERICAN INDIVIDUAL, HAD
A CERTAIN SEQUENCE BUT THAT
OTHER SEQUENCES OBTAINED FROM
NORTHERN EUROPEANS AND ASIAN
POPULATIONS HAD DIFFERENT POLY
MORPHIC FORMS OF P-GP AND THEY
WERE SUBTLE BUT REAL DIFFERENCES
THAT APPEARED TO BE DOING THESE
POLY MORPHISMS AND THE C3435T
WAS SILENT AND IT DID NOT ENCODE
A CHANGE IN AMINO ACIDS SO WE
GOT VERY INTERESTING IN THIS
OBVIOUSLY.
HOW DOES A SILENT POLY MORPHISM
CHANGE SUBSTRATE SPECIFICITY AND
ONE OF THE THINGS WE DISCOVERED
USIRNA FOOTPRINTING THERE WAS A
DELAY CAUSED BY A CHANGE IN THE
STRUCTURE OF THE RNA AND THAT IS
SHOWN IN THE SLIDE HERE AS A
PAUSE SIGNAL SO THE PROTEIN
WOULD BEGIN TO BE TRANSLATED AND
THEN IT WOULD STOP AND THEN
AFTER A LONG PAUSE, IT WOULD
START AGAIN AND THE STOP WAS DUE
TO THIS CHANGE AND MRNA
STRUCTURE AND THAT APPARENTLY
CHANGED RATHER SUBJECTLY THE
SUBSTRATE BINDING SITE AND
ENOUGH SO THAT SOME SUBSTRATES
WOULD BIND MORE READILY THAN
OTHER SUBSTRATES AND WOULD BE
TRANSPORTED.
SO THIS WAS ONE OF THE FIRST
EXAMPLES OF SILENT POLY
MORPHISMS SINCE THEN THERE ARE
MANY MORE AND IT'S PRETTY MUCH
UNDERSTOOD THAT MANY PROTEINS
HAVE MULTIPLEEL FOLDS AND THEY
CAN EXIST IN FOLD A OR FOLD B
DEPENDING ON SHAPER OWNS SO IT'S
A REDUNDANCY WHICH HAS HAD ADAPO
MANY DIFFERENT PROTEINS.
I THINK THIS ILLUSTRATES THE
POINT IF YOU STUDY ANYTHING IN
GREAT ENOUGH DETAIL YOU LEARN
SOMETHING EVEN THOUGH YOU ARE
STUDYING SOMETHING SPECIFIC, YOU
LEARN AGAKNOWLEDGE.
THE INTERACTIONS WITH MY
ADMINISTRATIVE JOB ARE EVEN MORE
COMPLICATED THAN THE ONES IN MY
SCIENTIFIC JOB.
I HAVE A SERIES OF SLIDES HERE
THAT SHOW THE VARIOUS GROUPS
WHICH I INTERACT ON I REGULAR
BASIS.
I REPORT TO THE NIH DIRECTOR,
I'M A DEPUTY DIRECTOR FOR IN TRA
MURAL RESEARCH AND REPORTING TO
ME IS THE DEPUTY DIRECTOR FOR IN
TRA MURAL CLINICAL RESEARCH AND
JANICE LEE.
WE'VE HAD DIFFERENT DDICRs
OVER THE LAST SEVERAL YEARS.
THERE'S NOT A REPORTER
REQUIREMENT BUT WE OVERSEE THE
BOARD OF SCIENTIFIC DIRECTOR
WHICH IS A GROUP WHO GETS
TOGETHER TO MAKE DECISIONS ABOUT
POLICIES AND THE INTRAMURAL
PROGRAM.
I ALSO GET INPUT FROM MANY
ADVISORY GROUPS CONSISTING OF
SCIENTISTS AT THE NIH, THE NIH
EQUITY COMMITTEE, WOMEN
SCIENTISTS, THE ASSEMBLY OF
SCIENTISTS, THE CENTRAL TEN YOUR
COMMITTEE AND OTHERS.
AND THEY ARE FREE IN THEIR
ADVICE TO ME AND I FREQUENTLY GO
TO THEM FOR ADVICE.
THEN THERE ARE MANY OFFICES IN
THE OFFICE OF THE DIRECTOR.
OFFICE OF RESEARCH SERVICES,
OFFICE RESEARCH FACILITIES,
MANY OTHERS WHICH I INTERACT
ABOUT ISSUES RELATED TO POLICY,
COMPLIANCE AND SO ON.
AND THEN THE BOARD OF SCIENTIFIC
DIRECTORS IN ADDITION THROUGH
THE IC DIRECTORS, INTERACTS WITH
THE CLINICAL DIRECTORS AND ALL
OF THIS CREATES A COMPLEX
NETWORK OF INTERACTIONS THAT
NEED TO BE MANAGED BUT ALSO ARE
HE A REAL ASSET TO ME AS I MEET
WITH MANY MANY GROUPS AS I CAN
AND DEVELOP POLICIES THAT ARE
BROADLY SUPPORTED AND THAT CAN
MOVE THE NIH FORWARD.
NOW, I HAVE ANOTHER DIAGRAM OF
WHAT GOES ON IN MY OFFICE WHICH
IS NOT A STRUCTURAL I DO A GRAM
BUT A FUNCTIONAL DIAGRAM AND
THIS IS KNOWN IN THE KINDEST WAY
IN MY OFFICE AS THE MEATBALL
SANDWICH.
SO WE GET MONEY FROM VARIOUS
SOURCES FROM THE OFFICE OF THE
DIRECTOR AND INDIRECTLY FROM THE
ICs AND OUR RESPONSIBILITIES
ARE THREEFOLD.
RESEARCH OVER SITE THAT YOU HAVE
HEARD A FAIR AMOUNT ABOUT AND
YOU WILL HEAR MORE ABOUT.
TRAINING AND CAREER DEVELOPMENT.
THE OFFICE OF INTRAMURAL
TRAINING AND EDUCATION IS IN MY
OFFICE.
THEY HAVE THE VISITING
SCIENTISTS AND THE REGULATORY
DEPARTMENT AND YOU HEARD THAT
I'M INSTITUTIONAL OFFICIAL FOR
HUMAN SUBJECTS RESEARCH ANIMAL
CARE AND USE TECH TRANSFER AND
THOSE ARE IMPORTANT ACTIVITIES
THAT KEEP THE NIH OUT OF TROUBLE
AND MABEL SURE OUR SCIENTISTS
ARE DOING THE RIGHT THING ON A
REGULAR BASIS.
WE MAKE POLICY WITH THE HELP OF
ALL THE GROUPS I MENTIONED AND
WE TRY TO COMMUNICATE CLEARLY
THAT POLICY, CHRIS WANCHECK IS
THE HEAD OF THE COMMUNICATIONS
OFFICE AND THAT IS SUPPORTING
THE INTRAMURAL PROGRAM.
THERE ARE ALL THESE COMPLEXITIES
THAT ARE GOING ON AT THE SAME
TIME THAT I'M TRYING TO RUN MY
RESEARCH PROGRAM.
SO, THE NEXT THING I WANTED TO
SAY, LESSON NUMBER FIVE, WE
SHOULD BE FOCUSING ON INTRA
PERSONAL SKILLS.
THERE'S EMPHASIS ON CIVIL LATELY
AND PEOPLE TREATING EACH OTHER
WELL AND ON MUTUAL RESPECT AND
ON LISTENING AND ON LEARNING AND
I GOT THIS ADD VOICE FROM AL
RABSON THE SCIENTIFIC DIRECTOR
AND DIVISION DIRECTOR IN NCI
WHEN I WAS RECRUITED WHO WAS AN
ADVISER TO MANY, MANY PEOPLE AT
NIH, UNFORTUNATELY DIED SEVERAL
YEARS AGO.
BUT HE USED TO SAY, TREAT
EVERYONE WHO WORKS FOR YOU WITH
KINDNESS AND RESPECT BECAUSE ONE
DAY YOU WILL BE WORKING FOR
THEM.
I THINK THAT WAS HIS SENSE OF
HUMOR, HE OBVIOUSLY KNEW THE
INTRINSIC RIGHTNESS OF BEING
CIVIL TO EVERYBODY.
HERE HE IS WITH KATIE COURIC WHO
REALLY LIKED AL, KATIE IS A
SPOKESPERSON FOR COLON CANCER
BECAUSE OF HER FAMILY
CIRCUMSTANCES WITH HER HUSBAND
DYING OF COLON CANCER.
SO THIS IS A GREAT PICTURE I
THOUGHT I WOULD SHARE.
LESSON NUMBER SIX, REALLY
IMPORTANT IF YOU ARE GOING TO BE
A GOOD SCIENCE MANAGER AND A
GOOD SCIENTIST, YOU HAVE TO KNOW
A LOT ABOUT SCIENCE AND I'VE HAD
THE GOOD FORTUNE TO INTEGRATE MY
INTEREST IN SCIENCE AND GENERAL
BIOLOGY IN PARTICULAR WITH BOTH
THE LAB AND WHAT I DO AT THE NIH
TO MAKE SURE YOU ARE ALL
EDUCATED ABOUT SCIENCE.
SO, OUR SCIENTIFIC PROJECT
INVOLVED MOLECULAR BIOLOGY,
BIOCHEMISTRY AND X-RAY CRYSTAL
OLE RA FEE AND BY OWE PHYSICS
AND IN EACH CASE WE LEARNED WHAT
WE NEEDED TO KNOW OR MOST LIKELY
WE WENT TO A COLLABORATOR AND
FOUND SOMEONE AT THE NIH.
WITH 1100PI THERE'S SOMEONE WITH
EQUIPMENT AND KNOWLEDGE YOU NEED
AND PEOPLE WILLING TO HELP.
SO WHAT DO WE DO IN MY OFFICE TO
MAKE SURE YOU ARE ALL EDUCATED?
WE SUPPORT A COUPLE OF LECTURE
SERIES, THE WEDNESDAY AFTERNOON
LECTURES AND FRIDAY MONTHLY
SPEAKERS AND OF COURSE MEDICAL
GRAND ROUNDS AT THE CLINICAL V
CLIN WE HAVETHE CATALYST WHICH U
KNOW.
THE DDIR WEB BOARD WHICH YOU MAY
NOT KNOW IS SUB DESCRIPTION ONLY
AND WE REMIND PEOPLE EVERY THREE
MONTHS THEY CAN SUB DESCRIBE
IT'S FULL OF INTEREST TIDBITS OF
INFORMATION SO SUB DESCRIBE TO
THAT AND THEN WE HAVE A ACTIVE
WEBSITE AND THEY HAVE MADE THAT
INTO A VERY ATTRACTIVE WAY OF
FINDING OUT WHO IS AT THE NIH
AND WHAT THEY'RE DOING AND WHAT
IS HOT AND WHAT IS NOT SO I URGE
YOU WHEN YOU GET THOSE REMINDERS
EVERY WEEK ABOUT ABOUT WHAT TO
LOOK UP, CLICK ON THEM AND SEE
WHAT IS HAPPENING IN THE IRP.
WE DEVELOPED A SCIENTIFIC
INTEREST GROUPS AND CLOSE TO 100
OF THOSE COVERING ALL KINDS OF
FIELDS FROM VERY BROAD AREAS TO
VERY FOCUSED ONES AND THE INTENT
THERE IS TO ENCOURAGE TRANS NIH
INTERACTIONS, KNOWLEDGE,
COLLABORATIONS.
AND THEN THERE'S SOMETHING ELSE
THAT MANY PEOPLE DO KNOW ABOUT,
THERE'S A DATABASE, ALL THOSE
ANNUAL REPORTS THAT YOU ARE
WRITE GO INTO A DATABASE WHICH
IS FULLY SEARCHABLE AND YOU CAN
FIND ANYTHING YOU NEED AT THE
NIH THROUGH THAT DATABASE.
WHO HAS A DIFFERENT CELL LINE, A
PIECE OF EQUIPMENT, WHO IS WORK
ON A SUBJECT YOU MIGHT BE
INTERESTED IN SO I URGE TO YOU
GO TO THAT DATABASE AND MAKE USE
OF IT AS WELL.
SO, LESSON NUMBER SEVEN, DON'T
BE TECHNIQUE LIMITED.
I LEARNED THIS FROM IRA.
YOU KNOW, WE WOULD COME UP
AGAINST A PROBLEM THAT WE NEEDED
TO SOLVE AND DIDN'T KNOW HOW.
WE KNEW CELL CULTURE, WE KNOW
CLONING, WE KNEW MOLECULAR
BIOLOGY BUT WE NEEDED BIO
PHYSICS OR SOMETHING ELSE AND
SO, WE ALWAYS TOOK ADVANTAGE OF
DECK KNOWLEDGES AS THEY WERE
EMERGING.
AND THERE HAVE BEEN MANY
ADVANCES AND STRUCTURAL AND CELL
BIOLOGY AND I'VE TRIED IN MY
SUPPORT OF ACTIVITIES, USING THE
LITTLE FUNDS THAT WE HAVE IN MY
OFFICE BUT ALSO STIMULATING
IDEAS AND DISCUSSIONS TO SUPPORT
THESE ACTIVITIES A CROSS THE NIH
AND I'VE JUST A FEW EXAMPLES
HERE, IN STRUCTURAL BIOLOGY AND
BIO ENGINEERING WE HAVE SUPPORT
CRYO EM AND THEY HAVE NICE, NIH,
INTRAMURAL CRYO EIM AND NMR, BOB
TIE CO AND IN NIDDK THERE'S A
LOT OF WORK ON SUPER RESOLUTION
INCLUDING NIBIB, A FACILITY
WE'RE ALL ABLE TO USE AND OF
COURSE, ENORMOUS ADVANCES IN
CLINICAL IMAGING, MRI, CT PET.
THE USE OF RADIOLOGICAL
APPROACHES TO BOTH IMAGE AND
TREAT DISEASES PO TONIC AND ON
AND ON AND ON.
>> THIS IS A HUB FOR A MORE
BROADLY-BASED BIO ENGINEERING
ACTIVITY AT THE NIH WITH MANY
IC-SPECIFIC INVESTMENTS.
THE PICTURE IS FROM NIEHS, CRYO
EM STUDY OF SARS-CoV-2, SPIKE
PROTEIN WITH THE BOUND TO THE
ARB RECEPTORS AND THIS IS
IMPORTANT, PARTICULARLY SOME OF
THESE VARIANTS COME UP THAT HAVE
A LOT TERRATIONS AND THESE
INTERACTIONS AND THIS PHOTO IS
FROM MARIO BORNIA WHO RUNS THE
CRYO EM FACILITY AT THE EHS.
HUGE ADVANCES IN CELL BOYOLOGY
OVER THE YEARS AND A LOT OF
BASED ON SINGLE CELL GENOMICS,
CHRIS PER AND TISSUE ON A SHIP
ADVANCES IN A CLINICAL CENTER
AND NCATS AND THE USE OF
ORGANOIDS TO STUDY BEHAVIOR OF
CELL COMPLEXES AND RNA, DNA,
PROTEIN LOCALIZATION EFFORTS.
OTHER OMIC APPROACHES, GLYCOLIC,
LIPID OMICS, AND ON AND ON AND
ON SOME OF HAVE LED TO CENTERS
THAT CAN HELP YOU SOLVE PROBLEMS
THAW MAY HAVE IN THE LAB.
AND OF COURSE, SUB CELLULAR
VISUALIZATION TECHNIQUES WHICH
WE'VE MENTIONED SOME.
AND I WANT TO SAY SOMETHING
ABOUT PHARMACOLOGY BECAUSE IT'S
THE FIELD IN WHICH WE'VE DONE
MOST OF OUR WORK.
WE HAVE, THANKS TO SOME OF THE
FACILITIES IN NCI IT'S EASY TO
DO HIGH THROUGH PUT SCREENS AND
THERE'S A LOT OF IN VITRO
MODELING AND MOLECULAR DYNAMIC
STIMULATION AND MODELING THAT
LAWS YOU TO MAKE PREDICTIONS
ABOUT WHAT KIND OF MOLECULES
WILL INTERACT WITH YOUR TARGETS.
COMMON CHEMISTRY AND WE MENTION
THE CRYO EM.
SO, LET ME, BEFORE I COME TO A
CLOSE HERE, SAY SOMETHING ABOUT
MY COLLEAGUE AND HELP ME OFFER
THE YEARS RICHARD WYATT.
RICHARD IS TAUGHT ME QUITE A
LOT.
ONE OF THE MOST IMPORTANT THINGS
THAT HE KEEPS REMINDING ME ABOUT
IS THAT THE SAFETY OF OUR
WORKFORCE AND OUR PATIENTS
ALWAYS COMES FIRST.
AND SO, WE'VE HAD OVER THE
YEARS, MANY POLICIES AND
PRACTICES TO ASSURE SAFETY OF
OUR STAFF AND JUST A REMINDER IF
YOU SEE PRACTICES THAT ARE
UNSAFE WE NEED TO KNOW ABOUT
THEM AND STOP THEM AND EDUCATE
PEOPLE ABOUT THE PROPER WAY TO
TAKE CARE OF THEIR EXPERIMENT
AND THEIR PATIENTS.
YOU ALL REMEMBER THE RED TEAM
REPORT.
THIS WAS A FORMATIVE EXPERIENCE
FOR AWFUL US.
AND LED TO MANY, MANY CHANGES IN
THE WAY THAT WE TAKE CARE OF
PATIENTS THAT ARE IMPROVED THE
SAFETY OF OUR PATIENTS AND THE
SAFETY OF THE INDIVIDUALS WHO
WORK WITH OUR PATIENTS.
THE NURSING STAFF, THE SUPPORT
STAFF AND SO ON.
AND WE WANT TO LIMIT THE
LABORATORY SAFETY PROBLEMS.
WE ARE ALL RESPONSIBLE FOR THE
PEOPLE WHO SUPERVISE IN OUR LABS
AND WE WANT TO MAKE SURE THAT WE
TAKE GOOD CARE THAT THEY ARE
HEALTHY AND WELL AND DON'T GET
INTO TROUBLE.
I CAN TELL THAW OVER THE YEARS,
THERE'S BEEN ISOLATED EXAMPLES,
USUALLY INVOLVING TRAINEES OF
PEOPLE WHO HAVE GONE INJURED AS
A RESULT OF SAFETY CONCERNS AND
WE TAKE THESE VERY, VERY
SERIOUSLY.
SO, GETTING BACK TO MY RESEARCH,
I'M AT A STAGE IN THE RESEARCH
NOW HOPING TO GO BACK TO THE LAB
FULL TIME SOON AND WE HAVE SOME
CHALLENGES TO SOLVE.
AS I MENTIONED, WE THINK MOST
DRUG RESISTANCE AND CANCER IS
MULTI FACTORIAL AND A BIG
QUESTION IS, IS THAT MEAN WHEN
YOU SEE A TUMOR DOES THE
RESISTANCE EXIST OR DOES IT LEAD
TO THE EVOLUTION OF DRUG
RESISTANCE.
THIS IS IMPORTANT ISSUE FOR
DEALING WITH DRUG RESISTANCE.
WE'VE START TODAY ASSEMBLE A
CATALOG OF DRUG RESISTANCE
GREENS.
WE'RE NOT JUST A ONE-INSTRUMENT
BAND.
ONE OF THE WAYS WE'VE DONE THAT
IS SELECTIONS BUT ALSO USING
CHRIS PER, A TOWERFUL TOOL TO
PULL OUT GOWNS THAT HAVE THE
SENSITIVITY CELLS, ANTI CANCER
DRUGS.
AND FINALLY IT'S IMPORTANT TO
KNOW WHETHER THEIR MECHANISMS
WERE DERIVING IN THE LAB ARE
RELEVANT AND WE NEED BETTER WAYS
OF ANALYZING THE EVOLUTION OF
TUMORS AND WHAT MECHANISMS ARE
PRE 'EM INANT TO'IMMINENT.
I WANT TO THANK THOSE IN MY LABS
FOR THE LAST 45 YEARS AND THOSE
ARE THE MINIMAL NUMBER OF PEOPLE
I HAVE WORKED OVER THE YEARS.
MANY HAVE BEEN POSITIVELY
INFLUENCED BY WHAT I HAD DO SAY
TO THEM AND I'VE HAD MANY, MANY
SENIORS COLLEAGUES, SOME OF WHOM
I'VE MENTIONED IN MY REPORT.
BEFORE I TAKE QUESTIONS IF YOU
HAVE ANY, I WANT TO REMIND
EVERYBODY HERE TO REMEMBER YOUR
FAMILY THIS IS MY FAMILY TAKEN
AT THE ACADEMY.
I'M THERE WITH SUSAN, IN THE
MIDDLE, TO MY LEFT IS MY
DAUGHTER REBECA AND HER HUSBAND
ED, AND TO MY RIGHT AT THE END
IS MY SON DANIEL AND JUST TO MY
RIGHT IS HIS WIFE, LUCY AND MY
THREE GRANDCHILDREN,LY A, NAOMI
AND PIPPEN AND THEY MAKE THIS
WORTH WHILE.
THEY'RE UNDERSTANDING,
SUPPORTIVE AND MANY OF THEM HAVE
TURNED OUT TO BE INTERESTED IN
SCIENCE AS WELL WHICH IS A
DOUBLE BLESSING.
WON'T BE PRESUMPTION TO LIST 10
LESSONS AND I THOUGHT NINE WOULD
BE TODAY.
I WILL END AND BE HAPPY TO TAKE
ANY QUESTIONS THAT YOU MAY HAVE.
>>THANK YOU FOR A WONDERFUL AND
ENGAGING LECTURE THAT REALLY
WELL-BALANCED SIMILAR TO YOUR
CAREER, YOUR ENDEAVORS IN THE
LABORATORY AND THE OVERSIGHT
LEADERSHIP AND ADMINISTRATIVE
SPACE FOR SUCH A LONG JOURNEY
THAT YOU'VE HAD.
I THINK THE WAY THAW APPROACHED
YOUR LECTURE WAS REALLY ENGAGING
AND A GREAT FORMAT SO WE DO HAVE
A QUESTION OR TWO BUT AS THE
MODERATOR, I'M GOING TO TAKE THE
LIBERTY TO START OFF WITH MY OWN
QUESTION.
I HAVE A COUPLE FOR YOU.
BUT I'LL START WITH ONE.
AND THIS QUESTION IS MEANT TO
TRY TO TAKE ADVANTAGE OF THE
WISDOM THAT YOU HAVE GLEANED
OVER THE YEARS THAT YOU'VE
SERVED AT NIH AND TO USE THAT
WISDOM TO SORT OF PROJECT INTO
THE FUTURE, AND THE QUESTION IS,
YOU KNOW, WHAT DO YOU SEE ARE
THE GREATEST CHALLENGES THAT ARE
BASIC TRANSLATIONAL AND CLINICAL
SCIENTIFIC WORKFORCE ARE FACING
NOW AND WILL FACE IN THE FUTURE
AND ARE THERE NOT INDIVIDUAL
LEVEL BUT STRUCTURAL LEVEL
CHANGES OR MODIFICATIONS THAT
YOU SEE THAT MIGHT HELP MITIGATE
OR OVERCOME SOME OF THOSE
CHALLENGES?
>> THANK YOU, DAN.
THAT IS A SOFTBALL QUESTION
BECAUSE I JUST WROTE AN ESSAY
FOR THE CATALYST ABOUT THE
CHALLENGES FACING THE NEW DDIR
WHEN I STEPPED DOWN.
AND THESE HAVE BEEN A MATTER OF
SOME DISCUSSION CONSIDERING ABLE
DISCUSSION WITH THE SCIENTIFIC
DIRECTOR AND THE CLINICAL
DIRECTOR BECAUSE WE'RE TRYING TO
PUT TOGETHER A SERIES OF
DESCRIPTIONS OF WHAT THE
CHALLENGES ARE AND PRESCRIPTIONS
FOR SOLUTIONS THAT MAY BE WOULD
BE POSSIBLE FOR THE NEW NIH
DIRECTOR AND THE NEW DDIR TO PUT
PLACE.
SO, NUMBER ONE AND THIS IS AN
APPROPRIATE SETTING TO BRING
THTHISSUPPOSE THE CHALLENGES FAG
THE CLINICAL V IT'S UNIVERSAL
WITH THE NIH AND ALL THE
DIRECTORS AND LEADERSHIP FIELDS
AT THE CLINICAL CENTER IS THE
HEART OF THE NIH AND IT'S AN
ESSENTIAL PART OF THE NIH AND
YET IT HAS BEEN UNDERFUNDED FOR
MANY YEARS AND THE MECHANISM FOR
FUND PARTICULAR IS COMPLICATED
AND IT'S SCHOOL TAX AND OTHER
KINDS OF CONTRIBUTIONS AND IT
NEEDS A STABLE INFLATION-PROVE
MECHANISM OF FUNDING.
SO, THAT'S A BIG CHALLENGE.
WE'VE HAD GROUPS IN THE PAST
COME TO THINK ABOUT THIS ISSUE
AND MANY PEOPLE HAVE DIFFERENT
IDEAS AND ALL OF THEM HAVE THEIR
PLUSES AND MINUSES AND IT'S COME
TO THE POINT AS MANY OF YOU WHO
WORK IN THE CLINICAL CENTER,
RESOURCES ARE LIMIT AND THAT
LIMITATION SO I THINK IT'S A
NUMBER ONE CHALLENGE AND A
SECOND CHALLENGE IS IS ABOUT
INFRASTRUCTURE AT THE NIH.
IN THE 30 YEARS I'VE BEEN IN
CHARGE OF THE INTRAMURAL PROGRAM
WE'VE REPLACED HALF OF OUR
RESEARCH FACILITIES WITH NEW
FACILITIES.
HALF OF THEM ARE STILL ANTIQUE
AT GREAT RISK OF BAIL YOU'RE AND
ANYONE WHO WORK IN THE CLINICAL
CENTER COMPLEX IN BUILDING 10,
THE OLD PART OF THE BUILDING,
KNOWS HARDLY A DAY GOES BY WHEN
THERE'S NOT A FLOOD.
SO THEY'RE MAJOR DESTRUCTIVE
ACTIVITIES AND MAINTAINING THE
BUILDING IS BECOMING
INCREASINGLY DIFFICULT AND DAN
USED TO BRING AROUND PIPES AND
THAT DAY AND WE ARE FINDING IN
THE WALLS OF THE OLD BUILDING
AND PLUMBING AND VENT LAKE THAT
LOOKED LIKE ADVANCE FOUR-VESSEL
CORN ARY ARTERY DISEASE AND THE
PIN HOLE IN THE MIDDLE, THROUGH
WHICH THE WATER WAS SUPPOSED TO
COME AND COR ORGANIZATION AND SO
ON AND SO FOURTH SO THE
INFRASTRUCTURE IS A PROBLEM AT
THE NIH AND SOME OF THAT CAN BE
FIXED.
THE RENOVATIONS HAVE BEEN MADE
IN BUILDING 10 AND WE'RE ADDING
SOME SURGICAL RADIOLOGY AND
LABORATORY MEDICINE PIECE TO THE
BUILDING TO REPLACE THE OLDER
FACILITIES IN BUILDING 10.
BUT THOSE ARE REALLY CRITICAL
INFRASTRUCTURE AND IT'S TRUE FOR
ALL OF OUR BUILDINGS, NOT JUST
THE CLINICAL CENTER.
ANY OF THE OLD BUILDINGS REALLY
NEED MASSIVE MAINTENANCE OR
REPLACEMENT.
YOU MAY KNOW THAT THE NATIONAL
ACADEMY OF SCIENCE IS
ENGINEERING MEDICINE CAME AND
WROTE A REPORT CLEARLY
INDICATING WE NEED A MUCH BIGGER
INVESTMENT IN INFRASTRUCTURE.
THE THIRD AREA FOR CONSIDERATION
HAS TO DO WITH NOT MAKING FULL
USE OF WHAT I DESCRIBED AS THE
COLLABORATIVE ENVIRONMENT AT THE
NIH.
THE OPPORTUNITY TO SOLVE
VIRTUALLY ANY PROBLEM AT THE NIH
EXISTS AND SOMETIMES THERE ARE
UNNECESSARY BARRIERS OR
SOMETIMES IT JUST LACK OF
KNOWLEDGE OF OF WHAT IS POSSIBLE
AND WHAT IS AVAILABLE AND
SOMETIMES THERE ARE
ADMINISTRATIVE REASONS WHY
PEOPLE ARE NOT WILLING TO WORK
TOGETHER.
JOWE HAVE AWARDS THAT WEGIVE NIT
WE GIVE EVERY YEAR FOR AN
INNOVATION AWARDS TO TRY TO
ENCOURAGE TRANS NIH
COLLABORATIONS BUT IT COULD BE
DONE ON A WIDER SCALE.
MARSHAL HAD TWO OR THROW PEOPLE
IN HIS LAB AND THEY COULD NOT
HAVE SOLVED ALL THE PROBLEMS
GIVEN WHAT HE HAD IN THE WAY OF
RESOURCES.
NIHERS FLOCKED TO HIS HELP AND A
DOZEN PEOPLE, VERY SENIOR PEOPLE
SAID, THE RESOURCE IN MY LAB ARE
AT YOUR COMMAND.
LET'S DO THIS, LET'S GET THIS
DONE.
AND SO WE NOW HAVE GENETIC CODE
AND HE DID IT IN SHORT ORDER.
THAT WAS A GREAT EXAMPLE OF
PEOPLE AT NIH COMING TOGETHER TO
SOLVE A REALLY IMPORTANT
PROBLEM.
I WARRANT THERE ARE OTHER SUCH
PROBLEMS THAT WE CAN DO A BETTER
JOB OF COMING TOGETHER ON AND
SOLVING.
SO, WE'VE BEEN THINKING ABOUT
WAYS TO ENCOURAGE COLLABORATIONS
AND I MENTIONED SOME OF THE
THINGS IN MY TALK.
AND THEN FINALLY, BY NO MEANS
LEAST, WE REALLY HAVE TO DO A
MUCH BETTER JOB AT IMPROVING THE
DIVERSITY, EQUITY INCLUSION AND
ACCESSIBILITY AT THE NIH.
WE ARE TRYING VERY HARD TO
RECRUIT PEOPLE WITH A DEDICATION
TO THIS ISSUE AND THE
DISTINGUISHED SCHOLARS PROBLEM
IS AN EXAMPLE AND WE'VE EXTENDED
IT NOW TO SENIOR FOLKS.
IT'S A REALLY BIG PROBLEM.
THERE ARE MANY, MANY TALENTED
PEOPLE OUT THERE WHO WOULD COME
TO WORK AT THE NIH.
WE NEED TO FIND THEM AND
INTEGRATE THEM FULLY IN OUR
ACTIVITIES AND IN SOME WAYS, WE
MAY NEED TO CHANGE THE CULTURE
OF NIH.
UNITE HAS BEEN DOING A GREAT JOB
OF IDENTIFYING BARRIERS THAT WE
ARE OURSELVES HAVE CREATED, TO
THAT DIVERSITY THAT WE WANT TO
HAVE.
ALL OF THOSE ARE GOING TO
ACQUIRE A LOT OF ATTENTION AND
INTEREST AND EVERYBODY SORT OF
PULLING TOGETHER TO GET THIS
DONE.
SO THOSE ARE THE FOUR KIND OF
MAJOR AREAS, MAYBE MORE THAN YOU
WANTED TO HEAR.
THEY'RE RIGHT AT THE TIP OF MY
TONGUE.
READ IT IN THE CATALYST YOU WILL
HEAR MORE ABOUT IT.
>> I FEEL FORTUNATE LIKE I ASKED
THE RIGHT QUESTION AND ARE
SPENCE IS EACH AND EVERY ONE OF
THE TOPICS THAT YOU RAISED IN
YOUR ITEMS RESINATES WITH ME SO
I THINK THOSE ARE ABSOLUTELY
SPOT ON.
WE HAVE SOME QUESTIONS FROM THE
AUDIENCE SO I WANT TO GIVE
INDIVIDUALS THEIR OPPORTUNITY TO
ASK YOU THEIR TARGETED
QUESTIONS.
WE HAVE A QUESTION FROM AN
AUDIENCE MEMBER AND PLEASE
FORGIVE ME IF I MISPRONOUNCED
YOUR NAME.
IT'S SIDAR HANAHLIE, CAN YOU PUT
A NUMBER ON THE FRACTION OF ALL
DRUG RESISTANT CASES IN THE
CLINIC, MEANING FOR CANCER
RESISTANCE, THAT CAN BE
EXPLAINED BY THE RESISTANCE
MECHANISMS THAT ARE DISCUSSED IN
YOUR TALK?
>> SO, FOR INDIVIDUAL TUMORS WE
HAVE SOME IDEA.
I'LL GIVE YOU SOME EXAMPLES.
SO, FOR OVARIAN CANCER, WHAT
HAPPENED, IT'S AN INTERESTING
TUMOR MOST PATIENTS PRESENT WITH
STAGE THREE OR FOUR DISEASE IT'S
SPREAD AND IT IS RESPONSIVE TO
CHEMOTHERAPY AND CHEMOTHERAPY
INCLUDES FIRST-LINE CHEMOTHERAPY
TWO DRUGS AND ONE OF PLAXOL AND
RESISTANCE DEVELOPS IN FIRST OF
ALL, HALF THE PATIENTS DO
RESPOND THAT WELL.
OF THOSE THAT RESPOND RESISTANCE
WILL DEVELOP IN HALF OF THOSE
AGAIN SO ONLY ABOUT 25% OF THE
PEOPLE WILL SURVIVE WITH STAGE 4
OVARIAN CANCER SO IT'S A LETHAL
DISEASE.
RESISTANCE SEEMS TO BE THE KEY
TO UNDERSTANDING WHAT GOES ON
THERE.
AMONG PATIENTS WHO HAVE
RESPONDED INITIALLY, AND THEN
RELAPSED, WHICH IS ABOUT HALF OF
THE PEOPLE WHO RESPOND, THERE
ARE REARRANGEMENTS INVOLVING
P-LACK PRE TEEN IN 10% OF THOSE
CASES.
SO, IN REARRANGEMENTS WHICH A
PROMOTER FROM UPSTREAM HAS
BROUGHT DOWNSTREAM TURNING ON
EXPRESSION OF THE GONE IT'S
PRETTY GOOD EVIDENCE IT'S BEING
SELECTED FOR AND THAT IS ONE OF
THE MAIN REASONS FOR THE
RESISTANCE.
IT'S MORE COMPLICATED BECAUSE
THERE ARE TWO DRUGS AND THEY
HAVE TO BE RESISTANT TO PLATINUM
AS WELL AND IT'S A MORE
COMPLICATED STORY.
SO I THINK THE ANSWER IS 10% OF
THE 50% RESPONDING PROBABLY ARE
REIS THE ANT ON THE BASES OF P
LACK OF PROTEIN.
AML IS ANOTHER DISEASE WE'VE
STUDIED IN DETAIL.
THE PATIENTS THAT DON'T RESPOND
TO TREATMENT THERE AND A PTP
SUBSTRATE.
A SUBSET OF THOSE PATIENTS ABOUT
30% OF INRESISTANT AND ABOUT A
THIRD OF THOSE ARE OR EXPRESS
ABDG2.
IT LOOKS AS IF WE'RE TALKING
ABOUT A SUBSET OF A SUBSET THAT
ARE CLEARLY DUE IN MANY CANCERS
TO PGP EXPRESSION.
IT'S PRESSED IN OVER 50% OF
TUMORS AND CONTRIBUTES TO
RESISTANCE, IT MAY NOT BE THE
ULTIMATE CAUSE OF RESISTANCE AT
THE END OF THE TREATMENT
SCHEDULE.
SO, IT PLAYS A ROLE AND WE NEED
TO GO BACK AND DO MORE DETAILS
TO STUDY TO FIGURE OUT WHETHER
IT'S WORTH ENTERSER SEENING BY
INTERVENING BUT EACH TUMORIS DI.
>> THANK YOU FOR THAT RESPONSE.
WE HAVE ANOTHER QUESTION FROM AN
AUDIENCE MEMBER HOWARD YOUNG.
WHO WANTS TO KNOW A LITTLE BIT
ABOUT YOUR GREATEST
UNACCOMPLISHED GOAL AT NIH?
>> IN THE LAB OR AT THE NIH?
[LAUGHTER]
>> THE LAB IS EASY, RIGHT.
THE NIH --
>> AT YOUR DISCRETION.
IT DOESN'T SAY THE LAB, IT SAYS
AT NIH.
>> I THINK I'M 80% OF MY EFFORT
IS GOING TO CHANGING CULTURE IN
A WAY THAT ACCEPTS DIVERSITY AS
BEING AN ESSENTIAL ELEMENT OF
OUTSTANDING SCIENCE.
AND THAT REQUIRES A CHANGE IN
THE WAY SOME PEOPLE THINK ABOUT
WHAT THEY DO, CHANGE IN THE WAY
WE DO BUSINESS, AND A CHANGE IN
THE PEOPLE WHO ARE WORKING AT
THE NIH AND AWFUL WHICH WILL
HAPPEN IN TIME AND I WILL BE
PATIENT AND I HOPE THAT OTHERS
WHO ARE REALLY INVOLVED DEEPLY
IN THIS WILL BE BUT WE NEED HELP
WITH EVERYBODY AT NIH TO DO
THIS.
>> PERFECT.
WE HAVE A QUESTION, I WANT TO
GET A COUPLE HERE.
WE HAVE A QUESTION FROM KEN
KRAMER WHO WANTS TO KNOW -- HOW
YOU ARE ABLE TO KEEP YOUR
RESEARCH EFFORTS SEPARATE FROM
POLITICAL INTERFERENCE SO, YOU
SHOWED A DIAGRAM WITH A LOT OF
INTERSECTING PIECES AND YOU HAVE
A LOT OF TOUCH POINTS.
DOES THAT INTER VEER YOU WITH
YOUR RESEARCH EFFORTS?
>> SO, I'M GOING TO KIND OF
CHANGE THE QUESTION, I MEAN, THE
HARD PART IS AVOIDING CONFLICT
OF INTEREST FOR ME.
SO, BECAUSE I'M CAPABLE OF
CHANGING POLICY AT NIH, I HAVE
TO BE CAREFUL NOT TO DO THINGS
THAT ARE IN MY SELF-INTEREST.
AND SO N.
>> Catherine: WILL FREQUENTLY
COMPLAIN.
RICK CLAUSENER USED TO EXPLAIN
TO ME ABOUT VARIOUS THINGS SAID
THE PROBLEM WITH YOU BE DDIR YOU
FEEL LIKE YOU HAVE TO BE EVEN
HANDED IN WHAT YOU DO.
SO THAT IS CERTAINLY BEEN AN
ISSUE AND I REALLY THINK ABOUT
THIS ALL THE TIME THAT WE NEED
TO BE FAIR TO THE SMALLER
INSTITUTES, TO THE BIGGER ONES
AND THAT REQUIRES A LOT OF
EFFORT AND A LOT OF THOUGHT.
AND I NEVER WOULD DO ANYTHING IN
THE WAY OF POLICY THAT WOULD
EFFECT MY ABILITY TO DO RESEARCH
EXCEPT TO PROVIDE AN ENVIRONMENT
IN WHICH EVERYBODY CAN DO
RESEARCH SO THAT WOULD BE MY
GOAL.
THANK YOU FOR THAT TRICKY
QUESTION.
[LAUGHTER]
WHILE WE'RE WAITING FOR
QUESTIONS, I'M GOING TO SPEAK
ANOTHER ONE OF MY QUESTIONS.
MY QUESTION RELATES TO BALANCING
A NEED FOR POLICY AND OVERSIGHT
WITH A NEED FOR NIMBLENESS TO
ADAPT AND INNOVATE.
AND DO YOU HAVE THOUGHTS ABOUT
THAT BALANCE AND HOW WELL WE'RE
ACHIEVING THAT BALANCE IN THE
INTRAMURAL AND EXTRAMURAL SPACES
AND ANOTHER WAY OF FRAMING THAT
IS ARE WE OVER INCUMBERED WITH D
BUREAUCRATIC REQUIREMENTS THAT
ARE EFFECTING OUR NIMBLENESS AND
OWE HAVE A TIVENESS.
>> THAT'S A VERY GOOD QUESTION.
THE BOTTOM-LINE ANSWER IS YES.
WE ARE OVER INCUMBERED.
I LIVE AT THE INNER FACE BETWEEN
THE LEGAL REQUIREMENTS, THE
COMPLIANCE REQUIREMENT AND
TRYING TO ADAPT THOSE AND
EXPLAIN THOSE TO THE SCIENTIFIC
STAFF.
WE CAN'T IGNORE THEM.
THEY'RE LEGAL REQUIREMENTS.
SOME OF THEM MAKE REALLY GOOD
SENSE.
SOME OF THEM RELATE TO SINGLE
INCIDENTS THAT HAPPEN 20 YEARS
AGO THAT HAVEN'T HAPPENED SINCE
BUT HAVE INCUMBERED OF US DOING
A WAY OF BUSINESS.
THE ANSWER IS THAT BUREAUCRACY
SAY PROBLEM.
IT'S A PROBLEM FOR AWFUL NIH.
YOU'VE HEARD ABOUT ARPA-H, AND
IT'S INTENT WAS TO CUT THROUGH
SOME OF THE BUREAUCRACY AND GET
FUNDING TO IMPORTANT PROJECTS
THAT NEED TO MOVE FORWARD
QUICKLY.
IT REMAINS TO BE SEEN WHETHER IT
WILL MAKE ANY DIFFERENCE.
ONE OF THE PROBLEMS IS IT'S
BEING SEPARATED FROM THE NIH SO
ALL THE EXPERIENCE, ALL THE
WONDERFUL TALENT OF NIH IS NOT
BEING BROUGHT NECESSARILY THE
BEAR ON ARPH-H.
IT SHOULD BE A RAPID RESPONSE
MECHANISM FOR DEALING WITH
PUBLIC-HEALTH ISSUES AND OUR
RESPONSE TO COVID-19 WAS
INSTANTANEOUS.
LITERALLY WITHIN WEEKS THERE WAS
A VACCINE DEVELOPED AT THE NIH
AND THIS IS MAZING AND 250P Is
ARE WORKING ON COVID AND MAKING
SUBSTANTIAL ADVANCE AND WE CAN
TURN ON TIME.
IT DIDN'T REQUIRE GETTING GRANT
MONEY OR ANYTHING ELSE.
IT'S I HOPE WHOEVER REPLACES ME
AND TO MAKE SURE THAT WHOEVER
COMES IN IS AWARE OF THOSE NEEDS
AND DAN, YOU COULDN'T BE MORE ON
TARGET IN SAYING WE HAVE TO
CLEAR AWAY UNNECESSARY
BUREAUCRACY AND EXPLAIN THE
BUREAUCRACY WE HAVE.
>> I WANT TO THANK YOU FOR YOUR
THOUGHTFUL RESPONSE TO THAT
QUESTION AND ALL THE QUESTIONS
AND FOR YOUR EXCELLENT
PRESENTATION TODAY AND FOR YOUR
DECADES OF TRUE SERVICE.
WE'RE OUT OF TIME BUT THANK YOU
SO MUCH FOR EVERYTHING THAT YOU
DO FOR US.