人類常見疾病的表觀遺傳學基礎 (The Epigenetic Basis of Common Human Disease)

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>> GOOD AFTERNOON, EVERYONE.
WELCOME TO THE FIRST OF THE
ACADEMIC YEAR WEDNESDAY
AFTERNOON LECTURES, GIVEN THIS
AFTERNOON BY A DISTINGUISHED
PROFESSOR FROM HOPKINS, ANDY
FEINBERG.
THOSE OF YOU NEW TO NIH, HOPE
YOU'LL MAKE A PRACTICE OF COMING
HERE ON WEDNESDAY AFTERNOONS, WE
LINE UP QUITE A REMARKABLE
NUMBER OF SPEAKERS, OFTEN TIMES
ASKING THEM TO PUT FORWARD NOT
JUST STUFF THAT WE ALL KNOW
ABOUT BUT PROVOCATIVE NEW IDEAS,
TODAY WILL BE NO EXCEPTION.
THE LIST OF SOME 35 SPEAKERS
LINED UP FOR THIS COMING
ACADEMIC YEAR IS AVAILABLE ON
THE WEB AND THE VARIOUS POSTERS
THAT YOU MIGHT NOTE AND GET ON
YOUR CALENDAR.
WELCOME TO ALL THOSE WATCHING ON
THE WEB, MASUR IS NICELY FULL.
THERE ARE HUNDREDS OF YOU WHO
ARE TRYING TO MULTI-TASK THERE
IN WHATEVER LOCATION YOU'RE IN
THE MIDDLE OF AND WELCOME, GLAD
YOU COULD JOIN US IN THIS
FASHION.
IT'S MY GREAT PRIVILEGE TO AS
NIH DIRECTOR TO INTRODUCE MANY
WEDNESDAY AFTERNOON LECTURERS,
WHEN I HAVE THE CHANCE TO DO SO
IT'S ALWAYS FUN TO REMIND MYSELF
A LITTLE BIT WHAT FIELD THEY
HAVE BEEN WORKING IN.
IN THIS INSTANCE, THIS IS
SOMEBODY I KNOW QUITE WELL.
ANDY FEINBERG AND I WERE FACULTY
TOGETHER AT THE UNIVERSITY OF
MICHIGAN BACK IN THE 1980'S, AND
EARLY 1990'S, AND HAVE REMAINED
FRIENDS AND COLLEAGUES EVER
SINCE.
HE IS IN FACT A REMARKABLY
CREATIVE SCIENTIST WHO HAS OVER
THE COURSE OF SEVERAL YEARS,
KNOW A COUPLE DECADES,
CONTRIBUTED IN SIGNIFICANT WAYS
TO OUR UNDERSTANDING,
PARTICULARLY OF EPIGENETICS, A
FIELD WHICH PERHAPS WHEN HE
STARTED INTO IT WAS ALMOST
NONEXISTENT OR CONSIDERED TO BE
SQUISHY AND LAMARCKIAN, AND NOW,
OF COURSE, IS THE SUBJECT OF A
GREAT DEAL OF INTEREST AND GREAT
DEAL OF NIH FUNDED WORK AND
GREAT DEAL OF INSIGHT,
UNDERSTANDING ABOUT HOW
MODIFICATION IN TERMS OF
METHYLATION OF DNA AND WHAT
HAPPENS WITH PROTEINS A BIND
DNA, HAVE A PROFOUND IMPACT ON
BIOLOGY AND MEDICINE.
ANDY STARTED AS A GEEK IN THE
MATHEMATICAL ARENA, HUNG UP ON
FIBONACCI NUMBERS.
HE GOT UNDERGRADUATE TRAINING AT
YALE AND
MOVED TO HOPKINS
PROGRAM.
ANDY AND BERT DEFINED
HYPOMETHYLATION AS A SIGNATURE
OF CANCER THAT HAD NOT BEEN
PREVIOUSLY NOTED, SUBJECT TH PUBLISHED IN
1982.
AFTER THAT HE HEADED TO THE
UNIVERSITY OF MICHIGAN, HIS LAB
AND MY LAB WERE IN AJAYSENTS ADJACENT
BUILDINGS, HE AND I WERE ALSO
BOTH TRAINED AS MEDICAL
GENETICISTS THAT WE WOULD SHARE
EXPERIENCES GOING TO
THE CLINIC,
SOMETIMES IN ANN ARBOR, I
BELIEVE IT WAS THERE HE
ENCOUNTERED THE SYNDROME WHICH
ULTIMATELY BECAME A SIGNIFICANT
INSIGHT FOR HIM AND FOR THE REST
OF US ABOUT HOW EPIGENOMICS CAN
PLAY A ROLE IN MEDICAL ILLNESS
IN A WAY NOT PREVIOUSLY
APPRECIATED.
EIGHT SPENDING EIGHT YEARS AT
MICHIGAN, HE WENT BACK TO
HOPKINS, CURRENTLY THE GILMAN
SCHOLAR, AND THE DIRECTOR OF THE
CENTER FOR EPIGENETICS, A MEMBER
OF THE INSTITUTE OF MEDICINE,
ELECTED TO THAT ROLE, AND PROUD
TO SAY HE'S ALSO FAIRLY RECENT
APPLICANT FOR PIONEER AWARD, WAY
TO PROVIDE CREATIVE
INVESTIGATORS WITH FREEDOM TO
PURSUE IDEAS THAT INSIDE THAT
NOT FIT THE RO-1 MECHANISM IN
WHICH HE USED IN A VARIETY OF
INTERESTING WAYS TO LOOK AT A
FANTASTIC EPIGENETIC MODEL FOR
EVOLUTION AND DISEASE STUDYING
HONEYBEES.
I DON'T KNOW WHAT HE'S GOING TO
PUT IN FRONT OF YOU BUT I'M SURE
YOU'LL FIND IT INTERESTING.
PLEASE JOIN ME IN WELCOMING DR.
ANDREW FEINBERG.
>> THANK YOU.
I'M THRILLED TO BE HERE, I'M
INCREDIBLY GRATEFUL TO FRANCIS
FOR THAT EXCEPTIONALLY KIND AND
GENEROUS INTRODUCTION, AND TO
LOUIE FOR NOMINATING ME TO GIVE
THIS TODAY.
I WANTED TO POINT OUT THAT THE
BECKWITH LEADERMAN PATIENT WAS
BROUGHT TO MY ATTENTION BY
FRANCIS, WITH HIS OTHER SKILLS
IS AN INCREDIBLY GIFTED CLINICAL
GENETICIST, RESEARCHING THE
PATIENT HAD BECKWITH, AND IT FIT
MY RESEARCH AND IT WAS
TRANSFORMATIVE FOR MANY YEARS.
I'M GOING TO TALK ABOUT THE
EPIGENETIC BASIS OF COMMON HUMAN
DISEASE.
ANTOINE, MY MICROPHONE IS GOOD?
THANKS.
THIS IS WHERE I WORK IN THE
CENTER FOR EPIGENETICS, A GOOGLE
EARTH VIEW.
SO LIKE ALL HOPKINS BUILDINGS,
IT LOOKS LIKE A PARKING
STRUCTURE BUT IN FACT THERE ARE
LABORATORIES IN THERE, AND SO
ALL GENERALETTISTS ARE
INTERESTED IN PHENOTIPPIC
VARIATIONS, INTERESTED IN ALL OF
THEM BUT WE'RE FUNDED TO LOOK AT
THE ONES RELEVANT
TO HUMAN
DISEASE.
I WOULD ARGUE IF YOU ASKED THE
BASIS OF PHENOTIPPIC VARIATION,
HOW IS A HUMAN DIFFERENT FROM A
CHIMPANZEE, WITH RESPECT TO DR.
GOODALL, DIFFERENCES ARE MODEST
COMPARED TO SOMETHING LIKE A
PLANT OR EPITHELIUM, WHICH IS
WHAT I WORKED ON BEFORE BERT'S
LAB, THEY ARE ENTIRELY EXPLAINED
BY INFORMATION WE HAVE.
WE DON'T KNOW HOW TO INTERPRET
IT BUT WE HAVE IT ALL.
WE KNOW WHAT THE COMPLETE
SEQUENCE IS OF THE SPECIES AND
THAT DEFIES WHAT TH DEFINES WHAT THE
DIFFERENCES ARE.
A MORE COMPLICATED QUESTION,
WHAT'S THE DIFFERENCE BETWEEN
THE BRAIN AND HEART AND LIVER
AND COLON?
HERE ARE ALL THESE DIFFERENT
TISSUES, IN FACT IT'S EASY TO
SEE THAT THE STOMACH, SAY, OF A
CHIMPANZEE IS FAR MORE DIFFERENT
THAN THE EYEBALL OF A CHIMPANZEE
AND THE STOMACH OF A CHIMPANZEE
THAN THE STOMACH OF A HUMAN
BEING AND YET THE TISSUES KNOW
WHAT THEY ARE.
THEY HAVE INFORMATION THAT
DEFINES THEIR FUNCTION, AND
TELLS THEM WHAT TO DO AND THEY
REMEMBER WHAT THEY ARE THE CELLS
DIVIDE.
THAT'S WHAT WE REALLY MEAN BY
EPIGENETIC INFORMATION.
THERE ARE MODIFICATION OF THE
GENOME THAT OCCUR DURING
DEVELOPMENT AND DEFINE
TISSUE-SPECIFIC DIFFERENCES,
OTHER THAN THE DNA SEQUENCE IT
SELF WHICH IS IDENTICAL ACROSS
THE TISSUE.
IT'S EVEN MORE COMPLICATED THAN
THAT BECAUSE YOU MAY KNOW DR.
FERUCCI ALSO HAS AN ADDRESS IN
FLORENCE, ITALY.
I WAS OVER THERE NOT THAT LONG
AGO, AND I ENCOUNTERED THIS
8-FOOT GUY, DAVID, I INVITED HIM
TO BE THE PERFECT EXAMPLE OF
HUMAN DEVELOPMENT, TO VISIT US
IN BALTIMORE.
AND HE WENT DOWN THE STREET AND
HAD ONE OF THESE DOUBLE WHOPPER
CHEESEBURGER THINGS AND I'M SAD
TO SAY HE WOUND UP LIKE THIS.
THE POINT IS THAT OUR
ENVIRONMENT SHAPES IN A
REMARKABLE WAY OUR PHENOTYPE,
BUT NOT THROUGH THE GENES
THEMSELVES, BUT THROUGH
INFLUENCING, HOW THE EPIGENETIC
MIGHT TAKE PLACE.
THE PERSON WHO COINED THE TERM,
EPIGENETICS, WAS CONRAD
WADDINGTON IN THE 1950'S AT CAME
CAMBRIDGE UNIVERSITY, HE SAID
THEY ARRIVED FROM GENOTYPE
THROUGH PROGRAMMED CHANGE AND
INTERACTION WITH THE
ENVIRONMENT, PULLED INTO A
PARTICULAR PATTERN OF, SAY,
TISSUE DEVELOPMENT.
HIS ORIGINAL MONO GRAPH WAS
SOMETHING LIKE THIS, WHERE YOU
HAVE APLEURIA POTENT CELL THAT
BECOMES A LIVER OR CELL BUT
PEOPLE POINTED OUT WATER RUNS IN
THE OTHER DIRECTION, LITERALLY,
HIS FRIEND, PIPER, THE LANDSCAPE
ARTEST, REDREIST, REDREW THE BALL ROLLING
DOWN THE HILL.
THE ENVIRONMENT MIGHT PUSH
THINGS UP THIS WAY, THEY
EVENTUALLY ROLL TO THIS ONE OR
THIS ONE, EACH OF THE DIFFERENT
TISSUE TYPES CONTROLLED
ACCORDING TO WADDINGTON, BY YOUR
SEQUENCE.
IT'S CALLED PANELLIZATION, THE
MODERN DEFINITION OF EPIGENETICS
IS DIFFERENT AND MORE FLEXIBLE
AND MORE INFORMATION-BASED.
THAT IS MODIFICATIONS OF DNA ARE
ASSOCIATIVE FACTORS CONTENT
MAINTAINED DURING CELL DIVISION
OTHER THAN THE SEQUENCE.
I ALLUDED TO THAT EARLIER.
TO GIVE YOU AN IDEA, HERE IS A
CELL, A GENE, THAT'S MAKING AN
RNA ACTIVE, AND A GENE
TRANSCRIPTIONALLY SILENT.
ONE THING IS DNA METHATION, CPG,
BUT ALSO KNOW THERE'S NONCPG
METHATION, WE KNOW OF NO
MECHANISM TO COPY THAT.
THIS IS COPIED.
DON'T HAVE TIME TO GO INTO THE
MECHANISMS BUT AN ENZYME DOES
THAT.
THAT'S ASSOCIATED IN GENERAL
WITH GENE SILENCING AND THOUGHT
UNTIL SOME RECENT STUDIES THAT
WE'RE GOING TO TALK ABOUT TO BE
ENRICHED OR ALMOST ENTIRELY AT
DENSE REGIONS WITH MANY CPG'S
CALLED CPG ISLANDINGS.
THERE'S HISTONE MODIFICATIONS.
THERE ARE SOME OF THESE
POSTTRANSLATIONAL MODIFICATIONS
OF HISTONES, YOU SEE THE DNA,
ASSOCIATED WITH ACTIVATION AND
OTHER ONES ASSOCIATED WITH
SILENCING, AND THEY ARE QUITE
DIFFERENT.
IT'S EITHER THIS MODIFICATION
FOR ACTIVATION OR THE SILENCING
BUT NEVER FOR BOTH.
AND THEN THERE ARE PROTEINS THAT
RECOGNIZE THE COMPLEXES, AND
THEN THOSE ARE TRIAUTHOTHORAX,
POLYCOMB, AND THE DENSITY OF
NUCLEOSUMEE NOT LIKE MY DAUGHTER
PACKS HER SUITCASE, WHICH IS
INTERESTING AND NO ORDER TO IT.
BUT IN AN ORDERED WAY.
NOW, I'M GOING TO TALK ABOUT
THINGS BOTHERING ME FOUR OR FIVE
YEARS AGO, HAUNTING ME.
ONE IS THE MISSING HERITABILITY
OF COMMON SCENES.
DISEASE, COMMON
VARIANTS EXPLAIN 1 TO 20% OF
GENETIC VARIANTS OF A DISEASE.
IT'S PUZZLING.
MANY GOOD EXPLANATIONS,
INCLUDING WHERE VARIANTS, THINGS
THAT WE CAN'T JUST IDENTIFY
BECAUSE OF THE WAY THAT OUR
STUDIES ARE -- EPIDEMIOLOGIC
COHORTS, IT'S AN ACTIVE AREA OF
STUDY, SOMETHING PEOPLE WONDER
ABOUT.
THERE WAS A PROVOCATIVE PAPER IN
SCIENCE TRANSLATIONAL MEDICINE
FROM MY FORMER MENTOR, BERT
FOGEL STEIN.
HE DIDN'T MEAN HARM BUT IT WAS A
TWIN STUDY AND SHOWED THAT IT'S
DIFFICULT TO EXPLAIN THE
CONTRIBUTION TO DISEASE GREATER
THAN THE FACTOR OF ABOUT 20%,
AND THERE MUST BE A VERY STRONG
THEREFORE ENVIRONMENTAL
COMPONENT.
THERE'S HUMOROUS GIVE AND TAKE,
ALL WELL MEANING REALLY, IN THE
COMMENTS THAT AID PERIOD AFTER
THAT PAPER CAME OUT.
APPEARED AFTER
THAT PAPER CAME OUT.
EPIGENETICS PLAY A ROLE.
AS FRANCE FRANCIS ALLUDED TO, IN THE
POPULAR SCIENCE, NOT SO MUCH
ANYMORE IN THE SCIENTIFIC
COMMUNITY, THERE MIGHT BE A
LAMARCKIAN ROLE, AND THAT IDEA
IS THAT -- YOU HAVE TO READ
LAMARCK HIMSELF, THE WAY HE
DESCRIBED IT, THERE ARE FLUXORS,
CAUSED BY ENVIRONMENTAL
EXPOSURE, SO THE GIRAFFE
OCCURRED BECAUSE SOME HORSE HAD
TO STRETCH HIS NECK TO EAT A
LEAF AND THE FLUXORS GOT
TRANSMITTED TO PROJECT AN PROGENY AND THAT
CARRIED ON.
THERE'S A PICTURE OF LAMARCK.
I'M NOT SAYING THERE ISN'T SOME
COMPONENT OF TRANSGENERATIONAL
INHERITANCE, BUT IT WOULD BE
STABLELY TRANSMITTED, HERE IS
THE IMPORTANT THING, OVER AND
OVER AND OVER AGAIN DESPITE GERM
1 REPROGRAMMING AND UNDERGOING
EVOLUTIONARY SOLUTION IS
DIFFICULT FOR ME.
I'LL COME BACK TO THAT IN JUST A
MOMENT.
SO ABOUT 12, 13 YEARS AGO, I
BECAME VERY INTERESTED IN
WHETHER OR NOT ONE COULD START
TO EXPLORE THE EPIGENETIC BASIS
OF COMMON DISEASE GENERALLY,
INCLUDING CANCER, BUT OTHER
DISEASES AS WELL.
CANCER IS ONE WHERE PEOPLE HAVE
FINALLY COME TO ACCEPT AN
EPIGENETIC COMPONENT BUT WHAT
ABOUT ALL THE OTHER DISEASES?
PARTICULARLY WHERE ENVIRONMENTAL
EXPOSURE MIGHT BE IMPORTANT.
AND IN 2004, A STUDENT, HANS AND
DANNY, AN EPIDEMIOLOGIST I WORK
CLOSELY WITH, WE DIDN'T CALL IT
EPIGENETIC EPIDEMIOLOGY.
WE HAD ANOTHER TERM.
THAT TERM BELONGS TO STEPHAN,
BUT OUR SUGGESTION WAS THAT YOU
COULD INTEGRATE ENVIRONMENTAL
EXPOSURE, DNA VARIATION IN
MODIFYING THE EPIGENETI UPY GENOME.
IT WOULD INTEGRATE INTO THE
EPIGENETIC TO DEFINE PHENOTYPES,
THAT DOESN'T MEAN IT EXPLAINS
ALL OR MOST OF GENETICS BUT
MIGHT EXPLAIN SOME, PARTICULARLY
THAT RELATED TO THE ENVIRONMENT.
THAT WAS THE IDEA.
WE SAID IN HERE, I THINK A NEAT
POINT, YOU COULD GET
QUANTITATIVE TRAITS OVER
MODIFYING THE EPIGENOME WITHOUT
INVOKING LOTS OF INDIVIDUAL
VARIANTS.
THEY COULD INTEGRATE, OR
TOGETHER WITH VARIATION, INTO A
QUANTITATIVE STRAIGHT.
WE PUT IN A GRANT I WAS THRILLED
TO GET FUNDED FOR CENTERS FOR
EPIGENETICS AT JOHNS HOPKINS,
THE GENOME INSTITUTION, T INSTITUTE TO LOO K FOR
TOOLS, A PROGRAM CREATED BY
FRANCIS WHEN HE WAS DIRECTOR, TO
DEVELOP AND APPLY TOOLS ACROSS
THE GENOME AND POPULATIONS OF
PATIENTS.
THE FIRST THING WE DID WAS WITH
THE HELP OF RAFAEL ROSARIO,
DEVELOP AN ARRAY-BASED ACRONYM,
CHARM, TO APPEAL TO THE MONIKER
FOR BALTIMORE, CHARM CITY, IT'S
ACTUALLY BALTIMORE, PEOPLE
SNICKER BECAUSE OF TV SHOWS, BUT
IT'S A GREAT TOWN.
AND THAT ENABLED US TO
INTERROGATE THE GENOME AT A
GREATER SCALE THAN PEOPLE HAD
DONE BEFORE, THAT THE TYPICAL
THING WAS 14,000 AND 40,000 OF
THESE ISLANDS.
THIS IS UP TO FOUR MILLION
SITES.
AND THEN WE DIDN'T INVENT WHOLE
GENOME BISULFITE SEQUENCING BUT
BEN LANGLEY INVENTED BOW TIE AND
A BRILLIANT STATISTICIAN NOW AT
JOHNS HOPKINS, DEVELOPING TOOLS
TO REDUCE THE COST OF ANALYSIS,
A CLEVER WAY TO IMPROVE
EXTRACTING EPIGENETIC
INFORMATION FROM SEQUENCING.
THE LATEST BONNET, THERE'S A
CENTER AT HOPKINS FOR KEEPING
TRACK OF STARS IN THE SKY, AND
ALEX LEADS THAT, THE IDEA IS TO
TRY TO USE THE GRAPHICAL
PROCESSORS, CHEAP LITTLE
PROCESSORS FOR $50, AND SO WE'RE
HOPING TO USE THAT POWER BECAUSE
I'LL TELL YOU, THE BIGGEST
BOTTLENECK IN OUR RESEARCH, I
HEAR THIS FROM OTHER
INVESTIGATORS TOO, PROBABLY A
PAPER ON THIS, THE COMPUTATION.
IT'S NOT THE EXPERIMENT ANYMORE.
IT'S JUST THE COMPUTER TIME AND
ANALYSIS.
SO I'M GOING TO SHOW YOU THE
SECOND BIG PUZZLE THAT WAS
EATING AT ME FROM A STUDY,
REALLY OUR FIRST BIG STUDY, OF
THE EPIGENOME OF NORMAL AND
CANCER CELLS AND THIS IS THE
RESULT OF THE CHARM ANALYSIS,
WE'RE LOOKING AT MILLIONS OF
SITES, DNA METHYLATION, ACROSS
THE GENOME.
THE QUESTION, HOW IS COLON
CANCER DIFFERENT FROM THE NORMAL
COAL MUCOSA, WE'RE ASKING CHARM.
RED IS MORE METH LATED
BLUE IS MORE METHYLATED.
YOU SEE THEY ARE VERY DIFFERENT.
HERE IS A GREAT BIG SURPRISE.
IF YOU LOOK AT THE DIAGRAM OVER
HERE, HE'S ARE THE SITES.
IF YOU ASK AN AUTOPSY SPECIMEN
HOW WELL THEY DIFFER, THEY DO IT
COMPLETELY.
THE WAY OF SAYING THAT FORMALLY,
THE CANCER DIFFERENTIAL METH WHY
LATEMETHYLATED, COLON CANCER, IT
ISN'T NORMAL, IT'S THE SAME
THING THAT GOES BACK TO MY
ORIGINAL ANALOGY TELLING THE
EYEBALL IT'S NOT A STOMACH.
WHY SHOULD IT BE GENERAL LIKE
THAT?
HOW DOES THAT RELATE TO
FUNCTION?
IT WAS A PUZZLE.
THE OTHER THING I NOTICED IS
THAT, YES, THE CHANGES ARE THE
SAME BUT THE EPIGENETIC TARGETS
ARE HYPERVARIABLE.
THERE'S A GREAT DEAL OF
VARIABILITY, YOU SEE IT IN THE
PATTERN OF TUMORS COMPARED TO
NORMAL, EVEN IN THE NORMAL
ITSELF, AND LOOK AT THIS.
THERE IS CLEARLY A GREAT DEAL OF
VARIABILITY IN THE NORMAL TISSUE
AS WELL.
THAT COULD BE CAUSED BY THE
GENOME SEQUENCE, RIGHT?
SEQUENCES WITH DNA METHYLATION.
IF YOU LOOK AT INBRED MICE, THE
SAMPLES RIGHT HERE AND THOSE
SAMPLES RIGHT THERE, LOOK AT THE
VARIABILITY.
THESE ARE BROTHER-SISTER INBRED
STRAINS, THEY STILL SHOW
VARIABILITY, EVEN THOUGH REGIONS
ARE CONSERVED FROM HUMAN TO
MOUSE, THERE ARE VARIABLE
LEGIONS FROM ANIMAL TO ANIMAL
BUT THE LOCATIONS ARE CONSERVED,
FROM ONE SPECIES TO ANOTHER.
THAT'S REALLY STRANGE RESULTS.
IT WAS EATING AT ME, AS WELL AS
THE IS MISSING HERATIBILITY.
I DON'T KNOW YOU CAN RELY ON
LAMARCKIANISM.
I CALL THIS MY EPIPHANY.
IT'S A WAY O SAYING A GOOD IDEA AT
CHURCH.
I WAS SIGHTSEEING WITH MY SON IN
LONDON.
WHAT REALLY HAPPENED, WE WANTED
TO GO UP BIG BEN, THERE'S A SIGN
THAT SAYS IN POLITE ENGLISH, IF
YOU'RE NOT BRITISH, GET LOST.
THAT'S NOT THE WORDS THEY USED.
RIGHT NEXT DOOR IS WESTMINSTER
ABBEY, AND THEY HAD A SIGN OUT
FRONT THAT SAID, IT'S THE
150th ANNIVERSARY OF ORIGIN OF
SPECIES, DARWIN IS DEAD BUT IT'S
STILL FUN TO SEE HIM.
I CHANGED THE LANGUAGE ON THE
POSTER.
I FOUND MYSELF STANDING ON
DARWIN'S GRAVE.
AND RIGHT NEXT TO DARWIN'S GRAVE
IS NEWTON'S GRAVE.
WHAT I'M NOT SHOWING YOU IS
THERE'S A VELVET ROPE RIGHT
HERE, AND THAT'S BECAUSE THE
BRITISH DO NOT WANT YOU TO PUT
YOUR FILTHY FEET ON ISAAC
NEWTON'S GRAVE BUT THEY DON'T
HAVE SUCH MISGIVINGS ABOUT
DARWIN AND THEY ALSO DECORATE
NEWTON'S GRAVE WITH CHERUBS AND
THINGS LIKE THAT.
THEY REALLY LIKE HIM A LOT.
AND JUST ABOVE DARWIN'S GRAVE IS
A PLAQUE TO DURAK, ONE OF THE
PEOPLE WHO FOUNDED QUANTUM
THEORY.
I THOUGHT MA MAYBE HE WAS BURIED
STANDING UP.
THE LABORATORY SAID, NO, NO,
IT'S AN URN.
I WAS EXPLAINING THIS TO PEOPLE
AT THE UNIVERSITY OF MIAMI, THEY
SAID HE'S BURIED IN BONITA
SPRINGS, FLORIDA.
THIS IS A COMMEMORATIVE PLAQUE.
THERE'S NOTHING LIKE THAT HERE
IN BIOLOGY.
SO MAYBE THERE'S SOMETHING ABOUT
THIS THAT'S THE CORE ELEMENT OF
QUANTUM THEORY THAT WOULD APPLY
TO BIOLOGY AND MAYBE SOLVE THIS
CONUNDRUM ABOUT WHERE
EPIGENETICS FITS IN AND WHERE
THAT VARIABILITY COMES FROM AND
MAYBE THAT WOULD MAKE SENSE IN
EVOLUTION.
THIS IS THE IDEA I HAD.
SO THAT YOU COULD HAVE FANTASTIC
EPIGENETIC VAIR YACK VARIATION AS A
DRIVINGS FOR.
YOU DON'T NEED THIS IN SINGLE
CELL ORGANISMS.
THERE ARE MUTATIONAL MECHANISMS
THAT DO WHAT I'M SAYING IN
BACTERIA.
BUT FOR A COMPLEX SPECIES,
MULTI-CELLED ORGANISM, I THOUGHT
IT WOULD MAKE SENSE.
BEAR IN MIND THESE ARE NOT
QUANTUM MECHANICAL DIFFERENCES
BUT THE IDEA IS JUST LIKE -- TO
BE COMPLETELY CORRECT, AN
ELECTRON FITS IN THIS ONE LITTLE
PLACE, FOR A CHEMICAL REACTION
TO TAKE PLACE IT HAS TO GO INTO
ONE PARTICULAR PLACE OVER HERE,
SO IT CAN BE SHARED BETWEEN TWO
ATOMS, IT WOULD NEVER HAPPEN.
THE ONLY WAY IT EVER HAPPENS, IF
THERE'S SOME SORT OF PROBABILITY
FIELD AND SOME INTERACTION.
SIMILARLY, I THINK IT MAKES MORE
SENSE IN DEVELOPMENTAL BIOLOGY
IF THE LIGAN'S AND
RESEPTEMBERRORS, IF THERE'S A
GRADIENT OR VARIABILITY IN THE
EXPRESSION OF BOTH SO SOME
CELLS, SIGNALLING MOLECULES FROM
THE ROOT OR BUD WOULD INTERACT
WITH RECEPTORS THERE AT THE
RIGHT CONCENTRATION IN THE
MESENCHYME.
MAYBE THAT'S THE REASON SO MANY
CELLS DIE DURING DEVELOPMENT.
YOU NEED STOCHASTICICITY.
IF THAT'S THE CASE, THE DEGREE
OF STOCHASTIC VARIATION COULD BE
CONTROLLED BY GENERAL IT
SEQUENCE.
THEY WOULD LEAD INHERENTLY BY
THE NAME OF SEQUENCE TO
EPIGENETIC VARIABILITY.
GENETIC VARIANTS THAT INCREASE
EPIGENETIC PLASTICITY COULD
INCREASE.
THE ENVIRONMENT IS ONE WAY, AND
THEN TOTALLY OPPOSITE IN AN
UNPREDICTABLE WAY, IT GOES BACK
AND FORTH FROM TIME TO TIME,
AFTER PERIODS OF SELECTION, YOU
WOULD SELECT SUCH VARIANTS.
I'M GOING TO SHOW A MOVE TO
ILLUSTRATE.
HERE IS THE CONVENTIONAL THEORY.
LET'S SAY YOU HAVE 100 PEOPLE.
I'M GOING TO TALKING ABOUT SIZES
OF PEOPLE BUT I'M NOT REALLY
TALKING ABOUT PEOPLE, I'M
TALKING ABOUT CIRCLES THAT I'M
CALLING PEOPLE.
THESE ARE NOT ACTUAL PEOPLE,
OKAY?
BUT LET'S SAY YOU HAVE 100
PEOPLE, AND THEY HAVE VARYING
SIZES NOTED BY THE SIZE OF THE
CIRCLE, SOME SMALL, SOME BIG,
CONTROLLED GENERALET REALLY SO
THE RED HAS THREE GAINES GENES
FOR BIG, BLUE THREE GENES FOR
BEING SMALL.
UNDER THE NORMAL WAY WE THINK
ABOUT EVOLUTIONALLY BIOLOGY, THE
LARGE SURVIVE, IF THERE'S
ABUNDANT NUTRITION AND RESOURCES
BECAUSE YOU'LL GET A BIGGER GUY
THAT ABOUT WIN THE JOUSTING
COMPETITION AND THE NEXT
GENERATION WILL HAVE LARGER
PEOPLE.
LIFE ON EARTH IS NOT FAIR.
YOU MIGHT SELECT FOR BEING BIG
BUT NUTRIENTS, THERE MIGHT BE A
NUMBER GENERATION, YOU'LL BE
SELECTED FOR SMALL AND BIG AND
SMALL.
PLAY OUT THE MOVIE AND SEE WHAT
HAPPENS.
WHAT WOULD HAPPEN IS YOU WOULD
BE SELECTING FOR BIG, BIG, BIG,
BIGGER, BIGGER, BIGGER.
NOW YOU SELECT FOR SMALL.
TOO BAD EVERYBODY DIED HERE AND
NOW THEY ARE LITTLE.
AND NOW THEY GET BIG AGAIN.
AND YOU GET THESE HUGE CHANGES
IN POPULATION.
WE DIDN'T KNOW THAT THERE
HAVEN'T BEEN THESE LARGE DIOPS
OVER DEVELOPMENT, THE HAPPENS IN
AN EXISTING
POPULATION.
WHAT ABOUT MODELS?
NOW YOU SELECT FOR THE
VARIABILITY ITSELF.
IT'S JUST THE VARIANTS, REALLY.
YOU HAVE GENETIC SITES THAT ARE
SELECTED FOR VARIANTS, NOT JUST
FOR MEADES.
IT'S GOING TO BE LIKE IT WAS
BEFORE AND YOU'LL HAVE A HUGE
CHAIN, AFTER ENOUGH FLUCTUATION
BACK AND FORTH LIKE THIS,
EVENTUALLY LOOK WHAT HAPPENS TO
THE VARIANTS OF GENETIC
SELECTION.
YOU WIND UP WITH A POPULATION
THAT IS EXTREMELY HETEROGENEOUS
THAT INCLUDES SOME PEOPLE WHO
ARE BIG AND SOME PEOPLE WH WITH GENES FOR BEING
SMALL AND SMALL PEOPLE WITH
GENES FOR BEING BIG, THAT MAKES
IS UNDERSTAND IN GENETIC DATA.
HOW DO YOU TEST THIS IDEA?
THE PREDICTION OF THE IDEA IS
THAT THERE WOULD BE A THING, A
VARIABLE METHYLATED REGION.
THIS IS A CHARM SLOT MORE MOTH
METHYLATION, LESS METHYLATION.
THEY DO EXIST.
YOU DO ONE OF THESE ANNOTATION
ANALYSIS AND FIND OUT THAT THEY
ARE INVOLVED IN
ANTERIOR/POSTERIOR PATTERN
FORMATION, DEVELOPMENT.
CENTRAL NERVOUS SYSTEM, GUT,
MESENCHYME.
I'VE NEVER SEEN A CHART LIKE
THAT WITH SO MANY IMPORTANT
PROCESSES THAT ARE ALL SHOWING
UP FOR THE SAME PHENOMENON.
SO HOW MIGHT THIS BE RELEVANT TO
DISEASE IN THE FIRST DISEASE
THAT SEEMS TO MAKE SENSE IS
CANCER.
CANCER INVOLVES REPEATED CHANGES
IN THE MICROENVIRONMENT.
IN A WAY, A CANCER CELL
SURVIVING THE COLON,
SELECTING -- BEING SELECTED FOR
BEING ABLE TO LIVE IN THAT SPACE
THAT IT'S INNOVATING, AND
SELECTING FOR BEING ABLE TO
TRAVEL THROUGH THE BLOOD AND THE
LUNG
AND THE LIVER, SUBJECTED TO
HUGE VARYING ENVIRONMENTAL
CHANGES.
LIKE OXYGEN BEING ONE OF THE
PRINCIPAL ONES, VERY HYPOXIC, IT
BECOMES I'M OF HYPEROXIC.
WE DID A STUDY TO SEE WHETHER OR
NOT SEQUENCES ARE CHANGING MORE
BY VARIANTS, THE LEVEL OF DNA
METHYLATION.
THIS IS A PRINCIPAL COMPONENT
SLOT.
IT INDICATES BY HOW CLOSE YOU
ARE, HOW SIMILAR YOU ARE TO
OTHER SAMPELS, MEASURING ACROSS
THE GENOME.
NORMAL TISSUES CLUSTER TOGETHER,
BREAST, THYROID, LUNG, IF
EPIGENETICS WHERE YOU HAVE A
DEFINED CHANGE THAT GOES IN A
PRECISE PLACE TO NORMAL TO
CANCER, FROM THE NORMAL LUNG,
SAY, TO NEW PATTERN OF LUNG
CANCER BUT THAT'S NEVER WHAT YOU
SEE.
WHAT YOU SEE IS THERE.
YOU GET A HUGE VARIABILITY IN
THE METHYLATION PATTERN AT THE
VERY SITE DEFINED NORMAL
TISSUES.
IT'S LIKE A NORMAL GROUP OF WHAT
I WAS SHOWING EARLIER, VISUALLY
IN THAT FIRST HEAT MAP I SHOWED
AT THE BEGINNING OF THE LECTURE.
AND WITH AS FEW AS 25 CPG'S,
USING THIS METHOD, YOU CAN
DISTINGUISH CANCER.
WHEN WE CONTINUE THIS WORK, AND
THEN TAKE IT TO THE LEVEL OF
SEQUENCING, WE GOT A NEW INSIGHT
INTO WHAT I DISCOVERED WITH
BIRDS IN 1982 IN THIS "NATURE"
PAPER.
THERE'S A PICTURE OF US BACK
THEN.
HERE IS A INTERESTING
INTERESTING THING FOR YOUNG
PEOPLE IN THE AUDIENCE.
WHEN I LOOK AT MYSELF IN THE
MIRROR NOT MORNING, THAT'S WHAT
I THINK I SEE.
IT'S REALLY INTERESTING.
SO THIS IS WHAT WE SAW.
THIS IS SEQUENCING NOW.
THIS IS A MILLION BASES DNA,
HIGHLY METHYLATED, LOW
METHYLATION, THIS IS NORMAL
COLON THAT'S BLUE, COAL AN COLON CANCER
IS RED.
THIS IS HYPER VARIABLE TOO.
AND NOT ONLY IS IT HYPER
AVAILABLE, THESE ARE INDIVIDUAL
GENES, THERE'S NORMAL, HERE IS
THE VARIABILITY, EVEN WHEN GENES
ARE TURNED OFF SOMETIMES, MOST
OF THE GENES INVOLVED IN
INVASION METASTASIS, IT'S A HALF
OF A GENOME IN THESE BIG BLOCKS
AND REPRESENTS A THIRD.
THIS IS A LOT OF STUFF IN A
GENOME.
THESE ARE GIANT DMR'S FROM THE
NOMENCLATURE I GAVE EARLIER.
WHAT ARE ARE THESE BIG BLOCKS?
THEY TURNED OUT TO BE SOMETHING
ELSE THAT WE'VE BEEN STUDYING
EARLIER, IN THIS PAPER, FROM THE
LAB, WE DESCRIBE THE LARGE
ORGANIZED CHROMATIN, DI
METHYLATION, TRIMETHYLATION.
THESE ARE NORMALLY -- THEY HAVE
THE INCREASE CHROMATIN
METHYLATION AND CORRESPOND WITH
THE REGION IDENTIFIED ASSOCIATED
WITH A NUCLEAR LAMINATE, THEY
ARE HIGHLY CORRESPONDING, THAT'S
WHAT THIS REPRESENTS AS WELL.
IMPORTANTLY, WE SHOWED THEY ARE
NOT PRESENT -- THEY DEVELOP IN
DIFFERENTIATION AND THERE ARE
TISSUE-SPECIFIC DIFFERENTIATIONS
IN THEM.
I HAD A POSTDOC IN THE LAB, AN
ACCIDENTAL DISCOVER, OLIVER
MacDONALD, A PATHOLOGIST, I
SUGGESTED HE LOOK AT THE -- HE
LOOKED TO SEE THE RESPONSE, EMT,
EPITHELIAL TRANSITION, INDUCED
INVOLVING CHANGES OF DNA
METHYLATION.
THERE WAS NO EVIDENCE OF THIS AT
ALL.
OLIVER, OF COURSE, STAINED
EVERYTHING, BEING A PATHOLOGIST.
HE SAID, ANDY, BY THE WAY, LOOK
HOW PALE THE NUCLEI ARE ON
EXPOSURE.
I KNEW HE WOULD KNOW THAT, HE
KNOWS EVERYTHING.
YOU COULD SEE THE TGF DATA
REDUCES THE METHYLATION
GLOBALLY.
YOU CAN SEE THE LOCK SPECIFIC
HERE.
THERE THEY ARE, VISUALIZED BY
EM.
AND THEY DISAPPEAR ON THIS
EXPOSURE AND COME BACK WHEN YOU
TAKE THIS OFF.
SO IT'S SOMETHING THAT'S NORMAL
REPROGRAMMABLE IN RESPONSE TO
TGF DATA.
I SUGGESTED A DYNAMIC LANDSCAPE
DIFFERENT THAN WHAT WADDINGTON
SAID.
IT'S NOT TOTALLY GENE DETERMINED
BUT IT'S ADAPTABLE.
THESE VALLEYS CAN BECOME MUCH
FLATTER AND ALLOW TRANSITION
FROM ONE TO ANOTHER, AND THAT IS
INCRUISED BY CHROMATIN
STRUCTURE, BASED ON THINGS THAT
OTHER PEOPLE HAVE DONE, THAT I
POINTED OUT IN THE REVIEW PAPER,
CHROMOSOME-CHROMOSOME
INTERACTING AS WELL.
THERE'S PLASTICITY THAT'S
IMPORTANT IN NORMAL DEVELOPMENT.
THAT'S WHAT I WAS SAYING
EARLIER, YOU NEED A MECHANISM OF
NORMAL DEVELOPMENT AND RESPONSE
TO INJURY AND CHALLENGES FOR
ADAPTING YOUR PROGRAM, YOU COULD
DO THIS BY ALTERING UP ALTERING EPIGENETIC
PLASTICITY.
THERE'S A SUBSEQUENT PAPER IN
"NATURE," IT'S NOT THAT HARD TO
MODEL HOW THIS MIGHT OCCUR,
FLATTENING THE VALLEY AND DOING
THINGS LIKE -- I'M NOT GOING
INTO THE NAMES.
THE ESSENTIAL IDEA, EVEN IF YOU
HAD, SAY, A DETERMINISTIC
ELEMENT PULLING THINGS BACK TO A
NORMAL LEVEL OF METHYLATION, SAY
LIKE A HOOKING AND SPRING KIND
OF VERY SIMPLE PROCESS, YOU
COULD ADD TO IT A VARIABLE
FACTOR AND THAT IF THAT WAS
RELAXED, YOU WOULD GET THIS
VARIABILITY AND IF YOU MODEL
THAT, THE DATA THAT YOU GET IN
TERMS OF DISTRIBUTION OF DNA
METHYLATION BETWEEN NORMAL AND
CANCER, THE REALITY OF WHAT YOU
SEE.
THIS IS DATA I THINK ARE
PUBLISHED.
I SAW IT A COUPLE DAYS AGO IN
MOLECULAR MEDICINE, THIS IS ALSO
FROM WINSTON TEMPLAR.
I WANT TO SHOW YOU THIS.
IT'S AMAZING.
WE SAW THIS CHANGE IN DNA
METHYLATION AND USE LARGE SCALE
METHYLATION, BUT THIS SHOWS, AND
THIS IS AN EXAMPLE OF BREAST
CANCER, HERE IS THE REGION OF
ISLANDS, AND THE NEARBY REGIONS
THAT WE CALL SHORES, WE DEFINE
THE HYPO METHYLATED SHORES IN
CANCER AND HYPER METHYLATED
ISLANDS.
IN THE CANCER, IF YOU COMPARE,
SAY, THE BREAST CANCER OUTSIDE
THE THESE BLOCK AGENTS, THERE'S
HIGH METHYLATION, YOU CAN GO TO
THE ISLAND, IT'S LOW AND BACK UP
NORMALLY.
INSIDE THE BLOCK, THESE ARE
ISLANDS INSIDE THE BLOCK, YOU
GET THIS HYPER METHYLATION OF
THE ISLAND, HYPO METHYLATION OF
THE SHORE BUT NOTHING MUCH
HAPPENS OUTSIDE
THE BLOCK.
EVEN THE CHANGES LOCALLY THAT
PEOPLE LOOKED A, CPG ISLANDS,
VARIABLE METHYLATION SEEMS TO BE
ABLE TO BE CONTROLLED BY THE
CHROMOSOMAL MECHANISMS.
THE BLOCKS ARE KIND OF ARE
EATING THE ISLANDS AND SHORES,
AT LEAST MATHEMATICALLY.
THERE'S SOME DATA THAT I'LL SHOW
YOU THAT'S UNPUBLISHED, THAT
WE'VE BEEN LOOKING AT AGING, AND
THIS IS DATA FROM AMY VANDERBER,
FROM HOPKINS, AND ARE THE
METHYLATED BLOCKS, WE SEE THEM
IN NONMALIGNANT TISSUE IN
PHOTO-AGED OLDER PEOPLE, NOT
REALLY WITHOUT THE COMBINATION
OF BOTH OF THOSE THINGS.
WE THINK OF THE ENVIRONMENT
INDUCING THESE CHANGES OVER
TIME.
AND THERE'S WORK -- THIS IS LIKE
MY MOST FAVORITE PAPER TO SHOW
YOU, BECAUSE IT ISN'T FROM ME,
BUT IT SUPPORTS THE IDEAS.
THIS IS WORK DONE PUBLISHED IN
GENOME MEDICINE IN 2012 SHOWING
THAT IF YOU TAKE BIOPSY
SPECIMENS WHO WOMEN WHO LATER
DEVELOPED CERVICAL CANCER OR
DIDN'T, WHY WOULD YOU HAVE THAT?
BECAUSE IT'S A REAL CONUNDRUM,
EVEN WITH THE VACCINES AND
EVERYTHING FOLLOWING ME, MAKING
HISTOLOGIC DIAGNOSIS.
WOMEN DID BIOPSIES, MOST DON'T
HAVE CANCER WHEN YOU DO THE
BIOPSY BUT SOME DEVELOP CANCER.
YOU CAN DEVELOP WHO WILL DEVELOP
CANCER LATER USING VARIABILITY
TESTING, YOU COULDN'T DO THAT
WITH METHYLATION.
I THINK THIS OCCURS EARLY, IT'S
PREDICTIVE OF CANCER
DEVELOPMENT.
WE HAVE AN IDEA ABOUT THAT.
THE IDEA IS THIS.
YOU'VE ALL HEARD ABOUT THE
HALLMARKS OF CANCER, I'M NOT
QUESTION THEIR EXISTENCE.
BUT I'M SUGGESTING THAT WHAT
REALLY MIGHT BE HAPPENING IS THE
CENTER OF THIS IS THE EPIGENOME
THAT NEEDS TO BE STABLE FOR A
GIVEN TISSUE, IF SOMETHING
DERAILS THAT TISSUE, AND LEADS
TO INCREASED PLASTICITY, IT WILL
ALLOW NATURAL SELECTION OF THOSE
CELLS AT THE EXPENSE OF THE
HOST.
AND THAT MODEL WILL ONLY MATTER
AND TAKE PLACE IF THERE'S
REPEATED CHANGES TO THE
ENVIRONMENT, CANCER ARISES FROM
DEPLETED CYCLES OF INJURY AND
REPAIR, MANY TIMES ARE KNOWN TO
OCCUR SPECIFICALLY BECAUSE OF
THAT, CIRRHOSIS OF THE LIVER,
EVEN COLON CANCER.
WE KNOW THERE ARE PRIMARY
CHANGES IN THE UP EPIGENETIC
GENOME.
I WOULD ARGUE THEY ARE AFFECTING
THE EPIGENOME SPECIFICALLY.
IT'S AN EVOLUTIONARY PROCESS
LIKE THE ONE I WAS DESCRIBING
EARLIER.
LET ME TALK ABOUT OTHER DISEASES
IN THE FINAL TEN MINUTES, THIS
IDEA OF COMBINING STUDIES TO
LOOK AT COMMONAGES WITH GWAS.
COMMON GENES.
THIS IS WHAT WAS DONE.
THE END RESULT WAS WE IDENTIFIED
A REASON THAT CHANGES DNA
METHYLATION NEARBY THE HLA
CLUSTER WITH DEFINED CHANGES IN
AMINO ACID SEQUENCE, WE THINK IT
HAS TO DO WITH EXPRESSION OF HLA
FAMILY OF GENES.
THIS IS VALIDATION OF RESULT BY
INDEPENDENT METHODS ON
INDEPENDENT SAMPLES, BUT HERE IS
WHAT WE REALLY SAW.
NOW HERE IS A DENSITY PLOT OF
THE METHYLATION FOR A GENOTYPE
THAT DOES NOT LEAD TO RHEUMATOID
ARTHRITIS, AND HERE IT DOES,
HERE IS FOR THE HETEROZYGOUS.
IT'S INCREASING VARIABILITY OF
METHYLATION IN THAT REGION AND
THESE INDIVIDUALS ARE WELL
AFTERWARDS, AND THESE
INDIVIDUALS ARE SICK.
IF YOU DON'T DID THE GWAC, YOU
DON'T SEE THIS.
IT'S BELOW THE RADAR SCREEN.
WHEN YOU COMBINE IT WITH
METHYLATION, YOU CAN PICK IT UP.
THIS IS A RECENT STUDY WITH THE
HELP OF THE DLSA LED BY LUIGI TO
LOOK AT HOW -- WHAT IS THE
NORMAL RELATIONSHIP ACROSS THE
GENOME THAT MIGHT BE REGULATING
DNA METTLATION METHYLATION.
METHYLATION ASSOCIATION IS VERY
SMALL DISTANCE BUT WHAT'S
SURPRISING ABOUT THAT IS YOU CAN
HAVE SNIPS DOWN HERE THAT ARE
REGULATING CLUSTERS OF CG FAR
APART, THESE ARE FROM SEVERAL
DIFFERENT REGIONS, YET THEY
FOLLOW IN THE POPULATION A
SIMILAR PATTERN UNDER THE
CONTROL OF THE SNIPS.
IT'S BECAUSE THESE ARE REGIONS
THAT HAVE ASSOCIATED WITH EACH
OTHER IN THE NOT-MY-DAUGHTER
PACKING METHOD.
THEY DON'T NECESSARILY LIE
WITHIN THE SAME LD BLOCKS.
THAT MEANS THAT THE INTEGRATION
OF EPI GENETIC INFORMATION COULD
REVEAL PATTERNS OF HUMAN DISEASE
AND A SUPPLEMENTARY FIGURE SHOWS
HOW THAT MIGHT BE.
HERE ARE SNIPS ASSOCIATED WITH
METABOLIC GENOTYPES BUT WHAT
THEY CONTROL IN METHYLATION IS A
REGION, WE CALL IT A GENE, JUST
BECAUSE WE LIKE BAD NAMES FOR
THINGS, BUT HERE IT IS AND IT'S
RIGHT
IN
THE REGION.
I WANT TO SHARE A STORY WE'RE
ABOUT TO SEND IN A JOURNAL.
THIS IS SOMETHING WE HAVE TO
ADDRESS.
THAT'S A 100-YEAR-OLD WOMAN WHO
LOOKS EXACTLY LIKE MY MOTHER.
I POINTED THIS OUT TO HER, SHE
DIDN'T TALK TO ME FOR ABOUT A
WEEK.
HAMBURGERS, STUFF THAT INFLAMES
THE COLON.
BY THE WAY, WHEN I SEE THESE
PICTURES, I WANT TO HAVE A
HAMBURGER AND A COCKTAIL.
OH WELL.
IT'S VERY DIFFICULT TO STUDY THE
ENVIRONMENT.
EPIDEMIOLOGIC STUDIES HAVE
EXPENSIVE.
THEY HAVE TOUGH TO DO.
THE REAL ISSUE, YOU CAN'T
CONTROL THE ENVIRONMENT IN HUMAN
POPULATIONS.
THERE'S NO WAY, IT'S RIDICULOUS
TO THINK ABOUT DOING IT.
HOW OFTEN ARE YOU GOING TO
REALLY STUDY THAT?
A LOT OF MY LAB IS NOW
INTERESTED IN FIGURING OUT THE
NEW MODEL OF THE HOUSE.
MOUSE.
WE TOOK MICE AND GIVE THEM A
NORMAL DIET OR HIGH FAT DIET,
WORK OF A GRADUATE STUDENT,
MICHAEL MOLTOFF, ANDREW DOCKERY.
WE DID CHARM ANALYSIS.
IT'S AN INEXPENSIVE WAY FOR
GETTING A LOT OF DATA FROM THESE
ANIMALS.
WE ASKED WHAT DOES THE HIGH FAT
DO VERSUS LOW FAT IN TERMS OF
DNA METHYLATION AND DIABETES AND
INSULIN TOLERANCE.
WE FIND LOTS OF THESE DMR'S
RELATED TO HIGH FAT OR LOW FAT
DIET OR ONE OF THESE PHENOTYPES.
WE FOUND 625 IN A POPULATION.
THEN WE SAID, ALL RIGHT, OF
THESE 625, 491 MAP ONTO OUR
TRAUMA IN HUMANS.
OF THOSE, HOW MANY ARE
CONSERVED?
80% ARE CONSERVED FROM MOUSE TO
HUMAN, REALLY ASTONISHING.
AND THEN WE FOUND METHYLATION
CHANGES USING TISSUES THAT WE
GOT FROM OUR COLLEAGUE, OBESE
VERSUS LEAN INDIVIDUALS, OR
PEOPLE WHO WERE OBESE AND
TREATED BY GA GASTRIC BYPASS, 249
SHOWED METHYLATION CHANGES, EVEN
THOUGH THEY ARE SO FAR APART,
THE MOUSE AND HUMAN.
WE MAPPED THEM FOR DIABETES.
THIS IS LARGELY PANCREATIC, THIS
IS LARGELY ADIPOSE.
IT'S AMAZING WE FIND ANY
OVERLAP.
30 SIGNIFICANTLY OVERLAPPING THE
REGION, BY PERMUTATION ANALYSIS.
THIS IS A DRAMATIC EXAMPLE.
HERE IS THE MOUSE DATA.
HERE IS THE EXACT SAME REGION
WHERE THE OBESE INDIVIDUAL HAS
THE SAME DIFFERENCE AND IT GOES
HALFWAY BACK, AFTER BARIATRIC
SURGERY, JUST TO SHOW YOU THAT.
SO THIS IS THE RESULT.
AND WHAT I'VE SHOWN HERE IS AN
INGENUITY SPOT WHERE I'VE SHOWN
OUR 30 GENES AND A COUPLE THAT
ARE PALE TO SHOW A CONNECTION
BETWEEN THEM.
I FIRST THING I WANT TO POINT
OUT, TWO OF THESE THAT WE FOUND
USING NOTHING TO DO WITH GENETIC
ANALYSIS TURNED OUT TO BE TOP
GWA, WE HAVE TO BE ON TO
SOMETHING.
THOSE ARE SHOWN IN BLUE, TWO
GENES HERE.
WE FOUND THERE WERE THE OTHER 28
OR SO WERE OVERLAPPED GWA THAT
HAD NOT RISEN TO GENOME
SIGNIFICANCE BY GWA BUT THEY ARE
SO CLOSE IN PATHWAY, HERE TO
HERE, THESE TO HERE AND SO
FORTH.
AND THE OTHER ONES SHOWN IN
PURPLE ARE CONSERVED MOUSE GENE
AND DMR, SHOWING CHANGES IN THE
SAME DIRECTION.
THE PLOT ITSELF SUGGESTS THAT
THERE'S SOMETHING REAL ABOUT
THIS MECHANISM, ABOUT THIS
PROCESS, AND THE ABILITY TO GO
FROM MOUSE TO HUMAN THAT MIGHT
TELL US SOMETHING THAT WE DIDN'T
KNOW ABOUT DIABETES OR OBESITY
ASSOCIATEDIABETES ASSOCIATED PHENOTYPE.
WE TOOK SIX FOR WHICH THERE WAS
NOT A PAPER IN THE LITERATURE
SUGGESTING A CONNECTION TO FAT
METABOLISM, DIABETES OR OBESITY.
HERE IS THE DATA FOR TWO, THE
CONTROL, OVEREXPRESSION.
FIVE OF THE SIX SHOWED THEY
REALLY ARE INVOLVING METABOLISM
THIS WAY.
I THINK THIS MIGHT BE A WAY TO
UNCOVER NEW TARGETS THAT ARE IF
NOT THE PRIMARY GENERATORS OF
THE PHENOTYPE, THEY MIGHT BE
DRUGGABLE, MIGHT BE ABLE TO COME
UP WITH COMPOUNDS TO MODIFY THE
PHENOTYPE.
IN SUMMARY, I THINK THAT
EPIGENETICS DOES TIE INTO
ENVIRONMENT OF GENETIC DISEASE.
I FORGET TO SAY THIS UNTIL NOW.
PLEASE DO NOT CONFUSE MY
ENTHUSIASM FOR THE IDEAS OF
CERTAINTY THAT THEY ARE RIGHT.
I DON'T POSSESS SUCH CERTAINTY.
I JUST GET EXCITED ABOUT THIS
STUFF.
EPIGENETICS CLEARLY DRIVES NOT
JUST CANCER BUT HAS A ROLE IN
COMMON DISEASE GENERALLY, THAT'S
EMERGING TO BE A TRUE STORY.
I DIDN'T MENTION BUT IN OLIVER'S
STUDY WE WERE ABLE TO REVERSE
IT.
SOME OF THE DRUGS CURRENTLY USED
FOR CANCER THERAPY MIGHT ALSO
HAVE AN EFFECT ON THIS AS WELL.
THEY WON'T COME UP IN THE USUAL
TOXICITY BUT THEY ARE BENEFICIAL
THIS WAY.
AND THE EPIGENETIC EPIDEMIOLOGY
COULD OFFER FASTER CHEAPER
RESULTS IN MEDICINE, COMBINED
WITH ANIMAL STUDIES I THINK ARE
APPLAUSIBLE WAY TA PLAUSIBLE WAY TO GO.
WHAT THIS MEANS IS THESE ARE
REGULATORY PATHWAYS.
WE'RE NOT SELECTED TO HAVE
DISEASE, RIGHT?
THESE ARE REGULATORY PATHWAYS
CORRUPTED BY THE THINGS WE EAT
OR BY LONGEVITY BUT THEY ARE
IMPORTANT FUNCTIONAL AND HAVE
BEEN AROUND A LONG TIME, AT
LEAST 50 MILLION YEARS.
THANK YOU VERY MUCH.
I APPRECIATE IT.
[APPLAUSE]
>> THANK YOU FOR A WONDERFUL
ROMP THROUGH A LOT OF IDEAS, AND
IT'S TIME FOR PEOPLE TO POSE
QUESTIONS.
THERE ARE MICROPHONES IN THE
AISLES, I'LL ASK YOU TO USE
THOSE BECAUSE PEOPLE WATCHING ON
THE WEB HAVE A CHANCE TO HEAR
THE QUESTIONS.
PLEASE DON'T BE SHY.
WHILE THEY ARE THINKING, ANDY,
IN TERMS OF WHAT YOU'RE SEEING
IN TERMS OF THIS VARIABILITY OF
METHYLATION, QUITE STRIKING WHEN
YOU LOOK EVEN AT INBRED MOUSE
STRAINS, SO IT'S HARD TO BLAME
THAT ON DNA SEQUENCE, WHAT
HAPPENS IF YOU LOOK, ASSUMING
YOU CAN, AT SINGLE CELLS WITHIN
A GIVEN ANIMAL?
IS THERE AS MUCH VARIABILITY
BETWEEN CELLS AS BETWEEN
ANIMALS?
>> WE -- OKAY.
SO WE DON'T KNOW, BECAUSE THE
TECHNOLOGY IS JUST COMING ALONG,
WE'RE WORKING HARD OUT OF A LOT
OF OTHER LABS, WORKING HARD.
WE THINK IT WOULD BE PROBABLY,
AT LEAST FOR CANCER, IN THE
EARLIEST STAGES, ADENOMAS.
WITH EARLIER WORK LOOKING FOR
CONVENTIONAL GENETICS CHANGES,
YOU SEE THE EMERGENCE OF LOTS OF
VARIABILITY.
AND THEN YOU GET SELECTION AND
THEN ALMOST A HOMOGENOUSIZATION.
THERE'S A LOT OF ADVANCES IN
VARIABILITY, EVEN IN THE EARLY
PRIMARIES.
DATA SUGGESTS SOMETHING LIKE
THAT WOULD BE GOING ON AT LEAST
IN TUMORS BUT THE REALLY
INTERESTING QUESTION IS HOW MUCH
IS THIS VARIABILITY PRESENT FROM
CELL TO CELL AND I THINK THAT'S
SOMETHING YOU HAVE TO ANSWER.
IT'S A GREAT QUESTION.
>> THANKS, ANDY, FOR THE VERY
INTERESTING.
SOME OF THE LIQUIDS,
MALIGNANCIES LIKE AML SHOW
NOTHING ON FISH.
THERE'S THE NORMAL GENOTYPES,
NORMAL SEQUENCE.
DOES EPIGENETIC THEORY APPLY TO
THAT, THIS ROLE?
>> IT MIGHT.
WE LOOKED HARD AT THAT.
IN DOING RESEARCH ON AML, WHAT
WE'RE LOOKING TO SEE IS WHETHER
THERE ARE DEFINING SIGNATURES
FOR THE GENOTYPES FOR SURVIVAL.
WE THINK SO, IN FACT.
BUT THIS EXPLOSION OF A HIGH
DEGREE OF PLASTICITY AND SO
FORTH, WE FIND VERY LITTLE
EVIDENCE OF THAT IN AML.
IF THERE, IT MIGHT BE CONFOUNDED
BY THE LARGE NUMBER OF MUTATIONS
THAT ARE PRESENT IN MUTATIONS
WITH THE DISEASE.
AS MUCH AS I WOULD LIKE TO SAY
LIQUID TUMORS ARE LIKE SOLID
TUMORS, DATA DOESN'T SUPPORT
THAT AS WELL.
>> YOU SPOKE ABOUT PRE-NATURE AL
PLASTIC CHANGES PRIOR TO
MORPHOLOGIC CHANGES.
CAN YOU COMMENT?
>> I CAN'T.
IT'S NOT MY STUDY.
THAT'S WHY I LIKED IT SO MUCH.
I DON'T MEAN TO MAKE LIGHT OF
THE QUESTION.
RIGHT OFF THE TOP OF MY HEAD, I
DON'T REMEMBER THAT WELL.
ANDREW TESTENDORF, ONE PAPER ON
CERVICAL CANCER, ONE ON BREAST
CANCER, GENOME MEDICINE OR
GENOME BIOLOGY.
HE WAS A GROUP IN SINGAPORE, THE
STATISTICIAN OF RECORD FOR THE
WOMEN'S GYNECOLOGICAL CANCER
REGISTRY.
THEY HAD ALL THESE SAMPLES,
DOING ORIGINALALLY 27K ARRAYS,
RECENTLY 457 K ARRAY.
THE REASON I REALLY LOVED THE
PAPER IS BECAUSE, I MEAN, HE
READ OUR FIRST PAPER ON THE IDEA
FROM WESTMINSTER ABBEY, AND THE
SUGGESTION, HE CITES THAT PAPER,
THAT WAS GENEROUS OF HIM, AND
SAID THAT HE'S GOING TO DEVELOP
A STATISTICAL TOOL FOR LOOKING
AT THE VARIABILITY, AND BOTH IN
OUR NATURE GENETIC PAPER AND
HIS, WE HAD TO BORROW A TOOL.
THIS DON'T USE THIS MATHEMATICAL
ANALYSIS, WE USE SOMETHING
CALLED THE -- OH, I'M GOING TO
REGRET IT FOR THE REST OF MY
LIFE, I'M BLOCKING ON THE NAME.
THE LEVINE TEST.
I DID REMEMBER IT.
AND HE USED HIS OWN TESTING,
EBORRA, I DON'T KNOW WHAT IT
STANDS FOR, MEASURES OF HETERO--
IT'S SOMETHING THE WALL STREET
GUYS USE TO MAKE ALL THAT MONEY
THAT WE DON'T GET.
[ LAUGHTER ]
>> ANDY, I ASKED YOU THIS
QUESTION TWO YEARS AGO, I'M
GOING TO ASK IT.
>> OKAY.
>> IF YOU COMPARE A YOUNG
INDIVIDUAL AND AN OLD
INDIVIDUAL, WHAT DO YOU THINK IS
GOING TO HAPPEN?
DO YOU FINE INCREASED
VARIABILITY OR NOT?
>> YEAH, SO, WELL, WE DON'T
KNOW.
YOU KNOW?
THAT'S THE GREAT EXPERIMENT.
HERE IS WHY WE DON'T KNOW.
WE DON'T KNOW BECAUSE THERE'S AN
ISSUE OF CELL TYPES.
SO YOUR CELL TYPE CHANGES AS YOU
GET OLDER.
THE SAMPLES THAT WE'VE BEEN
EXAMINING SO FAR ARE FROM BLOOD.
THERE ARE STILL DIFFERENT CELL
TYPES.
UNTIL SOMEONE CAN DO A STUDY
WHICH I THINK IS A FANTASTIC
THING TO DO, I KNOW YOU'RE DOING
IT, TO ISOLATE PURIFIED CELL
POPULATIONS, FROM INDIVIDUALS OF
DIFFERENT -- DIFFERENT
INDIVIDUALS OVER TIME, YOU CAN'T
REALLY ANSWER THE QUESTION.
SO I THINK IT WILL CHANGE.
MY GUESS IS THAT YOU WOULD
HAVE -- I'M JUST GUESSING, YOU
WOULD HAVE SOME OF THIS IS
PLASTICITY THAT MIGHT ACCOUNT
FOR THE REDUCED ADAPTABILITY OF
AGING DISTRESS.
A LOT OF AGING PROBLEMS ARE
RELATED TO INABILITY TO RESPOND
TO RAPIDLY CHANGING
ENVIRONMENTINGS AND GO BACK.
LITTLE JUST A GUESS, NOT BASED
ON FACT.
>> I WAS WONDERING IF YOU WOULD
ELABORATE ON THE MISSING
HERITABILITY COMPARING THE ROLE
OF EPIGENETICS AND INTERACTIONS
BETWEEN GENES, WHICH IS ALSO
SOMETHING THAT IS MISSED BY A
GWAP STUDY.
>> YEAH, SO -- WELL, I DON'T
KNOW.
THEY ARE FANTASTIC STUDIES.
IF YOU COULD DO A GWA STUDY AND
CONTROL THE ENVIRONMENT ON THE
POPULATION, THEN I THINK --
THAT'S THE PROBLEM.
I THINK IT'S NOT THAT THERE'S A
FLAW IN GWA, IT'S JUST VERY HARD
TO LOOK AT AN OUTBRED
POPULATION, WHICH WE ARE AND
HOPE TO REMAIN, WITH MANY
DIFFERENT EXPOSURES WHICH ALSO
GIVEN THE -- BOTH OF OUR
GASTRONOMY, WE HOPE THERE WILL
BE DIVERSITY IN DIET THAT WILL
PERSIST.
IT'S GOING TO BE DIFFICULT TO
GET ATTICLY TH AT PARTICULARLY THE
PHENOTYPE.
IT WILL BE DIFFICULT TO POWER
THAT.
I DON'T -- I WOULDN'T USE THE
TERM MIS MISINHERITTABILITY.
IT'S NOT THAT IT'S MISSING,
THERE'S DIFFERENCE THINGS YOU
HAVE TO DO TO RESOLVE DIFFERENT
QUESTIONS.
WHAT I'M ARGUING IN DIABETES
RESULTS, SOME OF THESE THINGS
WILL BE PURELY EPIGENETIC, THEY
ARE DOWNSTREAM OF THE PHENOTYPE
CHANGING WHICH DOESN'T MEAN
INTERVENTION -- STILL ONE CAN
BENEFIT MEDICALLY.
CERTAINLY THE GENETIC
MANIPULATION EXPERIMENT
SUGGESTED EXACTLY THAT.
YOU CAN MANIPULATE THE GENES,
YOU'LL GET A CHANGE IN
STRUCTURE.
THERE ARE GOING TO BE THINGS
THAT ARE GOING TO BE STILL ON
GENETICS, BUT YOU NEED TO LOOK
AT ALL OF THAT.
YOU KNOW, I MEAN, EVEN IN TOADS,
A GENETIC EXPERIMENT AND NOT --
IT IS EPIGENETIC BUT IF YOU LOOK
AT THE GENETIC DATA, THEY POINT
TO VARIANTS AND ENHANCERS.
THAT'S VERY MUCH PART OF THE
EPIGENETIC PROGRAM TOO.
A LOT OF LANGUAGE SOMETIMES GETS
IN THE WAY OF THESE, OF -- YOU
KNOW WHAT I MEAN.
IT'S LIKE GRAY SCIENCE, THESE
THINGS INTEGRATE WELL.
MY GOAL AND ALL OF THESE YEARS
I'VE BEEN DOING THIS, IT'S
REALLY EVEN THOUGH I WAS DOING
CANCER GENETICS, BUT CERTAINLY
SINCE WE GOT OUR SITE GRANT AND
THIS RECENT WORK, YOU HAVE TO
LOOK AT GENETICS AND EPIGENETICS
AS INTEGRATED TOGETHER.
YOU CAN'T THINK ABOUT
EPIGENETICS WITHOUT GENETICS.
I WOULD ARGUE OFTEN YOU NEAT NEED
EPIGENETICS TO UNDERSTAND PURELY
GENETIC DETAIL.
>> A WONDERFUL PRESENTATION AND
WONDERFUL CONVERSATION AMONGST
ALL OF YOU WITH OUR SPEAKER.
THERE WILL NOW BE A RECEPTION IN
THE NIH LIBRARY WHERE YOU CAN
CONTINUE THE CONVERSATION WITH
ANDY OVER COFFEE AND COOKIES.
EVERYBODY IS CORDALLY INVITED TO
THAT.
COME BACK NEXT WEEK.
MEANWHILE, LET'S THANK OUR
SPEAKER ONE MORE TIME.
[APPLAUSE]