Placeholder Image

字幕列表 影片播放

  • >> 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]

>> GOOD AFTERNOON, EVERYONE.

字幕與單字

單字即點即查 點擊單字可以查詢單字解釋

B1 中級

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

  • 82 11
    Kelvin 發佈於 2021 年 01 月 14 日
影片單字