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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