>>> GOOD AFTERNOON.

IT'S A PLEASURE FOR ME TO BE

ABLE TO INTRODUCE OUR SPEAKER

TODAY.

DR. RANDY JIRTLE WHO IS GOING TO

BE SPEAKING TO US ABOUT THE

EPIGENETICS ON HOW GENES AND

ENVIRONMENT INTERACT.

HIS BACKGROUND IS HE GOT HIS

Ph.D. ON RADIATION BIOLOGY AT

UNIVERSITY OF WISCONSIN IN

MADISON AND FROM THERE WENT ON

TO THE DEPARTMENT OF RADIOLOGY

AT DUKE UNIVERSITY WHERE HE

SPENT HIS PROFESSIONAL CAREER.

THERE ARE MANY CONTRIBUTION THAT

IS DR. JIRTLE HAS DONE TO THE

SCIENTIFIC FIELD AND

SPECIFICALLY TO EPIGENETICS.

WHAT WOULD HAPPEN HERE, IT IS

NOT FOR ME TO DESCRIBE.

BUT THERE ARE TWO OF THEM THAT

WERE CERTAINLY SALIENT IN MY

BRAIN THAT LED ME TO SHOT WAY I

THINK ABOUT THINGS AND THE WAY

THAT WITHIN OUR INSTITUTE AT THE

NATIONAL INSTITUTES AND PROGRAM

REVIEWS, WE HELP GUIDE SCIENCE.

THAT WAS THE PAPER WHERE HE

FIRST DEMONSTRATED THAT IN

PREGNANT RATS, YOU CAN ACTUALLY,

MOUSE, YOU CAN ACTUALLY CHANGE

THE LIKELIHOOD OF OBTAINING THE

AGOUTI ON THE BASIS OF THE

NUTRIENTS THE MOTHERS WERE GIVEN

DURING THE PREGNANCY.

SO THE NOTION YOU COULD HAVE A

GESTATION ON A MOTHER TO

TRANSFER TO THE NEWBORN COULD BE

MANIPULATED BY ENVIRONMENTAL

INTERVENTION THAT IN THIS CASE

WAS PROVIDING THE DO NORS SO THE

GENE COULD BE METHYLATED, COULD

PERFECT THOSE ANIMALS FROM

DEVELOPING THE PHENOTYPE.

IT ILLUSTRATES THE CONCEPT WHICH

WAS THAT THE DERMANISTIC ASPECT

WHAT HAVE OUR GENES ARE, SO

YOU'RE BORN WITH YOUR GENES,

THIS MAKES YOU VULNERABLE, AND

THEN THAT SHIFTS THE PARADIGM

ABOUT HOW TO ADDRESS PREVENTION

OF DISEASES.

AND HE CLEARLY ILLUSTRATED AN

EXAMPLE OF HOW EVEN WHEN YOU

HAVE THE GENETIC MUTATION BY

ENVIRONMENTAL INTERVENTION, YOU

CAN SILENCE THE EXPRESSION OF

THAT MUTATION AND THAT WAS VERY,

VERY TRANSFORMATIVE AND CRUCIAL

IN KEEPING OR MAKING THE TIPPING

POINT IN THE WHOLE AREA OF

EPIGENETIC SCIENCE.

ANOTHER VERY SEMINOLE

CONTRIBUTION THAT ALSO GOT HARD

WIRED INTO MY BRAIN WAS THE

CONCEPT OF IMPRINTING.

WITHIN EACH ONE OF US.

AND IT WAS RECOGNIZED THAT SOME

OF THOSE GENES WAS BELIEVED THAT

RELATIVELY SMALL NUMBER GOT

IMPRINTED EARLY ON SO ONE WOULD

BE SILENCED AND THE OTHER WOULD

BE EXPRESSED.

AND IN A SEMINOLE PAPER, HE

DEMONSTRATED THAT USING A VERY

COLORFUL ALGORITHM FOR

EXTRACTING PROBABILITY OF

IMPRINTING, HE DEMONSTRATED THE

NUMBER OF GENES WAS GREATER THAN

INITIALLY BELIEVED AND BY

DEVELOPING THESE METHODS

PROVIDED A TOOL FOR SCIENTISTS

TO INVESTIGATE AND UNDERSTAND

THE MECHANISMS BY WHICH

IMPRINTING HAPPENS AND THAT HAS

EXPLODED IN THE FIELD.

SO IT'S A BIG PLEASURE FOR ME TO

INTRODUCE DR. JIRTLE.

AND AGAIN, THANK YOU VERY MUCH

FOR WILLING TO COME TO US AT NIH

AND PRESENT YOUR WORK.

[ APPLAUSE ]

>> I WANT TO TRAFFIC YOU FOR

THAT WONDERFUL INTRODUCTION.

I ALSO WANT TO THANK ALL THE

PEOPLE THAT WERE INVOLVED IN

CHOOSING THE SPEAKERS FOR THE

WALS LECTURE THIS YEAR AND

INCLUDED ME AS ONE OF THEM,

WHICH IS A REAL, REAL HONOR.

AND FINALLY, I WANT TO THANK THE

AUDIENCE.

I KNOW HOW DIFFICULT IT WAS FOR

ME, FOR EXAMPLE, TO GET INTO

NIH.

SO I WON'T GO INTO IT.

BUT IT WAS AN EYE-OPENER.

AND I APPRECIATE ALL OF YOU

BEING HERE, AND I ALSO

APPRECIATE ALL OF THE PEOPLE

THAT ARE LISTENING AND WATCHING

THE WEBCAST RIGHT NOW.

I KNOW THAT IT TAKES TIME OUT OF

A BUSY SCHEDULE TO DO THIS.

AND IT SURE WOULDN'T BE VERY

INTERESTING TO GIVE A TALK WHEN

NOBODY IS THERE.

SO I APPRECIATE THE AUDIENCE,

VERY, VERY MUCH.

NOW, I CHOSE THIS TITLE FOR A

LOT OF REASONS.

ONE, IT IS RELATIVELY VAGUE SO I

CAN TALK ABOUT JUST ABOUT

ANYTHING I WANT.

BUT THE SECOND THING IS THAT IT

INCLUDES THE WORD "ENVIRONMENT."

AND I REALLY LIKE THIS WORD

BECAUSE THE WORD, "ENVIRONMENT,"

REALLY MEANS DIFFERENT THINGS

DEPENDING UPON THE ENVIRONMENT

THE PERSON IS IN THAT IS

THINKING ABOUT IT.

SO FOR EXAMPLE, IF YOU'RE A

NUTRITIONIST, IT CONJURES UP A

ENVIRONMENT, BASICALLY A FOOD

PYRAMID.

WHEREAS IF YOU'RE A

TOXICOLOGIST, YOU WHAT THINK

ABOUT PROBABLY IS GOING TO BE A

TOXIC WASTE SITE.

THAT'S THE ENVIRONMENT.

WHEREAS IF YOU'RE A

PSYCHOLOGIST, OR PSYCHIATRIST,

THE WORD "ENVIRONMENT" WOULD BE

THE NURTURING ENVIRONMENT OF THE

FAMILY AND THE SURROUNDINGS,

ET CETERA.

WHAT WE NOW KNOW VERY CLEARLY IS

THAT ALL OF THESE ENVIRONMENTS

ULTIMATELY IMPINGE UPON THE

GENOME THROUGH THE EPIGENOME.

AND THIS IS WHAT I'M GOING TO BE

TALKING ABOUT TODAY, THE

PHENOMENA OF THE EPIGENOME AND

IMPORTANCE IN DISEASE

SUSCEPTIBILITY.

NOW, I ATTEND A LOST MEETINGS.

AND AT ONE MEETING, AS WE WERE

BREAKING, ONE OF MY COLLEAGUES

PICKED UP A VILE AND SHOWED IT

TO US AS WE WERE LEAVING.

AND HE SAID, THIS VIAL CONTAINS

DNA.

AND IT'S BEEN SITTING IN FRONT

OF US FOR THE PAST FEW DAYS AND

IT HASN'T DONE A DAM THING.

JUST LIKE THE COMPUTER,

BASICALLY OUR GENOME IS IMPOTENT

WITHOUT THE SOFTWARE TELLING IT

WHEN, WHERE AND HOW TO WORK.

SO I, IN MY LIMITED WAY OF

THINKING ABOUT THINGS, BECAUSE I

GOT A DEGREE IN ENGINEERING AND

COMPUTER SCIENCE, SO IT'S MUCH

MORE RIGID MAYBE IN THOUGHT; I

THINK THE CELL IS BASICALLY A

PROGRAMMABLE COMPUTER.

THIS IS WHY YOU CAN HAVE ONE

GENOME HALF IN THE MOM AND HALF

FROM THE DAD BUT STILL HAVE

250-300 DIFFERENT CELL TYPES ALL

DOING DIFFERENT THINGS IN OUR

BODY.

WITHOUT THAT PROGRAMMABLE

SYSTEM, YOU WOULD BASICALLY HAVE

TO CHANGE THE HARDWARE EVERY

TIME YOU HAD A DIFFERENT CELL.

AND SO TODAY, I'M GOING TO BE

TALKING ABOUT THE EPIGENETIC

EFFECTS OF HOW GENES AND THE

ENVIRONMENT INTERACT.

NOW, I HAVE BEEN IN THE FIELD OF

EPIGENETICS FOR ABOUT 20 YEARS.

AND I WOULD LIKE TO THINK THAT

WE ARE IN THE ERA OF EPIGENETICS

BUT IT'S CLEAR WE ARE STILL IN

THEERA OF GENOMICS.

AND WE HEAR THAT THE MOST

IMPORTANT QUESTION RIGHT NOW IS

THAT, WHY DO INDIVIDUALS VARY

SUSCEPTIBILITY TOW DISEASES?

A LOT OF TIME, MONEY AND EFFORT

HAS BEEN PUT INTO FIRST FINDING

SINGLE NUCLEOTIDE POLYMORPHISMS

OR MUTATIONS, FOR EXAMPLE, THAT

ARE ALTERED FIRST IN EXONS AND

THEN INTRONS AND THEN PROMOTOR

REGIONS AND OUT IN NEVER NEVER

LAND.

NOW THIS HAS BEEN SUCCESSFUL,

PARTICULARLY IN THE FIELD OF

CANCER.

BUT IT HAS NOT BEEN AS

SUCCESSFUL IN THE FIELD OF

NEUROBIOLOGY.

AND TO ME, A MUCH MORE

FUNDAMENTALLY INTERESTING

QUESTION IS, WHY DO MONOZYGOTIC

TWINS, IDENTICAL TWINS, ALSO

VARY THEIR SUSCEPTIBILITY TOW

DISEASES IF THE ONLY THING

IMPORTANT IN THIS PROCESS IS

GENETIC VARIATION?

ONE OF THE REASONS FOR THAT IS,

EVEN THOUGH THEY HAVE THE SAME

GENOME, BASICALLY, THEY MORE

THAN LIKELY DO NOT HAVE THE SAME

EPIGENOME.

YOU ASK, HOW CAN YOU HAVE A

DIFFERENT EPIGENOME IN

PROGRAMMING IF THEY ARE IN THE

SAME WOMB?

IT'S POSSIBLE, AS AN EXAMPLE,

YOU CAN HAVE DIFFERENT BLOOD

FLOWS TO THESE TWO IDENTICAL

DEVELOPING EMBRYOS, AND THAT

ENVIRONMENT NOW IS SHOWED BITE

DIFFERENT COLORS OF THE WASHING

WE HAVE IN THIS PAINTING.

AND WE HAD THIS FOR THIS

ENVIRONMENTAL GENOMICS MEETING

THAT WE PUT ON IN 2005.

AND SLIGHT VARIATIONS IN BLOOD

FLOW CAN CHANGE, FOR EXAMPLE,

NUTRITION.

OR IT COULD CHANGE THE TOXICNESS

THE INDIVIDUALS ARE EXPOSED TO.

AS WE SHOW LATER, VERY SMALL

CHANGES IN NUTRITION, AT FLEET

ANIMAL MODELS, CAN HAVE PROFOUND

EFFECTS ON THE DEVELOPMENT AND

DISEASE SUSCEPTIBILITY.

NOW I LIKE THE HISTORY.

ONE THING I WANT TO GO OVER

BRIEFLY IS A HISTORY OF

EPIGENETIC RESEARCH.

THIS IS FROM MY PERSPECTIVE NOW.

I GOT INTO THIS FIELD IN THE

EARLY 90s.

AND WHAT I HAVE HERE IS PLOTTED

PUBLICATIONS, TOTAL

PUBLICATIONS, AND FUNCTION OF

TIME, YEAR.

AND ON A LINEAR GRAPH.

SO WHAT I DID FOR THIS IS, I

WANTED TO SHOW THAT BASICALLY UP

UNTIL AROUND THE YEAR 2000,

THERE IS AN INFLECTION POINT

AROUND 2005, RIGHT IN HERE,

WHERE IT LOOKS LIKE BASICALLY

NOTHING REALLY IS HAPPENING MUCH

IN THE FIELD OF EPIGENETICS, TO

THE POINT WHERE IT'S GOING

VERTICAL AND A LOT IS

HAPPENING -- HAPPENING IN THE

FIELD.

NOW IF YOU PLOT THIS RATHER THAN

ON LINEAR PAPER, SEMI LOG PAPER,

WHAT WILL FIND IS WHAT I'M

SHOWING IS AN EXPONENTIAL GROWTH

CURVE FOR PUBLICATIONS IN THE

FIELD OF EPIGENETICS.

AND THAT IN THE SCIENTIFIC

COMMUNITY, THERE IS A DOUBLING

OF THE EPIGENETICS PAPERS EVERY

1 1/2-TWO YEARS.

LAST YEAR ALONE, WE PUT INTO

PUBLICATION SOMEWHERE BETWEEN

15-20,000 PAPERS WHICH TOOK US

15 YEARS FROM 1990 TO 2005.

NOW THIS IS RESULTED IN SOME OF

WHAT I WOULD CALL, MORE

ENLIGHTENED SCIENTISTS, TO MAKE

THESE FOLLOWING COMMENTS.

EPIGENETICS IS NOW THE HOTTEST

THING IN BIOSCIENCE.

THAT'S ME.

AS NORA POINTED OUT, I BASICALLY

HAVE DONE WORK IN EPIGENETICS IN

TWO AREAS, ONE IS IN GENOMIC

IMPRINTING, PARTICULARLY

EVOLUTION OF THIS PHENOMENA.

IMPRINTED GENES ARE MONOLITHIC

EXPRESSED.

AND SINCE THERE IS ONLY ONE COPY

OF THESE GENES THAT IS

FUNCTIONAL, YOU DO NOT NEED TWO

HITS TO KNOCK OFF THE FUNCTION.

YOU ONLY NEED A SINGLE HIT.

AND THAT SINGLE HIT CAN BE BOTH

MUTATIONAL OR EPIGENETIC AND

DEPENDING UPON THE GENE, CAN

EITHER INCREASE OR ELIMINATE THE

FUNCTION OF THESE GENES.

LADIES AND GENTLEMEN, THESE

MONO'LILLICALLY EXPRESSED GENES

ARE ALL DISEASE SUSCEPTIBILITY

LOCI AND WE ARE NOT GOING TO

UNDERSTAND DISEASES UNTIL WE

HAVE DEFINED THE REPERTOIRE OF

THESE GENES THAT WE HAVE IN

HUMANS, BECAUSE THEY VARY

GREATLY BETWEEN SPECIES.

IT'S IMPORTANT WE WORK IN THE

SPECIES WE ARE INTERESTED FROM

THE STANDPOINT OF DISEASE

SUSCEPTIBILITY, WHICH IS THE

HUMAN.

THE OTHER AREA THAT I WORK IN

AND HAVE DONE A LOT, AND THIS IS

WHAT I'LL BE TALKING ABOUT

BASICALLY MOST OF THE TIME NOW,

IS THE FETAL ORIGINS OF ADULT

DISEASE SUSCEPTIBILITY.

SO THERE IS A LOT OF EVIDENCE,

BOTH IN ANIMAL MODELS AND ALSO

IN HUMANS THAT DISEASE

SUSCEPTIBILITY DOESN'T JUST

HAPPEN BUT MUCH OF IT OCCURS

VERY EARLY IN DEVELOPING.

MAYBE OFTEN VERY EARLY TO THE

POINT WHERE WE ARE TALKING RIGHT

AFTER FERTILIZATION.

AND THAT TWO GOLD STANDARDS THAT

I'M GOING TO BE TALKING ABOUT IN

HUMANS THAT SUGGEST THIS, THESE

ARE SITUATIONS THAT I CALL THEM

NATURAL EXPERIMENTS.

YOU WOULD NEVER WANT TO BE IN

BECAUSE THEY ARE HORRIFIC.

BUT THEY OCCURRED AND WE NOW

HAVE PEOPLE THAT WENT THROUGH

THIS AND THEY ARE BEING USED AS

TO SHOW AND DETERMINE THE FETAL

ORIGINS OF ADULT DISEASE

SUSCEPTIBILITY.

ONE THE IS THE DUTCH FAMILIAR

CHIN OCCURRED AT THE END OF THE

WORLD WAR II WHEN NAZIS PUT

EMBARGO ON HOLLAND.

DURING THAT PERIOD OF TIME,

THERE WAS A SEVERE RESTRICTION,

IT WAS A VERY, VERY COLD WINTER

AND THE SEVERE RESTRICTION IN

NUTRIENTS AND 16,000

APPROXIMATELY OR MORE PEOPLE

DIED.

NOW SOME PEOPLE WERE IN UTERO

DURING THIS PERIOD OF TIME.

AND THEY LATER FOUND AS THEY

FOLLOWED THESE PEOPLE THAT FIRST

OF ALL, WHEN THEY WERE BORN,

THEY WERE OFTEN OF SHORT

STAATURE AND LOW BIRTH WEIGHT.

BUT LATER ON IN ADULTHOOD, THEY

FOUND OUT THAT THEY HAD FIRST OF

ALL, IT SHOWED INCREASED

INCIDENTS OF CARDIOVASCULAR

DISEASE AND OBESITY AND THEN

DIABETES AND INTERESTINGLY, A

DOUBLING OR TRIPLING OF THE

INCIDENTS OF SCHIZOPHRENIA.

NOW, ANOTHER ONE OF THESE

NATURAL EXPERIMENTS OCCURRED,

UNFORTUNATELY, IN THE LATE 50s

AND EARLY 60s, IN CHINA.

IN THIS SITUATION, 20-40 MILLION

PEOPLE DIED AND BASICALLY WHEN

FOLLOWING THESE INDIVIDUALS THAT

WERE IN UTERO DURING THAT PERIOD

OF TIME, THEY ALSO SHOWN

BASICALLY THE SAME TYPE OF

SCENARIO AGAIN WITH THE DOUBLING

OR TRIPLING OF THE INCIDENTS OF

SCHIZOPHRENIA.

SO SEVERE LACK OF FOOD OR

NUTRITION, MATERNAL NUTRITION,

PARTICULARLY DURING THE FIRST

TRIMESTER OF DEVELOPMENT,

RESULTS IN A SIGNIFICANT

INCREASE IN PSYCHOSIS.

BUT UP UNTIL JUST RECENTLY, THE

STATE-OF-THE-ART OF THIS FIELD,

I THINK IS VERY NICELY SHOWN BY

ONE OF MY FAVORITE CARTOONS, BY

SIDNEY HARRIS, WHICH IS THEN A

MIRACLE OCCURRED.

SO WE KNOW BACK HERE THERE WAS A

SHORTAGE OF FOOD, NUTRITION.

OUT HERE THERE IS A

SIGNIFICANT -- IN TIME, THERE IS

A SIGNIFICANT INCREASE IN THE

DISEASE SUSCEPTIBILITY.

BUT WHAT IS THE GRAVITY OF THE

MEMORY SYSTEM THAT HOLDS THOSE

TWO TIME POINTS TOGETHER?

IT WAS NOT KNOWN UP UNTIL JUST

RECENTLY AT LEAST IN ANIMAL

MODELS.

AND THAT MIRACLE INVOLVES

EPIGENETIC MODIFICATIONS.

THIS PAPER THAT WE PUBLISHED IN

20003, WHICH WE HAVE ALREADY

TALKED ABOUT TO SOME DEGREE, WAS

TRANSFORMATIONAL, NOT ONLY FOR

THE FETAL ORIGINS OF ADULT

DISEASE SUSCEPTIBILITY, BUT ALSO

FOR THE FIELD OF EPIGENETICS.

BECAUSE IT WAS VERY CLEAR

INITIALLY SLOWLY AND GAINING

MOMENTUM NOW, THAT THE LARGE

TENTH OF EPIGENETICS BASICALLY

CAN ENCOMPASS ALL BIOLOGICAL

RESEARCH.

SO ONE OF THE REASONS WHY YOU

GET THIS EXPONENTIAL RISE IN

PUBLICATIONS IS NOT BECAUSE OF

PEOPLE OF MY AGE, EXPONENTIALLY

DOING MORE AND MORE RESEARCH,

BUT IT'S BECAUSE WE HAVE MORE

AND MORE PEOPLE COMING INTO THE

FIELD OF EPIGENETICS DOING

RESEARCH.

SO, WHAT IS EPIGENETICS?

EPIGENETICS LIKE EPICENTER JUST

MEANS, ABOVE, IN THIS CASE,

GENETICS.

AND EPIGENETICS RESEARCH REFERS

TO THE STUDY OF HERITABLE

CHANGES IN GENE FUNCTION THAT

OCCURRED WHERE OCCUR WITHOUT A

CHANGE IN THE SEQUENCE OF THE

DNA.

THE TWO MAIN COM PONENCE OF THIS

EPIGENETIC CODES ARE CYTOSIN

METHYLATIONS IN THE 5 PRIME OF

GUY 19 AND DNA AND RAPID AROUND

THE NUCLEOSOME COMPRISED OF

HISTONES AND THERE ARE MYRIADS

OF MARKS ON THESE HISTONE TAILS

THAT EITHER CAUSE THE CHROMATIN

TO BE CONDENSED OR LOOSE, SO IN

CONCERT WITH THE DNA

METHYLATION, THE CHROMATIN IS

EITHER CONDENSED AND

NONFUNCTIONAL OR OPEN AND

FUNCTIONAL.

AND THIS IS BASICALLY THE

CHEMICAL PROGRAMMING THAT OCCURS

ON THE CELL BASIS THAT ALLOWS A

LIVER CELL TO BE A LIVER CELL

AND A BRAIN CELL TO BE A BRAIN

CELL.

I'M NOW GOING TO TALK ABOUT THE

WORK THAT WE HAVE DONE WITH

THESE AGOUTI MICE.

AND IT CONTAINS WHAT IS CALLED A

METASTABLE EPIALLELES.

I CALL THESE AGOUTI SISTERS.

THESE ANIMALS ARE GENETICALLY

IDENTICAL BECAUSE THEY ARE

INBRED.

THE ONLY DIFFERENCE BETWEEN THIS

MOUSE AND THIS MOUSE IS WHAT THE

MOTHER WAS FED WHILE THEY WERE

IN UTERO.

IN THIS CASE, THE MOTHER ATE

NORMAL MOUSE CHOW.

IN THIS CASE, THE MOTHER ATE

NORMAL MOUSE CHOW THAT WAS SUB

MEANTED WITH VITAMIN B12,

COALINE, FOLIC ACID.

IF YOU LOOK AT THESE TWO

ANIMALS, THEIR GENETICALLY ARE

IDENTICAL, THEY ARE AGED MATCHED

AND BOTH GHEE MAIL.

AND IT APPRECIATES THE

IMPORTANCE OF EPIGENETICS AND

DISEASE SUSCEPTIBILITY.

I HATE TO SAY IT, BUT THERE

ISN'T ANY HOPE FOR YOU.

THERE ISN'T A BETTER VISUAL

MODEL TO DEMONSTRATE THIS.

I WANT TO GO A LITTLE MORE INTO

THIS NOW BECAUSE IT'S VERY

IMPORTANT.

WE USE THIS -- I ALMOST THINK OF

THIS AS BEING A BIOSENSOR, A

COLOR BIOSENSOR COMPARABLE TO

THESE LIQUID CRYSTALS WHEN YOU

PUT YOUR HAND ON IT AND THEY

CHANGE COLOR.

AND WE HAVE THAT NOW.

THAT SYSTEM, AND WE CAN LOOK AT

ANY KIND OF ENVIRONMENTAL

EXPOSURE AND ASK A SIMPLE

QUESTION ABOUT WHETHER IT ALTERS

THE EPIGENOME.

AND WE CAN SEE IT NOT ONLY IN

CODE COLOR, BUT YOU CAN SEE HERE

ALSO AT THE LEVEL OF DNA

METHYLATION.

SO FOR EXAMPLE, NORMAL HAIR

FOLLICLE DEVELOPMENT OCCURS AND

GROWS AND AT THE END OF THE HAIR

FOLLICLE DEVELOPMENT, YOU HAVE

THE AGOUTI GENE IS TURNED ON AND

YOU PUT A LITTLE BAND OF YELLOW

AT THE BASE OF A BLACK HAIR

SHAFT.

AND AS A CONSEQUENCE, WE NOW SEE

THAT MOUSE AS BROWN OR AGOUTI

RATHER THAN BLACK.

FOR THOSE OF YOU THAT WORK WITH

C57 MICE, WHICH ARE BLACK, THE

REASON FOR THIS IS THE AGOUTI

GENE IS MUTATED.

BUT IF THIS REGION IN THIS

STRAIN OF MICE IS AB LOCUS

AGOUTI MICE, A TRANSPOSABLE

ELEMENT UMPING UP STREAM OF THIS

GENE, AND SET UP AN ECTOPIC

START SITE FOR TRANSCRIPTION OF

THE AGOUTI GENE.

SO, WHEN THIS REGION IS

COMPLETELY U.N. METHYLATED, THE

AGOUTI GENE IS TURNED ON

INAPPROPRIATELY IN ALL CELLS OF

THE BODY, INCLUDING THE BRAIN,

BUT ALSO IN THE HAIR FOLLICLE

AND AS A CONSEQUENCE, YOU GET

THESE COMPLETELY BLONDE MICE.

WHEREAS THIS REGION IS TOTALLY

METHYLATED EARLY ON, YOU GO BACK

TO NORMAL REGULATION OF THE

AGOUTI GENE AND YOU GET WHAT ARE

CALLED PSEUDOAGOUTI BROWN MICE.

IF THE DECISION, STOCHASTIC

DECISION IS MADE LATER ON AFTER

THERE ARE SOME CELL DIVISION,

THEN YOU'RE GOING TO START

SEEING THIS MODELING APPEARANCE

WHERE ONE CELL IS HYPOMETHYLATED

AND THE OTHER CELL IS

HYPERMETHYLATED.

SO IT LOOKS ALMOST LIKE A CALICO

CAT.

SO YOU HAVE GOT THIS VARIATION

IN COAT COLOR TOTALLY DEPENDENT

UPON THE DEGREE OF METHYLATION

AT THE IAP.

SO ROB, WHEN HE WAS IN THE

LABORATORY, HE IS NOW DOWN AT

BAYLOR.

HE WAS A POSTDOC AT THIS TIME IN

MY LAB.

HE DID A VERY, VERY IMPORTANT

EXPERIMENT, AND THAT IS, HERE

YOU HAVE THE MOTHER EATING

CONTROLLED CHOW.

AND YOU CAN SEE THE MAJORITY OF

THE ANIMALS ARE YELLOW OR NEARLY

YELLOW.

AND ABOUT 20-30% OF THEM ARE

BROWN OR HEAVILY MODELED.

WHEREAS, WHEN YOU SUPPLEMENT THE

MOTHER'S DIET ALL THESE GROUPSA

THAT COME INTO THE CYTOSIN, THEY

SHOWED A FEW SLIDES BACK, COMING

FROM YOUR DIET.

DIET IS INCREDIBLY IMPORTANT IN

THIS WHOLE PROCESS AND

MAINTAINING THE GOOD NUTRITION

DURING THE DEVELOPMENT OF THESE

OFFSPRING IS INCREDIBLY

IMPORTANT IN HAVING PROPER

DEVELOPMENT.

WHEN YOU SUPPLEMENT THE DIET,

YOU CAN SEE CLEARLY THAT THE

DISTRIBUTION OF OFFSPRING'S COAT

COLOR IS SHIFTED TOWARDS BROWN

AND HAVE YOU MANY FEWER NOW THAT

ARE OVER IN THE YELLOW OR NEARLY

YELLOW.

YOU HAVE TAKEN A NORMAL

DISTRIBUTION AND SHOVED IT

TOWARDS THE BROWN.

BECAUSE THESE BROWN ANIMALS NO

LONGER BECOME OBESE AND OBESE

ANIMALS ALSO GET DIABETES AND

CANCER.

BY SUPPLEMENTING THE MOTHER'S

DIET, YOU HAVE SIGNIFICANTLY

ALTERED N-THIS CASE, REDUCED THE

INCIDENCE OF THESE CHRONIC

DISEASES.

WHY THESE ANIMALS HAVE BECOME

OBESE IS BECAUSE THEY

INAPPROPRIATELY EXPRESS THE

AGOUTI GENE IN THE SABRATION

CENTER OF THE BRAIN AND THESE

ANIMALS NEVER KNOW THEY ARE FULL

SO THEY LITERALLY EAT THEMSELVES

INTO OBESITY, DIABETES AND

CANCER.

YOU WOULD HAVE NEVER PREDICTED A

COAT COLOR GENE WOULD BE

INVOLVED IN OBESITY, BUT IN THIS

AND DIABETES AND CANCER, BUT IN

THIS MOUSE STRAIN THAT IS THE

CASE.

THAT WAS IMPORTANT, VERY

EXCITING.

BUT THIS WAS THE PART OF THE

STUDY THAT WAS THE MOST

IMPORTANT AND THAT IS THAT THIS

CHANGE IN COAT COLOR WAS SHOWN

TO BE BASICALLY COMPLETELY

DEPENDENT UPON THE DEGREE OF

METHYLATION AT THIS CRYPTIC

START SITE IN THE CONTROL OF THE

AGOUTI GENE.

SO IN THE CONTROL DIET, WHEN

MOTHERS ARE EATING JUST NORMAL

CHOW, THESE ARE CPG SITES IN

THIS REGION HERE.

THESE ARE THE CELLS THAT ARE

METHYLATED.

YOU CAN SEE THAT NORMALLY YOU

HAVE THE VAST MAJORITY OF THE

CELLS OR ANIMALS.

THESE ARE ALL THE OFFSPRING.

IT'S ABOUT 100.

HAVE VERY LOW LEVELS OF

METHYLATION WHICH CORRELATES

WITH THE FACT THAT THE VAST

MAJORITY OF THE ANIMALS ARE

YELLOW OR NEARLY YELLOW WHEN

THEIR MOTHER ATE CONTROLLED

DIETS.

WHEREAS WHEN YOU SUPPLEMENT THE

DIET WITH METHYL DONORS, EVEN

THE UNTRAINED EYE AND WITHOUT

STATISTICS, YOU CAN SEE THAT

HAVE YOU GREATLY INCREASED THE

AVERAGE METHYLATION AND THAT IS

VERY HIGHLY CORRELATED AND

ASSOCIATED WITH THE FACT THAT

NOW MOSTLY OFFSPRING, MAJORITY

OF THEM ARE BROWN OR NEARLY

BROWN.

SO SIMPLY CHANGING THE MOTHER'S

DIET, EARLY IN DEVELOPMENT,

ALTERED DISEASE SEPTEMBER BUILT

NEADULTHOOD -- SUSCEPTIBILITY IN

ADULTHOOD THROUGH ALTERING THE

EPIGENOME.

SO WE OFTEN ASK THE QUESTION

PEOPLE HAVE, WHAT IS MORE

IMPORTANT, NATURE OR NURTURE?

I THINK THIS STUDY VERY CLEARLY

SHOWS IN THIS SITUATION, WE

REALLY ARE GETTING NATURE BY

NURTURING.

NOW, I WANT TO GO THROUGH THIS

SORT OF MORE GRAPHICAL.

SO IF YOU THINK ABOUT THE AGOUTI

COAT COLOR DISTRIBUTION, THE

STUDY I JUST SHOWED YOU, IT'S

SORT OF A NORMAL DISTRIBUTION.

FEW TOTALLY BROWN.

A FEW TOTALLY YELLOW WITH THE

MOST HAVING SOME DEGREE OF

MODELING.

IF YOU SUPPLEMENT THE MOTHER'S

DIET WITH METHYL DONORS LIKE

DR. WATERMAN DID, YOU SHIFT THIS

COAT COLOR DISTRIBUTION SO YOU

HAVE MANY MORE BROWN OFFSPRING.

THE UNIVERSITY OF MICHIGAN ALSO

SHOWED THAT THE PHYTOESTROGENNIC

COMPOUND AT LEVELS PRESENT IN

ASIAN DIET.

ALSO IS CAPABLE AND DOES SHIFT

THIS COAT COLOR DISTRIBUTION

TOWARDS BROWN.

WHAT IS INTERESTING ABOUT THIS,

THIS DOES NOT DONATE A METHYL

GROUP.

SO THERE ARE COMP POUNDS THAT

ARE ALSO GOING TO ALTER THIS

EPIGENETIC RESPONSE THAT ARE NOT

METHYL DONORS THEMSELVES.

THE MECHANISM BY HOW THIS

OCCURS, WHAT IS THE SIGNAL

TRANSDUCTION PATHWAY FOR THIS IS

PRESENTLY UNKNOWN BUT VERY

IMPORTANT TO ULTIMATELY

DETERMINE IT.

THEN HE DID ANOTHER VERY

IMPORTANT STUDY.

IT'S THE FIRST ONE DONE WITH

THIS SYSTEM THAT LOOKED AT A

ENVIRONMENTAL TOX IICANT AND

ENDOCRINE DISRUPTING AGENT WHICH

IS USED TO MADE HARD, CLEAR

PLASTICS.

IN THE OLD DAYS, THE BIG BLUE

PLASTIC CONTAINERS REALLY HAD

WATER IN THEM.

THEY WERE MADE FROM PHENOLS.

IN THIS SITUATION, SHE CLEARLY

SHOWED THIS PHENOL IN LEVELS IN

MICE THAT WE'RE EXPOSED TO IN

OUR PLASMAS, YOU GET A

SIGNIFICANT INCREASE IN THE

INCIDENTS OF YELLOW MICE.

THIS IS NOT GOOD.

THIS IS DUE TO HYPOMETHYLATION.

AS MEMORY REMEMBER, THESE

ANIMALS HAVE HIGHER INCIDENTS OF

OBESITY, DIABETES AND CANCER.

DID DOESN'T TAKE A ROCKET

SCIENTIST VERY LONG.

WOULD IT BE POSSIBLE TO MITIGATE

THE NEGATIVE EFFECT OF THIS

ENVIRONMENTAL TOX IICANT BY

SUPPLEMENTING THE MOTHER'S DIET

WITH METHYL DONORS OR JENSTEIN.

SHE SHOWED THIS NEGATIVE EFFECT

COULD BE ELIMINATED BY

SUPPLEMENTITATION OF THE

MOTHER'S DONOR -- DIET.

SO WHAT WE HAVE HERE NOW, AND I

THINK THIS IS THE MOST EXCITING

PART OF THIS WHOLE STUDY THAT

THE FIELDS OF TOXCOLOGIY AND

NUTRITION HAVE MERGED.

JOINED AT THE HIP AND BEING THE

OTHER SIDE OF THE SAME COIN.

AND ALSO DEMSTRAITS BLOCK SOME

OF THE NEGATIVE EPIGENETIC

EFFECTS WITH THE VERY NUTRITION

THAT WE EAT.

THIS BECOMES VERY IMPORTANT, I

THINK, BECAUSE IT POTENTIALLY

ALLOWS IN THE FUTURE FOR

MEDICINE TO START GOING AWAY

FROM THINKING ABOUT COMPLETELY

THERAPEUTIC APPROACHES TO LIFE

AND POTENTIALLY EVEN STARTING TO

THINK MORE ABOUT PREVENTING

DISEASES.

NOW, AS IT WAS SAID, LET FOOD BE

THY MEDICINE AND MEDICINE BE THY

FOOD.

I THINK THIS STUDY REALLY SHOWS

THAT AT LEAST IN MICE THAT

NEGATIVE EFFECTS OF

ENVIRONMENTAL TOX IICANT THAT

ARE INVOLVED WITH THE EPIGENETIC

MODIFICATIONS CAN BE MITIGATED

BY BASICALLY FOOD ADDITIVES AND

NUTRITION THAT INDEED FOOD IS

MEDICINE, AND I THINK THIS IS

GOING TO BE A HUGE BARRIER OF

RESEARCH IN THE FUTURE.

SO, WE DEFINITELY KNOW WE ARE

WHAT WE EAT.

AND UNFORTUNATELY, THEY PUT A

DOUGHNUT SHOP FROM MY LAB AND I

DO KNOW WHERE THEY GO.

I THINK MAYBE I'LL STOP THERE.

BUT, I HOPE AFTER THIS VERY,

VERY SHORT INTRODUCTION THAT YOU

APPRECIATE WE MIGHT NOT ONLY BE

WHAT WE EAT, WE MIGHT ALSO BE,

TO SOME DEGREE, WHAT OUR MOTHER

WAS EXPOSED TO WHILE WE WERE IN

UTERO, AND SINCE THERE IS

EVIDENCE FROM OTHER

INVESTIGATORS THAT THESE

EPIGENETIC MARKS ARE NOT ALWAYS

TOTALLY ELIMINATED WHEN THEY ARE

PASSED THROUGH THE EGG AND

SPERM, THAT THERE IS IN OTHER

WORDS POTENTIAL FOR

TRANSGENERATIONAL INHERITANCE OF

EPIGENETICS EVENTS THAT WE MIGHT

BE WHAT OUR GRAND PARENTS AND

GREAT GRANDPARENTS WERE EXPOSED

TO.

I'M NOW GOING TO END THIS THAT

YOU CAN WITH SOME DATA WE JUST

REALLY JUST GOTTEN INVOLVING THE

RADIATION EFFECTS ON THE

EPIGENOME.

AND THIS WORK WAS STUDIED OR

SUPPORTED BY THE DOE LOW-DOSE

RADIATION RESEARCH PROGRAM AND A

GRANT THAT WE GOT FROM THE

O'KEEFE FOUNDATION.

AS I SAID, MY BACKGROUND IS IN

RADIATION BIOLOGY AND NUCLEAR

ENGINEERING.

SO THE WORK THAT I'M DESCRIBING

NOW BY AUTUMN BERNAL WHO IS A

GRADUATE STUDENT IN MY LAB AND

SUCCESSFULLY DEFENDED HIS

Ph.D. BASED ON THE STUDIES

I'VE BEEN SHOWN TWO WEEKS AGO.

IT'S EXCITING BECAUSE WHAT IT

HAS DONE IS BROUGHT THE FIELDS

OF RADIATION BIOLOGY AND FIELDS

OF EPIGENETICS TOGETHER.

DOES ANYBODY KNOW WHAT THIS IS?

THIS IS AUDIENCE PARTICIPATION.

>> [ INDISCERNIBLE ]

IT'S A REACTOR CORE.

WHY IS THIS BLUE LIGHT HERE?

>> [ INDISCERNIBLE ]

>> THIS IS SHRINK OFF RADIATION.

BECAUSE ELEC TONS ARE GOING

FASTER THAN THE SPEED OF LIGHT

IN THE MEDIA OF WATER.

I WAS A REACTOR OPERATOR WHETHER

I WAS AN UNDERGRADUATE LICENSED

AT THAT TIME BY THE ATOMIC

ENERGY COMMISSION.

I HAVE SEEN THIS.

IT'S THE PUREST BLUE YOU WILL

EVER SEE.

AND IT'S ALMOST MESMERIZING,

SORT OF LIKE LOOKING AT A FIRE

IN A FIREPLACE.

>> [ INDISCERNIBLE ]

>> SO THE ENVIRONMENTAL

EPIGENETIC STUDIES THAT HAVE

BEEN DONE THUS FAR ARE NOT MANY.

WE HAVE DONE ONE I DESCRIBED AND

THIS ONE I DESCRIBED AND THIS

ONE I DESCRIBED.

THERE IS ONE ADDITIONAL STUDY

WITH ETHANOL, AND THAT STUDY

ALSO SHOWED THAT 10% ETHANOL IN

THE DRINKING WATER RESULTED IN

FORMATION OF HYPERMETHYLATION

AND BROWN MICE TO A HIGHER

INCIDENCE.

BUT SO THIS IS PROTECTIVE FROM

THIS STANDPOINT.

BUT ALSO IN THIS STUDY, THEY

FOUND ALSO INCREASED INCIDENCE

EVER CRANIOFACIAL DEVELOPMENTAL

PROBLEMS.

SO THE IMPORTANT POINT OF THIS

IS HYPERMETHYLATION AT ONE LOCUS

MIGHT BE ADVANTAGEOUS BUT AT

ANOTHER, IT MIGHT NOT BE.

AND THE OTHER THING THAT IS

INTERESTING IS IN-VITRO CULTURE

WHICH HAS BEEN SHOWN IN HUMANS,

THERE IS EVIDENCE THAT IN-VITRO

FERTILIZATION RESULTS IN

INCREASED INCIDENTS OF SYNDROMES

THAT YOU SAUCEEE IN THIS

SITUATION, HYPE OR METHYLATION

IS INCREASED IN THE YELLOW

ANIMALS.

NOW ALL OF THESE STUDIES WERE

DONE WITH CHEMICALS AND THEY ARE

ALL DONE AT SINGLE DOSES.

THE ELECTROMAGNETIC RADIATION

SPECTRUM GOES ALL WAIT FROM

HIGH-ENERGY COSMIC TRIES VERY

LOW ENERGY RADIO WAVES.

AND THE ONLY PHOTONS, BASICALLY,

THAT ARE CALLED IONIZING

RADIATION, ARE THOSE UP HERE IN

THE HIGH FREQUENCY AND

HIGH-ENERGY, BECAUSE EACH PHOTON

POSSESS ENOUGH ENERGY TO BREAK A

BOND.

SO THIS TYPE OF RADIATION IS

BASICALLY A DOUBLE-EDGED SWORD

FOR US T IS VERY ADD VENTAGEES

FROM A DIAGNOSTIC STANDPOINT,

THERAPEUTIC STANDPOINT,

ET CETERA, BUT ALSO SHOWN

ALREADY IN THE 20s BY BUELLER,

THAT IT CAUSES MUTATIONS AND

MANY PEOPLE HAVE SHOWN THAT

SINCE THEN.

SO GENOMIC CHANGES ARE INDUCED,

STRAND BREAKS, DNA MUTATIONS,

ET CETERA, BY IONIZING

RADIATION.

BUT WE WANTED TO LOOK THEN AT

THE EFFECTS OF LOW-DOSE

RADIATION ON THE EPIGENOME.

AND THE TYPES OF EXPOSURE THAT

IS WE HAVE, IF EUROPE TO LOOK AT

PEOPLE AT THE END OF THE 20 OR

BEGINNING OF THE 20th

CENTURY, YOU BASICALLY ALL YOU

WOULD HAVE IS EXPOSURE FROM

NATURAL SOURCES.

AND AN ABSORBED DOSE TYPE OF

UNIT, WE WOULD HAVE BEEN EXPOSED

TO ABOUT .3 CENTER GRADE OR 200

MILLIONS -- I'M USING AN OLDER

VERSION OF DOSE UNIT.

BUT IN THE BEGINNING OF THE

21st CENTURY, THE LEVEL OF

RADIATION WOULD HAVE ALREADY

BEEN DOUBLED BECAUSE OF THE USE

OF DIAGNOSTIC RADIATION IN

OCCUPATIONAL RADIATION FROM

WORKING IN REACTORS, ET CETERA.

SO NOW, OUR TOTAL DOSE ON THE

AVERAGE WOULD BE SOMEWHERE

AROUND 500-600 MILLI RAMS 4.6

CENTER GRADE IF YOU'RE LOOKING

AT ABSORBED DOSE.

SO RADIATION INDUCED DAMAGE

OCCURS PRIMARILY THROUGH TWO

DIFFERENT MECHANISMS.

THERE IS A DIRECT ACTION AND

INDIRECT ACTION.

SO IF RADIATION AND PHOTON COMES

WITH ENOUGH ENERGY NOW TO KNOCK

OUT AN ELECTRON, OR TO DIRECTLY

INTERACT WITH THE DNA, YOU CAN

HAVE DNA DAMAGE THAT IS DIRECT.

THIS IS DIRECT EFFECT.

BUT THIS IS ABOUT 20% OF DNA

DAMAGE IS CAUSED BY THIS

MECHANISM.

80 CONSPIRACY CAUSED BY WHAT IS

CALLED INDIRECT ACTION WHERE

THIS ELECTRON NOW DOESN'T

INTERACT DIRECTLY WITH THE DNA

BUT RATHER IT INTERACTS WITH A

MOLECULE OF WATER CREATING

HYDROGEN FREE RADICALS.

AND THEN THESE HYDROGEN FREE

RADICALS DIFFUSE OVER AND CAUSE

THE DAMAGE.

SO, LOOKING AT THE STUDY NOW

THAT THIS IS WORK THAT NOW HAS

BEEN SUBMITTED FOR PUBLICATION,

LOW-DOSE RADIATION EXPOSURE

USING THE VIABLE YELLOW AGOUTI

MICE.

THIS IS THE SCHEMATIC OF HOW

THIS STUDY WAS DONE.

AT 4.5 DAYS AFTER TIME

PREGNANCIES, RADIATION WAS

DELIVERED.

AND THEN AT BASICALLY 21 DAYS

THE ANIMALS ARE BORN AND THEN

TISSUES WERE COLLECTED OUT HERE

AT 43 DAYS AND AT THAT POINT,

YOU CAN DETERMINE WHETHER THE

ANIMALS IN YELLOW OR BROWN.

AND THEN YOU GET THIS TYPE OF

DISTRIBUTION AGAIN OF THE COAT

COLOR DISTRIBUTION WHEN'S YOU'RE

NOT EXPOSED TO ANYTHING.

BUT IF YOU LOOK AT EXPOSURE TO

RADIATION, HERE WE IS HAVE GOT

RADIATION DOSES GOING FROM ZERO

UP TO 7.6 CENTER GRADE.

TO PUT THIS IN PERSPECTIVE,

MAMMOGRAMS WOULD BE DOWN HERE.

NATURAL BACKGROUND RADIATION,

REMEMBER THIS IS A SINGLE DOSE

BUT OVER A YEAR IS SOMEWHERE IN

HERE.

A CT SCAN WOULD BE SOMEWHERE

AROUND 1-2 CENTER GRADE IN HERE.

AND THE FIRST EVIDENCE BASICALLY

OF RADIATION CAUSING CANCER IS

GOING TO BE IN THE TENS OF

CENTER GRADES.

SO IT IS OUT HERE.

SO AUTUMN DID THESE STUDIES.

THE FIRST THING SHE LOOKED AT

WAS COAT COLOR AND CLEARLY SHE

SAW WAS A SIGNIFICANT DROP IN

THE NUMBER OF ANIMALS THAT

AREIOLEO.

THESE ARE OFFSPRING NOW.

SO THIS CURVE, THIS IS

DISAPPEARING.

CONCOMBINANT WITH THAT IS A

SIGNIFICANT INCREASE IN THE

NUMBER OF BROWN MICE TO THE

POINT THAT WHEN YOU'RE AT

1 1/2-1.4 OR SOMEWHERE BETWEEN

1-3 CENTER GRADE, HAVE YOU 14

TIMES AS MANY BROWN MICE AS YOU

HAVE YELLOW MICE.

THIS IS IN RESPONSE TO VERY LOW

DOSES OF IONIZING RADIATION.

AND IN FACT, AT 7.6, THERE IS

ACTUALLY NO YELLOW MICE AND

BROWN MICE YOU CAN'T EVEN

DETERMINE THE RATIO BECAUSE IT'S

INFINITE.

BUT IT'S INTERESTING AT THIS

POINT.

I DON'T SHOT DATA, BUT YOU'RE

STARTING TO SEE THIS

DISTRIBUTION GO BACK.

THE REASON THIS DROPPED IS

YOU'RE NOW SEEING A SIGNIFICANT

INCREASE IN THE AMOUNT OF

MODELED ANIMALS.

SO WHAT IS HAPPENING IS THE

DISTRIBUTION IS BEING SHIFTED

OVER TO BROWN DURING LOW DOSES

UP TO AROUND 3 CENTER GRADE AND

THEN IT LOOKS LIKE IT IS

STARTING TO COME BACK.

WE COULDN'T GO TO HIGHER DOSES

BECAUSE OF LETHALITY OF THIS

SYSTEM.

BUT THERE WAS NO SELECTION OF

OFFSPRING AT THIS POINT.

SO IF YOU LOOK AT METHYLATION,

THE SIGNAL IS HIGHLY CORRELATED

TO THE FORMATION OF THE BROWN

ANIMALS WHICH ARE ARE

HYPERMETHYLATED.

SO, LOW DOSES OF IONIZING

RADIATION DURING EARLY GESTATION

INCREASED THE INCIDENTS OF BROWN

AVY OFFSPRING IN THE SEX AND

DOSE DEPENDENT MANNER.

I FORGOT DO SAY THIS IS A MALE

MOUSE.

IN FEMALE MICE THERE IS NO

EFFECT AT ALL OVER THESE DOSES.

AND THIS IS CENTERED WITH

INCREASE IN DNA METHYLATION AT

THE AGOUTI LOCUS.

SINCE BROWN AVY MICE HAVE A

REDUCED INCIDENCE OF OBESITY,

DIABETES AND CANCER, AS COMPARED

TO THOSE IN YELLOW ANIMALS, THIS

MEANS THAT LOW DOSES OF

RADIATION AND A POSITIVE

ADAPTIVE RESPONSE THROUGH

ALTERCATIONS IN THE EPIGENOME.

NOW AS I SAID, 80% OF DNA

DAMAGES IS IN THE GENERATION OF

FREE RADICALS, OXYGEN FREE

RADICALS.

SO THE POSTLAT WAS THEN THAT

MAYBE ANTIOXIDANT

SUPPLEMENTATION WOULD BE ABLE TO

REDUCE THIS EFFECT THAT WE ARE

SEEING OF LOW DOSES OF IONIZING

RADIATION.

SO HERE YOU HAVE GOT THE YELLOW

AND BROWN MICE AT A RATIO OF

ABOUT ONE AND WHEN THEY ARE SHAM

ERATED OR NO RADIATION AT ALL.

SHAM DOESN'T CAUSE ANY EFFECT.

THEN IF YOU EXPOSE THE ANIMALS

TO 3 CENTER GRADE, YOU GET ABOUT

14 TIMES AS MANY BROWN ANIMALS

AS YOU HAVE YELLOW ANIMALS.

AND THEN WHEN YOU HAVE 3 CENTER

GRADE AND YOU ADD ANTIOXIDANTS

TO THE MOTHER'S DIET, YOU

COMPLETELY MITIGATE THIS EFFECT

THAT YOU HAVE OF IONIZING

RADIATION ITSELF.

IF YOU LOOK AT DNA METHYLATION,

AGAIN, YOU SEE HERE AT ZERO DOSE

SHAM OR ERADIATED, HAVE THE SAME

AND THIS IS PERCENT METHYLATION.

YOU ADD 3 CENTER GRADE OF

RADIATION AND YOU SIGNIFICANTLY

INCREASE THE AMOUNT OF

METHYLATION IN LINE WITH THE

FACT THAT THERE ARE MANY MORE

BROWN ANIMALS IN THE OFFSPRING

POPULATION.

THEN IF YOU ADD 3 GRADE PLUS

ANTIOXIDANTS, YOU GET THE DEGREE

OF METHYLATION BACK DOWN TO

NORMAL, WHICH IS YOU WHAT EXPECT

GIVEN THAT THE NUMBER OF ANIMALS

THAT ARE BROWN AND YELLOW ARE

BASICALLY IDENTICAL AND THE SAME

IS YOU WHAT SEE IN UNERADIATED

SITUATIONS.

SO MATERNAL ANTIOXIDANT

SUPPLEMENTATION MITIGATES

INCREASE IN DNA METHYLATION AND

THE INCIDENTS OF BROWN AVY

OFFSPRING CAUSED BY LOW-DOSE

IONIZING RADIATION EXPOSURE

DURING EARLY GESTATION.

OUR FINDINGS PROVIDE EVIDENCE

ALSO THAT THE POSITIVE ADAPTIVE

EPIGENETIC RESPONSE INDUCED BY

LOW-DOSE RADIATION IS MEDIATED

IN PART TO OXIDATIVE STRESS.

I MUST TELL YOU THAT THESE

RESULTS WERE UNEXPECTED WHEN WE

FIRST STARTED.

BUT THEY ARE TRUE.

I WANT TO END THIS TALK NOW WITH

A LITTLE TALK ABOUT RISK

ASSESSMENT RADIATION DISCOVERED

IN 1895.

AND IN 1896 HE TOOK THE X-RAY OF

HIS WIFE'S HAND.

IT WASN'T LONG THEREAFTER THAT

X-RAYS WERE USE TO SET BONES

THAT WERE BROKEN, ET CETERA.

BUT THE EARLY RAIDOLOGISTS USED

TO TUNE UP THEIR UNITS USING

THEIR OWN HANDS.

AND AS YOU CAN IMAGINE AFTER A

NUMBER OF TUNINGS, THEY RAN INTO

PROBLEMS WITH NECROSIS,

ULTIMATELY NOT ONLY NECROSIS,

BUT CANCER.

SO THE BIOLOGICAL EFFECTS,

NEGATIVE ONES OF HIGH DOSES OF

RADIATION WERE VERY APPARENT.

BUT WHEN WE LOOK AT LOW DOSES OF

RADIATION, AND LOOK AT

EPIGENETIC EFFECTS, WHAT THIS IS

BASICALLY AVY HYPOMETHYLATION,

IF YOU WANT TO THINK OF IT AS

YELLOW MICE GOING THIS WAY.

WE HAVE INCREASED NUMBERS OF

BROWN MICE AND DECREASES IN

HYPOMETHYLATION OR INCREASES IN

HYPERMETHYLATION.

SO YOU WHAT HAVE IS A CURVE THAT

GOES LIKE THIS.

AND WE THINK, ONLY

GUESSTIMATING, BECAUSE AT 7.6 IT

LOOKS LIKE IT'S GOING BACK.

THIS CURVE IS CROSSING 00

SOMEWHERE AT 10 CENTER GRADE OR

ABOVE.

SOMEWHERE IN HERE.

AND THEN GOES UP INTO THE HIGHER

DOSES, WHERE OTHER INVESTIGATORS

HAVE UNIFORMLY SEEN

HYPOMETHYLATION AND ALSO AN

EFFECT THAT IT IS MORE PREVALENT

IN MALES THAN IN FEMALES.

THIS SORT OF BYE PHASIC DOSE

RESPONSE CURVE OR HOCKEY-SHAPED

DOSE RESPONSE CURVE, IS

CONSISTENT WITH THE HORR MEDIC

DOSE RESPONSE CURVE, BUT IT IS

NOT CONSISTENT IN THE LINEAR

KNOWN THRESHOLD MODEL WHICH SAID

THAT EVERY DOSE OF RADIATION IS

PROBLEMATIC.

THIS IS NOT THE CASE WHEN YOU'RE

LOOKING AT EPIGENETIC CHANGES.

SO QUESTIONS IN FUTURE STUDIES.

THESE ARE MY SORT OF BIASES AND

THINGS THEY THINK ARE GOING TO

BE IMPORTANT TO DO IN THE

FUTURE.

ONE QUESTION IS, DOES LOW-DOSE

RADIATION EXPOSURE ALTER THE

HUMAN EPIGENOME?

REMEMBER ALL OF THIS IS DONE IN

MICE AND WE HAVE ONLY LOOKED AT

ONE METE STABLE EPIALLELE.

ANOTHER BIG QUESTION, IF YES,

ARE THE CHANGES IN THE EPIGENOME

INHERITED

TRANSGENERATIONALY -- THAT'S A

BIG ISSUE.

A BIG QUESTION.

SO HOW DO YOU DO THIS?

I BELIEVE THAT THE BEST

POPULATION, HUMAN POPULATIONS

FOR ADDRESSING THESE IMPORTANT

QUESTIONS WILL BE THE HIROSHIMA

AND NAG SAKI ATOMIC BOMB

SURVIVORS AND THEIR OFFSPRING.

THESE ARE AVAILABLE.

AND I THINK WE NEED TO THINK

SERIOUSLY ABOUT LOOKING AT THEM

FROM THE STANDPOINT OF EP JET

NEIC MODIFICATIONS  --

EPIGENETIC MODIFICATIONS.

I WANT TO END, THIS IS THE LAST

SLIDE, WITH A SLIDE I CALL, FOOD

FOR THOUGHT.

SOMETHING THAT YOU WILL BE ABLE

TO CHEW ON AND THINK ABOUT AFTER

YOU LEAVE THIS LECTURE.

ONE OFONE OF THEM A QUOTE BY A

PHYSICIST AND THE OTHER BY A

PHILOSOPHER.

THE PHYSICIST IS JOHN CANNON AT

THE UNIVERSITY OF WISCONSIN WHO

DEVELOPED THE FIRST SOLID STATE

LITHIUM FLUORIDE RADIATION

DETECTION SYSTEM AND STARTED THE

VERY FIRST RADIATION HEALTH

PHYSICS DEPARTMENT AT THE UW.

AND LATER TOWARDS THE END OF HIS

LIFE, HE WROTE THIS.

I AM NOW ALMOST CERTAIN THAT WE

NEED MORE RADIATION FOR BETTER

HEALTH.

AND THE SECOND QUOTE, WHAT DOES

NOT KILL ME, MAKES ME STRONGER.

THANK YOU.

ANY QUESTIONS?

[ APPLAUSE ]

>> YOU COVERED A LOT OF GROUND.

YOU MAKE SOME OF THIS FROM THE

STUDIES.

SO IS THE PROSYOU ARE

SUGGESTING, VERSATILE?

AFTER SOME MUTATIONS LIKE ME

-- [ INDISCERNIBLE ] COULD IT BE

EFFECTED BY SOME OF THE

ANTIOXIDANT EFFECTS?

>> IN OTHER WORDS, YOU'RE SAYING

IN ADULT ANIMAL THAT HAS A

NEGATIVE EFFECT, YOU CAN YOU

REVERSE THAT IN ADULT ANIMALS?

THAT'S AN EXCELLENT QUESTION.

TO MY KNOWLEDGE, NOBODY LOOKED

AT IT.

WE ALWAYS HAVE DONE WORK WITH

THE DEVELOPING FETUS AND THE

PROGRAMMING THERE BUT WE HAVE

NEVER ACTUALLY ADDRESSED THE

QUESTION THAT WE'RE TALKING

ABOUT.

IT'S VERY IMPORTANT AND IF

ANYBODY IS INTERESTED IN DOING

THIS, I WISH SOMEBODY WOULD.

BECAUSE WHEN OTHER PEOPLE ASK

THIS QUESTION, I WOULD BE ABLE

TO ANSWER IT.

>> AND THE SECOND QUESTION

REGARDING THE NAG SAKI -- THAT

HAS PROBABLY ONE OF THE MOST

STUDIED POPULATIONS IN TERMS OF

THE RECENT EXPOSURE AND THE

EFFECTS ON ALL OF THE ISSUES

RELATED TO CANCER AND OTHER

THINGS.

SO DID ANYBODY LOOK AT THE

DEGREE OF METHYLATION OF SOME OF

THE GENES IN THIS CATEGORY OF

JAPANESE VICTIMS?

>> IT'S NEVER BEEN LOOKED AT

EPIGENETICALLY.

THE ONLY THING THAT HAS BEEN

LOOKED AT ARE GENETIC MUTATIONS.

AND MOST OF THE EXPOSURES ARE

QUITE HIGH WITHIN THE TENS OF

HUNDREDS.

500 RAD OR A CENTER GRADE IS

LETHAL IF YOU GET IN THE WHOLE

BODY, FOR THOSE WHO DON'T KNOW

THAT.

THAT'S THE EDGE WE ARE TALKING

ABOUT.

SO THESE ARE DOWN IN PROBABLY

THE TENS OF RADS TO HUNDREDS OF

CENTER GRADE.

BUT THERE WERE ABOUT 6000

CHILDREN THAT WERE ACTUALLY

EXPOSED IN UTERO.

MY GUESS, I DON'T FINISH FOR A

FACT, THOSE EXPOSURES WILL BE

LOWER OTHERWISE MIGHT NOT HAVE

MADE IT THROUGH.

AND THOSE WOULD BE INTERESTING

TO LOOK AT FROM THE STANDPOINT

OF EP JET GENETIC MODIFICATIONS

AND PARTICULARLY SEEING WHETHER

THERE IS ANYTHING YOU CAN FIND

THAT THEY WILL BE CARRIED

THROUGH FROM GENERATION TO

GENERATION.

THAT'S ALL I KNOW.

THERE IS NO OTHER INFORMATION

KNOWN.

THIS IS THE VERY FIRST OF MY

KNOWLEDGE OF EPIGENETIC EFFECTS

EVEN IN THE ANIMAL MODELS THAT

HAS BEEN DONE AT THIS LOW OF

DOSE OF RADIATION.

>> DOES THE EFFECT OF RADIATION

EFFECT THE -- [ INDISCERNIBLE ]

>> WHAT?

>> RADIATION OF OTHER

ENVIRONMENTAL AFFECTS SUGGESTING

EFFECT THE --

>>

[ INDISCERNIBLE ]

>> YOU MEAN A DIRTY GUIDELINE I

DON'T KNOW.

WE DIDN'T SEQUENCE.

THAT IT'S UNLIKELY BUT IT COULD

HAPPEN  --

DIRTY GENE.

>> VERY WONDERFUL TALK.

I HAVE BEEN INTERESTED IN THE

WHOLE SCHIZOPHRENIC ATTITUDE

TOWARDS RADIATION.

PEOPLE USE RADIATION FOR HEALTH

EFFECTS.

RADIATION IS COMMON?

>> PEOPLE WITH HIGH LEVELS OF

RADIATION IN THEIR SURROUNDING

ENVIRONMENTS STEAM HAVE LOWER

INCIDENTS OF CANCER.

A LOT OF DATA ALONG THESE LINES.

THAT'S A GOOD QUESTION.

>> SO, AT SOME POINT, JOHN

THOUGHT THIS POINT WE ARE READY

FOR A PLACEBO-CONTROLLED

DOUBLE-BLIND STUDY OF RADIATION

IN HUMANS AT LOW DOSES TO LOOK

AT POSITIVE HEALTH EFFECTS.

BUT AGAIN, WE ARE WORRIED ABOUT

THE LINEAR THRESHOLD THEORY

WHICH SAYS THAT AT ANY DOSE,

RADIATION IS HARMFUL TO US.

FROM A CLINICAL STANDPOINT, WHAT

IS IT GOING TO TAKE FOR ME, AS A

PHYSICIAN, TO BE ABLE TO GET A

PROTOCOL PUT FORTH WHERE I CAN

GIVE LOW-DOSE RADIATION

WITHOUT -- AND LOOK FOR EFFECTS

ON INFLAMMATION OR CELLULAR

EFFECTS THAT WOULD BE BENEFICIAL

IN LIGHT OF SOME OF THE

-- [ INDISCERNIBLE ]

>> I THINK WHAT IS IT GOING TO

DO, FOR ONE, AS I SAID BEFORE,

JUST BECAUSE WE ARE SEEING THESE

PHENOMENA AT THE AGOUTI LOCUS,

THEY ARE POSITIVE ADAPTIVE

EFFECTS.

WE DON'T ALWAYS KNOW WHETHER

HYPERMETHYLATION GOING TO BE

POSITIVE AT ALL METASTABLE

ALLELE POSITIONS.

THEY WE DON'T KNOW.

WE ONLY LOOKED AT ONE.

THERE IS NO DOUBT THAT THE

EPIGENOMES IN HUMANS AND MICE

FOR EXAMPLE, ARE GREATLY

DIFFERENT.

WHICH MEANS THAT WE DON'T HAVE

ANY CLUE WHAT THE EPIGENETIC

LABEL TARGETS ARE GOING TO BE IN

HUMANS.

WE NEED TO IDENTIFY THEM.

I WOULD PUT MY EFFORT INITIALLY

ON THESE REGULATORY ELEMENTS AND

GENES.

THEY ARE GOOD BIOSENSE EXPOSALS

INCREDIBLY IMPORTANT.

AND WE CAN DETERMINE WHETHER OR

NOT THESE ARE ALTERED IN HUMANS.

AND AS I  SAY, WE WOULD HAVE TO

ACTUALLY LOOK AT SOME OF THESE

INDIVIDUALS THAT WORKS FOR US

THROUGH OUR DOSES OF IONIZING

RADIATION OR EXPOSE IN UTERO.

OTHER THAN THAT, I DON'T KNOW

WHETHER STILL PEOPLE WOULD WANT

TO THINK ABOUT USING IONIZING

RADIATION AS A POSITIVE EFFECT

FROM THE STANDPOINT OF HEALTH.

AS I SAID, I DID NOT PREDICT

THIS.

I DID NOT EXPECT THIS.

BUT IT'S WHAT WE SEE.

>> THANK YOU.

>> YOU TALKED A LOT ABOUT THE

EFFECTS OF THESE VARIOUS

RADIATION DURING PREGNANCY.

AND I WAS WONDERING, WHETHER

POST PREGNANCY TREATMENTS CAN

REVERSE THESE EFFECTS AT ALL OR

WHETHER WE ARE ESSENTIALLY

DOOMED BY WHAT OUR PARENTS DID

TO US?

>> THERE IS WHAT WAS ASKED

BEFORE AND MY ANSWER STILL IS,

NOBODY HAS REALLY DONE THIS.

THESE ARE VERY INTERESTING

STUDIES TO DO.

AND I WOULD HOPE -- THERE ARE A

LOST YOUNG PEOPLE OUT THERE AND

A LOT OF PEOPLE WORLDWIDE

WATCHING THIS WEBCAST.

THESE STUDIES NEED TO BE DONE.

I WILL NOT PROBABLY DO THEM.

BUT, SOMEBODY NEEDS TO.

>> THANK YOU VERY MUCH FOR A

VERY INTERESTING TALK.

WE ARE STARTING TO WORK ON THE

EFFECTS OF RADIATION ON

EPIGENETIC MARKS AND BECAUSE

OBVIOUSLY IT'S A PERFECT FIELD

TO USE THE EPIGENETIC TECHNOLOGY

TOW TRY TO UNDERSTAND WHAT THE

EFFECTS ARE OF THESE RADIATIONS.

JUST TO GET FROM THE MOLECULAR

BIOLOGY PERSPECTIVE, BUT THE

ONLY THOUGHT THAT OCCURRED TO ME

AS A NATION, I'M COMING FROM

BROOKHAVEN NATIONAL LABORATORY

WHERE A LOT OF RESEARCH ON THE

EFFECTS OF RADIATION ARE CURED

AND THERE WERE SCIENTISTS THAT

WERE PROPOSING THAT LOW DOSES OF

RADIATION MAY BE BENEFICIAL

BECAUSE THEY PRIME THE MACHINERY

OF THE CELL IN ORDER FOR IT TO

BE ABLE TO RESPOND BETTER IF IT

IS EXPOSED TO A LARGE IN SOLE.

SO MY QUESTION COMES AROUND THE

CONCEPT, IN THAT HEREY, EVEN

WHEN I WAS A AT BROOKHAVEN A LOT

OF CONCERN ABOUT THE POTENTIAL

OF CONTAMINATION FOR RADIATION.

WHAT HAPPENS WHAT HAPPENED

RECENTLY, RUSH YEAH, BUT NOW IN

JAPA

AS SOON AS IT HAPPENS, IS THERE

ANY INFORMATION, ANY PARTICULAR

CENTRES WORKING ON THESE TYPE OF

QUESTIONS?

>> TO MY KNOWLEDGE, NOBODY IS

WORKING ON THIS.

ONCE THIS GETS OUT THERE THERE

WILL BE A LOT MORE PEOPLE

WORKING ON IT.

THE OTHER THING IS THAT

HISTORICALLY, I WANT TO MAKE A

COMMENT TO SCIENTISTS IN

GENERAL, BECAUSE I HAVE TO ADMIT

I WAS GUILTY OF THIS MYSELF.

I HEARD ABOUT THIS PHENOMENA

PROBABLY 20 YEARS AGO AND I

THOUGHT, TO USE A NICE

TERMINOLOGY, IT WAS BS.

I DON'T THINK THAT ANYMORE.

AND THE RATIONAL FOR IT WAS,

WELL, THERE IS NO MECHANISM THAT

WILL ALLOW FOR THIS TO OCCUR.

BUT NO MECHANISM MEANS IT REALLY

IN WHAT YOU'RE SAYING IS NO

KNOWN MECHANISM, THAT WE KNOW AT

THAT TIME.

IT APPEARS THAT ONE MECHANISM

THAT ALLOWS FOR THIS RESPONSE TO

OCCUR IN INDIVIDUALS AND IN

ANIMALS, IS EPIGENETIC

ADAPTATIONS AND SABLIZATION OF

THE EPIGENOME IN RESPONSE TO

RADIATION AND A LOT OF DIFFERENT

TOX I CANTS.

EVEN THEE THIS HASN'T BEEN DONE

BUT I THOUGHT ABOUT THIS.

WE CAN BLACK THIS POSITIVE

EFFECT NOW AT THIS ONE LOCUS, BY

ANTIOXIDANT.

WE COULD WE ALSO BLOCK THE THE

INCREASE IN BROWN ANIMALS WE SEE

THEN THE MOTHERS 68 TOOK IN

METHYL DONORS?

IS THERE A COMMON MECHANISM

WHERE ALL OF THESE ARE GOING IN

THROUGH THE GENERATION OF FREE

RADICALS?

THAT'S WHAT THE CELL IS

SENTENCING.

AND IT'S STABILIZING THE GENOME

TO ALLOW FOR SURVIVAL.

I THINK THIS IS WHAT IS GOING ON

AND I THINK NOW THAT THERE IS A

POTENTIAL MECHANISM FOR THIS TO

OCCUR, I WOULD HOPE THAT WE'RE

GOING TO SEE A LOT MORE PEOPLE

STUDYING THIS THAN STUDIED IT IN

THE PAST.

>> RANDY, I HAD A QUICK

QUESTION.

COULD YOU SPECULATE ON WHY YOU

THINK YOU SEE THE GENDER

DIFFERENCES IN RESPONSE TO

LOW-DOSE RADIATION?

>> THAT I DON'T KNOW.

BUT AS I SAID, OTHER PEOPLE HAVE

SEEN THAT ALSO AT HIGH DOSES.

I DON'T KNOW.

>> I HAVE TWO VERY INTRIGUING

OBSERVATIONS FROM YOUR TALK THAT

MAKE YOU CAN SHED LIGHT ON.

IN LOW-DOSE RADIATION, YOU'RE

INDUCING SINGLE STRAND BREAK AND

THE --  -- HIGH DOSES OF

RADIATION WITH CANCER INDUCED

MORE, DOUBLE STRAND BREAK.

THERE IS GOING TO BE EPIGENETIC

CHANGES IN THE EPIGENOME AND

THEY HAVE TO BE BROUGHT BACK TO

THE SAME LEVEL THEY HAD BEFORE

OTHERWISE YOU TRULY VE NOT

REPAIRED THAT AREA.

SO THESE FIELDS ARE TIED

TOGETHER EVEN THOUGH INITIALLY I

HAVE TO ADMIT I DIDN'T THINK OF

THEM AS BEING TIED TOGETHER.

AND I WOULD IMAGINE MORE PEOPLE

LOOKING AT SINGEL AND DOUBLE

STRAND BREAKS THEY WILL START

LOOKING AT THE HISTONE MARKS IN

HOW THEY ARE REPAIRED AND THE

METHYLATION MARKS.

THIS IS STUFF THAT WILL BE DONE

IN THE FUTURE.

I WILL NOT DO THIS.

BUT SOMEBODY WILL.

BECAUSE IT'S IMPORTANT.

>> I WAS WONDERING IN THE AGOUTI

MICE WHO WERE TREATED WITH LOW

DOSES OF RADIATION WHO SAW --

>> I CAN'T HEAR YOU SO WELL.

>> THE AGOUTI MICE YOU TREATED

WITH LOW DOSES OF RADIATION,

WHERE YOU SAW THE REVERSAL ON

THE YELLOW COAT COLOR, DID YOU

ALSO SEE A DECREASE IN THE MORE

SEVERE HEALTH EFFECTS OF THE

DIABETES AND OBESITY AND CANCER

THAT OCCURRED LATER ON IN LIFE?

>> YOU WOULD SEE THAT BECAUSE

AUTOMATICALLY THE REASON THAT

YOU HAVE THESE PROBLEMS IS

BECAUSE THE AGOUTI GENE IS

INAPPROPRIATELY DISPOSED OF IN

THE BRAIN.

SO IT'S AN AUTOMATIC SITUATION

THAT OCCURS IN THIS ANIMAL

SYSTEM.

>> I WANT TO THANK YOU AGAIN.

THERE IS A RECESSION VERY CLOSE

BY.

I WILL GIVE YOU OPPORTUNITY TO

DIRECTLY ASK QUESTIONS AND

NETWORK WITH ONE ANOTHER.