>> OKAY, GOOD AFTERNOON.
SO FOR THIS WEEK THOSE WHO
TURNED IN REQUESTS FOR VISITING
THE CORES OR TUMOR BOARDS, I'LL
BE MAKING THOSE ASSIGNMENTS AND
MOST OF THE ASSIGNMENTS WILL BE
FOR THE MONTH OF OCTOBER.
A FEW WILL BACK UP INTO NOVEMBER
BUT WE HAVE ABOUT 50 PEOPLE OR
SO WHO HAVE SIGNED UP FOR THESE.
AND TODAY OUR SECOND LECTURE
WILL BE ON EPIGENETICS AND OUR
FIRST LECTURE IS FRANK
MALDARELLI, HE GOT A Ph.D.
FROM THE UNIVERSITY OF NEW YORK
AT MOUNT SINAI SCHOOL.
HE DID A RESIDENCY AT COLUMBIA
PRESBYTERIAN HOSPITAL IN
NEW YORK.
HE THEN JOINED THE NIAID AS A
MEDICAL STAFF FELLOW AND HE
JOINED THE NCI IN 1998 SO TODAY,
HE'S WITH THE HIV DRUG
RESISTANCE PROGRAM AT THE NCI
AND HE WILL BE DISCUSSING
RETROVIRUSES, FRANK?
>> THANK YOU VERY MUCH, TERRY,
CAN YOU ALL HEAR ME?
>> AND THANKS FOR COMING THIS
AFTERNOON BECAUSE I THINK THE
TOPIC, MAYBE IT'S JUST ME BUT I
THINK THE TOPIC IS ESPECIALLY
USEFUL AND INTERESTING AND
RELEVANT TOO SOME OF THE WORK
THAT AT LEAST I'VE HEARD THAT
YOU ALL WERE DOING AS WELL.
THERE ARE VERY FEW GROUPS OF
VIRUSES LIKE RETROVIRUSS AND
JUST FOR A SECOND IF YOU COULD
THINK OF SOMETHING THAT CAUSES
AN INHERITED DISEASE, A
TRANSMISSIBLE DISEASE AND AN
EPIDEMIC DISEASE AND WHAT GROUPS
OF VIRUSES ACTUALLY DO ALL OF
THOSE THINGS AND RETROVIRUS IS
THE ANSWER.
RIGHT.
AND I WONDER IF YOU CAN THINK OF
OF ANOTHER ONE BECAUSE I THINK
THAT'S TOUGH.
YES, YOU IN THE BACK?
PRIMATESONS, YES PRONS CAN DO
THE SAME THING SO THERE ARE VERY
FEW THINGS THAT CAN CAUSE AN
INHERIT THE DISEASE,
TRANSMISSIBLE DISEASE AN
EPIDEMIC DISEASE.
AND A LOT OF WHAT WE WILL TALK
ABOUT HAS TO DO WITH EPIDEMICS.
SO THAT'S WHY I HAVE TO ASK THIS
QUESTION TO START WITH AND YOU
ALL, TERRY HOLD ME HOW BRILLIANT
YOU ALL ARE, SO WHAT'S LIKE THE
WORST EPIDEMIC EVER, OKAY?
A REALLY BROAD SORT OF QUESTION.
IF YOU HAD A PICK, YOU HAVE TO
PICK, IF YOU HAD TO PICK WHAT
WOULD BE THE WORST EPIDEMIC THAT
YOU'VE EVER HEARD OF?
OKAY.
>> 1918 INFLUENZA, 10 MILLION,
RIGHT?
>> ANYBODY ELSE?
>> SMALLPOX?
>> SMALLPOX.
PLAGUE.
THESE ARE GREAT ANSWERS.
ANYBODY ELSE?
ALL RIGHT, SO NOW I ASK THE
REDICK LOWS QUESTION, DID
ANYBODY EVER TAKE A COURSE IN
HIGH SCHOOL CALLED AP WORLD
HISTORY?
ALL RIGHT, SO WHO WENT TO SCHOOL
IN MONTGOMERY COUNTY, RIGHT?
[LAUGHTER]
SO THEY HAVE A QUESTION:  WHAT
IS THE WORST EPIDEMIC AND THE
ANSWER IS SUPPOSED TO BE, THE
OFFICIAL ANSWER IS MEASLES.
BECAUSE IT CAUSES--EVIDENTLY IT
CAUSES MORE DISEASE THAN
SMALLPOX DID WHEN THE EUROPEANS
CAME TO THIS PART OF THE
COUNTRY.
BUT I WANT YOU TO JUST--I WANT
TO GET YOU THINKING ABOUT
EPIDEMICS AND HOW THEY OCCUR
BECAUSE THAT'S GOING TO BE AN
ISSUE THAT WE'RE GOING TO TALK
ABOUT TO SOME DEGREE AND SO
REALLY WHAT I'D LIKE TO DISCUSS
ARE THE ORIGINS OF RETROVIRUSES,
REPLICATION AND HOW THEY EMERGE
AND HOW THEY SPREAD AND SOME
EPIDEMIC TRENDS AND SOME LESSONS
WE MIGHT LEARN FROM--THANK
YOU--AND WHAT LESSONS WE MIGHT
LEARN FROM AT LEAST LEARNING
ABOUT RETROVIRUSS AND I THINK
THEY CAN HELP--THEY CAN HELP ON
A NUMBER OF LEVELS AT LEASTOT
LEVELS YOU WORKED AT AS WELL.
YOU KNOW THIS IS SOME OF THE
BEST DATA, NOT EXACTLY NEW IN
2007 BUT IT'S DISTRIBUTED VERY
WELL OF WHAT THE--WHAT THE
PANDEMIC OF HIV ONE OF THOSE
RETROVIRUSES LOOKS LIKE AND I'LL
BE USING IT IN AS AN EXAMPLE IN
THE WORLD.
SO YOU SEE THERE'S OVER 33
MILLION CASES, MANY OF THEM
LOCATED IN SUBSAHARAN AFRICA BUT
PLACES IN SOUTH ASIA AND IN THE
CARIBBEAN AND SOUTH AMERICA ALSO
CONTRIBUTE A LARGE NUMBER OF
CASES, AND I GUESS--OOPS.
ONE OF THE THINGS THAT'S
INTERESTING ABOUT EPIDEMICS IS
THAT THEY'RE NOT ALWAYS THE SAME
IN DIFFERENT PLACES.
SO HERE'S--HERE ARE THE RISK
FACTORS FOR HIV IN CENTRAL AND
EASTERN EUROPE AND THE MAJORITY
IN THIS SURVEY, WERE INTRA
VENOUS USERS AND THE REST WERE
THROUGH COMMERCIAL SEX WORKERS
AND OTHER MEN WHO HAVE SEX WITH
MEN.
IF YOU DO THE SAME EXPERIMENT OR
THE SAME ANALYSIS IN SOUTH ASIA
YOU'LL FIND A MUCH LARGER
FRACTION OF INDIVIDUALS WHO ARE
COMMERCIAL SEX WORKERS HAVING
BEEN AT RISK FOR HIV, FEWER IVD
USE, VERY FEW, BECAUSE OF THE
STIGMA ASSOCIATED WITH WITH
DISCLOSURE AND THEN HERE IN THE
CARIBBEAN A MUCH MORE EACHLY
INTRIEWBTED GROUPINGS.
SO A PANDEMIC, BUT REALLY THE
SUM OF A SERIES OF EPIDEMICS.
THE TREPPED IS REALLY DIFFERENT
AS WHEN IT CAME ON AS A
SPECTACULAR EVENT.
SO NOW AFRICAN AMERICANS NOW
EXCEED WHITE NONHISPANICS AS THE
MOST COMMON PATIENTS LIVING WITH
AIDS.
THERE'S BEEN A GREAT GEOGRAPHIC
SPREAD OF HIV, MAYBE YOU
REMEMBER IT BEING ASSOCIATED
WITH MAJORY CITIES AND THAT'S
STILL TRUE BUT 12% ON IN
LOCATIONS LESS THAN 50,000
INDIVIDUALS.
USED TO BE KNOWN AS A GAY MEN'S
DISEASE IN THE UNITED STATES
NOW, WOMEN COMPRISE 25% OF ALL
THE AIDS CASES AND IT USED TO BE
A YOUNG PERSON'S ILLNESS AND NOW
11% OF THE CASES ARE OF 50 YEARS
OF AGE AND OLDER AND BY 2015,
THE PEOPLE LIVING WITH HIV
INFECTION, HALF OF THEM WILL
LIKELY BE OVER 50.
SO, I'D LIKE TO TALK ABOUT THIS
DISEASE BECAUSE IT REPRESENTS A
USEFUL EXAMPLE FOR THE
RETROVIRUSES IN TERMS OF
REPLICATION AND TALK ABOUT
ORIGINS AND THERAPY AND THOSE
CONSEQUENCES AND WHEN WE TALK
ABOUT THE ORIGINS IN
RETROVIRUSES IN GENERAL, I'M NOT
SURE EVERYBODY APPRECIATES THAT
YES WE THINK OF THEM AS A
DISASTER OF AN EPIDEMIC
CURRENTLY BUT I WONDER HOW MANY
OF US THINK OF THEM AS--FOR
BETTER WAY OF PUTTING IT THE
STRATEGY AND FINANCIAL
INNOVATION JORS OF LIFE ON
EARTH, WHO KNOWS THAT RETROVIRUS
IS SAFE?
SO YOU PROBABLY KNOW THAT VERY
EARLY IN OUR HISTORY, LET'S SAY
THREE AND HALF BILLION YEARS
AGO, THE ATMOSPHERE IS SLIGHTLY
DIFFERENT IN THIS WORLD AND IT
WAS MUCH MORE REDUCING AND THE
ORGANISMS, OR SELF-REPLICATING
THAT ARE THOUGHT TO BE PRESENT,
I CAME ALONG PROBABLY MORE LIKE
THREE BILLION YEARS AGO, I'M NOT
THAT OLD, BUT, THOSE FIRST
ORGANISMS WERE THOUGHT TO BE
USED--USE RNA AS THEIR GENETIC
INFORMATION AND THEIR SO CALLED
RNA WORLD HYPOTHESIS, IS THAT
FOREIGN TO ANYBODY, OR IS THAT
SOMETHING THAT YOU'VE ALL HEARD
OF.
THAT THE FIRST REPLICATING
ORGANISMS WERE LIKELY TO BE
RNAs AND THAT'S BASED ON THE
FACT THAT SOME OF THE OLDEST
ENZYMES WE HAVE ARE RNA, SO THEN
WHAT HAPPENED?
WELL, IN THAT EARLY REDUCING
ATMOSHPHERE, SOME OF THE
EARLIEST ORGANISMS MADE AS A
BYPRODUCT.
THEIR POOP WAS OXYGEN, RIGHT?
PLANTS.
THEIR POOP WAS--ONCE YOU ADD
OXYGEN TO AN ATMOSPHERE, THE
SELF-REPLICATING ORGANISMS THAT
USE RNA AS NUCLEIC ACID ARE AT A
DISTINCT DISADVANTAGE AND THOSE
WHO YOU KNOW, IT'S DIFFICULT TO
WORK ON THE BENCH BECAUSE IT
DEGRADES SO QUICKLY AND THAT'S
BECAUSE THOSE TWO OXYGENS THAT
MAKE THE RIBOSE ARE SENSITIVE TO
OXYGEN RADICALS SO RNA AS A
GENETIC INFORMATION THAT YOU'RE
GOING TO STORE THE MOST
IMPORTANT THING THAT YOU HAVE AS
AN ORGANISMS IS NOT THE GREATEST
REPLICATION PLANT IF MANY OF
THESE ORGANISMS ARE ACCUMULATING
OXYGEN.
SO, THE THINGS THAT SURVIVED
WERE THOSE THAT WERE ABLE TO
STORE THEIR INFORMATION IN
SOMETHING A LITTLE BIT MORE
STABLE, LIKE DNA, WELL, HOW DO
YOU GET FROM RNA TO DNA, WE KNOW
HOW TO DO THAT WITH AN ENZYME OF
REVERSE TRANSCRIPT ACE, SO ONE
THEORY OF HOW WE ALL GOT HERE IS
THAT OUR RNA ORGANISMS THAT WERE
ABLE TO STORE THEIR INFORMATION
AS DNA USING ENZYMES THAT COULD
MAKE RNA INTO DNA WERE THE ONES
THAT WERE ABLE TO SURVIVE THE
ACCUMULATION OF OXYGEN IN THE
ATMOSPHERE AND SO, NOT THAT ANY
OF YOU EVER GET OUT BECAUSE I
CAN SEE THAT MANY OF YOU ARE
POST DOCS AND WORK CONSTANTLY,
BUT IF YOU EVER WERE TO GO OUT
AND GO FOR A WALK IN THE WOODS
AND THIS IS SENECA CREEK PARK UP
IN GAITHERSBURG, AND JUST TAKE A
LOOK AROUND, EVERYTHING HAS IN
THEIR GENOME, THE ELEMENTS OF
THAT ANCIENT STRUGGLE TO GET TO
THEIR NUCLEIC ACID INTO DNA, SO
THEY ALL HAVE RETROELEMENTS,
THEY ALL HAVE SEQUENCES RELATED
TO REVERSE TRANSCRIPT ACE AND
THAT'S ANYTHING FROM BACTERIA TO
ROUND WORMS TO FRUIT FLIES, ALL
THE WAY UP TO HUMAN BEINGS.
SO, THEY'RE ALL AROUND YOU AND
IT'S VERY POSSIBLE THAT THEY
CONTRIBUTE TO SAVING THE PLANET.
WELL THEY DID OTHER THINGS AS
WELL AND THE RETROVIRUSES THAT
WE KNOW TODAY CAUSING DISEASE
ARE DIVIDED UP INTO ABOUT SEVEN
FAMILIES BASED ON THE
NUCLEICACID SEQUENCE OF THAT
REVERSE ENZYME TRANSCRIPT ACE
AND THOSE ARE LISTED HERE IN A
FILEY GENETIC TREE THAT IS NOT
DRAWN TO SCALE AND I ONLY
PRESENT IT TO ILLUSTRATE A
COUPLE OF THINGS.
FIRST OF ALL THERE ARE A NUMBER
OF THEM AND THEY ARE MORE OR
LESS RELATED TO EACH OTHER BUT
THE ONES THAT ARE INFECTING
HUMANS ARE NOTE INDEED BOLD AND
THOSE ORGANISMS ARE NOT THE MOST
CLOSELY RELATED RETROVIRUSES TO
EACH OTHER.
SO, THE ONES THAT INFECT HUMANS
ARE LISTED AS SPUMA VIRUS, IT
COMES AS AN EXOGENOUS INFECTION
IN ANIMALS, USUALLY IN
VETERINARY WORKERS IT HAS NO
DISEASE ASSOCIATED WITH IT.
IT CAN BE SHOWN TO INFECT HUMANS
BUT NEVER BEEN ASSOCIATE WIDE
ANY DISEASE.
LENTIVIRUSES HERE'S A NICE LONG
LIST, HIV ONE, WE'LL TALK ABOUT
THAT A GREAT DEAL.
IT HAS ITS RELATIVES IN ANIMALS,
HAS VIRUSES LIKE IT IN HORSES
AND GOATS AND SHEEP, BUT THEY
COMPRISE A GROUP THAT ARE MORE
RELATED TO EACH OTHER THAN THEY
ARE TO THE OTHER VIRUSES.
THE OTHER GROUP THAT INFEBTS
HUMANS AND DOES CAUSE DISEASE,
HUMAN T-CELL LEUKEMIA VIRUS IS
ON AN ENTIRELY DIFFERENT BRANCH
SO EACH THOUGH THEY'RE ALL
RETROVIRUSES, THE ONES THAT
INFECT HUMANS ARE NOT ALL THAT
CLOSELY RELATED.
IF WE LOOK NOW AT JUST THE
LEAPTY VIRUSES FOR JUST A
MOMENT, YOU'LL SEE THERE ARE A
NUMBER DIFFERENT OF THEM.
THE ONES THAT INFECT HUMANS
BEGIN WITH AN H, HUMAN IMMUNO
DEFICIENCY VIRUS, THIS IS THE
ONE THAT'S RESPONSIBLE FOR OVER
33 MILLION OF THE 34ISH MILLION
CASES OF HUMAN IMMUNO DEFICIENCY
VIRUSES IN HUMANS, AND THEN A
RELATED VIRUS, HIV TWO WE'LL
COME BACK TO LATER ALSO INFECTS
HUMANS AND ONE THING YOU CAN
NOTICE IS THAT, THESE VIRUSES,
HIV ONE, IS MORE RELATED TO A
VIRUS THAT'S FOUND IN
CHIMPANZEES, SIMIAN IMMUNO
DEFICIENCY VIRUS THAN IT IS TO
THE HIV TWO THAT WE KNOW INFECTS
HAD YOU MANS IS SIMILARLY HIV
TWO IS MUCH MORE CLOSELY
RELATED.
98% IDENTICAL TO IMMUNO
DEFICIENCY VIRUS THAT'S FOUND IN
THE [INDISCERNIBLE], IN OTHER
WORDS THERE ARE VIRUSES THAT ARE
RELATED TO THE HUMAN VIRUSES
MUCH MORE CLOSELY IN ANIMALS
THAN THEY ARE TO EACH OTHER.
SO ONCE AGAIN, JUST BECAUSE THE
VIRUS IS INFECTED, THE SPECIFIC
SPECIES DOESN'T MEAN THEY'RE
MOST CLOSELY RELATED TO EACH
OTHER.
THEY'RE ACTUALLY MORE CLOSELY
RELATED TO VIRUSES THAT ARE
FOUND IN OTHER ANIMAL
POPULATIONS AND THAT SAYS A LOT
ABOUT PERHAPS HOW THEY GOT INTO
OUR POPULATION.
AND THERE ARE THOSE TWO.
SO I'D LIKE TO SPEND A FEW
MINUTES DISCUSS SAYS LIED IKE TO
START WITH THE GENOME, AND THE
AND IT'S A GENOME IN THE
INFECTED ANIMAL CELL, AND,--SO
FIRST OF ALL IT HAS A PUNCH OF
GENES AND THERE ARE NINE OF THEM
AND THERE'S A LIST IN YOUR
SYLLABUS OF WHAT MANY OF THESIS
THINGS NEED BUT NOTICE ONE
THING--THE THREE PRIMATES SO, IF
POSSIBLE, YOU AWIVE HAVE
PROMOTER BUT WHERE'S THE
POLYA-SEQUENCE FOR ALL OF THESE
RNAs, IT'S THE RNA THAT'S
ACTUALLY INCAP SURVEYSALATED
INTO THE THERAPY ANDON, THE
POLYA SIGNAL IS AT THE WRONG
END, LET'S SEE HOW THESE THINGS
GET SORTED OUT PLUS IF THEY
DON'T GET SORTED, THE POLYA
SEQUENCE AND THE PROMOTER HAVE
DISTINCT REGIONS, I KNOW YOU'RE
GOING TO FIND THIS INTERESTING
BECAUSE YOU'RE PROBABLY ALL
WORKED FOR SOMEBODY LIKE THIS,
BUT THESE WERE NAMED BY FOR ONE
OF A BETTER TERM, VERY CONCRETE
ONES.
SO R STANDS FOR REPEAT, THE
SEQZdr(Q THAT'S REPEATED,
SO--AND UNIQUE REGION AND UNIQUE
REGION AT THE THREE PRIMATES.
SO THEY WERE HIGHLY IMAGINE
NATIVE WHEN THEY CAME UP WITH
THESE NAMES, BUT THE POINT BEING
THAT THIS THING STARTS OUT THAT
HAS REPEAT, AND THEN AND I KNOW
THAT MANY OF YOU WERE IN THE--I
SEE THESE REAL TURNING ONES THE
HOUSES LIKE REPLICATE AND YOU'RE
EXACTLY RIGHT.
THE NAMES OF THE GENES ARE
ALWAYS LISTED IN LOWER CASE
ITALICS, AND TOLERANCE AND
TALKING ABOUT THE GENE
THEMSELVES.
BUT THEN IT'S GOING TO GET INTO
THE CELL AND REPLICATE, IT'S
GOING TO MAKE A GENE COPY OF
ITSELF AND ONCE IT'S DONE WITH
THAT, IT WILL INTEGRATE THE
DOUBLE STRAND DNA COPY INTO THE
HOST GENOME AND WHEN IT DOES
THAT, IT'S DIFFERENT.
AND THOSE ENDS NOW ARE CALLED
LONG-TERMINAL REPEATS BECAUSE
THEY'RE LONGER THAN THE REPEATS
HERE.
AND IT USED TO BE OVER HERE IS
REPEATED AT BOTH ENDS, RIGHT?
THE R IS STILL THERE, AND THE
U-FIVE REGION AND AND NOW YOU
SEE IT BOTH THE PROMOTER IS NOW
AT THAT FIVE WHERE I LIKE, I'M
JUST A BIT MORE COMFORTABLE WITH
IT BEING THERE, AND CERTAINLY
I'M ONLY COMFORTABLE WITH THE
WITH THE POLYACE BEING THE THREE
PRIME IN, SO DURING THE COURSE
OF REPLICATION, THE ORGANIZATION
OF THE PRIEF PRIME N AND THE
THREE PRIME IN CHANGES AND THE
PROMOTER IS ORGANIZED AND
THERE'S SOMETHING THAT CAN
ACTUALLY BE--PRODUCE A VERY
PRODUCTIVE INFECTION ONCE IT'S
INTEGRATED IN THE HOST GENOME.
ONCE IT'S DONE THAT, IT'S TERMED
THE PROVIRUS.
SO THE PRO VIRAL DNA IS IN
ITSELF, AND HERE'S JUST A
GLOSSARY OF TERMS PROTEIN THAT'S
CAUSED THE TRUCKURAL PART OF
THEY'RE CALLED GAG, NOT BECAUSE
THEY MAKE YOU SICK BUT BECAUSE
IT'S AN OLD TERM MEANING A GROUP
ANTIGEN.
THE ENVELOPE OF PROTEINOT
SURFACE OF THE VERYON, TAD IS A
TRANSACTIVATOR THAT WORKS TO
AUGMENT RNA REPLICATION, REF IS
A REGULATOR OF GETTING THE RNA
OUT.
AND HERE ARE A LIST OF ALL OF
THE SEQUENCES THAT ARE ALSO
IMPORTANT FOR REPLICATION.
HERE IN SORT OF A REGIONAL
ANATOMY KIND OF WAY IS WHERE
THOSE GENE PRODUCTS ARE IN A
CARTOONISH FASHION AND SO, THE
SURFACE PROTEINS, GLYCOPROTEINS
ARE ON THE SURFACE, AS
GLYCOPROTEINS INSERTED INTOED A
HOST MEMBRANE THAT IT ACQUIRES
AS IT'S SPLITTING OUT OF THE
MEMBRANE, THE STRUCTURAL
PROTEINS, GAG PROTEINS ARE FOUND
HERE.
TWO RNA COPIES AND BOTH OF THOSE
COPIES ARE ACTUALLY IDENTICAL,
THIS THING DOESN'T GO IN DOUBLE
STRANDED.
AND AND IT'S ENZYMES REVERSEMENT
AND THESE ARE ENCAPSIDDATED WITH
THE VERRION.
AND INFINITE STUPIDITY A MADE
THIS 100-NANOMETERS WHEN IN FACT
IT'S NANOMETERS SO IT'S NOT
VISIBLE OR BARELY VISIBLE BY THE
MICROSCOPE.
SO THIS IS A DEPICTION OF ITS
REPLICATION CYCLE AND I THINK IN
THE CONVERSION FROM MAC TO PC, I
THINK WE MOVED A COUPLE OF
LETTERS, BUT, THE KEY POINTS
ILLUSTRATED HERE, FIRST OF ALL
THIS VERRION HAS TO ATTACH TO
THE CELL SURFACE, IT HAS TO GET
IN, AND UNDERGO, AND THE D NA
MOLECULE, AND THEN ONCE THAT
ENEMY IS WITHIN, IT'S EXPRESSED
BY CELLULAR ENZYMES.
RNA PROCESSING BY CELLULAR
MACHINERY, TRANSLATION BY
CELLULAR MACHINERY ASSEMBLY.
MOSTLY AN AUTOASSEMBLY PROCESS
AND THEN A MATURATIONAL EVENT
CO-OPTING ELEMENTS OF ESCORT
PATHWAYS USED FOR ALL KINDS OF
OTHER THINGS BY THE CELL IS NOW
BEING USED BY THE VIRUS AS WELL.
SO, IT'S USEFUL TO SEE A SLIDE
LIKE THIS, OR A MUCH BETTER
SLIDE BUT IT'S USEFUL BECAUSE
ALL THE STEPS THAT ARE UNIQUE TO
THE VIRUS ARE PLACES THAT
REPRESENT OPPORTUNITIES TO
DEVELOP ANTIVIRALS AND IN FACT A
A NUMBER ALL OF THESE PLACES
DRUG VS BEEN DEVELOPED TO
SUPPRESS HIV REPLICATION.
--IT GETS TO THE CELL, BUT IT'S
FINE THAT BOTH GET INSIDE AND
ACTUALLY THE DISSOCIAL STEPS IN
VIRUS REPLICATION, SO THE ASHES
TACHMENT AND THE DIFFUSION ARE
DISTINCT AND THE FACT THAT
THEY'RE DISTINCT MEANS WE CAN
TARGET BOTH OF THEM FOR FOR
INHIBITION, SO THEY'RE--WE NEED
THE ENVELOPE GLYCOPROTEIN GP 120
WHICH IS GOING TO FIND SPECIFIC
HOST CELLS, BUT THAT'S NOT GOING
TO BE GOOD ENOUGH.
ATTACHMENT JUST ISN'T GOOD
ENOUGH STICKING ON THE OUTSIDE
OF A CELL ISN'T GOING GOING TO
MAKE IT.
AND ON THE FORECELL SIDE IT
NEEDS NOT JUST A RECEPTOR, CD4
BUT A KORESEPTORSOR AS WELL.
AND CYTOKINE RESECTOR GENES AND
CCR FOUR AND CCR FIVE, AND TWO
OF THE MOST PROMINENT AND
TYPICAL, BUT WITHOUT BOTH, NO
DEAL, SO ATTACHMENT AND ENTRY
ARE DISSOCIABLE, ATTACHMENT
MEANS BOTH THE RECEPTOR AND A
KORESEPTORSOR.
SO THAT CORECEPTOR IS AN
ABSOLUTE ESSENTIAL THE BINDING
OF THE VIRUS TO CD FOUR, THAT'S
BEEN KNOWN SINCE ALMOST THE
BEGINNING OF HIV RETRORIROLOGY,
85, 86, 87, BUT TO DATE, WE
DON'T HAVE A REALLY GOOD DRUG
TAKEN--THEY BLOCKS THE BINDING
OF THE VIRUS TO THE RECEPTOR
CD4, SAME'S NOT TRUE WITH THE
KORESEPTORSOR, THE KORESEPTORSOR
CAME ALONG BUT WE DO HAVE DRUGS
THAT TARGET AT LEAST ONE OF
THOSE IS, AND POTENT, INHIBITING
HIV REPLICATION WITH THAT
PARTICULAR KORESEPTORSOR CCR
FIVE AND SO WE HAVE TO DO SOME
LEVEL OF GYMNASTICS TO SEE
WHETHER OR NOT PATIENTS WILL BE
SUSEPTIBLE TO THAT DRUG IF AND
WHEN THEY NEED IT.
HERE'S WHAT SOME OF THOSE MODEL
INHIBITORS LOOK LIKE AND WHAT
THEY DO IS BASICALLY INTERACT
WITH THE INTERACTION.
SO THEY BLOCK THE INTERACTION OF
THE VIRAL ENVELOPE WITH THE
CELLULAR RECEPTOR AND RESISTANCE
CAN EMERGE TO THAT BINDING BY
REDUCING THE AFFINITY OF THE
DRUG OR BY JUST SHIFTING INTO A
VIRUS THAT NO LONGER USES THE
CCR FIVE KORESEPTORSOR BUT USES
THE OTHER KORESEPTORSOR INSTEAD,
SO CAN YOU GET RESISTANCE TO THE
ROCK ON TWO DIFFERENT LEVELS.
THE FUSION REACTION WHICH OCCURS
AFTER THE ATTACHMENT HAS ALSO
BEEN USEFUL FOR DEVELOPING
DRUGS.
SO YOU MIGHT THINK THAT THAT IT
WOULD DO WITH YOUNGER CHILDREN
THAT I TALK TO ABOUT HIV, DO YOU
EVER AND YOU GUYS ARE WAY TO
INTELLIGENCE WITH THIS WITH
THOSE BUBBLES WHEN YOU WERE
REALLY LITTLE?
THAT SOAP STUFF AND YOU BRO IT
AND THERE WOULD BE BUBBLES ALL
OVER THIS ROOM.
MIGHT BE WORTH WHILE, BETTER
THAN THE LECTURE RIGHT, BUT IF
THERE WERE BUBBLES FLOATING ALL
OVER THE ROOM, DANCE AROUND,
DARTING AND EVERY ONE IN A
WHILE, THEY COME TOGETHER AND
POP AND BECOME ONE BUBBLE AND A
LOT OF PEOPLE USED TO THINK
THAT'S HOW VIRUSES MUST GET IN,
THERE'S ATTACHMENT STAGE AND
THEN POOF SOMETHING HAPPENS AND
THEN THE VIRUS FUSES, THE VIRAL
MEMBRANE FUSES WITH THE CELLULAR
MEMBRANE AND THEN WE'RE DONE,
BUT IN FACT IT'S A MUCH MORE
ENERGY REREQUIRING STEP, OR THE
VIRUS HAS TO DRIVE IT'S MEMBRANE
THROUGH THE OTHER TO FUSE IT.
SO THERE'S A LOT OF PROTEIN, SO
IT'S NOT ALL THAT EASE, IT TAKES
A HIGH LEVEL OF ENERGY TO GET
THE VIRUS AND THE CORE INTO THE
CELL AND THAT'S THE JOB OF GP 41
AND HOW IT DOES THAT, IS AFTER
ATTACHMENT OCCURS IT'S LINKED TO
GP 120, NONCOVALENTLY, JUST BY
NONCOVALENT LINKAGES AND ONCE
THE BINDING OCCURS THAT CAUSES
SECONDARY CHANGES IN THE GP41
AND IT REARRANGES A PORTION OF
ITS MOLECULE INTO THESE SIX
HELIX BUNDLES AND THOSE SIX
HELIX BUNDLES AND YOU'LL SEEOT
NEXT SLIDE LOOK A LOT LIKE
CREATED WHAT'S CALLED THE TWO
MEMBRANES TO FUSION IN A VERY
DETAILED MECHANISM DEPICTED HERE
BY THIS QUESTION MARK.
BUT IN FACT THE FUSION REACTION
OCCURS AND THEN THE TWO
MEMBRANES BEHIND AND THE RESULT
OF THAT IS THAT THE CORE THAT
WAS IN THE VERRION IS NOW IN THE
CYTOPLASM OF THE VIRUS.
AND YOU CAN SEE HERE THEY KIND
OF LOOK LIKE SPRINGS HERE IF YOU
LOOK AT THEM ON THE LONG AXIS
HERE BUT IT ALSO SUGGESTS THAT
IF HAVE YOU SOMETHING THAT'S
REALLY WELL CONSERVED HERE AND
HIGHLY STRUCTURED THAT MAYBE YOU
COULD MUCK IT UP WITH THE DRUG
AND IN FACT, THE DRUG LOOKS VERY
MUCH LIKE PART OF THE SPRING
ONLY IN AN OPPOSITE DIRECTION.
IT BINDS BETTER TO THIS THAN ITS
NEIGHBORING HELIX BUNDLE DOES
AND AS A RESULT, YOU CAN DISRUPT
THE FUSION REACTION VERY, VERY,
WELL, THE DRUG'S CALLED T-20 AND
THERE ARE SOME NEW DRUGS ALONG
THE WAY THAT ARE BEING DEVELOPED
TO TRY AND INTERACT WITH THAT AS
WELL.
BUT I GUESS THE POINT, YOU KNOW
SORT OF THE MORE GENERAL POINT
IS THAT THE MORE YOU KNOW ABOUT
HOW THIS THING WORKS, THE BET
ARE YOU CAN DESIGN NEW DRUGS TO
BLOCK IT.
SO JUST KNOWING THAT A VIRUS HAS
TO BIND AND GET IN, TO BE ABLE
TO DISASSOCIATE THOSE TWO EVENTS
IS ACTUALLY PRETTY USEFUL FROM A
THERAPEUTIC STANDPOINT.
OKAY, SO ONCE IT GETS IN, LIKE
WE'RE DONE, RIGHT?
IT HAS ACCESS TO NUCLEOTIDE TRI
PHOSPHATE, THERE'S AN ENZYME
THERE, IT STARTS TO REPLICATE,
WELL IN FACT THERE'S ONE MORE
STEP THAT HAS TO OCCUR AND
THAT'S SOMETHING CALLED
ENCODING, NOW THE OTHER STUFF IS
EASIER, RIGHT, LET'S FACE TYOU
WORK IN A LAB, YOU KNOW WHAT A
BINDING ASSAY IS LIKE, YOU KNOW
WHAT A FUSION ASSAY COULD BE
DEVELOPED BUT AN UNCODING ASSAY.
NOW THAT ONE IS DIFFICULT
BECAUSE IT'S REAL LYE A SUM OF
PROTEIN-PROTEIN INTERACTIONS BUT
IT TURNS OUT KNOWING ABOUT THAT
DOESN'T TELL YOU, DOESN'T JUST
TELL YOU A LOT ABOUT HOW THE
VIRUS REPLICATES, IT TELLS YOU
ABOUT HOW WE GOT IN THIS
SIRCHGING MESS THAT WE'RE IN
WITH 33 MILLION PEOPLE INFECTED
WITH THE VIRUS.
SO THERE ARE CELLS, AND THERE
ARE OTHER CELLS THAT SO THIS
REQUIRES INTERACTIONS BETWEEN
VIRAL AND CELLULAR FROM THE
STANDPOINT IT'S MAJOR STRUCTURAL
PROTEIN GAG AND FROM THE CELL
STANDPOINT, IT'S SOMETHING
CALLED TRIM FIVE ALPHA.
THAT ALLOWS 33 MILLION PEOPLE TO
BE INFECT WIDE THIS VIRUS.
THERE BUT FOR A COUPLE OF AMINO
ACIDS GOES A SPECIES THAT CAN'T
BE INFECT WIDE HIV.
IT TURNS OUT THAT THAT HIV WILL
INFECT HUMANS BECAUSE OUR TRIM
FIVE ALPHA PROTEIN UNCOATS HIV
AND CHIMPS ARE REASONABLE WELL
AS WELL BUT MONKEYS DOES NOT
UNCODE HIV.
IF YOU LOOK AT THE CHIMP, RIGHT
AND LOOK AT A SIMEON VIRUS THAT
AFFECTS CHIMPS, YEAH TAFFECTS
CHIMPS REAL WELL, IT ALSO
INFECTS US REAL WELL, BECAUSE
OUR TRIM FIVE ALPHA UNCOATS THAT
VIRUS.
MONKEYS ON THE OTHER HAND, VERY
POORLY INFECTIOUS.
NOW, THEY DO HAVE A VIRUS, THAT
THEY UNCOAT REALLY, REALLY WELL.
AND IT TURNS OUT, OUR TRIM FIVE
ALPHA ALSO ENCODES THAT, SO
WE'RE SUSCEPTIBLE TO VIRUSES
FROM CHIMPS, AND FROM MONKEYS,
BUT THE REVERSE IS NOT THE CASE.
AND AS A RESULT, WE'RE STUCK
WITH THIS INFECTION, NOW HOW
COME WE GOT SO LUCKY THAT COATS
JUST ABOUT EVERYTHING AND THE
REASON IT'S LIKELY THAT WE
SELECTED IT.
THIS VIRUS THAT'S CAUSING US SO
MUCH TROUBLE THESE DAYS, IT'S
PROBABLY ONE, IT'S PROBABLY A
WAVE, ONE EXAMPLE OF A WAVE OF
VIRUSES THAT WE'VE BEEN DEALING
WITH FOR MILLIONS OF YEARS,
RIGHT?
SO THIS PROTEIN, TRIM FIVE ALPHA
IF YOU STUDY IT, FILE O
GENETICALLY, YOU'LL FIND THAT
IT'S PROBABLY ONE OF THE MOST
HIGHLY MOST RAPIDLY CHANGING
GENES IN THE HUMAN GENOME.
IN OTHER WORDS, IT'S RESPONDING
TO WAVES AND WAVES OF INFECTIONS
IT'S NOT JUST ENCODED BY THIS
VIRUS.
THERE ARE OTHERS AS WELL.
WE SELECT FOR THE TRIM FIVE
ALPHA THAT KEEPS US ALIVE OR
KEPT US ALIVE FROM THE LAST WAVE
OF INFECTION.
CHARLES DEGALL ONCE SAID,
GENERALS ARE ALWAYS FIGHTING THE
LAST WAR.
THAT'S OUR GENERAL.
>> ANY FUNCTIONAL STUDIES ON
[INDISCERNIBLE]
>> WHAT IT DOES?
>> YES.
>> THERE ARE TONS OF THAT.
IT LOOKS LIKE WHAT IT
DOES--OOPS--IT LOOKS LIKE WHAT
IT DOES IS IRPT ACT WITH GAG
INDIRECTLY IT HAS SOMETHING
CALLED A SPRY DOMAIN AND BY THAT
INTERACTION, IT UNFOLDS AND I'M
REACHING A BIT, BUT IT BREAKS
DOWN THE CORE AND WHEN IT BREAKS
DOWN THE CORE, THEN THE ENZYMES
REALLY DO HAVE ACCESS TO
NUCLEOTIDE TRI PHOSPHATES, SO IF
THAT DOESN'T HAPPEN, THE CORE
GETS SHUTTLED OFF TO THE
PROTEOSOME AND GETS DEGRADED.
>> [INDISCERNIBLE].
>> I THINK IF WE INFECT ENOUGH
PEOPLE WE'LL FIND THEM.
I DON'T THINK ONES HAVE BEEN
IDENTIFIED THAT ARE TRULY
RESISTANT AND THERE ARE SOME
THAT DO IT BETTER THAN OTHERS
BUT IT SEEMS LIKE--YOU CAN'T
LIKE FIND THE RIGHT PEOPLE YET,
BUT THAT'S PROBABLY WHAT
HAPPENED WHEN THE LAST WAVE.
THAT THERE WERE A COUPLE OF
THESE OR A WHOLE GROUP OF PEOPLE
WHO WERE RESISTANT TO THE VIRUS,
EVERYBODY ELSE DIED OFF AND
THESE--WE'RE THE ONES THAT
MERGED.
THAT'S--I THINK, YEAH, YOU KNOW,
IT'S AN EVOLUTIONARY ARGUMENT
AND EVEN I WASN'T AROUND FOR IT,
BUT IT DOES MAKE A LOT OF SENSE
WHEN YOU LOOK AT TRIM FIVE ALPHA
IN US, IN CHIMPS AND THEN YOU DO
THE LINE THROUGH PRIMATES AND
SEE THAT THINGS CHANGE VERY,
VERY, QUICKLY AND THEY DON'T
CHANGE AS FAST IN A LOT OF OTHER
GENES.
THAT'S REALLY--IT'S A VERY
COMPELLING ARGUMENT.
SO THAT ENCODING STEP TURNS OUT
TO BE POORLY DESCRIBED BUT VERY
ESSENTIAL.
ONCE THAT'S DONE, THE REVERSE
TRANSCRIPT ACE TAKES PLACE, AND
THEN I SHOW THE KRYSTALOGRAPHY
TO REMIND YOU SOMETHING YOU MAY
NOT REALIZE.
IS THAT YOUR ENTIRE LIVES,
YOU'VE BEEN CARRYING AROUND WITH
YOU, THE EXTRA KRYSTAL GRAPHIC
MODEL OF REVERSE TRANSCRIPT ACE,
IT'S YOUR RIGHT HAND, COZ THESE
ARE ALL CALLED RIGHT HAND MODELS
AND I'M NOT SURE I PUT THEM ALL
IN HERE BUT THERE'S THE SUM AND
IT HAS FINGERS AND A PALM AND
RIGHT AROUND AT THE BASE OF YOUR
THUMB IS THE CATALYTIC SITE OF
REVERSE TRANSCRIPT ACE SO YOU
CAN CHEESE
RIGHT?
SO BASED ON THIS MODEL WE'RE
ABLE TO FIND WHERE RESISTANCE
EMERGES AND A LOT OF THE
CATALYSIS FOR THIS ENZYME AS
BEEN DEVISED AND HERE FOR
INSTANCE ARE PLACES WHERE A DRUG
MAY BIND AND THEN RESIEVANCE
MUTATIONS EMERGE AND YOU CAN SEE
VERY CLEARLY THE DRUG BINDS HERE
AND THEN WHEN YOU GET MUTATIONS
HERE OR HERE OR HERE OR HERE AND
THE DRUG DOESN'T BIND AS WELL
AND IT EITHER DOESN'T BIND AT
ALL OR CLOSING THE--CLOSING
RANKS AROUND IT, IT CAN ACTUALLY
ACCESS THE SITE UNDERNEATH THE
CATALYTIC SITE, SO IT'S A NICE
PARADIGM FOR UNDERSTANDING HOW A
VIRUS REPLICATES, HOW DRUGS
WORK, HOW RESISTANCE EMERGES TO
IT, SO IT'S A NICE SET OF DATA
FROM THAT STANDPOINT.
AND IT'S SO GREAT, I CAN'T GET
PAST IT.
OKAY.
SO THESE ARE THE ENZYMATIC ONES
SO AND THE IRONY, RIGHT?
IT HAS AN RNA DEPENDEN
POLYMERASE, IT TAKES RNA, MAKE
ITS INTO DNA, ONCE IT MAKES THE
FIRST STRAND, IT HAS TO TAKE DNA
AND MAKE IT INTO ANOTHER STRAND.
SO IT HAS A DNA POLYMERASE, IT
HAS TO GET RID OF MOST OF THE
RNA TO MAKE THE SECOND TRAND
WITH RNA, IT HAS AN RNA STAGE.
SO, THAT'S PRETTY INTERESTING,
FINE, SO HERE'S AN RNA VIRUS
THAT CAN'T MAKE RNA, DNA FROM
RNA, YOU CAN MAKE DNA, FROM DNA,
IT JUST CAN'T MAKE AFTER THE
VIRUS INTEGRATED, THE ERROR RATE
IS SOMEWHERE ON THE ORDER OF
WHEN THE FORM TAKES IN THE
HUNDRED THOUSAND BASIS SIPGHT
CISER THAT DOESN'T SOUND LIKE A
LOT BUT IT'S ORDERS OF MAGNITUDE
FOUR OR FIVE MORE THAN THE
POLYMERASE MAKES AND IN FAIRNESS
TO THE RNA IS PRONE MAKES
MISTAKES ON THIS LEVEL
RECOMBINATION OCCURS THROUGH THE
REVERSEçó TRANSCRIPTION AND
REPLICATION IS BOTH RAPID SO IN
A HUMAN VIRUS REP LIAISON KITS
BETWEEN EVERY ONE TO TWO DAYS
AND IT MAKES THESE MANY
MISTAKES, THE COMBINATION OF
THOSE TWOw3 THINGS SO WHEN WE
TREAT WITH ABET VIRALS WE DON'T
SELECT THE MUTANTS.
WE SELECT THE ONES THAT WERE
THERE ALREADY.
SO THE DRUG RESISTANCE ISN'T
THAT WE START WITH A DRUG AND
IT'S SO
TO OCCUR, IT'S THAT THE VIRUS
LEAD EXPLORED THE SEQUENCE SPACE
AND ALREADY MADE SOME OF THOSE
CHANGES AND ALL WE DO IS SELECT
THEM.
EMPLOY SO HERE'S AN EXAMPLE OF
THAT AT A POSITION, 151 IN THE
REVERSE TRANSCRIPT ACE GENE IS A
GLUTEA MINE AND I KNOW YOU KNOW
THIS BUT I PUT IT THERE ANYWAY,
AND THE CODON IS CHE FOR THAT
AND IF YOU MAKE A SINGLE
NUCLEOTIDE CHANGE TO TCG, AND
YOU GET A LEUCINE THERE INSTEAD
OF GLOUTA MINE.
AND IF YOU GO TO CAG TO, AAG,
YOU GET A LYSINE AND IF YOU GO
FROM EITHER ONE OF THESE AND
MAKE ONE MORE CHANGE YOU CAN
MAKE IT AT 151.
THIS VIRUS THAT INCLUDES THE 151
GLUTEA MINE IS SENSITIVE TO ALL
THE SENT RETROVIRALS WE HAVE
THAT INHIBIT REVERSE
TRANSCRIPTATION AS THESE ARE.
THIS ONE IS MOST, A HUNDRED FOLD
OR MORE, SO THIS THING IS HIGHLY
RESISTANT, THESE THREE ARE
HIGHLY SENSITIVE MAKING THESE
CHANGES, THEY ALL EXIST AT A
VERY, VERY, LOW LEVEL BUT ALL
YOU NEED IS A FEW, ALL HAVE YOU
IS RESISTANT VIRUSES, AND THE
RESPOND RAPIDLY AND I THINK OF
OF THIS AS A PATHOGENIC
DETERMINANT FOR THE VIRUS NOT
BECAUSE OF DRUGS, BUT BECAUSE OF
IMMUNE SELECTION HAPPENS THE
SAME WAY, IT EXPLORES THE ENTIRE
SEQUENCE SPACE, IT MAKES LOTS OF
VARIANTS, THE BODY MAKES AN
IMMUNE RESPONSE, IT ALREADY HAS
VARIANTS THAT CAN GROW OUT AND
BE RESISTANT TO THE CTL OR THE
ANTIBODY RESPONSE.
SO ONCE HAVE YOU THE DNA
REPLICATED, THE NEXT STEP IS TO
INTEGRATE IT INTO A GENOME HOST
AND IT'S CARRIED OUT BY SPECIFIC
ENZYME AND IT'S THE GENERAL
MECHANISM FOR THAT IT'S A
MULTISTEP REACTION IT CAN BE
INHIBITED,--THE SECOND GROUP
THAT'S REPRESENTED HERE BY
BY--MOLECULAR BIOLOGY, THE
RESULT IS ONE OF BESTÑi DRUGS AND
AS I MENTIONED EVERYTHING IS
TAKEN OVER BY THE HOST, IN TERMS
OF THERE ARE VIRAL CHANGE AND
WITH THE PROCESS AND THOSE ONCE
AGAIN ARE COOPERATIONS BETWEEN
CELLULAR FACTORS, BINDING SITES
WITHIN THE VIRUS, AND AND VIRAL
GENE PRODUCTS, ONCE THE RNA GETS
OUT IT'S TRANSLATED TO TYPICAL
FASHION BY RIBOSOMES, ASSEMBLES
AND THEN THE VIRUS MATURESOT
CELL SURFACE, AND REALLY THAT
PARADIGM OF MATURATION IS REALLY
PROCESSING POLYPROTEIN
PRECURSORS IF YOU COULD SAY THAT
THREE TIMES FAST, YOU ARE MUCH
BETTER THAN I AM.
BUT THE ISSUE IS THAT THE VIRUS
MAKES MOLLY PROTEIN
PRECURIOUSORS, THEY DON'T WORK
UNLESS THEY'RE PROCESSED, RIGHT?
SO THE ONES THAT ARE ESSENTIAL
FOR STRUCTURAL ARE THE GAG GENE
PRODUCTS AND THOSE THEN WILL
GIVE YOU SOMETHING LIKE THIS.
SO IF THE VIRUS IS BUTTING OUT
OF THE CELL SURFACE, AND HERE'S
ELECTRON MICROGRAPH OF AN
INFECTED CELLS, HERE'S THE CELL
MEMBRANE AND HERE IT'S THREE
VIRIONS AND YOU CAN SEE THEY'RE
COMING OUT OF THIS CELL MEMBRANE
BUDDING THROUGH THERE AND THEN
OVER HERE, A MATURE PARTICLE AND
YOU CAN TELL THESE ARE IMMATURE
BECAUSE THEY'RE GROUP NOTHING
THE CORNER, GIGGLING AWAY, YOU
KNOW THEY'RE IMMATURE AND THIS
ONE IS STANDING BY ITSELF AND IT
KNOWS WHO IT IS, BUT CAN YOU SEE
THE DIFFERENCE BETWEEN THESE TWO
KINDS OF VIRUSES AND ANYBODY DO
ELECTRON MICROSCOPY, OKAY, SO
YOU--SOME OF YOU KNOW THAT WHEN
YOU STAIN THESE ULTRA THIN
THINGS YOU DO IT WITH WHAT, LED,
CONSTANT, RIGHT?
ALL OF THEM ARE POSITIVELY
CHARGED, HEAVY ATOMS THAT ARE
GOING TO DISTORT THE EXTRA BEAMS
AS THEY GO THROUGH, SO WHAT
YOU'RE LOOKING AT IS WHERE THE
TONGUE STONE IS, OR THE LED IS,
NOW WHERE IS THAT.
WHERE DO POSITIVE CHARGES GO,
THEY BIND TO NEGAATIVE CHARGE,
WELL, OKAY, PROTEINS, BUT A LOT
OF NUCLEIC, ACID, RIGHT?
ALL THOSE PHOSPHATE GROUPS NOW
ALL HAVE A TONGUE STONE ADAM OR
LEDDA ATOM STUCK TO IT, SO WHAT
YOU'RE LOOKING AT IS THE
DISTRIBUTION OF THE NUCLEICACID
AND SOME OF THE PROTEIN.
AND YOU CAN SEE HERE, IT'S
SMASHED UP AGAINST THE INSIDE OF
THE CELL MEMBRANE AND OVER HERE
ASTERISKS ACCUMULATED IN WHAT'S
CALLED A CORE.
RIGHT?
SO WHAT'S THE BIG DEAL HERE
FRANK?
HIV PROTEASE DOES THIS
PROCESSING REACTION THAT CONVERT
THIS IS RNA AND PROTEIN COMPLEX
THAT'S SMASHED UP ON THE INSIDE
OF THE MEMBRANE INTO SOMETHING
LIKE THIS.
THESE THINGS ARE NONINFECTIOUS,
THESE ARE INFECTIOUS, NOW THAT'S
COOL.
IF WE BLOCK PROTEASE HERE, WE
CAN--YOU KNOW GRAB VICTORY FROM
THE JAWS OF DEFEAT, HERE THE
VIRIONS ARE BEING PRODUCED AND
THEY'RE STILL NOT INFECTIOUS
UNTIL PROTEASE ACTS SO PROTEASE
ARE AN IMPORTANT PART OF ANY
APPROACH TO TREATING HIV,
BECAUSE THEY'RE POTENT STATANT
AND THEY DO A GREAT JOB.
SO THIS IS ACTUALLY THE LIST OF
ALL THE ANTIRETROVIRALS THAT
HAVE BEEN PRODUCED SINCE 1987
AZT IN THE EDGE HERE BUT RIGHT
ABOUT WHEN THIS DRUG CAME OUT,
THERE WAS THIS POSTER THAT WAS
CIRCULATING ON THE BUSS IN
WASHINGTON D. C. AND OTHER
PLACES IF YOU GET THE AIDS VIRUS
NOW, YOU AND YOUR LICENSE COULD
EXPIRE ABOUT THE SAME TIME AND
THAT WAS TRUE A COUPLE OF YEARS
WOULD BE ABOUT THE BEST YOU
COULD EXPECT.
BUT BECAUSE OF THESE DRUGS AND
BECAUSE THEY'RE USE INDEED
COMBINATION TO PREVENT RESISTANT
VIRUSES, IT'S POSSIBLE NOW THAT
PEOPLE LIVE FOR AN EXTENDED
PERIOD AND WE'RE TALKING ALMOST
AS LONG AS PEOPLE WHO ARE
UNINFECTED.
--OF THE FIELD AND OF
RETROVIRUSES WHERE THE VIRUS
CAME FROM BUT I WANT TO GO BACK
BRIEFLY TO THIS AND REMIND YOU
THAT THE TWO VIRUSES THAT
CIRCULATE ON THE PLANET, ONE OF
THEM IS MUCH MORE CLOSELY
RELATED TO A VIRUS THAT'S FOUND
IN CHIMPS, THE OTHER IS MUCH
MORE CLOSELY RELATED TO A VIRUS
FOUND IN CITY [INDISCERNIBLE],
IT I KNOW YOU KNOW IT MAY NOT
THINK IT MAKES A DIFFERENCE BUT
IT MAKES A DIFFERENCE TO THEM
LET'S TALK ABOUT HIV TWO FIRST.
SO IN WEST AFRICA, IN 1986,
INVESTIGATORS FOUND THAT THERE
WERE VIRUSES SO THIS IS AFTER
HIV ONE.
SO VIRUSES WERE CIRCULATING AND
CAUSING IMMUNE DEFICIENCY AND
YET THE INDIVIDUALS WERE NOT
REACTING AND THAT SUGGEST TREAD
MIGHT BE A DIFFERENT VIRUS
PRESENT, IT WAS CLONED OUT AND
CALLED HIV TWO.
AND HERE, ARE THE COUNTRIES AND
HERE AND HERE ARE THE COUNTRIES
WHERE IT'S PREVENTIVE LEAPT AT
LEAST ONE TO TWO% OF ALL THE
IMMUNO DEFICIENT PATIENTS IN
THOSE COUNTRIES FOR ECONOMIC
TIMES THERE, IN INDIAN.
AND THE INTERESTING THING WAS,
MAYBE ABOUT--THERE'S NEW DATA
ABOUT 180 CASES IN THE UNITED
STATES, SO VERY, VERY, FEW,
ALMOST ALL ARE IMMIGRANTS FROM
THAT AREA AND THE INTERESTING
THING WAS WHEN THEY SERVE A
PRIMATES IN WEST AFRICA, THEY
FOUND A VIRUS, HIGHLY PREVALENT
IN THE CITY MANNA BEES AND
HERE'S ONE OF THOSE THAT IS 98%
SIMILAR TO HIV TOO.
SO THAT MAKES YOU THINK, WELL,
THERE'S TONS OF IT IN AN ANIMAL
POPULATION AND THEN IT EXPLOATED
IN A HUMAN POPULATION AND A
LIKELY HYPOTHESIS IS THAT IT
STARTED OUT IN THE ANIMALS AND
THEN JUMPED INTO HUMANS.
AND HERE'S A POACHER WITH A
SODIUM MANGA BEE AND THAT SORT
OF SUGGESTS THE MECHANISM AND
WE'LL LOOK AT THAT IN A SECOND.
HIV ONE WAS A LITTLE BIT MORE
DIFFICULT BECAUSE THEY HAD TO GO
OUT AND SERVE A--CHIMPANZEES TO
SEE WHETHER OR NOT THAT GROUP,
IF THEY SORTED OUT AND LOOK AT
ALL DIFFERENT PRIMATE SPECIES
COULDN'T FIBBED ANYTHING CLOSELY
RELATED AS HIV TWO, IN THE CITY
VIRUS, AND SO HANN, AT THE
UNIVERSITY OF ALABAMA DECIDED TO
LOOK AT CHIMPS.
NOW THEY'RE NOT AS EASY AS YOU
THINK, BECAUSE YOU CAN'T GO OUT
AND BLOOD A CHIMP, THAT'S
AGAINST THE LAW.
SO THEY CONSULTED WITH GROUPS IN
CENTRAL AFRICA AND SOME OF THESE
PRESERVES AS TO HOW TO GET THIS,
JANE GOODALL WAS INVOLVED AND
THEY SAID NO, YOU CAN'T BLEED
THE CHIMPS.
YOU SO THAT'S THE BAD NEWS, BUT
THE GOOD NEWS IS YOU CAN HAVE
ALL THE URINE AND STOOL YOU CAN
COLLECT.
THAT'S THE GOOD NEWS, RIGHT?
SO THOSE WHO HAVE BEEN GRADUATE
STUDENTS THAT WAS A GRADUATE
STUDENT PROJECT--YES!
TO GO TO AFRICA AND THEY KNEW
ALL THESE CHIMPS THEY KNOW THEM
BY NAME, WHERE THEY SLEEP, WHERE
THEY EAT, THEY KNOW WHERE THEY
PEE AND THEY KNOW--YOU KNOW
THEY'RE LIKE A LOT OF OTHER
PRIMATES MAYBE YOU'VE MET SOME,
RIGHT, THEY GET UP IN THE
MORNING AND THEY MAY PEE AND THE
PLACES THEY GO, THEY WENT AND
COLLECT TODAY AND THEY KNEW
WHERE TRI POOPED AND THEY KNEW
WHAT THE HLA GENES LOOK AT
LOS ANGELES.
THE MOST HOST GENOMES, ARE WITH
THE POST DOCTORAL STUDENTS AND
STUDENTS WERE ABLE TO IDENTIFY
HIV LIKE SEQUENCES SO CAN YOU
JUST IMAGINE WHAT PEOPLE WENT
THROUGH HERE'S HIV THAT'S FOUND
IN HUMANS A LOT EASIER TO
SEQUENCE AND HERE'S A BUNCH OF
CHIMP ICELETS, AND THESE CAME
FROM THESE DIFFERENT CHIMP PUB
POPULATIONS THE INTERESTING
THING IS THAT THESE LAST THREE
ALL HAD HIV LIKE SEQUENCES, AND
THIS VIRUS, THIS GROUP OF
CHIMPS, GEOGRAPHICALLY DISTINCT,
THOUGHT TO MIGRATED AWAY FROM
THESE FAMILY DICE PUT, WHATEVER
YOU WANT TO SAY ABOUT 10,000
YEARS AGO, THEY YET TO FIND THE
POPULATION, THOSE ARE HERE SO
THIS IS LIKELY THE SOURCE OF HIV
IN HUMANS, IT'S LIKELY THE FACT
THAT HE'S AN WILLS, THESE CHIMPS
LIVE CLOSE TO HUMANS.
SO I'LL SKIP THAT IN THE
INTEREST OF TIME AND HOW DOES
ONE GET INTO THE OTHER.
SO THIS BUSH MY TRADE IN WEST
AFRICA IS THOUGHT TO BE THE
MECHANISM.
NOW PRIMATE VS BEEN EATING
PRIMATES IN AFRICA FOR THOUSANDS
OF YEARS, AND I THINK THIS
PROBABLY HAS BEEN HAPPENING FOR
THOUSANDS OF YEARS.
RIGHT?
OCCASIONALLY ONE VIRUS WILL JUMP
OVER INTO A DIFFERENT SPECIES
AND IN OUR CASE, WE THINK THAT
IT STARTED WITH PEOPLE LIKE
POACHERS, ALL RIGHT, SO YOU KNOW
FINDING THAT ANIMAL IS NOT
ALWAYS AS CLEAN AS IT LOOKS LIKE
HERE.
IT CAN BE A VERY VICIOUS AFFAIR.
IT'S CERTAINLY OPPORTUNITY IT IS
FOR TRANSMISSION OF A LOT OF
BLOOD AND BODY FLUIDS.
AND THEN ONCE THESE GET TO A
BUTCHER, OR A CHOP HOUSE,
THERE'S MORE OPPORTUNITY THAT
THE BLOOD FROM THE ANIMAL MAY
COME INTO CONTACT WITH MUCUS
MEMBRANES OR CUTS FROM HUMANS.
AND THEN IT GETS SOLD IN BUSH
MEAT MARKETS AND USED IN THE
HOME AND IN THE RESTAURANTS AND
HORRIBLE THINGS LIKE THIS BUT
THAT SEEMS TO BE AT LEAST A
PLAUSIBLE SO THE VIRUS IS
PROBABLY CIRCULATE NOTHING
HUMANS FOR ACTUALLY QUITE A
WHILE.
BUT HOW DOES IT PROP GATE, AND
PROP GATING, I THINK YOU KNOW
THOUGH, THE BIOLOGICAL METHODS
FOR GETTING THE VIRUSES TO USE
THE BLOOD AND BODY FLUIDS AND
MOTHER TO CHILD, BUT THEN WHAT
ABOUT THE NONBIOLOGIC METHODS,
BY HOW A VIRUS CAN SPREAD IN A
POPULATION.
AND I THINK THESE ARE POLITICAL
ECONOMICS OR AT LEAST THEY'VE
BEEN REPORTED TO BE POLITICAL
ECONOMIC AND FINDING OF MULTIPLE
EPIDEMICS SO HERE, I THINK THIS
IS--THIS IS A LITTLE VAGUE, BUT
HERE'S THE MAP OF AFRICA, IN
SOMETHING LIKE THE EARLY 1800S.
AND THEN THE LATE 1800S AND THEN
THE 1960S AND IT'S THE RESULT OF
A HUGE UPHEAVAL OF PEOPLES IN
DIFFERENT PLACES, LOTS OF WAR,
LOTS OF ARMIES MOVE NOTHING
DIFFERENT PLACES AND LOTS OF
PEOPLE DISRUPTED AND A
TREMENDOUS AMOUNT OF
MALNUTRITION, MALNUTRITION BY
ITSELF IS IMMUNO SUPPRESS ANT
AND I THINK A LOT OF PEOPLE
SUGGEST THAD HAVING A GROUP OF
PEOPLE, A LARGE NUMBER OF PEOPLE
CONCENTRATED IN AN AREA, MORE
AND MORE INDIVIDUALS LIVE
NOTHING ONE PLACE THAT MIGHT BE
RELATIVELY IMMUNO DEFICIENT WERE
FEATERILE GROUND FOR THE SPREAD
OF A ZOOA NOTTIC EVENT OCCURRING
ALL THE TIME JUST LIKE
SPREADING.
ALTHOUGH THAT'S ONE--I DON'T
KNOW, IT'S JUST ONE FEASIBLEt(
MECHANISM.
THIS WAS ONE OF THE OTHERS, THE
TRANSAFRICA HIGHWAY THAT WAS
BUILT IN FROM THE MIDDLE 60S,
FROM THE 70S, YOU THINK OF THE
HIGHWAY, IT LOOKS LIKE 270, IT
LOOKS JUST LIKE THIS.
IT'S PUNCTUATED WITH VILLAGE IT
IS AND STOPS ALONG THE WAY WHERE
PEOPLE TRAVEL GREAT DISTANCES
AND HAVE OPPORTUNITIES TO SPREAD
THE VIRUS IN VARIOUS PLACES.
SO IT SPREAD FROM AFRICA,
THROUGH ALL HABITED CONTINENTS
AND TO THE UNITED STATES,
PROBABLY THROUGH A COUPLE OF
PLACES, THE MOST CRITICAL WAS
PROBABLY HERE, AND THEY USED
FILE O GENETIC TECHNIQUES TO GET
THE VIRUS AND THE EARLY ESTHE
COULD FIND IN DIFFERENT PLACES
AND THE EARLY ESTARE STILL
YOUNGER THAN THE EARLIEST ONES
WHICH ARE YOUNGER THAN THE
EARLIEST ONES IN AFRICA.
AND IT'S LIKELY THAT THE VIRUS
MADE A COUPLE OF STOPS ON THE
UNITED STATES, AND IMPORTANT ONE
IN HAITI.
NOW THESE ARE DATA YOU'RE MORE
FAMILIAR WITH IN 1983, FOUND
HERE WHERE THESE POINTS ARE IN
JUST A FEW CASES AND THEN WITH
TIME, THESE ARE DATA FROM THE
CDC, IT INCREASED BY 1989, ABOUT
A HUNDRED THOUSAND CASES OF AIDS
ONCE AGAIN THIS LOOKS LIKE IF
YOU WERE FLYING OVER THE UNITED
STATES, THESE ARE THE
METROPOLITAN AREAS AND AS I
MENTIONED BEFORE, WITH TIME
THIS, IS SPREAD OUT NOW INTO
MUCH MORE OF THE REST OF THE
COUNTRY, WITH RETROVIRAL THERAPY
THERE'S BEEN VAST IMYOU
PROVEMENTS, AND HOW LONG PEOPLE
WILL LIVE.
AND SO, THE NUMBER OF CASES
CONTINUES TO INCREASE BECAUSE
THE NUMBER OF PEOPLE WHO DIE
FROM THE DISEASE ARE DECREASING
BECAUSE OF ANTIRETROVIRAL TERM.
I WANT TO TAKA THE LAST FEW
MINUTES TO TALK ABOUT THE OTHER
RETROVIRUS, HUMAN T-CELL
LEUKEMIA VIRUS, BECAUSE IT WAS
COMPLETELY DIFFERENT IN ITS
GENETIC COMPOSITION, MUCH
DIFFERENT THAN THESE
LENTIVIRUSES FROM ITS INTRUSION,
IT'S FOUND HIGHLY CONCENTRATE
INDEED A COUPLE OF PLACES.
NOTED HERE IN RED, THE
CARIBBEAN, CENTRAL AFRICA, FAR
EAST.
AND SO IN CENTRAL ASIA, SO A
VERY DIFFERENT KIND OF VIRUS
CONCENTRATED IN A VERY DIFFERENT
KIND OF WAY.
AND I KNOW WHAT YOU MUST BE
THINKING AND THEN--THAT--THAT'S
FINE BUT THAT'S JUST A COUPLE OF
CASES AND IF WE REALLY DON'T
CARE TYPICALLY.
THE INTERESTING THING IS THE
NUMBER OF PEOPLE INFECTED WITH
HTLV IN THE WORLD IS COMPARABLE
TO THE NUMBER OF PEOPLE INFECT
WIDE HIV IN THE WORLD.
IT'S SOMEWHERE AROUND 30
MILLION.
28, 30 MILLION.
WHY DON'T WE HEAR MORE ABOUT
THIS VIRUS.
I WANT TO HEAR MORE ABOUT HTLV,
WHEN WE HEAR ABOUT HIV, 33
MILLION MAY BE INFECTED, IF YOU
DON'T TREAT THEM, 32 MILLION
900,000 OF THEM ARE GOING TO
DIE, THEY'RE GOING TO BECOME
IMMUNO DEFICIENT EXCEPT FOR A
FEW INDIVIDUAL WHO IS CAN
CONTROL THE VIRUS NATURALLY.
WITH HTLV, IT'S ALMOST EXACTLY
THE OPPOSITE.
WE HAVE 30 MILLION PEOPLE
INFECTED BUT 95% OF THEM SPEND
THEIR ENTIRE LIVES AND NEVER
HAVE A PROBLEM.
AND IT'S THE FIVE% THAT HAVE
COMPLICATIONS.
SO, A VERY COMMON VIRUS, WITH AN
UNCOMMON PATHOGENIC
CONSEQUENCES.
THIS GEOGRAPHY, HISTORY,
MOLECULAR BIOLOGY AND A LOT OF
THIS, HAND WAVING, THE FACT IS
THIS IS FOBBED IN RELATIVELY
HIGH CONCENTRATIONS, AND
DIFFERENT AREAS BECAUSE PEOPLE
THINK IT MAY HAVE TO DO WITH THE
SPREAD AND OF PEOPLES AFTER THE
DISCOVERY OF THE NEW WORLD, BUT
HONESTLY, I DON'T THINK
ANYBODY'S GOT A DOUBT, IF
ANYBODY DOES IT'S PEOPLE HERE AT
THE NIH, JILL SLATTERY BEING ONE
OF THEM.
BUT ONE INTERESTING FACET, THIS
IS ONE OF THE CELLS, THE KIND OF
CELL THAT'S CALLED A FLOWER
CELL, THAT'S ACTUALLY INFECTED
WITH THLB ONE.
AND YOU CAN FIND IT IN
INDIVIDUAL WHO IS ARE INFECTED
AND MOST OF THE TIME IT'S THERE,
AND IT DOESN'T DO ANYTHING.
BUT, THERE ARE TWO CIRCUMSTANCES
WHERE IT STARTS TO CAUSE
TROUBLE.
THE INTEGRATION CAN PRACTICES
DUCE GENE PROTEIN CALLED TACKS
AND THAT CAN CAUSE UNCONTROLLED
GROWTH OF OF THESE INFECTED
CELLS, AND CAUSE AN ACUTE T-CELL
LEUKEMIA AND OTHER PULMONARY
DISORDERS, AVOWELAR PROCESSES,
SO THE VIRAL AFFECT IN ONE
DIRECTION OF THIS PROTEIN IS TO
TURN ON CELL REPLICATION AND
CAUSE LEUKEMIA.
THE SAME PROTEIN, RIGHT CAN BE
THE SOURCE OF A HOST IMMUNE
RESPONSE, AND THOSE IMMUNE
SYNDROMES DIRECTED AGAINST THE
VERY SAME PROTEIN CAN CAUSE AN A
COMLITELY INDEPENDENT KIND OF
PATHOGENESIS.
IT CAUSES A NEUROLOGIC DISEASE
CALLED TROPICAL PASTIC
COMPARASIS.
COMPLETELY DIFFERENT FROM
LEUKEMIA, HERE BEING--BEING A
REPLICATION GENE PRODUCT,
CAUSING THE CELLS TO REPLICATE
AT A VERY HIGH RATE AND IN THIS
CASE, THE IMMUNE RESPONSE TO THE
VERY SAME PROTEIN THAT CAUSES
THIS--THIS DISEASE AND SOME
OTHERS.
SO IT'S AN INTERESTING
DEMONSTRATION OF TWO INDEPENDENT
PATHOGENIC EVENTS HAPPENING IN
THE SAME VIRUS AND
HERE'S--HERE'S JUST WHAT THE
T-CELL LEUKEMIA LOOKS LIKE, IT'S
A CD4 EXPANDED CELL POPULATION,
YOU CAN SEE STAINED HERE, IN
BROWN OR HERE IN SKIN AND YOU
CAN VISUALIZE THAT HERE AT THE
NIH, WITH JUST ACCUMULATIONS IN
THE CELL.
SO A VERY DIFFERENT TYPE OF
DISEASE.
SO FOR SOME LESSON, WHETHER YOU
CAN SEE THIS OR NOT, VIRUSES ARE
BAD FOR YOU AND SHOULD BE
AVOIDED, YOU DIDN'T NEED TO COME
HERE TO HEAR THAT EXCEPT MAYBE
WHEN THEY SAVE YOU FROM THE
PLANET AND THE NEXT VIRUS.
EPIDEMICS ARE STUBBORN THINGS,
THEY'RE NOT ALWAYS SIGNAL
EFFECTS AND THEY MATURE AND
THEY'RE NOT SPECIFIC BY VIRUS
CLASS, AND I WANT TO COME BACK
TO THAT VERY--THAT VERY FIRST
QUESTION THAT I ASKED, WHAT THE
WORST EPIC IS, AND WHEN
YOU--WHEN YOU--YOU SOAK YOURSELF
IN STUFF LIKE THIS, THE NEXT
STEP, THE WORST EPIDEMIC MIGHT
BE THE ONE YOU HAVEN'T SEEN YET,
SO IT MIGHT BE THE NEXT ONE
COMING.
IF THE LESSON OF TRIM FIVE ALPHA
IS THAT WE'RE ALWAYS FIGHTING
THE LAST WAR, THEN I DON'T KNOW
WHAT THE NEXT ONE IS.
BUT I KNOW THAT LEARNING ABOUT
THIS ONE WILL HELP US CONTROL
AND PERHAPS PREVENT THE NEXT
ONE.
SO I'LL STOP THERE.
[ APPLAUSE ]
>> [INDISCERNIBLE].
>> OKAY, SO I THINK THE ANSWER
TO THAT IS YES.
AND HERE'S THE DATA.
SO THERE ARE A COUPLE OF HAPPY,
THINGS ABOUT IT, IN THE 1950S
THERE WAS THIS SAILOR, RIGHT?
IT'S A SAILOR; THERE WAS AN
UNUSUAL DISEASE, BUT THIS
PARTICULAR GUY WAS A DOCTOR WHO
SAID, I DON'T KNOW WHY, BUT I'M
GOING TO FREEZE THIS MAN'S
BLOOD.
AND SO, IT WAS FROZEN FOR ABOUT
30 YEARS.
40 YEARS AND SOMEBODY WENT BACK
AND SOMEBODY REMEMBERED, THIS IS
THE LUCK SCHETHE MIRACULOUS
RIGHT.
SOMEBODY REMEMBERED AND SOMEBODY
COULD FIND IN A FREEZER.
YOU GOT FREEZERS CAN YOU FIND
EVERYTHING?
SO SOMEBODY REMEMBERED, SOMEBODY
COULD FIND IT AND THEY TEST
TODAY AND IT HAD HIV.
RIGHT?
THE SECOND THING IS,--AND HE
WENT BACK TO BLOCKS MUCH
LYMPHOMAS THAT HAD BEEN
DIAGNOSED IN THE 1960S, SO THEY
WERE EMBEDDED IN PARAAND I KNOW
THEY SCRAPED THEM AND EXTRACTED
THE NUCLEIC ACID AND WAS VERY
SURE HE DIDN'T GET CONTAMINATION
AND FOUND THAT IF HIGH LOOKED AT
ENOUGH OF THEM, HE FOUND A FEW
OF THOSE LYMPHOMAS, BECAUSE HIV
IS ASSOCIATE WIDE LYMPHOMAS, HE
FOUND A FEW OF THEM HAD CELLS
THAT HAD HIV SEQUENCES IN THEM
AND THOSE HIV SEQUENCES WERE
DIFFERENT FROM EACH OTHER AND
DIFFERENT FROM THE DIVERSITY,
THAT THE VIRUS WAS AROUND
[INDISCERNIBLE] AND GOOD ENOUGH
TO CAUSE ENOUGH TROUBLE THAT
GENERATED THETIC DIVERSITY WOULD
OCCUR.
SO, YOU KNOW, I GUESS I'M A
COMMERCIAL FOR SEQUENCING BUT I
THINK IT REALLY IS A VERY USEFUL
TECHNIQUES AND CERTAINLY THE
BIOINFORMATIC APPLICATIONS THAT
MAY BE MANY OF YOU PROBABLY USE,
ARE VERY USEFUL IN DATING THE
SEQUENCES AND ET CETERA.
>> OKAY, WE SHOULD BE MOVING ON.
>> YEAH, SORRY TO TAKE UP SO
MUCH TIME.
>> SO OUR NEXT SPEAKER IS
MUKESH VERMA, HE'S WITH THE
DIVISION OF POPULATION CONTROL
AND SCIENCES AND HE WILL DISCUSS
EPIY GENETICS.
--EPIGENERATEDETTICS.
--EPIGENETICS.
MUKESH?
>> OKAY, GOOD AFTERNOON, I'M
FROM THE TECHNOLOGY BRANCH AND
WE ARE LOCATED IN THE DIVISION
OF CANCER CONTROL AND POPULATION
SCIENCES.
DID THIS IS ONE OF THE NCIAs
SIX DIVIDENDS AND THE REASON I'M
SHOWING YOU BECAUSE WHEN I
EXPLAIN ABOUT EPIGENETICS, HOW
WE CAN UTILIZE THIS FOR CANCER
ACHIEVEMENT OR &  THAT IT IS
VERY FORTUNATE UNDERSTAND
EPIDEMIOLOGIC.
FEW MUST HAVE SEEN THE ARTICLE
IN TIME MAGAZINE EMICIZE TAG
ALTHOUGH DNA IS NOT EVERYTHING,
WHICH DECIDES WHAT WILL HAPPEN
IN TERMS OF DISEASE OR IN TERPS
OF ABNORMALITY.
AND AFTER I FINISH MYLICATURE,
YOU GO BACK, YOU CAN READ THIS
ARTICLE IN A STUDY FORM, VERY
NICELY, THEY HAVE EXAMPLES THAT
HOW EPIGENETICS WAS
ORIGINATEDDED AND HOW IT
AFFECTED.
AND IF YOU DON'T FIND THIS
ARTICLE, I CAN SEND YOU.PDF.
IN OUR PROGRAM, WHICH IS CALLED
ERGP, WITH THE GENETIC RESEARCH
PROGRAM OUR FOCUS IS TO
UNDERSTAND CANCER RADIOLOGY,
WHAT ARE THE CAUSATIVE EVENTS ON
ARE AND HOW WE CAN PREVENT
CANCER.
SWEE STUDY ABOUT INFECTIOUS
LIGANDS AND OCCUPATION FACTOR,
DIET, GENETIC AND EPIGENETIC.
SO IN MY TALK, I WILL COVER THE
MOLECULAR BASIS OF EPIGENETICS.
PROFILING ESPECIALLY TECHNOLOGY,
HOW IT IS DONE DONE, SOME
EXAMPLES FROM CLINICAL STUDIES.
IMPLICATION AND PERSONAL HEALTH,
PERSONAL EPIGENOMICS AND ABOUT
NIH INITIATED WHICH APPLIES ON
ALL INSTITUTES IN NIH AND NIH
ROAD MAP, NOW IT IS WE CALL IT,
NIH.
AND ONE--ANOTHER ONE IS INTERN
NATIONAL CONSORTIUM, THE GENOME
WAS COMPLETED FOR HUMANS, EAR
AND WE ARE TRYING TO COMPLETE
HUMAN EPIY GENOME.
ABOUT CANCER THIS IS A VERY
SERIOUS DISEASE.
INCIDENCE IS 1.5 MILLION AND
ABOUT HALF MILLION DIE WITH
THAT.
AND THAT RATE AND DIFFERENT
TIMES ARE SHOWN HERE SOME
PROGRESS HAS BEEN MADE AND
BREAST CANCER OR COLON CANCER OR
LUNG CANCER, WHERE SCREENING
TECHNOLOGIES ARE SEARCHED
BIOCHEMICAL ASSAYS OR GENETIC OR
EPIY GENETIC ALSO, SO PROGRESS
HAS BEEN MADE, FAMILIES YOU SEE
ALREADY ARE NOT READY FOR
CANCER, AND THEY'RE READY TO USE
THE SAME, 35,000 NUCLEUSES WILL
COME AND 35,000 WILL DIE.
WHAT ARE THE FACAs ACCOUNTORS
OVERALL IN CANCER?
TO [INDISCERNIBLE] AS YOU KNOW
NOT JUST LUNG CANCER ABOUT SOME
OTHER CANCERS THEY ARE AFFECTED.
DIET IS MAJOR.
ALCOHOL, OCCUPATION,
[INDISCERNIBLE] ARE ALSO THERE
AND TIME TO TIME I WILL GIVE
EXAMPLES HOW THEY AFFECT
EPIGENETIC MECHANISM.
TO DO ALL THE STUDIES WE NEED
DIFFERENT POPULATIONS ANYTIME,
WE DEVELOP A NEW TEST OR
SCREENING METHOD FOR THE DRUG,
WE WANT TO FOLLOW INDIFFERENT
POPULATIONS AND THESE ARE THE
ONES, WHICH FROM THERE, WE HAVE
COLLECTED SAMPLES.
FROM DIFFERENT COUNTRIES.
BECAUSE NATIVE HAWAIIAN, THEIR
LIFESTYLEçó AND EXPOSURE WILL BE
DIFFERENT THAN AMERICAN OR
ISHERISH GROUPS.
--IRISH GROUPS.
THESE ARE THE COUNTRIES WHICH WE
HAVE ABOUT 2.3 MILLION SUBJECTS,
AS WELL AS BIOLOGICAL SAMPLES,
IN OUR PROGRAM.
WE MAINTAIN COHORTS AND FAMILY
INDUSTRY, COHORTS ARE SUCH THAT
THE DISEASE IS NOT DEVELOPED BUT
YOU HAVE FAMILIARLY HISTORY, OR
ANY OTHER RELATED FORMATION AND
BIOLOGICAL SAMPLES AND WHEN THE
DISEASE IS DEVELOPED YOU CAN GO
BACK TO ALL SAMPLES, IF YOU USE
ONE BIOMARKER ASSAY AND SEE WHEN
INITIALLY SAW THAT, FOR THE
SYMPTOM WAS THE SIGN.
SIMILARLY MAINTAIN FAMILY, COLON
CANCER, BREAST CANCER, OVARIAN
CANCER AND DENDRITIC CANCER.
YOU HAVE ONE CANCER GENETIC
CANCER, THESE ARE SOME OF THE
EXAMPLES OF COHORT AND FEW VALID
STARTED QUITE EARLY, THIS IS THE
STUDY OR PHYSICIAN STUDY, SO
HERE, AFTER EVERY THREE OR FOUR
YEARS, PEOPLE WILL COME, THEY
GIVE THEIR BLOOD OR OTHER
SAMPLES THIS IS NOTED AND VERY
IMPORTANT FOR DEVELOPING OR
PREVENTION OF ACHIEVEMENT
STRATEGIES.
AND WHEN WE SAY WE HAVE AND THEY
STUDY GENE INVOLVEMENT
INTERACTION, THEY'RE
EPIGENETICALLY, THEY ARE
INDIFFERENT.
AND NOW YOU ARE HEARING ABOUT
GWAS, BECAUSE TECHNOLOGY HAS
COME TO THE STATE OF THE WHOLE
GENOME.
THE HAPLOTYPE TAG
[INDISCERNIBLE] SO THAT IS THE
REASON.
IN OUR PROGRAM, WE TRY TO
ENCOURAGE COLLABORATION AND FOR
THAT, WHAT OUR PROJECTS WE
SUPPORT, AND THEN
GIVING--YOUOGRAPHICALLY WE
SUPPORT THESE ALL HYPER LINKED
PROJECTS OR PROJECT NUMBERS,
PEOPLE CAN CLICK THERE AND THEN
FIND OUT WHO ALL ARE
INVESTIGATORS AND THEN YOU START
COLLABORATION AND THEN THERAPIST
IS ONE OF THE EXAMPLES OF A
LARGE COHORT, IT'S CALLED BREAST
AND PROSTATE CONSER, AND SON
SORTIA.
AND IN THE SIXTH COHORT, NOT
ONLY FROM U.S., LIKE HOW OR
AMERICAN CANCER SOCIETY, BUT
FROM EUROPE ALSO, COHORT IS
THERE AND THIS INVESTIGATOR
ITSELF COLLECT SAMPLES FROM THE
COUNTRIES AND THEN WE PUT
TOGETHER AND THEN WE MADE
DIFFERENT CHEMICALS AND WE MEET
EVERY SIX MONTHS AND THEN YOU
STUDY THE PROGRESS AND THAT'S
ALL THESE KINDS OF PROGRAMS AND
SOME OF SEARCH PROGRAMS AT NCI
OR NIS LABELS I HAVE SHOWN HERE
AND FOR ALL OF THESE THAT THESE
SAVE A LOT OF TIME AND RESOURCES
SO BEFORE THEY ARE INITIATED
THEN WE HAVE TO HAVE A LOT OF
DISCUSSION AND SEE WHAT WILL BE
THE POSSIBLE OUTCOME AND LATER
ON I WILL GIVE YOU EXAMPLE OF
NIH ROAD MAP OF EPIGENOME AND
HOW THEY ARE STARTED AND WORKING
IN THAT.
CONCERN NOW COMING TO
EPIGENETICS AS YOU KNOW, DNA
SURROUNDED BY PROTEIN HISTONES
AND NONHISTONE PROTEINS AND IN
NUCLEOSOMES, WE HAVE HISTONE
PROTEINS OF STWOA, S-TWO B AND
S-FOUR.
AND THESE PROVIDE JOBS SO THAT
DNA CHARGE IS NEUTRALIZED IN THE
ABILITIES THERE.
ANYTIME, ESPECIALLY IN CANCER
DEVELOPMENT, GENOMIC
INSTABILITYS IS THE KEY WHICH IS
STARS, ABNORMAL SEQUENCES.
SO YOU HAVE GENETIC CODE, WE
HAVE THE SEQUENCE WHICH IS
DETERMINED WHAT WILL HAPPEN.
BUT TWO MORE CODES ARE THERE.
MATURATION CODE AND HISTONE CODE
AND THEN, EPIGENETIC COMES, AND
THEN I WANT TO EMPHASIZE THAT
GENOME HA DOES IT TELL, IT TELLS
WHAT YOU CAN DO, WHAT IS YOUR
POWER, WHEN SOMETHING SHOULD BE
DONE, WHEN IT SHOULD BE STOPPED
AND HOW THIS CAN BE USED, THAT
IS BY EPIGENETIC.
AM SO GENETIC MISSION PROVIDES
ONLY BLUEPRINT FOR MANUFACTURING
OF PROTEINS BUT THEN IT WILL BE
SYMPATHIZED IN THE EPIDEN
GENETICS, THESE ARE CHANGES IN
GENE EXPRESSION BUT WITHOUT
CHANGING DNA SEQUENCE.
SO ORIGINALLY PEOPLE TAUGHT ALL
DISEASES AND YOU START WITH
MUTATION OR SNP OR TRANSLOCATION
OR DELETION OF THOSE CHANGE, BUT
LATE OR WITHOUT THOSE CHANGES
ALSO, GENE EXPRESSION CAN ALTER
AND DISEASE CAN DEVELOP.
MAIN COP PONENT OF EPIY GENETIC,
IS MATURATION AND PROMORT REGION
AND FOR THAT, DIFFERENT AND OUT
THERE, THE DNA ENZYMES AND THEY
HAVE DIFFERENT FUNCTIONs AS
WELL, SOME INITIALIATE
MATURATION AND SOME MAINTAIN
METHYLATION.
SIMILARLY HISTONE MODIFICATION,
SEVERAL OF THEM HAVE BEEN
REPORTED AND NONCODING RNA, THEY
ARE ALSO ENROLL INDEED THIS
EPIGENETIC PROCESS.
GENOMIC IMPRINTING IS ALSO PART
OF THAT EITHER FROM
[INDISCERNIBLE], EITHER
[INDISCERNIBLE] THE INFORMATION
COUNTS AND THAT IS ONLY LIMITED
BY EPIGENETICS.
MOST HAS BEEN DONE ON
METHYLATION AND HISTONES AND
MICRORNA ALSO I WILL GIVE YOU.
SO WHOLE HOST FACTOR AND
ENVIRONMENTAL FACTOR, LIFESTYLE
FACTOR OR GENETIC SUSEPTIBLE,
ALL THOSE CAN CONTINUE TO
GENOMIC INSTABILITY, EITHER BY
GENETIC PATHWAY THROUGH
MUTATIONS AND GENETIC ALTERATION
OR EPIY GENETIC CHANGES BUT ALL
OF THEM CONTINUE TO DEVELOPMENT
OF CANCER.Ñi
IN GENERAL, THEY ARE DEVELOPED
OF AGE, BUT IN SPECIFIC REGIONS,
ESPECIALLY PROMOTER, UC HYPER
METHYLATION, OFF SPECIFIC GENES
AND HISTONES ALSO ARE MODIFIED.
AND THIS IS GIVEN ONE OF THE
EXAMPLE IN THE SKIN CANCER, FOR
DIFFERENT CANCERS LIKE
[INDISCERNIBLE] BREAST CANCER
COLON CANCER AND LEUKEMIA, THOSE
GENE VS BEEN ISHES DENTIFIED AND
THEY ARE THE KEY GENES WHICH
CONTINUE TO THEIR DRIVE DRIVE
THOSE CANCERS.
TO MAKE A POINT THAT
GENERATEDETTIC EPIY GENETIC'O HOW
THEY ARE IMPORTANT AND
DIFFERENT, THE STUDY IS IN
MENOZYGOTTIC TWINS AND DNA IS
EXACTLY THE SAME THEN THE TWINS
ARE FOLLOWED AND EVEN 400 OR 450
TWINS THEY WERE FOLLOWED AND
DIFFERENT DISEASES WERE
DEVELOPED SO THAT MADE A POINT
THAT EPIY GENETICS AND GENETICS
ARE DIFFERENT.
SO THESE CHANGES, THEY'RE
WITHOUT ANY CHANGES, DNA CODING
SEQUENCE, THEY HAPPEN QUITE
EARLY.
WHEN THE STUDY VS BEEN DONE IN
STEM CELLS OR THIS CELL IS FROM
TO TO FOUR OR 16 OR 18, THAT
TIME THERE ARE NO MUTATIONS O
THAT IS GRADUALLY, THE MARKET
START DEVELOPING.
THOSE CHANGES ARE NEEDED FOR
NORMAL DEVELOPMENT BUT IN CANCER
THOSE ARE ABNORMAL, SINCE
EPIGENETICS HAVE BEEN STUDY
INSIDE CANCER AND ALERT DISEASES
ALSO, SO IN SOME DISEASES,
STRONG GENETIC INFLUENCES THERE
ESPECIALLY MENTAL DISORDERS.
BUT IN CANCER AND OTHER
DISEASES, EPIGENETIC IS
DOMINATING CAUSATIVE FACTOR.
AND THEN THIS IS THE ONE WHO HAS
DONE THIS STUDY AND HE FOLLOWED
GLOBAL AND LOOK AT THESE OR DNA
ORIGINAL HISTON ACETYLATION AND
THEN, BECAUSE OF HIS STUDIES AND
FOLLOWED BY SOME OTHER STUDIES,
IT WAS APPRECIATED EPIGENETICS
MOVE.
WORK NOTHING THE LATE 90S OR
DECADE ON THE EPIGENETICS HAS
COME UP TO THAT EXAT THE PRESENT
TIME THAT WE ARE [INDISCERNIBLE]
TO THAT.
ENVIRONMENT PLAY A ROLE IN
CANCER, ONLY 10-15% CANCER.
ALL OF THAT HAS HAS TO BE BY
INVOLVEMENT AND SOME GENETIC
CHANGES YOU SEE, MORE THAN 40%
GENE CELL REGULAR EPIGENETICALLY
AND ENVIRONMENTAL CARC NO
GENERATED, SUCH AS ARSENIC, ALL
THOSE AFFECT METHYLATION AS WELL
AS HISTONE METHYLATION.
[INDISCERNIBLE] METHALATED FORMS
OF DIFFERENT TOX ISOTOPEIT AS
WELL AS DIFFERENT EFFECT ON
EPIGENETIC METHYLATION.
AND OTHER PARTIES THAT SOME
CHANGES WHICH ARE ESPECIALLY
HISTONE CHANGES, YOU CAN INDUCE
TRANSFORMATION THEN BY SOME
DRUGS THAT CAN BE REVERSED ALSO
AND THAT HAS MORE IMPLICATION IN
CLINICS.
SOME CHANGES DUE TO INVOLVEMENT
OR OTHER, THEY ARE MOST
PERMANENT, SOME ARE DYNAMIC OR
THEY ARE TRANSIENT, SO MOSTLY
MUTATION, DELETION
AMPPLIFICATION, AND CHANCE
LOCATION, THEY COME UNDER
GENETICS, THESE ARE
[INDISCERNIBLE] BUT SOME ARE
ABNORMAL FEATURE IS THERE OR ANY
EXPOSURE IS THERE, THEN FIRST TO
SELL, DEACTIVATE IN SUCH A WAY
THAT TRANSCRIPTION FACTOR IS
SUCH CHANGES, CHANGE AND THEN,
EPIGENETIC CHANGE, OCCUR AND IT
IS MUCH LATER THAN GENETIC
CHANGES HAPPEN BECAUSE IT IS
GOOD TO UNDERSTAND THOSE FACTORS
WHICH AFFECT EPIGENETICS BEFORE
THEM AND SEE WHETHER SOMETHING
CAN BE DONE IN THIS FIELD.
IN THE DNA, SOME SEQUENCES ARE
VERY COMMON.
THEY ARE G-C-FOLLOWED BY G AND
ANYTIME IN ABOUT [INDISCERNIBLE]
60%, CGC SEQUENCES ARE THERE,
THOSE OF COURSE, CPG IRELAND AND
THOSE BY HYPER METHYLATION OF
THOSE BECAUSE MUCH THE INN ZYME
THEY GET HYPER METHALATED AND
THEY RESULT IN ACTIVATION OF
GENE AND ONE EXAMPLE IS THE
TUMOR SUPPRESSOR GENE.
AT THE SAME TIME INN SOME DNA,
THE [INDISCERNIBLE] HAS ALREADY
METHALATED AND THEY GET
HYPOMETHYLATED AND THEN IT
CAUSES VIRUS GENES AND DUE TO
HYPOMETHYLATION, THEY GET
ACTIVATED SO BOTH WITH
METHYLATION IS DANGEROUS FOR
CANCER BECAUSE TUMOR SUPPRESSOR
GENES WE WANT ACTIVATED AND ONCA
GENES WE WANT DEACTIVATED.
JONES AND FINE BERG, THEY ARE
THE [INDISCERNIBLE] IN THESE
INITIAL HYPOTHESIS AND WORK AND
THEY WAY THEY PROPOSE THIS STEP,
INITIALLY CHROMATIN IS ACTIVE
AND HAPPENING BUT WHEN
DEACETYLATION OF HISTONE,
SPECIALLY ON S-THREE HISTONE,
LYSINE NINE, IT RECRUITS SOME OF
THOSE PROTEINS WHICH CAN DO
HISTONE METHYLATION AND THEN IT
WILL RECRUIT SOME
METHYLTRANSFERASE GENES AND IF
YOU WANT TO SEE, THIS NUCLEUS
ARE QUITE APART IN ACTIVE STAGE
WHERE TRANSCRIPTION FACTORS ARE
FURTHER PROTEINS THEY CAN GO IN,
BUT LATER STAGES IT BECOMES VERY
COMPACT.
AND THEN IT IS COMPACT AND
TRANSCRIPTION IS STOPS AND IN
THAT--I HAVE SHOWN METHYLATION,
SPECIFIC GENE METHYLATION STARTS
AND AT THE SAME TIME,
DEACETYLATION OF HISTONES, THAT
ALSO OCCURRED AND ALSO OF THESE
TOGETHER, GRATTUALLY THEY RESULT
IN ACTIVATION OF GENES SUCH AS
TUMOR SUPPRESSOR GENES.
WHAT ARE THE STEPS, EPIGENETIC
[INDISCERNIBLE], ALMOST ALL WHAT
IS IN CANCER, LIKE CELL CYCLE
DNA APOPTOSIS AND EX-CHROMOSOME
AND ACTIVATION AND IN AGE ALSO
WE SEE.
ENVIRONMENT, HEART, LUNG,
GENETIC ALL THESE CONTRIBUTE TO
THESE PROCESSES.
AS A RESULT OF HYPOMETHYLATION,
THOSE TUMOR SUPPRESSOR GENES GET
ACTIVATED AND THOSE GET
ACTIVATED AND IN HISTONE, THEY
GET DEACETALATED IN WHICH
ENZYMES LIKE HISTONE ACETYL
TRANSFER AS ACE OR THOSE AND A
[INDISCERNIBLE] IS NEEDED FOR
GENOMIC INSTABILITY.
FROM NCI, WE PUBLISHED CANCER
BULLETIN EVERY TWO WEEKS IN THAT
TIME FRAME, THOSE TOPICS ARE
COVERED, EPIGENETICS COVERED TWO
TIMES AND I WANT TO EMPHASIZE
HERE THAT IN MUTATION IF YOU SEE
SOME CHANGES, YOU CANNOT REVERSE
THAT.
BUT EPIGENETIC CHANGES,
METHYLATION AND HISTONE CHANGES,
THOSE YOU CAN REVERSE, SO THAT
IS THE--ADVANTAGE WE WANT TO
TAKE FOR THE ACHIEVEMENT OF
CANCER OF PREVENTION AND CERTAIN
ANIMAL MODELS HAVE BEEN
DEVELOPED.
WE ARE JUST CHANGING DIET OF
FOLLOWING EPIGENETIC CHANGES,
LOTS OF PHENOTYPIC AND OTHER
CHANGE CHANGES YOU CAN SEE IN
THOSE ANIMALS.
AND THEN, YOU CAN UTILIZE THOSE
MODELS TO UNDERSTAND NOT ONLY
THE CANCER MECHANISM, BUT
IDENTIFY VECTORS WHICH
CONTRIBUTE TO CANCER.
SO CANCER EPIGENETIC SYSTEM
IMPORTANT FOR PREVENTION BECAUSE
WE MAY BE ABLE TO USE
METHYLATION MARK TO IDENTIFY
PEOPLE AT RISK FOR CANCER AND
PERHAPS DETECT CANCER EARLIER.
SO IN THIS PROCESS, EACH TRAND
ONE BY ONE GETS METHALATED AND
THAT MEZZANINE IS DONOR
[INDISCERNIBLE] THESE KINDS OF
PRODUCTS ARE DONE IT'S ESSENTIAL
THAT [INDISCERNIBLE] ARE
SEQUENCED.
AND TECHNOLOGY WISE, DNA IS
TREATED WITH BISULFIDE AND WHAT
HAPPENS IS THAT CYTOSWINE AND
METHYL CYTOSWINE DEHAVE
DIFFERENTLY AND YOU CAN IDENTIFY
THAT WHICH CHANGES ARE THERE AND
GO BACK TO SEE THE SEQUENCE.
AND CYTOVENE AFTER ACHIEVEMENT,
IT WILL BEHAVE LIKE CAD WHAT.
SO C-BINDING WITH G, YOU CAN
BIND WITH A SO THAT IS THE
CHANGE THERE THAT YOU CAN
IDENTIFY WITH THE CYTOSWINE.
DIFFERENT TECHNOLOGIES ARE USED
TO MEASURE METHYLATION LIKE YOU
CAN DO PC R OF THE PRODUCT.
OR, METHYLATION SPECIFIC PC R,
YOU CAN IDENTIFY THOSE REGIONS
WHERE METHYLATION SEQUENCES ARE
THERE, AND YOU CAN IDENTIFY
REALTIME METHYLATION ALSO CAN BE
FOLLOWED.
IT DEPENDS WHICH KIND OF
EXPERIMENT IS THERE, HOW MANY
SAMPLES ARE THERE.
HI-THROUGH PUT TECHNOLOGIES
DEVELOPED SO NOW NANO CHIPS ARE
MOST OF THE STEPS ARE AUTOMATIC
AND LARGE NUMBER OF SAMPLES YOU
CAN ANALYZE FOR THAT.
IN SOME PROJECTS SOME
INVESTIGATOR THEY DON'T HAVE
ACCESS, THEY DON'T HAVE THE
TECHNOLOGY SO SOME CUTCHES ARE
ALSO THERE.
THEY DO ROUTINELY THOSE KINDS OF
PROGECS AND EPIDEMIOLOGICAL
STUDIES, THERE'S A LARGE NUMBER
OF SAMLES ANALYZED, THEN THESE
PROJECT K'S BE DONE BY
COLLABORATION OR BY GETTING
CONTRACTS SO I HAVE GIVEN THOSE
NAMES OF COMPANIES, WHERE THIS
IS DONE ROUTINELY.
AND THEN A RESEARCH EXPERIMENT
ARE DESIGNED, THEN YOU HAVE TO
THINK ABOUT METHYLATION CONTENT,
HOW MUCH IS THERE, AS WELL AS
METHYLATION LEVEL AT SPECIFIC
GENES, METHYLATION PATTERN OF
GROUP OF GENES, OR PROFILE OF
METHYLATION OF SPECIFIC GENE OR
A NUMBER OF GENES AND PATTERN OF
CO METHYLATION.
AND THIS--WE DO, TO REDUCE
FALSE-NEGATIVE AND
FALSE-POSITIVE RESULTS.
THIS IS THE ACTIVE FORM, THOSE
ARE IDENTIFIED AND THIS IS AT
JOHNS HOPKINS, THEY ARE THE
PIONEER IN THIS KIND OF WORK AND
WHEN IT IS ACTIVE YOU SEE THESE
IN THE ZONES.
THOSE PROTEINS HAVE ALSO BEEN
IDENTIFY THED LIKE THE COM--IEKS
DENTIFIED LIKE THE COMPLEX AND
THEY ARE [INDISCERNIBLE] AND
ANYTIME, IN SK327, IT'S TRI
METHALATED AND POLYCHROME THE
COMPLEX GETS ACTIVATED.
AGAINST THESE PROTEINS WHICH
HAVE BEEN IDEBTIFIED, IN THE
DESIGN BECAUSE IF WE CAN INHIBIT
THOSE, THEN EPIGENETIC PROCESS
CAN BE STOPPED.
AND FOR SOME KEY ENZYMES AND KEY
PROTEINS, THOSE STRUCTURES
WHEREVER ANY OF THOSE WILL BE
DESIGNED, THAT HAS BEEN
IDENTIFIED AND MANY
PHARMACEUTICAL COMPANIES LIKE
MERCK, GLAXOSMITHKLINE AND
JOHNSON &  JOHNSON.
THEY HAVE STRONG PROGRAM, AND
HISTONE OR ANY RETURNS.
SO IN METHYLATION AS I
MENTIONED, THREE POSSIBILITIES
CAN HAPPEN, EITHER ABNORMAL
INCREASE, ABNORMAL DECREASE OR
NO CHANGE.
IN ABNORMAL INCREASE AS IN TUMOR
SUPPRESSOR GENES EITHER BOTH
INSIDE METHALATED OVER ONE OR
ONE METHODALATED AND OTHER
METHALATED ALL BY IMPRIPTING
ALSO, IT CAN HAPPEN.
WHEN THE DECREASE IS THERE,
PROTOONCA GENES GET ACTIVATED
AND THEY GET ACTIVATED.
ESPECIALLY LDL REGION IN
RETROVIRUSES AND THE DNA OR
ANEUPLOIDY, AND SOMETIMES
CHEMICALLY ALSO THIS EITHER
REPAIR WILL BE POOR ORIGINAL
DE-AMMUNITION OF BASIS THERE AND
SO ALL OF THIS IS BY WHICH
METHYLATION OFF GENE IS
AFFECTED.
IN CANCER TAKES MANY, MANY YEARS
BY THE TIME YOU SEE FULL CANCER
ESPECIALLY OFF MEASURE CANCERS.
THE COLON PROSTATE AND LUNG, SO
IN THESE 14-18 YEARS, WE WANT TO
IDENTIFY THOSE CHANGES WHICH ARE
QUITE EARLY.
GENETIC CHANGE VS BEEN
IDENTIFIED BUT EPIGENETICS THEY
OCCUR MUCH EARLY SO FOCUS IS TO
IDENTIFY THOSE, AND PROTEIN
EPIDEMIOLOGY STUDY
[INDISCERNIBLE] ALSO AND THEN WE
WANT TO FOLLOW THE ACHIEVEMENT
IS WORKING OR NOT, SO THE DRUG
RESPONSE IS CHANGES IN WHATEVER
HAPPENED LATER ON, SO THOSE ARE
ALSO IMPORTANT AND FOLLOWED.
MOST OTHER TIME, IN RESEARCH AND
CLINIC, EITHER GENETIC OR ONCA
SELL USE, BUT NOW EPIGENETIC
MARKETERS ARE ALSO COMING UP F
CERTAIN WHY WE WANT TO USE THEM
BECAUSE TECHNOLOGY EXISTS WHERE
WE CAN USE THESE ASSAYS OR
MARKERS WHICH HAVE BEEN
COLLECTED PREVIOUSLY AND AS I
MENTIONED IN EPIDEMIOLOGY, WE GO
BACK TO THE SAMPLES WHEN DISEASE
IS NOT DEVELOPEDDED AND WE WANT
TO ADENTIFY WHAT WERE THE FIRST
INITIAL MARKS BASED ON THAT
ONLY, DIAGNOSIS AND PROGNOSEIS
IS DESIGNED.
IN SELECTED CANCERS, I HAVE
SHOWN THOSE GENES WHICH PLAY KEY
ROLE IN CANCER DEVELOPMENT AND
THERE COULD BE POSSIBLE TARGET
WHICH IS AFFECT TUMOR SUPPRESSOR
GENE AND AND FEW EXAMPLES I WILL
GIVE IN COLON CANCERS WHICH ARE
REGULATED EPIGENETICALLY, THOSE
ARE SHOWN HERE ESPECIALLY IN
THESE AND KITA, THEY GET
METHLIGHTED QUITE EARLY, SO
CHARACTERIZING THOSE IS VERY
USEFUL, AND IN ONE CASE, LARGE
NUMBER OF SAMPLES WILL ANALYZE
FOR METHYLATION PILING BUT
ANALYSIS OF FEW GENES.
AND MUTATION WAS FOLLOWED AND
MICROSETALATE AND ACTIVITY HIGH
OR LOW.
THAT WAS A STUDY, WHEN YOU SEE
DARKER REGION IS IT HYPER
METHYLATION, AND THEN
NONMETHYLATION OR HYPO.
SO, BASED ON THE PROFILE YOU CAN
IDENTIFY ONLY ONE MUTATION IS
THERE, BUT WHEN.
BE THERE AND ALL ARE THERE AND
METHYLATION IS ALSO THERE.
THAT'S HOW GENES ARE IDENTIFIED
WITH GENOMIC AND EPIY GEMONNIC
MARKER THEY CAN BE COMBINED AND
CAN USE USED TO CLEANING OFF
[INDISCERNIBLE] TO IDENTIFY WHO
IS LIKELY TO DEVELOP CANCER, ONE
TYPE IS CALLED SIMP, THAT WAS
TYPE WAS IDENTIFIED FOR COLON
CANCER AND NOW FOR OVARIAN ALSO
AND THAT HAS BEEN REPORTED.
--SPECIFICITY OF BIOMARKER IN
DETECTING LUNG CANCER.
THIS IS, AND POPULATION AND
LARGE NUMBER OF SAMPLES ANALYZED
AND BASED ON JUST METHYLATION
PROFILING, LARGE NUMBER OF
SAMPLELES FROM DIFFERENT PEOPLE
COULD BE ANALYZED INITIAL STAYS
OF THAT CANCER, THESE ARE THE
NUMBER OF GENES WE TRY TO
ANALYZE AND SAMPLES TAKEN AT
DIFFERENT TIMES OF DISEASE
DEVELOPMENT.
WHEN YOU SEE THAT METHYLATION OF
SOME GENES THAT START QUITE
EARLY, BUT IN SOME IT IS NOT TO
START THAT EARLY AND
QUANTITATION IN TERMS OF THEM
METHALATED, REGION THAT CAN BE
COMING AND SO PATHOLOGY YOU CAN
CORRELATE WITH METHYLATION.
AND YOU CAN SEE PROFILE SUGGEST
ALSO IMPORTANT AND THOSE THINGS
WE NEED FIRST OF ALL IS
SCREENING OR IDENTIFY HIGH RISK
PEOPLE AND LATE OR WHO IS GIVING
RESPONSE TO TREATMENT.
AND THEY ARE CORRELATED AND
CONFIRMED GENE EXPRESSION WAS
FOLLOWED BY ANTIBODY
[INDISCERNIBLE] IN PANCREATIC
CANCER THIS I MENTIONED IN THE
SEARCH, INCIDENCE AND DISEASE,
ALMOST IS THE SAME SO IF YOU
KNOW THAT A PERSON HAS LONG
STANDING [INDISCERNIBLE] THEY
ARE ALCOHOLIC AND K-RASE MODEL
MUTATIONS ARE THERE, THEN P16
AND 14 GET METHALATED, THEN YOU
CAN SEE THAT PERSON IS
[INDISCERNIBLE] AND BREAST
CANCER MESSAGE AND THOSE WERE
IDENTIFIED WHICH ARE AFFECT
INDEED BREAST CANCER ACHIEVEMENT
ALSO YOU CAN SEE WHATEVER GENES
BEHAVE DIFFERENTLY WHO ARE GENE
WHO IS ARE NOT METHALATED AND IN
BREAST CANCER AS YOU KNOW AND
DEPENDING ON RECEPTORS, PR OR
ER, OR DOUBLE NEGAATIVE,
SOMETIMES, TREAT DON'T WORK IN
ALSO THAT METHYLATION MARKER CAN
HELP, AND IN THIS EXAMPLE, AND
STROMAL EPITHELIUM, THAT WAS
CHARACTERIZED AND CORRELATION
WAS DEVELOPED AND EVOLVED
EXPRESSION OF HEART AND OTHER
RECEPTORS AND METHYLATION.
AND CLASSIFICATION OR
STRATIFICATION OF PATIENTS WHO
WILL RESPOND TO THAT ACHIEVEMENT
AND NOT RESPOND TO TREATMENT.
SOME EXAMPLES ARE HERE LIKE
HUMAN PAPILLOMA VIRUS OR
[INDISCERNIBLE] CANCER OR
DIFFERENT CANCER HAS BEEN
REPORTED HBV OR HCV, FOR LIVER
CANCER AND ALSO HHV FOR SARCOMA,
THEY ARE THERE, AND THEY ARE
FORPET RESPOND IN THOSE CASES,
LATENCY ASSOCIATED NUCLEAR
ANTIGEN.
THAT IS THE ONE WHICH IS
REGULATED EPIGENETICALLY AND
RECENTLY, COMPLETE METHLOAM OF
HPV AND EBV AND HBV, THAT HAS
BEEN COMPLETED.
AD ADVANTAGE OF COMPLETION WILL
BE WE CAN TELL INITIAL CHANGES
STARTED TO COME AND CHRONICALLY
INFECTED TISSUE OR YOU CAN
IDENTIFY JUST THE SIZE AGAINST
YOU HUMAN THAT HAS BEEN SHOWN,
SO FIRST WHY ALL OF THESE IN
THIS METHYLATION PROFILING AS
BEEN COMPLETED AND NOT
ONLY--THIS HAS BEEN COMPLETED
BUT AT DIFFERENT STAGES OF
CANCER.
THOSE SAMPLES WERE AALIZED SO WE
CAN DISTINGUISHED THIS FROM
PRIMARY OR THOSE ONES TO SIMPLY
ALL THOSE STAGES SO YOU CAN
IDENTIFY JUST BASED ON
METHYLATION PROFILING AND ALL
THIS DATA IS VIABLE FOR PEOPLE
TO COMTHESE RESULS AND TO SEE A
REFERENCE METHYLATION PROFILING.
AND IN ALL THESE CASES, 16, 18,
HBV AND THAT GRADUALLY
METHYLATION IS MORE WITH THE
AGGRESSIVE MASK OR DEVELOPMENT
OF THE DISEASE.
IN HEPATOCELLULAR CARCINOMA,
ALTHOUGH WITH A NEW GENE HAS
BEEN IDEBTIFIED IT IS CALLED
SOCS ONE GENE WHICH IS PRESENT
ONLY IN JAPANESE POPULATION SO
WE WANT TO ARKS DENTIFY THE
FACTORS OR WHY IT IS ONLY ONE
POPULATION, NOT IN OTHER.
ALTHOUGH OTHER GENES IN EFFECTOR
CARCINOMA, WE ARE KNOWN.
IN ORAL CANCER ALSO A LIST OF
THOSE GENES WHICH CONTINUE TO
CANCER, THOSE ARE SHOWN HERE.
IN IMMUNOLOGY GOING TO
DEVELOPMENT AND T-CELLS AND
GENES OR STEPS HAVE BEEN
IDENTIFIED WHICH ARE RELATED
EPIGENETICALLY.
IN PROSTATE CANCER, SO FAR, PSA
WAS THE TEST BUT IN THAT, IF 11
IS LESS THAN FOUR NANO GRAM THEN
DOCTOR CAN'T TELL IF THE PERSON
WILL DEVELOP PROSTASTY CANCER OR
NOT, GFP WAS CONSERVED AND IT
HAS BEEN REPEATED THAT KNEES
CHANGES ARE BETTER THAN PSA.
AND IN SOME SAMPLES, PSA HAS
BEEN SIDE BY SIDE WITH GSP
METHYLATION AND RECEIPTLY THIS
ASSAY HAS BEEN BROUGHT BY QUEST
DIAGNOSTICS.
, OF COURSE DISCIPLINARYING
NOVELTYICS HAS BEEN DONE SO IF
NUTTURE LISTENING ABOUT THIS
TEST ALSO.
FOR COLORECTAL PROST CANCER AND
PROSTATE--COLORECTAL CANCER AND
PROSTATE CANCER, IF THE MUTATION
IS IN COLON CANCER IF THEY
COMBINE THAT, THEN THE
SPECIFICITY IS MORE OR NOT.
SOMETIMES ESPECIALLY IN LIGHT OF
CANCER EVEN IN URINE WHATEVER
DNA COMES FROM THAT, THEY ARE
SUFFICIENT TO DETECT
METHYLATION.
IT IS FOR [INDISCERNIBLE] GENE
AND FROM THERE FROM UNIVERSITY
OF SOUTHERN CALIFORNIA, HE HAS
DEVELOPED SUCH TECHNIQUE THAT IN
THE SAME SAMPLE, DIFFERENT
CANCERS, ESPECIALLY IN SECONDARY
CANC OR MULTIPLE CANCER, WHAT
WILL BE DEVELOPING OR WHAT ARE
THE JANES CHANCES OF DEVELOPING
THOSE, THOSE YOU CAN IDENTIFY.
AS YOU KNOW ONCE CANCER IS
STARTED IN ONE ORGAN SO AFTER
NOTICE, THE T CAN GO TO OTHER
ORGANS ALSO.
BUT IF WE CAN IDENTIFY THOSE
CHANGES, WHICH ARE LIKELY TO
AFFECT OTHER ORGANS, THAT
INFORMATION WILL BE VERY USEFUL.
SOME EXAMPLES OF REAL PROJECT
AND THIS IS FOR ARSENIC, THIS
WHICH PATHWAY SYSTEM VERY MUCH
IMPORTANT FOR THIS BETTER CANCER
SO CHANGES IN EPIY GENOME AND
THAT BY EPIY GENOME I MEAN
METHYLATION AND FRILLING ALL
THAT--THOSE WORK DONE AND
ESPECIALLY IN SOME COUNTRIES
LIKE [INDISCERNIBLE] AND
DRINKING WATER AND THE
CONTAMINATION IS VERY HIGH.
AND ANOTHER EXAMPLE THESE ARE
STUDIES DONE AND RULE OF AND
PROFILING, AND THAT WAS DONE AND
PROFILING AND GENOME PROFILING
AND THAT WAS CORRELATED AND NOW
IN INITIAL PRODUCTS SOME OF THE
PROPERTIES OF METHYLATION
ANYTIME YOU FIND HISTONE OR AND
YOU FIND SOME EXAMPLES SHOWN
HERE AND--[INDISCERNIBLE]--THIS
IS ALSO AN AREA WHICH IS BEING
DEVELOPED, BECAUSE BY NATURE
ALSO, IF YOU GET THIS, THAT WILL
BE VERY USEFUL.
AND THEIR MECHANISM OF ACTION
HAS ALSO BEEN IDENTIFIED IN MOST
OF INHIBITORS.
IN THIS CASE, JUST BY CHANGING,
THE METHOD DONOR AND WITHOUT ANY
GENETIC MANIPULATION OR CARC NO
GENERATED ADDITION, JUST METHYL
CREATE SUBSTITUTION WITH THAT
KIND OF CANCER SO THAT MODEL HAS
ALWAYS BEEN DEVELOPED AND IN IT,
AND THOSE ARE QUANTITATIVE ALSO.
THOSE EXPERIMENTS ALSO AND
FOLLOW UP WITH DISEASE, IN TERMS
OF SAMPLES, EPIY GENETIC CHANGES
ARE SUCH THAT IN TISSUES, THESE
ARE TISSUE SPECIFIC CHANGES SO
THOSE ARE THE BEST SAMPLES, BUT
SOME CANCERS OTHER SAMPLES AND
BIOFLUIDS ARE EXPOLEIATED CELLS
AND THESE ARE ALSO USED.
AND THEN I SHOWED ABOUT BLADDER
CANCER FROM URINE YOU CAN
COLLECT.
THE METHYLATION OF THE PROJECT
THEN YOU CAN GO AND IDENTIFY
THERE, AND IT IS THERE WITH
THOSE KINDS OF SOFTWARE ARE ALSO
AVAILABLE AND AND THERE AND THAT
IS SHOWN ALSO.
NOW REGUARDING HISTONES, THEY
ARE THERE IN DIMER AND THEY ARE
PRESENT AND SFOUR AND S-THREE
AND SOMEHOW S-THREE GETS
MODIFIED MAXIMUM TIME AND THESE
ARE THE MODIFICATIONS WHICH HAVE
BEEN REPORTED.
ACTIVATION, PHOSPHORYLATION,
UCIBOL WINNATION AND THAT ALSO
HAS BEEN REPORTED.
AND RECENTLY I UPDATED THESE
MODIFICATIONS WHICH HAVE BEEN A
DIFFERENT SITES AND SEQUENCE OF
THESE MODIFICATIONS IS ALSO VERY
IMPORTANT.
AND AT NIH LEVEL IN ROAD MAP YOU
HAVE AND SO THAT BOTH PROJECTS
AND THE HISTONES IS BEING DONE.
N SOME CASES NONHISTONES ALSO
PLAY AN IMPORTANT RULE.
EXAMPLE IS P50, IN WHICH LYSINE
DEMETHYLASE OR OTHER IS
IDENTIFIED SO THAT IS ALSO
ENROLLED SO PREVIOUSLYOT
HISTONE, NONHISTONES, WITH THE
D
NA PROTEIN COMPLEX, THEN AND
AFTER THAT, IMMUNO PRESCRIBING
PERITATION THAT I SHOWED WITH
HISTONES THOSE ARE USE THE TO
IDENTIFY THAT, AND THEN DNA NOW
DE--DEPENDING ON WHAT TYPE OF
RESOLUTION YOU NEED, IF YOU NEED
JUST A LOW RESOLUTION, THEN THE
SEQUENCING METHYLITE THEY ARE,
SORT OF BUT IF YOU WANT,
RESOLUTION THANE DIRECT
SEQUENCING OR TIARAS REASON,
THOSE KINDS OF CONSIDERATION
ALSO SO YOU HAVE TO KEEP IN
MIND.
NOW NONCODING MicroRNA,
INITIALLY PEOPLE IN THE ROLE IN
EPIGENETICS AND THE HISTONE AND
THEY INITIATE HISTONE
METHYLATION.
AND SO THEY HAVE--AND THE WAY IT
IS IN THE CLINIC, AND TRANSITION
IN THESE SENSES, PROFILING OF
MICRORNA GROUP, THAT IS TAKEN AS
A REFERENCE.
SO FAR, IN LUNG COLON GASTRIC
AND EPPED O MEETRIAL PROSTASTY,
A NUMBER OF MICRORNA HAVE BEEN
IDENTIFIED.
SO MicroRNA IS IMPORTANT.
>> AND MICRORNA ENROLLED IN THIS
PRACTICE ALSO AND THEY
IDENTIFIED AND THIS BCL-NINE
THAT THOSE GENES WHICH WERE
ACTIVATED THEY WERE ACTIVATED BY
HISTONE AND METHYLATION AND
INICITTOR.
AND THAT IS THE FOUR OF MICRORNA
AND ENROLLMENT OF MICRORNA.
NOW SOMETIMES, DISCUSSION COMES
WHETHER MICRO RNA, IN THIS
EXAMPLE, MicroRNA CAN
DISTINGUISH WHAT KIND OF EXAMPLE
IS THERE, THAT IS IT BUT IN SOME
CASES, WHETHER THE SIMPLELE
SHOULD BE USED OR TISSUES ARE
THE BEST BUT IN SOME CASES THEY
CAN GIVE THAT KIND OF
CORRELATION SO INITIALLY YOU
CHECK WHETHER TISSUE ARE GIVING
THE SAME IN THOSE CASES WELL
THERE IT IS GIVING AND YOU CAN
PROCEED WITH ACEASESSIBLE
SAMPLE.
SO FOR DNA METHYLATION AND
HISTONE DEACETYLATION, THEY HAVE
BEEN IDENTIFIED AND THIS IS THE
LIST OF THOSE INHIBITOR, THESE
ARE THE DIFFERENT PHASES, AND
GENE PHASING IS MD ANDERSON,
HE'S THE PIE O NEAR WORKER IN
THAT.
AND THE COMPOUND THERE IT HAS
SOME SIDE EFFECTS BETTER THAN
OTHERS AND--AFFECTED COMPOUND,
THE PEPTIDES BEN SWRA MIGHT AND
WITH THE SDECK, DIFFERENT FORMS
HAVE BEEN IDENTIFIED SO THAT IT
CAN BE MADE SPECIFIC.
AND SOME OF THOSE INHIBITORS
THEY ARE SHOWN TO CELL CYCLE OR
DIFFERENTIATION OF MIGRATION
DIFFERENT IMPLICATIONS ARE THERE
NOW I WILL GIVE YOU TWO EXAMPLES
WE ARE IN CLINICAL TRIALS, THIS
INHIBITORS ARE BEING USED AND
SOME OF THOSE INHIBITORS THEY
WORK AS RADIO SENSITIZERS
MEANING LIKE IF YOU ARE USING
REGULAR DRUG TREATMENT IT MAY
NOT WORK BUT IN SOME CASES IT
DID NOT WORK, THEN IT WAS
TREATED WITH INHIBITOR AND
INHIBITOR FIRST AND THEN USED
OTHER DRUGS, THEN IT'S SMALLER
AMOUNT OF ORIGINAL DRUG WAS
NEEDED SO THAT RARE CYTOTOXICITY
WAS ALSO REDUCED.
IN THIS CASE, THE CYTODINE AND
ONE IS METHYLATION AND ANOTHER
IS CAD WHAT THOSE
THOSE--[INDISCERNIBLE] THOSE ARE
ADMINISTERED FOR 10 DAYS AND
THESE ARE DOSES AND SAMPLES
ANALYZEDDA 10 AND 20 YEARS AND
LARGE NUMBER, THEY GIVE,
RESPONSE TO THAT.
SIMILARLY, IN OTHER CASES, THE
THAT WAS COMBINED WITH ALL
TRANSLATING AND IN THIS CASE,
ALSO, PATIENT RESPONDED BETTER
AND MANY OF THOSE PATIENTS IN
THE CLINEICAL TRIALS ARE GOING
OUT OF NCI, AND NO OTHER
ACHIEVEMENT WAS WORKING.
SO BY USING THIS, CAN YOU
INCREASE SURVIVAL AND IMPROVE
QUALITY OF LIFE; YOU CAN USE THE
GENETIC EPIEN GENETIC INHIBITOR
AND THEY ARE IN SOLID TUMORS OR
LYMPHOMA OR LEUKEMIA OR BREAST
CANCER IN A VARIETY OF BREAST
CANCER THESE TRIALS ARE GOING
ON, THEY ARE RECRUITING PEOPLE
AND RESULTS ARE COMING UP.
AND HERE I HAVE SHOWN THAT GENE
INACTIVATION CAN BE THE WORK BY
ACHIEVEMENT OF THESE COMPOUNDS.
AND BASED ON THAT, FARM COO
EPIGENOMICS IS COMING UP BECAUSE
AS YOU KNOW, GENOMICS, YOUR
GENETIC--YOUR GENETIC BACKGROUND
WILL TELL WHETHER WE WILL
RESPOND TO SOME DRUGS OR NOT BUT
EPIGENOMIC IS ALSO IMPORTANT
WHICH WILL TELL WHETHER YOU
RESPOND TO THAT OR NOT.
AND EPIGENETIC INHIBITOR, THESE
ARE THE FOUR COMPOUND WHICH IS
HAVE BEEN APPROVED BY FDA AND
THEY'RE BEING USED IN CLINIC.
SO WHENEVER YOU COLLECTS SOME
SAMPLE, THEN KEEP IN MIND THAT
FROM TUMOR, TIME TO TIME.
THESE EXFOLIATOR CELLS COME OUT,
SO THOSE YOU CAN COLLECT BECAUSE
THOSE ARE USEFUL FOR THOSE KINDS
OF ANALYSIS AND WHEN YOU
CONSIDER ABOUT GENOTYPE OR
PHENOTYPE, YOU HAVE TO THINK
ABOUT EPIGENOTYPE ALSO WHICH IS
THE ANTI[INDISCERNIBLE] TYPE.
WHAT KIND OF QUESTIONS WE WANT
TO ANSWER THROUGH EPIGENETIC AND
EPIDEALIO LOGIC STUDIES.
WHETHER EPIGENETIC MARKER VS
BEEN IDENTIFYING NEW RISK
FACTORS.
OR WE CAN IDENTIFY ENRICH THIS
OF ETHNIC GROUPS WHICH CANCER
WILL BE REMOVED AS YOU KNOW IN
AFRICAN AMERICAN PROSTATE
OFICOLOGYON CANCER, WHY YOU DO
THAT?
THEN, THE CASE CONTROL STUDIES,
SENSITIVITY OR SPECIFICITY OF
MARKER WILL INCHEESE, AND
INCLUDE EPIGENETIC MARKER OR HOW
THEY ARE CORRELATED OR WHETHER
SPECIFIC MicroRNA EXIST WHICH
CAN CORRELATE ETHNICITY AND
RACE, AND THESE ARE THE A FEW OF
THE INVESTIGATORS AND NANCY AND
CHRISTINA AND RUSSELL WHO ARE
ENROLLED IN THESE KINDS OF
PROJECT AND FOR SOMETIME I LOOK
AT EPIGENETICS CANCER PREVENTION
FOR NEW YORK ACADEMY OF
SCIENTISTS AND THEY GEEP THESE
LESSONS AND TWO YEARSING AND,
AND IMMUNEIE LOGICAL, AND
CONTRIBUTES AND DOSE ACTIVE
ALCOHOL INVOLVEMENT AND DOSE
CONTRIBUTE.
>> IF YOU WANT TO GET ENROLLED,
THEÑi IDEAS EPIGENETIC GENERAL IS
THERE, EPIGENETIC,
[INDISCERNIBLE]--SO ANYTIME NIS
ROAD MAP STARTED THAT SHOULD
HAVE STARTED KEY FEATURES LIKE
IT WAS THERE FOR SUCH PROJECTS
WHICH ARE HIGH RISK BUT I HAVE
RETURN ALSO, AND THEY ARE
EMERGING OF MANY, MANY DISEASES
ARE AFFECTED BY SOME MECHANISMS,
SO IN THIS CASE, ONE TIME
MICROBIOME AND EPIGENETIC
BIOSELECTED AND HERE BASE OF
DISCOVERY SHOULD BE HIGH.
AND SHOULD BE TRUSTED IN THERE,
EPIGENETICS AND NIH INSTITUTES
ARE ENROLLED AND THIS IS CALLED
COMMON FUND SO INITIALLY WE SAW
HOW MUCH EPIGETTICS IS GOING,
AND THE DISEASE ARE NOT MUCH SO
THAT INSTITUTE TRUSTING THAT.
WE CAN UNDERSTAND DEVELOPMENT,
CELL DIFFERENTIATION AND EDGING
AS WELL AS IDENTIFY DOSE FACTORS
WHICH CONTRIBUTE TO THESE
DISEASES.
BY WHICH I MEAN PROFILING,
MICRORNA PROFILING AND NOW
MODELING IS ALSO BEING DONE.
AND THIS CAN BE USED TO COMPARE
WITH SAMPLES FROM OTHER
DISEASES.
SO THIS IDEA OF TAKING BASIC
SCIENCE TO CLINICAL SCIENCES,
THE REFERENCE EPIGENOMIC
DEVELOP, IT WILL WILL HELP US
UNDERSTAND DEVELOPMENTAL
BIOLOGY, USING THE PROCESS
TECHNOLOGY WILL BE DEVELOPED AND
ALL DATA WILL BE SHARED AND
THAT'S HOW THIS ROAD MAP OF
EPIGENOMICS THAT CAME.
AND IN THAT WE HAVE MAPPING
CENTERS.
ALL THE TIME SOME NOVEL MARKS
ALONG WITH THE EXISTING MARK,
THEY ALSO COME, NEW TECHNOLOGIES
ARE DEVELOPED, WE HAVE A ALL OUR
OWN DATA, DATA ACCESS AND
QUADINATING CENTER AND PREVIOUS
DATA WAS RESTORED BY NCBI WHAT
OUR DATA COORDINATING CENTER,
THEY ARE COLLECTING AND
DISTRIBUTING THAT DATA.
AND FEW OF THE RESULS REEBTLY
THEY HAVE COME ABOUT, THE
PROGENITOR CELLS OR THE STEM
CELLS ARE BASICALLY BEING
CHARACTERIZED AND WHATEVER
CHANGE VS LINKED AND WE CAN MAKE
A DIFFERENCE MAP.
AND 290 MILLION DOLLARS WAS
ASSIGNED THAT.
SO DIFFERENT TIMES WO, ON THIS
PROJECT AND THEN FOLLOW
INITIALLY WITH THE TECHNOLOGY
AND MORE INTRODUCED SO THAT
EVERYTHING AND UP TO 2015, WE
ARE GOING TO FOLLOW THAT.
AND IN THE MEAN TIME, EUROPEAN
COUNTRIES WORK TOGETHER AND
WHATEVER WE HAVE NOT COVERED
[INDISCERNIBLE] AGING AND OTHER
DISEASES WE WANT TO EMPHASIZE,
CARDIOVASCULAR DISEASES AND ALSO
MILLION EURO PROJECT, AND THERE
IS NO DUPLICATION OF THE
[INDISCERNIBLE] SO IN AN IDEAL
SITUATION WHEN A PATIENT COMES
WITH THIS [INDISCERNIBLE] SAMPLE
SHOULD BE TAKEN AND IF TREATMENT
IS GONE THOAN THOSE INHIBITORS
ARE GIVEN AND PROFILE CAN BE
IDENTIFIED AND TREATMENT CAN BE
DONE AND TELL HAVE DEFINITELY
PERSONALIZED MEDICINE BECAUSE AS
YOU KNOW, IN TERMS OF TREATMENT
EVERY PERSON IS DIFFERENT AND WE
WANT TO KNOW AS MUCH MOLECAR
ANINAL SCIZZ AS MUCH AS
POSSIBLE.
SO IN A SENSE IN CONCLUSION,
EPIGENETICS COVERS IT COVERS
PREDICTION AND FOLLOW UP.
SO FOR CANCER MANAGEMENT, IT IS
VERY IMPORTANT AND OUR HOPE IS
THAT THIS FIELD WILL DEVELOP AND
ONE DAY WE'LL FIND OUT HOW
USEFUL IT IS FOR CANCER CONTROL
AND TREATMENT.
THANK YOU.
[ APPLAUSE ]
>> SO ARE YOU GOING TO APPLY
THAT APPROACH TO THE
EPIGENETICS?
>> IN FACT FOR NCI, THOSE
PROVOCATIVE QUESTIONS, 28 WERE
IDENTIFY INDEED ONE LAB WHICH
WAS THE DRIVER EVENTS IN
EPIGENOME AND ALSO, TWO PAPERS
CAN, THEY SAY THAT CHROMATIN
DEMODELLING THEY ARE THE DRIVER.
SO IN TWO OR THREE CANCERS THEY
HAVE SHOWN, AND MORE IS BEING
DONE.
THOSE ARE IMPORTANT QUESTIONS.
>> THAT WILL DO IT.
THANK YOU.