SO I'M NOT GOING TO TAKE UP MUCH

TIME BUT I FELT OBLIGED TO SHOW

THIS PHOTOGRAPH.

I'M SURE ALL OF YOU RECOGNIZE

WHAT THIS IS.

DOES ANYBODY KNOW WHAT IT IS?

NONE OF YOU ARE FROM BROOKLYN.

THIS IS THE MOST FAMOUS BRIDGE

IN THE AMERICAN  BRIDGE AND IT'S A LOGO

FOR THE DEMYSTIFYING MEDICINE

COURSE BECAUSE THE WHOLE IDEA IS

TO LINK UP AND CLOSE THE GAP

BETWEEN EXCITING ADVANCES IN

BASIC BIOLOGICAL AND ENGINEERING

SCIENCES AND THEIR RELATIONSHIP

TO DISEASE MECHANISMS IN HUMAN

HEALTH.

AND THERE PROBABLY IS NO TOPIC

THAT IS MORE TIMELY, DRAMATIC,

EXCITING AND CHALLENGING THEN

THE TOPIC TODAY.

WE WERE INCREDIBLY FORTUNATE

BECAUSE WE HAVE TWO OF THE WORLD

LEADERS ON EITHER SIDE OF THE

BRIDGE TO DISCUSS THIS.

SO LET ME INTRODUCE THEM TO YOU

IF YOU DON'T KNOW THEM.

THEY BOTH ONE WAY OR ANOTHER ARE

PRODUCTS OF THE UNIVERSITY OF

WISCONSIN AS A SPECIAL PLUG-IN

FOR THE EXCELLENCE OF THEIR

PROGRAMS.

SO OUR FIRST SPEAKER IS ERIC

GREEN WHO TOOK HIS BACHELOR'S

DEGREE AT WISCONSIN AND HIS M.D.

AND PH.D. FROM UNIVERSITY OF

WASHINGTON AT ST. LOUIS.

LOUIS FORTE GENOMICS AND SINCE

HIS FIRST COMING TO THE NIH HE'S

RISEN TO THE POSITION WHERE HE'S

DIRECTOR OF THE NATIONAL

INSTITUTE ON GENOMIC RESEARCH.

SEVERAL OF THE REFERENCES

THROUGH HIS RECENT WORKS ARE ON

THE WEBSITE.

I ENCOURAGE YOU TO READ THEM

BECAUSE THEY GIVE THE OVERALL

PICTURE AND THE CHALLENGES AND

AS ALWAYS IN SCIENCE THERE ARE

MORE QUESTIONS AFTER YOU DO

SOMETHING THAN BEFORE.

BUT WE'RE GOING TO HEAR WHERE

THINGS STAND.

NOW ON THE OTHER SIDE OF THE

FENCE THOSE WHO ARE NOT

PHYSICIANS MAY THINK THAT ALMOST

ANY DISEASE KNOWN TO MAN CAN BE

READILY DIAGNOSED BY A FEW

LABORATORY TESTS AND CANS.

WHAT'S ALL THE EXCITEMENT ABOUT.

BUT THAT'S A VERY WARPED VIEW.

THERE ARE HUNDREDS, WHO KNOWS,

MAYBE THOUSANDS OF DISEASES

ABOUT WHICH WE DON'T HAVE THE

FOGGIEST IDEA.

AND MANY OF THEM ARE VERY VERY

SERIOUS.

OFTEN AFFECTING CHILDREN, YOUNG

ADULTS.

AND THESE FOLKS GO TO LEADING

MEDICAL CENTERS AND HAVE WHAT'S

KNOWN AS THE MILLION DOLLAR WORK

UP WITH EVERYTHING UNDER THE SUN

AT THE END OF THE IT.

THE PATIENT AND THE PHYSICIANS

ARE STILL SCRATCHING THEIR

HEADS.

NOW HOUR SECOND SPEAKER WHO IS

BILL GAHL DID HIS PH.D. WORK AT

THE UNIVERSITY OF WISCONSIN,

TRAINED IN PEDIATRICS AND

GENETICS.

HE CAME HERE AND BILL HAS RISEN

IN THE NIH RANKS AND HE IS THE

DIRECTOR OF A REMARKABLE PROGRAM

THAT HAS ATTRACTED NATIONAL AND

INTERNATIONAL ATTENTION.

UNDIAGNOSED DISEASES.

NOW THESE ARE PATIENTS WHO HAVE

DISEASES FOR READILY AVAILABLE

HAVE LED TO AN UNDERSTANDING OF

WHAT'S GOING ON.

AND BY A COMPLEX MECHANISM, SOME

ARE SELECTED TO COME HERE FOR

EXTENSIVE STUDY WHICH LINKS IT

INTO SEQUENCING AND ALL THE REST

THAT GOES WITH IT AND IT HAS

COME TO REMARKABLE

ACCOMPLISHMENTS.

NOT ONLY WITH THE RECOGNITION OF

WHAT SOME OF THESE DISEASES ARE

POW WHAT HAPPENS WHEN YOU

DISCOVER THAT A DISEASE IS

ASSOCIATED LET'S SEE WITH A

PARTICULAR GENETIC DEFECT, THEN

YOU BEGIN TO UNDERSTAND WHAT

THAT GENO PRODUCT DOES IN AN

ACQUIRED DISEASE SO THE WHOLE

THING SPINS OFF AND THERE ARE

MANY OTHER THINGS.

SO I'VE SAID TOO MUCH.

SO OUR FIRST SPEAKER IS ERIC

GREEN.

>> WELL, THANK YOU.

IT'S A PLEASURE TO BE HERE AND

THANK YOU FOR THE INVITATION TO

PARTICIPATE IN THIS INCREDIBLY

SUCCESSFUL SERIES.

I'M REALLY JUST THE WARM UP ACT

FOUR BILL GAHL TO SEARCH UP THE

CROWD AND THEN THE SHOW STARTS.

WHAT I'M GOING TO DO THE NEXT 30

TO 40 MINUTES IS REVIEW FOR YOU

WHAT IS AN INCREDIBLY DYNAMIC

AND CHANGING LANDSCAPE THAT HAS

BEEN BROUGHT ON IN GENOMICS.

AND WHAT THAT WILL I THINK VERY

MUCH SHOW YOU IS THE NEW

OPPORTUNITIES TO APPLY GENOMICS

TO PROBLEMS IN CLINICAL

MEDICINE.

THEN I'LL TURN THE PODIUM OVER

TO BILL WHO I THINK THROUGH THE

PROGRAM HE'S GOING TO DESCRIBE

WILL VERY NICELY ILLUSTRATE THE

FACT THAT GENOMICS HAVE A MAJOR

ROLE IN ADVANCING OUR

UNDERSTANDING OF THE GENETIC

BASIS OF DISEASE.

I COME HERE WITH A RICH HISTORY

BEHIND ME AND I WANT TO SPEND A

FAIR AMOUNT OF TIME REALLY

DESCRIBING THAT HISTORY REACHING

BACK REALLY 

YEARS AGO, WITH THE BEGINNING OF

THE HUMAN GENOME PROJECT.

BUT I'M ALSO GOING TO EMPHASIZE

REALLY WHAT TRANSPIRED SINCE THE

END OF THE GENOME PROJECT.

THIS EFFORT WHICH OF COURSE

DATES BACK TO THE ORIGINS OF THE

INSTITUTE THAT I NOW DIRECT

CREATED FOR DIRECTING THE NIH'S

CONSULTANT PUTION TO THIS LARGE

INTERNATIONAL EFFORT TO MAP AND

SEQUENCE THE HUMAN GENOME IS AT

THE TIME THE KINDS OF THINGS

THAT ARE TIPALLY DONE IN

BIOMEDICAL RESEARCH, BUT IT WAS

CAPITAL VAIFTING TO PARTICIPATE

IN.

I JOINED THIS PROJECT, ACTUALLY,

ON DAY ONE, AS A RECENTLY

GRADUATED.

I WAS A RESIDENT OF PATHOLOGY AT

THE TIME AND I THOUGHT THIS

AUDACIOUS MISSION OF TRYING TO

ALTER THE GENES.

I STARTED ON TEE ONE AND

COMPLETED TO THE VERY END AND

MADE MY CAREER IN GENOMICS.

WHEN THE GENOME PROJECT BEGAN,

IT WAS TERRIFYING.

WE DIDN'T REALLY KNOW WHAT WE

WERE DOING.

THEY HAD THIS GOAL AND WE HAD A

LOT OF IDEAS.

BUT THE TECHNOLOGIES WERE NOT IN

PLACE.

THE IDEAS WERE NOT FULLY FLUSHED

OUT BUT THE PURPOSE WAS SO

HIGHLY FOCUSED AND SO PROFOUND

THAT YOU GET HUNDREDS OF PEOPLE

FROM AROUND THE WORLD WORKING ON

A PROBLEM LIKE THAT AND REALLY

JUST A MERE TEN YEAR LATER YOU

ACTUALLY END UP BEING

SUCCESSFUL.

FIRST, GENERATING AND THEN

ANNOUNCING A DRAFT SEQUENCE OF

THE HUMAN GENOME AND THEN A

SHORT TIME AFTER THAT TO

ACTUALLY PUBLISHING THIS IN WHAT

WAS ARGUING ONE OF THE MOST

IMPORTANT PUBLICATIONS OF RECENT

YEARS IN NATURE, THE DESCRIPTION

OF THE FIRST ANALYSIS OF THE

DRAFT SEQUENCE OF THE HUMAN

GENOME IN NATURE IN FEBRUARY

2001.

THAT WAS NOT THE END OF THE

PROJECT, THAT WAS JUST A DRAFT

SEQUENCE, WE HAD TO GENERATE A

HIGHER QUALITY SEQUENCE BACK TO

THE LABILITY LABS WE WENT AND GETTING A

HIGH QUALITY REFERENCE SEQUENCE

OF THE HUMAN GENOME.

IN APRIL OF 2003, SORT OF

ANNOUNCED COMPLETION OF THAT

SEQUENCE, AND WITH IT CAME AN

END TO THE HUMAN GENOME.

NOW A LOT HAS HAPPENED UNDER

GENOMICS IN VARIOUS WAYS AND IN

VARIOUS FIELDS.

OUR EMPHASIS HERE AT THE

NATIONAL INSTITUTES OF HEALTH,

OF COURSE AND OUR INSTITUTE IN

PARTICULAR HAS BEEN TO THINK

ABOUT HOW TO USE THE KNOWLEDGE

GENERATED BY THE HUMAN GENOME

PROJECT AND THE TECHNOLOGIES

THAT CAME OUT OF STUDYING

GENOMES FOR BETTER UNDERSTANDING

THE MOLECULAR BASIS OF DISEASE

AND EVENTUALLY MAYBE CHANGING

THE PRACTICE OF MEDICINE.

NOW THIS IS NOT A TOTALLY CRAZY

IDEA.

IN FACT THE POPULAR PRESS PICKED

THIS UP AS WELL AS THE

SCIENTIFIC PRESS PICKED THIS UP

ALMOST AS SOON AS THE GENOME

PROJECT CONCLUDED.

RECOGNIZING THAT THE

OPPORTUNITIES TO USE GENOMICS TO

CHANGE THE PRACTICE OF MEDICINE

WERE VERY ENTICING AND WERE VERY

MUCH IN FRONT OF US.

GIVING RISE TO THE NOTION OF

GENOMICS MEDICINE AS A

POPULARIZED ON THESE.

NOW BY GENOMIC MEDICINE, WHAT I

MEAN IS HEALTHCARE TAILORED TO

THE INDIVIDUAL BASED ON GENOMIC

INFORMATION.

IN OTHER WORDS, NOT TAKING

PATIENTS AND TREATING THEM.

>THEM.

>GENERICALLY BUT RECOGNIZING EACH

OF US HAS OUR OWN UNIQUE GENETIC

MAKE UP.

IF WE CAN UTILIZE THAT YITION AS

PAR AS CLINICAL CARE WE HAVE A

MORE POWERFUL APPROACH PERHAPS

FOR TAKING CARE OF THOSE

INDIVIDUALS.

SO I WOULD TELL YOU I'VE NOWABLE

AT NIH FOR ABOUT 17, 18 YEARS.

TWO YEARS AGO I BECAME DIRECTOR

OF THE INSTOOVMENT  INSTITUTE.

VERY MUCH WE VIEW THE PURSUIT OF

GENOMIC MEDICINE AS SORT OF THE

THING THAT WE NEED TO BE DOING

AS AN INSTITUTE, ULTIMATELY SORT

OF THE GOAL WE HAVE FOR WHAT THE

INSTITUTE NEEDS TO ACHIEVE.

AND SO I THINK ABOUT, A LOT

ABOUT THIS AND WE DO A LOT OF

STRATEGIC PLANNING AROUND THIS

IDEA.

AND I GUESS WHAT I'VE CONCLUDED

IS THAT WE HAVE A VERY IMPORTANT

PATH THAT WE STARTED TO

TRAVERSE, ALMOST AS SOON AS THE

GENOME PROJECT ENDED.

IN FACT THE GENOME PROJECT IN

MANY WAYS WAS THE STARTING LINE

OF THIS JOURNEY.

AT THE OTHER END OF THIS JOURNEY

IS GOING TO BE THE REALIZATION

OF GENOMIC MEDICINE BROADLY

DEFINED.

WE SPEND A LOT OF TIME THINKING

ABOUT ALL THE STEPS THAT ARE

GOING TO BE REQUIRED TO GET US

THERE.

BUT WE DON'T PRETEND FOR A

MINUTE TO KNOW WHAT ALL THOSE

STEPS ARE GOING TO BE.

LIKE ANY JOURNEY, YOU KNOW

THERE'S GOING TO BE SOME

SURPRISES.

BUT WITH THAT SAID, ARE WE GO

INTO THIS JOURNEY WITH A FAIR

AMOUNT OF OPTIMISM HAVING BEEN

SUCCESSFUL, MILY SUCCESSFUL AT

THE -- HIGHLY SUCCESSFUL AT THE

GENOME PROBLEM.

WE HAVE TO REALIZE GENOMIC

MEDICINE WITH THESE GREAT

OPPORTUNITIES AND IN DOING SO WE

WILL FULFILL 9 PROMIS THE PROMISE WHY WE

SEQUENCE THE HUMAN GENOME IN THE

FIRST PLACE.

I WILL TELL YOU WHAT I THINK ARE

SORT OF THE FIVE MAJOR STEPS

THAT ARE PART OF THIS JOURNEY,

STARTING WITH THE END OF THE

HUMAN GENOME PROJECT.

SO REALLY, WHAT HAS HAPPENED

SINCE 2003 WITH THE COMPLETION

OF THE SEQUENCE OF THE HUMAN

GENOME?

I THOUGHT I WOULD TELL YOU WITH

THOSE FIVE STEPS JUST VERY

BRIEFLY.

I DON'T HAVE TIME TO DRILL IN

ANY DETAIL BUT I WANT TO GIVE

YOU A HIGH LEVEL VIEWS BECAUSE I

THINK YOU CAN SEE WITH EACH OF

THOSE STEPS WE ARE INCHING OUR

WAY A LITTLE BIT CLOSER, A

LITTLE BIT CLOSER, A LITTLE BIT

CLOSER TOWARDS THE REALIZATION

OF GENOMIC MEDICINE.

SO THINKING ABOUT THIS JOURNEY,

THE VERY FIRST STEP WHICH

OCCUPIED A TREMENDOUS AMOUNT OF

TIME OVER THE PAST EIGHT YEARS

OR SO IS BASICALLY UNDERSTANDING

THE FUNCTION OF THE HUMAN GENOME

SEQUENCE.

WHAT DOES THAT MEAN?

WHAT IT REALLY MEANS IS WHAT THE

HUMAN GENOME PROJECT WAS ALL

ABOUT WAS JUST THIS, GENERATING

SEQUENCE, ORDERING THE ROUGHLY

THREE BILL MILLION T'S AND C'S

THAT MAKE UP THE HUMAN GENOME.

IT'S NOT AT ALL REALISTIC WE

WOULD UNDERSTAND THE SEQUENCE AT

THE END OF THE PROJECT.

WE JUST NEEDED TO GET THING

ORDERED.

WE RECOGNIZED THERE WAS GOING TO

BE AN IMMENSE AMOUNT OF

BIOLOGICAL INFORMATION ENCODE

THE IN THOSE 3 BILLION LETTERS

AND IT WOULD TAKE DECADES TO

FULLY UNDERSTAND ALL OF THE

NUANCES IN THE WAYS THAT DNA CAN

FIRST FUNCTION.

WE'VE LEARNED A TREMENDOUS

AMOUNT IN EIGHT YEARS.

THERE HAVE BEEN PROJECTS THAT

WE'VE PUT ON SUCH AS THE ENCODE

PROJECT, ENCYCLOPEDIA DNA

ELEMENT.

IT'S A LARGE INTERNATIONAL

CONSORTIUM THAT HAS GONE ABOUT

USING LABORATORY METHODS AND

COMPUTATIONAL METHODS TO CATALOG

VARIOUS FUNCTIONAL ELEMENTS IN

THE HUMAN GENOME.

WHERE ARE ALL THE GENES.

WHERE ARE ALL THE SEQUENCES THAT

ARE MADE IN RNA.

WHERE ARE ALL THE SCWEANLSZ THAT

ARE BOUND BY PROTEEN THAT MIGHT

REGULATE WHEN GENES ARE TURNED

ON AND OFF.

AND WHERE ARE REGIONS OF THE

CHROMOSOME THAT OPENED UP, WHERE

THERE'S OPEN CHROME TONE WITH

PROTEIN BINDINGS.

COMING WITH THIS IS AN AMOUNT OF

KNOWLEDGE OF HOW THE GENTLELADY

WORKS.

BY THE WAY IN THE LAST EIGHT -- 

HOW THE GENOME WORKS.

WE RECOGNIZE IT'S IN THE

LETTERS, IN FACT THERE'S A WHOLE

LOT OF WAYS THAT DNA GETS

DECORATED WITH MESSA METHYL GROUPS AND

HISTONE.

THE MARX CONFER LOTS OF

INFORMATION AND WE'RE JUST

SCRATCHING THE SURFACE

UNDERSTANDING HOW THIS GENOME

WORKS.

YOU CAN GO TO THE INTERNET AND

YOU CAN GO TO BROWSERS THAT HAVE

TONS OF DATA THAT GENOMISTS HAVE

LEARN AND YOU WILL GET GREAT

INSIGHTS AND LOTS OF CLUES AND

ALL THE THINGS THAT ARE

DESCRIBED YOU.

REALISTICALLY EIGHT YEARS AFTER

WE FIRST OPENED UP AND ACTUALLY

READ OUR GENETIC BLUE PRINT, AT

BEST, AT BEST WE HAVE A CLIFF

NOTE'S VIEW OF THE HUMAN GENOME.

BUT DECADES FROM THOUSAND WE

WILL STILL BE INTERPRETING,

REINTERPRETING AND REFINING OUR

UNDERSTANDING OF THIS INCREDIBLY

COMPLICATED BLEU PRINT.

BUT WE'VE LEARNED QUITE A BIT

AND WE CONTINUE TO WORK HARD TO

UNDERSTAND MORE AND MORE BIT.

SO THAT'S SORT OF BEEN ONE OF

THE STEPS WE'VE BEEN PURSUING.

THE SECOND STEP THAT WE'VE BEEN

PURSUING IS THE RECOGNITION THAT

WE DON'T JUST CARE ABOUT A

HYPOTHETICAL REFERENCE HUMAN

GENOME AND HOW IT RUSHED.

WE'RE INTERESTED IN OUR GENOMES

AND HOW THEY WORK INDIVIDUALLY

AND EVENTUALLY HOW OUR

INDIVIDUAL PATIENTS GENOMES

WORK.

SO THE NOTION OF VARIATION, HOW

OUR GENOMES DIFFER FROM ONE

ANOTHER REALLY HAS BEEN A

PRIORITY AREA OF STUDY OVER THE

LAST EIGHT YEARS.

SPECIFICALLY WHAT I MEAN BY

THAT, EACH OF YOU BY THE WAY HAS

TWO GENOMES IN YOU.

YOU GOT ONE FROM MOM YOU GOT ONE

FROM DAD.

ACROSS ARE SIX BILLION LETTERS

BECAUSE YOU HAVE TWO GENOMES,

YOU HAVE A WHOLE BUNCH OF PLACES

WHERE YOU VARY COMPARED TO SAY

THE PERSON SITTING NEXT TO YOU.

I INDICATE THESE BY THESE.

WHEN YOU LOOK TO THE LEFT OR

RIGHT THE PERSON SITTING NEXT TO

YOU THERE'S PROBABLY 3 TO 5

MILLION PLACES IN YOUR GENOME

THAT YOUR LETTER AT THAT

POSITION IS DIFFERENT THAN THE

PERSON SITTING NEXT TO YOU.

AND THERE'S PROBABLY TENS OF

THOUSANDS OF PLACES WHERE YOUR

GENOMES ARE EVEN MORE

COMPLICATED IN TERM OF BEING

DIFFERENT.

EITHER THAT YOU HAVE A STRETCH

OF DNA THAT'S FIVE COPIES AND

THE PERSON SITTING NEXT TO YOU

IS THREE COPIES OR MAYBE IT'S

SLIGHTLY REARRANGED.

THOSE STRUCTURAL VAIRNTSZ ARE

ALSO VERY -- VARIANTS ARE ALSO

VERY IMPORTANT.

WE ARE CATALOG THOSE DIFFERENCES

THROUGH EFFORTS SUCH AS THE HAT

PROJECT TO DETERMINE COMMON

VARIANTS THAT EXIST IN THE

POPULATIONS, IN FACT IN

POPULATIONS ACROSS THE WORLD.

MORE RECENTLY THE THOUSAND

GENOMES PROJECT, ANOTHER LARGE

PROJECT TO SEQUENCE NOT JUST ITS

NAME OF A THOUSAND GENOMES, IT'S
 GENOMES COLLECTED

FROM GEE GRAPHAL REGIONS ACROSS

THE WORLD, SEQUENCING THEM AND

CATALOGING THE VARIANTS THAT

EXIST AND PUTTING IT OUT ON THE

INTERNET FOR EVERYBODY TO

STEEVMENTD THE REASOSTUDY.THE REASON WE'RE
 GETTING TO

CATALOG THE MORE MUST NOT

VARIANTS AND THE RARE VARIANTS

BECAUSE WE WANT TO KNOW WHICH

ONE OF THESE VARIANTS SHOULD WE

WORRY ABOUT.

WHICH ONES HAVE FUNCTIONAL

CONSEQUENCES.

IN FACT THE GREAT MAJORITY OF

YOUR 3 TO 5 MILLION VARIANTS

THAT YOU HAVE, NO TON PHENOTYPIC

CONSEQUENCES WHATSOEVER.

SOME OF WHICH MIERTD B MIGHT BE

DETRIMENT.

IT MIGHT BE A GOOD VARIANT.

OF COURSE OUR INTEREST IN HAVING

A CATALOG OF THESE VARIANTS IS

TO ALLOW US TO GO IN AND STUDY

WHICH OF THE VARIANTS ARE

BIOLOGICALLY IMPORTANT AND

IMPORTANT THE PURPOSE OF MEDICAL

CARE WHICH OF THEM IS MEDICALLY

RELEVANT AND INFLUENTIAL IN

TAILORING HOW YOU MIGHT CARE FOR

A PATIENT.

THAT'S ANOTHER MAJOR AREA.

DEVELOP CATALOGS OF VARIANTS

ACROSS HUMAN POPULATIONS WITH

RESPECT TO THE REGIONS OF THE

GENOME THAT DIFFER FROM

INDIVIDUAL TO INDIVIDUAL.

THE THIRD STEP THAT HAS BEEN

PURSUED OVER THE LAST EIGHT

YEARS AND HAS BEEN RELEVANT TO

WHAT YOU'RE GOING TO HEAR ABOUT

IN THE SECOND TALK RELATES TO

USING THE KNOWLEDGE ABOUT HOW

THE HUMAN GENOME WORKED.

AND USING THE KNOWLEDGE ABOUT

HOW THESE HUMAN GENOME VARIES

FROM INDIVIDUAL TO INDIVIDUAL

CAN NOW START TO UNDERSTAND WHAT

IS THE GENOMIC BASIS FOR HUMAN

DISEASE.

NOW KEEP IN MIND OF COURSE THAT

ESSENTIALLY EVERY DISEASE YOU

CAN NAME HAS A GENETIC ORIGIN OR

HAS A GENETIC INFLUENCE WITH THE

DISEASE.

THE COMPLEXITIES ASSOCIATED WITH

THE GENETICS FOR DIFFERENT

DISEASES VARY CONSIDERABLY.

FOR PURPOSES OF DISCUSSION, AND

TO SORT OF GIVE YOU JUST A QUICK

235E8 FOFEEL FOR WHAT IS HAPPENED IT'S

USEFUL TO THINK ABOUT GENETIC

DISEASES IN TWO VERY BROAD

CATEGORIES.

ON THE ONE HAND, YOU HAVE RARE

GENETIC DISEASES BUT THEY'RE

GENETICALLY SIMPLE.

THE REASON IS BECAUSE THEY'RE

CAUSED BY DEFECT IN THE SINGLE

GENE.

IN OTHER WORDS THEY ARE MONO

GENIC, THEY PUT UP THE NAME --

AFTER THE FAMES JEANETT GENETICIST

MENTAL.

THIS IS SICKLE CELL DISEASE,

HUNTINGTON'S DISEASE AND IN FACT

THESE ARE THE KINDS OF DISEASES

BILL GAHL WILL TALK ABOUT.

THESE ARE MUTE TAKES OF A SINGLE

GENE ARE THE DOMINANT RISK

FORGETTING THAT DISEASE.

MEANWHILE THERE MIGHT BE SOME

OTHER GENERIC INFLUENCE AND

MAYBE A LITTLE BIT OF

ENVIRONMENTAL CONTRIBUTION BUT

FANTMENTALLY DEFECTS IN A SINGLE

GENE CAUSE THE DISEASE.

BUT THESE ARE REQUIRE.

AND THEY'RE IMPORTANT AND

THEY'RE INSIGHTFUL.

BUT THEY DON'T NECESSARILY

REPRESENT THE MAJOR HEALTHCARE

BURDENS AROUND THE WORLD.

IN FACT HOSPITALS AND CLINICS

AROUND THE WORLD IN A MUCH MORE

SIGNIFICANT WAY ARE THESE

DISEASES.

THESE ARE THE COMMON GENETIC

DISEASES.

NOW, IT TURN OUT THAT COMMON

JEANETTE I BEEN DISEASES

UNFORTUNATELY ARE COMPLEX AND

THE REASON THEY'RE COMPLEX IS

BECAUSE THEY INVOLVE MULTIPLE

GENES.

IT'S NOT A DEFECT IN A SINGLE

GENE THAT IS THE ONLY RISK

FACTOR BUT RATHER IT IS A SERIES

OF SQUA GENETIC VARIANTS THAT

TOGETHER CONSPIRE WITH WHAT IS

TYPICALLY A LARGER INFLUENCE OF

THE ENVIRONMENT TO ACTUALLY

CONFER WITH FORGETTING THAT

DISEASE.

WELL, IT WAS ALWAYS IMAGINED

THAT THE HUMAN GENOME PROJECT

AND WE MAP AND SEQUENCE THE

HUMAN GENOME IT WOULD PROVIDE

THE VALUATIONAL RESOURCES AND

TECHNOLOGIES FOR DOING THE

DETECTIVE WORK TO FIGURE OUT THE

MOLECULAR BASIS OF THESE SIMPLE

CASES WHERE YOU'RE LOOKING FOR A

SINGLE GENE.

ALWAYS WONDERED WHETHER WE'D

BEEN ABLE TO FIGURE OUT THIS

COMPLEXITY, REPRESENTING THESE

COMPLICATED SERIES OF SMALL

GENETIC INFLUENCES THAT EVEN UP

RESULTING IN SOMEBODY GETTING

DIE BOATS O BOATSDIEDIABETES OR NOT GETTIN
G DIABETES

OR ASTHMA AND SO FORTH.

THIS IS A MYSTERY.

WE HAVE NOW USED THE NEW

KNOWLEDGE OF GENOMIC

TECHNOLOGIES OVER THE LAST EIGHT

YEARS, LET'S START WITH MONO

GENIC DISEASES THOSE SIMPLE RARE

MEN DILLIAN DISORDERS.

SHOWN HERE IS AN CUMULATIVE

GRAPH OF GENES IDENTIFIED WHEN

MUTATION RESULTS IN A SINGLE

GENE DEFECT REMIND YOU THAT THE

GENOME PROJECT BEGAN HERE.

AND IT'S REALLY HARD TO ARGUE

THAT AS SOON AS SOME OF THE

EARLIEST MAPS AND SEQUENCE THE

HUMAN GENOME CAME UP, IT

IMMEDIATELY ACCELERATED THE PACE

AT WHICH WE WERE ABLE TO DO THE

DETECTIVE WORK TO FIGURE OUT THE

GENETIC BASIS OF SIMPLE GENETIC

DISORDERS.

AND IN FACT, IT HAS CONTINUED UP

TO THE PRESENT TIME AND IN FACT

IS EVEN PICKING UP THE PACE AS

YOU'RE GOING TO HEAR ABOUT IN

THE SECOND TALK.

WELL, WHAT HAS HAPPENED WITH

THAT INCREASING KNOWLEDGE ABOUT

THE DISEASES.

FOR EXAMPLE, IN WE TAKE ALL THE

KNOWN MENDELLIAN DISEASES AND WE

CAN INCLUDE TRACE IN THIS CASE,

WE HAVE NOW IDENTIFIED THE

MOLECULAR BASIS FOR ABOUT 3500

OF THEM.

AND THAT IS BASICALLY THE GLASS

HALF FULL.

THERE IS A GLASS HALF EMPTY PART

OF THE STORY.

IT TOWRNL TURNS OUT THERE ARE ANOTHER

2000 DISEASES THAT EXIST BUT WE

DON'T KNOW THE MOLECULAR 3W5EUSZ

FOR AND ANOTHER 2000 OR SO WHERE

WE THINK WE HAVE A SINGLE GENE

INVOLVED WITH THAT DISEASE WITH

THAT TRADE BUT WE TONIGHT KNOW

THE MOLECULAR BASIS FOR.

REMEMBER THIS PIE CHART I'LL

COME BACK TO IN 15 MINUTES.

SO THIS HAS BEEN A SUCCESS

STORY, THOUGH, 23EU FILLING UP THIS

BIG GREEN SLICE OF THE PIE OVER

THE LAST EIGHT YEARS.

WHAT'S TRANSFIRE TRANSPIRED WITH COMPLEX

GENETIC DISEASES.

IT'S A MUCH MORE COMPLICATED

STORY TO TELL YOU ABOUT BECAUSE

IT BASICALLY INVOLVES A WHOLE

NEW PARADIGM FOR DOING STUDIES,

WHEREBY YOU TAKE LARGE NUMBERS

OF INDIVIDUALS WITH A COMPLEX

DISEASE LIKE HYPERTENSION AND A

LOT OF INDIVIDUALS WITHOUT, AND

THEN DO A PROCESS KNOWN AS

GENOME-WIDE ASSOCIATION STUDY,

WHEREBY YOU ARE TRYING TO

DEVELOP A STATISTICAL

ASSOCIATION BETWEEN INHERITING A

LITTLE BIT OF THE GENOME AND

GETTING THAT DISEASE.

AND IT'S ALL A BIG STATISTICAL

CHALLENGE OF GETTING ENOUGH

PEOPLE AND STUDYING ENOUGH

REGIONS OF THE GENOME TO FIGURE

OUT WHETHER YOU CAN TEASE OUT

VERY SMALL CONTRIBUTIONS FROM

INHERITING SPECIFIC REGIONS IN

WHICH RESIDES SPECIFIC VAIRMTS

THAVAIRMTS -- VARIANTSING TWEAKING

A LITTLE BIT OF RISKS IN ORDER

TO GET THAT DISORDER.

WHAT HAS HAPPENED IS RASH MANY.

ONCE UPON A TIME THE BACK OF THE

ENVELOPE CLASS O CALCULATION CALCULATION O
F IT

SHOULD WORK TURNED OUT TO WORK

PRETTY WELL.

FIVE YEARS AGO WHEN YOU HOPED A

MAJOR SCIENTIFIC JOURNAL, CROSS

GENETICS, HUMAN MOLECULAR

GENETICS, YOU WOULD FIND OFTEN

TIMES MULTIPLE STUDIES REPORTING

SUCCESSFUL ASSOCIATION STUDIES

THAT FOUND DISCRETE REGIONS OF

THE HUMAN GENOME, ASSOCIATED,

STATISTICALLY ASSOCIATED WITH

IMPORTANT DISEASES LIKE

DIABETES, HYPERTENSION,

CARDIOVASCULAR DISEASE, ASTHMA

AND SO FORTH.

AND WE ACTUALLY HERE AT NIH HAVE

CATALOGED THIS.

IF YOU WERE INTERESTED IN THE

WEBSITE I WILL POINT YOU THERE.

EVERY SINGLE TIME THERE WAS A

PAPER THAT WILL STICK A LAWFLY

POP ON THAT PARTICULAR REGION OF

THE BEEN CHROMOSOME WHICH

INDICATED THAT WAS A REGION

STUDIED IN GREATER DETAIL.

BACK IN 2003 WAS THE FIRST

SUCCESSFUL ASSOCIATION STUDY OF

THIS KIND FOR COMPLEX DISEASES.

FOUR OR FIVE MONTHS AGO WE

FINISHED THE 1-T 1,000TH

COMPILATION.

WE WENT TO HAVE THOUSANDS OF

SUCCESS STUDIES WITH THAT GENOME

LOLLIPOP TO INTERROGATE WHICH OF

THE VARIANTS IN THAT REGION IS

CONFERRING THE RISK OF DISEASE.

WE HAVE NOT IDENTIFIED ALL OF

THEM WE HAVE NOT SOLVED GENETIC

DISEASES, BUT WE HAVE THE

DETECTIVE WORK NEEDED TO TEASE

OUT THESE SMALL GENETIC

INFLUENCES FOR THESE IMPORTANT

DISEASES.

SO WHILE WE DON'T HAVE THE SAME

SUCCESS YET AS WE HAVE FOR RARE

DISEASES, OVER THE NEXT TEN

YEARS, WE FULLY EXPECT TO

UNDERSTAND ONLY INCREDIBLE

AMOUNT MORE ABOUT THE GENETIC

BASIS OF THESE COMPLEX GENETIC

DISEASES.

2450E89S THTHAT'S THE GLASS HALF FULL

AGAIN.

THERE'S A SLIGHTLY MORE DAUNTING

TASK AHEAD OF US WHICH WILL KEEP

US VERY EMPLOYED AND BUSY FOR

THE NEXT TEN OR 20, 30 YEARS IS

WE LEARNED A LITTLE BIT MORE

ABOUT THE ACTUAL MOLECULAR

STRAINTS OVARIANTS OR THE SQUAWATE GENETIC
 VARIANTS

CAUSING THESE DISORDERS.

IT TURNS OUT THE GREAT GREATER

MAJORITY OF THOSE OTHER

MUTATIONS ARE THE CODING REGION

OF THE GENOME.

PART OF THE GENOME THAT DIRECTLY

COAT PROTEABLES.

THE PART OF THE GENOME WE REALLY

UNDERSTAND WELL BECAUSE WE

UNDERSTAND THAT DNA MAKES RNA

WHICH MAKES PROTEIN AND WE GET

THAT.

HOW DO WE INTERPRET THAT AND

IT'S A PATH THAT'S STRAIGHT

FORTH.

IT TURNS OUT THAT WE'VE LEARNED

A SIGNIFICANT AMOUNT ABOUT

ANOTHER PART OF THE GENOME

THAT'S FUNCTIONALLY IMPORTANT IN

WAYS NOT BY CODING FOR PROTEIN

BUT BY DOING OTHER THINGS.

LIKE REGULATING WHEN GENES GET

TURNED ON AND OFF, AND VARIOUS

THINGS IMPORTANT FOR CHROMOSOME

FUNCTION.

AND THOSE ARE NON-CODED PARTS OF

THE GENOME THAT WE'RE BARELY

SCRATCHING THE SURFACE ON AT

BEST, POOR CHAPTER OF THOSE

CLIFF NOTES.

IT'S TURNING OUT INCREASINGLY

WE'RE LEARNING THAT A LOT OF THE

VAIRNTSZ THAVARIANTS THAT ARE COMPLEX

GENETIC DISEASES ARE NOT IN

CODING REGIONS BUT NON-CODING

REGIONS OF THE GENOME.

TWIKING PARTS OF THTWEAKING PART OF THE GE
NOME

INSTEAD OF BREAKING THE PROTEINS

OUTRIGHT.

WE NEED A MUCH BETTER

INTERPRETIVE UNDERSTANDING OF

THE GENOME AND THIS IS THE VERY

REGION THAT IS SO MEDICALLY

IMPORTANT TO UNDERSTANDING THESE

VERY VERY IMPORTANT CLASS OF

COMPLEX DISEASES.

SO AGAIN, LOTS OF ADVANCEMENT

BUT A LOT MORE TO LEARN.

WHAT'S GOING TO BE CRITICALLY

IMPORTANT TO FULLY SEIZE ALL OF

THIS OUT ESPECIALLY FOR COMPLEX

DISEASES.

AS YOU'RE GOING TO HEAR FROM

BILL GAHL GETTING AT THE GENETIC

BASES OF THESE REMAINING TWO TO

4,000 RARE MEN DELLIAN DISORDERS

IS BETTER FOR GENOME.

AND THE NECESSITY TO DEVELOP NEW

MOTHERS THAT WOULD ALLOW --

METHODS THAT WOULD ALLOW US TO

SEQUENCE GENOMES.

THIS IS NOT A COMPLETELY NEW

IDEA .

IN FACT AS SOON AS THE HUMAN

GENOME PROJECT ENDED, WE LOOKED

AT HOW MUCH IT COST US ROUGHLY

TO SEQUENCE THAT FIRST HUMAN

GENOME.

PRICE TAG CAME IN JUST ABOUT A

BILLION DOLLARS.

IT WAS THE BEST BILLION TOLLS WE

PROBABLY EVER SPENT -- BILLION

DOLLARS WE PROBABLY EVER SPENT

BUT IT WAS THE BEST BILLION

DOLLARS.

THIS IS NOT GOING TO BE THE

KINDS OF TECHNOLOGY THAT WOULD

ALLOW US TO DO THE KIND OF

STUDIES TO UNDERSTAND THE

MOLECULAR BASIS OF STUDIES.

THEY STARTED INVESTING QUITE

HEAVILY IN DEVELOPING NEW

TECHNOLOGIES THAT ONE DAY WOULD

REDUCE THE COST OF SUENCING

THE HUMAN GENOME AND STHAGHT

WOULD APPROACH A VERY REASONABLE

CLINICAL PATH.

SOMETHING LIKE $1,000.

IN FACT WE PUBLISHED A PAPER IN

2003 CALLING FOR EFFORTS THAT

WOULD GENERATE A TECHNOLOGY THAT

WOULD RESULT IN THE THOUSAND

DOLLAR GENOME.

IN FACT THIS BECAME ALMOST A

BATTLE CRY FOR THE FIELD.

CAN WE DEVELOP TECHNOLOGIES THAT

WOULD ALLOW US TO SEQUENCE AN

INDIVIDUAL'S GENOME FOR A

THOUSAND BUCKS.

AND ALL I COULD TELL YOU IS THIS

HAS BEEN WILDLY SUCCESSFUL.

AND IN FACT IT'S NOT LIKE

THERE'S ONE NEW MACHINE OR TWO

OR THREE OR FOUR OR FIVE SIX OR

SEVEN, BUT NINE NEW TECHNOLOGIES

THAT HAVE COME ON THE SCENE.

EACH ONE A LITTLE GIVE, EACH ONE

A LITTLE BETTER OR DIFFERENT

FROM THE OTHER.

AND BY THE WAY, WHATEVER I SHOW

HERE, I WILL BE SHOWING

SOMETHING DIFFERENT TWO, THREE

FOUR YEARS FROM NOW.

THERE WILL CONTINUE TO BE NEW

TECHNOLOGIES I KNOW ABOUT THAT

ARE COMING OUT IN THE NEXT FEW

YEARS.

PROBABLY WILL REPLACE ALL OF

THESE CONTINUING TO DRIVE DOWN

THE COST OF SEQUENCING THE

GENOME.

IN FACT, IF YOU ASK ME TODAY HOW

MUCH DOES IT COST TO SEQUENCE A

HUMAN GENOME, ARE WE DOWN TO

$1,000ATE.

TO SEQUENCE A WHOLE HUMAN GENOME

COSTS ABOUT THE ORDER OF $5,000,

$4,000, DEPENDS HOW, WHAT KIND

OF QUALITY, DEPENDS EXACTLY WHAT

YOU DO, HOW YOU MEASURE THE

COSTS.

BUT WE'RE VERY CLOSE.

IF YOU ASK ME WHAT KEEPS ME UP

AT NIGHT, NOT THIS.

WE'LL COAST TO $1,000 GENOME.

IN FACT WE HAVE VERY VALUABLE

SHORT CUTS WE CAN USE.

FOR EXAMPLE WE CAN NOW SEQUENCE

THE CODING REGIONS.

YOU'RE GOING TO HEAR ABOUT THAT

IN YOUR NEXT TALK.

FORGET ABOUT THE WHOLE GENOME

JUST SEQUENCE THE REGIONS WHERE

MOST OF THE ACTION IS FOR RARE

GENETIC DISEASES.

HOW MUCH DOES THAT COST?

LESS THAN A THOUSAND BUCKS.

IN FACT I JUST GOT AN E-MAIL

YESTERDAY FOR A COMPANY OFFERING

IT FOR 799 BUCKS.

AND IT'S BECOMING AN INDUSTRY, A

COMMODITY.

SO WE HAVE SUCCESSFULLY LOST

TREMENDOUS AMOUNT OF ZEROES OFF

THIS PRICE TAG.

WE'LL GET TO THE WHOLE GENOME

AND MEANWHILE WE'LL GET THE

CODING REGIONS OF THE GENOME

KNOWN AS  MANY SSOME FOR

LESS THAN $1,000.

IS THE GLASS HALF FULL?

IT'S VERY MUCH THE GLASS HALF

EMPTY BECAUSE THE TISSUE OUT THE

I -- IT TURNS OUT THE FIFTH STEP

FOR RIDICULOUSLY AMOUNTS OF

MONEY THAT WE DOUBLE OUR ABILITY

TO INTERPRET HAT SEQUENCE.

THE FIFTH STEP IS ROUTINELY

BEING ABLE TO ANALYZE THE DATA

WE'RE GENERATING AND IT TURNS

OUT THIS NOW REPRESENTS THE

NUMBER ONE BOTTLE NECK IN

GENOMIC.

I THINK IT'S THE NUMBER ONE

BOTTLE NECK IN ALL OF BIO

MEDICAL RESEARCH.

I HEAR ABOUT THIS CONSTANTLY.

WE'RE IN A WORLD WE WEREN'T IN

BEFORE.

WHEN THE GENOME PROJECT BEGAN,

WE WERE STARVING FOR DATA.

AS SOON AS ANY DATA WAS

GENERATED, WE WOULD ANALYZE IT.

BUT NOW YOU CAN GENERATE SO MUCH

MORE DATA AND WE'RE STARVING FOR

THE ABILITY TO ANALYZE ALL THE

DATA WE'RE GENERATING.

THE BOTTLE NECK HAS MULTIPLE

COMPONENTS.

WE HAVE HARDWARE ISSUES WE

GENERATE SO MUCH DATA WE CAN'T

STORE IT AT ALL.

WE DON'T EVEN HAVE ENOUGH BAND

WIDTH TO QUICKLY GIVE A GENOME

SEQUENCE GENERATED FOR BELL GALL

AND -- BILL GAHL AND GET IT DOWN

HERE QUICK ENOUGH TO ANALYZE IT.

IT ACTUALLY PUTS THE SEQUENCES

ON HARD DRIVE AND FEDEX THEM

FROM ONE END OF THE COUNTRY

BECAUSE IT'S QUICKER THAN TRYING

TO PUSH IT ACROSS THE INTERNET.

THAT'S A HARDWARE PROBLEM WE'RE

TRYING TO ADDRESS.

THERE ARE ALL SORTS OF SOFTWARE

PROBLEMS, JUST HAVING THE TOOLS

EACH OF THESE MACHINES, IT'S A

LITTLE DIRTY AND HAVING THE

TOOLS AVAILABLE FOR ANY USER TO

BE ABLE TO ACCESS THE KINDS OF

DATA ANALYSIS PIPELINES THAT ARE

NEEDED FOR THAT TECHNOLOGY.

WE'RE WORKING ON THAT.

FOR ANY OF THE TRAINEES IN THE

AUDIENCE, WE'VE GOT A WORK FORCE

ISSUE HERE.

WE NEED MORE AND MORE PEOPLE

TRAINED AND ANALYZING LARGE DATA

SETS BUT ALSO UNDERSTAND

BIOLOGY, UNDERSTAND MEDICINE,

UNDERSTAND PHYSIOLOGY.

IN THE 2350U67 FUTURE, WE NODE MORE

INDIVIDUALS BECAUSE IT -- WE

NEED MORE INDIVIDUALS BECAUSE IT

WILL HELP US BREAK DOWN THE

BOTTLE NECK.

WE'LL SOLVE THIS ON A CASE BY

CASE 3W5EU7SZ, IN THE LONG RUN

WE'LL SAW IT.

IT WON'T BE THE ONLY BOTTLE NECK

WE'LL FACE.

THE TRUTH IS RIGHT NOW WE HAVE

AN INFORMATIONAL BOTTLE NECK.

BECAUSE THEY FANCY METHODS FOR

SEQUENCING DNA, THEY'RE

INCREDIBLY EFFECTIVE AT

OVERWHELMING US WITH DATA AND

BILL'S GOING TO DESCRIBE THIS.

AND WE CAN EVEN SORT OF SLUG OUR

WAY THROUGH THE BOTTLE NECK OF

JUST DEALING WITH ALL THAT DATA

AND GET DOWN TO A POINT OF

KNOWING 3 TO 5 MILLION VARIANTS

THAT MIGHT EXIST ACROSS THE

GENOMOGENOME OR THE THOUSANDS OF

VARIANTS.

IT DOESN'T MEAN WE DON'T KNOW

WHAT THAT VARIANT MEANS WHEN YOU

THINK ABOUT IT WHAT A CLINICAL

PERSPECTIVE.

THERE'S A BIG GAP BETWEEN HAVING

THE VARIANTS AND KNOWING THE

CLINICAL IMPLICATIONS.

PEEBILL GAHL WILL TELL YOU AFTER

ALL THAT DATE, WHAT DOES THAT

MEAN TO THE INDIVIDUAL PATIENTS.

WHEN BILL GOES ON ROUNDS THIS IS

WHAT HE FEELS LIKE SORT OF

LOOKING AT THE SEQUENCE OF THAT

PATIENT AND JUST WONDERING WHICH

OF THESE VARIANTS MIGHT BE ONE

THAT'SCLINICAL RELEVANT.

BUT AGAIN I THINK WE WILL SOLVE

THIS BUT IT JUST REPRESENTS

WHERE ARE WE IN 2012.

A NAME ALL OF YOU KNOW IN 2010

WROTE IN HIS EDITORIAL TALKING

ABOUT THE GENOME SEQUENCE OF THE

DECADE.

THE PHYSICIANS ARE STILL A LONG

WAY FROM SUBMITTING -- THE

SEQUENCING NOT BECAUSE THE PRICE

IS HIGH BUT BECAUSE THE DATA ARE

DIFFICULT TO INTERPRET.

IT SAYS THE BOTTLE NECK BUT IT'S

THE REASON WHY WE MUST RECOGNIZE

OUR ABILITY TO FULLY UTILIZE

GENOMIC IS GOING TO REQUIRE, IS

GOING TO NEED MUCH MORE ROBUST

DATA ANALYSIS PIPELINE AND

BASICALLY BREAKING DOWN THE

INFORMATIONAL 3W5U8G9S NEC BOTTLE NECK AS

WELL.

THOSE ARE THE FIVE STEPS THAT

HAVE BASICALLY REPRESENTED WHAT

HAS GONE ON OVER THE LAST EIGHT

YEARS.

BUT THERE ARE OTHER STATEMENTS

LONG THIS JOURNAL -- OTHER STEPS

ALONG THIS JOURNEY.

WE'VE GOT TO THINK ABOUT

DIAGNOSTICS AND HOW TO USE THIS

INFORMATION FOR IMPROVING

DIAGNOSTICS, DEVELOPING NEW

THERAPIES, NEW PREVENTIVE

MEASURES AND OTHER STEPS I

HAVEN'T THOUGHT HOW FAR AND

YOU'RE THINKING OF IT.

I'M SURE WE COULD INTERPRET THIS

SLIDE IN VARIOUS WAY.

THE TRUTH OF THE MATTER IS WHERE

WE ARE IN JANUARY OF 20   126789

I --2012.

ARE WE AT WHERE WE THOUGHT THE

GENOME PROJECT ENDED.

WE HAVE LARGE AMOUNTS OF DATA.

AS YOU CAN FELL FROM THESE

ENGINES, WE HAVIMAGES WE HAVE OPPORTUNITIE
S TO

START APPLYING GENOMICS TO ALL

SORTS OF PROBLEMS IN CLINICAL

MEDICINE.

YES WE HAVE BOTTLE NECKS BUT WE

HAVE THE CAPACITY TO DO THINGS

THAT WAS THE IMAGINABLE, FIVE

YEARS AGO THREE YEARS AGO AND

EVEN TWO YEARS AGO.

BILL WILL ECHO THE FACT THE PACE

WHICH ALL OF THIS IS HAPPENING

IS SURPRISING ALL OF US.

IN MANY WAYS IT WAS VERY

OPPORTUNE FOR OUR INSTITUTE

RESPONSIBLE FOR SORT OF LEADING

GENOMIC RESEARCH HERE AT NIH TO

SORT OF REASSESS WHERE WE ARE

HAVING SORT OF NOW EIGHT YEARS

MOIST THE GENOME PROJECT.

IN FACT WE DID THAT AND WE DID A

STRATEGIC PLANNING PROCESS

STARTING SEVERAL YEARS AGO AND

THEN JUST ABOUT A YEAR AGO,

ABOUT 11 MONTHS AGO OR SO

PUBLISHED A NEW STRATEGIC PLAN

FOR THE FIELD OF GENOMICS THAT

REALLY EMPHASIZED THE

APPLICATIONS OF GENOMICS, THE

CLINICAL MEDICINE AND THE PATH

TOWARDS GETTING THIS TOWARDS

GENOMIC MEDICINE.

AND I HAVE A COPY OF THIS HERE

AND I HAVE IT ON THE TABLE I

KNOW MANY OF YOU PICKED UP.

PLEASE PICK UP OF THES ONE OF THESE UP.

I URGE YOU TO READ IT.

IT'S WRITTEN FOR A BROAD

AUDIENCE AND I THINK YOU WOULD

APPRECIATE SORT OF ACTUALLY

READING IT FROM COVER, FROM TOP

TO BOTTOM.

BUT I JUST IN THE LAST TEN

MINUTES OR SO WHAT I WANT TO DO

IS JUST TELL YOU THE HIGHLIGHTS

OF THIS HOPING THAT YOU WILL

READ THE DETAILS.

IT BECAME VERY CLEAR BY

LISTENING TO LITERALLY HUNDREDS

AND LUNGS OF COLLEAGUE HUNDREDS OF:00COLLE
AGUES AROUND

THE WORLD THAT ADVISED US, AS I

TRIED TO EXPLAIN TO YOU FOR

MAKING THIS JOURNEY FROM -- WERE

UNPRECEDENTED NOW AND

UNANTICIPATED TO COME ON THE

SCENE AS QUICKLY AS THEY DID.

IN FACT IT WAS TIME TO BE MORE

SOPHISTICATED AND MORE SPECIFIC

IN DESCRIBING WHAT THIS JOURNEY

WAS GOING TO BE LIKE, ESPECIALLY

FOR THINKING ABOUT THE RESEARCH

STEPS THAT ARE GOING TO BE

NEEDED TO GET THERE.

AT THE END OF THE DAY THE WAY WE

ORGANIZE THIS PLAN IT'S VERY

USEFUL TO THINK ABOUT THIS

BECAUSE I THINK ABOUT THE FIVE

DOMAINS OF ACTIVITIES, YOU CAN

VERY MUCH SEE A NATURAL

PROGRESSION THAT'S VERY

RATIONALIST SPECIALLY WHEN YOU

START THINKING ABOUT THE FUTURE.

SO THE FIVE DOMAIN OF WHICH WE

ORGANIZE OUR STRATEGIC THINKING

STARTED WITH USING GENOMIC TO

UNDERSTAND THE STRUCTURE OF

GENOMES.

SOUNDS LIKE THE HUMAN GENOME

PROJECT.

ALSO USING GENOMICS THEN TO

STUDY, UNDERSTAND THE BIOLOGY OF

GENOMES, HOW GENOMES WORK.

DEVELOPING A BETTER AND BETTER

COMPENDIUM OF THE FUNCTIONAL

ELEMENTS OF THE HUMAN GENOME.

BUT THEN USING THAT KNOWLEDGE TO

USE GENOMICS TO UNDERSTAND THE

BIOLOGY OF DISEASE, TRULY

GETTING OUT THE MOLECULAR

3W5EUSZ OBASISOF DISEASE AND USING THAT

KNOWLEDGE TO ADVANCE THE SCIENCE

OF MEDICINE.

MEDICAL SCIENCE.

POTENTIALLY CHANGING THE

PRACTICE OF MEDICINE BUT

REALIZING YOU CAN'T STOP THERE

JUST BECAUSE YOU HAVE A GOOD

IDEA, YOU THINK IT'S GOING TO

WORK.

YOU HAVE TO IMPLEMENT THAT IN A

HEALTHCARE DELIVERY SYSTEM AND

DEMONSTRATE THROUGH RESEARCH

THAT YOU TRULY HAVE IMPROVED THE

EFFICIENTIVENESS OF HEALTHCARE

USING THAT GENOMIC INFORMATION.

THESE FIVE DOUGH MAINS OF

RESEARCH ACTIVITY REALLY PROVIDE

A FIELD OF VISION GOING FORWARD

TO RECOGNIZE GENOMIC MEDICINE.

IT PROVIDES A VERY USEFUL

REFERENCE POINT THINKING ABOUT

WHAT HAS HAPPENED AND ALSO

PREDICTING THE FUTURE.

WHAT DO I MEAN BY THAT.

THE WAY WE REPRESENT IT WAS

THROUGH A SERIES OF HYPOTHETICAL

DENSITY PLAWFLTS THAT JUST

SIMPLY REPRESENTED BLUE DOTS AS

HYPOTHETICAL RESEARCH

ACCOMPLISHMENTS OR GENOMIC

ACCOMPLISHMENTS OVER DIFFERENT

DOMAINS OVER DIFFERENT PERIOD OF

TIME.

DURING THE HUMAN GENOME PROJECT

I WILL TELL YOU ALL

ACCOMPLISHMENTS WERE IN THAT

DOMAIN.

WE FIGURED OUT THE STRUC STRUCTURE OF

GENOMES.

WE FIGURE THE OUT HOW THEY

WORKED AND SOMETHING ABOUT

DISEASE.

THE DENSITY PLOT PILES UP IN RED

AROUND THE FIRST DOMAIN.

WHAT DID I TELL YOU ABOUT THOSE

FIVE STEPS.

SINCE THE GENOME PROJECT ENDED?

WELL THE 1KWR50E7 GENOME PROJECT ENDED IT

WAS LEARNING ABOUT STRUCTURE OF

GENOME BUT ALSO USING THAT

KNOWLEDGE TO UNDERSTAND HOW THE

GENOME WORKS.

AND THE CENTER OF GRAVITY WAS

FIRMLY PLACED ON THESE FIRST TWO

DOMAINS, SURE WE LEARNED A LOT

ABOUT RARE GENETIC DISEASES AND

INCREASINGLY MORE AND MORE ABOUT

COMPLEX DISEASES AND A FEW WHERE

WE CAN SHOW WE ADVANCED MEDICAL

SCIENCE AND MAYBE IMPROVED

HEALTHCARE.

BUT FUNDAMENTALLY THAT CENTER OF

GRAPH THEY WAS ON THESE FIRST

TWO DOMAINS.

WHAT ABOUT THE NEXT DECADE.

WHAT DO WE SEE IS HAPPENING.

WHO IS GOING TO SHIFT IN THE

CENTER OF THAT GRAVITY AND THE

REAL EMPHASIS OVER THE NEXT

DECADE WILL BE BETTER

UNDERSTANDING HOW GENOMES WORK.

PARTICULARLY USING THAT

KNOWLEDGE TO TRULY UNDERSTAND

THE GENOMIC BASIS OF DISEASE.

WITH THAT WILL COME MORE

ADVANCES IN MEDICAL SCIENCE AND

MAYBE IN A FEW MORE HOME RUNS IN

HEALTHCARE.

BUT LET'S BE REALISTIC HERE,

TRULY MAKING ACCOMPLISHMENTS OUT

HERE IN THE CLINICAL DOMAINS

WILL TAKE MORE THAN FIVE, TEN,

15 YEARS.

BEYOND 2020 WE'LL SEE A LOT OF

ACCOMPLISHMENTS BUT THE NEXT

DECADE THE MOST EXCITING

DEVELOPMENTS WILL BE IN THE

SECOND AND THIRD DOMAIN.

NOW THE TRUTH OF THE MATTER IS,

THIS IS AUDACIOUS AGENDA HERE.

THE IDEA TO TRULY UNDERSTAND THE

BIOLOGY OF ALL DISEASES AND

CHANGING MEDICAL SCIENCE AND

IMPROVING HEALTHCARE.

THIS IS NOT GOING TO BE

SOMETHING THAT WE'RE GOING TO DO

JUST HERE AT NHGR I.

IT'S A WORLD VIEW OF GENOMICS

FAR FAR MORE THAN WHAT ONE

LITTLE INSTITUTE, IN FACT IT'S

FAFAR MORE THAN ONE FUNDING

AGENCY, FAR FAR MORE THAN WHAT

ONE COUNTRY WILL DO.

WHAT WE DESCRIBE IS REALLY A

WORLD VIEW OF USING GENOMICS TO

UNDERSTAND DISEASE AND

EVENTUALLY TO IMPROVE

HEALTHCARE.

AND SO IT'S WITHIN THAT CONTEXT,

THOUGH, I THOUGHT I WOULD JUST

TELL YOU IN THE LAST FIVE

MINUTES SORT OF WHAT I THINK THE

FUTURE'S GOING TO BRING

SPECIFICALLY FOR THE THINGS THAT

WE THINKING ABOUT MOST

AGGRESSIVELY HERE AT NIH, AND

PARTICULARLY THE ARENA -- I'M

SORT OF TELEGRAPHING THE FUTURE

BY TELLING YOU WHAT OUR

IMPERATIVES FOR GENOMIC

MEDICINE, THIS IS TEXT DOT 2.

IT'S THINGS WE HAVE TO DO AND

OUR INSTITUTE HERE AT N IT H

WILL BE INVESTING IT.

IT REALLY DOES PREDICT THE

FUTURE.

WHAT THE FUTURE WILL BRING I

WILL AT THE YOU IS VERY MUCH

INVOLVED IN SEQUENCING LOTS OF

PEOPLE'S GENOMES.

THAT'S PART OF CLINICAL RESEARCH

AND EVENTUALLY SICKLE CARE.

I'M NOT TALKING ABOUT HUNDREDS

OF PEOPLE GENOMES I'M NOT EVEN

TALKING ABOUT THOUSANDS OF

PEOPLE'S GENOMES I'M TALKING

ABOUT 10 OF THOUSANDS AND

HUNDREDS OF THOUSANDS OF

INDIVIDUALS TO GET SUFFICIENT

KNOWLEDGE DISEASES TO FULLY

INTERPRET WHICH VARIANTS ARE THE

ONES THAT ARE RELEVANT FOR

DISEASE.

WHEN THIS HAPPENS ACROSS TENS OF

THOUSANDS OF PEOPLE, IT'S NOT

GOING TO HAPPEN OUT IN THE

CLINICS NECESSARILY, OUT IN

COMMUNITY HOSPITALS.

IT'S FIRST GOING TO HAPPEN IN

RESEARCH INSTITUTIONS SUCH AS

HERE IN THE CLINICAL CENTER AS

BILL'S GOING TO DESCRIBE.

EVENTUALLY WE WILL LEARN HOW TO

USE THIS INFORMATION FOR

CLINICAL CARE BUT THAT'S NOT

GOING TO HAPPEN OVER NIGHT.

IT'S GOING TO HAPPEN THROUGH A

FOUNDATION OF STRONG CLINICAL

RESEARCH.

IF YOU'RE INTERESTED IN READING

MORE ABOUT SOME OF THESE

EARLIEST CLINICAL APPLICATIONS,

ONLY FROM OUR INSTITUTE AND I

WROTE TO WRITE A COMMENTARY AND

I WOULD POINT TO THIS PAPER THAT

CAME OUT LAST FALL.

WHAT SPECIFICALLY DO I THINK IS

GOING TO HAPPEN AND WE START TO

USE THESE POWERFUL NEW

SEQUENCING TECHNOLOGIES AND

USING THEM FOR CONTINUE CLUL

RESEARCH TO GET -- FOR CLINICAL

RESEARCH TO GET AT MOLECULAR

BASIS FOR DISEASE.

I PREDICT OVER THE NEXT TEN

YEARS THERE'S GOING TO BE A

SIGNIFICANT ADVANCE IN OUR

UNDERSTANDING OF THE MOLECULAR

BASIS OF THESE REMAINING RARE

GENETIC DISEASES.

I TOLD YOU WE WOULD COME BACK TO

THE PIE CHART.

WE BELIEVE A PRIORITY AREA OF

RESEARCH IS GOING TO HAVE A

CONCERTED EFFORT TO NOW USE ARE

GENOME SEQUENCING TO UNDERSTAND

THE CAUSES OF THESE REMAINING

RARE GENETIC DISEASES.

BILL GAHL IS GOING TO DESCRIBE

SOME OF THESE CASES TO YOU IN

HIS TALKS.

MEANWHILE WE IMAGINE

INDUSTRIALIZING THIS PROCESS FOR

THAT WE KNEW EXIST.

WE DECIDED TO LAUNCH A NEW

TISSUIVE THATISSUETISSUIVE.

WE HAVE GENOME CENTERS DEDICATED

TO STUDYING MENDELIAN DISORDERS.

THE IDEA IS TO DISCOVER GENETIC

BASIS FOR AS MANY DISORDERS AS

POSSIBLE BY COORDINATING HOW

SAMPLES ARE COLLECTED, HOW THE

DE IS ANALYZED, HOW THE

SEQUENCING IS DONE.

AND OF COURSE ESTABLISHING,

DISSEMINATING THE BEST DESIGNS

FOR MAKING THIS HAPPEN AND HAVE

THE INK ENGINES OF DISCOVERY AT

THESE CENTERS WE'RE CREATING TO

ALLOW PHYSICIAN ANDS GENETICISTS

FROM AROUND THE WORLD TO PROVIDE

SAMPLES TO ACCELERATE THE PACE

TO FIGURE THIS OUT.

AND COORDINATE A LIST OF SAMPLES

SO PEOPLE AROUND THE WORLD

COORDINATING WITH OTHER EFFORTS

AROUND THE WORLD COULD BE VERY

ORGANIZED IN TRYING TO GET AT

THE REMAINING TO FOUR THOUSAND

GENETIC DISEASES TRYING TO

FIGURE OUT THE MOLECULAR BASIS

FOR.

HERE IN THE UNITED STATES WHAT

WE ARE DOING, WE SPHRUNLDED

THREE GROUPS.

-- FUNDED THREE GROUPS.

ONE AT THE UNIVERSITY OF

WASHINGTON, YALE AND COMBINED AT

BAYLOR WE HAVE HUMAN GENOME

1EUSCYSTS INVOLVED IN THIS.

THIS IS GOING TO PUSH THE

ACCELERATOR TO HELP US INCREASE

THE PACE AT THE DISCOVERY BASIS

FOR THESE RARE GENETIC DISEASES.

BUT SIMILARLY WE WILL BE USING

ALL SORTS OF PROGRAMSAT OUR

INSTITUTE AND OTHER INSTITUTES

COORDINATED WITH THOSE IN

SUBSTITUTES AND AROUND THE WORLD

TO GO FROM THESE LOLLIPOP

REGIONS OF THE HUMAN GENOME FOR

SEQUENCING LOTS OF INDIVIDUALS

GENOMES WITH DIFFERENT COMPLEX

DISEASES AND USING THAT

KNOWLEDGE TO TRY TO GET AT THE

NEXT ROUND OF STUDY TO SORT

THROUGH ALL THE VARIANTS THAT

ARE THERE AND FIGURE OUT WHICH

OF THOSE VARIANTS ARE THE RUNS

CONFERRING RISKS FOR COMPLEX

DISEASES.

A MORE COMPLICATED SET OF

STUDIES THAT HAVE TO BE PURSUED

DECREASING COSTS OF SEQUENCING

AND NEXT IDEA ON THE NEXT ROUND

OF APPROACHES BUT THIS IS ALSO

GOING TO BE ACCELERATED IN THE

COMING YEARS.

THE THIRD HIGHLIGHT I WILL TELL

YOU WHICH IS VERY MUCH LOW

HANGING FRUIT IS THE USE OF THE

GENOME SEQUENCING METHODS TO

STUDY CANCER.

THIS IS A TALK ACTUALLY IT'S

PROBABLY TWO-THREE TALKS IN AND

OF ITSELF BECAUSE CANCER IS A

DISEASE OF THE GENOME AND THE

USE OF THESE NEW IMMEDIATE

ALWAYS, STUDY CANCER GENOMES AND

TO CATALOG THE VARIANTS THAT ARE

FORMED AND THE STRUCTURAL

CHANGES THAT TAKE PLACE IN THE

CANCER GENOME.

IT IS ABSOLUTELY SOME OF THE

GREATEST OPPORTUNITIES TO

ADVANCE CANCER RESEARCH.

THAT IS THE REASON WHY A NUMBER

OF YEARS AGO OUR INSTITUTE

PARTNERED UP WITH THE CANCER

INSTITUTE TO LAUNCH THE CANCER

GENOME AT LAST WHICH IS A ATLAS WHICH IS T
HE

EVIDENT TO TAKE DIFFERENT KINDS

OF CANCERS, SEQUENCE THE GENOMES

AND CATALOG SOME OF THE COMMON

VARIANTS THAT ARE FOUND IN THOSE

CANCER GENOMES TO PROVIDE BOTH

DIAGNOSTIC CLUES AND CLUES ABOUT

THE BASIC MECHANISMS THAT MIGHT

LEAD TO NEW RESULTS AND

THERAPIES.

THIS IS MET WITH A WHOLE SERIES

OF INTERNATIONAL EFFORTS FROM

COUNTRIES ALL BEING VERY

COORDINATED.

NEEDLESS TO SAY ADVANCES IN

CANCER GENOMICS ARE GOING TO BE

PROFOUND OVER THE NEXT DECADE.

BUT WITH THAT KNOWLEDGE OF ALL

THESE VAIRPT VARIANTS ASSOCIATED WITH

RARE OR COMMON DISEASES, CANCER

GENOMES IT WILL BECOME

OVERWHELMING FOR PRACTICING

PHYSICIANS AND CLINICAL

RESEARCHERS.

JUST AS THERE IS THIS

COMPUTATIONAL BOTTLE NECK

THERE'S AN INFORMATIONAL BOTTLE

NECK IN GENERAL.

IF YOU PUT ON TOP OF THAT

CLINICAL INFORMATION, WE ARE

HEARING MORE AND MORE ABOUT THE

NEED FOR MORE ROBUST CLINICAL

GENOMICS INFORMATION SYSTEMS.

AND WE ARE VERY MUCH TRYING TO

ACCELERATE THE DEVELOPMENT TO

SORT OF KEEP PACE WITH THESE

GENOMIC ADVANCES.

INTEGRATING ALL THIS GENOMIC

INFORMATION INCREASINGLY INTO

ELECTRONIC HEALTH RECORD,

PROBLEMS IN AND OF THEMSELVES,

WE'RE LOOKING AT THAT.

BUT ALSO COMING UP WITH SIMPLE

TOOLS FOR PRACTICING PHYSICIANS

TO KNOW WHICH VARIANTS ARE ONES

THAT ARE RELEVANT FOR THE CARE

OF THAT PATIENT, WHAT

MEDICATIONS TO GIVE THEM, HOW TO

STRATIFY THEM AND SO FORTH.

INCREASINGLY WE'RE THINKING

ABOUT HOW TO BEST FACILITATE

THIS THROUGH SOME INITIALLY

RESEARCH EFFORTS AND EVENTUALLY

SOME DEVELOPMENT EFFORTS.

SO I WILL LEAVE YOU WITH THAT BY

REVIEWING THE FACT THAT I'VE

DESCRIBED TO YOU THIS JOURNEY

FROM THE GENOME PROJECT TO THE

REALIZATION OF GENOMIC MEDICINE.

WE'VE SIMPLY GOTTEN MORE

SOPHISTICATED IN HOW WE'RE

DESCRIBING THIS BY HAVING A

PROGRESSIVE SET OF DEMAINS THAT

GET US CLOSER -- DOMAINS GETTING

US CLOSER AND CLOSER TO THE

BEDSIDE OF PATIENTS.

YOU WILL HEAR CERTAINLY THE NEXT

SPEAKER IS A PARTICULAR

ACCELERATION AT WHICH WE WILL

SEE DISCOVERIES ABOUT THE

GENTLELADYIGENETIC BASIS AND INCREASING

AMOUNTS OF GENOMIC INFORMATION.

WITH THAT I WILL STOP EXCEPT TO

TELL YOU I DON'T MEAN TO IMPLY

FOR A MINUTE THAT ANY OF THIS IS

GOING TO BE EASY.

THIS IS ALL VERY HARD.

DO YOU KNOW WHAT'S HARD,

INTERPRETING THE GENOME IS HARD

AND CERTAINLY GETTING AT THE

COMPLEXITIES OF HUMAN DISEASE

ARE GOING TO BE INCREDIBLY HARD.

THERE ARE VERY TALENTED PEOPLE

THAT HAVE BEEN RECRUITED TO THIS

EFFORT THAT HAVE ALWAYS BEEN

ASSOCIATED WITH GENOMICS.

I WANT TO LEAVE YOU WITH A QUOTE

BECAUSE I THINK IT CAPTURES BOTH

WHAT RESPECTS OUR FIELD AND

REFLECTS THE SECOND PARYK YOU'LL

HEAR FROM IN A WIN.

THE --  THOSE OF US INVOLVED IN

THE GENOME PROJECT, WE ARE VERY

MUCH OPTIMISTS AND WHILE WE HAVE

LOTS OF DIFFICULTIES AHEAD OF US

WE'RE VERY EXCITED ABOUT THAT

OPPORTUNITY.

I WILL STOP THERE.

DO I TAKE QUESTIONS NOW OR

SHOULD BILL GO AND THEN TAKE

QUESTIONS.

WHENEVER YOU WANT.

>> OKAY.

THANK YOU ERIC.

THAT WAS MARVELOUS.

[APPLAUSE]

I REA MIND YO REMIND YOU TO THE COPIES THA
T

ERIC PUT HERE, THIS IS ALSO

POSTED ON THE WEBSITE FOR

DEMYSTIFYING MEDICINE SO YOU CAN

ACCESS IT THERE.

SO WE HAVE TIME IF SOME OF YOU

HAVE A FEW BRIEF QUESTIONS OR IF

YOU WANT TO HOLD THEM UNTIL

AFTER.

>> I WILL BE HAPPY TO ANSWER

QUESTIONS AFTER BILL AS WELL.

>> HI.

A NICE TALK.

MOST OF WHAT YOU TOUCHED ON, IS

REALLY THE DIAGNOSTIC AND

CAUSATIVE SIDE OF MEDICINE BUT

THERE'S THE OTHER SIDE, THE

TREATMENT.

SO CAN YOU COMMENT A LITTLE BIT

ON HOW YOU'RE LOOKING AT THE

GENETICS OF RESPONSE TO

DIFFERENT THERAPIESOR EVEN,

IMMUNLOGICAL RESPONSES TO

VACCINATIONS AND SO FORTH.

>> ABSOLUTELY.

I HINTED TEND I DIDN'T TALK

ABOUT IS THAT IN UNDERSTANDING

THE COMPLEXITIES OF THE GENOME,

NOT ONLY ARE WE LEARNING ABOUT

THE GENETIC VARIANTS THAT LEAD

TO RISK FORGETTING DISEASESSOR

CAUSING DISEASES, WE'RE ALSO

LEARNING ABOUT THE GENETIC

VARIANTS THAT INFLUENCE OUR

RESPONSE TO TREATMENT.

IN FACT THERE'S A WHOLE FIELD

WHICH YOU PROBABLY KNOW ABOUT

CALLED PHARMACOGENOMICS,

PHARMACOLOGY AND JUST A JUST  -- GENOMICS.

BASED ON THAT DETERMINING

WHETHER A PERSON WILL BE A GOOD

RESPONDER OR BAD RERESPONDER.

I THINK THAT SCRATCHES THE

SERVICE, FIVE TEN YEARS FROM NOW

THERE WILL BE LOTS OF

MEDICATION.

SIMILARLY THERE'S NO QUESTION

THAT OUR IMMUNOLOGIC RESPONSE IS

TOGETHER TO BE HEAVILY

GENETICALLY BASED AND

RESPONSIBILITIES TO VACCINES.

IT MAY GUIDE PREVENTIVE MEASURES

AND VACCINATION REGIMENS AND SO

FORTH BASED ON GENOMIC

KNOWLEDGE.

>> [INDISCERNIBLE]

>> SO THE QUESTION WAS HOW MUCH

WOULD YOU MISS BY JUST DO EXSO

MANY SEQUENCING VERSUS WHOLE

GENOME SEQUENCING AND OF COURSE

IT DEPENDS WHAT YOU'RE LOOKING

FOR.

IT'S A COST BENEFIT ANALYSIS.

IF THE ANSWER SITS -- IF IT'S

NOT, IF IT'S OUGHT THERE IN

NON-CODING DNA, YOU BETTER DO

WHOLE GENOME SEQUENCING BUT YOU

HAVE TO BE ABLE TO INTERPRET IT.

AS OF TODAY, OUR ABILITY TO

INTERPRET THAT IS QUITE POOR SO

A LOT OF PEOPLE ARE TRYING TO GO

WHERE, ARE SORT OF CONSIDERED

THE LOW HANGING FRUIT IN SOME

WAYS.

A LOT OF WHAT BILL GAHL

DESCRIBES IS WHOLE GENOME SCWEPS

BECAUSE HE BELIEVES THAT'S THE

MOST LIKELY PLACE HE WILL FIND

HIS MUTATION.

IF HE DOESN'T HE WILL DO A WHOLE

GENOME SEQUENCE AND TRY TO

FIGURE IT OUT LATER.

>> OKAY, WE WILL MOVE ON AND

THEN WE'LL HAVE TIME AT THE END

FOR QUESTIONS FOR ALL.

>> I NEED SOMEONE TO HELP WITH

THE SCREEN AND AT THE RISK OF

SEEMING AW AWK AWK -- YOU DID A GOOD JOB.

WE HAVE SOME GUESTS TODAY.

WE HAVE MR. AND MRS. CLADINSKY.

SHE'S ONE OF OUR MEASURES AND

WE'LL AS -- OURPATIENTS AND WE'LL ASK HER

QUESTIONS WHEN WE GET TO THAT

SLIDE.

THE END DISEASE DISEASE PROGRAM

DOES MORE THAN GENETICKICS BUT

BECAUSE WE ARE ROOTED IN THE

STAFF WE DO A LOT OF GENETICS.

THERE ARE A LOT OF PEOPLE THAT

CONTRIBUTE TO THIS.

AND WE ARE ALSO ABLE TO SEE OUR

PATIENT WITHOUT CHARGING THE

PATIENT.

OUR GOAL IS TO MAKE DIAGNOSIS

FOR PEOPLE WHO SEARCH FOR A LONG

TIME FOR ONE AND HAVEN'T GOTTEN

ONE AND ALSO TO FINE NEW

DISEASES AND NEW INSIGHTS INTO

CELL BIOLOGY AND BIO CHEMISTRY.

THE WAY WE WORK THIS PROGRAM IS

THAT PEOPLE APPLY BY GIVING US

THEIR MEDICAL RECORDS AND BY

HAVING THEIR PHYSICIAN GIVE US A

SUMMARY LETTER.

THEN I LOOK OVER THOSE RECORDS

AND DECIDE WHICH CONSULTANTS

SHOULD LOOK THEM OVER AND

USUALLY IT'S BETWEEN ONE AND

FIVE CONSULTANTS.

THEY TELL ME IF THEY THINK IT'S

A GOOD CASE, AND I SORT OF AGREE

WITH THEM.

THEN I WRITE THE NOTES, WHICH IS

EITHER AN ACCEPTANCE OR

REJECTION.

AND THE ACCEPTED PATIENTS COME

FOR ABOUT A WEEK AT THE NIH.

IN THAT TIME WE GET DONE ABOUT

WHAT'S DONE ON AN OUTPATIENT

BASIS IN A YEAR OR TWO YEARS.

AND THE REASON IS BECAUSE WE

DON'T HAVE TO ASK INSURANCE

COMPANIES.

IF YOU HAVE OUTPATIENTS, THEY

HAVE TO GET ONE INSURANCE, ONE

STUDY APPROVED BY INSURANCE

BEFORE THEY CAN GET THE OTHER

ONE DONE AND THAT TAKES ANOTHER

MONTH OR TWO TO SCHEDULE.

SO WE GET A LOT DONE DURING THAT

TIME.

WE HAVE OPEN MEETINGS, ABOUT

ONCE A MONTH WHICH WE DISCUSS

THE PATHOLOGY AND RADIOLOGY, AND

HAVE A BUNCH OF EXPERTS AROUND

THE ROOM.

THOSE ARE INTERESTING.

IN FACT THE NEXT MEETING IS

GOING TO BE FRIDAY FEBRUARY

10TH.

SO A WEEK FROM FRIDAY AT 11:00

IN THE MEDICAL BOARD ROOM OF THE

CLINICAL CENTER.

THAT'S CRC4-2551.

YOU'RE ALL INVITED.

IN THE LAST THREE AND-A-HALF

YEARS SINCE ITS INITIAL

INFORMATION ON MAY 19, 2008,

WE'VE SEEN ABOUT 500 PATIENTS.

AND WE HAD ABOUT 6,000

INQUIRIES.

AND OVER 2000 MEDICAL RECORDS.

THE AVERAGE MEDICAL RECORD'S

ABOUT AN INCH AND-A-HALF THICK

OR SO AND WE REJECTED TWO THIRDS

TO THREE QUARTERS OF THESE

INDIVIDUALS.

THE ONES WE ACCEPT ARE LARGELY

NEUROLOGICAL CASES.

MORE THAN HALF.

AND A LOT OF COMPLEX GENETIC

CASES IN KIDS.

WE DO AT LEAST THRE AT AT LEAST THREE TYPE
S.

COMMERCIAL MOL CLOWR DIAGNOSTICS

MILLION SNP ARRAY AND WHOLE

EXOME SEQUENCING.

THIS IS SOME OF THE SOFTWARE

THAT'S USED.

BUT THE CONCEPT OF A SINGLE

NEUCLO TYPE PAULO MOREOVERRISM WRY

POLYMORPHISM IS SOMETHING YOU

MIGHT WANT TO KNOW.

WE HAVE OUR DNA STRAND AND IF

YOU LOOK AT A MILLION SNIPS THAT

MEANS YOU WILL BE LOOKING ON

AVERAGE ONE OVER 3,000 OF THOSE

BASIS.

AND THOSE MILLION SNIPS ARE

CHOSEN BY A COMPANY TO BE

SPECIFICALLY POLY MORPHIC AND

NOT 1 TO 199 BUT POLY MORPHIC AT

60/40 OR SOMETHING LIKE THAT.

IT'S GOING TO BE A AT OR CG OR

WHATEVER.

THERE ARE TWO POSSIBILITIES AND

THEY ARE DIVIDED ROUGHL ROUGHLY EVENLY.

BUT THESE ARE SELECTED RESIDUES.

THEY ARE SELECTED BASES WITHIN

THAT SO THAT THEY ARE POLY

MORPHIC BY NATURE.

AND THEN THE TECHNOLOGY

INVOLVES, CREATING HYBRIDIZATION

PROBES OUT OF THE NUCLEOTIDES

THAT VARY ONLY IN THE POLY

MORPHIC BASE.

SO YOU CAN DETERMINE WHETHER ONE

IS AN A OR T IN THIS CASE OR C

OR G IN THIS CASE.

YOU CAN SEE THESE.

YOU CAN JUST READ THAT ACTUALLY.

BY CONVENTION, THE MORE COMMON

OF THE TWO ALLELES, THE TWO POLY

MORPHIC ALLELES IS CALLED A AND

THE LESS COMMON IS CALLED B.

SO THAT DIE S DISOMIC INDIVIDUALS

THOSE WITH TWO STRANDS WILL BE

AA OR AB.

AB IS THE HETEROZYGOTE AND AA

AND AB WEB THE HOMO SIGH GUT.

FURTHERMORE THE DEGREE OF

FLUORESCENCE IS RELATED TO THE

AMOUNT OF NUMBER OF ALLELES THAT

ARE PRESENT.

SO FOR EXAMPLE IN THIS CASE BOTH

HERE HAVE TO DO WITH

FLUORESCENCE.

IF YOU ARE DISOMIC YOU CAN HAVE

THIS MUCH OR THIS MUCH OR THIS

MUCH FOR THESE POSSIBILITIES.

IF YOU ARE MONO S SOMIC, DELETED

IN THESE ALLELES.

IF YOU'RE DELETED IN BOTH OF

THEM YOU'LL HAVE THIS MUCH

FLUORESCENCE.

YOU CAN TELL BECAUSE IT'S

MEASURED FOR ALL OF THESE

MILLION SNIPS.

FOR EXAMPLE, THIS IS A LOG R

RATIO.

IT DEPECKS TECHS THE COPY NUMBER

VARIANTS.

IN OTHER WORDS DO YOU HAVE TWO

OR ONE SINGLE DELETION, DO YOU

HAVE ZERO, DOUBLE DELETION OR DO

YOU HAVE THREE, A DUPLICATION.

AND EACH OF THESE DOTS

REPRESENTS ONE OF THOSE SNIPS.

SO YOU CAN SEE HOW MANY SNIPS

ARE ON HERE AND IF YOU LOOK

HERE, ON THE ORDINATE IS THE

INTENSITY.

THIS IS AN AVERAGE INTENSITY.

IT'S REASONABLE.

BUT LOOK AT ALL OF THESE SNIPS.

THEY HAVE SEVERAL LOGS BELOW THE

AVERAGE INTENSITY.

SO THEREFORE THEY ARE DELETED.

IN FACT THEY ARE DOUBLY DELETED.

THEY ARE HOMOZYGOUSLY DETAILED.

IN THIS CASE IT'S 32 SNIPS IN A

ROW.

EACH ONE IS 3000 BASES.

IT TURNS OUT THESE ARE CLOSER

TOGETHER.

THEY ONLY GIVE ABOUT 60 OR SO

KILL BASIKILO BASIS AND THAT'S WHAT WE

SEE IN THE -- GENE WHICH IS

CTNS.

AND THIS DELETION IS RESPONSIBLE

FOR ABOUT 50% OF ALL THE

INDIVIDUALS WHO HAVE CYSTNOSIS

IN THE UNITED STATES AND NORTH

AMERICA.

THIS HARKENS BACK TO WHAT ERIC

TALKED ABOUT THE HUMAN GENOME.

ACROSS THIS ENTIRE BILLION

BASES, WE HAVE DISTRIBUTED A

MILLION SNIPS AND WIT KNOW WHICH

SNIPS ARE MISSING IN A ROW.

IN OTHER WORDS WHICH REGIONS ARE

DELETED.

THAT GENOME IS ANNOTATED BY THE

HUMAN GENOME KNOWLEDGE AND WE

CAN JUST LOOK DOWN AND SEE ARE

THERE GENES ASSOCIATED WITH

THOSE DELETIONS.

ARE THE GENES ASSOCIATED WITHIAN

DELETION, A DOUBLE DELETION OR A

TO CASE.

AND EVERY TIMCASE -- DUPLICATION.

WE IDENTIFY GENES THAT ARE

CAUSAL TO THE DISEASES IN OUR

PATIENTS.

I WILL GIVE YOU SOME EXAMPLES OF

THAT AS WE MOVE ON.

THAT IS ONE OF THE BENEFITS OF

DOING A MILLION SNIP ARRAY, THAT

IS TO DETERMINE COPY NUMBER

VARIANTS.

THERE'S SOMETHING MISSING.

THE OTHER, THE OTHER WAY TO

ANALYZE THESE DATA, THE MILLION

SNIP ARRAY DATA IS TO LOOK AT

WHETHER THE PATIENT HAS BB, AB

OR AA.

AND THESE TOP AND THE BOTTOMER

HOMOZYGOUS AND THE MIDDLE IS

HETEROZYGOUS AND EACH ONE OF

THESE DOTS REPRESENTS EACH ONE

OF THOSE SNIMS.

YOTHERE ARE NO

SNIMS ISNIPS IN THE CENTER CENTROMERE.

IT WILL TELL YOU HOW MUCH

HOMOZYGOUSITY THERE IS.

LET'S FORGET ABOUT THE TOP AND

BOTTOM AND JUST PLOT THE MIDDLE.

LET'S DO THAT FOR A WHOLE BUNCH

OF DIFFERENT INDIVIDUALS FOR THE

SNIPS THAT CONSTITUTE CHROMOSOME

10.

EACH ONE OF THESE IS A DIFFERENT

INDIVIDUAL HERE.

THIS IS ACTUALLY BLOWN UP SO

THIS IS THE CENTROMERE HERE.

SO NOW WE ARE NO LONGER

CONSIDERING THE BB OR THE AA

WE'RE ONLY LOOKING AT THE MIDDLE

BANDS, THE AB.

SO THIS IS THE MEASURE OF THE

HETEROZYGOUS SNIPS.

WELL HERE'S AN INDIVIDUAL WHO

HAS A REGION HERE WHERE THERE

ARE NO HETEROZYGOUS SNIPS, A

WHOLE LONG REGION.

HERE'S ANOTHER REGION IN THAT

INDIVIDUAL.

WHY IS IT BENEFICIAL TO KNOW

THIS.

IT'S BECAUSE WHEN YOU HAVE HOME

SIGHOMOZYGOUSITY AND YOU HAVE A

DISEASE, THERE COULD HAVE BEEN A

SINGLE MUTATION IN AN ANCESTOR

AND THAT PARTICULAR MUTATION WAS

INHERITED FROM BOTH THE MOTHER

AND THE FATHER IN THIS

INDIVIDUAL, AND THEREFORE IS

HOMOZYGOUS FOR IT.

AND THEN IT REQUIRES ONLY A

SINGLE MUTATION.

SO YOU'RE BASICALLY TAKING

ADVANTAGE OF DISTANT KAWBILITY CONTINUITY

IN WHAT IS A HOMOZYGOUS DISEASE.

IF YOU HAVE A RUN OF HOMO

ZYGOUSITY, LACK OF HOE MOW

ZYGOSITY HERE, ANNOTATED BY THE

HUMAN GENOME PROJECT CAN TELL

YOU WHAT GENES ARE ASSOCIATED

AND THOSE BECOME YOUR AMEND DATE

GENES FOR LOOKING FOR A SINGLE

HEMHOMOZYGOUS MUTATION.

THESE ARE TWO INDIVIDUALS WHO

HAVE DIFFERENT REGIONS OF

ABSENCE OF HETEROZYGOUSITY.

NOW HERE'S A GUY THAT COMES IN,

HE'S ACTUALLY A RUSSIAN

IMMIGRANT WHO CAME IN TO OUR

PROGRAM WITH INFLAMMATORY INSELF INSELF

LAWITY -- HE HAD IT AT THE LEVEL

OF A SECOND COUSIN.

HOW DO YOU KNOW THAT?

BECAUSE FIRST COUSIN SHARE ONE

NTH OF THEIR GENES SECOND SHARES

1/32ND AND SO ONE 1/32ND IS

ABOUT 3%.

BY MY CALCULATIONS THIS IS ABOUT

RIGHT.

SO IT DOESN'T MEAN THAT HE WAS

THE PRODUCT OF A SECOND COUSIN

RELATIONSHIP HE COULD HAVE BEEN

THE PRODUCT OF A FIRST COUSIN

RELATIONSHIP ONCE REMOVE PLUS

SOMETHING ELSE THAT CONTRIBUTED

ON THE OTHER SIDE.

OKAY.

SO YOU CAN SEE THAT DOING A

MILLION SNIP ARRAY CAN TELL US

ABOUT NUMBER OF VARIANTS, YOU

HAVE A DELETION, AND RUNS OF

HOMHOMO ZYGOSITY.

WE FIND SO MANY GENES, THAT'S

THE PROBLEM.

THE SECOND MODALITY IS EXOME

SEQUENCING WHICH IS REALLY A

SCWEDGES OSEQUENCING OF EVERY GENE.

NOT THE SEQUENCE THAT

CORRESPONDS TO GENES BUT JUST

THE GENES.

ACTUALLY, THOSE REGIONS

CONSTITUTE ABOUT 1.7% OF OUR

GENOME.

SO IT'S LIKE 50 SOME MILLION.

WE'RE ABLE TO SEQUENCE THOSE AT

ABOUT 85-90% COVERAGE OR SO.

REMEMBER ERIC SAID, AND HE WAS

RIGHT.

GOOD WORK, ERIC.

HE WAS RIGHT.

THAT IF YOU HAVE ONE INDIVIDUAL

AND ANOTHER INDIVIDUAL, THEY

WILL VARY BY 20,000 IN THEIR

VARIANTS.

SO THIS IS GOING TO GIVE YOU

HUGE NUMBERS OF CANDIDATES FOR

WHAT YOU MIGHT CONSIDER TO BE

CAUSAL OF THIS DISEASE.

SO WHAT YOU NEED TO DO FOR THIS

IS TO FILTER DOWN.

YOU NEED TO REDUCE THIS NUMBER

OF 20,000 BECAUSE REMEMBER EACH

OF THESE VARIANTS IS A POTENTIAL

DISEASE-CAUSING MUTATION.

YOU JUST DON'T KNOW WHICH ONE OF

THOSE 20,000 IT IS.

YOU NEED TO RULES THIS NUMBER OF

CANDIDATES, VARIANTS FROM 20,000

DOWN TO A REASONABLE NUMBER,

LIKE 10.

OR 20 OR SOMETHING LIKE THAT

THAT YOU CAN ACTUALLY TEST OUT.

AND THE WAY YOU DO THAT IS WHAT

WE CALL FILTERS.

SOME OF THE BEST FILTER IS

RELATIVES.

SO IF YOU HAVE A MODEL IN WHICH

YOU HAVE, LET'S SAY TWO

SIBLINGS, ONE ONE'S AFFECTED AND

ONE'S NOT AND YOU CONSIDER THIS

TO BE RECESSIVE LIKE AN BEHIND

INHERITANCE.

YOU LOOK AT THE MUTATIONS THAT

HAVE ONE MUTATION IN THE PARENT

AND ONE MUTATION IN THE OTHER

PARENT AND IN THE UNAFFECTED SIB

HAS EITHER ZERO OR ONE MUTATION.

ALL THOSE REQUIREMENTS CAN BE

PUT INTO A PROGRAM, A SOFTWARE

PROGRAM THAT IS A FILTERING

PROGRAM AND CAN REMOVE THE

VARIANTS THAT DO NOT FIT THAT

MODEL.

AND THEN YOU CAN BRING THAT DOWN

TO A CERTAIN NUMBER.

I'LL GIVE YOU AN EXAMPLE OF

THIS.

AND THEN THERE ARE OTHER FILTERS

LIKE DATA BASES OF KNOWN

NON-PATHOGENIC VARIANTS.

AND LET'S SAY, LET'S SAY

PROGRAMS THAT WILL REQUIRE THE

FOLLOWING OF HARDY WEINBERG

PRINCIPLES.

SO MENDELIAN INHERITANCE.

AND OTHERS THAT YOU CAN USE WHEN

YOU MODEL DOMINANT INHERITANCE.

SO FOR EXAMPLE, IF YOU HAVE, IF

YOU CONSIDER A NEW MUTATION TO

HAVE OCCURRED.

AND THEN THE MUTATION WOULD HAVE

TO BE ONE THAT OCCURRED IN THE

EFFECTED INDIVIDUAL BUT NOT IN

EITHER OF THE PARENTS.

SO ALL THOSE MODELS ALLOW YOU TO

DEVELOP FILTERING SOFTWARE
 NUMBER OF

VARIANTS THAT ARE CANDIDATES FOR

CAUSING THE DISEASE.

I'LL GIVE YOU SOME EXAMPLES.

SO HERE'S AN EXAMPLE OF A FAMILY

FROM KENTUCKY, OHIO, SOMETHING

OF THAT SORT.

YES, IT'S LIKE ON THE BORDER,

WHERE YOU HAVE FIVE AFFECTED

INDIVIDUALS HERE.

AND THEY'RE ALL ADULTS BY NOW

AND THE PARENTS ARE THIRD

COUSINS.

ACTUALLY A THIRD CUZ IMIS A

WONDERFUL RELATIONSHIP TO HAVE.

THAT IS FOR US JEANETT JAW GENETICISTS.

YOU GOT 12.5 PERCENT OF THE

ENTIRE GENOME THAT'S HOMOZYGOUS.

IF YOU GOT ONE COUSIN THAT'S

LESS THAN 1% AND THAT LIMITS YOU

DOWN VERY NICELY.

SO WE LIKE THESE FOLKS.

SO THESE INDIVIDUALS HAD THIS ON

THEIR PLANE FILMS.

WHEN I SEE THIS, IT WASN'T VERY

HARD FOR ME TO ACCEPT THIS

FAMILY.

SO PLANE FILMS SO THIS OF COURSE

IS THE FEMUR AND PATELLA AND

FIBULA.

AND THIS IS THE VESSEL.

THAT IS, THIS IS THE FEMORAL

ARTERY AND THE POPLITEAL ARTERY.

NO CONTRAST.

SO THIS IS CALCIFICATION.

AND YOU'LL NEVER SEE THIS IN

YOUR LIFE.

IF YOU'RE PHYSICIANS YOU WILL

NEVER SEE THIS IN YOUR LIFE

ALMOST CERTAINLY EXCEPT MAYBE

HERE.

AND THESE INDIVIDUALS ALL HAD

CLAUDE CASE.

THEY WERE RELYING UPON THEIR

COLLATERALS HERE.

THE TREATMENT IS TO WALK A LOT

EVEN THOUGH IT HURTS SO THEY

TOLD MORE CLA COLLATERALS.

THEY NEED MORE CIRCULATION

THERE.

THIS IS UP AT THE PELVIS AND

THIS IS THE VESSEL HERE.

IT'S A LITTLE HARD FOR ME TO

SEE.

THESE ARE BIG CALCIFIED VESSELS

AND THEY ALSO HAD SOME

CALCIFICATION OF THEIR JOINTS.

HERE THE META CA METACARPAL FLANGEAL.

WE'RE CONSIDERING THAT THIS IS

LIKELY TO BE AN AUTOSOMAL

RECESSIVELY INHERITED DISORDER

WITH HOMO GU ZYGOSITY.

AND LOOK FOR REGIONS OF HOMO

ZYGOSITY SHARED BY ALL FIVE

AFFECTED SIBLINGS AND NOT THE

PARENTS.

THERE'S ONLY ONE REGION IN THE

ENTIRE GENOME FOR WHICH THIS WAS

TRUE.

THAT WAS ON CHROMOSOME SIXTH,

THIS HOMOZYGOUS REGION.

THAT REGION WAS 22 MEG BASES.

THERE WERE 92 GENES THERE.

BUT IN THIS CASE -- LET ME TELL

YOU ABOUT THAT.

CD73 IS AN OWN SUOMI THAT

CONVERTS PHOSPHATE TO ADENOSINE

PLUS INORGANIC FAST FATE AT THE

VASCULAR AND -- CELLS.

INTERESTING THERE'S ALREADY A

DISEASE THAT HAD TO DO WITH

CALCIFICATION OF VESSELS IN OPEN

OPEN -- INFANCY AND THAT WAS THE

CONVERSE OF ATP TO MP PLUS --

THAT'S AN INCREDIBLY RARE

DISEASE.

PROBABLY ABOUT, YOU KNOW, 10, 20

PATIENTS REPORTED IN THE WORLD.

FATAL IN THE FIRST ROUGHLY TWO,

THREE YEARS TO LIFE.

FROM OUR PATIENT THAT HAVE THIS

PARTICULAR DEFECT.

AGAIN, WE HAD SMART CELL

BIOLOGISTS, ETCETERA.

WE DID COME WORK IN OUR OWN LAB

TOO.

IT COULD BE MUTATIONAL ANALYSIS

AND FOUNDED IN THAT FAMILY OF

HIGH THEY WERE HOMOZYGOUS FOR

NONSENSE MUTATION.

WE HAD ANOTHER FAMILY IN ITALY

WHICH THEY WERE HOMOZYGOUS FOR A

MISS -- MUTATION AND THEN WE HAD

A COMPOUND HETEROZYGOUS FROM

INDIVIDUALS IN SAN FRANCISCO.

MEASURED EXPRESSION OF THE IS AN

TIE 5E THAT WAS NORMAL AND RUED.

MEASURED 73 PROTEIN AND IT WAS

ESSENTIALLY ABSENT.

MEASURED THE AMOUNT OF ENZYME

ACTIVITY AND IT WAS VASTLY

REDUCED.

RESCUED WITH A VECTOR THAT

CONTAINED CD73 AND RESCUE THE

ENZYME ACTIVITY.

AND THEN DETERMINE THE AMOUNT OF

RESIDUAL ACTIVITY IN EACH OF THE

MUTANTS WE HAD DISCOVERED

COMPARED TO NORMAL AND FOUND

THAT WAS REDUCED.

AND HERE'S AN INCREDIBLE FINDING

IN THIS CASE, WE ARE SORT OF

LUCKY.

WE DO SKIN FIBRO BLASTS.

THEY DO THE CULTURE OF THESE

CELLS.

AND WHEN THESE CELLS ARE

CULTURED AND YOU PUT THEM UNDER

CONDITIONS

 OF CALCIFICATION, AND

STAIN, YOU SEE THAT COMPARED TO

THE CONTROL, THE AFFECTED

INDIVIDUAL HAS A LOT OF ALKALINE

PHOSPHATASE.

REMEMBER ADENOSINE IS THE

PROJECT OF THE I'M SUOM ENSEAM THAT'S

MISSING.

IF YOU USE A RED STAIN FOR THIS

YOU SEE IN THE AFFECTED CELLS

IT'S ALL RED, IN THE CONTROL

IT'S NOT.

AND THIS CAN BE REMOVED BY

TRANSDUCING THE VIRUS CONTAINING

CD73.

IT CAN BE MITIGATED BY ADENOSINE

AND REMOVED BY LAVASOL WHICH IS

A PHOSPHATE INHIBITOR WHICH

BRINGS UP THE WAY TO TREAT THESE

INDIVIDUALS.

I'LL GET TO THAT IN A SECOND.

HERE'S THE SCHEMA.

THIS WILL PRODUCE ADENOSINE.

ADENOSINE WILL INTACT WITH

ADENOSINE RECEPTORS PLUS SECOND

MESSENGERS INTRACELLULARLY TO

INHIBIT TISSUE NON-SPECIFIC

ALKALINE FALSE FA TASTE.

THITASTE --

PHOSPHATASE.

IT WILL ALLOW -- TO INHIBIT

MINERALIZATION.

ON THE OTHER HAND, WHEN YOU HAVE

THE MUTANT CASE, YOU DON'T HAVE

THE ADENOSINE, YOU DON'T HAVE

THE INHIBITION OF ALKALINE

PHOSPHATASE.

IT BUILDS UP AS WE SAW IN THE

CELLS.

IT CONVERTS PYRO PHOSPHATE TO

INORGANIC PHOSPHATE AND THERE'S

NO INHIBITION OF MINERALIZATION

BY -- BUT THERE IS STIMULATION

OF MINERAL STIMULATION OF --

THIS IS UNKNOWN TO HAVE OCCURRED

AS A CAUSE IN THIS CASE

ECTOPIC -- SO WITH WHAT THIS

MENIAL IS THAT WE CAN TREAT

INDIVIDUALS WITH INHIBITERS OF

ALKALINE PHOSPHATASE.

AND WHAT IS THAT?

HAVE YOU EVER HAD SALLY FIELDS

IN YOUR HOME?

YES, BONIVA.

SO THAT WAS AN ILLUSION.

OKAY.

BONIVA IS AN INHIBITOR.

IT INHIBITS ALKALINE FALSE FA

TASTE AND CAN PROBABLY BE USED

FOR THESE INDIVIDUALS.

AND NOW OUR DIFFICULTY IS TO

DETERMINE WHAT WILL BE AN

OUTCOME MEASURE FOR THIS.

BECAUSE THE ACQUISITION OF THIS

DISEASE AND THE CALCIUM IS SO

SLOW.

SO WHAT WE'RE TRYING TO DO IS TO

MEASURE THE CALCIUM BURDEN BY CT

SCAN IN THE VESSELS OVER A

DIFFERENT PERIODS OF TIME.

SO HERE'S A FIVE YEAR OLD BOY

WHO HAS CLUB FOOT AND A DUCTED

THUMB AND HE ALSO GETS BLEEDING

EPISODES.

SO HEMATOMA'S THAT DON'T

RESOLVE.

HE FELL OFF HIS SCOOTER AND HAD

THIS FOR A MONTH.

SO HE CAN'T GO OUT.

IT'S BASICALLY WHAT WE WOULD

CALL A CARDIAC CRIPPLE.

IN OTHER WORDS AVOID ACTIVITY

BECAUSE AFRAID YOUR HEART'S

GOING TO GO BAD.

IT'S A BAD SITUATION.

PARENTS ARE FIRST COUSIN ONCE

REMOVED.

SO TWO NORMAL SIBS.

WE DID A SNIP ANALYSIS AND FOUND

THERE'S A 26 MEGA BASE REGION OF

HOMOZYGOSITY SO WE EXPECT THIS

TO BE A RECESSIVE DISEASE IN

WHICH THE INDIVIDUAL HAS A

HOMOZYGOUS MUTATION.

AND ON ONE GENE OF THE 72

CANDIDATES THAT ACTUALLY FIT,

AND THAT'S A GENE WHOSE PRODUCT

WILL, IS AN ENZYME THAT PUTS A

SULFATE GROUP ON THE FOUR

POSITION OF DETERMINE AWETAN--

DERMA TAN.

IT'S STORED IN THE -- THINGS

LIKE THAT.

YOU CAN ACTUALLY GOOGLE THAT.

BUT IN THIS CASE, YOU CAN'T

ACTUALLY MAKE DERMATAN SULFATE.

THE POINT IS IT'S IMPORTANT FOR

CONNECTIVE TISSUE.

THAT'S WHY THIS GUY IN

DEVELOPMENT HAS CLUB FOOT AND

DUCTED THUMBS.

SO THERE ARE NO PATIENTS IN THE

UNITED STATES WITH THIS EXCEPT

THITHIS GUY.

THERE ARE SOME PATIENTS IN

AUSTRIA AND SOME 20 OR SO

PATIENTS IN JAPAN.

IT'S THAT RARE.

THOSE ARE THE TYPES OF PATIENTS

THAT WE GEVMENT I GET.

IT TURNS OUT DERMATAN SULFATE IS

IMPORTANT FOR CLOTS.

THIRD CASE, TWO PRUTS WHOSE

PARENTS WERE FIRST COUSINS AND

HAD NEUROLOGICAL DISEASE.

ONE OF THEM ACTUALLY DIED BEFORE

WE SAW HIM.

THE OTHERS, BOTH OF THEM HAD

ATAXIA AND MYO COLONIC SIRTSZ --

CIRCUMSTANCES ANSEIZURES AND DIFFICULTY WA
LKING.

THIS IS A CASE WHERE WE'RE GOING

TO EXAMINE EVERY ONE OF THE 40,

50 MILLION BASI BASES THAT ENCODES

GENES AND FOUND ONE PARTICULAR

MUTATION HERE.

IN FACT, THIS IS THE WAY THAT WE

FILTERED.

BECAUSE WE'RE DOING BOTH PARENTS

AND BOTH AFFECTED BROTHERS AND

THE UNAFFECTED BROTHERS, THERE

WERE 120,000 VARIANTS SHARED BY

THEM.

WE NEEDED TO FILLER THIS DOWN.

WE LOOKED AT THE VARIANTS

PRESENT IN THE THOUSAND GENOME

PROJECT AND ELIMINATED THEM AS

BEING NON-CAUSAL.

THEN DID THE SNIP TRIP LINKAGE

SINCE WE HAD A MODEL SYSTEM FOR

DEALING INHERITANCE AND GOT RID

OF 6,000 MORE.

WE EXPECT THIS TO BE HOMOZYGOUS

RECESSIVE SO WE LOOKED AT THOSE

VARIANTS THAT WERE HOMOZYGOUS

RECESSIVE.

IN OTHER WORDS, THAT YOU HAD THE

SAME MUTATION IN BOTH AFFECTED

AND ONLY A SINGLE MUTATION IN

EACH PARENT.

THAT GIVES US ONLY 11.

AND THEN NOT IN THE SNIP WHICH

IS A DATA BASE OF KNOWN NON-PAT

GENERALLIC VARIANTS ANGENERAL -- PATHOGENI
C VARIANTS.

SO THIS IS A MITOCHONDRIAL

PROTEASE THAT'S FUNCTIONAL WITH

AN AX AWNTZ.

AX -- A AXONS.

THIS IS IN ITSELF WITH A --

HETERO DIMER.

THEY ARE DISEASES ASSOCIATED

WITH BOTH PAIR LEGIONIC AND F --

THE ONE ASSOCIATED WITH

PARAPLEGIC IS TYPE 7.

THE ONE ASSOCIATED WITH AFG3L2

IS SPINE OWE CEREBELLUM ATAXIA

28.

I TURNS OUT THE MUTATION IS

HOMOZYGOUS IN THESE TWO BROTHERS

WAS AT THE EXACT POINT WHERE THE

PROTEIN INTERACTS BOTH WITH

ITSELF AND WITH PARAPLEGIC.

AS A CONSEQUENCE, THESE BOYS HAD

BOTH DISEASES IN ONE DUE TO THE

SINGLE MUTATION, RECESSIVE

MUTATION.

AND ELSE, THESE BOYS ARE THE

FIRST ONES IN THE WORLD TO BE

DESCRIBED WITH THIS PARTICULAR

NEUROLOGICAL MANIFESTATION OF

THIS DISEASE.

WHICH YOU SEE POINTS OUT THAT

THERE ARE ACTUALLY MORE DISEASES

THAN THERE ARE GENES.

BECAUSE HERE'S A GENE THAT IS

DOMINANT IN SOME CASES AND

RECESSIVE IN OTHERS DEPENDING

UPON WHERE THE MUTATION IS.

AND OF COURSE THERE ARE OTHER

EXAMPLES OF THAT IN TERMS OF

LAMIN A AND THINGS OF THAT SORT.

OKAY.

I DON'T HAVE A WHOLE HELL OF A

LOT OF TIME SO I'M JUST GOING TO

LET THIS THING GO.

THIS IS ANOTHER NEW DISEASE GENE

THAT WE FOUND THAT ONE OF OUR

PEOPLE IS WORKING ON.

IT'S A MYOPATHY THAT'S DOMINANT.

NEVER ASSOCIATED WITH HEM HEM HEP 3

BEFORE.

I'VE DISCUSSED A COUPLE OF

THESE.

RARE RARE DISEASES.

REMEMBER THE DEFINITION OF A

RARE DISEASE IN THE UNITED

STATES IS ONE THAT AFFECTS FEWER

THAN 200,000 INDIVIDUALS.

THIS IS BY A LAW, THE 1983

ORPHAN DRUG BILL.

BUT WHAT WE'RE SEEING IS

DISEASES THAT AFFECT FEWER THAN

50 OLE WORLD.

AND IT'S BECAUSE THEY'VE BEEN

SCREENED BY HOPKINS AND MAYO AND

CLEVELAND CLINIC.

THEY HAVEN'T FOUND THEM SO NOW

WE'RE ABLE TO APPLY THIS SORT OF

NEW TYPE OF GENETICS TO THIS

BECAUSE WE HAVE THE CLINICAL

CENTER, IT'S FREE AND WE HAVE

PRETTY SMART DOCTORS I THINK.

SO HERE ARE SOME OF THE OTHER

DIAGNOSIS THAT WE'VE MADE.

AND I TELL THE AUDIENCES, IF YOU

KNOW MORE THAN A COUPLE OF THESE

DISEASES, YOU NEED TO ACTUALLY

GET OUT MERE.

GET A LIFE, PLAY BALL, GARDEN.

DO THINGS, READ A BOOK, PLAY

SOFTBALL, WHATEVER, THINGS LIKE

THAT.

BECAUSE THESE ARE INCREDIBLY

RARE DISORDERS.

MOST OF THEM, EXCEPT MAYBE FIBRO

MYALGIA AND MORGAN SYNDROME THAT

I DON'T TALK ABOUT.

THESE ARE ONE THAT WE HAVE NOT

DISCOVERED AS BEING A CLINICAL

ENTITY.

STILL MYSTERIES.

NOW LET ME TELL YOU ABOUT A

YOUNG LADY HERE AND I'M ACTUALLY

GOING TO BRING KELLY TO THE

FRONT.

COME ON UP HERE, KELLY.

AND I'M ACTUALLY NOT GOING TO

HAVE YOU SIT DOWN RIGHT AWAY,

THANK YOU.

WHAT DID THIS REMIND ME OF?

THIS REMINDS ME OF FEDERAL

GOVERNMENT.

EVERYTHING GOES TO THE LOW

BIDDER.

THIS IS THE LOWEST BIDDER.

I WANT TO THANK THE LOW I WAS LOWEST

BIDDER.

WHERE ARE YOU FROM KELLY.

>> LOUISIANA.

>> DOES IT HURT TO YOU TALK?

THAT'S OKAY.

THESE A MIC, YES, SLINLT.

OKAY.

ONE, TWO, THREE, TESTING.
 LOUISIANA.

IT ONCE CAME TO OCCUR THAT YOU

WERE IN A HOSPITAL HAVING AN

OPERATION AT ONE TIME DURING A

HURRICANE, IS THAT CORRECT.

>> IT WASN'T A HURRICANE, IT

WAS, YOU MEAN WHEN THE MAIN --

>> THE POWER WENT OUT.

>> THE WATER MAIN FLOOD, I WAS

IN THE ICU.

AND THE WATER MAIN FLOOD RIGHT

IN MY ROOM.

THEY HAD TO EVACUATE ME.

>> HAD TO GET RID OF YOU.

>> YES.

>> YOU HAD A TUBE IN.

YOU WERE INTUBATED.

>> YES.

>> BUT WHEN THEY MOVED YOU THEY

COULDN'T BREATHE OFF THE WALL

ANYMORE.

SO WHAT DID THEY DO.

>> THEY PUT THE BREATHING PUMP

IN MY MOUTH AND THE NURSE, I

DON'T KNOW WHAT SHE WAS DOING

BUT SHE DIDN'T KNOW HOW TO

OPERATE IT SO I GRABBED IT FROM

HER BECAUSE I COULDN'T BREATHE

SO I STARTED PUMPING IT MYSELF.

THEY WERE TRYING TO GET ME OUT

OF THE WATER.

>> THE WEAKER SEX, RIGHT.

NOT TRUE.

THIS IS A TOUGH TOUGH WOMAN.

OKAY.

SO TELL ME ABOUT YOUR DISORDER.

WHEN WAS THE FIRST TIME THAT YOU

RECOGNIZED THAT SOMETHING WAS

AMISS?

>> I WAS IN THE 9TH GRADE AND I

NOTICED A SMALL NODULE IN MY

JAW.

AND IT STARTED TO KIND OF, I HAD

BRACES AT THE TIME.

I THOUGHT IT MAY HAVE TO DO WITH

THAT, BUT IT KIND OF STARTED

AFFECTING MY JAW OPENING.

I COULDN'T OPEN MY MOUTH AS WIDE

AND IT GOT WORSE AND WORSE AND

WORSE.

>> OKAY.

AND LATER ON YOU HAD NODULES IN

YOUR LUNG.

I'LL JUST SHOW FOLKS NODULES IN

THE LUNG RIGHT HERE.

SO THERE'S ONE THERE'S ONE.

THEY DON'T BELONG THERE.

AND YOU ALSO HAD A KINK IN YOUR

URETER.

AND AS A CONSEQUENCE, THIS

KIDNEY HERE IS MUCH BIGGER THAN

ON THE OTHER SIDE.

OKAY.

AND THAT'S BECAUSE THE URINE

BACKED UP AND MADE THE KIDNEY

BIGGER.

SO IT'S HYDRO NEPHROSIS.

WE'LL SHOW YOU THE PATHOLOGY

THERE.

BUT BECAUSE OF THIS TUMOR YOU

WERE UNABLE TO OPEN YOUR MOUTH

COMPLETELY.

HOW FAR CAN YOU OPEN YOUR MOUTH

NOW?

IT DOESN'T HURT DOES IT.

SO THAT'S 12 OR 14 MILLIMETERS

OR SO.

THIS WAS A TIME WHEN YOU COULD

ONLY OPEN YOUR MOUTH 20

MILLIMETERS.

DIFFICULT TO EAT BECAUSE OF

THAT.

THAT'S BECAUSE THE TUMOROUS

TISSUE WHICH I'LL SHOW YOU HERE

AND IT ATE AWAY AT THE

CRIBRIFORM PLATE.

IF YOU EVER SAW THE SKULL AND AT

THE FRONT OF THE SKULL THEY HAVE

THOSE THIN BONES THOSE ARE THE

CRIBRIFORM PLATES.

THIS TUMOR IT'S NOT REALLY

MALIGNANT IN TERMS OF SPREADI

AROUND THE BODY BUT LOCALLY IT

ATE AWAY THAT THAT BONE WHICH IS

SORT OF A BIG DEAL AND IT ALSO

RUINED YOUR ABILITY TO OPEN YOUR

MOUTH WITH YOUR MUSCLES.

WERE YOU EVER GIVEN A FEEDING

TUBE OR ANYTHING?

NOTHING LIKE THAT.

>> IT WOULDN'T FIT THROUGH MY

TEETH.

>> OKAY.

SO HERE'S THE PATHOLOGY SHOWING

SOME LYMPHOCYTES AND SOME

FIBROUS TISSUE.

OKAY, SO.

SO THE FIBROUS TISSUE HERE AND

THEN THE LYMPHOCYTES HERE.

AND IT'S ALL THE SAME.

IN THE CHEEK AND IN THE LUNG.

SO THE SAME DERIVATION.

>> [INDISCERNIBLE] I'VE HAD

RECURRING -- EVER SINCE IT ALL

STARTED TOO.

THEY BIOPSIED THAT FLUID, THEY

HAD TO TAP IT.

IT CAME BACK THE SAME THEY HAD

GOTTEN FROM THEOFF AND MY LUNG

BIOPSY AND THE SINUS.

>> AND ALSO IN THE LIVER.

HERE ARE THINGS THAT ARE FIBRIL,

EXCITATORY AND CYTOKINES ARE

ELEVATED.

WE HAVE NO GENETIC ETIOLOGY FOR

THIS AT THIS TIME.

SO THIS IS ONE OF THE CASES

WHERE WE'RE LOOKING FOR THE

DIAGNOSE BUT WE'RE NODIAGNOSIS BUT WE'RE N
OT ABLE TO

USE ALL OF THE GENETIC

TECHNIQUES.

YOU HAVE A SISTER AND BROTHER

TOO.

>> I HAVE A TWIN SISTER AND

OLDER SISTER.

>> SO THERE WAS DNA FROM BOTH OF

THEM.

>> JUST ONE OF THEM.

>> SO THIS IS SOMETHING THAT WE

CAN WORK ON SOME MORE.

BUT REALLY THE PROBLEM IS THAT

WE'LL HAVE TOO MANY VARIANTS AND

WE HAVEN'T BEEN ABLE TO FILTER

IT DOWN ENOUGH.

ON THE OTHER HAND, WE'VE BEEN

ABLE TO CULTURE YOUR CELLS FROM

THE -- MAXILLARY BIOPSY.

OUR SURGEONS TOOK A PIECE OF

THAT AT THE NIH.

HAVE YOU EVER SEEN THESE BEFORE.

>> NOT THOSE.

>> THAT'S A LITTLE BIT BIZARRE

SHAPED.

THEY'RE NOT COMPLETELY NORMAL.

THAT'S BECAUSE IT'S FROM THAT

TISSUE.

AND YOU HAD OVER THE COURSE OF

THESE YEARS PROGRESSIVE

ENLARGEMENT OF THE RIGHT

PTERYGOID MAXILLARY SINUS.

SO HERE IS THE SINUSES.

IT'S SUPPOSED TO BE OPEN LIKE

THIS.

AND AS TIME GOES ON, THIS

BECOMES SMALLER AND SMALLER

BECAUSE THE TUMOR AROUND IT  IT.

LIKE THAT, OVER THE COURSE OF

THOSE YEARS.

SO WHAT WE DID IN THE LABORATORY

WAS TO GUESS AT WHAT MIGHT

REDUCE THE RATE OF GROWTH OF

THESE ESSENTIALLY TUMOR CELLS.

AND ONE OF THE THINGS WE TRIED

WAS HYDROX OWE CLOSE HYDROXY CLOSER I -- A
 WEAK BASE USED

FOR MALARIA.

YOU KNOW HOW -- HELPS MALARIA BY

ALKALINIZING IT.

IN ANY EVENT IT SEEMS TO HELP.

IT DECREASES THE GROWTH RATE.

SO WE GAVE YOU HYDROXY -- AND

YOU'VE BEEN TAKING THAT FOR HOW

LONG NOW?

>> TWO YEARS.

>> OKAY.

AND WHAT'S HAPPENED TO YOUR

MOUTH DURING THAT TIME?

>> I HAVEN'T HAD ANY PROBLEMS.

I HAVEN'T HAD ANY FLARE UPS.

EVERYTHING'S PRETTY MUCH STAYED

AT BAY.

>> SO PRETTY MUCH NOTHING HAS

HAPPENED WHEN PREVIOUSLY THINGS

WERE GROWING RATHER RAPIDLY.

SO THIS IS A CRP WHICH IS THE

MEASURE OF INFLAMMATION.

SO THAT WENT DOWN AND HAS SORT

OF BEEN BOUNCING AROUND ARE AT

THE HIGH LEVEL BUT NOT NEARLY AS

HIGH AS IT WAS BEFORE.

AND HERE ARE THE LUNG NODULES

BEFORE AND YOU CAN SEE, LET'S

SEE, WHAT WOULD BE A NODULE.

THIS IS A NODULE, PROBABLY THIS

IS A NODULE.

PROBABLY THESE ARE LITTLE

NODULES.

AND IT'S ESSENTIALLY STABILIZED.

AND HERE IS THE PTERYGOID

MAXILLARY SINUS BEFORE AND AFTER

HERE.

THERE'S EITHER NO DIFFERENCE OR

MAYBE A LITTLE BIT BETTER OR

SOME SUCH.

THIS IS THE TYPE OF THING IT'S

NOT AN EXAMPLE YET OF OUR

ABILITY TO APPLY NEXT GENERATION

JETGENETICS BUT IT IS A

DEMONSTRATION OF OUR ABILITY TO

TAKE TISSUE FROM YOU.

ALMOST DONE.

JUST A SECOND.

AND DO SOME STUDIES THAT MAY BE

OF BENEFIT TO A PATIENT.

LET ME JUST ASK, ARE THERE ANY

QUESTIONS?

YES.

>> [INDISCERNIBLE]

YOU MENTION IT IS A MUSCLE

TUMOR.

>> I DIDN'T SAY IT WAS A PLASMA

CELL TUMOR.

WHAT I SAID WAS THAT IT WAS

FIBROUS AND INFLAMMATORY.

IT HAD LYMPHOCYTES.

THERE WAS AN OCCASIONAL PLASMA

CELL BUT THAT WAS THE THE

PRIMARY THING.

WE WOULDN'T TREAT WITH -- YOU

COULD FOR OTHER REASONS BUT NOT

TO GET RID OF THE PLASMA CELLS.

OKAY.

ANYTHING ELSE?

SO THANK YOU VERY MUCH FOR

COMING.

I REALLY PRESSURE IT.

 -- I REALLY

APPRECIATE IT.

AND GOOD WORK.

[APPLAUSE]

>> THANK YOU VERY MUCH TOO

BECAUSE AS A HUSBAND I KNOW WHAT

THAT'S LIKE TOO.

SO NOW I'M GOING TO SHOW YOU

SOME UGLY PICTURES.

DO YOU WANT ME TO QUIT RIGHT

NOW?

>> NO, GO AHEAD.

>> BECAUSE I DON'T WANT TO --

OKAY.

SO HERE'S -- I'LL DO THIS

QUICKLY.

HERE'S A MAN WHO IS 34 YEARS OLD

AND HE HAS THIS INFLAMMATORY

LESIONS THAT ARE ULCERATING.

HE'S HAD HIS RIGHT HAND CUT OFF

BY SURGEONS BECAUSE HE WAS GANG

GANGRENOUS.

HERE'S HIS FACE.

HE'S GOT A PURPOSE RATED SEPTUM

HERE.

THIS IS VERY PAINFUL AND

INFLAMMATORY.

IT'S AN INFLAMMATORY DISEASE.

HERE IT IS GRADUATION FROM HIGH

SCHOOL.

THIS HAS ALL OCCURRED OVER THE

LAST 15 YEARS OWE SO.

AND WE TREAT HIM WITH MAGGOTS TO

ESSENTIALLY CLEAN OUT HIS WOUND.

IT'S INTERESTING, YOU CAN

ACTUALLY BUY THESE MAGGOTS FROM

A COMPANY AND HAVE THEM

DELIVERED TWO DAYS LATER OR SO.

IT'S LIKE A DRUG.

OF COURSE THEY'RE A PRIVACY

ISSUE, SO WE HAVE TO BE CAREFUL

WITH SOME OF THESE THINGS.

WE HAVE MEDICAL MONITORS WHO

WATCH THIS.

OKAY, FINE.

SO HERE THE PATHOLOGY.

AND IT'S REALLY HISTO SIDIC AND

LYMPHOSIDIC.

IT'S AN UNUSUAL CASE BUT WE

SUBSEQUENTLY HAVE ANOTHER

APPLICANT, BECAUSE REMEMBER

WE'RE REALLY ENRICHING FOR THE

INCREDIBLY UNUSUAL.

AND YOU SEE THIS INDIVIDUAL,

ACTUALLY YOU HAVEN'T SEEN HER

YET.

BUT HERE SHE IS AND SHE'S LOST

THE CARTILAGE OF HER NOSE AND

SHE HAS SOMETHING VERY SIMILAR

TO THE FIRST CASE, THE PREVIOUS

CASE I SHOWED YOU.

SO WE THINK HAT THI THIS TYPE OF THING

CAN HELP US UNDERSTAND WHAT THE

PATHOLOGY MIGHT BE INVOLVED

HERE.

SO THE RHEUMATOLOGIST AND THE

PERIODIC FEVER DOCTORS ARE VERY

INTERESTED IN THESE CASES.

AND THE FIRST CASE ACTUALLY

TREATING THE -- WHICH IS AN IO6

INHIBITOR.

IT'S NOT ME, THEY ACTUALLY KNOW

WHAT THEY'RE DOING.

BUT THIS YOUNG LADY IS 17 YEARS

OLD.

SHE'S DEVELOPMENTMEN DEVELOPMENTAL DELAYS 
AND

OBVIOUSLY MORE AFFECTED THAN THE

OTHER INDIVIDUAL WAS WITH THIS.

WHAT I WANTED TO DO WAS TO GIVE

YOU AN IDEA OF THE WAY THAT WE

CAN APPLY THIS MODERN GENETICS

TO HUMAN DISEASES AND USE REALLY

RARE UNUSUAL UNDIAGNOSED

DISORDERS TO TRY TO FIND NEW

DISEASES AND MAYBE FIND OUT

VARIANTS OF KNOWN DISORRS TO

EXPAND THE KNOWN PHENOTYPE OF

THESE DISORDERS.

WE WANT TO HAVE BASIC SCIENTISTS

STUDY THESE DISORDERS.

WE HAVE PROBABLY 50 THAT COULD

USE ME BASIC SCIENCE EXPERTS

IN A PARTICULAR FIELD.

WE'D LIKE TO EXPAND THIS EVEN

POSSIBLY TO CTSA'S AROUND THE

COUNTRY.

AND REALLY HELP INDIVIDUALS

ALONG THE WAY.

SO THAT WOULD BE OUR GOAL.

SO I CAN PROBABLY TAKE

QUESTIONS.

IF YOU WANT OR NOT.

WHATEVER.

[APPLAUSE]

>> THANK YOU VERY VERY MUCH,

BILL.

SO PLEASE, DO WE HAVE SOME

QUESTIONS OR COMMENTS?

HOW MUCH OF THIS IS A GLOBAL

ENTERPRISE IN THE SENSE OF

PATIENTS AND REFERRALS FROM ALL

OVER THE WORLD?

>> WELL, ALTHOUGH WE DO GET

INQUIRIES, WE DON'T TAKE TOO

MANY FROM OUTSIDE THE UNITED

STATES EXCEPT MAYBE CANADA.

BUT I WOULD SAY OVER 95% OF OUR

PATIENTS ARE U.S. CITIZENS.

PEOPLE ARE TRYING TO EMULATE

THIS IN, I GOT A CALL FROM THE

HEALTH SERVICE OF BRITAIN, FROM

SINGAPORE AND FROM CHINA.

AND NOT TO MENTION ABOUT FIVE

DIFFERENT PLACES IN THE UNITED

STATES, BUT YOU KNOW, THEY'RE

NOT GOING TO ACTUALLY HAVE THE

MONEY UNLESS THEY GET MAYBE 10

TO $15 N MILLION FROM A BENEFACTOR

OR SOMETHING LIKE THAT.

IT'S NOT A REQUIREMENT FOR THEM

TO BE UNITED STATES CITIZENS.

BU IT'S ALSO TRUE IN MANY

PLACES IN THE WORLD THE WORK UPS

ARE NOT SUFFICIENT FOR US TO

ACCEPT ANYBODY.

IN OTHER WORDS THEY HAVE TOOK

PRETTY WELL, THEY HAVE TO HAVE

ELIMINATED ALL SORTS OF

CANDIDATE DISORDERS FOR US TO BE

WILLING TO TAKE A PATIENT.

>> THE QUESTION IS WHAT IS A

GOOD CASE.

>> BILL, COULD YOU REPEAT THE

QUESTION.

>> THE QUESTION IS WHAT IS A

GOOD CASE.

A GOOD CASE IS ONE IN WHICH

THERE'S A FAMILY THAT HAS A

PATTERN OF INHERITANCE THAT WE

RECOGNIZE BECAUSE THEN WE CAN

APPLY THE MODEL FILTERS AND WE

CAN ALSO HAVE DNA FROM THOSE

FAMILY MEMBERS TO ANALYZE IT.

THAT'S A GOOD CASE.

ANOTHER ISSUE IS WHERE YOU HAVE

A LOT OF OBJECTIVE FINDINGS.

AND IT ISN'T JUST PEOPLE

COMPLAINING.

AND SOMETHING THAT'S NEW.

SO WE HAVEN'T SEEN IT BEFORE.

>> IT'S KIND OF INTERESTING, WE

SET UP THE PROGRAM OF THIS

COURSE ON THE BASIS OF OLD

FASHIONED GRAND MEDICAL ROUNDS.

WHEREIN SOMEONE PATIENT WAS

PRESENTED WHICH RARELY IF EVER

HAPPENS, A LIVE PATIENT IN

MEDICAL ROUNDS, ANY PLACE IN THE

COUNTRY TODAY WHICH WE'RE VERY

GRATEFUL TO, WHERE A CLINICAL

INVESTIGATOR WHO HACK STUDYING

PRESENT THE CLINICAL ASPECTS AND

THE BASIC SCIENCE.

THAT FORMAT HAS DISAPPEARED IN

MEDICAL EDUCATION.

AND I WOULD VENTURE TO GUESS

THAT ONE OF THE GREAT

ACCOMPLISHMENTS BROUGHT ABOUT IS

TO GET ALL OF THESE DIFFERENT

MINDS IN THE SAME ROOM THINKING

ABOUT THINGS THAT THEY NORMALLY

DON'T THINK ABOUT.

YOU WANT TO COMMENT ABOUT THAT

AS A KIND OF A PHILOSOPHIC

APPROACH TO THE WAY EDUCATION

AND MEDICAL CARE SHOULD E.

>> I'LL MAKE A COUPLE COMMENTS.

ACTUALLY I'VE BEEN CRITICIZED

FOR PRESENTING PATIENTS O OUR

PATIENTS AT THE GENETICS ROUNDS.

THEY THOUGHT IT WAS AN

IMPOSITION ON THE PATIENTS, EVEN

THOUGH HE WE ASKED FOR THEIR

PERMISSION.

VIRTUALLY EVERY PATIENT IS

ANXIOUS TO TELL HER OR HIS STORY

AND FIND THIS TO BE ACTUALLY

THERAPEUTIC.

I'VE BEEN CRITICIZED FOR THAT

10, 15 YEARS AGO AND STILL AM.

SO THAT'S AN ISSUE OF THE

CHANGING WAY THAT WE DO BUSINESS

AS EDUCATORS OF MEDICAL

STUDENTS.

I THINK IT'S JUST COMPLETELY

NUTTY TO NOT ALLOW MICHIGANS TO

TELL THEIR STLEERS -- ALLOW

PATIENTS TO TELL THEIR STORIES.

THAT'S ONE THING.

BUT THE SECOND THING IS WHY ARE

WE ANY DIFFERENT FROM MAYO

CLINIC OR CLEVELAND CLINIC OR

HOPKINS OR ANY OF THOSE PLACES.

ONE OF THE REASON IS AT MANY OF

THOSE INSTITUTIONS, INDUSTRIALLY -- VIRTUA
LLY

ALL OF THEM IT'S DIFFICULT FOR

THE DOCTORS TO GET AWAY FROM

THEIR CLINICS.

THE CHAIRS OF THEIR DEPARTMENTS

DON'T ALLOW THEM TO ATTEND A

MULTIDISCIPLINARY CONFERENCE

OVER PATIENTS BECAUSE THEY'RE

LOSING CLINIC MONEY.

ESSENTIALLY IT'S A BUSINESS AND

THAT ACTUALLY DOESN'T OCCUR MUCH

HERE WHERE THE PHYSICIANS ARE

PROVIDING PROBONO SERVICE TO THE

UNDIAGNOSED DISEASE PROGRAM AND

WILL ACTUALLY COME TO A MEETING

AND DISCUSS THIS.

AND THEN YOU HAVE THE BASIC

SCIENTISTS WHO WILL OFTEN COME

TO A MEETING TOO.

SO THAT'S UNIQUE AND IT'S UNIQUE

ABOUT THE NIH, I THINK.

WHAT AN INCREDIBLE PRIVILEGE TO

WORK HERE AND TO HAVE YOUR TEXT

PAIR DOLLARS PAY FOR US AND OUR

SALARIES AND PAY FOR THE

CLINICAL CENTER TO SEE PATIENTS

WITHOUT HAVING TO GET INSURANCE.

OF COURSE CONGRESS WANTS TO

CHANGE THAT AND MAKE US ACCEPT

AND FORCE US TO RECEIVE THIRD

PARTY REIMBURSEMENT WHICH IS

ANOTHER TERRIBLE IDEA AND WILL

ACTUALLY TRY PEOPL DRIVE PEOPLE LIKE ME

AWAY FROM THE NIH.

I MAY AS WELL WORK ELSEWHERE IF

I HAVE TO FILL OUT INSURANCE

WORK.

THAT'S PHILOSOPHICAL.

BUT I'M NOT UPSET ABOUT THIS.

>> I HAVE TO THROW IN A LITTLE

BIT OF ADDED PHILOSOPHY TO THAT

IN THAT THERE'S A GREAT TENDENCY

IN MEDICINE AND SCIENCE TO BE

TOTALLY POLARIZED.

THERE ARE EVEN ARLSZ WRITTEN

ABOUT HOW, YOU KNOW, YOU TONIGHT

REALLY NEED PHYSICIANS ANYMORE

HARDLY BECAUSE YOU LOOK AT THE

SEQUENCES AND YOU CAN PREDICT.

NOW OBVIOUSLY THAT'S OFF THE

WALL.

FOR THE YOUNG PEOPLE HERE WHO

ARE POST DOCS IN PARTICULAR,

THERE'S AN ENORMOUS OPPORTUNITY

ON BOTH SIDES OF THIS BRIDGE,

AND YOU DON'T HAVE TO HAVE A

LABEL THAT STICKS YOU IN BOTH,

IN EITHER ONE.

YOU CAN BELONG IN BOTH.

AND THE VIRTUE OF LIKE THESE

MEETINGS AND CONFERENCES IS YOU

MAY NOT KNOW ANYTHING ABOUT BONE

OR CALCIUM OR ANYTHING.

BUT THE CHANCES ARE YOU'RE GOING

TO START TO THINK ABOUT IT

THROUGH THE VISION OF WHAT I

DON'T REMEMBER OWN EXPERTISE IS.

AND THAT'S REALLY THE WAY THAT

PROGRESS IS USUALLY MADE, ISN'T

IT?

>> YES, I THINK SO.

SO I HATE THOSE POLARIZING

PEOPLE.

>> I JUST LIKE TO SAY I'M THE

LEAST AMONG YOU BECAUSE YOU GUYS

ARE PH.D.

I WORK AT THE WE HAVE CASE WHERE A PERSON

COMES IN WITH TTP.

AND THEN SO THEY'RE MISSING THAT

ADAM'S 13 ENZYME THAT BREAKS

DOWN T THE -- CHAIN BECAUSE THEY

DON'T HAVE THE BREAK DOWN OF THE

VAUGHN -- PROTEIN CHAIN BY THAT

ENZYME THEY DEVELOP THE

PLATELETS CLOT AND THEY HAVE A

BIG DISEASE AND EVERYTHING.

OUR THERAPIST IS TO DO PLASMA

FREEZES AND THAT SUPPLIES THE

PATIENT WITH THE ENZYMES.

THERE ARE OTHER THERAPIES LIKE

BONE MARROW TRANSPLANTS SAY FOR,

YOU KNOW, IN THE FUTURE FOR

SICKLE CELL PATIENTS TO CHANGE

THEIR GENETICS THERE.

WHAT IS YOUR FUTURE?

WHAT IN I DON'T REMEMBER MIND DO

YOU HAVE FOR THE VECTOR TO

CHANGE THE GENOME.

IF YOU LOOK AT THE GENOME WHAT'S

THE NORMAL BIOLOGY.

WHAT'S THE DISEASE BIOLOGY.

THE THERAPISTS ARE GOING TO BE

AN ANTIBODY IN THE CASE OF

CANCER DIRECTED SPECIFICALLY AT

THAT TUMOR, THE THERAPY IS GOING

TO BE PLASMA FREEZE.

THE THERAPIST IS GOING TO BE

SUPPLYING A DRUG TO JEAN MODIFY

TO TURN A GENE  OR OFF.

WHAT'S THE VECTOR.

THEY HAVE THE INSERTION OF A

GENE TO CHANGE THE GENETICS OF

THE MICE SO NOW THIS MICE WILL

EXPRESS WHAT'S MISSING.

WHAT IN THE FUTURE DO YOU SEE?

>> I'M SURE THAT THERE WILL BE

CUSCUSTOMIZED THERAPY.

THE IT GETS TO ALL THE TISSUES

OF THE BODY.

SO THAT WILL BE BETTER THAN GENE

THERAPY THAT'S DIRECTED

AUTHORIZE A PARTICULAR ORGAN

SYSTEM.

SO I THINK SOME PEOPLE WILL

STILL WANT TO DEVELOP SMALL

MOLECULE THERAPISTS.

FOR OTHER PATIENTS, YOU'LL HAVE

TO HAVE GENE THERAPY THAT WILL

BE DIRECTED TOWARDS THIS

ORGANNOR THAT ORGAN OORGANOR THAT ORGAN AN
D I'M HOPEFUL

WE'LL BE ABLE TO PULL VECTORS

OFF THE SHELF TO DIRECT DRUGS TO

PARTICULAR TISSUES AND TO DIRECT

GENES TO PARTICULAR TISSUES AS

WELL.

BUT THERE'S NOT GOING TO BE ANY

CLEAR SOLUTION THAT IS

UNIVERSAL.

BUT I DO THINK THAT EVERY TIME

YOU FIND A GENE IN A MECHANISM

OF ACTION, THAT THAT GIVES RISE

TO ANOTHER FIELD IN WHICH YOU

CAN APPLY, DIRECT YOURSELF

TOWARDS REMEDYING THAT

PARTICULAR PATHWAY.

NOW THAT'S WHY THE CALCIFICATION

THING WAS SORT OF INTERESTING.

PEOPLE ARE GOING TO USE THAT FOR

CALCIFICATION AND THINGS OF THAT

SORT.

>> ERIC, DO YOU WANT TO COMMENT

ABOUT THIS?

OKAY WELL, I WANT TO THANK BOTH

OF YOU.

ON BEHALF OF EVERYBODY THIS HAS

REALLY BEEN A MARVELOUS EXCITING

THING.

THANK YOU VERY MUCH.