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SO, GOOD MORNING, EVERYONE.

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MY NAME IS MICHAEL GOTTESMAN,

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CHIEF OF THE LABORATORY OF CELL

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BIOLOGY AT THE NCI AND THE

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FORMER DEPUTY DIRECTOR FOR

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INTRAMURAL RESEARCH AT THE NIH.

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AND I'VE KNOWN AND KNEW PHIL FOR

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MANY, MANY YEARS.

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ON BEHALF OF THE NIH ACTING 

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DIRECTOR, DR. LARRY TABAK AND

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CURRENT DEPUTY DIRECTOR NINA

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SCHOR I'D LIKE TO WELCOME YOU TO

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THE SYMPOSIUM HONORING THE

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EXTRAORDINARY ACCOMPLISHMENTS OF

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PHIL LEDER, A SCIENTIST BOTH AT

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THE NIH AND AT HARVARD.

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AS YOU'LL SEE, WAS INSTRUMENTAL

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IN PROBABLY MOST OF THE MAJOR

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MOLECULAR ACCOMPLISHMENTS OF THE

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LAST 50 YEARS, AND IN GENERATING

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AN INCREDIBLE NUMBER OF TRAINEE 

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TRAINEES.

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THERE WILL BE NINE FORM MEMBERS

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OF THE LABORATORY, THE TENTH

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COULDN'T MAKE IT, WE'RE SORRY

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ABOUT THAT.

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IT GIVES MORE TIME I THINK AND

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ALLOWS US TO PUT A BREAK IN

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WHICH WE DIDN'T HAVE SCHEDULED

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BEFORE.

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I WOULD LIKE TO WELCOME THE

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LEDER FAMILY.

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LET'S SEE, THERE YOU ARE!

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I KNOW IRIS IS NOT HERE BUT WILL

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WATCH REMOTELY, AND THEIR

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CHILDREN AND PHIL'S CHILDREN,

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AND I WELCOME YOU AND THANK YOU

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FOR BEING GENEROUS PARTICIPANTS

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IN THIS PROGRAM.

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I ALSO WANT TO THANK THE FAES

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WHICH IS SPONSORING THE PROGRAM,

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HOSTING THIS ACTIVITY, WE'RE

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VERY GRATEFUL AND YOU'LL HEAR

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MORE LATER FROM CHRISTINA ABOUT

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THE FAES.

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AND THE ORGANIZING COMMITTEE WHO

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HELPED COME UP WITH THE PROGRAM.

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I'VE NEVER BEEN INVOLVED IN AN

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ACTIVITY IN WHICH EVERY SINGLE

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PERSON WHO WAS ASKED TO SPEAK

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SAID ABSOLUTELY YES, I WILL

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COME.

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SO, THIS IS I THINK A TESTAMENT

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TO PHIL'S LEGACY AS WELL.

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I SEE THERE ARE SOME YOUNGER

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CAREER SCIENTISTS IN THE

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AUDIENCE, AND SO LET ME TELL YOU

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ABOUT PHIL LEDER.

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MOST OF US KNOW QUITE A LOT

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ABOUT HIS ACCOMPLISHMENTSES BUT

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IF YOU WERE BORN AFTER 1980 YOU

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MIGHT NOT REALIZE HOW MUCH HE

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DID. 

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UNDERGRADUATE AT HARVARD

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COLLEGE, M.D. HARVARD MEDICAL

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SCHOOL, DURING COLLEGE ABOUT

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INTERNSHIP WITH MARTHA VAUGHN,

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NATIONAL HEART INSTITUTE, A

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LEGENDARY NIH SCIENTIST AND I

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THINK HE LEARNED REALLY

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WONDERFUL BIOCHEMISTRY FROM HER.

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AFTER HIS MEDICAL INTERNSHIP AND

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RESIDENCY AT THE UNIVERSITY OF

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MINNESOTA, HE RETURNED TO NIH TO

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DO POSTDOCTORAL WORK WITH

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MARSHAL NUREMBERG AND DESIGNED

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EXPERIMENTS THAT MADE POSSIBLE 

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DECIPHERING OF GENETIC CODE,

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WEIZMANN INSTITUTES IN ISRAEL,

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CAME BACK TO NIH, MOVED TO NICHD

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TO BECOME CHIEF OF LABORATORY OF

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 MOLECULAR GENETICS, AND THIS 

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WAS A REALLY LANDMARK

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CONTRIBUTION TO THE MOLECULAR

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BIOLOGY.

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HE ALSO ASKED ANOTHER IMPORTANT

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QUESTION, HOW IS IT POSSIBLE

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THAT THERE'S SO MUCH ANTIBODY

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DIVERSITY IF THE NUMBER OF GENES

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ARE SO LIMITED, AND BEGAN

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WORKING ON THAT AT NIH AS WELL.

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HIS INTEREST IN TEACHING WAS

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EXEMPLIFIED BY STINT AS

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PRESIDENT FOR ADVANCED EDUCATION

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IN SCIENCE, OUR HOST FOR TODAY,

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HEAD OF THE FAES CHEMISTRY

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DEPARTMENT.

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IN 1980 WAS RECRUITED TO HARVARD

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FIRST CHAIR OF MEDICAL GENETICS 

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DEPARTMENT AND AN DEMONSTRATED

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ROLE OF C MICK IN BURKITT'S

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LYMPHOMA AND PATENTED THE

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ONCOMOUSE, AS YOU KNOW

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GENETICALLY ENGINEERED MICE FORM

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THE BASIS FOR MUCH OF THE

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RESEARCH THAT'S BEEN DONE

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RECENTLY, OVER THE YEARS

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ACTUALLY, TO UNDERSTAND THE

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MOLECULAR BASIS OF CANCER.

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PHIL'S WORK WAS RECOGNIZED BY A

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GREAT MANY AWARDS, INCLUDING

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LASKER MEDICAL RESEARCH AWARD,

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NATIONAL MEDAL OF SCIENCE,

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ELECTED TO MULTIPLE SOCIETIES

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INCLUDING NATIONAL ACADEMIES OF

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SCIENCE AND MEDICINE, NATIONAL

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ACADEMY OF ARTS AND SCIENCES.

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AT NIH AND HARVARD MENTORED AND

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INSPIRED A GENERATION OF

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RESEARCHERS FORTUNATE ENOUGH TO

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SPEND TIME IN HIS LAB.

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HE DIED ON FEBRUARY 6, 2020, AT

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AGE 85.

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SO, WHAT WAS THE SECRET SAUCE

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THAT ALLOWED PHIL TO BE SO

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SUCCESSFUL?

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FIRST OF ALL, HE CHOSE THE MOST

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CRITICAL QUESTIONS OF HIS TIME,

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AND ANSWERED THEM WITH CAREFULLY

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DESIGNED AND BRILLIANTLY

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EXECUTED EXPERIMENTS.

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AND HE WAS ABLE TO COMMUNICATE

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HIS FINDINGS WERE BEAUTIFULLY

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PREPARED LECTURES AND PAPERS AND

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COULD ATTRACT SOME REALLY

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WONDERFUL EARLY CAREER

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SCIENTISTS TO WORK WITH HIM,

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MANY OF WHOM ARE HERE TODAY.

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LOOKING AT TODAY'S PROGRAM, I'M

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REMINDED OF A FAMOUS QUOTE FROM

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JOHN KENNEDY, WHO OFFICIATED AT

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THE WHITE HOUSE OVER A MEETING

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OF NOBEL LAUREATES, AND MANY OF

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YOU MAY REMEMBER THIS QUOTE AND

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COMMENTED, I THINK THIS IS THE

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MOST EXTRAORDINARY COLLECTION OF

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TALENT OF HUMAN KNOWLEDGE THAT

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HAS EVER BEEN GATHERED TOGETHER

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AT THE WHITE HOUSE, WITH THE

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POSSIBLE EXCEPTION OF WHEN

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THOMAS JEFFERSON DINED ALONE.

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SO OUR SPEAKERS TODAY ARE AN

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AMAZING COLLECTION OF TALENT AT

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THE NIH, ONLY EXCEEDED BY THE

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TIME WHEN PHIL LEDER WAS CHIEF

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OF THE LABORATORY OF MOLECULAR

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GENETICS AT NICHD.

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LET ME FINISH WITH A PERSONAL

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ANECDOTE.

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I MENTIONED HE WAS A DEDICATED

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TEACHER AND TAUGHT A VERY

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POPULAR FAES COURSE, DNA

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REPLICATION, TRANSCRIPTION, AND

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TRANSLATION.

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DURING MY POSTDOCTORAL YEARS AT

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NIH MY MENTOR, MARTY GELLER,

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ASKED ME ONE YEAR TO TAKE OVER

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THE TEACHING OF THE DNA

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REPLICATION PART OF THE COURSE

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BECAUSE HE COULD NOT DO IT.

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I WOULD MEET REGULARLY WITH PHIL

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TO DISCUSS THE CURRICULUM, WHAT

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I WOULD BE PRESENTING, WHAT HE

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WOULD  SUBSEQUENTLY BE

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PRESENTED.

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ONE WARM SUMMER DAY AS I WAS

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TALKING TO HIM ON THE PHONE I

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NOTICED THERE SOUNDED LIKE AN

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ECHO, HE COULD HEAR HIS VOICE

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TWICE, IN DIFFERENT BUILDINGS A

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FEW HUNDRED YARDS APART, WE USED

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TO BE ABLE TO OPEN THE WINDOWS,

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CAN YOU IMAGINE?

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HE WAS A FEW HUNDRED YARDS AWAY.

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I REALIZED I COULD HEAR HIM ON

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THE PHONE BUT ALSO COULD HEAR

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HIS VOICE PROJECTING ACROSS THE

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SPACE BETWEEN THE TWO BUILDINGS.

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HE HAD A BEAUTIFUL SPEAKING

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VOICE, WHICH PROJECTED EXTREMELY

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WELL, I'M SURE YOU ALL REMEMBER

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THE TALKS THAT HE GAVE.

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SO HOW CAN RERECOGNIZE SUCH

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IMMENSE TALENT?

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THIS SYMPOSIUM IS ONE WAY TO

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HIGHLIGHT PHIL LEDER'S LEGACY OF

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SCIENCE AND TRAINING AND WITH

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THE HELP OF DONORS FAES DONATED

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A HOUSE ACROSS ON CEDAR LANE IN

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HIS NAME.

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I'D LIKE TO INTRODUCE THE CEO

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AND EXECUTIVE DIRECTOR OF THE

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FAES WHO WILL TELL YOU MORE

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ABOUT THIS PROJECT.

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CHRISTINA?

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[APPLAUSE] 

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>> GOOD MORNING, AND THANK
YOU

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SO VERY MUCH FOR BEING HERE WITH

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US TODAY.

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MY NAME IS CHRISTINA, IN MY 12

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YEARS HERE WORKING WITH THE NIH

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COMMUNITY, I HAVE NEVER BEEN

213
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MORE PROUD.

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00:08:38,912 --> 00:08:41,047
FAES WAS CREATED IN 1959 BY NIH

215
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SCIENTISTS FOR THE NIH AND

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BROADER BIOMEDICAL COMMUNITY,

217
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OVER THE LAST 64 YEARS WE HAVE

218
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TRAINED AND EDUCATED MORE THAN

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150,000 INDIVIDUALS.

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SOME PEOPLE THINK OF US AS A

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SLEEPING GIANT, A SMALL

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ORGANIZATION, BUT WE GET TO HAVE

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SUCH AN AMAZING BROAD IMPACT.

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00:09:00,734 --> 00:09:04,971
AND WHEN I WAS DOING MY RESEARCH

225
00:09:04,971 --> 00:09:08,608
ABOUT DR. PHIL LEDER, I WAS

226
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TREMENDOUSLY PROUD AND HUMBLED

227
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BY NOT ONLY HIS ACCOMPLISHMENTS

228
00:09:11,878 --> 00:09:14,014
AT NIH OF COURSE AND BEYOND, BUT

229
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THE FACT HE SERVED AS ONE OF OUR

230
00:09:17,250 --> 00:09:18,685
BOARD PRESIDENTS.

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WE'VE HAD THE PRIVILEGE OF

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HAVING WONDERFUL PRESIDENTS AND

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BOARD MEMBERS BUT I HAVE TO SAY

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PHIL LEDER HAS DONE SOME

235
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SPECTACULAR THINGS, AND I THINK

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IT'S CERTAINLY EVIDENT, I'M

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GOING TO ECHO WHAT DR. GOTTESMAN

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SAID, EVIDENCED BY THE SPEAKERS

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YOU'LL HEAR TODAY.

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WE WERE SO EXCITED WE THOUGHT WE

241
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WOULD EXTEND ALL INVITATIONS AND

242
00:09:42,642 --> 00:09:44,177
WHEN EVERYONE ACCEPTED, I

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00:09:44,177 --> 00:09:47,680
THOUGHT, OH MY GOODNESS, THESE

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00:09:47,680 --> 00:09:49,349
WONDERFUL GENIUS PEOPLE NOW HAVE

245
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ONLY 20 MINUTES TO TALK TO YOU.

246
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I'M SURE THEY ARE GOING TO

247
00:09:53,553 --> 00:09:55,955
IMPOSE WONDERFUL WISDOM AND

248
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SHARE ABOUT THE NIH COMMUNITY,

249
00:09:58,691 --> 00:10:00,126
THE BROADER BIOMEDICAL

250
00:10:00,126 --> 00:10:02,829
COMMUNITY, ALSO HARVARD, AND HOW

251
00:10:02,829 --> 00:10:03,630
WORKING TOGETHER AS SCIENTISTS

252
00:10:03,630 --> 00:10:06,166
THE WORLD IS A BETTER PLACE FOR 

253
00:10:06,166 --> 00:10:07,100
ALL OF US.

254
00:10:07,100 --> 00:10:11,071
SO THANK YOU SO MUCH FOR BEING

255
00:10:11,071 --> 00:10:11,604
HERE.

256
00:10:11,604 --> 00:10:14,340
WE ARE ALL SO LUCKY TO HAVE

257
00:10:14,340 --> 00:10:17,077
DONORS WHO HELPED US AND WILL BE

258
00:10:17,077 --> 00:10:20,013
DEDICATED ONE OF OUR SCHOLAR

259
00:10:20,013 --> 00:10:21,214
RESIDENCES TO DR. PHIL LEDER.

260
00:10:21,214 --> 00:10:24,150
WE WILL HAVE A WEBSITE UPDATED,

261
00:10:24,150 --> 00:10:25,819
AND A QR CODE IS ON YOUR PROGRAM

262
00:10:25,819 --> 00:10:28,688
AND WILL BE ON THE SCREEN.

263
00:10:28,688 --> 00:10:29,355
PLEASE FOLLOW ALONG BECAUSE THIS

264
00:10:29,355 --> 00:10:31,758
IS GOING TO BE A LIVING STORY.

265
00:10:31,758 --> 00:10:34,794
WE WANT TO NOT ONLY TALK ABOUT

266
00:10:34,794 --> 00:10:37,664
THE HISTORY OF DR. LEDER, WE

267
00:10:37,664 --> 00:10:40,500
WANT TO THANK HIS FAMILY FOR

268
00:10:40,500 --> 00:10:41,601
PARTICIPATING WITH US, AND ALSO

269
00:10:41,601 --> 00:10:44,237
ALL OF THESE WONDERFUL PEOPLER

270
00:10:44,237 --> 00:10:45,572
HERE TODAY.

271
00:10:45,572 --> 00:10:48,241
SO, WITH THAT, WE WILL START OUR

272
00:10:48,241 --> 00:10:48,908
SYMPOSIUM.

273
00:10:48,908 --> 00:10:51,344
THANK YOU ALL FOR BEING HERE.

274
00:10:51,344 --> 00:10:53,613
IT'S REALLY MY HONOR AND

275
00:10:53,613 --> 00:10:53,880
PRIVILEGE.

276
00:10:53,880 --> 00:11:02,088
THANK YOU. 

277
00:11:02,088 --> 00:11:12,132
 

278
00:11:16,236 --> 00:11:17,170
>> I MENTIONED SHIRLEY
TILLMAN

279
00:11:17,170 --> 00:11:18,605
COULD NOT BE HERE TODAY.

280
00:11:18,605 --> 00:11:21,841
AS I WAS SPEAKING TO A NUMBER OF

281
00:11:21,841 --> 00:11:22,909
SPEAKERS, EVERYBODY HAD A

282
00:11:22,909 --> 00:11:25,578
SHIRLEY TILLMAN ANECDOTE.

283
00:11:25,578 --> 00:11:27,881
IN HONOR OF SHIRLEY NOT BEING

284
00:11:27,881 --> 00:11:30,483
HERE IF YOU COULD EACH TELL AN

285
00:11:30,483 --> 00:11:33,486
ANECDOTE, I WOULD APPRECIATE IT.

286
00:11:33,486 --> 00:11:35,188
BECAUSE SHE'S NOT HERE, IT MEANS

287
00:11:35,188 --> 00:11:37,190
WE CAN IN ADDITION TO LIMITING

288
00:11:37,190 --> 00:11:39,125
THE SPEAKERS TO 20 MINUTES, WE

289
00:11:39,125 --> 00:11:40,660
CAN HAVE A 20-MINUTE BREAK AND

290
00:11:40,660 --> 00:11:44,063
DEAL WITH THAT AFTER THE FIFTH

291
00:11:44,063 --> 00:11:46,166
SPEAKER, WHICH IS A NATURAL

292
00:11:46,166 --> 00:11:47,567
DIVISION BETWEEN SPEAKERS WHO

293
00:11:47,567 --> 00:11:49,969
WERE WITH PHIL AT HIS NIH LAB

294
00:11:49,969 --> 00:11:52,038
AND THOSE WITH PHIL AT HIS

295
00:11:52,038 --> 00:11:55,308
HARVARD LAB.

296
00:11:55,308 --> 00:11:56,409
NOW, BECAUSE WE DON'T -- SHIRLEY

297
00:11:56,409 --> 00:11:58,611
WAS GOING LEAD A SESSION ON

298
00:11:58,611 --> 00:11:59,913
MENTORING, AND BECAUSE WE WILL

299
00:11:59,913 --> 00:12:01,347
NOT BE HAVING THAT SESSION, IF I

300
00:12:01,347 --> 00:12:03,516
COULD ASK EACH OF THE SPEAKERS,

301
00:12:03,516 --> 00:12:05,251
I THINK THEY ARE AWARE, TO TALK

302
00:12:05,251 --> 00:12:07,253
A LITTLE BIT ABOUT HOW THEIR

303
00:12:07,253 --> 00:12:09,255
EXPERIENCE IN PHIL'S LAB

304
00:12:09,255 --> 00:12:10,323
AFFECTED THEIR SCIENTIFIC

305
00:12:10,323 --> 00:12:11,191
JOURNEYS AND HOPEFULLY WE'LL

306
00:12:11,191 --> 00:12:14,928
HEAR MORE ABOUT THEIR SCIENCE AS

307
00:12:14,928 --> 00:12:15,562
WELL.

308
00:12:15,562 --> 00:12:16,296
AND IF TIME PERMITS AT THE END

309
00:12:16,296 --> 00:12:17,797
WE'LL HAVE A Q&A SESSION.

310
00:12:17,797 --> 00:12:20,600
SO IF YOU HAVE QUESTIONS, HOLD

311
00:12:20,600 --> 00:12:22,669
THEM UNTIL THE END.

312
00:12:22,669 --> 00:12:25,338
NOW, LET'S GET ON WITH THE

313
00:12:25,338 --> 00:12:25,772
PROGRAM.

314
00:12:25,772 --> 00:12:28,942
OUR FIRST SPEAKER IS STUART

315
00:12:28,942 --> 00:12:29,609
ORKIN, DAVID NATHAN

316
00:12:29,609 --> 00:12:31,611
DISTINGUISHED PROFESSOR AT

317
00:12:31,611 --> 00:12:35,815
PEDIATRICS AT HARVARD MEDICAL

318
00:12:35,815 --> 00:12:36,649
SCHOOL.

319
00:12:36,649 --> 00:12:41,521
S TU DEFINED MOLECULAR BASIS OF

320
00:12:41,521 --> 00:12:42,155
BLOOD DISORDERS, ESPECIALLY

321
00:12:42,155 --> 00:12:45,892
THALASSEMIAS, B.S. FROM M.I.T.,

322
00:12:45,892 --> 00:12:47,894
M.D. HARVARD, RESEARCH ASSOCIATE

323
00:12:47,894 --> 00:12:51,598
WITH PHIL LEDER AT NIH FROM 1973

324
00:12:51,598 --> 00:12:52,465
TO 1975.

325
00:12:52,465 --> 00:12:57,170
FOLLOWING HIS EXPERIENCE AT NIH,

326
00:12:57,170 --> 00:13:01,007
STU RETURNED TO BOSTON, TRAINED 

327
00:13:01,007 --> 00:13:02,542
IN PEDIATRICS AND HEMATOLOGY

328
00:13:02,542 --> 00:13:05,078
ONCOLOGY, CHAIRMAN OF DEPARTMENT

329
00:13:05,078 --> 00:13:08,581
OF PEDIATRIC ONCOLOGY AT 

330
00:13:08,581 --> 00:13:09,749
DANA-FARBER CANCER INSTITUTE,

331
00:13:09,749 --> 00:13:11,551
ELECTED MEMBER, THIS WILL SOUND

332
00:13:11,551 --> 00:13:13,419
FAMILIAR, NATIONAL ACADEMIES OF

333
00:13:13,419 --> 00:13:14,053
SCIENCE AND MEDICINE, AMERICAN

334
00:13:14,053 --> 00:13:17,991
ACADEMY OF ARTS AND SCIENCES,

335
00:13:17,991 --> 00:13:20,493
AMERICAN PHILOSOPHICAL SOCIETY,

336
00:13:20,493 --> 00:13:26,532
WON MANY AWARDS INCLUDING

337
00:13:26,532 --> 00:13:28,167
ALPERT, GRUBER PRIZE, CANADIAN

338
00:13:28,167 --> 00:13:30,203
INTERNATIONAL AWARD.

339
00:13:30,203 --> 00:13:37,343
STU. 

340
00:13:37,343 --> 00:13:38,544
>> THANKS VERY MUCH.

341
00:13:38,544 --> 00:13:41,047
IT'S A PLEASURE AND AN HONOR TO

342
00:13:41,047 --> 00:13:43,549
BE HERE TO CELEBRATE PHIL.

343
00:13:43,549 --> 00:13:46,386
I THINK YOU'LL SEE THAT THERE'S

344
00:13:46,386 --> 00:13:49,055
A DIRECT LINE BETWEEN MY

345
00:13:49,055 --> 00:13:50,757
EXPERIENCE AT THE NIH AND WHAT

346
00:13:50,757 --> 00:13:52,725
I'VE BEEN DOING EVER SINCE.

347
00:13:52,725 --> 00:13:56,729
SO, THIS WAS PHIL PRIOR TO MY

348
00:13:56,729 --> 00:13:58,564
ARRIVAL, I ARRIVED IN 1973.

349
00:13:58,564 --> 00:13:59,899
I GUESS HE HAD A UNIFORM, I

350
00:13:59,899 --> 00:14:00,867
DIDN'T HAVE A UNIFORM.

351
00:14:00,867 --> 00:14:02,435
I WAS AT A PUBLIC HEALTH

352
00:14:02,435 --> 00:14:04,504
SERVICE, BUT I NEVER GOT MY

353
00:14:04,504 --> 00:14:04,837
UNIFORM.

354
00:14:04,837 --> 00:14:09,309
AND THIS IS WHEN I WAS HERE AS

355
00:14:09,309 --> 00:14:10,743
PUBLIC HEALTH SERVICE ASSOCIATE,

356
00:14:10,743 --> 00:14:12,278
BUILDING 6, WHICH WAS A QUARTER

357
00:14:12,278 --> 00:14:14,147
OF THE SIZE IT IS NOW.

358
00:14:14,147 --> 00:14:15,815
THERE'S MY PICTURE FROM THE LAB

359
00:14:15,815 --> 00:14:17,317
NOTEBOOK, I HAD MORE HAIR IN

360
00:14:17,317 --> 00:14:19,552
THOSE DAYS, A PICTURE OF THE

361
00:14:19,552 --> 00:14:19,919
LAB.

362
00:14:19,919 --> 00:14:22,755
IF YOU NOTICE, PHIL IS NOT IN

363
00:14:22,755 --> 00:14:24,657
THIS PICTURE, NOR IS AYA,

364
00:14:24,657 --> 00:14:25,725
BECAUSE THEY ARE ON SABBATICAL

365
00:14:25,725 --> 00:14:27,794
FOR ONE OF THE TWO YEARS I WAS

366
00:14:27,794 --> 00:14:29,128
AT THE NIH.

367
00:14:29,128 --> 00:14:30,963
THAT WAS BEFORE E-MAIL AND ALL

368
00:14:30,963 --> 00:14:32,298
THIS SO IT WAS HARD TO

369
00:14:32,298 --> 00:14:35,134
COMMUNICATE BUT HE CAME BACK AND

370
00:14:35,134 --> 00:14:37,870
FORTH, WE STILL MANAGED TO

371
00:14:37,870 --> 00:14:38,304
COMMUNICATE.

372
00:14:38,304 --> 00:14:43,576
IN 2004, THERE WAS A TRAINING

373
00:14:43,576 --> 00:14:45,978
REUNION AT -- UP IN BOSTON, AND

374
00:14:45,978 --> 00:14:47,513
LOTS OF PEOPLE WERE THERE.

375
00:14:47,513 --> 00:14:48,481
THERE'S SHIRLEY.

376
00:14:48,481 --> 00:14:52,318
SHE TOOK MY LAB BENCH WHEN I

377
00:14:52,318 --> 00:14:52,518
LEFT.

378
00:14:52,518 --> 00:14:55,621
A PICTURE OF ME AND PHIL, TO THE

379
00:14:55,621 --> 00:14:57,990
RIGHT IS PHIL WITH PAUL, A

380
00:14:57,990 --> 00:15:04,664
VISITING SCIENTIST FROM HUNGARY,

381
00:15:04,664 --> 00:15:11,504
PAUL WAS A BIOCHEMISTRY

382
00:15:11,504 --> 00:15:13,639
INSTRUCTOR FOR THE PERSON WHO

383
00:15:13,639 --> 00:15:14,640
JUST WON THE NOBEL PRIZE.

384
00:15:14,640 --> 00:15:19,379
I HAD A CHAIR AT HARVARD NAMED

385
00:15:19,379 --> 00:15:21,581
AFTER ME, DOESN'T HAVE MY NAME

386
00:15:21,581 --> 00:15:24,183
UNTIL I THINK I'M DEAD, PHIL WAS

387
00:15:24,183 --> 00:15:26,486
AT THIS RECEPTION WITH AYA, WE

388
00:15:26,486 --> 00:15:27,887
HAVE A LONG HISTORY.

389
00:15:27,887 --> 00:15:29,889
WHAT I LEARNED FROM PHIL?

390
00:15:29,889 --> 00:15:32,725
TO CHOOSE A GOOD PROBLEM, BE

391
00:15:32,725 --> 00:15:35,328
FOCUSED AND GOAL ORIENTED.

392
00:15:35,328 --> 00:15:37,730
DON'T SWEAT THE SMALL STUFF,

393
00:15:37,730 --> 00:15:39,165
TELL YOUR STORY WELL, AND BE

394
00:15:39,165 --> 00:15:39,932
HUMAN AND AUTHENTIC.

395
00:15:39,932 --> 00:15:44,637
I DON'T HAVE TIME TO TELL

396
00:15:44,637 --> 00:15:46,305
STORIES ABOUT THE LAST POINT BUT

397
00:15:46,305 --> 00:15:48,474
I WAS CLOSE TO FILL BECAUSE OF

398
00:15:48,474 --> 00:15:49,575
SOME PERSONAL THINGS THAT

399
00:15:49,575 --> 00:15:51,644
HAPPENED IN MY FAMILY WHILE I

400
00:15:51,644 --> 00:15:57,116
WAS AT THE NIH, A FEW WEEKS 

401
00:15:57,116 --> 00:15:58,785
AFTER I ACTUALLY ARRIVED.

402
00:15:58,785 --> 00:16:00,887
WHAT HAVE I DONE SINCE?

403
00:16:00,887 --> 00:16:09,462
I STUDIED BLOOD CELLS EARLY,

404
00:16:09,462 --> 00:16:11,664
PART OF THE GLOBIN PART OF THE

405
00:16:11,664 --> 00:16:14,267
LAB, WHERE DO THEY COULD FROM,

406
00:16:14,267 --> 00:16:16,702
WHAT DO THEY DO, AND SINCE

407
00:16:16,702 --> 00:16:19,205
LEAVING PHIL, FIRST THING I DID

408
00:16:19,205 --> 00:16:21,274
IN BOSTON WAS DETERMINE

409
00:16:21,274 --> 00:16:22,875
MUTATIONS RESPONSIBLE FOR BETA

410
00:16:22,875 --> 00:16:23,943
THALASSEMIA, AT THE TIME WE

411
00:16:23,943 --> 00:16:25,812
THOUGHT THAT WOULD TELL US ABOUT

412
00:16:25,812 --> 00:16:29,849
RED CELL DEVELOPMENT WHICH IT

413
00:16:29,849 --> 00:16:32,251
RAIL DIDN'T.

414
00:16:32,251 --> 00:16:42,762
CLONED THE FIRST TRANSCRIPTION

415
00:16:43,129 --> 00:16:43,663
FACTOR FOR HEMATOPOIESIS, AND

416
00:16:43,663 --> 00:16:45,932
FOR A LONG PERIOD OF TIME

417
00:16:45,932 --> 00:16:53,906
DEFINED MANY REQUIREMENTS FOR 

418
00:16:53,906 --> 00:16:55,475
TRANSCRIPTION FACTORS IN

419
00:16:55,475 --> 00:16:55,808
HEMATOPOIESIS.

420
00:16:55,808 --> 00:16:58,144
WE'VE BEEN WORKING ON THIS

421
00:16:58,144 --> 00:16:59,879
LONGSTANDING PROBLEM IN THE

422
00:16:59,879 --> 00:17:03,282
FIELD, SWITCH FROM FETAL TO

423
00:17:03,282 --> 00:17:10,957
ADULT HEMOGLOBIN, AND I'LL JUST

424
00:17:10,957 --> 00:17:11,924
SUMMARIZE THAT'S BEEN AN ACTIVE

425
00:17:11,924 --> 00:17:12,658
AREA OF LATE.

426
00:17:12,658 --> 00:17:14,227
FOR MANY YEARS BEFORE I EVEN

427
00:17:14,227 --> 00:17:22,535
CAME TO THE NIH, WE KNEW THE

428
00:17:22,535 --> 00:17:25,371
GLOBIN GENES CHANGED, WE HAVE

429
00:17:25,371 --> 00:17:27,607
FETAL GLOBIN, DURING ADULT LIFE

430
00:17:27,607 --> 00:17:29,108
OBVIOUSLY ADULT GLOBIN.

431
00:17:29,108 --> 00:17:32,845
IT WAS RECOGNIZED ACTUALLY IN

432
00:17:32,845 --> 00:17:38,885
1948 BY AN ASTUTE PEDIATRICS

433
00:17:38,885 --> 00:17:39,752
NEWBORNS WITH SICKLE CELL

434
00:17:39,752 --> 00:17:41,420
DISEASE WHEN THEY WERE OLDER

435
00:17:41,420 --> 00:17:44,257
WERE NOT SICK IN UTERO, NOT SICK

436
00:17:44,257 --> 00:17:47,093
IN EARLY NEONATAL PERIOD, AND

437
00:17:47,093 --> 00:17:48,728
SHE SURMISED THIS IS BECAUSE

438
00:17:48,728 --> 00:17:50,029
THEY HAD FETAL HEMOGLOBIN WHICH

439
00:17:50,029 --> 00:17:51,497
WAS PROTECTIVE AND SHE WAS

440
00:17:51,497 --> 00:17:51,764
CORRECT.

441
00:17:51,764 --> 00:17:54,033
THAT LED TO THE NOTION IN THE

442
00:17:54,033 --> 00:17:56,969
FIELD FOR MANY YEARS THAT WE

443
00:17:56,969 --> 00:18:00,806
SHOULD STRIVE TO INCREASE LEVEL

444
00:18:00,806 --> 00:18:04,310
OF FETAL HEMOGLOBIN TO PARTLY

445
00:18:04,310 --> 00:18:07,046
OFFSET THE ADULT HEMOGLOBIN,

446
00:18:07,046 --> 00:18:08,047
BECAUSE GENES ARE EXPRESSED ON

447
00:18:08,047 --> 00:18:11,317
CHROMOSOME THIS WOULD LEAD TO

448
00:18:11,317 --> 00:18:13,185
DECREASE IN ADULT HEMOGLOBIN FOR

449
00:18:13,185 --> 00:18:15,454
THE BETA CHAIN, AND THIS COULD

450
00:18:15,454 --> 00:18:16,789
BE THERAPEUTIC.

451
00:18:16,789 --> 00:18:19,125
AND THE VISION IN THE FIELD FOR

452
00:18:19,125 --> 00:18:22,695
AS LONG AS I'VE BEEN IN IT IS TO

453
00:18:22,695 --> 00:18:27,266
RAISE LEVEL TO ROUGHLY 20% OR SO

454
00:18:27,266 --> 00:18:37,810
IN A CELL ON AVERAGE, REGULATION

455
00:18:44,650 --> 00:18:46,886
IS ACCOMPLISHED, LOCUS CONTROL

456
00:18:46,886 --> 00:18:53,559
REGION IN THE CHROMOSOME 11 IS

457
00:18:53,559 --> 00:18:56,929
THE BASIC DRIVER IN FETAL STAGE

458
00:18:56,929 --> 00:19:00,032
LOOPS TO TWO GAMMA GENES, WHICH

459
00:19:00,032 --> 00:19:10,076
ARE FETAL GENES, IN ADULT BONE 

460
00:19:10,076 --> 00:19:13,045
MARROW LOOPS TO THE BETA GENE,

461
00:19:13,045 --> 00:19:17,350
EARLY 2000s WE WERE KIND OF

462
00:19:17,350 --> 00:19:18,351
WANDERING IN THE DESERT BECAUSE

463
00:19:18,351 --> 00:19:20,653
WE HAD A LOT OF INFORMATION

464
00:19:20,653 --> 00:19:22,388
ABOUT HOW GLOBIN GENES WERE

465
00:19:22,388 --> 00:19:24,457
REGULATED, NOTHING ABOUT THE

466
00:19:24,457 --> 00:19:25,858
TEMPORAL OR STAGE-SPECIFIC

467
00:19:25,858 --> 00:19:28,728
EXPRESSION. 

468
00:19:28,728 --> 00:19:30,229
AND THE BREAK CAME FROM

469
00:19:30,229 --> 00:19:31,564
ASSOCIATION STUDIES, INVOLVED

470
00:19:31,564 --> 00:19:33,766
WITH A GROUP IN SARDINIA, AND

471
00:19:33,766 --> 00:19:42,174
THIS LED TO THE DISCOVERY OF B

472
00:19:42,174 --> 00:19:44,010
CELL SWITCH FACTOR.

473
00:19:44,010 --> 00:19:46,979
WE WORKED ON THE MECHANISM BY

474
00:19:46,979 --> 00:19:50,149
WHICH IT CONTROLS THE SWITCH,

475
00:19:50,149 --> 00:19:56,555
LEVERAGED FOR GENETIC THERAPIES,

476
00:19:56,555 --> 00:20:01,427
AND I THINK WE DISCOVERED IT BUT

477
00:20:01,427 --> 00:20:03,029
IS IT REALLY IMPORTANT?

478
00:20:03,029 --> 00:20:11,370
THIS WAS A CRITICAL EXPERIMENT, 

479
00:20:11,370 --> 00:20:15,441
WITH ENGINEERED MICE, SICKLE

480
00:20:15,441 --> 00:20:17,176
CELL NICE INTERBRED, RESTRICTED

481
00:20:17,176 --> 00:20:18,811
THE KNOCKOUT, ASKED WOULD THAT

482
00:20:18,811 --> 00:20:19,879
RESCUE THE PHENOTYPE.

483
00:20:19,879 --> 00:20:21,781
THE RESULT WAS BETTER THAN WE

484
00:20:21,781 --> 00:20:26,485
MIGHT HAVE GUESSED OR HOPED FOR.

485
00:20:26,485 --> 00:20:28,654
THE SICKLE CELL MOUSE IS IN THE

486
00:20:28,654 --> 00:20:33,192
MIDDLE, MICE WERE RESCUED IN

487
00:20:33,192 --> 00:20:34,827
TERMS OF HEMATOPOIESIS BECAUSE

488
00:20:34,827 --> 00:20:36,562
THEY HAVE FETAL HEMOGLOBIN

489
00:20:36,562 --> 00:20:38,397
EXPRESSION, HIGH LEVEL IN

490
00:20:38,397 --> 00:20:41,901
VIRTUALLY ALL CELLS, REALLY THE

491
00:20:41,901 --> 00:20:44,437
BASIS FOR TREMENDOUS AMOUNT OF

492
00:20:44,437 --> 00:20:47,339
ONGOING CLINICAL WORK RIGHT NOW

493
00:20:47,339 --> 00:20:50,242
IN TRANSLATION CLINICAL TRIALS

494
00:20:50,242 --> 00:20:53,846
FOR BOTH BETA THALASSEMIA AND

495
00:20:53,846 --> 00:20:55,047
SICKLE CELL DISEASE.

496
00:20:55,047 --> 00:21:03,022
IT COMES OUT IN ADULT STAGE AND

497
00:21:03,022 --> 00:21:07,593
DISPLACES ACTIVATORS AND

498
00:21:07,593 --> 00:21:08,928
REPRESSED GAMMA SCREEN, TAKING

499
00:21:08,928 --> 00:21:13,599
PLACE ON A 30 BASE PAIR TEMPLATE

500
00:21:13,599 --> 00:21:16,469
IN THE GAMMAGLOBIN PROMOTER.

501
00:21:16,469 --> 00:21:20,773
BUT THE QUESTION WAS WHAT DOES

502
00:21:20,773 --> 00:21:21,974
GWAS HAVE TO DO?

503
00:21:21,974 --> 00:21:25,144
THERE'S NO CHANGE IN PROTEIN

504
00:21:25,144 --> 00:21:27,613
SEQUENCING COMMON VARIATION BUT

505
00:21:27,613 --> 00:21:30,116
THE VARIATION AFFECTS REGULATORY

506
00:21:30,116 --> 00:21:32,017
ELEMENT ENHANCER WITHIN THE GENE

507
00:21:32,017 --> 00:21:36,622
AND THIS HAPPENS TO BE SPECIFIC

508
00:21:36,622 --> 00:21:39,592
ENHANCER, ADULT SPECIFIC SHOWN

509
00:21:39,592 --> 00:21:42,428
AT THE BOTTOM, ABOUT 13

510
00:21:42,428 --> 00:21:45,464
KILOBASES IN LENGTH, RED CELL

511
00:21:45,464 --> 00:21:50,069
SPECIFIC ELEMENT IN A

512
00:21:50,069 --> 00:21:50,870
STAGE-SPECIFIC AND

513
00:21:50,870 --> 00:21:52,271
ERYTHROID-SPECIFIC MANNER WHICH

514
00:21:52,271 --> 00:21:53,773
GOES ALONG WITH LOTS OF WORK IN

515
00:21:53,773 --> 00:21:57,143
THE GWAS AREA THAT MOST COMMON

516
00:21:57,143 --> 00:22:00,012
VARIATION OCCURS IN REGULATORY

517
00:22:00,012 --> 00:22:00,279
ELEMENTS.

518
00:22:00,279 --> 00:22:02,815
AND FORTUNATELY, ABOUT THIS TIME

519
00:22:02,815 --> 00:22:06,752
CRISPR CAME ON THE SCENE,

520
00:22:06,752 --> 00:22:11,991
ALLOWED US TO DISSECT ENHANCER, 

521
00:22:11,991 --> 00:22:13,092
DONE BY PEPPERING ENHANCER AND

522
00:22:13,092 --> 00:22:16,595
ASKING WAS THERE A PLACE IN

523
00:22:16,595 --> 00:22:20,366
13,000 BASE PAIRS WE MIGHT USE

524
00:22:20,366 --> 00:22:24,904
FOR TRANSLATION TO THE CLINIC.

525
00:22:24,904 --> 00:22:27,206
AND REALLY QUITE SURPRISINGLY

526
00:22:27,206 --> 00:22:32,578
THERE'S A SINGLE CITE, ACHILLES 

527
00:22:32,578 --> 00:22:35,014
HEEL, WITHIN THE ENHANCER, GATA

528
00:22:35,014 --> 00:22:37,049
BINDING SITE REQUIRED FOR THE

529
00:22:37,049 --> 00:22:39,118
ACTIVITY OF THE ENHANCER TO THE

530
00:22:39,118 --> 00:22:41,554
EXTENT OF ABOUT 2/3 TO 3/4 OF

531
00:22:41,554 --> 00:22:42,988
THE ENHANCER FUNCTION, AND WE

532
00:22:42,988 --> 00:22:45,858
SAID AT THAT TIME THIS WOULD BE

533
00:22:45,858 --> 00:22:49,361
A REALLY IDEAL SITE FOR GENE

534
00:22:49,361 --> 00:22:49,728
EDITING.

535
00:22:49,728 --> 00:22:51,964
SO THIS TURNED OUT TO BE UNIQUE

536
00:22:51,964 --> 00:22:52,932
IN THAT BOTH COMMON VARIATION

537
00:22:52,932 --> 00:22:57,436
AND I HAVEN'T TOLD YOU BUT RARE

538
00:22:57,436 --> 00:22:59,505
GENETIC VARIATION, SO-CALLED

539
00:22:59,505 --> 00:23:01,440
HEREDITARY PERSISTENCE OF FETAL

540
00:23:01,440 --> 00:23:05,644
HEMOGLOBIN SYSTEM CONVERGE,

541
00:23:05,644 --> 00:23:07,580
BINDING SITE AND HOW IT'S

542
00:23:07,580 --> 00:23:08,614
REGULATED.

543
00:23:08,614 --> 00:23:11,317
HERE IS THE ACHILLES HEEL,

544
00:23:11,317 --> 00:23:12,384
SINGLE SITE WITHIN ENHANCER

545
00:23:12,384 --> 00:23:15,821
RESPONSIBLE FOR A GOOD BIT OF

546
00:23:15,821 --> 00:23:18,991
THE ACTIVITY, AND BASICALLY

547
00:23:18,991 --> 00:23:20,326
WHAT'S BEEN TRANSLATED NOW TO

548
00:23:20,326 --> 00:23:22,494
PATIENTS IS SHOWN HERE, THIS IS

549
00:23:22,494 --> 00:23:26,232
TO TAKE HEMATOPOIETIC STEM AND

550
00:23:26,232 --> 00:23:28,100
PROGENITOR CELLS, EDIT THEM AT

551
00:23:28,100 --> 00:23:31,136
THE ACHILLES HEEL, IN THIS CASE

552
00:23:31,136 --> 00:23:33,606
WITH CRISPR/CAS9, AND THEN

553
00:23:33,606 --> 00:23:36,208
REINFUSE THOSE CELLS INTO

554
00:23:36,208 --> 00:23:37,543
PRECONDITIONED PATIENTS, AND

555
00:23:37,543 --> 00:23:40,379
WHAT THIS DOES IS BASICALLY TURN

556
00:23:40,379 --> 00:23:42,014
ON FETAL HEMOGLOBIN IN AN

557
00:23:42,014 --> 00:23:42,815
OTHERWISE ADULT CELL.

558
00:23:42,815 --> 00:23:44,516
WE'RE NOT TURNING THE CELL BACK

559
00:23:44,516 --> 00:23:45,651
TO A FETAL STAGE.

560
00:23:45,651 --> 00:23:50,122
AND THE WAY THIS IS DONE IS

561
00:23:50,122 --> 00:23:51,757
ESSENTIALLY BONE MARROW

562
00:23:51,757 --> 00:23:53,926
TRANSPLANTATION, AND THERE ARE

563
00:23:53,926 --> 00:23:55,027
MANY PARAMETERS WHICH ARE

564
00:23:55,027 --> 00:23:55,594
CRITICAL.

565
00:23:55,594 --> 00:23:56,929
I DON'T HAVE TIME TO GO OVER

566
00:23:56,929 --> 00:23:58,631
REALLY ANY OF THEM EXCEPT TO SAY

567
00:23:58,631 --> 00:24:03,135
THAT THEY NEED TO BE EXECUTED

568
00:24:03,135 --> 00:24:04,403
PRECISELY TO ACCOMPLISH THIS

569
00:24:04,403 --> 00:24:07,973
WELL, AND THIS HAS BEEN

570
00:24:07,973 --> 00:24:14,079
TRANSLATED BY COLLABORATION OF 

571
00:24:14,079 --> 00:24:16,949
CRISPR THERAPEUTICS AND BRITAX

572
00:24:16,949 --> 00:24:17,683
PHARMACEUTICAL LEVERAGING

573
00:24:17,683 --> 00:24:18,751
ACHILLES HEEL WITH A SINGLE

574
00:24:18,751 --> 00:24:21,654
GUIDE, THESE ARE THE FIRST TWO

575
00:24:21,654 --> 00:24:25,124
PATIENTS, REPORTED WITH BETA

576
00:24:25,124 --> 00:24:26,125
THALASSEMIA, SICKLE CELL DISEASE

577
00:24:26,125 --> 00:24:29,995
IN THE NEW ENGLAND JOURNAL, BOTH

578
00:24:29,995 --> 00:24:31,730
PATIENTS WERE ESSENTIALLY CURED.

579
00:24:31,730 --> 00:24:35,100
THIS IS FROM AN FDA ADVISORY

580
00:24:35,100 --> 00:24:36,502
MEETING EARLIER THIS WEEK,

581
00:24:36,502 --> 00:24:38,938
BASICALLY YOU CAN SEE AS THEY

582
00:24:38,938 --> 00:24:41,307
CONTINUED THE TRIAL IN SICKLE

583
00:24:41,307 --> 00:24:48,881
CELL  PATIENTS THEY ARE FREE OF

584
00:24:48,881 --> 00:24:50,849
PAINFUL CRISES OF SICKLE CELL

585
00:24:50,849 --> 00:24:53,585
DISEASE, MORE THAN 95% OF

586
00:24:53,585 --> 00:24:57,156
PATIENTS HAVE BEEN RENDERED

587
00:24:57,156 --> 00:24:58,757
ESSENTIALLY CURED, AND "NEW YORK

588
00:24:58,757 --> 00:25:02,695
TIMES" COVERED THIS, THIS WEEK,

589
00:25:02,695 --> 00:25:06,532
A FORMAL APPROVAL IS EXPECTED IN

590
00:25:06,532 --> 00:25:08,334
DECEMBER 8, NOT DECEMBER 3,

591
00:25:08,334 --> 00:25:12,304
SHOULD BE APPROVED, THE FIRST

592
00:25:12,304 --> 00:25:13,806
GENETIC EDITING THERAPY.

593
00:25:13,806 --> 00:25:16,241
AND I THINK WE HAVE TO

594
00:25:16,241 --> 00:25:17,242
APPRECIATE HOW PROFOUND THIS IS

595
00:25:17,242 --> 00:25:18,844
FOR THE PATIENTS.

596
00:25:18,844 --> 00:25:20,479
THIS IS ACTUALLY THE FIRST

597
00:25:20,479 --> 00:25:22,047
PATIENT TREATED WHO HAS BEEN

598
00:25:22,047 --> 00:25:24,350
SORT OF A SPOKESPERSON,

599
00:25:24,350 --> 00:25:25,985
BASICALLY SAID HER LIFE -- SHE

600
00:25:25,985 --> 00:25:27,119
DIDN'T HAVE A LIFE BEFORE THIS

601
00:25:27,119 --> 00:25:31,190
THERAPY AND NOW SHE HAS A LIFE

602
00:25:31,190 --> 00:25:33,993
AND ACTUALLY CAN GO ON AND LOOK

603
00:25:33,993 --> 00:25:35,961
TO THE FUTURE.

604
00:25:35,961 --> 00:25:37,930
SO, GENETIC THERAPY IS NOW

605
00:25:37,930 --> 00:25:38,464
VALIDATED.

606
00:25:38,464 --> 00:25:40,299
THE REAL CHALLENGE NOW IS HOW TO

607
00:25:40,299 --> 00:25:42,634
EXPAND THIS TO THE MANY NUMBER

608
00:25:42,634 --> 00:25:45,037
OF PATIENTS WHO COULD BENEFIT

609
00:25:45,037 --> 00:25:47,973
FROM IT, AND QUESTION AS I THINK

610
00:25:47,973 --> 00:25:50,509
COULD BE DONE IN VIVO GENETIC

611
00:25:50,509 --> 00:25:51,710
THERAPY AS OPPOSED TO EX VIVO,

612
00:25:51,710 --> 00:25:53,479
WHICH IS THE CURRENT SCHEME.

613
00:25:53,479 --> 00:25:56,982
THIS HAS BEEN A LONG TIME IN

614
00:25:56,982 --> 00:25:57,850
COMING.

615
00:25:57,850 --> 00:25:59,518
FROM JANET WATSON IN 1948 TO THE

616
00:25:59,518 --> 00:26:00,819
ANTICIPATED APPROVAL AT THE END

617
00:26:00,819 --> 00:26:03,956
OF THIS YEAR, AND IT WAS A LONG

618
00:26:03,956 --> 00:26:05,157
GAP IN BETWEEN.

619
00:26:05,157 --> 00:26:06,925
I THINK I SEE A THREAD RIGHT

620
00:26:06,925 --> 00:26:11,063
BACK TO MY WORK AT THE NIH WITH

621
00:26:11,063 --> 00:26:11,463
PHIL.

622
00:26:11,463 --> 00:26:14,133
I JUST WANT TO IN CLOSING SAY A

623
00:26:14,133 --> 00:26:19,605
FEW THINGS ABOUT WHY THIS IS

624
00:26:19,605 --> 00:26:23,575
REALLY A SOLUTION TO THE

625
00:26:23,575 --> 00:26:24,309
HEMOGLOBIN OPATHIES, AND

626
00:26:24,309 --> 00:26:28,280
ACTIVATION OF HEMOGLOBIN F IS

627
00:26:28,280 --> 00:26:29,214
VALIDATED BY GENETIC, AND

628
00:26:29,214 --> 00:26:30,449
CLINICAL TRIALS, MAINTAINS THE

629
00:26:30,449 --> 00:26:35,020
BALANCE OF GENE EXPRESSION, NOT 

630
00:26:35,020 --> 00:26:36,221
THE CASE IN LENTIVIRALGLOBIN

631
00:26:36,221 --> 00:26:42,995
ADDITION PAIN THERAPY, SUITABLE

632
00:26:42,995 --> 00:26:45,764
FOR HEMOGLOBIN OPATHIES, THERE'S

633
00:26:45,764 --> 00:26:46,732
A FIRST GENERATION METHOD BUT I

634
00:26:46,732 --> 00:26:49,034
THINK THERE WILL BE OTHERS

635
00:26:49,034 --> 00:26:50,302
COMING ALONG, MODIFYING THE

636
00:26:50,302 --> 00:26:52,905
BINDING SITE IN THE GAMMA

637
00:26:52,905 --> 00:26:54,840
PROMOTER, USING BASE EDITING

638
00:26:54,840 --> 00:26:55,941
RATHER THAN CRISPR/CAS9, BUT

639
00:26:55,941 --> 00:26:58,777
THESE WILL BE SECOND AND THIRD

640
00:26:58,777 --> 00:26:59,545
GENERATION THERAPIES.

641
00:26:59,545 --> 00:27:01,847
I THINK IT AVOIDS DIFFICULTIES

642
00:27:01,847 --> 00:27:03,916
THAT ARE TECHNICAL IN SINGLE

643
00:27:03,916 --> 00:27:06,885
BASE REPAIR, FOR EXAMPLE, IN

644
00:27:06,885 --> 00:27:10,189
SICKLE CELL DISEASE.

645
00:27:10,189 --> 00:27:12,691
WHAT CONTRIBUTES TO SUCCESS?

646
00:27:12,691 --> 00:27:14,626
MANY UNIQUE ASPECTS OF PROTEIN

647
00:27:14,626 --> 00:27:16,728
AND ITS ROLE WHICH I DON'T HAVE

648
00:27:16,728 --> 00:27:18,597
TIME TO GO INTO, BUT IT'S

649
00:27:18,597 --> 00:27:21,667
REALLY -- THE SYSTEM IS UNIQUELY

650
00:27:21,667 --> 00:27:27,139
HARD WIRED, VERY FEW TARGETS OF

651
00:27:27,139 --> 00:27:29,608
ERYTHROID CELLS OTHER THAN

652
00:27:29,608 --> 00:27:31,710
GLOBINS, CELL IS INSENSITIVE TO

653
00:27:31,710 --> 00:27:33,145
DOWNREGULATION OF THE FACTOR,

654
00:27:33,145 --> 00:27:36,115
NOT TRUE OF MANY TRANSCRIPTION

655
00:27:36,115 --> 00:27:37,116
FACTORS.

656
00:27:37,116 --> 00:27:39,118
THERE'S EXCEEDINGLY ROBUST HUMAN

657
00:27:39,118 --> 00:27:40,819
GENETICS SUPPORTING THE WORK,

658
00:27:40,819 --> 00:27:41,920
STRONG DEPENDS OF HEMOGLOBIN F

659
00:27:41,920 --> 00:27:46,925
ON THIS ONE REPRESSOR, THERE'S A

660
00:27:46,925 --> 00:27:49,094
SECOND REPRESSOR AS WELL THOUGH.

661
00:27:49,094 --> 00:27:52,064
WE HAVE MANY EXPERIMENTAL

662
00:27:52,064 --> 00:27:54,133
RESOURCES IN PLACE, REALLY TO

663
00:27:54,133 --> 00:27:56,301
STUDY THIS FACTOR.

664
00:27:56,301 --> 00:27:59,438
WE HAD MANY OBVIOUSLY

665
00:27:59,438 --> 00:28:00,372
OUTSTANDING COMMITTED TRAINEES,

666
00:28:00,372 --> 00:28:04,776
I ALSO ATTRIBUTE TO DUMB LUCK,

667
00:28:04,776 --> 00:28:09,014
BEING IN THE RIGHT PLACE AT THE

668
00:28:09,014 --> 00:28:11,083
RIGHT TIME.

669
00:28:11,083 --> 00:28:13,852
THIS INVOLVES EX VIVO

670
00:28:13,852 --> 00:28:15,287
MANIPULATION OF CELLS,

671
00:28:15,287 --> 00:28:16,021
PRECONDITIONING, BONE MARROW

672
00:28:16,021 --> 00:28:18,056
TRANSPLANTATION, IT'S GOING TO

673
00:28:18,056 --> 00:28:20,092
BE AT LEAST $2 MILLION, THE

674
00:28:20,092 --> 00:28:21,927
PRICE IS NOT SET BUT I THINK

675
00:28:21,927 --> 00:28:25,898
IT'S A BARGAIN IN TERMS OF

676
00:28:25,898 --> 00:28:28,000
SAVING THESE PATIENTS AND GIVING

677
00:28:28,000 --> 00:28:30,802
THEM A LIFE AND ALSO REDUCING

678
00:28:30,802 --> 00:28:34,206
MEDICAL COSTS. 

679
00:28:34,206 --> 00:28:36,175
BUT IT IS CUMBERSOME,

680
00:28:36,175 --> 00:28:36,742
INSUFFICIENT NUMBER OF

681
00:28:36,742 --> 00:28:38,911
TRANSPLANT CENTERS TO TREAT ALL

682
00:28:38,911 --> 00:28:39,778
THE PATIENTS, NOT TRANSFERABLE

683
00:28:39,778 --> 00:28:41,747
TO MANY PARTS OF THE WORLD WHERE

684
00:28:41,747 --> 00:28:43,615
THERE ARE MANY PATIENTS, AND SO

685
00:28:43,615 --> 00:28:46,385
UNLESS WE CAN DO IN VIVO EDITING

686
00:28:46,385 --> 00:28:48,086
AT HIGH EFFICIENCY, I THINK WE

687
00:28:48,086 --> 00:28:50,155
STILL HAVE A NEED FOR SMALL

688
00:28:50,155 --> 00:28:54,126
MOLECULES OR DRUGS TO ACTUALLY

689
00:28:54,126 --> 00:28:56,195
DO WHAT GENETICS CAN DO FOR US.

690
00:28:56,195 --> 00:28:58,564
IT'S BEEN A LONG AND REWARDING

691
00:28:58,564 --> 00:29:00,465
JOURNEY WHERE WE'VE GONE FROM

692
00:29:00,465 --> 00:29:02,434
OVER THE LAST 15 YEARS FROM A

693
00:29:02,434 --> 00:29:06,572
GWAS RIGHT THROUGH TO WHAT WE

694
00:29:06,572 --> 00:29:07,806
BELIEVE WILL BE AN APPROVED

695
00:29:07,806 --> 00:29:09,575
THERAPY BUT I THINK THIS WOULD

696
00:29:09,575 --> 00:29:11,243
NOT HAVE BEEN POSSIBLE WITHOUT,

697
00:29:11,243 --> 00:29:14,046
YOU KNOW, THE MUCH EARLIER WORK,

698
00:29:14,046 --> 00:29:16,014
PARTICULARLY PHIL'S WORK, SO

699
00:29:16,014 --> 00:29:19,418
WE'RE IN A NEW ERA, NEW

700
00:29:19,418 --> 00:29:21,587
TECHNOLOGY IS BEING BROUGHT,

701
00:29:21,587 --> 00:29:24,923
SOME INVOLVING STEM CELLS, AND I

702
00:29:24,923 --> 00:29:26,525
THINK I MUST THANK PHIL AND SAY

703
00:29:26,525 --> 00:29:28,193
HE PROVIDED A GREAT FOUNDATION

704
00:29:28,193 --> 00:29:29,828
FOR GOING FORWARD.

705
00:29:29,828 --> 00:29:30,162
THANK YOU.

706
00:29:30,162 --> 00:29:32,864
[APPLAUSE]

707
00:29:32,864 --> 00:29:38,904
 

708
00:29:38,904 --> 00:29:48,947
 

709
00:29:52,351 --> 00:29:53,385
>> THANKS, STU.

710
00:29:53,385 --> 00:29:55,921
WHAT A WONDERFUL EXAMPLE OF HOF

711
00:29:55,921 --> 00:29:59,758
BASIC SCIENCE LEADS TO CLINICAL

712
00:29:59,758 --> 00:30:02,160
IMPROVE.

713
00:30:02,160 --> 00:30:03,829
NEXT SPEAKER IS JONATHAN

714
00:30:03,829 --> 00:30:07,266
SEIDMAN, PROFESSOR OF

715
00:30:07,266 --> 00:30:08,500
CARDIOVASCULAR GENETICS AT

716
00:30:08,500 --> 00:30:09,901
HARVARD, A GRADUATE OF HARVARD

717
00:30:09,901 --> 00:30:13,672
COLLEGE, Ph.D. IN MOLECULAR

718
00:30:13,672 --> 00:30:14,406
BIOLOGY FROM UNIVERSITY OF

719
00:30:14,406 --> 00:30:16,508
WISCONSIN, WAS A POSTDOC IN

720
00:30:16,508 --> 00:30:22,981
PHIL'S LAB AT NIH FROM 1979 TO

721
00:30:22,981 --> 00:30:24,516
1981, WORK REVOLUTIONED

722
00:30:24,516 --> 00:30:25,150
UNDERSTANDING OF GENETIC

723
00:30:25,150 --> 00:30:35,661
DISORDERS THAT LEAD TO CARDIO 

724
00:30:41,800 --> 00:30:44,036
CARDIOMYOPATHIES, HE AND HIS

725
00:30:44,036 --> 00:30:45,671
WIFE CRICKET, WHO IS ALSO VERY

726
00:30:45,671 --> 00:30:48,273
WELL KNOWN AT NIH, HAS BEEN A

727
00:30:48,273 --> 00:30:50,475
PARTNER IN MUCH OF THEIR JOINT

728
00:30:50,475 --> 00:30:52,577
RESEARCH, RECOGNIZED BY A NUMBER

729
00:30:52,577 --> 00:30:55,147
OF AWARDS, INCLUDING THE

730
00:30:55,147 --> 00:30:56,515
DISTINGUISHED SCIENTIST AWARD,

731
00:30:56,515 --> 00:30:58,583
AMERICAN HEART ASSOCIATION, KATZ

732
00:30:58,583 --> 00:30:59,785
PRIZE, DISTINGUISHED ACHIEVEMENT

733
00:30:59,785 --> 00:31:02,387
AWARDS FROM SOCIETIES FOR

734
00:31:02,387 --> 00:31:03,722
CARDIOVASCULAR PATHOLOGY,

735
00:31:03,722 --> 00:31:13,699
BRISTOL MYERS SQUIBB AND 

736
00:31:13,699 --> 00:31:14,599
McGILL HEART INSTITUTE.

737
00:31:14,599 --> 00:31:18,270
>> THANK YOU, MIKE AM.

738
00:31:18,270 --> 00:31:21,540
GOOD MORNING.

739
00:31:21,540 --> 00:31:23,442
FIRST, THAT'S A TOUGH ACT TO

740
00:31:23,442 --> 00:31:23,709
FOLLOW.

741
00:31:23,709 --> 00:31:27,079
WHAT I'D LIKE TO DO TODAY IS 

742
00:31:27,079 --> 00:31:28,146
FIRST OF ALL MENTION THAT ALL

743
00:31:28,146 --> 00:31:31,116
THE WORK I'M GOING TO TALK ABOUT

744
00:31:31,116 --> 00:31:37,956
TODAY WAS DONE BY MYSELF AND

745
00:31:37,956 --> 00:31:39,324
KRICKET SEIDMAN.

746
00:31:39,324 --> 00:31:42,260
YOU'RE TRAINING MANY PEOPLE,

747
00:31:42,260 --> 00:31:46,331
MANY PEOPLE WILL STAY, THE LEDER

748
00:31:46,331 --> 00:31:51,703
HOUSE WILL HAVE PhDs, SOME 

749
00:31:51,703 --> 00:31:53,238
MAY HAVE MD/PHD, WE WORKED THIS

750
00:31:53,238 --> 00:31:55,207
OUT IN A BETTER WAY, WAY BETTER

751
00:31:55,207 --> 00:31:58,243
TO GET YOUR M.D. BY MARRIAGE, I

752
00:31:58,243 --> 00:32:00,345
DON'T KNOW IF THAT'S A METHOD

753
00:32:00,345 --> 00:32:02,114
THAT CAN BE BROAD TO THE FAES

754
00:32:02,114 --> 00:32:03,749
BUT I STRONGLY RECOMMEND IT.

755
00:32:03,749 --> 00:32:09,755
I WOULD LIKE TO POINT OUT I WAS

756
00:32:09,755 --> 00:32:11,189
A CO-FOUNDER WITH KRICKET AND

757
00:32:11,189 --> 00:32:17,429
OTHERS OF A SMALL COMPANY 

758
00:32:17,429 --> 00:32:22,467
MYOCARDIA, NO LONGER IN

759
00:32:22,467 --> 00:32:24,669
CONFLICT, WHAT I WANT TO DO

760
00:32:24,669 --> 00:32:29,808
ASSUMING I CAN ADVANCE -- YEAH.

761
00:32:29,808 --> 00:32:33,178
DID THAT WORK?

762
00:32:33,178 --> 00:32:39,117
 

763
00:32:39,117 --> 00:32:39,351
SORRY.

764
00:32:39,351 --> 00:32:41,086
WHAT I WANT TO DO IS TELL YOU

765
00:32:41,086 --> 00:32:45,457
ABOUT THE WORK THAT WE'VE BEEN

766
00:32:45,457 --> 00:32:50,295
DOING, SOMEHOW I WENT TOO FAR. 

767
00:32:50,295 --> 00:32:51,029
YEAH, OKAY.

768
00:32:51,029 --> 00:32:51,630
SORRY.

769
00:32:51,630 --> 00:32:53,965
A LITTLE BIT ABOUT LIFE IN

770
00:32:53,965 --> 00:32:55,801
BUILDING 6 IN PHIL LEDER'S LAB,

771
00:32:55,801 --> 00:32:58,703
WHEN I WENT TO PHIL'S LAB IT WAS

772
00:32:58,703 --> 00:33:00,138
AN EYE-OPENING EXPERIENCE FOR

773
00:33:00,138 --> 00:33:02,474
ONE THING PHIL AND I WERE

774
00:33:02,474 --> 00:33:03,708
WORKING TOGETHER, AND THAT WAS

775
00:33:03,708 --> 00:33:05,710
SOMETHING THAT I SAID THAT'S A

776
00:33:05,710 --> 00:33:07,045
GREAT IDEA, HOW COME I DIDN'T

777
00:33:07,045 --> 00:33:08,880
THINK OF THAT?

778
00:33:08,880 --> 00:33:10,215
SOMETHING KRICKET AND I HAVE

779
00:33:10,215 --> 00:33:13,151
TAKEN TO HEART AND HAVE FOLLOWED

780
00:33:13,151 --> 00:33:14,052
EVER SINCE.

781
00:33:14,052 --> 00:33:15,821
BUT IN ADDITION TO THE FACT PHIL

782
00:33:15,821 --> 00:33:18,690
AND I WERE WORKING TOGETHER

783
00:33:18,690 --> 00:33:20,892
THERE WERE -- HIS LAB AND STU

784
00:33:20,892 --> 00:33:22,160
WENT THROUGH SOME OF THE

785
00:33:22,160 --> 00:33:25,764
FEATURES THAT MADE IT A SPECIAL

786
00:33:25,764 --> 00:33:27,899
PLACE, IN PARTICULAR THERE WAS A

787
00:33:27,899 --> 00:33:30,469
SOLUTION BOOK, I DON'T KNOW IF

788
00:33:30,469 --> 00:33:32,304
YOU CAN SEE MY CURSOR, YOU DON'T

789
00:33:32,304 --> 00:33:33,939
FIND IT IN EVERY LABORATORY IN

790
00:33:33,939 --> 00:33:36,041
THE UNITED STATES.

791
00:33:36,041 --> 00:33:38,310
ONLY MOSTLY LABS THAT DESCENDED

792
00:33:38,310 --> 00:33:40,979
FROM PHIL'S LAB HAVE SOLUTION

793
00:33:40,979 --> 00:33:41,480
BOOKS.

794
00:33:41,480 --> 00:33:43,849
AT SOME INSTITUTIONS, THEY ARE

795
00:33:43,849 --> 00:33:46,184
MAKING US CONVERT TO ELECTRONIC

796
00:33:46,184 --> 00:33:47,219
LAB NOTEBOOKS, TRUST ME A

797
00:33:47,219 --> 00:33:51,056
SOLUTION BOOK IS WAY BETTER.

798
00:33:51,056 --> 00:33:54,025
THERE WAS, AS STU POINTED OUT,

799
00:33:54,025 --> 00:33:56,728
THERE'S A PICTURE OF STU AS

800
00:33:56,728 --> 00:33:59,498
EVERYBODY HAD THE SOLUTION

801
00:33:59,498 --> 00:34:03,301
NUMBER, LEN IS GOING TO TELL US

802
00:34:03,301 --> 00:34:04,503
ABOUT HIS, SHIRLEY, I'M SORRY

803
00:34:04,503 --> 00:34:05,737
YOU'RE NOT HERE BECAUSE I WANT

804
00:34:05,737 --> 00:34:07,572
TO POINT OUT NOT ONLY ARE YOU IN

805
00:34:07,572 --> 00:34:10,509
THE SOLUTION BOOK BUT YOU'RE

806
00:34:10,509 --> 00:34:12,511
DOCUMENTED AS BREAKING AN NIH

807
00:34:12,511 --> 00:34:12,711
RULE.

808
00:34:12,711 --> 00:34:14,679
FORTUNATELY FOR ALL OF US THE

809
00:34:14,679 --> 00:34:15,780
STATUTE OF LIMITATIONS HAS

810
00:34:15,780 --> 00:34:18,850
EXPIRED AND THE FACT THAT YOU

811
00:34:18,850 --> 00:34:20,385
WERE CONSUMING ALCOHOL IN

812
00:34:20,385 --> 00:34:22,787
BUILDING 6 IN CELEBRATION, WHICH

813
00:34:22,787 --> 00:34:24,990
HAPPENED MORE FREQUENTLY THAN

814
00:34:24,990 --> 00:34:27,058
YOU MIGHT HAVE EXPECTED, IS JUST

815
00:34:27,058 --> 00:34:29,060
SOMETHING YOU JUST HAVE TO KEEP

816
00:34:29,060 --> 00:34:30,228
TRACK OF.

817
00:34:30,228 --> 00:34:31,897
I WANT TO MENTION WE WERE USING

818
00:34:31,897 --> 00:34:33,598
IN THOSE DAYS A MAJOR

819
00:34:33,598 --> 00:34:34,232
TECHNOLOGY, I WOULD GUESS THAT

820
00:34:34,232 --> 00:34:37,869
HALF THE PEOPLE IN THE AUDIENCE

821
00:34:37,869 --> 00:34:40,171
DON'T KNOW WHAT AN R-LOOP IS.

822
00:34:40,171 --> 00:34:41,606
HERE THEY ARE.

823
00:34:41,606 --> 00:34:43,408
A VERY USEFUL METHOD OF

824
00:34:43,408 --> 00:34:45,844
COMPARING RNA AND DNA SEQUENCES,

825
00:34:45,844 --> 00:34:48,713
NOT DEVELOPED IN PHIL'S LAB, HE

826
00:34:48,713 --> 00:34:56,321
USED IT, HIS LAB USED IT 

827
00:34:56,321 --> 00:34:57,722
PRODUCTIVELY FOR SEVERAL YEARS.

828
00:34:57,722 --> 00:34:59,491
STU POINTED OUT A NUMBER OF

829
00:34:59,491 --> 00:34:59,824
RULES.

830
00:34:59,824 --> 00:35:01,760
I THINK THEY ARE PRINCIPLES THAT

831
00:35:01,760 --> 00:35:02,894
WE SHOULD LIVE BY.

832
00:35:02,894 --> 00:35:04,629
PHIL TAUGHT ME A LOT.

833
00:35:04,629 --> 00:35:07,032
HE HAD A VERY STRONG IMPACT ON

834
00:35:07,032 --> 00:35:11,303
THE WAY WE DO SCIENCE.

835
00:35:11,303 --> 00:35:14,439
AND YOU'LL NOTICE HERE THERE'S

836
00:35:14,439 --> 00:35:15,974
NOT A PRINCIPLE NUMBER 1.

837
00:35:15,974 --> 00:35:21,146
ONE OTHER MENTOR POINTED OUT YOU

838
00:35:21,146 --> 00:35:22,013
THEY NEVER HAVE PRINCIPLE NUMBER

839
00:35:22,013 --> 00:35:25,717
1 BECAUSE EVERYBODY HAS ONE.

840
00:35:25,717 --> 00:35:27,118
WE WENT RIGHT TO PRINCIPLE

841
00:35:27,118 --> 00:35:27,886
NUMBER 2.

842
00:35:27,886 --> 00:35:29,354
ONE WAS PEOPLE DON'T CHANGE.

843
00:35:29,354 --> 00:35:30,755
IMPORTANT WHEN YOU LOOK FOR

844
00:35:30,755 --> 00:35:32,257
REVIEWERS FOR YOUR PAPER.

845
00:35:32,257 --> 00:35:35,994
SO YOU WANT PEOPLE WHO ARE GEE

846
00:35:35,994 --> 00:35:38,830
WHIZ PEOPLE, WHO YOU HAVE SHOW

847
00:35:38,830 --> 00:35:40,131
THEM ALMOST ANY RESULT, LIKE THE

848
00:35:40,131 --> 00:35:42,667
NIH SHUTTLE THAT BROUGHT US HERE

849
00:35:42,667 --> 00:35:44,970
TODAY, SOME SAY GEE WHIZ, OTHERS

850
00:35:44,970 --> 00:35:49,007
SAY SO WHAT, BUT YOU WANT A GEE

851
00:35:49,007 --> 00:35:50,408
WHIZ PERSON.

852
00:35:50,408 --> 00:35:51,943
YOU CAN'T DO SCIENCE BY

853
00:35:51,943 --> 00:35:52,344
COMMITTEE.

854
00:35:52,344 --> 00:35:53,945
THAT'S CHANGED OVER THE YEARS,

855
00:35:53,945 --> 00:35:57,115
NOW WE TRIED TO MODIFY THAT WITH

856
00:35:57,115 --> 00:36:00,518
ZOOM, WE NOW HAVE ZOOMS BUT

857
00:36:00,518 --> 00:36:04,222
DOING SCIENCE BY COMMITTEE

858
00:36:04,222 --> 00:36:05,890
DEFINITELY IS A PROBLEM.

859
00:36:05,890 --> 00:36:09,160
I'VE TOLD YOU ABOUT SOLUTION

860
00:36:09,160 --> 00:36:09,361
BOOKS.

861
00:36:09,361 --> 00:36:11,363
ANOTHER RULE THAT I THINK WE

862
00:36:11,363 --> 00:36:12,864
THINK ABOUT QUITE FREQUENTLY,

863
00:36:12,864 --> 00:36:16,201
IT'S NOT WHAT YOU DID FOR ME

864
00:36:16,201 --> 00:36:17,769
YESTERDAY, IT'S NOT THAT PHIL

865
00:36:17,769 --> 00:36:19,004
FOUND CODONS THAT WERE PART OF

866
00:36:19,004 --> 00:36:23,141
THE GENETIC CODE OR THAT HE

867
00:36:23,141 --> 00:36:27,646
IDENTIFIED A METHOD OF CELLULOSE

868
00:36:27,646 --> 00:36:29,381
FOR CAPTURING RNA, TECHNIQUES

869
00:36:29,381 --> 00:36:30,682
STILL USED, VERY IMPORTANT IN

870
00:36:30,682 --> 00:36:31,883
BIOLOGY STILL TODAY, IT'S WHAT

871
00:36:31,883 --> 00:36:34,152
YOU DO FOR ME TODAY AND WHAT

872
00:36:34,152 --> 00:36:38,990
YOU'RE GOING TO DO FOR ME

873
00:36:38,990 --> 00:36:39,257
TOMORROW.

874
00:36:39,257 --> 00:36:42,594
I'M GOING TO DISCUSS, CARRY ON

875
00:36:42,594 --> 00:36:44,996
HOW THOSE RULES PHIL INTRODUCED

876
00:36:44,996 --> 00:36:46,765
ME TO, THE FACT THAT THE SCIENCE

877
00:36:46,765 --> 00:36:50,935
THAT I HAVE DONE FOR THE NEXT 30

878
00:36:50,935 --> 00:36:51,136
YEARS.

879
00:36:51,136 --> 00:36:56,941
SO, AS STU POINTED OUT IN 1980 

880
00:36:56,941 --> 00:37:00,945
1980, PHIL MOVED TO BOSTON, THEY

881
00:37:00,945 --> 00:37:02,447
STARTED A NEW GENETICS

882
00:37:02,447 --> 00:37:02,747
DEPARTMENT.

883
00:37:02,747 --> 00:37:06,484
HARVARD MEDICAL SCHOOL NEVER HAD

884
00:37:06,484 --> 00:37:08,153
A GENETICS DEPARTMENT BEFORE

885
00:37:08,153 --> 00:37:08,687
1980, IT'S CHANGED HARVARD

886
00:37:08,687 --> 00:37:10,221
MEDICAL SCHOOL AS WELL AS

887
00:37:10,221 --> 00:37:12,390
CREATING A GREAT PLACE TO DO

888
00:37:12,390 --> 00:37:12,624
SCIENCE.

889
00:37:12,624 --> 00:37:17,228
JUST TO SHOW HOW EFFICIENTLY OR

890
00:37:17,228 --> 00:37:17,862
EFFECTIVELY PHIL'S

891
00:37:17,862 --> 00:37:20,098
ADMINISTRATIVE CAPACITIES WERE

892
00:37:20,098 --> 00:37:22,934
THESE ARE PICTURES OF DEPARTMENT

893
00:37:22,934 --> 00:37:24,669
GROWING FROM 1981 THROUGH 1994.

894
00:37:24,669 --> 00:37:26,137
BY 1994, THE DEPARTMENT WAS SO

895
00:37:26,137 --> 00:37:28,606
BIG THAT WE REALLY COULDN'T FIT

896
00:37:28,606 --> 00:37:31,342
IT INTO A LARGE SINGLE PICTURE

897
00:37:31,342 --> 00:37:34,946
SO WE STOPPED TAKING THESE

898
00:37:34,946 --> 00:37:35,213
PICTURES.

899
00:37:35,213 --> 00:37:38,883
AND PHIL HAD A SERIES OF MORE

900
00:37:38,883 --> 00:37:40,318
PRINCIPLES, FOR GUIDING HIS

901
00:37:40,318 --> 00:37:40,719
DEPARTMENT.

902
00:37:40,719 --> 00:37:43,688
ONE WAS TO RECOGNIZE THE AWESOME

903
00:37:43,688 --> 00:37:47,225
POW EVERY GENETICS, AND THERE

904
00:37:47,225 --> 00:37:48,626
WAS ADMINISTRATIVE THINGS LIKE

905
00:37:48,626 --> 00:37:49,794
DEFINITELY AS A PERSON RUNNING A

906
00:37:49,794 --> 00:37:51,663
LAB YOU HAVE TO LEARN HOW TO SAY

907
00:37:51,663 --> 00:37:55,834
NO IN AN ACADEMIC ENVIRONMENT.

908
00:37:55,834 --> 00:37:59,070
DEVELOPED A SYSTEM, TWO THINGS

909
00:37:59,070 --> 00:38:00,839
MOST IMPORTANT, CHANGED THE WAY

910
00:38:00,839 --> 00:38:04,175
THEY THOUGHT ABOUT DOING TENURE

911
00:38:04,175 --> 00:38:04,509
AT HARVARD.

912
00:38:04,509 --> 00:38:06,578
IN 1980 IN GENERAL IF YOU WERE

913
00:38:06,578 --> 00:38:08,113
IN A DEPARTMENT AS ASSISTANT

914
00:38:08,113 --> 00:38:09,080
PROFESSOR THEY WOULD SAY YOU

915
00:38:09,080 --> 00:38:10,248
LOOK TO YOUR LEFT AND RIGHT,

916
00:38:10,248 --> 00:38:12,684
ONLY ONE OF YOU IS GOING TO BE

917
00:38:12,684 --> 00:38:17,055
HERE IN A YEAR OR TWO, THAT

918
00:38:17,055 --> 00:38:19,124
CHANGED DRAMATICALLY SO

919
00:38:19,124 --> 00:38:22,193
ESSENTIALLY WITH FEW EXCEPTIONS

920
00:38:22,193 --> 00:38:23,762
ALL ARE STILL IN THE DEPARTMENT

921
00:38:23,762 --> 00:38:26,197
TODAY, SO IT'S QUITE REMARKABLE.

922
00:38:26,197 --> 00:38:28,366
ONE OTHER PRINCIPLE THAT I

923
00:38:28,366 --> 00:38:31,002
THOUGHT WAS REALLY QUITE -- HE

924
00:38:31,002 --> 00:38:32,837
FELT YOU NEEDED COMMUNICATION,

925
00:38:32,837 --> 00:38:33,705
EVEN FACE-TO-FACE COMMUNICATION,

926
00:38:33,705 --> 00:38:35,907
AND THE WAY HE BROUGHT THAT

927
00:38:35,907 --> 00:38:37,742
ABOUT WAS TO -- WHEN THE

928
00:38:37,742 --> 00:38:38,676
DEPARTMENT ACTUALLY MOVED

929
00:38:38,676 --> 00:38:40,678
SEVERAL TIMES TO DIFFERENT

930
00:38:40,678 --> 00:38:42,280
BUILDINGS, AND PART OF THAT WAS

931
00:38:42,280 --> 00:38:45,016
TO ENSURE THAT AS DEPARTMENT GOT

932
00:38:45,016 --> 00:38:47,218
BIGGER AND MOVED THERE WAS GOOD

933
00:38:47,218 --> 00:38:48,186
COMMUNICATION BETWEEN THE

934
00:38:48,186 --> 00:38:49,154
FLOORS.

935
00:38:49,154 --> 00:38:54,759
IF YOU LOOK AROUND HARVARD,

936
00:38:54,759 --> 00:38:55,960
THERE ARE IMPRESSIVE STAIRCASES.

937
00:38:55,960 --> 00:38:58,363
AS WE MOVED UP, THE STAIRCASES

938
00:38:58,363 --> 00:39:00,331
GOT BIGGER AND MORE IMPRESSIVE

939
00:39:00,331 --> 00:39:02,734
AND THEY ARE LITTERED THROUGHOUT

940
00:39:02,734 --> 00:39:05,170
THE HARVARD CAMPUS, THAT WAS

941
00:39:05,170 --> 00:39:05,703
TERRIFIC.

942
00:39:05,703 --> 00:39:08,873
ANOTHER RULE PHIL HAD, THE POWER

943
00:39:08,873 --> 00:39:10,308
OF HUMAN GENETICS IS REMARKABLE,

944
00:39:10,308 --> 00:39:12,310
IT'S LIKE PLAYING THE LOTTERY.

945
00:39:12,310 --> 00:39:15,914
SOMETIMES YOU MAP A GENE AND AS

946
00:39:15,914 --> 00:39:22,053
PHIL DID HERE, HE FOUND THAT MYC

947
00:39:22,053 --> 00:39:24,022
WAS TRANSLOCATED, THAT

948
00:39:24,022 --> 00:39:26,057
TRANSLOCATION ACTIVATED, LEADING

949
00:39:26,057 --> 00:39:27,258
TO BURKITT'S LYMPHOMA, HE FOUND

950
00:39:27,258 --> 00:39:28,827
A TRANSCRIPTION FACTOR IN A

951
00:39:28,827 --> 00:39:29,894
REGULATED EXPRESSION OF HIS

952
00:39:29,894 --> 00:39:32,363
GENES, LIKE WINNING THE LOTTERY.

953
00:39:32,363 --> 00:39:33,731
OTHERS, OTHER TIMES, I'LL SHOW

954
00:39:33,731 --> 00:39:38,036
AN EXAMPLE IN OUR LAB, WHERE WE

955
00:39:38,036 --> 00:39:40,205
FOLLOWED THE SAME PRINCIPLE,

956
00:39:40,205 --> 00:39:42,273
MAPPED A GENETIC LOCUS, IN A WAY

957
00:39:42,273 --> 00:39:45,310
NOT EXACTLY AS EXCITING AS WE

958
00:39:45,310 --> 00:39:47,512
HAD THOUGHT.

959
00:39:47,512 --> 00:39:49,914
SO JUST TO GO BACK, WE FIRST

960
00:39:49,914 --> 00:39:52,016
STARTED, AND PART OF THIS ISSUE

961
00:39:52,016 --> 00:39:54,185
OF MAKING SURE WE DON'T ALL WORK

962
00:39:54,185 --> 00:39:58,423
ON THE SAME TOPIC, WE DECIDED --

963
00:39:58,423 --> 00:40:00,658
KRICKET AND I DECIDED NOT TO

964
00:40:00,658 --> 00:40:03,161
STAY, THE COMMUNITY IS BROAD,

965
00:40:03,161 --> 00:40:04,929
INTERNATIONALLY AS WE'LL HEAR

966
00:40:04,929 --> 00:40:07,665
THERE ARE MANY IMMUNOLOGISTS AND

967
00:40:07,665 --> 00:40:09,500
THOUGHT WE WOULD GO IN DIFFERENT

968
00:40:09,500 --> 00:40:12,570
DIRECTION, I NEEDED AN ADULT

969
00:40:12,570 --> 00:40:13,504
CARDIOLOGIST, SO KRICKET

970
00:40:13,504 --> 00:40:15,673
INTRODUCED ME TO A DISEASE WHICH

971
00:40:15,673 --> 00:40:21,446
IN 1980 WAS STILL CALLED IHSS,

972
00:40:21,446 --> 00:40:23,982
WHICH ROLLS OFF YOUR TONGUE,

973
00:40:23,982 --> 00:40:25,049
MANY PEOPLE MIGHT NOT HAVE HEARD

974
00:40:25,049 --> 00:40:28,019
OF IT BUT IT WAS DISCOVERED IN

975
00:40:28,019 --> 00:40:32,857
THIS BUILDING OR NAMED BY GENE

976
00:40:32,857 --> 00:40:33,958
BRANWALD, 1970s, A DISEASE

977
00:40:33,958 --> 00:40:35,493
THAT'S BEEN AROUND FOR QUITE

978
00:40:35,493 --> 00:40:35,827
SOME TIME.

979
00:40:35,827 --> 00:40:37,795
YOU MAY HAVE HEARD OF IT BECAUSE

980
00:40:37,795 --> 00:40:41,866
EVERY NOW AND THEN YOU HEAR

981
00:40:41,866 --> 00:40:43,468
ABOUT AN ATHLETE WHO DIES

982
00:40:43,468 --> 00:40:47,772
SUDDENLY ON THE FIELD, 50% WHO

983
00:40:47,772 --> 00:40:53,344
DIE SUDDENLY HAVE IHSS, NO 

984
00:40:53,344 --> 00:40:57,148
LONGER IDIOPATHIC, BUT IN

985
00:40:57,148 --> 00:40:59,617
ADDITION THERE ARE OTHER CARDIAC

986
00:40:59,617 --> 00:41:02,287
DISEASES THAT CAN BE TREATED FOR

987
00:41:02,287 --> 00:41:05,256
THEIR ACTUAL SYMPTOM BUT YOU

988
00:41:05,256 --> 00:41:06,791
ACTUALLY UNTIL RECENTLY THERE

989
00:41:06,791 --> 00:41:08,559
WAS NO TREATMENT FOR THE ACTUAL

990
00:41:08,559 --> 00:41:11,896
CAUSE OF THE DISEASE.

991
00:41:11,896 --> 00:41:18,436
SO, IT TURNED OUT THAT IHSS IS

992
00:41:18,436 --> 00:41:23,541
INHERITED IN MANY INSTANCES

993
00:41:23,541 --> 00:41:26,077
AUTOSOMAL DOMINANT TRAIT, FOUND

994
00:41:26,077 --> 00:41:26,611
FAMILIES CORRECTIVELY AND

995
00:41:26,611 --> 00:41:28,046
STARTED TO MAP THE GENES.

996
00:41:28,046 --> 00:41:29,881
SOMETIMES YOU WOULD LAND ON THE

997
00:41:29,881 --> 00:41:33,518
LOCUS OF EXCITING LIKE MYC OR

998
00:41:33,518 --> 00:41:37,889
Bcl11 OR A GENE THAT MANY

999
00:41:37,889 --> 00:41:38,990
WOULD CONSIDER BORING.

1000
00:41:38,990 --> 00:41:49,534
SO WHAT IS MYOSIN HEAVY CHAIN? 

1001
00:41:51,703 --> 00:41:54,639
HERE YOU SEE AN iPS CELL,

1002
00:41:54,639 --> 00:41:56,874
GREEN, FOR THOSE WHO REMEMBER

1003
00:41:56,874 --> 00:41:58,376
YOUR LIGHT MICROSCOPY FROM HIGH

1004
00:41:58,376 --> 00:42:03,414
SCHOOL, YOU MEMBER SKELETAL

1005
00:42:03,414 --> 00:42:07,118
MILLION IS STRIATED MUSCLE

1006
00:42:07,118 --> 00:42:08,786
SARCOMERES THAT CONTRACT AND

1007
00:42:08,786 --> 00:42:15,827
RELAX, IT IS A COMPONENT OF THAT

1008
00:42:15,827 --> 00:42:18,830
CONTRACTILE APPARATUS, WE MAPPED

1009
00:42:18,830 --> 00:42:22,433
A NUMBER OF OTHER GENES, ALL

1010
00:42:22,433 --> 00:42:30,575
CAUSED MUTATIONS, EACH CAUSED

1011
00:42:30,575 --> 00:42:31,576
HYPERTROPHIC CARDIOMYOPATHY,

1012
00:42:31,576 --> 00:42:37,448
PART OF THE COMPLEX, THICK OR

1013
00:42:37,448 --> 00:42:38,783
THIN FILAMENT.

1014
00:42:38,783 --> 00:42:47,091
SO, OLD MODEL WAS THAT THE WAY

1015
00:42:47,091 --> 00:42:48,159
SARCOMERES WORKED, STEPPED

1016
00:42:48,159 --> 00:42:48,926
ALONG, THESE SMALL MOLECULES

1017
00:42:48,926 --> 00:42:52,430
THAT ARE GOING ON AND OFF ARE

1018
00:42:52,430 --> 00:42:56,367
ATP AND CALCIUM, SO BASICALLY

1019
00:42:56,367 --> 00:43:04,242
THE MYOSIN HEAD WAS ACTING LIKE

1020
00:43:04,242 --> 00:43:06,444
ATPase, IT TURNED OUT THIS IS

1021
00:43:06,444 --> 00:43:09,714
WHERE ONE OF PHIL'S RULES ABOUT

1022
00:43:09,714 --> 00:43:13,251
LAMP POST SCIENCE -- YEAH,

1023
00:43:13,251 --> 00:43:18,589
OKAY -- CAME INTO EFFECT. 

1024
00:43:18,589 --> 00:43:21,192
SO HISTORICALLY TO STUDY

1025
00:43:21,192 --> 00:43:23,661
BIOCHEMISTS WITH CLEAVE AND

1026
00:43:23,661 --> 00:43:27,331
ISOLATE S1 HEAD, CONTAINED THE

1027
00:43:27,331 --> 00:43:28,766
MYOSIN ATPase WITH A SINGLE

1028
00:43:28,766 --> 00:43:31,469
ACTIVITY, THAT WAS LOOKING WHERE

1029
00:43:31,469 --> 00:43:33,037
WE COULD LOOK BECAUSE THEY WERE

1030
00:43:33,037 --> 00:43:35,106
ONLY LOOKING AT THE HEAD.

1031
00:43:35,106 --> 00:43:38,176
WHEN YOU CLEAVED THE MYOSIN

1032
00:43:38,176 --> 00:43:40,445
HEAD, THE ROD WHICH LOOKS TO BE

1033
00:43:40,445 --> 00:43:42,580
BORING, TURNED OUT THAT THE HEAD

1034
00:43:42,580 --> 00:43:49,987
ACTUALLY HAS A DOCKING SPOT,

1035
00:43:49,987 --> 00:43:53,925
ALONG THE MYOSIN ROD, WHEN THEY

1036
00:43:53,925 --> 00:43:57,528
DOCK THAT REDUCES ATPase

1037
00:43:57,528 --> 00:44:00,965
ACTIVITY FIVE FOLD, PRESERVING

1038
00:44:00,965 --> 00:44:03,534
ENERGY FOR CARDIOMYOCYTE, ONLY

1039
00:44:03,534 --> 00:44:06,838
ACTIVE ON THE OTHER HAND WHEN

1040
00:44:06,838 --> 00:44:09,040
THE HEAD IS SEPARATED FROM THE

1041
00:44:09,040 --> 00:44:11,742
ROD AND IS OUT BINDING THE THIN

1042
00:44:11,742 --> 00:44:12,276
FILAMENT.

1043
00:44:12,276 --> 00:44:14,846
AT ANY GIVEN TIME IN ALL OF US

1044
00:44:14,846 --> 00:44:16,781
90% OF OUR MYOSIN HEADS ARE

1045
00:44:16,781 --> 00:44:18,783
RESTING IN THE SUPER RELAXED

1046
00:44:18,783 --> 00:44:20,384
STATE, 10% OF TIME ARE THEY OUT

1047
00:44:20,384 --> 00:44:22,887
CHEWING UP ENERGY AND MAKING

1048
00:44:22,887 --> 00:44:24,021
MUSCLES CONTRACT.

1049
00:44:24,021 --> 00:44:25,556
SO, THE MUTATIONS THAT WE

1050
00:44:25,556 --> 00:44:27,725
IDENTIFIED WERE ONES THAT

1051
00:44:27,725 --> 00:44:28,226
PRIMARILY DISRUPTED THE

1052
00:44:28,226 --> 00:44:29,727
INTERACTION OF THE HEAD WITH THE

1053
00:44:29,727 --> 00:44:32,563
ROD, AND SO THEY WERE FORCING

1054
00:44:32,563 --> 00:44:34,398
THE MYOSIN MOLECULE CONTINUALLY

1055
00:44:34,398 --> 00:44:36,434
INTO THE DISORDERED STATE WHERE

1056
00:44:36,434 --> 00:44:39,470
IT WAS CHEWING UP ATP AND SO THE

1057
00:44:39,470 --> 00:44:40,571
REAL PROBLEM ASSOCIATED WITH

1058
00:44:40,571 --> 00:44:44,642
THIS CONDITION WAS THAT WE WERE

1059
00:44:44,642 --> 00:44:46,277
USING UP ATP AT A HIGHER RATE

1060
00:44:46,277 --> 00:44:49,347
THAN THEY NEEDED TO AND THAT

1061
00:44:49,347 --> 00:44:52,283
EVENTUALLY LED TO MYOCYTE DEATH

1062
00:44:52,283 --> 00:44:53,618
AND DYSFUNCTION.

1063
00:44:53,618 --> 00:45:02,460
SO, ABOUT TEN YEARS AGO

1064
00:45:02,460 --> 00:45:07,131
COLLECTIVELY WE COLLABORATED AND

1065
00:45:07,131 --> 00:45:08,499
PUT TOGETHER BY SOMEONE WHO IS

1066
00:45:08,499 --> 00:45:11,769
THE GODFATHER OF OUR COMPANY, WE

1067
00:45:11,769 --> 00:45:12,570
GOT TOGETHER, DECIDED IT WOULD

1068
00:45:12,570 --> 00:45:15,273
BE USEFUL TO HAVE A MOLECULE

1069
00:45:15,273 --> 00:45:17,275
THAT INHIBIT THE MYOSIN

1070
00:45:17,275 --> 00:45:18,543
ATPase, AND AFTER SCREENING A

1071
00:45:18,543 --> 00:45:20,411
LARGE NUMBER OF MOLECULES WE WON

1072
00:45:20,411 --> 00:45:22,079
THE LOTTERY, WE FOUND A MOLECULE

1073
00:45:22,079 --> 00:45:23,714
THAT YOU COULD TAKE IT ORALLY

1074
00:45:23,714 --> 00:45:24,916
AND IT DIDN'T JUST GO ANY, WHERE

1075
00:45:24,916 --> 00:45:27,084
JUST WENT TO THE HEART MUSCLE,

1076
00:45:27,084 --> 00:45:28,619
AND IN THE HEART MUSCLE WOULD

1077
00:45:28,619 --> 00:45:32,056
HAVE A BENEFICIAL EFFECT OF

1078
00:45:32,056 --> 00:45:34,325
REDUCING MYOSIN ATPase

1079
00:45:34,325 --> 00:45:34,592
ACTIVITY.

1080
00:45:34,592 --> 00:45:35,660
AND THEN AT HARVARD MEDICAL

1081
00:45:35,660 --> 00:45:37,929
SCHOOL IN PHIL'S MOUSE ROOM WE

1082
00:45:37,929 --> 00:45:41,532
COULD SHOW MICE AT HARVARD NEVER

1083
00:45:41,532 --> 00:45:44,569
NEED TO HAVE HYPERTROPHIC

1084
00:45:44,569 --> 00:45:45,636
CARDIOMYOPATHY AND DEVELOP HCM

1085
00:45:45,636 --> 00:45:54,946
BECAUSE WEIGH COULD GIVE THEM

1086
00:45:54,946 --> 00:45:55,179
MYK-461.

1087
00:45:55,179 --> 00:45:57,682
IF YOU WATCH CABLE NEWS, YOU

1088
00:45:57,682 --> 00:45:58,816
KNOW THEY FREQUENTLY ADVERTISE

1089
00:45:58,816 --> 00:46:00,651
MOLECULES THAT WE NEVER HEARD

1090
00:46:00,651 --> 00:46:01,852
OF, ONE THAT YOU MIGHT NEVER

1091
00:46:01,852 --> 00:46:07,892
HAVE HEARD OF IS NOW CALLED

1092
00:46:07,892 --> 00:46:08,993
CAMZIOS, APPROVED BY THE FDA AS

1093
00:46:08,993 --> 00:46:15,866
A DRUG FOR THE TREATMENT OF 

1094
00:46:15,866 --> 00:46:20,471
HYPERTROPHIC  CARDIOMYOPATHY,

1095
00:46:20,471 --> 00:46:23,841
CAN YOU SEE ADVERTISEMENTS ON

1096
00:46:23,841 --> 00:46:24,375
MSNBC.

1097
00:46:24,375 --> 00:46:25,843
WE BENEFITED FROM FOLLOWING

1098
00:46:25,843 --> 00:46:26,877
PHIL'S PRINCIPLES TAKING

1099
00:46:26,877 --> 00:46:28,913
ADVANTAGE OF POWER OF HUMAN

1100
00:46:28,913 --> 00:46:29,647
GENETICS.

1101
00:46:29,647 --> 00:46:30,948
I WANT TO MENTION THAT AS I SAID

1102
00:46:30,948 --> 00:46:33,251
IT'S NOT WHAT YOU DID FOR US

1103
00:46:33,251 --> 00:46:34,252
YESTERDAY, IT'S WHAT YOU'RE

1104
00:46:34,252 --> 00:46:35,553
GOING TO DO FOR US TODAY AND

1105
00:46:35,553 --> 00:46:39,390
WHAT YOU WILL DO FOR US

1106
00:46:39,390 --> 00:46:40,558
TOMORROW.

1107
00:46:40,558 --> 00:46:43,661
SO JUST QUICKLY, ONE THING THAT

1108
00:46:43,661 --> 00:46:47,231
STUDIES OF THE HUMAN HEART

1109
00:46:47,231 --> 00:46:48,633
PROGRESSED RAPIDLY BECAUSE OFFED

1110
00:46:48,633 --> 00:46:53,604
A VEND OF SINGLE NUCLEI RNA

1111
00:46:53,604 --> 00:46:54,505
SEQUENCING ANALYSIS, IT LOOKS

1112
00:46:54,505 --> 00:46:58,276
LIKE A SMALL THING BUT THERE WAS

1113
00:46:58,276 --> 00:47:00,344
A MAJOR BREAKTHROUGH WHEN RUN

1114
00:47:00,344 --> 00:47:01,912
RECOGNIZE IT'S YOU CAN DO THESE

1115
00:47:01,912 --> 00:47:04,415
BY LOOKING AT NUCLEI INSTEAD OF

1116
00:47:04,415 --> 00:47:05,650
WHOLE CELLS, FREEZE HUMAN TISSUE

1117
00:47:05,650 --> 00:47:09,954
AND JUST LOOK AT THE NUCLEUS TO

1118
00:47:09,954 --> 00:47:12,189
REMIND YOU CARDIAC MYOCYTE IS

1119
00:47:12,189 --> 00:47:13,391
100 MICRONS IN LENGTH, BIG

1120
00:47:13,391 --> 00:47:15,426
ENOUGH TO CLOG UP EVERYBODY'S

1121
00:47:15,426 --> 00:47:21,265
SINGLE CELL  DEVICE BUT NOW YOU

1122
00:47:21,265 --> 00:47:23,067
CAN DO IT, INSTEAD OF THE SIMPLE

1123
00:47:23,067 --> 00:47:27,405
CARDIAC TISSUE WE THOUGHT WE

1124
00:47:27,405 --> 00:47:28,506
HAD, BASICALLY CARDIOMYOCYTES,

1125
00:47:28,506 --> 00:47:31,208
WE HAVE 11 CELL POPULATIONS,

1126
00:47:31,208 --> 00:47:32,977
INTERESTINGLY WOMEN HAVE MORE

1127
00:47:32,977 --> 00:47:33,944
CARDIOMYOCYTES THAN MEN AND THAT

1128
00:47:33,944 --> 00:47:36,380
MAY ACCOUNT AT LEAST IN PART FOR

1129
00:47:36,380 --> 00:47:39,250
WHY MEN ARE MORE SUSCEPTIBLE TO

1130
00:47:39,250 --> 00:47:41,385
HEART DISEASE THAN WOMEN.

1131
00:47:41,385 --> 00:47:42,953
MALE CARDIOMYOCYTES ARE SLIGHTLY

1132
00:47:42,953 --> 00:47:44,055
LARGER THAN FEMALE.

1133
00:47:44,055 --> 00:47:47,625
TO MAKE MATTERS EVEN WORSE, THE

1134
00:47:47,625 --> 00:47:51,228
DICTIONARY IS MORE COMPLICATED,

1135
00:47:51,228 --> 00:47:53,764
11 CELL TIMES, THEY CAN BE

1136
00:47:53,764 --> 00:47:54,565
BROKEN DOWN INTO SUBPOPULATIONS,

1137
00:47:54,565 --> 00:47:56,200
I DON'T HAVE TIME TODAY BUT YOU

1138
00:47:56,200 --> 00:47:58,569
CAN START TO LOOK AT THESE

1139
00:47:58,569 --> 00:48:02,873
SUBPOPULATIONS AND UNDERSTAND IN

1140
00:48:02,873 --> 00:48:07,678
VERY EXQUISITE LEVEL WHY IT

1141
00:48:07,678 --> 00:48:10,948
LEADS TO THICKENING OF HEART

1142
00:48:10,948 --> 00:48:15,353
WALL AND SHAPE IN THE LEFT

1143
00:48:15,353 --> 00:48:18,489
VENTRICULAR WALLS, CHAMBERS GET 

1144
00:48:18,489 --> 00:48:20,925
LARGE, BY LOOKING AT SINGLE

1145
00:48:20,925 --> 00:48:22,159
NUCLEI CAN HAVE A CLEAR PICTURE

1146
00:48:22,159 --> 00:48:23,461
WHY THAT'S GOING ON BUT YOU HAVE

1147
00:48:23,461 --> 00:48:24,862
TO READ ABOUT THIS IN THE

1148
00:48:24,862 --> 00:48:27,598
LITERATURE, I DON'T HAVE TIME TO

1149
00:48:27,598 --> 00:48:28,366
DISCUSSED TODAY.

1150
00:48:28,366 --> 00:48:31,302
LAST THING IN LINE WITH WHAT STU

1151
00:48:31,302 --> 00:48:32,636
WAS TALKING ABOUT, CLEARLY SMALL

1152
00:48:32,636 --> 00:48:33,971
MOLECULES ARE NICE, GENE THERAPY

1153
00:48:33,971 --> 00:48:35,306
IS EVEN BETTER.

1154
00:48:35,306 --> 00:48:37,908
ONE BIG ISSUE IN THE HEART IS

1155
00:48:37,908 --> 00:48:40,544
HOW DID THE LIVER VECTORSES TO

1156
00:48:40,544 --> 00:48:42,980
TO THE HEART ALLOW SINGLE BASED

1157
00:48:42,980 --> 00:48:46,317
EDITING, TURNS OUT ONE NICELY

1158
00:48:46,317 --> 00:48:49,019
AAV GETS INTO THE MOUSE HEART,

1159
00:48:49,019 --> 00:48:53,023
YOU CAN PAINT THE HEART RED

1160
00:48:53,023 --> 00:48:59,830
USING TOMATO OR GREEN USING GFP,

1161
00:48:59,830 --> 00:49:02,566
GET TRANSDUCTION, USING BASE

1162
00:49:02,566 --> 00:49:09,507
EDITORS YOU CAN ACTUALLY TREAT

1163
00:49:09,507 --> 00:49:10,541
AGAIN HYPERTROPHIC

1164
00:49:10,541 --> 00:49:11,542
CARDIOMYOPATHY, WE'VE CHANGED

1165
00:49:11,542 --> 00:49:14,412
THEIR BASE OR EDITED THEIR BASES

1166
00:49:14,412 --> 00:49:16,247
SO THEY ARE BASICALLY CURED OR

1167
00:49:16,247 --> 00:49:17,948
THEY HAVE A NORMAL GENETIC

1168
00:49:17,948 --> 00:49:18,516
SEQUENCE.

1169
00:49:18,516 --> 00:49:19,850
AND THAT'S QUITE EFFICIENT,

1170
00:49:19,850 --> 00:49:21,519
WHETHER WE CAN TRANSLATE THAT TO

1171
00:49:21,519 --> 00:49:24,722
HUMANS HAS ALL THE ISSUES THAT

1172
00:49:24,722 --> 00:49:27,558
STU TOLD US ABOUT, DELIVERY, WE

1173
00:49:27,558 --> 00:49:29,059
WANT TO EDIT IN VIVO, WE DON'T

1174
00:49:29,059 --> 00:49:31,929
HAVE THE OPPORTUNITY OF GROWING

1175
00:49:31,929 --> 00:49:34,131
CELLS IN CULTURE THE WAY ONE CAN

1176
00:49:34,131 --> 00:49:35,766
DO IN THE HUMAN HEMATOPOIETIC

1177
00:49:35,766 --> 00:49:37,401
SYSTEM, SO MANY ISSUES TO GO,

1178
00:49:37,401 --> 00:49:41,105
THAT'S WHERE WE'RE GOING FOR THE

1179
00:49:41,105 --> 00:49:41,472
FUTURE.

1180
00:49:41,472 --> 00:49:44,341
I JUST WANT TO SAY AS I SAID NOW

1181
00:49:44,341 --> 00:49:47,111
IN ORDER TO AVOID THE PROBLEM OF

1182
00:49:47,111 --> 00:49:47,778
DOING PROBLEMS ASSOCIATED WITH

1183
00:49:47,778 --> 00:49:49,847
SCIENCE BY COMMITTEE WE DO

1184
00:49:49,847 --> 00:49:50,748
SCIENCE BY ZOOM.

1185
00:49:50,748 --> 00:49:52,950
THIS IS THE CURRENT ZOOM PICTURE

1186
00:49:52,950 --> 00:49:54,018
FROM OUR GROUP.

1187
00:49:54,018 --> 00:49:55,719
EVERY NOW AND THEN I LOOK AT

1188
00:49:55,719 --> 00:49:57,321
THIS PICTURE AND I SAY, YOU

1189
00:49:57,321 --> 00:49:59,290
KNOW, IT'S HARD DOING SCIENCE BY

1190
00:49:59,290 --> 00:50:00,791
COMMITTEE BUT SCIENCE BY ZOOM IS

1191
00:50:00,791 --> 00:50:02,026
A LITTLE BETTER.

1192
00:50:02,026 --> 00:50:03,227
THEN I WANTED TO TAKE THIS

1193
00:50:03,227 --> 00:50:04,328
OPPORTUNITY TO THANK THE

1194
00:50:04,328 --> 00:50:06,697
PATIENTS AND THE DONORS AND

1195
00:50:06,697 --> 00:50:14,205
FAMILIES WHO CONTRIBUTED, ALSO 

1196
00:50:14,205 --> 00:50:15,172
THANK THE LEDER LAB AND

1197
00:50:15,172 --> 00:50:17,241
COMMUNITY, THANK YOU FOR THE

1198
00:50:17,241 --> 00:50:18,409
MANY YEARS WE ENJOYED BEING WITH

1199
00:50:18,409 --> 00:50:22,513
YOU AND THANK FAES FOR MAKING 

1200
00:50:22,513 --> 00:50:23,781
THE PHIL LEDER HOUSE, A LOT OF

1201
00:50:23,781 --> 00:50:26,183
EDUCATION WILL COME FROM THAT

1202
00:50:26,183 --> 00:50:27,618
BEYOND THE 150,000 PEOPLE YOU

1203
00:50:27,618 --> 00:50:29,520
ALREADY EDUCATED SO THANK YOU.

1204
00:50:29,520 --> 00:50:32,122
[APPLAUSE]

1205
00:50:32,122 --> 00:50:39,230
 

1206
00:50:39,230 --> 00:50:48,873
 

1207
00:50:48,873 --> 00:50:51,709
>> NEXT SPEAKER IS PHIL
HIETER,

1208
00:50:51,709 --> 00:50:54,345
PROFESSOR IN THE SMITH

1209
00:50:54,345 --> 00:50:54,912
LABORATORIES, DEPARTMENT OF

1210
00:50:54,912 --> 00:50:58,449
MEDICAL GENETICS, UNIVERSITY OF

1211
00:50:58,449 --> 00:51:01,051
BRITISH COLUMBIA, ENTERED THE

1212
00:51:01,051 --> 00:51:02,453
FAES JOHNS HOPKINS GRADUATE

1213
00:51:02,453 --> 00:51:04,655
PROGRAM, YOU MAY BE MEMBERS OF

1214
00:51:04,655 --> 00:51:07,091
THAT PROGRAM, AS A Ph.D.

1215
00:51:07,091 --> 00:51:09,927
STUDENT IN 1976, CONDUCTED

1216
00:51:09,927 --> 00:51:13,364
DOCTORAL RESEARCH WITH PHIL 

1217
00:51:13,364 --> 00:51:15,032
LEDER FROM 1978 TO 1981.

1218
00:51:15,032 --> 00:51:18,369
HE WAS A POSTDOCTORAL FELLOW AT

1219
00:51:18,369 --> 00:51:20,170
STANFORD WITH RON DAVIS, JOINED

1220
00:51:20,170 --> 00:51:21,472
FACULTY AT JOHNS HOPKINS SCHOOL

1221
00:51:21,472 --> 00:51:24,942
OF MEDICINE IN LATE '80s AND

1222
00:51:24,942 --> 00:51:25,543
'90s, MOVED TO UNIVERSITY OF

1223
00:51:25,543 --> 00:51:33,617
BRITISH  BRITISH COLUMBIA IN

1224
00:51:33,617 --> 00:51:36,353
1997, PRESIDENT OF THE GENETIC

1225
00:51:36,353 --> 00:51:37,988
SOCIETY OF AMERICA IN 2012 AND

1226
00:51:37,988 --> 00:51:41,792
PRESIDENT OF THE CANADIAN

1227
00:51:41,792 --> 00:51:42,993
SOCIETY FOR MOLECULAR

1228
00:51:42,993 --> 00:51:44,028
BIOSCIENCES IN 2017, CURRENTLY

1229
00:51:44,028 --> 00:51:46,163
CO-DIRECTOR OF THE CANADIAN RARE

1230
00:51:46,163 --> 00:51:48,866
DISEASES MODELS AND MECHANISMS

1231
00:51:48,866 --> 00:51:49,600
NATIONAL NETWORK.

1232
00:51:49,600 --> 00:51:52,870
RECOGNIZED FOR WORK ON

1233
00:51:52,870 --> 00:51:53,737
STRUCTURAL AND REGULATORY

1234
00:51:53,737 --> 00:51:55,973
PROTEINS THAT ENSURE FAITHFUL

1235
00:51:55,973 --> 00:51:56,674
SEGREGATION OF CHROMOSOMES IN

1236
00:51:56,674 --> 00:51:58,342
CELL DIVISION AND FOR RELATING

1237
00:51:58,342 --> 00:52:00,511
FINDINGS IN YEAST TO HUMAN

1238
00:52:00,511 --> 00:52:01,512
CANCER AND THERAPEUTICS.

1239
00:52:01,512 --> 00:52:04,048
HE'S A MEMBER OF THE NATIONAL

1240
00:52:04,048 --> 00:52:09,420
ACADEMY OF SCIENCES, ROYAL 

1241
00:52:09,420 --> 00:52:10,821
SOCIETY OF CANADA.

1242
00:52:10,821 --> 00:52:15,225
PHIL.

1243
00:52:15,225 --> 00:52:19,163
 

1244
00:52:19,163 --> 00:52:29,206
 

1245
00:52:29,607 --> 00:52:30,741
>> IT'S A GREAT HONOR TO
BE

1246
00:52:30,741 --> 00:52:31,075
HERE.

1247
00:52:31,075 --> 00:52:33,577
SO GREAT TO SEE THE FAMILY.

1248
00:52:33,577 --> 00:52:37,548
AND TO SEE MY FORMER COLLEAGUES.

1249
00:52:37,548 --> 00:52:39,717
A LITTLE BIT OF DEJA VU

1250
00:52:39,717 --> 00:52:40,684
EXPERIENCE TODAY WALKING BY

1251
00:52:40,684 --> 00:52:43,654
BUILDING 6 BECAUSE IT WAS IN

1252
00:52:43,654 --> 00:52:47,458
1975 I VISITED BUILDING 6, 

1253
00:52:47,458 --> 00:52:49,093
INTERVIEWING WITH PHIL LEDER,

1254
00:52:49,093 --> 00:52:50,794
AND I WAS TOTALLY BLOWN AWAY,

1255
00:52:50,794 --> 00:52:53,864
MEETING WITH HIM IN HIS OFFICE,

1256
00:52:53,864 --> 00:52:56,834
THE INCREDIBLE ENTHUSIASM AND

1257
00:52:56,834 --> 00:52:59,670
PASSION THAT HE ARTICULATED, AND

1258
00:52:59,670 --> 00:53:03,641
JOHN SEIDMAN CAME IN WITH AN

1259
00:53:03,641 --> 00:53:05,976
ELECTRON MICROGRAPH OF AN

1260
00:53:05,976 --> 00:53:07,311
R-LOOP, DEJA VU AGAIN, IT WAS

1261
00:53:07,311 --> 00:53:07,645
FANTASTIC.

1262
00:53:07,645 --> 00:53:09,713
I WAS FORTUNATE TO BE ACCEPTED

1263
00:53:09,713 --> 00:53:10,514
IN THE LAB.

1264
00:53:10,514 --> 00:53:11,949
IT WAS REALLY SOME OF THE BEST

1265
00:53:11,949 --> 00:53:12,783
YEARS OF MY LIFE.

1266
00:53:12,783 --> 00:53:16,453
HOW DO I CHANGE THE SLIDE?

1267
00:53:16,453 --> 00:53:22,660
 

1268
00:53:22,660 --> 00:53:24,828
WHAT DO I DO?

1269
00:53:24,828 --> 00:53:35,039
WHICH ONE? 

1270
00:53:43,313 --> 00:53:46,750
AM I IN CONTROL OF THIS?

1271
00:53:46,750 --> 00:53:51,455
THIS IS A PICTURE OF THE GROUP

1272
00:53:51,455 --> 00:53:52,589
BACK IN 1979-ISH.

1273
00:53:52,589 --> 00:53:59,763
AND THIS GIVES ME AN OPPORTUNITY

1274
00:53:59,763 --> 00:54:02,299
TO SAY -- EXPRESS GRATITUDE, IT

1275
00:54:02,299 --> 00:54:04,168
WAS AN INCREDIBLE EXPERIENCE.

1276
00:54:04,168 --> 00:54:06,670
NOT IN THE PICTURE BUT THANKS TO

1277
00:54:06,670 --> 00:54:06,937
JON.

1278
00:54:06,937 --> 00:54:08,305
JON BASICALLY WAS THE ONE WHO

1279
00:54:08,305 --> 00:54:10,040
TOOK ME UNDER HIS WINGS AND

1280
00:54:10,040 --> 00:54:13,744
TAUGHT ME CLONING AND HOW TO DO

1281
00:54:13,744 --> 00:54:16,947
EXPERIMENTS FAST.

1282
00:54:16,947 --> 00:54:17,681
AND WELL.

1283
00:54:17,681 --> 00:54:18,348
I REALLY APPRECIATE THAT.

1284
00:54:18,348 --> 00:54:19,883
THANKS TO THE WHOLE GROUP.

1285
00:54:19,883 --> 00:54:21,218
YOU'LL SEE FAMILIAR FACES THAT

1286
00:54:21,218 --> 00:54:26,256
WE'LL HEAR FROM IN A FEW

1287
00:54:26,256 --> 00:54:26,990
MINUTES.

1288
00:54:26,990 --> 00:54:28,759
I THOUGHT I WOULD JUST LIST A

1289
00:54:28,759 --> 00:54:31,962
FEW WHAT I CAME UP WITH, A FEW

1290
00:54:31,962 --> 00:54:33,597
CHARACTERISTICS OF THE AWESOME

1291
00:54:33,597 --> 00:54:34,932
POWER OF PHIL LEDER, FIRST I

1292
00:54:34,932 --> 00:54:36,433
WOULD SAY AS WE'VE HEARD BEFORE

1293
00:54:36,433 --> 00:54:42,973
HE KNEW HOW TO PICK IMPORTANT

1294
00:54:42,973 --> 00:54:43,373
RESEARCH PROBLEMS.

1295
00:54:43,373 --> 00:54:45,242
HE EMPHASIZED TO ME AND I THINK

1296
00:54:45,242 --> 00:54:46,176
EVERYBODY THE IMPORTANCE OF

1297
00:54:46,176 --> 00:54:47,945
TECHNOLOGY, IMPORTANCE OF

1298
00:54:47,945 --> 00:54:49,546
DEVELOPING NEW TECHNOLOGY,

1299
00:54:49,546 --> 00:54:50,647
HAVING TECHNOLOGY REALLY WORKING

1300
00:54:50,647 --> 00:54:54,251
IN THE LAB, SO YOU COULD

1301
00:54:54,251 --> 00:54:56,019
RELIABLY GET DATA AND REALLY

1302
00:54:56,019 --> 00:54:59,089
MAKE PROGRESS. 

1303
00:54:59,089 --> 00:55:01,925
OF COURSE HE WAS CREATIVE AND

1304
00:55:01,925 --> 00:55:02,659
RIGOROUS SCIENTIST, EXUDED

1305
00:55:02,659 --> 00:55:06,196
PASSION AND JOY IN THE LAB, THAT

1306
00:55:06,196 --> 00:55:07,264
WAS JUST INFECTIOUS.

1307
00:55:07,264 --> 00:55:09,233
THE OTHER THING THAT FOR ME

1308
00:55:09,233 --> 00:55:10,567
PERSONALLY HE REALLY MADE ME

1309
00:55:10,567 --> 00:55:12,536
APPRECIATE THE VALUE OF

1310
00:55:12,536 --> 00:55:13,070
EVOLUTIONARY CONSERVATION

1311
00:55:13,070 --> 00:55:14,071
BECAUSE OF THE PROJECT THAT HE

1312
00:55:14,071 --> 00:55:17,674
GAVE ME WHEN I WAS A GRADUATE

1313
00:55:17,674 --> 00:55:19,209
STUDENT.

1314
00:55:19,209 --> 00:55:21,111
MOVING FROM HOUSE TO HUMAN

1315
00:55:21,111 --> 00:55:21,845
IMMUNOGLOBULIN GENES, USING

1316
00:55:21,845 --> 00:55:24,348
THOSE BASICALLY TO USE HUMAN

1317
00:55:24,348 --> 00:55:25,249
CELL LINES AND HUMAN PATIENTS

1318
00:55:25,249 --> 00:55:29,186
CELLS AS A MODEL FOR

1319
00:55:29,186 --> 00:55:29,853
UNDERSTANDING GENE

1320
00:55:29,853 --> 00:55:31,188
REARRANGEMENTS AND DEVELOPMENT.

1321
00:55:31,188 --> 00:55:33,690
AND THIS MAYBE GAVE ME THE

1322
00:55:33,690 --> 00:55:35,092
COURAGE TO JUMP TO YEAST AFTER

1323
00:55:35,092 --> 00:55:36,760
LEAVING THE LAB AND USING THAT

1324
00:55:36,760 --> 00:55:39,396
AS A MODEL SYSTEM FOR STUDYING

1325
00:55:39,396 --> 00:55:43,433
BIOLOGY RELEVANT TO HUMANS AND 

1326
00:55:43,433 --> 00:55:44,668
HUMAN DISEASE, HUMAN BIOLOGY.

1327
00:55:44,668 --> 00:55:46,937
THE OTHER THING I LEARNED IS THE

1328
00:55:46,937 --> 00:55:51,642
POWER OF COLLABORATION AND

1329
00:55:51,642 --> 00:55:53,177
COLLEGIALITY, AND COMPETITION,

1330
00:55:53,177 --> 00:55:55,045
JOYFUL COMPETITION TO GET THINGS

1331
00:55:55,045 --> 00:56:00,384
DONE AND BE THE FIRST TO GET

1332
00:56:00,384 --> 00:56:03,453
THERE, AND HE REALLY SHOWED US

1333
00:56:03,453 --> 00:56:06,089
HOW COLLABORATING WITH OTHER

1334
00:56:06,089 --> 00:56:07,491
LABORATORIES, RESEARCH EXPERTISE

1335
00:56:07,491 --> 00:56:08,759
AND RESOURCES, COULD SYNERGIZE

1336
00:56:08,759 --> 00:56:10,027
AND DRIVE THINGS FORWARD.

1337
00:56:10,027 --> 00:56:11,428
AND THAT'S SOMETHING I'VE TAKEN

1338
00:56:11,428 --> 00:56:13,630
WITH ME THROUGH MY WHOLE CAREER.

1339
00:56:13,630 --> 00:56:16,366
HE ALSO INTRODUCED TO THE

1340
00:56:16,366 --> 00:56:17,234
CLINICIAN SCIENTIST, BASIC

1341
00:56:17,234 --> 00:56:18,035
SCIENTIST INTERACTION, AT LEAST

1342
00:56:18,035 --> 00:56:20,938
HALF THE PEOPLE IN THE LAB WERE

1343
00:56:20,938 --> 00:56:22,906
M.D.s, I WAS THE SOLE GRADUATE

1344
00:56:22,906 --> 00:56:32,349
STUDENT  WITH EIGHT POSTDOCS AND

1345
00:56:32,349 --> 00:56:33,183
FANTASTIC CLINICIANS.

1346
00:56:33,183 --> 00:56:34,818
THERE WAS A VERY MEANINGFUL

1347
00:56:34,818 --> 00:56:38,255
CONNECTION THAT WAS MADE DURING

1348
00:56:38,255 --> 00:56:41,358
MY THESIS WORK.

1349
00:56:41,358 --> 00:56:45,495
HIS MENTORSHIP, HE WAS TRULY

1350
00:56:45,495 --> 00:56:46,697
ENGAGED, REALLY CARED ABOUT

1351
00:56:46,697 --> 00:56:48,232
PEOPLE IN THE LAB.

1352
00:56:48,232 --> 00:56:49,533
HE EMPOWERED US, GAVE US

1353
00:56:49,533 --> 00:56:51,068
OWNERSHIP OF THE WORK WE WERE

1354
00:56:51,068 --> 00:56:52,936
DOING TO GIVE US CONFIDENCE.

1355
00:56:52,936 --> 00:56:54,238
HE TAUGHT US LOTS OF THINGS, HOW

1356
00:56:54,238 --> 00:56:55,873
TO GIVE A GOOD TALK.

1357
00:56:55,873 --> 00:56:57,241
EVERYONE HAS A STORY ABOUT

1358
00:56:57,241 --> 00:57:04,882
LEARNING HOW TO GIVE A GOOD 

1359
00:57:04,882 --> 00:57:05,716
TALK.

1360
00:57:05,716 --> 00:57:06,617
TRANSITIONS BETWEEN SLIDES AND

1361
00:57:06,617 --> 00:57:08,051
GROUPS OF SLIDES, FANTASTIC.

1362
00:57:08,051 --> 00:57:11,221
HAD HE A HUGE IMPACT ON MY

1363
00:57:11,221 --> 00:57:12,956
FUTURE CAREER, AND PROVIDES A

1364
00:57:12,956 --> 00:57:15,726
ROLE MODEL FOR ME, AND ACTUALLY

1365
00:57:15,726 --> 00:57:18,328
EVERYBODY SO I THOUGHT I WOULD

1366
00:57:18,328 --> 00:57:21,431
GO THROUGH A COUPLE THINGS,

1367
00:57:21,431 --> 00:57:23,567
LOOKING BACK AT THE THESIS WORK,

1368
00:57:23,567 --> 00:57:24,668
THE VALUE OF EVOLUTIONARY

1369
00:57:24,668 --> 00:57:26,203
CONSERVATION THAT STUCK WITH ME

1370
00:57:26,203 --> 00:57:27,838
I WOULD SAY.

1371
00:57:27,838 --> 00:57:32,776
AND SO PHIL'S AND JON SEIDMAN'S

1372
00:57:32,776 --> 00:57:35,646
GIFT TO ME IN 1978 AFTER TWO

1373
00:57:35,646 --> 00:57:39,349
YEARS IN BALTIMORE WAS TO

1374
00:57:39,349 --> 00:57:50,027
SUGGEST THE AUDACIOUS -- I DON'T

1375
00:57:50,027 --> 00:57:50,594
KNOW, AUDACIOUS -- THEY HAVE

1376
00:57:50,594 --> 00:57:52,129
ALREADY CLONE THE MOUSE GENES,

1377
00:57:52,129 --> 00:57:57,267
WOULD KEY CLONE THE HUMAN GENES

1378
00:57:57,267 --> 00:57:59,369
BY CROSS-SPECIES HYBRIDIZATION,

1379
00:57:59,369 --> 00:58:00,671
PROBE HEME PRE-B AND B CELL

1380
00:58:00,671 --> 00:58:04,408
LEUKEMIAS TO GET INFORMATION

1381
00:58:04,408 --> 00:58:06,944
ABOUT GENE REARRANGEMENTS AT

1382
00:58:06,944 --> 00:58:13,183
DIFFERENT LEVELS OF DEVELOPMENT.

1383
00:58:13,183 --> 00:58:18,956
IN THOSE DAYS,  SEPARATED IN THE

1384
00:58:18,956 --> 00:58:24,761
LAB BY TWO DIMENSION METHOD,

1385
00:58:24,761 --> 00:58:26,163
CHROMATOGRAPHY AND FRACTIONS RUN

1386
00:58:26,163 --> 00:58:28,365
ON A GEL, PURIFIED BY SIZE ON

1387
00:58:28,365 --> 00:58:30,867
WHAT WAS CALLED THE GENE

1388
00:58:30,867 --> 00:58:31,101
MACHINE.

1389
00:58:31,101 --> 00:58:32,636
THAT ALLOWED YOU TO TAKE A

1390
00:58:32,636 --> 00:58:34,237
MILLION FRAGMENTS AND GET THEM

1391
00:58:34,237 --> 00:58:36,673
DOWN TO, SAY, THOUSANDS.

1392
00:58:36,673 --> 00:58:39,209
AND MADE IT POSSIBLE,

1393
00:58:39,209 --> 00:58:40,544
TECHNICALLY FEASIBLE, TO CLONE

1394
00:58:40,544 --> 00:58:42,713
GENOMIC FRAGMENTS OF DNA.

1395
00:58:42,713 --> 00:58:50,821
WHAT THEY HAD PREVIOUSLY SHOWN,

1396
00:58:50,821 --> 00:58:51,621
THREE CROSS-HYBRIDIZING

1397
00:58:51,621 --> 00:58:52,556
FRAGMENTS IN THE GENOME, AFTER

1398
00:58:52,556 --> 00:58:57,194
MUCH TIME IN A YEAR OR SO WE 

1399
00:58:57,194 --> 00:59:04,468
FOUND THE SEQUENCE AND IT WAS A

1400
00:59:04,468 --> 00:59:06,336
REPEAT IN THE FRAGMENT OF THE

1401
00:59:06,336 --> 00:59:07,871
MOUSE GENE, VERY DISAPPOINTING

1402
00:59:07,871 --> 00:59:10,841
BUT, AGAIN, I MEAN IN TYPICAL

1403
00:59:10,841 --> 00:59:12,342
PHIL LEDER FASHION HE WAS LET'S

1404
00:59:12,342 --> 00:59:15,212
GET RIGHT BACK TO IT AND FIGURE

1405
00:59:15,212 --> 00:59:16,880
THIS OUT.

1406
00:59:16,880 --> 00:59:18,949
SO, THE SOLUTION WAS TO RESTRICT

1407
00:59:18,949 --> 00:59:20,250
THE PROBE TO THE OPEN READING

1408
00:59:20,250 --> 00:59:23,420
FRAME AND THAT SHOWED THE 2 1/2

1409
00:59:23,420 --> 00:59:25,622
KB FRAGMENT WAS THE KEY.

1410
00:59:25,622 --> 00:59:28,158
SO, THAT LED TO CLONING OF THE

1411
00:59:28,158 --> 00:59:32,329
HUMAN KAPPA GENE.

1412
00:59:32,329 --> 00:59:34,297
THIS PARTICULAR FIGURE STICKS IN

1413
00:59:34,297 --> 00:59:39,669
MY MIND, WHERE IT'S A

1414
00:59:39,669 --> 00:59:41,638
HETERODUPLEX BETWEEN -- I WON'T

1415
00:59:41,638 --> 00:59:46,476
TRY TO POINT ON THIS, BUT 

1416
00:59:46,476 --> 00:59:49,613
BETWEEN THE HUMAN KAPPA GENE

1417
00:59:49,613 --> 00:59:51,114
WITH J REGION GENES IN THE MOUSE

1418
00:59:51,114 --> 00:59:53,050
GENE, YOU CAN SEE HOMOLOGY

1419
00:59:53,050 --> 00:59:55,952
SEGMENTS THAT CORRESPOND TO THE

1420
00:59:55,952 --> 00:59:57,821
C REGION, CONSTANT REGION,

1421
00:59:57,821 --> 00:59:58,688
CONSERVED SEQUENCE IN

1422
00:59:58,688 --> 01:00:01,792
INTERVENING SEQUENCE, EACH OF

1423
01:00:01,792 --> 01:00:03,427
THE J REGIONS FORMING

1424
01:00:03,427 --> 01:00:05,262
HETERODUPLEX, SO YOU CAN MAP

1425
01:00:05,262 --> 01:00:07,898
WHERE ON THESE CLONES THESE

1426
01:00:07,898 --> 01:00:10,634
ELEMENTS ARE, AND THE SEQUENCE

1427
01:00:10,634 --> 01:00:13,236
WAS VERY REVEALING, SHOWED

1428
01:00:13,236 --> 01:00:15,672
EVOLUTIONARY CONSERVED NOT ONLY 

1429
01:00:15,672 --> 01:00:20,377
AT THE AMINO ACID LEVEL BUT

1430
01:00:20,377 --> 01:00:22,312
SEQUENCES IMPORTANT FOR VJ

1431
01:00:22,312 --> 01:00:24,448
RECOMBINATION AND PROBABLY

1432
01:00:24,448 --> 01:00:24,848
SPLICING.

1433
01:00:24,848 --> 01:00:30,554
ONCE WE SUCCESSFULLY CLONED THE

1434
01:00:30,554 --> 01:00:31,755
IMMUNOGLOBULIN KAPPA GENE WERE

1435
01:00:31,755 --> 01:00:35,792
ABLE TO GET HUMAN LAMBDA GENES, 

1436
01:00:35,792 --> 01:00:37,694
ARRANGED IN A TANDEM, EACH WITH

1437
01:00:37,694 --> 01:00:40,163
A SINGLE J REGION.

1438
01:00:40,163 --> 01:00:42,699
AND THEN WITH THOSE CLONES IN

1439
01:00:42,699 --> 01:00:44,801
HAND THIS GETS TO THE POWER OF

1440
01:00:44,801 --> 01:00:46,303
COLLABORATION AND THE LINKAGE

1441
01:00:46,303 --> 01:00:49,706
BETWEEN CLINICIAN AND BASIC

1442
01:00:49,706 --> 01:00:50,907
SCIENTIST.

1443
01:00:50,907 --> 01:00:52,109
PHIL AFTER CLONING THE KAPPA

1444
01:00:52,109 --> 01:00:54,644
GENE BASICALLY SET UP AN

1445
01:00:54,644 --> 01:00:57,047
APPOINTMENT WITH TOM WALDMAN, AN

1446
01:00:57,047 --> 01:00:59,049
IMMUNOLOGIST AT -- WAS AT NIH,

1447
01:00:59,049 --> 01:01:01,651
AND I REMEMBER HIM TAKING ME

1448
01:01:01,651 --> 01:01:03,086
ACROSS CAMPUS AND SITTING IN THE

1449
01:01:03,086 --> 01:01:04,821
OFFICE AS A GRADUATE STUDENT

1450
01:01:04,821 --> 01:01:07,224
WITH PHIL AND TOM WALDMAN, AND

1451
01:01:07,224 --> 01:01:09,292
HE EXPLAINED WE WERE CLONING

1452
01:01:09,292 --> 01:01:11,628
THESE GENES, WANTED TO USE THEM

1453
01:01:11,628 --> 01:01:13,730
AT PROBES TO LOOK AT B CELL

1454
01:01:13,730 --> 01:01:17,834
DEVELOPMENT STAGES.

1455
01:01:17,834 --> 01:01:21,271
HE WANTED ME TO HOOK UP WITH A

1456
01:01:21,271 --> 01:01:22,439
RESEARCH FELLOW THAT'S IN HIS

1457
01:01:22,439 --> 01:01:23,874
GROUP AND WANTED TO BE THE BEST

1458
01:01:23,874 --> 01:01:26,443
ONE, THAT'S WHAT HE TOLD ME.

1459
01:01:26,443 --> 01:01:30,981
OKAY, WHO WAS IT?

1460
01:01:30,981 --> 01:01:33,183
STAN KORSMEYER, QUITE AN AMAZING

1461
01:01:33,183 --> 01:01:33,717
GUY.

1462
01:01:33,717 --> 01:01:36,019
HE WAS A FELLOW IN WALDMAN'S

1463
01:01:36,019 --> 01:01:38,655
GROUP, AND WE ESTABLISHED A

1464
01:01:38,655 --> 01:01:39,723
COLLABORATION WHERE HE HAD THE

1465
01:01:39,723 --> 01:01:43,126
SORT OF CELL LINES AND HAD

1466
01:01:43,126 --> 01:01:44,661
PATIENTS WITH DIFFERENT TYPES OF

1467
01:01:44,661 --> 01:01:47,063
KINDS OF LEUKEMIA, AND THOSE

1468
01:01:47,063 --> 01:01:49,900
WERE THE CELLS WE USED TO LOOK

1469
01:01:49,900 --> 01:01:59,109
AT GENE REARRANGEMENTS AT 

1470
01:01:59,109 --> 01:02:00,644
DIFFERENT STAGES OF DEVELOPMENT.

1471
01:02:00,644 --> 01:02:02,479
BASICALLY WE SHOWED A HIERARCHY

1472
01:02:02,479 --> 01:02:06,316
IN THE GENE REARRANGEMENT

1473
01:02:06,316 --> 01:02:08,518
PROGRAM, SO THE MU HEAVY CHAIN

1474
01:02:08,518 --> 01:02:10,287
WOULD REARRANGE FIRST FOLLOWED

1475
01:02:10,287 --> 01:02:12,255
BY KAPPA REGION, LAMBDA GENE,

1476
01:02:12,255 --> 01:02:14,191
SOME KIND OF FEEDBACK WHEN THERE

1477
01:02:14,191 --> 01:02:15,725
WAS A FUNCTIONAL REARRANGEMENT,

1478
01:02:15,725 --> 01:02:19,996
THE PROCESS STOPPED.

1479
01:02:19,996 --> 01:02:26,570
SO, THIS WAS KIND OF EXPLAINED,

1480
01:02:26,570 --> 01:02:30,407
EXCLUSION WERE BIG ISSUES, VERY

1481
01:02:30,407 --> 01:02:30,707
SATISFYING.

1482
01:02:30,707 --> 01:02:32,108
STAND WENT ON TO DO TERRIFIC

1483
01:02:32,108 --> 01:02:33,977
WORK IN HIS OWN RIGHT AND

1484
01:02:33,977 --> 01:02:34,878
UNFORTUNATELY PASSED AWAY AT A

1485
01:02:34,878 --> 01:02:35,645
YOUNG AGE.

1486
01:02:35,645 --> 01:02:38,415
AND THEN THE LAST PIECE IS THE

1487
01:02:38,415 --> 01:02:39,015
MENTORSHIP PIECE.

1488
01:02:39,015 --> 01:02:42,352
AS I SAID, HE WAS JUST AN

1489
01:02:42,352 --> 01:02:43,520
INCREDIBLE MENTOR, AND ONE OF

1490
01:02:43,520 --> 01:02:45,222
THE THINGS I REMEMBER HIM DOING

1491
01:02:45,222 --> 01:02:46,690
ABOUT A YEAR BEFORE I WAS

1492
01:02:46,690 --> 01:02:48,225
FINISHED IN THE LAB WAS TO COME

1493
01:02:48,225 --> 01:02:50,627
TO ME IN THE HALLWAY AND SAY YOU

1494
01:02:50,627 --> 01:02:52,162
NEED TO THINK ABOUT WHAT YOU

1495
01:02:52,162 --> 01:02:53,263
WANT TO DO, WHAT'S YOUR NEXT

1496
01:02:53,263 --> 01:02:55,799
PHASE, WHERE DO YOU WANT TO DO A

1497
01:02:55,799 --> 01:02:56,399
POSTDOC?

1498
01:02:56,399 --> 01:02:58,969
AND HE SAID, GO AWAY FOR A

1499
01:02:58,969 --> 01:03:00,070
MONTH, AND TALK TO AS MANY

1500
01:03:00,070 --> 01:03:03,039
PEOPLE AS YOU CAN.

1501
01:03:03,039 --> 01:03:03,907
COME BACK AND LET'S, YOU KNOW,

1502
01:03:03,907 --> 01:03:05,475
DECIDE WHERE YOU WANT TO GO AND

1503
01:03:05,475 --> 01:03:06,343
LET'S GO FOR IT.

1504
01:03:06,343 --> 01:03:07,644
I DID THAT.

1505
01:03:07,644 --> 01:03:11,715
I TALKED TO ALL THESE PEOPLE IN

1506
01:03:11,715 --> 01:03:12,349
THE LMG.

1507
01:03:12,349 --> 01:03:14,751
I REMEMBER REALLY GREAT

1508
01:03:14,751 --> 01:03:16,519
DISCUSSIONS WITH BOB CROUCH,

1509
01:03:16,519 --> 01:03:18,154
MIKE CASHELL AND OTHERS ON THE

1510
01:03:18,154 --> 01:03:19,623
FLOOR, THEY INTRODUCED ME TO THE

1511
01:03:19,623 --> 01:03:24,661
WORK OF RON DAVIS WHICH I DID 

1512
01:03:24,661 --> 01:03:28,898
NOT KNOW ABOUT.

1513
01:03:28,898 --> 01:03:32,168
HE HAD IDENTIFIED YEAST DATA,

1514
01:03:32,168 --> 01:03:32,669
REPLICATION, INVOLVED IN

1515
01:03:32,669 --> 01:03:33,470
DEVELOPING A LOT OF CLONING

1516
01:03:33,470 --> 01:03:35,105
TECHNIQUES THAT WE WERE USING IN

1517
01:03:35,105 --> 01:03:36,539
THE LAB.

1518
01:03:36,539 --> 01:03:37,674
AND THIS SEEMED LIKE -- AND THEY

1519
01:03:37,674 --> 01:03:39,109
WERE WORKING IN YEAST.

1520
01:03:39,109 --> 01:03:41,077
I THOUGHT, PHIL SAID LET'S DO

1521
01:03:41,077 --> 01:03:42,779
SOMETHING TOTALLY DIFFERENT AND

1522
01:03:42,779 --> 01:03:44,781
TRY TO COMBINE THEM INTO YOUR

1523
01:03:44,781 --> 01:03:46,650
FUTURE LAB.

1524
01:03:46,650 --> 01:03:48,918
SO I WAS -- THIS WAS TAKING AN

1525
01:03:48,918 --> 01:03:50,387
EVOLUTIONARY JUMP FROM THE

1526
01:03:50,387 --> 01:03:52,122
MAMMALIAN MODELS TO YEAST AS A

1527
01:03:52,122 --> 01:03:55,859
MODEL, OVER A BILLION YEARS OF

1528
01:03:55,859 --> 01:03:58,561
EVOLUTION AS A MODEL SYSTEM FOR

1529
01:03:58,561 --> 01:04:00,530
STUDYING BASIC EUKARYOTIC

1530
01:04:00,530 --> 01:04:00,864
BIOLOGY.

1531
01:04:00,864 --> 01:04:03,400
AND THAT WAS AROUND THE EARLY

1532
01:04:03,400 --> 01:04:06,169
'80s, THAT WAS TIME WHEN DNA

1533
01:04:06,169 --> 01:04:07,904
MEDIATED TRANSFORMATION HAD JUST

1534
01:04:07,904 --> 01:04:10,940
BEEN WORKED OUT AND WAS SEEN

1535
01:04:10,940 --> 01:04:13,076
THAT DNA ACTUALLY BEHAVED IN

1536
01:04:13,076 --> 01:04:14,244
HOMOLOGOUS REGIONS IN THE

1537
01:04:14,244 --> 01:04:16,212
CHROMOSOME AND WE CAN DO GENE

1538
01:04:16,212 --> 01:04:17,247
REPLACEMENTS IN THE GENOME IN

1539
01:04:17,247 --> 01:04:20,684
THE EARLY '80s, AT THE SAME

1540
01:04:20,684 --> 01:04:22,552
TIME CENTROMERES AND ORIGINS

1541
01:04:22,552 --> 01:04:24,220
REPLICATION WERE BEING DEFINED

1542
01:04:24,220 --> 01:04:26,656
THAT ALLOWED DEVELOPMENT AT THE

1543
01:04:26,656 --> 01:04:27,624
SOMAL VECTORS FOR INTRODUCING

1544
01:04:27,624 --> 01:04:28,491
GENES IN THE YEAST.

1545
01:04:28,491 --> 01:04:31,027
THIS WAS A VERY POWERFUL SYSTEM,

1546
01:04:31,027 --> 01:04:36,032
AWESOME POWER OF YEAST GENETICS,

1547
01:04:36,032 --> 01:04:37,100
AND THE OTHER THING I'LL MENTION

1548
01:04:37,100 --> 01:04:40,503
IS REALLY BY THE END OF THE

1549
01:04:40,503 --> 01:04:42,939
'80s THERE WAS THIS PUSH TO

1550
01:04:42,939 --> 01:04:46,242
SEQUENCE THE HUMAN GENOME,

1551
01:04:46,242 --> 01:04:50,413
RECOGNIZED BY A PANEL RUN BY THE

1552
01:04:50,413 --> 01:04:51,915
NRC, THE COMMITTEE ON HUMAN

1553
01:04:51,915 --> 01:04:54,117
GENOME PROJECT WHICH RELEASED

1554
01:04:54,117 --> 01:04:57,287
REPORT IN 1988 THAT REALLY THE

1555
01:04:57,287 --> 01:04:58,922
GENOME PROJECT NEEDED TO INCLUDE

1556
01:04:58,922 --> 01:05:02,759
THE HUMAN GENOME AND MODELS

1557
01:05:02,759 --> 01:05:08,198
SYSTEMS, YEAST, FLIES, MICE.

1558
01:05:08,198 --> 01:05:15,205
ON THAT COMMITTEE, STU ORKIN AND

1559
01:05:15,205 --> 01:05:18,274
SHIRLEY TILGHMAN, I WAS GOING TO

1560
01:05:18,274 --> 01:05:24,614
THANK THEM FOR THAT BRILLIANT 

1561
01:05:24,614 --> 01:05:26,750
ARCHITECTS REALIZED WE NEEDED

1562
01:05:26,750 --> 01:05:30,253
MODEL SYSTEMS TO FUNCTIONALIZE

1563
01:05:30,253 --> 01:05:31,421
THE GENES.

1564
01:05:31,421 --> 01:05:32,856
AND SO VERY QUICKLY, I'M NOT

1565
01:05:32,856 --> 01:05:35,024
GOING TO DESCRIBE ALL THE WORK

1566
01:05:35,024 --> 01:05:36,893
WE'VE DONE BUT WE DECIDED THE

1567
01:05:36,893 --> 01:05:39,429
PROBLEM WAS TO USE YEAST AS A

1568
01:05:39,429 --> 01:05:46,436
MODEL FOR STUDYING MECHANISMS OF

1569
01:05:46,436 --> 01:05:47,070
CHROMOSOME SEGREGATION,

1570
01:05:47,070 --> 01:05:47,670
STABILITY, THEREFORE CANCER

1571
01:05:47,670 --> 01:05:50,573
BIOLOGY BECAUSE IT WAS

1572
01:05:50,573 --> 01:05:52,675
RECOGNIZED THAT TUMORS HAVE

1573
01:05:52,675 --> 01:05:54,744
PROPERTY OF GENOME INSTABILITY,

1574
01:05:54,744 --> 01:05:55,879
THIS DRIVES THE EVOLUTION OF

1575
01:05:55,879 --> 01:05:57,080
PROGENITOR CELLS SO THEY CAN

1576
01:05:57,080 --> 01:05:58,915
ACCUMULATE ALL OF THE GENES

1577
01:05:58,915 --> 01:06:02,752
REQUIRED FOR THE CANCER CELL

1578
01:06:02,752 --> 01:06:03,153
PHENOTYPE.

1579
01:06:03,153 --> 01:06:06,990
BUT WE COULD USE THE YEAST

1580
01:06:06,990 --> 01:06:09,492
SYSTEM TO DEFINE THE GENES,

1581
01:06:09,492 --> 01:06:11,928
STUDY BIOLOGY AND BY DEFINITION

1582
01:06:11,928 --> 01:06:12,896
THESE REPRESENTED CROSS-SPECIES

1583
01:06:12,896 --> 01:06:14,764
CANDIDATE GENES THAT COULD BE

1584
01:06:14,764 --> 01:06:16,533
MUTATED IN TUMORS AND THEN GO ON

1585
01:06:16,533 --> 01:06:20,670
TO USE YEAST AS A GENETIC SYSTEM

1586
01:06:20,670 --> 01:06:23,873
TO CONSIDER THESE GENES, THESE

1587
01:06:23,873 --> 01:06:24,841
MUTATIONS AS GENETIC

1588
01:06:24,841 --> 01:06:27,577
VULNERABILITIES THROUGH THE

1589
01:06:27,577 --> 01:06:28,244
CONCEPT OF SYNTHETICICALLY

1590
01:06:28,244 --> 01:06:29,546
VALIDATED FINDING GENES THAT

1591
01:06:29,546 --> 01:06:32,215
WOULD SELECTIVELY KILL A CANCER

1592
01:06:32,215 --> 01:06:38,221
MUTANT, DEFECT  DEFECTIVE IN

1593
01:06:38,221 --> 01:06:48,631
CHROMOSOME  SEGREGATION.

1594
01:06:48,998 --> 01:06:50,600
IN 1985 ONE THING PHIL DID WAS

1595
01:06:50,600 --> 01:06:57,040
GIVE THEM COURAGE TO TACKLE BIG

1596
01:06:57,040 --> 01:06:58,441
PROBLEMS, REQUIRING NEW

1597
01:06:58,441 --> 01:06:59,008
TECHNOLOGIES.

1598
01:06:59,008 --> 01:07:00,743
THIS COMES FROM TRAINING FROM

1599
01:07:00,743 --> 01:07:02,645
JON SEIDMAN AND OTHERS IN THE

1600
01:07:02,645 --> 01:07:05,782
LAB WAS TO DEVELOP A SYSTEM

1601
01:07:05,782 --> 01:07:08,318
WHERE WE COULD GENERATE

1602
01:07:08,318 --> 01:07:10,520
ARTIFICIAL CHROMOSOMES, EXTRA

1603
01:07:10,520 --> 01:07:14,424
CHROMOSOMES, AS MARKERS TO

1604
01:07:14,424 --> 01:07:16,192
MONITOR THE STABILITY OF

1605
01:07:16,192 --> 01:07:19,596
CHROMOSOME SEGREGATION, IN A

1606
01:07:19,596 --> 01:07:21,464
SECTOR ASSAY, CARRYING A COLONY

1607
01:07:21,464 --> 01:07:23,633
COLORED MARKER WHICH GAVE RISE

1608
01:07:23,633 --> 01:07:25,735
TO RED SECTORS ON CHROMOSOME

1609
01:07:25,735 --> 01:07:28,805
LOSS AT RARE FREQUENCY, IDENTIFY

1610
01:07:28,805 --> 01:07:31,207
MUTANTS THAT INCREASE FREQUENCY

1611
01:07:31,207 --> 01:07:33,176
OF SEGREGATION AND USE AS POINT

1612
01:07:33,176 --> 01:07:34,410
FOR CLONING BY COMPLEMENTATION,

1613
01:07:34,410 --> 01:07:37,213
YOU SEE AN EXPERIMENT WHERE

1614
01:07:37,213 --> 01:07:40,884
GENOMIC LIBRARY WAS PLACED IN A

1615
01:07:40,884 --> 01:07:42,285
MUTANT, THERE'S A COMPLEMENTED

1616
01:07:42,285 --> 01:07:43,853
CLONE, WE CAN RESCUE THE PLASMID

1617
01:07:43,853 --> 01:07:48,758
AND FIND THE GENE.

1618
01:07:48,758 --> 01:07:50,793
THERE WAS A LOT OF -- ONE AREA

1619
01:07:50,793 --> 01:07:56,666
WAS THE YEAST GENETIC CORE, MANY

1620
01:07:56,666 --> 01:07:59,302
CTF MUTANTS WERE INVOLVED IN

1621
01:07:59,302 --> 01:08:04,774
FUNCTION, ANOTHER CLASS INVOLVED

1622
01:08:04,774 --> 01:08:06,242
SISTER CHROMATID COHESION,

1623
01:08:06,242 --> 01:08:08,978
CENTROMERE FUNCTION AND COHESION

1624
01:08:08,978 --> 01:08:10,079
ARE INTIMATELY INTERTWINED IN

1625
01:08:10,079 --> 01:08:12,916
TERMS OF FUNCTION BECAUSE THAT

1626
01:08:12,916 --> 01:08:15,351
ALLOWS THE CELL TO ACHIEVE

1627
01:08:15,351 --> 01:08:17,420
BIPOLAR ATTACHMENT OF

1628
01:08:17,420 --> 01:08:21,024
CHROMOSOMES TO ACHIEVE META

1629
01:08:21,024 --> 01:08:21,691
PHASE, THERE'S A SIGNAL

1630
01:08:21,691 --> 01:08:23,326
TRANSDUCTION MECHANISM THROUGH

1631
01:08:23,326 --> 01:08:30,099
THE SPINDLE CHECKPOINT THAT 

1632
01:08:30,099 --> 01:08:34,170
REGULATES THE META

1633
01:08:34,170 --> 01:08:35,705
PHASE/ANAPHASE TRANSMISSION,

1634
01:08:35,705 --> 01:08:37,106
INVOLVING DEGRADATION OF KEY

1635
01:08:37,106 --> 01:08:37,774
CYCLE REGULATORS.

1636
01:08:37,774 --> 01:08:41,511
SO THE STORY THAT GETS US BACK

1637
01:08:41,511 --> 01:08:47,050
TO PHIL WAS IN 1992, I WAS THE

1638
01:08:47,050 --> 01:08:50,219
FIRST -- BEGINNING TO CLONE

1639
01:08:50,219 --> 01:08:52,021
HUMAN ORTHOLOGS OF YEAST GENES,

1640
01:08:52,021 --> 01:08:54,057
STUDYING YEAST, OF COURSE THERE

1641
01:08:54,057 --> 01:09:04,567
WAS NO  HUMAN GENE, NO

1642
01:09:04,567 --> 01:09:04,767
ORTHOLOGS.

1643
01:09:04,767 --> 01:09:10,573
A STUDENT STARTED TO DO THE 

1644
01:09:10,573 --> 01:09:12,942
ORTHOLOGS, IN A RESTED META

1645
01:09:12,942 --> 01:09:16,112
PHASE, A CHECKPOINT THAT

1646
01:09:16,112 --> 01:09:17,880
MONITORINGS DNA DAMAGE, WE

1647
01:09:17,880 --> 01:09:19,415
THOUGHT THESE WERE COMPONENTS OF

1648
01:09:19,415 --> 01:09:20,950
THE SPINDLE.

1649
01:09:20,950 --> 01:09:24,220
AND HE TRIED ALL WAYS TO CLONE

1650
01:09:24,220 --> 01:09:27,757
THESE THINGS BY FUNCTIONAL

1651
01:09:27,757 --> 01:09:29,959
COMPLEMENTATION, AND OTHER

1652
01:09:29,959 --> 01:09:32,996
METHODS TO GENERATE PCR, IT WAS

1653
01:09:32,996 --> 01:09:33,863
UNSUCCESSFUL.

1654
01:09:33,863 --> 01:09:35,898
BUT WHAT THE BREAKTHROUGH CAME

1655
01:09:35,898 --> 01:09:39,235
WHEN THE FIRST ROUND OF

1656
01:09:39,235 --> 01:09:41,204
EXPRESSED SEQUENCE TAGS WERE

1657
01:09:41,204 --> 01:09:44,707
RELEASED PUBLICLY, 8,000,

1658
01:09:44,707 --> 01:09:48,544
ORIGINALLY FOUND AT NIH BY CRAIG

1659
01:09:48,544 --> 01:09:50,213
BENTNER, ACATCHED TO A CLONE IN

1660
01:09:50,213 --> 01:09:55,618
THE FREEZER, A WEAK HOMOLOGY

1661
01:09:55,618 --> 01:09:58,554
BETWEEN CDC27 AND OPEN READING

1662
01:09:58,554 --> 01:10:00,390
FRAME ON THE EST.

1663
01:10:00,390 --> 01:10:06,863
WE BEING AT HOPKINS IN THE

1664
01:10:06,863 --> 01:10:11,701
MEDICAL GENETICS COMMUNITY, WE 

1665
01:10:11,701 --> 01:10:14,404
MAPPED THIS CLONE, FULL LENGTH

1666
01:10:14,404 --> 01:10:16,205
COPY WITH 20% IDENTITY OF THE

1667
01:10:16,205 --> 01:10:22,145
AMINO ACID LEVEL, AN ORTHOLOGUE,

1668
01:10:22,145 --> 01:10:30,353
IT MAPPED AND WAS IN THE BRCA1

1669
01:10:30,353 --> 01:10:31,487
800 KB SEGMENT, BECAME A

1670
01:10:31,487 --> 01:10:35,591
CANDIDATE GENE FOR A MONTH, WE

1671
01:10:35,591 --> 01:10:36,926
SENT PROBES.

1672
01:10:36,926 --> 01:10:39,462
THIS HAD A HUGE IMPRESSION ON

1673
01:10:39,462 --> 01:10:39,729
ME.

1674
01:10:39,729 --> 01:10:43,132
WHAT IF WE DID THIS

1675
01:10:43,132 --> 01:10:47,303
SYSTEMATICALLY AND IDENTIFIED 

1676
01:10:47,303 --> 01:10:51,107
ESTs RELATED TO PROTEINS BEING

1677
01:10:51,107 --> 01:10:54,210
ACTIVELY STUDIED IN YEAST WITH

1678
01:10:54,210 --> 01:10:56,512
ANNOTATE MAPS WITH BIOLOGY OF

1679
01:10:56,512 --> 01:11:03,586
YEAST AS CANDIDATE GENES, AND 

1680
01:11:03,586 --> 01:11:06,322
THE STORY I'LL TELL, IT'S A

1681
01:11:06,322 --> 01:11:08,524
LITTLE OVERKILL HERE, BUT IN

1682
01:11:08,524 --> 01:11:11,794
1992 I WAS RECRUITED TO BE ON

1683
01:11:11,794 --> 01:11:12,795
THE GENOME COMMITTEE, SO I HAD

1684
01:11:12,795 --> 01:11:18,334
TO GO TO THE MEETINGS.

1685
01:11:18,334 --> 01:11:23,406
I SUBMITTED AN ABSTRACT, AND IT

1686
01:11:23,406 --> 01:11:25,508
WAS REJECTED.

1687
01:11:25,508 --> 01:11:26,375
THE ABSTRACT WAS REJECTED.

1688
01:11:26,375 --> 01:11:27,343
I WENT TO THE MEETING.

1689
01:11:27,343 --> 01:11:29,912
I DON'T THINK IT WAS A

1690
01:11:29,912 --> 01:11:31,748
REFLECTION OF THE HUMAN

1691
01:11:31,748 --> 01:11:33,416
GENETICIST VIEW AS A MODEL

1692
01:11:33,416 --> 01:11:34,584
SYSTEM BUT THERE WAS SKEPTICISM

1693
01:11:34,584 --> 01:11:38,654
ABOUT THE VALUE OF YEAST AT THE 

1694
01:11:38,654 --> 01:11:40,289
TIME, I WOULD SAY.

1695
01:11:40,289 --> 01:11:44,227
WE GOT A GRANT TO DO THIS

1696
01:11:44,227 --> 01:11:49,065
SYSTEMATICALLY AND WE MAPPED 300

1697
01:11:49,065 --> 01:11:53,469
YEAST GENE EST-RELATED CLONES TO

1698
01:11:53,469 --> 01:11:55,238
THE HUMAN MAP AND WHICH BRINGS

1699
01:11:55,238 --> 01:11:58,307
US BACK TO PHIL THAT THIS WAS

1700
01:11:58,307 --> 01:12:00,676
ONE OF THE MOST GRATIFYING TALKS

1701
01:12:00,676 --> 01:12:04,347
I'VE GIVEN IN MY CAREER,

1702
01:12:04,347 --> 01:12:05,815
AMERICAN SOCIETY OF HUMAN

1703
01:12:05,815 --> 01:12:07,683
GENETICS HAD A SESSION ON

1704
01:12:07,683 --> 01:12:12,622
LESSONS OF MODEL ORGANISM TO

1705
01:12:12,622 --> 01:12:17,193
HUMAN DISEASE.

1706
01:12:17,193 --> 01:12:20,830
PHIL LEDER WAS AWARDED THE

1707
01:12:20,830 --> 01:12:23,432
ALLLAN AWARD AND GAVE A TALK TO

1708
01:12:23,432 --> 01:12:25,201
THE GENETIC APPROACH TO CANCER

1709
01:12:25,201 --> 01:12:26,702
PROBLEM, MY TALK WAS IMMEDIATELY

1710
01:12:26,702 --> 01:12:28,104
AFTER HIS, I WAS ABLE TO

1711
01:12:28,104 --> 01:12:30,573
PUBLICLY THANK HIM WITH HIM IN

1712
01:12:30,573 --> 01:12:33,643
THE ROOM, VERY SPECIAL, TO ME,

1713
01:12:33,643 --> 01:12:35,611
HERE MY SECOND CHANCE TO THANK

1714
01:12:35,611 --> 01:12:39,515
HIM, IN FRONT OF HIS FAMILY, SO

1715
01:12:39,515 --> 01:12:40,950
THAT'S REALLY GREAT.

1716
01:12:40,950 --> 01:12:43,619
ONE THING I WOULD LIKE TO SAY

1717
01:12:43,619 --> 01:12:49,959
WE, IN CANADA, AS YOU KNOW AFTER

1718
01:12:49,959 --> 01:12:52,028
2010, WHEN IT DROPPED FOUR

1719
01:12:52,028 --> 01:12:53,429
ORDERS OF MAGNITUDE SCIENTISTS

1720
01:12:53,429 --> 01:12:55,798
IDENTIFIED RARE DISEASE GENES

1721
01:12:55,798 --> 01:12:59,035
THROUGH WHOLE EXOME OR WHOLE

1722
01:12:59,035 --> 01:13:00,503
GENOME SEQUENCING, AND OVER THE

1723
01:13:00,503 --> 01:13:02,738
LAST TEN YEARS THERE'S BEEN A

1724
01:13:02,738 --> 01:13:05,608
RARE DISEASE GENE DISCOVERED PER

1725
01:13:05,608 --> 01:13:08,878
DAY, OVER 300 PER DAY FOR THE

1726
01:13:08,878 --> 01:13:16,419
LAST TEN YEARS, CANADIAN

1727
01:13:16,419 --> 01:13:17,420
SCIENTISTS IDENTIFIED 700 RARE

1728
01:13:17,420 --> 01:13:19,922
DISEASE GENES IN THE LAST TEN

1729
01:13:19,922 --> 01:13:22,325
YEARS, INITIATING A NETWORK THAT

1730
01:13:22,325 --> 01:13:25,161
ESSENTIALLY WAS A DATING

1731
01:13:25,161 --> 01:13:25,928
SERVICE, WHEN A CLINICIAN

1732
01:13:25,928 --> 01:13:31,634
SCIENTISTS FINDS A RARE GENE WE

1733
01:13:31,634 --> 01:13:33,302
CREATE A DATABASE, WE TRY TO

1734
01:13:33,302 --> 01:13:36,873
CONNECT THEM AT THE TIME OF GENE

1735
01:13:36,873 --> 01:13:38,541
DISCOVERY, SEED FUNDING MONEY TO

1736
01:13:38,541 --> 01:13:42,044
ESTABLISH A COLLABORATION, AND 

1737
01:13:42,044 --> 01:13:43,813
THAT HAS BEEN VERY PRODUCTIVE

1738
01:13:43,813 --> 01:13:49,619
EXERCISE AND WE HAVE FUNDING TO

1739
01:13:49,619 --> 01:13:51,387
2027.

1740
01:13:51,387 --> 01:13:53,990
LET ME END BY SUMMARIZING WHAT I

1741
01:13:53,990 --> 01:13:55,391
THINK PHIL'S LEGACY HAS BEEN TO

1742
01:13:55,391 --> 01:13:57,994
ME AND SO MANY PEOPLE.

1743
01:13:57,994 --> 01:14:00,196
HIS SCIENCE, FIRST OF ALL,

1744
01:14:00,196 --> 01:14:03,466
PICKING AN IMPORTANT PROBLEM,

1745
01:14:03,466 --> 01:14:06,102
IMPORTANCE OF TECHNOLOGY, TO

1746
01:14:06,102 --> 01:14:10,840
ATTACK THOSE PROBLEMS.

1747
01:14:10,840 --> 01:14:11,908
HIS CRITICAL THINKING,

1748
01:14:11,908 --> 01:14:13,009
INCREDIBLE TALENT IN SCIENCE

1749
01:14:13,009 --> 01:14:17,380
THAT WE ALL TRY TO EMULATE, THE

1750
01:14:17,380 --> 01:14:18,347
SECOND IS HIS MENTORSHIP AND,

1751
01:14:18,347 --> 01:14:28,791
AGAIN, HE WAS JUST SUCH A CARING

1752
01:14:28,791 --> 01:14:31,527
AMAZING MENTOR, EXUDED PASSION

1753
01:14:31,527 --> 01:14:33,296
AND OPTIMISM, HE WAS JUST A

1754
01:14:33,296 --> 01:14:34,297
WONDERFUL PERSON.

1755
01:14:34,297 --> 01:14:35,564
IT WAS JUST WONDERFUL TO HEAR

1756
01:14:35,564 --> 01:14:36,065
HIM TALK.

1757
01:14:36,065 --> 01:14:38,100
I DON'T KNOW IF YOU'VE LISTENED

1758
01:14:38,100 --> 01:14:40,169
TO OR LOOKED UP HIS INTERVIEWS

1759
01:14:40,169 --> 01:14:43,239
WHEN HE WON THE -- FROM THE

1760
01:14:43,239 --> 01:14:44,006
ALBERT LASKER FOUNDATION, BUT

1761
01:14:44,006 --> 01:14:44,774
THEY ARE AMAZING.

1762
01:14:44,774 --> 01:14:48,077
I'D RECOMMEND YOU CHECK IT OUT.

1763
01:14:48,077 --> 01:14:49,946
AND AS A ROLE MODEL.

1764
01:14:49,946 --> 01:14:52,148
AND I THINK, YOU KNOW, I'VE

1765
01:14:52,148 --> 01:14:54,850
STRIVED TO EMULATE PHIL IN MY

1766
01:14:54,850 --> 01:14:57,586
OWN CAREER AND NEVER COULD QUITE

1767
01:14:57,586 --> 01:14:59,221
REACH THAT LEVEL BUT I WANTED TO

1768
01:14:59,221 --> 01:15:00,756
SHOW THIS PICTURE BECAUSE WE GO

1769
01:15:00,756 --> 01:15:03,392
BACK TO THE LAB OF ABOUT TEN

1770
01:15:03,392 --> 01:15:06,128
PEOPLE IN 1979, THAT'S MY FIRST

1771
01:15:06,128 --> 01:15:09,198
LAB AT HOPKINS, I'VE ACTUALLY

1772
01:15:09,198 --> 01:15:10,866
MAINTAINED -- I THINK IT'S A

1773
01:15:10,866 --> 01:15:12,702
MAGIC NUMBER, TEN PEOPLE MY

1774
01:15:12,702 --> 01:15:14,203
ENTIRE CAREER.

1775
01:15:14,203 --> 01:15:16,605
SO OVER THE YEARS THIS IS MY

1776
01:15:16,605 --> 01:15:21,110
CREW NOW, THERE'S ABOUT TEN

1777
01:15:21,110 --> 01:15:21,510
PEOPLE.

1778
01:15:21,510 --> 01:15:24,613
32 PhDs GRADUATED, 16

1779
01:15:24,613 --> 01:15:29,852
POSTDOCS, AND I SEE A DIRECT

1780
01:15:29,852 --> 01:15:30,720
CONNECTION BETWEEN PHIL'S

1781
01:15:30,720 --> 01:15:32,021
MENTORSHIP OF ME AND WHAT HE

1782
01:15:32,021 --> 01:15:34,123
GAVE TO ME, AND ALL THESE PEOPLE

1783
01:15:34,123 --> 01:15:35,858
THAT I'VE TRAINED OVER THE

1784
01:15:35,858 --> 01:15:36,058
YEARS.

1785
01:15:36,058 --> 01:15:37,860
SO THANK YOU VERY MUCH.

1786
01:15:37,860 --> 01:15:40,229
[APPLAUSE]

1787
01:15:40,229 --> 01:15:46,302
 

1788
01:15:46,302 --> 01:15:56,345
 

1789
01:16:01,784 --> 01:16:03,252
>> WOW!

1790
01:16:03,252 --> 01:16:08,391
NEXT SPEAKER IS JEFF RAVETCH,

1791
01:16:08,391 --> 01:16:09,392
PROFESSOR AT ROCKEFELLER

1792
01:16:09,392 --> 01:16:11,894
UNIVERSITY, HEAD OF THE WAGNER

1793
01:16:11,894 --> 01:16:14,530
LABORATORY OF MOLECULAR GENETICS

1794
01:16:14,530 --> 01:16:17,500
AND IMMUNOLOGY, UNDERGRADUATE AT

1795
01:16:17,500 --> 01:16:19,435
YALE UNIVERSITY, RECEIVED MD/PHD

1796
01:16:19,435 --> 01:16:21,737
FROM CORNELL MEDICAL SCHOOL, GOT

1797
01:16:21,737 --> 01:16:27,009
HIS Ph.D. IN 1978 IN GENETICS,

1798
01:16:27,009 --> 01:16:29,845
POSTDOC AT THE NIH WITH PHIL,

1799
01:16:29,845 --> 01:16:31,814
IDENTIFIED AND CHARACTERIZED

1800
01:16:31,814 --> 01:16:33,582
GENES FOR HUMAN ANTIBODIES AND

1801
01:16:33,582 --> 01:16:38,054
DNA ELEMENTS INVOLVED IN SWITCH

1802
01:16:38,054 --> 01:16:38,387
RECOMBINATION.

1803
01:16:38,387 --> 01:16:42,525
FROM 1982 TO  1996 A MEMBER OF

1804
01:16:42,525 --> 01:16:47,797
THE FACULTY AT SLOAN-KETTERING

1805
01:16:47,797 --> 01:16:49,765
AND CORNELL, LABORATORY

1806
01:16:49,765 --> 01:16:51,167
ESTABLISHED FC DOMAIN FUNCTIONAL

1807
01:16:51,167 --> 01:16:53,702
DIVERSITY AND PREEMINENCE OF FCR

1808
01:16:53,702 --> 01:16:56,338
PATHWAYS IN HOST DEFENSE

1809
01:16:56,338 --> 01:16:57,306
INFLAMMATION AND TOLERANCE.

1810
01:16:57,306 --> 01:16:58,774
A MEMBER OF THE NATIONAL

1811
01:16:58,774 --> 01:17:00,142
ACADEMIES OF SCIENCE AND

1812
01:17:00,142 --> 01:17:02,144
MEDICINE, AMERICAN ACADEMY OF

1813
01:17:02,144 --> 01:17:02,778
ARTS AND SCIENCES.

1814
01:17:02,778 --> 01:17:08,717
HIS WORK HAS BEEN RECOGNIZED BY

1815
01:17:08,717 --> 01:17:10,986
NUMEROUS AWARDS, INCLUDING PEW

1816
01:17:10,986 --> 01:17:13,489
SCHOLAR, WOLF PRIZE IN MEDICINE,

1817
01:17:13,489 --> 01:17:15,324
AND MOST RECENTLY I THINK OF

1818
01:17:15,324 --> 01:17:18,461
INTEREST TO THIS AUDIENCE THE

1819
01:17:18,461 --> 01:17:21,297
WILLIAM POHL MEMORIAL AWARD.

1820
01:17:21,297 --> 01:17:21,497
JEFF?

1821
01:17:21,497 --> 01:17:27,436
>> THANKS. 

1822
01:17:27,436 --> 01:17:28,104
>> THANK YOU.

1823
01:17:28,104 --> 01:17:37,613
IT'S GREAT TO BE BACK AND TO SEE

1824
01:17:37,613 --> 01:17:41,016
OLD FACES. 

1825
01:17:41,016 --> 01:17:45,754
WE HAVE THE SAME SLIDES, OUR

1826
01:17:45,754 --> 01:17:46,822
IMAGINATIONS ARE LIMITED BY WHAT

1827
01:17:46,822 --> 01:17:48,557
PHIL LEFT US.

1828
01:17:48,557 --> 01:17:50,659
THIS REMIND ME OF WONDERFUL

1829
01:17:50,659 --> 01:17:52,294
ANECDOTES WE CAN TALK ABOUT AT

1830
01:17:52,294 --> 01:17:52,828
LUNCH.

1831
01:17:52,828 --> 01:18:00,169
I CAN'T RESIST THE IDEA LOOKING

1832
01:18:00,169 --> 01:18:05,074
AT PHIL HIETER NEXT TO PHIL

1833
01:18:05,074 --> 01:18:07,910
LEDER, LADY DI WAS IN OUR

1834
01:18:07,910 --> 01:18:09,879
THOUGHTS AND YOU MAY RECALL HIM

1835
01:18:09,879 --> 01:18:12,948
DRESSING UP AT LADY DI FOR

1836
01:18:12,948 --> 01:18:14,583
HALLOWEEN.

1837
01:18:14,583 --> 01:18:15,918
1979, LATE SPRING, GIVEN A CART

1838
01:18:15,918 --> 01:18:20,089
TO DO MY WORK INSTEAD OF A DESK.

1839
01:18:20,089 --> 01:18:22,057
IT WAS PHIL'S WAY OF TESTING MY

1840
01:18:22,057 --> 01:18:27,196
RESOLVE, WOULD I SURVIVE?

1841
01:18:27,196 --> 01:18:30,499
I PROCEEDED TO PARK MYSELF AT

1842
01:18:30,499 --> 01:18:32,568
ANY BENCH TEMPORARILY VACATED,

1843
01:18:32,568 --> 01:18:33,335
DISPLACING THE LEGITIMATE

1844
01:18:33,335 --> 01:18:35,337
OCCUPANT IN THE PROCESS.

1845
01:18:35,337 --> 01:18:38,707
AFTER SEVERAL MONTHS OF THIS

1846
01:18:38,707 --> 01:18:41,577
ITINERANT LIFESTYLE I ACQUIRED A

1847
01:18:41,577 --> 01:18:43,979
STABLE SPOT, BIGGER THAN AN ICE

1848
01:18:43,979 --> 01:18:54,456
BUCK ET WITH A POWER OUTLED.

1849
01:18:57,593 --> 01:18:58,627
IT WAS EXCITING.

1850
01:18:58,627 --> 01:19:02,031
THERE WERE NEVER ENOUGH GEL

1851
01:19:02,031 --> 01:19:06,835
BOXES, POWER SUPPLIES, WATER

1852
01:19:06,835 --> 01:19:08,070
BATHS, ENZYMES, ALL THE REAGENTS

1853
01:19:08,070 --> 01:19:13,976
WE NEEDED TO CLONE AND SEQUENCE

1854
01:19:13,976 --> 01:19:17,046
GENES, IN A RACE TO CHARACTERIZE

1855
01:19:17,046 --> 01:19:19,982
HEAVY GENES, PHIL WOULD LOOK

1856
01:19:19,982 --> 01:19:23,252
OVER AS THE SEQUENCING GELS CAME

1857
01:19:23,252 --> 01:19:32,461
OUT, EAGER TO SEE WHAT WE FOUND.

1858
01:19:32,461 --> 01:19:33,662
WE CRAMMED OURSELVES INTO THE

1859
01:19:33,662 --> 01:19:35,631
LAB DURING THE DAY, WORKED IN

1860
01:19:35,631 --> 01:19:36,732
SHIFTS NIGHTS AND WEEKENDS TO

1861
01:19:36,732 --> 01:19:41,003
COMPLETE THE WORK IN RECORD TIME

1862
01:19:41,003 --> 01:19:44,173
TAKING TURNS, WATCHING THE

1863
01:19:44,173 --> 01:19:48,110
LIBRARY SCREENS, SETTING UP

1864
01:19:48,110 --> 01:19:48,877
HYBRIDIZATIONS, INOCULATING

1865
01:19:48,877 --> 01:19:49,878
CULTURES TO GROW.

1866
01:19:49,878 --> 01:19:52,715
IN THE BACKGROUND WE LISTENED TO

1867
01:19:52,715 --> 01:19:59,488
THE RADIO FAVORING CLASSICAL

1868
01:19:59,488 --> 01:20:02,658
MUSIC, PHIL WAS A CON STAND

1869
01:20:02,658 --> 01:20:04,159
PRESENCE, STOPPING AT OUR

1870
01:20:04,159 --> 01:20:07,162
BENCHES WHEN DATA WAS COMING.

1871
01:20:07,162 --> 01:20:10,866
WE WORKED TO CLONE cDNA IT'S

1872
01:20:10,866 --> 01:20:12,301
AND GERMLINE REARRANGE FOR EACH

1873
01:20:12,301 --> 01:20:15,638
OF THE HEAVY CHAINS USING

1874
01:20:15,638 --> 01:20:18,240
CROSS-SPECIES HOMOLOGY WHEN WE

1875
01:20:18,240 --> 01:20:19,942
COULD.

1876
01:20:19,942 --> 01:20:24,013
PHIL WOULD LISTEN AND RETURN

1877
01:20:24,013 --> 01:20:31,020
LATER REPEATING RESULTS IN A

1878
01:20:31,020 --> 01:20:35,257
POLISHED VERSION. 

1879
01:20:35,257 --> 01:20:38,460
I WAS BEWILDERED UNTIL I

1880
01:20:38,460 --> 01:20:39,995
RELATESSED HE WAS READY TO

1881
01:20:39,995 --> 01:20:41,730
LAUNCH INTO A MANUSCRIPT FOR A

1882
01:20:41,730 --> 01:20:42,631
TALK.

1883
01:20:42,631 --> 01:20:43,932
HE TAUGHT US RULES, NEVER

1884
01:20:43,932 --> 01:20:45,134
PRESENT A DATA SLIDE WITHOUT

1885
01:20:45,134 --> 01:20:46,769
PREPARING THE GROUND WORK, MAKE

1886
01:20:46,769 --> 01:20:48,270
THE AUDIENCE THINK THEY REACHED

1887
01:20:48,270 --> 01:20:50,806
THE CONCLUSION ON THEIR OWN

1888
01:20:50,806 --> 01:20:51,607
WITHOUT BEING TOLD.

1889
01:20:51,607 --> 01:20:54,009
AND LESS IS ALWAYS MORE.

1890
01:20:54,009 --> 01:20:57,646
WE TEAMED UP TO CHARACTERIZE MU

1891
01:20:57,646 --> 01:21:00,282
AND ALPHA HEAVY CHAINS, CLONED, 

1892
01:21:00,282 --> 01:21:06,722
IN THE FIRST PAPER -- NOW I'M

1893
01:21:06,722 --> 01:21:08,257
TRYING TO FIGURE IT OUT.

1894
01:21:08,257 --> 01:21:09,825
WHAT'S THE SECRET?

1895
01:21:09,825 --> 01:21:11,960
THERE YOU GO.

1896
01:21:11,960 --> 01:21:15,264
GOT IT. 

1897
01:21:15,264 --> 01:21:19,401
SO FIRST PAPER PUBLISHED IN

1898
01:21:19,401 --> 01:21:21,170
PNAS, WE USED HETERODUPLEX

1899
01:21:21,170 --> 01:21:22,037
MAPPING TO DEFINE RELEVANT

1900
01:21:22,037 --> 01:21:24,106
REGIONS OF THE MU AND ALPHA

1901
01:21:24,106 --> 01:21:26,075
GENES WITHOUT HAVING TO SEQUENCE

1902
01:21:26,075 --> 01:21:26,575
THEM.

1903
01:21:26,575 --> 01:21:28,310
IT'S STILL A FAVORITE BRINGING

1904
01:21:28,310 --> 01:21:30,913
BACK MEMORIES OF NIGHT IN THE

1905
01:21:30,913 --> 01:21:33,982
BASEMENT OF BUILDING 6 STARING

1906
01:21:33,982 --> 01:21:36,251
AT EM GRADES.

1907
01:21:36,251 --> 01:21:37,486
A PRESCIENT STUDY DEFINING

1908
01:21:37,486 --> 01:21:40,122
SWITCH REGIONS WITH HOMOLOGY AND

1909
01:21:40,122 --> 01:21:44,259
SWITCH RECOMBINATION, NOT TOO

1910
01:21:44,259 --> 01:21:44,493
SHABBY.

1911
01:21:44,493 --> 01:21:46,562
NEXT CAME DEMAND FOR SEQUENCING

1912
01:21:46,562 --> 01:21:48,630
GEL BOXES, PLATES, POWER

1913
01:21:48,630 --> 01:21:56,605
SUPPLIES AND FREEZER SPACE, TO

1914
01:21:56,605 --> 01:21:59,808
SEQUENCE I DECIDED TO START MY

1915
01:21:59,808 --> 01:22:03,245
EXPERIMENT ALSO ON A CHRISTMAS

1916
01:22:03,245 --> 01:22:05,147
EVE AND WORK THROUGH THE HOLIDAY

1917
01:22:05,147 --> 01:22:07,616
TAKING OVER GEL BOX, POWER

1918
01:22:07,616 --> 01:22:10,119
SUPPLY AND BENCH IN THE EMPTY

1919
01:22:10,119 --> 01:22:11,920
LAB, AS SOON AS I MOVED FROM ONE

1920
01:22:11,920 --> 01:22:14,223
END TO THE OTHER IT WAS TIME TO

1921
01:22:14,223 --> 01:22:19,395
START ALL OVER WITH A SECOND AND

1922
01:22:19,395 --> 01:22:20,796
THIRD LOAD UNTIL I REACHED MAX

1923
01:22:20,796 --> 01:22:26,201
UNIT, THE TERM WE COINED TO

1924
01:22:26,201 --> 01:22:30,472
ACKNOWLEDGE 5.5  KILOBASES AND

1925
01:22:30,472 --> 01:22:32,408
TOLD BY PHIL IT WAS GOOD ENOUGH,

1926
01:22:32,408 --> 01:22:35,577
AND PUT THE DATA TOGETHER

1927
01:22:35,577 --> 01:22:38,947
RESULTING IN A CELL PAPER THAT

1928
01:22:38,947 --> 01:22:41,617
DEFINED THE LOCUS.

1929
01:22:41,617 --> 01:22:42,718
 

1930
01:22:42,718 --> 01:22:48,690
NEXT SLIDE PLEASE. 

1931
01:22:48,690 --> 01:22:49,892
THANK YOU.

1932
01:22:49,892 --> 01:22:56,165
OTHER PAPERS FOLLOWED WHICH STAN

1933
01:22:56,165 --> 01:22:57,666
KORSMEYER AND OTHERS.

1934
01:22:57,666 --> 01:23:01,870
SO MY THREE YEARS IN HIS LAB

1935
01:23:01,870 --> 01:23:03,872
WITH ONE OF THE MOST EXCITING

1936
01:23:03,872 --> 01:23:08,744
TIMES IN MY CAREER.

1937
01:23:08,744 --> 01:23:11,613
THE FOREFRONT OF IMMUNOLOGY,

1938
01:23:11,613 --> 01:23:14,783
USING CUTTING EDGE EXPERIMENTS,

1939
01:23:14,783 --> 01:23:15,717
YIELDING UNEXPECTED RESULT,

1940
01:23:15,717 --> 01:23:16,752
GIVING ME A TASTE FOR WHAT I

1941
01:23:16,752 --> 01:23:19,488
WANTED TO DO FOR THE NEXT 40

1942
01:23:19,488 --> 01:23:21,356
YEARS APPLYING TOOLS TO PROBLEMS

1943
01:23:21,356 --> 01:23:22,257
IN THE IMMUNOLOGY.

1944
01:23:22,257 --> 01:23:25,761
I RECALL THE DAY I SAT IN HIS

1945
01:23:25,761 --> 01:23:27,563
OFFICE THREE YEARS LATER, TIME

1946
01:23:27,563 --> 01:23:30,098
TO SET OFF ON MY OWN, LAB MOVING

1947
01:23:30,098 --> 01:23:32,734
TO BOSTON, I WAS GOING HALFWAY

1948
01:23:32,734 --> 01:23:35,137
BACK TO NEW YORK WHERE I DID MY

1949
01:23:35,137 --> 01:23:35,771
GRADUATE STUDIES.

1950
01:23:35,771 --> 01:23:38,407
PHIL ASKED WHAT I WAS PLANNING

1951
01:23:38,407 --> 01:23:39,508
ON WORK ON.

1952
01:23:39,508 --> 01:23:41,610
I SAID I THINK I'D LIKE TO WORK

1953
01:23:41,610 --> 01:23:43,045
ON SWITCH RECOMBINATION.

1954
01:23:43,045 --> 01:23:45,647
PHIL SAID NOTHING FOR WHAT SEEMS

1955
01:23:45,647 --> 01:23:46,415
LIKE MINUTES.

1956
01:23:46,415 --> 01:23:47,950
AND THEN SAID I WOULDN'T

1957
01:23:47,950 --> 01:23:48,817
RECOMMEND THAT.

1958
01:23:48,817 --> 01:23:51,220
FIND SOMETHING NO ONE IS WORKING

1959
01:23:51,220 --> 01:23:51,487
ON.

1960
01:23:51,487 --> 01:23:53,589
PROBABLY THE BEST ADVICE I'VE

1961
01:23:53,589 --> 01:23:53,922
EVER RECEIVED.

1962
01:23:53,922 --> 01:23:58,794
FORCED KNEE  -- ME INTO A

1963
01:23:58,794 --> 01:23:59,895
PROBLEM THAT OCCUPIED ME FOR THE

1964
01:23:59,895 --> 01:24:01,396
REST OF MY CAREER.

1965
01:24:01,396 --> 01:24:05,033
NO ONE CARED ABOUT THE FC, THEY

1966
01:24:05,033 --> 01:24:07,536
ASSUMED IT WAS ACCOUNTED FOR BY

1967
01:24:07,536 --> 01:24:10,005
THE CLASSICAL PATHWAY OF

1968
01:24:10,005 --> 01:24:11,607
CONFLICT ACTIVATION, FC

1969
01:24:11,607 --> 01:24:13,342
RECEPTORS NOT ON ANYONE'S RADAR.

1970
01:24:13,342 --> 01:24:16,178
I TOOK MY FREEZER BOXES AND

1971
01:24:16,178 --> 01:24:18,380
PACKAGING EXTRACTS AND GENES I

1972
01:24:18,380 --> 01:24:20,716
CLONED, TWO WEEK OLD SON, HEADED

1973
01:24:20,716 --> 01:24:21,984
BACK TO NEW YORK.

1974
01:24:21,984 --> 01:24:22,951
NEXT SLIDE PLEASE.

1975
01:24:22,951 --> 01:24:25,587
TO START MY LAB AT

1976
01:24:25,587 --> 01:24:27,222
SLOAN-KETTERING.

1977
01:24:27,222 --> 01:24:37,766
THIS IS MY ATTEMPT TO CHANNEL MY

1978
01:24:38,901 --> 01:24:42,771
INNER FORESTER.

1979
01:24:42,771 --> 01:24:44,306
NEXT SLIDE.

1980
01:24:44,306 --> 01:24:44,806
SLOAN-KETTERING IN THE

1981
01:24:44,806 --> 01:24:46,375
BACKGROUND, ROCKEFELLER

1982
01:24:46,375 --> 01:24:47,309
UNIVERSITY IN THE FOREGROUND,

1983
01:24:47,309 --> 01:24:48,577
CORNELL MEDICAL ON THE

1984
01:24:48,577 --> 01:24:51,413
RIGHT-HAND SIDE OF THE SLIDE.

1985
01:24:51,413 --> 01:24:54,216
IT SET ME ON THE PATH PHIL HAD

1986
01:24:54,216 --> 01:24:57,920
SHOWN ME.

1987
01:24:57,920 --> 01:25:00,055
WE DEFINED THE cDNAS AFTER

1988
01:25:00,055 --> 01:25:02,257
YEARS OF EFFORT USING TRICKS

1989
01:25:02,257 --> 01:25:04,760
PHIL TAUGHT US AND NEXT SLIDE

1990
01:25:04,760 --> 01:25:08,163
WERE ABLE TO DEFINE COMPLEX

1991
01:25:08,163 --> 01:25:11,533
FAMILY OF FC RECEPTORS THAT

1992
01:25:11,533 --> 01:25:12,234
MODULATED BIOLOGICAL ACTIVITY OF

1993
01:25:12,234 --> 01:25:16,705
ANTIBODIES IN A VARIETY OF

1994
01:25:16,705 --> 01:25:17,039
APPLICATIONS.

1995
01:25:17,039 --> 01:25:20,409
SO GOING INTO THE DETAILS OF

1996
01:25:20,409 --> 01:25:22,044
THESE FC RECEPTORS, MEMBERS OF

1997
01:25:22,044 --> 01:25:26,949
THE IG SUPER FAMILY ON ONE CASE,

1998
01:25:26,949 --> 01:25:29,351
FUNCTION TO COUPLE THE

1999
01:25:29,351 --> 01:25:35,958
RECOGNITION DOMAINS OF THE FAB

2000
01:25:35,958 --> 01:25:38,093
MEDIATING POSITIVE AND NEGATIVE

2001
01:25:38,093 --> 01:25:39,328
SIGNALING PATHWAYS, WE KNOCKED

2002
01:25:39,328 --> 01:25:41,630
OUT THE GENES IN VARIOUS MOUSE

2003
01:25:41,630 --> 01:25:43,966
MODELS, AND DEFINED HOW THEY

2004
01:25:43,966 --> 01:25:45,334
IMPACTED ON THE BIOLOGY OF THE

2005
01:25:45,334 --> 01:25:47,436
SYSTEM AND THEN DID THE

2006
01:25:47,436 --> 01:25:51,239
COORDINATE MAPPING OF FC REGIONS

2007
01:25:51,239 --> 01:25:53,442
TO DETERMINE WHERE ENGAGEMENT

2008
01:25:53,442 --> 01:25:56,712
WOULD OCCUR, LEADING TO ABILITY

2009
01:25:56,712 --> 01:25:59,147
TO MANIPULATE THE FC REGION TO

2010
01:25:59,147 --> 01:26:00,148
DEVELOP NOVEL THERAPEUTICS AND

2011
01:26:00,148 --> 01:26:02,417
THIS IS A LIST OF SOME HALF

2012
01:26:02,417 --> 01:26:04,720
DOZEN ANTIBODIES THAT HAVE BEEN

2013
01:26:04,720 --> 01:26:07,689
FDA APPROVED WHOSE FCs WERE

2014
01:26:07,689 --> 01:26:09,891
MODIFIED TO SELECTIVELY ENGAGE

2015
01:26:09,891 --> 01:26:12,494
SPECIFIC FC RECEPTORS TO ENHANCE

2016
01:26:12,494 --> 01:26:14,463
OR MODULATE THE BIOLOGICAL

2017
01:26:14,463 --> 01:26:17,766
ACTIVITY OF ANTITUMOR ANTIBODIES

2018
01:26:17,766 --> 01:26:22,371
AS WELL AS ANTI-INFLAMMATORY

2019
01:26:22,371 --> 01:26:22,671
ANTIBODIES.

2020
01:26:22,671 --> 01:26:24,973
SO OVER THE YEARS WE'VE FOCUSED

2021
01:26:24,973 --> 01:26:27,309
ON HOW WE CAN COUPLE THIS SYSTEM

2022
01:26:27,309 --> 01:26:30,712
TO A VARIETY OF PATHWAYS, NEXT

2023
01:26:30,712 --> 01:26:35,017
SLIDE, YOU CAN SEE THE CURRENT

2024
01:26:35,017 --> 01:26:37,719
EXCITEMENT IN THE FIELD OF

2025
01:26:37,719 --> 01:26:38,920
MEDICAL ONCOLOGY, USING

2026
01:26:38,920 --> 01:26:41,790
ANTIBODIES TO BLOCK VARIOUS

2027
01:26:41,790 --> 01:26:43,625
CHECKPOINTS ON T CELLS, OUR

2028
01:26:43,625 --> 01:26:44,760
FOCUS HAS BEEN ON THE RIGHT-HAND

2029
01:26:44,760 --> 01:26:49,564
SIDE HOW WE CAN ACTIVATE APC BY

2030
01:26:49,564 --> 01:26:52,067
USING MOLECULE CALLED CD40, WELL

2031
01:26:52,067 --> 01:26:53,502
KNOWN TO THE IMMUNOLOGICAL

2032
01:26:53,502 --> 01:26:55,904
COMMUNITY, ALWAYS USED WHEN WE

2033
01:26:55,904 --> 01:26:57,572
WANT TO ENHANCE BIOLOGICAL

2034
01:26:57,572 --> 01:27:00,509
RESPONSE IN AN ANIMAL.

2035
01:27:00,509 --> 01:27:02,044
BUT WHEN ATTEMPTS WERE MADE,

2036
01:27:02,044 --> 01:27:05,480
NEXT SLIDE, TO USE THE ANTI-CD40

2037
01:27:05,480 --> 01:27:07,182
APPROACH AS THERAPEUTIC, NEXT

2038
01:27:07,182 --> 01:27:10,585
SLIDE PLEASE, IT WAS FOUND THAT

2039
01:27:10,585 --> 01:27:12,354
THE ANTI-C 40 AGONISTIC

2040
01:27:12,354 --> 01:27:14,122
ANTIBODIES WERE HIGHLY TOXIC AND

2041
01:27:14,122 --> 01:27:18,026
GAVE ESSENTIALLY NO IN VIVO

2042
01:27:18,026 --> 01:27:19,127
BIOLOGICAL RESPONSE, A SHOCK.

2043
01:27:19,127 --> 01:27:20,462
GOING BACK TO THE WAY PHIL

2044
01:27:20,462 --> 01:27:22,197
TAUGHT US TO THINK ABOUT THESE

2045
01:27:22,197 --> 01:27:25,233
TYPES OF PROBLEMS, IT MEANT THAT

2046
01:27:25,233 --> 01:27:29,471
OUR CROSS-SPECIES MODELS WERE

2047
01:27:29,471 --> 01:27:30,072
INADEQUATE, NOT ACCOMMODATING

2048
01:27:30,072 --> 01:27:31,673
THE SYSTEMS WHERE THE ANTIBODIES

2049
01:27:31,673 --> 01:27:33,442
WERE FIRST DEVELOPED AND

2050
01:27:33,442 --> 01:27:35,410
TRANSLATION INTO THE CLINICAL

2051
01:27:35,410 --> 01:27:35,644
ASPECT.

2052
01:27:35,644 --> 01:27:40,015
SO WE DID THAT BILLING 

2053
01:27:40,015 --> 01:27:40,882
BILLING -- BUILDING MOUSE

2054
01:27:40,882 --> 01:27:43,185
MODELS, NEXT SLIDE, WE

2055
01:27:43,185 --> 01:27:45,587
APPRECIATED A SIMPLE NOTION THAT

2056
01:27:45,587 --> 01:27:48,890
FOR MEMBERS OF THE SUPER FAMILY

2057
01:27:48,890 --> 01:27:50,625
OF WHICH CD40 IS ONE THE

2058
01:27:50,625 --> 01:27:53,261
INTERACTION OF LIGAND IS A

2059
01:27:53,261 --> 01:27:54,229
TRIMER-TRIMER INTERACTION.

2060
01:27:54,229 --> 01:27:55,230
ANTIBODIES DIMERIZE AND

2061
01:27:55,230 --> 01:27:56,231
THEREFORE WERE VERY INEFFICIENT

2062
01:27:56,231 --> 01:28:02,671
WHEN IT CAME TO STIMULATING AN 

2063
01:28:02,671 --> 01:28:05,440
AGONISTIC RESPONSE ON DENDRITIC

2064
01:28:05,440 --> 01:28:09,578
CELL, WE CAN USE THE FC AS A

2065
01:28:09,578 --> 01:28:10,879
SCAFFOLD TO CROSS-LINK IN

2066
01:28:10,879 --> 01:28:16,585
TRENDS, THE WAY IS TO USE AN FC

2067
01:28:16,585 --> 01:28:20,455
RECEPTOR, BUT WILL ACT INERTLY

2068
01:28:20,455 --> 01:28:26,828
SO WE REENGINEERED AN EXISTING 

2069
01:28:26,828 --> 01:28:27,496
THERAPEUTIC ANTIBODY IN SEVEN

2070
01:28:27,496 --> 01:28:28,830
PHASE 1 STUDIES.

2071
01:28:28,830 --> 01:28:29,798
NEXT SLIDE.

2072
01:28:29,798 --> 01:28:31,633
DEMONSTRATING WE COULD ENHANCE

2073
01:28:31,633 --> 01:28:34,069
THE IN VIVO ACTIVITY QUITE

2074
01:28:34,069 --> 01:28:34,402
DRAMATICALLY.

2075
01:28:34,402 --> 01:28:36,905
YOU CAN SEE IF YOU COMPARE THE

2076
01:28:36,905 --> 01:28:40,275
PARENT ANTIBODY WHICH IS SHOWN

2077
01:28:40,275 --> 01:28:42,277
IN GREEN TO THE FC ENHANCED

2078
01:28:42,277 --> 01:28:45,347
VERSION OF THE SAME FAB IN

2079
01:28:45,347 --> 01:28:48,784
PURPLE WE CAN SHOW COMPLETE

2080
01:28:48,784 --> 01:28:53,088
ERADICATION OF MG 38 AND

2081
01:28:53,088 --> 01:28:58,126
METASTATIC MELANOMA MODEL IN THE

2082
01:28:58,126 --> 01:28:58,693
LUNG.

2083
01:28:58,693 --> 01:29:01,429
SO WE WERE FACED WITH A DILEMMA,

2084
01:29:01,429 --> 01:29:05,567
I COULD SATISFY MY WIFE'S

2085
01:29:05,567 --> 01:29:07,669
CRITERIA, WHAT DOES YOUR HUSBAND

2086
01:29:07,669 --> 01:29:09,504
DO, HER ANSWER WAS IF YOU WERE A

2087
01:29:09,504 --> 01:29:10,839
MOUSE HE COULD CURE YOU.

2088
01:29:10,839 --> 01:29:13,809
WE WANT TO GO BEYOND THAT, COULD

2089
01:29:13,809 --> 01:29:15,977
WE DO THIS IN A CLINICAL

2090
01:29:15,977 --> 01:29:16,611
SETTING?

2091
01:29:16,611 --> 01:29:19,181
THIS WAS A SYSTEM DEMONSTRATED

2092
01:29:19,181 --> 01:29:22,450
MULTIPLE TIMES, FAILED IN THE

2093
01:29:22,450 --> 01:29:23,985
CLINIC, NOBODY WANTED TO TOUCH

2094
01:29:23,985 --> 01:29:24,519
IT.

2095
01:29:24,519 --> 01:29:31,827
AT ROCKEFELLER WE HAD INSIGHTFUL

2096
01:29:31,827 --> 01:29:32,427
TRUSSEES INCLUDING JULIAN

2097
01:29:32,427 --> 01:29:39,734
ROBINSON, WHEN I PRESENTED THIS,

2098
01:29:39,734 --> 01:29:41,169
USING A REENGINEERED ANTIBODY HE

2099
01:29:41,169 --> 01:29:44,739
SAID I CAN WRITE A CHECK, AND HE

2100
01:29:44,739 --> 01:29:47,976
DID, USING PHILANTHROPIC FUNDING

2101
01:29:47,976 --> 01:29:51,313
WE WERE ABLE TO GMP MANUFACTURE

2102
01:29:51,313 --> 01:29:56,251
AND DO FIRST IN HUMAN STUDIES OF

2103
01:29:56,251 --> 01:29:59,654
FC ENGINEERED AGONISTIC

2104
01:29:59,654 --> 01:30:01,156
ANTI-CD40 ANTIBODY.

2105
01:30:01,156 --> 01:30:03,391
IT HAS HIGH SYSTEMIC TOXICITY.

2106
01:30:03,391 --> 01:30:08,096
WE CONFIRMED WHEN WE 

2107
01:30:08,096 --> 01:30:10,298
REENGINEERED TO INCREASE

2108
01:30:10,298 --> 01:30:11,366
POTENCY, BUT WHY GIVE

2109
01:30:11,366 --> 01:30:13,068
SYSTEMICALLY WHEN YOU TRY TO

2110
01:30:13,068 --> 01:30:15,270
ACTIVATE IMMUNE RESPONSE IN THE

2111
01:30:15,270 --> 01:30:17,405
HUMAN MICROENVIRONMENT TO THEN

2112
01:30:17,405 --> 01:30:20,141
GIVE RISE TO SYSTEMIC 

2113
01:30:20,141 --> 01:30:20,642
DIVERSIFICATION?

2114
01:30:20,642 --> 01:30:21,977
THAT'S WHAT VACCINATION DOES.

2115
01:30:21,977 --> 01:30:23,845
WE DECIDED TO ACTIVATE TUMOR

2116
01:30:23,845 --> 01:30:26,248
LOCALLY AND COUNT ON THE FACT

2117
01:30:26,248 --> 01:30:29,451
THAT THE ACTIVATED CD8 CELLS

2118
01:30:29,451 --> 01:30:33,488
WOULD THEN MIGRATE TO LYMPH

2119
01:30:33,488 --> 01:30:38,426
NODES AND DISPERSE THROUGH

2120
01:30:38,426 --> 01:30:39,461
ORGANISM TO ERADICATE OTHER

2121
01:30:39,461 --> 01:30:39,694
TUMORS.

2122
01:30:39,694 --> 01:30:43,598
DOES IT WORK? 

2123
01:30:43,598 --> 01:30:44,799
YEAH, AMAZING.

2124
01:30:44,799 --> 01:30:46,735
MELANOMA IN TRANSIT, TEN YEARS

2125
01:30:46,735 --> 01:30:52,574
AGO, CAME BACK TEN YEARS LATER,

2126
01:30:52,574 --> 01:30:53,341
SLOAN-KETTERING, DIFFUSE

2127
01:30:53,341 --> 01:30:55,610
METASTATIC MELANOMA, YOU CAN SEE

2128
01:30:55,610 --> 01:30:59,781
BOTH DARK SPOTS AS WELL AS

2129
01:30:59,781 --> 01:31:04,085
LESIONS ON THE FOOT DOWN TO THE

2130
01:31:04,085 --> 01:31:04,419
FOOT.

2131
01:31:04,419 --> 01:31:07,622
WE DECIDED TO INJECT INTO THAT

2132
01:31:07,622 --> 01:31:12,494
ONE LESION A 2-MILLIGRAM DOSE,

2133
01:31:12,494 --> 01:31:13,461
AFTER MULTIPLE CYCLES OF

2134
01:31:13,461 --> 01:31:15,664
TREATMENT YOU CAN SEE PARTIAL

2135
01:31:15,664 --> 01:31:17,432
RESPONSE BY SIX CYCLES, AND BY

2136
01:31:17,432 --> 01:31:18,833
THE 15th CYCLE THERE WAS

2137
01:31:18,833 --> 01:31:21,369
NOTHING LEFT TO INJECT.

2138
01:31:21,369 --> 01:31:29,444
WE SAW RESIDUAL REGIONS OF

2139
01:31:29,444 --> 01:31:30,211
MELANOTIC FIGMENTATION, NO

2140
01:31:30,211 --> 01:31:31,212
TUMOR, COMPLETE RESPONSE.

2141
01:31:31,212 --> 01:31:32,447
WASN'T THE ONLY ONE.

2142
01:31:32,447 --> 01:31:35,050
NEXT SLIDE SHOWS EXAMPLE OF WHAT

2143
01:31:35,050 --> 01:31:38,186
HAPPENED IN A PATIENT, NEXT

2144
01:31:38,186 --> 01:31:41,323
SLIDE PLEASE, WHO HAD RECURRENCE

2145
01:31:41,323 --> 01:31:43,158
OF METASTATIC BREAST CARCINOMA,

2146
01:31:43,158 --> 01:31:46,861
THIS IS AN ESTROGEN RECEPTOR

2147
01:31:46,861 --> 01:31:47,896
POSITIVE HER2-NEGATIVE

2148
01:31:47,896 --> 01:31:54,736
METASTATIC BREAST CANCER, 

2149
01:31:54,736 --> 01:31:56,471
MULTIPLE ROUND OF CHEMOTHERAPY,

2150
01:31:56,471 --> 01:31:58,106
RADIATION, OF COURSE SURGERY,

2151
01:31:58,106 --> 01:32:00,342
AND PRESENTED ONCE AGAIN WITH

2152
01:32:00,342 --> 01:32:03,545
MULTIPLE LESIONS IN HER AXILLA

2153
01:32:03,545 --> 01:32:07,482
AND SHOULDER, AND DEEP LIVER

2154
01:32:07,482 --> 01:32:09,417
METASTASES, WE INJECTED IN THE

2155
01:32:09,417 --> 01:32:11,920
TWO SITES WITH BLUE ARROWS,

2156
01:32:11,920 --> 01:32:13,688
LOCAL INJECTION, 5 MILLIGRAMS AT

2157
01:32:13,688 --> 01:32:16,391
EACH SITE.

2158
01:32:16,391 --> 01:32:19,461
YOU SEE IMMEDIATE RESPONSE, BY

2159
01:32:19,461 --> 01:32:22,097
SECOND CYCLE LESIONS STARTING TO

2160
01:32:22,097 --> 01:32:23,665
LEVEL OUT, BY FOURTH CYCLE

2161
01:32:23,665 --> 01:32:25,266
NOTHING LEFT TO INJECT,

2162
01:32:25,266 --> 01:32:27,035
COMPLETELY RESOLVED AS WELL AS

2163
01:32:27,035 --> 01:32:28,103
DEEP LIVER METASTASIS.

2164
01:32:28,103 --> 01:32:29,471
WHAT'S GOING ON?

2165
01:32:29,471 --> 01:32:30,972
NEXT SLIDE.

2166
01:32:30,972 --> 01:32:33,508
WHEN YOU BIOPSY THE SITES OF

2167
01:32:33,508 --> 01:32:35,610
NON-INJECTED TUMORS FROM BOTH

2168
01:32:35,610 --> 01:32:38,213
PATIENTS, WHAT YOU SEE ARE NOT

2169
01:32:38,213 --> 01:32:43,551
TUMOR CELLS, YOU INSTEAD SEE 

2170
01:32:43,551 --> 01:32:46,855
INFILTRATION OF LYMPHOID CELLS, 

2171
01:32:46,855 --> 01:32:49,024
THEY HAVE WELL ORGANIZED T CELL

2172
01:32:49,024 --> 01:32:54,262
ZONES, B CELL ZONES, DENDRITIC

2173
01:32:54,262 --> 01:32:59,200
CELLS, CANONICAL DENDRITIC

2174
01:32:59,200 --> 01:32:59,534
CELLS.

2175
01:32:59,534 --> 01:33:03,438
WHEN WE INTRODUCE TREATMENT YOU

2176
01:33:03,438 --> 01:33:05,006
SEE IMMEDIATE DECLINE IN THE

2177
01:33:05,006 --> 01:33:07,742
LEVEL OF TUMOR BURDEN IN THIS

2178
01:33:07,742 --> 01:33:13,314
PATIENT DEMONSTRATING IN FACT

2179
01:33:13,314 --> 01:33:14,549
INTRATUMOR EFFECTS CAN BE

2180
01:33:14,549 --> 01:33:19,621
MOBILIZED, IT'S NOT ONLY 

2181
01:33:19,621 --> 01:33:21,589
RECOGNITION OF FAB ENGAGING

2182
01:33:21,589 --> 01:33:25,060
TARGET ANTIGEN BUT CAN PLAY

2183
01:33:25,060 --> 01:33:28,563
DRAMATIC ROLE IN EFFICACY.

2184
01:33:28,563 --> 01:33:31,399
LET ME END WITH AN ILLUSTRATION

2185
01:33:31,399 --> 01:33:37,105
I FOUND A LECTURE GIVEN IN 1900 

2186
01:33:37,105 --> 01:33:39,340
FOLLOWING ON THE WORK OF THE

2187
01:33:39,340 --> 01:33:41,776
DESCRIPTION OF ANTI-TOXINS AS A

2188
01:33:41,776 --> 01:33:52,220
THERAPEUTIC  MODALITY FOR

2189
01:33:53,188 --> 01:33:54,289
TREATING TETANUS, NATURE OF

2190
01:33:54,289 --> 01:33:56,124
ANTI-TOXIN, THEY ARE PRESENT IN

2191
01:33:56,124 --> 01:33:57,559
THE ORGANISM, IMMUNE BODIES SO

2192
01:33:57,559 --> 01:33:59,327
CONSTITUTED THAT THEY ARE

2193
01:33:59,327 --> 01:34:00,995
ENDOWED NOT ONLY WITH AFFINITIES

2194
01:34:00,995 --> 01:34:11,306
OF  AFFINITIES ...

2195
01:34:12,740 --> 01:34:16,411
THE ILLUSTRATION SHOWN HERE, SO

2196
01:34:16,411 --> 01:34:17,645
ANTIGEN IS CLEARLY DENOTED.

2197
01:34:17,645 --> 01:34:18,746
NEXT CLICK PLEASE.

2198
01:34:18,746 --> 01:34:20,815
IMMUNE BODY HAS A REGION OF

2199
01:34:20,815 --> 01:34:24,252
AFFINITY WHICH IS THE FAB

2200
01:34:24,252 --> 01:34:25,820
REGION.

2201
01:34:25,820 --> 01:34:26,921
CLICK AGAIN PLEASE.

2202
01:34:26,921 --> 01:34:28,123
FAB REGION.

2203
01:34:28,123 --> 01:34:29,424
NEXT REGION WOULD BE THE FC

2204
01:34:29,424 --> 01:34:29,924
REGION.

2205
01:34:29,924 --> 01:34:34,129
ALL OF THIS ALLOWS FOR 

2206
01:34:34,129 --> 01:34:36,231
ENGAGEMENT IN FC RECEPTOR, SO

2207
01:34:36,231 --> 01:34:40,368
WHAT WE'VE COME TO RECOGNIZE IS

2208
01:34:40,368 --> 01:34:43,004
THAT THE IDEA BEHIND ANTIBODY

2209
01:34:43,004 --> 01:34:45,406
COUPLING TO EFFECTOR RESPONSES

2210
01:34:45,406 --> 01:34:46,808
IS NOT NEW.

2211
01:34:46,808 --> 01:34:48,610
WE'VE WORKED OUT DETAILS AND

2212
01:34:48,610 --> 01:34:50,445
JUST ILLUSTRATES THE IMPORTANCE

2213
01:34:50,445 --> 01:34:53,248
OF THE LEGACY OF THESE

2214
01:34:53,248 --> 01:34:54,048
REMARKABLE SCIENTISTS.

2215
01:34:54,048 --> 01:34:55,783
PHIL'S LEGACY LIVES ON IN EACH

2216
01:34:55,783 --> 01:34:58,653
OF US, IN THE WORK WE DO, THE

2217
01:34:58,653 --> 01:35:05,026
STUDENT WE TRAIN, STANDARDS WE

2218
01:35:05,026 --> 01:35:06,528
STRIVE FOR AND GOALS WE SET.

2219
01:35:06,528 --> 01:35:08,163
I COULDN'T BE MORE GRATEFUL TO

2220
01:35:08,163 --> 01:35:09,731
HIM AND HIS FIERCE DEVOTION TO

2221
01:35:09,731 --> 01:35:11,366
SCIENCE AT THE HIGHEST LEVEL.

2222
01:35:11,366 --> 01:35:12,667
THANKS, PHIL. 

2223
01:35:12,667 --> 01:35:13,101
THANK YOU.

2224
01:35:13,101 --> 01:35:15,503
[APPLAUSE]

2225
01:35:15,503 --> 01:35:21,543
 

2226
01:35:21,543 --> 01:35:31,586
 

2227
01:35:33,521 --> 01:35:38,059
>> ONE MORE TALK BEFORE
THE

2228
01:35:38,059 --> 01:35:48,303
COFFEE BREAK. 

2229
01:35:49,037 --> 01:35:51,072
THAT'S ILAN KIRSCH, PEDIATRIC

2230
01:35:51,072 --> 01:35:52,740
RESIDENCY AT CHILDREN'S HOSPITAL

2231
01:35:52,740 --> 01:35:54,275
MEDICAL CENTER IN BOSTON,

2232
01:35:54,275 --> 01:35:55,276
FELLOWSHIP IN PEDIATRIC

2233
01:35:55,276 --> 01:35:57,845
HEMATOLOGY AND ONCOLOGY AT THE

2234
01:35:57,845 --> 01:35:58,213
NCI.

2235
01:35:58,213 --> 01:36:01,382
HE THEN DID A POSTDOC WITH PHIL

2236
01:36:01,382 --> 01:36:04,018
LEDER FROM 1979 TO 1982,

2237
01:36:04,018 --> 01:36:05,320
MOLECULAR GENETICS, YOU'VE SEEN

2238
01:36:05,320 --> 01:36:08,289
HIS PICTURE TEN TIMES ALREADY,

2239
01:36:08,289 --> 01:36:10,792
IN THE LABORATORY OF PHIL AT

2240
01:36:10,792 --> 01:36:14,729
NICHD AND SPENT 20 YEARS AT NCI

2241
01:36:14,729 --> 01:36:17,632
AS BASIC RESEARCHER, ATTENDING

2242
01:36:17,632 --> 01:36:23,171
PHYSICIAN IN PEDIATRIC BRANCH 

2243
01:36:23,171 --> 01:36:25,473
ULTIMATELY CHIEF OF GENETICS

2244
01:36:25,473 --> 01:36:27,442
BRANCH, FOCUSED ON STRUCTURE AND

2245
01:36:27,442 --> 01:36:28,209
FUNCTION OF T-CELL RECEPTOR

2246
01:36:28,209 --> 01:36:31,613
GENES AND USE OF PROBES FROM

2247
01:36:31,613 --> 01:36:39,954
THESE LOCI TO STUDY 

2248
01:36:39,954 --> 01:36:41,055
CANCER-SPECIFIC GENETIC

2249
01:36:41,055 --> 01:36:43,024
INSTABILITY, IN 2005 JOINED

2250
01:36:43,024 --> 01:36:47,128
AMGEN, HEADING ONCOLOGY RESEARCH

2251
01:36:47,128 --> 01:36:52,634
GROUP IN SEATTLE, HAS BEEN A

2252
01:36:52,634 --> 01:36:53,701
CONSULTANT WITH EXTENDED

2253
01:36:53,701 --> 01:36:55,370
ASSIGNMENTS FOCUSED ON

2254
01:36:55,370 --> 01:36:57,105
DEVELOPMENT OF ANTIBODY

2255
01:36:57,105 --> 01:36:57,805
THERAPEUTICS AND MOLECULAR

2256
01:36:57,805 --> 01:37:05,847
DIAGNOSTICS. 

2257
01:37:05,847 --> 01:37:15,456
 

2258
01:37:15,456 --> 01:37:19,060
>> I WANT TO UNDERSCORE
THE

2259
01:37:19,060 --> 01:37:20,361
SENTIMENT HEARD, WHAT AN HONOR

2260
01:37:20,361 --> 01:37:23,431
AND PLEASURE IT IS TO BE INVITED

2261
01:37:23,431 --> 01:37:25,867
TO JOIN THESE COLLEAGUES AND

2262
01:37:25,867 --> 01:37:28,703
SPEAK AT THIS DEDICATION OF THE

2263
01:37:28,703 --> 01:37:31,873
FAES PHIL LEDER RESIDENCE HOUSE.

2264
01:37:31,873 --> 01:37:33,875
WHEN I WAS A POSTDOCTORAL FELLOW

2265
01:37:33,875 --> 01:37:37,545
I KNEW I WAS IN A VERY GOOD LAB.

2266
01:37:37,545 --> 01:37:40,848
BUT I ASSUMED THAT IT WAS JUST

2267
01:37:40,848 --> 01:37:43,785
ONE OF MANY VERY GOOD LABS.

2268
01:37:43,785 --> 01:37:46,287
IT WAS ONLY AFTER LEAVING THE

2269
01:37:46,287 --> 01:37:47,422
LAB AND SETTING UP A RESEARCH

2270
01:37:47,422 --> 01:37:50,692
GROUP OF MY OWN AND VISITING AND

2271
01:37:50,692 --> 01:37:52,327
MORE CLOSELY OBSERVING THE LABS

2272
01:37:52,327 --> 01:37:55,229
OF OTHERS BOTH ACADEMIC AND

2273
01:37:55,229 --> 01:37:57,265
COMMERCIAL, THAT I REALIZED HOW

2274
01:37:57,265 --> 01:38:00,535
SPECIAL WAS THE LEDER LAB.

2275
01:38:00,535 --> 01:38:02,470
IT'S BEEN REINFORCED TODAY AS

2276
01:38:02,470 --> 01:38:04,172
I'VE LISTENED TO THE SPEAKERS

2277
01:38:04,172 --> 01:38:07,075
WHO HAVE PRECEDED ME SO FAR AT

2278
01:38:07,075 --> 01:38:11,813
THIS PODIUM. 

2279
01:38:11,813 --> 01:38:15,450
AS A MEDICAL STUDENT, AND

2280
01:38:15,450 --> 01:38:19,487
RESIDENT I CAME TO KNOW STUART

2281
01:38:19,487 --> 01:38:20,888
ORKIN, THE FIRST TO SHOW ME HOW

2282
01:38:20,888 --> 01:38:22,857
TO DO A SOUTHERN BLOT.

2283
01:38:22,857 --> 01:38:24,359
WAS ACCEPTED INTO PHIL'S LAB,

2284
01:38:24,359 --> 01:38:26,294
BEFORE I LEFT BOSTON FOR

2285
01:38:26,294 --> 01:38:28,830
BETHESDA, I WAS SPEAKING WITH

2286
01:38:28,830 --> 01:38:30,765
STUART AND VOICING MY CONCERN

2287
01:38:30,765 --> 01:38:32,433
OVER WHETHER I'D BE ABLE TO

2288
01:38:32,433 --> 01:38:38,005
MEASURE UP TO THE CALIBER OF THE

2289
01:38:38,005 --> 01:38:39,640
PEOPLE IN THE LEDER LAB.

2290
01:38:39,640 --> 01:38:41,275
MANY YOU JUST HEARD SPEAK.

2291
01:38:41,275 --> 01:38:43,378
I REMEMBER DISTINCTLY THE

2292
01:38:43,378 --> 01:38:45,346
COMFORTING INSULT THAT STUART

2293
01:38:45,346 --> 01:38:55,857
GAVE ME, SAYING, DON'T WORRY,

2294
01:38:56,057 --> 01:39:00,094
LANNY, PHIL COULD GET  GOOD

2295
01:39:00,094 --> 01:39:02,063
RESEARCH OUT OF A STONE.

2296
01:39:02,063 --> 01:39:04,065
OVER THE PAST 60 YEARS

2297
01:39:04,065 --> 01:39:04,999
ACHIEVEMENTS HAVE BEEN MENTIONED

2298
01:39:04,999 --> 01:39:06,667
BY OTHER SPEAKERS.

2299
01:39:06,667 --> 01:39:12,440
MY OWN LIST IS INCOMPLETE BUT

2300
01:39:12,440 --> 01:39:13,641
STILL DESERVES LISTING IN

2301
01:39:13,641 --> 01:39:13,975
REPUTATION.

2302
01:39:13,975 --> 01:39:15,443
ANY ONE OF THESE ACCOMPLISHMENTS

2303
01:39:15,443 --> 01:39:16,744
WOULD BE REASON ENOUGH TO BRING

2304
01:39:16,744 --> 01:39:19,447
US HERE TODAY TO HONOR PHIL

2305
01:39:19,447 --> 01:39:19,981
LEDER.

2306
01:39:19,981 --> 01:39:23,050
THE FACT HE WAS ABLE TO ACHIEVE

2307
01:39:23,050 --> 01:39:25,019
THEM ALL IS SIMPLY AWE

2308
01:39:25,019 --> 01:39:25,453
INSPIRING.

2309
01:39:25,453 --> 01:39:27,088
AND ALL THE WHILE THAT HE WAS

2310
01:39:27,088 --> 01:39:31,159
DOING THIS SCIENCE HE WAS A

2311
01:39:31,159 --> 01:39:33,461
PROTOTYPE, MENTOR, AND AS FAES

2312
01:39:33,461 --> 01:39:38,032
KNOWS WELL AN INCREDIBLY SKILLED

2313
01:39:38,032 --> 01:39:38,766
EDUCATOR.

2314
01:39:38,766 --> 01:39:40,802
WHEN A PERSON FROM HIS LAB WAS

2315
01:39:40,802 --> 01:39:42,537
SCHEDULED TO GIVE A TALK, HE

2316
01:39:42,537 --> 01:39:44,305
WOULD INVITE THAT PERSON INTO

2317
01:39:44,305 --> 01:39:48,142
THE BUILDING 6  6 LIBRARY AROUND

2318
01:39:48,142 --> 01:39:50,411
HAVE HIM OR HER DELIVER THE TALK

2319
01:39:50,411 --> 01:39:54,849
WITH SLIDES TO AN AUDIENCE OF

2320
01:39:54,849 --> 01:39:55,316
ONE, PHIL.

2321
01:39:55,316 --> 01:39:58,186
HE WOULD THEN QUESTION,

2322
01:39:58,186 --> 01:39:59,821
INSTRUCT, MODIFY, AND SUGGEST

2323
01:39:59,821 --> 01:40:02,323
WAYS THAT THE PRESENTATION MIGHT

2324
01:40:02,323 --> 01:40:02,957
BE IMPROVED.

2325
01:40:02,957 --> 01:40:06,394
WHAT A PRIVILEGE TO BE ABLE TO

2326
01:40:06,394 --> 01:40:07,628
HAVE THIS ONE-ON-ONE INSTRUCTION

2327
01:40:07,628 --> 01:40:10,398
BY A MASTER IN THE ART OF

2328
01:40:10,398 --> 01:40:12,733
SCIENTIFIC PRESENTATION AND

2329
01:40:12,733 --> 01:40:13,534
PUBLIC SPEAKING.

2330
01:40:13,534 --> 01:40:15,903
I, LIKE SO MANY PEOPLE, SPEAKING

2331
01:40:15,903 --> 01:40:17,405
TODAY, WAS DIRECTLY INTRODUCED

2332
01:40:17,405 --> 01:40:21,676
TO PHIL DURING ONE OF HIS PUBLIC

2333
01:40:21,676 --> 01:40:23,644
PRESENTATIONS.

2334
01:40:23,644 --> 01:40:27,348
MY FIRST EXPOSURE WAS AT THE 

2335
01:40:27,348 --> 01:40:28,916
STILL AMAZING IN RETROSPECT COLD

2336
01:40:28,916 --> 01:40:32,854
SPRING HARBOR SYMPOSIUM ON

2337
01:40:32,854 --> 01:40:34,288
QUANTITATIVE BIOLOGY HELD IN

2338
01:40:34,288 --> 01:40:35,923
1976 ON LYMPHOCYTE DIVERSITY.

2339
01:40:35,923 --> 01:40:38,659
I REALLY CAN'T RECALL HOW I, A

2340
01:40:38,659 --> 01:40:42,063
MERE STUDENT, MANAGED TO GET

2341
01:40:42,063 --> 01:40:46,667
MYSELF INTO THAT MEETING.

2342
01:40:46,667 --> 01:40:50,271
PHIL SPOKE ON THE FINAL DAY,

2343
01:40:50,271 --> 01:40:52,340
INTRODUCING THE FOUNDATIONAL

2344
01:40:52,340 --> 01:40:54,008
PRINCIPLE OF VDJ RECOMBINATION,

2345
01:40:54,008 --> 01:41:03,284
PHIL'S TALK WAS A TOUR DU FORCE

2346
01:41:03,284 --> 01:41:05,686
PRESENTING WORK FROM HIS LAB.

2347
01:41:05,686 --> 01:41:06,487
THE AUDIENCE RECOGNIZED THE

2348
01:41:06,487 --> 01:41:07,755
IMPORTANCE OF WHAT IT WAS

2349
01:41:07,755 --> 01:41:08,756
HEARING.

2350
01:41:08,756 --> 01:41:10,691
I REMEMBER THAT JIM WATSON

2351
01:41:10,691 --> 01:41:12,426
SPECIFICALLY ASKED THAT THE TIME

2352
01:41:12,426 --> 01:41:14,228
CONSTRAINTS BE LIFTED SO THAT HE

2353
01:41:14,228 --> 01:41:17,932
COULD ASK PHIL AN ADDITIONAL

2354
01:41:17,932 --> 01:41:18,232
QUESTION.

2355
01:41:18,232 --> 01:41:21,068
A FEW YEARS AFTER THAT I WAS IN

2356
01:41:21,068 --> 01:41:22,436
PHIL'S LAB, AND A FEW YEARS

2357
01:41:22,436 --> 01:41:25,139
AFTER THAT PHIL LEFT NIH FOR

2358
01:41:25,139 --> 01:41:25,773
HARVARD.

2359
01:41:25,773 --> 01:41:27,208
ABOUT A YEAR OR SO AFTER PHIL

2360
01:41:27,208 --> 01:41:29,977
HAD LEFT THE NIH, HE WAS ASKED

2361
01:41:29,977 --> 01:41:33,381
TO RETURN TO GIVE A SPECIAL

2362
01:41:33,381 --> 01:41:35,750
NAMED LECTURESHIP, RIGHT HERE IN

2363
01:41:35,750 --> 01:41:37,618
THIS MASUR AUDITORIUM.

2364
01:41:37,618 --> 01:41:41,822
I WAS SITTING ABOUT TEN ROWS UP,

2365
01:41:41,822 --> 01:41:43,090
IN THE MIDDLE SECTION.

2366
01:41:43,090 --> 01:41:45,860
SO AS NOT TO MISS A SINGLE WORD

2367
01:41:45,860 --> 01:41:48,062
OR BIT OF DATA.

2368
01:41:48,062 --> 01:41:49,897
PHIL SHOWED A SLIDE ON THE

2369
01:41:49,897 --> 01:41:50,464
SCREEN.

2370
01:41:50,464 --> 01:41:52,500
A PICTURE OF A MOUSE.

2371
01:41:52,500 --> 01:41:56,170
PERHAPS IT WAS THIS VERY SAME

2372
01:41:56,170 --> 01:41:56,537
MOUSE.

2373
01:41:56,537 --> 01:41:59,106
FOR AT LEAST FIVE FULL MINUTES,

2374
01:41:59,106 --> 01:42:00,308
THAT MOUSE REMAINED THE ONLY

2375
01:42:00,308 --> 01:42:05,079
THING ON THE SCREEN WHILE PHIL

2376
01:42:05,079 --> 01:42:06,514
DETAILED THE STORY AND

2377
01:42:06,514 --> 01:42:08,583
IMPLICATIONS OF THE FIRST

2378
01:42:08,583 --> 01:42:08,983
ONCOMOUSE.

2379
01:42:08,983 --> 01:42:11,586
DURING THOSE MINUTES, AS THE

2380
01:42:11,586 --> 01:42:13,087
AUDIENCE SAT IN RAPT ATTENTION,

2381
01:42:13,087 --> 01:42:16,057
I FOUND MYSELF BOTH LISTENING

2382
01:42:16,057 --> 01:42:18,225
INTENTLY BUT ALSO TRYING TO

2383
01:42:18,225 --> 01:42:18,926
GLEAN ADDITIONAL PRACTICAL

2384
01:42:18,926 --> 01:42:21,362
KNOWLEDGE IN TERMS OF PUBLIC

2385
01:42:21,362 --> 01:42:22,096
SPEAKING.

2386
01:42:22,096 --> 01:42:26,233
HOW IS HE MANAGING TO DO THIS, I

2387
01:42:26,233 --> 01:42:27,234
ASKED MYSELF.

2388
01:42:27,234 --> 01:42:36,510
AS I MARVELED AT THIS EXAMPLE OF

2389
01:42:36,510 --> 01:42:41,082
ORATORY, I WAS INTERRUPTED BY A

2390
01:42:41,082 --> 01:42:42,783
STAGE WHISPER OF A PERSON BEHIND

2391
01:42:42,783 --> 01:42:43,951
ME, FOUR MINUTES IN TURNED TO

2392
01:42:43,951 --> 01:42:47,021
HIS FRIEND NEXT TO HIM AND SAID,

2393
01:42:47,021 --> 01:42:49,523
THIS GUY CAN DO ANYTHING!

2394
01:42:49,523 --> 01:42:52,393
HE COULD BE PRESIDENT!

2395
01:42:52,393 --> 01:42:53,194
[LAUGHTER]

2396
01:42:53,194 --> 01:42:56,330
YEP, EXACTLY, I THOUGHT TO

2397
01:42:56,330 --> 01:42:56,564
MYSELF.

2398
01:42:56,564 --> 01:42:59,166
I THINK THAT THE BROAD RANGE OF

2399
01:42:59,166 --> 01:43:00,468
PHIL'S SUCCESSFUL CONTRIBUTIONS

2400
01:43:00,468 --> 01:43:03,604
MAY HAVE AFFECTED ME TOO MUCH.

2401
01:43:03,604 --> 01:43:06,474
I WANTED TO EMULATE HIS REACH

2402
01:43:06,474 --> 01:43:10,544
AND GRASP, BUT REALIZED SOON 

2403
01:43:10,544 --> 01:43:11,846
ENOUGH THAT THERE WAS ONLY ONE

2404
01:43:11,846 --> 01:43:12,947
PHIL LEDER.

2405
01:43:12,947 --> 01:43:15,116
I WORRIED MY OWN RESEARCH

2406
01:43:15,116 --> 01:43:16,584
ACTIVITIES WERE TOO DIFFUSE, I

2407
01:43:16,584 --> 01:43:19,854
WAS ENVIOUS OF COLLEAGUES

2408
01:43:19,854 --> 01:43:21,389
BUILDING SCIENTIFIC UNIVERSES

2409
01:43:21,389 --> 01:43:24,458
FROM THE GROUND UP.

2410
01:43:24,458 --> 01:43:27,194
LIKE STAN KORSMEYER, DEVOTING

2411
01:43:27,194 --> 01:43:31,699
HIMSELF TO THE PROGRAMMED CELL

2412
01:43:31,699 --> 01:43:37,405
DEATH PATHWAY OR JEFF RAPHETCH

2413
01:43:37,405 --> 01:43:40,141
WITH FC RECEPTORS.

2414
01:43:40,141 --> 01:43:43,811
A THEME GOVERNED MY CAREER 

2415
01:43:43,811 --> 01:43:46,547
SPRINGING FROM MY TIME IN THE

2416
01:43:46,547 --> 01:43:48,182
LEDER LAB.

2417
01:43:48,182 --> 01:43:52,253
I'VE MADE A LIST OF INVOLVEMENTS

2418
01:43:52,253 --> 01:43:56,190
BUILT ON FOUNDATION OF GENOMIC

2419
01:43:56,190 --> 01:43:56,691
REARRANGEMENTS OF

2420
01:43:56,691 --> 01:43:59,660
IMMUNOGLOBULIN, AND T-CELL

2421
01:43:59,660 --> 01:44:01,162
RECEPTOR LOCI.

2422
01:44:01,162 --> 01:44:02,997
I THINK IF PHIL WERE LOOKING, HE

2423
01:44:02,997 --> 01:44:06,734
MIGHT THINK I HAD LEFT OUT A

2424
01:44:06,734 --> 01:44:08,769
PARTICULARLY IMPORTANT

2425
01:44:08,769 --> 01:44:09,437
INVOLVEMENT.

2426
01:44:09,437 --> 01:44:11,872
NAMELY, MY INTRODUCING HIM TO

2427
01:44:11,872 --> 01:44:15,042
THE MAGNIFICENT CYNTHIA MORTON.

2428
01:44:15,042 --> 01:44:16,343
POINT WELL TAKEN.

2429
01:44:16,343 --> 01:44:18,412
I'M GOING TO FOCUS THE NEXT PART

2430
01:44:18,412 --> 01:44:21,115
OF THIS TALK ON TWO PARTICULAR

2431
01:44:21,115 --> 01:44:21,582
SCIENTIFIC AND MEDICAL

2432
01:44:21,582 --> 01:44:22,483
APPLICATIONS OF THE WORK THAT

2433
01:44:22,483 --> 01:44:25,086
FIRST BEGAN FOR ME IN PHIL'S

2434
01:44:25,086 --> 01:44:25,286
LAB.

2435
01:44:25,286 --> 01:44:29,223
OF COURSE, IT BEGINS WITH THE

2436
01:44:29,223 --> 01:44:30,558
FOUNDATIONAL DIAGRAM THAT YOU

2437
01:44:30,558 --> 01:44:32,526
SAW MANY TIMES THAT SUMMARIZE

2438
01:44:32,526 --> 01:44:41,836
RESOLUTION OF THE QUESTION OF

2439
01:44:41,836 --> 01:44:45,206
THE ORIGIN OF LYMPHOCYTE

2440
01:44:45,206 --> 01:44:47,475
DIVERSITY, EXISTING IN OUR

2441
01:44:47,475 --> 01:44:50,478
GERMLINE DNA AS DISCRETE

2442
01:44:50,478 --> 01:45:01,021
DISCONTIGUOUS SEGMENTS, VARIABLE

2443
01:45:03,124 --> 01:45:04,825
FOR SOME LOCI.

2444
01:45:04,825 --> 01:45:12,566
THERE IS RANDOM  ASSORTMENT THAT

2445
01:45:12,566 --> 01:45:13,868
PREVIOUSLY RANDOM ASSORTED WITH

2446
01:45:13,868 --> 01:45:18,706
Js TO FORM A NOW CONTIGUOUS

2447
01:45:18,706 --> 01:45:20,341
VDJ REGION.

2448
01:45:20,341 --> 01:45:24,278
THE SEQUENCE CREATED BY THESE

2449
01:45:24,278 --> 01:45:28,115
REARRANGEMENTS FORMS

2450
01:45:28,115 --> 01:45:31,719
HYPERVARIABLE REGION 3 OR CDR 3

2451
01:45:31,719 --> 01:45:33,387
PART OF IMMUNOGLOBULIN OR T-CELL

2452
01:45:33,387 --> 01:45:33,654
RECEPTOR.

2453
01:45:33,654 --> 01:45:37,958
THE PART OF THE MOLECULE MOST

2454
01:45:37,958 --> 01:45:43,230
RESPONSIBLE FOR SPECIFICITY. 

2455
01:45:43,230 --> 01:45:44,398
THIS RECONFIGURATION OF GENOMIC

2456
01:45:44,398 --> 01:45:47,401
DNA CREATES A SPECIFIC MARKER OF

2457
01:45:47,401 --> 01:45:49,236
EACH LYMPHOCYTE THAT HAS REACHED

2458
01:45:49,236 --> 01:45:51,372
THE DEVELOPMENTAL STAGE WHERE

2459
01:45:51,372 --> 01:45:58,779
THIS RANDOM ASSORTMENT AND 

2460
01:45:58,779 --> 01:46:01,248
RE-LIGATION OCCURS, THIS WAS

2461
01:46:01,248 --> 01:46:02,449
RECOGNIZED IN AND ELUCIDATED BY

2462
01:46:02,449 --> 01:46:03,984
PHIL IN THE LABORATORY BUT IN

2463
01:46:03,984 --> 01:46:07,388
ORDER FOR IT TO ACHIEVE ITS

2464
01:46:07,388 --> 01:46:09,223
CURRENT LEVEL OF PRACTICAL

2465
01:46:09,223 --> 01:46:10,591
APPLICATION, THREE BROAD STREAMS

2466
01:46:10,591 --> 01:46:13,093
OF KNOWLEDGE NEEDED TO BE

2467
01:46:13,093 --> 01:46:14,461
BROUGHT TOGETHER.

2468
01:46:14,461 --> 01:46:15,496
THE ORIGIN OF LYMPHOCYTE

2469
01:46:15,496 --> 01:46:18,465
DIVERSITY THAT I'VE JUST

2470
01:46:18,465 --> 01:46:19,099
DESCRIBED, MARKED IMPROVEMENTS

2471
01:46:19,099 --> 01:46:22,269
IN THE COST AND EFFICIENCY OF

2472
01:46:22,269 --> 01:46:24,672
DNA SEQUENCING, AND THE

2473
01:46:24,672 --> 01:46:27,341
COMPUTATIONAL ABILITY TO HANDLE

2474
01:46:27,341 --> 01:46:29,276
ENORMOUS AMOUNTS OF DATA.

2475
01:46:29,276 --> 01:46:32,546
THIS HAS RESULTED IN A PRACTICAL

2476
01:46:32,546 --> 01:46:35,950
SCALABLE AND ENORMOUSLY

2477
01:46:35,950 --> 01:46:36,750
INFORMATION RICH

2478
01:46:36,750 --> 01:46:39,386
IMMUNOSEQUENCING PROCESS, SHOWN

2479
01:46:39,386 --> 01:46:40,321
HERE.

2480
01:46:40,321 --> 01:46:42,289
IN WHICH FOUR PRIMERS RECOGNIZE

2481
01:46:42,289 --> 01:46:45,025
EACH AND EVERY KNOWN V SEGMENT

2482
01:46:45,025 --> 01:46:49,530
AND REVERSE PRIMERS  RECOGNIZE

2483
01:46:49,530 --> 01:46:50,965
EVERY J SEGMENT FOR THE SAME

2484
01:46:50,965 --> 01:46:52,600
LOCUS, APPLIED TO DNA EXTRACTED

2485
01:46:52,600 --> 01:46:56,871
FROM ANY SAMPLE OF INTEREST, AND

2486
01:46:56,871 --> 01:46:59,607
AMPLIFICATION OCCURS ACROSS THAT

2487
01:46:59,607 --> 01:47:02,243
HIGHLY SPECIFIC CDR 3 REGION FOR

2488
01:47:02,243 --> 01:47:05,312
EACH AND EVERY B OR T CELL

2489
01:47:05,312 --> 01:47:08,215
PRESENT IN THE SAMPLE.

2490
01:47:08,215 --> 01:47:09,650
ALL AMPLIFIED MOLECULES ARE THEN

2491
01:47:09,650 --> 01:47:11,185
SEQUENCED.

2492
01:47:11,185 --> 01:47:13,487
THE NUMBER OF UNIQUE CDR 3s

2493
01:47:13,487 --> 01:47:14,622
CORRELATES WITH NUMBER OF UNIQUE

2494
01:47:14,622 --> 01:47:17,992
B OR T CELLS PRESENT IN THE

2495
01:47:17,992 --> 01:47:18,525
SAMPLE.

2496
01:47:18,525 --> 01:47:21,996
THE NUMBER OF TIMES ANY GIVEN

2497
01:47:21,996 --> 01:47:23,564
CDR 3 SEQUENCE IS SEEN

2498
01:47:23,564 --> 01:47:26,200
CORRELATES WITH THE SIZE OF THAT

2499
01:47:26,200 --> 01:47:29,336
B OR T CELL CLONE WITHIN THAT

2500
01:47:29,336 --> 01:47:29,570
SAMPLE.

2501
01:47:29,570 --> 01:47:32,306
EVERY TIME THE ASSAY IS RUN,

2502
01:47:32,306 --> 01:47:33,407
MORE INFORMATION IS GENERATED

2503
01:47:33,407 --> 01:47:36,143
THAN WAS GENERATED FOR THE FIRST

2504
01:47:36,143 --> 01:47:38,746
HUMAN GENOME SEQUENCE PROJECT.

2505
01:47:38,746 --> 01:47:41,682
AND THAT INFORMATION IS NOT

2506
01:47:41,682 --> 01:47:41,916
STATIC.

2507
01:47:41,916 --> 01:47:43,250
IT CHANGES OVER TIME, DEPENDING

2508
01:47:43,250 --> 01:47:46,520
ON WHAT ANTIGENS OR PATHOGENS AN

2509
01:47:46,520 --> 01:47:48,656
INDIVIDUAL ENCOUNTERS, OR FOR

2510
01:47:48,656 --> 01:47:51,792
THAT MATTER IF A PERSON DEVELOPS

2511
01:47:51,792 --> 01:47:53,961
A LYMPHOID MALIGNANCY.

2512
01:47:53,961 --> 01:47:55,829
SO, FOR EXAMPLE, IF APPLIED TO

2513
01:47:55,829 --> 01:47:58,565
BONE MARROW OF A HEALTHY

2514
01:47:58,565 --> 01:48:00,768
INDIVIDUAL, THE ENTIRE IMMUNE

2515
01:48:00,768 --> 01:48:02,403
REPERTOIRE OF THAT SAMPEL IS

2516
01:48:02,403 --> 01:48:04,738
PROFILED BUT NO ONE SEQUENCE OR

2517
01:48:04,738 --> 01:48:06,206
SEQUENCES STANDS OUT HIGH ABOVE

2518
01:48:06,206 --> 01:48:09,510
THE FREQUENCIES OF THE BULK

2519
01:48:09,510 --> 01:48:09,944
REPERTOIRE.

2520
01:48:09,944 --> 01:48:13,347
IN CONTRAST, IN A PATIENT WITH

2521
01:48:13,347 --> 01:48:15,950
LEUKEMIA LYMPHOMA OR MYELOMA,

2522
01:48:15,950 --> 01:48:16,850
BECAUSE OF THE DYSREGULATED

2523
01:48:16,850 --> 01:48:19,787
GROWTH OF THAT PARTICULAR CLONE,

2524
01:48:19,787 --> 01:48:22,790
THE CDR 3 SEQUENCE OR SEQUENCES

2525
01:48:22,790 --> 01:48:26,226
THAT RESIDE WITHIN THAT CLONE

2526
01:48:26,226 --> 01:48:27,328
ARE HIGHLY OVERREPRESENTED.

2527
01:48:27,328 --> 01:48:29,730
THAT SEQUENCE CAN THEN BE TAGGED

2528
01:48:29,730 --> 01:48:30,831
FOR SUBSEQUENT TRACKING DURING

2529
01:48:30,831 --> 01:48:34,234
THAT PATIENT'S COURSE OF

2530
01:48:34,234 --> 01:48:36,403
THERAPY, PROVIDING A DIRECT

2531
01:48:36,403 --> 01:48:38,372
DETERMINATION OF MEASURABLE

2532
01:48:38,372 --> 01:48:39,907
RESIDUAL DISEASE, MRD, IN THAT

2533
01:48:39,907 --> 01:48:40,574
PATIENT.

2534
01:48:40,574 --> 01:48:43,610
THIS IS THE BASIS FOR WHAT IS

2535
01:48:43,610 --> 01:48:47,047
NOW THE ONE AND ONLY FDA CLEARED

2536
01:48:47,047 --> 01:48:51,719
ASSAY IN PATIENTS WITH LYMPHOID

2537
01:48:51,719 --> 01:48:53,153
LEUKEMIA AND MYELOMA.

2538
01:48:53,153 --> 01:48:55,022
AT DIAGNOSIS, A HIGH TUMOR

2539
01:48:55,022 --> 01:48:55,789
BURDEN SAMPLE WAS RECEIVED,

2540
01:48:55,789 --> 01:48:58,726
REPORT LIKE THIS ONE IS

2541
01:48:58,726 --> 01:48:58,993
GENERATED.

2542
01:48:58,993 --> 01:49:01,395
THE NUMBER OF DOMINANT IMMUNE

2543
01:49:01,395 --> 01:49:02,596
RECEPTORS SEQUENCES RESIDING

2544
01:49:02,596 --> 01:49:05,432
WITHIN THE CLONE OF INTEREST ARE

2545
01:49:05,432 --> 01:49:05,733
ENUMERATED.

2546
01:49:05,733 --> 01:49:06,533
EACH DOMINANT SEQUENCE IS

2547
01:49:06,533 --> 01:49:10,237
PRESENTED ALONG WITH FREQUENCY

2548
01:49:10,237 --> 01:49:11,305
OF THAT SEQUENCE FOR TOTAL

2549
01:49:11,305 --> 01:49:14,408
NUCLEATED CELLS PRESENT IN THE

2550
01:49:14,408 --> 01:49:14,875
SAMPLE.

2551
01:49:14,875 --> 01:49:16,710
SAMPLE CLONALITY, NUMBER OF

2552
01:49:16,710 --> 01:49:20,314
UNIQUE CDR 3s, TOTAL NUMBER OF

2553
01:49:20,314 --> 01:49:21,415
CDRs 3 WHICH PROVIDES ESTIMATE

2554
01:49:21,415 --> 01:49:23,250
MUCH TOTAL NUMBER OF B OR T

2555
01:49:23,250 --> 01:49:27,755
CELLS IN THE SAMPLE ARE ALL

2556
01:49:27,755 --> 01:49:28,255
PROVIDED.

2557
01:49:28,255 --> 01:49:29,356
IF SOMATIC HYPERMUTATION IS

2558
01:49:29,356 --> 01:49:32,226
PRESENT IT IS NOTED, AND THE

2559
01:49:32,226 --> 01:49:35,829
SPECIFIC V SEGMENT INVOLVED IS

2560
01:49:35,829 --> 01:49:36,196
DEFINED.

2561
01:49:36,196 --> 01:49:38,565
IN SUBSEQUENT SAMPLES, THE

2562
01:49:38,565 --> 01:49:40,100
ENTIRE REPERTOIRE AGAIN IS

2563
01:49:40,100 --> 01:49:41,735
PROFILED, BUT THE SPECIFIC

2564
01:49:41,735 --> 01:49:44,238
SEQUENCE OR SEQUENCES IDENTIFIED

2565
01:49:44,238 --> 01:49:46,340
AS DOMINANT AT DIAGNOSIS ARE

2566
01:49:46,340 --> 01:49:52,246
SEARCHED FOR AND REPORTED, AS AN

2567
01:49:52,246 --> 01:49:54,348
INTEGER VALUE PER ONE MILLION

2568
01:49:54,348 --> 01:49:55,416
NUCLEATED CELLS, CLINICAL

2569
01:49:55,416 --> 01:49:56,850
REPORTS SENT TO ANY HEALTH CARE

2570
01:49:56,850 --> 01:49:58,485
PROVIDER WHO ORDERS THESE

2571
01:49:58,485 --> 01:50:00,988
CLONALITY AND TRACKING TESTS.

2572
01:50:00,988 --> 01:50:04,024
NOW HAVING ASSISTED IN CLINICAL

2573
01:50:04,024 --> 01:50:05,292
MANAGEMENT OF OVER 50,000

2574
01:50:05,292 --> 01:50:07,428
INDIVIDUAL PATIENTS, AND

2575
01:50:07,428 --> 01:50:09,430
HUNDREDS OF CLINICAL TRIALS.

2576
01:50:09,430 --> 01:50:11,398
INCREDIBLY INFORMATION RICH AND

2577
01:50:11,398 --> 01:50:13,367
FILLED WITH ADDITIONAL POSSIBLE

2578
01:50:13,367 --> 01:50:14,268
MEDICAL AND BIOLOGICAL INSIGHTS

2579
01:50:14,268 --> 01:50:18,505
OF WHICH WE'RE JUST BECOMING

2580
01:50:18,505 --> 01:50:18,939
AWARE.

2581
01:50:18,939 --> 01:50:21,341
THE SAME FUNDAMENTAL ASSAY CAN

2582
01:50:21,341 --> 01:50:22,776
BE EXTENDED TO ANY SITUATION IN

2583
01:50:22,776 --> 01:50:24,978
WHICH THE IMMUNE RESPONSE PLAYS

2584
01:50:24,978 --> 01:50:27,581
A ROLE, FOR LEUKEMIA LYMPHOMA

2585
01:50:27,581 --> 01:50:29,683
AND MYELOMA THE SEQUENCES FIND

2586
01:50:29,683 --> 01:50:30,017
US.

2587
01:50:30,017 --> 01:50:33,720
FOR OTHER SITUATIONS WE FIND THE

2588
01:50:33,720 --> 01:50:34,188
SEQUENCES THROUGH TWO

2589
01:50:34,188 --> 01:50:40,961
APPROACHES, ONE OF WHICH IS THE

2590
01:50:40,961 --> 01:50:43,597
REALIZATION OF ASPIRATION GOAL

2591
01:50:43,597 --> 01:50:46,633
SINCE VDJ RECOMBINATION WAS

2592
01:50:46,633 --> 01:50:50,137
REFINED, LINKAGE OF A SPECIFIC

2593
01:50:50,137 --> 01:50:51,138
T-CELL RECEPTOR NUCLEOTIDE

2594
01:50:51,138 --> 01:50:53,740
SEQUENCED TO THE TARGET OF THE T

2595
01:50:53,740 --> 01:50:57,578
CELL WITHIN WHICH THAT RECEPTOR

2596
01:50:57,578 --> 01:50:59,446
IS ENCODED.

2597
01:50:59,446 --> 01:51:04,685
THE METHODOLOGY OF  OF THE

2598
01:51:04,685 --> 01:51:08,722
APPROACH IS STRAIGHTFORWARD. 

2599
01:51:08,722 --> 01:51:10,157
T CELLS ARE ALIQUOTED AND

2600
01:51:10,157 --> 01:51:11,892
EXPOSED TO POOLS OF ANTIGEN

2601
01:51:11,892 --> 01:51:14,761
THROUGH PEPTIDE PULSING OR

2602
01:51:14,761 --> 01:51:18,132
TRANSFECTION, AND ENDOGENOUS

2603
01:51:18,132 --> 01:51:19,133
PRESENTATION BY

2604
01:51:19,133 --> 01:51:20,334
ANTIGEN-PRESENTING CELLS.

2605
01:51:20,334 --> 01:51:22,503
EACH ANTIGEN HAS A DISTINCT SET

2606
01:51:22,503 --> 01:51:25,139
OF WELL ADDRESSES ON THE

2607
01:51:25,139 --> 01:51:27,241
EXPERIMENTAL PLATE.

2608
01:51:27,241 --> 01:51:28,742
AFTER INCUBATION, CELLS FROM

2609
01:51:28,742 --> 01:51:31,378
EACH WELL ARE SORTED FOR

2610
01:51:31,378 --> 01:51:34,548
ACTIVATION MARKERS, AND THEN

2611
01:51:34,548 --> 01:51:35,215
SEQUENCED.

2612
01:51:35,215 --> 01:51:39,153
AND ACTIVATION MARKER POSITIVE

2613
01:51:39,153 --> 01:51:43,557
REPERTOIRES ARE DELINEATED

2614
01:51:43,557 --> 01:51:44,625
THROUGH DECONVOLUTION PROCESS,

2615
01:51:44,625 --> 01:51:46,226
RESPONDING TO, FOR EXAMPLE,

2616
01:51:46,226 --> 01:51:47,895
ANTIGEN 1 CAN BE DISTINGUISHED

2617
01:51:47,895 --> 01:51:50,664
FROM THOSE RESPONDING TO

2618
01:51:50,664 --> 01:51:53,400
ANTIGENS 2 OR 3, AND ALL OF

2619
01:51:53,400 --> 01:51:57,037
THOSE DISTINGUISHED FROM ANY

2620
01:51:57,037 --> 01:51:59,606
BACKGROUND NON-SPECIFIC

2621
01:51:59,606 --> 01:52:00,307
RESPONDING CELLS.

2622
01:52:00,307 --> 01:52:02,609
HUNDREDS OF T-CELL RECEPTORS

2623
01:52:02,609 --> 01:52:05,546
RESPONDING TO THOUSANDS OF

2624
01:52:05,546 --> 01:52:07,314
EPITOPES FROM VIRUSES,

2625
01:52:07,314 --> 01:52:08,081
AUTOIMMUNE ANTIGENS,

2626
01:52:08,081 --> 01:52:09,449
TUMOR-SPECIFIC ANTIGENS HAVE NOW

2627
01:52:09,449 --> 01:52:11,051
BEEN IDENTIFIED.

2628
01:52:11,051 --> 01:52:16,323
FOR EXAMPLE, EARLY ON IN THE 

2629
01:52:16,323 --> 01:52:22,229
DEVELOPMENT AN  ANALYSIS WAS

2630
01:52:22,229 --> 01:52:23,430
DONE AND PERFORMED AND PUBLISHED

2631
01:52:23,430 --> 01:52:24,965
BY THIS GROUP.

2632
01:52:24,965 --> 01:52:26,900
RESULTS OF T-CELL RECEPTOR

2633
01:52:26,900 --> 01:52:28,468
IDENTIFICATION OF THESE EPITOPES

2634
01:52:28,468 --> 01:52:30,637
FROM ONE ROUND OF MIRA FROM A

2635
01:52:30,637 --> 01:52:33,907
SINGLE PATIENT IS SHOWN HERE.

2636
01:52:33,907 --> 01:52:36,543
THE TUMOR ASSOCIATED GENES ARE

2637
01:52:36,543 --> 01:52:40,914
SHOWN IN DIFFERENT COLORS ON THE

2638
01:52:40,914 --> 01:52:42,249
X-AXIS WITH DIFFERENT EPITOPES

2639
01:52:42,249 --> 01:52:44,851
IN SEPARATE COLUMNS, EACH POINT

2640
01:52:44,851 --> 01:52:47,054
REPRESENTS A T-CELL RECEPTOR

2641
01:52:47,054 --> 01:52:49,556
ENRICHED BY EXPOSURE TO A

2642
01:52:49,556 --> 01:52:50,324
SPECIFIC EPITOPE.

2643
01:52:50,324 --> 01:52:52,960
AS THE EXPERIMENT IS REPEATED,

2644
01:52:52,960 --> 01:52:54,795
ADDITIONAL DONORS ARE ADDED AND

2645
01:52:54,795 --> 01:52:56,563
DONORS OF DIFFERENT HLA TYPES

2646
01:52:56,563 --> 01:52:58,865
ARE INCLUDED AND PATTERN OF

2647
01:52:58,865 --> 01:53:00,300
PUBLIC AND PRIVATE T-CELL

2648
01:53:00,300 --> 01:53:02,569
RESPONSES BECOMES MORE AND MORE

2649
01:53:02,569 --> 01:53:03,036
ROBUST.

2650
01:53:03,036 --> 01:53:05,138
THIS PROVIDES A MUCH MORE

2651
01:53:05,138 --> 01:53:06,106
ACCURATE AND SENSITIVE APPROACH

2652
01:53:06,106 --> 01:53:09,176
THAN ANY OTHER METHOD OF LINKAGE

2653
01:53:09,176 --> 01:53:10,677
OF T CELL TO TARGET.

2654
01:53:10,677 --> 01:53:12,579
ADDING TO THIS CAPABILITY IS THE

2655
01:53:12,579 --> 01:53:14,348
WELL KNOWN DESIGN OF CASE

2656
01:53:14,348 --> 01:53:16,083
CONTROL STUDIES.

2657
01:53:16,083 --> 01:53:19,353
IF WE CAN DEFINE A POPULATION

2658
01:53:19,353 --> 01:53:21,555
WITH A PARTICULAR EXPOSURE, FOR

2659
01:53:21,555 --> 01:53:23,757
EXAMPLE A RECENT POSITIVE PCR

2660
01:53:23,757 --> 01:53:25,726
TEST TO SARS-COV-2, AND HAVE A

2661
01:53:25,726 --> 01:53:26,827
CONTROL POPULATION FOR WHICH

2662
01:53:26,827 --> 01:53:30,097
WE'RE QUITE CERTAIN THERE WAS NO

2663
01:53:30,097 --> 01:53:32,065
EXPOSURE, FOR EXAMPLE SAMPLES IN

2664
01:53:32,065 --> 01:53:34,801
THE DATABASE PRIOR TO 2019, THEN

2665
01:53:34,801 --> 01:53:37,004
WE CAN INTERROGATE T CELL

2666
01:53:37,004 --> 01:53:38,972
REPERTOIRES FROM THE TWO

2667
01:53:38,972 --> 01:53:41,275
POPULATIONS AND EXTRACT A

2668
01:53:41,275 --> 01:53:42,376
CLASSIFIER SET OF T-CELL

2669
01:53:42,376 --> 01:53:44,111
RECEPTORS THAT IDENTIFY THOSE

2670
01:53:44,111 --> 01:53:45,579
WHO HAVE BEEN EXPOSED.

2671
01:53:45,579 --> 01:53:48,282
THE BULK OF THE RESPONSE FOR ANY

2672
01:53:48,282 --> 01:53:49,983
INDIVIDUAL WILL BE PRIVATE.

2673
01:53:49,983 --> 01:53:52,185
OCCURRING ONLY WITHIN THAT

2674
01:53:52,185 --> 01:53:52,953
INDIVIDUAL.

2675
01:53:52,953 --> 01:53:55,055
HOWEVER, THERE ARE ENOUGH SHARED

2676
01:53:55,055 --> 01:53:56,890
RECEPTORS AND MORE WITH

2677
01:53:56,890 --> 01:54:02,696
INCLUSION OF DIFFERENT HLA

2678
01:54:02,696 --> 01:54:06,967
TYPES, THIS WAS THE BASIC FOR

2679
01:54:06,967 --> 01:54:09,269
DIAGNOSTICS THAT RECEIVED

2680
01:54:09,269 --> 01:54:16,476
EMERGENCY USE AUTHORITIATION 

2681
01:54:16,476 --> 01:54:17,778
AUTHORIZATION EARLY IN THE

2682
01:54:17,778 --> 01:54:21,415
PANDEMIC, IT TOOK LESS THAN TEN

2683
01:54:21,415 --> 01:54:21,748
MONTHS.

2684
01:54:21,748 --> 01:54:24,051
WHEN THE MIRA ASSAY IS COMBINED,

2685
01:54:24,051 --> 01:54:26,653
EVEN GREATER POWER IS ACHIEVED.

2686
01:54:26,653 --> 01:54:29,489
WE CAN DISSECT A DIFFERENTIAL

2687
01:54:29,489 --> 01:54:31,458
IMMUNOGENICITY OF DELTA OR

2688
01:54:31,458 --> 01:54:33,427
OMICRON COVID VARIANTS AND KNOW

2689
01:54:33,427 --> 01:54:35,295
PRECISELY WHICH T CELLS WILL

2690
01:54:35,295 --> 01:54:37,931
STILL RECOGNIZE A NEW EMERGENT

2691
01:54:37,931 --> 01:54:39,333
VIRUS, WE CAN DISTINGUISH T

2692
01:54:39,333 --> 01:54:41,301
CELLS THAT RECOGNIZE THE SPIKE

2693
01:54:41,301 --> 01:54:43,236
FROM NON-SPIKE PARTS OF THE

2694
01:54:43,236 --> 01:54:45,772
VIRAL GENOME, AND IN SO DOING

2695
01:54:45,772 --> 01:54:47,407
DISTINGUISH VACCINE RESPONSE

2696
01:54:47,407 --> 01:54:50,410
FROM RESPONSES DUE TO ENDOGENOUS

2697
01:54:50,410 --> 01:54:50,811
INFECTION.

2698
01:54:50,811 --> 01:54:52,279
THESE EXAMPLES THAT I PROVIDED

2699
01:54:52,279 --> 01:54:57,084
ARE JUST A SNAPSHOT OF THE POWER

2700
01:54:57,084 --> 01:54:59,920
OF IMMUNOSEQUENCING, THE ABILITY

2701
01:54:59,920 --> 01:55:01,788
TO ENUMERATE, SPECIFY, QUANTIFY

2702
01:55:01,788 --> 01:55:03,657
EACH AND EVERY B AND/OR T CELL

2703
01:55:03,657 --> 01:55:06,827
IN ANY SAMPLE OF INTEREST.

2704
01:55:06,827 --> 01:55:11,465
IT REINFORCES THE FUNDAMENTAL

2705
01:55:11,465 --> 01:55:16,837
REALIZATION THE IMMUNE SYSTEM IS

2706
01:55:16,837 --> 01:55:18,572
AN EVOLUTIONARY MARVEL AND

2707
01:55:18,572 --> 01:55:20,540
IMMUNOSEQUENCING OFFERS A

2708
01:55:20,540 --> 01:55:21,675
SPECIFIC STANDARDIZED AND

2709
01:55:21,675 --> 01:55:27,514
SENSITIVE METHOD FOR 

2710
01:55:27,514 --> 01:55:28,715
DETERMINATION, PROVIDES

2711
01:55:28,715 --> 01:55:30,283
CLASSIFIERS FOR EVALUATION OF

2712
01:55:30,283 --> 01:55:32,686
IMMUNE RESPONSIVENESS TO

2713
01:55:32,686 --> 01:55:34,221
SPECIFIC ANTIGENS AND PATHOGENS,

2714
01:55:34,221 --> 01:55:35,088
HIGH-THROUGHPUT AND SCALABLE

2715
01:55:35,088 --> 01:55:37,858
PROCESS IS NOW AVAILABLE FOR

2716
01:55:37,858 --> 01:55:39,359
LINKING A T-CELL RECEPTOR

2717
01:55:39,359 --> 01:55:41,561
NUCLEOTIDE SEQUENCED TO TARGET

2718
01:55:41,561 --> 01:55:44,631
OF THE RECEPTOR THAT SEQUENCE

2719
01:55:44,631 --> 01:55:47,634
ENCODES, IMMUNOSEQUENCING LEADS

2720
01:55:47,634 --> 01:55:50,270
TO SPECIFIC IMMUNOGLOBULIN AND T

2721
01:55:50,270 --> 01:55:50,670
CELL THERAPEUTICS.

2722
01:55:50,670 --> 01:55:53,940
IMMUNE REPERTOIRE IS A DIARY,

2723
01:55:53,940 --> 01:55:55,342
IMMUNE RECEPTOR PROFILING CAN

2724
01:55:55,342 --> 01:55:58,178
PROVIDE INSIGHT INTO ONCOLOGY,

2725
01:55:58,178 --> 01:55:59,780
INFECTIOUS DISEASE,

2726
01:55:59,780 --> 01:56:02,149
AUTOIMMUNITY, AGING, ET CETERA.

2727
01:56:02,149 --> 01:56:03,283
I WANT TO CONCLUDE BY RETURNING

2728
01:56:03,283 --> 01:56:05,419
TO WHERE MY PERSONAL STORY WITH

2729
01:56:05,419 --> 01:56:07,053
PHIL BEGAN.

2730
01:56:07,053 --> 01:56:08,922
YOU'VE SEEN THIS PICTURE MANY

2731
01:56:08,922 --> 01:56:09,256
TIMES.

2732
01:56:09,256 --> 01:56:11,124
THIS IS A PICTURE OF PHIL FROM

2733
01:56:11,124 --> 01:56:15,695
AROUND THE TIME OF THAT COLD

2734
01:56:15,695 --> 01:56:17,330
SPRING HARBOR SYMPOSIUM I

2735
01:56:17,330 --> 01:56:18,165
MENTIONED EARLIER.

2736
01:56:18,165 --> 01:56:20,400
IN CASE IT'S NOT APPARENT SO

2737
01:56:20,400 --> 01:56:22,836
FAR, NOTE THE DIAGRAM ON THE

2738
01:56:22,836 --> 01:56:23,637
BOARD BEHIND HIM.

2739
01:56:23,637 --> 01:56:26,106
I WISH THAT PHIL COULD BE HERE

2740
01:56:26,106 --> 01:56:28,275
TO BE ACKNOWLEDGED FOR THE

2741
01:56:28,275 --> 01:56:29,976
PROGRESS THAT HAS BEEN MADE IN

2742
01:56:29,976 --> 01:56:33,013
THE APPLICATION OF THE

2743
01:56:33,013 --> 01:56:34,681
FOUNDATIONAL PRINCIPLES OF VDJ

2744
01:56:34,681 --> 01:56:36,750
RECOMBINATION TO BIOLOGY AND

2745
01:56:36,750 --> 01:56:37,384
MEDICINE.

2746
01:56:37,384 --> 01:56:38,919
I'M SURE HE WOULD REFLECT THAT

2747
01:56:38,919 --> 01:56:40,787
WE'VE ONLY SCRATCHED THE SURFACE

2748
01:56:40,787 --> 01:56:43,557
OF THE IMPLICATIONS AND

2749
01:56:43,557 --> 01:56:45,258
APPLICATIONS OF THIS PROCESS.

2750
01:56:45,258 --> 01:56:47,627
I WISH THAT IN PREPARATION FOR

2751
01:56:47,627 --> 01:56:49,329
THIS TALK, I MIGHT HAVE ONCE

2752
01:56:49,329 --> 01:56:51,565
AGAIN BEEN AT THE PODIUM IN THE

2753
01:56:51,565 --> 01:56:53,467
LIBRARY OF BUILDING 6 WITH PHIL

2754
01:56:53,467 --> 01:56:56,203
SEATED BY HIMSELF NO MORE THAN

2755
01:56:56,203 --> 01:56:58,271
TEN FEET AWAY, STOPPING ME TO

2756
01:56:58,271 --> 01:57:01,808
SUGGEST A BETTER SLIDE TO SHOW

2757
01:57:01,808 --> 01:57:03,643
OR PHRASE TO USE.

2758
01:57:03,643 --> 01:57:05,812
FOR YOU ALL, IT WOULD HAVE MADE

2759
01:57:05,812 --> 01:57:07,714
THE PAST 20 MINUTES MORE

2760
01:57:07,714 --> 01:57:09,449
ENJOYABLE AND INSTRUCTIVE.

2761
01:57:09,449 --> 01:57:12,185
IT WOULD ALSO HAVE PROVIDED ME

2762
01:57:12,185 --> 01:57:13,186
WITH ADDITIONAL INSIGHTS AND

2763
01:57:13,186 --> 01:57:15,689
UNDERSTANDING OF MY OWN WORK AND

2764
01:57:15,689 --> 01:57:17,657
THE WORK OF OTHERS, INSIGHTS

2765
01:57:17,657 --> 01:57:20,660
THAT FRUSTRATINGLY I MAY NOW

2766
01:57:20,660 --> 01:57:21,595
NEVER REALIZE.

2767
01:57:21,595 --> 01:57:24,231
I WANT, AGAIN, TO THANK THE FAES

2768
01:57:24,231 --> 01:57:25,899
FOR ITS RECOGNITION AND TRIBUTE

2769
01:57:25,899 --> 01:57:28,401
TO PHIL IN THE BUILDING THAT NOW

2770
01:57:28,401 --> 01:57:30,470
IS DEDICATED TO HIM, AND THANK

2771
01:57:30,470 --> 01:57:33,874
YOU ALL FOR ALLOWING ME TO SHARE

2772
01:57:33,874 --> 01:57:34,374
MY RECOLLECTIONS AND

2773
01:57:34,374 --> 01:57:35,642
PERSPECTIVE.

2774
01:57:35,642 --> 01:57:37,043
[APPLAUSE]

2775
01:57:37,043 --> 01:57:43,049
 

2776
01:57:43,049 --> 01:57:50,924
 

2777
01:57:50,924 --> 01:57:52,158
>> THANK YOU.

2778
01:57:52,158 --> 01:57:54,094
WE'LL TAKE A TEN-MINUTE BREAK.

2779
01:57:54,094 --> 01:57:56,730
PLEASE ONLY TAKE TEN MINUTES AND

2780
01:57:56,730 --> 01:57:57,631
BE BACK AT 11:41.

2781
01:57:57,631 --> 01:58:03,213
THANK YOU.

2782
01:58:03,213 --> 01:58:05,982
OUR NEXT SPEAKER IS KATHLEEN

2783
01:58:05,982 --> 01:58:09,019
KELLY, WHO IS A DEPUTY

2784
01:58:09,019 --> 01:58:10,654
SCIENTIFIC DIRECTOR, CENTER FOR

2785
01:58:10,654 --> 01:58:12,455
CANCER RESEARCH, AND CHIEF OF

2786
01:58:12,455 --> 01:58:18,728
THE LABORATORY OF , RECEIVED A

2787
01:58:18,728 --> 01:58:20,130
Ph.D. IN CELLULAR IMMUNOLOGY

2788
01:58:20,130 --> 01:58:25,635
FROM UNIVERSITY OF CALIFORNIA

2789
01:58:25,635 --> 01:58:28,405
IRVINE, JOINED THE LEDER LAB AT

2790
01:58:28,405 --> 01:58:31,241
HARVARD MEDICAL SCHOOL, WHILE IN

2791
01:58:31,241 --> 01:58:33,510
THE LAB KATHY MET AND MARRIED

2792
01:58:33,510 --> 01:58:36,813
ANOTHER POSTDOCTORAL FELLOW IN

2793
01:58:36,813 --> 01:58:42,585
THE LEDER LAB, AFTER COMPLETING

2794
01:58:42,585 --> 01:58:49,259
THEIR POSTDOCTORAL TRAINING BOTH

2795
01:58:49,259 --> 01:58:52,629
ESTABLISHED PROGRAMS AT NIH AND

2796
01:58:52,629 --> 01:58:55,832
NIAID AT NIH, DR. STEPHEN LIST

2797
01:58:55,832 --> 01:58:59,569
WHO STUDIED THE NF-kappaB

2798
01:58:59,569 --> 01:59:01,838
FAMILY OF TRANSCRIPTION FACTORS

2799
01:59:01,838 --> 01:59:03,406
PASSED AWAY FROM PANCREATIC

2800
01:59:03,406 --> 01:59:07,777
CANCER IN 2020, WE WISH  HE

2801
01:59:07,777 --> 01:59:09,446
COULD HAVE BEEN WITH US BUT

2802
01:59:09,446 --> 01:59:12,782
KATHY PROMISED TO TALK ABOUT HIS

2803
01:59:12,782 --> 01:59:15,218
CONTRIBUTION AS WELL.

2804
01:59:15,218 --> 01:59:17,454
SHE FOCUSES ON ONCOGENESIS,

2805
01:59:17,454 --> 01:59:19,923
ADVANCED PROSTATE CANCER AS

2806
01:59:19,923 --> 01:59:30,400
RELATED TO ASSOCIATED DRUG 

2807
01:59:33,903 --> 01:59:36,539
VULNERABILITIES AND RESISTANCE.

2808
01:59:36,539 --> 01:59:38,241
 

2809
01:59:38,241 --> 01:59:42,045
>> THANK YOU VERY MUCH.

2810
01:59:42,045 --> 01:59:45,949
IT REALLY IS A DISTINCT PLEASURE

2811
01:59:45,949 --> 01:59:52,222
TO BE HERE TO HONOR PHIL LEDER, 

2812
01:59:52,222 --> 01:59:54,357
AND WHAT I WILL DO IS SHARE SOME

2813
01:59:54,357 --> 01:59:55,458
MEMORIES WITH YOU.

2814
01:59:55,458 --> 01:59:56,926
LIKE THOSE THAT YOU'VE ALREADY

2815
01:59:56,926 --> 01:59:58,661
HEARD THIS MORNING, THEY WILL

2816
01:59:58,661 --> 02:00:02,899
REALLY UNDERSCORE NOT ONLY

2817
02:00:02,899 --> 02:00:04,034
PHIL'S IMMENSE SCIENTIFIC

2818
02:00:04,034 --> 02:00:05,869
TALENT, ALSO HIS DEDICATION TO

2819
02:00:05,869 --> 02:00:10,640
MENTORS AND SUPPORTING THE 

2820
02:00:10,640 --> 02:00:11,441
SCIENTIFIC COMMUNITY.

2821
02:00:11,441 --> 02:00:13,176
HIS LEGACY AT NIH IS HUGE,

2822
02:00:13,176 --> 02:00:14,878
COULDN'T BE MORE APPROPRIATE TO

2823
02:00:14,878 --> 02:00:19,015
HAVE A PHIL LEDER HOUSE TO

2824
02:00:19,015 --> 02:00:21,418
PROMOTE SCIENTIFIC TRAINING.

2825
02:00:21,418 --> 02:00:23,820
I'M ONE OF THE SMALL GROUP OF

2826
02:00:23,820 --> 02:00:25,121
TRAINEES WHO BRIDGE NIH AND

2827
02:00:25,121 --> 02:00:25,488
HARVARD YEARS.

2828
02:00:25,488 --> 02:00:27,157
I THINK I MAN THE ONLY ONE IN

2829
02:00:27,157 --> 02:00:30,293
THIS GROUP WHO IS HERE TODAY.

2830
02:00:30,293 --> 02:00:32,028
I COMPLETED MY GRADUATE TRAINING

2831
02:00:32,028 --> 02:00:34,898
AT U.C. IRVINE IN CELLULAR

2832
02:00:34,898 --> 02:00:39,636
IMMUNOLOGY, AND DURING MY 

2833
02:00:39,636 --> 02:00:40,370
GRADUATE YEARS IMMUNOGLOBULIN

2834
02:00:40,370 --> 02:00:41,004
REARRANGEMENTS WERE DISCOVERED

2835
02:00:41,004 --> 02:00:47,477
THAT YOU'VE BEEN HEARD ABOUT,

2836
02:00:47,477 --> 02:00:53,383
AND THIS WAS VERY CONCEPTUALLY

2837
02:00:53,383 --> 02:00:54,584
TRANSFORMATIVE STIMULATING OUR

2838
02:00:54,584 --> 02:00:56,219
IMAGINATIONS ABOUT UNKNOWN

2839
02:00:56,219 --> 02:00:57,120
POSSIBILITIES OF GENOMIC

2840
02:00:57,120 --> 02:01:00,590
STRUCTURE AND FUNCTION TO COME.

2841
02:01:00,590 --> 02:01:03,026
IT ALSO UNDERSCORED THE VALUE

2842
02:01:03,026 --> 02:01:05,195
AND IMPORTANCE OF OBTAINING

2843
02:01:05,195 --> 02:01:12,102
MOLECULAR GENETIC SKILLS AS PHIL

2844
02:01:12,102 --> 02:01:14,270
HIETER POINTED OUT.

2845
02:01:14,270 --> 02:01:17,140
I COULD HARDLY BELIEVE MY GOOD

2846
02:01:17,140 --> 02:01:18,007
FORTUNE WHEN PHIL INVITE

2847
02:01:18,007 --> 02:01:19,509
IMMEDIATE TO JOIN HIS LAB.

2848
02:01:19,509 --> 02:01:22,145
I ARRIVED IN SUMMER OF 1980,

2849
02:01:22,145 --> 02:01:24,114
PHIL JUST ACCEPTED A POSITION AT

2850
02:01:24,114 --> 02:01:25,415
CHAIR OF GENETICS AT HARVARD,

2851
02:01:25,415 --> 02:01:28,585
ASKED ME TO MOVE WITH THE LAB

2852
02:01:28,585 --> 02:01:29,619
THE FOLLOWING SPRING, THIS WAS

2853
02:01:29,619 --> 02:01:30,620
FINE WITH ME.

2854
02:01:30,620 --> 02:01:32,355
I HAD SPENT MY LIFE TO THAT

2855
02:01:32,355 --> 02:01:34,791
POINT ON THE WEST COAST, AND I

2856
02:01:34,791 --> 02:01:38,695
WAS HAPPY TO EXPLORE MORE OF THE

2857
02:01:38,695 --> 02:01:39,696
EAST COAST.

2858
02:01:39,696 --> 02:01:40,663
MY FIRST PROJECT YOU'VE SEEN

2859
02:01:40,663 --> 02:01:44,801
PICTURES OF WHERE WE WERE IN

2860
02:01:44,801 --> 02:01:47,804
BUILDING 6, WAS AN AMBITIOUS

2861
02:01:47,804 --> 02:01:48,037
ONE.

2862
02:01:48,037 --> 02:01:50,507
TO CLONE THE T-CELL RECEPTOR.

2863
02:01:50,507 --> 02:01:51,741
ULTIMATELY, OUR APPROACH DIDN'T

2864
02:01:51,741 --> 02:01:53,943
PAN OUT BUT IN THE PROCESS I

2865
02:01:53,943 --> 02:01:55,778
LEARNED HOW TO DO MOLECULAR

2866
02:01:55,778 --> 02:01:56,246
GENETICS.

2867
02:01:56,246 --> 02:01:59,749
THIS FIRST YEAR TURNED OUT TO BE

2868
02:01:59,749 --> 02:02:05,221
AN IMMENSELY EXCITING TIME,

2869
02:02:05,221 --> 02:02:05,688
RECURRING CHROMOSOMAL

2870
02:02:05,688 --> 02:02:07,123
TRANSLOCATION IN BURKITT'S

2871
02:02:07,123 --> 02:02:10,160
LYMPHOMA AND CML WERE

2872
02:02:10,160 --> 02:02:11,127
IDENTIFIED, LANNY'S BRILLIANT

2873
02:02:11,127 --> 02:02:13,530
MOVE TO INTRODUCE CYNTHIA TO

2874
02:02:13,530 --> 02:02:16,266
PHIL, THE CONCEPT OF ONCOGENES,

2875
02:02:16,266 --> 02:02:18,902
CELLULAR HOMOLOGS OF GENES AND

2876
02:02:18,902 --> 02:02:22,839
TRANSFORMING RETROVIRUSES WAS

2877
02:02:22,839 --> 02:02:24,807
RAPIDLY EVOLVING, THE

2878
02:02:24,807 --> 02:02:26,576
TRANSFORMATION ASSAY HAD

2879
02:02:26,576 --> 02:02:28,545
IDENTIFIED THE RAS ONCOGENES,

2880
02:02:28,545 --> 02:02:29,412
ONCOGENE AND OTHERS.

2881
02:02:29,412 --> 02:02:33,149
AND SO AS YOU'VE HEARD FROM

2882
02:02:33,149 --> 02:02:38,588
LANNY, HE, BECKY AND CYNTHIA

2883
02:02:38,588 --> 02:02:40,456
IDENTIFIED MYC ONCOGENE IN

2884
02:02:40,456 --> 02:02:41,357
BURKITT'S LYMPHOMA.

2885
02:02:41,357 --> 02:02:43,960
FROM THE VANTAGE NOW OF HAVING

2886
02:02:43,960 --> 02:02:46,029
DIRECTED COMPETITIVE PROJECTS IN

2887
02:02:46,029 --> 02:02:53,703
MY OWN LAB, I CAN NOW REALLY 

2888
02:02:53,703 --> 02:02:55,338
APPRECIATE HOW EXCITED PHIL WAS

2889
02:02:55,338 --> 02:03:00,076
BY SCIENCE BUT HOW HE MAINTAINED

2890
02:03:00,076 --> 02:03:02,579
A DIGNIFIED DEMEANOR.

2891
02:03:02,579 --> 02:03:08,484
THIS FIRST YEAR WASN'T ONLY

2892
02:03:08,484 --> 02:03:09,919
SCIENTIFICALLY MOMENTOUS BUT

2893
02:03:09,919 --> 02:03:11,020
PERSONALLY MOMENTOUS, AS MICHAEL

2894
02:03:11,020 --> 02:03:13,323
JUST SAID PRIOR TO MOVING TO

2895
02:03:13,323 --> 02:03:16,392
BOSTON I MARRIED ANOTHER POSTDOC

2896
02:03:16,392 --> 02:03:18,027
FELLOW IN PHIL'S LAB, AND I'LL

2897
02:03:18,027 --> 02:03:21,431
TALK ABOUT BOTH OF OUR CAREER

2898
02:03:21,431 --> 02:03:21,898
JOURNEYS.

2899
02:03:21,898 --> 02:03:23,933
SO, PRIOR TO JOINING PHIL'S LAB

2900
02:03:23,933 --> 02:03:32,675
ULI WAS A GRAD STUDENT AT 

2901
02:03:32,675 --> 02:03:39,749
HARVARD DURING THE DEVELOPMENT

2902
02:03:39,749 --> 02:03:42,085
OF SEQUENCING, RNA POLYMERASE

2903
02:03:42,085 --> 02:03:42,986
INTERACTION WITH PROKARYOTIC

2904
02:03:42,986 --> 02:03:45,488
PROMOTERS. 

2905
02:03:45,488 --> 02:03:47,890
HERE IS A PICTURE OF STEVE ON

2906
02:03:47,890 --> 02:03:52,729
THE LEAVE,  ULLI AND CARL WU.

2907
02:03:52,729 --> 02:03:55,999
I CHOSE THIS PHOTO BECAUSE ALL

2908
02:03:55,999 --> 02:03:57,200
THREE OF THESE SCIENTISTS SPENT

2909
02:03:57,200 --> 02:04:00,503
AT LEAST PART OF THEIR

2910
02:04:00,503 --> 02:04:04,007
SCIENTIFIC CAREER HERE AT NIH.

2911
02:04:04,007 --> 02:04:09,445
SO, ULLI JOINED PHIL'S LAB, AND

2912
02:04:09,445 --> 02:04:12,081
DURING THE FIRST FEW YEARS

2913
02:04:12,081 --> 02:04:14,484
WORKED ON IMMUNOGLOBULIN GENE

2914
02:04:14,484 --> 02:04:15,785
STRUCTURE AND REARRANGEMENT

2915
02:04:15,785 --> 02:04:19,722
WHICH FOR THE IMMUNOLOGISTS IN

2916
02:04:19,722 --> 02:04:23,359
THE AUDIENCE INCLUDED DISCOVERY

2917
02:04:23,359 --> 02:04:24,260
OF D SEGMENTS.

2918
02:04:24,260 --> 02:04:26,963
A SMALL GROUP WENT WITH PHIL

2919
02:04:26,963 --> 02:04:30,700
FROM NIH TO HARVARD, HERE YOU

2920
02:04:30,700 --> 02:04:33,236
SEE ULLI, AND TIM STEWART JOINED

2921
02:04:33,236 --> 02:04:34,737
US IN HARVARD, I WANTED TO

2922
02:04:34,737 --> 02:04:35,505
INCLUDE THIS PICTURE.

2923
02:04:35,505 --> 02:04:38,708
TIM WAS THE PERSON THAT MADE THE

2924
02:04:38,708 --> 02:04:41,878
ONCOMOUSE THAT YOU'VE HEARD MUCH

2925
02:04:41,878 --> 02:04:42,078
ABOUT.

2926
02:04:42,078 --> 02:04:43,846
SO, ONE MEMBER OF THE GROUP THAT

2927
02:04:43,846 --> 02:04:47,483
SPENT TIME AT BOTH NIH AND

2928
02:04:47,483 --> 02:04:49,185
HARVARD WAS JIM BATTEY, WHICH

2929
02:04:49,185 --> 02:04:50,553
UNFORTUNATELY HE'S NOT HERED

2930
02:04:50,553 --> 02:04:54,357
THAT BUT JIM RETURNED TO NIH AND

2931
02:04:54,357 --> 02:04:56,426
EVENTUALLY BECAME DIRECTOR OF

2932
02:04:56,426 --> 02:04:58,594
NIDCD, PRIOR TO HIS RETIREMENT A

2933
02:04:58,594 --> 02:04:59,629
FEW YEARS AGO.

2934
02:04:59,629 --> 02:05:03,099
JUST ANOTHER EXAMPLE OF PHIL'S

2935
02:05:03,099 --> 02:05:05,601
NIH LEGACY.

2936
02:05:05,601 --> 02:05:09,739
ANYWAY, DURING THE THAT TIME AT

2937
02:05:09,739 --> 02:05:13,242
HARVARD THE FIELD OF ONCOGENES

2938
02:05:13,242 --> 02:05:16,012
EXPLODED, HOW DO THEY WORK?

2939
02:05:16,012 --> 02:05:19,615
NICK WAS PARTICULARLY PUZZLING

2940
02:05:19,615 --> 02:05:26,289
IN THE SENSE THERE WERE NO CLEAR

2941
02:05:26,289 --> 02:05:26,689
SOMATIC MUTATIONS.

2942
02:05:26,689 --> 02:05:28,491
SO, DRAWING ON MY BACKGROUND IN

2943
02:05:28,491 --> 02:05:29,359
CELLULAR IMMUNOLOGY WHERE I

2944
02:05:29,359 --> 02:05:32,862
WORKED ON B CELL ACTIVATION, AND

2945
02:05:32,862 --> 02:05:36,032
USING A NEWLY DEVELOPED AND

2946
02:05:36,032 --> 02:05:38,101
SENSITIVE RNAASE ASSAY AS YOU'VE

2947
02:05:38,101 --> 02:05:40,636
HEARD PHIL ALWAYS ENABLED NEW

2948
02:05:40,636 --> 02:05:41,604
TECHNOLOGIES AND PROMOTED THEM

2949
02:05:41,604 --> 02:05:44,340
IN THE LAB, I WAS ABLE TO

2950
02:05:44,340 --> 02:05:47,176
DETERMINE THAT MYC RNA WAS

2951
02:05:47,176 --> 02:05:52,148
TRANSCRIPTIONAL INDUCED BY B 

2952
02:05:52,148 --> 02:05:53,116
CELL MITOGENS, IT MIGHT FUNCTION

2953
02:05:53,116 --> 02:05:57,387
AS A RESULT OF EXCESSIVE OR

2954
02:05:57,387 --> 02:05:59,222
MISTIMED EXPRESSION.

2955
02:05:59,222 --> 02:06:02,158
IN ADDITION, WE WORKED WITH

2956
02:06:02,158 --> 02:06:05,027
CHUCK STYLES AT DANA-FARBER TO

2957
02:06:05,027 --> 02:06:07,630
DEMONSTRATE THE SAME PATTERN OF

2958
02:06:07,630 --> 02:06:13,669
MITOGEN RESPONSIVNESS AND AT THE

2959
02:06:13,669 --> 02:06:14,971
TIME THE TOOLS WEREN'T ABLE TO

2960
02:06:14,971 --> 02:06:18,808
LOOK AT MORE THAN ONE GENE AT A

2961
02:06:18,808 --> 02:06:21,177
TIME, AND THIS OBSERVATION OF

2962
02:06:21,177 --> 02:06:23,646
MYC REGULATION WAS OF GREAT

2963
02:06:23,646 --> 02:06:24,614
INTEREST TO OUR ONCOGENE

2964
02:06:24,614 --> 02:06:25,181
COMMUNITY.

2965
02:06:25,181 --> 02:06:27,717
SO WE WROTE UP THE PAPER AND

2966
02:06:27,717 --> 02:06:30,620
DECIDED TO TRY A SUBMISSION TO

2967
02:06:30,620 --> 02:06:30,853
"CELL."

2968
02:06:30,853 --> 02:06:32,722
PHIL DID SOMETHING AT THIS POINT

2969
02:06:32,722 --> 02:06:35,892
THAT MEANT A LOT TO ME,

2970
02:06:35,892 --> 02:06:38,628
EXEMPLIFIES HOW HE SUPPORTED AND

2971
02:06:38,628 --> 02:06:40,430
PROMOTED HIS TRAINEES.

2972
02:06:40,430 --> 02:06:43,433
THE CELL OFFICES WERE IN

2973
02:06:43,433 --> 02:06:43,966
CAMBRIDGE.

2974
02:06:43,966 --> 02:06:45,735
WE PACKAGED UP OUR SUBMISSION

2975
02:06:45,735 --> 02:06:47,804
INTO MANILA ENVELOPE, I THINK WE

2976
02:06:47,804 --> 02:06:50,807
WROTE BEN'S NAME ON THE FRONT

2977
02:06:50,807 --> 02:06:52,442
WITH FELT WRITING PEN.

2978
02:06:52,442 --> 02:06:54,310
SO, THERE WAS NOTHING LIKE

2979
02:06:54,310 --> 02:06:56,145
ONLINE SUBMISSIONS IN THOSE

2980
02:06:56,145 --> 02:06:57,113
DAYS.

2981
02:06:57,113 --> 02:06:59,115
AND PHIL DROVE ME OVER THE RIVER

2982
02:06:59,115 --> 02:07:01,517
WHERE I HANDED IN OUR

2983
02:07:01,517 --> 02:07:01,984
SUBMISSION.

2984
02:07:01,984 --> 02:07:05,455
ON THE WAY HOME HE INSISTED WE

2985
02:07:05,455 --> 02:07:10,059
STOP AND EACH GET A GIANT COOKIE

2986
02:07:10,059 --> 02:07:12,061
FROM THE BAKERY TO CELEBRATE.

2987
02:07:12,061 --> 02:07:14,430
THE PAPER WAS ACCEPTED,

2988
02:07:14,430 --> 02:07:16,833
FOLLOWING THIS PUBLICATION PHIL

2989
02:07:16,833 --> 02:07:19,368
GENEROUSLY PASSED ON TO ME MANY

2990
02:07:19,368 --> 02:07:21,103
OF THE SEMINAR AND MEETING

2991
02:07:21,103 --> 02:07:23,306
INVITATIONS HE RECEIVED TO TALK

2992
02:07:23,306 --> 02:07:25,274
ABOUT THE WORK AND CRITICIZED MY

2993
02:07:25,274 --> 02:07:30,646
TALK AS LANNY HAS DESCRIBED TO 

2994
02:07:30,646 --> 02:07:30,880
YOU.

2995
02:07:30,880 --> 02:07:37,420
SO, ULLU USED HIS EXPERIENCE IN 

2996
02:07:37,420 --> 02:07:45,528
CHROMATIN STRUCTURE  MAPPED THE

2997
02:07:45,528 --> 02:07:46,496
SEQUENCE.

2998
02:07:46,496 --> 02:07:48,030
SHORTLY THEREAFTER, IN EARLY

2999
02:07:48,030 --> 02:07:50,099
1984, ULLI AND I RETURNED TO NIH

3000
02:07:50,099 --> 02:07:55,404
TO SET UP AN INDEPENDENT LAB, AT

3001
02:07:55,404 --> 02:07:56,539
NIAID AND NCI.

3002
02:07:56,539 --> 02:07:58,674
WE WORKED TOGETHER TO ISOLATE

3003
02:07:58,674 --> 02:08:00,943
AND IDENTIFY GENES THAT WERE

3004
02:08:00,943 --> 02:08:09,919
TRANSCRIPTIONALLY REGULATED IN 

3005
02:08:09,919 --> 02:08:10,786
HUMAN ACTIVATED T CELLS,

3006
02:08:10,786 --> 02:08:21,297
NF-kappaB BECAME THE FOCUS OF

3007
02:08:25,535 --> 02:08:27,270
ULLI'S WORK HE PASSED AWAY IN

3008
02:08:27,270 --> 02:08:28,671
2020, AS YOU HEARD.

3009
02:08:28,671 --> 02:08:30,006
WHEN PHIL WAS ON CAMPUS HE WOULD

3010
02:08:30,006 --> 02:08:31,607
SAY HI, CHECK UP ON THE FAMILY,

3011
02:08:31,607 --> 02:08:33,576
SHARE NEWS ABOUT HIS FAMILY.

3012
02:08:33,576 --> 02:08:36,779
HE ALWAYS STAYED IN TOUCH.

3013
02:08:36,779 --> 02:08:39,282
SO, I'LL RETURN TO MY OWN WORK

3014
02:08:39,282 --> 02:08:40,249
IN A MOMENT.

3015
02:08:40,249 --> 02:08:43,419
AND END WITH A VIGNETTE OF

3016
02:08:43,419 --> 02:08:44,654
INVESTIGATIONS TO GIVE YOU A

3017
02:08:44,654 --> 02:08:47,256
FLAVOR OF WHERE I HAVE ENDED UP

3018
02:08:47,256 --> 02:08:48,491
AFTER 40 YEARS.

3019
02:08:48,491 --> 02:08:49,926
BEFORE DOING THAT, I JUST WANT

3020
02:08:49,926 --> 02:08:52,528
TO SAY IT IS SO APPROPRIATE THAT

3021
02:08:52,528 --> 02:08:56,098
THE LEDER HOUSE WOULD BE HOME TO

3022
02:08:56,098 --> 02:08:59,368
STUDENTS WHO PARTICIPATE IN 

3023
02:08:59,368 --> 02:09:00,303
COLLABORATIVE AND LARGELY

3024
02:09:00,303 --> 02:09:02,972
MULTI-DISCIPLINARY PROJECTS.

3025
02:09:02,972 --> 02:09:05,341
AS A SCIENTIST, PHIL HAD A RANGE

3026
02:09:05,341 --> 02:09:08,411
OF INTEREST IN BIOLOGICAL

3027
02:09:08,411 --> 02:09:11,280
MEDICINE, BIOLOGICAL MECHANISMS

3028
02:09:11,280 --> 02:09:13,215
AND MEDICINE, INCLUDING

3029
02:09:13,215 --> 02:09:15,217
ONCOLOGY, IMMUNOLOGY,

3030
02:09:15,217 --> 02:09:15,985
DEVELOPMENT, GENE REGULATION.

3031
02:09:15,985 --> 02:09:17,620
HE SET AN IMPORTANT EXAMPLE FOR

3032
02:09:17,620 --> 02:09:22,425
ALL OF US TO CONDUCT ETHICAL AND

3033
02:09:22,425 --> 02:09:23,526
COMPLETE RESEARCH WHILE

3034
02:09:23,526 --> 02:09:25,828
MAINTAINING RESPECT AND HUMANITY

3035
02:09:25,828 --> 02:09:26,329
TOWARD OTHERS.

3036
02:09:26,329 --> 02:09:32,201
SO, I'D LIKE TO SHARE AN E-MAIL

3037
02:09:32,201 --> 02:09:40,042
I RECEIVED, LET'S SEE.

3038
02:09:40,042 --> 02:09:41,811
THIS IS GOING TO BE HARD BECAUSE

3039
02:09:41,811 --> 02:09:46,115
I THINK THE E-MAIL GOT BLACKED

3040
02:09:46,115 --> 02:09:48,818
OUT SOMEHOW.

3041
02:09:48,818 --> 02:09:56,392
 

3042
02:09:56,392 --> 02:09:57,693
OKAY, THANK YOU.

3043
02:09:57,693 --> 02:09:58,794
THAT'S GREAT, OKAY.

3044
02:09:58,794 --> 02:10:00,196
WE'RE GOOD.

3045
02:10:00,196 --> 02:10:02,732
SO I WANT TO SHARE THIS E-MAIL

3046
02:10:02,732 --> 02:10:05,001
THAT I RECEIVED A FEW DAYS AGO

3047
02:10:05,001 --> 02:10:08,537
FROM HOWARD YOUNG, WHO LIKE ME

3048
02:10:08,537 --> 02:10:10,373
IS AN INVESTIGATOR FOR MANY

3049
02:10:10,373 --> 02:10:12,875
YEARS AT THE NCI.

3050
02:10:12,875 --> 02:10:15,077
SO, HE WROTE, I WANTED TO

3051
02:10:15,077 --> 02:10:17,580
MENTION ONE INTERACTION I HAD

3052
02:10:17,580 --> 02:10:21,317
WITH DR. LEDER THAT I NEVER HAVE

3053
02:10:21,317 --> 02:10:23,152
FORGOTTEN, WORKING AT THE LABS

3054
02:10:23,152 --> 02:10:26,789
WHEN THE COMPANY ANNOUNCED

3055
02:10:26,789 --> 02:10:28,424
ONE-THIRD OF EMPLOYEES WERE

3056
02:10:28,424 --> 02:10:28,958
BEING TERMINATED.

3057
02:10:28,958 --> 02:10:30,393
I WAS NOT IN THE GROUP.

3058
02:10:30,393 --> 02:10:32,395
DR. LEDER TOLD ME HE WOULD HELP

3059
02:10:32,395 --> 02:10:34,997
ME FIND A NEW POSITION.

3060
02:10:34,997 --> 02:10:36,565
THIS WAS INCREDIBLY GRACIOUS OF

3061
02:10:36,565 --> 02:10:38,100
HIM, ESPECIALLY SINCE WE DID NOT

3062
02:10:38,100 --> 02:10:40,036
HAVE A LOT OF PERSONAL

3063
02:10:40,036 --> 02:10:40,670
INTERACTIONS.

3064
02:10:40,670 --> 02:10:42,004
TO THIS DAY, I'M NOT SURE WHAT

3065
02:10:42,004 --> 02:10:43,973
PROMPTED HIM TO REACH OUT TO ME

3066
02:10:43,973 --> 02:10:46,042
BUT IT CERTAINLY HAS REMAINED

3067
02:10:46,042 --> 02:10:50,279
WITH ME ALL THESE YEARS.

3068
02:10:50,279 --> 02:10:52,615
SO, THIS MADE ME THINK ABOUT THE

3069
02:10:52,615 --> 02:10:55,117
FACT THAT THERE IS LIKELY SO

3070
02:10:55,117 --> 02:10:57,853
MUCH PHIL HAS DONE FOR OTHERS

3071
02:10:57,853 --> 02:11:02,124
THAT WE CANNOT FULLY APPRECIATE

3072
02:11:02,124 --> 02:11:02,425
EVEN TODAY.

3073
02:11:02,425 --> 02:11:04,660
SO, FINALLY THEN I'LL TURN TO MY

3074
02:11:04,660 --> 02:11:07,697
OWN WORK, WHICH HAS REVOLVED

3075
02:11:07,697 --> 02:11:08,964
AROUND ONCOGENIC MECHANISMS FOR

3076
02:11:08,964 --> 02:11:11,834
THE MOST PART, IN THE PAST 20

3077
02:11:11,834 --> 02:11:15,838
YEARS I'VE CONCENTRATED ON

3078
02:11:15,838 --> 02:11:17,740
ADVANCED PROSTATE CANCER, PHIL

3079
02:11:17,740 --> 02:11:27,183
WAS AN INNOVATOR PUSHING BOUND 

3080
02:11:27,183 --> 02:11:28,584
A RIES.

3081
02:11:28,584 --> 02:11:29,185
IN INVESTIGATING PROSTATE

3082
02:11:29,185 --> 02:11:31,120
CANCER, ONE OF THE MOST

3083
02:11:31,120 --> 02:11:33,856
PERSISTENT PROBLEMS HAS BEEN A

3084
02:11:33,856 --> 02:11:36,659
LACK OF MODELS THAT RECAPITULATE

3085
02:11:36,659 --> 02:11:37,593
RANGE OF HUMAN DISEASE.

3086
02:11:37,593 --> 02:11:39,328
IN RESPONSE TO THAT CHALLENGE,

3087
02:11:39,328 --> 02:11:41,831
MY LAB HAS DEVELOPED A PLATFORM

3088
02:11:41,831 --> 02:11:43,766
OF MODELS THAT PREVIOUSLY

3089
02:11:43,766 --> 02:11:44,967
COULDN'T BE MAINTAINED IN A

3090
02:11:44,967 --> 02:11:46,569
CULTURE DISH TO WORK WITH.

3091
02:11:46,569 --> 02:11:54,777
BUT USING A NEW TYPE OF 

3092
02:11:54,777 --> 02:11:55,778
CULTURING METHOD, CALLED

3093
02:11:55,778 --> 02:11:58,180
ORGANOID CULTURES, WE HAVE BEEN

3094
02:11:58,180 --> 02:12:04,186
ABLE TO ESTABLISH A MORE 

3095
02:12:04,186 --> 02:12:05,187
REPRESENTATIVE APPROACH.

3096
02:12:05,187 --> 02:12:07,490
SO, CAN WE GO BACK TO THE WHITE

3097
02:12:07,490 --> 02:12:09,425
BACKGROUND MAYBE AND THE BLACK

3098
02:12:09,425 --> 02:12:10,192
LETTERING?

3099
02:12:10,192 --> 02:12:15,464
WOULD THAT BE POSSIBLE? 

3100
02:12:15,464 --> 02:12:25,975
SOMETHING CHANGED SOMEWHERE. 

3101
02:12:31,614 --> 02:12:33,182
WELL, I'LL GET STARTED, IF YOU

3102
02:12:33,182 --> 02:12:34,817
CAN PUT IT BACK TO THE ORIGINAL

3103
02:12:34,817 --> 02:12:36,685
WAY, THE SLIDE WAS, WITH THE

3104
02:12:36,685 --> 02:12:37,787
WHITE BACKGROUND AND BLACK

3105
02:12:37,787 --> 02:12:41,857
LETTERING THEN WE COULD INCLUDE

3106
02:12:41,857 --> 02:12:42,158
EVERYTHING.

3107
02:12:42,158 --> 02:12:43,926
SO, WHAT I'M SHOWING HERE IS A

3108
02:12:43,926 --> 02:12:46,362
SUMMARY OF THE SEQUENCE OF

3109
02:12:46,362 --> 02:12:48,764
EXPERIMENTS THAT SPANS SEVERAL

3110
02:12:48,764 --> 02:12:51,634
YEARS, AND THAT START BY

3111
02:12:51,634 --> 02:12:54,436
DETERMINING THERAPEUTIC RESPONSE

3112
02:12:54,436 --> 02:12:57,072
TO ABOUT 100 DRUGS, ACROSS --

3113
02:12:57,072 --> 02:12:59,809
GREAT, THANK YOU, ACROSS 35

3114
02:12:59,809 --> 02:13:02,011
MODELS OF ADVANCED PROSTATE

3115
02:13:02,011 --> 02:13:02,244
CANCER.

3116
02:13:02,244 --> 02:13:06,348
AND WHAT'S EMPHASIZED HERE IS

3117
02:13:06,348 --> 02:13:12,521
THE RESPONSE TO A COMMONLY

3118
02:13:12,521 --> 02:13:13,155
DOCETAXEL THAT INHIBITS FOR A

3119
02:13:13,155 --> 02:13:15,691
WHILE IN A PORTION OF ADVANCED

3120
02:13:15,691 --> 02:13:17,359
PROSTATE CANCER PATIENTS.

3121
02:13:17,359 --> 02:13:20,729
SO, HAVING A LARGE GROUP OF

3122
02:13:20,729 --> 02:13:22,164
RESPONDERS AND NON-RESPONDERS

3123
02:13:22,164 --> 02:13:24,867
ALLOWED US TO IDENTIFY A

3124
02:13:24,867 --> 02:13:25,868
CONSISTENT DIFFERENCE BETWEEN

3125
02:13:25,868 --> 02:13:26,435
GROUPS.

3126
02:13:26,435 --> 02:13:31,540
AND THAT DIFFERENCE IS THAT

3127
02:13:31,540 --> 02:13:33,075
NON-RESPONDERS EXPRESSED THE

3128
02:13:33,075 --> 02:13:34,376
HNF1 TRANSCRIPTION FACTOR.

3129
02:13:34,376 --> 02:13:36,779
SO, LOOKING MORE INTO THE

3130
02:13:36,779 --> 02:13:38,447
MECHANISM OF ACTION, WE

3131
02:13:38,447 --> 02:13:41,483
DETERMINED THAT THE PRESENCE OF

3132
02:13:41,483 --> 02:13:46,455
HNF1 STIMULATES EXPRESSION OF

3133
02:13:46,455 --> 02:13:49,191
ANOTHER PROTEIN, BIRK 3, THAT

3134
02:13:49,191 --> 02:13:50,492
HELPS TREATED CELLS.

3135
02:13:50,492 --> 02:13:53,028
THERE'S A CLASS THAT INHIBITS

3136
02:13:53,028 --> 02:13:56,966
THE ACTION OF BIRK 3, ACTIVE IN

3137
02:13:56,966 --> 02:13:58,968
MODEL THAT EXPRESS HNF1 AND DO

3138
02:13:58,968 --> 02:14:07,476
NOT RESPOND TO DOCETAXEL.

3139
02:14:07,476 --> 02:14:09,778
WHAT THIS MEANS, POSSIBLE TO

3140
02:14:09,778 --> 02:14:12,514
IDENTIFY PATIENTS THAT MAY NOT

3141
02:14:12,514 --> 02:14:13,749
RESPOND TO DOCETAXEL AND THERE

3142
02:14:13,749 --> 02:14:17,119
MAY BE A TREATMENT THAT WILL

3143
02:14:17,119 --> 02:14:20,389
COMPLEMENT DOCETAXEL FOR

3144
02:14:20,389 --> 02:14:21,390
NONRESPONSIVE PATIENTS.

3145
02:14:21,390 --> 02:14:25,427
I'M GOING TO END AND AGAIN JUST

3146
02:14:25,427 --> 02:14:34,837
SAY PHIL'S LEGACY AT NIH IS

3147
02:14:34,837 --> 02:14:36,171
SIMPLY IMMENSE, HE'S TOUCHED

3148
02:14:36,171 --> 02:14:38,674
MANY OF US, CERTAINLY MY LIFE.

3149
02:14:38,674 --> 02:14:40,209
THANK YOU VERY MUCH FOR YOUR

3150
02:14:40,209 --> 02:14:42,611
ATTENTION.

3151
02:14:42,611 --> 02:14:43,145
[APPLAUSE]

3152
02:14:43,145 --> 02:14:49,184
 

3153
02:14:49,184 --> 02:14:59,228
 

3154
02:15:00,863 --> 02:15:03,532
>> NEXT IS LOTHAR
HENNIGHAUSEN,

3155
02:15:03,532 --> 02:15:06,602
GREW UP IN GERMANY, RECEIVED A

3156
02:15:06,602 --> 02:15:09,004
Ph.D. IN GENETICS FROM

3157
02:15:09,004 --> 02:15:13,809
UNIVERSITY OF C COLOGNE, JOINED

3158
02:15:13,809 --> 02:15:17,746
THE LEDER LAB IN 1983, RECRUITED

3159
02:15:17,746 --> 02:15:20,816
TO THE NIH, CHIEF OF THE

3160
02:15:20,816 --> 02:15:21,717
GENETICS AND PHYSIOLOGY SECTION

3161
02:15:21,717 --> 02:15:23,986
IN LABORATORY OF CELL AND

3162
02:15:23,986 --> 02:15:25,287
MOLECULAR BIOLOGY.

3163
02:15:25,287 --> 02:15:28,257
HIS RESEARCH FOCUSES ON HOW

3164
02:15:28,257 --> 02:15:30,125
CYTOKINES CONTROL ORGAN

3165
02:15:30,125 --> 02:15:30,993
PHYSIOLOGY, INCLUDING MAMMARY

3166
02:15:30,993 --> 02:15:41,403
GLAND DURING PREGNANCY.

3167
02:15:43,105 --> 02:15:43,272
WELCOME.

3168
02:15:43,272 --> 02:15:45,641
>> I BROUGHT THIS BOOK
WHICH

3169
02:15:45,641 --> 02:15:55,117
PROBABLY IS THE MOST IMPORTANT 

3170
02:15:55,117 --> 02:16:02,558
BOOK I EVER READ. 

3171
02:16:02,558 --> 02:16:06,962
WE TALKED ABOUT TECHNOLOGY, THIS

3172
02:16:06,962 --> 02:16:14,503
AFFECTED ME DURING MY Ph.D.,

3173
02:16:14,503 --> 02:16:17,139
IN GERMANY TASKED WITH CLONING

3174
02:16:17,139 --> 02:16:27,616
GENES FROM THE MOUSE MAMMARY

3175
02:16:43,465 --> 02:16:43,632
GLAND.

3176
02:16:43,632 --> 02:16:46,635
YOU HAD TO ISOLATE MESSENGER

3177
02:16:46,635 --> 02:16:48,737
RNA, FIRST STEP TO ISOLATE

3178
02:16:48,737 --> 02:16:49,438
GENES.

3179
02:16:49,438 --> 02:16:59,848
AND THE FIRST PAPER I READ WAS

3180
02:16:59,848 --> 02:17:02,017
1972, CELLULOSE TO ISOLATE

3181
02:17:02,017 --> 02:17:05,421
MESSENGER RNA. 

3182
02:17:05,421 --> 02:17:14,930
YOU COULDN'T JUST ORDER FROM THE

3183
02:17:14,930 --> 02:17:24,940
COMPANY, YOU MIXED IT TOGETHER,

3184
02:17:24,940 --> 02:17:25,707
LOWED COLUMNS.

3185
02:17:25,707 --> 02:17:27,743
YOU CAN SEE AN EXPERIMENT OF A

3186
02:17:27,743 --> 02:17:28,744
Ph.D. STUDENT PUBLISHED A FEW

3187
02:17:28,744 --> 02:17:33,882
YEARS LATER, ON THE LEFT INPUT

3188
02:17:33,882 --> 02:17:35,884
RNA, 28 AND 18 RNS, ON THE RIGHT

3189
02:17:35,884 --> 02:17:42,758
YOU CAN SEE ENRICHMENT, ARROWS

3190
02:17:42,758 --> 02:17:52,267
POINT TO ABUNDANT SPECIES CLONED

3191
02:17:52,267 --> 02:17:53,035
LATER ON.

3192
02:17:53,035 --> 02:17:54,903
1982, ONE SENTENCE TO POINT OUT

3193
02:17:54,903 --> 02:17:57,406
IS I THINK YOU WILL FIND THE

3194
02:17:57,406 --> 02:17:59,708
ATMOSPHERE IN OUR LABORATORY

3195
02:17:59,708 --> 02:18:02,678
BOTH FRIENDLY AND STIMULATING.

3196
02:18:02,678 --> 02:18:07,816
AND THIS WAS ABSOLUTELY TRUE.

3197
02:18:07,816 --> 02:18:10,552
WHAT WAS IT HERE?

3198
02:18:10,552 --> 02:18:14,823
THIS OFFER PRESUMES YOU'LL BE 

3199
02:18:14,823 --> 02:18:16,792
ABLE TO OBTAIN FELLOWSHIP

3200
02:18:16,792 --> 02:18:27,336
SUPPORT, I SECURED A FELLOWSHIP.

3201
02:18:27,736 --> 02:18:37,012
YOU MAY RECOGNIZE SOME PEOPLE.

3202
02:18:37,012 --> 02:18:38,380
THIS MUST BE CYNTHIA HOLDING A

3203
02:18:38,380 --> 02:18:46,788
CAN OF BEER, PHIL AND I, TALKING

3204
02:18:46,788 --> 02:18:52,928
TO MYSELF, OH, AND CHRIS OVER

3205
02:18:52,928 --> 02:18:53,395
THERE.

3206
02:18:53,395 --> 02:18:55,230
WE TALKED ABOUT WHAT WE LEARNED

3207
02:18:55,230 --> 02:18:56,532
FROM PHIL, MESSAGES HE PASSED ON

3208
02:18:56,532 --> 02:18:58,066
TO US.

3209
02:18:58,066 --> 02:18:59,768
AND ACTUALLY ALMOST EVERYBODY

3210
02:18:59,768 --> 02:19:05,641
HAS THE FIRST ONE, IDEAS ARE

3211
02:19:05,641 --> 02:19:06,408
CHEAP.

3212
02:19:06,408 --> 02:19:09,444
WE ALWAYS BOUNCED IDEAS OFF HIM.

3213
02:19:09,444 --> 02:19:10,846
HE ALWAYS SAID IDEAS ARE CHEAP,

3214
02:19:10,846 --> 02:19:15,717
YOU HAVE TO FOLLOW UP.

3215
02:19:15,717 --> 02:19:16,952
STILL TRUE TODAY.

3216
02:19:16,952 --> 02:19:19,755
HE SAID, I'M A LINEAR THINKING,

3217
02:19:19,755 --> 02:19:23,292
IN THE MODERN WORLD HE WOULD SAY

3218
02:19:23,292 --> 02:19:24,459
I'M A STRATEGIC THINKER.

3219
02:19:24,459 --> 02:19:26,762
THIS ALSO I LEARNED FROM HIM.

3220
02:19:26,762 --> 02:19:28,697
LENNY AND KATHY MENTIONED

3221
02:19:28,697 --> 02:19:32,267
ALREADY THAT WE HAD TO GIVE 

3222
02:19:32,267 --> 02:19:34,102
PRACTICE TALKS TO PHIL.

3223
02:19:34,102 --> 02:19:35,637
PHIL WAS INVITED TO GIVE A

3224
02:19:35,637 --> 02:19:38,941
LECTURE AT THE CONFERENCE AT THE

3225
02:19:38,941 --> 02:19:40,442
MIDWEST IMMUNOLOGISTS, DOES THIS

3226
02:19:40,442 --> 02:19:40,776
STILL EXIST?

3227
02:19:40,776 --> 02:19:43,011
THEY ARE BASED IN CHICAGO, NOT

3228
02:19:43,011 --> 02:19:44,313
SURE THE ORGANIZATION STILL

3229
02:19:44,313 --> 02:19:44,680
EXISTS.

3230
02:19:44,680 --> 02:19:46,281
PHIL DIDN'T WANT TO GO AND SENT

3231
02:19:46,281 --> 02:19:46,615
ME.

3232
02:19:46,615 --> 02:19:49,117
THEN I GAVE MY PRACTICE TALK TO

3233
02:19:49,117 --> 02:19:49,351
PHIL.

3234
02:19:49,351 --> 02:19:53,055
AND AT THE END OF THE TALK HE

3235
02:19:53,055 --> 02:19:54,590
SAID, LOTHAR, NOBODY IN THIS

3236
02:19:54,590 --> 02:19:58,427
AUDIENCE WILL HAVE FOLLOWED YOUR

3237
02:19:58,427 --> 02:19:59,027
WORK.

3238
02:19:59,027 --> 02:20:00,295
THEY WOULDN'T HAVE UNDERSTOOD A

3239
02:20:00,295 --> 02:20:01,597
SINGLE WORD YOU SAID.

3240
02:20:01,597 --> 02:20:03,265
WE WENT THROUGH THE SLIDES AND I

3241
02:20:03,265 --> 02:20:08,070
THINK I IMPROVED THE TALK TO

3242
02:20:08,070 --> 02:20:08,837
SOME EXTENT.

3243
02:20:08,837 --> 02:20:10,372
I'M STILL STRUGGLING WITH THAT.

3244
02:20:10,372 --> 02:20:13,075
ONE OF OUR LAST VISITS,

3245
02:20:13,075 --> 02:20:15,611
PRISCILLA, MY WIFE AND I,

3246
02:20:15,611 --> 02:20:18,247
VISITED A COUPLE YEARS AGO, PHIL

3247
02:20:18,247 --> 02:20:21,083
AND AYA AND I WENT OUT FOR

3248
02:20:21,083 --> 02:20:21,316
DINNER.

3249
02:20:21,316 --> 02:20:24,253
HE SAID IN MY CAREER, I GAVE IT

3250
02:20:24,253 --> 02:20:24,786
ALL.

3251
02:20:24,786 --> 02:20:28,757
THIS REFLECTS HIM, GIVING IT

3252
02:20:28,757 --> 02:20:29,291
ALL, THE PASSION.

3253
02:20:29,291 --> 02:20:38,533
SO NOW LET'S GO TO PHILS LAB,

3254
02:20:38,533 --> 02:20:42,971
1983, KATHY INTRODUCED THE LIST.

3255
02:20:42,971 --> 02:20:50,178
LOOKING FOR ELEMENTS THAT COULD 

3256
02:20:50,178 --> 02:20:52,481
REGULATE GENES ESPECIALLY C-MYC,

3257
02:20:52,481 --> 02:20:54,449
ENHANCERS JUST BEING DISCOVERED

3258
02:20:54,449 --> 02:21:00,055
AT NIH, ULLI SET OUT TO MAP

3259
02:21:00,055 --> 02:21:01,823
CANDIDATE ENHANCERS USING DNA

3260
02:21:01,823 --> 02:21:02,457
HYPERSENSITIVITY STUDIES, OPEN

3261
02:21:02,457 --> 02:21:04,426
CHROMATIN WHICH WOULD NOT BIND

3262
02:21:04,426 --> 02:21:07,095
TO HISTONES BUT REGULATORY

3263
02:21:07,095 --> 02:21:07,362
PROTEINS.

3264
02:21:07,362 --> 02:21:11,533
AND MY TASK WAS ACTUALLY -- PHIL

3265
02:21:11,533 --> 02:21:12,968
WAS KIND, HE SAID JUST TALK TO

3266
02:21:12,968 --> 02:21:14,603
PEOPLE AND FIND A PROJECT.

3267
02:21:14,603 --> 02:21:16,571
HE DIDN'T IMPOSE ANY PROJECT.

3268
02:21:16,571 --> 02:21:19,308
JUST FIND ONE WHICH INTERESTS

3269
02:21:19,308 --> 02:21:20,175
YOU.

3270
02:21:20,175 --> 02:21:21,510
I WAS INTERESTED IN PROTEINS

3271
02:21:21,510 --> 02:21:23,812
BINDING TO DNA.

3272
02:21:23,812 --> 02:21:29,384
AND, AGAIN, HOW DO YOU IDENTIFY

3273
02:21:29,384 --> 02:21:32,120
PROTEINS BY DNA?

3274
02:21:32,120 --> 02:21:33,021
CHIP-seq, RNAseq, BACK IN

3275
02:21:33,021 --> 02:21:35,190
THE DAY IT WAS MORE PRIMITIVE.

3276
02:21:35,190 --> 02:21:36,992
ALL OF YOU KNOW THIS PICTURE.

3277
02:21:36,992 --> 02:21:41,563
IF YOU GO TO THE MUSEUM AT NIH

3278
02:21:41,563 --> 02:21:42,964
YOU'LL SEE PHIL'S ORIGINAL

3279
02:21:42,964 --> 02:21:50,405
DEVICE USED TO CRACK THE GENETIC

3280
02:21:50,405 --> 02:21:53,775
CODE WITH NUREMBERG, IT WAS

3281
02:21:53,775 --> 02:21:56,445
PATENTED. 

3282
02:21:56,445 --> 02:21:58,714
I USE THIS DEVICE, A MORE

3283
02:21:58,714 --> 02:22:01,116
UPDATED VERSION, THE WAY WE

3284
02:22:01,116 --> 02:22:06,722
IDENTIFIED DNA BINDING PROTEINS 

3285
02:22:06,722 --> 02:22:10,592
WE LAID DNA FRAGMENTS, KINASE,

3286
02:22:10,592 --> 02:22:12,127
FRAGMENTS INCUBATED WITH NUCLEAR

3287
02:22:12,127 --> 02:22:14,596
EXTRACTS. 

3288
02:22:14,596 --> 02:22:16,898
AND THEN YOU PASSED OVER THE

3289
02:22:16,898 --> 02:22:19,134
MEMBRANE IN THE FILTRATION

3290
02:22:19,134 --> 02:22:19,701
APPARATUS.

3291
02:22:19,701 --> 02:22:25,340
FREE DNA, NOT BOUND TO DNA, 

3292
02:22:25,340 --> 02:22:35,851
FLOWING THROUGH THE MEMBRANE,

3293
02:22:36,718 --> 02:22:38,086
NITRO CELLULOUS.

3294
02:22:38,086 --> 02:22:38,587
THEY WERE LABELED.

3295
02:22:38,587 --> 02:22:43,191
ON THE LEFT SIDE YOU CAN SEE THE

3296
02:22:43,191 --> 02:22:44,493
INPUT DNA WITHOUT PROTEIN,

3297
02:22:44,493 --> 02:22:46,995
FRAGMENTS WENT THROUGH THE

3298
02:22:46,995 --> 02:22:48,096
MEMBRANE, RIGHT-HAND SIDE,

3299
02:22:48,096 --> 02:22:50,298
NUCLEAR EXTRACT, YOU CAN SEE

3300
02:22:50,298 --> 02:22:51,933
PROTEIN BIND TO THE UPPER

3301
02:22:51,933 --> 02:22:52,200
FRAGMENT.

3302
02:22:52,200 --> 02:22:57,706
THIS WAS IN A PAPER IN 1984, THE

3303
02:22:57,706 --> 02:22:59,474
DRIVING FORCE IN THIS STUDY,

3304
02:22:59,474 --> 02:23:04,446
GENE REGULATION IN BURKITT

3305
02:23:04,446 --> 02:23:04,813
LYMPHOMA.

3306
02:23:04,813 --> 02:23:15,323
WE WANT TO KNOW WHERE PROTEINS

3307
02:23:16,324 --> 02:23:20,762
BIND, YOU USE YOUR FRAGMENTS,

3308
02:23:20,762 --> 02:23:26,001
DUMP THE PROTEIN, PARTIAL

3309
02:23:26,001 --> 02:23:26,701
DIGESTION.

3310
02:23:26,701 --> 02:23:29,237
IT'S A FOOTPRINT, RESISTANT TO

3311
02:23:29,237 --> 02:23:29,738
ONE DIGESTION.

3312
02:23:29,738 --> 02:23:31,406
AND WE DIDN'T KNOW WHAT THE

3313
02:23:31,406 --> 02:23:38,413
PROTEINS WERE AT THAT POINT, NOW

3314
02:23:38,413 --> 02:23:40,282
CALLED STAT PROTEINS AND NFIB

3315
02:23:40,282 --> 02:23:48,190
FOLLOWED MY CAREER FOR THE NEXT

3316
02:23:48,190 --> 02:23:49,891
ALMOST 40 YEARS.

3317
02:23:49,891 --> 02:23:55,030
SO, TIME TO MOVE ON, AND

3318
02:23:55,030 --> 02:23:56,798
EVERYBODY ELSE MOVED TO THEIR

3319
02:23:56,798 --> 02:23:58,467
OWN CAREER, GOT THE SOLUTION

3320
02:23:58,467 --> 02:24:00,402
BOOK, THE IDEA WAS YOU ACTUALLY

3321
02:24:00,402 --> 02:24:01,937
RECORD ALL THE SOLUTIONS YOU

3322
02:24:01,937 --> 02:24:03,805
GENERATE AND ALL THE CLONES AND

3323
02:24:03,805 --> 02:24:05,674
ALL THE IMPORTANT THINGS

3324
02:24:05,674 --> 02:24:06,508
INCLUDING PICTURES.

3325
02:24:06,508 --> 02:24:07,776
AND ALWAYS THE PERSON WHO LEFT

3326
02:24:07,776 --> 02:24:10,345
THE LAB WAS NUMBER ONE.

3327
02:24:10,345 --> 02:24:11,813
AND THIS WAS ME BACK IN THE DAY,

3328
02:24:11,813 --> 02:24:13,448
THOSE OF YOU WHO KNOW THE LAB IN

3329
02:24:13,448 --> 02:24:15,517
BOSTON THIS WAS THE DOOR TO

3330
02:24:15,517 --> 02:24:16,184
PHIL'S OFFICE.

3331
02:24:16,184 --> 02:24:18,386
ACTUALLY I SHARED A BENCH WITH

3332
02:24:18,386 --> 02:24:18,687
PHIL.

3333
02:24:18,687 --> 02:24:20,021
AND NORMALLY PHIL DIDN'T WORK

3334
02:24:20,021 --> 02:24:24,192
TOO MUCH AT THE BENCH BUT WHEN

3335
02:24:24,192 --> 02:24:27,329
ONCOMASS CAME ALONG HE WAS THERE

3336
02:24:27,329 --> 02:24:29,764
EVERY DAY, HIS WHITE LAB COAT,

3337
02:24:29,764 --> 02:24:34,636
CAMERA, AROUND ALL THE TIME.

3338
02:24:34,636 --> 02:24:37,072
HE SAYS, LOTHAR, IN 1983 IN HIS

3339
02:24:37,072 --> 02:24:38,373
TEMPORARY CORNER, I WAS SUPPOSED

3340
02:24:38,373 --> 02:24:40,475
TO GET A PROPER DESK BUT I STATE

3341
02:24:40,475 --> 02:24:43,445
FOR MORE THAN TWO YEARS ON THIS

3342
02:24:43,445 --> 02:24:45,514
TINY DESK WITH THE GEL BOX NEXT

3343
02:24:45,514 --> 02:24:51,319
TO IT.

3344
02:24:51,319 --> 02:24:51,753
VERY CONVENIENT.

3345
02:24:51,753 --> 02:24:55,590
SO I MOVED ON STARTING SOMETHING

3346
02:24:55,590 --> 02:24:56,825
NEW, FOLLOWING YOUR DREAMS,

3347
02:24:56,825 --> 02:24:58,960
STARTING SOMETHING NEW.

3348
02:24:58,960 --> 02:25:01,263
AND I'VE CLONED THE GENES FROM

3349
02:25:01,263 --> 02:25:03,798
THE MAMMARY GLAND IN THE MOUSE

3350
02:25:03,798 --> 02:25:05,767
AND DECIDED HAVING LEARNED NEW

3351
02:25:05,767 --> 02:25:16,211
THINGS IN PHIL'S LAB MOUSE

3352
02:25:16,745 --> 02:25:17,345
GENTLES COULD BE REGULATED, WENT

3353
02:25:17,345 --> 02:25:18,146
BACK TO THIS.

3354
02:25:18,146 --> 02:25:21,650
WHY IS THIS SUCH A FASCINATING

3355
02:25:21,650 --> 02:25:23,051
PROBLEM?

3356
02:25:23,051 --> 02:25:25,887
MAMMARY GLAND IS AN ORGAN ONE

3357
02:25:25,887 --> 02:25:28,723
SOLE PURPOSE TO PRODUCE LARGE

3358
02:25:28,723 --> 02:25:30,492
QUANTITIES OF MILK, IN THE MOUSE

3359
02:25:30,492 --> 02:25:34,329
THE MOUSE COULD DO PRODUCE 20%

3360
02:25:34,329 --> 02:25:38,934
OF BODY WEIGHT IN MILK EVERY

3361
02:25:38,934 --> 02:25:39,167
DAY.

3362
02:25:39,167 --> 02:25:48,443
YOU CAN SEE THE  MEMORY ALVEOLI,

3363
02:25:48,443 --> 02:25:50,579
PURPOSE TO MAKE MILK PROTEINS,

3364
02:25:50,579 --> 02:25:53,148
ACCOUNTING FOR 90% OF MESSENGER

3365
02:25:53,148 --> 02:25:57,552
RNA IN THOSE CELLS, ONE REASON

3366
02:25:57,552 --> 02:26:02,991
WHY EASY, IN QUOTATION MARKS, TO

3367
02:26:02,991 --> 02:26:04,993
CLONE GENES.

3368
02:26:04,993 --> 02:26:11,533
NEXT DECADE WE USED TECHNOLOGIES

3369
02:26:11,533 --> 02:26:12,400
TRANSGENIC ANIMALS, KNOCKOUT

3370
02:26:12,400 --> 02:26:14,269
ANIMALS TO IDENTIFY HOW GENES

3371
02:26:14,269 --> 02:26:17,706
ARE REGULATED.

3372
02:26:17,706 --> 02:26:20,642
ONE KEY TRANSCRIPTION FACTOR IN

3373
02:26:20,642 --> 02:26:22,711
THE '90s, STAT5, KEY DRIVER OF

3374
02:26:22,711 --> 02:26:23,478
MAMMARY GLAND DEVELOPMENT.

3375
02:26:23,478 --> 02:26:26,514
IF YOU KNOCK OUT STAT5 THERE'S

3376
02:26:26,514 --> 02:26:32,320
NO MAMMARY GLAND DEVELOPMENT

3377
02:26:32,320 --> 02:26:35,323
DURING PREGNANCY MUCH IT'S

3378
02:26:35,323 --> 02:26:37,592
IMPORTANT FOR ACTIVATION OF

3379
02:26:37,592 --> 02:26:40,762
GENES, WE IDENTIFY USING MOUSE

3380
02:26:40,762 --> 02:26:50,238
GENETICS AND MUTATIONS AND

3381
02:26:50,238 --> 02:26:51,039
DELETIONS.

3382
02:26:51,039 --> 02:26:59,347
HOW THREE COMPONENTS DRIVE 

3383
02:26:59,347 --> 02:27:00,882
10,000 FOLD, PROMOTERS,

3384
02:27:00,882 --> 02:27:07,555
ENHANCERS, SUPERENHANCERS,

3385
02:27:07,555 --> 02:27:07,989
DEPENDENT ON STAT5.

3386
02:27:07,989 --> 02:27:11,493
MOST GENES IN THE MAMMARY GLAND

3387
02:27:11,493 --> 02:27:13,461
ARE SINGLE GENE LOCI, SOME ARE

3388
02:27:13,461 --> 02:27:14,596
IN CLUSTERS.

3389
02:27:14,596 --> 02:27:17,165
AND THERE'S ONE LOCUS WHICH IS

3390
02:27:17,165 --> 02:27:27,609
QUITE UNIQUE, IT'S CALLED

3391
02:27:29,344 --> 02:27:30,979
CASEINS, IN THE MAMMARY GRANDS,

3392
02:27:30,979 --> 02:27:34,482
OTHERS IN THE SALIVARY GLAND,

3393
02:27:34,482 --> 02:27:35,483
OTHERS EXPRESSED IN MAMMARY

3394
02:27:35,483 --> 02:27:39,788
ANDEL IS -- SALIVARY

3395
02:27:39,788 --> 02:27:41,923
WHAT IS THE LOCATION OF SUCH A

3396
02:27:41,923 --> 02:27:42,891
COMPLEX LOCUS WITH EIGHT

3397
02:27:42,891 --> 02:27:44,893
DIFFERENT GENES?

3398
02:27:44,893 --> 02:27:50,932
ARE THERE ANY SPECIFIC ENHANCER

3399
02:27:50,932 --> 02:27:51,266
ELEMENTS?

3400
02:27:51,266 --> 02:27:53,635
LEE SOLVED THE QUESTION AND

3401
02:27:53,635 --> 02:27:55,036
IDENTIFIED SUPER ENHANCER, AND

3402
02:27:55,036 --> 02:27:58,073
WE THOUGHT THE SUPER ENHANCER

3403
02:27:58,073 --> 02:28:00,241
WOULD COVER THE ENTIRE LOCUS,

3404
02:28:00,241 --> 02:28:03,078
RESPONSIBLE FOR ACTIVATION OF

3405
02:28:03,078 --> 02:28:06,548
ALL THE GENES, BUT IN THE

3406
02:28:06,548 --> 02:28:10,785
MAMMARY GLAND THIS CONTROLS ONLY

3407
02:28:10,785 --> 02:28:11,920
TWO MAMMARY SPECIFIC GENES AND

3408
02:28:11,920 --> 02:28:15,523
ONE SHARED GENES.

3409
02:28:15,523 --> 02:28:20,295
THE OTHER PROMOTERS, OWN

3410
02:28:20,295 --> 02:28:22,931
ENHANCERS, RESTRICTED.

3411
02:28:22,931 --> 02:28:26,668
THIS LOCUS IS UNIQUE,

3412
02:28:26,668 --> 02:28:29,504
INTERSPERSED IN MAMMARY AND

3413
02:28:29,504 --> 02:28:31,372
SALIVARY GLAND, SUPER ENHANCER

3414
02:28:31,372 --> 02:28:36,044
IS DUAL ACTIVITY, ACTIVATE GENES

3415
02:28:36,044 --> 02:28:44,819
IN MAMMARY GLAND OR SPECIFICALLY

3416
02:28:44,819 --> 02:28:55,096
SALIVARY GLAND. 

3417
02:28:57,165 --> 02:29:00,135
HIGHLY ACTIVATED GENES.

3418
02:29:00,135 --> 02:29:02,437
STAT5 IS CENTRAL, BUT THE NEXT

3419
02:29:02,437 --> 02:29:04,305
QUESTION WAS HOW IMPORTANT IS

3420
02:29:04,305 --> 02:29:06,674
THIS PROTEIN IN ANCHORING OR

3421
02:29:06,674 --> 02:29:08,543
ESTABLISHING THE ENTIRE SUPER

3422
02:29:08,543 --> 02:29:14,682
ENHANCER OR ENHANCER COMPLEX? 

3423
02:29:14,682 --> 02:29:17,652
AND HERE'S A SCHEMATIC,

3424
02:29:17,652 --> 02:29:19,721
IDENTIFIED ENHANCER, WHICH IS

3425
02:29:19,721 --> 02:29:22,524
VERY COMPLEX BINDING NUMEROUS

3426
02:29:22,524 --> 02:29:27,495
PROTEINS, NFIB WHEN I WORKED IN

3427
02:29:27,495 --> 02:29:29,230
PHIL'S LAB.

3428
02:29:29,230 --> 02:29:32,200
SEVERAL PROTEINS BIND TO DNA,

3429
02:29:32,200 --> 02:29:34,903
BUT IT TURNS OUT THAT ONLY ONE

3430
02:29:34,903 --> 02:29:40,241
IS THE ANCHOR FOR THIS TTC GAA

3431
02:29:40,241 --> 02:29:42,944
MOTIF RECOGNIZED BY STAT5.

3432
02:29:42,944 --> 02:29:44,546
THE GENE MUTATES ONE NUCLEOTIDE,

3433
02:29:44,546 --> 02:29:46,748
G TO A IN THE MOUSE.

3434
02:29:46,748 --> 02:29:49,951
NOT ONLY STAT5 FALLS OFF, BUT

3435
02:29:49,951 --> 02:29:52,787
THE ENTIRE LOCUS, ENTIRE

3436
02:29:52,787 --> 02:29:56,825
ENHANCER COMPLEX DISAPPEARS, 

3437
02:29:56,825 --> 02:29:58,459
CANNOT BIND ANYMORE.

3438
02:29:58,459 --> 02:30:00,662
SINGLE ANCHOR WHICH RECRUITS

3439
02:30:00,662 --> 02:30:02,297
OTHER PROTEINS, WHICH ALSO WOULD

3440
02:30:02,297 --> 02:30:05,700
BIND TO DNA, BUT THEY DON'T BIND

3441
02:30:05,700 --> 02:30:09,103
TO SPECIFIC MOTIFS.

3442
02:30:09,103 --> 02:30:15,009
SO, IN BOSTON, KATHY MENTIONED

3443
02:30:15,009 --> 02:30:18,613
ULLI, I ALSO FOUND A MATE,

3444
02:30:18,613 --> 02:30:20,481
PRISCILLA WORKED ACROSS THE QUAD

3445
02:30:20,481 --> 02:30:21,182
IN BERNIE'S LAB.

3446
02:30:21,182 --> 02:30:25,987
IT OF I WENT ON A BLIND -- I ON

3447
02:30:25,987 --> 02:30:27,589
A BLIND DATE, KELSEY MIGHT

3448
02:30:27,589 --> 02:30:31,226
REMEMBER, THE PIZZA PLACE,

3449
02:30:31,226 --> 02:30:33,194
CORRECT?

3450
02:30:33,194 --> 02:30:43,738
ACTUALLY PHIL ADOPTED PRISCILLA,

3451
02:30:43,972 --> 02:30:44,939
 MOLECULAR EXPERIMENTS, MANY

3452
02:30:44,939 --> 02:30:48,176
TEST TUBES, JUST SEQUENCE IT,

3453
02:30:48,176 --> 02:30:55,984
JUST SEQUENCE IT, REMEMBER THAT?

3454
02:30:55,984 --> 02:30:58,152
AND SO WE ALWAYS STOPPED IN

3455
02:30:58,152 --> 02:31:00,121
PHIL'S LAB, ON VACATION, THIS IS

3456
02:31:00,121 --> 02:31:01,990
THE BUILDING WHERE WE STARTED

3457
02:31:01,990 --> 02:31:02,223
IT.

3458
02:31:02,223 --> 02:31:04,893
YOU CAN SEE THREE CHILDREN, THE

3459
02:31:04,893 --> 02:31:07,328
HUMAN REPRODUCTION.

3460
02:31:07,328 --> 02:31:10,131
AND IN HONOR OUR SON ZAK, HIS

3461
02:31:10,131 --> 02:31:15,436
MIDDLE NAME IS  BOSTON, HE MOVED

3462
02:31:15,436 --> 02:31:16,771
BACK TO BOSTON AND PEOPLE DON'T

3463
02:31:16,771 --> 02:31:19,040
BELIEVE HIM SHOW HE HAS TO SHOW

3464
02:31:19,040 --> 02:31:20,241
HIS DRIVER'S LICENSE.

3465
02:31:20,241 --> 02:31:23,311
THOSE WERE THE GOOD OLD DAYS.

3466
02:31:23,311 --> 02:31:24,312
YOU MIGHT RECOGNIZE YOURSELF.

3467
02:31:24,312 --> 02:31:26,080
JOHN, YOU STILL LOOK THE SAME.

3468
02:31:26,080 --> 02:31:28,616
PHIL ALWAYS VERY PROPER.

3469
02:31:28,616 --> 02:31:34,822
AYA, YOU CAN SEE MYSELF OVER

3470
02:31:34,822 --> 02:31:35,156
THERE.

3471
02:31:35,156 --> 02:31:38,393
KATHY, JIM BATTEY ALSO MENTIONED

3472
02:31:38,393 --> 02:31:41,195
BY KATHY, AND JAY. 

3473
02:31:41,195 --> 02:31:41,896
THANK YOU VERY MUCH.

3474
02:31:41,896 --> 02:31:44,499
[APPLAUSE]

3475
02:31:44,499 --> 02:31:50,471
 

3476
02:31:50,471 --> 02:32:00,515
 

3477
02:32:05,453 --> 02:32:09,257
>> IT'S A SMALL WORLD,
ISN'T IT?

3478
02:32:09,257 --> 02:32:12,860
OUR NEXT SPEAKER IS THE MUCH

3479
02:32:12,860 --> 02:32:15,029
REFERENCED CYNTHIA MORTON.

3480
02:32:15,029 --> 02:32:16,931
WILLIAM LAMBERT RICHARDSON

3481
02:32:16,931 --> 02:32:23,571
PROFESSOR OF  OBSTETRICS AND

3482
02:32:23,571 --> 02:32:29,811
GYNECOLOGY, DIRECTOR OF 

3483
02:32:29,811 --> 02:32:31,679
CYTOGENETICS, PROFESSOR OF

3484
02:32:31,679 --> 02:32:32,347
PATHOLOGY HARVARD, UNDERGRAD

3485
02:32:32,347 --> 02:32:33,181
FROM COLLEGE OF WILLIAM AND

3486
02:32:33,181 --> 02:32:35,183
MARY, Ph.D. FROM MEDICAL

3487
02:32:35,183 --> 02:32:36,184
COLLEGE OF VIRGINIA.

3488
02:32:36,184 --> 02:32:40,855
SHE WAS A POSTDOC IN THE

3489
02:32:40,855 --> 02:32:48,096
LABORATORIES  OF PHIL LEDER,

3490
02:32:48,096 --> 02:32:49,197
JOINED THE HARVARD FACULTY,

3491
02:32:49,197 --> 02:32:53,334
OVERALL THEME IS APPLICATION OF

3492
02:32:53,334 --> 02:32:56,938
EVOLVING TECHNIQUES IN MOLECULAR

3493
02:32:56,938 --> 02:33:03,711
CYTOGENETICS TO ADDRESS PROBLEMS

3494
02:33:03,711 --> 02:33:05,580
IN HUMAN CYTO GENETICS, THERE IS

3495
02:33:05,580 --> 02:33:07,148
INCLUDE IDENTIFYING GENES IN

3496
02:33:07,148 --> 02:33:08,549
HEARING, DEAFNESS DISORDERS, AS

3497
02:33:08,549 --> 02:33:10,418
WELL AS OTHER DEVELOPMENTAL

3498
02:33:10,418 --> 02:33:10,818
DISORDERS.

3499
02:33:10,818 --> 02:33:12,620
SHE'S BEEN THE PRESIDENT OF THE

3500
02:33:12,620 --> 02:33:15,123
AMERICAN SOCIETY OF HUMAN

3501
02:33:15,123 --> 02:33:16,991
GENETICS, SERVED NIH IN MANY

3502
02:33:16,991 --> 02:33:19,160
CAPACITIES INCLUDING BEING CHAIR

3503
02:33:19,160 --> 02:33:27,301
OF THE NIDCD BOARD OF SCIENTIFIC

3504
02:33:27,301 --> 02:33:37,578
COUNSELORS, RECIPIENT OF THE

3505
02:33:37,578 --> 02:33:38,780
DISTINGUISHED CYTOGENTETICIST

3506
02:33:38,780 --> 02:33:46,621
AWARDS AMONG OTHERS.

3507
02:33:46,621 --> 02:33:49,657
[APPLAUSE] 

3508
02:33:49,657 --> 02:33:50,191
OF.

3509
02:33:50,191 --> 02:33:55,029
>> GOOD AFTERNOON.

3510
02:33:55,029 --> 02:33:57,198
WHAT AMAZING MEMORIES HAVE COME

3511
02:33:57,198 --> 02:34:02,070
UP IN ME BEING HERE TODAY.

3512
02:34:02,070 --> 02:34:04,439
IT'S REALLY BEEN ENORMOUSLY

3513
02:34:04,439 --> 02:34:04,705
SPECIAL.

3514
02:34:04,705 --> 02:34:12,747
SO, I HAVE A WARM MEMORY OF THE 

3515
02:34:12,747 --> 02:34:13,414
FIRST IN-PERSON MEETING WITH

3516
02:34:13,414 --> 02:34:15,817
PHIL LEDER AT A RECEPTION IN THE

3517
02:34:15,817 --> 02:34:19,153
GARDEN OF THE JERUSALEM MUSEUM 

3518
02:34:19,153 --> 02:34:20,421
IN THE FALL OF 1981.

3519
02:34:20,421 --> 02:34:27,895
I WAS A FIFTH YEAR GRADUATE

3520
02:34:27,895 --> 02:34:30,431
STUDENT, IN HUMAN GENETICS,

3521
02:34:30,431 --> 02:34:32,567
MEDICAL COLLEGE OF VIRGINIA IN

3522
02:34:32,567 --> 02:34:32,834
RICHMOND.

3523
02:34:32,834 --> 02:34:35,336
THE STORY IS ONE THAT'S A

3524
02:34:35,336 --> 02:34:39,507
FAVORITE IN MY LIFE THAT BEGINS

3525
02:34:39,507 --> 02:34:47,515
AT A WORKSHOP AT THE SHORT 

3526
02:34:47,515 --> 02:34:50,551
COURSE IN EXPERIMENTAL MAMMALIAN

3527
02:34:50,551 --> 02:34:53,054
GENETIC, IN BAR HARBOR, CONNECTS

3528
02:34:53,054 --> 02:34:56,557
WITH RICK, AMAZING THESE THINGS

3529
02:34:56,557 --> 02:34:57,425
HAPPENED IN LIFE.

3530
02:34:57,425 --> 02:35:01,429
AS A GRAD STUDENT I HAD CHOSEN

3531
02:35:01,429 --> 02:35:03,631
HUMAN CYTOGENETICS AS MY

3532
02:35:03,631 --> 02:35:03,965
SPECIALLY.

3533
02:35:03,965 --> 02:35:09,504
I VOLUNTEERED TO  ASSIST IN

3534
02:35:09,504 --> 02:35:11,005
KARYOTYPING WORKSHOP WITH AN

3535
02:35:11,005 --> 02:35:12,673
OPPORTUNITY TO CUT PHOTOGRAPHS

3536
02:35:12,673 --> 02:35:19,247
OF PRO METAPHASE AND META PHASE,

3537
02:35:19,247 --> 02:35:24,719
ALIGN IN SPARES WITH DOUBLE

3538
02:35:24,719 --> 02:35:25,920
STICKY TAPE.

3539
02:35:25,920 --> 02:35:30,858
THROUGH A CHANCE MEETING AT THE

3540
02:35:30,858 --> 02:35:35,863
TABLE, I JOINED, TO ASSIST 

3541
02:35:35,863 --> 02:35:41,235
STUDENTS I MET LANNY KIRSCH WHO

3542
02:35:41,235 --> 02:35:43,638
ATTENDED THE SHORT COURSE IN

3543
02:35:43,638 --> 02:35:49,544
1981, I MET JON, KRICKET, AND A

3544
02:35:49,544 --> 02:35:52,413
WORK IN PROBLEM WHO BECAME THEIR

3545
02:35:52,413 --> 02:35:53,447
DAUGHTER ANIKA.

3546
02:35:53,447 --> 02:35:55,583
I LISTENED TO LANNY DESCRIBING

3547
02:35:55,583 --> 02:35:56,751
EXCITING EXPERIMENTS UNDERWAY IN

3548
02:35:56,751 --> 02:35:59,086
THE LEDER LABORATORY TO MAP

3549
02:35:59,086 --> 02:36:01,756
HUMAN GENES.

3550
02:36:01,756 --> 02:36:05,526
BY CHROMOSOMAL IN SITU

3551
02:36:05,526 --> 02:36:08,963
HYBRIDIZATION WITH DNA LABELED

3552
02:36:08,963 --> 02:36:09,297
PROBES.

3553
02:36:09,297 --> 02:36:11,666
A MISSING ELEMENT WAS IN THE

3554
02:36:11,666 --> 02:36:14,302
EXPERIMENTAL PLAN, SOMEONE TO

3555
02:36:14,302 --> 02:36:15,403
READ THE SLIDES.

3556
02:36:15,403 --> 02:36:19,106
I WANTED TO OFFER HELP, AND

3557
02:36:19,106 --> 02:36:20,575
PROPOSE APPLYING THE METHOD I

3558
02:36:20,575 --> 02:36:23,978
WAS USING IN MY DISSERTATION

3559
02:36:23,978 --> 02:36:26,447
RESEARCH TO STAIN CHROMOSOMES

3560
02:36:26,447 --> 02:36:30,384
WITH A SILVER NITRATE SOLUTION,

3561
02:36:30,384 --> 02:36:32,820
AND THEN ILLUMINATE THE

3562
02:36:32,820 --> 02:36:37,525
CHROMOSOMES BY USING

3563
02:36:37,525 --> 02:36:38,893
FLUORESCENCE MICROSCOPY.

3564
02:36:38,893 --> 02:36:43,364
FOLLOWING THE SILVER STAINING,

3565
02:36:43,364 --> 02:36:46,834
YOU CAN SEE BY CHANGING THE

3566
02:36:46,834 --> 02:36:48,269
BRIGHT FIELD AND FLUORESCENCE

3567
02:36:48,269 --> 02:36:50,838
AND SCORE THE SILVER STAINING

3568
02:36:50,838 --> 02:36:52,840
AND THEN DETERMINE WHICH

3569
02:36:52,840 --> 02:36:55,376
CHROMOSOME IT WAS.

3570
02:36:55,376 --> 02:36:59,247
SO, THERE'S SOME OVERLAP IN THE

3571
02:36:59,247 --> 02:37:00,615
EXPERIMENTAL METHOD, SILVER

3572
02:37:00,615 --> 02:37:08,055
STAIN ON THE ACTIVE NUKE LEOLA

3573
02:37:08,055 --> 02:37:09,090
ORGANIZER REGIONS GENES

3574
02:37:09,090 --> 02:37:10,491
ILLUMINATED IN THE PHOTOGRAPHIC

3575
02:37:10,491 --> 02:37:16,931
EMULSION BUT IT WAS REALLY JUST

3576
02:37:16,931 --> 02:37:17,598
DUMB LUCK.

3577
02:37:17,598 --> 02:37:20,101
NEVERTHELESS, ONE DAY A BOX OF

3578
02:37:20,101 --> 02:37:23,838
SLIDES ARRIVED IN RICHMOND FROM

3579
02:37:23,838 --> 02:37:25,273
LANNY, FOR ME TO ANALYZE.

3580
02:37:25,273 --> 02:37:27,008
FRANKLY I DIDN'T THINK FOR ONE

3581
02:37:27,008 --> 02:37:30,711
MOMENT WHAT GENE THEY MIGHT BE

3582
02:37:30,711 --> 02:37:31,679
MAPPING.

3583
02:37:31,679 --> 02:37:33,314
LANNY CALLED ME ONE AFTERNOON

3584
02:37:33,314 --> 02:37:36,550
AND I WAS AT THE FLUORESCENCE

3585
02:37:36,550 --> 02:37:37,084
MICROSCOPE.

3586
02:37:37,084 --> 02:37:39,120
I ANSWERED THE PHONE, TO ASK

3587
02:37:39,120 --> 02:37:42,356
WHETHER I LOOKED AT THE SLIDES.

3588
02:37:42,356 --> 02:37:43,124
I HADN'T.

3589
02:37:43,124 --> 02:37:46,360
AFTER ALL, I WAS BUSY WITH MY

3590
02:37:46,360 --> 02:37:47,928
OWN DISSERTATION RESEARCH, BUT I

3591
02:37:47,928 --> 02:37:54,802
STOPPED AND STAINED THE LIDS  --

3592
02:37:54,802 --> 02:37:57,905
SLIDES AND WENT TO THE

3593
02:37:57,905 --> 02:38:00,274
FLUORESCENT MICROSCOPES.

3594
02:38:00,274 --> 02:38:02,510
I KNEW IN AN HOUR THE LOCATION

3595
02:38:02,510 --> 02:38:06,881
OF THE DNA PROBE.

3596
02:38:06,881 --> 02:38:09,917
LATER THAT AFTERNOON, CAME THE

3597
02:38:09,917 --> 02:38:12,753
LIFE-CHANGING PHONE CALL FROM

3598
02:38:12,753 --> 02:38:13,788
LANNY.

3599
02:38:13,788 --> 02:38:15,289
HE INQUIRED AS TO WHETHER I

3600
02:38:15,289 --> 02:38:18,492
COULD DETERMINE THE LOCATION OF

3601
02:38:18,492 --> 02:38:23,064
THE SILVER GRAINS, AND I SAID,

3602
02:38:23,064 --> 02:38:23,831
YES, 14.

3603
02:38:23,831 --> 02:38:26,901
AND THEN HE ASKED IF I COULD

3604
02:38:26,901 --> 02:38:29,437
DETERMINE WHERE THEY WERE, ON

3605
02:38:29,437 --> 02:38:33,240
CHROMOSOME 14, AND I SAID, OH,

3606
02:38:33,240 --> 02:38:37,078
YES, THEY ARE AT 14Q 32.

3607
02:38:37,078 --> 02:38:41,682
SO THIS IS A SORT OF FUZZY IMAGE

3608
02:38:41,682 --> 02:38:44,618
FROM THE MICROSCOPE WHERE YOU

3609
02:38:44,618 --> 02:38:47,588
CAN SORT OF SEE JUST THE

3610
02:38:47,588 --> 02:38:49,557
FLUORESCENCE AND THEN THE

3611
02:38:49,557 --> 02:38:50,891
FLUORESCENCE WITH THE BRIGHT

3612
02:38:50,891 --> 02:38:54,662
FIELD TURNED UP, AND YOU CAN SEE

3613
02:38:54,662 --> 02:38:58,799
ON BOTH CHROMOSOMES 14 THEY HAD

3614
02:38:58,799 --> 02:39:02,770
THIS LARGE BLACK AREA OF

3615
02:39:02,770 --> 02:39:03,037
STAINING.

3616
02:39:03,037 --> 02:39:07,108
AND WE PREPARED THESE TYPES OF

3617
02:39:07,108 --> 02:39:08,309
IDIOGRAMS FOR PUBLICATION.

3618
02:39:08,309 --> 02:39:13,781
THERE WAS NO POWERPOINT AT THAT

3619
02:39:13,781 --> 02:39:14,348
POINT.

3620
02:39:14,348 --> 02:39:15,182
OKAY.

3621
02:39:15,182 --> 02:39:17,084
SO, THERE'S AN EVEN LARGER

3622
02:39:17,084 --> 02:39:19,920
VERSION OF WHAT THE CHROMOSOME

3623
02:39:19,920 --> 02:39:22,123
14 LOOKED LIKE.

3624
02:39:22,123 --> 02:39:24,725
SO, THEN THERE'S ANOTHER PLAYER.

3625
02:39:24,725 --> 02:39:26,160
LANNY ASKED IF SOMEONE IN THE

3626
02:39:26,160 --> 02:39:29,897
LAB COULD PICK UP THE PHONE AND

3627
02:39:29,897 --> 02:39:33,033
JUST ANSWER SOME QUESTIONS THAT 

3628
02:39:33,033 --> 02:39:36,470
I HAD JUST ANSWERED.

3629
02:39:36,470 --> 02:39:36,971
SURE.

3630
02:39:36,971 --> 02:39:40,808
THAT SOMEONE WAS JEFF RADISH.

3631
02:39:40,808 --> 02:39:42,910
AND SO LANNY REPEATED THE SAME

3632
02:39:42,910 --> 02:39:43,677
QUESTIONS.

3633
02:39:43,677 --> 02:39:45,279
YOU KNOW, WHAT CHROMOSOME IT'S

3634
02:39:45,279 --> 02:39:49,683
ON, DO YOU KNOW WHERE IT IS ON

3635
02:39:49,683 --> 02:39:50,518
CHROMOSOME 14.

3636
02:39:50,518 --> 02:39:54,088
AND THAT WAS THE MAPPING OF THE

3637
02:39:54,088 --> 02:39:56,023
IMMUNOGLOBULIN HEAVY CHAIN

3638
02:39:56,023 --> 02:39:56,657
LOCUS.

3639
02:39:56,657 --> 02:39:57,625
AND I REMEMBER JUST STANDING IN

3640
02:39:57,625 --> 02:39:59,960
THE LAB FOR A LITTLE BIT

3641
02:39:59,960 --> 02:40:03,564
THINKING, WHAT JUST HAPPENED?

3642
02:40:03,564 --> 02:40:05,666
LITTLE DID I REALIZE THAT THIS

3643
02:40:05,666 --> 02:40:08,302
WOULD CHANGE MY ENTIRE CAREER.

3644
02:40:08,302 --> 02:40:13,207
AND THEN WE WENT ON TO ACTUALLY

3645
02:40:13,207 --> 02:40:16,644
MAP LOTS OF GENES, AND IT WAS

3646
02:40:16,644 --> 02:40:19,914
JUST TERRIFICALLY FUN, I'LL TELL

3647
02:40:19,914 --> 02:40:20,314
YOU.

3648
02:40:20,314 --> 02:40:22,116
SO, THEN ANOTHER SORT OF CHANCE

3649
02:40:22,116 --> 02:40:24,151
THING HAPPENED, IN THAT I HAD

3650
02:40:24,151 --> 02:40:28,255
ACCEPTED A POSITION AT A POSTDOC

3651
02:40:28,255 --> 02:40:32,059
AT HARVARD, BOSTON CHILDREN'S

3652
02:40:32,059 --> 02:40:35,029
HOSPITAL, WITH A JUNIOR

3653
02:40:35,029 --> 02:40:36,997
INVESTIGATOR THERE, AND THE

3654
02:40:36,997 --> 02:40:39,867
LEDER LAB WAS SO EXCITING, IT

3655
02:40:39,867 --> 02:40:41,602
WAS REALLY HARD, IT WAS LIKE AT

3656
02:40:41,602 --> 02:40:46,941
NIGHT I WOULD GO OVER THERE, AND

3657
02:40:46,941 --> 02:40:50,811
DO MORE GENE MAPPING.

3658
02:40:50,811 --> 02:40:51,745
EVENTUALLY, I DECIDED THAT THIS

3659
02:40:51,745 --> 02:40:54,715
IS WHAT I REALLY WANTED TO DO.

3660
02:40:54,715 --> 02:40:58,652
AND I WANTED TO ASK PHIL IF I

3661
02:40:58,652 --> 02:41:01,055
COULD JOIN HIS LABORATORY.

3662
02:41:01,055 --> 02:41:03,457
SO, I JUST WAS STANDING IN THE

3663
02:41:03,457 --> 02:41:04,859
DOOR AND ASKED HIM THIS

3664
02:41:04,859 --> 02:41:05,125
QUESTION.

3665
02:41:05,125 --> 02:41:10,564
HE SAID, CLOSE THE DOOR AND SIT

3666
02:41:10,564 --> 02:41:11,699
DOWN.

3667
02:41:11,699 --> 02:41:12,099
OKAY.

3668
02:41:12,099 --> 02:41:14,735
AND AFTER I POPPED THAT

3669
02:41:14,735 --> 02:41:16,370
QUESTION, HE TOLD ME THAT IT

3670
02:41:16,370 --> 02:41:18,739
REALLY WOULDN'T BE GOOD FOR HIM

3671
02:41:18,739 --> 02:41:21,976
TO BE RECRUITED TO THE FACULTY

3672
02:41:21,976 --> 02:41:24,578
AND FOR HIM TO THEN TAKE THE

3673
02:41:24,578 --> 02:41:27,681
POSTDOCS FROM THE JUNIOR

3674
02:41:27,681 --> 02:41:28,082
FACULTY.

3675
02:41:28,082 --> 02:41:30,584
I SAID, I UNDERSTAND THAT.

3676
02:41:30,584 --> 02:41:33,120
BUT I'M NOT GOING TO STAY WHERE

3677
02:41:33,120 --> 02:41:33,888
I AM.

3678
02:41:33,888 --> 02:41:35,556
I'M TELLING YOU THAT FOR SURE.

3679
02:41:35,556 --> 02:41:38,559
AND I KNOW BOSTON HAS LOTS OF

3680
02:41:38,559 --> 02:41:40,227
OPPORTUNITIES, SO PROBABLY I'LL

3681
02:41:40,227 --> 02:41:43,731
BE LEAVING THAT LAB ANYWAYS.

3682
02:41:43,731 --> 02:41:48,602
IT'S JUST THAT THE LAB WAS SUCH

3683
02:41:48,602 --> 02:41:50,504
AN EXCITING PLACE, MOST OF THE

3684
02:41:50,504 --> 02:41:51,872
FOLKS IN THE CHILDREN'S

3685
02:41:51,872 --> 02:41:54,508
DEPARTMENT AT THAT POINT HAD

3686
02:41:54,508 --> 02:41:56,577
FAMILIES AND CHILDREN AND THEY

3687
02:41:56,577 --> 02:41:59,079
WERE GOING HOME AT NIGHT AND I

3688
02:41:59,079 --> 02:42:00,981
WAS THERE BY MYSELF.

3689
02:42:00,981 --> 02:42:03,117
AND SO IT REALLY BECAME AT THAT

3690
02:42:03,117 --> 02:42:04,518
POINT -- I CAN'T SPEAK FOR WHAT

3691
02:42:04,518 --> 02:42:12,960
WAS GOING ON ON THE SIXTH FLOOR,

3692
02:42:12,960 --> 02:42:14,929
STU WAS ON THE 6th FLOOR, I

3693
02:42:14,929 --> 02:42:17,898
WAS EXCITED TO JOIN THE LAB.

3694
02:42:17,898 --> 02:42:20,668
AND THEN THERE WAS THE NEXT

3695
02:42:20,668 --> 02:42:23,237
EXPERIMENT, ONE OF THE NEXT

3696
02:42:23,237 --> 02:42:25,439
MAPPING EXPERIMENTS, WHICH WAS

3697
02:42:25,439 --> 02:42:28,776
THE MYC GENE.

3698
02:42:28,776 --> 02:42:34,114
YOU CAN SEE THE SPIKE AT 8Q24.

3699
02:42:34,114 --> 02:42:36,417
THIS WAS TRULY A DREAM COME

3700
02:42:36,417 --> 02:42:41,455
THROUGH FOR A YOUNG

3701
02:42:41,455 --> 02:42:44,558
CYTOGENETICIST, A PATH TO

3702
02:42:44,558 --> 02:42:45,392
DISCOVER THE CHROMOSOMAL

3703
02:42:45,392 --> 02:42:48,262
REARRANGEMENTS, BUT FOR MYC AND

3704
02:42:48,262 --> 02:42:51,198
IMMUNOGLOBULIN THIS REALLY ONLY

3705
02:42:51,198 --> 02:42:54,635
TOOK PLACE IN SEPTEMBER --

3706
02:42:54,635 --> 02:42:57,071
PUBLICATION IN SEPTEMBER IN

3707
02:42:57,071 --> 02:43:01,008
"SCIENCE" LAST YEAR, 2022.

3708
02:43:01,008 --> 02:43:04,445
SO, THERE WAS A PAPER THAT

3709
02:43:04,445 --> 02:43:08,082
SHOWED THAT REPLICATION TIMING 

3710
02:43:08,082 --> 02:43:11,251
IS RELATED TO TRANSLOCATION

3711
02:43:11,251 --> 02:43:12,853
REARRANGEMENTS, AND THAT

3712
02:43:12,853 --> 02:43:16,290
IMMUNOGLOBULIN IS IN THE SAME

3713
02:43:16,290 --> 02:43:18,826
TOPOLOGICAL-ASSOCIATED DOMAIN AS

3714
02:43:18,826 --> 02:43:19,793
IS MYC.

3715
02:43:19,793 --> 02:43:22,062
SO, DOUBLE-STRAND BREAKS OCCUR,

3716
02:43:22,062 --> 02:43:30,604
AS YOU KNOW, IN THE ONTOGENY OF 

3717
02:43:30,604 --> 02:43:32,506
IMMUNOGLOBULIN BIOLOGY, AND THEN

3718
02:43:32,506 --> 02:43:35,776
SOME STATES TAKE PLACE IN MYC,

3719
02:43:35,776 --> 02:43:37,544
DOUBLE-STRAND BREAKS OCCUR,

3720
02:43:37,544 --> 02:43:42,616
THAT'S THE ORIGIN OF THE

3721
02:43:42,616 --> 02:43:42,983
TRANSLOCATIONS.

3722
02:43:42,983 --> 02:43:45,185
SO IT'S POSSIBLE THAT MAYBE

3723
02:43:45,185 --> 02:43:48,255
THERE WOULD BE SOME POTENTIAL

3724
02:43:48,255 --> 02:43:50,157
THERAPY BY ACTUALLY PUSHING MYC

3725
02:43:50,157 --> 02:43:53,327
INTO A DIFFERENT REPLICATION

3726
02:43:53,327 --> 02:43:54,094
TIMING DOMAIN.

3727
02:43:54,094 --> 02:43:57,698
I WANTED TO SHARE THAT PAPER

3728
02:43:57,698 --> 02:44:01,535
WITH PHIL TO SAY NOW WE KNOW, 39

3729
02:44:01,535 --> 02:44:03,437
YEARS LATER, WHICH WENT BY LIKE

3730
02:44:03,437 --> 02:44:05,572
A FLASH.

3731
02:44:05,572 --> 02:44:10,711
BUT I TOOK THE SECOND BEST IDEA,

3732
02:44:10,711 --> 02:44:13,147
WHICH WAS TO GO AND SHARE THIS

3733
02:44:13,147 --> 02:44:15,683
WITH AYA.

3734
02:44:15,683 --> 02:44:19,053
SO WE SAT FOR HOURS TALKING

3735
02:44:19,053 --> 02:44:20,254
ABOUT THIS PAPER.

3736
02:44:20,254 --> 02:44:23,223
IT WAS JUST AMAZINGLY FUN, JUST

3737
02:44:23,223 --> 02:44:25,259
TOTALLY HAD A GREAT TIME, ABOUT

3738
02:44:25,259 --> 02:44:28,762
6 TO 8 WEEKS AGO NOW.

3739
02:44:28,762 --> 02:44:32,299
THE LEDER LAB WAS A FAMILY

3740
02:44:32,299 --> 02:44:33,100
PLACE.

3741
02:44:33,100 --> 02:44:35,903
SOME OF MY HAPPIEST DAYS IN THE

3742
02:44:35,903 --> 02:44:36,870
LAB WERE THERE.

3743
02:44:36,870 --> 02:44:44,645
THE RULES WERE EASY TO LIVE BY.

3744
02:44:44,645 --> 02:44:45,979
I OFTEN ORIENTED NEW MEMBERS OF

3745
02:44:45,979 --> 02:44:49,016
THE LAB, TELLING THEM NOT TO PUT

3746
02:44:49,016 --> 02:44:53,187
TAPE ON THE WALLS OR FURNITURE 

3747
02:44:53,187 --> 02:44:54,655
OF THE LABORATORY.

3748
02:44:54,655 --> 02:45:00,027
[LAUGHTER] 

3749
02:45:00,027 --> 02:45:04,398
SO, ONCE WHILE LOOKING OVER MY

3750
02:45:04,398 --> 02:45:06,233
SHOULDER, PHIL REMINDED ME THAT

3751
02:45:06,233 --> 02:45:09,002
IT WAS POSSIBLE TO USE BOTH ENDS

3752
02:45:09,002 --> 02:45:10,604
OF THE TOOTHPICK.

3753
02:45:10,604 --> 02:45:14,074
[LAUGHTER] 

3754
02:45:14,074 --> 02:45:16,577
I SAID, OKAY.

3755
02:45:16,577 --> 02:45:17,878
SO, THAT'S JUST BEING THRIFTY,

3756
02:45:17,878 --> 02:45:18,178
RIGHT?

3757
02:45:18,178 --> 02:45:20,180
THAT WAS A GOOD IDEA.

3758
02:45:20,180 --> 02:45:22,516
HE WAS A FABULOUS SPEAKER.

3759
02:45:22,516 --> 02:45:25,519
AND THERE WERE TIMES WHEN I

3760
02:45:25,519 --> 02:45:27,054
ATTENDED HIS TALKS AT HARVARD

3761
02:45:27,054 --> 02:45:30,924
JUST TO WATCH HIM GIVE THE TALK.

3762
02:45:30,924 --> 02:45:34,728
AND AT SOME TIMES I FELT THAT HE

3763
02:45:34,728 --> 02:45:37,131
WAS GAZING UP FOR DIVINE

3764
02:45:37,131 --> 02:45:39,333
INSPIRATION AND THEN WOULD TELL

3765
02:45:39,333 --> 02:45:41,835
YOU ABOUT THIS EXPERIMENT.

3766
02:45:41,835 --> 02:45:43,537
IT WAS REALLY FABULOUS.

3767
02:45:43,537 --> 02:45:46,540
I KNOW THAT THERE ARE MANY

3768
02:45:46,540 --> 02:45:48,275
MEMORIES LIKE THIS, AMONG OTHERS

3769
02:45:48,275 --> 02:45:50,577
HERE, THAT SHAPED THEIR LIVES,

3770
02:45:50,577 --> 02:45:54,615
AND HE LED US ALL BY EXAMPLE.

3771
02:45:54,615 --> 02:45:56,717
HIS PASSION FOR SCIENCE, HIS

3772
02:45:56,717 --> 02:46:00,087
SKILL AS A TEACHER AND

3773
02:46:00,087 --> 02:46:01,855
COMMUNICATOR, THROUGH HIS

3774
02:46:01,855 --> 02:46:03,357
HUMANITY, AND DECENCY, HE MADE

3775
02:46:03,357 --> 02:46:07,427
US ALL BETTER PEOPLE AND BETTER

3776
02:46:07,427 --> 02:46:08,061
SCIENTISTS.

3777
02:46:08,061 --> 02:46:11,698
SO, I'M JUST GOING TO WRAP UP

3778
02:46:11,698 --> 02:46:13,500
HERE BY THANKING THE ORGANIZERS

3779
02:46:13,500 --> 02:46:18,438
OF THIS MEETING FOR GIVING US

3780
02:46:18,438 --> 02:46:20,607
THIS OPPORTUNITY TO BE TOGETHER.

3781
02:46:20,607 --> 02:46:26,046
AND THANK YOU SO MUCH FOR

3782
02:46:26,046 --> 02:46:26,713
CONSTRUCTING THIS HOUSE, WHICH

3783
02:46:26,713 --> 02:46:29,750
THERE'S NO DOUBT HE WOULD LOVE

3784
02:46:29,750 --> 02:46:30,184
THIS.

3785
02:46:30,184 --> 02:46:33,554
HE WOULD ABSOLUTELY LOVE THIS.

3786
02:46:33,554 --> 02:46:36,356
SO, I BELIEVE THAT THIS HOME

3787
02:46:36,356 --> 02:46:39,059
WILL NOURISH AMONG ITS OCCUPANTS

3788
02:46:39,059 --> 02:46:42,696
SOME OF THE CHARACTER TRAITS AND

3789
02:46:42,696 --> 02:46:44,598
SCIENTIFIC GENIUS OF A GREAT MAN

3790
02:46:44,598 --> 02:46:47,267
WHO LOVED HIS FAMILY.

3791
02:46:47,267 --> 02:46:49,336
I HOPE THAT THOSE OF YOU WHO ARE

3792
02:46:49,336 --> 02:46:51,338
SO FORTUNATE TO LIVE WITHIN

3793
02:46:51,338 --> 02:46:52,840
THESE WALLS, AND I IMAGINE THE

3794
02:46:52,840 --> 02:46:56,143
STUDENTS ARE BUSY SO THEY ARE

3795
02:46:56,143 --> 02:46:57,911
NOT HERE TODAY, BUT WILL ACQUIRE

3796
02:46:57,911 --> 02:47:02,583
AT LEAST A BIT OF HIS REMARKABLE

3797
02:47:02,583 --> 02:47:03,584
CHARACTER.

3798
02:47:03,584 --> 02:47:05,853
FOR CERTAIN, THERE'S NEVER A DAY

3799
02:47:05,853 --> 02:47:09,156
WHEN I'M HAPPIER THAN ONE WHERE

3800
02:47:09,156 --> 02:47:10,858
I HAVE AN OPPORTUNITY TO SEIZE

3801
02:47:10,858 --> 02:47:12,359
THE MOMENT AND TO SHARE THAT I

3802
02:47:12,359 --> 02:47:16,296
WAS A POSTDOC IN THE LEDER

3803
02:47:16,296 --> 02:47:16,864
LABORATORY.

3804
02:47:16,864 --> 02:47:18,565
HE TRULY SHAPED MY LIFE AND MY

3805
02:47:18,565 --> 02:47:22,436
CAREER, AND HE WAS SIMPLY THE

3806
02:47:22,436 --> 02:47:25,272
BEST. 

3807
02:47:25,272 --> 02:47:35,482
[APPLAUSE] 

3808
02:47:46,159 --> 02:47:47,461
>> OKAY.

3809
02:47:47,461 --> 02:47:49,596
FINAL SPEAKER IS RICHARD

3810
02:47:49,596 --> 02:47:51,765
WOYCHIK, DIRECTOR OF THE

3811
02:47:51,765 --> 02:47:53,000
NATIONAL INSTITUTES OF

3812
02:47:53,000 --> 02:47:54,501
ENVIRONMENTAL HEALTH SCIENCES.

3813
02:47:54,501 --> 02:47:56,803
RICK DID HIS UNDERGRADUATE WORK

3814
02:47:56,803 --> 02:48:00,974
AT UNIVERSITY OF WISCONSIN, GOT 

3815
02:48:00,974 --> 02:48:01,909
HIS Ph.D. FROM CASE WESTERN

3816
02:48:01,909 --> 02:48:02,809
RESERVE UNIVERSITY.

3817
02:48:02,809 --> 02:48:13,320
JOINED THE LEDER LAB 1984 TO 

3818
02:48:17,157 --> 02:48:18,926
1987 AT HARVARD, MOVED TO OAK

3819
02:48:18,926 --> 02:48:21,094
RIDGE FOR TEN YEARS, DIRECTING

3820
02:48:21,094 --> 02:48:23,830
THE OFFICE OF FUNCTIONAL

3821
02:48:23,830 --> 02:48:24,865
GENOMICS, BEFORE RETURNING TO

3822
02:48:24,865 --> 02:48:27,834
CASE WESTERN AS A PROFESSOR IN

3823
02:48:27,834 --> 02:48:29,303
THE DEPARTMENT OF PEDIATRICS AND

3824
02:48:29,303 --> 02:48:32,406
VICE CHAIRMAN FOR RESEARCH

3825
02:48:32,406 --> 02:48:32,606
THERE.

3826
02:48:32,606 --> 02:48:37,210
HE WAS HEAD OF THE PARKE-DAVIS

3827
02:48:37,210 --> 02:48:39,379
LABORATORY FOR MOLECULAR

3828
02:48:39,379 --> 02:48:40,948
GENETICS DEVELOPMENT AND LINKS

3829
02:48:40,948 --> 02:48:41,615
THERAPEUTICS BEFORE BECOMING

3830
02:48:41,615 --> 02:48:45,319
PRESIDENT AND CEO OF THE JACKSON

3831
02:48:45,319 --> 02:48:47,154
LABORATORY IN BAR HARBOR.

3832
02:48:47,154 --> 02:48:49,556
IN 2011, HE WAS RECRUITED BACK

3833
02:48:49,556 --> 02:48:53,527
TO THE NIH AS DEPUTY DIRECTOR OF

3834
02:48:53,527 --> 02:48:56,263
NIEHS, AND IN 2020 BECAME THE

3835
02:48:56,263 --> 02:48:56,997
DIRECTOR.

3836
02:48:56,997 --> 02:48:59,633
HIS RESEARCH PRIOR TO JOINING

3837
02:48:59,633 --> 02:49:01,468
NIEHS FOCUSED ON IDENTIFYING

3838
02:49:01,468 --> 02:49:03,470
GENES RESPONSIBLE FOR VARIETY OF

3839
02:49:03,470 --> 02:49:04,938
HUMAN INHERITED DISORDERS.

3840
02:49:04,938 --> 02:49:07,307
RICK.

3841
02:49:07,307 --> 02:49:13,280
 

3842
02:49:13,280 --> 02:49:23,323
 

3843
02:49:26,626 --> 02:49:28,862
>> WELL, LET ME START BY
SAYING

3844
02:49:28,862 --> 02:49:30,097
THAT, AGAIN, IT'S TRULY AN HONOR

3845
02:49:30,097 --> 02:49:31,064
TO BE HERE.

3846
02:49:31,064 --> 02:49:33,867
PHIL WAS JUST A REMARKABLE

3847
02:49:33,867 --> 02:49:34,301
INDIVIDUAL.

3848
02:49:34,301 --> 02:49:36,303
SO IF ANY OF YOU TRAINEES IN THE

3849
02:49:36,303 --> 02:49:37,738
AUDIENCE OR IF YOU'RE NOT HERE

3850
02:49:37,738 --> 02:49:40,007
THEN PASS ON THE WORD, BE VERY

3851
02:49:40,007 --> 02:49:43,176
CAREFUL WHO YOU CHOOSE AS YOUR

3852
02:49:43,176 --> 02:49:43,810
MENTOR.

3853
02:49:43,810 --> 02:49:46,580
YOUR MENTOR CAN HAVE A VERY

3854
02:49:46,580 --> 02:49:48,015
POWERFUL INFLUENCE, NOT ONLY ON

3855
02:49:48,015 --> 02:49:50,217
THE PERIOD IN WHICH YOU'RE

3856
02:49:50,217 --> 02:49:51,084
TRAINING BUT ACTUALLY ON THE

3857
02:49:51,084 --> 02:49:52,052
REST OF YOUR CAREER.

3858
02:49:52,052 --> 02:49:53,687
I'M GOING TO GIVE YOU A STORY

3859
02:49:53,687 --> 02:49:55,455
ABOUT WHAT HAPPENED IN MY

3860
02:49:55,455 --> 02:49:55,922
CAREER.

3861
02:49:55,922 --> 02:49:59,192
I STARTED OFF IN THE LABORATORY

3862
02:49:59,192 --> 02:50:01,495
AS A MOLECULAR BIOLOGIST,

3863
02:50:01,495 --> 02:50:03,363
LOOKING AT SOUTHERN BLOTS AND

3864
02:50:03,363 --> 02:50:07,501
THEN I ENDED UP AS A MOUSE

3865
02:50:07,501 --> 02:50:07,801
GENETICIST.

3866
02:50:07,801 --> 02:50:08,835
LET ME TAKE YOU THROUGH WHAT

3867
02:50:08,835 --> 02:50:10,270
HAPPENED OVER THE COURSE OF THE

3868
02:50:10,270 --> 02:50:11,605
THREE-YEAR PERIOD OF TIME WHEN I

3869
02:50:11,605 --> 02:50:15,976
WAS IN THE LEDER LABORATORY FROM

3870
02:50:15,976 --> 02:50:17,644
1984 TO 1987.

3871
02:50:17,644 --> 02:50:21,782
SO, I ARRIVED IN JUNE OF 1984,

3872
02:50:21,782 --> 02:50:27,587
WHEN PHIL HAD JUST -- TIM 

3873
02:50:27,587 --> 02:50:31,591
STEWART MADE THE TRANSGENIC

3874
02:50:31,591 --> 02:50:35,896
MOUSE, MADE THE COVER OF "CELL,"

3875
02:50:35,896 --> 02:50:36,663
LINKING THE DYSREGULATED

3876
02:50:36,663 --> 02:50:40,934
EXPRESSION OF MYC WITH A

3877
02:50:40,934 --> 02:50:42,669
TUMIROGENIC TRAIT IN MAMMARY

3878
02:50:42,669 --> 02:50:43,270
TISSUE.

3879
02:50:43,270 --> 02:50:44,771
ONE OF MY PROJECTS, I CHOSE TO

3880
02:50:44,771 --> 02:50:46,940
CONTINUE TO WORK ON THIS

3881
02:50:46,940 --> 02:50:47,707
WONDERFUL MOUSE.

3882
02:50:47,707 --> 02:50:50,210
AND I WANTED TO STUDY THE

3883
02:50:50,210 --> 02:50:51,344
MOLECULAR ONCOGENESIS AND DO ALL

3884
02:50:51,344 --> 02:50:54,948
THE TINES  -- TYPES OF THINGS

3885
02:50:54,948 --> 02:50:56,116
YOU CAN DO WITH THIS POWERFUL

3886
02:50:56,116 --> 02:50:57,317
MOUSE MODEL.

3887
02:50:57,317 --> 02:50:58,418
I DISCOVERED THEY WERE WAITING

3888
02:50:58,418 --> 02:51:00,187
FOR A POSTDOC TO COME THERE WERE

3889
02:51:00,187 --> 02:51:03,190
HUNDREDS OF MICE THAT NEEDED TO

3890
02:51:03,190 --> 02:51:05,992
BE GENOTYPED TO DETERMINE

3891
02:51:05,992 --> 02:51:08,795
WHETHER THEY CARRIED THE GENE, I

3892
02:51:08,795 --> 02:51:11,331
SPENT THE FIRST SEVERAL WEEKS

3893
02:51:11,331 --> 02:51:13,533
SNIPPING TAILS IN THE MOUSE ROOM

3894
02:51:13,533 --> 02:51:14,835
SORTING THROUGH MICE, SNIPPING

3895
02:51:14,835 --> 02:51:15,702
TAILS, MAKING DNA.

3896
02:51:15,702 --> 02:51:17,471
AFTER A FEW WEEKS I THOUGHT, IS

3897
02:51:17,471 --> 02:51:18,705
THIS WHAT I SIGNED UP FOR?

3898
02:51:18,705 --> 02:51:24,811
THERE HAS TO BE AN EASIER WAY.

3899
02:51:24,811 --> 02:51:28,215
TAKE A MALE AND FEMALE THAT

3900
02:51:28,215 --> 02:51:30,183
CARRY THE GENE AND MAKE A HOMOZY

3901
02:51:30,183 --> 02:51:34,688
COAT Z YGOTE, THAT STARTED MY

3902
02:51:34,688 --> 02:51:37,390
CAREER IN MOUSE GENETICS.

3903
02:51:37,390 --> 02:51:40,227
ONE OF THOSE MMTV MYC MICE

3904
02:51:40,227 --> 02:51:47,300
HAD -- WHEN YOU MADE -- 25% OF 

3905
02:51:47,300 --> 02:51:48,668
OFFSPRING EXHIBIT A LIMB

3906
02:51:48,668 --> 02:51:49,102
ABNORMALITY.

3907
02:51:49,102 --> 02:51:50,103
IT WAS INTERESTING BECAUSE I

3908
02:51:50,103 --> 02:51:50,837
STILL REMEMBER THE SATURDAY

3909
02:51:50,837 --> 02:51:53,206
MORNING PHIL WAS IN HIS OFFICE,

3910
02:51:53,206 --> 02:51:55,075
I BROUGHT IN THE STAINED

3911
02:51:55,075 --> 02:51:56,877
SKELETONS, CHECKING TO SEE

3912
02:51:56,877 --> 02:51:58,979
WHETHER THIS NEW MUTATION THAT

3913
02:51:58,979 --> 02:52:00,981
AROSE BY INSERTION OF IMMUNOGEN

3914
02:52:00,981 --> 02:52:03,683
SIS IN THIS TRANSGENIC LINE WAS

3915
02:52:03,683 --> 02:52:05,752
SIMILAR, SIMILAR PHENOTYPE TO

3916
02:52:05,752 --> 02:52:08,221
ANY OF THE EXISTING MUTATIONS IN

3917
02:52:08,221 --> 02:52:16,062
MARGARET GREEN'S BOOK.

3918
02:52:16,062 --> 02:52:18,899
I-- PHIL WAS READING THE

3919
02:52:18,899 --> 02:52:20,267
DESCRIPTION OF LIMB DEFORMITY,

3920
02:52:20,267 --> 02:52:21,968
INDICATING THERE WAS A FUSION OF

3921
02:52:21,968 --> 02:52:26,006
THE RADIUS AND ULNA IN THE

3922
02:52:26,006 --> 02:52:26,840
FORELIMB, INTERESTING, THAT'S

3923
02:52:26,840 --> 02:52:28,542
WHAT WE'RE SEEING.

3924
02:52:28,542 --> 02:52:30,410
THERE WAS A REPLACEMENT OF THE

3925
02:52:30,410 --> 02:52:33,713
TIBIA AND FIBULA IN HIND WITH

3926
02:52:33,713 --> 02:52:34,548
SINGLE TRIANGULAR BONE.

3927
02:52:34,548 --> 02:52:37,050
WOW, THAT'S EXACTLY WHAT WE'RE

3928
02:52:37,050 --> 02:52:37,384
SEEING!

3929
02:52:37,384 --> 02:52:39,519
AND WENT TO TO DESCRIBE OTHER

3930
02:52:39,519 --> 02:52:40,921
ASPECTS OF THE PHENOTYPE.

3931
02:52:40,921 --> 02:52:42,789
TURNS OUT THERE WERE SPONTANEOUS

3932
02:52:42,789 --> 02:52:44,724
MUTATIONS OF LIMB DEFORMITY AT

3933
02:52:44,724 --> 02:52:50,630
THE JACKSON LABORATORY, AND ALSO

3934
02:52:50,630 --> 02:52:51,398
OAK RIDGE.

3935
02:52:51,398 --> 02:52:52,699
WE ACQUIRED ALLELES, DISCOVERED

3936
02:52:52,699 --> 02:52:55,468
WE HAD A NEW MUTATION OF LIMB

3937
02:52:55,468 --> 02:52:57,871
DEFORMITY BUT IN OUR CASE THE

3938
02:52:57,871 --> 02:53:01,241
MUTATION AROADS BY INSERT OF

3939
02:53:01,241 --> 02:53:03,243
MMVT MYC.

3940
02:53:03,243 --> 02:53:05,212
REMEMBER, THIS IS IN 1984 AND

3941
02:53:05,212 --> 02:53:07,280
85, THERE WERE NO GENOME

3942
02:53:07,280 --> 02:53:09,916
SEQUENCES AND THINGS YOU CAN DO.

3943
02:53:09,916 --> 02:53:12,619
HAD TO DO POSITIONAL CLONING.

3944
02:53:12,619 --> 02:53:14,120
WHAT WE DID ARE OUR ALLELE WAS

3945
02:53:14,120 --> 02:53:17,157
USED MYC GENE AS A MOLECULAR

3946
02:53:17,157 --> 02:53:17,390
TAG.

3947
02:53:17,390 --> 02:53:20,594
WHEN TIM STEWART MADE THE MICE

3948
02:53:20,594 --> 02:53:25,765
HE INJECTED ONE OF THE --

3949
02:53:25,765 --> 02:53:30,570
REPLICATION ORIGIN AND

3950
02:53:30,570 --> 02:53:32,639
ANTIBIOTIC RESISTANT GENE, DID A

3951
02:53:32,639 --> 02:53:34,107
PLASMA RESCUE, CLONED THE

3952
02:53:34,107 --> 02:53:35,342
FLANKING SEQUENCES.

3953
02:53:35,342 --> 02:53:37,377
THAT WAS QUITE REVEALING.

3954
02:53:37,377 --> 02:53:39,746
WHAT IT WAS CLEAR TO ME, THIS IS

3955
02:53:39,746 --> 02:53:43,049
A GREAT WAY TO CONNECT GENES AND

3956
02:53:43,049 --> 02:53:45,352
WE DISCOVERED THIS RATHER NOVEL

3957
02:53:45,352 --> 02:53:48,855
GENE ON MOUSE CHROMOSOME 2 WITH

3958
02:53:48,855 --> 02:53:51,291
VERY INTERESTING DEVELOPMENTAL

3959
02:53:51,291 --> 02:53:54,327
AND HUMAN RELEVANT PHENOTYPES.

3960
02:53:54,327 --> 02:53:56,496
AFTER FINISHING THAT CAREER I

3961
02:53:56,496 --> 02:54:01,868
DECIDED, I'M GOING TO MAKE  A

3962
02:54:01,868 --> 02:54:04,104
BUNCH OF MUTATIONS, ONE PLACE

3963
02:54:04,104 --> 02:54:05,305
WAS JACKSON LABORATORY, OTHER

3964
02:54:05,305 --> 02:54:06,506
WAS OAK RIDGE.

3965
02:54:06,506 --> 02:54:09,009
I DECIDED TO GO DOWN, MAKE

3966
02:54:09,009 --> 02:54:12,746
HUNDREDS OF LINES OF TRANSGENIC

3967
02:54:12,746 --> 02:54:16,049
MICE AND SCREEN FOR INTERESTING

3968
02:54:16,049 --> 02:54:21,855
PHENOTYPES. 

3969
02:54:21,855 --> 02:54:26,693
WE USED PERMACLUDE TECHNIQUE, 

3970
02:54:26,693 --> 02:54:31,031
WEREN'T DOING HOMOLOGOUS BACK

3971
02:54:31,031 --> 02:54:34,000
THEN, NO CRISPR TECHNOLOGY.

3972
02:54:34,000 --> 02:54:39,806
WE USED A MINI GENE TO CORRECT

3973
02:54:39,806 --> 02:54:40,674
THE ALBINISM DETECT, YOU COULD

3974
02:54:40,674 --> 02:54:43,710
TELL IF THE MOUSE HAD A PIGMENT

3975
02:54:43,710 --> 02:54:45,612
THE COAT COLOR IT CARRIED THE

3976
02:54:45,612 --> 02:54:48,548
GENE, IF IT IT DOUBLE THE DOSE

3977
02:54:48,548 --> 02:54:51,451
OR DOUBLE COLOR IN ITS COAT IT

3978
02:54:51,451 --> 02:54:52,819
WAS A HOMOZYGOTE.

3979
02:54:52,819 --> 02:54:56,823
WE ASSIGNED NUMBERS TO EACH OF

3980
02:54:56,823 --> 02:54:58,458
THE ANIMALS, WE GENERATED LOTS

3981
02:54:58,458 --> 02:54:59,659
OF DIFFERENT MUTANT LINES.

3982
02:54:59,659 --> 02:55:01,728
I COULD TELL YOU ABOUT MANY BUT

3983
02:55:01,728 --> 02:55:04,164
I SELECTED ONE TO TELL YOU WHAT

3984
02:55:04,164 --> 02:55:07,000
I HOPE YOU'LL FIND AS WE DID A

3985
02:55:07,000 --> 02:55:10,337
VERY INTERESTING STORY. 

3986
02:55:10,337 --> 02:55:13,940
BACK IN THE EARLY 1980s AND

3987
02:55:13,940 --> 02:55:16,142
'90s PEOPLE WERE TRYING TO

3988
02:55:16,142 --> 02:55:18,511
FIND GENES ASSOCIATED WITH

3989
02:55:18,511 --> 02:55:23,550
POLYCYSTIC KIDNEY DISEASE. 

3990
02:55:23,550 --> 02:55:24,451
WHEN YOU MADE HOMOZYGOTES, THERE

3991
02:55:24,451 --> 02:55:27,253
WERE HOLES IN THE KIDNEY, IT

3992
02:55:27,253 --> 02:55:28,888
LOOKED LIKE.

3993
02:55:28,888 --> 02:55:30,090
IT WASN'T HOLES.

3994
02:55:30,090 --> 02:55:32,726
IN THE COLLECTING TUBULES

3995
02:55:32,726 --> 02:55:35,261
THERE'S A LOCALIZED

3996
02:55:35,261 --> 02:55:36,363
PROLIFERATION OF EPITHELIAL

3997
02:55:36,363 --> 02:55:37,597
CELLS, CYSTIC LESIONS.

3998
02:55:37,597 --> 02:55:39,332
WE WERE SLICING AND DICING AND

3999
02:55:39,332 --> 02:55:41,601
SO IT APPEARED THERE WERE HOLES,

4000
02:55:41,601 --> 02:55:43,803
THIS WAS -- WE WORKED WITH A

4001
02:55:43,803 --> 02:55:48,608
PATHOLOGIST, THIS WAS A CLASSIC 

4002
02:55:48,608 --> 02:55:50,710
EXAMPLE OF AUTOSOMAL RECESSIVE

4003
02:55:50,710 --> 02:55:52,445
POLYCYSTIC KIDNEY DISEASE, WE

4004
02:55:52,445 --> 02:55:53,446
COULD CLONE THE GENE, THIS IS

4005
02:55:53,446 --> 02:55:55,048
AMINO ACID SEQUENCE WHICH YOU

4006
02:55:55,048 --> 02:55:58,284
CAN'T READ BUT HAD SOME

4007
02:55:58,284 --> 02:56:04,357
CHARACTERISTIC FEATURES VERY

4008
02:56:04,357 --> 02:56:04,958
INTERESTING, PEPTIDE REPEATS,

4009
02:56:04,958 --> 02:56:06,226
SUGGESTING INTERACTION WITH

4010
02:56:06,226 --> 02:56:07,660
OTHER PROTEINS.

4011
02:56:07,660 --> 02:56:09,195
WE MADE A KNOCKOUT.

4012
02:56:09,195 --> 02:56:13,933
THIS IS A FEW YEARS LATER ONCE

4013
02:56:13,933 --> 02:56:15,135
TECHNOLOGY WAS AVAILABLE, TO

4014
02:56:15,135 --> 02:56:18,104
MAKE CERTAIN THE GENE IS THE ONE

4015
02:56:18,104 --> 02:56:21,040
ASSOCIATED WITH PKD.

4016
02:56:21,040 --> 02:56:24,110
SO, WHAT WE DID WAS WENT IN AND

4017
02:56:24,110 --> 02:56:33,086
DELETED SOME OF THE CODING

4018
02:56:33,086 --> 02:56:35,255
SEQUENCES, IF YOU BALANCE THE

4019
02:56:35,255 --> 02:56:37,557
INSERTION MUTATION WITH KNOCKOUT

4020
02:56:37,557 --> 02:56:42,395
ALLELE YOU HAVE POLYCYSTIC

4021
02:56:42,395 --> 02:56:44,164
KIDNEY DISEASE.

4022
02:56:44,164 --> 02:56:45,565
WITH THE BETA GALACTIC WE COULD

4023
02:56:45,565 --> 02:56:49,169
SEE WHERE IS THE GENE INVOLVED

4024
02:56:49,169 --> 02:56:50,804
IN POLYCYSTIC KIDNEY DISEASE

4025
02:56:50,804 --> 02:56:51,237
EXPRESSED?

4026
02:56:51,237 --> 02:56:52,772
SPECIFICALLY INTERESTED IN

4027
02:56:52,772 --> 02:56:53,873
LOOKING AT WHAT EMBRYONIC

4028
02:56:53,873 --> 02:56:54,474
DEVELOPMENT.

4029
02:56:54,474 --> 02:56:58,645
ON THE LEFT IN PANEL C WE

4030
02:56:58,645 --> 02:57:00,580
STAINED FOR LAC C, REFERRED TO

4031
02:57:00,580 --> 02:57:02,882
AS THE NODE, ONE OF THE SIGNAL

4032
02:57:02,882 --> 02:57:05,952
CENTERS OF THE EMBRYO WITH A

4033
02:57:05,952 --> 02:57:08,555
VERY IMPORTANT ROLE IN

4034
02:57:08,555 --> 02:57:09,255
LEFT-RIGHT DETERMINATION.

4035
02:57:09,255 --> 02:57:14,594
EACH OF THE CELLS IN THE NODE IS

4036
02:57:14,594 --> 02:57:17,430
EPITHELIAL CELLS, HAS A

4037
02:57:17,430 --> 02:57:18,565
FINGER-LIKE STRUCTURE, THIS

4038
02:57:18,565 --> 02:57:21,367
IS -- I'M NOT A DEVELOPMENTAL

4039
02:57:21,367 --> 02:57:22,902
BIOLOGIST BUT APPARENTLY THESE

4040
02:57:22,902 --> 02:57:24,204
STRUCTURES CREATE SOMETHING

4041
02:57:24,204 --> 02:57:29,909
CALLED NODAL FLOW AND THAT

4042
02:57:29,909 --> 02:57:31,878
DIRECTS MORPHOGENS TO ALIGN LEFT

4043
02:57:31,878 --> 02:57:37,250
AND RIGHT POLARITY IN THE

4044
02:57:37,250 --> 02:57:37,817
EMBRYOS.

4045
02:57:37,817 --> 02:57:40,854
WE MADE KNOCKOUT MICE HOMOZYGOUS

4046
02:57:40,854 --> 02:57:46,426
AND FOUND IT CAUSE THE EMBRYONIC

4047
02:57:46,426 --> 02:57:48,728
LETHALITY, STAINED WITH LEFTY 2,

4048
02:57:48,728 --> 02:57:52,465
ON PANEL A YOU GET ASYMMETRIC

4049
02:57:52,465 --> 02:57:55,034
STAINING BUT IN MUTANT EMBRYOS

4050
02:57:55,034 --> 02:57:55,935
GETTING BILATERAL STAINING,

4051
02:57:55,935 --> 02:57:58,004
BOTTOM LINE HERE IS THAT THE

4052
02:57:58,004 --> 02:58:00,406
INACTIVATION OF THE GENE THAT

4053
02:58:00,406 --> 02:58:03,209
CAUSE THE POLYCYSTIC KIDNEY

4054
02:58:03,209 --> 02:58:04,244
DISEASE CAUSED LEFT-RIGHT

4055
02:58:04,244 --> 02:58:05,879
POLARITY DEFECTS IN THE EMBRYO.

4056
02:58:05,879 --> 02:58:09,048
WE DECIDED TO NAME THE GENE

4057
02:58:09,048 --> 02:58:09,649
POLARIS.

4058
02:58:09,649 --> 02:58:11,918
THAT'S WHERE IT COMES FROM.

4059
02:58:11,918 --> 02:58:13,887
IT TOLD US THAT THE ORIGIN

4060
02:58:13,887 --> 02:58:15,522
SEGREGATIONS MUTATION WAS A

4061
02:58:15,522 --> 02:58:17,190
HYPOMORPHIC ALLELE, WASN'T A

4062
02:58:17,190 --> 02:58:18,591
KNOCKOUT, A COMPLETE KNOCKOUT OF

4063
02:58:18,591 --> 02:58:19,225
THE GENE.

4064
02:58:19,225 --> 02:58:21,127
SO, IT'S VERY INTERESTING.

4065
02:58:21,127 --> 02:58:22,595
WHAT'S THE CONNECTION BETWEEN

4066
02:58:22,595 --> 02:58:23,563
THE NODE?

4067
02:58:23,563 --> 02:58:27,033
CELLS WITH THE CENTRAL PSYLLIUM

4068
02:58:27,033 --> 02:58:31,404
AND POLYCYSTIC KIDNEY DISEASE?

4069
02:58:31,404 --> 02:58:35,608
THE POSTDOC IS NOW A PROFESSOR

4070
02:58:35,608 --> 02:58:38,311
AT UNIVERSITY OF ALABAMA, AND HE

4071
02:58:38,311 --> 02:58:40,613
DEVELOPED AN ANTIBODY TO THIS

4072
02:58:40,613 --> 02:58:43,049
POLARIS GENE AND ALSO LOOKED AT

4073
02:58:43,049 --> 02:58:44,250
THE SURFACE OF THE EPITHELIAL

4074
02:58:44,250 --> 02:58:48,054
CELLS AND YOU CAN SEE THIS

4075
02:58:48,054 --> 02:58:51,357
PUNCTATE STAINING, IF YOU

4076
02:58:51,357 --> 02:58:55,395
STAINED FOR CENTRAL PSYLLIUM YOU

4077
02:58:55,395 --> 02:58:58,464
CAN SEE THE CILIATED FINGER-LIKE

4078
02:58:58,464 --> 02:59:02,135
STRUCTURE, INVOLVED IN THE

4079
02:59:02,135 --> 02:59:12,679
STRUCTURE AND FUNCTION OF THE

4080
02:59:12,679 --> 02:59:14,113
CENTRAL CILIUM.

4081
02:59:14,113 --> 02:59:17,183
THERE WERE MANY OTHER LABS THAT

4082
02:59:17,183 --> 02:59:18,952
CLONED GENES ASSOCIATED WITH

4083
02:59:18,952 --> 02:59:22,121
POLYCYSTIC KIDNEY DISEASE, ALSO

4084
02:59:22,121 --> 02:59:23,756
COMPONENTS OF THE CENTRAL

4085
02:59:23,756 --> 02:59:24,991
CILIUM.

4086
02:59:24,991 --> 02:59:27,160
I HAVEN'T FOLLOWED THE PKD WORK.

4087
02:59:27,160 --> 02:59:30,296
HOW ARE THESE GENES ASSOCIATED

4088
02:59:30,296 --> 02:59:32,398
WITH THE CILIATED STRUCTURE

4089
02:59:32,398 --> 02:59:33,700
SOMEHOW CAUSING POLYCYSTIC

4090
02:59:33,700 --> 02:59:36,102
KIDNEY DISEASE?

4091
02:59:36,102 --> 02:59:38,771
A VERY INTERESTING INSIGHT INTO

4092
02:59:38,771 --> 02:59:40,406
GENES AND GENE FUNCTION.

4093
02:59:40,406 --> 02:59:50,950
I ALSO WANT TO TALK ABOUT MOUSE

4094
02:59:52,952 --> 02:59:55,188
AGOUTI GENE.

4095
02:59:55,188 --> 03:00:00,460
A COLLEAGUE AT OAK RIDGE HAD

4096
03:00:00,460 --> 03:00:07,400
JUST GENERATED RADIATION INDUCED

4097
03:00:07,400 --> 03:00:10,503
MUTATION ON CHROMOSOME 2, THERE

4098
03:00:10,503 --> 03:00:14,641
WAS A MUTATION IN LIMB DEFORMITY

4099
03:00:14,641 --> 03:00:23,216
AS WELL AS IN AGOUTI GENES.

4100
03:00:23,216 --> 03:00:27,587
WE GOT THE COVER OF "CELL" IN

4101
03:00:27,587 --> 03:00:33,493
199  1992 BECAUSE AGOUTI WAS A

4102
03:00:33,493 --> 03:00:39,399
TARGET OF A TEST AT THE OAK

4103
03:00:39,399 --> 03:00:40,366
RIDGE LABORATORY, THEY COULD

4104
03:00:40,366 --> 03:00:41,934
DETERMINE WHETHER OR NOT

4105
03:00:41,934 --> 03:00:48,408
DIFFERENT PHYSICAL OR CHEMICAL

4106
03:00:48,408 --> 03:00:51,811
AGENTED CAUSED MUTATION, A BANK

4107
03:00:51,811 --> 03:00:55,381
WAS AVAILABLE TO ANALYZE, THERE

4108
03:00:55,381 --> 03:00:59,786
WERE 19 DISTINGUISHABLE ALLELES

4109
03:00:59,786 --> 03:01:03,856
OF AGOUTI THAT RANGED FROM

4110
03:01:03,856 --> 03:01:06,025
EMBRYONIC LETHALITY TO A COAT

4111
03:01:06,025 --> 03:01:08,428
COLOR ALTERATIONS TO ADULT ONSET

4112
03:01:08,428 --> 03:01:11,431
OBESITY AND TYPE 2 DIABETES.

4113
03:01:11,431 --> 03:01:17,036
SO, A SINGLE GENE GIVING RISE TO

4114
03:01:17,036 --> 03:01:18,871
ALL PHENOTYPICALLY PHENOTYPES,

4115
03:01:18,871 --> 03:01:20,506
MUST BE A COMPLICATED GENE.

4116
03:01:20,506 --> 03:01:25,044
SO WE CLONED THE GENE AND

4117
03:01:25,044 --> 03:01:29,348
REMARKABLE THE SIMPLEST, THREE

4118
03:01:29,348 --> 03:01:33,753
CODING EXONS ON THE RIGHT, 1

4119
03:01:33,753 --> 03:01:38,057
COMES TOGETHER AS MESSAGE RNA

4120
03:01:38,057 --> 03:01:39,225
PRODUCES A SMALL SECRETED

4121
03:01:39,225 --> 03:01:40,426
PROTEIN WHICH MADE SENSE

4122
03:01:40,426 --> 03:01:42,595
RELATIVE TO WHAT WE KNEW ABOUT

4123
03:01:42,595 --> 03:01:44,597
HOW AGOUTI WORKS IN THE HAIR

4124
03:01:44,597 --> 03:01:47,166
GROWTH CYCLE TO REGULATE

4125
03:01:47,166 --> 03:01:48,201
PIGMENTATION OF FUR.

4126
03:01:48,201 --> 03:01:55,007
THAT MADE A LOT OF SENSE.

4127
03:01:55,007 --> 03:01:58,177
SO, WE WENT ON AND ANALYZED MANY

4128
03:01:58,177 --> 03:02:02,582
MUTATIONS, AND IT WAS JUST

4129
03:02:02,582 --> 03:02:03,950
REMARKABLE THE WAYS YOU CAN

4130
03:02:03,950 --> 03:02:05,518
MUTATE A GENERAL AND TO GIVE

4131
03:02:05,518 --> 03:02:09,088
RISE TO THE BROAD ASSORTMENT OF

4132
03:02:09,088 --> 03:02:10,990
PHENOTYPES.

4133
03:02:10,990 --> 03:02:15,528
SO MAYBE YOU'VE USED C57 BLACK 6

4134
03:02:15,528 --> 03:02:20,399
JACK, THIS IS THE STRUCTURE,

4135
03:02:20,399 --> 03:02:21,467
SMALL A PANEL HERE.

4136
03:02:21,467 --> 03:02:24,437
TURNS OUT IT'S NOT A MUTATION IN

4137
03:02:24,437 --> 03:02:28,641
THE CODING SEQUENCE OF AGOUTI,

4138
03:02:28,641 --> 03:02:31,978
IT'S A COMPLICATED STRUCTURE.

4139
03:02:31,978 --> 03:02:33,880
TWO RETROVIRAL-LIKE ELEMENTS

4140
03:02:33,880 --> 03:02:44,423
INSERTED WITHIN THE FIRST INTRON

4141
03:02:45,424 --> 03:02:48,895
OF AGOUTI, LTR, LTR-A, AND

4142
03:02:48,895 --> 03:02:50,663
ANOTHER VIRAL INSERTION.

4143
03:02:50,663 --> 03:02:53,432
THAT'S WHAT BLACK 6 LOOKS LIKE.

4144
03:02:53,432 --> 03:02:57,270
SO THIS WAS INTERESTING BECAUSE

4145
03:02:57,270 --> 03:03:04,610
IF YOU BRED ENOUGH C57 BLACK 6J

4146
03:03:04,610 --> 03:03:06,145
MICE MUTATIONS HAPPEN WITH

4147
03:03:06,145 --> 03:03:07,013
REMEMBER LATER, ONE TO BLACK AND

4148
03:03:07,013 --> 03:03:09,949
TAN IN THE FIRST SLIDE, MICE

4149
03:03:09,949 --> 03:03:12,285
THAT HAVE A YELLOW BELLY AND

4150
03:03:12,285 --> 03:03:14,720
BLACK BACK, A FINE LINE ACROSS

4151
03:03:14,720 --> 03:03:18,191
THE LATERAL SURFACES.

4152
03:03:18,191 --> 03:03:24,897
TURNS OUT WHEN YOU RECOMBINE THE

4153
03:03:24,897 --> 03:03:27,133
INSIDE RETROVIRAL ELEMENTS, LTR

4154
03:03:27,133 --> 03:03:30,269
B 5 AND 3 PRIME, IF YOU

4155
03:03:30,269 --> 03:03:34,941
RECOMBINE OUT THROUGH THE LTR-A,

4156
03:03:34,941 --> 03:03:37,343
AND LTRs YOU'RE LEFT WITH SOLO

4157
03:03:37,343 --> 03:03:42,415
LTR THAT GIVES RISE TO DIFFERENT

4158
03:03:42,415 --> 03:03:44,350
PHENOTYPE WHITE BELLY AGOUTI.

4159
03:03:44,350 --> 03:03:46,485
PART OF THE REASON I'M AT THE

4160
03:03:46,485 --> 03:03:47,954
NATIONAL INSTITUTE FOR

4161
03:03:47,954 --> 03:03:49,055
ENVIRONMENTAL HEALTH SCIENCES IS

4162
03:03:49,055 --> 03:03:50,923
IT GOES BACK TO THE ANALYSIS WE

4163
03:03:50,923 --> 03:03:53,125
DID ON THIS OTHER VERY

4164
03:03:53,125 --> 03:03:54,493
INTERESTING MUTATION.

4165
03:03:54,493 --> 03:03:56,529
IT'S A DOMINANT MUTATION THAT

4166
03:03:56,529 --> 03:03:58,798
CAUSES YELLOW COAT COLOR, AND

4167
03:03:58,798 --> 03:04:01,234
THE MICE THAT HAVE A TOTAL

4168
03:04:01,234 --> 03:04:06,339
YELLOW COAT COLOR ALSO HAVE THE

4169
03:04:06,339 --> 03:04:07,773
PROPENSITY TO DEVELOP SEVERE

4170
03:04:07,773 --> 03:04:09,442
OBESITY AND TYPE 2 DIABETES.

4171
03:04:09,442 --> 03:04:12,612
LOWER RIGHT-HAND CORNER IS AN

4172
03:04:12,612 --> 03:04:14,080
EXAMPLE OF 85-GRAM MOUSE,

4173
03:04:14,080 --> 03:04:16,649
COMPARED TO 25-GRAM LITTER MATE.

4174
03:04:16,649 --> 03:04:19,819
DIFFERENCE IN WEIGHT IS ADIPOSE

4175
03:04:19,819 --> 03:04:20,753
TISSUE.

4176
03:04:20,753 --> 03:04:23,089
SO, WHAT WE WENT ON LEARNING

4177
03:04:23,089 --> 03:04:27,193
ABOUT THE AGOUTI GENE, WE

4178
03:04:27,193 --> 03:04:29,829
DEMONSTRATED THE MICE HE CAN

4179
03:04:29,829 --> 03:04:30,563
TOPICALLY EXPRESS AGOUTI

4180
03:04:30,563 --> 03:04:31,864
SIGNALING PROTEIN IN PLACES IT'S

4181
03:04:31,864 --> 03:04:34,667
NOT SUPPOSED TO BE NOTABLY IN

4182
03:04:34,667 --> 03:04:35,568
THE BRAIN.

4183
03:04:35,568 --> 03:04:37,470
WHAT'S HAPPENING IS ATOPIC

4184
03:04:37,470 --> 03:04:40,840
EXPRESSION OF THIS SECRETED

4185
03:04:40,840 --> 03:04:43,776
PROTEIN IS SHORT CIRCUITING THE

4186
03:04:43,776 --> 03:04:45,211
SATIETY RESPONSE, MICE WILL HAVE

4187
03:04:45,211 --> 03:04:46,779
LUNCH, THE BRAIN WILL SAY I'VE

4188
03:04:46,779 --> 03:04:48,614
HAD ENOUGH TO EAT, I CAN STOP

4189
03:04:48,614 --> 03:04:50,049
EATING, BUT IN THIS CASE THE

4190
03:04:50,049 --> 03:04:51,918
BRAIN WAS TELLING THEM I'M

4191
03:04:51,918 --> 03:04:53,653
STARVING, I'M STARVING, SO THEY

4192
03:04:53,653 --> 03:04:56,422
KEEP EATING AND EATING, AND THEY

4193
03:04:56,422 --> 03:04:59,191
DEVELOP TYPE 2 DIABETES.

4194
03:04:59,191 --> 03:05:00,660
WHAT WAS REALLY INTERESTING IN

4195
03:05:00,660 --> 03:05:02,595
OUR CASE IS THAT THE MICE THAT

4196
03:05:02,595 --> 03:05:04,263
YOU'RE SEEING, WE MADE THE COVER

4197
03:05:04,263 --> 03:05:14,774
OF GENES AND DEVELOPMENT, ALL 

4198
03:05:14,774 --> 03:05:23,349
MICE ARE GENETICALLY IDENTICAL 

4199
03:05:23,349 --> 03:05:29,855
AND CARRY THIS AIPY,

4200
03:05:29,855 --> 03:05:31,090
PHENOTYPICALLY DIFFERENT.

4201
03:05:31,090 --> 03:05:32,825
THEY CARRY THE MUTATION GIVING

4202
03:05:32,825 --> 03:05:35,328
RISE TO THESE YELLOW MICE THAT

4203
03:05:35,328 --> 03:05:37,063
DEVELOP OBESITY AND TYPE 2

4204
03:05:37,063 --> 03:05:37,330
DIABETES.

4205
03:05:37,330 --> 03:05:38,497
WE DID THE ANALYSIS.

4206
03:05:38,497 --> 03:05:46,305
TURNS OUT THESE ARE CAUSED BY --

4207
03:05:46,305 --> 03:05:47,707
INSERTION OF RETROVIRAL

4208
03:05:47,707 --> 03:05:49,241
DEVELOPMENT, IAP ELEMENT,

4209
03:05:49,241 --> 03:05:52,211
THERE'S A CRYPTIC PROMOTER IN

4210
03:05:52,211 --> 03:05:54,747
THE 3 PRIME LTR THAT HIJACKS

4211
03:05:54,747 --> 03:05:56,349
NORMAL EXPRESSION.

4212
03:05:56,349 --> 03:05:58,651
YOU'RE PRODUCING NOW A FUSION

4213
03:05:58,651 --> 03:06:01,721
TRANSCRIPT, CONTAINS ALL OF THE

4214
03:06:01,721 --> 03:06:03,155
NORMAL CODING SEQUENCES BUT THE

4215
03:06:03,155 --> 03:06:05,358
5 PRIME MESSENGER RNA IS FROM

4216
03:06:05,358 --> 03:06:07,960
THE LTR OF THE IAP.

4217
03:06:07,960 --> 03:06:13,432
SO WHAT WE ALSO DETERMINED IS

4218
03:06:13,432 --> 03:06:23,943
THAT VARIABLE PENETRANCE AND 

4219
03:06:24,543 --> 03:06:33,719
HIERARCHY IS AAATTRIBUTE USUAL 

4220
03:06:33,719 --> 03:06:36,622
TOABLE TO OF -- ATTRIBUTABLE TO

4221
03:06:36,622 --> 03:06:37,990
EPIGENETICS.

4222
03:06:37,990 --> 03:06:39,025
IN MOUSE WITH MODELING, SOME

4223
03:06:39,025 --> 03:06:41,360
CELLS LOOK LIKE TOP PANEL AND

4224
03:06:41,360 --> 03:06:47,066
SOME LOOK LIKE THE BOTTOM PANEL.

4225
03:06:47,066 --> 03:06:50,736
CELLULAR  MOSAICS.

4226
03:06:50,736 --> 03:06:54,040
HOW DOES ONE GENERATE MICE WITH

4227
03:06:54,040 --> 03:06:56,042
VARIABLE PHENOTYPE WHEN IT WAS

4228
03:06:56,042 --> 03:06:59,745
INBRED STRAIN?

4229
03:06:59,745 --> 03:07:01,947
GENETICS IN NUCLEUS WERE

4230
03:07:01,947 --> 03:07:02,314
IDENTICAL.

4231
03:07:02,314 --> 03:07:04,650
A POSTDOC CAME UP WITH A GREAT

4232
03:07:04,650 --> 03:07:06,752
IDEA THAT, RICK, THEY ARE NOT

4233
03:07:06,752 --> 03:07:08,721
TOTALLY IDENTICAL BECAUSE THERE

4234
03:07:08,721 --> 03:07:10,923
MAY BE DIFFERENT MITOCHONDRIAL

4235
03:07:10,923 --> 03:07:11,290
FUNCTION.

4236
03:07:11,290 --> 03:07:13,859
SO IS THERE ROLE FOR DIFFERENT

4237
03:07:13,859 --> 03:07:14,627
DEGREES IN MITOCHONDRIAL

4238
03:07:14,627 --> 03:07:16,929
FUNCTION IN THE DIFFERENT

4239
03:07:16,929 --> 03:07:17,897
INDIVIDUAL ANIMALS?

4240
03:07:17,897 --> 03:07:20,132
IS THAT SOMEHOW CONNECTED WITH

4241
03:07:20,132 --> 03:07:21,200
THIS VARIABLE PHENOTYPE?

4242
03:07:21,200 --> 03:07:24,036
SO WE DECIDED TO TEST THAT.

4243
03:07:24,036 --> 03:07:27,573
TURNS OUT THERE'S A GOOD

4244
03:07:27,573 --> 03:07:32,945
OLD-FASHIONED NATURAL PESTICIDE

4245
03:07:32,945 --> 03:07:35,014
THAT'S DANGEROUS, ROTENONE, THE

4246
03:07:35,014 --> 03:07:35,915
TOXICOLOGY COMMUNITY IS

4247
03:07:35,915 --> 03:07:38,317
ANALYZING THIS, IT BINDS TO

4248
03:07:38,317 --> 03:07:40,386
COMPLEX 1 OF THE ELECTRON

4249
03:07:40,386 --> 03:07:43,556
TRANSPORT CHANGE AND TURNS IT

4250
03:07:43,556 --> 03:07:44,056
OFF.

4251
03:07:44,056 --> 03:07:53,099
AT 10 PARTS PER MILLION WE COULD

4252
03:07:53,099 --> 03:07:55,401
TICKLE THE MITOCHONDRIA, CAN WE

4253
03:07:55,401 --> 03:07:56,068
INFLUENCE DEGREE OF PENETRANCE

4254
03:07:56,068 --> 03:07:57,570
OF THE HIERARCHY?

4255
03:07:57,570 --> 03:07:59,672
WE DID THAT.

4256
03:07:59,672 --> 03:08:01,874
TESTED THIS DURING DEVELOPMENT.

4257
03:08:01,874 --> 03:08:06,045
THE BOTTOM LINE, AGAIN,  YOU

4258
03:08:06,045 --> 03:08:07,213
HAVE VARIABLE PHENOTYPES ON THE

4259
03:08:07,213 --> 03:08:09,014
LEFT, ON THE RIGHT YOU CAN SEE

4260
03:08:09,014 --> 03:08:10,816
SPECIFICALLY WITH THE NUMBER OF

4261
03:08:10,816 --> 03:08:13,219
MICE THAT ARE FULLY YELLOW AND

4262
03:08:13,219 --> 03:08:14,520
HAVE PROPENSITY FOR OBESITY AND

4263
03:08:14,520 --> 03:08:15,855
TYPE 2 DIABETES YOU CAN INCREASE

4264
03:08:15,855 --> 03:08:19,158
THE NUMBER OF MICE THAT HAVE

4265
03:08:19,158 --> 03:08:21,127
THAT PHENOTYPE BY TICKLING THE

4266
03:08:21,127 --> 03:08:22,995
MITOCHONDRIA.

4267
03:08:22,995 --> 03:08:25,598
WE ASKED MORE RECENTLY IS AGOUTI

4268
03:08:25,598 --> 03:08:28,033
AND THIS UNIQUE STRUCTURE OF

4269
03:08:28,033 --> 03:08:31,837
AGOUTI THE ONLY GENE THAT

4270
03:08:31,837 --> 03:08:33,806
RESPONDS TO THE MITOCHONDRIAL

4271
03:08:33,806 --> 03:08:35,341
PERTURBATION OR TREATMENT WITH

4272
03:08:35,341 --> 03:08:35,641
PESTICIDES?

4273
03:08:35,641 --> 03:08:37,343
OR DOES IT HAPPEN WITH LOTS OF

4274
03:08:37,343 --> 03:08:37,543
GENES?

4275
03:08:37,543 --> 03:08:40,079
A LOT OF DATA ON HERE BUT THE

4276
03:08:40,079 --> 03:08:43,149
BOTTOM LINE WE WENT IN AND DID

4277
03:08:43,149 --> 03:08:46,085
WHOLE GENOME BUT SULFIDE

4278
03:08:46,085 --> 03:08:48,721
SEQUENCING WITH ZERO PARTS PER

4279
03:08:48,721 --> 03:08:49,788
MILL THE EPIGENOME CHANGES OVER

4280
03:08:49,788 --> 03:08:52,158
THE COURSE OF TIME, LOOKED AT

4281
03:08:52,158 --> 03:08:53,959
DAY 22, SIX MONTHS, 12 MONTHS,

4282
03:08:53,959 --> 03:08:54,627
18 MONTHS.

4283
03:08:54,627 --> 03:08:59,465
THERE ARE A NUMBER OF DIFFERENT

4284
03:08:59,465 --> 03:09:00,132
DIFFERENTIALLY METHYLATED LOCI

4285
03:09:00,132 --> 03:09:01,667
ACROSS THE LIFESPAN.

4286
03:09:01,667 --> 03:09:02,735
IF YOU LOOK SPECIFICALLY AT THE

4287
03:09:02,735 --> 03:09:04,103
LIVES OF THE ANIMALS TREATED

4288
03:09:04,103 --> 03:09:05,938
WITH 10 PARTS PER MILLION YOU'LL

4289
03:09:05,938 --> 03:09:15,347
SEE THERE IS A MASSIVE 

4290
03:09:15,347 --> 03:09:16,949
REORGANIZATION OF THE EPIGENOME,

4291
03:09:16,949 --> 03:09:20,786
OR THE STATUS, AT 18 MONTHS THEY

4292
03:09:20,786 --> 03:09:22,555
PRESERVE THAT ALTERED

4293
03:09:22,555 --> 03:09:26,492
METHYLATION PATTERN, OKAY, THAT

4294
03:09:26,492 --> 03:09:30,629
WAS ATTRIBUTABLE ONLY TO

4295
03:09:30,629 --> 03:09:31,931
ROTENONEEXPOSURE IN DEVELOPMENT.

4296
03:09:31,931 --> 03:09:34,633
A BIG REASON I'M AT NIEHS.

4297
03:09:34,633 --> 03:09:37,903
HOW DO MANY OF THE ENVIRONMENTAL

4298
03:09:37,903 --> 03:09:42,641
TOXICANTS, PESTICIDES, YOU KNOW,

4299
03:09:42,641 --> 03:09:43,976
PFAS, HOW ARE THEY INFLUENCED

4300
03:09:43,976 --> 03:09:45,311
HUMAN BIOLOGY, AND TO WHAT

4301
03:09:45,311 --> 03:09:49,915
EXTENT IS THERE NOW A CONNECTION

4302
03:09:49,915 --> 03:09:50,916
WITH ALTERATIONS IN THE

4303
03:09:50,916 --> 03:09:54,486
EPIGENOME OF THE MICE.

4304
03:09:54,486 --> 03:09:56,722
IN THE INTEREST OF TIME I'LL

4305
03:09:56,722 --> 03:10:01,627
FINISH UP BY TALKING ABOUT PHIL.

4306
03:10:01,627 --> 03:10:03,662
SO IT'S EXEMPLARY SCIENCE, AN

4307
03:10:03,662 --> 03:10:04,563
OUTSTANDING MENTOR.

4308
03:10:04,563 --> 03:10:06,098
THERE ARE LOTS OF THINGS I'VE

4309
03:10:06,098 --> 03:10:06,966
LEARNED FROM PHIL.

4310
03:10:06,966 --> 03:10:10,236
I THINK YOU'VE HEARD THIS FROM

4311
03:10:10,236 --> 03:10:10,703
MANY OTHERS.

4312
03:10:10,703 --> 03:10:12,871
DON'T BE AFRAID TO SEEK BOLD AN

4313
03:10:12,871 --> 03:10:14,139
INNOVATIVE DIRECTIONS.

4314
03:10:14,139 --> 03:10:15,941
YOU SHOULD DO THAT.

4315
03:10:15,941 --> 03:10:18,277
AND IF NECESSARY, MAYBE INVENT

4316
03:10:18,277 --> 03:10:21,880
NEW TECHNOLOGIES, EXPERIMENTAL 

4317
03:10:21,880 --> 03:10:25,784
APPROACHES TO DO THIS.

4318
03:10:25,784 --> 03:10:27,253
OLIGO DT, PHIL INVENTED IT.

4319
03:10:27,253 --> 03:10:32,491
WHEN HAD HE TO CLONE A GENE HE

4320
03:10:32,491 --> 03:10:34,059
INVENTED THE TECHNOLOGY, I THINK

4321
03:10:34,059 --> 03:10:36,895
LAMBDA GT WEST IF I REMEMBER

4322
03:10:36,895 --> 03:10:37,529
CORRECTLY.

4323
03:10:37,529 --> 03:10:38,731
TREAT ALL YOUR COLLEAGUES WITH

4324
03:10:38,731 --> 03:10:39,131
RESPECT.

4325
03:10:39,131 --> 03:10:42,034
I WAS SO STRUCK BY MY FIRST HOUR

4326
03:10:42,034 --> 03:10:44,236
IN THE LAB, PHIL TOOK ME THROUGH

4327
03:10:44,236 --> 03:10:48,173
AND INTRODUCED ME TO SOME NOBEL

4328
03:10:48,173 --> 03:10:50,643
LAUREATES, TO POSTDOCS, THE

4329
03:10:50,643 --> 03:10:53,012
SUPPORT STAFF WORKING IN THE

4330
03:10:53,012 --> 03:10:55,648
DEPARTMENT OF GENETICS.

4331
03:10:55,648 --> 03:10:57,349
AND THE ENTHUSIASM OF THIS

4332
03:10:57,349 --> 03:10:58,050
INTRODUCTION WAS INDEPENDENT OF

4333
03:10:58,050 --> 03:10:59,418
WHERE THEY WERE IN THEIR

4334
03:10:59,418 --> 03:11:00,386
SCIENTIFIC CAREER.

4335
03:11:00,386 --> 03:11:01,153
THE SUPPORT STAFF WERE

4336
03:11:01,153 --> 03:11:04,556
INTRODUCED WITH THE SAME DEGREE

4337
03:11:04,556 --> 03:11:05,557
OF ENTHUSIASM AS THE NOBEL

4338
03:11:05,557 --> 03:11:06,292
LAUREATES.

4339
03:11:06,292 --> 03:11:09,595
SO I THINK I REALIZED, YOU KNOW,

4340
03:11:09,595 --> 03:11:11,363
THE MESSAGE IT SENT TO ME

4341
03:11:11,363 --> 03:11:12,564
EVERYONE WORKING THERE IS

4342
03:11:12,564 --> 03:11:14,967
IMPORTANT AND TREAT PEOPLE WITH

4343
03:11:14,967 --> 03:11:15,401
RESPECT.

4344
03:11:15,401 --> 03:11:17,903
SO ENCOURAGE YOUR TRAINEES TO

4345
03:11:17,903 --> 03:11:19,672
ACHIEVE THE BEST THEY CAN DO TO

4346
03:11:19,672 --> 03:11:22,074
ADVANCE THEIR CAREERS.

4347
03:11:22,074 --> 03:11:24,076
AND HE WAS ESPECIALLY CAREFUL TO

4348
03:11:24,076 --> 03:11:26,378
MAKE SURE IN OUR PRESENTATIONS

4349
03:11:26,378 --> 03:11:27,880
WE WERE POLISHED IN THE WAY WE

4350
03:11:27,880 --> 03:11:29,081
GAVE OUR TALKS.

4351
03:11:29,081 --> 03:11:31,317
SO I STILL THREAP WAS ONE CASE

4352
03:11:31,317 --> 03:11:36,922
WHERE ONE OF THE POSTDOCS WAS

4353
03:11:36,922 --> 03:11:39,692
TALKING ABOUT RESEARCH AT A LAB

4354
03:11:39,692 --> 03:11:41,894
MEETING, EXCUSE MY FRENCH, HE

4355
03:11:41,894 --> 03:11:44,330
SAID THERE WAS A SHIT LOAD OF

4356
03:11:44,330 --> 03:11:47,399
EXPRESSION IN THE CELL TYPE.

4357
03:11:47,399 --> 03:11:48,167
I FELT PALPABLE NERVOUSNESS IN

4358
03:11:48,167 --> 03:11:49,101
THE ROOM.

4359
03:11:49,101 --> 03:11:52,638
OH MY GOD, PHIL WOULD NEVER TALK

4360
03:11:52,638 --> 03:11:53,739
LIKE THAT.

4361
03:11:53,739 --> 03:11:56,308
SO, WHEN WE ALL CAME AND GOT OUR

4362
03:11:56,308 --> 03:12:01,580
WITS ABOUT IT PHIL SAID, DAN,

4363
03:12:01,580 --> 03:12:06,385
DOES THAT MEAN THERE'S A LOT?

4364
03:12:06,385 --> 03:12:09,488
ANYWAY, HE HELPED US TO POLISH

4365
03:12:09,488 --> 03:12:11,757
THOSE PRESENTATIONS, SO I THINK

4366
03:12:11,757 --> 03:12:12,825
LOTHAR TALKED ABOUT PRACTICE

4367
03:12:12,825 --> 03:12:14,460
TALKS, MANY OF US HAD THE SAME

4368
03:12:14,460 --> 03:12:15,761
EXPERIENCE THE FIRST TIME

4369
03:12:15,761 --> 03:12:16,061
THROUGH.

4370
03:12:16,061 --> 03:12:21,967
IT WASN'T QUITE AS POLISHED AS

4371
03:12:21,967 --> 03:12:24,970
IT ULTIMATELY WAS.

4372
03:12:24,970 --> 03:12:26,472
PHIL CARED BUT AS A PERSON.

4373
03:12:26,472 --> 03:12:29,208
WHEN I MADE THE DECISION TO DO A

4374
03:12:29,208 --> 03:12:33,245
POSTDOC WITH PHIL, I MET

4375
03:12:33,245 --> 03:12:33,612
SHIRLEY.

4376
03:12:33,612 --> 03:12:35,447
SHIRLEY SAID, GIVE PHIL MY LOVE.

4377
03:12:35,447 --> 03:12:36,849
I THOUGHT, THAT'S INTERESTING.

4378
03:12:36,849 --> 03:12:38,817
NOW WHEN I LOOK BACK, I REALIZE

4379
03:12:38,817 --> 03:12:42,221
THAT I THINK MOST OF US HAVE AN

4380
03:12:42,221 --> 03:12:44,056
AFFECTION FOR PHIL THAT GOES

4381
03:12:44,056 --> 03:12:47,359
BEYOND AN APPRECIATION FOR HIS

4382
03:12:47,359 --> 03:12:47,826
SCIENTIFIC MENTORING.

4383
03:12:47,826 --> 03:12:49,428
HE'S A PERSON THAT CARED ABOUT

4384
03:12:49,428 --> 03:12:49,762
YOU.

4385
03:12:49,762 --> 03:12:50,896
I REALLY CARED ABOUT HIM.

4386
03:12:50,896 --> 03:12:53,499
SO IT WAS JUST A REMARKABLE

4387
03:12:53,499 --> 03:12:53,866
TIME.

4388
03:12:53,866 --> 03:12:59,972
MY FINAL SLIDE IS THIS IS AT THE

4389
03:12:59,972 --> 03:13:01,640
EVENT, IN 2004, IT'S -- YOU'RE

4390
03:13:01,640 --> 03:13:04,143
LOOKING AT PHIL AND I, IT

4391
03:13:04,143 --> 03:13:05,978
REMINDS ME OF THE BEST YEARS OF

4392
03:13:05,978 --> 03:13:08,046
MIGHT HAVE SCIENTIFIC CAREER

4393
03:13:08,046 --> 03:13:09,615
WHEN I WAS THERE WITH PHIL AND

4394
03:13:09,615 --> 03:13:12,418
MANY OF THE REST OF YOU, AT

4395
03:13:12,418 --> 03:13:13,786
HARVARD MEDICAL SCHOOL.

4396
03:13:13,786 --> 03:13:16,288
SO, THANKS, PHIL.

4397
03:13:16,288 --> 03:13:20,559
THANKS, AYA. 

4398
03:13:20,559 --> 03:13:22,628
SO, IT WAS JUST AN INCREDIBLY

4399
03:13:22,628 --> 03:13:24,062
POWERFUL TIME.

4400
03:13:24,062 --> 03:13:26,632
SO THANK YOU ALL.

4401
03:13:26,632 --> 03:13:28,801
[APPLAUSE]

4402
03:13:28,801 --> 03:13:34,773
 

4403
03:13:34,773 --> 03:13:38,844
 

4404
03:13:38,844 --> 03:13:40,679
>> SO, THANK YOU.

4405
03:13:40,679 --> 03:13:42,648
THAT WAS QUITE AMAZING.

4406
03:13:42,648 --> 03:13:47,719
I HAVE TO SAY AGAIN, TO 

4407
03:13:47,719 --> 03:13:49,321
REITERATE, QUITE HUMBLING.

4408
03:13:49,321 --> 03:13:51,089
THIS SYMPOSIUM HAS BEEN

4409
03:13:51,089 --> 03:13:52,157
ABSOLUTELY OUTSTANDING.

4410
03:13:52,157 --> 03:13:55,928
THERE HAVE BEEN SOME COMMON

4411
03:13:55,928 --> 03:13:59,765
THEMES WE'VE HEARD TODAY.

4412
03:13:59,765 --> 03:14:01,133
EDUCATION, COMMUNICATION,

4413
03:14:01,133 --> 03:14:03,902
COLLABORATION, MENTORSHIP.

4414
03:14:03,902 --> 03:14:06,338
WE ALL THANK PHIL AND FOR MANY

4415
03:14:06,338 --> 03:14:09,575
THINGS, FOR HIS CONTRIBUTIONS TO

4416
03:14:09,575 --> 03:14:11,477
SCIENCE, TO EDUCATION, ALSO HE

4417
03:14:11,477 --> 03:14:13,979
HAS AN AMAZING FAMILY.

4418
03:14:13,979 --> 03:14:15,714
THANK YOU, MICKI, ETHAN, BEN.

4419
03:14:15,714 --> 03:14:17,115
THANK YOU TO AYA WHO

4420
03:14:17,115 --> 03:14:20,118
UNFORTUNATELY COULDN'T BE HERE.

4421
03:14:20,118 --> 03:14:22,521
WHAT AN AMAZING FAMILY.

4422
03:14:22,521 --> 03:14:25,090
SO WE CAN'T PAY PHIL BACK.

4423
03:14:25,090 --> 03:14:28,727
BUT WE CAN PAY IT FORWARD.

4424
03:14:28,727 --> 03:14:31,396
FAES IS CONNECTING NIH ALUMNI

4425
03:14:31,396 --> 03:14:34,099
AND ALL ACTIVITIES WE DO WHETHER

4426
03:14:34,099 --> 03:14:37,202
THROUGH EDUCATION, EVENTS LIKE

4427
03:14:37,202 --> 03:14:38,570
THIS, OR NETWORKING EVENTS.

4428
03:14:38,570 --> 03:14:40,973
WE'RE WORKING ON SOME NEW

4429
03:14:40,973 --> 03:14:43,308
PROGRAMS IN THE NEXT SEVERAL

4430
03:14:43,308 --> 03:14:45,143
MONTHS TO YEARS, TO DO THINGS TO

4431
03:14:45,143 --> 03:14:46,078
HONOR WONDERFUL PEOPLE LIKE

4432
03:14:46,078 --> 03:14:49,081
PHIL, AND WE WOULD LOVE TO HAVE

4433
03:14:49,081 --> 03:14:50,282
THE FAMILY BACK.

4434
03:14:50,282 --> 03:14:54,620
SO, PLEASE KEEP AN EYE OUT FOR 

4435
03:14:54,620 --> 03:14:56,755
THE THINGS WE'RE DOING.

4436
03:14:56,755 --> 03:15:00,359
WE ARE ALSO VERY EXCITED TO

4437
03:15:00,359 --> 03:15:02,561
ALWAYS HAVE NIH-ERS AND OTHER

4438
03:15:02,561 --> 03:15:03,362
BIOMEDICAL SCIENTISTS, EXPERTS,

4439
03:15:03,362 --> 03:15:04,863
TEACH FOR US AND LECTURE NOW

4440
03:15:04,863 --> 03:15:06,498
THAT THINGS ARE ONLINE.

4441
03:15:06,498 --> 03:15:08,567
WE CAN DO THINGS REMOTELY AS

4442
03:15:08,567 --> 03:15:08,934
WELL.

4443
03:15:08,934 --> 03:15:10,469
SO PLEASE REACH OUT.

4444
03:15:10,469 --> 03:15:12,771
TAKE A CLASS WITH FAES OR TEACH

4445
03:15:12,771 --> 03:15:14,039
A CLASS WITH FAES.

4446
03:15:14,039 --> 03:15:16,675
WE WOULD BE VERY HUMBLED TO HAVE

4447
03:15:16,675 --> 03:15:17,442
YOU JOIN US.

4448
03:15:17,442 --> 03:15:20,412
THINK OF FAES FOR YOUR

4449
03:15:20,412 --> 03:15:21,079
EDUCATION.

4450
03:15:21,079 --> 03:15:22,881
AND FINALLY, THANK YOU, DR.

4451
03:15:22,881 --> 03:15:25,918
GOTTESMAN, FOR WORKING WITH ME

4452
03:15:25,918 --> 03:15:28,186
ON THIS PROJECT AND THIS

4453
03:15:28,186 --> 03:15:30,055
SYMPOSIUM, LEADING THIS, NOT

4454
03:15:30,055 --> 03:15:31,323
ONLY THE LEDER DEDICATION BUT

4455
03:15:31,323 --> 03:15:33,859
ALSO THE PROJECT TO BUILD HOUSES

4456
03:15:33,859 --> 03:15:35,627
HAS BEEN EXCITING AND HUMBLING

4457
03:15:35,627 --> 03:15:38,130
AND IT GIVES FAES AN OPPORTUNITY

4458
03:15:38,130 --> 03:15:41,833
TO PAY SOME THINGS BACK, BUT

4459
03:15:41,833 --> 03:15:42,734
CERTAINLY RECOGNIZE THE

4460
03:15:42,734 --> 03:15:44,503
EXCELLENCE THAT HAPPENS HERE AT

4461
03:15:44,503 --> 03:15:44,803
NIH.

4462
03:15:44,803 --> 03:15:49,274
SO, THANK YOU FOR BEING HERE. 

4463
03:15:49,274 --> 03:15:51,176
WE'RE VERY EXCITED.

4464
03:15:51,176 --> 03:15:52,477
AND THANK YOU.

4465
03:15:52,477 --> 03:15:53,178
WE REALLY APPRECIATE IT.

4466
03:15:53,178 --> 03:15:55,213
SOME OF YOU WILL BE JOINING US

4467
03:15:55,213 --> 03:15:57,382
FOR THE PHIL LEDER DEDICATION

4468
03:15:57,382 --> 03:16:01,320
FROM 2:30 TO 3:30.

4469
03:16:01,320 --> 03:16:02,955
WE WILL BE TOASTING PHIL LEDER

4470
03:16:02,955 --> 03:16:04,723
AND HIS FAMILY AT THAT EVENT.

4471
03:16:04,723 --> 03:16:08,760
THANK YOU AND HAVE A WONDERFUL

4472
03:16:08,760 --> 03:16:09,962
DAY.

4473
03:16:09,962 --> 03:16:19,962
[APPLAUSE]