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GOOD MORNING EVERYBODY.

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FOR THOSE WHO DON'T KNOW ME I

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AM THE DIRECTOR OF THE HIV

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DYNAMICS AND REPLICATION

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PROGRAM.

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IT IS AN HONOR AND A PRIVILEGE

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TO HAVE THIS OPPORTUNITY TO

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KICK OFF STEVE'S RETIREMENT

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SYMPOSIUM AND ON BEHALF OF THE

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ENTIRE DRP.

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STARTING WITH A FEW OBLIGATORY

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BIOGRAPHICAL DETAILS, STEVE

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RECEIVED HIS PHD FROM HARVARD

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1975.

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ABOUT THAT TIME MOVING TO

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UNIVERSITY OF UTAH AND AND

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THEN MOVED TO UC SOUTH TO DO

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POSTDOCTORAL FELLOWSHIP IN THE

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LABORATORY.

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1979 STEVENS RECRUITED TO

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HARVARD AS A SENIOR STAFF

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INVESTIGATOR.

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AND IN 1984 RECRUITED TO THE

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RESEARCH PROGRAM.

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HE SERVED AS DEPUTY DIRECTOR

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FOR OVER TEN YEARS AND BETWEEN

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1995 AND 1999 DIRECTOR OF THE

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LABORATORY AT EBL.

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WITH THAT WAS ROLLED INTO THE

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FEDERAL GOVERNMENT IN 1989

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STEVE JOINED THE HIV DRP

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PROGRAM FOR KEEPING THE

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ACRONYM IN PLACE.

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HE SERVED AS THE CHIEF FROM

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1999 THROUGH HIS RETIREMENT

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EARLY THIS YEAR ALSO SERVING

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AS THE ACTING CHIEF FROM THE

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DRP AND BETWEEN 2006 WAS

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DIRECTOR OF THE HIV DRP.

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HE HAS MADE A GROUNDBREAKING

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CONTRIBUTION TO THOSE AREAS OF

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VIROLOGY LIKE STRUCTURE AND

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FUNCTION OF HIV-1 AND

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MECHANISM SEPARATE RESISTANCE

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TO THE INHIBITORS AND ALSO HIV

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RESISTANCE JUST TO ELABORATE

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BRIEFLY TOGETHER WITH EDDIE

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ARNOLD WITH THE STRUCTURE WITH

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THE ENZYME AND COMPLEX

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DOUBLE-STRANDED DNA IT WAS

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LANDMARK PAPER PUBLISHED 1983

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AND DURING HIS TIME HE MADE

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IMPORTANT CONTRIBUTIONS TO

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UNDERSTAND THE RETROVIRAL

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INTEGRATION BY DEFINING THE

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STRUCTURES OF THE VIRUSES FROM

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RSV INFECTED CELLS.

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STEVE HAS MADE NUMEROUS

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CONTRIBUTIONS TO THE

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UNDERSTANDING TO THE

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INHIBITORS WORKING IN

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COLLABORATION WITH A NUMBER OF

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GROUPS INCLUDING EDDIE ARNOLD

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AND OTHERS.

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THEN RECENTLY STEVE HAS TURNED

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MUCH OF HIS ATTENTION TO THE

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UNDERSTANDING OF MECHANISMS OF

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PERSISTENCE TO ACHIEVE THIS

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LANDMARK PAPER IN 2014 TO SHOW

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THAT HIV-INFECTED CELLS ARE

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CAPABLE OF EXPANSION IN

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INFECTED INDIVIDUALS AND

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RECENTLY JUST LAST YEAR

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SHOWING THE PRO- VICE VIRUSES

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OF THE T CELL.

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SO I HAVE TO CONFESS THAT AS A

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YOUNG STUDENT MANY YEARS AGO

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WHEN I FIRST MET STEVE I FOUND

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HIM TO BE SEMI- INTIMIDATING.

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[LAUGHTER]

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I'M SURE MANY OF THE AUDIENCE

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HAD THE EXPERIENCE HAVING

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STEVE IN THE FRONT ROW READY

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TO POUNCE THE MOMENT ANYTHING

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WAS NOT CLEAR ASKING QUESTIONS

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I THINK WERE DESIGNED NOT TO

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HAVE A SIMPLE ANSWER.

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WHEN I WAS RECRUITED TO THE

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DAP NEARLY 20 YEARS AGO AS A

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NEWLY TENURED PI FROM THE

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START THAT WAS MY LAP SHE AND

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WE BECAME CLOSE FRIENDS.

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I VALUED HIS MENTORSHIP IS

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STRONG SUPPORT AND HIS KEEN

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INTELLECT AND APPRECIATED HIS

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KEEN FEEDBACK FOR MY

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RESEARCH.

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ADMINISTRATIVELY OUR ROLES

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SPLIT IN 2015 WHEN I BECAME

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DRP DIRECTOR HE PROVIDED

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VALUABLE ADVICE AND FEEDBACK.

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I HAVE MET FEW PEOPLE IN MY

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LIFE AS DEDICATED IN MY LIFE

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AS STEVE AND NO ONE IS DEVOTED

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TO FISHING.

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[LAUGHTER]

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HIS ENTHUSIASM IS CONTAGIOUS I

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MYSELF WAS AN AVID FISHERMAN

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CO-OWNER OF THE DEMANDS OF TO

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PUSH FISHING TO THE BACK

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BURNER.

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AS HE STARTED FISHING AGAIN WE

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HAD MANY OUTINGS ON THE

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CHESAPEAKE BAY AND ON STREAMS

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LOCALLY IN WESTERN MARYLAND

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AND PENNSYLVANIA CATCHING A

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BEAUTIFUL RAINBOW TROUT IN THE

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STREAM IN PENNSYLVANIA NEXT

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THEM ON SCHEDULE TO ACCOMPANY

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HIM ON A FLOAT TRIP TO ALASKA

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THAT I THINK WE WILL HEAR MORE

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ABOUT THAT IT WAS THE PICTURE

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TAKEN FROM LAST SUMMER FROM A

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DRONE.

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WE CAN SEE THE CAMP AND THE

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THREE VOTES.

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I WILL END THIS PART OF

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INTRODUCTION BY CONGRATULATING

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STEPHEN HIS ILLUSTRIOUS CAREER

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OF THE FORWARD TO MORE

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SCIENTIFIC AND UNSCIENTIFIC

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INTERACTION.

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WE HOPE YOUR TIME IS UP WITH

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SUNNY SKIES AND CALM WATERS

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AND BEAUTIFUL SUNRISES.

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HERE IS THE PROGRAM AT A

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GLANCE TALKS FROM FORMER

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MENTORS AND COLLEAGUES AND

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COLLABORATORS.

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AT THE END OF THE DAY WE WILL

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RECONVENE FOR AN INFORMAL

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GATHERING AT THE BREWERY AND I

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HOPE YOU CAN ALL JOIN US FOR

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THAT.

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SO THAT IS MY PLEASURE TO

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INTRODUCE THE FIRST SPEAKER.

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FROM THE UNIVERSITY OF UTAH

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HAS RECEIVED MANY AWARDS

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INCLUDING 2007 NOBEL PRIZE IN

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PHYSIOLOGY OR MEDICINE IN THE

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STEVE'S ADVISORS I MENTIONED

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THE UNIVERSITY OF UTAH.

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>>IT IS A PLEASURE TO BE

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HERE.

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FIRST A FEW WORDS ABOUT STEVE.

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I WAS REALLY FORTUNATE HE WAS

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ONE OF THE VERY FIRST GRADUATE

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STUDENTS IN MY LAB.

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AND AS A MENTOR YOU'RE NOT

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SUPPOSED TO HAVE FAVORITES BUT

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STEVE WAS A FAVORITE HE WAS

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NOT ONLY BRIGHT AND ENERGETIC

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BUT LOVES TO ARGUE.

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[LAUGHTER]

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BUT THE NICE THING ABOUT THE

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ARGUMENT IS THAT AFTERWARDS

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SCIENCE HAS IMPROVED.

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AND AS A GRADUATE STUDENT AND

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A PLEASURE TO HAVE AS A

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COLLEAGUE CONGRATULATIONS.

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>>SO MANY TIMES I GET
BORED

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WITH WHAT I AM DOING AND I

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MOVE ON.

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BUT ANXIETY IS A ENORMOUS

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PROBLEM IN TERMS OF HUMAN

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HEALTH.

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THE NATIONAL INSTITUTE OF

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MENTAL HEALTH REPORTED THE

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LIFETIME OCCURRENCE OF CHRONIC

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ANXIETY IS AS HIGH AS

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20 PERCENT EVEN HIGHER IN

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WOMEN THAN MEN.

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AND THIS IS EVEN WORSE FOR

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YOUNG ADULTS AND ADOLESCENTS.

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AND THEN WITH THE DISABLING

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DISEASE IT IS A BIG PROBLEM.

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SO THE DISRUPTION GIVES RISE

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TO CHRONIC ANXIETY AND THESE

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OVER GROOMING OF COMORBIDITY.

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AND WITH THE TRANSCRIPTION

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FACTOR AND THE PRIMARY

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FUNCTION IS TO MAKE SURE YOUR

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HEAD IS IN THE RIGHT PLACE AND

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SOMEONE.

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AND IT RESULTS IN PATHOLOGICAL

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BEHAVIOR.

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AND HERE WE SHOW THAT THEY

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KEEP GROOMING THROUGH THE

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LACERATIONS.

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AND THEN TO EXHIBIT ALL STRONG

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MALE SEX BIAS AND THIS IS A

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MAP OF 20 DIFFERENT MICE

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SHOWING THAT FEMALES SHOULD

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HAVE MUCH MORE AGGRESSIVE

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PATHOLOGY THAN MALES.

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AND THOSE RELATED TO

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PRODUCTION OF FEMALE HORMONES

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AND THE ANSWER IS YES.

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WOMEN AND FOR THE ENZYME

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REQUIRED.

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SO AGAIN WHAT YOU CAN SEE IF

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YOU DO THAT TO A FEMALE MOUSE

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THEN YOU GO DOWN TO THE MAIL

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LEVELS.

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SO IF WE SPEAK OF THE SAME

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HORMONES SITE PROGESTERONE

217
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INTO MEALS THEN YOU CAN

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INCREASE THEIR LEVEL OF

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ANXIETY CLOSE TO THAT OF

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FEMALES.

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THAT IS SHOWN HERE.

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THAT OTHERWISE IT DOESN'T DO

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ANYTHING TO IT.

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DOESN'T TELL YOU HOW THAT

225
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INTERACTS.

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SO THE FIRST QUESTION IS ARE

227
00:11:45,840 --> 00:11:51,560
THE CELLS RESPONSIBLE I'M

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SORRY WHAT IS THE CAUSE OF THE

229
00:11:54,520 --> 00:11:56,040
AGENT?

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SO SIMPLY WE DO SOME ANALYSIS.

231
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AND THEN DRIVE THAT EXPRESSION

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00:12:07,160 --> 00:12:16,280
AND BUT THEN PUT THE SIGNAL

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WITH THE T SITES AND THEN

234
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WHEREVER THAT IS EXPRESSED AND

235
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THEN WHEN YOU TURN ON GFP.

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BUT I WANT TO EMPHASIZE THIS

237
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IS NOT A TRANSCRIPTION MARKER.

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BUT HERE WE HAVE AN ENORMOUS

239
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SURPRISE.

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SO THAT YOU WILL KNOW EVEN

241
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MORE.

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00:12:50,400 --> 00:12:56,200
AND THEN HERE YOU SEE THE

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LABELS 30 PERCENT POPULATION

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IN THE BRAIN.

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SO THESE ARE THE CELLS OF THE

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BRAIN AND CELLS THAT GO INTO

247
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THE BRAIN AFTER THE RAIN

248
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STARTS TO FORM AND THEN THEY

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ARE THEY ARE TO CLEAR CELLULAR

250
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DEBRIS AND THEN HAS A RESPONSE

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TO INFECTION THIS IS WHAT THEY

252
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SAID TO BE DOING WHEN WE

253
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STARTED THIS WORK.

254
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BUT WE SAY SOMETHING QUITE

255
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DIFFERENT.

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WE ARE SUGGESTING LABELED WITH

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THE MARKER REGULATES THE

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MIDDLE OF CIRCUITS THAT

259
00:13:47,320 --> 00:13:51,400
DISRUPTION OF THAT REGULATION

260
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LEADS TO THE PATHOLOGY I WAS

261
00:13:51,960 --> 00:14:00,280
TALKING ABOUT.

262
00:14:00,280 --> 00:14:03,800
SO IT HAS BEEN POSITIVE DURING

263
00:14:03,800 --> 00:14:10,800
THE FIRST WEEK AND THEN

264
00:14:10,800 --> 00:14:14,640
DIRECTLY INTO THE BRAIN AND

265
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THEN ONCE THE SYSTEM HAS BEEN

266
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DEVELOPED THAT CAN GET INTO

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00:14:18,040 --> 00:14:20,480
THE BRAIN AND THIS IS BEEN

268
00:14:20,480 --> 00:14:25,600
REPEATED SO OFTEN BECAUSE THAT

269
00:14:25,600 --> 00:14:29,320
WE COME ALONG AND SAY MAYBE

270
00:14:29,320 --> 00:14:29,840
THERE IS MORE TO THE STORY

271
00:14:29,840 --> 00:14:34,640
THAN WE THINK THE THEN READING

272
00:14:34,640 --> 00:14:38,360
THE PAPER CAREFULLY FROM THEIR

273
00:14:38,360 --> 00:14:38,960
OWN DESCRIPTION THEY CAN ONLY

274
00:14:38,960 --> 00:14:40,360
ACCOUNT FOR ABOUT 60 PERCENT

275
00:14:40,360 --> 00:14:50,800
OF REDUCING THEIR MARKER.

276
00:14:56,640 --> 00:15:02,880
AND THEN TO LABEL THAT HAS A

277
00:15:02,880 --> 00:15:07,040
STOP SIGN AND THEN THE CELLS

278
00:15:07,040 --> 00:15:12,040
BECOME RED SO THOSE THAT ARE

279
00:15:12,040 --> 00:15:22,520
LABELED WITH CR ONE AND HERE

280
00:15:24,680 --> 00:15:26,200
BUT THEN USING THE TWO

281
00:15:26,200 --> 00:15:27,160
PHOTON.

282
00:15:27,160 --> 00:15:34,640
SO THE FIRST THING TO

283
00:15:34,640 --> 00:15:36,640
INTEGRATE AND THEN I MENTIONED

284
00:15:36,640 --> 00:15:39,360
THE OTHER POPULATION OF

285
00:15:39,360 --> 00:15:49,840
70 PERCENT AND THEN THAT TO

286
00:15:50,320 --> 00:15:54,400
CREATE AFTER BIRTH AND THAT IS

287
00:15:54,400 --> 00:15:57,840
ABOUT 30 PERCENT SO THERE IS

288
00:15:57,840 --> 00:16:01,600
TWO POSSIBILITIES AND ONE IS

289
00:16:01,600 --> 00:16:06,600
AT THE GREEN CELLS TURN ON

290
00:16:06,600 --> 00:16:09,400
WITH THE POSSIBILITY THERE IS

291
00:16:09,400 --> 00:16:18,240
ANOTHER SEPARATE WAY AND

292
00:16:18,240 --> 00:16:22,640
LOOKING TO SEE ONE IT IS

293
00:16:22,640 --> 00:16:25,120
EXPRESSED IN OF THOSE SYSTEMS

294
00:16:25,120 --> 00:16:27,040
AND THEN YOU SEE A STRONG

295
00:16:27,040 --> 00:16:31,120
EXPRESSION THE EE SEVEN AND A

296
00:16:31,120 --> 00:16:35,720
HALF THERE IS NOTHING.

297
00:16:35,720 --> 00:16:37,760
AND THEN TO START SEEING THE

298
00:16:37,760 --> 00:16:39,760
EXPRESSION THERE IS LITTLE BIT

299
00:16:39,760 --> 00:16:46,240
LEFT YOU CAN EASILY DETECT BUT

300
00:16:46,240 --> 00:16:52,680
THERE'S FAR LESS AND THAT

301
00:16:52,680 --> 00:16:55,600
RULES OUT THE FIRST

302
00:16:55,600 --> 00:16:58,280
HYPOTHESIS.

303
00:16:58,280 --> 00:17:03,120
SO E-SEVEN AND A HALF HAS THE

304
00:17:03,120 --> 00:17:04,160
YIELD THAT GOES DIRECTLY TO

305
00:17:04,160 --> 00:17:10,120
THE BRAIN AND THEN THEY ARE

306
00:17:10,120 --> 00:17:14,080
BORN AGAIN IN THE YOLK SAC

307
00:17:14,080 --> 00:17:24,560
WITH THE GESTATION AND THEN

308
00:17:28,960 --> 00:17:29,200
STARTING AT.

309
00:17:29,200 --> 00:17:29,800
>>DR. PARKER: AND A HALF
IN A

310
00:17:29,800 --> 00:17:30,400
VERY DIFFERENT ROUTE OF ENTRY

311
00:17:30,400 --> 00:17:31,480
AND OBVIOUSLY IF YOU DO THAT

312
00:17:31,480 --> 00:17:33,480
TO HAVE THESE DIFFERENT

313
00:17:33,480 --> 00:17:37,560
PROPERTIES.

314
00:17:37,560 --> 00:17:37,960
>>SO WHAT ARE THE

315
00:17:37,960 --> 00:17:39,640
SIMILARITIES BETWEEN THESE TWO

316
00:17:39,640 --> 00:17:43,480
POPULATIONS?

317
00:17:43,480 --> 00:17:46,520
BECAUSE I HAVE TO GO THROUGH

318
00:17:46,520 --> 00:17:51,120
THIS THAT THERE IS NO

319
00:17:51,120 --> 00:17:54,080
POPULATION.

320
00:17:54,080 --> 00:17:54,640
SO THERE ARE THREE MARKERS

321
00:17:54,640 --> 00:18:01,640
THAT ARE SPECIFIED IT WITH A

322
00:18:01,640 --> 00:18:05,160
TRANSCRIPTION FACTOR WHICH IS

323
00:18:05,160 --> 00:18:11,160
THE RECEPTOR AND THESE ARE

324
00:18:11,160 --> 00:18:18,480
BONA FIDE AND IF ALL EXPRESSED

325
00:18:18,480 --> 00:18:20,400
EQUALLY IN THE TWO POPULATIONS

326
00:18:20,400 --> 00:18:22,400
SO THEREFORE WE CAN SAY WITH

327
00:18:22,400 --> 00:18:30,080
CONFIDENCE IT IS BONA FIDE.

328
00:18:30,080 --> 00:18:33,760
SO AS THESE POPULATIONS BEHAVE

329
00:18:33,760 --> 00:18:34,320
WITH THE DIFFERENT HISTORIES

330
00:18:34,320 --> 00:18:36,720
DO THEY BEHAVE SIMILARLY?

331
00:18:36,720 --> 00:18:47,160
SO HOPEFULLY THIS WORKS.

332
00:18:49,480 --> 00:18:57,400
THAT WAS QUICK.

333
00:18:57,400 --> 00:19:04,000
NOW KEEP GOING.

334
00:19:04,000 --> 00:19:04,560
THE MOVIE ISN'T WORKING BUT

335
00:19:04,560 --> 00:19:09,680
WHAT YOU WOULD HAVE SEEN IS

336
00:19:09,680 --> 00:19:13,520
SENDING THE PROJECTIONS YOU

337
00:19:13,520 --> 00:19:14,600
CAN WATCH IT AND IT TAKES

338
00:19:14,600 --> 00:19:17,240
ABOUT 20 SECONDS WE HAD IT

339
00:19:17,240 --> 00:19:18,280
DOWN TO ABOUT THREE SECONDS

340
00:19:18,280 --> 00:19:22,280
AND THEN IT COMES DOWN AND THE

341
00:19:22,280 --> 00:19:32,640
FIELD IS SURROUNDED.

342
00:19:33,840 --> 00:19:34,560
ANYWAY.

343
00:19:34,560 --> 00:19:38,240
NOW THE OTHER PROPERTY IS THAT

344
00:19:38,240 --> 00:19:44,720
THEY DO SYNAPTIC PRUNING AND

345
00:19:44,720 --> 00:19:45,160
ABOUT TWICE AS MANY

346
00:19:45,160 --> 00:19:45,760
CONNECTIONS THAT YOU NEED AND

347
00:19:45,760 --> 00:19:47,560
THEN USE PRUNING TO PULL OUT

348
00:19:47,560 --> 00:19:51,520
THE WEAKER CONNECTIONS AND

349
00:19:51,520 --> 00:19:54,560
THEN REINFORCE THE STRONG

350
00:19:54,560 --> 00:19:58,960
PROJECTIONS.

351
00:19:58,960 --> 00:20:02,000
NOW SOMETHING IS GOING REALLY

352
00:20:02,000 --> 00:20:08,120
WRONG.

353
00:20:08,120 --> 00:20:08,360
ANYBODY?

354
00:20:08,360 --> 00:20:13,440
[INAUDIBLE CONVERSATIONS]

355
00:20:13,440 --> 00:20:16,560
THERE WE GO.

356
00:20:16,560 --> 00:20:20,000
SO ANOTHER ASSAY FROM PRUNING

357
00:20:20,000 --> 00:20:22,920
WAS DEVELOPED FROM HARVARD AND

358
00:20:22,920 --> 00:20:29,360
WHAT SHE DID WAS TAKE THE UNIT

359
00:20:29,360 --> 00:20:30,240
WITH A VERY HIGH AFFINITY FOR

360
00:20:30,240 --> 00:20:33,200
THE SYNAPSE BUT THE LABEL ON

361
00:20:33,200 --> 00:20:34,680
AND INJECTED INTO THE BRAIN

362
00:20:34,680 --> 00:20:38,320
INTO THE EYE AND THEN IT GOES

363
00:20:38,320 --> 00:20:44,120
TO THE THALAMUS AND THEN THOSE

364
00:20:44,120 --> 00:20:47,880
WE CONNECTIONS ARE TAKEN UP SO

365
00:20:47,880 --> 00:20:48,960
THEN YOU HAVE A LABEL INSIDE

366
00:20:48,960 --> 00:20:53,040
THE CELLS.

367
00:20:53,040 --> 00:20:59,920
SO THAT IS DOUBLY LABELED AND

368
00:20:59,920 --> 00:21:00,920
THEN YOU CAN DO THIS FOR

369
00:21:00,920 --> 00:21:03,360
HUNDREDS OF CELLS AND PRETTY

370
00:21:03,360 --> 00:21:10,680
MUCH INDISTINGUISHABLE.

371
00:21:10,680 --> 00:21:13,640
SO MOLECULARLY THEY ARE

372
00:21:13,640 --> 00:21:13,840
SIMILAR.

373
00:21:13,840 --> 00:21:19,200
THERE ARE 40 GENES ESSENTIALLY

374
00:21:19,200 --> 00:21:21,720
SO THE POPULATIONS ARE QUITE

375
00:21:21,720 --> 00:21:24,400
SIMILAR MOLECULARLY.

376
00:21:24,400 --> 00:21:29,480
SO THEN THE NEXT QUESTION IS

377
00:21:29,480 --> 00:21:36,360
THE CAUSE FOR THE ANXIETY WE

378
00:21:36,360 --> 00:21:40,240
WILL ADJUST THIS.

379
00:21:40,240 --> 00:21:46,320
SO YOU TAKE A MOUSE BUT THEN

380
00:21:46,320 --> 00:21:51,800
YOU FILL IT UP HOWEVER YOU

381
00:21:51,800 --> 00:21:56,680
WANT AND WE CAN PUT THAT IN

382
00:21:56,680 --> 00:21:57,680
FROM A NORMAL MOUSE OR A

383
00:21:57,680 --> 00:22:01,200
MUTANT MOUSE IT WITH THAT

384
00:22:01,200 --> 00:22:04,920
EXPERIMENT THIS IS A GROWTH

385
00:22:04,920 --> 00:22:08,760
FACTOR RECEPTOR AND THEY

386
00:22:08,760 --> 00:22:11,720
REQUIRE A RECEPTOR FOR

387
00:22:11,720 --> 00:22:11,960
SURVIVAL.

388
00:22:11,960 --> 00:22:13,800
SO WE CAN USE THIS METHOD

389
00:22:13,800 --> 00:22:15,120
SIMPLY TO ELIMINATE FROM THE

390
00:22:15,120 --> 00:22:19,600
BRAIN AND THEN USE THE

391
00:22:19,600 --> 00:22:26,640
PROCEDURES AND WITH THE

392
00:22:26,640 --> 00:22:31,120
DEVELOPMENT AND THEN REINJECT

393
00:22:31,120 --> 00:22:33,840
ON BOTH SIDES AND THEN WAIT A

394
00:22:33,840 --> 00:22:37,520
FEW MONTHS AND WITH THE

395
00:22:37,520 --> 00:22:47,880
POPULATION WE GO BACK.

396
00:22:48,720 --> 00:22:53,400
AND THEN 100 PERCENT

397
00:22:53,400 --> 00:22:55,240
ENGRAFTMENT.

398
00:22:55,240 --> 00:23:01,080
SO THIS IS INJECTING NORMAL OF

399
00:23:01,080 --> 00:23:05,520
HOW MUCH TIME THEY SPENT

400
00:23:05,520 --> 00:23:06,800
GROOMING.

401
00:23:06,800 --> 00:23:11,520
AND THEN HERE IS LOOKING AT

402
00:23:11,520 --> 00:23:16,960
ANXIETY AND LOOKING AT THE TWO

403
00:23:16,960 --> 00:23:18,680
PLATFORMS.

404
00:23:18,680 --> 00:23:19,160
AND THIS IS WHAT WE CALL

405
00:23:19,160 --> 00:23:24,280
CLOSED AND ENCLOSED AND

406
00:23:24,280 --> 00:23:26,440
ACTUALLY SUPPORTS BOTH

407
00:23:26,440 --> 00:23:28,120
PLATFORMS EQUALLY WHERE A

408
00:23:28,120 --> 00:23:30,400
MUTANT MOUSE LOOKS DOWN AND IT

409
00:23:30,400 --> 00:23:34,960
WAS SCARY.

410
00:23:34,960 --> 00:23:38,280
SO MOST OF THE ASSAY IS

411
00:23:38,280 --> 00:23:42,560
AVOIDANCE TYPE.

412
00:23:42,560 --> 00:23:45,560
SO THAT SAYS THAT PURIFIED

413
00:23:45,560 --> 00:23:47,680
CELLS ARE CAUSAL THAT ONLY BY

414
00:23:47,680 --> 00:23:50,960
THEMSELVES WITH THE PHENOTYPE

415
00:23:50,960 --> 00:24:00,240
THEN IT IS A NORMAL BEHAVIOR.

416
00:24:00,240 --> 00:24:00,840
SO WITH THE UNDERSTANDING OF

417
00:24:00,840 --> 00:24:08,840
THE PROCESS.

418
00:24:08,840 --> 00:24:10,880
NOW WE REALLY NEED HELP.

419
00:24:10,880 --> 00:24:21,040
[LAUGHTER]

420
00:25:09,920 --> 00:25:12,920
SO I WILL TAKE YOU THROUGH

421
00:25:12,920 --> 00:25:21,600
THESE.

422
00:25:21,600 --> 00:25:32,000
AND A WAY OF ACTIVATING.

423
00:25:50,840 --> 00:26:01,200
[INAUDIBLE CONVERSATIONS]

424
00:26:11,960 --> 00:26:15,040
SO THE FIRST STEP IS WHAT WE

425
00:26:15,040 --> 00:26:22,400
WANT TO DO IS MODULATE.

426
00:26:22,400 --> 00:26:27,480
SO THE FIRST PERSON IS HOW IS

427
00:26:27,480 --> 00:26:33,240
THAT POSSIBLE?

428
00:26:33,240 --> 00:26:35,360
AND THEN WITH THOSE ACTION

429
00:26:35,360 --> 00:26:35,640
POTENTIALS.

430
00:26:35,640 --> 00:26:40,000
SO WHAT DOES THAT MEAN CRACKS

431
00:26:40,000 --> 00:26:42,400
SIMPLY OF CELL FUNCTION

432
00:26:42,400 --> 00:26:47,440
PUMPING INTO THE CELL AND THAT

433
00:26:47,440 --> 00:26:53,760
IS ENOUGH ESSENTIALLY THROUGH

434
00:26:53,760 --> 00:27:04,160
TRANSCRIPTION AND SO ON.

435
00:27:05,520 --> 00:27:08,520
AND WITH GENERAL DOBSON AND

436
00:27:08,520 --> 00:27:12,480
THEN WITH THE REGIONALS OF THE

437
00:27:12,480 --> 00:27:17,200
BRAIN.

438
00:27:17,200 --> 00:27:17,760
AND WITH THE WATTAGE OF THE

439
00:27:17,760 --> 00:27:21,400
LASER AND SO SHOWING YOU 20

440
00:27:21,400 --> 00:27:25,080
CONTROL SLIDES SO YOU JUST

441
00:27:25,080 --> 00:27:25,680
HAVE TO TAKE MY WORD FOR IT IS

442
00:27:25,680 --> 00:27:33,120
VERY SPECIFIC CUTS.

443
00:27:33,120 --> 00:27:33,360
PERIOD.

444
00:27:33,360 --> 00:27:35,360
SPACE AND SPECIFICITY IS

445
00:27:35,360 --> 00:27:35,640
IMPORTANT.

446
00:27:35,640 --> 00:27:37,760
BUT IF YOU DO THE RIGHT ONE

447
00:27:37,760 --> 00:27:41,200
SOMETHING HAPPENS.

448
00:27:41,200 --> 00:27:47,480
IS ALSO IMPORTANT ASTROCYTES

449
00:27:47,480 --> 00:27:48,040
AND NOTHING HAPPENS FINALLY

450
00:27:48,040 --> 00:27:57,200
HAS BEEN REPORTED OF NON-

451
00:27:57,200 --> 00:27:57,720
EXPRESSING NEURONS BUT THE

452
00:27:57,720 --> 00:27:58,640
LEAKAGE IS EXTREMELY LOVING

453
00:27:58,640 --> 00:28:03,280
CANNOT BE DETECT ON —-

454
00:28:03,280 --> 00:28:03,800
DETECTED IN THE RESPONSE.

455
00:28:03,800 --> 00:28:08,200
THAT IT IS UNDETECTABLE.

456
00:28:08,200 --> 00:28:12,280
BUT NONE THE LION NOT ON —-

457
00:28:12,280 --> 00:28:14,680
NONETHELESS WE DON'T SEE THE

458
00:28:14,680 --> 00:28:15,200
EFFECT IF WE LEAVE OUT THE

459
00:28:15,200 --> 00:28:17,840
COMPONENT THAT WE TALKED ABOUT

460
00:28:17,840 --> 00:28:19,920
THAT SHOULD NOT AFFECT FREE

461
00:28:19,920 --> 00:28:25,680
EXPRESSION WHAT MAKES THIS

462
00:28:25,680 --> 00:28:29,120
RECEPTIVE IN THE NEURON.

463
00:28:29,120 --> 00:28:32,160
SO WE HAVE DONE ALL OF THOSE

464
00:28:32,160 --> 00:28:35,480
CONTROLS THAT YOU WILL NOT SEE

465
00:28:35,480 --> 00:28:36,080
ANY OF THEM SO NOW LET'S MOVE

466
00:28:36,080 --> 00:28:38,440
ON TO THE ACTIVE EXPERIMENTS

467
00:28:38,440 --> 00:28:43,520
THEMSELVES.

468
00:28:43,520 --> 00:28:44,120
SO HERE WE PUT IT INTO THAT

469
00:28:44,120 --> 00:28:48,160
PART OF THE BRAIN.

470
00:28:48,160 --> 00:28:49,200
SO WHAT YOU DO IS TAKE MOVIES

471
00:28:49,200 --> 00:28:52,680
FOR TWO MINUTES TURN ON THE

472
00:28:52,680 --> 00:28:53,160
LASER KEEP IT ON FOR TWO

473
00:28:53,160 --> 00:28:55,160
MINUTES THEN TURN OFF THE

474
00:28:55,160 --> 00:29:00,360
LASER KEEP RECORDING.

475
00:29:00,360 --> 00:29:05,160
SO HERE WE HAVE SEE 57 CONTROL

476
00:29:05,160 --> 00:29:10,920
THAT'S FOR MANY GENERATIONS SO

477
00:29:10,920 --> 00:29:11,920
IF YOU TURN ON THE LASER

478
00:29:11,920 --> 00:29:20,600
NOTHING HAPPENS BUT THEN THEY

479
00:29:20,600 --> 00:29:27,160
DEPENDED.

480
00:29:27,160 --> 00:29:32,680
THAT HERE IS THAT CONTROLS IT

481
00:29:32,680 --> 00:29:33,720
IS 100 FOR LESS SO IF YOU TURN

482
00:29:33,720 --> 00:29:38,120
OFF THE LASER INDEPENDENT EASY

483
00:29:38,120 --> 00:29:38,720
SOME BACKGROUND NOISE THAT HAS

484
00:29:38,720 --> 00:29:39,960
NOTHING TO DO WITH THE LASER

485
00:29:39,960 --> 00:29:45,440
BUT AN EXPERIMENT THIS IS PRE-

486
00:29:45,440 --> 00:29:50,840
AND POST, OR DURING BUT THEN

487
00:29:50,840 --> 00:29:51,880
IT IS VARIABLE THEN BETTER

488
00:29:51,880 --> 00:29:57,480
THAN OTHERS.

489
00:29:57,480 --> 00:29:58,520
>>AND THEN WITH THE

490
00:29:58,520 --> 00:30:04,200
PREFRONTAL CORTEX AND THEN

491
00:30:04,200 --> 00:30:10,320
THEY TURN ON THE LASER AND THE

492
00:30:10,320 --> 00:30:13,320
RESULTS ARE QUITE ROBUST AND

493
00:30:13,320 --> 00:30:16,240
MEASURABLE AND QUANTITATIVE

494
00:30:16,240 --> 00:30:17,280
THAT TELLS US WE CAN TURN ON

495
00:30:17,280 --> 00:30:24,960
THE SYSTEM WITH THE PREFRONTAL

496
00:30:24,960 --> 00:30:27,880
CORTEX AND THEN WE ONLY GET

497
00:30:27,880 --> 00:30:38,320
THE RESPONSE AND THEN THE

498
00:30:43,280 --> 00:30:51,120
CENTRAL AMYGDALA.

499
00:30:51,120 --> 00:30:55,520
SO HERE IS THE MAZE AGAIN

500
00:30:55,520 --> 00:31:01,040
EXPLORING BOTH AND THEN IT

501
00:31:01,040 --> 00:31:04,920
STARTS TO EXPLORE AGAIN AND

502
00:31:04,920 --> 00:31:05,440
THEN TO QUANTITATE THIS IN

503
00:31:05,440 --> 00:31:15,720
DIFFERENT WAYS.

504
00:31:17,320 --> 00:31:20,280
AND THEN TO EXPLORE THE ENTIRE

505
00:31:20,280 --> 00:31:24,960
SURFACE IF IT IS A MUTANT

506
00:31:24,960 --> 00:31:27,960
MOUSE THEN IT STAYS OUT IN THE

507
00:31:27,960 --> 00:31:28,200
CENTER.

508
00:31:28,200 --> 00:31:36,320
SO WHAT YOU CAN SEE ANOTHER

509
00:31:36,320 --> 00:31:36,920
REACTION IS FREEZING WHICH IS

510
00:31:36,920 --> 00:31:39,680
A REACTION OF ANXIETY.

511
00:31:39,680 --> 00:31:50,160
SO FOR EXAMPLE WITH PRE- AND

512
00:31:54,280 --> 00:31:58,480
THEN POST DURING THE LASER

513
00:31:58,480 --> 00:32:03,680
THAT PATTERN DOES NOT CHANGE

514
00:32:03,680 --> 00:32:04,720
FOR THE BLA AND THEN YOU CAN

515
00:32:04,720 --> 00:32:08,880
QUANTITATE THAT.

516
00:32:08,880 --> 00:32:12,000
IF YOU GO INTO THE HIPPOCAMPUS

517
00:32:12,000 --> 00:32:15,080
THEN YOU CAN INDUCE BOTH

518
00:32:15,080 --> 00:32:15,680
BEHAVIORS AS WELL AS HIGHER

519
00:32:15,680 --> 00:32:19,200
LEVELS OF ANXIETY THAT IS

520
00:32:19,200 --> 00:32:25,920
SHOWN HERE FREE AND DURING AND

521
00:32:25,920 --> 00:32:32,880
THEN AFTER THEN YOU CAN SEE

522
00:32:32,880 --> 00:32:40,480
QUANTITATIVE AND THEN WITH THE

523
00:32:40,480 --> 00:32:41,040
CONTROL AND THEN HERE WE CAN

524
00:32:41,040 --> 00:32:45,600
SEE THAT CONTROL WITH THE OPEN

525
00:32:45,600 --> 00:32:51,600
FIELD TEST AND THEN SO THAT

526
00:32:51,600 --> 00:32:57,360
ESSENTIALLY SAYS WITH THAT

527
00:32:57,360 --> 00:33:02,120
BEHAVIOR BUT THAT IS THE SAME

528
00:33:02,120 --> 00:33:08,360
SO SO FAR IT IS ACTIVATING SO

529
00:33:08,360 --> 00:33:13,200
WHAT HAPPENS IF YOU ACTIVATE

530
00:33:13,200 --> 00:33:16,880
OTHERS?

531
00:33:16,880 --> 00:33:17,480
SO UNFORTUNATELY WE CANNOT DO

532
00:33:17,480 --> 00:33:24,080
THAT EXPERIMENT BUT WE CAN

533
00:33:24,080 --> 00:33:30,960
ACTIVATE BOTH POPULATIONS AND

534
00:33:30,960 --> 00:33:35,000
WE ARE EXPRESSING THIS IN BOTH

535
00:33:35,000 --> 00:33:36,080
POPULATIONS AND HERE'S WHAT WE

536
00:33:36,080 --> 00:33:39,760
WERE EXPECTING SO ONE

537
00:33:39,760 --> 00:33:41,680
POSSIBILITY IS IT IS NO

538
00:33:41,680 --> 00:33:47,360
DIFFERENCE WITH ALTERNATIVE

539
00:33:47,360 --> 00:33:51,480
YOU WOULD SEE HIGHER LEVELS IN

540
00:33:51,480 --> 00:33:53,520
THAT SAYS THAT BOTH ARE

541
00:33:53,520 --> 00:33:55,480
PARTICIPATING SO WHAT WE HAVE

542
00:33:55,480 --> 00:33:57,280
DONE IS COMPLETE THE

543
00:33:57,280 --> 00:33:58,480
UNEXPECTED.

544
00:33:58,480 --> 00:34:04,720
IT ACTUALLY INHIBITED AND NOW

545
00:34:04,720 --> 00:34:09,440
IT'S BACK DOWN TO ZERO.

546
00:34:09,440 --> 00:34:14,400
AND THEN TO THINK ABOUT THIS

547
00:34:14,400 --> 00:34:18,280
SO THROW EVERYTHING AWAY.

548
00:34:18,280 --> 00:34:18,800
YOU HAVE TO REVISE HOW YOU

549
00:34:18,800 --> 00:34:22,840
LOOK AT IT.

550
00:34:22,840 --> 00:34:27,560
SO AT THE GENETICS EXPERIMENT

551
00:34:27,560 --> 00:34:34,200
EXIST IS THAT AS IT ACTS AS A

552
00:34:34,200 --> 00:34:41,840
BREAK AND REDUCES ANXIETY AND

553
00:34:41,840 --> 00:34:42,440
THEN WORKING AS AN ACCELERATOR

554
00:34:42,440 --> 00:34:44,880
TO INCREASE ANXIETY AND

555
00:34:44,880 --> 00:34:49,560
BEHAVIOR AND TOGETHER WITH ANY

556
00:34:49,560 --> 00:34:50,360
STATUS THAT THEY WANT AND THEN

557
00:34:50,360 --> 00:34:55,360
YOU CAN REGULATE HOW MUCH

558
00:34:55,360 --> 00:34:55,600
ANXIETY.

559
00:34:55,600 --> 00:34:56,200
BECAUSE REMEMBER A LITTLE BIT

560
00:34:56,200 --> 00:34:59,440
OF ANXIETY IS GOOD.

561
00:34:59,440 --> 00:34:59,960
GETS US EXCITED AND MOVING

562
00:34:59,960 --> 00:35:06,800
THAT TOO MUCH IS PATHOLOGICAL.

563
00:35:06,800 --> 00:35:07,360
SO NOW YOU HAVE A VERY FINE

564
00:35:07,360 --> 00:35:09,960
SYSTEM CONTROLLING THAT

565
00:35:09,960 --> 00:35:16,480
BEHAVIOR.

566
00:35:16,480 --> 00:35:17,080
SO I DO HAVE MICROGLIA IN THE

567
00:35:17,080 --> 00:35:17,400
FIRST PLACE?

568
00:35:17,400 --> 00:35:23,080
WE ARE DOING THE SAME THING

569
00:35:23,080 --> 00:35:23,600
THEY HEAR THEY ARE WORKING

570
00:35:23,600 --> 00:35:26,680
OPPOSITE TO EACH OTHER.

571
00:35:26,680 --> 00:35:30,640
SO THE MODEL MAKES A STRONG

572
00:35:30,640 --> 00:35:35,160
PREDICTION OTHERWISE WE SHOULD

573
00:35:35,160 --> 00:35:41,240
GET NOTHING OTHERWISE IT

574
00:35:41,240 --> 00:35:41,840
SHOULD BE ELEVATED FOR ANXIETY

575
00:35:41,840 --> 00:35:44,440
IN THAT SECTION WHICH YOU SEE.

576
00:35:44,440 --> 00:35:44,920
NO ONE WOULD HAVE EVER

577
00:35:44,920 --> 00:35:47,160
PREDICTED THIS.

578
00:35:47,160 --> 00:35:48,280
SO WITH THAT I WILL STOP.

579
00:35:48,280 --> 00:35:48,880
THANK YOU.

580
00:35:48,880 --> 00:35:50,840
[LAUGHTER]

581
00:35:50,840 --> 00:35:59,000
[APPLAUSE]

582
00:35:59,000 --> 00:36:01,520
>>THANK YOU VERY MUCH.

583
00:36:01,520 --> 00:36:03,720
WE HAVE TIME FOR A LITTLE BIT

584
00:36:03,720 --> 00:36:10,200
OF QUESTIONS.

585
00:36:10,200 --> 00:36:20,280
>>

586
00:36:23,840 --> 00:36:25,560
[INAUDIBLE]

587
00:36:25,560 --> 00:36:27,720
>>WE CAN MAKE MICE THAT
HAVE

588
00:36:27,720 --> 00:36:32,000
EITHER ONE.

589
00:36:32,000 --> 00:36:36,080
>>AND AT DIFFERENT TIMES

590
00:36:36,080 --> 00:36:36,280
QUICK.

591
00:36:36,280 --> 00:36:40,440
>>CERTAINLY WE CAN USE
THAT.

592
00:36:40,440 --> 00:36:43,360
WE STILL DON'T HAVE A WAY OF

593
00:36:43,360 --> 00:36:46,800
REGULATING OR ANY MARKERS

594
00:36:46,800 --> 00:36:53,360
SPECIFIC WITH THE SEQUENCING.

595
00:36:53,360 --> 00:36:54,480
BUT MY GUESS IS TO FIGURE OUT

596
00:36:54,480 --> 00:36:59,760
A WAY TO MODULATE BOTH

597
00:36:59,760 --> 00:37:00,080
POPULATIONS.

598
00:37:00,080 --> 00:37:06,920
WHAT I SHOULD POINT OUT WE CAN

599
00:37:06,920 --> 00:37:11,120
PUT ANYTHING WE WANTED SO WE

600
00:37:11,120 --> 00:37:13,720
COULD CHANGE THAT TO ADDRESS

601
00:37:13,720 --> 00:37:19,360
THE QUESTION.

602
00:37:19,360 --> 00:37:19,880
>>SOME OF THOSE DIFFERENT

603
00:37:19,880 --> 00:37:20,440
PROPORTIONS WITH THE MOUSE

604
00:37:20,440 --> 00:37:20,640
STRAINS?

605
00:37:20,640 --> 00:37:24,160
>>WE DON'T KNOW.

606
00:37:24,160 --> 00:37:33,480
>>SO IF YOU HAVE LESS

607
00:37:33,480 --> 00:37:34,120
EXPRESSION YOU SEE THAT THERE

608
00:37:34,120 --> 00:37:34,320
AS WELL?

609
00:37:34,320 --> 00:37:37,960
>>YOU MODULATE.

610
00:37:37,960 --> 00:37:42,560
>>

611
00:37:42,560 --> 00:37:45,040
[INAUDIBLE]

612
00:37:45,040 --> 00:37:46,640
>>AND HETEROZYGOTES WE
DON'T

613
00:37:46,640 --> 00:37:49,400
SEE THAT.

614
00:37:49,400 --> 00:37:50,480
BUT IN BETWEEN WE SHOULD SEE

615
00:37:50,480 --> 00:37:52,200
THE PHENOTYPE.

616
00:37:52,200 --> 00:37:55,080
AND THEN I THINK WE CAN DO

617
00:37:55,080 --> 00:37:55,280
THAT.

618
00:37:55,280 --> 00:38:03,440
WHAT I SHOULD POINT OUT BUT

619
00:38:03,440 --> 00:38:08,560
THEN THEY KEEP DIVIDING AND

620
00:38:08,560 --> 00:38:09,320
DIVIDING AND THEN WENT TO STOP

621
00:38:09,320 --> 00:38:15,680
AND REPLICATE.

622
00:38:15,680 --> 00:38:16,760
AND THEN TO KNOW WHAT THE

623
00:38:16,760 --> 00:38:19,560
GROWTH RATES AND THEN GO A

624
00:38:19,560 --> 00:38:26,640
LITTLE BIT FASTER.

625
00:38:26,640 --> 00:38:29,680
SO THOSE EXPERIMENTS CAN BE

626
00:38:29,680 --> 00:38:33,640
DONE.

627
00:38:33,640 --> 00:38:36,800
>>ANY ASSOCIATED TO
HUMANS?

628
00:38:36,800 --> 00:38:47,320
>>VERY INTERESTING
QUESTION.

629
00:38:48,960 --> 00:38:49,400
THAT FOR SOME REASON THEY

630
00:38:49,400 --> 00:38:49,960
CHOSE THE OTHER AS WHAT YOU

631
00:38:49,960 --> 00:38:52,400
NORMALLY HAVE.

632
00:38:52,400 --> 00:38:55,800
BUT IN MOST POPULATIONS IN THE

633
00:38:55,800 --> 00:38:59,760
ROLE THAT IS AT 90 PERCENT.

634
00:38:59,760 --> 00:39:03,840
SO IT COMES IN FROM HIGHER

635
00:39:03,840 --> 00:39:05,040
PRIMATES THEN TO MAINTAIN A

636
00:39:05,040 --> 00:39:10,880
VERY HIGH LEVEL IN HUMANS.

637
00:39:10,880 --> 00:39:12,920
AND WE HAVE TAKEN THAT

638
00:39:12,920 --> 00:39:16,160
POLYMORPHISM STICKING INTO

639
00:39:16,160 --> 00:39:19,280
MICE.

640
00:39:19,280 --> 00:39:22,720
IT FUNCTIONS AS A MUTATION SO

641
00:39:22,720 --> 00:39:25,120
THE HIGHER LEVELS OF ANXIETY.

642
00:39:25,120 --> 00:39:32,560
SO WITH THE SYSTEM IT IS

643
00:39:32,560 --> 00:39:32,800
SIMILAR.

644
00:39:32,800 --> 00:39:35,120
SO THERE IS ONLY ONE

645
00:39:35,120 --> 00:39:40,680
POPULATION NOW AND THAT IS THE

646
00:39:40,680 --> 00:39:45,640
AFRICA POPULATION.

647
00:39:45,640 --> 00:39:49,440
ALL OTHERS ARE REALLY HIGH.

648
00:39:49,440 --> 00:39:54,440
SO THERE IS POLYMORPHISM.

649
00:39:54,440 --> 00:39:54,800
>>FASCINATING.

650
00:39:54,800 --> 00:39:57,520
THANK YOU.

651
00:39:57,520 --> 00:40:04,240
>>DO YOU SEE ANY EFFECT
ON

652
00:40:04,240 --> 00:40:04,600
GENDER WITH YOUR

653
00:40:04,600 --> 00:40:05,200
TRANSPLANTATION EXPERIMENTS?

654
00:40:05,200 --> 00:40:05,400
>>NOW.

655
00:40:05,400 --> 00:40:15,880
ALL OF THOSE TOOK PLACE THEN

656
00:40:21,440 --> 00:40:21,880
WITH THOSE HUNDREDS AND

657
00:40:21,880 --> 00:40:30,360
HUNDREDS OF EXPERIMENTS.

658
00:40:30,360 --> 00:40:30,840
>>THANK YOU VERY MUCH.

659
00:40:30,840 --> 00:40:32,480
WE SHOULD MOVE ON.

660
00:40:32,480 --> 00:40:35,400
[APPLAUSE]

661
00:40:35,400 --> 00:40:39,800
THE NEXT SPEAKER FROM CORNELL

662
00:40:39,800 --> 00:40:40,080
MEDICINE.

663
00:40:40,080 --> 00:40:43,200
OUR SECOND OF THREE TODAY

664
00:40:43,200 --> 00:40:46,920
SHARING THE NOBEL PRIZE IN

665
00:40:46,920 --> 00:40:50,280
1989 FOR DISCOVERING THE

666
00:40:50,280 --> 00:40:53,280
ORIGIN IN MANY OF US ALSO

667
00:40:53,280 --> 00:41:03,800
KNOWN HER AS A FORMER AND THEN

668
00:41:07,680 --> 00:41:08,200
GOING FROM 1976 THROUGH 1979.

669
00:41:08,200 --> 00:41:08,640
THANK YOU.

670
00:41:08,640 --> 00:41:19,040
>>THANK YOU VERY MUCH.

671
00:41:27,520 --> 00:41:37,280
NICE TO BE HERE.

672
00:41:37,280 --> 00:41:37,880
THERE ARE SEVERAL WAYS TO GET

673
00:41:37,880 --> 00:41:38,280
THIS KIND OF TALK.

674
00:41:38,280 --> 00:41:43,400
ONE OF COURSES TO SAY HI TO

675
00:41:43,400 --> 00:41:44,560
STEVE AND WE LOVE YOU AND GO

676
00:41:44,560 --> 00:41:45,240
ON TO TALK ABOUT YOUR GREAT

677
00:41:45,240 --> 00:41:48,720
NEW WORK IN MY HEAD WORK IS ON

678
00:41:48,720 --> 00:41:52,520
THIS BEAUTIFUL AS WHAT YOU

679
00:41:52,520 --> 00:41:53,040
JUST SAW THEN I WOULD DO

680
00:41:53,040 --> 00:41:53,240
THAT.

681
00:41:53,240 --> 00:41:57,200
THE SECOND WAY IS TO SAY HI

682
00:41:57,200 --> 00:41:57,400
STEVE.

683
00:41:57,400 --> 00:42:03,160
WHAT YOU DOING RECENTLY AND

684
00:42:03,160 --> 00:42:03,720
TALK ABOUT THAT BUT I KNOW

685
00:42:03,720 --> 00:42:04,320
THERE IS PLENTY TO COME FROM

686
00:42:04,320 --> 00:42:05,240
ALL OF YOU THAT HE IS BEEN

687
00:42:05,240 --> 00:42:06,920
DOING THE LAST TEN YEARS.

688
00:42:06,920 --> 00:42:09,760
THE THIRD AND MOST FUN AND

689
00:42:09,760 --> 00:42:11,680
APPROPRIATE UNDER THE

690
00:42:11,680 --> 00:42:14,560
CIRCUMSTANCES IS TO TALK ABOUT

691
00:42:14,560 --> 00:42:19,240
THINGS WE DID TOGETHER BOTH AT

692
00:42:19,240 --> 00:42:19,840
THE TIME WHEN HE WAS A POSTDOC

693
00:42:19,840 --> 00:42:21,320
IN THE LATE SEVENTIES IN SAN

694
00:42:21,320 --> 00:42:24,800
FRANCISCO AND ENCOUNTERS

695
00:42:24,800 --> 00:42:26,920
THEREAFTER.

696
00:42:26,920 --> 00:42:27,520
STILL COME IN DOING THIS IT'S

697
00:42:27,520 --> 00:42:31,080
NICE TO HAVE A THEME AND THAT

698
00:42:31,080 --> 00:42:33,080
CAME FROM A MOST UNUSUAL

699
00:42:33,080 --> 00:42:40,560
JOURNALISTIC AND THEN CRUISING

700
00:42:40,560 --> 00:42:42,960
THE INTERNET WHILE LOOKING FOR

701
00:42:42,960 --> 00:42:50,760
SOME PICTURES BUT THE CAPTION

702
00:42:50,760 --> 00:42:53,480
SAID STEVE USES TRUTH IN

703
00:42:53,480 --> 00:42:53,760
TEAMWORK.

704
00:42:53,760 --> 00:42:56,240
AS I THINK ABOUT MOST

705
00:42:56,240 --> 00:43:06,480
IMPORTANT AND NOW APPROACHING

706
00:43:06,480 --> 00:43:07,040
50 YEARS ALTHOUGH NOT QUITE

707
00:43:07,040 --> 00:43:07,520
BUT I NOTICED THERE IS A

708
00:43:07,520 --> 00:43:08,920
PATTERN EVERY CURRENT BEHAVIOR

709
00:43:08,920 --> 00:43:11,080
THAT INVOLVES TRYING TO DO

710
00:43:11,080 --> 00:43:13,400
IMPORTANT THINGS FOR THE

711
00:43:13,400 --> 00:43:15,480
COMMUNITY AT THE SAME TIME

712
00:43:15,480 --> 00:43:16,760
EXHIBITING HIS OWN EXCELLENCE

713
00:43:16,760 --> 00:43:21,800
AS A SCIENTIST AND A NARRATOR.

714
00:43:21,800 --> 00:43:27,040
I WILL SPEND SOME TIME TALKING

715
00:43:27,040 --> 00:43:27,640
ABOUT THREE EPISODES OUT OF

716
00:43:27,640 --> 00:43:30,680
SEVERAL THAT EXEMPLIFY WORKING

717
00:43:30,680 --> 00:43:34,080
AS A COMMUNITY TO ACHIEVE THE

718
00:43:34,080 --> 00:43:41,200
AMBITIONS OF INDIVIDUALS.

719
00:43:41,200 --> 00:43:41,760
I WILL DO THAT STARTING WITH

720
00:43:41,760 --> 00:43:42,360
POSTDOCTORAL WORK AND THEN TO

721
00:43:42,360 --> 00:43:44,320
OTHER ASPECTS OF OUR LIFE

722
00:43:44,320 --> 00:43:46,080
TOGETHER AS A RETROVIRAL

723
00:43:46,080 --> 00:43:47,960
ADJUST TO EXEMPLIFY THE

724
00:43:47,960 --> 00:43:52,360
QUALITIES IT IS A BIG DAY FOR

725
00:43:52,360 --> 00:43:52,560
HIM.

726
00:43:52,560 --> 00:43:53,320
SO THE FIRST THING I WANT TO

727
00:43:53,320 --> 00:43:55,920
TALK ABOUT.

728
00:43:55,920 --> 00:43:57,920
WHAT IS GOING ON?

729
00:43:57,920 --> 00:44:06,040
[LAUGHTER]

730
00:44:06,040 --> 00:44:06,640
DO I NEED TO CALL FOR HELP OR

731
00:44:06,640 --> 00:44:08,160
JUST DISPLAY ANXIETY?

732
00:44:08,160 --> 00:44:18,320
[LAUGHTER]

733
00:44:33,800 --> 00:44:35,120
I ALWAYS USE A MATH.

734
00:44:35,120 --> 00:44:35,400
[LAUGHTER]

735
00:44:35,400 --> 00:44:38,160
YOU CAN AFFORD IT.

736
00:44:38,160 --> 00:44:45,160
[LAUGHTER]

737
00:44:45,160 --> 00:44:45,720
BUT I DO NEED TO SCRATCH AT

738
00:44:45,720 --> 00:44:50,520
THE MOMENT.

739
00:44:50,520 --> 00:44:56,920
ONE —- I DO NEED THE CRUTCH AT

740
00:44:56,920 --> 00:44:57,200
THE MOMENT.

741
00:44:57,200 --> 00:44:57,680
I'M TOLD PLEASE WAIT.

742
00:44:57,680 --> 00:44:59,160
THAT IS NOT IN MY CHARACTER.

743
00:44:59,160 --> 00:45:00,920
[LAUGHTER]

744
00:45:00,920 --> 00:45:03,000
>>ANY QUESTIONS SO FAR?

745
00:45:03,000 --> 00:45:03,800
[LAUGHTER]

746
00:45:03,800 --> 00:45:10,400
WHAT ARE YOU DOING NOW?

747
00:45:10,400 --> 00:45:20,600
OTHER USER?

748
00:45:27,440 --> 00:45:27,920
FORTUNATELY MY TALK IS NOT

749
00:45:27,920 --> 00:45:35,720
THAT SO WE WILL DEFINE.

750
00:45:35,720 --> 00:45:38,720
SO TRUTH IN TEAMWORK AND I

751
00:45:38,720 --> 00:45:39,960
WILL TALK ABOUT MOST

752
00:45:39,960 --> 00:45:42,760
EXTENSIVELY ABOUT THE TRUTH AS

753
00:45:42,760 --> 00:45:44,720
STEVE WAS IN OUR GROUP.

754
00:45:44,720 --> 00:45:50,800
HE WAS NOT THERE UNTIL 81

755
00:45:50,800 --> 00:45:51,400
THAT'S WHY THE DATES APPEAR TO

756
00:45:51,400 --> 00:45:56,640
UNDERSTAND THE STRUCTURE OF

757
00:45:56,640 --> 00:45:56,960
PROVIRAL DNA.

758
00:45:56,960 --> 00:45:57,520
THAT WORK WAS DONE TO A VERY

759
00:45:57,520 --> 00:46:00,520
LARGE EXTENT BY STEVE.

760
00:46:00,520 --> 00:46:01,160
BUT THERE WAS A PROVIRAL TEAM

761
00:46:01,160 --> 00:46:06,000
IN THE LAB AND PETER ALSO

762
00:46:06,000 --> 00:46:07,800
RECENTLY RETIRED FROM BROWN

763
00:46:07,800 --> 00:46:10,360
UNIVERSITY WHO WAS STEVE'S

764
00:46:10,360 --> 00:46:19,840
PARTNER ON THIS WORK BUT IN

765
00:46:19,840 --> 00:46:20,760
LOOKING AT THE INTEGRATED

766
00:46:20,760 --> 00:46:24,560
FORMS OF DNA AND PETER IS A

767
00:46:24,560 --> 00:46:26,880
KEY COMPONENT.

768
00:46:26,880 --> 00:46:29,720
IN ADDITION TO PUT THIS IN OUR

769
00:46:29,720 --> 00:46:38,760
OWN LAB BUT WE ALSO HAD THE

770
00:46:38,760 --> 00:46:39,760
ADVANTAGE OF WORKING WITH THE

771
00:46:39,760 --> 00:46:46,160
WEST COAST TUMOR VIRUS.

772
00:46:46,160 --> 00:46:52,280
EVERYBODY WAVED TO PETER I SAW

773
00:46:52,280 --> 00:46:55,280
HIM RECENTLY IN SAN DIEGO FOR

774
00:46:55,280 --> 00:46:59,160
DINNER.

775
00:46:59,160 --> 00:47:00,200
AND THEN TO HAVE DINNER IN SAN

776
00:47:00,200 --> 00:47:04,320
DIEGO BUT MANY OTHERS THAT

777
00:47:04,320 --> 00:47:08,560
MANY INSTITUTIONS GATHERED

778
00:47:08,560 --> 00:47:12,040
REGULARLY TO TALK ABOUT THINK

779
00:47:12,040 --> 00:47:19,760
THEMES OF TUMOR VIROLOGY AND

780
00:47:19,760 --> 00:47:20,360
THERE'S MORE TO SAY ABOUT THAT

781
00:47:20,360 --> 00:47:20,960
IN A MOMENT BUT IT'S IMPORTANT

782
00:47:20,960 --> 00:47:26,600
TO REMEMBER WHAT I TELL YOU

783
00:47:26,600 --> 00:47:27,200
ABOUT WHAT HE ACCOMPLISHED IN

784
00:47:27,200 --> 00:47:27,800
POSTDOCTORAL TIMES WAS CARRIED

785
00:47:27,800 --> 00:47:29,080
OUT IN THE CONTEXT OF THIS

786
00:47:29,080 --> 00:47:33,640
VERY INTERACTIVE GROUP PLUS

787
00:47:33,640 --> 00:47:35,640
THE MUCH LARGER GROUP THAT

788
00:47:35,640 --> 00:47:44,840
SHARED RESULTS OPENLY WITH

789
00:47:44,840 --> 00:47:45,880
COLLABORATIONS AND IMPORTANT

790
00:47:45,880 --> 00:47:48,400
TIMES TOGETHER AND THOSE

791
00:47:48,400 --> 00:47:58,880
INSIGHTS WERE WIDELY SHARED.

792
00:47:59,480 --> 00:48:01,480
COME ON.

793
00:48:01,480 --> 00:48:11,720
ARE YOU KIDDING?

794
00:48:13,520 --> 00:48:13,720
SERIOUSLY?

795
00:48:13,720 --> 00:48:17,640
I CANNOT ADVANCE THE SLIDES.

796
00:48:17,640 --> 00:48:20,720
AND THEY HAD NO PROBLEM

797
00:48:20,720 --> 00:48:21,520
BEFORE.

798
00:48:21,520 --> 00:48:31,960
WHAT THE HELL IS GOING ON?

799
00:48:34,680 --> 00:48:38,320
SO WE KNOW HOW THE VIRUS

800
00:48:38,320 --> 00:48:43,920
REPLICATES MAYBE IT'S NOT SO

801
00:48:43,920 --> 00:48:45,320
RECENT THAT WE DID NOT KNOW

802
00:48:45,320 --> 00:48:46,960
THE ANSWERS TO SOME BIG

803
00:48:46,960 --> 00:48:51,960
QUESTIONS HOW MANY SITES WERE

804
00:48:51,960 --> 00:48:53,000
AVAILABLE AND THE VITAL ROLE

805
00:48:53,000 --> 00:48:57,080
DNA AND THOSE CHROMOSOMES HOW

806
00:48:57,080 --> 00:48:58,800
THEY ORGANIZED IS IT A

807
00:48:58,800 --> 00:49:01,440
SUITABLE TEMPLATE FOR THEIR

808
00:49:01,440 --> 00:49:11,920
GENOMES AND MESSENGER RNA IS

809
00:49:12,200 --> 00:49:16,680
THAT VIRUS ACTUALLY INFECTIOUS

810
00:49:16,680 --> 00:49:19,760
AND WHAT IS THAT INTEGRATION

811
00:49:19,760 --> 00:49:21,680
ITSELF SO THINKING ABOUT THOSE

812
00:49:21,680 --> 00:49:25,160
QUESTIONS AT THE TIME STEVE

813
00:49:25,160 --> 00:49:27,160
ARRIVED AND WERE ANSWERED AT

814
00:49:27,160 --> 00:49:30,200
THAT POINT IS WHAT TYPE OF

815
00:49:30,200 --> 00:49:30,800
TECHNOLOGIES WERE REVEALED AND

816
00:49:30,800 --> 00:49:34,960
I TALKED TO STUDENTS SO WHAT

817
00:49:34,960 --> 00:49:44,600
IS THE BIG DEAL WE COULDN'T ON

818
00:49:44,600 --> 00:49:47,840
THE CHICKEN CELLS FOR HERE IS

819
00:49:47,840 --> 00:49:53,600
THE COLLABORATION CAME IN

820
00:49:53,600 --> 00:49:54,120
LOOKING AT CLONE INFECTED

821
00:49:54,120 --> 00:49:58,240
NONPERMISSIVE RAT CELLS AND WE

822
00:49:58,240 --> 00:50:01,200
COULD CLONE CELLS AND NOT

823
00:50:01,200 --> 00:50:06,320
MOLECULES BY LOOKING AT THE

824
00:50:06,320 --> 00:50:09,200
CLONES THE CELLS AND P.M.

825
00:50:09,200 --> 00:50:13,520
PRESCRIPTION ENZYMES WITH A

826
00:50:13,520 --> 00:50:17,240
LOT OF EXTRA ENZYMES AND

827
00:50:17,240 --> 00:50:23,480
THINGS TO PEOPLE IN THE

828
00:50:23,480 --> 00:50:23,960
INTERNAL GROUP AND THOSE

829
00:50:23,960 --> 00:50:24,960
PROBES THAT WERE VERY SPECIFIC

830
00:50:24,960 --> 00:50:31,640
FOR THE VIRAL GENOME AND THEN

831
00:50:31,640 --> 00:50:33,520
THE ENVELOPE GENE IS DEFINED

832
00:50:33,520 --> 00:50:37,600
BY THOSE MUTATIONS THAT PETER

833
00:50:37,600 --> 00:50:42,640
HAS SUPPLIED TO US THE DEAD

834
00:50:42,640 --> 00:50:46,520
MIRACULOUSLY WITH THE STAGE

835
00:50:46,520 --> 00:50:50,760
CAN DO THE MAPPING REQUIRED

836
00:50:50,760 --> 00:50:53,880
BUT THEN THE OTHER THINGS WE

837
00:50:53,880 --> 00:50:56,760
WOULD HAVE LIKED TO BE ABLE TO

838
00:50:56,760 --> 00:51:07,360
DO AND THEN IN SOME WAYS TO

839
00:51:07,360 --> 00:51:09,120
STUDY THAT TO BE AVAILABLE SO

840
00:51:09,120 --> 00:51:11,800
WHAT WERE THE'S KEY FINDINGS

841
00:51:11,800 --> 00:51:15,400
OF STEVE?

842
00:51:15,400 --> 00:51:18,040
FIRST AS WE HAD DEDUCED ONLY

843
00:51:18,040 --> 00:51:28,520
ONE OR TWO PRO VIRUSES THERE

844
00:51:29,520 --> 00:51:37,280
WERE A FEW WITH ALL THE PRO

845
00:51:37,280 --> 00:51:47,520
VIRUSES WERE THAT PETER SHANK

846
00:51:47,520 --> 00:51:52,800
HAD DESCRIBED A VERY SIMILAR

847
00:51:52,800 --> 00:51:54,360
TECHNIQUES BUT ALL OF THEM HAD

848
00:51:54,360 --> 00:51:59,520
CELL DNA FOR THOSE SEQUENCES

849
00:51:59,520 --> 00:52:01,360
AND DERIVED FROM BOTH ENDS OF

850
00:52:01,360 --> 00:52:08,720
VIRAL RNA AND NOTING THAT THE

851
00:52:08,720 --> 00:52:14,920
SEQUENCE IS UNIQUE TO THE DNA

852
00:52:14,920 --> 00:52:15,440
AND OF COURSE THAT CREATED

853
00:52:15,440 --> 00:52:18,120
SOME ISSUES OF THEIR OWN.

854
00:52:18,120 --> 00:52:21,640
AND PERHAPS MOST IMPORTANTLY

855
00:52:21,640 --> 00:52:24,240
ALL THOSE VIRUSES LIKE THAT

856
00:52:24,240 --> 00:52:27,040
HAVE DIFFERENT RESTRICTION

857
00:52:27,040 --> 00:52:31,400
MAPS SO THEY ALL SEEM TO BE IN

858
00:52:31,400 --> 00:52:32,000
DIFFERENT SITES THERE WERE TWO

859
00:52:32,000 --> 00:52:35,400
FEATURES ABOUT THIS BUT THERE

860
00:52:35,400 --> 00:52:41,920
ARE SOME FEATURES HERE WORTH

861
00:52:41,920 --> 00:52:42,960
RECALLING BECAUSE THEY EXUDE A

862
00:52:42,960 --> 00:52:45,320
CERTAIN TONE OR FEELING THE

863
00:52:45,320 --> 00:52:53,800
FIRST TO SHOW WITH THE

864
00:52:53,800 --> 00:52:59,440
NONPERMISSIVE CELLS THAT THEY

865
00:52:59,440 --> 00:53:04,240
WERE INDEED INFECTIOUS

866
00:53:04,240 --> 00:53:04,800
SECONDLY WE DID SOMETHING IN

867
00:53:04,800 --> 00:53:08,480
THE ACKNOWLEDGMENTS AS THEY

868
00:53:08,480 --> 00:53:13,320
WERE PUBLISHED IN 1878 THAT

869
00:53:13,320 --> 00:53:15,240
ILLUSTRATED THE SENSE OF

870
00:53:15,240 --> 00:53:18,600
CAMARADERIE WE WERE TROUBLED

871
00:53:18,600 --> 00:53:21,480
BY THE FACT THERE WERE

872
00:53:21,480 --> 00:53:26,040
SEQUENCES AND WE DIDN'T KNOW

873
00:53:26,040 --> 00:53:28,880
HOW YOU COULD POSSIBLY GET

874
00:53:28,880 --> 00:53:31,200
THAT AT THE FAR END OF THE PRO

875
00:53:31,200 --> 00:53:36,560
VIRUS AND THEN GOING ON WITH A

876
00:53:36,560 --> 00:53:41,520
DIFFERENT FIELD ENTIRELY BUT

877
00:53:41,520 --> 00:53:46,120
THEN TO PIPE UP AND SAY

878
00:53:46,120 --> 00:53:46,560
JUMPING FROM THE FIRST

879
00:53:46,560 --> 00:53:48,480
TEMPLATE TO THE SECOND WHAT

880
00:53:48,480 --> 00:53:57,840
ABOUT TO THE THIRD AND THEN AS

881
00:53:57,840 --> 00:53:58,440
FAR AS WE CAN TELL THAT IS THE

882
00:53:58,440 --> 00:53:58,960
EXPLANATION AND REVERSE

883
00:53:58,960 --> 00:53:59,560
TRANSCRIPTION INTO DID HOLD US

884
00:53:59,560 --> 00:54:04,440
TO AN ACCOUNT WAS CREATED AND

885
00:54:04,440 --> 00:54:08,080
GOING OUT OF THE DEEP PAST A

886
00:54:08,080 --> 00:54:12,480
MATHEMATICAL ANALYSIS TO SAY

887
00:54:12,480 --> 00:54:15,560
WE ONLY MAP 13 INTEGRATION

888
00:54:15,560 --> 00:54:18,480
SITE BUT ONLY TEN VIGOROUSLY

889
00:54:18,480 --> 00:54:19,040
SO THERE MUST BE A LOT MORE

890
00:54:19,040 --> 00:54:21,160
THAN TEN OR 15 SITES IN THE

891
00:54:21,160 --> 00:54:23,200
GENOME.

892
00:54:23,200 --> 00:54:24,960
AND HE DID THAT BY USING THE

893
00:54:24,960 --> 00:54:26,960
TRADITIONAL BIRTHDAY PROBLEM

894
00:54:26,960 --> 00:54:31,400
BUT I WILL NOT TRY TO RECITE.

895
00:54:31,400 --> 00:54:36,520
AND THAT THERE ARE AT LEAST 40

896
00:54:36,520 --> 00:54:39,440
REGIONAL SITES WITH THAT

897
00:54:39,440 --> 00:54:42,320
SPECIFICITY OF A LOCAL

898
00:54:42,320 --> 00:54:47,960
SEQUENCE AND FOR THOSE THAT

899
00:54:47,960 --> 00:54:53,360
MUST BE PERMISSIVE AND I WOULD

900
00:54:53,360 --> 00:54:58,240
LIKE TO THINK ABOUT STEVE'S

901
00:54:58,240 --> 00:55:05,080
ATTITUDE.

902
00:55:05,080 --> 00:55:05,600
WE DID SOME SIGNIFICANTLY

903
00:55:05,600 --> 00:55:06,520
LATER ONE PERSON PUBLISHED A

904
00:55:06,520 --> 00:55:08,000
LOT EARLIER AND I WAS

905
00:55:08,000 --> 00:55:08,960
DISTRESSED BY THIS I DID NOT

906
00:55:08,960 --> 00:55:12,240
LIKE HAVING SOMEONE BEFORE

907
00:55:12,240 --> 00:55:18,840
THEY HAD THE GOODS BUT IT WAS

908
00:55:18,840 --> 00:55:23,840
PUBLISHED ANYWAY.

909
00:55:23,840 --> 00:55:26,880
BUT THEN WE ARTFULLY PUT

910
00:55:26,880 --> 00:55:29,760
TOGETHER THE PAPER WAS THE

911
00:55:29,760 --> 00:55:31,520
STATEMENT THAT DISCUSSION

912
00:55:31,520 --> 00:55:34,840
SESSION THAT SAID THEY ARE AS

913
00:55:34,840 --> 00:55:45,360
CONSISTENT AS OUR FINDINGS BUT

914
00:55:45,360 --> 00:55:47,720
THE FACT THAT STEVE WAS MY DAD

915
00:55:47,720 --> 00:55:55,080
ON THAT OCCASION BUT STEVE WAS

916
00:55:55,080 --> 00:55:57,000
CALLED AND SAID IN THE LONG

917
00:55:57,000 --> 00:56:04,360
RUN THE GOOD THINGS OPEN UP

918
00:56:04,360 --> 00:56:06,640
THAT'S IN A RELATED TO HAD THE

919
00:56:06,640 --> 00:56:12,600
RIGHT PERSON WORKING FOR ME.

920
00:56:12,600 --> 00:56:13,200
SO HERE IS THE DESCRIPTION OF

921
00:56:13,200 --> 00:56:19,120
WHAT STEVE WAS DESCRIBING SO

922
00:56:19,120 --> 00:56:19,520
IT'S NOT JUST THE

923
00:56:19,520 --> 00:56:20,040
INTERPRETATION AT THE TIME

924
00:56:20,040 --> 00:56:21,560
THAT THE DEFINITION OF WHAT

925
00:56:21,560 --> 00:56:25,120
COULD BE DONE IN THE FUTURE SO

926
00:56:25,120 --> 00:56:28,120
THAT'S WHY IT'S USEFUL TO LOOK

927
00:56:28,120 --> 00:56:31,400
BACK TO THINK ABOUT WHERE IT

928
00:56:31,400 --> 00:56:35,600
STANDS IN HISTORY OF

929
00:56:35,600 --> 00:56:38,080
RETROVIROLOGY.

930
00:56:38,080 --> 00:56:44,600
SO WE CONCLUDED AND PROVEN ITS

931
00:56:44,600 --> 00:56:45,200
TO BE A TOTALLY APPROPRIATE

932
00:56:45,200 --> 00:56:51,560
TEMPLATE FOR TRANSCRIPTION AND

933
00:56:51,560 --> 00:56:54,600
THAT WITH VIRAL RNA THAT COULD

934
00:56:54,600 --> 00:56:57,960
PROVIDE SO WITH THE MORE

935
00:56:57,960 --> 00:57:04,600
EFFORTS FOR THOSE VIRUS TO SAY

936
00:57:04,600 --> 00:57:07,520
THIS IS TRUE THAT WE DON'T

937
00:57:07,520 --> 00:57:10,320
HAVE TIME TO REVIEW IN DETAIL

938
00:57:10,320 --> 00:57:12,760
BUT THAT IS KNOWING THERE IS A

939
00:57:12,760 --> 00:57:15,480
LOT OF POTENTIAL INTEGRATION

940
00:57:15,480 --> 00:57:17,680
SITES BUT IT WAS POSSIBLE TO

941
00:57:17,680 --> 00:57:22,880
THINK ABOUT THE PRO VIRUS AND

942
00:57:22,880 --> 00:57:30,800
THEN TO ACTIVATE THE GAINS BUT

943
00:57:30,800 --> 00:57:31,400
THIS IS AN IDEA THAT WE TALKED

944
00:57:31,400 --> 00:57:36,560
ABOUT A LOT I AM ON SABBATICAL

945
00:57:36,560 --> 00:57:39,240
IN 78 AND 79 TO UNDERTAKE THE

946
00:57:39,240 --> 00:57:43,320
TASK TO SHOW IT COULD ACT

947
00:57:43,320 --> 00:57:46,360
USING THE LEUKEMIA VIRUS TO

948
00:57:46,360 --> 00:57:52,320
REVERT BY INTEGRATING INTO THE

949
00:57:52,320 --> 00:57:55,040
PRO VIRUS AND WITH THE HARD

950
00:57:55,040 --> 00:57:57,880
WORK AND THEN TO SHOW THE FACT

951
00:57:57,880 --> 00:58:01,040
THAT HAPPEN.

952
00:58:01,040 --> 00:58:11,600
AND THEN TO INSPIRE EFFORTS SO

953
00:58:11,600 --> 00:58:13,920
THAT MIGHT CAUSE CANCER EVEN

954
00:58:13,920 --> 00:58:16,800
THOUGH MORE SLOWLY BY

955
00:58:16,800 --> 00:58:21,240
INSERTING TWO AND ACTIVATING

956
00:58:21,240 --> 00:58:23,600
SO AT THAT POINT WE ARE

957
00:58:23,600 --> 00:58:27,400
LOOKING FOR SIGNS OF THE

958
00:58:27,400 --> 00:58:29,400
PRECURSORS TO OTHER GENES WITH

959
00:58:29,400 --> 00:58:32,040
A SIMILAR POTENTIAL THAT COULD

960
00:58:32,040 --> 00:58:35,880
BE IMPLICATED AS A RESULT OF

961
00:58:35,880 --> 00:58:44,320
THE RETRO FILE A ASSERTION AND

962
00:58:44,320 --> 00:58:54,680
THEN TO DO SIMILAR WORK AND

963
00:58:54,680 --> 00:58:58,120
THAT IS THE GENESIS FOR THE

964
00:58:58,120 --> 00:59:01,600
DISCOVERY OF GENES SO THE

965
00:59:01,600 --> 00:59:04,640
THIRD POINT IS THAT THE PRO

966
00:59:04,640 --> 00:59:10,080
VIRUS AND THAT MADE US THINK

967
00:59:10,080 --> 00:59:13,360
HOW THE RETROVIRUS MAY SERVE

968
00:59:13,360 --> 00:59:20,120
AS GENETIC FACTORS FROM

969
00:59:20,120 --> 00:59:23,120
ARTIFICIALLY WHEN THEY ARE

970
00:59:23,120 --> 00:59:25,440
MOLDED AND AS YOU KNOW IS A

971
00:59:25,440 --> 00:59:28,520
REASONABLY COMMON PRACTICE BUT

972
00:59:28,520 --> 00:59:31,160
WE ARE ALSO ABLE TO SAY THAT

973
00:59:31,160 --> 00:59:31,760
THERE ARE SOME THINGS THAT WE

974
00:59:31,760 --> 00:59:35,440
NEED TO KNOW THAT WE WILL AND

975
00:59:35,440 --> 00:59:39,800
WITHOUT MORE DEVELOPMENTS AND

976
00:59:39,800 --> 00:59:40,760
TECHNOLOGY IN ONE IS THAT

977
00:59:40,760 --> 00:59:45,080
DETAILED MECHANISM TO CLONE

978
00:59:45,080 --> 00:59:48,280
AND SEQUENCE OF THE PRO VIRUS

979
00:59:48,280 --> 00:59:52,040
UNDERCURRENT RESTRICTIONS WE

980
00:59:52,040 --> 00:59:52,600
KNOW A LOT ABOUT THAT NOW I

981
00:59:52,600 --> 00:59:54,520
WILL NOT DESCRIBE IT THAT

982
00:59:54,520 --> 00:59:57,080
STILL DIDN'T HAVE THE TOOLS

983
00:59:57,080 --> 00:59:59,360
FOR DOING IN VITRO INTEGRATION

984
00:59:59,360 --> 01:00:04,120
AND NOT UNTIL PAT BROWN CAME

985
01:00:04,120 --> 01:00:08,280
ALONG TO BUILD THE BASE AND

986
01:00:08,280 --> 01:00:12,840
HIS COLLEAGUES CAME ALONG AND

987
01:00:12,840 --> 01:00:13,280
LEARNED HOW TO USE THE

988
01:00:13,280 --> 01:00:17,920
PURIFIED REACTIONS AND THIS IS

989
01:00:17,920 --> 01:00:18,480
AN AREA WHICH IS STILL GOING

990
01:00:18,480 --> 01:00:19,080
STRONG AND YOU WILL HEAR MORE

991
01:00:19,080 --> 01:00:24,320
ABOUT THIS.

992
01:00:24,320 --> 01:00:27,320
BUT THEN STILL THERE WAS THE

993
01:00:27,320 --> 01:00:31,120
QUESTION KNOWING WHAT IS THE

994
01:00:31,120 --> 01:00:41,600
REAL PRECURSOR AND LEARNING

995
01:00:42,680 --> 01:00:43,440
FROM MY GROUPS AND OTHERS THAT

996
01:00:43,440 --> 01:00:47,680
THEY HAD TO FIND NOT JUST A

997
01:00:47,680 --> 01:00:51,200
LINEAR FORM OF DNA BUT TO

998
01:00:51,200 --> 01:00:56,200
CIRCULAR FORMS AND ANY ONE OF

999
01:00:56,200 --> 01:01:02,160
THOSE BY SOME MODEL COULD HAVE

1000
01:01:02,160 --> 01:01:04,000
PROVIDE A SUITABLE PRECURSOR

1001
01:01:04,000 --> 01:01:07,400
BUT THAT WAS NOT INTEL IN

1002
01:01:07,400 --> 01:01:11,920
VITRO REACTIONS WERE SUITABLY

1003
01:01:11,920 --> 01:01:14,760
DEPLOYED IT WAS POSSIBLE TO BE

1004
01:01:14,760 --> 01:01:20,040
CLEAR THAT LEAVING OPEN SOME

1005
01:01:20,040 --> 01:01:21,880
QUESTIONS WHY THAT DNA IS

1006
01:01:21,880 --> 01:01:22,440
THERE BUT MAYBE IT IS THERE

1007
01:01:22,440 --> 01:01:26,280
BECAUSE IT CAN BE WITH THE

1008
01:01:26,280 --> 01:01:31,240
ENDS OF LINEAR DNA AND THEN

1009
01:01:31,240 --> 01:01:35,320
FINALLY INTEGRATES FROM THE

1010
01:01:35,320 --> 01:01:40,000
DRUG TARGET AND YOU'LL HEAR

1011
01:01:40,000 --> 01:01:40,880
ABOUT THAT FROM DIMITRI IN

1012
01:01:40,880 --> 01:01:46,760
JUST A MOMENT SO FIRST I WILL

1013
01:01:46,760 --> 01:01:48,640
SAY WORD OR TWO ABOUT THAT

1014
01:01:48,640 --> 01:01:51,280
COLLABORATION ABOUT A DECADE

1015
01:01:51,280 --> 01:01:59,680
AFTER HE LEFT TO SAN FRANCISCO

1016
01:01:59,680 --> 01:02:02,720
WITH JOHN YOUNG AND PAUL BATES

1017
01:02:02,720 --> 01:02:07,520
HAD OVERCOME THE PROBLEM OF

1018
01:02:07,520 --> 01:02:08,120
NOT KNOWING WHAT THE RECEPTOR

1019
01:02:08,120 --> 01:02:10,160
WAS OR SUBGROUP A WHICH WAS

1020
01:02:10,160 --> 01:02:14,560
THE MOST COMMON FORM AND THEY

1021
01:02:14,560 --> 01:02:19,200
HAD SOME DIFFICULTY WITH A

1022
01:02:19,200 --> 01:02:27,640
SMALL GENE WITH THE TVA

1023
01:02:27,640 --> 01:02:30,040
RECEPTOR AND THEN ADD GENE

1024
01:02:30,040 --> 01:02:36,680
WHICH INTERESTINGLY THEY WERE

1025
01:02:36,680 --> 01:02:39,600
NOT VERY SURE WHAT TO DO WITH

1026
01:02:39,600 --> 01:02:45,360
THIS BUT THEN THIS WAS A NICE

1027
01:02:45,360 --> 01:02:47,160
IDEA TO USE THIS AS A WAY TO

1028
01:02:47,160 --> 01:02:52,520
TARGET VACUUMS WITH CELL TYPES

1029
01:02:52,520 --> 01:02:54,600
TO CARRY THAT GENE INTO THE

1030
01:02:54,600 --> 01:02:57,640
CONTROL OF THE SPECIFIC

1031
01:02:57,640 --> 01:03:00,440
PROMOTER SO HIS POSTDOC STILL

1032
01:03:00,440 --> 01:03:06,440
WORKS ON THIS PROBLEM TO BUILD

1033
01:03:06,440 --> 01:03:09,480
A TRANSGENIC ANIMAL THAT

1034
01:03:09,480 --> 01:03:14,680
ALLOWED THE MUSCLE CELLS BUT

1035
01:03:14,680 --> 01:03:19,440
AS SHOWN BY ANOTHER COMMUNITY

1036
01:03:19,440 --> 01:03:21,480
WITH THAT GROUP OF

1037
01:03:21,480 --> 01:03:24,000
INVESTIGATORS WHO ARE WORKING

1038
01:03:24,000 --> 01:03:29,720
TO MAKES USE OF THAT

1039
01:03:29,720 --> 01:03:30,640
TRANSGENIC MICE FOR A VARIETY

1040
01:03:30,640 --> 01:03:36,880
OF PURPOSES AND WITH SOME

1041
01:03:36,880 --> 01:03:40,480
OTHER TISSUES TO START MEETING

1042
01:03:40,480 --> 01:03:46,080
FAIRLY REGULARLY AT THE NIH

1043
01:03:46,080 --> 01:03:46,640
AND ELSEWHERE IN THE SPIRIT

1044
01:03:46,640 --> 01:03:47,920
NOT DISSIMILAR FROM WHAT WE

1045
01:03:47,920 --> 01:03:50,440
EXPERIENCED IN THE WEST COAST

1046
01:03:50,440 --> 01:03:52,280
IN THE CONTRIBUTION TO THIS

1047
01:03:52,280 --> 01:03:54,480
DEVELOPMENT TRYING TO SEEK

1048
01:03:54,480 --> 01:03:57,040
TRUTH BY MORE MAKING MORE

1049
01:03:57,040 --> 01:04:03,080
USEFUL ANIMAL MODELS.

1050
01:04:03,080 --> 01:04:03,640
SO BRIEFLY I WANT TO TALK

1051
01:04:03,640 --> 01:04:06,160
ABOUT STEVE'S ROLES IN

1052
01:04:06,160 --> 01:04:08,400
CREATION WITH ALL OF THE

1053
01:04:08,400 --> 01:04:15,720
TEXTBOOKS THAT WERE PUBLISHED

1054
01:04:15,720 --> 01:04:16,280
THAT HAVE BEEN GUIDES FOR

1055
01:04:16,280 --> 01:04:20,720
EVERYBODY AROUND THE WORLD FOR

1056
01:04:20,720 --> 01:04:21,760
THE LAST 40 SOME YEARS AND IN

1057
01:04:21,760 --> 01:04:25,160
THIS CASE IT'S A LOT OF

1058
01:04:25,160 --> 01:04:28,000
EDITORS AND WRITERS AND

1059
01:04:28,000 --> 01:04:31,280
READERS AND OTHERS WHO MAKE

1060
01:04:31,280 --> 01:04:33,760
CONTRIBUTIONS SO NOW I DRAW

1061
01:04:33,760 --> 01:04:36,640
YOUR ATTENTION TO A COUPLE OF

1062
01:04:36,640 --> 01:04:43,760
ASPECTS THAT HAD GONE ON SONG.

1063
01:04:43,760 --> 01:04:48,480
SO MIRACULOUSLY PUBLISHED IN

1064
01:04:48,480 --> 01:04:51,520
1997 AND THEN STILL 25 YEARS

1065
01:04:51,520 --> 01:04:54,520
LATER WAR AND PEACE HAS

1066
01:04:54,520 --> 01:05:02,760
SURVIVED BUT THIS IS A PRETTY

1067
01:05:02,760 --> 01:05:03,360
DURABLE BOOK BUT PEOPLE FORGET

1068
01:05:03,360 --> 01:05:08,480
THE PREDECESSORS BUT FROM 1872

1069
01:05:08,480 --> 01:05:16,880
THOSE THAT HAVE AND THOSE THAT

1070
01:05:16,880 --> 01:05:19,680
HAVE COPIES OF THAT BUT WE

1071
01:05:19,680 --> 01:05:23,720
RECOGNIZE THINKING ABOUT HOW

1072
01:05:23,720 --> 01:05:24,520
TO PROCEED TO MAINTAIN

1073
01:05:24,520 --> 01:05:27,400
AUTHORITATIVE TEXT WERE AWARE

1074
01:05:27,400 --> 01:05:31,120
BY THE EARLY EIGHTIES THE

1075
01:05:31,120 --> 01:05:35,480
FOLKS IN THE TWO FIELDS JUST

1076
01:05:35,480 --> 01:05:38,360
BEING SEPARATED SO THE TEXT IS

1077
01:05:38,360 --> 01:05:40,800
ALSO BE SEPARATE.

1078
01:05:40,800 --> 01:05:44,840
SO IN THE FIRST VOLUME WHICH

1079
01:05:44,840 --> 01:05:48,040
JOHN AND I WERE BOTH EDITORS

1080
01:05:48,040 --> 01:05:50,320
IN APPENDIX WAS NEEDED YOU

1081
01:05:50,320 --> 01:05:52,040
HAVE TO ACCUMULATE A LOT MORE

1082
01:05:52,040 --> 01:05:53,480
INFORMATION THAN COULD BE

1083
01:05:53,480 --> 01:05:55,960
INCORPORATED INTO THE

1084
01:05:55,960 --> 01:05:58,000
CHAPTER.

1085
01:05:58,000 --> 01:06:00,520
STEVE VOLUNTEERED OR COERCED

1086
01:06:00,520 --> 01:06:02,200
INTO BEING THE EDITOR OF THE

1087
01:06:02,200 --> 01:06:04,440
APPENDIX WHICH PROVED TO BE

1088
01:06:04,440 --> 01:06:05,160
100 PAGES LONG.

1089
01:06:05,160 --> 01:06:10,080
HE DID GET SOME HELP BUT THAT

1090
01:06:10,080 --> 01:06:18,840
WAS 100 PAGES OF STUFF AND

1091
01:06:18,840 --> 01:06:21,840
THEN TO ASSEMBLE ALL THE

1092
01:06:21,840 --> 01:06:27,520
STUFF.

1093
01:06:27,520 --> 01:06:28,520
AND WITH THE RETROVIRUS

1094
01:06:28,520 --> 01:06:36,960
ESPECIALLY ABOUT THE SEQUENCE.

1095
01:06:36,960 --> 01:06:40,000
AND THEN TO PUT OUT A SECOND

1096
01:06:40,000 --> 01:06:46,120
ADDITION AND IN 1985 AND THAT

1097
01:06:46,120 --> 01:06:46,720
PAPER HAD THE APPENDICES THAT

1098
01:06:46,720 --> 01:06:48,680
STEVE WAS THE LEAD TO DEVELOP

1099
01:06:48,680 --> 01:06:57,520
THIS OF 650 PAGES.

1100
01:06:57,520 --> 01:06:58,120
SO IT IS LIKE THE APPENDIX TO

1101
01:06:58,120 --> 01:07:03,080
THE APPENDIX BUT THIS IS A

1102
01:07:03,080 --> 01:07:10,680
GARGANTUAN TASK SO THANK YOU

1103
01:07:10,680 --> 01:07:16,600
TO THE'S SLIDE DELAYS MY TIME

1104
01:07:16,600 --> 01:07:18,880
IS COMING TO AN END BUT MY

1105
01:07:18,880 --> 01:07:22,600
LIFE AND RETROVIROLOGY AS IT

1106
01:07:22,600 --> 01:07:33,080
WAS THAT FROM BACK IN MY TIME

1107
01:07:37,880 --> 01:07:38,360
STEVE IS A VERY LARGE PERSON

1108
01:07:38,360 --> 01:07:38,920
WHO MAKES A LARGE ENTRANCE

1109
01:07:38,920 --> 01:07:43,240
WITH A LARGE EFFECT IT IS

1110
01:07:43,240 --> 01:07:43,840
DIFFICULT FOR ME TO IMAGINE SO

1111
01:07:43,840 --> 01:07:48,080
I STILL DO NOT BELIEVE THAT

1112
01:07:48,080 --> 01:07:51,200
THIS IS A RETIREMENT DAY YOU

1113
01:07:51,200 --> 01:07:53,120
CAN BETTER EXPRESS THE

1114
01:07:53,120 --> 01:07:54,600
ENTHUSIASM.

1115
01:07:54,600 --> 01:08:00,440
THANK YOU.

1116
01:08:00,440 --> 01:08:01,440
[APPLAUSE]

1117
01:08:01,440 --> 01:08:06,800
I'M HAPPY TO TAKE QUESTIONS OR

1118
01:08:06,800 --> 01:08:14,240
COMMENTS.

1119
01:08:14,240 --> 01:08:24,280
THANK YOU VERY MUCH.

1120
01:08:24,280 --> 01:08:25,360
>>NOW GOING FROM THE PAST
TO

1121
01:08:25,360 --> 01:08:30,560
THE PRESENT THE ASSISTANT

1122
01:08:30,560 --> 01:08:33,560
PROFESSOR IS A LEADER OF

1123
01:08:33,560 --> 01:08:38,000
STRUCTURAL BIOLOGY AND LOOKING

1124
01:08:38,000 --> 01:08:48,400
AT THE HIV-1 STRUCTURE.

1125
01:08:59,560 --> 01:09:00,000
>>THANK YOU VERY MUCH.

1126
01:09:00,000 --> 01:09:00,600
IT IS A DISTINCT PLEASURE TO

1127
01:09:00,600 --> 01:09:02,000
BE HERE.

1128
01:09:02,000 --> 01:09:11,440
AND THEN TO TELL YOU AND THEN

1129
01:09:11,440 --> 01:09:17,800
TO DISCUSS OR TO INTRODUCE

1130
01:09:17,800 --> 01:09:18,400
CONGRATULATIONS IT IS AN HONOR

1131
01:09:18,400 --> 01:09:19,040
TO WORK WITH YOU OVER THE LAST

1132
01:09:19,040 --> 01:09:22,720
FIVE YEARS I AM TALKING TODAY

1133
01:09:22,720 --> 01:09:28,520
TO UNDERSTAND MECHANISMS AND

1134
01:09:28,520 --> 01:09:33,520
THE DRUG-RESISTANT VARIANT.

1135
01:09:33,520 --> 01:09:34,000
SO BEGIN WITH A VIRAL

1136
01:09:34,000 --> 01:09:34,560
REPLICATION CYCLE WE DO KNOW

1137
01:09:34,560 --> 01:09:39,640
THAT THERE IS AN WITH THE

1138
01:09:39,640 --> 01:09:43,200
REVERSE TRANSCRIPTION PUTTING

1139
01:09:43,200 --> 01:09:52,760
IT INTO NUCLEAR IMPORT AND

1140
01:09:52,760 --> 01:09:53,760
THEN THE PROTEINS WILL GO TO

1141
01:09:53,760 --> 01:10:00,480
THE LINEAR AND WITH THE DNA TO

1142
01:10:00,480 --> 01:10:01,120
FORM BUT THAT REFER TO IT AS A

1143
01:10:01,120 --> 01:10:04,120
PRE- INTEGRATION COMPLEX AND

1144
01:10:04,120 --> 01:10:07,600
THEN TO CONDUCT INTEGRATION TO

1145
01:10:07,600 --> 01:10:08,200
ESTABLISH THE PRO VIRUS AND

1146
01:10:08,200 --> 01:10:10,200
THE TARGET CELL WITH A

1147
01:10:10,200 --> 01:10:13,360
PARTICULAR PREFERENCE AND IN

1148
01:10:13,360 --> 01:10:21,880
THE CASE OF HIV-1 SO ONE OF

1149
01:10:21,880 --> 01:10:27,520
PARTICULAR INTEREST AND IT'S

1150
01:10:27,520 --> 01:10:33,000
NOT A MEDICAL TO STRUCTURAL

1151
01:10:33,000 --> 01:10:35,360
BIOLOGY FOR WHAT YOU CAN DO IS

1152
01:10:35,360 --> 01:10:37,280
RECAPITULATE THE STRUCTURE OF

1153
01:10:37,280 --> 01:10:46,680
THE PIC SO BIOCHEMICALLY THE

1154
01:10:46,680 --> 01:10:51,480
WAY THAT YOU DO THIS IS THAT

1155
01:10:51,480 --> 01:10:54,560
WITH A VIRAL DNA THERE ARE 27

1156
01:10:54,560 --> 01:10:58,280
VERSIONS AND THOSE BIOCHEMICAL

1157
01:10:58,280 --> 01:11:02,720
CONDITIONS WITH THAT SYNAPTIC

1158
01:11:02,720 --> 01:11:05,200
COMPLEX.

1159
01:11:05,200 --> 01:11:09,280
AND THE NUCLEOTIDES.

1160
01:11:09,280 --> 01:11:14,080
BUT THEN WITH THAT TARGET DATA

1161
01:11:14,080 --> 01:11:16,720
AND THEN IT COMPLEX THAT DATA

1162
01:11:16,720 --> 01:11:20,440
AND THEN SOON THEREAFTER AS

1163
01:11:20,440 --> 01:11:27,320
THE CATALYTIC REFORM.

1164
01:11:27,320 --> 01:11:28,320
SO WITH THE TARGET DNA WE HAVE

1165
01:11:28,320 --> 01:11:34,960
STRUCTURAL BIOLOGIST AND NOW

1166
01:11:34,960 --> 01:11:38,000
THEIR STRUCTURES FROM MANY

1167
01:11:38,000 --> 01:11:42,960
DIFFERENT RETROVIRUSES.

1168
01:11:42,960 --> 01:11:46,000
AND FAIRLY DIVERSE

1169
01:11:46,000 --> 01:11:51,840
ARCHITECTURALLY.

1170
01:11:51,840 --> 01:11:58,080
AND THEN TO SHARE A CONCERN

1171
01:11:58,080 --> 01:12:03,320
WHICH IS SIMILAR TO THE PFC.

1172
01:12:03,320 --> 01:12:03,880
AND THROUGHOUT THE ENDS OF

1173
01:12:03,880 --> 01:12:08,680
VIRAL DNA.

1174
01:12:08,680 --> 01:12:16,560
SO THIS IS FROM THOSE SUMS SO

1175
01:12:16,560 --> 01:12:17,000
MY TALK IS FOCUSED HIV

1176
01:12:17,000 --> 01:12:19,200
SUSPICION ONE —- SPECIFICALLY

1177
01:12:19,200 --> 01:12:19,760
WITH THEIR UNDERSTANDING OF

1178
01:12:19,760 --> 01:12:20,040
RESISTANCE.

1179
01:12:20,040 --> 01:12:23,640
SO I JUST HAVE TO POINT OUT

1180
01:12:23,640 --> 01:12:26,040
THERE ARE FIVE MEDICALLY

1181
01:12:26,040 --> 01:12:31,680
APPROVED DRUGS USING TO TREAT

1182
01:12:31,680 --> 01:12:32,280
AND THEN THE FIRST-GENERATION

1183
01:12:32,280 --> 01:12:35,640
NOW SECOND-GENERATION DRUGS

1184
01:12:35,640 --> 01:12:36,240
THAT ARE BETTER BECAUSE THERE

1185
01:12:36,240 --> 01:12:38,320
IS LESS RESISTANCE.

1186
01:12:38,320 --> 01:12:43,680
THEN THE IMPORTANT COMPOUNDS

1187
01:12:43,680 --> 01:12:54,160
FROM OUR COLLEAGUES AT NCI.

1188
01:12:56,360 --> 01:12:56,840
TERRY AND STEVE HAVE HAD A

1189
01:12:56,840 --> 01:12:57,840
LONG COLLABORATION TO TEST ALL

1190
01:12:57,840 --> 01:13:01,640
OF THESE.

1191
01:13:01,640 --> 01:13:06,760
SO THEN ADDRESSING THAT BASIS

1192
01:13:06,760 --> 01:13:13,920
FOR INHIBITION OF INTEGRATION.

1193
01:13:13,920 --> 01:13:14,440
AND THEN OF THE CHEMICAL

1194
01:13:14,440 --> 01:13:18,280
FEATURES OF POTENCY ESPECIALLY

1195
01:13:18,280 --> 01:13:18,800
AGAINST CHEMICAL RESISTANT

1196
01:13:18,800 --> 01:13:19,080
VARIANTS.

1197
01:13:19,080 --> 01:13:22,200
SO THE FIRST QUESTION.

1198
01:13:22,200 --> 01:13:29,400
SO A NUMBER OF YEARS AGO THIS

1199
01:13:29,400 --> 01:13:31,320
WAS THE LEADING CLINICALLY

1200
01:13:31,320 --> 01:13:34,400
APPROVED SECOND GENERATION

1201
01:13:34,400 --> 01:13:36,640
DRUG.

1202
01:13:36,640 --> 01:13:47,120
BUT THEN TO SYNTHESIZE SO THEY

1203
01:13:49,440 --> 01:13:50,280
WERE CHEERED TO CAPTURE DNA

1204
01:13:50,280 --> 01:13:56,000
AND THEN YOU CAN WITH THE

1205
01:13:56,000 --> 01:13:58,920
COMPOUNDS FOUND.

1206
01:13:58,920 --> 01:14:08,480
SO HERE WE CAN SHOW THEY ARE

1207
01:14:08,480 --> 01:14:10,480
COMPETENT TO INHIBIT

1208
01:14:10,480 --> 01:14:12,480
INTEGRATION AND THEN TO START

1209
01:14:12,480 --> 01:14:15,240
DOING THAT STRUCTURAL

1210
01:14:15,240 --> 01:14:17,160
VIROLOGY.

1211
01:14:17,160 --> 01:14:21,440
AND NOW WE HAVE A WORKFLOW TO

1212
01:14:21,440 --> 01:14:28,560
DETERMINE THE STRUCTURES.

1213
01:14:28,560 --> 01:14:29,120
AND HERE THIS IS WORK FROM A

1214
01:14:29,120 --> 01:14:35,320
COUPLE OF YEARS AGO SO THESE

1215
01:14:35,320 --> 01:14:41,560
ARE THE AFTER SITES.

1216
01:14:41,560 --> 01:14:44,600
AND THEN YOU CAN SEE CLEAR

1217
01:14:44,600 --> 01:14:49,720
DENSITY.

1218
01:14:49,720 --> 01:14:50,280
THERE ARE THREE IMPORTANT

1219
01:14:50,280 --> 01:14:53,720
FEATURES OF THE COMPOUNDS.

1220
01:14:53,720 --> 01:14:54,080
THERE ARE THREE

1221
01:14:54,080 --> 01:15:00,760
ELECTRONEGATIVE ATOMS THAT SO

1222
01:15:00,760 --> 01:15:07,000
THEY UNLOCK THE D ACTIVE

1223
01:15:07,000 --> 01:15:07,200
SITES.

1224
01:15:07,200 --> 01:15:13,240
BUT ON THE RIGHT SIDE THIS TAX

1225
01:15:13,240 --> 01:15:15,800
ON THE VIRAL DNA.

1226
01:15:15,800 --> 01:15:20,960
IT MAKES UP THAT AT THE SITE

1227
01:15:20,960 --> 01:15:23,720
AND THAT'S WHY THEY ARE

1228
01:15:23,720 --> 01:15:24,880
COMPOUNDS.

1229
01:15:24,880 --> 01:15:29,840
ON THE LEFT SIDE TO THE

1230
01:15:29,840 --> 01:15:37,920
COMPOUNDS OF THOSE VARIANCE.

1231
01:15:37,920 --> 01:15:38,480
BUT THEY ARE TILTED AND THAT

1232
01:15:38,480 --> 01:15:43,240
IS SIMPLY BECAUSE THE NEGATIVE

1233
01:15:43,240 --> 01:15:46,080
ADAMS IS EMBEDDED INTO THE

1234
01:15:46,080 --> 01:15:49,000
CORE SO THE RIGHT SIDE IS

1235
01:15:49,000 --> 01:15:51,840
IDENTICAL AND THE LEFT SIDE IS

1236
01:15:51,840 --> 01:15:57,400
THE REGION OF FIRST POTENCY.

1237
01:15:57,400 --> 01:15:57,800
SO THAT IS GREAT.

1238
01:15:57,800 --> 01:15:59,760
WE DISCUSSED HOW THEY BIND TO

1239
01:15:59,760 --> 01:16:05,920
THAT STRUCTURAL BASIS.

1240
01:16:05,920 --> 01:16:09,280
AND OVER A DECADE.

1241
01:16:09,280 --> 01:16:12,400
AND OF COURSE A LOT OF THIS

1242
01:16:12,400 --> 01:16:16,320
WAS KNOWN FROM EARLY ON ALL

1243
01:16:16,320 --> 01:16:21,440
THOSE MECHANISMS.

1244
01:16:21,440 --> 01:16:25,040
BUT ALSO WHICH THE HIV

1245
01:16:25,040 --> 01:16:34,280
DEPENDENT HOW YOU ALIGN SO

1246
01:16:34,280 --> 01:16:34,840
THEY ARE NOT DISTINCT IT IS

1247
01:16:34,840 --> 01:16:40,880
THE ACTIVE SITE OF THE HIV AND

1248
01:16:40,880 --> 01:16:49,480
THEN IT IS COLORED BUT YOU CAN

1249
01:16:49,480 --> 01:16:50,040
APPRECIATE THAT THERE ARE

1250
01:16:50,040 --> 01:16:50,800
REGIONS THAT ARE SIMILAR BUT

1251
01:16:50,800 --> 01:16:52,640
OTHERS THAT ARE DISTINCT ALL

1252
01:16:52,640 --> 01:16:58,680
THESE MESSAGES ARE IMPORTANT

1253
01:16:58,680 --> 01:17:00,080
DRUG-RESISTANT PERIOD ON —-

1254
01:17:00,080 --> 01:17:02,840
VARIANCE THAT ARISE IN THE

1255
01:17:02,840 --> 01:17:05,240
POPULATIONS.

1256
01:17:05,240 --> 01:17:08,280
AND THOSE THAT ARE NOT

1257
01:17:08,280 --> 01:17:11,880
IDENTICAL.

1258
01:17:11,880 --> 01:17:15,160
SO ONE OF THE CONSEQUENCES IS

1259
01:17:15,160 --> 01:17:16,240
THAT IF YOU TAKE THE EXACT

1260
01:17:16,240 --> 01:17:26,720
SAME COMPOUND AND WITH THAT

1261
01:17:27,040 --> 01:17:37,480
AND THEN AND THAT IS RATHER

1262
01:17:40,160 --> 01:17:40,960
DISTINCT AND THEN THE SAME

1263
01:17:40,960 --> 01:17:51,480
THING HAPPENS AND THEN NOT TO

1264
01:17:57,000 --> 01:17:57,960
ASK IT WE ARE BEGINNING TO

1265
01:17:57,960 --> 01:18:01,640
FIND OUT SO THAT'S WITH THE

1266
01:18:01,640 --> 01:18:03,680
NATURE OF THE ACTIVE SITE

1267
01:18:03,680 --> 01:18:14,160
THERE IS A DISPARITY HERE SO

1268
01:18:15,760 --> 01:18:19,160
THEN THEY ARE PERFORMING WITH

1269
01:18:19,160 --> 01:18:21,800
THOSE PROPENSITIES FOR THE

1270
01:18:21,800 --> 01:18:26,800
DRUGS AND THE PRELIMINARY DATA

1271
01:18:26,800 --> 01:18:30,080
THEN WITH THIS COMPOUND TO

1272
01:18:30,080 --> 01:18:37,680
EXTEND OUT.

1273
01:18:37,680 --> 01:18:38,120
AND TO VALIDATE THIS.

1274
01:18:38,120 --> 01:18:40,840
SO THIS LEADS TO THE SECOND

1275
01:18:40,840 --> 01:18:46,160
PART THERE ARE MANY

1276
01:18:46,160 --> 01:18:46,720
DRUG-RESISTANT VARIANCE THIS

1277
01:18:46,720 --> 01:18:49,160
IS A SNAPSHOT FROM THE

1278
01:18:49,160 --> 01:18:51,360
PUBLICATION THERE ARE HUNDREDS

1279
01:18:51,360 --> 01:18:54,960
IF NOT THOUSANDS OF DRUG

1280
01:18:54,960 --> 01:19:01,920
RESISTANCE ANY WITH THE CLOSE

1281
01:19:01,920 --> 01:19:11,760
COLLABORATION SO WE SELECTED

1282
01:19:11,760 --> 01:19:19,560
THOSE THREE POSITIONS.

1283
01:19:19,560 --> 01:19:23,880
AND THEN WHAT STEVE SMITH DID

1284
01:19:23,880 --> 01:19:24,880
THE SINGLE AND DOUBLE AND

1285
01:19:24,880 --> 01:19:29,680
TRIPLE MUTANT AND THEN THE

1286
01:19:29,680 --> 01:19:31,520
POTENCIES OF THE

1287
01:19:31,520 --> 01:19:40,520
SECOND-GENERATION AND THEN TO

1288
01:19:40,520 --> 01:19:43,800
HIGHLIGHT TWO THINGS IT WAS

1289
01:19:43,800 --> 01:19:52,040
MORE POTENT SO WE FOUND SOME

1290
01:19:52,040 --> 01:19:57,280
WEAK SPOTS AND THAT IS WITH

1291
01:19:57,280 --> 01:20:06,600
THE MUTATIONS.

1292
01:20:06,600 --> 01:20:07,200
AND THEN WE WILL TALK ABOUT

1293
01:20:07,200 --> 01:20:07,440
THIS NOW.

1294
01:20:07,440 --> 01:20:16,880
SO COMPREHENSIVE VIROLOGY AND

1295
01:20:16,880 --> 01:20:17,480
THEN TO PRESENT WHAT WE ARE

1296
01:20:17,480 --> 01:20:19,880
FINDING FOR STRUCTURAL

1297
01:20:19,880 --> 01:20:23,920
VIROLOGY ALONG THE PATHWAY

1298
01:20:23,920 --> 01:20:26,840
THAT THIS WAS THE TRIPLE

1299
01:20:26,840 --> 01:20:33,880
MUTANT SO WHAT ARE WE FINDING

1300
01:20:33,880 --> 01:20:37,720
FROM THE STRUCTURE OF VIROLOGY

1301
01:20:37,720 --> 01:20:40,720
THERE ARE FOUR IMPORTANT

1302
01:20:40,720 --> 01:20:48,640
RESIDUES AND THEN HISTIDINE

1303
01:20:48,640 --> 01:20:51,360
THAT IS NOT A RESISTANT

1304
01:20:51,360 --> 01:20:55,080
VARIANT SO LET'S LOOK AT THE

1305
01:20:55,080 --> 01:20:59,040
SINGLE-USE SO THAT SINGLE

1306
01:20:59,040 --> 01:21:02,680
MUTANT TO MAKE THAT

1307
01:21:02,680 --> 01:21:04,840
INTERACTION AND THEN TO

1308
01:21:04,840 --> 01:21:13,400
COMPARE THAT SO WITH THE G1 40

1309
01:21:13,400 --> 01:21:17,320
MUTATION AND THEN THAT LEADS

1310
01:21:17,320 --> 01:21:27,680
TO THAT CONFIGURATION.

1311
01:21:29,280 --> 01:21:30,120
[INAUDIBLE]

1312
01:21:30,120 --> 01:21:35,320
2148 K MUTATION THERE IS A

1313
01:21:35,320 --> 01:21:40,960
SHIFT IN THE BACKBONE SO THOSE

1314
01:21:40,960 --> 01:21:44,080
THAT ARE SHIFTED OUTWARDS AND

1315
01:21:44,080 --> 01:21:51,600
HIM BEING 114 WITH THE EFFECTS

1316
01:21:51,600 --> 01:21:52,680
OF 138.

1317
01:21:52,680 --> 01:21:56,240
THIS IS A STRUCTURE OF

1318
01:21:56,240 --> 01:22:00,800
DETRIMENTAL MUTATION SUPPORTED

1319
01:22:00,800 --> 01:22:07,280
BY AND TO MARGIE AND VIROLOGY.

1320
01:22:07,280 --> 01:22:16,080
AND THEN AS A SINGLE MUTANT

1321
01:22:16,080 --> 01:22:16,640
WITH THE POSITION OF 148 AND

1322
01:22:16,640 --> 01:22:18,400
THAT DOUBLE MUTANT IS

1323
01:22:18,400 --> 01:22:24,240
INTERESTING BUT IF THE RESIDUE

1324
01:22:24,240 --> 01:22:30,280
IS THAT POSITION IT DOESN'T

1325
01:22:30,280 --> 01:22:36,960
HAVE THE DETRIMENTAL EFFECTS.

1326
01:22:36,960 --> 01:22:43,320
WE THINK THIS ONE THAT WE

1327
01:22:43,320 --> 01:22:46,280
CONFIGURATION OF THE

1328
01:22:46,280 --> 01:22:46,680
MOLECULES.

1329
01:22:46,680 --> 01:22:47,560
BUT THAT WE DON'T COMPLETELY

1330
01:22:47,560 --> 01:22:53,600
UNDERSTAND THIS THAT THE

1331
01:22:53,600 --> 01:22:56,960
ENTOMOLOGY AND VIROLOGY SEEMS

1332
01:22:56,960 --> 01:23:05,880
TO BEHAVE.

1333
01:23:05,880 --> 01:23:09,720
SO WITH Q1 48 K IT IS

1334
01:23:09,720 --> 01:23:11,600
INTERESTING IN TERMS OF

1335
01:23:11,600 --> 01:23:17,200
RESISTANCE SO THAT INFLUENCE

1336
01:23:17,200 --> 01:23:22,160
POSITION BUT NOW IT EXTENDS

1337
01:23:22,160 --> 01:23:22,760
OUT.

1338
01:23:22,760 --> 01:23:26,200
I FORGOT TO MENTION THESE ARE

1339
01:23:26,200 --> 01:23:31,240
THE TWO MAGNESIUM'S.

1340
01:23:31,240 --> 01:23:31,800
IT AFFECTS THE LOCAL CHARGE

1341
01:23:31,800 --> 01:23:41,720
DISTRIBUTION OF MAGNESIUM AND

1342
01:23:41,720 --> 01:23:48,080
THEN WE SEE THE SAME THING.

1343
01:23:48,080 --> 01:23:51,000
SO RESISTANCE ONLY ARISES WITH

1344
01:23:51,000 --> 01:23:56,800
THE MUTATION.

1345
01:23:56,800 --> 01:23:57,360
SO IF YOU HAVE THE SINGLE

1346
01:23:57,360 --> 01:24:06,880
MUTANT OR THE DOUBLE MUTANT.

1347
01:24:06,880 --> 01:24:12,480
SO NOW IF YOU HAVE THAT DOUBLE

1348
01:24:12,480 --> 01:24:16,320
MUTANT BUT THEN IT EXTENDS OUT

1349
01:24:16,320 --> 01:24:21,360
TO THE TWO MAGNESIUM IONS

1350
01:24:21,360 --> 01:24:21,920
THAT'S WE SEE SUBSTANTIAL

1351
01:24:21,920 --> 01:24:22,600
DIFFERENCE IN POTENCY.

1352
01:24:22,600 --> 01:24:29,000
WE THINK THE LOCAL CHARGE THEN

1353
01:24:29,000 --> 01:24:38,200
THE DISTRIBUTION IS AFFECTED.

1354
01:24:38,200 --> 01:24:40,920
SO NOTICE THAT FORWARD THE

1355
01:24:40,920 --> 01:24:51,560
REMAINS POTENT SO THEN IN

1356
01:24:51,560 --> 01:24:53,120
ADDITION WE NOW HAVE

1357
01:24:53,120 --> 01:24:57,960
STRUCTURES OF THE VARIANT AND

1358
01:24:57,960 --> 01:24:58,520
THE HISTIDINE VARIANT THAT

1359
01:24:58,520 --> 01:25:00,960
ARISES IN PATIENTS QUITE

1360
01:25:00,960 --> 01:25:03,800
FREQUENTLY BUT THIS ONE MOST

1361
01:25:03,800 --> 01:25:05,920
FREQUENTLY THAN OTHERS.

1362
01:25:05,920 --> 01:25:10,120
AND WHAT WE ARE FINDING IS

1363
01:25:10,120 --> 01:25:13,120
THAT PROXIMITY IN THE CHARGE

1364
01:25:13,120 --> 01:25:19,800
THAT MATTERS.

1365
01:25:19,800 --> 01:25:26,800
AND IT'S QUITE CLOSE AND THE

1366
01:25:26,800 --> 01:25:29,720
DRUG LOSES SIGNIFICANT

1367
01:25:29,720 --> 01:25:34,720
POTENCY.

1368
01:25:34,720 --> 01:25:37,760
AND IT REMAINS A LITTLE MORE

1369
01:25:37,760 --> 01:25:42,440
POTENT THAT IS THE FURTHEST

1370
01:25:42,440 --> 01:25:48,240
AWAY AND THE WEAKEST OF THE

1371
01:25:48,240 --> 01:25:49,120
THREE AND THE DRUG REMAINS

1372
01:25:49,120 --> 01:25:53,760
HIGHLY POTENT SO THEY CAN BE

1373
01:25:53,760 --> 01:25:58,960
PRIMARILY ATTRIBUTED Q1 48

1374
01:25:58,960 --> 01:26:02,000
THIS IS SIMILAR AND THERE ARE

1375
01:26:02,000 --> 01:26:06,200
SOME SIMILARITIES FROM A FEW

1376
01:26:06,200 --> 01:26:10,080
YEARS AGO.

1377
01:26:10,080 --> 01:26:16,400
AND WE HAVE MORE INSIGHTS NOW.

1378
01:26:16,400 --> 01:26:16,960
AND WITH THAT COMPREHENSIVE

1379
01:26:16,960 --> 01:26:23,480
NATURE OF THE STUDY.

1380
01:26:23,480 --> 01:26:26,840
AND THIS IS REORIENTING THE

1381
01:26:26,840 --> 01:26:30,120
POSITIVELY CHARGED POSITION.

1382
01:26:30,120 --> 01:26:34,480
IT IS A POSITIVE CHARGE TO

1383
01:26:34,480 --> 01:26:38,800
DRIVE RESISTANCE SO AS THE

1384
01:26:38,800 --> 01:26:43,040
LAST FEW SLIDES ESPECIALLY THE

1385
01:26:43,040 --> 01:26:45,800
DRUG-RESISTANT VARIANCE.

1386
01:26:45,800 --> 01:26:49,400
GETTING BACK TO THE PLOTS NOW

1387
01:26:49,400 --> 01:26:52,880
FOR THE REMAINS HIGHLY POTENT

1388
01:26:52,880 --> 01:26:53,440
AGAINST THE DEVIL AND THE

1389
01:26:53,440 --> 01:26:56,000
TRIPLE MUTANT.

1390
01:26:56,000 --> 01:26:57,200
SPECIFICALLY LOOKING AT THE

1391
01:26:57,200 --> 01:27:07,680
TRIPLE MUTANT AND THERE ARE

1392
01:27:10,560 --> 01:27:11,040
SOME INSIGHTS WE ARE JUST

1393
01:27:11,040 --> 01:27:11,560
LEARNING ABOUT AND WE JUST

1394
01:27:11,560 --> 01:27:12,160
DESCRIBED PREVIOUSLY WITH THE

1395
01:27:12,160 --> 01:27:13,360
CHEMICAL FEATURES OF THE

1396
01:27:13,360 --> 01:27:13,960
DRUGS.

1397
01:27:13,960 --> 01:27:14,960
SO I WILL JUST HIGHLIGHT ONE

1398
01:27:14,960 --> 01:27:19,120
NEW ASPECT AND THIS IS A

1399
01:27:19,120 --> 01:27:27,000
RECENT DEVELOPMENT.

1400
01:27:27,000 --> 01:27:33,680
SO I MENTIONED THAT VIRAL DNA

1401
01:27:33,680 --> 01:27:36,280
FORMS THE TERMINAL DNA COULD

1402
01:27:36,280 --> 01:27:41,240
EITHER HAVE ONE WITHOUT ONE

1403
01:27:41,240 --> 01:27:51,760
CONFIGURATION BUT THAT IS NOT

1404
01:27:56,320 --> 01:27:58,440
CONTRIBUTING SOMEWHAT WE ARE

1405
01:27:58,440 --> 01:28:04,640
FINDING THAT TRIPLE MUTANT

1406
01:28:04,640 --> 01:28:06,640
THAT ADAPTS MULTIPLE

1407
01:28:06,640 --> 01:28:12,000
CONFIRMATIONS BUT WHEN THAT IS

1408
01:28:12,000 --> 01:28:17,880
FOUND IS LARGELY IN THE STACK

1409
01:28:17,880 --> 01:28:18,440
THIS ISN'T JUST SPECIFIC TO

1410
01:28:18,440 --> 01:28:19,040
THESE TWO STRUCTURES IN FACT

1411
01:28:19,040 --> 01:28:29,560
WE SEE THIS ACROSS THE BOARD.

1412
01:28:31,320 --> 01:28:33,160
AND THEN IT MAKES SENSE FROM

1413
01:28:33,160 --> 01:28:38,160
THE PERSPECTIVE WHEN YOU HAVE

1414
01:28:38,160 --> 01:28:43,840
THAT STACKED CONFIGURATION SO

1415
01:28:43,840 --> 01:28:54,320
THE IDEA AND THEN AT TEMPLE

1416
01:28:54,560 --> 01:29:02,800
UNIVERSITY SO THIS IS AN

1417
01:29:02,800 --> 01:29:04,640
EXPLANATION FROM THOSE DYNAMIC

1418
01:29:04,640 --> 01:29:08,680
CONSIDERATIONS AND THEN YOU

1419
01:29:08,680 --> 01:29:12,400
CAN HAVE THE ENZYME TO HAVE

1420
01:29:12,400 --> 01:29:17,120
THE STACK CONFIGURATION IS A

1421
01:29:17,120 --> 01:29:21,520
THERMODYNAMIC SITE AND THEN

1422
01:29:21,520 --> 01:29:24,320
THEY TAKE THAT EXPERIMENTAL

1423
01:29:24,320 --> 01:29:34,800
OCCUPANCY AND THEN WITH THE

1424
01:29:39,680 --> 01:29:41,440
DELTA GEO.

1425
01:29:41,440 --> 01:29:48,880
OF NON- STACKING.

1426
01:29:48,880 --> 01:29:53,480
AND THAT'S TO SUPPORT THE IDEA

1427
01:29:53,480 --> 01:29:58,440
WITH A CONSTRUCTIVE INTERFACE

1428
01:29:58,440 --> 01:30:02,520
WITH THOSE WITH A RESISTANT

1429
01:30:02,520 --> 01:30:12,440
VARIANCE AND THEN TO IDENTIFY

1430
01:30:12,440 --> 01:30:14,480
WAYS OF COMBATING DRUG

1431
01:30:14,480 --> 01:30:23,480
RESISTANCE AND THEN HIV THE

1432
01:30:23,480 --> 01:30:30,360
THAT CAN PROBABLY TRANSLATE.

1433
01:30:30,360 --> 01:30:33,960
AND THE CENTRAL HYPOTHESIS IS

1434
01:30:33,960 --> 01:30:37,600
SEVERAL WELL-DEFINED

1435
01:30:37,600 --> 01:30:40,000
TREATMENTS AND THEN TO HAVE A

1436
01:30:40,000 --> 01:30:46,640
COMPREHENSIVE UNDERSTANDING

1437
01:30:46,640 --> 01:30:53,480
THEN THE WITH THOSE EFFICACIES

1438
01:30:53,480 --> 01:30:58,560
ACROSS BIBLE SUBTYPES.

1439
01:30:58,560 --> 01:30:59,160
SO THANK YOU THERE IS A LOT OF

1440
01:30:59,160 --> 01:30:59,720
PEOPLE TO THINK MANY ARE IN

1441
01:30:59,720 --> 01:31:09,960
THE AUDIENCE.

1442
01:31:12,400 --> 01:31:12,920
AND THEN AS NOW AS A POSTDOC

1443
01:31:12,920 --> 01:31:17,600
IN MY GROUP AND ALL THOSE THAT

1444
01:31:17,600 --> 01:31:26,280
THE NCI NOT JUST AS A

1445
01:31:26,280 --> 01:31:33,800
COLLEAGUE AND THEN TO CONVINCE

1446
01:31:33,800 --> 01:31:38,520
ME WHEN YOU THINK ABOUT THIS

1447
01:31:38,520 --> 01:31:47,400
WORK IN THE BEST POSSIBLE WAY

1448
01:31:47,400 --> 01:31:47,920
AND THEN SEE A MENTOR AND

1449
01:31:47,920 --> 01:31:49,640
COLLEAGUE OVER THE YEARS.

1450
01:31:49,640 --> 01:31:49,920
THANK YOU.

1451
01:31:49,920 --> 01:31:59,560
[APPLAUSE]

1452
01:31:59,560 --> 01:32:01,600
>>AND THAT LOW-KEY

1453
01:32:01,600 --> 01:32:03,080
INTEGRATION THOSE THAT

1454
01:32:03,080 --> 01:32:08,080
OCCURRED NATURALLY.

1455
01:32:08,080 --> 01:32:18,560
AND WITH THOSE RETROVIRUSES

1456
01:32:19,000 --> 01:32:20,480
AND MAYBE EVEN SOME THAT YOU

1457
01:32:20,480 --> 01:32:28,520
HAVE LOOKED AT.

1458
01:32:28,520 --> 01:32:30,520
>>THAT'S A GOOD QUESTION.

1459
01:32:30,520 --> 01:32:39,960
[LAUGHTER]

1460
01:32:39,960 --> 01:32:42,640
I WILL HAVE TO GET BACK TO YOU

1461
01:32:42,640 --> 01:32:49,360
ON THAT.

1462
01:32:49,360 --> 01:32:49,880
AND WITH THE HIV THAT'S A

1463
01:32:49,880 --> 01:33:00,200
LITTLE SURPRISING.

1464
01:33:01,240 --> 01:33:10,160
AND THEN BASED ON GENOMIC AND

1465
01:33:10,160 --> 01:33:10,680
IT SEEMS TO BE THERE IS

1466
01:33:10,680 --> 01:33:12,320
ANOTHER WAY TO SLICE THAT.

1467
01:33:12,320 --> 01:33:15,880
>>WE ARE FINDING THAT
THERE

1468
01:33:15,880 --> 01:33:21,160
ARE SIMILARITIES OF COURSE AND

1469
01:33:21,160 --> 01:33:23,640
THOSE THAT ARE ABOUT

1470
01:33:23,640 --> 01:33:34,160
40 PERCENT CONCERNED OF COURSE

1471
01:33:34,160 --> 01:33:40,480
THERE IS IMPORTANT DIFFERENCES

1472
01:33:40,480 --> 01:33:47,000
OF THE Q1 86 IT IS A RESCUE

1473
01:33:47,000 --> 01:33:50,440
THAT HAS AN IMPORTANT AND

1474
01:33:50,440 --> 01:33:57,440
LARGE AFFECT.

1475
01:33:57,440 --> 01:33:59,520
SO I GUESS WE HAVE NOT THOUGHT

1476
01:33:59,520 --> 01:34:04,600
EXTENSIVELY WITH INHIBITION OF

1477
01:34:04,600 --> 01:34:11,320
OTHER RETROVIRAL'S BUT PERHAPS

1478
01:34:11,320 --> 01:34:13,360
WE SHOULD THINK MORE OF THOSE

1479
01:34:13,360 --> 01:34:15,440
IMPLICATIONS.

1480
01:34:15,440 --> 01:34:18,120
>>I WOULD BE ON THE
LOOKOUT.

1481
01:34:18,120 --> 01:34:24,920
>>I AGREE THAT THIS IS OF

1482
01:34:24,920 --> 01:34:30,840
INTEREST.

1483
01:34:30,840 --> 01:34:33,840
>>

1484
01:34:33,840 --> 01:34:41,280
[INAUDIBLE]

1485
01:34:41,280 --> 01:34:49,160
THERE IS NOTHING FUNDAMENTAL

1486
01:34:49,160 --> 01:34:50,600
FOR THOSE REACTIONS.

1487
01:34:50,600 --> 01:35:01,120
>>SO IT IS QUITE
CONCERNING.

1488
01:35:02,280 --> 01:35:04,240
WE THINK IT HAS TO DO WITH A

1489
01:35:04,240 --> 01:35:08,440
POSITIONING WITH THE PROXIMITY

1490
01:35:08,440 --> 01:35:16,840
TO CARRY OUT THE INTEGRATION.

1491
01:35:16,840 --> 01:35:22,680
SO THEN THE FILE HAS TO BE

1492
01:35:22,680 --> 01:35:25,440
POSITIONED IN THIS SPECIFIC

1493
01:35:25,440 --> 01:35:27,360
WAY IN A MEETING AFTER THE

1494
01:35:27,360 --> 01:35:35,640
STRUCTURE AND THE POSITION.

1495
01:35:35,640 --> 01:35:36,160
>>THANK YOU VERY MUCH.

1496
01:35:36,160 --> 01:35:37,760
GREAT WORK.

1497
01:35:37,760 --> 01:35:41,200
[APPLAUSE]

1498
01:35:41,200 --> 01:35:43,600
WE WILL NOW TAKE A 15 MINUTE

1499
01:35:43,600 --> 01:35:43,840
BREAK.

1500
01:35:43,840 --> 01:35:54,280
[INAUDIBLE CONVERSATIONS]

1501
01:52:42,280 --> 01:52:47,040
>>WE SHOULD START TO
FILTER

1502
01:52:47,040 --> 01:52:57,400
IN AND TAKE OUR SEATS.

1503
01:53:13,120 --> 01:53:13,600
OKAY WE SHOULD GET STARTED

1504
01:53:13,600 --> 01:53:15,120
AGAIN SO WE STAY ON TIME.

1505
01:53:15,120 --> 01:53:20,680
THE NEXT SPEAKER FROM SCRIPPS

1506
01:53:20,680 --> 01:53:22,680
RESEARCH IN LA JOLLA

1507
01:53:22,680 --> 01:53:24,360
CALIFORNIA PETER HAS BEEN A

1508
01:53:24,360 --> 01:53:30,240
WORLD LEADER IN MOST RECENTLY

1509
01:53:30,240 --> 01:53:33,360
FOCUSING AND JOINING US

1510
01:53:33,360 --> 01:53:34,600
REMOTELY AS YOU CAN SEE THIS

1511
01:53:34,600 --> 01:53:37,000
WILL GO SMOOTHLY THANK YOU

1512
01:53:37,000 --> 01:53:41,680
VERY MUCH.

1513
01:53:41,680 --> 01:53:47,640
>>THANK YOU FOR INVITING
ME

1514
01:53:47,640 --> 01:53:57,960
AND TO PARTICIPATE.

1515
01:54:16,480 --> 01:54:26,840
[INAUDIBLE CONVERSATIONS]

1516
01:54:40,040 --> 01:54:40,560
>>I WANT TO TALK ABOUT
THE

1517
01:54:40,560 --> 01:54:44,040
COLLABORATIONS IN SCIENCE AND

1518
01:54:44,040 --> 01:54:47,080
THIS ECHOES SOME OF THE

1519
01:54:47,080 --> 01:54:52,560
THOUGHTS EXPRESSED TO ENGULFED

1520
01:54:52,560 --> 01:55:00,240
IN THE COLLABORATIONS AND IT

1521
01:55:00,240 --> 01:55:05,040
STARTED AND CONTINUES TO THIS

1522
01:55:05,040 --> 01:55:05,240
DAY.

1523
01:55:05,240 --> 01:55:11,520
ONE OF THE HIGH POINTS WAS THE

1524
01:55:11,520 --> 01:55:22,000
BISHOPS LAB IN SAN FRANCISCO

1525
01:55:22,680 --> 01:55:23,160
AND ALL OF THAT COOPERATIVE

1526
01:55:23,160 --> 01:55:33,680
AND THAT MARKS WITH MY TIME IN

1527
01:55:35,400 --> 01:55:40,800
SCIENCE AND OF COURSE I WAS

1528
01:55:40,800 --> 01:55:47,240
ABLE TO PARTICIPATE IN WORK ON

1529
01:55:47,240 --> 01:55:52,840
THE VIRUS THAT YOU LEFT ME

1530
01:55:52,840 --> 01:55:57,240
WITH A GIFT.

1531
01:55:57,240 --> 01:56:02,360
SO OVER THE PAST 20 PLUS YEARS

1532
01:56:02,360 --> 01:56:05,280
AND HAS BEEN AN IMPORTANT

1533
01:56:05,280 --> 01:56:07,360
FACTOR IN MY SCIENCE.

1534
01:56:07,360 --> 01:56:13,760
THANK YOU STEVE.

1535
01:56:13,760 --> 01:56:16,800
SO THEY ARE STARTED AND THEY

1536
01:56:16,800 --> 01:56:18,400
GROW AND FLOURISH AND THEY

1537
01:56:18,400 --> 01:56:22,120
BECOME DORMANT FACED WITH NEW

1538
01:56:22,120 --> 01:56:29,680
COLLABORATIONS SO WHEN I

1539
01:56:29,680 --> 01:56:30,280
JOINED SCRIPPS I WAS FORTUNATE

1540
01:56:30,280 --> 01:56:30,800
TO BE HOUSED AT THE ONLY

1541
01:56:30,800 --> 01:56:34,080
BIOLOGY LAB.

1542
01:56:34,080 --> 01:56:36,280
ANDERSON'S THE INTERACTION

1543
01:56:36,280 --> 01:56:43,440
THAT IS IMPORTANT SO NOW LET

1544
01:56:43,440 --> 01:56:48,280
ME TURN TO MORE SPECIFICS.

1545
01:56:48,280 --> 01:56:48,840
I WANT TO TALK ABOUT SOME OF

1546
01:56:48,840 --> 01:56:54,200
THE RECENT DATA.

1547
01:56:54,200 --> 01:57:02,520
AS YOU MAY KNOW EXISTING AS A

1548
01:57:02,520 --> 01:57:09,280
SUBUNIT AND P1 TEN AND WE

1549
01:57:09,280 --> 01:57:15,000
TALKED IN THE GENERATION THIS

1550
01:57:15,000 --> 01:57:21,880
IS FIRST LINKED TO CANCER THAT

1551
01:57:21,880 --> 01:57:28,440
WAS CARRIED OUT IN THE TUMOR

1552
01:57:28,440 --> 01:57:34,360
VIRUS THAT USED BY THE DNA

1553
01:57:34,360 --> 01:57:39,320
TUMORS AND LATER I DISCOVERED

1554
01:57:39,320 --> 01:57:44,880
THE GENE IN THE RETROVIRUS AND

1555
01:57:44,880 --> 01:57:53,720
THEN WE EXPRESS THAT BUT THEN

1556
01:57:53,720 --> 01:57:54,280
ALSO INDUCE TUMORS INTO THE

1557
01:57:54,280 --> 01:57:59,840
ANIMAL THEN FINALLY THAT IT IS

1558
01:57:59,840 --> 01:58:10,320
MUTATED FREQUENTLY AND THEY

1559
01:58:23,360 --> 01:58:29,000
CONFER TO THE PROTEIN AND ALSO

1560
01:58:29,000 --> 01:58:32,320
INDUCE TUMORS.

1561
01:58:32,320 --> 01:58:38,440
SO THESE FINDINGS MAKE THEM A

1562
01:58:38,440 --> 01:58:42,160
POPULAR AND PROMISING TARGET.

1563
01:58:42,160 --> 01:58:48,120
BUT AFTER MORE THAN 20 YEARS

1564
01:58:48,120 --> 01:58:50,880
AND MORE THAN INHIBITORS WE

1565
01:58:50,880 --> 01:58:53,000
HAVE NO BREAKTHROUGH.

1566
01:58:53,000 --> 01:58:58,800
WE HAVE FIVE FDA APPROVED

1567
01:58:58,800 --> 01:58:59,080
INHIBITORS.

1568
01:58:59,080 --> 01:59:07,080
FOUR OF THESE ARE EXCLUSIVELY

1569
01:59:07,080 --> 01:59:10,160
ONLY ONE WORKS WITH SOLID

1570
01:59:10,160 --> 01:59:14,840
TUMORS AND THEN TO USE THE

1571
01:59:14,840 --> 01:59:18,040
REFERENCE AND THE TERMINOLOGY.

1572
01:59:18,040 --> 01:59:25,840
>>I'M SORRY I HAVE TO
STOP

1573
01:59:25,840 --> 01:59:26,240
YOU FOR A SECOND.

1574
01:59:26,240 --> 01:59:28,760
YOU ARE NOT SHARING YOUR

1575
01:59:28,760 --> 01:59:29,440
SLIDES.

1576
01:59:29,440 --> 01:59:32,920
>>ACTUALLY I AM STILL
TALKING

1577
01:59:32,920 --> 01:59:35,840
ABOUT INTRODUCTORY STUFF.

1578
01:59:35,840 --> 01:59:40,120
>>I'M SORRY.

1579
01:59:40,120 --> 01:59:42,040
>>I AM NOT ON THE DATA
SLIDE

1580
01:59:42,040 --> 01:59:42,240
YET.

1581
01:59:42,240 --> 01:59:43,760
THAT WILL COME IN THE SECOND.

1582
01:59:43,760 --> 01:59:48,160
>>OKAY.

1583
01:59:48,160 --> 01:59:48,360
SORRY.

1584
01:59:48,360 --> 01:59:48,880
>>SORRY ABOUT THE LONG

1585
01:59:48,880 --> 01:59:52,360
INTRODUCTION BUT I WANTED TO

1586
01:59:52,360 --> 01:59:58,160
COMMENT ON THE IMPORTANCE OF

1587
01:59:58,160 --> 01:59:59,560
COLLABORATION.

1588
01:59:59,560 --> 02:00:03,840
SO TALKING ABOUT INHIBITORS

1589
02:00:03,840 --> 02:00:08,800
TALK ABOUT ONE SPECIFIC

1590
02:00:08,800 --> 02:00:12,440
INHIBITOR THE BENEFITS FOR THE

1591
02:00:12,440 --> 02:00:14,920
PATIENT COMES AT THE COST OF

1592
02:00:14,920 --> 02:00:19,680
SIGNIFICANT RISK AND THE SIDE

1593
02:00:19,680 --> 02:00:25,960
EFFECTS REPRESENT INHIBITION.

1594
02:00:25,960 --> 02:00:30,000
SO THE INHIBITOR HAS NOT

1595
02:00:30,000 --> 02:00:40,440
DISCRIMINATED AND THAT IS

1596
02:00:40,760 --> 02:00:44,480
INJURIOUS BUT THE OBVIOUS

1597
02:00:44,480 --> 02:00:46,040
SOLUTION IS TO MAKE THOSE

1598
02:00:46,040 --> 02:00:48,840
SPECIFIC INHIBITORS THAT THERE

1599
02:00:48,840 --> 02:00:57,440
IS A PROBLEM USUALLY WE DON'T

1600
02:00:57,440 --> 02:00:58,360
HAVE THE CHEMICAL SPACE THAT

1601
02:00:58,360 --> 02:01:06,960
IS NEEDED.

1602
02:01:06,960 --> 02:01:07,520
SECOND WE DON'T HAVE THAT

1603
02:01:07,520 --> 02:01:12,680
STRUCTURAL INFORMATION THAT

1604
02:01:12,680 --> 02:01:14,000
DISTINGUISHES MUTANT.

1605
02:01:14,000 --> 02:01:15,960
WE HAVE PARTIAL INFORMATION

1606
02:01:15,960 --> 02:01:24,560
BUT NOT COMPLETE INFORMATION.

1607
02:01:24,560 --> 02:01:25,200
I WOULD LIKE TO TALK ABOUT THE

1608
02:01:25,200 --> 02:01:29,240
STRUCTURAL STUDY AND IT IS A

1609
02:01:29,240 --> 02:01:34,280
COLLABORATION WHICH IN THIS

1610
02:01:34,280 --> 02:01:44,760
CASE IS TRANSCONTINENTAL AND

1611
02:01:45,520 --> 02:01:48,840
AFTER FIVE YEARS WE HAD ZERO

1612
02:01:48,840 --> 02:01:51,360
RESULTS SO IN ORDER TO MAKE

1613
02:01:51,360 --> 02:01:55,320
PROGRESS WE NEEDED A LOT MORE

1614
02:01:55,320 --> 02:01:57,880
INSTRUMENT TIME THAN WE EVER

1615
02:01:57,880 --> 02:02:02,680
COULD GET LOCALLY AT SCRIPPS.

1616
02:02:02,680 --> 02:02:05,360
SO I TALKED ABOUT THIS WITH A

1617
02:02:05,360 --> 02:02:09,960
FRIEND IN SHANGHAI AND HE HAD

1618
02:02:09,960 --> 02:02:14,160
SEVERAL INSTRUMENTS SO WE

1619
02:02:14,160 --> 02:02:18,320
DECIDED TO COLLABORATE.

1620
02:02:18,320 --> 02:02:20,360
AND HAVING PERMISSION FOR THAT

1621
02:02:20,360 --> 02:02:23,360
COLLABORATION AND THE REQUEST

1622
02:02:23,360 --> 02:02:26,280
HAD TO GO ALL THE WAY TO THE

1623
02:02:26,280 --> 02:02:32,640
EMBASSY IN BEIJING BUT AT THE

1624
02:02:32,640 --> 02:02:35,840
BEGINNING WE HAD NO LUCK TO

1625
02:02:35,840 --> 02:02:42,440
THE PROTEIN AND THEN IF IT WAS

1626
02:02:42,440 --> 02:02:43,360
COLLECTED AT THE EDGE OF THE

1627
02:02:43,360 --> 02:02:46,240
SCREEN AND IT TOOK FIVE

1628
02:02:46,240 --> 02:02:49,160
MINUTES BEFORE THEY SAW

1629
02:02:49,160 --> 02:02:50,840
SOMETHING AND THEN THIS IS THE

1630
02:02:50,840 --> 02:02:59,920
FIRST PICTURE THAT WE SAW BUT

1631
02:02:59,920 --> 02:03:03,080
THEN WE HAD A MODEL.

1632
02:03:03,080 --> 02:03:06,560
SO THEN THE NEXT QUESTION IS

1633
02:03:06,560 --> 02:03:14,200
HOW CLOSE IS THAT MODEL TO THE

1634
02:03:14,200 --> 02:03:14,480
STRUCTURE?

1635
02:03:14,480 --> 02:03:15,080
IT IS VERY CLOSE BUT THERE ARE

1636
02:03:15,080 --> 02:03:19,040
SOME SIGNIFICANT DIFFERENCES

1637
02:03:19,040 --> 02:03:29,560
WE TRY TO IDENTIFY THE DOMAINS

1638
02:03:30,280 --> 02:03:31,240
HE WANTS TEN FOR THAT

1639
02:03:31,240 --> 02:03:34,040
CATALYTIC SUBUNIT AND THE

1640
02:03:34,040 --> 02:03:35,960
WELL-DEFINED STRUCTURALLY AND

1641
02:03:35,960 --> 02:03:46,200
FUNCTIONALLY.

1642
02:03:47,160 --> 02:03:53,240
P-LETTER 85 ALSO HAS FIVE

1643
02:03:53,240 --> 02:04:01,360
DOMAINS.

1644
02:04:01,360 --> 02:04:09,880
WE COULD IDENTIFY ALL OF THE

1645
02:04:09,880 --> 02:04:12,120
DOMAINS.

1646
02:04:12,120 --> 02:04:17,880
BUT ONLY TWO OF THE DOMAINS OF

1647
02:04:17,880 --> 02:04:20,440
P-85 SO THAT LEFT US AT A

1648
02:04:20,440 --> 02:04:26,200
POINT, AT THE SAME POINT THEY

1649
02:04:26,200 --> 02:04:36,320
COULD NOT SEE AND WE COULD NOT

1650
02:04:36,320 --> 02:04:36,880
SEE THAT EITHER AND THAT IS

1651
02:04:36,880 --> 02:04:45,680
EXTREMELY MOBILE AND FLEXIBLE

1652
02:04:45,680 --> 02:04:46,240
SO WE DECIDED TO USE A TRICK

1653
02:04:46,240 --> 02:04:52,120
THAT IS SOMETIMES SUCCESSFUL

1654
02:04:52,120 --> 02:04:53,200
TO BIND A SMALL MOLECULE TO

1655
02:04:53,200 --> 02:05:01,160
THE PROTEIN AND TO USE THIS

1656
02:05:01,160 --> 02:05:03,680
OFFICE SPECIFIC.

1657
02:05:03,680 --> 02:05:08,280
AND ON —- ALPHA SPECIFIC TO

1658
02:05:08,280 --> 02:05:12,000
SEE THE DENSITY OF ELECTRON

1659
02:05:12,000 --> 02:05:13,160
DENSITY AND WITH THESE

1660
02:05:13,160 --> 02:05:18,840
ADDITIONAL AREAS ARE ABOUT THE

1661
02:05:18,840 --> 02:05:23,480
EXPECTED SIZE OF THE MISSING

1662
02:05:23,480 --> 02:05:27,520
DOMAINS WE COULD NOT IDENTIFY

1663
02:05:27,520 --> 02:05:29,520
THOSE BECAUSE IT WAS SIMPLY

1664
02:05:29,520 --> 02:05:33,560
TOO LOW FOR WHAT WE DID SEE

1665
02:05:33,560 --> 02:05:39,520
HOWEVER WAS ONE OF THESE SAT

1666
02:05:39,520 --> 02:05:43,280
ON THE ACTIVE SIDE AND IN THAT

1667
02:05:43,280 --> 02:05:47,200
POSITION IT WOULD PREVENT FROM

1668
02:05:47,200 --> 02:05:51,240
APPROACHING THE CELL MEMBRANE

1669
02:05:51,240 --> 02:05:55,400
AND WOULD ALSO BLOCK GETTING

1670
02:05:55,400 --> 02:05:59,120
INTO THE ACTIVE SIDE.

1671
02:05:59,120 --> 02:06:02,160
SO THAT WAS THE INHIBITORY

1672
02:06:02,160 --> 02:06:05,880
EFFECT INDUCED BY BILL 719

1673
02:06:05,880 --> 02:06:08,880
THAT IS NOMINALLY A

1674
02:06:08,880 --> 02:06:12,480
COMPETITIVE INHIBITOR AND WHAT

1675
02:06:12,480 --> 02:06:13,800
WE HAVE SEEN HERE IS THAT IN

1676
02:06:13,800 --> 02:06:16,200
ADDITION FROM THAT COMPETITION

1677
02:06:16,200 --> 02:06:20,960
IT ALSO INDUCES HAS A SEPARATE

1678
02:06:20,960 --> 02:06:25,560
CONFIRMATION ALL CHANGE BY

1679
02:06:25,560 --> 02:06:30,680
BLOCKING THE ACTIVE SIDE.

1680
02:06:30,680 --> 02:06:33,800
SO THAT MADE IT VERY IMPORTANT

1681
02:06:33,800 --> 02:06:36,880
TO IDENTIFY THE IDENTITY OF

1682
02:06:36,880 --> 02:06:41,360
THIS PARTICULAR DOMAIN.

1683
02:06:41,360 --> 02:06:41,960
IN ORDER TO DO THIS WE HAVE

1684
02:06:41,960 --> 02:06:48,000
TWO APPROACHES AND WE USED

1685
02:06:48,000 --> 02:06:55,040
CHEMICALS WITH IT WAS

1686
02:06:55,040 --> 02:06:57,560
INTERESTING BECAUSE IT'S NOT

1687
02:06:57,560 --> 02:07:00,360
THE RESULTS THAT WE WANTED

1688
02:07:00,360 --> 02:07:06,000
WITH THE DOMAINS BUT TO

1689
02:07:06,000 --> 02:07:09,640
CROSS-LINK FOLLOWED BY

1690
02:07:09,640 --> 02:07:14,320
DIGESTION IS THE NUMBER OF

1691
02:07:14,320 --> 02:07:17,760
PEPTIDES THAT ARE ESSENTIALLY

1692
02:07:17,760 --> 02:07:18,480
HYBRIDS WITH PART OF THE

1693
02:07:18,480 --> 02:07:22,040
SEQUENCE DERIVED FROM ONE

1694
02:07:22,040 --> 02:07:23,360
GROUPING AND THE OTHER FROM

1695
02:07:23,360 --> 02:07:32,320
THE OTHER PROTEIN AND TO BE ON

1696
02:07:32,320 --> 02:07:32,880
THE IDENTITY OF THE CONTACT

1697
02:07:32,880 --> 02:07:33,160
PROTEINS.

1698
02:07:33,160 --> 02:07:39,320
AND IF WE DO THIS SO LET'S

1699
02:07:39,320 --> 02:07:42,320
SKIP THIS SLIDE WE DO FIND

1700
02:07:42,320 --> 02:07:47,680
THAT SITTING ON THE ACTIVE

1701
02:07:47,680 --> 02:07:53,000
SIDE IS THE DOMAIN THAT HAS

1702
02:07:53,000 --> 02:07:56,600
NEVER BEEN KNOWN TO BE

1703
02:07:56,600 --> 02:08:00,920
INVOLVED IN THE AUTOREGULATION.

1704
02:08:00,920 --> 02:08:09,880
AND OBVIOUSLY THAT HAPPENS AS

1705
02:08:09,880 --> 02:08:10,440
A SOLID POSITION ONLY IN THE

1706
02:08:10,440 --> 02:08:14,040
PRESENCE OF AN INHIBITOR

1707
02:08:14,040 --> 02:08:14,680
KNOWINGLY ON —- NORMALLY THIS

1708
02:08:14,680 --> 02:08:20,640
DOMAIN MOVES AROUND BUT THERE

1709
02:08:20,640 --> 02:08:24,840
IS AN ADDITIONAL BLOCK AND WE

1710
02:08:24,840 --> 02:08:32,440
ALSO IDENTIFIED AS AGE THREE

1711
02:08:32,440 --> 02:08:33,320
SO NOW WE WERE ENCOURAGED BY

1712
02:08:33,320 --> 02:08:37,240
THE DATA SO NOW WE CAN

1713
02:08:37,240 --> 02:08:43,240
ACTUALLY ATTACK THE MUTANTS.

1714
02:08:43,240 --> 02:08:49,160
THEY ARE MAPPED ONTO SIDES OF

1715
02:08:49,160 --> 02:08:55,480
THE CATALYTIC SUBUNIT TO

1716
02:08:55,480 --> 02:09:00,000
MUTATIONS ONE IN THE KINDNESS

1717
02:09:00,000 --> 02:09:03,640
DOMAIN.

1718
02:09:03,640 --> 02:09:09,040
SO THESE TWO ARE COMPLETELY

1719
02:09:09,040 --> 02:09:12,240
DIFFERENT SO WE LOOK AT THIS

1720
02:09:12,240 --> 02:09:16,880
BIOLOGICAL AND GENETIC METHODS

1721
02:09:16,880 --> 02:09:20,720
AND WE CAN SEE THAT KINDNESS

1722
02:09:20,720 --> 02:09:21,720
DOMAIN MUTATION DOESN'T

1723
02:09:21,720 --> 02:09:27,560
REQUIRE BINDINGS WE CAN MUTATE

1724
02:09:27,560 --> 02:09:28,160
AND THERE'S NO DIFFERENCE IN

1725
02:09:28,160 --> 02:09:36,840
ACTIVITY BUT IT DOES NEED PAD

1726
02:09:36,840 --> 02:09:40,000
FIVE SO IS NEEDED TO RECRUIT

1727
02:09:40,000 --> 02:09:49,920
THE PROTEIN SO THOSE ARE

1728
02:09:49,920 --> 02:09:52,920
EXACTLY THE OPPOSITE.

1729
02:09:52,920 --> 02:09:58,320
THEY ARE DEPENDENT ON

1730
02:09:58,320 --> 02:10:01,360
RESPONDING AND THAT MAY

1731
02:10:01,360 --> 02:10:08,000
MEDIATE THEY DO NOT NEED THAT

1732
02:10:08,000 --> 02:10:16,760
DOMAIN AND P-85.

1733
02:10:16,760 --> 02:10:17,240
SOME OF THOSE SUFFICIENT

1734
02:10:17,240 --> 02:10:18,640
AMOUNTS OF PROTEIN WITH THAT

1735
02:10:18,640 --> 02:10:21,560
GAIN OF FUNCTION.

1736
02:10:21,560 --> 02:10:22,640
WE HAVE TO GROW THE PROTEIN IN

1737
02:10:22,640 --> 02:10:28,080
THE PRESENCE AND THEN USE BILL

1738
02:10:28,080 --> 02:10:32,680
719 TO DO THAT WITH THAT

1739
02:10:32,680 --> 02:10:36,160
NEGATIVE FEEDBACK LOOP THAT

1740
02:10:36,160 --> 02:10:38,440
HAS HIGH CONCENTRATION FOR

1741
02:10:38,440 --> 02:10:43,200
GAIN OF FUNCTION'S YOU CAN

1742
02:10:43,200 --> 02:10:48,840
NEVER PRODUCE ENOUGH SO YOU

1743
02:10:48,840 --> 02:10:51,800
ALWAYS HAVE TO HAVE AN

1744
02:10:51,800 --> 02:10:53,760
INHIBITOR.

1745
02:10:53,760 --> 02:10:57,320
THIS BECOMES IMPORTANT LATER.

1746
02:10:57,320 --> 02:11:02,040
SO IF WE LOOK AT THE KINDNESS

1747
02:11:02,040 --> 02:11:08,560
WE RECEIVE A NUMBER OF CHANGES,E

1748
02:11:08,560 --> 02:11:09,560
 CHANGES IN THE STRUCTURE OF

1749
02:11:09,560 --> 02:11:13,000
THE PROTEIN.

1750
02:11:13,000 --> 02:11:14,400
I WANT TO COMMENT ON SOME OF

1751
02:11:14,400 --> 02:11:15,440
IT.

1752
02:11:15,440 --> 02:11:22,240
THE MAIN CHANGES OCCUR AROUND

1753
02:11:22,240 --> 02:11:26,680
THE ORIGIN THAT GOES AWAY FROM

1754
02:11:26,680 --> 02:11:32,000
THE CORE OF THE ENZYME AND IT

1755
02:11:32,000 --> 02:11:40,720
ALSO ALLOWS THE KINDNESS

1756
02:11:40,720 --> 02:11:41,160
DOMAIN TO BECOME VERY

1757
02:11:41,160 --> 02:11:41,440
FLEXIBLE.

1758
02:11:41,440 --> 02:11:43,120
THAT IN TURN MENACES THE

1759
02:11:43,120 --> 02:11:46,080
LISTED BINDINGS SO THE

1760
02:11:46,080 --> 02:11:48,680
APPROACH IS ENHANCED AT THE

1761
02:11:48,680 --> 02:11:59,200
SAME TIME THE ACTIVATION LOOP

1762
02:12:01,880 --> 02:12:02,360
IS FROM WHAT IS ORIGINALLY

1763
02:12:02,360 --> 02:12:07,120
HERE AND THE ACTIVATION

1764
02:12:07,120 --> 02:12:11,800
CHANGING IS INCREASING ENZYME

1765
02:12:11,800 --> 02:12:12,080
ACTIVITY.

1766
02:12:12,080 --> 02:12:16,560
THE NEXT ITEM THAT WE SAW IS

1767
02:12:16,560 --> 02:12:19,560
THAT NOW HERE WE HAVE THE

1768
02:12:19,560 --> 02:12:29,480
PROTEIN AND BILL 1759.

1769
02:12:29,480 --> 02:12:38,480
SO THEN THIS TO THE KINDNESS

1770
02:12:38,480 --> 02:12:42,240
DOMAIN SO NOW AS THAT BECOMES

1771
02:12:42,240 --> 02:12:46,560
FLEXIBLE AGAIN WITH THE ACTIVE

1772
02:12:46,560 --> 02:12:48,760
SIDE OF THE KINDNESS DOMAIN IS

1773
02:12:48,760 --> 02:12:57,000
TOTALLY ACCESSIBLE.

1774
02:12:57,000 --> 02:12:59,040
AND HERE IS A DETAILED

1775
02:12:59,040 --> 02:13:09,520
ILLUSTRATION AND THAT BECOME

1776
02:13:09,760 --> 02:13:12,480
STREAM ON —- EXTREMELY

1777
02:13:12,480 --> 02:13:13,280
FLEXIBLE TO INTERACT WITH THE

1778
02:13:13,280 --> 02:13:23,520
CELL MEMBRANE.

1779
02:13:26,600 --> 02:13:27,000
AND THEN THAT AND WAS

1780
02:13:27,000 --> 02:13:29,600
TRANSLATED INTO FURTHER

1781
02:13:29,600 --> 02:13:34,240
CHANGES SO THOSE MULTIPLE

1782
02:13:34,240 --> 02:13:36,840
CHANGES AT ALL CAN BE

1783
02:13:36,840 --> 02:13:40,040
INTERPRETED TO THE GAIN OF

1784
02:13:40,040 --> 02:13:50,520
FUNCTION AND MY GUESS THAT ARE

1785
02:13:50,520 --> 02:13:52,880
INTRINSIC TO THE MOLECULE THE

1786
02:13:52,880 --> 02:13:57,560
INCREASE KINDNESS ACT WITH

1787
02:13:57,560 --> 02:14:04,200
IMPROVED RECRUITMENT.

1788
02:14:04,200 --> 02:14:07,040
BUT WE DON'T HAVE A UNIFIED

1789
02:14:07,040 --> 02:14:10,040
MOLECULAR MECHANISMS WE HAVE

1790
02:14:10,040 --> 02:14:15,680
CHANGES BUT WE DON'T HAVE THE

1791
02:14:15,680 --> 02:14:18,880
MECHANISM.

1792
02:14:18,880 --> 02:14:23,320
SO NOW LET'S SWITCH.

1793
02:14:23,320 --> 02:14:31,680
THERE IS A BIG SURPRISE SO THE

1794
02:14:31,680 --> 02:14:37,200
REGULATORY SUBUNIT AND THE ABD

1795
02:14:37,200 --> 02:14:40,680
SO THAT BRINGS THE QUESTION

1796
02:14:40,680 --> 02:14:43,240
ARE THEY STILL LINKED OR

1797
02:14:43,240 --> 02:14:49,240
COMPLETELY DISASSOCIATED WITH

1798
02:14:49,240 --> 02:14:52,200
THIS REGULATORY AND CATALYTIC

1799
02:14:52,200 --> 02:14:58,920
SUBUNIT AND THE ANSWER IS YES

1800
02:14:58,920 --> 02:15:07,000
THEY ARE.

1801
02:15:07,000 --> 02:15:08,120
AND YOU CAN SHOW THAT THEY ARE

1802
02:15:08,120 --> 02:15:14,480
TOGETHER SO THAT LINK BETWEEN

1803
02:15:14,480 --> 02:15:18,600
THE ABD IS NOT DISRUPTIVE.

1804
02:15:18,600 --> 02:15:21,600
BUT THE ABD BECOMES VERY

1805
02:15:21,600 --> 02:15:24,120
FLEXIBLE AND THAT FLEXIBILITY

1806
02:15:24,120 --> 02:15:33,560
IS INCREASED WITHIN P-85.

1807
02:15:33,560 --> 02:15:38,880
SO WE HAVE HERE A MECHANISM

1808
02:15:38,880 --> 02:15:41,400
THAT IS PART OF THE MOLECULE

1809
02:15:41,400 --> 02:15:46,600
AND TO BE DISENGAGED FROM

1810
02:15:46,600 --> 02:15:49,760
INTERACTION AND IN DETAIL THAT

1811
02:15:49,760 --> 02:15:54,680
DISENGAGEMENT IS TRIGGERED BY

1812
02:15:54,680 --> 02:16:03,320
THE MUTATION THAT DISRUPTS SO

1813
02:16:03,320 --> 02:16:08,680
WITH THAT DOMAIN AND THE

1814
02:16:08,680 --> 02:16:13,600
DISRUPTION DATES TO THE

1815
02:16:13,600 --> 02:16:17,600
DISENGAGEMENT.

1816
02:16:17,600 --> 02:16:18,200
ESSENTIALLY THIS IS ALL I WANT

1817
02:16:18,200 --> 02:16:20,680
TO SAY ABOUT THE EXPERIMENTAL

1818
02:16:20,680 --> 02:16:21,600
RESULTS.

1819
02:16:21,600 --> 02:16:22,080
IT IS CLEAR WE HAVE VERY

1820
02:16:22,080 --> 02:16:28,920
DETAILED INFORMATION WITH THE

1821
02:16:28,920 --> 02:16:31,840
STRUCTURAL DIFFERENCES BETWEEN

1822
02:16:31,840 --> 02:16:40,760
MUTANT.

1823
02:16:40,760 --> 02:16:43,800
SO WE LIKE TO COME BACK TO THE

1824
02:16:43,800 --> 02:16:48,600
QUESTION SO WE HAVE SHOWN THAT

1825
02:16:48,600 --> 02:16:59,080
INHIBITOR BY ITSELF SO THAT IS

1826
02:17:02,200 --> 02:17:07,920
DUE TO THE INHIBITOR TO GROW

1827
02:17:07,920 --> 02:17:10,600
THE MUTANT DOOR IS THAT TO THE

1828
02:17:10,600 --> 02:17:12,640
ORIENTATION?

1829
02:17:12,640 --> 02:17:14,160
AND THE BEST ANSWER WE CAN

1830
02:17:14,160 --> 02:17:18,160
GIVE IS WHEN WE DEFINE MUTANT

1831
02:17:18,160 --> 02:17:21,600
SPECIFIC DIFFERENCES USING

1832
02:17:21,600 --> 02:17:26,440
THAT AS A STANDARD BUT THE

1833
02:17:26,440 --> 02:17:31,520
PRESENCE OF THE INHIBITOR IS A

1834
02:17:31,520 --> 02:17:32,080
POSSIBLE COMPLICATING FACTOR

1835
02:17:32,080 --> 02:17:37,880
AND THEN THE NEXT STEP IS A

1836
02:17:37,880 --> 02:17:45,120
CHANGE OR IMPROVEMENT IN THE

1837
02:17:45,120 --> 02:17:50,240
ABSENCE.

1838
02:17:50,240 --> 02:18:00,480
SO ALREADY PHARMA AND STARTUPS

1839
02:18:00,480 --> 02:18:02,640
ARE STARTING TO MAKE MUTANT

1840
02:18:02,640 --> 02:18:06,520
SPECIFIC INHIBITORS WITH SOME

1841
02:18:06,520 --> 02:18:07,120
FOR SUCCESS BUT NONE OF THESE

1842
02:18:07,120 --> 02:18:11,240
CLAIMS HAVE BEEN SUBSTANTIATED

1843
02:18:11,240 --> 02:18:11,840
SO IT IS IMPORTANT TO LOOK IN

1844
02:18:11,840 --> 02:18:15,680
THE NEAR FUTURE TO HAVE SOUND

1845
02:18:15,680 --> 02:18:19,640
INHIBITORS BUT HERE ARE THE

1846
02:18:19,640 --> 02:18:22,440
PEOPLE WHO HAVE DONE THEIR

1847
02:18:22,440 --> 02:18:26,120
WORK SO THOSE DEVELOPING THAT

1848
02:18:26,120 --> 02:18:35,520
PURIFICATION PROCEDURE AND

1849
02:18:35,520 --> 02:18:36,120
THEN TAUGHT THAT PROCEDURE TO

1850
02:18:36,120 --> 02:18:46,240
THE COLLABORATORS IN SHANGHAI.

1851
02:18:46,240 --> 02:18:46,840
SO MOST OF THAT COMPUTATIONAL

1852
02:18:46,840 --> 02:18:52,280
WORK THAT IS NECESSARY AND TO

1853
02:18:52,280 --> 02:18:56,760
INTERPRET THE RAW DATA WITH

1854
02:18:56,760 --> 02:19:00,440
THE TEAM IN SHANGHAI INCLUDES

1855
02:19:00,440 --> 02:19:06,280
A GRADUATE STUDENT AND THEN

1856
02:19:06,280 --> 02:19:15,760
THE YOUNG SCIENTISTS TO SEND A

1857
02:19:15,760 --> 02:19:20,520
STATA AND THEN THAT PERSONAL

1858
02:19:20,520 --> 02:19:25,520
ACTION WITH HIM HE IS

1859
02:19:25,520 --> 02:19:28,480
EXTREMELY BRIGHT AND VERY

1860
02:19:28,480 --> 02:19:29,080
DEDICATED.

1861
02:19:29,080 --> 02:19:32,000
WE HAVE A VERY GOOD

1862
02:19:32,000 --> 02:19:35,600
RELATIONSHIP.

1863
02:19:35,600 --> 02:19:38,680
AND THEN WITH THE HEAD OF THE

1864
02:19:38,680 --> 02:19:41,080
INSTITUTE.

1865
02:19:41,080 --> 02:19:46,040
AND JAPAN DID MUCH.

1866
02:19:46,040 --> 02:19:50,120
SO WITH THIS I WOULD LIKE TO

1867
02:19:50,120 --> 02:19:54,040
AND AND BY ENDING AND WANT TO

1868
02:19:54,040 --> 02:19:56,920
WISH STEVE A WONDERFUL AND

1869
02:19:56,920 --> 02:19:58,080
SUNNY RETIREMENT.

1870
02:19:58,080 --> 02:20:08,560
THANK YOU I CANNOT HEAR YOU.

1871
02:20:38,160 --> 02:20:38,600
I THINK SOMEHOW WE ARE CUT

1872
02:20:38,600 --> 02:20:38,760
OFF.

1873
02:20:38,760 --> 02:20:44,120
I CANNOT HEAR.

1874
02:20:44,120 --> 02:20:54,440
I WILL STOP SHARE.

1875
02:21:04,320 --> 02:21:08,080
>>WE CAN STILL HEAR YOU

1876
02:21:08,080 --> 02:21:11,560
ONLINE.

1877
02:21:11,560 --> 02:21:16,600
>>WE CANNOT HEAR ERIC.

1878
02:21:16,600 --> 02:21:17,080
THE MICROPHONE AT THE

1879
02:21:17,080 --> 02:21:26,760
AUDITORIUM IS NOT WORKING.

1880
02:21:26,760 --> 02:21:37,200
[INAUDIBLE CONVERSATIONS]

1881
02:22:26,240 --> 02:22:36,600
IT IS REMARKABLY QUIET.

1882
02:22:40,680 --> 02:22:41,080
APPARENTLY THERE IS A

1883
02:22:41,080 --> 02:22:41,600
MICROPHONE IN THE AUDIENCE

1884
02:22:41,600 --> 02:22:42,200
THAT IS MUTED AND IT NEEDS TO

1885
02:22:42,200 --> 02:22:52,560
BE TURNED ON AGAIN.

1886
02:23:02,520 --> 02:23:05,440
>>YOU DID A WONDERFUL
TALK.

1887
02:23:05,440 --> 02:23:09,680
I JUST THINK IT IS ODD THAT A

1888
02:23:09,680 --> 02:23:15,080
SYMPOSIUM IN DOCTOR HUGHES

1889
02:23:15,080 --> 02:23:15,640
HONOR IS KEPT INTENTIONALLY

1890
02:23:15,640 --> 02:23:17,200
SILENT FOR SO LONG.

1891
02:23:17,200 --> 02:23:19,000
[LAUGHTER]

1892
02:23:19,000 --> 02:23:19,600
SOMEHOW THAT SEEMS MAYBE THAT

1893
02:23:19,600 --> 02:23:29,800
WAS PLANNED.

1894
02:23:29,800 --> 02:23:30,080
>>HI PETER.

1895
02:23:30,080 --> 02:23:33,760
CAN YOU HEAR ME?

1896
02:23:33,760 --> 02:23:41,240
HOW MANY MUTATIONS ARE THERE

1897
02:23:41,240 --> 02:23:41,760
IF YOU WERE GOING TO MAKE

1898
02:23:41,760 --> 02:23:44,440
INHIBITORS TO SEPARATE

1899
02:23:44,440 --> 02:23:47,480
MUTATIONS?

1900
02:23:47,480 --> 02:23:53,040
>>ACTUALLY THAT ACCOUNTS
FOR

1901
02:23:53,040 --> 02:23:55,080
80 PERCENT SO WITH THE

1902
02:23:55,080 --> 02:23:59,960
INHIBITORS AND ACTUALLY THERE

1903
02:23:59,960 --> 02:24:03,160
IS ONE INHIBITOR THAT EXPOSE

1904
02:24:03,160 --> 02:24:06,360
THE MUTATIONS THAT IT IS A

1905
02:24:06,360 --> 02:24:09,240
LITTLE HARD TO BELIEVE BECAUSE

1906
02:24:09,240 --> 02:24:12,960
THOSE ALSO STRUCTURALLY ARE

1907
02:24:12,960 --> 02:24:15,720
VERY DIFFERENT.

1908
02:24:15,720 --> 02:24:21,240
BUT ANYWAY IF YOU MAKE THE

1909
02:24:21,240 --> 02:24:27,080
INHIBITOR AND WITH 80 PERCENT

1910
02:24:27,080 --> 02:24:37,360
OF THE PATIENTS.

1911
02:24:44,360 --> 02:24:54,520
>>THANK YOU.

1912
02:25:00,640 --> 02:25:01,160
>>THEY ARE SILENT AGAIN
BUT

1913
02:25:01,160 --> 02:25:01,720
TO FOLLOW UP ON THAT WHAT IS

1914
02:25:01,720 --> 02:25:03,760
THE LIKELIHOOD TO SELECTIVELY

1915
02:25:03,760 --> 02:25:04,880
TARGET THOSE DOMAINS?

1916
02:25:04,880 --> 02:25:06,720
IT SEEMS LIKE THAT IS

1917
02:25:06,720 --> 02:25:09,080
CHALLENGING.

1918
02:25:09,080 --> 02:25:12,400
>>THERE ARE ACTUALLY
QUITE A

1919
02:25:12,400 --> 02:25:21,960
FEW STRUCTURES AND WITH THOSE

1920
02:25:21,960 --> 02:25:24,800
FIGURES.

1921
02:25:24,800 --> 02:25:25,400
>>IT SOUNDS LIKE WE HAVE
THE

1922
02:25:25,400 --> 02:25:32,120
AUDITORIUM BACK.

1923
02:25:32,120 --> 02:25:32,720
>>IT SHOULD BE POSSIBLE
TO

1924
02:25:32,720 --> 02:25:35,840
MAKE THE INHIBITOR.

1925
02:25:35,840 --> 02:25:43,920
>>THANK YOU.

1926
02:25:43,920 --> 02:25:54,160
>>THANK YOU.

1927
02:25:57,000 --> 02:26:06,840
>>'S OVER THE PAST 36
YEARS

1928
02:26:06,840 --> 02:26:07,320
WANT TO REFLECT ON THE

1929
02:26:07,320 --> 02:26:07,760
ADVENTURES WE HAVE HAD

1930
02:26:07,760 --> 02:26:08,040
TOGETHER.

1931
02:26:08,040 --> 02:26:10,840
BUT BASICALLY WE HAVE BEEN

1932
02:26:10,840 --> 02:26:13,720
ABLE TO LEVERAGE BASIC

1933
02:26:13,720 --> 02:26:17,280
RESEARCH INTO HELP TO CREATE

1934
02:26:17,280 --> 02:26:20,480
SOME OF THE DRUGS FOR TREATING

1935
02:26:20,480 --> 02:26:25,520
HIV INFECTION.

1936
02:26:25,520 --> 02:26:30,560
I HAPPEN TO HAVE GREAT FORTUNE

1937
02:26:30,560 --> 02:26:34,520
WORKING IN BOSTON AS A POSTDOC

1938
02:26:34,520 --> 02:26:37,720
THIS WAS IN THE MID- EIGHTIES

1939
02:26:37,720 --> 02:26:39,480
AND THIS LED TO SO MANY

1940
02:26:39,480 --> 02:26:44,200
INSIGHTS ABOUT VIRUSES HOW

1941
02:26:44,200 --> 02:26:46,800
THEY WORK AND FUNCTION AND

1942
02:26:46,800 --> 02:26:48,840
ASSEMBLE.

1943
02:26:48,840 --> 02:26:57,000
AND WHEN HIV WAS ALL IN THE

1944
02:26:57,000 --> 02:27:01,920
NEWS AND THEN TO HAVE A DEAF

1945
02:27:01,920 --> 02:27:02,520
SENTENCE AND CLEARLY SOMETHING

1946
02:27:02,520 --> 02:27:07,520
NEEDED TO BE DONE I WAS VERY

1947
02:27:07,520 --> 02:27:14,960
COMMITTED TO USE MY SKILLS

1948
02:27:14,960 --> 02:27:15,520
WITH THAT DESIGNED TO HELP

1949
02:27:15,520 --> 02:27:22,560
FIND A SOLUTION AND I MET

1950
02:27:22,560 --> 02:27:24,520
STEVE AT A VERY FORTUNATE TIME

1951
02:27:24,520 --> 02:27:28,920
HE WAS ALREADY EXTREME —-

1952
02:27:28,920 --> 02:27:31,680
EXCEEDINGLY TALENTED NATURAL

1953
02:27:31,680 --> 02:27:38,320
VIROLOGIST WITH SUCH WONDERFUL

1954
02:27:38,320 --> 02:27:38,680
ORIGINS.

1955
02:27:38,680 --> 02:27:44,520
AND HE HAD MUCH THE SAME

1956
02:27:44,520 --> 02:27:45,400
PASSION AS I DID.

1957
02:27:45,400 --> 02:27:54,800
WE MET INITIALLY WITH THAT

1958
02:27:54,800 --> 02:27:56,640
INFRASTRUCTURE OF THE

1959
02:27:56,640 --> 02:28:07,280
RHINOVIRUS 14 AND THEY ALSO ON

1960
02:28:07,280 --> 02:28:10,040
THE VISIT WITH STEVE HUGHES SO

1961
02:28:10,040 --> 02:28:13,360
WE TALK ABOUT THINGS WITH

1962
02:28:13,360 --> 02:28:16,960
RETROVIRUS AND EXPRESSION SO

1963
02:28:16,960 --> 02:28:18,920
THAT WAS BEYOND MY TIME SO

1964
02:28:18,920 --> 02:28:24,520
IT'S VERY PASSIONATE TO BE

1965
02:28:24,520 --> 02:28:32,280
EXTREMELY TALENTED SO THAT THE

1966
02:28:32,280 --> 02:28:40,600
RETREAT IN THE MOUNTAINS SO

1967
02:28:40,600 --> 02:28:47,040
THAT WAS A FUN TIME AND THAT

1968
02:28:47,040 --> 02:28:52,520
STEVE SAID THEY HAD JUST

1969
02:28:52,520 --> 02:29:01,080
SUCCESSFULLY EXPRESSED.

1970
02:29:01,080 --> 02:29:01,600
AND I SAID WAIT I REALLY

1971
02:29:01,600 --> 02:29:06,640
WANTED TO WORK ON THESE

1972
02:29:06,640 --> 02:29:07,200
PROTEINS AND THIS IS EXACTLY

1973
02:29:07,200 --> 02:29:09,480
HOW I WANT TO GET MY LAB

1974
02:29:09,480 --> 02:29:09,720
STARTED.

1975
02:29:09,720 --> 02:29:15,400
I DIDN'T HAVE A JOB YET BUT

1976
02:29:15,400 --> 02:29:19,720
FOR THE TENURE-TRACK POSITIONS

1977
02:29:19,720 --> 02:29:23,680
BECAUSE OF THIS COLLABORATION

1978
02:29:23,680 --> 02:29:25,960
AND FORTUNATELY I MOVED TO

1979
02:29:25,960 --> 02:29:35,240
WHERE I COULD IMMEDIATELY IN

1980
02:29:35,240 --> 02:29:36,400
FACT DROVE TO THE VERY FIRST

1981
02:29:36,400 --> 02:29:40,760
WEEKEND AFTER ARRIVING AND

1982
02:29:40,760 --> 02:29:48,520
THEN TO MAKE MESSES THAT THIS

1983
02:29:48,520 --> 02:29:54,120
WAS A VERY CHARGED BEGINNING

1984
02:29:54,120 --> 02:29:57,200
BUT THEN THERE WERE SOME DARK

1985
02:29:57,200 --> 02:29:59,600
YEARS WE SPENT TIME AND MONEY

1986
02:29:59,600 --> 02:30:03,880
TRYING TO GET CRYSTALS AND

1987
02:30:03,880 --> 02:30:13,080
SPENT FOUR YEARS WE ENDED UP

1988
02:30:13,080 --> 02:30:17,040
WE TRIED DNA.

1989
02:30:17,040 --> 02:30:20,280
WE TRIED TO WORK WITH P60 SIX

1990
02:30:20,280 --> 02:30:27,640
TO AVOID THE COMPLEXITIES BUT

1991
02:30:27,640 --> 02:30:28,720
AFTER A YEAR AND A HALF OF THE

1992
02:30:28,720 --> 02:30:32,280
CRYSTALS GROWING THE ONLY ONES

1993
02:30:32,280 --> 02:30:38,760
THAT DIFFRACTED AT ALL THIS

1994
02:30:38,760 --> 02:30:46,680
WAS IN 1989 AND WE WERE

1995
02:30:46,680 --> 02:30:47,680
WORKING WITH THE HETERO SO

1996
02:30:47,680 --> 02:30:53,040
DURING THIS ENTIRE PERIOD THE

1997
02:30:53,040 --> 02:30:54,000
PROTEIN WAS PRODUCED IN

1998
02:30:54,000 --> 02:31:03,440
STEVE'S LAB AND ALSO VERY

1999
02:31:03,440 --> 02:31:09,640
INVOLVED IN THIS AND IN TERMS

2000
02:31:09,640 --> 02:31:12,960
THAT A LOT OF THE GROUNDWORK

2001
02:31:12,960 --> 02:31:15,040
HAD BEEN MADE FOR THE

2002
02:31:15,040 --> 02:31:19,520
RETROVIRUS SOME OF THE FIGURES

2003
02:31:19,520 --> 02:31:23,320
HERE IT WAS A THERAPEUTIC

2004
02:31:23,320 --> 02:31:27,480
TOPIC STUDYING BASIC

2005
02:31:27,480 --> 02:31:32,280
BIOCHEMISTRY LIKE A GREAT

2006
02:31:32,280 --> 02:31:41,760
BASIS AND NERVOUS OF THE

2007
02:31:41,760 --> 02:31:45,440
COMPLEXITY AND WE WILL JUST GO

2008
02:31:45,440 --> 02:31:50,560
GET IT.

2009
02:31:50,560 --> 02:31:53,600
BUT NOT UNTIL 1992 THAT WE

2010
02:31:53,600 --> 02:32:02,680
START THIS WAS 180 WITH THAT

2011
02:32:02,680 --> 02:32:11,040
PART STRUCTURE AND IT WAS ONLY

2012
02:32:11,040 --> 02:32:11,640
PART OF IT BUT NATURE TOOK IT

2013
02:32:11,640 --> 02:32:13,320
BECAUSE IT DID NOT KNOW.

2014
02:32:13,320 --> 02:32:21,640
[LAUGHTER]

2015
02:32:21,640 --> 02:32:29,640
BUT THEN TO USE THAT AS A

2016
02:32:29,640 --> 02:32:34,080
YARDSTICK.

2017
02:32:34,080 --> 02:32:37,480
SORRY FOR ACTUALLY FIGURING

2018
02:32:37,480 --> 02:32:43,080
OUT AT THE SAME TIME WE HAVE

2019
02:32:43,080 --> 02:32:47,600
MUCH BETTER RESOLUTION DATA

2020
02:32:47,600 --> 02:32:48,640
BUT THIS WAS AFTER FOR A VERY

2021
02:32:48,640 --> 02:32:55,600
DARK YEARS AND THEY WERE

2022
02:32:55,600 --> 02:32:56,520
WORKING AND THREE OR FOUR HAD

2023
02:32:56,520 --> 02:33:03,360
THE SOLUTIONS BUT THIS WAS TOO

2024
02:33:03,360 --> 02:33:06,240
IMPORTANT.

2025
02:33:06,240 --> 02:33:08,920
SO ANYWAY WE SUCCEEDED TO HAVE

2026
02:33:08,920 --> 02:33:16,720
THE FULL STRUCTURE AND THAT

2027
02:33:16,720 --> 02:33:21,000
WAS PHENOMENAL.

2028
02:33:21,000 --> 02:33:23,000
THIS WAS FOLLOWING A

2029
02:33:23,000 --> 02:33:29,360
PUBLICATION WITH THE INHIBITOR

2030
02:33:29,360 --> 02:33:35,000
THAT THEY COULD DESCRIBE THE

2031
02:33:35,000 --> 02:33:35,480
STRUCTURE WITH COMPLETE

2032
02:33:35,480 --> 02:33:39,720
SIDECHAINS AND OF COURSE THIS

2033
02:33:39,720 --> 02:33:40,280
IS THE FIRST STRUCTURE WITH

2034
02:33:40,280 --> 02:33:44,320
ANY NUCLEIC FOUND ONE —- BOUND

2035
02:33:44,320 --> 02:33:47,640
SO BE LEARNED HOW THE RACES

2036
02:33:47,640 --> 02:33:58,160
WORK AND HOW TO ENGAGE IT WAS

2037
02:33:58,680 --> 02:34:01,040
VERY INFORMATIVE.

2038
02:34:01,040 --> 02:34:03,400
AND BRIEFLY WITH THAT AND

2039
02:34:03,400 --> 02:34:05,320
RANGE ON —- WITH THAT

2040
02:34:05,320 --> 02:34:15,840
ARRANGEMENT IT WAS P6 SIX ONLY

2041
02:34:16,080 --> 02:34:21,240
BUT THOSE STRUCTURES VERY

2042
02:34:21,240 --> 02:34:24,280
BEAUTIFUL INCLUDING THE RIGHT

2043
02:34:24,280 --> 02:34:27,520
HAND ARRANGEMENT THAT IS THE

2044
02:34:27,520 --> 02:34:31,600
MOST IMPORTANT PART BECAUSE

2045
02:34:31,600 --> 02:34:35,640
THAT IS THE CATALYTIC

2046
02:34:35,640 --> 02:34:40,320
INCORPORATION A BEAUTIFUL

2047
02:34:40,320 --> 02:34:41,440
ASPECT OF THOSE STRUCTURES

2048
02:34:41,440 --> 02:34:45,320
THAT WE PROCEEDED TO OBTAIN

2049
02:34:45,320 --> 02:34:45,920
ALSO IN COLLABORATION WITH THE

2050
02:34:45,920 --> 02:34:56,440
REST OF THE WORLD BY THAT TIME

2051
02:34:59,560 --> 02:35:00,000
AND THEN WE CAN GET IN

2052
02:35:00,000 --> 02:35:01,480
UNDERSTANDING OF THAT

2053
02:35:01,480 --> 02:35:04,920
MECHANISM AT THE ATOMIC LEVEL

2054
02:35:04,920 --> 02:35:09,000
AND PART OF WHAT WAS INVOLVED

2055
02:35:09,000 --> 02:35:17,840
WITH MASSIVE CHANGES IN THOSE

2056
02:35:17,840 --> 02:35:18,800
ARE THE MANY DIFFERENT TYPES

2057
02:35:18,800 --> 02:35:25,480
OF CRYSTALS IT HAS ALLOWED US

2058
02:35:25,480 --> 02:35:26,360
TO HAVE MANY DIFFERENT

2059
02:35:26,360 --> 02:35:33,120
INSIGHTS IT IS VERY SIMILAR

2060
02:35:33,120 --> 02:35:36,160
WITH A TWO DECADE EARLIER

2061
02:35:36,160 --> 02:35:44,600
LEVEL BUT THIS ALSO ESPECIALLY

2062
02:35:44,600 --> 02:35:47,520
ALLOWED US TO DESCRIBE ANY

2063
02:35:47,520 --> 02:35:53,080
FUNCTIONAL SPACE THAT WAS

2064
02:35:53,080 --> 02:35:57,040
ELUSIVE SUCH OF THE STRUCTURE

2065
02:35:57,040 --> 02:36:04,400
WITH THE INHIBITORS THAT TOOK

2066
02:36:04,400 --> 02:36:04,880
US TWO DECADES TO GET.

2067
02:36:04,880 --> 02:36:07,400
PEOPLE THOUGHT WE WERE LAZY OR

2068
02:36:07,400 --> 02:36:17,560
STUPID.

2069
02:36:20,120 --> 02:36:20,520
AT THIS POINT IN YOUR

2070
02:36:20,520 --> 02:36:23,120
ATTENTION WITH THE GOLD

2071
02:36:23,120 --> 02:36:33,560
MARBLES AND I ALSO WANT TO

2072
02:36:37,320 --> 02:36:37,720
POINT OUT SOME OF THIS

2073
02:36:37,720 --> 02:36:38,200
ESSENTIAL ASPECTS OF THE

2074
02:36:38,200 --> 02:36:48,680
CATALYTIC MECHANISM AND WITH

2075
02:36:49,560 --> 02:36:52,480
THAT ACID RESIDUE AND THEN

2076
02:36:52,480 --> 02:36:59,120
THAT INCOMING INCORPORATES AND

2077
02:36:59,120 --> 02:37:06,080
THAT WAS CATALYZED.

2078
02:37:06,080 --> 02:37:13,120
AS YOU SEE THE CHEMISTRY

2079
02:37:13,120 --> 02:37:14,760
OCCURS.

2080
02:37:14,760 --> 02:37:25,120
WITH THE LOSS WITH THE

2081
02:37:27,240 --> 02:37:30,120
PHOSPHATE AND THEN ONCE GETS

2082
02:37:30,120 --> 02:37:30,560
THAT TRANSLOCATION.

2083
02:37:30,560 --> 02:37:40,920
SO THIS IS RELEVANT.

2084
02:37:42,720 --> 02:37:46,520
SO STEVE AND I WERE VERY

2085
02:37:46,520 --> 02:37:48,360
INTERESTED TO TRY TO USE THIS

2086
02:37:48,360 --> 02:37:51,040
INFORMATION TO ACCELERATE THE

2087
02:37:51,040 --> 02:38:01,480
PROCESS OF DRUG DISCOVERY.

2088
02:38:02,880 --> 02:38:03,840
TO INCORPORATE EMPLOYEES IN

2089
02:38:03,840 --> 02:38:06,720
THE PROCESS BUT THEN VERY MUCH

2090
02:38:06,720 --> 02:38:17,240
LIKE THE NORMAL SUBSTRATE AND

2091
02:38:19,520 --> 02:38:20,200
WE WILL TELL YOU MORE ABOUT

2092
02:38:20,200 --> 02:38:21,320
THEM BUT THERE ARE SIX THAT

2093
02:38:21,320 --> 02:38:25,520
ARE FDA APPROVED GOING INTO A

2094
02:38:25,520 --> 02:38:33,360
HYDROPHOBIC POCKET.

2095
02:38:33,360 --> 02:38:43,280
AND THOSE THAT WERE APPROVED

2096
02:38:43,280 --> 02:38:46,920
AND THAT NONE INHIBITORS

2097
02:38:46,920 --> 02:38:57,360
ESPECIALLY SO ONE OF THE

2098
02:38:58,560 --> 02:38:59,000
THINGS THAT STEVE AND I

2099
02:38:59,000 --> 02:38:59,560
ENTERED THE PROJECT WITH IS

2100
02:38:59,560 --> 02:39:04,800
THE APPRECIATION THAT THE

2101
02:39:04,800 --> 02:39:05,360
DRUGS COULD BREAK DUE TO

2102
02:39:05,360 --> 02:39:11,240
RESISTANCE SO WE ANTICIPATED

2103
02:39:11,240 --> 02:39:11,840
IT WOULD BE A MAJOR PROBLEM

2104
02:39:11,840 --> 02:39:14,120
FOR A REVERSE TRANSCRIPTION.

2105
02:39:14,120 --> 02:39:16,960
IT WAS RELATIVELY CONSERVED

2106
02:39:16,960 --> 02:39:21,120
TARGET SO WE SOLVE THE

2107
02:39:21,120 --> 02:39:24,040
STRUCTURES OF ALL THE DRUG

2108
02:39:24,040 --> 02:39:34,600
RESISTANCE IS ONE —- MUTANTS

2109
02:39:36,200 --> 02:39:41,760
AND IF YOU WANT TO DEFEAT THAT

2110
02:39:41,760 --> 02:39:42,360
SO TO DETERMINE THE MECHANISM

2111
02:39:42,360 --> 02:39:51,920
OF INNOVATION MOST OF THOSE

2112
02:39:51,920 --> 02:40:02,440
ARE FAIRLY STRAIGHTFORWARD BUT

2113
02:40:02,840 --> 02:40:11,600
IN THE CASE OF THE NUCLEUS BUT

2114
02:40:11,600 --> 02:40:14,600
NOT JUST AT THE ACTIVE SITE

2115
02:40:14,600 --> 02:40:21,240
BUT AND TO HAVE THAT MECHANISM

2116
02:40:21,240 --> 02:40:29,720
OF RESISTANCE AND WITH THAT

2117
02:40:29,720 --> 02:40:39,160
ENHANCED ABILITY AND THAT

2118
02:40:39,160 --> 02:40:42,080
COULD OCCUR EITHER THROUGH

2119
02:40:42,080 --> 02:40:51,200
EXCLUSION BUT IN ONE OF THE

2120
02:40:51,200 --> 02:40:53,000
PAPERS THAT WE PUBLISH

2121
02:40:53,000 --> 02:40:57,640
TOGETHER IN 1989 SO THERE'S

2122
02:40:57,640 --> 02:41:05,400
RESISTANCE MOST SITES HAVE GO

2123
02:41:05,400 --> 02:41:12,760
BELOW THE LINE BUT THEN WITH

2124
02:41:12,760 --> 02:41:21,920
OPPOSITE STEREOCHEMISTRY.

2125
02:41:21,920 --> 02:41:27,320
AND THEN WITH THAT CASE THAT

2126
02:41:27,320 --> 02:41:30,520
WAS ACTUALLY THE EXACT SAME

2127
02:41:30,520 --> 02:41:32,800
PLACE WHERE IT WOULD BE

2128
02:41:32,800 --> 02:41:39,440
LOCATED EXPLAINING WHY TO HAVE

2129
02:41:39,440 --> 02:41:47,560
GREATER RESISTANCE SO IN TERMS

2130
02:41:47,560 --> 02:41:50,440
OF ONE OF THE MOST FASCINATING

2131
02:41:50,440 --> 02:41:59,320
ASPECTS WE ARE HOPING THAT

2132
02:41:59,320 --> 02:41:59,920
WALTER SCOTT WAS INVESTIGATING

2133
02:41:59,920 --> 02:42:05,880
THE POSSIBILITY THAT IT WOULD

2134
02:42:05,880 --> 02:42:09,280
ACTUALLY EXERCISE AFTER

2135
02:42:09,280 --> 02:42:11,680
INCORPORATED AND THEN TO

2136
02:42:11,680 --> 02:42:15,440
UNDERSTAND THE MUTATIONS THAT

2137
02:42:15,440 --> 02:42:25,960
WERE ADDED DISTANCE AND TO SEE

2138
02:42:29,040 --> 02:42:31,960
THAT AROMATIC RING CAN STACK

2139
02:42:31,960 --> 02:42:34,920
WITH THE MOLECULE AND THE

2140
02:42:34,920 --> 02:42:37,280
ENHANCED BONDING WITH THAT

2141
02:42:37,280 --> 02:42:44,960
SOCIAL MECHANISM.

2142
02:42:44,960 --> 02:42:45,560
SO WHAT THEY WILL SHOW YOU IN

2143
02:42:45,560 --> 02:42:46,480
THIS DIAGRAM IS BASICALLY WHAT

2144
02:42:46,480 --> 02:42:51,680
IS HAPPENING AND THAT

2145
02:42:51,680 --> 02:42:58,760
PHOSPHATE AND THEN IT ATTACHES

2146
02:42:58,760 --> 02:42:59,440
TO THE PEACE SITE BECAUSE THAT

2147
02:42:59,440 --> 02:43:07,880
IS AVAILABLE AND THEN THAT CAN

2148
02:43:07,880 --> 02:43:09,760
OCCUR FOLLOWED BY

2149
02:43:09,760 --> 02:43:15,120
TRANSLOCATION YOU CAN ACTUALLY

2150
02:43:15,120 --> 02:43:19,760
HAVE ONE WAY OF REDUCING THAT

2151
02:43:19,760 --> 02:43:25,440
EXTENSION AND ANOTHER CAN

2152
02:43:25,440 --> 02:43:27,400
OCCUR.

2153
02:43:27,400 --> 02:43:37,920
AND THE OTHER IS IN THIS CASE

2154
02:43:40,680 --> 02:43:51,120
SO WITH THAT PETRO PHOSPHATE

2155
02:43:57,880 --> 02:43:58,400
SO WE HAVE DETERMINED THIS IS

2156
02:43:58,400 --> 02:44:01,800
EXCISED BY THE ATTACHMENT AND

2157
02:44:01,800 --> 02:44:12,240
THAT SUCH AS THE CLOSING AND

2158
02:44:17,000 --> 02:44:23,760
THEN WITH THOSE MUTATIONS TO

2159
02:44:23,760 --> 02:44:24,320
PROMOTE THAT PROCESS AND TO

2160
02:44:24,320 --> 02:44:34,720
BACK UP THE MECHANISM.

2161
02:44:36,040 --> 02:44:36,280
[INAUDIBLE]

2162
02:44:36,280 --> 02:44:40,800
BUT THEN THEY SHOWED EXACTLY

2163
02:44:40,800 --> 02:44:49,880
HOW THAT AND THEN TO STABILIZE

2164
02:44:49,880 --> 02:44:56,760
THE BINDING.

2165
02:44:56,760 --> 02:45:00,120
AND HOW WE COULD LEVERAGE THE

2166
02:45:00,120 --> 02:45:05,160
WORK AND WITH THAT HIV

2167
02:45:05,160 --> 02:45:08,200
INFECTIONS SO WHILE STEVE AND

2168
02:45:08,200 --> 02:45:14,680
I WERE SCHEMING IT WAS UP TO

2169
02:45:14,680 --> 02:45:19,600
PAUL JANSEN IN BELGIUM AND HE

2170
02:45:19,600 --> 02:45:25,880
BEGAN THE SEARCH OF THE

2171
02:45:25,880 --> 02:45:27,480
COMPOUNDS OF THE NON-

2172
02:45:27,480 --> 02:45:32,800
NUCLEOSIDE INHIBITORS.

2173
02:45:32,800 --> 02:45:35,960
SO WE BEGAN CRYSTALLIZATION

2174
02:45:35,960 --> 02:45:39,000
AND PROTEIN THAT STEVE WAS

2175
02:45:39,000 --> 02:45:40,600
PRODUCING AND IN 1890 DOCTOR

2176
02:45:40,600 --> 02:45:45,600
PAUL PUBLISHED A PAPER AND

2177
02:45:45,600 --> 02:45:55,400
WITH THE TIVO COMPOUNDS WITH A

2178
02:45:55,400 --> 02:46:02,120
TWO PAGE PROPOSAL AND SO WHAT

2179
02:46:02,120 --> 02:46:05,360
ARE THE POSSIBILITIES THAT WE

2180
02:46:05,360 --> 02:46:06,280
DON'T HEAR BACK AND THE ANSWER

2181
02:46:06,280 --> 02:46:13,160
IS NO SO I WAS ASKING SO WHEN

2182
02:46:13,160 --> 02:46:16,600
I COULD COME TO MEET AND

2183
02:46:16,600 --> 02:46:22,080
INSTEAD WE HAVE GOT SOMETHING

2184
02:46:22,080 --> 02:46:25,040
AND DOCTOR PAUL TURNED OUT TO

2185
02:46:25,040 --> 02:46:28,480
BE THAT STEVE AND I HAD A

2186
02:46:28,480 --> 02:46:29,480
CHANCE TO MEET WITH HIM

2187
02:46:29,480 --> 02:46:33,520
MULTIPLE TIMES HE TURNED OUT

2188
02:46:33,520 --> 02:46:43,960
TO BE A VERY WARM PERSON.

2189
02:46:49,440 --> 02:46:52,480
WHAT IS THE PH OF THE

2190
02:46:52,480 --> 02:46:57,040
SOLUTION?

2191
02:46:57,040 --> 02:46:57,440
AND THEN TO DO RETRO

2192
02:46:57,440 --> 02:46:57,720
SYNTHESIS.

2193
02:46:57,720 --> 02:47:00,120
HE HAD DISCOVERED 75 DRUGS IN

2194
02:47:00,120 --> 02:47:04,840
HIS CAREER AND IS SO TOTALLY

2195
02:47:04,840 --> 02:47:12,520
COMMITTED SO THROUGH THESE

2196
02:47:12,520 --> 02:47:15,160
COLLABORATIONS THAT MAKE THESE

2197
02:47:15,160 --> 02:47:21,960
THINGS POSSIBLE.

2198
02:47:21,960 --> 02:47:32,440
SO THEN HAVING THE STRUCTURE

2199
02:47:33,440 --> 02:47:36,400
AND THEN WE COULD SEE THESE

2200
02:47:36,400 --> 02:47:36,960
COMPOUNDS HAVE VERY SIMILAR

2201
02:47:36,960 --> 02:47:41,800
SHAPE IN COMMON BINDING AND

2202
02:47:41,800 --> 02:47:47,560
ACTUALLY THAT EXPANDED.

2203
02:47:47,560 --> 02:47:50,600
SO THEN WE WERE CARRYING OUT

2204
02:47:50,600 --> 02:47:51,240
STUDIES DRIVING THE SYNTHESIS

2205
02:47:51,240 --> 02:47:55,160
OF THE INHIBITORS BUT AGAIN

2206
02:47:55,160 --> 02:48:01,000
THIS WAS WITH PROTEINS AND

2207
02:48:01,000 --> 02:48:04,000
EVENTUALLY WE CAME UP WITH

2208
02:48:04,000 --> 02:48:07,640
COMPOUNDS THAT ARE STILL IN

2209
02:48:07,640 --> 02:48:13,920
USE TREATMENT TODAY BUT AND

2210
02:48:13,920 --> 02:48:19,120
THE DESIGN ESPECIALLY PROVE

2211
02:48:19,120 --> 02:48:19,680
THOSE CONNECTIONS AND THE

2212
02:48:19,680 --> 02:48:20,240
TYPES THAT WERE INVOLVED TO

2213
02:48:20,240 --> 02:48:25,080
THE EXTENT THAT THE EVENTUAL

2214
02:48:25,080 --> 02:48:26,600
COMPOUNDS HAD PHENOMENAL

2215
02:48:26,600 --> 02:48:26,960
CHARACTERISTICS.

2216
02:48:26,960 --> 02:48:31,200
AND ESPECIALLY DURING THE

2217
02:48:31,200 --> 02:48:36,240
PROCESS SO TO DETERMINE THE

2218
02:48:36,240 --> 02:48:38,000
STRUCTURES OF MANY OF THE

2219
02:48:38,000 --> 02:48:40,280
DERIVATIVES AND WE HAVE SEEN

2220
02:48:40,280 --> 02:48:43,080
IN A SEPARATE PROJECT IN THE

2221
02:48:43,080 --> 02:48:46,600
LATE EIGHTIES A POSSIBLE ROUTE

2222
02:48:46,600 --> 02:48:50,360
WAS FOR THE COMPOUND TO OTHER

2223
02:48:50,360 --> 02:48:54,640
UNDERGO CONFORMATIONAL

2224
02:48:54,640 --> 02:48:54,880
CHANGES.

2225
02:48:54,880 --> 02:48:59,360
SO TO CRYSTALLIZE THESE IDEAS

2226
02:48:59,360 --> 02:49:03,320
IN THE 2004 PAPER WHEN WE

2227
02:49:03,320 --> 02:49:10,480
SHOWED THE INHIBITOR FOR

2228
02:49:10,480 --> 02:49:14,040
EXAMPLE FOR RESISTANCE IT IS A

2229
02:49:14,040 --> 02:49:14,880
FLEXIBLE AND HAVE BETTER COULD

2230
02:49:14,880 --> 02:49:19,080
ADAPT TO CHANGES IF IT IS

2231
02:49:19,080 --> 02:49:24,320
RELATIVELY COMPACT SO IT IS

2232
02:49:24,320 --> 02:49:28,840
ONE WAY THAT YOU CAN OVERCOME

2233
02:49:28,840 --> 02:49:34,560
RESISTANCE AND THEN YOU CAN

2234
02:49:34,560 --> 02:49:39,360
GET TO MORE ACTIVITY AND THOSE

2235
02:49:39,360 --> 02:49:39,960
RESISTANT VARIANTS BUT THE KEY

2236
02:49:39,960 --> 02:49:47,120
WAS ALL THE WAY THE COMPOUND

2237
02:49:47,120 --> 02:49:47,640
WAS SCREAMING AGAINST THE

2238
02:49:47,640 --> 02:49:48,200
DRUG-RESISTANT VARIANT AND

2239
02:49:48,200 --> 02:49:53,480
EVEN THEN THE CALCULATIONS ALL

2240
02:49:53,480 --> 02:49:56,480
OF THOSE REUSED IN THE DESIGN

2241
02:49:56,480 --> 02:49:59,000
CALCULATIONS.

2242
02:49:59,000 --> 02:50:03,080
AND THE OUTCOME IS THAT THESE

2243
02:50:03,080 --> 02:50:07,320
INHIBITORS FOR THOSE HIV

2244
02:50:07,320 --> 02:50:15,160
MEDICATIONS AND THEN TO FIX

2245
02:50:15,160 --> 02:50:18,800
THOSE COMBINATIONS THAT HE

2246
02:50:18,800 --> 02:50:25,640
MADE ROYALTY-FREE ALSO

2247
02:50:25,640 --> 02:50:27,360
COMBINED WITH ONE OF THE

2248
02:50:27,360 --> 02:50:32,960
INHIBITORS AND THEN IT KEEPS

2249
02:50:32,960 --> 02:50:38,440
ON GIVING AND IN 2001 IT WAS

2250
02:50:38,440 --> 02:50:41,520
LIKE ONCE EVERY TWO MONTHS

2251
02:50:41,520 --> 02:50:44,800
CAME OUT OF A COMBINATION OF

2252
02:50:44,800 --> 02:50:49,440
THE INHIBITOR SO I ALSO WANT

2253
02:50:49,440 --> 02:50:52,240
TO MENTION THIS BEAUTIFUL

2254
02:50:52,240 --> 02:50:53,640
STRUCTURE IN COLLABORATION

2255
02:50:53,640 --> 02:50:54,440
WITH STEVE HUGHES THE PAST

2256
02:50:54,440 --> 02:50:56,680
SEVERAL YEARS THE WAY THAT WE

2257
02:50:56,680 --> 02:51:04,120
HAVE BECOME WITH THE

2258
02:51:04,120 --> 02:51:10,520
PROCESSING AND THEN IN THIS

2259
02:51:10,520 --> 02:51:15,800
FORM THAT WE TRY TO UNDERSTAND

2260
02:51:15,800 --> 02:51:20,040
THE STRUCTURE AND TO

2261
02:51:20,040 --> 02:51:22,680
UNDERSTAND MORE ABOUT POLY

2262
02:51:22,680 --> 02:51:22,920
PROTEIN.

2263
02:51:22,920 --> 02:51:27,440
SO AT THIS STAGE I LIKE TO

2264
02:51:27,440 --> 02:51:30,360
THINK THE INCREDIBLE TEAMS OF

2265
02:51:30,360 --> 02:51:40,840
PEOPLE SO THE LATE PAT CLARK

2266
02:51:43,760 --> 02:51:54,200
AND ESPECIALLY I CAN'T IMAGINE

2267
02:51:56,480 --> 02:52:02,280
AND IT IS FUNDED THROUGH THE

2268
02:52:02,280 --> 02:52:12,000
PROJECTS FOR THOSE PERIODS AND

2269
02:52:12,000 --> 02:52:15,000
STEVE HAS GENEROUSLY FOUND

2270
02:52:15,000 --> 02:52:19,560
WAYS TO FUND THROUGH NCI BUT

2271
02:52:19,560 --> 02:52:24,800
SO WITH THOSE IMAGES OF STEVE

2272
02:52:24,800 --> 02:52:27,800
WHO ALL HAPPEN TO BE FROM

2273
02:52:27,800 --> 02:52:30,400
ITALY TWO OF MY GREATEST

2274
02:52:30,400 --> 02:52:34,600
FRIENDS AND MENTORS STEVE AND

2275
02:52:34,600 --> 02:52:39,160
MIKE HERE WE ARE HAVING FUN.

2276
02:52:39,160 --> 02:52:39,480
BUT ANYWAY.

2277
02:52:39,480 --> 02:52:42,080
THANK YOU SO MUCH.

2278
02:52:42,080 --> 02:52:47,320
STEVE, I WISH YOU ALL THE BEST

2279
02:52:47,320 --> 02:52:47,920
AND ALL THE BEST ENJOYMENT IN

2280
02:52:47,920 --> 02:52:49,440
LIFE.

2281
02:52:49,440 --> 02:52:59,600
[APPLAUSE]

2282
02:53:01,600 --> 02:53:02,080
>>OUR TYPING HAS SLIPPED
A

2283
02:53:02,080 --> 02:53:04,640
LITTLE BIT SO WE HAVE TO SKIP

2284
02:53:04,640 --> 02:53:05,440
QUESTIONS BUT YOU CAN ASK

2285
02:53:05,440 --> 02:53:09,400
DURING THE LUNCH BREAK.

2286
02:53:09,400 --> 02:53:10,480
SO LIKE ALL OF THE OTHER

2287
02:53:10,480 --> 02:53:16,320
SPEAKERS TODAY, JOHN NEEDS NO

2288
02:53:16,320 --> 02:53:16,840
INTRODUCTION THE LEADING

2289
02:53:16,840 --> 02:53:18,160
EXPERT OF ALL THINGS

2290
02:53:18,160 --> 02:53:22,680
RETROVIROLOGY AND FOR TODAY'S

2291
02:53:22,680 --> 02:53:29,880
EVENT THE FOUNDING DIRECTOR

2292
02:53:29,880 --> 02:53:33,320
WEDNESDAY BECAME DIRECTOR AND

2293
02:53:33,320 --> 02:53:39,320
STEVE IN PARTICULAR AND WITH

2294
02:53:39,320 --> 02:53:49,640
THAT HIV PERSISTENCE.

2295
02:53:49,640 --> 02:53:50,240
THANK YOU ERIC IT IS AN HONOR

2296
02:53:50,240 --> 02:53:55,200
TO BE HERE AND THEN TO HEAR

2297
02:53:55,200 --> 02:54:05,760
ALL OF THESE WONDERFUL STORIES.

2298
02:54:21,120 --> 02:54:28,000
[LAUGHTER]

2299
02:54:28,000 --> 02:54:28,600
SO I PROGRAMMED THIS A LITTLE

2300
02:54:28,600 --> 02:54:30,560
BIT DIFFERENTLY.

2301
02:54:30,560 --> 02:54:37,000
I WON'T SHOW TOO MUCH DATA

2302
02:54:37,000 --> 02:54:37,600
EXCITING THOSE STUDIES AT THE

2303
02:54:37,600 --> 02:54:38,200
VERY END SO DESPITE THE VERY

2304
02:54:38,200 --> 02:54:43,080
LONG FRIENDSHIPS.

2305
02:54:43,080 --> 02:54:43,640
SO THEN COLLABORATING ON ANY

2306
02:54:43,640 --> 02:54:44,280
RESEARCH PROJECT OVER THE LAST

2307
02:54:44,280 --> 02:54:51,800
FEW YEARS.

2308
02:54:51,800 --> 02:55:02,280
AND THAT CAME OUT VERY WELL.

2309
02:55:08,920 --> 02:55:13,680
>>STEVE AND ME OUR
FRIENDSHIP

2310
02:55:13,680 --> 02:55:19,120
GOES BACK A VERY LONG TIME.

2311
02:55:19,120 --> 02:55:25,480
SO IN PARTICULAR WITH THIS

2312
02:55:25,480 --> 02:55:31,880
PARTICULAR THING BUT IT WAS

2313
02:55:31,880 --> 02:55:34,600
GOING AROUND THE PHRASE THAT

2314
02:55:34,600 --> 02:55:36,440
AS I THOUGHT ABOUT IT MORE AND

2315
02:55:36,440 --> 02:55:42,520
MORE A VERY LARGE AMOUNT WHAT

2316
02:55:42,520 --> 02:55:43,120
WE HAVE ACCOMPLISHED OVER THE

2317
02:55:43,120 --> 02:55:51,200
YEARS WITH DRP THAT RELATES TO

2318
02:55:51,200 --> 02:55:51,720
GETTING RID OF THE FEELING

2319
02:55:51,720 --> 02:55:54,680
THAT IS EXPRESSED IN THIS RACE.

2320
02:55:54,680 --> 02:55:56,760
THAT IS THE SHINY DOGMA.

2321
02:55:56,760 --> 02:55:57,040
[LAUGHTER]

2322
02:55:57,040 --> 02:55:59,480
I WILL ILLUSTRATE THIS BY

2323
02:55:59,480 --> 02:56:04,520
POINTING OUT BECAUSE I COULD

2324
02:56:04,520 --> 02:56:09,840
NOT FIND ANYTHING.

2325
02:56:09,840 --> 02:56:10,320
AND THEN THE SHINY DOG

2326
02:56:10,320 --> 02:56:13,920
PICTURES APPEAR.

2327
02:56:13,920 --> 02:56:21,640
SO I AM QUITE SURE BY 1977

2328
02:56:21,640 --> 02:56:31,040
THAT THIS TALK NOW MEETING THE

2329
02:56:31,040 --> 02:56:33,840
RETROVIRUS AND YOU CAN TELL

2330
02:56:33,840 --> 02:56:37,160
THIS IS A STUDY THAT HAROLD

2331
02:56:37,160 --> 02:56:40,080
WAS REFERRING TO AS SOME

2332
02:56:40,080 --> 02:56:46,000
LENGTH.

2333
02:56:46,000 --> 02:56:48,040
AND IT WAS A VERY IMPORTANT

2334
02:56:48,040 --> 02:56:53,080
DESCRIPTION THAT ORIGINALLY

2335
02:56:53,080 --> 02:56:57,240
THE GENOME.

2336
02:56:57,240 --> 02:56:59,760
AND THEN THE FACT THAT COULD

2337
02:56:59,760 --> 02:57:10,040
BE INTEGRATED.

2338
02:57:10,040 --> 02:57:11,280
>>AND SO WITH THE
INTEGRATION

2339
02:57:11,280 --> 02:57:13,680
SITE THE QUESTION TO

2340
02:57:13,680 --> 02:57:17,960
UNDERSTAND WHAT'S GOING ON

2341
02:57:17,960 --> 02:57:25,720
WITH THE HIV INFECTION.

2342
02:57:25,720 --> 02:57:36,240
SO SO IN FACT AFTER SOME YEARS

2343
02:57:37,240 --> 02:57:37,720
WE BECOME FAMOUS FOR ALWAYS

2344
02:57:37,720 --> 02:57:40,760
SITTING IN THE FRONT EACH ONE

2345
02:57:40,760 --> 02:57:44,920
WHO ALWAYS SHOWED UP FIRST

2346
02:57:44,920 --> 02:57:48,040
WOULD PUT A MARKER ON BOTH OF

2347
02:57:48,040 --> 02:57:50,600
THOSE SEATS TO CONSUME THE

2348
02:57:50,600 --> 02:57:58,720
TRADITION YEAR AFTER YEAR I

2349
02:57:58,720 --> 02:57:59,240
DON'T KNOW HOW FAR BACK IT

2350
02:57:59,240 --> 02:58:01,800
GOES BUT IT GOES BACK A LONG

2351
02:58:01,800 --> 02:58:03,320
TIME.

2352
02:58:03,320 --> 02:58:03,840
SO AS WE PLAY THAT OUT WE

2353
02:58:03,840 --> 02:58:06,640
BECOME FAIRLY WELL-KNOWN FOR

2354
02:58:06,640 --> 02:58:08,480
THIS.

2355
02:58:08,480 --> 02:58:13,880
AND THE OTHER THING THAT WHAT

2356
02:58:13,880 --> 02:58:14,760
HAROLD ALLUDED TO WAS THE

2357
02:58:14,760 --> 02:58:17,040
RETROVIRUS BOOK THAT THE THREE

2358
02:58:17,040 --> 02:58:20,560
OF US WORKED OUT FOR A LONG

2359
02:58:20,560 --> 02:58:26,560
TIME IN THE BOOK WAS PUBLISHED

2360
02:58:26,560 --> 02:58:32,080
IN 97 ABOUT THE TIME WITH NCI

2361
02:58:32,080 --> 02:58:36,400
TO FORM THE DRP.

2362
02:58:36,400 --> 02:58:37,440
STARTING WITH A MEETING IN

2363
02:58:37,440 --> 02:58:41,400
WASHINGTON DC AND HAROLD HAD

2364
02:58:41,400 --> 02:58:46,120
JUST BEEN APPOINTED THE ANY

2365
02:58:46,120 --> 02:58:54,600
AGE DIRECTOR AND SIMILAR TO

2366
02:58:54,600 --> 02:59:01,280
THE POT CIRCLE SO WE ACTUALLY

2367
02:59:01,280 --> 02:59:01,840
LAID OUT THE WHOLE STRUCTURE

2368
02:59:01,840 --> 02:59:06,400
OF THE BOOK AND WE PRETTY MUCH

2369
02:59:06,400 --> 02:59:08,080
ENDED UP BEING THE FINAL

2370
02:59:08,080 --> 02:59:13,960
CHAPTER WITH A LIST OF AUTHORS.

2371
02:59:13,960 --> 02:59:16,000
AND THE MEETING WAS QUITE

2372
02:59:16,000 --> 02:59:24,200
PRODUCTIVE BUT THEY HAD

2373
02:59:24,200 --> 02:59:25,120
FLIGHTS TO CATCH AND I HAD TO

2374
02:59:25,120 --> 02:59:30,280
GET HOME AND HAROLD I

2375
02:59:30,280 --> 02:59:33,320
RECOLLECT WOULD GIVE A BIG

2376
02:59:33,320 --> 02:59:35,360
LECTURE AND THEN TO BE GREETED

2377
02:59:35,360 --> 02:59:39,400
WITH THE RED CARPET.

2378
02:59:39,400 --> 02:59:44,280
BUT THEN IT RAN A LITTLE LONG.

2379
02:59:44,280 --> 02:59:47,400
BUT IT WAS ONLY IN VERY SHORT

2380
02:59:47,400 --> 02:59:48,640
TOPICS.

2381
02:59:48,640 --> 02:59:52,280
TO THE NATIONAL AIRPORT BUT

2382
02:59:52,280 --> 02:59:58,000
GOING IN THE WRONG DIRECTION

2383
02:59:58,000 --> 03:00:01,080
AND THEN GETTING MORE AND MORE

2384
03:00:01,080 --> 03:00:01,280
ANSI.

2385
03:00:01,280 --> 03:00:04,280
AND SAY HAVE A MAP IN THE

2386
03:00:04,280 --> 03:00:05,560
TRUCK.

2387
03:00:05,560 --> 03:00:08,600
AND THEN SAID HURRY DON'T

2388
03:00:08,600 --> 03:00:08,880
STOP.

2389
03:00:08,880 --> 03:00:19,400
>>AND THEN TURNING UP ON
ROCK

2390
03:00:19,840 --> 03:00:24,360
CREEK PARKWAY EXCEPT THAT IT

2391
03:00:24,360 --> 03:00:24,880
TURNS AROUND AND GOES THE

2392
03:00:24,880 --> 03:00:34,520
WRONG WAY AT RUSH HOUR.

2393
03:00:34,520 --> 03:00:35,120
SO THEN FINALLY MAKING IT UP

2394
03:00:35,120 --> 03:00:41,120
TO THE RED CARPET.

2395
03:00:41,120 --> 03:00:46,360
AND THEN LENDING TO A QUESTION

2396
03:00:46,360 --> 03:00:49,440
TO RECOGNIZE THE THEME OF THIS

2397
03:00:49,440 --> 03:00:52,640
AND HAVE A MORE OR LESS LOST

2398
03:00:52,640 --> 03:01:00,800
ONE SIDE?

2399
03:01:00,800 --> 03:01:03,720
SO MANY WOULD AGREE IT IS

2400
03:01:03,720 --> 03:01:04,040
SUCCESSFUL.

2401
03:01:04,040 --> 03:01:09,880
THAT WAS THE STORY.

2402
03:01:09,880 --> 03:01:17,880
SO WHAT GOT ME INTO THE DRP.

2403
03:01:17,880 --> 03:01:20,400
SO AT THE TIME AFTER HIV WAS

2404
03:01:20,400 --> 03:01:24,960
DISCOVERED WITH THE VIRUS TO

2405
03:01:24,960 --> 03:01:26,920
SEQUENCE IT WAS MORE THAN

2406
03:01:26,920 --> 03:01:33,600
OTHER RETROVIRUSES THEN YOU

2407
03:01:33,600 --> 03:01:36,520
HAVE A LARGE AMOUNT OF GENETIC

2408
03:01:36,520 --> 03:01:40,040
DIVERSITY.

2409
03:01:40,040 --> 03:01:43,120
SO THAT WENT TO THE GENERAL

2410
03:01:43,120 --> 03:01:47,240
DOGMA.

2411
03:01:47,240 --> 03:01:52,400
AND THEN AT THE TIME IN THE

2412
03:01:52,400 --> 03:01:55,400
NINETIES AND PATIENTS WERE

2413
03:01:55,400 --> 03:01:56,160
CONSTANTLY FAILING THEM WITH

2414
03:01:56,160 --> 03:02:01,840
THE EXISTENCE AND WITH THE LOW

2415
03:02:01,840 --> 03:02:05,400
POTENCY SO I PUBLISHED THIS

2416
03:02:05,400 --> 03:02:12,120
REVIEW THIS IS THE SAME AS HIV

2417
03:02:12,120 --> 03:02:17,280
TO SHOW THE RATE AT WHICH IT

2418
03:02:17,280 --> 03:02:21,920
OCCURS IN THIS PARTICULAR CASE

2419
03:02:21,920 --> 03:02:29,160
I HAD DONE AN EXPERIMENT BUT

2420
03:02:29,160 --> 03:02:31,880
OF K BUT OF COURSE THE

2421
03:02:31,880 --> 03:02:35,400
PATIENTS WERE CHICKENS THERE

2422
03:02:35,400 --> 03:02:37,880
WAS VERY LITTLE DIVERSITY BUT

2423
03:02:37,880 --> 03:02:41,800
IF YOU TAKE THAT VIRUS THEN

2424
03:02:41,800 --> 03:02:46,720
YOU GET GENETIC DIVERSITY SO

2425
03:02:46,720 --> 03:02:53,960
THE CONCLUSION IS THAT HIV

2426
03:02:53,960 --> 03:02:58,640
DOES NOT HAVE THAT PATIENT

2427
03:02:58,640 --> 03:03:04,240
RATE AND THAT THE LIFESTYLE IS

2428
03:03:04,240 --> 03:03:04,800
CONSTANTLY REPLICATING OVER

2429
03:03:04,800 --> 03:03:07,200
AND OVER AGAIN.

2430
03:03:07,200 --> 03:03:12,360
SO THAT REPLICATION OVER AND

2431
03:03:12,360 --> 03:03:14,280
OVER IS THE PROPERTY OR THE

2432
03:03:14,280 --> 03:03:19,120
CONSEQUENCE THAT ALLOWS THE

2433
03:03:19,120 --> 03:03:21,280
ACCUMULATION IN THE POPULATION

2434
03:03:21,280 --> 03:03:23,560
AND DRUG RESISTANCE IS

2435
03:03:23,560 --> 03:03:30,120
SLIGHTLY DELETERIOUS AND WITH

2436
03:03:30,120 --> 03:03:35,360
THE VIRUS THAT THEY COME FROM

2437
03:03:35,360 --> 03:03:35,920
BECAUSE OTHERWISE THEY WOULD

2438
03:03:35,920 --> 03:03:39,440
BE SLIGHTLY FAVORABLE.

2439
03:03:39,440 --> 03:03:42,880
HE WOULD NEVER SEE AN

2440
03:03:42,880 --> 03:03:46,080
EFFECTIVE DRUG.

2441
03:03:46,080 --> 03:03:54,560
SO THE IDEA IS THAT THE

2442
03:03:54,560 --> 03:04:01,040
FAILURE OF HIV THERAPY IS NOT

2443
03:04:01,040 --> 03:04:05,160
DUE TO THE POTENCY OF THE

2444
03:04:05,160 --> 03:04:05,720
DRUGS THAT ALREADY RESISTANT

2445
03:04:05,720 --> 03:04:09,160
TO THE POPULATION.

2446
03:04:09,160 --> 03:04:11,240
SO THIS ATTRACTED THE

2447
03:04:11,240 --> 03:04:16,680
ATTENTION OF STEVE AND GEORGE

2448
03:04:16,680 --> 03:04:18,000
BECAUSE THE BUILDING HAD JUST

2449
03:04:18,000 --> 03:04:27,600
BEEN BUILT.

2450
03:04:27,600 --> 03:04:30,680
AND THEY WERE LOOKING TO FILL

2451
03:04:30,680 --> 03:04:34,240
IT.

2452
03:04:34,240 --> 03:04:34,760
THAT OCCUPIED A COUPLE OF

2453
03:04:34,760 --> 03:04:35,360
FLOORS BUT THERE WERE SEVERAL

2454
03:04:35,360 --> 03:04:41,200
FLOORS STILL TO BE FILLED.

2455
03:04:41,200 --> 03:04:41,800
SO DRUG RESISTANCE WOULD BE A

2456
03:04:41,800 --> 03:04:43,920
GOOD TEAM TO FOCUS ON AND THEN

2457
03:04:43,920 --> 03:04:47,840
OBVIOUSLY DEMONSTRATED TO

2458
03:04:47,840 --> 03:04:48,440
THINK ABOUT DRUG RESISTANCE

2459
03:04:48,440 --> 03:04:57,520
THE ONLY THING IS TO DO IT.

2460
03:04:57,520 --> 03:05:00,520
AND THEN MANAGED TO PERSUADE

2461
03:05:00,520 --> 03:05:04,760
ME THAT FOR PERSONAL REASONS

2462
03:05:04,760 --> 03:05:06,000
PART-TIME SUGGEST 25 YEARS AGO

2463
03:05:06,000 --> 03:05:15,960
WE GOT STARTED FROM 1997.

2464
03:05:15,960 --> 03:05:19,000
AND WITH THAT RESISTANCE

2465
03:05:19,000 --> 03:05:22,560
PROGRAM AND WITH THOSE CURRENT

2466
03:05:22,560 --> 03:05:30,160
PIS IN THE PROGRAM AND THEN IT

2467
03:05:30,160 --> 03:05:33,040
CAME TO BE OUR FAVORITE

2468
03:05:33,040 --> 03:05:33,720
RESTAURANT.

2469
03:05:33,720 --> 03:05:36,600
AND WITH THE SPEAKER AT THE

2470
03:05:36,600 --> 03:05:41,640
LECTURE A FEW YEARS AGO.

2471
03:05:41,640 --> 03:05:43,680
AND THEN THAT IS REMARKABLY

2472
03:05:43,680 --> 03:05:51,800
SUCCESSFUL AND THEN FOR THAT

2473
03:05:51,800 --> 03:05:53,680
TRANSFORMATIONAL BIOCHEMICAL

2474
03:05:53,680 --> 03:06:03,880
AND SO ON.

2475
03:06:04,240 --> 03:06:08,040
AND THEN AFTER HE RECRUITED ME

2476
03:06:08,040 --> 03:06:08,560
ONE OF MY FIRST RECRUITS.

2477
03:06:08,560 --> 03:06:08,840
[LAUGHTER]

2478
03:06:08,840 --> 03:06:13,520
BECAUSE THE PROGRAM THAT HE

2479
03:06:13,520 --> 03:06:20,680
WAS IN WAS CLOSED TO BRING

2480
03:06:20,680 --> 03:06:26,160
SOME OF THE STAFF INTO THE

2481
03:06:26,160 --> 03:06:29,400
NCI.

2482
03:06:29,400 --> 03:06:30,440
SO STEVE BECAME A VERY

2483
03:06:30,440 --> 03:06:33,880
IMPORTANT PART NOT ONLY

2484
03:06:33,880 --> 03:06:36,920
GETTING THE DRP GOING BUT A

2485
03:06:36,920 --> 03:06:40,880
VERY IMPORTANT MEMBER GOING

2486
03:06:40,880 --> 03:06:46,280
FORWARD AND THEN EVENTUALLY

2487
03:06:46,280 --> 03:06:49,040
INTEGRATES THE INHIBITORS AS

2488
03:06:49,040 --> 03:06:52,400
WELL SO BUNCH OF BASIC

2489
03:06:52,400 --> 03:06:56,200
STUDIES.

2490
03:06:56,200 --> 03:06:56,640
AND OVERALL WITH THE

2491
03:06:56,640 --> 03:06:59,840
DIRECTIONS OF THE PROGRAM I

2492
03:06:59,840 --> 03:07:04,880
WAS HELPING AND TO WORK MOSTLY

2493
03:07:04,880 --> 03:07:15,360
WITH THE CRITICAL GROUP AND

2494
03:07:17,040 --> 03:07:20,000
THEN WITH THE ORIGINAL GOAL TO

2495
03:07:20,000 --> 03:07:26,120
TAKE THIS POSITION IS WITH THE

2496
03:07:26,120 --> 03:07:36,600
PERSPECTIVE AND SO THAT WAS

2497
03:07:43,120 --> 03:07:47,680
ONE OF THE THINGS ALSO BETTER

2498
03:07:47,680 --> 03:07:50,720
THAN ON A MORE PERMANENT

2499
03:07:50,720 --> 03:07:56,000
BASIS.

2500
03:07:56,000 --> 03:07:58,440
BUT NOW IT WAS TRANSLATIONAL

2501
03:07:58,440 --> 03:08:05,120
RESEARCH SECTION AND THEN THE

2502
03:08:05,120 --> 03:08:10,840
FIRST GOAL WITH ADVANCED

2503
03:08:10,840 --> 03:08:11,280
TECHNOLOGY FOR HIGHLY

2504
03:08:11,280 --> 03:08:19,720
SENSITIVE ASSAYS.

2505
03:08:19,720 --> 03:08:20,320
AND THEN WITH THAT REPLICATION

2506
03:08:20,320 --> 03:08:22,800
AND SO ONE OF WHAT IS

2507
03:08:22,800 --> 03:08:26,200
HAPPENING.

2508
03:08:26,200 --> 03:08:26,800
AND ALSO AT THE TIME TO DISPEL

2509
03:08:26,800 --> 03:08:27,360
A FEW MORE SHAGGY DOGMAS.

2510
03:08:27,360 --> 03:08:34,200
FOR EXAMPLE A DOGMA THAT STILL

2511
03:08:34,200 --> 03:08:40,280
HAS LONG-TERM PERSISTENCE THAT

2512
03:08:40,280 --> 03:08:43,280
REPLICATION OF CELL TO CELL

2513
03:08:43,280 --> 03:08:44,160
TRANSFER.

2514
03:08:44,160 --> 03:08:51,400
AND WITH THOSE SANCTUARY SITES

2515
03:08:51,400 --> 03:08:53,480
AND THEN AS HAS BEEN SHOWN

2516
03:08:53,480 --> 03:08:57,800
REPEATEDLY WITH THE GROUP AND

2517
03:08:57,800 --> 03:09:06,360
COLLABORATORS AND IN THE FIRST

2518
03:09:06,360 --> 03:09:09,840
PLACE WITH A VERY LARGE LEVEL.

2519
03:09:09,840 --> 03:09:12,840
AND MOST INDIVIDUALS ON

2520
03:09:12,840 --> 03:09:15,280
THERAPY.

2521
03:09:15,280 --> 03:09:16,360
AND THEN THAT WAS SHOWN THAT

2522
03:09:16,360 --> 03:09:19,600
WASN'T SENSITIVE TO KEEP

2523
03:09:19,600 --> 03:09:22,600
THROWING DRUGS IT AND THEN TO

2524
03:09:22,600 --> 03:09:29,320
BRING THAT DOWN A LITTLE BIT.

2525
03:09:29,320 --> 03:09:34,720
AND THEN TO BE PUBLISHED IS

2526
03:09:34,720 --> 03:09:43,520
THE ATTORNEY GROUP.

2527
03:09:43,520 --> 03:09:47,760
SO IF YOU LOOK AT THE SYMBOLS

2528
03:09:47,760 --> 03:09:55,680
AT THE VIRUS SEQUENCE BEFORE

2529
03:09:55,680 --> 03:09:58,600
THEY STARTED A RETROVIRAL

2530
03:09:58,600 --> 03:10:01,320
THERAPY AND THAT WAYS IDENTITY

2531
03:10:01,320 --> 03:10:10,560
MY —- IDENTICAL AND TAKE THAT

2532
03:10:10,560 --> 03:10:11,120
OTHER PERSON THREE YEARS IN

2533
03:10:11,120 --> 03:10:19,320
THERAPY AND THE SEQUENCES AND

2534
03:10:19,320 --> 03:10:29,080
ALL OF THE INDIVIDUALS AND

2535
03:10:29,080 --> 03:10:29,560
THAT MEANS ABSENCE OF

2536
03:10:29,560 --> 03:10:32,120
APPLICATION TO ANY SIGNIFICANT

2537
03:10:32,120 --> 03:10:42,080
EXTENT.

2538
03:10:42,080 --> 03:10:42,640
THAT WE HAVE SUCH NICE DATA

2539
03:10:42,640 --> 03:10:52,280
SHOWING THIS.

2540
03:10:52,280 --> 03:10:52,800
THE PATIENTS HAD BEEN ON

2541
03:10:52,800 --> 03:11:03,200
THERAPY FOR A LONG TIME.

2542
03:11:08,680 --> 03:11:09,120
>>UP TO THIS POINT I HAVE

2543
03:11:09,120 --> 03:11:09,760
BEEN WORKING BASIC STUDIES ON

2544
03:11:09,760 --> 03:11:18,600
INTEGRATION BUT ALSO A LOT AND

2545
03:11:18,600 --> 03:11:20,600
THAT WAS INHIBITORS IN THE

2546
03:11:20,600 --> 03:11:30,320
RESISTANCE AND THAT WAS OVER

2547
03:11:30,320 --> 03:11:40,520
THE RTA F.

2548
03:11:41,120 --> 03:11:42,080
AND THEN WITH THAT INTEGRATION

2549
03:11:42,080 --> 03:11:52,600
FOR THE SITES AND THAT THIS IS

2550
03:11:54,840 --> 03:11:58,920
SENSITIVE ENOUGH AND THAT YOU

2551
03:11:58,920 --> 03:12:02,720
CAN STILL USE THAT WITH THAT

2552
03:12:02,720 --> 03:12:05,080
INTEGRATION SITES AND AT THE

2553
03:12:05,080 --> 03:12:09,520
SAME TIME FRANK BROUGHT THE

2554
03:12:09,520 --> 03:12:09,920
FAMOUS PATIENT.

2555
03:12:09,920 --> 03:12:11,480
I HAVE TO TELL YOU THIS PERIOD

2556
03:12:11,480 --> 03:12:18,160
ON —- PERSON WAS NAMED PATIENT

2557
03:12:18,160 --> 03:12:19,080
ONE NOW IT WOULD BE CALLED

2558
03:12:19,080 --> 03:12:22,520
PARTICIPANT ONE.

2559
03:12:22,520 --> 03:12:29,280
AND HE HAD A HISTORY AND WHERE

2560
03:12:29,280 --> 03:12:38,320
HE SHOWED UP FIRST SHOWING UP

2561
03:12:38,320 --> 03:12:38,880
AT THE CLINICAL STUDY THAT

2562
03:12:38,880 --> 03:12:42,840
FRANK WAS MANAGING AND

2563
03:12:42,840 --> 03:12:43,400
OBVIOUSLY HAVE BEEN INFECTED

2564
03:12:43,400 --> 03:12:50,960
FOR QUITE A LONG TIME SO HE

2565
03:12:50,960 --> 03:12:51,520
WAS NOT VERY HEALTHY AT THE

2566
03:12:51,520 --> 03:12:52,080
TIME HE SHOWED UP HE WAS PUT

2567
03:12:52,080 --> 03:12:54,720
ON A COMBINATION THERAPY AND

2568
03:12:54,720 --> 03:12:58,280
THEN RAPIDLY BROUGHT HIS LEVEL

2569
03:12:58,280 --> 03:13:01,320
DOWN AND THEN MAINTAINED WITH

2570
03:13:01,320 --> 03:13:11,800
CHANGING THERAPIES UNTIL HE

2571
03:13:14,280 --> 03:13:14,800
HAD A COUPLE OF PROBLEMS WITH

2572
03:13:14,800 --> 03:13:19,520
ACCESS TO DRUGS.

2573
03:13:19,520 --> 03:13:20,120
SO THEN THE VIRUS CAME BACK UP

2574
03:13:20,120 --> 03:13:25,760
AND WAS BACK DOWN AGAIN AND

2575
03:13:25,760 --> 03:13:30,080
THEN AFTER TEN YEARS DESPITE

2576
03:13:30,080 --> 03:13:34,280
THE FACT YOU ARE ON GOOD THERE

2577
03:13:34,280 --> 03:13:40,720
APPEARS STARTED TO GO UP.

2578
03:13:40,720 --> 03:13:46,840
SO FRANK RECOGNIZED THIS IS

2579
03:13:46,840 --> 03:13:49,720
BRILLIANT WITH THOSE OF

2580
03:13:49,720 --> 03:13:55,120
SEVERAL INTERESTING THINGS.

2581
03:13:55,120 --> 03:14:01,720
SO IT INVOLVES IN TO SHARE THE

2582
03:14:01,720 --> 03:14:11,920
DNA IN —- YOUR POINT WOULD BE

2583
03:14:11,920 --> 03:14:16,000
DIFFERENT.

2584
03:14:16,000 --> 03:14:16,600
AND THOSE THAT COME FROM THAT

2585
03:14:16,600 --> 03:14:22,360
ORIGINAL MOLECULE.

2586
03:14:22,360 --> 03:14:28,920
AND WITH THAT PRIMER.

2587
03:14:28,920 --> 03:14:31,760
AND THEN WITH THAT METHODS IF

2588
03:14:31,760 --> 03:14:36,120
YOU WANT AND WITH THAT

2589
03:14:36,120 --> 03:14:39,040
SEQUENCING YOU GET ONE

2590
03:14:39,040 --> 03:14:41,760
SEQUENCE AND THAT SHOWS YOU

2591
03:14:41,760 --> 03:14:50,400
ARE THAT DNA MOLECULE.

2592
03:14:50,400 --> 03:14:53,440
AND WITH THAT SAME INTEGRATION

2593
03:14:53,440 --> 03:14:55,280
SITE COMING FROM DIFFERENT

2594
03:14:55,280 --> 03:15:00,120
ORIGINALS CELLS.

2595
03:15:00,120 --> 03:15:01,800
AND FROM THAT ORIGINAL

2596
03:15:01,800 --> 03:15:05,800
INFECTED CELL.

2597
03:15:05,800 --> 03:15:14,040
AND WHAT WAS A BIG SURPRISE

2598
03:15:14,040 --> 03:15:14,600
AND THEN THE DAD CAME IN ON

2599
03:15:14,600 --> 03:15:18,040
THE IPHONE.

2600
03:15:18,040 --> 03:15:22,400
AND SAID AND WITH THOSE

2601
03:15:22,400 --> 03:15:30,240
DIFFERENT BREAKPOINTS I DON'T

2602
03:15:30,240 --> 03:15:33,600
THINK ANYBODY EVER THOUGHT OF

2603
03:15:33,600 --> 03:15:39,720
THE DOGMA AT THE TIME.

2604
03:15:39,720 --> 03:15:42,320
AND THEN TO BE BEFORE YOU

2605
03:15:42,320 --> 03:15:52,600
STARTED THERAPY.

2606
03:15:54,760 --> 03:15:55,240
AND THEN THE CLONES THE GRAY

2607
03:15:55,240 --> 03:15:58,680
ONES INDICATE YOU ONLY SAW IT

2608
03:15:58,680 --> 03:16:00,440
WANTS BUT THEN I YOU CANNOT

2609
03:16:00,440 --> 03:16:00,880
SAY THEY ARE CLONES.

2610
03:16:00,880 --> 03:16:01,400
I WOULD BE WILLING TO BET

2611
03:16:01,400 --> 03:16:03,960
EVERY SINGLE ONE OF THESE IS

2612
03:16:03,960 --> 03:16:04,520
OPERATING ON ITS OWN BECAUSE

2613
03:16:04,520 --> 03:16:13,320
THAT SENSITIVITY.

2614
03:16:13,320 --> 03:16:16,400
THAT LOOKING AT ONE IN

2615
03:16:16,400 --> 03:16:19,800
100,000.

2616
03:16:19,800 --> 03:16:21,880
AND SO THEY WOULD YOU GET DOWN

2617
03:16:21,880 --> 03:16:23,640
TO ONE YOU ARE SEEING 100,000

2618
03:16:23,640 --> 03:16:29,680
ARE GREATER.

2619
03:16:29,680 --> 03:16:38,040
SO THE ONE THAT IS MARK THERE.

2620
03:16:38,040 --> 03:16:40,760
SO WITH THESE DESIRES AND THEN

2621
03:16:40,760 --> 03:16:41,880
THAT VIRUS COMING UP SLOWLY IN

2622
03:16:41,880 --> 03:16:46,680
THE PATIENT THAT WE SAW AS THE

2623
03:16:46,680 --> 03:16:53,200
INCREASING PERSISTENCE.

2624
03:16:53,200 --> 03:17:01,440
AND THEN ADDING MORE DRUGS AND

2625
03:17:01,440 --> 03:17:01,800
THEN IT IS NOT A

2626
03:17:01,800 --> 03:17:07,480
DRUG-RESISTANT VIRUS.

2627
03:17:07,480 --> 03:17:10,520
BUT EVER THESE VERY LARGE

2628
03:17:10,520 --> 03:17:17,280
CLONES.

2629
03:17:17,280 --> 03:17:18,320
SO WHAT IS IT THAT ALLOWS

2630
03:17:18,320 --> 03:17:23,160
THEIR SURVIVAL AND ONLY VERY

2631
03:17:23,160 --> 03:17:28,040
QUITE A FEW FRACTIONS OF ANY

2632
03:17:28,040 --> 03:17:34,880
OTHER CLONES YOU COULD FIND

2633
03:17:34,880 --> 03:17:39,600
EVEN IN THE SMALL QUANTITIES.

2634
03:17:39,600 --> 03:17:47,720
AND THEN TO BE SUPPRESSING AND

2635
03:17:47,720 --> 03:17:48,720
THAT I VERY SKEPTICAL ABOUT

2636
03:17:48,720 --> 03:17:51,280
CELL CULTURE LOOKING AT THIS

2637
03:17:51,280 --> 03:18:00,280
FIREBALL LATENCY.

2638
03:18:00,280 --> 03:18:01,960
BECAUSE THOSE POPULAR CULTURE

2639
03:18:01,960 --> 03:18:07,800
LOOKING AT THE VIRAL DNA WHICH

2640
03:18:07,800 --> 03:18:12,680
IS A VERY COMMON METHODS OF

2641
03:18:12,680 --> 03:18:17,040
WORKING QUITE HARD.

2642
03:18:17,040 --> 03:18:25,160
AND THEN AND THEN TO MAKE THE

2643
03:18:25,160 --> 03:18:25,760
INFECTIOUS VIRUS SAID THAT CAN

2644
03:18:25,760 --> 03:18:27,760
SHOW VERY NICELY THAT YOU

2645
03:18:27,760 --> 03:18:34,600
COULD NOT SEE SO WHATEVER IT

2646
03:18:34,600 --> 03:18:37,640
IS HE STILL DON'T KNOW WHAT IT

2647
03:18:37,640 --> 03:18:43,160
IS WITH THE PRO VIRUS IS NOT

2648
03:18:43,160 --> 03:18:43,880
DNA METHYLATION AS IT IS THE

2649
03:18:43,880 --> 03:18:50,240
MOST POPULAR CELL CULTURE.

2650
03:18:50,240 --> 03:18:50,760
SO THIS IS STILL SOMETHING

2651
03:18:50,760 --> 03:18:53,920
THAT WE NEED TO WORK OUT.

2652
03:18:53,920 --> 03:19:01,240
THE FREQUENCY IS VERY VERY

2653
03:19:01,240 --> 03:19:06,440
SMALL ONE OUT OF 10000 AND A

2654
03:19:06,440 --> 03:19:09,720
GOOD ONE AND A GOOD

2655
03:19:09,720 --> 03:19:17,240
INDIVIDUAL.

2656
03:19:17,240 --> 03:19:18,600
SO THAT IS PRESENT WITH MORE

2657
03:19:18,600 --> 03:19:19,880
THAN 10 MILLION CELLS SO IF

2658
03:19:19,880 --> 03:19:24,480
YOU WANT TO GET RID OF THESE

2659
03:19:24,480 --> 03:19:33,680
THE CHALLENGES VERY LARGE.

2660
03:19:33,680 --> 03:19:37,640
AND THEN TO HAVE SPECIFIC

2661
03:19:37,640 --> 03:19:38,200
ANTIGENS BUT THEN THE OTHER

2662
03:19:38,200 --> 03:19:45,640
THING THAT CAME OUT OF THIS

2663
03:19:45,640 --> 03:19:46,200
AND THEN TO BRING OF THAT

2664
03:19:46,200 --> 03:19:48,720
IDEAL CONSTRUCTION.

2665
03:19:48,720 --> 03:19:53,600
AND THAT WAS NEVER THOUGHT OF

2666
03:19:53,600 --> 03:19:57,320
NOW PEOPLE ARE DOING GENE

2667
03:19:57,320 --> 03:20:01,480
THERAPY.

2668
03:20:01,480 --> 03:20:04,520
AND THEN WITH THAT COUPLE OF

2669
03:20:04,520 --> 03:20:06,680
GENES WITH THOSE DRAMATIC OF

2670
03:20:06,680 --> 03:20:09,720
CLUSTERS WITHIN A VERY SMALL

2671
03:20:09,720 --> 03:20:16,800
REGION AND THOSE THAT ARE

2672
03:20:16,800 --> 03:20:19,400
CLUSTERED.

2673
03:20:19,400 --> 03:20:22,520
SO IN A REGION IF YOU THINK

2674
03:20:22,520 --> 03:20:26,120
ABOUT IT A COUPLE OF TINY

2675
03:20:26,120 --> 03:20:31,320
AXONS IN THERE SO YOU CAN SEE

2676
03:20:31,320 --> 03:20:37,480
THAT IS NOT TO SURPRISING VERY

2677
03:20:37,480 --> 03:20:38,000
EASILY MISSED EVEN IF THEY

2678
03:20:38,000 --> 03:20:41,360
WOULD BE THERE THEY ARE ALL

2679
03:20:41,360 --> 03:20:44,200
POINTING IN THE SAME

2680
03:20:44,200 --> 03:20:47,400
DIRECTION.

2681
03:20:47,400 --> 03:20:48,000
SO THEN YOU GET INTEGRATIONS

2682
03:20:48,000 --> 03:20:50,720
AND THOSE DIRECTIONS AND NO

2683
03:20:50,720 --> 03:20:55,480
PARTICULAR BIAS MAY BE A

2684
03:20:55,480 --> 03:20:56,240
SLIGHT INTEGRATION BIAS BUT

2685
03:20:56,240 --> 03:21:01,640
THAT IS A DIFFERENT STORY.

2686
03:21:01,640 --> 03:21:04,680
SO WHEN YOU LOOK AT A BUNCH OF

2687
03:21:04,680 --> 03:21:09,680
THESE THOSE THAT HAVE THE SAME

2688
03:21:09,680 --> 03:21:11,320
PROPERTY OF CLUSTERED

2689
03:21:11,320 --> 03:21:15,560
INTEGRATIONS THESE ARE

2690
03:21:15,560 --> 03:21:16,880
EXPANDED LIKE EVERYTHING ELSE

2691
03:21:16,880 --> 03:21:20,160
BUT WITH THE EXPANSION AS I

2692
03:21:20,160 --> 03:21:26,440
WILL SHOW YOU IN A SECOND.

2693
03:21:26,440 --> 03:21:26,960
SO THIS IS RELATIVE TO THE

2694
03:21:26,960 --> 03:21:34,880
PROTEIN AND BASICALLY THEY ARE

2695
03:21:34,880 --> 03:21:41,040
DEREGULATING THE EXPRESSION SO

2696
03:21:41,040 --> 03:21:44,720
ACTUALLY IT IS INSIDE THE GENE

2697
03:21:44,720 --> 03:21:47,120
IT IS WELL-PLACED TO BE

2698
03:21:47,120 --> 03:21:50,160
REMOVING A NEGATIVE REGULATORY

2699
03:21:50,160 --> 03:22:00,640
DOMAIN AND THEN THAT ALL TIME

2700
03:22:03,040 --> 03:22:08,080
RETRO- VIROLOGY.

2701
03:22:08,080 --> 03:22:14,560
THAT'S CANCER FROM BEFORE.

2702
03:22:14,560 --> 03:22:22,960
AND THESE ARE CANCERS.

2703
03:22:22,960 --> 03:22:28,160
AND THOSE THAT YOU CAN SEE.

2704
03:22:28,160 --> 03:22:31,920
AND WITH THE PW H.

2705
03:22:31,920 --> 03:22:37,440
THEY ARE NOT CANCERS WITH

2706
03:22:37,440 --> 03:22:37,960
UNIMPEDED GROWTH AND DOING

2707
03:22:37,960 --> 03:22:42,680
SOMETHING ELSE.

2708
03:22:42,680 --> 03:22:43,720
SO ONE OF THE THINGS TO KEEP

2709
03:22:43,720 --> 03:22:49,400
IN MIND SO THIS IS A LIST OF

2710
03:22:49,400 --> 03:22:49,920
GENES THAT WE CAME UP WITH

2711
03:22:49,920 --> 03:22:50,400
FROM THE PAPER THAT WE

2712
03:22:50,400 --> 03:22:58,280
PUBLISHED A YEAR AGO.

2713
03:22:58,280 --> 03:22:58,840
SO WITH THAT INTEGRATION CAN

2714
03:22:58,840 --> 03:23:02,480
BE QUITE DRAMATIC IT'S ONLY A

2715
03:23:02,480 --> 03:23:07,640
COUPLE OF PERCENT SO IT'S NOT

2716
03:23:07,640 --> 03:23:08,240
A HUGE PART OF WHAT'S GOING ON

2717
03:23:08,240 --> 03:23:10,640
THE CHEST THE MOST STRIKING

2718
03:23:10,640 --> 03:23:12,720
PART THAT PROBABLY DOING

2719
03:23:12,720 --> 03:23:17,320
SOMETHING INTERESTING ONE OF

2720
03:23:17,320 --> 03:23:23,560
THE THINGS THAT WE DID WAS TO

2721
03:23:23,560 --> 03:23:26,600
LOOK AT THE PATIENTS ON

2722
03:23:26,600 --> 03:23:27,160
THERAPY WHEN IT'S A LITTLE

2723
03:23:27,160 --> 03:23:31,800
MORE COMPLICATED BUT SO WE

2724
03:23:31,800 --> 03:23:34,800
LOOK AT THAT AMPLIFICATION

2725
03:23:34,800 --> 03:23:42,880
RATIO SO TO HAVE A SITE THAT

2726
03:23:42,880 --> 03:23:43,440
IS AMPLIFIED YOU SEE THAT

2727
03:23:43,440 --> 03:23:43,960
TWICE IN YOUR SAMPLE THAT

2728
03:23:43,960 --> 03:23:45,720
WOULD HAVE THE AMPLIFICATION

2729
03:23:45,720 --> 03:23:51,880
RATIO.

2730
03:23:51,880 --> 03:23:55,280
SO ALL OF THOSE ARE AMPLIFIED

2731
03:23:55,280 --> 03:23:58,400
TO EXACTLY THE SAME EXTENT IT

2732
03:23:58,400 --> 03:24:00,360
IS NOT DRIVING THE

2733
03:24:00,360 --> 03:24:01,840
AMPLIFICATION IT'S BEING

2734
03:24:01,840 --> 03:24:07,840
DRIVEN BY CELL BIOLOGY AND THE

2735
03:24:07,840 --> 03:24:11,480
ENERGY RECOGNITION AND WITH

2736
03:24:11,480 --> 03:24:15,720
THE INFECTED CELL AND EVEN THE

2737
03:24:15,720 --> 03:24:17,680
GENES BECAUSE THE NUMBERS ARE

2738
03:24:17,680 --> 03:24:19,760
SMALL EVEN THOSE THAT WE

2739
03:24:19,760 --> 03:24:23,360
IDENTIFIED IF YOU LOOK AT THE

2740
03:24:23,360 --> 03:24:26,360
AVERAGE IN THE GENES THAT WE

2741
03:24:26,360 --> 03:24:27,840
IDENTIFIED TO HAVE THESE

2742
03:24:27,840 --> 03:24:30,120
CLUSTERS AND INTEGRATION SITES

2743
03:24:30,120 --> 03:24:36,440
IT'S NOT SIGNIFICANTLY GREATER

2744
03:24:36,440 --> 03:24:37,000
THAN FOR THE GENES OVERALL

2745
03:24:37,000 --> 03:24:37,840
THIS EXPERIMENT WAS NOT DONE

2746
03:24:37,840 --> 03:24:46,040
BY US BUT IT WAS DONE BY ONE

2747
03:24:46,040 --> 03:24:56,480
OF OUR FAVORITE ALUMNI AND

2748
03:24:56,880 --> 03:25:03,280
WHAT HE DID WAS TO ISOLATE THE

2749
03:25:03,280 --> 03:25:06,480
CELLS FROM THOSE PATIENTS BY

2750
03:25:06,480 --> 03:25:12,040
THEIR SPECIFICITY INCLUDING

2751
03:25:12,040 --> 03:25:16,360
HIV SO WE TAKE THOSE CLONE

2752
03:25:16,360 --> 03:25:17,440
CELLS IN THE TWO WHERE THE

2753
03:25:17,440 --> 03:25:22,920
INTEGRATION SITES WERE SO THAT

2754
03:25:22,920 --> 03:25:29,920
ALMOST ALL OF THESE ARE VERY

2755
03:25:29,920 --> 03:25:32,840
HIGHLY EFFECTIVE WITH ONE

2756
03:25:32,840 --> 03:25:34,680
EXCEPTION BUT IF YOU LOOK AT

2757
03:25:34,680 --> 03:25:44,800
THE RED ONE SO LOOK AT THOSE

2758
03:25:44,800 --> 03:25:51,560
IN THE GENES SO IN THIS CASE

2759
03:25:51,560 --> 03:25:57,280
OVER ONE THIRD OF THEM MORE

2760
03:25:57,280 --> 03:26:02,440
THAN ONE THIRD OF THESE HAVE

2761
03:26:02,440 --> 03:26:05,400
INTEGRATION SITES WITH THESE

2762
03:26:05,400 --> 03:26:09,640
GENES THAT THERE IS A SYNERGY

2763
03:26:09,640 --> 03:26:18,680
BETWEEN THE STIMULATION OF

2764
03:26:18,680 --> 03:26:21,760
THESE GENES AND ONE GUEST THAT

2765
03:26:21,760 --> 03:26:27,040
I HAVE IS NOT JUST THE GROWTH

2766
03:26:27,040 --> 03:26:31,800
OF THE CELLS BUT THE EXTENT TO

2767
03:26:31,800 --> 03:26:32,800
WHICH THEY ARE LOST DURING THE

2768
03:26:32,800 --> 03:26:35,800
DK PHASE BECAUSE THE GROWTH OF

2769
03:26:35,800 --> 03:26:41,120
THE CELLS FROM WHAT THESE

2770
03:26:41,120 --> 03:26:43,920
REPRESENT HAVE THE UP-AND-DOWN

2771
03:26:43,920 --> 03:26:47,960
PATTERN IF THE EXPRESSION OF

2772
03:26:47,960 --> 03:26:54,640
THE GENES IS INHIBITORY THEN

2773
03:26:54,640 --> 03:26:55,600
THEY WILL BE SELECTIVE BECAUSE

2774
03:26:55,600 --> 03:27:00,680
OF THAT SO THAT IS A GUESS

2775
03:27:00,680 --> 03:27:06,520
RIGHT NOW.

2776
03:27:06,520 --> 03:27:10,720
>>SO WE LEARNED SURVIVAL
BY

2777
03:27:10,720 --> 03:27:13,600
THE CELLS THESE ARE FOR

2778
03:27:13,600 --> 03:27:20,600
IMPORTANT CONTRIBUTIONS AND

2779
03:27:20,600 --> 03:27:26,600
THEY WILL SHOW YOU THIS BUT A

2780
03:27:26,600 --> 03:27:27,160
BUNCH OF OTHER PEOPLE HERE

2781
03:27:27,160 --> 03:27:31,320
CO-AUTHORED A PAPER YOU COULD

2782
03:27:31,320 --> 03:27:37,520
ALREADY SEE WHEN THEY STARTED

2783
03:27:37,520 --> 03:27:38,080
THE ANTIRETROVIRAL THERAPY

2784
03:27:38,080 --> 03:27:42,200
WITHIN A FEW WEEKS IT MUST BE

2785
03:27:42,200 --> 03:27:43,200
UP TO 100,000 OR MAYBE

2786
03:27:43,200 --> 03:27:47,480
1 MILLION CELLS SO THE IDEA

2787
03:27:47,480 --> 03:27:53,400
THAT IT JUST DOESN'T WORK THEY

2788
03:27:53,400 --> 03:27:54,000
CANNOT HAVE BEEN RESTING VERY

2789
03:27:54,000 --> 03:27:55,080
LONG BECAUSE THEY ARE

2790
03:27:55,080 --> 03:28:00,080
PROVIDING CONSTANTLY AND ALSO

2791
03:28:00,080 --> 03:28:03,360
TO BE MODIFIED I HAVE NOT

2792
03:28:03,360 --> 03:28:07,640
SHOWED YOU THIS EITHER BUT THE

2793
03:28:07,640 --> 03:28:10,640
PATTERN OF INTEGRATION CHANGES

2794
03:28:10,640 --> 03:28:13,400
AFTER YOU START THERAPY

2795
03:28:13,400 --> 03:28:18,800
BECAUSE OF THE SELECTION THOSE

2796
03:28:18,800 --> 03:28:25,840
OF THE SAME ORIENTATION.

2797
03:28:25,840 --> 03:28:27,840
TALKING ABOUT CLUSTERS OF

2798
03:28:27,840 --> 03:28:34,200
INTEGRATION SO WITH THAT I

2799
03:28:34,200 --> 03:28:35,280
WILL CLOSE.

2800
03:28:35,280 --> 03:28:40,640
THANK YOU TO THOSE OF YOU WHO

2801
03:28:40,640 --> 03:28:41,240
ARE HERE AND HAVE DONE SO MUCH

2802
03:28:41,240 --> 03:28:45,280
WONDERFUL WORK OVER THE YEARS

2803
03:28:45,280 --> 03:28:52,840
AND TO SEVERAL PEOPLE AND OF

2804
03:28:52,840 --> 03:28:53,440
COURSE THANK YOU TO STEVE FOR

2805
03:28:53,440 --> 03:28:54,880
ALL OF HIS YEARS WITH US.

2806
03:28:54,880 --> 03:29:05,040
[APPLAUSE]

2807
03:29:05,280 --> 03:29:09,400
>>SORRY TO SLIP A LITTLE
BIT

2808
03:29:09,400 --> 03:29:11,200
YOU CAN ASK QUESTIONS AT LUNCH

2809
03:29:11,200 --> 03:29:14,440
SO THE NEXT SPEAKER IS LARRY

2810
03:29:14,440 --> 03:29:15,880
WHO HAD THAT DISTINGUISHED

2811
03:29:15,880 --> 03:29:19,160
CAREER AND ALSO SERVED

2812
03:29:19,160 --> 03:29:21,160
ADMINISTRATIVE GOALS HERE IN

2813
03:29:21,160 --> 03:29:24,040
FREDERICK INCLUDING THE

2814
03:29:24,040 --> 03:29:26,160
PRESIDENT THERE ON THAT SHE'LL

2815
03:29:26,160 --> 03:29:29,840
BE GIVING US THE FIRST OF

2816
03:29:29,840 --> 03:29:30,440
SEVERAL MAD SCIENCE AND THERE

2817
03:29:30,440 --> 03:29:32,800
WOULD BE SOME FISHING SCIENCE

2818
03:29:32,800 --> 03:29:39,480
AS PART OF THE STOCK ONE —-

2819
03:29:39,480 --> 03:29:39,880
PART OF HIS TALK.

2820
03:29:39,880 --> 03:29:42,960
>>I MAY TALK A LITTLE BIT

2821
03:29:42,960 --> 03:29:44,960
ABOUT STEVE'S FISHING

2822
03:29:44,960 --> 03:29:47,520
CAPABILITY FIRST OF ALL

2823
03:29:47,520 --> 03:29:50,120
CONGRATULATIONS ON YOUR

2824
03:29:50,120 --> 03:29:56,080
RETIREMENT AND ALL OF THE

2825
03:29:56,080 --> 03:29:56,680
SCIENTIFIC ACCOMPLISHMENTS YOU

2826
03:29:56,680 --> 03:29:57,280
HAVE HAD DURING YOUR CAREER.

2827
03:29:57,280 --> 03:29:59,720
I WILL CONCENTRATE TODAY ON

2828
03:29:59,720 --> 03:30:01,720
STAGE PREPARATION FOR

2829
03:30:01,720 --> 03:30:03,480
POSTRETIREMENT.

2830
03:30:03,480 --> 03:30:04,040
HE HAS WORKED REALLY HARD AT

2831
03:30:04,040 --> 03:30:05,520
THAT.

2832
03:30:05,520 --> 03:30:08,680
[LAUGHTER]

2833
03:30:08,680 --> 03:30:09,680
AND IS QUESTIONING WHETHER OR

2834
03:30:09,680 --> 03:30:20,040
NOT HE IS DEDICATED.

2835
03:30:27,240 --> 03:30:27,680
SO WE MOSTLY HAVE FISH IN

2836
03:30:27,680 --> 03:30:30,120
WESTERN MARYLAND BUT LET ME

2837
03:30:30,120 --> 03:30:33,480
TELL YOU HE SENDS HIS

2838
03:30:33,480 --> 03:30:35,720
APOLOGIES TO NOT MAKE THE

2839
03:30:35,720 --> 03:30:35,920
TRIP.

2840
03:30:35,920 --> 03:30:45,440
WHEN BOB RETIRED HE TALKS HE

2841
03:30:45,440 --> 03:30:46,000
BY THE HOUSE IMPORTANT SHORT

2842
03:30:46,000 --> 03:30:46,640
ON —- PORT CHARLOTTE THE LAST

2843
03:30:46,640 --> 03:30:47,200
HURRICANE THE I WENT RIGHT

2844
03:30:47,200 --> 03:30:47,600
OVER THERE HOUSE.

2845
03:30:47,600 --> 03:30:51,800
I AM GLAD TO REPORT THEY

2846
03:30:51,800 --> 03:30:52,240
SUFFERED MINOR DAMAGE.

2847
03:30:52,240 --> 03:30:54,760
THEY NOW HAVE ELECTRICITY AND

2848
03:30:54,760 --> 03:30:58,480
WATER IN THEIR HOUSE.

2849
03:30:58,480 --> 03:31:05,000
BUT UNFORTUNATELY BOB CANNOT

2850
03:31:05,000 --> 03:31:05,520
ATTEND BUT HE SENT ME SOME

2851
03:31:05,520 --> 03:31:06,120
SLIDES AND I USE THOSE IN MY

2852
03:31:06,120 --> 03:31:06,760
PRESENTATION AS WELL.

2853
03:31:06,760 --> 03:31:13,160
SO LIKE I MENTIONED WE DECIDED

2854
03:31:13,160 --> 03:31:18,200
IN 2061 OF HIS FRIENDS JOINED

2855
03:31:18,200 --> 03:31:21,960
US AS WELL SO THE FOUR OF US

2856
03:31:21,960 --> 03:31:29,400
MONTHS BEFORE I HAD BEEN NOT

2857
03:31:29,400 --> 03:31:32,480
THAT WE HAD NOT BEEN ON THE

2858
03:31:32,480 --> 03:31:35,160
RIVER.

2859
03:31:35,160 --> 03:31:39,880
SO WE FLEW TO BATTLE WITH THE

2860
03:31:39,880 --> 03:31:44,920
MATERIAL THAT WE NEEDED AND HE

2861
03:31:44,920 --> 03:31:47,920
FLEW WAS UP TO THE TOP OF THE

2862
03:31:47,920 --> 03:31:54,600
LAKE AND THEN TO PUMP UP THE

2863
03:31:54,600 --> 03:32:00,360
RAFT.

2864
03:32:00,360 --> 03:32:00,960
AND NONE OF US HAVE EVER WROTE

2865
03:32:00,960 --> 03:32:05,840
A RAFT LIKE THIS BEFORE.

2866
03:32:05,840 --> 03:32:08,880
SOMETIMES WE WORRY ABOUT THE

2867
03:32:08,880 --> 03:32:10,360
DECISION-MAKING.

2868
03:32:10,360 --> 03:32:10,960
SOMETIMES WE WORRY ABOUT THAT

2869
03:32:10,960 --> 03:32:13,400
EVEN MORE.

2870
03:32:13,400 --> 03:32:18,600
BUT WE FOUND OUT QUICKLY BY

2871
03:32:18,600 --> 03:32:22,600
SAYING GOODBYE TO THE FLOOD

2872
03:32:22,600 --> 03:32:24,600
PLANE BUT THEN WE REALIZED WE

2873
03:32:24,600 --> 03:32:27,080
WOULD NOT SEE ANOTHER PERSON

2874
03:32:27,080 --> 03:32:30,000
FOR FIVE OR SEVEN DAYS OF OUR

2875
03:32:30,000 --> 03:32:31,240
TRIP.

2876
03:32:31,240 --> 03:32:37,480
WE DID NOT EVEN SEE A CAMPSITE

2877
03:32:37,480 --> 03:32:38,080
THIS ENTIRE TIME THAT WE DID

2878
03:32:38,080 --> 03:32:42,960
FIND ONE MORE ELEMENT.

2879
03:32:42,960 --> 03:32:44,000
HE WAS QUITE GOOD AND IS

2880
03:32:44,000 --> 03:32:47,120
IMPORTANT BECAUSE THE SNOWFALL

2881
03:32:47,120 --> 03:32:50,000
THAT THEY GET NOTES IN THE

2882
03:32:50,000 --> 03:32:52,440
SPRING AND THEN IT BRINGS NEW

2883
03:32:52,440 --> 03:32:57,520
CHANNELS AND THEY HAVE TREES

2884
03:32:57,520 --> 03:33:00,760
HANGING OVER THE BRAIDS.

2885
03:33:00,760 --> 03:33:05,880
THEY ARE CALLED SWEEPERS FOR A

2886
03:33:05,880 --> 03:33:06,200
GOOD REASON.

2887
03:33:06,200 --> 03:33:11,360
HE HAS FOUND WAYS WITH AN

2888
03:33:11,360 --> 03:33:14,320
UNSCHEDULED SWIM YOU WILL

2889
03:33:14,320 --> 03:33:16,280
NOTICE HIS CLOSE ARE HANGING

2890
03:33:16,280 --> 03:33:21,560
AND DRYING OUT ANY QUESTIONS

2891
03:33:21,560 --> 03:33:23,440
JUST ASK STEVE.

2892
03:33:23,440 --> 03:33:26,720
[LAUGHTER]

2893
03:33:26,720 --> 03:33:27,280
THE OTHER THING WE FOUND OUT

2894
03:33:27,280 --> 03:33:30,280
RAPIDLY ON THE TRIP IS THAT

2895
03:33:30,280 --> 03:33:40,840
STEVE IS A CHEF EXTRAORDINAIRE.

2896
03:33:40,840 --> 03:33:41,440
ONCE WE FINISHED OUR DAY AND

2897
03:33:41,440 --> 03:33:42,200
SET UP CAMP TO BUILD A FIRE

2898
03:33:42,200 --> 03:33:45,720
GOT EVERYTHING READY PULL UP A

2899
03:33:45,720 --> 03:33:49,960
CHAIR STEVE OWEN SIT IN IT AND

2900
03:33:49,960 --> 03:33:50,480
TELL US WHAT HE NEEDED BE

2901
03:33:50,480 --> 03:33:51,080
WOULD BRING HIM EVERY SINGLE

2902
03:33:51,080 --> 03:33:53,000
THING HE NEEDED.

2903
03:33:53,000 --> 03:33:55,680
NOW YOU CAN SEE HE HAS GROWN

2904
03:33:55,680 --> 03:34:01,520
SOME SALMON BUT IT WAS PRETTY

2905
03:34:01,520 --> 03:34:02,440
EASY TO KEEP THE MASTER CHEF

2906
03:34:02,440 --> 03:34:10,040
AT WORK SINCE WE DIDN'T HAVE

2907
03:34:10,040 --> 03:34:10,600
TO CARRY ANYTHING ONCE WE

2908
03:34:10,600 --> 03:34:15,160
BROUGHT INTO THE RAFT WE HAD

2909
03:34:15,160 --> 03:34:17,040
STEAK AND BAKED POTATOES AND

2910
03:34:17,040 --> 03:34:24,840
SALADS AND HE MADE SPAGHETTI

2911
03:34:24,840 --> 03:34:25,360
AND THEN WE DID NOT SUFFER

2912
03:34:25,360 --> 03:34:28,040
FROM A LACK OF FOOD.

2913
03:34:28,040 --> 03:34:31,120
I SHOW HERE AND HERE WITH A

2914
03:34:31,120 --> 03:34:34,480
RAINBOW TROUT THAT HE GOT AND

2915
03:34:34,480 --> 03:34:37,560
ALTHOUGH FISHERMEN ARE KNOWN

2916
03:34:37,560 --> 03:34:38,600
TO STRETCH THE TRUTH THAT HE

2917
03:34:38,600 --> 03:34:41,400
GOT OVER 100 FISH ON THE TRIP

2918
03:34:41,400 --> 03:34:47,640
DOES NOT STRETCH THE TRUTH.

2919
03:34:47,640 --> 03:34:58,120
AND THEN AND THEN WE DECIDED

2920
03:35:00,520 --> 03:35:01,040
THAT WE WERE CHECKING OUT THE

2921
03:35:01,040 --> 03:35:02,720
FOLLOWING AND ALSO WE HAD A

2922
03:35:02,720 --> 03:35:08,560
CLOSER LOOK AT IT SO EVEN WITH

2923
03:35:08,560 --> 03:35:15,880
STEVE WE CANNOT RUN IT.

2924
03:35:15,880 --> 03:35:18,920
SO OUR LAST RAFTING TRIP TO

2925
03:35:18,920 --> 03:35:20,640
ALASKA THAT TURNED OUT TO BE

2926
03:35:20,640 --> 03:35:27,160
ONE OF THE BEST DECISIONS WE

2927
03:35:27,160 --> 03:35:27,680
HAD ADDITIONAL PEOPLE JOIN

2928
03:35:27,680 --> 03:35:27,880
US.

2929
03:35:27,880 --> 03:35:29,720
YOU ARE RECOGNIZED.

2930
03:35:29,720 --> 03:35:35,040
AND OF COURSE FUTURE SATELLITE

2931
03:35:35,040 --> 03:35:40,760
JOINS US AS WELL.

2932
03:35:40,760 --> 03:35:41,280
AND I HAD TO PUT THIS IN

2933
03:35:41,280 --> 03:35:43,920
BECAUSE IT WAS QUITE AN

2934
03:35:43,920 --> 03:35:47,200
ADVENTURE.

2935
03:35:47,200 --> 03:35:50,520
THAT WE HAD TO TAKE A SHORT

2936
03:35:50,520 --> 03:35:51,600
CUT AND TAKE EVERYTHING OUT OF

2937
03:35:51,600 --> 03:35:55,960
THE PLANE BECAUSE THEY HAVE TO

2938
03:35:55,960 --> 03:36:00,760
LAND IN THE TUNDRA AND THEN

2939
03:36:00,760 --> 03:36:05,640
THEY HAVE TO TAKE OFF AGAIN.

2940
03:36:05,640 --> 03:36:08,040
AS SOON AS THE PILOT LOOKED AT

2941
03:36:08,040 --> 03:36:12,840
STEVE SO THEY NEVER HAD ANYONE

2942
03:36:12,840 --> 03:36:13,360
LIKE THIS BEFORE THEN THE

2943
03:36:13,360 --> 03:36:15,080
CHILLS RAN DOWN MY SPINE.

2944
03:36:15,080 --> 03:36:15,520
[LAUGHTER]

2945
03:36:15,520 --> 03:36:18,400
BUT THE FLIGHT WAS ONLY A 30

2946
03:36:18,400 --> 03:36:21,680
MINUTE FLIGHT BUT 15 MINUTES

2947
03:36:21,680 --> 03:36:22,480
OF THOSE GETTING STEVE INTO

2948
03:36:22,480 --> 03:36:27,920
THE PLANE.

2949
03:36:27,920 --> 03:36:29,440
[LAUGHTER]

2950
03:36:29,440 --> 03:36:35,680
SO HE HAD TO CRAWL THROUGH

2951
03:36:35,680 --> 03:36:36,280
WHERE THE PILOT SEAT WAS OVER

2952
03:36:36,280 --> 03:36:36,880
THE CONTROLS AND GOT INTO THE

2953
03:36:36,880 --> 03:36:41,360
PASSENGER SEAT.

2954
03:36:41,360 --> 03:36:41,960
AND THE FRAME OF THE PLANE WAS

2955
03:36:41,960 --> 03:36:44,560
SO LOW HE COULD NOT GET HIS

2956
03:36:44,560 --> 03:36:48,520
HEAD AND I WAS REALLY

2957
03:36:48,520 --> 03:36:48,760
CONCERNED.

2958
03:36:48,760 --> 03:36:49,360
BUT HE WENT UP AND AROUND AND

2959
03:36:49,360 --> 03:36:51,400
EXTENDED HIS HEAD ABOVE THE

2960
03:36:51,400 --> 03:36:52,800
FRAME THE PILOT SAID PLEASE

2961
03:36:52,800 --> 03:36:53,280
DON'T YOUR HEAD TO THE

2962
03:36:53,280 --> 03:36:54,120
FABRIC.

2963
03:36:54,120 --> 03:36:54,400
[LAUGHTER]

2964
03:36:54,400 --> 03:37:00,280
SO WE LANDED NO PROBLEM.

2965
03:37:00,280 --> 03:37:06,680
THIS SHOWS THE TROUT CLOSE TO

2966
03:37:06,680 --> 03:37:07,000
CAMP.

2967
03:37:07,000 --> 03:37:11,000
I DON'T KNOW IF JEFF TOOK THIS

2968
03:37:11,000 --> 03:37:17,760
OR WHO BUT WE HAVE SOME

2969
03:37:17,760 --> 03:37:20,560
ABSOLUTELY WONDERFUL DRONE

2970
03:37:20,560 --> 03:37:22,360
SHOTS.

2971
03:37:22,360 --> 03:37:22,960
SO KNOWING THAT BOB HAD MOVED

2972
03:37:22,960 --> 03:37:24,400
TO FLORIDA THIS IS ANOTHER

2973
03:37:24,400 --> 03:37:29,600
OPPORTUNITY AND THAT 100-POUND

2974
03:37:29,600 --> 03:37:32,440
TARPON HE BROUGHT UP TO THE

2975
03:37:32,440 --> 03:37:34,520
BOAT.

2976
03:37:34,520 --> 03:37:35,000
AND DID I SAY STEVE IS

2977
03:37:35,000 --> 03:37:40,200
COMMITTED TO FISHING?

2978
03:37:40,200 --> 03:37:40,680
HE WOULD BE TAKING A NAP

2979
03:37:40,680 --> 03:37:41,280
ALTHOUGH HE SAID HE WAS JUST

2980
03:37:41,280 --> 03:37:43,600
RESTING HIS BACK YOU KNOW HE

2981
03:37:43,600 --> 03:37:45,080
HAS A FISHING ROUTE RIGHT

2982
03:37:45,080 --> 03:37:45,280
HERE.

2983
03:37:45,280 --> 03:37:45,520
[LAUGHTER]

2984
03:37:45,520 --> 03:37:48,840
HE WILL NOT NOT GIVE UP THE

2985
03:37:48,840 --> 03:37:50,440
OPPORTUNITY TO CATCH MORE

2986
03:37:50,440 --> 03:37:51,480
FISH.

2987
03:37:51,480 --> 03:37:55,720
SO STEVE HAS JOINED US AT A

2988
03:37:55,720 --> 03:37:56,720
FLY FISH ON —- FLY FISHING

2989
03:37:56,720 --> 03:38:00,600
CLUB NEAR GETTYSBURG.

2990
03:38:00,600 --> 03:38:03,000
IT'S A NICE FLY FISHING AREA

2991
03:38:03,000 --> 03:38:06,240
WE HAVE A NUMBER OF PEOPLE.

2992
03:38:06,240 --> 03:38:16,640
I NEED TO SHOW HIS FISH.

2993
03:38:16,640 --> 03:38:19,800
THERE IS A TIGER THERE IS A

2994
03:38:19,800 --> 03:38:20,120
RAINBOW.

2995
03:38:20,120 --> 03:38:26,680
CLICK ON HIS NAME.

2996
03:38:26,680 --> 03:38:37,200
SO THEY HAVE A NICE THING THAT

2997
03:38:40,200 --> 03:38:42,560
SO THEN AN OLD FISHING BUDDY

2998
03:38:42,560 --> 03:38:46,160
FROM THE UNIVERSITY OF

2999
03:38:46,160 --> 03:38:49,240
MINNESOTA WE HAD PEOPLE IN THE

3000
03:38:49,240 --> 03:38:55,200
AUDIENCE AND THEN TO BE UP

3001
03:38:55,200 --> 03:38:59,280
THERE THAT IS A NICE PLACE TO

3002
03:38:59,280 --> 03:39:01,160
VISIT SO JUST BECOME FRIENDS

3003
03:39:01,160 --> 03:39:02,520
WITH STEVE AND HE WILL FIX YOU

3004
03:39:02,520 --> 03:39:02,680
UP.

3005
03:39:02,680 --> 03:39:07,680
THE OTHER THING WE DO THAT IS

3006
03:39:07,680 --> 03:39:10,280
REWARDING TO PARTICIPATE WITH

3007
03:39:10,280 --> 03:39:13,440
PROJECT HEALING WATERS TO

3008
03:39:13,440 --> 03:39:17,440
BRING OUT FROM WALTER REED AND

3009
03:39:17,440 --> 03:39:22,680
TO SERVE AS GUIDES WHEN IN

3010
03:39:22,680 --> 03:39:23,280
FACT STEVE WAS THE GUY TWO

3011
03:39:23,280 --> 03:39:28,080
WEEKS AGO FOR ONE OF THESE

3012
03:39:28,080 --> 03:39:33,560
OUTINGS.

3013
03:39:33,560 --> 03:39:34,960
SO BRADY HAS BEEN FISHING WITH

3014
03:39:34,960 --> 03:39:38,200
HIM FOR A NUMBER OF YEARS AND

3015
03:39:38,200 --> 03:39:41,240
NOW LAST WEEK THIS IS A

3016
03:39:41,240 --> 03:39:46,680
PICTURE LAST WEEK LOOKING

3017
03:39:46,680 --> 03:39:49,520
FURTHER TO GETTING OUT TO THE

3018
03:39:49,520 --> 03:39:50,480
FISHING AREA IT WAS

3019
03:39:50,480 --> 03:39:55,720
3:00 O'CLOCK IN THE MORNING SO

3020
03:39:55,720 --> 03:39:56,320
LET ME TELL YOU THAT IF ANYONE

3021
03:39:56,320 --> 03:40:02,480
IS WORRIED ABOUT STEVE WRITING

3022
03:40:02,480 --> 03:40:03,000
OUT TO THE SUNSET WITH HIS

3023
03:40:03,000 --> 03:40:03,520
RETIREMENT I THINK HE IS

3024
03:40:03,520 --> 03:40:06,960
HEADED INTO THE SUNRISE.

3025
03:40:06,960 --> 03:40:17,160
[APPLAUSE]

3026
03:40:18,440 --> 03:40:26,040
>>THANK YOU VERY MUCH.

3027
03:40:26,040 --> 03:40:26,600
SO I WILL BE GOING ON A TRIP

3028
03:40:26,600 --> 03:40:27,120
TO ALASKA NEXT SUMMER SO I

3029
03:40:27,120 --> 03:40:29,480
WILL REPORT BACK HOW THAT

3030
03:40:29,480 --> 03:40:29,680
GOES.

3031
03:40:29,680 --> 03:40:32,720
WE WILL BREAK FOR LUNCH WE ARE

3032
03:40:32,720 --> 03:40:36,840
RUNNING A LITTLE BIT BEHIND

3033
03:40:36,840 --> 03:40:39,240
THE LET'S RECONVENE AT 1:30

3034
03:40:39,240 --> 03:40:43,720
WE'LL GET STARTED.

3035
03:40:43,720 --> 03:40:48,320
NEXT SPEAKER IS JEFF, RECRUITED

3036
03:40:48,320 --> 03:40:54,160
WITH STEVE BY GEORGE VANDER WOOD

3037
03:40:54,160 --> 03:40:59,880
IN THE 1980s, SENIOR 

3038
03:40:59,880 --> 03:41:00,800
INVESTIGATOR, DEPUTY DIRECTOR AT

3039
03:41:00,800 --> 03:41:02,000
NCI CANCER RESEARCH, A LONGTIME

3040
03:41:02,000 --> 03:41:03,200
FISHING BUDDY AND I EXPECT WE'LL

3041
03:41:03,200 --> 03:41:09,080
HEAR ABOUT THAT IN THIS TALK.

3042
03:41:09,080 --> 03:41:10,280
>>WELL, THANK YOU.

3043
03:41:10,280 --> 03:41:14,240
IT'S A REAL HONOR TO BE IN

3044
03:41:14,240 --> 03:41:17,200
POSITION TO BRAG ABOUT STEVE,

3045
03:41:17,200 --> 03:41:20,120
AND STAY A LITTLE BIT ABOUT THE

3046
03:41:20,120 --> 03:41:22,760
RELATIONSHIP I'VE HAD WITH HIM

3047
03:41:22,760 --> 03:41:25,040
THAT SPANS THE TOPIC OF SCIENCE,

3048
03:41:25,040 --> 03:41:27,480
AN IMPORTANT FEATURE THAT

3049
03:41:27,480 --> 03:41:29,840
RELATES TO OUR FAMILIES, AND

3050
03:41:29,840 --> 03:41:32,200
FISHING.

3051
03:41:32,200 --> 03:41:37,040
 

3052
03:41:37,040 --> 03:41:42,840
STEVE IS A BIG BY, OKAY?

3053
03:41:42,840 --> 03:41:45,320
AND HIS HANDSHAKE IS FIRM AND

3054
03:41:45,320 --> 03:41:46,280
WELCOMING.

3055
03:41:46,280 --> 03:41:51,440
HE'S STRONG ENOUGH TO BREAK A

3056
03:41:51,440 --> 03:41:53,400
SLEDGEHAMMER WHILE HITTING THE

3057
03:41:53,400 --> 03:41:55,600
ROCK IN FAIR FASHION, NOT

3058
03:41:55,600 --> 03:41:58,040
OVERREACHING A SPIKE OR

3059
03:41:58,040 --> 03:41:58,480
SOMETHING.

3060
03:41:58,480 --> 03:42:04,760
BUT IN ADDITION, HE'S GOT A HUGE

3061
03:42:04,760 --> 03:42:06,280
PERSONALITY, A BIG INTELLECT,

3062
03:42:06,280 --> 03:42:09,640
HELPED LOTS OF PROJECTS WHEN HE

3063
03:42:09,640 --> 03:42:10,320
WAS INVOLVED.

3064
03:42:10,320 --> 03:42:12,640
STEVE MOVED IN NEXT DOOR TO MY

3065
03:42:12,640 --> 03:42:16,840
FAMILY, MY WIFE ANN AND MY

3066
03:42:16,840 --> 03:42:18,520
DAUGHTER LESLIE.

3067
03:42:18,520 --> 03:42:22,480
IN THE TOP TWO FLOORS OF THE

3068
03:42:22,480 --> 03:42:23,320
BUILDING BEHIND US IN COLD

3069
03:42:23,320 --> 03:42:24,320
SPRING HARBOR.

3070
03:42:24,320 --> 03:42:31,200
WE SHARED A WALL.

3071
03:42:31,200 --> 03:42:32,280
YOU COULD WALK THROUGH THIS, I

3072
03:42:32,280 --> 03:42:34,280
DON'T KNOW WHAT THAT WAS ABOUT.

3073
03:42:34,280 --> 03:42:36,440
A FEW MONTHS AFTER STEVE MOVED

3074
03:42:36,440 --> 03:42:41,280
IN, MY SON RUSSELL WAS BORN.

3075
03:42:41,280 --> 03:42:43,360
SO, HAVING THAT EXTENDED FAMILY

3076
03:42:43,360 --> 03:42:46,960
WAS AN ESSENTIAL COMPONENT OF

3077
03:42:46,960 --> 03:42:49,280
DEALING WITH THE 24/7 RESEARCH

3078
03:42:49,280 --> 03:42:50,360
ENVIRONMENT AT COLD SPRING

3079
03:42:50,360 --> 03:42:51,640
HARBOR.

3080
03:42:51,640 --> 03:42:54,280
IT IS A MARVELOUSLY INTENSE

3081
03:42:54,280 --> 03:42:56,080
PLACE TO WORK.

3082
03:42:56,080 --> 03:42:59,200
BUT OUR FAMILIES SORT OF

3083
03:42:59,200 --> 03:43:01,640
FUNCTIONED AS ONE EXTENDED

3084
03:43:01,640 --> 03:43:01,880
FAMILY.

3085
03:43:01,880 --> 03:43:03,160
WE ATE DINNER TOGETHER THREE OR

3086
03:43:03,160 --> 03:43:08,760
FOUR NIGHTS A WEEK FOR FOUR

3087
03:43:08,760 --> 03:43:12,000
YEARS, OKAY?

3088
03:43:12,000 --> 03:43:14,960
AND THE KIDS, MY DAUGHTER,

3089
03:43:14,960 --> 03:43:17,960
LESLIE, RUSSELL, MY SON, PHILIP

3090
03:43:17,960 --> 03:43:21,240
AND CHRISTINA, WHO IS IN THE

3091
03:43:21,240 --> 03:43:24,720
AUDIENCE OVER HERE, WERE RAISED

3092
03:43:24,720 --> 03:43:28,000
PRACTICALLY AS SIBLINGS.

3093
03:43:28,000 --> 03:43:29,000
AND THEY CELEBRATED BIRTHDAYS

3094
03:43:29,000 --> 03:43:32,360
TOGETHER AND I THINK THAT'S

3095
03:43:32,360 --> 03:43:33,720
PROBABLY EASTER.

3096
03:43:33,720 --> 03:43:36,120
SOMETIMES THEY WERE LOOKED AFTER

3097
03:43:36,120 --> 03:43:38,840
BY STEVE, THE TWO DAUGHTERS, AND

3098
03:43:38,840 --> 03:43:43,880
SOMETIMES BY ME, THE TWO

3099
03:43:43,880 --> 03:43:44,200
DAUGHTERS.

3100
03:43:44,200 --> 03:43:48,600
BUT OF COURSE -- LET'S GET THIS 

3101
03:43:48,600 --> 03:43:48,960
RIGHT.

3102
03:43:48,960 --> 03:43:51,640
MOST FREQUENTLY, BY MY WIFE,

3103
03:43:51,640 --> 03:43:54,600
ANN, AND ALL THE KIDS, OR

3104
03:43:54,600 --> 03:43:56,920
VICTORIA AND ALL THE KIDS.

3105
03:43:56,920 --> 03:44:01,600
I DON'T THINK WE COULD HAVE

3106
03:44:01,600 --> 03:44:02,600
SURVIVED WITHOUT HIM.

3107
03:44:02,600 --> 03:44:07,200
WELL, STEVE AND I WORKED IN THE

3108
03:44:07,200 --> 03:44:12,120
LAB, REALLY 24/7.

3109
03:44:12,120 --> 03:44:13,960
AND THERE WERE LATE, LATE

3110
03:44:13,960 --> 03:44:14,200
NIGHTS.

3111
03:44:14,200 --> 03:44:15,280
WE FINALLY RECOGNIZED YOU DON'T

3112
03:44:15,280 --> 03:44:17,920
MAKE A DAY ANY LONGER BY CUTTING

3113
03:44:17,920 --> 03:44:20,360
HOURS OFF OF THE END OF THE DAY

3114
03:44:20,360 --> 03:44:21,880
AND SEWING THEM TO THE MORNING.

3115
03:44:21,880 --> 03:44:24,280
SO WE MADE A PACT, THE PACT WAS

3116
03:44:24,280 --> 03:44:27,480
THE FIRST PERSON DONE IN THE LAB

3117
03:44:27,480 --> 03:44:28,760
AFTER MIDNIGHT WOULD GO AND HAUL

3118
03:44:28,760 --> 03:44:31,200
THE OTHER PERSON OUT OF THE

3119
03:44:31,200 --> 03:44:31,480
LABORATORY.

3120
03:44:31,480 --> 03:44:32,640
INDEED THAT HAPPENED MANY TIMES

3121
03:44:32,640 --> 03:44:34,920
IN THE YEARS WE WORKED THERE

3122
03:44:34,920 --> 03:44:36,040
TOGETHER.

3123
03:44:36,040 --> 03:44:46,560
SO MY WORK WAS ON THE CONTROL OF

3124
03:44:48,360 --> 03:44:49,200
SACCHAROMYCES CEREVISIAE,

3125
03:44:49,200 --> 03:44:53,560
STEVE'S WORK ON RETROVIRAL

3126
03:44:53,560 --> 03:44:59,480
VECTORS, ISOLATION OF

3127
03:44:59,480 --> 03:45:01,560
CYTOSKELETAL GENES.

3128
03:45:01,560 --> 03:45:02,760
LET'S SEE.

3129
03:45:02,760 --> 03:45:03,520
RIGHT HERE.

3130
03:45:03,520 --> 03:45:06,080
THERE WASN'T MUCH TIME FOR

3131
03:45:06,080 --> 03:45:07,880
RECREATION.

3132
03:45:07,880 --> 03:45:09,000
BUT WE DID FINALLY DISCOVER THAT

3133
03:45:09,000 --> 03:45:12,600
WE HAD A LOVE OF FISHING.

3134
03:45:12,600 --> 03:45:15,360
AND I HAD TO DIG THROUGH MY

3135
03:45:15,360 --> 03:45:17,480
PICTURES TO FIND ONE IN WHICH I

3136
03:45:17,480 --> 03:45:19,520
HAD THE BIGGER FISH.

3137
03:45:19,520 --> 03:45:19,880
[LAUGHTER]

3138
03:45:19,880 --> 03:45:22,240
MOST OF WHAT WE DID WAS FROM A

3139
03:45:22,240 --> 03:45:26,400
CANOE WITH A LIGHT WEIGHT FLY

3140
03:45:26,400 --> 03:45:28,800
RODS CATCHING FISH ABOUT 6

3141
03:45:28,800 --> 03:45:30,560
INCHES LONG.

3142
03:45:30,560 --> 03:45:33,040
BUT THAT SHARED LOVE WAS

3143
03:45:33,040 --> 03:45:35,840
IMPORTANT COMPONENT OF EARLY

3144
03:45:35,840 --> 03:45:36,160
RELATIONSHIP.

3145
03:45:36,160 --> 03:45:41,840
NOW, AS WE MOVED TO FREDERICK IN

3146
03:45:41,840 --> 03:45:43,240
1984 GEORGE RETHE VIEWED FIRST

3147
03:45:43,240 --> 03:45:46,200
STEVE, THEN ME, ON THE BASIS OF

3148
03:45:46,200 --> 03:45:47,080
STEVE'S RECOMMENDATION, GEORGE

3149
03:45:47,080 --> 03:45:51,360
AND ME OR MY WORK AT THE TIME,

3150
03:45:51,360 --> 03:45:53,080
AND GEORGE CHEATED.

3151
03:45:53,080 --> 03:45:56,040
WE TOOK THE FAMILIES, HE BROUGHT

3152
03:45:56,040 --> 03:45:57,760
THEM TO HIS FARM IN VIRGINIA,

3153
03:45:57,760 --> 03:45:59,800
RIGHT, TOLD THE KIDS THEY DO

3154
03:45:59,800 --> 03:46:02,440
COULD HAVE A FARM IF STEVE AND I

3155
03:46:02,440 --> 03:46:04,000
ACCEPTED HIS INVITATION TO WORK

3156
03:46:04,000 --> 03:46:06,240
IN FREDERICK.

3157
03:46:06,240 --> 03:46:06,600
[LAUGHTER]

3158
03:46:06,600 --> 03:46:09,880
SO, THE END RESULT WAS STEVE HAS

3159
03:46:09,880 --> 03:46:14,680
A 63-ACRE FARM IN WEST

3160
03:46:14,680 --> 03:46:16,120
FREDERICK, I HAVE 28-ACRE FARM

3161
03:46:16,120 --> 03:46:23,360
EAST OF FREDERICK.

3162
03:46:23,360 --> 03:46:25,400
NOW, LET'S SEE.

3163
03:46:25,400 --> 03:46:26,960
THE CONVERSATIONS RESULTED IN

3164
03:46:26,960 --> 03:46:27,680
FORMAL COLLABORATIONS.

3165
03:46:27,680 --> 03:46:31,320
THIS IS ONE OF OUR PAPERS,

3166
03:46:31,320 --> 03:46:33,600
ANALYSIS OF THE CLEAVAGE SITE

3167
03:46:33,600 --> 03:46:35,600
FOR ENZYME THAT CUTS AT A SINGLE

3168
03:46:35,600 --> 03:46:41,680
SPOT IN THE YEAST GENOME, TO

3169
03:46:41,680 --> 03:46:47,840
INITIATE SWITCHING.

3170
03:46:47,840 --> 03:46:49,280
THAT ENZYME, SINGLE-BASED

3171
03:46:49,280 --> 03:46:50,320
RESOLUTION, THAT ENZYME WAS

3172
03:46:50,320 --> 03:46:52,080
USEFUL IN MY SUBSEQUENT WORK

3173
03:46:52,080 --> 03:46:56,600
BECAUSE WE USED IT TO INITIATE

3174
03:46:56,600 --> 03:46:58,680
COMBINATION AND WENT ON LOOK AT

3175
03:46:58,680 --> 03:47:00,000
FIDELITY OF RECOMBINATION AND

3176
03:47:00,000 --> 03:47:04,320
GENES INVOLVED, BUNCH OF OTHER 

3177
03:47:04,320 --> 03:47:04,560
ASSAYS.

3178
03:47:04,560 --> 03:47:10,400
KEY WORK.

3179
03:47:10,400 --> 03:47:13,840
IDENTIFICATION OF A GENE THAT 

3180
03:47:13,840 --> 03:47:17,960
WAS A CANDIDATE FOR A GENE 

3181
03:47:17,960 --> 03:47:19,480
IDENTIFIED IN STEVE'S LAB, AS

3182
03:47:19,480 --> 03:47:20,280
MENTIONED EARLY, SEQUENCING

3183
03:47:20,280 --> 03:47:21,720
SOMETHING WAS A BIG DEAL.

3184
03:47:21,720 --> 03:47:22,680
THEY DID SEQUENCE IT.

3185
03:47:22,680 --> 03:47:25,200
WE HAD MAPPED INTO THE YEAST

3186
03:47:25,200 --> 03:47:26,520
GENOME, KNOCKED IT OUT,

3187
03:47:26,520 --> 03:47:33,520
DEMONSTRATED IT WAS AN ESSENTIAL

3188
03:47:33,520 --> 03:47:34,800
GENE.

3189
03:47:34,800 --> 03:47:43,240
AND FUN12 MORE RECENTLY

3190
03:47:43,240 --> 03:47:45,560
IDENTIFIED INITIATION FACTOR

3191
03:47:45,560 --> 03:47:45,800
ELF5B.

3192
03:47:45,800 --> 03:47:50,400
THE BEST COLLABORATION WAS WHEN

3193
03:47:50,400 --> 03:47:55,520
WE PUT THE HIV REVERSE

3194
03:47:55,520 --> 03:48:02,680
TRANSSCRIPTASE INTO THE YEAST

3195
03:48:02,680 --> 03:48:08,160
RETROTRANSPOSON TI1. 

3196
03:48:08,160 --> 03:48:14,400
THIS IS THE ASSAYS BASED ON 

3197
03:48:14,400 --> 03:48:18,840
YEAST TRANSPOSON, IN WHICH RT 

3198
03:48:18,840 --> 03:48:20,960
DOMAIN WAS SUBSTITUTED, MARKED

3199
03:48:20,960 --> 03:48:26,440
WITH A METABOLIC SCREEN, WHEN

3200
03:48:26,440 --> 03:48:30,920
THE RNA WAS MADE IT WAS REVERSE

3201
03:48:30,920 --> 03:48:35,600
TRANSCRIBED, AFTER THE INTRON

3202
03:48:35,600 --> 03:48:38,240
WAS SPLICED OUT, GENERATED

3203
03:48:38,240 --> 03:48:40,880
FUNCTIONAL HISTORY GENE, BEING

3204
03:48:40,880 --> 03:48:43,200
ABLE TO MAKE HISTIDINE, EACH OF

3205
03:48:43,200 --> 03:48:45,800
THESE IS RESULT OF TRANSPOSITION

3206
03:48:45,800 --> 03:48:46,440
EVENT.

3207
03:48:46,440 --> 03:48:48,280
THAT TURNED OUT TO BE USEFUL IN

3208
03:48:48,280 --> 03:48:50,640
A LOT OF PROJECTS.

3209
03:48:50,640 --> 03:48:55,160
FIRST OF WHICH WAS TY ELEMENTS

3210
03:48:55,160 --> 03:48:58,440
ARE RESISTANT TO NON-NUCLEOTIDE

3211
03:48:58,440 --> 03:49:01,280
REVERSE TRANSCRIPTATION

3212
03:49:01,280 --> 03:49:01,680
INHIBITORS.

3213
03:49:01,680 --> 03:49:03,320
HIV BASED ELEMENTS WERE

3214
03:49:03,320 --> 03:49:06,880
SENSITIVE, IF YOU ISOLATED HIV

3215
03:49:06,880 --> 03:49:08,480
RT DOMAIN FROM RESISTANT

3216
03:49:08,480 --> 03:49:14,840
VIRUSES, THEY WERE IN TURN IN

3217
03:49:14,840 --> 03:49:17,240
YEAST RESISTANT TO NNRTIs,

3218
03:49:17,240 --> 03:49:19,520
BASIS OF SEVERAL EXPERIMENTS

3219
03:49:19,520 --> 03:49:20,600
FROM THE LAB.

3220
03:49:20,600 --> 03:49:24,800
HERE BEGINS THE INITIAL ASSAY.

3221
03:49:24,800 --> 03:49:31,480
HERE IS WILD TYPE THAT IN THE --

3222
03:49:31,480 --> 03:49:33,560
WHEN INDUCED MADE

3223
03:49:33,560 --> 03:49:35,840
(INDISCERNIBLE) BUT IN THE

3224
03:49:35,840 --> 03:49:36,600
PRESENCE RARELY MADE

3225
03:49:36,600 --> 03:49:38,920
TRANSPOSITION EVENT, WE WERE

3226
03:49:38,920 --> 03:49:44,480
ABLE TO ISOLATE HIV RT DOMAIN

3227
03:49:44,480 --> 03:49:46,680
FROM PATIENTS, THE VECTOR MADE A

3228
03:49:46,680 --> 03:49:47,880
LIBRARY, SCREENED FOR ONES

3229
03:49:47,880 --> 03:49:49,760
RESISTANT TO THE DRUG,

3230
03:49:49,760 --> 03:49:53,080
IDENTIFIED FROM THE PATIENTS

3231
03:49:53,080 --> 03:49:54,400
RESISTANT, SLIGHTLY RESISTANT

3232
03:49:54,400 --> 03:49:54,640
ALLELES.

3233
03:49:54,640 --> 03:49:57,200
SO RESULTS OF THE BASIS OF THE

3234
03:49:57,200 --> 03:50:02,680
SCREEN FOR NEW NNRTIs WE

3235
03:50:02,680 --> 03:50:05,480
DEMONSTRATED, COMPOUNDS AND

3236
03:50:05,480 --> 03:50:09,200
EXTRACTS THAT HAD -- WERE ABLE

3237
03:50:09,200 --> 03:50:12,280
TO INHIBIT, WE VERSE

3238
03:50:12,280 --> 03:50:14,120
TRANSCRIPTASE IN YEAST FOR HIV.

3239
03:50:14,120 --> 03:50:16,560
THE IMPACT ON MY WORK, STEVE HAD

3240
03:50:16,560 --> 03:50:18,000
IMPACTS THROUGHOUT THE COMMUNITY

3241
03:50:18,000 --> 03:50:20,600
AS YOU'VE SEEN TODAY.

3242
03:50:20,600 --> 03:50:25,840
ONE OF THE FEATURES THAT STEVE

3243
03:50:25,840 --> 03:50:28,080
PROVIDED WAS INPUT ON PEOPLE'S

3244
03:50:28,080 --> 03:50:28,800
SITE VISIT.

3245
03:50:28,800 --> 03:50:31,440
HE WROTE A BOOKLET HOW TO

3246
03:50:31,440 --> 03:50:32,440
SURVIVE SITE VISITS.

3247
03:50:32,440 --> 03:50:33,720
IT HAD SEVERAL IMPORTANT

3248
03:50:33,720 --> 03:50:35,360
LICENSES LIKE THE TITLE SHOULD

3249
03:50:35,360 --> 03:50:36,120
BE THE CONCLUSION.

3250
03:50:36,120 --> 03:50:38,400
YOU'RE GOING TO HAND OUT COPIES

3251
03:50:38,400 --> 03:50:39,280
OF THE SLIDES, AND THEN THEY ARE

3252
03:50:39,280 --> 03:50:40,680
GOING TO WALK AWAY WITH A PIECE

3253
03:50:40,680 --> 03:50:42,120
OF PAPER THAT HAS EVERY

3254
03:50:42,120 --> 03:50:46,080
CONCLUSION FROM EVERY SLIDE ON

3255
03:50:46,080 --> 03:50:46,720
IT.

3256
03:50:46,720 --> 03:50:48,600
A SLIDE, IT'S NECESSARY,

3257
03:50:48,600 --> 03:50:51,000
MINIMIZE WHITE SPACE, BLOW

3258
03:50:51,000 --> 03:50:55,200
THINGS UP, AND MAYBE MOST

3259
03:50:55,200 --> 03:50:56,000
IMPORTANTLY IF THEY DON'T

3260
03:50:56,000 --> 03:51:00,040
BELIEVE YOU CAN DO THE 

3261
03:51:00,040 --> 03:51:01,360
EXPERIMENT YOU'RE SCREWED.

3262
03:51:01,360 --> 03:51:02,200
SO UNDERSTAND CONTROLS.

3263
03:51:02,200 --> 03:51:06,000
THEN DON'T SHOW ALL THE DATA 

3264
03:51:06,000 --> 03:51:07,840
THAT YOU EVER PRODUCED.

3265
03:51:07,840 --> 03:51:10,040
ALSO APPRECIATED STEVE'S ROLE IN

3266
03:51:10,040 --> 03:51:12,080
MY EFFORTS AS DEPUTY, TO

3267
03:51:12,080 --> 03:51:13,400
INCREASE COMMUNICATION BETWEEN

3268
03:51:13,400 --> 03:51:21,160
THE LABORATORIES, SO I INITIATED

3269
03:51:21,160 --> 03:51:25,760
WHAT WAS CALLED A LAB CHIEF

3270
03:51:25,760 --> 03:51:27,600
LUNCH, ALL LAB CHIEFS COULD

3271
03:51:27,600 --> 03:51:29,720
COME, AN OPPORTUNITY TO EXCHANGE

3272
03:51:29,720 --> 03:51:30,920
BETWEEN THE LABS ONGOING

3273
03:51:30,920 --> 03:51:33,520
RESEARCH, WHAT WAS HOT THIS WEEK

3274
03:51:33,520 --> 03:51:35,520
OR LAST.

3275
03:51:35,520 --> 03:51:36,720
FURTHERMORE STEVE'S CONTRIBUTION

3276
03:51:36,720 --> 03:51:39,040
ALONG WITH ME IN THE SITE VISIT

3277
03:51:39,040 --> 03:51:41,200
OF ALL THE LABORATORIES UP IN

3278
03:51:41,200 --> 03:51:43,200
HERE, FREDERICK, AGAIN CREATED A

3279
03:51:43,200 --> 03:51:48,320
NEXUS POINT FOR THE DISPERSAL OF

3280
03:51:48,320 --> 03:51:49,760
INFORMATION THAT WOULD SAY YOU

3281
03:51:49,760 --> 03:51:52,400
TWO GO HAVE A BEER TOGETHER

3282
03:51:52,400 --> 03:51:53,800
BECAUSE YOUR EXPERIMENTS ARE

3283
03:51:53,800 --> 03:51:59,280
FOCUSED ON SIMILAR OUTCOME.

3284
03:51:59,280 --> 03:52:00,800
NOW, AGAIN, THE FIRST SEVERAL

3285
03:52:00,800 --> 03:52:02,360
YEARS WE WERE HERE WE DIDN'T

3286
03:52:02,360 --> 03:52:04,240
FISH AT ALL.

3287
03:52:04,240 --> 03:52:08,240
I KNOW THAT'S SURPRISING.

3288
03:52:08,240 --> 03:52:11,000
BUT FINALLY IT GOT TO THE POINT

3289
03:52:11,000 --> 03:52:13,280
STEVE AND I AGREED THAT IF WE

3290
03:52:13,280 --> 03:52:15,160
WERE TO EVER DO THIS, YOU KNOW,

3291
03:52:15,160 --> 03:52:16,800
AGAIN, WE HAD TO GET BACK INTO

3292
03:52:16,800 --> 03:52:16,960
IT.

3293
03:52:16,960 --> 03:52:19,000
SO WE DID A LITTLE BIT OF

3294
03:52:19,000 --> 03:52:19,240
FISHING.

3295
03:52:19,240 --> 03:52:21,600
I HAVE A POND ON MY PROPERTY,

3296
03:52:21,600 --> 03:52:23,120
NICE RIVERS AROUND HERE TO TAKE

3297
03:52:23,120 --> 03:52:23,720
A CANOE ON.

3298
03:52:23,720 --> 03:52:27,400
BUT THIS IS ONE OF THE FIRST

3299
03:52:27,400 --> 03:52:31,760
FISH STEVE CAUGHT ON A FLY ROD,

3300
03:52:31,760 --> 03:52:33,200
STRIPED BASS, I KNOW THAT

3301
03:52:33,200 --> 03:52:35,840
BECAUSE THAT'S MY FLY ROD FROM

3302
03:52:35,840 --> 03:52:40,320
MY FISHING DAYS IN OREGON FOR 

3303
03:52:40,320 --> 03:52:43,400
STEEL HEAD TROUT. 

3304
03:52:43,400 --> 03:52:44,920
THE CAPTAIN THOUGHT WE WERE

3305
03:52:44,920 --> 03:52:47,080
CRAZY BUT THE SOLUTION IS GET A

3306
03:52:47,080 --> 03:52:47,680
NEW CAPTAIN, RIGHT?

3307
03:52:47,680 --> 03:52:50,160
AND SO WE DID.

3308
03:52:50,160 --> 03:52:55,560
WE GOT BRADY, REFERRED TO 

3309
03:52:55,560 --> 03:52:57,520
EARLIER, AND WE MADE OUR OWN FLY

3310
03:52:57,520 --> 03:52:58,720
RODS, TIED OUR FLIES.

3311
03:52:58,720 --> 03:53:05,040
HERE OFF NORTH CAROLINA, SOUTH

3312
03:53:05,040 --> 03:53:06,560
CAROLINA, CATCHING FALSE ALBA

3313
03:53:06,560 --> 03:53:11,400
DOOR, TUNA ON A FLY ROD, ON

3314
03:53:11,400 --> 03:53:13,520
FLIES YOU TIED, DOESN'T GET A

3315
03:53:13,520 --> 03:53:14,880
LOT BETTER THAN THAT.

3316
03:53:14,880 --> 03:53:17,360
STEVE WAS, AS I SAID, A BIG

3317
03:53:17,360 --> 03:53:18,440
HELP, LOTS OF PROJECTS.

3318
03:53:18,440 --> 03:53:20,400
HERE HE IS HELPING ME PUT

3319
03:53:20,400 --> 03:53:21,920
TOGETHER THE FOURTH OF MY

3320
03:53:21,920 --> 03:53:23,560
ADDITIONS TO MY HOUSE, WHICH WAS

3321
03:53:23,560 --> 03:53:27,280
A THREE-CAR GARAGE WITH A

3322
03:53:27,280 --> 03:53:28,360
TRACTOR BAY.

3323
03:53:28,360 --> 03:53:30,760
AND SOMEWHERE I COULD NOT FIND

3324
03:53:30,760 --> 03:53:32,880
THE APPROPRIATE PICTURES,

3325
03:53:32,880 --> 03:53:36,240
THERE'S A FOUR-HOUR VIDEO OF 24

3326
03:53:36,240 --> 03:53:38,320
SCIENTISTS AND 12 AMISH MEN

3327
03:53:38,320 --> 03:53:39,960
RAISING A BARN ON STEVE'S

3328
03:53:39,960 --> 03:53:41,560
PROPERTY AFTER HIS BIG BARN

3329
03:53:41,560 --> 03:53:42,040
BURNED DOWN.

3330
03:53:42,040 --> 03:53:44,120
IT WAS ONE OF THE BEST DAYS OF

3331
03:53:44,120 --> 03:53:45,840
MY LIFE.

3332
03:53:45,840 --> 03:53:47,840
SO INTERESTING AND SOMEDAY MAYBE

3333
03:53:47,840 --> 03:53:48,960
YOU'LL TALK STEVE INTO SHOWING

3334
03:53:48,960 --> 03:53:54,920
THAT YOU VIDEO.

3335
03:53:54,920 --> 03:53:58,480
IT WAS FANTASTIC.

3336
03:53:58,480 --> 03:54:02,560
OUR FAMILIES HAVE BEEN TOGETHER

3337
03:54:02,560 --> 03:54:04,280
SINCE 1979.

3338
03:54:04,280 --> 03:54:05,120
OKAY?

3339
03:54:05,120 --> 03:54:07,880
AND WE'VE HAD THANKSGIVING

3340
03:54:07,880 --> 03:54:09,760
DINNER AND CHRISTMAS DINNER

3341
03:54:09,760 --> 03:54:13,440
EVERY YEAR SINCE THEN, OKAY?

3342
03:54:13,440 --> 03:54:15,320
WITH AN EXCEPTION FOR COVID, WE

3343
03:54:15,320 --> 03:54:17,160
EVEN DID THAT BY SKYPE.

3344
03:54:17,160 --> 03:54:20,160
HERE'S ONE OF THE RECENT ONES.

3345
03:54:20,160 --> 03:54:22,240
YOU'LL NOTICE IN IT A SCOTTISH

3346
03:54:22,240 --> 03:54:25,840
TOAST, I HOPE IT WILL PLAY.

3347
03:54:25,840 --> 03:54:28,160
MY DAUGHTER, LESLIE.

3348
03:54:28,160 --> 03:54:31,520
MY GRANDDAUGHTER, KAYLY ANN.

3349
03:54:31,520 --> 03:54:41,120
MY SON, RUSSELL.

3350
03:54:41,120 --> 03:54:41,920
PHILIP.

3351
03:54:41,920 --> 03:54:42,440
VICKIE AND STEVE.

3352
03:54:42,440 --> 03:54:45,440
WE CAN'T HEAR IT.

3353
03:54:45,440 --> 03:54:46,320
 

3354
03:54:46,320 --> 03:54:49,600
I'LL TELL WHAT YOU THE SCOTTISH

3355
03:54:49,600 --> 03:54:58,440
TOAST IS. 

3356
03:54:58,440 --> 03:55:04,640
IT'S HERE'S TO US ... MORE'S THE

3357
03:55:04,640 --> 03:55:04,840
PITY.

3358
03:55:04,840 --> 03:55:15,360
PEOPLE LIKE STEVE ARE DAMN FEW.

3359
03:55:19,240 --> 03:55:22,360
HIS INFLUENCE ON EVERYBODY WAS

3360
03:55:22,360 --> 03:55:23,640
INCREDIBLE.

3361
03:55:23,640 --> 03:55:25,840
OUR DEAR DEPARTED FRIEND, AMAR,

3362
03:55:25,840 --> 03:55:30,320
WITH MY WIFE, ANN, THE IMPACT WE

3363
03:55:30,320 --> 03:55:32,520
ALL HAD.

3364
03:55:32,520 --> 03:55:35,480
FISHING PICTURES, OF COURSE, MY

3365
03:55:35,480 --> 03:55:39,880
FRIEND STEVE. 

3366
03:55:39,880 --> 03:55:49,680
GOOD LUCK. 

3367
03:55:49,680 --> 03:55:53,520
[APPLAUSE] 

3368
03:55:53,520 --> 03:55:57,840
TIGHT LINES. 

3369
03:55:57,840 --> 03:56:03,120
>>THANKS VERY MUCH.

3370
03:56:03,120 --> 03:56:09,480
NEXT SPEAKER IS CUED UP, BOB

3371
03:56:09,480 --> 03:56:10,880
SILICIANO JOINS US REMOTELY FROM

3372
03:56:10,880 --> 03:56:13,280
JOHNS HOPKINS, PIONEER IN THE

3373
03:56:13,280 --> 03:56:17,040
STUDY OF ANTIRETROVIRAL THERAPY

3374
03:56:17,040 --> 03:56:22,320
AND HIV PERSISTENCE, PROFOUNDLY

3375
03:56:22,320 --> 03:56:23,560
INFLUENCED RESEARCH DONE

3376
03:56:23,560 --> 03:56:25,720
PARTICULARLY WORK ON HIV

3377
03:56:25,720 --> 03:56:26,240
PERSISTENCE.

3378
03:56:26,240 --> 03:56:27,560
>>THANKS.

3379
03:56:27,560 --> 03:56:31,120
IT'S A PLEASURE TO BE HERE FOR

3380
03:56:31,120 --> 03:56:32,080
THIS SYMPOSIUM HONORING STEVE.

3381
03:56:32,080 --> 03:56:34,360
I'D LIKE TO TALK ABOUT

3382
03:56:34,360 --> 03:56:35,200
PROLIFERATION OF LATENTLY

3383
03:56:35,200 --> 03:56:36,320
INFECTED CELLS, A BARRIER TO

3384
03:56:36,320 --> 03:56:37,320
CURE.

3385
03:56:37,320 --> 03:56:40,400
THIS IS A TOPIC THAT STEVE TOOK

3386
03:56:40,400 --> 03:56:43,880
UP RELATIVELY LATE IN HIS

3387
03:56:43,880 --> 03:56:46,000
REMARKABLE CAREER, AND MADE

3388
03:56:46,000 --> 03:56:48,400
PROFOUND CONTRIBUTIONS THAT I'LL

3389
03:56:48,400 --> 03:56:49,360
TRY TO DESCRIBE, CONTRIBUTIONS

3390
03:56:49,360 --> 03:56:51,760
THAT WENT TO THE HEART OF THE

3391
03:56:51,760 --> 03:56:56,280
PROBLEM OF TRYING TO FIND A CURE

3392
03:56:56,280 --> 03:56:57,720
FOR HIV INFECTION.

3393
03:56:57,720 --> 03:56:59,000
WHEN PATIENTS STARTED ON

3394
03:56:59,000 --> 03:57:03,200
COMBINATION THERAPY THERE WAS A

3395
03:57:03,200 --> 03:57:06,880
RAPID DECREASE IN VIREMIA BELOW

3396
03:57:06,880 --> 03:57:08,080
LIMIT OF DETECTION, REFLECTING

3397
03:57:08,080 --> 03:57:09,200
SHORT HALF-LIFE OF CELLS THAT

3398
03:57:09,200 --> 03:57:10,400
PRODUCE MOST OF THE PLASMA

3399
03:57:10,400 --> 03:57:10,600
VIRUS.

3400
03:57:10,600 --> 03:57:13,240
NO MATTER HOW LONG PEOPLE HAVE

3401
03:57:13,240 --> 03:57:23,640
BEEN ON ART, VIREMIA REBOUNDS

3402
03:57:23,640 --> 03:57:27,560
RAPIDLY BECAUSE OF LATENTLY

3403
03:57:27,560 --> 03:57:28,920
INFECTED CDPOSITIVE 4 CELLS,

3404
03:57:28,920 --> 03:57:31,800
ARISE WHEN ACTIVATED CELLS

3405
03:57:31,800 --> 03:57:32,800
BECOME INFECTED TRANSITIONING

3406
03:57:32,800 --> 03:57:34,680
BACK TO MEMORY STATE

3407
03:57:34,680 --> 03:57:36,440
NON-PERMISSIVE FOR VIRAL GENE

3408
03:57:36,440 --> 03:57:37,000
EXPRESSION.

3409
03:57:37,000 --> 03:57:38,600
AND THESE CELLS CAN PERSIST

3410
03:57:38,600 --> 03:57:41,680
THROUGH THE NORMAL MECHANISMS

3411
03:57:41,680 --> 03:57:43,080
THAT MAINTAIN MEMORY.

3412
03:57:43,080 --> 03:57:44,840
SUBSEQUENT ACTIVATION THROUGH

3413
03:57:44,840 --> 03:57:47,160
THE ANTIGEN RECEPTOR CAN LEAD TO

3414
03:57:47,160 --> 03:57:49,000
REVERSAL OF LATENCY, AND VIRAL

3415
03:57:49,000 --> 03:57:50,760
REBOUND, IF TREATMENT HAS BEEN

3416
03:57:50,760 --> 03:57:52,440
INTERRUPTED, BUT CAN ALSO AS

3417
03:57:52,440 --> 03:57:55,360
I'LL SHOW YOU LEAD TO

3418
03:57:55,360 --> 03:57:57,920
PROLIFERATION OF INFECTED CELLS

3419
03:57:57,920 --> 03:58:00,320
WITHOUT VIRUS PRODUCTION

3420
03:58:00,320 --> 03:58:01,920
GENERATING NEW LATENTLY INFECTED

3421
03:58:01,920 --> 03:58:02,160
CELLS.

3422
03:58:02,160 --> 03:58:03,360
THESE ARE PRESENT IN EVERYBODY

3423
03:58:03,360 --> 03:58:04,720
WITH HIV INFECTION BECAUSE FROM

3424
03:58:04,720 --> 03:58:07,360
A SIMPLE BLOOD SAMPLE YOU CAN

3425
03:58:07,360 --> 03:58:08,520
PURIFY RESTING CD4 CELLS, THEY

3426
03:58:08,520 --> 03:58:11,360
ARE NOT PRODUCING ANY VIRUS, BUT

3427
03:58:11,360 --> 03:58:13,120
YOU PLATE THEM IN DILUTION AND

3428
03:58:13,120 --> 03:58:18,480
ACTIVATE WITH MITOGEN AND CAN

3429
03:58:18,480 --> 03:58:24,680
GROW OUT ENOUGH VIRUS TO MEASURE

3430
03:58:24,680 --> 03:58:26,280
BY ELISA ASSAY, VIREMIAS COMING

3431
03:58:26,280 --> 03:58:30,200
FROM THE LATENTLY INFECTED CELLS

3432
03:58:30,200 --> 03:58:31,920
THAT'S BEEN ACTIVATED UNDERGOES

3433
03:58:31,920 --> 03:58:32,520
EXPONENTIAL GROWTH.

3434
03:58:32,520 --> 03:58:36,120
THERE ARE LIKELY OTHER

3435
03:58:36,120 --> 03:58:38,320
RESERVOIRS, THIS ASSAY WE THINK

3436
03:58:38,320 --> 03:58:40,960
IS THE MOST CHALLENGING BARRIER

3437
03:58:40,960 --> 03:58:42,360
TO CURE.

3438
03:58:42,360 --> 03:58:44,520
NOW, WE KNOW VIRUS IN ACTIVATED

3439
03:58:44,520 --> 03:58:48,600
CELLS AND PRODUCTIVELY INFECTED

3440
03:58:48,600 --> 03:58:51,040
CELLS, LIKELY PROXIMAL SOURCE OF

3441
03:58:51,040 --> 03:58:53,520
VIRAL REBOUND BUT MAY HAVE BEEN

3442
03:58:53,520 --> 03:58:54,480
GENERATED THROUGH ACTIVATION AND

3443
03:58:54,480 --> 03:58:57,120
TEND TO HAVE OTHER SHORT

3444
03:58:57,120 --> 03:58:59,960
HALF-LIFE DUE TO VIRAL

3445
03:58:59,960 --> 03:59:01,520
CYTOPATHIC EFFECT OR SAMPLING

3446
03:59:01,520 --> 03:59:03,480
NORMAL CONTRACTION PHASE OF THE

3447
03:59:03,480 --> 03:59:06,400
IMMUNE RESPONSE WHICH ELIMINATES

3448
03:59:06,400 --> 03:59:09,560
MOST ACTIVATED CELLS.

3449
03:59:09,560 --> 03:59:12,120
LEAVING BEHIND RESTING MEMORY

3450
03:59:12,120 --> 03:59:13,760
CELLS TO PROVIDE IMMUNOLOGIC

3451
03:59:13,760 --> 03:59:14,600
MEMORY.

3452
03:59:14,600 --> 03:59:20,120
IN THESE HIGHLY QUIESCENT CELLS,

3453
03:59:20,120 --> 03:59:22,520
VIRUS REMAINS LATENT, BECAUSE

3454
03:59:22,520 --> 03:59:27,000
KEY HOST TRANSCRIPTION FACTORS

3455
03:59:27,000 --> 03:59:31,600
INCLUDING NF-kappaB ARE 

3456
03:59:31,600 --> 03:59:36,520
SEQUESTERED, SO THAT THE VIRUS 

3457
03:59:36,520 --> 03:59:37,920
REMAINS LATENT AND AVOIDS

3458
03:59:37,920 --> 03:59:41,480
CYTOPATHIC EFFECT AND CLEARANCE.

3459
03:59:41,480 --> 03:59:43,320
USING THIS MEASURE OF THIS

3460
03:59:43,320 --> 03:59:46,920
LATENT FORM OF THE VIRUS, SHOWN

3461
03:59:46,920 --> 03:59:49,880
MANY YEARS AGO, THE HALF-LIFE OF

3462
03:59:49,880 --> 03:59:52,600
THIS RESERVOIR IS EXTREMELY

3463
03:59:52,600 --> 03:59:53,720
LONG, 3.7 YEARS.

3464
03:59:53,720 --> 03:59:58,640
THIS WORK WAS PUBLISHED IN 1999

3465
03:59:58,640 --> 04:00:02,240
AND 2003, AND IN 2015 DAVID 

3466
04:00:02,240 --> 04:00:05,080
MARGOLIS REPEATED THIS STUDY ON

3467
04:00:05,080 --> 04:00:06,320
PATIENTS ON A INTEGRASE

3468
04:00:06,320 --> 04:00:10,280
INHIBITORS AND FOUND EXACTLY THE

3469
04:00:10,280 --> 04:00:11,480
SAME HALF-LIFE.

3470
04:00:11,480 --> 04:00:17,280
NOW IN 2022 WE CAN ASK WHETHER

3471
04:00:17,280 --> 04:00:18,160
THIS SLOW DECAY CONTINUES IN

3472
04:00:18,160 --> 04:00:21,360
PEOPLE WHO HAVE BEEN ON VERY

3473
04:00:21,360 --> 04:00:23,400
LONG-TERM ART, AND WE FIND IT

3474
04:00:23,400 --> 04:00:24,320
DOES NOT.

3475
04:00:24,320 --> 04:00:29,000
THERE'S A HIGHER THAN EXPECTED

3476
04:00:29,000 --> 04:00:30,240
FREQUENCY OF LATENTLY EFFECTED

3477
04:00:30,240 --> 04:00:33,400
CELLS ON PEOPLE ON VERY

3478
04:00:33,400 --> 04:00:36,360
LONG-TERM ART, NOT DUE TO ANY

3479
04:00:36,360 --> 04:00:38,440
KIND OF FAILURE TO SUPPRESS

3480
04:00:38,440 --> 04:00:40,400
REPLICATION, WE SHOWED IN A

3481
04:00:40,400 --> 04:00:41,680
SERIES OF PAPERS THAT AS FAR AS

3482
04:00:41,680 --> 04:00:45,920
I CAN TELL NEVER READ BY ANYONE

3483
04:00:45,920 --> 04:00:47,760
THAT THERE IS UNEXPECTED

3484
04:00:47,760 --> 04:00:50,280
COOPERATIVITY IN DOSE-RESPONSE

3485
04:00:50,280 --> 04:00:52,240
CURVES OF SOME ANTIRETROVIRAL

3486
04:00:52,240 --> 04:00:54,880
DRUGS AND ENERGIES BETWEEN DRUG

3487
04:00:54,880 --> 04:00:56,840
CLASS THAT ALLOW 5 TO 10 LOG

3488
04:00:56,840 --> 04:00:58,480
SUPPRESSION OF SINGLE ROUND

3489
04:00:58,480 --> 04:01:01,440
INFECTION BY ART, SUFFICIENT TO

3490
04:01:01,440 --> 04:01:03,520
PREVENT ANY REPLICATION AND

3491
04:01:03,520 --> 04:01:07,800
PREVENT VIRAL EVOLUTION IN

3492
04:01:07,800 --> 04:01:11,480
ADHERENT PATIENTS, SHOWN IN MANY

3493
04:01:11,480 --> 04:01:14,480
OTHER STUDIES INCLUDING BY MARY

3494
04:01:14,480 --> 04:01:15,360
KEARNEY.

3495
04:01:15,360 --> 04:01:18,000
SO, WE WANTED TO CONFIRM THIS

3496
04:01:18,000 --> 04:01:19,520
HIGHER THAN EXPECTED FREQUENCY

3497
04:01:19,520 --> 04:01:21,400
OF LATENTLY INFECTED CELLS ON

3498
04:01:21,400 --> 04:01:23,560
PEOPLE ON LONG-TERM ART WAS REAL

3499
04:01:23,560 --> 04:01:29,160
AND SO WE USED INDEPENDENT

3500
04:01:29,160 --> 04:01:36,200
ASSAY, THIS IS A DIGITAL DROPLET

3501
04:01:36,200 --> 04:01:37,840
THAT MEASURES LACKING DEFECTS

3502
04:01:37,840 --> 04:01:42,280
AND GOT EXACTLY THE SAME RESULT.

3503
04:01:42,280 --> 04:01:44,720
SO, IT'S NOT DUE TO DE NOVO

3504
04:01:44,720 --> 04:01:46,680
INFECTION EVENTS, DOESN'T

3505
04:01:46,680 --> 04:01:48,880
REPRESENT THE PROLIFERATION OF

3506
04:01:48,880 --> 04:01:50,400
LATENTLY INFECTED CELLS.

3507
04:01:50,400 --> 04:01:52,360
SO MY FIRST INDICATION THAT THIS

3508
04:01:52,360 --> 04:01:53,800
KIND OF SITUATION MIGHT BE

3509
04:01:53,800 --> 04:01:56,360
TAKING PLACE CAME FROM AN

3510
04:01:56,360 --> 04:01:57,840
ANALYSIS OF RESIDUAL VIREMIA.

3511
04:01:57,840 --> 04:02:00,760
THIS IS THE TRACE LEVEL OF FREE

3512
04:02:00,760 --> 04:02:02,400
VIRUS IN THE PLASMA OF PEOPLE

3513
04:02:02,400 --> 04:02:07,240
WHO ARE DOING WELL ON ART.

3514
04:02:07,240 --> 04:02:09,080
STUDIES BY JOHN COFFIN'S GROUP

3515
04:02:09,080 --> 04:02:11,960
SHOWED THAT IN MOST PEOPLE YOU

3516
04:02:11,960 --> 04:02:14,040
CAN DETECT RESIDUAL VIREMIA

3517
04:02:14,040 --> 04:02:17,480
OFTEN AT LEVEL AROUND 1 COPY PER

3518
04:02:17,480 --> 04:02:19,680
MIL, WE SPENT A LONG TIME

3519
04:02:19,680 --> 04:02:23,240
EXPENSING AND SHOWED IT IS

3520
04:02:23,240 --> 04:02:24,440
ARCHIVAL IN CARE, DRUG SENSITIVE

3521
04:02:24,440 --> 04:02:32,120
THAT CONTINUES TO BE RELEASED 

3522
04:02:32,120 --> 04:02:35,640
WITHOUT ANY EVOLUTION, FOR YEARS

3523
04:02:35,640 --> 04:02:37,360
VIRUS COMING FROM LATENT

3524
04:02:37,360 --> 04:02:41,640
AFFECTED CELLS  ACTIVATED, CAN'T

3525
04:02:41,640 --> 04:02:43,640
REPLICATE BUT CAN BE DETECTED

3526
04:02:43,640 --> 04:02:44,160
WITH SENSITIVE ASSAY.

3527
04:02:44,160 --> 04:02:46,840
THE MOST INTERESTING THING ABOUT

3528
04:02:46,840 --> 04:02:51,760
THIS VIRUS, I SHOULD POINT OUT

3529
04:02:51,760 --> 04:02:53,920
IN STUDIES WE SHOWED THAT

3530
04:02:53,920 --> 04:02:56,280
ADDITION OF ANOTHER DRUG TO

3531
04:02:56,280 --> 04:03:05,640
THREE DRUG REGIMEN COULD NOT

3532
04:03:05,640 --> 04:03:08,640
SUPPRESS RESIDUAL VIREMIA, IT'S 

3533
04:03:08,640 --> 04:03:10,840
COMING FROM CELLS.

3534
04:03:10,840 --> 04:03:12,920
DESPITE EXTENSIVE AMOUNT OF

3535
04:03:12,920 --> 04:03:15,360
DIVERSIFICATION IN INDIVIDUAL

3536
04:03:15,360 --> 04:03:17,000
PATIENTS DURING UNTREATED

3537
04:03:17,000 --> 04:03:17,840
INFECTION, THE RESIDUAL VIREMIA

3538
04:03:17,840 --> 04:03:20,440
YOU SEE IN THE SETTING OF ART

3539
04:03:20,440 --> 04:03:23,240
WAS OFTEN DOMINATED BY A SINGLE

3540
04:03:23,240 --> 04:03:31,280
SEQUENCE, THAT IS A  A SINGLE

3541
04:03:31,280 --> 04:03:32,480
SEQUENCE, SINGLE NUCLEOTIDE

3542
04:03:32,480 --> 04:03:34,560
DIFFERENCE OVER 2 TO 3-YEAR

3543
04:03:34,560 --> 04:03:42,760
PERIOD, WE THOUGHT THIS MUST 

3544
04:03:42,760 --> 04:03:43,200
REPRESENT EXTENSIVE

3545
04:03:43,200 --> 04:03:44,480
PROLIFERATION COPYING WITHOUT

3546
04:03:44,480 --> 04:03:46,600
AREA INTO PROJECTY ELSE IN.

3547
04:03:46,600 --> 04:03:50,160
BUT PROOF OF INFECTED CELL

3548
04:03:50,160 --> 04:03:50,640
PROLIFERATION REQUIRES

3549
04:03:50,640 --> 04:03:53,000
INTEGRATION SITE ANALYSIS.

3550
04:03:53,000 --> 04:03:59,560
MY WIFE JANET IN 2004 PROVIDEDED

3551
04:03:59,560 --> 04:04:01,200
FIRST MAPPING USING INVERSE PCR

3552
04:04:01,200 --> 04:04:02,720
TECHNIQUE AND MOST OF

3553
04:04:02,720 --> 04:04:05,160
INTEGRATION SITES THAT SHE FOUND

3554
04:04:05,160 --> 04:04:09,280
WERE IN TRANSCRIPTIONAL UNITS 

3555
04:04:09,280 --> 04:04:11,440
CONSISTENT WITH EARLIER STUDY

3556
04:04:11,440 --> 04:04:12,960
USING IN VITRO INFECTION.

3557
04:04:12,960 --> 04:04:16,520
ALL THE SITES WE FOUND WERE 

3558
04:04:16,520 --> 04:04:18,120
UNIQUE.

3559
04:04:18,120 --> 04:04:20,160
AND THEN STEVE DEVELOPED A

3560
04:04:20,160 --> 04:04:23,480
HIGH-THROUGHPUT METHOD FOR HIV

3561
04:04:23,480 --> 04:04:25,120
INTEGRATION SITE ANALYSIS.

3562
04:04:25,120 --> 04:04:26,200
AS HAS BEEN DESCRIBED.

3563
04:04:26,200 --> 04:04:31,480
AND FOUND THAT THE SITES WERE IN

3564
04:04:31,480 --> 04:04:32,720
GENES, SOMETIMES GENES

3565
04:04:32,720 --> 04:04:34,640
ASSOCIATED WITH CELL

3566
04:04:34,640 --> 04:04:35,280
PROLIFERATION BUT MOST

3567
04:04:35,280 --> 04:04:38,920
IMPORTANTLY OVER A THIRD OF THE

3568
04:04:38,920 --> 04:04:41,440
SITES WERE IN GENES, SORRY, OVER

3569
04:04:41,440 --> 04:04:43,960
A THIRD OF THE INTEGRATION SITES

3570
04:04:43,960 --> 04:04:45,400
WERE IN EXPANDED CLONES.

3571
04:04:45,400 --> 04:04:48,960
IN OTHER WORDS, THE SAME SITE

3572
04:04:48,960 --> 04:04:50,320
WAS FOUND IN MULTIPLE CELLS,

3573
04:04:50,320 --> 04:04:51,920
PRESENT IN THE SAME SAMPLE,

3574
04:04:51,920 --> 04:04:55,040
SOMETHING THAT COULD ONLY BE

3575
04:04:55,040 --> 04:04:56,520
EXPLAINED BY PROLIFERATION OF

3576
04:04:56,520 --> 04:04:58,240
INFECTED CELLS.

3577
04:04:58,240 --> 04:05:01,240
I THINK IT'S REALLY HARD TO

3578
04:05:01,240 --> 04:05:04,240
OVERSTATE THE IMPORTANCE OF THIS

3579
04:05:04,240 --> 04:05:04,520
FINDING.

3580
04:05:04,520 --> 04:05:06,880
AFTER ALL, THE STIMULI THAT

3581
04:05:06,880 --> 04:05:09,200
DRIVE T CELL PROLIFERATION ALSO

3582
04:05:09,200 --> 04:05:11,120
INDUCE VIRAL GENE EXPRESSION AND

3583
04:05:11,120 --> 04:05:12,080
MOST PRODUCTIVELY INFECTED CELLS

3584
04:05:12,080 --> 04:05:13,800
HAVE A SHORT HALF-LIFE.

3585
04:05:13,800 --> 04:05:16,880
SO, IT WASN'T AT ALL CLEAR THAT

3586
04:05:16,880 --> 04:05:18,040
INFECTED CELLS COULD

3587
04:05:18,040 --> 04:05:18,360
PROLIFERATE.

3588
04:05:18,360 --> 04:05:21,080
THIS STUDY BY STEVE AND

3589
04:05:21,080 --> 04:05:22,640
COLLEAGUES REALLY DEMONSTRATED

3590
04:05:22,640 --> 04:05:24,400
THAT THIS COULD HAPPEN IN VIVO,

3591
04:05:24,400 --> 04:05:27,960
AND NOT ONLY DOES IT HAPPEN IN

3592
04:05:27,960 --> 04:05:31,960
VIVO BUT TO A REMARKABLE EXTENT

3593
04:05:31,960 --> 04:05:32,920
THAT YOU COULD CAPTURE PROGENY

3594
04:05:32,920 --> 04:05:34,800
CELLS DERIVED FROM THE SAME

3595
04:05:34,800 --> 04:05:39,200
INITIAL INFECTED CELL, IN CELL,

3596
04:05:39,200 --> 04:05:44,040
IN A SINGLE BLOOD SAMPLE.

3597
04:05:44,040 --> 04:05:48,960
AROUND THIS TIME USED WHOLE

3598
04:05:48,960 --> 04:05:52,360
GENOME SEQUENCING TO SHOW HIGHLY

3599
04:05:52,360 --> 04:05:55,200
DEFECTIVE DUE TO LARGE DELETION,

3600
04:05:55,200 --> 04:05:55,960
ANALYSIS CAPTURES ONLY THE END

3601
04:05:55,960 --> 04:05:59,160
OF THE VIRAL GENOME SO IT'S

3602
04:05:59,160 --> 04:06:02,680
POSSIBLE MANY SITES IDENTIFIED 

3603
04:06:02,680 --> 04:06:04,080
WITH INTEGRATION SITE ANALYSIS

3604
04:06:04,080 --> 04:06:06,600
ARE PROVIRUSES THAT ARE

3605
04:06:06,600 --> 04:06:06,840
DEFECTIVE.

3606
04:06:06,840 --> 04:06:09,240
BUT THIS CONCEPT OF INFECTED

3607
04:06:09,240 --> 04:06:11,520
CELL PROLIFERATION WAS EXTENDED

3608
04:06:11,520 --> 04:06:17,760
TO CELLS CARRYING REPLICATION 

3609
04:06:17,760 --> 04:06:19,920
COMPETENT VIRUS IN STUDIES, AND

3610
04:06:19,920 --> 04:06:21,640
IN FACT USING VIRAL ASSAY YOU

3611
04:06:21,640 --> 04:06:24,200
CAN SHOW MANY OF THE INDEPENDENT

3612
04:06:24,200 --> 04:06:26,600
ISOLATES FROM A SINGLE BLOOD

3613
04:06:26,600 --> 04:06:33,600
SAMPLE ACTUALLY CARRY THE SAME

3614
04:06:33,600 --> 04:06:34,800
PROVIRAL SEQUENCE, 57% WITH

3615
04:06:34,800 --> 04:06:36,640
EXTRAORDINARY DEGREE OF IN VIVO

3616
04:06:36,640 --> 04:06:38,440
PROLIFERATION OF INFECTED CELLS.

3617
04:06:38,440 --> 04:06:40,640
AND IF YOU FOLLOW CLONES OF

3618
04:06:40,640 --> 04:06:43,680
INFECTED CELLS OVER A PERIOD OF

3619
04:06:43,680 --> 04:06:49,840
ONE TO FOUR YEARS, YOU SEE SOME

3620
04:06:49,840 --> 04:06:53,320
PERSIST, DETECTED AS FRACTION OF

3621
04:06:53,320 --> 04:06:55,920
ISOLATES BUT OTHERS APPEAR AND

3622
04:06:55,920 --> 04:06:57,920
DISAPPEAR DURING THIS TIME

3623
04:06:57,920 --> 04:06:58,160
FRAME.

3624
04:06:58,160 --> 04:07:00,320
SO THAT THESE CLONES ARE

3625
04:07:00,320 --> 04:07:03,800
ESSENTIALLY WAXING AND WANING, A

3626
04:07:03,800 --> 04:07:06,000
FINDING THAT'S INCONSISTENT WITH

3627
04:07:06,000 --> 04:07:08,080
A CONTINUOUS CELL AUTONOMOUS

3628
04:07:08,080 --> 04:07:11,040
STIMULUS AS THE SOLE DRIVER OF

3629
04:07:11,040 --> 04:07:13,040
PROLIFERATION, AND RATHER IT

3630
04:07:13,040 --> 04:07:14,880
APPEARS THAT ANOTHER MAJOR

3631
04:07:14,880 --> 04:07:18,760
FACTOR IS ACTUALLY ANTIGEN 

3632
04:07:18,760 --> 04:07:24,960
DRIVEN PROLIFERATION SHOWN BY 

3633
04:07:24,960 --> 04:07:28,360
SIMONETTI IN THE AUDIENCE,

3634
04:07:28,360 --> 04:07:31,680
ISOLATED CELLS RESPONDING, AND

3635
04:07:31,680 --> 04:07:33,400
SHOWED AMONG CMV RESPONDING

3636
04:07:33,400 --> 04:07:35,520
CELLS, VERY LARGE CLONES OF

3637
04:07:35,520 --> 04:07:38,160
INFECTED CELLS HAD SAME

3638
04:07:38,160 --> 04:07:40,200
INTEGRATION SITE, SAME PROVIRAL

3639
04:07:40,200 --> 04:07:41,640
SEQUENCE, SOMETIMES COMPRISING

3640
04:07:41,640 --> 04:07:45,080
OVER 80% OF ALL OF THE

3641
04:07:45,080 --> 04:07:45,840
CMV-RESPONSIVE HIV INFECTED

3642
04:07:45,840 --> 04:07:46,920
CELLS, SOME CLONES ARE LARGE

3643
04:07:46,920 --> 04:07:51,520
ENOUGH TO BE SEEN AMONG CELLS

3644
04:07:51,520 --> 04:07:54,240
RESPONDING NON-SPECIFICALLY TO

3645
04:07:54,240 --> 04:07:55,880
CD3, CD28.

3646
04:07:55,880 --> 04:07:58,640
SO, EVEN THOUGH IMMUNE SYSTEM

3647
04:07:58,640 --> 04:08:02,040
CAREFULLY CONTROLS TC 

3648
04:08:02,040 --> 04:08:03,360
PROLIFERATION, REPEATED EXPOSURE

3649
04:08:03,360 --> 04:08:06,440
TO THE SAME ANTIGEN CAN GENERATE

3650
04:08:06,440 --> 04:08:07,640
LARGE CLONES TRANSFORMING THIS

3651
04:08:07,640 --> 04:08:09,280
RESERVOIR FROM COLLECTION OF

3652
04:08:09,280 --> 04:08:14,080
QUIESCENT CELLS TO ONE THAT'S 

3653
04:08:14,080 --> 04:08:15,960
DOMINATED BY LARGE POPULATIONS

3654
04:08:15,960 --> 04:08:19,120
OF INFECTED CELLS ALL DERIVED

3655
04:08:19,120 --> 04:08:23,400
FROM A SINGLE CELL, LARGE

3656
04:08:23,400 --> 04:08:23,640
CLONES.

3657
04:08:23,640 --> 04:08:25,200
AND THE THING WE HAVEN'T YET

3658
04:08:25,200 --> 04:08:29,120
EXPLAINED IS HOW DOES THIS

3659
04:08:29,120 --> 04:08:31,040
HAPPEN, GIVEN THAT THE STIMULI

3660
04:08:31,040 --> 04:08:34,200
THAT DRIVE T CELL PROLIFERATION

3661
04:08:34,200 --> 04:08:35,600
ALSO INDUCE VIRAL GENE

3662
04:08:35,600 --> 04:08:37,240
EXPRESSION, AND MOST

3663
04:08:37,240 --> 04:08:39,560
PRODUCTIVELY INFECTED CELLS DIE

3664
04:08:39,560 --> 04:08:41,600
VERY QUICKLY SO HOW DOES THIS

3665
04:08:41,600 --> 04:08:42,080
HAPPEN?

3666
04:08:42,080 --> 04:08:48,560
TURNS OUT THERE'S UNCOUPLING

3667
04:08:48,560 --> 04:08:50,280
PREEN T CELL PROLIFERATION AND

3668
04:08:50,280 --> 04:08:52,160
PROVIRAL INDUCTION, WE CAN SHOW

3669
04:08:52,160 --> 04:08:56,200
THIS IN ASSAYS, SPLIT THE WELLS

3670
04:08:56,200 --> 04:08:58,400
AND TAKE HALF OF EACH WELL,

3671
04:08:58,400 --> 04:08:59,880
SUBJECT CELLS TO ADDITIONAL

3672
04:08:59,880 --> 04:09:01,120
ROUND OF STIMULATION, AND YOU

3673
04:09:01,120 --> 04:09:04,280
CAN SHOW THAT EVEN THOUGH ALL OF

3674
04:09:04,280 --> 04:09:05,720
THE CELLS HAVE PROLIFERATED,

3675
04:09:05,720 --> 04:09:07,760
SOME OF THEM DON'T PRODUCE VIRUS

3676
04:09:07,760 --> 04:09:10,880
UNTIL AFTER A SECOND OR THIRD OR

3677
04:09:10,880 --> 04:09:14,160
EVEN A FOURTH ROUND OF T CELL

3678
04:09:14,160 --> 04:09:15,760
ACTIVATION.

3679
04:09:15,760 --> 04:09:16,640
SO THERE'S SOME STOCHASTIC

3680
04:09:16,640 --> 04:09:18,840
FEATURE THAT DETERMINES WHETHER

3681
04:09:18,840 --> 04:09:21,400
A PROVIRUS IS INDUCED FOLLOWING

3682
04:09:21,400 --> 04:09:22,880
AN INITIAL STIMULUS OR

3683
04:09:22,880 --> 04:09:24,840
SUBSEQUENT STIMULUS SO THAT IT'S

3684
04:09:24,840 --> 04:09:27,480
A T CELL ACTIVATION DOES NOT

3685
04:09:27,480 --> 04:09:28,440
ALWAYS CAUSE PROVIRAL INDUCTION

3686
04:09:28,440 --> 04:09:31,280
SO WE THINK THIS IS HOW VIRUS

3687
04:09:31,280 --> 04:09:32,960
CLONES CAN BE GENERATED.

3688
04:09:32,960 --> 04:09:36,760
BUT SO WHAT ARE THE CLINICAL

3689
04:09:36,760 --> 04:09:38,040
CONSEQUENCES OF THIS

3690
04:09:38,040 --> 04:09:39,760
PROLIFERATION OF INFECTED CELLS?

3691
04:09:39,760 --> 04:09:41,040
WELL, IT REALLY ALL COMES DOWN

3692
04:09:41,040 --> 04:09:41,720
TO REBOUND.

3693
04:09:41,720 --> 04:09:45,360
THIS IS THE WHOLE ROLE OF HIV

3694
04:09:45,360 --> 04:09:47,440
CURE RESEARCH IS TO PREVENT

3695
04:09:47,440 --> 04:09:48,120
VIRAL REBOUND.

3696
04:09:48,120 --> 04:09:49,960
AND SO ONE QUESTION WE CAN ASK

3697
04:09:49,960 --> 04:09:53,000
IS DO THESE EXPANDED CLONES OF

3698
04:09:53,000 --> 04:09:54,200
LATENTLY EXPECTED CELLS

3699
04:09:54,200 --> 04:09:56,280
CONTRIBUTE TO VIRAL REBOUND, WE

3700
04:09:56,280 --> 04:10:00,920
CAN DETECT CLONES WITH OUR IN

3701
04:10:00,920 --> 04:10:03,720
VITRO SAMPLING, IN VIVO SAMPLING

3702
04:10:03,720 --> 04:10:09,080
THE RESERVOIR CURVES

3703
04:10:09,080 --> 04:10:12,160
CONTINUOUSLY AND ANTIGEN WILL

3704
04:10:12,160 --> 04:10:13,720
INDUCE T-CELL ACTIVATION,

3705
04:10:13,720 --> 04:10:16,440
PRODUCTION OF VIRUS, THIS MAY

3706
04:10:16,440 --> 04:10:25,520
EXPLAIN THE CLONAL NATURE OF

3707
04:10:25,520 --> 04:10:26,720
RESIDUAL VIREMIA BUT WHEN

3708
04:10:26,720 --> 04:10:29,440
REMOVED DO THEY GIVE RISE TO

3709
04:10:29,440 --> 04:10:30,120
REBOUND?

3710
04:10:30,120 --> 04:10:31,320
REBOUND MAY NOT ALWAYS COME FROM

3711
04:10:31,320 --> 04:10:32,320
THESE LARGE CLONES.

3712
04:10:32,320 --> 04:10:36,040
THIS WAS FIRST SHOWN BY KATIE

3713
04:10:36,040 --> 04:10:39,560
BARR AND MICHELE, IN STUDIES

3714
04:10:39,560 --> 04:10:42,480
USING ASSAY TO SHOW EVEN IN

3715
04:10:42,480 --> 04:10:44,520
PATIENTS WHO HAD A RESERVOIR

3716
04:10:44,520 --> 04:10:47,880
THAT WAS DOMINATED BY A SINGLE

3717
04:10:47,880 --> 04:10:50,160
LARGE CLONE VIRAL REBOUND

3718
04:10:50,160 --> 04:10:51,560
FOLLOWING TREATMENT AND ERUPTION

3719
04:10:51,560 --> 04:10:59,000
OFTEN CAME FROM MINOR VARIANTS,

3720
04:10:59,000 --> 04:11:00,000
PHYLOGENETICALLY NOT PREVIOUSLY

3721
04:11:00,000 --> 04:11:01,320
DETECTED, A NUMBER OF

3722
04:11:01,320 --> 04:11:03,640
EXPLANATIONS OFFERED FOR THIS

3723
04:11:03,640 --> 04:11:06,560
SURPRISING FINDING, THIS IS WHY 

3724
04:11:06,560 --> 04:11:09,120
IT WAS SUGGESTED IT MIGHT BE DUE

3725
04:11:09,120 --> 04:11:12,160
TO RECOMBINATION DURING REBOUND.

3726
04:11:12,160 --> 04:11:19,360
BUT WE HYPOTHESIZE A SIMPLER 

3727
04:11:19,360 --> 04:11:21,320
EXPLANATION, AUTOLOGOUS COULD

3728
04:11:21,320 --> 04:11:23,120
BLOCK RESIDUE, RELATIVELY LITTLE

3729
04:11:23,120 --> 04:11:28,320
ATTENTION PAID TO AUTOLOGOUS

3730
04:11:28,320 --> 04:11:29,800
NEUTRALIZING ANTIBODIES, BUT IT

3731
04:11:29,800 --> 04:11:33,200
IS THE EFFICACY OF THE

3732
04:11:33,200 --> 04:11:34,080
AUTOLOGOUS NEUTRALIZING ANTIBODY

3733
04:11:34,080 --> 04:11:35,800
RESPONSE THAT DRIVES VIRAL

3734
04:11:35,800 --> 04:11:37,000
EVOLUTION AND THAT FUNDAMENTALLY

3735
04:11:37,000 --> 04:11:39,960
IS RESPONSIBLE FOR THE FACT WE

3736
04:11:39,960 --> 04:11:50,440
DON'T HAVE AN HIV VACCINE. 

3737
04:11:50,760 --> 04:11:51,920
THESE ANTIBODIES ARE EFFECTING

3738
04:11:51,920 --> 04:11:54,080
BUT ESCAPE OCCURS QUICKLY.

3739
04:11:54,080 --> 04:11:56,120
THE ABSENCE OF ANTIBODIES AND

3740
04:11:56,120 --> 04:11:59,120
PRESENCE OF CONTROL ITT FROM HIV

3741
04:11:59,120 --> 04:12:02,280
NEGATIVE OR AUTOLOGOUS, LOOK FOR

3742
04:12:02,280 --> 04:12:04,000
REDUCTION IN VIRAL OUTGROWTH AND

3743
04:12:04,000 --> 04:12:05,560
COMPARED TO CULTURES WITHOUT

3744
04:12:05,560 --> 04:12:07,000
ANTIBODY OR WITH CONTROL IgG

3745
04:12:07,000 --> 04:12:10,920
WE FOUND THAT IN MANY CASES

3746
04:12:10,920 --> 04:12:14,200
OUTGROWTH IN THE PRESENCE OF

3747
04:12:14,200 --> 04:12:15,720
AUTOLOGOUS IgG WAS GREATLY

3748
04:12:15,720 --> 04:12:18,680
REDUCED, AND THIS IS LIKELY A

3749
04:12:18,680 --> 04:12:20,160
DRAMATIC UNDERESTIMATE OF IN

3750
04:12:20,160 --> 04:12:22,440
VIVO EFFECT BECAUSE 50 MICROGRAM

3751
04:12:22,440 --> 04:12:24,440
PER mL READINGS IN THESE

3752
04:12:24,440 --> 04:12:25,600
EXPERIMENTS IS OVER TWO LOGS

3753
04:12:25,600 --> 04:12:28,320
LESS THAN IN VIVO CONCENTRATION

3754
04:12:28,320 --> 04:12:28,880
OF IgG.

3755
04:12:28,880 --> 04:12:34,440
SO, ON AVERAGE WE GOT A 4.6-FOLD

3756
04:12:34,440 --> 04:12:37,280
REDUCTION IN FREQUENCY OF

3757
04:12:37,280 --> 04:12:39,960
OUTGROWTH, IN 6 OF 15 DONORS

3758
04:12:39,960 --> 04:12:41,920
OUTGROWTH OF OVER 80% OF THE

3759
04:12:41,920 --> 04:12:43,400
RESERVOIR VIRUS WAS BLOCKED BY

3760
04:12:43,400 --> 04:12:47,640
LOW CONCENTRATION OF AUTOLOGOUS

3761
04:12:47,640 --> 04:12:48,640
IgG.

3762
04:12:48,640 --> 04:12:50,680
WE SEQUENCED OUTGROWTH VIRUSES,

3763
04:12:50,680 --> 04:12:52,440
TO UNDERSTAND THIS PHENOMENA,

3764
04:12:52,440 --> 04:12:53,760
AND STRUCTURE OF THE RESERVOIR

3765
04:12:53,760 --> 04:12:56,600
IS APPRECIATED BY CONSIDERING

3766
04:12:56,600 --> 04:12:59,880
FIRST THE VIRUSES THAT GREW

3767
04:12:59,880 --> 04:13:07,000
WITHOUT ANTIBODIES, TWO BRANCHES

3768
04:13:07,000 --> 04:13:09,640
OF THE PHYLOGENETIC TREE

3769
04:13:09,640 --> 04:13:11,080
INCLUDING ONE LARGE EXPANDED

3770
04:13:11,080 --> 04:13:11,280
GROWN.

3771
04:13:11,280 --> 04:13:12,480
OUTSIDE THE PRESENCE THEY ARE

3772
04:13:12,480 --> 04:13:14,600
CONFINED TO UPPER BRANCH OF THE

3773
04:13:14,600 --> 04:13:16,800
TREE, WHERE THERE ARE MUTATIONS

3774
04:13:16,800 --> 04:13:21,400
IN THE B 3 AND B 4 REGIONS OF

3775
04:13:21,400 --> 04:13:23,240
ENVELOPE GENE CONSISTENT WITH

3776
04:13:23,240 --> 04:13:24,760
ESCAPE FROM NEUTRALIZING

3777
04:13:24,760 --> 04:13:29,480
ANTIBODY RESPONSE, WE CAN PROVE

3778
04:13:29,480 --> 04:13:30,320
THIS IN NEUTRALIZATION ASSAYS,

3779
04:13:30,320 --> 04:13:32,640
SHOWING VIRUS IN UPPER PART OF

3780
04:13:32,640 --> 04:13:34,600
THE TREE ARE HIGHLY RESISTANT

3781
04:13:34,600 --> 04:13:40,320
SHOWN BY RED COLORS, OTHER

3782
04:13:40,320 --> 04:13:42,280
ISOLATES INCLUDING THIS LARGE

3783
04:13:42,280 --> 04:13:45,600
CLONE ARE HIGHLY SENSITIVE,

3784
04:13:45,600 --> 04:13:47,000
READILY NEUTRALIZED.

3785
04:13:47,000 --> 04:13:49,280
PRESENCE OF LARGE CLONES

3786
04:13:49,280 --> 04:13:50,720
PROVIDES A SIMPLE EXPLANATION

3787
04:13:50,720 --> 04:13:52,880
FOR DISCREPANCY BETWEEN VIRAL

3788
04:13:52,880 --> 04:13:55,200
OUTGROWTH ASSAY AND VIRUSES THAT

3789
04:13:55,200 --> 04:13:55,960
APPEAR UPON REBOUND.

3790
04:13:55,960 --> 04:14:04,000
WE'VE GONE ON TO SHOW THERE'S A

3791
04:14:04,000 --> 04:14:04,520
PHYLOGENETIC RELATIONSHIP

3792
04:14:04,520 --> 04:14:06,400
BETWEEN IN VITRO AND VIRUSES

3793
04:14:06,400 --> 04:14:08,240
THAT CAUSE REBOUND IN VIVO.

3794
04:14:08,240 --> 04:14:12,320
IN OTHER WORDS, REBOUND IS A

3795
04:14:12,320 --> 04:14:13,040
SELECTION PROCESS.

3796
04:14:13,040 --> 04:14:17,120
AND THE RESERVOIR IS ACTUALLY

3797
04:14:17,120 --> 04:14:19,720
CONTINUOUSLY SORT OF SAMPLED IN

3798
04:14:19,720 --> 04:14:21,240
VIVO THROUGH EXPOSURE TO ANTIGEN

3799
04:14:21,240 --> 04:14:25,440
AND THEN WE CAN SEE WHETHER THE

3800
04:14:25,440 --> 04:14:26,960
VIRUSES INDUCED CAN NOW

3801
04:14:26,960 --> 04:14:28,760
REPLICATE ONCE ART IS REMOVED

3802
04:14:28,760 --> 04:14:32,560
AND IT TURNS OUT SOME OF THEM

3803
04:14:32,560 --> 04:14:33,760
CANNOT BECAUSE THEY ARE

3804
04:14:33,760 --> 04:14:36,920
NEUTRALIZED BY EXISTING ANTIBODY

3805
04:14:36,920 --> 04:14:37,880
RESPONSE.

3806
04:14:37,880 --> 04:14:38,520
HOWEVER, BECAUSE THIS SAMPLING

3807
04:14:38,520 --> 04:14:40,400
PROCESS OF THE RESERVOIR THAT

3808
04:14:40,400 --> 04:14:44,160
OCCURS IN VIVO IS CONTINUOUS, IT

3809
04:14:44,160 --> 04:14:47,720
CAN FIND MINOR VARIANTS THAT ARE

3810
04:14:47,720 --> 04:14:52,120
NOT NEUTRALIZED, THIS IS WHAT 

3811
04:14:52,120 --> 04:14:54,040
LEADS TO VIRAL REBOUND.

3812
04:14:54,040 --> 04:14:58,080
I THINK IT'S ENCOURAGING THAT

3813
04:14:58,080 --> 04:15:01,240
THE SIZE OF WHAT JEFF LIFSON

3814
04:15:01,240 --> 04:15:02,360
CALLS REBOUND COMPETENT

3815
04:15:02,360 --> 04:15:04,200
RESERVOIR IS SMALLER THAN WE

3816
04:15:04,200 --> 04:15:04,680
THOUGHT.

3817
04:15:04,680 --> 04:15:09,120
BUT I SHOULD POINT OUT THAT IN

3818
04:15:09,120 --> 04:15:12,960
SOME INDIVIDUALS, THESE LARGE

3819
04:15:12,960 --> 04:15:13,840
EXPANDED CLONES CARRY

3820
04:15:13,840 --> 04:15:15,920
NEUTRALIZATION RESISTANT VIRUS.

3821
04:15:15,920 --> 04:15:22,040
THE PROCESS BY WHICH THE VIRUS

3822
04:15:22,040 --> 04:15:22,800
ESCAPES FROM AUTOLOGOUS

3823
04:15:22,800 --> 04:15:25,640
NEUTRALIZING ANTIBODIES SORT OF

3824
04:15:25,640 --> 04:15:28,400
PREDATES AND IS ORTHOGONAL TO

3825
04:15:28,400 --> 04:15:32,120
THE PROCESS OF ANTIGEN-DRIVEN

3826
04:15:32,120 --> 04:15:33,440
CLONAL EXPANSION.

3827
04:15:33,440 --> 04:15:35,720
SO THINKING ABOUT REBOUND, IT'S

3828
04:15:35,720 --> 04:15:37,600
USEFUL TO CONSIDER THE RESERVOIR

3829
04:15:37,600 --> 04:15:40,640
SORT OF ON THE LOG SCALE.

3830
04:15:40,640 --> 04:15:44,360
AND IT'S VERY CLEAR THAT THE

3831
04:15:44,360 --> 04:15:46,760
CLONAL EXPANSION PROCESS THAT

3832
04:15:46,760 --> 04:15:49,200
STEVE PROVIDED EVIDENCE FOR IS

3833
04:15:49,200 --> 04:15:51,720
REALLY VERY IMPORTANT IN SORT OF

3834
04:15:51,720 --> 04:15:54,160
THE MAINTENANCE OF THE LATENT

3835
04:15:54,160 --> 04:15:54,560
RESERVOIR.

3836
04:15:54,560 --> 04:15:58,400
WE ALSO KNOW RAPID REBOUND CAN

3837
04:15:58,400 --> 04:16:00,280
COME FROM MINOR VARIANTS PRESENT

3838
04:16:00,280 --> 04:16:03,400
AT FREQUENCY LET'S SAY LESS THAN

3839
04:16:03,400 --> 04:16:03,720
1%.

3840
04:16:03,720 --> 04:16:04,760
AND THE CONTINUOUS SORT OF

3841
04:16:04,760 --> 04:16:07,680
SAMPLING OF THE RESERVOIR THAT

3842
04:16:07,680 --> 04:16:10,800
OCCURS IN VIVO CAN FIND THESE

3843
04:16:10,800 --> 04:16:13,440
MINOR VARIANTS.

3844
04:16:13,440 --> 04:16:15,400
THIS GIVES RISE TO SOBERING VIEW

3845
04:16:15,400 --> 04:16:20,440
OF THE PROSPECT OF ACHIEVING

3846
04:16:20,440 --> 04:16:20,960
ERADICATION.

3847
04:16:20,960 --> 04:16:24,280
SOME YEARS AGO ALLISON HEAL

3848
04:16:24,280 --> 04:16:29,840
DEVELOPED A MODEL FOR THE DEGREE

3849
04:16:29,840 --> 04:16:31,400
OF RESERVOIR REDUCTION REQUIRED

3850
04:16:31,400 --> 04:16:33,880
TO ACHIEVE A GIVEN DEGREE OF

3851
04:16:33,880 --> 04:16:36,760
DELAY IN VIRAL REBOUND, AND SHE

3852
04:16:36,760 --> 04:16:46,640
BASED THIS MODEL ON LEVEL OF

3853
04:16:46,640 --> 04:16:47,400
RESIDUAL VIREMIA, THIS AGREES

3854
04:16:47,400 --> 04:16:49,680
VERY WELL WITH KNOWN CASES OF

3855
04:16:49,680 --> 04:16:53,200
VERY LONG TIME TO REBOUND, WHAT

3856
04:16:53,200 --> 04:16:55,520
THE MODEL SHOWS IS FOR A SORT OF

3857
04:16:55,520 --> 04:16:58,560
TWO LOG REDUCTION IN SIZE OF THE

3858
04:16:58,560 --> 04:17:00,800
RESERVOIR, YOU ONLY GET A FEW

3859
04:17:00,800 --> 04:17:02,280
WEEKS DELAY IN REBOUND.

3860
04:17:02,280 --> 04:17:06,120
I THINK THIS IS A VERY SOBERING

3861
04:17:06,120 --> 04:17:10,000
VIEW OF POSSIBILITY OF ACHIEVING

3862
04:17:10,000 --> 04:17:11,600
CURE THROUGH RESERVOIR

3863
04:17:11,600 --> 04:17:12,040
REDUCTION.

3864
04:17:12,040 --> 04:17:14,000
99% REDUCTION IN RESERVOIR.

3865
04:17:14,000 --> 04:17:18,400
ONLY REALLY CAUSING MINOR DELAY,

3866
04:17:18,400 --> 04:17:19,400
NOWHERE NEAR ACHIEVING THAT

3867
04:17:19,400 --> 04:17:20,160
DEGREE OF REDUCTION.

3868
04:17:20,160 --> 04:17:22,320
IN FACT I WOULD SAY IN CLINICAL

3869
04:17:22,320 --> 04:17:26,520
STUDIES THERE REALLY ISN'T ANY 

3870
04:17:26,520 --> 04:17:29,040
CONVINCING EVIDENCE IN STUDIES

3871
04:17:29,040 --> 04:17:31,640
THAT DON'T INVOLVE BONE MARROW

3872
04:17:31,640 --> 04:17:32,000
TRANSPLANTATION.

3873
04:17:32,000 --> 04:17:34,040
I DON'T WANT TO END ON THIS

3874
04:17:34,040 --> 04:17:38,000
DEPRESSING NOTE SO I'LL SHOW

3875
04:17:38,000 --> 04:17:40,800
THIS PHYLOGENETIC TREE FROM AN

3876
04:17:40,800 --> 04:17:42,040
SIV-INFECTED MACAQUE, AND THIS

3877
04:17:42,040 --> 04:17:45,240
SHOWS ALL THE EVOLUTION THAT

3878
04:17:45,240 --> 04:17:46,200
OCCURS FROM INITIAL STOCK

3879
04:17:46,200 --> 04:17:49,360
SEQUENCE OVER THE COURSE OF ONE

3880
04:17:49,360 --> 04:17:50,440
YEAR OF UNTREATED INFECTION,

3881
04:17:50,440 --> 04:17:53,080
ANIMAL IS PUT ON ART AND

3882
04:17:53,080 --> 04:17:55,840
FOLLOWED FOR FOUR YEARS,

3883
04:17:55,840 --> 04:17:58,080
REPRESENTATIVE OF TEN ANIMALS IN

3884
04:17:58,080 --> 04:18:00,000
COMBINATION WITH DAN'S GROUP.

3885
04:18:00,000 --> 04:18:02,520
VIRUSES REPLICATING AT THE TIME

3886
04:18:02,520 --> 04:18:04,480
OF ART INITIATION FOUND IN

3887
04:18:04,480 --> 04:18:10,080
PLASMA SHOWN IN BLACK, AND THESE

3888
04:18:10,080 --> 04:18:11,160
VIRUSES HAVE ACCUMULATED

3889
04:18:11,160 --> 04:18:13,160
MUTATIONS IN VARIABLE REGIONS OF

3890
04:18:13,160 --> 04:18:16,320
THE ENVELOPE GENE CONSISTENT

3891
04:18:16,320 --> 04:18:18,840
WITH ESCAPE FROM AUTOLOGOUS

3892
04:18:18,840 --> 04:18:21,040
NEUTRALIZING ANTIBODIES.

3893
04:18:21,040 --> 04:18:23,760
OTHER VARIANTS THAT ARE

3894
04:18:23,760 --> 04:18:26,720
ANCESTRAL AND THAT HAVE FEWER

3895
04:18:26,720 --> 04:18:29,680
MUTATIONS ARE ALSO PRESENT AND

3896
04:18:29,680 --> 04:18:31,520
ARE PRESERVED IN THE RESERVOIR,

3897
04:18:31,520 --> 04:18:35,120
AND IN FACT ACTUALLY BECOME MORE

3898
04:18:35,120 --> 04:18:36,120
PROMINENT WITH TIME, DECREASING

3899
04:18:36,120 --> 04:18:38,720
TIME, FOR REASONS I DON'T HAVE

3900
04:18:38,720 --> 04:18:41,080
TIME TO GO INTO.

3901
04:18:41,080 --> 04:18:42,320
BUT WHAT'S REALLY INTERESTING IS

3902
04:18:42,320 --> 04:18:44,720
WHY AREN'T ALL OF THESE VARIANTS

3903
04:18:44,720 --> 04:18:46,680
REPLICATING AT THE TIME OF ART

3904
04:18:46,680 --> 04:18:47,080
INITIATION?

3905
04:18:47,080 --> 04:18:48,800
OF COURSE ONE HYPOTHESIS IS THAT

3906
04:18:48,800 --> 04:18:51,640
THEY CAN'T REPLICATE.

3907
04:18:51,640 --> 04:18:53,040
THEY ARE ALREADY NEUTRALIZED BY

3908
04:18:53,040 --> 04:19:01,160
YOU A TOLL -- AUTOLOGOUS

3909
04:19:01,160 --> 04:19:02,120
NEUTRALIZING ANTIBODIES, A

3910
04:19:02,120 --> 04:19:03,560
DIFFERENT WAY TO LOOK AT THE

3911
04:19:03,560 --> 04:19:04,560
PROBLEM INSTEAD OF THINKING

3912
04:19:04,560 --> 04:19:06,880
ABOUT HOW MANY LOGS OF REDUCTION

3913
04:19:06,880 --> 04:19:10,680
IN THE RES WE -- RESERVOIR WE

3914
04:19:10,680 --> 04:19:12,640
HAVE TO ACHIEVE WE CAN THINK

3915
04:19:12,640 --> 04:19:14,400
ABOUT SIMPLY FINDING A WAY TO

3916
04:19:14,400 --> 04:19:15,840
PREVENT OUTGROWTH OF THE SUBSET

3917
04:19:15,840 --> 04:19:19,680
OF VIRUSES THAT ARE NOT ALREADY

3918
04:19:19,680 --> 04:19:21,120
CONTROLLED BY THE IMMUNE

3919
04:19:21,120 --> 04:19:21,400
RESPONSES.

3920
04:19:21,400 --> 04:19:23,280
I'M GOING TO STOP THERE.

3921
04:19:23,280 --> 04:19:25,240
I WANT TO, AGAIN, CONGRATULATE

3922
04:19:25,240 --> 04:19:26,320
STEVE ON HIS REMARKABLE

3923
04:19:26,320 --> 04:19:28,760
CONTRIBUTIONS NOT ONLY TO THE

3924
04:19:28,760 --> 04:19:30,960
CURE FIELD BUT TO RETROVIROLOGY

3925
04:19:30,960 --> 04:19:34,280
IN GENERAL, AND I WANT TO THANK

3926
04:19:34,280 --> 04:19:35,480
THE PEOPLE FROM OUR GROUP

3927
04:19:35,480 --> 04:19:37,000
INVOLVED IN THIS WORK, WORKING

3928
04:19:37,000 --> 04:19:40,400
WITH MY WIFE JANET FOR MANY

3929
04:19:40,400 --> 04:19:42,920
YEARS, HO DID THE ORIGINAL WORK,

3930
04:19:42,920 --> 04:19:50,480
AND SHE NOW HAS A LAB AT YALE,

3931
04:19:50,480 --> 04:19:55,200
FRANCESCO HAS A LAB AT JOHNS

3932
04:19:55,200 --> 04:19:56,640
HOPKINS, ALLISON HEEL IS NOW

3933
04:19:56,640 --> 04:20:04,920
ASSISTANT PROFESSOR AT JOHNS 

3934
04:20:04,920 --> 04:20:06,760
HOPKINS, AND DANIEL ROSENBLUM,

3935
04:20:06,760 --> 04:20:13,120
WE HAVE A TERRIFIC TEAM,

3936
04:20:13,120 --> 04:20:15,760
LONG-TERM ART PROJECT, EMILY AND

3937
04:20:15,760 --> 04:20:16,120
KUMAR.

3938
04:20:16,120 --> 04:20:23,880
I WANT TO THANK DAN, STEVE,

3939
04:20:23,880 --> 04:20:27,320
LUIS, PEOPLE WHO INSPIRED OUR

3940
04:20:27,320 --> 04:20:28,360
WORK AND FUNDING AGENCIES.

3941
04:20:28,360 --> 04:20:30,960
I'LL STOP THERE TO ANSWER ANY

3942
04:20:30,960 --> 04:20:33,040
QUESTIONS.

3943
04:20:33,040 --> 04:20:34,360
-789D.

3944
04:20:34,360 --> 04:20:34,640
[APPLAUSE]

3945
04:20:34,640 --> 04:20:44,920
>>THANKS, BOB.

3946
04:20:47,280 --> 04:20:47,720
INSPIRING AS ALWAYS.

3947
04:20:47,720 --> 04:20:51,760
>>WE HAVE TIME FOR ONE OR
TWO

3948
04:20:51,760 --> 04:20:55,600
QUICK QUESTIONS, IF THERE ARE 

3949
04:20:55,600 --> 04:20:55,760
ANY.

3950
04:20:55,760 --> 04:20:58,600
>>VERY NICE TALK.

3951
04:20:58,600 --> 04:21:00,240
IT FOLLOWS ALONG WITH SOMETHING

3952
04:21:00,240 --> 04:21:09,880
I DON'T LIKE TO SAY BUT IT'S

3953
04:21:09,880 --> 04:21:11,640
(INDISCERNIBLE).

3954
04:21:11,640 --> 04:21:14,480
BUT YOU TALK ABOUT PERSISTENT

3955
04:21:14,480 --> 04:21:18,200
VIREMIA, HAVE YOU LOOKED TO SEE

3956
04:21:18,200 --> 04:21:19,400
PERSISTENT VIRUS STILL BEING

3957
04:21:19,400 --> 04:21:24,880
SHAPED BY THE SAME ANTIBODY 

3958
04:21:24,880 --> 04:21:25,720
COURSES?

3959
04:21:25,720 --> 04:21:26,600
>>SO, WE HAVEN'T -- GOOD

3960
04:21:26,600 --> 04:21:26,880
QUESTION.

3961
04:21:26,880 --> 04:21:28,480
WE HAVEN'T HAD A CHANCE TO DO

3962
04:21:28,480 --> 04:21:31,840
THAT YET.

3963
04:21:31,840 --> 04:21:33,600
WE'RE PARTICULARLY INTERESTED IN

3964
04:21:33,600 --> 04:21:35,920
LOOKING AT THIS, PARTICULARLY IN

3965
04:21:35,920 --> 04:21:37,000
THESE PATIENTS, BUT LONG-TERM

3966
04:21:37,000 --> 04:21:42,240
ART TO SEE WHAT THE NATURE OF

3967
04:21:42,240 --> 04:21:45,400
THE VIREMIA IS, NATURE OF LARGE

3968
04:21:45,400 --> 04:21:48,120
CLONES, TURNS OUT IN THE

3969
04:21:48,120 --> 04:21:51,320
PATIENT -- IN LONG-TERM ART 

3970
04:21:51,320 --> 04:21:54,640
STUDY I SHOWED YOU, THE

3971
04:21:54,640 --> 04:21:55,480
RESERVOIR WAS ACTUALLY DOMINATED

3972
04:21:55,480 --> 04:21:57,800
BY -- AT LEAST IN PEOPLE WHO

3973
04:21:57,800 --> 04:22:01,960
STUDIED SO FAR BY SINGLE CLONES

3974
04:22:01,960 --> 04:22:08,480
AND VARIATIONS TO EXTENT WHICH 

3975
04:22:08,480 --> 04:22:12,400
THOSE ARE AFFECTED BY AUTOLOGOUS

3976
04:22:12,400 --> 04:22:12,880
NEUTRALIZING ANTIBODIES.

3977
04:22:12,880 --> 04:22:13,640
>>ANYBODY ELSE?

3978
04:22:13,640 --> 04:22:15,520
ALL RIGHT.

3979
04:22:15,520 --> 04:22:16,040
THANK YOU VERY MUCH.

3980
04:22:16,040 --> 04:22:18,600
[APPLAUSE]

3981
04:22:18,600 --> 04:22:23,640
 

3982
04:22:23,640 --> 04:22:25,080
NEXT IS RON SWANSTROM,

3983
04:22:25,080 --> 04:22:29,680
UNC-CHAPEL HILL, LEADER IN HIV

3984
04:22:29,680 --> 04:22:32,840
RESEARCH, UNDERSTANDING OF

3985
04:22:32,840 --> 04:22:34,040
DIVERSITY, RESISTANCE, TROPISM,

3986
04:22:34,040 --> 04:22:42,880
I'M HAPPY RON COULD BE HERE, HE 

3987
04:22:42,880 --> 04:22:44,360
ALMOST WASN'T FOR A REASON MAYBE

3988
04:22:44,360 --> 04:22:47,160
HE WILL TELL US.

3989
04:22:47,160 --> 04:22:53,160
 

3990
04:22:53,160 --> 04:23:02,720
 

3991
04:23:02,720 --> 04:23:09,960
>>A THIRD OF MY SLIDES
HAVE 

3992
04:23:09,960 --> 04:23:10,200
BEEN USED.

3993
04:23:10,200 --> 04:23:12,640
[LAUGHTER]

3994
04:23:12,640 --> 04:23:18,480
 

3995
04:23:18,480 --> 04:23:28,520
 

3996
04:23:36,600 --> 04:23:47,040
[ INDISCERNIBLE CONVERSATION ]

3997
04:23:52,680 --> 04:23:55,360
>>MY TALK IS DIFFERENT.

3998
04:23:55,360 --> 04:23:56,840
A LITTLE MORE IRREVERENT.

3999
04:23:56,840 --> 04:24:01,320
I'M REMINDED OF THE TIME WHEN WE

4000
04:24:01,320 --> 04:24:09,720
WENT TO COLD SPRING HARBOR AS A

4001
04:24:09,720 --> 04:24:10,960
YOUNG POSTDOC, STUDYING

4002
04:24:10,960 --> 04:24:12,720
(INDISCERNIBLE) AND THE

4003
04:24:12,720 --> 04:24:14,440
MICROPHONE WAS OUT.

4004
04:24:14,440 --> 04:24:22,120
I WAS A SECOND-YEAR POSTDOC,

4005
04:24:22,120 --> 04:24:23,320
TERRIFIED WITH NO MICROPHONE TO

4006
04:24:23,320 --> 04:24:25,120
ENTERTAIN THE CROWD FOR WHAT 

4007
04:24:25,120 --> 04:24:28,560
SEEMED LIKE AN ETERNITY.

4008
04:24:28,560 --> 04:24:32,400
 

4009
04:24:32,400 --> 04:24:36,640
I WANT TO SAY THIS TALK WOULD BE

4010
04:24:36,640 --> 04:24:37,960
DIFFERENT, I GUESS THAT'S

4011
04:24:37,960 --> 04:24:39,400
BECAUSE MY RELATIONSHIP WITH

4012
04:24:39,400 --> 04:24:41,360
STEVE HAS BEEN DIFFERENT THAN

4013
04:24:41,360 --> 04:24:44,840
MANY OF YOURS. 

4014
04:24:44,840 --> 04:24:45,160
STILL GOOD.

4015
04:24:45,160 --> 04:24:55,360
[LAUGHTER] 

4016
04:24:57,120 --> 04:24:59,920
ANYONE WANT TO LOOK AT MY MUSIC

4017
04:24:59,920 --> 04:25:00,320
LIST?

4018
04:25:00,320 --> 04:25:02,640
[LAUGHTER]

4019
04:25:02,640 --> 04:25:08,680
 

4020
04:25:08,680 --> 04:25:18,720
 

4021
04:25:37,840 --> 04:25:41,480
IT IS KIND OF WEIRD, YOU GET TO

4022
04:25:41,480 --> 04:25:44,400
SEE OTHER PEOPLE'S COMPUTERS.

4023
04:25:44,400 --> 04:25:45,200
[LAUGHTER]

4024
04:25:45,200 --> 04:25:46,360
NOT NECESSARILY THE PRETTIEST

4025
04:25:46,360 --> 04:25:48,480
THING.

4026
04:25:48,480 --> 04:25:54,480
 

4027
04:25:54,480 --> 04:25:59,640
 

4028
04:25:59,640 --> 04:26:01,000
THIS IS WHERE WE WERE FIVE

4029
04:26:01,000 --> 04:26:03,440
MINUTES AGO.

4030
04:26:03,440 --> 04:26:11,160
 

4031
04:26:11,160 --> 04:26:14,080
>>WELL DONE. 

4032
04:26:14,080 --> 04:26:14,520
>>OKAY.

4033
04:26:14,520 --> 04:26:15,840
THANK YOU.

4034
04:26:15,840 --> 04:26:19,760
SO, YEAH, JOHN STOLE MY TITLE.

4035
04:26:19,760 --> 04:26:23,600
I TRIED TO BE MORE THEATRICAL.

4036
04:26:23,600 --> 04:26:27,320
I WANT EVERYONE TO NOTE THE

4037
04:26:27,320 --> 04:26:28,320
SYDNEY POWELL DISCLAIMER DOWN

4038
04:26:28,320 --> 04:26:30,080
THERE THAT I WILL USE AS PART OF

4039
04:26:30,080 --> 04:26:30,520
MY TALK.

4040
04:26:30,520 --> 04:26:38,200
IF ANYBODY I SAY IS NOT TRUE,

4041
04:26:38,200 --> 04:26:39,840
LET'S BLAME SYDNEY POWELL.

4042
04:26:39,840 --> 04:26:48,120
45 YEARS IS A REAL NUMBER.

4043
04:26:48,120 --> 04:26:49,280
I SUSPECT HAROLD MAY HAVE MET

4044
04:26:49,280 --> 04:26:50,520
STEVE BEFORE I DID.

4045
04:26:50,520 --> 04:26:53,920
OTHER THAN THAT, IT'S US, BUDDY.

4046
04:26:53,920 --> 04:27:00,640
SO WE'RE THE ONES THAT MADE IT

4047
04:27:00,640 --> 04:27:01,480
THROUGH UCSF, AND WE'RE NOT

4048
04:27:01,480 --> 04:27:03,160
GOING TO MAKE IT TO THE NEXT

4049
04:27:03,160 --> 04:27:03,360
SLIDE.

4050
04:27:03,360 --> 04:27:05,640
[LAUGHTER]

4051
04:27:05,640 --> 04:27:11,640
 

4052
04:27:11,640 --> 04:27:21,680
 

4053
04:27:22,080 --> 04:27:30,800
SO, YEAH, THIS IS WHERE WE

4054
04:27:30,800 --> 04:27:33,360
WORKED AT UCSF, I WAS THERE

4055
04:27:33,360 --> 04:27:34,720
BEFORE STEVE, STILL THERE A

4056
04:27:34,720 --> 04:27:36,600
LITTLE AFTER STEVE TOO.

4057
04:27:36,600 --> 04:27:40,440
WE BOTH HAD THIS COMMON

4058
04:27:40,440 --> 04:27:41,640
INTEREST.

4059
04:27:41,640 --> 04:27:43,200
RETROVIRAL DNA.

4060
04:27:43,200 --> 04:27:44,960
I CAN'T FULLY DISENTANGLE MY OWN

4061
04:27:44,960 --> 04:27:48,240
CAREER FROM HAVING STEVE AROUND.

4062
04:27:48,240 --> 04:27:50,840
SO THIS TALK IS REALLY

4063
04:27:50,840 --> 04:27:55,440
INTERSECTIONS WHICH WERE IN MANY

4064
04:27:55,440 --> 04:27:58,840
WAYS LESS OBVIOUS, LESS DIRECT,

4065
04:27:58,840 --> 04:27:59,720
BUT STILL THERE.

4066
04:27:59,720 --> 04:28:04,760
SO STEVE OF COURSE CAME FROM

4067
04:28:04,760 --> 04:28:07,920
HARVARD, WHILE I CAME FROM

4068
04:28:07,920 --> 04:28:13,040
UC-IRVINE WHICH WAS KNOWN FOR

4069
04:28:13,040 --> 04:28:13,480
(INDISCERNIBLE).

4070
04:28:13,480 --> 04:28:18,000
WE HAD REALLY DIFFERENT

4071
04:28:18,000 --> 04:28:19,720
BACKGROUNDS WHEN WE ARRIVED AT

4072
04:28:19,720 --> 04:28:21,600
UCSF.

4073
04:28:21,600 --> 04:28:30,240
THIS IS A FAMOUS PICTURE 

4074
04:28:30,240 --> 04:28:31,800
EVERYONE IMPORTANT AT UCSF --

4075
04:28:31,800 --> 04:28:34,320
YOU'LL SEE STEVE IN THE MIDDLE.

4076
04:28:34,320 --> 04:28:36,800
I'M ON THE SIDE BY THE OTHER

4077
04:28:36,800 --> 04:28:38,560
POSTDOCS IN THE LAB OFF TO THE

4078
04:28:38,560 --> 04:28:40,040
EDGE OVER THERE.

4079
04:28:40,040 --> 04:28:43,840
THAT WAS MY INTRODUCTION.

4080
04:28:43,840 --> 04:28:48,120
AND PETE SAME UP HERE, I THINK

4081
04:28:48,120 --> 04:28:50,800
ON AN EXTENDED OR RETIREMENT

4082
04:28:50,800 --> 04:28:51,840
VACATION IN FLORENCE WHICH IS

4083
04:28:51,840 --> 04:28:52,920
THE ONLY THING THAT KEPT HIM

4084
04:28:52,920 --> 04:28:54,840
FROM BEING HERE AND I PROMISED

4085
04:28:54,840 --> 04:28:58,840
WOULD BRING HIM UP.

4086
04:28:58,840 --> 04:29:01,440
HE CAME TO UCSF FROM UNC, AND

4087
04:29:01,440 --> 04:29:09,080
WHICH IS WHERE I WOUND UP. 

4088
04:29:09,080 --> 04:29:10,320
BUT WE REMAIN FANS.

4089
04:29:10,320 --> 04:29:12,000
YOU'VE SEEN THIS PAPER BEFORE.

4090
04:29:12,000 --> 04:29:15,320
I WANT TO POINT OUT PETER AND

4091
04:29:15,320 --> 04:29:17,360
STEVE WORKED TOGETHER TO PUBLISH

4092
04:29:17,360 --> 04:29:20,320
THESE PAPERS BACK TO BACK IN

4093
04:29:20,320 --> 04:29:22,960
"SCIENCE," AND THE FIRST ONE,

4094
04:29:22,960 --> 04:29:27,000
THIS IMPORTANT CONCEPTUAL 

4095
04:29:27,000 --> 04:29:28,760
ORGANIZATION, VIRAL GENOME, AND

4096
04:29:28,760 --> 04:29:32,280
STEVE AND THEN PETER'S PAPER 

4097
04:29:32,280 --> 04:29:33,360
LOOKING AT THE INTEGRATION, AS

4098
04:29:33,360 --> 04:29:36,120
YOU HEARD. 

4099
04:29:36,120 --> 04:29:37,280
I WAS IMPRESSED LOOKING BACK TO

4100
04:29:37,280 --> 04:29:39,600
GO SO FAR AS TO ORGANIZE GENETIC

4101
04:29:39,600 --> 04:29:41,880
MAP OF THE VIRUS WITH BIOLOGICAL

4102
04:29:41,880 --> 04:29:43,680
ABILITY TO RESCUE THESE VIRUSES,

4103
04:29:43,680 --> 04:29:47,360
WHETHER OR NOT THEY WERE

4104
04:29:47,360 --> 04:29:48,520
DEFECTIVE OR NOT, INTELLECTUAL

4105
04:29:48,520 --> 04:29:49,440
LEAPS AT THE TIME.

4106
04:29:49,440 --> 04:29:51,840
ONE OF THE THINGS I NOTICED IN

4107
04:29:51,840 --> 04:29:56,680
THE SAME ISSUE OF "CELL,"

4108
04:29:56,680 --> 04:30:00,440
MICHELE AND JEFF PUBLISHED THAT

4109
04:30:00,440 --> 04:30:03,840
TM9 TRANSPOSITION RESULTED IN

4110
04:30:03,840 --> 04:30:05,720
REPEAT DURING INSERTION IN

4111
04:30:05,720 --> 04:30:06,800
GENOME, WE CAN'T BE SURPRISED

4112
04:30:06,800 --> 04:30:08,200
STEVE PICKED UP ON THAT AND

4113
04:30:08,200 --> 04:30:11,120
MONTHS LATER WAS ABLE TO SHOW

4114
04:30:11,120 --> 04:30:12,040
RETROVIRUSES ALSO GENERATED

4115
04:30:12,040 --> 04:30:15,120
DIRECT REPEAT IN CELLULAR DNA

4116
04:30:15,120 --> 04:30:16,360
WHEN THEY INTEGRATE.

4117
04:30:16,360 --> 04:30:19,320
SO MY, AS I SAID, MY OWN LIFE IN

4118
04:30:19,320 --> 04:30:25,800
ALL OF THIS AT THE SAME TIME, IN

4119
04:30:25,800 --> 04:30:29,400
THAT MILIEU WHEN CLAUDIA BECAME

4120
04:30:29,400 --> 04:30:30,080
AVAILABLE, HOFFMAN, FAR RIGHT,

4121
04:30:30,080 --> 04:30:32,240
KIND ENOUGH TO GIVE ME THE

4122
04:30:32,240 --> 04:30:34,320
CHANCE TO SEQUENCE DNA HE

4123
04:30:34,320 --> 04:30:36,520
CLONED, I WAS ABLE TO SEQUENCE

4124
04:30:36,520 --> 04:30:42,560
THE CIRCLE JUNCTION AND GET SOME

4125
04:30:42,560 --> 04:30:45,000
NUCLEOTIDE SEQUENCES TO LIKE

4126
04:30:45,000 --> 04:30:46,120
PPT, THINGS LIKE THAT.

4127
04:30:46,120 --> 04:30:51,080
IT WAS AS HAROLD MENTIONED AN

4128
04:30:51,080 --> 04:30:55,240
ENVIRONMENT THAT WAS FUN TO BE

4129
04:30:55,240 --> 04:30:56,000
PART OF.

4130
04:30:56,000 --> 04:30:58,120
SOMETIMES, MOST OF THE TIME, I'M

4131
04:30:58,120 --> 04:31:02,400
ENVIOUS OF STEVE FOR THE WORK HE

4132
04:31:02,400 --> 04:31:02,800
DOES.

4133
04:31:02,800 --> 04:31:04,720
SOMETIMES I'M DISMAYED.

4134
04:31:04,720 --> 04:31:11,320
SO, CORRECT ME IF I'M WRONG.

4135
04:31:11,320 --> 04:31:15,480
A POSTDOC IS GOING TO TELL 

4136
04:31:15,480 --> 04:31:16,080
EVERYBODY WHAT ENDOGENOUS

4137
04:31:16,080 --> 04:31:18,000
VIRUSES LOOK AT IN CHICKENS, AND

4138
04:31:18,000 --> 04:31:19,920
SHOWS ONE SLIDE.

4139
04:31:19,920 --> 04:31:22,720
NO TALK.

4140
04:31:22,720 --> 04:31:23,960
AND THIS IS ACTUALLY -- THIS IS

4141
04:31:23,960 --> 04:31:25,160
FROM THE PAPER, I DON'T KNOW IF

4142
04:31:25,160 --> 04:31:28,760
IT'S EXACTLY THE SAME AS THE

4143
04:31:28,760 --> 04:31:32,720
SLIDE, BUT CASUAL GLANCE THAT'S 

4144
04:31:32,720 --> 04:31:36,080
WHAT IT LOOKED LIKE.

4145
04:31:36,080 --> 04:31:38,640
SO, I'M FORTUNATE ENOUGH TO

4146
04:31:38,640 --> 04:31:41,240
PARTICIPATE IN THIS BOOK.

4147
04:31:41,240 --> 04:31:43,440
I'M GRATEFUL TO HAROLD FOR

4148
04:31:43,440 --> 04:31:48,880
GIVING ME THIS OPPORTUNITY TO BE

4149
04:31:48,880 --> 04:31:49,760
CO-AUTHOR, YOUNG POSTDOCS,

4150
04:31:49,760 --> 04:31:52,400
REALLY GRATEFUL HE PICKED ME.

4151
04:31:52,400 --> 04:31:53,920
IT'S A WAY A YOUNG PERSON GETS

4152
04:31:53,920 --> 04:31:56,760
TO BE PART OF A COMMUNITY.

4153
04:31:56,760 --> 04:31:59,440
HAROLD WAS VERY COMPLIMENTARY OF

4154
04:31:59,440 --> 04:32:00,480
STEVE FOR DOING APPENDICES.

4155
04:32:00,480 --> 04:32:01,560
I HAD A DIFFERENT VIEW.

4156
04:32:01,560 --> 04:32:03,760
I WAS HAPPY TO HAVE MY FACE AND

4157
04:32:03,760 --> 04:32:06,600
MY NAME ON THE TABLE OF

4158
04:32:06,600 --> 04:32:07,520
CONTENTS.

4159
04:32:07,520 --> 04:32:10,520
STEVE MANAGED TO ENGINEER HIS

4160
04:32:10,520 --> 04:32:11,080
NAME SIX TIMES.

4161
04:32:11,080 --> 04:32:13,280
[LAUGHTER]

4162
04:32:13,280 --> 04:32:19,280
 

4163
04:32:19,280 --> 04:32:23,480
 

4164
04:32:23,480 --> 04:32:27,440
SO THREE LESSONS I LEARNED EARLY

4165
04:32:27,440 --> 04:32:35,520
ON. 

4166
04:32:35,520 --> 04:32:41,400
I  -- ONE-UPMANSHIP CAN BE AN

4167
04:32:41,400 --> 04:32:42,400
ART FORM.

4168
04:32:42,400 --> 04:32:45,240
I CAN HANG OUT WITH BIG PEOPLE.

4169
04:32:45,240 --> 04:32:46,360
THEN I LEARNED THAT IF YOU

4170
04:32:46,360 --> 04:32:47,560
DIDN'T GET ASKED A QUESTION

4171
04:32:47,560 --> 04:32:49,760
AFTER YOUR TALK, YOU HAVE TO

4172
04:32:49,760 --> 04:32:53,800
ANSWER ONE OF THREE WAYS.

4173
04:32:53,800 --> 04:32:54,800
PROBABLY PARAPHRASE, IF YOU

4174
04:32:54,800 --> 04:32:57,280
LISTEN TO STEVE ANSWER

4175
04:32:57,280 --> 04:33:01,360
QUESTIONS, IT'S ONE  ONE OF

4176
04:33:01,360 --> 04:33:02,240
THESE THREE ANSWERS.

4177
04:33:02,240 --> 04:33:04,920
YOU TOLD YOU THAT BUT YOU

4178
04:33:04,920 --> 04:33:05,360
WEREN'T LISTENING.

4179
04:33:05,360 --> 04:33:07,680
I TOLD YOU THAT BUT I GUESS YOU

4180
04:33:07,680 --> 04:33:10,640
AREN'T SMART ENOUGH TO

4181
04:33:10,640 --> 04:33:11,800
UNDERSTAND.

4182
04:33:11,800 --> 04:33:17,000
YOU'RE TRYING TO REINTERPRET MY

4183
04:33:17,000 --> 04:33:18,200
DATA, YOU'RE WRONG.

4184
04:33:18,200 --> 04:33:23,240
STEVE AND I LEFT UCSF, WENT ON 

4185
04:33:23,240 --> 04:33:24,320
OUR OWN.

4186
04:33:24,320 --> 04:33:28,600
I CAN THINK OF MYSELF AS A

4187
04:33:28,600 --> 04:33:29,920
SMALLER PART, TRAVELING TOO

4188
04:33:29,920 --> 04:33:33,760
FAST, NOT STAYING AT ONE PLACE

4189
04:33:33,760 --> 04:33:34,840
LONG ENOUGH.

4190
04:33:34,840 --> 04:33:38,240
STEVE LARGER PLANET ON THE

4191
04:33:38,240 --> 04:33:39,560
OUTSIDE, MOVING SLOWLY, THINKING

4192
04:33:39,560 --> 04:33:41,320
MORE DEEPLY ABOUT PROBLEMS,

4193
04:33:41,320 --> 04:33:43,560
MAKING NICE CONTRIBUTIONS.

4194
04:33:43,560 --> 04:33:47,200
AND WE HAVE THIS KIND OF COMMON

4195
04:33:47,200 --> 04:33:48,160
SET OF INTERESTS, WHICH ARE

4196
04:33:48,160 --> 04:33:49,600
IMPORTANT IN THE FIELD OF LAW,

4197
04:33:49,600 --> 04:33:52,000
BUT WE SEEM TO COVER A LOT OF

4198
04:33:52,000 --> 04:33:53,800
THE SAME TERRITORY OVER THE

4199
04:33:53,800 --> 04:33:54,120
YEARS.

4200
04:33:54,120 --> 04:33:59,800
I'LL NOT GO INTO STEVE'S

4201
04:33:59,800 --> 04:34:00,440
GENETICALLY MODIFIED ORGANISMS.

4202
04:34:00,440 --> 04:34:00,680
[LAUGHTER]

4203
04:34:00,680 --> 04:34:03,200
ONE OF THE THINGS THAT HAPPENED

4204
04:34:03,200 --> 04:34:06,160
IN THE LAB WHEN WE WERE

4205
04:34:06,160 --> 04:34:07,800
POSTDOCS, THE TECHNIQUE OF

4206
04:34:07,800 --> 04:34:09,720
CLONING VIRAL DNA BY CLONING

4207
04:34:09,720 --> 04:34:17,560
CIRCLES  AFTER THIS TECHNIQUE OF

4208
04:34:17,560 --> 04:34:18,280
PHENOL EXTRACTION.

4209
04:34:18,280 --> 04:34:24,000
WE WERE ABLE TO CLONE CIRCLES,

4210
04:34:24,000 --> 04:34:25,280
STUDY CIRCLE JUNCTIONS, WHICH IN

4211
04:34:25,280 --> 04:34:27,480
A MATERIAL WAY LOOKED AT, THAT'S

4212
04:34:27,480 --> 04:34:30,800
NICE, THEN LOOKED ON, BUT THE

4213
04:34:30,800 --> 04:34:33,000
NEXT VERSION OF THIS REALLY

4214
04:34:33,000 --> 04:34:34,080
BENEFITED FROM STEVE BECAUSE AS

4215
04:34:34,080 --> 04:34:43,600
YOU KNOW STEVE WAS MAKING

4216
04:34:43,600 --> 04:34:48,320
COMPETENT VECTORS.

4217
04:34:48,320 --> 04:34:50,680
WE MADE THIS REPLICATION

4218
04:34:50,680 --> 04:34:53,000
COMPETENT, AFFECTING CELLS WITH

4219
04:34:53,000 --> 04:34:54,320
T ANTIGEN.

4220
04:34:54,320 --> 04:34:56,720
YOU COULD SEE ACCUMULATION OF

4221
04:34:56,720 --> 04:34:59,240
CIRCULAR DNA, CLONE THINGS OUT,

4222
04:34:59,240 --> 04:35:03,480
ACTUALLY FIGURE OUT IF YOU --

4223
04:35:03,480 --> 04:35:07,840
ABOUT HALF THE DNA IS DEFECTIVE.

4224
04:35:07,840 --> 04:35:11,160
THAT WAS SOMETHING I HAD TO

4225
04:35:11,160 --> 04:35:14,920
ADMIT STRUCTURES LOOK MORE

4226
04:35:14,920 --> 04:35:15,880
INTERESTED TODAY, MORE

4227
04:35:15,880 --> 04:35:16,920
UNDERSTANDABLE THAN WE WERE ABLE

4228
04:35:16,920 --> 04:35:17,880
TO FIGURE OUT AT THE TIME.

4229
04:35:17,880 --> 04:35:20,160
FUN TO LOOK BACK AT THEM.

4230
04:35:20,160 --> 04:35:24,120
SO STEVE REALLY TOOK TO ASKING

4231
04:35:24,120 --> 04:35:27,400
QUESTIONS ABOUT THE REPLICATION

4232
04:35:27,400 --> 04:35:28,480
FUNCTIONS AROUND THE LTR, IT

4233
04:35:28,480 --> 04:35:29,600
STARTED SLOW.

4234
04:35:29,600 --> 04:35:33,160
YOU CAN SIGH ONE PAPER, IN TEN

4235
04:35:33,160 --> 04:35:34,400
YEARS TO START WITH.

4236
04:35:34,400 --> 04:35:37,560
THEN NOTICE A PERIOD OF THREE

4237
04:35:37,560 --> 04:35:40,400
YEARS WHERE HE PUBLISHED TEN

4238
04:35:40,400 --> 04:35:46,320
PAPERS, ALL ABOUT U 5, U3,

4239
04:35:46,320 --> 04:35:47,920
POLYPURINE TRACK, CIRCLE

4240
04:35:47,920 --> 04:35:50,120
JUNCTIONS, ALL OVER.

4241
04:35:50,120 --> 04:35:56,960
BUT HUGE AMOUNT OF ENERGY.

4242
04:35:56,960 --> 04:36:01,920
AND I HAVE TO ADMIT, SIMILAR,

4243
04:36:01,920 --> 04:36:05,240
NICE PAPERS, BUT TEN IN THREE

4244
04:36:05,240 --> 04:36:09,200
YEARS, SOMETIMES IT WAS TEDIOUS,

4245
04:36:09,200 --> 04:36:15,400
I MEAN READING THOSE.

4246
04:36:15,400 --> 04:36:15,680
[LAUGHTER]

4247
04:36:15,680 --> 04:36:23,040
SO THIS IS JUST A RECENT PAPER

4248
04:36:23,040 --> 04:36:29,720
WHERE STORIES ABOUT MUTATIONS 

4249
04:36:29,720 --> 04:36:30,240
AND POLYPURINE TRACT,

4250
04:36:30,240 --> 04:36:38,280
RESISTANCE, NOT  SENT TO THE DOG

4251
04:36:38,280 --> 04:36:38,720
HOUSE.

4252
04:36:38,720 --> 04:36:44,440
NO CHANGES IN SENSITIVITY TO A

4253
04:36:44,440 --> 04:36:51,880
VARIETY OF INTEGRASE INHIBITORS.

4254
04:36:51,880 --> 04:36:54,960
ONE OF THE MANY THINGS HE WILL

4255
04:36:54,960 --> 04:36:56,120
BE REMEMBERED FOR.

4256
04:36:56,120 --> 04:36:58,480
STEVE AND I HAD THIS BIFURCATION

4257
04:36:58,480 --> 04:36:59,760
IN OUR CAREERS.

4258
04:36:59,760 --> 04:37:03,680
LOOKING BACK I CAN SEE IT REALLY

4259
04:37:03,680 --> 04:37:03,920
CLEARLY.

4260
04:37:03,920 --> 04:37:09,720
HIV SHOWS UP, STEVE AND I ON OUR

4261
04:37:09,720 --> 04:37:11,280
OWN, REVERSE TRANSCRIPTION.

4262
04:37:11,280 --> 04:37:14,760
INDEPENDENTLY DECIDE IT WOULD BE

4263
04:37:14,760 --> 04:37:18,480
IMPORTANT TO MAKE AMOUNTS OF HIV

4264
04:37:18,480 --> 04:37:23,480
RT AND E. COLI.

4265
04:37:23,480 --> 04:37:25,800
SPOILER, YOU CAN SEE, IT'S NOT

4266
04:37:25,800 --> 04:37:31,360
FROM MY PAPER. 

4267
04:37:31,360 --> 04:37:36,560
OUR EFFORTS, WE WERE PUTTING IN 

4268
04:37:36,560 --> 04:37:41,560
FRAGMENTS OF HIV FRAGMENTS.

4269
04:37:41,560 --> 04:37:43,760
AND GETTING SOME LITTLE

4270
04:37:43,760 --> 04:37:45,240
ACTIVITY, ONE DAY, NOT THE NEXT

4271
04:37:45,240 --> 04:37:45,600
DAY.

4272
04:37:45,600 --> 04:37:47,000
A COLLEAGUE SAID WHY DON'T YOU

4273
04:37:47,000 --> 04:37:49,920
GET ANTIBODIES AND DO A WESTERN

4274
04:37:49,920 --> 04:37:50,120
BLOT.

4275
04:37:50,120 --> 04:37:51,480
WE DID THAT.

4276
04:37:51,480 --> 04:37:55,880
WE SAW IN THE SECOND LANE OVER,

4277
04:37:55,880 --> 04:37:56,360
PROCESSED RT.

4278
04:37:56,360 --> 04:37:58,360
SO IT WAS THERE, WE DIDN'T MAKE

4279
04:37:58,360 --> 04:38:00,840
VERY MUCH OF IT.

4280
04:38:00,840 --> 04:38:01,840
WE DECIDED GOSH, IF WE CAN'T

4281
04:38:01,840 --> 04:38:05,000
MAKE VERY MUCH BUT HAVE NICE

4282
04:38:05,000 --> 04:38:09,360
ASSAY FOR PROTEASE, LET'S STUDY

4283
04:38:09,360 --> 04:38:10,680
THE PROTEASE.

4284
04:38:10,680 --> 04:38:11,800
A BIG BIFURCATION.

4285
04:38:11,800 --> 04:38:15,720
I USED A CRAPPY EXPRESSION

4286
04:38:15,720 --> 04:38:16,160
SYSTEMS.

4287
04:38:16,160 --> 04:38:16,800
COULDN'T MAKE BIOCHEMICAL

4288
04:38:16,800 --> 04:38:17,800
ANALYSIS BUT ENOUGH TO DO A

4289
04:38:17,800 --> 04:38:21,240
WESTERN, AND THAT WAS MY START

4290
04:38:21,240 --> 04:38:24,800
IN PROTEASE.

4291
04:38:24,800 --> 04:38:28,480
WELL, STEVE FIGURED OUT HOW TO

4292
04:38:28,480 --> 04:38:30,680
MAKE CHEMICAL AMOUNTS, IT HAS

4293
04:38:30,680 --> 04:38:33,840
SET THE STAGE FOR A NUMBER OF

4294
04:38:33,840 --> 04:38:35,920
IMPORTANT STUDIES.

4295
04:38:35,920 --> 04:38:38,320
YOU HEARD FROM EDDY ARNOLD

4296
04:38:38,320 --> 04:38:38,560
TODAY.

4297
04:38:38,560 --> 04:38:39,960
I SHOW THIS SLIDE BECAUSE I SHOW

4298
04:38:39,960 --> 04:38:42,000
IT TWICE A YEAR IN CLASSES THAT

4299
04:38:42,000 --> 04:38:50,120
I TEACH, THAT YOU CAN SEE,

4300
04:38:50,120 --> 04:38:52,640
BARELY SEE THE N 3, AZT BLOCKING

4301
04:38:52,640 --> 04:38:57,440
THE  NUCLEOTIDE POSITION, ATP

4302
04:38:57,440 --> 04:39:02,880
GETTING ORGANIZED TO GO IN THERE

4303
04:39:02,880 --> 04:39:04,600
AND BE PRIMORDIAL EXONUCLEUS

4304
04:39:04,600 --> 04:39:05,600
ACTIVITY, ELEGANT STUDY, I THINK

4305
04:39:05,600 --> 04:39:09,880
IF I HAD JUST PICKED A DIFFERENT

4306
04:39:09,880 --> 04:39:10,960
EXPRESSION VECTOR, COULD HAVE

4307
04:39:10,960 --> 04:39:15,760
BEEN A DIFFERENT RESPONSE ALL

4308
04:39:15,760 --> 04:39:18,080
THESE YEARS.

4309
04:39:18,080 --> 04:39:18,400
[LAUGHTER]

4310
04:39:18,400 --> 04:39:24,760
WE DID AN EXPERIMENT IN

4311
04:39:24,760 --> 04:39:26,000
HUTCHINSON'S LAB, EXPRESSING

4312
04:39:26,000 --> 04:39:28,360
PROTEINS IN E. COLI, IF THEY

4313
04:39:28,360 --> 04:39:30,840
FOLD NICE THEY LOOK NICE IN

4314
04:39:30,840 --> 04:39:32,480
WESTERN, IF YOU DON'T FOLD RIGHT

4315
04:39:32,480 --> 04:39:33,840
YOU GET THIS DEGRADED.

4316
04:39:33,840 --> 04:39:37,040
YOU CAN USE THIS ASSAY, ENZYME

4317
04:39:37,040 --> 04:39:38,080
ACTIVITY, INTERESTING THINGS

4318
04:39:38,080 --> 04:39:38,960
ABOUT POSITIONS.

4319
04:39:38,960 --> 04:39:42,560
AND STEVE ALSO USED THIS ASSAY.

4320
04:39:42,560 --> 04:39:43,920
HE ACTUALLY FIGURED OUT THAT YOU

4321
04:39:43,920 --> 04:39:49,480
COULD DO IT IN A VARIANT,  SAME

4322
04:39:49,480 --> 04:39:52,040
THING HAPPENED IN THE VARIANT,

4323
04:39:52,040 --> 04:39:53,640
TEMPERATURE SENSITIVITY AT 37,

4324
04:39:53,640 --> 04:39:57,680
BUT NOT AT 42.

4325
04:39:57,680 --> 04:40:00,960
SO YOU CAN DO IT IN THE VIRUS

4326
04:40:00,960 --> 04:40:01,200
ITSELF.

4327
04:40:01,200 --> 04:40:04,680
NOW, STEVE DID DO A PROTEASE

4328
04:40:04,680 --> 04:40:06,560
EXPERIMENT ONCE, ANOTHER FRIEND

4329
04:40:06,560 --> 04:40:08,720
OF HIS, LOOKING AT FUSION

4330
04:40:08,720 --> 04:40:10,160
PROTEIN IN BACTERIA, SIMILAR

4331
04:40:10,160 --> 04:40:13,440
TYPE OF ASSAY SO WE DID CROSS

4332
04:40:13,440 --> 04:40:15,400
OVER ONCE IN A WHILE.

4333
04:40:15,400 --> 04:40:20,360
WE BOTH DEVELOPED AN INTEREST IN

4334
04:40:20,360 --> 04:40:21,560
DUG RESISTANCE.

4335
04:40:21,560 --> 04:40:23,840
I'LL POINT OUT I'M SURE PAUL

4336
04:40:23,840 --> 04:40:26,600
BOYER FEELS LIKE HE SENT YEARS

4337
04:40:26,600 --> 04:40:27,920
PURIFYING RT AND DOING ASSAYS.

4338
04:40:27,920 --> 04:40:30,520
IT'S LED TO MANY STUDIES.

4339
04:40:30,520 --> 04:40:34,360
THIS IS IN PREPARATION FOR

4340
04:40:34,360 --> 04:40:38,480
RECENT DRUG RESISTANCE PAPER

4341
04:40:38,480 --> 04:40:42,560
SHOWING VARIANTS, CHEMICALLY

4342
04:40:42,560 --> 04:40:46,600
ACTIVE IN PRESENCE OF ATPs.

4343
04:40:46,600 --> 04:40:48,840
WE SPENT TWO YEARS SELECTING

4344
04:40:48,840 --> 04:40:49,680
RESISTANCE TO PROTEASE

4345
04:40:49,680 --> 04:40:50,480
INHIBITORS.

4346
04:40:50,480 --> 04:40:51,640
DON'T LIKE THE PROFILES.

4347
04:40:51,640 --> 04:40:54,160
SPEND ANOTHER TWO YEARS

4348
04:40:54,160 --> 04:40:56,560
SELECTING FOR PROTEASE INHIBITOR

4349
04:40:56,560 --> 04:40:58,320
RESISTANCE, FIFTH YEAR GET TO

4350
04:40:58,320 --> 04:41:03,280
SEQUENCE THEM AND SEE THIS DRUG 

4351
04:41:03,280 --> 04:41:04,400
RESISTANCE IN CELL CULTURE.

4352
04:41:04,400 --> 04:41:08,400
THIS CAME IN PLAY WITH

4353
04:41:08,400 --> 04:41:12,080
OBSERVATION WITH FRANCOIS MADE,

4354
04:41:12,080 --> 04:41:15,040
HE NOTED THAT VIRUSES WITH

4355
04:41:15,040 --> 04:41:15,880
RESISTANCE TO PROTEASE

4356
04:41:15,880 --> 04:41:17,880
INHIBITORS BECAME MORE SENSITIVE

4357
04:41:17,880 --> 04:41:19,760
TO AZT.

4358
04:41:19,760 --> 04:41:20,680
STEVE AND ALEXANDRIA FIGURED

4359
04:41:20,680 --> 04:41:23,560
THAT OUT.

4360
04:41:23,560 --> 04:41:27,320
YOU CAN SEE WHAT THEY DID WAS

4361
04:41:27,320 --> 04:41:28,760
THEY TITRATED -- INTERPRETATION

4362
04:41:28,760 --> 04:41:31,480
IS THAT PROTEASE IS BAD,

4363
04:41:31,480 --> 04:41:35,400
CLEAVAGE IS BAD, LESS SRT IN THE

4364
04:41:35,400 --> 04:41:37,160
VARIANT, THEY TESTED DIRECTLY

4365
04:41:37,160 --> 04:41:43,160
AND GOT INTERESTING RESULT, WE 

4366
04:41:43,160 --> 04:41:44,600
REPRODUCED PROTEASE.

4367
04:41:44,600 --> 04:41:53,920
YOU'RE CAPPING THE N, IT'S A 

4368
04:41:53,920 --> 04:41:54,920
TERMINAL THING, SO AC 50 DOESN'T

4369
04:41:54,920 --> 04:41:55,120
CHAIN.

4370
04:41:55,120 --> 04:42:03,240
IF YOU TITRATE WITH A MUTANT YOU

4371
04:42:03,240 --> 04:42:05,760
MAKE IT -- RESIDUAL RT IS MORE

4372
04:42:05,760 --> 04:42:07,280
SENSITIVE BECAUSE THERE'S NOT

4373
04:42:07,280 --> 04:42:15,160
VERY MUCH, YOU CAN TITRATE OUT.

4374
04:42:15,160 --> 04:42:22,920
AZT, YOU WITH SEE, IT'S MORE

4375
04:42:22,920 --> 04:42:26,160
LIKE NAVAPANE THAN 3TC, WE DID

4376
04:42:26,160 --> 04:42:27,200
THE SAME THING, TITRATING.

4377
04:42:27,200 --> 04:42:30,280
WE DID THE SAME THING, TITRATING

4378
04:42:30,280 --> 04:42:35,440
PROTEASE WHICH HAS THIS INDIRECT

4379
04:42:35,440 --> 04:42:37,960
EFFECT ON RT, YOU BECOME MORE

4380
04:42:37,960 --> 04:42:40,360
SENSITIVE TO PROTEASE INHIBITORS

4381
04:42:40,360 --> 04:42:42,200
BECAUSE PROTEASE INHIBITORS ARE

4382
04:42:42,200 --> 04:42:44,000
TITRATING ACTIVITY.

4383
04:42:44,000 --> 04:42:49,960
YOU REQUEST SEE TENOFOVIR

4384
04:42:49,960 --> 04:42:52,400
SLIGHTLY AFFECTED.

4385
04:42:52,400 --> 04:42:54,480
OTHERS LOOK JUST LIKE EXPERIMENT

4386
04:42:54,480 --> 04:42:56,480
STEVE DID.

4387
04:42:56,480 --> 04:42:58,080
TO ME, FASCINATING THING, IT

4388
04:42:58,080 --> 04:43:02,440
TELLS YOU THE DIFFERENCE IS AZT

4389
04:43:02,440 --> 04:43:03,320
CAN BE REMOVED.

4390
04:43:03,320 --> 04:43:05,520
WHAT THIS TELLS YOU IS THAT THE

4391
04:43:05,520 --> 04:43:07,480
RT THAT PUTS IT ON IS NOT THE

4392
04:43:07,480 --> 04:43:09,760
SAME THAT TAKES IT OFF.

4393
04:43:09,760 --> 04:43:11,600
AND SO I THOUGHT THAT WAS A

4394
04:43:11,600 --> 04:43:13,400
WONDERFUL INSIGHT TO GET TO

4395
04:43:13,400 --> 04:43:16,120
PARTICIPATE IN.

4396
04:43:16,120 --> 04:43:18,000
SO, STEVE HAS BEEN GENEROUS TO

4397
04:43:18,000 --> 04:43:21,040
ME OVER THE YEARS.

4398
04:43:21,040 --> 04:43:24,120
ONE PLACE, WHEN YOU HOST THE

4399
04:43:24,120 --> 04:43:26,200
RETROVIRUS MEETING SOMEONE GETS

4400
04:43:26,200 --> 04:43:27,720
ASKED, AND THEY GET TOLD FIND

4401
04:43:27,720 --> 04:43:29,480
SOMEONE ELSE YOU THINK YOU CAN

4402
04:43:29,480 --> 04:43:32,000
WORK WITH.  STEVE WAS ASKED,

4403
04:43:32,000 --> 04:43:36,000
INVITED ME TO DO IT, I GREATLY

4404
04:43:36,000 --> 04:43:37,840
ENJOY, PICK THE COVERS.

4405
04:43:37,840 --> 04:43:39,320
YOU SAW THIS.

4406
04:43:39,320 --> 04:43:42,560
THIS IS 1993, YOU SAW THIS

4407
04:43:42,560 --> 04:43:45,040
EARLIER IN EDDY'S TALK, HARD TO

4408
04:43:45,040 --> 04:43:46,600
TAKE THE EXCITING WORK AND PUT

4409
04:43:46,600 --> 04:43:56,000
IT ON THE COVER, THE OTHER THING

4410
04:43:56,000 --> 04:43:58,560
WAS, IT WAS HARD TO FIGURE OUT

4411
04:43:58,560 --> 04:44:00,560
THE FIRST PAPER PEER REVIEWED WE

4412
04:44:00,560 --> 04:44:03,640
PUBLISHED, I THINK ABOUT THE

4413
04:44:03,640 --> 04:44:05,600
PROVIRUS ID, I THINK THAT'S IT,

4414
04:44:05,600 --> 04:44:08,040
BUT WE PUT THAT ON THE BACK.

4415
04:44:08,040 --> 04:44:10,440
A WAY OF MAKING SURE HOWARD KNEW

4416
04:44:10,440 --> 04:44:15,240
WE WERE THINKING ABOUT HIM.

4417
04:44:15,240 --> 04:44:18,200
THIS IS MY COPY OF THE

4418
04:44:18,200 --> 04:44:26,920
RETROVIRUS BOOK.

4419
04:44:26,920 --> 04:44:27,960
IT'S AN OLD COPY.

4420
04:44:27,960 --> 04:44:29,840
IT WAS WONDERFUL TO BE INVITED

4421
04:44:29,840 --> 04:44:31,600
TO WRITE A CHAPTER, AND I'M

4422
04:44:31,600 --> 04:44:33,120
GRATEFUL FOR THAT.

4423
04:44:33,120 --> 04:44:35,640
YOU'LL SEE BECAUSE I USED THE

4424
04:44:35,640 --> 04:44:40,680
WRONG EXPRESSION SYSTEM, I HAD

4425
04:44:40,680 --> 04:44:43,080
TO WRITE THE PROCESSING OF VIRAL

4426
04:44:43,080 --> 04:44:43,320
PROTEINS.

4427
04:44:43,320 --> 04:44:44,600
I WONDERED IF IT WAS A SPLIT

4428
04:44:44,600 --> 04:44:49,760
VOTE WHETHER OR NOT I WOULD GET

4429
04:44:49,760 --> 04:44:51,160
TO BE AN AUTHOR.

4430
04:44:51,160 --> 04:44:53,400
I WAS TOLD I HAD TO TELL A

4431
04:44:53,400 --> 04:44:54,120
FISHING STORY.

4432
04:44:54,120 --> 04:44:57,280
HOW MANY TIMES A YEAR TO DATE,

4433
04:44:57,280 --> 04:44:59,240
HOW MANY PEOPLE HAS STEVE TAKEN

4434
04:44:59,240 --> 04:44:59,480
FISHING?

4435
04:44:59,480 --> 04:45:00,480
IT'S LIKE EVERYBODY, RIGHT?

4436
04:45:00,480 --> 04:45:02,320
HALF THE PEOPLE IN THE ROOM.

4437
04:45:02,320 --> 04:45:04,520
STEVE, HOW MANY TIMES HAVE WE

4438
04:45:04,520 --> 04:45:05,840
BEEN FISHING?

4439
04:45:05,840 --> 04:45:09,400
>>HOW MANY TIMES HAVE I
ASKED

4440
04:45:09,400 --> 04:45:09,680
YOU?

4441
04:45:09,680 --> 04:45:10,280
>>I'M AVAILABLE.

4442
04:45:10,280 --> 04:45:10,800
[LAUGHTER]

4443
04:45:10,800 --> 04:45:12,600
SO THE ANSWER IS ZERO.

4444
04:45:12,600 --> 04:45:15,000
HOW DO I FEEL?

4445
04:45:15,000 --> 04:45:15,760
HE TAKES STRANGERS FISHING.

4446
04:45:15,760 --> 04:45:18,000
[LAUGHTER]

4447
04:45:18,000 --> 04:45:21,640
 

4448
04:45:21,640 --> 04:45:24,040
ED SAID I HAD TO TELL A FISHING

4449
04:45:24,040 --> 04:45:25,360
STORY.

4450
04:45:25,360 --> 04:45:27,880
I GREW UP FISHING IN THE

4451
04:45:27,880 --> 04:45:31,600
SIERRAS, AND HERE'S A COUPLE

4452
04:45:31,600 --> 04:45:39,080
YEARS AGO, A LONG TRIP. 

4453
04:45:39,080 --> 04:45:40,360
THERE'S THE BACKGROUND, CRABTREE

4454
04:45:40,360 --> 04:45:43,280
MEADOW, YOU CAN FISH FOR GOLDEN

4455
04:45:43,280 --> 04:45:44,680
TROUT, GORGEOUS BUT THE SIDES OF

4456
04:45:44,680 --> 04:45:45,440
YOUR HAND.

4457
04:45:45,440 --> 04:45:50,320
YOU WOULD CATCH AS MANY ON

4458
04:45:50,320 --> 04:45:52,280
VELVEETA CHEESE AS A FLY.

4459
04:45:52,280 --> 04:45:53,440
NOT HARD TO CATCH.

4460
04:45:53,440 --> 04:45:55,960
THAT ONE GOT RIGHT BACK IN THE

4461
04:45:55,960 --> 04:45:56,280
WATER.

4462
04:45:56,280 --> 04:45:58,960
I FOUND MY LOVE FOR FISHING.

4463
04:45:58,960 --> 04:46:04,240
IT'S NOT -- YOU CATCH ALSO TROUT

4464
04:46:04,240 --> 04:46:06,360
BUT IN WESTERN MONTANA YOU CAN

4465
04:46:06,360 --> 04:46:08,120
CATCH REAL TROUT.

4466
04:46:08,120 --> 04:46:11,200
THERE'S A FAMOUS GUIDE OUT

4467
04:46:11,200 --> 04:46:14,360
THERE, FOR THE RICH. 

4468
04:46:14,360 --> 04:46:19,400
THE RICH AND FAMOUS SCIENTISTS.

4469
04:46:19,400 --> 04:46:23,480
JACK MEYER TAKES THEM FISHING.

4470
04:46:23,480 --> 04:46:24,960
THAT WAS THE WAY -- THERE ARE

4471
04:46:24,960 --> 04:46:26,760
TWO WAYS THAT I THINK THAT I

4472
04:46:26,760 --> 04:46:28,360
REACHED MY HEAVEN FOR FISHING.

4473
04:46:28,360 --> 04:46:29,760
ONE, THESE FISH ARE KIND OF BIG

4474
04:46:29,760 --> 04:46:31,840
FOR ME TO HANDLE WITH MY HANDS.

4475
04:46:31,840 --> 04:46:33,960
YOU TRY TO GET THE FISH BACK IN

4476
04:46:33,960 --> 04:46:35,920
THE WATER SO IT DOESN'T DO GOOD

4477
04:46:35,920 --> 04:46:37,880
TO HAVE ME DROP THEM IN THE

4478
04:46:37,880 --> 04:46:38,200
BOAT.

4479
04:46:38,200 --> 04:46:42,880
THE OTHER, YOU BORROW A LINE,

4480
04:46:42,880 --> 04:46:46,400
JACK, WE'RE GOING TO NEED A

4481
04:46:46,400 --> 04:46:46,960
BIGGER NET!

4482
04:46:46,960 --> 04:46:47,400
[LAUGHTER]

4483
04:46:47,400 --> 04:46:50,800
THE OTHER THING THAT WAS

4484
04:46:50,800 --> 04:46:52,760
INTERESTING ABOUT THE TRIP, JACK

4485
04:46:52,760 --> 04:46:54,320
TURNS AROUND, THERE'S A FLY IN

4486
04:46:54,320 --> 04:46:55,720
THE BACK OF HIS SHIRT.

4487
04:46:55,720 --> 04:46:57,320
JACK, YOU'VE GOT A FLY BACK

4488
04:46:57,320 --> 04:47:00,240
THERE. 

4489
04:47:00,240 --> 04:47:02,280
SO, THAT'S DR. X.

4490
04:47:02,280 --> 04:47:03,920
I SAID, I KNOW A LOT OF PEOPLE

4491
04:47:03,920 --> 04:47:05,200
WHO KNOW DR. X, I'M GOING TO

4492
04:47:05,200 --> 04:47:06,120
TELL THAT STORY.

4493
04:47:06,120 --> 04:47:10,000
HE MADE ME PROMISE I COULDN'T 

4494
04:47:10,000 --> 04:47:10,480
TELL IT.

4495
04:47:10,480 --> 04:47:11,000
[LAUGHTER]

4496
04:47:11,000 --> 04:47:15,040
AT  LEAST I CAN'T TELL YOU WHO

4497
04:47:15,040 --> 04:47:17,560
DR. X IS BUT EVERY ONE OF YOU

4498
04:47:17,560 --> 04:47:18,160
KNOWS DR. X.

4499
04:47:18,160 --> 04:47:18,480
[LAUGHTER]

4500
04:47:18,480 --> 04:47:23,720
SO GOING OUT ON TOP, IT'S GREAT

4501
04:47:23,720 --> 04:47:25,080
TO SEE THE WORK, YOU'VE SEEN

4502
04:47:25,080 --> 04:47:27,040
THIS SEVERAL TIMES.

4503
04:47:27,040 --> 04:47:31,240
REALLY WONDERFUL TO SEE THIS 

4504
04:47:31,240 --> 04:47:33,920
BECAME AN INSTANT CLASSIC.

4505
04:47:33,920 --> 04:47:34,800
WHAT YOU CAN IMMEDIATELY INFER

4506
04:47:34,800 --> 04:47:36,880
FROM IT.

4507
04:47:36,880 --> 04:47:39,880
YOU TALK ABOUT INTEGRATION

4508
04:47:39,880 --> 04:47:40,720
SITES, THERE'S A GAZILLION.

4509
04:47:40,720 --> 04:47:42,920
IF YOU WANT TO TALK ABOUT

4510
04:47:42,920 --> 04:47:44,200
ANYPLACE IN THE GENOME, THEY

4511
04:47:44,200 --> 04:47:47,600
HAVE A LOT TO SAY ABOUT IT.

4512
04:47:47,600 --> 04:47:50,240
AND SO MANY OF YOU KNOW I HAVE

4513
04:47:50,240 --> 04:47:52,960
AN INTEREST IN MACROPHAGE

4514
04:47:52,960 --> 04:47:54,680
VIRUSES, THE WHOLE IDEA MOVING

4515
04:47:54,680 --> 04:47:56,400
FROM ACTIVATED T CELL TO

4516
04:47:56,400 --> 04:48:00,840
MACROPHAGE IS PROBABLY NOT AS

4517
04:48:00,840 --> 04:48:02,920
PROFOUND AS INSECT TO MAMMALIAN

4518
04:48:02,920 --> 04:48:05,760
CELL BUT MUST BE SOMETHING ALONG

4519
04:48:05,760 --> 04:48:12,160
THOSE LINES, RAISING THE

4520
04:48:12,160 --> 04:48:14,840
POSSIBILITY, IT TOOK A LONG TIME

4521
04:48:14,840 --> 04:48:19,560
BUT HE DID  AGREE.

4522
04:48:19,560 --> 04:48:23,600
I NEED FIVE MILLION INTEGRANTS,

4523
04:48:23,600 --> 04:48:25,320
I WANT 10% EFFICIENCY TO DO A

4524
04:48:25,320 --> 04:48:25,640
COMPARISON.

4525
04:48:25,640 --> 04:48:27,440
MY HOPE IS WE'LL SEE CERTAIN

4526
04:48:27,440 --> 04:48:29,600
GENES DROP OUT AND WE CAN FIGURE

4527
04:48:29,600 --> 04:48:31,120
OUT WHAT CELLS ARE BEING

4528
04:48:31,120 --> 04:48:33,920
AFFECTED BY THE PATTERN OF

4529
04:48:33,920 --> 04:48:34,640
INTEGRATION SITES NOW.

4530
04:48:34,640 --> 04:48:39,520
THERE'S SOME -- TURNS OUT TO BE

4531
04:48:39,520 --> 04:48:42,320
ERP, WE'LL SEE WHAT HAPPENS.

4532
04:48:42,320 --> 04:48:45,480
WE'VE BEEN WORKING ON GETTING

4533
04:48:45,480 --> 04:48:46,800
FIVE BILL INTEGRANTS.

4534
04:48:46,800 --> 04:48:48,960
I GOT ANEMIC AND HAD TO STOP FOR

4535
04:48:48,960 --> 04:48:49,760
A WHILE.

4536
04:48:49,760 --> 04:48:52,320
I'M FEELING BETTER NOW AND WE'LL

4537
04:48:52,320 --> 04:48:55,120
GET BACK TO IT.

4538
04:48:55,120 --> 04:49:00,880
[LAUGHTER]

4539
04:49:00,880 --> 04:49:02,880
MY CONFIDENCE IS SHAKEN TODAY,

4540
04:49:02,880 --> 04:49:05,160
WHETHER OR NOT HE'S RETIRING.

4541
04:49:05,160 --> 04:49:09,440
I STOPPED BY THE HOUSE AND GOT A

4542
04:49:09,440 --> 04:49:10,240
LETTER, NICE LETTER.

4543
04:49:10,240 --> 04:49:11,760
FIRST I WANT TO THANK YOU FOR

4544
04:49:11,760 --> 04:49:14,040
MANY YEARS OF SERVICE TO OUR

4545
04:49:14,040 --> 04:49:15,960
COUNTRY THROUGH YOUR EFFORTS AS

4546
04:49:15,960 --> 04:49:18,560
A RESEARCHER, FROM THE WHITE

4547
04:49:18,560 --> 04:49:20,120
HOUSE.

4548
04:49:20,120 --> 04:49:21,200
THE MOST IMPORTANT

4549
04:49:21,200 --> 04:49:23,600
CONTRIBUTIONS, HIV SPECIFICALLY.

4550
04:49:23,600 --> 04:49:26,440
YOUR WORK WILL FOREVER BE PHONE

4551
04:49:26,440 --> 04:49:27,280
FOR QUALITY.

4552
04:49:27,280 --> 04:49:29,160
THAT'S REALLY NICE, COMING FROM

4553
04:49:29,160 --> 04:49:31,480
THE PRESIDENT.

4554
04:49:31,480 --> 04:49:32,320
THEN HE SAID MORE.

4555
04:49:32,320 --> 04:49:33,880
ONE OF YOUR COLLEAGUES HAS

4556
04:49:33,880 --> 04:49:36,080
CONVINCED ME THAT YOUR UNFUND

4557
04:49:36,080 --> 04:49:37,240
PROJECT MAPPING INTEGRATION

4558
04:49:37,240 --> 04:49:38,240
SITES IN MACROPHAGES IS

4559
04:49:38,240 --> 04:49:41,720
ESSENTIAL FOR OUR GOAL OF

4560
04:49:41,720 --> 04:49:42,320
CONQUERING HIV.

4561
04:49:42,320 --> 04:49:43,080
[LAUGHTER]

4562
04:49:43,080 --> 04:49:44,360
THEREFORE USING THE POWERS

4563
04:49:44,360 --> 04:49:50,280
INVESTED IN ME, IN THE

4564
04:49:50,280 --> 04:49:52,160
CONSTITUTION, I AM SUSPENDED ALL

4565
04:49:52,160 --> 04:49:53,240
YOUR FISHING LICENSES UNTIL THAT

4566
04:49:53,240 --> 04:49:54,960
PROJECT IS COMPLETE.

4567
04:49:54,960 --> 04:49:56,840
LET DR. COLLINS KNOW SO THE

4568
04:49:56,840 --> 04:49:58,600
ACTION CAN BE REVERSED, SIGNED

4569
04:49:58,600 --> 04:50:00,120
BY THE PRESIDENT.

4570
04:50:00,120 --> 04:50:05,160
[APPLAUSE] 

4571
04:50:05,160 --> 04:50:07,360
WHEN YOU GO TO PubMed, STEVE

4572
04:50:07,360 --> 04:50:11,200
AND I APPEAR TOGETHER ONCE.

4573
04:50:11,200 --> 04:50:15,520
IT SURPRISES ME, BUT THAT'S THE 

4574
04:50:15,520 --> 04:50:17,440
WAY IT TURNED OUT.

4575
04:50:17,440 --> 04:50:19,640
IT'S NICE THAT THAT'S THE SAME

4576
04:50:19,640 --> 04:50:24,800
NUMBER OF PAPERS HE'S PUBLISHED

4577
04:50:24,800 --> 04:50:25,320
WITH MY DAUGHTER.

4578
04:50:25,320 --> 04:50:26,000
[LAUGHTER]

4579
04:50:26,000 --> 04:50:27,520
MANY OF YOU KNOW ADRIAN, SHE

4580
04:50:27,520 --> 04:50:29,960
JUST HAD A BABY GIRL, ELEANOR.

4581
04:50:29,960 --> 04:50:31,840
WE'RE IN GOOD SHAPE.

4582
04:50:31,840 --> 04:50:35,400
SHE'LL BE BACK SOON.

4583
04:50:35,400 --> 04:50:38,560
 

4584
04:50:38,560 --> 04:50:39,840
 

4585
04:50:39,840 --> 04:50:42,280
WHAT CAN I SAY, ALL THE BODIES

4586
04:50:42,280 --> 04:50:52,800
IN THE SOLAR SYSTEM, IT'S TRUE

4587
04:50:57,920 --> 04:50:59,480
FOR STEVE.

4588
04:50:59,480 --> 04:51:00,680
JUPITER'S GRAVITY AFFECTS ALL

4589
04:51:00,680 --> 04:51:03,120
BODIES IN THE SOLAR SYSTEM.

4590
04:51:03,120 --> 04:51:07,800
IT'S TRUE FOR STEVE.

4591
04:51:07,800 --> 04:51:08,640
SUNSET, MAYBE IN FREDERICK, BUT

4592
04:51:08,640 --> 04:51:11,960
CERTAIN DAYS THE SUN IS SETTING

4593
04:51:11,960 --> 04:51:15,600
IN FREDERICK, IT'S RISING IN THE

4594
04:51:15,600 --> 04:51:18,200
WESTERN SIDE OF ALASKA.

4595
04:51:18,200 --> 04:51:20,040
HAVE FUN.

4596
04:51:20,040 --> 04:51:21,080
[APPLAUSE]

4597
04:51:21,080 --> 04:51:27,120
 

4598
04:51:27,120 --> 04:51:31,160
 

4599
04:51:31,160 --> 04:51:34,240
I DON'T KNOW IF THAT'S AMENABLE

4600
04:51:34,240 --> 04:51:35,880
TO QUESTIONS.

4601
04:51:35,880 --> 04:51:36,840
>>ANY COMMENTS, QUESTIONS
OR

4602
04:51:36,840 --> 04:51:37,120
OTHERWISE?

4603
04:51:37,120 --> 04:51:41,520
IF NOT, THANK YOU VERY MUCH.

4604
04:51:41,520 --> 04:51:46,840
>>THAT'S A TOUGH ACT TO
FOLLOW.

4605
04:51:46,840 --> 04:51:48,680
IT'S A PLEASURE TO INTRODUCE THE

4606
04:51:48,680 --> 04:51:52,400
FIRST OF OUR TWO DRP SPEAKERS,

4607
04:51:52,400 --> 04:51:57,320
FIRST A MEMBER SINCE FOUNDING,

4608
04:51:57,320 --> 04:51:58,080
CURRENTLY DEPUTY DIRECTOR, WITH

4609
04:51:58,080 --> 04:52:01,040
STEVE AND I HAVE BEEN CLOSE

4610
04:52:01,040 --> 04:52:11,200
FRIENDS FOR 35 YEARS, SINCE WE 

4611
04:52:11,200 --> 04:52:13,840
WERE IN MADISON TOGETHER.

4612
04:52:13,840 --> 04:52:19,920
 

4613
04:52:19,920 --> 04:52:23,760
 

4614
04:52:23,760 --> 04:52:25,080
>>THANK YOU SO MUCH.

4615
04:52:25,080 --> 04:52:26,160
RON, THANKS A LOT.

4616
04:52:26,160 --> 04:52:29,440
THIS IS HARD TO FOLLOW.

4617
04:52:29,440 --> 04:52:31,800
SO I WOULD LIKE TO ECHO WHAT

4618
04:52:31,800 --> 04:52:33,560
EVERYBODY SAID.

4619
04:52:33,560 --> 04:52:35,760
THIS IS TRULY A WONDERFUL

4620
04:52:35,760 --> 04:52:37,640
OPPORTUNITY TO CONGRATULATE

4621
04:52:37,640 --> 04:52:40,000
STEVE AND ALSO I WOULD LIKE TO

4622
04:52:40,000 --> 04:52:42,600
FIRST TALK A LITTLE BIT ABOUT

4623
04:52:42,600 --> 04:52:44,000
THE TRIBUTE TO STEVE.

4624
04:52:44,000 --> 04:52:48,480
I FIRST MET STEVE IN COLD SPRING

4625
04:52:48,480 --> 04:52:50,800
HARBOR IN 1989, I WAS A POSTDOC

4626
04:52:50,800 --> 04:52:53,200
FROM HOWARD'S LAB, MY FIRST

4627
04:52:53,200 --> 04:52:53,680
ROTATION.

4628
04:52:53,680 --> 04:52:58,320
AND HE WAS CHAIRING THE SESSION.

4629
04:52:58,320 --> 04:53:02,080
I WAS PRESENTING SO, FIRST TIME,

4630
04:53:02,080 --> 04:53:06,160
I WAS A LITTLE INTIMIDATED.

4631
04:53:06,160 --> 04:53:08,560
VERY MUCH INTIMIDATED.

4632
04:53:08,560 --> 04:53:10,120
ESPECIALLY NOTICED HOW WHEN

4633
04:53:10,120 --> 04:53:11,840
PEOPLE WENT OVER TIME, HOW STEVE

4634
04:53:11,840 --> 04:53:13,600
WOULD SNEAK UP BEHIND THEM AND

4635
04:53:13,600 --> 04:53:18,880
PEOPLE LOOKED AT THEM AND

4636
04:53:18,880 --> 04:53:22,360
JUMPED, WAS REALLY INTIMIDATED.

4637
04:53:22,360 --> 04:53:24,640
I ALWAYS RESPECTED HIM ABOUT HIS

4638
04:53:24,640 --> 04:53:25,760
SCIENTIFIC INSIGHT BUT REALLY

4639
04:53:25,760 --> 04:53:30,240
GOT TO KNOW STEVE AFTER I JOINED

4640
04:53:30,240 --> 04:53:34,520
DRP HERE IN 1999.

4641
04:53:34,520 --> 04:53:36,800
AS MY COLLEAGUE HAS IMPACTED ME

4642
04:53:36,800 --> 04:53:37,440
IN DIFFERENT WAYS.

4643
04:53:37,440 --> 04:53:41,960
ONE OF THE WAYS HE IMPACTED MY

4644
04:53:41,960 --> 04:53:43,000
SCIENTIFIC CAREER HE'S ONE OF

4645
04:53:43,000 --> 04:53:45,080
THE LUMINARIES IN OUR FIELD,

4646
04:53:45,080 --> 04:53:47,400
INSPIRED ME TO EXPLORE MORE

4647
04:53:47,400 --> 04:53:49,160
INTERESTING TOPIC, TOOK LONGER

4648
04:53:49,160 --> 04:53:52,520
VIEWS OF THINGS, TAKE MORE

4649
04:53:52,520 --> 04:53:54,480
CHANCES.

4650
04:53:54,480 --> 04:53:56,440
AND ALSO HIS QUESTIONS, ALSO NOT

4651
04:53:56,440 --> 04:53:59,240
JUST ME BUT A LOT OF PEOPLE IN

4652
04:53:59,240 --> 04:54:02,160
LINE, IF YOU WANT TO SHOW DATA

4653
04:54:02,160 --> 04:54:03,920
YOU BETTER BE PREPARED, HE WILL

4654
04:54:03,920 --> 04:54:06,440
ASK IF YOU'VE DONE CONTROL TO DO

4655
04:54:06,440 --> 04:54:08,320
XYZ, AND IF YOU WANT TO PRESENT

4656
04:54:08,320 --> 04:54:09,160
YOUR FAVORITE HYPOTHESIS YOU

4657
04:54:09,160 --> 04:54:12,000
HAVE TO THINK ABOUT OTHER

4658
04:54:12,000 --> 04:54:16,960
POSSIBILITIES, IS HE GOING TO 

4659
04:54:16,960 --> 04:54:18,920
ASK IF IT'S POLICY, EXPLANATION

4660
04:54:18,920 --> 04:54:20,880
FOR THAT, ALSO IN ADDITION ALSO

4661
04:54:20,880 --> 04:54:26,120
HELPED US EDUCATE A LOT OF 

4662
04:54:26,120 --> 04:54:28,440
JUNIOR COLLEAGUES, AND HE ASKED

4663
04:54:28,440 --> 04:54:30,760
A QUESTION GENTLE, VERY

4664
04:54:30,760 --> 04:54:33,600
INSIGHTFUL QUESTIONS IN

4665
04:54:33,600 --> 04:54:34,200
SCIENTIFIC WORKING PROGRESS

4666
04:54:34,200 --> 04:54:36,560
MEETINGS, SOME OF MIGHT HAVE

4667
04:54:36,560 --> 04:54:39,360
STUDENTS HAD COMMENTED THAT

4668
04:54:39,360 --> 04:54:40,920
BASICALLY WE HAVE COLD SPRING

4669
04:54:40,920 --> 04:54:42,000
HARBOR FIRST ROLE IN WORK IN

4670
04:54:42,000 --> 04:54:43,720
PROGRESS SO I'M NOT NERVOUS WHEN

4671
04:54:43,720 --> 04:54:46,560
I PRESENT AT COLD SPRING HARBOR.

4672
04:54:46,560 --> 04:54:48,360
SECOND THING I WANT TO MENTION

4673
04:54:48,360 --> 04:54:51,760
IS THAT WE HAVE AT NIH OUR

4674
04:54:51,760 --> 04:54:53,840
ANNUAL ETHICS REVIEW THAT WE

4675
04:54:53,840 --> 04:54:56,600
HAVE TALKED ABOUT RESEARCH

4676
04:54:56,600 --> 04:54:56,920
ETHICS.

4677
04:54:56,920 --> 04:54:59,000
STEVE HAS GENEROUSLY OPENED HIS

4678
04:54:59,000 --> 04:55:02,400
DISCUSSION TO EVERYBODY IN DRP,

4679
04:55:02,400 --> 04:55:04,440
SO FOR ONE DAY MOSTLY IN

4680
04:55:04,440 --> 04:55:06,440
DECEMBER WE GET TOGETHER AND

4681
04:55:06,440 --> 04:55:08,840
DISCUSS THE ONE CASE WE HAVE TO

4682
04:55:08,840 --> 04:55:12,560
DISCUSS, STEVE ALWAYS MANAGED TO

4683
04:55:12,560 --> 04:55:14,200
MAKE IT VERY ENTERTAINING, VERY

4684
04:55:14,200 --> 04:55:15,920
INTERESTING, AND WE ALWAYS HAVE

4685
04:55:15,920 --> 04:55:20,280
A VERY NICE DISCUSSION, SO THAT

4686
04:55:20,280 --> 04:55:22,720
I ALWAYS REALLY APPRECIATE.

4687
04:55:22,720 --> 04:55:25,880
SO, I HAVE TO SAY, STEVE TOOK ME

4688
04:55:25,880 --> 04:55:27,320
FISHING ONCE AND TURNED OUT TO

4689
04:55:27,320 --> 04:55:30,600
BE I WAS NOT COORDINATED ENOUGH

4690
04:55:30,600 --> 04:55:32,560
TO GET THE FISH AND PUT IT BACK

4691
04:55:32,560 --> 04:55:35,400
IN THE WATER WITHOUT MAKING A

4692
04:55:35,400 --> 04:55:36,840
BIG MESS.

4693
04:55:36,840 --> 04:55:38,800
SO, BUT WE FOUND SOMETHING IN

4694
04:55:38,800 --> 04:55:41,080
ADDITION TO SCIENCE THAT BOTH OF

4695
04:55:41,080 --> 04:55:46,240
US ENJOYED VERY MUCH, GOOD FOOD.

4696
04:55:46,240 --> 04:55:50,080
SO, THIS IS ONE PICTURE AFTER A

4697
04:55:50,080 --> 04:55:52,080
SYMPOSIUM WE HAD THE SPEAKERS IN

4698
04:55:52,080 --> 04:55:56,400
A RESTAURANT, AND THIS IS

4699
04:55:56,400 --> 04:55:59,800
ANOTHER PICTURE OF US IN OUR

4700
04:55:59,800 --> 04:56:02,120
FAVORITE THAI RESTAURANT BETWEEN

4701
04:56:02,120 --> 04:56:02,920
BETHESDA AND FREDERICK THAT

4702
04:56:02,920 --> 04:56:04,720
AFTER WE GO TO A MEETING IN

4703
04:56:04,720 --> 04:56:07,360
BETHESDA WE OFTEN STOP AT THIS

4704
04:56:07,360 --> 04:56:08,880
THAI RESTAURANT, REASON BEING

4705
04:56:08,880 --> 04:56:11,480
THE TRAFFIC IS REALLY BACKED UP

4706
04:56:11,480 --> 04:56:13,120
ON 270, WE MAY AS WELL HAVE

4707
04:56:13,120 --> 04:56:14,320
DINNER FIRST.

4708
04:56:14,320 --> 04:56:16,680
THIS IS MANY A GREAT MEAL, I

4709
04:56:16,680 --> 04:56:21,320
SHARED WITH STEVE, I ENJOY

4710
04:56:21,320 --> 04:56:22,000
STEVE'S FRIENDSHIP AND

4711
04:56:22,000 --> 04:56:23,440
SCIENTIFIC IMPACT, LOOKING FOR

4712
04:56:23,440 --> 04:56:26,920
MANY MORE INTERACTIONS TO COME.

4713
04:56:26,920 --> 04:56:30,320
SO TODAY I'LL TELL YOU ABOUT OUR

4714
04:56:30,320 --> 04:56:33,960
WORK, HOW HIV SELECT VIRAL

4715
04:56:33,960 --> 04:56:35,920
GENOME.

4716
04:56:35,920 --> 04:56:38,400
SO, TO GENERATE INFECTIOUS VIRUS

4717
04:56:38,400 --> 04:56:39,920
HIV MUST MINE RNA AND PACKAGE

4718
04:56:39,920 --> 04:56:42,040
INTO PARTICLES.

4719
04:56:42,040 --> 04:56:44,200
IN INFECTED CELLS HIV RNA,

4720
04:56:44,200 --> 04:56:46,280
THERE'S LITTLE RNA, SO IT HAS A

4721
04:56:46,280 --> 04:56:47,360
TOUGH, TOUGH JOB.

4722
04:56:47,360 --> 04:56:49,680
BUT IN ADDITION TO THAT MAKE

4723
04:56:49,680 --> 04:56:52,000
THINGS MORE DIFFICULT, MORE

4724
04:56:52,000 --> 04:56:57,480
RECENTLY SHOWN THAT NOT ALL HIV

4725
04:56:57,480 --> 04:57:01,960
RNA ARE CREATED EQUAL, AND ONLY 

4726
04:57:01,960 --> 04:57:06,880
A SUBSET OF RNA IS

4727
04:57:06,880 --> 04:57:08,520
PREFERENTIALLY PACKAGED, STUDIES

4728
04:57:08,520 --> 04:57:14,520
FROM MASUDA'S GROUP AND THEN

4729
04:57:14,520 --> 04:57:18,320
ALICE, BASICALLY THREE IN A ROW,

4730
04:57:18,320 --> 04:57:23,680
IN HIV IN OUR REGION.

4731
04:57:23,680 --> 04:57:24,920
SOMETIMES POLYMERASE STARTS AT

4732
04:57:24,920 --> 04:57:27,120
FIRST, SECOND, OR THIRD.

4733
04:57:27,120 --> 04:57:28,960
SOMETIMES FURTHER DOWN.

4734
04:57:28,960 --> 04:57:31,480
AND GENERATE IF YOU USE ONE OF

4735
04:57:31,480 --> 04:57:42,000
THESE TO GENERATE RNA WITH THREE

4736
04:57:43,000 --> 04:57:46,480
GUANOCINES, THE SAME EXCEPT THIS

4737
04:57:46,480 --> 04:57:48,000
BEGINNING NUCLEOTIDE.

4738
04:57:48,000 --> 04:57:51,160
HOWEVER, IT'S BEEN SHOWN THAT

4739
04:57:51,160 --> 04:57:56,880
THREEG RNA IS THE MOST ABUNDANT,

4740
04:57:56,880 --> 04:57:59,280
BUT 1 GNA IS PROFESSIONAL

4741
04:57:59,280 --> 04:57:59,880
DAMAGED.

4742
04:57:59,880 --> 04:58:02,520
WE GO HUH, HAVE TO TRY IT

4743
04:58:02,520 --> 04:58:04,680
OURSELVES. 

4744
04:58:04,680 --> 04:58:07,120
WE DID THE EXPERIMENT, WHAT YOU

4745
04:58:07,120 --> 04:58:10,960
SEE IS THE INITIATION POINTS OF

4746
04:58:10,960 --> 04:58:14,240
ALL HIV WITH RNA IN CELL VERSUS

4747
04:58:14,240 --> 04:58:15,440
THE VIRUS.

4748
04:58:15,440 --> 04:58:17,640
AND IS SHOWN IN DIFFERENT COLOR

4749
04:58:17,640 --> 04:58:22,240
AS YOU CAN SEE, 3G BLUE MOST

4750
04:58:22,240 --> 04:58:25,000
ABUNDANT IN THE CELL, 1G IS MOST

4751
04:58:25,000 --> 04:58:26,720
ABUNDANT IN THE VIRUS.

4752
04:58:26,720 --> 04:58:30,800
SO WHAT THIS SAYS IS THAT HIV

4753
04:58:30,800 --> 04:58:34,400
MANAGED TO DISTINGUISH TWO RNA,

4754
04:58:34,400 --> 04:58:39,080
THAT'S 9 KB LONG, ONLY DIFFERENT

4755
04:58:39,080 --> 04:58:39,960
BY 2 NUCLEOTIDES.

4756
04:58:39,960 --> 04:58:50,520
TO DO THIS, WE COLLABORATED WITH

4757
04:58:51,000 --> 04:58:51,680
KARIN'S LAB.

4758
04:58:51,680 --> 04:58:54,080
HYPOTHESIS, MIKE SUMMERS AS WELL

4759
04:58:54,080 --> 04:58:58,680
AS OUR GROUP, VERY LIMB  --

4760
04:58:58,680 --> 04:59:01,320
SIMILAR WE THINK IT MUST RELEASE

4761
04:59:01,320 --> 04:59:02,400
RNA INTO STRUCTURES AND THAT'S

4762
04:59:02,400 --> 04:59:08,400
HOW THEY CAN TELL THE 

4763
04:59:08,400 --> 04:59:08,880
DIFFERENCE.

4764
04:59:08,880 --> 04:59:10,920
SO, THE HIV HAS A COMPLEX

4765
04:59:10,920 --> 04:59:14,880
STRUCTURE, WHAT PEOPLE THINK

4766
04:59:14,880 --> 04:59:16,080
THEY LOOK LIKE.

4767
04:59:16,080 --> 04:59:18,360
TO TELL YOU THE PART WE WANT TO

4768
04:59:18,360 --> 04:59:22,000
NOTE, I WILL DISCUSS THE POLY-A

4769
04:59:22,000 --> 04:59:30,600
STEM RIGHT HERE AND SL1 AND DIS.

4770
04:59:30,600 --> 04:59:35,040
DIS IS SIGNAL, THIS IS THE

4771
04:59:35,040 --> 04:59:40,040
SEQUENCE WE THINK RNA

4772
04:59:40,040 --> 04:59:41,600
DIMERIZATION IS.

4773
04:59:41,600 --> 04:59:42,560
PREVAILING HYPOTHESIS EARLIER

4774
04:59:42,560 --> 04:59:48,720
WAS RNA FOLDING TO DIFFERENT

4775
04:59:48,720 --> 04:59:49,480
CONFIRMATION, DIMERIZATION

4776
04:59:49,480 --> 04:59:58,760
SIGNALS OPEN SO.

4777
04:59:58,760 --> 05:00:02,160
IN THIS DIS SEQUENCE, NO LONGER

4778
05:00:02,160 --> 05:00:06,200
AVAILABLE TO MAKE DIMER, AND SO

4779
05:00:06,200 --> 05:00:08,840
NOW PACKAGABLE.

4780
05:00:08,840 --> 05:00:10,400
IT'S THOUGHT THIS STRUCTURE WAS

4781
05:00:10,400 --> 05:00:12,680
EXTENDED TO BE LONGER.

4782
05:00:12,680 --> 05:00:17,560
HOW DOES THE TWO STRUCTURES TELL

4783
05:00:17,560 --> 05:00:19,760
US HOW VIRUS MANAGES TO RNA, THE

4784
05:00:19,760 --> 05:00:25,160
IDEA IS THAT IN THIS STRUCTURE

4785
05:00:25,160 --> 05:00:28,000
IT'S DIFFERENT IN 1G.

4786
05:00:28,000 --> 05:00:36,920
IN 1G RNA IT'S SHORTER, 3B RNA

4787
05:00:36,920 --> 05:00:38,840
IT'S LONGER.

4788
05:00:38,840 --> 05:00:40,680
MAKES NON-PACKAGABLE FORM MORE

4789
05:00:40,680 --> 05:00:42,520
OFTEN, WE TESTED THIS HYPOTHESIS

4790
05:00:42,520 --> 05:00:45,120
BY MUTATING DIS AND YOU FIND TO

4791
05:00:45,120 --> 05:00:48,200
MAKE THE SEQUENCE MORE OR LESS

4792
05:00:48,200 --> 05:00:50,000
STABLE, OUR DATA DOES NOT

4793
05:00:50,000 --> 05:00:51,600
SUPPORT THIS PARTICULAR

4794
05:00:51,600 --> 05:00:52,120
HYPOTHESIS.

4795
05:00:52,120 --> 05:00:55,640
IF THAT'S THE CASE WHAT COULD BE

4796
05:00:55,640 --> 05:00:58,360
THE POSSIBLE MECHANISM?

4797
05:00:58,360 --> 05:01:02,080
SO, WE ACTUALLY THINK THAT A

4798
05:01:02,080 --> 05:01:04,600
LARGE RNA FORMS MULTIPLE

4799
05:01:04,600 --> 05:01:07,560
STRUCTURES, AND THEY HAVE

4800
05:01:07,560 --> 05:01:08,880
ENSEMBLE STRUCTURES, WE THINK 3G

4801
05:01:08,880 --> 05:01:12,640
RNA TEND TO FLOAT INTO

4802
05:01:12,640 --> 05:01:13,680
CONFIRMATIONS, MULTIPLE

4803
05:01:13,680 --> 05:01:17,440
CONFIRMATIONS, MOST NOT SUITABLE

4804
05:01:17,440 --> 05:01:19,600
FOR PACKAGING.

4805
05:01:19,600 --> 05:01:23,200
1G CAN FOLD SUITABLE FOR

4806
05:01:23,200 --> 05:01:23,680
PACKAGING.

4807
05:01:23,680 --> 05:01:30,000
IN VITRO TRANSCRIPTION WAS DONE,

4808
05:01:30,000 --> 05:01:31,960
AND THESE MADE A PAGE TO

4809
05:01:31,960 --> 05:01:33,400
SEPARATE THEM.

4810
05:01:33,400 --> 05:01:35,400
YOU CAN SEE SOMETHING DIFFERENT

4811
05:01:35,400 --> 05:01:38,080
RIGHT AWAY, IN THE 1G RNA YOU

4812
05:01:38,080 --> 05:01:41,240
CAN SEE BOTH DIMER AND MONOMER.

4813
05:01:41,240 --> 05:01:44,600
IN 3G RNA, MOSTLY MONOMERS.

4814
05:01:44,600 --> 05:01:49,400
SO HOW ARE THESE STRUCTURES

4815
05:01:49,400 --> 05:01:54,920
DIFFERENT? 

4816
05:01:54,920 --> 05:01:57,080
KARIN'S LAB PERFORMED CHEMICAL

4817
05:01:57,080 --> 05:01:59,280
PROTEIN LOOKING AT THESE TWO,

4818
05:01:59,280 --> 05:02:01,440
MOST OF THEM STRUCTURE TENDS TO

4819
05:02:01,440 --> 05:02:06,800
BE WHAT THEY CALL EXPOSED, THAT

4820
05:02:06,800 --> 05:02:14,120
IS THEY FORM BOTH POLY- A AND

4821
05:02:14,120 --> 05:02:15,000
SL1.

4822
05:02:15,000 --> 05:02:22,760
MONOMERIC FORMS THAT ARE

4823
05:02:22,760 --> 05:02:23,080
SEQUESTERED.

4824
05:02:23,080 --> 05:02:24,280
THERE ARE MULTIPLE STRUCTURES,

4825
05:02:24,280 --> 05:02:24,960
TWO DOMINANT STRUCTURES I'M

4826
05:02:24,960 --> 05:02:26,040
GOING TO SHOW YOU.

4827
05:02:26,040 --> 05:02:29,440
THIS IS WHAT WE CALL EXPOSED

4828
05:02:29,440 --> 05:02:30,200
STRUCTURE.

4829
05:02:30,200 --> 05:02:32,720
IN THIS CASE, POLY-A IS FORMED.

4830
05:02:32,720 --> 05:02:35,720
HERE IS DIS.

4831
05:02:35,720 --> 05:02:39,800
READY TO BASE PAIR.

4832
05:02:39,800 --> 05:02:41,600
NC BINDING SIDES ARE EXPOSED,

4833
05:02:41,600 --> 05:02:45,520
READY TO BE BOUND BY PROTEIN.

4834
05:02:45,520 --> 05:02:48,840
ON THE OTHER HAND 3G RNA, POLY-A

4835
05:02:48,840 --> 05:02:50,240
IS MELTED.

4836
05:02:50,240 --> 05:02:55,920
YOU CAN SEE THE DIS IS

4837
05:02:55,920 --> 05:02:56,360
SEQUESTERED.

4838
05:02:56,360 --> 05:02:58,040
AND TWO NC BINDING SITES ARE NO

4839
05:02:58,040 --> 05:02:59,000
LONGER AVAILABLE.

4840
05:02:59,000 --> 05:03:01,200
WE THINK THAT'S THE DIFFERENCE.

4841
05:03:01,200 --> 05:03:04,040
TO BETTER PROBE THIS AND TO FIND

4842
05:03:04,040 --> 05:03:08,080
OUT MORE, WE HAVE TO ASK CAN YOU

4843
05:03:08,080 --> 05:03:12,920
CHANGE IT?

4844
05:03:12,920 --> 05:03:18,040
WE IDENTIFIED TWO TYPES OF

4845
05:03:18,040 --> 05:03:21,440
MUTANT THAT 2G RNA CAN BE

4846
05:03:21,440 --> 05:03:21,800
PACKAGED.

4847
05:03:21,800 --> 05:03:25,000
THESE MUTANT TURN OUT TO BE

4848
05:03:25,000 --> 05:03:27,680
MUTANT AROUND POLY-A REGION.

4849
05:03:27,680 --> 05:03:31,880
FIRST TYPE OF MUTANT WE CHANGED

4850
05:03:31,880 --> 05:03:33,520
STABILITY OF POLY-A, A LITTLE

4851
05:03:33,520 --> 05:03:34,560
SHORTER AND LESS STABLE.

4852
05:03:34,560 --> 05:03:38,080
AS YOU CAN SEE IN THIS CASE IN

4853
05:03:38,080 --> 05:03:40,520
THE CELL LINING THE DISTRIBUTION

4854
05:03:40,520 --> 05:03:41,920
IS SIMILAR TO THE WILD TYPE.

4855
05:03:41,920 --> 05:03:46,800
HOWEVER, IN THE VIRUS RNA YOU

4856
05:03:46,800 --> 05:03:49,240
CAN SEE NOW IN THE PACKAGE ALLOW

4857
05:03:49,240 --> 05:03:52,760
MORE 3G RNA, IT CAN ALSO BE

4858
05:03:52,760 --> 05:03:53,120
PACKAGED.

4859
05:03:53,120 --> 05:03:57,240
THE SECOND TYPE OF MUTANT WE

4860
05:03:57,240 --> 05:04:07,720
MADE, WE ADDED TWO NUCLEOTIDE 

4861
05:04:10,440 --> 05:04:12,880
AND ADD ADDED, CG RNA CAN ALSO

4862
05:04:12,880 --> 05:04:13,960
BE PACKAGED.

4863
05:04:13,960 --> 05:04:17,360
SO WE HAVE ALSO LOOKED AT RNA

4864
05:04:17,360 --> 05:04:18,760
STRUCTURE WITH THESE.

4865
05:04:18,760 --> 05:04:20,640
AND WE TAKE ALL MUTANTS AND PUT

4866
05:04:20,640 --> 05:04:26,640
THEM IN THE SHELL LIKE I SHOWED

4867
05:04:26,640 --> 05:04:27,200
EARLIER.

4868
05:04:27,200 --> 05:04:32,160
SO WHAT YOU CAN SEE, IF YOU ADD

4869
05:04:32,160 --> 05:04:35,680
NUCLEOTIDES BETWEEN THE TAR AND

4870
05:04:35,680 --> 05:04:38,400
POLY-A, WHETHER IT'S 3G OR 1G

4871
05:04:38,400 --> 05:04:43,720
RNA NOW YOU CAN SEE MOSTLY

4872
05:04:43,720 --> 05:04:44,040
DIMERIC RNA.

4873
05:04:44,040 --> 05:04:46,720
ON THE OTHER HAND IF YOU

4874
05:04:46,720 --> 05:04:49,360
DESTABILIZE POLY-A STEM, MOST OF

4875
05:04:49,360 --> 05:04:54,000
THE RNA REGARDLESS OF 3G OR 1G

4876
05:04:54,000 --> 05:05:01,840
RNA ARE MONOMERIC IRAN. -- RNA.

4877
05:05:01,840 --> 05:05:06,720
HIV HAS A DYNAMIC STRUCTURE, IF 

4878
05:05:06,720 --> 05:05:09,360
YOU CAN FOLD 5-PRIME POLY-A

4879
05:05:09,360 --> 05:05:11,440
HAIRPIN RNA CAN FOLD INTO

4880
05:05:11,440 --> 05:05:12,440
PACKAGABLE FORM.

4881
05:05:12,440 --> 05:05:16,360
AND THEY ARE DIMER READY.

4882
05:05:16,360 --> 05:05:17,600
EXPOSED, HAVE EXPOSED GAG

4883
05:05:17,600 --> 05:05:19,240
BINDING SITE, READY TO BE

4884
05:05:19,240 --> 05:05:21,760
PACKAGED AS GENOME. 

4885
05:05:21,760 --> 05:05:26,120
ON THE OTHER HAND, IF THESE RNA

4886
05:05:26,120 --> 05:05:34,320
ARE NOT FOLDING TO POLY-A HAIR 

4887
05:05:34,320 --> 05:05:35,760
HAIRPIN, THEY GET SEQUESTERED

4888
05:05:35,760 --> 05:05:38,240
AND CANNOT BE PACKAGED AS

4889
05:05:38,240 --> 05:05:40,280
GENOME.

4890
05:05:40,280 --> 05:05:44,280
AND THIS IS THE DIFFERENCE, THIS

4891
05:05:44,280 --> 05:05:47,040
IS HOW HIV DISTINGUISH BETWEEN

4892
05:05:47,040 --> 05:05:49,120
1G AND 3G RNA, LIKE THEIR

4893
05:05:49,120 --> 05:05:49,320
GENOME.

4894
05:05:49,320 --> 05:05:52,160
THEN WE ASK IS THIS UNIQUE?

4895
05:05:52,160 --> 05:05:54,800
IS THIS UNIQUE HIV OR DOES IT

4896
05:05:54,800 --> 05:05:56,400
EXTEND TO OTHER VIRUSES?

4897
05:05:56,400 --> 05:05:59,560
AND THIS IS DONE IN

4898
05:05:59,560 --> 05:06:01,000
COLLABORATION WITH BRENDA'S LAB,

4899
05:06:01,000 --> 05:06:02,120
ALSO RENEE'S LAB.

4900
05:06:02,120 --> 05:06:05,960
THE FIRST THING WE WANT TO DO IS

4901
05:06:05,960 --> 05:06:06,920
ASK ABOUT HIV.

4902
05:06:06,920 --> 05:06:09,880
OUR STUDY AS WELL AS OTHER

4903
05:06:09,880 --> 05:06:20,400
STUDIES ARE BASED ON NL4-3, DO

4904
05:06:21,800 --> 05:06:22,600
THEY ALSO USE TRANSCRIPTION

4905
05:06:22,600 --> 05:06:26,520
START SITES AND DO THE SAME

4906
05:06:26,520 --> 05:06:27,240
THING?

4907
05:06:27,240 --> 05:06:30,240
THIS IS EXAMPLE IN ALPHA 3, AS

4908
05:06:30,240 --> 05:06:30,480
EXAMPLE.

4909
05:06:30,480 --> 05:06:34,520
FIRST THING WE WANT TO KNOW

4910
05:06:34,520 --> 05:06:38,360
OTHER TYPE OF VIRUSES, WE TOOK

4911
05:06:38,360 --> 05:06:41,960
THREE ISOLATES AND ASKED TO SEE

4912
05:06:41,960 --> 05:06:42,760
WHAT HAPPENED.

4913
05:06:42,760 --> 05:06:47,320
ONE STRAIN TURNED OUT TO BE VERY

4914
05:06:47,320 --> 05:06:49,960
SIMILAR TO NL4-3.

4915
05:06:49,960 --> 05:06:52,800
THE SURPRISE SAME WITH WHO OTHER

4916
05:06:52,800 --> 05:06:55,640
STRAINS OF ISOLATE, TURNED OUT

4917
05:06:55,640 --> 05:06:58,920
TO BE THEY SHIFTED SIGNAL

4918
05:06:58,920 --> 05:07:04,720
TRANSCRIPTION A LITTLE BIT,

4919
05:07:04,720 --> 05:07:06,680
STARTED THE TRANSCRIPTION, 1G,

4920
05:07:06,680 --> 05:07:09,760
ALSO HAD VERY LOW 3G, SHIFTED

4921
05:07:09,760 --> 05:07:18,080
DOWN TO USE THE FIFTH XYLAZINE

4922
05:07:18,080 --> 05:07:19,600
AS A START SITE.

4923
05:07:19,600 --> 05:07:22,880
IF YOU LOOK AT CELLULAR RNA

4924
05:07:22,880 --> 05:07:24,120
STILL USED MULTIPLE

4925
05:07:24,120 --> 05:07:28,240
TRANSCRIPTION SITE, SECOND IF

4926
05:07:28,240 --> 05:07:30,120
YOU LOOK, STILL PACKAGED, THOSE

4927
05:07:30,120 --> 05:07:34,720
TWO ARE STILL TRUE.

4928
05:07:34,720 --> 05:07:37,160
WE THEN LOOKED AT HEPATITIS C

4929
05:07:37,160 --> 05:07:39,480
VIRUS, VERY PREVALENT IN THE

4930
05:07:39,480 --> 05:07:43,480
WORLD, USING MJ 4 AND CDH 185.

4931
05:07:43,480 --> 05:07:47,000
IN SIMILARLY, CAN YOU SEE THEY

4932
05:07:47,000 --> 05:07:51,800
HAVE MULTIPLE TRANSCRIPTION, 1G

4933
05:07:51,800 --> 05:07:54,080
IS PREFERENTIALLY PACKAGED.

4934
05:07:54,080 --> 05:08:00,360
THESE TWO ARE MORE 1G RNA IN THE

4935
05:08:00,360 --> 05:08:03,840
CYTOPLASM TO BEGIN WITH.

4936
05:08:03,840 --> 05:08:05,920
SO WE'RE FAIRLY CONFIDENT HIV

4937
05:08:05,920 --> 05:08:07,920
GENERALLY USE NEIGHBORING SITES

4938
05:08:07,920 --> 05:08:10,960
AND MAKE MULTIPLE FULL LENGTH

4939
05:08:10,960 --> 05:08:12,920
RNA, AND SUBPOPULATION IS

4940
05:08:12,920 --> 05:08:13,520
PACKAGED.

4941
05:08:13,520 --> 05:08:18,600
BUT WHERE DO THESE COME FROM?

4942
05:08:18,600 --> 05:08:19,600
FROM PROGENITOR VIRUSES OR

4943
05:08:19,600 --> 05:08:24,640
SOMEHOW HIV GOT INTO THE HUMAN

4944
05:08:24,640 --> 05:08:27,480
POPULATION AND THEY DO THESE

4945
05:08:27,480 --> 05:08:27,920
THINGS?

4946
05:08:27,920 --> 05:08:32,480
WE LOOK AT PROGENITOR VIRUSES,

4947
05:08:32,480 --> 05:08:38,960
HIV ORIGINATED FROM SIV CTC,

4948
05:08:38,960 --> 05:08:41,680
THESE TWO ARE THE ISOLATES

4949
05:08:41,680 --> 05:08:42,880
THOUGHT TO BE SIMILAR TO THE

4950
05:08:42,880 --> 05:08:53,400
VIRUS THAT GOT INTO THE HUMAN

4951
05:08:57,640 --> 05:08:57,960
POPULATION.

4952
05:08:57,960 --> 05:08:59,400
WE TALKED TO BRENDAN AND HAVE

4953
05:08:59,400 --> 05:09:01,680
GOTTEN SOME VIRUS FROM HIM AND

4954
05:09:01,680 --> 05:09:06,400
WE LOOK AT WHAT HAPPENED TO THE

4955
05:09:06,400 --> 05:09:12,400
VIRUSES SIMILAR TO PROGENITOR OF

4956
05:09:12,400 --> 05:09:19,960
GROUPM AND N, THEY BEHAVE

4957
05:09:19,960 --> 05:09:21,800
SIMILAR IN L4, 3.

4958
05:09:21,800 --> 05:09:23,280
THEY PACKAGE 1G RNA.

4959
05:09:23,280 --> 05:09:27,080
WE LOOK AT WHAT HAPPENED TO

4960
05:09:27,080 --> 05:09:30,160
GROUP O VIRUS, SIV GORILLA, THEY

4961
05:09:30,160 --> 05:09:32,240
EXHIBIT SIMILAR THINGS EXCEPT IN

4962
05:09:32,240 --> 05:09:33,000
THEIR CASE IN GORILLA THEY SEEM

4963
05:09:33,000 --> 05:09:35,480
TO HAVE A LITTLE BIT MORE 1G TO

4964
05:09:35,480 --> 05:09:37,360
BEGIN WITH.

4965
05:09:37,360 --> 05:09:41,320
SO, WE WOULD LIKE TO PUSH THIS A

4966
05:09:41,320 --> 05:09:44,440
LITTLE FURTHER AND ASK HOW FAR

4967
05:09:44,440 --> 05:09:51,280
DOES THIS CONSERVATION GO?

4968
05:09:51,280 --> 05:09:54,600
SIV CPC IS THOUGHT TO BE

4969
05:09:54,600 --> 05:09:54,880
RECOMBINANT.

4970
05:09:54,880 --> 05:09:56,200
THERE'S NOT A LOT OF REAGENT

4971
05:09:56,200 --> 05:10:00,600
AVAILABLE SO WE WERE ABLE TO

4972
05:10:00,600 --> 05:10:05,160
OBTAIN ONE STRAIN OF RCM

4973
05:10:05,160 --> 05:10:06,960
INFECTIOUS VIRUS, THIS GUY WAS

4974
05:10:06,960 --> 05:10:11,080
NOT LIKE ANYBODY ELSE.

4975
05:10:11,080 --> 05:10:12,600
MOSTLY PRODUCED 3G RNA AND

4976
05:10:12,600 --> 05:10:14,560
CELLULAR AND VIRUS ARE NOT TOO

4977
05:10:14,560 --> 05:10:15,120
DIFFERENT.

4978
05:10:15,120 --> 05:10:16,120
THIS GUY IS ACTUALLY THE

4979
05:10:16,120 --> 05:10:18,080
EXCEPTION TO THE RULE.

4980
05:10:18,080 --> 05:10:22,000
SO WE STILL CANNOT CONCLUDE AT

4981
05:10:22,000 --> 05:10:23,000
THIS POINT BEYOND DIRECTLY

4982
05:10:23,000 --> 05:10:25,560
RELATED VIRUS HOW FAR DOES THIS

4983
05:10:25,560 --> 05:10:27,280
CONSERVATION GO.

4984
05:10:27,280 --> 05:10:29,360
HOWEVER, WE CAN LOOK AT ANOTHER

4985
05:10:29,360 --> 05:10:33,080
VIRUS, AND SO WE LOOK AT HIV-2

4986
05:10:33,080 --> 05:10:34,080
AND RELATED VIRUSES.

4987
05:10:34,080 --> 05:10:36,600
AND BECAUSE OF TIME CONSTRAINT I

4988
05:10:36,600 --> 05:10:40,080
WON'T SHOW YOU THE DETAIL,

4989
05:10:40,080 --> 05:10:44,920
BOTTOM LINE IS THAT HIV-2 CAUSES

4990
05:10:44,920 --> 05:10:47,320
AIDS, AND CAME FROM ZOONOTIC

4991
05:10:47,320 --> 05:10:48,960
TRANSMISSION OF DIFFERENT VIRUS

4992
05:10:48,960 --> 05:10:52,040
SIV SMM, SO WE LOOK AT THESE

4993
05:10:52,040 --> 05:10:55,960
VIRUSES AND FIND THAT THEY ALSO

4994
05:10:55,960 --> 05:10:58,240
USE MULTIPLE TRANSCRIPTION START

4995
05:10:58,240 --> 05:11:04,800
SITES, BOTH HIV 2 AND SIVMAC

4996
05:11:04,800 --> 05:11:05,840
SELECTIVELY PACKAGE A

4997
05:11:05,840 --> 05:11:07,480
SUBPOPULATION OF RNA.

4998
05:11:07,480 --> 05:11:10,360
TO BRIEFLY SUMMARIZE, I SHOWED

4999
05:11:10,360 --> 05:11:14,480
YOU TODAY HIV  ACTUALLY USES

5000
05:11:14,480 --> 05:11:15,400
NEIGHBORING SEQUENCES TO

5001
05:11:15,400 --> 05:11:18,680
GENERATE MULTIPLE FULL LENGTH

5002
05:11:18,680 --> 05:11:21,640
RNA, AND THE CONTEXT AFFECT THE

5003
05:11:21,640 --> 05:11:24,240
RNA STRUCTURE AND FUNCTIONS.

5004
05:11:24,240 --> 05:11:26,760
ONLY A SUBSET OF THEM ARE

5005
05:11:26,760 --> 05:11:29,600
PREFERENTIALLY PACKAGED.

5006
05:11:29,600 --> 05:11:31,560
THESE FEATURES LARGELY CONSERVED

5007
05:11:31,560 --> 05:11:36,600
IN MANY PRIMATE LENTIVIRUSES

5008
05:11:36,600 --> 05:11:43,800
INCLUDING THE PROGENITOR OF

5009
05:11:43,800 --> 05:11:45,880
HIV-1.

5010
05:11:45,880 --> 05:11:47,440
THESE FEATURES PREEXIST PRIOR TO

5011
05:11:47,440 --> 05:11:48,280
INTRODUCTION INTO HUMAN

5012
05:11:48,280 --> 05:11:52,760
POPULATION, AND HIV 2 AND HIV-2

5013
05:11:52,760 --> 05:11:54,520
RELATED ALSO HAVE SIMILAR

5014
05:11:54,520 --> 05:11:54,800
FEATURES.

5015
05:11:54,800 --> 05:11:56,840
I WOULD LIKE TO ACKNOWLEDGE THE

5016
05:11:56,840 --> 05:12:02,600
PEOPLE IN MY LAB.

5017
05:12:02,600 --> 05:12:06,680
A LOT OF PEOPLE IN THE LAB,

5018
05:12:06,680 --> 05:12:07,760
MOSTLY EVERYBODY CONTRIBUTED TO

5019
05:12:07,760 --> 05:12:09,600
SOME CURRENT OR FUTURE WORK, AND

5020
05:12:09,600 --> 05:12:11,640
THESE ARE THE FORMER MEMBERS,

5021
05:12:11,640 --> 05:12:17,080
AND THESE STUDIES ARE DONE IN

5022
05:12:17,080 --> 05:12:18,680
COLLABORATION WITH KARIM'S LAB,

5023
05:12:18,680 --> 05:12:21,840
JONATHAN WAS A GRADUATE STUDENT

5024
05:12:21,840 --> 05:12:26,080
IN HIS LAB, NOW HE'S IN MY LAB

5025
05:12:26,080 --> 05:12:36,520
LOOKING AT RNA BIOLOGY.

5026
05:12:40,120 --> 05:12:42,600
AND BRENDAN KEEL, AND WE WANT TO

5027
05:12:42,600 --> 05:12:44,120
THANK ERIC AND UNIVERSITY OF

5028
05:12:44,120 --> 05:12:45,160
ALABAMA FOR REAGENTS.

5029
05:12:45,160 --> 05:12:45,800
THANK YOU SO MUCH.

5030
05:12:45,800 --> 05:12:48,160
[APPLAUSE]

5031
05:12:48,160 --> 05:12:54,160
 

5032
05:12:54,160 --> 05:12:57,280
 

5033
05:12:57,280 --> 05:12:57,960
>>QUESTIONS?

5034
05:12:57,960 --> 05:12:59,880
>>WONDERFUL WORK.

5035
05:12:59,880 --> 05:13:03,040
ENJOY THE SPECIALIZED PACKAGING.

5036
05:13:03,040 --> 05:13:04,480
IS THERE SPECIALIZATION RNAs

5037
05:13:04,480 --> 05:13:05,480
GET TRANSLATED?

5038
05:13:05,480 --> 05:13:06,320
>>GREAT QUESTION!

5039
05:13:06,320 --> 05:13:10,280
I WOULD LIKE TO TELL YOU ABOUT

5040
05:13:10,280 --> 05:13:12,760
THAT ANSWER IN A COUPLE OF

5041
05:13:12,760 --> 05:13:13,160
MONTHS.

5042
05:13:13,160 --> 05:13:14,560
WE'RE IN THE PROCESS OF DOING

5043
05:13:14,560 --> 05:13:15,000
THAT.

5044
05:13:15,000 --> 05:13:19,040
ONE THING I DO WANT TO SAY IS

5045
05:13:19,040 --> 05:13:19,960
THERE ARE SPECIALIZED BUT

5046
05:13:19,960 --> 05:13:21,480
DIVISION IS NOT ABSOLUTE.

5047
05:13:21,480 --> 05:13:24,520
SOME 3G IS STILL PACKAGED.

5048
05:13:24,520 --> 05:13:28,480
SO WE ARE CURRENTLY LOOKING AT

5049
05:13:28,480 --> 05:13:30,000
THAT AND IT'S COMPLICATED.

5050
05:13:30,000 --> 05:13:34,520
IT'S NOT ONE OR THE OTHER.

5051
05:13:34,520 --> 05:13:35,520
THERE'S REALLY INTERESTING

5052
05:13:35,520 --> 05:13:38,120
MECHANISTIC THINGS THERE.

5053
05:13:38,120 --> 05:13:39,760
>>I'M WONDERING WHY, WHY
DOES

5054
05:13:39,760 --> 05:13:42,320
IT HAVE SUCH A COMPLICATED

5055
05:13:42,320 --> 05:13:42,560
SYSTEM.

5056
05:13:42,560 --> 05:13:43,480
>>AH, GREAT QUESTION.

5057
05:13:43,480 --> 05:13:45,120
WHY DO THEY EVEN BOTHER WITH

5058
05:13:45,120 --> 05:13:47,080
THIS, RIGHT?

5059
05:13:47,080 --> 05:13:49,960
HIV IS A SERIOUS VIRUS, THEY

5060
05:13:49,960 --> 05:13:50,920
DON'T DO SOMETHING THIS

5061
05:13:50,920 --> 05:13:52,120
COMPLICATED FOR NO REASON AT

5062
05:13:52,120 --> 05:13:52,400
ALL.

5063
05:13:52,400 --> 05:13:55,080
THERE'S A GOOD REASON FOR THAT.

5064
05:13:55,080 --> 05:13:57,160
SO THAT'S ANOTHER QUESTION WE'RE

5065
05:13:57,160 --> 05:13:59,640
CURIOUS ABOUT.

5066
05:13:59,640 --> 05:14:01,640
WHAT DO YOU REALLY NEED THE

5067
05:14:01,640 --> 05:14:04,480
DIVERSITY FOR THE VIRUS TO WORK?

5068
05:14:04,480 --> 05:14:05,600
YEAH.

5069
05:14:05,600 --> 05:14:06,560
YES, RON?

5070
05:14:06,560 --> 05:14:08,880
>>SIMILAR QUESTION,
SPLICING,

5071
05:14:08,880 --> 05:14:11,920
WHERE THE DECISION TO NOT BE

5072
05:14:11,920 --> 05:14:13,360
AVAILABLE FOR SPLICING IN TERMS

5073
05:14:13,360 --> 05:14:15,240
OF THESE STRUCTURES.

5074
05:14:15,240 --> 05:14:16,640
>>YEAH, I KNOW.

5075
05:14:16,640 --> 05:14:19,040
I HATE TO SOUND SO REPETITIVE

5076
05:14:19,040 --> 05:14:24,640
BUT WE'RE TRYING TO DO THIS.

5077
05:14:24,640 --> 05:14:27,640
AS YOU KNOW, BEAUTIFUL STUDIES

5078
05:14:27,640 --> 05:14:31,760
LOOKING TO FIGURE OUT USING NGS

5079
05:14:31,760 --> 05:14:34,200
TO LOOK AT SPLICING CURRENTLY

5080
05:14:34,200 --> 05:14:35,040
DEVELOPING SIMILAR METHODS TO

5081
05:14:35,040 --> 05:14:37,080
LOOK AT 5 PRIME END.

5082
05:14:37,080 --> 05:14:40,280
I THINK WE'RE GETTING THERE BUT

5083
05:14:40,280 --> 05:14:42,120
HOPEFULLY WE'LL HAVE SOME

5084
05:14:42,120 --> 05:14:44,960
ANSWERS FOR YOU SOON.

5085
05:14:44,960 --> 05:14:48,720
 

5086
05:14:48,720 --> 05:14:49,720
YES?

5087
05:14:49,720 --> 05:14:51,440
>>IS THERE A WAY TO
SUPPRESS

5088
05:14:51,440 --> 05:14:54,760
ONE OR THE OTHER RNA TO SEE WHAT

5089
05:14:54,760 --> 05:14:55,920
THAT DOES?

5090
05:14:55,920 --> 05:14:56,200
>>YES.

5091
05:14:56,200 --> 05:14:58,680
THERE IS A WAY.

5092
05:14:58,680 --> 05:15:02,280
SO WE MAKE MUTATIONS NEAR THE

5093
05:15:02,280 --> 05:15:06,440
PROMOTER REGION AND YOU CAN'T

5094
05:15:06,440 --> 05:15:07,400
SHIFT TRANSCRIPTION, OBVIOUSLY

5095
05:15:07,400 --> 05:15:09,720
WHAT HAPPENS WHEN YOU SHIFT THE

5096
05:15:09,720 --> 05:15:12,280
TRANSCRIPTION, YEAH, HOPEFULLY

5097
05:15:12,280 --> 05:15:20,280
WE'LL FIND OUT SOON.

5098
05:15:20,280 --> 05:15:20,840
>>THANKS VERY MUCH.

5099
05:15:20,840 --> 05:15:23,480
[APPLAUSE]

5100
05:15:23,480 --> 05:15:25,760
WE'LL TAKE A 15-MINUTE BREAK AND

5101
05:15:25,760 --> 05:15:31,200
RESUME.

5102
05:15:31,200 --> 05:15:33,480
>>IT'S A GREAT HONOR TO

5103
05:15:33,480 --> 05:15:36,080
INTRODUCE THE NEXT SPEAKER, MIKE

5104
05:15:36,080 --> 05:15:41,560
BISHOP FROM SAN FRANCISCO,

5105
05:15:41,560 --> 05:15:43,120
PROFESSOR EMERITUS AS UCSF

5106
05:15:43,120 --> 05:15:52,400
SHARED THE  NOBEL PRIZE FOR

5107
05:15:52,400 --> 05:15:55,360
HAROLD VARMUS, MIKE ALSO SERVED

5108
05:15:55,360 --> 05:15:57,800
AS CHANCELLOR OF UCSF, A BIG

5109
05:15:57,800 --> 05:15:58,720
ADMINISTRATIVE JOB.

5110
05:15:58,720 --> 05:16:02,280
IT'S AN HONOR FOR YOU TO JOIN US

5111
05:16:02,280 --> 05:16:02,480
TODAY

5112
05:16:02,480 --> 05:16:09,240
>>THANK YOU VERY MUCH.

5113
05:16:09,240 --> 05:16:11,680
THE NOBEL PRIZE, AN ANECDOTE

5114
05:16:11,680 --> 05:16:12,680
ABOUT THAT.

5115
05:16:12,680 --> 05:16:21,120
I WAS SHARING A ROOM AT COLD

5116
05:16:21,120 --> 05:16:26,560
SPRING HARBOR, LET'S SAY RATHER

5117
05:16:26,560 --> 05:16:30,040
GRIM LIGHT, A DOUBLE-DECKER BED,

5118
05:16:30,040 --> 05:16:34,200
I HURRIED OVER TO GET THE OTHER

5119
05:16:34,200 --> 05:16:34,440
BUNK.

5120
05:16:34,440 --> 05:16:36,280
WORRIED THE BUILDING MIGHT

5121
05:16:36,280 --> 05:16:36,640
COLLAPSE ON ME.

5122
05:16:36,640 --> 05:16:38,920
[LAUGHTER]

5123
05:16:38,920 --> 05:16:46,480
 

5124
05:16:46,480 --> 05:16:48,480
THERE WE ARE, BOTH HAD GOTTEN IN

5125
05:16:48,480 --> 05:16:51,200
AFTER A LATE NIGHT.

5126
05:16:51,200 --> 05:16:53,320
AND FROM BELOW, STEVE GROWLS AT

5127
05:16:53,320 --> 05:16:55,560
ME, HE SAYS, DO YOU REALIZE,

5128
05:16:55,560 --> 05:16:59,320
BISHOP, YOU'RE GOING TO

5129
05:16:59,320 --> 05:17:00,760
STOCKHOLM!

5130
05:17:00,760 --> 05:17:02,160
I SAID WHAT?

5131
05:17:02,160 --> 05:17:07,320
SO, THE FIRST ANYONE RAISED THE

5132
05:17:07,320 --> 05:17:08,520
POSSIBILITY, AND IT DIDN'T

5133
05:17:08,520 --> 05:17:12,360
HAPPEN AGAIN UNTIL THE LEGENDARY

5134
05:17:12,360 --> 05:17:14,240
3 A.M. BUNKO EVERYBODY TALKS

5135
05:17:14,240 --> 05:17:14,800
ABOUT.

5136
05:17:14,800 --> 05:17:15,240
OKAY.

5137
05:17:15,240 --> 05:17:17,720
LET ME JUST SAY I'M REALLY

5138
05:17:17,720 --> 05:17:20,080
DISAPPOINTED I CAN'T BE THERE

5139
05:17:20,080 --> 05:17:21,120
BECAUSE OF PERSONAL

5140
05:17:21,120 --> 05:17:23,880
CIRCUMSTANCES. 

5141
05:17:23,880 --> 05:17:26,280
STEVE WAS A WONDERFUL COLLEAGUE

5142
05:17:26,280 --> 05:17:29,240
DURING HIS TIME WITH HAROLD AND

5143
05:17:29,240 --> 05:17:30,960
ME, GREAT SCIENTIST,

5144
05:17:30,960 --> 05:17:33,520
ENTERTAINING INDIVIDUAL, AND

5145
05:17:33,520 --> 05:17:35,360
HE'S REMAINED A FRIEND OVER THE

5146
05:17:35,360 --> 05:17:37,240
YEARS EVEN THOUGH WE'VE BEEN

5147
05:17:37,240 --> 05:17:40,000
SEPARATED BY, WELL, THE WHOLE

5148
05:17:40,000 --> 05:17:41,240
CONTINENT.

5149
05:17:41,240 --> 05:17:45,080
WHEN STEVE WAS WITH US, I HAD A

5150
05:17:45,080 --> 05:17:46,760
NICKNAME WITH HIM WHICH NO ONE

5151
05:17:46,760 --> 05:17:47,960
ELSE ADOPTED FOR REASONS THAT

5152
05:17:47,960 --> 05:17:49,520
MIGHT BE OBVIOUS.

5153
05:17:49,520 --> 05:17:55,080
MY NICKNAME FOR STEVE WAS

5154
05:17:55,080 --> 05:17:55,280
"HUGE."

5155
05:17:55,280 --> 05:17:58,120
IT'S EASY TO EXTRACT FROM HIS

5156
05:17:58,120 --> 05:18:02,080
FAMILY NAME, HUGHES, AND IT

5157
05:18:02,080 --> 05:18:05,360
EMBODIES THE SORT OF PRODIGIOUS

5158
05:18:05,360 --> 05:18:06,760
HEFT OF BODY, MIND AND SOUL THAT

5159
05:18:06,760 --> 05:18:09,360
IS THIS MAN.

5160
05:18:09,360 --> 05:18:10,200
HE'S QUITE A PACKAGE.

5161
05:18:10,200 --> 05:18:12,360
AND I'M GOING TO OPEN THAT

5162
05:18:12,360 --> 05:18:17,640
PACKAGE BY MEANS OF ANECDOTES.

5163
05:18:17,640 --> 05:18:20,480
I WAS A PARTICIPANT OR WITNESS

5164
05:18:20,480 --> 05:18:24,080
IN MOST OF THESE.

5165
05:18:24,080 --> 05:18:30,000
BUT IN A FEW, I'VE HAD TO RELY

5166
05:18:30,000 --> 05:18:31,840
UPON SECONDHAND ACCOUNTS,

5167
05:18:31,840 --> 05:18:35,240
SUPPLEMENTED BY MY OWN

5168
05:18:35,240 --> 05:18:35,520
IMAGINATION.

5169
05:18:35,520 --> 05:18:37,320
TO BEGIN, STEVE NEVER HESITATES

5170
05:18:37,320 --> 05:18:40,480
TO SPEAK TRUTH TO POWER.

5171
05:18:40,480 --> 05:18:44,800
I'M GOING TO GIVE TWO EXAMPLES.

5172
05:18:44,800 --> 05:18:49,720
THE FIRST INVOLVED A TATTERED

5173
05:18:49,720 --> 05:18:59,480
T-SHIRT THAT STEVE WORE ALMOST

5174
05:18:59,480 --> 05:19:00,440
CONTINUOUSLY TO ME.

5175
05:19:00,440 --> 05:19:05,120
THE IMAGE WAS A BARBED WIRE

5176
05:19:05,120 --> 05:19:05,360
FENCE.

5177
05:19:05,360 --> 05:19:08,880
THE TEXT READ "STEVE LUBBOCK."

5178
05:19:08,880 --> 05:19:10,720
STEVE WAS ACQUAINTED WITH

5179
05:19:10,720 --> 05:19:12,800
LUBBOCK, HE SPENT SOME TIME

5180
05:19:12,800 --> 05:19:15,000
THERE, BECAUSE HIS MOTHER TAUGHT

5181
05:19:15,000 --> 05:19:19,720
AT THE STATE COLLEGE IN LUBBOCK.

5182
05:19:19,720 --> 05:19:22,720
AT SOME POINT, HAROLD TOOK 

5183
05:19:22,720 --> 05:19:30,520
NOTICE OF THE T-SHIRT.

5184
05:19:30,520 --> 05:19:34,600
AND REMARKED, THAT I TOOK AT A

5185
05:19:34,600 --> 05:19:35,040
JEST.

5186
05:19:35,040 --> 05:19:39,280
STEVE, OBLIVIOUS TO THE JEST, IN

5187
05:19:39,280 --> 05:19:49,040
THAT TONE HE GENERALLY USES TO

5188
05:19:49,040 --> 05:19:51,360
DELIVER COUP DE GRAS, YOU HAVE

5189
05:19:51,360 --> 05:19:57,160
NOT SKIED LUBBOCK.

5190
05:19:57,160 --> 05:20:03,040
A POSTDOC MIGHT HAVE ASKED ABOUT

5191
05:20:03,040 --> 05:20:03,800
VERTICAL DROP.

5192
05:20:03,800 --> 05:20:08,840
NOT STEVE.

5193
05:20:08,840 --> 05:20:12,760
A POSTDOCAL FELLOW WHO I SHALL

5194
05:20:12,760 --> 05:20:14,840
CALL OMICRON.

5195
05:20:14,840 --> 05:20:19,800
OMICRON WAS A VIRTUOSO

5196
05:20:19,800 --> 05:20:21,000
EXPERIMENTALIST WITH A MAIN

5197
05:20:21,000 --> 05:20:21,360
FAULT.

5198
05:20:21,360 --> 05:20:23,520
HE LEFT BEHIND HIM WORKBENCHES

5199
05:20:23,520 --> 05:20:27,600
THAT RESEMBLED THE AFTERMATH OF 

5200
05:20:27,600 --> 05:20:29,400
THE BATTLE OF VERDUNNES.

5201
05:20:29,400 --> 05:20:32,160
AND HE NEVER CLEANED THEM UP.

5202
05:20:32,160 --> 05:20:35,560
SO, ONE EVENING STEVE 

5203
05:20:35,560 --> 05:20:38,080
ENCOUNTERED THE AFTERMATH IN A

5204
05:20:38,080 --> 05:20:41,160
ROOM DIVERTED WORK TO

5205
05:20:41,160 --> 05:20:41,800
RADIOISOTOPES, STEPHEN HAD

5206
05:20:41,800 --> 05:20:42,160
ENOUGH.

5207
05:20:42,160 --> 05:20:43,080
IT WAS IN SHAMBLES.

5208
05:20:43,080 --> 05:20:47,920
AT 10 P.M. OR SO HE PHONED ME AT

5209
05:20:47,920 --> 05:20:48,120
HOME.

5210
05:20:48,120 --> 05:20:52,320
OUR CONVERSATION WENT SOMETHING 

5211
05:20:52,320 --> 05:20:55,400
LIKE THIS.

5212
05:20:55,400 --> 05:20:56,560
STEVE SPEAKING.

5213
05:20:56,560 --> 05:20:56,920
BISHOP

5214
05:20:56,920 --> 05:20:58,880
ALWAYS BISHOP, NEVER MIND, NOT

5215
05:20:58,880 --> 05:21:01,280
EVEN J MICHAEL, JUST BISHOP.

5216
05:21:01,280 --> 05:21:03,840
BISHOP, YOU HAVE TO DO SOMETHING

5217
05:21:03,840 --> 05:21:06,640
ABOUT THIS!

5218
05:21:06,640 --> 05:21:07,640
I AGREED AND ASSURED STEVE I

5219
05:21:07,640 --> 05:21:11,960
WOULD TAKE IT ON IMMEDIATELY THE

5220
05:21:11,960 --> 05:21:13,360
FOLLOWING MORNING.

5221
05:21:13,360 --> 05:21:15,520
STEVE. 

5222
05:21:15,520 --> 05:21:16,920
NO, BISHOP, NOW!

5223
05:21:16,920 --> 05:21:18,600
THAT TONE AGAIN.

5224
05:21:18,600 --> 05:21:20,320
SO, THIS TIME IT WAS I WHO

5225
05:21:20,320 --> 05:21:23,520
PICKED UP THE PHONE AND CALLED

5226
05:21:23,520 --> 05:21:24,040
OMICRON.

5227
05:21:24,040 --> 05:21:26,240
WITHIN THE HOUR, THE RADIO

5228
05:21:26,240 --> 05:21:26,960
ISOTOPE ROOM LOOKED LIKE IT

5229
05:21:26,960 --> 05:21:30,520
MIGHT BE OF MIGHT BE ON THE

5230
05:21:30,520 --> 05:21:31,400
MARKET FOR SALE, AND I CREDIT

5231
05:21:31,400 --> 05:21:33,800
THE SUCCESS OF THE PHONE CALL TO

5232
05:21:33,800 --> 05:21:36,080
THE FACT OMICRON KNEW STEVE

5233
05:21:36,080 --> 05:21:38,160
STARTED THE WHOLE THING AND

5234
05:21:38,160 --> 05:21:43,080
THAT'S WHAT OMICRON MOST FEARED.

5235
05:21:43,080 --> 05:21:49,520
STEVE'S HEFT. 

5236
05:21:49,520 --> 05:21:50,680
ON OCCASION, HOWEVER, HE SPENT

5237
05:21:50,680 --> 05:21:57,400
TIME IN SALT LAKE CITY WITH HIS

5238
05:21:57,400 --> 05:21:58,720
DOCTORAL MENTOR, AND HOW CAN I

5239
05:21:58,720 --> 05:22:00,160
PUT THIS?

5240
05:22:00,160 --> 05:22:05,800
STEVE DID NOT TAKE WELL TO THE 

5241
05:22:05,800 --> 05:22:08,360
PROMINENCE THERE OF MORMON

5242
05:22:08,360 --> 05:22:12,400
THEOLOGY, WHICH HE DENIGRATED BY

5243
05:22:12,400 --> 05:22:17,760
TELLING MORMON BACK YARDS,

5244
05:22:17,760 --> 05:22:18,520
NOMROM.

5245
05:22:18,520 --> 05:22:21,280
HE USED THE TERM IN OCCASIONAL

5246
05:22:21,280 --> 05:22:28,280
DIATRIBES ABOUT THE MORES OF

5247
05:22:28,280 --> 05:22:29,040
MORMONISM, ENTERTAINING FELLOW

5248
05:22:29,040 --> 05:22:33,840
WORKERS AROUND HIM.

5249
05:22:33,840 --> 05:22:35,040
EVENTUALLY, I DON'T HEAR

5250
05:22:35,040 --> 05:22:38,200
ANYBODY, IS THAT OKAY, JOE?

5251
05:22:38,200 --> 05:22:38,840
>>YES.

5252
05:22:38,840 --> 05:22:43,560
>>WE HEAR YOU LOUD AND
CLEAR.

5253
05:22:43,560 --> 05:22:46,440
>>WE MUTED THE AUDITORIUM
SO WE

5254
05:22:46,440 --> 05:22:53,440
DIDN'T DISTURB YOUR TALK.

5255
05:22:53,440 --> 05:22:53,680
 

5256
05:22:53,680 --> 05:23:01,440
>>OKAY. 

5257
05:23:01,440 --> 05:23:04,040
SO NOMROM.

5258
05:23:04,040 --> 05:23:10,160
 

5259
05:23:10,160 --> 05:23:15,200
QUITE AMUSING BUT THERE WAS A

5260
05:23:15,200 --> 05:23:16,200
SUBDUED POSTDOC BEHIND STEVE WHO

5261
05:23:16,200 --> 05:23:17,000
SPOKE UP.

5262
05:23:17,000 --> 05:23:18,400
STEVE, YOU MIGHT WANT TO KNOW

5263
05:23:18,400 --> 05:23:21,960
THAT I AM A BISHOP IN THE MORMON

5264
05:23:21,960 --> 05:23:22,200
CHURCH.

5265
05:23:22,200 --> 05:23:25,200
[LAUGHTER]

5266
05:23:25,200 --> 05:23:29,360
 

5267
05:23:29,360 --> 05:23:35,280
WE HEARD NO MORE DIATRIBES ABOUT

5268
05:23:35,280 --> 05:23:35,600
THE NOMROM.

5269
05:23:35,600 --> 05:23:37,560
IT CAME TO PASS STEVE HAD TO

5270
05:23:37,560 --> 05:23:39,640
MOVE ON.

5271
05:23:39,640 --> 05:23:42,360
HIS SEARCH FOR LANDING PLACE HAD

5272
05:23:42,360 --> 05:23:42,840
ONE REQUIREMENT.

5273
05:23:42,840 --> 05:23:44,920
OUT OF THE FEAR OF EARTHQUAKES,

5274
05:23:44,920 --> 05:23:47,760
HE WOULD NOT SETTLE ON THE WEST

5275
05:23:47,760 --> 05:23:48,200
COAST.

5276
05:23:48,200 --> 05:23:55,200
HE WAS ADAMANT ABOUT THIS OF .

5277
05:23:55,200 --> 05:23:58,320
I TALKED TO HIM REPEATEDLY.

5278
05:23:58,320 --> 05:24:00,760
I THOUGHT HE WAS A DAMN FOOL,

5279
05:24:00,760 --> 05:24:04,600
KNOWING HIS LOVE OF THE

5280
05:24:04,600 --> 05:24:05,200
OUTDOORS.

5281
05:24:05,200 --> 05:24:07,560
AND HE WOULD NOT, NO

5282
05:24:07,560 --> 05:24:10,200
STATISTICAL -- NO AMOUNT OF

5283
05:24:10,200 --> 05:24:10,960
STATISTICAL ARGUMENT WOULD

5284
05:24:10,960 --> 05:24:12,280
PERSUADE HIM.

5285
05:24:12,280 --> 05:24:17,640
SO WE HAD TO SURRENDER HIM TO

5286
05:24:17,640 --> 05:24:18,760
THE EAST COAST.

5287
05:24:18,760 --> 05:24:20,080
OFF HE WENT.

5288
05:24:20,080 --> 05:24:23,280
AS YOU'VE HEARD BEFORE, TO THE

5289
05:24:23,280 --> 05:24:25,000
COLD SPRING HARBOR LABORATORY

5290
05:24:25,000 --> 05:24:27,240
WHERE I SUSPECTED THAT THE

5291
05:24:27,240 --> 05:24:29,040
PRINCIPAL ATTRACTION OF THE

5292
05:24:29,040 --> 05:24:31,360
PLACE, TO HIM, WAS EASY ACCESS

5293
05:24:31,360 --> 05:24:34,720
TO THE STRIPED BASS OF LONG

5294
05:24:34,720 --> 05:24:37,280
ISLAND SOUND.

5295
05:24:37,280 --> 05:24:38,600
IT WAS ALSO EXPECTED AN

5296
05:24:38,600 --> 05:24:42,880
EARTHQUAKE OF SORTS TO OCCUR THE

5297
05:24:42,880 --> 05:24:44,600
FIRST TIME STEVE CROSSED WITH

5298
05:24:44,600 --> 05:24:45,760
J.D. WATSON, PRESIDENT OF THE

5299
05:24:45,760 --> 05:24:50,560
LAB AT THE TIME, OF COURSE.

5300
05:24:50,560 --> 05:24:54,200
TO MY KNOWLEDGE, THAT EARTHQUAKE

5301
05:24:54,200 --> 05:24:55,480
NEVER HAPPENED.

5302
05:24:55,480 --> 05:24:57,800
INSTEAD, STEVE KEPT HIS HEAD

5303
05:24:57,800 --> 05:25:02,480
DOWN, MADE GOOD USE OF THE 

5304
05:25:02,480 --> 05:25:04,600
RESOURCES AT HIS DISPOSAL, AND

5305
05:25:04,600 --> 05:25:05,960
EARNED A PROMINENT APPOINTMENT

5306
05:25:05,960 --> 05:25:07,200
AT NCI FREDERICK, THAT

5307
05:25:07,200 --> 05:25:09,680
EVENTUALLY BROUGHT HIM BACK INTO

5308
05:25:09,680 --> 05:25:12,000
MY ORBIT, A BIT BECAUSE HAROLD

5309
05:25:12,000 --> 05:25:14,520
WAS DIRECTOR OF NIH AT THE TIME,

5310
05:25:14,520 --> 05:25:16,840
AND HAD RECRUITED ME TO CHAIR

5311
05:25:16,840 --> 05:25:19,560
REVIEW OF THE INTRAMURAL PROGRAM

5312
05:25:19,560 --> 05:25:20,760
OF THE NATIONAL CANCER

5313
05:25:20,760 --> 05:25:22,640
INSTITUTE, WHICH WAS LOSING A

5314
05:25:22,640 --> 05:25:25,400
BIT OF ITS LUSTER.

5315
05:25:25,400 --> 05:25:26,960
SO, STEVE HAD BEEN AT FREDERICK

5316
05:25:26,960 --> 05:25:30,600
BY THAT TIME LONG ENOUGH TO BE

5317
05:25:30,600 --> 05:25:31,000
DISSATISFIED.

5318
05:25:31,000 --> 05:25:34,040
NOW HE SAW AN OPPORTUNITY AND

5319
05:25:34,040 --> 05:25:35,120
POUNCED.

5320
05:25:35,120 --> 05:25:39,280
HE PRESENTED ME WITH A

5321
05:25:39,280 --> 05:25:40,160
NON-NEGOTIATABLE PROPOSAL, TRUTH

5322
05:25:40,160 --> 05:25:42,680
TO POWER, I WOULD BOLSTER THE

5323
05:25:42,680 --> 05:25:45,120
RESEARCH PROGRAM AT FREDERICK TO

5324
05:25:45,120 --> 05:25:46,400
THE POINT WHERE IT WAS EQUAL TO

5325
05:25:46,400 --> 05:25:49,280
WHAT WAS GOING ON IN BETHESDA,

5326
05:25:49,280 --> 05:25:52,760
OR MOVE THE ELIGIBLE SCIENTISTS

5327
05:25:52,760 --> 05:25:55,520
AT NCI FREDERICK TO THE MAIN

5328
05:25:55,520 --> 05:25:55,880
CAMPUS.

5329
05:25:55,880 --> 05:25:56,360
DO IT, BISHOP.

5330
05:25:56,360 --> 05:25:58,800
NOW OF COURSE I COULDN'T DO IT,

5331
05:25:58,800 --> 05:26:01,240
I COULD ONLY TRY TO PERSUADE MY

5332
05:26:01,240 --> 05:26:05,920
COMMITTEE TO TRY TO DO IT, IF I

5333
05:26:05,920 --> 05:26:09,320
WAS SO DISPOSED. 

5334
05:26:09,320 --> 05:26:11,360
STEVE'S STILL IN FREDERICK.

5335
05:26:11,360 --> 05:26:13,040
DRAW WHATEVER CONCLUSION YOU

5336
05:26:13,040 --> 05:26:13,240
WISH.

5337
05:26:13,240 --> 05:26:15,080
I SUSPECT THERE ARE QUITE A FEW

5338
05:26:15,080 --> 05:26:20,320
PEOPLE WHO ARE GLAD STEVE STAYED

5339
05:26:20,320 --> 05:26:22,320
IN FREDERICK.

5340
05:26:22,320 --> 05:26:27,240
STEVE'S MOVE TO FREDERICK 

5341
05:26:27,240 --> 05:26:31,520
ALLOWED HIM TO MIMIC MARIO

5342
05:26:31,520 --> 05:26:37,200
CAPECCHI, BEING OFF THE BEATING

5343
05:26:37,200 --> 05:26:37,400
PATH.

5344
05:26:37,400 --> 05:26:39,640
HE BOUGHT A FORM AT THE FOOT OF

5345
05:26:39,640 --> 05:26:43,640
A MOUNTAIN, ALONG A NARROW AND

5346
05:26:43,640 --> 05:26:45,280
POORLY PAVED ROAD, NEAR WHERE

5347
05:26:45,280 --> 05:26:46,840
THE UNION AND CONFEDERATE ARMY

5348
05:26:46,840 --> 05:26:49,560
SKIRMISHED BEFORE THEY MOVED TO

5349
05:26:49,560 --> 05:26:51,320
ANTIETAM WHERE THEY WOULD FIGHT

5350
05:26:51,320 --> 05:26:53,840
ONE OF THE BLOODIEST BATTLES IN

5351
05:26:53,840 --> 05:26:55,120
THE HISTORY OF WARFARE.

5352
05:26:55,120 --> 05:26:57,880
IT WAS IN CONVERSATION ABOUT

5353
05:26:57,880 --> 05:26:59,600
THAT LOCALE THAT I DISCOVERED

5354
05:26:59,600 --> 05:27:03,040
STEVE IS, AMONG OTHER THINGS, AN

5355
05:27:03,040 --> 05:27:04,360
AMATEUR HISTORIAN.

5356
05:27:04,360 --> 05:27:08,320
PROBABLY NOT UP TO HIS

5357
05:27:08,320 --> 05:27:10,920
CAPABILITIES BUT NEVERTHELESS

5358
05:27:10,920 --> 05:27:11,360
ENTERTAINING.

5359
05:27:11,360 --> 05:27:12,760
THIS FARM, YOU'VE HEARD ALLUSION

5360
05:27:12,760 --> 05:27:14,960
TO THIS, WAS REPLETE WITH A

5361
05:27:14,960 --> 05:27:15,480
BARN.

5362
05:27:15,480 --> 05:27:25,680
AND I SAW THAT BARN AT THE TIME,

5363
05:27:25,680 --> 05:27:26,680
RATHER BEDRAGELLED, WITH

5364
05:27:26,680 --> 05:27:28,360
SOLIDIFIED RESIDUE OF PREVIOUS

5365
05:27:28,360 --> 05:27:30,520
OCCUPANTS AND LITTLE ELSE IN IT.

5366
05:27:30,520 --> 05:27:32,800
IN DUE COURSE THE BARN DID WHAT

5367
05:27:32,800 --> 05:27:33,720
BARNS OFTEN DO.

5368
05:27:33,720 --> 05:27:38,200
IT BURNED TO THE GROUND.

5369
05:27:38,200 --> 05:27:39,840
AH, ANOTHER OPPORTUNITY.

5370
05:27:39,840 --> 05:27:41,840
STEVE RESOLVED TO REBUILD AND TO

5371
05:27:41,840 --> 05:27:48,040
DO IT IN STYLE.  IN STYLE.

5372
05:27:48,040 --> 05:27:50,480
HE EVEN HAD THE REQUISITE

5373
05:27:50,480 --> 05:27:50,800
INSURANCE.

5374
05:27:50,800 --> 05:27:54,280
I CAN'T ACQUIESCE TO YOUR

5375
05:27:54,280 --> 05:27:55,280
SUSPICIONS.

5376
05:27:55,280 --> 05:27:58,240
YOU HEARD STEVE RECRUITED SOME

5377
05:27:58,240 --> 05:27:59,960
AMISH, KNOWN FOR TRADITIONAL

5378
05:27:59,960 --> 05:28:01,320
BARN RAISINGS, AND THEY WERE

5379
05:28:01,320 --> 05:28:02,400
HANDY IN HIS NEIGHBORHOOD.

5380
05:28:02,400 --> 05:28:04,560
SO HE GOT HIS BARN RAISING,

5381
05:28:04,560 --> 05:28:11,360
START TO FINISH, IN ONE DAY.

5382
05:28:11,360 --> 05:28:16,720
THE BARN IS A SPLENDID EDIFICE,

5383
05:28:16,720 --> 05:28:18,400
DEVOID OF ANYTHING RESEMBLING A

5384
05:28:18,400 --> 05:28:21,240
FARM ANIMAL OR HAY, AT LEAST

5385
05:28:21,240 --> 05:28:24,320
LAST TIME I VISITED, STEVE WILL

5386
05:28:24,320 --> 05:28:25,840
TELL YOU GROUCHILY, SOME YEARS

5387
05:28:25,840 --> 05:28:28,600
AGO NOW.

5388
05:28:28,600 --> 05:28:32,000
NOW, THE BARN RAISED STEVE, TO

5389
05:28:32,000 --> 05:28:33,320
OCCUPY HIM DURING RETIREMENT.

5390
05:28:33,320 --> 05:28:36,080
I DON'T KNOW WHAT STEVE PLANS TO

5391
05:28:36,080 --> 05:28:40,640
DO WITH ALL OF HIS NEWFOUND FREE

5392
05:28:40,640 --> 05:28:42,280
TIME, BUT I'M CERTAIN THAT SOME

5393
05:28:42,280 --> 05:28:46,400
OF IT WILL BE DEVOTED TO THE ROD

5394
05:28:46,400 --> 05:28:47,080
AND REEL.

5395
05:28:47,080 --> 05:28:49,920
NOW, YOU'VE SEEN EVIDENCE OF

5396
05:28:49,920 --> 05:28:52,040
THIS ALREADY, SO I TOOK OUT MY

5397
05:28:52,040 --> 05:28:53,600
SLIDES TO DOCUMENT IT.

5398
05:28:53,600 --> 05:28:56,920
BUT STEVE, AND THIS IS NO

5399
05:28:56,920 --> 05:28:59,040
SURPRISE, STEVE PREFERS BIG

5400
05:28:59,040 --> 05:29:09,560
FISH, REALLY BIG FISH.

5401
05:29:09,560 --> 05:29:11,360
AND HE'S TAKEN SOME OUT OF THE

5402
05:29:11,360 --> 05:29:12,280
CHESAPEAKE AND THE RIVER IN THE

5403
05:29:12,280 --> 05:29:16,520
HEART OF THE ALASKA WHICH HE

5404
05:29:16,520 --> 05:29:17,360
VISITED REPEATEDLY OVER THE

5405
05:29:17,360 --> 05:29:18,880
YEARS AND SENT ME A PHOTOGRAPH

5406
05:29:18,880 --> 05:29:20,680
OF THE TERRAIN, WITH THE RIVER

5407
05:29:20,680 --> 05:29:23,760
RUNNING THROUGH IT, SO TO SPEAK.

5408
05:29:23,760 --> 05:29:27,560
AND IT'S JUST VAST, AS FAR AS

5409
05:29:27,560 --> 05:29:32,760
YOU CAN SEE, EMPTY WILDERNESS.

5410
05:29:32,760 --> 05:29:39,360
AND IT'S AWE INSPIRING.

5411
05:29:39,360 --> 05:29:41,800
AND I THINK IT SUGGESTED TO ME

5412
05:29:41,800 --> 05:29:47,360
HOW STEVE MAY VIEW HIS

5413
05:29:47,360 --> 05:29:48,000
RETIREMENT, UNBOUNDED

5414
05:29:48,000 --> 05:29:48,320
OPPORTUNITY.

5415
05:29:48,320 --> 05:29:50,440
WHERE IT WILL LEAD HIM, I CANNOT

5416
05:29:50,440 --> 05:29:50,720
IMAGINE.

5417
05:29:50,720 --> 05:29:55,480
I CAN ONLY PREDICT HE WILL NOT

5418
05:29:55,480 --> 05:29:59,640
LIE IDLE.

5419
05:29:59,640 --> 05:30:00,600
SO, HERE'S HUGE CONGRATULATIONS

5420
05:30:00,600 --> 05:30:03,480
ON THE COMPLETION OF A SPLENDID

5421
05:30:03,480 --> 05:30:05,400
CAREER, I WISH YOU THE BEST IN

5422
05:30:05,400 --> 05:30:07,520
WHAT IS TO COME.

5423
05:30:07,520 --> 05:30:08,040
THANK YOU.

5424
05:30:08,040 --> 05:30:10,480
[APPLAUSE]

5425
05:30:10,480 --> 05:30:18,560
 

5426
05:30:18,560 --> 05:30:19,720
>>THANK YOU VERY MUCH.

5427
05:30:19,720 --> 05:30:23,960
ANOTHER TOUGH ACT TO FOLLOW.

5428
05:30:23,960 --> 05:30:27,240
SO, IT'S A PLEASURE TO WELCOME

5429
05:30:27,240 --> 05:30:31,200
MARY KEARNEY AS OUR SPEAKER,

5430
05:30:31,200 --> 05:30:37,240
CURRENTLY DRP DEPUTY DIRECTOR

5431
05:30:37,240 --> 05:30:43,920
WITH WEI SHAU HU WHO YOU HEARD

5432
05:30:43,920 --> 05:30:44,920
FROM, PIONEERING ASSAYS,

5433
05:30:44,920 --> 05:30:47,920
COLLABORATED WITH STEVE ON WORK

5434
05:30:47,920 --> 05:30:50,560
ON HIV RESERVOIRS.

5435
05:30:50,560 --> 05:30:54,040
 

5436
05:30:54,040 --> 05:30:57,040
>>THANK YOU.

5437
05:30:57,040 --> 05:30:57,280
OKAY.

5438
05:30:57,280 --> 05:30:59,160
WELL, I DIDN'T GET THE MEMO THAT

5439
05:30:59,160 --> 05:31:02,880
WE HAD TO INCLUDE FISHING

5440
05:31:02,880 --> 05:31:04,600
STORIES, LIKE JEFF DID, I THINK

5441
05:31:04,600 --> 05:31:06,480
IT'S BECAUSE EVERYONE KNOWS I'VE

5442
05:31:06,480 --> 05:31:08,040
NOT BEEN FISHING WITH STEVE.

5443
05:31:08,040 --> 05:31:10,840
I HAVE HEARD MANY FISHING

5444
05:31:10,840 --> 05:31:13,480
STORIES, HOWEVER, AT OUR MANY

5445
05:31:13,480 --> 05:31:15,800
DINNERS TOGETHER, OVER THE YEARS

5446
05:31:15,800 --> 05:31:16,440
AT OUR FAVORITE RESTAURANT WITH

5447
05:31:16,440 --> 05:31:19,400
ALL OF THE P.I.s AND INVITED

5448
05:31:19,400 --> 05:31:22,240
SPEAKERS, AND THE ONLY ONE I

5449
05:31:22,240 --> 05:31:25,520
RECALL IS ONE THAT INCLUDED A

5450
05:31:25,520 --> 05:31:27,480
NEW FISHING BOAT THAT SOMEHOW

5451
05:31:27,480 --> 05:31:30,240
INCLUDED USING A PINK OR PURPLE

5452
05:31:30,240 --> 05:31:31,560
CONDOM IN SOME WAY.

5453
05:31:31,560 --> 05:31:34,480
THE STORY I HEARD WAS THAT WHEN

5454
05:31:34,480 --> 05:31:38,520
HIS WIFE FOUND A CONDOM IN HIS

5455
05:31:38,520 --> 05:31:40,400
PANTS POCKET, IT DIDN'T OCCUR TO

5456
05:31:40,400 --> 05:31:43,640
HER MAYBE HER HUSBAND WAS HAVING

5457
05:31:43,640 --> 05:31:44,360
AN AFFAIR.

5458
05:31:44,360 --> 05:31:47,920
INSTEAD SHE  THOUGHT WHAT KIND

5459
05:31:47,920 --> 05:31:49,640
OF NEW-FANGLED FISHING THING IS

5460
05:31:49,640 --> 05:31:50,120
HE DOING NOW.

5461
05:31:50,120 --> 05:31:50,480
[LAUGHTER]

5462
05:31:50,480 --> 05:31:55,560
WE WOULD ALL COME TO THE SAME

5463
05:31:55,560 --> 05:31:57,800
CONCLUSION IF WE FOUND THAT IN

5464
05:31:57,800 --> 05:31:59,320
THE PANT POCKET OR OFFICE OR

5465
05:31:59,320 --> 05:31:59,560
SOMEWHERE.

5466
05:31:59,560 --> 05:32:01,760
I'M GOING TO TELL YOU ABOUT MY

5467
05:32:01,760 --> 05:32:04,360
COLLABORATIONS WITH STEVE AND HE

5468
05:32:04,360 --> 05:32:06,600
HAS SUPPORTED ME SO MUCH IN MY

5469
05:32:06,600 --> 05:32:08,800
CAREER HERE AT THE DRP OVER THE

5470
05:32:08,800 --> 05:32:11,040
LAST 20 YEARS.

5471
05:32:11,040 --> 05:32:14,040
AND I TITLED IT CLONAL

5472
05:32:14,040 --> 05:32:15,000
EXPANSIONS WITH HIV DRP BECAUSE

5473
05:32:15,000 --> 05:32:21,680
THEY ARE NOT JUST WITH STEVE BUT

5474
05:32:21,680 --> 05:32:24,080
THEY INCLUDE COLLABORATIONS WITH

5475
05:32:24,080 --> 05:32:26,200
JOHN AND FRANK AND MANY OTHERS

5476
05:32:26,200 --> 05:32:28,280
IN THE HIV DRP.

5477
05:32:28,280 --> 05:32:34,600
SO, WHILE STEVE WAS STUDYING

5478
05:32:34,600 --> 05:32:35,520
TRANSCRIPTASE AND INTEGRASE, I

5479
05:32:35,520 --> 05:32:41,040
STARTED IN 2001 IN JOHN 

5480
05:32:41,040 --> 05:32:41,920
HAWKINS'S LAB, PERSISTENCE

5481
05:32:41,920 --> 05:32:45,240
DURING THERAPY.

5482
05:32:45,240 --> 05:32:48,040
WHEN INDIVIDUALS INITIATE ART,

5483
05:32:48,040 --> 05:32:49,920
LEVELS OF PLASMA VIREMIA DROP

5484
05:32:49,920 --> 05:32:51,440
PRECIPITOUSLY AND DECLINED TO

5485
05:32:51,440 --> 05:32:53,640
LEVELS THAT WERE BELOW DETECTION

5486
05:32:53,640 --> 05:32:56,480
WITH CLINICAL ASSAYS.

5487
05:32:56,480 --> 05:32:59,440
SO, IN JOHN COFFIN'S LAB, PALMER

5488
05:32:59,440 --> 05:33:00,960
DEVELOPED AN ASSAY WHERE THEY

5489
05:33:00,960 --> 05:33:06,760
COULD MEASURE LOW LEVELS OF

5490
05:33:06,760 --> 05:33:07,960
PLASMA VIREMIA, AND PLASMA

5491
05:33:07,960 --> 05:33:10,480
VIREMIA PERSISTS IN MOST

5492
05:33:10,480 --> 05:33:12,000
INDIVIDUALS AROUND A SINGLE

5493
05:33:12,000 --> 05:33:15,200
VIRUS PARTICLE PER mL OF

5494
05:33:15,200 --> 05:33:17,800
PLASMA, FOLLOWED UP WITH STUDIES

5495
05:33:17,800 --> 05:33:25,400
IN JOHN'S LAB I COLLABORATED ON 

5496
05:33:25,400 --> 05:33:26,720
WHERE THE THEY MEASURED DNA

5497
05:33:26,720 --> 05:33:28,200
COPIES, MUCH HIGHER THAN NUMBER

5498
05:33:28,200 --> 05:33:31,280
OF RNA COPIES, SO DNA COPIES IN

5499
05:33:31,280 --> 05:33:32,560
INDIVIDUALS ON ART WILL REFLECT

5500
05:33:32,560 --> 05:33:35,040
NUMBER OF INFECTED CELLS THAT

5501
05:33:35,040 --> 05:33:39,280
PERSIST IN THESE INDIVIDUALS.

5502
05:33:39,280 --> 05:33:41,000
SO, WHERE THE COLLABORATION WITH

5503
05:33:41,000 --> 05:33:42,880
STEVE BEGAN WAS WHERE WE STARTED

5504
05:33:42,880 --> 05:33:46,480
TO STUDY GENETICS OF THE DNA, OR

5505
05:33:46,480 --> 05:33:47,680
PROVIRUSES THAT PERSISTED IN

5506
05:33:47,680 --> 05:33:49,680
INDIVIDUALS IN THERAPY, I'LL

5507
05:33:49,680 --> 05:33:53,920
START WITH SHOWING SLIDES

5508
05:33:53,920 --> 05:33:55,680
REPRESENTED AT THE THINK TANK IN

5509
05:33:55,680 --> 05:33:58,000
2012, BECAUSE THIS IS WHEN THE

5510
05:33:58,000 --> 05:34:00,720
COLLABORATION, MY COLLABORATIONS

5511
05:34:00,720 --> 05:34:04,320
WITH STEVE, BEGAN.

5512
05:34:04,320 --> 05:34:07,520
SO, IN THIS TALK I SHOWED

5513
05:34:07,520 --> 05:34:08,720
GENETICS OF SINGLE PROVIRAL

5514
05:34:08,720 --> 05:34:09,800
SEQUENCES IN INDIVIDUALS WHO HAD

5515
05:34:09,800 --> 05:34:14,080
BEEN ON ART FOR MANY YEARS, AND

5516
05:34:14,080 --> 05:34:15,160
COLLECTED LONGITUDINAL SAMPLES,

5517
05:34:15,160 --> 05:34:20,400
IN COLLABORATION WITH FANG  AND

5518
05:34:20,400 --> 05:34:21,760
-- FRANK AND HIS LAB.

5519
05:34:21,760 --> 05:34:23,280
WE CAME TO EIGHT FINDINGS.

5520
05:34:23,280 --> 05:34:27,960
THE FIRST IS WE FOUND THAT

5521
05:34:27,960 --> 05:34:31,360
IDENTICAL SEQUENCES WERE IN

5522
05:34:31,360 --> 05:34:32,240
PBMCs, IDENTICAL PROVIRAL

5523
05:34:32,240 --> 05:34:34,640
SEQUENCES IN DONORS ON LONG-TERM

5524
05:34:34,640 --> 05:34:37,920
ART, YOU SAW SOME FROM A

5525
05:34:37,920 --> 05:34:38,920
PRESENTATION EARLIER TODAY

5526
05:34:38,920 --> 05:34:39,920
WORKING ON SIMILAR STUDIES AT

5527
05:34:39,920 --> 05:34:41,280
THE TIME.

5528
05:34:41,280 --> 05:34:42,760
THESE WERE LONGITUDINAL SAMPLES

5529
05:34:42,760 --> 05:34:44,960
IN THIS INDIVIDUAL, SAMPLE

5530
05:34:44,960 --> 05:34:48,160
COLLECTED 27 DAYS ON ART, FOUR

5531
05:34:48,160 --> 05:34:51,760
YEARS AND NINE YEARS ON ART.

5532
05:34:51,760 --> 05:34:53,520
YOU CAN SEE POPULATIONS, ONE

5533
05:34:53,520 --> 05:34:55,440
CIRCLES DOWN AT THE BOTTOM,

5534
05:34:55,440 --> 05:35:02,360
WHERE I HAD CAL PRO -- WITH

5535
05:35:02,360 --> 05:35:05,960
IDENTICAL PROVIRAL SEQUENCES,

5536
05:35:05,960 --> 05:35:07,200
SOME CONTAINED HYPERMUTANTS, WE

5537
05:35:07,200 --> 05:35:09,360
KNEW SOME THAT PERSISTED WERE

5538
05:35:09,360 --> 05:35:10,680
NOT REPLICATION COMPETENT, AND

5539
05:35:10,680 --> 05:35:12,680
WE FOUND NO EVIDENCE FOR

5540
05:35:12,680 --> 05:35:13,880
EVOLUTION, VIRAL EVOLUTION, ON

5541
05:35:13,880 --> 05:35:15,000
ART.

5542
05:35:15,000 --> 05:35:17,040
WHEN YOU SEE EVOLUTION, BRANCHES

5543
05:35:17,040 --> 05:35:18,560
GET LONGER AND LONGER,

5544
05:35:18,560 --> 05:35:20,560
LONGITUDINAL SAMPLES, HERE YOU

5545
05:35:20,560 --> 05:35:22,200
CAN SEE THAT SEQUENCES COLLECTED

5546
05:35:22,200 --> 05:35:24,400
NINE YEARS ON ART IN THE

5547
05:35:24,400 --> 05:35:26,840
DIAMONDS NOT ON LONGER BRANCHES

5548
05:35:26,840 --> 05:35:30,320
THAN THOSE COLLECTED 27 DAYS ON

5549
05:35:30,320 --> 05:35:31,840
ART IN THE CIRCLES.

5550
05:35:31,840 --> 05:35:36,120
SO, WE ALSO FOUND THERE WAS NO

5551
05:35:36,120 --> 05:35:40,280
CLUSTERING OF SEQUENCES BY

5552
05:35:40,280 --> 05:35:41,680
SOURCE, SO THERE WERE THE

5553
05:35:41,680 --> 05:35:43,440
SEQUENCES THAT WE COLLECTED IN

5554
05:35:43,440 --> 05:35:45,960
THE PLASMA, RNA SEQUENCES IN

5555
05:35:45,960 --> 05:35:46,840
PLASMA, AND SEQUENCES WE

5556
05:35:46,840 --> 05:35:50,160
COLLECTED IN CELLS, DNA

5557
05:35:50,160 --> 05:35:54,840
SEQUENCES, WERE NOT SEGREGATED

5558
05:35:54,840 --> 05:35:57,440
SUGGESTING  PLASMA VIRUSES WAS

5559
05:35:57,440 --> 05:35:59,440
COMING FROM INFECTED CELLS IN

5560
05:35:59,440 --> 05:36:05,120
THE BLOOD WITH YEARS ON ART, AND

5561
05:36:05,120 --> 05:36:07,440
IDENTICAL SEQUENCE ON ART

5562
05:36:07,440 --> 05:36:08,280
MATCHED PRESENCE SHORTLY AFTER

5563
05:36:08,280 --> 05:36:12,880
ART, ONE OF THESE A CIRCLE 14

5564
05:36:12,880 --> 05:36:15,160
DAYS AFTER ART SO POPULATIONS OF

5565
05:36:15,160 --> 05:36:17,280
IDENTICAL SEQUENCES SEEM TO

5566
05:36:17,280 --> 05:36:21,320
PERSIST FOR THE DURATION OF

5567
05:36:21,320 --> 05:36:21,920
TREATMENT.

5568
05:36:21,920 --> 05:36:28,120
WE ALSO FOUND THAT IF WE

5569
05:36:28,120 --> 05:36:29,520
SAMPLED, OPEN CIRCLES, AT EARLY

5570
05:36:29,520 --> 05:36:32,360
TIME POINT IN PRE-THERAPY AND

5571
05:36:32,360 --> 05:36:35,000
YEARS LATER BEFORE STARTING ART

5572
05:36:35,000 --> 05:36:37,400
WE SAW CLEAR EVOLUTION, SO THREE

5573
05:36:37,400 --> 05:36:38,920
SAMPLES BEFORE STARTING ART IN

5574
05:36:38,920 --> 05:36:42,320
OPEN CIRCLES SO WE CAN SEE

5575
05:36:42,320 --> 05:36:44,960
DISTINCT POPULATIONS, SO TWO

5576
05:36:44,960 --> 05:36:46,480
SAMPLES THREE YEARS APART

5577
05:36:46,480 --> 05:36:48,880
WITHOUT ART CLEAR EVOLUTION, BUT

5578
05:36:48,880 --> 05:36:52,320
WHEN COLLECTED LONGITUDINALLY ON

5579
05:36:52,320 --> 05:36:54,280
ART THERE WAS NO DIVERGENT OVER

5580
05:36:54,280 --> 05:36:56,000
3 YEARS WITH ART AND SEQUENCES

5581
05:36:56,000 --> 05:36:58,640
THAT PERSISTED MANY YEARS ON ART

5582
05:36:58,640 --> 05:37:00,720
IN THE CELLS UP TO 9 YEARS WERE

5583
05:37:00,720 --> 05:37:03,960
THE SAME AS SEQUENCES THERE JUST

5584
05:37:03,960 --> 05:37:05,320
BEFORE INITIATING ART, THREE

5585
05:37:05,320 --> 05:37:06,600
SEQUENCES THAT REALLY DOMINATE

5586
05:37:06,600 --> 05:37:10,000
THE POPULATION FOR YEARS AND

5587
05:37:10,000 --> 05:37:11,880
YEARS ON ART.

5588
05:37:11,880 --> 05:37:12,960
IDENTICAL SEQUENCES THAT WERE

5589
05:37:12,960 --> 05:37:15,480
FOUND IN THE PLASMA DID NOT

5590
05:37:15,480 --> 05:37:17,880
ALWAYS MATCH IDENTICAL SEQUENCES

5591
05:37:17,880 --> 05:37:19,680
THAT PERSISTED IN THE CELLS,

5592
05:37:19,680 --> 05:37:22,160
SUGGESTING THAT NOT ALL OF THE

5593
05:37:22,160 --> 05:37:23,840
INFECTED CELLS CONTRIBUTED TO

5594
05:37:23,840 --> 05:37:26,760
PERSISTENT VIREMIA YOU SEE

5595
05:37:26,760 --> 05:37:28,120
DURING TREATMENT.

5596
05:37:28,120 --> 05:37:29,640
BUT WHAT WE FOUND TO BE MOST

5597
05:37:29,640 --> 05:37:31,960
INTERESTING IS THAT SOME OF

5598
05:37:31,960 --> 05:37:34,120
THESE POPULATIONS OF IDENTICAL

5599
05:37:34,120 --> 05:37:38,280
SEQUENCES WERE DUE TO

5600
05:37:38,280 --> 05:37:39,600
HYPERMUTANTS STOP CODONS LEADING

5601
05:37:39,600 --> 05:37:45,840
TO COLLABORATION WITH STEVE WHO

5602
05:37:45,840 --> 05:37:51,000
DEVELOPED ASSAY WITH SHAU HU,

5603
05:37:51,000 --> 05:37:53,280
THE ONLY WAY THEY COULD HAVE

5604
05:37:53,280 --> 05:37:54,720
ARISEN TO BE IDENTICAL AFTER

5605
05:37:54,720 --> 05:37:56,880
MANY YEARS ON ART WOULD BE IF A

5606
05:37:56,880 --> 05:37:59,880
SINGLE CELL WAS INFECTED WITH

5607
05:37:59,880 --> 05:38:01,280
DEFECTIVE PROVIRUS AND CLONALLY

5608
05:38:01,280 --> 05:38:01,760
EXPANDED.

5609
05:38:01,760 --> 05:38:05,600
AND SO WHAT WE HAD SUMMARIZED AT

5610
05:38:05,600 --> 05:38:07,840
THIS MEETING IN 2012 IN OUR

5611
05:38:07,840 --> 05:38:09,720
CONCLUSIONS LED TO REALLY THIS

5612
05:38:09,720 --> 05:38:11,200
COLLABORATION WITH STEVE HUGHES

5613
05:38:11,200 --> 05:38:13,560
THAT LED TO SEMINAL PAPER THAT

5614
05:38:13,560 --> 05:38:15,720
CHANGED OUR UNDERSTANDING OF HIV

5615
05:38:15,720 --> 05:38:17,000
PERSISTENCE, PUBLISHED IN

5616
05:38:17,000 --> 05:38:19,240
"SCIENCE" A COUPLE YEARS LATER.

5617
05:38:19,240 --> 05:38:21,520
SO WE FOUND WHAT WE SUMMARIZED

5618
05:38:21,520 --> 05:38:26,000
THAT THERE'S A RESTRICTED GROUP

5619
05:38:26,000 --> 05:38:27,520
OF HIV VARIANTS, DETECTED FOR

5620
05:38:27,520 --> 05:38:29,400
YEARS ON SUPPRESSIVE ART IN

5621
05:38:29,400 --> 05:38:31,480
PLASMA AND BLOOD CELLS,

5622
05:38:31,480 --> 05:38:32,920
SUGGESTING THAT RESULT FROM

5623
05:38:32,920 --> 05:38:35,520
EXPAND OF ONE OR MORE INFECTED

5624
05:38:35,520 --> 05:38:36,640
CELLS, THE IDENTICAL SEQUENCES

5625
05:38:36,640 --> 05:38:39,800
WERE NOT ON LONGER BRANCHES

5626
05:38:39,800 --> 05:38:42,120
WHICH SUGGESTED THAT CELLS WERE

5627
05:38:42,120 --> 05:38:43,960
INFECTED BEFORE INITIATING

5628
05:38:43,960 --> 05:38:45,160
THERAPY AND THAT THESE CELLS ARE

5629
05:38:45,160 --> 05:38:47,480
THE SOURCE OF THESE IDENTICAL

5630
05:38:47,480 --> 05:38:48,360
SEQUENCES SO THEY PERSISTED FOR

5631
05:38:48,360 --> 05:38:52,160
ALL OF THESE YEARS ON ART LIKE

5632
05:38:52,160 --> 05:38:53,680
CLONAL EXPANSION.

5633
05:38:53,680 --> 05:38:54,600
IDENTICAL SEQUENCES MATCH

5634
05:38:54,600 --> 05:38:57,640
VARIANTS THAT WERE PRESENT

5635
05:38:57,640 --> 05:39:00,480
SHORTLY AFTER INITIATING ART AND

5636
05:39:00,480 --> 05:39:02,680
SO THIS LED TO A LOT OF STUDIES

5637
05:39:02,680 --> 05:39:05,880
WHERE WE DEMONSTRATED THAT ART

5638
05:39:05,880 --> 05:39:07,160
WAS FULLY SUPPRESSIVE, FULLY

5639
05:39:07,160 --> 05:39:11,000
POTENT, THERE WAS NO ONGOING

5640
05:39:11,000 --> 05:39:12,880
REPLICATION DURING TREATMENT.

5641
05:39:12,880 --> 05:39:17,360
SO, THOSE STUDIES AND ONE OF

5642
05:39:17,360 --> 05:39:18,920
THOSE PATIENTS WAS ACTUALLY

5643
05:39:18,920 --> 05:39:20,280
PATIENT 1.

5644
05:39:20,280 --> 05:39:28,000
AND SO THAT PATIENT AND FOUR 

5645
05:39:28,000 --> 05:39:30,360
OTHERS WERE USED TO MAP

5646
05:39:30,360 --> 05:39:33,000
INTEGRATION SITES AND FOUND

5647
05:39:33,000 --> 05:39:34,880
IDENTICAL SEQUENCES HAD

5648
05:39:34,880 --> 05:39:37,920
IDENTICAL INTEGRATION SITES, SO

5649
05:39:37,920 --> 05:39:42,200
YOU SEE THIS PIECHART MANY TIMES

5650
05:39:42,200 --> 05:39:44,520
TODAY, THIS IS THE DATA FROM ALL

5651
05:39:44,520 --> 05:39:47,440
OF THE PATIENT 1 AND ALL OF THE

5652
05:39:47,440 --> 05:39:48,800
PATIENTS COLLECTIVELY TOGETHER

5653
05:39:48,800 --> 05:39:51,280
SHOWING THAT SOME OF THE SITES

5654
05:39:51,280 --> 05:39:53,000
DETECTED ONLY ONCE, MANY OF THEM

5655
05:39:53,000 --> 05:39:54,200
ARE DETECTED OVER AND OVER

5656
05:39:54,200 --> 05:39:56,520
AGAIN, AND SOME OF THEM ARE

5657
05:39:56,520 --> 05:39:57,720
VERY, VERY LARGE CLONES IN THESE

5658
05:39:57,720 --> 05:40:01,240
INDIVIDUALS AND THIS IS WHAT LED

5659
05:40:01,240 --> 05:40:03,680
TO MY FIRST COLLABORATION WITH

5660
05:40:03,680 --> 05:40:05,880
STEVE, WITH THIS INTEGRATION

5661
05:40:05,880 --> 05:40:08,080
SITE ANALYSIS, SOME FOLKS ARE

5662
05:40:08,080 --> 05:40:17,080
MISSING IN THIS PICTURE 

5663
05:40:17,080 --> 05:40:19,320
INCLUDING FRANZISKA SIMONETTI.

5664
05:40:19,320 --> 05:40:21,840
THE OBVIOUS NEXT QUESTION WAS

5665
05:40:21,840 --> 05:40:24,680
CAN THESE CLONES CARRY

5666
05:40:24,680 --> 05:40:25,800
REPLICATION CONFIDENT VIRUS?

5667
05:40:25,800 --> 05:40:27,640
"SCIENCE" PAPER SHOWED HIV

5668
05:40:27,640 --> 05:40:29,280
PERSISTED BECAUSE CELLS INFECTED

5669
05:40:29,280 --> 05:40:30,720
BEFORE INITIATING ART COULD

5670
05:40:30,720 --> 05:40:32,800
UNDERGO CLONAL EXPANSION AND

5671
05:40:32,800 --> 05:40:34,120
RESULTED IN RENEWABLE --

5672
05:40:34,120 --> 05:40:35,440
CONTINUOUS RENEWABLE SOURCE OF

5673
05:40:35,440 --> 05:40:36,560
INFECTED CELLS DURING TREATMENT

5674
05:40:36,560 --> 05:40:39,280
DESPITE THE FACT THERE WAS NO

5675
05:40:39,280 --> 05:40:40,760
ONGOING VIRAL REPLICATION BUT

5676
05:40:40,760 --> 05:40:43,720
THE OBVIOUS QUESTION WAS, CAN

5677
05:40:43,720 --> 05:40:45,160
THESE CLONES CARRY REPLICATION

5678
05:40:45,160 --> 05:40:47,920
COMPETENT PROVIRUSES, AND I WILL

5679
05:40:47,920 --> 05:40:49,880
SAY THAT I THINK -- IF I HAD TO

5680
05:40:49,880 --> 05:40:51,200
GUESS THE BULK OF THE PEOPLE IN

5681
05:40:51,200 --> 05:40:52,520
THE ROOM, CONVERSATIONS I HAD,

5682
05:40:52,520 --> 05:40:56,120
DID NOT SEEM TO THINK THEY COULD

5683
05:40:56,120 --> 05:41:01,360
CARRY REPLICATION COMPETENT

5684
05:41:01,360 --> 05:41:05,200
PROVIRUSES BUT FRANZISKA IN 

5685
05:41:05,200 --> 05:41:06,840
COLLABORATION DID SHOW THAT

5686
05:41:06,840 --> 05:41:12,080
IN -- FIRST TO SHOW CLONES EVEN

5687
05:41:12,080 --> 05:41:14,600
VERY LARGE CLONES WERE

5688
05:41:14,600 --> 05:41:16,040
REPLICATION COMPETENT AND SOURCE

5689
05:41:16,040 --> 05:41:19,240
OF PLASMA VIREMIA IN THIS

5690
05:41:19,240 --> 05:41:20,160
INDIVIDUAL.

5691
05:41:20,160 --> 05:41:21,400
THIS PAPER WAS FOLLOWED BY

5692
05:41:21,400 --> 05:41:27,080
ANOTHER PAPER IN JOHN MELLOR'S

5693
05:41:27,080 --> 05:41:30,160
LAB, FOUND THE SAME IN FIVE

5694
05:41:30,160 --> 05:41:31,640
PATIENTS, IN THESE INDIVIDUALS

5695
05:41:31,640 --> 05:41:33,760
REPLICATION COMPETENT PROVIRUSES

5696
05:41:33,760 --> 05:41:35,800
WERE THE SOURCE OF PERSISTENT

5697
05:41:35,800 --> 05:41:38,440
VIREMIA DURING ART AND BOB TOLD

5698
05:41:38,440 --> 05:41:40,960
YOU TODAY SOMETIMES IT APPEARS,

5699
05:41:40,960 --> 05:41:42,320
OFTENTIMES, THESE CELLS MAY NOT

5700
05:41:42,320 --> 05:41:46,480
BE THE SOURCE OF VIRAL REBOUND

5701
05:41:46,480 --> 05:41:49,960
BACKUP IT'S NOT KNOWN IN THESE

5702
05:41:49,960 --> 05:41:50,760
INDIVIDUALS WHETHER THE CLONES

5703
05:41:50,760 --> 05:41:54,040
WOULD HAVE BEEN A SOURCE OF

5704
05:41:54,040 --> 05:41:56,320
PERSISTENT VIREMIA HAD THEY

5705
05:41:56,320 --> 05:41:57,320
STOPPED ART SO MORE STUDIES

5706
05:41:57,320 --> 05:42:05,320
SHOULD BE DONE ON THAT.

5707
05:42:05,320 --> 05:42:08,480
STEVE SAID HOW DO INFECTED CELL

5708
05:42:08,480 --> 05:42:09,320
CLONES PERSIST WITH REPLICATION

5709
05:42:09,320 --> 05:42:10,880
COMPETENT VIRUS, WE KNOW THEY

5710
05:42:10,880 --> 05:42:12,320
ARE THE SOURCE OF PERSISTENT

5711
05:42:12,320 --> 05:42:13,840
VIREMIA BECAUSE WE CAN DETECT

5712
05:42:13,840 --> 05:42:16,120
VIREMIA IN THESE INDIVIDUALS, WE

5713
05:42:16,120 --> 05:42:17,760
CAN SEQUENCE THE VIRUS, IT

5714
05:42:17,760 --> 05:42:19,080
MATCHES THE PROVIRUS IN THE

5715
05:42:19,080 --> 05:42:20,080
LARGE EXPANDED CLONES, SO WE

5716
05:42:20,080 --> 05:42:22,200
KNOW THAT THEY ARE NOT BLATANTLY

5717
05:42:22,200 --> 05:42:24,560
INFECTED, WE KNOW THEY ARE

5718
05:42:24,560 --> 05:42:25,360
PRODUCING VIRUS PARTICLES, WE

5719
05:42:25,360 --> 05:42:27,440
CAN DETECT THEM IN THE BLOOD AND

5720
05:42:27,440 --> 05:42:29,240
IN SOME CASES CAN DETECT THEM AT

5721
05:42:29,240 --> 05:42:33,200
FAIRLY HIGH LEVELS IN THE BLOOD.

5722
05:42:33,200 --> 05:42:35,560
SO, WE FORMED HYPOTHESIS AND

5723
05:42:35,560 --> 05:42:39,800
MADE THIS SLIDE, IT WAS STEVE'S

5724
05:42:39,800 --> 05:42:40,120
IDEA.

5725
05:42:40,120 --> 05:42:42,000
AND USING THESE EVIL GUYS TO

5726
05:42:42,000 --> 05:42:44,000
SHOW CELL CLONE WITH A

5727
05:42:44,000 --> 05:42:49,120
REPLICATION COMPETENT VIRUS, IN

5728
05:42:49,120 --> 05:42:50,480
THIS CASE EMB1 VIRUS, WHICH YOU

5729
05:42:50,480 --> 05:42:53,600
HEARD ABOUT, IT MUST BE A SMALL

5730
05:42:53,600 --> 05:42:55,800
FRACTION OF THE CELLS IN THE

5731
05:42:55,800 --> 05:42:58,720
CLONE THAT HAVE ACTIVE

5732
05:42:58,720 --> 05:43:01,560
PROVIRUSES, MAKING VIRAL RNA,

5733
05:43:01,560 --> 05:43:02,680
THERE ARE VIRUS PARTICLES WE CAN

5734
05:43:02,680 --> 05:43:07,800
DETECT IN THE BLOOD, CELLS

5735
05:43:07,800 --> 05:43:08,800
LIKELY DIE, THE VIRUS THEY ARE

5736
05:43:08,800 --> 05:43:11,000
PRODUCING IS GOING TO KILL THE

5737
05:43:11,000 --> 05:43:16,400
CELLS BUT WHEN THEY DIE OTHERS

5738
05:43:16,400 --> 05:43:18,120
CELLS MUST BE REACTIVATE,

5739
05:43:18,120 --> 05:43:24,160
PROVIRUS ANYWAY, TO PRODUCE MORE

5740
05:43:24,160 --> 05:43:26,040
VIRAL, IT PERSISTS OVER

5741
05:43:26,040 --> 05:43:26,600
LONGITUDINAL SAMPLES, THOSE

5742
05:43:26,600 --> 05:43:28,200
CELLS THAT ARE STILL EXISTING

5743
05:43:28,200 --> 05:43:29,960
THAT ARE NOT PRODUCING VIRAL RNA

5744
05:43:29,960 --> 05:43:34,920
BECAUSE THEY HAVE LATENT

5745
05:43:34,920 --> 05:43:37,520
PROVIRUSES CONTINUE TO DIVIDE.

5746
05:43:37,520 --> 05:43:43,080
WE SET OUT TO ADDRESS THIS

5747
05:43:43,080 --> 05:43:44,960
HYPOTHESIS, WE DEVELOPED AN

5748
05:43:44,960 --> 05:43:47,600
ASSAY WHERE WE COULD DETECT

5749
05:43:47,600 --> 05:43:48,800
POPULATIONS OF EXPANDED CELL

5750
05:43:48,800 --> 05:43:54,720
CLONES WITH IDENTICAL PROVIRUS,

5751
05:43:54,720 --> 05:43:56,880
COULD ASSAY CELLS DIRECTLY FROM

5752
05:43:56,880 --> 05:43:58,320
THE INDIVIDUALS WITHOUT

5753
05:43:58,320 --> 05:43:59,200
CULTURING THEM, WITHOUT

5754
05:43:59,200 --> 05:44:02,480
MANIPULATING THEM IN ANY WAY,

5755
05:44:02,480 --> 05:44:04,680
DIRECTLY FROM THE DONORS, AND

5756
05:44:04,680 --> 05:44:06,960
DETERMINE WHETHER OR NOT THEY

5757
05:44:06,960 --> 05:44:09,720
HAD VIRAL RNA.

5758
05:44:09,720 --> 05:44:12,320
AND THEN THESE CLONES ATTACKED

5759
05:44:12,320 --> 05:44:14,160
PROVIRUSES, VIRAL RNA IS

5760
05:44:14,160 --> 05:44:16,040
PRODUCING VIRUS PARTICLES THE

5761
05:44:16,040 --> 05:44:17,360
SOURCE OF PERSISTENT VIREMIA IN

5762
05:44:17,360 --> 05:44:19,200
THESE INDIVIDUALS, AND WITH THIS

5763
05:44:19,200 --> 05:44:23,080
ASSAY COULD REPORT THE FRACTION

5764
05:44:23,080 --> 05:44:25,240
OF CELLS WITH PROVIRUSES

5765
05:44:25,240 --> 05:44:26,200
TRANSCRIPTIONAL ACTIVE AND

5766
05:44:26,200 --> 05:44:27,360
FRACTION WITH PROVIRUSES THAT

5767
05:44:27,360 --> 05:44:35,880
ARE LATENT AND WE SET OUT TO DO

5768
05:44:35,880 --> 05:44:36,280
THIS.

5769
05:44:36,280 --> 05:44:39,360
THIS ASSAY WAS USED IN PATIENT

5770
05:44:39,360 --> 05:44:42,920
1, IDENTIFIED 34 INFECTED CELL

5771
05:44:42,920 --> 05:44:44,520
CLONES, WHAT FACTION HAD

5772
05:44:44,520 --> 05:44:51,440
DETECTABLE LEVELS OF VIRAL RNA?

5773
05:44:51,440 --> 05:44:56,000
THREE HAD INTERACT PROVIRUS, ONE

5774
05:44:56,000 --> 05:44:57,000
CHARACTERIZED BY SIMONETTI, TWO

5775
05:44:57,000 --> 05:44:58,800
OTHERS SHORTLY AFTER THIS WERE

5776
05:44:58,800 --> 05:45:01,640
ALSO IDENTIFIED THAT HAD INTACT

5777
05:45:01,640 --> 05:45:04,120
PROVIRUSES, SO THREE OF THE CELL

5778
05:45:04,120 --> 05:45:05,440
CLONES HAD REPLICATION COMPETENT

5779
05:45:05,440 --> 05:45:07,280
PROVIRUSES AND WHEN WE MEASURED

5780
05:45:07,280 --> 05:45:09,160
THE FRACTION OF CELLS WITHIN

5781
05:45:09,160 --> 05:45:10,480
THESE INDIVIDUAL CELLS THAT HAD

5782
05:45:10,480 --> 05:45:12,680
VIRAL RNA IT WAS ABOUT 2% OF

5783
05:45:12,680 --> 05:45:15,520
THEM AND BY THE WAY ANDREW MUSIC

5784
05:45:15,520 --> 05:45:22,560
IN MY LAB TWO DID THIS STUDY 

5785
05:45:22,560 --> 05:45:25,160
ASSAY AND JOHN SDREMLE, 1200

5786
05:45:25,160 --> 05:45:28,360
SINGLE CELLS CARRIED, 2% HAD

5787
05:45:28,360 --> 05:45:30,040
DETECTABLE LEVELS OF VIRAL RNA

5788
05:45:30,040 --> 05:45:32,200
USING A SENSITIVE ASSAY.

5789
05:45:32,200 --> 05:45:40,080
AND SO THEY THEN LOOKED AT 

5790
05:45:40,080 --> 05:45:41,280
ANOTHER ABOUT 30-SOME CLONES, 5

5791
05:45:41,280 --> 05:45:42,720
OTHERS HAD PROVIRUSES, KNOWN TO

5792
05:45:42,720 --> 05:45:45,360
BE EFFECTIVE.

5793
05:45:45,360 --> 05:45:46,920
FULL LENGTH PROVIRUSES WEREN'T

5794
05:45:46,920 --> 05:45:47,760
CHARACTERIZED, DON'T FLOW IF

5795
05:45:47,760 --> 05:45:49,520
THEY WERE INTACT OR DEFECTIVE

5796
05:45:49,520 --> 05:45:51,720
BUT IT WAS JUST AROUND 2 TO 5%

5797
05:45:51,720 --> 05:45:55,000
OF THE CELLS WITHIN THESE LARGE

5798
05:45:55,000 --> 05:45:56,760
EXPANDED CLONES THAT HAD VIRAL

5799
05:45:56,760 --> 05:45:56,960
RNA.

5800
05:45:56,960 --> 05:46:01,600
SO MOST OF THE CELLS WITHIN 

5801
05:46:01,600 --> 05:46:04,200
THESE CLONES HAVE PRO VIRUS,

5802
05:46:04,200 --> 05:46:05,960
SOME OF THESE CLONES DID HAVE A

5803
05:46:05,960 --> 05:46:14,840
HIGH FRACTION OF CELLS THAT HAD

5804
05:46:14,840 --> 05:46:15,920
PROVIRUSES TRANSCRIPTIONALLY

5805
05:46:15,920 --> 05:46:17,000
ACTIVE, FURTHER WILL DETERMINE

5806
05:46:17,000 --> 05:46:18,040
IF INTEGRATION SITES OR OTHER

5807
05:46:18,040 --> 05:46:25,200
FACTORS PLAY A ROLE , WHY DOES

5808
05:46:25,200 --> 05:46:28,720
IT VARY CLONE TO CLONE?

5809
05:46:28,720 --> 05:46:29,800
WE CONCLUDED EXPANDED CELL

5810
05:46:29,800 --> 05:46:32,000
CLONES PERSIST BECAUSE MOST OF

5811
05:46:32,000 --> 05:46:35,160
THE MEMBERS HAVE LATENT

5812
05:46:35,160 --> 05:46:35,520
PROVIRUSES.

5813
05:46:35,520 --> 05:46:38,000
SO FROM THERE, STEVE AND I AND

5814
05:46:38,000 --> 05:46:41,960
OTHERS IN THE DRP WENT ON TO

5815
05:46:41,960 --> 05:46:43,720
PUBLISH MANY PAPERS, ONE IS THE

5816
05:46:43,720 --> 05:46:46,480
PAPER, I JUST TOLD YOU ABOUT, WE

5817
05:46:46,480 --> 05:46:49,520
SHOWED IT'S JUST A SMALL

5818
05:46:49,520 --> 05:46:51,680
FRACTION OF CELLS, BUT SINCE

5819
05:46:51,680 --> 05:46:53,920
THAT TIME, I WAS SURPRISED TO

5820
05:46:53,920 --> 05:46:56,080
SEE, STEVE, HOW PRODUCTIVE WE'VE

5821
05:46:56,080 --> 05:46:58,880
BEEN OVER THE PANDEMIC AND HOW

5822
05:46:58,880 --> 05:46:59,840
MANY STUDIES WE'VE PUBLISHED

5823
05:46:59,840 --> 05:47:03,040
SINCE 2019 WHEN WE PUBLISHED

5824
05:47:03,040 --> 05:47:04,680
THIS STUDY, WE'VE PUBLISHED A

5825
05:47:04,680 --> 05:47:06,600
LOT OF STUDIES, LOOKED IN LYMPH

5826
05:47:06,600 --> 05:47:10,760
NODES, SHOWN THE SAME EXPANDED

5827
05:47:10,760 --> 05:47:15,240
CELL CLONES ARE IN LYMPH NODES, 

5828
05:47:15,240 --> 05:47:17,000
LOOKED AT ACUTE INFECTION,

5829
05:47:17,000 --> 05:47:21,240
CLONES ARISE EARLY, THIS PAPER

5830
05:47:21,240 --> 05:47:25,400
HERE. 

5831
05:47:25,400 --> 05:47:30,560
WE TRACKED SIZE OF CLONES

5832
05:47:30,560 --> 05:47:32,160
LONGITUDINALLY, NOW WE HAVE BIG

5833
05:47:32,160 --> 05:47:34,480
PLANS MOVING FORWARD BUT I'M

5834
05:47:34,480 --> 05:47:36,240
SURE STEVE, ALTHOUGH RETIRED,

5835
05:47:36,240 --> 05:47:39,560
ABOUT CONSULT WITH US, ADVISE US

5836
05:47:39,560 --> 05:47:42,240
AS HE ALWAYS HAS SO WE CAN

5837
05:47:42,240 --> 05:47:44,040
CONTINUE TO DO AMAZING SCIENCE

5838
05:47:44,040 --> 05:47:44,840
IN THE DRP.

5839
05:47:44,840 --> 05:47:46,000
STEVE, THANK YOU SO MUCH FOR

5840
05:47:46,000 --> 05:47:51,360
EVERYTHING I HAVE LEARNED FROM

5841
05:47:51,360 --> 05:47:54,400
YOU, AND YOUR SUPPORT OF MY

5842
05:47:54,400 --> 05:47:54,880
CAREER.

5843
05:47:54,880 --> 05:48:04,040
I MUST SAY AS DEPUTY DIRECTOR OF

5844
05:48:04,040 --> 05:48:07,000
DRP WITH WEI SU, STEVE WAS

5845
05:48:07,000 --> 05:48:09,440
BRANCH CHIEF, SOMETHING LIKE

5846
05:48:09,440 --> 05:48:12,040
DEPUTY DIRECTOR AT THE TIME, I

5847
05:48:12,040 --> 05:48:14,240
NEVER IMAGINED THIS DAY THAT I

5848
05:48:14,240 --> 05:48:17,520
WOULD BE IN A POSITION THAT WITH

5849
05:48:17,520 --> 05:48:19,040
ONCE BEEN FILLED BY STEVE

5850
05:48:19,040 --> 05:48:19,480
HUGHES.

5851
05:48:19,480 --> 05:48:20,440
IT'S REMARKABLE THAT IT'S

5852
05:48:20,440 --> 05:48:21,440
HAPPENED, AND HAPPENED BECAUSE

5853
05:48:21,440 --> 05:48:22,880
OF THE SUPPORT I'VE HAD FROM

5854
05:48:22,880 --> 05:48:24,640
STEVE AND FROM JOHN COFFIN AND

5855
05:48:24,640 --> 05:48:26,080
OTHERS IN THE DRP.

5856
05:48:26,080 --> 05:48:27,680
STEVE, THANK YOU SO MUCH FROM

5857
05:48:27,680 --> 05:48:29,880
THE BOTTOM OF MY HEART.

5858
05:48:29,880 --> 05:48:30,320
THANK YOU.

5859
05:48:30,320 --> 05:48:31,880
I'LL JUST LEAVE IT THERE.

5860
05:48:31,880 --> 05:48:34,600
[APPLAUSE]

5861
05:48:34,600 --> 05:48:41,480
 

5862
05:48:41,480 --> 05:48:43,080
>>ALSO HAPPENED BECAUSE
OF YOUR

5863
05:48:43,080 --> 05:48:43,560
GREAT WORK.

5864
05:48:43,560 --> 05:48:46,000
QUESTIONS?

5865
05:48:46,000 --> 05:48:51,560
 

5866
05:48:51,560 --> 05:48:54,520
>>SEQUENCES THAT WE FIND
IN RNA

5867
05:48:54,520 --> 05:48:57,480
VIREMIA ARE NOT ALWAYS EASY TO

5868
05:48:57,480 --> 05:48:59,560
FIND IN DNA, THERE'S A VERY

5869
05:48:59,560 --> 05:49:01,280
SMALL FRACTION OF THE CELLS

5870
05:49:01,280 --> 05:49:03,760
PRODUCING THIS VIRUS, SOMETIMES

5871
05:49:03,760 --> 05:49:05,080
PEOPLE COULD HAVE THOUSANDS AND

5872
05:49:05,080 --> 05:49:07,760
TENS OF THOUSANDS OF COPIES OF

5873
05:49:07,760 --> 05:49:07,920
RNA.

5874
05:49:07,920 --> 05:49:10,720
HAVE YOU TRIED TO WORK THAT

5875
05:49:10,720 --> 05:49:12,120
BACKWARD, OH, HERE'S THE VIRAL

5876
05:49:12,120 --> 05:49:14,440
LOAD IN THIS PERSON ON THERAPY,

5877
05:49:14,440 --> 05:49:19,200
OH, THEY HAVE THIS MANY CELLS 

5878
05:49:19,200 --> 05:49:20,200
THAT ARE PRODUCING VIRUS?

5879
05:49:20,200 --> 05:49:21,760
>>WE HAVE NOT DONE THAT.

5880
05:49:21,760 --> 05:49:25,400
I HAVEN'T THOUGHT OF DOING THAT.

5881
05:49:25,400 --> 05:49:28,800
I DON'T THINK THERE WOULD BE

5882
05:49:28,800 --> 05:49:31,440
CORRELATION BECAUSE IN THE

5883
05:49:31,440 --> 05:49:33,600
FAMOUS PATIENT NUMBER 1, THE

5884
05:49:33,600 --> 05:49:35,320
AMB1 CLONE WAS A VERY LARGE

5885
05:49:35,320 --> 05:49:37,080
CLONE, I THINK THE LARGEST

5886
05:49:37,080 --> 05:49:39,200
INFECTED CELL CLONE IN THAT

5887
05:49:39,200 --> 05:49:40,040
INDIVIDUAL, LEVEL OF VIREMIA

5888
05:49:40,040 --> 05:49:41,080
STILL QUITE LOW IN THAT

5889
05:49:41,080 --> 05:49:43,520
INDIVIDUAL COMPARED TO THE

5890
05:49:43,520 --> 05:49:46,320
LEVELS OF VIREMIA IN THE

5891
05:49:46,320 --> 05:49:51,200
SUBSEQUENT PAPER FROM JOHN

5892
05:49:51,200 --> 05:49:52,480
MELLOR'S LAB, AND COLLABORATIONS

5893
05:49:52,480 --> 05:49:54,080
WITH MY LAB AT WELL, THOSE

5894
05:49:54,080 --> 05:49:56,000
INDIVIDUALS HAD HIGHER LEVELS OF

5895
05:49:56,000 --> 05:49:57,240
PERSISTENT VIREMIA THAN PATIENT

5896
05:49:57,240 --> 05:50:01,640
1, BUT THE CLONES WERE SMALLER,

5897
05:50:01,640 --> 05:50:03,400
YEAH, QUITE SURE, AND SOME WERE

5898
05:50:03,400 --> 05:50:05,680
I THINK VERY SMALL, THE SOURCE

5899
05:50:05,680 --> 05:50:07,440
OF PERSISTENT VIREMIA DESPITE

5900
05:50:07,440 --> 05:50:08,600
HIGHER LEVELS THAN IN PATIENT

5901
05:50:08,600 --> 05:50:11,080
NUMBER 1.

5902
05:50:11,080 --> 05:50:15,120
 

5903
05:50:15,120 --> 05:50:16,320
>>VERY BEAUTIFUL WORK.

5904
05:50:16,320 --> 05:50:18,200
WHAT DISTINGUISHES CELLS THAT

5905
05:50:18,200 --> 05:50:21,720
PRODUCE RNA FROM THOSE THAT

5906
05:50:21,720 --> 05:50:22,160
DON'T.

5907
05:50:22,160 --> 05:50:24,120
WHEN YOU GET THIS RNA, FROM A

5908
05:50:24,120 --> 05:50:31,240
CELL THAT YOU CAN DO SINGLE CELL

5909
05:50:31,240 --> 05:50:31,480
RNAseq?

5910
05:50:31,480 --> 05:50:35,760
>>SO, I THINK WE HAVE NOT
DONE

5911
05:50:35,760 --> 05:50:36,840
SINGLE CELL RNAseq.

5912
05:50:36,840 --> 05:50:39,680
I THINK THERE ARE PROBABLY

5913
05:50:39,680 --> 05:50:45,720
MULTIPLE THINGS THAT LEAD TO

5914
05:50:45,720 --> 05:50:46,080
LATENCY.

5915
05:50:46,080 --> 05:50:47,720
VERSE HAVE DATA THAT SUGGEST

5916
05:50:47,720 --> 05:50:49,760
INTEGRATION SITE COULD BE

5917
05:50:49,760 --> 05:50:50,040
IMPORTANT.

5918
05:50:50,040 --> 05:50:51,080
I THINK THERE'S A LOT MORE WORK

5919
05:50:51,080 --> 05:50:54,160
TO BE DONE IN THAT AREA, IF IT'S

5920
05:50:54,160 --> 05:50:57,120
A SMALL N, SO THERE'S MORE WORK

5921
05:50:57,120 --> 05:50:58,960
TO BE DONE, IF THE INTEGRATION

5922
05:50:58,960 --> 05:51:01,400
SITE HAS ANYTHING TO DO WITH IT.

5923
05:51:01,400 --> 05:51:05,000
IT COULD BE THE STATE OF THE

5924
05:51:05,000 --> 05:51:05,600
CELL, MAYBE THE DIFFERENTIATION

5925
05:51:05,600 --> 05:51:07,480
STATE OF THE CELL, LEVEL OF

5926
05:51:07,480 --> 05:51:09,160
ACTIVATION OF THE CELL, IT COULD

5927
05:51:09,160 --> 05:51:11,000
BE THE CELL CYCLE, COULD EVEN BE

5928
05:51:11,000 --> 05:51:14,560
SOMETHING TO DO WITH CIRCADIAN

5929
05:51:14,560 --> 05:51:14,800
RHYTHMS.

5930
05:51:14,800 --> 05:51:20,920
THERE'S A LOT OF DATA COMING OUT

5931
05:51:20,920 --> 05:51:22,920
NOW, VARYING OVER THE DAY.

5932
05:51:22,920 --> 05:51:27,080
THERE'S  MORE WORK TO BE DONE TO

5933
05:51:27,080 --> 05:51:30,280
DETERMINE THAT.

5934
05:51:30,280 --> 05:51:30,560
>>OKAY.

5935
05:51:30,560 --> 05:51:30,960
THANKS VERY MUCH.

5936
05:51:30,960 --> 05:51:33,000
[APPLAUSE]

5937
05:51:33,000 --> 05:51:40,040
 

5938
05:51:40,040 --> 05:51:41,040
 

5939
05:51:41,040 --> 05:51:44,200
NEXT SPEAKERS, NEIGHBOR JEFF

5940
05:51:44,200 --> 05:51:45,240
LIFTON, IN THE FREDERICK

5941
05:51:45,240 --> 05:51:46,520
NATIONAL LAB FOR CANCER

5942
05:51:46,520 --> 05:51:47,840
RESEARCH, SPENT HIS CAREER AT

5943
05:51:47,840 --> 05:51:51,240
THE FOREFRONT OF THE FIELD OF

5944
05:51:51,240 --> 05:51:51,720
RETROVIRAL PATHOGENESIS,

5945
05:51:51,720 --> 05:51:53,840
PARTICULARLY KNOWN FOR WORK ON

5946
05:51:53,840 --> 05:51:57,080
SIV, COLLABORATED WITH STEVE ON

5947
05:51:57,080 --> 05:51:58,320
SEVERAL PROJECTS, WE'LL LIKELY

5948
05:51:58,320 --> 05:52:01,840
HEAR MORE DURING HIS TALK TODAY.

5949
05:52:01,840 --> 05:52:07,880
 

5950
05:52:07,880 --> 05:52:11,960
 

5951
05:52:11,960 --> 05:52:13,040
>>THANKS.

5952
05:52:13,040 --> 05:52:16,480
IT'S NOT THE SAME WITHOUT THE

5953
05:52:16,480 --> 05:52:21,480
SIZE  14s ON THE STAGE.

5954
05:52:21,480 --> 05:52:24,400
I'M GLAD I WAS ABLE TO FIND THIS

5955
05:52:24,400 --> 05:52:24,640
PICTURE.

5956
05:52:24,640 --> 05:52:26,600
MOST OF THE PICTURES TODAY HAVE

5957
05:52:26,600 --> 05:52:28,800
BEEN FROM WEBSITES AND THINGS,

5958
05:52:28,800 --> 05:52:30,520
HE LOOKS WAY MORE DOUR THAN IS

5959
05:52:30,520 --> 05:52:31,520
TYPICAL OF HIM.

5960
05:52:31,520 --> 05:52:34,040
I SURROUNDED HIM WITH FOUR OF

5961
05:52:34,040 --> 05:52:35,840
HIS FAVORITE THINGS, A SMILING

5962
05:52:35,840 --> 05:52:38,000
FACE TO CAPTURE SOMETHING THAT'S

5963
05:52:38,000 --> 05:52:41,520
MORE REFLECTIVE OF MY EXPERIENCE

5964
05:52:41,520 --> 05:52:44,440
WITH STEVE.

5965
05:52:44,440 --> 05:52:47,320
TO HAROLD'S INTRODUCTION, MY 

5966
05:52:47,320 --> 05:52:49,840
PRESENTATION WILL FALL INTO THAT

5967
05:52:49,840 --> 05:52:50,680
CATEGORY, BASICALLY PRAISING

5968
05:52:50,680 --> 05:52:50,880
STEVE.

5969
05:52:50,880 --> 05:52:54,480
I WANT TO PRESENT IT FROM SORT

5970
05:52:54,480 --> 05:52:55,840
OF TWO SYNERGISTIC PERSPECTIVES.

5971
05:52:55,840 --> 05:52:57,280
ONE, TO TALK ABOUT THE

5972
05:52:57,280 --> 05:53:00,320
INTERACTIONS I'VE HAD WITH HIM

5973
05:53:00,320 --> 05:53:01,720
SCIENTIFICALLY, BUT ALSO ABOUT

5974
05:53:01,720 --> 05:53:03,800
THE INTERACTIONS I'VE HAD WITH

5975
05:53:03,800 --> 05:53:06,760
HIM OUTSIDE THE LAB, REINFORCING

5976
05:53:06,760 --> 05:53:09,600
THINGS THAT WE'VE HEARD ABOUT

5977
05:53:09,600 --> 05:53:11,480
TODAY THAT REINFORCE WHO STEVE

5978
05:53:11,480 --> 05:53:13,120
IS AS A PERSON, WHOSE DEEP

5979
05:53:13,120 --> 05:53:15,080
KNOWLEDGE OF MANY FIELDS HAS

5980
05:53:15,080 --> 05:53:17,600
CRITICAL ASSESSMENT OF THAT

5981
05:53:17,600 --> 05:53:21,960
KNOWLEDGE, HIS CLEAR, DIRECT,

5982
05:53:21,960 --> 05:53:24,680
BUT ALWAYS GRACEFUL EFFECTIVE

5983
05:53:24,680 --> 05:53:25,680
COMMUNICATION OF HIS INSIGHTS,

5984
05:53:25,680 --> 05:53:28,880
AND ALONG WITH THAT A GREAT

5985
05:53:28,880 --> 05:53:29,720
SENSE OF HUMOR, BOUNDLESS

5986
05:53:29,720 --> 05:53:31,040
ENTHUSIASM FOR THE THINGS HE'S

5987
05:53:31,040 --> 05:53:35,000
INTERESTED IN, AND AT THE SAME

5988
05:53:35,000 --> 05:53:36,760
TIME ENTHUSIASM FOR

5989
05:53:36,760 --> 05:53:38,520
COMMUNICATING AND SHARING THAT

5990
05:53:38,520 --> 05:53:41,040
ENTHUSIASM, THAT KNOWLEDGE, AND

5991
05:53:41,040 --> 05:53:42,200
SEEMINGLY INEXHAUSTIBLE PATIENCE

5992
05:53:42,200 --> 05:53:43,840
FOR DOING SO, TAKING GREAT PRIDE

5993
05:53:43,840 --> 05:53:45,400
AND PLEASURE WHEN HE'S ABLE TO

5994
05:53:45,400 --> 05:53:48,160
GET SOMETHING ACROSS IN A WAY

5995
05:53:48,160 --> 05:53:49,560
THAT BENEFITS SOMEONE ELSE.

5996
05:53:49,560 --> 05:53:51,080
SO FROM THAT PERSPECTIVE I'LL

5997
05:53:51,080 --> 05:53:54,960
START OUT BY SAYING I HAVEN'T

5998
05:53:54,960 --> 05:53:56,600
KNOWN STEVE AS LONG AS MANY

5999
05:53:56,600 --> 05:53:59,280
OTHER SPEAKERS.

6000
05:53:59,280 --> 05:54:01,480
I WAS RECRUITED TO FREDERICK IN

6001
05:54:01,480 --> 05:54:08,160
199  5, I CAME TO UNDERSTAND THE

6002
05:54:08,160 --> 05:54:10,600
SIGNIFICANCE OF THE SPREAD-HANDS

6003
05:54:10,600 --> 05:54:10,840
GESTURE.

6004
05:54:10,840 --> 05:54:11,120
[LAUGHTER]

6005
05:54:11,120 --> 05:54:16,080
BUT WHEN I FIRST CAME, AS A

6006
05:54:16,080 --> 05:54:19,360
NATIVE CALIFORNIAN, MY MODE OF

6007
05:54:19,360 --> 05:54:21,920
TRANSPORTATION WAS LESS DRAMATIC

6008
05:54:21,920 --> 05:54:22,960
THAN DOROTHY'S TRIP OVER THE

6009
05:54:22,960 --> 05:54:26,360
RAINBOW BUT WHEN I GOT TO

6010
05:54:26,360 --> 05:54:30,000
FREDERICK IT WAS SORT OF

6011
05:54:30,000 --> 05:54:30,840
EQUIVALENTLY STRANGE AND

6012
05:54:30,840 --> 05:54:32,280
DIFFERENT WORLD RELATIVE TO WHAT

6013
05:54:32,280 --> 05:54:35,800
I WAS USED TO AS A LONGTIME BAY

6014
05:54:35,800 --> 05:54:36,680
AREA RESIDENT, NEVER LIVED ON

6015
05:54:36,680 --> 05:54:39,280
THE EAST COAST, IF YOU ASKED ME

6016
05:54:39,280 --> 05:54:40,560
BEFORE I CAME HERE WILL YOU

6017
05:54:40,560 --> 05:54:42,720
SPEND THE NEXT 25 YEARS OF YOUR

6018
05:54:42,720 --> 05:54:44,480
CAREER WORKING ON AN ARMY BASE,

6019
05:54:44,480 --> 05:54:47,080
I WOULD HAVE LOOKED LIKE YOU

6020
05:54:47,080 --> 05:54:48,560
SHOULD BE COMMITTED.

6021
05:54:48,560 --> 05:54:50,160
BUT NEVERTHELESS THAT WAS THE

6022
05:54:50,160 --> 05:54:50,720
SITUATION.

6023
05:54:50,720 --> 05:54:51,880
WHAT WAS REMARKABLE IS THAT

6024
05:54:51,880 --> 05:54:54,200
SOMEONE WHO STARTED IN SCIENCE

6025
05:54:54,200 --> 05:54:58,600
AS A CELLULAR IMMUNOLOGIST, SORT

6026
05:54:58,600 --> 05:54:59,240
OF GOT INTO RETROVIROLOGY

6027
05:54:59,240 --> 05:55:01,040
THROUGH THE BACK DOOR BECAUSE OF

6028
05:55:01,040 --> 05:55:03,960
HIV AND AIDS, I REALIZED THAT I

6029
05:55:03,960 --> 05:55:08,720
HAD LANDED DOWN  NOT ON TOP OF

6030
05:55:08,720 --> 05:55:12,720
THE WISHED WITCH OF THE WEST BUT

6031
05:55:12,720 --> 05:55:14,720
THE BIGGEST GROUP OF

6032
05:55:14,720 --> 05:55:16,120
RETROVIROLOGYISTS ANY, A GREAT

6033
05:55:16,120 --> 05:55:16,720
OPPORTUNITY BUT INTIMIDATING

6034
05:55:16,720 --> 05:55:18,960
BECAUSE THESE WERE THE PEOPLE

6035
05:55:18,960 --> 05:55:20,360
THAT WE'VE SEEN LITERALLY WROTE

6036
05:55:20,360 --> 05:55:22,160
AND EDITED THE BOOK ON THE

6037
05:55:22,160 --> 05:55:22,360
SUBJECT.

6038
05:55:22,360 --> 05:55:24,680
I WAS ENTHUSIASTIC ABOUT TRYING

6039
05:55:24,680 --> 05:55:26,400
TO FIND OPPORTUNITIES TO WORK

6040
05:55:26,400 --> 05:55:29,680
WITH SOME OF THESE FOLKS, IN

6041
05:55:29,680 --> 05:55:31,360
SPITE OF NOT HAVING

6042
05:55:31,360 --> 05:55:33,720
COLLABORATIVE PROJECTS FOR A

6043
05:55:33,720 --> 05:55:35,240
LONG TIME, IT WAS A GREAT

6044
05:55:35,240 --> 05:55:36,840
OPPORTUNITY TO LEARN AN AWFUL

6045
05:55:36,840 --> 05:55:37,000
LOT.

6046
05:55:37,000 --> 05:55:40,200
I THINK ONE OF THE REASONS WHY I

6047
05:55:40,200 --> 05:55:41,200
STRUGGLED TO FIND COLLABORATIVE

6048
05:55:41,200 --> 05:55:43,280
PROJECTS IS THAT MUCH OF MY WORK

6049
05:55:43,280 --> 05:55:45,360
AFTER I CAME TO FREDERICK

6050
05:55:45,360 --> 05:55:47,880
FOCUSED ON TRYING TO USE --

6051
05:55:47,880 --> 05:55:50,920
DEVELOP AND USE NON-HUMAN

6052
05:55:50,920 --> 05:55:52,240
PRIMATE MODELS FOR QUESTIONS

6053
05:55:52,240 --> 05:55:53,760
THAT COULDN'T AS READILY BE

6054
05:55:53,760 --> 05:55:55,000
APPROACHED IN THE CLINICAL

6055
05:55:55,000 --> 05:55:55,240
CONTEXT.

6056
05:55:55,240 --> 05:55:57,320
SO A LOT OF THE WORK WAS SORT OF

6057
05:55:57,320 --> 05:55:58,600
A LITTLE BIT OFF TO THE SIDE TO

6058
05:55:58,600 --> 05:56:01,000
SOME OF THE THINGS THAT STEVE

6059
05:56:01,000 --> 05:56:02,560
WAS INTERESTED IN.

6060
05:56:02,560 --> 05:56:04,200
NEVERTHELESS RETAINED A GREAT

6061
05:56:04,200 --> 05:56:07,640
INTEREST IN TRYING TO FIND A

6062
05:56:07,640 --> 05:56:09,360
PROJECT UNSUCCESSFULLY FOR MANY

6063
05:56:09,360 --> 05:56:10,880
YEARS, FORTUNATELY IN SPITE OF

6064
05:56:10,880 --> 05:56:12,840
THE LACK OF OVERLAP ON NON-HUMAN

6065
05:56:12,840 --> 05:56:20,960
PRIMATE, THERE WAS ANOTHER 

6066
05:56:20,960 --> 05:56:23,600
SPECIES THAT PROVIDED

6067
05:56:23,600 --> 05:56:28,400
(INDISCERNIBLE) LARRY AND STEVE

6068
05:56:28,400 --> 05:56:29,600
SHARED PASSION FOR FISHING AND

6069
05:56:29,600 --> 05:56:34,400
MANAGED TO GET  ME TO THE TROUT

6070
05:56:34,400 --> 05:56:35,960
STREAM IN PENNSYLVANIA, AND WITH

6071
05:56:35,960 --> 05:56:37,600
THE PASSION FOR FISHING WAS

6072
05:56:37,600 --> 05:56:39,360
THEIR PASSION FOR SHARING LOVE

6073
05:56:39,360 --> 05:56:40,440
OF FISHING.

6074
05:56:40,440 --> 05:56:42,760
HERE IS LARRY INSTRUCTING A

6075
05:56:42,760 --> 05:56:48,880
COLLEAGUE, JIM HOXY, AS A 

6076
05:56:48,880 --> 05:56:50,960
NEOPHPYTE FLY FISHERMAN.

6077
05:56:50,960 --> 05:56:54,040
PARDON THE BAD PUN BUT I WAS

6078
05:56:54,040 --> 05:56:54,280
HOOKED.

6079
05:56:54,280 --> 05:56:58,400
EVEN TO THE POINT OF TRYING TO

6080
05:56:58,400 --> 05:57:00,480
FAMILIARIZE MYSELF WITH SORT OF

6081
05:57:00,480 --> 05:57:02,960
A FOREIGN AND UNAPPROACHABLE

6082
05:57:02,960 --> 05:57:04,400
ETHOS AND CULTURE FOR SOME PARTS

6083
05:57:04,400 --> 05:57:06,040
OF THE ANGLING COMMUNITY I

6084
05:57:06,040 --> 05:57:09,880
DIDN'T QUITE FULLY UNDERSTAND 

6085
05:57:09,880 --> 05:57:10,880
WHERE THESE FOLKS WERE COMING

6086
05:57:10,880 --> 05:57:16,160
FROM BUT OVER TIME BEGAN TO GET 

6087
05:57:16,160 --> 05:57:18,440
A FEEL FOR IT.

6088
05:57:18,440 --> 05:57:18,800
[LAUGHTER]

6089
05:57:18,800 --> 05:57:19,520
AND IT'S INTERESTING.

6090
05:57:19,520 --> 05:57:20,960
WE HAVE A LOT OF THINGS GOING

6091
05:57:20,960 --> 05:57:23,680
ON, A LOT OF DISTRACTIONS IN

6092
05:57:23,680 --> 05:57:26,640
LIFE, THE IDEA OF FINDING

6093
05:57:26,640 --> 05:57:29,120
YOURSELF IN THE BEAUTIFUL SPOT

6094
05:57:29,120 --> 05:57:32,640
WADING IN THE STREAM, AND ASKING

6095
05:57:32,640 --> 05:57:34,160
YOURSELF, NOW, AT THIS TIME OF

6096
05:57:34,160 --> 05:57:35,600
YEAR WITH THESE LIKE CONDITIONS

6097
05:57:35,600 --> 05:57:38,160
AND THIS TEMPERATURE AND THIS

6098
05:57:38,160 --> 05:57:46,200
WEATHER, IF I WERE A RAINBOW

6099
05:57:46,200 --> 05:57:47,640
TROUT WHERE IN THE POND WOULD I

6100
05:57:47,640 --> 05:57:48,200
BE?

6101
05:57:48,200 --> 05:57:50,600
THINKING ABOUT THE MINDS OF FISH

6102
05:57:50,600 --> 05:57:52,640
IS A WONDERFUL DIVERSION,

6103
05:57:52,640 --> 05:57:54,320
ESPECIALLY IN BEAUTIFUL OUTDOOR

6104
05:57:54,320 --> 05:57:56,160
PLACES, TO ME IT BETS THE HELL

6105
05:57:56,160 --> 05:58:02,000
OUT OF WHACKING A WHITE BALL

6106
05:58:02,000 --> 05:58:05,480
OVER PESTICIDE TREATED GRASS.

6107
05:58:05,480 --> 05:58:06,840
WITH STEVE'S TUTELAGE AND

6108
05:58:06,840 --> 05:58:08,880
SHARING OF EQUIPMENT AND

6109
05:58:08,880 --> 05:58:10,720
GUIDANCE, EVEN A TOTAL BEGINNER

6110
05:58:10,720 --> 05:58:12,920
LIKE ME ACTUALLY BEGAN TO HAVE A

6111
05:58:12,920 --> 05:58:15,640
LITTLE BIT OF SUCCESS, STEVE

6112
05:58:15,640 --> 05:58:17,960
MANAGED TO CONVEY A FEEL FOR THE

6113
05:58:17,960 --> 05:58:20,680
PROCESS OF FISHING AND BEING IN

6114
05:58:20,680 --> 05:58:24,160
THE MOMENT AND IT WASN'T

6115
05:58:24,160 --> 05:58:25,400
NECESSARILY ABOUT CATCHING THE

6116
05:58:25,400 --> 05:58:28,080
FISH, WHAT FISH YOU CAUGHT, AND

6117
05:58:28,080 --> 05:58:29,760
WHAT I REMEMBER IN PARTICULAR,

6118
05:58:29,760 --> 05:58:31,640
ONE TRIP THAT BROUGHT THAT HOME,

6119
05:58:31,640 --> 05:58:34,200
ONE STEVE WAS PROUD OF, THIS ONE

6120
05:58:34,200 --> 05:58:35,720
HE MANAGED TO LAND.

6121
05:58:35,720 --> 05:58:39,520
BUT STEVE ALSO CONVEYED TO ME

6122
05:58:39,520 --> 05:58:40,600
THERE'S NOTHING WRONG WITH

6123
05:58:40,600 --> 05:58:44,000
LANDING A BIG BEAUTIFUL FISH

6124
05:58:44,000 --> 05:58:44,240
EITHER.

6125
05:58:44,240 --> 05:58:45,640
THAT HAS BEEN A BOND.

6126
05:58:45,640 --> 05:58:47,720
THEY CONTINUED TO INSTRUCT ME.

6127
05:58:47,720 --> 05:58:50,720
I WAS A TOTAL NEWBIE, AS YOU CAN

6128
05:58:50,720 --> 05:58:53,640
OBSERVE FROM THIS PICTURE.

6129
05:58:53,640 --> 05:58:57,160
AND THEY SOON INSTRUCTED ME IN

6130
05:58:57,160 --> 05:58:58,440
THE LARRY ARTHUR TECHNIQUE OF

6131
05:58:58,440 --> 05:58:59,800
PRESENTING THE FISH TO THE

6132
05:58:59,800 --> 05:59:03,280
CAMERAMAN WITH THE ARMS FULLY

6133
05:59:03,280 --> 05:59:04,400
EXTENDED TO EXAGGERATE THE

6134
05:59:04,400 --> 05:59:04,680
EXPERIENCE.

6135
05:59:04,680 --> 05:59:08,120
I'VE GOT THAT DOWN NOW TOO.

6136
05:59:08,120 --> 05:59:10,200
I DIDN'T REALLY DEVELOP A

6137
05:59:10,200 --> 05:59:11,080
COLLABORATIVE PROJECT WITH STEVE

6138
05:59:11,080 --> 05:59:13,680
FOR THE FIRST TIME BUT MY FIRST

6139
05:59:13,680 --> 05:59:14,440
PROFESSIONAL INTERACTION WITH

6140
05:59:14,440 --> 05:59:16,160
STEVE WAS REALLY WITH REGARD TO

6141
05:59:16,160 --> 05:59:17,760
OUR SITE VISIT.

6142
05:59:17,760 --> 05:59:22,120
YOU CAN'T IMAGINE COMING FROM

6143
05:59:22,120 --> 05:59:24,200
THE OUTSIDE, IT'S TAKEN

6144
05:59:24,200 --> 05:59:26,400
SERIOUSLY BUT FOR GRANTED, BUT

6145
05:59:26,400 --> 05:59:29,280
UNFAMILIAR IF YOU'RE NOT

6146
05:59:29,280 --> 05:59:29,840
ACCUSTOMED.

6147
05:59:29,840 --> 05:59:31,920
JEFF ALERTED TO STEVE'S SURVIVAL

6148
05:59:31,920 --> 05:59:33,480
GUIDE FOR SITE VISITS,

6149
05:59:33,480 --> 05:59:35,320
INVALUABLE PIECE OF GUIDANCE AND

6150
05:59:35,320 --> 05:59:35,680
DOCUMENT.

6151
05:59:35,680 --> 05:59:38,480
WHAT WAS AMAZING TO ME WAS

6152
05:59:38,480 --> 05:59:41,680
STEVE'S WILLINGNESS TO SIT IN ON

6153
05:59:41,680 --> 05:59:44,080
OUR REHEARSAL SESSIONS AND

6154
05:59:44,080 --> 05:59:48,640
PROVIDE INCREDIBLE CONSTRUCTIVE

6155
05:59:48,640 --> 05:59:54,160
FEEDBACK IN HIS DIRECT, 

6156
05:59:54,160 --> 05:59:56,560
SOMETIMES US HUMOROUS BUT COGENT

6157
05:59:56,560 --> 05:59:57,200
WAY, TO EXPRESS GRATIFICATION

6158
05:59:57,200 --> 05:59:58,840
WHEN YOU TOOK HIS GOOD ADVICE

6159
05:59:58,840 --> 06:00:02,040
AND THAT WORKED OUT WELL FOR

6160
06:00:02,040 --> 06:00:02,560
YOU.

6161
06:00:02,560 --> 06:00:05,440
JUST THE LAST FEW YEARS, MANAGED

6162
06:00:05,440 --> 06:00:06,640
TO FIND A COLLABORATIVE PROJECT

6163
06:00:06,640 --> 06:00:09,280
TO WORK ON WITH STEVE, AND I'M

6164
06:00:09,280 --> 06:00:11,920
NOT GOING TO BELABOR THE

6165
06:00:11,920 --> 06:00:13,520
BACKGROUND INFORMATION ABOUT

6166
06:00:13,520 --> 06:00:15,280
WORK A CLONAL PROLIFERATION IN

6167
06:00:15,280 --> 06:00:19,120
RELATION TO PERSISTENCE OF AID

6168
06:00:19,120 --> 06:00:20,440
VIRUSES SINCE IT WAS WELL

6169
06:00:20,440 --> 06:00:24,520
COVERED BY OTHER SPEAKERS THIS

6170
06:00:24,520 --> 06:00:27,000
AFTERNOON, BUT GOING FROM THIS

6171
06:00:27,000 --> 06:00:29,760
LANDMARK PAPER FROM STEVE AND

6172
06:00:29,760 --> 06:00:32,280
COLLEAGUES, DRP AND SEVERAL

6173
06:00:32,280 --> 06:00:33,600
OTHER CONCOMITANT PUBLICATIONS,

6174
06:00:33,600 --> 06:00:35,480
THE QUESTION ARISES WHAT IS

6175
06:00:35,480 --> 06:00:37,960
MECHANISM, WHAT IS IT DRIVING

6176
06:00:37,960 --> 06:00:40,040
THE PERSISTENCE IN CLONAL

6177
06:00:40,040 --> 06:00:42,840
PROLIFERATION OF CELLS HAVING

6178
06:00:42,840 --> 06:00:46,920
IDENTICAL PROVIRAL INTEGRATION

6179
06:00:46,920 --> 06:00:47,120
SITES?

6180
06:00:47,120 --> 06:00:48,680
AND IT BECAME MUTUAL INTEREST

6181
06:00:48,680 --> 06:00:50,120
FOR STEVE AND FOR ME, WHETHER OR

6182
06:00:50,120 --> 06:00:52,520
NOT SOME OF THE WORK THAT WE'VE

6183
06:00:52,520 --> 06:00:53,360
BEEN DOING IN DEVELOPING

6184
06:00:53,360 --> 06:00:54,800
NON-HUMAN PRIMATE MODELS MIGHT

6185
06:00:54,800 --> 06:01:01,600
BE APPLICABLE TO ADDRESSING SOME

6186
06:01:01,600 --> 06:01:02,600
RELEVANT QUESTIONS.

6187
06:01:02,600 --> 06:01:04,160
NOW, THEY HAVE ADVANTAGES IN

6188
06:01:04,160 --> 06:01:05,760
TERMS OF EXPERIMENTAL CONTROL.

6189
06:01:05,760 --> 06:01:07,960
YOU CAN CONTROL IDENTITY OF THE

6190
06:01:07,960 --> 06:01:09,480
INOCULATING VIRUS, EXACT TIMING

6191
06:01:09,480 --> 06:01:10,880
OF THE INOCULATION, ROUTE AND

6192
06:01:10,880 --> 06:01:15,280
DOSE OF INFECTION.

6193
06:01:15,280 --> 06:01:19,280
AND IN DEVELOPMENT FROM A 

6194
06:01:19,280 --> 06:01:22,600
PROGRAM DEVELOPED BARCODED

6195
06:01:22,600 --> 06:01:28,400
VIRUSES TO TRACK DISTINCT

6196
06:01:28,400 --> 06:01:31,080
BARCODE CLONAL TYPES ON ISOGENIC

6197
06:01:31,080 --> 06:01:33,320
BACKGROUNDS IN INFECTED HOST.

6198
06:01:33,320 --> 06:01:41,200
YOU CAN CONTROL TIMING OF

6199
06:01:41,200 --> 06:01:42,080
INITIATION, DURATION,

6200
06:01:42,080 --> 06:01:42,640
INTERACTION.

6201
06:01:42,640 --> 06:01:44,480
ONE THING THAT WOULD BE

6202
06:01:44,480 --> 06:01:48,760
INTERESTING TO UTILIZE

6203
06:01:48,760 --> 06:01:54,240
IMMUNIZATION WITH EXOGENOUS

6204
06:01:54,240 --> 06:01:56,200
ANTIGEN, TO EXPLORE THIS

6205
06:01:56,200 --> 06:01:58,160
QUESTION IN MACAQUES.

6206
06:01:58,160 --> 06:02:02,440
WE DID MORE TISSUE SAMPLING

6207
06:02:02,440 --> 06:02:06,240
INCLUDING UP TO ELECTIVE

6208
06:02:06,240 --> 06:02:09,240
NECROPSY, BUT THERE ARE

6209
06:02:09,240 --> 06:02:11,200
LIMITATIONS.

6210
06:02:11,200 --> 06:02:12,560
THE RHESUS MACAQUE SEQUENCE AND

6211
06:02:12,560 --> 06:02:16,600
PATIENT ARE NOT AS WELL

6212
06:02:16,600 --> 06:02:18,240
DEVELOPED FOR HUMANS, TISSUE

6213
06:02:18,240 --> 06:02:19,640
SAMPLING IS AVAILABLE BUT

6214
06:02:19,640 --> 06:02:22,600
MACAQUES HAVE LIMITED BLOOD

6215
06:02:22,600 --> 06:02:25,120
LINE, WE OVERCAME BY DEVELOPED

6216
06:02:25,120 --> 06:02:26,480
PROCEDURES FOR LEUKAPHERESIS IN

6217
06:02:26,480 --> 06:02:27,200
THESE ANIMALS.

6218
06:02:27,200 --> 06:02:29,920
LET ME ASK A QUESTION, CAN WE

6219
06:02:29,920 --> 06:02:33,640
USE THIS MODEL TO FIRST ASSESS

6220
06:02:33,640 --> 06:02:35,080
SIV INTEGRATION BIOLOGY,

6221
06:02:35,080 --> 06:02:37,160
CAPITULATE FEATURES OF HIV IN

6222
06:02:37,160 --> 06:02:39,360
VITRO AND IN VIVO.

6223
06:02:39,360 --> 06:02:41,080
THE SECRET, I TOLD YOU THERE ARE

6224
06:02:41,080 --> 06:02:43,720
MANY ADVANTAGES TO WORKING WITH

6225
06:02:43,720 --> 06:02:44,800
NON-HUMAN PRIMATE PRODUCT ALSO,

6226
06:02:44,800 --> 06:02:46,200
THROUGH BITTER EXPERIENCE OVER

6227
06:02:46,200 --> 06:02:49,160
MANY YEARS WE'VE LEARNED THAT

6228
06:02:49,160 --> 06:02:51,040
BASED ON REAGENTS AND

6229
06:02:51,040 --> 06:02:53,680
INFORMATION SORT OF HIERARCHY OF

6230
06:02:53,680 --> 06:02:54,760
DIFFICULTY OF EXPERIMENTS FROM

6231
06:02:54,760 --> 06:02:56,720
MOUSE TO HUMAN TO MACAQUES,

6232
06:02:56,720 --> 06:02:59,240
SEEMS TO BE HARDER TO DO THINGS

6233
06:02:59,240 --> 06:03:00,240
IN NON-HUMAN PRIMATE MODELS BUT

6234
06:03:00,240 --> 06:03:05,560
IN THE RIGHT CONTEXT CAN BE WELL

6235
06:03:05,560 --> 06:03:07,760
WORTH THE EFFORT.

6236
06:03:07,760 --> 06:03:09,960
WITH STEVE'S APPROACH FOR RIGOR

6237
06:03:09,960 --> 06:03:13,600
WE SET OUT TO SEE, LET'S ASSIST

6238
06:03:13,600 --> 06:03:15,640
SIMILARITY OR DIFFERENCES IN

6239
06:03:15,640 --> 06:03:18,040
INTEGRATION PROCESS FOR HIV AND

6240
06:03:18,040 --> 06:03:21,160
SIV IN MACAQUE AND HUMAN PBMCs

6241
06:03:21,160 --> 06:03:22,240
USING VARIATION ON INTEGRATE

6242
06:03:22,240 --> 06:03:24,160
SITE ANALYSIS YOU HEARD ABOUT

6243
06:03:24,160 --> 06:03:27,160
EARLIER THROUGH THE PROGRAM.

6244
06:03:27,160 --> 06:03:28,720
AND INITIALLY WE CONDUCTED

6245
06:03:28,720 --> 06:03:31,360
COMPARATIVE SITE ANALYSIS FOR IN

6246
06:03:31,360 --> 06:03:34,720
VITRO INFECTION OF HIV VERSUS

6247
06:03:34,720 --> 06:03:36,600
SIV IN PRIMARY HUMAN CELLS CELL

6248
06:03:36,600 --> 06:03:37,360
TO VIRUSES, EXPLORING THE ROLE

6249
06:03:37,360 --> 06:03:41,760
OF THE VIRUS IN CONTRIBUTING

6250
06:03:41,760 --> 06:03:42,640
DIFFERENCES, AND COMPARED

6251
06:03:42,640 --> 06:03:46,040
INTEGRATION SITE ANALYSIS OF SIV

6252
06:03:46,040 --> 06:03:49,200
IN PRIMARY HUMAN PBMCS AND

6253
06:03:49,200 --> 06:03:51,040
MACAQUE PBMC TO EXPLORE HOST

6254
06:03:51,040 --> 06:03:54,360
CELLS, HIV AND MACAQUE CELLS WAS

6255
06:03:54,360 --> 06:03:55,440
A NON-STARTER, IN

6256
06:03:55,440 --> 06:03:56,320
SPECIES-SPECIFIC RESTRICTION

6257
06:03:56,320 --> 06:03:56,880
FACTORS.

6258
06:03:56,880 --> 06:03:59,480
IN ANY EVENT THAT WORK WENT

6259
06:03:59,480 --> 06:04:01,080
REASONABLY WELL, WE PUBLISHED A

6260
06:04:01,080 --> 06:04:02,120
PAPER TOGETHER, MY FIRST AND SO

6261
06:04:02,120 --> 06:04:07,920
FAR ONLY ONE WITH STEVE.

6262
06:04:07,920 --> 06:04:08,560
GRATIFYING PROJECT NONETHELESS.

6263
06:04:08,560 --> 06:04:10,880
A I LONG THE WAY I GOT EXPOSURE

6264
06:04:10,880 --> 06:04:12,320
TO NOT ONLY LEARNING NEW

6265
06:04:12,320 --> 06:04:13,360
TECHNIQUES BUT IN THE PROCESS

6266
06:04:13,360 --> 06:04:16,240
GETTING A FEEL FOR HOW STEVE

6267
06:04:16,240 --> 06:04:18,760
APPROACHES SCIENCE AND THINKS

6268
06:04:18,760 --> 06:04:20,600
ABOUT THINGS AND TELLINGLY THE

6269
06:04:20,600 --> 06:04:23,160
SENSE OF RIGOR HE BROUGHT TO THE

6270
06:04:23,160 --> 06:04:23,920
PROJECT, PARTICULARLY IMPRESSIVE

6271
06:04:23,920 --> 06:04:26,320
FOR ME AS I WAS GETTING EXPOSURE

6272
06:04:26,320 --> 06:04:30,040
AND LEARNING ENTIRELY NEW FIELD 

6273
06:04:30,040 --> 06:04:32,760
IN TERMS OF SOME OF THE ASPECTS

6274
06:04:32,760 --> 06:04:35,720
OF THE INTEGRATION SITE

6275
06:04:35,720 --> 06:04:37,600
ANALYSIS, THE BIOLOGY AND

6276
06:04:37,600 --> 06:04:39,000
INFORMATICS OF IT.

6277
06:04:39,000 --> 06:04:41,320
AND THIS QUOTE SAYS IT ALL.

6278
06:04:41,320 --> 06:04:44,520
THE LEVEL OF RIGOR HE BROUGHT IN

6279
06:04:44,520 --> 06:04:47,240
GOING THROUGH THE ANALYSIS,

6280
06:04:47,240 --> 06:04:51,360
WHICH AGAIN STEVE SHARED WITH ME

6281
06:04:51,360 --> 06:04:53,360
THE CONSIDERATIONS AND MAKING ME

6282
06:04:53,360 --> 06:04:54,560
REALIZE, OH, I HADN'T THOUGHT

6283
06:04:54,560 --> 06:04:55,360
ABOUT THAT.

6284
06:04:55,360 --> 06:04:58,280
WE NEED TO TAKE THAT INTO

6285
06:04:58,280 --> 06:05:01,040
CONSIDERATION HOW WE LOOK AT

6286
06:05:01,040 --> 06:05:02,640
INTEGRATION SITES, BUT YOU'RE

6287
06:05:02,640 --> 06:05:04,440
ABSOLUTELY RIGHT.

6288
06:05:04,440 --> 06:05:05,280
REPEATEDLY GOING THROUGH THINGS,

6289
06:05:05,280 --> 06:05:09,040
WITH ALL THAT SAID, APPLYING

6290
06:05:09,040 --> 06:05:12,760
RIGOROUS THOUGHTS, WE'RE ABLE TO

6291
06:05:12,760 --> 06:05:13,720
SHOW BROAD SIMILARITIES BETWEEN

6292
06:05:13,720 --> 06:05:16,240
SIV AND HIV INTEGRATION AND

6293
06:05:16,240 --> 06:05:18,560
HUMAN AND MACAQUE CELLS BY

6294
06:05:18,560 --> 06:05:22,240
LOOKING AT SITES OF INTEGRATION,

6295
06:05:22,240 --> 06:05:24,240
AND WHEEL THERE WERE MODEST

6296
06:05:24,240 --> 06:05:26,400
DIFFERENCES IN BOTH THE VIRUS

6297
06:05:26,400 --> 06:05:28,040
AND THE HOST CELL SEEMED TO

6298
06:05:28,040 --> 06:05:31,360
CONTRIBUTE TO DIFFERENCES WHEN 

6299
06:05:31,360 --> 06:05:32,440
WE DID APPROPRIATE ANALYSES, ON

6300
06:05:32,440 --> 06:05:34,560
BALANCE THINGS TO BE QUITE

6301
06:05:34,560 --> 06:05:34,800
SIMILAR.

6302
06:05:34,800 --> 06:05:38,240
AND THIS FIGURE FROM THE PAPER

6303
06:05:38,240 --> 06:05:42,000
SUMMARIZED THE MAPPING OF

6304
06:05:42,000 --> 06:05:47,440
INTEGRATION SITES, HIV INTO

6305
06:05:47,440 --> 06:05:48,880
HUMAN PBMCs, SIV INTEGRATION,

6306
06:05:48,880 --> 06:05:55,440
HIV INTO RESEARCH, YOU CAN SEE

6307
06:05:55,440 --> 06:05:56,200
CONCORDANCE BETWEEN INTEGRATION

6308
06:05:56,200 --> 06:05:58,840
PLOT AS YOU LOOK AT THE CIRCOS

6309
06:05:58,840 --> 06:06:01,360
PLOTTING ON THE HUMAN GENOME

6310
06:06:01,360 --> 06:06:03,720
ALTERNATIVE MAPPING TO HUMAN OR

6311
06:06:03,720 --> 06:06:07,000
RHESUS MACAQUE GENOME SYNTHETIC

6312
06:06:07,000 --> 06:06:10,760
LESIONS ON THE ALTERNATIVE

6313
06:06:10,760 --> 06:06:11,720
CIRCOS PLOT.

6314
06:06:11,720 --> 06:06:13,600
ESTABLISHING IN VITRO ANALYSIS

6315
06:06:13,600 --> 06:06:14,680
SUPPORTED GENERAL CONTENTION

6316
06:06:14,680 --> 06:06:16,320
SYSTEMS WERE SIMILAR ENOUGH TO

6317
06:06:16,320 --> 06:06:17,320
POTENTIALLY BE INFORMATIVE WAS

6318
06:06:17,320 --> 06:06:20,520
OUR INITIAL IN VIVO ANALYSIS

6319
06:06:20,520 --> 06:06:23,000
LOOKING AT GROUP OF ANIMALS THAT

6320
06:06:23,000 --> 06:06:25,320
WERE INFECTED, STARTING ON ART

6321
06:06:25,320 --> 06:06:27,760
AT 4 WEEKS INTO INFECTION, AND

6322
06:06:27,760 --> 06:06:29,360
MAINTAINED FOR ABOUT A YEAR

6323
06:06:29,360 --> 06:06:32,160
BEFORE ANALYSIS, A LITTLE OVER A

6324
06:06:32,160 --> 06:06:33,480
YEAR.

6325
06:06:33,480 --> 06:06:35,920
AND WHAT WE OBSERVED WAS THAT

6326
06:06:35,920 --> 06:06:37,480
EVEN IN SOME PRE-ART SAMPLES

6327
06:06:37,480 --> 06:06:41,480
WERE ABLE TO IDENTIFY AS EARLY 

6328
06:06:41,480 --> 06:06:46,760
AS 2 OR 4 WEEKS POST-INFECTION

6329
06:06:46,760 --> 06:06:49,520
EVIDENCE OF CLONALLY EXPANDED

6330
06:06:49,520 --> 06:06:50,600
CELLS, SOME PERSISTENT INTO A

6331
06:06:50,600 --> 06:06:51,480
YEAR ON ART.

6332
06:06:51,480 --> 06:06:52,920
AND THIS WAS CONSISTENT WITH

6333
06:06:52,920 --> 06:06:56,320
SOME OF THE DATA THAT HAS BEEN

6334
06:06:56,320 --> 06:06:59,080
ALLUDED TO EARLIER, ON

6335
06:06:59,080 --> 06:07:01,280
HIV-INFECTED PEOPLE STARTED ON

6336
06:07:01,280 --> 06:07:02,480
EARLY ART.

6337
06:07:02,480 --> 06:07:04,880
WE WERE ABLE TO IDENTIFY UPWARDS

6338
06:07:04,880 --> 06:07:06,760
OF 100 CLONES SEEN AFTER A YEAR

6339
06:07:06,760 --> 06:07:08,840
ON ART, 20% OF THE INTEGRATION

6340
06:07:08,840 --> 06:07:12,080
SITES AFTER A YEAR ON ART WERE

6341
06:07:12,080 --> 06:07:13,400
FROM EXTENDED CLONES INCLUDING

6342
06:07:13,400 --> 06:07:15,600
CLONES WE SHOWED IN MULTIPLE

6343
06:07:15,600 --> 06:07:15,840
TISSUES.

6344
06:07:15,840 --> 06:07:19,520
TO BE CLEAR, THIS IS NOT A MODEL

6345
06:07:19,520 --> 06:07:22,400
FOR LOOKING AT EXTENDED CLONES

6346
06:07:22,400 --> 06:07:24,400
AND INTEGRATION SITES AND SO ON,

6347
06:07:24,400 --> 06:07:26,120
SUBJECT OF THE MULTIPLE

6348
06:07:26,120 --> 06:07:27,800
SELECTIVE PROCESSES THAT

6349
06:07:27,800 --> 06:07:30,120
OCCURRED OVER DECADES OF ART BUT

6350
06:07:30,120 --> 06:07:31,840
IT IS INTERESTING THAT A LOT OF

6351
06:07:31,840 --> 06:07:33,920
BASIC BIOLOGY THAT LEADS TO

6352
06:07:33,920 --> 06:07:35,760
THOSE THINGS IS ESTABLISHED AND

6353
06:07:35,760 --> 06:07:36,760
READILY DEMONSTRABLE IN THE

6354
06:07:36,760 --> 06:07:37,760
FIRST YEAR.

6355
06:07:37,760 --> 06:07:41,920
WE DID SEE ALSO INTEGRATIONS IN 

6356
06:07:41,920 --> 06:07:44,440
SOME OF THESE OVERREPRESENTED

6357
06:07:44,440 --> 06:07:48,080
SITES, ASSOCIATED WITH POTENTIAL

6358
06:07:48,080 --> 06:07:50,040
INCREASED SURVIVAL OF CELLS

6359
06:07:50,040 --> 06:07:51,840
HARBORING INTEGRATION, JUST TO

6360
06:07:51,840 --> 06:07:54,760
SHOW THAT MOTHER NATURE HAS A

6361
06:07:54,760 --> 06:07:56,720
SENSE OF HUMOR, WHEN WE -- AT

6362
06:07:56,720 --> 06:07:58,080
THE TIME WHEN YOU'RE FIRST

6363
06:07:58,080 --> 06:08:02,200
ANALYZING DATA, WE WERE THINKING

6364
06:08:02,200 --> 06:08:03,520
THAT INTEGRATION SITE MIGHT PLAY

6365
06:08:03,520 --> 06:08:05,720
MORE COMMON OR FREQUENT ROLE

6366
06:08:05,720 --> 06:08:06,800
THAN WE CURRENTLY UNDERSTAND,

6367
06:08:06,800 --> 06:08:10,120
THE VERY FIRST CLONE WE

6368
06:08:10,120 --> 06:08:14,080
IDENTIFIED WAS ACTUALLY A

6369
06:08:14,080 --> 06:08:14,720
BLASTOMA LOCUS, INTERESTING TO

6370
06:08:14,720 --> 06:08:16,000
SAY THE LEAST.

6371
06:08:16,000 --> 06:08:18,520
ON ART WE DID EVEN JUST WITHIN

6372
06:08:18,520 --> 06:08:20,480
THE YEAR SEE EVIDENCE OF

6373
06:08:20,480 --> 06:08:21,680
SELECTION FOR INTEGRATION

6374
06:08:21,680 --> 06:08:23,240
OPPOSITE ORIENTATION OF

6375
06:08:23,240 --> 06:08:25,520
TRANSCRIPTION AS SEEN WITH

6376
06:08:25,520 --> 06:08:28,680
HIV-INFECTED PEOPLE AND OVERALL

6377
06:08:28,680 --> 06:08:30,440
CLONAL EXPANSION IN MACAQUES WAS

6378
06:08:30,440 --> 06:08:30,760
SIMILAR.

6379
06:08:30,760 --> 06:08:32,640
THIS MIGHT BE A USEFUL MODEL WE

6380
06:08:32,640 --> 06:08:37,440
COULD TRY TO USE TO STUDY

6381
06:08:37,440 --> 06:08:38,520
BIOLOGY POTENTIALLY PASS

6382
06:08:38,520 --> 06:08:39,920
INTERVENTIONS AND IN PARTICULAR

6383
06:08:39,920 --> 06:08:43,360
SETTING OUT TO TRY AND

6384
06:08:43,360 --> 06:08:45,760
UNDERSTAND ROLE OF

6385
06:08:45,760 --> 06:08:46,760
ANTIGEN-DRIVEN THROUGH

6386
06:08:46,760 --> 06:08:48,560
IMMUNIZATION PROLIFERATION OR

6387
06:08:48,560 --> 06:08:52,400
CYTOKINE DRIVEN PROLIFERATION,

6388
06:08:52,400 --> 06:08:57,480
TRYING TO TEST WHO LEADING

6389
06:08:57,480 --> 06:09:00,240
HYPOTHESES OF ANTIGEN DRIVEN

6390
06:09:00,240 --> 06:09:03,440
PROLIFERATION AND CYTOKINE

6391
06:09:03,440 --> 06:09:03,880
DRIVEN PROLIFERATION.

6392
06:09:03,880 --> 06:09:06,680
A LOT OF CHALLENGES, WE DID A

6393
06:09:06,680 --> 06:09:07,960
LOT OF CALCULATIONS TO DECIDE IF

6394
06:09:07,960 --> 06:09:13,880
WE WERE SPITTING INTO A GALE

6395
06:09:13,880 --> 06:09:16,160
FORCE WIND, DIFFICULT BECAUSE

6396
06:09:16,160 --> 06:09:17,480
OBTAINING SUFFICIENT IN

6397
06:09:17,480 --> 06:09:20,440
VIVO-DERIVED INTEGRATION SITES

6398
06:09:20,440 --> 06:09:21,960
TO ANALYZE FROM ANTIGEN-SPECIFIC

6399
06:09:21,960 --> 06:09:23,400
CELLS IN MACAQUES WAS GOING TO

6400
06:09:23,400 --> 06:09:26,240
BE DIFFICULT BECAUSE CURRENT

6401
06:09:26,240 --> 06:09:28,480
PROCESSES ARE ONLY ABOUT 10%

6402
06:09:28,480 --> 06:09:30,200
DEFICIENT, WE NEED TO SEE --

6403
06:09:30,200 --> 06:09:33,880
NEEDS TO BE AT LEAST 10 TO THE

6404
06:09:33,880 --> 06:09:37,640
6th CELLS TO IDENTIFY EXPANDED

6405
06:09:37,640 --> 06:09:39,600
CLONE, ONLY 100 TO 1,000 CELLS

6406
06:09:39,600 --> 06:09:40,920
ARE INFECTED.

6407
06:09:40,920 --> 06:09:45,520
THE SIGNS OF CD4 IN RESPONSES IS

6408
06:09:45,520 --> 06:09:46,520
OFTEN LOWER THAN CD8 T-CELL

6409
06:09:46,520 --> 06:09:49,640
RESPONSES AND SO THAT WAS A

6410
06:09:49,640 --> 06:09:49,960
LIMITATION.

6411
06:09:49,960 --> 06:09:51,600
AND INFECTED CELLS CAN BE

6412
06:09:51,600 --> 06:09:54,200
ELIMINATED EITHER THROUGH VIRAL

6413
06:09:54,200 --> 06:09:56,200
PROCESSES, MEDIATED CLEARANCE,

6414
06:09:56,200 --> 06:09:58,600
AND/OR ANTIGEN INDUCED CELL

6415
06:09:58,600 --> 06:09:59,560
DEATH PROCESSES.

6416
06:09:59,560 --> 06:10:01,800
ALSO WHILE WE HAD ADVANTAGES FOR

6417
06:10:01,800 --> 06:10:03,440
SAMPLING WERE THERE WERE

6418
06:10:03,440 --> 06:10:04,840
LIMITATIONS, AND FINALLY NEEDED

6419
06:10:04,840 --> 06:10:08,120
TO DEVELOP APPROACH FOR

6420
06:10:08,120 --> 06:10:09,680
SEPARATING IMMUNIZING ANTIGEN

6421
06:10:09,680 --> 06:10:12,720
SPECIFIC VERSUS OTHER CD4 CELLS

6422
06:10:12,720 --> 06:10:14,160
FOR INTEGRATION ANALYSIS.

6423
06:10:14,160 --> 06:10:20,160
I WANT TO CALL OUT OUR GROUP FOR

6424
06:10:20,160 --> 06:10:21,840
DEVELOPING THE APPROACH FOR

6425
06:10:21,840 --> 06:10:24,000
DOING THAT, INITIALLY SCREENING

6426
06:10:24,000 --> 06:10:25,680
MANY ANTIGENS, FINALLY

6427
06:10:25,680 --> 06:10:29,240
IDENTIFYING A HUMAN B CELL LINE 

6428
06:10:29,240 --> 06:10:31,400
PRODUCING THE MOST ROBUST CD4

6429
06:10:31,400 --> 06:10:35,920
RESPONSES UP TO 3 TO 4% OF TOTAL

6430
06:10:35,920 --> 06:10:36,840
CD4 CELLS.

6431
06:10:36,840 --> 06:10:40,120
DEVELOPED A SCHEME FOR PRIME

6432
06:10:40,120 --> 06:10:43,200
BOOST IMMUNIZATION PRIOR TO

6433
06:10:43,200 --> 06:10:45,320
INFECTION, REBOOST AFTER 6

6434
06:10:45,320 --> 06:10:49,280
MONTHS ON ART, FOUR WEEKS POST

6435
06:10:49,280 --> 06:10:50,720
INFECTION, WE KNEW SOME CLONES

6436
06:10:50,720 --> 06:10:54,560
HAD BEEN ESTABLISHED BY THAT

6437
06:10:54,560 --> 06:10:54,960
TIME.

6438
06:10:54,960 --> 06:10:58,040
INFECTED ANIMALS WITH THE

6439
06:10:58,040 --> 06:11:00,240
BARCODED VIRUS, STARTED ON 4

6440
06:11:00,240 --> 06:11:02,400
WEEK SAMPLED BEFORE EACH

6441
06:11:02,400 --> 06:11:03,200
INTERVENTION, DEVELOPED AND

6442
06:11:03,200 --> 06:11:04,720
APPLIED PROCESS LOOKING AT BOTH

6443
06:11:04,720 --> 06:11:08,360
BLOOD CELLS AND LYMPH NODE CELLS

6444
06:11:08,360 --> 06:11:10,760
TO ENRICH FOR CD4 POSITIVE CELLS

6445
06:11:10,760 --> 06:11:13,280
USING A SHORT-TERM ANTIGEN

6446
06:11:13,280 --> 06:11:15,480
STIMULATION TO IDENTIFY CELLS

6447
06:11:15,480 --> 06:11:17,400
THAT SHOWED SPECIFIC RECOGNITION

6448
06:11:17,400 --> 06:11:20,840
OF THAT ANTIGEN BASED ON

6449
06:11:20,840 --> 06:11:25,440
INDUCTION OF ACTIVATION MARKER 

6450
06:11:25,440 --> 06:11:27,160
BY FLOW CYTOMETRY, USING

6451
06:11:27,160 --> 06:11:27,760
INTEGRATION SITE ANALYSIS

6452
06:11:27,760 --> 06:11:30,160
APPROACH TO ASK A QUESTION, IS

6453
06:11:30,160 --> 06:11:31,920
THERE EVIDENCE FOR INCREASED

6454
06:11:31,920 --> 06:11:32,960
RATIO OF CLONAL INTEGRATION

6455
06:11:32,960 --> 06:11:35,080
SITES RELATIVE TO TOTAL

6456
06:11:35,080 --> 06:11:36,960
INTEGRATION SITES IN ANTIGEN

6457
06:11:36,960 --> 06:11:40,840
REACTIVE CD4 CELLS, FROM THE

6458
06:11:40,840 --> 06:11:42,200
IMMUNIZING ANTIGEN VERSUS TOTAL

6459
06:11:42,200 --> 06:11:45,160
CD4s, SORT OF A FALSE SETUP

6460
06:11:45,160 --> 06:11:52,680
BECAUSE IT'S BEEN ALLUDED TO ALL

6461
06:11:52,680 --> 06:11:55,240
REPRESENT CLONES BUT IN THE

6462
06:11:55,240 --> 06:11:56,840
LIMIT OF SENSITIVITY IS

6463
06:11:56,840 --> 06:11:58,720
OVERREPRESENTING, WE'RE TRYING

6464
06:11:58,720 --> 06:12:01,480
TO LOOK AT FOR VISUAL LEARNERS

6465
06:12:01,480 --> 06:12:05,200
SUMMARIZING THE SCHEME BEFORE

6466
06:12:05,200 --> 06:12:07,840
INFECTION, IMMUNIZING TWICE, AND

6467
06:12:07,840 --> 06:12:08,720
THEN INFECTING THE ANIMALS

6468
06:12:08,720 --> 06:12:13,320
STARTING THEM ON ART AT 4 WEEKS,

6469
06:12:13,320 --> 06:12:16,920
AND BOOSTING AGAIN AT 6 MONTHS

6470
06:12:16,920 --> 06:12:23,360
ON ART, WITH LEUKAPHERESIS,

6471
06:12:23,360 --> 06:12:25,160
BECAUSE OF COVID-RELATED DELAYS

6472
06:12:25,160 --> 06:12:30,960
HAS GONE ON LONGER, LOOKING AT

6473
06:12:30,960 --> 06:12:34,680
SITE ANALYSIS INCLUDING AFTER

6474
06:12:34,680 --> 06:12:35,480
IL-15 ADMINISTRATION.

6475
06:12:35,480 --> 06:12:37,400
REALLY WHEN I FOUND OUT ABOUT

6476
06:12:37,400 --> 06:12:38,800
THIS SYMPOSIUM I WAS HOPING WE

6477
06:12:38,800 --> 06:12:40,720
WOULD HAVE THIS PROJECT FURTHER

6478
06:12:40,720 --> 06:12:42,120
ALONG, THIS IS ONE OF THE

6479
06:12:42,120 --> 06:12:43,440
PROJECTS WHERE NOTHING HAS GONE

6480
06:12:43,440 --> 06:12:45,520
AS QUICKLY AS WE WERE HOPING IT

6481
06:12:45,520 --> 06:12:46,960
WOULD.

6482
06:12:46,960 --> 06:12:49,840
SO I DON'T HAVE THE DATA TO

6483
06:12:49,840 --> 06:12:51,800
PRESENT TODAY, WHAT I MOSTLY

6484
06:12:51,800 --> 06:12:53,760
HAVE IS JUST TEASER DATA, A LOT

6485
06:12:53,760 --> 06:12:55,280
OF HARD WORK IN OPTIMIZING

6486
06:12:55,280 --> 06:12:57,120
PROCEDURES TRYING TO MAKE THEM

6487
06:12:57,120 --> 06:12:58,480
RIGOROUS TO STANDARDS THAT STEVE

6488
06:12:58,480 --> 06:12:59,960
WOULD BE COMFORTABLE WITH ON

6489
06:12:59,960 --> 06:13:03,920
BOTH WET LAB SIDE OF THINGS AND

6490
06:13:03,920 --> 06:13:06,120
INFORMATICS SIDE AGAIN WITH A

6491
06:13:06,120 --> 06:13:07,960
LOT OF ADAPTATIONS OF THINGS

6492
06:13:07,960 --> 06:13:09,800
WELL WORKED OUT FOR HIV BUT

6493
06:13:09,800 --> 06:13:12,800
ADAPTING THEM TO MILIEU OF SIV

6494
06:13:12,800 --> 06:13:14,240
INFECTION IN MACAQUES.

6495
06:13:14,240 --> 06:13:15,320
ANALYSES ARE IN PROGRESS.

6496
06:13:15,320 --> 06:13:18,600
AND JUST AS A TEASER, WE DO HAVE

6497
06:13:18,600 --> 06:13:21,560
A PRELIMINARY SUGGESTS OF

6498
06:13:21,560 --> 06:13:22,520
INCREASED FREQUENCY, INCREASED

6499
06:13:22,520 --> 06:13:24,240
PROPORTION OF CLONAL INTEGRATION

6500
06:13:24,240 --> 06:13:26,360
SITES TO TOTAL INTEGRATION SITES

6501
06:13:26,360 --> 06:13:30,280
AND ALSO A LARGER SIZE OF THE

6502
06:13:30,280 --> 06:13:37,120
CLONES IN TERMS OF THE NUMBER OF

6503
06:13:37,120 --> 06:13:41,360
 DIFFERENT REPRESENTATIVES FOR 

6504
06:13:41,360 --> 06:13:42,360
IMMUNIZING ANTIGEN, LIMITED

6505
06:13:42,360 --> 06:13:43,560
NUMBER OF SPECIMENS WE'VE BEEN

6506
06:13:43,560 --> 06:13:45,880
ABLE TO ANALYZE TO DATE, AND

6507
06:13:45,880 --> 06:13:48,480
WE'RE WORKING ON SOME OF THE

6508
06:13:48,480 --> 06:13:49,680
COMPLETED ANALYSIS ALSO LOOKING

6509
06:13:49,680 --> 06:13:53,400
FORWARD TO LONGITUDINAL WITHIN

6510
06:13:53,400 --> 06:13:55,040
ANIMAL AND ALSO COMPARISONS,

6511
06:13:55,040 --> 06:13:56,400
JUST A BRIEF SUMMARY TO GIVE YOU

6512
06:13:56,400 --> 06:13:59,120
A FEEL FOR THE KINDS OF DATA

6513
06:13:59,120 --> 06:14:01,760
THAT WE'RE GENERATING, ON THE

6514
06:14:01,760 --> 06:14:12,240
LEFT SIDE  CIRCOS PLOT, WITH

6515
06:14:14,800 --> 06:14:23,480
REASONS IN RED, ORANGE, UNIQUE

6516
06:14:23,480 --> 06:14:24,480
WITHIN THE ANALYSIS, PRE AND

6517
06:14:24,480 --> 06:14:26,080
POST THIRD BOOSTER, WE GOT A TON

6518
06:14:26,080 --> 06:14:28,560
OF DATA AND A LOT MORE TO

6519
06:14:28,560 --> 06:14:29,560
GENERATION BUT WE'RE EXCITED

6520
06:14:29,560 --> 06:14:31,960
THAT AFTER A LOT OF HARD WORK WE

6521
06:14:31,960 --> 06:14:34,040
THINK WE MAY HAVE AN INFORMATIVE

6522
06:14:34,040 --> 06:14:35,880
EXPERIMENT HERE TO ADDRESS THIS.

6523
06:14:35,880 --> 06:14:38,080
SO NEXT STAGE OF THINGS IS TO

6524
06:14:38,080 --> 06:14:40,120
COMPLETE THE IN VIVO PHASE OF

6525
06:14:40,120 --> 06:14:42,680
THE EXPERIMENT, THESE ARE VERY

6526
06:14:42,680 --> 06:14:44,000
LABOR INTENSIVE EXPERIMENTS ON

6527
06:14:44,000 --> 06:14:45,720
THE IN VIVO PART, AND SO THEY

6528
06:14:45,720 --> 06:14:47,720
ARE STAGGERED IN PAIRS OF

6529
06:14:47,720 --> 06:14:49,480
ANIMALS BECAUSE THAT'S ALL THE

6530
06:14:49,480 --> 06:14:52,320
ANIMAL FACILITY CAN HANDLE AT

6531
06:14:52,320 --> 06:14:53,960
ANY ONE TIME BUT IT'S GOING

6532
06:14:53,960 --> 06:14:57,000
WELL, COMPLETING ALL THE

6533
06:14:57,000 --> 06:14:57,800
INTEGRATION SITE ANALYSIS, AND

6534
06:14:57,800 --> 06:15:01,960
WE'RE IN THE PROCESS OF TRYING 

6535
06:15:01,960 --> 06:15:08,440
TO ADAPT TECHNIQUES TO DO NOT

6536
06:15:08,440 --> 06:15:17,600
JUST INTEGRATE CELL ANALYSIS BUT

6537
06:15:17,600 --> 06:15:19,040
FOR BARCODE ANALYSIS AND

6538
06:15:19,040 --> 06:15:21,200
ASPIRATIONALLY HOPE TO DO SOME

6539
06:15:21,200 --> 06:15:24,960
OF THE FANCIER THINGS PEOPLE

6540
06:15:24,960 --> 06:15:27,680
LIKE OTHERS HAVE DONE, SINGLE

6541
06:15:27,680 --> 06:15:29,080
CELL RNA SEQUENCING AS ALLUDED

6542
06:15:29,080 --> 06:15:30,840
TO IN A PROFESSIONAL QUESTION TO

6543
06:15:30,840 --> 06:15:34,320
GET A FEEL FOR TRANSCRIPTOMICS,

6544
06:15:34,320 --> 06:15:38,160
TCR SEQUENCING ON SOME OF THESE

6545
06:15:38,160 --> 06:15:40,920
EXPANDED CLONES, LOOKING AT THE

6546
06:15:40,920 --> 06:15:47,480
SECOND HYPOTHESIS, THE ROAM OF

6547
06:15:47,480 --> 06:15:48,920
CYTOKINES, HOMEOSTATIC CYTOKINES

6548
06:15:48,920 --> 06:15:50,440
CONTRIBUTING TO CLONAL

6549
06:15:50,440 --> 06:15:51,200
PERSISTENCE OR EXPANSION, THIS

6550
06:15:51,200 --> 06:15:52,320
IS IMPORTANT BECAUSE SOME OF THE

6551
06:15:52,320 --> 06:15:54,840
WORK THAT WE'RE DOING AND MANY

6552
06:15:54,840 --> 06:15:58,440
IN THE FIELD ARE DOING TO LOOK

6553
06:15:58,440 --> 06:16:02,480
AT APPROACHES FOR REDUCING OR

6554
06:16:02,480 --> 06:16:03,680
ELIMINATING BIORESERVOIRS,

6555
06:16:03,680 --> 06:16:05,560
INCORPORATING CYTOKINES AS PART

6556
06:16:05,560 --> 06:16:06,720
OF IMMUNOTHERAPY APPROACH,

6557
06:16:06,720 --> 06:16:08,680
IMPORTANT TO UNDERSTAND IMPACT.

6558
06:16:08,680 --> 06:16:13,560
FINALLY IN ANOTHER DELAYED

6559
06:16:13,560 --> 06:16:15,160
PROJECT, SEEMS IRONIC IT'S

6560
06:16:15,160 --> 06:16:16,800
TAKING OFF AS STEVE IS

6561
06:16:16,800 --> 06:16:19,520
OFFICIALLY DEPARTING BUT LIKE

6562
06:16:19,520 --> 06:16:24,720
OTHERS I HOPE IT'S MORE

6563
06:16:24,720 --> 06:16:26,720
FIGURATIVE THAN LITERAL, WORKING

6564
06:16:26,720 --> 06:16:31,360
WITH HARRY BURKE AND COLLEAGUES

6565
06:16:31,360 --> 06:16:34,360
TO EVALUATE INHIBITOR THAT IS

6566
06:16:34,360 --> 06:16:37,000
ACTIVE AGAINST RESISTANT

6567
06:16:37,000 --> 06:16:38,760
VARIANTS THAT DMITRY PRESENTED

6568
06:16:38,760 --> 06:16:43,000
LOOKING AT OPTIMIZATION OF

6569
06:16:43,000 --> 06:16:43,560
FORMULATION AND

6570
06:16:43,560 --> 06:16:46,040
PHARMACOKINETICS, HOPING TO MOVE

6571
06:16:46,040 --> 06:16:47,920
TO EVALUATE ACTIVITY IN VIVO AND

6572
06:16:47,920 --> 06:16:48,600
NON-HUMAN PRIMATE.

6573
06:16:48,600 --> 06:16:50,560
I WANT TO ACKNOWLEDGE SOME FOLKS

6574
06:16:50,560 --> 06:16:52,080
THAT MADE KEY CONTRIBUTIONS TO

6575
06:16:52,080 --> 06:16:56,040
THE WORKS THAT I PRESENTED, YOU

6576
06:16:56,040 --> 06:16:59,520
PLAYED A KEY ROLE IN DEVELOPING

6577
06:16:59,520 --> 06:17:04,800
PROCEDURES FOR PROCESSING THE 

6578
06:17:04,800 --> 06:17:07,880
ORIGINAL SPECIMEN FROM ANIMALS,

6579
06:17:07,880 --> 06:17:11,680
DEVELOPING TECHNIQUES FOR

6580
06:17:11,680 --> 06:17:13,200
ISOLATING CELLS, ADRIAN

6581
06:17:13,200 --> 06:17:15,400
SWANSTROM WHO HAS WRITTEN ON

6582
06:17:15,400 --> 06:17:16,720
COMPLICATED EXPERIMENTS, MAKING

6583
06:17:16,720 --> 06:17:17,600
SURE EVERYTHING GOT DONE AT THE

6584
06:17:17,600 --> 06:17:21,200
TIME IT WAS SUPPOSED TO,

6585
06:17:21,200 --> 06:17:22,000
QUANTITATIVE MOLECULAR

6586
06:17:22,000 --> 06:17:26,760
DIAGNOSTIC CORES THAT DID

6587
06:17:26,760 --> 06:17:27,440
MONITORING, NON-HUMAN PRIMATE

6588
06:17:27,440 --> 06:17:30,120
SUPPORT CORE FOLKS WHO PROCESSED

6589
06:17:30,120 --> 06:17:36,880
ANIMALS INCLUDING GEORGE AT THE 

6590
06:17:36,880 --> 06:17:38,280
BETHESDA NON-HUMAN PRIMATE

6591
06:17:38,280 --> 06:17:38,640
FACILITY.

6592
06:17:38,640 --> 06:17:40,560
VAN AND CHRISTINE RESPONSIBLE

6593
06:17:40,560 --> 06:17:42,080
FOR OVERSEEING THE SEQUENCING

6594
06:17:42,080 --> 06:17:43,720
INVOLVED IN INTEGRATE SITE

6595
06:17:43,720 --> 06:17:45,720
ANALYSIS, CHARLIE GOODMAN FOR

6596
06:17:45,720 --> 06:17:46,680
INFORMATICS AND OPTIMIZATION OF

6597
06:17:46,680 --> 06:17:51,640
THE PIPELINE FOR LOOKING AT THIS

6598
06:17:51,640 --> 06:17:53,360
ALONG WITH HELPERS OF

6599
06:17:53,360 --> 06:17:54,600
STATISTICAL ANALYSIS TO MAKE

6600
06:17:54,600 --> 06:17:59,440
SURE WE CAN BELIEVE THE THINGS

6601
06:17:59,440 --> 06:18:00,720
WE'RE SEEING.

6602
06:18:00,720 --> 06:18:04,680
CELLULAR IMMUNOLOGY CORE HELPED

6603
06:18:04,680 --> 06:18:06,200
WITH FLOW CYTOMETRY SORTING, THE

6604
06:18:06,200 --> 06:18:09,800
CHEMISTRY CORE WORKED WITH

6605
06:18:09,800 --> 06:18:10,680
BIOLOGICAL PROTEIN PRODUCTS

6606
06:18:10,680 --> 06:18:14,600
CORE, AND GEORGE ON PREPARING,

6607
06:18:14,600 --> 06:18:15,800
ISOLATING, PURIFYING AND

6608
06:18:15,800 --> 06:18:17,440
CHARACTERIZING L15 WE'RE USING

6609
06:18:17,440 --> 06:18:20,840
AND VETERINARY STAFF IN BETHESDA

6610
06:18:20,840 --> 06:18:23,040
FACILITY, CRITICAL TO THESE

6611
06:18:23,040 --> 06:18:26,040
STUDIES, WITHIN THE DRP ANDREA

6612
06:18:26,040 --> 06:18:30,920
MADE KEY CONTRIBUTIONS TO THE 

6613
06:18:30,920 --> 06:18:31,800
FIRST PUBLICATION, JOHN AND

6614
06:18:31,800 --> 06:18:33,240
STEVE HAVE BEEN INVALUABLE AND A

6615
06:18:33,240 --> 06:18:39,040
PLEASURE TO WORK WITH, 

6616
06:18:39,040 --> 06:18:40,120
SUPPLEMENTED WITH WORK FROM SOME

6617
06:18:40,120 --> 06:18:41,520
COLLEAGUES AND DRUGS FOR

6618
06:18:41,520 --> 06:18:45,160
SUPPRESSION OF VIRUS IN THE

6619
06:18:45,160 --> 06:18:48,120
ANIMALS, I'D LIKE TO RECOGNIZE

6620
06:18:48,120 --> 06:18:54,560
OUR COLLEAGUES AT GILEAD.

6621
06:18:54,560 --> 06:18:56,840
I'LL STOP THERE SO IT'S BEEN AN

6622
06:18:56,840 --> 06:18:58,280
ABSOLUTE PLEASURE TO GET A

6623
06:18:58,280 --> 06:19:01,680
CHANCE TO FINALLY AFTER ALL

6624
06:19:01,680 --> 06:19:05,400
THESE YEARS WORK TOGETHER ON A

6625
06:19:05,400 --> 06:19:06,960
PROJECT, I'M REGRETFUL THAT, YOU

6626
06:19:06,960 --> 06:19:07,480
KNOW, THINGS ARE FINALLY

6627
06:19:07,480 --> 06:19:09,760
STARTING TO HEAT UP AND GET

6628
06:19:09,760 --> 06:19:11,760
EXCITING AT THE TIME THAT YOU'RE

6629
06:19:11,760 --> 06:19:12,960
AT LEAST PARTIALLY DEPARTING BUT

6630
06:19:12,960 --> 06:19:14,960
AT THE SAME TIME I WANT TO

6631
06:19:14,960 --> 06:19:16,160
CONCLUDE BY SAYING THANK YOU FOR

6632
06:19:16,160 --> 06:19:16,480
EVERYTHING.

6633
06:19:16,480 --> 06:19:18,360
IT'S BEEN A JOY TO HAVE A CHANCE

6634
06:19:18,360 --> 06:19:21,080
TO WORK WITH YOU AND GET TO KNOW

6635
06:19:21,080 --> 06:19:21,240
YOU.

6636
06:19:21,240 --> 06:19:23,800
I WISH YOU MUCH HAPPINESS AND

6637
06:19:23,800 --> 06:19:26,720
FULFILLMENT IN RETIREMENT AND

6638
06:19:26,720 --> 06:19:30,200
HOPE I CONTINUE TO CONSULT YOU

6639
06:19:30,200 --> 06:19:31,360
IN SCIENCE AND TRYING TO FIGURE

6640
06:19:31,360 --> 06:19:33,360
OUT THE MINDS OF FISH.

6641
06:19:33,360 --> 06:19:34,040
THANK YOU, STEVE.

6642
06:19:34,040 --> 06:19:37,120
[APPLAUSE]

6643
06:19:37,120 --> 06:19:43,120
>>THANKS VERY MUCH.

6644
06:19:43,120 --> 06:19:43,800
QUESTIONS?

6645
06:19:43,800 --> 06:19:46,400
>>THIS IS A QUESTION
ABOUT HOW

6646
06:19:46,400 --> 06:19:50,240
LONG WE HAVE TO WAIT TO

6647
06:19:50,240 --> 06:19:51,360
(INDISCERNIBLE) AND WONDERING

6648
06:19:51,360 --> 06:19:58,200
IF -- YOU MENTIONED IN A RATIO

6649
06:19:58,200 --> 06:19:59,360
OF INTEGRANT (INDISCERNIBLE) TO

6650
06:19:59,360 --> 06:20:01,280
CHANGE OVER TIME.

6651
06:20:01,280 --> 06:20:05,320
AFTER A YEAR WHERE ARE YOU ON

6652
06:20:05,320 --> 06:20:08,760
THE RATIO RELATIVE TO

6653
06:20:08,760 --> 06:20:09,360
(INDISCERNIBLE)?

6654
06:20:09,360 --> 06:20:09,800
>>GOOD QUESTION.

6655
06:20:09,800 --> 06:20:15,840
I CAN'T ANSWER OFF THE CUFF.

6656
06:20:15,840 --> 06:20:19,920
BUT I WILL  DREDGE UP NUMBERS.

6657
06:20:19,920 --> 06:20:21,880
WE CAN LOOK AT ONE YEAR, AND

6658
06:20:21,880 --> 06:20:24,600
COMPARE THAT TO SOME OF THE HIV

6659
06:20:24,600 --> 06:20:26,600
LITERATURE I USE AT VARIOUS

6660
06:20:26,600 --> 06:20:28,040
TIMES AND TRY AND GET BACK TO

6661
06:20:28,040 --> 06:20:34,840
YOU. 

6662
06:20:34,840 --> 06:20:35,120
>>THANKS.

6663
06:20:35,120 --> 06:20:38,280
[APPLAUSE]

6664
06:20:38,280 --> 06:20:46,080
 

6665
06:20:46,080 --> 06:20:47,920
 

6666
06:20:47,920 --> 06:20:53,800
>>WE'RE JOINED BY NITA
MAIHLE,

6667
06:20:53,800 --> 06:20:55,160
ON SIGNAL TRANSDUCTION, ONE OF

6668
06:20:55,160 --> 06:20:59,520
THE FIRST POSTDOCS, WILL KNOW 

6669
06:20:59,520 --> 06:21:01,480
DOUBT SHARE WITH US RECOLLECTION

6670
06:21:01,480 --> 06:21:05,640
OF THE EARLY DAYS OF STEVE'S

6671
06:21:05,640 --> 06:21:09,360
CAREER. 

6672
06:21:09,360 --> 06:21:10,640
>>A PLEASURE TO BE HERE
WITH

6673
06:21:10,640 --> 06:21:12,880
STEVE TO HEAR HIM ROASTED AND

6674
06:21:12,880 --> 06:21:14,280
ADMIRED BY SO MANY.

6675
06:21:14,280 --> 06:21:16,360
WE WOULD BE REMISS IF WE DIDN'T

6676
06:21:16,360 --> 06:21:22,720
THINK ABOUT THE LARGE NUMBER OF

6677
06:21:22,720 --> 06:21:23,720
TRAINEES INCLUDING MYSELF STEVE

6678
06:21:23,720 --> 06:21:25,560
HAD THROUGH THE YEARS.

6679
06:21:25,560 --> 06:21:31,280
WE'VE HEARD OF HIS PROFESSIONAL

6680
06:21:31,280 --> 06:21:34,640
ATTRIBUTES INCLUDING KEEN

6681
06:21:34,640 --> 06:21:36,400
INTELLECT, AMBITION, CURIOSITY,

6682
06:21:36,400 --> 06:21:39,920
BOUNDLESS ENERGY AND GENEROUS

6683
06:21:39,920 --> 06:21:41,880
SPIRIT, THERE ARE AT LEAST THREE

6684
06:21:41,880 --> 06:21:43,520
I CAN THINK OF THAT CONTRIBUTED

6685
06:21:43,520 --> 06:21:47,120
A LOT TO OUR FIELD.

6686
06:21:47,120 --> 06:21:48,280
BIOMEDICAL RESEARCH AND THE

6687
06:21:48,280 --> 06:21:51,960
LIVES OF MANY OF THE FOLKS HE'S

6688
06:21:51,960 --> 06:21:53,720
MENTORED INCLUDING MYSELF.

6689
06:21:53,720 --> 06:22:02,240
I WAS STEVE'S THIRD FELLOW,

6690
06:22:02,240 --> 06:22:04,800
FIRST WAS FOUNDER OF STRATEGY,

6691
06:22:04,800 --> 06:22:10,880
THIRD WAS WELL KNOWN WATCHER

6692
06:22:10,880 --> 06:22:18,440
BIOLOGIST OF THE ACTIN MYOSIN

6693
06:22:18,440 --> 06:22:19,840
FAMILY, AND MYSELFA CANCER

6694
06:22:19,840 --> 06:22:21,200
BIOLOGIEST AT THE MAYO CLINIC

6695
06:22:21,200 --> 06:22:23,480
FOR 15 YEARS, AND YALE SCHOOL OF

6696
06:22:23,480 --> 06:22:26,000
MEDICINE FOR TEN YEARS, AND MORE

6697
06:22:26,000 --> 06:22:27,640
RECENTLY I'VE BEEN WORKING A

6698
06:22:27,640 --> 06:22:28,640
COUPLE SMALLER MEDICAL SCHOOLS

6699
06:22:28,640 --> 06:22:34,600
IN THE SOUTH HELPING THEM BUILD

6700
06:22:34,600 --> 06:22:36,600
RESEARCH AND EDUCATION PROGRAMS,

6701
06:22:36,600 --> 06:22:39,880
STILL ACTIVELY SERVE AS DEAN FOR

6702
06:22:39,880 --> 06:22:43,280
VIRTUAL ACADEMY FOR OVARIAN

6703
06:22:43,280 --> 06:22:43,960
CANCER.

6704
06:22:43,960 --> 06:22:46,560
COMING BACK TO STEVE'S

6705
06:22:46,560 --> 06:22:48,520
ATTRIBUTES, I THINK ONE OF THE

6706
06:22:48,520 --> 06:22:54,880
THINGS FOLKS DON'T OFTEN 

6707
06:22:54,880 --> 06:22:56,080
R EALIZE, HE'S BEEN A TREMENDOUS

6708
06:22:56,080 --> 06:22:57,920
CHAMPION FOR WOMEN IN SCIENCE

6709
06:22:57,920 --> 06:22:59,560
AND WOMEN IN MEDICINE INCLUDING

6710
06:22:59,560 --> 06:23:02,120
MY OWN CAREER.

6711
06:23:02,120 --> 06:23:04,600
HE'S BEEN A STALWART ADVOCATE.

6712
06:23:04,600 --> 06:23:07,120
I RANDOMLY SPOKE WITH A WOMAN

6713
06:23:07,120 --> 06:23:10,520
WHO SAT DOWN AT LUNCH TODAY, LIZ

6714
06:23:10,520 --> 06:23:13,920
FROM UTAH, FIRST THING SHE SAID,

6715
06:23:13,920 --> 06:23:15,000
STEVE BEEN A CHEERLEADER FOR ME

6716
06:23:15,000 --> 06:23:16,120
AND MY WORK.

6717
06:23:16,120 --> 06:23:18,120
NO SURPRISE TO ME AT ALL.

6718
06:23:18,120 --> 06:23:22,040
AND I THINK IT'S VERY IMPORTANT

6719
06:23:22,040 --> 06:23:24,120
THAT FOLKS OF STEVE'S CALIBER

6720
06:23:24,120 --> 06:23:26,840
HAVE BEEN ABLE TO MOVE THE

6721
06:23:26,840 --> 06:23:28,480
NEEDLE IN THIS REGARD, WE HEAR A

6722
06:23:28,480 --> 06:23:30,680
LOT OF RHETORIC ABOUT THAT

6723
06:23:30,680 --> 06:23:32,760
TOPIC, PARTICULARLY TRENDY RIGHT

6724
06:23:32,760 --> 06:23:34,280
NOW, BUT THESE ARE VALUES STEVE

6725
06:23:34,280 --> 06:23:37,800
HAD FROM EARLY DAYS OF HIS

6726
06:23:37,800 --> 06:23:45,800
CAREER AND HE'S ACTED ON THEM

6727
06:23:45,800 --> 06:23:46,120
ACCORDINGLY.

6728
06:23:46,120 --> 06:23:47,960
SECOND, AGENDA RHETORIC IN

6729
06:23:47,960 --> 06:23:50,240
ACADEMIC MEDICAL CENTERS ABOUT

6730
06:23:50,240 --> 06:23:51,040
INTEGRITY AND CHARACTER RUNS

6731
06:23:51,040 --> 06:23:56,520
DEEP BUT WE HAVE VERY FEW ROLE

6732
06:23:56,520 --> 06:23:59,040
MODELS WHO HAVE STRONG PERSONAL

6733
06:23:59,040 --> 06:24:00,800
VALUES, PROFESSIONAL VALUES,

6734
06:24:00,800 --> 06:24:02,240
THAT THEY LIVE BY EVERY DAY.

6735
06:24:02,240 --> 06:24:05,080
IT WAS MY BISHOP EARLIER WHO

6736
06:24:05,080 --> 06:24:06,360
SPOKE ABOUT STEVE HAVING A

6737
06:24:06,360 --> 06:24:09,120
PENCHANT FOR SPEAKING TRUTH TO

6738
06:24:09,120 --> 06:24:10,320
POWER, AND CERTAINLY EVERYONE

6739
06:24:10,320 --> 06:24:13,040
WHO KNOWS HIM KNOWS THAT THAT IS

6740
06:24:13,040 --> 06:24:15,960
A PENCHANT THAT HE HAS.

6741
06:24:15,960 --> 06:24:18,920
HE'S REALLY SERVED AS TREMENDOUS

6742
06:24:18,920 --> 06:24:24,400
ROLE MODEL FOR ALL OF US IN 

6743
06:24:24,400 --> 06:24:27,600
LIVING BY THOSE STANDARDS, AND

6744
06:24:27,600 --> 06:24:29,640
FINALLY THE LAST COMMENT IN

6745
06:24:29,640 --> 06:24:36,480
TERMS OF PERSONAL ATTRIBUTES,

6746
06:24:36,480 --> 06:24:40,080
STEVE IS EXCEPTIONAL IN MAKING

6747
06:24:40,080 --> 06:24:41,920
TIME TO BUILD RELATIONSHIP WITH

6748
06:24:41,920 --> 06:24:43,360
ANYONE HE CONSIDERS IMPORTANT

6749
06:24:43,360 --> 06:24:47,320
AND HE CONSIDERS EVERYONE HERE 

6750
06:24:47,320 --> 06:24:50,360
IMPORTANT AND LOVES PEOPLE.

6751
06:24:50,360 --> 06:24:51,960
AS HIS MASTERY AT DOING THAT

6752
06:24:51,960 --> 06:24:55,160
WHEN I WAS A POSTDOC, I HELPED

6753
06:24:55,160 --> 06:24:58,600
HIM MOVE HIS LAB IN A U-HAUL

6754
06:24:58,600 --> 06:25:02,680
TRUCK FROM COLD SPRING HARBOR TO

6755
06:25:02,680 --> 06:25:06,440
THIS CAMPUS IN 1984.

6756
06:25:06,440 --> 06:25:09,480
AND ELAINE AND I USED TO JOKE

6757
06:25:09,480 --> 06:25:11,040
ABOUT STEVE ALWAYS BEING ON THE

6758
06:25:11,040 --> 06:25:15,320
THRONE, WE  -- PHONE, AND WE

6759
06:25:15,320 --> 06:25:17,560
WOULD LIKE TO BE ON THE OTHER

6760
06:25:17,560 --> 06:25:18,920
END OF THE PHONE FOR FIVE

6761
06:25:18,920 --> 06:25:19,920
MINUTES BUT NOW HAVING BEEN ON

6762
06:25:19,920 --> 06:25:21,560
THE OTHER END OF THE PHONE OR

6763
06:25:21,560 --> 06:25:23,040
E-MAIL OR WHATEVER FOR MANY

6764
06:25:23,040 --> 06:25:27,400
YEARS I CAN TELL YOU ONE OF THE

6765
06:25:27,400 --> 06:25:28,640
THINGS ABOUT HIM, THE IMPORTANCE

6766
06:25:28,640 --> 06:25:31,160
THAT HE'S PUT IN OUR

6767
06:25:31,160 --> 06:25:33,520
RELATIONSHIP AND HIS

6768
06:25:33,520 --> 06:25:36,320
RELATIONSHIP WITH OTHERS, I 

6769
06:25:36,320 --> 06:25:41,200
THINK IT'S A REALLY IMPORTANT 

6770
06:25:41,200 --> 06:25:43,280
PERSONAL ATTRIBUTE TO HAVE,

6771
06:25:43,280 --> 06:25:45,680
SERVES AS A ROLE MODEL FOR US

6772
06:25:45,680 --> 06:25:47,680
ALL, DESERVINGS A ROUND OF

6773
06:25:47,680 --> 06:25:50,320
APPLAUSE FOR NOT ONLY THESE

6774
06:25:50,320 --> 06:25:51,520
ATTRIBUTES BUT MANY

6775
06:25:51,520 --> 06:25:54,680
CONTRIBUTIONS HE'S MADE IN OUR

6776
06:25:54,680 --> 06:25:56,960
CAREERS AND SIMILAR THINGS AS

6777
06:25:56,960 --> 06:25:57,360
WELL, STEVE.

6778
06:25:57,360 --> 06:26:05,520
[APPLAUSE] 

6779
06:26:05,520 --> 06:26:09,120
 

6780
06:26:09,120 --> 06:26:09,720
>>THANK YOU.

6781
06:26:09,720 --> 06:26:10,560
EXTREMELY WELL SAID.

6782
06:26:10,560 --> 06:26:12,320
THIS BRINGS US ALMOST TO THE END

6783
06:26:12,320 --> 06:26:14,440
OF THE VERY REMARKABLE DAY.

6784
06:26:14,440 --> 06:26:18,000
I'D LIKE TO THANK ALL OF THE

6785
06:26:18,000 --> 06:26:19,960
SPEAKERS FOR TALKS BOTH EXCITING

6786
06:26:19,960 --> 06:26:20,360
AND ENTERTAINING.

6787
06:26:20,360 --> 06:26:22,480
I'D LIKE TO THANK YOU FOR

6788
06:26:22,480 --> 06:26:22,880
ATTENDING.

6789
06:26:22,880 --> 06:26:24,600
ALSO WOULD LIKE TO THANK THE

6790
06:26:24,600 --> 06:26:28,960
ONLINE AUDIENCE, WHICH HAS BEEN

6791
06:26:28,960 --> 06:26:30,440
QUITE LARGE, 200 PEOPLE, AND I

6792
06:26:30,440 --> 06:26:32,960
FEEL BAD THEY WERE NEGLECTED IN

6793
06:26:32,960 --> 06:26:34,600
TERMS OF CONTRIBUTING QUESTIONS

6794
06:26:34,600 --> 06:26:36,200
AND DISCUSSION BUT WE JUST HAD

6795
06:26:36,200 --> 06:26:38,200
TO BE ON A TIGHT SCHEDULE.

6796
06:26:38,200 --> 06:26:40,520
ALL THE TALKS TODAY HAVE BEEN

6797
06:26:40,520 --> 06:26:40,800
RECORDED.

6798
06:26:40,800 --> 06:26:42,520
THEY WILL BE AVAILABLE WITHIN

6799
06:26:42,520 --> 06:26:45,120
ABOUT A WEEK, I THINK ALL THE

6800
06:26:45,120 --> 06:26:45,720
REGISTERED PARTICIPANTS WILL

6801
06:26:45,720 --> 06:26:48,400
RECEIVE AN E-MAIL WITH A LINK TO

6802
06:26:48,400 --> 06:26:48,720
THAT.

6803
06:26:48,720 --> 06:26:50,480
IF YOU CAN'T FIND THAT OR DON'T

6804
06:26:50,480 --> 06:26:53,680
GET THAT, YOU KNOW ME OR TERRY

6805
06:26:53,680 --> 06:26:53,960
BURDETTE.

6806
06:26:53,960 --> 06:26:57,800
I'D LIKE TO THANK TERRY AND VAL

6807
06:26:57,800 --> 06:26:59,760
TURNQUIST FOR THE HARD WORK

6808
06:26:59,760 --> 06:27:08,200
PUTTING LOGISTICS TOGETHER, A

6809
06:27:08,200 --> 06:27:10,320
LOT OF THINGS CHANGED SINCE

6810
06:27:10,320 --> 06:27:11,720
COVID INCLUDING HOW YOU GET ON

6811
06:27:11,720 --> 06:27:14,000
THE BASE, HOW WE RUN THINGS HERE

6812
06:27:14,000 --> 06:27:17,240
IN THIS NEW HYBRID FORMAT, SO A

6813
06:27:17,240 --> 06:27:18,200
SHOUT OUT TO THEM.

6814
06:27:18,200 --> 06:27:20,600
I HOPE YOU CAN JOIN US THIS

6815
06:27:20,600 --> 06:27:24,960
EVENING FOR AN INFORMAL 

6816
06:27:24,960 --> 06:27:26,280
GATHERING AT STEINHART'S BREWERY

6817
06:27:26,280 --> 06:27:27,600
IN DOWNTOWN FREDERICK, FLYERS

6818
06:27:27,600 --> 06:27:28,840
HAVE BEEN DISTRIBUTED TO FIND

6819
06:27:28,840 --> 06:27:30,320
YOUR WAY DOWN THERE.

6820
06:27:30,320 --> 06:27:32,640
AND I THOUGHT IT WOULD BE MOST

6821
06:27:32,640 --> 06:27:34,520
FITTING FOR STEVE TO HAVE THE

6822
06:27:34,520 --> 06:27:36,560
LAST WORD TODAY.

6823
06:27:36,560 --> 06:27:36,880
STEVE?

6824
06:27:36,880 --> 06:27:39,360
[APPLAUSE]

6825
06:27:39,360 --> 06:27:45,400
 

6826
06:27:45,400 --> 06:27:50,760
 

6827
06:27:50,760 --> 06:27:55,560
>>I REALLY WANT TO SAY
THREE

6828
06:27:55,560 --> 06:27:58,920
THINGS QUICKLY.

6829
06:27:58,920 --> 06:28:00,560
I'M HUMBLED, HONORED, TOUCHED BY

6830
06:28:00,560 --> 06:28:02,480
ALL OF YOU FOR HAVING COME AND

6831
06:28:02,480 --> 06:28:07,040
FOR ALL THE KIND WORDS THAT HAVE

6832
06:28:07,040 --> 06:28:07,520
BEEN SAID.

6833
06:28:07,520 --> 06:28:10,000
BUT I THINK ONE OF THE THINGS

6834
06:28:10,000 --> 06:28:14,080
THAT I'D LIKE TO EMPHASIZE

6835
06:28:14,080 --> 06:28:17,480
DERIVES FROM WHAT SEVERAL

6836
06:28:17,480 --> 06:28:18,440
SPEAKERS SAID.

6837
06:28:18,440 --> 06:28:21,000
HAROLD BEGAN BY POINTING OUT WE

6838
06:28:21,000 --> 06:28:22,720
REALLY DON'T WORK AS

6839
06:28:22,720 --> 06:28:23,120
INDIVIDUALS.

6840
06:28:23,120 --> 06:28:30,400
YOU MAY SEE ON LATE NIGHT TV,

6841
06:28:30,400 --> 06:28:32,960
THE MAD SCIENTIST IS BY

6842
06:28:32,960 --> 06:28:40,000
THEMSELVES MAKING GREAT DISCOVE.

6843
06:28:40,000 --> 06:28:40,760
THAT'S COMPLETELY UNTRUE.

6844
06:28:40,760 --> 06:28:43,560
FOR ME TODAY I GET TO RELIVE

6845
06:28:43,560 --> 06:28:46,040
SOME OF THE REALLY WONDERFUL

6846
06:28:46,040 --> 06:28:47,000
COLLABORATIONS AND INTERACTIONS

6847
06:28:47,000 --> 06:28:49,960
AND HEAR FROM SOME FRIENDS AND

6848
06:28:49,960 --> 06:28:52,800
THINK ABOUT ALL THE THINGS THAT

6849
06:28:52,800 --> 06:28:55,360
WE ACCOMPLISHED, NOT AS

6850
06:28:55,360 --> 06:28:59,920
INDIVIDUALS BUT AS

6851
06:28:59,920 --> 06:29:00,680
COLLABORATORS, COLLEAGUES, I'VE

6852
06:29:00,680 --> 06:29:03,440
BENEFITED AS I HOPE YOU CAN

6853
06:29:03,440 --> 06:29:07,280
TELL, IMMENSELY, FROM HAVING

6854
06:29:07,280 --> 06:29:10,000
BOTH FABULOUS MENTORS AND ALSO

6855
06:29:10,000 --> 06:29:12,080
FROM HAVING REALLY WONDERFUL

6856
06:29:12,080 --> 06:29:12,640
COLLEAGUES.

6857
06:29:12,640 --> 06:29:15,800
AND THE THINGS YOU HEARD TODAY

6858
06:29:15,800 --> 06:29:17,880
NONE OF THOSE WERE THINGS I

6859
06:29:17,880 --> 06:29:21,440
EITHER DID OR COULD HAVE DREAMED

6860
06:29:21,440 --> 06:29:23,600
OF ACCOMPLISHING BY MYSELF.

6861
06:29:23,600 --> 06:29:25,160
THEY WERE ALL ACCOMPLISHED AS

6862
06:29:25,160 --> 06:29:26,560
PART OF LARGER COLLABORATIONS.

6863
06:29:26,560 --> 06:29:28,960
IT'S THROUGH THE STRENGTH OF

6864
06:29:28,960 --> 06:29:31,160
THOSE COLLABORATIONS AND THE

6865
06:29:31,160 --> 06:29:33,800
HELP AND HARD WORK AND INSIGHT

6866
06:29:33,800 --> 06:29:35,320
OF MY COLLEAGUES THAT I WAS ANY

6867
06:29:35,320 --> 06:29:39,560
KIND OF A SUCCESS AT ALL.

6868
06:29:39,560 --> 06:29:44,120
I WOULD LIKE TO SAY IN CLOSING,

6869
06:29:44,120 --> 06:29:46,360
THERE ARE UNFORTUNATELY A FEW

6870
06:29:46,360 --> 06:29:47,680
PEOPLE WHO REALLY LITERALLY

6871
06:29:47,680 --> 06:29:50,120
CAN'T BE WITH US, EITHER IN

6872
06:29:50,120 --> 06:29:50,960
PERSON OR VIRTUALLY.

6873
06:29:50,960 --> 06:29:53,280
AND I'M NOT GOING TO TRY AND

6874
06:29:53,280 --> 06:29:54,360
GIVE YOU A COMPREHENSIVE LIST

6875
06:29:54,360 --> 06:29:56,680
BUT WANT TO CALL OUT THREE

6876
06:29:56,680 --> 06:29:58,880
INDIVIDUALS I'M PARTICULARLY

6877
06:29:58,880 --> 06:30:04,800
SORRY ARE NOT HERE.

6878
06:30:04,800 --> 06:30:08,720
GEORGE OF COURSE, GEORGE WAS THE

6879
06:30:08,720 --> 06:30:12,760
PERSON WHO SET UP THE PROGRAM I

6880
06:30:12,760 --> 06:30:15,960
JOINED HERE IN 1984, BROUGHT MY

6881
06:30:15,960 --> 06:30:19,000
COLLEAGUE JEFF AND OUR GREAT

6882
06:30:19,000 --> 06:30:19,920
COLLEAGUE MARK DOWN FROM COLD

6883
06:30:19,920 --> 06:30:21,640
SPRING HARBOR.

6884
06:30:21,640 --> 06:30:26,480
GEORGE WAS A TRUE -- PEOPLE SAY

6885
06:30:26,480 --> 06:30:28,640
I'M LARGER THAN LIFE, GEORGE WAS

6886
06:30:28,640 --> 06:30:30,000
REALLY LARGER THAN LIFE IN THE

6887
06:30:30,000 --> 06:30:31,720
MOST WONDERFUL POSSIBLE WAY.

6888
06:30:31,720 --> 06:30:36,640
I MISS HIM INTENSELY TO THIS

6889
06:30:36,640 --> 06:30:37,760
DAY.

6890
06:30:37,760 --> 06:30:38,840
THE OTHER NAME FAMILIAR, I'M

6891
06:30:38,840 --> 06:30:47,280
PLEASED TO SEE MENTIONED BY

6892
06:30:47,280 --> 06:30:50,280
SEVERAL, CLARK, GRAND QUANTITIES

6893
06:30:50,280 --> 06:30:53,800
OF PURIFIED HIV REVERSE

6894
06:30:53,800 --> 06:30:56,640
TRANSCRIPTASE ENABLING ORIGINAL

6895
06:30:56,640 --> 06:30:58,360
STRUCTURAL WORK FROM EDDY AND

6896
06:30:58,360 --> 06:31:03,600
COLLEAGUES AND CHEMISTRY BY PAUL

6897
06:31:03,600 --> 06:31:04,600
BOYER AND OTHERS ALTHOUGH PAUL

6898
06:31:04,600 --> 06:31:06,760
WAS THE ONE WHO MADE IMMENSE

6899
06:31:06,760 --> 06:31:08,720
CONTRIBUTIONS TO THAT PROGRAM.

6900
06:31:08,720 --> 06:31:12,040
AND PAT, WHO WE LOST A COUPLE

6901
06:31:12,040 --> 06:31:19,480
YEARS AGO, IN HEARTBREAKING

6902
06:31:19,480 --> 06:31:19,760
FASHION.

6903
06:31:19,760 --> 06:31:28,360
WE DID COUPLE THINGS TOGETHER, I

6904
06:31:28,360 --> 06:31:30,480
MISSED DORSEY, AND WE'LL HAVE

6905
06:31:30,480 --> 06:31:32,080
THE DORSEY MEMORIAL LECTURE AT

6906
06:31:32,080 --> 06:31:34,960
SOME POINT, I'LL INVITE YOU

6907
06:31:34,960 --> 06:31:35,200
BACK.

6908
06:31:35,200 --> 06:31:37,120
VIRTUALLY, IF YOU CAN'T COME IN

6909
06:31:37,120 --> 06:31:40,800
PERSON, HEAR A WONDERFUL TALK IN

6910
06:31:40,800 --> 06:31:43,280
MEMORY OF JOE DORSEY, A VALUED

6911
06:31:43,280 --> 06:31:45,440
COLLEAGUE WE LOST MUCH TOO SOON.

6912
06:31:45,440 --> 06:31:47,520
I'LL THANK YOU ALL AND HOPE TO

6913
06:31:47,520 --> 06:31:51,920
SEE YOU A LITTLE LATER FOR A

6914
06:31:51,920 --> 00:00:00,000
BEER.