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GOOD AFTERNOON FROM BETHESDA, 

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MARYLAND.

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YOU ARE ATTENDING A SESSION OF 

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THE 21st YEAR OF DEMYSTIFYING 

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MEDICINE AT THE NATIONAL 

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INSTITUTES OF HEALTH.

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AS WE HAVE POINTED OUT OVER THE 

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COURSE OF ALL THESE TALKS THAT 

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THIS IS AN ATTEMPT TO BRIDGE THE

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EXCITING DEVELOPMENTS IN 

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BIOLOGY, ENGINEERING AND 

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COMPUTER SCIENCES WITH MEDICINE 

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AND HUMAN HEALTH.

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THE LOGO, THE BROOKLYN BRIDGE, 

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DAVID McCULLOUGH SAID ONCE YOU 

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BUILD THE BRIDGE LIFE IS NEVER 

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THE SAME ON EITHER SIDE AND 

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TODAY'S TALK IS A FURTHER 

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EXAMPLE OF THAT PRINCIPLE WHICH 

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WE WILL GET YOU AND THE COURSE 

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IS TUESDAYS 4:00 TO 6:00 EASTERN

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STANDARD TIME APE -- NOW TO ME 

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MIDDLE OF MAY AND THE CME CODE 

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IS 52090 AND URGE YOU TO SUBMIT 

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QUESTIONS VIA THE SEND LIVE 

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FEEDBACK ON THE VIDEOCAST 

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DISPLAY.

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YOU DO THAT DURING THE TALKS, 

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THE QUESTION AND ANSWER PERIOD 

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THAT WILL FOLLOW.

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I CALL YOUR ATTENTION TO THE 

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FACT THAT ALL PREVIOUS SESSIONS 

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FOR 21 YEARS ARE ARCHIVED AND 

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THE LINK IS PRESENTED THERE AND 

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IF YOU HAVE ANY OTHER QUESTIONS 

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JUST GET IN TOUCH WITH US.

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NOW, IN THE LOGO MUCH THE 

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BROOKLYN BRIDGE, THERE WERE TWO 

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PEOPLE STANDING.

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AND ONE CAN VISUALIZE THAT ONE 

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OF THEM MAY HAVE SOME DIRECT 

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RELATIONSHIP TO PATIENTS AND IS 

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CONCERNED WITH THE TERRIBLE 

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PROBLEM THAT BOTH INFECTION AND 

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IN CANCER ONE OF THE MOST 

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DEVASTATING EFFECTS IS WHEN 

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NOTHING WORKS BECAUSE OF THE 

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DEVELOPMENT OF RESISTANCE.

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AND THE OTHER THE MOST ADVANCED 

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TECHNOLOGIES TO TRY TO BEGIN TO 

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UNDERSTAND HOW THIS HAPPENS.

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 SO IN CONSIDERING THIS PROPOSE 

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QUESTIONS WE COULD ALL THINK 

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ABOUT DURING TODAY'S 

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PRESENTATIONS.

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IS DRUG RESISTANCE PART OF A 

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LARGER PHENOMENON OF SURVIVAL 

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AND HOW DOES IT RELATE TO 

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EVOLUTION, NATURAL SELECTION.

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THERE'S A HUGE PRICE THAT'S PAID

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FOR THESE EVENTS AS YOU PROBABLY

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KNOW VIRUSES AND BACTERIA ARE 

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KILLED OFF IN THE MILLIONS IF 

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NOT BILLIONS WHERE AS EUKARYOTIC

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CELLS THE PROCESS IS FAR SLOWER.

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I THINK THE QUESTION IS NOT WHY 

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THE BACTERIA MAY BE WHY CANCER 

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VIRUSES WANT TO SURVIVE BUT THE 

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QUESTION IS HOW DO THEY DO IT.

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AND IF WE UNDERSTOOD HOW WE 

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THINK ABOUT IT, WE MIGHT 

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UNDERSTAND HOW WILL ADVANCE 

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KNOWLEDGE OF THE ORIGIN OF LIFE 

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AND EVOLUTION.

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SO, OUR FIRST SPEAKER IS MICHAEL

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GOTTESMAN WHO IS OBVIOUSLY 

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EXTREMELY WELL KNOWN HERE AND 

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ABROAD.

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MICHAEL GRADUATE FROM HARVARD, 

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TOOK TRAINING HIS CLINICAL 

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TRAINING IN BOSTON AND THEN DID 

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A POST-DOCTORAL FELLOWSHIP IN 

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MOLECULAR GENETICS AT THE NIH 

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WITH MARTIN GELARD AND RETURNED 

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TO HARVARD BRIEFLY AND CAME TO 

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NIH IN 1976.

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IN 1994 UNTIL 2022, MICHAEL WAS 

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THE DEPUTY DIRECTOR OF THE 

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INTRAMURAL RESEARCH AT THE NIH 

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WHICH IS A GIGANTIC CHALLENGING 

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POSITION.

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HE WAS CHIEF OF THE LABORATORY 

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OF CELL BIOLOGY AT THE NATIONAL 

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CANCER INSTITUTE AND MICHAEL HAS

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WON MANY AWARDS INCLUDING 

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ELECTION TO THE NATIONAL ACADEMY

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OF SCIENCE AND MEDICINE.

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THE CAREER PUBLIC HEALTH SERVICE

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AWARD OF THE AMERICAN MEDICAL 

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ASSOCIATION AND SO FORTH.

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AND FOR MANY YEARS HE AND HIS 

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COLLEAGUES HAVE BEEN LEADING 

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RESEARCH ON DRUG RESISTANCE MAIN

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IN CANCER AND APPLICATIONS AND 

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IN THE COURSE OF THIS HE HAS 

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TRAINED AN EXTRAORDINARY NUMBER 

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PEOPLE WHO HAVE BECOME LEADERS 

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IN THIS FIELD AND THROUGHOUT THE

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WORLD.

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THE SECOND SPEAKER IS JOHN 

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DEKKER.

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JOHN RECEIVED BOTH AN M.D. AND 

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Ph.D. FROM HARVARD.

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HE DID A PATHOLOGY RESIDENCY 

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FELLOWSHIP IN MEDICAL 

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MICROBIOLOGY AT THE MASS GENERAL

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HOSPITAL AND CAME TO NIH IN 2013

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AS A CLINICAL CENTER SENIOR 

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STAFF IN THE MICROBIOLOGY PART 

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OF THE MEDICINE LABORATORY 

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BRANCH WHERE HE WAS ACTING 

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CHIEF.

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IN 2018 HE WAS AWARDED THE 

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LASKAR CLINICAL RESEARCH 

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FELLOWSHIP INVESTIGATOR IN THE 

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NATIONAL INSTITUTES OF ALLERGY 

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AND INFECTIOUS DISEASES.

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SO JOHN HAS SERVED ON THE 

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ADVISORY COMMITTEES, BEEN AN 

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EDITOR OF THE JOURNAL OF 

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CLINICAL MICROBIOLOGY AND 

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RECEIVED AWARDS INCLUDING ONE 

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FOR THE AMERICAN SOCIETY OF 

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MICROBIOLOGY AND NIH CLINICAL 

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CENTER AWARD AND IN 2020 A YOUNG

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PHYSICIAN SCIENTIST AWARD FROM 

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THE AMERICAN ASSOCIATION FOR 

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CLINICAL INVESTIGATION.

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JOHN'S FORTE IS USING 

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NEXT-GENERATION BASED SEQUENCING

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METHODS TO STUDY EPIDEMIOLOGY 

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AND IN INFECTIOUS DISEASE AND 

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CHIEF OF THE BACTERIAL 

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PATHOGENESIS ANTIMICROBIAL 

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RESISTANCE AND STUDIES THE 

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GENOMIC SESSION OF MICROBIOLOGY 

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AT NIH.

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THE LATEST NEWS JUST RECEIVED 

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TODAY AND WE CONGRATULATION JOHN

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IS THAT TODAY HE RECEIVED TENURE

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AT THE NATIONAL INSTITUTES OF 

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HEALTH.

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SO WE WELCOME ALL OF YOU AROUND 

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THE WORLD AS WELL AS HERE OF 

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COURSE AT THE NIH WATCHING THIS 

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ONLINE AND WE LOOK FORWARD TO 

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THE PRESENTATIONS AND MICHAEL 

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WOULD YOU -- 

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>> LET ME START BY THANK
YOU FOR

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THAT INCREDIBLY GENEROUS 

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INTRODUCTION.

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IT'S A DELIGHT TO BE HERE.

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THIS IS NOT THE FIRST TIME I'VE 

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SPOKEN IN THE SESSION AND I 

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THINK I SPOKE IN THE FIRST YEAR,

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21 YEARS AGO.

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THAT WAS A LOT EASIER BECAUSE WE

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KNEW THE BASIS OF DRUG 

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RESISTANCE AND NOW, SINCE WE 

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DON'T THIS IS GOING TO BE A MUCH

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MORE INTERESTING TALK THAN THE 

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OLD ONE.

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SO THIS IS CME COURSE AND WE 

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HAVE OBJECTIVES EXPLAINING HOW 

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RESISTANCE TO CANCER DRUGS LEADS

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TO IMMUNOTHERAPY AND EPNEUM -- 

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ENUMERATE SEVERAL MECHANISMS OF 

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RESISTANCE WHICH ARE SPECIFIC 

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FOR CANCER CELL TYPE AND 

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SELECTING DRUG AND WE WANT TO 

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BRIDGE THE GAP BETWEEN CLINICAL 

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AND LABORATORY AND SOMETIMES 

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THEY'RE ABLE TO BRING PATIENTS 

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TO ILLUSTRATE COMMENTS THEY'LL 

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MAKE.

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I THOUGHT IT WOULD BE REDUNDANT 

187
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TO HEAR ABOUT THE FACT THAT 

188
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CANCER BASICALLY IS RESISTANT TO

189
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MANY KINDS OF THERAPY AND THESE 

190
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ARE SOME STATISTICS.

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YOU CAN SEE FOR BOTH MEN AND 

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WOMEN THERE'S ABOUT A MILLION 

193
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NEW CASE AS A YEAR IN DIFFERENT 

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SITES AND ABOUT 300,000 PATIENTS

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DIE FOR MEN AND WOMEN.

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THE PATIENT WHO'S SURVIVE CANCER

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ARE FREQUENTLY TREATED 

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EFFECTIVELY BY SURGERY OR 

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RADIATION THERAPY IF THE CANCER 

200
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IS LOCALIZED.

201
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IF IT SPREAD, ME TTASTASIZES IT 

202
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MORE DIFFICULT TO TREAT AND 

203
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ALMOST EVERYONE IN THE UNITED 

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STATES WHEN HAS CANCER THAT HAS 

205
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SPREAD GETS CHEMOTHERAPY.

206
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YOU CAN READ IN THE NEWSPAPER 

207
00:10:45,382 --> 00:10:47,084
EXCITING RESULTS ABOUT 

208
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IMPROVEMENTS IN TREATMENT THAT 

209
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EXTEND LIFE AND IMPROVE QUALITY 

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OF LIFE BUT THE REALITY IS THAT 

211
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VIRTUALLY EVERYONE WHO DIES OF 

212
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CANCER DIES OF DRUG RESISTANT 

213
00:10:57,861 --> 00:10:58,295
CANCER.

214
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SO WE'RE TALKING ABOUT A LOT OF 

215
00:11:00,564 --> 00:11:02,399
PATIENTS AND I WOULD IMAGINE 

216
00:11:02,399 --> 00:11:03,867
THAT VIRTUALLY EVERYONE IN THE 

217
00:11:03,867 --> 00:11:05,736
ROOM KNOWS SOMEBODY WHO DIED OF 

218
00:11:05,736 --> 00:11:09,106
DRUG RESISTANT CANCER.

219
00:11:09,106 --> 00:11:11,976
SO THERE'S A KIND OF THEME TO 

220
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THE ISSUE OF DRUG RESISTANCE 

221
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INCLUDING MICROBIAL AGENTS AND 

222
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INFORMATION HOW THIS OCCURS AND 

223
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I'LL GO QUICKLY THROUGH THIS AND

224
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THINK IT'S RELEVANT TO WHAT JOHN

225
00:11:34,398 --> 00:11:35,399
HAS TO SAY AS WELL.

226
00:11:35,399 --> 00:11:37,434
WHEN YOU TREAT A PATIENT WITH 

227
00:11:37,434 --> 00:11:40,804
CHEMO THERAPY AND USE A DRUG TO 

228
00:11:40,804 --> 00:11:42,573
WHICH THEY'RE SENSITIVE AND IT 

229
00:11:42,573 --> 00:11:45,075
TURNS OUT THAT SOMETIMES WITHIN 

230
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THE POPULATION OF CELLS THAT ARE

231
00:11:47,344 --> 00:11:49,580
BEING TREATED THERE ARE A FEW 

232
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CELLS RESISTANT AND WHAT HAPPENS

233
00:11:51,281 --> 00:11:53,617
IS THAT EITHER YOU DON'T GET A 

234
00:11:53,617 --> 00:11:55,919
RESPONSE TO THE CHEMOTHERAPY OR 

235
00:11:55,919 --> 00:11:59,890
GET A TRANSIENT RESPONSE AND 

236
00:11:59,890 --> 00:12:01,425
RESISTANT CELLS GROW OUT.

237
00:12:01,425 --> 00:12:06,697
THE CONCEPT INTRINSIC RESISTANCE

238
00:12:06,697 --> 00:12:09,266
GOES BACK TO RESISTANCE IN 

239
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VIRUSES AND BACTERIA AND WE'VE 

240
00:12:10,434 --> 00:12:13,237
DONE SIMILAR STUDIES LOOKING AT 

241
00:12:13,237 --> 00:12:14,104
RESISTANCE TO VARIOUS DIFFERENT 

242
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DRUGS AND CULTURED CELLS AND 

243
00:12:19,276 --> 00:12:22,646
WHAT YOU SEE IS THAT IN MANY 

244
00:12:22,646 --> 00:12:25,149
CASES THE CELLS THAT EXIST, 

245
00:12:25,149 --> 00:12:26,450
PREEXIST IN THE POPULATION.

246
00:12:26,450 --> 00:12:28,619
THEY'RE AT LOW LEVELS BUT 

247
00:12:28,619 --> 00:12:30,054
PREEXIST AND NO MATTER WHAT YOU 

248
00:12:30,054 --> 00:12:31,155
DO, THEY'LL POP UP.

249
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IT'S NOT TRUE OF ALL RESISTANCE.

250
00:12:32,923 --> 00:12:35,693
IN SOME CASES THE DRUGS 

251
00:12:35,693 --> 00:12:37,995
THEMSELVES INDUCE RESISTANCE OR 

252
00:12:37,995 --> 00:12:40,931
ENABLE SURVIVAL OF THE CELLS AND

253
00:12:40,931 --> 00:12:43,133
EXAMPLES MAY INCLUDE THE 

254
00:12:43,133 --> 00:12:45,235
TRANSPORTERS YOU'LL BE HEARING 

255
00:12:45,235 --> 00:12:47,805
LATE ABOUT TODAY, TRANSCRIPTION 

256
00:12:47,805 --> 00:12:50,107
FACTORS, METABOLIZING ENZYMES 

257
00:12:50,107 --> 00:12:51,175
ALL TO BE INDUCED IN THE SHORT 

258
00:12:51,175 --> 00:12:53,911
TERM AND WHEN THEY ARE THE CELLS

259
00:12:53,911 --> 00:12:55,312
CAN SURVIVE FOR A WHILE.

260
00:12:55,312 --> 00:13:02,319
THESE MECHANISMS TEND TO BE 

261
00:13:02,319 --> 00:13:03,454
PRETTY INEFFICIENT AND AS SOON 

262
00:13:03,454 --> 00:13:06,557
AS THE CELL CAN FIND A WAY TO 

263
00:13:06,557 --> 00:13:08,325
FIX A MUTATION FOR EXAMPLE IN A 

264
00:13:08,325 --> 00:13:09,593
TARGET UP A SPECIFIC FACTOR 

265
00:13:09,593 --> 00:13:14,431
THAT'S ESSENTIAL FOR THE CELLS 

266
00:13:14,431 --> 00:13:17,634
TO BE KILLED BY THE DRUG WILL 

267
00:13:17,634 --> 00:13:20,104
HAPPEN IN FIXED MUTATIONS AND 

268
00:13:20,104 --> 00:13:21,538
WHEN WE SELECT FOR LONG-TERM 

269
00:13:21,538 --> 00:13:23,907
RESISTANCE TO DRUG MOST OF WHAT 

270
00:13:23,907 --> 00:13:26,176
WE TALK ABOUT IS THE MIXED 

271
00:13:26,176 --> 00:13:31,048
MUTATIONS AND MISSING THE 

272
00:13:31,048 --> 00:13:32,750
INDUCED RESISTANCE AND I SUSPECT

273
00:13:32,750 --> 00:13:33,584
JOHN WILL HAVE MORE TO SAY ABOUT

274
00:13:33,584 --> 00:13:40,124
THIS PROBLEM.

275
00:13:40,124 --> 00:13:45,329
SO WHAT RAIN SHOWER GOALS I'LL 

276
00:13:45,329 --> 00:13:52,636
SPEND ON THE ENERGY DEPENDENT 

277
00:13:52,636 --> 00:13:54,238
STORIES AND DETERMINE THE 

278
00:13:54,238 --> 00:13:58,075
CLINICAL RELEVANCE OF MECHANISMS

279
00:13:58,075 --> 00:14:04,014
DERIVED FROM IN VITRO STUDIES 

280
00:14:04,014 --> 00:14:06,383
AND DEVELOPMENT NEW APPROACHES 

281
00:14:06,383 --> 00:14:09,586
TO COMPLOIT OR CIRCUMVENT 

282
00:14:09,586 --> 00:14:10,854
CLINICALLY SIGNIFICANT RESISTANT

283
00:14:10,854 --> 00:14:13,257
MECHANISMS AND TALK ABOUT THE 

284
00:14:13,257 --> 00:14:15,559
BLOOD BRAIN BARRIER.

285
00:14:15,559 --> 00:14:20,230
SO HOW DO CELLS GET RESISTANT?

286
00:14:20,230 --> 00:14:22,399
IF YOU HAVE A SPECIFICALLY 

287
00:14:22,399 --> 00:14:24,067
TARGETED DRUG AIMING FOR EXAMPLE

288
00:14:24,067 --> 00:14:30,207
AT A RECEPTOR ON THE SURFACE AND

289
00:14:30,207 --> 00:14:40,284
SOME TARGET KINASE RECEPTORS AND

290
00:14:40,284 --> 00:14:42,853
BYPASS MUTATIONS ALLOW CANCER 

291
00:14:42,853 --> 00:14:47,691
CELLS TO GROW.

292
00:14:47,691 --> 00:14:50,394
A SECOND WAY IS THROUGH WHAT WE 

293
00:14:50,394 --> 00:14:53,530
CALL ALTERED CELL PHARMACOLOGY, 

294
00:14:53,530 --> 00:14:56,934
FAILURE TO TAKE UP A DRUG.

295
00:14:56,934 --> 00:14:58,936
MECHANISM TO E-FLUX DRUGS AND 

296
00:14:58,936 --> 00:15:01,205
SEQUESTER DRUGS AND TO 

297
00:15:01,205 --> 00:15:02,739
METABOLIZE DRUGS.

298
00:15:02,739 --> 00:15:06,743
A PANOPLY OF POSSIBILITIES CELLS

299
00:15:06,743 --> 00:15:09,746
CAN USE TO SURVIVE AND THIS IS 

300
00:15:09,746 --> 00:15:10,414
AN INTERESTING ISSUE.

301
00:15:10,414 --> 00:15:14,184
I THINK SIMILAR TO ONE RAISED TO

302
00:15:14,184 --> 00:15:17,020
BE A LIFE FORM ON EARTH YOU HAVE

303
00:15:17,020 --> 00:15:19,823
TO BE RESISTANT TO A LOT OF 

304
00:15:19,823 --> 00:15:20,557
TOXIC INSULTS.

305
00:15:20,557 --> 00:15:24,228
LIFE EVOLVED IN A TOXIC SEA.

306
00:15:24,228 --> 00:15:25,262
MEMBRANES WERE PUT AROUND LIFE 

307
00:15:25,262 --> 00:15:28,498
FORMS AND THERE HAD TO BE A WAY 

308
00:15:28,498 --> 00:15:29,633
TO SURVIVE.

309
00:15:29,633 --> 00:15:31,101
SOME TIME AGO WHEN PEOPLE BEGAN 

310
00:15:31,101 --> 00:15:33,036
TO KNOCK OUT GENES IN YEAST THEY

311
00:15:33,036 --> 00:15:35,606
DISCOVERED THERE WERE ONLY A FEW

312
00:15:35,606 --> 00:15:38,208
ESSENTIAL GENES UNDER LABORATORY

313
00:15:38,208 --> 00:15:43,313
CONDITIONS BUT HALF THE GENOME 

314
00:15:43,313 --> 00:15:45,749
CAN HAVE SENSITIVITY TO 

315
00:15:45,749 --> 00:15:47,451
CHEMICALS AND YEAST THAT 

316
00:15:47,451 --> 00:15:54,124
SURVIVED BUT WHEN YOU ADD 

317
00:15:54,124 --> 00:15:57,628
CHEMICAL Z IT DIDN'T DO AS WELL 

318
00:15:57,628 --> 00:15:59,363
AND WILD TYPE AND THE THOUGHT IS

319
00:15:59,363 --> 00:16:03,033
EVERY ONE OF THE GENES IS 

320
00:16:03,033 --> 00:16:03,901
SOMETHING THAT GETS EXPRESSED TO

321
00:16:03,901 --> 00:16:04,968
HELP US SURVIVE IN A NASTY 

322
00:16:04,968 --> 00:16:10,173
ENVIRONMENT.

323
00:16:10,173 --> 00:16:12,309
ANOTHER WAY IN WHICH RESISTANCE 

324
00:16:12,309 --> 00:16:14,578
CAN DEVELOP IS BY MORE DRAMATIC 

325
00:16:14,578 --> 00:16:17,547
CHANGES IN DEVELOPMENTAL OR 

326
00:16:17,547 --> 00:16:18,181
DIFFERENTIATION PATHWAYS AND THE

327
00:16:18,181 --> 00:16:20,517
CLASSIC WAY FOR CULTURED OR 

328
00:16:20,517 --> 00:16:24,288
CANCER CELLS TO GET RESISTANCE 

329
00:16:24,288 --> 00:16:28,091
IS A TRANSITION AND IT MEANS THE

330
00:16:28,091 --> 00:16:32,329
CELLS GO FROM AN EPITHELIAL FORM

331
00:16:32,329 --> 00:16:34,331
SAY LIVER CANCER OR COLON 

332
00:16:34,331 --> 00:16:36,800
CANCER, THOSE ARE EPITHELIAL 

333
00:16:36,800 --> 00:16:39,069
CELLS AND THE CELLS CHANGE THE 

334
00:16:39,069 --> 00:16:41,772
DIFFERENTIATION PROFILE IN 

335
00:16:41,772 --> 00:16:43,607
BECOMING MORE FIBROBLAST LIKE 

336
00:16:43,607 --> 00:16:45,575
AND THE PATTERN TO SENSITIVITY 

337
00:16:45,575 --> 00:16:47,477
TO DRUGS CHANGES AND THEY MAY 

338
00:16:47,477 --> 00:16:49,179
BECOME QUITE RESISTANCE AND A 

339
00:16:49,179 --> 00:16:51,715
WAY OF USING ENTIRE PATHWAYS 

340
00:16:51,715 --> 00:16:54,384
EXPRESSED IN CELLS TO CHANGE 

341
00:16:54,384 --> 00:16:55,552
EITHER METABOLISM OF DRUGS OR 

342
00:16:55,552 --> 00:16:58,689
TRANSPORTIVE DRUGS OR THE 

343
00:16:58,689 --> 00:17:01,258
SENSITIVITY THE CELL HAS TO THE 

344
00:17:01,258 --> 00:17:03,760
SPECIFIC TARGET IN THE CELL.

345
00:17:03,760 --> 00:17:05,662
YOU CAN CONSIDER FOR EXAMPLE THE

346
00:17:05,662 --> 00:17:08,498
PROBLEM OF PERSISTENCE WHICH IS 

347
00:17:08,498 --> 00:17:10,400
DESCRIBED IN BACTERIA AS A 

348
00:17:10,400 --> 00:17:13,337
POPULATION OF BACTERIA ABLE TO 

349
00:17:13,337 --> 00:17:17,474
SURVIVE IN THE FACE OF 

350
00:17:17,474 --> 00:17:19,743
ANTIBIOTIC TREATMENT IN A 

351
00:17:19,743 --> 00:17:21,144
VEGETATIVE STATE AND SAME IN 

352
00:17:21,144 --> 00:17:23,113
CANCER CELLS THAT STOP DOING 

353
00:17:23,113 --> 00:17:24,982
THINGS, THEY BECOME LESS 

354
00:17:24,982 --> 00:17:26,717
SENSITIVE BUT THE PRECISE 

355
00:17:26,717 --> 00:17:27,584
MECHANISMS BY WHICH THAT 

356
00:17:27,584 --> 00:17:31,521
HAPPENED ARE NOT WELL DESCRIBED.

357
00:17:31,521 --> 00:17:33,523
AND WE FINALLY BECAUSE CANCER 

358
00:17:33,523 --> 00:17:35,959
CELLS ARE NOT LIVING IN AN OPEN 

359
00:17:35,959 --> 00:17:41,531
ENVIRONMENT BUT PART OF AN 

360
00:17:41,531 --> 00:17:43,500
ORGANISM THERE ARE LOTS OF WAYS 

361
00:17:43,500 --> 00:17:47,037
IN WHICH THE LOCAL ENVIRONMENT 

362
00:17:47,037 --> 00:17:49,873
CAN AFFECT THE ABILITY OF THE 

363
00:17:49,873 --> 00:17:52,976
CANCER CELLS TO ADVISER AND 

364
00:17:52,976 --> 00:17:58,382
BLOOD SUPPLY, OXYGEN 

365
00:17:58,382 --> 00:18:04,654
CONCENTRATION, SUCH AS PHYSICAL 

366
00:18:04,654 --> 00:18:05,322
PROPERTIES OF THE ENVIRONMENT 

367
00:18:05,322 --> 00:18:08,525
AND YOU SEE CHANGES IN DRUG 

368
00:18:08,525 --> 00:18:09,826
SENSITIVITY AND RESISTANCE.

369
00:18:09,826 --> 00:18:11,895
IN ADDITION THERE'S THE WHOLE 

370
00:18:11,895 --> 00:18:13,597
BUSINESS ABOUT THE MICROBIOME 

371
00:18:13,597 --> 00:18:16,600
AND IT AFFECT THE WAY DRUGS ARE 

372
00:18:16,600 --> 00:18:17,334
METABOLIZED, HOW THE IMMUNE 

373
00:18:17,334 --> 00:18:22,372
SYSTEM RESPONDS TO DRUGS, 

374
00:18:22,372 --> 00:18:23,607
ETCETERA.

375
00:18:23,607 --> 00:18:31,915
THIS IS A HUGE AREA.

376
00:18:31,915 --> 00:18:36,219
THERE'S CANCER CELL METRO GEN 

377
00:18:36,219 --> 00:18:37,521
EIGHT AND WE THOUGHT THEY WERE 

378
00:18:37,521 --> 00:18:41,758
CLONAL AND IF YOU DO SINGLE CELL

379
00:18:41,758 --> 00:18:43,660
SEQUENCES YOU GET AN ARRAY OF 

380
00:18:43,660 --> 00:18:45,328
MUTATIONS ALL OF WHICH CAN 

381
00:18:45,328 --> 00:18:46,396
CONTRIBUTE TO RESISTANCE.

382
00:18:46,396 --> 00:18:48,331
THE PATHWAY OF CELLS SURVIVAL 

383
00:18:48,331 --> 00:18:50,300
ARE QUITE ROBUST IN CANCER 

384
00:18:50,300 --> 00:18:50,500
CELLS.

385
00:18:50,500 --> 00:18:56,840
THEY ARE SURVIVORS.

386
00:18:56,840 --> 00:19:00,444
ALL THIS DOESN'T HAPPEN 

387
00:19:00,444 --> 00:19:04,848
INSTANTANEOUSLY AND EVOLUTION 

388
00:19:04,848 --> 00:19:06,383
OCCURS IN THE TIME ITSELF AND 

389
00:19:06,383 --> 00:19:11,788
CANCER CELLS HAVE AN INCREASED 

390
00:19:11,788 --> 00:19:22,466
RATE OF GENETIC AND EPIGE GEGEN 

391
00:19:22,466 --> 00:19:24,201
AND THE IT'S STACK AGAINST THE 

392
00:19:24,201 --> 00:19:25,001
CANCER CELL.

393
00:19:25,001 --> 00:19:27,304
THERE'S TWO WAYS TO STUDY THIS 

394
00:19:27,304 --> 00:19:31,274
IN THE LABORATORY FIRST IS AN 

395
00:19:31,274 --> 00:19:36,246
APPROPRIATE CULTURED MODEL AND A

396
00:19:36,246 --> 00:19:38,849
CELL DERIVED FROM A SPECIFIC 

397
00:19:38,849 --> 00:19:40,350
CANCER AND SELECT FOR RESISTANCE

398
00:19:40,350 --> 00:19:42,385
AND TRY TO IDENTIFY GENES AND 

399
00:19:42,385 --> 00:19:46,490
THE ONE WE'RE BEST KNOWN FOR THE

400
00:19:46,490 --> 00:19:49,759
ABC1 AND ABC TRANSPORTER IS 

401
00:19:49,759 --> 00:19:51,728
IDENTIFIED BY THE FACT THE GENES

402
00:19:51,728 --> 00:19:54,164
WERE AMPLIFIED.

403
00:19:54,164 --> 00:19:59,169
THE PHENOMENON NOT KNOWN IN 

404
00:19:59,169 --> 00:19:59,703
BACTERIA AS WELL.

405
00:19:59,703 --> 00:20:01,271
AND THEN RECENTLY AS THE 

406
00:20:01,271 --> 00:20:03,540
TECHNOLOGY HAS CHANGED WE'VE 

407
00:20:03,540 --> 00:20:07,043
BEEN USING RNA SEQ INTERROGATING

408
00:20:07,043 --> 00:20:12,516
WHAT THE RNAs ARE EXPRESSED IN 

409
00:20:12,516 --> 00:20:13,550
RESISTANT CELLS AND ANY 

410
00:20:13,550 --> 00:20:15,986
RESPONSIBLE FOR RESISTANCE?

411
00:20:15,986 --> 00:20:18,221
AND UNTIL RECENTLY TRYING TO 

412
00:20:18,221 --> 00:20:20,490
KEEP UP WITH THE TECHNOLOGY 

413
00:20:20,490 --> 00:20:21,858
WE'VE USED CRISPR BASED 

414
00:20:21,858 --> 00:20:24,027
APPROACHES TO IDENTIFY GENES AND

415
00:20:24,027 --> 00:20:26,296
I SHOULD SAY THE SELECTIONS ARE 

416
00:20:26,296 --> 00:20:30,400
SHORT TERM.

417
00:20:30,400 --> 00:20:33,603
WHEN WE SELECT FOR CELLS 

418
00:20:33,603 --> 00:20:34,871
RESISTANT WE GROW THEM FOR A 

419
00:20:34,871 --> 00:20:38,241
LONG TIME TO BECOME REALLY 

420
00:20:38,241 --> 00:20:38,508
RESISTANT.

421
00:20:38,508 --> 00:20:39,943
WHEN WE DO CRISPR THE EXPOSURE 

422
00:20:39,943 --> 00:20:40,944
IS TRANSIENT FOR TWO OR THREE 

423
00:20:40,944 --> 00:20:41,211
WEEKS.

424
00:20:41,211 --> 00:20:42,379
WE'RE LOOKING FOR SURVIVAL 

425
00:20:42,379 --> 00:20:50,053
FACTORS.

426
00:20:50,053 --> 00:20:52,455
GENES WHICH CAN BE INDUCED OR 

427
00:20:52,455 --> 00:20:54,324
EXPRESSED THAT WILL ALLOW CELLS 

428
00:20:54,324 --> 00:20:55,225
TO SURVIVE UNDER THE SELECTION 

429
00:20:55,225 --> 00:20:57,160
CONDITIONS AND I'LL GET INTO 

430
00:20:57,160 --> 00:21:00,997
THAT A LITTLE LATER.

431
00:21:00,997 --> 00:21:03,166
OKAY NOW I'LL GO BACK AND TELL 

432
00:21:03,166 --> 00:21:04,167
YOU A BIT OF HISTORY BECAUSE 

433
00:21:04,167 --> 00:21:06,403
IT'S AN INTERESTING STORY HOW 

434
00:21:06,403 --> 00:21:10,240
DID WE HAPPEN TO DISCOVER THE 

435
00:21:10,240 --> 00:21:14,377
ABC TRANSPORTER GENES.

436
00:21:14,377 --> 00:21:17,914
WE WERE ASKED BY THE DIRECTOR OF

437
00:21:17,914 --> 00:21:20,817
OUR DIVISION AT THE NATIONAL 

438
00:21:20,817 --> 00:21:21,885
CANCER INSTITUTE TO DO SOMETHING

439
00:21:21,885 --> 00:21:24,321
ABOUT THE PROBLEM OF MULTI-DRUG 

440
00:21:24,321 --> 00:21:25,288
RESISTANCE.

441
00:21:25,288 --> 00:21:28,024
A PHENOMENON DESCRIBED IN TISSUE

442
00:21:28,024 --> 00:21:29,626
CULTURE AND TRUE CLINICALLY IN 

443
00:21:29,626 --> 00:21:31,695
WHICH A PATIENT WHO WAS EXPOSED 

444
00:21:31,695 --> 00:21:33,563
TO ONE DRUG BECAME RESISTANT TO 

445
00:21:33,563 --> 00:21:34,998
MANY OTHER DRUGS.

446
00:21:34,998 --> 00:21:37,133
HOW CAN THAT BE?

447
00:21:37,133 --> 00:21:40,804
WE BEGAN TO SELECT CELLS AND AS 

448
00:21:40,804 --> 00:21:42,405
WE SELECTED TO HIGHER LEVELS OF 

449
00:21:42,405 --> 00:21:43,673
RESISTANCE WE MADE SURE THEY 

450
00:21:43,673 --> 00:21:46,643
WERE CROSS-RESISTANT.

451
00:21:46,643 --> 00:21:48,478
WE WERE FAVORING THE 

452
00:21:48,478 --> 00:21:49,613
AMPLIFICATION OF THE SPECIFIC 

453
00:21:49,613 --> 00:21:52,048
MECHANISM THAT LED TO THE 

454
00:21:52,048 --> 00:21:54,050
CROSS-RESISTANCE PHENOMENON AND 

455
00:21:54,050 --> 00:21:55,185
REPEATED THAT WITH MULTIPLE 

456
00:21:55,185 --> 00:21:59,356
DIFFERENT DRUGS AND WE WERE 

457
00:21:59,356 --> 00:22:04,294
FORTUNATELY ABLE TO RECRUIT A 

458
00:22:04,294 --> 00:22:09,566
FASTIDIOUS TISSUE CULTURE CELL 

459
00:22:09,566 --> 00:22:13,270
BIOLOGIST AND THOUGHT AND 

460
00:22:13,270 --> 00:22:20,777
THERE'S LITERATURE SHOWING 

461
00:22:20,777 --> 00:22:23,747
REDUCTASE INDUCTERS WERE 

462
00:22:23,747 --> 00:22:25,282
RESISTANT AND WE STARTED THINK 

463
00:22:25,282 --> 00:22:25,982
THE GENE RESPONSIBLE WOULD BE 

464
00:22:25,982 --> 00:22:32,422
AMPLIFIED.

465
00:22:32,422 --> 00:22:35,992
IN DEED IT WAS AND I WAS AT A 

466
00:22:35,992 --> 00:22:37,427
GORDON CONFERENCE AT A 

467
00:22:37,427 --> 00:22:40,697
RELATIVELY YOUNG FACULTY MEMBER 

468
00:22:40,697 --> 00:22:42,098
AND A GOOD REASON TO HAVE 

469
00:22:42,098 --> 00:22:44,668
CONFERENCES IN PERSON, BY THE 

470
00:22:44,668 --> 00:22:50,940
WAY, AND MET THIS TALENTED 

471
00:22:50,940 --> 00:22:51,808
SCIENTIST AND WHO WAS RUSSIAN 

472
00:22:51,808 --> 00:22:53,610
AND TRYING TO FIND A JOB AND HAD

473
00:22:53,610 --> 00:22:55,512
A POSTER NEXT TO MINE HOW TO 

474
00:22:55,512 --> 00:23:06,022
CLONE AMPLIFIED GENES AND HE 

475
00:23:06,790 --> 00:23:09,592
RENATURED IT IN A CELL AND THE 

476
00:23:09,592 --> 00:23:12,862
GENES THAT WERE HIGH COPY NUMBER

477
00:23:12,862 --> 00:23:16,266
WERE DOUBLE STRANDED AND 

478
00:23:16,266 --> 00:23:18,668
HYBRIDIZED MORE QUICKLY AND WERE

479
00:23:18,668 --> 00:23:22,238
ABLE TO PULL PROBES AGAINST GENE

480
00:23:22,238 --> 00:23:25,308
X THAT WAS AMPLIFIED IN THE 

481
00:23:25,308 --> 00:23:25,775
CELLS.

482
00:23:25,775 --> 00:23:27,944
YOU CAN SEE ALL THE CELL LINES 

483
00:23:27,944 --> 00:23:30,880
WE HAD AND AS THEY BECAME MORE 

484
00:23:30,880 --> 00:23:33,450
RESISTANT THE COPY NUMBER 

485
00:23:33,450 --> 00:23:35,051
INCREASED THIS IS A CELL BLOT 

486
00:23:35,051 --> 00:23:37,387
BASED ON THE PROBE WE WERE ABLE 

487
00:23:37,387 --> 00:23:40,156
TO GET THANKS TO IGGOR'S WORK 

488
00:23:40,156 --> 00:23:45,562
AND NEXT WAS TO PROVE IT HAD 

489
00:23:45,562 --> 00:23:47,864
SOMETHING TO DO WITH DRUG 

490
00:23:47,864 --> 00:23:50,133
RESISTANCE AND A POSTDOC WAS 

491
00:23:50,133 --> 00:23:52,802
ABLE TOO PULL TOGETHER ALL THE 

492
00:23:52,802 --> 00:23:57,374
CDNAs AND WE HAD A LIBRARY OF 

493
00:23:57,374 --> 00:23:58,908
THEM AND YOU'RE ALL THINKING WHY

494
00:23:58,908 --> 00:24:02,078
DON'T YOU LOOK UP THE SEQUENCE 

495
00:24:02,078 --> 00:24:04,314
AND FIGURE IT OUT.

496
00:24:04,314 --> 00:24:05,615
WE HAD NO SUCH DATABASES AT THE 

497
00:24:05,615 --> 00:24:09,853
TIME AND WE PUT TOGETHER AND PUT

498
00:24:09,853 --> 00:24:12,689
IN A VIRUS AND INFECTED CELLS 

499
00:24:12,689 --> 00:24:14,424
AND SURE ENOUGH THEY WERE 

500
00:24:14,424 --> 00:24:16,259
RESISTANT TO ALL THE DRUGS THEY 

501
00:24:16,259 --> 00:24:18,094
WERE RESISTANT TO.

502
00:24:18,094 --> 00:24:21,431
A SINGLE VIRUS WAS ABLE TO 

503
00:24:21,431 --> 00:24:25,635
CONFER THE ENTIRE RESISTANCE AND

504
00:24:25,635 --> 00:24:27,237
TURNED OUT COLLEAGUES OF HOURS 

505
00:24:27,237 --> 00:24:30,607
DESCRIBED A PROTEIN OF RESISTANT

506
00:24:30,607 --> 00:24:34,878
CELLS CALLED P GLYCOPROTEIN AND 

507
00:24:34,878 --> 00:24:37,714
P STOOD FOR PERMEABILITY AND IT 

508
00:24:37,714 --> 00:24:41,418
TURNED OUT THE GENE CLONED WAS A

509
00:24:41,418 --> 00:24:43,286
GENE FOR THE PROTEIN AND WE 

510
00:24:43,286 --> 00:24:43,787
PUBLISHED A PAPER THAT 

511
00:24:43,787 --> 00:24:50,794
DEMONSTRATED THAT.

512
00:24:50,794 --> 00:24:54,097
NOW I'LL GO THROUGH THE STORY OF

513
00:24:54,097 --> 00:24:56,065
ABC TRANSPORTER AND THIS IS AN 

514
00:24:56,065 --> 00:24:58,201
EXAMPLE OF A TRANSPORTER THAT 

515
00:24:58,201 --> 00:25:01,337
BELONGED TO WHAT BECAME A LARGER

516
00:25:01,337 --> 00:25:04,908
FAMILY OF 48 HUMAN ABA TRANS 

517
00:25:04,908 --> 00:25:08,445
PORTERS IN SEVEN CATEGORIES 

518
00:25:08,445 --> 00:25:12,982
KNOWN AS ABCDEF AND G.

519
00:25:12,982 --> 00:25:19,289
AND WHAT THEY HAVE IN COMMON IS 

520
00:25:19,289 --> 00:25:22,826
THEY HAVE TRANS MEMBRANE REGIONS

521
00:25:22,826 --> 00:25:24,961
AND TWO ATM SITES.

522
00:25:24,961 --> 00:25:28,631
SOME ARE HALF MOLECULES BUT IT'S

523
00:25:28,631 --> 00:25:31,301
LATER SHOWN THEY'RE DIMERIZE TOE

524
00:25:31,301 --> 00:25:33,136
FORM THIS STRUCTURE AND THIS IS 

525
00:25:33,136 --> 00:25:35,472
THE STRUCTURE OF P GLYCOPROTEIN 

526
00:25:35,472 --> 00:25:36,039
SHOWN HERE.

527
00:25:36,039 --> 00:25:37,273
AND THERE'S MANY EXAMPLES OF 

528
00:25:37,273 --> 00:25:39,342
THIS AND IT TURNED OUT THEY'RE 

529
00:25:39,342 --> 00:25:40,877
RESPONSIBLE FOR MOVING ALL KINDS

530
00:25:40,877 --> 00:25:43,446
OF THINGS INTO AND OUT OF CELLS 

531
00:25:43,446 --> 00:25:45,315
IT AND IN AND OUT OF 

532
00:25:45,315 --> 00:25:47,417
COMPARTMENTS OF CELLS AND COUPLE

533
00:25:47,417 --> 00:25:48,985
ENERGY TO THE TRANSPORT PROCESS.

534
00:25:48,985 --> 00:25:50,887
THERE'S A THERE'S TWO EXAMPLES 

535
00:25:50,887 --> 00:25:57,393
WHERE THE ENGINE EXISTS THE ATP 

536
00:25:57,393 --> 00:26:00,363
BINDING CASSETTE INVOLVED IN 

537
00:26:00,363 --> 00:26:01,364
TRANSCRIPTION BUT NO TRANS 

538
00:26:01,364 --> 00:26:02,765
MEMBRANE COMPONENT AND THESE ARE

539
00:26:02,765 --> 00:26:06,069
LITTLE ENGINES THAT CAN AND DO 

540
00:26:06,069 --> 00:26:11,341
AND PRECISELY WHAT THEY'RE ROLE 

541
00:26:11,641 --> 00:26:17,847
IS, IS NOT ENTIRELY CLEAR YET.

542
00:26:17,847 --> 00:26:22,585
WE'RE BACK TO P GLYCOPROTEIN AND

543
00:26:22,585 --> 00:26:24,420
WHY IS THIS GENE THAT PUMPS OUT 

544
00:26:24,420 --> 00:26:31,461
OF CELLS AND AGAIN THIS WORK WAS

545
00:26:31,461 --> 00:26:35,231
DONE SHOWING IT WAS EXPRESSED AT

546
00:26:35,231 --> 00:26:38,635
BARRIER FUNCTIONS IN THE HUMAN.

547
00:26:38,635 --> 00:26:42,405
THIS IS AN ULTIMATE HUMAN 

548
00:26:42,405 --> 00:26:46,643
TOTALLY ROUND AND YOU CAN SEE 

549
00:26:46,643 --> 00:26:49,345
THERE'S PUMPS THAT PUMP THINGS 

550
00:26:49,345 --> 00:26:51,281
OUT OF THE PLACENTA.

551
00:26:51,281 --> 00:26:53,316
PUMP THINGS OUD OF OUT OF THE 

552
00:26:53,316 --> 00:26:56,953
KIDNEY AND LIVER AND INTESTINE 

553
00:26:56,953 --> 00:26:58,821
OUT OF THE BODY.

554
00:26:58,821 --> 00:27:01,724
THERE'S A BLOOD BRAIN BARRIER AS

555
00:27:01,724 --> 00:27:03,860
WELL AS A PLACENTAL BARRIER AND 

556
00:27:03,860 --> 00:27:06,429
IF YOU'RE A TUMOR THE BLOOD IS 

557
00:27:06,429 --> 00:27:07,530
BUSY PUMPING THINGS IN THE 

558
00:27:07,530 --> 00:27:07,797
BLOOD.

559
00:27:07,797 --> 00:27:17,607
IT TURNED OUT THERE WERE DOZENS 

560
00:27:17,607 --> 00:27:19,342
AND HUNDREDS AND PROBABLY 

561
00:27:19,342 --> 00:27:20,443
THOUSANDS RECOGNIZED BY THIS 

562
00:27:20,443 --> 00:27:22,011
SYSTEM AND PUMPED OUT AND SOME 

563
00:27:22,011 --> 00:27:23,313
DRUGS ARE LISTED HERE AND 

564
00:27:23,313 --> 00:27:24,180
THERE'S INTERESTING STORIES AND 

565
00:27:24,180 --> 00:27:26,749
IF I HAD MORE TIME I'D GO INTO 

566
00:27:26,749 --> 00:27:28,985
THEM BUT A LOT OF THE DRUGS THAT

567
00:27:28,985 --> 00:27:30,887
ARE IN COMMON USE ARE SUBSTRATES

568
00:27:30,887 --> 00:27:36,826
FOR THE TRANSPORT SYSTEMS.

569
00:27:36,826 --> 00:27:40,229
SO THERE ARE THREE OF THE 48 

570
00:27:40,229 --> 00:27:41,130
TRANSPORTERS POLY SPECIFIC AND 

571
00:27:41,130 --> 00:27:41,731
CAN RECOGNIZE MANY DIFFERENT 

572
00:27:41,731 --> 00:27:43,633
DRUGS.

573
00:27:43,633 --> 00:27:49,639
ONE IS CALLED ABCG2 A DIMER OF 

574
00:27:49,639 --> 00:27:51,474
TWO HALF MOLECULES.

575
00:27:51,474 --> 00:27:55,912
ONE IS ABC1 OR PGP SHOWN HERE 

576
00:27:55,912 --> 00:28:00,750
AND ONE IS MRP 1 WITH AN 

577
00:28:00,750 --> 00:28:02,885
INTERNAL EXTENSION WHICH IS 

578
00:28:02,885 --> 00:28:04,020
INTEGRATED INTO THE PLASMA 

579
00:28:04,020 --> 00:28:05,688
MEMBRANE AND THE FUNCTION IS NOT

580
00:28:05,688 --> 00:28:06,956
ENTIRELY CLEAR.

581
00:28:06,956 --> 00:28:09,125
YOU CAN CUT IT OFF AND THE 

582
00:28:09,125 --> 00:28:11,227
TRANSPORTER STILL WORKS.

583
00:28:11,227 --> 00:28:13,329
SO THESE THINGS LOOK SOMEWHAT 

584
00:28:13,329 --> 00:28:14,631
ALIKE BUT NOT IDENTICAL.

585
00:28:14,631 --> 00:28:16,799
THE STRUCTURES HAVE BEEN 

586
00:28:16,799 --> 00:28:19,369
DETERMINED BY A VARIETY OF 

587
00:28:19,369 --> 00:28:24,007
DIFFERENT LABS IN OUR LABORATORY

588
00:28:24,007 --> 00:28:26,876
AND THERE WERE MAJOR 

589
00:28:26,876 --> 00:28:30,046
CONTRIBUTION.

590
00:28:30,046 --> 00:28:32,281
THERE ARE WONDERFUL EXAMPLES BY 

591
00:28:32,281 --> 00:28:36,853
STEVE A BUNCH OF PEOPLE 

592
00:28:36,853 --> 00:28:38,154
CONTRIBUTED AND WE HAVE SOME 

593
00:28:38,154 --> 00:28:42,425
IDEA HOW THE TRANSPORTER 

594
00:28:42,425 --> 00:28:42,692
FUNCTIONS.

595
00:28:42,692 --> 00:28:47,363
MOST THE TRANS MEMBRANE REGIONS 

596
00:28:47,363 --> 00:28:49,666
STICK IN THE PLASMA MEMBRANE 

597
00:28:49,666 --> 00:28:52,068
REGION AND MOST FROM IN THE ATP 

598
00:28:52,068 --> 00:28:53,636
AND WE THINK IT ENTERS THROUGH 

599
00:28:53,636 --> 00:28:57,173
THE PLASMA MEMBRANE AND ATP 

600
00:28:57,173 --> 00:28:59,909
BINDS TO THE SITES AND THE TWO 

601
00:28:59,909 --> 00:29:03,246
SITES COME TOGETHER, ATP'S NOT 

602
00:29:03,246 --> 00:29:08,251
YET HYDROLYZED BUT CATALYZE THE 

603
00:29:08,251 --> 00:29:11,387
ATP BINDING SITE AND THE DRUG IS

604
00:29:11,387 --> 00:29:11,921
EXTRUDED.

605
00:29:11,921 --> 00:29:15,525
THEN THE ATP IS HYDROLYZED, 

606
00:29:15,525 --> 00:29:17,927
RELEASED, ATP COMES OFF AND THE 

607
00:29:17,927 --> 00:29:20,196
TWO ATP SITES SEPARATE.

608
00:29:20,196 --> 00:29:22,198
THIS IS A VERY GLOBAL 

609
00:29:22,198 --> 00:29:22,498
DESCRIPTION.

610
00:29:22,498 --> 00:29:23,933
THE EXACT DETAILS ARE STILL 

611
00:29:23,933 --> 00:29:25,334
BEING WORKED OUT.

612
00:29:25,334 --> 00:29:31,174
AND IN PARTICULARLY EXACTLY HOW 

613
00:29:31,174 --> 00:29:34,477
IT'S LINKED TO THE TRANSPORT 

614
00:29:34,477 --> 00:29:36,546
FUNCTION OF THE TRANSPORTERS.

615
00:29:36,546 --> 00:29:38,214
IF YOU LOOK AT THE SPECIFICITY 

616
00:29:38,214 --> 00:29:39,849
OR LACK OF THE SPECIFICITY OF 

617
00:29:39,849 --> 00:29:41,684
THE TRANSPORTERS.

618
00:29:41,684 --> 00:29:45,121
THREES A VEN DIAGRAM THAT SHOWS 

619
00:29:45,121 --> 00:29:47,123
SOME DRUGS INCLUDING MANY 

620
00:29:47,123 --> 00:29:48,391
STANDARD ANTICANCER DRUGS 

621
00:29:48,391 --> 00:29:50,059
RECOGNIZED BY ALL THREE 

622
00:29:50,059 --> 00:29:50,393
TRANSPORTERS.

623
00:29:50,393 --> 00:29:51,527
SOME SPECIFICALLY BY ONE OR THE 

624
00:29:51,527 --> 00:29:55,665
OTHER OR BOTH OR TWO AT A TIME 

625
00:29:55,665 --> 00:30:00,002
AND SO UPON SO THIS IS IN THE 

626
00:30:00,002 --> 00:30:00,203
HUMAN.

627
00:30:00,203 --> 00:30:01,170
IN THE MOUSE IT'S DIFFERENT AND 

628
00:30:01,170 --> 00:30:03,639
IN THE RAD IT'S DIFFERENT AND 

629
00:30:03,639 --> 00:30:05,208
WE'VE BEEN WORK ON THE ZEBRAFISH

630
00:30:05,208 --> 00:30:10,480
AND IT'S DIFFERENT AND IT'S A 

631
00:30:10,480 --> 00:30:13,516
VERY COMPLICATED AND IT MAKES IT

632
00:30:13,516 --> 00:30:15,985
HARD HOW TO INHIBIT OR FIND 

633
00:30:15,985 --> 00:30:16,819
DRUGS WHAT MOST PHARMACEUTICAL 

634
00:30:16,819 --> 00:30:18,454
COMPANIES DO IS TRY TO FIND 

635
00:30:18,454 --> 00:30:21,090
DRUGS NOT SUBSTRATES FOR ANY OF 

636
00:30:21,090 --> 00:30:23,226
THESE TRANSPORTERS AND THAT'S 

637
00:30:23,226 --> 00:30:30,166
BEEN TO SOME EXTENT SUCCESSFUL.

638
00:30:30,166 --> 00:30:32,635
SO ONE QUESTION IS HOW ARE THE 

639
00:30:32,635 --> 00:30:33,202
DRUGS RECOGNIZED.

640
00:30:33,202 --> 00:30:35,705
IT FLIES IN THE FACE OF WHAT WE 

641
00:30:35,705 --> 00:30:38,174
LEARNED ABOUT SPECIFICITY OF 

642
00:30:38,174 --> 00:30:40,743
TRANSPORT AND ENZYMATIC 

643
00:30:40,743 --> 00:30:46,115
SPECIFICITY AND CAME UP WITH THE

644
00:30:46,115 --> 00:30:49,352
IDEA THE DIFFERENCE IS WAS IN 

645
00:30:49,352 --> 00:30:54,624
THE PLASMA MEMBRANE.

646
00:30:54,624 --> 00:30:59,028
THE DRUGS WERE GOING FROM THE 

647
00:30:59,028 --> 00:30:59,929
OUTER AND RECOGNIZED IN THE 

648
00:30:59,929 --> 00:31:06,402
BINDING SITE WITHIN THE 

649
00:31:06,402 --> 00:31:16,612
TRANSPOR

650
00:31:31,661 --> 00:31:34,063
TRANSPORTER -- AND THERE'S NOW 

651
00:31:34,063 --> 00:31:34,931
QUITE A BIT OF EVIDENCE 

652
00:31:34,931 --> 00:31:37,166
SUGGESTING HOW THEY WORKED AND 

653
00:31:37,166 --> 00:31:39,001
THE LACK OF SPECIFICITY NOT 

654
00:31:39,001 --> 00:31:44,006
WITHIN THE POLY SPECIFIC DRUG 

655
00:31:44,006 --> 00:31:46,275
BINDING SITES BUT THE DELIVERY 

656
00:31:46,275 --> 00:31:49,345
IS THROUGH THE HYDROPHOBIC 

657
00:31:49,345 --> 00:31:58,921
MEMBRANE.

658
00:31:58,921 --> 00:32:00,323
WITH DISCOVERED THE ORIGINAL 

659
00:32:00,323 --> 00:32:03,292
GENE WAS A POLY MORPHIC FORM AND

660
00:32:03,292 --> 00:32:06,295
CLONED OUT OF HELA CELLS AND 

661
00:32:06,295 --> 00:32:09,432
ANYBODY NOW KNOWS HELA CAME FROM

662
00:32:09,432 --> 00:32:18,441
A WOMAN CALLED HENRIETTA LACKS 

663
00:32:18,441 --> 00:32:22,411
AND THERE'S A NUMBER OF 

664
00:32:22,411 --> 00:32:25,281
POLYMORPHISMS FROM PEOPLE WITH 

665
00:32:25,281 --> 00:32:27,516
ASI

666
00:32:27,516 --> 00:32:30,219
ASIAN DESCENT AND IT DIDN'T 

667
00:32:30,219 --> 00:32:37,260
CHANGE THE AMINO ACID BUT THE 

668
00:32:37,260 --> 00:32:37,560
NUCLEOTIDE.

669
00:32:37,560 --> 00:32:41,297
A

670
00:32:41,297 --> 00:32:44,467
AND IT WAS DISCOVERED THIS 

671
00:32:44,467 --> 00:32:48,437
POLYMORPHISM EXISTED IN A PLACE 

672
00:32:48,437 --> 00:32:51,107
THAT ALLOWED IT TO FORM IN THE 

673
00:32:51,107 --> 00:32:53,009
RNA AND WHEN WE DID THE 

674
00:32:53,009 --> 00:32:54,944
FOOTPRINTING THERE WAS A LONG 

675
00:32:54,944 --> 00:32:57,346
PAUSE THAT OCCURRED WHILE THE 

676
00:32:57,346 --> 00:33:01,384
RNA WAS BEING TRANSLATED ON THE 

677
00:33:01,384 --> 00:33:03,486
RIBOSOME AND BELIEVE THERE WAS A

678
00:33:03,486 --> 00:33:05,621
SLIGHT ALTERATION IN THE FOLDING

679
00:33:05,621 --> 00:33:06,789
OF THE TRANS MEMBRANE REGION 

680
00:33:06,789 --> 00:33:11,894
WHICH IS WHERE THE DRUG BIENGD 

681
00:33:11,894 --> 00:33:12,528
SITES RAND THEY MAI HAVE LED TO 

682
00:33:12,528 --> 00:33:16,866
THE ALTERATION INCLUDING 

683
00:33:16,866 --> 00:33:19,035
INCREASED RESISTANCE.

684
00:33:19,035 --> 00:33:23,372
AND YOU COULD IMAGINE THIS WOULD

685
00:33:23,372 --> 00:33:25,341
HAVE ADVANTAGE DUE TO THE 

686
00:33:25,341 --> 00:33:28,744
EXPOSURE OR TOXIC MATERIALS IN 

687
00:33:28,744 --> 00:33:39,055
THE PERSON'S DIET.

688
00:33:45,928 --> 00:33:49,332
THEY DON'T CONFER AND THIS IS 

689
00:33:49,332 --> 00:33:51,000
TURNED OUT TO BE MORE TRUE THAN 

690
00:33:51,000 --> 00:34:02,278
WE THOUGHT ORIGBINDING THOUGHT .

691
00:34:03,279 --> 00:34:13,756
IS AFTER TREATMENT SOME EXPRESS 

692
00:34:15,224 --> 00:34:17,460
AND SOME DON'T EXPRESS PGP AND 

693
00:34:17,460 --> 00:34:18,027
NOT SURPRISING THEY DON'T 

694
00:34:18,027 --> 00:34:19,328
RESPOND TO A LOT OF THE DRUGS WE

695
00:34:19,328 --> 00:34:22,698
USE AND THEY'RE ANIMAL MODELS IN

696
00:34:22,698 --> 00:34:26,569
WHICH CANCER XENO GRAPHS CAN BE 

697
00:34:26,569 --> 00:34:28,404
SELECTED IN THE ANIMAL FOR 

698
00:34:28,404 --> 00:34:30,406
EXPRESSION AS A REASON FOR 

699
00:34:30,406 --> 00:34:32,775
RESISTANCE IN THE ANIMALS.

700
00:34:32,775 --> 00:34:36,512
BASED ON ALL THE DATA WE 

701
00:34:36,512 --> 00:34:41,517
CONCLUDED P GLYCO PROTPROTEIN I 

702
00:34:41,517 --> 00:34:45,888
ENOUGH FOR RESISTANCE AND MAY 

703
00:34:45,888 --> 00:34:47,056
NOT BE NECESSARY, IN OTHER 

704
00:34:47,056 --> 00:34:49,325
WORDS, THERE'S OTHER CAUSES OF 

705
00:34:49,325 --> 00:34:53,396
DRUG RESISTANCE.

706
00:34:53,396 --> 00:34:56,132
RECENTLY THERE'S BEEN A FAIR 

707
00:34:56,132 --> 00:34:58,401
AMOUNT OF ADDITIONAL EVIDENCE 

708
00:34:58,401 --> 00:35:06,108
THAT PRETTY MUCH MAKES IT, IT 

709
00:35:06,108 --> 00:35:08,644
CAN BE RESPONSIBLE FOR 

710
00:35:08,644 --> 00:35:10,913
RESISTANCE TO CANCER AND IN SOME

711
00:35:10,913 --> 00:35:12,048
TUMORS THERE'S HIGH LEVEL OF 

712
00:35:12,048 --> 00:35:16,318
EXPRESSION, NOT ALL BUT SOME.

713
00:35:16,318 --> 00:35:20,990
AND SOME CASES THERE'S R

714
00:35:20,990 --> 00:35:23,259
REAARRANGEMENTS THAT TURN ON 

715
00:35:23,259 --> 00:35:24,527
EXPRESSION AND THOSE ARE 

716
00:35:24,527 --> 00:35:26,395
SELECTED FOR BY THE DRUGS.

717
00:35:26,395 --> 00:35:29,832
-- REARRANGEMENTS THAT TURN ON.

718
00:35:29,832 --> 00:35:33,135
THERE'S SUBSET OF PATIENTS WITH 

719
00:35:33,135 --> 00:35:35,805
HIGH LEVELS OF PGP2 AND AS WE 

720
00:35:35,805 --> 00:35:37,506
BEGIN TO USE MORE TARGETED DRUGS

721
00:35:37,506 --> 00:35:39,508
WE FIND RESISTANCE DEVELOPING 

722
00:35:39,508 --> 00:35:40,876
AGAINST THOSE DRUGS THAT ARE 

723
00:35:40,876 --> 00:35:50,019
SUBSTRATES FOR THE TRANSPORTER.

724
00:35:50,019 --> 00:35:55,324
NON-SMALL CELL IS AN EXAMPLE AND

725
00:35:55,324 --> 00:36:04,366
THERE'S AN EXAMPLE A CON GUE -- 

726
00:36:04,366 --> 00:36:06,402
CONJUGATE AND ONE BASIS OF THE 

727
00:36:06,402 --> 00:36:09,638
RESISTANCE OF THE DRUG APPROVED 

728
00:36:09,638 --> 00:36:13,809
BY THE FDA TO TREAT HODGKIN'S 

729
00:36:13,809 --> 00:36:14,910
LYMPHOMA IS AN EXPRESSION OF THE

730
00:36:14,910 --> 00:36:18,447
PROTEIN AND THOSE THAT ARE 

731
00:36:18,447 --> 00:36:19,615
NAYSAYERS MOST OF THE CLINICAL 

732
00:36:19,615 --> 00:36:21,283
TRIALS WHERE PATIENTS WERE 

733
00:36:21,283 --> 00:36:23,185
TREATED WITH TO THE PGP AND 

734
00:36:23,185 --> 00:36:25,354
FAILED TO RESPONSE TO 

735
00:36:25,354 --> 00:36:28,157
CHEMOTHERAPY AND THEY SAID PGP 

736
00:36:28,157 --> 00:36:30,559
CAN'T BE RESPONSE IN ALMOST ALL 

737
00:36:30,559 --> 00:36:32,695
THE TRIALS PGP WASN'T 

738
00:36:32,695 --> 00:36:34,230
DEMONSTRATED TO BE PRESENT AND 

739
00:36:34,230 --> 00:36:36,665
IF'S ONLY PRESENT IN IF 5% TO 

740
00:36:36,665 --> 00:36:38,400
10% THERE'S NO CLINICAL TRIAL TO

741
00:36:38,400 --> 00:36:40,202
DESIGN EXCEPT FOR ONE WHERE 

742
00:36:40,202 --> 00:36:45,040
YOU'RE SPECIFICALLY LOOKING AT 

743
00:36:45,040 --> 00:36:46,609
PGP EXPRESSING CELLS.

744
00:36:46,609 --> 00:36:48,744
BOTTOM LINE IT'S EXPRESSED IN 

745
00:36:48,744 --> 00:36:53,048
SOME DRUG-RESISTANT CANCERS AND 

746
00:36:53,048 --> 00:36:55,484
THERE'S THOUGHT IT'S THE CAUSE 

747
00:36:55,484 --> 00:36:57,720
BUT THERE'S OTHER MECHANISMS OF 

748
00:36:57,720 --> 00:36:58,053
RESISTANCE.

749
00:36:58,053 --> 00:36:59,355
ONE THING THAT BECAME CLEAR TO 

750
00:36:59,355 --> 00:37:01,724
US IS THOUGH IT MAY NOT BE 

751
00:37:01,724 --> 00:37:04,527
RESPONSIBLE FOR ALL DRUG 

752
00:37:04,527 --> 00:37:07,696
RESISTANCE, IT CERTAINLY IN ITS 

753
00:37:07,696 --> 00:37:08,697
PHYSIOLOGICAL ROLE OF THE BLOOD 

754
00:37:08,697 --> 00:37:10,266
BRAIN BARRIER WAS RESPONSIBLE 

755
00:37:10,266 --> 00:37:11,400
FOR KEEPING A LOT OF THE DRUGS 

756
00:37:11,400 --> 00:37:13,769
OUT OF THE BRAIN AND TREATING 

757
00:37:13,769 --> 00:37:17,173
PRIMARY BRAIN TUMORS IS 

758
00:37:17,173 --> 00:37:17,773
ESPECIALLY DIFFICULT BECAUSE 

759
00:37:17,773 --> 00:37:19,175
MANY OF THE DRUGS WE'D LIKE TO 

760
00:37:19,175 --> 00:37:21,877
USE ARE NOT ABLE TO GET IN THE 

761
00:37:21,877 --> 00:37:22,077
BRAIN.

762
00:37:22,077 --> 00:37:32,555
WE BEGAN TO STUDY THE BLOOD 

763
00:37:32,788 --> 00:37:34,423
BRAIN BARRIER AND THE TRANS 

764
00:37:34,423 --> 00:37:42,431
PORTERS ARE PGP AND ABCG2 AND 

765
00:37:42,431 --> 00:37:52,808
THERE'S EXAMPLES HERE.

766
00:38:08,591 --> 00:38:11,694
AND WE LOOK AT OF THE 

767
00:38:11,694 --> 00:38:13,329
ACCUMULATION OF THE DRUG IN THE 

768
00:38:13,329 --> 00:38:18,434
BRAIN AND RED MEANS A LOT OF 

769
00:38:18,434 --> 00:38:21,904
DRUG IN THE BRAIN BUT IF YOU 

770
00:38:21,904 --> 00:38:23,906
KNOCK OUT DRUG YOU SEE 

771
00:38:23,906 --> 00:38:29,845
REDUNDANCY AND HAVE TO KNOCKOUT 

772
00:38:29,845 --> 00:38:31,180
BOTH, INHIBIT BOTH TO GET DRUGS 

773
00:38:31,180 --> 00:38:32,548
IN THE BRAIN.

774
00:38:32,548 --> 00:38:34,850
WE WANTED TO STUDY THE 

775
00:38:34,850 --> 00:38:36,952
PHENOMENON AND DO A BETTER JOB 

776
00:38:36,952 --> 00:38:38,954
OF GET DRUGS IN THE BRAIN.

777
00:38:38,954 --> 00:38:40,556
MATT HALL WHO JUST BECAME A 

778
00:38:40,556 --> 00:38:46,095
SCIENTIFIC DIRECTOR OF NCATS A 

779
00:38:46,095 --> 00:38:56,372
WEEK AGO SO THERE WAS A MODEL IN

780
00:38:56,372 --> 00:39:06,882
THE MOUSE ARE WE TOOK VOE VOS 

781
00:39:10,452 --> 00:39:14,123
IFASE AND IS SUBSTRATE ABCG2 A 

782
00:39:14,123 --> 00:39:15,224
TRANSPORTER THAT SITS AT THE 

783
00:39:15,224 --> 00:39:16,792
BLOOD BRAIN BARRIER.

784
00:39:16,792 --> 00:39:19,328
THEY COULDN'T GET ACROSS THE 

785
00:39:19,328 --> 00:39:23,932
BLOOD BRAIN BARRIER UNLESS YOU 

786
00:39:23,932 --> 00:39:27,736
INHIBITED ABCG2 AND YOU LIGHT UP

787
00:39:27,736 --> 00:39:34,009
THE BRAINS OF THESE MICE.

788
00:39:34,009 --> 00:39:36,845
YOU HAVE MORE INHIBITER AND GET 

789
00:39:36,845 --> 00:39:38,280
MORE LIGHT.

790
00:39:38,280 --> 00:39:40,549
THE INTERESTING FEATURE OF THE 

791
00:39:40,549 --> 00:39:42,017
MODEL IS IT DOESN'T DEPEND ON 

792
00:39:42,017 --> 00:39:43,686
THE INHIBITION OF THE 

793
00:39:43,686 --> 00:39:45,087
TRANSPORTER.

794
00:39:45,087 --> 00:39:46,989
ANYTHING THAT DISRUPTS THE 

795
00:39:46,989 --> 00:39:48,457
JUNCTION BETWEEN THE EPITHELIAL 

796
00:39:48,457 --> 00:39:51,360
CELLS ALLOWS THE DRUGS TO GET IN

797
00:39:51,360 --> 00:39:53,495
AND THIS SEEMED LIKE A GOOD 

798
00:39:53,495 --> 00:39:54,763
MODEL.

799
00:39:54,763 --> 00:39:55,931
THE THROUGHPUT WAS SOMEWHAT 

800
00:39:55,931 --> 00:39:58,067
LIMITED IF WE WANTED TO FOR 

801
00:39:58,067 --> 00:39:58,267
DRUGS.

802
00:39:58,267 --> 00:40:00,302
IN FACT WE DECIDED TO START 

803
00:40:00,302 --> 00:40:06,709
WORKING WITH ZEBRAFISH.

804
00:40:06,709 --> 00:40:09,278
IT TURNS OUT THE ZEBRAFISH BLOOD

805
00:40:09,278 --> 00:40:18,787
BRAIN BARRIER HAS MANY ATOMIC 

806
00:40:18,787 --> 00:40:19,121
SIMILARITIES.

807
00:40:19,121 --> 00:40:20,823
AND WE HAD TO FIGURE OUT WHAT 

808
00:40:20,823 --> 00:40:23,359
THE ABC TRANSPORTERS WERE 

809
00:40:23,359 --> 00:40:25,327
EXPRESSED IN THE BLOOD BRAIN 

810
00:40:25,327 --> 00:40:27,463
BARRIER IN ZEBRAFISH.

811
00:40:27,463 --> 00:40:37,973
TURNS OUT THERE'S A HOMEO -- 

812
00:40:40,642 --> 00:40:43,545
HOMEOLOGUE AND THIS IS WORK DONE

813
00:40:43,545 --> 00:40:48,817
BY JOE THOMAS IN OUR LAB.

814
00:40:48,817 --> 00:40:51,153
WHAT IS THE SUBSTRATE OF THE 

815
00:40:51,153 --> 00:40:59,928
INHIBITOR SPECIFICITY OF THE 

816
00:40:59,928 --> 00:41:04,299
ZEBRAFISH MULTI DRUG 

817
00:41:04,299 --> 00:41:08,437
TRANSPORTERS WE WERE ABLE TO USE

818
00:41:08,437 --> 00:41:13,308
A MORE SENSITIVE LUCIFERASE AND 

819
00:41:13,308 --> 00:41:15,244
THE WORK IS ONGOING AND NEXT 

820
00:41:15,244 --> 00:41:16,278
TIME I COME BACK I'LL TELL YOU 

821
00:41:16,278 --> 00:41:26,688
ALL ABOUT IT IN DETAIL.

822
00:41:34,263 --> 00:41:40,169
YOU CAN USE CRISPR TO HOOK UP 

823
00:41:40,169 --> 00:41:50,679
THE KAS 9 NUCLEASE TO A ZINC 

824
00:41:55,417 --> 00:41:58,954
INHIBITER CALLED KRAB OR FOUR 

825
00:41:58,954 --> 00:42:03,625
COPIES OF THE VB16 OF THE HERPES

826
00:42:03,625 --> 00:42:06,495
VIRUS AND THEY WORK WELL IF IT 

827
00:42:06,495 --> 00:42:09,431
TURNS ON OR TURNS OFF DOWN 

828
00:42:09,431 --> 00:42:11,867
STREAM GENES OR KNOCK OUT THE 

829
00:42:11,867 --> 00:42:12,267
GENES.

830
00:42:12,267 --> 00:42:15,003
THERE'S LIBRARIES AVAILABLE THAT

831
00:42:15,003 --> 00:42:18,140
HAVE GUARD RNAs FOR THE ENTIRE 

832
00:42:18,140 --> 00:42:18,841
GENOME.

833
00:42:18,841 --> 00:42:22,344
I WON'T GO INTO THIS IN DETAIL 

834
00:42:22,344 --> 00:42:28,350
BUT YOU CAN INTRODUCE THE CAS9 

835
00:42:28,350 --> 00:42:29,952
TOO THE ABOUT WHAT IS OF 

836
00:42:29,952 --> 00:42:32,187
INTEREST AND PUT IN THE RNAs.

837
00:42:32,187 --> 00:42:34,056
YOU CAN SELECT FOR THE DRUG YOU 

838
00:42:34,056 --> 00:42:36,625
WANT THE CELLS TO BE RESISTANT 

839
00:42:36,625 --> 00:42:38,427
TO AND ASK WHAT GENES GET TURNED

840
00:42:38,427 --> 00:42:45,701
ON AND OFF.

841
00:42:45,701 --> 00:42:51,974
THE FIRST EFFORT WAS DONE BY THE

842
00:42:51,974 --> 00:42:56,645
PERSON SHOWN HERE AND SHE DID AN

843
00:42:56,645 --> 00:42:58,413
EXPERIMENT AND ASKED WHAT GENES 

844
00:42:58,413 --> 00:43:02,351
MADE CELLS RESISTANT TO TAXOL A 

845
00:43:02,351 --> 00:43:05,387
WELL KNOWN ANTI-CANCER DRUG AND 

846
00:43:05,387 --> 00:43:08,190
DID A STATISTICAL ANALYSIS OF 

847
00:43:08,190 --> 00:43:16,865
THE GUARD RNAs AND FOUND BY TEN 

848
00:43:16,865 --> 00:43:20,836
ORDERS OF MAGNITUDE 

849
00:43:20,836 --> 00:43:22,671
STATISTICALLY THE GENE LIKELY TO

850
00:43:22,671 --> 00:43:25,107
SURVIVE IN THE CELLS IS OUR 

851
00:43:25,107 --> 00:43:26,942
FAVORITE GENE, ABCD1.

852
00:43:26,942 --> 00:43:29,077
THESE EXPERIMENTS TAKE A COUPLE 

853
00:43:29,077 --> 00:43:29,511
MONTHS.

854
00:43:29,511 --> 00:43:32,681
IT ORIGINALLY TOOK US TWO TO 

855
00:43:32,681 --> 00:43:36,184
THREE YEARS TO CLONE THE 

856
00:43:36,184 --> 00:43:36,418
PROTEIN.

857
00:43:36,418 --> 00:43:38,186
THIS IS A VERY EFFICIENT 

858
00:43:38,186 --> 00:43:38,487
TECHNOLOGY.

859
00:43:38,487 --> 00:43:41,223
THERE'S OTHER GENES IN HERE AS 

860
00:43:41,223 --> 00:43:43,091
WELL BUT SIX LOGS LESS LIKELY TO

861
00:43:43,091 --> 00:43:45,160
BE CRITICAL.

862
00:43:45,160 --> 00:43:46,328
WE REPEATED THE EXPERIMENT WITH 

863
00:43:46,328 --> 00:43:47,763
THE SAME RESULTS AND NOW WE'RE 

864
00:43:47,763 --> 00:43:49,731
DOING AN EXPERIMENT IN WHICH WE 

865
00:43:49,731 --> 00:43:52,167
INHIBIT PGP SO IT CAN'T BE 

866
00:43:52,167 --> 00:43:53,735
RESPONSIBLE FOR RESISTANCE AND 

867
00:43:53,735 --> 00:43:58,407
ASKED WHETHER ANY OR ALL OF 

868
00:43:58,407 --> 00:43:59,975
THESE BECOME THE MAJOR MEDICAL 

869
00:43:59,975 --> 00:44:03,078
SYSTEM AND YOU CAN PLAY LOTS OF 

870
00:44:03,078 --> 00:44:04,513
GAMES WITH THE SYSTEM AND WE'RE 

871
00:44:04,513 --> 00:44:08,650
LOOKING AT RESISTANCE AND EACH 

872
00:44:08,650 --> 00:44:11,486
WOULD BE A SEMINAR ON ITS OWN 

873
00:44:11,486 --> 00:44:14,156
BUT EVERY TIME WE TAKE A CELL 

874
00:44:14,156 --> 00:44:17,059
TYPE OF COLON OR LIVER CANCER, 

875
00:44:17,059 --> 00:44:18,160
PANCREATIC CANCER AND A DRUG 

876
00:44:18,160 --> 00:44:21,029
USED TO TREAT THAT, WE GET A 

877
00:44:21,029 --> 00:44:23,699
WHOLE LUNCH OF GENES THAT CONFER

878
00:44:23,699 --> 00:44:26,868
SENSITIVITY OR RESISTANCE AND 

879
00:44:26,868 --> 00:44:28,503
SORTING THROUGH THESE AND 

880
00:44:28,503 --> 00:44:30,706
FIGURING OUT WHICH ONES ARE 

881
00:44:30,706 --> 00:44:31,974
CLINICALLY IMPORTANT ARE THE 

882
00:44:31,974 --> 00:44:36,645
NEXT GENERATION'S JOB.

883
00:44:36,645 --> 00:44:36,845
OKAY.

884
00:44:36,845 --> 00:44:39,181
TWO VERY QUICK STORIES MAYBE 

885
00:44:39,181 --> 00:44:40,449
REALLY QUICK.

886
00:44:40,449 --> 00:44:42,084
SO WE HAVE BEEN ALL ALONG 

887
00:44:42,084 --> 00:44:46,922
SELECTING CELLS AND LOOKING FOR 

888
00:44:46,922 --> 00:44:50,325
RESISTANCE AND HAD A VARYING 

889
00:44:50,325 --> 00:44:56,431
CELL LINE RESISTANCE TO AN 

890
00:44:56,431 --> 00:44:59,534
IMPORTANT ANTI-CANCER DRUG AND 

891
00:44:59,534 --> 00:45:01,336
RESISTANCE IS HARD TO COME BY 

892
00:45:01,336 --> 00:45:03,405
WHICH IS WHY IT'S GOOD BUT CAN 

893
00:45:03,405 --> 00:45:07,342
SELECT CELLS THAT ARE 

894
00:45:07,342 --> 00:45:07,643
RESISTANCE.

895
00:45:07,643 --> 00:45:10,946
IT KNOCKS OUT DNA BY DAMAGING 

896
00:45:10,946 --> 00:45:13,548
DNA AND RESISTANCE DEVELOPS BY 

897
00:45:13,548 --> 00:45:23,859
IMPROVING DNA REPAIR.

898
00:45:23,859 --> 00:45:26,728
AND WE GOT A GENE THAT MORE 

899
00:45:26,728 --> 00:45:30,532
POWERED THAN OTHER CALLED TTPP3.

900
00:45:30,532 --> 00:45:33,702
AND THIS GENE IT TURNS OUT 

901
00:45:33,702 --> 00:45:36,538
LITTLE WAS KNOWN AND TURNED OUT 

902
00:45:36,538 --> 00:45:40,909
TO BE A GENE WHOSE PRODUCT 

903
00:45:40,909 --> 00:45:49,151
STABILIZES MICROTUBE S AND THE 

904
00:45:49,151 --> 00:45:54,289
CELLS BECAME SENSITIVE TO THE 

905
00:45:54,289 --> 00:45:54,489
DRUG.

906
00:45:54,489 --> 00:45:58,727
AND WE ADDED IT BACK AND CELLS 

907
00:45:58,727 --> 00:46:02,564
BECAME RESISTANT AND IT BECAME 

908
00:46:02,564 --> 00:46:05,434
CLEAR THEY WERE THE FACTOR AND 

909
00:46:05,434 --> 00:46:10,405
WHEN WE DID ADDITIONAL STUDIES 

910
00:46:10,405 --> 00:46:13,608
IN THE NEUROLOGY CENTER AND 

911
00:46:13,608 --> 00:46:14,776
MICROTUBULES ARE REALLY 

912
00:46:14,776 --> 00:46:21,316
IMPORTANT AND THEY WERE CAPABLE 

913
00:46:21,316 --> 00:46:23,318
OF DOING IN VITRO MICROTUBULE 

914
00:46:23,318 --> 00:46:26,988
ASSAYS AT ACHIEVABLE DOSES AND 

915
00:46:26,988 --> 00:46:28,123
LO AND BEHOLD THE MICROTUBULES 

916
00:46:28,123 --> 00:46:29,725
WERE NOT HAPPY AND THE DYNAMICS 

917
00:46:29,725 --> 00:46:31,693
WERE CHANGE.

918
00:46:31,693 --> 00:46:38,266
WE ADDED TPPP3 AND THEY WERE 

919
00:46:38,266 --> 00:46:41,770
STABILIZED AND HAPPY AGAIN AND 

920
00:46:41,770 --> 00:46:43,939
IT LOOKS LIKE THERE'S A 

921
00:46:43,939 --> 00:46:46,408
MICROTUBULE DAMAGING AGENT AND 

922
00:46:46,408 --> 00:46:48,210
IT EXPLAINS SOMETHING ABOUT THE 

923
00:46:48,210 --> 00:46:50,212
TOXICITY AND WHY IT'S SUCH A 

924
00:46:50,212 --> 00:46:52,180
GOOD DRUG AND HITS THE SENSITIVE

925
00:46:52,180 --> 00:46:53,181
REGIONS OF THE CANCER CELL.

926
00:46:53,181 --> 00:46:54,416
SO THIS IS KIND OF AN 

927
00:46:54,416 --> 00:47:04,726
INTERESTING STORY.

928
00:47:06,461 --> 00:47:11,533
AND THEY SELECTED CELLS 

929
00:47:11,533 --> 00:47:18,507
RESISTANT TO THE ASSCETYLASE 

930
00:47:18,507 --> 00:47:24,946
INHIBITORS AND WE DID A 

931
00:47:24,946 --> 00:47:27,415
SELECTION IN THE PRESENCE OF AN 

932
00:47:27,415 --> 00:47:31,720
INHIBITER AND DID RNA SEQ 

933
00:47:31,720 --> 00:47:37,826
ANALYSIS AND GOT THIS GENE, MCF7

934
00:47:37,826 --> 00:47:44,966
AND TURNS OUT IT'S A METHYL 

935
00:47:44,966 --> 00:47:47,903
TRANSFERASE AND OVEREXPRESSION 

936
00:47:47,903 --> 00:47:53,642
OF THE GENE WAS ABLE TO 

937
00:47:53,642 --> 00:48:03,451
INACTIVATE THE ROMIDEPSIN SO WE 

938
00:48:03,451 --> 00:48:07,289
HAVE AN EXAMPLE OF ALMOST 

939
00:48:07,289 --> 00:48:09,324
EVERYTHING AND DRUG RESISTANCE 

940
00:48:09,324 --> 00:48:11,092
CAN OCCUR IN MANY DIFFERENT WAYS

941
00:48:11,092 --> 00:48:14,996
AND YOU'LL HEAR THE SAME STORY 

942
00:48:14,996 --> 00:48:17,199
FROM JOHN IT DEPENDS ON THE CELL

943
00:48:17,199 --> 00:48:22,037
LINE AND DRUG AND THE WAY IN 

944
00:48:22,037 --> 00:48:23,605
WHICH YOU CAN MAKE THE 

945
00:48:23,605 --> 00:48:24,005
SELECTION.

946
00:48:24,005 --> 00:48:28,176
IT'S MULTI-FACTORIAL AND NEED TO

947
00:48:28,176 --> 00:48:29,778
SEE IF IT'S PREEXISTING OR 

948
00:48:29,778 --> 00:48:30,946
OCCURS DURING THE EVOLUTION OF 

949
00:48:30,946 --> 00:48:31,713
THE TUMOR.

950
00:48:31,713 --> 00:48:34,015
I'LL GET TO THAT IN A MOMENT.

951
00:48:34,015 --> 00:48:36,251
IF IT'S PREEXISTING IT'S 

952
00:48:36,251 --> 00:48:38,720
POSSIBLE THEN TO DO MOLECULAR 

953
00:48:38,720 --> 00:48:40,355
SCREENING WITH HIGH SENSITIVITY 

954
00:48:40,355 --> 00:48:43,792
AND FIGURE OUT WHAT GENES ARE 

955
00:48:43,792 --> 00:48:45,827
LIKELY TO BE RESPONSIBLE AND 

956
00:48:45,827 --> 00:48:47,963
MAYBE DEVELOP A THERAPY THAT 

957
00:48:47,963 --> 00:48:49,231
TAKES THAT INTO ACCOUNT.

958
00:48:49,231 --> 00:48:50,498
IF IT OCCURS DURING TUMOR WE 

959
00:48:50,498 --> 00:48:51,466
NEED SOME WAY OF MONITORING THE 

960
00:48:51,466 --> 00:48:54,736
TUMOR.

961
00:48:54,736 --> 00:48:58,340
WE ARE COLLECTING ALL THE DRUG 

962
00:48:58,340 --> 00:49:02,744
RESISTANT MECHANISMS AND CRISPR 

963
00:49:02,744 --> 00:49:05,146
IS GIVING A NEW SUPPLY OF NEW 

964
00:49:05,146 --> 00:49:07,582
ONES AND SO WE'LL GET A CATALOG 

965
00:49:07,582 --> 00:49:12,120
AND I'M HOPING THE CATALOG IS 

966
00:49:12,120 --> 00:49:13,722
SHORT ENOUGH TO SEE THE 

967
00:49:13,722 --> 00:49:15,090
COMPLETED CATALOG BEFORE I'M NOT

968
00:49:15,090 --> 00:49:16,358
WORKING ON THIS ANYMORE.

969
00:49:16,358 --> 00:49:18,660
THE THIRD POINT IS THE CLINICAL 

970
00:49:18,660 --> 00:49:20,662
RELEVANCE OF ALL THE MECHANISMS 

971
00:49:20,662 --> 00:49:22,030
STILL NEED TO BE DETERMINED.

972
00:49:22,030 --> 00:49:23,365
WE NEED BETTER WAYS TO DO 

973
00:49:23,365 --> 00:49:24,666
SCREENING MORE CLINICALLY 

974
00:49:24,666 --> 00:49:31,373
RELEVANT AND NEED TO BE ABLE TO 

975
00:49:31,373 --> 00:49:32,774
ASSESS THE EXPRESSION OF GENES 

976
00:49:32,774 --> 00:49:34,409
AND EVOLUTION OF GENES DURING 

977
00:49:34,409 --> 00:49:41,983
THE TUMOR AND ONE WAY IS THROUGH

978
00:49:41,983 --> 00:49:43,351
LIQUID BIOPSIES OR SOME IMAGING 

979
00:49:43,351 --> 00:49:44,686
APPROACH AND ON THAT LET ME 

980
00:49:44,686 --> 00:49:48,223
THANK A FEW PEOPLE WHO ARE 

981
00:49:48,223 --> 00:49:48,657
RESPONSIBLE.

982
00:49:48,657 --> 00:49:51,493
THIS IS MY CURRENT LAB GROUP.

983
00:49:51,493 --> 00:49:55,330
MANY OF WHOM ARE HERE.

984
00:49:55,330 --> 00:49:57,165
MY GOODNESS, EXTRA CREDIT AND 

985
00:49:57,165 --> 00:49:58,767
OVER THE YEARS THERE'S BEEN MANY

986
00:49:58,767 --> 00:50:01,336
MANY POST-DOCTORAL FELLOWS AND 

987
00:50:01,336 --> 00:50:04,306
MORE SENIOR FELLOW.

988
00:50:04,306 --> 00:50:08,009
ALL THE WORK BEGAN AS A 

989
00:50:08,009 --> 00:50:08,977
DESTRUCTION BETWEEN MYSELF AND 

990
00:50:08,977 --> 00:50:10,412
OTHER AND I'M GRATEFUL FOR THE 

991
00:50:10,412 --> 00:50:11,880
SUPPORT I'VE HAD OVER THE YEARS 

992
00:50:11,880 --> 00:50:18,687
FROM THE NIH SO THANK YOU ALL.

993
00:50:18,687 --> 00:50:22,223
>> THANK YOU, VERY MUCH
FOR THIS

994
00:50:22,223 --> 00:50:23,925
INSIGHTFUL AND EXCITING 

995
00:50:23,925 --> 00:50:25,327
PRESENTATION.

996
00:50:25,327 --> 00:50:28,630
I ENCOURAGE THOSE HERE AND 

997
00:50:28,630 --> 00:50:31,366
WATCHING TO PLEASE SUBMIT 

998
00:50:31,366 --> 00:50:32,334
QUESTIONS ONLINE.

999
00:50:32,334 --> 00:50:35,337
AS WAS EXPLAINED BEFORE AND WE 

1000
00:50:35,337 --> 00:50:38,740
WILL HAVE A SESSION AT THE 

1001
00:50:38,740 --> 00:50:39,975
CONCLUSION OF JOHN DEKKER'S 

1002
00:50:39,975 --> 00:50:48,984
TALK.

1003
00:50:48,984 --> 00:50:50,652
>> OKAY.

1004
00:50:50,652 --> 00:50:54,222
SO THANK YOU ALL FOR JOINING.

1005
00:50:54,222 --> 00:50:55,623
THANK YOU FOR THE OPPORTUNITY TO

1006
00:50:55,623 --> 00:50:57,192
SPEAK AND THANK YOU FOR THAT 

1007
00:50:57,192 --> 00:50:57,859
VERY GENEROUS INTRODUCTION IN 

1008
00:50:57,859 --> 00:50:58,660
THE BEGINNING.

1009
00:50:58,660 --> 00:51:01,262
IT'S VERY DIFFICULT TO FOLLOW 

1010
00:51:01,262 --> 00:51:02,063
DR. GOTTESMAN.

1011
00:51:02,063 --> 00:51:06,868
I'LL DO MY BEST HERE.

1012
00:51:06,868 --> 00:51:09,037
FIRST, I HAVE NO CONFLICTS OF 

1013
00:51:09,037 --> 00:51:10,905
INTEREST BUT I WILL BE 

1014
00:51:10,905 --> 00:51:12,907
DISCUSSING A NUMBER OF SPECIFIC 

1015
00:51:12,907 --> 00:51:14,109
COMMERCIAL PHARMACEUTICAL 

1016
00:51:14,109 --> 00:51:15,577
PRODUCTS AND THIS DISCUSSION 

1017
00:51:15,577 --> 00:51:17,278
SHOULD NOT BE CONSTRUED TO 

1018
00:51:17,278 --> 00:51:19,147
CONSTITUTE ENDORSEMENT BY THE 

1019
00:51:19,147 --> 00:51:21,082
NIH OR U.S. GOVERNMENT.

1020
00:51:21,082 --> 00:51:22,817
THESE WILL OUR LEARNING S BY THE

1021
00:51:22,817 --> 00:51:24,552
END OF THE TALK YOU SHOULD BE 

1022
00:51:24,552 --> 00:51:27,922
ABLE TO DESCRIBE THE GENERAL 

1023
00:51:27,922 --> 00:51:30,792
CLASSES OF ANTIBIOTIC RESISTANCE

1024
00:51:30,792 --> 00:51:33,228
MECHANISMS TO BE USED IN 

1025
00:51:33,228 --> 00:51:37,732
BACTERIA AND UNDERSTAND THE 

1026
00:51:37,732 --> 00:51:48,476
OUTCOME OF LACTAMS AND LACK  

1027
00:51:57,585 --> 00:51:58,920
LACTAMASES AND YOU'LL SEE THE 

1028
00:51:58,920 --> 00:51:59,220
OUTLINE.

1029
00:51:59,220 --> 00:52:01,923
WE'LL START WITH A BROAD 

1030
00:52:01,923 --> 00:52:05,660
OVERVIEW OF ANTIMICROBIALS AND 

1031
00:52:05,660 --> 00:52:12,067
LOOK AT RESISTANCE AND LOOK AT 

1032
00:52:12,067 --> 00:52:18,873
THE EVOLUTION OF BETA LACTAMS 

1033
00:52:18,873 --> 00:52:22,143
AND THEY'RE THE CLASSIC 

1034
00:52:22,143 --> 00:52:24,946
ANTIBIOTICS SUCH AS PENICILLIN 

1035
00:52:24,946 --> 00:52:27,549
AND THERE'S ARGUABLY THE MOST 

1036
00:52:27,549 --> 00:52:32,087
IMPORTANT CLASS OF ANTIBIOTICS 

1037
00:52:32,087 --> 00:52:36,491
USED AND THERE'S A LARGE FAMILY 

1038
00:52:36,491 --> 00:52:45,600
THAT INCLUDE E. COLI AND OTHERS 

1039
00:52:45,600 --> 00:52:56,144
AND WE'LL TURN TO  THE DIFFERENT

1040
00:53:03,418 --> 00:53:05,086
BACTERIA AND LOOK WHERE 

1041
00:53:05,086 --> 00:53:10,592
ANTIBIOTIC RESISTANCE EVOLVES IN

1042
00:53:10,592 --> 00:53:21,136
THE AND IN TREATING INFECTIONS 

1043
00:53:29,310 --> 00:53:31,012
IN OTHERWISE HEALTHY INDIVIDUALS

1044
00:53:31,012 --> 00:53:33,348
THEY ENABLED ADVANCES IN SURGERY

1045
00:53:33,348 --> 00:53:35,683
AND TRANSPLANTATION THAT WOULD 

1046
00:53:35,683 --> 00:53:36,518
NOT HAVE BEEN POSSIBLE WITHOUT 

1047
00:53:36,518 --> 00:53:40,054
THE ABILITY TO CONTROL 

1048
00:53:40,054 --> 00:53:40,922
INFECTIONS THAT OCCUR IN THE 

1049
00:53:40,922 --> 00:53:47,162
TISSUE BARRIERS AND IMMUNOLOGIC 

1050
00:53:47,162 --> 00:53:48,863
DEFENSES.

1051
00:53:48,863 --> 00:53:50,465
ANTIBIOTICS ARE THE MOST COMMON 

1052
00:53:50,465 --> 00:53:53,568
TYPE OF MEDICATION PRESCRIBE AND

1053
00:53:53,568 --> 00:53:55,336
ONE OF THE MOST IMPORTANT 

1054
00:53:55,336 --> 00:53:56,104
MEDICAL INTERVENTIONS MADE.

1055
00:53:56,104 --> 00:53:58,273
THE FIRST CONCEPT I WANT TO 

1056
00:53:58,273 --> 00:54:00,975
START WITH IS IN THINKING ABOUT 

1057
00:54:00,975 --> 00:54:03,278
THE EVOLUTION OF ANTIBIOTIC 

1058
00:54:03,278 --> 00:54:08,349
RESISTANCE IT'S ESSENTIAL TO 

1059
00:54:08,349 --> 00:54:10,418
UNDERSTAND THAT MOST ARE 

1060
00:54:10,418 --> 00:54:12,220
CHEMICALLY MODIFIED NATURAL 

1061
00:54:12,220 --> 00:54:16,591
PRODUCTS PRODUCED BY BACTERIA 

1062
00:54:16,591 --> 00:54:20,595
MOLDS THAT ARE ARMAMENT OF 

1063
00:54:20,595 --> 00:54:23,464
MICROBIAL WARFARE AND DEFENSE 

1064
00:54:23,464 --> 00:54:24,866
MECHANISMS HAVE EMERGED TO 

1065
00:54:24,866 --> 00:54:27,001
PROTECT THE ARMS PRODUCERS AND 

1066
00:54:27,001 --> 00:54:32,240
THE INTENDED RECIPIENTS AND MANY

1067
00:54:32,240 --> 00:54:34,242
LAYERS OF DEFENSIVE AND COUNTER 

1068
00:54:34,242 --> 00:54:36,110
DEFENSIVE STRATEGY HAVE BEEN 

1069
00:54:36,110 --> 00:54:37,512
ELABORATED BY THE PARTIES.

1070
00:54:37,512 --> 00:54:40,348
THIS IS RELEVANT BECAUSE IT'S 

1071
00:54:40,348 --> 00:54:41,983
THE ANCIENT DEFENSE MECHANISMS 

1072
00:54:41,983 --> 00:54:45,620
PLACED UNDER SELECTION BY THE 

1073
00:54:45,620 --> 00:54:48,189
HUMAN CLINICAL USE OF 

1074
00:54:48,189 --> 00:54:49,591
DERIVATIVES OF NATURAL 

1075
00:54:49,591 --> 00:54:49,891
ANTIBIOTICS.

1076
00:54:49,891 --> 00:54:58,833
LET'S LOOK AT AN EXAMPLE.

1077
00:54:58,833 --> 00:55:04,706
THIS ANTIBODY IS USED TO TREAT 

1078
00:55:04,706 --> 00:55:10,211
INFECTIONS SUCH AS STAPH.

1079
00:55:10,211 --> 00:55:12,247
VANCOMYCIN SUPPRESS THE GROWTH 

1080
00:55:12,247 --> 00:55:13,448
OF ITS NEIGHBORS COMPETING FOR 

1081
00:55:13,448 --> 00:55:17,051
LIMITED RESOURCES.

1082
00:55:17,051 --> 00:55:27,962
AND ADVANTVANCOMYCIN RESISTANT  

1083
00:55:28,196 --> 00:55:30,698
EMERGED AND BY THE 1990s THEY 

1084
00:55:30,698 --> 00:55:31,332
WERE PRESENT IN MOST HOMES 

1085
00:55:31,332 --> 00:55:37,238
AROUND THE WORLD.

1086
00:55:37,238 --> 00:55:41,109
AND VANCOMYCIN RESISTANCE IS 

1087
00:55:41,109 --> 00:55:42,777
MEDIATED BY A CLUSTER OF GENES.

1088
00:55:42,777 --> 00:55:53,321
THERE'S VARIATIONS ON THE GENES 

1089
00:55:56,658 --> 00:55:59,994
AND THE GENES CAN BE MOBILIZED 

1090
00:55:59,994 --> 00:56:02,997
BETWEEN BACTERIA AND CONFER 

1091
00:56:02,997 --> 00:56:05,833
RESISTANCE TO NEW HOST.

1092
00:56:05,833 --> 00:56:07,335
WE'LL LOOK IN A LITTLE BIT OF 

1093
00:56:07,335 --> 00:56:10,805
THE MECHANISMS TO CONFER 

1094
00:56:10,805 --> 00:56:16,778
MOBILITY TO ANTIMICROBIAL 

1095
00:56:16,778 --> 00:56:17,512
RESISTANT GENES.

1096
00:56:17,512 --> 00:56:20,648
I EMPHASIZE VANCOMYCIN IS A 

1097
00:56:20,648 --> 00:56:22,717
NATURAL PRODUCT AND INDEED 

1098
00:56:22,717 --> 00:56:24,319
RESISTANCE TO IT IS NATURAL AND 

1099
00:56:24,319 --> 00:56:26,854
ALSO ANCIENT IN ORIGIN.

1100
00:56:26,854 --> 00:56:30,391
THIS IS DEMONSTRATED BY A STUDY 

1101
00:56:30,391 --> 00:56:33,161
THAT WAS PERFORMED IN THE YUKON 

1102
00:56:33,161 --> 00:56:37,965
NEAR ALASKA IN WHICH VANCOMYCIN 

1103
00:56:37,965 --> 00:56:40,601
RESISTANT GENES WERE DISCOVERED 

1104
00:56:40,601 --> 00:56:42,403
UNDER 30,000-YEAR-OLD 

1105
00:56:42,403 --> 00:56:50,411
PERMAFROST.

1106
00:56:50,411 --> 00:56:56,918
 ON THE LEFT SIDE IS THE 

1107
00:56:56,918 --> 00:56:58,386
STRATOGRAPHIC DESIGN AND MORE 

1108
00:56:58,386 --> 00:57:05,693
THAN 6 METERS BELOW THE SURFACE 

1109
00:57:05,693 --> 00:57:08,663
INCLUDED GENES SIMILAR TO THE 

1110
00:57:08,663 --> 00:57:12,367
VAN A AND H AND F GENES THAT 

1111
00:57:12,367 --> 00:57:14,869
MEDIATE VANCOMYCIN RESISTANCE IN

1112
00:57:14,869 --> 00:57:20,475
MODERN DAY V.E.R. AND THE 

1113
00:57:20,475 --> 00:57:21,876
ANCIENT PROTEIN IN BLUE OVERLAYS

1114
00:57:21,876 --> 00:57:25,346
WITH THE MODERN DAY PROTEIN 

1115
00:57:25,346 --> 00:57:35,623
SHOWN IN GREEN.

1116
00:57:52,540 --> 00:57:58,479
AND THE NATURAL AND ANCIENT 

1117
00:57:58,479 --> 00:58:06,421
ORIGINS OF MANY RESISTANT 

1118
00:58:06,421 --> 00:58:11,692
CATEGORIES HAVE BEEN SHOWN AND 

1119
00:58:11,692 --> 00:58:15,830
RESISTANCE IS NATURAL AND 

1120
00:58:15,830 --> 00:58:19,066
ANCIENT IN ITS ORIGINS.

1121
00:58:19,066 --> 00:58:29,610
THE SECOND CONCEPT IS RESISTANCE

1122
00:58:30,077 --> 00:58:34,315
TO NATURAL ANTIBIOTICS IS 

1123
00:58:34,315 --> 00:58:35,349
WIDESPREAD IN THE ENVIRONMENT.

1124
00:58:35,349 --> 00:58:40,154
THIS IS DEMONSTRATED BY A STUDY 

1125
00:58:40,154 --> 00:58:43,024
THAT SEQUENCED SPOIL MICROBIOMES

1126
00:58:43,024 --> 00:58:48,062
AND RESISTANT GENES IN SOIL 

1127
00:58:48,062 --> 00:58:48,329
MICROBES.

1128
00:58:48,329 --> 00:58:50,965
WHAT WAS FUND THEY WERE LOADED 

1129
00:58:50,965 --> 00:58:57,939
WITH A LARGE NUMBER OF 

1130
00:58:57,939 --> 00:59:04,312
ANTMICROBIAL RESISTANT GENES AND

1131
00:59:04,312 --> 00:59:14,856
SHOWS THE CLASSES OF RESISTANT 

1132
00:59:18,192 --> 00:59:21,662
MICRO BIOTICS AND THE GENES ARE 

1133
00:59:21,662 --> 00:59:24,966
DIVERSELY DISTRIBUTED THROUGHOUT

1134
00:59:24,966 --> 00:59:26,067
THE BACTERIAL KINGDOM.

1135
00:59:26,067 --> 00:59:28,769
THESE FINDINGS HAVE BEEN 

1136
00:59:28,769 --> 00:59:33,841
CONFIRMED BY A NUMBER OF 

1137
00:59:33,841 --> 00:59:39,146
SUBSEQUENT STUDIES AND OTHER 

1138
00:59:39,146 --> 00:59:43,351
SCENARIOS AND IN ADDITION TO 

1139
00:59:43,351 --> 00:59:46,387
BEING NATURAL AND ANCIENT 

1140
00:59:46,387 --> 00:59:48,256
RESISTANCE TO MODERN DAY 

1141
00:59:48,256 --> 00:59:50,358
ANTIBODIES ARE INCREDIBLY 

1142
00:59:50,358 --> 00:59:51,759
WIDESPREAD IN THE ENVIRONMENT 

1143
00:59:51,759 --> 01:00:02,270
AND RANDOMLY SAMPLED SOIL CAN 

1144
01:00:06,841 --> 01:00:08,743
MEDIATE ANTIBIOTICS AND 

1145
01:00:08,743 --> 01:00:10,578
ANTIBIOTICS REPRESENT AS A SMALL

1146
01:00:10,578 --> 01:00:13,114
SUBSET OF THE WORLD'S NATURAL 

1147
01:00:13,114 --> 01:00:14,815
ANTIBIOTICS IN PART BECAUSE GOOD

1148
01:00:14,815 --> 01:00:19,353
CLINICAL ANTIBIOTICS HAVE BOB 

1149
01:00:19,353 --> 01:00:22,557
BIO AVAILABLE AND NON-TOXIC AND 

1150
01:00:22,557 --> 01:00:25,526
HIT TARGETS NOT SHARED BY HUMAN 

1151
01:00:25,526 --> 01:00:27,795
CELLS AND EUKARYOTICS AND 

1152
01:00:27,795 --> 01:00:31,332
THERE'S PROCESSES THAN TARGETED,

1153
01:00:31,332 --> 01:00:33,601
MOST MODERN ANTIBIOTICS TARGET A

1154
01:00:33,601 --> 01:00:35,469
SMALL NUMBER OF THE PROCESSES.

1155
01:00:35,469 --> 01:00:37,171
THIS IS RELEVANT AS A 

1156
01:00:37,171 --> 01:00:41,876
CONSEQUENCE THE ARSENAL OF 

1157
01:00:41,876 --> 01:00:43,277
MODERN ANTIBODIES GOES TO A 

1158
01:00:43,277 --> 01:00:45,846
SMALL NUMBER OF RESISTANT 

1159
01:00:45,846 --> 01:00:46,147
MECHANISMS.

1160
01:00:46,147 --> 01:00:48,015
WE'LL LOOK AT SOME OF THE 

1161
01:00:48,015 --> 01:00:50,851
MECHANISMS THAT CONFER 

1162
01:00:50,851 --> 01:00:55,923
RESISTANCE IN GROUND NEGATIVE 

1163
01:00:55,923 --> 01:00:59,427
BACTERIA AND FOCUS ON THEM IN 

1164
01:00:59,427 --> 01:01:01,329
MORE DETAIL.

1165
01:01:01,329 --> 01:01:03,598
THERE'S AN OUTER AND INNER 

1166
01:01:03,598 --> 01:01:03,898
MEMBRANE.

1167
01:01:03,898 --> 01:01:07,368
THE FIRST IS THE FIRST BARRIER 

1168
01:01:07,368 --> 01:01:18,045
AGAINST ANTIBIOTICS AND MOST ARE

1169
01:01:18,045 --> 01:01:25,786
POORLY PERMEABLE AND AROUND THIS

1170
01:01:25,786 --> 01:01:30,791
IS ESSENTIAL FOR METABOLISM.

1171
01:01:30,791 --> 01:01:33,060
ANTIBIOTICS CAN HIJACK THE 

1172
01:01:33,060 --> 01:01:33,327
PATHWAYS.

1173
01:01:33,327 --> 01:01:35,329
THE FIGURE ON THE LEFT SHOWS THE

1174
01:01:35,329 --> 01:01:42,570
STRUCTURE MUCH AN OUT EVER ER --

1175
01:01:42,570 --> 01:01:46,841
OUTER MEMBRANE AND CONFER 

1176
01:01:46,841 --> 01:01:47,108
PRIMERS.

1177
01:01:47,108 --> 01:01:48,709
THE FIGURE ON THE RIGHT SHOWS 

1178
01:01:48,709 --> 01:01:54,081
THE STRUCTURE OF A MON AMER WITH

1179
01:01:54,081 --> 01:02:04,558
A MOLECULE OF THE ANTIBODY  

1180
01:02:15,670 --> 01:02:18,472
MEROPENEM AND IT MAY ALTER THE 

1181
01:02:18,472 --> 01:02:21,308
STRUCTURE OF THE PERMEATION 

1182
01:02:21,308 --> 01:02:23,844
PATHWAY AND EXCLUDE ANTIBIOTICS 

1183
01:02:23,844 --> 01:02:26,247
BUT DOWN REGULATE POINTS THAT 

1184
01:02:26,247 --> 01:02:29,383
HAVEN'T ESSENTIAL FOR VIABILITY 

1185
01:02:29,383 --> 01:02:30,718
TO CONFER ANTIBIOTIC RESISTANCE 

1186
01:02:30,718 --> 01:02:34,955
AND THEY'RE THE FIRST LINE OF 

1187
01:02:34,955 --> 01:02:42,163
DEFENSE AGAINST ANTIBIOTICS FOR 

1188
01:02:42,163 --> 01:02:43,197
THE BACTERIA AND THE SECOND 

1189
01:02:43,197 --> 01:02:47,568
CLASS PUMPS IT OUT BY A NUMBER 

1190
01:02:47,568 --> 01:02:50,971
OF PUMPS IN TRANSPORTERS AND IN 

1191
01:02:50,971 --> 01:02:55,376
CONTRAST TO PASSIVE DIFFUSION 

1192
01:02:55,376 --> 01:02:59,814
THESE ARE MOSTLY ACTIVE OR 

1193
01:02:59,814 --> 01:03:00,548
SECONDARY ACTIVE TRANSPORTERS 

1194
01:03:00,548 --> 01:03:03,050
AND THIS ALLOWS THE TRANSPORTERS

1195
01:03:03,050 --> 01:03:05,953
TO MOVE ANTIBODIES OUT OF THE 

1196
01:03:05,953 --> 01:03:06,520
CELL AGAINST CONCENTRATION 

1197
01:03:06,520 --> 01:03:10,891
GRADIENTS.

1198
01:03:10,891 --> 01:03:13,627
THESE ARE FIVE OF THE PRINCIPLE 

1199
01:03:13,627 --> 01:03:15,296
TRANSPORTERS IN BACTERIAL CELLS 

1200
01:03:15,296 --> 01:03:17,164
ON THE LEFT AND RIGHT HAND SIDES

1201
01:03:17,164 --> 01:03:22,436
ARE THE ABC SUPER FAMILY WHICH 

1202
01:03:22,436 --> 01:03:29,577
ARE ANCIENT CELLS OF THE 

1203
01:03:29,577 --> 01:03:32,780
TRANSPORTERS AND EUKARYOTIC 

1204
01:03:32,780 --> 01:03:34,415
CELLS AND IN BACTERIA THEY'RE 

1205
01:03:34,415 --> 01:03:36,283
LOCATED IN THE INNER MEMBRANE 

1206
01:03:36,283 --> 01:03:38,819
AND HYDROLYZE ATP AND CAN MOVE 

1207
01:03:38,819 --> 01:03:42,156
ANTIBODIES AND OTHER SUBSTRATES 

1208
01:03:42,156 --> 01:03:47,128
FROM THE CYTOPLASM INTO THE 

1209
01:03:47,128 --> 01:03:47,428
PERIPLASM.

1210
01:03:47,428 --> 01:03:49,363
OR CAN BE CONNECTED WITH 

1211
01:03:49,363 --> 01:03:52,133
ADDITIONAL MACHINERY THAT ALLOWS

1212
01:03:52,133 --> 01:03:54,635
THE MOVEMENT OF SUBSTRATES 

1213
01:03:54,635 --> 01:03:55,636
THROUGH THE OUTER MEMBRANE INTO 

1214
01:03:55,636 --> 01:04:00,674
THE CELL.

1215
01:04:00,674 --> 01:04:06,413
THE MFS AND SMR FAMILIES OF 

1216
01:04:06,413 --> 01:04:08,215
TRANSPORTERS CAN MOVE ANTIBODIES

1217
01:04:08,215 --> 01:04:18,726
FROM THE CYTOTO CYTOPLASM TO 

1218
01:04:21,495 --> 01:04:23,430
PERIPLASM AND THE TRANSPORTERS 

1219
01:04:23,430 --> 01:04:25,866
COUPLE AND CAN MOVE SUBSTRATES 

1220
01:04:25,866 --> 01:04:28,969
FROM THE CYTOPLASM OR PERIPLASM 

1221
01:04:28,969 --> 01:04:30,471
ACROSS THE OUTER MEMBRANE OUT OF

1222
01:04:30,471 --> 01:04:31,338
THE CELL.

1223
01:04:31,338 --> 01:04:36,010
AND SIMILAR TO WHAT WE HEARD IN 

1224
01:04:36,010 --> 01:04:43,250
THE FIRST TALK THEY CONSTITUTE A

1225
01:04:43,250 --> 01:04:53,460
FORMID 

1226
01:04:58,465 --> 01:05:00,100
FORMIDABLE THE NEXT LINE OF 

1227
01:05:00,100 --> 01:05:03,270
DEFENSE IS TO HYDROLYZE OR 

1228
01:05:03,270 --> 01:05:05,539
MODIFY CHEMICALLY AND BACTERIA 

1229
01:05:05,539 --> 01:05:07,541
HAVE EVOLVED A DIVERSE ARRAY OF 

1230
01:05:07,541 --> 01:05:09,677
SYSTEMS THAT CAN MODIFY MOST 

1231
01:05:09,677 --> 01:05:12,813
CLASSES OF ANTIBIOTICS USED IN 

1232
01:05:12,813 --> 01:05:14,415
MODERN MEDICINE.

1233
01:05:14,415 --> 01:05:17,218
THERE'S A MECHANISM GRAM 

1234
01:05:17,218 --> 01:05:21,288
NEGATIVES USE TO ACTIVATE.

1235
01:05:21,288 --> 01:05:25,893
AND THIS IS CARRIED OUT BY AN 

1236
01:05:25,893 --> 01:05:33,834
ENZYME AND STARTS WITH AN ATP 

1237
01:05:33,834 --> 01:05:38,939
AND MAKES UP THE STRUCTURE.

1238
01:05:38,939 --> 01:05:49,416
THIS AND MODIFY THE SITE OF 

1239
01:05:52,386 --> 01:05:53,621
ACTION OF THE ANTIBODY AND WE'LL

1240
01:05:53,621 --> 01:05:55,356
LOOK AT A CLASS OF ENZYMES IN 

1241
01:05:55,356 --> 01:05:58,459
MORE DETAIL IN A BIT AND THESE 

1242
01:05:58,459 --> 01:06:00,728
ARE ENZYMES THAT CROSS-LINK THE 

1243
01:06:00,728 --> 01:06:05,432
CELL WALLS AND THE MAIN TARGET 

1244
01:06:05,432 --> 01:06:11,805
FOR BETA LACTAMS AND WHAT 

1245
01:06:11,805 --> 01:06:17,144
MODIFIES BETWEEN THESE CAN 

1246
01:06:17,144 --> 01:06:23,317
CONFER RESISTANCE.

1247
01:06:23,317 --> 01:06:28,155
AND YOU CAN APPRECIATE THE 

1248
01:06:28,155 --> 01:06:28,756
INTERACTIONS AND THESE ARE 

1249
01:06:28,756 --> 01:06:31,425
HIGHLY SPECIFIC CONTRACTIONS AND

1250
01:06:31,425 --> 01:06:40,534
SINGLE MUTATIONS CAN ALTER AND 

1251
01:06:40,534 --> 01:06:46,006
NOW WE'LL LOOK AT A SPECIFIC AND

1252
01:06:46,006 --> 01:06:56,483
IMPORTANT AND BETA LACTAMS 

1253
01:06:58,953 --> 01:07:05,993
INCLUDE PENICILLINS AND THERE'S 

1254
01:07:05,993 --> 01:07:09,363
A COMMON FAMILY OF BACTERIA THAT

1255
01:07:09,363 --> 01:07:15,436
ARE ENTEROGRAM NEGATIVES, E. 

1256
01:07:15,436 --> 01:07:24,645
COLI AND OTHERS AND IT'S ONE OF 

1257
01:07:24,645 --> 01:07:25,913
THE MORE SERIOUS PROBLEMS IN 

1258
01:07:25,913 --> 01:07:31,352
MODERN MEDICINE AND WHY WE'LL 

1259
01:07:31,352 --> 01:07:41,562
FOCUS ON IT.

1260
01:07:43,030 --> 01:07:45,632
AND THIS IS SANDWICHED IN THE 

1261
01:07:45,632 --> 01:07:47,501
WALL AND THE CROSS LINKS ARE 

1262
01:07:47,501 --> 01:07:51,939
BETWEEN THE RESIDUES AND SERVE 

1263
01:07:51,939 --> 01:08:02,483
TO RIGIDIFY THE CELL WALL OF THE

1264
01:08:19,433 --> 01:08:22,069
PEPTIDOGLYCAN AND IT CONTAINS A 

1265
01:08:22,069 --> 01:08:29,009
BOND A STRUCTURAL MIMIC AND THE 

1266
01:08:29,009 --> 01:08:39,386
NATURAL STRABT AT THE 

1267
01:08:40,621 --> 01:08:41,221
PEPTIDODASE AND THEY SEAR THE 

1268
01:08:41,221 --> 01:08:43,090
SITE KNOCKING THEM OUT OF 

1269
01:08:43,090 --> 01:08:43,457
COMMISSION.

1270
01:08:43,457 --> 01:08:47,127
THIS RESULTS IN DECREASED CROSS 

1271
01:08:47,127 --> 01:08:51,498
LINK OF THE CELL WALL AND 

1272
01:08:51,498 --> 01:08:53,534
INABILITY TO WITHSTAND STRESSES 

1273
01:08:53,534 --> 01:08:58,338
AND THIS IS HOW BETA LACTAMS 

1274
01:08:58,338 --> 01:08:58,605
WORK.

1275
01:08:58,605 --> 01:09:01,475
THEY'RE AN ANCIENT CHEMICAL 

1276
01:09:01,475 --> 01:09:04,511
WEAPON IN RESPONSE THERE'S AN 

1277
01:09:04,511 --> 01:09:06,013
ANCIENT DEFENSE MECHANISM THESE 

1278
01:09:06,013 --> 01:09:09,716
ARE THE ENZYMES THAT HYDROLYZE 

1279
01:09:09,716 --> 01:09:11,852
THE BETA LACTAMS AND A CLASS 

1280
01:09:11,852 --> 01:09:15,122
THAT'S MORE THAN 100 MILLION 

1281
01:09:15,122 --> 01:09:19,093
YEARS OLD AND THE CLASSIFICATION

1282
01:09:19,093 --> 01:09:21,929
SYSTEM DIVIDE THE BETA 

1283
01:09:21,929 --> 01:09:23,797
LACTAMASES INTO FOUR GROUPS 

1284
01:09:23,797 --> 01:09:26,500
BASED ON STRUCTURE AND HOMOLOGY.

1285
01:09:26,500 --> 01:09:28,502
THE FOUR GROUPS ARE CLASS A, B, 

1286
01:09:28,502 --> 01:09:32,039
C AND D.

1287
01:09:32,039 --> 01:09:42,382
THE CLASS D ARE ENZYMES AND THE 

1288
01:09:42,382 --> 01:09:49,356
B AND C ARE HAVE A MECHANISM OF 

1289
01:09:49,356 --> 01:09:55,262
ACTION IS SIMILAR TO PROTEASES 

1290
01:09:55,262 --> 01:10:00,767
AND THEY OPEN IT UP AND THE RING

1291
01:10:00,767 --> 01:10:02,402
OPENED BETA LACTAM IS NO LONGER 

1292
01:10:02,402 --> 01:10:12,546
ACTIVE.

1293
01:10:25,159 --> 01:10:27,227
AND THESE ARE YOU'VE TO EXTEND 

1294
01:10:27,227 --> 01:10:33,934
THE LIFE OF THE ACTIVITY OF THE 

1295
01:10:33,934 --> 01:10:35,936
BETA LACTAMASE AND CLINICALLY 

1296
01:10:35,936 --> 01:10:40,908
THERE'S TWO CLASSES OF BETA 

1297
01:10:40,908 --> 01:10:46,213
LACTAMASE INHIBITERS AND THE 

1298
01:10:46,213 --> 01:10:55,289
CLASS BASED ON THE MOLECULE AND 

1299
01:10:55,289 --> 01:11:05,265
THERE'S A TAZOBACTAM AND THE 

1300
01:11:05,265 --> 01:11:09,436
OCTAN

1301
01:11:09,436 --> 01:11:09,670
OCTANES.

1302
01:11:09,670 --> 01:11:12,306
I TOLD YOU THE CLASSIFICATION 

1303
01:11:12,306 --> 01:11:17,211
SYSTEM CLASSIFIES BETA LACTA

1304
01:11:17,211 --> 01:11:20,781
LACTAMASES INTO A, B, C AND D 

1305
01:11:20,781 --> 01:11:29,690
AND THE MOST CLASSIC ACTIVATION 

1306
01:11:29,690 --> 01:11:32,092
RESISTANCE AND THERE'S THREE 

1307
01:11:32,092 --> 01:11:36,163
PRINCIPLE CLASSES OF BETA 

1308
01:11:36,163 --> 01:11:42,202
LACTAMASES AND WITH ACTIVITY 

1309
01:11:42,202 --> 01:11:43,470
HIERARCHICALLY ORGANIZED.

1310
01:11:43,470 --> 01:11:47,574
AND WE HAVE ENZYMES THAT 

1311
01:11:47,574 --> 01:11:50,010
HYDROLYZE FIRST AND SECOND 

1312
01:11:50,010 --> 01:11:52,546
GENERATIONS AND OCCASIONALLY CAN

1313
01:11:52,546 --> 01:11:58,385
HYDROLYZE THIRD AND FOURTH 

1314
01:11:58,385 --> 01:11:58,685
GENERATIONS.

1315
01:11:58,685 --> 01:12:09,229
ABOVE THE EXTENDED SPECTRUM IT'S

1316
01:12:09,529 --> 01:12:13,367
EXTENDED BEYOND AND THE THIRD 

1317
01:12:13,367 --> 01:12:16,003
AND FOURTH GENERATIONS.

1318
01:12:16,003 --> 01:12:25,379
AT THE TO THE HIERARCHY WE HAVE 

1319
01:12:25,379 --> 01:12:35,922
THE CARBAPENEMMASES AND THEY'RE 

1320
01:12:36,923 --> 01:12:47,200
A CRITICAL CONCERN.

1321
01:12:47,501 --> 01:12:50,604
AND THEY'RE RESISTANCE TO MOST 

1322
01:12:50,604 --> 01:12:54,408
OR ALL AND A SUBSET AREN'T 

1323
01:12:54,408 --> 01:13:01,348
RESISTANT TO ALL ANTIBIOTICS.

1324
01:13:01,348 --> 01:13:11,892
THE SO-CALLED CARBAPENEMASES AND

1325
01:13:16,530 --> 01:13:26,973
THESE FALL INTO CLASS A AND D.

1326
01:13:31,578 --> 01:13:32,979
ALL ARE IMPORTANT BUT WE'LL 

1327
01:13:32,979 --> 01:13:37,918
FOCUS ON C -- KPC.

1328
01:13:37,918 --> 01:13:43,223
IT WAS FIRST IDENTIFIED IN 199 6

1329
01:13:43,223 --> 01:13:48,795
IN NORTH CAROLINA AND ALL RIGHT 

1330
01:13:49,429 --> 01:13:51,598
 -- REPORTED IN 2001 AND IT'S 

1331
01:13:51,598 --> 01:13:57,404
ASSUMED TO BE DERIVED FROM AN 

1332
01:13:57,404 --> 01:13:57,971
ENVIRONMENTAL SOURCE.

1333
01:13:57,971 --> 01:14:00,841
SOME ARE WIDESPREAD IN THE 

1334
01:14:00,841 --> 01:14:02,409
ENVIRONMENT AND IT'S NOT KNOWN 

1335
01:14:02,409 --> 01:14:10,384
EXACTLY HOW THE GENE GOT IN THIS

1336
01:14:10,384 --> 01:14:17,023
ICE  ISOLATE BUT THIS SPREAD THE

1337
01:14:17,023 --> 01:14:19,292
RESISTANCE AROUND THE WORLD 

1338
01:14:19,292 --> 01:14:20,994
THROUGH HORIZONTAL GENE TRANS 

1339
01:14:20,994 --> 01:14:21,161
PER.

1340
01:14:21,161 --> 01:14:31,671
WE'LL LOOK AT HOW THAT WORKS.

1341
01:14:34,307 --> 01:14:41,615
WE HAVE PLASMIDS AND OTHERS AND 

1342
01:14:41,615 --> 01:14:45,352
THEY'RE  THEY CAN CARRY 

1343
01:14:45,352 --> 01:14:46,353
DIFFERENT GENES INCLUDING 

1344
01:14:46,353 --> 01:14:48,221
ANTIBIOTIC RESISTANT GENES AND 

1345
01:14:48,221 --> 01:14:52,325
ENCODE ALL THE MECHANISMS THEY 

1346
01:14:52,325 --> 01:14:55,996
NEED SO EFFICIENTLY MOVE BETWEEN

1347
01:14:55,996 --> 01:14:56,563
BACTERIAL CELLS.

1348
01:14:56,563 --> 01:15:00,834
WHEN ONE OF THE GENETIC ELEMENTS

1349
01:15:00,834 --> 01:15:04,104
PICKS UP AN ANTIMICROBIAL 

1350
01:15:04,104 --> 01:15:10,811
RESISTANCE GENE AND INFECTS A 

1351
01:15:10,811 --> 01:15:12,913
BACTERIUM, IN UNDER SELECTION 

1352
01:15:12,913 --> 01:15:17,317
PRESSURE WITH TO THE RIGHT 

1353
01:15:17,317 --> 01:15:20,887
ANTIBIOTIC THE GENE AND HOST CAN

1354
01:15:20,887 --> 01:15:23,590
BE CO-SELECTED INTO A 

1355
01:15:23,590 --> 01:15:25,492
RELATIONSHIP UNLESS IT'S THE 

1356
01:15:25,492 --> 01:15:28,995
DRIVING FORCE THAT RESULTS IN 

1357
01:15:28,995 --> 01:15:30,297
HORIZONTAL GENE TRANSFER.

1358
01:15:30,297 --> 01:15:35,702
BROAD SPECTRUM RESISTANCE TO 

1359
01:15:35,702 --> 01:15:37,838
OTHER CLASSES OF ANTIBIOTICS IS 

1360
01:15:37,838 --> 01:15:42,476
MEDIATED BY TRANSFERRED GENES.

1361
01:15:42,476 --> 01:15:45,946
AND THIS IS IMPORTANT BECAUSE 

1362
01:15:45,946 --> 01:15:48,615
THE HORIZONTAL GENE TRANSFER 

1363
01:15:48,615 --> 01:15:50,250
REQUIRES A COMMUNITY OF 

1364
01:15:50,250 --> 01:15:51,785
INTERACTIONS BETWEEN BACTERIA 

1365
01:15:51,785 --> 01:15:56,990
AND MAY BE FACILITATED BY 

1366
01:15:56,990 --> 01:15:57,991
ANTIBIOTIC SELECTION.

1367
01:15:57,991 --> 01:15:59,726
THIS EXCHANGE HAS BEEN 

1368
01:15:59,726 --> 01:16:01,962
DEMONSTRATED TO OCCUR IN SOIL, 

1369
01:16:01,962 --> 01:16:06,399
FARMS, SEWAGE WITHIN THE HOSTILE

1370
01:16:06,399 --> 01:16:09,102
ENVIRONMENT INCLUDING WITHIN THE

1371
01:16:09,102 --> 01:16:11,271
HOSPITAL SYSTEM OR IN THE 

1372
01:16:11,271 --> 01:16:12,672
MICROBIOMES OF THE PATIENTS 

1373
01:16:12,672 --> 01:16:13,640
THEMSELVES AND THERE'S 

1374
01:16:13,640 --> 01:16:17,377
REMARKABLE DIVERSITY OF GENETIC 

1375
01:16:17,377 --> 01:16:19,246
ELEMENT IMMEDIATE HORIZONTAL 

1376
01:16:19,246 --> 01:16:20,180
GENE TRANSFER.

1377
01:16:20,180 --> 01:16:24,784
THE KPC GENE EARLY ON ENDED UP 

1378
01:16:24,784 --> 01:16:29,456
IN A HIGHLY MOBILE TRANSPOSON 

1379
01:16:29,456 --> 01:16:35,962
AND IT WAS LOCATED WITHIN 

1380
01:16:35,962 --> 01:16:37,364
PLASMIDS.

1381
01:16:37,364 --> 01:16:43,403
THEY'RE EXTRA CHROMOSOMAL DNA 

1382
01:16:43,403 --> 01:16:45,939
AND IT ENCODED ALL THE MACHINERY

1383
01:16:45,939 --> 01:16:49,342
IT NEEDED TO INSERT COPIES OF 

1384
01:16:49,342 --> 01:16:53,613
ITSELF INTO OTHER PLASMIDS.

1385
01:16:53,613 --> 01:16:55,181
INDEED, THIS TRANSPOSON MADE 

1386
01:16:55,181 --> 01:16:56,783
LOTS OF COPIES AND MOVED AROUND 

1387
01:16:56,783 --> 01:17:00,186
TO A NUMBER OF PLASMIDS WITH A 

1388
01:17:00,186 --> 01:17:03,356
VARIETY OF HOST CARRYING THE KPC

1389
01:17:03,356 --> 01:17:13,600
GENE WITH IT.

1390
01:17:15,435 --> 01:17:19,806
THIS WAS IN COMBINATION AND IT 

1391
01:17:19,806 --> 01:17:30,350
DISSEMINATED THE DESCENDANTS AND

1392
01:17:36,623 --> 01:17:39,125
CAUSED A NUMBER OF OUTBREAKS 

1393
01:17:39,125 --> 01:17:41,261
AROUND THE WORLD INCLUDING THE 

1394
01:17:41,261 --> 01:17:42,529
2011 OUTBREAK THAT OCCURRED HERE

1395
01:17:42,529 --> 01:17:44,364
IN THE CLINICAL CENTER.

1396
01:17:44,364 --> 01:17:54,908
MANY WERE RESISTANT TO CAR  C

1397
01:18:10,924 --> 01:18:14,394
CARBAPENMENS AND THERE WAS AN 

1398
01:18:14,394 --> 01:18:17,797
INHIBITER MENTIONED EARLIER WAS 

1399
01:18:17,797 --> 01:18:24,204
INTRODUCED AND ANTI-BACTAM HAD 

1400
01:18:24,204 --> 01:18:30,377
STRONG ACTIVITY AGAINST AND THE 

1401
01:18:30,377 --> 01:18:34,414
COMBINATION WAS EFFECTIVE IN 

1402
01:18:34,414 --> 01:18:38,585
TRE

1403
01:18:38,585 --> 01:18:40,587
TREATING INFECTIONS AND THIS 

1404
01:18:40,587 --> 01:18:43,123
CHANGED THE NATURE OF THE 

1405
01:18:43,123 --> 01:18:43,823
OUTBREAK OVERNIGHT IN AREAS 

1406
01:18:43,823 --> 01:18:52,632
WHERE IT WAS AVAILABLE.

1407
01:18:52,632 --> 01:18:53,533
AND THERE WERE REPORTS OF 

1408
01:18:53,533 --> 01:19:03,910
RESISTANCE TO FOR THE 

1409
01:19:11,951 --> 01:19:16,122
CEFTAZIDIME LINEAGES WE WERE 

1410
01:19:16,122 --> 01:19:18,825
BACK TO SQUARE ONE.

1411
01:19:18,825 --> 01:19:24,097
WE'LL COME BACK TO CEFTAZIDIME 

1412
01:19:24,097 --> 01:19:29,069
RESISTANCE AND WE'LL RETURN TO 

1413
01:19:29,069 --> 01:19:32,038
PSEUDOMONAS AERUGINOSA AND 

1414
01:19:32,038 --> 01:19:37,877
MULTI-DRUG RESISTANT PSEUDOMONAS

1415
01:19:37,877 --> 01:19:40,280
HAS BEEN LABELLED AS BY THE CDC 

1416
01:19:40,280 --> 01:19:45,151
AND THERE'S OTHER CLASSES OF 

1417
01:19:45,151 --> 01:19:48,354
ANTIBODIES AND WE LOOKED AT THE 

1418
01:19:48,354 --> 01:19:51,124
IMPLICATIONS AND IT REQUIRES A 

1419
01:19:51,124 --> 01:19:55,395
COMMUNITY AND OCCURS IN CERTAIN 

1420
01:19:55,395 --> 01:20:05,939
CONTEXT AND IT CAN ACT AS A LONE

1421
01:20:19,018 --> 01:20:20,520
AGENT AND GENERATE RESISTANCE 

1422
01:20:20,520 --> 01:20:22,655
DURING THE COURSE OF TREATMENT 

1423
01:20:22,655 --> 01:20:25,992
AND THIS HAS DIAGNOSTIC, 

1424
01:20:25,992 --> 01:20:27,360
CLINICAL AND THERAPEUTIC 

1425
01:20:27,360 --> 01:20:27,694
CONSEQUENCES.

1426
01:20:27,694 --> 01:20:31,364
WE'LL LOOK AT THE MECHANISMS 

1427
01:20:31,364 --> 01:20:41,875
THAT MEDIATE RESISTANCE ENS

1428
01:20:42,375 --> 01:20:52,852
ENSUED -- IN PSEUDOMONAS AND THE

1429
01:20:55,722 --> 01:20:58,391
GENOME OCCURS MORE THAN 12 AND 

1430
01:20:58,391 --> 01:20:59,959
THERE'S A VARIETY OF 

1431
01:20:59,959 --> 01:21:01,594
SPECIFICITIES THAT COVER MOST 

1432
01:21:01,594 --> 01:21:05,365
THE CLASSES OF ANTIBIOTICS 

1433
01:21:05,365 --> 01:21:06,633
MODERN PHYSICIANS USE.

1434
01:21:06,633 --> 01:21:14,908
THE OPRM EFFLUX PUMP IS 

1435
01:21:14,908 --> 01:21:17,977
EFFECTIVE AND OVER EXPRESSION OF

1436
01:21:17,977 --> 01:21:22,348
THE PUMP IS ONE OF THE MAIN 

1437
01:21:22,348 --> 01:21:27,387
MECHANISMS CONFIRMED RESISTANCE 

1438
01:21:27,387 --> 01:21:29,088
AND ALL PSEUDOMONAS AERUGINOSA 

1439
01:21:29,088 --> 01:21:32,926
HAVE IT INTEGRATED IN THE CHROME

1440
01:21:32,926 --> 01:21:33,760
SOME.

1441
01:21:33,760 --> 01:21:42,335
IT COMES WITH AN AN ANCIENT 

1442
01:21:42,335 --> 01:21:49,342
LACTAMASE AND TOGETHER THEY CAN 

1443
01:21:49,342 --> 01:21:54,614
GENERATE HIGHLY RESISTANT 

1444
01:21:54,614 --> 01:22:00,086
BACTERIA.

1445
01:22:00,086 --> 01:22:06,159
THERE'S NOT MANY WE CAN TURN TO.

1446
01:22:06,159 --> 01:22:13,433
TWO OF THE DRUGS ARE BACTAM AND 

1447
01:22:13,433 --> 01:22:23,977
A COMBINATION OF THE TAZO BACTAM

1448
01:22:23,977 --> 01:22:25,712
AND WHEN RESISTANCE EMERGES TO 

1449
01:22:25,712 --> 01:22:29,515
ONE OR BOTH OF THE DRUGS IT'S A 

1450
01:22:29,515 --> 01:22:30,383
PRETTY SERIOUS CONCERN.

1451
01:22:30,383 --> 01:22:32,952
WE'LL LOOK AT A CLINICAL CASE 

1452
01:22:32,952 --> 01:22:34,654
FROM THE NIH CLINICAL CENTER IN 

1453
01:22:34,654 --> 01:22:42,395
WHICH RESISTANCE TO THE TWO 

1454
01:22:42,395 --> 01:22:52,305
DRUGS, CEFTOLAZIMINE AND THE 

1455
01:22:52,305 --> 01:22:54,641
OTHER WERE RESISTED BY A PATIENT

1456
01:22:54,641 --> 01:22:57,443
WITH LEUKEMIA.

1457
01:22:57,443 --> 01:23:00,847
THE PATIENT WAS INITIALLY 

1458
01:23:00,847 --> 01:23:03,650
ADMITTED TO THE NIH CLINICAL 

1459
01:23:03,650 --> 01:23:11,024
CENTER UNDER THE PROTOCOL AND 

1460
01:23:11,024 --> 01:23:15,328
DEVELOPED FEVER AND THE TWO 

1461
01:23:15,328 --> 01:23:20,199
BLOOD CULTURES BOTH FOR 

1462
01:23:20,199 --> 01:23:22,769
PSEUDOMONAS AERUGINOSA AND THE 

1463
01:23:22,769 --> 01:23:25,371
ISOLATES WERE SUSCEPTIBLE AND 

1464
01:23:25,371 --> 01:23:32,378
THE REGIMENT WAS ADJUSTED TO 

1465
01:23:32,378 --> 01:23:42,922
CREV CEFTAZIDIME AND THEY DID A 

1466
01:23:43,423 --> 01:23:44,891
CULTURE OBTAINED FOR PSEUDOMONAS

1467
01:23:44,891 --> 01:23:49,362
AERUGINOSA THAT WAS SUSCEPTIBLE 

1468
01:23:49,362 --> 01:23:50,463
TO CEFTAZIDIME.

1469
01:23:50,463 --> 01:23:55,134
THE THERAPY WAS FURTHER ADJUSTED

1470
01:23:55,134 --> 01:24:02,241
AND ON DAY EIGHT AMIKACIN WAS 

1471
01:24:02,241 --> 01:24:05,678
DISCONTINUED AND AFTER DAY 9 

1472
01:24:05,678 --> 01:24:07,113
HYPOTENSION AND FEVER OCCURRED 

1473
01:24:07,113 --> 01:24:14,787
AND THIS TIME RESISTANT TO 

1474
01:24:14,787 --> 01:24:22,295
CEFTAZIDIME AND AMIKACIN AND THE

1475
01:24:22,295 --> 01:24:25,031
PATIENT DEVELOPED RESPIRATORY 

1476
01:24:25,031 --> 01:24:26,132
FAILURE AND EXPIRED AND THE MAIN

1477
01:24:26,132 --> 01:24:28,868
POINT I WANT TO MAKE ON THE 

1478
01:24:28,868 --> 01:24:30,436
SLIDE IS THE INITIAL BLOOD AND 

1479
01:24:30,436 --> 01:24:35,241
ISOLATES WERE SUSCEPTIBLE TO THE

1480
01:24:35,241 --> 01:24:37,410
BACTAM WITHIN MICs OF ONE 

1481
01:24:37,410 --> 01:24:39,379
MICROGRAM PER MILL BUT OVER A 

1482
01:24:39,379 --> 01:24:42,382
WEEK A HIGH LEVEL RESISTANCE 

1483
01:24:42,382 --> 01:24:47,220
EMERGED AND ISOLATES WERE 

1484
01:24:47,220 --> 01:24:51,424
GREATER THAN 256 WERE ISOLATED.

1485
01:24:51,424 --> 01:24:53,593
HOW DID RESISTANCE OCCUR SO 

1486
01:24:53,593 --> 01:24:54,861
RAPIDLY IN THE CONTEXT UNDER 

1487
01:24:54,861 --> 01:24:55,294
TREATMENT?

1488
01:24:55,294 --> 01:24:56,462
TO ANSWER THE QUESTION WE 

1489
01:24:56,462 --> 01:24:59,165
SEQUENCED THE GENOME TO THE 

1490
01:24:59,165 --> 01:25:01,868
ISOLATES IN MY RESEARCH LAB AND 

1491
01:25:01,868 --> 01:25:12,311
IDENTIFIED THE RESISTANCE 

1492
01:25:12,512 --> 01:25:12,712
MECHANISM.

1493
01:25:12,712 --> 01:25:23,256
AND THIS CONFERRED RESISTANCE TO

1494
01:25:24,490 --> 01:25:27,326
AND EXPLAIN THE MECHANISM OF 

1495
01:25:27,326 --> 01:25:29,996
TREATMENT FAILURE AND TALKS 

1496
01:25:29,996 --> 01:25:31,831
ABOUT THE RESISTANCE OF 

1497
01:25:31,831 --> 01:25:32,265
MECHANISMS.

1498
01:25:32,265 --> 01:25:38,638
WE'LL LOOP BACK TO THE STORY OF 

1499
01:25:38,638 --> 01:25:49,415
THE RESIST ANANCE AND SAW MUTATS

1500
01:25:52,251 --> 01:25:54,587
CONFERRED RESISTANCE.

1501
01:25:54,587 --> 01:25:58,524
AND WE SEE IN PSEUDOMONAS 

1502
01:25:58,524 --> 01:26:00,860
AERUGINOSA THE CHROMOSOMAL 

1503
01:26:00,860 --> 01:26:07,834
BACTAMASE CONFERS RESISTANCE AND

1504
01:26:07,834 --> 01:26:09,969
ANCIENT ENZYMES CAN CONFER 

1505
01:26:09,969 --> 01:26:15,007
RESISTANCE TO NEW CLASSES SUCH 

1506
01:26:15,007 --> 01:26:18,678
AS AVIBACTAM AND BACTERIA HAVE 

1507
01:26:18,678 --> 01:26:21,614
NOT BEEN ABLE TO EVADE IN SOME 

1508
01:26:21,614 --> 01:26:21,814
FORM.

1509
01:26:21,814 --> 01:26:24,317
THIS SUGGESTS COMPETING WITH 

1510
01:26:24,317 --> 01:26:29,522
EVOLUTION MAY REQUIRE NOVEL 

1511
01:26:29,522 --> 01:26:29,822
STRATEGIES.

1512
01:26:29,822 --> 01:26:36,562
THERE'S A FEW USED TO COMPLIMENT

1513
01:26:36,562 --> 01:26:38,264
ANTIBIOTICS OR WHEN THEY FAIL.

1514
01:26:38,264 --> 01:26:40,099
THESE ARE ALL AT EARLY STAGE 

1515
01:26:40,099 --> 01:26:43,236
DEVELOPMENT AND NOT IN WIDE 

1516
01:26:43,236 --> 01:26:43,936
SUPPRESS CLINICAL USE.

1517
01:26:43,936 --> 01:26:46,973
THE FIRST APPROACH IS VACCINES 

1518
01:26:46,973 --> 01:26:49,775
TO MONOCLONAL ANTIBODIES AND THE

1519
01:26:49,775 --> 01:26:53,346
CONCEPT IS SIMILAR TO OTHER 

1520
01:26:53,346 --> 01:26:53,613
VACCINES.

1521
01:26:53,613 --> 01:26:55,748
IT'S DEVELOPED AGAINST A 

1522
01:26:55,748 --> 01:27:01,354
MULTI-DRUG RESISTANT STRAIN AND 

1523
01:27:01,354 --> 01:27:04,991
SIMILAR HOW TO WE VACCINE AGAIN 

1524
01:27:04,991 --> 01:27:06,726
DIPHTHERIA AND THE GOAL IS NOT 

1525
01:27:06,726 --> 01:27:09,162
TO BECOME INFECTED WITH THE 

1526
01:27:09,162 --> 01:27:11,531
BACTERIA IN THE FIRST PLACE.

1527
01:27:11,531 --> 01:27:13,699
IN RELATED STRATEGY AMONG 

1528
01:27:13,699 --> 01:27:16,502
MONOCLONAL ANTIBODIES AND THE 

1529
01:27:16,502 --> 01:27:19,071
THOUGHT IS THEY'D BE RAISED 

1530
01:27:19,071 --> 01:27:20,473
AGAINST MULTI-DRUG RESISTANT 

1531
01:27:20,473 --> 01:27:21,674
STRAINS AND ADMINISTERED TO 

1532
01:27:21,674 --> 01:27:26,179
TREAT ACUTE INFECTIONS.

1533
01:27:26,179 --> 01:27:28,347
A SECOND APPROACH THAT'S 

1534
01:27:28,347 --> 01:27:32,351
RECEIVED A LOT OF ATTENTION IS 

1535
01:27:32,351 --> 01:27:33,653
BACTERIA PHAGE THERAPY AND 

1536
01:27:33,653 --> 01:27:39,292
THEY'RE IDENTIFIED OR RAISED 

1537
01:27:39,292 --> 01:27:45,231
AGAINST PARTICULAR MULTI-DRUG 

1538
01:27:45,231 --> 01:27:46,265
RESISTANT STRAINS AND THEY THEN 

1539
01:27:46,265 --> 01:27:49,368
CONTACT THEIR TARGETS, INFECT 

1540
01:27:49,368 --> 01:27:51,671
THEM, REPLICATE WITHIN THEM AND 

1541
01:27:51,671 --> 01:27:52,505
CAUSE LYSIS.

1542
01:27:52,505 --> 01:27:54,807
THE STRATEGY HAS BEEN USED IN A 

1543
01:27:54,807 --> 01:27:58,778
NUMBER OF CASE STUDIES 

1544
01:27:58,778 --> 01:28:00,713
RELATIVELY EFFECTIVELY BUT ONE 

1545
01:28:00,713 --> 01:28:02,615
CHALLENGE IS THAT IN MANY OF 

1546
01:28:02,615 --> 01:28:09,055
THESE CASE STUDIES THE BACTERIA 

1547
01:28:09,055 --> 01:28:10,156
PHAGES ARE SPECIFIC AND HIGHLY 

1548
01:28:10,156 --> 01:28:20,833
STALE  -- TAIL JORE -- TAILORED 

1549
01:28:25,571 --> 01:28:26,172
AND THERE'S CLINICAL TRIALS IN 

1550
01:28:26,172 --> 01:28:30,776
PLANNING STAGE OR UNDERWAY.

1551
01:28:30,776 --> 01:28:34,880
AND THE THIRD AND LAST APPROACH 

1552
01:28:34,880 --> 01:28:43,556
IS CRISPR CAS BASED PROGRAMMABLE

1553
01:28:43,556 --> 01:28:43,889
ANTIBIOTICS.

1554
01:28:43,889 --> 01:28:52,465
THIGH HAVE BEEN RE-ENGINEERED TO

1555
01:28:52,465 --> 01:28:57,103
BE EDITORS AND YOU CAN PROGRAM A

1556
01:28:57,103 --> 01:29:00,673
CRISPR CAS SYSTEM IT EDIT OR 

1557
01:29:00,673 --> 01:29:02,808
DISRUPT A PARTICULAR 

1558
01:29:02,808 --> 01:29:08,047
ANTIMICROBIAL RESISTANT GENE OR 

1559
01:29:08,047 --> 01:29:10,016
MDR STRAIN.

1560
01:29:10,016 --> 01:29:11,784
SHE'S COULD BE DELIVERED WITH 

1561
01:29:11,784 --> 01:29:12,752
BACTERIA PHAGES SIMILAR TO THE 

1562
01:29:12,752 --> 01:29:21,560
SECOND APPROACH WE LOOKED AT.

1563
01:29:21,560 --> 01:29:24,697
I HOPE I'VE CONVINCED YOU HUMANS

1564
01:29:24,697 --> 01:29:30,536
WILL NOT WIN THE WAR WITH SMALL 

1565
01:29:30,536 --> 01:29:33,339
MOLECULES AND BY MANY BACTERIA 

1566
01:29:33,339 --> 01:29:34,373
WE'RE WORSE OFF TODAY THAN A 

1567
01:29:34,373 --> 01:29:35,808
NUMBER OF TIMES IN THE PAST.

1568
01:29:35,808 --> 01:29:37,076
I WILL LEAVE YOU WITH THE 

1569
01:29:37,076 --> 01:29:39,045
THOUGHT THAT NEW APPROACHES 

1570
01:29:39,045 --> 01:29:43,382
MAYBE NEEDED FOR CASES OF SEVERE

1571
01:29:43,382 --> 01:29:46,452
RESISTANCE OF PAN RESISTANT 

1572
01:29:46,452 --> 01:29:54,427
ISOLATES AND ENVIRONMENTAL 

1573
01:29:54,427 --> 01:29:57,997
ANTIBIOTIC RESISTANT RESERVOIRS 

1574
01:29:57,997 --> 01:30:01,701
AND USAGE IN THE FARMS AND FOOD 

1575
01:30:01,701 --> 01:30:04,537
CHAIN AND I'D LIKE TO 

1576
01:30:04,537 --> 01:30:06,105
ACKNOWLEDGE THE NIH CLINICAL 

1577
01:30:06,105 --> 01:30:07,373
CENTER PATIENTS AND THEIR 

1578
01:30:07,373 --> 01:30:09,342
FAMILIES WHO PARTNER WITH US IN 

1579
01:30:09,342 --> 01:30:10,509
THIS IMPORTANT WORK.

1580
01:30:10,509 --> 01:30:12,311
I'D LIKE TO THANK THE PEOPLE IN 

1581
01:30:12,311 --> 01:30:15,948
MY LAB WHO DID THE SEQUENCING IN

1582
01:30:15,948 --> 01:30:17,483
THE CLINICAL CASES I SHOWED YOU 

1583
01:30:17,483 --> 01:30:22,521
AND THANK YOU FOR YOUR 

1584
01:30:22,521 --> 01:30:32,698
ATTENTION.

1585
01:30:33,866 --> 01:30:34,400
THANK YOU.

1586
01:30:34,400 --> 01:30:38,204
THIS IS LIKE A BRAVE NEW WORLD I

1587
01:30:38,204 --> 01:30:43,709
SUSPECT MOST WHO DON'T WORK IN 

1588
01:30:43,709 --> 01:30:54,253
EITHER OF THESE AREAS HAVE WE'RE

1589
01:30:56,489 --> 01:30:58,591
GRATEFUL FOR OPENING UP OUR 

1590
01:30:58,591 --> 01:31:03,929
MINDS ANDIZE TO THE COMPLEXITIES

1591
01:31:03,929 --> 01:31:08,401
AND CHALLENGE FOR ALL AND WE 

1592
01:31:08,401 --> 01:31:09,769
HAVE A HUGE NUMBER OF QUESTIONS 

1593
01:31:09,769 --> 01:31:11,237
AND I'M SURE WE CAN ALL STAY 

1594
01:31:11,237 --> 01:31:12,938
HERE FOR NEXT THREE HOURS AND 

1595
01:31:12,938 --> 01:31:14,774
FOR THOSE THEY DON'T GET TO 

1596
01:31:14,774 --> 01:31:16,208
WE'LL DO OUR BEST TO FORWARD 

1597
01:31:16,208 --> 01:31:20,746
THEM TO THE SPEAKERS AND MAYBE 

1598
01:31:20,746 --> 01:31:22,281
MAYBE RESPOND.

1599
01:31:22,281 --> 01:31:24,884
ONE QUESTION PEOPLE HAVE ASKED 

1600
01:31:24,884 --> 01:31:27,987
IS HOW DO CELL LINES DIFFER FROM

1601
01:31:27,987 --> 01:31:29,288
PRIMARY CELLS IN TERMS OF 

1602
01:31:29,288 --> 01:31:30,423
EXPRESSION OF THESE 

1603
01:31:30,423 --> 01:31:40,666
TRANSPORTERS?

1604
01:31:49,074 --> 01:31:51,010
>> HOW MANY WITHOUT
SELECTION?

1605
01:31:51,010 --> 01:31:51,911
IN OTHER WORDS, IF YOU TAKE A 

1606
01:31:51,911 --> 01:31:53,879
LIVER CELL AND PUT IT IN CULTURE

1607
01:31:53,879 --> 01:31:56,715
AND IT RETAINS SOX THE 

1608
01:31:56,715 --> 01:31:58,984
DIFFERENTIATED PROPERTIES OF THE

1609
01:31:58,984 --> 01:32:01,387
LIVER CELL IT WILL EXPRESS P 

1610
01:32:01,387 --> 01:32:02,087
GLYCOPROTEIN AND YOU CAN TELL ME

1611
01:32:02,087 --> 01:32:03,689
IF THAT'S THE CASE.

1612
01:32:03,689 --> 01:32:04,223
>> ALL RIGHT.

1613
01:32:04,223 --> 01:32:05,958
>> THE ANSWER IS DEPENDING
ON 

1614
01:32:05,958 --> 01:32:08,794
THE ORIGIN OF THE CELL TYPE.

1615
01:32:08,794 --> 01:32:11,230
CELLS WILL GENERALLY RETAIN THE 

1616
01:32:11,230 --> 01:32:16,469
CHARACTERISTIC OF THE ORIGINAL.

1617
01:32:16,469 --> 01:32:23,976
>> SO HAVE ORGANOIDS
BECOME PART

1618
01:32:23,976 --> 01:32:28,714
OF THE NEW APPROACH?

1619
01:32:28,714 --> 01:32:31,584
IN AN EFFORT TO GET GENES MORE 

1620
01:32:31,584 --> 01:32:32,852
CLINICALLY RELEVANT WE'RE 

1621
01:32:32,852 --> 01:32:35,154
BEGINNING TO WORK WITH CANCER 

1622
01:32:35,154 --> 01:32:36,722
ORGANOIDS WHICH ARE PRIMARILY 

1623
01:32:36,722 --> 01:32:39,925
THE CELLS THAT ARE THE BASIS OF 

1624
01:32:39,925 --> 01:32:40,693
THE CANCER PLUS PERHAPS 

1625
01:32:40,693 --> 01:32:43,395
ADDITIONAL CELLS THAT MAY BE 

1626
01:32:43,395 --> 01:32:44,797
CONTRIBUTING ELEMENTS OF 

1627
01:32:44,797 --> 01:32:45,764
RESISTANCE AND WE'RE HOPING WITH

1628
01:32:45,764 --> 01:32:53,138
THE NEW MODELS THAT WE ARE ABLE 

1629
01:32:53,138 --> 01:32:55,040
TO GET A SET OF GENES MORE 

1630
01:32:55,040 --> 01:32:57,009
LIKELY TO BE CLINICALLY RELEVANT

1631
01:32:57,009 --> 01:32:58,410
BUT WE DON'T KNOW IF THAT'S THE 

1632
01:32:58,410 --> 01:33:03,983
CASE.

1633
01:33:03,983 --> 01:33:10,823
>> I'M A POSTDOC IN THE
V.R.C.

1634
01:33:10,823 --> 01:33:13,792
THANK YOU FOR YOUR TALKS THEY 

1635
01:33:13,792 --> 01:33:15,761
WERE FUN.

1636
01:33:15,761 --> 01:33:17,062
MY QUESTION RELATE TO BOTH THEM 

1637
01:33:17,062 --> 01:33:19,331
AND YOU TOUCHED ON THIS WITH THE

1638
01:33:19,331 --> 01:33:22,167
VACCINES AND MONOCLONAL 

1639
01:33:22,167 --> 01:33:22,601
THERAPIES.

1640
01:33:22,601 --> 01:33:24,503
HOW DOES THE IMMUNE SYSTEM 

1641
01:33:24,503 --> 01:33:26,338
FACTOR IN TO OUR UNDERSTANDING 

1642
01:33:26,338 --> 01:33:30,175
OF DRUG RESISTANCE OR THERAPY 

1643
01:33:30,175 --> 01:33:31,977
RESISTANCE IN THE FUTURE?

1644
01:33:31,977 --> 01:33:32,611
SPECIFICALLY FIRST FOR THE 

1645
01:33:32,611 --> 01:33:37,383
CANCER SITUATION.

1646
01:33:37,383 --> 01:33:40,686
IF WE HAVE IMMUNOTHERAPY 

1647
01:33:40,686 --> 01:33:42,955
RESISTANCE WHICH WE'VE SEEN SOME

1648
01:33:42,955 --> 01:33:45,257
INSTANCES OF, WHEN THE IMMUNE 

1649
01:33:45,257 --> 01:33:46,959
SYSTEM GETS INVOLVED, HOW DOES 

1650
01:33:46,959 --> 01:33:49,395
THAT CHANGE THE FITNESS 

1651
01:33:49,395 --> 01:33:57,169
LANDSCAPE OF RESISTANCE?

1652
01:33:57,169 --> 01:33:59,471
THE CANCER NOW NEEDS TO DEAL 

1653
01:33:59,471 --> 01:34:01,874
WITH THE IMMUNE SYSTEM USED WITH

1654
01:34:01,874 --> 01:34:05,811
RAPIDLY EVOLVING PATHOGENS.

1655
01:34:05,811 --> 01:34:07,379
MAYBE ANTIGEN PRESENTATION OR 

1656
01:34:07,379 --> 01:34:11,717
IMMUNE SIGNALLING IT MAY GET 

1657
01:34:11,717 --> 01:34:14,787
INTERFERED AND THAT'S ONE I 

1658
01:34:14,787 --> 01:34:16,622
WANTED TO ASK ABOUT AND FOR 

1659
01:34:16,622 --> 01:34:18,190
BACTERIA IF YOU'RE NOT USING A 

1660
01:34:18,190 --> 01:34:26,398
VACCINE DOES THE PROBLEM SHIFT 

1661
01:34:26,398 --> 01:34:29,368
FROM DRUG RESISTANCE?

1662
01:34:29,368 --> 01:34:31,604
AND IS THAT EASIER TO HANDLE 

1663
01:34:31,604 --> 01:34:33,439
KNOWS WHAT WE KNOW?

1664
01:34:33,439 --> 01:34:35,574
>> I HAVE SPECIFICALLY
AVOIDED 

1665
01:34:35,574 --> 01:34:38,444
STUDYING WHY CANCER CELLS ARE 

1666
01:34:38,444 --> 01:34:40,546
RESISTANT TO IMMUNE THERAPY, 

1667
01:34:40,546 --> 01:34:41,981
HOWEVER, THERE ARE LOTS OF 

1668
01:34:41,981 --> 01:34:46,885
INTERACTION OF IMMUNE SYSTEM 

1669
01:34:46,885 --> 01:34:49,521
WITH THE SURFACE ANTIGENS 

1670
01:34:49,521 --> 01:34:51,957
RESPONSIBLE FOR DRUG RESISTANCE.

1671
01:34:51,957 --> 01:34:55,394
ONE HYPOTHETICAL, WE'RE KIND OF 

1672
01:34:55,394 --> 01:34:57,062
SURPRISED MORE CANCERS DON'T 

1673
01:34:57,062 --> 01:35:02,001
EXPRESS ABC TRANSPORTERS.

1674
01:35:02,001 --> 01:35:05,971
ONE REASON MAY BE THEIR 

1675
01:35:05,971 --> 01:35:08,140
ENERGETICALLY NOT VERY FAVORABLE

1676
01:35:08,140 --> 01:35:13,379
AND USE A LOT OF ATP AND IF YOU 

1677
01:35:13,379 --> 01:35:19,785
CAN FIX A MUTATION IT'S A BETTER

1678
01:35:19,785 --> 01:35:24,923
WAY AND GLYCOPROTEIN NOT EXPOSED

1679
01:35:24,923 --> 01:35:27,459
TO THE BLOOD AND IMMUNE SYSTEM.

1680
01:35:27,459 --> 01:35:29,328
IT'S SITTING IN THE KIDNEY, 

1681
01:35:29,328 --> 01:35:31,864
LIVER, COLON ON EXTERIOR SURFACE

1682
01:35:31,864 --> 01:35:33,032
OF CELLS.

1683
01:35:33,032 --> 01:35:35,200
IT MAY BE A COMPONENT OF THE 

1684
01:35:35,200 --> 01:35:37,403
IMMUNE SYSTEM IN REGULATING THE 

1685
01:35:37,403 --> 01:35:39,138
EXPRESSION OF CERTAIN 

1686
01:35:39,138 --> 01:35:39,471
TRANSPORTERS.

1687
01:35:39,471 --> 01:35:41,106
IT MAY NOT BE DESIRABLE FOR A 

1688
01:35:41,106 --> 01:35:43,275
CELL TO HAVE A LOT OF THE FUNNY 

1689
01:35:43,275 --> 01:35:44,543
MOLECULES ON THE SURFACE.

1690
01:35:44,543 --> 01:35:46,378
THE OTHER ASPECT WHICH IS REALLY

1691
01:35:46,378 --> 01:35:52,418
FASCINATING HAS TO DO WITH THE 

1692
01:35:52,418 --> 01:35:53,786
MICROBIOME.

1693
01:35:53,786 --> 01:35:55,220
THERE'S A FAIR AMOUNT OF 

1694
01:35:55,220 --> 01:35:57,890
EVIDENCE ONE THING THE 

1695
01:35:57,890 --> 01:36:00,626
MICROBIOME DOES IS ACTIVATES THE

1696
01:36:00,626 --> 01:36:04,029
IMMUNE SYSTEM AND IN ORDER TO 

1697
01:36:04,029 --> 01:36:05,898
CURE CANCER WITH PLATINUM YOU 

1698
01:36:05,898 --> 01:36:07,199
NEED THE ACTIVITY OF THE IMMUNE 

1699
01:36:07,199 --> 01:36:10,402
SYSTEM AND THE ACTIVITY OF THE 

1700
01:36:10,402 --> 01:36:14,239
DRUG.

1701
01:36:14,239 --> 01:36:18,243
IF YOU ANNIHILATE THE MICROBIOME

1702
01:36:18,243 --> 01:36:20,546
YOU AFFECT THE ABILITY OF THE 

1703
01:36:20,546 --> 01:36:25,551
BODY IN THE IMMUNE RESPONSE.

1704
01:36:25,551 --> 01:36:28,320
THERE'S DIFFERENT KINDS OF 

1705
01:36:28,320 --> 01:36:30,422
LEVELS -- I TRY NOT TO GET 

1706
01:36:30,422 --> 01:36:31,790
INVOLVED BUT IT'S PROBABLY 

1707
01:36:31,790 --> 01:36:34,059
IMPORTANT IN TREATING CANCER TO 

1708
01:36:34,059 --> 01:36:37,463
WHY CR THE IMMUNE SYSTEM -- TO 

1709
01:36:37,463 --> 01:36:39,431
CONSIDER THE IMMUNE SYSTEM.

1710
01:36:39,431 --> 01:36:46,071
>> SO, IN TERMS OF
VACCINES, 

1711
01:36:46,071 --> 01:36:49,441
THERE ISN'T JUST ENOUGH 

1712
01:36:49,441 --> 01:36:51,710
EXPERIENCE BUT THERE'S 

1713
01:36:51,710 --> 01:36:54,646
EVOLUTIONARY DYNAMICS AND WE CAN

1714
01:36:54,646 --> 01:37:05,190
SEE THEM AGAINST PERTUSSIS AND 

1715
01:37:12,364 --> 01:37:14,399
PNEUMOCAUCUS AND ONE WAY IT'S 

1716
01:37:14,399 --> 01:37:16,435
USED WITH OTHER VACCINES WITH 

1717
01:37:16,435 --> 01:37:19,571
EPITOPES AND THAT LIMITS THE 

1718
01:37:19,571 --> 01:37:23,842
POSSIBILITY OF ESCAPE FROM ONE 

1719
01:37:23,842 --> 01:37:27,346
AND NOT DOING ANTIBIOTIC 

1720
01:37:27,346 --> 01:37:28,781
MONOTHERAPY.

1721
01:37:28,781 --> 01:37:31,650
SO MY GUESS IS THAT I THINK 

1722
01:37:31,650 --> 01:37:33,218
VACCINES PERSONALLY THERE'LL BE 

1723
01:37:33,218 --> 01:37:35,154
A STRATEGY THAT'S PROBABLY GOING

1724
01:37:35,154 --> 01:37:40,592
TO BE AN IMPORTANT PIECE OF HOW 

1725
01:37:40,592 --> 01:37:42,628
WE DEAL WITH MULTI-DRUG 

1726
01:37:42,628 --> 01:37:43,695
RESISTANT STRAINS IN THE FUTURE.

1727
01:37:43,695 --> 01:37:44,997
TO ADDRESS ONE OF THE OTHER 

1728
01:37:44,997 --> 01:37:49,401
QUESTIONS YOU RAISED AT THE 

1729
01:37:49,401 --> 01:37:51,570
BEGINNING ANTIBIOTICS IN MANY 

1730
01:37:51,570 --> 01:37:55,507
CASES DAMAGE BACTERIAL BUT DON'T

1731
01:37:55,507 --> 01:37:57,509
KILL THEM AND THE HOST IMMUNE 

1732
01:37:57,509 --> 01:37:59,378
SYSTEM IS IMPORTANT TO MOP UP 

1733
01:37:59,378 --> 01:38:00,913
THE DAMAGED CELLS.

1734
01:38:00,913 --> 01:38:03,215
WE SEE THIS WHEN WE TREAT 

1735
01:38:03,215 --> 01:38:05,350
PATIENTS WHO HAVE SERIOUSLY 

1736
01:38:05,350 --> 01:38:07,019
COMPROMISED IMMUNE SYSTEMS WITH 

1737
01:38:07,019 --> 01:38:08,620
ANTIBIOTICS THEY TAKE LONGER TO 

1738
01:38:08,620 --> 01:38:10,889
WORK OR DON'T WORK AT ALL AND 

1739
01:38:10,889 --> 01:38:13,025
THERE'S A SECOND FEATURE MORE 

1740
01:38:13,025 --> 01:38:20,666
EVOLUTIONARY FOR EVOLUTION TO 

1741
01:38:20,666 --> 01:38:22,434
HAPPEN YOU NEED MUTAGENESIS AND 

1742
01:38:22,434 --> 01:38:24,102
ALL THAT OTHER STUFF.

1743
01:38:24,102 --> 01:38:25,537
IF YOU HAVE AN EFFECTIVE IMMUNE 

1744
01:38:25,537 --> 01:38:30,375
SYSTEM THAT MAINTAINS A SMALL 

1745
01:38:30,375 --> 01:38:33,478
CRITICAL POPULATION SIZE THERE'S

1746
01:38:33,478 --> 01:38:37,382
THE IMMUNE SYSTEM THE ANTIBIOTIC

1747
01:38:37,382 --> 01:38:40,652
RESISTANCE IS LESS LIKELY TO 

1748
01:38:40,652 --> 01:38:46,458
ARISE AND THIS HAS BEEN STUDIED 

1749
01:38:46,458 --> 01:38:49,695
AND WHERE WE SEE MUTAGENESIS 

1750
01:38:49,695 --> 01:38:51,830
DRIVEN ANTIBIOTIC RESISTANCE 

1751
01:38:51,830 --> 01:38:52,865
WHERE WE SEE HYPERMUTATED 

1752
01:38:52,865 --> 01:38:54,533
BACTERIA IS OFTEN IN THE CONTEXT

1753
01:38:54,533 --> 01:38:59,671
OF PATIENTS WITH COMPROMISED 

1754
01:38:59,671 --> 01:39:01,373
IMMUNITY PARTICULARLY INNATE 

1755
01:39:01,373 --> 01:39:06,912
IMMUNITY.

1756
01:39:06,912 --> 01:39:17,422
>> WE HAVE A QUESTION.

1757
01:39:17,422 --> 01:39:25,397
CAN TALK ABOUT RESISTANT GENES 

1758
01:39:25,397 --> 01:39:27,866
ALTERING AND CREATING 

1759
01:39:27,866 --> 01:39:29,401
ENVIRONMENTS AND CAN YOU COMMENT

1760
01:39:29,401 --> 01:39:31,403
ON THE PERVASIVE PROBLEM THAT 

1761
01:39:31,403 --> 01:39:32,938
MAY BE IN THE CATEGORY OF 

1762
01:39:32,938 --> 01:39:33,772
CLIMATE CHANGE.

1763
01:39:33,772 --> 01:39:34,339
IS THERE ANYTHING WE CAN DO 

1764
01:39:34,339 --> 01:39:44,516
ABOUT IT?

1765
01:39:48,787 --> 01:39:51,690
>> I KNOW THERE ARE A LOT
OF 

1766
01:39:51,690 --> 01:39:53,292
PEOPLE VERY INTERESTED IN 

1767
01:39:53,292 --> 01:39:54,826
STUDYING THAT BUT I DON'T THINK 

1768
01:39:54,826 --> 01:39:58,397
CAN SAY ANYTHING MEANINGFUL 

1769
01:39:58,397 --> 01:39:58,730
ABOUT IT.

1770
01:39:58,730 --> 01:40:07,339
>> WHAT ABOUT THE
MICROPLASTIC 

1771
01:40:07,339 --> 01:40:07,572
ASPECT?

1772
01:40:07,572 --> 01:40:09,074
>> THAT'S ANOTHER AREA
WHERE I 

1773
01:40:09,074 --> 01:40:10,042
WOULD SAY I DON'T THINK SHOULD 

1774
01:40:10,042 --> 01:40:11,510
COMMENT BECAUSE I DON'T THINK I 

1775
01:40:11,510 --> 01:40:17,749
CAN SAY ANYTHING INTELLIGENT.

1776
01:40:17,749 --> 01:40:19,384
>> WE HAVE NOTICED A
CHANGE IN 

1777
01:40:19,384 --> 01:40:23,555
THE PATTERN OF CANCERS IN YOUNG 

1778
01:40:23,555 --> 01:40:24,156
PEOPLE.

1779
01:40:24,156 --> 01:40:26,959
COLON CANCER USED TO BE PRETTY 

1780
01:40:26,959 --> 01:40:30,429
UNHEARD OF IS NOW BECOMING MORE 

1781
01:40:30,429 --> 01:40:35,067
COMMON IN YOUNGER PEOPLE.

1782
01:40:35,067 --> 01:40:38,403
AND THERE'S A STORY ABOUT 

1783
01:40:38,403 --> 01:40:40,339
ASBESTOS IN THE ENVIRONMENT THAT

1784
01:40:40,339 --> 01:40:48,013
ACT AS INFLAMMATORY FOSI THAT 

1785
01:40:48,013 --> 01:40:53,552
LEAD TO THELIOMAS AND OTHERS AND

1786
01:40:53,552 --> 01:40:55,153
THE WAY THEY COULD INDUCE GENE 

1787
01:40:55,153 --> 01:40:57,723
EXPRESSION RELATED TO DRUG 

1788
01:40:57,723 --> 01:41:00,025
RESISTANCE IS NOT UNDERSTOOD BUT

1789
01:41:00,025 --> 01:41:02,394
NOT ENTIRELY CRAZY THAT 

1790
01:41:02,394 --> 01:41:03,128
MICROPLASTICS MAY HAVE A SIMILAR

1791
01:41:03,128 --> 01:41:06,665
KIND OF ROLE.

1792
01:41:06,665 --> 01:41:08,834
I DON'T WANT TO READ ABOUT THIS 

1793
01:41:08,834 --> 01:41:11,069
IN THE WASHINGTON POST TOMORROW.

1794
01:41:11,069 --> 01:41:16,875
>> PLEASE IDENTIFY
YOURSELF.

1795
01:41:16,875 --> 01:41:20,345
>> I'M JAMES A MEDICAL
STUDENT 

1796
01:41:20,345 --> 01:41:21,513
DOING RESEARCH IN THE DENNY LAB.

1797
01:41:21,513 --> 01:41:24,549
I HAD A QUESTION ABOUT CAREER 

1798
01:41:24,549 --> 01:41:24,916
DEVELOPMENT.

1799
01:41:24,916 --> 01:41:28,453
WHAT MADE YOU SELECT MORE OF THE

1800
01:41:28,453 --> 01:41:31,289
RESEARCH FOCUSSED TOWARDS BEING 

1801
01:41:31,289 --> 01:41:34,426
AN M.D. SERVICE THE MORE 

1802
01:41:34,426 --> 01:41:40,065
CLINICAL SIDE?

1803
01:41:40,065 --> 01:41:42,367
>> SO I WAS ALWAYS
INTERESTED IN

1804
01:41:42,367 --> 01:41:42,634
RESEARCH.

1805
01:41:42,634 --> 01:41:43,902
I GUESS THE QUESTION WOULD BE 

1806
01:41:43,902 --> 01:41:49,474
WHY DID I GO TO MEDICAL SCHOOL.

1807
01:41:49,474 --> 01:41:50,175
THERE'S A LOT OF REASONS.

1808
01:41:50,175 --> 01:41:52,878
MOST OF WHICH RELATE THE TO THE 

1809
01:41:52,878 --> 01:41:54,046
FACT THAT I WAS KIND OF 

1810
01:41:54,046 --> 01:41:55,847
INTERESTED IN HUMAN MEDICINE AND

1811
01:41:55,847 --> 01:41:58,417
HUMAN DISEASE BUT I ALWAYS HAD A

1812
01:41:58,417 --> 01:42:00,419
RESEARCH ORIENTATION.

1813
01:42:00,419 --> 01:42:03,388
I EVEN IN MEDICAL SCHOOL DIDN'T 

1814
01:42:03,388 --> 01:42:04,122
THINK I'D ACTUALLY END UP 

1815
01:42:04,122 --> 01:42:13,899
PRACTICING MEDICINE.

1816
01:42:13,899 --> 01:42:16,935
I'M A BOARD CERTIFIED INTERNIST 

1817
01:42:16,935 --> 01:42:18,870
BUT MY MEDICAL ADVICE IS TO FIND

1818
01:42:18,870 --> 01:42:23,675
A GOOD DOCTOR.

1819
01:42:23,675 --> 01:42:27,879
I'M AN Ph.D. ORIENTED PHYSICIAN.

1820
01:42:27,879 --> 01:42:29,581
I SUSPECT JOHN IS THE SAME.

1821
01:42:29,581 --> 01:42:33,985
>> I KNEW FROM EARLY ON I
WANTED

1822
01:42:33,985 --> 01:42:35,153
TO RESEARCH AND I THINK THAT'S 

1823
01:42:35,153 --> 01:42:37,389
FOR ANYBODY WHO IS INTERESTED IN

1824
01:42:37,389 --> 01:42:38,723
GOING TO MEDICAL SCHOOL IT'S 

1825
01:42:38,723 --> 01:42:39,324
IMPORTANT TO FIGURE OUT EARLY 

1826
01:42:39,324 --> 01:42:42,661
ON.

1827
01:42:42,661 --> 01:42:45,797
I WENT INTO PATHOLOGY WHICH IS A

1828
01:42:45,797 --> 01:42:47,532
FIELD OF MEDICINE WHICH IS 

1829
01:42:47,532 --> 01:42:53,138
PROBABLY EASIER TO DO RESEARCH 

1830
01:42:53,138 --> 01:42:53,872
THAN OTHERS.

1831
01:42:53,872 --> 01:43:00,011
I WOULD SAY THERE WERE VARIOUS 

1832
01:43:00,011 --> 01:43:03,682
STAGES IN MY CAREER WHERE I WAS 

1833
01:43:03,682 --> 01:43:05,450
MORE INTERESTED IN MEDICINE AND 

1834
01:43:05,450 --> 01:43:06,918
MORE INTERESTED IN RESEARCH BUT 

1835
01:43:06,918 --> 01:43:08,286
THERE ARE THINGS YOU CAN FIGURE 

1836
01:43:08,286 --> 01:43:13,792
OUT AS YOU GO ALONG.

1837
01:43:13,792 --> 01:43:19,898
A LOT OF IT HAS TO DO BIG -- 

1838
01:43:19,898 --> 01:43:25,971
WITH WHAT YOU'RE SUCCESSFUL AT 

1839
01:43:25,971 --> 01:43:26,138
TOO.

1840
01:43:32,410 --> 01:43:40,852
>> JOHN, WHY DOES
PSEUDOMONAS 

1841
01:43:40,852 --> 01:43:43,922
HAS EXTRA OF EVERYTHING READY TO

1842
01:43:43,922 --> 01:43:44,656
GO?

1843
01:43:44,656 --> 01:43:49,794
>> I ALWAYS WONDERED MAYBE
THE 

1844
01:43:49,794 --> 01:43:58,637
REVERSE IS WHY DO OTHERS HAVE 

1845
01:43:58,637 --> 01:44:02,707
THE MICROBIAL RESISTANCE AND WHY

1846
01:44:02,707 --> 01:44:07,445
DON'T WE SEE TRANSPORTER 

1847
01:44:07,445 --> 01:44:11,983
MEDIATED RESISTANCE LIKE WE SEE 

1848
01:44:11,983 --> 01:44:22,494
IN PSEUDO NOE -- PSEUDOMONAS.

1849
01:44:24,729 --> 01:44:28,266
>> IT SEEMS TO WANT TO GET
RID 

1850
01:44:28,266 --> 01:44:31,870
OF THE COMMUNITY.

1851
01:44:31,870 --> 01:44:38,276
>> THERE ARE AND THERE'S 

1852
01:44:38,276 --> 01:44:39,344
NON-FERMENTERS LIKE PSEUDOMONAS 

1853
01:44:39,344 --> 01:44:42,814
AND WOULD BE INTERESTING TO DO A

1854
01:44:42,814 --> 01:44:44,849
STUDY TO FIGURE OUT WHAT THE 

1855
01:44:44,849 --> 01:44:45,817
ULTIMATE DRIVERS ARE.

1856
01:44:45,817 --> 01:44:52,624
IT'S A FASCINATING QUESTION.

1857
01:44:52,624 --> 01:44:55,360
>> THERE'S A QUESTION OF
THE 

1858
01:44:55,360 --> 01:44:59,864
BLOOD BRAIN BARRIER.

1859
01:44:59,864 --> 01:45:04,903
I REFERRED TO THE PERFORM OF 

1860
01:45:04,903 --> 01:45:05,870
DEALING WITH SYSTEMS OF THE 

1861
01:45:05,870 --> 01:45:06,838
BRAIN.

1862
01:45:06,838 --> 01:45:08,974
DO YOU WANT TO ELABORATE WHAT 

1863
01:45:08,974 --> 01:45:10,442
DISEASES OF THE BRAIN YOU'RE 

1864
01:45:10,442 --> 01:45:16,081
THINK ABOUT AND THE PART B TO 

1865
01:45:16,081 --> 01:45:23,822
THAT IS WHERE IS PGP EXPRESSED 

1866
01:45:23,822 --> 01:45:28,627
AND WHERE IS IT IN THE BRAIN?

1867
01:45:28,627 --> 01:45:31,029
>> I'LL ANSWER THE SECOND 

1868
01:45:31,029 --> 01:45:31,596
QUESTION FIRST.

1869
01:45:31,596 --> 01:45:34,199
THE P GLYCOPROTEIN IS EXPRESSED 

1870
01:45:34,199 --> 01:45:37,736
AT HIGH LEVELS IN THE CAPILLARY 

1871
01:45:37,736 --> 01:45:42,240
ENDOTHELIAL CELLS IN THE BRAIN 

1872
01:45:42,240 --> 01:45:49,848
IN THE VESSELS THAT FEED THE 

1873
01:45:49,848 --> 01:45:52,784
PART OF THE BRAIN THAT INTERACTS

1874
01:45:52,784 --> 01:46:01,226
WITH THE PER CEREBRAL SPINAL 

1875
01:46:01,226 --> 01:46:07,332
FLUID PARENCHYMAL PART OF THE 

1876
01:46:07,332 --> 01:46:08,700
BRAIN.

1877
01:46:08,700 --> 01:46:10,902
AND ONE PROBLEM WITH TREATING 

1878
01:46:10,902 --> 01:46:19,110
DISEASES IS YOU CAN'T GET IN 95%

1879
01:46:19,110 --> 01:46:23,515
OF THE DRUGS YOU WANT TO GET IN 

1880
01:46:23,515 --> 01:46:29,054
BLOCKED BY THE BLOOD BRAIN 

1881
01:46:29,054 --> 01:46:30,021
BARRIER AND THERE'S EXPRESSIONS 

1882
01:46:30,021 --> 01:46:34,426
OF TRANSPORTERS OF THE BLOOD 

1883
01:46:34,426 --> 01:46:41,866
BRAIN BARRIER.

1884
01:46:41,866 --> 01:46:43,868
AND CHRONIC DISEASE AND THERE'S 

1885
01:46:43,868 --> 01:46:45,437
TRANSPORT FUNCTIONS AND SOME 

1886
01:46:45,437 --> 01:46:47,972
BELIEVE PGP CAN RECOGNIZE AND 

1887
01:46:47,972 --> 01:46:51,242
PUMP OUT BETA AMYLOID AND THERE 

1888
01:46:51,242 --> 01:47:00,218
MAY BE A DEFECT THERE.

1889
01:47:00,218 --> 01:47:02,487
AND THERE ARE NOW ANTIBODIES 

1890
01:47:02,487 --> 01:47:05,023
THAT ARE BEING USED BUT THE 

1891
01:47:05,023 --> 01:47:06,057
EFFICIENCY IS VERY LOW AND YOU 

1892
01:47:06,057 --> 01:47:08,293
NEED TO BE ABLE TO MANIPULATE 

1893
01:47:08,293 --> 01:47:09,794
THE BLOOD BRAIN BARRIER TO GET 

1894
01:47:09,794 --> 01:47:12,697
HIGH LEVELS IN FACT IT THERE WAS

1895
01:47:12,697 --> 01:47:15,967
AN ARTICLE IN THE NEW YORK TIMES

1896
01:47:15,967 --> 01:47:17,602
AND WASHINGTON JOURNAL USING 

1897
01:47:17,602 --> 01:47:19,404
ULTRASOUND TO GET HIGHER LEVELS 

1898
01:47:19,404 --> 01:47:20,538
OF ANTIBODIES IN THE BRAIN.

1899
01:47:20,538 --> 01:47:27,212
THE BLOOD BRAIN BARRIER IS A 

1900
01:47:27,212 --> 01:47:29,647
REAL PROBLEM IN TREATMENT OF 

1901
01:47:29,647 --> 01:47:30,949
METASTATIC BRAIN TUMORS AND 

1902
01:47:30,949 --> 01:47:34,352
WE'RE GETTING SO MUCH BETTER AT 

1903
01:47:34,352 --> 01:47:38,189
TREATING SYSTEMIC METASTASIS 

1904
01:47:38,189 --> 01:47:40,425
WITH THE SECOND AND THIRD 

1905
01:47:40,425 --> 01:47:42,861
GENERATION ANTI-CANCER DRUGS YOU

1906
01:47:42,861 --> 01:47:45,463
READ ABOUT BUT FOR MANY TUMORS, 

1907
01:47:45,463 --> 01:47:52,804
LUNG CANCER AND  BREAST CANCERS 

1908
01:47:52,804 --> 01:47:54,239
CAN BE CONTROLLED BUT OCCUR IN 

1909
01:47:54,239 --> 01:47:54,839
THE BRAIN WHERE THEY'RE MORE 

1910
01:47:54,839 --> 01:48:05,183
DIFFICULT TO TREAT.

1911
01:48:05,950 --> 01:48:13,158
>> THERE'S APPROACHES FOR
DRUG 

1912
01:48:13,158 --> 01:48:13,491
RESISTANCE.

1913
01:48:13,491 --> 01:48:18,430
IS THERE SOMETHING COMPARABLE IN

1914
01:48:18,430 --> 01:48:19,431
THE MAMMALIAL SYSTEM OF A 

1915
01:48:19,431 --> 01:48:29,808
SUICIDE DRUG APPROACH?

1916
01:48:30,575 --> 01:48:33,812
>> MOST CELLS IF YOU
ACTIVATE 

1917
01:48:33,812 --> 01:48:38,416
THE KILLING MECHANISMS OF WHICH 

1918
01:48:38,416 --> 01:48:43,621
THERE'S FOUR OR FIVE DIFFERENT 

1919
01:48:43,621 --> 01:48:47,459
ONES AND YOU CAN DEVELOP DRUGS 

1920
01:48:47,459 --> 01:48:49,394
THAT WOULD ACTIVATE THE SYSTEMS 

1921
01:48:49,394 --> 01:48:51,162
AND MANY DO THAT'S THE FINAL 

1922
01:48:51,162 --> 01:48:53,264
COMMON PATHWAY FOR KILLING.

1923
01:48:53,264 --> 01:48:55,633
THAT'S THE ANALOG TO SUICIDE IN 

1924
01:48:55,633 --> 01:49:04,209
BACTERIA.

1925
01:49:04,209 --> 01:49:13,585
>> MY NAME IS JOE ANNA
THOMAS 

1926
01:49:13,585 --> 01:49:17,155
AND I LEARNED A LOT IN YOUR TALK

1927
01:49:17,155 --> 01:49:27,699
AND I LEARNED A NEW WORD CALLED 

1928
01:49:36,007 --> 01:49:38,409
BACTERIAMIA AND MY FIRST 

1929
01:49:38,409 --> 01:49:41,346
QUESTION WAS IS THAT COMMON OR 

1930
01:49:41,346 --> 01:49:48,853
SOMETHING YOU CAN USE TO STUDY 

1931
01:49:48,853 --> 01:49:51,589
THE EVOLUTION WITHIN A PATIENT 

1932
01:49:51,589 --> 01:49:53,958
AND ARE YOU THEN IDENTIFYING A 

1933
01:49:53,958 --> 01:49:56,995
PATIENT AND PUTTING THEM ON 

1934
01:49:56,995 --> 01:49:58,563
LOCKDOWN WORRYING ABOUT THE 

1935
01:49:58,563 --> 01:50:00,665
PLUMBING OF THE HOSPITAL AND THE

1936
01:50:00,665 --> 01:50:02,100
SPREAD OF RESISTANCE?

1937
01:50:02,100 --> 01:50:04,369
>> THOSE ARE ALL GREAT 

1938
01:50:04,369 --> 01:50:05,370
QUESTIONS.

1939
01:50:05,370 --> 01:50:15,880
I WOULD SAY FIRST, WITH BACK 

1940
01:50:20,118 --> 01:50:25,590
TEAR TERRE -- BACTEREMIA NOT 

1941
01:50:25,590 --> 01:50:29,994
GROWN AND IN A TYPICAL 

1942
01:50:29,994 --> 01:50:32,397
BACTEREMIA INVOLVES 1 IN 500 

1943
01:50:32,397 --> 01:50:34,699
COLONY FORMING UNITS MEANING 

1944
01:50:34,699 --> 01:50:37,368
CELLS PER MILLILITER.

1945
01:50:37,368 --> 01:50:46,377
SO THEY'RE NOT DENSE SQUARE IN 

1946
01:50:46,377 --> 01:50:47,478
THE INTRAVASCULAR SPACE AND SO 

1947
01:50:47,478 --> 01:50:49,047
NOW THE SECOND QUESTION THOUGH 

1948
01:50:49,047 --> 01:50:53,851
IN CASES OF PATIENTS WHO AREN'T 

1949
01:50:53,851 --> 01:50:56,020
IN THAT STAGE CAN WE MONITOR 

1950
01:50:56,020 --> 01:50:58,022
INFECTIONS AT OTHER SITES BY 

1951
01:50:58,022 --> 01:51:03,094
SAMPLING BLOOD AND YES WE CAN.

1952
01:51:03,094 --> 01:51:06,230
YOU CAN SEE CIRCULATING DNA THAT

1953
01:51:06,230 --> 01:51:09,934
CAN BE SEQUENCED ON SHOTGUN 

1954
01:51:09,934 --> 01:51:10,768
BASED METHODS AND CAN LEARN A 

1955
01:51:10,768 --> 01:51:13,404
LOT ABOUT INFECTIONS IN OTHER 

1956
01:51:13,404 --> 01:51:14,772
SITES IN THE BODY AND THERE'S 

1957
01:51:14,772 --> 01:51:15,039
STUDIES.

1958
01:51:15,039 --> 01:51:17,208
TO GET TO THE OTHER QUESTION 

1959
01:51:17,208 --> 01:51:20,478
WHAT CAN WE LEARN ABOUT 

1960
01:51:20,478 --> 01:51:22,880
ANTIMICROBIAL RESISTANCE IN THE 

1961
01:51:22,880 --> 01:51:27,151
EVOLUTION OF ANTIMICROBIAL 

1962
01:51:27,151 --> 01:51:27,719
RESISTANCE CERTAINLY IN A 

1963
01:51:27,719 --> 01:51:32,156
PATIENT IN THIS STAGE YOU CAN 

1964
01:51:32,156 --> 01:51:38,396
GET ISOLATES BUT EVEN WITH AN 

1965
01:51:38,396 --> 01:51:45,403
PATIENT THAT NOT BACTEREMIA WE 

1966
01:51:45,403 --> 01:51:51,175
MAY BE ABLE TO DEDUCE RESISTANCE

1967
01:51:51,175 --> 01:51:53,444
BY LOOKING AT CIRCULATING DNA 

1968
01:51:53,444 --> 01:51:54,479
AND WHAT PEOPLE ARE INTERESTED 

1969
01:51:54,479 --> 01:51:55,380
IN AND THERE'S EXCITING PROGRESS

1970
01:51:55,380 --> 01:52:00,852
BEING MADE.

1971
01:52:00,852 --> 01:52:01,419
>> THANK YOU.

1972
01:52:01,419 --> 01:52:05,690
>> WE HAVE TIME FOR ONE
MORE 

1973
01:52:05,690 --> 01:52:06,557
GENERAL KIND OF QUESTION.

1974
01:52:06,557 --> 01:52:09,661
MAYBE BOTH WOULD LIKE TO COMMENT

1975
01:52:09,661 --> 01:52:14,365
ABOUT YOUR VIEWS ON DEALING WITH

1976
01:52:14,365 --> 01:52:20,338
THE EVOLUTIONARY BIOLOGY OF DRUG

1977
01:52:20,338 --> 01:52:22,340
RESISTANCE AND DIFFERENT LIVING 

1978
01:52:22,340 --> 01:52:22,607
THINGS.

1979
01:52:22,607 --> 01:52:26,411
DO WE HAVE ANY KNOWLEDGE ABOUT 

1980
01:52:26,411 --> 01:52:34,285
THINGS LIKE ARCHIA OR YEAST AND 

1981
01:52:34,285 --> 01:52:41,526
CAN YOU COMMENT ON ABOUT THIS?

1982
01:52:41,526 --> 01:52:44,228
THERE WAS CONCERN MANY YEARS AGO

1983
01:52:44,228 --> 01:52:45,797
WHEN THE FIRST ROCKETS WERE 

1984
01:52:45,797 --> 01:52:48,533
BEING SENT TO THE MOON AND IF 

1985
01:52:48,533 --> 01:52:51,069
YOU MANAGED TO LAND E. COLI ON 

1986
01:52:51,069 --> 01:52:53,638
THE MOON IT WOULD COVER THE 

1987
01:52:53,638 --> 01:52:58,409
SURFACE OR SOMETHING LIKE THAT.

1988
01:52:58,409 --> 01:53:03,881
IS THERE THINK IN THE ASTRO 

1989
01:53:03,881 --> 01:53:05,550
PHYSICAL WORLD ABOUT THE 

1990
01:53:05,550 --> 01:53:06,317
MICROBIOLOGY OF SPACE AND 

1991
01:53:06,317 --> 01:53:10,421
POSSIBLE INTERACTION WE SEE ON 

1992
01:53:10,421 --> 01:53:10,621
EARTH?

1993
01:53:10,621 --> 01:53:14,659
TWO SMALL QUESTIONS.

1994
01:53:14,659 --> 01:53:17,195
>> I'M A SCIENCE FICTION
FAN SO 

1995
01:53:17,195 --> 01:53:18,229
THESE ARE ALL INTERESTING 

1996
01:53:18,229 --> 01:53:19,197
QUESTIONS.

1997
01:53:19,197 --> 01:53:24,502
GIVEN WE HAVE NOT DEFINITIVELY 

1998
01:53:24,502 --> 01:53:26,404
DISCOVERED LIFE ANYWHERE ELSE IN

1999
01:53:26,404 --> 01:53:29,006
THE LIMITED PART OF THE UNIVERSE

2000
01:53:29,006 --> 01:53:30,141
WE'VE EXPLORED I DON'T KNOW HOW 

2001
01:53:30,141 --> 01:53:34,412
TO ANSWER THAT BUT I THINK THE 

2002
01:53:34,412 --> 01:53:37,281
UNIVERSE IS LIKELY TEEMING WITH 

2003
01:53:37,281 --> 01:53:40,418
LIFE AND THERE'S GALAXIES AND 

2004
01:53:40,418 --> 01:53:45,423
THERE'S A HUNDRED BILLION 

2005
01:53:45,423 --> 01:53:47,525
GALAXIES WITH A HUN HUN DREAD 

2006
01:53:47,525 --> 01:53:49,393
BILLION SYSTEMS AND IF WE BRING 

2007
01:53:49,393 --> 01:53:54,198
BACK AN ALIEN MICROBIAL LIFE 

2008
01:53:54,198 --> 01:53:55,767
FORM, WHATEVER IT IS BASED ON 

2009
01:53:55,767 --> 01:53:58,202
SOME POLYMER REPLICATION SYSTEM 

2010
01:53:58,202 --> 01:54:03,007
THAT FEEDS ON NITROGEN, OXYGEN 

2011
01:54:03,007 --> 01:54:06,878
AND SULFUR MAYBE IT WOULD 

2012
01:54:06,878 --> 01:54:10,114
REPLICATE ON EARTH AND IN TERMS 

2013
01:54:10,114 --> 01:54:12,850
OF ANTIMICROBIAL RESISTANCE I'M 

2014
01:54:12,850 --> 01:54:13,417
NOT SURE HOW TO MAKE THE 

2015
01:54:13,417 --> 01:54:22,360
CONNECTION THERE.

2016
01:54:22,360 --> 01:54:25,897
>> THERE'S RESISTANCE
FITNESS 

2017
01:54:25,897 --> 01:54:31,202
AND MANY MECHANISMS ARE COSTLY 

2018
01:54:31,202 --> 01:54:33,871
FOR THE ORGANISM.

2019
01:54:33,871 --> 01:54:35,740
AS EVOLUTION GOES ON THE 

2020
01:54:35,740 --> 01:54:38,276
MECHANISMS WILL BE EVOLVED.

2021
01:54:38,276 --> 01:54:41,012
MY WIFE REMINDS ME FREQUENTLY 

2022
01:54:41,012 --> 01:54:45,850
THAT BACTERIA E. COLI DIVIDE 

2023
01:54:45,850 --> 01:54:49,220
EVERY 20 MINUTES AND WE DIVIDE 

2024
01:54:49,220 --> 01:54:50,488
EVERY 20 YEARS.

2025
01:54:50,488 --> 01:54:51,923
BACTERIA ARE MORE EVOLVED THAN 

2026
01:54:51,923 --> 01:54:52,490
HUMANS.

2027
01:54:52,490 --> 01:54:53,724
IF THERE'S A WAY TO DO IT, THEY 

2028
01:54:53,724 --> 01:54:57,628
HAVE FIGURED IT OUT.

2029
01:54:57,628 --> 01:54:59,964
THERE'S EXCHANGE OF INFORMATION.

2030
01:54:59,964 --> 01:55:03,034
THERE'S SOME EVIDENCE THAT YOU 

2031
01:55:03,034 --> 01:55:04,468
HEAR ABOUT BACTERIA EXCHANGING 

2032
01:55:04,468 --> 01:55:06,137
GENES BUT PROBABLY SOME OF THE 

2033
01:55:06,137 --> 01:55:09,874
GENES WE HAVE IN OUR OWN BODY 

2034
01:55:09,874 --> 01:55:14,545
WERE DERIVED AT SOME POINT FROM 

2035
01:55:14,545 --> 01:55:14,912
MICROORGANISMS.

2036
01:55:14,912 --> 01:55:17,281
I THINK THIS CONCEPT OF FITNESS 

2037
01:55:17,281 --> 01:55:19,684
IS REALLY IMPORTANT AND THE 

2038
01:55:19,684 --> 01:55:22,386
MECHANISMS THAT WORK BEST ARE 

2039
01:55:22,386 --> 01:55:24,388
THE ONES THAT PICK THE LEAST 

2040
01:55:24,388 --> 01:55:26,257
AWAY FROM THE NORMAL FUNCTION OF

2041
01:55:26,257 --> 01:55:30,895
THE ORGANISM WHATEVER IT IS.

2042
01:55:30,895 --> 01:55:33,898
>> WELL, ON BEHALF OF THE
SELECT

2043
01:55:33,898 --> 01:55:36,767
AUDIENCE HERE TODAY AND THOSE 

2044
01:55:36,767 --> 01:55:39,003
LISTENING THROUGHOUT THE NIH AND

2045
01:55:39,003 --> 01:55:41,439
THROUGHOUT THE WORLD WE WANT TO 

2046
01:55:41,439 --> 01:55:47,845
THANK BOTH OF YOU FOR A REALLY 

2047
01:55:47,845 --> 01:55:48,946
EXTRAORDINARILY EXCITING 

2048
01:55:48,946 --> 01:55:49,280
PRESENTATION.

2049
01:55:49,280 --> 01:55:50,414
IT GIVES EVERYBODY A LOT TO 

2050
01:55:50,414 --> 01:55:52,350
THINK ABOUT AND PARTICULARLY 

2051
01:55:52,350 --> 01:55:54,418
YOUNG PEOPLE POSTDOCS AND SO 

2052
01:55:54,418 --> 01:55:58,923
FORTH WHO MAY BE WORKING IN 

2053
01:55:58,923 --> 01:56:01,192
VASTLY DIFFERENT AREAS OF 

2054
01:56:01,192 --> 01:56:06,230
SCIENCE AND THERE'S A GREAT 

2055
01:56:06,230 --> 01:56:09,734
COMMONALITY HERE IN TERMS OF 

2056
01:56:09,734 --> 01:56:10,301
METHODOLOGY, IDEAS.

2057
01:56:10,301 --> 01:56:13,404
THERE'S A LOT OF ROOM FOR BRIDGE

2058
01:56:13,404 --> 01:56:14,839
BUILDING.

2059
01:56:14,839 --> 01:56:15,373
THANK YOU VERY MUCH FOR A 

2060
01:56:15,373 --> 01:56:15,873
WONDERFUL PRESENTATION.

2061
01:56:15,873 --> 01:56:18,342