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>>WELCOME TO THE 

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WEDNESDAY AFTERNOON LECTURE 

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SERIES.  I'M GIGI S, A PRINCIPLE

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INVESTIGATOR AND IT IS MY GREAT 

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PLEASURE TO INTRODUCE TODAY'S 

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SPEAKER ON BEHALF OF THE 

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INTEREST GROUP.  SO DR. S. WAS A

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TOP VOTE GETTER FOR LAMBDA LUNCH

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FOR SEVERAL YEARS IN A ROW SO WE

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ARE SO PLEASED THAT HE WAS ABLE 

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TO COME THIS WEEK.  

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HE'S THE INCUMBENT OF THE SYLVIA
 

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CHAIR IN THE DEPARTMENT AT THE 

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WEISSMAN INSTITUTE IN ISRAEL.  

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HE RECEIVED A BULK OF THE 

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EDUCATION AT TEL AVIV UNIVERISTY

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WHERE HE EARNED A MASTER'S 

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DEGREE IN GENETICS AND A PH.D. 

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IN HUMAN GENETICS.  I DIDN'T 

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KNOW THAT.  HE FOLLOWED UP WITH 

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POST-DOCTORAL FELLOWSHIP AT THE 

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BERKLEY LAB IN CALIFORNIA AND 

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RETURNED TO ISRAEL WHERE HE WENT

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TO THE WEISSMAN AND HAS BEEN 

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GOING UP THE RANKS, MOVING UP 

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THE RANKS AT THE WEISSMAN.  SO 

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HE HAS HAD MANY RECOGNITIONS AND

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ACCOLADES INCLUDE THE GERMAN 

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NATIONAL ACADEMY OF SCIENCES, 

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THE ANDRE PRIZE FOR SCIENTIFIC 

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RESEARCH.  THE RAH PA IMPORTANT 

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PRIZE FOR EXCELLENCE AND 

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ELECTION TO BOTH THE AMERICAN 

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ACADEMY OF MICROBIOLOGY.  SO 

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RECOGNITION ALL AROUND THE 

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WORLD.  BUT MOST IMPORTANTLY 

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ONTO HIS RESEARCH WHICH COMBINES

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COMPUTATIONAL GENOMICS, SYSTEMS 

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BIOLOGY, METAGENOMICS, HIGH 

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THROUGHPUT SEQUENCING AND MODERN

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EXPERIMENTAL APPROACHES AND 

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MICROBIOLOGY AND PHAGE BIOLOGY. 

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AMONG THE MOST SIGNIFICANT 

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RESULTS ARE MULTIPLE DISCOVERS 

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ABOUT THE ARMS RACE BETWEEN 

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BACTERIA AND PHAGE.  SO MANY 

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PEOPLE HAVE HEARD ABOUT KRIS PER

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THAT IS NOT THE WHOLE STORY.  AS

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YOU WILL SEE HERE. EXCITING 

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FINDINGS THAT HAVE COME FROM THE

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LAB INCLUDE THE DISCOVERY OF AN 

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ASTONISHING NUMBER OF SYSTEMS, 

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DEFENSE SYSTEMS BEYOND CRSPR.  

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THE DISCOVERY THAT PHAGES USE 

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SMALL MOLECULE COMMUNICATION TO 

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COORDINATE THEIR INFECTION 

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DYNAMICS.  SMALL RNAS AND SMALL 

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PROTEINS WHICH ARE CLOSE TO MY 

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HEART ARE INVOLVED IN THE 

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PROCESS AND MOST INTRIGUINGLY 

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THE PARALLELS BETWEEN THESE.  I 

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THINK SOME OF THESE TOPICS ARE 

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THE FOCUS OF THE TALK TODAY.  

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LET ME STOP THERE AND THANK YOU 

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THEM FOR COMING TO VISIT US 

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IN-PERSON.

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>>THANK YOU SO MUCH IT'S
A 

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GREAT PLEASURE AND HONOR FOR ME 

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TO GIVE A LECTURE IN THIS FORUM 

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AND I THANK THE LAMBDA FORUM FOR

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THE INVITATION AND FOR HOSTING 

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ME FOR SUCH AN INTERESTING 

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MEETING.  THESE LAST TWO DAYS 

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HAVE BEEN FASCINATING.  I WILL 

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TALK ABOUT OUR ADVENTURE 

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STUDYING BACTERIA AND WHAT WE 

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LEARNED IN THE BAHS PAST FEW 

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YEARS.  BACTERIA ARE VERY RARELY

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INFECTED BY PHAGES.  PHAGES ARE 

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VIRUSES, THEY USE SPECIFIC 

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RECEPTOR ON THE BACTERIUM 

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SURFACE AND WILL INJECT THEIR 

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GENETIC MATERIAL.  AND WITH THE 

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PHAGES WE STUDY IN THE LAB, 

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AFTER BETWEEN HALF AN HOUR TO 

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TWO HOURS THEY BURST OPEN THE 

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BACTERIA AND ONE HUNDRED PHAGES 

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WILL EMERGE FROM IT AND SEARCH 

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BY DIFFUSION FOR OTHER BACTERIA 

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TO INFECT AND THESE ARE SUPER 

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ABUNDANT IN THE ENVIRONMENT.  

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MORE ON THE OTHER AND IF YOU 

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WEIGH ALTOGETHER THEY MAY MORE 

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THAN ENTIRETY OF HUMANITY 

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ALTOGETHER.  BUT YOU CAN ONLY 

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SEE WHEN YOU LOOK AT THE 

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MICROSCOPE.  SO BACTERIA ARE 

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INFECTED AND HENCE THEY NEED TO 

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DEVELOP AND EVOLVE AN IMMUNE 

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SYSTEM AND THE IMMUNE SYSTEM OF 

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BACTERIA WE KNOW OF IT FOR MANY 

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YEARS NOW.  WE HAVE TWO, OR AT 

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LEAST WHAT WE KNEW UP TO FOUR OR

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FIVE YEARS AGO THAT WE HAVE TWO 

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ARMS OF IMMUNITY.  ONE IS THE 

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ADAPTIVE IMMUNE SYSTEM CALLED 

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KRIS PER CAS THAT PUTS PIECES IN

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THE BACTERIAL GENOME AND USES 

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THESE PIECES TO MITIGATE FUTURE 

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INFECTION BY THE SAME PHAGE.  WE

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HAVE RESTRICTION MODIFICATION.  

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THESE ARE BASICALLY RESTRICTION 

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ENZYMES THAT CLEAVE THE INCOMING

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DNA IN SPECIFIC KNOW TIES.  

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THERE'S ALWAYS GOING TO BE 

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ANOTHER PROTEIN THAT YOU MODIFY 

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THE SAME MOTIFS TO PREVENT 

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AUTOIMMUNITY.  PREVENT SELF 

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CLEAVAGE BUT A NUMBER OF YEARS 

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AGO WE STARTED THINKING THAT 

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THERE MIGHT BE OTHER DEFENSE 

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MECHANISMS IN BACTERIA THAT WE 

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ARE NOT AOF YET AND THE REASON 

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WHY WE THOUGHT THERE MAY BE NOT 

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SUCH MECHANISMS IS FIRST OF ALL 

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CRISPER IS ABSENT FROM MOST.  

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AND YOU ASK HOW DO THEY SURVIVE 

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PHAGES AND KRIS PER WAS 

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DISCOVERED SO LATE.  DISCOVERED 

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ONLY 1  -- 90 YEARS AFTER THE 

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DISCOVERY OF THE PHAGE AND 

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DURING THIS TIME, FANLS HAVE 

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BEEN THE MAJOR DRIVING FORCE FOR

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STUDYING MOLECULAR BAY YOOLG.  

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HOW TRANSLATION GOES, GENETIC 

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CODE WAS ALL DISCOVERED UPON 

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INFECTION OF PHAGES IN BACTERIA 

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SINCE E. COLI DOESN'T HAVE A 

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WORKING KRIS PER.  SO KRIS PER 

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AND E. COLI IS NOT WORKING VERY 

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WELL SO THAT'S WHY IT WAS NOT 

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DISCOVERED DURING ALL THESE 

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DECADES OF RESEARCH.  WE THOUGHT

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THERE MIGHT BE OTHER MECHANISMS 

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THAT E. COLI DOESN'T HAVE BUT 

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OTHER BACTERIA MAY HAVE AND 

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THESE WE COULD DISCOVER.  THE 

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REASON WE WERE SO INTERESTED TO 

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FIND NEW IMMUNE SYSTEMS IS FIRST

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OF ALL, IF WE WANT TO UNDERSTAND

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THE EVOLUTION, THE CONFLICT OF 

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THESE PHAGES THE DEFENSE SYSTEMS

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ARE A MAJOR PART OF THAT 

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CONFLICT.  SO WE NEED TO 

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UNDERSTAND HOW THEY OVERCOME 

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THEMSELVES AND AND DEFENSE.  FOR

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A MORE PRACTICAL POINT OF VIEW 

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IT SEEMS TO US THAT IN THE PAST 

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WHEN NEW IMMUNE SYSTEMS HAVE 

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BEEN DISCOVERED AND STUDIED, IT 

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FREQUENTLY LED TO REVOLUTIONS IN

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BIOLOGY SO THE DISCOVERY OF 

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RESTRICTION ENZYMES ALLOWED THE 

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FIRST GENETIC ENGINEERING, 

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BEFORE THAT PEOPLE DIDN'T KNOW 

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HOW TO DO IT.  DISCOVERY OF KRIS

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PER LEADS TO A REVOLUTION IN 

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GENOME ENGINEERING AND IF YOU 

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THINK ABOUT THE BACTERIA, THE 

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DISCOVERY OF RN IAI WHICH IS AN 

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ANTIVIRAL MACHINE THAT SILENCE 

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EUCARYOTES AND THE WAY WE WORK 

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WITH ANTIBODIES IS ALSO 

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PATHOLOGICALLY, YOU KNOW, VERY 

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RICH TOOL AND THE REASON THEY 

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ARE SO BENEFICIAL IS AN IMMUNE 

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SYSTEM BY DEFINITION IS TO 

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IDENTIFY A SPECIFIC MOLECULAR.  

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IN SELF INFECTING FOREIGN 

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ELEMENT AND THEN DO SOMETHING TO

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THAT MOLECULE, CLEAVE IT OR 

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REMOVE AND IT THAT'S EXACTLY 

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WHAT WE NEED AS MOLECULAR 

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BIOLOGISTS WE NEED THESE 

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PRECISION TOOLS TO BIND, CLEAVE 

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OR REMOVE OR MOVE AWAY OR DO 

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SOMETHING TO A SPECIFIC 

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MOLECULE.  SO WE HOPE THAT IF WE

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FIND NEW DEFENSE SYSTEMS, NEW 

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IMMUNE SYSTEMS THEY MIGHT OH 

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INVOLVE INTO BECOMING NEW 

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MOLECULAR TOOLS BENEFICIAL FOR 

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HUMANITY.  HOW CAN WE FIND NEW 

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IMMUNE SYSTEMS IN A SYSTEMATIC 

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MANNER GIVEN THAT ALL THESE 

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IMMUNE SYSTEMS IN THE PAST WERE 

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DISCOVERED JUST BY CHANCE?  

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PEOPLE STUMBLED UPON THEM AND 

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THEN REALIZED WHAT THEY SEE AND 

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SAW LATER ON SO WE'VE BEEN 

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TRYING TO FIND IMMUNE SYSTEMS 

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THROUGH MULTIPLE DIFFERENT KINDS

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OF METHODOLOGIES AND WE FAILED 

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IN MOST OF THEM.  BUT THE THING 

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THAT EVENTUALLY WORKED FOR US 

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COMES FROM A VERY PECULIAR 

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BEHAVIOR OF DEFENSE SYSTEMS IF 

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WE LOOK AT GENOMES OF BACTERIA. 

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GENOME COLLIE SPEAKING, 

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CLUSTERED AS DEFENSE ISLANDS 

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THESE AREAS ARE RICH IN DEFENSE 

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SYSTEMS.  WE CAN SEE THAT IN THE

213
00:08:59,320 --> 00:09:02,040
GENOME OF THIS MICRO ORGANISM 

214
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I'M SHOWING YOU A SMALL PIECE OF

215
00:09:04,040 --> 00:09:06,920
THAT GENOME.  YOU SEE THE GENES 

216
00:09:06,920 --> 00:09:10,040
THAT CODE FOR CRISPR ARE CODED 

217
00:09:10,040 --> 00:09:13,320
NOT FOR FOR THOSE RESTRICTION 

218
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ENZYMES, THESE ARE THE DIFFERENT

219
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SUB UNITS AND THEY ARE ENCODED 

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NOT FAR FROM ANOTHER DEFENSE 

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GENE THAT IS NOKNOWN.  SO WE 

222
00:09:24,600 --> 00:09:26,880
THOUGHT THAT IF WE'RE -- IF WE 

223
00:09:26,880 --> 00:09:33,320
CAN LOOK FOR GENES OR MORE OFTEN

224
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GENE CASSETTE THAT CURRENTLY 

225
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OCCUR AND ARE ENRICHED NEXT TO 

226
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THESE DIFFERENT SYSTEMS WE MIGHT

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FIND NEW IMMUNE SYSTEMS THAT 

228
00:09:45,320 --> 00:09:49,360
WERE NOT KNOWN YET.  AND SO A 

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PH.D. STUDENT FROM MY LAB 

230
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ANALYZED GENOMES THAT ARE 

231
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OCCURRING NEXT TO CRISPR AND 

232
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RESTRICTION ENZYMES AND TO OUR 

233
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SURPRISE FOUND MANY CASSETTES 

234
00:10:04,040 --> 00:10:05,760
THAT WERE OF UNKNOWN FUNCTION 

235
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BACK THEN.  SO TO SEE WHETHER 

236
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THEY'RE INDEED FUNCTIONING IN 

237
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DEFENSE AGAINST PHAGES WE 

238
00:10:12,120 --> 00:10:13,320
DEVELOPED THIS EXPERIMENTAL 

239
00:10:13,320 --> 00:10:14,880
PLATFORM TO TEST THEM SO WHAT WE

240
00:10:14,880 --> 00:10:17,320
DO WHEN WE SUSPECT THAT WE FOUND

241
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NEW DIFFERENTS DEFENSE SYSTEM WE

242
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LOOK IS THE ALL THE GENOMES IN 

243
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THE DEFENSE DATABASE THAT HAVE 

244
00:10:24,440 --> 00:10:27,040
THIS OPERA AND WE SELECT THE 

245
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GENOMES THAT ARE AS CLOSE AS 

246
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POSSIBLE TO OUR LAB ORDER 

247
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ORGANISMS AND WE SYNTHESIZE THE 

248
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DNA AND EXPOSE THIS DE BACTERIA 

249
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TO A SERIES OF PHAGES.  

250
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SO SINGLE STRAND DNA, RNA, ET 

251
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CETERA.  AND WE LOOK FOR CASES 

252
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IN WHICH THE SYSTEM WE CLONE.  

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IF THE BACK TEAR YUM PROTECTED 

254
00:11:01,000 --> 00:11:01,800
AGAINST THAT PHAGE. 

255
00:11:01,800 --> 00:11:04,000
AND WHEN WE STARTED DOING THESE 

256
00:11:04,000 --> 00:11:05,680
EXPERIMENTS, WE WERE HOPING TO 

257
00:11:05,680 --> 00:11:07,840
FIND ONE OR TWO NEW DEFENSE 

258
00:11:07,840 --> 00:11:09,320
SYSTEMS WHICH WE THOUGHT WOULD 

259
00:11:09,320 --> 00:11:11,080
BE SUPER EXCITING BUT WE WERE 

260
00:11:11,080 --> 00:11:14,880
SUPER, SUPER SURPRISED TO FIND 

261
00:11:14,880 --> 00:11:16,720
NUMEROUS DEFENSE SYSTEMS IN 

262
00:11:16,720 --> 00:11:18,760
MICROBIAL GENOMES SO FAR I THINK

263
00:11:18,760 --> 00:11:22,040
MY LAB DESCRIBED MORE THAN 40 

264
00:11:22,040 --> 00:11:23,120
DIFFERENT DEFENSE SYSTEMS THAT 

265
00:11:23,120 --> 00:11:26,520
ARE ABANDONED IN MICROBES AND 

266
00:11:26,520 --> 00:11:29,320
OTHER LABS NOW THAT DID 

267
00:11:29,320 --> 00:11:31,560
EXPERIMENTS INSPIRED BY US FOUND

268
00:11:31,560 --> 00:11:33,320
DOZENS OF DEFENSE SYSTEMS.  NOW 

269
00:11:33,320 --> 00:11:37,440
WE KNOW SINCE 2018 OF, YOU KNOW,

270
00:11:37,440 --> 00:11:39,200
ABOUT 100 DIFFERENT KINDS OF 

271
00:11:39,200 --> 00:11:41,320
IMMUNE SYSTEMS OR DEFENSE 

272
00:11:41,320 --> 00:11:43,840
SYSTEMS THAT BACTERIA ENCODE IN 

273
00:11:43,840 --> 00:11:44,480
NATURE AND PROTECT THEM AGAINST 

274
00:11:44,480 --> 00:11:46,880
PHAGES AND SO WHAT YOU SEE HERE,

275
00:11:46,880 --> 00:11:48,520
THIS FIGURE LET ME TRY TO 

276
00:11:48,520 --> 00:11:50,760
EXPLAIN WHAT YOU SEE.  THIS IS A

277
00:11:50,760 --> 00:11:53,320
FIGURE FROM OUR 2018 PAPER WHERE

278
00:11:53,320 --> 00:11:54,840
WE DESCRIBE 9-10 DIFFERENT 

279
00:11:54,840 --> 00:11:55,720
DEFENSE SYSTEMS WHAT YOU SEE IS 

280
00:11:55,720 --> 00:11:58,760
A TWO GENE SYSTEM.  THIS GENE IS

281
00:11:58,760 --> 00:12:00,960
A DOMAIN OF UNKNOWN FUNCTION AND

282
00:12:00,960 --> 00:12:04,000
THEN WE HAVE A CASE DOMAIN THAT 

283
00:12:04,000 --> 00:12:05,560
MANIPULATES DNA OR RNA AND THE 

284
00:12:05,560 --> 00:12:07,240
SIZE OF THESE GENES IS ABOUT THE

285
00:12:07,240 --> 00:12:08,640
SIZE OF CLASS NINE SO IT'S A 

286
00:12:08,640 --> 00:12:12,800
PRETTY LARGE PROTEIN.  WE CLONE 

287
00:12:12,800 --> 00:12:15,920
IT.  AND WE INFECTED THE 

288
00:12:15,920 --> 00:12:17,320
BACTERIUM WITH TEN DIFFERENT 

289
00:12:17,320 --> 00:12:19,480
PHAGES AND WHENEVER YOU SEE A 

290
00:12:19,480 --> 00:12:21,320
RED COLOR HERE MEANS THAT THE 

291
00:12:21,320 --> 00:12:22,880
SYSTEM PROTECTED THE BACTERIUM 

292
00:12:22,880 --> 00:12:23,880
AGAINST THE PHAGE AND THIS COLOR

293
00:12:23,880 --> 00:12:26,360
MEANS WE NEEDED TO INFECT THE 

294
00:12:26,360 --> 00:12:28,800
BACTERIA BY TEN MILLION TIMES 

295
00:12:28,800 --> 00:12:31,200
MORE PHAGES OR ONE THOUSAND 

296
00:12:31,200 --> 00:12:33,320
TIMES MORE IN ORDER TO SEE THIS.

297
00:12:33,320 --> 00:12:35,200
AND IN THE PAST FOUR OR FIVE 

298
00:12:35,200 --> 00:12:37,480
YEARS, SINCE THE DISCOVERIES OF 

299
00:12:37,480 --> 00:12:41,320
THE SYSTEMS WE SHIFTED THE 

300
00:12:41,320 --> 00:12:45,320
GRAVITY OF THE LABS WORK FROM 

301
00:12:45,320 --> 00:12:48,920
MOSTLY GENETICS TO MUCH MORE 

302
00:12:48,920 --> 00:12:50,840
BIOCHEMISTRY IN ORDER TO START 

303
00:12:50,840 --> 00:12:55,760
SOLVING THE MECHANISMS OF HOW 

304
00:12:55,760 --> 00:12:57,960
THESE SYSTEMS WORK.  ONE THING 

305
00:12:57,960 --> 00:13:00,760
WE SAW QUITE EARLY ON, WHICH WAS

306
00:13:00,760 --> 00:13:03,720
VERY SURPRISING FOR US, IS THIS 

307
00:13:03,720 --> 00:13:05,320
SYSTEM THAT TO THE OTHER SYSTEM.

308
00:13:05,320 --> 00:13:07,880
THIS IS ONE OF THE DEFENSE 

309
00:13:07,880 --> 00:13:12,200
SYSTEM WE CHARACTERIZE.  AND IT 

310
00:13:12,200 --> 00:13:13,320
INTERESTED US BECAUSE IT HAS 

311
00:13:13,320 --> 00:13:16,000
PROTEINS WITH TIER DOMAINS AND 

312
00:13:16,000 --> 00:13:18,720
TIER DOMAINS ARE ALREADY KNOWN 

313
00:13:18,720 --> 00:13:20,680
TO PARTICIPATE IN IMMUNITY BUT 

314
00:13:20,680 --> 00:13:23,440
IN OUR OWN IMMUNE SYSTEM.  THE 

315
00:13:23,440 --> 00:13:25,320
IMMUNE SYSTEM OF HUMANS.  IT'S 

316
00:13:25,320 --> 00:13:28,280
WITH THE RECEPTORS AND THESE ARE

317
00:13:28,280 --> 00:13:30,200
PIECES OF OUR RECEPTORS THAT 

318
00:13:30,200 --> 00:13:32,760
PARTICIPATE IN OUR OWN IMMUNITY.

319
00:13:32,760 --> 00:13:35,120
SO THIS GAVE US THE NOTION THAT 

320
00:13:35,120 --> 00:13:37,320
FOR SOME DEFENSE SYSTEMS, THE 

321
00:13:37,320 --> 00:13:40,400
REASON ANCIENT EVOLUTIONARY LINK

322
00:13:40,400 --> 00:13:43,160
BETWEEN BACTERIA AND HUMAN AND 

323
00:13:43,160 --> 00:13:46,040
MORE ACCURATELY, WE HAVE 

324
00:13:46,040 --> 00:13:47,600
EVIDENCE THAT SOME IMMUNE 

325
00:13:47,600 --> 00:13:52,000
SYSTEMS IN BACTERIA GAVE RISE, 

326
00:13:52,000 --> 00:13:53,000
EVOLUTIONARILY TO COMPETENCE OF 

327
00:13:53,000 --> 00:13:55,040
OUR OWN IMMUNE SYSTEMS AND WE 

328
00:13:55,040 --> 00:13:56,240
STARTED ASKING OURSELVES WHETHER

329
00:13:56,240 --> 00:13:58,040
THERE MIGHT BE OTHER COMPONENTS 

330
00:13:58,040 --> 00:14:01,320
OF OUR INNATE IMMUNE SYSTEM THAT

331
00:14:01,320 --> 00:14:02,960
EVOLVED FROM BACTERIA DEFENSE 

332
00:14:02,960 --> 00:14:03,960
MECHANISMS AGAINST PHAGE AND THE

333
00:14:03,960 --> 00:14:05,720
ANSWER IS YES, I'M GOING TO SHOW

334
00:14:05,720 --> 00:14:09,160
YOU A FEW EXAMPLES FOR SUCH 

335
00:14:09,160 --> 00:14:10,800
COMPETENCE.  SO FIRST OF ALL, 

336
00:14:10,800 --> 00:14:12,800
LET'S LOOK AT THIS, IT'S CALLED 

337
00:14:12,800 --> 00:14:15,960
THE PATHWAY, IT'S AN IMMUNE 

338
00:14:15,960 --> 00:14:18,400
PATHWAY IN ANIMALS THAT ALLOW 

339
00:14:18,400 --> 00:14:19,480
ANIMAL CELL TO IDENTIFY THAT 

340
00:14:19,480 --> 00:14:21,960
THEY HAVE BEEN INFECTED.  

341
00:14:21,960 --> 00:14:23,560
BASICALLY, THIS PATHWAY IS 

342
00:14:23,560 --> 00:14:25,280
PRESENT IN MANY CELLS.  NOT 

343
00:14:25,280 --> 00:14:28,040
NECESSARILY IMMUNE CELLS BUT 

344
00:14:28,040 --> 00:14:30,440
MANY CELLS IN OUR BODY AND 

345
00:14:30,440 --> 00:14:35,880
COMPRISES A PROTEIN CALLED CGAS 

346
00:14:35,880 --> 00:14:38,800
WHICH IS THE CYTOPLASMIC DNA.  

347
00:14:38,800 --> 00:14:41,320
WHICH WE KNOW IS NOT SUPPOSED TO

348
00:14:41,320 --> 00:14:45,320
BE IN THE CYTOPLASM TO HAVE DNA.

349
00:14:45,320 --> 00:14:47,160
IT'S ILLEGAL IN THE SAY TO 

350
00:14:47,160 --> 00:14:50,080
EXAMPLE.  THE DNA IS PERCEIVED 

351
00:14:50,080 --> 00:14:50,800
AS VIRAL INFECTION. 

352
00:14:50,800 --> 00:14:53,320
AND THE SENSE FOR THAT IS THE 

353
00:14:53,320 --> 00:14:58,480
PROTEIN CALLED CGAS AND THE NAME

354
00:14:58,480 --> 00:15:00,960
CGAS PRODUCES A UNIQUE 

355
00:15:00,960 --> 00:15:03,840
SIGNALLING MOLECULE WHICH IS 

356
00:15:03,840 --> 00:15:08,360
CYCLIC GMP-AMP.  THESE ARE TWO 

357
00:15:08,360 --> 00:15:10,560
NUCLEAR TYPE.  WHICH ARE BOUND 

358
00:15:10,560 --> 00:15:12,880
ONE TO EACH OTHER IN A SICKLY 

359
00:15:12,880 --> 00:15:15,200
SIZED FORM.  AND THE MOLECULE 

360
00:15:15,200 --> 00:15:16,840
ACCUMULATES IN THE CELL AND 

361
00:15:16,840 --> 00:15:19,280
BINDS ANOTHER PROTEIN CALLED 

362
00:15:19,280 --> 00:15:23,440
STING.  AN ACRONYM.  AND I 

363
00:15:23,440 --> 00:15:25,920
REALLY ENVY THE ACRONYMS.  THEY 

364
00:15:25,920 --> 00:15:28,720
ARE SUPER COOL AND INFORMATIVE 

365
00:15:28,720 --> 00:15:31,160
BECAUSE WHAT IT DOES IS IT 

366
00:15:31,160 --> 00:15:33,640
ACTIVATES AN ESCAPE THAT 

367
00:15:33,640 --> 00:15:35,880
EXPRESSES INTERFERON AND OTHER 

368
00:15:35,880 --> 00:15:37,640
INTERFERON RELATED GENES SO THIS

369
00:15:37,640 --> 00:15:39,080
PATHWAY WAS DESCRIBED ABOUT TEN 

370
00:15:39,080 --> 00:15:45,280
YEARS AGO.  2013.  IN SEMINAL 

371
00:15:45,280 --> 00:15:49,360
PAPERS.  BUT AROUND THE SAME 

372
00:15:49,360 --> 00:15:52,440
TIME, THE LAB IN HARVARD FOUND 

373
00:15:52,440 --> 00:15:54,840
THAT SOME BACTERIA CAN ALSO 

374
00:15:54,840 --> 00:16:00,360
PRODUCE THE SAME MOLECULE, 

375
00:16:00,360 --> 00:16:01,320
CYC

376
00:16:01,320 --> 00:16:07,360
CYCLIC GMP-AMP L IN QUITE 

377
00:16:07,360 --> 00:16:09,320
RECENTLY THE BIOLOGICAL ROLE WAS

378
00:16:09,320 --> 00:16:10,040
COMPLETELY UNKNOWN. 

379
00:16:10,040 --> 00:16:11,600
AND THE REASON I'M SHOWING YOU 

380
00:16:11,600 --> 00:16:14,840
THIS IS BECAUSE WHEN WE LOOK AT 

381
00:16:14,840 --> 00:16:18,720
THE PROTEIN, THE BACTERIAL 

382
00:16:18,720 --> 00:16:24,680
PROTEIN, AND WE LOOK AT THE 

383
00:16:24,680 --> 00:16:26,800
BACTERIAL SIGNALS WE SEE IT IS 

384
00:16:26,800 --> 00:16:30,240
FOUND NEXT TO CRISPR SO IN THIS 

385
00:16:30,240 --> 00:16:33,280
IT'S FOUND NEXT TO A CRISPR AND 

386
00:16:33,280 --> 00:16:35,560
IN THIS IT'S FOUND NEXT TO A 

387
00:16:35,560 --> 00:16:37,320
RESTRICTION ENZYME AND IN 

388
00:16:37,320 --> 00:16:39,400
ANOTHER BACTERIA, THE GENE IS 

389
00:16:39,400 --> 00:16:41,040
FOUND NEXT TO OTHER DEFENSE 

390
00:16:41,040 --> 00:16:42,880
SYSTEMS THAT WE CHARACTERIZE 

391
00:16:42,880 --> 00:16:44,920
RECENTLY AND THIS 

392
00:16:44,920 --> 00:16:46,800
CHARACTERIZATION WAS DONE BY 

393
00:16:46,800 --> 00:16:48,480
DEMINIMUM FROM MY LAB AND 

394
00:16:48,480 --> 00:16:55,960
MOREOVER YOU CAN SEE THAT THE

395
00:16:55,960 --> 00:16:58,040
CGAS IS PRESENT.  ONE I WILL 

396
00:16:58,040 --> 00:17:00,520
TALK ABOUT THIS, GENE, SHORTLY. 

397
00:17:00,520 --> 00:17:02,960
AND SO THE REASON -- I MEAN, THE

398
00:17:02,960 --> 00:17:05,360
FACT THAT THIS OPERATING SO 

399
00:17:05,360 --> 00:17:07,600
FREQUENTLY BEING PRESENT NEXT TO

400
00:17:07,600 --> 00:17:10,040
CRISPR AND RESTRICTION LED US TO

401
00:17:10,040 --> 00:17:14,560
THINK THAT IT MIGHT HAVE AN 

402
00:17:14,560 --> 00:17:15,840
ANTIVIRAL ACTIVITY AND AN 

403
00:17:15,840 --> 00:17:17,320
ANTIVIRAL SYSTEM IN THE 

404
00:17:17,320 --> 00:17:18,840
BACTERIAL CODE.  AS I TOLD YOU, 

405
00:17:18,840 --> 00:17:22,360
WHAT WE DO WHEN WE EXPECT IT TO 

406
00:17:22,360 --> 00:17:23,880
FUNCTION IN AN ANTIVIRAL SYSTEM 

407
00:17:23,880 --> 00:17:26,360
WE TAKE IT FROM ITS ORIGIN AND 

408
00:17:26,360 --> 00:17:28,400
CLONED IT TO E. COLI THAT 

409
00:17:28,400 --> 00:17:33,320
DOESN'T ENCODE IT.  AND THEN WE 

410
00:17:33,320 --> 00:17:38,360
INFECT THE E. COLI BY PHAGES AND

411
00:17:38,360 --> 00:17:39,800
THIS IS A TYPICAL EXPERIMENT 

412
00:17:39,800 --> 00:17:41,200
DONE IN MY LAB EVERYDAY I GUESS.

413
00:17:41,200 --> 00:17:44,080
WHAT YOU SEE HERE, THE LIGHTER 

414
00:17:44,080 --> 00:17:46,640
PARTS ARE LONG OF BACTERIA AND 

415
00:17:46,640 --> 00:17:52,040
GROWING ON A PETRI DISH AND WE 

416
00:17:52,040 --> 00:17:54,000
PUT THE FEW PHAGES HERE, TEN 

417
00:17:54,000 --> 00:17:56,080
TIMES MORE PHAGES, A HUNDRED 

418
00:17:56,080 --> 00:17:58,040
TIMES, A THOUSAND TIMES MORE AND

419
00:17:58,040 --> 00:18:02,920
MORE PHAGES IN EACH SERIAL 

420
00:18:02,920 --> 00:18:05,320
DILUTION.  WHEN ONE PHAGE 

421
00:18:05,320 --> 00:18:10,800
TOUCHES ONE BACTERIUM ON THAT 

422
00:18:10,800 --> 00:18:12,600
PLATE.  ONE HUNDRED WILL EMERGE 

423
00:18:12,600 --> 00:18:15,120
AND INFECT CELLS AND WE SEE THIS

424
00:18:15,120 --> 00:18:17,320
AREA OF CLEARANCE WHICH ARE THE 

425
00:18:17,320 --> 00:18:19,760
PLAQUES.  REGIONS WHERE THE 

426
00:18:19,760 --> 00:18:21,320
SINGLE PHAGE HAS BEEN AND KILL 

427
00:18:21,320 --> 00:18:23,000
THE BACTERIA.  WHAT YOU SEE HERE

428
00:18:23,000 --> 00:18:26,880
IS WHEN THE BACTERIA ENCODES THE

429
00:18:26,880 --> 00:18:31,480
SYSTEM NOW WE NEED TO INFECT THE

430
00:18:31,480 --> 00:18:32,360
BACTERIA WITH MORE PHAGES BUT 

431
00:18:32,360 --> 00:18:34,520
MORE PHAGES MEANING THAT THE 

432
00:18:34,520 --> 00:18:37,320
SYSTEM PROTECTS THE BACTERIA 

433
00:18:37,320 --> 00:18:40,920
AGAINST THE PHAGE.  AND THIS 

434
00:18:40,920 --> 00:18:42,720
OBSERVATION THAT WAS DONE BY 

435
00:18:42,720 --> 00:18:45,640
SARAH IN MY LAB LED US TO, YOU 

436
00:18:45,640 --> 00:18:48,400
KNOW, YOU KNOW, STARTED 

437
00:18:48,400 --> 00:18:51,200
ADVENTURE WHICH INVOLVED 

438
00:18:51,200 --> 00:18:51,840
GENETICS AND BIOCHEMISTRY AND 

439
00:18:51,840 --> 00:18:53,320
EVENTUALLY WE REALIZED OUT THE 

440
00:18:53,320 --> 00:18:55,320
SYSTEM WORKS OR AT LEAST HOW THE

441
00:18:55,320 --> 00:19:00,200
MAJOR PARTS OF IT WORKS.  SO WE 

442
00:19:00,200 --> 00:19:04,040
UNDERSTAND NOW THAT THE 

443
00:19:04,040 --> 00:19:10,000
BACTERIAL CGAS ENZYME IS 

444
00:19:10,000 --> 00:19:12,720
EXPRESSED MORE MATERIALLY.  

445
00:19:12,720 --> 00:19:15,320
PHAGE ACTIVATION ACTIVATES THIS 

446
00:19:15,320 --> 00:19:16,280
PROTEIN.  BUT IT'S NOT THE DNA 

447
00:19:16,280 --> 00:19:18,600
OF THE PHAGES THAT ACTIVATES.  

448
00:19:18,600 --> 00:19:19,600
IT'S SOMETHING ELSE WITHIN THE 

449
00:19:19,600 --> 00:19:21,160
PHAGE INFECTION.  THE DNA IS NOT

450
00:19:21,160 --> 00:19:27,440
A GOOD ACTY VA DOOR FOR SENSING 

451
00:19:27,440 --> 00:19:31,120
DNA WOULD BE FUTILE.  IT'S 

452
00:19:31,120 --> 00:19:33,240
SOMETHING ELSE THAT ACTIVATES 

453
00:19:33,240 --> 00:19:33,880
THE PROTEIN. 

454
00:19:33,880 --> 00:19:36,480
WE EXPECT IT IS PART OF THE 

455
00:19:36,480 --> 00:19:38,400
CAPSID OF THE PHAGE AND WHEN THE

456
00:19:38,400 --> 00:19:43,920
PROTEINS ACTIVATED IT PRODUCES 

457
00:19:43,920 --> 00:19:49,200
CYCLIC GMP-AMP THAT BIND AND 

458
00:19:49,200 --> 00:19:54,840
ACTIVATE IT.  AND THIS ACTIVE 

459
00:19:54,840 --> 00:19:56,560
PHOSPHOLIPASE, EACH INNER 

460
00:19:56,560 --> 00:19:58,000
MEMBRANE OF THE CELL AND KILLS 

461
00:19:58,000 --> 00:20:00,440
IT.  AND THE CELL DIES BEFORE 

462
00:20:00,440 --> 00:20:02,240
THE PHAGE REPLICATION IS 

463
00:20:02,240 --> 00:20:04,040
COMPLETE AND I KNOW THAT FOR 

464
00:20:04,040 --> 00:20:06,760
SOME PEOPLE IT SOUNDS WEIRD THAT

465
00:20:06,760 --> 00:20:08,280
BACTERIA WOULD KILL THEMSELVES 

466
00:20:08,280 --> 00:20:10,040
BEING SINGLE CELLED ORGANISMS.  

467
00:20:10,040 --> 00:20:11,880
WHY WOULD BACTERIA KILL 

468
00:20:11,880 --> 00:20:16,080
THEMSELVES AS PART OF THEIR 

469
00:20:16,080 --> 00:20:19,400
DEFENSIVE MEASURE.  SO 

470
00:20:19,400 --> 00:20:20,720
BASICALLY, VERY FREQUENTLY IN 

471
00:20:20,720 --> 00:20:23,560
NATURE BACTERIA LIVE IN COLONIES

472
00:20:23,560 --> 00:20:26,160
EITHER IN SOLID SURFACES OR IN 

473
00:20:26,160 --> 00:20:28,040
LIQUID CULTURE AND THESE 

474
00:20:28,040 --> 00:20:30,600
COLONIES ARE NEARLY SAY AYE SEW 

475
00:20:30,600 --> 00:20:32,000
GENERALIC MEANING THEY START 

476
00:20:32,000 --> 00:20:34,080
FROM ONE BACTERIA THAT 

477
00:20:34,080 --> 00:20:35,400
REPLICATED AND THEN WE HAVE A 

478
00:20:35,400 --> 00:20:36,720
SMALL COLONY OF BACTERIA. 

479
00:20:36,720 --> 00:20:40,760
AND PHAGES DON'T HAVE A WAY TO 

480
00:20:40,760 --> 00:20:43,440
BE MOBILE.  SO THE INFECTION 

481
00:20:43,440 --> 00:20:45,880
USUALLY STARTS BY INFUSION OF A 

482
00:20:45,880 --> 00:20:48,120
SINGLE PHAGE IN THAT COLONY AND 

483
00:20:48,120 --> 00:20:49,320
THIS PHAGE REPLICATES WITHIN 

484
00:20:49,320 --> 00:20:52,800
THAT BACTERIUM AND THEN AFTER 

485
00:20:52,800 --> 00:20:55,080
AWHILE, PHAGE PARTICLES EMERGE 

486
00:20:55,080 --> 00:20:58,040
FROM THE BACTERIUM AND 

487
00:20:58,040 --> 00:20:59,200
EVENTUALLY, THE ENTIRE COLONY 

488
00:20:59,200 --> 00:21:02,800
WILL DEMISE, BUT IF THE BACTERIA

489
00:21:02,800 --> 00:21:04,040
HAVE AN ABILITY TO SENSE THAT 

490
00:21:04,040 --> 00:21:06,400
THEY HAVE BEEN INFECTED, AND 

491
00:21:06,400 --> 00:21:08,080
THEN KILL THEMSELVES THE SINGLE 

492
00:21:08,080 --> 00:21:11,240
CELL THAT IS INFECTED WOULD KILL

493
00:21:11,240 --> 00:21:13,800
ITSELF BEFORE THE CYCLE IS 

494
00:21:13,800 --> 00:21:15,040
COMPLETE THEN ONLY ONE CELL IS 

495
00:21:15,040 --> 00:21:17,320
LOST AND THE COLONY SURVIVES SO 

496
00:21:17,320 --> 00:21:21,320
BASICALLY GENETICALLY SPEAK, 

497
00:21:21,320 --> 00:21:23,600
EVOLUTION PREFERS THAT.  AND 

498
00:21:23,600 --> 00:21:26,400
WE -- NOW UNDERSTAND THAT MOST 

499
00:21:26,400 --> 00:21:29,560
BACTERIA IN NATURE HAVE AT LEAST

500
00:21:29,560 --> 00:21:33,320
ONE DEFENSE SYSTEM THAT WORKS 

501
00:21:33,320 --> 00:21:36,280
THIS WAY.  MEANING THAT WE'LL 

502
00:21:36,280 --> 00:21:37,520
SENSE THE PHASE INFECTION AND 

503
00:21:37,520 --> 00:21:39,440
THEN KILL THE CELL.  THERE ARE 

504
00:21:39,440 --> 00:21:41,040
MULTIPLE PRINCIPLES THAT GOVERN 

505
00:21:41,040 --> 00:21:42,960
DEFENSE -- THAT WORKS THIS WAY. 

506
00:21:42,960 --> 00:21:46,040
ONE OF THEM IS THAT THESE 

507
00:21:46,040 --> 00:21:48,280
SYSTEMS USUALLY BECOME ACTIVE 

508
00:21:48,280 --> 00:21:49,280
RELATIVELY LATE IN THE INFECTION

509
00:21:49,280 --> 00:21:52,480
CYCLE OF THE PHAGE SO THAT 

510
00:21:52,480 --> 00:21:53,920
DEFENSE SYSTEMS THAT CAN 

511
00:21:53,920 --> 00:21:56,040
OVERCOME THE PHAGE WITHOUT 

512
00:21:56,040 --> 00:21:58,440
KILLING THE CELL COULD WORK 

513
00:21:58,440 --> 00:21:59,320
FIRST LIKE CRISPR SHOULD BE ABLE

514
00:21:59,320 --> 00:22:01,280
TO WORK FIRST.  IF THEY DON'T 

515
00:22:01,280 --> 00:22:03,400
WORK ONLY THEN THE OTHER DEFENSE

516
00:22:03,400 --> 00:22:05,120
SYSTEMS THAT KILL THE CELL COME 

517
00:22:05,120 --> 00:22:07,600
INTO ACTION.  SO WE SEE THAT 

518
00:22:07,600 --> 00:22:09,320
VERY FREQUENTLY.  SO AROUND THE 

519
00:22:09,320 --> 00:22:13,320
SAME TIME WE DISCOVER THESE CGAS

520
00:22:13,320 --> 00:22:17,320
SYSTEM IN BACTERIA.  PHILLIP AND

521
00:22:17,320 --> 00:22:19,520
AARON FROM HARVARD MEDICAL 

522
00:22:19,520 --> 00:22:22,080
SCHOOL, THEY FOUND THAT THE 

523
00:22:22,080 --> 00:22:25,800
BACTERIA CGAS IS JUST ONE 

524
00:22:25,800 --> 00:22:27,200
REPRESENTATION OF A LARGER 

525
00:22:27,200 --> 00:22:29,920
FAMILY OF PROTEINS THAT PRODUCE 

526
00:22:29,920 --> 00:22:31,720
THIS PROTOTYPE.  SO WHAT THEY 

527
00:22:31,720 --> 00:22:33,320
FOUND IS THAT THIS REPRESENTS 

528
00:22:33,320 --> 00:22:35,200
THE FAMILY TREE.  THE TREE OF 

529
00:22:35,200 --> 00:22:39,960
THIS FAMILY OF ENZYMES, THE 

530
00:22:39,960 --> 00:22:41,680
CGAS-LIKE ENZYMES.  SOME OF THEM

531
00:22:41,680 --> 00:22:46,040
PRODUCE CYCLIC GMP BUT OTHER 

532
00:22:46,040 --> 00:22:48,320
PRODUCE OTHER MOLECULES LIKE 

533
00:22:48,320 --> 00:22:53,040
CYCLIC AMP OR CYCLIC UU OR 

534
00:22:53,040 --> 00:22:56,560
CYCLIC TRINUCLEOTIDES AND IN MY 

535
00:22:56,560 --> 00:22:57,800
LAB LOOKED AT WHETHER THESE 

536
00:22:57,800 --> 00:23:00,040
FAMILIES OF PROTEINS FREQUENTLY 

537
00:23:00,040 --> 00:23:01,320
OCCUR NEXT TO KNOWN DEFENSE 

538
00:23:01,320 --> 00:23:05,760
SYSTEMS SO IN 64% OF THE CASES, 

539
00:23:05,760 --> 00:23:07,880
GENES THAT PRODUCE PROTEINS THAT

540
00:23:07,880 --> 00:23:11,600
PRODUCE GMP-AMP, THE GENES WERE 

541
00:23:11,600 --> 00:23:14,200
NEXT TO SYSTEMS BUT THIS WAS 

542
00:23:14,200 --> 00:23:14,840
ALSO TRUE FOR OTHER PROTEINS 

543
00:23:14,840 --> 00:23:17,920
FROM THIS FAMILY.  AND THIS LED 

544
00:23:17,920 --> 00:23:21,040
US TO REALIZE THAT ALL THESE 

545
00:23:21,040 --> 00:23:22,040
PROTEINS PARTICIPATE IN DEFENSE 

546
00:23:22,040 --> 00:23:24,720
AGAINST PHAGE AND THAT WHAT WE 

547
00:23:24,720 --> 00:23:26,920
ACTUALLY SEE AND THIS IS -- 

548
00:23:26,920 --> 00:23:29,760
FOUND IN -- BETWEEN 13-15% OF 

549
00:23:29,760 --> 00:23:32,280
THOSE IN THE GENENOMAS WE NOW 

550
00:23:32,280 --> 00:23:35,040
UNDERSTAND THAT THERE IS A LARGE

551
00:23:35,040 --> 00:23:37,320
DIVERSITY OF ANTIPHAGE 

552
00:23:37,320 --> 00:23:39,280
SIGNALLING SYSTEMS IN THESE 

553
00:23:39,280 --> 00:23:40,760
GENOMES AND THESE HAVE A 

554
00:23:40,760 --> 00:23:42,160
UNIFYING PRINCIPLE OF ACTIVITY. 

555
00:23:42,160 --> 00:23:44,040
THERE'S ALWAYS A PROTEIN FROM 

556
00:23:44,040 --> 00:23:45,520
THE CGAS FAMILY THAT RECOGNIZES 

557
00:23:45,520 --> 00:23:47,480
PHAGE INFECTION AND PRODUCES A 

558
00:23:47,480 --> 00:23:49,040
SIGNALLING MOLECULE.  THE 

559
00:23:49,040 --> 00:23:50,160
SIGNALLING MOLECULE COULD BE 

560
00:23:50,160 --> 00:23:53,200
CYCLIC GMP-AMP THAT CAN BE 

561
00:23:53,200 --> 00:23:54,920
ANOTHER KIND OF SIGNALLING 

562
00:23:54,920 --> 00:23:57,200
MOLECULE AND BINDS AN INFECTOR 

563
00:23:57,200 --> 00:23:59,840
THAT KILLS THE CELL THAT COULD 

564
00:23:59,840 --> 00:24:01,880
BE A PHOSPHOLIPASE BUT COULD 

565
00:24:01,880 --> 00:24:05,880
ALSO BE A DNA AND THE NUCLEASE 

566
00:24:05,880 --> 00:24:07,920
THAT DEGRADES THE BACTERIUM AND 

567
00:24:07,920 --> 00:24:09,400
OF THE PHAGE TO KILL BOTH OF 

568
00:24:09,400 --> 00:24:13,320
THEM DURING INFECTION.  AND 

569
00:24:13,320 --> 00:24:17,560
COULD ALSO BE THE PROTEINS THAT 

570
00:24:17,560 --> 00:24:19,440
DEPOLARIZE THE MEMBRANE AND WE 

571
00:24:19,440 --> 00:24:21,680
NOW HAVE PAPER COMING OUT 

572
00:24:21,680 --> 00:24:23,480
SHOWING THAT SOME EFFECTORS 

573
00:24:23,480 --> 00:24:25,600
DEGRADE THE ATP POOL FROM THE 

574
00:24:25,600 --> 00:24:27,440
CELL DURING INFECTION TO ABORT 

575
00:24:27,440 --> 00:24:29,120
THE REPLICATION OF THE PHAGE AND

576
00:24:29,120 --> 00:24:31,240
WE CALL THIS FAMILY OF 

577
00:24:31,240 --> 00:24:33,240
SIGNALLING SYSTEM, WE CALL THEM 

578
00:24:33,240 --> 00:24:36,320
IN THE UNIFYING NAME, CALLED 

579
00:24:36,320 --> 00:24:39,680
CBAS WHICH IS THE ACRONYM OF THE

580
00:24:39,680 --> 00:24:42,560
NUCLEAR BASE ANTIPHAGING 

581
00:24:42,560 --> 00:24:45,320
SYSTEMS.  SO AGAIN TO PUT -- TO 

582
00:24:45,320 --> 00:24:50,400
PUT THE PRINCIPLE OF CBASS INTO 

583
00:24:50,400 --> 00:24:53,560
WITHIN -- BLUE COLLARED FIG 

584
00:24:53,560 --> 00:24:55,000
INSTEAD OF THE RED COLORS. 

585
00:24:55,000 --> 00:24:57,000
THE UNIFYING PRINCIPLE IS 

586
00:24:57,000 --> 00:24:58,200
THERE'S AN ENZYME THAT 

587
00:24:58,200 --> 00:25:01,320
RECOGNIZES PHAGE.  PRODUCES A 

588
00:25:01,320 --> 00:25:03,360
SIGNALLING MOLECULE THAT BINDS 

589
00:25:03,360 --> 00:25:05,040
AN EFFECTOR THAT KILLS THE 

590
00:25:05,040 --> 00:25:07,680
CELLS.  WE IDENTIFIED CBASS 

591
00:25:07,680 --> 00:25:10,040
WHICH IS FOUND WITHIN 13-15% OF 

592
00:25:10,040 --> 00:25:12,560
GENOMES BUT LATER ON WE FOUND 

593
00:25:12,560 --> 00:25:13,680
THAT THERE ARE ADDITIONAL 

594
00:25:13,680 --> 00:25:15,960
FAMILIES OF IMMUNE SYSTEMS THAT 

595
00:25:15,960 --> 00:25:17,480
WORK ACCORDING TO THE SAME 

596
00:25:17,480 --> 00:25:20,560
PRINCIPLE.  SO ONE OF THEM WE 

597
00:25:20,560 --> 00:25:24,200
CALL PIXAR AND THIS IS A STUDY 

598
00:25:24,200 --> 00:25:28,040
DONE WITH PHILLIP FROM HIS LAB 

599
00:25:28,040 --> 00:25:30,360
AND PH.D. STUDENT FROM MY LAB 

600
00:25:30,360 --> 00:25:33,200
AND WE FOUND THIS FAMILY PRODUCE

601
00:25:33,200 --> 00:25:38,800
CYCLIC CMP OR SO MONO NUCLEOTIDE

602
00:25:38,800 --> 00:25:41,000
THAT ACTIVATE AN EFFECTOR 

603
00:25:41,000 --> 00:25:42,560
PROTEIN AND THEN WE FOUND 

604
00:25:42,560 --> 00:25:44,080
ANOTHER FAMILY OF IMMUNE SYSTEMS

605
00:25:44,080 --> 00:25:46,720
THAT WORK IN THE SAME PRINCIPLE.

606
00:25:46,720 --> 00:25:48,760
THIS IS A TWO AREA SYSTEM IN 

607
00:25:48,760 --> 00:25:52,920
WHICH TWO MAIN PROTEINS PRODUCE 

608
00:25:52,920 --> 00:25:55,080
CYCLIC ATP RIBOSE ISOMER WHICH 

609
00:25:55,080 --> 00:25:58,240
WE WILL NOT TALK MUCH ABOUT 

610
00:25:58,240 --> 00:25:59,800
HERE.  SO ALTOGETHER, MORE THAN 

611
00:25:59,800 --> 00:26:03,160
20% OF ALL BACTERIA IN NATURE OR

612
00:26:03,160 --> 00:26:05,320
AT LEAST ALL THE BACTERIA FOR 

613
00:26:05,320 --> 00:26:06,640
WHICH WE HAVE THE GENOME 

614
00:26:06,640 --> 00:26:07,960
SEQUENCES HAVE AT LEAST ONE OF 

615
00:26:07,960 --> 00:26:09,880
THESE DEFENSE SYSTEMS.  VERY 

616
00:26:09,880 --> 00:26:13,480
ABUNDANT DEFENSE SYSTEMS IN 

617
00:26:13,480 --> 00:26:22,800
MICROBIAL GENES.  HOW CAN PHAGES

618
00:26:22,800 --> 00:26:26,800
OVERCOME THAT?  CAN PHAGES 

619
00:26:26,800 --> 00:26:28,080
DEFEND BACTERIA AND APPARENTLY 

620
00:26:28,080 --> 00:26:30,760
THEY DON'T STUDYINGS FROM OUR 

621
00:26:30,760 --> 00:26:33,560
COLLEAGUE, AS YOU CAN SEE WE 

622
00:26:33,560 --> 00:26:38,480
HAVE A VERY DEEP DEEP 

623
00:26:38,480 --> 00:26:40,040
UNDERSTANDING WITH PHILLIP.  THE

624
00:26:40,040 --> 00:26:43,640
LAB HAS DISCOVERED ENZYMES THAT 

625
00:26:43,640 --> 00:26:46,040
SOME PHAGES BRING THAT CLEAVE 

626
00:26:46,040 --> 00:26:49,280
THE SIGNALLING MOLECULE AND 

627
00:26:49,280 --> 00:26:52,080
INACTIVATE THEM ESCAPING DEFENSE

628
00:26:52,080 --> 00:26:56,320
BY PHAGES AND A SIMILAR KIND OF 

629
00:26:56,320 --> 00:26:58,080
CLEAVING ENZYMES WERE FOUND ALSO

630
00:26:58,080 --> 00:27:01,760
IN VIRUSES THAT INFECT US.  SOME

631
00:27:01,760 --> 00:27:04,080
WILL HAVE AN ENZYME THAT CLEAVES

632
00:27:04,080 --> 00:27:06,560
THE MOLECULE OF HUMANS.  

633
00:27:06,560 --> 00:27:08,200
SOMETHING THAT WAS ALSO 

634
00:27:08,200 --> 00:27:09,400
DISCOVERED BY PHILLIP AND IN A 

635
00:27:09,400 --> 00:27:13,000
MORE RECENT STUDY TOGETHER WITH 

636
00:27:13,000 --> 00:27:15,160
PHILLIP LED BY SOMEONE FROM MY 

637
00:27:15,160 --> 00:27:17,640
LAB AND ALAN FROM PHILLIP'S LAB 

638
00:27:17,640 --> 00:27:21,120
WE FOUND THAT OTHER ANTIDEFENSE 

639
00:27:21,120 --> 00:27:24,160
PROTEINS, PHAGES L BIND THE 

640
00:27:24,160 --> 00:27:26,480
SIGNALLING MOLECULE VERY TIGHTLY

641
00:27:26,480 --> 00:27:27,840
AND SEQUESTER IT AND THEREBY, 

642
00:27:27,840 --> 00:27:29,360
AGAIN, NOT ALLOWING THE 

643
00:27:29,360 --> 00:27:31,520
SIGNALLING MOLECULE TO BIND THE 

644
00:27:31,520 --> 00:27:33,320
EFFECTOR PROTEIN AND SAVING THE 

645
00:27:33,320 --> 00:27:39,480
PHAGE FROM THE DEFENSE SYSTEM.  

646
00:27:39,480 --> 00:27:42,920
ALL RIGHT SO LET'S GO BACK TO 

647
00:27:42,920 --> 00:27:44,520
THE CELL AUTONOMOUS IMMUNE 

648
00:27:44,520 --> 00:27:46,400
SYSTEM THAT OUR OWN BODY HAS.  

649
00:27:46,400 --> 00:27:48,320
CELLS IN OUR BODY HAVE THE 

650
00:27:48,320 --> 00:27:49,320
ABILITY TO SENSE THAT THEY HAVE 

651
00:27:49,320 --> 00:27:52,040
BEEN INFECTED AND I'M NOT 

652
00:27:52,040 --> 00:27:54,080
TALKING ABOUT IMMUNE CELLS OR T 

653
00:27:54,080 --> 00:27:56,880
CELLS OR B CELLS BUT ANY KIND OF

654
00:27:56,880 --> 00:28:00,080
CELL IN OUR BODY HAS A CELL 

655
00:28:00,080 --> 00:28:00,960
AUTONOMOUS INNATE IMMUNE SYSTEM 

656
00:28:00,960 --> 00:28:02,720
THAT ALLOW THE CELL TO IDENTIFY 

657
00:28:02,720 --> 00:28:04,960
THAT IT HAS BEEN INFECTED AND 

658
00:28:04,960 --> 00:28:05,880
THEN THROUGH SOME KIND OF 

659
00:28:05,880 --> 00:28:08,800
SIGNALLING CASCADE TO ACTIVATE 

660
00:28:08,800 --> 00:28:09,880
FIRST OF ALL SECRETION OF 

661
00:28:09,880 --> 00:28:11,560
INTERFERON AND SECOND OF ALL THE

662
00:28:11,560 --> 00:28:13,160
PRODUCTION OF EFFECTORS WITHIN 

663
00:28:13,160 --> 00:28:15,400
THE CELL THAT ALLOW THE CELL TO 

664
00:28:15,400 --> 00:28:16,480
FIGHT AGAINST THE INFECTION OR 

665
00:28:16,480 --> 00:28:19,800
AT LEAST THE CELL TRIES TO FIGHT

666
00:28:19,800 --> 00:28:20,840
AGAINST THE INFECTION BEFORE IT 

667
00:28:20,840 --> 00:28:24,480
SPREADS.  AS I TOLD YOU, SOME OF

668
00:28:24,480 --> 00:28:27,000
THE SENSORS ARE CONSERVED 

669
00:28:27,000 --> 00:28:29,040
BETWEEN BACTERIA AND HUMAN AND 

670
00:28:29,040 --> 00:28:31,680
THIS IS NOT THE ONLY THING 

671
00:28:31,680 --> 00:28:34,080
CONSERVED IN THE INNATE IMMUNE 

672
00:28:34,080 --> 00:28:36,280
SYSTEM OF HUMANS.  AM GOING TO 

673
00:28:36,280 --> 00:28:38,680
SHOW YOU ANOTHER STORY OF A 

674
00:28:38,680 --> 00:28:40,360
PROTEIN CALLED VIE WRITTEN WHICH

675
00:28:40,360 --> 00:28:43,600
IS PRODUCED BY INFECTED CELLS 

676
00:28:43,600 --> 00:28:45,880
AFTER THEY SENSE THEY HAVE BEEN 

677
00:28:45,880 --> 00:28:46,720
INFECTED AND HAS ANTIVIRAL 

678
00:28:46,720 --> 00:28:48,680
CAPACITY.  SO IT WAS KNOWN FOR 

679
00:28:48,680 --> 00:28:51,360
MANY YEARS I THINK MAYBE TWO OR 

680
00:28:51,360 --> 00:28:53,800
THREE DECADES THAT THE VIPER RIN

681
00:28:53,800 --> 00:28:57,320
PROTEIN.  IT'S ANOTHER CALL 

682
00:28:57,320 --> 00:28:58,840
ACRONYM VIRUS INHIBITOR PROTEIN 

683
00:28:58,840 --> 00:29:00,720
SOMETHING SOMETHING.  NICE 

684
00:29:00,720 --> 00:29:02,200
ACRONYM.  AND IT WAS KNOWN THAT 

685
00:29:02,200 --> 00:29:03,600
IT PROTECTS CELLS FROM 

686
00:29:03,600 --> 00:29:05,240
INFECTION, IF YOU OVER EXPRESS 

687
00:29:05,240 --> 00:29:08,680
IT CELLS ARE LESS INCLINED TO BE

688
00:29:08,680 --> 00:29:10,080
INFECTED BY SEVERAL DIFFERENT 

689
00:29:10,080 --> 00:29:11,280
FAMILIES OF VIRUS BUT ONLY ABOUT

690
00:29:11,280 --> 00:29:12,720
FIVE YEARS AGO THE MECHANISM OF 

691
00:29:12,720 --> 00:29:17,320
ACTION WAS DISCOVERED BY A GR

692
00:29:17,320 --> 00:29:19,960
GROUP -- A CLEVER GROUP IN MOUNT

693
00:29:19,960 --> 00:29:21,960
SINAI I THINK AND WHAT THEY 

694
00:29:21,960 --> 00:29:24,160
FOUND IS THAT THE VIPER RIN IS 

695
00:29:24,160 --> 00:29:28,880
AN ENZYME THAT TAKES THE 

696
00:29:28,880 --> 00:29:31,480
NUCLEOTIDE AND MODIFIES IT BY 

697
00:29:31,480 --> 00:29:33,320
REMOVING THE THREE PRIME OH AND 

698
00:29:33,320 --> 00:29:35,360
INSTALLING A DOUBLE BOND INSTEAD

699
00:29:35,360 --> 00:29:38,880
AND NOW INSTEAD OF A REGULAR 

700
00:29:38,880 --> 00:29:41,320
NUCLEOTIDE, THIS MODIFIED 

701
00:29:41,320 --> 00:29:45,320
NUCLEOTIDE IS A POISON FOR THE 

702
00:29:45,320 --> 00:29:46,320
VIRUS REPLICATION AND THE REASON

703
00:29:46,320 --> 00:29:48,920
IT FORMS A POISON WHICH S WHEN 

704
00:29:48,920 --> 00:29:53,320
THE VIRUS TAKES THE NUCLEOTIDE 

705
00:29:53,320 --> 00:29:59,800
TO POLYMERIZE ITS NASCENT CHAIN 

706
00:29:59,800 --> 00:30:01,520
YOU TAKE THE STRAND AND PUT IT 

707
00:30:01,520 --> 00:30:02,960
AGAINST THE TEMPLATE STRAND.  

708
00:30:02,960 --> 00:30:05,280
YOU REMOVE THE TWO PHOSPHATES 

709
00:30:05,280 --> 00:30:08,760
AND THE LAST PHOSPHATES YOU 

710
00:30:08,760 --> 00:30:09,320
ATTACH IT TO THE PREVIOUS 

711
00:30:09,320 --> 00:30:12,760
NUCLEOTIDE SO IF THE VIRUS HAS 

712
00:30:12,760 --> 00:30:16,440
TAKEN THE MODIFIED NUCLEOTIDE 

713
00:30:16,440 --> 00:30:18,640
THERE'S NOW NONE.  AND THE VIRUS

714
00:30:18,640 --> 00:30:21,320
CANNOT CONTINUE TO REPLICATE ITS

715
00:30:21,320 --> 00:30:25,320
GENOME AND THIS NUCLEOTIDE IS 

716
00:30:25,320 --> 00:30:27,240
NON TOIKSIC TO HUMAN CELLS MOST 

717
00:30:27,240 --> 00:30:28,800
PROBABLY BECAUSE THE IT DOESN'T 

718
00:30:28,800 --> 00:30:31,080
NEED TO WORK AS FAST AS THE 

719
00:30:31,080 --> 00:30:34,080
POLYMERASE OF THE VIRUS AND IT 

720
00:30:34,080 --> 00:30:35,600
CAN BE MODIFIED.  THE REASON I'M

721
00:30:35,600 --> 00:30:40,040
TELLING YOU THIS IS BECAUSE WE 

722
00:30:40,040 --> 00:30:44,280
FOUND THIS PROTEIN IN BACTERIA. 

723
00:30:44,280 --> 00:30:46,080
THIS WAS FOUND BY A POSTDOC IN 

724
00:30:46,080 --> 00:30:49,360
MY LAB.  SHE HAS HER OWN LAB, A 

725
00:30:49,360 --> 00:30:50,680
VERY SUCCESSFUL LAB AT AN 

726
00:30:50,680 --> 00:30:54,520
INSTITUTE NOW AND WHAT SHE FOUND

727
00:30:54,520 --> 00:30:57,320
IS THAT THERE ARE LOADS OF THE 

728
00:30:57,320 --> 00:30:58,960
VIPER RIN.  THESE ARE FOUND.  

729
00:30:58,960 --> 00:31:00,800
AND THESE ARE VERY, VERY 

730
00:31:00,800 --> 00:31:05,320
FREQUENTLY FOUND NEXT TO CRISPR 

731
00:31:05,320 --> 00:31:07,040
AND ENZYMES.  WE THOUGHT AS YOU 

732
00:31:07,040 --> 00:31:09,320
KNOW NOW, THIS TELLS US THAT 

733
00:31:09,320 --> 00:31:13,160
THIS PROTEIN HAS A FUNCTION, HAS

734
00:31:13,160 --> 00:31:14,280
AN ANTIVIRAL FUNCTION IN 

735
00:31:14,280 --> 00:31:16,080
BACTERIA AS WELL SO, AGAIN, WE 

736
00:31:16,080 --> 00:31:18,160
TOOK A BUNCH OF THESE PROTEINS, 

737
00:31:18,160 --> 00:31:20,000
WE CLONED THEM IN BACTERIA.  IN 

738
00:31:20,000 --> 00:31:24,080
THIS CASE I'M SHOWING YOU T 7.  

739
00:31:24,080 --> 00:31:28,080
ONE, TEN, THESE ARE HUGE 

740
00:31:28,080 --> 00:31:32,160
PLAQUES.  T 7 HAS A SHORT CYCLE.

741
00:31:32,160 --> 00:31:35,760
THAT'S WHY IT FORMS A HUGE 

742
00:31:35,760 --> 00:31:36,800
PLAQUE AFTER OVERNIGHT. 

743
00:31:36,800 --> 00:31:40,960
AND WHAT YOU SEE IS THAT WHEN WE

744
00:31:40,960 --> 00:31:44,240
EXPRESS -- THE VIPER RIN WITHIN 

745
00:31:44,240 --> 00:31:49,320
E. COLI CELLS WE SEE MUCH FEWER 

746
00:31:49,320 --> 00:31:56,120
PLAQUES.  THIS TOOK US TO 

747
00:31:56,120 --> 00:32:00,320
ADVENTURE THAT INVOLVES A LOT OF

748
00:32:00,320 --> 00:32:04,400
CHEMISTRY.  AND EVENTUALLY WHAT 

749
00:32:04,400 --> 00:32:06,360
AUDE FOUND WAS THIS PRODUCED A 

750
00:32:06,360 --> 00:32:08,400
FAMILY OF MOLECULES.  SOME OF 

751
00:32:08,400 --> 00:32:10,800
THEM ARE THE SAME LIKE THE HUMAN

752
00:32:10,800 --> 00:32:15,840
MOLECULE WHILE OTHERS ARE BASED 

753
00:32:15,840 --> 00:32:17,040
ON A DIFFERENT NUCLEOTNUCLEOTID 

754
00:32:17,040 --> 00:32:19,400
CASES THE OH FROM THE 3 PRIME 

755
00:32:19,400 --> 00:32:21,320
END IS DEHYDRATED AND A DOUBLE 

756
00:32:21,320 --> 00:32:24,760
BOND BECOMES -- IS INSTALLED AND

757
00:32:24,760 --> 00:32:29,320
POISONS THE PHAGE REPLICATION.  

758
00:32:29,320 --> 00:32:33,320
SO WHEN WE TAKE ALL THE 

759
00:32:33,320 --> 00:32:35,960
BACTERIAL ENZYMES AND PUT THEM 

760
00:32:35,960 --> 00:32:39,720
ON THE TREE WHAT WE SEE IS THAT 

761
00:32:39,720 --> 00:32:43,440
EWE SEE MULTIPLE CLAIFS THAT ARE

762
00:32:43,440 --> 00:32:45,320
FORMED.  SOME OF THEM HAVE MORE 

763
00:32:45,320 --> 00:32:47,440
TENDENCY TO PRODUCE THE OTHER 

764
00:32:47,440 --> 00:32:48,600
NUCLEOTIDES AND WHEN WE ADD TO 

765
00:32:48,600 --> 00:32:52,480
THIS TREE, THE SEQUENCES OF ALL 

766
00:32:52,480 --> 00:32:59,480
THE YOU KARYOTIC.  WE SEE ALL OF

767
00:32:59,480 --> 00:33:01,760
THEM CLUSTER ON A SINGLE CLAYED 

768
00:33:01,760 --> 00:33:04,000
THAT EMERGES FROM THE CLAYED 

769
00:33:04,000 --> 00:33:05,360
THAT PRODUCES THE CTP AND THAT 

770
00:33:05,360 --> 00:33:09,360
IS MOSTLY UNREACHED.  SO WE 

771
00:33:09,360 --> 00:33:12,760
THINK WE HAVE PRETTY STRONG 

772
00:33:12,760 --> 00:33:14,120
REASONS TO BELIEVE NOW THAT 

773
00:33:14,120 --> 00:33:16,080
THERE HAS BEEN A SINGLE 

774
00:33:16,080 --> 00:33:18,360
ACQUISITION EVENT IN THE VERY 

775
00:33:18,360 --> 00:33:21,320
EVOLUTION OF EUKARYOTES WHERE 

776
00:33:21,320 --> 00:33:25,280
THE EARLY EUCARYOTE ACQUIRED ONE

777
00:33:25,280 --> 00:33:27,720
VIPER RIN FROM BACTERIA AND 

778
00:33:27,720 --> 00:33:29,920
STARTED ON THIS ACQUISITION AND 

779
00:33:29,920 --> 00:33:31,640
LED TO WHAT WE SEE TODAY IN 

780
00:33:31,640 --> 00:33:33,440
HUMANS AND OTHER EUKARYOTES.  

781
00:33:33,440 --> 00:33:35,280
ONE THING THAT REALLY -- AGAIN, 

782
00:33:35,280 --> 00:33:37,320
THERE ARE MANY SURPRISES IN THIS

783
00:33:37,320 --> 00:33:38,760
STORY.  THAT WAS ANOTHER 

784
00:33:38,760 --> 00:33:40,680
SURPRISE THAT BACTERIA CAN 

785
00:33:40,680 --> 00:33:44,840
PRODUCE ANTIVIRAL MOLECULES.  

786
00:33:44,840 --> 00:33:49,240
WE'RE USED TO THINKING ABOUT 

787
00:33:49,240 --> 00:33:51,200
BACTERIA HAS A SOURCE MORE 

788
00:33:51,200 --> 00:33:53,840
MOLECULES BUT THEY MOUSSE MORE 

789
00:33:53,840 --> 00:33:54,640
MOLECULES TO PROTECT THEMSELVES 

790
00:33:54,640 --> 00:33:56,840
FROM PHAGES.  THESE OF YOU WHO 

791
00:33:56,840 --> 00:33:59,160
UNDERSTAND HOW ANTIVIRALS WORK, 

792
00:33:59,160 --> 00:34:01,400
REALIZE THAT IN MANY CASES, 

793
00:34:01,400 --> 00:34:02,880
ANTIVIRALS THAT WE USE AGAINST 

794
00:34:02,880 --> 00:34:06,640
VIRUSES THAT INFECT US ARE ALSO 

795
00:34:06,640 --> 00:34:08,960
BASED ON MODIFIED NUCLEOTIDES.  

796
00:34:08,960 --> 00:34:11,320
THIS MOLECULE IN THE MIDDLE IS 

797
00:34:11,320 --> 00:34:13,520
PART OF THE THREE DRUG COCKTAIL 

798
00:34:13,520 --> 00:34:15,760
THAT PEOPLE TAKE AGAINST HIV.  

799
00:34:15,760 --> 00:34:18,600
AND THIS IS A NUCLEOTIDE THAT 

800
00:34:18,600 --> 00:34:20,640
HAS INSTEAD OF THE THREE PRIME 

801
00:34:20,640 --> 00:34:23,000
OH HAS THREE NITROGENS.  THIS IS

802
00:34:23,000 --> 00:34:25,000
THE DRUG THAT PEOPLE TAKE 

803
00:34:25,000 --> 00:34:25,960
AGAINST HERPES VIRUSES THAT YOU 

804
00:34:25,960 --> 00:34:28,720
PUT ON YOUR LIPS, THIS OINTMENT 

805
00:34:28,720 --> 00:34:32,640
WHEN YOU HAVE HERPES, THIS IS A 

806
00:34:32,640 --> 00:34:33,320
MODIFY NUCLEOTIDE THAT BLOCKS 

807
00:34:33,320 --> 00:34:35,880
THE BOTTOM PART OF THE VIRALS.  

808
00:34:35,880 --> 00:34:38,640
THIS WORKS THE SAME WAY.  IT 

809
00:34:38,640 --> 00:34:45,320
TAKES IT IN AND SO WE THINK NOW 

810
00:34:45,320 --> 00:34:47,800
REALIZING THAT BACTERIA PRODUCE 

811
00:34:47,800 --> 00:34:50,160
AGAINST PHAGES WE WONDER WHETHER

812
00:34:50,160 --> 00:34:51,240
THESE MOLECULES CAN WORK AGAINST

813
00:34:51,240 --> 00:34:52,360
VIRUSES THAT INFECT US AND WE 

814
00:34:52,360 --> 00:34:54,640
ARE TRYING TO SEE WHETHER THEY 

815
00:34:54,640 --> 00:34:59,800
CAN BE NEW DRUGS IN THE FUTURE. 

816
00:34:59,800 --> 00:35:01,040
HERE'S ANOTHER DEFENSE SYSTEM 

817
00:35:01,040 --> 00:35:08,480
THAT IS VERY, VERY -- STUDIED 

818
00:35:08,480 --> 00:35:10,920
ONE DAY IN HUMANS.  SO IN ANIMAL

819
00:35:10,920 --> 00:35:13,920
CELLS INCLUDING IN OUR OWN CELLS

820
00:35:13,920 --> 00:35:18,240
THERE IS A SYSTEM THAT, OR AN 

821
00:35:18,240 --> 00:35:20,920
APPARATUS CALLED THE INFLAM MA 

822
00:35:20,920 --> 00:35:22,840
SOME THAT RECOGNIZES INFECTION 

823
00:35:22,840 --> 00:35:26,840
AND ONCE THE INFECTION IS 

824
00:35:26,840 --> 00:35:29,200
RECOGNIZED.  PROTEINS CALLED CAS

825
00:35:29,200 --> 00:35:31,640
PACES BECOME ACTIVATED. 

826
00:35:31,640 --> 00:35:37,280
AND THIS CAS PACE IS BY DOING 

827
00:35:37,280 --> 00:35:40,600
SOME CLEAVAGE EVENT ON A PROTEIN

828
00:35:40,600 --> 00:35:42,680
CALLED GAS DER MIN, ONCE IT'S 

829
00:35:42,680 --> 00:35:44,920
CLEAVED BECOMES ACTIVITY AND 

830
00:35:44,920 --> 00:35:47,120
MAKES A GIANT PORE IN THE CELL 

831
00:35:47,120 --> 00:35:50,200
MEMBRANE AND BASICALLY THE CELL 

832
00:35:50,200 --> 00:35:51,360
LEAKS OUT AND DIES AT THE SAME 

833
00:35:51,360 --> 00:35:57,320
TIME THAT THE CELL DIES IT 

834
00:35:57,320 --> 00:36:01,200
SECRETES INTERNAL TO THE SITE OF

835
00:36:01,200 --> 00:36:04,360
THE INFECTION AND THAT'S WHY 

836
00:36:04,360 --> 00:36:08,160
THIS IS CALLED PYRO TO SIS 

837
00:36:08,160 --> 00:36:11,560
BECAUSE IT'S DEATH THAT CAUSES 

838
00:36:11,560 --> 00:36:13,440
INFECTION.  IN MY LAB, WAS 

839
00:36:13,440 --> 00:36:17,280
DISCOVERED HOMOLOGS OF THE HUMAN

840
00:36:17,280 --> 00:36:19,440
GAS DER MIN AND FOUND THAT IN 

841
00:36:19,440 --> 00:36:23,440
ALL CASES, THIS HOMO LOGS ARE 

842
00:36:23,440 --> 00:36:26,720
FOUND NEXT TO A PROTEASE EITHER 

843
00:36:26,720 --> 00:36:29,080
FROM THE CAS PACE FAMILY OR 

844
00:36:29,080 --> 00:36:30,560
ANOTHER KIND OF PROTEASE SO WE 

845
00:36:30,560 --> 00:36:31,800
SUSPECTED AND ALSO THESE ARE 

846
00:36:31,800 --> 00:36:35,400
FOUND NEXT TO CRISPR SO WE 

847
00:36:35,400 --> 00:36:36,000
SUSPECTED THIS IS ANOTHER 

848
00:36:36,000 --> 00:36:43,960
DEFENSE SYSTEM IN BACTERIA.  AND

849
00:36:43,960 --> 00:36:46,120
TOGETHER WITH OTHERS, THEY 

850
00:36:46,120 --> 00:36:49,960
SHOWED THAT INDEED DURING 

851
00:36:49,960 --> 00:36:52,080
INFECTION, THIS IS FROM MY LAB, 

852
00:36:52,080 --> 00:36:53,280
DURING INFECTION THE CASPASES 

853
00:36:53,280 --> 00:36:58,680
ARE ACTIVATED.  THE CASPASE-LIKE

854
00:36:58,680 --> 00:37:01,200
PROTEINS ARE SENSING THE PHAGE 

855
00:37:01,200 --> 00:37:03,600
AND WE VERIFY THE CLEAVAGE AND 

856
00:37:03,600 --> 00:37:05,320
THEY MAKE GIANT HOLES IN THE 

857
00:37:05,320 --> 00:37:07,400
MEMBRANE THAT KILL THE CELL.  A 

858
00:37:07,400 --> 00:37:09,200
SYSTEM THAT KILLS THE CELL 

859
00:37:09,200 --> 00:37:10,400
BEFORE THE PHAGE IS READY.  

860
00:37:10,400 --> 00:37:11,840
BEFORE THE PHAGE PARTICLES ARE 

861
00:37:11,840 --> 00:37:22,360
RIPE WITHIN THE INFECTED CELL 

862
00:37:22,720 --> 00:37:24,520
LET ME KNOW YOU ANOTHER PECULIAR

863
00:37:24,520 --> 00:37:27,720
MODE OF DEFENSE.  THIS IS FOUND 

864
00:37:27,720 --> 00:37:32,320
IN MY LAB BY A PH.D. STUDENT.  

865
00:37:32,320 --> 00:37:33,480
SOMEONE WHO HAS BEEN VERY 

866
00:37:33,480 --> 00:37:35,120
SUCCESSFUL IN HER DISCOVERS.  

867
00:37:35,120 --> 00:37:37,200
THERE ARE FAMILIES OF ENZYMES 

868
00:37:37,200 --> 00:37:41,320
THAT RECOGNIZE PHAGE INFECTION, 

869
00:37:41,320 --> 00:37:43,400
MOST PROBABLY THEY RECOGNIZE THE

870
00:37:43,400 --> 00:37:45,680
PHASE AS INHIBITED FROM THE 

871
00:37:45,680 --> 00:37:46,800
TRANSCRIPTION AND ONCE THIS IS 

872
00:37:46,800 --> 00:37:50,600
SENSED THESE ENZYMES TAKE ONE OF

873
00:37:50,600 --> 00:37:51,280
THE NUCLEOTIDES IN THE CELL 

874
00:37:51,280 --> 00:37:52,840
WHICH ARE THE BUILDING BLOCKS 

875
00:37:52,840 --> 00:37:55,440
FOR DNA REPLICATION AND 

876
00:37:55,440 --> 00:37:57,160
BASICALLY DEGRADES THAT 

877
00:37:57,160 --> 00:37:59,240
NUCLEOTIDE.  SO SHE FOUND TWO 

878
00:37:59,240 --> 00:38:04,120
FAMILIES OF ENZYME ONE IS THAT 

879
00:38:04,120 --> 00:38:12,960
THE DPASE AND ANOTHER FAMILY OF 

880
00:38:12,960 --> 00:38:14,520
ENZYMES IS THE AM MIN NICES 

881
00:38:14,520 --> 00:38:22,080
WHICH REMOVED THE NH FROM THE 

882
00:38:22,080 --> 00:38:24,440
CTP.  BASICALLY THESE ENZYMES 

883
00:38:24,440 --> 00:38:28,000
HIDE ONE OF THE OXY NUCLEOTIDES 

884
00:38:28,000 --> 00:38:30,160
AWAY FROM THE PHAGE AND THEY TRY

885
00:38:30,160 --> 00:38:33,280
TO REPLICATE THE GENOME AND 

886
00:38:33,280 --> 00:38:35,880
WITHOUT THE NUCLEOTIDE IT GETS 

887
00:38:35,880 --> 00:38:38,160
STUCK AND IS NOT REPLICATED.  

888
00:38:38,160 --> 00:38:40,840
THE REASON I'M SHOWING YOU THE 

889
00:38:40,840 --> 00:38:42,880
CONTEXT OF THIS IS BECAUSE, WE 

890
00:38:42,880 --> 00:38:45,320
WERE VERY PROUD OF OURSELVES FOR

891
00:38:45,320 --> 00:38:47,480
DISCOVERING A NEW MODE, A NEW 

892
00:38:47,480 --> 00:38:48,080
STRATEGY TO PROTECT AGAINST 

893
00:38:48,080 --> 00:38:49,440
INFECTION BUT THEN WE REALIZED 

894
00:38:49,440 --> 00:38:51,800
THAT A LONG TIME AGO IT WAS 

895
00:38:51,800 --> 00:38:53,520
ALREADY DISCOVERED IN THE HUMAN 

896
00:38:53,520 --> 00:38:55,040
IMMUNE SYSTEM AND THIS IS 

897
00:38:55,040 --> 00:39:02,000
MANIFESTED BY A PROTEIN CALLED H

898
00:39:02,000 --> 00:39:03,960
21.  IT IS AN ANTI-HIV FACTOR 

899
00:39:03,960 --> 00:39:05,880
THAT BLOCKS INFECTION BY 

900
00:39:05,880 --> 00:39:09,320
DEGRADING THE OXY NTPS INTO THE 

901
00:39:09,320 --> 00:39:16,920
THREE PHOSPHATES AND SUGAR AND 

902
00:39:16,920 --> 00:39:18,160
BASE MOIETY BUT IT DOES THAT FOR

903
00:39:18,160 --> 00:39:21,720
ALL PROTOTYPES.  SO WE NEVER 

904
00:39:21,720 --> 00:39:23,960
REALIZED THAT MULTIPLE 

905
00:39:23,960 --> 00:39:25,280
COMPONENTS OF OUR INNATE IMMUNE 

906
00:39:25,280 --> 00:39:27,640
SYSTEMS HAVE PARALLELS IN THE 

907
00:39:27,640 --> 00:39:29,280
BACTERIAL IMMUNE SYSTEM AND IN 

908
00:39:29,280 --> 00:39:32,280
SOME CASES WE HAVE VERY SOLID 

909
00:39:32,280 --> 00:39:33,000
PROOF THAT THE HUMAN COMPONENT 

910
00:39:33,000 --> 00:39:38,240
HAS EVOLVED FROM THE BACTERIAL 

911
00:39:38,240 --> 00:39:39,920
COMPONENT.  YOU KNOW, 

912
00:39:39,920 --> 00:39:41,280
GENETICALLY BASED PROOF.  SO 

913
00:39:41,280 --> 00:39:43,800
WHAT WE THINK HAPPENED IS THAT, 

914
00:39:43,800 --> 00:39:45,320
I MEAN, WHAT CAN EXPLAIN THAT IS

915
00:39:45,320 --> 00:39:47,760
THAT PHAGES, AND THAT'S VERY 

916
00:39:47,760 --> 00:39:49,720
WELL ACCEPTED.  THAT PHAGES HAVE

917
00:39:49,720 --> 00:39:52,120
BEEN IN THE WORLD WELL BEFORE 

918
00:39:52,120 --> 00:39:54,760
EUKARYOTES EVEN WERE HERE.  SO 

919
00:39:54,760 --> 00:39:56,440
PHAGES WERE INFECTING BACTERIA 

920
00:39:56,440 --> 00:39:59,320
VERY LONG TIME AGO, VERY EARLY 

921
00:39:59,320 --> 00:40:04,080
ON AFTER THE BACTERIA WAS 

922
00:40:04,080 --> 00:40:05,280
INVENTED AND DEFENSE SYSTEMS 

923
00:40:05,280 --> 00:40:08,880
HAVE INVOLVED IN BACTERIA BEFORE

924
00:40:08,880 --> 00:40:11,960
EUKARYOTES CAME TO BE AND THESE 

925
00:40:11,960 --> 00:40:14,600
DEFENSE SYSTEMS HAVE BEEN IN 

926
00:40:14,600 --> 00:40:16,120
BACTERIA FOR HUNDRED OF YEARS 

927
00:40:16,120 --> 00:40:19,200
AND AT SOME POINT THE FIRST 

928
00:40:19,200 --> 00:40:21,720
EUKARYOTE CAME TO BE MOSTLY BY 

929
00:40:21,720 --> 00:40:24,200
DIFFUSION AND THESE THIS 

930
00:40:24,200 --> 00:40:25,360
BACTERIUM USED TO HAVE DEFENSE 

931
00:40:25,360 --> 00:40:27,160
SYSTEMS IN THEM AND THESE 

932
00:40:27,160 --> 00:40:28,560
DEFENSE SYSTEMS WERE THE BASIS 

933
00:40:28,560 --> 00:40:32,560
OF THE IMMUNE SYSTEM THAT WE 

934
00:40:32,560 --> 00:40:36,360
KNOW TODAY SO THIS TEACHES US 

935
00:40:36,360 --> 00:40:40,080
ABOUT THE EVOLUTION OF OUR OWN 

936
00:40:40,080 --> 00:40:41,280
IMMUNE SYSTEM BUT CAN ALSO BE 

937
00:40:41,280 --> 00:40:43,120
BENEFICIAL FOR UNDERSTANDING 

938
00:40:43,120 --> 00:40:43,880
IMMUNE SYSTEMS OF HUMANS.  AND 

939
00:40:43,880 --> 00:40:48,440
WHAT DO I MEAN?  WE ARE GOING TO

940
00:40:48,440 --> 00:40:50,920
FIND NOW DEFENSE SYSTEMS THAT WE

941
00:40:50,920 --> 00:40:52,920
KNOW EXIST IN HUMAN BUT WE DON'T

942
00:40:52,920 --> 00:40:54,360
KNOW HOW THEY WORK AND WE NOW 

943
00:40:54,360 --> 00:40:56,480
FIND THEM IN BACTERIA.  SO THIS 

944
00:40:56,480 --> 00:40:59,720
IS ONE INTERESTING IMMUNE 

945
00:40:59,720 --> 00:41:02,920
SYSTEM.  IT'S CALLED I 15.  IT'S

946
00:41:02,920 --> 00:41:06,840
A YOU WICK WE TIN LIKE PROTEIN 

947
00:41:06,840 --> 00:41:11,200
THAT IS PRODUCED BY INTERFERON. 

948
00:41:11,200 --> 00:41:15,760
IT'S DEDUCED TOGETHER WITH 

949
00:41:15,760 --> 00:41:17,280
UBIQUITIN CHARGING ENZYMES THAT 

950
00:41:17,280 --> 00:41:19,880
ARE SPECIFIC AND PROTECTS 

951
00:41:19,880 --> 00:41:21,640
OURSELVES AGAINST SOME VIRUSES. 

952
00:41:21,640 --> 00:41:26,120
AND HAS SOME ROLES IN COVID 

953
00:41:26,120 --> 00:41:27,360
PROTECTION FROM COVID INFECTION.

954
00:41:27,360 --> 00:41:30,440
BUT WE DON'T KNOW HOW IT WORKS. 

955
00:41:30,440 --> 00:41:31,560
PEOPLE IN IMMUNOLOGY FEEL THEY 

956
00:41:31,560 --> 00:41:34,040
DON'T KNOW HOW IT WORKS.  NOW WE

957
00:41:34,040 --> 00:41:36,680
REALIZE THAT SUCH A SYSTEM 

958
00:41:36,680 --> 00:41:41,280
EXISTS IN BACTERIA.  THERE IS AN

959
00:41:41,280 --> 00:41:45,680
INTERFERON IN PROTEINS AND THE 

960
00:41:45,680 --> 00:41:48,360
UBIQUITIN DOMAIN AND WE SHOW IT 

961
00:41:48,360 --> 00:41:49,840
PROTECTS AGAINST PHAGES.  NOW 

962
00:41:49,840 --> 00:41:51,920
WE'RE TRYING TO FIGURE OUT WHY 

963
00:41:51,920 --> 00:41:54,280
AND WE HOPE IF WE SOLVE THE 

964
00:41:54,280 --> 00:41:56,600
MECHANISM IN BACTERIA THIS CAN 

965
00:41:56,600 --> 00:41:58,840
TRANSLATE INTO UNDERSTANDING HOW

966
00:41:58,840 --> 00:41:59,720
THE HUMAN MECHANISMS WORK AS 

967
00:41:59,720 --> 00:42:02,240
WELL.  WE HAVE A BUNCH OF IMMUNE

968
00:42:02,240 --> 00:42:04,120
MECHANISMS THAT ARE FOUND BOTH 

969
00:42:04,120 --> 00:42:06,360
IN HUMANS AND IN BACTERIA BUT WE

970
00:42:06,360 --> 00:42:09,000
DON'T KNOW YET HIGH THEY WORK IN

971
00:42:09,000 --> 00:42:13,280
HUMAN.  WE HOPE TO SOLVE THIS 

972
00:42:13,280 --> 00:42:21,280
RIDDLE.  NOT ALL OF THE DEFENSE 

973
00:42:21,280 --> 00:42:23,840
SYSTEMS HAVE HOMO LOGS IN 

974
00:42:23,840 --> 00:42:25,080
HUMANS.  

975
00:42:25,080 --> 00:42:27,480
FOR EXAMPLE, WE FOUND THIS 

976
00:42:27,480 --> 00:42:31,160
PROTEIN CALLED RADAR.  THIS IS A

977
00:42:31,160 --> 00:42:34,520
SYSTEM THAT WAS FOUND.  WHICH 

978
00:42:34,520 --> 00:42:36,320
COMPRISES TWO VERY BIG GENES.  

979
00:42:36,320 --> 00:42:40,080
ONE OF THEM AS A DOMAIN, THE 

980
00:42:40,080 --> 00:42:45,200
OTHER HAS AN ATPASE DOMAIN.  AND

981
00:42:45,200 --> 00:42:46,840
TOGETHER IN THE LAB, THEY SHOWED

982
00:42:46,840 --> 00:42:49,560
THAT THESE PROTEINS FORM A GIANT

983
00:42:49,560 --> 00:42:53,240
COMPLEX IN THE CELL.  THIS GIANT

984
00:42:53,240 --> 00:42:56,080
COMPLEX IS BUILT FROM TWELVE 

985
00:42:56,080 --> 00:42:59,600
MONOMERS OF THIS.  THEY FORM 

986
00:42:59,600 --> 00:43:06,600
LIKE THIS KIND OF A SOCCER BALL.

987
00:43:06,600 --> 00:43:10,800
AND THIS PROTEIN FORMS THE HEP 

988
00:43:10,800 --> 00:43:13,000
TAMIR AND EACH HEP TAMIR SITS ON

989
00:43:13,000 --> 00:43:15,800
ONE FACE OF THE SOCCER -- THE 

990
00:43:15,800 --> 00:43:19,640
DECK KA HER TO FORM A GIANT 

991
00:43:19,640 --> 00:43:19,920
COMPLEX.  

992
00:43:19,920 --> 00:43:23,520
THAT IS FOUR TIMES AS HEAVY AS A

993
00:43:23,520 --> 00:43:26,040
RIBOSOME SO A VERY BIG COMPLEX 

994
00:43:26,040 --> 00:43:29,240
AND WHAT WE SHOWED IS THAT THIS 

995
00:43:29,240 --> 00:43:32,800
COMPLEX CONVERTS MASSIVELY ATP 

996
00:43:32,800 --> 00:43:34,480
TO ADEKNOW SIGN DURING INFECTION

997
00:43:34,480 --> 00:43:36,680
WE DON'T KNOW HOW IT PROTECTS 

998
00:43:36,680 --> 00:43:37,240
AGAINST PHAGE. 

999
00:43:37,240 --> 00:43:40,080
BUT THIS CONVERSION, MAYBE IT'S 

1000
00:43:40,080 --> 00:43:41,320
PROTECTION AGAINST PHAGE, WE'RE 

1001
00:43:41,320 --> 00:43:43,560
STILL STUDYING THAT.  THE 

1002
00:43:43,560 --> 00:43:46,080
COMPLEX IS SOMETHING LIKE -- WE 

1003
00:43:46,080 --> 00:43:48,080
HAVEN'T SEEN ANYTHING LIKE THAT.

1004
00:43:48,080 --> 00:43:51,320
IT'S SUCH A GIANT COMPLEX IN 

1005
00:43:51,320 --> 00:43:53,960
ORDER TO MEDIATE THIS ACTIVITY. 

1006
00:43:53,960 --> 00:43:55,760
ANOTHER THING THAT IS VERY 

1007
00:43:55,760 --> 00:43:58,080
INTERESTING TO US WE FOUND IS 

1008
00:43:58,080 --> 00:44:00,320
SOMETHING CALLED LET TRONS.  

1009
00:44:00,320 --> 00:44:03,840
THIS IS A VERY PECULIAR ENTITY 

1010
00:44:03,840 --> 00:44:10,120
IN BACTERIA.  IT'S COMPRISING 

1011
00:44:10,120 --> 00:44:13,320
RNA AND THERE ARE REVERSE 

1012
00:44:13,320 --> 00:44:17,280
TRANSCRIPTASE THAT CONVERT INTO 

1013
00:44:17,280 --> 00:44:22,720
CDNA LEAVING IT BOUND.  SO THIS 

1014
00:44:22,720 --> 00:44:25,280
IS RNA AND DNA THAT WAS KNOWN IN

1015
00:44:25,280 --> 00:44:27,360
BACTERIA FOR MANY YEARS IT'S 

1016
00:44:27,360 --> 00:44:29,280
FOUND IN MORE THAN 10% OF ALL 

1017
00:44:29,280 --> 00:44:30,920
BACTERIA AND THE FUNCTION OF 

1018
00:44:30,920 --> 00:44:32,040
THIS WAS NOT KNOWN.  WE FOUND 

1019
00:44:32,040 --> 00:44:34,640
THAT IT PARTICIPATES IN DEFENSE 

1020
00:44:34,640 --> 00:44:36,880
AGAINST PHAGES AND WE FOUND THAT

1021
00:44:36,880 --> 00:44:39,000
ONE OF THESE -- IT'S CALLED A 

1022
00:44:39,000 --> 00:44:40,600
LET TRON.  ONE OF THESE LET TRON

1023
00:44:40,600 --> 00:44:43,080
IS A GUARDIAN OF ANOTHER DEFENSE

1024
00:44:43,080 --> 00:44:44,480
SYSTEM.  SO THERE IS A DEFENSE 

1025
00:44:44,480 --> 00:44:47,920
SYSTEM OR THERE IS A COMPLEX 

1026
00:44:47,920 --> 00:44:51,920
CALLED RECK BCD IN THE CELL THAT

1027
00:44:51,920 --> 00:44:55,520
ALSO CLEAVES LINEAR DNA. 

1028
00:44:55,520 --> 00:44:57,400
YOU KNOW WHEN THE PHAGE EJECTS 

1029
00:44:57,400 --> 00:45:00,400
THIS FROM THE CELL IT EATS THE 

1030
00:45:00,400 --> 00:45:01,320
DNA VERY RAPIDLY AND FOR THIS 

1031
00:45:01,320 --> 00:45:04,080
REASON MANY PHAGES ARE ALSO 

1032
00:45:04,080 --> 00:45:09,280
BRINGING PROTEINS TO INHIBITORY 

1033
00:45:09,280 --> 00:45:12,080
RECK BCD.  WE FOUND THESE GUARD 

1034
00:45:12,080 --> 00:45:16,120
THE REC BCD AND WHEN IT COMES 

1035
00:45:16,120 --> 00:45:19,080
INTO ACTION AND TOGETHER KILLS 

1036
00:45:19,080 --> 00:45:20,880
ANOTHER CELL.  IT'S A GUARDIAN 

1037
00:45:20,880 --> 00:45:22,240
OF ANOTHER DEFENSE SYSTEM AND IF

1038
00:45:22,240 --> 00:45:23,840
THIS OTHER DEFENSE SYSTEM 

1039
00:45:23,840 --> 00:45:27,520
BECOMES INHIBITED BY PHAGE, THIS

1040
00:45:27,520 --> 00:45:28,920
GUARDIAN KILLS THE CELL.  WE 

1041
00:45:28,920 --> 00:45:32,560
DON'T YET UNDERSTAND WHY WE NEED

1042
00:45:32,560 --> 00:45:36,760
THIS A CHI MARA BETWEEN DNA AND 

1043
00:45:36,760 --> 00:45:38,400
RNA.  THERE ARE MANY OPEN 

1044
00:45:38,400 --> 00:45:40,040
QUESTIONS.  THIS HAPPENS FAST, 

1045
00:45:40,040 --> 00:45:41,800
THESE DISCOVERS AND WE STILL 

1046
00:45:41,800 --> 00:45:45,280
DON'T UNDERSTAND MUCH.  FOR 

1047
00:45:45,280 --> 00:45:51,520
EXAMPLE, FOR MANY SYSTEMS WE 

1048
00:45:51,520 --> 00:45:52,600
KNOW WHAT HAPPENS AFTER THE 

1049
00:45:52,600 --> 00:45:54,320
PHAGE.  IN SOME CASES THEY DO 

1050
00:45:54,320 --> 00:45:55,240
SOMETHING ELSE.  BUT WE DON'T 

1051
00:45:55,240 --> 00:45:58,400
KNOW WHAT IS BEING RECOGNIZED.  

1052
00:45:58,400 --> 00:46:01,440
HOW THEY RECOGNIZE PHAGE 

1053
00:46:01,440 --> 00:46:02,600
INFECTION.  NOW WE HAVE SOMEONE 

1054
00:46:02,600 --> 00:46:06,280
FROM MY LAB, SHE RECENTLY DID A 

1055
00:46:06,280 --> 00:46:08,120
VERY LARGE SCREENING EXPERIMENT.

1056
00:46:08,120 --> 00:46:09,200
WHERE SHE TOOK ALL THE DEFENSE 

1057
00:46:09,200 --> 00:46:11,440
SYSTEMS THAT WE HAVE.  ABOUT 50 

1058
00:46:11,440 --> 00:46:12,520
DEFENSE SYSTEMS THAT WE HAVE IN 

1059
00:46:12,520 --> 00:46:14,680
THE LAB AND EACH DEFENSE SYSTEM 

1060
00:46:14,680 --> 00:46:17,280
SHE INFECTED THE CELL THAT 

1061
00:46:17,280 --> 00:46:18,880
ENCODES THE SYSTEM WITH A PHAGE 

1062
00:46:18,880 --> 00:46:20,880
THAT IS NORMALLY BLOCKED BY THE 

1063
00:46:20,880 --> 00:46:23,360
SYSTEM AND SHE SEARCHED FOR 

1064
00:46:23,360 --> 00:46:24,920
PHAGE MUTANTS THAT CAN OVERCOME 

1065
00:46:24,920 --> 00:46:26,760
THE DEFENSE SYSTEM THEN 

1066
00:46:26,760 --> 00:46:29,080
SEQUENCED THE PHASE GENOME TO 

1067
00:46:29,080 --> 00:46:34,600
SEE WHAT GOT MUTATED AND IN MANY

1068
00:46:34,600 --> 00:46:36,480
CASES IT'S THE GENE THAT GETS 

1069
00:46:36,480 --> 00:46:41,600
RECOGNIZED BY THE DEFENSE 

1070
00:46:41,600 --> 00:46:45,280
REALIZED AND SHE REALIZED THEY 

1071
00:46:45,280 --> 00:46:47,720
FREQUENTLY IDENTIFY EITHER THE 

1072
00:46:47,720 --> 00:46:52,080
COMPONENTS OF THE PHAGE.  THESE 

1073
00:46:52,080 --> 00:46:55,240
ARE THE PROTEIN THAT FORM THE 

1074
00:46:55,240 --> 00:46:57,320
REPLICATION MACHINERY.  THIS IS 

1075
00:46:57,320 --> 00:47:04,960
A VERY RELATIVELY CONSERVATIVE. 

1076
00:47:04,960 --> 00:47:06,760
OTHER SYSTEMS RECOGNIZE 

1077
00:47:06,760 --> 00:47:07,840
STRUCTURAL COMPETENCE OF THE 

1078
00:47:07,840 --> 00:47:09,720
PHAGE.  WOULD BE, YOU KNOW, THE 

1079
00:47:09,720 --> 00:47:14,400
PHAGE TWO PROTEIN OR THE CAPSID 

1080
00:47:14,400 --> 00:47:16,080
OR SOMETHING ELSE THIS THE 

1081
00:47:16,080 --> 00:47:18,840
STRUCTURE.  AND SO OTHER SYSTEMS

1082
00:47:18,840 --> 00:47:21,000
RECOGNIZE THE PHAGES TAKING OVER

1083
00:47:21,000 --> 00:47:22,000
THE CELL.  YOU KNOW, SOME OF 

1084
00:47:22,000 --> 00:47:23,600
THEM RECOGNIZE THAT ANOTHER 

1085
00:47:23,600 --> 00:47:25,280
DEFENSE SYSTEM GETS INHIBITED 

1086
00:47:25,280 --> 00:47:32,920
AND SOME OTHERS RECOGNIZED THAT 

1087
00:47:32,920 --> 00:47:34,680
TRANSCRIPTION BECOMES INHIBITED.

1088
00:47:34,680 --> 00:47:36,160
THIS BECOMES UNIFYING PRINCIPLE 

1089
00:47:36,160 --> 00:47:40,120
IN HOW DEFENSE SYSTEMS ARE 

1090
00:47:40,120 --> 00:47:43,240
RECOGNIZED, INFECTION BY PHAGE. 

1091
00:47:43,240 --> 00:47:46,640
ANOTHER OPEN QUESTION IS, WHAT 

1092
00:47:46,640 --> 00:47:48,720
ARE THOSE DEFENSE ODDS?  SO I 

1093
00:47:48,720 --> 00:47:50,680
TOLD YOU THAT WE IDENTIFIED 

1094
00:47:50,680 --> 00:47:52,920
MULTIPLE DEFENSE SYSTEMS BASED 

1095
00:47:52,920 --> 00:47:55,160
ON THE PRESENCE FREQUENTLY NEXT 

1096
00:47:55,160 --> 00:47:57,520
TO DEFENSE SYSTEMS.  AND THIS 

1097
00:47:57,520 --> 00:47:59,600
DEFENSE ISLAND WAS VERY FRUITFUL

1098
00:47:59,600 --> 00:48:02,120
FOR US WITH THE DISCOVERY OF NEW

1099
00:48:02,120 --> 00:48:04,120
SYSTEMS BUT THE QUESTION OF WHAT

1100
00:48:04,120 --> 00:48:05,840
ARE THE DEFENSE ISLANDS BOTHERED

1101
00:48:05,840 --> 00:48:10,120
US FOR A NUMBER OF YEARS AND A 

1102
00:48:10,120 --> 00:48:12,560
PH STUDENT IN MY LAB FOUND THAT 

1103
00:48:12,560 --> 00:48:14,880
THE DEFENSE SYSTEMS ARE CARRIED 

1104
00:48:14,880 --> 00:48:17,200
USUALLY BY MOBILE GENETIC 

1105
00:48:17,200 --> 00:48:18,760
ELEMENTS.  THIS ISN'T STUDYING 

1106
00:48:18,760 --> 00:48:21,280
E. COLI.  SHE SHOWED THAT 

1107
00:48:21,280 --> 00:48:24,600
DIFFERENT STRAINS OF E. COLI 

1108
00:48:24,600 --> 00:48:26,120
HAVE DIFFERENT STRAINS THAT ARE 

1109
00:48:26,120 --> 00:48:29,280
CARRIED ON DEDICATED MOBILE 

1110
00:48:29,280 --> 00:48:31,360
GENOMIC ELEMENTS.  THIS IS THE 

1111
00:48:31,360 --> 00:48:33,040
LAB STRAIN THAT LACKS MOST OF 

1112
00:48:33,040 --> 00:48:34,080
THE DEFENSE SYSTEMS THAT WE 

1113
00:48:34,080 --> 00:48:35,440
FOUND.  AND THESE ARE DIFFERENT 

1114
00:48:35,440 --> 00:48:39,720
STRAINS OF E. COLI.  YOU SEE IN 

1115
00:48:39,720 --> 00:48:44,120
EACH OF THESE STRAINS AN ISL

1116
00:48:44,120 --> 00:48:45,920
ISLAND -- A MOBILE ISLAND HAS 

1117
00:48:45,920 --> 00:48:49,320
INTEGRATED IN THE SAME PLACE.  

1118
00:48:49,320 --> 00:48:52,960
AND SO, IF YOU LOOK AT, WE 

1119
00:48:52,960 --> 00:48:56,080
LOOKED AT ABOUT 1,000 E. COLI 

1120
00:48:56,080 --> 00:48:57,280
GENOMES.  WE SEE OUR ABILITY IN 

1121
00:48:57,280 --> 00:49:00,720
THE DEFENSE SYSTEMS IN THESE 

1122
00:49:00,720 --> 00:49:02,240
GENOMES.  MOST OF THE SYSTEMS 

1123
00:49:02,240 --> 00:49:05,280
ARE CARRIED BY MOBILE GENETIC 

1124
00:49:05,280 --> 00:49:07,560
ELEMENTS SO HERE, THIS IS THE 

1125
00:49:07,560 --> 00:49:08,960
ELEMENT THAT BRINGS MANY KINDS 

1126
00:49:08,960 --> 00:49:11,240
OF DEFENSE SYSTEMS INTO THE SAME

1127
00:49:11,240 --> 00:49:13,120
POSITION IN THE E. COLI GENOME 

1128
00:49:13,120 --> 00:49:15,000
BUT IN EACH STRAIN IT'S A 

1129
00:49:15,000 --> 00:49:16,680
DIFFERENT SET OF DEFENSE SYSTEMS

1130
00:49:16,680 --> 00:49:19,280
FORMING THESE DEFENSE ISLANDS 

1131
00:49:19,280 --> 00:49:21,280
AND THIS PANNED OUT INTO 

1132
00:49:21,280 --> 00:49:23,840
SOMETHING THAT WE DIDN'T EXPECT.

1133
00:49:23,840 --> 00:49:26,680
IN TERMS OF THE DISTRIBUTION OF 

1134
00:49:26,680 --> 00:49:28,640
DEFENSE SYSTEMS IN MICROBIAL 

1135
00:49:28,640 --> 00:49:31,240
GENOMES.  WE SEE THAT THEY ARE 

1136
00:49:31,240 --> 00:49:32,320
VERY SPORADICALLY PRESENT IN 

1137
00:49:32,320 --> 00:49:34,120
MICROBES.  WHAT YOU SEE HERE, 

1138
00:49:34,120 --> 00:49:36,680
EACH ROW HERE IS A STRAIN OF E. 

1139
00:49:36,680 --> 00:49:38,920
COLI.  AND EACH COLUMN IS THE 

1140
00:49:38,920 --> 00:49:41,280
DEFENSE SYSTEM.  SO THIS IS A 

1141
00:49:41,280 --> 00:49:42,920
RESTRICTION ENZYME TYPE ONE, 

1142
00:49:42,920 --> 00:49:45,120
TWO, THREE, FOUR.  OTHER DEFENSE

1143
00:49:45,120 --> 00:49:47,760
SYSTEMS THAT WE DISCOVERED, 

1144
00:49:47,760 --> 00:49:49,240
CRISPR, WHENEVER YOU SEE THE 

1145
00:49:49,240 --> 00:49:50,840
COLORED BOX MEANS THIS STRAIN 

1146
00:49:50,840 --> 00:49:53,160
HAS THE SYSTEM.  AND YOU SEE 

1147
00:49:53,160 --> 00:49:55,520
THAT THE SYSTEMS SPORADICALLY 

1148
00:49:55,520 --> 00:49:58,120
OCCUR IN STRAINS.  THE FIRST 

1149
00:49:58,120 --> 00:50:02,480
STRAIN HAS THIS SYSTEM AND THE 

1150
00:50:02,480 --> 00:50:05,120
THIRD STRAIN, YOU KNOW, HAS A 

1151
00:50:05,120 --> 00:50:06,960
TYPE FOUR RESTRICTION ENZYME.  

1152
00:50:06,960 --> 00:50:13,280
IT HAS A SYSTEM, ET CETERA.  AND

1153
00:50:13,280 --> 00:50:15,920
SO THESE SYSTEMS ARE 

1154
00:50:15,920 --> 00:50:17,080
SPORADICALLY OCCURRING AND WE 

1155
00:50:17,080 --> 00:50:18,320
CALL THAT THE PAN IMMUNE SYSTEM 

1156
00:50:18,320 --> 00:50:21,320
OF BACTERIA.  WE THINK THAT A 

1157
00:50:21,320 --> 00:50:23,880
SINGLE BACTERIUM CANNOT ENCODE 

1158
00:50:23,880 --> 00:50:26,160
ALL THE DEFENSE SYSTEMS AT ONCE 

1159
00:50:26,160 --> 00:50:33,280
BECAUSE THE TIME IT EMERGES AS 

1160
00:50:33,280 --> 00:50:36,400
AUTOIMMUNITY OCCURS TO TOO MUCH 

1161
00:50:36,400 --> 00:50:37,280
TOXICITY BUT ON THE OTHER HAND 

1162
00:50:37,280 --> 00:50:40,120
THE OTHER BACTERIA THAT ENCODE 

1163
00:50:40,120 --> 00:50:41,280
COULD CONTRIBUTE THAT THROUGH 

1164
00:50:41,280 --> 00:50:42,640
HORIZONTAL GENE TRANSFER AND 

1165
00:50:42,640 --> 00:50:45,120
THESE SYSTEMS COULD BE ACQUIRED 

1166
00:50:45,120 --> 00:50:48,080
BY NATURE IF THEY'RE NEEDED.  

1167
00:50:48,080 --> 00:50:50,800
AND SO I WANT TO END, YOU KNOW 

1168
00:50:50,800 --> 00:50:52,120
BY SHOWING THIS POSTER WE WERE 

1169
00:50:52,120 --> 00:50:54,120
ASKED TO PUT WHAT WE KNOW ON 

1170
00:50:54,120 --> 00:50:55,800
DEFENSE SYSTEMS OF BACTERIA ON A

1171
00:50:55,800 --> 00:50:58,120
SINGLE POSTER.  OBVIOUSLY IT'S 

1172
00:50:58,120 --> 00:51:01,280
TOO SMALL FOR YOU TO SEE.  WE 

1173
00:51:01,280 --> 00:51:08,480
HAVE RESTRICTION ENZYMES HERE.  

1174
00:51:08,480 --> 00:51:10,360
WHAT FASCINATES ME ABOUT THE 

1175
00:51:10,360 --> 00:51:12,560
POSTER, WE PUBLISHED IT LAST 

1176
00:51:12,560 --> 00:51:13,320
YEAR AND NOW MANY ADDITIONAL 

1177
00:51:13,320 --> 00:51:15,440
SYSTEMS AND MECHANISMS WERE 

1178
00:51:15,440 --> 00:51:17,160
DISCOVERED SINCE THEN.  BUT WHAT

1179
00:51:17,160 --> 00:51:19,320
REALLY FASCINATES ME IS THAT 

1180
00:51:19,320 --> 00:51:22,520
MANY OF THE MECHANISMS THAT ARE 

1181
00:51:22,520 --> 00:51:24,840
DESCRIBED HERE ARE ONLY THE 

1182
00:51:24,840 --> 00:51:27,320
PRODUCT OF STUDIES OF OUR LAB 

1183
00:51:27,320 --> 00:51:29,280
AND MANY OTHER LABS AND THE 

1184
00:51:29,280 --> 00:51:31,640
VERY, YOU KNOW, VERY RECENTLY.  

1185
00:51:31,640 --> 00:51:33,280
MUCH OF THE IMMUNE SYSTEMS WE 

1186
00:51:33,280 --> 00:51:35,600
JUST DIDN'T KNOW AND NOW IT'S 

1187
00:51:35,600 --> 00:51:39,320
LIKE, YOU KNOW, LIFTING, OR 

1188
00:51:39,320 --> 00:51:41,280
DIGGING A GIANT EXCAVATION SITE 

1189
00:51:41,280 --> 00:51:42,520
AND REALIZING THERE HAS BEEN A 

1190
00:51:42,520 --> 00:51:45,640
CITY BELOW AND MOVER WHAT YOU 

1191
00:51:45,640 --> 00:51:48,800
SEE IN THE TINY FONT ARE THE 

1192
00:51:48,800 --> 00:51:51,680
LIST OF NAMES.  OF DEFENSE 

1193
00:51:51,680 --> 00:51:52,680
SYSTEMS THAT WE KNOW PROTECT 

1194
00:51:52,680 --> 00:51:54,200
AGAINST PHAGE BUT WE DON'T KNOW 

1195
00:51:54,200 --> 00:51:58,120
YET HOW.  VERY LARGE, YOU KNOW, 

1196
00:51:58,120 --> 00:51:59,720
VERY LARGE GROUNDS FOR HAVING, 

1197
00:51:59,720 --> 00:52:01,560
YOU KNOW, MAKING FUN BIOLOGY AND

1198
00:52:01,560 --> 00:52:10,120
FUTURE DISCOVERIES.  AND I WANT 

1199
00:52:10,120 --> 00:52:12,880
TO END BY THANKING MY LAB WHICH 

1200
00:52:12,880 --> 00:52:15,840
ARE VERY TALENTED GROUP OF 

1201
00:52:15,840 --> 00:52:17,000
PEOPLE.  VERY GLAD TO HELP WITH 

1202
00:52:17,000 --> 00:52:20,080
THEM TO WORK WITH THEM.  AND 

1203
00:52:20,080 --> 00:52:22,360
ALSO OUR DEAR COLLABORATORS 

1204
00:52:22,360 --> 00:52:24,880
PHILLIP AND MANY MEMBERS OF HIS 

1205
00:52:24,880 --> 00:52:26,160
LAB.  WE'VE BEEN HAVING A 

1206
00:52:26,160 --> 00:52:27,560
WONDERFUL COLLABORATION OVER A 

1207
00:52:27,560 --> 00:52:29,200
VERY SHORT TIME PERIOD AND MOST 

1208
00:52:29,200 --> 00:52:31,560
OF THIS COLLABORATION WAS DONE 

1209
00:52:31,560 --> 00:52:32,840
UNDER COVID SO WE HAVEN'T MET 

1210
00:52:32,840 --> 00:52:35,520
UNTIL RECENTLY.  WE PUBLISHED 

1211
00:52:35,520 --> 00:52:40,120
PAPERS TOGETHER AND ONLY MET 

1212
00:52:40,120 --> 00:52:44,160
ONCE.  BUT ON ZOOM.  AND THANK 

1213
00:52:44,160 --> 00:52:48,120
YOU VERY MUCH MORE LISTENING.

1214
00:52:48,120 --> 00:52:51,160
>>(APPLAUSE).

1215
00:52:51,160 --> 00:52:53,240
>>OF COURSE ANYONE HERE
IS FREE

1216
00:52:53,240 --> 00:52:55,080
TO USE THE MICS AND AS YOU ARE 

1217
00:52:55,080 --> 00:52:56,280
MAKING YOUR WAY OVER THERE I DO 

1218
00:52:56,280 --> 00:52:59,280
HAVE A COUPLE QUESTIONS FROM THE

1219
00:52:59,280 --> 00:53:00,480
ONLINE.  THIS ONE COMES RATHER 

1220
00:53:00,480 --> 00:53:03,080
EARLY IN THE TALK.  DOES 

1221
00:53:03,080 --> 00:53:05,320
EXPRESSION OF VIRAL CAPSID 

1222
00:53:05,320 --> 00:53:07,880
PROTEINS LEAD TO CELL DEATH VIA 

1223
00:53:07,880 --> 00:53:09,760
THE CGAS SYSTEM?

1224
00:53:09,760 --> 00:53:12,280
>>THAT'S A GREAT
QUESTION.  SO 

1225
00:53:12,280 --> 00:53:14,440
IN SOME CASES, IN SOME DEFENSE 

1226
00:53:14,440 --> 00:53:17,280
SYSTEMS, EXPRESSION OF THE 

1227
00:53:17,280 --> 00:53:18,800
STRUCTURAL COMPONENTS OF THE 

1228
00:53:18,800 --> 00:53:22,680
PHAGE IS DIRECTLY LEADING TO 

1229
00:53:22,680 --> 00:53:24,640
TOXICITY, LEADS TO CELL DEATH IN

1230
00:53:24,640 --> 00:53:26,760
THE CASE OF CGAS WE COULDN'T 

1231
00:53:26,760 --> 00:53:31,560
FIND -- IN ANOTHER CALLED PYCSAR

1232
00:53:31,560 --> 00:53:34,080
WHERE WE FOUND IT IN THE CAPSID 

1233
00:53:34,080 --> 00:53:37,680
THERE WAS NO TOXICITY.  THE 

1234
00:53:37,680 --> 00:53:41,040
DEFENSE IS GONE.  SO WE THINK 

1235
00:53:41,040 --> 00:53:43,320
THAT EITHER THE LARGER CONTEXT 

1236
00:53:43,320 --> 00:53:44,800
OF THE PHAGE THAT'S BEING 

1237
00:53:44,800 --> 00:53:47,400
ASSEMBLED WITHIN THE MATERIAL IS

1238
00:53:47,400 --> 00:53:50,720
THE TRIGGER FOR THE CGAS 

1239
00:53:50,720 --> 00:53:52,400
ACTIVATION OR YOU NEED MULTIPLE 

1240
00:53:52,400 --> 00:53:53,960
SIGNALS, YOU KNOW, BOTH THE 

1241
00:53:53,960 --> 00:53:55,040
CAPSID AND SOMETHING ELSE THAT 

1242
00:53:55,040 --> 00:53:57,280
WE DON'T KNOW OF YET SO WE DON'T

1243
00:53:57,280 --> 00:53:59,480
SEE ACTIVATION JUST BY 

1244
00:53:59,480 --> 00:54:02,760
EXPRESSING THE CAPSID FOR THE 

1245
00:54:02,760 --> 00:54:03,720
SPECIFIC CASE.

1246
00:54:03,720 --> 00:54:04,880
>>YOU MAY HAVE TOUCHED ON
THIS 

1247
00:54:04,880 --> 00:54:06,760
RIGHT AT THE END AND I MAY HAVE 

1248
00:54:06,760 --> 00:54:09,960
JUST MISSED IT.  DO YOU FIND THE

1249
00:54:09,960 --> 00:54:14,320
BACTERIA STEALING PIECES OF THE 

1250
00:54:14,320 --> 00:54:15,120
FABL

1251
00:54:15,120 --> 00:54:17,080
PHAGE AS MAKING A BOARD.  OR 

1252
00:54:17,080 --> 00:54:18,520
MAKING SOME UNITS THAT DON'T 

1253
00:54:18,520 --> 00:54:22,120
WORK OR OTHER SORTS OF THINGS?

1254
00:54:22,120 --> 00:54:25,600
>>WE DON'T FIND EVIDENCE
THAT 

1255
00:54:25,600 --> 00:54:27,000
BACTERIA, THAT THE DEFENSE 

1256
00:54:27,000 --> 00:54:29,120
SYSTEMS THAT ARE WITHIN THIS 

1257
00:54:29,120 --> 00:54:32,320
DEFENSE ISLANDS, WE DIDN'T YET 

1258
00:54:32,320 --> 00:54:34,120
FIND EVIDENCE THAT THEY COMPRISE

1259
00:54:34,120 --> 00:54:36,680
ANCIENT PIECES OF PHAGES.  IT 

1260
00:54:36,680 --> 00:54:38,160
DOESN'T MEAN THAT THIS IS NOT A 

1261
00:54:38,160 --> 00:54:42,600
STRATEGY OF BACTERIA.  IT COULD 

1262
00:54:42,600 --> 00:54:44,560
BE THAT SOME BACTERIA PROTECTS 

1263
00:54:44,560 --> 00:54:46,880
BY THIS BUT MAYBE THESE PROTEINS

1264
00:54:46,880 --> 00:54:49,280
ARE NOT TRAVELING ON DEFENSE 

1265
00:54:49,280 --> 00:54:51,360
ISLANDS LIKE THESE SYSTEMS.

1266
00:54:51,360 --> 00:54:53,320
>>IT WOULD BE A FOLLOW UP
WITH 

1267
00:54:53,320 --> 00:54:54,720
A DOUBLE QUESTION ABOUT THE 

1268
00:54:54,720 --> 00:54:56,640
ISLANDS.  NO QUESTION IS AN 

1269
00:54:56,640 --> 00:55:01,280
ISLAND I GUESS.  ARE DEFENSE 

1270
00:55:01,280 --> 00:55:02,040
ISLANDS TRANSCRIPTIONALLY 

1271
00:55:02,040 --> 00:55:04,120
ORGANIZED WITH THEIR RESPONSE TO

1272
00:55:04,120 --> 00:55:06,680
PHAGE AND DO DEFENSE ISLANDS 

1273
00:55:06,680 --> 00:55:09,680
DEFEND AGAINST COMPETITOR 

1274
00:55:09,680 --> 00:55:11,920
BIOFILMS, PROTEIN AGGREGATES.

1275
00:55:11,920 --> 00:55:13,720
>>RIGHT.  SO BASED ON THE

1276
00:55:13,720 --> 00:55:14,920
ORGANIZATION OF THE GENES IN 

1277
00:55:14,920 --> 00:55:18,000
DEFENSE ISLANDS WE DON'T THINK 

1278
00:55:18,000 --> 00:55:24,560
THAT THERE IS ORGANIZATION BY 

1279
00:55:24,560 --> 00:55:26,320
GENE EXPRESSION.  WE SEE THE 

1280
00:55:26,320 --> 00:55:29,000
DEFENSE SYSTEMS WILL DISCOVER 

1281
00:55:29,000 --> 00:55:32,160
OUR EXPRESS.  AND FIND THOSE 

1282
00:55:32,160 --> 00:55:34,120
PROTEINS BEFORE IT INFECTS.  THE

1283
00:55:34,120 --> 00:55:35,360
REASON WE THINK THIS IS 

1284
00:55:35,360 --> 00:55:37,680
ESSENTIAL IS BECAUSE SOME PHAGES

1285
00:55:37,680 --> 00:55:40,120
ARE QUICKLY KILLING THE CELLS.  

1286
00:55:40,120 --> 00:55:43,240
SOME PHAGES WILL DEGRADE THE 

1287
00:55:43,240 --> 00:55:45,280
INFECTED CELL AFTER FOUR 

1288
00:55:45,280 --> 00:55:46,560
MINUTES.  THIS IS SOMETHING IT 

1289
00:55:46,560 --> 00:55:48,680
DOES.  AND SO THIS IS NOT ENOUGH

1290
00:55:48,680 --> 00:55:51,920
TIME TO ACTIVATE EXPRESSION AND 

1291
00:55:51,920 --> 00:55:53,640
THEN DEFENSE.  SO USUALLY THE 

1292
00:55:53,640 --> 00:55:54,480
ACTIVATION OF THE SYSTEMS IS 

1293
00:55:54,480 --> 00:55:58,240
DONE IN THE PROTEIN LEVEL.  

1294
00:55:58,240 --> 00:56:00,800
THERE ARE EVIDENCE THAT YOU CAN 

1295
00:56:00,800 --> 00:56:02,040
ELEVATE THE EXPRESSION OF SOME 

1296
00:56:02,040 --> 00:56:05,600
DEFENSE SYSTEMS USING EXTERNAL 

1297
00:56:05,600 --> 00:56:07,280
SIGNALS.  MOST OF THEM ARE 

1298
00:56:07,280 --> 00:56:12,240
INVOLVED IN THE DENSITY OF THE 

1299
00:56:12,240 --> 00:56:13,240
CULTURE.  AND SOME OF THEM ARE 

1300
00:56:13,240 --> 00:56:14,520
NOT DONE YET.  SO THAT'S THE 

1301
00:56:14,520 --> 00:56:16,120
ANSWER FOR THE FIRST QUESTION.  

1302
00:56:16,120 --> 00:56:21,800
THE SECOND QUESTION, DO DEFENSE 

1303
00:56:21,800 --> 00:56:22,120
ISLAND --

1304
00:56:22,120 --> 00:56:25,880
>>COMPETITORS LIKE
PROTEIN 

1305
00:56:25,880 --> 00:56:26,520
AGGREG

1306
00:56:26,520 --> 00:56:26,800
AGGREGATES.

1307
00:56:26,800 --> 00:56:27,640
>>NOT THAT I KNOW OF. 
WE'VE 

1308
00:56:27,640 --> 00:56:30,760
BEEN STUDYING THE DEFENSE 

1309
00:56:30,760 --> 00:56:33,600
SYSTEMS IN AN ISOLATED MANNER.  

1310
00:56:33,600 --> 00:56:35,680
BASICALLY WHAT WE'VE BEEN DOING 

1311
00:56:35,680 --> 00:56:37,200
IS TAKE A DEFENSE ISLAND AND 

1312
00:56:37,200 --> 00:56:39,680
STORE IT IN ECO LIE.  WE'VE 

1313
00:56:39,680 --> 00:56:41,280
TAKEN ONE SYSTEM AND STUDY WHAT 

1314
00:56:41,280 --> 00:56:42,280
IT DOES. 

1315
00:56:42,280 --> 00:56:45,480
WE DON'T KNOW IF THESE ISLANDS 

1316
00:56:45,480 --> 00:56:48,720
DO OTHER STUFF.

1317
00:56:48,720 --> 00:56:50,640
>>I NOTICED EARLIER IN
YOUR 

1318
00:56:50,640 --> 00:56:52,120
TALK WHEN YOU WERE GIVING US 

1319
00:56:52,120 --> 00:56:53,280
SPECIFIC DEFENSE MECHANISMS THAT

1320
00:56:53,280 --> 00:56:55,920
THE NAMES WERE ACRONYMS BASED ON

1321
00:56:55,920 --> 00:56:57,160
WHAT THEY DO.  BUT AT THE END 

1322
00:56:57,160 --> 00:56:59,720
YOU GAVE US A LIST OF FIFTY 

1323
00:56:59,720 --> 00:57:03,920
NAMES THAT SOUNDED A LOT MORE 

1324
00:57:03,920 --> 00:57:05,880
IMAGINATIVE.  WHERE ARE THOSE 

1325
00:57:05,880 --> 00:57:06,760
NAMES COMING FROM?

1326
00:57:06,760 --> 00:57:08,280
>>THANK YOU FOR THIS
QUESTION. 

1327
00:57:08,280 --> 00:57:10,000
YEAH, WE STARTED QUOTING THE 

1328
00:57:10,000 --> 00:57:11,960
DEFENSE SYSTEMS AS THE FIRST 

1329
00:57:11,960 --> 00:57:17,280
SYSTEM WE EVER DISCOVERED WAS 

1330
00:57:17,280 --> 00:57:20,560
CALLED BRICKS.  THE SECOND WAS 

1331
00:57:20,560 --> 00:57:21,840
DISARM, WHICH WAS WITH 

1332
00:57:21,840 --> 00:57:24,680
MODIFICATION.  AND THEN WE RAN 

1333
00:57:24,680 --> 00:57:26,480
OUT OF ACRONYMS SO WE STARTED 

1334
00:57:26,480 --> 00:57:28,560
CALLING THEM OF PROTECTIVE GODS 

1335
00:57:28,560 --> 00:57:35,400
FROM DIFFERENT MYTHOLOGIES.  WE 

1336
00:57:35,400 --> 00:57:39,360
HAVE THE LITHUANIA GOD.  WE HAVE

1337
00:57:39,360 --> 00:57:41,920
A CELTIC GOD OF THE FOREST.  WE 

1338
00:57:41,920 --> 00:57:44,240
HAVE AN EGYPTIAN GODDESS.  

1339
00:57:44,240 --> 00:57:45,080
THAT'S THE NAMES.

1340
00:57:45,080 --> 00:57:47,480
>>ON A MORE SERIOUS NOTE,
SINCE

1341
00:57:47,480 --> 00:57:51,840
A LOT OF THE MECHANISMS KILL 

1342
00:57:51,840 --> 00:57:52,840
BACTERIA, IS THERE AN OBVIOUS 

1343
00:57:52,840 --> 00:57:53,840
WAY AND I'M SURE YOU'VE THOUGHT 

1344
00:57:53,840 --> 00:57:57,280
ABOUT THIS, TO USE THOSE 

1345
00:57:57,280 --> 00:57:59,880
MECHANISMS, TO ACTIVATE THEM AS 

1346
00:57:59,880 --> 00:58:00,160
ANTIBIOTICS?

1347
00:58:00,160 --> 00:58:01,240
>>THIS IS A GREAT
QUESTION.  

1348
00:58:01,240 --> 00:58:03,000
I'M NOT SURE HOW USEFUL WOULD 

1349
00:58:03,000 --> 00:58:05,920
THIS BE BECAUSE THE SYSTEMS ARE 

1350
00:58:05,920 --> 00:58:07,840
SO SPORADICALLY PRESENT IN 

1351
00:58:07,840 --> 00:58:11,120
BACTERIA.  SO, YOU KNOW, THE 

1352
00:58:11,120 --> 00:58:12,240
CBASS SYSTEM WHICH IS PRESENT IN

1353
00:58:12,240 --> 00:58:16,000
ABOUT 15% OF THE GENOMES, YOU 

1354
00:58:16,000 --> 00:58:17,600
CAN IMAGINE THAT IF YOU GIVE 

1355
00:58:17,600 --> 00:58:19,800
THEM THE SIGNAL IN HEIGHT OF 

1356
00:58:19,800 --> 00:58:23,520
CONCENTRATION THAT THE PSYCHLY 

1357
00:58:23,520 --> 00:58:24,440
GMP-AMP, SOME OF THEM WILL FORCE

1358
00:58:24,440 --> 00:58:28,120
THE CELL TO DIE.  SOME OF THEM 

1359
00:58:28,120 --> 00:58:31,520
USED PSYCHLY UMP, TRINUCLEOTIDE 

1360
00:58:31,520 --> 00:58:33,880
SO YOU'D BE ABLE TO ONLY KILL A 

1361
00:58:33,880 --> 00:58:36,920
SMALL NUMBER OF THEM AND SINCE 

1362
00:58:36,920 --> 00:58:38,720
IT'S NOT THAT YOU WILL EVER BE 

1363
00:58:38,720 --> 00:58:41,320
ABLE TO KILL ALL THE E. COLIS.  

1364
00:58:41,320 --> 00:58:48,640
BECAUSE THE M  SYSTEMS ARE 

1365
00:58:48,640 --> 00:58:49,200
SPORADICALLY PRESENT. 

1366
00:58:49,200 --> 00:58:52,120
SO YOU'D BE ABLE TO KILL JUST 

1367
00:58:52,120 --> 00:58:53,280
SPECIFIC STRANDS OF THE 

1368
00:58:53,280 --> 00:58:55,640
BACTERIUM AND WILL NOT BE 

1369
00:58:55,640 --> 00:58:57,280
PROFITABLE FOR A DRUG COMPANY TO

1370
00:58:57,280 --> 00:59:02,400
BE SO SPECIFIC I IMAGINE.

1371
00:59:02,400 --> 00:59:04,960
>>YES.  THERE ARE
COLLEAGUE 

1372
00:59:04,960 --> 00:59:06,320
FROM YOURS AND PROBABLY 

1373
00:59:06,320 --> 00:59:08,120
SWITZERLAND FOR THE WEDNESDAY 

1374
00:59:08,120 --> 00:59:13,240
EVENING LECTURE SERIES WE HAVE 

1375
00:59:13,240 --> 00:59:15,320
THERE.  LUKE.  GREAT TALK, WHY 

1376
00:59:15,320 --> 00:59:17,280
ARE RESTRICTION ENZYMES SO 

1377
00:59:17,280 --> 00:59:18,760
PREVALENT COMPARED TO OTHER 

1378
00:59:18,760 --> 00:59:21,280
INNATE DEFENSE SYSTEMS?

1379
00:59:21,280 --> 00:59:26,880
>>WELL E  RESTRICTION
ENZYMES 

1380
00:59:26,880 --> 00:59:29,840
GIVE A VERY GOOD ABILITY TO 

1381
00:59:29,840 --> 00:59:30,440
PROTECT AGAINST THE PHAGE 

1382
00:59:30,440 --> 00:59:32,640
WITHOUT KILLING ITSELF. 

1383
00:59:32,640 --> 00:59:34,120
THAT'S A GOOD REASON TO KEEP 

1384
00:59:34,120 --> 00:59:36,880
THEM THERE.  SOME PHAGES BRING 

1385
00:59:36,880 --> 00:59:37,440
ANTIRESTRICTION.  THAT IS 

1386
00:59:37,440 --> 00:59:40,040
SOMETHING THAT IS COMMON IN 

1387
00:59:40,040 --> 00:59:41,280
PHAGES.  PROTEINS THAT PROHIBIT 

1388
00:59:41,280 --> 00:59:43,320
RESTRICTION ENZYMES IN CASES 

1389
00:59:43,320 --> 00:59:45,040
WHERE YOUR RESTRICTION ENZYMES 

1390
00:59:45,040 --> 00:59:45,920
ARE PROHIBITED I GUESS THE CELL 

1391
00:59:45,920 --> 00:59:47,920
WOULD WANT TO ACTIVATE THE 

1392
00:59:47,920 --> 00:59:52,360
SYSTEM THAT LEADS TO DEATH.

1393
00:59:52,360 --> 00:59:58,360
>>AND WHAT, FIFTY YEARS
AGO ON 

1394
00:59:58,360 --> 01:00:01,280
THE SUBJECT, WHEN THE PHAGE 

1395
01:00:01,280 --> 01:00:04,280
INFECTS E. COLI, THE VERY FIRST 

1396
01:00:04,280 --> 01:00:07,520
THING THAT HAPPENS, AT THIS I 

1397
01:00:07,520 --> 01:00:12,600
DON'T KNOW, BUT IMMEDIATELY 

1398
01:00:12,600 --> 01:00:17,080
INACTIVATES THE POLYMERASE TR

1399
01:00:17,080 --> 01:00:20,200
TRANSCRIPTION OF THE E. COLI.  

1400
01:00:20,200 --> 01:00:23,960
BECAUSE IT HAS THE SIGMA FACTOR 

1401
01:00:23,960 --> 01:00:27,080
AND ONLY THIS, AS WAS EARLIER 

1402
01:00:27,080 --> 01:00:29,600
STATED, ON THE POLYMERASE.  IT 

1403
01:00:29,600 --> 01:00:33,800
CAN TRANSCRIBE THE T4 DNA AND 

1404
01:00:33,800 --> 01:00:35,800
THAT IS HOW THE WHOLE PROCESS 

1405
01:00:35,800 --> 01:00:37,880
PROCEEDS DOWN THE ROAD.  SO THAT

1406
01:00:37,880 --> 01:00:40,840
IS I THINK LONG BACK DISCOVERED.

1407
01:00:40,840 --> 01:00:42,360
VERY FIRST THING, THE 

1408
01:00:42,360 --> 01:00:43,680
MODIFICATION.  VERY IMPORTANT 

1409
01:00:43,680 --> 01:00:45,880
SIGMA FACTOR WHICH IS INVOLVED 

1410
01:00:45,880 --> 01:00:47,800
IN THE INITIATION OF THE 

1411
01:00:47,800 --> 01:00:51,360
TRANSCRIPTION OF RNA AND DNA.

1412
01:00:51,360 --> 01:00:56,240
>>YEAH.  YEAH.

1413
01:00:56,240 --> 01:00:58,160
>>DO YOU HAVE ANOTHER
QUESTION?

1414
01:00:58,160 --> 01:00:59,000
>>NO.

1415
01:00:59,000 --> 01:01:00,560
>>SO IT'LL BE ONE LAST
QUESTION

1416
01:01:00,560 --> 01:01:03,080
ONLINE.  WE'RE JUST PAST THE 

1417
01:01:03,080 --> 01:01:06,800
HOUR.  GIVEN HEMOLOGY BETWEEN 

1418
01:01:06,800 --> 01:01:09,040
BACTERIAL AND EUCARYOTE 

1419
01:01:09,040 --> 01:01:10,720
IMMUNITY, IS THERE ANY EVIDENCE 

1420
01:01:10,720 --> 01:01:12,560
FOR HEMOLOGY BETWEEN ANTIDEFENSE

1421
01:01:12,560 --> 01:01:16,120
GENES OF PHAGES AND VIRUSES 

1422
01:01:16,120 --> 01:01:18,640
ATTACKING EUKARYOTIC CELLS?

1423
01:01:18,640 --> 01:01:22,080
>>IT IS A GREAT QUESTION.
WE 

1424
01:01:22,080 --> 01:01:25,280
HAVEN'T FOUND -- SO FAR WE 

1425
01:01:25,280 --> 01:01:27,640
DIDN'T DISCOVER TOO MANY PHAGE 

1426
01:01:27,640 --> 01:01:30,880
PROTEINS THAT INHIBIT DEFENSES. 

1427
01:01:30,880 --> 01:01:33,640
MAYBE FOUR OR FIVE SUCH FAMILIES

1428
01:01:33,640 --> 01:01:35,600
AND WE HAVEN'T FOUND HEMOLOGIES 

1429
01:01:35,600 --> 01:01:37,800
TO PROTEINS AND VIRUSES THAT 

1430
01:01:37,800 --> 01:01:39,480
INFECT HUMANS.  SOMETIMES THERE 

1431
01:01:39,480 --> 01:01:43,280
IS ANALOGY.  SO AS I TOLD YOU 

1432
01:01:43,280 --> 01:01:44,560
THERE ARE ENZYMES THAT PHAGES 

1433
01:01:44,560 --> 01:01:46,960
BRING THAT CLEAVE THE SIGNALLING

1434
01:01:46,960 --> 01:01:49,280
MOLECULE TO THE DEFENSE SYSTEM 

1435
01:01:49,280 --> 01:01:52,280
AND THERE ARE ENZYMES THAT 

1436
01:01:52,280 --> 01:01:54,760
CLEAVE THE SAME MOLECULE IN 

1437
01:01:54,760 --> 01:01:55,560
HUMAN BUT THESE ARE NOT THE SAME

1438
01:01:55,560 --> 01:01:58,440
FAMILY SO THEY EVOLVED 

1439
01:01:58,440 --> 01:02:01,320
SEPARATELY IN THOSE LINEAGES.  

1440
01:02:01,320 --> 01:02:03,760
THERE'S NO STRUCTURAL HEMOLOGY 

1441
01:02:03,760 --> 01:02:04,680
THERE.  I IMAGINE THERE MIGHT 

1442
01:02:04,680 --> 01:02:06,680
BE.  WE HAVEN'T FOUND THEM YET.

1443
01:02:06,680 --> 01:02:09,280
>>ONE MORE IF YOU DON'T
MIND.

1444
01:02:09,280 --> 01:02:10,120
>>LAST ONE.

1445
01:02:10,120 --> 01:02:12,440
>>I PROMISE.  DO YOU SEE
ANY 

1446
01:02:12,440 --> 01:02:15,360
ROLE FOR MODIFIED NUCLEOTIDES 

1447
01:02:15,360 --> 01:02:18,440
MADE IN BACTERIA IN A MICROBIOME

1448
01:02:18,440 --> 01:02:21,000
CONTEXT BEING TAKEN UP BY THE 

1449
01:02:21,000 --> 01:02:24,440
SURROUNDING EUKARYOTIC CELLS?  

1450
01:02:24,440 --> 01:02:26,440
ARE THESE ABSOLUTE CONVERSIONS 

1451
01:02:26,440 --> 01:02:28,760
OF THE ENTIRE POOL INSIDE THE 

1452
01:02:28,760 --> 01:02:28,960
CELL?

1453
01:02:28,960 --> 01:02:30,880
>>WE HAVEN'T LOOKED INTO
THAT. 

1454
01:02:30,880 --> 01:02:33,280
GOOD QUESTION, BUT WE HAVEN'T 

1455
01:02:33,280 --> 01:02:34,120
EXPLORED IT.

1456
01:02:34,120 --> 01:02:36,640
>>OKAY.  MY LIPS ARE
SEALED.

1457
01:02:36,640 --> 01:02:40,040
>>ON THAT NOTE, ON BEHALF
OF 

1458
01:02:40,040 --> 01:02:40,840
LAMBDA LUNCH I WANT TO THANK YOU

1459
01:02:40,840 --> 01:02:43,240
FOR SUCH A FASCINATING TALK AND 

1460
01:02:43,240 --> 01:02:45,200
THE AUDIENCE FOR SUCH A GREAT 

1461
01:02:45,200 --> 01:02:48,240
DISCUSSION.  I WANT TO INVITE 

1462
01:02:48,240 --> 01:02:51,240
EVERYBODY HERE, LIVE AND PRESENT

1463
01:02:51,240 --> 01:02:53,280
IN THE AUDIENCE TO RECEPTION.  

1464
01:02:53,280 --> 01:02:56,480
WITH COOKIES AND COFFEE, 

1465
01:02:56,480 --> 01:02:58,120
SPONSORED BY LAMBDA LUNCH.  

1466
01:02:58,120 --> 01:03:00,000
THEY'RE REAL COOKIES AND REAL 

1467
01:03:00,000 --> 01:03:00,760
COFFEE.  PLEASE JOIN US OUT 

1468
01:03:00,760 --> 01:03:02,320
THERE TO CONTINUE THE 

1469
01:03:02,320 --> 01:03:03,480
DISCUSSION.  SO THANK YOU VERY 

1470
01:03:03,480 --> 01:03:03,680
MUCH.

1471
01:03:03,680 --> 01:03:04,840
>>THANK YOU VERY MUCH. 
THANK 

1472
01:03:04,840 --> 01:03:05,280
YOU.

1473
01:03:05,280 --> 01:03:15,560
>>(APPLAUSE).