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WELCOME, EVERYONE, TO TODAY'S

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SESSION OF THE WEDNESDAY

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AFTERNOON LECTURE SERIES HERE AT

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THE NIH.

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I AM A SENIOR INVESTIGATOR IN

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THE INTRAMURAL PROGRAMME OF

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NICHD AND TODAY'S LECTURE IS

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HOSTED BY THE MEDALS IN BIOLOGY

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SCIENTIFIC INTEREST GROUP.

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IT'S A GREAT HONOUR AND PLEASURE

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TO INTRODUCE TODAY'S SPEAKERS

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WHO IS OUR NEXT DOOR NEIGHBOUR,

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PROFESSOR IQBAL HAMZA AT THE

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CENTRE OF BLOOD OXYGEN TRANSPORT

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AT THE MARYLAND SCHOOL OF

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MEDICINE.

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IQBAL GREW UP IN INDIA, IN BOR

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BAY,BOMBAY AND RECEIVED HIS DEGS

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IN BIO CHEMISTRY FROM THE

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UNIVERSITY OF BOMBAY.

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HE THEN CAME OVER TO THE U.S. TO

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THE STATE UNIVERSITY OF

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INTERSECT BUFFALO CAMPUS IN THE

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LAUGH OF MARK BRIAN, WHERE HIS

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WORK WAS THE ROLE OF BACTERIAL

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IRON RESPONSE REGULATE OR IN

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COORDINATING IRON HOMEOSTASIS

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AND HEME SYNTHESIS ASK THIS IS

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WHEN THE BUG OF METALS BIOLOGY

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BIT IQBAL BECAUSE HE WENT ON TO

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DO A POSTDOCTORAL RESEARCH WHERE

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HE EXPANDED HIS TWO CHAIRS TO

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TRANSGENIC MICE TO MODEL HUMAN

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GENETIC DISEASE OF COPPER MET

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BOLISM AND WILL SONS AND

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ESTABLISHED THE MOLECULAR FOR

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COPPER TRAFFICKING BY SHAPER OWN

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AND IN HIS OWN WORDS WITH A

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THREE-WEEK CRASH COURSE AT THE

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COLD SPRING HARBOUR LAB, HE

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STARTED AT THE UNIVERSITY OF

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MARYLAND WHERE HE EMBARKED

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OBJECT A COMPLETELY NEW

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DIRECTION THAT OF HIM

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TRAFFICKING PATHWAY IN YOU

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CHARIOT SO THERE ARE NUGGETS AND

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LOOKING TO START YOUR LAB.

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HIS CHOICE WAS PRECISE BECAUSE

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IT TURNS OUT THAT IT DOES NOT

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UTILIZE HEME BUT ACTUALLY

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UTILIZES ENVIRONMENT, IT DOES

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NOT MAKE ITS OWN HEME BUT

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UTILIZES ENVIRONMENTAL HEME AND

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WITH THE SYSTEMIC LAB, THEY HAVE

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GONE ON TO MAKE PIONEERING

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DISCOVERIES IN TRAFFICKING AND

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ESTABLISHED CONNECTIONS TO A

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NUMBER OF HUMAN DISEASES SOME OF

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WHICH I HOPE HE TOUCHED ON

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TODAY.

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HE HAS RECEIVED NUMEROUS AWARDS

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INCLUDING THE NIH RESEARCH

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CARRIER DEVELOPMENT AWARD AND

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THE JUNE FACULTY EXCELLENCE

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AWARD AND THE FACULTY RESEARCH

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AND SCHOLARSHIP PRICE AT THE

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UNIVERSITY OF MARYLAND AND HE IS

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A FELLOW OF THE JAPAN SOCIETY OF

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PROMOTION OF SCIENCE AND A

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FELLOW OF THE AMERICAN

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ASSOCIATION FOR THE ADVANCEMENT

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OF SCIENCE.

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BUT MORE IMPORTANTLY, HE HAS

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BEEN A PARTICULARLY STRONG

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MENTOR OF YOUNG SCIENTISTS, IN

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THE AREA OF METAL BIOLOGY, NOT

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ONLY IN HIS OWN DEPARTMENT BUT

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OUTSIDE IN THE COMMUNITY.

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AND IT'S REALLY VERY HIGHLY

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APPRECIATED BECAUSE OF THAT.

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HE HAS HAD A LONG INTERACTION

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WITH THE NIH INTRAMURAL AND WE

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LOOK FORWARD TO CONTINUING

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INTERACTIONS AND THANK YOU VERY

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MUCH FOR ACCEPTING OUR

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INVITATION, IQBAL.

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>>IT'S REALLY AN HONOUR AND A

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PLEASURE TO BE HERE.

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IT'S NOT THE FACT I'M AT NIH

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AND IT IS AN HONOUR HALF OF THIS

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AUDIENCE, RIGHT, AND THE JOKE

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ASIDE, ONE OF THE BEST THINGS OF

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BEING AT MARYLAND IS

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THE FACT THAT IT'S SO CLOSE TO

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THE NIH AND I HAVE SOME I CAN

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CAN COLLABORATE WITH THEM AND

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SOME OF THEM ARE IN THE AUDIENCE

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AND WHAT IS NOT CLEAR FROM THE

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PRODUCTION IS THAT TWO OF MY SA

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BAT CALECHES ARE 2010 IN 2019 AT

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THE NIH THE FIRST ONE WITH AND

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THE SECOND ONE WITH DAVID 

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BODINE AND YOU WILL ALSO SEE

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THERE'S A THEME AND THE TALK

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TODAY AND THAT IS THE POWER OF

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USING MODEL SYSTEMS TO UNCOVER

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UNANSWERED QUESTIONS AND YOU

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WILL SEE THAT AND THE USE OF

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THOSE ORGANISMS SHOWN HERE AS

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ELEGANS SO OUR FUNDAMENTAL

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QUESTIONS ARE TO UNDERSTAND THE

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BIOLOGY OF HEME.

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I DON'T FIT IN AS A

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MICROBIOLOGIST, HEMATOLOGIST, A

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FUNDAMENTAL QUESTION IS SIMPLE,

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HOW DOES HEME, AS YOU WILL SEE

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IN THE NEXT SLIDE, HYDRO PHOBIC,

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SER A TOXIC, SICK LICK, ORGANIC

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RING MOVES AROUND BETWEEN CELLS

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AND WITHIN CELLS.

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SO ANSWER THAT WE USE ELEGANS

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AND TO BE ABLE TO UNCON THESE

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PATHWAYS AND IN HUMAN HEALTH AND

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DISEASE AND WE HAVE TO CROSS

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MANY DIFFERENT BARRIERS AND WE

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USE MANY DIFFERENT MODEL SYSTEMS

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AND I DID MY PHD DOING BACTERIAL

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GENETICS SO FROM BACTERIA TO MAN

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OR TO MOUSE, THERE ARE OTHER

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ORGANISMS THAT YOU CAN TRANSCEND

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AND EACH ORGANISM THAT YOU USE

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CAN BE EXPLOITED FOR ITS PURPOSE

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IT BRINGS TO TH TO THE GENETIC

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TOOLBOX.

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WE USE ZEBRAFISH AND SO WE HAVE

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A LARGE MOUSE COLONY AND

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SOMETHING THAT I DID NOT

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ANTICIPATE 20 YEARS AGO, WHEN I

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STARTED THE UNIVERSITY OF

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MARYLAND IS OUR INTEREST SO NOW

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MY LAB WORKS ON INTERESTING

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PARASITES INCLUDING LEISHMANIA

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AND SO, AT THE END, IF YOU LOOK

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AT THIS SCALE BAR, YOU CAN SEE

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THE SCALE BAR WE KNOW MICE AND

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FORMS ARE ALMOST THE SAME

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BECAUSE FOR US, THE WARM IS AS

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LARGE AS A MOUSE IN TERMS OF ITS

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GENETIC POWER.

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AND ITS IMPLICATIONS IN HUMAN

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HEALTH AND DISEASE.

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SO THE REASON I PUT THIS SLIDE

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UP, IS BECAUSE PEOPLE OFTEN

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CONFUSE HEME WITH GLOBINS.

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HEMES ARE NOT JUST FOR GLOB

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INNS, WHY DON'T YOU JUST PUT A

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GFP TAG ON THE HEME, RIGHT.

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SO THIS IS A MISNOMER BECAUSE

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PEOPLE OFTEN CONFUSE HEME WITH

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GLOBINS AND IT'S A PLANER RING

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AND IT'S GOT TIE DEGREE PHOBIC

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SITE CHAINS THAT MAKES THIS

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MOLECULE HYDRO PHOBIC AND IN THE

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BIOLOGICAL MEMBRANES AND CAUSE

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TOXICITY BECAUSE OF THE IRON IN

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THE MIDDLE THAT GENERATES

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RADICALS AND THE RING ITSELF

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CATALYZES IS IT'S CHARACTERIZED

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AND OVER 400 CLASS OF GLOBINS

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HAVE BEEN CRYSTALLIZED AND BIO

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FISCAL AND BIOCHEMICAL BUT HERE

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IS THE INTERESTING QUESTION, WE

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DON'T KNOW HOW HEME GETS INTO

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GLOBIN AFTER 70 YEARS.

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THIS IS REALLY A PHENOMENALLY

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OPEN QUESTION.

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THESE ENORMOUS GAPS IN OUR

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KNOWLEDGE.

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HEMES ARE NOT FOR GLOB INS BUT

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THEY'RE INVOLVED IN OTHER

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INTERESTING BIOLOGICAL FUNCTIONS

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SUCH AS SYNTHESIS OF NITRIC

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OXIDE AND ENZYME AND AND THEY'RE

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AND BEFORE 50 SIDE CHAIN ENZYMES

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ARE INVOLVED IN STERILE

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METABOLISM AND OX CASES IN ATP

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SYNTHESIS AND REACTIONS AND THE

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VOLUME PRODUCING PUSS AND NUTRI

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FILLS AND THEY ARE INVOLVED IN

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THE CONVERSION OF T3 TO T4 SO

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HEMES PERFORM REALLY DIVERSE

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BIOLOGICAL FUNCTIONS IN ALL OF

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THESE CASES, THEY SIT AT THE

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SIDE AND DO INTERESTING CHEMICAL

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REACTIONS BUT A NEW CLAUSE OF

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PROTEINS HAVE BEEN RECENTLY

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DISCOVERED WHERE THEY'RE NOT

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STATIC PROSTHETIC GROUPS DURING

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CATALYTIC FUNCTIONS BUT THEY'RE

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CO FACTORS INVOLVED IN

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CONTROLLING BIOLOGICAL FUNCTIONS

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AS SIGNALING MOLECULES AND SO

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HEME BINDING TO TRANSCRIPTION

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FACTOR ARE CONTROLS CIRCADIAN

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CLOCK AND COUPLES WITH

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METABOLISM AND BINDING ALLOWS

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HOW MUCH MICRO RNA IS PRODUCED

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AND TO THE POTASSIUM CHANNEL OR

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THE ALLOWS YOU TO OPEN AND CLOSE

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QUICKER AND SLOWER AND HEME

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BINDING WITH A SYNTHESIS ALLOWS

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HOW MUCH HYDROGEN TO GO PRODUCE

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SO WITHIN THING IS CLEAR FROM

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THIS SLIDE, THAT HEME IS THE

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INTERSECTION OF FOUR GASES THAT

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HAS PHYSIOLOGICAL GOALS.

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SYNTHESIS AND HYDROGEN SULFIDE

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AND IF YOU DEGRADE THIS MOLECULE

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BY BREAKING THE METHANE BRIDGES

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YOU OPEN UP THE RING, YOU

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RELEASE IRON BUT YOU ALSO

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PRODUCE CARBON MONOXIDE AND I'LL

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COME BACK TO THAT LATER.

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SO, THIS IS THE QUESTION THAT I

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GOT INTERESTED 21 YEARS AGO WHEN

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I WAS STILL A POSTDOC AT

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WASHINGTON UNIVERSITY.

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HEME IS MADE OF THE CELLS AND

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IT'S MADE THROUGH A HEIDI

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DEFINED BIOCHEMICAL PATHWAY

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SHOWN HERE THAT IS SPATIALLY

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SEPARATED BETWEEN THE

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MITOCHONDRIA AND THE SITE OWE

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SOL.

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THESE ARE EIGHT INGVA INGVAR' AE

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INSIMS THAT ARE CONSERVED ACROSS

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ORGANISMS.

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IN PLANTS, THE FIRST STEP IS

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THROUGH A TRNA INTER MEDIATE.

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THE IRON ENTERS IN THE LAST STEP

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OF SYNTHESIS WHILE THE RING THAT

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YOU SAW IN THE PROCEEDING SLIDE,

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GETS INSERTED THROUGH A CAD A

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LID I CAN REACTION BY AN ENZYME

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AND THEN YOU MAKE THAT HEME THAT

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YOU SAW IN THE PREVIOUS SLIDE.

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IT'S MADE IN THE MITOCHONDRIAL

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MATRIX AND THE QUESTION I GOT

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REALLY INTERESTED IN, HOW DOES

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THE HYDRO PHOBIC GET OUT OF THE

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INTER MEMBRANE DO WE PUT INTO C

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AND ALL THE HEME CONTAINING

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PROTEINS THAT I GAVE YOU

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EXAMPLES OF AND HOW DOES HEME

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GET INTO GLOBE INNS, HOW DOES IT

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GET INTO THE NUCLEUS TO PRESS

257
00:11:51,240 --> 00:12:01,840
GOWNS AND HOW DOES HEME GET IN.

258
00:12:01,840 --> 00:12:04,840
THE REASON WHY THIS QUESTION HAS

259
00:12:04,840 --> 00:12:06,880
BEEN SO DIFFICULT TO ANSWER AND

260
00:12:06,880 --> 00:12:09,160
IT'S BECAUSE OF HEME SYNTHESIS

261
00:12:09,160 --> 00:12:11,040
ITSELF WHICH IS A HIGHLY

262
00:12:11,040 --> 00:12:15,160
COMPLICATED AND REGULATED

263
00:12:15,160 --> 00:12:15,720
PATHWAY.

264
00:12:15,720 --> 00:12:17,600
IT'S REGULATED BY THE AMOUNT OF

265
00:12:17,600 --> 00:12:22,480
IRON THAT IS AVAILABLE AND IT'S

266
00:12:22,480 --> 00:12:24,000
REGULATED BY THE FLUX OF THE

267
00:12:24,000 --> 00:12:26,640
STEPS BECAUSE THESE INTERMEDIATE

268
00:12:26,640 --> 00:12:33,720
PRODUCTS ARE SUBSTRATES ARE

269
00:12:33,720 --> 00:12:39,720
HIGHLY TOXIC SO YOU HAVE A TOXIC

270
00:12:39,720 --> 00:12:43,000
SUBSTRATE AND A TOXIC PRODUCT

271
00:12:43,000 --> 00:12:47,080
MADE BUT IT'S CRUCIAL FOR LIFE.

272
00:12:47,080 --> 00:12:50,400
SO THEREFORE, HEME THIN A SIS IS

273
00:12:50,400 --> 00:12:52,600
COUPLED WITH PROTEIN SYNTHESIS

274
00:12:52,600 --> 00:12:55,760
REGULATED BY A FACTOR SUCH AS

275
00:12:55,760 --> 00:12:59,640
IRON, HEME ITSELF AND GASES.

276
00:12:59,640 --> 00:13:01,040
SO HOW'S TUESDAY ONE SPATIALLY

277
00:13:01,040 --> 00:13:02,480
SEPARATE SYNTHESIS FROM

278
00:13:02,480 --> 00:13:03,160
TRAFFICKING?

279
00:13:03,160 --> 00:13:06,560
THAT WAS THE PROBLEM.

280
00:13:06,560 --> 00:13:08,280
SO AS I GOT INTERESTED IN THE

281
00:13:08,280 --> 00:13:11,040
QUESTION, MY COLLEAGUE JANE

282
00:13:11,040 --> 00:13:15,960
UNCOVER A PROTEIN WHICH THEY

283
00:13:15,960 --> 00:13:18,160
NAMED A PROTEIN THAT WAS TRANCE

284
00:13:18,160 --> 00:13:23,560
MEMBRANE DOMAIN PROTEIN BINDS

285
00:13:23,560 --> 00:13:25,160
HEME AND IS ABLE TO EXPORT HEME

286
00:13:25,160 --> 00:13:27,200
THE WAY SHE UNCOVER IT WAS

287
00:13:27,200 --> 00:13:29,400
SHOWING THAT CATS INFECTED WITH

288
00:13:29,400 --> 00:13:37,480
THE DELINEFELINE LEUKEMIA IS WHE

289
00:13:37,480 --> 00:13:39,600
VIRUS INFECTS IT BINDS TO THIS

290
00:13:39,600 --> 00:13:41,160
PROTEIN, INTERNALIZES IT AND

291
00:13:41,160 --> 00:13:43,520
DEGRADES IT AND CAUSES APOPTOSIS

292
00:13:43,520 --> 00:13:45,480
OF RUN CELLS BECAUSE THEY'RE

293
00:13:45,480 --> 00:13:47,520
UNABLE TO EXPORT HEME OUT.

294
00:13:47,520 --> 00:13:50,720
WHILE THIS WAS A DECADES-LONG

295
00:13:50,720 --> 00:13:55,640
INQUIRY INTO WHY, HOW FELINE

296
00:13:55,640 --> 00:13:58,040
LEUKEMIA CAUSES RED CELL A

297
00:13:58,040 --> 00:13:59,520
POLICE STATION I AND WANTED TO

298
00:13:59,520 --> 00:14:01,600
SEPARATE SYNTHESIS FROM

299
00:14:01,600 --> 00:14:02,000
TRAFFICKING.

300
00:14:02,000 --> 00:14:04,760
SO WHEN I WAS STILL A POSTDOC AT

301
00:14:04,760 --> 00:14:06,400
WASHU, I WAS REALLY CONSIDERING

302
00:14:06,400 --> 00:14:10,560
HOW DO I GO ABOUT ANSWERING THIS

303
00:14:10,560 --> 00:14:10,880
QUESTION.

304
00:14:10,880 --> 00:14:15,600
SO, HERE ARE THE SEVEN STEPS OF

305
00:14:15,600 --> 00:14:16,320
HEME SYNTHESIS.

306
00:14:16,320 --> 00:14:18,960
I HAVE NOT PUT THE FIRST ENZYME

307
00:14:18,960 --> 00:14:19,720
BECAUSE THEY'RE DIFFERENT

308
00:14:19,720 --> 00:14:21,400
BETWEEN PLANTS AND NON PLANT

309
00:14:21,400 --> 00:14:21,720
ORGANISMS.

310
00:14:21,720 --> 00:14:24,560
AS YOU CAN SEE FROM THE BLAST

311
00:14:24,560 --> 00:14:28,000
MALL I COULD PUT THE SAME

312
00:14:28,000 --> 00:14:30,360
SYNTHETIC PATHWAY ENZYMES.

313
00:14:30,360 --> 00:14:34,560
IF YOU LOOK AT THE GEE MOM WE

314
00:14:34,560 --> 00:14:39,480
COULD NOT FIND ANY HOMO.

315
00:14:39,480 --> 00:14:44,600
THIS WAS REALLY INTERESTING

316
00:14:44,600 --> 00:14:46,600
BECAUSE WHEN BOB WATERSON

317
00:14:46,600 --> 00:14:50,640
PUBLISHED THIS IN 1997, NONE OF

318
00:14:50,640 --> 00:14:52,440
THESE GENES WERE IDENTIFIED AS

319
00:14:52,440 --> 00:14:54,720
POSSIBLE AND THEY MISSED A PART

320
00:14:54,720 --> 00:14:59,440
OF CHROMOSOME AND IT'S ALSO

321
00:14:59,440 --> 00:15:00,640
POSSIBLE THAT C ELEGANS DOESN'T

322
00:15:00,640 --> 00:15:02,520
CARE FOR IT SAYS SOME ORGANISMS

323
00:15:02,520 --> 00:15:06,280
AND MICRO ORGANISMS.

324
00:15:06,280 --> 00:15:10,600
THE OTHER POSSIBILITY IS C.

325
00:15:10,600 --> 00:15:11,840
ELEGANS MAKES IT THROUGH A

326
00:15:11,840 --> 00:15:14,640
PATHWAY WHICH WOULD BE VERY

327
00:15:14,640 --> 00:15:15,840
INTERESTING AND THE FOURTH

328
00:15:15,840 --> 00:15:20,120
POSSIBILITY WAS THAT C. ELEGANS

329
00:15:20,120 --> 00:15:22,840
DOES NOT MAKE HEME BUT ACQUIRES

330
00:15:22,840 --> 00:15:23,000
IT.

331
00:15:23,000 --> 00:15:25,320
THIS IS WHERE I TOOK A

332
00:15:25,320 --> 00:15:27,480
THREE-WEEK COURSE AT COLD SPRING

333
00:15:27,480 --> 00:15:28,840
HARBOUR BECAUSE I THOUGHT MAYBE

334
00:15:28,840 --> 00:15:32,920
IT CAN ESPECIALLY SEPARATE

335
00:15:32,920 --> 00:15:34,040
SYNTHESIS FROM TRAFFICKING.

336
00:15:34,040 --> 00:15:37,000
AFTER TAKING THE COURSE I

337
00:15:37,000 --> 00:15:38,480
REALISED THAT C. ELEGANS IS

338
00:15:38,480 --> 00:15:38,760
BACTERIA.

339
00:15:38,760 --> 00:15:41,800
E. COLI IN THE LAB AND E. COLI

340
00:15:41,800 --> 00:15:43,320
HAS THE PATHWAY SAME WAY THAT

341
00:15:43,320 --> 00:15:44,560
YOU AND I DO.

342
00:15:44,560 --> 00:15:49,200
SO HOW CAN CAN ONE GO WORMS BY

343
00:15:49,200 --> 00:15:51,600
STILL CONTROLLING THE LEVELS OF

344
00:15:51,600 --> 00:15:51,920
HEME?

345
00:15:51,920 --> 00:15:56,280
SO, I WAS ABLE TO SEND MY

346
00:15:56,280 --> 00:15:58,440
AMERICAN POSTDOC TO THE U.S.

347
00:15:58,440 --> 00:16:00,640
MILITARY BASE AT FORT DETRICK

348
00:16:00,640 --> 00:16:02,360
BECAUSE THE U.S. ARMY WAS

349
00:16:02,360 --> 00:16:05,920
INTERESTED IN USING C. ELEGANS

350
00:16:05,920 --> 00:16:08,600
AND THEY HAD LIQUID CULTURE THAT

351
00:16:08,600 --> 00:16:11,080
THEY NAMED CH R AND SHE CAME TO

352
00:16:11,080 --> 00:16:16,480
THE LAB AND I DO NOT GE COULD NN

353
00:16:16,480 --> 00:16:17,760
THE MILITARY BASE AND I SAID

354
00:16:17,760 --> 00:16:21,200
WHAT IS IN THE LIQUID SYNTHETIC

355
00:16:21,200 --> 00:16:22,680
MEDIUM AND IN SIGHT OWE CHROME

356
00:16:22,680 --> 00:16:22,920
C.

357
00:16:22,920 --> 00:16:25,480
IF YOU TAKE OUTSIDE FROM THIS

358
00:16:25,480 --> 00:16:28,200
LIQUID CULTURE THE WORMS DON'T

359
00:16:28,200 --> 00:16:32,120
GROW AND IF YOU START ADDING

360
00:16:32,120 --> 00:16:33,400
PURE HEMEN, THEY GROW WELL AND

361
00:16:33,400 --> 00:16:35,680
THERE'S A 20 MICRO MOLAR AND AS

362
00:16:35,680 --> 00:16:39,000
YOU INCREASE THE CONCENTRATION

363
00:16:39,000 --> 00:16:39,640
OF THE HEME, WORM STOPS GROWING

364
00:16:39,640 --> 00:16:42,880
AND EVENTUALLY IT BECOMES REALLY

365
00:16:42,880 --> 00:16:43,760
TOX SICK THIS WAS A YEAR AFTER

366
00:16:43,760 --> 00:16:46,480
IT STARTED MY LAB AT MARYLAND

367
00:16:46,480 --> 00:16:50,160
STILL TRYING TO UNCOVER WHERE

368
00:16:50,160 --> 00:16:54,200
THE C. ELEGANS MAKE HEME OR

369
00:16:54,200 --> 00:16:56,400
ACQUIRES HEME EX.

370
00:16:56,400 --> 00:16:58,280
WE CAN DO SOME INTERESTING

371
00:16:58,280 --> 00:17:01,760
EXPERIMENTS INCLUDING WITH HEME

372
00:17:01,760 --> 00:17:05,120
TO SHOW IN DEED C. ELEGANS DOES

373
00:17:05,120 --> 00:17:11,360
NOT MAKE HEME BUT GET IT EX --

374
00:17:11,360 --> 00:17:17,560
THE LASTEN TIME AND NONE

375
00:17:17,560 --> 00:17:18,480
DETECTED AND FOR ELEGANS AND

376
00:17:18,480 --> 00:17:19,440
SINCE WE'RE IN CLOSE PROXIMITY

377
00:17:19,440 --> 00:17:21,960
TO THE USDA I GOT TO THE HEMA

378
00:17:21,960 --> 00:17:27,840
POLL GEE LAB AND LOOKED AT OTHER

379
00:17:27,840 --> 00:17:29,600
FREE-LIVING AND WE WENT TO THE

380
00:17:29,600 --> 00:17:32,280
ANIMAL HEMATOLOGY LABORATORY AND

381
00:17:32,280 --> 00:17:37,760
THIS IS A HUGE EDGE DOES TREE,

382
00:17:37,760 --> 00:17:40,080
PARASITIC ALSO HAULED HELMINTH

383
00:17:40,080 --> 00:17:44,200
SO WE HAVE YOUR FRED WORK, HOOK

384
00:17:44,200 --> 00:17:45,720
WORM, AND ROUND WORM AND IN

385
00:17:45,720 --> 00:17:52,760
FACTS HUMAN LIVE STOCKS AND

386
00:17:52,760 --> 00:17:53,160
PLANTS.

387
00:17:53,160 --> 00:17:57,640
THIS IS IS PRE GENOME ERA AND WE

388
00:17:57,640 --> 00:18:00,840
KNOW C. ELEGANS ARE ALL HEME AND

389
00:18:00,840 --> 00:18:01,840
THEY HAVE LOST ALL A GOMES

390
00:18:01,840 --> 00:18:03,720
INFORM SYNTHESIS SO IF YOU HAVE

391
00:18:03,720 --> 00:18:06,720
BEEN TO SAY WORM LAB, I'M

392
00:18:06,720 --> 00:18:08,720
TELLING YOU IT'S A POWERFUL

393
00:18:08,720 --> 00:18:11,320
MODEL SYSTEM FOR US

394
00:18:11,320 --> 00:18:11,680
SPECIFICALLY.

395
00:18:11,680 --> 00:18:13,720
SMALL SIZE, A LOT SMALLER THAN

396
00:18:13,720 --> 00:18:16,400
MICE YOU CAN DO SOME POWERFUL

397
00:18:16,400 --> 00:18:18,640
GENETICS OF TRANCE LOOSE ENTER

398
00:18:18,640 --> 00:18:20,320
FROM AN EGG LAYING ADULT AND

399
00:18:20,320 --> 00:18:22,080
SHORT LIFE CYCLE, THREE AND A

400
00:18:22,080 --> 00:18:26,800
HALF DAYS, EACH HERMAPHRODITE

401
00:18:26,800 --> 00:18:37,360
LAYS BETWEEN 300 TO 500 PRO GENI

402
00:18:37,840 --> 00:18:48,320
CAVITT AND AND EACH CELL HAS BEN

403
00:18:49,840 --> 00:18:50,080
MAPPED.

404
00:18:50,080 --> 00:18:51,560
THE ENTIRE ANIMAL HAS BEEN

405
00:18:51,560 --> 00:18:54,760
SECTIONS FROM THE MOUTH TO THE

406
00:18:54,760 --> 00:18:55,840
SAIL AT EM LEVEL, RIGHT.

407
00:18:55,840 --> 00:18:57,800
AND FOR US, THE MOST POWERFUL

408
00:18:57,800 --> 00:19:00,240
THING FOR US, THAT WE CAN GROW

409
00:19:00,240 --> 00:19:03,080
THEM IN A LARGE-SCALE TO DO

410
00:19:03,080 --> 00:19:04,720
INTERESTING METABOLISM AND BY

411
00:19:04,720 --> 00:19:08,400
OWE CHEMICAL STUDIES BECAUSE IT

412
00:19:08,400 --> 00:19:10,760
IS A NATURAL MUTANT FOR HEME

413
00:19:10,760 --> 00:19:16,960
SYNTHESIS SO AS GONE OWE GENOTYO

414
00:19:16,960 --> 00:19:18,160
NOT MAKE HEME BUT ACQUIRE HEME

415
00:19:18,160 --> 00:19:19,880
FROM THE ENVIRONMENT.

416
00:19:19,880 --> 00:19:22,240
SO SINCE C. ELEGANS IS AN

417
00:19:22,240 --> 00:19:24,760
ANIMAL, THE HERMAPHRODITE HAS 20

418
00:19:24,760 --> 00:19:28,080
BEAUTIFUL POLARIZING CELLS

419
00:19:28,080 --> 00:19:30,480
THROUGH WHICH IT EATS AND IT HAS

420
00:19:30,480 --> 00:19:32,040
ABSORBED AND STORAGE FUNCTIONS

421
00:19:32,040 --> 00:19:33,800
AND SO HERE IS A SINGLE CARTOON

422
00:19:33,800 --> 00:19:37,160
OF A POLARIZING INTESTINAL CELL

423
00:19:37,160 --> 00:19:41,240
AND THIS IS THE LUMIN OF THE

424
00:19:41,240 --> 00:19:44,200
INTESTINE AND SINCE IT ACTS IT

425
00:19:44,200 --> 00:19:46,480
TAKES UP HEME FROM ITS FOOD AND

426
00:19:46,480 --> 00:19:47,920
DIRECTLY INCORPORATES IT AS WE

427
00:19:47,920 --> 00:19:50,440
HAVE SHOWN USING RADIO LABEL

428
00:19:50,440 --> 00:19:57,640
TRACER EXPERIMENTS INTO HEME

429
00:19:57,640 --> 00:20:06,280
PROTEINS AND WE HAVE 33

430
00:20:06,280 --> 00:20:08,720
DIFFERENT GLOBE INNS AND THEY

431
00:20:08,720 --> 00:20:12,720
BLIND HEME AND OVER 84 PEOPLE

432
00:20:12,720 --> 00:20:16,960
AND SO WE HAVE COMPLETE CONTROL

433
00:20:16,960 --> 00:20:18,120
OF THE FLUX OF HEME ALL WITHIN

434
00:20:18,120 --> 00:20:20,440
THE CONTEXT OF A TRANSPARENT

435
00:20:20,440 --> 00:20:21,840
ANIMAL APPROXIMATE MORE

436
00:20:21,840 --> 00:20:27,080
IMPORTANTLY, NOT ONLY AND

437
00:20:27,080 --> 00:20:29,840
INCORPORATING TO PROTEINS BUT WE

438
00:20:29,840 --> 00:20:33,640
CAN TAKE IT FROM THE INTESTINE

439
00:20:33,640 --> 00:20:35,680
AND TRANSPORT IT ACROSS THE

440
00:20:35,680 --> 00:20:39,000
INTESTINE TO ALL THE OTHER

441
00:20:39,000 --> 00:20:48,200
TISSUE, MUSCLE, NEURONS, AND THE

442
00:20:48,200 --> 00:20:48,440
PROGENY.

443
00:20:48,440 --> 00:20:49,840
SO HERE IS THE FIRST PIECE OF

444
00:20:49,840 --> 00:20:51,520
DATA, IF YOU GROW WORMS UNDER

445
00:20:51,520 --> 00:20:53,280
THE LOWEST HEME CONCENTRATION

446
00:20:53,280 --> 00:20:58,320
WHICH IS 1.5 MICRO POLAR HEME

447
00:20:58,320 --> 00:20:59,880
AND THEY TAKE NINE DAYS TO GO

448
00:20:59,880 --> 00:21:01,480
HERE THEY'RE OPTIMAL AND THEY

449
00:21:01,480 --> 00:21:07,520
ACQUIRE THREE DAYS TO FREE AND

450
00:21:07,520 --> 00:21:12,680
AND YOU GIVE THEM A ANALOGUE

451
00:21:12,680 --> 00:21:14,680
CALLED SINC HOMEOSTASIS AND YOU

452
00:21:14,680 --> 00:21:18,360
CAN CAN TAKE THE IRON AND PUT IN

453
00:21:18,360 --> 00:21:20,480
OTHER MEDALS SO IT'S A AND YOU

454
00:21:20,480 --> 00:21:26,480
CAN CAN KNEW HOUSE IT AND WE

455
00:21:26,480 --> 00:21:32,520
HAVE IT WITHIN THE THEY DON'T

456
00:21:32,520 --> 00:21:36,520
TAKE IT UP AS WELL AND EVEN

457
00:21:36,520 --> 00:21:37,120
THOUGH HEME IS ESSENTIAL AND

458
00:21:37,120 --> 00:21:38,440
THAT WOULD MEAN THAT THEY'RE

459
00:21:38,440 --> 00:21:41,200
UPTICK SYSTEM NEEDS TO BE

460
00:21:41,200 --> 00:21:41,480
REGULATED.

461
00:21:41,480 --> 00:21:43,960
YOU CAN QUANTIFY THIS

462
00:21:43,960 --> 00:21:47,080
FLUORESCENS INTENSITY HERE SO

463
00:21:47,080 --> 00:21:48,560
THE GROWTH CURVE I SHOWED YOU

464
00:21:48,560 --> 00:21:50,280
DIFFERENT IN CONCENTRATIONS AND

465
00:21:50,280 --> 00:21:53,680
HERE IS THE FLUORESCENT HEME

466
00:21:53,680 --> 00:21:55,640
ANALOGUE SO WORMS GROW AT LOW

467
00:21:55,640 --> 00:21:57,680
HEME CONDITIONS TAKE UP HEME

468
00:21:57,680 --> 00:21:58,520
EFFECTIVELY AND WARMS GROW AT

469
00:21:58,520 --> 00:22:00,080
HIGH FEMALE CONCENTRATIONS AND

470
00:22:00,080 --> 00:22:01,320
SWITCH IT OFF.

471
00:22:01,320 --> 00:22:03,160
IT'S REGULATED AND SO THIS

472
00:22:03,160 --> 00:22:04,360
ALLOWED US TO USE THREE

473
00:22:04,360 --> 00:22:09,240
DIFFERENT APPROACHES.

474
00:22:09,240 --> 00:22:11,200
UNBIASEDLY, AGAIN ET TICKS,

475
00:22:11,200 --> 00:22:14,680
GENETICS, GENETICS, WITH THE

476
00:22:14,680 --> 00:22:19,480
ENTIRE GENOME USING EMS AND

477
00:22:19,480 --> 00:22:21,640
REVERSE GENETICS KNOCKING DOWN

478
00:22:21,640 --> 00:22:23,240
ALL 19,000 GENES ONE AT A TIME

479
00:22:23,240 --> 00:22:28,960
AND ENDING THE TRANSCRIPT TOPICS

480
00:22:28,960 --> 00:22:29,520
IDENTIFYING HEME RESPONSIVE

481
00:22:29,520 --> 00:22:29,720
GOWNS.

482
00:22:29,720 --> 00:22:31,080
HERE IS WHAT WE HAVE DISCOVERED

483
00:22:31,080 --> 00:22:32,600
USING, THIS IS WHERE I USE THE

484
00:22:32,600 --> 00:22:35,640
TERM THE AWESOME POWER OF C

485
00:22:35,640 --> 00:22:40,960
ELEGANS AGAIN GENETICS.

486
00:22:40,960 --> 00:22:44,240
THE FIRST RESPONSIVE GOWNS ARE

487
00:22:44,240 --> 00:22:47,480
FOLLOW THREE AND NOW FOUR-LETTER

488
00:22:47,480 --> 00:22:48,360
CODES.

489
00:22:48,360 --> 00:22:52,840
SO THESE ARE HEME IMPORTERS

490
00:22:52,840 --> 00:22:55,320
SINCE C. ELEGANS DOESN'T MAKE

491
00:22:55,320 --> 00:22:57,600
HEME IT'S DUPLICATED AND IT

492
00:22:57,600 --> 00:23:00,080
LOCALIZES TO THE COMPARTMENT

493
00:23:00,080 --> 00:23:05,440
FOUR, FIVE AND SIX AND A SMALL

494
00:23:05,440 --> 00:23:07,040
PEP SIDE THE MOTHER SECRETS THAT

495
00:23:07,040 --> 00:23:08,800
TAKES THE HEME AND DELIVERING IT

496
00:23:08,800 --> 00:23:15,440
TO THE EMBRYO AND LOCALIZED IN

497
00:23:15,440 --> 00:23:17,760
THE HYPER DERMIS ALLOWS THE

498
00:23:17,760 --> 00:23:19,560
HYPER DERMIS TO UTILIZE HEME

499
00:23:19,560 --> 00:23:21,000
EFFECTIVELY AND HEME HE CAN

500
00:23:21,000 --> 00:23:23,040
PORTER WHICH LOCALIZES TO THE

501
00:23:23,040 --> 00:23:24,960
SURFACE EXPORT HEME TO ALL THE

502
00:23:24,960 --> 00:23:26,800
OTHER TISSUES IN ITS ABSENCE AND

503
00:23:26,800 --> 00:23:28,480
THE MOTHER AS WELL AS THE

504
00:23:28,480 --> 00:23:37,760
EMBRYOS ARE DEAD AND THIS IS

505
00:23:37,760 --> 00:23:39,280
UNDER LOW HEME CONDITIONS

506
00:23:39,280 --> 00:23:40,680
INTERNALIZES IN THE SENSORY

507
00:23:40,680 --> 00:23:44,640
NEURONS AND THE FENCE REAND HOME

508
00:23:44,640 --> 00:23:46,720
A LOG CALLED DOUBLE 1 WHICH

509
00:23:46,720 --> 00:23:49,040
TURNS ON THIS MAD TRANSCRIPTION

510
00:23:49,040 --> 00:23:51,440
FACTORS AND REMESSES THIS GENE

511
00:23:51,440 --> 00:23:53,360
SO THIS IS THE ACCELERATOR AND

512
00:23:53,360 --> 00:23:55,120
THIS IS THE BREAK WHICH A LOUSE

513
00:23:55,120 --> 00:24:00,560
THE ENTIRE ORGANISM TO RESPONDS

514
00:24:00,560 --> 00:24:01,200
TO DIETARY HEME BECAUSE ALL OF

515
00:24:01,200 --> 00:24:03,360
IT IS DEPENDING ON THE HEME

516
00:24:03,360 --> 00:24:04,520
COMING FROM THE FOOD AND THROUGH

517
00:24:04,520 --> 00:24:06,720
THE INTESTINE.

518
00:24:06,720 --> 00:24:09,240
SO THE ULTIMATE GOAL FOR US

519
00:24:09,240 --> 00:24:12,960
REMAINS CAN CAN WE EXPLOIT C.

520
00:24:12,960 --> 00:24:15,480
ELEGANS TO IDENTIFY PATHWAYS AND

521
00:24:15,480 --> 00:24:17,920
VERTEBRAES AND CAN WE EXPLOIT

522
00:24:17,920 --> 00:24:21,720
DIFFERENCES BETWEEN THE HUMAN

523
00:24:21,720 --> 00:24:22,960
ACQUISITION PATHWAYS TO THE

524
00:24:22,960 --> 00:24:26,920
PARADISE BECAUSE AS I MENTIONED

525
00:24:26,920 --> 00:24:30,800
BEFORE, MOST ARE HELMINTH TO NOT

526
00:24:30,800 --> 00:24:32,400
HAVE THE CAPACITY TO TRANSPORT.

527
00:24:32,400 --> 00:24:33,800
THIS I'M GOING TO DISCUSS ABOUT

528
00:24:33,800 --> 00:24:36,280
ONE TRANSPORTER TODAY WHICH WE

529
00:24:36,280 --> 00:24:44,080
NAMED HRG1 OR NOW IT'S CALLED

530
00:24:44,080 --> 00:24:44,280
HRG41.

531
00:24:44,280 --> 00:24:45,600
IT WAS PROTEINS AND GENES THAT

532
00:24:45,600 --> 00:24:48,560
ARE HIGHLY EXPRESSED UNDER LOW

533
00:24:48,560 --> 00:24:48,920
HEME CONDITIONS.

534
00:24:48,920 --> 00:24:52,120
THEY'RE REGULATED TRANSCRIPTION

535
00:24:52,120 --> 00:24:54,840
LOW AS WELL AS TRANSLATIONALLY

536
00:24:54,840 --> 00:24:57,400
AND THEY ARE PARALLEL

537
00:24:57,400 --> 00:24:58,480
TRANSPORTERS AND C. ELEGANS HAS

538
00:24:58,480 --> 00:25:01,480
FOUR OF THEM AND THESE TWO ARE

539
00:25:01,480 --> 00:25:04,400
HIGHLY RESPONSE SHOWN HERE AND

540
00:25:04,400 --> 00:25:07,400
FIVE OR SEX OR REGULATED AT A

541
00:25:07,400 --> 00:25:08,800
POST TRANSCRIPTION LEVEL, WE

542
00:25:08,800 --> 00:25:10,920
HAVE ONLY ONE OF THESE

543
00:25:10,920 --> 00:25:12,080
TRANSPORTERS SO I'M GOING TO

544
00:25:12,080 --> 00:25:13,360
DISCUSS THROUGH THIS MANY

545
00:25:13,360 --> 00:25:14,560
DIFFERENT ORGANISMS AND WITH THE

546
00:25:14,560 --> 00:25:17,440
ROLE OF THESE FIRST CLASS OF

547
00:25:17,440 --> 00:25:19,480
HEME IMPORTERS LOOK LIKE.

548
00:25:19,480 --> 00:25:21,520
SO THESE ARE FOUR TRANCE

549
00:25:21,520 --> 00:25:23,720
MEMBRANE DOMAIN PROTEINS WHICH

550
00:25:23,720 --> 00:25:27,400
IS NOT WHAT I WOULD HAVE

551
00:25:27,400 --> 00:25:28,000
PREDICTED.

552
00:25:28,000 --> 00:25:31,480
THEY ARE 570 ORGANICS AND

553
00:25:31,480 --> 00:25:32,760
MOLECULES AND I WOULD HAVE

554
00:25:32,760 --> 00:25:34,760
THOUGHT THAT THESE TRANCE

555
00:25:34,760 --> 00:25:36,760
MEMBRANE DOMAIN PROTEINS HAVE

556
00:25:36,760 --> 00:25:39,160
EIGHT TO 12 PROTEINS SO I CAN

557
00:25:39,160 --> 00:25:40,920
SAY AT THIS POINT IS THESE ARE

558
00:25:40,920 --> 00:25:44,440
TRIMER IF NOT A AT THE TIME TREE

559
00:25:44,440 --> 00:25:49,200
OK AND THIS IS H RG FOUR AND

560
00:25:49,200 --> 00:25:50,600
LACKS GREN AND BLUE RESIDUE AND

561
00:25:50,600 --> 00:25:51,480
FOR THOSE PEOPLE THAT ARE

562
00:25:51,480 --> 00:25:53,000
INTERESTED IN MEMBER AND

563
00:25:53,000 --> 00:25:55,280
TRAFFICKING, THIS GREEN RESIDUE

564
00:25:55,280 --> 00:26:00,400
ARE SORTING MOR TIVE AND BASED

565
00:26:00,400 --> 00:26:01,960
MOW TEASE AND FOR RETREATS OF

566
00:26:01,960 --> 00:26:04,480
THE PROTEIN FROM THE Mrs. MA

567
00:26:04,480 --> 00:26:06,200
WOMEN RAIN TAKING PROTEINS TO

568
00:26:06,200 --> 00:26:09,760
THE LYSOZOME FOR LAX THOSE AND

569
00:26:09,760 --> 00:26:12,400
IT HAS BEEN REPLACED BY A SCENE

570
00:26:12,400 --> 00:26:15,800
AND REFERS BINDING AND REACHING

571
00:26:15,800 --> 00:26:21,120
WITH OXIDIZED STEAM THE HUMAN

572
00:26:21,120 --> 00:26:23,920
AND BUT IF YOU LOOK AT IT IT'S

573
00:26:23,920 --> 00:26:25,480
PROTEINS BUT THOSE CRITICAL

574
00:26:25,480 --> 00:26:28,240
RESIDUES THAT HAVE SHADED IN

575
00:26:28,240 --> 00:26:30,240
RED, RIGHT HERE, THEY'RE HEALEY

576
00:26:30,240 --> 00:26:32,280
CONSERVED IN THE HUMAN PROTEINS

577
00:26:32,280 --> 00:26:34,120
AND IT YOU KNEW TAY THOSE AND

578
00:26:34,120 --> 00:26:36,200
THE TRANSPORTER IS DEAD AND IT'S

579
00:26:36,200 --> 00:26:39,360
UNABLE TO TRANSPORT AND SO WHAT

580
00:26:39,360 --> 00:26:43,840
DO THESE GUYS LOOK LIKE IN VIVO?

581
00:26:43,840 --> 00:26:46,240
HERE WE SEE C. ELEGANS THESE ARE

582
00:26:46,240 --> 00:26:48,200
THE INTESTINAL FOR ALLIESED

583
00:26:48,200 --> 00:26:50,360
CELLS AND OPPOSING EACH OTHER

584
00:26:50,360 --> 00:26:53,520
AND THIS IS THE DARK LUMIN

585
00:26:53,520 --> 00:26:55,120
BETWEEN AND IT LOCALIZES AND I

586
00:26:55,120 --> 00:26:59,800
CAN CAN SEE FOR SURE, THIS IS

587
00:26:59,800 --> 00:27:01,280
THE FIRST HEME ANALOGUE AND

588
00:27:01,280 --> 00:27:04,720
THESE ARE THE OREGONELS AND THE

589
00:27:04,720 --> 00:27:12,480
COMPLETELY SURROUND THESE LROs

590
00:27:12,480 --> 00:27:15,080
AND IT'S LAX THE GREEN AND BLUE

591
00:27:15,080 --> 00:27:18,320
RESIDUE AND THEY LOCALIZE TO THE

592
00:27:18,320 --> 00:27:19,800
PLASMA MEMBRANE AND THIS DARK

593
00:27:19,800 --> 00:27:21,840
SIDE IS THE LIEU MINUTE, YOU CAN

594
00:27:21,840 --> 00:27:25,280
CAN CHANGE THE LOCALIZATION BY

595
00:27:25,280 --> 00:27:26,240
FLIP-FLOPPING SO IT'S

596
00:27:26,240 --> 00:27:29,680
LOCALIZATION IS DICTATED BY C

597
00:27:29,680 --> 00:27:32,000
AND HERE IS THE HUMANIZED WORM.

598
00:27:32,000 --> 00:27:33,840
WE HAVE DELETED ALL FOUR

599
00:27:33,840 --> 00:27:36,560
TRANSPORTERS AND PUT IN THE

600
00:27:36,560 --> 00:27:39,280
HUMAN GENE TO THE WORM AND IT

601
00:27:39,280 --> 00:27:43,920
FULLY RESCUES THE C. ELEGANS

602
00:27:43,920 --> 00:27:45,160
QUADRUPLE MUTANT AND IT

603
00:27:45,160 --> 00:27:47,160
LOCALIZES TO THE PLASMA MEMBER

604
00:27:47,160 --> 00:27:51,880
BAINMEMBRANESO IT'S TAKEN OVER N

605
00:27:51,880 --> 00:27:55,200
OF BOTH HRG1 AS WELL AS FOUR.

606
00:27:55,200 --> 00:27:57,560
SO THE QUESTION THAT WE ALWAYS

607
00:27:57,560 --> 00:28:01,240
GOT WHEN WE SUBMIT A PAPER TO A

608
00:28:01,240 --> 00:28:06,800
JOURNAL, IS THIS -- DO MA MALE

609
00:28:06,800 --> 00:28:07,480
YAN CELLS UTILIZE HEME BECAUSE

610
00:28:07,480 --> 00:28:12,520
ALL OF THE WORK WITH THE C.

611
00:28:12,520 --> 00:28:16,560
ELEGANS STUFF TELLS US YES C IS

612
00:28:16,560 --> 00:28:18,520
A HEME OK TROVE AND IT

613
00:28:18,520 --> 00:28:19,000
TRANSPORTS HEME.

614
00:28:19,000 --> 00:28:22,160
SO THERE'S ABSOLUTELY NO

615
00:28:22,160 --> 00:28:23,720
EVIDENCE THAT HEME HAS A SINGLE

616
00:28:23,720 --> 00:28:24,920
MOLECULE MOVED DIRECTLY FROM

617
00:28:24,920 --> 00:28:28,760
CELL TO CELL IN MAMMALS AND

618
00:28:28,760 --> 00:28:30,920
LIKELY ALL VERTEBRAES.

619
00:28:30,920 --> 00:28:34,800
AFTER HEME MADE A MAMMAL AN CELL

620
00:28:34,800 --> 00:28:37,280
IT REMAINS UNTIL THE PROTEINS

621
00:28:37,280 --> 00:28:39,640
CAT ABOLISED.

622
00:28:39,640 --> 00:28:41,640
I USED THESE REVIEWS TO PIVOT

623
00:28:41,640 --> 00:28:44,120
MYSELF AND REFOCUS.

624
00:28:44,120 --> 00:28:46,400
SO, THE WAY TO ADDRESS THIS

625
00:28:46,400 --> 00:28:52,960
QUESTION WAS TO SEE DO MA MALE

626
00:28:52,960 --> 00:28:54,440
YAN CELLS AND IT'S BEEN LOAN IN

627
00:28:54,440 --> 00:29:05,000
THE 1970s THAT PATIENTS AND THEY

628
00:29:09,160 --> 00:29:10,240
HAVE SYNTHESIS IS THESE

629
00:29:10,240 --> 00:29:14,680
INDIVIDUALS CAN BE TREATED WITH

630
00:29:14,680 --> 00:29:14,880
HEME.

631
00:29:14,880 --> 00:29:16,800
THAT WOULD MEAN THAT SALTS COULD

632
00:29:16,800 --> 00:29:20,880
TAKE UP HEME IF GIVEN EX ON

633
00:29:20,880 --> 00:29:21,960
OBVIOUSLY SO WE ADDRESS THE THE

634
00:29:21,960 --> 00:29:24,000
QUESTION IN A DIFFERENT WAY.

635
00:29:24,000 --> 00:29:28,760
WE TOOK TWO PEROXIDASE AND

636
00:29:28,760 --> 00:29:31,880
THEY'RE BOTH PLANT PROTEINS AND

637
00:29:31,880 --> 00:29:32,840
THEY BIND HEME WITH THE

638
00:29:32,840 --> 00:29:36,840
RELATIVELY DESEPTEMBER AFFINITY

639
00:29:36,840 --> 00:29:39,640
OF 270 TO 350 NANA MOLAR AND

640
00:29:39,640 --> 00:29:44,080
THEN WE TOOK THOSE PEROXIDASE

641
00:29:44,080 --> 00:29:49,760
AND LOCALIZED IT TO OREGON HEELD

642
00:29:49,760 --> 00:29:56,960
THE Mr PLASMA MEMBRANE AND THE

643
00:29:56,960 --> 00:29:58,360
NUCLEUS AND WE ASKED THIS

644
00:29:58,360 --> 00:30:04,560
QUESTION, DO MAMMALIAN SELLS

645
00:30:04,560 --> 00:30:04,880
USE.

646
00:30:04,880 --> 00:30:07,960
WHAT WE CAN DO IS TAKE OFF ANY

647
00:30:07,960 --> 00:30:08,880
CONTAMINATING HEME AND THERE IS

648
00:30:08,880 --> 00:30:11,280
SOME IN THE SERUM IN CULTURAL

649
00:30:11,280 --> 00:30:14,840
CELLS SO WE CAN HEME DEPLETE

650
00:30:14,840 --> 00:30:16,040
THEM AND SWITCH OFF THE PATHWAY

651
00:30:16,040 --> 00:30:18,760
USING A CHEMICAL CALLED AS OWE

652
00:30:18,760 --> 00:30:21,800
TEEN WHICH BLOCKS THE SECOND

653
00:30:21,800 --> 00:30:25,760
STEP OF THE PATHWAY AND BECAUSE

654
00:30:25,760 --> 00:30:29,800
IT'S HRP IT CAN DO AND USING

655
00:30:29,800 --> 00:30:30,960
DIAMOND OWE BENCE DEAN YOU CAN

656
00:30:30,960 --> 00:30:37,400
DO PLATE READERS OR YOU CAN TO

657
00:30:37,400 --> 00:30:39,080
MYRIOSCOPY SO WE CAN CANNOT

658
00:30:39,080 --> 00:30:41,200
BADLY DETECTIVE TEE IN ALL OF

659
00:30:41,200 --> 00:30:43,040
THESE SIX COMPARTMENTS AND YOU

660
00:30:43,040 --> 00:30:44,600
TURN ON THE FAUCET FROM THE

661
00:30:44,600 --> 00:30:47,040
OUTSIDE SO YOU BRING IN FROM THE

662
00:30:47,040 --> 00:30:49,240
OUTSIDE AND YOU RETURN ONE TO

663
00:30:49,240 --> 00:30:50,880
FOUR MICRO MOLAR IS SUFFICIENT

664
00:30:50,880 --> 00:30:52,960
TO RESTORE HEME LEVELS IN ALL OF

665
00:30:52,960 --> 00:30:54,920
THOSE COMPARTMENTS SO THESE ARE

666
00:30:54,920 --> 00:30:57,240
A RESULT SAY THAT MAMMALIAN

667
00:30:57,240 --> 00:31:02,080
CELLS ARE FLEXIBLE AND THEY CAN

668
00:31:02,080 --> 00:31:04,920
MAKE HEME BUT IF IT SWITCHES OFF

669
00:31:04,920 --> 00:31:05,680
THEY REQUIRE HEME FROM THE

670
00:31:05,680 --> 00:31:09,560
OUTSIDE THEY CAN TAKE IT UP.

671
00:31:09,560 --> 00:31:12,160
SO LET'S GO BACK TO THIS

672
00:31:12,160 --> 00:31:12,520
QUESTION.

673
00:31:12,520 --> 00:31:15,600
TO MAMMALIAN CELLS REQUIRE A

674
00:31:15,600 --> 00:31:16,360
HEME TRANSPORTER?

675
00:31:16,360 --> 00:31:18,640
SO, WE MADE ANTIBODIES AGAINST

676
00:31:18,640 --> 00:31:24,440
THE HUMAN HOM OWE LOG OF C

677
00:31:24,440 --> 00:31:27,400
ELEGANS HRG1 AND THIS IS HIGHLY

678
00:31:27,400 --> 00:31:37,240
ENRICHED MACROPHAGES.

679
00:31:37,240 --> 00:31:39,800
AND THEY'RE IN THE SYSTEM AND

680
00:31:39,800 --> 00:31:43,240
THE RES MACROPHAGES LAY A REALLY

681
00:31:43,240 --> 00:31:46,440
CRITICAL ROLE IN IRON METABOLISM

682
00:31:46,440 --> 00:31:48,760
AND WE HAVE 25 TRILLION RED

683
00:31:48,760 --> 00:31:51,400
BLOOD CELLS AND EACH RED BLOOD

684
00:31:51,400 --> 00:31:55,840
CELL CONTAINS ABOUT A BILLION

685
00:31:55,840 --> 00:31:56,560
HEME MOLECULES AND EVERY SECOND

686
00:31:56,560 --> 00:31:59,400
JUST LIKE THIS, WE'RE RECYCLING

687
00:31:59,400 --> 00:32:01,440
FIVE MILLION RED BLOOD CELLS

688
00:32:01,440 --> 00:32:03,720
BECAUSE THE LIFESPAN OF A RED

689
00:32:03,720 --> 00:32:06,120
CELL IS 120 DAYS IN HUMANS AND

690
00:32:06,120 --> 00:32:08,720
IN MICE BETWEEN 40 TO 60 DAYS.

691
00:32:08,720 --> 00:32:14,320
SO AS THEY UNDERGO THEIR OUTSIDE

692
00:32:14,320 --> 00:32:16,320
MEMBRANE SLIGHTLY DIFFERS AND

693
00:32:16,320 --> 00:32:19,600
THESE ARE RECOGNIZED BY THE

694
00:32:19,600 --> 00:32:24,200
RECEPTOR IN THEIR SYSTEM

695
00:32:24,200 --> 00:32:25,040
MACROPHAGES.

696
00:32:25,040 --> 00:32:28,160
AND THE PHAGO CYTO SIS ARE DYING

697
00:32:28,160 --> 00:32:31,000
RED BLUE CELLS AND IT MATURES

698
00:32:31,000 --> 00:32:33,120
INTO THE COMPARTMENT AND THE RED

699
00:32:33,120 --> 00:32:36,040
CELLS ARE DEGRADED AND THEY'RE

700
00:32:36,040 --> 00:32:38,240
RELEASED THE HEME.

701
00:32:38,240 --> 00:32:40,640
THIS HEME IS THEN IMPORTED INTO

702
00:32:40,640 --> 00:32:44,520
THE SITE OWE SOL AND IT DOGMA IS

703
00:32:44,520 --> 00:32:47,000
THAT THIS HEME IS THEN

704
00:32:47,000 --> 00:32:50,960
EXCLUSIVELY DEGRADED BY HEME

705
00:32:50,960 --> 00:32:52,680
OXYGENASIS TO OPEN UP THE RING

706
00:32:52,680 --> 00:32:54,000
BY BREAKING UP ONE OF THE

707
00:32:54,000 --> 00:32:58,000
BRIDGES AND RELEASING THE IRON,

708
00:32:58,000 --> 00:33:00,920
CARBON MONOXIDE AND MAKES THAT

709
00:33:00,920 --> 00:33:04,360
LINEAR RING NOW INTO IT GETS

710
00:33:04,360 --> 00:33:07,280
CONVERTED TO BILLY RUBEN IN

711
00:33:07,280 --> 00:33:08,080
EXCRETED OUT.

712
00:33:08,080 --> 00:33:09,880
THE IRON THAT IS RELEASED THEN

713
00:33:09,880 --> 00:33:13,360
IS EXPORTED OUT BY A PICKED UP

714
00:33:13,360 --> 00:33:15,720
BY THE TRANSPARENT PROTEIN IN

715
00:33:15,720 --> 00:33:17,400
THE CIRCULATION AND TAKEN TO THE

716
00:33:17,400 --> 00:33:19,960
BONE MARROW AND PICKED UP BY THE

717
00:33:19,960 --> 00:33:21,920
RECEPTORS AND THE BONE MARROW TO

718
00:33:21,920 --> 00:33:24,200
MAKE NEW RED BLOOD CELLS AND THE

719
00:33:24,200 --> 00:33:25,960
EXCESS GETS STORED SO HERE IS

720
00:33:25,960 --> 00:33:29,040
THE OPEN QUESTION, RIGHT.

721
00:33:29,040 --> 00:33:34,000
EVERY SECOND, WE DEGRADE FIVE

722
00:33:34,000 --> 00:33:38,240
QUADRILLION MOLECULES TO MAKE

723
00:33:38,240 --> 00:33:40,280
FIVE MOLECULES BACK IN THE BONE

724
00:33:40,280 --> 00:33:42,000
MARROW FOR NEW RED CELL

725
00:33:42,000 --> 00:33:42,280
PRODUCTION.

726
00:33:42,280 --> 00:33:44,480
THAT IS THE CURRENT THINKING.

727
00:33:44,480 --> 00:33:46,320
AND I CAN BE HAPPY TO ANSWER

728
00:33:46,320 --> 00:33:47,160
QUESTIONS FOR THAT.

729
00:33:47,160 --> 00:33:49,440
SO THE QUESTION WE ASKED WAS,

730
00:33:49,440 --> 00:33:55,120
GIVEN THE FACT THAT IT'S HIGHLY

731
00:33:55,120 --> 00:33:55,960
EXPRESSED IN MACROPHAGES IT

732
00:33:55,960 --> 00:34:00,160
LOCALIZES TO THE HIGH SO SOME IS

733
00:34:00,160 --> 00:34:02,400
IT POSSIBLE IT'S THE MACROPHAGES

734
00:34:02,400 --> 00:34:04,240
TRANSPORTER THAT PUTS IT

735
00:34:04,240 --> 00:34:08,040
UPSTREAM GENETICALLY AND CELL

736
00:34:08,040 --> 00:34:11,680
BIOLOGY AND TO DO THIS, WE

737
00:34:11,680 --> 00:34:14,240
ISOLATED BON MARROW MACROPHAGES,

738
00:34:14,240 --> 00:34:15,800
AND WE FOUND OUT THAT IT I AM I

739
00:34:15,800 --> 00:34:19,560
CAN LOW YES IN BONE MARROW

740
00:34:19,560 --> 00:34:21,080
MACROPHAGES IT LOCALIZES TO THE

741
00:34:21,080 --> 00:34:27,880
LATE END OWE AND IT WILL GO DECK

742
00:34:27,880 --> 00:34:30,200
RAID THE COMPARTMENTS AND IT

743
00:34:30,200 --> 00:34:31,200
REALIZES IT'S BEEN TRICKED AND

744
00:34:31,200 --> 00:34:33,600
GOES BACK TO THE LATE

745
00:34:33,600 --> 00:34:36,200
COMPARTMENT BUT IF YOU GIVE THEM

746
00:34:36,200 --> 00:34:41,360
OX SA DIESED RED BLOOD CELLS,

747
00:34:41,360 --> 00:34:46,240
THOSE HRG1 WILL GET ENRICHED AND

748
00:34:46,240 --> 00:34:48,440
SHOWN HERE AND THIS

749
00:34:48,440 --> 00:34:49,560
SYSTEMATICALLY CONTINUOUSLY IS

750
00:34:49,560 --> 00:34:54,800
BEING RECRUITED FROM THE GUY

751
00:34:54,800 --> 00:34:56,520
SHOWN HERE.

752
00:34:56,520 --> 00:35:01,160
SO IS HRB1 UPSTREAM IS FERRATIN

753
00:35:01,160 --> 00:35:04,520
SO IF YOU ARE NOT, WE GET ABOUT

754
00:35:04,520 --> 00:35:08,240
80 TO 90% KNOCK TOWN AND NO IF

755
00:35:08,240 --> 00:35:11,120
YOU FED THEM RED BLOOD CELLS BY

756
00:35:11,120 --> 00:35:15,080
THE PROCESS, YOU CAN CAN SEE

757
00:35:15,080 --> 00:35:19,640
THAT DURING HEME OXYGEN IS

758
00:35:19,640 --> 00:35:23,280
IMPORTANT BUT IF YOU KNOCKDOWN

759
00:35:23,280 --> 00:35:24,560
HRG1, AWFUL THOSE DOWNSTREAM

760
00:35:24,560 --> 00:35:26,280
MARKERS ARE REDUCED SO THESE

761
00:35:26,280 --> 00:35:28,440
RESULTS TELL YOU THAT YES,

762
00:35:28,440 --> 00:35:31,040
BIOLOGICALLY HRG1 IS UPSTREAM

763
00:35:31,040 --> 00:35:36,440
FROM ALL OF THROW MAJOR

764
00:35:36,440 --> 00:35:36,920
CONTRIBUTING.

765
00:35:36,920 --> 00:35:41,000
SO WE KNOCKED ON HRG1 IN MICE

766
00:35:41,000 --> 00:35:42,600
AND IT WAS DID NOT RIGHT HERE

767
00:35:42,600 --> 00:35:45,160
WITH MY FRIEND DAVID BOWDINE.

768
00:35:45,160 --> 00:35:48,680
THE INITIAL HYPOTHESIS WAS

769
00:35:48,680 --> 00:35:48,920
SIMPLE.

770
00:35:48,920 --> 00:35:52,160
A KNOCKOUT MOUSE WILL BE

771
00:35:52,160 --> 00:35:53,120
EMBRYONIC.

772
00:35:53,120 --> 00:35:56,800
THESE MICE LOOK

773
00:35:56,800 --> 00:35:58,040
INDISTINGUISHABLE FROM Y TYPE

774
00:35:58,040 --> 00:36:00,440
MICE WHEN YOU LOOK FROM THE

775
00:36:00,440 --> 00:36:00,800
OUTSIDE.

776
00:36:00,800 --> 00:36:02,400
UNTIL YOU OPEN UP AND DISSECT

777
00:36:02,400 --> 00:36:06,840
THE MOUSE AND OPEN UP THE RIB

778
00:36:06,840 --> 00:36:08,800
KINGS ARE TARKANIAN AND YOU LOOK

779
00:36:08,800 --> 00:36:09,520
AT THE SPLEEN, THE SPLEEN IS

780
00:36:09,520 --> 00:36:13,000
DARK AND THE LIVER IS

781
00:36:13,000 --> 00:36:13,920
DISCOLORED, AND THIS IS WHAT A

782
00:36:13,920 --> 00:36:15,240
SINGLE FEMALE LOOKS LIKE FOR A

783
00:36:15,240 --> 00:36:16,560
KNOCK OUT SO IT'S REALLY DARK

784
00:36:16,560 --> 00:36:18,160
BUT IT'S NOT THE BONE ITSELF

785
00:36:18,160 --> 00:36:21,240
BECAUSE IF WE FLUSH OUT THE

786
00:36:21,240 --> 00:36:23,160
MARROW, THESE ARE A SINGLE CELL

787
00:36:23,160 --> 00:36:25,400
WITH THIS DARK BLACK PIGMENT

788
00:36:25,400 --> 00:36:28,240
WITHIN THE CELL AND HERE IS THE

789
00:36:28,240 --> 00:36:28,600
MARROW.

790
00:36:28,600 --> 00:36:30,920
SO THERE'S SOMETHING REALLY

791
00:36:30,920 --> 00:36:32,080
UNUSUAL ABOUT THESE MICE.

792
00:36:32,080 --> 00:36:37,760
IF YOU LOOK AT THE THREE TISSUE

793
00:36:37,760 --> 00:36:39,960
THE SPLEEN, LIVER AND BON

794
00:36:39,960 --> 00:36:40,360
MARROW.

795
00:36:40,360 --> 00:36:43,080
THEY'RE THE REALLY DARK PIGMENT

796
00:36:43,080 --> 00:36:45,840
THAT APPEARS TO HAVE

797
00:36:45,840 --> 00:36:47,640
PRECIPITATED WITHIN THESE CELLS

798
00:36:47,640 --> 00:36:56,040
AND THESE CELLS ARE MACROPHAGES.

799
00:36:56,040 --> 00:36:57,680
WE CAN GRIND THEM UP AND HAVE

800
00:36:57,680 --> 00:36:59,480
THE DARK PIGMENT AND THE ONLY

801
00:36:59,480 --> 00:37:02,720
PIGMENT KNOWN TO CONSIDER IN

802
00:37:02,720 --> 00:37:04,320
LIVING BIOLOGICAL SYSTEMS THAT

803
00:37:04,320 --> 00:37:07,920
WE KNEW OF WAS HEMA SEW AN AND

804
00:37:07,920 --> 00:37:09,960
UNTIL THEN IT WAS DISCOVERED TO

805
00:37:09,960 --> 00:37:15,960
BE MADE BY PLAS MODE YUM

806
00:37:15,960 --> 00:37:16,280
PARASITES.

807
00:37:16,280 --> 00:37:21,760
AND SEE GUESS TERES AS CRYSTALS

808
00:37:21,760 --> 00:37:25,120
INTO ITS LIE SO SOME AND THE

809
00:37:25,120 --> 00:37:27,440
BUFFER AND TO THIS PALLET WHICH

810
00:37:27,440 --> 00:37:37,960
WAS INSOLUBLE AND A COMPLETE IT

811
00:37:41,560 --> 00:37:44,240
IS DISSOLVED AND GIVES YOU THE

812
00:37:44,240 --> 00:37:44,840
BEAUTIFUL HEME SPECIFIC TRUST

813
00:37:44,840 --> 00:37:46,760
AND WE CAN TAKE THIS BALANCE AT

814
00:37:46,760 --> 00:37:49,000
AND DO SOMETHING DEFRACTION AND

815
00:37:49,000 --> 00:37:53,800
WE GOT BACK THE STRUCTURE AND IS

816
00:37:53,800 --> 00:37:54,680
IDENTICAL TO PLAS MODE YAN.

817
00:37:54,680 --> 00:37:56,600
SO THESE RESULTS TOLD US THAT

818
00:37:56,600 --> 00:38:01,040
YES, THE MOUSE APPEARS TO BE

819
00:38:01,040 --> 00:38:02,360
NORMAL BECAUSE IT'S TAKING UP

820
00:38:02,360 --> 00:38:05,120
THE PEOPLE IN THESE MACROPHAGES

821
00:38:05,120 --> 00:38:07,400
AND BRINGING THEM TO THESE

822
00:38:07,400 --> 00:38:10,480
CRYSTALS AND THIS IS WHY THE

823
00:38:10,480 --> 00:38:11,600
PLAS MODE YAN CRYSTAL LOOKS LIKE

824
00:38:11,600 --> 00:38:16,280
AND IN SCANNING, EM, HERE IS

825
00:38:16,280 --> 00:38:18,160
WHAT THE LIVER AND BONE MARROW

826
00:38:18,160 --> 00:38:20,000
LOOKS LIKE AND EVEN THOUGH

827
00:38:20,000 --> 00:38:23,120
THERE'S SURFACE LOOKS SLIGHTLY

828
00:38:23,120 --> 00:38:23,880
DIFFERENT THAN PLAS MODE YUM,

829
00:38:23,880 --> 00:38:31,000
THEY'RE THE ULTRASTRUCTURE LEVEL

830
00:38:31,000 --> 00:38:41,520
AND THIS IS THE BEAUTIFUL HRG1,

831
00:38:41,760 --> 00:38:48,160
POSITIVE COMPARTMENT AND A HRG1

832
00:38:48,160 --> 00:38:48,760
NULL MOUSE AND THEY'RE PSEUDO

833
00:38:48,760 --> 00:38:49,600
COLOURED FROM BLACK TO RED AND

834
00:38:49,600 --> 00:38:54,480
THEY'RE IN THIS SURROUNDED BY

835
00:38:54,480 --> 00:38:56,760
THE LYSOZOME MEMBRANE AND

836
00:38:56,760 --> 00:38:58,680
THEY'RE LARGER IN THE KNOCK OUT

837
00:38:58,680 --> 00:39:01,680
AND SO THESE MACROPHAGES ARE

838
00:39:01,680 --> 00:39:02,680
ACCUMULATING HEME IN THE FORM OF

839
00:39:02,680 --> 00:39:07,960
HEMA SEW ININ THIS LYSOZOMAL

840
00:39:07,960 --> 00:39:10,280
COMPARTMENT SO HOW AND WHY DO

841
00:39:10,280 --> 00:39:13,320
THESE MICE MAKE HEMEAZOIN AND

842
00:39:13,320 --> 00:39:17,080
WHAT IS THE BASIS FOR TOLERATING

843
00:39:17,080 --> 00:39:17,320
THE HEME.

844
00:39:17,320 --> 00:39:20,160
TO ADDRESS THAT WE TOOK A DONOR

845
00:39:20,160 --> 00:39:22,320
MOUSE, A WILD LIFE MOUSE,

846
00:39:22,320 --> 00:39:25,480
INJECTED WITH THE COMPOUND AND

847
00:39:25,480 --> 00:39:28,880
IT CAUSES GIVING THEM AND 59 AND

848
00:39:28,880 --> 00:39:30,480
AFTER THREE DAYS WE CAN

849
00:39:30,480 --> 00:39:32,600
SACRIFICE THIS MOUSE AND

850
00:39:32,600 --> 00:39:35,000
MAJORITY OF THIS RADIO LABEL

851
00:39:35,000 --> 00:39:39,040
GETTING THE RED CELLS AND THE

852
00:39:39,040 --> 00:39:42,680
HEMOGLOBIN WILL GET LABELLED BY

853
00:39:42,680 --> 00:39:46,680
IN59 SO IT IS 89% GETS

854
00:39:46,680 --> 00:39:48,720
INCORPORATED INTO HEME AND WE

855
00:39:48,720 --> 00:39:52,320
CAN TAKE THIS LABELLED RED CELLS

856
00:39:52,320 --> 00:39:55,240
AND DAMAGE THEM AND GIVE THEM TO

857
00:39:55,240 --> 00:39:57,320
RECIPIENT MICE IN THE WILD TYPE

858
00:39:57,320 --> 00:40:00,800
AND KNOCK OUT AND SACRIFICE THE

859
00:40:00,800 --> 00:40:04,200
MOUSE LATER TO LOOK AT THE

860
00:40:04,200 --> 00:40:05,800
CONNETICS OF CLEARANCE OF THESE

861
00:40:05,800 --> 00:40:07,880
RED CELLS AND HERE IS AN

862
00:40:07,880 --> 00:40:08,120
EXAMPLE.

863
00:40:08,120 --> 00:40:10,920
JUST LOOKING AT THE SPLEEN.

864
00:40:10,920 --> 00:40:12,560
WILD TYPE MICE CLEAR MOST OF

865
00:40:12,560 --> 00:40:13,640
THESE LABELLED RED CELLS AND

866
00:40:13,640 --> 00:40:16,160
THIS IS ALL THAT IS REMAINING

867
00:40:16,160 --> 00:40:17,760
AFTER 96 HOURS AND HERE IS THE

868
00:40:17,760 --> 00:40:19,720
KNOCK OUT MICE AND DUNCE OF

869
00:40:19,720 --> 00:40:27,840
RADIO LABELLED IRON AND WE CAN

870
00:40:27,840 --> 00:40:28,760
DISTINGUISH HEME FROM NON

871
00:40:28,760 --> 00:40:31,680
EASTIRON ANDYOU CAN SEE THERE'SA

872
00:40:31,680 --> 00:40:34,040
SIGNIFICANT AMOUNT OF HEME STUCK

873
00:40:34,040 --> 00:40:36,960
IN THE ORGANIC FACE IN THE KNOCK

874
00:40:36,960 --> 00:40:37,240
OUT.

875
00:40:37,240 --> 00:40:40,080
BUT THIS PLUS NON HEME IRON DOES

876
00:40:40,080 --> 00:40:42,280
NOT EQUATE TO THAT AND WE'RE

877
00:40:42,280 --> 00:40:43,400
LOSING SOMEWHERE SO IF YOU ARE

878
00:40:43,400 --> 00:40:48,080
NOW LOOKING AT THE PALLET, THE

879
00:40:48,080 --> 00:40:50,160
MAJORITY OF THE IRON 59 COUNTS

880
00:40:50,160 --> 00:40:52,200
ARE IN THE PALLETE, YOU CAN CAN

881
00:40:52,200 --> 00:40:55,440
TAKE THAT HEMA SEW INPEL AT AND

882
00:40:55,440 --> 00:41:00,000
USE TH DISSOLVING BUFFER AND ITS

883
00:41:00,000 --> 00:41:01,320
WHERE IT'S GOING AND HERE IT IS,

884
00:41:01,320 --> 00:41:04,400
THE MAJORITY OF THE IRON 59 IS

885
00:41:04,400 --> 00:41:07,680
GOING INTO HEMA ZONE HEAT.

886
00:41:07,680 --> 00:41:10,160
SO WHY ARE THESE MICE SURVIVING

887
00:41:10,160 --> 00:41:14,640
IF THEY'RE UNABLE TO RECYCLE THE

888
00:41:14,640 --> 00:41:14,920
HEME IRON.

889
00:41:14,920 --> 00:41:17,040
BECAUSE A NORMAL IRON IS FED WAY

890
00:41:17,040 --> 00:41:19,760
TOO MUCH IRON IN THEIR CHILD AND

891
00:41:19,760 --> 00:41:23,440
A TYPICAL MOUSE NEEDS ABOUT 20

892
00:41:23,440 --> 00:41:24,880
BITES HER MILLION OF IRON AND

893
00:41:24,880 --> 00:41:27,160
STANDARD HAS 380 PARTS PER

894
00:41:27,160 --> 00:41:29,360
MILLION SO IF YOU TAKE THESE

895
00:41:29,360 --> 00:41:31,320
WILD TYPE AND KNOCK OUT MICE AND

896
00:41:31,320 --> 00:41:33,520
FEED THEM LOW IRON DIET WHICH

897
00:41:33,520 --> 00:41:35,920
TWO PARTS PER MILLION, BOTH THE

898
00:41:35,920 --> 00:41:38,360
WILD TYPE AND KNOCK OUT MOUSE

899
00:41:38,360 --> 00:41:40,440
DROPS ABOUT 45 AND DONE ALL THE

900
00:41:40,440 --> 00:41:41,960
WAY TO 20 FOR THE FIRST FIVE

901
00:41:41,960 --> 00:41:46,200
WEEKS HERE IS YOUR CONTROL.

902
00:41:46,200 --> 00:41:49,000
THEY REMAIN NOT SIGNIFICANTLY

903
00:41:49,000 --> 00:41:50,480
DIFFERENT UNTIL AFTER FIVE

904
00:41:50,480 --> 00:41:51,920
WEEKS, AFTER FIVE WEEKS, THEY

905
00:41:51,920 --> 00:41:54,640
REACHED A NEW STUDY STATE LEVEL

906
00:41:54,640 --> 00:41:56,320
AND WHERE THEY'RE SOLELY RELYING

907
00:41:56,320 --> 00:41:58,520
UPON RECYCLED IRON AND AS THE

908
00:41:58,520 --> 00:42:01,080
KNOCK OUT BECAUSE IT'S UNABLE TO

909
00:42:01,080 --> 00:42:02,560
RECYCLE IRON CONTINUOUSLY

910
00:42:02,560 --> 00:42:06,560
ACCUMULATES HEMA ZONE AND

911
00:42:06,560 --> 00:42:07,840
EVENTUALLY THEY SUCCUMB BECAUSE

912
00:42:07,840 --> 00:42:10,280
OF SEVERE ANAEMIA SO THERE'S

913
00:42:10,280 --> 00:42:12,480
MASSIVE CHANGES IN GENE

914
00:42:12,480 --> 00:42:13,160
EXPRESSION BETWEEN THE WILD TYPE

915
00:42:13,160 --> 00:42:15,760
AND KNOCK OUT MOUSE IF YOU LOOK

916
00:42:15,760 --> 00:42:17,600
AT THE GENE EXPRESSION PROFILE

917
00:42:17,600 --> 00:42:18,440
AT FIVE WEEKS.

918
00:42:18,440 --> 00:42:25,640
SO THE MODEL FOR HOW DOES H RG1

919
00:42:25,640 --> 00:42:27,600
KNOCK OUT MOUSE SURVIVES AND AS

920
00:42:27,600 --> 00:42:30,160
I SAID BEFORE, BODY IRON IS A

921
00:42:30,160 --> 00:42:31,640
COMPOSITE OF THE AMOUNT OF

922
00:42:31,640 --> 00:42:32,880
EASTERN COMING FROM FOOD AND

923
00:42:32,880 --> 00:42:34,280
VERSUS THE AMOUNT OF IRON THAT

924
00:42:34,280 --> 00:42:37,560
IS BEING RECYCLED AND IF THROW

925
00:42:37,560 --> 00:42:39,600
MAJOR ORGANS SPLEEN, LIVER, AND

926
00:42:39,600 --> 00:42:41,840
BONE MARROW AND BONE MARROW

927
00:42:41,840 --> 00:42:44,080
PRODUCES NEW RED CELLS IN THE

928
00:42:44,080 --> 00:42:46,880
ABSENCE OF HRG1 THERE'S NO

929
00:42:46,880 --> 00:42:49,360
RECYCLING GOING ON FROM THE

930
00:42:49,360 --> 00:42:51,600
SPLEEN, LIVER OR MARROW THE

931
00:42:51,600 --> 00:42:52,800
SPLEEN ACCUMULATES AND LIVER

932
00:42:52,800 --> 00:42:54,760
STARTS MAKING HEMA SEW INAND THE

933
00:42:54,760 --> 00:42:58,960
BONE MARROW STARTS MAKING AND

934
00:42:58,960 --> 00:43:00,840
EVENTUALLY YOU WILL END UP IN

935
00:43:00,840 --> 00:43:04,080
SOMETHING CALLED INEFFECTIVE SO

936
00:43:04,080 --> 00:43:06,080
THE BONE MARROW SAYS SPLEEN,

937
00:43:06,080 --> 00:43:08,400
COULD YOU GIVE ME A HAND?

938
00:43:08,400 --> 00:43:10,480
THE SPLEEN TRIES TO EXPANDS BUT

939
00:43:10,480 --> 00:43:12,640
IT CAN'T UNDERGO STRESS TO HELP

940
00:43:12,640 --> 00:43:18,840
MAINTAIN NORMAL AND EVENTUALLY,

941
00:43:18,840 --> 00:43:25,720
THESE MICE START DEVELOPING

942
00:43:25,720 --> 00:43:28,320
LARGEMENTS AND THEIR ORGANS ARE

943
00:43:28,320 --> 00:43:30,640
MESSED AND THEY'RE LARGE LIPID

944
00:43:30,640 --> 00:43:32,520
DROPLETS BUT THEN TISSUE AND

945
00:43:32,520 --> 00:43:34,640
THESE MICE CONTINUE TO SURVIVE

946
00:43:34,640 --> 00:43:37,280
EVEN THOUGH THEY'RE UNABLE TO

947
00:43:37,280 --> 00:43:38,440
RECYCLE BECAUSE THEY'RE GETTING

948
00:43:38,440 --> 00:43:41,280
A LOT OF THEIR IRON TO BE ABLE

949
00:43:41,280 --> 00:43:43,920
TO MAKE NEW RED BLOOD CELLS IF

950
00:43:43,920 --> 00:43:46,640
YOU REMOVE THE IRON SOURCE AS WE

951
00:43:46,640 --> 00:43:48,360
DID UNDER LOW IRON CONDITIONS,

952
00:43:48,360 --> 00:43:55,240
THESE MICE DIE.

953
00:43:55,240 --> 00:43:59,000
I'M GOING TO DISCUSS HOW DO

954
00:43:59,000 --> 00:44:00,640
PARASITES ACQUIRE HEME.

955
00:44:00,640 --> 00:44:04,400
AS I MENTIONED BEFORE, IF IT'S

956
00:44:04,400 --> 00:44:06,440
MORE OR LESS HIGHLY CONSERVED ON

957
00:44:06,440 --> 00:44:10,600
THIS PLANET AND WE HAVE SHOWN

958
00:44:10,600 --> 00:44:15,280
THAT PARASITIC C. ELEGANS LACKS

959
00:44:15,280 --> 00:44:17,840
THE ABLE TO SIN THAT SIGHS BUT

960
00:44:17,840 --> 00:44:18,640
HIGHJACKS HEME FROM THE OUTSIDE

961
00:44:18,640 --> 00:44:21,560
AND SO WHAT DOES THAT MEAN IN

962
00:44:21,560 --> 00:44:23,640
TERMS OF AN EVOLUTIONARY

963
00:44:23,640 --> 00:44:24,280
PERSPECTIVE?

964
00:44:24,280 --> 00:44:27,560
WOULD THAT MEAN THAT THE

965
00:44:27,560 --> 00:44:29,160
ANCESTORIAL WORM OR THE INAS

966
00:44:29,160 --> 00:44:31,800
TREAL ORGANISM WAS A PARASITE

967
00:44:31,800 --> 00:44:34,560
THAT WAS LIVING IN A HEME-RICH

968
00:44:34,560 --> 00:44:35,200
ENVIRONMENT THAT UP IT SAID WHY

969
00:44:35,200 --> 00:44:37,760
TO I NEED TO MAKE IT WHEN I CAN

970
00:44:37,760 --> 00:44:39,600
EAT IT?

971
00:44:39,600 --> 00:44:44,280
OR IS IT POSSIBLE THAT IT WAS

972
00:44:44,280 --> 00:44:47,680
LIVING IN AN RELATIONSHIP SUCH

973
00:44:47,680 --> 00:44:49,760
THAT IT WAS PROGRESS HEME IN

974
00:44:49,760 --> 00:44:50,600
EXCHANGE FOR KNEW TREMENDOUS

975
00:44:50,600 --> 00:44:51,680
ENTERS FROM THE HOST, WHILE BOTH

976
00:44:51,680 --> 00:44:55,640
OF THIS SCENARIOS COULD BE TRUE,

977
00:44:55,640 --> 00:44:57,560
HOOK WORMS LIVE IN THE INTESTINE

978
00:44:57,560 --> 00:45:02,160
AND GEORGES ON HUGE AMOUNTS OF

979
00:45:02,160 --> 00:45:05,560
BLOOD AND AN BACTERIA THAT LIVES

980
00:45:05,560 --> 00:45:08,200
WITHIN MALAI AND IF YOU KNOCK

981
00:45:08,200 --> 00:45:17,080
OUT THE PATHWAY AND IT DIES AND

982
00:45:17,080 --> 00:45:20,480
NONE OF THESE ORGANISMS ARE

983
00:45:20,480 --> 00:45:21,320
GENETICALLY TRACTABLE AND TO BE

984
00:45:21,320 --> 00:45:23,800
ABLE TO GET TO A GENETICALLY

985
00:45:23,800 --> 00:45:25,880
TRACTABLE ORGANISM WE STARTED

986
00:45:25,880 --> 00:45:31,760
WORKING WITH THE PARASITE VISH

987
00:45:31,760 --> 00:45:36,080
MANIA AND IT LACKS THE APPARATUS

988
00:45:36,080 --> 00:45:37,920
FOR HEME SYNTHESIS AND THE MOST

989
00:45:37,920 --> 00:45:47,320
INTERESTING THING FOR US IT'S

990
00:45:47,320 --> 00:45:50,280
TRANSMITTED BY FLIES SO IT HAS A

991
00:45:50,280 --> 00:45:51,640
STAGE AND WHEN IT'S INJECTED

992
00:45:51,640 --> 00:45:58,720
INTO THE HOST, THEY INVADE AND

993
00:45:58,720 --> 00:46:00,720
THE MACK MACROPHAGES IN THE CASE

994
00:46:00,720 --> 00:46:04,520
OF LEISHMANIA AND THEY LIVE

995
00:46:04,520 --> 00:46:08,880
INSIDE THE SEEM OF THE SAME

996
00:46:08,880 --> 00:46:10,480
MACROPHAGES RECYCLING ALL OF THE

997
00:46:10,480 --> 00:46:11,640
HEME THE IRON AND THESE CONTINUE

998
00:46:11,640 --> 00:46:15,600
TO REPLICATE INSIDE THE

999
00:46:15,600 --> 00:46:16,600
MACROPHAGES UNTIL THEY CAUSE THE

1000
00:46:16,600 --> 00:46:20,400
MICE OF THE HOST RED CELLS NEW

1001
00:46:20,400 --> 00:46:22,200
RELEASED AND THEY INFECT

1002
00:46:22,200 --> 00:46:23,040
NEIGHBORING CELLS.

1003
00:46:23,040 --> 00:46:25,400
SO THE BEAUTY OF LEISHMANIA IS

1004
00:46:25,400 --> 00:46:27,200
THAT THEY ARE GENETICALLY

1005
00:46:27,200 --> 00:46:28,400
ATTRACTABLE AND YOU CAN KNOCK

1006
00:46:28,400 --> 00:46:30,560
OUT GENES, YOU CAN CAN KNOCK IN

1007
00:46:30,560 --> 00:46:33,120
GOWNS, YOU CAN RESOLVE THEM BY

1008
00:46:33,120 --> 00:46:34,760
GREG THEM IN LIQUID CULTURE AND

1009
00:46:34,760 --> 00:46:36,920
YOU CAN INFECT MACROPHAGES IN

1010
00:46:36,920 --> 00:46:39,080
CELL CULTURE TO LOOK AT HOST

1011
00:46:39,080 --> 00:46:40,880
PARA SIDE INTERACTIONS AND YOU

1012
00:46:40,880 --> 00:46:44,360
CAN DO IN VIVO EXPERIMENTS WITH

1013
00:46:44,360 --> 00:46:47,040
GENETICALLY ALTERED MICE OR

1014
00:46:47,040 --> 00:46:48,600
HAMSTERS.

1015
00:46:48,600 --> 00:46:51,000
SO, BY INTERROGATE SOME

1016
00:46:51,000 --> 00:46:53,160
INTERESTING BIO FORMAT TICKS WE

1017
00:46:53,160 --> 00:46:55,000
IDENTIFIED THE FIRST PARASITE SO

1018
00:46:55,000 --> 00:46:59,840
WE JUST NAMED HIM LEISHMANIA

1019
00:46:59,840 --> 00:47:03,800
HRG1 AND LAUCH MANIA IS A DIP

1020
00:47:03,800 --> 00:47:05,800
LLOYD SO IF YOU MAKE A SINGLE

1021
00:47:05,800 --> 00:47:10,240
KNOCK OUT AND MAMMALIANS AND THE

1022
00:47:10,240 --> 00:47:11,760
AMOUNT OF HEME TROOPS BY HALF

1023
00:47:11,760 --> 00:47:13,920
YOU CANNOT MAKE A DOUBLE KNOCK

1024
00:47:13,920 --> 00:47:15,520
OUT BECAUSE IT IS LETHAL AND YOU

1025
00:47:15,520 --> 00:47:18,000
CAN PUT IN A TRANS GENE AND YOU

1026
00:47:18,000 --> 00:47:20,040
CAN RESTORE HEME LEVELS ALMOST

1027
00:47:20,040 --> 00:47:24,640
AS GOOD AS WILD TYPE.

1028
00:47:24,640 --> 00:47:27,840
HERE IS A SINGLE KNOCK OUT FOR

1029
00:47:27,840 --> 00:47:29,880
LHR1 AND IT'S UNABLE TO FORM

1030
00:47:29,880 --> 00:47:33,280
LESIONS IN MICE COM PARED TO

1031
00:47:33,280 --> 00:47:38,280
WILD TYPE MICE AND GENETICALLY

1032
00:47:38,280 --> 00:47:40,040
RESCUED.

1033
00:47:40,040 --> 00:47:41,720
SO REGULATES DIFFERENTLY AND IN

1034
00:47:41,720 --> 00:47:46,960
THE ABSENCE OF HEME, LHR1 IS UP

1035
00:47:46,960 --> 00:47:50,320
REGULATED AND THIS PAR SIGHT CAN

1036
00:47:50,320 --> 00:47:51,440
CANNOT MAKE HEME.

1037
00:47:51,440 --> 00:47:52,480
IT REQUIRES HEME TO SURVIVE SO

1038
00:47:52,480 --> 00:47:54,760
HAS TO HIJACK HEME SO THE

1039
00:47:54,760 --> 00:47:56,560
PROTEIN IS TURNED ON IN THE

1040
00:47:56,560 --> 00:47:58,480
ABSENCE OF HEME AND AS HEME

1041
00:47:58,480 --> 00:48:01,000
CONCENTRATION GOES UP AND DIALS

1042
00:48:01,000 --> 00:48:05,480
IT DOWN AND UNLIKE THAT, HUMAN

1043
00:48:05,480 --> 00:48:08,440
HRG1 IS TURNED ON WHEN THERE'S

1044
00:48:08,440 --> 00:48:09,640
HEME AS YOU WOULD EXPECT WHEN

1045
00:48:09,640 --> 00:48:12,800
IT'S ACQUIRED TO UNDERGO SO THE

1046
00:48:12,800 --> 00:48:17,240
DYNAMICS AND REGULATION OF

1047
00:48:17,240 --> 00:48:20,840
MACROPHAGE HRG1 AND HOST HRG1

1048
00:48:20,840 --> 00:48:22,080
ARE QUITE DIFFERENT.

1049
00:48:22,080 --> 00:48:32,640
SO HERE IT IS, THIS IS HOST HRGI

1050
00:48:33,040 --> 00:48:35,240
ON THE MACROPHAGES AND THEY ARE

1051
00:48:35,240 --> 00:48:37,440
INFECTED BY LAUCH MANIA AND IT'S

1052
00:48:37,440 --> 00:48:40,880
A OXY OPEN AND IT REQUIRES HEME

1053
00:48:40,880 --> 00:48:42,520
FOR ITS OWN SURVIVAL AND IT HAS

1054
00:48:42,520 --> 00:48:45,240
A DIFFERENT VARIATION OF THE

1055
00:48:45,240 --> 00:48:48,600
SAME FOUR TRANS MEMBRANE DOMAIN

1056
00:48:48,600 --> 00:48:50,400
PROTEIN, IT'S TRYING TO HIJACK

1057
00:48:50,400 --> 00:48:52,960
THE SAME SUBSTRATE OR NUTRIENT

1058
00:48:52,960 --> 00:48:55,640
TO BE ABLE REPLICATE AND DIVIDE.

1059
00:48:55,640 --> 00:48:58,760
THE INTERESTING THING, IS THAT

1060
00:48:58,760 --> 00:49:03,520
LHR1 AND HRG1 ARE ONLY 13%

1061
00:49:03,520 --> 00:49:03,800
IDENTICAL.

1062
00:49:03,800 --> 00:49:05,240
WHICH HAS IMPLICATIONS FOR THE

1063
00:49:05,240 --> 00:49:06,000
NEXT SLIDE.

1064
00:49:06,000 --> 00:49:08,280
SO THE QUESTION WE ARE ASKING IS

1065
00:49:08,280 --> 00:49:11,080
THAT DOES THIS COMPETITION OR

1066
00:49:11,080 --> 00:49:13,880
HEME TUG OF WAR OCCURS IN THE

1067
00:49:13,880 --> 00:49:17,040
SAME INTRA CELLULAR COMPARTMENT.

1068
00:49:17,040 --> 00:49:19,240
WE HAVE DONE A HIGH THROUGH PUT

1069
00:49:19,240 --> 00:49:22,200
DRUG SCREEN TO BE ABLE TO

1070
00:49:22,200 --> 00:49:32,600
IDENTIFY COMPOUNDS IS.

1071
00:49:49,040 --> 00:49:52,480
>> CONCENTRATIONS TO
TARGET LHR

1072
00:49:52,480 --> 00:49:55,360
WITHIN THE HOST MACROPHAGES

1073
00:49:55,360 --> 00:49:57,160
WITHOUT KILLING THE HOST CELL.

1074
00:49:57,160 --> 00:50:00,560
SO, ULTIMATELY, THERE ARE SOME

1075
00:50:00,560 --> 00:50:01,680
REALLY OUTSTANDING QUESTIONS

1076
00:50:01,680 --> 00:50:03,160
THAT WE WANT TO ANSWER.

1077
00:50:03,160 --> 00:50:05,600
THESE ARE NOT OUTSTANDING AS AN

1078
00:50:05,600 --> 00:50:07,400
AMAZING QUESTIONS BUT OUT STAND

1079
00:50:07,400 --> 00:50:09,320
BEING BECAUSE THEY STILL NEED TO

1080
00:50:09,320 --> 00:50:11,080
BE ANSWERED.

1081
00:50:11,080 --> 00:50:12,920
HOW IS HEME HOMEOSTASIS

1082
00:50:12,920 --> 00:50:15,080
REGULATED AT THE ORGANISMAL

1083
00:50:15,080 --> 00:50:15,360
LEVEL.

1084
00:50:15,360 --> 00:50:17,000
WE'VE BEEN ABLE TO GET SOME

1085
00:50:17,000 --> 00:50:18,480
INFORMATION AT THE CELLULAR

1086
00:50:18,480 --> 00:50:21,560
LEVEL AND SOME INFORMATION AT

1087
00:50:21,560 --> 00:50:23,520
HOW MULTIPLE CELLS COMMUNICATE

1088
00:50:23,520 --> 00:50:25,440
BUT HOW DOES THE ENTIRE ORGANISM

1089
00:50:25,440 --> 00:50:26,240
DEAL WITH THIS?

1090
00:50:26,240 --> 00:50:29,520
IS THERE A HEME SENSING

1091
00:50:29,520 --> 00:50:29,960
MECHANISM?

1092
00:50:29,960 --> 00:50:32,880
WHAT IS THE PATH OF

1093
00:50:32,880 --> 00:50:34,200
PHYSIOLOGICAL ROLE IN HUMANS AND

1094
00:50:34,200 --> 00:50:37,160
WE ARE STILL LOOKING FOR HUMAN

1095
00:50:37,160 --> 00:50:40,240
MUTATIONS THAT IF THEY ARE

1096
00:50:40,240 --> 00:50:41,120
THERE.

1097
00:50:41,120 --> 00:50:42,800
HOW IS HEME ACQUIRED AT THE OFF

1098
00:50:42,800 --> 00:50:45,960
THE HOST-PARASITE INTERFACE AND

1099
00:50:45,960 --> 00:50:47,160
HOW DOES HEME TRAFFIC IN LIVING

1100
00:50:47,160 --> 00:50:49,040
CELLS AND EARLY EMBRYOS.

1101
00:50:49,040 --> 00:50:50,240
WHICH WE REALLY DON'T UNDERSTAND

1102
00:50:50,240 --> 00:50:53,160
AND WE'RE ADDRESSING IT BY USING

1103
00:50:53,160 --> 00:50:55,080
GENETIC SCREENS IN C. ELEGANS TO

1104
00:50:55,080 --> 00:50:56,480
BE ABLE TO LOOK AT HOW ORGANS

1105
00:50:56,480 --> 00:50:58,400
AND TISSUES COMMUNICATE AND WHAT

1106
00:50:58,400 --> 00:51:00,840
IS THE PATH OF PHYSIOLOGICAL

1107
00:51:00,840 --> 00:51:03,760
ROLE IS THERE ALL THE HUMAN

1108
00:51:03,760 --> 00:51:06,360
VARIANTS WHICH ARE GENETIC

1109
00:51:06,360 --> 00:51:09,560
MODIFIERS OF DISEASE AND SUCH AS

1110
00:51:09,560 --> 00:51:13,800
SICKLE CELL, PLASMODIUM

1111
00:51:13,800 --> 00:51:17,400
INFECTIONS IT WAS DESCRIBED A #

1112
00:51:17,400 --> 00:51:20,920
HUNDRED YEARS AGO CALLED AFRICAN

1113
00:51:20,920 --> 00:51:23,120
EYE ON OVERLOAD IS THIS THE

1114
00:51:23,120 --> 00:51:26,080
GENETIC OF BOFTO SEE ROW SIS AND

1115
00:51:26,080 --> 00:51:28,880
HOW IS THE INTERFACE AND CAN YOU

1116
00:51:28,880 --> 00:51:31,520
USE SMALL MOLECULE INHIBITORS

1117
00:51:31,520 --> 00:51:35,400
AND FINALLY CAN WE DEVISE HEME

1118
00:51:35,400 --> 00:51:36,720
SENSORS AND NON-INVASIVE LABEL

1119
00:51:36,720 --> 00:51:40,960
FREE IMAGING TO BE ABLE TO LOOK

1120
00:51:40,960 --> 00:51:41,800
AT HEME AS ITS MOVING ON BETWEEN

1121
00:51:41,800 --> 00:51:46,120
CELLS AND WITHIN CELLS?

1122
00:51:46,120 --> 00:51:49,440
WITH THAT, THESE ARE THE AMAZING

1123
00:51:49,440 --> 00:51:51,120
GROUP OF PEOPLE THAT HAVE BEEN

1124
00:51:51,120 --> 00:51:52,800
DOING ALL THE WORK AND WITHIN

1125
00:51:52,800 --> 00:51:55,360
THING THAT YOU WILL NOTICE FROM

1126
00:51:55,360 --> 00:51:57,240
PHENOMENAL SET OF COLLABORATORS,

1127
00:51:57,240 --> 00:52:00,080
THAT NUMBER OF PEOPLE THAT HAVE

1128
00:52:00,080 --> 00:52:03,080
COLLABORATED AT THE NIH.

1129
00:52:03,080 --> 00:52:05,520
THEY HAVE BEEN VERY GENEROUS

1130
00:52:05,520 --> 00:52:07,600
WITH THEIR TIME, WITH THEIR

1131
00:52:07,600 --> 00:52:09,360
RESOURCES, AND HAVE DEEPLY

1132
00:52:09,360 --> 00:52:11,200
APPRECIATED THEIR HELP OVER THE

1133
00:52:11,200 --> 00:52:12,760
LAST 20 YEARS AND WITH THAT, I

1134
00:52:12,760 --> 00:52:14,840
WILL BE VERY HAPPY TO ANSWER

1135
00:52:14,840 --> 00:52:15,120
QUESTIONS.

1136
00:52:15,120 --> 00:52:16,320
THANK YOU FOR YOUR TIME AND FOR

1137
00:52:16,320 --> 00:52:17,760
YOUR ATTENTION.

1138
00:52:17,760 --> 00:52:27,960
 [APPLAUSE]

1139
00:52:32,960 --> 00:52:34,080
>> GREAT AS USUAL.

1140
00:52:34,080 --> 00:52:35,000
I ALWAYS LEARN A LOT.

1141
00:52:35,000 --> 00:52:39,920
IF I REMEMBER THE SLIDE WITH THE

1142
00:52:39,920 --> 00:52:43,560
LEISHMANIA, IF YOU PUT THAT

1143
00:52:43,560 --> 00:52:46,000
LEISHMANIA INTO YOUR HRG1,

1144
00:52:46,000 --> 00:52:50,160
MINUS, MINUS MICE WHERE THE

1145
00:52:50,160 --> 00:52:52,200
HEME, TUESDAY THAT MAKE IT

1146
00:52:52,200 --> 00:52:53,760
RESISTANT TO LEISHMANIA?

1147
00:52:53,760 --> 00:52:59,840
>> OK, SO, THEY'VE BORDANE
ASKED

1148
00:52:59,840 --> 00:53:02,480
ME THIS QUESTION IF YOU ARE

1149
00:53:02,480 --> 00:53:04,880
INFECT HRG1 KNOCK OUT MICE WHICH

1150
00:53:04,880 --> 00:53:07,480
IS ACCUMULATING A TON OF HEME AS

1151
00:53:07,480 --> 00:53:10,280
HEMA SEW INWITH LEISHMANIA, WHAT

1152
00:53:10,280 --> 00:53:12,600
WOULD HAPPEN?

1153
00:53:12,600 --> 00:53:14,640
SO, MY REGISTRANT MELISSA PERRY

1154
00:53:14,640 --> 00:53:16,320
HAS BEEN DOING THESE EXPERIMENTS

1155
00:53:16,320 --> 00:53:19,560
AND THE ANSWER IS, THAT THEY

1156
00:53:19,560 --> 00:53:22,760
HAVE VERY LOW PARASITE LOWER.

1157
00:53:22,760 --> 00:53:24,840
IF YOU TAKE THE SINGLE KNOCK OUT

1158
00:53:24,840 --> 00:53:31,560
PARASITE WHICH IS QUITE

1159
00:53:31,560 --> 00:53:34,440
CRIPPLED, AND INFECT THEM.

1160
00:53:34,440 --> 00:53:36,960
THEY DO WORSE THAN WILD TYPE

1161
00:53:36,960 --> 00:53:37,360
PARASITE.

1162
00:53:37,360 --> 00:53:38,680
BUT IF YOU LOOK AT THEIR ORGANS

1163
00:53:38,680 --> 00:53:49,200
THAT ARE INFECTED, IT'S A SIGN

1164
00:53:49,200 --> 00:53:56,960
OF THE MOR PARASITES YOU SEE IN

1165
00:53:56,960 --> 00:54:00,160
THE KNOCK OUT WHEN YOU INFECT

1166
00:54:00,160 --> 00:54:01,800
THEM WITH LEISHMANIA BUT WE'RE

1167
00:54:01,800 --> 00:54:06,240
TRYING TO FIGURE OUT WHY THAT IS

1168
00:54:06,240 --> 00:54:16,640
THE CASE.

1169
00:54:16,640 --> 00:54:19,520
>> ARE THE MA MALIA CELLS
MAKING

1170
00:54:19,520 --> 00:54:21,280
IT AND FOR THUR USE AND A CREM

1171
00:54:21,280 --> 00:54:24,200
CELLS HAVE A REFERENCE OR DO YOU

1172
00:54:24,200 --> 00:54:28,360
THINK IT'S EVOLVED IS A

1173
00:54:28,360 --> 00:54:32,560
PRODUCTIVE MECHANISM.

1174
00:54:32,560 --> 00:54:34,000
>> I'LL COME TO A POINT
WHERE I

1175
00:54:34,000 --> 00:54:35,320
DON'T KNOW THE INVESTIGATOR.

1176
00:54:35,320 --> 00:54:35,720
 [LAUGHTER] 

1177
00:54:35,720 --> 00:54:38,240
>> BUT ASHLEY ASKED ME
THIS

1178
00:54:38,240 --> 00:54:42,280
QUESTION THAT DO MAMMALIAN CELLS

1179
00:54:42,280 --> 00:54:46,120
MAKE A CHOICE THAT THEY CAN MAKE

1180
00:54:46,120 --> 00:54:46,960
THEIR OWN HEME AND THEY WANT TO

1181
00:54:46,960 --> 00:54:49,480
AND WHERE THEY CAN TAKE UP THE

1182
00:54:49,480 --> 00:54:50,640
HEME FROM THE OUTSIDE WHEN THEY

1183
00:54:50,640 --> 00:54:51,080
HAVE TO?

1184
00:54:51,080 --> 00:54:55,600
SO I'M GOING TO ANSWER THIS

1185
00:54:55,600 --> 00:54:56,800
QUESTION IN COLLABORATION WITH

1186
00:54:56,800 --> 00:54:59,440
MY COLLEAGUE AT MOUNT SINAI AND

1187
00:54:59,440 --> 00:55:01,840
WE KNOCKED OUT THE HEME

1188
00:55:01,840 --> 00:55:04,160
SYNTHESIS PATHWAY AND PARADISE

1189
00:55:04,160 --> 00:55:06,560
AND THIS IS UNPUBLISHED, RIGHT.

1190
00:55:06,560 --> 00:55:08,960
THE INITIAL THINKING WAS HEME

1191
00:55:08,960 --> 00:55:11,440
SYNTHESIS IS SO CRUCIAL THAT YOU

1192
00:55:11,440 --> 00:55:13,880
ARE KNOCK THEM OUT THE CELLS

1193
00:55:13,880 --> 00:55:15,600
SHOULD NOT GO THROUGH ONE ROUND

1194
00:55:15,600 --> 00:55:17,680
OF REPLICATION BUT WHEN DO YOU

1195
00:55:17,680 --> 00:55:21,360
IT IN VIVO USING LOCKS P AND

1196
00:55:21,360 --> 00:55:24,200
CREE EXCISION, ASK YOU KNOCK OUT

1197
00:55:24,200 --> 00:55:25,200
HEME SYNTHESIS THEY HAVE NORMAL

1198
00:55:25,200 --> 00:55:28,360
HEME IN THE PARASITES.

1199
00:55:28,360 --> 00:55:30,080
AND I'M GOING TO MACK A LONG

1200
00:55:30,080 --> 00:55:32,480
STORY SHORT OF DOING EXPERIMENTS

1201
00:55:32,480 --> 00:55:33,640
OVER THE LAST TWO AND A HALF

1202
00:55:33,640 --> 00:55:35,000
YEARS AND THE SHORT ANSWER IS

1203
00:55:35,000 --> 00:55:36,960
THAT, THEY GET A SIGNIFICANT

1204
00:55:36,960 --> 00:55:41,520
PORTION OF THEIR HEME FROM KUPER

1205
00:55:41,520 --> 00:55:42,160
CELLS.

1206
00:55:42,160 --> 00:55:44,440
SO, I HAVE EVOLVED WITH THIS

1207
00:55:44,440 --> 00:55:47,800
THINKING NOW IN THE LAST SIX

1208
00:55:47,800 --> 00:55:50,840
MONTHS, THAT MAMMALIAN CELLS ARE

1209
00:55:50,840 --> 00:55:55,000
QUITE PLASTIC AND THE IF THEY

1210
00:55:55,000 --> 00:55:59,520
NEED TO MAKE HEME, THEY WILL

1211
00:55:59,520 --> 00:56:00,320
MAKE IT AND THEY NEED BEYOND A

1212
00:56:00,320 --> 00:56:03,360
SPECIFIC THRESHOLD, THEY'LL GET

1213
00:56:03,360 --> 00:56:05,320
IT FROM THE SURROUNDING CELL AND

1214
00:56:05,320 --> 00:56:07,280
WHAT BETTER CELLS TO GET IT FROM

1215
00:56:07,280 --> 00:56:09,720
THAN A PROFESSIONAL HEME

1216
00:56:09,720 --> 00:56:12,960
RECYCLING CELL SUCH AS A

1217
00:56:12,960 --> 00:56:13,240
MACROPHAGES.

1218
00:56:13,240 --> 00:56:16,000
SO IN ANY SENSE I THINK THAT

1219
00:56:16,000 --> 00:56:20,560
THIS IS EVOLVING INTO SOMETHING

1220
00:56:20,560 --> 00:56:21,440
WHICH C. ELEGANS HAS DECIDE A

1221
00:56:21,440 --> 00:56:31,960
LONG TIME AND THE EME CODE IS

1222
00:56:41,320 --> 00:56:44,240
44431.

1223
00:56:44,240 --> 00:56:44,400
OK.

1224
00:56:44,400 --> 00:56:54,920
>> IT'S A MOLECULE THAT
WOULD

1225
00:56:54,920 --> 00:56:56,400
NEED TO BE SHAPER OWNED.

1226
00:56:56,400 --> 00:56:58,640
I'M CURIOUS, DO YOU THINK THAT

1227
00:56:58,640 --> 00:57:05,040
WE HAVE A SENSE OF THE GAMUT

1228
00:57:05,040 --> 00:57:06,480
THAT THEY UTILIZE OR DO YOU

1229
00:57:06,480 --> 00:57:08,120
THINK THERE WILL BE PRIZES THERE

1230
00:57:08,120 --> 00:57:09,600
AND I'M CURIOUS TO KNOW YOUR

1231
00:57:09,600 --> 00:57:11,160
GENERAL THOUGHTS ABOUT THIS.

1232
00:57:11,160 --> 00:57:13,720
>> DO I HAVE A SENSE OF
THE

1233
00:57:13,720 --> 00:57:13,920
GAMUT?

1234
00:57:13,920 --> 00:57:15,880
I DON'T HAVE A SENSE.

1235
00:57:15,880 --> 00:57:22,200
PARTLY BECAUSE I WOULDN'T HAVE A

1236
00:57:22,200 --> 00:57:26,720
SENSE 15 YEARS AGO AS A HEME

1237
00:57:26,720 --> 00:57:28,480
TRANSPORTER BUT DOES IT MAKE

1238
00:57:28,480 --> 00:57:29,600
BIOCHEMICAL SENSE THAT THEY

1239
00:57:29,600 --> 00:57:31,480
SHOULD HAVE ONE, ABSOLUTELY.

1240
00:57:31,480 --> 00:57:35,360
AND I GIVE THIS EXAMPLE A LOT,

1241
00:57:35,360 --> 00:57:35,760
ACTUALLY.

1242
00:57:35,760 --> 00:57:39,800
THAT WHEN CHOLESTEROL SYNTHESIS

1243
00:57:39,800 --> 00:57:42,760
PATHWAY AS YOU SEE

1244
00:57:42,760 --> 00:57:44,760
SYSTEMATICALLY DISSECTED PEOPLE

1245
00:57:44,760 --> 00:57:46,560
SAID THERE'S NO REASON TO

1246
00:57:46,560 --> 00:57:48,360
TRANSPORT CHOLESTEROL, SINCE

1247
00:57:48,360 --> 00:57:49,800
THEN, INVESTIGATORS ARE

1248
00:57:49,800 --> 00:57:53,160
IDENTIFYING AN INTRICATE NETWORK

1249
00:57:53,160 --> 00:57:54,160
OF CHOLESTEROL TRANSPORT

1250
00:57:54,160 --> 00:57:56,560
PATHWAYS AS I WOULD CONSIDER

1251
00:57:56,560 --> 00:58:01,720
COLLEST TO BE INNOCUOUS COMPARED

1252
00:58:01,720 --> 00:58:02,640
TO HEME AND CHOLESTEROL, IF YOU

1253
00:58:02,640 --> 00:58:04,360
ARE KNOCK OUT THE PRE TEEN WHICH

1254
00:58:04,360 --> 00:58:07,240
WILL BE ALMOST EQUAL TO HRG1,

1255
00:58:07,240 --> 00:58:12,880
WALL IT NCP1, THE CHOLESTEROL

1256
00:58:12,880 --> 00:58:14,840
WITHIN THE MACROPHAGES AND

1257
00:58:14,840 --> 00:58:18,360
WITHIN THE LOOM INCONTAINS MMPC2

1258
00:58:18,360 --> 00:58:20,560
WHICH IS A CHOLESTEROL SHAPER

1259
00:58:20,560 --> 00:58:23,480
OWN WHICH TAKES UP AND DELIVERS

1260
00:58:23,480 --> 00:58:27,400
IT TO MCP1 SO IF THE CHOLESTEROL

1261
00:58:27,400 --> 00:58:30,240
CAN HAVE A CHAPERON AND A

1262
00:58:30,240 --> 00:58:31,880
TRANSPORTER, YOU WOULD BET THAT

1263
00:58:31,880 --> 00:58:35,240
THERE WOULD BE A HEME CHAPERON

1264
00:58:35,240 --> 00:58:38,880
WITHIN THE LOOMIN OF THE LIME SO

1265
00:58:38,880 --> 00:58:40,760
SEEM TO PICK UP THE HEME,

1266
00:58:40,760 --> 00:58:42,960
DELIVER IT AND THAT HEME THEN

1267
00:58:42,960 --> 00:58:45,000
SHOULD BE ROW LAID FROM HRG1 TO

1268
00:58:45,000 --> 00:58:47,880
EVEN OF THE DOWNSTREAM FACTORS

1269
00:58:47,880 --> 00:58:51,200
SO WORE DOING THAT IN VIVO USING

1270
00:58:51,200 --> 00:58:52,360
THIS MICE THAT WE DEVELOPED IN

1271
00:58:52,360 --> 00:58:55,040
THE LAST TWO YEARS.

1272
00:58:55,040 --> 00:59:00,840
>> THE QUESTION IS ABOUT
THE YOU

1273
00:59:00,840 --> 00:59:03,560
KNOCKED OUT THE HEME PATHWAY IN

1274
00:59:03,560 --> 00:59:07,240
THE HIGH PATHO SIDES SO IS HRG1

1275
00:59:07,240 --> 00:59:12,000
UP REGUL REGULATED THERE OR IS 1

1276
00:59:12,000 --> 00:59:17,880
GOING TO THE M PLASMA MEMBRANE.

1277
00:59:17,880 --> 00:59:21,120
>> SO, WIN ASKED ME THIS

1278
00:59:21,120 --> 00:59:24,000
QUESTION THAT IF YOU LOCK AT THE

1279
00:59:24,000 --> 00:59:29,000
PARASITES THAT IS NOW, THAT CAN

1280
00:59:29,000 --> 00:59:32,720
CANNOT MAKE HEME, IS HRG1 UP

1281
00:59:32,720 --> 00:59:33,400
REGULAR GATED AND I DON'T KNOW

1282
00:59:33,400 --> 00:59:35,200
THE ANSWER BECAUSE WE JUST GOT

1283
00:59:35,200 --> 00:59:38,240
THESE RESULTS FROM THOSE.

1284
00:59:38,240 --> 00:59:43,160
BUT ALL I CAN CAN SAY THAT HRG1

1285
00:59:43,160 --> 00:59:45,720
FROM MACROPHAGES IS IMPORTANT

1286
00:59:45,720 --> 00:59:51,400
FOR SITES TO GET IT HEME AND I

1287
00:59:51,400 --> 00:59:53,280
DO NOT WHETHER IF IT'S IMPORTANT

1288
00:59:53,280 --> 00:59:55,680
OR NOT AND THE ONLY WAY TO DO

1289
00:59:55,680 --> 00:59:58,440
THAT EXPERIMENT NOW AND IS TO

1290
00:59:58,440 --> 01:00:08,960
KNOCK OUT HRB1 AND TO THE BONE

1291
01:00:09,640 --> 01:00:12,680
MR. OWE --

1292
01:00:12,680 --> 01:00:15,640
>> CAN YOU COMMENT ON

1293
01:00:15,640 --> 01:00:16,000
TRANSPORTING?

1294
01:00:16,000 --> 01:00:18,000
>> BY HRG1?

1295
01:00:18,000 --> 01:00:18,480
>> YES.

1296
01:00:18,480 --> 01:00:23,800
>> I CAN HAND WAVE AND I
CAN SAY

1297
01:00:23,800 --> 01:00:27,200
THIS AND THAT THERE'S A HISS TA

1298
01:00:27,200 --> 01:00:30,920
TEEN IN THE CENTRE CELLULAR LOOP

1299
01:00:30,920 --> 01:00:31,680
WHICH IS CRITICAL FOR TRANSPORT

1300
01:00:31,680 --> 01:00:34,840
SO IT GOES FROM EXTRA CELLULAR

1301
01:00:34,840 --> 01:00:36,960
INTO THE CYTOPLASM IS IN THE

1302
01:00:36,960 --> 01:00:38,920
TRANS MEMBRANE DOMAIN IF YOU

1303
01:00:38,920 --> 01:00:41,440
KNOCK IT OUT AND THE TRANSPORT

1304
01:00:41,440 --> 01:00:43,160
DOESN'T HAPPEN AND THERE ARE

1305
01:00:43,160 --> 01:00:46,720
THROW RESIDUES IN THE TAIL WHICH

1306
01:00:46,720 --> 01:00:49,120
IS ESSENTIAL FOR HEME TO GET

1307
01:00:49,120 --> 01:00:51,240
OUT, LET'S CALL IT A CHANNEL FOR

1308
01:00:51,240 --> 01:00:52,320
THE SAKE OF ANYTHING ELSE.

1309
01:00:52,320 --> 01:00:55,200
TO GET OUT OF THE CHANNEL INTO

1310
01:00:55,200 --> 01:00:56,440
THE (INAUDIBLE).

1311
01:00:56,440 --> 01:01:01,200
IT'S COUPLED TO A V TYPE ATPAs

1312
01:01:01,200 --> 01:01:04,640
SO IF YOU KNOCK OUT THE V-TYPE

1313
01:01:04,640 --> 01:01:07,840
THEN H RG1 CANNOT TRANSPORT

1314
01:01:07,840 --> 01:01:08,040
HEME.

1315
01:01:08,040 --> 01:01:09,560
IT'S A SECONDARY TRANSPORTER.

1316
01:01:09,560 --> 01:01:12,320
I DO NOT KNOW ANYTHING ABOUT

1317
01:01:12,320 --> 01:01:14,800
WHAT ITS STRUCTURE IS.

1318
01:01:14,800 --> 01:01:17,760
IT RUNS MINIMALLY AS A TRIMER

1319
01:01:17,760 --> 01:01:20,160
THAT COULD BE A TETRAMER.

1320
01:01:20,160 --> 01:01:22,640
>> ARE YOU TARGETING THAT

1321
01:01:22,640 --> 01:01:22,840
DOMAIN?

1322
01:01:22,840 --> 01:01:24,160
>> I AM.

1323
01:01:24,160 --> 01:01:25,720
>> YOUR INHIBITOR.

1324
01:01:25,720 --> 01:01:30,280
>> CAN YOU COMMENT ON YOUR
--

1325
01:01:30,280 --> 01:01:31,760
WHAT DOES IT LOOK LIKE?

1326
01:01:31,760 --> 01:01:42,280
>> CHEM BEING TREE, I'VE
BEEN

1327
01:01:45,240 --> 01:01:46,760
WORKING WITH THE CHEMIST AND ALL

1328
01:01:46,760 --> 01:01:56,160
I CAN CAN TELL YOU AND THIS ALL

1329
01:01:56,160 --> 01:01:59,320
THE BLOCK AND OUR INITIAL GOAL

1330
01:01:59,320 --> 01:02:00,960
AND I'M GOING TO FINISH BY

1331
01:02:00,960 --> 01:02:05,720
SAYING IF ORGANISMS CAN TOLERATE

1332
01:02:05,720 --> 01:02:10,600
10 OR 20 FOLD BY SEQUESTERING

1333
01:02:10,600 --> 01:02:13,960
AND IT'S POSSIBLE TO USE AN

1334
01:02:13,960 --> 01:02:24,160
TAGGISM OF HRBBT AS A WAY.

1335
01:02:24,160 --> 01:02:29,840
>> WE HAVE A BASIC
QUESTION.

1336
01:02:29,840 --> 01:02:33,320
WHAT IS THE BASIS OF HEME

1337
01:02:33,320 --> 01:02:34,840
TOXICITY AND WHY HAS THE BODY

1338
01:02:34,840 --> 01:02:36,640
CHOSEN TO TRANSPORT IRON IN A

1339
01:02:36,640 --> 01:02:41,360
TOXIC MOLECULE?

1340
01:02:41,360 --> 01:02:44,480
>> WHY HAS THE BODY CHOSEN
TO

1341
01:02:44,480 --> 01:02:48,560
TRANSPORT IRON IN A TOXIC

1342
01:02:48,560 --> 01:02:49,400
MOLECULE?

1343
01:02:49,400 --> 01:02:50,720
OH, I SEE.

1344
01:02:50,720 --> 01:02:57,440
I AM WITHIN HEME AS A TOX HE CAC

1345
01:02:57,440 --> 01:02:57,960
MOLECULE.

1346
01:02:57,960 --> 01:03:00,760
IRON CLUSTERS COPPER, HEME SO IF

1347
01:03:00,760 --> 01:03:02,680
YOU WERE TO LOOK FROM AN

1348
01:03:02,680 --> 01:03:05,880
EVOLUTIONARY PERSPECTIVE, HEMES

1349
01:03:05,880 --> 01:03:10,720
HAVE EVOLVED MUCH LATER IN LIFE

1350
01:03:10,720 --> 01:03:16,680
THROUGH EVOLUTION THAT ARE

1351
01:03:16,680 --> 01:03:20,280
INVOLVED IN OXYGEN TRANSPORT.

1352
01:03:20,280 --> 01:03:23,600
CRABS AND LOBSTER DON'T HAVE

1353
01:03:23,600 --> 01:03:25,520
HEMOGLOBIN BASED.

1354
01:03:25,520 --> 01:03:26,200
I LOOK AT IT.

1355
01:03:26,200 --> 01:03:27,400
>> I'M TRYING TO PLAY THE
PART

1356
01:03:27,400 --> 01:03:27,760
AS WELL.

1357
01:03:27,760 --> 01:03:30,600
>> SO I THINK THAT THE

1358
01:03:30,600 --> 01:03:32,320
REACTIVITY AS THE OXYGEN

1359
01:03:32,320 --> 01:03:36,640
CONCENTRATION INCREASED IN THE

1360
01:03:36,640 --> 01:03:37,960
ATMOSPHERE, HEMES ARE FAR MORE

1361
01:03:37,960 --> 01:03:42,360
CATALYTICALLY SUPERIOR THAN

1362
01:03:42,360 --> 01:03:43,880
OTHER FORMS OF FACTORS.

1363
01:03:43,880 --> 01:03:49,280
>> SO WHY HAS THE CELL
CHOSEN TO

1364
01:03:49,280 --> 01:03:51,720
TRANSPORT HEME INSTEAD OF NON

1365
01:03:51,720 --> 01:03:53,160
HEME BASED CO FACTORS.

1366
01:03:53,160 --> 01:03:56,200
I CAN CAN REALLY HAND WAVE.

1367
01:03:56,200 --> 01:03:57,960
I DON'T HAVE FULL ANSWERS FOR

1368
01:03:57,960 --> 01:04:01,640
THAT, ALLEN.

1369
01:04:01,640 --> 01:04:02,800
>> THANK YOU THAT YOU'VE

1370
01:04:02,800 --> 01:04:06,360
INSPIRED AT LEAST A DOZEN PEOPLE

1371
01:04:06,360 --> 00:00:00,000
TO JOIN WALS LISTSERV