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  • >> GOOD AFTERNOON, EVERYONE.

  • THIS IS A SPECIAL DAY BECAUSE WE

  • ARE IN THE FIRST DAY OF THE NIH

  • RESEARCH FESTIVAL AND A SPECIAL

  • DAY BECAUSE WE HAVE A REMARKABLE

  • LECTURER AS PART OF OUR REGULAR

  • WEDNESDAY AFTERNOON SERIES WHO

  • IS HERE TO TEACH US SOMETHING

  • PRETTY INTERESTING ABOUT VIRAL

  • HEMORRHAGIC FEVER, SPECIFICALLY EBOLA VIRUS.

  • ERICA OLLMANN SAPHIRE HAS AN

  • INTERESTING AND VERY PRODUCTIVE

  • CAREER BRINGING HER TO WHERE SHE

  • IS A PROFESSOR IN IMMUNOLOGY AND

  • MICROBIAL SCIENCE AT THE SCRIPPS

  • RESEARCH INSTITUTE.

  • WE FOUND A PROFILE OF HER IN THE

  • SAN DIEGO UNION TRIBUNE WHERE

  • SHE WAS CALLED, THE VIRUS

  • HUNTER.

  • AND VARIOUS COMMENTS WERE MADE

  • ABOUT HER CONTRIBUTIONS, WHICH

  • ARE OBVIOUSLY SUBSTANTIAL.

  • I WON'T COMMENT UPON WHAT THEY

  • CALLED HER, ALIAS, STEEL

  • MAGNOLIA.

  • I THOUGHT THAT WAS ODD TO BE

  • PUTTING IN A PROFILE OF A

  • SCIENTIST BUT YOU CAN DECIDE FOR

  • YOURSELF.

  • SHE GOT HER UNDERGRADUATE DEGREE

  • AT RICE WITH A DOUBLE MAJOR IN

  • BIOCHEM AND CELL BIOLOGY AND

  • ECOLOGIY AND EVOLUTIONARY

  • BIOLOGY AND PH.D. AT THE SCRIPPS

  • IN THE YEAR 2000.

  • AND HAS BEEN THERE IN THIS

  • REMARKABLE PRODUCTIVE ENTERPRISE

  • FOCUSED ON TRYING TO UNDERSTAND

  • HOW PATHOGENS EVADE AND USURP

  • THE INNATE AND ADAPTIVE IMMUNE

  • RESPONSES.

  • SHE HAS QUITE A DIVERSITY OF

  • PROJECTS GOING ON IN THE LAB

  • INCLUDING LASSA AND MARRER AND

  • EBOLA FEVER AND SHE IS AN EXPERT

  • IN INCORPORATING DIFFERENT

  • APPROACHES TO INTERESTING THIS

  • INCLUDING IMFROG NOLOGY AND

  • EXTRA CRYSTALLOGRAPHY --

  • IMMUNOLOGY -- AND I WANT TO

  • POINT OUT AT THE END OF THE

  • LECTURE, WE WILL HAVE TIME FOR

  • QUESTIONS AND THE MICROPHONES

  • ARE IN THE AISLE AND WELCOME TO

  • THOSE OF YOU WHO ARE WATCHING ON

  • THE WEB.

  • WE'LL TRY TO BE SURE THAT

  • QUESTIONS ARE POSED FROM THE

  • MICROPHONE SO YOU CAN HEAR THEM

  • AND THEN AT 4:00, WE'LL ADJOURN

  • DOWN THE HALL FOR CONTINUATION

  • OF INFORMAL CONVERSATIONS WITH

  • OUR SPEAKER BUT ALSO THE ACTUAL

  • FORMAL UNVEILING OF THE NEW FAES

  • CENTER, WHICH I THINK YOU'LL

  • WANT TO COME AND HAVE A LOOK AT

  • BECAUSE IT IS REALLY QUITE

  • BEAUTIFUL FACILITY AND WE'LL

  • HAVE A RIBBON CUTTING AND A FEW

  • HOPEFULLY SHORT SPEECHES AND

  • THAT WILL MORPH INTO A POSTER

  • SESSION WHERE THE SCIENTIFIC

  • DIRECTORS WHO ARE THEMSELVES

  • STANDING BY THEIR POSTERS

  • TALKING ABOUT THEIR SCIENCE

  • GIVING YOU A CHANCE TO HAD THE

  • THEM UP WITH REALLY HARD

  • QUESTIONS.

  • SO IT WILL BE QUITE AN

  • AFTERNOON.

  • BUT, TO GET US GOING HERE, IN MA

  • SUR, LET ME ASK YOU PLEASE TO,

  • GIVE A WARM WELCOME TO ERICA

  • OLLMANN SAPHIRE.

  • [ APPLAUSE ]

  • >> THANK YOU, DR. COLLINS.

  • IT'S A REAL PLEASURE TO BE HERE.

  • MY LABORATORY WORKS ON A LOT OF

  • DIFFERENT VIRUSES.

  • TODAY I'M GOING SHOW YOU CHAMPS

  • FROM TWO OF THEM.

  • THE FIRST ONE IS EBOLA VIRUS, A

  • LONG VIRUS AND THE SECOND ONE IS

  • A SMALLER ROUNDER PARTICLE AND

  • IT BELONGS TO THE ARENA VIRUS

  • FAMILY.

  • WHAT THEY HAVE IN COMMON IS A

  • SIMILAR DISEASE.

  • THEY BOTH CAUSE HEMORRHAGIC

  • FEVER AND THE SYMPTOMS LOOK

  • SIMILAR ESPECIALLY AT FIRST.

  • WHEREAS EBOLA IS QUITE RARE,

  • LASSA IS UNFORTUNATELY EXTREMELY

  • COMMON.

  • THERE ARE HUNDREDS OF THOUSANDS

  • OF CASES EVERY YEAR IN WESTERN

  • AFRICA AND THE FEVER IS MOST

  • FREQUENTLY IS IMPORTED TO THE

  • UNITED STATES AND EUROPE.

  • NOW WHAT ELSE THESE VIRUS VS. IN

  • COMMON IS A VERY SMALL GENOME.

  • EBOLA ENCODES SEVEN GENES LASSA

  • ONLY 4.

  • SO WHERE YOU HAVE 25,000 GENES

  • AND YOU CAN MAKE 25,000

  • PROTEINS, THESE VIRUSES MAKE

  • ONLY A FEW.

  • SO, USING THIS VERY LIMITED

  • PROTEIN TOOLKIT, HOW DOES A

  • VIRUS ACHIEVE ALL THE DIFFERENT

  • FUNCTIONS OF THE VIRUS LIFE

  • CYCLE FROM ATTACH WANT TO A NEW

  • HOST CELL, FUSION AND ENTRY AND

  • ENCODING AND TRANSCRIPTIONS AND

  • ASSEMBLY AND EXIT AND SOME OF

  • THE MORE SOPHISTICATED FUNCTIONS

  • FOR LOTS OF DIFFERENT PATHWAYS.

  • HOW DO THEY DO THAT?

  • ONLY A VERY FEW PROTEINS AT

  • THEIR DISPOSAL.

  • THIS IS THE GENOME OF LASSA

  • VIRUS.

  • THOSE ARE -- THAT WAS EBOLA AND

  • THIS IS LASSA.

  • SO HOW DOES A HANDFUL OF

  • PROTEINS CONSPIRE TO CREATE SUCH

  • EXTRAORDINARY PATHOGENESIS IN

  • HEMORRHAGIC FEVER?

  • THE ANSWER IS THAT EACH PROTEIN

  • THESE VIRUSES DO ENCODE IS

  • ESSENTIAL.

  • THESE VIRUS VS. NO JUNK.

  • MANY OF THESE PROTEINS ARE

  • MULTI-FUNCTIONAL AND SOME ARE

  • EXTREMELY ADAPTABLE.

  • BY STUDYING THE PROTEINS THESE

  • VIRUSES MAKE, WE SEE THE

  • VULNERABILITIES OF THE VIRUS,

  • THE ACHILLES HEEL, THE PLACE TO

  • TARGET A DRUG OR VACCINE OR

  • ANTIBODY.

  • BUT PERHAPS MORE IMPORTANTLY, WE

  • CAN UNDERSTAND SOMETHING MORE

  • ABOUT PROTEINS THEMSELVES.

  • BECAUSE EVOLUTION HAS COMPELLED

  • THESE PROTEINS TO BE REMARKABLE,

  • TO DO MORE WITH LESS THAN OTHER

  • PROTEINS BY STUDYING WHAT THESE

  • PROTEINS ARE CAPABLE OF, WE

  • LEARN ABOUT THE CAPABILITIES OF

  • PROTEINS IN MOLECULAR BIOLOGY.

  • SO I'LL SHOW YOU A FEW EXAMPLES.

  • THE FIRST ONE COMES FROM THE

  • FIRST STEP OF THE VIRUS LIFE

  • CYCLE.

  • SO THE FIRST STEP, THE VIRUS HAS

  • TO FIND AND ATTACH TO A NEW HOST

  • CELL.

  • THIS IS ACHIEVED BY THE

  • GLYCOPROTEIN CALLED GP.

  • BOTH VIRUSES EXPRESS ONLY ONE

  • PROTEIN ON THE SURFACE CALLED GP

  • AND IT IS SOLELY RESPONSIBLE FOR

  • ATTACHING WITH THAT CELL.

  • SO EBOLUS VIRUS FILAMENT US.

  • THIS HAS A MEMBRANE OF GREEN

  • SURROUNDING A NUCLEO CAP SID.

  • AND THERE ARE SPIKES.

  • THOSE ARE FORMING 450

  • KILLADALTON TRIMERS AND THEY ARE

  • QUITE HEAVILY GLYCOSYLATED.

  • SO THE QUESTION YOU MIGHT ASK

  • IS, IF THIS SPIKE IS IMPORTANT

  • FOR ATTACHMENT AND ENTRY, WHAT

  • DOES IT LOOK LIKE AND HOW DOES

  • IT WORK?

  • WE HAD TO MAKE ABOUT 140

  • VERSIONS OF THIS GP TO GET ONE

  • THAT WOULD CRYSTALLIZE WELAND WE

  • HAD TO THROW BACK 150.

  • BEFORE WE HAVE A STRUCTURE, WE

  • THINK OF A PROTEIN WITH AN END

  • TERMINUS AND C TERMINUS.

  • THIS IS CLEAVED IN THE PRODUCER

  • CELL, WITH 2 SUB UNITS.

  • A GP1 WHICH MEDIATES THE

  • RECEPTOR BINDING AND GP2 WHICH

  • MEDIATES FUSION.

  • SO THE BP1 HAS RECEPTOR BINDING

  • DOMAINS AND THE GP2 HAS TO

  • UNDERGO A CHANGE.

  • ALSO IN GP1 IS THIS UNUSUAL MUSE

  • IN-LIKE DOMAIN IT'S VERY HEAVILY

  • GLYCOSYLATED.

  • THERE IS A LOT OF UNSTRUCTURED

  • PROTEIN HERE.

  • SO THIS IS THE CRYSTAL STRUCTURE

  • OF THE EBOLA VIRUS GP.

  • YOU CAN SEE THE 3GP1 SUBUNITS IN

  • BLUE AND GREEN.

  • THESE RECEPTOR BINDING ARE TIED

  • TOGETHER AT THE BOTTOM BY THE

  • GP2 FUSION SUBUNITS.

  • NOW THERE IS SOMETHING

  • INTERESTING HERE.

  • WHEN YOU THINK ABOUT A FUSION

  • PEPTIDE OR FLU OR HIV, IT'S A

  • HYDROPHOBIC PEPTIDE TUCKED UP

  • INSIDE THE STRUCTURE.

  • HERE ARE THE FUSION LOOP IT IS

  • TACKED ON TO THE OUTSIDE.

  • THIS REACHES ALONG THE OUTSIDE

  • AND BINDS INTO THE NEXT ONE.

  • IN ORDER TO GET THIS TO

  • CRYSTALLIZE, WE HAD TO EXIZE AND

  • WE WANT TO UNDERSTAND WHAT THE

  • REAL GP LOOKS LIKE ON THE

  • SURFACE.

  • IT HAS HEAVILY GLYCOSYLATED

  • DOMAINS ATTACHED AT THE TOP.

  • NOTE GP ONE TAINING THAT DOMAIN

  • CRYSTALLIZES AND WE HAD TO USE A

  • DIFFERENT TECHNIQUE.

  • A SMALL SCATTERING, TINY X-RAYS

  • AND PROTEIN MOLECULES TUMBLING

  • AROUND IN SOLUTION GET A LOW

  • RESOLUTION VIEW, MAYBE 10

  • RESOLUTION.

  • AND THEN THIS, TURNS OUT THIS IS

  • THE SOLUTION SCATTERING ENVELOPE

  • OF THE GLYCOSYLATED EBOLA VIRUS

  • GP.

  • SO THE CRYSTAL SHUCK STRUCTURE

  • IS IN THE RIBBON CENTER.

  • SO THESE ARE THE DOMAINS

  • ATTACHED.

  • SO THE EFFECTIVELY TRIPLE THE

  • SIZE OF THE MOLECULE.

  • AND THIS IS A HELL OF A GLYCAN

  • SHE WOULD.

  • THEY REACH ABOUT 100 FROM THE

  • CORE OF THE G.

  • AND THEY ARE QUITE FLEXIBLE SO I

  • EXPECT THE ACTUAL WILT OF THIS

  • DOMAIN TO BE HALF THAT.

  • I THINK VISUALIZING THE

  • FLEXIBILITY AS WELL.

  • THE SALIENT FEATURE OF THIS IS

  • THAT THESE MUSE IN-LIKE DOMAINS

  • ARE MASSIVE AND THEY DOMINATE

  • THE STRUCTURE.

  • S OKAY?

  • SO THIS IS WHAT IS ON THE