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

BIOSURFACE.

HOW DOES IT WORK?

HOW DOES IT FIND AND GET INTO A

NEW CELL?

WELL, THIS I'M SHOWING AGAIN THE

CRYSTAL STRUCTURE AND COLORING

THE SURFACE WHITE.

PATCHES THAT ARE COLORED PINK

ARE AREAS THAT MUTAGENESIS TELLS

US ARE IMPORTANT FOR

INFECTIVITY.

THEY ARE SEQUESTERED INSIDE THE

BOWL SHIP THAT IT MAKES.

THE RESIDUES MOST IMPORTANT TO A

SEPARATE BINDING ARE VERY

SEQUESTERED.

INSIDE STRUCTURE UNDER THIS

DOMAIN.

SO THAT IS SORT OF A

REPRESENTATION OF WHERE THE

DOMAINS ARE.

THE PARTS THAT ARE IMPORTANT FOR

THE RECEPTOR BINDING ARE PINK

AND THEY ARE UNDER THESE DOMAINS

CALLED THE GLYCAN CAP.

SO, DOES THIS MAKE INNOCENCE HOW

ON EARTH IS THIS AFFECTED UNDER

THIS ENTIRE CANOPY OF PROTEIN

CARBOHYDRATES?

THE ANSWER IS THAT IT IS KNOWN

FROM BIOLOGY THAT GP NEEDS TO BE

CLEAVED BY HOST CAPSAICIN

ENZYMES FOR THIS TO OCCUR.

THIS IS ESPECIALLY IMPORTANT FOR

EBOLA VIRUS.

SO, WHY?

WELL, IN SOLVING THE CRYSTAL