I'M PATRICK STILL.
DIRECTOR IN THE BRANCH AT
THE NATIONAL CENTER FOR
COMPLEMENTARY AND INTEGRATIVE
HEALTH, OR NCCIH AT THE NATIONAL
INSTITUTES OF HEALTH.
THANK YOU FOR JOINING US FOR
EXPANDING TRANSLATIONALLY
RELEVANT CHEMICAL SPACE,
INSIGHTS INTO NATURAL PRODUCT
RESOURCES, TECHNOLOGIES, AND
MECHANISMS.
THE SECOND PART OF A TWO-PART
WEBINAR SERIES.
FIRST I WOULD LIKE TO TAKE A FEW
MOMENTS TO ACKNOWLEDGE THE MANY
PEOPLE THAT BROUGHT THIS WEBINAR
TO FRUITION, INCLUDING DR.
EMMELINE EDWARDS, DIRECTOR OF
OUR DIVISION OF EXTRAMURAL
RESEARCH, WHO REALLY CHAMPIONED
THIS WEBINAR.
DR. CRAIG HOPP, DIRECTOR OF OUR
EXTRAMURAL RESEARCH BRANCH AND
DR. WEN CHEN, CHIEF OF
MECHANICISTIC AND RESEARCH
BRANCH AS WELL AS THE MANY
COLLEAGUES WHO PLANNED LOGISTICS
AND PROMOTIONS OF THIS EVENT,
CATHERINE LAW, IRENE LOU, MS.
WILLIAMS, MS. EILEEN AMADOR AND
MANY OTHERS WHO WORKED BEHIND
THE SCENES.
BEFORE WE BEGIN TODAY, A FEW
LOGISTICS.
FOR NIH VIDEO CAST VIEWERS, YOU
CAN PROVIDE FEEDBACK IN THE FORM
BELOW YOUR SCREEN FOR VIEWING
THE LIVE STREAM.
WE WILL TRY TO GET TO AS MANY
QUESTIONS AS POSSIBLE DURING THE
QUESTION AND ANSWER PERIODS, BUT
WE ARE UNLIKELY TO GET TO EVERY
QUESTION.
HOWEVER, ALL QUESTIONS SUBMITTED
WILL BE COLLECTED AND SHARED
WITH THE PLANNING TEAM.
FINALLY, THIS EVENT IS BEING
RECORDED AND WILL BE ARCHIVED ON
THE NIH VIDEO CAST WEBSITE FOR
FUTURE VIEWING.
OKAY.
SO WITH THOSE REMINDERS COVERED,
I'M NOW PLEASED TO INTRODUCE DR.
EMMELINE EDWARDS, DIRECTOR OF
THE NCCIH DIVISION OF EXTRAMURAL
RESEARCH WHO WILL SHARE WORDS OF
WELCOME BEFORE WE DIVE INTO OUR
PRESENTATIONS.
DR. EDWARDS.
>>THANK YOU, PATRICK.
WELCOME, EVERYONE.
IT IS REALLY A PLEASURE TO
REALIZE THE INTEREST THAT THOSE
WEBINARS HAVE ENCOUNTERED.
AND I'M REALLY PLEASED TO TELL
YOU A LITTLE BIT ABOUT THE
IMPORTANCE OF NATURAL PRODUCT AS
ESSENTIAL PORTION OF OUR
PORTFOLIO AT NCCIH.
WE SUPPORT RESEARCH ACROSS THE
RESEARCH CONTINUUM.
WE SUPPORT IN VITRO, IN VIVO AS
WELL AS CLINICAL TRIALS.
THE LAST COUPLE OF YEARS WE HAVE
FOCUSED IMPACT ON THE
CANNABINOID ON THERAPEUTIC
POTENTIAL, NATURAL PRODUCTS IN
GENERAL IN PAIN AND NUTRITION
FOR PRECISION HEALTH.
ALL OF THIS FALL VERY NICELY
WITH OUR VISION OF WHOLE-PERSON
HEALTH PERSON HEALTH AND
INTEGRATION OF NATURAL PRODUCT
INTO, YOU KNOW, PHYSIOLOGY,
IMPACTING PHYSIOLOGY.
WE'VE ALSO HAD A LONG STANDING
INTEREST IN IMPROVING THE
TECHNOLOGY THAT WOULD ADVANCE
THE FIELD OF NATURAL PRODUCTS.
AND, IN FACT, FOR THE PAST
COUPLE OF YEARS WE HAVE HAD
FUNDING OPPORTUNITY THAT
ACTUALLY ENCOURAGED NEW
METHODOLOGY AND TECHNOLOGY IN
THAT FIELD.
NOW WITH THE ADVANCE OF MACHINE
LEARNING, ARTIFICIAL
INTELLIGENCE, OMIX, WE WANT TO
ENCOURAGE INVESTIGATORS TO
EMPLOYEE THOSE SOPHISTICATED
TECHNOLOGY TO MOVE THEIR
RESEARCH FORWARD.
SO THE SPEAKERS AT THIS PART TWO
OF THIS WEBINAR SERIES REALLY
WILL HIGHLIGHT SOME TECHNOLOGIES
THAT ARE SPECIFIC TO STRUCTURE
ELUCIDATION AND APPLICATION OF
THOSE TECHNOLOGY SO THAT THEY
BECOME MORE AVAILABLE TO THE
BROADER NATURAL PART OF RESEARCH
COMMUNITY.
SO WE ARE PLEASED TO TURN THIS
OVER TO PATRICK WHO WILL NOW
INTRODUCE THE SPEAKERS.
THANK YOU VERY MUCH AND HOPE YOU
ENJOY THOSE PRESENTATIONS.
>>THANK YOU VERY MUCH, DR.
EDWARDS.
AND AS I MENTIONED, DIRECTOR AT
NCCIH IN OUR BASIC AND
MECHANISTIC RESEARCH BRANCH AND
I MANAGE A PORTFOLIO THAT SPANS
NCCIH'S PRIORITIES IN
TRANSLATIONAL AND CLINICAL
APPLICATIONS OF NATURAL
PRODUCTS.
AS DR. EDWARDS MENTIONED OUR
FIRST WEBINAR FOCUSED ON
FOUNDATIONAL RESOURCES AND
TECHNOLOGIES THAT ENAVAILABLE
DISCOVERY OF NATURAL PRODUCTS
AND IN PART TWO WE ARE PICKING
UP WITH ADDITIONAL TECHNOLOGY
SPECIFIC TO UNAMBIGUOUS
STRUCTURE ELUCIDATION AND
APPLICATION OF THOSE
TECHNOLOGIES IN PROTEIN
STRUCTURAL BIOLOGY FOR EXAMPLE,
BUT WE WILL TOUCH GUT MICROBE
AND HOST RESPONSES.
TODAY WE ARE JOINED BY OUR
EXCELLENT SPEAKERS AS WELL AS
NIH PARTNERS WHO WILL SHARE
THEIR PERSPECTIVES ON WEBINAR
THEMES AND NATURAL PRODUCT
CONTEXT IN THEIR INSTITUTE AND
CENTER PRIORITIES.
AND IN INTRODUCING OUR SPEAKERS,
I WOULD FIRST LIKE TO INTRODUCE
YOU TO DR. HOSEA NELSON,
PROFESSOR OF CHEMISTRY IN THE
DIVISION OF CHEMISTRY AND
CHEMICAL ENGINEERING AT CALTECH,
WHO WILL DISCUSS ELECTRON
MICROSCOPY TECHNIQUES TO ENABLE
CHARACTERIZATION OF COMPLEX
NATURAL PRODUCTS.
FOLLOWING DR. NELSON'S TALK, WE
WILL HEAR FROM DR. MELINDA
DIVER, ASSISTANT MEMBER OF THE
STRUCTURAL BIOLOGY PROGRAM AT
THE SLOAN KETERRING INSTITUTE
WHO WILL PRESENT ON STRUCTURAL
INSIGHTS ON I ONCHANNEL
DETECTION OF PHYSICAL AND
CHEMICAL STIMULI.
OUR THIRD SPEAKER IS CHELSI
CASSILLY, POST DOCTORAL FELLOW
AT CLARDY LABORATORY DEPARTMENT
OF BIOLOGICAL KEM TRI AND
MOLECULAR FARM LOLG AT HARVARD
MEDICAL SCHOOL WHO WILL TALK
ABOUT CHEMICAL CORRELATIONS
BETWEEN GUT MICROBES AND HOST
RESPONSES.
I WOULD LIKE TO TURN THINGS OVER
TO OUR FIRST SPEAKER, DR. HOSEA
NELSON TO BEGIN OUR
PRESENTATIONS.
DR. NELSON, PLEASE FEEL FREE TO
SHARE YOUR SLIDES.
>>YEAH.
THANK YOU FOR THAT KIND
INTRODUCTION.
IT IS AN ABSOLUTE HONOR TO BE
HERE TODAY TALKING ABOUT SOME OF
THE RESEARCH FOCUSED ON
UNAMBIGUOUSLY DETERMINING THE
STRUCTURES OF NATURAL PRODUCTS.
BEFORE I GET INTO THAT, I WOULD
LIKE TO FIRST ACKNOWLEDGE ALL OF
THE INDIVIDUALS WHO DID THE
RESEARCH.
I DON'T DO THAT MUCH PHYSICALLY.
THESE GRADUATE STUDENTS AND
UNDERGRADUATES AND POSTDOCTORAL
FELLOWS ARE REALLY THE FUEL
BEHIND ALL OF THE COOL THINGS I
WILL SHOW YOU TODAY.
THEY ARE AN INCREDIBLY
PASSIONATE AND BRILLIANT GROUP
OF YOUNG RESEARCHERS.
MOST OF ALL THE WORK I WILL TELL
YOU WAS FUNDED BY NCCIH, AS MANY
OF YOU KNOW IN TODAY'S
SOCIOECONOMIC CLIMATE, IT TAKES
A VILLAGE TO FUND A PROGRAM LIKE
I AM SHOWING YOU TODAY.
I'M A SYNTHETIC ORGANIC CHEMIST.
NATURAL PRODUCTS STARTS IN A
DIFFERENT AREA.
MY GROUP FOCUSES ON REACTION
DISCOVERY.
WE WANT TO DEVELOP NEW METHODS
THAT WILL ALLOW THE CONSTRUCTION
OF COMPLEX BIOACTIVE COMPOUNDS
IN THE PHARMACEUTICAL INDUSTRY
AND ACADEMICS FOR CHEMICAL
BIOLOGY.
WHAT WE DO IS TRY TO THINK ABOUT
MAKING BONDS WAYS THAT ARE
NONTRADITIONAL.
WAY BACK WHEN IN 2017 WHEN MY
GROUP FIRST STARTED WE
DISCOVERED THESE INTERESTING
INTERACTIONS WHERE YOU COULD
TAKE THESE CHEMICALS TO FORM
CARBON/CARBON BONDS AND BUILD A
MOLECULAR COMPLEXITY.
WE WANTED TO UNDERSTAND THE
MECHANISM AND WE SINGLED OUT
THESE TWO SPECIES I'M SHOWING
HERE CALLED PHENYL CATIONS THAT
WERE NOT STRUCTURED.
WE DID CALCULATIONS OF HOW THEY
BEHAVE.
THIS IS A COMPUTATIONAL SLIDE
THAT YOU SHOULDN'T WORRY ABOUT
EXPECT THE STRUCTURE ON THE
LEFT.
THIS IS ONE OF THE INTERMEDIATES
WE LEVERAGED I JUST DESCRIBED
AND HAVE UNUSUAL BONDING.
I DIDN'T BELIEVE OUR THEORISTS
AND OUR GROUP THIS WAS THE
STRUCTURE.
WE DECIDED TO GET AN X-RAY
CRYSTAL STRUCTURE IN THE
SPECIES.
WE COULD ONLY GET MICROCHRIS CAL
COMPOUNDS OF THIS COMPOUND.
I WAS DRINKING BEER AND HAVING
LUNCH WITH COLLEAGUES OF MINE
AND THEY SUGGESTED THAT WE TRY
TO USE TRANSMISSIONAL ELECTRON
MICROSCOPY TO SOLVE THE
STRUCTURE.
THEY HAD A LOT OF SUCCESSES
WORKING WITH MICROCRYSTALINE
POUDERS FROM PROTEIN AND
POLYPEPTIDES.
I DON'T THINK ANYONE ORGANIC KEM
CYST KNEW THIS TECHNIQUE,
MICROCRYSTAL ELECTRON
TRANSMISSION.
YOU PUT THEM IN ELECTRON
MICROSCOPES AND GET THESE NANO
METER TYPE CRYSTALS.
IF YOU SWITCH YOUR MICROSCOPE
AND SELECT THIS AP PATURE.
YOU COULD GET DATA IF IF YOU
ROTATE.
THE DATA SO MUCH SO YOU COULD
USE X-RAY SOFTWARE TO SOLVE
THREE DIMENSIONAL STRUCTURES OF
THE MOLECULES THAT MADE UP THOSE
CRYSTALS.
THE WAY THIS WORKS IN THIS VIDEO
YOU HAVE SUSPENSION OF
MICROCRYSTALS WHICH LOOK LIKE
POWDER AND YOU PUT THEM ON TO A
TEM GRID AND BASICALLY YOU WILL
INSERT THIS INTO AN ELECTRON
MICROSCOPE.
THIS IS A VIDEO DETAILING HOW WE
WOULD USE THE STANDARD
MICROSCOPE FOR DOING STRUCTURAL
BIOLOGY, SAME TOOL, YOU SHOOT
YOUR ELECTRON BEAM AND WHILE IN
ROLLING SHUTTER MODE COLLECT THE
FRACTION IMAGES AND THE IMAGES
CAN BE PIECED TOGETHER INTO A
DEFRACTION MOVIE AND YOU CAN PUT
IT INTO XDX AND SHELL X AND ALL
THESE SUCCESSFUL AND GET A THREE
DIMENSIONAL STRUCTURE.
WE PUBLISHED OUR FIRST PAPER
DESCRIBING.
THIS.
I THINK THE WORLD WAS SURPRISED
YOU COULD DO THIS.
WHAT BLEW MY MIND IS YOU COULD
HAVE MIXTURES OF NATURAL
PRODUCTS OR NATURAL PRODUCT LIKE
MOLECULES AND SINGLE STRUCTURE
TO OSOLVE.
EEP OF THESE PARTICLES OR NANO
CHRIS CALS ARE SUB MICRON SIZE.
BIOTIN IS A PHENTOGRAM MATERIAL.
WE GET A THREE DIMENSIONAL
STRUCTURE AND THIS BLEW MY MIND.
THE AMOUNT OF MATERIAL WE NEEDED
TO GET STRUCTURES WAS REMARK
BLG.
-- REMARKABLE.
SO MY GROUP FOUND YOU CAN TAKE
AH COMPLEX NATURAL PRODUCT AND
ACQUIRE DATA SUFFICIENT TO SOLVE
STRUCTURE.
AT THAT POINT WE STARTED
THINKING THE COMPLEX MOLECULES
LIKE NATURAL PRODUCTS ARE IN
SMALL AMOUNTS.
PERHAPS WE COULD LEVERAGE THIS
TECHNIQUE AND INTRODUCE A
GAME-CHANGING METHOD INTO THE
NATURAL PRODUCT STRUCTURE
ELUCIDATION.
WE STARTED REACHING OUT TO
COLLABORATETORS ALL OVER THE
WORLD IN THE NATURAL PRODUCT
SPACE.
ONE OF THE FIRST WAS WITH THE
SCHROEDER LAB AT CORNELL.
THEY WERE HAVING DIFFICULTY
DESCRIBING THIS.
THERE WAS A QUESTION OF THE
CHEMICALS.
WE WERE QUICKLY ABLE TO
DETERMINE THE STRUCTURE WAS IN
9, USING MIKE KRO CHRIS CAL
ELECTRON DETRACTION.
ONE OF THE OTHER EXAMPLES THAT
IS PRETTY COOL IS THERE A
MOLECULE HERE, A MEMBER OF THE
LOMAVIDICIN FAMILY.
IT IS $10 MILLION OF FEDERAL
GRANTS TO STUDY ITS SYNTHESIS
AND BIOLOGY AND BIOACTIVITY.
WE LOOKED AT THE DIFFICULTY OF
MAKING THIS COMPOUND.
WITH SETH HERZON QUESTIONED IF
WE WERE WORKING WITH THE RIGHT
STRUCTURE.
THE HERZON LAB AT YALE AND OUR
LAB AT UCLA COLLABORATED AND
FROM A VERY SMALL SAMPLE OF
MICROGRAM AMOUNT, DETERMINED OR
REASSIGNED THE STRUCTURE.
AND I THINK THAT IS ONE OF THE
MOST IMPORTANT INITIATE EXAMPLES
OF A REAL WORLD APPLICATION OF
USING MIKE ED TO SOLVE
STRUCTURES.
THIS WILL ENABLE THE CHEMICAL
SYNTHESIS AND GREATER
UNDERSTANDING OF BIOACTIVITY.
WE HAVE A MAJOR COLLABORATION
UNDER OUR NCCIH FUNDING WITH THE
TONG LAB AT UCLA AND DEVELOPING
METHODS TO DISCOVER NEW NATURAL
PRODUCTS.
THIS IS ONE OF TP NEW METHOD,
THIS IS AN INTERESTING EXAMPLE
WHERE WE WERE ABLE TO TAKE A
SMALL SAMPLE FROM MATERIAL FROM
THE TONL LAB AT UCLA AND IN A
FEW HOURS SIGN THE STRUCTURE OF
THIS NONPEPTIDYL NEW NATURAL
PRODUCT.
OUR WORK IN THE METHOD EXTENDS
BEYOND NATURAL PRODUCT
DISCOVERY.
THIS IS A COOL EXAMPLE THAT
HASN'T BEEN PUBLISHED.
IT WAS NOT PUBLISHABLE FOR OTHER
REASONS FOR MANY YEARS.
THIS WAS IN A THESIS FROM MY
GROUP, GILEAD REACHED OUT TO US
TO HELP THEM SOLVE THE STRUCTURE
OF A COMPOUND THEY WERE WORKING
ON.
THERE WAS -- THEY WERE NOT ABLE
TO UNAMBIGUOUSLY ASSIGN THE
ISOMER OR WANTED FURTHER
CONFIRMATION.
THEY HAD REALLY SMALL CRYSTALS
AND WE WERE ABLE TO ASSIGN THE
ISOMER OF THIS MOLECULE.
DR. JESSICA BIRCH IN MY LAB.
SO WE HAD SOME SUCCESSES
ASSIGNING STRUCTURES OF NATURAL
PRODUCTS IN ONE OFF CASES.
TO BE HONEST, BY THE TIME THESE
SAMPLES GOT TO US, THEY WERE
VERY DIFFICULT SAMPLES COMING
FROM REALLY GOOD RESEARCH GROUPS
COMING FROM STRUCTURAL
ELUCIDA
ELUCIDATION.
OUR HIT RATE IS PROBABLY AROUND
10%.
I'M AN ORGANIC SYNTHETIC CHEMIST
AND WE LIKE TO DO STUFF IN BULK.
I WANTED TO THINK ABOUT WAYS OF
HOW TO GET MORE NATURAL PRODUCT
STRUCTURES.
ONE OF THE IDEAS WE HAD IF WE
CAN DEVELOP A HIGH-THREWPUT
STRUCTURE, WE COULD LOOK AT A
MILLION SAMPLES AND SOLVE
100,000 NATURAL PRODUCT
STRUCTURES THAT WOULD BE AN
EXCITING DEVELOPMENT IN THE
COMMUNITY.
WE STARTED CLAP RATING WITH A
FEW PEOPLE, IN PARTICULAR CASSIE
CLAVE AND WE DECIDED TO COME
TOGETHER AND PUT TOGETHER A
LIBRARY OF NATURAL PRODUCTS SO
FAR AROUND 13,000 EXTRACTS AND
SEE IF WE COULD DEVELOP A HIGH
THROUGHPUT PLATFORM FOR NATURAL
PRODUCT DISCOVERY.
THE EXTRACTS CAME FROM ALL OVER,
SPONGES, PLANTS, FUNGI AND
BACTERIA.
TO REFRESH YOUR MEMORY, I HAD
SHOWN YOU WE CAN SOLVE
STRUCTURES OF NATURAL PRODUCTS
FROM COMPLEX MIXTURES, KIND OF.
THIS IS A RIGGED SYSTEM WHERE WE
HAVE PURE NATURAL PRODUCT
POUDERS AND MIX THEM TOGETHER
AND SOLVE STRUCTURES OF
INDIVIDUAL KRYSTALITES.
YOU KNOW THAT IS UNREALISTIC.
IF YOU HAVE A NATURAL PRODUCT
EXTRACT, YOU PIT' IT ON AN HBLC
AND GET SOMETHING WHAT I'M
SHOWING HERE.
NOT A MIXTURE OF PURIFIED
POUDERS, BUT A MIXTURE OF
COMPOUNDS AND SOLUTION YOU HAVE
TO FIGURE OUT HOW TO SEPARATE
AND STRUCK CHURLGLY
CHARACTERIZE.
WHAT WE WANTED TO DO WAS GO
THROUGH AND GRAB EVERY PEAK AND
GET DEFRACTION DATA.
AND SO THAT TURNS OUT THAT IS
REALLY DIFFICULT.
IT TAKES OFTENTIMES AN HOUR TO
PUT ONE SAMPLE IN AN
ELECTROMICROSCOPE.
IF WE HAVE 13,000 EXTRACTS, WE
ARE TALKING ABOUT TENS OF
THOUSANDS OF DATA COLLECTION ON
A TEM, WHICH IS A LITTLE
EXPENSIVE.
WE HAD TO MINIATURIZE THE
SAMPLES.
SO WE DECIDED TO TAKE HPLC
FRACTION NATION AND DO TIME
BASED FRACTIONATION AND COLLECT
IN WELL PLATES AND USE A DNA
MICRO ARRAYER AND TAKE SAMPLES
AND DEPOSIT THEM ON TEM GRIDS TO
ADD HUNDREDS OF FRACTIONS OR
HUNDREDS OF POTENTIAL NATURAL
PRODUCT FRACTIONS DIRECTLY INTO
A TEM GRID IN ONE OPERATION.
SHOWN HERE IS A CRUDE EXTRACT,
115 MILLIGRAMS OF CRUDE EXTRACT
PROVIDED BY THE QUAVE LAB.
WE SEPARATED AND THAT AND
DEPOSITED IT ON A TEM GRID.
WE WERE EXCITED TO COLLECT
ELECTRON DEFRACTION DATA.
I SHOULD NOTE ONLY IN SOME CASES
WERE WE ABLE TO SOLVE STRUCTURES
FROM THE DROPLETS.
WE HAVE ENGINEERING STRUCTURES
TO DO THAT MORE OFTEN.
WE CAN IDENTIFY CRYSTALINE
PRODUCTS.
I SHOULD MENTION THIS TERPINE
WAS SOLVED FROM THIS ARRAY ED
GRID.
THE OTHER COMPOUNDS, THE THREE
WE ISOLATED FROM THIS EXTRACT
TOOK A LITTLE BIT MORE WORK.
THIS METHOD IS SOMEWHAT GENERAL.
WE LOOKED AT MORE EXTRACTS.
THIS IS ONE OF THE OTHER
EXTRACTS, FROM A FUNGAL EXTRACT
AND WE ARE ABLE TO SOLVE FOR
NATURAL PRODUCTS.
I SHOULD NOTE SOME OF THESE
COMPOUNDS WOULDN'T HAVE BEEN SO
APPARENT USING STANDARD LCMS
WORK FLOW.
FOR EXAMPLE, THIS IS MAYBE NOT
THE MOST EXCITING NATURAL
PRODUCT, IT IS CALCIUM OXOLATE.
YOU WOULDN'T NECESSARILY SEE
COMING UP IN UV TRACE OR MASS
SPEC TRACE.
THIS RELATIVELY SMALL DIF RIF
SHOWN DELOW WOULD ALSO BE A
SITUATION WHERE THAT MIGHT FALL
BELOW THE LOWER LIMIT OF M/Z FOR
MASS SPEC AND COLLECT FRACTION
DATA AND ASSIGN STRUCTURE
WITHOUT ANY OTHER INFORMATION.
SO WE ARE STILL IN THE FIRST
YEAR OF THE NCCIH-FUNDED
PROJECT.
WE ARE STILL WORKING ON
AUTOMATION AND AUTOMATED DATA
ANALYSIS USING MACHINE LEARNING
ANALYSIS AND ADVANCED DATA
TECHNIQUES.
IN OUR FIRST RUN THROUGH OF 20
EXTRAKTS -- EXTRACTS WE HAVE
BEEN ABLE TO STRUCTURALLY
CHARACTERIZE MORE THAN 15
NATURAL PRODUCTS AND MORE THAN
10 ARE BRAND NEW CRYSTAL
STRUCTURES.
WE THINK THAT IS AN EXCITING
ADVANCE FOR THE FIELD.
WE DISCOVERED WEIRD THINGS.
HERE IS AN EXAMPLE OF ONE OF
THEM.
HERE IS A TRACE, THE DOTTED
LINES ARE EVERYWHERE WE TOOK A
FRACTION.
THIS BIG PEAK AT 15 MINUTES WAS
SPLIT INTO THREE FRACTIONS.
WHEN WE STARTED COLLECTING DATA
ON THESE FRACTIONS WE WERE
INTERESTED TO FIND FRACTION E7
WAS THIS NATURAL PRODUCT
PACHYBACIN.
FRACTION EN WAS CHRYSOPHANOL,
THIS FRACTION E8 WAS A
CO-CRYSTAL OF THE TWO NATURAL
PRODUCTS.
WE ARE NOT QUITE SURE HOW THAT
WILL BECOME RELEVANT IN THE
METHOD.
IT EXEMPLIFIES OF THE DIFFERENT
FRACTIONATION ALLOWS US TO FIND
DIFFERENT INFORMATION.
IN THIS FIRST ROUND OF 20
EXTRACT SEARCH WERE ABLE, USING
MNR AND MASS SPEC IN COMBINATION
WITH MICROED TO SOLVE THE
STRUCTURES OF THESE PRODUCTS.
WE THOUGHT THESE WOULDN'T BE A
CRYSTALINE.
SO ONE OF THE MOST SURPRISING
THINGS AND I GUESS I'M ALMOST
OUT OF TIME HERE, ONE OF THE
MOST SURPRISING THINGS WE FOUND
IS REALLY ENCOURAGING.
WHEN WE STARTED THIS PROJECT, I
ANTICIPATED WE WOULD HAVE 5% OF
THE COMPOUNDS OR FRACTIONS WE
OBSERVED WOULD BE CRYSTALINI.
20% OF THE FRACTIONS ARE
CRYSTALINE.
WE ARE NOT GETTING ALL THE
STRUCTURES, NOT YET ANYWAY.
THAT IS ENCOURAGING AND
HIGHLIGHTS THE POTENTIAL USING
DEFRACTION WITH LICK KWID --
ARRAY ED TO ELUCIDATE THE
STRUCTURES THAT ARE KRAS TALINE
AND LEND THEMSELVES TO THAT TYPE
OF ANALYSIS.
I'M GOING TO CUT IT THERE
BECAUSE I AM OUT OF TIME.
I WANT TO THANK YOU ALL FOR YOUR
ATTENTION.
MY AWESOME RESEARCH LAB, THEY
DID ALL OF THIS WORK AND HAD
MOST OF THESE GD -- IDEAS.
GENEROUS FUNDING FROM THE NIH
ESPECIALLY NCCIH AND ALL THOSE
WHO HAVE WORKS WITH US ON THIS
OVER THE YEARS SO THANK YOU VERY
MUCH.
>>THANK YOU DR. NELSON.
AND AS A REMINDER WE WILL HOLD
QUESTIONS TO THE END OF THE
THREE SPEAKERS AND WITH THAT, I
WOULD LIKE TO NOW MOVE TO DR.
DIVER FOR HER TALK.
PLEASE FEEL FREE TO SHARE YOUR
SLIDES.
>>HELLO.
IT IS WONDERFUL TO BE HERE.
IN THE DIVER LAB AT SLOAN
KETERRING INSTITUTE WE ARE
INTERESTED IN UNDERSTANDING AT A
MOLECULAR LEVEL HOW WE SENSE THE
WORLD AROUND US.
TODAY I'M GOING TO TALK ABOUT
TRIP M8, OUR PRIMARY COLD SENSOR
IN THE BODY AND WHAT HELPS US
SENSE NATURAL PRODUCT COOLING
AGENTS LIKE MINT OR MENTHOL AND
EUCALYPTUS.
I'M GOING TO SHARE WHAT WE
OBTAINED.
HOW DO WE INTERFACE WITH OUR
ENVIRONMENT.
SIGNALS IN OUR ENVIRONMENT
NONPAIN CAUSING AND INNOCUOUS
AND THOSE THAT ARE PAIN CAUSING
ARE DETECTED BY NEURONS, CALL
NOCESEPTORS.
THEY ARE IN OUR SKIN, OUR LUNGS
AND OUR GUT.
IT IS A VARIETY OF ION CHANNELS
THAT HELP US DETECT LIKE ITCH,
TEMPERATURE, LIKE MECHANICAL
PAIN.
BUT ALSO CHEMICAL AND CHEMICAL
IRRITANTS.
AND THESE CAN INCLUDE A WIDE
VAST VARIETY OF NATURAL PRODUCT.
THINGS FROM PLANTS LIKE TRIP M8
BUT ALSO THINGS THAT COME FROM
VENOMOUS ANIMALS LIKE THIS
SCORPION SHOWN HERE THAT MAKES
THIS PEPTIDE TOXIN.
SO MANY OF THE ION CHANNELS THAT
DO THIS DETECTION ARE PART OF
THE LARGER TRIP ION CHANNEL
FAMILY.
TRIP CHANNELS ARE A VERY, VERY
LARGE FAMILY OF ION CHANNELS.
THERE ARE ALMOST 30 MEMBERS IN
MAMMALS.
IT IS SECOND ONLY TO POTASSIUM
CHANNELS.
AND THEY HAVE VERY DIVERSE
FUNCTIONS IN TERMS OF PHYSIOLOGY
AND BIOLOGY.
THE ONES WE UNDERSTAND WELL WE
BASICALLY UNDERSTAND BECAUSE OF
NATURAL PRODUCTS.
I'M HIGHLIGHTING THREE OF THE
MOST BEST STUDIED AND BEST
UNDERSTOOD ION CHANNELS WE KNOW
HERE AND ALSO THE NATURAL
PRODUCTS IT HELPED US TO
IDENTIFY THEM.
SO WE HAVE TRIP V1.
TRIP V1 IS OUR PRIMARY HEAT
SENSOR, BUT IT IS SENSITIVE TO
THE NATURAL PRODUCT CAP SASIN IN
PEPPERS.
WE HAVE TRM8 MENT OL.
AT THE BOTTOM TRPA1 IS A GENERAL
IRRITANT SENSOR.
SOME THINGS IT SENSES ARE
NATURAL PRODUCTS LIKE CHEMICAL
COMPOUNDS IN GARLIC, ONION, AND
WASABI.
IN TERMS OF WHAT WE UNDERSTAND
ABOUT THE MOLECULAR MECHANISMS
OF TRPM8, WE UNDERSTAND THERE
ARE THREE STATES OF THIS ION
CHANNEL.
THE ION CHANNEL CAN BE CLOSED.
IT CAN ALSO BE OPENED.
THIS IS WHEN ACTUAL IONS ARE
ALLOW TO FLOW THROUGH.
THESE ARE POSITIVELY CHARGED
IONS, LIKE CALCIUM AND SODIUM.
THERE IS A VERY UNIQUE STATE
CALLED THE DESENSITIZED STATE.
DESENSITIZED BASICALLY MEANS
THERE IS SOME TYPE OF STIMULUS
AROUND LIKE MENTHOL, BUT IT IS
NOT ALLOWING IONS TO FLOW
THROUGH.
THIS IS AN INTERESTING STATE TO
ME AND TO STUDY AND HOW THIS
RECEPTOR WORKS IN RESPONSE TO
THINGS BECAUSE IT HAS LARGE
IMPLICATIONS IN HOW WE AS HUMANS
ADAPT TO COLD TEMPERATURES.
SO FROM A MORE THERAPEUTIC POINT
OF VIEW, IT HAS BEEN LONG KNOWN
TARGETING TRYPM8 HAS AN
ANALGESIC EFFECT.
REMEMBER WHEN YOU WERE A SMALL
CHILD YOU HAD A SPRAIN ANKLE AND
YOU PUT ICE.
YOU FEEL A COLD AND A BIT OF
COUGH AND YOU GO TO THE
DRUGSTORE AND PURCHASE VICKS
VAPORUB OR YOU HAVE RUN A
MARATHON AND YOU GET ICY COOLING
GELS OR PATCHES.
THEY ARE ACTIVE INGREDIENTS OR
NATURAL PRODUCTS THAT ACT ON
TRPM8, MENTHOL AND EUCOLLYPTOL
AND CAMPHOR.
IF WE CAN UNDERSTAND THESE
NATURAL PRODUCT DRUGS WE COULD
EXTEND THEM TO SYNTHETIC SPACE
AND EXPAND USAGE FROM A LIMITED
PAIN, ACUTE PAIN FROM SPORTS
INJURIES OR MINOR COLDS TO SOME
LARGER CONCEPT FOR PAIN
TREATMENT.
SO MY WORK PRIMARILY UTILIZES
SINGLE PARTICLE CROEEM TO
CAPTURE HIGH RESOLUTION
SNAPSHOTS OF ION CHANNELS AND
HOPEFULLY BOUND TO THINGS LIKE
NATURAL PRODUCT ACTIVATORS TO
UNDERSTAND WHERE THEY BIND AND
HOW THEY WORK AND ACT ON THE
CHANNEL.
WE HAD A BIT OF AN INTRODUCTION
JUST BEFORE THIS TO MICROED AND
OTHER THINGS YOU CAN DO IN THE
CHEMICAL SPACE.
IN SING HL-PARTICLE CRYO-EM, WE
PURIFY THE PROTEIN, TAKE THEM
OUT OF THE PLASMA MEMBRANE TO DO
THIS AND REPLACE THE MEMBRANE
WITH DETERGENTS.
THESE ARE DIFFERENT MEMBRANE
MEMBETICS TO KEEP OUR PROTEIN
HAPPY IN SOLUTION OUT OF THE
PROTEIN.
-- VERY RELEVANT TO DRUG
DISCOVERY AND UNDERSTANDING HOW
NATURAL PRODUCTS WORK.
ONE OF THE MOST EXCITING THING
ABOUT SINGLE-PARTICLE CRYO-EM,
NOT ONLY CAN WE CAPTURE A
STRUCTURE, EVERYTHING IS IN
SOLUTION, FROZEN SOLUTION, BUT
SOLUTION.
WE DON'T JUST CAPTURE ONE STATE.
WE CAN CAPTURE MANY, MANY RANGES
OF STATES AND EVEN DEFINE
MOVEMENTS BETWEEN THESE STATES.
SO IN ONE SAMPLE IT COULD BE
POSSIBLE TO SEE CLOSED OR OPENED
OR TRANSITIONS OR HOW WE GO FROM
THESE DIFFERENT STATES.
SO I SET OUT TO USE THIS
TECHNIQUE ON TRYPM8.
THIS IS THE FIRST HIGH
RESOLUTION WE GOT.
LIKE OTHER TRYP CHANNELS THAT
SHARE A SIMILAR TYPOLOGY, IT IS
A TETROMER.
IT HAS A REGION THAT FITS WITHIN
THE PLASMA MEMBRANE AND A VERY,
VERY LARGE REGION THAT SITS OUT
OF THE REGION.
THIS REGION IS POORLY UNDERSTOOD
WHAT IT DOES.
YOU ARE GOING TO NOTICE AS I
FOCUS ON IT AND TELL YOU WHAT I
LEARNED, I'M FOCUSING ON THE
TRANSMEMBRANE DOMAIN.
HOPEFULLY FURTHER STUDIES WILL
ELUCIDATE WHY, THERE ARE ALL
THESE PROTEINS WE CAN'T
ATTRIBUTE A FUNCTION TO YET.
SO THAT WE ARE ABLE TO ORIENT
OURSELVES AND TALK ABOUT DRUG
BINDING TO TALK ABOUT WHERE
THESE NATURAL PRODUCTS SIT, I
WANT TO GIVE YOU IDEA ABOUT THE
TOPOLOGY OF THIS ION CHANNEL.
WITHIN THE MEMBRANE THERE ARE
SIX TRANSMEMBRANE HELOCES.
S1-S4.
ANYONE WHO THINKS ABOUT BOLTED
GATED CHANNELS, THIS IS
SYNONYMOUS TO THE BOLDED SENSOR
IN THOSE.
IN THE MIDDLE HERE WE HAVE OUR
PORE HELIXES, S5 AND S6.
THEY LINE THE SPACE WHERE THE
IONS ARE GOING TO GO THROUGH AND
MOVE AND REARRANGE IN ORDER TO
LET THOSE IONS THROUGH OR NOT.
SO IF I WANT TO UNDERSTAND
SOMETHING ABOUT THE, YOU KNOW,
CAPTURING, REALLY, OF A STIMULI,
THE UNDERSTANDING OF PHYSICAL
AND CHEMICAL STIMULI AND HOW
THEY WORK ON THE ION CHANNEL, I
NEED TO BIAS MY BIOCHEMICAL
SYSTEM.
YOU CAN IMAGINE DOING THESE
EXPERIMENTS WITH NO STIMULUS
AROUND TO SEE HOW IT IS BEHAVING
IN SOLUTION.
YOU CAN SHIFT THE EQUILIBRIUM TO
SEE HOW IT WOULD RESPOND IN OUR
BODY.
SUCH AS IN THE CASE OF TRYPM8 ON
COLD OR MAYBE ADDING SOME OF
THESE NATURAL PRODUCTING INGAGO.
OR A LOT OF SYNTHETIC DRUGS THAT
ARE ANTAGONISTS AND AGONISTS
COMMERCIALLY AVAILABLE AT ONE'S
DISPOSAL.
WORKING WITH TWO DIFFERENT
SYNTHETIC ANTAGONISTS, I WAS
ABLE TO IDENTIFY DRUGS BIND TO
TRYPM8 THROUGH THE S-1 THROUGH
S-4 POCKET.
IT WAS REALLY UNCLEAR WHAT THIS
ENTIRE REGION OF TRYP CHANNELS
WERE DOING.
IT IS CONSERVED IN ALL CHANNELS,
BUT NOT VOLTAGE SENSING.
THIS IS ONE OF THE FIRST CASES
WE WERE ABLE TO ATTRIBUTE WHY DO
THEY HAVE THESE CHANNELS AND
WHAT CAN IT DO.
BY BEING ABLE TO CAPTURE
CHEMICAL -- IN THIS POCKET, WE
WERE ABLE TO SEE THAT IT IS
BASICALLY THE SHAPE OF THE
POCKET, NOT SO MUCH THE
CHEMISTRY OR THE SPECIFIC SIDE
CHAINS OF IT.
THAT ALLOW FOR MOLECULES TO SIT
IN IT.
IT IS INCREDIBLY ADAPTABLE.
SO BASICALLY YOU PUT SOMETHING
DIFFERENT IN, IT SITS GENERALLY
IN A DIFFERENT CONFIRMATION.
THE SIDE CHAINS ALMOST MOVE
AROUND IT TO MATCH THE
CHEMICALS.
THIS IS REALLY EXPLAINS WHY
THERE IS SUCH A DIVERSE CHEMICAL
SPACE FOR SOMETHING LIKE THE ION
CHANNEL TRYPM8.
NOT ONLY ANTAGONISTS FIND THIS
AREA, BUT AGONISTS FIND THIS
AREA, TOO.
YOU CAN SEE THE DENSITY FOR A
SYNTHETIC COOLING AGENT CALLED
ICILIN.
WE HAVEN'T SEEN THIS
STRUCTURALLY, IT IS CONCLUSIVE
FROM STRUCTURE FUNCTION ANALYSIS
THIS IS THE BINDING SITE FOR
MENTHOL.
SO NOW YOU HAVE A SITUATION
WHERE YOU HAVE A VERY ADAPTABLE
BINDING POCKET, THINGS THAT
COMBINE THERE THAT CAN CLOSE THE
GATE AND THINGS THAT COMBINE
THAT CAN OPEN THE GATE.
IT IS REALLY INTERESTING TO
THINK ABOUT HOW THIS ALL COMES
TOGETHER AND HOW YOU COULD
FURTHER THIS CHEMICAL SPACE.
SO TO MAKE THE SITUATION MORE
EXCITING AND INTERESTING, I
WOULD SAY, IT TURNS OUT IT IS
NOT ONLY CHEMICALS THAT COMBINE
IN THIS SPACE, BUT IT IS
ACTUALLY LIPIDS, TOO.
THIS COULD HAVE INTERESTING
IMPLICATIONS FOR THE REGULATION
OF HOW THESE NATURAL PRODUCTS
WORK.
SO WHEN I SOLVE MY STRUCTURES I
CAN SEE PROBABLY NOT
SURPRISINGLY SO THERE WERE A
BUNCH OF LIPIDS THAT SAT BETWEEN
THE TETROMERS.
THIS IS EMPTY SPACE.
YOU CAN IMAGINE THEY HAVE TO BE
THERE STRUCTURALLY SO AS THE
MEMBRANE AND PROTEIN UNITE AND
ARE ONE.
IT TURNS OUT THE TAIL OF ONE OF
THESE LIPIDS ACTUALLY STRETCHES
RIGHT UP INTO THE LIGAND BINDING
POCKET WHEN NO CHEMICALS HAVE
BEEN ADDED TO THE PROTEIN --.
IT SEEMS LIKE IF WE DON'T HAVE
AN ACTIVATOR OR AGONTIST AROUND
A LIPID TAIL LIKES TO SIT IN
THERE.
OBVIOUSLY, MAYBE NOT OBVIOUSLY,
BUT OBVIOUSLY FROM THE
STRUCTURES I HAVE LOOKED AT, YOU
NEED TO REMOVE THE LIPID TAIL TO
HAVE MENTHOL SIT IN THAT BINDING
POCKET.
THE SPACE IS COMPLETELY
OVERLAPPING.
SO SOMETHING THAT IS EVEN MORE
INTERESTING TO THINK ABOUT IS
WHAT COULD THIS LIPID BE AND IS
IT AN IMPORTANT SIGNALLING
LIPID?
ONE OF THE MOST IMPORTANT
SIGNALLING LIPIDS IN OUR BODY,
KNOWN TO NEGATIVELY AND
POSITIVELY REGULATE THEM IS
PIP2.
IT IS OF LOW ABUNDANCE AND
SYNTHESIS IS HEAVILY CONTROLLED.
WE KNOW TRYPM8 IS POSITIVELY
REGULATED BY PIP2.
IT LEADS TO FURTHER ACTIVATION
OF THE CHANNEL.
WE KNOW ITS HEAD GROUPS SITS IN
THIS VICINITY AND IN TERMS OF
SPACE IT WOULD MAKE SENSE IF
THIS WAS A LIPID TAIL.
HOW PIP 2 IS IN THE BINDING IS A
CONTINUING AIR UH YEAH OF
RESEARCH.
SO THIS WORK ON TRYPM8 AND OTHER
WORK THAT HAS COME ALONG SIDE
HAVE REALLY ALLOWED US TO COME
UP WITH WHAT I WOULD CALL GATING
MODELS OR IDEAS HOW THESE
DIFFERENT NATURAL PRODUCT
RECEPTORS WORK.
SO WHAT YOU SEE ON THE LEFT-HAND
SIDE IS TRPV1, THE HEAT SENSORS,
RESPONSIVE TO CAPSASIN.
AND ON THE RIGHT TRPM8, THE COLD
WE HAVE BEEN TALKING ABOUT.
FOR TRPV1 YOU SEE VERY, VERY
LIMITS MOTION.
PERHAPS YOU SHALL SQUINT AT YOUR
SCREEN.
ON THE RIGHT-HAND SIDE YOU SEE
THOSE MOTIONS IN TRPM8 AND YOU
SEE HOW MUCH THEY ARE INVOLVING
THAT DOMAIN WE UNDERSTAND SO
LITTLE ABOUT.
SO THIS HAS LED US TO PROPOSE
THE FOLLOWING.
THE IMPORTANCE OF WHERE THESE
NATURAL PRODUCT DRUGS BIND LEAD
TO THE GATING MECHANISMS FOR
THESE CHANNELS.
IN THE CASE OF TRPV1 CAB SAICIN
BINDS RIGHT NEAR THE PORE.
IT CAUSES A REARRANGEMENT OF A
COUPLE OF RESIDUES IN THE PORE
AND IT IS OPEN AND IONS CAN FLY
THROUGH.
WE DISCOVERED THE BINDING POCKET
FOR MENTHOL IS PRETTY FAR FROM
THE GATE HERE.
SO WHAT ACTUALLY HAPPENS IN THIS
CASE IS LARGE CONFIRMATIONAL
MOVEMENTS FROM S-1 THROUGH S-4
DOMAIN ARE NEEDED IN ORDER TO
MAKE LARGE MOVEMENTS OF THE TRP
DOMAIN THAT BASICALLY SPANS THE
SPACE BETWEEN THE PORE AND WHERE
THE CHEMICAL BINDS.
AND THIS WAS ALSO VERY
INTERESTING TO SEE BECAUSE IT
WASN'T KNOWN FOR A VERY LONG
TIME WHAT THE ROLE OF THE TRP
DOMAIN WAS.
OBVIOUSLY, PEOPLE THOUGHT IT WAS
IMPORTANT AS IT WAS NAMED AFTER
THE ENTIRE FAMILY.
SO THAT WAS QUITE NEAT TO SEE.
SINGLE PARTICLE CRO-EM IS
IMPORTANT FOR STUDYING.
WE HAVE CLOSED STRUCTURES, OPEN
STRUCTURES AND DESENSITIZED
STRUCTURES NOW.
WHAT WE ARE STILL WORKINGEN ON
IS DETECTION OF TEMPERATURE.
IT IS A VERY ACTIVE AREA IN THE
FIELD.
EVERYONE IS EXCITED AND WE ARE
SCRATCHING OUR HEADS THINKING
HOW CAN WE DO THIS, HOW CAN WE
CAPTURE THESE THINGS?
MORE IMPORTANTLY, HOW DO WE KNOW
THE CHANGE WE SEE, WHERE IT
STARTED FROM AND HOW IT
PROPAGATED AND PROBABLY IT
>>NOW WE WITH RIGHT AT OUR LAST
SPEAKER WHO WILL SHARE HER
SLIDES, DR. CHELSI CASSILLY.
THANK YOU SO MUCH FOR THE
INVITATION TO JOIN AND TO SPEAK
AT THIS SEMINAR.
SO THIS IS AS PATRICK SAID, WHEN
HE WAS INTRODUCING, I HAVE NOT
BEEN IN THE CLARDY LAB FOR ABOUT
TWO YEARS NOW, SO THE WORK I'M
GOING TO BE PRESENTING IS VERY
FOND TO MY HEART, BUT I HAVEN'T
REALLY BEEN DOING IT IN PERSON
IN A WHILE.
SO IT WAS REALLY FUN FOR ME TO
LOOK BACK ON THIS RESEARCH AND
REFAMILIARIZE MYSELF WITH
SOMETHING I REALLY ENJOYED QUITE
A BIT.
TODAY I'M GOING TO BE TALKING
ABOUT THE CHEMICAL CORRELATIONS
BETWEEN GUT MICROBES AND THEIR
HOST RESPONSES.
I JUST WANT TO POINT OUT THIS IS
WORK THAT WAS DONE WHEN I WAS A
POSTDOCTORAL FELLOW AT THE
CLARDY LAB AT THE HARVARD MIDDLE
SCHOOL AND WORKED WITH
INDIVIDUALS AT THE BROAD
INSTITUTE AS WELL.
THE ORGANISM I'M TALKING ABOUT
TODAY IS AN ORGANISM YOU HAVE
HEARD OF BECAUSE OF HOW POPULAR
AND INTERESTING THIS ORGANISM
IS.
IT IS CONSIDERED UNIQUE IN TERMS
OF THE GUT MICROBE BIOTA.
IT IS AT THIS POINT THE ONLY
SPECIES WITHIN THE GENE US IN
AKKERMANSIA WE KNOW OF IN THE
GUT.
IT MAKES UP ON AVERAGE 3% OF THE
HEALTHY HUMAN GUT.
NOW, 3% MAY NOT SOUND LIKE VERY
MUCH, BUT WHEN WE ARE TALKING
ABOUT THE INSANE COMPLEXITY OF
THE HUMAN GUT MICROBIOME, 3% IS
AN AMAZING AMOUNT OF REAL ESTATE
FOR THIS ONE ORGANISM TO TAKE
UP.
THIS ORGANISM IS DOING SOMETHING
THAT IS CLEARLY IMPORTANT TO
HAVE THAT MUCH SPACE WITHIN THE
GUT.
THERE ARE LINKS THAT HAVE BEEN
DESCRIBED THAT POINT OUT THAT
WHEN AKKERMANSIA IS PRESENT
WITHIN A HOST, A HUMAN, IT SEEMS
TO LOWER THE RISK OF OBESITY OR
CERTAIN TYPES OF DIABETES.
AND FURTHERMORE, THAT WHENEVER
PATIENTS WOULD DRINK HEAT
INACTIVATED AKKERMANSIA
MUCINIPHILA THEY SAW ALLEVIATION
OF METABOLIC SYNDROME IN
OVERWEIGHT OR OBESE PATIENTS.
THIS AS WELL AS MANY OTHER TYPES
OF PUBLICATIONS OUT THERE POINT
OUT AKKERMANSIA WHEN PRESENT
WITHIN A HUMAN DOES SEEM TO HAVE
THIS RELATIONSHIP IT IS HELPING
TO PREVENT INFLAMMATORY DISEASES
OR INFLAMMATORY STATES WITHIN
ITS HOST.
HOWEVER, IT IS NOT COMPLETELY
KNOCKING OUT INFLAMMATION.
BECAUSE WE DO SEE THAT IT HAS A
POSITIVE CORRELATION WITH A
POSITIVE RESPONSE TO IMMUNO
THERAPIES.
WHEN IT IS PRESENT THERE IS A
BETTER RESPONSE TO PD1 BLOCKADE
CANCER IMMUNO THERAPY.
THERE SEEMS TO BE A CONTROL OR
HOME YO STATIC RESPONSE, WHEN
AKKERMANSIA IS PRESENT, SOMEONE
IS ABLE TO PREVENT OR HOPEFULLY
NOT SEE THE SYMPTOMS OF
INFLAMMATORY DISEASES.
HOWEVER, THEY ARE ALSO ABLE TO
MOUNT AN APPROPRIATE IMMUNE
RESPONSE IN RELATION TO IMMUNO
THERAPIES.
THE PAPER I'M PRESENTING TODAY
DESCRIBES THIS NATURE A LITTLE
MORE, BUT WE ALSO WROTE A LITTLE
BLOG POST IN SMALL THINGS
CONSIDERED AND WE KIND OF
RELATED THIS ORGANISM TO
GOLDILOCKS AND SAID THIS
ORGANISM HELPS TO MAINTAIN
SOMEWHERE RIGHT IN THE MIDDLE
WHEN WE TALK ABOUT INFLAMMATION.
NOT TOO MUCH, NOT TOO LITTLE.
AKKERMANSIA IS TRYING TO KEEP IT
RIGHT THERE IN THE MIDDLE.
SO WITH THIS IN MIND, THE LAB
WAS VERY INTERESTED IN
UNDERSTANDING WHAT THE ORGANISM
WAS DOING SPECIFICALLY IN TERMS
OF MOLECULES.
SO HOW IS IT CONTROLLING THIS
HOMEO STATIC STATE WHEN
AKKERMANSIA IS PRESENT.
IN ORDER TO ASSESS WHAT
MOLECULES MIGHT BE HELPING OR
CONTRIBUTES TO THIS INTERESTING
RESPONSE, WE RELIED UPON AN
ASSAY THAT WAS ALREADY VERY WELL
DESCRIBED AND DEVELOPED WITHIN
OUR LAB AND THE BROAD LAB WE
WERE COLLABORATING WITH.
AND SO THIS ASSAY IS PREVIOUSLY
DESCRIBED IN OTHER PUBLICATIONS.
ESSENTIALLY WE WERE LOOKING FOR
A RELEASE OF A CYTOKINE, AN
INFLAMMATORY PROTEIN AND USING
BONE-MARROW-DERIVED DENDRITIC
CELLS.
WE COLLECT FEMURS AND TIBIAS,
CHOP OFF THE ENDS OF THE BONE
AND PUSH THE BONE MARROW THROW.
WE MATURE THAT INTO DENDRITIC
CELLS IN SEVEN DAYS.
THEN YOU CAN TREAT THEM WITH A
VARIETY OF NATURAL PRODUCTS OR
BACTERIAL FRACTIONS.
THAT IS WHAT WE DID WITH
AKKERMANSIA MUCINIPHILA.
WE FRACTIONATED IT AND TREATED
THE DENDRITIC CELLS AND LOOKED
FOR CYTOKINE RELEASE.
I'M FOCUSING ON TUMOR NECROSIS
ALPHA, BUT WE DID LOOK AT A
VARIETY OF CYTOKINES.
THIS IS AN ASSAY YOU CAN CHANGE
MANY POINTS TO ANSWER DIFFERENT
QUESTIONS.
AS I MENTIONED WE DID THIS
PROCESS WITH AKKERMANSIA.
AND I WANT TO POINT OUT A LOT OF
THIS INITIAL WORK WITH GROWING
ORGANISM AND STARTING TO
FRACTIONATE WAS DONE BY MY
CO-FIRST AUTHOR DR. BAE.
HE GREW COPIOUS AMOUNTS OF
AKKERMANSIA.
YOU CAN SEE FROM THIS SLIDE, THE
SECTION ON THE LEFT HERE, THAT
HE GREW THE ORGANISM, STARTED
SEPARATING OUT MATERIALS IN
VARIOUS WAYS.
PHYSICAL SEPARATION AND CHEMICAL
SEPARATION.
AT VARIOUS POINTS WITHIN HIS
PROCESS HE WOULD GIVE ME THE
FRACTIONS AND I WOULD DO THE
ASSAYS.
I'M MORE OF A BIOLOGIST SO I
WOULD HELP DO THE ASSAYS.
I WOULD TELL HIM IN WHICH
FRACTIONS THE ACTIVITY OR
INFLAMMATORY ACTIVITY WOULD LIE.
HE WOULD GO BACK AND DO MORE
FRACTIONATION UNTIL WE
EVENTUALLY FOUND, FOLLOWING THE
RED NUMBERS, THAT WAS WHERE THE
ACTIVITY WAS FOUND AND WE ENDED
UP WITH AKKERMANSIA
MUCINIPHILA -- OR AMPE.
THAT WAS A GENERAL FRACTION THAT
HAD SEVERAL ACETYL.
WE HAVE RELIEF ON THE Y AXIS AND
TREATMENTS ON THE X.
IF YOU LOOK AT THE AMPE THERE IS
RELEASE F DMSO IS OUR NEGATIVE
CONTROL.
TWO POSITIVES ARE INFLAMMATORY
LIGINS, LPS AND PAM3CSK.
HE FURTHER PURIFIED OUT A SINGLE
MOLECULE RESPONSIBLE FOR THIS
ACTIVITY.
AND THAT MOLECULE LOOKS LIKE
THIS.
SO LIKE I SAID, IT WAS A
PHOSPHATAL STRUCTURE.
THE ONLY REAL DIFFERENCE HERE IS
IT HAS SOME BRANCHES ON THE
PHOSPH LIPID TAILS.
ON ONE CHAIN IT HAS AN ISOBRANCH
AND THE OTHER CHAIN HAS AN
ANTI-ISOBRANCH.
AT THIS POINT I DON'T SAY WE
WERE BUMMED WITH THE STRUCTURE,
BUT THIS IS A TYPICAL MOLECULE,
NOT SUPER EXCITING, BUT WHAT WAS
INTERESTING IS THAT THIS WAS
RESPONSIBLE FOR THE ACTIVITY WE
WERE SEEING.
WE DECIDED TO CONFIRM THAT
WITHOUT A DOUBT BY PERFORMING A
SYNTHETIC REACTION WITH OUR
COLLABORATORS IN THE DANA FASHER
INSTITUTE.
-- DANA FARBER INSTITUTE.
WE WERE CALLING A15 AND I15 IN
THE LAP BECAUSE OF THE VERY LONG
NAME.
HE SYNTHESIZED THE EXACT
REPLICATED PRODUCT IN THE BLUE
TRIANGLES.
AND THEN HE ALSO SWITCHED THE
BRANCHED CHAINS TO THE OPPOSITE
LOCATIONS.
HE SWAPPED WHERE THE BRANCHES
WERE AND THAT WAS IN THE GREEN
DIAMONDS.
AND SO YOU CAN SEE THAT THEY
WERE ABLE TO REPLICATE THE
ACTIVITY OF THE NATURAL PRODUCT
VERY WELL AND SO THIS INDICATED
THAT WHAT WE WERE SEEING WAS
REALLY ACTIVITY BASED ON THIS
ALMOST PRETTY COMMON
PHOSPHATAL --.
WE WERE INTERESTED IN
UNDERSTANDING WHAT WAS HAPPENING
TO TRIGGER THIS RESPONSE.
IT WAS PROBABLY A TOLL LIKE
RECEPTOR BINDS TO THIS NATURAL
PRODUCT.
AND WE DECIDED TO LOOK AND SEE
IF IT WAS TLR2 SPECIFIC.
WE THOUGHT SO BECAUSE IT WAS --
IT IS A LIPID.
TLR2 IS KNOWN TO BIND TO LIPIDS.
AND SO WHAT WE DID WAS WE TOOK
THE SAME ASSAY I HAVE DESCRIBED
TO YOU PREVIOUSLY.
WE USED MICE THAT DIDN'T HAVE
TLR2.
THEY WERE MUTANTS OR DIDN'T HAVE
TLR1 OR TLR6.
SO WE WENT THROUGH THE BATTERY
OF THOSE, TREATED THOSE CELLS
WITH THE MOLECULE AND FOUND WHEN
MICE OR WHEN THE CELLS WERE
MISSING TLR2 OR TLR1 WE SAW NO
ACTIVITIES.
I'M NOT SHOWING THAT DATA.
WE SAW LOSS OF ACTIVITY WHEN
THOSE TWO TLRs WERE MISSING.
THIS MOLECULE IS BINDING TO TLR1
AND TLR2 DIMER.
WE DECIDED TO LOOK AT A MODELING
APPROACH.
THIS WAS DONE WITH A STUDENT AT
THE UNIVERSITY OF ATAGO IN NEW
ZEALAND.
HE MODELLED HOW THIS MOLECULE
MIGHT BE BINDING TO THE DIMER.
YOU CAN SEE FROM THE RIGHT IMAGE
THE MOLECULE REALLY DIGS DEEP
INTO THE BINDING POCKET.
IT IS PRETTY HIDDEN.
THIS WAS REALLY INTERESTING TO
US BECAUSE WE THOUGHT MAYBE THE
BRANCH CHAINS MIGHT PREVENT IT
FROM GOING FAR INTO THE BINDING
POCKET.
MAYBE THAT WAS CAUSING THIS
RESPONSE WE WERE SEEING.
IT IS GENERALLY THOUGHT THAT
HEAD GROUPS ARE PRETTY IMPORTANT
TO TRIGGER THE IMMUNE RESPONSE.
THIS HEAD GROUP SEEMS TO BE
BURIED WITHIN THE MODEL WE ARE
LOOKING AT.
NOT ONLY THAT, BUT WE SAW AN
INTERESTING SPLIT OF THE TAIL.
ONE TAIL LOOKING ON THE LEFT,
ONE TAIL IS GOING INTO THE LR2
AND ONE IS FITTING INTO TLR1.
AGAIN, WE WEREN'T SURE EXACTLY
HOW THAT WAS GOING TO HAPPEN.
THIS DIMER TYPICALLY BINDS TO
LIPIDS WITH THREE TAILS.
AND SO WE WERE JUST VERY
INTERESTED AND THIS WAS A LITTLE
BIT OF A SURPRISING RESULT IT
WAS RELYING AND BINDING THROUGH
TLR1 AND TLR2.
AND FINALLY, THE LAST EXPERIMENT
THAT I WANT TO SHOW IS A LITTLE
BIT MORE CHALLENGING TO EXPLAIN
SO I'M GOING TO MOVE A LITTLE
SLOWER THROUGH THIS.
THIS WAS PROBABLY ONE OF THE
MOST INTERESTING RESPONSES THAT
WE SAW WITH THIS LIPID.
SO THIS WAS DONE IN HUMAN CELLS.
SO I WANT TO POINT OUT WE WERE
ABLE TO REPRODUCE OUR RESULTS IN
HUMAN CELLS AS WELL.
WHAT WE DID IS TOOK THE HUMAN
CELLS AND WE EITHER TREATED THEM
WITH NOTHING, SO THAT IS WHAT IS
SHOWN IN RED.
OR WE TREATED IT WITH VARIOUS
CONCENTRATIONS OF THE NATURAL
PRODUCT.
SO .1, 1, OR 10 MICROGRAM PER
MIL OF THE A15I15 NATURAL
PRODUCT.
WE DID THAT FOR 18 HOURS.
THEY WERE TREATED FOR 18 HOURS.
AFTER THAT 18-HOUR PRETREATMENT,
WE DECIDED TO LEAVE THEM ALONE
AND LOOK AT THE IMMUNE RESPONSE
FOR THAT.
THAT IS WHAT IS IN THE CONTROL.
OR WE THEN TREATED THEM WITH THE
TWO KNOWN LIGANDS, PAM 3CYS OR
THE LPS.
WE WANTED TO SEE IF WE HAD A
PRETREATMENT WITH THE NATURAL
PRODUCT AND A KNOWN STIMULANT.
WHEN WE DID THAT WE SAW VERY
INTERESTING RESULTS.
SO I'M LOOKING HERE AT THE
MIDDLE SECTION WHERE THE NORMAL
RESPONSE TO PAM 3CYSK IS SHOWN
IN RED.
WHEN WE HAD A PRETREATMENT WITH
A NATURAL PRODUCT WE SAW A
DEPRESSION OR REDUCTION IN
RESPONSE TO PAM 3CSK.
IT DOESN'T SEEM TO BE AS ROBUST
WITH THE HIGHER CONCENTRATIONS
OF THE NATURAL PRODUCT.
WHEN WE LOOK AT LPS, WE SEE THE
PRODUCT ALONE IN RED SHOWS VERY
SHY IMMUNE RESPONSE.
HOWEVER, WHEN PRETREATED WITH
THE NATURAL PRODUCT, WE SEE,
AGAIN, A DEPRESSION OF THAT
RESPONSE.
AND WHAT WE THINK IS THAT THIS
IS SOMEHOW DOING SORT OF A RESET
OF THE IMMUNE SYSTEM.
SO THIS MOLECULE IS ABLE TO
CHANGE THE THRESHOLD OF WHAT IS
NEEDED FOR AN IMMUNE RESPONSE.
SO WE THINK THIS BEHAVIOR MAY BE
RESPONSIBLE FOR SOME OF THAT
HOME YO -- HOMEO STATIC
RESPONSE.
I'M GETTING CLOSE TO THE END SO
I'M GOING TO WRAP UP AND JUST
SAY THAT, SO MEMBRANE LIPIDS ARE
TYPICALLY OVERLOOKED.
A LOT OF TIMES THEY ARE THOUGHT
TO BE UBIQUITOUS THAT PEOPLE
TEND TO IGNORE THEM.
WE WANTED TO POINT OUT THAT IS
WHAT WE THOUGHT, TOO, BUT THEY
CAN BE IMMUNE SIGNALS AND THEY
SHOULDN'T BE IGNORED.
THEY CAN REALLY BE DOING SOME
INTERESTING THINGS.
I WANT TO POINT OUT, I KNOW MY
PRESENTATION WASN'T NECESSARILY
ABOUT NEWER METHODS OF LOOKING
FOR MOLECULES, BUT THIS BIOASSAY
GUIDED FRACTIONATION MAY BE OLD
FASHIONED OR CLASSICAL, IS STILL
RELEVANT.
IT DOESN'T HAVE TO BE ONE OR THE
OTHER.
WE CAN DO HAND IN HAND APPROACH
WHERE WE USE NEW METHODS AND OLD
AND FIND EVEN MORE MOLECULES.
I WANTED TO POINT OUT AGAIN THE
AKKERMANSIA MAY BE BALANCING
INFLAMMATORY RESPONSES IN THE
GUT RESULTING IN META IMMUNE
HOMEOSTASIS AND CONTROL IN
DISEASES OR CANCER IMMUNO
THERAPY RESPONSES.
WE ARE INTERESTED IN DOING
FURTHER RESEARCH LOOKING AT IN
VIVO RESPONSING WITH NATURAL AND
SYNTHESIZED COMPOUNDS.
FINALLY, I WANT TO SAY THANK YOU
TO THE PEOPLE WHO HAVE HELPED
THE MOST.
MY PROFESSOR, MY ADVISOR JOHN
CLARDY WAS AMAZING.
MY CO-FIRST ON THIS PAPER, WE
HAD A KUN ON V OF PEOPLE
HELPING.
IT WAS ON AN F32 DURING THIS
WORK SO I WANT TO ACKNOWLEDGE
THAT AS WELL.
WITH THAT I'M DONE AND THANK YOU
SO MUCH FOR YOUR ATTENTION.
>>WELL, THIS IS CRAIG HOPP.
THANK YOU SO MUCH TO ALL OF OUR
SPEAKERS.
DOCTORS NELSON, DIVER, AND
CASSILLY.
I APPRECIATE THE INTERESTING
TALKS.
I ENCOURAGE VIDEOCAST AUDIENCE
TO PUT IN QUESTIONS YOU MIGHT
HAVE THROUGH THE FEEDBACK FORM
ON THE VIDEOCAST LINK.
SO FOR NOW WE ARE GOING TO MOVE
INTO SOME QUESTIONS.
WE HAVE TIME FOR SEVERAL.
MY FIRST IS, I GUESS, FOR BOTH
DR. NELSON AND DR. DIVER.
AT THE MOMENT CRYO EM, IT STARTS
OFF BEING EXPENSIVE.
HOPE YOU HAVE ASPECTS A DECADE
LATER.
WHEN DO YOU THINK OR WHAT WILL
IT TAKE DO YOU THINK FOR THIS
SORT OF TECHNOLOGY TO BE MORE
WIDELY AVAILABLE TO MORE PEOPLE,
BASICALLY?
>>I CAN START OFF.
I THINK A COUPLE OF THINGS.
I THINK THAT THE TECHNOLOGICAL
REQUIREMENTS FOR DOING ELECTRON
DEFRACTION AND MICROED ARE
SMALLER FOR LARGER
MACROMOLECULAR SYSTEMS.
I THINK THERE IS AN OPPORTUNITY
FOR MICROSCOPE VENDORS TO
LEVERAGE THAT AND MAKING LOWER
COST INSTRUMENTS LESS THAN $1
MILLION.
BECAUSE OF THE CRYO-EM
REVOLUTION, MOST UNIVERSITIES
HAVE THESE TOOLS.
SO WHAT IT REALLY BOILS DOWN
FROM MY PERSPECTIVE IS HAVING
THE RIGHT SOFTWARE AND WORK
FLOWS AVAILABLE TO THE COMMUNITY
WHERE FOLKS CAN WALK UP AND DO
THESE TYPES OF EXPERIMENTS.
THAT IS PART OF IT.
THE OTHER PART IS WE ARE STILL
IN RESEARCH MODE.
IT IS NOT -- SOMETIMES IT WORKS
INCREDIBLY WELL.
WE HAVE SOLVED MANY, MANY
STRUCTURES IN A SINGLE DAY, BUT
SOMETIMES WE SPEND SIX MONTHS
WORKING ON A STRUCTURE.
AT LEAST GETTING A WORK FLOW OUT
THERE THAT ALLOWS PEOPLE TO DO
THE QUOTE-UNQUOTE EASY STUFF
WOULD BE A POWERFUL ADVANCE ON
THE ELECTRON DEFRACTION SIDE.
>>I COMPLETELY AGREE WITH ALL
THAT AND WILL ADD ONE THING.
IN ADDITION TO MANY, MANY PLACES
HAVING ACTIVE CENTERS, THERE ARE
ALSO NATIONAL CENTERS SPONSORED
BY THE NIH THAT ARE FABULOUS.
AND PEOPLE SHOULD USE THEM.
THERE IS ONE IN OREGON.
THERE IS STUFF GOING ON IN
COLORADO.
THERE IS A GIANT CENTER IN NEW
YORK AND IT IS NOT, YOU HAVE
TRAINING THERE.
YOU HAVE TONS OF INFRASTRUCTURE,
IT IS ALL AVAILABLE AT YOUR
FINGERTIPS AND THEY ARE AN
AMAZING TEAM.
IF YOU ARE SOMEWHERE WITHOUT IT,
CONTACT THEM AND THEY WILL HELP
YOU.
>>GREAT.
I SEE SOME OF MY NIH COLLEAGUES
ON THE TEAM HERE HAVE SOME
QUESTIONS.
SO NIDES, ASK YOUR QUESTION.
>>CAN YOU HEAR ME?
>>YES.
>>THANKS, CRAIG.
I HAVE A QUESTION ON THE
STRUCTURAL INSIGHT ON TRYP
CHANNELS.
ANY THOUGHTS ON HOW YOU CAN
LEVERAGE ON THE INFORMATION,
STRUCTURAL INFORMATION IN A
MULTIPLE TRYP CHANNEL AND THEN
REALLY, AGGREGATE THOSE IN A
THERAPEUTIC SITE.
ANY THOUGHTS ON THAT?
>>IT IS A VERY, VERY
INTERESTING QUESTION.
SO WHAT I THINK THE SINGLE
PARTICLE CO EM RESOLUTION HAS
COME TO BASICALLY ILLUMINATE.
WE HAVE MANY TRYP CHANNEL
STRUCTURES NOW.
SOME WE KNOW A LOT ABOUT THEIR
BIOLOGY AND ARE INTERESTING DRUG
TARGETS AND PAIN DRUG TARGETS.
AND SOME WE DON'T KNOW MUCH.
THEY ARE UNIQUE.
THE BINDING SITES WHERE THEY
BIND DRUGS ARE YUNIQUE, AND THEE
ISN'T USUALLY ONE SITE.
YOU CAN FIND LIPID MODULATORS,
CHEMICAL MODULATORS.
IT IS PUSHING THE RESOLUTION AND
TRYING TO OVERCOME SOME OF THE
PROBLEMS WE HAVE HAD IN THE
CLINIC.
I DIDN'T TALK ABOUT THAT HERE,
BUT THERE HAS BEEN A BIG EFFORT
TO DEVELOP DRUGS TO TARGET OUR
HEAT AND PAIN RECEPTOR TRYPV1
FOR 20 YEARS.
WE HAVE TO OVERCOME THE PRODUCTS
WHEN YOU DRUG THESE TEMPERATURE
SENSORS IN OUR BODY, THERM
OREGULATION GOES QUITE AWRY.
WE FINALLY HAVE THE STRUCTURAL
TOOLS AND THE KNOWLEDGE AND IT
IS ALL POURING IN, BUT WE HAVE
SOME THINGS TO FIGURE OUT
PROBABLY IN THE CLINIC, TOO.
>>ABSOLUTELY.
WELL SAID.
AND THAT IS THE CORE OF
QUESTION.
HOW TO REALLY LEVERAGE ON THIS
INHERENT PROPERTIES OF THE
CHANNELS AND HOW TO ALLOCATE
THOSE STRUCTURAL ASPECTS SO YOU
CAN TARGET THESE CHANNELS
WITHOUT INFLUENCING THE
TEMPERATURE SENSORS OF THE BODY,
OTHER THAN JUST FOCUSING ON THE
PAIN TRANSDUCTION MECHANISM, NOT
MUCH ON THE CORE TEMPERATURE.
>>IT IS VERY INTERESTING TO
THINK ABOUT.
I THINK YOU ARE NAILING INTO THE
PERFECT FACT.
IF WE COULD UNDERSTAND --
BASICALLY AT THIS POINT WE DON'T
KNOW IF THERE ARE DIFFERENCES OF
HOW THESE CHANNELS RESPOND TO
PHYSICAL AND CHEMICAL STIMULI.
IF WE COULD JUST START WITH ONE
RESPOND TO TEMPERATURE WE COULD
TARGET ONE OVER THE OTHER.
THAT IS GOING TO BE ESSENTIAL.
WE HAVE BEEN LIMITED BY
TECHNOLOGY, BUT I THINK THINGS
IN THE BENCH AND COMPUTATIONALLY
THAT WILL PUSH THAT FORWARD I
HOPE WITHIN THE NEXT FIVE YEARS.
>>SO WE HAVE A QUESTION FOR DR.
CASSILLY.
>>HI CHELSEA, THIS IS RYAN FROM
NIAND.
YOU MENTIONED YOUR APPROACH, YOU
SAID OLD FASHIONED IN TERMS OF
FRACTIONATING EXTRACTS FROM
AKKERMANSIA.
WHAT I WAS WONDERING DO YOU
THINK -- HAVE YOU EVER TRIED OR
THOUGHT ABOUT A WHOLESALE
APPROACH?
USING THE BUG ITSELF, OF COURSE,
IN THOSE ASSAYS?
AND I'M THINKING MY THOUGHTS ARE
THAT YOU MIGHT NOT HAVE ACTUALLY
DETECTED THAT ACTIVITY.
THAT MOLECULE THERE IN TERMS OF
ITS EXPRESSION AND INTERACTION
AND THE BIOLOGY, I WONDERED IF
YOU HAD THOUGHT ABOUT THAT?
I THINK I THINK THAT IS A REALL
POWERFUL THING.
SO, YES, VERY INTERESTING.
I THINK THERE WERE TIMES THAT WE
DID EARLY IN THE LAB INTERESTED
IN DOING WHOLE SALE TYPES OF
DOING THAT WITH THAT ASSAY.
BUT I THINK THAT ANSWERS A BIT
OF A DIFFERENT QUESTION THAN
WHAT WE WERE LOOKING AT.
AND I DON'T REALLY REMEMBER IF
WE DID IT WITH AKKERMANSIA
BECAUSE OF THE AN AEROBIC NATURE
OF THE ORGANISM.
>>I APPRECIATE THAT.
I WAS THINKING HOW PEOPLE ARE
FRACTIONATING THE MICROBIOME
LOOKING FOR CONSORTIA THAT HAVE
THAT ACTIVITY.
I HAVE A SECOND QUESTION AND IT
MAY BE UNFAIR AND YOU CAN
TOTALLY PASS.
IT IS A QUESTION ABOUT HOW DOES
THAT ACTIVITY RELATE TO THE
BIOLOGY OF OBESITY AND DIABETES.
I WONDER IF YOU CAN EXTEND THAT
AND IF IT IS
MAYBE WE CAN STOP THE WHOLE
HUMAN GETTING TO A FULL BLOWN
DISEASE.
I KNOW THAT WAS PROBABLY A BIT
CONFUSING.
I THINK THAT IDEA OF RESETTING
WHAT IT TAKES TO GET TO A
DISEASE STATE MAY HELP THIS
ORGANISM CONTROL THAT BETTER.
SCHL
>>I THINK THAT MAKES PERFECT
SENSE.
SOME OF THE TERMINOLOGY IS --
WHERE YOU ARE REALLY REDUCING
THE EXTREME SPOBSS.
THAT IS VERY INTERESTING.
>>THANK YOU.
>>I WILL CHIME IN.
ONE OF THE BUZZ WORDS.
NCCIH IS INTERESTED IN, ACROSS
NICHE IS THE TERM RESILIENCE.
SO MAYBE THERE IS SOMETHING
ABOUT AKKERMANSIA THAT HELPS
MAKE THE HOST MORE RESILIENT TO
SOME OF THESE INFLAMMATORY
INSULTS, IF YOU WILL, THAT MIGHT
OTHERWISE RESULT IN MORE
DRAMATIC REACTIONS.
>>OR NO TURNING BACK TYPE
POINT.
YEAH.
ABSOLUTELY.
>>THE OTHER QUESTION FOR YOU
DR. CASSILLY FROM THE AUDIENCE,
YOU SHOWED THE STRUCTURE OF THIS
COMPOUND, SYNTHETIC, OR THE
NATURAL, OR THE TAILS, THEY ARE
EQUI POTENT.
THE QUESTIONER IS ASKING THIS
SEEMS LIKE A PARADOX GIVEN THE
SPECIFICITY OF THE RECEPTOR.
CAN YOU COMMENT ON WHY SWAPPING
THOSE TAILS SEEMS TO HAVE NO
IMPACT ON THE ACTIVITY?
IS
>>SO I WANT TO POINT OUT THERE
WAS A LITTLE BIT OF ACTIVITY.
THE ONE WHERE WE SWAPPED THE
CHAINS, WE DID SEE MAYBE A
LITTLE BIT OF A DECREASE IN
ACTIVITY.
I THINK THE POINT WAS AND I
DIDN'T MENTION THIS, IT IS IN
THE PAPER.
WE DID SYNTHESIZE MANY OTHER
VERSIONS WHERE WE SHORTENED THE
CHAINS OR WE CHANGED WHERE THE
BRANCHES WERE EVEN FURTHER OR WE
JUST REMOVED THE BRANCHES ALL
TOGETHER AND WE SAW NO ACTIVITY
WITH THAT.
WITH ANY OF THOSE.
SO IT REALLY DOES SAY THAT THERE
IS SOMETHING INTERESTING ABOUT
THE WAY THAT THOSE BRANCHES ARE.
MAYBE THE CHAIN ON WHICH THE
ANTI-VERSUS ISO, MAYBE THAT IS
NOT SO IMPORTANT.
IF YOU CHANGE THEM AT ALL OR
EVEN IF YOU PUT BOTH OF THEM
ANTI-ISO OR ISO, WE DID NOT SEE
ACTIVITY IN THOSE CASES.
THERE IS SOMETHING SPECIFIC AND
INTERESTING AND BUT IT IS
DEFINITELY AND IMPORTANT
QUESTION OF LOOKING AT THE
STRUCTURE RELATED TO THE
FUNCTION.
THERE IS MORE TO ASK AS WELL.
>>GREAT.
THANK YOU.
SO QUESTION FOR DR. NELSON.
SO ONE OF THE AUDIENCE MEMBERS
ASKS, HOW DOES ONE DETERMINE IF
ONE'S FAVORITE OILY NATURAL
PRODUCT CAN MAKE MICROCRYSTALS
FOR ED?
IS THERE A BIAS FOR CRYSTALINE
COMPOUNDS AND THE OILS ARE
PASSED BY?
>>THAT IS A GREAT QUESTION.
WE NEED CRYSTALINE COMPOUNDS.
WE HAVE GOTTEN CRYSTAL
STRUCTURES AT THE MSO, OPERATING
MINUS 170 COLLECTING DATA, WE
HAVE COLLECTED FATTY ACIDS.
IT IS TRUE WE WILL ONLY SOLVE
STRUCTURES OF CRYSTALINE
COMPOUNDS.
IF YOU LOOK AT THE PERCENTAGE OF
COMPOUNDS THAT ARE KNOWN VERSUS
UNKNOWN, EVEN IF WE COULD SOLVE
THE STRUCTURES OF 1% OF THAT
SPACE, IT WOULD BE DRAMATIC.
I THINK THE QUESTION IS DEAD ON.
WE CAN ONLY GET CRYSTALS OR
STRUCTURES THAT ARE THINGS ARE
CRYSTALINE IN ORDER, BUT ONE HAS
TO RECOGNIZE FROM CHEMICAL SPACE
THAT IS A SIGNIFICANT NUMBER OF
COMPOUNDS.
MOREOVER, THE TYPES OF
CONDITIONS IN A MICROSCOPE ARE
CONDUCIVE TO CRYSTALLIZATION.
WITHOUT THINKING OF OTHER THINGS
CRYSTAL FORMING A CHEMICAL
SPECIES.
>>ANOTHER RELATED QUESTION FOR
YOU DR. NELSON.
YOU WERE EXPECTING ONLY 5%, BUT
YOU GOT 20%.
WHAT WAS WRONG WITH THE OTHER
80%?
WHY DON'T THEY CRYSTALLIZE?
>>I WAS CAREFUL IN MY WORDS,
BUT VAGUE.
20% OF THE FRACTIONS WE LOOK AT
DISPLAY CRYSTAL INITIY THAT
SOLVENT WERE LOST.
WHEN WE.
>>FRACTIONING THEM, OUT OF 100
FRACTIONS, 20 WILL BE CRYSTALINE
OR DEFRACTURE.
PROBABLY A LOT OF OTHEM ARE
EMPTY WELLS THAT DON'T HAVE
COMPOUNDS.
ANOTHER SUBSET WOULD CRYSTAL LIE
ISOPROPINOL.
IF WE TO FIGURE OUT THE FRACTION
ARE CRYSTALINE, I DON'T HAVE AN
ANSWER.
I DON'T HAVE AN IDEA.
WHEN WE FRACTIONATED THIS
COMPOUNDS ON AVERAGE WE GET 20
THINGS THAT DEFRACTURE THAT ARE
UNIQUE.
SO I DON'T HAVE AN ANSWER FOR
THAT QUESTION, BUT I THINK IN
REALITY THE NUMBER OF THINGS AT
THAT TEMPERATURE THAT ARE
CRYSTAL IS GREATER THAN 20%.
MY SBU TIGS OF A
THE SLIDES ARE KNOWN, I DON'T
KNOW IF THAT IS ENTIRELY TRUE,
THOSE BIOLOGICAL ACTIVITIES CAN
BE PRODETECTIVABLE.
I'M THINKING HOW THESE TECH LINK
TO DISCOVERY THAT ARE NOT CYTO
STATIC MOLECULES.
ANYBODY FEEL LIKE THEY ARE ABLE
TO ANSWER THAT?
>>I DON'T UNDERSTAND THE
BIOLOGY, BUT ONLY ONE WAS IN
KNOWN SOLID STATE STRUCTURE AND
WE SHOWED YOU A LOT OF
STRUCTURES.
>>I THINK, TOO, EVEN IF WE
KNEW, LET'S SAY FOR TRPM8 WE
KNOW ITS BIOLOGY, IT IS
IMPORTANT, WE HAD SOME
CHEMICALS, WE DIDN'T UNDERSTAND
WHY THERE WERE SO MANY CHEMICALS
THAT BIND TO IT AND WHY THEY
BIND SO POORLY AND SUCH TERRIBLE
DRUGS.
THEY ARE HYDROPHOBIC, POOR
EFFICACY.
AND NOW YOU SEE THE POCKET, IT
CAN ADAPT AND CHANGE TO THE
DIFFERENT MOLECULES, IT GIVES
YOU SPACE TO SYNTHESIZE AND THIN
OF SOMETHING THAT COULD BE MORE
SPECIFIC AND MORE DRUG LIKE.
>>I GUESS ONE MORE GENERIC
QUESTION, FOR MYSELF MORE THAN
PATIK, WHAT IS THE NCCIH
INTEREST IN PHENOTYPIC.
NOT DIRECTLY TO THE TALKS WE
HEARD.
NCCIH IS VERY INTERESTED.
WE ARE IN THE IGNITE PROGRAM
ACTIVELY SEEKING ASSAYS, FEEN
TYPE ASSAY S.
WE ARE FUNDING THAT AREA.
THERE IS ONE MORE GENERAL
QUESTION I WILL SCROLL BACK TO.
IT IS NOT FOR ANYBODY, PER SE
DIRECTLY ADDRESSING THE TALKS.
I WILL ASK IT ANY WAY.
SO THE QUESTION IS MANY OF THE
MEASUREMENTS WE USE IN NATURAL
PRODUCTS RESEARCH ARE THE MASS
SPEC ESPECIALLY ARE DESTRUCTIVE.
WITH PROHIBITS OTHER DOWNSTREAM
ASSAYS FROM USING THOSE SAME
PRODUCTS.
WHAT ROLE DO YOU FEEL
NONDESTRUCTIVE, NONINVASIVE
CHEMICAL ASSAYS, FTIR, RAMN,
WHICH IS THEIR ROLE IN
DETERMINING CHEMICAL COMPOSITION
AND HOW IMPORTANT IT IS TO HAVE
NONDESTRUCTIVENESS TO DEVELOP
CELL LINES WITH PHENOTYPE.
THE LAST PART WAS NON SEQUITUR
OF THE FIRST PART.
WHAT ARE YOUR THOUGHTS ON
NONDESTRUCTIVE METHODS?
>>IT IS POINT ON.
NONDESTRUCTIVE METHODS ARE
REALLY IMPORTANT.
WHAT WE DO IS DESTRUCTIVE IN
PRACTICAL SENSES, BUT THE AMOUNT
OF STUFF WE ARE LOOKING AT IS SO
SMALL EVEN IF YOU HAVE A
NANOGRAM MATERIAL, IT IS OKAY TO
DRAW OFF A PICO GRAM PART OF THE
SOLUTION.
FROM MY PERSPECTIVE AS A
CHEMIST, MULTIPLEXING OF METHODS
WILL PROVIDE THE MOST THOROUGH
PICTURE TR FROM A CHEMICAL AND
BIOLOGICAL STANDPOINT SO IT IS
REALLY IMPORTANT TO DEVELOP
NONDESTRUCTIVE METHODS.
>>TWO MORE QUESTIONS AND WE
HAVE TO MOVE ON.
LOOKS LIKE BOTH ARE FOR YOU DR.
NELSON.
DO YOU SEE FOOD SCIENCE OR FOOD
PRODUCT DEVELOPMENT RESEARCH
BEYOND NEW DRUG DEVELOPMENT
APPLICATIONS.
THE QUESTIONER IS THINKING ABOUT
NANO IMMULSIONS OR OTHER FOOD
OPPORTUNITIES.
>>I THINK ANYWHERE THERE IS
MOLECULAR ORDER THERE IS AN
APPLICATION POTENTIALLY.
ONE OF THE THINGS WE LOOK AT
THAT MIGHT BE RELATED IN THE
PHARMACEUTICAL INDUSTRY IS FROM
A FORMULATION STANDPOINT.
IF YOU FORMULATE AN API WITH A
BINDER OR LOOKING AT HOW THE
CRYSTAL MOR FOLG CHANGES AS A
FUNCTION OF FORMATION IS
IMPORTANT FOR BIOAVAILABILITY.
YOU CAN THINK OF THOSE SAME
TIMES OF THINGS IN THE FOOD
MEDICINE INDUSTRY.
IN GENERAL, WE ARE CERTAINLY
OPEN TO THOSE THINGS.
WE HAVEN'T THOUGHT ABOUT IT.
ANYWHERE THERE IS ORDER, WE ARE
EXCITED ABOUT LOOKING.
>>ONE MORE CRYO EM QUESTION FOR
DR. DIVER, DR. NELSON.
WHAT TYPES OF NATURAL PRODUCTS
OR PROTEINS ARE PARTICULARLY
WELL SUITED FOR CRYO-EM AND THIS
ONES PRAPS ARE NOT?
PERHAPS ARE NOT?
>>I'M HAPPY TO COMMENT ON THAT.
WHEN I FIRST STARTED OUT,
WORKING ON SINGLE PARTICLE CRYO,
TRPM8 IS PERFECT.
IT IS BIG.
DYNAMIC.
IT WAS NOT ABLE TO BE
CRYSTALLIZED.
MANY TRIES FOR TRYP CHANNELS FOR
DECADES AND DECADES.
THE ANSWER NOW IS EVERYTHING IS
A GOOD TARGET.
IT IS AMAZING FOR RECEPTORS AND
COMPLEXES AND THE THINGS THAT
USED TO BOG US DOWN, SMALLER
SIZE, NOT MUCH OUT OF THE
MEMBRANE, WHICH DOESN'T GIVE THE
PROGRAMS A LOT TO ALIGN THE
PARTICLES TO.
ALL OF THOSE THINGS HAVE
SOLUTIONS AND ALL OF IT IS
FIXABLE AND PRACTICALLY THEY ALL
WORK.
WE ARE BASICALLY AT A NO LIMIT.
>>THAT IS EXCITING.
ANYTHING ELSE TO ADD DR. NELSON?
>>YEAH.
SURE WE HAVEN'T FIGURED THAT OUT
YET.
WE HAVEN'T SOLVED ENOUGH
STRUCTURES.
THINGS THAT SHOULDN'T BE
CRYSTALINE, BUT DARN IT, THEY
ARE.
I HAD TO TRUNCATE A FATTY ACID
CHAIN THAT HAS 20 PLUS CARBON
CHAINS FLOPPING IT AND WE HAVE A
CRYSTAL STRUCTURE.
IT IS WILD IF YOU LOOK AT THE
PACKING, IT LOOKS LIKE AN
INVERSE LIPID BILAYER.
IT IS A REMARKABLE STRUCTURE.
THE MORE STRUCTURES WE SOLVE, WE
MIGHT BE ABLE TO GET SOME IDEAS
OF WHAT ARE THE CHEMICAL
FEATURES THAT LEND THEMSELVES TO
ORDER BEYOND WHAT WE KNOW NOW,
BUT AT THIS POINT IT IS A WILD
WEST.
>>YEAH.
STILL EARLY DAYS FOR THE SMALL
MOLECULE SIDE.
THANK YOU EVERYONE WHO POSED
THOSE QUESTIONS.
WE ARE GOING TO SHIFT OVER TO
THE NEXT PHASE OF THE WEBINAR
NOW WHERE WE ARE HEARING FROM
OUR NIH COLLEAGUES, DR. MOHA'
ATRA AND DR. MICHELLE BOND, WHO
IS WITH NIGMS.
WE WANT TO ASK THESE FOLKS SOME
GENERAL QUESTIONS ABOUT HOW THE
SCIENCE WE TACKED ABOUT TODAY
RELATED TO THEIR DIFFERENT
INTERESTS WITHIN THEIR IC.
SO THE FIRST -- SO I HAVE A
SERIES OF QUESTIONS I'M
INTERESTED IN MANY ASKING.
THE FIRST ONE IS, I GUESS WE'LL
ASK MICHELLE FIRST, DR. BOND.
HOW HAS YOUR IC'S INTEREST IN
NATURAL PRODUCT TECHNOLOGY
EVOLVED OVER TIME.
AFTER SHE ANSWERS WE CAN ASK
OTHERS TO FILL IN THE BLANKS.
DR. BOND, WHICH IS NIGS'S IDEA.
>>HOPEFULLY YOU CAN SEE ME AND
HEAR ME.
WE ARE HAVING WEATHER HERE.
I WILL MENTION I AM AT THE
NATIONAL INSTITUTE OF GENERAL
MEDICAL SCIENCES.
THE APPLICATIONS AND AWARDS I
OVERSEE ARE TYPICALLY IN THE
NATURAL PRODUCTS AND GLYCO
SCIENCE AREA.
WHAT I WILL MENTION IS THAT WE
ARE INTERESTED IN SUPPORTING
CUTTING-EDGE RESOURCE.
THAT IS WITHIN OUR MISSION AND
TO SUPPORT SEARCH THAT INCREASES
OUR UNDERSTANDING OF BIOLOGICAL
PROCESSES AND LAYS A FOUNDATION
FOR DISEASE DIAGNOSIS,
TREATMENT, AND PREVENTION.
AND NIGMS IS INTERESTED IN
INVESTIGATOR-INITIATED EFFORTS.
SO OFTEN THE PARTICULAR AREAS OF
SCIENCE WE SUPPORT REFLECT THE
INTEREST AND IMPORTANCE OF THE
SCIENTIFIC COMMUNITY PLACES ON
PARTICULAR AREAS OF
INVESTIGATION.
THAT BEING SAID, WE ARE
INTERESTED IN TECHNOLOGIES THAT
ARE THE AT THE VERY BEGINNING
STAGE OF TECHNOLOGY DEVELOPMENT.
SO THE CONCEPTUAL STAGE.
THERE IS NO FEASIBILITY THAT HAS
BEEN PROVEN TO TECHNOLOGIES THAT
ARE READY FOR DISSEMINATION
COMMERCIALLY.
OUR EMPHASIS ON SUPPORTING
EFFORTS IN THIS WIDE RANGE HAS
BECOME A KEY FOCUS AS WE
RECOGNIZE THERE IS AN ITERATIVE
AND CYCLICAL NATURE OF
TECHNOLOGY DEVELOPMENT AND
ASKING BIOMEDICAL RELATED
RESEARCH QUESTIONS WITH THAT
TECHNOLOGY AND GOING BACK AND
FORTH IN THAT WAY.
SO I THINK, CRAIG, YOU HAVE A
COUPLE OF OTHER QUESTIONS AND I
WILL LEAVE IT THERE FOR NOW.
I WILL GO INTO MORE DEPTH AS WE
GET FARTHER ALONG.
>>I WAS MUTED.
SO DOCTOR MOHAPATRA OR DR.
RANALLO, ANYTHING TO ADD?
>>DEFINITELY.
AS YOU KNOW -- CAN YOU HEAR ME
BY THE WAY?
>>YES.
>>NINDS MAINLY SUPPORTS
CLINICAL RESEARCH ON THE BRAIN
AND UTILIZED THAT KNOWLEDGE
TO -- WE ARE INTERESTED IN THE
RESEARCH WITH THE TRYP CHANNELS.
ALL THOSE RESEARCH CAME THROUGH
THE NATURAL, UTILIZATION OF
NATURAL PRODUCT.
THAT IS HOW LIFTED THE DISCOVERY
AND FIELD NATURAL EXPANSION.
NDS HAS BEEN SUPPORTING THAT FOR
QUITE SOME TIME.
AS CRAIG MENTIONED WE HAVE A
PARTNERING PROGRAM ON DEVELOPING
SPECIFICALLY THE NATURAL
PRODUCTS AND DEVELOPING THOSE
FOR THERAPEUTICS FOR PAIN AS FOR
OTHER NEUROLOGICAL.
NINDS HAS ALSO SUMMITED A NUMBER
OF TECHNOLOGY DEVELOPMENT
THROUGH SMALL BUSINESSES,
RESEARCH AND NATURAL PRODUCTS.
IN ADDITION TO THAT NINDS
ACTIVELY PARTICIPATES AS ONE OF
THE NIH INSTITUTE CENTERS
DEVELOPING THESE MULTICENTER
LIKE TECHNOLOGIES, LIKE CRYO-EM.
THESE FACILITIES WE ACTIVELY
SUPPORT THOSE.
OUR OVERALL MISSION AND INTEREST
REMAINS VERY STRONG IN THE
DISCOVERY AND USE OF NATURAL
PRODUCTS AND DEVELOPING
THERAPEUTICS.
WE ARE FOCUSING ON NATURAL
PRODUCTS AS WELL AS UTILIZING
THOSE TO UNDERSTAND THE BASIC
BIOLOGY OF THE NERVOUS SYSTEM
AND
[INDISCERNIBLE] WE ARE COMMITTED
THERE SO I WILL STOP HERE AND
TAKE ANY QUESTIONS IN CASE
ANYONE HAS ANY.
>>THANK YOU.
I WILL INSERT HERE BRIEFLY, THE
AUDIENCE IS WELCOME TO ASK
QUESTIONS OF THE NIH COLLEAGUES
IF YOU HAVE SPECIFIC QUESTIONS
ABOUT AREAS OF INTEREST.
IF THEY ARE VERY SPECIFIC, TAKE
THEM OFFLINE, BUT GENERAL
QUESTIONS YOU CAN ASKED AT THE
END OF THIS SEGMENT.
DR. RANALLO, ANYTHING ELSE TO
ADD?
>>A LITTLE BIT.
AN OVERVIEW OF NIAD'S MISSION.
IT IS A LARGE INSTITUTE.
IN THE SPOTLIGHT RECENTLY AND
ULTIMATELY OUR MENTION IS TO
TREAT, PREVENT INFECTIOUS AND'
ALLERGIC DISEASES.
PRIMARILY IN THE REALM OF
ANTI-INFECTIVES, WE KNOW THAT.
WE FOCUS, AT LEAST IN MY
DIVISION, WE HAVE THREE LARGE
EXTRAMURAL DIVISIONS MINE IS THE
MICROBIOLOGY AND INFECTIOUS
DISEASES.
MINE IS ON THE GUT MICROBIOME
AND CLUSTERING.
AND SO THINGS THAT TRADITIONALLY
HAVE BEEN CONSIDERED NATURAL
PRODUCTS, ANTI-INFECTIVE
PRODUCED BY MICROBES ARE CLEARLY
IN OUR AREA OF INTEREST.
WE HAVE ADVANCING TECHNOLOGIES
THAT ALLOWS US TO LOOK AT THESE
PRODUCTS COMING FROM WHOLE
MICROBAL COMMUNITIES, RECENT
ANTIBIOTIC DISCOVERIES IN THAT
REALM.
WE HEARD FROM CHELSI.
WE LOOK AT THESE BUGS, BOTH AT
THE WHOLE, THE WHOLE BACTERIA
LEVEL AS WELL AS IN THE SENSE OF
INDIVIDUAL, YOU KNOW, ELEMENTS
OF THOSE MICROBES.
SO, AGAIN, I THINK FROM MY
PERSPEC
PERSPECTIVE, AGAIN, I WILL THINK
ABOUT IT IN THE CONTEXT OF LIVE
BACTERIA OR PROBIOTICS, FAGE,
THEY FALL INTO NEW PRODUCTS.
THERE ARE COOL NEW TECHNOLOGIES,
CULTURAL TECHNOLOGIES,
ASSOCIATED MICROBES WITH
MULTIDIMENSIONAL AND
MULTICELLULAR IN VITRO SYSTEMS.
RELATING TO DISCOVERY.
TECHNOLOGIES THAT ALLOW YOU TO
FRACTIONATE BUGS OR EXTRACTS IN
THE CONTEXT OF BACTERIA,
MICROBIOME TO METTA GENETIC
SEQUENCING TO GENOMES IN THE
SENSE OF IDENTIFYING DIFFERENT
BACTERIA WITHIN THERE.
I WILL STOP THERE, BUT
ESSENTIALLY WE DON'T HAVE ANY
LARGE OVERARCHING NATURAL
PRODUCT TECHNOLOGY INITIATIVES
RIGHT NOW.
IT IS A CONSTANT NEED AND INFLUX
IN OUR GRANT PORTFOLIO.
I'LL STOP THERE.
>>YEAH.
THANKS.
WE DID HAVE A FOURTH PROGRAM
OFFICER WHO WAS ORIGINALLY GOING
TO JOIN US THAT HAD A
LAST-SECOND CONFLICT, DR. YALI
FU AT NCI.
SHE SHARED WITH DR. STILL.
IF YOU HAVE ANYTHING YOU WANT TO
SHARE ON BEHALF OF NCI.
>>YES.
SO YALI WAS NICE ENOUGH TO SEND
A BRIEF OVERVIEW OF THEIR
INTERESTS AND SHE WANTED TO
CONVEY TO EVERYONE THAT THEY ARE
INTERESTED IN IN KNOW VATIVE
METHODS AND NEW TECHNOLOGIES
THAT ADVANCE CULTURING ACTIVE
NATURAL AND UNNATURAL PRODUCTS.
ACCORDING TO DR. FU, THEY HAVE
DOT HAVE A SPECIFIC QUEUE, BUT
THEY ENCOURAGE INNOVATIVE
APPROACHES ON SELECTIVE DELIVERY
OF NATURAL PRODUCTS VIO BUYO
ENGINEERING AND NANO TECHNOLOGY
AND NATURAL PRODUCT ANTI-CANCER
EFFECTS TO BRING NEW DRUGS TO
THE CLINIC, WHICH ARE A
PARTICULAR INTEREST.
SO WE ENCOURAGE YOU TO REACH OUT
TO DR. FU WITH ANY FURTHER
QUESTIONS RELATED TO NCI.
>>ALL RIGHT.
THANK YOU FOR THAT.
SO, THE NEXT QUESTION FOR THE
NIH FOLKS.
CAN YOU GIVE EXAMPLES OF NATURAL
PRODUCT RELEVANT, IF YOU WILL,
TECHNOLOGIES SUPPORTED BY YOUR,
IC.
I WILL ASK DR. RANALLO IF YOU
HAVE EXAMPLES THAT NIAID
SUPPORTED IN THE PAST OR DIRECT
IMPLICATIONS TO NATURAL PRODUCT
RESEARCH IN YOUR OPINION OF AND
YOUR IC.
>>I HAVE ONE IN THINKING HOW TO
RESPOND.
IT IS REPRESENTATIVE OF WHAT I
WAS SAYING BEFORE WHERE A LOT OF
THE NATURAL PRODUCT DISCOVERY
THAT IS HAPPENING IS AT THE R &
D LEVEL.
THE TECHNOLOGIES PEOPLE ARE
DEVELOPING OFTENTIMES WE ARE
TRYING TO LOOK IN THEIR NATURAL
ENVIRONMENT.
SO FOR EXAMPLE, AN ANTIBIOTIC
DISCOVERY.
TAKING HARD TO GROW BACTERIA OR
UNCULTURABLE AND TAKING THESE
BACTERIA AND LETTING THEM GROW
IN THE ENVIRONMENT AND USING
TECHNOLOGIES WHAT IS CALLED AN
I-CHIP TECHNOLOGY WHERE YOU ARE
ABLE TO EMBED THESE MICROBES IN
THEIR NATURAL ENVIRONMENT, ALLOW
THEM TO GROW TO PRODUCE
METABOLITES.
AT THE END OF THE DAY, IT IS A
STANDARD TECHNOLOGY TO LOOK FOR
ANTI-MICROBIAL ACTIVITY.
SO FOR US IN THE ANTI-INFECTIVE
SPACE, I ALSO MENTIONED A BIT OF
THE TECHNOLOGIES THAT WE'RE
SUPPORTING ON CO-CULTURE
SYSTEMS, WHOLE BACTERIA
FRACTIONATIONS AND LOOKING FOR
ACTIVITY IN CELLULAR-BASED
MODELS.
THESE ARE UP-AND-COMING
TECHNOLOGIES WE ARE ENCOURAGING
RATHER THAN GOING TO THE RFAs
THAT HAVE SUPPORTED THEM BECAUSE
THEY ARE NOT RELATED TO NATURAL
PRODUCTS.
BAUGH THEY ALL FEED INTO THIS
OVERALL EFFORT.
I'LL STOP THERE.
>>THANK YOU VERY MUCH.
I GUESS CONTINUING THE REVERSE
ORDER THEME, I WILL ASK DR.
MOHAPATRA IF THERE ARE NATURAL
PRODUCTS RELEVANT TECHNOLOGIES
THAT NINDS HAS SUPPORTED?
>>I WOULD ECHO WHAT DR. RANALLO
SAID.
WE HAVE SUPPORTED THE CRYO-EM
DEVELOPMENT AND EXPANSION OF THE
CRYO-EM FACILITIES AND
TECHNOLOGY STANDARDIZING AND
OPTIMIZING THOSE.
IN ADDITION NINDS HAS BEEN
SUPPORTING TECHNOLOGIES OF
CULTURES, DEVELOPING MICROFLUID
CO-CULTURE SYSTEMS AND DEVICES
TO PROBE MORE OF NEURON
INTERACTION WITH NEURON OTHER
INTERACTION, NEUROMUSCULAR
JUNCTIONS AND DEVELOPING THOSE
TECHNIQUES TO UNDERSTAND EFFECTS
OF TOXINS.
WE HAVE PARTNERED IN SUPPORTING
THESE TECHNOLOGY.
A VAST MAJORITY OF THE STUDIES
DEFINITELY ARE GEARED TOWARD
DISCOVERY OF NEUROBIOLOGICAL
MECHANISM, UNDERSTANDING THE
NEUROSCIENCE USING NATURAL
PRODUCTS.
IN TERMS OF THERAPEUTIC
TECHNOLOGIES, NOT REALLY THINK
IMMEDIATELY WHAT SPECIFIC ONES
WE HAVE BEEN DEVELOPING, BUT IF
I REMEMBER CORRECTLY, THERE ARE
SOME WHICH WE ARE GIVEN TO SDIA
MECHANISMS MAINLY FOR CELL
CULTURE OR SCREENING OR
SIMULATION DEVICES, THOSE KIND
OF TECHNOLOGIES TO REALLY
ENHANCE UNDERSTANDING THE ROLE
OF THIS NATURAL PRODUCT
SCREENING THOSE AND FINDING
THOSE FOR THERAPEUTIC
DEVELOPMENT.
>>AND DR. BOND, ANYTHING ELSE
TO ADD FROM NIGMS.
>>SURE.
WE SUPPORT BROAD AVAILABILITY
AND APPLICABILITY DISSEMINATION
OF TECHNOLOGIES SUCH AS THOSE
THAT REPORT RAPID DETECTION AND
DE -- OF NATURAL PRODUCTS.
SOFTWARE AND ALGORITHM
DEVELOPMENT FOR INTEGRATION AND
PROCESSING OF A VARIETY OF
DIFFERENT DATA TYPES.
PRODUCTION OF MOLECULES OF
INTEREST OR ANALOGS SO THAT YOU
HAVE A SUFFICIENT QUANTITY FOR
DOWNSTREAM QUERIES.
STRUCTURAL ANALYSIS AND HIGH
THROUGHPUT EFFORTS.
>>THANKS.
I GUESS I'LL JUST ADD FROM
NCCH'S PERSPECTIVE, WE OVERLAP A
FAIR AMOUNT IN THIS SPACE OF
TECHNOLOGY DEVELOPMENT.
WE HAVE SUPPORTED A FAIR AMOUNT
IN HETEROLOGOUS APPLICATION.
THERE IS A NICE PAPER FROM
DOCTORS CZECH AND OTHERS WHERE
SHE IS DEVELOPING COMPUTATIONAL
METHODS WHERE THEY CAN TRY TO
GET AT THE PRESENCE OF
SYNERGISTIC COMPONENTS AND
MIXTURES.
THIS IS ONE OF THE BIG -- I
STILL CALL IT HYPOTHESIS, HOW
FREQUENTLY THAT HAPPENS.
IT CERTAINLY HAPPENS WITH MANY
EXAMPLES.
HOW YOU FIND THOSE.
NCCIH IS SUPPORTING THAT AS
WELL.
EVERYONE HAS TALKED ABOUT THE
EXISTENCE OF FUNDING.
I THOUGHT I WOULD LEAVE IT OPEN
TO MY NIH COLLEAGUES IF THERE IS
ANY PARTICULAR NATURAL PRODUCT
OR NATURAL PRODUCTS TANGENTIAL
FOAs YOU WOULD LIKE TO HIGHLIGHT
TO THIS AUDIENCE, I WOULD
WELCOME YOU TO CALL THEM OUT FOR
THE AUDIENCE TO MAKE THEM AWARE.
I WILL OPEN IT UP FOR ANYONE TO,
IF YOU HAD ANYTHING YOU HADN'T
ALREADY SAID OR WANT TO RESTATE
CERTAIN FUNDING OPPORTUNITIES,
FEEL FREE TO DO SO AT THIS
POINT.
>>CRAIG, I WILL GO FIRST, IF
YOU DON'T MIND.
GM HAS A TECHNOLOGY DEVELOPMENT
PIPELINE I WOULD LIKE TO
HIGHLIGHT.
IT STARTS WITH A R-21 NOTICE OF
FUNDING OPPORTUNITY THAT
REQUIRES THAT THERE IS NO
PRELIMINARY DATA OR BIOLOGICAL
HYPOTHESES.
SO THIS IS VERY EARLY STAGES OF
TECHNOLOGY DEVELOPMENT.
A COMPANION FUNDING OPPORTUNITY
THAT IS AN RO1, THE OBJECTIVE IS
TO ALLOW FOR PROTOTYPE
VALIDATION WITHOUT HAVING TO
HAVE A BIOLOGICAL HYPOTHESES
ASSOCIATED WITH IT.
ONCE YOU DO HAVE THAT BIOLOGICAL
HYPOTHESIS, YOU CAN MOVE ON TO
THE TRADITIONAL PARENT RO1 OR
NIGMS MIRROR.
I WOULD BE HAPPY TO TALK ABOUT
LATER OR WITH SOMEONE OFFLINE.
I WOULD BE REMISS IF I DIDN'T
POINT OUT WE HAVE A FUNDING
OPPORTUNITY CALLED AN RM1.
THIS IS FOR, LET ME MAKE SURE I
GET THE ACRONYM CORRECT,
BIOMEDICAL TECHNOLOGY
OPTIMIZATION AND DISSEMINATION
CENTER.
THIS IS FOR STATE OF THE ART
LATE STAGE TECHNOLOGIES THAT
ADDRESSES BIOMEDICAL QUESTIONS
IN GM RELATED AREAS.
THE OBJECT ICH IS TO TRY AND
ENSURE WE CAN DISSEMINATE
TACTOLOGIES THAT ARE READY FOR
DISSEMINATION.
THE TECHNOLOGIES SHOULD BE AT
THE FOREFRONT OF THEIR FIELDS.
THEY ARE UNIQUE, BUT NOT WIDELY
AVAILABLE, DEMONSTRATED
FEASIBILITY OR UTILITY.
ONCE THEY ARE OPTIMIZED THROUGH
THIS PROCESS THEY CAN BE BROADLY
DISSEMINATED.
THAT IS AN RM1 THAT MIGHT BE OF
INTEREST TO SOME.
>>EXCELLENT.
THANK YOU SO MUCH, MICHELLE.
ANYTHING ELSE TO ADD FROM DR.
MOHAPATRA OR RANALLO?
>>I WILL ADD, WE DON'T HAVE ANY
DIRECT FOAs OR NOFOS.
THEY ARE MORE TANGENT.
WE ARE PARTICIPATING IN A PAR, A
PROGRAM ANNOUNCEMENT.
21-253, IDENTIFICATION OF ACTIVE
METABOLITES ON MICROBE DIET AND
HOST INTERACTIONS.
IT IS MULTI-IC.
IT IS VERY BROAD.
EACH IC HAS THEIR OWN INTEREST.
I WILL SAY THEY ARE VERY ROBUST
AND IT IS REALLY THE FUNCTIONAL
CURRENCY OF THOSE HOST MICROBE
INTERACTIONS AND WE ARE TRYING
TO ENCOURAGE IDENTIFICATION AND
CHARACTERIZATION OF THOSE SO WE
CAN UNDERSTAND THEIR BIOLOGY AND
LEVERAGE THEM FOR OUR MISSION.
I'LL STOP THERE.
>>GREAT.
THANK YOU.
>>I CAN JUST ADD THE SAME WAY,
AT NINDS WE DON'T HAVE A FOCUS
FUNDING FOR NATURAL PRODUCT
UNFORTUNATELY AT THIS POINT.
BUT WE HAVE MANY DIFFERENT
FUNDING OPPORTUNITIES FROM
DISCOVERY HYPOTHESIS TO
THERAPEUTIC RESEARCH
SPECIFICALLY IGNITE LIKE
PROGRAMS WHERE YOU CAN COME UP
WITH ANY MORTAL SYSTEM
DEVELOPMENT OR TECHNOLOGY
DEVELOPMENT -- MODEL SYSTEM
DEVELOPMENT OR TECHNOLOGY
DEVELOPMENT FOR THERAPEUTIC
SCREEN.
THOSE ARE ALL SUPPORTED AND WE
ARE INTERESTED AND COMMITTED AT
THE NATURAL PRODUCT IN THE
[INDISCERNIBLE].
>>THANKS.
AND I THINK JUST TO CLARIFY,
THERE IS SOME LINGO, WHATEVER
YOU HAVE IN NIH GROUP, YOU HAVE
ACRONYMS.
THE TERM NOFO WAS THROWN OUT.
USED TO BE CALLED FOA, FUNDING
OPPORTUNITY ANNOUNCEMENT.
JUST IN THE LAST WEEKS OR
MONTHS, WE HAVE BEEN TOLD THEY
ARE CHANGING TO CALL IT NOTICE
OF FUNDING OPPORTUNITY, OR NOFO.
THIS ALIGNS NIH WITH WHAT OTHER
PARTS OF THE FEDERAL GOVERNMENT
ARE DOING IN TERMS OF HOW THEY
CALL -- WHAT THEY CALL THESE
THINGS.
WHICH WILL PROBABLY CONTINUE.
YOU WILL PROBABLY HEAR NOFO AND
FOA USED INTERCHANGEABLY.
IF YOU HEAR A NOFO AND DON'T
KNOW WHAT THAT MEANS AND THINK
IT IS AN INSULT, IT WAS NOT.
THAT IS WHAT WE ARE CALLING
THESE THINGS THESE DAYS.
I THINK I WILL TURN IT OVER TO
MY COLLEAGUE DR. STILL AND WE
WILL MAYBE TAKE SOME QUESTIONS
FROM THE VIDEOCAST AUDIENCE FOR
OUR NIH COLLEAGUES.
THANK YOU FOR ANSWERING THE
QUESTIONS WE HAD SO FAR.
GO AHEAD, PATRICK.
>>OKAY.
WE ARE MOVING INTO THE QUESTION
AND ANSWER SESSION AND I DON'T
SEE TOO MANY QUESTIONS IN THE
CHAT AS OF YET IN TERMS OF FOR
THE NIH COLLEAGUES.
I DID WANT TO MENTION IN
ADDITION TO WHAT NCI PUT
FORWARD, A NOTICE THAT THEY
RECENTLY RELEASED ON EXPANDING
TRANSLATIONALLY RELEVANT SPACE
AND THIS IS LOOKING FOR
APPLICATIONS IN DRUG DISCOVERY
AS IT RELATES TO IMMUNE
COMPOUNDS.
AND SO SOME OF THOSE HANDLES CAN
BE USED TO SEARCH THAT FUNDING
OPPORTUNITY.
AND I'M NOT SURE IF CRAIG, YOU
HAD MENTIONED PREVIOUSLY IN
TERMS OF NCCIH, BUT WE DID HAVE
A METHODS DEVELOPMENT NOTICE
THAT I DID WANT TO MAKE SURE
EVERYONE WAS AWARE OF AND THAT
EXPLAINS A LOT OF NCCIH'S
INTEREST IN THIS SPACE.
WE ARE FUNDING SOME INTERESTING
SMALL BUSINESS INVESTIGATIONS
LOOKING AT ELECTROKEMLY
CONDUCTIVE NANO MATERIALS AND
IMPROVING SEPARATION PERFORMANCE
AT A LOWER COST.
THAT WOULD FALL WITHIN OUR
MISSION IN ADDITION TO
ANNOTATING COMPLEX METABOLIC
DATASETS.
AND SO, YEAH.
SO IF WE DON'T HAVE ANY FURTHER
QUESTIONS FROM THE AUDIENCE, OH,
ONE JUST ACTUALLY CAME IN.
LET'S SEE.
I'M NOT SURE IF WAS A COMMENTS
OR AN ACTUAL QUESTION, BUT IT
INVOLVES, YEAH, I THINK WE CAN
MOVE PAST THAT ONE SINCE IT WAS
MORE OF A COMMENT FROM A
PREVIOUS SECTION.
>>THERE WAS A QUESTION, I
THINK, IT WAS A SECOND HALF OF A
COMMENT SOMEBODY HAD ASKING
WHICH INSTITUTES ARE INTERESTED
IN DRUG DISCOVERY APPLICATIONS?
AND MAYBE I WILL LET MY
COLLEAGUES INDICATE THEIR
INTEREST IN THAT TOPIC, WHICH I
KNOW THERE IS INTEREST.
>>YEAH.
DEFINITELY NINDS IS INTERESTED
INCLUDING NATURAL PRODUCT.
>>THIS IS RYAN.
I WILL ADD, FOR US, ONE OF THE
THINGS WE SET UP IN OUR
DIVISION, WE ARE INTERESTED IN
VACCINES DIAGNOSTICS AND WE HAVE
SCIENCE GRANT AWARDS, BUT
PARALLEL TO THOSE FUNDED
PROJECTS, WE ALSO HAVE A SUITE
OF CONTRACTS THAT SERVE THE --
AS A PRECLINICAL SERVICES AT
NIAID.
THESE ARE FREE TO EXTERNAL
REQUESTERS.
ONE OF THE KEY REASONS I'M
MENTIONING IT IS ONCE YOU HAVE A
NATURAL PRODUCT WITH ACTIVITY
THAT YOU WANT TO EXPLORE MORE,
IT IS POSSIBLE TO DO IT THROUGH
A NONGRANT BASED MECHANISM.
AND THE SERVICES THAT ARE
SUPPORTED, SOME OF THE
SERVICES -- THERE ARE A LOT OF
SERVICES THAT ARE SUPPORTED, BUT
SOME IN THE CONTEXT OF OUR
DISCUSSION ARE IN VITRO
ANAMICROBIAL ACTION, AGAINST A
WHOLE SEETHE OF BACTERIA, ANIMAL
TESTING, PK, PD, AND IN VIVO
EFFICACY TESTING DEPENDING ON
THE AVAILABILITY OF A MODEL.
WE HAVE A DEAD KALTED AND
SUSTAINED EFFORT TO GET YOU OUT
OF THE VALLEY OF THE DEATH IF
YOU WILL WITH A LEAD AND MORE
TRANSLATIONAL FOOTING.
I WOULD BE HAPPY TO FOLLOW UP
WITH ANYBODY WHO IS LISTENING ON
THOSE ACTIVITIES.
IT IS AS SIMPLE AS PROVIDES A
LINK TO OUR NIAD PAGE.
I WILL STOP THERE.
>>I WILL BOOKEND THIS BY SAYING
NIGMS, IF YOU ARE SPECIFICALLY
STUDYING A DRUG OR SET OF DRUGS
FOR A UNIQUE DISEASE OR
DISORDER, IT IS MORE LIKELY IT
WILL GO TO A CATEGORICAL
INSTITUTE THAN NIGMS.
IF YOU HAVE QUESTIONS ABOUT
THIS, YOU ARE WELCOME TO REACH
OUT TO ME.
>>I THINK WE DID HAVE ANOTHER
QUESTION FROM PRIOR WHETHER
NCCIH IS LOOKING AT FUNCTIONAL
FOODS OR MEDICINAL FOOD RESEARCH
AND DEVELOPMENT AND COULD THIS
POTENTIALLY BE A NEW AVENUE TO
EXPLORE.
SO NCCIH IS PARTICIPATING IN THE
NUTRITION FOR PRECISION HEALTH
PROGRAM, WHICH IS PART OF THE
NIH COMMON FUND PROGRAM.
AND I BELIEVE, CRAIG, YOU ARE A
WORKING GROUP MEMBER FOR THIS
AND SO WE ARE INTERESTED IN THIS
AREA.
AND IF YOU WOULD LIKE TO FILL IN
WHAT THAT IS ABOUT.
>>YEAH.
THAT PROGRAM IS A VERY, VERY
LARGE FUND PROGRAM.
OVER $100 MILLION.
AND IT IS JUST BEGINNING, SO
THEY ARE ONLY GETTING STARTED.
THEY WILL BE ENROLLING THOUSANDS
AND THOUSANDS OF PEOPLE AND
LOOKING AT HOW THEIR DIETS, HOW
THEY VARY IN THEIR RESPONSE TO
SPECIFIC DIETS.
IT IS VERY EXCITING, BUT EARLY
STAGE FOR THAT.
REGARDING FUNCTIONAL FOOD AND
MEDICAL FOOD, SOME OF THOSE ARE
SPECIFIC TERMINOLOGIES AND NCCIH
COULD BE INTERESTED.
OBVIOUSLY, WE HAVE A LONG
STANDING INTEREST IN FUNDING
DIETARY SUPPLEMENT RESEARCH.
WE FUND QUITE A BIT CURRENTLY.
IF YOU ARE LOOKING AT PARTICULAR
FUNCTIONAL FOODS OR MEDICAL
FOODS IT IS BEST TO REACH OUT
OFFLINE AND WE COULD HAVE A MORE
DETAILED CONVERSATION ABOUT WHAT
IT IS YOU WANT TO DO AND WHETHER
OR NOT NCCIH SHOULD BE THE BEST.
NIDDK, ALSO FUNDS QUITE A BIT OF
NUTRITION RESEARCH AT NIH.
DEPENDING ON WHAT YOU ARE
PROPOSING.
IT MIGHT BE APPROPRIATE FOR US
OR IT MIGHT BE MORE APPROPRIATE
FOR THEM.
I SEE ANOTHER COMMENT HERE TO
REMIND US THERE IS AN RFI, A
REQUEST FOR INFORMATION, ON A --
THERE WAS RECENTLY A WHITE HOUSE
CONFERENCE ON NUTRITION AND
HUNGER.
I'M FORGETTING EXACTLY THE NAME
OF IT.
THIS CONCEPT OF FOOD AS MEDICINE
HAS COME OUT OF THAT.
AND THERE IS AN EFFORT TO GET
INPUT BASICALLY ON WHERE NIH AND
THE FEDERAL GOVERNMENT WRIT
LARGE, WHERE SHOULD WE BE
FOCUSING OUR EFFORTS WHEN IT
COMES TO THIS CONCEPT OF FOOD AS
MEDICINE.
THIS HAS A LOT OF THREADS TO IT.
SOME OF WHICH ARE RELATED TO NIH
SPECIFICALLY AND A LOT OF THEM
ARE ABOUT ACCESS TO HEALTHY
FOODS AND FOOD INSECURITY.
IT IS A VERY WIDE RANGING
CONCEPT.
CERTAINLY SOME PARTS ARE
RELEVANT TO NIH AND NCCIH'S
INTERESTS.
>>GREAT.
AND THANKS, CRAIG, FOR THAT.
AND I SEE THAT WE'RE A LITTLE
BIT AHEAD OF TIME IN TERMS OF
THE Q&A, WHICH IS TO WRAP UP
AROUND 2:50 EASTERN TIME.
SO NOW THAT WE ARE NOT REALLY
SEEING ANY ADDITIONAL QUESTIONS
IN THE CHAT, WE CAN MOVE TO
THANKING THE SPEAKERS.
WE COVERED QUITE A FEW TOPICS
TODAY FROM SINGLE PARTICLE
CRYO-EM TO THE STRUCTURE OF THE
TRYP ION CHANNEL TO LOOKING AT
CRYO-EM IN GENERAL AND ALSO, YOU
KNOW, WE DISCUSSED DIFFERENT
PROGRAMATIC PRIORITIES ACROSS
THE NIH.
SO WE JUST WANTED TO THANK
EVERYBODY FOR JOINING THE
WEBINAR TODAY AND I'M NOT SURE,
CRAIG, IF YOU HAD ANY ADDITIONAL
CLOSING REMARKS, THAT WOULD BE
GREAT?
>>YEAH.
THANKS, PAT.
I THINK YOU SUMMED UP NICELY.
IT IS A VERY EXCITING
TECHNOLOGIES THAT I'M LOOKING
FORWARD TO WHERE THEY WILL LEAD
US AS WE HEARD, YOU KNOW,
ESPECIALLY RELATED TO CRYO-EM.
IT SEEMS LIKE WE ARE SCRATCHING
THE SURFACE.
DR. CASSILLY POINTED OUT, YOU
DON'T HAVE TO HAVE THE LATEST
MILLION-DOLLAR INSTRUMENT TO DO
IMPACTFUL RESEARCH.
THEY DID THE OLD BIOACTIVITY
GUIDE FRACTIONATION.
YOU DON'T HAVE TO HAVE THE MOST
INCREDIBLE STRUCTURE TO HAVE THE
MOST INCREDIBLE IMPACT.
THE STRUCTURE SHE DISCOVERED WAS
AS SHE SAID A FAIRLY COMMON OR
NOT TERRIBLY UNIQUE STRUCTURE,
BUT YET THAT SEEMED TO BE VERY
IMPORTANT FOR MODULATING THE
ACTIVITY WE ASSOCIATE WITH THAT
PARTICULAR PRO BIOTIC COMPOUND.
WE ENCOURAGE ALL THOSE IN
ATTENDANCE TO REACH OUT TO THOSE
AT NIH THAT MIGHT BE MOST
RELEVANT TO WHAT YOU ARE DOING.
WE ALL ACTIVELY SUPPORT NATURAL
PRODUCTS RESEARCH AND WE WILL
CONTINUE TO DO SO.
WE LOOK FORWARD TO SEEING YOUR
APPLICATIONS AND INTERESTS AND
INQUIRIES.
AND THIS VIDEOCAST HAS BEEN
RECORDED AND YOU, IF YOU WERE
REGISTER, IF YOU ARE ON THIS,
YOU WILL GET AN EMAIL ALERTING
YOU TO WHEN THE LINK IS
AVAILABLE FOR THE VIDEOCAST.
YOU CAN REWATCH PARTS OF THIS OR
SHARE WITH COLLEAGUES WHO MIGHT
BE INTERESTED.
WITH THAT, WE WILL WRAP THINGS
UP.
I THANK YOU ALL OF MY NIH
COLLEAGUES FOR YOUR
PARTICIPATION AND ALL OF THOSE
ATTENDING AND ASKED QUESTIONS
AND HOPEFULLY WERE INSPIRED BY
SOME WAY, SHAPE OR FORM WITH
WHAT YOU HEARD TODAY.
WITH THAT, I GUESS MAYBE WE WILL
SIGN OFF.
THANK YOU, EVERYONE.