>>WELCOME.
I'M CATHERINE LAW, DIRECTOR OF
COMMUNICATIONS AT THE NATIONAL
CENTER FOR COMPLEMENTARY AND
INTEGRATIVE HEALTH (OR
N-C-C-I-H), 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 FIRST OF A
TWO-PART WEBINAR SERIES.
FIRST, I WANT TO TAKE A FEW
MOMENTS TO ACKNOWLEDGE THE MANY
PEOPLE THAT BROUGHT THIS WEBINAR
TO FRUITION, INCLUDING, FIRST
AND FOREMOST, DR. EMMELINE
EDWARDS, DIRECTOR OF OUR
DIVISION OF EXTRAMURAL RESEARCH
WHO CHAMPIONED THIS WEBINAR; DR.
CRAIG HOPP, DEPUTY DIRECTOR OF
OUR DIVISION OF EXTRAMURAL
RESEARCH; DR. PATRICK STILL,
PROGRAM DIRECTOR IN OUR BASIC
AND MECHANISTIC RESEARCH BRANCH;
AND DR. WEN CHEN, CHIEF OF OUR
BASIC AND MECHANISTIC RESEARCH
BRANCH, AS WELL AS MANY
COLLEAGUES WHO PLANNED THE
LOGISTICS AND PROMOTION OF THIS
EVENT INCLUDING MS. IRENE LIU,
MS. ANITA MCRAE-WILLIAMS, MS.
SAHAR FAKHRUDDIN, MS. AILEEN
AMADOR, AND MANY OTHERS WORKING
BEHIND THE SCENES.
BEFORE WE BEGIN, A FEW LOGISTICS
FOR TODAY'S MEETING.
FOR OUR NIH VIDEOCAST VIEWERS,
YOU ARE WELCOME TO SUBMIT
QUESTIONS AT ANY TIME USING THE
VIDEOCAST FEEDBACK FORM; THE
LINK FOR THE FORM SHOULD BE
LOCATED BELOW YOUR SCREEN FOR
VIEWING THE LIVESTREAM.
WE WILL TRY TO GET TO AS MANY
QUESTIONS AS POSSIBLE DURING
QUESTION AND ANSWER PERIODS.
WE'LL SHARE IT WITH OUR PLANNING
TEAM.
FINALLY, THIS EVENT IS BEING
RECORDED AND WILL BE ARCHIVED ON
THE NIH VIDEOCAST WEBSITE FOR
FUTURE VIEWING.
WITH THOSE REMINDERS COVERED, I
AM NOW PLEASED TO INTRODUCE DR.
DAVID SHURTLEFF, DEPUTY DIRECTOR
OF NCCIH, WHO WILL SHARE A FEW
WORDS OF WELCOME BEFORE HANDING
THINGS OFF TO DR. PATRICK STILL.
WHO WILL COVER WHAT WE'RE GOING
TO GET INTO TODAY AND DR. DAVID
SHURLEFF WILL HAND THINGS OFF TO
DR. STILLS.
SO DAVID, PLEASE TAKE IT AWAY.
>>THANK YOU, CATHERINE AND
THANK YOU FOR BEING HERE AND
WELCOME TO OUR -- PARTICIPANTS
HERE IN ZOOM AND ON THE
VIDEOCAST.
IT'S AN EXCITING TIME TO BE IN
NATURAL PRODUCTS.
AN AREA WHICH WE HAVE FOSTERED
SINCE THE BEGINNING.
WE SUPPORTED NATURAL PRODUCTS
FOR OUR ENTIRE HISTORY NOW OVER
20 YEARS IN SUPPORTING RESEARCH
ACROSS THE CONTINUUM FROM IN
VITRO, IN-VIVO, CLINICAL TRIALS
RESEARCH AND ENGAGED WITH OUR
COLLEAGUES ACROSS THE NIH IN
AREAS OF SHARED INTEREST, FOR
EXAMPLE, OUR INTEREST IN
CANNABINOID RESEARCH, NATURAL
PRODUCTS AND PAIN, NUTRITION FOR
PREDICTION HEALTH, A STUDY WE
HOPE TO LAUNCH HERE AT NIH, AND
THE LIST GOES ON AND ON.
TO QUOTE WAYNE GRETZKY, WHEN HE
WAS ASKED ABOUT HIS SUCCESS, HE
WOULD SAY, HE SKATES TO WHERE
THE PUCK IS GOING TO BE AND NOT
WHERE IT HAS BEEN.
AND I FAKE THAT AS -- TAKE THAT
AS THIS SEMINAR IS SKATING TO
WHERE THE PUCK WILL BE HERE AT
NCCIH AND AT THE NIH AT LARGE.
WE WANT TO KNOW AND SUPPORT
WHERE THE NATURAL PRODUCTS
RESEARCH IS GOING AND HOW IT CAN
BEST CAPITALIZE ON CUTTING-EDGE
TECHNOLOGIES AND METHODOLOGIES.
AND I'M VERY EXCITED TO SAY AND
TO HEAR FROM AND LOOK FORWARD TO
THIS SYMPOSIUM FROM OUR ESTEEMED
EXPERTS TODAY WHO WILL HIGHLIGHT
SOME OF THE RESOURCES CURRENTLY
IN DEVELOPMENT, THE CUTTING-EDGE
APPROACHES THAT CAN REALLY SERVE
THE BROADER NATURAL PRODUCTS
RESEARCH COMMUNITIES.
I'M VERY GRATEFUL FOR THIS
SEMINAR AND LOOK FORWARD TO THE
MANY TALKS TODAY.
AND WITH THAT, I'LL TURN IT OVER
TO PATRICK FOR A FEW WORDS.
PATRICK?
>>THANK YOU VERY MUCH, AND GOOD
AFTERNOON.
I'M PATRICK STILL, A PROGRAM
DIRECTOR AT NCCIH IN THE BASIC
AND MECHANISTIC RESEARCH BRANCH.
A MANAGE A PORTFOLIO THAT SPANS
THE NCCIH PRIORITIES IN
TRANSLATIONAL AND
CLINICAL APPLICATIONS OF NATURAL
PRODUCTS.
I WOULD LIKE TO WELCOME EVERYONE
TO THIS FIRST OF TWO EXCITING
WEBINARS!
TO PARAPHRASE A PASSAGE FROM
DRS. NEWMAN AND CRAGG'S
COMPREHENSIVE REVIEWS ON
"NATURAL PRODUCTS AS SOURCES OF
NEW DRUGS," THAT MANY OF YOU ARE
FAMILIAR WITH, [QUOTE] "THAT
NATURE IN ONE GUISE OR ANOTHER
HAS CONTINUED TO INFLUENCE THE
DESIGN OF FDA APPROVED DRUGS,
MANY OF WHICH ARE BASED ON
NATURAL PRODUCT SCAFFOLDS,
REALLY SETS THE TONE FOR THE
TOPIC OF THIS WEBINAR."
ADVANCES IN AUTOMATED SYNTHETIC
CHEMISTRY, HIGH- THROUGHPUT
BIOLOGY, ARTIFICIAL INTELLIGENCE
TECHNOLOGIES, AND INCREASING
ACCESS TO SEQUENCE DATA TO
ASSESS WITH VARIOUS
BIOINFORMATIC TOOLS, THE
BIOSYNTHETIC POTENTIAL OF A
SOURCE ORGANISM FOR TARGETED
DISCOVERY OF NEW NATURAL
PRODUCTS, IS INDEED EXPANDING
TRANSLATIONALLY RELEVANT
CHEMICAL SPACE.
THIS TWO-PART WEBINAR WILL START
TODAY WITH FOUNDATIONAL
RESOURCES AND TECHNOLOGIES THAT
ENABLE DISCOVERY OF NATURAL
PRODUCTS.
AND IN PART 2, PICK UP WITH
ADDITIONAL TECHNOLOGIES SPECIFIC
TO STRUCTURE ELUCIDATION AND
APPLICATIONS OF THOSE
TECHNOLOGIES.
DURING EACH WEBINAR, WE'RE
JOINED BY NIH PARTNERS WHO WILL
SHARE THEIR PERSPECTIVES ON
WEBINAR THEMES AND NATURAL
PRODUCTS RESEARCH IN THE CONTEXT
OF THEIR INSTITUTE OR CENTER
PRIORITIES.
I WOULD NOW LIKE TO INTRODUCE
OUR THREE SPEAKERS FOR TODAY'S
WEBINAR, WHO WILL GIVE THEIR
PRESENTATIONS FOLLOWED BY Q&A
SESSION.
FIRST IS DR. BARRY O'KEEFE,
CHIEF, NATURAL PRODUCTS BRANCH,
DIVISION OF CANCER TREATMENT AND
DIAGNOSIS AT THE NATIONAL CANCER
INSTITUTE, WHO WILL DISCUSS
DISCOVERY AND DEVELOPMENT OF
NATURAL PRODUCTS AND THE NCI
NATURAL PRODUCT COLLECTION;
FOLLOWING DR. O'KEEFE'S TALK
WILL BE DR. ROGER LININGTON,
PROFESSOR AND CANADA RESEARCH
CHAIR IN HIGH-THROUGHPUT
SCREENING AND NATURAL PRODUCTS
DISCOVERY AT SIMON FRASER
UNIVERSITY WHO WILL PRESENT ON
HIGH-THROUGHPUT FUNCTIONAL
ANNOTATION OF NATURAL PRODUCTS
USING INTEGRATED ACTIVITY
PROFILING; WHICH WILL BE
FOLLOWED BY OUR THIRD SPEAKER,
DR. MANDË HOLFORD, ASSOCIATE
PROFESSOR IN DEPARTMENT OF
CHEMISTRY AND BIOCHEMISTRY AT
THE CITY UNIVERSITY OF NEW YORK
AND RESEARCH ASSOCIATE AT THE
SACKLER INSTITUTE FOR
COMPARATIVE GENOMICS, AMERICAN
MUSEUM OF NATURAL HISTORY, WHO
WILL FOCUS ON DEVELOPING MODELS
FOR CHARACTERIZING VENOM-BASED
MARINE NATURAL PRODUCTS.
WITH THIS, I'D LIKE TO WELCOME
OUR SPEAKERS AND THANK EVERYONE
IN THE AUDIENCE FOR JOINING THIS
WEBINAR TODAY, AND I WILL TURN
THINGS OVER TO DR. BARRY O'KEEFE
FOR HIS PRESENTATION.
>>THANK YOU, PATRICK AND THANK
EVERYBODY FOR THIS REALLY
OUTSTANDING MENU.
I THINK THIS IS A GREAT IDEA,
EXPANDING TRANSLATIONAL AND
CHEMICAL SPACE, A FANTASTIC
THEME FOR EVERYTHING.
LET ME SHARE MY SLIDES AND I
WILL START THINGS OFF.
HOPEFULLY YOU CAN SEE THESE NOW.
SO TODAY I WOULD LIKE TO TALK A
LITTLE BIT ABOUT WHAT WE'RE
DOING AT THE NATIONAL CANCER
INSTITUTE IN THE NATURAL
PRODUCTS BRANCH TO TRY AND
EXPAND CHEMICALLY-RELEVANT
NATURAL PRODUCT SPACE FOR
EVERYONE.
A LITTLE BACKGROUND.
THESE ARE COMPOUNDS THAT ARE
PROBABLY USED EVERY DAY IN
THOUSANDS AND THOUSANDS OF
PLACES AROUND THE WORLD.
AND MANY OF YOU PROBABLY USED
MANY OF THESE OVER THE YEARS.
BUT NOT AS MANY PEOPLE OUT IN
THE BIDE WORLD KNOW THAT THESE
ARE THE SOURCE ORGANISMS FOR ALL
THESE AGENTS.
AND THAT THERE IS A HISTORY OF
PHARMACEUTICAL UTILITY FOR
NATURAL PRODUCTS.
AND IT AFFECTS US EVERY DAY AND
THERE IS STILL A LOT MORE THAT
CAN BE DONE.
SO FOR EXAMPLE, I BELIEVE MY
PREDECESSORS, DOCTORS NEW MAN
AND CRAIG, HAVE REPORTED A
VARIETY OF STATISTICS FOR THE
PERCENT OF NEW SMALL MOLECULE
DRUGS FROM NATURAL PRODUCT
SCAFFOLDER.
IN PARTICULAR I USE MORE
CONSERVATIVE ANALYSIS OF THEIRS,
BUT IT IS SAFE TO SAY THAT AT
LEAST 25% OF ALL NEW SMALL
MOLECULE DRUGS APPROVED BY THE
FDA ARE BASED ON NATURAL PRODUCT
SCAFFOLDS.
WHICH IS THE SIGNIFICANT PART OF
THE DRUGS WE USE EVERY DAY.
BUT AT THE NCI WHEN WE TOOK A
LOOK AT IT INTERNALLY WITH
ANOTHER REVIEW THAT WAS
PUBLISHED BY MY COLLEAGUE, BRICE
WILSON, NATURAL PRODUCTS REPORT
IN 2020, IF WE LOOK AT THE
NUMBER OF PAPERS THAT ARE IN
PUBMED BASED ON HIGH-THROUGHPUT
SCREENS, THE MAJOR WAY A LOT OF
DRUGS ARE STILL DISCOVERED
TODAY, WE SEE THESE IN GEE
METRIC PROGRESSION HERE IN
PAPERS COMING OUT AND TOPS OFF
HERE SOMEWHERE AROUND IN THE
2010s.
BUT WHAT WE SEE WITH NATURAL
PRODUCTS, THE NUMBER OF THOSE
SHOWN IN BLUE, VERY SMALL
PERCENT OF ALL THE
HIGH-THROUGHPUT SCREENS ACTUALLY
INCLUDE NATURAL PRODUCT SAMPLES.
NOW THIS MAKES US NATURAL
PRODUCT REACHERS FEEL GOOD
BECAUSE IF YOU'RE GETTING 25% OF
DRUGS FROM WHAT LOOKS TO BE ONE
OR 2% OF THE SCREENS, THAT'S A
PRETTY GOOD RETURN ON
INVESTMENT.
BUT FROM THE NCI'S PERSPECTIVE,
WHAT IF WE COULD INCREASE THIS
PERCENT?
WHAT DO WE NEED TO DO TO GET
MORE PEOPLE SCREENING, INCLUDING
NATURAL PRODUCT SAMPLES IN THOSE
SCREENS SO WE CAN IMPROVE ON
THAT 25%?
AND SO, THERE IS SOME REASONS
WHY PEOPLE HAVEN'T INCLUDED
THESE IN SCREENS.
FOR EXAMPLE, THIS IS AN IMAGE OF
CRUDE EXTRACTS.
THEY POTENTIALLY COULD BE VERY
DIFFICULT TO SCREEN IN THEIR
CRUDE FORM.
THEY CONTAIN NUMEROUS COMPOUNDS
AT DIFFERENT CONCENTRATIONS.
THE PURIFICATION AND STRUCTURAL
ELUCIDATION OF THE ACTIVE
MOLECULES FROM THESE CAN TAKE A
LONG TIME AND DIDN'T REALLY MESH
WELL WITH HIGH-THROUGHPUT
SCREENING WHERE PEOPLE ARE DOING
HUNDREDS OF THOUSANDS OF SAMPLES
A DAY IN SOME CASES.
AND SO OVERALL, THIS RESULTED IN
A SLOW PROCESS THAT INCREASED
THE OVERALL COST NOT JUST FOR
CHEMISTRY, BUT FOR THE
HIGH-THROUGHPUT SCREENING
ITSELF, KEEPING THE CELLS ALIVE,
KEEPING THE ASSAYS RUNNING FOR
LONGER PERIODS OF TIME.
AND SO, WE FELT THE NEED TO
ADDRESS THESE CHALLENGES TO
EFFICIENTLY ACCESS THIS UNIQUE
CHEMICAL DIVERSITY IN THESE
EXTRACTS.
AND YOU MIGHT WONDER WHY DOES
THE NCI CARE ABOUT THIS?
WE HAVE A RATHER LARGE
REPOSITORY OF NATURAL PRODUCT
CRUDE EXTRACTS THAT NUMBER OVER
200,000.
WHAT YOU'RE SEEING HERE IS THE
BREAKDOWN ON THE RIGHT-HAND SIDE
OF PLANTS, MARINE ORGANISMS AND
MICROBIAL SOURCES THAT WERE IN
THIS REPOSITORY, AND ON THE
LEFT, YOU SEE A MAP OF WHERE
THESE HAVE BEEN COLLECTED AROUND
THE WORLD.
THE SIZES OF THE HEXAGON ARE
INDICATIVE OF THE SIZE OF THE
COLLECTION IN THOSE AREAS AND
THE COLORS ARE INDICATIVE OF
WHETHER THEY ARE PLANTS IN
GREEN, MARINE ORGANISMS IN BLUE
OR IN MICROBIAL COLLECTIONS IN
BROWN.
SO WE HAVE A BIG COLLECTION OF
NATURAL PRODUCT EXTRACTS AT THE
NCI ABOUT YOU NOBODY WANTED TO
SCREEN THEM.
SO, WHAT ARE WE GOING TO DO?
WE WERE ABLE TO CONVINCE TWO
DIFFERENT DIVISIONS OF THE NCI,
DIVISION OF CANCER TREATMENT AND
DIAGNOSIS AND THE CENTER FOR
CANCER RESEARCH, TO WORK
TOGETHER AND SET UP THE NCI
PROGRAM FOR NATURAL PRODUCT
DISCOVERY WHICH IS DESIGNED TO
FACILITATE INTRAPURE AND
EXTRAMURAL RESEARCH AND ADDRESS
CURRENT CHALLENGES IN NATURAL
PRODUCT DISCOVERY.
THIS HAS BEEN FUNDED BY THE
CANCER MOONSHOT PROGRAM.
THESE ARE THE SPECIFIC AIMS OF
THAT PROGRAM.
WE NEEDED TO CREATE NEW
TECHNOLOGIES, TO CREATE A PRE
FRACTIONATEY LIBRARY MORE
AMENABLE TO HIGH-THROUGHPUT
SCREENING.
INCREASE SCREENING FOR CULTURAL
MICROORGANISMS.
PROVIDE THAT LIBRARY TOW
SCREENING CENTERS WORLDWIDE AND
THEN ENCOURAGE THE
HIGH-THROUGHPUT SCREENING,
SUPPORT THOSE RESEARCHERS,
PROVIDE FASTER ANALYTICAL
RESOURCES AND THEN PULL
EVERYTHING TOGETHER AS MUCH AS
POSSIBLE IN A DATABASE AND MAKE
AS MUCH OF THAT AS PUBLIC AS IT
IS JUST A VIABLE AND ACCEPTABLE
TO OUR COLLABORATORS WHO ALLOWED
THESE COLLECTIONS TO TAKE PLACE
IN THEIR HOST COUNTRIES.
SO, THE FIRST ISSUE WAS TO PRE
FRACTIONATE THE LIBRARY.
THE GOAL IS EVENTUALLY TO CREATE
A LIBRARY OF OVER A MILLION
SEMI--PURE NATURAL PRODUCT
FRACTIONS.
AND TO SUPPLY THIS TO
RESEARCHERS FOR FREE FOR
SCREENING AGAINST ALL DISEASE
TARGETS, NOT JUST CANCER.
THIS REQUIRED A LOT OF METHOD
DEVELOPMENT.
WE ENDED UP PURIFYING THESE
COMPOUNDS BASED ON PO LATERY.
WE NEEDED TO OPTIMIZE FOR MASK,
COMPOUND SEPARATION, BIOLOGICAL
ACTIVITY.
WE HAD TO BE ABLE TO PRODUCE IF
ABOUT 150,000 FRACTIONS PER YEAR
AND TO DO SO WITH SUFFICIENT
MASS TO SUPPORT AT LEAST 20
SCREENING PROGRAMS A YEAR FOR A
DECADE.
AND THEN WE HAD TO HAVE
AUTOMATED ACCESS TO THESE
FRACTIONS ONCE THEY WERE
PRODUCED.
SO THERE WAS A LOT OF EFFORT
THAT WENT INTO THIS.
I'M NOT GOING TO GO INTO ALL
THIS DETAIL AND THIS HAS ALL
BEEN AUTOMATED NOW.
WE WORKED WITH A LOT OF
DIFFERENT VENDORS FOR EQUIPMENT
TO BE ABLE TO PRE FRACTIONATE
EXTRACTS IN A HIGH-THROUGHPUT
MANNER.
THIS DATA JUST SHOWS A LITTLE
BIT OF THE REPRODUCIBILITY OF
THAT PROCESS.
THIS IS A GRAPH THAT SHOWS MASS
OF 88 EXTRACTS FRACTIONATED INTO
7 FRACTIONS EACH RESULTING IN
OVER 600 INDIVIDUAL FRACTIONS
AND THIS JUST SHOWS THAT IF WE
RAN THE SAME EXACT DATA, THE
SAME PROCESS MONTHS LATER THAT
THE MASSES IN EACH FRACTION WERE
HIGHLY REPRODUCIBLE.
SO THE CHEMISTRY, WE BELIEVE, IN
EACH FRACTION IS HIGHLY
REPRODUCIBLE.
DOWN BELOW YOU'RE SEEING THE
SAME THING.
THIS TIME WE ARE USING ACTIVITY
ANALYSIS AND LOOKING AT THE MEAN
GI50 AND AGAIN, YOU SEE THINGS
ARE GENERALLY HIGHLY
REPRODUCIBLE, A LITTLE BIT MORE
PLAY WITH AN ACTIVITY ASSAY AND
THE MEAN POINT OF A SIGMOID.
BUT STILL, VERY GOOD DATA
OVERALL.
TO GET TO THE POINT OF HOW MANY
COMPOUNDS ARE IN EACH FRACTION,
WE USED A VARIETY OF WAYS TO
ANALYZE THEM.
ELSD, MASS SPEC, AND IN GENERAL,
WE GO WITH THE TOTAL MASS SPEC
AS THE NUMBER OF POTENTIAL
COMPOUNDS IN EACH INDIVIDUAL
FRACTION AND SO YOU CAN SEE HERE
BY FRACTION 1, 2, 3, 4, 5, 6, 7,
HOW MANY COMPOUNDS MIGHT BE IN
EACH.
ON AVERAGE 20-25 COMPOUNDS PER
FRACTION.
SO, WHERE ARE WE NOW ON THIS
PROCESS?
WE HAVE MADE ABOUT 580 THOUSAND.
YOU CAN SEE THIS AUTOMATED
FRACTIONATION TAKING PLACE.
WE HAVE RELEASED OVER A HALF
MILLION TO THE PUBLIC.
WE PLATED OUT 25 MILLION WELLS
OF THESE.
THEY ARE STORED, READY TO SHIP.
WE HAVE SHIPPED ABOUT 5 MILLION
OF THESE SO FAR.
INCLUDING ABOUT TWO MILLION JUST
LAST YEAR.
WE HAVE INITIAL PUBLICATIONS IF
PEOPLE ARE INTERESTED IN HOW
THIS LIBRARY WAS CREATED.
AND THE METHODS AND THE CHEMICAL
BIOLOGY BACK IN 2018, AND AS USE
FOR SCREENING, HOW TO DAP ASSAYS
FOR NATURAL PRODUCT SCREENING,
WE PUBLISHED IN 2020 IN NATURAL
PRODUCT REPORTS.
WE HAVE SEEN A LOT OF OTHER
GROUPS ADAPT AND ADOPT THESE
METHODS FOR THEIR OWN USES, BOTH
IN THE UNITED STATES AND AROUND
THE WORLD, SOUTH AFRICA AND
BRAZIL, SWEDEN, AS WELL AS
SEVERAL STATES IN THE UNITED
STATES.
AND FINALLY THIS IS A SHOUT OUT
TO MANDY.
WE ARE THIS YEAR, WORKING ON A
NEW MARINE ACHUOUS, PRE
FRACTIONATED LIBRARY
PARTICULARLY RICH IN
BIOTHERAPEUTICS, SMALL PEPTIDES
AND PROTEINS FOUND IN THESE
MARINE INVERTEBRATES THAT ARE
THE BASIS OF THE NCI CRUDE
FRACTION LIBRARY.
WE HOPE TO MAKE THOSE AVAILABLE
NEXT YEAR MAYBE A LIBRARY OF UP
TO 100,000 FRACTIONS
SPECIFICALLY ENHANCED FOR
POTENTIAL PROTEINS AND PEPTIDES
AND BIOTHERAPEUTICS.
WE ALSO SAID THAT WE WOULD WORK
ON CONSULTERABLE ORGANISMS.
WE SET UP A PARTNERSHIP WITH THE
UNIVERSITY OF OKLAHOMA, CITIZEN
SCIENCE PROGRAM AND WHO HELPED
US IN WORKING WITH US TO COLLECT
A VARIETY OF SOIL FURNY FROM
AROUND THE U.S. AND -- FUNGI --
AND HE PROVIDED 4000 A YEAR TO
THE NCI.
WHAT YOU SEE IS A MAP OF THE
UNITED STATES SHOWING WHERE
THOSE COLLECTIONS TOOK PLACE ALL
OVER THE COUNTRY.
WE SET UP A NEW FIRM ENITATION
FACILITY AND NEW METHODS HERE AT
THE NCI IN FREDRICK.
YOU CAN SEE A TAXINOMIC
BREAKDOWN OF SOME OF THE SOIL
FUNGI INCLUDED IN THIS
COLLECTION AND WE ARE GETTING
READY TO SUBMIT A PAPER SOON ON
SOME OF THE PILOT WORK THAT WE
HAVE DONE ON THIS.
JUST TO GIVE YOU A LITTLE TASTE,
THIS IS SOME OF THE COMPOUNDS
THAT WERE ISOLATED IN A RANDOM
SELECTION OF A VARIETY OF THESE
SOIL FUNGI FROM AROUND THE
UNITED STATES.
AND WE ARE SEEING A SIGNIFICANT
AMOUNT OF CHEMICAL DIVERSITY IN
THESE.
WE PLAN TO NOT ONLY MAKE
FRACTIONS AVAILABLE FROM THESE
SOURCE ORGANISMS BUT ALSO THE
SOURCE ORGANISMS THEMSELVES
COULD BE AVAILABLE TO
RESEARCHERS AROUND THE WORLD TO
ENABLE RESEARCH WE COULDN'T EACH
CONCEIVE OF AT THE NCI TO DO
WITH THEM.
SO WE HAVE HAD A PRETTY GOOD
UPTAKE IN PEOPLE INTERESTED IN
GETTING THE FRACTION LIBRARY.
THIS SHOWS WHO HAS REQUESTED
THESE AND COMPLETED MTAs.
WE HAVE COMPLETED ABOUT ONE MTA
A MONTH TO GET THESE LIBRARIES
IN THEIR HANDS.
IF YOUR UNIVERSITY OR RESEARCH
ORGANIZATION ISN'T ON THIS LIST,
CONTACT US.
WE'D LOVE TO BE ABLE TO SEND YOU
SAMPLES AND HAVE YOU SCREEN
THEM.
I'M GOING TO GO ON A LITTLE BIT
MORE DETAIL ON SOME OF OUR U.S.
GOVERNMENT PARTNERS.
NCCIH IN PARTICULAR IS BOTH
ISSUED A GRANT FOR GLOBAL
NATURAL PRODUCT DATABASE, HUGELY
IMPORTANT OVERALL BUT ALSO
FUNDING NPNPD HEAL INITIATIVE OR
HELPING END ADDICTION LONG TERM,
INITIATIVE EFFORTS AND IGNITE
SCREENING GRANTS.
AND I'LL SAY A LITTLE BIT OF
THOSE AT THE END HERE AS WE HAVE
JUST AN EXAMPLE.
WE ALSO SEE PARTNERSHIPS WITH
NIAID THE DEPARTMENT OF DEFENSE,
NCATS AND NOAA, THE NCI,
DIVISION OF CANCER CHEMO
PREVENTION RECENTLY INITIATED A
GRANT PROGRAM.
I THINK IT WILL BE UP AND GOING
THIS COMING FISCAL YEAR TO
ENCOURAGE ASSAY DEVELOPMENT
SCREENING OF NATURAL PRODUCT
SAMPLES AGAINST CHEMO PREVENTION
TARGETS.
AND JUST LAST WEEK I WAS
CONTACTED BY THE NATIONAL
INSTITUTE OF AGING.
PERHAPS WE'LL HAVE ANOTHER
PERSON TO ADD ON THIS WILLS AND
I'LL HAVE TO DECREASE THE SIZE
OF THE FONT AT THAT THE POINT.
SO, IF ALL OF THESE PEOPLE ARE
GOING TO GET THESE SAMPLES, ONE
OF THE ISSUES IS HOW TO GET TO
THE STRUCTURAL ELUCIDATION OF A
ACTIVE COMPOUND FROM A PRE
FRACTIONATED SAMPLE.
SO WE SET UP A HIGHLY AUTOMATED
SECOND STAGE PURIFICATION SYSTEM
WHERE SOMEONE COULD SEND US A
HIT LIST OF 500,000 AND WITHIN
TWO WEEKS WE WOULD FRACTIONATE
ALL 500 OF THOSE ACTIVE
FRACTIONS INTO 22 SUB FRACTIONS
AND PROVIDE THEM APPROXIMATELY
11,000 FRACTIONS BACK WITHIN TWO
WEEKS FOR THEM TO SCREEN.
THAT WAY THEIR ASSAY IS UP AND
RUNNING.
THE EFFICIENCY IS MUCH BETTER
OVERALL IN THEIR LABORATORY AND
OURS.
SO THIS AT THIS POINT IS WHERE
WE COLLECT NMR, MASS SPEC AND IR
DATA.
IT GENERATION CHEMICAL
INFORMATION ON THE IDENTITY OF
THESE COMPOUNDS AND REDUCES THE
COST TO SCREENING AND
IMPORTANTLY, WE ARE DOING THIS
WITH ONLY ONE MILLIGRAM OF A
FRACTION DERIVED FROM 250
FRACTIONS OF A CRUDE EXTRACT.
WE ARE CONSERVING THE EXTRACTS
THEMSELVES WHICH IS VITALLY
IMPORTANT.
SO FAR, WE HAVE DONE PROBABLY
65,000 OF THESE WITH RESEARCH
GROUPS.
THIS IS JUST A PIE CHART SHOWING
A VARIETIY OF ASSAYS AND GROUPS
WE WORKED WITH AND HOW MANY
SAMPLES WE SCREENED AND WORKED
THROUGH PROCESS FOR SECOND STAGE
PURIFICATION.
IMPORTANTLY, ACROSS ALL OF THESE
ASSAYS AND MORE AT THIS POINT,
AFTER THIS STAGE OF
PURIFICATION, 22 SUBFRACTIONS,
ABOUT 70% OF ACTIVE COMPOUND
CLASSES CAN BE DETERMINED
WITHOUT ANY FURTHER
PURIFICATION.
SO SOMEONE SENDS US A HIT LIST
OF 500 THINGS, WE CAN LIKELY
IDENTIFY WHAT IS RESPONSIBLE FOR
THE ACTIVITY AND ABOUT 300, 325
OF THOSE WITHOUT ANY FURTHER
PURIFICATION.
AND SO OVERALL, WE HAVE SET UP
METHODS AND AGAIN IN
HIGH-THROUGHPUT MANNER SO THIS
REQUIRES SIGNIFICANTLY LESS
CHEMIST TIME.
MOST OF THESE PROJECTS CAN BE
DONE WITH A COUPLE OF POCKETS.
AND FINALLY, AND IMPORTANTLY,
ABOUT 80% OF THE TIME WHEN WE
SEE AN ACTIVE FRACTION, WE DO
NOT SEE THE CRUDE EXTRACT
TESTING ACTIVE IN THE SAME ASSAY
TESTED IN THE SAME
CONCENTRATION.
WE PLAYED OUT THE SAMPLE WITH
THE FRACTION SO PEOPLE CAN TEST
IT SIMULTANEOUSLY AND THE
MAJORITY OF THE TIME, 4-5 TIMES,
WHEN WE SEE ACTIVITY IN A
FRACTION, THAT CRUDE EXTRACT
WOULD NOT HAVE BEEN SEEN AS
ACTIVE INDICATING WE ARE FINDING
A LOT OF NEW CHEMICAL DIVERSITY
THAT MIGHT HAVE BEEN HIDDEN
BEFORE.
AGAIN, THE METHODS AND HOW WE DO
THIS IS ALL PUBLISHED BACK IN
2020.
IT WAS PUBLISHED IN ACS CHEMICAL
BIOLOGY.
TO GET AN IDEA, ARE WE GETTING
TO MOLECULES THAT CAN TRANSLATE
TOO?
THAT'S PART OF WHAT THIS SEMINAR
IS ABOUT TODAY.
AND WHAT WE DID IS TOOK A LOOK
AT THE COMPOUNDS THAT CAME
THROUGH A PILOT PROGRAM OR
COMPOUNDS IN RED AND COMPARING
THEM TO APPROVED NATURAL PRODUCT
DRUGS FROM 19 EIGHTY ONE-2010.
YOU CAN SEE HERE IF WE'RE LOOK
AGO - 1981 -- LOOKING AT A
VARIETY OF PARAMETERS ON
COMPOUNDS.
THIS IS PRINCIPLE COMPONENT
ANALYSIS, THE THREE TOP
PRINCIPLE COMPONENTS RESPONSIBLE
FOR ABOUT 75% OF THE
DIFFERENTIAL OF THESE COMPOUNDS
AND THESE ARE BASICALLY SO YOU
KNOW, MOLECULAR WEIGHT, AND SP3
CAR BOBS.
YOU CAN SEE HERE A VERY GOOD
OVERLAP OF THE NPNPD COMPOUNDS
WITH THE DRUGS THAT HAVE BEEN
APPROVED INDICATING WE ARE
GETTING TO MOLECULES THAT ARE
TRANSLATABLE.
FINALLY, WE ALSO HAVE DATA
SYSTEMS TO HANDLE ALL OF THIS.
IT'S SECURE AND WEB ACCESSIBLE.
WE CAN TRACK ALL OF OUR
PROJECTS.
WE MONITOR FRACTION PRODUCTION,
384 WELL PLATE PRODUCTION.
WE HAVE INDIVIDUAL COLLABORA
COLLABORATORS, MONITOR OUR
INTERACTIONS WITH OUR
COLLABORATORS TO TRACK PROGRESS
AND MAKE SURE WE ARE NOT BEING
SLOW ON ANYTHING FROM EVERYTHING
THEY GET.
WE CAN ALSO VISUALIZE AND HAVE
DATA ON THE GEOGRAPHIC
INFORMATION.
WE HAVE ANNOTATION ON ALL OF
THESE SAMPLES BACK TO THE
PHOTOGRAPH AS SHOWN HERE OF THE
SOURCE ORGANISM, GPS COORDINATES
AND KEEP TRACK OF ALL THE
CHEMISTRY BEING GENERATE FRIDAY
THIS TOO.
AS PEOPLE COME BACK TO US WITH
HIT LISTS AND WE DO THIS AGAIN,
THIS BUILDS A VIRTUAL CYCLE
WHEREBY PREVIOUS RESEARCH DONE
ON THIS HELPS TO INCREASE THE
EFFICIENCY OF FUTURE RESEARCHERS
USING THESE CHEMICAL LIBRARIES.
SO FINALLY I WANT TO JUST TALK
QUICKLY FOR MY LAST SLIDE HERE,
NPNPD COLLABORATIONS ON THE HEAL
INITIATIVE WITH NCCIH AND NCATS
AND IN THIS EXAMPLE, TARGETS
ASSOCIATED WITH PAIN ARE WHAT IS
INDICATIVE OF THE ASSAYS AND THE
FUNDING THAT IS GOING INTO THIS.
SO, THESE ARE FUNDED THROUGH AN
NCCIH NOsY.
IT IS PERFORMED AT NCATS AND
IDENTIFIES COMPOUNDS, SENDS THEM
INTO LABS.
TWO INITIAL SCREENS HAVE BEEN
COMPLETED ON THESE TWO RECEPTORS
A GAL AN IN AND/OR FAN RECEPTOR.
COLLABORATORSA -- ORPHAN
RECEPTOR.
AND THEY HAVE ALREADY SCREENED
150,000 FRACTIONS AND GOT BACK
11,000 SUBFRACTIONS WITHIN TWO
WEEKS.
AND SO FAR WE HAVE ISOLATED TWO
COMPOUND CLASSES OF PARTICULAR
INTEREST WHICH MIGHT BE
TRANSLATABLE FURTHER DOWN THE
ROAD AS WE PASS THESE BACK TO
THE RESEARCHERS AT MOUNT SINAI
AND NIDA AND SEE HOW WILL THEY
WORKED IN THEIR SYSTEMS.
AND I WOULD LIKE TO ACKNOWLEDGE
EVERYTHING WHO HAS DONE SO MUCH
WORK TO MAKE ALL OF THIS
POSSIBLE I SHOWED YOU TODAY AND
THE NATURAL PRODUCT SUPPORT
GROUP AND THE NATURAL PRODUCT
BRANCH AND OUR COLLABORATORS.
AND THANK YOU ALL FOR YOUR
ATTENTION.
>>THANK YOU.
WE WILL HAVE A Q&A SESSION
FOLLOWING ALL THE TALKS.
AND NOW DR. ROGER LININGTON HAS
OUR NEXT TALK.
>>THANK YOU VERY MUCH.
I'M JUST GETTING SET UP HERE.
SO I'M GOING TO TELL YOU ABOUT
HIGH-THROUGHPUT FUNCTIONAL
ANNOTATION OF NATURAL PRODUCTS
USING INTEGRATED ACTIVITY
PROFILING.
THIS IS REPRESENTATIVE PROJECT
FROM THE HIGH FAN PROGRAM, ONE
OF THE U41 PROJECTS SUPPORTED BY
NCCIH AND UNDER CARBON PROGRAM.
SO I THINK THE INTRODUCTORY
TITLE IS A VERY TELLING REMINDER
OF THE RICHNESS AND COMPLEXITY
OF NATURAL PRODUCTS CHEMISTRY.
AND NICELY HIGHLIGHTS SOME OF
THE CHALLENGES WHICH FACE
NATURAL PRODUCTS IN THE 21ST
CENTURY IN TERMS OF DISCOVERY
AND DEVELOPMENT.
IN PARTICULAR, I THINK IT'S
CLEAR IF YOU TAKE ANY ORGANISM
OR SET OF ORGANISMS AND HERE I
GIVE A MACRO ORGANISM AS AN
EXAMPLE BUT THIS COULD BE
BOTANICAL SAMPLES, BONDS, MARINE
INVERTEBRATES.
WE HAVE A LOT OF VERY POWERFUL
PROFILING TECHNOLOGIES.
AND THIS MIGHT BE GENOME
SEQUENCING OR BY CHROME GRAPHIC
METHODS, LCMS BEING POPULAR.
I WOULD ARGUE THAT IT'S STILL
VERY DIFFICULT AT THIS STAGE TO
BE CONFIDENT ABOUT THE CHEMICAL
COMPOSITION OF ANY SINGLE SAMPLE
LET ALONE LARGE LIBRARIES OF
SAMPLES.
IF YOU DON'T KNOW WHAT YOU HAVE,
IT'S DIFFICULT TO UNDERSTAND
WHAT YOU SHOULD DO WITH THOSE
MATERIALS.
HOWEVER, I WOULD ALSO ARGUE THAT
TECHNOLOGIES IN THIS AREA ARE
REVOLVING VERY QUICKLY.
AND I THINK WE WILL COME TO A
POINT AS A FIELD IN THE NEAR
FUTURE WHERE THESE QUESTIONS
ABOUT COMPOSITION MEANING HOW
MANY MOLECULES ARE IN THE SAMPLE
AND HOW THEY ARE DISTRIBUTED
BETWEEN SAMPLES AND THEN ALSO
IDENTIFICATION, SO WHAT ARE THE
STRUCTURES?
PERHAPS THE CLASS SPACE LEVEL
AND ULTIMATELY AT THE FULL
STRUCTURAL LEVEL.
THESE QUESTIONS ARE THE SUBJECT
OF INTENSE RESEARCH IN THE
INFORMATICS AND TECHNOLOGY SPACE
IN NATURAL PRODUCTS.
I THINK WE ARE ALREADY SEEING A
NUMBER OF PLATFORMS WHICH HAVE
BEEN HELPFUL IN TRYING TO SOLVE
THESE ISSUES AND MORE ARE ON THE
WAY.
SO THIS CONCEPT THAT
COMPOSITIONAL QUESTIONS WILL
START TO BE ANSWERED GIVES US AN
OPPORTUNITY AS A FIELD TO
APPROACH THE WAY WE DISCOVER
NATURAL PRODUCTS REALLY QUITE
RADICALLY DIFFERENTLY THAN THE
WAY WE DO TODAY.
IF WE LOOK AT A TYPICAL CARTOON
WORK FLOW OF WHAT MOST NATURAL
PRODUCT PROGRAMS LOOK LIKE, IN
GENERAL, ONE STARTS WITH SOME
SOURCE OF NATURAL PRODUCTS
DIVERSITY WHICH GETS CONVERTED
TO EXTRACT LIBRARIES AS
DESCRIBED.
AND THEN THOSE LIBRARIES ARE
SUBJECT JECTED TO CHROME GRAPHIC
INVESTIGATION AND ALSO SOME
ELEMENT OF BIOLOGICAL STUDY.
AND HERE BIOLOGICAL STUDY IS
LOOSELY DEFINED.
SO I SHOWED HERE A CELL-BASED
ASSAY AND TOXICITY READ OUT BUT
THAT COULD BE A BEHAVIORAL AS A
OR CHEMICAL ECOLOGY AS A.
BUT SOME SORT OF FUNCTIONAL
ASSESSMENT.
AND THEN THERE IS ALWAYS ONCE
THOSE TWO STAGES ARE COMPLETE, A
STEP WHERE ONE NEEDS TO
INTEGRATE THE INFORMATION FROM
THOSE TWO DIFFERENT EXPERIMENTS
IN ORDER TO CONNECT CHEMO TYPES
AND PHENOTYPES AND TO RECOGNIZE
WHICH MOLECULES ARE RELEVANT FOR
THE PROPERTY OR BEHAVIOR WE ARE
LOOKING FOR.
AND THEN LASTLY, ONE HAS TO MAKE
DECISIONS ABOUT WHICH OF THESE
PRODUCTS TO FOCUS ATTENTION ON
AND WHERE TO INVEST THE
LABOR-INTENSIVE EFFORT IN
MATERIAL STUDIES, ET CETERA.
SO WE DEVELOPED A LOT OF TOOLS
AND TECHNOLOGIES WHICH TRY TO
ASSIST IN THESE VARIOUS AREAS.
SOME OF THESE THINGS ARE ALREADY
PUBLISHED.
SOME YOU WILL SEE COMING OUT IN
THE NEXT 12 MONTHS.
ESSENTIALLY WE AND MANY OTHERS
IN THE FIELD OF INFORMATICS
RELATED NATURAL PRODUCTS TRYING
TO DEVELOP METHODOLOGIES THAT
WILL LOWER THE VARIOUS ENTRY AND
IMPROVED QUALITY AND SPEC IN ALL
THESE DIFFERENT AREAS.
I THINK IT'S OPENING UP AN
OPPORTUNITY TO DO NATURAL
PRODUCTS DISCOVERY ON SCALE TO
MOVE FROM A SCENARIO WHERE
PERHAPS ONE STUDENT MIGHT STUDY
ONE OR A FEW SAMPLES AT A TIME
OR PROJECTS ARE SAMPLE-BASED TO
A SITUATION WHERE PROJECTS ARE
REALLY LIVELY BASED AND THE
NATURAL PRODUCTS CATCHES UP WITH
SOME OF THE OTHER
HIGH-THROUGHPUT METHODOLOGIES
WHICH ARE COMMON IN SMALL
MOLECULE LIBRARIES AND SYNTHETIC
CHEMISTRY LIBRARIES.
AND I THINK ALONG WITH THIS
COMES HIGHER QUALITY HARDWARE
AND MASS SPECTROMETRY, GREATER
ACCESS IN THE ACADEMIC
ENVIRONMENT, HIGH-THROUGHPUT
SCREENING TOOLS AND
TECHNOLOGIES.
SO OBVIOUSLY I DON'T HAVE TIME
TO TELL YOU ABOUT ALL THE TOOLS
IN 15 MINUTES.
I'M JUST GOING TO FOLK ON ONE.
THAT'S THIS TOOL HERE, NP
ANALYST.
WHAT NP ANALYST DOES IS IT
OFFERS AN OPPORTUNITY TO
INTEGRATE DATA FROM THESE TWO
PARALLEL STAGES OF DISCOVERY.
SO IT WILL TAKE DATA FROM
UNTARGETED METABOLOMICS ANALYSIS
OF LIBRARIES AND PAIR THAT WITH
RESULTS FROM HIGH-THROUGHPUT
SCREENING OR OTHER BIOLOGICAL
CHARACTERIZATION IN ORDER TO
PRIORITIZE AND HIGHLIGHT
MOLECULES WITH THE HIGHEST VALUE
FOR DOWNSTREAM ISOLATION.
AND THIS IS A STEP WHICH IS
HISTORICALLY BEING QUITE
DIFFICULT TO DO.
IT'S DIFFICULT TO DO MANUALLY
AND IT'S BEING CHALLENGING TO DO
COMPUTATIONALLY.
SO, IF WE LOOK BRIEFLY AT EACH
OF THESE TWO TYPES OF UP PUT
DATA, THE FIRST IS UNTARGETED
METABOLOMICS DATA.
AND IT REMAINS VERY COMPLICATED
DATA TYPE TO HANDLE.
SO THIS IS HIGH RESOLUTION MASS
SPEC TROM TERON THE LEFT.
THIS MACHINE GENERATES ON THE
ORDER OF 5 GIGABYTES OF RAW DATA
AN HOUR.
AND THE DATA ON THE RIGHT GIVE
SOME IDEA THE DATA POINT
COMPLEXITY OF THAT DATASET MIGHT
LOOK LIKE.
AND OF COURSE, AT THE BEGINNING
WHEN THE EXPERIMENT IS FINISHED,
THOSE MASS SPECTROMETRY DATA ARE
ALL VERY POORLY STRUCTURED.
A LARGE NUMBER OF INDIVIDUAL
DISTANCE TELL YOU ABOUT THE MASS
SPECTRA OF THE MASS SAMPLE AT
ANY PARTICULAR TIME POINT BUT
DON'T NECESSARILY TELL YOU ABOUT
COMPOSITION.
SO THERE ARE A LOT OF CHALLENGES
INVOLVED IN DATA PROCESSING AND
DATA ANALYSIS.
LOTS OF DIFFERENT WAYS ONE CAN
DO THAT AND AT THE MOMENT THERE
IS RELATIVELY LOW CONSENSUS
AMONG THE NATURAL PRODUCTS
COMMUNITY.
SO THIS IS ONE CHALLENGE.
THE ONLY THING I WOULD NOTE HERE
IS OF COURSE, NOT ALL OF THESE
DATA POINTS CORRESPOND TO UNIQUE
MOLECULES IN THE SAMPLE.
ONE MOLECULE CAN GENERATE MANY
DIFFERENT MASS SPEC FEATURES BE
IT THROUGH FRAGMENTATION, THE
FORMATION OF DIFFERENT ADDUCTS
OR DIFFERENT CHARGE STATES,
ET CETERA.
AND SO THERE WAS A LEVEL OF
COMPLEXITY HERE WHICH GOES
BEYOND THE COMPLEXITY OF THE
CHEMISTRY AND THE SAMPLE ITSELF.
BUT IF WE THINK ABOUT THE
PROJECT FROM A NATURAL PRODUCTS
DISCOVERY PERSPECTIVE, THEN
REALLY EVERY EXPERIMENT BOILS
DOWN TO THIS SIMPLE GRAPHIC.
ON THE LEFT WE HAVE A COMPOUND
CHROME ATOGRAM AND ON THE RIGHT
WE HAVE SOME BIOLOGICAL
FINGERPRINT.
I'LL COME BACK TO THE BIOLOGICAL
BARCODE WE HAVE HERE IN JUST A
SECOND.
AND IF WE THINK ABOUT THE
WORKLOAD, WHAT WE WANT TO KNOW
ABOUT ANY OF THESE.
WE TAKE ONE AS AN EXAMPLE, WE
WANT TO KNOW THE ANSWERS TO TWO
QUESTIONS.
WE WOULD LIKE TO KNOW IS THIS
METABOLITE PREDICTED TO BE
BIOACTIVE?
AND IF SO, IS IT CORRELATED WITH
A PARTICULAR PHENOTYPE OR
BIOLOGICAL FINGERPRINT?
BUT WE WANT TO KNOW THAT
INFORMATION NOT JUST FOR A
SINGLE MOLECULE IN THE SAMPLE
BUT RATHER WE WOULD LIKE TO KNOW
THAT INFORMATION COMPREHENSIVELY
FOR ALL THE MOLECULES IN THE
SAMPLE.
AND I THINK THIS SHIFT TOWARDS
DATA-CENTRIC APPROACHES TO
NATURAL PRODUCTS GIVES THE FIELD
THE OPPORTUNITY TO DO THESE
KINDS OF THINGS IN WHICH
PREVIOUSLY HAVE BEEN
FUNCTIONALLY IMPOSSIBLE TO DO.
REQUEST WE THINK ABOUT
BIOLOGICAL FINGERPRINTS AND WHAT
THAT MEANS, THERE ARE LOTS OF
WAYS IN WHICH ONE CAN DEFINE
BIOLOGICAL FINGERPRINTS.
IT COULD BE AS SIMPLE AS A
SINGLE READ OUT.
IT COULD BE A LIVE READ OUT FROM
A SINGLE CELL LINE.
A NUMBER OF TECHNOLOGIES ARE
COMING ON LINE AND AVAILABLE.
TWO THAT I PARTICULARLY AM
INTERESTED IN.
CELL PAINTING IS ONE.
THIS IS AN IMAGE-BASED SCREENING
METHODOLOGY THAT LOOKS AT
HUNDREDS OF SIZE AND SHAPE
PARAMETER TERS AT THE INDIVIDUAL
CELL LEVEL FOR CELLS UNDER DRUG
TREATMENT AND COMPARES THOSE TO
CELLS THAT ARE NOT UNDER DRUG
TREATMENT AND THEN USES GUILT BY
ASSOCIATION MECHANISM TO RELATE
THE SIZE AND SHAPE VARIATIONS OF
CELLS UNDER DRUG PRESSURE FROM
KNOWN DRUGS TO THE SIZE AND
SHAPE VARIATIONS FOR CELLS UNDER
DRUG PRESSURE WITH EXPERIMENTAL
DRUGS OR TEST EXTRACTS LIKE
NATURAL PRODUCTS.
IT'S A WAY OF DEVELOPING AN
UNBIASED PLATFORM FOR MAKING
MECHANISTIC PROTECTIONS ABOUT
ANY SEGMENT SAMPLE.
SO THIS IS ONE CELL LINE.
ALTERNATIVELY, LAB AUTOMATION
TECHNOLOGIES MEAN WE CAN RUN
STRAIGHTFORWARD ASSAYS SUCH AS
ANTIMICROBIAL ASSAYS.
NOW ON VERY HIGH-THROUGHPUT.
IT'S NOT UNREASONABLE FOR A
SINGLE RESEARCH GROUP TO RUN A
SET LIKE THIS.
ON THE RIGHT WE HAVE BIOMELT
RICK PANEL AND MICROBIAL PANEL
BASED IN MY LAB AND HERE WE TAKE
A SET OF 20 DIFFERENT PATHOGENS
AND SCREEN THE NATURAL PRODUCTS
LIBRARY AGAINST EVERY MEMBER IN
THIS SET AND LOOK AT THE PROFILE
OF ACTIVITY OF EACH NATURAL
PRODUCTS EXTRACT ACROSS THE FULL
SET OF PATHOGENS IN THE LIBRARY.
AND IN THIS WAY, YOU'RE LOOKING
AT THE SPECTRUM OF ACTIVITY OF
THE NATURAL PRODUCT AGAINST A
BROAD PANEL OF DIFFERENT
STRAINS, RATHER THAN JUST
LOOKING AT LIVE DATA RESULTS
AGAINST A SINGLE STRAIN.
IN BOTH CASES, WHAT COMES FROM
THIS IS AN ABILITY TO GROUP --
BASED ON SIGNATURES.
IF WE IMAGINE WE RUN CELL
PAINTING ANALYSIS ON THREE
DIFFERENT SAMPLES, PERHAPS THOSE
THREE SAMPLES GIVE US BIOLOGICAL
FINGERPRINTS LIKE THIS WHICH ARE
ALL VERY SIMILAR TO ONE ANOTHER.
YET IF WE LOOK AT THE
METABOLOMICS DATA, HERE WE HAVE
ON THE LEFT THE CARTOON OF THEIR
HBLCMS PROFILES.
THERE IS NO OBVIOUS CORRELATION
BETWEEN THESE THREE PROFILES.
AND YET, IF WE ASK WHETHER OR
NOT THERE ARE ANY MOLECULES
WHICH ARE COMMON TO THIS THRE
THREE-SET OF CHROMOGRAMS, WE
FIND THERE ARE TWO MOLECULES
HERE COMMON TO ALL THREE CASES
AND SO ONE TESTABLE HYPOTHESIS
IS THAT ONE OR BOTH OF THESE
MOLECULES ARE RESPONSIBLE FOR
THE PHENOTYPE.
AND SO REALLY THAT PROCESS OF
TAKING LARGE UNSTRUCTURED
METABOLOMICS DATASETS, PAIRING
THEM WITH BIOLOGICAL PROFILING
DATA FROM PROFILING SCREEN OF
CHOICE AND STILLING THOSE
INFORMATION DOWN TO MOLECULES
FOR FEATURE IDENTIFICATION, THAT
IS REALLY AT THE HEART OF THIS
PLATFORM WHICH I WOULD LIKE TO
TELL YOU A LITTLE BIT MORE
ABOUT.
SO NP ANALYST WAS RELEASED EARLY
LAST YEAR.
AN OPEN-SOURCE COMPLETELY FREE
PLATFORM.
IT HAS A -- MASS SPEC PLATFORM
INDEPENDENT.
IT'S ALSO LARGELY BIOASSAY
INDEPENDENT SO YOU CAN USE
BIOASSAYS WITH READ OUTS OF MOST
TYPES YOU MIGHT ENCOUNTER LIVE,
DEAD, ET CETERA.
IT HAS BOTH ONLINE WEB SERVER
WHICH YOU CAN ACCESS HERE AS
WELL AS A LOCAL VERSION IF YOU
WOULD RATHER RUN IT ON YOUR
LOCAL MACHINE AND NOT PUT YOUR
DATA ON OUR WEB SERVER.
AND IT HAS A SUPPORT NETWORK SO
YOU CAN ASK QUESTIONS AND GET
HELP.
REALLY THE SYSTEM WORKS IN FOUR
WAYS.
IT HAS A STAGE FOR UP LOADING
YOUR DATA.
WE DO A NUMBER EVER DATA
VALIDATION, QUALITY CONTROL
CHECKS TO MAKE SURE THE DATASET
YOU HAVE UP LOADED IS
APPROPRIATE FOR ANALYSIS AND TRY
AND GIVE FEEDBACK IN CASES WHERE
THERE ARE PROBLEMS.
THEN WE PERFORM THE CORE
ACTIVITY MAPPING, WHICH MAKES
PREDICTIONS ABOUT WHICH NATURAL
PRODUCTS ARE RELEVANT TO THE
OBSERVED ACTIVITIES AND THEN WE
HAVE ON LOAN DATA VISUALIZATION
TOOLS TO HELP INTERPRET THE DATA
AT THE END.
SO, WHAT I WOULD LIKE TO DO IN
THE NEXT FEW SLIDES IS JUST
EXPLAIN A LITTLE BIT ABOUT HOW
THIS PLATFORM WORKS UNDER THE
HOOD AND HOW IT MIGHT BE APPLIED
TO NATURAL PRODUCTS DISCOVERY
PROGRAMS BUT HOPEFULLY ARE
RELEVANT TO MANY OF YOU HERE IN
THE AUDIENCE.
SO IF WE START BY THINKING ABOUT
A SET OF SAMPLES, SO HERE WE
HAVE JUST NINE SAMPLES IN OUR
CARTOON VIEW.
IF WE SCREEN THOSE IN SOME
PROFILING ASSAY, AGAIN THIS
COULD BE ANYTHING.
THIS COULD BE EACH COLUMN IS
DIFFERENT BIOASSAY READ OUT.
THESE COULD BE DIFFERENT SIZE
AND SHAPE FEATURES FROM IMAGE
BASED SCREENING.
THEY COULD BE THE RESPONSES OF
DIFFERENT ORGANISMS PERHAPS A
PANEL OF DIFFERENT TYPES OF ORG
NITION.
OR THEY COULD BE DIFFERENT
RESISTANT MUTANTS OF THE SAME
ORGANISM OR SOMETHING LIKE THIS.
IN ANY CASE, HERE WE HAVE A SORT
OF HEAT MAP WHICH SHOWS THE
RELATIVE EFFICACY OF EACH SAMPLE
IN EACH OF THE READ OUTS AND
THEN WE COMPARE THIS WITH
METABOLOMICS DATA AND THEN IN
THIS CASE, THE ROWS -- EACH ROW
IS A SAMPLE AND IN THIS CASE,
THE COLUMNS ARE INDIVIDUAL MASS
SPEC FEATURES.
SO EACH COLUMN IS A SINGLE MASS
SPEC FEATURE FROM YOUR RUN AND
THE GRAY AND WHITE DENOTES
WHETHER THAT MASS SPEC FEATURE
IS PRESENT IN THAT SAMPLE OR
NOT.
SO YOU CAN MANAGE THIN MASS SPEC
FEATURE IS HIGHLY PREVALENT IN
ALL CASE WHERE IS IT'S THIS ONE
NEXT DOOR IS ONLY PRESENT IN A
SINGLE SAMPLE.
SO IF WE LOOK AT THESE DATA, IN
THE PAST, IT WILL BE LEFT TO
STUDENTS OR RESEARCHERS TO TRY
AND EMPIRICALLY DRAW
CONNECTIVITY BETWEEN PRESENCE OR
ABSENCE OF PARTICULAR PHENOTYPES
AND PRESENCE OR ABSENCE OF
CHEMISTRY WHICH MIGHT BE WORTH
ISOLATING.
THIS IS WHERE WE ENDED UP WITH
REPETITIVE BIOASS I GUIDED
FRACTIONATION METHODOLOGY.
BUT IF WE EXTRACT OR LOOK AT THE
DATA CAREFULLY, WE FIND THAT
FOUR OF THESE SAMPLES GIVE US
FINGERPRINTS WHICH ARE VERY,
VERY SIMILAR.
AND IF WE EXTRACT JUST THESE
ROWS OF THE DATASET, AND WE CAN
SEE THAT IF WE LOOK AT THE
METABOLOMICS DATA FOR THESE FOUR
SAMPLES, THERE ARE TWO SAMPLES
HERE.
THIS ONE OUTLINED IN RED AND
THIS ONE OUTLINED IN GREEN THAT
ARE PRESENT IN ALL FOUR CASES.
AND SO ONE HYPOTHESIS IS, ONE OF
THESE TWO IS RESPONSIBLE FOR THE
BIOLOGICAL ACTIVITY.
BUT IF WE LOOK BACKWARDS AT THE
ORIGINAL DATASET, WE FIND THIS
SAMPLE HIGHLIGHTED IN RED
ALTHOUGH IT IS PRESENT IN ALL
THE SAMPLES WHICH HAVE THIS
PHENOTYPE, IT IS ALSO PRESENT IN
QUITE A FEW SAMPLES WHICH DID
NOT HAVE THAT PHENOTYPE.
THE PROBABILITY THAT THIS
PARTICULAR FEATURE IS THE DRIVER
OF THIS PARTICULAR BIOLOGICAL
PROFILE IS LOW.
BY CONTRAST, IN THE SECOND
EXAMPLE, IT'S PRESENT IN EVERY
CASE WHERE THIS PHENOTYPE IS
OBSERVED AND ONLY PRESENT IN
MOST CASES.
SO THAT WOULD BE HIGH PRIORITY.
SO REALLY NP ANALYST JOB IS TO
PRIORITIZE THOSE WHICH ARE
RELEVANT.
THE IMPORTANT THING ABOUT THIS,
THIS STEPS AWAY FROM THE MORE
TRADITIONAL MODEL WHERE MA TAB
LIGHTS WERE STUDIED BECAUSE THEY
HAD GOOD CHROMATIC PROPERTIES OR
THEY WERE A REASONABLE TITER OR
IN SOME OTHER WAY SORT OF
PRIORITIZED AFTER THE RAW DATA
BY HUMAN OPERATORS.
AND IN THIS CASE, REALLY WE ARE
ASKING ONLY ABOUT THE
STATISTICAL RELEVANCE FOR EACH
FEATURE AND IN TURN, THAT COULD
HIGHLIGHT THE NEXT GENERATION
DATA IN THE NATURAL PRODUCTS
PHASE.
SO IF WE THINK ABOUT HOW TO
SCORE THESE, WE WANT TO HAVE TWO
THINGS.
WE'D LIKE TO KNOW HOW STRONG IS
THE PHENOTYPE AND HOW CONSISTENT
IS IT?
SO IN TERMS OF STRICT OF THE
PHENOTYPE F WE PICK ONE OF THESE
FEATURES AND EXTRACT THE
BIOASSAY DATA FOR THE SAMPLES
THIS FEATURE IS N WE GET A
REDUCED TABLE LIKE THIS.
YOU CAN SEE IF WE LOOK AT ANY
PARTICULAR BIOASSAY READ OUT
WHICH IS EACH OF THESE COLUMNS,
THE CONSISTENCY IS VERY POOR.
SO IF WE AVERAGE THE BIOASSAY
SCORES DOWN EACH COLUMN, WE FIND
THAT AVERAGE FRIENDSHIP IS WEAK.
IF WE TAKE OUR OTHER CANDIDATE
MOLECULE AND EXTRACT THOSE ROWS,
BECAUSE OF THE CONSISTENCY IN
EACH COLUMN IS HIGH, WE AVERAGE
THOSE VALUES FOR CONSISTENCY IN
THE AVERAGE FINGERPRINT SOURCE
IS VERY HIGH.
THIS IS A WAY TO MEASURE THE
STRENGTH OF THE ACTIVITY IN EACH
OF YOUR READ OUTS AND THAT TELLS
YOU SOMETHING ABOUT THE POWER OF
THE SYSTEM.
AND THEN THE OTHER QUESTION IS,
HOW CONSISTENT IS THIS READ OUT?
AND WE COMPARE THE FINGERPRINTS
AGAIN TO ONE ANOTHER.
SO ESSENTIALLY WE LOOK AT ALL
THE SAMPLES OF THAT PARTICULAR
METABOLITE IS IN.
WE COMPARE THEM AGAINST
THEMSELVES AND IN THIS CASE, YOU
CAN SEE BECAUSE OF THE
CONSISTENCY IS QUITE LOW, MANY
OF THE COMPARATIVE VALUES ARE
QUITE LOW.
SO WE CAN TAKE THE AVERAGE OF
THESE VALUES AND USE THAT AS AN
INDEPENDENT PHENOTYPIC
INDEPENDENT SCORE AND THEN SAY
SOMETHING ABOUT THE RELATIVE
CONSISTENCY.
>>I THINK YOU HAVE ABOUT A
MINUTE LEFT.
>>OKAY.
WE ARE JUST WRAPPING UP SO IT
WILL BE FINE.
>>THANK YOU.
>>SO, IF WE GIVE ONE EXAMPLE
HERE, WE TOOK 154 MARINE
BACTERIA AND TURNED THEM INTO
925 PRE FRACTIONS AND RAN THAT
IN TRIPLICATE ON THE MASS SPEC
TROM TERFOR UNDER 2800 SAMPLES.
IF WE LOOK QUICKLY AS ONE
EXAMPLE HERE, WE FIND IN THIS
CASE, MANY OF THE SAMPLES, MANY
OF THE SQUARES ARE ALL CONNECTED
BY A SINGLE MASS SPEC FEATURE.
IF WE LOOK AT THE CHROME
ATOGRAM, TOP IS THE RAW AND THE
BOTTOM IS THE EXTRACTED FOR THIS
FEATURE, WE FIND THAT FEATURE
ALTHOUGH LARGELY OBSCURED IN THE
ORIGINAL IS EASY TO IDENTIFY
HERE.
AND IF WE THEN LOOK AT WHAT THAT
CHEMISTRY IS, WE CAN YUSILA LATE
THOSE MATERIALS AND SOLVE THESE
STRUCTURES.
SO THE TAKE HOME MESSAGE IS
INFORMATICS AND TECHNOLOGY
APPROACHES ARE INFLUENCING
HEAVILY THE WAY RESEARCH GROUPS
DEVELOP NATURAL PRODUCTS
DISCOVERY AND THAT WE AND OTHERS
IN THIS AREA ARE REVISING THOSE
PLATFORMS.
IT'S BRINGING A WHOLE NEW WORLD
OF DISCOVERY TO THE FIELD.
THE LAST THING I SHOULD DO IS
THANK THE COLLABORATORS.
THE FOLKS FROM MY LAB WHO
DEVELOPED A NUMBER OF THESE
TOOLS AND THE FUNDING AGENCIES
FOR THEIR SUPPORT AND YOU HAVE
TO ASK QUESTIONS IN THE Q&A.
>>THANK YOU VERY MUCH FOR YOUR
PRESENTATION.
VERY VALUABLE INSIGHTS INTO
INTEGRATING BIOLOGICAL SCREENING
AND MASS SPECTRO METRIC DATA.
WE'LL GIVE THE FLOOR NOW TO OUR
NEXT AND FINAL SPEAKER BEFORE
OUR Q&A CISION AND THAT IS
DR. MANDE HOLFORD.
>>HI, EVERYONE.
THANK YOU FOR JOINING US TODAY.
THANK YOU TO CRAIG AND PATRICK
FOR THE INVITATION TO PRESENT
AND SHARE OUR WORK.
I WANT TO TELL YOU, AND THEY
PROBABLY DIDN'T PLAN IT THIS
WAY, BUT IT'S VERY GOOD ORDERING
OF HAVING US SPEAK IN THE ORDER
WE DID BARRY FOLLOWED BY ROGER
AND THEN MYSELF.
AND WE REALLY ARE TALKING ABOUT
WHERE WE WANT TO GO WITH NATURAL
PRODUCTS DEVELOPMENT IN MY TALK.
SO SEEING WHERE THE HOCKEY PUCK
IS GOING TO BE INSTEAD OF WHERE
IT IS.
SO WE'RE GOING TO TALK ABOUT
DEVELOPING MODELS FOR
CHARACTERIZING VENOM BASED
MARINE NATURAL PRODUCTS.
AND I WANT TO START OFF WITH
THIS QUOTE, PROGRESS IN SCIENCE
DEPENDS MOSTLY ON NEW
TECHNIQUES, NEW DISCOVERIES AND
NEW IDEAS.
PROBABLY IN THAT PARTICULAR
ORDER.
AND SO, I THINK WE ARE AT THIS
MOMENT WHERE TECHNOLOGICAL
INNOVATIONS ARE MEETING THE
SCIENTIFIC COMPLEXITY AS
WITNESSED OR EVIDENCED BY HUBBLE
VERSUS JWST IMAGE.
WE ARE IN RAY PLACE WHERE FOR
NATURAL PRODUCTS, PARTICULARLY
VENOM-BASED, THERE ARE TWO
TECHNOLOGICAL THINGS THAT NEED
TO HAPPEN FOR US TO ADVANCE HOW
WE DISCOVER AND CHARACTERIZE
NATURAL PRODUCTS FROM THESE
VENOMOUS ORGANISMS.
ONE IS TO CONSTRUCT A VENOM'S
KNOWLEDGE BASE, AND I'LL TALK
ABOUT THIS SOME MORE, AND THE
OTHER IS TO DEVELOP MODEL
SYSTEMS FOR CHARACTERIZING VENOM
GENETIC REGULATION AND
EXPRESSION.
AND I'LL TALK ABOUT THIS IN TWO
PLACES WHERE I'D LIKE MY LAB TO
GO.
AND THAT IS LOOKING AT THE VENOM
GLANCED IN DEVELOPING ORGANOIDS
FROM CONES, AND SNAILS AND
LOOKING AT SEF LOW PODS AND
BEING ABLE TO DO GENOME EDITING
OF THE EMBRYONIC STAGE OF THESE
ANIMALS IN ORDER TORD DEVELOP
TRANSGENIC VENOMOUS ORGANISMS.
SO THE POWER OF GENOME
SEQUENCING HAS REALLY CHANGED
THE WAY THAT WE DO SCIENCE
EVERYWHERE.
EVERY SINGLE THING FROM NATURAL
PRODUCT CHEMIST TO THE
TRADITIONAL BIOLOGISTS IN THE
TURN OF THE CENTURY IN 2000,
WHEN THEY SOLVED THE HUMAN
GENOME OR STARTED TO SOLVE IT,
IT LED TO NOW ALL OF THESE
INCREASES WE SEE IN PRECISION
HEALTH.
IN A SINGULAR WAY A RECENT
PROJECT WAS DESCRIBED WHERE THEY
HOPED TO SEQUENCE ALL EUKARYOTIC
LIFE ON EARTH FOR THE POTENTIAL
OF TRYING TO SUSTAIN AND FURTHER
FUTURE LIFE.
AND SO AFTER CENTURIES OF DOING
SORT OF REDUCTIONIST AND SILOED
KINDS OF RESEARCH, THIS QUOTE IS
VERY PERTINENT IN OUR TASK IS TO
RESYNTHESIZE BIOLOGY, PUT
ORGANISMS BACK INTO THE ITS
ENVIRONMENT AND CONNECT AGAIN TO
EVOLUTIONARY PAST AND LET US
FEEL THAT COMPLEX FLOW THAT IS
ORGANISM, EVOLUTION AND
ENVIRONMENT UNITED.
SO I THINK THERE IS NO BETTER
EXAMPLE OF THAT COMPLEX FLOW OF
ORGANISM EVOLUTION AND
ENVIRONMENT THAN VENOM.
SO VENOM AND VENOMOUS ANIMALS.
WHEN MOST PEOPLE THINK OF THESE
THINGS THEY THINK OF AGENTS OF
FEAR.
I THINK OF THEM AS AGENTS OF
CHANGE AND INNOVATION AS NATURE
HAS SHOWN THEM.
MY LAB IS FOCUSED ON SNAILS AND
THEY USE VENOM AS A MEANS THE
WAY NATURE USED IT TO TRANSFORM
A PHYSICAL WARFARE INTO A
BIOCHEMICAL ONE.
THIS SNAIL IS UNDER THE SAND T
WILL INJECT VENOM INTO THE FISH,
THE PREY, AND THEN IT WILL
SWALLOW THE PREY WHOLE.
IF THIS IS AN INNOVATION IN
NATURE, I DON'T KNOW WHAT IS.
THE REASON THAT THESE SNAILS ARE
ABLE TO DO THIS IS BECAUSE VENOM
IS A VERY COMPLEX THING.
THESE SNAILS PREY ON FISH, WORMS
AND OTHER MARINE ORGANISMS.
VENOM HAS BEEN CONVERGENT
EVOLUTION THROUGHOUT THE TREE OF
LIFE.
EVERYWHERE YOU'RE SEEING RED
INDICATES A VENOMOUS ORGANISM.
AND VENOM ITSELF IS INTEGRATED
PROCESS OF SPECIALIZED TISSUES
USUALLY GLANCED, AND IT'S
DELIVERED THROUGH ASSOCIATED
STRUCTURES, FANGS OR HARPOONS
AND AS THE ULTIMATE PAIRING OF
THE ORGANISM WITH THE
ENVIRONMENT, VENOM CAN LINK
PHENOTYPE AND GENOTYPE BEHAVIORS
THAT ARE MEASURABLE BECAUSE
VENOM IS ONCE USED, IT'S USUALLY
USED IN ECOLOGICAL BEHAVIORS OF
PREDATION, DEFENSE OR SEXUAL
COMPETITION.
AND SO I THINK THAT THIS IS THE
ULTIMATE TOOL THAT ENABLES US TO
ASK A SET OF INTEGRATED
QUESTIONS THAT ARE ALSO
COMPLEMENTARY.
TO GIVE YOU A LITTLE BIT MORE ON
THE MOLECULAR STRUCTURE, THEY
ARE NOT ONE THING, THEY ARE
SEVERAL THINGS.
SO MADE UP OF SMALL MOLECULES,
PEPTIDES AND PROTEINS.
WE FOCUS MOSTLY ON THE PEPTIDES.
PEPTIDES FROM VENOMOUS SNAILS,
WHICH CAN HAVE -- EACH SNAIL
VENOM CONTAINS ANYWHERE FROM 250
UNIQUE PEPTIDES TO MORE.
NO TWO SNAILS HAVE EXACTLY THE
SAME PEPTIDE, SO WHETHER INTEROR
INTRASPECIES, VENOM IS VERY
SPECIES SPECIFIC.
SECOND, THEY ATTACK CONSERVED
PHYSIOLOGICAL TARGETS.
THEY ARE CUSTER BOMBS WORKING IN
CONCERTED FASHION.
THAT'S WHY YOU'RE ABLE TO SEE
THE SNAIL EAT THE FISH SO VERY
QUICKLY.
THAT FISH DOESN'T HAVE A CHANCE.
THEY GO FOR BLOOD BRAINS AND
MEMBRANES BECAUSE -- AND THEY DO
SO IN A RAPID FIRE ACTION.
SO THE THIRD PART IS THAT THESE
MOLECULES WORK.
SO THEY ARE VERY SUCCESSFUL
MOLECULAR INNOVATION AND VERY
GOOD AT WHAT THEY DO.
AND IN TERMS OF VENOM PEPTIDES,
VERY GOOD AT MANIPULATING
CELLULAR COMMUNICATION.
SO OUR JOB AS SCIENTISTS AS
ROGER AND BARRY WERE POINTING
OUT IS TO FIGURE OUT HOW THEY
WORK.
WE HAVE DONE A LOT OF
HIGH-THROUGHPUT METHODS TO TRY
TO FIGURE THAT OUT BUT WE STILL
DON'T KNOW.
WE HAVE BEEN SUCCESSFUL IN
UNDERSTANDING SOME OF HOW VENOM
PUP TIDES CAN BE TURNED INTO
THERAPIES FOR TREATING HUMAN
DISEASE AND DISORDERS.
HERE YOU SEE SCREENSHOT OF
SEVERAL PEPTIDES THEMSELVES OR
COMPOUNDS DERIVED FROM VENOM
PEPTIDES USED TO TREAT
EVERYTHING FROM HYPERTENSION TO
DIABETES TO CHRONIC PAIN.
AND SO WHAT IS EXCITING IS NOT
ONLY WE ARE GETTING NEW
COMPOUNDS FROM THESE VENOMOUS
ORGANISMS BUT ALSO FINDING NEW
PATHWAYS IN HOW TO TREAT THESE
THINGS.
FOR EXAMPLE, IN THE CONE SNAIL
DRUG, IT IS USED TO TREAT
CHRONIC PAIN AND HIV IN CANCER
PATIENTS BUT IT DOESN'T WORK ON
OPIOID RECEPTORS T WORKS ON
ANTI-CALCIUM CHANNEL.
SO WE HAVE RIGHT NOW THE MEANS
TO STUDY AND CHARACTERIZE VENOM
FROM BIOLOGY USING ALL THE TOOLS
THAT ARE CURRENTLY AVAILABLE,
PROTEOMICS, GENOMICS, BIOEN
FORMATTICS AND FUNCTIONAL
ASSAYS.
I THINK WE ARE MISSING A VERY
VALUABLE PIECE OF THE PUZZLE.
THIS IS WHERE MY VENOM EVOLUTION
MATHEMATICS COMES IN.
MANIPULATE THE VENOM ARSENAL WE
HAVE TO MANIPULATE THE GENES.
MOST RESEARCH HAVE FOCUSED
STRICTLY ON THE TOXINS, SMALL
MOLECULES, PEPTIDES AND THE
PROTEINS.
ESPECIALLY IN NATURAL PRODUCTS
DEVELOPMENT.
THE PROBLEM WITH THAT IS THAT
THE TOXINS EVOLVE VERY RAPIDLY.
THEY HAVE COMPLEX PATTERNS OF
EXPRESSION AND THEY RECENTLY
INCORPORATED INTO THE VENOM
ARSENAL WHICH MEANS THEY ARE
CRUDE MIXTURES AND VERY
DIFFICULT TO PURIFY.
AND SO, I THINK MOST IMPORTANTLY
WHEN WE FOCUS ONLY ON THE SMALL
MOLECULES, PEPTIDES AND
PROTEINS, WE ARE MISSING THAT
GRAND OPPORTUNITY WHERE WE ARE
ABLE TO LOOK AT THE COMPLEX
MIXTURE AT THE GENETIC AND
ORGANISMAL PHENOTYPIC BIOLOGY.
SO THE QUESTION THAT IS GOING
FORWARD IN MY LAB, I WANT TO
FOCUS ON HOW VENOM GENES
WEAPONIZE FOR ECOLOGICAL AND
WHEN WE DEVELOP THEM AS NATURAL
PRODUCTS, THERAPEUTIC ADVANTAGE.
IN ORDER TO ADDRESS THAT
QUESTION, WE HAVE TO LOOK AT NOT
JUST THE SMALL MALL COOLS,
PEPTIDES AND PROTEINS, BUT WE
HAVE TO LOOK AT THE GENE ITSELF.
SO NOT FOCUSING ON THE FINISHED
PRODUCTS BUT LOOKING AT THE
GENE.
AND SO ALL VENOM PEPTIDES AND
PROTEINS ARE EXPRESSED AS A
SINGLE GENE WITH A SIGNAL
SEQUENCE THAT IS HIGHLY
CONSERVED AND THEN A MATURE
PEPTIDE AT THE END THAT BECOMES
BIOACTIVE TOXIN.
WHAT IS GREAT IS EACH VENOM GENE
CAN BE TRADES TO A DISTINCT
LOCI.
THAT ENABLES US TO HAVE A LEVEL
OF GENETIC ATTRACTABILITY THAT
IS HARDLY SEEN IN MOST OTHER
TRAITS.
IF WE ARE ABLE TO DEVELOP TOOLS
IN WHICH WE HAVE GENETIC
ATTRACTABLE MODELS, WE ARE ABLE
TO MANIPULATE A LOT OF HOW THESE
PROTEINS AND SMALL MOLECULES ARE
EXPRESSED AND REGULATED.
AND BECAUSE AGAIN WE ARE ABLE TO
DO THIS IN A VERY COMPARATIVE
MANNER WHICH WE CAN LINK AGAIN
AS I SAID BEFORE, GENOTYPE TO
PHENOTYPE AND IMPORTANT FOR THIS
AUDIENCE, WE START TO REALLY
UNDERSTAND HOW VENOM PEPTIDES
FUNCTION TO MANIPULATE CELLULAR
PHYSIOLOGY.
AND SO TO DO THESE TWO THINGS, I
THINK WE NEED NUMBER 1,
KNOWLEDGE BASE FOR THE VENOM
COMMUNITY.
SIMILAR TO HOW THE FLY BASE AND
ZEN BASE DEVELOPED, THEY
GALVANIZED THE COMMUNITY, SET
STANDARDS AND PROTOCOL AND ALLOW
US TO MAKE BIG LEAPSES IN TERMS
OF IDEAS AND DISCOVERIES.
WE NEED TO DEVELOP AND CONSTRUCT
A VENOM'S KNOWLEDGE BASE AND
BECAUSE I WORK WITH THE MARINE
ORGANISMS, THE FIRST SHOULD BE
THE MARINE VENOM BASE BUT IT
COULD BE IN GENERAL.
AND WHILE GENOMES FROM HUMANS
AND OTHER ORGANISMS HAVE BEEN
AVAILABLE SINCE THE EARLY TWO
THOUSANDS, THE FIRST GENOME FROM
CONE SNAILS ONLY CAME OUT TWO
YEARS AGO.
AND WE RECENTLY HAVE GENOMES FOR
OCTOPUS AND THE SQUID WHICH IS
UNPUBLISHED FROM COLLEAGUES AT
THE MARINE BIOLOGICAL
LABORATORY.
IT'S A VERY NASCENT FIELD WHENY
WE THINK ABOUT HOW TO LOOK AT
VENOMS NATURAL PRODUCT
DEVELOPMENT AT A GENETIC AND
GENOMIC LEVEL BECAUSE WE DON'T
HAVE ENOUGH GENOMES TO DO THAT.
WE NEED MORE.
TO GIVE YOU AN EXAMPLE OF WHAT
IS POSSIBLE FROM OUR OWN WORK IN
OUR APPROACH, WE COMBINE
PHYLOGENETIC STORY OF HOW THESE
SNAILS DEVELOPED OVER TIME,
EVOLVED, WITH THE TRANSCRIPTOMIC
AND PROTEOMICS DATA TO GIVE US A
VALIDATED DATABASE OF TOXIN
SPECIFICS FROM THE SNAILS USING
THIS INTEGRATED METHOD.
WE HAVE IDENTIFIED OUR SNAIL
TOXINS ARE NEW AND DISTINCT FROM
THE SNAILS SNAIL TOXINS THAT ARE
KNOWN.
WE DID THIS WITH CONEIS AND --
TWO REPOSITORIES ON THE MARKET
RIGHT NOW FOR HELPING US TO
DECIPHER VENOMOUS SEQUENCES.
BUT WHILE THEY WORK, THEY ARE
VERY LIMITED IN WHAT THEY CAN
DO.
WE WERE ALSO THE FIRST TO THEN
IDENTIFY ACTIVITY OF THE TOXINS
AS PERIPHERAL ANALGESIC
COMPOUNDS USING A WHOLE ANIMAL
ASSAY AND THEN WE ALSO
IDENTIFIED THE ACTIVITY OF OUR
PEPTIDES, ONE OF THE PEPTIDES N
HELPING TO TARGET DYSREGULATED
ION CHANNELS IN LIVER CANCER.
SO OUR VENOM MOLECULE IS SHOWN
IN GREEN, TESTED AGAINST
DOXORUBICIN AND THEN NOT TREATED
IN RED.
OUR VENOM PEPTIDE IS GOOD AT
TARGETING LIVER CANCER TUMORS.
BUT AGAIN, BY FOCUSING MOSTLY ON
THE PEPTIDES ITSELF, IT HASN'T
GIVEN US MUCH IN SIGHT AS TO WHY
THIS PEPTIDE TARGETS THE
PARTICULAR CHANNEL IT IS IT.
TO DO THAT, WE REALLY NEED TO
DEVELOP MODEL SYSTEMS TO
CHARACTERIZE VENOM GENETIC
REGULATION AND EXPRESS.
AND THE SO, THESE MOL ED SYSTEMS
HAVE BEEN INFLUENTIAL AND
TRANSFORMATIVE AND CONTINUE TO
BE TO HELP US FIGURE OUT A LOT
ABOUT CELLULAR PHYSIOLOGY AND
ABOUT NATURAL PRODUCTS
DEVELOPMENT.
BUT NONE OF THESE ANIMALS ARE
VENOMOUS.
SO IN ORDER TO REALLY BE ABLE TO
MAKE AND MANIPULATE VENOM GENE
EXPRESSION AND REGULATION, WE
ARE GOING TO FOCUS ON TWO
DIFFERENT MODELS.
ONE IS USING VENOM GLAND
ORGANOIDS.
THERE ARE NO INVERTEBRATE
ORGANOIDS IN EXISTENCE.
SO IF WE ARE ABLE TO PULL THIS
OFF, IT WOULD BE PRETTY BIG.
MOST ORGANIZED COME FROM
VERTEBRATE SYSTEMS.
AND SO, THE SECOND THING IS TO
DO GENETIC -- GENOME-MODIFIED
VERSIONS OF SEF LOW PODS,
PARTICULARLY OCTOPUS, SQUIDS AND
CUDDLE FISH IN COLLABORATION
WITH THE MARINE BIOLOGICAL
LABORATORY WHERE WE CAN
GENETICALLY ALTER AND ENGINEER
THE SALIVARY GLANDS OF THESE SEF
LOW PODS IN ORDER TO MAKE A
TRANSGENIC SEF LOW POD.
SO FIRST HOWEVER HAVE WE GOTTEN
ON THE ORGANOIDS?
ALL ORGANOIDS FOR THE MOST PART
ARE MADE FROM EPITHELIAL CELLS
SO OUR FIRST STEP WAS TO
IDENTIFY DID WE HAVE EPITHELIAL
CELLS IN THESE VENOM GLANCED?
WE DO WHEN WE DID
IMMUNOHISTOCHEMISTRY.
AND THE SECOND THING IS THE
GROWTH FRACTORS ARE VERY
IMPORTANT FOR GROWING ORGANOIDS
AND MOST OF THEM COME FROM THE
WHITE SYSTEM, SO WE TOOK OUR
TRANSCRIPTOME AND SEARCHED TO
SEE IF THESE INVERTEBRATES HAVE
SIMILAR GROWTH FACTORS.
THEY DO.
HAPPY DAY.
SO, WE HAVE BEEN ABLE TO
SUCCESSFULLY CULTURE THESE
MARINE SNAIL VENOM GLAND CELLS
FROM TWO SNAILS BUT THEY DON'T
SURVIVE VERY LONG.
WE CAN SEE THEM.
THEY GROW FOR A FEW WEEKS AND
THEN THEY GET INFECTED AND DIE.
SO WE ARE CURRENTLY AT THE STAGE
WHERE WE ARE MESSING WITH OUR
GROWTH COCKTAIL, MESSING WITH
OUR DIGESTION METHODS, MESSING
WITH THE WHOLE THING TO FIGURE
OUT HOW TO KEEP THEM ALIVE AND
THEN HOW TO GET THEM TO THE
POINT WHERE WE CAN ACTUALLY
CHARACTERIZE WHAT KIND OF VENOM
IS GROWING IN THE ORGANOID IF AT
ALL.
AND THEN LAST SUMMER I SPENT --
I WAS A WHITMAN FELLOW AND I
WILL BE AGAIN THIS SUMMER AT THE
MARINE BIOLOGICAL INSTITUTE --
LABORATORY NEWOODS HOLE.
AND THERE I LEARNED ABOUT THE
CULTURE PROGRAM FOR SEF LOW
PODS, TO ME IS MANNY FROM HEAVEN
BECAUSE IT HELPS ME TO FIGURE
OUT HOW TO MAKE VENOM MODEL
SYSTEMS FROM A COMPLEX ORGANISM.
SO THERE ARE SYSTEMS GENETICALLY
TRACTABLE AND ALSO PRODUCE VENOM
BUT NOTHING FOR MORE COMPLEX
ORGANISM.
SO THEY FIGURED OUT WAYS TO GROW
CERTAIN SPECIES OF SEF LOW PODS
FROM THE EMBRYONIC STAGE AND
WILL THEY GROW PRETTY QUICKLY IN
A MATTER OF 6 WEEKS OR SO AND
THEN YOU'RE ALLOWED TO DO GENOME
EDITING AT THE EMBRYONIC STAGE
OF THESE ANIMALS.
WHAT WE ARE INTERESTED IN IS
TRACK TRAING HOW THE SALIVARY
GLAND THAT HAS THE TOXINS,
SIMILAR TO THE VENOM GLANCED IN
SNAILS, HOW THAT GLAND IS
DEVELOPED, HOW THE GENES THAT
ARE EXPRESSED IN DIFFERENT AREAS
OF THE SALIVARY GLAND ARE
DETERMINED BECAUSE CERTAIN GENES
ARE EXPRESSING DEFENSIVE VENOM
AND OTHER VENOMS AND CAN WE
TWEAK THAT SO WE END UP WITH A
TRANSGENIC VENOM ANIMAL TO GIVE
US MORE INFORMATION ABOUT HOW
THE VENOM PRODUCT ARE MADE.
SO BASICALLY WE ARE GOING TO DO
COMPARATIVE GENOMIC AND
TRANSCRIPTOMIC ANALYSIS OF THESE
ANIMALS WHICH ARE ALREADY
AVAILABLE FOR SOME OF EM THIS
WITH COLLABORATORS AT THE MARINE
BIOLOGICAL LABORATORY AND THEN
WE ARE GOING TO PERFORM A SERIES
OF GLAND DEVELOPMENTAL STUDIES
TO INVESTIGATE HOW EXACTLY THE
TOXINS ARE BEING MADE AND
REGULATED.
WE STARTED DOING SOME OF THE
COMPARATIVE GENOMIC WORK LOOKING
AT THE DOCKSINS FROM THE SEF LOW
PODS IN PARTICULAR THIS ONE IN
THE CUDDLE FISH LOOKING AT BOTH
MALE AND FEMALE ANIMALS.
WE IDENTIFIED SERIES OF TOXINS
THAT ARE COMMON TO TOXINS FOUND
IN SNAKES AND SNAILS AND OTHER
THINGS.
SO WHILE IT'S NOT VERY
WELL-KNOWN THAT SEF LOW POD
TOXINS EXIST, THEY DO AND THEY
HAVE SIMILAR THINGS TO WHAT WE
FIND IN SNAILS.
AND THEN IN RECENT WORK FROM
SNAKES, WHERE THEY IDENTIFIED A
GENE REGULATORY NET FOOTWORK FOR
TOXIN GENES THAT ARE INVOLVED IN
PROTEIN MODIFICATION AND
TRANSPORT, PARTICULARLY THE
UNFOLDED PROTEIN UPR AND ERAD
ENDOPLAST MICK RETICK
LUMASSOCIATEOD BEGREDATION
PATHWAYS.
THEY IDENTIFIED A BUNCH OF GENES
INVOLVED IN MAKING SURE PROTEINS
AND PEPTIDE FOLD CORRECTLY OR IN
CASE OF THE PROTEIN DISULFIDE
STRUCTURES THAT WHICH ALL VENOM
PEPTIDES HAVE, ARE ABLE TO FORM
CORRECTLY.
SO WE ALREADY KNOW CERTAIN
TARGETS IN THE GENE REGULATORY
PATHWAY WE'D LIKE TO MANIPULATE
OR GENETICALLY MODIFY IF WE ARE
ABLE TO MAKE OUR GENETICALLY SEF
LOW POD MODELS.
WE KNOW THAT THOSE PATHWAYS
USUALLY ARE ACTIVATED IN MOMENTS
OF STRESS BUT THEY CAN ALSO BE
ACTIVATED IN DEVELOPMENTAL AND
CELL SURFACING AND PHYSIOLOGICAL
TIMES AS WELL.
SO IN TEAMS OF NON STRESS.
WE ARE HOPING TO MANIPULATE
THESE PATHWAYS AND SEE HOW IT
ALTERS THE EXPRESSION OF THE
PEPTIDES AND PROTEINS THAT ARE
INVOLVED.
I'M AT THE END.
OUT OF THE SEA AND INTO THE
WELL, DEVELOPING VENOM MODEL
SYSTEMS WILL HELP US TO ADDRESS
THESE THREE BIG QUESTIONS ABOUT
WHERE WE WOULD LIKE TO GO.
SO WE STILL DON'T REALLY KNOW
HOW VENOM PEPTIDES HAVE EVOLVED,
WHAT DRIVES THE VENOM VARIATION,
WHY ARE THEIR SO MANY OF THESE
COMPOUNDS AND HOW DO THEY
FUNCTION?
WHY DO THEY TARGET THE MOLECULAR
TARGETS THEY DO?
SO WHEN YOU START TO ASK THESE
QUESTIONS THERE IS A BUNCH OF
OTHER QUESTIONS THAT ARE NESTED
AND AS IMPORTANT AND
COMPLEMENTARY.
FOR THIS PARTICULAR AUDIENCE,
THE IDEA OF HOW VENOMS FUNCTION
IS DOES THE FORM, MEANING IN THE
TISSUE IN THE SALIVARY GLANDS D
THAT DICTATE THE FUNCTION?
ARE THERE SIMILAR MECHANISMS FOR
THESE TARGETS?
ION CHANNELS AND RECEPTORS OF
ALL VARIOUS KINDS AND THEN
LOOKING'S PHYSIOLOGICAL
MANIPULATION, SPECIFIC TO THE
NATURAL PRODUCTS DEVELOPMENT HOW
CAN WE GET THEM TO IN THESE
CASES, TARGET THE DYSREGULATIONS
I ON CHALLENGES VERSUS NORMAL
CELLS SO I THINK WE ARE AT A
SWEET SPOT OF WHERE WE HAVE
TECHNOLOGICAL INNOVATIONS
MEETING SCIENTIFIC COMIT AND WE
ARE ABLE TO BE ABLE TO ANSWER
HOW THE ORGANISM, THE
ENVIRONMENT AND EVOLUTION PAST
COME TOGETHER WITH VENOM AND
VENOMOUS ANTHILLS TO LOOK AT HOW
TO CHANGE THE IDENTIFICATION AND
CHARACTERIZATION OF NATURAL
PRODUCTS DEVELOPMENT SO IT'S NO
LONGER A HIT-OR-MISS BUT REALLY
TRYING TO PREDICT AND GUIDE
WHERE WE GO.
AND WITH THAT, I'D LIKE TO THANK
THE LAB MEMBERS, PEOPLE DRIVING
THIS WORK IS MOSTLY TWO GRAD
STUDENTS STUDENTS.
AND I'D ALSO LIKE TO THANK OUR
COLLABORATORS.
WE STARTED THE ORGANOID WORK IN
HAHN'S LAB ANDIGENCE HAS HIS OWN
LAP IN GERMANY AND AT THE MARINE
BIOLOGICAL LABORATORY PEOPLE ARE
WORKING IN THE PROGRAM INCLUDING
CAYY AND JOSH AND ROGER.
WE STARTED WORKING WITH THEM AND
RICHARD'S LAB LEADING THE CUDDLE
FISH BRIGADE.
WITH THAT, I THANK YOU AND I ASK
YOU FOR ANY QUESTIONS.
>>THANK YOU ALL FOR THOSE
WONDERFUL TALKS.
WE DO HAVE A LOT OF QUESTIONS
COMING IN.
WE HAVE ABOUT 600 PEOPLE ON
LINE.
SO YOU CAN IMAGINE WE ARE
GETTING A LARGE VOLUME AND
TRYING TO GET TO AS MANY AS WE
CAN.
FIRST QUESTION FOR DR. O'KEEFE,
ARE THE FRACTIONS OBTAINED
THROUGH YOUR PROTOCOL STANDARD
OR DOES THE METHOD CHANGE
DEPENDING ON THE ORGANISM YOU'RE
MUTED.
>>SORRY ABOUT THAT.
SO THE METHOD IS UNIFORM FOR
EXAMPLE, FOR PLANT ORGANIC
EXTRACTS ALL GO THROUGH THE
METHOD, MARINE ORGANIC EXTRACTS
DO.
GO THROUGH A SIMILAR METHOD BUT
FOR EXAMPLE THE MARINE AQUEOUS
GOES THROUGH A DIFFERENT METHOD
THAN OTHERS.
IT CAN CHANGE DEPENDING UPON THE
TYPE OF EXTRACT BEING PRE
FRACTIONATED.
>>THANK YOU.
ANOTHER FOR DR. O'KEEFE.
YOU PRESENTED A LOT OF DATA ON
THE RESOURCES BEING DEVELOPED
BUT WHAT DOES YOUR GROUP DO TO
ADVANCE AS NATURAL THERAPEUTICS
IS.
>>WE WORK WITH A VARIETY OF
FOLKS.
IN THE NCI, THERE IS THE NCI
NEXT PROGRAM WHICH CAN TAKE
PROJECTS FROM SOMETHING THAT IS
DISCOVERED AND HAS SOME BASIC
DATA UP THROUGH CLINICAL
DEVELOPMENT OF THAT.
WE HAVE A PROJECT I'M WORKING
WITH FOLKS AT THE CHILDREN'S
HOSPITAL PHILADELPHIA RIGHT NOW
FOR THAT SORT OF THINGS.
WE ALSO HAVE A STEPPING STONES
PROGRAM.
ALSO HELPS RESEARCHERS WITH
GRANTS TRY AND MOVE THINGS DOWN
THE TRANSLATIONAL LINE.
>>THANK YOU.
MOVING TO DR. ROGER LININGTON.
SOMEONE WANTS TO KNOW HOW CAN
PEOPLE PARTNER OR HOW DO YOU
FIND PEOPLE TRAINED TO DO
HIGH-THROUGHPUT SCREENING IN
THEIR PARTICULAR DEPARTMENT THEY
DON'T NECESSARILY HAVE ALL THE
NECESSARY RESOURCES TO DO ALL OF
THE PARTS OF THIS.
SO DO YOU HAVE ANY SUGGESTIONS
FOR HOW PEOPLE WHO ARE DEFICIENT
IN ONE ASPECT OR ANOTHER CAN
FIND PEOPLE TO PARTNER WITH?
>>THAT'S A GOOD QUESTION.
I THINK THE NUMBER OF GROUPINGS
WHO ARE EQUIPPED TO DO BOTH
SIDES EQUALLY IS RELATIVELY LOW.
I WOULD SAY BOTH OF THOSE FIELDS
ARE SORT OF RICH IN ROBUST
FIELDS WHICH HAVE HUNDREDS OF
INVESTIGATORS IN THEM.
SO CERTAINLY ON THE METABOLOMICS
AND SCREENING SIDE METABOLOMICS
IS A ENORMOUS SUBJECT AREA,
METABOLOMICS ASSOCIATION OF
NORTH AMERICA IS A PLACE TO
START.
I WOULD SAY THAT THERE IS A
DISCONNECT AT THE MOMENT BETWEEN
THE TIME REQUIRED TO DO
HIGH-THROUGHPUT SCREENING ON
50,000 WELLS AND THE TIME TO
REQUIRE MASS SPECTROMETRY DATA
ON 50,000 WELLS.
THE MASS SPEC DATA ACQUISITION
IS SLOWER AND THAT'S A
CHALLENGE.
ONE OF THE THINGSING THAT WE ARE
WORKING ON AT THE MOMENT
MULTIPLEXING METHODS TO ALLOW
YOU TO ACQUIRE THOSE MASS
SPECTROMETRY DATA AS
COMPUTATIONAL AND DECONVOLUTE
THEM AFTERWARDS.
WHEN THAT IS RELEASED, THAT WILL
REDUCE THE AMOUNT OF MACHINE
TIME REQUIRED.
THEN CONTINUE MAKES ITABLE TO
USE DEPARTMENTAL CONTRACT
FACILITIES MASS SPEC FACILITIES
WITHOUT PUNISHINGLY HIGH COSTS
FOR ACCESS TO INSTRUMENT TIME.
I THINK THERE ARE TECHNOLOGIES
COMING ALONG WHICH WILL
DRAMATICALLY DECREASE THE COST
TO DATA ACQUISITION AND
HOPEFULLY IMPROVE THROUGH PUT
AND MAKE IT EASIER FOR PEOPLE TO
DO THAT.
>>THANK YOU.
AND THEN ONE MORE QUESTION.
IT'S A BIT OF A HYBRID BETWEEN
YOU, BARRY AND ROGER.
FOR NP ANALYST, THE PERSON IS
ASKING, IS THERE EXISTING MS
DATA ON THE NCI NATURAL PRODUCTS
LIBRARY?
IF SO, IS THERE A WAY TO COMBINE
WITH MY BIOASSAY DATA TO TRY TO
FIGURE OUT WHAT THE LIBRARY IS
RESPONSIBLE FOR CERTAIN
ACTIVITIES?
>>THAT'S A GREAT QUESTION.
WE WOULD LOVE TO ACQUIRE DATA ON
THE WHOLE LIBRARY.
THAT'S A PRETTY AMBITIOUS
OBJECTIVE.
THERE ARE A LOT OF FRACTIONS IN
THERE BUT WE ARE RUNNING A PILOT
AT THE MOMENT.
WE WILL RUN MASS SPEC DATA ON A
SET OF 50,000 FRACTIONS AND
THOSE DATA WILL BE RETURNED TO
THE NCI AND SO PROVIDED THAT YOU
WORK WITH THE NCI TO DEVELOP
YOUR MTA, IN PRINCIPLE THOSE
DATA COULD BE MADE AVAILABLE TO
YOU.
SO YES, WE ARE STARTING AN EARLY
PILOT AT THE MOMENT AND WE'LL
SEE HOW THAT GOES AND WITH LUCK
WE WILL BE ABLE TO DO MORE IN
THE FUTURE.
>>ANYTHING ELSE TO ADD, BARRY?
>>JUST ONE THING TO FOLLOW-UP
WHAT ROGER SAID.
WORN OF THE ISSUES WE DEAL IN
NATURAL PRODUCTS IS ECK QUITABLE
DISTRIBUTION AND BENEFIT SHARING
WITH COUNTRIES THAT HAVE ALLOWED
THESE COLLECTIONS TO TAKE PLACE.
IF WE DID METABOLOMICS ON THE
WHOLE NCI LABORY AND MADE NA
GLOBALLY AVAILABLE TO EVERYONE
FOR FREE AND WITHOUT ANY SORT OF
AGREEMENT TO ENABLE BENEFIT
SHARING WITH HOST COUNTRIES,
THAT REALLY WOULD GO AGAINST THE
AGREEMENTS WITH THOSE HOST
COUNTRIES THAT ALLOWED THE
COLLECTIONS TO TAKE PLACE IN THE
FIRST PLACE.
AND SO WHAT WE ARE TRYING TO DO
IS WORK OUT MECHANISMS THAT ARE
EQUITABLE FOR THEM AS WELL SO
PEOPLE WILL BE WILLING TO CYB AN
MTA THAT GAINER TEASE SOME
BENEFIT SHARING RIGHTS TO GET
ACCESS TO THAT LARGE DATASET SO
THOSE HOST COUNTRIES CAN STILL
HAVE A SEAT AT THE TABLE SHOULD
ANYTHING BE DEVELOPED.
>>ALL RIGHT.
ONE MORE QUESTION FOR ROGER.
HOW DO YOU TEST FOR SYNERGISTIC
EFFECTS OF CONSTITUENTS PLANT
BASED NATURAL PRODUCTS?
IT IS ONE WE THINK ABOUT A LOT.
>>THIS STAY REALLY INTERESTING
PROBLEM.
SO THE CURRENT VERSION OF THIS
ONLY TAKES SINGLE AGENTS.
IT ASSUMES EVERY AGENTS ACTS ON
ITS OWN.
SO VERY RECENTLY A GROUP JUST
PUBLISHED A PAPER IN THE -- IS
IT PUBLISHED YET?
IF IT'S NOT PUBLISHED IT'S
COMING OUT ANY SECOND IN THE
JOURNAL OF NATURAL PRODUCTS.
SO YOU CAN MAKE COMPUTATIONAL
PAIRS ESSENTIALLY, WHERE YOU
TAKE EVERY COMPONENT AND YOU
COMPARE IT WITH EVERY OTHER
COMPONENT AND YOU MAKE THESE
PAIRINGS AND THEN ALLOW THE
STATISTICAL PROGRAM TO SEE THERE
ARE ANY PAIRING THAT SHOWS UP
REPEATEDLY IN THE DATASET TO
START TO FIND EXAMPLES WHERE A
ALONE DOESN'T HAVE ANY EFFECT, B
ALONE DOESN'T HAVE ANY EFFECT
BUT WHEN YOU SEE THE AB PAIR YOU
DO SEE THE EFFECT.
THIS IS ONE WAY TO LOOK AT THAT
SYNERGISTIC.
IT DOESN'T TAKE INTO ACCOUNT
FAMILY-WIDE GROUPINGS.
>>THANK YOU.
QUESTION FOR DR. MANDE HOLFORD.
YOU GAVE SOME PRETTY INTERESTING
IDEAS FOR RESOURCES FOR THESE
VENOM PRODUCING ORGANISMS.
DO YOU HAVE AN OPTIMISTIC
TIMEFRAME FOR WHEN YOU THINK
THEY MIGHT BE READY FOR
PRIME-TIME.
>>OPTIMISTICALLY I WOULD SAY
HOPEFULLY IN THE NEXT 5 YEARS,
ALL DEPENDING ON GRANT FUNDING.
WHAT WE CAN AND CAN'T DO.
THE KNOWLEDGE BASE CAN COME ON
PRETTY QUICKLY WITH VERY LOW
FUNDING IS POSSIBLE FOR US TO
COLLATE THE DATA THAT IS ALL
RIGHT OUT THERE, WHAT IS NEEDED
TO REALLY MAKE IT USEFUL ARE
MORE GENOMES.
SO AS GENOMES BECOME CHEAPER AND
PEOPLE ARE ABLE TO DO MORE
GENOMES, THERE ARE ONLY A FEW, A
FEW SNAKES, PLATYPUS HAS BEEN
DONE BUT IN TERMS OF MARINE
ORGANISMS THERE WERE VERY FEW
OTHER THAN NEDARIANS AND THE FOX
JELLYFISH AND THINGS OF THAT
SORT.
SO WE JUST NEED MORE GENOMES BUT
I THINK DRIVING THAT KNOWLEDGE
BASE WOULD HELP TO GALVANIZE THE
COMMUNITY AND HELP STANDARDS AND
PROTOCOLS SO WE CAN SHARE DATA
ROBUSTLY AND WITHOUT QUESTION
ABOUT QUALITY AND DATA.
AND THAT CAN COME ON LINE QUITE
FASTER THAN THE ORGANOIDS.
>>ONE MORE QUESTION FOR BARRY.
CAN YOU GIVE ANY EXAMPLES OF
THERAPEUTICS THAT HAVE COME
SPECIFICALLY OUT OF THE NCI
NATURAL PRODUCTS LIBRARY?
>>OVER THE YEARS THINGS
INCLUDING TAXOL WERE REGALLY
COLLECTED THROUGH THE NCI
PROGRAM.
-- SIGNIFICANT PARTICIPATIONING
AND NOW SOLD AS HALLOW DEN, A
COUPLE OF ANTI-CANCER AGENTS.
THE PROTEIN GRAY BITS IN IS
CURRENTLY IN CLINICAL TRIALS FOR
SARS-COV-2 PREVENTION.
>>WONDERFUL.
CATHERINE DO WE HAVE ANYMORE
TIME OR DO WE NEED TO MOVE ON?
>>LET'S TAKE ONE MORE AND THEN
ANYTHING WE DIDN'T GET TO, DON'T
WORRY, WE WILL GRAB THEM FOR
LATER BUT WE NEED TO MOVE ON TO
OUR NEXT SESSION.
SO ONE FINAL QUESTION YOU WANT
TO POSE?
>>SURE.
I GUESS ANOTHER FOR BARRY.
CAN THESE LIBRARIES BE UPSCALED
WHEN THE MOLECULES ARE FOUND,
FOR EXAMPLE, PARTICULARLY
COMPLEX MOLECULES THAT CAN'T BE
SYNTHESIZED, IS THERE POTENTIAL
TO OBTAIN ENOUGH PRODUCTS TO
KEEP THE PIPELINE ROLLING?
>>YES.
THAT IS A GOOD POINT.
AND ONE OF THE WAYS WE HAVE
BUILT THIS PROGRAM WAS ON
PARALLEL PROCESSING.
SO THE SAME WAY WE MIGHT DO 88
FRACTIONATION SIMULTANEOUSLY,
WITH 215 MILLIGRAMS EACH, WE
DOCK THAT ALL WITH ONE ORGANISM
AND THE SAME WAY WITH THE SECOND
STAGE PURIFICATION WHERE WE ARE
DOING 22 SUB FRACTIONS WITH ONE
MILLIGRAM INJECTED.
WE DOCK THAT WITH 44 THINGS
OVERNIGHT ON ONE INSTRUMENT.
WE HAVE 3 OF THOSE AND CAN DO
OVER 100 A NIGHT.
WE CAN DO THAT WITH 5 MILLIGRAM
INJECTIONS ON THE SAME COLUMNS
FROM THE SAME THING.
SO WE COULD PROCESS 20 GRAMS OF
EXTRACT IN LESS THAN A WEEK TO
GET THE AMOUNT OF MATERIAL
NECESSARY FOR THAT FIRST ANIMAL
TRIAL OR TO MOVE THINGS FURTHER
DOWN.
AND THEN AS FAR AS NEW THINGS
CONCENTRATING ON CULTURAL
ORGANISMS SO WE CAN SCALE THOSE
UP AGAIN WITH PROCESSING AND THE
FACILITY WE BUILT.
>>THANK YOU VERY MUCH.
>>THANK YOU TO ALL OF OUR
SPEAKERS.
WONDERFUL TALKS AND FASCINATING
AND THE QUESTIONS HAVE BEEN
FLOWING.
SO WE'LL GET ANY ADDITIONAL
QUESTIONS OUT TO THE GROUP.
I'M GOING TO TURN THINGS OVER TO
PATRICK TO TAKE IT INTO OUR NEXT
SESSION WHERE WE WILL HEAR FROM
OUR FELLOW NIH COLLEAGUES WITH
SOME THEIR PRIORITIES AROUND
THIS RESEARCH SO PATRICK TAKE IT
AWAY.
>>WE ARE MOVING INTO THE
SESSION FROM OUR NIH PARTNERS
AND IN PARTICULAR, ON THEIR
PERSPECTIVES ON THE WEBINAR
THEMES WE HAVE HEARD AND NATURAL
PRODUCTS RESEARCH IN THE CONTEXT
OF THEIR INSTITUTE OR CENTER
PRIORITIES.
JOINING US TODAY ARE DR. YALI FU
FROM NCI'S DEVELOPMENTAL
THERAPEUTICS PROGRAM; DR. D.P.
MOHAPATRA FROM THE NATIONAL
INSTITUTE OF NEUROLOGICAL
DISORDERS AND STROKE'S PAIN,
SOMATOSENSATION, AND
GLIA/NEUROIMMUNE BIOLOGY
PROGRAM; DR. MICHELLE BOND FROM
THE NATIONAL INSTITUTE OF
GENERAL MEDICAL SCIENCES'
DIVISION OF PHARMACOLOGY,
PHYSIOLOGY AND BIOLOGICAL
CHEMISTRY; AND DR. RYAN RANALLO
FROM THE NATIONAL INSTITUTE OF
ALLERGY AND INFECTIOUS DISEASES
AND CO-CHAIR OF THE TRANS-NIH
MICROBIOME WORKING GROUP.
WE POSED A FEW QUESTIONS TO OUR
COLLEAGUES TO GUIDE THEIR
COMMENTS TODAY:
WE'LL START WITH THE FIRST
QUESTION WHICH IS, HOW DO THE
EMERGING IDEAS IN NATURAL
PRODUCTS RESEARCH PRESENTED IN
THIS WEBINAR INTERSECT WITH YOUR
IC STRATEGIC PLAN?
I DIWANT TO THE START FIRST WITH
RYAN FIRST.
>>THANK YOU, PATRICK, THANK YOU
FOR INVITING ME AND THANKS FOR
ALLOWING ME THE OPPORTUNITY TO
SPEAK.
IN TERMS OF PREPARATION FOR MY
COMMENT, I THINK I HAVE AT LEAST
SOME ASPECT OF ALL THREE TALKS I
CAN TALK ABOUT.
WE DON'T HAVE A DEDICATED
PROGRAM TO NATURAL PRODUCT
RESEARCH BUT AS I THOUGHT ABOUT
WHERE THIS INTERSECTS, THE
NATURAL PRODUCT FOCUS AREA
DOESN'T INTERSECT WITH NIAID'S
ANTIBIOTIC RESISTANCE RESEARCH
FRAMEWORK.
IT'S PART OF OUR OVERALL
STRATEGIC PLAN AND WE HAD A
FORWARD-LEADING DOCUMENT PUT OUT
IN 2019 AND PART OF THAT
DOCUMENT TALKS ABOUT SOME OF THE
ASPECTS OF HIGH-THROUGHPUT
SCREENING FOR NEW ANTIBIOTICS.
AND ONE SECTION WITHIN THERE AND
I'LL QUOTE FURTHER, EXPLORING
NATURAL PRODUCTS, THE SOURCE OF
MANY TWISTING ANTIBIOTICS COULD
ALSO ENHANCE LIBRARIES OF NEW
CHEMICALS STARTING POINT FOR
ANTIBIOTIC COMPOUNDS.
SO OUR INSTITUTE'S MISSION IS TO
SUPPORT BASIC AND APPLIED
RESEARCH TO BETTER UNDERSTAND
TREAT AND ULTIMATELY PREVENT
DISEASES.
A LOT OF THE NATURAL PRODUCT
RESEARCH FOCUSES ON
ANTIMICROBIALS BUT ALSO SOME
REAL INNOVATION THAT IS MAYBE I
CAN TOUCH ON LATER IN TERMS OF
HOW THIS WORKS WITH MICROBIAL
ECOLOGY AND OTHER MICROBIAL
PRODUCTS THAT WE ARE LEARNING
ABOUT.
I'LL STOP THERE FOR TIME AND LET
OTHERS SPEAK.
THANK YOU.
>>THANK YOU.
DID ANY OTHER PO WANT TO THE
VOLUNTEER TO CHIME IN NEXT?
>>I'M MICHELLE BOND FROM THE
INITIAL INSTITUTE OF GENERAL
MEDICAL SCIENCE.
SO THANK YOU PATRICK AND ALL FOR
MY PARTICIPATION TODAY.
THERE WERE SOME REALLY GREAT
THINGS THAT WE GOT TO HEAR
ABOUT, BOTH FROM THE STANDPOINT
OF TECHNOLOGIES THAT ARE
AVAILABLE AND THE QUESTIONS THAT
CAN BE ANSWERED WITH THEM.
SO, WHAT I'LL POINT OUT IS THAT
NIGMS SUPPORTS BASIC RESEARCH
THAT INCREASES OUR UNDERSTANDING
OF BIOLOGICAL PROCESSES AND LAYS
THE FOUNDATION FOR ADVANCES OF
DISEASE, DIAGNOSIS AND TREATMENT
AND PREVENTION.
AND SO, RATHER THAN HAVING A
PARTICULAR FUNDING OPPORTUNITY
ANNOUNCEMENT OR SOMETHING LIKE
THAT TO TALK ABOUT, WHAT I THINK
IS IMPORTANT TO POINT OUT IS
THAT MANY OF THE THINGS THAT
WERE DISCUSSED TODAY, ALIGN IN
THE SENSE THAT NIGMS SUPPORTS
TRAINING AND DEVELOPMENT FOR
BOTH INDIVIDUALS AND
INSTITUTIONS, RESEARCH PROJECT
GRANTS, LATER STAGE TECHNOLOGY
DEVELOPMENT AND DISSEMINATION
SUCH AS RPDT CENTERS AND
TECHNOLOGIES, USER RESOURCES OR
COMMERCIALIZATION THROUGH A
NUMBER OF DIFFERENT FUNDING
OPPORTUNITIES.
AND SO I'D BE HAPPY TO TALK
ABOUT THOSE IN MORE DETAIL BUT I
THINK THERE IS A PLACE FOR
NATURAL PRODUCTS RESEARCH IN
MANY OF THOSE INDIVIDUAL AREAS
ALL THE WAY FROM TRAINING
THROUGH COMMERCIALIZATION AND I
WILL STOP AND ANSWER QUESTIONS
AS THEY COME UP.
>>THANK YOU, MICHELLE.
DP WOULD YOU LIKE TO GO NEXT.
>>SURE.
THANK YOU AGAIN FOR INVITING US
TO THIS REALLY EXCITING -- I'M
VERY INTERESTED IN WORK ON VENOM
FOR PAIN.
SO IT WAS REALLY WONDERFUL
LISTENING TO THAT LECTURE.
FROM NINDS SIDE, WE ARE
INTERESTED IN ALL STARTING FROM
BASIC SCIENCE, THERAPEUTIC
DEVELOPMENT, MANAGEMENT AND IN
FACT LOOKING INTO MY OWN YEARS
OF INTEREST IN BIOLOGY NATURAL
PRODUCTS HAVE BEEN TREMENDOUSLY
BENEFICIAL FOR THIS AREA.
AND NATURAL PRODUCTS HIGHLIGHTED
AS HEAVILY INTERESTED IN NATURAL
PRODUCTS.
NEW JEN, THERAPEUTICS THROUGH
INITIATIVE LONG TERM.
WE HAVE BEEN SUPPORTING A LOT OF
STUDIOS AND WE HAVE REALLY BIG
THINGS FOR A DIFFERENT PROGRAM
THAT WE HAVE WE HAVE TIME BUT
I'M HAPPY --
>>THANK YOU VERY MUCH.
AND DR. YALI FU.
>>THIS IS YALI FU FROM THE
NATIONAL CANCER INSTITUTE.
I WANT TO CONGRATULATE MY
COLLEAGUES AT THE NCCIH FOR THIS
EXCITING WEBINAR.
I LEARNED A LOT.
IT'S EXCITING TO HEAR THIS NEW
DEVELOPMENT PRESENTED BY ALL
THREE SPEAKERS.
I'M FROM THE SAME DIVISION AS
FIRST SPEAKER, DR. O'KEEFE, AS
MANY OF YOU KNOW.
NCI HAS FRANK LONGO HISTORY OF
COLLECTING AND SCREENING AND
LOOKING AT ANTI-CANCER AND
ANTI-HIV AGENTS FROM THE NATURAL
PRODUCTS AND THE COLLECTIONS
THAT DR. O'KEEFE TALKED ABOUT
CAME FROM THAT PAST MORE THAN 50
YEARS OF HISTORY.
AT THIS TIME, IN TERMS OF GRANT
SUPPORT, WE STILL HAVE NATURAL
PRODUCT DISCOVERY PROGRAM.
LIKE BARRY ALLUDED TO.
WE HAVE A NEXT PROGRAM WHICH
SUPPORTS NEW AGENTS THAT IS NOT
JUST LIMITED TO NATURAL PRODUCTS
BUT ALSO NEW CHEMICAL ENTITIES,
THERAPEUTIC APPROACH AND THE
STEPPING STONE PATHWAY THAT WE
HAVE IS SUPPORTING EXTRAMURAL
FUNDED RO1 PROJECT GENERATED
LEADS THAT NEED A LITTLE BIT OF
A BOOST.
SO NCI CAN INVOLVE SOME INTERNAL
DEVELOPMENT RESOURCES TO HELP
ACADEMIC RESEARCHERS TO PUSH
FORWARD THESE LEADS FOR FURTHER
DEVELOPMENT.
FROM THE NATURAL PRODUCTS
STANDPOINT, WE ARE STILL VERY
INTERESTED IN ALL SORTS OF
NATURAL PRODUCTS.
HOW DOES THIS, THE LANDSCAPE
CHANGE OVER THE PAST 10-15
YEARS?
AS YOU CAN SEE THAT LIKE
DR. ROGER LININGTON SAID AS
OPPOSED TO HAVING THE
INTERSECTION OF CHEMISTRY WITH
THE BIOLOGICAL ACTIVITY DURING
THE ITERATIVE FRACTIONATION.
THERE IS A URGENT NEED LIKE
DR. O'KEEFE MENTIONED FOR
HIGH-THROUGHPUT AND HIGH SPEED
DECONVOLUTION AND IDENTIFYING
DERATIFICATION, IDENTIFYING
INTERESTING LEADS.
IN ADDITION TO THE TRADITIONAL
WAY OF THINKING ABOUT FINDING
NEW NATURAL PRODUCTS AS
THERAPEUTIC AGENT WHETHER FROM
VENOM OR MY REASON ORGANISMS OR
MICROBES OR PLANTS, THE --
MARINE -- WE ARE LOOKING AT A
LOT OF IMMUNOLOGY AS WE KNOW,
AND WE CAN LOOK AT THE NATURAL
PRODUCTS IN TERMS OF HOW THEY
MODULATE IMMUNE SYSTEM AS
OPPOSED TO JUST ONE SIMPLE
PROTEIN TARGET AND THINKING IN
TERMS OF COMBINATION THERAPY
EITHER WITH CHEMO OR WITH
IMMUNOAGENTS.
IN ADDITION, WE ALSO LOOKING AT
THE ADDITIONAL CHEMISTRY
PERSPECTIVE IN TERMS OF
MONITORING, IN TERMS OF
GENERATING NEW LEADS AND WE HAVE
PEOPLE LIKE -- WORKING ON THE
NEXT GENERATION OF NEW AGENTS
AND AND MANIPULATING COMPLEX
NATURAL PRODUCTS.
AND ANOTHER INTERESTING TWIST WE
SEE RECENTLY IS A PLANT-BASED
VESICLE DELIVERY AGENT.
AND SO THESE ARE CLEARLY WE NEED
NEW TOOLS AND TECHNOLOGIES TO
MOVE THE NATURAL PRODUCT FIELD
TO THE NEXT LEVEL.
TODAY I THINK WE HEARD ABOUT
THESE NEW DEVELOPMENTS.
WE DO NEED THIS FIELD TO
REINVENT OURSELVES LIKE THE
SPEAKERS HAVE SHOWN.
SO THE PUBLIC AND THE GENERAL
PUBLIC HEALTH CAN BENEFIT STILL
FROM THE HUGE RESERVOIR OF
NATURAL RESOURCES.
THANK YOU.
>>THANK YOU VERY MUCH.
NOW I WOULD ALSO LIKE TO EXPRESS
NCCIH'S ANSWER TO THIS QUESTION
AS WELL IN THE CONTEXT OF WHAT
WE HAVE HEARD FROM THE WEBINAR
SO FAR.
AND THAT'S THAT NCCIH HAS A
BROUGHT INTEREST IN STUDYING THE
BIOLOGICAL ACTIVITIES OF NATURAL
PRODUCTS INCLUDING PREBIOTICS,
PROBIOTICS, DIETARY SUPPLEMENTS,
BOTANICALS AND VITAMINS AND
ALTHOUGH WE ARE ONE OF THE
SMALLER ICs AT NIH
HISTORICALLY AROUND HALF OF OUR
PORTFOLIO HAS BEEN IN NATURAL
PRODUCT FUNDING.
AND OUR NEW STRATEGIC PLAN FOR
2021-2025 REALLY EMPHASIZES AN
ORGANIZING PRINCIPLE CALLED
WHOLE PERSON HEALTH WHICH AIMS
TO IDENTIFY GAPS IN OUR
KNOWLEDGE ON THE PROGRESSION
FROM HEALTH TO DISEASE AND FROM
DISEASE TO HEALTH.
THIS FOR EXAMPLE, COULD INCLUDE
RESEARCH THAT EMPLOYS
BIOINFORMATIC METHODS TO ADDRESS
SYSTEMS LEVEL-TYPE RESEARCH AND
WE HAVE REALLY ROBUST FRAMEWORK
FOR CLINICAL RESEARCH AS WELL
FROM BASIC AND MECHANISTIC
THROUGH FEASIBILITY STUDIES
THROUGH PRAGMATIC CLINICAL
TRIALS.
AND SO WITH THAT, FIRST QUESTION
ANSWERED, I DID WANT TO MOVE TO
OUR SECOND QUESTION FOR OUR
PROGRAM STAFF.
THAT IS, COULD YOU HIGHLIGHT ANY
INITIATIVES OR FUNDING
OPPORTUNITIES FROM YOUR
INSTITUTE THAT FACILITATES
LEVERAGING NATURAL PRODUCTS
RESEARCH RESOURCES?
AND DON'T WANT TO PICK ON
ANYONE, BUT I GUESS WE COULD
START WITH GM FIRST.
>>ONE OF THE THINGS I WOULD
HIGHLIGHT IS WE SUPPORT VEST
RESEARCH.
SO WHEN WE ARE THINKING FUNDING
OPPORTUNITY ANNOUNCEMENTS THAT
MIGHT BE APPROPRIATE, IT'S
SOMETHING THAT IS COMING FROM
INVESTIGATORS WHO ARE INTERESTED
IN A PARTICULAR QUESTION AND
THOSE ANSWERS.
SO, THE TYPES OF QUESTIONS THAT
INDIVIDUALS OFTEN ASK, IN
ASSOCIATION WITH NATURAL
PRODUCTS EFFORTS AT NIGMS
INCLUDE WHAT ARE THE PRINCIPLES,
MECHANISMS AND PROCESSES THAT
UNDERLIE LIVING ORGANISMS AND
WHAT ARE THE PRODUCTS PRODUCED
BY THOSE ORGANISMS THAT MAKE UP
FOR THE FOUNDATION FOR THE
DEVELOPMENT OF THERAPEUTICS IN
THE LONG RUN?
AND WHERE ARE THESE COMPOUNDS
MADE?
NIGMS, AMONG OTHER AREAS,
SUPPORTS NATURAL PRODUCTS
DISCOVERY AND ANALYSIS AS WELL
AS NATURAL PRODUCTS SYNTHESIS
AND BIOSYNTHESIS.
I WOULD LIKING TO HIGHLIGHT A
COUPLE OF RESEARCH PROJECT GRANT
FUNDING OPPORTUNITY
ANNOUNCEMENTS THAT MAINLY HAVE
INTEREST, SPECIFICALLY OUR
TECHNOLOGY DEVELOPMENT SERIES.
SO IT IS A PAIR OF R21 AND RO1
FUNDING OPPORTUNITY
ANNOUNCEMENTS IN WHICH FOR THE
R21 THE OBJECTIVE IS TO PROVIDE
A PROOF-OF-CONCEPT.
IT'S VERY EXPLORATORY AND
REQUIRES THAT THERE IS NO
PRELIMINARY DATA WITHIN THE
APPLICATION.
THE TECHNOLOGY DEVELOPMENT RO1
IS FOR PROTOTYPE VALIDATION AND
THIS SHOULD NOT INCLUDE ANY SORT
OF BIOLOGICAL HYPOTHESES.
HOWEVER, IN MANY CASES, WE HAVE
INDIVIDUALS WHO ARE INTERESTED
IN ADDRESSING THIS AND IN THAT
CASE, THE PARENT RO1 IS
APPROPRIATE AS WELL AS OUR R35.
SO THIS IS THE LAST ONE I'D LIKE
TO HIGHLIGHT, WHICH IS THE
MAXIMIZING INVESTIGATORS
RESEARCH AWARD.
AND IT COMES IN TWO FLAVORS, ONE
IS FOR EARLY-STAGE INVESTIGATORS
AND THE SECOND IS FOR NEW
INVESTIGATORS AND ESTABLISHED
INVESTIGATORS.
AND THIS IS INTENDING TO SUPPORT
RATHER THAN SPECIFIC AIMS BY
PROGRAM OR RESEARCH WITHIN AN
INDIVIDUAL'S LAB AND WITH FEW
EXCEPTIONS IT WOULD BE THE AWARD
FROM NIGMS AND EFFORT
COMMITMENT.
THAT BEING SAID TO PURSUE WHAT
IS MOST INTERESTING WITHIN THE
NIGMS MISSION AND IS NOT TIED TO
SPECIFIC AIMS.
SO I WOULD SAY THAT THESE ARE
SOME OF THE MOST APPROPRIATE AND
INTERESTING FUNDING OPPORTUNITY
ANNOUNCEMENTS AND SHOULD ANYONE
HAVE ANY QUESTIONS, YOU'RE
WELCOME TO REACH OUT TO ME AND
I'D BE HAPPY TO TALK TO YOU.
>>THANK YOU.
NEXT WE CAN MOVE TO RYAN.
>>SO THAT WAS HARD TO FOLLOW.
THAT WAS REALLY WELL
ARTICULATED.
IN THE SAME VAIN, NIAID IS LARGE
LOO AN INVESTIGATOR-INITIATED
PORTFOLIO.
WE DRIVE A LOT OF FUNDING
DECISIONS BY OUR PUBLISHED PAY
LINE.
BUT I DO HAVE A COUPLE OF THINGS
THAT I WANTED TO HIGHLIGHT THAT
AS I SAID, IT REALLY ALLIANCE
WITH OUR STRATEGIC PLAN ON
ANTIMICROBIALS AND ANY TYPE OF
NATURAL PRODUCTS THAT CAN IMPACT
HOST IMMUNITY OF THE UM MINE
DEVELOPMENT AND IMMUNOLOGICAL
DISEASES.
WE RECENTLY JOINED UP WITH A
COUPLE OF ICs TO PARTICIPATE
IN A FOA CALLED -- IT'S A
PROGRAM ANNOUNCEMENT 21-253.
IT'S TITLED -- IT'S AN RO1, NO
CLINICAL TRIAL REQUIRED ENTITLED
IDENTIFICATION OF
CHARACTERIZATION OF BIOACTIVE
MICROBIAL METABOLITES FOR
ADVANCING RESEARCH ON HOST -- OR
DIET MICROBE HOST INTERACTIONS.
THE GOAL FOR NIAID'S PROGRAM AS
A PARTICIPATION ON THIS FOA IS
TO IDENTIFY MICROBIAL
METABOLITES THAT IMPACT
MICROBIAL VIABILITY, PATHOGEN
INVASION, THESE COMPOUNDS THAT
CAN DISARM PATHOGENS.
WE KNOW THERE ARE MICROBIAL
METABOLITES THAT ALTER AND
IMPACT HOST IMMUNE SYSTEM
DEVELOPMENT AND HOST IMMUNITY,
INFLAMMATION AND THE DEVELOPMENT
OF IMMUNOLOGICAL DISEASES.
AND WE ARE QUITE INTERESTED IN
THIS AREA.
IT ALLIANCE WITH MY ROLE AS THE
CO-CHAIR OF THE TRANSMICROBIOME
WORKING GROUP IN TERMS OF OUR
INTEREST, BUT WE RECENTLY FUNDED
FOUR RO1s ON THIS PROGRAM AND
SOME OF THESE RO1S ALIGN WITH
IDENTIFYING GENE CLUSTERS FOR
NATURAL PRODUCT PRODUCTION.
THE OTHER PROGRAM THAT WAS
LAUNCHED A FEW YEARS AGO IS
SOMETHING CALLED THE CHEMISTRY
CENTER FOR COMBATING ANTIBIOTIC
RESISTANT BACTERIA.
IT IS A PROGRAM THAT IS AN NIAID
LED INITIATIVE.
IT'S A CHEMISTRY CENTER, AN
INNOVATIVE CHEMISTRY CENTER
FOCUSED ON SYNTHESIS AND
DELIVERY OF RATIONALLY DESIGNED
LIBRARIES FOR USING GRAM
NEGATIVE ANTIBACTERIAL DRUG
DISCOVERY PROGRAMS TO CREATE A
LARGE COLLECTION OF CHEMICAL
MATTER SPECIFICALLY TARGETING
GRAM NEGATIVES ALIGNING WITH OUR
STRATEGIC PLAN, AS I SAID.
AND THEN THE LAST THING I WANTED
TO MENTION AND IT'S NOT A
FULL-FLEDGED PROGRAM BUT IT'S AN
EXAMPLE OUT OF MY PROGRAM.
MY PROGRAM IS A PORTFOLIO
MANAGER FOCUSED ON THE GUT
MICROBIOME.
AND ONE BACTERIA CLUSTER
PRODUCES A NATURAL HIGHLY TOXIC
COMPOUND TOXIN CALLED BOTCH LINE
UM TOXIN.
IT'S A NATURAL PRODUCT THAT IS
REFERRED TO AS BOTOX USED TO
TREAT THERAPEUTICALLY.
SO JUST WANTED TO SAY THAT IS A
NASCENT PROGRAM BUT IT IS ONE
THAT WE HOLD BOTH FROM A
BIODEFENSE PERSPECTIVE AND FOR
NATURAL PRODUCT DEVELOPMENT
PERSPECTIVE.
AND THEN THE LAST THING I'LL
MENTION AND AGAIN, JUST TRYING
TO GET IT ALL IN, IS THE NATURAL
PRODUCT BASED THERAPEUTICS
PROGRAM, IT'S BASICALLY LOOKING
AT ASPECTS OF THE GUT MICROBIOME
AND MICROBIAL ECOLOGY AS A WAY
TO PRODUCE BOTH MICRO-BASED
THERAPEUTICS AND SO-CALLED LIVE
BIOTHERAPEUTICS OR NEXT
GENERATION PROBIOTICS
PRINCIPALLY DIFFERENT IN TERMS
OF NATURAL PRODUCTS.
THEY OPERATE ON PRINCIPLES OF
DRUG DISCOVERY AND DRUG
DEVELOPMENT THAT WE DON'T QUITE
UNDERSTAND IN TERMS OF MICROBIAL
ECOLOGY.
AND THEN THE LAST PART ARE THE
PRODUCTS THESE MICROBIAL
COMMUNITIES PRODUCE.
WE KNOW THEY PRODUCE ANTIBIOTICS
AND TOXINS AND OTHER THINGS THAT
EFFECT THE OVERALL DYNAMICS OF
THESE ECOLOGYIES.
AND SO WITH THAT, I'LL STOP AND
SAY THOSE ARE MOSTLY OUR
INTEREST IN THIS AREA.
AND THAT WE DO HAVE A
PRE-CLINICAL SERVICES PROGRAM
THAT SUPPORTS ALL THERAPEUTIC
DEVELOPMENT.
IT'S A FREE SERVICE FOR
PROMISING DISCOVERIES TO HELP
MOVE PRODUCTS ALONG THE PRODUCT
DEVELOPMENT PIPELINE AND WE HAVE
PROVIDED IN VITRO AND MICROBIAL
TESTING, ANIMAL TESTING,
APPROXIMATE.
K, PD AND OTHER TYPES OF
THERAPEUTIC DEVELOPMENT TESTING.
AND I'LL STOP THERE.
>>THANK YOU, RYAN.
AND NEXT WE CAN MOVE TO DR.
MOHAPATRA.
SO, WE HAVE, AS I JUST ALLUDED
TO BEFORE, WE HAVE A LOT OF
DIFFERENT FUNDING OPPORTUNITIES
I HAVE A SLIDE I'D LIKE TO
SHARE.
>>ALSO CAN YOU SPEAK UP A
LITTLE BIT?
YOU'RE A LITTLE SOFT.
>>IS THAT BETTER NOW?
>>YES.
>>OKAY.
LET ME JUST SHARE -- LET ME KNOW
IF YOU CAN SEE MY --
>>WE CAN INDEED.
>>THROUGH THE NIH INITIATIVE OR
HELPING TO END ADDICTION LONG
TERM INITIATIVE, WE HAVE THREE
OF THE PROGRAMS IN THE PAIN
MANAGEMENT SIDE STARTING FROM
THE DISCOVERY.
YOU CAN SEE ON THE LEFT SIDE
FROM DISCOVERY WHERE GOOD
VALIDATION FOR THERAPEUTICS OR
PLANNING STUDIES TO DEVELOPMENT
AND THEN PRODUCING THE LEAD AND
THEN OPTIMIZE AND ALSO HAVE
PROGRAM WITH ANIMAL MODELS FOR
PAIN THERAPEUTIC PROGRAM.
AND ALSO SCREENING MULTIPLE
THERAPEUTICS LIKE SCREENING STEM
CELL-BASED ASSAYS AND NOW WE
HAVE HUMAN CELL-BASED GENE ASS
ASSAYS.
JOINT PAIN SPECIFIC AS MODEL
DEVELOPMENT AND THEN CLINICAL
TRIALS.
SO NATURAL URN OUTS ALL OF THESE
HERE WHERE YOU CAN UTILIZE THE
NATURAL PRODUCT TO UNDERSTAND
AND DISCOVER AND VALIDATE A
TARGET AND DEVELOP NEW
THERAPEUTICS AND UTILIZE NATURAL
PRODUCTS TO UNDERSTAND THE
BIOLOGY OF HUMAN PAIN CONDITION
AND THOSE NATURAL PRODUCTS ONCE
THEY HAVE A LEAD, THEY CAN GO
THROUGH THE THERAPEUTIC
DEVELOPMENT AND SCREENING
PROGRAMS BUT ALSO SMALL BUSINESS
PROGRAMS CAN SUPPORT THOSE
ALONGSIDE LIKE CLINICAL STUDIES
INCLUDING CLINICAL TRIALS.
AND JUST TO LET THE GENERAL
E-MAIL FOR THE INITIATIVE, IF
YOU'RE INTERESTED IN ANY OF
THESE, SEND AN E-MAIL TO THIS
SPECIFIC E-MAIL ID AND THEY WILL
SEND EACH INDIVIDUAL -- EACH OF
THESE PROGRAM AND THEY HAVE
CONTACTS FOR YOUR SPECIFIC
INTEREST.
IN ADDITION TO THESE INITIATIVES
AND NINDS, WE STILL REMAIN
HEAVILY INTERESTED IN THE
NATURAL PRODUCTS AND
UNDERSTANDING THE BIOLOGY OF
THESE AS WELL AS MANAGEMENT I'LL
STOP THERE.
>>THANK YOU, DP.
AND ON TO NCI.
>>HI.
NCI STILL ARE INTERESTED IN
NATURAL PRODUCTS.
I HAVE ALWAYS BEEN AND LIKE
NIGMS, WE SUPPORT ALL LEVELS OF
INVESTIGATOR-INITIATED PROJECTS
FROM R15, RL3, R21, R01 AND
PROGRAM PROJECT, P01.
WE HAVE CURRENTLY LONGSTANDING
PROGRAM PROJECT WITH A GROUP AT
THE -- HE WAS AT OHIO STATE
UNIVERSITY.
AND SO -- YES, IN COLLABORATION
WITH SEVERAL OTHER INSTITUTIONS
AND COMPANIES.
IN TERMS OF SPECIAL INITIATIVES,
RECENTLY TRANS-NCI, WE DEVELOPED
WITH ANOTHER -- JUST OUR
DIVISION, A DIVISION CANCER
TREATMENT AND DIAGNOSIS WITH
DIVISION OF CANCER PREVENTION
POPULATION SCIENCES AND OTHERS.
WE HAVE SENT OUT A NOSI CANIS
AND TREATMENT OF CANCER-RELATED
PAIN.
-- CANNABIS.
THIS IS STILL ACTIVE.
ONE CAN LOOK IT UP IF YOU'RE
INTERESTED.
IN ADDITION WE ARE ALSO
INTERESTED IN MICROBIOME AND HOW
DISPARITY RELATED PROJECTS IN
ADDITION TO NATURAL SOURCES AND
NEW NOVEL TARGETS USING NATURAL
PRODUCTS TOO.
IN ADDITION, SOME OF THESE VERY
POTENT TOXINS COULD BE USED AS
WARHEAD FOR THE -- DRUG
CONJUGATES TO DELIVER
SPECIFICALLY TO THE TARGET TUMOR
CELLS AND TUMOR ENVIRONMENT.
SO THESE ARE THE THINGS THAT I
LIKE TO HIGHLIGHT.
IF YOU HAVE ANY QUESTIONS, FEEL
FREE TO E-MAIL ME THANK YOU.
>>THANK YOU.
FROM THE NCCIH PERSPECTIVE, I
WOULD LIKE TO HIGHLIGHT A
FUNDING OPPORTUNITY IN BASIC AND
MECHANISTIC RESEARCH ON NATURAL
PRODUCTS AS AN EXAMPLE.
AND THIS IS A NOTICE OF SPECIAL
INTEREST OR NOSI THAT IS LINKED
TO THE PARENT RO1 OR R21 ON
FUNDAMENTAL SCIENCE RESEARCH ON
COMPLEMENTARY AND INTEGRATIVE
HEALTH APPROACHES.
AND SOME KEY POINTS FROM THIS
FUNDING OPPORTUNITY ARE
MECHANISMS OF COMPLEMENTARY AND
INTEGRATIVE HEALTH INTERVENTIONS
AND TECHNOLOGY DEVELOPMENT
RESEARCH.
AND FOR THE MECHANISMS OF CIH
INTERVENTIONS AREAS OF HIGH
PROGRAM PRIORITY COULD INCLUDE
EXPLORING THE MECHANISTIC
EFFECTS OF MULTIMODAL
INTERVENTIONS OR INTEGRATIVE
HEALTH APPROACHES ON ONE OR MORE
PHYSIOLOGICAL SYSTEMS AND THEIR
INTERACTIONS ON ANIMAL MODELS
AND IN IN TERMS OF THE
TECHNOLOGY AND METHOD
DEVELOPMENT COMPONENT OF THIS
FUNDING OPPORTUNITY, THIS
INCLUDES FOR EXAMPLE, TARGETED
AND UNTARGETED BIOINFORMATIC
APPROACHES THAT IDENTIFY ACTIVE
COMPONENTS IN A NATURAL PRODUCT
MIXTURE.
OR THE DEVELOPMENT OF PHENOTYPIC
MODELS CAPABLE OF ILLUMINATING
MECHANISMS OF ACTION.
AND AS DR. DR. MOHAPATRA
MENTIONED IN TERMS OF THE HEAL
INITIATIVE, NCCIH ALSO SIGNED ON
TO THE PHASED R61-R33 IGNITE
INNOVATION GRANT TO NURTURE
INITIAL TRANSLATIONAL EFFORTS
FUNDING OPPORTUNITY ANNOUNCEMENT
AND IF YOU'RE NOT FAMILIAR WITH
THESE MECHANISMS, IT'S BY-PART
FUNDING OPPORTUNITY WHERE -- TWO
PART -- SPECIFIC MILESTONES ARE
MET IN THE FIRST PHASE BEFORE
FUNDING IS GIVEN FOR THE
CONTINUATION OF THE GRANT AND
THE R33 PHASE.
THIS FUNDING OPPORTUNITY, WE AND
OTHER INSTITUTES THAT ARE SIGNED
ON TO THIS ANNOUNCEMENT ARE
FIRST INTERESTED IN DEVELOPMENT
OF NEW IN VITRO OR EX-VIVO
ASSAYS AND SCREENING EFFORTS TO
IDENTIFY NOVEL THERAPEUTIC
AGENTS FOR NEUROLOGICAL AND
NEUROMUSCULAR DISORDERS.
AND THAT REALLY IN THE R61 PHASE
SUPPORTS THE INITIAL DEVELOPMENT
REFINEMENT AND VALIDATION OF
THESE ASSAYS AND THEN THE R33
PHASE ITERATIVE SCREENING AND
CHARACTERIZATION OF THE
THERAPEUTIC AGENT FROM THE
SCREEN INCLUDING DESIGN AND
PREPARATION FOR FURTHER
CHARACTERIZATION OF OTHER AGENTS
RELATED TO THE INITIAL HITS
USING A MEDICINAL CHEMISTRY
APPROACH.
AND SO, SO WITH THAT SNAPSHOT OF
DIFFERENT FUNDING OPPORTUNITIES
AND HOW THE WEBINAR THEMES
INTERSECT WITH VARIOUS NIH
PRIORITIES, I WOULD NOW LIKE TO
THANK EACH OF OUR PROGRAM FERNAL
COLLEAGUES AND MOVE INTO THE Q&A
SESSION AND WE WOULD BE GLAD TO
TAKE SOME QUESTIONS FROM THE
CHAT.
THE FIRST QUESTION THAT WE HAVE
IS FOR DR. MOHAPATRA.
IT IS, IS THERE A MECHANISM FOR
BIOTECH COMPANIES TO ASSESS SOME
OF THE OPPORTUNITIES THAT YOU
MENTIONED?
>>ABSOLUTELY.
ALL THE DEVELOPMENT PROGRAMS AND
OPTIMIZING AND ALL OPEN TO --
ENCOURAGED TO APPLY.
AND THE I CAN GIVE YOU THE
NUMBER AND MORE THAN 60
COMPANIES ARE IN THE SBIR BASE
ON THE PAIN SIDE RIGHT NOW.
GOOD IF YOU'RE INTERESTED IN
THAT AND THEN LOOK INTO THE SBIR
PROGRAM AND WE GO DOWN TO THE
PROGRAM CONTACT AND MAKE
SPECIFIC INTEREST.
>>THANK YOU.
>>I'M GOING TO PICK UP A
QUESTION THAT CAME IN IN OUR
EARLIER SESSION WHICH IS, I'M
GOING DROP IT INTO THE CHAT
HERE.
IT WAS ONE ABOUT WHETHER OR NOT
THERE IS ANY EFFORT TO COLLECT
PATIENT DATA SINCE MANY PATIENTS
ARE TAKING -- I BELIEVE NATURAL
PRODUCTS, AND THEY ARE SORT OF
WONDERING POTENTIALLY COULD THIS
DATA PROVIDE A SIGNAL FOR THE
TYPE OF NATURAL PRODUCTS AND THE
TYPE OF CANCER SPECIFIED THERE?
I DON'T KNOW IF ANYBODY -- IF
ANY OF OUR SPEAKERS OR ANY OF
OUR PROGRAM FOLKS WOULD LIKE TO
MAYBE TAKE ON THAT QUESTION?
>>I CAN TAKE THAT.
PRIMARY HUMAN TISSUES ASSOCIATED
WITH PAIN AND PROCESSING PAIN,
LIKE ALL STAGES OF THE PAIN
PROCESSING IS BEING COLLECTED
FOR MULTIMODAL -- AND FOR ONE
AREA -- COLLECT THE DATA
ASSOCIATED, INCLUDING PREVIOUS
THERAPEUTIC DRUGS AND SO THOSE
METADATA ARE COLLECTED AND COULD
BE TAKEN INTO ACCOUNT WHEN
THESE --
[ INAUDIBLE ]
>>DR. O'KEEFE OR PATRICK, IF
THERE IS ANY THOUGHTS THERE?
YALI FU?
YOU'RE MUTED IF YOU WANTED TO
COMMENT ON THAT QUESTION AT ALL.
THE QUESTION ABOUT, IS THERE AN
EFFORT TO COLLECT PATIENT DATA
SINCE MANY ARE TAKING NATURAL
PRODUCTS, POTENTIALLY COULD THIS
DATA PROVIDE A SIGNAL FOR THE
TYPE OF NATURAL PRODUCT IN THE
CANCER TYPE?
>>THIS IS A LITTLE BIT
COMPLICATED, I THINK.
THERE ARE A LOT OF IN THE 15, 20
YEARS AGO, A BIG BOOST ABOUT
THAT SUPPLEMENT AND TAKING --
ARE PURE.
I HAVEN'T SEEN HOW THIS HAS
GUIDED THE CURRENT MOLECULAR
GENOMIC-BASED CANCER RESEARCH.
I HAVE TO SAY.
BUT I THINK WE SHOULD THIS KIND
OF DATABASE.
IT WOULD BE VARIABLE BUT SOME OF
THESE I DON'T KNOW LIKE A
DIVISION CANCER PREVENTION HAS
SOME KIND OF, THIS KIND OF MASS
DATA THAT I KNOW THEY DO HAVE
VITAMIN E, BUT I DON'T KNOW
ABOUT COMPLEX NATURAL PRODUCTS,
TAKING IT FOR YEARS AND YEARS
AND DO THEY HAVE LONGITUDINAL
AND DATASETS ON THIS.
>>THANK YOU.
I DON'T SEE ANY CONTINUING
QUESTIONS FROM THE VIDEOCAST.
AND I DID HAVE A QUESTION FOR
THE STAFF, PROGRAM STAFF THAT
ARE HERE, AND THAT IS THE USE OF
DIFFERENT FUNDING OPPORTUNITY
ANNOUNCEMENTS AND THE MECHANISM
YOU USE AT YOUR INSTITUTE.
IS THERE A PARTICULAR FUNDING
MECHANISM YOUR INSTITUTE TENDS
TO GRAVITATE TOWARDS FOR THE
AUDIENCE?
I'LL START BY ANSWERING THE
QUESTION ON BEHALF OF NCCIH AND
THE THAT IS THAT WHILE WE DO
ACCEPT INVESTIGATOR-INITIATED
APPLICATIONS, WE ARE ALSO QUITE
PRIVY TO THE NOSI.
SO WE GENERATE A LOT OF NOTICES
OF SPECIAL INTEREST, DECLARE A
PARTICULAR AREA THAT WE ARE
FOCUSING ON.
I KNOW THAT IS NOT THE SAME
ACROSS NIH AND I WANTED TO GIVE
THE OPPORTUNITY FOR MY
COLLEAGUES TO WEIGH IN ON THEIR
INSTITUTE.
>>THIS IS MICHELLE FROM NIGMS.
I WILL START AND EMPHASIZE AGAIN
THAT NIGMS IS VERY MUCH
INTERESTED IN
INVESTIGATOR-INITIATED EFFORTS.
SO, THE AREAS IN WHICH WE ARE
INTERESTED IN SUPPORTING
SCIENTIFIC RESEARCH ARE DEFINED
ON OUR WEBSITE.
THERE IS AN AGGRESSIVE WEB PAGE
WITH DIVISION CONTACTS AND THE
AREAS IN WHICH WE ARE INTERESTED
IN ADDITION, I THINK THAT THE
NIGMS AND 35 MERA IS ONE THAT IS
ROUTINELY HIGHLIGHTED IN THE
LAST FEW YEARS AS SOMETHING THAT
IS OF INTEREST FOR NIGMS TO
SUPPORT RESEARCH PROJECT GRANT
EFFORTS.
>>I CAN ADD TO THAT.
SO FROM NINDS PROSPECT, WE HAVE
REALLY GOTTEN -- IN TERMS OF
WHAT IS THE NEED?
WHAT IS THE GOAL?
WE TEND TO -- WHICH ARE MORE
LIKE A MECHANISM OR EVEN LIKE --
THERE ARE MECHANISMS LIKE
THERAPEUTIC PROGRAM AND -- THEY
HAVE A LOT OF LIKE CONTRACT AND
A LOT OF OTHER -- WHICH BRING
THE COLLECTIVE THEME OF DRUG
DEVELOPMENT SO THEY CAN REALLY
SUPPORT AND CHANNEL YOUR DRUG
DEVELOPMENT OR THERAPEUTIC
DEVELOPMENT FROM THE VERY BASIC
CONCEPT OF EARLY STAGES ALL THE
WAY THROUGH THE TRIALS AND THEN
ULTIMATELY PUSHING TOWARDS THE
PHASE II TRIALS.
SO WE TRIED TO, BASED ON A NEED
BASIS AND BASED ON WHAT THE GOAL
IS THERE.
THAT IS OUR APPROACH.
FOR MOST BASICS, WE TRY TO GO
THROUGH THE INVESTIGATOR
INITIATED BUT MANY COME WITH
THERAPEUTIC OR DEVICE
DEVELOPMENT BUT MORE TOWARDS THE
WELL STRUCTURED AND SUPPORTED
PROGRAM WHERE THERAPEUTIC
DEVELOPMENT CAN BE A TARGET.
>>NCI SIDE, I KNOW FROM MY
DIVISION WE ARE GRAVITATING
TOWARDS MORE TRADITIONAL
INVESTIGATOR INITIATED RO1s.
I THINK THAT TAKES A BIG PART OF
OUR OVERALL FUNDING PORTFOLIO.
WE HAVE SMALLER PROJECTS AND
R15, R21 AND R33 WHICH ARE
PHASE-IN PROJECTS WITH
MILESTONES REQUIREMENTS.
AND THEN WE HAVE PROGRAM
PROJECT.
WE HAVE A HUGE CHUNK OF R35 IS
FROM INVESTIGATORS.
THESE ARE REVIEWED NOT BY
SPECIFIC AIMS AND TRADITIONAL
RO1s BUT RATHER BY THE VISION
AND THE LONG TERM PERSPECTIVE OF
THE INVESTIGATOR.
AND ALL OF THESE ANNOUNCEMENTS
CAN BE FOUND FROM OUR WEBSITE OR
NIH GUIDE OF JUST A SEARCH UNDER
NCI.
OUR DIVISION OF CANCER
PREVENTION, I THINK THEY ARE
INTERESTED IN NATURAL PRODUCTS
AS A CHEMO PREVENTIVE AGENTS AND
THEN IN COMBINATION WITH --
CHEMO AND IMMUNOTHERAPY AS WELL.
SO, THESE ARE THE PROBABLY JUST
THE LANDSCAPE OF OUR FUNDING
PURCHASE RIGHT NOW.
>>GREAT.
THANK YOU.
AND GIVEN THAT WE ARE RIGHT AT
THE TOP OF THE HOUR, I DID WANT
TO THANK EACH OF THE PROGRAM
STAFF FROM EACH OF OUR SISTER
INSTITUTES AND THANK ALL THE
AUDIENCE AS WELL FOR THE
QUESTIONS AND I DID WANT TO NOW
MOVE INTO THE LAST PART OF OUR
AGENDA WHICH IS TO DR. HOP TO
OFFER A FEW CLOSING REMARKS TO
CLOSE US OUT.
>>THANK YOU, PATRICK.
I THINK MY OVERALL THEME FOR
TODAY IS, IT'S EXCITING TIMES.
IT'S EXCITING TIMES TO BE IN
NATURAL PRODUCTS RESEARCH.
I THINK WE HEARD SOME REALLY
INCREDIBLY STRONG TALKS FROM OUR
THREE SPEAKERS, DEVELOPING SOME
REALLY SOPHISTICATED RESOURCES
THAT ARE ONLINE OR WILL BE
COMING ON LINE VERY SOON, WHICH
I THINK IN GENDERS A LOT OF
ENTHUSIASM FOR THIS COMMUNITY.
AND FOR WHAT THE FUTURE HOLDS.
WE HEARD A LOT FROM THE NIH
FOLKS ABOUT THEIR CONTINUED
INTEREST IN COMMITMENT TO
NATURAL PRODUCTS RESEARCH
THROUGH A VARIETY OF WAYS.
THERE IS RESOURCES AVAILABLE
BOTH TO HELP INVESTIGATORS GET
THEIR FOOTED IN DOOR IN TERMS OF
GRANT FUNDING BUT ALSO RESOURCES
WE HEARD TO HELP PEOPLE IF THEY
HAVE REALLY STRONG PRODUCTS THAT
NEED A LITTLE BIT OF HELP WITH
DEVELOPMENT.
SO THERE IS INTERNAL RESOURCES
AS WELL AS GREAT RESOURCES.
SO I THINK THE FUTURE IS BRIGHT.
I KNOW THAT NCCIH AND THE REST
OF THE FOLKS OUR PARTNERS AT
NIH, CONTINUE TO BE INTERESTED
IN NATURAL PRODUCTS FOR ALL OF
THE OBVIOUS REASONS THAT WE
HEARD ABOUT TODAY.
AND SO, FOR THAT, I THINK THAT I
WOULD ENCOURAGE OUR AUDIENCE TO
KEEP SUBMITTING THE APPLICATIONS
AND KEEP COMMUNICATING WITH US
ABOUT YOUR IDEAS AND WE WILL DO
OUR BEST TO WORK WITH YOU AND
POINT YOU IN THE RIGHT DIRECTION
ABOUT THE BEST POTENTIAL TO
SUPPORT THIS IDEA.
AND WITH THAT, I GUESS I WILL
TURN IT OVER TO CATHERINE AND
WRAP THINGS UP.
>>THANK YOU SO MUCH, CRAIG AND
PATRICK AND THEN A HUGE THANK
YOU TO OUR SPEAKERS DR. ROGER
LININGTON.
DR. MANDE HOLFORD.
>>DR.O KEEP, OUR NIH PARTNERS.
DR. MOHAPATRA AND OTHERS.
THOSE WERE FASCINATING TALKS AND
WONDERFUL TO HEAR FROM EVERYONE
TODAY.
THANK YOU TO OUR AUDIENCE FOR
JOINING US FOR ASKING YOUR
QUESTIONS AND IF TWEE DIDN'T GET
TO A QUESTION THAT YOU HAD
TODAY, DON'T WORRY.
WE WILL COLLECT ANY UNANSWERED
QUESTIONS AND SHARE THEM WITH
OUR PLANNING TEAM.
AND I ALSO WANT TO REMIND YOU
THAT THIS WAS RECORDED BY THE
NIH VIDEOCAST SERVICE TODAY AND
IT WILL BE ARCHIVED AND STORED
ON THE NIH VIDEOCAST WEBSITE FOR
FUTURE VIEWING.
SO CIRCLE IN THERE AND SEE THESE
FASCINATING TALKS AND HEAR THESE
PERSPECTIVES TO YOUR HEART'S
CONTENT.
WE HOPE YOU'LL JOIN US ON APRIL
28 FOR OUR SECOND WEBINAR IN
THIS SERIES.
AND WE'LL BE BACK WITH WITH OUR
TEAM.
SO AGAIN, A HUGE THANK YOU AND
I'M GOING CLOSE IT OUT NOW AND
EVERYBODY HAVE A WONDERFUL
EVENING.
BYE-BYE.
THANK YOU VERY MUCH.