WELCOME TO OUR SECOND DAY OF THE
ICCVAM PUBLIC FORUM.
GLAD TO SEE SMILING FACES HERE
IN THE ROOM TODAY, HOPE ALL OF
YOU HAVE YOUR CUP OF COFFEE AT
HOME.
TODAY WILL BE A NICE DAY, WE
HAVE A BUNCH OF PUBLIC COMMENTS
COMING IN.
NICOLE WILL KICK US OFF WITH
SUMMARY OF WRITTEN PUBLIC
STATEMENTS AND SEVERAL PEOPLE IN
THE AUDIENCE WITH PUBLIC
COMMENTS TO COME IN, AND WE'LL
HAVE SEVERAL TALKS FROM ICCVAM,
NICEATM, DEPARTMENT OF
AGRICULTURE, DEPARTMENT OF
DEFENSE, NIH AND OTHERS WITH A
QUESTION AND ANSWER PERIOD AT
THE END.
LET'S GET STARTED ON DAY 2.
THANK YOU FOR COMING.
>> THANK YOU, JOHN.
SO, WE DO ALSO HAVE ADDITION TO
AGENDA TODAY, WHERE OUR
COLLEAGUE FROM THE V.A. OFFICE
OF RESEARCH AND DEVELOPMENT WAS
ABLE TO JOIN US TODAY, AND SO
WE'RE STILL HAVING A COUPLE
TECHNICAL ISSUES WITH THE ZOOM
MEETING SO HE WILL -- I'M NOT
SURE ANYONE HEARD YOU, JOHN,
BECAUSE YOU WERE MUTED.
WOULD YOU LIKE TO COME BACK UP
AND WELCOME EVERYONE AGAIN?
>> OKAY.
>> FOR THOSE OF YOU WHO ARE NOT
LIPREADERS, SORRY ABOUT THAT.
WELCOME TO DAY 2.
A REALLY GOOD DAY, A BUNCH OF
GOOD PUBLIC COMMENTS THAT ARE
GOING TO BE DOWN HERE IN A
COUPLE MINUTES, NICOLE WILL KICK
US OFF WITH SUMMARY OF WRITTEN
STATEMENT, SEVERAL PEOPLE IN THE
ROOM WILL DO PUBLIC COMMENTS,
SOME ONLINE AS WELL.
AND SEVERAL TALKS FROM THE V.A.,
NICEATM, ICCVAM, DEPARTMENT OF
AGRICULTURE, DoD, NIH, IF YOU
HAVE QUESTIONS TOWARDS THE END
LET US KNOW.
AND HOPEFULLY YOU HEARD ME THIS
TIME.
>> OKAY.
GREAT.
THANKS, APPARENTLY IT WAS JUST
THE ZOOM THAT WAS MUTED, THE
WEBCAST WAS STILL OKAY.
ALL RIGHT.
SO, AS JOHN MENTIONED, OUR
COLLEAGUE FROM THE V.A. OFFICE
OF RESEARCH AND DEVELOPMENT WILL
BE ABLE TO JOIN US TODAY, WE'LL
DO THAT PRESENTATION LATER IN
THE AGENDA.
FIRST WE'LL START WITH OUR
PUBLIC COMMENTS THAT WE'VE
RECEIVED.
I WILL DRAW YOUR ATTENTION TO
THE WRITTEN PUBLIC COMMENTS THAT
ARE AVAILABLE ON THE ICCVAM
WEBSITE, SPECIFICALLY ON THE
ICCVAM PUBLIC FORUM, THE SAME
PLACE YOU REGISTERED FOR THE
MEETING.
THERE ARE PDFs AVAILABLE OF
THE WRITTEN COMMENTS RECEIVED
FROM THE PHYSICIANS COMMITTEE
FOR RESPONSIBLE MEDICINE,
CRUELTY FREE INTERNATIONAL AND
HUMANE SOCIETY AND TWO OF THE
THREE GROUPS ARE GIVING ORAL
PUBLIC COMMENTS TODAY.
I'M GOING TO KICK OFF THE ORAL
PUBLIC STATEMENTS PORTION OF THE
AGENDA.
DO WE HAVE AMY KYLE ONLINE?
OUR FIRST PUBLIC COMMENTER.
IF NOT WE CAN CERTAINLY CIRCLE
BACK AND -- OKAY.
WE DO HAVE JESSE SALK FROM
TWINSTRAND BIOSCIENCE ONLINE.
WE'LL TURN IT OVER TO JESSE.
THANK YOU FOR HAVING ME AND
LETTING ME GIVE A COMMENT.
I'M HERE AT 6 A.M. IN SEATTLE,
SO HOPEFULLY THINGS ARE GOING
WELL AT 9 A.M. ON THE EAST
COAST.
I'M GOING TO TALK ABOUT NEW
TECHNOLOGY WE THINK IS GOING TO
BE VERY SIGNIFICANT FOR THE
FUTURE OF GENOMIC SAFETY
TESTING, WANTED TO BRING THIS TO
THE PUBLIC'S ATTENTION.
THIS IS SOMETHING WE'VE BEEN
WORKING ON WITH A VARIETY OF
COLLABORATORS WHO ARE AT FDA,
OTHER REGULATORY BODIES, HESSE
AND WHAT NOT.
THE BROAD CATEGORY OF TECHNOLOGY
IS AIR CORRECTED SEQUENCING, NEW
TOOLS THAT A ALLOW EXISTING DANK
EXISTING DNA
SEQUENCERS TO BE MORE ACCURATE
TO USE GENOMIC SAFETY ASSAYS
WHICH ARE SELECTION BASED IN
ANIMALS OR BACTERIA TO
POTENTIALLY BE REPLACED OR
AUGMENTED USING DIRECT
SEQUENCING OF DNA.
I'M WITH TWINSTRAND BIOSCIENCE
IN SEATTLE, TECHNOLOGY OUT OF
THE UNIVERSITY OF WASHINGTON,
DEVELOPED DUPLEX SEQUENCING,
HIGH ACCURACY FORM OF AIR
CORRECTED DNA SEQUENCING.
THE WAY THIS WORKS WITHOUT GOING
INTO ALL THE DETAILS IS THAT WE
LABEL INDIVIDUAL DNA MOLECULES
WITH SPECIAL MOLECULAR BARCODES
THAT RECAPITULATE SOMETHING THAT
HAPPENS IN NATURE, WHICH IS
DURING CELL REPLICATION TO
ENSURE HIGH FIDELITY OF COPYING
OF CELLS.
WE ESSENTIALLY ARE ABLE TO READ
THE INDIVIDUAL -- THE SEQUENCES
OF INDIVIDUAL STRANDS OF
INDIVIDUAL MOLECULES AND COMPARE
THE SEQUENCE TOGETHER AT THE END
WHICH ALLOWS US TO ACHIEVE ERROR
RATES BETWEEN LOW 1 IN 10
MILLION.
THIS REMOVES TRADITIONAL ERRORS,
SEEN IN CONVENTIONAL DNA
SEQUENCING.
IT'S PREDOMINANTLY USED NOW
WHICH HAS AN ERROR RATE OF
AROUND 1%, THIS LETS YOU -- YOU
CAN SEE AN EXAMPLE ON THE RIGHT
STANDARD - LEFT STANDARD, ON THE
RIGHT DUPLEX SEQUENCING,
ESSENTIALLY ALL THE BACKGROUND
NEWS WITH STANDARD GOES AWAY AND
THERE'S ONE TRUE MUTATION HERE.
THIS GIVES YOU A VISUAL TO
UNDERSTANDING WHAT THIS
TECHNOLOGY DOES.
HOW IT CAN BE APPLIED IS RATHER
THAN FOR MUTAGENESIS TESTING,
EXAMPLE, RATHER THAN NEEDING TO
TAKE BACTERIA OR CELLS OR
ANIMALS THAT HAVE INTEGRATED
REPORTERS THAT IF A MUTATION
HAPPENS AND ALLOWS, YOU KNOW, A
POPULATION OF CELLS TO GROW LIKE
AIMS ASSAY AND CULTURE OR A
PLAQUE, TRANSGENIC RODENT ASSAY
WE'RE DIRECTLY ABLE TO SEQUENCE
BILLIONS OF NUCLEOTIDES DIRECTLY
FROM ANY TISSUE, ANY SPECIES,
AND BASICALLY COUNT HOW MANY
MUTATIONS THERE ARE IF WE
SEQUENCE A BILLION NUCLEOSIDES
THEN WE SEE, YOU KNOW, A HUNDRED
MUTATIONS, MUTANT FREQUENCY IS
100 DIVIDED BY A BILLION, THAT'S
THE ORDER OF MAGNITUDE WE'RE
TYPICALLY LOOKING AT.
WE TAKE A REPRESENTATIVE PANEL,
SEQUENCES ACROSS REPRESENTATIVE
PORTION OF THE GENOME VARIABLE
TO SEE ANY TYPE OF MUTATION,
THIS ALLOWS US TO GET VERY
QUANTITATIVE MUTANT FREQUENCY IN
SPECTRA AND DETAILED
TRINUCLEOTIDE SIGNATURES, VERY
RELEVANT TO MUTATIONAL
PROCESSES.
AND ALLOWS US TO NOT ONLY DO
THIS QUICKLY AND EFFICIENTLY
WITHOUT ANY ENGINEERED SYSTEMS
BUT IT CAN BE APPLIED BOTH IN
VIVO AND IN VITRO.
THE TECHNOLOGY IS BROADLY
APPLICABLE TO DIFFERENT FORMS OF
GENOMIC SAFETY.
WE CAN APPLY TO CLASSIC
MUTAGENESIS WHICH IS WHAT I'M
MOSTLY TALKING ABOUT TODAY, CAN
BE APPLIED TO CRISPR, NEW
MODALITIES OF POTENTIAL MUTAGENS
THAT CAN HAVE ALL-TARGET EFFECTS
IN OTHER AREAS, MORE BROAD TO
CARCINOGEN IS DETECTING
NON-GENOTOXIC CARCINOGENS.
WE DEVELOPED -- WE WORKED WITH
PARTNERS AND CURE RATED LARGE
AMOUNT OF EVIDENCE TO DATE
BRIDGING STUDIES FROM PASS,
STANDARD ASSAYS, TRANSGENIC
RODENT, PIG-A, INTERLAB,
REPRODUCIBILITY STUDIES, AROUND
10 PUBLICATIONS, THAT HAVE BEEN
PROGRESSIVELY MOVING ALONG FROM
SHOWING EQUIVALENCY TO REALLY
FOCUSING ON HOW WE CAN THINK
BROADLY WHAT SPECIFICALLY IT
WOULD TAKE TO APPLY THIS
TECHNOLOGY IN A REGULATORY
SETTING.
WE WORK WITH HESSE CONSORTIUM,
HAD A PUBLICATION THAT GROUP PUT
OUT A FEW MONTHS AGO, A POSITION
PAPER, SHOWING A FEW EXAMPLES
HERE MUTANT FREE QUINCY, EXAMPLE
OF BEING ABLE TO QUANTITATIVELY
TAKE DNA OUT OF THE BONE MARROW
OF ANIMALS AND ABLE TO SEE A
NICE DOSE-RESPONSE, TIME
COURSES, IN ANOTHER SPECIES,
DIFFERENT TISSUES RESPOND AT
DIFFERENT RATES BASED ON CELL
POSITION RATE.
DIRECT SEQUENCE WITH DNA ALLOWS
US TO LOOK AT THE SPECTRUM,
EXACT TYPE OF BASE CHANGES WITH
MUTAGENS WHICH GIVES A SENSE OF
MECHANISM.
THIS IS AN EXAMPLE OF MOUSE
TISSUE, MUTATIONAL PATTERN OF
URETHANE IS DIFFERENT BETWEEN
VEHICLE CONTROL ANIMAL ON THE
OTHER SIDE.
WE CAN ASSESS NUCLEOTIDE
SIGNATURES, EVEN MORE NUANCED
PATTERNS LOOKING AT PATTERNS OF
BASE CHANGES AND CONSIDERING
FLANKING ADJACENT BASES WHICH
MODULATE SENSITIVITY TO CERTAIN
MUTAGENS, AND THIS TYPE OF STUDY
HAS BEEN USED TO SEQUENCE TUMORS
IN HUMANS AND INFER MUTATIONAL
PROCESS THAT LED TO TUMORS BUT
NOW WE'RE ABLE TO AFTER A FEW
DAYS OF EXPOSURE IDENTIFY THESE
PATTERNS IN THE NORMAL TISSUES
OF HEALTHY HUMANS OR CELLS IN
CULTURE, ANIMALS, AND CAN YOU
SEE DISTINCT PATTERNS THAT
PROVIDE PRE-CLINICAL BRIDGING TO
WHAT'S KNOWN IN CLINICAL
MEDICINE NOW.
THIS CAN BE APPLIED IN CELL
CULTURE, APPLIED IN
RECONSTRUCTIVE 3D TISSUE
SYSTEMS, OR GAN ON A CHIP, MOVIG
AWAY FROM AND REDUCING AMOUNT OF
ANIMAL TESTING NEEDED, BEING
ABLE TO USE THESE STIMULUS
BECAUSE WE DON'T NEED
GENETICALLY MODIFIED SYSTEM.
ANY SOURCE OF DNA FROM ANY
ORGANISM WILL WORK FOR THIS
TECHNOLOGY.
IT COMPANY APPLIED IN HUMANS
DIRECTLY.
THIS IS EXAMPLE OF BLOOD AND
URINE FROM INDIVIDUALS WHO HAVE
KNOWN EXPOSURE TO A CHEMICAL
WHICH IS A KNOWN MUTAGENIC
CHEMICAL, CAN BE -- IT'S
ASSOCIATED WITH KIDNEY AND LIVER
CANCER, AND NON-INVASIVE
SAMPLING FROM HUMANS CAN SEE
PATTERNS OF MUTATIONS, THIS
OPENS THE OPPORTUNITY FOR OTHER
STUDIES WE HAVE ONGOING WITH
COLLABORATORS LOOKING IN OTHER
INDIVIDUALS WITH OCCUPATIONAL
EXPOSURES LIKE FIREFIGHTERS OR
ASTRONAUTS OR MILITARY BURN PIT,
SOMETHING WE HAVEN'T DONE, WE'RE
INTERESTED IN BEING ABLE TO
OBJECTIVELY MEASURE EXPOSURES IN
A QUANTITATIVE WAY, EVEN IN
NON-INVASIVE SAMPLING IN HUMANS.
OUR ASK WE WANT TO BRING THIS
TECHNOLOGY TO YOUR ATTENTION AND
HELP RAISE AWARENESS, WE HAVE A
LOT OF PUBLICATIONS YOU CAN LOOK
AT.
WE'RE INTERESTED IN YOUR HELP,
GIVING GUIDANCE TO WHAT A
REALISTIC REGULATORY PATHWAY
MIGHT BE, THIS IS A CHALLENGING
TECHNOLOGY INSOFAR AS IT HAS A
LOT OF BROAD APPLICATIONS, CAN
BE APPLIED IN VITRO, IN VIVO, TO
ORGAN ON A CHIP, TO HUMANS, HOW
DOES ONE THINK ABOUT A
REGULATORY PATHWAY NOT SO
PRESCRIPTIVE THAT IT REQUIRES
ONE STRAIN OF ANIMALS OR CELL IN
CULTURE BUT BROADLY CONSIDERED.
HOW CAN IT BE USED AS ENDPOINT
IN REGULATORY ASSAYS.
WE'VE HEARD ABOUT DIFFERENT
OPPORTUNITIES OF CASE STUDIES OR
GUIDELINES, TEST GUIDELINES
VERSUS CASE STUDIES VERSUS OTHER
APPROACHES, AND INTERESTED WITH
THIS, YOU KNOW, NEW SITUATION
HOW ONE WOULD BEST GO ABOUT
GETTING THIS OUT IN THE WORLD IN
A WAY IT CAN BENEFIT THE
COMMUNITY.
WE'D LOVE YOUR IDEAS AND HOW
THIS CAN BE APPLIED TO PROBLEMS
RELEVANT TO YOU AND WE'D LOVE
PARTNERSHIPS OF ANY AREAS YOU
THINK WOULD BE RELEVANT.
SO THANK YOU.
>> GREAT.
THANK YOU VERY MUCH, JESSE.
[APPLAUSE]
SO, MOVING TO PUBLIC
COMMENTER -- I CAN PAUSE AND ASK
IF THERE'S ANY CLARIFYING
QUESTIONS.
GO AHEAD, JOHN.
ONE SECOND, WE'LL GET YOU THE
MIC, JOHN.
>> THANKS FOR THE TALK.
INTERESTING.
A LITTLE HEADS UP, WHATEVER
DIRECTION YOU THINK YOU'RE
HEADING WITH THIS, MOST
REGULATORY AGENCIES HAVE
GUIDANCE DOCUMENTS AVAILABLE.
SO WHEN YOU'RE LOOKING FOR
REGULATORY ACCEPTANCE, THINK
ABOUT WHAT DIRECTION YOU'RE
GOING WITH THIS, FIND THOSE
GUIDANCES, AND CALL THOSE PEOPLE
TOO.
DON'T JUST READ THE DOCUMENT BUT
CALL THOSE FOLKS, OR E-MAIL AND
LET THEM KNOW YOU'RE DOING THIS
SO THAT WHEN IT COMES TO THEIR
DESK THEY WILL BE AWARE OF IT
AND THEY WILL BE ABLE TO HELP
AND GUIDE YOU.
>> THANKS.
YEAH, ONE OF THE CHALLENGES IS
MANY OF THESE REGULATORY
GUIDELINES HAVE BEEN -- THAT
WE'VE SEEN HAVE BEEN REALLY
FOCUSED ON A SPECIFIC IN VIVO
ASSAY OR SPECIFIC IN VITRO
ASSAY.
AND THINKING ABOUT THIS, SORT OF
A BROAD NEW APPROACH, HOW DOES
ONE THINK ABOUT THAT IN THE
CONTEXT OF PERHAPS EXACT TEST
SYSTEM AGNOSTIC TOOL THAT CAN BE
APPLIED.
WE HAVEN'T SEEN A LOT OF
GUIDANCE DOCUMENTS THAT TAKE
THAT BROADER APPROACH, AND
WONDERED WHAT YOUR THOUGHTS WERE
ON THAT.
>> SOME OF THEM ARE FAIRLY
BROAD.
FDA, EPA, DoD, CPSC ALL HAVE
GUIDANCE OUT THERE FAIRLY BROAD
IN THEIR APPROACH, BUT ALSO
THINK ABOUT WHERE YOU'RE TAKING
THIS AND CONTACT THE -- MAYBE
THE ICCVAM REPRESENTATIVE OR
WHOEVER YOU'RE TAKING THIS TO,
LIKE CPSC GET HOLD OF ME, FOR
FDA SUZIE FITZPATRICK, WE'RE ALL
HAPPY TO DISCUSS WHAT YOU NEED
TO DO.
>>AWESOME.
WE'LL REACH OUT.
THANK YOU.
>> THANKS, JOHN.
I WILL ADD THAT THAT IS
ABSOLUTELY ONE OF THE OBJECTIVES
OF HAVING PUBLIC COMMENTERS JOIN
THE ICCVAM PUBLIC FORUM TO RAISE
AWARENESS OF THESE TECHNOLOGIES
FOR POTENTIAL AGENCY USE AND
I'LL ADD THE NIEHS DIVISION OF
TRANSLATIONAL TOXICOLOGY WORKED
EXTENSIVELY WITH TWINSTRAND
BIOSCIENCE AND HEALTH CANADA,
THERE'S BEEN QUITE A BIT OF
INITIAL WORK DONE IN LOOKING AT
THE UTILITY.
IN THE INTEREST OF TIME I'M
GOING TO MOVE TO OUR NEXT PUBLIC
COMMENTER, AMY KYLE FROM --
RETIRED FROM UC-BERKELEY.
ARE YOU ONLINE?
>> I AM.
>> GREAT.
DO YOU HAVE SLIDES YOU WOULD
LIKE TO SHARE OR WILL YOU JUST
BE PROVIDING ORAL COMMENT?
>> I DO HAVE A FEW SLIDES.
SO CAN I SHARE MY SCREEN?
>>ABSOLUTELY.
YOU SHOULD BE ABLE TO HIT THE
GREEN BUTTON AND HOPEFULLY IT
WILL WORK SEAMLESSLY.
>>OKAY.
HELLO FIRST.
LET'S SEE.
>>WE'RE SEEING SOME KIND OF
VIDEO FEED BUT IT'S NOT SLIDES.
NOW WE SEE YOU.
WONDERFUL.
>> OKAY.
I WANT TO SAY HELLO.
>> GREAT.
>> I'M NOT A ROBOT.
LET'S SEE IF I CAN GET THIS UP
HERE.
THE LITTLE THINGS COVER UP THE
THING YOU NEED TO CLICK HERE.
>> CLICK ON SLIDE SHOW UP
ABOVE, THREE OVER FROM VIEW.
>> OKAY I ALWAYS CLICK ON THE
BOTTOM.
>> ALMOST.
KEEP GOING TO THE LEFT.
>> THANK YOU SO MUCH.
>> NO WORRIES.
>> THAT DOESN'T SEEM TO BE
WORKING.
>> CLICK FROM BEGINNING, TOP
LEFT BUTTON UNDER THAT MENU.
>> I USUALLY USE LOWER BUTTONS,
I'M NOT AS ADAPTABLE AS I SHOULD
BE.
THANK YOU FOR HAVING ME.
I APPRECIATE THE PUBLIC COMMENT.
I'VE GOTTEN A LOT OUT OF THE
FORUM TOO.
I APPRECIATE ALL OF THE
PRESENTATIONS AND SPEAKERS.
WHY AM I HERE?
I'M RETIRED NOW BUT MY WORK IS
AND HAS BEEN ABOUT HOW WE USE
INFORMATION IN PUBLIC POLICY.
I STARTED MY CAREER IN PUBLIC
SERVICE, I WAS A REGULATOR FOR A
NUMBER OF YEARS AND MY SECOND
CAREER WAS IN ACADEMIA AT
UC-BERKELEY WHERE I WORKED ON A
LOT OF RESEARCH TRANSLATION AND
ENGAGEMENT ISSUES FROM THE
PERSPECTIVE OF PROGRAM DEVOTED
TO ENVIRONMENTAL HEALTH
SCIENCES.
AND I AM VERY INTERESTED IN ALL
THIS WORK AND WHAT IT CAN DO,
HOW WE CAN BRING IT FORWARD IN A
WAY THAT HELPS US THE MOST WITH
ADDRESSING THE ENVIRONMENTAL
HEALTH ISSUES THAT WE HAVE.
I WORK A LOT WITH PEOPLE WHO
ARE -- HAVE MORE OF A LAY
BACKGROUND.
WE CALL THEM ENGAGED LAY
AUDIENCE, PEOPLE INTERESTED AND
DEVOTED TO THESE ISSUES BUT
DON'T A LOT OR MAYBE ANY
SCIENTIFIC TRAINING.
I WRITE A LOT OF THINGS THAT
START WITH QUESTIONS LIKE, WHAT
IS NAMs?
OR WHAT ARE AIR TOX, THINGS LIKE
THAT, TO TRY TO HELP ALLOW FOR
DIALOGUE AND DISCUSSION AND
CONSULTATION, PEOPLE WHO DON'T
SPEAK THIS LANGUAGE AT ALL AND
NEVER WILL.
IT'S NOT A QUESTION OF SCIENCE
EDUCATION PARTICULARLY BECAUSE
PEOPLE DON'T HAVE TIME TO LEARN
ALL THIS.
BUT STILL THERE'S A NEED FOR THE
PEOPLE WHO ARE BEING SPOKEN FOR
IN SOME WAY OR REPRESENTED WHOSE
NEEDS NEED TO BE MET HERE TO
HAVE A WAY OF ENGAGING AND
UNDERSTANDING.
AND BRINGING THEIR PERSPECTIVE
AND INPUT HERE.
AND I THINK THAT'S IN THE
FUTURE, BUT WHAT I'M LOOKING
TOWARD AND THAT'S WHY I'M HERE.
IT SEEMS RANDOM, WHAT ARE YOU
DOING HERE, AMY?
YOU'RE NOT DROPPING ANY OF THESE
METHODS.
BETTER METHODS ARE CRUCIAL
THOUGH.
I ALSO WANT TO SAY I REALLY
APPRECIATE THE QUALITY OF WORK,
BRILLIANCE OF SOME OF THIS WORK
THAT IT'S STUNNING.
IT'S INSPIRING.
ACTUALLY I THINK I HAVE THIS ON
MY SLIDE.
IT'S IMPRESSIVE, IMPORTANT,
INSPIRING, THREE Is.
I WANT TO ACKNOWLEDGE THAT.
THAT THERE'S A HUGE AMOUNT OF
INSIGHT AND KNOWLEDGE THAT'S
GONE INTO ALL OF THIS.
I HONOR THAT EVEN AS I'M GOING
TO SAY SOME THINGS THAT I THINK
NEED MORE ATTENTION.
BUT IT'S THIS SPIRIT OF MAKING
THE HIGHEST AND BEST USE OUT OF
THIS, THESE INVESTMENTS AND THIS
TIME.
I HAVE THREE MAIN POINTS.
CONFIDENCE, SHOWING UP IN YOUR
TALK, THE THREE Cs AND I'M NOT
SURE IF THAT'S ONE OF THE THREE
Cs BUT DISCUSSIONS OF
FRAMEWORKS, ISSUES OF
COMMUNICATION ARE SO KEY TO
THAT.
I'VE BEEN HERE BEFORE TO TALK
ABOUT THAT.
I SEE PROGRESS SO I HAVE A FEW
THINGS TO SAY ABOUT THAT.
SECOND MOST IMPORTANT THING IS
HOW TO ENVISION WHO ARE THE FULL
RANGE OF STAKEHOLDERS HERE.
BECAUSE THIS WORK IS ENGAGING
PEOPLE FROM A CERTAIN PART OF
THE COMMUNITY BUT I THINK IT
NEEDS TO ALSO FIGURE OUT HOW TO
BRING IN THE FULL COMMUNITY.
AND THEN MY LAST POINT IS ABOUT
HOW CAN THIS BE APPLIED TO MORE
FUTURE-LOOKING UNDERSTANDING OF
WHAT WE NEED TO KNOW AND ACT ON.
AND OF COURSE IT STARTED OUT --
STARTS OUT AS REPLACING EXISTING
METHODS WITHOUT USING ANIMALS
WHICH I THINK EVERYONE SUPPORTS
THAT, AS LONG AS THE NEW METHODS
WORK.
I'M NOT SURE ANYONE'S IN FAVOR
OF MORE UNNECESSARY USE OF
ANIMALS.
BUT ALSO THERE ARE OTHER
QUESTIONS OUT THERE BEYOND THAT.
SO DO WE HAVE TO ONLY REPLACE
THE METHODS THAT WE HAVE OR CAN
WE TAKE ON NEW BIGGER ISSUES
THAT MAYBE MAKE IT BETTER, NOT
JUST LESS ANIMALS.
SO THOSE ARE MY MAIN POINTS.
AND I'M GOING TO TRY TO MOVE
QUICKLY, YOU HAVE A LOT OF
PEOPLE TO HEAR FROM.
CONFIDENCE, GO BACK TO
CONFIDENCE.
IN METHODS FOR REGULATION FOR
PUBLIC HEALTH IT NEEDS TO EXTEND
BEYOND THIS AUDIENCE TO PEOPLE
INVOLVED ONCE YOU GET TO THE
REGULATORY SIDE.
THIS INCLUDES WORKERS, PEOPLE
WHO LIVE OR WORK IN HIGHLY
IMPACTED COMMUNITIES, YOU KNOW,
OTHER KINDS AS WELL BECAUSE
REGULATORY ACTIONS OCCUR OUTSIDE
CONFINES OF THE SCIENTIFIC
COMMUNITY AND RESPOND TO OTHER
IMPERATIVES AND INPUTS, ET
CETERA.
PEOPLE ARE PARTICIPATING IN
THAT, NEED TO BE ABLE TO AT
LEAST HAVE A FUNCTIONAL
UNDERSTANDING OF WHAT IT'S BASED
ON.
SO SOMEHOW THAT NEEDS TO EXTEND
OUT.
AND THERE'S LOTS OF THINGS ABOUT
HOW THAT CAN BE DONE AND IT
CAN'T BE DONE BY TEACHING
EVERYONE ALL OF WHAT YOU KNOW, I
KNOW THAT, BUT THERE ARE WAYS TO
CONNECT KEY HAND-HOLDS AND SET
UP MAYBE WHAT SOME PEOPLE CALL
CIRCLES OF TRUST OR ENGAGEMENT
THAT CAN REACH OUT BEYOND WHERE
YOU ARE NOW.
I THINK THAT'S AN IMPORTANT
THING TO DO.
THE QUESTION OF COMMUNICATION
ALSO IS VERY KEY, HOW TO DEVELOP
BOTH VOCABULARY IS IMPORTANT.
I'VE NOTICED THIS TIME THERE'S
LESS ACRONYMS AND MORE OF THE
PRESENTATIONS ARE
UNDERSTANDABLE, EVEN TO ME.
I CAN FEEL LIKE THERE'S BEEN
SOME EMPHASIS ON SPEAKING ACROSS
DISCIPLINES AND OUT MAYBE BEYOND
A LAB CONTEXT.
I APPRECIATE THAT.
I THINK THERE'S MORE THAT NEEDS
TO BE DONE IN THAT SPECIFIC
FOCUSED WAY TO BUILD SOME
VOCABULARY THAT CAN LINK WORK
AND IDEAS THAT HAVE NO
TRANSLATION RIGHT NOW INTO A
PUBLIC DISCOURSE.
AND THEN ALSO THE OTHER THING
THAT'S REALLY IMPORTANT ARE SOME
OF THE METRICS USED TO DESCRIBE
THESE -- THE IMPACT OR IMPORT OF
VARIOUS METHODS, THE
REPRESENTATIVE FROM NIST
YESTERDAY WAS TALKING ABOUT HOW
TO FRAME THINGS AS RATES OF
FALSE NEGATIVES, FALSE
POSITIVES, FOR EXAMPLE.
A CONCEPT LIKE THAT IS VERY
IMPORTANT, IT MATTERS TO RULE
THINGS IN, RULE THINGS OUT, HOW
WELL YOUR TESTS CAN DO THAT IS
FUNDAMENTALLY ESSENTIAL QUESTION
TO TIERED FRAMEWORKS, ALSO TO
HOW THOSE ARE INTERPRETED IN A
POLICY CONTEXT.
I THINK THAT MIGHT NOT BE THE
RIGHT METAPHOR BUT THAT'S
SOMETHING THAT PEOPLE CAN
UNDERSTAND AND EXIST OUTSIDE THE
NAMs BUBBLE.
I DON'T MEAN ANY DISRESPECT BY
THAT BUT IT IS A WORLD THAT HAS
ITS OWN -- IT CAN BE DEFINED AND
HAS ITS OWN VOCABULARY.
I WOULD RECOMMEND FOCUSED
ATTENTION.
HE MENTIONED CONFIDENCE
INTERVALS, STATISTICAL METRICS
ARE MORE COMPLICATED BUT THINGS
THAT CAN BE USED CONSISTENTLY
ACROSS TESTS OR ACROSS
APPROACHES, AND THEN PEOPLE CAN
COME TO UNDERSTAND WHAT THEY
MEAN.
THEY ARE USE CONSISTENTLY, THEY
CAN BE MORE COMPLICATED BUT
STILL USEFUL.
AGAIN, THERE'S A LOT OF PLAYERS.
YOU CAN LOOK AT ANY DOCKET TO
SEE THE RANGE OF PLAYERS THAT
NEED TO HAVE SOME DEGREE OF
CONTACT WITH THE SCIENTIFIC
BASIS FOR REGULATIONS.
AND I DON'T KNOW IF THIS IS
POLITICALLY INCORRECT TO BRING
UP, IT MIGHT BE, BUT THERE'S
ALSO THE LITIGATION COMPONENT OF
REGULATORY ACTIONS, IN THAT MOST
OF THE IMPORTANT REGULATIONS ARE
LITIGATED, AND CAN BE BY BOTH
SIDES, OR FROM MULTIPLE
PERSPECTIVES.
BUT THAT BRINGS US TO THE
QUESTION WHAT ABOUT THE
JUDICIARY?
WHAT CAN BE COMMUNICATED TO
THEM?
I'M JUST GOING TO SAY THIS OUT
LOUD.
I DON'T KNOW, MAYBE I SHOULDN'T,
BUT THERE ARE ENTITIES YOU'RE
USING 1980 STYLE RULES AND
ASSAYS BECAUSE THOSE HAVE
SURVIVED JUDICIAL REVIEW, NOT
THE ONLY REASON, BUT NEW ISN'T
GOOD IF NO JUDGE WILL TRUST IT,
AND I THINK THE PROGRESS THAT
COULD BE MADE TOWARDS SOME OF
THESE METHODS IS GOING TO NEED
EVOLUTION AND UNDERSTAND.
THAT'S MY FIRST MAIN POINT.
MY SECOND -- MY THIRD POINT ON
THE SLIDE IN TERMS OF
ENCOMPASSING THE NEEDS OF THE
FUTURE LET'S NOT REMODELEL HOUSE
WE HAVE.
LET'S MAKE IT A BETTER ONE AND
THINK ABOUT SOME OF THESE
CRITICAL CHALLENGES AND I ASKED
THE QUESTION YESTERDAY ABOUT IS
ANYBODY CONSIDERING ANY ASPECTS
OF WHAT WE CALL REALITY BASED
METHODS, SORT OF THIS LINE FOR
THAT, BUT METHODS THAT CAN LOOK
AT THE ACTUAL COMBINATIONS OF
CHEMICALS, PERHAPS IN THIS CASE,
BUT ALSO PERHAPS SUSCEPTIBILITY
METRICS AND ENVIRONMENTAL
REALITIES PEOPLE ACTUALLY LIVE
IN, CHEMICAL METHODS JUST DON'T
DO THAT.
THAT NEEDS TO BE DONE IN A WAY,
INTERAGENCY, INTERMETRIC,
INTERENVIRONMENT APPROACH LIKE
YOU'VE ESTABLISHED AT ICCVAM.
AT EPA DIFFERENT OFFERSES HAVE
DIFFERENT PIECE, ACROSS THE
FEDERAL SPECTRUM DIFFERENT
AGENCIES HAVE DIFFERENT PIECES
OF IT.
AND SO THE MODEL OF THINKING
TOGETHER AND PLANNING TOGETHER
AND HARMONIZING IN WAYS THAT CAN
ADVANCE THIS, I KNOW IT'S NOT
EXACTLY THE LEGAL MANDATE OF
ICCVAM BUT MAYBE IT IS IN SOME
WAY IN THAT YOU'RE SUPPOSED TO
BE ALSO PROVIDING EVIDENCE THAT
CAN BE USED FOR ENVIRONMENTAL
HEALTH AND ENVIRONMENTAL
PROTECTION.
AND SO MAYBE THERE'S SOME PART
OF THAT COULD BE INCORPORATED.
THE ISSUE OF THE EARLIER
PREDICTORS OF IMPACT, KEY
CHARACTERISTICS, THESE OTHER
THINGS, BRINGING THOSE FORWARD
IN A WAY THAT CAN BECOME
ESTABLISH AND ACCEPTED TO
SCIENCE IS SOMETHING THAT WILL
TAKE I THINK A LOT OF FOCUSED
ATTENTION WITH OUTSIDE PARTIES,
AND THAT'S A CRITICAL NEED FOR
THE FUTURE I THINK, FOR THESE
BETTER METHODS.
AND WE'RE IN A TIME NOW WHERE
THERE'S A RECOGNITION OF THE
IMPORTANCE OF DOING THIS WITH
THE WORK ON CUMULATIVE RISK
THAT'S GOING ON AT EPA AND OTHER
AGENCIES.
WITH THE EMPHASIS ON
ENVIRONMENTAL JUSTICE AND THE
NEEDS OF COMMUNITIES AND THE NEW
EXECUTIVE ORDERS AND ALL THOSE
INITIATIVES THAT ARE GOING INTO
THAT.
THERE'S A LOT OF MONEY BEING
SPENT THERE.
THERE'S A LOT OF INTENT TO MAKE
A DIFFERENCE, AND WE STILL DON'T
HAVE THE TOOLS TO DO EVERYTHING
THAT NEEDS TO BE DONE.
WE HAVE TOOLS WE CAN USE BUT IT
WOULD BE GOOD IF THOSE COULD
GO -- PEOPLE LIKE TO SAY NEXT
GEN, I DON'T KNOW IF THAT'S
OUTDATED SLANG NOW BUT HOW COULD
WE MAKE GAINS USING SOME OF THE
METHODS PERHAPS THAT YOU ALL ARE
WORKING ON.
AND THEN ALSO -- I'M SURE I'M
OUT OF TIME BUT THE LAST THING I
WANT TO SAY IS THERE ARE ALSO
THE -- WHEN WE THINK ABOUT
ANIMALS, HUMAN POPULATIONS, BUT
ALSO THE ANIMAL POPULATIONS ARE
AFFECTED BY THE CHEMICAL
RELEASES AND SO ON.
AND I INCLUDED THIS SLIDE IN
HERE, I DON'T HAVE TIME TO SHOW
MY SLIDES, I KNOW THAT, FOR
EXAMPLE STUDY ON IMPACTS ON
WHALES, CUMULATIVE EFFECTS, THE
RIGHT WHALE, IT'S GOING EXTINCT,
POPULATIONS ARE DIMINISHING AND
THEY ARE NOT SURE OF THE REASONS
BUT CHEMICALS COULD BE PART OF
IT FOR THAT SPECIES AND FOR
OTHERS, AND SO WHEN WE THINK
ABOUT ANIMAL WELFARE AND
SURVIVAL OF SPECIES, YOU KNOW,
THE CUMULATIVE IMPACT ON -- AT
THE POPULATION LEVEL IS RELEVANT
FOR SPECIES, MAYBE THAT COULD
BECOME A CONCERN THAT WE ALSO
THINK OF WHEN WE'RE WORKING ON
METHODS.
THANK YOU FOR THE OPPORTUNITY TO
SPEAK.
I'M SORRY I WENT OVER BUT I
APPRECIATE IT.
THANK YOU.
>> THANK YOU, DR. KYLE.
THESE ARE REALLY CRITICALLY
IMPORTANT POINTS THAT YOU'RE
MAKING PARTICULARLY IN TERMS OF
COMMUNITY ENGAGEMENT,
UNDERSTANDING CUMULATIVE RISK,
COMMUNICATION, SO REALLY
APPRECIATE YOU JOINING US TODAY
AND GIVING FEEDBACK.
WE'LL POST YOUR SLIDES IN THEIR
ENTIRETY, IF IT'S ALL RIGHT WITH
YOU, ON THE THE ICCVAM SITE AND
WE HAVE FOLLOW-UP MEETINGS NEXT
WEEK TO DISCUSS IN PARTICULAR
THE PUBLIC COMMENTS, WE'LL DIVE
INTO MORE DETAIL IN OUR CLOSED
SESSION.
THANK YOU VERY MUCH.
NEXT PUBLIC COMMENTER IS AMY
CLIPPINGER FROM PETA SCIENCE
CONSORTIUM INTERNATIONAL, HERE
WITH US IN PERSON.
PLEASE MAKE YOUR WAY TO THE
PODIUM.
THANK YOU.
>> THANKS, NICOLE.
THANKS, EVERYBODY, FOR TAKING
THE TIME TO HEAR PUBLIC COMMENTS
THIS MORNING.
I'LL TRY TO BE BRIEF.
AT THE BE ON SET OF THE MEETING,
A COUPLE PEOPLE SAID HOW THIS IS
ONE OF THEIR FAVORITE MEETINGS
OF THE YEAR.
I HAVE TO AGREE, IT'S BEEN NICE
SITTING IN THE AUDIENCE
YESTERDAY AND TODAY, HEARING THE
UPDATES FROM THE AGENCIES AND
GREAT WORK THAT HAS BEEN MADE,
PROGRESS MADE OVER THE PAST
YEAR.
IN PARTICULAR IT'S BEEN NICE TO
SEE THAT EFFORTS HAVE ADDRESSED
THE WHOLE PROGRESS FROM METHOD
DEVELOPMENT THROUGH CONFIDENCE
IN THAT METHOD, DEVELOPING
GUIDANCE, COMMUNICATING WITH
BOTH SCIENTISTS AND AS THE OTHER
AMY JUST POINTED OUT NICELY,
NON-SCIENTISTS AS WELL.
I WAS REALLY HAPPY TO HEAR ABOUT
THE VALIDATION EFFORTS TAKING
PLACE WITHIN BOTH OECD AND
ICCVAM.
THERE'S A REALLY NEED TO UPDATE
THAT 20+ YEAR OLD PROCESS FOR
VALIDATING NEW METHODS SO WE CAN
GET THE BEST SCIENCE OUT, GET
THOSE TOOLS OUT INTO THE HANDS
OF RESEARCHERS, FASTER.
WHILE STILL HOLDING TRUE AND
STICKING TO THOSE PRINCIPLES OF
VALIDATION THAT HOLD TRUE TODAY.
I WAS ALSO HAPPY TO HEAR ABOUT
SOME OF THE GUIDANCE THAT HAS
COME OUT IN THE PAST YEAR AT THE
OECD AND OTHERWISE.
THIS IS SOMETHING THAT'S SO
CRITICALLY IMPORTANT.
I THINK IT'S ONE OF THE FINAL
STEPS BEFORE WE REACH THE FINISH
LINE, AND THERE ARE CERTAINLY
CASES WHERE COMPANIES AREN'T
EITHER AWARE OF THE NAM OR THEY
MIGHT BE AWARE BUT NOT CERTAIN
IT WILL BE ACCEPTED OR WILL IT
BE ACCEPTED IN A TIMELY MANNER,
OR WILL IT BE ACCEPTABLE FOR
THEIR SPECIFIC CONTEXT OF USE,
SO I THINK INCREASING THE AMOUNT
OF COMMUNICATION, GUIDANCE,
WHETHER NAMs CAN BE USED, WHEN
THEY CAN BE USED
IS CRITICALLY IMPORTANT AS ONE
FAMILIAR PELL, SUZIE TALKED
ABOUT THE GREAT WORK THAT THE
FDA DID TO REVIEW RODENT AND DOG
STUDIES.
AND THAT STRIKES ME, WE WANT TO
MAKE SURE THE REGULATED
COMMUNITY KNOWS THAT AS QUICKLY
AS POSSIBLE.
I WILL LEAVE IT AT THAT.
THANKS AGAIN, EVERYBODY.
LOOKING FORWARD TO DOING THIS
NEXT YEAR.
[APPLAUSE]
>> NEXT IS ELIZABETH BAKER,
PHYSICIANS COMMITTEE FOR
RESPONSIBLE MEDICINE.
>> HELLO TO EVERYONE.
I REGRET NOT BEING ABLE TO BE
THERE IN PERSON TO SEE YOU ALL,
BUT APPRECIATE THE ABILITY TO
PARTICIPATE FROM A AFAR.
I WANT TO ECHO WHAT DB
CLIPPINGER SAID AND MANY OTHERS
THAT I LOOK FORWARD TO THIS
FORUM HEARING EVERYONE'S
UPDATES.
THE PRESENTATIONS HAVE
DEMONSTRATED COMMITMENT TO
INTEGRATING TESTING STRATEGIES
THAT PROTECT HUMAN HEALTH AND
THE ENVIRONMENT WHILE REPLACING
AND REDUCING ANIMAL USE.
IT'S CLEAR NICEATM AND ICCVAM
ARE DOING THE HARD AND NECESSARY
WORK TO ADVANCE SCIENCE.
THANK YOU FOR THAT.
MY COMMENTS ARE DEVELOPED WITH
THE HELP OF OUR TEAM AT
PHYSICIANS COMMITTEE.
JESSICA PONDER, JOHN, ERIN, AND
EMILY ANDERSON, AND WRITTEN
COMMENTS ARE DIFFERENT SO I
ENCOURAGE PEOPLE TO TAKE A LOOK
AT THOSE AS WELL.
ONE THING I REALLY APPRECIATE
ABOUT THE FORUM WE SHARE IDEAS
TO COMPLEMENT THE GREAT WORK
BEING ACCOMPLISHED ALREADY.
I THINK THAT WE'VE ALL COME TO
UNDERSTAND THAT DEVELOPING AND
EVALUATING SCIENCE IS JUST ONE
IMPORTANT FACTOR IN ADVANCING
NEW APPROACHES, BUT ALSO
POLICIES MUST ADVANCE, TRAINING
AND EDUCATIONAL OPPORTUNITIES
ARE REALLY IMPORTANT AS WELL.
SO I'D LIKE TO THANK DR. GORDON
FOR HIS COMMENTS YESTERDAY ON
THE NEED FOR AGENCIES TO TAKE A
LEADING ROLE IN COMMUNICATING
WHEN AND HOW NAMs CAN BE USED.
WE CONSISTENTLY HEAR FROM
COMPANIES THAT THEY KNOW HOW TO
USE ANIMALS AND THAT CAN IT BE
HARD TO MAKE A CASE FOR USING
NAMs WITHOUT THE VERY CLEAR
COMMUNICATION REGARDING
ACCEPTANCE.
AND EVERY AGENCY THAT HAS
PRESENTED IS DOING GREAT WORK TO
ADVANCE NAMs, AND SO I HOPE
THAT AGENCIES WILL VIEW UPDATING
THEIR OWN POLICIES TO CLEARLY
REFLECT NAM ACCEPTANCE AS
COMPLEMENTARY TO ALL THE OTHER
GREAT WORK THAT IS HAPPENING.
ALONG THOSE LINES WE APPRECIATE
THE MANY EFFORTS BY ICCVAM AND
NICEATM STAFF TO INTEGRATE
METHODS AND REDUCE ANIMAL USE
THROUGH PARTICIPATION AT THE
OECD, STAFF ARE PARTICULARLY
EXCITED ABOUT THE COLLABORATION
TO DEVELOP AOP AND PRIORITIZE --
I HAVE A PROBLEM WITH THIS WORD,
EPIDEMIOLOGICAL DATA, WEIGHT OF
EVIDENCE APPROACH TO DEFINING
RESPIRATORY SENSITIZERS BASED ON
HUMANS.
THIS IS A REALLY STRONG EXAMPLE
OF NEGATIVE EFFECT IN HUMANS NOT
OBSERVED IN ANIMALS SO WE
APPRECIATE OECD SUPPORTING THIS
EFFORT TO PRIORITIZE AND
IMPLEMENT NAMs, AND OUR STAFF
ARE LOOKING FORWARD TO
COLLABORATING ON THE UPCOMING
DETAILED REVIEW PAPER.
IN TERMS OF VALIDATION,
QUALIFICATION, EVALUATION,
WHATEVER YOU CALL IT, I'M
NOTICING A THEME.
THAT IS THAT MORE AND MORE
ORGANIZATIONS ARE LOOKING TO
UNDERSTAND THE CAPABILITIES AND
EVEN LIMITATIONS OF EXISTING
METHODS.
NICEATM HAS DONE A REALLY GREAT
JOB CHAMPIONING SCIENTIFICALLY
SOUND AND OBJECTIVE EVALUATION
OF NOT ONLY IN VITRO AND IN
SILICO METHODS BUT ALSO IN VIVO
METHODS ADOPTED BEFORE FORMAL
VALIDATION PROCESSES WERE
ESTABLISHED.
EPA AND OTHERS ARE DOING THIS
WORK AND WE THINK IT'S IMPORTANT
FOR HUMAN-SPECIFIC NAMs TO BE
EVALUATED USING HUMAN
INFORMATION WHEREVER POSSIBLE.
I'VE NOTICED SOME ARE VIEWING
NAMs AS POTENTIAL TO FILL
GAPS, AND WHILE THAT IS A
BENEFIT OF NAMs, I THINK IT'S
IMPORTANT, I THINK WE ALSO NEED
TO KEEP IN MIND THAT WE ALSO
NEED TO IMPROVE EXISTING TESTING
AND REDUCE ANIMAL USE.
SO JUST I GUESS A COMMENT TO BE
MORE BROAD AND HOW WE'RE
THINKING ABOUT NAMs AND NOT
JUST AS GAP FILLERS.
MULTIPLE PRESENTERS INCLUDED
METRICS AS PART OF THEIR NAMs
WORK, AND I HAVE SAID THIS
BEFORE, I DON'T THINK IT'S BEEN
VERY WELL RECEIVED BUT I DO
THINK IT'S IMPORTANT SO I'LL SAY
IT AGAIN.
WE REALLY DON'T KNOW HOW MANY
ANIMALS ARE USED IN TESTING.
AND I THINK A LOT OF US ARE HERE
BECAUSE WE WANT TO ADVANCE NEW
APPROACHES, WE ALSO WANT TO HELP
REDUCE ANIMAL USE.
AND IF WE'RE GOING TO REDUCE
ANIMAL USE, WE NEED TO
UNDERSTAND AND KNOW HOW TO
MEASURE IT.
I HAVE A REALLY HARD TIME
UNDERSTANDING HOW WE CAN MEASURE
PROGRESS IF WE DON'T HAVE A
BASELINE, AND SO I KNOW IT'S NOT
AN EASY ISSUE, AND THAT THERE
ARE INHERENT CHALLENGES AROUND
COLLECTING AND REPORTING THIS
INFORMATION.
BUT I DO THINK THAT SOME
PROGRESS COULD BE MADE WITH
AGENCY LEADERSHIP, AND SO WE
THINK ONE -- A GOOD START WOULD
BE FOR ICCVAM AGENCIES TO START
TRACKING THE NUMBER OF ANIMALS
SUBMITTED BY SPECIES TEST AND
ENDPOINT AND MAKE THESE PUBLICLY
AVAILABLE.
SO WE KNOW IT WON'T COVER ALL
ANIMALS USED BUT THINK IT WOULD
BE A GOOD START.
I WANTED TO COMMENT ON QUESTION
DR. KYLE ASKED AND EXPANDED UPON
TODAY THAT WAS VERY INSIGHTFUL
ABOUT THE IMPORTANT
OPPORTUNITIES -- AN UPON
OPPORTUNITY FOR NAMs, THAT'S
THE OPPORTUNITY TO DEVELOP
NAMs TO ADDRESS CO-EXPOSURES
TO PESTICIDES.
THIS IS A MAJOR REAL WORLD
CONCERN AND ENVIRONMENTAL
JUSTICE, AS FARM WORKERS AND
FAMILIES AS WELL AS COMMUNITIES
ARE NOT EXPOSED TO PESTICIDE
MIXTURES OR FORMULATIONS ONE AT
A TIME BUT RATHER CHRONICALLY
OVER THE COURSE OF A LIFETIME.
SOMETIMES EVEN STARTING IN
GESTATION.
SO WE'D LIKE TO SUGGEST THAT THE
EPA ENGAGE PESTICIDE PROGRAM
DIALOGUE COMMITTEE TO PRIORITIZE
DEVELOPMENT OF NAMs THAT CAN
ASSESS EPIGENETIC EFFECTS
CHRONIC EXPOSURES AS PART OF THE
CHANCE TO ADVANCE ENVIRONMENTAL
JUSTICE.
THAT'S IT.
>> NEXT IS RANDOLPH ASHTON FROM
NEUROSETTA.
DO YOU HAVE SLIDES?
>>YES.
>> ARE YOU LOOKING AT MY SLIDE
SHOW?
>> THANKS VERY MUCH.
>> AWESOME.
THANK YOU.
GOOD MORNING FROM WISCONSIN THIS
TIME OF YEAR.
I'M RANDOLPH ASHTON, ASSOCIATE
PROFESSOR OF BIOMEDICAL
ENGINEERING AT UNIVERSITY OF
WISCONSIN-MADISON.
MY LAB OVER THE LAST COUPLE
PANDEMIC YEARS DECIDED TO DO A
START-UP, STUCK AT HOME,
TECHNOLOGY FUNDED BY THE EPA,
NOW BY NIEHS, AND IT'S SOMETHING
THAT'S BEEN GEARED FOR
REGULATORY.
ONE WOULD LIKE THE CHANCE TO USE
I'M EMBRYOS, BUT YOU CAN'T, A
CRITICAL POINT OF HUMAN
DEVELOPMENT.
IN THE LAST COUPLE DECADES THE
USE OF HUMAN STEM CELLS DERIVED
FROM PATIENTS, AND YOU CAN GUIDE
THEM DOWN THE NEURAL
DIFFERENTIAL CHANGES, THEY
RECAPITULATE ASPECTS OF HUMAN
CENTRAL NERVOUS SYSTEM
DEVELOPMENT, THE TOOL HAS
LIMITATIONS IN THE
REPRODUCIBILITY OF THE SYSTEM,
AND THE ABILITY TO ANALYZE
WHAT'S GOING ON INSIDE THESE
TISSUES WHICH CAN BE MILLIMETERS
IN SIZE.
AND SO WHAT WE'VE DONE AT IS
NEUROSETTA IS BIOLOGICALLY
ENGINEERED INTO A
HIGH-THROUGHPUT SYSTEM.
IF YOU'RE LOOKING AT EARLY HUMAN
DEVELOPMENT, SIMILAR TO A CHICK,
TOP-DOWN ON THE CHICK EMBRYO,
NEURAL TUBE FORMS, HEAD REGION,
THROUGH THE SPINAL CORD,
TRANSVERSE SLICE HEAD-ON YOU CAN
SEE THE NEURAL TUBE STRUCTURE.
THIS STRUCTURE IS COMPOSED OF
NEURAL STEM CELLS AND THIS IS
WHAT ALL TISSUES OF THE BRAIN,
RETINA AND SPINAL CORD ARE
DERIVED FROM.
AND WHEN YOU DIFFERENTIATE
PLURIPOTENT STEM CELLS, THE STEM
CELLS, THE FIRST CELL TYPE YOU
GET TO, THEY ARE PROGRAMMED TO
UNDERGO THIS NEURAL TUBE TYPE
MORPHOGENESIS, NEARLY ROSETTES
FORM IN AN UNCONTROLLED MANNER,
YOU LOSE CONTROL OF CULTURE OF
MULTIPLE FORMING IN AN EMBRYO,
EMBRYONIC LETHAL DEFECT.
WE ASKED HOW CAN YOU GENERATE
SINGLE ROSETTES?
IS SOMEBODY TRYING TO ASK A
QUESTION?
NO, OKAY.
WE'VE INTEGRATED WITH
SUBSTRATES, THINK OF CULTURAL
ENGINEERED, IF YOU GET THOSE
DIMENSIONS JUST RIGHT IN SHAPE
AND SIZE, YOU CAN INDUCE
AGGREGATE OF HUMAN PLURIPOTENT
STEM CELLS AND FORM ROSETTE
STRUCTURES, THREE DIMENSIONAL,
RED IS NEURAL STEM CELL MARKER,
BLUE IS NUCLEI, GREEN IS A
PROTEIN THAT GETS POLARIZED TO
THE CENTRAL REGION, YOU'LL SEE
AS WE GO THROUGH YOU CAN SEE THE
POLARIZED ROSETTE STRUCTURE IN
THE MIDDLE OF THE 3D TISSUE.
WE HAVE HUNDREDS OF THESE IN A
SINGLE WELL BECAUSE WE HAVE
ENGINEERED SURFACE TO INSTRUCT
THIS FORMATION PROCESS.
WE WORK ON TRYING TO GENERATE
NEURAL STEM CELLS ACROSS THE
REGION OF THE DEVELOPING CENTRAL
NERVOUS SYSTEM SO WE CAN
GENERATE NEURAL STEM CELLS FROM
FOREBRAIN THROUGH SPINAL CORD,
THIS IS ONE OF THE ADVANTAGES OF
THE SYSTEM.
YOU CANNOT JUST PROBE FORE BRAIN
BUT ALL THE WAY THROUGH THE
DEVELOPING NEURAL TUBE.
WE COLLABORATE WITH COMPUTER
VISION EXPERTS TO CREATE
HIGH-THROUGHPUT IMAGE ANALYSIS
OFT WARE, SO THAT WHEN YOU
COLLECT THESE IMAGES YOU CAN RUN
IT THROUGH A PIPELINE THAT
COUNTS THE NUMBER OF ROSETTES
AND TISSUES, SINGLE ROSETTE
STRUCTURE, AGAIN AN IN VITRO
ANALOG TO NEURAL TUBE FORMATION.
AND SO IF COMBINE THIS YOU CAN
MAKE A WELL PLATE ASSAY, ROSETTE
AWAY, PATTERN TO THE LED TO TAIL
REGIONS OF THE DEVELOPING
CENTRAL NERVOUS SYSTEM IN ORDER
TO PROBE OR HAVE ASSAY WHERE YOU
CAN PROBE HOW CHEMICALS AND
GENETIC MUTATION WILL AFFECT
THIS PROCESS.
SO WE HAVE MADE THIS AN OFF THE
SHELF ASSAY, CRYOPRESERVE BANKS
OF CELLS AND FOLLOW THIS
DIRECTLY INTO OUR MICROPATTERN
CULTURE SUBSTRATE, 5 TO 7 DAY
CULTURE PERIOD, AT THE END
SINGLE IMMUNOCYTO CHEMICAL
STAINING, IMAGING WITH A
MICROSCOPE AND FROM THAT SINGLE
IMAGE YOU CAN GET DATA ON CELL
VIABILITY, PROLIFERATION, NEURAL
DIVERSITY, EQUITY,
-- NEURAL
DIFFERENTIATION, AND MORPHOGEN
SIS, THIS IS A SENSITIVE METRIC.
IN PRACTICE WE CAN TAKE OUR
CRYOPRESERVED CELLS, SEED THEM
INTO OUR ROSETTE ARRAY PLATES
WHICH WE MANUFACTURE AT THE
UNIVERSITY AND THEN GROW OUR
ROSETTES IN THE PRESENCE OR
ABSENCE OF CHEMICALS IN EACH
WELL OF A 96 WELL PLATE, FROM
100 TO 500 TISSUE IN THE FORE
BRAIN THROUGH SPINAL CORD, YOU
CAN USE ADAPTIVE CONFOCAL
IMAGING TO COLLECT, TYPICALLY 40
TO 50 PER WELL, 4,000 PER PLATE,
RUN THROUGH SOFTWARE THAT WE
HAVE, CONTINUING TO UPDATE TO
MAKE IT A.I. NOW.
AND FROM THAT YOU CAN GET VERY
NICE DOSE-RESPONSE CURVES,
PROLIFERATION IS A NUMBER OF
CELLS PER TISSUE, NEURAL
DIFFERENTIAL RATE IS A NEURAL
EPIDERMAL DETERMINANT FOR NEURAL
STEM CELLS AND ROSETTE FORMATION
METRIC.
AS YOU CAN SEE HERE FOR KNOWN
DEVELOPMENTAL NEUROTOXIC
CHEMICAL METHOTREXATE, THE MOST
SENSITIVE.
THE JUXTAPOSITION OF THESE
CURVES CHANGES BASED ON
CHEMICALS AND WHICH PATHWAYS
THEY ARE AFFECTING, THAT
DIFFERENCE IN POSITION TELLS YOU
NOT JUST WHETHER SOMETHING IS
TOXICS BUT GIVES MECHANISTIC
INSIGHT INTO WHAT PATHWAYS ARE
BEING AFFECTED BY THOSE
CHEMICALS.
IF YOU LOOK AT STANDARD
SCREENING BATTERY, A NUMBER OF
ASSAYS, THIS IS COMING FROM
RECENT PUBLICATIONS, THERE ARE
MORE OUT THERE.
BUT THIS COVERS THE FIRST 6 TO 7
WEEKS OF HUMAN CNS DEVELOPMENT,
STREAMS LINES A -- STREAMLINES
INTO A SINGLE QUANTITATIVE ASSAY
THAT LASTS A WEEK WITH A
SINGULAR READOUT, WORKING ON A
SECOND GENERATION WHERE THE
SURFACE WILL INSTRUCT
MORPHOGENESIS TO COVER A LOT OF
OTHER ASSAYS AS WELL IN THIS
SINGLE PLATFORM.
SO WE KNOW IT WORKS WITH DMSO
CHEMICAL LIBRARIES, UP TO .1%,
AND REPRODUCIBILITY WE SCALED
AND RUN THE ASSAY, SEE THE
ASSAY, AND GET REALLY GOOD
EFFICIENCIES ACROSS OUR
DIFFERENT REGIONS THAT WE'RE
ASSAYING.
WE KNOW WE CAN INTEGRATE HUMAN
METABOLISM INTO THIS ASSAY, NOT
ONLY TEST CHEMICALS BUT ALSO
TEST METABOLIZED FORMS, AND
WE'VE SEEN THAT ACTUALLY CHANGES
PROFILES, SOME MORE AND SOME
LESS TOXICS, FOR A SMALL NUMBER
OF COMPOUNDS, AGAIN FUNDED BY
NIEHS, TO DO A HUNDRED COMPOUND
LIBRARIES THAT WE'RE CURRENTLY
PUSHING AND DOING NOW, BUT WE'VE
DONE THIS FOR 30 POSITIVE AND
NEGATIVE CONTROLS FROM
LITERATURE KNOWN TO CAUSE NEURAL
TUBE DEFECTS OR DISRUPTION OF
NEURAL TUBE FORMATION AS WELL AS
CHEMICALS AND PESTICIDES THAT
CORRELATE WITH NEURAL TUBE
DEFECTS SO WE SEE GOOD
SENSITIVITY AND SPECIFICITY, OF
COURSE THIS IS A SMALL NUMBER OF
COMPOUNDS BUT WE'RE RAMPING UP
AND DOING MORE.
WE SEE UNIQUE DOSE-RESPONSE IF
YOU'RE LOOKING AT FORE BRAIN
VERSUS SPINAL ROSETTE ARRAYSA
CRITICAL FACTOR BECAUSE RODENT
MODELS FOR TUBE DEFECTS OCCUR IN
THE FOREBRAIN, THERE'S ONE OUT
OF 400 THAT SHOWS A SPINAL
PHENOTYPE.
IN HUMANS THE CLINICAL ASSAY,
CLINICAL PRESENTATION, IS
PRIMARILY SPINA BIFIDA AND SO WE
SEE THAT RESPONDING ROSETTE
RATES ARE SENSITIVE TO MOST
COMPOUNDS IN THE FOREBRAINS
RECAPITULATING ASPECTS OF CNS
DEVELOPMENT.
WE'RE READY FOR SORT OF DIPPING
OUR TOES INTO GETTING THIS INTO
REGULATORY HANDS AND TESTING
THIS AND WE HAVE GUIDANCE
DOCUMENTS, STARTING TO DO PLAN
FOR REGULATORY INTRODUCTION OF
THE ASSAY, AND SO WE'LL BE
READING THROUGH THOSE AND
CONTACTING YOU, WE ALREADY
REACHED OUT TO A COUPLE.
OUR GOAL TO ALLOW THE COMMUNITY
TO CONDUCT DEVELOPMENTAL
NEUROTOX IS ISTY IN A
QUANTITATIVE HIGH-THROUGHPUT
FORMAT, WONDERFUL ASSAY, HIGHLY
REPRODUCE ABLE FOR THE GOAL.
WE DO THIS AS A CONTRACT
RESEARCH SERVICE, WHERE WE CAN
CONDUCT SCREENS.
IF YOU'RE INTERESTED IN
COLLABORATIONS PLEASE CONTACT
US.
THE PLATES WE CAN SELL RIGHT
NOW.
WE'RE FINISHING LICENSES WITH
WISCONSIN, WE'LL BE ABLE TO SELL
A FULL KIT IN THE NEAR FUTURE SO
PEOPLE CAN CONDUCT ASSAYS AS
THEIR OWN FACILITY.
WE HAVE A WEB ACCESSIBLE IMAGE
SOFTWARE BETA TESTED, THAT WILL
BE AVAILABLE SOON, SUCH THAT
WHEN YOU USE A SINGLE PLATE AND
GENERATE 4,000 IMAGES, YOU CAN
UPLOAD THOSE TO HAVE THEM
ANALYZED WITHIN A MATTER OF
MINUTES.
WE THINK THIS WILL BE A REALLY
NICE TOOL FOR THE COMMUNITY TO
CONDUCT HUMAN DEVELOPMENTAL
NEUROTOXICITY AND OF COURSE
WE'RE EXPLORING OTHER AVENUES
FOR THIS.
WE HAVE A GRANT FROM NIEHS TO
TAKE THIS ASSAY THROUGH PACES,
WE'LL HAVE PUBLICATION COMING
OUT THIS SUMMER, OR THIS FALL,
AND THAT WILL INTRODUCE THE
SCALEUP AND UTILITY OF THIS
ASSAY AND THEN OF COURSE THAT
100-POUND SCREEN WE'LL BE
PUBLISHING THAT IN THE NEAR
FUTURE AS WELL.
THIS IS OUR ASSAY.
OUR MODEL IS HUMAN BRAIN AND
SPINAL CORD DEVELOPMENT, AND
THIS TECHNOLOGY WAS ALL FUNDED
BY REGULATORY FUNDING, BOROUGHS
WELLCOME, AND THEN EPA, NOW
NIEHS, SO WE HOPE THAT IT WILL
BE PUT INTO USE IN THE
REGULATORY COMMUNITY.
WITH THAT I'LL TAKE ANY
QUESTIONS.
>> THANKS VERY MUCH, RANDY.
WE HAVE MAYBE A MINUTE FOR ANY
QUICK CLARIFYING QUESTION IN THE
ROOM.
OKAY, NOT SEEING ANY.
THANKS VERY MUCH.
NOW WE'LL GO TO OUR LAST PUBLIC
COMMENTER, FRANK BARILE FROM
HUMANE SOCIETY OF THE UNITED
STATES.
>> EXCUSE ME, NICOLE?
>> CHARLES, DO YOU HAVE A
QUESTION FOR DR. ASHTON?
>> I DO.
THANKS.
I THINK TWO OR THREE SLIDES FROM
YOUR LAST SLIDE YOU HAD A GRAPH,
CHARLES KOVATCH, EPA.
A SLIDE SHOWING THE NEUROROSETTE
RESPONSE VERSUS I THINK
CONCENTRATION AND SOMETHING
ELSE.
I WONDER IF YOU COULD QUICKLY
DESCRIBE -- THAT'S THE ONE.
WHY WERE YOU SEEING -- WHY IS
THE ROSETTE FORMATION, YOU KNOW,
SO DIFFERENT THAN THE CELL
VIABILITY AND NEURAL
DIFFERENTIAL RATION?
>> YEAH, THAT'S A GREAT
QUESTION.
THE MORPHOGENESIS, THE POWER OF
ORGANIZE THEY MODEL HUMAN
MORPHOGENESIS, AND TO OCCUR
SIMULTANEOUSLY IN AN
ORCHESTRATED FASHION, WHEN WE
DID AN ASSAY, BATTERY, THE
ORCHESTRATION OF THOSE FACETS IS
WHAT GOVERNS CNS DEVELOPMENT.
WE OFTEN FIND -- NOT ALWAYS BUT
WE OFTEN FIND THE FORMATION
METRIC IS MORE SENSITIVE THAN
THE OTHER TWO, BECAUSE IF ANY OF
THE PERTURBATIONS THAT WON'T
KILL A CELL BUT MAY SLOW DOWN
PROLIFERATION, THAT ALTERS THE
ORCHESTRATION OF THAT ENTIRE
PROCESS TO AFFECT ROSETTE
FORMATION.
THE SHORT ANSWER IS LIGHT
PERTURBATION AND NEURAL
DIFFERENTIATION OR CELL
VIABILITY OR PROLIFERATION WOULD
BE HARD TO DETECT WHEN YOU LOOK
AT THOSE METRICS.
WE THINK ARE AMPLIFIED WHEN YOU
LOOK AT SORT OF THE
MORPHOGENESIS ASPECT WHICH
REQUIRES THOSE TO SIMULTANEOUSLY
OCCUR.
WE THINK IT'S AMPLIFIED LOOKING
AT MORPHOGENESIS AND OFTEN FIND
THAT METRIC IS MORE SENSITIVE.
>> GREAT.
THANK YOU.
>> THANK YOU.
IT'S REALLY EXCITING TO SEE THE
PROGRESS THAT'S BEING MADE IN
THING OR NIGHT SPACE.
LAST IS FRANK BARILE.
WE SEE YOUR NAME ONLINE.
CAN YOU UNMUTE AND --
>>CAN YOU HEAR ME?
>>YES, VERY WELL.
>> I HAD THE VIDEO ON BUT IT
DOESN'T SEEM TO BE SHOWING.
>> UNFORTUNATELY WECANNOT SEE
YOU.
>> HOPEFULLY YOU CAN HEAR ME.
>>WE HEAR YOU WELL.
>> THANK YOU FOR THE
OPPORTUNITY TO MAKE THE
PRESENTATION TODAY, ORAL
COMMENTS BEING TRANSMITTED TO
YOU FROM SUNNY TOWN IN SOUTHERN
ITALY, JUST NORTH OF NAPLES.
AND SIX HOURS AHEAD, FOUR IN THE
AFTERNOON.
ON BEHALF OF THE HUMANE SOCIETY
OF THE UNITED STATES, HSOF AND
MEMBERS AND SUPPORTERS, WE
APPRECIATE THE OPPORTUNITY TO
PROVIDE COMMENTS IN RESPONSE TO
THE APRIL 6, 2023 NOTICE, ICCVAM
PUBLIC FORUM.
I'D LIKE TO GIVE AN OVERVIEW OF
THE HISTORICAL ACCOMPLISHMENTS
ACHIEVED BY ICCVAM SINCE THE
ESTABLISHMENT AUTHORIZATION ACT
OF 2000, HR 4281, THE
ORGANIZATION HAS PROGRESSED IN
MOVING TOWARD DEVELOPMENT,
ACCEPTANCE, INCORPORATION OF
ALTERNATIVE APPROACHES TO ANIMAL
TESTING IN DRUG AND CHEMICAL
SAFETY ASSESSMENT.
THE STRONG LEADERSHIP AT NTP AND
NICEATM, NON-ANIMAL APPROACHES
CONTINUE TO BE ACKNOWLEDGED
THROUGH THE DEVELOPMENT.
AND ACCEPTANCE IN THE GLOBAL
TOXICOLOGY TESTING ARENA.
THROUGH REGULAR ENGAGEMENT WITH
REGULATORS, INDUSTRY,
STAKEHOLDERS ON LATEST TESTING
STRATEGIES, NICEATM PROVIDES
GUIDELINES, INFORMATION,
LEADERSHIP ABOUT MODERNIZING
SAFETY ASSESSMENTS AND
MINIMIZING ANIMAL USE.
WHILE WE ARE PLEASED TO SEE THAT
SOME OF THE ITEMS OF THE ICCVAM
MEETING FOCUSED ON ADVANCING
ALTERNATIVES I'M COMPELLED TO
SHARE HISTORICAL VIEW THAT WHILE
DEVELOPMENT AND ACCEPTANCE OF
NEW APPROACH METHODOLOGIES WITH
REGULATORY AGENCIES AND
STAKEHOLDERS HAS PROGRESSED, THE
RATE OF PROGRESS OVER THE LAST
TWO DECADES IS DISAPPOINTING.
PARTICULARLY CONCERNING
REGULATORY ACCEPTANCE OF NAMs.
SCIENTIFIC DEVELOPMENTS IN THE
FIELD OF TOXICOLOGY TESTING AND
PROGRESS ALONGSIDE REGULATORY,
INDUSTRIAL, PUBLIC STAKEHOLDERS
HAS BEEN EXPANDING FOR OVER 40
YEARS.
INITIAL RECOGNITION HAS BEEN
HISTORICALLY CHALLENGING.
SINCE THEN THERE'S BEEN
ACKNOWLEDGMENT OF SCIENCE AND
IMPROVEMENT AND ACCEPTANCE OF
GUIDANCE DOCUMENTS AND
REGULATORY FRAMEWORKS.
HOWEVER, THE CURRENT SITUATION
REGULATORY STATUS OF THE MODELS,
23 YEARS AFTER THE ESTABLISHMENT
OF ICCVAM, HAS BEEN SLIGHTLY
DISAPPOINTING.
THE NUMBER OF METHODOLOGIES
ACCEPTED BY OECD AS STANDARD
BEARER HAS INCREASED, THE NUMBER
OF PROTOCOLS AND PROCEDURES
ACCEPTED BY SOME U.S. FEDERAL
AGENCIES HAVE PROGRESSED SLOWLY.
A LONG LIST ACCEPTABLE DEMANDS
ON THE WRITTEN COMMENTS, THERE'S
A LINK TO THE CITATION, EPA.GOV.
DESPITE ADVANCEMENTS, TO
ACCURATELY ASSESS SAFETY AND
REPLACE ANIMAL TESTING FOR DRUG
DEVELOPMENT HAS BEEN THE WAY FOR
TWO DECADES.
IT'S OUR HOPE ICCVAM WILL
IMPROVE HISTORICAL RECORD BY
ASSUMING A MORE ACTIVE ROLE IN
ENCOURAGING FORMAL ACCEPTANCE OF
NAMs BY THE MEMBER AGENCIES.
I'D LIKE TO POINT OUT A FEW
THINGS ABOUT THE CURRENT LEVEL
OF TECHNOLOGY MPS AND MAKING
THEM OVER WITH SYSTEMS AND
LINKING WITH NAMs, PARTNERSHIP
BETWEEN NATIONAL CENTER FOR
ADVANCING TRANSLATIONAL
SCIENCES, NCATS, DARPA, AND THE
FDA, THAT INITIATED THE HUMAN
MICROPHYSIOLOGICAL SYSTEMS,
ORGANS ON CHIPS FOR DRUG SAFETY
AND EFFICACY TESTING PROGRAM,
HAS MET AND SURFACED
EXPECTATIONS IN THE RAPID
DEVELOPMENT AND
COMMERCIALIZATION OF SEVERAL
ORGAN ON A CHIP SYSTEMS THAT ARE
IN DIFFERENT PHASES OF
IMPLEMENTATION AND
COMMERCIALIZATION, THIS
COLLABORATION SHOULD SERVE AS
MODEL FOR OTHER TECHNOLOGY
DEVELOPMENT PROJECTS, AND FOR
PROJECTS THAT ADDRESS COMMON
INFORMATION NEEDS.
ATTEMPTS AT SIMULATING HAS
ACHIEVED TREMENDOUS SUCCESS IN
THE LAST TEN YEARS BUT
IMPLEMENTATION IS STILL TO BE
REALIZED.
AT THE CURRENT RATE
IMPLEMENTATION WILL PROBABLY NOT
OCCUR FOR AT LEAST ANOTHER 25
YEARS.
THERE'S A TREMENDOUS OPPORTUNITY
HERE FOR ICCVAM TO ACCELERATE
THIS TIMELINE.
COMMENTING ON VALIDATION, WITH
THE RECOGNITION THAT MANY IN
VITRO METHODS WERE ENDORSED 10
TO 15 YEARS AGO NOT INTEGRATED
OR ACCEPTED BY REGULATORY
AGENCIES AS APPROVED MODELS FOR
TOXICITY TESTING ICCVAM
PUBLISHED A STRATEGIC ROADMAP,
ALSO THE CITATION IS IN THE
WRITTEN COMMENTS AS A LINK,
PUBLISHED STRATEGIC ROADMAP IN
JANUARY 2018 AS A NEW STRATEGY
FOR TOXICITY TESTING.
IN ORDER TO EXPEDITE DEVELOPMENT
AND USE OF NAMs AND PROVIDE
INFORMATION MORE RELEVANT TO
HUMAN HEALTH AND EXISTING
ANIMAL-BASED METHODS.
SUCCESSFUL DEVELOPMENT AND
IMPLEMENTATION OF THESE NOVEL
AND INNOVATIVE APPROACHES
REQUIRES COORDINATED EFFORTS,
THAT ADDRESS THREE STRATEGIC
GOALS.
CONNECT END USERS WITH
DEVELOPERS
USE OF ROBUST PRACTICES, AND,
THREE, ENCOURAGE ADOPTION AND
ALLS OF NEW METHODS AND
APPROACHES BY FEDERAL AGENCIES
AND REGULATED INDUSTRIES.
RECENTLY, PUBLICATION OF 2022
AGAIN CITATION HAS A LINK IN THE
WRITTEN COMMENTS, IN THE
PUBLICATION ENTITLED A FRAMEWORK
FOR ESTABLISHING SCIENTIFIC
CONFIDENCE IN NEW APPROACH
METHODOLOGIES OFFER A MODERN
FLEXIBLE BASIS TO ESTABLISH
SCIENTIFIC CONFIDENCE IN NAMs
THAT REGULATORY ASSESSMENT OF
CHEMICALS FOR HUMAN HEALTH
EFFECTS, THE AUTHORS PROPOSE, I
QUOTE, FIVE ESSENTIAL ELEMENTS
THAT FORM THE BASIS OF A
FRAMEWORK THAT CAN BE APPLIED BY
REGULATORS OR OTHER END USERS TO
ESTABLISH CONFIDENCE IN NAMs
USED INTERNATIONALLY TO ASSESS
POTENTIAL CHEMICAL EFFECTS ON
HUMANS AND PROVIDE INFORMATION
NEEDED FOR REGULATORY DECISION
MAKING, END QUOTE.
INTENDED TO PROVIDE CLARITY, IN
MODELS, AND ESTABLISH A PROCESS
FOR DETERMINING THE ADEQUACY OF
NAMs, OVERALL PERFORMANCE.
TOGETHER AS PART OF INTEGRATED
APPROACH TESTING AND ASSESSMENT,
OR AS STAND ALONE ASSAYS.
THE FRAMEWORK CONSISTS OF FIVE
ESSENTIAL ELEMENTS, WHICH HAVE
BEEN NOTED IN PREVIOUS
PRESENTATIONS YESTERDAY.
THEY INCLUDE FITNESS FOR
PURPOSE, HUMAN BIOLOGICAL
RELEVANCE, TECHNICAL
CHARACTERIZATION, DATA INTEGRITY
AND TRANSPARENCY, INDEPENDENT
REVIEW.
THIS FRAMEWORK AND ELEMENTS
BEARS RESEMBLANCE TO VARIOUS
OTHER HISTORICAL PROPOSALS MADE
BY A NUMBER OF AUTHORS AND
ORIGINALLY DESCRIBED EARLIER IN
1994.
AND LATER CHARACTERIZED IN
GUIDANCE DOCUMENTs BY OECD
BOTH WITH CITATIONS IN WRITTEN
COMMENTS.
SOME CORRESPONDING COMPARABLE
TERMS AND PROPOSED DEFINITIONS
SUCH AS RELEVANCE, RELIABILITY,
SENSITIVITY, SPECIFICITY,
STANDARDIZATION, AND
MULTI-LABORATORY MULTI-METHOD
PROGRAMS, MANY WERE PROMOTED AS
PART OF VALIDATION PROGRAMS FOR
ACUTE ORAL, DERMAL, TOXICITY
TESTING TOOK YEARS TO COMPLETE
AND THEN WEREN'T FULLY
INTEGRATED BY ALL AGENCIES.
THE POINT OF THIS BEING THE
ICCVAM CAN PROVIDE GUIDANCE AND
ENCOURAGE AGENCIES TO
ACKNOWLEDGE AND ACCEPT NEW
FRAMEWORK WHILE INCORPORATING
SOME OF THE OLD FRAMEWORKS SO
THAT REPETITION AND
CLARIFICATION SAME OR SIMILAR
TERMS IN THE NEXT 20 YEARS DOES
NOT IMPEDE PROGRESS WITH
STANDARDIZATION AND VALIDATION
OF NEW METHODOLOGIES.
AND ICCVAM GROUP WAS ESTABLISHED
IN 2021 CREATE NEW VALIDATION
SCHEME WHICH WE ANTICIPATE WILL
SOON RELEASE A DRAFT UPDATING
1997 DOCUMENT.
CITATION LINK.
WE REQUEST THAT ICCVAM TO
ENCOURAGE ITS MEMBER AGENCIES TO
EMBRACE THIS APPROACH, CREATING
SCIENTIFIC CONFIDENCE NEEDED TO
ADVANCE NAMs IN A TANGIBLE
WAY.
IN CONCLUSION, TO SUCCESSFULLY
IMPLEMENT ORIGINAL OBJECTIVES
ESTABLISHED WITH THE FORMATION
OF ICCVAM, FURTHER REDUCE
RELIANCE ON ANIMAL TEST METHODS,
HSUS AND HSLF URGE MEMBER
AGENCIES TO FOCUS ON
COORDINATING EFFORTS TO ENSURE
NAMs ARE ACCEPTED FOR LAYINGER
TO USE, ALSO PROTECTING HUMAN
AND ENVIRONMENTAL SAFETY.
HSLF AND HSUS WILL WORK WITH
NICEATM OR ANY ICCVAM AGENCY TO
HAVE ACHIEVED COMMON GOAL OF
REPLACING ANIMALS WITH RELEVANT
STRATEGIES.
THANKS FOR YOUR CONSIDERATION OF
THESE COMMENTS.
>> THANK YOU VERY MUCH.
THAT WAS AN EXCELLENT SEGUE INTO
THE PRESENTATIONS THAT MYSELF
AND DR. DAVE ALLEN WILL GIVE
LATER IN THE AGENDA BECAUSE
THERE WERE A NUMBER OF TOPICS
MENTIONED IN THOSE COMMENTS WE
WILL PROVIDE SOME FEEDBACK AND
UPDATES ON.
APPRECIATE THAT.
WE'RE OUT OF TIME FOR THIS
PARTICULAR AGENDA ITEM.
WE NOW ARE ABLE TO REVISIT
PRESENTATION THAT WAS SCHEDULED
FOR YESTERDAY BUT WERE ABLE TO
REARRANGE THE AGENDA AND DR.
LATHROP IS ONLINE TO GIVE A
DEVELOPMENT ON THEIR PROGRESS ON
NINE, V.A. OFFICE OF RESEARCH
AND DEVELOPMENT.
>> LET ME SEND MY APOLOGIES FOR
NOT BEING ABLE TO BE ALONG
YESTERDAY.
I HAD A COUPLE PROBLEMS.
I GOT TO PARTICIPATE IN JUDGING
POSTERS FOR POSTDOCS AND
RESEARCHERS AT ATLANTA V.A.
ANNUAL NOW SECOND ANNUAL
RESEARCH DAY.
BUT, AGAIN, THANKFUL TO BE HERE.
I'M THE CHIEF VETERINARY MEDICAL
CENTER FOR VETERANS
ADMINISTRATION, AND NEXT SLIDE.
ADVANCE.
>> I'M GETTING THERE.
THERE WE GO.
>> THE V.A., WE'RE THE NEWEST
MEMBER OF ICCVAM, JOINED A
COUPLE YEARS AGO.
THE PREMISE FOR US JOINING WAS
THE FACT V.A. WAS REQUIRED BY
LAW FIVE-YEAR PLAN NOW, WE'RE IN
THE THIRD YEAR OF THAT, TO
ELIMINATE EITHER REDUCE, REFINE,
OR ELIMINATE USE OF CANINES,
FELINES, NON-HUMAN PRIMATES IN
OUR RESEARCH ENVIRONMENT.
WE'VE BEEN VERY SUCCESSFUL ON
THAT.
AS YOU CAN SEE, PUBLIC LAW
116-94, THIS IS ONE OF MY FIRST
FORAYS INTO BEING MANDATED TO
REDUCE USE OF ANIMALS AND IT HAS
WORKED OUT.
NEXT SLIDE.
AS YOU CAN SEE, STARTED IN 2018
WITH 2019 AND 2020, FINAL
ITERATION IS A WELL-DESIGNED
(INDISCERNIBLE) AND WE'RE
HEARING FROM THAT.
ONE OF THE PARTS WE SUDDENLY
REALIZED IN.
V.A. I'VE BEEN IN THIS 2 1/2
YEARS, ROOM FOR US TO IMPROVE
USING ANIMALS FOR RESEARCH TO
INVOLVE NAMs IN RESEARCH
APPROACHES TOO.
WE WENT TO ICCVAM, AND I LEARNED
QUITE A BIT IN 2 1/2 YEARS,
PRETTY MUCH MORE PURE ANIMAL
USERS MOST OF MY CAREER INTO
USING USE OF NAMs AND
EDUCATING RESEARCH OTHERS
DIFFERENT AVENUES, DIFFERENT
APPROACHES.
NEXT.
SO, FIRST THING I DO, WENT OUT
AND IDENTIFIED WHAT ARE SOME
RESEARCHERS ACROSS THE UNITED
STATES DOING, WE HAVE 70
RESEARCH MODALITIES IN OUR
VETERANS HOSPITALS ACROSS THE
UNITED STATES, MICRO FLUEDIC
TUBULAR, FUNCTIONAL TISSUE
MODEL, IN VITRO MODELS OF
TOXOPLASMOSIS.
ONE OF THE FIRST THINGS WE DID,
EXECUTIVE COMMITTEE FORMED, MUCH
TO THE V.A.'S CREDIT WE HAVE NOW
PUT OUT RFAs FOR DEVELOPING
AND VALIDATING ALTERNATIVES FOR
CANINES, FELINES, NON-HUMAN
PRIMATE, AND THANKS TO OUR
ADMINISTRATION WE'VE EXTENDED
THAT TO DEVELOPING AND
VALIDATING ALTERNATIVES TO USE
OF ANIMALS IN RESEARCH ACROSS
OUR RESEARCH ENDEAVORS.
NEXT.
AND SO PROGRAMMATIC APPROACH TO
ALTERNATIVE METHODS HOW WE'VE
BEEN UTILIZING OUR MONEY,
UTILIZING OUR EFFORTS, ONE THING
WE DO IS EXPAND OPPORTUNITIES TO
UTILIZE ALTERNATIVE METHODS TO
MEMORANDUMS ARE OUR AFFILIATES.
V.A. STRUCTURE IS THAT.
WE USE A LOT OF UNIVERSITIES AND
OTHER AFFILIATES TO GET OUR
RESEARCH ACCOMPLISHED.
AND ALL OF OUR MOUs IN THE
LAST TWO YEARS, WE'RE UTILIZING
THESE AFFILIATES AND THEIR
APPROACH TO NAMs AND MAKING IT
A UNIFIED APPROACH WITH V.A.
WE'VE SIGNIFICANTLY EXPANDED
MONETARY INCENTIVES.
NOW INVESTIGATORS CAN ACTUALLY,
IF THEY HAVE ARE DEVELOPING
ALTERNATIVE METHOD, THEY CAN
APPLY TO ANIMAL MODELS AND WE
WILL FUND THEM.
TO DATE WE HAVE THREE FUNDED
STUDIES, AND WE'RE ANTICIPATING
MANY MORE.
WE'VE DEVELOPED REVIEW CRITERIA,
ONE THING MISSING IN V.A.
APPROACH TO USING NAMs WAS
INVESTIGATORS WERE NOT QUITE
AWARE OF IT.
THANKS TO OUR EXECUTIVE
COMMITTEE, WE NOW HAVE A VERY
REASONABLE SUPPLEMENTAL
EDUCATION PROGRAMS, WE REACH OUT
TO INVESTIGATORS, MAKE SURE THEY
ARE AWARE OF ALL THE TOOLS
ICCVAM OFFERS AND ALTERNATIVE
METHODS WE OFFER AND ARE
AVAILABLE.
ONE OF THE OUTCOMES WILL BE FOR
THE V.A., COME BOOK IS THIS
APPROACH LATE, I SEE HOW WE
TRANSITIONED ANIMAL STUDIES
TOWARDS NAMs.
SEEING WHICH ONE CAN BE
REPLACED, WHERE WE HAD SUCCESS,
ALSO GENERATING ALTERNATIVE
APPROACHES.
TO MONITOR THIS PROGRESS HAVE
RETAINED SERVICES OF INDEPENDENT
RESEARCH ORGANIZATION, ANALYZE
AND EVALUATE NOT ONLY
REFINEMENT, REDUCTION,
ELIMINATION, THEY ARE
INCORPORATING ANALYSIS HOW WE'RE
ACTIVELY PROMOTING ALTERNATIVE
METHODS AND HOW EFFICIENT AND
HOW SUCCESSFUL THE V.A. HAS BEEN
IN ALTERING OUR APPROACH, WHY
NOT ANIMAL RESEARCH FOR SOME
AREAS.
ONE OF THE THINGS EVERYBODY IS
AWARE OF, IN CONGRESS, A LOT OF
V.A.s DO USE ANIMALS IN
RESEARCH AREAS OUT THERE, MOST
APPROACHES TO THE PATH ACT
BECAUSE OF BURN PIT EXPOSURE AND
OTHER EXPOSURES, TOXICOLOGICAL
EXPOSURES THEY INCORPORATED IS
PUSHING TO NON-TRADITIONAL, YOU
KNOW, ALTERNATIVE METHODS.
NEXT.
FOR THOSE WHO WANT TO FIND OUT
HOW WELL WE'RE DOING, V.A. IS
VERY, VERY TRANSPARENT.
YOU CAN GO TO OUR V.A. ANIMAL
RESEARCH PROGRAM TO FIND OUT HOW
WE'RE ALTERING OUR PROGRAMS.
IN THE SPIRIT OF OUR MOUs, A
PROGRAM WITH THE UNIVERSITY OF
WISCONSIN USING AN EXISTING
POPULATION OF QUIET OWNED
ANIMALS, THERE BY REDUCING USE
OF OUR ANIMALS IN RESEARCH.
DO YOU HAVE ANY QUESTIONS?
I KNOW THIS IS VERY SHORT AND
VERY TO THE POINT AND AGAIN WE
ARE -- THE V.A. IS NEW AT THIS
BUT WE'RE GRASPING IT
WHOLEHEARTEDLY.
>>VERY EXCITING TO SEE THE
PROGRESS BEING MADE AT THE V.A.
DO WE HAVE ANY CLARIFYING
QUESTIONS IN THE ROOM?
OR ONLINE?
JUST A REMINDER TO FOLKS
PARTICIPATING VIA THE WEBCAST
THAT YOU CAN ALWAYS SUBMIT
QUESTIONS VIA THE ICCVAM
QUESTIONS E-MAIL ADDRESS THAT
WAS PROVIDED TO YOU VIA YOUR
REGISTRATION REMINDER E-MAIL AND
ALSO HAS BEEN DISPLAYED
THROUGHOUT THE COURSE OF THE
MEETING.
OKAY.
NOW WE WILL MOVE ON TO OUR NEXT
PRESENTATION.
OKAY.
I'M NICOLE KLEINSTREUER.
I HAVE THE PRIVILEGE OF BEING
DIRECTOR OF THE NTP INTERAGENCY
CENTER FOR EVALUATION OF
ALTERNATIVE TOXICOLOGICAL
METHODS, NICEATM.
IT'S EVEN HARD FOR ME TO SAY,
AND EXECUTIVE DIRECTOR OF
ICCVAM.
TODAY I WILL GIVE A
PRESENTATION, FIRST HALF IS
GOING TO FOCUS ON NAMs WORK
THAT'S ONGOING AT THE NIEHS
DIVISION OF TRANSLATIONAL
TOXICOLOGY, NIEHS PRINCIPAL
REPRESENTATIVE IS IN THE BRITISH
VIRGIN ISLANDS, WARREN CASEY
CAN'T BE HERE TO GIVE THIS PART
OF THE PRESENTATION SO I'M DOING
DOUBLE DUTY HERE.
THE SECOND HALF IS GOING TO TALK
ABOUT SOME EFFORTS, RECENT
UPDATES ON ACTIVITIES THAT
NICEATM HAS ONGOING IN ADDITION
TO GREAT WORK THAT YOU HEARD
ABOUT YET FROM KAMEL MANSOURI IN
COMPUTATIONAL TOOLS SPACE.
THE DIVISION OF TRANSLATIONAL
TOXICOLOGY AT NIEHS HAS FOUR
PROGRAM AREAS, EXPOSURE BASED
RESEARCH, HEALTH EFFECTS
INNOVATIONS, RESPONSIVE RESEARCH
PROGRAMS, AND PROGRAMS IN
STRENGTHENING CAPABILITIES LIKE
SCIENTIFIC CYBER INFRASTRUCTURE.
THESE PROGRAMS TOGETHER TRY TO
COLLABORATIVELY ADDRESS PUBLIC
HEALTH CHALLENGES, AND GENERATE
TRUSTED SCIENTIFIC NFC TO
SUPPORT DECISION MAKING
PARTICULARLY BY OUR REGULATORY
COLLEAGUES, AND ARE FOCUSED ON
DEVELOPING AND APPLYING
INNOVATIVE TOOLS AND STRATEGIES,
AND I WISH THAT I HAD TIME TO
NAME EVERY PERSON IN THIS PHOTO
BECAUSE THEY HAVE CONTRIBUTED
TREMENDOUSLY TO THE WORK THAT
I'M GOING TO SHOW TODAY, IN THE
NEXT COUPLE SLIDES.
BUT THAT'S ONE OF OUR MORE
RECENT GROUP PHOTOS FROM THE END
OF 2019, AND ON THE RIGHT-HAND
SIDE YOU CAN SEE THE
TRANSLATIONAL TOXICOLOGY
PIPELINE, SO THIS IS THE PREMISE
OF HOW WE OPERATE ACROSS MANY
PROJECTS, SO BRINGING ALL THE
TOOLS IN THE TOOLBOX TO BEAR ON
TACKLING DIFFICULT PUBLIC HEALTH
CHALLENGES AND THAT OBVIOUSLY
INCLUDES SOME DEGREE OF ANIMAL
MODELS BUT ALSO INCLUDES A
TREMENDOUS AMOUNT OF NAMs FROM
COMPLEX IN VITRO SYSTEMS TO
HIGH-THROUGHPUT SCREENING UNDER
THE TOX21 PROGRAM, COMPUTATIONAL
ANALYSES, SYSTEM THE AIC
REVIEWS,
REVIEWS.
THE DNT HEI TO EVALUATE RISK TO
DEVELOPING NERVOUS SYSTEM.
SO IN COORDINATION WITH OUR EPA
COLLEAGUES, WITH COLLEAGUES AT
OECD, STRATEGY ENCOMPASSES
APPROACHES, IN VITRO INCLUDES
ASSAYS THAT COVER KEY PROCESSES
OF NEURODEVELOPMENT AND WE HEARD
YESTERDAY ABOUT OECD GUIDANCE
DOCUMENT THAT WAS RECENTLY
APPROVED BY THE WNT AND
PUBLISHED LATER THIS SUMMER.
DNT IN VITRO BATTERY IS USED TO
TEST A NUMBER OF CHEMICALS,
CRITERIA HIGHLIGHTED ON THE
SLIDE IN THE BLUE BOX, AND PHASE
1 COMPRISED OF 115 CHEMICALS
THAT TESTING HAS BEEN FINALIZED,
DATA ANALYSIS HAS ALSO BEEN
DONE, AND MANUSCRIPT IN
PREPARATION.
AND PHASE 2 IS ADDITIONAL 100
CHEMICALS SENT OUT FOR TESTING
TO THE VARIOUS CONTRACT LABS.
THE NEXT HEI PROGRAM IS FOCUSED
ON CARCINOGENESIS AND FOCUSED ON
TRYING TO DEVELOP A PROGRAM
AROUND TRANSLATIONAL HUMAN
RESEARCH, SO DDT PARTNERED WITH
DEPARTMENT OF DEFENSE WHICH HAS
A TREMENDOUS RESOURCE IN THEIR
SERUM REPOSITORY, OVER 70
MILLION SAMPLES FROM SERVICE
MEMBERS SINCE THE LATE 198 0s,
LONGITUDINAL SAMPLE, BEGINNING
WHEN THEY ENLIST AND COLLECTED
EVERY YEAR DURING TERM OF
SERVICE.
THOSE CAN BE PAIRED WITH HEALTH
RECORDS FROM THE SERVICE MEMBERS
AND FROM THINGS LIKE KNOWN
EXPOSURES BASED ON ENVIRONMENTS
THEY WERE WORKING IN OR SERVING
IN.
SO USING NOVEL OMICS APPROACHES
LIKE PROTEOMICS, METABOLOMICS,
TO UNDERSTAND BETWEEN EXPOSURES
AND PRE-NEOPLASTIC PATHOBIOLOGY
ALL THE WAY TO DISEASE OUTCOMES
IN THE CANCER SPACE.
THE NEXT PROGRAM IS THE
CARDIOVASCULAR HEI, AND THIS IS
TRYING TO UNDERSTAND THE
CONTRIBUTIONS OF ENVIRONMENTAL
CHEMICAL EXPOSURES TO
CARDIOVASCULAR RISK ACROSS THE
POPULATION.
AND ALONG TRANSLATIONAL
TOXICOLOGY PIPELINE WE HAVE
NAMs APPROACHES BEING
DEVELOPED AND APPLIED TO
UNDERSTANDING CARDIOVASCULAR
RISK.
ONE OF THEM IS SYSTEMATIC
EVIDENCE MAP TO LOOK IT THE THE
BODY OF EVIDENCE CONNECTING
CHEMICAL EXPOSURE TO
CARDIOVASCULAR EFFECTS, AND THAT
IS IN THE FINAL STAGES AND IS
BEING DEVELOPED AND WRITTEN FOR
PUBLICATION, IT'S A VERY COOL
INTERACTIVE TABLEAU DASHBOARD
WHERE YOU CAN LOOK AT DIFFERENT
TYPES OF EXPOSURES, LINES OF
EVIDENCE, IN VIVO, IN VITRO,
HUMAN EPIDEMIOLOGICAL AND
UNDERSTAND WHAT IS THE BODY OF
EVIDENCE CONNECTING CERTAIN
EXOGENOUS EXPOSURES TO DIFFERENT
CARDIOVASCULAR ENDPOINTS.
AND THEN WE HAVE A WHOLE PROGRAM
AROUND COMPUTATIONAL MODELING OF
CARDIOVASCULAR RISK SO
INTEGRATING HIGH-THROUGHPUT
SCREENING DATA FROM TOX21
PROGRAM, MAPPING THAT TO TWO
CARDIOVASCULAR ENDPOINTS,
MOLECULAR AND CELLULAR LEVEL.
THE COMBINED EXPOSURES AND
MIXTURES PROGRAM IS A
PARTNERSHIP WITH BOTANICAL
SAFETY CONSORTIUM SO THIS
INCLUDES NIEHS, FDA, AND HEFI,
AN INDUSTRY CONSORTIUM, THERE'S
OVER 150 MEMBERS FROM ACADEMIA,
GOVERNMENT, INDUSTRY LOOKING AT
SUIT BUILT OF NAM-BASED TOXICITY
ASSAYS TO ASSESS THE POTENTIAL
TOXICITY OR RISK OF COMPLEX
MIXTURES OF BOTANICAL
INGREDIENTS, TECHNICAL WORKING
GROUPS WITH EXPERTISE IN EACH
PRIOR AREA, TO IDENTIFY
BOTANICAL INGREDIENTS AND ASSAYS
THAT MIGHT BE APPROPRIATE FOR
TESTING THOSE INGREDIENTS AND
EVALUATING TOXICITIES, END GOAL
TO DEVELOP COMPREHENSIVE
FRAMEWORK AND TOOLBOX FOR
EVALUATING SAFETY OF OF
BOTANICALS, IDENTIFYING ASSAYS
READY FOR PRIME TIME, THOSE
AREAS THAT NEED FURTHER
DEVELOPMENT, AND EVENTUALLY
EXTEND THE TOOLBOX BEYOND
BOTANICALS.
OCCUPATIONAL EXPOSURES PROGRAM
AT THE DIVISION OF TRANSLATIONAL
TOXICOLOGY IS EVALUATING
CAPABILITIES FOR PREDICTING
ADVERSE HEALTH EFFECTS IN THE
INHALATION TOXICOLOGY SPACE,
LOOKING AT A NUMBER OF NAMs
THAT COVER DIFFERENT IN VITRO
MODELS AND MICROPHYSIOLOGIC
SYSTEMS LIKE LUNG ON A CLIP TO
EVALUATE HUMAN RESPIRATORY
TOXICITY USING HUMAN CELL-BASED
APPROACHES, ONE IS AIR-LIQUID
INTERFACE, USING HUMAN DERIVED
PRIMARY AIRWAY CELLS TO TEST
CHEMICAL EXPOSURES IN HUMAN
RELEVANT SYSTEM AND DO THINGS
LIKE UNDERSTAND DIVERSITY OF
RESPONSE ACROSS HETEROGENEOUS
POPULATION BY USING MULTIPLE
DONORS AND LOOKING AT THE
VARIABILITY OF THAT RESPONSE AND
SENSITIVITY OF THOSE RESPONSES.
AT THE MOMENT, THERE'S A STUDY
IN PROGRESS LOOKING AT 2,
3-PENTANEDION VAPORS, ARTIFICIAL
BUTTER FLAVOR IN POPCORN,
ADVERSE EFFECT IN WORKERS IN
FACTORIES.
AND THE FIRST AREA FOCUSED ON
HERE IS TRYING TO IMPROVE AND
UPDATE METHODS AROUND APPROACHES
TO CLUSTERING AND CLASSIFICATION
OF COMPOUNDS, BASED ON
STRUCTURES, SO LOOKING AT REALLY
BEST PRACTICES AROUND DEFINING
CONCEPTS OF STRUCTURAL
SIMILARITY USING SUPERVISED AND
UNSUPERVISED APPROACHES.
THERE WAS A WORKSHOP, KAMEL
MANSOURI, LAST YEAR, SCAN THE QR
CODE, HOW TO DEFINE SIMILARITY
IN A GENERAL WAY BUT REALLY IN
AN ENDPOINT-SPECIFIC WAY.
SO THINKING ABOUT ENDPOINT THAT
YOU'RE TRYING TO PREDICT OR
UNDERSTAND AND LOOKING AT
SIMILARITY WITH RESPECT TO THAT
PARTICULAR ENDPOINT AND THERE'S
A WORKSHOP REPORT BEING WRITTEN
UP FOR THAT RIGHT NOW.
AND THEN CPT PROGRAM ALSO DOES A
LOT OF SYSTEMATIC EVIDENCE
MAPPING SIMILAR TO WHAT I
DESCRIBED FOR CARDIOVASCULAR HEI
TEAM AND WE WORK CLOSELY WITH --
ACROSS MEMBERS OF THE DIFFERENT
TEAMS TO APPLY BEST PRACTICES
AND APPROACHES TO DOING
SYSTEMATIC EVIDENCE MAPPING AND
THEY HAVE ONE RIGHT NOW LOOKING
AT ORGANOPHOSPATE FLAME
RETARDANTS, PERSONAL CARE
PRODUCTS AND EFFECT ON PUBERTY
AND FETAL DEVELOPMENT,
DEVELOPING TREMENDOUS RESOURCES
THERE.
OTHER WORK AT OTHER PMTs,
SCIENTIFIC CYBER INFRASTRUCTURE
PMT, INCLUDES CHARLES SCHMITT
AND JENNIFER FOSTEELL LEADING
EFFORTS TO MAKE THE VALUABLE
DATA THE DIVISION OF
TRANSLATIONAL TOXICOLOGY AND
BROADER NATIONAL TOXICOLOGY
PROGRAM HAVE PRODUCED OVER THE
LAST SEVERAL DECADES, MAKING
THAT ACCESSIBLE.
SO I'M SURE MANY OF YOU HAVE
HEARD OF FAIR PRINCIPLES, DATA
OBJECTS AND DATA RESOURCES
SHOULD BE FINDABLE, ACCESSIBLE,
INTEROPERABLE, REUSABLE, THAT
MEANS THEY ARE RESOURCES THAT
SHOULD BE UNDERSTANDABLE BY
HUMANS AND MACHINES IN A WAY
THAT ALLOWS THEM TO BE COMBINED
INTO LARGE SUPER SETS OF DATA
USED TO BUILD AND TRAIN MODELS,
TO VALIDATE NEW APPROACHES, ET
CETERA.
AND SO CHARLES AND JENNIFER ARE
LEADING EFFORTS TO EFFORTS DTT
DATA DICTIONARIES, TO USE OUR
IN-HOUSE ONTOLOGICAL EXPERTISE
TO APPLY THINGS LIKE CONTROLLED
VOCABULARIES, STANDARDIZED
TERMINOLOGIES WITH SUBGROUPS
LIKE KNOWLEDGE MANAGEMENT TEAM
COLLABORATING WITH FEDERAL
PARTNERS LIKE EPA AND ENGAGING
WITH OTHER ONTOLOGY COMMUNITIES
AND OUR NIEHS GRANTEES.
ONE SPECIFIC EXAMPLE IS THE
ENVIRONMENTAL HEALTH LANGUAGE
COLLABORATIVE, THEIR MISSION IS
TO PROMOTE INTEROPERABLE
TERMINOLOGIES AND BEST PRACTICES
AROUND CREATING FAIR DATASETS
SUCH THAT WE CAN LEVERAGE THE
WEALTH OF DATA AVAILABLE TO US
IN A WAY THAT ALLOWS FOR
STANDARDIZEIZATION AND
UTILIZATION ACROSS APPLICATIONS.
IF YOU'RE INTERESTED CONTACT
STEPHANIE HOLMGREN AT THE DTT.
AND YOU CAN SEE A NUMBER OF
DIFFERENT USE CASES THAT ARE
BRIG LED BY EHLC COLLABORATORS
AT OUR FEDERAL AGENCY PARTNERS
LIKE EPA BUT ALSO ACADEMIC
PARTNERS LIKE HARVARD AND
COLUMBIA TO ANSWER QUESTIONS,
YOU KNOW, FAIRLY BASIC QUESTIONS
LIKE WHAT DATA EXIST FOR A GIVEN
EXPOSURE SCENARIO, GIVEN
CHEMICAL EXPOSURE, HOW DOES THAT
RELATE TO AN ENDPOINT, HOW CAN
WE COMPILE RELEVANT DATA IN A
WAY THAT IS FAIR AND ACCESSIBLE.
THAT WAS A WHIRLWIND TOUR OF
NAMs AT DTT.
I'LL SWITCH GEARS AND TALK ABOUT
WORK NICEATM IS DOING IN SUPPORT
OF ICCVAM.
SO NICEATM IS ALSO A PART OF THE
DIVISION OF TRANSLATIONAL
TOXICOLOGY, AND WE WORK CLOSELY
WITH ALL OF THE PROGRAM
MANAGEMENT TEAMS THAT I
MENTIONED IN THE LAST TEN SLIDES
OR SO.
BUT OUR PRIMARY RESPONSIBILITY
IS TO FULFILL OUR CONGRESSIONAL
MANDATE TO PROVIDE SUPPORT TO
THE INTERAGENCY COORDINATING
COMMITTEE FOR VALIDATION OF
ALTERNATIVE METHODS, ICCVAM, 17
FEDERAL AGENCIES.
WE HAVE A VERY BROAD PORTFOLIO
OF WORK.
I WON'T HAVE THE OPPORTUNITY TO
TALK ABOUT EVERY SINGLE ONE OF
THESE BULLETED ITEMS TODAY BUT
IF YOU'RE INTERESTED IN ANY
SPECIFIC TOPIC AREA PLEASE
FOLLOW UP WITH ME, I'M ALWAYS
DELIGHTED TO TALK OFFLINE ABOUT
WORK WE'RE DOING.
I ALSO HOPE THAT MOST OF YOU WHO
FOUND YOUR WAY HERE TODAY IN
PERSON OR ON THE WEBCAST ARE
ALREADY SUBSCRIBED TO THE
NICEATM NEWS E-MAIL LIST, BUT IF
YOU'RE NOT SCAN THE QR CODE OR
GO TO THE LINK AND MAKE SURE YOU
GET SUBSCRIBED TO THE
NEWSLETTER.
IT COMES OUT ALMOST WEEKLY AND
PROVIDES A WEALTH OF INFORMATION
ABOUT DEVELOPMENTS IN THE FIELD,
FUNDING OPPORTUNITIES, JOB
OPPORTUNITIES, NEW PUBLICATION,
CONFERENCES, ET CETERA.
AND THE BIENNIAL PROGRESS REPORT
IS PART OF THE CONGRESSIONAL
MANDATE, COMES OUT EVERY TWO
YEARS, ONE PARAGRAPH SUMMARY OF
EACH ACTIVITY OF ICCVAM
AGENCIES, THE WORK NICEATM DOES
TO SUPPORT AND WORK INDIVIDUALLY
OR IN PARTNERSHIP WITH ONE
ANOTHER.
ONE EXAMPLE OF WORK THAT WE'VE
BEEN CONTINUING OVER THE LAST
FIVE OR SIX YEARS THAT KAMEL
TOUCHED ON BRIEFLY YESTERDAY IS
THIS APPROACH WE'VE TAKEN TO
GLOBAL CROWDSOURCING OF
PREDICTIVE MODELS.
THESE ARE QUANTITATIVE STRUCTURE
ACTIVITY RELATIONSHIP MODELS,
MOST PEOPLE ARE FAMILIAR BUT
BASIC PREMISE IF YOU HAVE ENOUGH
DATA ON A DIVERSE CHEMICAL SET
YOU CAN USE ARTIFICIAL
INTELLIGENCE AND MACHINE
LEARNING APPROACHES TO TRAIN
ROBUST AND RELIABLE MODELS THAT
IDENTIFY COMPLEX RELATIONSHIPS
BETWEEN CHEMICAL FEATURES LIKE
MOLECULAR DESCRIPTORS OR
PhysChem CAL PRODUCTS AND
ENDPOINTS THAT YOU ARE TRIAL TO
PREDICT.
OPERA IS A SUITE OF THESE MODELS
INCLUDING PHYSICOCHEMICAL AND
TOXICITY PREDICTION MODELS.
WE CURATED DATASETS, SHARED WITH
COMPUTATIONAL CHEMISTRY GROUPS
AROUND THE WORLD, HAD THEM
SUBMIT MODELS BACK ON A TRAINING
SET AND HOLDOUT TEST SAID WE
USED TO EVALUATE PERFORMANCE AND
COMBINED THEM USING ENSEMBLE
APPROACH INTO THESE CONSENSUS
MODELS THAT CAN BE USED TO
PREDICT TOXICITY ACROSS THE
CHEMICAL UNIVERSE WITH DEFINED
STRUCTURE AND ARE ROBUST AND
RELIABLE.
WE HAVE THESE FOR ENDOCRINE
DISRUPTION, YESTERDAY MONIQUE
MENTIONED A WHITE PAPER PUT OUT
AT THE BEGINNING OF THE YEAR,
REFERS TO THE MODELS FOR E.R.
AND A.R., ESTROGEN AND ANDROGEN
RECEPTOR PATHWAY PREDICTION
BEING ACCEPTABLE FOR WEIGHT OF
EVIDENCE AND PRIORITIZATION OF
COMPOUNDS SO EXCITING TO SEE
REGULATORY APPLICATION OF THOSE
MODELS BY THE EPA.
WE ALSO HAVE COLLABORATIVE ACUTE
TOXICITY SUITE, CATMoS,
PREDICTS ORAL ACUTE SYSTEMIC
TOXICITY, BASED ON A DATASET OF
10,000 CHEMICALS WITH RODENT
DATA.
ONE OF THE WAYS IN WHICH WE'VE
STARTED TO ENLIST EVALUATING
MODEL PERFORMANCE IS TRY TO
UNDERSTAND VARIABILITY AND
REPRODUCIBILITY OF OUR
BENCHMARKS OF OUR BASELINES.
SO IT STANDS TO REASON THAT YOU
CAN'T EXPECT A MODEL TO DO
BETTER AT PREDICTING AN ENDPOINT
THAN THAT ENDPOINT DOES AT
PREDICTING ITSELF, RIGHT?
YOUR BASELINE FOR ASSESSING
PERFORMANCE OF A NEW APPROACH
SHOULD BE THE REPRODUCIBILITY OF
THAT EXISTING REFERENCE
STANDARD, IN THIS CASE IN VIVO
ANIMAL TEST.
SO, AS PART OF THIS PROJECT WE
HAD INDEPENDENTLY REPLICATED IN
VIVO ANIMAL DATA ON A COUPLE
THOUSAND CHEMICALS SO WE WERE
ABLE TO USE STATISTICAL
BOOTSTRAPPING APPROACH TO BOOT
STRAP THROUGH STANDARD
DEVIATIONS AROUND LD 50s OF
CHEMICALS WITH REPLICATE STUDIES
AND USE THAT TO DERIVE A 95%
CONFIDENCE INTERVAL WHICH
EQUATES TO A QUARTER LOG, PLUS
OR MINUS 25, SHOWN IN THE BLUE
SHADING AROUND THAT DOT PLOT,
WHICH, YOU KNOW, SERVES AS A
REASONABLE RANGE FOR EVALUATING
ACCEPTABLE LD 50 ESTIMATE ON AS
CHEMICAL BY CHEMICAL BASIS
LOOKING AT PREDICTIONS OF NEW
MODELS, AND SO CATMoS QSAR
PREDICTIONS PERFORM JUST AS WELL
AS PREDICTING ORAL TOXICITY
OUTCOME AND YOU HEARD MONIQUE
MENTION YESTERDAY WE'RE WORKING
WITH EPA AND ECOLOGICAL EFFECTS
DIVISION TO EVALUATE WHETHER OR
NOT YOU COULD USE THE PREDICTED
LD 50 VALUES IN RISK ASSESSMENTS
AND ARRIVE AT THE SAME
CONCLUSIONS OR BE JUST AS
PROTECTIVE AS THE IN VIVO LD 50
VALUE, THAT MANUSCRIPT IS BEING
WRITTEN FOR PUBLICATION RIGHT
NOW.
OUR NEXT GLOBAL COLLABORATIVE
VOWED SOURCING PROJECT EXTENDS
TO INHALATION, LC 50, WHERE YOU
SEE LETHALITY IN ANIMALS AFTER
INHALATION EXPOSURE, WE'VE
LOOKED ACROSS RECURSES FROM
ECHA, CHEMICOIDPLUS, DEPARTMENT
DEFENSE, EPA, EVALUATING UNITS
ARE STANDARDIZES, CONVERTING,
DETERMINING PHASE OF EXPOSURE,
WHETHER GAS, VAPOR, AEROSOL,
WE'VE BEEN ABLE TO LEAN ON
OPERA, OPERA PREDICTS MELTING
POINT, VAPOR POINT TO PREDICT
PHASE OF EXPOSURE BECAUSE ONLY
28% OF THE STUDY REPORTS WE
FOUND ACTUALLY REPORT THAT
PHASE.
BUT THE LONG AND SHORT IS AFTER
THIS MULTI-YEAR DATA CURATION
PROCESS WE'VE ENDED UP WITH A
PRETTY ROBUST DATASET FOR THE
MODELING EFFORTS SO WE HAVE OVER
A THOUSAND UNIQUE CHEMICALS IN
THE DATABASE, AND WE'RE GOING TO
BE KICK STARTING THIS GLOBAL
COLLABORATIVE EFFORT SOON, KAMEL
WILL LEAD THAT ON OUR SIDE AS
WELL.
MOST OF YOU ARE FAMILIAR WITH
THE WORK THAT WE'VE DONE OVER
THE LAST DECADE OR SO IN SKIN
SENSITIZATION.
AND THE ACCOMPLISHMENT FROM 2021
OF GETTING THE FIRST EVER
DEFINED APPROACH GUIDELINE UNDER
OECD, FOR SKIN SENSITIZEIZATION,
MAPPING TO CELLULAR AND KEY
EVENTS, AND PROVIDE A PREDICTION
OF THAT ENDPOINT, SKIN SENSE
ADVERTIS -- SENSITIZATION, GOOD
OR BETTER, WE KNOW DEFINED
APPROACHES BASED ON HUMAN
BIOLOGY ARE SUPERIOR TO THE
ANIMAL TEST, AND SO AS A
FOLLOW-UP TO THAT DASS GUIDELINE
UNDER OECD WANTED TO MAKE THE
APPLICATION OF THOSE DEFINED
APPROACHES MUCH MORE ACCESSIBLE
ACROSS THE USER COMMUNITY, SO
KIM FROM THE NICEATM GROUP LED
DEVELOPMENT OF A USER FRIENDLY
DASS APP, YOU CAN ACCESS ONLINE
THROUGH THAT WEB LINK OR BY
SCANNING THE QR CODE, AND ALLOWS
USERS TO DOWNLOAD A TEMPLATE AND
SPREADSHEET THEY CAN UPLOAD
THEIR OWN DATA IN AND WITH A
CLICK APPLY DIFFERENT DEFINED
APPROACHES TO PREDICT HAZARDS OR
POTENCY CATEGORIES AND HELPS TO
AVOID ANY OPERATOR ERROR AND
CONSISTENCY OF APPROACHES AND
APPLYING DEFINED APPROACHES.
WE ALSO HAVE A COLLABORATION
WITH UNILEVER TO DEVELOP,
FURTHER DEVELOP AND APPLY A
DEFINED APPROACH FOR SKIN
ALLERGY RISK ASSESSMENT, THIS IS
SOMETHING THAT GOES BEYOND
HAZARD AND POTENCY AND PROVIDES
A QUANTITATIVE POINT OF
DEPARTURE TO USE IN RISK
DEVELOPMENT APPLICATION, IT'S A
BAYESIAN MODEL WHICH MEANS IT
ACCOUNTS FOR VARIABILITY AND
PROVIDES PROBLEMISTIC OUTPUT
INCLUDING UNCERTAINTY, IF THERE
ARE EXISTING ANIMAL DATA OR
EXISTING HUMAN DATA THAT CAN BE
COMBINED WITH IN VITRO DATA OR
YOU CAN USE IN VITRO DATA ALONE
AND DEPENDING ON NUMBER OF
INPUTS YOU PUT INTO THE MODEL
YOU'LL GET VARYING
QUANTIFICATION OF UNCERTAINTY
AROUND THE OUTPUTS.
AND OUTPUT OF THE MODEL IS HUMAN
RELEVANT METRIC OF SENSITIZER
POTENCY DEFINED AS THE DOSE THAT
HAS A 1% CHANCE OF SENSITIZATION
ACROSS A POPULATION, TERMED THE
ED01, IT'S BEEN ACCEPTED ON THE
OECD WORK PLAN FOR EVALUATION
FOR INCLUSION IN DEFINED
APPROACH GUIDELINE, TG 497, WORK
ACTIVELY ONGONNA -- ONGOING.
MANY OF THE PROJECTS THAT I'VE
TALKED ABOUT ALREADY RELY VERY,
VERY HEAVILY ON HAVING ROBUST
REFERENCE DATASETS, AND MOST OF
THAT REFERENCE DATA CURATION IS
STILL DONE MANUALLY.
FROM IDENTIFICATION OF RELEVANT
PAPERS IN LITERATURE OR
SUBMISSIONS TO REGULATORY
AGENCIES, TO EXTRACTING ALL OF
THAT INFORMATION, TO Q.C.-ING
EXTRACTION, TO HARMONIZE
TERMINOLOGIES TO BE COMBINED
WITH OTHER EXTRACTED
INFORMATION, INTO LARGE FAIR
DATASETS, AND WE'RE LOOKING AT
APPLYING AUGMENTED INTELLIGENCE
APPROACHES SO USING
COMPUTATIONAL RESOURCES, LIKE
NATURAL LANGUAGE PROCESSING,
ARTIFICIAL INTELLIGENCE, DEEP
IMAGE PROCESSING, TO ACTUALLY
AUTOMATE EVERY STEP OF THAT
PROCESS, SO AUTOMATING
IDENTIFICATION OF PAPERS THAT
FULFILL CERTAIN MINIMUM
CRITERIA, IN TERMS OF THEIR
STUDY PROTOCOLS TO BE CONSIDERED
HIGH QUALITY GUIDELINE-LIKE
PAPERS THAT REGULATORY AGENCIES
WOULD CONSIDER TO AUTOMATING
EXTRACTION OF INFORMATION, NOT
JUST FROM THE TEXT OF THE PAPERS
BUT ALSO FROM TABLES AND
FIGURES, TO PROGRAMMATICALLY
AUTOMATING ANNOTATION OF THAT
EXTRACTED INFORMATION AND
APPLYING THOSE STANDARDIZED
TERMINOLOGYING SO THEY CAN BE
COMBINED WITH OTHER DATASETS
THAT ARE ALSO USING CONTROLLED
VOCABULARIES OR STANDARDIZED
TERMINOLOGIES.
THE LAST PIECE, ANNOTATION
PIECE, WE'RE MAKING GREAT
PROGRESS BUT THAT PIECE IS
FURTHEST ALONG.
WE HAVE A PAPER UNDER REVIEW AT
EHP RIGHT NOW DEMONSTRATES THE
APPLICATION OF SOFTWARE TO
AUTOMATE ANNOTATION PORTION, TO
A SET OF DEVELOPMENTAL TOXICITY
GUIDELINE STUDIES.
ONE THING THAT WAS HIGHLIGHTED
DURING THE PUBLIC COMMENTING
PIECE IS IMPORTANCE OF COMMUNITY
ENGAGEMENT AND OF THE
OPPORTUNITIES TORE NEW APPROACH
METHODOLOGIES TO ADDRESS REALLY
CRITICAL CONSIDERATIONS OF
HETEROGENEOUS RESPONSES ACROSS
POPULATIONS.
UNDERSTANDING THAT NOT ONLY ARE
HUMANS NOT 200-POUND RATS, WE'RE
ALSO NOT THE SAME AS ONE
ANOTHER, RIGHT?
THERE'S QUITE A DIVERSITY OF
RESPONSES, AND THERE'S
SUSCEPTIBILITY FACTORS THAT COME
INTO PLAY DRIVEN BY GENETICS,
EPIGENETICS, COMORBIDITIES,
CO-EXPOSURES, ENVIRONMENTAL
JUSTICE ISSUES.
IN OCTOBER LAST YEAR WE
ORGANIZED THE FIRST WORKSHOP OF
WHAT WE HOPE WILL BE MANY IN A
SERIES ON OPPORTUNITIES TO USE
NEW APPROACH METHODOLOGIES TO
ADDRESS VARIABILITY AND
SUSCEPTIBILITY, DIVIDED INTO A
COUPLE SESSIONS.
IT WAS LOOKING AT STATE OF THE
SCIENCE, WHERE DO WE HAVE NAMs
THAT ARE CAPABLE OF REPRESENTING
THINGS LIKE GENETIC DIVERSITY
ACROSS POPULATIONS OR
REPRESENTING DISEASE STATES THAT
COULD CONFER VULNERABILITY ON
INSENSITIVE POPULATIONS, ALSO
LISTENING AND UNDERSTANDING FROM
THE COMMUNITY WHAT ARE THE
CONCERNS THAT THEY HAVE WHEN IT
COMES TO THEIR EXPERIENCE AND
ENVIRONMENTAL EXPOSURES AND
SENSITIVE AND SUSCEPTIBLE
SUBPOPULATIONS, THAT WORKSHOP
WAS CO-LED BY THE NIEHS DEPUTY
DIRECTOR AROUND ALISON HARRILL
OUR COLLEAGUE FROM THE U.S. EPA.
ONE AREA WE'RE TRYING TO
INCORPORATE VARIABILITY IN
POPULATIONS IN OUR TOOLS IN ICE
IN PARTICULAR IS THROUGH MA
METABOLISM.
WE HAVE SOME LEVEL INCORPORATED
BUT IT'S ONLY INTEGRATED VIA
VIRTUAL POPULATION SIMULATIONS,
GENERIC PBPK MODELS,
DISTRIBUTION OF PARAMETERS, AGE,
WEIGHT, CARDIAC OUTPUT, ET
CETERA, ALLOWS US TO AT LEAST
ESTIMATE SOME CONFIDENCE
INTERVALS AROUND INTERNAL
CONCENTRATIONS.
BUT WE KNOW THAT GENETIC
POLYMORPHISMS IN THE POPULATION
IN METABOLIC ENZYMES CAN REALLY
EXPERT STRONG INFLUENCES ON
PEOPLE'S ABILITY TO METABOLIZE
ANTIBIOTICS AND POTENTIALLY HAVE
HOW THEY MAY REACT TO XENOBIOTIC
EXPOSURE, PARTNERING WITH THE
EUROPEAN FOOD SAFE AGENCY
LOOKING AT ENZYMATIC ACTIVITIES
IN VITRO AND IN VIVO AND LOOK AT
ALLELIC FREQUENCY OF SINGLE
NUCLEOTIDE POLYMORPHISMS IN
METABOLIC ENZYMES SO WE'RE
INCORPORATING ALL OF THAT
INFORMATION INTO OUR
COMPUTATIONAL MODELS.
SO THIS IS OUR WORK FLOW FOR
THAT.
BASICALLY THE WORK FLOW PROVIDES
TISSUE LEVEL CONCENTRATIONS OF
METABOLITES WITH CONFIDENCE
INTERVALS DERIVED FROM THE
VARIABILITY AND ENZYME
EXPRESSION ACROSS THE
POPULATION.
THAT'S INCORPORATED INTO PBBK
MODELS WITH CLEARANCE RATES
BASED ON COEFFICIENT OF
VARIATION ACROSS A POPULATION
AND SO FOR WE'VE DONE THIS FOR
CYP 3A4 AND 2D 6 TRYING TO MOVE
INTO OTHER COMMONLY EXPRESSED
CYP ENZYMES.
I'M EXCITED ABOUT THIS ABILITY
TO LOOK NOT ONLY AT THE
CONCENTRATION OF PARENT
CHEMICALS BUT ALSO PREDICTED
CONCENTRATION OF METABOLITE
CHEMICALS AND HAVE CONFIDENCE
INTERVAL THAT REPRESENTS THAT
POPULATION RANGE AND WE CAN FEED
THOSE INTO OUR TOXICITY
PREDICTION MODELS AND GET BETTER
REPRESENTATION OF SUSCEPTIBILITY
ACROSS A POPULATION.
ANOTHER IS TRY AND EXTEND
UTILITY OF THE IN VITRO
HIGH-THROUGHPUT SCREENING DATA
FROM TOX21 SAND INCORPORATE
EXPOSURE INFORMATION FROM FROM
DATABASES TO PREDICT THE
GEOSPATIAL RISK ACROSS
POPULATIONS AND ACROSS
COMMUNITIES.
AND SO WHAT WE'VE DONE HERE,
THIS IS A PROOF OF CONCEPT WHERE
WE LOOKED AT 41 CHEMICALS, THAT
ARE KNOWN AIR TOXIC, FROM THE
NATIONAL AIR TOXICS ASSESSMENT
DATABASE, AND THESE COMPOUNDS
HAVE A COMMON MOLECULAR TARGET,
SO THEY HAVE ALL PERTURBED
HIGH-THROUGHPUT SCREENING ASSAY
FOR UPREGULATION WHICH IS A
TARGET INVOLVED IN DISEASE
ETIOLOGY INCLUDING METABOLIC
DISRUPTION.
WE FIRST APPLIED IN VITRO AND IN
VIVO EXTRAPOLATION TO ESTIMATE
INTERNAL EXPOSURES BY CONVERTING
INHALED CONCENTRATION TO PLASMA
CONCENTRATION USING PBBK MODELS
CAN COUNTY SPECIFIC INFORMATION
AND USED THAT ESTIMATED PLASMA
CONCENTRATION AND CONCENTRATION
RESPONSE CURVES FROM IN VITRO
HIGH-THROUGHPUT SCREENING ASSAYS
TO DETERMINE CHEMICAL-SPECIFIC
EFFECTS IN EACH OF THE MIXTURE
COMPONENTS AND COMBINE THOSE
USING THREE MIXTURE MODELING
METHODS TO ESTIMATE THE JOINT
EFFECT FROM EXPOSURES TO THOSE
CHEMICAL MIXTURES ON THE
ACTIVITY LEVELS WHICH ARE THEN
GEOSPATIALLY MAPPED ACROSS THE
UNITED STATES.
AND SO THIS IS REALLY A PROOF OF
CONCEPT WORK FLOW THAT CAN CHEM
STRAIGHT USING NAMs LIKE
HIGH-THROUGHPUT DATA TO PREDICT
EARLY PERTURBATIONINGS AND MAP
THAT GEOSPATIALLY, THE NEXT STEP
WOULD BE TO CONNECT TO ADVERSITY
FROM ELECTRONIC HEALTH RECORDS.
ANOTHER PROJECT OFF THE GROUND
IN THE LAST SIX MONTHS IS
SUPPORTING METHOD DEVELOPED BY
OUR COLLEAGUES AT THE U.S. EPA
OFFICE OF RESEARCH AND
DEVELOPMENT, CHAD IS THE LEAD
HERE FROM RUSTY THOMAS' GROUP,
DEVELOPED A 3D HUMAN THYROID
MICROTISSUE ASSAY, SO CONSISTING
OF PRIMARY HUMAN THYROID CELLS
AND ASSESSING THYROID HORMONE
INHIBITION, IN A 96 WELL FORMAT,
HAS SHOWN PROMISING DATA IN
RESPONSE TO REFERENCE CHEMICALS,
SO WE'RE COORDINATING
INTERLABORATORY PRE-VALIDATION
STUDY, THERE'S A NUMBER OF LABS
THAT ARE ENGAGED HERE, LIFE NET
HEALTH, BAYER CROPSCIENCE,
CORTEVA, RECRUITED DOMESTIC AND
INTERNATIONAL REPRESENTATIVES TO
OUR VALIDATION MANAGEMENT TEAM,
REVIEWED THE SOP PROVIDED A
NUMBER OF POINTS OF FEEDBACK
THAT HAVE BEEN INCORPORATED, AND
SO NOW WE HAVE THE MATERIALS,
AGREEMENTS, MCRADA IN PLACE TO
DO TRANSFERABILITY TO LABS, VERY
EXCITED ABOUT THIS PROJECT.
AND WITH THE EVENTUAL GOAL OF
SOMEDAY TAKING THIS TO OECD AS
POTENTIAL TEST GUIDELINE.
MOST OF YOU HEARD ME TALK ABOUT
THE MPSCoRE WORK GROUP,
STARTED AT THE BEGINNING OF THE
PANDEMIC IN RESPONSE TO QUICKLY
EMERGING EVIDENCE ANIMAL MODELS
WERE NOT GOOD SURROGATES FOR
UNDERSTANDING PATHOPHYSIOLOGY OF
SARS-COV-2 IN HUMANS AND
POTENTIALLY NOT VERY GOOD
TESTING PLATFORMS FOR
UNDERSTANDING UTILITY OF
THERAPEUTICS.
SO THIS WAS GRAVE HUMAN HEALTH,
PUBLIC HEALTH CRISIS BUT ALSO
REALLY STRONG OPPORTUNITY FOR
NEW APPROACH METHODS IN
PARTICULAR MICROPHYSIOLOGIC
SYSTEMS REPRESENTING COMPLEXITY
OF HUMAN BIOLOGY TO PROVIDE
INFORMATION ON PATHOPHYSIOLOGY,
DISEASE MECHANISMS, AND
PLATFORMS TO TEST NOVEL
THERAPEUTICS.
SO WE FORMED THIS GLOBAL WORKING
GROUP, MPSCoRE, CO-LED BY
PARTNERS IN THE U.K., NC3Rs,
FUNDING PROJECTS UNDER THIS
MPSCoRE CORE INCLUDING
DEVELOPMENT OF A PORTAL IN THE
DATABASE, NOW BIOSTATISTICS
PLATFORM FUNDED BY NCATS UNDER
TISSUE CHIPS GRANT PROGRAM.
WE'RE NOW EXTENDING, CO-IS CO-E
TRANSITIONING TO LOOK AT MORE
BROAD APPLICABILITY OF THESE
MODELS NOT JUST TO COVID BUT
OTHER INFECTIOUS DISEASES.
SO AT THE END OF THIS MONTH, MAY
31 AND JUNE 1, WE HAVE TWO HALF
DAYS IN THE MORNING, SYMPOSIUM
ON ADVANCING RESEARCH AND
REGULATORY ACCEPTANCE FOR
INFECTIOUS DISEASE APPLICATIONS
AND WE HAVE A REALLY EXCITING
AGENDA, UP ON THE WEBSITE, WE'VE
GOT PARTICIPANTS FROM FDA, FROM
NIAID, FROM U.S. ARMY, NATIONAL
BIODEFENSE ANALYSIS AND
COUNTERMEASURES CENTER, U.K.
HEALTH SECURITY AGENCY, A NUMBER
OF ACADEMIC COLLABORATORS FROM
HARVARD WYSS INSTITUTE, AND ONE
OF MY PARTNERS IN CRIME DAN
TAGLE IS IS HERE IN THE ROOM AD
WE'LL HEAR FROM HIM.
THE LAST THING I'LL JUST BRING
TO YOUR AWARENESS IS A WORKSHOP
WE'RE PLANNING AT THE END OF
THIS YEAR, IN THE FALL ACTUALLY,
IN OCTOBER, ON NEW APPROACH
METHODOLOGIES TO MODEL
GASTROINTESTINAL TRACT FOR A
VARIETY OF DIFFERENT PURPOSES.
SO ONE LOOKING AT DE-RISKING
CHEMICALS FOR SYSTEMIC TOXICITY,
UNDERSTANDING IF YOU HAVE ORAL
EXPOSURE TO CHEMICALS ARE THOSE
CHEMICALS METABOLIZED, ABSORBED
THROUGH THE GUT WALL, DO THEY
JUST GET PASSED THROUGH THE
BODY, DO THEY CAUSE G.I.
TOXICITY THROUGH MICROBIOME OR
OTHERWISE, DO THEY CAUSE
ALLERGENAGAIN ISTY -- GENICITY,
IF YOU'RE INTERESTED IN BEING
INVOLVED AS A SPEAKER OR HAVE
RECOMMENDATIONS PLEASE REACH
OUT.
WE'RE NOT FINALIZED IN TERMS OF
AGENDA YET BUT THIS WILL BE AN
IN-PERSON MEETING IN BETHESDA
WITH A SERIES OF WEBINARS TO SET
THE SCENE FOR THIS TOPIC.
THANK YOU SO MUCH FOR YOUR
ATTENTION.
I SHOWED YOU THE BIG PICTURE OF
THE DTT FOLKS HALFWAY THROUGH
THE PRESENTATION, I DIDN'T HAVE
ROOM TO FIT THEM ON THE SLIDE
BUT THIS IS THE NICEATM GROUP
THAT I HAVE THE INCREDIBLE
PRIVILEGE OF WORKING WITH EVERY
DAY, IN PARTICULAR OUR
CONTRACTORS PROVIDE ABSOLUTELY
AMAZING SUPPORT FROM A
SCIENTIFIC AND OPERATIONAL
PERSPECTIVE AND NONE OF THE WORK
THAT NICEATM DOES IN SUPPORT OF
ICCVAM WOULD BE POSSIBLE WITHOUT
THIS WONDERFUL GROUP OF PEOPLE.
THANKS VERY MUCH AND I'LL TAKE
ANY QUESTIONS.
[APPLAUSE]
>> SO, THE HUMAN GUT MODEL,
THAT WILL INCORPORATE THE
MICROBIOME AS WELL?
>>THAT'S A FOCAL AREA WE
IDENTIFIED AS BEING IMPORTANT.
WE HAVE A NUMBER OF POTENTIAL
SPEAKERS IDENTIFIED FOR THAT BUT
WE'RE ALWAYS LOOKING FOR
ADDITIONAL SUGGESTIONS.
>> EXCELLENT.
THANKS.
OKAY.
AND REMEMBER, FOLKS ON THE
WEBCAST, PLEASE DO SEND YOUR
QUESTIONS TO THE ICCVAM
QUESTIONS E-MAIL ADDRESS.
NOW IT IS MY PLEASURE TO --
WE'RE RUNNING BEHIND TIME BUT I
THINK WE'RE FINE.
WE'RE GOING TO CONTINUE ON THE
AGENDA AND DO THE ICCVAM
WORKGROUP UPDATE THAT DR. ALLEN
IS GOING TO GIVE, AND THEN WE
WILL BREAK.
PROBABLY I'M GUESSING WE'LL
BREAK AT 11:15 OR 11:20, BUT
TAKE YOUR TIME, DAVE.
>> THANKS, NICOLE.
I'VE ONLY GOT 332 SLIDES.
SHOULDN'T BE LONG.
NO, AS NICOLE SAID, I'M DAVE
ALLEN, PRINCIPAL INVESTIGATOR
FOR THE CONTRACTOR FOR NICEATM,
IT'S A PLEASURE TO BE HERE TO
TALK ABOUT THE GREAT WORK THE
COMMITTEE HAS BEEN INVOLVED IN
THROUGH THEIR WORK GROUPS.
FOLKS HERE, MOST FOLKS ARE AWARE
OF THIS BUT ICCVAM A COMMITTEE
OF VOLUNTEERS, FOLKS ON THE
FORMAL ICCVAM COMMITTEE, THIS IS
REALLY THEIR OTHER DUTIES IN
THEIR JOB DESCRIPTION, THEY PUT
A LOT OF EFFORT INTO WHAT THEY
ARE DOING BUT THEY NEED EXPERTS
WITHIN THEIR AGENCIES TO GET
SOME QUESTIONS ANSWERED OR SOME
OF THESE DETAILS ADDRESSED, SO
THEY DO THAT VIA WORK GROUPS.
MANY OF THE FOLKS PARTICIPATE IN
THE ICCVAM WORK GROUPS BUT
CERTAINLY IT'S INCUMBENT ON
OTHERS IN THE AGENCIES AND
INSTITUTES TO PROVIDE EXPERTISE
AND THEN US AT THE NICEATM
SUPPORT CONTRACT TEAM AS NICOLE
MENTIONED WE PROVIDE SCIENTIFIC
AND OPERATIONAL SUPPORT BEHIND
THE SCENES AND SORT OF THE
PROVIDE INFORMATION, DETAILED,
OFFER MODELS AND NEW INFORMATION
FOR COMMENT FROM THE WORK GROUPS
TO MOVE FORWARD THAT WAY.
SO, THERE ARE NOW A TOTAL OF
SEVEN ACTIVE ICCVAM WORK GROUPS,
YOU CAN SEE THEM LISTED HERE.
NEWEST ONE ASSOCIATED WITH PFAS
TOXICITY, AND WE'LL TALK BRIEFLY
ABOUT THAT AT THE END BUT
CERTAINLY A LOT OF EFFORT AND
THIS IS ALSO -- FRANK BARILE'S
COMMENTS WERE A NICE SEGUE TO
THE WORK ICCVAM HAS DONE OVER
THE PAST FIVE YEARS SINCE IT
MODERNIZED OR EVOLVED SINCE
REINVENTING ITSELF AND FOCUSING
THROUGH A STRATEGIC ROAD MAP
PUBLISHED IN 2018 ON FOCUSING ON
END USERS, MATILY -- ULTIMATELY
WHAT QUESTIONS NEED TO BE ANSWER
AND MODELS DEVELOPED
ACCORDINGLY.
ACUTE TOXICITY, A TREMENDOUS
AMOUNT OF INVOLVEMENT AND
PROGRESS OVER THE LAST SEVERAL
YEARS.
CERTAINLY IN THE AREA OF ACUTE
ORAL AND DERMAL SYSTEMIC
TOXICITY, AND EACH ONE OF THESE
SLIDES, EACH WORK GROUP WHEN
IT'S CREATED, IT'S INCUMBENT ON
ICCVAM AGENCIES TO HAVE A
SPONSORING -- ONE OR MORE
SPONSORING AGENCY, THEY HAVE
QUESTIONS OR PROBLEMS THAT THEY
ARE TRYING TO ADDRESS, AND THE
WORK GROUP DEVELOPS A SCOPE AND
CHARGE THAT THEY THEN
METHODICALLY WORK THROUGH WITH
THE SUPPORT OF NICEATM, AND AT
THE END ULTIMATELY THEY HAVE ALL
THEIR BOXES CHECKED WITH ALL
THEIR SCOPE AND CHARGE AND CAN
SEND TO EXPERT GROUP OR BE
TASKED WITH ADDITIONAL EFFORT.
EACH OF THE SLIDES WALK THROUGH
THAT SCOPE AND CHARGE FORMAT.
THE INITIAL THING WAS TO FOCUS
ON UTILITY OF USING LD 50 DATA
FROM ACUTE ORAL TOXICITY TEST,
COULD THAT BE USED TO WEIGH THE
LD 50 FOR DERMAL ACUTE SYSTEMIC
TOXICITY, WHAT WE FOUND THAT
COULD BE DONE AND EPA
SUBSEQUENTLY PUBLISHED A WAIVER
GUIDANCE.
NEXT, INTERESTED IN EVALUATING
AND CHARACTERIZING STATE OF THE
SCIENCE AND AVAILABLE MODELS IN
VITRO AND IN SILICO FOR
PRODUCING -- PREDICTING ACUTE
SYSTEMIC TOXICITY, BY THE ORAL
AND INHALATION ROUTES, AND BACK
IN 2018 A MODELING WORKSHOP WAS
CONVENED, A REPORT PUBLISHED, A
NUMBER OF MODELS, CROWD SOURCED
THE MATHEMATICAL AND MODELING
COMMUNITY TO BUILD I BELIEVE 132
MODELS ASSOCIATED WITH ACUTE
ORAL TOXICITY AND AS KAMEL
MANSOURI LED AN EFFORT TO BUILD
CONSENSUS MODEL, CATMoS,
SUBSEQUENTLY PUBLISHED, AND IS
UNDER REGULATORY CONSIDERATION
AS WE SPEAK.
AND ASSOCIATED WITH THAT A LOT
OF EFFORT WE'VE PUT INTO
CHARACTERIZING THE VARIABILITY
OF REFERENCE TEST METHODS,
RECOGNIZING THAT PERHAPS A
ONE-TO-ONE COMPARISON OF A NAM
TO TRADITIONAL REFERENCE METHOD
IS MAYBE NOT IDEAL BUT IF WE'RE
GOING TO DO THAT YOU NEED TO
FACTOR IN THE VARIABILITY
ASSOCIATED WITH THAT REFERENCE
METHOD BECAUSE IF THE REFERENCE
METHOD CAN'T REPEAT ITSELF 100%
OF THE TIME, YOU CAN'T POSSIBLY
THINK A NAM WOULD REPEAT THE
REFERENCE TEST METHOD 100% OF
THE TIME.
WE'VE PUBLISHED VARIABILITY
ANALYSIS OVER THOUSANDS OF LD 50
CHEMICALS TO DEMONSTRATE THAT.
AND JOHN HAMM LED AN EFFORT TO
DO A RETROSPECTIVE ANALYSIS
ASSOCIATED WITH GHSED A ACTIVITY
FORMULA, WE HAVE AVAILABLE
LD50s, COMBINED TO DETERMINE A
PREDICTED OUTCOME FOR A MIXTURE,
TO DEMONSTRATE THAT MANUSCRIPT
PUBLISHED AND UNDER
CONSIDERATION FOR REGULATORY
USE.
ONE OF THE FIRST THINGS WORK
GROUPS DO IS CATALOG AGENCY
NEEDS, AGAIN STARTING WITH THOSE
END USERS IN MIND, TO PUBLISH A
SCOPING DOCUMENT THAT OUTLINES
NOT ONLY U.S. BUT ULTIMATELY
INTERNATIONAL REQUIREMENTS AS
WELL SO WE'RE HARMONIZED
INTERNATIONALLY.
2018 PUBLISHED U.S. REQUIREMENTS
AND WE'VE JUST COMPLETED A DRAFT
OF THE INTERNATIONAL
REQUIREMENTS AND THAT'S BEEN
COMMITTED AND IS UNDER REVIEW AT
CRITICAL REVIEWS IN TOXICOLOGY.
LAST BUT NOT LEAST NICOLE
DETAILED THE TREMENDOUS EFFORT
ASSOCIATED WITH CHARACTERIZING,
CLEANING, CURATING INHALATION
DATA SAT, AND SUPER EXCITED TO
GET HANDS ON THAT AND DO SIMILAR
CROWDSOURCING EFFORT TO BUILD
CONSENSUS MODELS ASSOCIATED WITH
ACUTE INHALATION TOXICITY.
NEXT I'LL MOVE TO CONSIDERATION
OF ALTERNATIVE METHODS WORK
GROUP, JESSE CARTER IS HERE IN
THE ROOM FROM USDA, CHAIR OF
THAT GROUP.
CO-CHAIR OF THAT GROUP.
AND THAT GROUP HAS BEEN TASKED
WITH WORKING DIRECTLY WITH
STAKEHOLDERS TO SORT OF DEVELOP
THAT CATALOG OF WHAT INCENTIVES
COULD BE IDENTIFIED OR
ENCOURAGED OR PROPOSED TO CAUSE
FOLKS TO MORE SERIOUSLY CONSIDER
USE OF ALTERNATIVE METHODS.
ULTIMATELY THAT INVOLVES
REVIEWING THE REQUIREMENTS
ASSOCIATED WITH THE
CONSIDERATION OF NAMs AND HOW
THOSE PERHAPS MIGHT BE MODIFIED,
EXPANDED UPON, CERTAINLY
FOSTERING ADDITIONAL
CONSIDERATION BY STAKEHOLDERS
NOT THE LEAST COULD BE
INSTITUTIONAL ANIMAL CARE AND
USE COMMITTEES.
THE WORK GROUP WORKED WITH
STAKEHOLDER ORGANIZATIONS FROM A
VARIETY OF INDUSTRY, ACADEMIC
AND NON-GOVERNMENT ORGANIZATIONS
TO UNDERSTAND REALLY WHAT SOME
OF THOSE ISSUES ARE, AND YOU CAN
SEE A LIST OF QUESTIONS THAT HAS
BEEN DISCUSSED WITH THESE GROUPS
FROM PHARMACEUTICAL COMPANIES,
AGRI CHEMICALS, INDUSTRIAL
CHEMICALS, CONSUMER PRODUCTS.
LATEST STAKEHOLDERS GROUPS ARE
THOSE INSTITUTIONAL ANIMAL CARE
AND USE COMMITTEES TO UNDERSTAND
QUESTIONS AND INCENTIVIZE USE OF
NAMs, ULTIMATELY THE INTENTS
TO PUBLISH A SUMMARY IN WHITE
PAPER FORMAT.
ECOTOXICITY PUBLISHED AN AGENCY
NEEDS MANUSCRIPT TO CHARACTERIZE
THOSE DATA REQUIREMENTS AS
RELATES TO REGISTRATION AND
REGULATION OF CHEMICALS, IT I
WAS MONITORING, THE AREA IS
QUITE BROAD, UNDERSTANDING
SPECIFIC NEEDS ACROSS OUR
FEDERAL AGENCIES HAS REALLY BEEN
A YEOMAN'S TASK.
NOW THAT THAT WORK GROUP HAS
PIVOTED, FOCUSING ON IDENTIFYING
OR PRIORITIZING ALTERNATIVES
WITH FISH TOXICITY TEST, THAT
MANUSCRIPT IS BEING FINALIZED
FOR PUBLICATION, EXPECT TO SEE
THAT IN PEER-REVIEWED LITERATURE
THIS YEAR.
IN VITRO TO IN VIVO
EXTRAPOLATION, A LOT OF
PRODUCTIVITY FROM THAT GROUP TO
TAKE IN VITRO BIOACTIVE
CONCENTRATION AND CONTEXTUALIZE
INTO IN VIVO SITUATION.
YOU KNOW, AGAIN STARTING WITH
THE CATALOG OF AVAILABLE
METHODS, UNDERSTANDING HOW THEY
MIGHT BE USED, APPLIED TO
SPECIFIC REGULATORY QUESTIONS,
AND SPECIFIC RISK ASSESSMENT
PURPOSES THAT CAN BE ACHIEVED
WITH THE CURRENTLY AVAILABLE
APPROACHES AND OF COURSE
IDENTIFY GAPS, AND THAT WAS
PUBLICATION THAT CAME OUT IN
TOXICS IN 2022, RECEIVED A
NUMBER OF ACCOLADES OVER THE
PAST YEAR REALLY, RECOGNIZED BY
JOURNAL TOXICS AS RECOMMENDED
REVIEW FOR 2022, ALSO MOST
RECENTLY ONE OF THE CO-CHAIRS OF
THE IVIVE FROM ATSDR RECEIVED
THE -- PUBLICATION RECEIVED THE
2022 OUTSTANDING PUBLICATION
AWARD, YOU CAN SEE THE PICTURE
OF THE TROPHY THERE.
NANOMATERIALS, THIS GROUP
FOCUSED ALMOST SOLELY ON PULLING
TOGETHER NEEDS ASSOCIATINGED
WITH NANOMATERIALS TOX TESTING
AND IDENTIFYING A NUMBER OF
ONGOING EFFORTS, THAT CAME OUT
IN A PUBLICATION.
EXCUSE ME.
THIS IS ONE EXAMPLE OF A WORK
GROUP THEY HAVE COMPLETED THEIR
TASK, HAVE DONE THAT CATALOG,
AND AT THE BOTTOM YOU CAN SEE
THEY HAVE COMPLETED THEIR
CHARGES AND HAVE BEEN CONVERTED
TO EXPERT GROUP WHICH MEANS
THAT'S A GROUP THAT'S AVAILABLE
FOR CONSULTATION, IT'S AN E-MAIL
DISTRIBUTION LIST TO CONTACT
AGENCY EXPERTS IN THE AREA OF
NANOMATERIAL TESTING BUT COULD
BE REACTIVATED AT ANY POINT IN
DEEMED NECESSARY.
NICOLE ALLUDED TO EFFORTS
ONGOING TO UPDATE GUIDANCE FOR
ESTABLISHING CONFIDENCE.
SO THIS HAS BEEN REALLY A MUCH
NEEDED TASK TO UPDATE VALIDATION
GUIDANCE THAT WAS PUBLISHED IN
1997 BY ICCVAM AND I THINK WE
CAN ALL APPRECIATE WITH THE
EVOLUTION AND MODERNIZATION OF
TOXICOLOGY RESEARCH AND TESTING
THERE'S A NEED TO MODERNIZE THE
WAY THAT CONFIDENCE IS
ESTABLISHED, SO THIS WORK GROUP
WAS PUT TOGETHER TO DO JUST
THAT.
LED BY JOHN GORDON, SUZIE
FITZPATRICK AND ELIJAH PETERSEN
AS CHAIRS, UPDATING THE DOCUMENT
PUBLISH THE IN 1997 BASED ON
PRINCIPLES FROM OECD GUIDANCE
DOCUMENT 34, THOSE WILL REMAIN
THE SAME IN THE NEW GUIDANCE BUT
IMPORTANTLY INTRODUCING THAT
CONTEXT OF USE TERMINOLOGY INTO
THIS DOCUMENT THAT'S SO NEEDED
AND IMPORTANT IN THESE
EVALUATIONS.
AND WE'VE HEARD A LOT ABOUT A
WONDERFUL PAPER VANDERSONE,
ESTABLISHING CONFIDENCE AND
GUIDING PRINCIPLES, AND UPDATED
FIGURE ADAPTED FROM THAT THAT
WILL BE INCLUDED IN THE NEW
ICCVAM GUIDANCE FOCUSING ON USE
OF EFFICIENT, FLEXIBLE, ROBUST
PRACTICES, DELINEATING CONTEXT
REQUIREMENTS, PROMOTING NEW
APPROACHES FOR ESTABLISHING
CONFIDENCE, AND IMPORTANTLY
UTILIZING PUBLIC/PRIVATE
PARTNERSHIPS THAT WE'VE SEEN SO
PRODUCTIVE OVER THE PAST FEW
YEARS WITH ENGAGING DIRECTLY
WITH STAKEHOLDER ORGANIZATIONS
TO UNDERSTAND THEIR CHALLENGES
AND ALLOW THEM THE OPPORTUNITY
TO UNDERSTAND SPECIFIC NEEDS
FROM THE FEDERAL AGENCIES.
SO THE DRAFT DOCUMENT IS
CURRENTLY UNDERGOING AGENCY
CLEARANCE PROCESSES AS WE SPEAK.
OUR ANTICIPATION IS THOSE
PROCESSES WILL BE DONE LATER
THIS SUMMER, AND IMPORTANT FOR
THIS GROUP THERE WILL BE A
PUBLIC COMMENT PERIOD FOR THE
DOCUMENT WE HOPE WILL HAPPEN ON
OR ABOUT MID-JULY.
SO STAY TUNED FOR THAT.
AND THAT WILL GO OUT THROUGH A
VARIETY OF COMMUNICATION
CHALLENGES NOT THE LEAST OF
WHICH IS THE NICEATM LISTSERV
THAT NICOLE ALLUDED TO EARLY.
LAST BUT NOT LEAST I MENTIONED A
NEW WORK GROUP THAT HAS JUST
BEEN FORMED VIA LAST ICCVAM
MEETING.
REALLY SPONSORED BY DoD, EPA,
FDA.
RECOGNIZING THE NEED WITH ALL
THE AREAS OF CHALLENGES AND
INTEREST AND TESTING NEEDS
ACROSS A NUMBER OF AGENCIES, THE
PERVASIVE NATURE OF THESE
COMPOUNDS ACROSS SO MANY
DIFFERENT SECTORS AND TYPES OF
CHEMICALS, NEED TO IDENTIFY HOW
TO APPLY NAMs IN EVALUATING
TOXICITIES, BECAUSE AT PRESENT
THEY ARE NOT BROADLY BEING
APPLIED AND THE COMMITTEE
RECOGNIZES THERE'S A NEED FOR
DIRECT INPUT THERE.
SO THAT WORK GROUP SCOPE AND
CHARGE IS UNDER DEVELOPMENT AS
WE SPEAK.
SO I WON'T PRESENT THAT PUBLICLY
TODAY BUT YOU CAN LOOK FORWARD
AT THE MEETING THIS FALL WHEN I
EXPECT THAT TO BE REFINED.
I WILL CLOSE WITH INVITING ANY
QUESTIONS.
THANKS.
[APPLAUSE]
>> ARE THERE ANY QUESTIONS IN
THE ROOM FOR DAVE?
THERE IS A QUESTION THAT HAS
COME THROUGH ONLINE FOR MYSELF
AND/OR DAVE.
FROM KATHERINE PAGE, ALSO
SCIENTIFIC ADVISORY COMMITTEE,
ARE THERE PLANS TO ADAPT ACUTE
INHALATION ACUTE TOXICITY WORK
TO MIXTURES?
SO THE FIRST THING I'LL SAY WE
HAVE NOT YET BEEN ABLE TO ADAPT
THE ACUTE ORAL SYSTEMIC TOXICITY
APPROACH FROM THE IN SILICO
PERSPECTIVE TO MIXTURES YET
ALTHOUGH I DIDN'T SHOW IT BUT
THERE WAS A PUBLICATION FROM OUR
U.S. AIR FORCE COLLEAGUES THAT I
ACTUALLY EVALUATED THE ABILITY
OF USING CATMoS TO PREDICT
ORAL LD50 FOR MIXTURES
COMPONENTS AND ADD TO PREDICT
LD50 OF THE MIXTURE AND FOUNT IT
WAS VERY EFFECTIVE AND RELIABLE.
SO OUR HOPE IS THAT THAT
FOUNDATIONAL WORK COULD MAYBE
HELP MOVE THAT FORWARD TO
ACCEPTANCE OF AN IN SILICO
APPROACH TO PREDICTING LD 50 OF
A MIXTURE.
NO REASON WE COULDN'T TAKE THAT
APPROACH WITH LC50s AND ACUTE
INHALATION TOXICITY AS WELL.
THE FIRST STEP WOULD BE GETTING
RECOGNITION WITH THE LD 50s IF
HAVE EXPERIMENTAL VALUES YOU CAN
USE GHS APPROACH TO CALCULATE
APPLYING TO LC 50 AND COMBINE
THE PREDICTED LC50 TO PREDICT
THE MIXTURE.
I THINK THE OTHER EXCITING AREA
THAT HAS A LOT OF POTENTIAL IN
UNDERSTANDING INHALATION
TOXICITY OF MIXTURES ARE SOME OF
THE EXPERIMENTAL PLATFORMS THAT
DTT AND OTHERS ARE INVESTIGATING
USING AIR LIQUID INTERFACE
MODELS AND SOME EXPOSURE CHAMBER
SYSTEMS THAT CAN ALLOW TO DEFINE
TO UNDERSTAND IN IN VITRO SYSTEM
AS WELL.
DAVE, WE HAVE ANOTHER QUESTION
ONLINE.
>> YEAH, THERE'S A COMMENT FOR
YOU, NICOLE, FROM AMY KYLE.
IMPORTANT TO ENGAGE COMMUNITIES
TO IDENTIFY WHETHER DATA SOURCES
REPRESENT ELEMENTS THEY VIEW AS
MOST IMPORTANT.
FOR EXAMPLE, IS A COUNTY LEVEL
SCALE APPROPRIATE?
THE PRESENTATION OUTLINED MORE
AUTOMATED APPROACHES TO
INTEGRATING -- THAT WAS JUST A
COMMENT FROM AMY, EXCUSE ME.
WE HAVE ANOTHER QUESTION THAT
SAYS THE PRESENTATION --
>>THANK YOU FOR YOUR COMMENT,
AMY, WE'LL BE FOLLOWING UP
OFFLINE ON THAT COMMENT AND SOME
COMMENTS FROM THE PUBLIC
COMMENTING PERIOD.
>> YOUR PRESENTATION OUTLINED
MORE AUTOMATED APPROACHES TO
INTEGRATING NEW DATA INTO NIEHS
CURATE THE DATA SOURCE, I'M
WONDERING ABOUT LINKING TO
AGENCY ACTIONS AT EPA FOR
EXAMPLE, IS THERE CONSIDERATION
OF FLAGGING RESEARCH RESULTS
THAT WOULD SUGGEST NEED TO
UPDATE REFERENCE VALUES IN RIGHT
NOW THEY ARE RARELY UPDATED,
COULD WE BUILT A SYSTEM THAT
LINKS NEW FINDINGS FROM THE
SCIENCE COMMUNITY TO THE
REGULATORY COMMUNITY IN REAL
TIME, NOT NECESSARILY WAITING
UNTIL THE NEXT SYSTEMATIC REVIEW
OR OTHER PROMPT?
>> A REALLY INTERESTING
QUESTION.
THERE'S A LOT OF LAYERS IN THAT
QUESTION.
AND EXCELLENT SUGGESTIONS,
HIDDEN WITHIN THE QUESTION FORM
AS WELL.
I KNOW THAT CPHEA AND IRIS UNDER
LEADERSHIP OF CHRIS THAYER HAS
MODERNIZED APPROACHES TO
SYSTEMATIC REVIEWS AND
INCORPORATING MORE AUTOMATION
AND MORE A.I.-ENABLED METHODS OF
ASSESSING STUDY QUALITY AND
INTEGRATING ADDITIONAL
SCIENTIFIC DATA AND LITERATURE
STUDIES, INTO THEIR VERY
COMPREHENSIVE ASSESSMENTS, SO WE
ARE IN VERY CLOSE COMMUNICATION
WITH THAT GROUP AND SOME OTHER
REGULATORY DECISION MAKING
COLLEAGUES TO ENSURE THAT THE
WORK THAT WE'RE DOING WILL
SUPPORT EXACTLY WHAT'S BEING
PREPAREDDED, MORE RAPID
INTEGRATION OF INFORMATION FROM
THE SCIENTIFIC LITERATURE THAT
IS RELIABLE AND OF HIGH QUALITY
TO UPDATE REGULATORY VALUES.
THANK YOU FOR THAT.
>> ONE LAST QUESTION THAT'S
RELATED TO ORGANS ON THE CHIPE
BEST TO SAVE AFTER THE BREAK
AFTER TWO PRESENTATIONS
ASSOCIATINGED WITH THAT
TECHNOLOGY.
>> PERFECT.
EXCELLENT QUESTIONS.
ONE IN THE ROOM.
YEP.
>> THANK YOU, DAVE.
FIRST A PLUG FOR GOOD IN VITRO
PRACTICES, A QUESTION TOO.
THE GOOD IN VITRO METHOD
PRACTICES WERE BROUGHT ABOUT
BECAUSE OF THE CHALLENGES IN
HAVING LESS THAN STELLAR
CONFIDENCE AFTER SUBSTANTIAL
VALIDATION STUDIES CONDUCTED,
GOING BACK OVER THE LAST 20 OR
30 YEARS, AND AFTER INVESTING
QUITE A BIT AND SEVERAL HUNDRED
CHEMICALS, MULTIPLE
LABORATORIES, SEVERAL REASONS
FOR FAILURES, SOME HE TEST
METHODS NOT PLANNED FROM
RELEVANCE PERSPECTIVE FOR
BIOLOGICAL RELEVANCE OR PURPOSE.
ALSO RELIABILITY, WE FOUND THAT
RELIABILITY QUESTIONS CAME UP.
MANY PRESENTATIONS, EXCELLENT
PRESENTATIONS, MANY FOCUSED ON
HOW DO YOU GAIN CONFIDENCE IN
TEST METHODS, AND REALLY
APPRECIATE ELIJAH PETERSENS
METHOD, ONE ON PIPETTING.
WE TAKE FOR GRANTED WE CAN
PIPETTE, RIGHT?
AND THE GLPs SAY, OKAY, IF YOU
HAVE METHODS TO PIPETTE 100
MICRO LITERS MINUS, YOU NEED
DOCUMENTATION TO SHOW THAT.
WHAT'S GOOD, IT FORCES A
PERSON'S -- TEST METHOD
DEVELOPERS, TO THINK ABOUT
CRITICAL POINTS IN THE TEST
METHOD EARLY ON, 100 MICRO
LITERS PLUS MINUS 1 SUFFICIENT,
APPROPRIATE, HOW DOES IT IMPACT,
WHAT OTHER COMPONENTS?
CELL SYSTEM, OR THE TEST TO BE
EVALUATED, SO ON, BUT ON
RELIABILITY SIDE YOU ASK WHAT
ARE THE CONSEQUENCES OF
VARIABILITY.
GOOD PRACTICES FORCE A PERSON TO
CHARACTERIZE QUALITY OF TEST
METHOD AHEAD OF TIME.
ONE OF THE THINGS WE FOUND
RECENTLY AS WE'VE BEEN TALKING
ABOUT GOOD IN VITRO METHOD
PRACTICES THERE SEEMS TO BE
GUIDELINES OR DOCUMENTS FIVE
YEARS BACK AND SEEMS TO BE QUITE
A BIT OF NAIVETE, SO I'LL PUT IN
AN APOLOGY, A PLUG FOR SERVICES
TO REVIEW FRAMEWORK WITH
PERSPECTIVE TEST METHOD
DEVELOPERS AND DOWNSTREAM TO
PROVIDE AN EVALUATION OF GOOD IN
VITRO METHOD PRACTICES AS A TOOL
TO HELP THEM BUILD THOSE TYPE OF
CRITERIA AND TEST METHODS OR
APPLICATIONS.
BUT THE SECOND PART COMES TO A
QUESTION HERE, HOW AS WE MOVE
FORWARD WITH REVIEWING GUIDANCE
DOCUMENT 34 HOW WOULD REGULATORY
AGENCIES SEE THEMSELVES FITTING
IN GOOD IN VITRO METHOD
PRACTICES AS A CRITERIA PRIOR TO
ACCEPTING TEST METHODS FOR
VALIDATION?
>> THANK YOU, HANS, FOR THE
INFORMATIVE COMMENT/QUESTION.
I THINK THAT THE GOOD IN VITRO
METHODS PRACTICES IS A REALLY
OUTSTANDING RESOURCE, AND IT'S
ONE THAT WE CITE HEAVILY IN
ICCVAM VALIDATION GUIDANCE THAT
DAVE MENTIONED IN HIS
PRESENTATION, CURRENTLY IN FINAL
DRAFT FORM, GOING THROUGH
CLEARANCE AT 17 AGENCIES, WE
ANTICIPATE OUT FOR PUBLIC
COMMENT IN JULY.
SO IF YOU READ IT IN JULY AND
FEEL LIKE THERE'S NOT ENOUGH
TECHNICAL INFORMATION THEIR --
OR THAT WE NEED ADDITIONAL
DETAILS IN THAT AREA SUBMIT THAT
THROUGH PUBLIC COMMENT.
IT'S ALSO SOMETHING THAT'S
ABSOLUTELY FEEDING INTO THE
PROJECT ON REVISION OF GD 34 AT
OECD DOCUMENT TOO AND JRC WAS
INVOLVED AND CO-LEADING REVISION
OF GD 34 WITH US AND WE INTEND
TO HAVE ALL OF OUR ICCVAM
REGULATORY PARTNERS ALSO
CONTRIBUTING TO THE REVISION OF
GD 34 AND ADVISING US ON THAT AS
WELL.
THANK YOU.
>> THANK YOU.
>> OKAY.
I HAVE 11:25.
WE'LL TAKE A FIVE-MINUTE BREAK
BECAUSE WE'RE BEHIND SCHEDULE.
SO WE'LL TAKE A FIVE-MINUTE
BREAK, RECONVENE AT 11:30, SO
FOR THOSE ONLINE WE WILL BE BACK
IN FIVE MINUTES.
CONTINUING ALONG, EXCITED ABOUT
THIS LAST SESSION.
WE HAVE EXCELLENT TALKS.
FIRST IS FROM USDA AWIC,
PRESENTED BY JESSIE CARTER.
>> HOPE YOU ENJOYED THE SHORT
BREAK.
I'LL BE TALKING ABOUT THE ANIMAL
WELFARE INFORMATION CENTER, A
PART OF THE NATIONAL
AGRICULTURAL LIBRARY.
IT'S DIFFERENT THAN WHAT YOU
HEARD EARLIER, A LOT OF
PRESENTERS FOCUS ON RESEARCH IN
THIS AREA BUT WE'RE MORE THE
INFORMATION ARM OF THE USDA.
I'LL TALK HOW WE HELP PEOPLE
FIND INFORMATION ON NAMs AND
RESEARCH ALTERNATIVES.
>> I'M GOING TO GIVE CONTEXT OF
THE ANIMAL WELFARE INFORMATION
CENTER, LOCATED AT THE NATIONAL
AGRICULTURAL LIBRARY, IN
FELTSVILLE MARYLAND, CREATED IN
1862 BY THE SIGNING OF THE
ORGANIC ACT WITH PRESIDENT
LINCOLN, AND THE MISSION IS TO
FACILITATE CREATION OF
AGRICULTURAL KNOWLEDGE THROUGH
ACQUISITION, CURATION,
DISSEMINATION OF INFORMATION
NEEDED TO SOLVE AGRICULTURAL
CHALLENGES TODAY AND IN THE
FUTURE.
AND THERE ARE EIGHT INFORMATION
CENTERS AT NAL, SUBJECT MATTER
BASED, ONE BEING THE ANIMAL
WELFARE INFORMATION CENTER.
SO IT WAS CREATED OUT OF THE
1985 ANIMAL WELFARE ACT
AMENDMENT, THAT FOCUSED ON
ANIMAL CARE IN USE AND RESEARCH,
MINIMIZING PAIN AND DISTRESS TO
ANIMALS IN RESEARCH.
THE REASON THIS CAME ABOUT,
AWIC, P.I.s WOULD BE ASKED TO
CONSIDER ALTERNATIVE TO PAINFUL
PROCEDURES THAT CONGRESS THOUGHT
IT WAS IMPERATIVE TO PUT AN
INFORMATION SERVICE TO PROVIDE
INFORMATION PERTINENT TO
EMPLOYEE TRAINING WHICH COULD
PREVENT UNINTENDED DUPLICATION
AND DON'T IMPROVE METHODS OF
EXPERIMENTATION WHICH COULD
REDUCE OR REPLACE ANIMAL MUSE
AND MINIMIZE PAIN AND DISTRESS,
THE INTENT WAS TO HELP PEOPLE
FIND THIS TYPE OF INFORMATION.
MAIN STAKEHOLDERS WORK IN THE
ANIMAL RESEARCH SPACE.
P.I.s, LIBRARIANS, ANYONE
LOOKING FOR THIS LITERATURE.
WE PUT ON WORKSHOPS AND
TRAINING, IT'S INTERESTING THAT
THE ANIMAL WELFARE ACT
REGULATIONS SAY EMPLOYEES HAVE
TO RECEIVE TRAINING IN THE
FOLLOWING FIVE AREAS ON THE
SLIDE.
AND THE FIFTH AREA EVEN SAYS
UTILIZATION OF SERVICES SUCH AS
NATIONAL AGRICULTURAL LIBRARY,
AWIC, TO HELP YOU FIND
INFORMATION, ALTERNATIVES,
PREVENTION OF UNNECESSARY
DUPLICATION OF ANIMAL RESEARCH,
AND A TENTH OF THE REGULATIONS
OF THE ANIMAL WELFARE ACT.
NOW I'M GOING OVER PRODUCTS AND
SERVICES AVAILABLE TO YOU.
YOU MAY BE FAMILIAR WITH THE
WEBSITE.
WE DID GO OVER A HUGE REVAMP IN
THE LAST YEAR, MADE THE WEBSITE
MORE MODERN AND USER FRIENDLY,
MORE CONDENSED, MORE
AESTHETICALLY PLEASING.
A LOT OF WHAT YOU CAN FIND HAS
TO DO WITH THREE Rs
ALTERNATIVES, NAMs, WE HAVE
INFORMATION ON ANIMAL WELFARE
ACT AND FEDERAL LAWS GOVERNING
ANIMAL WELFARE, INSTRUCTIONS ON
HOW TO CONDUCT A LITERATURE
SEARCH FOR NAMs AND ANIMAL USE
ALTERNATIVES AND ALSO
BIBLIOGRAPHIES ON ANIMAL
RESEARCH TOPICS, EASIER FOR USER
TO FIND THAT INFORMATION VERSUS
SEARCHING ON YOUR OWN.
WE HAVE COMPILED BIBLIOGRAPHIES
WE KEEP UP TO DATE ANNUALLY.
ONE SPECIFIC WEB PAGE IS
ECO-TOXICITY PAGE, WHEN THEY
WERE WRITING CURRENT NEEDS OF
ECOTOXICITY, SO WE CONDUCTED A
SEARCH ON THE NAMs AND FROM
2010 TO 2022, UP TO DATE AND WE
PLAN TO UPDATE THIS YEAR AS
WELL, AND MADE IT PUBLICLY
AVAILABLE ON OUR WEBSITE.
IT'S A GREAT RESOURCE IF YOU'RE
TRYING TO FIND NAMs IN THIS
AREA.
MORE ON THIS PAGE THOUGH, WOE
HAVE CANNED LITERATURE SEARCHES
WHICH MEANS WE PRE-DEVELOPED
SEARCH STRING ON ECOTOXICITY
LITERATURE, IF YOU CLICK IT WILL
TAKE YOU TO THE MOST UPDATED
LITERATURE, WE MAKE THAT
AVAILABLE AND ALSO HAVE
DIFFERENT ECOTOXICITY TOOLS AND
TRAININGS IN THAT AREA.
THIS PROVIDES STEP-BY-STEP
INSTRUCTIONS FOR THE SEARCH, THE
MAIN PURPOSE OF THE PAGE BUT WE
ALSO PROVIDE OTHER TIPS AND
TRICKS, EXAMPLES, SYNTAX CHEAT
SHEETS AVAILABLE WHEN CONDUCTING
A SEARCH AND NEED TO KNOW WHICH
SYNTAX TO USE, DIFFERENT
PRACTICE WORKSHEETS, RESEARCH
PLANNING AND PUBLISHING GUYED
LINES SUCH AS ARRIVE, AND
FREQUENTLY ASKED QUESTIONS.
YOU CAN REACH OUT TO AWIC IF YOU
NEED HELP.
SOMETHING THAT YOU ALL MIGHT BE
FAMILIAR WITH, THE DATABASE THAT
IS MADE PUBLICLY AVAILABLE,
BIOMEDICAL SCIENCE, AGRICULTURE,
ANIMAL USE ALTERNATIVES.
YOU MAY BE FAMILIAR WITH
AGRICOLA, YOU CAN SEARCH PUBLIC
AG, DIGITAL COLLECTIONS IN ONE
PLATFORM, AND IT'S A LOT LESS
CLUNKY, USER FRIENDLY, IN
GENERAL MORE ADVANCED SEARCH AND
CAPABILITIES.
WHEN YOU'RE SEARCHING THE NEW
SEARCH INTERFACE YOU'LL LOOK AT
OUR JOURNAL ARTICLES, BOOKS,
DISSERTATIONS, CONFERENCE
PROCEEDINGS, A LOT OF MATERIAL
YOU'LL GET FROM NAL WILL BE
UNIQUE COMPARED TO WHERE YOU
WOULD FIND ELSEWHERE.
ANOTHER SERVICE WE OFFER IS OUR
MEETING REQUIREMENTS OF THE
ANIMAL WELFARE ACT WORKSHOP.
WE OFFER THIS THREE TIMES A YEAR
IN MARCH, MAY, OCTOBER, IT IS
FREE TO ATTEND, AND THIS FALL IT
WILL BE VIRTUAL ACROSS TWO HALF
DAYS.
THE MAIN PURPOSE OF THIS
WORKSHOP IS TO PROVIDE
INFORMATION ON THE ANIMAL
WELFARE ACT, REGULATIONS P.I.s
HAVE TO FOLLOW AND WHY, NEW AND
UPDATED ANIMAL USE ALTERNATIVE
EXAMPLES AND NAMs, AND BULK OF
THE PRESENTATION IS TEACHING
PATRONS HOW TO SEARCH FOR ANIMAL
USE ALTERNATIVES IN THE
LITERATURE, A SYSTEMATIC
APPROACH VERSUS KEY WORDS TO
PLUG IN TO GOOGLE OR GOOGLE
SCHOLAR.
IF YOU'RE NOT ABLE TO ATTEND A
LIVE WORKSHOP WE RECOMMEND, WE
DID LAUNCH OUR WORKSHOP ONLINE
IN A FREE ON-DEMAND AND
SELF-PACED FORMAT.
IF YOU CAN'T MAKE ONE OF THE
STAGNANT DATES THROUGHOUT THE
YEARS, ACCESS OUR ONLINE
WORKSHOP AT ANY TIME AND TAKE IT
AT YOUR OWN PACE.
THE DOWN SIDE IS YOU WON'T HAVE
THOSE LIVE INTERACTIONS AND
DISCUSSIONS AND ENGAGEMENTS THAT
YOU MIGHT MIGHT WITH WORKSHOPS.
AND CUSTOMIZABLE TRAININGS, WE
OFFER ON REQUEST.
IF AN AGENCY OR INSTITUTION
SAYS, HEY, WE DON'T NEED ANY
REFRESHER ON THE REGULATIONS OR
ACT BUT WE NEED HELP FINDING
LITERATURE ON THIS TOPIC, WE CAN
CONDENSE OR CREATE A SPECIFIC
PRESENTATION BASED ON NEEDS OF
FACILITY OR INSTITUTION.
TOPICS ARE FLEXIBLE AND DEPEND
ON WHAT FACILITY OR AGENCY IS
INTERESTED IN.
AND THEY CAN BE AS LONG OR SHORT
AS THEY WANT.
TIMING AND TOPICS ARE FLEXIBLE.
WHILE WE TEACH PEOPLE HOW TO
CONDUCT LITERATURE SEARCHES, WE
DO THEM ON REQUEST SO IF YOU ARE
HAVING TROUBLE FINDING
INFORMATION ON A SPECIFIC NAM OR
ANIMAL USE ALTERNATIVE YOU CAN
E-MAIL US AND WE CAN HELP YOU
FIND THAT INFORMATION.
FOR MORE TRADITIONAL PROTOCOLS,
P.I.s MIGHT NEED HELP
CONDUCTING THE SEARCH AND SO IF
THEY SEND THEIR PROTOCOL IF THEY
ARE ABLE TO WE CAN CONDUCT THAT
SEARCH FOR THEM AND IDENTIFY
ALTERNATIVES IN THAT RESEARCH
SPACE.
AND THEN THIS LINK IS TAKING YOU
TO OUR LITERATURE SEARCH REQUEST
FOR.
IN GENERAL IF YOU HAVE QUESTIONS
ON NAMs OR ANIMAL USE
ALTERNATIVES FEEL FREE TO E-MAIL
US.
IF WE CAN'T TELL YOU THE EXACT
ANSWER WE CAN POINT YOU IN THE
DIRECTION OF SOMEONE WHO CAN.
AND THEN LASTLY, OUR AWIC
NEWSLETTER WE SEND THESE OUT
ONCE A MONTH COVERING NEW THREE
Rs RESEARCH OR NAMs,
TIPS, ORGANIZE CONFERENCE AND
TRAININGS, NEW UPDATES COMING
OUT FROM THE ANIMAL WELFARE ACT,
OR AWIC.
IT'S A GOOD WAY TO STAY UP TO
DATE.
AND WE HAVE A DIGITAL
COLLECTION, ESSENTIALLY THIS
HOLDS FULL TEXT SEARCHABLE
REGULATORY AND LEGISLATIVE
DOCUMENTS SO IF YOU WANT TO FIND
A SPECIFIC HEARING OR BILL OR
PROPOSED RULE OR LAW, YOU'LL
FIND IT IN THIS DIGITAL
COLLECTION.
IT'S GOOD FOR PEOPLE WHO WANT TO
KNOW WHY SOMETHING WAS PASSED,
WHAT WAS THE REAL INTENT,
CONVERSATIONS THAT LED TO IT,
THAT'S THE KIND OF INFORMATION
THAT YOU'LL FIND HERE.
IF YOU WANT A MORE BROAD
OVERVIEW THERE'S AN INTERACTIVE
TIMELINE ON OUR HOME PAGE, SO
THAT WILL TAKE YOU THROUGH THE
AMENDMENTS OF THE ANIMAL WELFARE
ACT OVER TIME SO GIVES AN IDEA
HOW THE ACT SHAPED AND WAS
EVOLVED.
I WANTED TO GO OVER TWO PROJECTS
THAT AWIC IS WORKING ON OF
INTEREST TO YOU.
FIRST IS SOMEWHAT SIMILAR TO A
PROJECT THAT NICOLE PRESENTED
ON.
TYPICALLY, P.I.s WHEN WRITING
PAPERS MIGHT NOT BE EXPLICITLY
USING THE TERMS, NEW APPROACH
METHODOLOGY, NAMs, THREE Rs,
THOSE TERMS THAT THE AVERAGE
LITERATURE SEARCHER MIGHT BE
PLUGGING IN.
THEY WILL USE MORE SPECIFIC AN
RELEVANT TERMINOLOGY TO THEIR
RESEARCH.
WHAT WE'RE TRYING TO DO IS
UPDATE THE THESAURUS, AND ALSO
IMPROVING CONTROLLED VOCABULARY
AND TAXONOMY TO IMPROVE CITATIN
INDEXING.
WE'RE DOING USER TESTING TRYING
TO TRAIN ARTIFICIAL INTELLIGENCE
TECHNOLOGY TO RECOGNIZE NAMs
CITATIONS WITHOUT MAYBE HAVING
THOSE TERMS THAT WE THINK OF
WHEN WE THINK OF NAMs AND
ANIMAL USE ALTERNATIVES,
TEACHING A.I. TECHNOLOGY CONTEXT
CLUES TO FIND THESE CITATIONS
EVEN IF NOT EXPLICITLY TALKED
ABOUT IN THAT WAY.
WE'RE DOING SOME USER TESTING
THIS SUMMER SO HOPEFULLY WE'LL
HAVE NEW UPDATE SOON.
LAST INITIATIVE IS OUR 3 Rs
SEARCH STRINGS, YOU AREN'T
FAMILIAR WITH WHAT A HEDGE IS
BUT A SEARCH HEDGE IS A
PRE-DETERMINED OR PRE-DEVELOPED
SEARCH STRING SO IN THEORY THE
LIBRARIANS AND SUBJECT MATTER
EXPERTS ARE DEVELOPING TECHNICAL
BUT COMPREHENSIVE SEARCH STRINGS
SO THE P.I. CAN COPY AND PASTE
WHATEVER SEARCH STRING IS
RELEVANT TO THEIR RESEARCH AND
PLUG IT INTO THE DATA DATABASED
TWEAK BUT AT LEAST GIVES THEM A
STARTING POINT.
FOR EXAMPLE THIS IS BASIC, A
SIMPLE EXAMPLE ON RATS.
YOU WOULDN'T JUST INCLUDE THE
TERM RAT OR RATS.
YOU WOULD WAND TO INCLUDE ALL
THESE ADDITIONAL TERMS TO MAKE
SURE YOU'RE ACCOUNTING FOR ALL
THE DIFFERENT WAYS P.I.s MIGHT
REFER, SCIENTIFIC NAME, LATIN
NAME, SPECIES STRAIN, THOSE
KINDS OF SPECIFIC DETAILS.
THERE SHOULD BE, YEAH, ANOTHER
ONE.
THE SECOND ONE IS ON HOUSING.
IF YOU'RE LOOKING FOR
REFINEMENTS IN YOUR HOUSING
ENVIRONMENT FOR YOUR ANIMALS,
YOU MIGHT USE THIS KIND OF
SEARCH STRING WHICH ISN'T JUST
USING THE TERMS ENCLOSURE, CAGE,
HOUSING.
IT'S GETTING AT SOCIAL HOUSING,
GROUP HOUSING, PAIR HOUSING,
BEHAVIORAL MANAGEMENT, THOSE
TERMS IN THE PAPERS THAT YOU'RE
LOOKING FOR THAT MIGHT NOT REFER
TO IT AS ALTERNATIVE OR
REFINEMENT.
WE'RE STILL TRYING TO VALIDATE
AND DO SOME USER TESTING SO I
DIDN'T WANT TO SHOW SOME WITHOUT
BEING, QUOTE, PERFECT.
WE'VE MADE SOME PUBLICLY
AVAILABLE ON THE LINK ON THE
SLIDE.
AGAIN, THEY WILL FOCUS MORE ON
GENERAL 3 R SPACE AND ANIMAL
SPECIES SPRING BUT -- STRING BT
WE'RE COMING OUT WITH NAMs
STRINGS HOPEFULLY AVAILABLE NEXT
MONTH.
AND THEN THAT'S ALL I HAVE TO
SHARE TODAY BUT FEEL FREE TO
REACH OUR CONTACT INFORMATION TO
REACH OUT FOR COMMENTS,
QUESTIONS, CONCERNS.
THANKS.
[APPLAUSE]
>>GREAT.
THANKS, JESSIE.
DO WE HAVE ANY QUESTIONS ONLINE
OR IN THE ROOM?
>> QUICK COMMENT AND A
QUESTION.
THAT IN DOI WE USE CUSTOMIZABLE
TRAINING.
JESSICA LEE.
YEAH, BARNETT AND I WORKED WITH
JESSIE TO CREATE CUSTOMIZABLE
TRAINING, IT WAS EXTREMELY
HELPFUL, JUST A PLUG FOR THE
USEFULNESS OF THAT.
THAT WAS PART OF OUR METRICS
THAT WE'RE DOING.
YOU SAID THERE'S UPDATED
TRAINING FOR THE MEETING THAT
ANIMAL WELFARE ACT, IS THAT
THROUGH AWIC AS OPPOSED TO THE
OSU TRAINING OR IS IT STILL THAT
OSU TRAINING?
>>IT'S ALWAYS BEEN THROUGH
AWIC.
WE CONTRACT WITH A UNIVERSITY,
BUT WENT THROUGH MAIN UPDATES
ABOUT A YEAR AND A HALF AGO AND
ANOTHER SET OF UPDATES TO MAKE
SURE THE CONTENT IS TRUE.
>> IN DOI WE HAD TO USE A
DIFFERENT E-MAIL.
THAT WAS WEIRD.
OKAY FANTASTIC.
THANK YOU.
>> PERFECT.
ANY QUESTIONS FROM ONLINE?
OKAY.
THANK YOU SO MUCH.
SO, LET ME STOP SHARING BECAUSE
OUR NEXT PRESENTER IS ONLINE.
DR. VALERIO FROM FDA CTP.
WE CAN SEE YOU.
>>GREAT.
I'LL SHARE MY SCREEN.
I'M LUIS VALERIO, CENTER FOR
TOBACCO PRODUCTS, I'LL REFER TO
THAT AS CTP, PROBABLY A NEW
ACRONYM FOR YOU.
DELIGHTED TO SPEAK TO HOW WE'RE
ADVANCING NEW APPROACH METHODS
IN SUPPORT OF OUR REGULATORY
REVIEW OF TOBACCO PRODUCTS IN
THE CONTEXT OF TOXICOLOGY.
SO, THIS PRESENTATION WILL
CONTAIN MY VIEWS AND OPINIONS
AND MAY NOT NECESSARILY REFLECT
THAT OF THE FDA.
IF I MENTION ANY COMMERCIAL
PRODUCTS, THERE'S NO INTENDED
ENDORSEMENT OR IMPLIED.
BASICALLY, I WANT TO TALK ABOUT
OBVIOUSLY TOBACCO PRODUCTS, I
THINK IT'S IMPORTANT FOR YOU TO
GET A GRASP BEFORE WE GET INTO
THE SPECIFIC NAMs OF OUR
REGULATORY AUTHORITY, KIND OF
PRODUCTS, AND THEN CONTINUALLY
THROUGHOUT THE SHORT TALK I'LL
BE DRIVING AT OUR LONG-TERM
COMMITMENT AND INTEREST TO NEW
APPROACH METHODS.
BUT IF THERE'S ANYTHING THAT YOU
TAKE AWAY FROM THIS I'D LIKE YOU
TO -- LIKE A TAKEHOME MESSAGE
PROGRAMMATIC APPROACH TO NAMs,
AGAIN, THAT'S TO SUPPORT -- I'M
FROM DIVISION OF NON-CLINICAL
SCIENCE, A DIVISION OF
TOXICOLOGISTS, AND HOW WE
SUPPORT REGULATORY TOXICOLOGY
REVIEWS.
I KNOW THERE'S BEEN A LOT OF --
THERE'S GREAT METHODS AND
EVERYBODY WANTS TO KNOW HOW CAN
WE GET THESE THINGS REGULATORY
ACCEPTED, AND SO I'LL COVER SOME
PROGRAMMATIC APPROACH, WHICH
THAT WAS TOUCHED UPON BY MY
COLLEAGUE AT THE V.A. EARLIER
TODAY, GEORGE LATHROP, GREAT TO
HEAR.
BUT I'LL COVER SOME ACTIVITIES.
FIRST I WANT TO KIND OF PROVIDE
CONTEXT, OUR MISSION IS TO
PROTECT AMERICANS FROM
TOBACCO-RELATED DEATH AND
DISEASE.
THAT'S THROUGH REGULATION OF THE
PRODUCTS.
AND ESPECIALLY IMPORTANT IS
EDUCATING THE PUBLIC AND
PARTICULARLY OUR YOUTH, TO
PROTECT THEM FROM DANGERS THESE
PRODUCTS POSE.
WE DERIVE FROM TAKE CONTROL ACT
SIGNED IN 2009, AND GAVE FDA
BROAD AUTHORITY TO REGULATE
CIGARETTES, CIGARETTE TOBACCO,
SMOKELESS TOBACCO, ROLL-YOUR-OWN
TOBACCO.
LATER IN AUGUST 2016 THE
AUTHORITY WAS EXTENDED TO OTHER
TOBACCO PRODUCTS, INCLUDING
CIGARS, I'VE LISTED SOME HERE,
BUT THERE'S BEEN A LOT IN THE
NEWS AND DISCUSSION AND RESEARCH
ABOUT ELECTRONIC CIGARETTES, WE
CALL THESE ELECTRONIC NICOTINE
DELIVERY SYSTEMS.
CONGRESS PASSED A LAW JUST IN
APRIL 2022 THAT GAVE FDA
AUTHORITY TO REGULATE SYNTHETIC
NICOTINE, NON-TOBACCO-DERIVED
NICOTINE, R-ISOMER.
REGULATING ANYTHING THAT
CONTAINS NICOTINE EXCEPT FOR
THOSE PRODUCTS WITH THERAPEUTIC
PURPOSE OR FOOD OR OTHER CENTERS
WOULD REGULATE THOSE PRODUCTS.
SO, THAT GIVES A PICTURE,
IMPORTANT BACKDROP.
ALSO PROBABLY MAY NOT BE
FAMILIAR WITH BASICALLY THE KIND
OF PATHWAYS TO MARKET.
THERE ARE THREE FOR TOBACCO.
SE, EXEMPTION AND PMTA.
A LOT OF ELECTRONIC CIGARETTES
COME THROUGH THIS PATHWAY,
STATUTORY STANDARD IS
APPROPRIATE FOR PROTECTION OF
PUBLIC HEALTH.
WITH THAT WE NEED TO UNDERSTAND
HEALTH EFFECTS ON THE WHOLE
POPULATION SO THAT INCLUDES
RISK/BENEFIT BUT HOW THE PRODUCT
COULD IMPACT NON-USERS AS WELL
INCLUDING IF THERE'S A MARKETING
AUTHORIZATION ON ENVIRONMENTAL
ASSESSMENT, BUT THAT'S A
DIFFERENT REGULATION, NATIONAL
ENVIRONMENTAL POLICY ACT.
TOXOLOGICAL EFFECTS WHERE WE
FOCUS ON HERE WITH NAMs, THIS
GIVES YOU A PICTURE OF WHERE IN
OUR REGULATORY OVERSIGHT COULD
WE BE SEEING THAT.
I WOULD BE REMISS IF I DID NOT
TALK ABOUT THE FANTASTIC
COLLEAGUES IN OFFICE OF SCIENCE
AT THE CENTER FOR TOBACCO
PRODUCTS, AND THIS IS KIND OF A
SKETCH OF ALL THE DISCIPLINES
THAT COME TOGETHER WHEN THERE
IS, FOR EXAMPLE, A PMTA, AND IT
REALLY TAKES A LOT OF TEAM WORK,
COORDINATION, AND TOXICOLOGY IS
JUST ONE FIELD HERE.
WE COULDN'T DO OUR WORK WITHOUT
OUR COLLEAGUES IN CHEMISTRY, TO
VALIDATE CHEMICALS THAT WE'RE
GOING TO ANALYZE IN NAMs.
IT'S REALLY A LOT OF HARD WORK.
I GIVE ALL THE RESPECT TO MY
COLLEAGUES THERE THAT WORK ON
THESE MANY APPLICATIONS, THAT'S
AN UNDERSTATEMENT.
AND SO BUT ALSO THE POINT HERE
TOO IS THAT WE'RE KEEPING PUBLIC
HEALTH IN MIND AND OUR
REGULATION, REGULATORY LAW, AND
SO THAT COMES INTO PLAY WHEN
WE'RE CONSIDERING HOW TO APPLY
THESE PRODUCTS OR THESE NAMs
TO THE PRODUCTS.
AND I THINK WE ALL PROBABLY HAVE
HEARD OR KNOW ABOUT CIGARETTES
BUT MANY MAY NOT BE FAMILIAR
WITH SOME OF THE OTHER PRODUCTS.
THIS GIVES A PICTURE OF WHAT
SOME OTHER THINGS LOOK LIKE.
IT'S A HIGH DIVERSITY, WIDE
SPECTRUM, EVEN WITH E-CIGS.
THAT TAKES US TO A PICTURE OF
DEALING WITH A MYRIAD OF
CHEMICALS, SYNTHETICS, FOR
EXAMPLE, WITH E-CIGARETTES, A
RECENT REPORT BY JOHNS HOPKINS
UNIVERSITY SCHOOL OF PUBLIC
HEALTH THAT IDENTIFIED ALMOST
2,000 CHEMICALS IN AEROSOL OF
e-CIGS AND e-LIQUIDS, VERY
DAUNTING AND SETS THE STAGE FOR
USING NAMs GIVEN ALL THE
PRESENTATIONS WE'VE HEARD TODAY
AND YESTERDAY, EVEN PREVIOUS
PUBLIC FORUMS, WHERE THERE'S
REALLY CAPABILITY FOR
HIGH-THROUGHPUT ASSESSMENT
STRATEGIES.
AND SO WE ALSO WANTS TO BE
MAKING EVIDENCE BASED DECISIONS
AND I THINK NAMs CAN MEET THAT
CHALLENGE AND MOVE FORWARD WITH
USING THEM IN A PROGRAMMATIC AND
OPERATIONAL WAY TO INFORM OUR
TOBACCO REGULATORY SCIENCE.
THAT'S CRITICAL.
CRITICAL TO UNDERSTANDING IMPACT
ON VARIOUS ASPECTS OF TOBACCO
PRODUCTS ON PUBLIC HEALTH.
AND SO THIS IS JUST TO SAY WE'RE
VERY DEDICATED TO AN EVIDENCE
BASED ANALYSIS.
THE OTHER THING HERE LIKE I SAID
EARLIER I WANT YOU TO TAKE HOME
ABOUT PROGRAMMATIC APPROACH, AND
SO IF YOU WERE TO REDUCE ALL THE
ACTIVITIES THAT WE DO, NOT ALL
BUT THE ONES YOU COULD THINK OF
AT LEAST INTO FOUR PARTS, THIS
WOULD BE ONE WAY TO LOOK EIGHT.
APPLIED RESEARCH, REGULATORY
SCIENCE, APPLICATION REVIEW, AND
THEN WE'LL-WORLD PUBLIC HEALTH
IMPACT, WHICH IS WHAT WE'RE HERE
TODAY FOR.
AND SO NAMs IS AT THE
INTERSECTION OF ALL OF THESE.
SO IF YOU CAN IMAGINE WE CAN SEE
THE LOGIC IN DEVELOPING METHOD
FOR NAMs IN APPLIED RESEARCH,
COLLEAGUES AT NICEATM, ET
CETERA, AND THAT TO HELP INFORM
AND IMPROVE OUR REGULATORY
SCIENCE KNOWLEDGE BASE AND THEN
THAT IN TURN HELPS QUALITY OF
OUR REVIEWS.
SO THAT IN TURN WOULD TRANSLATE
INTO REAL WORLD HEALTH IMPACT.
BUT IT'S NOT TO SAY APPLIED
RESEARCH CAN'T MAKE A DIRECT
PUBLIC HEALTH IMPACT.
IT SURE CAN.
AND SO REALLY JUST KIND OF THINK
OF THIS AS NAMs REALLY IS AT
THE HUB OF ALL OF THESE AREAS.
I FIRST TRIED TO INSTRUCT THIS
SLIDE AND THOUGHT DRAWING ARROWS
BUT IT DOESN'T WORK THAT WAY.
THERE REALLY IS A MESH BETWEEN
THESE.
SO, AGAIN, APPLIED RESEARCH WE
TALK A LOT ABOUT THAT.
IT'S VERY MULTI-FACETED BECAUSE
TECHNOLOGIES, THERE ARE MANY
KIND OF TECHNOLOGIES BUT ONE OF
THE GOALS HERE TOO IS TO HELP
INFORM OUR POLICY DEVELOPMENT SO
WE CAN MAKE BETTER DECISIONS.
SO I WANT TO SHIFT GEARS NOW TO
THE RESEARCH AND WHERE WE'RE
ENGAGED AT CTP, EXAMPLES, AND I
WON'T BE ABLE TO SHOW EVERY
PROJECT, NOT ENOUGH TIME, BUT I
THOUGHT THIS IS VERY
INTERESTING.
IT'S A BROAD AGENCY ANNOUNCEMENT
WHICH WE FUNDED, AND WE HAVE A
TEAM OF TOXICOLOGISTS, WORKING
TOGETHER, WITH THE COLLABORATOR.
THIS IS AT THE UNIVERSITY OF
PITTSBURGH DEVELOPING A HUMAN
VAPING MEMETIC ANALYZER, ONGOING
FOR A WHILE.
THERE'S SOME PAPERS THAT
BASICALLY THE POINT HERE IS TO
HELP US -- ENABLING TECHNOLOGY
TO HELP US UNDERSTAND THE
PARTICLE SIZE IN AEROSOL, WHICH
RESEARCH HAS SHOWN THAT WITH
VITAMIN E AND MENTHOL CAN
INCREASE PARTICLE SIZE AND THAT
WOULD BE OBVIOUSLY NOT A GOOD
THING TO INCREASE THAT THIS IS
AN ILLUSTRATION WHAT IT LOOKS
LIKE.
IT'S A VAPING ROBOT.
AND SO, AGAIN, THIS IS A LOT OF
BIOMEDICAL ENGINEERING.
SOME LATEST RESEARCH HAS SHOWN,
HERE ARE SOME PAPERS, THAT WITH
ADDITION OF MENTHOL VERSUS
NON-MENTHOL, IT INCREASES
DISTRIBUTION SIZE, THE ANALYZER
CAN MEASURE FOUR DIFFERENT
MICRON-TO-MICRON SIZES OF
PARTICLES AND ANOTHER PRIOR
STUDY WHICH CTP PARTICIPATED IN
AUTHORSHIP WHICH IS WITH VITAMIN
E ADDITION, IT LED TO INCREASE
OF PARTICLES.
AND SO THAT WAS RELEVANT BECAUSE
OF THE ELECTRONIC CIGARETTE
VAPING ASSOCIATED LUNG INJURY
OUTBREAK THAT OCCURRED IN 2021,
AND SO -- ACTUALLY 2019.
ESSENTIALLY THESE SYSTEMS WE
THINK ARE GOING THE WAY OF
REALLY FINE TUNING AND HELPING
US UNDERSTAND THE IMPACT OF
THESE CONSTITUENTS OF THESE
COMPLEX MIXTURES, VERY
DIFFICULT.
I THINK IT WAS COMMENTED EARLIER
THEY VERY DIFFICULT TO ASSESS.
SO THIS IS A NEW
NEUROTECHNOLOGY, WE'RE CERTAINLY
ENGAGED HERE AND REALLY HAPPY
ABOUT THE PROGRESS.
SO WITH THAT I WANT TO TALK MORE
ABOUT COMPUTATIONAL MODEL.
WE DO USE ARTIFICIAL
INTELLIGENCE BUT IN THE CONTEXT
OF SUBSET OF IT, MACHINE
LEARNING, AND THE GOAL HERE
AGAIN IS TO MAKE BETTER
DECISIONS.
SO, BY INCORPORATING INTO OUR
PROGRAMMATIC AND EXTRA --
STRATEGIC PLANS AND WE THINK WE
CAN IMPROVE ON THE INFORMATION
BASE TO MAKE BETTER DECISIONS.
THAT'S THE GOAL.
AND I THINK EVERYBODY HAS HEARD
ABOUT A.I.
THERE'S A LOT OF DIFFERENT KINDS
OF A.I.
AND SO THE APPROACHES THAT WE'RE
USING ARE INFORMATIC BASED.
WE'VE HEARD ABOUT OPERA, WHICH
LOOKS LIKE A VERY INTERESTING
SYSTEM.
I'LL FOLLOW UP WITH MY
COLLEAGUES AT NICEATM BECAUSE
IT'S A TRANSPARENT SYSTEM.
BUT THESE ALGORITHMS THAT DRIVE
THESE SYSTEMS ARE COMMON AND
HAVE BEEN USED MANY OTHER
INDUSTRIES FOR A LONG TIME.
AND SO I THINK IT IS A GREAT
THING TOXICOLOGY TAKES ADVANTAGE
TO HARNESS AND TO HELP LEVERAGE
EXISTING DATA, AND AVOID FURTHER
ANIMAL TESTING.
SO THAT'S SORT WHERE WE'RE
COMING FROM IN TERMS OF USING
COMPUTATIONAL TOXICOLOGY RIGHT
NOW.
WE'RE USING SOME COMMERCIAL
SYSTEMS, AND WITH THAT WE HAVE
DONE SOME RESEARCH.
THIS WAS LED BY DR. GOAL IN OUR
DIVISION, AND WAS PUBLISHED LAST
YEAR.
IT'S A SCREENING OF FLAVORS,
SINCE FLAVORS ARE COMMONLY FOUND
IN e-CIGARETTES, DEVELOPED A
LIBRARY OF OVER 3,000 CHEMICALLY
DEFINED FLAVORS, TO SCREEN FOR
RESPIRATORY TOXIFORES, USING
STRATEGY WHETHER COMPOUNDS HAVE
GHS, GLOBALLY HARMONIZED SYSTEM,
TO CHARACTERIZE THAT, AND SO THE
RESULTS, I DON'T HAVE THEM ALL
HERE BUT I THOUGHT TO SHOW YOU
SOME OF THEM, YOU KNOW, A LARGE
PERCENTAGE OF THESE HAVE, IF WE
APPLY THAT CRITERIA TO THIS, AND
ANOTHER TECHNIQUE THAT WAS USED
MOLECULAR FILTERING, SO THIS IS
VERY HIGH-THROUGHPUT, AND
ESSENTIALLY YOU CAN INSERT A
REACTIVE GROUP, LET'S SAY YOU'RE
INTERESTED IN, THE IDEA HERE IS
WE'RE NOT DOING THIS REALTIME
FOR OUR APPLICATION REVIEW OF
COURSE.
BUT THE IDEA HERE IS TO PERHAPS
DEMONSTRATE TO OUR STAKEHOLDERS,
MAYBE THIS IS SOMETHING THAT
COULD BE DONE TO HELP MITIGATE
THE RISKS, HELP MITIGATE TO
REDUCE THIS, SINCE THIS GOES
BACK TO THE MISSION STATEMENT OF
REDUCING HARM.
SO SCREENING, EARLY DETECTION
SYSTEMS, WHICH COMPUTATIONAL
SYSTEMS ARE REALLY ALL ABOUT
COULD BE HELPFUL.
HERE'S ANOTHER SITUATION, WELL
KNOWN FOR THE OCCUPATIONAL
EXPOSURE ISSUE YEARS AGO, WITH
POPCORN LUNG DISEASE, DAACETYL.
THERE'S ANALOGS CLOSELY RELATED,
THIS WOULD SAY, WHEN ASKED THE
QUESTION WHY WOULD I WANT TO ADD
THIS COMPOUND TO THIS e-LIQUID
IN ABSENCE OF EXPERIMENTAL
TESTING, THIS IS SORT OF WHAT
THE PHARMACEUTICAL INDUSTRY DOES
IS IN THE EARLY STAGES OF
DISCOVERY, TO TRY TO REDUCE ARM,
MITIGATE LIABILITY.
THEY ARE CHEMISTRY DRIVEN, DATA
DRIVEN, WE'RE INTERESTED IN
EXPLORING THAT.
AND THIS IS ANOTHER PROCEDURE
USING COMMON SUBSTRUCTURES TO
IDENTIFY, YOU CAN APPLY A LOT OF
CRITERIA THAT WOULD BE UP TO --
IF IT'S AN INDUSTRY OR WHOEVER
IS DEVELOPING A PRODUCT, TO MAKE
THOSE DECISIONS BEFORE THEY
DEVELOP THINGS.
THERE'S A LOT OF TECHNIQUES
BEGINNING WITH CHEMISTRY.
GETTING BACK TO WHAT I WANTED TO
EMPHASIZE TODAY, ABOUT
PROGRAMMATIC APPROACH, WE
ESSENTIALLY ESTABLISHED A TEAM,
NON-CLINICAL COMPUTATIONAL
TOXICOLOGY TEAM, NCTP, A GREAT
BRIGHT TEAM OF SCIENTISTS IN OUR
DIVISION THAT'S DEDICATED TO
SERVICING AND SUPPORTING
BASICALLY ACTIVITIES IN
PROGRAMMATIC AREAS FROM RESEARCH
TRAINING & EDUCATION,
COLLABORATION, AN INTERNAL GROUP
AND REVIEWS SUPPORT, A PRIMARY
FOCUS RIGHT NOW.
IF WE HAVE A REVIEWER THEY GET
COMPUTATIONAL TOXICOLOGY DATA,
THIS TEAM IS THERE TO SUPPORT
THEM TO HELP ANSWER THEIR
QUESTIONS.
OH, OKAY, WHAT DO DO YOU IF YOU
GET A PREDICTION, HOW DO I
APPRAISE THAT INFORMATION?
THINGS LIKE THAT.
STAYING ON TOP OF THE
TECHNOLOGY, YOU KNOW, DOING
TRAINING FOR THEMSELVES TO KEEP
UP WITH IT.
AND SO BASICALLY, YOU KNOW, IT'S
A PROGRAMMATIC APPROACH TO
SUPPORT OURSELVES SO THAT WE CAN
DO A BETTER JOB AND EVALUATE
THESE PRODUCTS MUCH BETTER.
A BIG PLUG FOR THEM, PRIVILEGED
AND DELIGHTED TO BE ABLE TO WORK
WITH THEM.
SO HAPPY ABOUT THAT.
A LOT OF THINGS LISTED ARE
ALREADY WELL KNOWN BY THIS
AUDIENCE.
BUT I DID WANT TO MAKE THE POINT
THAT AT CTP WHAT WE'RE DOING
WITH NAMs DOES REFLECT THE
GOALS OF THE PREDICTIVE TOX ROAD
MAP RELEASED IN 2017.
SO EVERYBODY KNOWS ABOUT
EFFICIENCY, THINGS LIKE THAT.
BUT WE'RE ALSO THINKING ABOUT
THIS AS A STRATEGY TO SUPPORT
PRIORITIZATION FOR FOLLOW-UP,
THANKED DOESN'T NECESSARILY MEAN
TESTING.
IT MIGHT MEAN FOLLOW-UP MORE
LITERATURE, THERE ARE OTHER
DIFFERENT WAYS, READ ACROSS, FOR
EXAMPLE.
PART OF THE -- SPEAKING OF THAT,
WE'RE ALSO DOING OUTREACH WITH
OUR OTHER CENTERS LIKE CFSAN,
WE'VE STARTED TO WORK WITH THEM.
THEY HAVE A COMPUTATIONAL
TOXICOLOGY GROUP AND SO TO HELP
HARMONIZE AND LEARN FROM THEM,
THEY HAVE BEEN DOING IT FOR A
LONG TIME.
AND SO AGAIN GETTING BACK TO THE
OVERALL STRATEGY FOR EVERYBODY'S
LEVERAGE EXISTING KNOWLEDGE SO
WE CAN REDUCE ANIMAL TESTING AND
MAXIMIZE RESOURCES AND USE THE
BEST TECHNOLOGY THAT WE CAN.
THAT SOUNDS GREAT BUT WE ALSO
HAVE TO KEEP THINGS IN MIND.
AND THAT'S CONSIDERATIONS, NOT
PERFECT, ONE OF THE BIG THINGS
WE'RE LOOKING AT RIGHT NOW ARE
HUMAN EXPERT REVIEW PREDICTIONS,
AND SO WE DON'T JUST LOOK AT
PREDICTION AND SAY COMPUTER SAID
THAT, SO WE'LL MOVE FORWARD.
WE WANT EXPLAINABILITY,
TRANSPARENCY, THE THINKING IS,
YOU KNOW, ONE SHOULD CONSIDER S
A MODEL FIT FOR THIS TECHNICAL
QUESTION, DIFFICULT TO
GENERALIZE MODEL OVER
EVERYTHING.
THIS IS SCIENCE.
SO THAT'S JUST THE WAY IT GOES.
WE HAVE TO MAKE SURE THAT THE
MODEL AND PREDICTION DATA IS
REALLY APPROPRIATE FOR THE DATA
CIRCUMSTANCE.
SO, YEAH, WE WANT EFFICIENCY BUT
NOT AT THE EXPENSE OF LESS
SCIENTIFIC RIGOR.
WE WANT RELIABILITY AND MAINTAIN
THE QUALITY AND INTEGRITY TO
FIELDING THE SCIENTIFIC QUESTION
AT HAND.
HERE IS THIS -- THIS IS A
THINKING ABOUT, AGAIN, GOING
BACK TO, FOR EXAMPLE,
QUANTITATIVE STRUCTURE ACTIVITY
RELATIONSHIP MODEL, QSAR, USING
THEM TO IDENTIFY DNA DAMAGE AND
THEN APPLYING HUMAN EXPERT
KNOWLEDGE TO THAT PREDICTIVE
DATA, AND THEN TAKE A WEIGHT OF
EVIDENCE APPROACH AND WHAT WE'RE
LOOKING AT RIGHT, THERE ARE
OTHER ENDPOINTS OBVIOUSLY,
RESPIRATORY TOXICITY.
RIGHT NOW THERE'S QUITE A BIT OF
AVAILABILITY, IF YOU WILL, FOR
PREDICTIVE MODELS FOR THESE
ENDPOINTS BUT IT'S DIFFICULT TO
BUILD FRAMEWORK BECAUSE OF THE
DATA ISSUE, EVERY APPLICATION IS
DIFFERENT.
SO DATA, THERE MIGHT BE
INFORMATION ON XYZ TYPE OF
DAMAGE AND MAYBE NOT THE OTHER
KIND.
AND SO THERE REALLY IS A
CASE-BY-CASE BASIS.
BUT LIKE I SAID WE'RE REACHING
OUT WITH OUR COLLEAGUES AT OTHER
CENTERS TO LEARN FROM THEM AS
WELL AND TO -- WE'RE IN
DIFFERENT SITUATION, INHALATION
EXPOSURES, BUT ALTHOUGH WE HAVE
SMOKELESS EXPOSURES TOO WITH
OTHER PRODUCTS, SO THE OTHER
TAKEHOME HERE IS HOW WE'RE USING
THIS FOR CHEMICAL HAZARD I.D.,
SO WITH THE QSARs, YOU'RE
FAMILIAR WITH THE RAISE THE RED
FLAG, THE WHOLE GOAL HERE IS TO
SEE IF THERE'S A CONCERN, HOW
CAN WE SET PRIORITIES, IS IT
NECESSARY TO FOLLOW UP, AND THAT
IS GOING TO ENHANCE OUR DECISION
MAKING AT THE LEVEL OF
REGULATORY REVIEW.
I KNOW I'M RUNNING A LITTLE BIT
SHORT OR LONG ON TIME.
SO I'M ALMOST DONE.
ESSENTIALLY, THIS HAS BEEN SAID
MANY TIMES AT THE ICCVAM AND FOR
GOOD REASON, CONTEXT OF USE IN
EVIDENCE-BASED WAY, AND THIS IS
TRUE.
THE WAY WE'RE LOOKING AT IT AND
MOVING FORWARD, OUR CALL TO
ACTION IS CONTINUALLY BETTERING
THE SCIENCE TO HELP SUPPORT OUR
REGULATORY TOX REVIEW EVALUATION
SITUATIONS.
THERE'S ISSUES THAT WE RUN INTO.
MAYBE DATA, THERE'S NO
PREDICTION NARRATIVE IF THE
APPLICANT SAYS IT'S POSITIVE,
NEGATIVE, FROM CLASSIFIER MODEL
MODEL
THAT MAY NOT GIVE ENOUGH
INFORMATION.
IS THE MODEL FIT FOR THAT
PURPOSE?
THIS IS WHERE LIKE WE'RE MOVING
THE DIRECTION AS WELL AS WORKING
ON WEIGHT OF EVIDENCE.
WE NEED TO BE CONSERVATIVE, TO
PROTECT POPULATION, AS I
MENTIONED BEFORE, AND UNDER THE
PMTA AND OTHER REGULATORY
PATHWAYS.
I THINK I'M BASICALLY DONE BUT I
WANT TO THANK -- THESE ARE THE
MEMBERS OF THE NCPT TEAM THAT'S
NEW.
IT'S A PLEASURE TO WORK WITH
THEM IN MY OFFICE.
SO THANK YOU FOR YOUR TIME.
I'M SURE YOU MIGHT HAVE A FEW
QUESTIONS AND I APPRECIATE IT.
[APPLAUSE]
>> THANK YOU, LUIS, EXCELLENT
PRESENTATION.
I KNOW THERE ARE A NUMBER OF
OPPORTUNITIES FOR FOLLOW-UP
BETWEEN OUR GROUPS.
YOU MENTIONED LOOKING AT OPERA,
ALSO SOME OUTCOMES OF THE
CLUSTERING AND CLASSIFICATION
WORKSHOP THAT DTT RAN IN THE
FALL ARE PARTICULARLY RELEVANT
TO SOME OF THE APPLICATIONS THAT
YOU DISCUSSED HERE, THINKING
ABOUT EXTENSION, YOU KNOW, NOT
SOLE RELIANCE ON GENERAL
SIMILARITY TECHNIQUES BUT
ENDPOINT-SPECIFIC SIMILARITY
TECHNIQUES AS WELL SO REALLY
LOOK FORWARD TO FOLLOWING UP ON
THAT AS WELL.
I'M SURE I CAN COUNT ON KAMEL
MANSOURI TO FOLLOW UP.
>>GREAT.
THANK YOU, NICOLE.
ANY OTHER QUESTIONS?
IS THERE ONE ONLINE?
>> YEAH, A QUESTION FROM JOE
FROM PCRM FOR YOUR LUIS, HOW CL
ARE STUDIES FOR ELECTRONIC
NICOTINE DELIVERY SYSTEMS GIVEN
THAT THEY HAVE STATED STATED
SUCH STUDIES ALONE -- I'M SORRY.
SUCH STUDIES ALONE WILL NOT
MEET, QUOTE, APPROPRIATE FOR
PROTECTION OF PUBLIC HEALTH
STANDARD, SPECIFICALLY HOW IS
ONE OF THE FIRST APPROVED
PMTAs ABLE TO SEEK APPROVAL
WHILE ANOTHER INCLUDED RAT
INHALATION STUDIES.
>> YEAH, THERE'S A LOT THERE IN
THAT QUESTION.
LET ME TRY TACKLE.
I CAN'T ANSWER THE QUESTION
ABOUT CARISA, MORE OF A QUESTION
FOR OUR CENTER BUT PMT FINAL
RULE WHICH CAME IN EFFECT
NOVEMBER BASICALLY SAYS THAT NOT
REQUIRED FOR APPLICATION
ACCEPTANCE OR FILING IT
RECOMMENDS TOXOLOGICAL STUDIES
ESPECIALLY THOSE ON CHRONIC
EFFECTS, AND SO IT'S IN --
>>OH DEAR.
WE SEEM TO HAVE LOST DR.
VALERIO.
WE'LL GIVE IT A COUPLE MORE
SECONDS.
IF WE DON'T GET HIM BACK WE'LL
HAVE TO FOLLOW UP ONLINE.
YEAH, UNFORTUNATELY WE'LL HAVE
TO MOVE ON BECAUSE DR. VALERIO
HAS LOST CONNECTION, WE'LL BE
SURE TO PROVIDE THAT QUESTION
AND ANY OTHER QUESTIONS THAT
COME UP FOR HIM VIA E-MAIL AND
ENCOURAGE DIRECT FOLLOW-UP WITH
THE SUBMITTER.
SO, NEXT PRESENTATION IS FROM
DEPARTMENT OF DEFENSE, TYLER
GORALSKI ABOUT
SOLDIER-ON-A-CHIP.
CAN YOU SHARE YOUR SLIDES
PLEASE?
LOOKS PERFECT.
THANK YOU.
>> OKAY.
THANK YOU, NICOLE.
THANK YOU ALL FOR HAVING ME.
I'M TYLER GORALSKI, RESEARCH
BIOLOGIST WITH DEVCOM BIOLOGICAL
CENTER WHERE I MANAGE OUR MPS OR
ORGAN ON A CHIP STUDIES.
TODAY I'M GOING GIVE AN OVERVIEW
OF THE CAPABILITIES AND
SPECIFICALLY DESCRIBE OUR
EFFORTS TO INTERROGATE EFFECTS
OF CHEMICAL AND BIOLOGICAL
THREAT AGENTS USING A
MULTI-ORGAN ON A CHIP SYSTEM.
TO PROVIDE CONTEXT WHAT MY GROUP
DOES WE'RE FOCUSED ON PREDICTIVE
TOXICOLOGIES, WITH THAT WE
DEVELOP, ACQUIRE, IMPLEMENT IN
VITRO MODELS AND SYSTEMS THAT WE
CAN USE TO PERFORM TOXICOLOGICAL
ASSESSMENTS, AND WE USE DATA FOR
IT TO GUIDE DOWNSTREAM IN VIVO
ASSESSMENTS WITH HOPES OF
REDUCING NUMBER OF ANIMALS WE'RE
USING FOR THOSE STUDIES.
HERE I HAVE OUR OPERATIONAL IN
VITRO SYSTEMS BROKEN DOWN BY
ORGAN TYPE.
THIS LIST IS EVER GROWING.
YOU CAN SEE 2D, 3D MODELS,
REALTIME ANALYSIS WITH CARDIAC
SYSTEM, ABILITY TO LOOK AT
ORGANOIDS.
IN THE LAST FIVE YEARS WORKING
TO ADAPT A NUMBER OF NPS MODELS,
OR ORGAN ON A CHIP.
SO DON INGBRID SHOWCASES BREADTH
OF DIFFERENT ORGAN ON A CHIP
SYSTEMS DEVELOPED THROUGHOUT THE
FIELD.
TODAY I'LL HIGHLIGHT THREE
SYSTEMSE COMMERCIAL SYSTEMS
WE'RE USING IN HOUSE DEVELOPED
BY THREE COMPANIES, EMULATE, CN
BIO, AND TISSUSE.
FIRST IS A 12 WELL PLATE, WITH A
TRANSWELL WITH A SCAFFOLD.
YOU CAN INSERT YOUR PRIMARY
TISSUES INTO THE SCAFFOLDS, THEY
GENERATE 3D STRUCTURES LIKE
ORGANOIDS, WITHIN THERE'S A
UNILATERAL CIRCULATING FLOW,
HIGH-THROUGHPUT NATURE IS GREAT
FOR US, USING THIS FOR LIVER,
EXAMPLE OF A FIRST PASS SYSTEM
WE WOULD BE USING TO TEST
TOXICITY OF CHEMICAL AGENT PER
SE.
NEXT IS EMULATE SYSTEM.
HERE'S AN OVERVIEW OF THE CHIP,
IT'S SMALL, ABOUT THE SIZE OF A
FLASH DRIVE, WITH A NUMBER OF
COMPONENTS TO THIS CHIP.
I'M INCREASING THE LEVEL OF
COMPLEXITY WITH EACH OF THE
SYSTEMS.
WITH EMULATE, IT'S A TWO-CHANNEL
CHIP, TOP CHANNEL YOU WOULD SEE
EPITHELIUM, SEPARATED BY
PERMEABLE MEMBRANE, IN THE
BOTTOM CHANNEL YOU SEE YOUR
ENDOTHELIUM.
IT HAS VACUUM CHANNELS ON EITHER
SIDE USED TO IMPLEMENT STRETCH
WITH THE LUNG MODEL,
GASTROINTESTINAL MODEL,
CURRENTLY USING IT FOR LIVER,
ALVEOLUS, SMALL AIRWAY AND BRAIN
MODEL COMING IN SOON.
THIRD MODEL I'M GOING TO DISCUSS
IS THE TISSUSE MULTI-ORGAN CHIP.
HERE IS A PICTURE, DIAGRAM TO
THE RIGHT.
EACH OF THE THREE COMPARTMENTS
HOUSE AN ORGAN TYPE, AMENABLE TO
DIFFERENT ORGANS, iPSC CELLS
OR EVEN CELL LINES.
THEY ARE HOUSED IN A POLY CARBON
CHIP, UNDER THAT IS A PBMS
MICROFLUIDIC LATER PROVIDING
FLOW OF THE MEDIA IN THE CHIP,
UNDER IS MICROSCOPE SLIDE, THE
CHIPS ARE AMENABLE TO VIEWING
THE CELLS IN REAL TIME.
THERE'S THREE PUMPS IN THE BACK
OF THE CHIP3 SYSTEM
EXCHANGING AND PUMPING THROUGH.
THERE'S A CHIP4 SYSTEM, THERE
ARE TWO SEPARATE CIRCUITS WITHIN
THE CHIP.
THERE'S THE KIDNEY CIRCUIT AND
BLOOD CIRCUIT.
YOU HOUSE WITHIN THE CHIP
GLOMERULAR CELLS AND RENAL CELLS
KEEPING IT SEPARATE FROM THE
LIVER COMPONENT AND TWO OTHER
TISSUE TYPES FOR SKIN AND GUT
AND LUNG AND GUT.
ONE OF THE GREAT FEATURE, YOU
CAN DOSE AND LOOK FOR SUBSEQUENT
EFFECTS AT SURROUNDING ORGANS.
THIS MICROSCOPY IMAGE ON THE
RIGHT ARE HEALTHY CARDIAC
ORGANOIDS IN CHIP3, DOSED THESE
IN THE LUNG COMPARTMENT, DOSED
WITH HD, MUSTARD, FLOWED FOR 24
HOURS AND LOOKED AT EFFECTS OF
CARDIAC TISSUE, ORGANOIDS ARE
STARTING TO FALL APART.
YOU CAN SEE A GOOD NUMBER OF
CELLS WITHIN THE ORGANOID ARE
DEAD SO THIS IS JUST A WAY TO
SHOWCASE ONE OF THE NICE
FEATURES OF THIS SYSTEM, THAT
YOU CAN LOOK AT SUBSEQUENT
EFFECTS OF OTHER ORGANS NOT
DIRECTLY DOSING ON.
ONE OF THE ONGOING STUDIES TODAY
IS USE OF THIS CHIP3 SYSTEM TO
TEST EFFECTS OF A NUMBER OF
BIOLOGICAL AND CHEMICAL AGENTS,
ANALYZING USING DOWNSTREAM
MULTIOMICS ANALYSIS.
WE'RE SEEDING WITH CARDIAC
ORGANOIDS, LUNG AND SKIN TISSUE,
DOSING THE CHIPS DIRECTLY ON TO
THE LUNG AND LOOKING AT EFFECTS
OF ALL THREE ORGANS AFTER
LC-MS/MS ACQUISITION AND
BIOINFORMATIC IDENTIFICATION.
PROTEOMEICS AND METABOLOMICS,
THERE'S ALSO A NUMBER OF
DOWNSTREAM ANALYSES THAT CAN BE
DONE USING THIS MULTI-ORGAN
CHIP, GREAT FOR STAINING AND
IMAGING, CAN RUN ELISAS AND
IMMUNOASSAYS, CARDIAC ORGANOIDS
WE'RE LOOKING INTO TESTING THOSE
USING ELECTROPHYSIOLOGY METHODS,
AND THE LIST GOES ON WITH TYPES
OF ANALYSES WITH THESE CHIPS.
FOR THE SAKE OF TIME, I'M GOING
TO GIVE A SNAPSHOT OF SOME DATA
THAT WE'VE ACQUIRED FROM THIS
STUDY ALREADY.
HERE'S AN OVERVIEW OF THE
PROTEOMICS DATA FROM ONE OF OUR
CAR FENTANYL EXPOSURES, WITH
CHANGED PROTEINS, WE HAVE
PROTEIN FEATURES IDENTIFY WE
ANALYZE USING HUMAN PROTEIN
ATLAS DATABASE, AND THIS ALLOWS
US TO LOOK FOR ACTUAL
TISSUE-SPECIFIC DYSREGULATIONS
THAT ARE OCCURRING AS A RESULT
OF THE EXPOSURE, AS OPPOSED TO A
GLOBAL APPROACH, SEEING
DYSREGULATION THAT MIGHT BE
ATTRIBUTED TO OTHER ORGAN TYPES,
HERE WE CAN LOOK DIRECTLY AT
WHAT'S AFFECTING THE SKIN, THE
LUNG, THE CARDIAC TISSUE.
SO THESE VOLCANO PLOTS ARE
BREAKING THAT DOWN FURTHER, INTO
SIGNIFICANTLY DOWN AND
UPREGULATED PROTEINS, MAPPED IN
HEAT MAPS TO SHOW TOTAL NUMBER
OF PROTEINS IDENTIFY AND
DYSREGULATED.
I'M GOING TO HIGHLIGHT THESE TWO
GRAPHS HERE SHOWING RELATIVE
PROTEIN ABUNDANCE COMPARED TO
THE UNTREATED CARDIAC ORGANOIDS
IN THIS CASE, THESE TWO PROTEINS
ARE PIVOTAL IN CALCIUM HANDLING
FOR THE CELLS.
ONE THING I DIDN'T MENTION WITH
THE STUDY, SPECIFICALLY
INTERESTED IN LOOKING AT
PHYSIOLOGICAL EFFECTS THAT ARE
OCCURRING AS A RESULT OF
EXPOSURE TO THESE AGENTS, FUNDED
BY DITRA INTERESTED IN
BIOMARKERS TO DEVELOP WEARABLE
DEVICES.
PROTEIN DYSREGULATIONS STOOD OUT
TO US BECAUSE OF THE CALCIUM
HANDLING IMPLICATION, AND THIS
CAN BE DIRECTLY CORRELATED TO
ARRHYTHMIA WITHIN THE HEART.
WE'RE LOOKING AT SAME TIMES OF
DYSREGULATIONS IN THE LUNG AND
SKIN, SKIN YOU'RE SEEING A LOT
OF PROTEINS INVOLVED IN THE
INTEGRITY OF THE SKIN TISSUE
BEING AFFECTED AND THERE'S A LOT
OF LUNG CELL SIGNALING THAT'S
BEING AFFECTED AS WELL.
WE ALSO LOOKED AT EXPOSURES TO
THE TOXIN STAPHYLOCOCCUS
ENTEROTOXIN B, THE NUMBER OF
PROTEINS FOUND AND SIGNIFICANTLY
CHANGED AS WELL AS VOLCANO PLOTS
FOR DIFFERENT ORGANS WE LOOKED
INTO AND HEAT MAPS.
SO WHEN WE WERE ANALYZING THIS
DATA, THESE DATA, ONE OF THE
PROTEIN DYSREGULATIONS THAT
STOOD OUT TO OUR
BIOINFORMITICIAN WAS THIS.
IT STAND FOR SMALL
UBIQUITIN-LIKE MODIFYING
PROTEIN, SUMO.
LIKE UBIQUITIN THIS MOLECULE
REGULATES A NUMBER OF CELLULAR
RESPONSES, CELLULAR PATHWAYS AND
FACTORS WHICH ARE SHOWN AT THE
BOTTOM OF THE SLIDE.
USUALLY REPRESSION A LOT OF
THESE DIFFERENT PROCESSES.
THIS ENZYME IS ABSOLUTELY
REQUIRED FOR SIMULATION TO
OCCUR.
WITHOUT THAT SIMULATIONS ARE
NON-OCCURRING.
FROM THERE WE LOOKED INTO EACH
OF THESE INDIVIDUAL PROCESSES,
PROTEINS ASSOCIATED WITH THEM
AND LOOKED FOR FURTHER
DYSREGULATION TO TEASE APART
WHAT'S GOING ON WITH THE
SUBEXPOSURE.
AND WHAT WE FOUND WAS
DYSREGULATION OCCURRING IN THIS
PROTEIN PHASE 1.
SO THIS IS AN ADAPTIVE PROTEIN,
INVOLVED IN PERIPHERAL DIVISION
OF MITOCHONDRIA, SO
MITOCHONDRIAL FISSION, IMPORTANT
WHEN THEY UNDERGO DEVELOP
STRESSES, SO WHEN STRESSES
OCCUR, IN ORDER TO MAKE NEW
MITOCHONDRIA THEY HAVE TO FUSE
SICK MITOCHONDRIA OR DIVIDE
HEALTHY MITOCHONDRIA TO KEEP THE
ENERGETICS OF THE CELL GOING.
WE LOOKED FURTHER AND JUST
SEARCHED FOR MITOCHONDRIAL
DYSREGULATIONS IN EACH OF THE
THREE DIFFERENT TISSUE TIMES
THAT WE TESTED, WITH OUR
ENRICHMENT MAPPING SHOWING
DYSREGULATION IN PROCESSES AND
HIGHLIGHTED IN PURPLE WERE ALL
THE MITOCHONDRIAL ASSOCIATED
DYSREGULATIONS IN EACH OF THE
THREE ORGAN TYPES SO WE KNEW
SOMETHING WAS REALLY HAPPENING
WITH MITOCHONDRIA.
WHEN YOU BREAK THAT DOWN INTO
TOP DYSFUNCTIONS AS SHOWN IN THE
ENRICHMENT MAPPING YOU SEE A LOT
OF RESPONSES ASSOCIATED WITH
SIMULATION, SO THREE I'VE
HIGHLIGHTED DOWNREGULATED, THEY
ARE ALL INVOLVED IN SIMULATION.
AND THEN AT THE TOP THE
UPREGULATED PROCESSES WOULD BE
POTENTIAL BIOMARKERS THAT WE
COULD GO AFTER THAT WERE
ASSOCIATED WITH SUBEXPOSURE.
SO PENTOSE PHOSPATE WOULD
INDICATE SWITCH TO ANAEROBIC
RESPIRATION, LOOKING AT LACTIC
ACID BIOMARKERS, BUILDUP, WE
WOULD LOOK AT CALCIUM HANDLING,
DUE TO MITOCHONDRIA BEING SICK.
VASOPRESENT SYNTHESIS
UPREGULATED, INDICATOR THERE WAS
EFFECT WITH BLOOD PRESSURE, AND
WE CAN LOOK AT ADRENALINE AS A
READOUT, ATP ANOTHER GOOD THING
TO LOOK INTO AND THERE'S GOING
TO BE A FOLLOW-ON STUDY
ADDRESSING THESE MITOCHONDRIAL
DYSFUNCTIONS.
SO NOW I WANT TO GET INTO SOME
OF THE OTHER EFFORTS USING
MULTI-ORGAN CHIP SYSTEMS, SHOWN
HERE ON THIS SLIDE IS AN AEROSOL
DELIVERY SYSTEM, DEVELOPED BY
PHILIP MORRIS INTERNATIONAL.
THIS RECAPITULATES THE ENTIRE
RESPIRATORY TRACT.
THERE'S THREE SEPARATE MODULES
WITHIN THIS AEROSOL DELIVERY
SYSTEM, ORAL MODULE, LUNG
MODULE, AIRWAY MODEL.
YOU CAN ACTUALLY LOOK AT THE MA
-- MATURATION, THEY ADAPTED
CHANGES IN THE HUMAN AIRWAY,
THIS INHALES MODEL HAS RECENTLY
BEEN ADAPTED TO SMALL T ORGAN
CHIP, WORKING WITH TISSUSE SO
YOU CAN LOOK AT THE DIFFERENT
EFFECTS AT DIFFERENT PARTS IN
THE AIR WAY, TAKE TISSUES OUT
AND DO DOWNSTREAM ANALYSIS.
WE'RE GETTING THIS SYSTEM IN
HOUSE AT THE END OF THE SUMMER,
BETA TESTING FOR THEM TO SEE HOW
IT WORKS WITH THE CHIPS.
A NUMBER OF OTHER MOC PROJECTS
IN THE WORKS, FIRST WOULD BE
RECREATING ADME MOC, AS I
MENTIONED THE CHIP4 HAS TWO
CIRCUITS, KIDNEY AND BLOOD.
WE CAN LOOK AT ABSORPTION,
DISTRIBUTION, METABOLISM,
EXCRETION, WITHIN THESE CHIPS,
IN THIS CASE WITH
WELL-CHARACTERIZED ANTIBIOTICS.
SO THAT'S ONE COMPONENT OF IT.
WE'RE TRYING TO ESTABLISH
INFECTION MODEL USING THESE
CHIPS, ADD A DRUG, LOOK AT
EFFICACY OF DRUGS WITHIN THE
CONTEXT OF THE TISS-USE CHIP AND
COMPARE WITH DATA TO SEE
TRANSLATIONAL CAPABILITY OF THIS
CHIP FOR THAT PURPOSE.
WE'RE ALSO WORKING TO LOOK AT
VOCs EMITTED FROM THE LUNG
COMPARTMENT OF THE CHIP, WHAT
THEY HAVE BECOME GOOD AT IS
BREATH MASS SPEC, SO THEY ARE
GENERATING PROFILES OF HUMAN
BREATH AND VOCs THAT THEY CAN
DETECT FROM NORMAL HUMAN BREATH
AND OUR AIM IS TO COLLECT VOCs
FROM THE MULTI-ORGAN CHIP AND
SEE HOW THAT COMPARES TO THE
DATA THAT THEY HAVE ALREADY
GENERATED, AGAIN LOOKING AT
TRANSLATIONAL CAPABILITY OF
THESE CHIPS.
FINALLY, OUR LAST EFFORT THAT
WE'RE CURRENTLY WORKING ON IS TO
CREATE A DIAGNOSTIC TRANSLATION
CHIP, SO WE'RE USING THE CHIP3
SYSTEM FOR THIS, AND WE ARE
PICKING DRUGS THAT ARE
WELL-CHARACTERIZED THAT HAVE
GONE THROUGH CLINICAL TRIALS AND
WE HAVE OMICS DATA ON THOSE
DRUGS.
AND ADD THOSE TO THE CHIPS,
COLLECT THOSE SAME OMICS AND SEE
HOW IT COMPARES TO THE HUMAN
DATA.
MY LAST SLIDE IS JUST AGAIN AN
OVERVIEW OF ALL OF OUR
OPERATIONAL SYSTEMS THAT WE HAVE
IN HOUSE AND WHAT WE HAVE IN
DEVELOPMENT.
ONE THING I DIDN'T REALLY TOUCH
ON IS MORE OF THE AIR SOME
EXPOSURE EFFORTS THAT WE HAVE IN
PLACE, ONE OF THE MAJOR
DRAWBACKS THEY ARE NOT TUNED FOR
AIL SORE -- AEROSOL EXPOSURES,
IT'S HARD TO EXPOSE THEM.
THEY ARE CLOSE SYSTEMS.
WE'RE WORKING TO DESIGN OUR OWN
CHIP SYSTEM AND AEROSOL DELIVERY
SETUPS THAT WE'RE 3D PRINTING IN
HOUSE TO DO THOSE AEROSOL
EXPOSURES.
WITH THAT, I WOULD LIKE TO THANK
MY TEAM MEMBERS FROM THE
MOLECULAR TOXICOLOGY BRANCH AS
WELL AS BIODEFENSE BRANCH SO A
NUMBER OF THESE GUYS ARE WORKING
ON THE CHIP EFFORTS THEMSELVES
OR GOING INTO THE BSL3 AND DOING
SELECT AGENT EXPOSURES AND WITH
THAT I WILL TAKE ANY QUESTIONS.
[APPLAUSE]
>> THANK YOU, TYLER.
I HAVE ONE QUESTION.
IN TERMS OF LOOKING AT THE
AEROSOL EXPOSURE SYSTEMS ARE YOU
INCORPORATING CONSIDERATION OF
SYSTEMS THAT WOULD ALLOW
EXPOSURES OF DEFINED MIXTURES?
>> YES.
SO THAT IS DEFINITELY SOMETHING
IN THE WORKS, SOMETHING WE'VE
BEEN TALKING ABOUT FOR YEARS
NOW.
NOT EVEN IN THE CONTEXT OF ORGAN
ON A CHIP BUT STARTING TO CREATE
MATRICES AND TESTING IN VIVO OR
ZEBRAFISH.
>> DO YOU HAVE PLATFORMS YOU'RE
DOING THAT WITH NOW OR IS THAT
STILL SORT OF IN THE DEVELOPMENT
STAGE?
>> YEAH, THAT'S STILL IN THE
DEVELOPMENT STAGE.
I THINK THE REAL GOAL WOULD BE
DOING SOMETHING LIKE THAT WITH
THE INHALE SYSTEM BUT WE'RE JUST
BETA TESTING WITH INNOCUOUS
MATERIAL TO SHOW ITS METTLE.
>> OKAY.
GREAT.
THANK YOU SO MUCH.
ANY OTHER QUESTIONS IN THE ROOM
YEAH, ANOTHER QUESTION HERE.
>> GREAT TALK.
THANK YOU.
DO YOU FLOW IF THE ORGAN A CHIP
SYSTEMS ARE AMENABLE TO LARGE
MOLECULE OR CELL-BASED THERAPY
TESTING?
>> SO, LARGE MOLECULE TESTING
WOULD DEFINITELY BE DOABLE WITH
SOMETHING LIKE THE CN BIOOR
TISS-USE SYSTEM.
FOR EMULATE, IT DEPENDS HOW BIG
YOU'RE TALKING.
YEAH, SOME COMMERCIAL SYSTEMS
WOULD BE AMENABLE TO THAT.
WHAT WAS THE SECOND QUESTION?
>> CELL THERAPY.
>>CELL THERAPY.
ARE YOU TALKING ABOUT
INTEGRATING GENETICALLY MODIFIED
LINES INTO THE SYSTEM?
>> SO ACTUALLY YES,
SPECIFICALLY CAR Ts.
JUST TO SEE, YOU KNOW, IF YOU
COULD RUN IT THROUGH THERE IN
THAT SYSTEM AND SEE HOW THEY
BIND AND DO THEIR THING.
>> I MEAN, THAT'S NOT SOMETHING
WE'VE LOOKED INTO.
YOU KNOW, OUR GROUP, THAT'S OUT
OF OUR PURVIEW BUT I DON'T SEE
WHY YOU COULDN'T.
>> I THINK OUR NEXT PRESENTER
DR. DAN TAGLE MAY HAVE SOME
INFORMED PERSPECTIVE ON THAT
QUESTION AS WELL.
ANY OTHER QUESTIONS ONLINE?
OKAY.
AND JUST TO NOTE, WE SEE DR.
VALERIO REJOINED.
AT THE END AFTER THIS LAST
PRESENTATION WE'LL COME BACK TO
A FINAL OPEN DISCUSSION SECTION
WHERE WE CAN REVISIT ANY OF THE
QUESTIONS WE DIDN'T DO, GENERAL
COMMENTS THAT HAVE COME FROM OUR
ONLINE PARTICIPANTS, ET CETERA.
SO LET ME JUST TRY AND PULL UP
DAN'S SLIDES.
IT ONLY TOOK THE ENTIRE TWO DAYS
FOR ME TO FIGURE OUT HOW TO WORK
THIS SYSTEM.
HERE WE GO, DAN.
>> THANK YOU.
ALL IN PREPARATION FOR ME.
GOOD AFTERNOON, TO THOSE IN
PERSON AND ATTENDING ONLINE, A
PLEASURE TO BE HERE.
THANK YOU, NICOLE, FOR THE KIND
INVITATION.
JUST TO BRIEFLY ANSWER THE LAST
QUESTION, WE HAVE HAD EXPERIENCE
IN OUR FUNDED PROJECTS IN TERMS
OF MACROMOLECULES OF VACCINES,
BIOLOGICS, AND AS WELL AS CELL
THERAPIES.
SOMATIC CELL GENE EDITING AND
EXOSOME BASED FOR EVALUATION OF
EFFICACY AND BIODISTRIBUTION.
I WON'T BE ABLE TO TOUCH BASE ON
THAT IN THIS PRESENTATION.
MY TALK TODAY IS GOING TO BE
MORE OF A LARGE OVERVIEW OF
WHAT'S BEEN GOING ON IN TERMS OF
DEVELOPING TISSUE CHIPS OR
MICROPHYSIOLOGIC SYSTEMS
PRIMARILY IN CONTEXT OF DRUG
DEVELOP AM.
I COME FROM NATIONAL CENTER FOR
ADVANCING TRANSLATIONAL
SCIENCES.
>> I'M JUST GOING TO MOVE -- I
THOUGHT I FIGURED IT OUT.
LET ME MOVE THE MEETING CONTROLS
SO EVERYONE CAN SEE THE FULL
CONTENT OF YOUR SLIDES.
THERE WE GO.
>> THANK YOU, NICOLE.
YEAH, NATIONAL CENTER FOR
ADVANCING TRANSLATIONAL SCIENCES
IS WITHIN THE NIH.
AND WE HAVE OUR MISSION, OUR
GOAL, TO ADDRESS LONGSTANDING
BOTTLENECKS OR WHAT WE CALL ROAD
BLOCKS INTO TRANSLATIONAL
PIPELINE, SOME IN INDUSTRY CALL
IT THE VALLEY OF DEATH.
IN THIS PARTICULAR EXAMPLE, IN
TERMS OF RELATIONSHIP TO
DEVELOPING TISSUE CHIPS, THE
TRANSLATIONAL PROBLEMS THAT
WE'RE TRYING TO SOLVE IS
PRIMARILY LOOKING AT SMALL
MOLECULES, 90% FAIL IN THE
CONTEXT OF DRUG DEVELOPMENT FROM
EARLY DISCOVERY, PRE-CLINICAL,
TO CLINICAL TRIALS, TAKES AN
AVERAGE OF 10 TO 15 YEARS TO
COME TO MARKET, $2.6 BILLION PER
MARKET-APPROVED DRUG.
SO, THOSE IN THE INDUSTRY IN THE
PHARMA INDUSTRY HAVE LONG LOOKED
AT WHERE THE INEFFICIENCIES ARE,
AND THEY HAVE LOOKED AND POINTED
TO INSUFFICIENT TOOLS AND
TECHNOLOGIES THAT ARE CERTAINLY
NOT CAPABLE OF ACCURATELY
PREDICTING HUMAN SAFETY AS WELL
AS EFFICACY OF CANDIDATE DRUGS.
SO OUR SOLUTION IN TERMS OF
NCATS SOLUTION IS TO COME UP
WITH BETTER PREDICTIVE TOOLS,
AND THAT ARE MORE HUMAN BASED
BECAUSE THE ANIMAL MODELS BEING
USED IN THE TRADITIONAL METHODS
OF DRUG DEVELOPMENT SHOWS
SPECIES-SPECIFIC DIFFERENCES.
WE ALSO ARE LOOKING AT MODELS
THAT MIMIC STRUCTURE AND
FUNCTION OF HUMAN DISEASES, OF
COURSE.
AND MODELS THAT MEET NEED FOR
NEW THERAPEUTIC MODALITIES, THAT
GOES BACK TO THE LAST QUESTION
BECAUSE MORE AND MORE OF THE
TREATMENT EVEN FOR SMALL
MOLECULES ARE BECOMING MORE
SPECIFIC TO SPECIFIC HUMAN
MUTATIONS, ANTIBODIES, VACCINES
ARE MORE HUMAN SPECIFIC IN TERMS
OF HOW THEY ARE BEING DEVELOPED.
AND SOMATIC GENE EDITING, LIKE
COMING INTO VOGUE AND ESPECIALLY
FOR GENE THERAPIES, ESSENTIALLY
TESTED ONLY ON HUMAN SEQUENCES
AND SO YOU EITHER HAVE TO
HAVE -- TO DEVELOP COST AND TIME
TO DEVELOP HUMANIZED ANIMAL
SYSTEM, USING HUMAN TISSUES PUT
ON MICROPHYSIOLOGICAL SYSTEMS
WOULD ADDRESS THAT PURPOSE.
AND SO THE NCATS TISSUE CHIP
PROGRAM TAKES INTO ACCOUNT
FACTORS INTO CONSIDERATION, AND
REALLY IS INTERDISCIPLINARY
APPROACH BRINGING TOGETHER
MULTI-DISCIPLINES, OUR TEAM,
PROJECT TEAMS, ARE TYPICALLY
MULTI-DISCIPLINARY, MADE OF
BIOMEDICAL ENGINEERS, STEM CELL
BIOLOGISTS, MICROFLUIDIC
EXPERTS, AND PHARMACOLOGISTS AND
TOXICOLOGISTS.
ALL INFORMING AND COMING
TOGETHER TO SEE HOW WE COULD
DEVELOP SYSTEMS THAT WOULD MIMIC
AT LEAST TEN MAJOR ORGAN SYSTEMS
IN THE BODY, ALL LISTED HERE,
CIRCULATORY, ENDOCRINE,
GASTRODES SPINDLE --
GASTROINTESTINAL, IMMUNE, SKIN.
THEY ARE MORE TISSUES ON CHIPS,
BECAUSE WE GO FROM THE BOTTOM
UP, LOOK AT THE BASIC FUNCTIONAL
UNIT OF ORGAN SYSTEM, SUCH AS
LUNGS, WITH ALVEOLI, AIR SACS,
RENDERING THAT HAS BEEN
MENTIONED IN THIS WORKSHOP A FEW
TIMES, EMULI, CYCLIC VACUUMING,
STRETCHING MEMBRANE, BLUE WOULD
BE HUMAN LUNG EPITHELIAL CELLS,
VASCULAR ENDOTHELIUM ON THE
BOTTOM SIDE OF THE MEMBRANE, AND
THE LUNG EPITHELIAL CELLS IS
EXPOSED TO AIR SO THERE'S
AIR-LIQUID INTERFACE BECAUSE THE
BOTTOM WOULD BE MEDIA FLOW.
THAT'S STRETCHING BY ITSELF,
BIOMECHANICAL PROPERTIES OF THE
CHIP ALLOWS FOR MORE PHYSIOLOGIC
RESPONSE OF THE CELLS.
SO THAT'S THAT EXAMPLE OF THE
EMULATE SINGLE ORGAN CHIP THAT
TYLER ADEQUATELY DESCRIBED IN
HIS PRESENTATION.
WE ALSO HAVE EFFORTS TO FORM
MULTI-ORGAN SYSTEMS.
THIS IS AN EXAMPLE OF A COMPANY
THAT NCATS FUNDED, IT'S ABOUT
THE SIZE OF YOUR iPHONE, FIVE
COMPARTMENTS, CONTAINING LIVER,
MUSCLE TISSUE, BOTH SKELETAL,
AND CARDIAC MUSCLES, AS WELL AS
KIDNEY AND BRAIN CELLS IN THE
OUTER COMPARTMENTS.
WE STARTED WORKING ON THIS
PROGRAM IN 2012 SPECIFICALLY
FOCUSING ON PRIMARILY HOW TO
VERY MANY TECHNOLOGY, PRIMARILY
FIRST LOOKING AT HOW TO PREDICT
DRUG SAFETY, AND TOXICOLOGY SO
THESE ARE SOME OF THE FUNDED
PROJECTS, AND WE WERE JOINED BY
PARTNERS WITHIN THE NIH, THROUGH
THE NIH COMMON FUND, NIBIB, NCI,
NICHD, NIEHS, AND THE OFFICE OF
RESEARCH FOR WOMEN'S HEALTH.
JUST TO GIVE AN EXAMPLE OF SOME
OF THE THINGS THAT ARE BEING
DONE IN TERMS OF DRUG
DEVELOPMENT, AND HOW WE'RE
APPROACHING QUALIFICATION OR IN
SOME CASES VALIDATION OF THIS
TECHNOLOGY, THIS IS AN EXAMPLE I
THINK I'VE HEARD IN THE CONTEXT
AT LEAST THIS MORNING OF
SPECIFIC CONTEXT OF USE, SO THIS
IS A SPECIFIC CONTEXT OF USE FOR
A LIVER SINUSOID, A LIVER CHIP
REPRESENTED ESSENTIALLY THE
LIVER SINUSOID MADE UP OF
PARENCHYMAL CHANNELS, OF COURSE
WE HAVE THE HEPATOCYTES, HUMAN
HEPATOCYTES, ALSO CELLS ARE
KUPFFER CELLS, ENDOTHELIAL,
KUPFFER CELLS, VASCULAR
COMPARTMENT AND PARENCHYMAL
COMPARTMENT, RESPONSIBLE FOR
METABOLIZING A NUMBER OF
MEDICATIONS.
DRUG INDUCED LIVER INJURY,
SPECIFIC CONTEXT OF USE THAT
WE'RE LOOKING AT, IS THE MOST
COMMON CAUSE OF ACUTE LIVER
FAILURE, 15 TO 20 PER 100,000,
AND CERTAINLY ADVERSE DRUG
REACTIONS IS AN IMPORTANT CAUSE
OF LIVER INJURY.
SO IN THIS CASE IF YOU LOOK AT
EXAMPLE OF DEVELOPMENT OF
PARTICULAR DRUG, IT WAS
DEVELOPED AS AN ANTI-VIRAL AGENT
FOR HEPATITIS B, FIALURIDINE
WENT THROUGH PRE-CLINICAL
TESTING IN RATS AND DOGS IN
VIVO, FDA, GOT APPROVED, KILLED
FIVE OF THE 15 HUMAN SUBJECTS
ENROLLED, THIS WAS EARLY PHASE 1
TRIALS, HEALTHY HUMAN SUBJECTS,
IT KILLED FIVE.
FDA WITHDREW IT OF COURSE.
IN THAT PARTICULAR CASE THE RAT
AND DOG IN VIVO MODELS DID NOT
PREDICT TOXICITY.
SO THE QUESTION BEING ASKED
WOULD THE HUMAN LIVER CHIP HAVE
BEEN ABLE TO PREDICTS PREDICT S
TOXICITY?
TOOK RAT LIVER CHIP, CONSTRUCTED
THE SAME WAY AS HUMAN, DOSED
WITH 0, 1, 20, 30 MICROMOLARS OF
FIALURIDINE AND STAINED WITH
RED, TO SHOW FATTY DEPOSITS, AND
IF THERE'S FATTY DEPOSIT SHOWING
UP AT YELLOW, AND THAT WOULD BE
AN INDICATION OF STEATOSIS.
EVEN WITH INCREASING DOSE OF
FIALURIDINE THE RAT LIVER CHIP
DID NOT SHOW STAINING, HUMAN
LIVER CHIP SHOWED DOSE DEPENDENT
INCREASE SHOWN HERE BY
ACCUMULATION OF FATTY DEPOSITS,
AND THAT CAN BE QUANTITATED ON
THIS CHART.
IT'S NOT TO JUST RELY ON
HISTOLOGICAL MARKERS OR
MOLECULAR MARKERS BUT ALSO
LOOKING AT FUNCTION, SO
FUNCTIONALITY, ALBUMIN SECRETION
IS ONE OF THE MOST IMPORTANT
ASSAYS TO LOOK AT LIVER
FUNCTION, SO IF YOU LOOK AT THE
RAT LIVER CHIP, VARYING DOSES,
THERE'S NO CHANGE IN ALBUMIN
SECRETION, IN THE HUMAN LIVER
CHIP THERE'S DOUGH DEPENDENT
DECREASE AND IF YOU LOOK AT
MOLECULAR MARKERS OF LIVER
INJURY SUCH AS MIR 122,
TRANSFERASE, KERATIN, THERE'S
DOSE DEPENDENT INCREASE IN
EXPRESSION OF THIS LIVER INJURY
MARKERS.
THAT'S ONE DRUG.
THIS WAS TO SHOW IN TERMS OF
REPRODUCIBILITY AND ROBUSTNESS
OF THIS SYSTEM FOR DRUG INDUCED
LIVER INJURY, 22 COMPOUNDS WITH
KNOWN HEPATOTOXIC PROPERTIES
USED, COLLECTIVELY 22 COMPOUNDS
CAUSED 200 DEATHS JUST LIKE WITH
THE FIALURIDINE THEY WENT
THROUGH PRE-CLINICAL STUDY, INTO
CLINICAL TRIALS, AND KILLED 200
PATIENTS, ALL 22 COMPOUNDS WERE
SUBSEQUENTLY WITHDRAWN.
SO THE QUESTION IS, AGAIN, JUST
LIKE WITH THE FIALURIDINE, LIVER
CHIP BEING ABLE TO PREDICT THAT
AND THE ANSWER IS YES, WITH 87%
SENSITIVITY, 100% SPECIFICITY
BEING ABLE TO PREDICT TOXICITY
THAT ONLY THE SPHEROID MODEL WAS
ABLE TO SHOW AT BEST 47%
SENSITIVITY.
ALL OF THESE ARE NOW PUBLISHED.
SWITCHING GEARS WE HAVE ALSO IN
ADDITION TO LOOKING AT SAFETY
USE OF TISSUE CHIPS, ALSO
LOOKING AT DISEASE MODELING AND
EFFICACY STUDIES, IN THIS CASE
BEING ABLE TO CAPTURE NOT JUST
NORMAL HUMAN CELLS AND TISSUES
BUT ALSO LOOKING AT
PATIENT-DERIVED MATERIALS, IN
THIS CASE SO WE CAN CAPTURE THE
DISEASE MECHANISM OR DISEASE
PATHOLOGY ON THE CHIPS.
AND OF COURSE TISSUE PHENOTYPE
OVER WEEKS AND MONTHS, ALSO
REFLECT MULTI-ORGAN POTENTIAL
APPROACHESSOLOGY.
SO THESE ARE FUNDED PROJECTS
THAT NCATS HAVE DONE.
MODELING ESSENTIALLY COMMON
DISEASES LOOKING AT ALZHEIMER'S,
PARKINSON'S, EVEN TYPE 2
DIABETES, WITH MULTI-ORGAN
CHIPS, AS WELL AS RARE DISEASES
LOOKING AT BART SYNDROME, A RARE
CARDIOMYOPATHY, ALSO LOOKING AT
RARE VASCULAR THUNDERSTORMATION,
NOW BEING STUDIED IN THE CONTEXT
OF DISEASE MODELING.
JUST TO GIVE AN EXAMPLE OF THE
POWER OF THIS TECHNOLOGY BEING
ABLE TO CAPTURE HUMAN DISEASES
WHICH TAKES YEARS TO DEVELOP
ANIMAL MODELS FOR, IN A RARE
AUTOIMMUNE DISEASE DEMYELINATING
NEUROPATHY, IN PARTICULAR
CHRONIC INFLAMMATORY
DEMYELINATING POLY NEUROPATHY,
CIDP, MULTI-FOCAL MOTOR
NEUROPATHY.
SO THERE ARE NO EXISTING ANIMAL
MODELS FOR THIS BECAUSE IT'S A
RARE DISEASE.
THE ANTIBODIES GENERATED BY THE
PATIENT ATTACKS THE NERVOUS
SYSTEM, IN THIS CASE
NEUROMUSCULAR JUNCTION ON A CHIP
WAS DEVELOPED CONSISTING OF
HUMAN PRIMARY SCHWANN CELLS AND
INDUCE THE PLURIPOTENT CELLS
DERIVED FROM MOTOR NEURONS,
AUTOIMMUNE, SO SERA FROM
PATIENTS ARE COLLECTED, AND THIS
NEUROMUSCULAR JUNCTION TREATED
WITH PATIENT SERA, IF THERE IS
AN IMMUNE RESPONSE YOU CAN SEE
THIS IN VARIOUS STAINING, GREEN
FOR SHOWING ACTIVATION OF
COMPLEMENT PATHWAY C3B AND RED
SHOWING ACTIVATION AND YELLOW
WOULD BE LIKE A CO-LOCALIZATION.
IN THIS EXAMPLE THESE ARE 15
NEUROMUSCULAR JUNCTIONS ON A
CHIP, EACH TREATED WITH SERA
FROM 15 PATIENTS AND AGAIN
CONSISTENTLY ALL 15 SERA SHOWED
STAINING, THIS IS AN EXAMPLE OF
DRUG REPURPOSING, THERE'S AN
FDA-APPROVED DRUG, TNT 005,
MONOCLONAL ANTIBODY THAT
INHIBITS C1S PROTEASE.
IF YOU PRE-TREAT THE
NEUROMUSCULAR JUNCTION ON CHIP
AND ADD THE SERUM, THIS IS WHAT
YOU GET.
NO ACTIVATION OF COMPLEMENT, IN
ANY OF THE -- AGAINST ANY 15
SERA, SO THIS WAS DEVELOPED
WITHIN MONTHS AND THE CANDIDATE
DRUG WAS IDENTIFIED WITHIN
MONTHS, AND IT'S NOW IN PHASE 2
CLINICAL TRIALS SPONSORED BY
SANOFI.
ONE OF THE THINGS THAT WE HAVE
BEEN FORTUNATE TO DO AS WELL IS
TO BE ABLE TO PIVOT TISSUE CHIP
TECHNOLOGY TO RESPOND TO
NATIONAL HEALTH EMERGENCIES,
PRIOR TO THE PANDEMIC WE HAD THE
OPIOID CRISIS SO WE WERE FUNDED
TO DEVELOP MODEL SYSTEMS TO
DEVELOP MODELS THAT COULD MIMIC
SENSORY PAIN CIRCUITRY, AS YOU
KNOW MOST MODELS IN PAIN INVOLVE
RAT AND INVOLVES PUTTING THE
PAWS ON A HEAT PAD.
EVEN WITH THAT IT'S STILL
INADEQUATE.
WE'VE BEEN DEVELOPING MODELS TO
ALSO MIMIC THE BLOOD-BRAIN
BARRIER, AND WITH THE PANDEMIC
BEING ABLE TO ALSO AS NICOLE
INDICATED IN HER TALK NOT VERY
MANY ANIMALS, THE FERRET AND
HAMSTER SUBJECT TO INFECTION BY
SARS-COV-2, SO WE WERE ABLE TO
SHOW THAT TISSUE CHIPS CAN BE
DEVELOPED TO BE ABLE TO
UNDERSTAND MODEL INFECTION AND
ALSO TO TEST CANDIDATE DRUGS AS
WELL AS VACCINES.
ONE OF THE THINGS THAT WE HAVE
BEEN FORTUNATE TO HAVE IS A
PARTNERSHIP WITHIN NCATS, NASA,
CENTER FOR ADVANCEMENT OF
SCIENCE IN SPACE, INTERNATIONAL
SPACE STATION, NATIONAL
LABORATORY, THIS IS ALSO AN
EXAMPLE WHERE WE'RE PUSHING THE
BOUNDARIES IN THIS CASE INTO
OUTER SPACE TO MODEL DISEASES,
TYPICALLY WILL TAKE YEARS IF NOT
DECADES TO MODEL HERE ON EARTH,
BUT AS IT TURNED OUT UNDER
EXPOSURE OF THE MICRO GRAVITY
ENVIRONMENT ACCELERATING AGING
CAN BE MIMICKED WITHIN WEEKS,
EXPOSURE TO MICRO GRAVITY, SO WE
HAVE PROJECTS THAT HAVE GONE TO
THE SPACE STATION, THE CULTURE
LIFE OF ORGANS AND CHIPS.
WHAT THEY HAVE BEEN DEVELOPED TO
ADDRESS THE FDA REQUIREMENT OF
28-DAY EXPOSURE, AND SO MOST OF
THE CHIPS HAVE CERTAINLY MET
THAT AND THEY ARE GOING ON FOR
30 DAYS UP TO IN SOME CASES
THREE MONTHS, BUT WE WANTED TO
SEE IF WE CAN PUSH THIS SYSTEM
AND DEVELOP PLATFORMS TO EXTEND
TO SIX MONTHS LOOKING AT DISEASE
MECHANISMS, LOOKING AT BEING
ABLE TO HAVE A SYSTEM IN A WOULD
SUBJECT -- THAT WOULD BE SUBJECT
TO CHRONIC EXPOSURE IN DRUGS AND
THINGS INTERESTING TO THIS GROUP
FOR ENVIRONMENTAL AGENTS AS
WELL.
ANOTHER AREA, THE MORE RECENT
ONE, CLINICAL TRIALS ON CHIPS.
CO-FUNDED BY NCI, NICHD, AND
NIAMS, AND THE QUESTION HERE IS
CAN WE DEVELOP TISSUE CHIPS THAT
CAN INCORPORATE DIVERSITY, NOT
ONLY IN TERMS OF PATIENT
DIVERSITY, IN TERMS OF PATIENT
POPULATION, BUT ALSO PEDIATRIC
POPULATIONS, VARIOUS GROUPS THAT
ARE AMENABLE OR NOT AMENABLE BUT
SUSCEPTIBLE IN TERMS OF
ETHNIC-SPECIFIC OR
POPULATION-SPECIFIC GROUPS THAT
MIGHT BE AT RISK TO CERTAIN
DISEASES.
AND BE ABLE TO THEN INFORM HOW
TO INFORM CLINICAL TRIALS IN
TERMS OF RECRUITMENT, ABLE TO
STRATIFY THE PATIENT, VERY MANY
CLINICALLY RELEVANT BIOMARKERS
WITH THE GOAL OF ESSENTIALLY
SHORTENING THE CLINICAL TRIAL
PIPELINE, AND MAKING IT MORE
SUCCESSFUL BY IDENTIFYING
PATIENTS WHO ARE MOST LIKELY TO
BE SUBJECT TO ADVERSE EVENT AND
THOSE MOST LIKELY TO RESPOND TO
THE TREATMENT.
AND SO THESE ARE ESSENTIALLY
LOOKING AT INCORPORATING UPWARDS
OF 200 PATIENTS ON 200 CHIPS, SO
MANY INDIVIDUALS BEING
REPRESENTED ON THE CHIPS,
REPRESENTING AGAIN THE PATIENT
DIVERSITY AS WELL, AS WELL AS
POPULATION DIVERSITY, AND THEN
ACTUALLY RUN IT ALONGSIDE AN
ONGOING CLINICAL TRIAL SO THIS
INVOLVES PARTNERSHIP WITH
PHARMA, AND TESTING ALONGSIDE
THE CLINICAL TRIALS TO SEE IF
THERE'S GOING TO BE CORRELATION
OF THE RESULTS FROM THE PATIENT
TRIALS VERSUS THOSE RESULTS
COMING OUT FROM THE CHIPS.
SO THESE ARE SOME OF THE
PROJECTS THAT WE'RE FUNDING FROM
NON-ALCOHOL FATTY DELIVER
DISEASE, PROGERIA, MUSCULAR
DYSTROPHY, TEND INFLAMMATION,
ALS, HEART DISEASE, PRE-TERM
BIRTH, PLACENTA ON A CHIP, AND
THEN PROSTATE CANCER, METASTASIS
INTO THE BONE MARROW.
SWITCHING GEARS WE'RE ALSO OF
COURSE INTERESTED IN DEVELOPING
TECHNOLOGY AND BUILDING
CONFIDENCE, INTO TECHNOLOGY SO
IT COULD LEAD TO WIDESPREAD USE
AND COMMERCIALIZATION, SO THIS
IS ESSENTIALLY A THREE-STEP
VALIDATION PROCESS THAT WE PUT
TOGETHER AS PART OF OUR
FRAMEWORK, PHYSIOLOGICAL
VALIDATION WOULD BE AS MENTIONED
IN PREVIOUS SLIDES TO MIMIC
ORGAN FUNCTION AT THE BASICS
FUNCTIONAL UNIT, AND USE THEM TO
SEE THE RESPONSE ON THE SET OF
REFERENCE COMPOUND OR TRAINING
COMPOUNDS, I'VE SHOWN WITH THE
FIALURIDINE AS AN EXAMPLE.
ALL OF THOSE HAVE BEEN
PUBLISHED, AS A RESULTS HAVE
BEEN PUBLISHED.
NEXT WE SET UP ANALYTICAL
VALIDATION, ESSENTIALLY CREATING
OR ESTABLISHING INDEPENDENT
TESTING CENTERS, THAT WOULD TEST
ROBUSTNESS, REPRODUCIBILITY,
RELIABILITY, RELEVANCE AS WELL
AS PORTABILITY OF THIS
TECHNOLOGY, THESE TECHNOLOGIES,
BY PUTTING THEM INTO TESTING
CENTERS THAT HAVE NOT WORKED ON
THIS TISSUE CHIP SYSTEMS, BUT
BEING ABLE TO SHOW THAT THEY CAN
IN THEIR OWN HANDS BE ABLE TO
REPLICATE THE DATA THAT WAS
GENERATED BY THE DEVELOPERS.
AND SO IN THAT REGARD WE HAVE
FUNDED -- M.I.T. IS A TESTING
CENTER, TEXAS A & M, AND
CREATING DATABASE AT UNIVERSITY
OF PITTSBURGH.
THE LAST STEP IN THE VALIDATION
FRAMEWORK IS INDUSTRIAL
VALIDATION, WHERE INDUSTRY AND
REGULATORY AGENCIES ARE NOW
STARTING TO USE THIS HEAVILY, I
WON'T GO INTO THAT IN MY TALK
BUT THERE'S PLENTY OF PAPERS TO
SHOW THERE'S INDUSTRY USE, AS
WELL AS FDA INTEREST OR
REGULATORY INTEREST, AND THIS IS
DONE EITHER IN THEIR OWN
LABORATORIES OR THROUGH A
CRO-TYPE ENVIRONMENT.
IN THAT REGARD OUR TESTING
CENTERS EVOLVE INTO LIKE M.I.T.
BECAME JAVELIN BIOTECH, NOW A
CRO, AND TEXAS A & M IS NOW A
TESTING CONSORTIUM WHICH IS A
PAY FOR PLAY MODEL, MPS DATABASE
NOW ALSO SELF-STAINING IN THE
SENSE THEY HAVE BOTH DATA THAT'S
FREELY ACCESSIBLE TO THE PUBLIC
AND FIRE WALL-PROTECTED DATA
SITE THINGS AND CALLED A
BIOCYSTIC ANALYTICS PLATFORM,
ESSENTIALLY TAKES IN DATA FROM
TISSUE CHIPS AND INCORPORATION
THAT WITH CLINICAL DATA,
PRE-CLINICAL DATA, ALL THE
UNIVERSE OF COMPOUNDS AND
CHEMISTRIES HAVE BEEN TESTED IN
HUMANS TO BE ABLE TO INFORM
MODEL REPRODUCIBILITY, IDENTIFY
COMPOUNDS THAT ARE SAFE AND
EFFECTIVEE DISEASE PROGRESSION,
AS WELL AS DEVELOP MODELS FOR
ADME AND TOXICITY STUDIES.
TYLER MENTIONED SOME OF THIS IN
HIS PRESENTATION SO THERE'S
TISS-USE, EMULATE, BIO, SPINOFF
COMPANIES OR STARTUPS, WORKING
ON VARIOUS ASPECTS OF MIMICKING
HUMAN PHYSIOLOGY AN FUNCTION AND
TO A CERTAIN DEGREE NIH HAS
SUPPORTED THESE COMPANIES
THROUGH SMALL BUSINESS EFFORTS,
WHICH IS ALSO SIGNIFICANT IN THE
SENSE THAT WE ARE EXPECTING
REALLY A BIG JUMP IN THE USE OF
THIS TECHNOLOGY, FOR EXAMPLE, IN
STUDY DONE SHOWING THE CURRENT
UTILITY OF TISSUE CHIPS, IT'S
GOING TO GROW TO A $600 MEDICAL
ENTERPRISE IN A FEW YEARS FROM
NOW, IN 2028, WITH ABOUT A 40%
ANNUAL GROWTH RATE.
JUST TO SUMMARIZE, ASPECTS WERE
TISSUE CHIPS EMPLOYED, GOES FROM
EARLIEST STAGES OF DRUG
DEVELOPMENT FROM TARGET
IDENTIFICATION AND VALIDATION TO
CLINICAL ASSESSMENT, AND
CERTAINLY IT'S ALSO GOING TO BE,
YOU KNOW, ANTICIPATED TO BE A
HUGE COST SAVINGS.
I THINK WE FROZE.
YEP.
SO, WITH ANTICIPATED UP TO 26%
COST SAVINGS IN DRUG DEVELOPMENT
COST, IN FIVE YEARS, EVEN AT
JUST CURRENT RATE OF USAGE BUT
OF COURSE WE'RE SEEING AN
INCREASE IN USE OF THIS
TECHNOLOGY.
LASTLY I'D LIKE TO PUT IN A PLUG
FOR MICROPHYSIOLOGICAL WORLD
SUMMIT, SOMETHING NCATS
ESTABLISHED BY FUNDING
CONFERENCE GRANT TO HOPKINS,
JOHNS HOPKINS UNIVERSITY, AND
OUR GOAL IS TO REALLY BRING THE
INTERNATIONAL COMMUNITY THAT'S
WORKING ON TISSUE CHIPS SO WE
CAN WORK TOWARDS GLOBAL
HARMONIZATION OF REGULATORY USE
AND STANDARDIZATION OF
PLATFORMS, AS WELL AS TO TRAIN
THE NEXT GENERATION OF
SCIENTISTS OF ESTABLISHING
INTERNATIONAL MICROPHYSIOLOGICAL
SYSTEMS SOCIETY THAT ACTUALLY
WOULD BE FORMALLY ANNOUNCED AT
THE BERLIN CONFERENCE NEXT
MONTH, INAUGURAL CONFERENCE WAS
LAST YEAR IN NEW ORLEANS, AND
WE'RE HOPING TO RETURN BACK TO
THE UNITED STATES IN 2024.
WITH THAT, I'LL JUST END.
THIS IS MY SUMMARY SLIDE IN
TERMS OF THE TISSUE PROGRAM,
WORKING WITH THE DEVELOPERS AND
SUPPLIERS, WITH PHARMA
COMPANIES, REGULATORY AGENCIES,
IDENTIFYING COMMON AREAS, AND
CONSORTIUM OF INVESTIGATORS CAN
WORK WITH PHARMA AND REGULATORY
AGENCIES, IN BUILDING TOGETHER
PLATFORMS THAT CAN BE ENABLING
AND WOULD CERTAINLY STREAMLINE
COST AND EFFICIENCY OF DRUG
DEVELOPMENT AND I'VE SHOWN
HOPEFULLY BRIEFLY IN MY
PRESENTATION DEMONSTRATION IN
TERMS OF TOXIN SAFETY STUDIES,
HOW WE ESTABLISH TESTING CENTERS
AND DATABASE CENTERS,
DEMONSTRATION AND VALIDATION FOR
RARE AND COMMON DISEASE
MODELING, CLINICAL TRIALS ON
CHIPS, ADOPTION AND USE BY
PHARMA AND DRUG DEVELOPMENT,
HARMONIZATION, TRAINING OF NEXT
GENERATION SCIENTISTS, OUR BIG
NEXT STEP WITHIN NCATS IS
ESTABLISHMENT, I HAVEN'T PUT A
CHECK MARK THERE, BUT LATER THIS
YEAR WE'LL BE ANNOUNCING
ESTABLISHMENT OF TRANSLATIONAL
CENTERS FOR MPS WHICH WOULD BE
U.S.-BASED CENTERS THAT WOULD
SEEK TO QUALIFY MANY OF THE
PLATFORMS AS DRUG DEVELOPMENT
TOOLS SO THAT THE FDA CAN
ACTUALLY FORMALLY RECOGNIZE THEM
AS TOOLS AND SO THEN BE ABLE TO
LEAD TO COMMERCIALIZATION AND
SCALE OF PRODUCTION.
AND MY ACKNOWLEDGMENT SLIDE,
PRIVILEGED WORKING WITH A VERY
TALENTED GROUP OF PEOPLE WITHIN
MY OFFICE, THE REST OF THE NIH
AND SOME OF THE PARTNERS WE HAVE
ACROSS THE VARIOUS AGENCIES.
THANK YOU VERY MUCH.
[APPLAUSE]
>> FANTASTIC.
IT'S OBVIOUS FROM THE
PRESENTATION TRANSFORMATIVE WORK
NCATS HAS DONE IN THIS SPACE.
DAN HIMSELF HAS DONE IN LEADING
THE PROGRAM.
SO, WE ARE A LITTLE OVER TIME
BUT THIS IS THE END OF THE DAY
SO WE'D LOVE TO HAVE A FEW MORE
MINUTES FOR ADDITIONAL QUESTIONS
AND COMMENTS.
ONE QUESTION THAT DID COME IN
AFTER TYLER'S PRESENTATION THAT
IS OBVIOUSLY RELEVANT TO DAN'S
PRESENTATION AS WELL FROM CAROL
CLARK, WHAT ARE THE DRAW BACKS
TO USING ORGANS ON A CHIPS AND
HOW HAS TECHNOLOGY HELPED TO
REDUCE THIS?
I THINK THAT'S ALSO RELATED TO
THE IDEAS AROUND REGULATORY
QUALIFICATION AND MORE
WIDESPREAD IMPLEMENTATION WHICH
WE HOPE TRANSLATIONAL CENTERS
WILL ADDRESS BUT I WONDER IF YOU
WANT TO SAY ANYTHING ELSE ABOUT
EXISTING -- I CAN ASK TYLER IF
YOU WANT TO UNMUTE AND ADDRESS
ANY ASPECT OF THAT?
I DON'T KNOW IF HE'S STILL ON.
YOU START.
>> THANK YOU FOR THAT QUESTION.
IN TERMS OF DRAWBACKS, THE
TECHNOLOGY CERTAINLY IS STILL IN
EARLY STAGES, WE ESTABLISHED
THIS PROGRAM IN 2012, OVER 10
YEARS OLD, JUST BARELY LEARNING
HOW TO WALK AND RUN.
SO THERE ARE STILL TECHNOLOGICAL
NEEDS.
IT STILL TAKES -- THE MAIN
THINGS THAT COMES TO MIND WOULD
BE LEARNING CURVE, IT WOULD TAKE
TO PUT -- INCORPORATE INTO THE
LABORATORIES.
SO THAT'S WHY EVEN WITH
COMMERCIAL COMPANIES PUTTING IN
THOSE NICE PLATFORMS, EMULATE
AND TISS-USE, IT TAKES A FEW
MONTHS TO EVEN A YEAR TO GET
THINGS UP AND RUNNING, AND SO
WITH THAT IN MIND WE'RE ACTUALLY
LAUNCHING ANOTHER ASPECT OF OUR
PROGRAM PROBABLY IN LATE SUMMER,
IN TERMS OF PROMOTING PLATFORM
AND INSTRUMENTATION IMPROVEMENTS
TOWARDS AUTOMATION, TO MAKE IT
MORE TURNKEY SO YOU CAN RUN THE
SYSTEM WITH THE PUSH OF A
BUTTON.
THAT'S A TECHNOLOGICAL DRAWBACK
IN TERMS OF THE BIG LEARNING
CURVE.
THE OTHER WOULD BE THE BIOLOGY
SIDE OF THINGS.
I THINK THE ENGINEERING SIDE CAN
ALL BE ADDRESSED EVENTUALLY WITH
INNOVATIONS IN ENGINEERING AND
PROCESS ENGINEERING BUT WITH THE
BIOLOGY INHERENT IN THAT IS
DIVERSITY, YOU KNOW, PROPER
SOURCING OF CELLS, HOW
REPRODUCIBLE ARE THE STEM CELLS,
EVEN FROM PRIMARY DERIVED
MATERIALS.
CHECK SITES CAN VARY.
STANDARDIZING THOSE, CREATING A
BANK OF PLURIPOTENT STEM CELLS
FOR CONTROLS AS WELL AS FOR
PATIENTS WOULD ALSO BE A BIG
EFFORT THAT NEEDS TO BE
ADDRESSED.
AND THEN OF COURSE EVENTUALLY IF
WE'RE GOING TO USE THIS REALLY
HAVING A RELIABLE BANK OF
WELL-DIFFERENTIATED LINES OF
REPRESENTING VARIOUS LINEAGES OF
TISSUES AND CELLS THAT CAN BE
READILY INCORPORATED INTO THESE
PLATFORMS.
RIGHT NOW YOU HAVE TO SOURCE OUT
YOUR OWN STEM CELLS, INDUCE THEM
TO PLURIPOTENCY AND OF COURSE
DEVELOP DIFFERENTIATION
PROCEDURES FOR YOUR VARIOUS
TISSUE TIMES THAT YOU WANT TO
STUDY, AND THEN BE ABLE TO SEED
THEM INTO YOUR PLATFORM SO THOSE
ARE LIKE THE -- I WOULD CONSIDER
TO BE THE MAJOR DRAWBACKS.
>> THANKS, DAN.
THAT WAS IMPRESSIVE TALK.
QUESTION ABOUT YOU MENTIONED
COLLABORATIONS WITH SO MANY
DIFFERENT ORGANIZATIONS,
AGENCIES, AND IN ADDITION TO THE
HIGHER LEVEL BIG PICTURE
ENGAGEMENT AND SUPPORT FOR THESE
PROJECTS IS THAT TRICKLING DOWN
TO THE REVIEWER LEVEL, SO
TAKING, FOR EXAMPLE, THE SANOFI
SUBMISSION YOU MENTIONED, WHEN
THAT REVIEWER IN FDA OR EMA OR
OTHER AGENCY GETS THE SUBMISSION
DO THEY KNOW WHAT TO DO WITH IT
AND HOW TO INTERPRET THE DATA?
>>YEAH, THAT'S A GOOD POINT.
COMING FROM THE NIH WHEN WE TALK
ABOUT PEER REVIEW, YOU'RE
TALKING ABOUT REGULATORY REVIEW,
SO CERTAINLY THAT'S A
RECOGNITION THAT WE HAVE HAD IN
THE VERY BEGINNING OF THE
PROGRAM, WAY BACK IN 2009, EVEN
PRECEDING THE TISSUE CHIP
PROGRAM, WITH MY OFFICE, MY
GROUP HAS BEEN WORKING WITH THE
FDA PRIMARILY AS REGULATORY
AGENCY TO MAKE SURE THAT THEY
ARE AWARE OF THESE DEVELOPMENTS,
SO WE'VE BEEN WORKING WITH THEM
SINCE 2012 WHEN THE PROGRAM WAS
INITIALLY -- CAME INTO
INCEPTION, AND SINCE THEN WE'VE
HAD A NUMBER OF WORKSHOPS WITH
THE FDA, WITHIN THE FDA, AND
RECENTLY FDA OF COURSE HAS SET
UP THEIR OWN LABORATORIES TO
UNDERSTAND WHAT THE TECHNOLOGY
IS ABOUT, UNDERSTAND WHERE
LIMITATIONS ARE, WHERE THE GAPS
ARE, AS WELL AS WHERE THE
OPPORTUNITIES ARE.
AND PART OF THAT IS ALSO
CREATING GLOBAL COMMUNITY THAT
REGULATORY AGENCIES, THE
REVIEWERS, CAN ENTER AC --
INTERACT AND INTERFACE WITH
DEVELOPERS.
THAT'S THE FRAMEWORK WE HAD IN
MIND WHEN WE ESTABLISHED TISSUE
CHIP PROGRAM, CONSORTIUM OF
INVESTIGATORS, ON A MONTHLY
BASIS, AT LEAST ON CALLS, IN
PERSON, SEMI ANNUAL BASIS, WOULD
BE INTERACTING WITH THE FDA.
AND SO THEY ARE GOING TO BE
WORKING WITH THEM ALONGSIDE.
FOR EXAMPLE, THE TRANSLATIONAL
CENTERS THAT I MENTIONED, IT'S
ACTUALLY IN PARTNERSHIP WITH THE
FDA.
WE HAVE, YOU KNOW, THIS WAS
SOMETHING THAT DEVELOPED EVEN
TWO YEARS AGO WHEN JANET WILCOCK
WAS ACTING COMMISSIONER OF FDA
SO IN TERMS OF ACTIVITIES WITH
THIS WOULD BE ALONG ACTIVE FDA
ENGAGEMENT SO THAT ANY CENTER
THAT WE FUND AT THE NIH WOULD
HAVE FDA REGULATORS COMING
ALONGSIDE THEM AND ADVISING THEM
IN TERMS OF WHAT THE PLATFORMS
ARE GOING TO BE THAT'S GOING TO
BE QUALIFIED FOR SPECIFIC
CONTEXT OF USE.
YEAH, SO THAT'S PART OF THE
THINGS.
WE HAVE WORKED WITH THE
REGULATORY SUMMIT AS WELL, THAT
WAS MPS WAS THE SUBJECT OF THE
REGULATORY SUMMIT IN TERMS OF
EMERGING TECHNOLOGY I THINK IN
2022 OR 2021, YEAH, SO THERE'S
CONSTANT ENGAGEMENT.
THANK YOU.
>> GREAT TALK.
ENJOYED THAT VERY MUCH.
A COUPLE QUESTIONS, NOT
NECESSARILY FOR US TO ANSWER
TODAY, BUT HOW IS THIS GOING TO
BE SCALABLE?
IS ONE CHIP EQUIVALENT TO ONE
ANIMAL OR ONE HUMAN SO IF WE'RE
RUNNING A CLINICAL TRIAL ON A
CHIP DO YOU NEED TENS OR IF
YOU'RE DOING TOX TESTING WOULD
YOU NEED HUNDREDS OF CHIPS TO BE
ABLE TO SCALE THIS UP?
>>YEAH, I JUST CAME BACK FROM A
TISSUE MODEL CONFERENCE IN
BOSTON.
THAT WAS A BIG DISCUSSION.
HOW DO WE REPRESENT AN ENTIRE
ORGANISM ON A CHIP?
THE ANSWER, IT DEPENDS ON THE
BIOLOGICAL QUESTION YOU'RE
TRYING TO ANSWER.
MY PHILOSOPHY IS DON'T
OVERBUILD, JUST DEVELOP
SOMETHING THAT WOULD ANSWER THE
BIOLOGICAL QUESTION YOU HAVE.
SO THERE ARE PARTICULAR
BIOLOGICAL QUESTIONS THAT WOULD
BE SUFFICIENT TO ANSWER WITH A
SINGLE ORGAN CHIP, COULD BE
MULTI-ORGAN CHIP AS WELL, SO
THAT WOULD STILL BE ONE CHIP BUT
IF YOUR QUESTION INVOLVES
POPULATION VARIATION,
DIFFERENCES IN RESPONSE, RISK,
ESSENTIALLY MULTI-ORGAN CHIPS,
MANY CHIPS, AND MANY, MANY CELL
SOURCES AS WELL.
THAT GROWS EXPONENTIALLY
DEPENDING ON THE TYPE OF
QUESTIONS.
>> THE NEXT QUESTION IS WHO IS
GOING TO PAY FOR THIS?
IT'S ONE THING FOR US THAT ARE
BLESSED TO WORK WITHIN THE
FEDERAL GOVERNMENT AND HAVE
THESE RESOURCES, IN PARTICULAR
NCATS WITH THE AUTOMATION AND
INCREDIBLE RESOURCES THAT YOU
HAVE THERE, HOW IS THIS GOING TO
BE AFFORDABLE TO THE INDUSTRY
AND FOR CROs TO VENTURE INTO
THIS AREA AND OPERATE AS A
SERVICE?
>> RIGHT, YES.
THERE'S ESSENTIALLY APPROACHES
TO SCALE UP IN MANUFACTURING.
MOST OF THIS, COMMERCIAL
COMPANIES ARE ESSENTIALLY
EXISTING TO MANUFACTURE THEM,
AND COMMERCIALIZE THEM.
THEY ARE STILL EXPENSIVE BECAUSE
IT HASN'T GONE INTO THE LARGE
SCALE MANUFACTURING.
I THINK THAT'S WHERE THE
STANDARDS AND QUALIFICATION DRUG
DEVELOPMENT TOOLS WILL COME IN
BECAUSE ONCE QUALIFIED, I THINK
LARGE MANUFACTURERS WOULD THEN
SAY THERE IS GOING TO BE A HUGE
MARKET SHARE FOR THIS.
AND SO THEY CAN ESSENTIALLY STEP
IN AND PRODUCE THOUSANDS IF NOT
MILLIONS OF CHIPS.
THAT SHOULD TECHNICALLY DRIVE
DOWN THE COST OF THIS
TECHNOLOGY, ESPECIALLY IF WE ARE
ABLE TO ADDRESS THE ISSUE OF
AUTOMATION, BECAUSE THAT'S A BIG
THING.
IT'S ONE -- THOSE ARE
CONSUMABLES BUT THE PLATFORM OR
THE SUPPORTING INSTRUMENTATION
CAN BE A ONE-TIME EXPENSE BUT
THERE'S A LARGE ACQUISITION COST
THAT YOU NEED TO INVEST IN, AND
NOT EVERY LABORATORY IS ABLE
TO -- UNLESS THEY HAVE AN
INSTRUMENTATION GRANT FROM THE
NIH, BUT OUR GOAL IS TO MAKE
THIS SORT OF LIKE YOUR PCR
MACHINE THAT CAN SIT ON EVERY
BENCH TOP AND PLUG IN YOUR CHIPS
AND RUN YOUR EXPERIMENTS AND
WALK AWAY, TO GO TO A COFFEE
BREAK, OR LUNCH BREAK, AS WE'RE
HEADING NOW.
>> THANK YOU ALL SO MUCH.
SO WE'VE REACHED THE END OF OUR
PROGRAM NOW.
I DO WANT TO READ A GENERAL
COMMENT WE GOT FROM AMY KYLE
THAT I THINK REFLECTS ONE OF THE
THINGS I WANTED TO MENTION.
SHE SAID I WANT TO THANK THE
SUPPORT GROUP FOR MAKING IT
POSSIBLE TO PARTICIPATE IN THIS
EVENT AND THANK NICEATM FOR
ENTERTAINING COMMENTS FROM
OUTSIDE IN A MEANINGFUL WAY.
I APPRECIATE YOUR WORK AND
THOUGHTFULNESS VERY MUCH.
THANK YOU FOR THOSE POSITIVE
COMMENTS.
AND THEY REFLECT HOW I FEEL
ABOUT THE SUPPORT THAT HAS BEEN
PROVIDED FROM BOTH OUR SUPPORT
CONTRACTORS AND ALSO AV SUPPORT
TEAM HERE AT THE NIH BETHESDA
CENTER, I WANT TO THANK IN
PARTICULAR STEPHEN MOREFIELD,
CATHY SPRANGEL AND DAVE ALLEN
FOR THEIR LEADERSHIP MAKING SURE
THIS HAPPENED AND I DIDN'T GO
CRAZY IN THE PROCESS.
WHICH THAT'S UP FOR DEBATE
PROBABLY.
BUT IF I COULD STOP SHARING
THIS, OKAY.
SO, AGAIN, THANK YOU ALL.
THIS CONCLUDES AND INCREDIBLY
INFORMATIVE AND PRODUCTIVE AND
EXCITING TWO DAYS OF THE ICCVAM
PUBLIC FORUM.
I CERTAINLY HAVE A THOUSAND
IDEAS IN MY HEAD TO RUMINATE AND
FOLLOW UP ON.
I'LL LEAVE IT TO DR. GORDON TO
SEE IF HE WANTS TO SAY ANYTHING
IN CLOSING.
NO?
YOU'RE HAPPY FOR ME TO CLOUT
OUT?
ALL RIGHT, JOHN.
THANK YOU FOR COMING IN PERSON.
A DELIGHT TO SEE YOU ALL.
THANKS TO EVERYBODY ON THE
WEBCAST FOR TAKING SO MUCH TIME
OUT OF YOUR BUSY SCHEDULES TO
SPEND WITH US.
AND WE'LL LOOK FORWARD TO NEXT
YEAR AND LOTS OF FOLLOW-UP
ACTIVITIES IN BETWEEN.
THANKS, EVERYONE.
[APPLAUSE]