I'M ASHLEY VARGAS, A PROGRAM DIRECTOR AT EUNICE KENNEDY SHRIVER. I'M GOING TO START LIKE YESTERDAY WITH HOUSEKEEPING RULES. THIS SESSION IS BEING RECORDED, INTENDED TO BE AVAILABLE TO THE PUBLIC. SPEAKERS AND STAFF REMAIN ON MUTE UNLESS YOU'RE ANSWERING QUESTIONS. ATTENDEES, SUBMIT YOUR QUESTIONS. BIOACTIVES.IF.WORKSHOP@MAIL.GOV. THIS WORKSHOP IS NOT INTENDED TO ADVISE ANY FEDERAL AGENCY AND THE FOCUS IS TRULY ON THE STATE OF THE SCIENCE, PROMISING ADVANCES, RESEARCH OPPORTUNITIES. WE ARE FOCUSED ON EXPLAINING FOCUS OF BIOACTIVE HUMAN MILK COMPONENTS. WE ARE FOCUSED ON INFANT FORMULA THAT IS INTENDED FOR USE IN TERM HEALTHY INFANTS UP TO 12 MONTHS OF AGE, WE'VE DEVELOPED THIS DEFINITION FOR THE PURPOSES OF THIS WORKSHOP TO DEFINE WHAT WE'RE TALKING ABOUT WHEN WE SAY BIOACTIVE INGREDIENTS. AGAIN, WE'RE HONORED TO HAVE IN THE VIRTUAL ROOM WORLD RENOWNED SCIENTISTS IN EARLY LIFE. THERE IS PRE-SESSION MATERIAL AVAILABLE ON THE WEBSITE THAT TALKS MORE ABOUT NIH BACKGROUND AND FDA BACKGROUND, WE'RE FOCUSED ON THE STATE OF THE SCIENCE OF THE SAFETY AND FUNCTION OF INFANT FORMULA BIOACTIVE ACTIVE INGREDIENTS. I WANT TO START WITH A FUN REQUEST FOR THE SPEAKERS. IN THE ZOOM CHAT, LIST ONE AREA OF SCIENCE THAT GETS YOU EXCITED WHEN YOU SEE A CAN OR BOTTLE OF INFANT FORMULA. THIS IS ONE OF THE QUESTIONS WE LEFT OFF WITH YESTERDAY. I WANTED TO START ON A FUN NOTE, THE FUTURE, WHAT EXCITING THINGS YOU SEE ON THE HORIZON. BEFORE WE DIVE INTO TOUGHER QUESTIONS YOU HAVE BEEN WILLING TO ENTERTAIN, EVEN SAYING WE'RE NOT SURE OR WE DON'T KNOW YET IS A PERFECTLY ACCEPTABLE ANSWER. YESTERDAY WAS TRULY A MASTER CLASS IN HOW TO PRESENT COMPLEX INFORMATION THAT CLEARLY LED ALL THE AUDIENCE THROUGH DECADES OF RESEARCH, SYNTHESIZED AND CAME OUT WITH SOME SPECIFIC POINTS. SO THANK YOU TO OUR SPEAKERS. I KNOW HAVING PEEKED AT SLIDES FOR TODAY WE WILL FIND THE SAME WONDERFUL WORK. IN ADDITION, AGAIN LIKE I SAID, THERE'S A LOT WE DON'T KNOW. I THINK YESTERDAY WE CO-OPTED A HASHTAG. KNOWING WHAT WE DON'T KNOW IF THE FIRST STEP IN IDENTIFYING WHAT TO DO NEXT. TWO OTHER THEMES THAT CAME OUT WERE TEAM SCIENCE. AND I WOULD POSITED THAT THE DIVERSITY OF SPEAKER EXPERTISE AND DIVERSITY OF SPEAKERS THAT WE HAVE ON THE CALL TODAY REPRESENTS WHY THERE'S A NEED FOR TEAM SCIENCE. EVERYONE CAN TALK ABOUT IDEAS AND SPECIFIC AREA OF FOCUS BUT GETTING EVERYONE TO WORK TOGETHER AND WORK IN CONCERT, THIS WORKSHOP IS A GREAT EXAMPLE OF DISCIPLINES WORKING TOGETHER. THE OTHER PIECE THAT I WANTED TO HIGHLIGHT WAS THIS NEED FOR EQUITY AS A MAJOR OUTCOME. I THINK AS WE'RE MOVING FORWARD IN ANY OF THE SPACES THAT WE'VE TALKED ABOUT THROUGHOUT THE WORKSHOP ONE OF THE MOST IMPORTANT OUTCOMES WE CAN THINK ABOUT IS EQUITY. AGAIN, I WANT TO THANK OUR AUDIENCE FOR THE THOUGHTFUL AND BROAD RANGING QUESTIONS THAT CAME IN YESTERDAY. WE HAVE TRIED TO RECYCLE SOME FOR TODAY THAT WE DIDN'T GET TO, AND I KNOW WE'LL GET A LOT MORE TODAY. WE'VE GOTTEN SOME THIS MORNING SO THANK YOU FOR THOSE. THE SPEAKERS ALSO HAVE DONE AN AMAZING JOB USING EXAMPLES WHILE ALSO BEING ABLE TO PULL THE AUDIENCE BACK AND THINK AT A HIGH LEVEL ABOUT HOW BIOACTIVE INGREDIENTS ARE AFFECTING SAFETY AND FUNCTION OR PERFORMING EITHER FUNCTION. SO WHILE WE'RE NOT GOING TO FOCUS ON ANY PARTICULAR BIOACTIVE IN THE WORKSHOP, I WANT TO GIVE KUDOS TO OUR SPEAKERS WHO ARE ABLE TO USE SPECIFIC EXAMPLES WHILE REMINDING US WE'RE NOT FOCUSING ON ANY SPECIFIC BIOACTIVE. AND THEN THIS IS JUST ONE POINT OF CLARITY BASED ON SOME E-MAILS WE GOT. THE INTENT FOR THIS WORKSHOP IS NOT TO GET FEDERAL ADVICE OR REGULATORY RECOMMENDATIONS FROM THE GOVERNMENT. THE FOCUS IS ON THE STATE OF THE SCIENCE AND RESEARCH GAPS. THAT'S WHY WE'RE SO HONORED TO HAVE OUR SPEAKERS HERE WITH US TODAY. THIS IS A HEADS-UP FOR THE SPEAKERS ABOUT SOME OF THE QUESTIONS THAT WE'RE HOPING TO REVISIT TODAY IN ADDITION TO THE ONES THAT WILL COME FROM OTHER SPEAKERS AND FROM THE E-MAIL. THE FIRST IS A DISCUSSION WAS STARTED AND PROGRESSED BUT WE'D LIKE TO SPEND MORE TIME TALKING ABOUT BIOMARKERS, BIOINDICATORS FOR IMAGING, FOR OUTCOMES, WHAT SHOULD BE PRIORITIZED IN THIS SPACE. I THINK THAT THE GREAT THING ABOUT OUTCOMES IS THAT IF WE HAVE BETTER OUTCOMES THIS NOT ONLY HELPS INFANT FORMULA SCIENCE, IT'S GOING TO HELP MANY AREAS OF EXPOSURE SCIENCE. THERE'S SOME REALLY GREAT PRESENTATIONS TODAY THAT WE'LL TALK ABOUT MODEL SYSTEMS. THE CONVERSATION WAS BROUGHT UP YESTERDAY AS WELL THAT THERE ARE A NUMBER OF MODEL SYSTEMS NECESSARY ESPECIALLY IF WE'RE GOING TO LOOK AT INTERACTIONS BETWEEN BIOACTIVES. WE'LL TALK MORE IF WE HAVE TIME ABOUT HOW WE MIGHT PRIORITIZE THESE MODEL SYSTEMS. AND THOUGHTS FOR SPEAKERS TO DWELL ON, ARE THERE ANY CLASSES OF BIOACTIVES WHERE THERE ISN'T A LARGE CONCERN FOR SAFETY? MAYBE THE ANSWER IS NO, BUT IF IT'S YES IT WOULD BE GREAT TO HEAR THOUGHTS ON THAT. AND SIMILARLY, ARE THERE ANY CLASSES OF BIOACTIVES, LARGE GROUPS OF THEM, WHERE WE'RE SORT OF GETTING TO THE POINT WHERE WE KNOW ENOUGH TO MAKE A CALL ON SAFETY OR FUNCTION? AND SO, AGAIN, THE ANSWER MIGHT BE WE DON'T KNOW YET, THAT'S OKAY, BUT WE'D LOVE TO HEAR THOUGHTS ON THOSE TOPICS. I WON'T GO OVER THE AGENDA. IT'S ON THE WEBSITE. TODAY WE HAVE TWO SCIENTIFIC SESSIONS FOLLOWED BY A MUCH MORE LENGTHY Q&A. THIS IS THE OPPORTUNITY FOR PEOPLE TO SUBMIT QUESTIONS, FOR SPEAKERS TO SUBMIT QUESTIONS, AND TO CONTINUE THE DIALOGUE WE STARTED YESTERDAY. HERE IS A SERIES OF IMPORTANT LINKS, ALL OF THESE ARE ON THE WEBSITE. THE PRE-SESSION MATERIAL WITH BACKGROUND INFORMATION FOR NIH AND FDA IS AVAILABLE. WE HAVE THE GENERAL WORKSHOP INFORMATION INCLUDING AGENDA, THE LINKS TO WATCH THE LIVE VIDEOCAST. AND THEN THE E-MAIL ADDRESS I MENTIONED. AND YOU'LL SEE THAT ON MULTIPLE SLIDES AS A REMINDER THROUGHOUT THE PRESENTATIONS. WE ARE GOING TO MOVE TO SESSION 4. I WILL STOP SHARING MY SCREEN AND TURN IT OVER TO THE MODERATORS. >> WELCOME TO SESSION 4, FUNCTIONAL EQUIVALENCE OF BIOACTIVE INGREDIENTS. I'M JAIME GAHCHE CO-MODERATING WITHER IS MY A FASANO. THIS WILL COVER HOW THE HOURS OF A BIOACTIVE INGREDIENT MAY AFFECT FUNCTION OR SAFETY. WE'LL BEGIN WITH A BRIEF INTRODUCTION, FULL BIOGRAPHIES FOUND AT THE WORKSHOP WEBSITE. QUESTIONS AND COMMENTS CAN BE SUBMITTED TO THE WORKSHOP E-MAIL ADDRESS THROUGHOUT THE PRESENTATION. SO FIRST SPEAKER IS DR. SUSAN CARLSON FROM UNIVERSITY OF KANSAS MEDICAL CENTER. DR. CARLSON IS A.J. RICE PROFESSOR OF NUTRITION AND UNIVERSITY DISTINGUISHED PROFESSOR IN DEPARTMENT OF DIETETICS AND NUTRITION, SPEAKING ON THE HISTORY OF THE DHA IN FORMULA-FED INFANTS AND HOW RESEARCH CAN HELP INFORM US ON HOW TO ASSESS SAFETY AND FUNCTION OF OTHER BIOACTIVES. SECOND SPEAKER DR. CARLITO LEBRILL UNIVERSITY OF CALIFORNIA DAVIS, A DISTINGUISHED PROFESSOR, DEPARTMENT OF CHEMISTRY, DEPARTMENT OF BIOCHEMISTRY AND MOLECULAR MEDICINE, SCHOOL OF MEDICINE, AND WILLING SPEAKING ON HUMAN MILK OLIGOSACCHARIDES AND THOSE PRESENT IN OTHER ANIMAL SOURCES. THIRD SPEAKER IS DR. DAVID DALLAS ARE FROM UNIVERSITY STATE UNIVERSITY, ASSISTANT PROFESSOR IN NUTRITION PROGRAM IN SCHOOL OF BIOLOGICAL AND POPULATION HEALTH SCIENCES, WILL BE SPEAKING ON DIGESTION AND FUNCTION, EMPHASIS ON MILK PROTEINS, PEPTIDES AND PROTEASES. DR. CARLSON, PLEASE SHARE YOUR SLIDES. I WILL START MY VIDEO ALSO. ARE YOU SEEING MY SLIDES? ARE YOU SEEING MY FIRST SLIDE? >> YES. >> ALL RIGHT. WELL, THANK YOU VERY MUCH FOR THAT INTRODUCTION. YES, I'M PLEASED TO GIVE PERSPECTIVE ON ADDITION OF DHA TO INFANT FORMULA. THESE WERE THE FIRST TWO BIOLOGICALS OUTSIDE OF THE TYPICAL MACRONUTRIENTS AND VITAMIN MINERALS ADDED TO INFANT FORMULA. IT HAPPENED IN 2002. THERE WAS 20 YEARS OF RESEARCH BEFORE THAT, I'M GOING TO TELL THAT STORY. WHAT I WON'T MENTION WITH ONE EXCEPTION, NUMBER OF ANIMAL STUDIES CONDUCTED PRIOR TO 1982 AND DURING THE CLINICAL STUDIES THAT WERE ONGOING IN THOSE 20 YEARS. THERE WAS ALSO A LOT OF REGULATORY WORK GOING ON RELATED TO THE SAFETY OF THE SOURCES THAT WERE ADDED TO U.S. INFANT FORMULAS. I KNOW THAT'S A CONSIDERATION AS YOU TALK ABOUT FRAMEWORK FOR NEW INGREDIENTS. SO, HISTORICALLY, I'M TALKING ABOUT THE '70s AND EARLY '80s WE WERE FOCUSED ON PARENTS FATTY ACIDS FOR OMEGA 6 AND OMEGA 3 FAMILIES. THERE'S BEEN MORE WORK DONE IN THE LAST 40 YEARS ON LONG CHAIN METABOLITES, AND I THINK NUTRITIONALLY -- SO SORRY. NUTRITIONALLY, THE CONVERSION OF THESE FATTY ACIDS TO THE LONGER CHAIN METABOLITES -- THIS IS MY HOME PHONE AND IT RINGS IN MY OFFICE. I CAN'T SHUT IT OFF. THEIR ROLES, A LOT MORE KNOWN ABOUT THEIR ROLES IN TERMS OF PHYSIOLOGIC FUNCTION. THIS IS SOMETHING THAT WE REALLY NEED TO WORK ON, OUR NATIONAL ACADEMY OF MEDICINE SETS A RECOMMENDATION FOR LINOLEIC AND ALPHA-LINOLENIC ACIDS. WHERE THE STORY BEGAN FOR US WAS WHEN A GRADUATE STUDENT SHOWED UP MANY YEARS AGO AT THE UNIVERSITY OF SOUTH FLORIDA, AND THERE WERE TWO INFANT FORMULAS ON THE MARKET ROTATED THROUGH HOSPITALS, IF YOU LOOK AT THE CONTENT, YOU CAN SEE THEY ARE DIFFERENT. ONE WAS ABOUT 22.5% ENERGY COMING FROM A SINGLE FATTY ACID, LINOLENIY ACID. I THOUGHT THESE WOULD HAVE A STRANGE EFFECT ON MEMORIES, FINDING DIFFERENCE IN MEMBRANE FAT ACIDS, I PUT THE TONIGHT ON THE PROJECT. WHAT WE DIDN'T REALLY CONSIDER WAS THE SMA WAS HUMANIZED FORMULA, BUT DIDN'T CONTAIN THESE LONG CHAIN FATTY ACIDS WHICH WERE IN HUMAN MILK. WE HAD A GROUP OF INFANTS FED HUMAN MILK IN THE STUDY. WE FOUND NOT A LOT OF DIFFERENCE BETWEEN THE FORMULAS WHICH WAS SURPRISING, BUT WE FOUND HIGHER ARACHIDONIC IN THE PHOSPHOLIPIDS OF THE INFANTS. WE MIGHT HAVE IGNORED THAT EXCEPT THAT WHEN I STARTED TO LOOK AT -- I NEVER HEARD OF DHA, I BEGAN TO LOOK INTO DHA AND FOUND SOME WORK BY TOM CLANDIN WHO PUBLISHED THERE WAS VERY LITTLE IN THE BRAIN OF PRE--TERM INFANTS, ACCUMULATES AT 22 WEEKS GESTATION, LATER SHOWN BY MARTINEZ ACCUMULATES PRETTY DRAMATICALLY OVER THE FIRST TWO YEARS OF AN INFANT'S LIFE EVEN AFTER BIRTH. THERE WAS THIS INTRIGUING IDEA THAT MAYBE DHA WAS IMPORTANT AND ACTUALLY I DON'T REMEMBER SEEING THIS PAPER AT THE TIME BUT TOM HIGH PRESSURE PUBLISHED PUBLISHED THE ARTICLE WHICH TURNED OUT TO BE A VERY IMPORTANT QUESTION THAT I THINK GOT ANSWERED AS YES, THE ANSWER IS YES. BUT THE OTHER THING WAS THERE HAD BEEN A PUBLICATION AT OREGON HEALTH SCIENCE CENTER SUGGESTING THAT WHEN YOU GET A REDUCTION IN BRAIN DHA IT'S ASSOCIATED WITH LOSS IN VISUAL ACUITY, CORTICAL, BRAIN RELATED. SO, THIS SUGGESTED A DECREASE IN DHA MIGHT BE FUNCTIONAL, SPECIFICALLY REDUCE VISUAL ACUITIY, THAT WAS THE FOCUS OF SOME EARLY STUDIES, VISUAL ACUITY. SO, I FELT LIKE TOM, I HADN'T SEEN HIS PAPER, WOW, I NEED TO GO TO NEONATOLOGY AND BEGIN STUDYING PRE-TERM INFANTS. IS ANYBODY IS DEFICIENT IN DHA IT'S PRE-TERM INFANT. WE BEGAN STUDIES IN 1982, UNIVERSITY OF MISSISSIPPI MEDICAL CENTER, I WENT TO DIVISION OF NEONATOLOGY THERE. AND WE DID A COUPLE OF STUDIES WITH MAX EPA, SOURCE OF DHA. INITIALLY GIVEN A BOLUS, I WON'T EXPLAIN, IT WAS PUBLISHED MANY YEARS AGO, BUT IT SHOWS A BOLUS IS VERY POORLY TAKEN UP BY PRE-TERM INFANTS. WE EVENTUALLY MICRODISPERSED MAXEPA INTO PRE-TERM FOR LA AND NEONATOLOGIST FED IT TO BABIES AND FOUND WE COULD FEED MUCH LOWER AMOUNT. ONE OF THE THINGS AS AN ASIDE BEFORE I DID THIS, THE EXPERIMENT, THESE EXPERIMENTS, I CALLED UP THE FDA AND SAID IS THERE ANY REASON I SHOULD NOT PUT FISH OIL IN PRE-TERM FORMULA AND FEED IT TO BABIES. THE ANSWER I GOT WAS, NO, DO IT AND LET US KNOW WHAT YOU FIND OUT. WHICH AMUSES ME TODAY BECAUSE THIS IS NOT THE WAY THINGS WOULD HAPPEN, OBVIOUSLY, TODAY. BUT AFTER THESE INITIAL STUDIES AND WE TRIED TO DEFINE HOW MUCH DHA WE NEEDED TO GIVE TO GET MEMORY LEVELS UP, IT BECAME CLEAR WE NEEDED A STABLE FORMULA THAT COULD BE FED TO IMPROVE DHA STATUS, IF WE WOULD START LOOKING AT FUNCTIONAL OUTCOMES, IF WE COULD IMPROVE IT, WE COULD ACTUALLY TEST VISUAL ACUITY. AND I WAS ALSO VERY INTERESTED IN COGNITIVE DEVELOPMENT. IF THERE'S REDUCTION IN DHA IN THE BRAIN IT SHOULD AFFECT ALL THINGS THE BRAIN DOES, RIGHT? SO, AFTER SOME YEARS, YOU SEE WE FAST FORWARD, NOW WE'RE IN THE '90s. WITHIN ABOUT THREE MONTHS, PUBLISHED IN INVESTIGATIVE OPHTHALMOLOGY, GIVEN PRE-TERM BABIES DHA WOULD IMPROVE VISUAL ACUITY. THEY USED CORTICAL MEASURE. I USED ANOTHER MEASURE, THE CARDS, WHICH IS NOT NECESSARILY CORTICAL -- INCLUDES CORTICAL BUT IS ALSO BEHAVIORAL. AND THE BOTTOM LINE WAS, YES, YOU COULD IMPROVE VISUAL ACUITY IN PRE-TERM INFANTS BY GIVING THEM DHA. SO, ABOUT A YEAR LATER, THIS PAPER WAS PUBLISHED SHOWING WHAT WERE HYPOTHESIZING, THERE WAS DHA, AND THE PURPLE LINE IS BREASTFED INFANTS. AND INTERESTINGLY, HUMAN MILK WAS .26. I'LL ENVIRONMENTAL MORE TO SAY ON A FUTURE SLIDE. I WANTED TO LOOK AT COGNITION. THERE WAS A TEST THAT WAS SUPPOSED TO BE A WAY TO TEST I.Q., IF YOU WILL, IN INFANCY. I WENT OFF TO NEW YORK TO LEARN HOW TO DO THAT TEST. I'M A NUTRITIONIST, NOT A PSYCHOLOGIST OR BEHAVIORIST. AND AS I LEFT, THE TEST WAS DESIGNED TO LOOK AT NOVELTY PREFERENCE, LIKE BABIES SPEND MORE TIME LOOKING AT A NOVEL PICTURE THAN A FAMILIAR PICTURE. BUT AS I LEFT, THE SCIENTIST I WAS WORKING WITH SAID, BE SURE YOU GET THIS EXPERIMENTAL SOFTWARE WHICH ALLOWS YOU TO LOOK AT DURATION, WE FOUND NO DIFFERENCE IN NOVELTY PREFERENCE BECAUSE THESE KIDS WERE NORMAL, IN MOST WAYS, BUT THERE WAS SIGNIFICANT REDUCTION IN LOOK DURATION IN THE DHA SUPPLEMENTED INFANTS. KNISH WE - INITIALLY WE DIDN'T KNOW WHAT I MEANT. I PRESENTED. MARTHA DID THE SAME TEST IN HER MONKEYS WITH LOW BRAIN DHA AND SENT ME THIS SLIDE WHICH SHE SUBSEQUENTLY PUBLISHED SHOWING THAT IN HER MONKEYS WITH LOW BRAIN DHA THEY HAD LONGER LOOK DURATION, WHICH DURATION OF LOOKING IS SPEED OF PROCESSING, EVIDENCE THERE WAS SOME IMPROVEMENT IN A COGNITIVE FUNCTION IN INFANCY. AND WE SUBSEQUENTLY PUBLISHED A MONOGRAPH TOGETHER ON INFANT VISUAL AND COGNITIVE FUNCTION. SO, I WAS WORKING WITH ROSS LABS DURING THIS TIME. THERE WERE OTHER PEOPLE WORKING WITH LEE JOHNSON. ROSS LABORATORIES WAS MAKING EXPERIMENTAL FORMULAS FOR US. DHA REALLY JUST WANT TO INDICATE THE STUDIES LIMITED BY WHAT WAS COMMERCIALLY AVAILABLE TO PUT INTO INFANT FORMULA, EVEN FOR EXPERIMENTAL PURPOSES. SO OVER THE YEARS I THINK WE STUDIED TUNA OIL, EGG PHOSPHOLIPIDS, REGULAR FISH OIL, LOW EPA FISH OIL, IN ALL THE NIH STUDIES, AND MOST WERE FUNDED BY NATIONAL EYE INSTITUTE OR NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT. ULTIMATELY EVERYONE SETTLED ON THE ALGAL DHA, A SOURCE FOUND AND WAS CONSISTENT. THERE WERE SOURCES OF ARA WERE NOT AVAILABLE AND INITIAL ONES USED FOR EGG PHOSPHOLIPIDS. IT BECAME CLEAR THESE TWO FATTY ACIDS NEEDED TO BE IN SOME BALANCE. AND THIS PAPER WE PUBLISHED IN PNAS ACTUALLY WAS NOT DONE WITH ARA BUT WHICH WE SHOWED THAT PRE-TERM INFANTS WHO ACHIEVE A NORMAL WEIGHT AND LENGTH BY THE END OF THE FIRST YEAR CORRECTED AGE WERE THE ONES WHO HAD THE HIGHEST LEVELS. SO THAT REALLY SAY WE PROBABLY BETTER NOT JUST FEED DHA ALONE, SHOULD ADD ARACHIDONIC ACID TO THE FORMULAS. I'M SHOWING HERE BECAUSE PEOPLE ARE LEARNING THINGS AS YOU GO ALONG, AND THEN YOU HAVE TO SORT OF ADAPT TO THAT. AS I MENTIONED, WE WERE FEEDING FORMULAS WITH .2% DHA, NO ARACHIDONIC ACID, EVENTUALLY ADDED ARACHIDONIC BUT PEOPLE WERE LOOKING AT HUMAN MILK ALL OVER THE WORLD, DHA WAS RELATED TO DHA INTAKE OF THE MOMS. WE SETTLED ON A MEDIAN LEVEL OF DHA IN MILL AROUND .32%. THE BIRCH HAD A HIGH LEVEL. WE NOTICED ARACHIDONIC ACID IS ALWAYS IN MILK, ALMOST ALWAYS MORE ARACHIDONIC ACID THAN DHA, AND SO SOME OF THE INTERESTS OVER THE YEARS HAS BEEN IN WHAT IS THE PROPER RATIO FOR THAT. I'LL FINISH WITH SOME EVIDENCE ON THAT. SO, THE FIRST STUDY WE DID WITH DHA AND ARACHIDONIC ACID, LOOKING AT COGNITION, WE FOUND ALSO DRAMATIC REDUCTION IN NECROTIZING ENTEROCOLITIS, UNIVERSITY OF MISSISSIPPI MEDICAL CENTER, ONE OF THE HIGHEST NEC RATES, PREDOMINANTLY AFRICAN BABIES, A MUCH HIGHER INCIDENCE, NO ONE WAS GETTING HUMAN MILK IN ANY FORM IN THOSE DAYS. WE PUBLISHED THAT LATER. IT'S SOME EVIDENCE THAT HAVING ARACHIDONIC ACID IS ALSO IMPORTANT FOR OTHER REASONS BESIDES PERHAPS COGNITION. SO, BY 2002, THERE WERE A LOT OF OTHER REPORTS ON VISUAL OUTCOMES, NOT ALL WERE RANDOMIZED TRIALS, SOME WERE CORRELATIONS BETWEEN INFANT BLOOD DAH LEVELS AND VISUAL OUTCOMES. BUT ALSO A SIMILAR BODY OF LITERATURE WAS ACCUMULATING ON COGNITIVE OUTCOMES. AND SO I JUST WANT TO TELL YOU ABOUT ONE STUDY THAT OCCURRED. IT BEGAN IN 2002, JUST AS INFANT FORMULA WAS STARTING TO HAVE DHA AND ARACHIDONIC ACID ADDED TO IT. AND IT WAS DONE IN TERM INFANTS, IN KANSAS CITY AND DALLAS, THE PRIMARY PURPOSE TO SEE WHAT DOSE WOULD BE BETTER. AT THAT TIME, THEY HAD ADDED .32% DHA TO INFANT FORMULA BUT LEE JOHNSON FUNDED THIS STUDY AND WANTED TO KNOW IF THEY BE SHOULD BE PUTTING MORE IN. WE HELD ARACHIDONIC CONSTANT. WE FOLLOWED CHILDREN TO AGE 6 IN ANSWER AS CITY, HALF THE COHORT IN KANSAS CITY WE FOLLOWED TO AGE 9, THERE WERE A NUMBER OF PAPERS THAT CAME OUT THAT SHOWED THAT NOT ONLY ARE THESE EFFECTS ON COGNITION EARLY BUT LAST TO 9 YEARS OF AGE. I'LL END WITH THIS SLIDE. HOW DHA AND ARA MIGHT DIFFER FROM SOME BIOLOGICALS NOW CONSIDERED. I THINK THE FIRST THING IS THAT A MEMBRANE BIOMARKER WAS HOW WE ACTUALLY BEGAN THIS STORY. IF WE HADN'T NOTICED LOWER LEVELS OF DHA AND ARACHIDONIC ACID IN INFANTS FED HUMAN MILK COMPARED TO INFANT FORMULA THIS STORY MIGHT NEVER ACTUALLY HAPPENED. AND SO IT WAS KIND OF THE FIRST INDICATION THAT THEY MIGHT BE IMPORTANTS FOR BABIES. THERE WAS EVIDENCE OF ACCUMULATION INCOMPLETE AT BIRTH AND NON-HUMAN PRIMATE STUDIES LOW BRAIN ACCUMULATION AND PERMANENT REDUCTION IN CORTICAL VISUAL ACUITIY. AND POSSIBLE FUNCTIONAL DEFICITS EXISTED AND COULD BE TESTED, LOWER LEVELS IN INFANTS DID NOT PROVING THEY WERE NEEDED THERE WAS A TESTABLE HYPOTHESIS THAT ADDING THESE FATTY ACIDS TO INFANT FORMULA COULD IMPROVE VISUAL ACUITIY AND ULTIMATELY COG NITION. I'LL CONCLUDE THERE. THANK YOU. >> THANK YOU SO MUCH, DR. CARLSON, FOR A WONDERFUL PRESENTATION. SO, WE'RE GOING TO HOLD ALL QUESTIONS UNTIL THE END OF THIS SESSION. AND NOW I WELCOME DR. LEBRILLA. PLEASE SHARE YOUR SLIDES. >> SO, I'M GOING TO TALK TODAY ABOUT HUMAN MILK OLIGOSACCHARIDES. AND THIS IS A DISCLOSURE. BASED ON SOME RESEARCH, WE STARTED A FEW COMPANIES, THAT'S LISTED HERE. WHEN WE FIRST STARTED WORKING WITH HUMAN MILK OLIGOSACCHARIDES, THERE WAS A MYTH, ONE SIMILAR TO ELEPHANT MILK, THE OTHER THERE WERE MILLIONS OR BILLIONS OF HUMAN MILK OLIGOSACCHARIDES. WE BROUGHT ADVANCED ANALYTICAL TOOLS TO THE STUDY OF HUMAN MILK OLIGOSACCHARIDES TO PROFILE DEEPLY AND MORE RAPIDLY AND WITH MUCH GREATER SENSITIVITY. WHAT THIS INVOLVED WAS A LOT OF MASS SPECTROMETERS, THE KIND OF TOOLS WE HAVE IN OUR LAB. WHAT IT OFFERED US WAS AN EXTENSIVE MAP OF WHAT WAS AVAILABLE IN TERMS OF HUMAN MILK OLIGOSACCHARIDES. WHEN YOU START ANALYZING THESE COMPOUND, WHAT YOU FIND WAS THAT THERE WERE NOT MILLIONS OF OLIGOSACCHARIDES, THERE WERE ACTUALLY A PRETTY FINITE NUMBER. THE OTHER THING WAS THAT YOU CAN PHENOTYPE THEM. YOU CAN ALMOST SEPARATE THEM INTO TWO GROUPS. AND SO IF YOU TAKE ONE OF THE COMPOUNDS THAT IS A DIFFERENTIATOR AND YOU SEE THE OVERLAP, ONE GROUP HAD HIGH LEVELS, NON-SECRETERS, NOT ZERO BUT OFTENTIMES LOW LEVEL. SOMETIMES VERY LOW. THIS WAS -- WE VALIDATED USING GENOMIC -- GENETICS OF THE MOTHER, AND SO THE MOTHERS'S MILK HAD 2 FUCOSYLATION, AND THE NON-SECRETORS WOULD HAVE A PROFILE LIKE THIS, REALLY AFTER THE ANALYSIS. IF YOU ANALYZE HUNDREDS AND THOUSANDS OF SAMPLES YOU COME UP WITH THIS CONCLUSION. SO, IF YOU LOOK AT THE STRUCTURES OF THESE COMPOUNDS CAREFULLY, WHAT YOU FIND IS THAT THEY ARE NOT TOO DISSIMILAR FROM OUR BLOOD GROUPS. IF YOU'RE TYPE O, BECAUSE EVER THESE OLIGOSACCHARIDES IN YOUR BLOOD CELLS. IF YOU'RE A TYPE A, HAVE YOU THESE TYPES OF OLIGOSACCHARIDES. IF YOU'RE TYPE B YOU HAVE THESE TYPES OF OLIGOSACCHARIDES. YOU FIND THESE ANTIGENS ON THE OLIGOSACCHARIDE STRUCTURES, SO YOU CAN QUANTITATE THE TYPES OF ANTIGENS, LEWIS A, LEWIS X, LEWIS B, LEWIS Y. YOU CAN QUANTITATE THOSE COMPOUNDS THAT ARE FUCOSLYATED, CONTAIN SIALIC ACIDS AND THOSE THAT CONTAIN NEITHER. WE ALSO -- THERE HAVE BEEN SEVERAL STUDIES INCLUDING THIS ONE, INCLUDING MANY, THAT SHOW OLIGOSACCHARIDES BIND TO PATHOGENS. IN ADDITION TO IMMUNOMODULATING ANOTHER FUNCTION FOR OLIGOSACCHARIDE WAS REALLY THAT THEY WOULD SORT OF PROTECT THE INFANT. SO, BUT WHAT WE SHOULD THINK ABOUT, THREE ARE NOT AS EFFECTIVE AS THEY ARE IN GLYCOOH CONJUGATE. IF YOU HAVE A FREE OLIGOSACCHARIDE COMPARED TO GLYCOLIPID OR GLYCOPROTEIN IT DOESN'T WORK AS WELL IN MODULATING IMMUNE SYSTEM AND DOESN'T WORK AS WELL IN BINDING PATHOGENS. THERE ARE OTHER ROLES AT THAT TIME, WASN'T REALLY QUITE WELL ESTABLISHED YET. SO WE ALSO LOOKED AT WITH VARIOUS -- I COLLABORATED WITH MANY SPEAKERS HERE BUT WE'VE LOOKED AT THINGS LIKE DIET, HOW DOES DIET AFFECT PRODUCTION? IT AFFECTS IT UNDER EXTREME STRESS, SO WE LOOKED IN THE WET AND DRY SEASON IN THE AGRARIAN SOCIETY. MOTHERS LACTATING DURING THE HUNGER SEASON PRODUCED LESS OLIGOSACCHARIDES THAN THOSE DURING THE -- NOT A LOT LESS BUT LESS DURING THE HUNGER SEASON. THE OTHER THING WE FOUND WAS THAT WE LOOKED AT THE MOBILITY, THERE WERE STRUCTURES ASSOCIATED WITH INFANTS BEING MORE OR LESS SICK, COUNTED SICK DAYS AND FOUND WHEN THEY HAD MORE SICK DAYS, THEY HAD MORE OF THIS COMPOUND, LNT, WHEN THEY HAD LESS SICK DAYS THEY HAD MORE OF THIS COMPOUND. AND THE TWO COMPOUNDS ARE SAME STRUCTURE, THIS IS ALPHA-1-2 FUCOSE ADDED TO IT. YOU COULD LOOK AT RATIOS AND THE MORBIDITY. WE LOOKED AT EVERY FLUID THAT THE MOTHER AND INFANT HAD AND FOUND HUMAN MILK OLIGOSACCHARIDES IN EVERY FLUID. IF YOU LOOK AT THE MOTHER, THE MILK HAD IT. HER BLOOD THERE WERE ALSO OLIGOSACCHARIDE. THE INFANT, BLOOD, URINE HAD IT, AND FECES HAD HUMAN MILK OLIGOSACCHARIDES BUT FRAGMENT OF HUMAN MILK OLIGOSACCHARIDES AND FRAGMENTS OF GLYCANS FROM THE GLYCOPROTEINS, NOT JUST LACTOFERRIN PRESENT IN THE FECES. IN SOME CASES THE AMOUNT DECREASED, WERE DECREASED OR INCREASED DEPENDING ON THE MICROBES IN THE INFANT. THAT LED US, DAVID MILLS, TO THIS CONCLUSION THAT HUMAN MILK OLIGOSACCHARIDE FEEDS THE MICROBIOME AND NOT JUST THE MICROBIOME BUT SPECIFICALLY ONE BACTERIA, THAT WAS BIFIDOLONGHUM INFANTIS. WHEN YOU FEED THESE THINGS, PURIFY THE HUMAN MILK OLIGOSACCHARIDES AND THROW WITH THESE BACTERIA, MONITORING WHAT CAME OUT, WHAT YOU FOUND WAS SIALICASE AND FUCOSIDASE. THEY LOOKED AT THE SPECIFIC ENZYMES AND EXPRESSED THEM AND WE TESTED THEM AGAIN USING THE SAME MILK OLIGOSACCHARIDES AND FOUND THE VERY HIGH SPECIFICITY OF COMPOUNDS. IT INTERACTS WELL WITH DIFFERENT STRUCTURES INCLUDING SPECIFIC LINKAGING OF EACH OF THE MONO SACCHARIDES AND DIFFERENT COMPOSITIONS. BUT TURNS OUT WHAT THESE ARE YOU FIND THE DIFFERENT COMPOUNDS, DIFFERENT BACTERIA, DIFFERENT STRAINS HAVE VERY UNIQUE CONSUMPTION PROFILE. BUT IN THE END THEY WERE ALL ABLE TO PRETTY MUCH CONSUME A LOT OF MILK OLIGOSACCHARIDES. THAT DISCOVERY LED US, THE FACT WE FOUND THIS BACTERIA WAS DIMINISHING INFANTS LED US TO CREATE A PRODUCT, YOU CAN BUY THIS NOW, IT'S BEING GIVEN TO INFANTS, BEING USED IN NICUs. WE LOOKED AT SYSTEMATIC ANALYSIS OF HUMAN MILK OLIGOSACCHARIDES, THEY START SMALL BUT THEY ARE MUCH LARGER. THE SIALIC ACID CONTAINED DIFFERENT TYPES COMPARED TO THE OTHER ANIMALS. WE HAVE NEU-AC, PRIMATES HAD NEU-GC, COWS ALSO. IF YOU PUT THEM ON A SCALE, WHAT YOU FIND IS THAT COWS END UP HERE, HUMANS HERE. YOU SEE ELEPHANTS ARE MORE LIKE COWS, THE DIFFERENTIATING FACTOR IS AMOUNT OF SIALIC ACID AND AMOUNT OF FUCOSE. HUMANS AND OTHER PRIMATES ARE RICHER IN FUCOSE COMPARED TO THOSE -- COMPARED TO PRIMATES, AND THEN PIGS HAVE MUCH -- EVEN MUCH LESS, COWS HAVE VERY LITTLE FUCOSE, MAINLY SIALIC ACID. IF YOU LOOK AT CATS AND DOGS, THEIR MILK IS VERY SIMILAR TO HUMANS. IF YOU LOOK AT CATS, CATS SORT OF ARE ONE PHENOTYPE, THEY LOOK LIKE NON-SECRETOR MOTHERS. DOGS LOOK LIKE SECRETORS. WOULD LOVE PEOPLE TO GIVE ME MONEY TO FIND THAT OUT. WE LOOKED AT SAMPLES, HUMAN MILK OLIGOSACCHARIDES, AND WE DECIDED TO DEFINE THE MILK. COLLECTING ALL THESE DIFFERENT SAMPLES, S+ MILK LIKE THIS, S NEGATIVE LOOKS LIKE THAT, RIGHT? IF YOU LOOK AT DIFFERENT PARTS OF THE WORLD, THEN WHAT WE COULD SEE, THE AMOUNT OF S NEGATIVE MILK WAS DIFFERENT DEPENDING ON THE REGION YOU WERE LOOKING AT. ONE OF THE COMMON MYTHS NOW IS THAT SECRETORS MAKE UP 20% OF THE POPULATION BUT THAT'S NOT TRUE. THAT'S ONLY TRUE FOR EUROPEANS. AND EUROPEAN -- AMERICANS OF EUROPEAN DESCENT. HOWEVER, IF YOU GO TO PLACES IN AFRICA, FOR EXAMPLE, GAMBIA, AMOUNT OF S NEGATIVE MILK IS 36, SOUTH AFRICA 37%, IF YOU LOOK AT OTHER PLACES IN AFRICA IT'S 17% IN NAMIBIA. BANG AND THESE ARE INDIGENOUS TRIBES IN SOUTH AMERICA, ALMOST NO NON-SECRETORS, NO S NEGATIVE MILK, PRIMARILY S POSITIVE MILK EXCEPT FOR ARGENTINA, A LITTLE IN BRAZIL. THERE'S 60 STRUCTURES THAT YOU FIND GENERALLY COMMON IN MOST MOTHERS. AND THE OTHER THING IS THAT 2FL IS NOT HIGHLY ABUNDANT. NEPAL AND NAMAIBIA THEY WERE MORE ABUNDANT. WE LOOKED AT THE DIFFERENT PATTERNS, WELL KNOWN HMO IT'S DROP BUT WHAT WE SAW WAS DIFFERENT COUNTRIES, DIFFERENT SITES, HAD MORE HMOs AT THE BEGINNING. REMONITORED, FUCOSLYATED WAS MORE ABUNDANT, SYLATE 10%, FUCOSLYATE 60%, FOUND DIFFERENCES BETWEEN S NEGATIVE MILLING, SLIGHT DROP IN SOME AND IN OTHER COUNTRIES THEY ARE QUITE EVEN WITH EACH OTHER. WE FOUND IN GENERAL SYLATED IS HIGHER, S NEGATIVE MILK, BUT NOT ALWAYS. AND IN SOME CASES IT'S EVEN LOWER. SOME OF THIS, WE'RE LIMITED BY THE NUMBER OF SAMPLES WE HAVE. SO WITH THAT, YOU COULD MAKE A LOT OF CONCLUSIONS. ONE WE WERE ASKED TO DO WAS EXPLORE CAN ALL STRUCTURALLY DIFFERENT INDIVIDUAL HUMAN MILK BE CLASSIFIED AS FUNCTIONALLY EQUIVALENT. MAYBE. UP TO A POINT. CAN HUMAN AND NON-HUMAN HOMOLOGS BE CLASSIFIED AS FUNCTIONALLY EQUIVALENT. IT DEPENDS. IF YOU BELIEVE HMOs MAINLY FEED THE GUT MICROBIOME AND ALL BENEFITS COMES FROM, YOU CAN TAKE SOME SHORTCUTS. YOU CAN'T USE GOS, FOS OR MOS. IF YOU FUCOSLYATE OR SYLATE, YOU MAY HAVE SOMETHING. COMPOUND DON'T NECESSARILY NEED TO BE HMOs BECAUSE YOU CAN GET -- USE BMOs, THERE'S ABOUT 20% SIMILARITY BETWEEN BMOs AND BOVINE MILK OLIGOSACCHARIDES AND HMOs. WHAT WOULD BE BETTER IS CAT AND DOG MILK OLIGOSACCHARIDES BUT THAT WON'T HAPPEN. YOU CAN GET AWAY A SMALL COMBINATION OF FUCOSLYATED AND SYLATED, AND THOSE ARE THE STRUCTURES. IF YOU DON'T BELIEVE THE GUT MICROBIOME DOES EVERYTHING, STRUCTURES WILL INTERACT DISTINCTLY, AND YOU'RE NOT GOING TO BE ABLE TO SUBSTITUTE THE HMOs IN THIS CASE. SO WITH THAT I'D LIKE TO THANK YOU ALL FOR YOUR ATTENTION. >> THANK YOU FOR A REALLY INFORMATIVE PRESENTATION. WE'LL MOVE TO OUR NEXT PRESENTER, WE'RE GOING TO AGAIN DO THE QUESTIONS AFTER THIS ONE. IF WE COULD WELCOME DR. DALLAS. SHARE YOUR SLIDES PLEASE. >> ARE YOU ABLE TO SEE MY PRESENTATION OR NOTE SLIDE? >> PRESENTATION SLIDE. >> LOOKS GOOD? >> YES. >> GREAT. HI. I'M DAVE DALLAS. I'M ASSISTANT PROFESSOR AT OREGON STATE UNIVERSITY, NUTRITION. AND THANKS TO THE ORGANIZERS FOR ISSUE INVITING ME TO SHARE. SORRY, SLIDE MALFUNCTION. I HAVE NO PERSONAL FINANCIAL INTERESTS TO DECLARE BUT DO HAVE CURRENT GRANT FUNDING FROM SEVERAL COMPANIES IN THE HUMAN OR BOVINE MILK SPACE. HISTORICALLY AND CURRENTLY, THE FDA ALLOWED DIFFERENT SOURCES OF PROTEIN, BOVINE AND SOY, AND VARIOUS HEAT TREATMENTS, WHICH KASPER TALKED ABOUT YESTERDAY HOW THEY ALTER MILK PROTEIN AND FUNCTION AND DEGREES OF ENZYMATIC HYDROLYSIS TYPICALLY USED FOR COLIC OR POTENTIAL ALLERGY. HISTORICALLY WE PERCEIVED, PROVIDING HIGHLY DIGESTED PROTEIN AND AMINO ACIDS AS BUILDINGS BLOCKS FOR SYNTHESIS, BASED ON THE ASSUMPTION PROTEINS WERE DIGESTED AND THUS SERVED AS A SOURCE OF AMINO ACIDS. WHAT ARE EFFECTS? FROM A SAFETY AND BASIC NUTRITION PERSPECTIVE INFANT FORMULA PROVIDES ADEQUATE, SAFE PROTEIN. FORMULA FED INFANTS ARE GETTING AMINO ACIDS THEY NEED TO GROW. BUT WHAT MIGHT BE MISSING? WE KNOW BABIES FED HUMAN MILK HAVE NUMEROUS BIOLOGICAL BENEFITS OVER FORMULA INCLUDING REDUCED RISK OF INFECTION, DECREASED RISK OF NEC, DECREASED ALLERGY AND IMPROVED NEURODEVELOPMENTAL OUTCOMES, COULD RELATE TO DIFFERENCE IN PROTEINS PROVIDED. HUMAN MILK PROTEINS HAVE ARRAY OF FUNCTIONS BEYOND AMINO ACID PROVISION. PROTEOMICS REVEALED HUNDREDS OF THOUSANDS OF PROTEINS IN HUMAN MILK, MANY HAVE PARTIALLY KNOWN FUNCTIONS LIKE LACTOFERRIN AND LIPASES, MANY HAVE UNDISCOVERED FUNCTION IN THE CONTEXT OF NEONATE. MILK PROTEINS PROVIDE MORE THAN SIMPLE AMINO ACID NOURISHMENT. THE PARTIAL DIGESTION OF MANY MILK PROTEINS RELEASED ARRAY OF PROTEINS, PEPTIDE FRAGMENTS. OUR GROUP ANALYZED GASTRIC AND STOOL SAMPLES. THIS WORK ALSO SUGGESTS THAT MILK IS PROVIDING MORE THAN THAT SIMPLE AMINO ACID NOURISHMENT. MANY COMPANIES WANT TO IMPROVE FORMULA BY ADDING NEW VALUE-ADDED FUNCTIONAL INGREDIENTS AS NOVEL ISOLATED BOVINE MILK PROTEINS OR RECOMBINANT HUMAN MILK PROTEINS. DAIRIY PROCESSING COMPANIES ESTABLISHED METHODS TO EXACT ON A COMMERCIAL SCALE SPECIFIC PROTEIN COMPONENTS FROM BOVINE MILK INCLUDING IMMUNOGLOBULINS, GLYCOMACRO PEPTIDES, BETA LACTOGLOBULIN, AND OTHERS, USING ARRAY OF UNIT PROCESSES. TO THESE COMPANIES, EACH EXTRACTED PROTEIN REPRESENTS POTENTIAL VALUE ADDED INGREDIENT FOR VARIOUS CONSUMERS INCLUDING INFANTS FED FORMULA. COMPANIES ARE NOW PROVIDING RECOMBINANT PROTEINS INCLUDING YEAST AND OTHER FUNGI, THESE CAN HAVE IDENTICAL AMINO ACIDS TO NATIVE HUMAN MILK PROTEINS. IT'S NOW POSSIBLE TO PRODUCE PRETTY MUCH ANY HUMAN MILK PROTEIN IN THESE SYSTEMS. IT'S CLEAR MANY OF THE COMPANIES WOULD LIKE TO BE ABLE TO ADD THESE PROTEINS TO FORMULA TO IMPROVE ITS FUNCTION. THIS INNOVATION IS FANTASTIC NEWS IN THAT CHANGES WE MAKE TO NUTRITION IN EARLY LIFE COULD IMPROVE HEALTH ACROSS THE LIFE COURSE. HOW ARE THESE EVALUATED? CURRENTLY AS FAR AS I COULD GLEAN FROM INFORMATION ONLINE FORMULAS MUST PROVIDE ADEQUATE LEVELS OF SPECIFIC NUTRIENTS, GENERALLY RECOLLECT RECOGNIZE -- RECOGNIZED AS SAFE. NOVEL RECOMBINANT PROTEINS ALSO NEED TO BE CLASSIFIED AS GRAS, A COMPANY CALLED PERFECT DAY APPLIED FOR GRAS STATUS FOR BOVINE BETA LACTOGLOBULIN, FOR USE IN NON-FORMULA FOODS. THE TYPES OF DATA INCLUDED PURITY, LACK OF CONTAMINANTS, SAFETY OF FUNGAL SYSTEM AND MILK PROTEIN THE VERSION IS BASED ON. SHOULD WE CONSIDER HAVING A SIMILAR SEQUENCE TO A KNOWN HUMAN MILK PROTEIN AS DEMONSTRATION OF SAFETY OR EFFICACY? WHAT EVIDENCE IS NEEDED PRIOR TO ADDING THESE COMPONENTS TO FORMULA? BEYOND SAFETY EACH NOVEL PROTEIN'S USE IN FORMULA SHOULD BE SUBSTANTIATED BY DEMONSTRATED STRUCTURE, FUNCTION, DIGEST ACTIVE BEHAVIOR THAT IS SIMILAR TO THAT OF THE COUNTERPART. THEY SHOULD MATCH NATIVE STRUCTURE OF HUMAN MILK. THESE SHOULD BE EXAMINED BY TECHNIQUES LIKE LC-MS. IDENTICAL STRUCTURE MAY NOT BE NECESSARY FOR SIMILAR FUNCTIONALITY TO HUMAN MILK PROTEINS. BOVINE MILK DIFFERS IN STRUCTURES SEQUENCE AND GLYCOSYLATION FROM HUMAN MILK LACTOFERRIN BUT POSSESSES MANY SIMILAR FUNCTIONS AND COULD SERVE AS ADEQUATE ALTERNATIVE TO HUMAN MILK LACTOFERRIN. I THINK IT'S NECESSARY TO HAVE FUNCTIONAL DATA SHOWING FUNCTIONALITY OF THE NOVEL PROTEIN TO BE THE NATUREIVE HUMAN MILK PROTEIN. WHAT LEVEL? AT LEAST IN VITRO ASSAYS WHICH COULD RANGE, POTENTIALLY ASSAYS WITH MICROBES, GUT CELLS, IMMUNE CELLS. IT'S NOT EFFICIENT TO BE EXAMINE SOLELY THE STARTING MATERIAL STRUCTURE AND FUNCTION. MILK PROTEINS ARE EXPOSED TO PROTEASE IN STOMACH, SMALL INTESTINE AND COLON. IT'S ESSENTIAL TO DETERMINE WHERE HUMAN MILK PROTEINS SURVIVE TOP IN THE GUT, AS A MEANS TO ASSESS POTENTIAL RELEVANCE OF THEIR PROPOSED FUNCTIONS. NOVEL MILK PROTEINS SHOULD MATCH OF THE EXTENT OF SURVIVAL OF HUMAN MILK PROTEINS. PROTEINS INTENDED TO PROVIDE BIOACTIVE PEPTIDES SHOULD BE COMPARED. IN OUR EXPERIENCE, JUST HAVING A SIMILAR AMINO ACID SEQUENCE DOES NOT ENSURE SIMILAR DIGESTIVE SURVIVAL AND FUNCTIONALITY WITHIN THE INFANT. FOR EXAMPLE, WE COMPARED SURVIVAL OF NATURALLY OCCURRING MILK ANTIBODIES ACROSS IN VITRO, EX VIVO, IN VIVO INFANT DIGESTION. IN VIVO STAMPELS COLLECTED AFTER FEEDING HUMAN MILK. WORK DEMONSTRATED THAT RECOMBINANT WAS DIGESTED TO GREATER EXTENT IN PRE-TERM INFANT GUT THAN NATURALLY OCCURRING ANTIBODIES. THIS IS POSSIBLY DUE TO DIFFERENCE IN GLYCOSYLATION OR DIFFERENCES IN FOLDING. THIS HAS LARGE IMPLICATIONS, IMMUNOGLOBULINS NEED TO SURVIVE INTACT, ENGINEERED TO HAVE HIGHER STABILITY THAN WHAT WE OBSERVED FROM PAVOLIDUMAB. A STUDY RECOMPLETED WITH BOVINE MILK BIOSTIFF GLYCOMACROPEPTIDE. THIS WAS WITH ADULTS, NOT INFANTS, A GOOD EXAMPLE. IT IS KNOWN TO HAVE PATHOGEN ANTI-ADHESIVE AND MODULATORY EFFECTS. COMPANIES SCALED UP METHODS FOR EXTRACTION AND WOULD LIKE TO EXPLORE OPPORTUNITIES. WE STUDIED EXTENT TO WHICH IT SURVIVES IN GUT OF ADULTS, PLACE THE TUBES IN ADULT SUBJECTS, INCLUDING ME, SAMPLED AFTER CONSUMING GLYCOMACRO PEPTIDE. WE FOUND THE MAJORITY DOES NOT ACTUALLY SURVIVE INTACT IN THE UPPER SMALL INTESTINE AS PREVIOUSLY THOUGHT. WE DID FIND THAT A NUMBER OF FRAGMENTS OF THE PEPTIDE WERE PRESENT. THIS FINDING AGAIN SHOWS WE CAN'T ASSUME BIOACTIVE COMPONENTS PRESENT IN THE FEED SOURCE WILL SURVIVE TO ENABLE PROPOSED INTERACTIONS IN THE GUT. WE MUST TEST THEM. FRAGMENTS MA WE OBSERVED MAY BE SPOKEN FOR FUNCTIONS OBSERVED IN EATING STUDIES. SIMILAR TESTING IS NEEDED FOR EACH BIOACTIVE MILK COMPONENT. A FINAL EXAMPLE COMES FROM WORK OUTSIDE MY GROUP WITH REDOM BIN ANT BSS -- RECOMBINANT BSSL. PRE-TERM INFANTS WITH POOR DIGESTION FELD PASTEURIZED DONOR MILK FROM LOWER FAT ABSORPTION AND REDUCED GROWTH WHEN COMPARED TO THOSE FED RAW MOTHERS MILK. A RANDOM ORDER CROSSOVER STUDY IN 63, LESS THAN 32 WEEK GESTATIONAL AGE INFANTS FED RECOMBINANT HUMAN BSS PRODUCED IN CHINESE HAMSTER OVARY CELLS OR PLACEBO SPIKED INTO A PASTEURIZED HUMAN MILK OR FORMULA FOR SEVEN DAYS DID NOT SHOW INCREASED LIPID ABSORPTION BUT DID INDICATE IMPROVED GROWTH, LED TO A PLACEBO CONTROLLED CLINICAL TRIAL WITH 410 INFANTS IN LESS THAN 32 WEEKS IN GESTATIONAL AGE AT BIRTH FED RECOMBINANT BSSL SPIKED IN DONOR MILK FOR FOUR WEEKS. FAILED TO SHOW INCREASED GROWTH AND WAS ENDED EARLY DUE TO INCREASED ADVERSE EVENTS OBSERVED IN THE RECOMBINANT HUMAN BSDL GROUP MOSTLY GASTROINTESTINAL EFFECTS. NEITHER EXAMINED WERE RECOMBINANT HUMAN BSSL WAS ABLE TO SURVIVE WITHIN THE INFANT'S DIGESTIVE TRACT TO THE SAME EXTENT AT NATURALLY OCCURRING FORM IN HUMAN MILK. LACK OF IMPROVED FAT ABSORPTION IN THE FIRST STUDY AND LACK OF IMPROVED GROWTH IN THE SECOND STUDY COULD POSSIBLY BE DUE TO POOR DIGESTIVE SURVIVAL. ASSESSMENT IS CLEARLY IMPORTANT FOR NOVEL PROTEIN COMPONENTS TO BE PROPOSED, ADDED TO FORM LA. IF NOVEL PROTEINS ARE DELIVERED TO INFANTS, WE NEED TO ENSURE THAT THEY SURVIVE OR ARE DIGESTED SIMILARLY TO HUMAN MILK PROTEINS. OPTIMALLY IN VIVO TESTING FOLLOWED BY MASS SPECTROMETRY ANALYSIS, ELISA, FUNCTIONAL TESTING. ONE PARTICULAR CHALLENGE HOWEVER IS THAT WE'RE CURRENTLY ABLE TO OBTAIN DIGESTIVE SAMPLES FROM PRE-TERM AND SICK TERM INFANTS IN THE NICU. HOW CAN WE DESIGN STUDIES TO COLLECT DATA FROM HEALTHY TERM INFANTS WHICH WOULD BE MOST RELEVANT TO FORMULA CREATED FOR TERM INFANTS? WHEN NOT POSSIBLE TO OBTAIN APPROVAL FOR DIRECT FEEDING OF A PROTEIN TO INFANTS, EX VIVO INCUBATION IN SAMPLES CAN PROVIDE APPROXIMATION OF IN VIVO DIGESTION. A LOWER FORM OF EVIDENCE COULD BE SIMULATED GASTROINTESTINAL DIGESTION TO MIMIC THAT OF INFANTS. A MAJOR ISSUE HOWEVER IS THAT WE CANNOT BE CERTAIN HOW WELL THEY MATCH THE COMPLEX CONDITIONS IN VIVO. ANOTHER ASPECT TO BE CONSIDERED IS WHETHER WE NEED TO ASSESS HOW CHANGES IN INFANT DIGESTIVE AFFECT PROTEIN DIGESTION. OTHER STRATEGIES COULD INCLUDE FEEDING TO PIGLETS OR PRIMATE MODELS, MATCHING THAT OF HUMANS IS NOT CLEAR PARTICULARLY ON AN INDIVIDUAL PROTEIN BASIS. A FINAL THOUGHT FOR PROTEINS OR PEPTIDES SUGGESTED TO HAVE BIOLOGICAL ACTIONS THAT WOULD REQUIRE SYSTEMIC ABSORPTION BLOOD SAMPLING AND ANALYSIS WOULD BE NEEDED. WE HAVE POOR DATA OR NO DATA ON SPECIFIC PROTEIN BE ABSORPTION FOR MANY MILK PROTEINS, FOR EXAMPLE FOR PEPTIDES PROPOSED TO HAVE CENTRALS REDUCING EFFECTS. OVERALL I SUGGEST THAT IT IS ESSENTIAL TO EVALUATE NOVEL PROTEINS ADDED TO FORMULA, ISOLATES FROM BOVINE MILK OR RECOMBINANT. THANKS FOR THE OPPORTUNITY TO SHARE MY THOUGHTS AND I WELCOME FURTHER DISCUSSION. >> THANK YOU, DR. DALLAS. A WONDERFUL PRESENTATION. LET'S NOW TURN TO SOME QUESTIONS AND FOR THESE I'M GOING TO INTRODUCE JEREMIAH FASANO, HE'S GOING TO START US OFF. >> YES, THANK YOU. THOSE WERE SOME FANTASTIC TALKS FROM ALL THE PRESENTERS. A LOT TO THINK ABOUT. I WAS JOTTING DOWN NOTES AND I SAW QUITE A LOT OF OTHER PEOPLE DOING THE SAME THING. I THOUGHT PERHAPS WE COULD START OFF WITH SOMETHING THAT STRUCK ME LISTENING TO DR. CARLSON'S TALK. JUST ABOUT THE EXTENSTIONIVE BODY OF WORK AND RESEARCH THAT'S GONE INTO UNDERSTANDING APPROPRIATE WAY TO USE DHA, ARA IN INFANT FORMULA. IT MADE ME WONDER HOW COULD WE GET TO THE SAME PLACE WITH BIOACTIVE INGREDIENTS WHERE IN MANY CASES THERE MAY BE EVEN MORE COMPLICATED STRUCTURE FUNCTION QUESTIONS INVOLVED. ARE THERE RECOGNIZED STRATEGIES OR BEST PRACTICES FOR HELPING US KIND OF CHARACTERIZE THOSE KEY FUNCTIONALITIES, AND ESPECIALLY TO MAKE SURE THE ONES WE'RE LOOKING AT WHEN WE DO, SAY, CROSS-SPECIES COMPARISONS OR THINK ABOUT RELATED STRUCTURES ENDPOINTS ARE THE ONES THAT WOULD BE MOST IMPACTFUL FOR HUMAN HEALTH AND FOOD SAFETY ASSESSMENT. THAT'S A BIG QUESTION. BUT IT'S REALLY PROMPTED BY LOOKING AT ALL THE WORK THAT DR. CARLSON SHARED, HOW CAN WE PURSUE THAT SAME LEVEL OF DEPTH AND WHAT KIND OF TOOLS WOULD WE NEED FOR SOME OF THE OTHER BIOACTIVES. >> I DON'T THINK THERE ARE ANY SHORT CUTS, I'M NOT TALKING ABOUT SAFETY BUT FUNCTIONALITY SIDE. I THINK SAFETY IS SOMETHING THAT OTHER PEOPLE CAN ADDRESS BETTER THAN I. IF NEED TO DEMONSTRATE A FUNCTION YOU HAVE TO DO A CLINICAL STUDY AND HAVE AN OUTCOME THAT'S PLAUSIBLE. AND I KNOW THAT'S NOT THE PRIMARY CONCERN OF THE FDA, BUT -- >> DR. LEBRILLA, YOU TALKED AT THE END OF YOUR PRESENTATION ABOUT MULTIPLE FUNCTIONALITIES, POTENTIALLY COULD BE ASSOCIATED WITH HMOs AND IT STRUCK ME MAYBE THIS IS SORT OF A LOGICAL NEXT STEP. FOLKS ARE INTERESTED IN FUNCTIONALITY, ALSO THINKING ABOUT POTENTIAL ENDPOINT THAT MAY BE RELEVANT TO SAFETY, A LOT OF THINGS TO POTENTIALLY PURSUE. DO YOU HAVE THOUGHTS ABOUT HOW YOU COULD DECIDE ORDER OF IMPORTANCE OR THINGS TO LOOK AT? >> YEAH, I MEAN, I THINK THE INDUSTRY IS ALREADY THERE. WE KNOW THERE ARE SEVERAL COMPANIES MANUFACTURING AT LEAST THE MORE COMMON ONES. AND I KNOW CLINICAL TRIALS ARE ALREADY BEING PERFORMED ON THOSE. I THINK THAT'S THE RIGHT APPROACH. AT LEAST YOU REPRESENT A FUCOSLYATED SPECIES AND SYLATED SPECIES, FOR EXAMPLE. AND PERHAPS ONE THAT'S NOT DECORATED WITH SIALIC OR FUCOSLYATED RESIDUES. SO, IN THAT REGARD, I THINK WE'RE THERE. SO, I THINK THE FIRST GENERATION IS GOING TO BE THAT. TO GET SORT OF A SMALL REPRESENTATION. ONE OF THE ISSUES OF COURSE IS THAT AT THE MOMENT THEY ARE ALL JUST BEING ADDED AS A SORT OF COMMERCIAL, AN AD. THEY ARE IN SUCH SMALL AMOUNTS THAT THEY DON'T REALLY DO ANYTHING. OR WE WON'T EXPECT THEM TO DO ANYTHING. WHAT YOU NEED TO START PUTTING IN AMOUNTS THAT ARE FOUND IN MOTHERS MILK. AND I THINK THERE'S ALSO ROOM FOR NOVEL COMPOUNDS BUT OF COURSE THEY HAVE TO GET, YOU KNOW, IND APPROVAL AND THINGS, SO THAT WILL CONTAIN FUCOSLYATED OR SYLATED SPECIES BUT NOT NECESSARILY MILK. IF YOU'RE TARGETING THE MICROBIOME, A LOT OF ENZYMES ARE PRETTY DIVERSE. SO THEY CAN TAKE PRETTY MUCH ALL THE DIFFERENT FUCOSLYATED STRUCTURES AND ALL DIFFERENT SYLATED STRUCTURES SO THEY HAVE TO BE SAFE BUT I THINK THAT WOULD BE ANOTHER STRATEGY, YOU KNOW, CREATING SMALL OLIGOSACCHARIDES THAT ARE FUCOSLYATED AND SYLATED, AND OTHER PEOPLE ARE DOING THAT. THE BEAUTY OF THE HUMAN MILK PRODUCT IT'S GRAS, THE REGULATORY IS A LOT LOWER BARRIER THAN CREATING SOMETHING NEW THAT'S NOT HUMAN. >> DR. DALLAS, I ADDED ADDITIONAL QUESTIONS RELATED TO QUANTITATIVE USE LEVELS BUT DID YOU HAVE ANYTHING TO ADD TO THE GENERAL QUESTION WHAT ARE GOOD STRATEGIES OR ENDPOINTS FOR DEFINING COMPARABILITY? I FELT LIKE YOU TOUCHED ON SOME OF OF THAT IN YOUR TALK. >> YEAH, I THINK THE THINGS I TALKED ABOUT, YOU KNOW, STRUCTURE ANALYSIS IS REALLY IMPORTANT, FUNCTIONAL ANALYSIS, DIGESTIVE SURVIVAL. CLINICAL STUDIES NEEDED. THERE IS A NEED TO ENCOURAGE CONTINUE THE INNOVATION WITHOUT CREATING OVERLY HIGH REGULATORY BARRIERS. WHILE ENSURING SAFETY. >> MAYBE A FOLLOW-UP QUESTION, INSPIRED INITIALLY BY DR. CARLSON'S TALK. A QUESTION WAS ABOUT RANGE OF DHA THAT HEALTHY INFANTS WOULD REQUIRE, IS THERE A BIG RANGE OF POTENTIAL REQUIREMENTS FOR THIS? ARE THERE SOME THAT NEED A LOT AND SOME A LITTLE OR IS IT RELATIVELY COMPRESSED RANGE OF REQUIREMENTS? >> I THINK ALL INFANTS PROBABLY NEED SOME. THERE'S NEVER BEEN -- HASN'T BEEN A SINGLE STUDY WHERE DHA HAS BEEN FED BUT DIDN'T INCREASE DHA STATUS COMPARED TO A FORMULATION WITHOUT IT IN ANY SINGLE INFANT OR ANY SINGLE GROUP. BUT IN THE DONOVAN TRIAL, THE DOSE-RESPONSE TRIAL, WE DID FIND SOME DIFFERENCES BETWEEN OUR LOW SES POPULATION AND THE MORE MIDDLE CLASS POPULATION STUDIED IN DALLAS, AND AS WE FOLLOWED THE CHILDREN TO AGE 9, THE GROUP THAT GOT .64% COULD BE SEEN TO HAVE HIGHER SCORES THAN THE OTHERS. IT WASN'T ALWAYS SIGNIFICANT. THE GROUPS WERE SMALL BY THIS POINT BY THE TIME THEY WERE 9, DIDN'T HAVE A LOT OF CHILDREN. THERE HAVE BEEN OTHERS WHO HAVE WRITTEN THAT IDEALLY A RATIO OF ARACHIDONIC ACID AND DHA, AT THIS POINT THEY ARE ALL .32 OR LOWER IN SOME COMPANIES. >> THANK YOU. TO BUILD ON THIS, THIS WAS TOUCHED ON IN DIFFERENT WAYS, JUST THINKING ABOUT THE ACTUAL USE LEVEL IN FORMULA OR POTENTIAL AMOUNT OF EXPOSURE. YOU HAD ALLUDED TO WHAT YOU THOUGHT MIGHT BE APPROPRIATE USE LEVELS FOR THESE HMOs. DR. DALLAS, SOMETHING THAT STRUCK ME QUANTIFYING WHAT AND HOW MUCH IS PRESENT IN THE G.I. TRACT TO BE AVAILABLE FOR SUBSEQUENT IMPACT ON INFANT HEALTH SEEMED LIKE A REALLY IMPORTANT PIECE. I WOULD SAY TO THE GROUP GENERALLY, DO WE HAVE A SENSE OF WHAT KINDS OF BIOACTIVE MILK CONSTITUENTS THERE MIGHT BE, A QUANTITATIVE RELATIONSHIP BETWEEN THE AMOUNT THE INFANT IS EXPOSED TO AND PHYSIOLOGICAL IMPACT, IS THAT SOMETHING WE SHOULD BE SORT OF FACTORING IN WHEN WE'RE THINKING ABOUT COMPARING SIMILAR STRUCTURES OR HOMOLOGOUS SUBSTANCES FROM DIFFERENT SOURCES? >> MY RESPONSE WOULD BE THAT NATURE IS PRETTY SLOPPY, NOT TIGHT REGULATION OF THINGS. PARTICULARLY FOOD. AND SO AS LONG AS YOU HIT THE RANGE, THAT MOTHERS ARE PRODUCING, AND, YOU KNOW, IT'S -- FOR HMOs YOU START OFF AT BETWEEN 20 GRAMS PER LITER AT BIRTH TO 9 GRAMS OR LOWER, AT SIX MONTHS, AND STABLE AFTER THAT. WE'VE LOOKED AT MILK UP TO TWO YEARS. EVEN FOUR YEARS. HMOs WERE STABLE. I THINK RATHER THAN TRY TO CATCH THE DYNAMIC ASPECT OF IT, IF YOU SORT OF CATCH THE ENDPOINT, AT LEAST INITIALLY THAT WOULD PROBABLY BE SUFFICIENT. IF YOU COULD PUT IN A TOTAL OF 9 GRAMS PER LITER, FOR EXAMPLE, FOR HMO THAT WOULD PROBABLY COVER EVERYTHING. AND THAT DROP IS WITHIN A FEW MONTHS. SO YOU CAN ARGUE WHETHER MORE IS NEEDED AT THE BEGINNING BUT I THINK JUST HAVING IT IN THERE WOULD GO A LONG WAY TOWARDS MAKING IT MORE LIKE BREAST MILK. >> I WOULD ADD FROM THE PROTEIN PERSPECTIVE I THINK FROM ONE PERSPECTIVE YOU COULD KEEP IT SIMPLE, THESE PROTEINS SHOULD MATCH THE AMOUNTS ARE OBSERVED IN MILK, THE RANGES, FIGURE OUT OPTIMAL, BUT THEN FROM ANOTHER PERSPECTIVE IF YOU'RE ADDING COMPONENTS NOT FROM HUMAN MILK WE SHOULD THINK ABOUT BOTH THE VARIATION IN THEIR DEGREE OF DIGESTION AND DIFFERENCES IN BASE FUNCTIONALITY. SO IF SOMETHING IS LESS FUNCTIONAL PERHAPS YOU NEED TO ADD MORE TO COMPENSATE FOR ITS DECREASED FUNCTIONALITY COMPARED TO THE HUMAN MILK OR ADD DIFFERENT AMOUNTS TO COMPENSATE. I THINK THOSE KIND OF QUESTIONS ARE REALLY IMPORTANT WHEN FIGURING OUT THE DOSAGE THAT YOU WOULD NEED. >> TO REPEAT THAT BACK, YOU DO HAVE A GENERAL SENSE THAT IN SOME CONTEXTS LIKE LET'S SAY IF THERE'S DIFFERENCES IN RECEPTOR AFFINITY OR SOMETHING RELATED TO STRUCTURE, BOVINE AND HUMAN, THAT YOU COULD POTENTIALLY BE DIFFERENT PLACES ALONG THE RESPONSE CURVE AND MIGHT NEED TO TRY TO DO ALMOST CONVERSION TO MATCH ANTICIPATED IMPACT THAT YOU WOULD GET FROM, SAY, DIFFERENT VERSION. >> I THINK SO, YEAH. I THOUGHT ABOUT THAT A LOT WITH THE PAVOLIZUMAB STUDY, FOR A RESPIRATORY NOT DIGESTIVE VIRUS BUR THE CONCEPTS STILL MAKE SENSE. FIRST HOW FUNCTION YAM FUNCTIONAL IS THE MONOCLONAL ANTIBODIES COMPARED TO NATIVE FORM, DIFFERENT IN TERMS OF EFFICACY, ON TOP OF THAT WITH PAVOLIZUMAB IT WAS DIE DIGESTED AS GREATER EXTENT. YOU WOULD NEED MORE COMPOUND TO REACH FUNCTIONAL EQUIVALENCY. OR CHANGE HOW THE PROTEIN IS DELIVERED. MAYBE WE WILL MOVE TO SESSION 5 AND TALK MORE AT THE END OF THE DAY. THANK YOU AGAIN FOR THREE FANTASTIC TALKS, LOTS TO THINK ABOUT. >> THANKS YOU. MORE TO COME THIS AFTERNOON. I'LL HAND IT OVER TO OUR MODERATORS FOR THE FINAL SCIENTIFIC SESSION, NUMBER 5. >> GOOD AFTERNOON. OR GOOD MORNING. WELCOME TO SESSION NUMBER 5. THIS IS CONSIDERATION OF INTERACTIONS BETWEEN BIOACTIVE INGREDIENTS. I'M KIMBERLEA GIBBS FROM NICHD, CO-MODERATING THIS SESSION WITH MY COLLEAGUE DR. RACHEL MORRISETTE, FDA, CFSAN. WE'LL COVER THE INTERACTIONS OF BIOACTIVE INGREDIENTS IN INFANT FORMULA AND HOW IT AFFECTS FUNCTION AND SAFETY. WE'LL AGAIN START WITH INTRODUCTION OF SPEAKERS IN PRESENTATION ORDER. YOU CAN FIND BIOGRAPHIES ON THE WEBSITE. FIRST DR. LARS BODE FROM UNIVERSITY OF CALIFORNIA SAN DIEGO, PROFESSOR OF PEDIATRICS IN DIVISION OF NEONATOLOGY AND DIVISION OF GASTROENTEROLOGY, HEPATOLOGY, NUTRITION. ALSO THE CHAIR OF COLLABORATIVE YOU HUMAN HUMAN MILK REVERSE DIRECTOR OF THE FOUNDATION, MOTHER MILK INFANT CENTER OF RESEARCH EXCELLENCE, PROVIDING OVERVIEW OF THIS TOPIC AS WELL AS SPEAKING ON HIS EXPERTISE IN OLIGOSACCHARIDES TODAY. >> SECOND IS DR. SHARON DONOVAN, UNIVERSITY OF ILLINOIS, PROFESSOR AND CHAIR IN NUTRITION AND HEALTH, DEPARTMENT OF FOOD SCIENCE AND HUMAN NUTRITION, INAUGURAL DIRECTOR OF THE PERSONALIZED NUTRITION INITIATIVE AT THE UNIVERSITY OF ILLINOIS AND WILL SPEAK ON EVALUATING INTERACTIONS BETWEEN BIOACTIVE INGREDIENTS TODAY. THIRD DR. JAE KIM, DIVISION DIRECTOR OF NEONATOLOGY, PERINATAL INSTITUTE AT CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER, PROFESSOR OF PEDIATRICS. DR. KIM WILL SPEAK FROM CLINICAL PERSPECTIVE TO HELP US BEGIN TO PRIORITIZE MEASUREMENTS IN THIS COMPLEX SPACE TODAY. >> DR. BODE, PLEASE START WHEN YOU'RE READY. >> GOOD MORNING, EVERYONE. THANKS FOR HAVING ME. ONE SECOND. THERE WE GO. WE'RE GOING TO MAKE IT EVEN MORE COMPLICATED TALKING ABOUT INTERACTIONS OF DIFFERENT INGREDIENTS AND SAFETY AND EFFICACY. DISCLOSURES BEFORE I DIVE IN. NOTHING TO DISCLOSE. DO NOT OWN ANY COMPANIES. SCIENCE IS PURELY SCIENCE. LET'S START WITH HUMAN MILK BIOACTIVES, WE TACKED ABOUT THEM THROUGHOUT THE WORKSHOP. I'LL BE FOCUS THROUGHOUT THE TALK ON LIPIDS, COMPLEX STRUCTURES, WE HEARD FROM SUSAN CARLSON INDIVIDUAL FATTY ACIDS BUT THE GLOBULE IS COMPLEX. DAVE DALLAS WAS TALKING ABOUT PROTEINS AND PROTEASE ACTIVITY AND PEPTIDES, SO ON. AND THERE'S A BUNCH OF OTHER STUFF IN THERE. WE HAVE CELLS. WE HAVE MICROBES. WE HAVE TRADITIONAL MICRONUTRIENTS AND MANY THINGS IN THIS MIRACLE TISSUE, HUMAN MILK. SOME OR MANY OF THESE INTERACT WITH EACH OTHER. LOOKING AT ONE COMPOUND AT A TIME HOW DO WE ASSESS SAFETY AND EFFICACY, TAKING MANY COMPONENTS AND INGREDIENTS TOGETHER. WHICH OF COURSE MAKES IT EVEN MORE COMPLICATED. AND IF WE THINK ABOUT THE TRIAD, WE'VE TALKED ABOUT THIS IN MANY SESSIONS, MANY CONFERENCES, WE CAN'T SEE HUMAN MILK IN ISOLATION, IT'S PART OF THE TRIAD THAT INVOLVES THE MOTHER, INFANT, NOT ALL INGREDIENTS WORK THE SAME WAY, NOT THE SAME OVER TIME. KEEP THAT IN MIND WITHOUT GOING INTO DETAIL. I'LL FOCUS ON HUMAN MILK OLIGOSACCHARIDE, STRUCTURES ARE DIFFERENT. THESE AN ARSENAL OF STRUCTURES, NOT JUST ONE OLIGOSACCHARIDE, IT'S 150, 200 STRUCTURES. WITHOUT GOING INTO DETAIL HERE WE HAVE THESE DIFFERENT GROUPS, NEUTRAL, NON-FUCOSLYATED, NEUTRAL FUCOSLYATED, ACIDIC. WE'RE TALKING ABOUT 2 FL BECAUSE IT WAS THE FIRST OLIGOSACCHARIDE INTRODUCED IN INFANT FORMULA CURRENTLY ON THE MARKET. KEEP IN MIND YES THIS IS ONE OF THE MOST ABUNDANT HMOs IN MILK OF MOST WOMEN BUT SOME MAKE HARDLY ANY AND WE'LL COME THROUGH THAT IN THE DURATION OF THE TALK HERE. DATA I'D LIKE TO HIGHLIGHT WE SEE DIFFERENCE IN OLIGOSACCHARIDE COMPOSITION IN DIFFERENT WOMEN, DIFFERENT COLORS BEING DIFFERENT OLIGOSACCHARIDES. IF YOU LOOK AT RELATIVE ABUNDANCE THE COMPETITION IS DIFFERENT BETWEEN DIFFERENT WOMEN. AGAIN, HIGHLIGHTING 2FL AS THE BLUE BAR, YOU CAN SIGH WITH THE NAKED EYE THERE IS TWO CLUSTERS, SECRETORS AND NON-SECRETORS AND WHY IS THAT IS THE QUESTION. SIMILAR SLIDE LOOKING AT PERCENTAGES WITH SEEK CREATOR STATUS OR NON--- SECRETOR STATUS OR NON-CREATOR STATUS. THIS IS RELEVANT TO SAFETY AND EFFICACY. WE ARE VERY EXCITED ABOUT THIS DEVICE, YOU CAN DROP IN MILK, AT POINT OF CARE, BLUETOOTH ENABLED, SENDS DATA DIRECTLY TO YOUR CELL PHONE, YOU CAN SEE IS MOM A SECRETOR OR NON, AND YOU CAN MEASURE IN THE DEVICE, A GAME CHANGER FOR OLIGOSACCHARIDE ANALYSIS, EXPANDING TO OTHER OLIGOSACCHARIDES AT THE MOMENT. SO WE TALKED ABOUT THE VARIATION OF DIFFERENT OLIGOSACCHARIDES BETWEEN MOMS. IT'S REMARKABLY CONSTANT, OVER THE COURSE OF A WEEK CONSTANT, OVER THE COURSE OF A DAY NOT THE SAME FOR OTHER COMPONENTS BUT FOR OLIGOSACCHARIDE REMARKABLE CONSTANT, DIFFERENT BETWEEN DIFFERENT MOMS. TWO SUBJECT IT'S, DIFFERENT PATTERNS, BUT PATTERNS ARE REMARKABLY CONSTANT OVER A SHORT PERIOD OF TIME. THAT'S NOT THE CASE OVER LONG PERIOD OF TIME. DA FROM ONE MONTH TO 24 MONTHS POSTPARTUM, THE QUESTION IS, IS THAT RELEVANT, IMPORTANT, WE'RE CHANGING THE DIFFERENT INTERACTIONS, DIFFERENT COMPOSITIONS ARE DIFFERENT OVER THE COURSE OF TIME. THE QUESTION, IS THAT RELEVANT? WHAT HAPPENS TO OLIGOSACCHARIDES WHEN THEY GET INGESTED? STABLING TO THE LOW PH IN INTESTINE, SOME GET ABSORBED, WE FIND THEM IN THE URINE, REST DEGRADED IN COLON OR EXCRETED IMPACT. WHAT WE THINK OLIGOSACCHARIDES DO, THEY HAVE PRE-BIOTIC EFFECT, FEED BENEFICIAL BACTERIA, THAT HAVE SOME HEALTH BENEFITS BUT WE BELIEVE THERE IS -- HMOs ARE MORE THAN FOOD FOR BUGS. THEY HAVE EFFECTS ON EPITHELIAL CELLS AND THEY HAVE EFFECT ON IMMUNE CELLS AND THAT CAN BE LOCALLY IN THE GUT, ALSO ON SYSTEMIC LEVEL. AND THIS IS PROBABLY JUST THE TIP OF THE ICEBERG, AS WE HAVE MORE STRUCK AVAILABLE AT LARGER SCALE AND LOWER COST TO DO MORE RESEARCH. THERE'S A HUGE OPPORTUNITY HERE AS WELL TO DO MORE RESEARCH AND FIND OUT WHAT THESE OLIGOSACCHARIDES ARE ACTUALLY DOING. LET'S TALK ABOUT HMO INTERACTIONS, THAT'S WHAT THIS SESSION IS TALKING ABOUT, INGREDIENT INTERACTIONS, FOCUS ON THE PRE-BIOTICS FOR A MOMENT. WE STARTED TO BELIEVE IF HMOS FEED MICROBES CAN THEY BREAK DOWN THE FUCOSLYATED OLIGOSACCHARIDES, CAN THEY CLEAVE OFF SIALIC ACID AND MAKE OTHER STRUCTURES AVAILABLE TO OTHER BUGS? A BLEND WILL LEAD TO DIFFERENT MICROBIAL COMMUNITY STRUCTURE AND FUNCTION COMPARED TO USING SINGLE OLIGOSACCHARIDES JUST LIKE 2FL. THIS DATA IS OLD ALREADY, 16S EXPENSING, IT REALLY HIGHLIGHTS NICELY THE DIFFERENT OLIGOSACCHARIDES DO DIFFERENT THINGS WHEN IT COMES TO PRE-BIOTICS. WE ISOLATED CULTURE FROM INFANT BREAST FED INFANT, COMMUNITY OF BACTERIA, AND INCUBATED THEM WITH POOLED HUMAN MILK OLIGOSACCHARIDES AND SEE HOW IT DEVELOPS AND CHANGES OVER TIME, 24 HOURS, 48 HOURS, IT MOVES IN THE TWO DIMENSION SPACE. IF YOU FEED WITH LMT IT MOVES TO A DIFFERENT SPACE AFTER 24 AND 48 HOURS, USING 2FL IT MOVES TO COMPLETELY DIFFERENT SPACE, THESE COMMUNITIES ARE QUITE DIFFERENT. AGAIN, THIS IS ONLY 16S SEQUENCING, NOT NECESSARILY FUNCTION, AND FUNCTIONALITY WILL BE SOMETHING TO STUDY BUT THE QUESTION OF COURSE IS HOW ABOUT SAFETY, WHAT HAPPENS IF WE TAKE INDIVIDUAL OLIGOSACCHARIDES AND MOVE MICROBIAL COMMUNITIES IN A CERTAIN DIRECTION WHERE THEY WOULD NOT BE IF WE FED THE MIX LIKE THEY COME WITH HUMAN MILK. LET'S TALK SPECIFICALLY ABOUT OUTCOMES, GROWTH IN INFANCY AND EARLY CHILDHOOD. WE LOOKED AT THE SKOT III COHORT, EXCLUSIVELY BREASTFED, SOME HAVE EXCESSIVE WEIGHT GAIN, IS THERE DIFFERENCE IN OLIGOSACCHARIDE COMPOSITION RELATED TO THIS? NO DIFFERENCE IN TOTAL HMOs, NOT PARTICULARLY SIGNIFICANT DIFFERENCE WITH FUCOSE OR SIALIC ACID BUT WE SEE THE HIGH WEIGHT GROUP, THE GROUP WITH EXCESSIVE WEIGHT GAIN RECEIVED MORE 2FL FROM MOM'S MILK. IT RECEIVED SIGNIFICANTLY LESS LMT, WHERE ARE WE CURRENTLY ADDING TO INFANT FORMULA, 2FL AT THE LOW SPECTRUM. MULTIPLE PEOPLE TALKED ABOUT THAT. LMT WE SHALL IN THE MIDDLE OF WHAT TO EXPECT. WE WENT SINCE THIS WAS A PILOT STUDY RECEIVED FUNDING FROM THE NICHD TO DO THIS IN A LARGER COHORT, STEPS COHORT IN FEIGN LAND. HEIGHT, NORMALIZED HEIGHT, LOOK AFTER THOSE INFANTS THAT RECEIVE HIGHEST QUARTILE AND LOWEST QUARTILE 2FL, ORANGE, INDEED A DIFFERENCE BETWEEN HEIGHT AND THE SAME TRUE FOR WEIGHT, DEPENDING HOW MUCH 2FL THESE INFANTS RECEIVED, EXTENDING PAST BREASTFEEDING TO FIVE YEARS OF AGE. THE OPPOSITE IS TRUE, JUST LIKE THE DANISH STUDY LOWER LNNNT ASSOCIATED WITH WEIGHT. AND HMO/HMO INTERACTION THERE IS A DIFFERENCE UP TO HALF STANDARD DEVIATION IN HEIGHT AND WEIGHT, DEPENDING ON THE RATIO OF 2FL AND NEOLNNT. THIS IS HOW DIFFERENT OLIGOSACCHARIDES CAN HAVE DIFFERENT EFFECTS, RATIOS MIGHT BE IMPORTANT. WE DO KNOW DIFFERENT PATHOGENS HAVE ARSENAL OF GROWTH FACTORS, THOSE CONTRIBUTE IN ATTACHMENT, PROLIFERATION, INVASION, SURVIVAL, MANY ARE GLYCAN DEPENDENT POTENTIALLY INTERCEPTED BY HMOs. THE QUESTION IS AS A BLEND REQUIRED TO OVERCOME REDUNDANCIES, IS IT MORE EFFECTIVE THAN INDIVIDUAL HMOs, IS THERE A SAFETY CONCERN TO THAT? SAME TRUE WHEN IT COMES TO IMMUNE CELLS. WE TALK ABOUT IMMUNE CELL MODULATORS. IT'S MANY DIFFERENT IMMUNE CELLS, IMMUNE CELLS DO NOT ACT IN ISOLATION. THEY ACT IN A CONCERTED WAY, EACH IMMUNE CELL HAS ARSENAL OF RECEPTORS, MANY INTERACT WITH GLYCANS, GALECTINS, AND MANY MORE. DIFFERENT HMOs AFFECT DIFFERENT IMMUNE CELLS DIFFERENTLY. DOES A PLENTY ACT DIFFERENTLY WITH IMMUNE CELL DEVELOPMENT? VERY LIKELY. WE HAVE SOME PRECEDENCE FOR THAT. THAT DRIVES THE SAFETY QUESTION AGAIN, WHAT IF WE ONLY GET ONE OLIGOSACCHARIDE THAT ENTERTAINS ONE AND SHOOTS THIS OUT OF ORDER. AND THIS REPRESENTED HERE IN DATA WE HAVE. FOR INDIVIDUAL OLIGOSACCHARIDE, PRODUCT MACROPHAGE INFLAMMATION INDIVIDUAL OLIGOSACCHARIDES CAN INDEED TRIGGER SOME. I'LL SHOW YOU SOME OF THE DATA LATER. 3SL WE SEE THAT FOR EXAMPLE. INFANT OUTCOMES, WE FIND THERE IS NOT AN ASSOCIATION WITH ONE OLIGOSACCHARIDE BUT REALLY WITH MIX OR BLEND OF DIFFERENT OLIGOSACCHARIDES. WE'VE SEEN THIS IN MULTIPLE STUDIES, COWS MILK ALLERGY, FOOD SENSITIZATION TO 18 YEARS OF AGE WITH THE MAX COHORT IN MELBOURNE. IT'S NOT ONE OLIGOSACCHARIDE BUT A BLEND OF DIFFERENT OLIGOSACCHARIDES, THAT ARE ASSOCIATED WITH REDUCED OR BETTER HEALTH OUTCOME. WHAT ABOUT HMO PROBIOTIC INTERACTIONS, AS PRE-BIOTICS AND BEYOND? WE STRONGLY BELIEVE WE DO NOT WANT TO METABOLIZE ALL OF THE OLIGOSACCHARIDES, SPARE SOME TO BE ANTIMICROBIAL, CHANGING IMMUNE CELL RESPONSES, ET CETERA. WHAT I SHOW HERE IS THREE DIFFERENT PROBIOTICS. WE'LL START WITH A. YOU SEE THERE'S TWO CHROMATOGRAMS ON THE LEFT, BUT YOU CAN SEE IT'S TWO BECAUSE THEY ARE COMPLETELY OVERLAPPING, THAT'S BEFORE AND AFTER DIGESTION WITH PROBIOTIC A, IN OTHER WORDS IT DOES NOT UTILIZE ANY OLIGOSACCHARIDES, THAT'S FINE. THEN WE HAVE A DIFFERENT EXAM HERE PROBIOTIC B. YOU SEE A LOT OF REDUCED PEAKS, OTHERS POP UP WHERE WE DON'T KNOW WHERE THEY ARE AND WHAT THEY DO BUT FACT IS IT REDUCES AMOUNT OF MANY OLIGOSACCHARIDES INCLUDING THIS HERE, DSLNT. WE AND OTHERS HAVE SHOWN IT PROTECTS FROM NECROTIZING ENTEROCOLITIS IN THE PRE-TERM INFANT. IF WE USE PROBIOTICS THAT DEGRADE ALL OLIGOSACCHARIDES INCLUDING DSLNT WE MIGHT MISS OUT ON OPPORTUNITY IT PROTECTS THE INFANT ON NEC, THAT OFFERS GREAT OPPORTUNITIES. HERE IS PROBIOTIC C NOW, SPECIFICALLY GOES AFTER LNT. IT GROWS NICELY B DSLNT IS INTACT AND CAN DO WONDERFUL THINGS IT WOULD BE DOING TO PROTECT FROM NEC. HAVING THIS OPPORTUNITY TO DEVELOP PROBIOTICS AND PRE-BIOTICS BASED ON WHAT KIND OF OLIGOSACCHARIDES ARE ACTUALLY UTILIZED AND WHAT ARE SPARED AS WE AS A HUGE RESEARCH OPPORTUNITY. THE LIST GOES ON, WHERE WE SCREENED HUNDREDS OF STRAINS, WHAT OLIGOSACCHARIDES THEY MIGHT BE UTILIZING, SOME DON'T UTILIZE ANY, YOU SEE RED COLOR UTILIZED A LOT, A WAY FOR US TO DEVELOP SMART AND TARGETED SYMBIOTICS. DID WE ADD 2FL TO THE FIRST FORMULAS? BECAUSE IT WAS AVAILABLE, EASY TO SYNTHESIZE, A TANGIBLE TARGET TO GO AFTER. MANY PEOPLE BACK IN THE DAYS WERE CITING WORK IN A COHORT IN MEXICO THOSE INSTANTS THAT RECEIVED MILK WITH MORE 2FL HAD LOWER RISK FOR DIARRHEA DISEASES. INFANTS ARE LESS LIKELY TO DEVELOP DIARRHEA IF FED THIS. A PAPER JUST CAME OUT THIS YEAR THAT SHOWS THE OPPOSITE. THIS IS FROM THE COHORT IN THE U.K. SHOWING INFANTS FED HUMAN MILK LOW IN 2FL ARE LESS LIKE TO DEVELOP DIARRHEA. NOT AT THE IMMEDIATE TIME OF BREASTFEEDING. NONETHELESS THE CONCLUSION STANDS AND WE HAVE THESE TWO CONFLICTING CONCLUSIONS HERE, ONE SAYING INFANTS HUMAN MILK LESS LIKELY, SO YOU MAKE SENSE OF THAT. THERE'S MORE DATA THAT RAISES SAFETY CONCERNS ABOUT 2FL, DATA WE PUBLISHED THIS YEAR IN CELLULAR MOLECULAR G.I. AND HEPATOLOGY, LOOKING AT MICE THAT ARE NON-SECRETOR RECIPIENTS, DO NOT MAKE ALPHA-1-2 FUCOSLYATED GLYCANS ON INTESTINAL EPITHELIAL CELLS, LESS PRONE TO DEVELOP OBESITY AND STEATOHEPATITIS ON WESTERN MORE DIET, MORE PROTECTED FROM OBESITY. WE SHOWED IF YOU SUPPLEMENT NON-SECRETOR THAT IS GONE. HERE IS JUST THE BODY WEIGHT. NOT SURE IF YOU CAN SEE MY MOUSE, TWO IMPORTANT LINES. THERE'S SIGNIFICANTS DIFFERENCES IN BODY WEIGHT, TRANSLATES TO BODY WEIGHT AND LIVER, TRIGLYCERIDES, WITH 2FL YOU SEE SIGNIFICANT CHANGES IN LIVER TISSUE ARCHITECTURE. HOW DOES THAT TRANSLATE TO HUMAN MILK COMPOSITION AND INGREDIENT SAFETY? THIS IS MICE, IT'S ADULT MICE, THESE MICE WERE PUT ON WESTERN STYLE DIED WHEN ALREADY ADULTS, NOTHING THAT WAS HAPPENING IN THE BREASTFEEDING SPACE. IT'S A WESTERN STYLE DIET COMPARED TO INFANT FORMULA, YOU COULD ARGUE INFANT FORMULA IS HIGH IN FAT, HIGH IN CHOLESTEROL, WE COULD CONSIDER THAT A WESTERN STYLE DIET. THIS IS A DIFFERENT STUDY, NOT PUBLISHED, HERE WE DID SOMETHING DIFFERENT. WE LOOK AT MICE DURING THE BREASTFEEDING PERIOD WHERE WE DO THREE WAY CROSSOVER STUDY, DAMS, SO MOMS THAT MAKE 3 SIGH LACTOSE OR DON'T, CROSSED THEM TO KNOCKOUT MICE WITH SPECIFIC ATHEROSCLEROTIC OR LIPID PHENOTYPE AND SEE WHAT HAPPENS TO THE ATHEROSCLEROTIC. SPECIFICALLY IN THE MALE MOUSE, SPECIFICALLY IN THE MALE MOUSE WE SEE 3SL DURING BREASTFEEDING, THERE IS SIGNIFICANTLY LOWER LEVEL OF CHOLESTEROL TRIGLYCERIDES COMPARED TO MICE THAT NEVER SAW 3SL IN THE BREASTFEEDING PERIOD. EXPOSURE EARLY ON IN LIFE HUGE DIFFERENCE WITH ATHEROSCLEROSIS LATER IN LIFE. WE JUST A GRANT TOGETHER WITH MELBOURNE, WE'LL SEE IF THIS TRANSLATES TO HUMANS AS WELL. RUNNING OUT OF TIME. BRINGING BACK THE TOPIC OF THE WORKSHOP HERE, CONSIDERATIONS FOR ASSESSMENT FRAMEWORK, IT'S COMPLICATED. LET'S MAKE IT AS SIMPLE AS POSSIBLE. LET'S NOT MAKE THIS TOO SMALL AND TOO HOT SO COMPANIES WILL NOT BE ABLE TO JUMP THROUGH THIS. YES, WE'RE AGREEING WE NEED TO PROTECT AND PROMOTE BREASTFEEDING AND HAVE AN OBLIGATION TO MAKE INFANT FORMULA AS GOOD AS WE CAN, IT NEEDS TO BE SAFE AND SOME EFFICACY IDEALLY. THE GOAL TO DEVELOP A FRAMEWORK THAT DECREASES REGULATORY HURDLES AND AT THE SAME TIME INCREASES SAFETY STANDARDS. I HOPE TO GET A CHANCE TO DISCUSS THAT AT THE END OF THIS WORKSHOP, TO NOT JUST PILE UP MORE PROBLEMS BUT COME UP WITH SOLUTIONS ON HOW WE CAN REDUCE SOME OF THOSE HURDLES. AND I'LL LEAVE YOU WITH THAT, THANK YOU VERY MUCH. >> PLEASE JOIN ME IN WELCOMING DR. DONOVAN. WE'LL HOLD QUESTIONS UNTIL THE END. THANK YOU. >> LET ME SEE IF I CAN SHARE MY OTHER VERSION. I'M REALLY SORRY. I'M HAVING TROUBLE SHARING MY FULL SCREEN. LET ME SHARE THE OLDER WIDER VERSION. LET'S SEE IF THAT WORKS BETTER. >> WE'RE HAPPY TO WAIT. WE'RE LOOKING FORWARD TO YOUR TALK. >> I WANT YOU TO SEE THE WHOLE. >> US TOO, YES. >> OKAY. SO THANK YOU FOR THE OPPORTUNITY TO CONTRIBUTE TO THIS VERY IMPORTANT WORKSHOP. THESE ARE MY DISCLOSURES. SHELLY MCGUIRE AND I MUST HAVE GONE TO THE SAME SCHOOL, I'LL START WITH QUESTIONS AND END WITH QUESTIONS, BUT THIS IS CONSIDERATIONS FOR COMPLEX INTERACTIONS, TOUCH ON SOME MODELS, AND TWO EXAMPLES FOR THE SAKE OF TIME. THE QUESTIONS WE WERE ASKED TO ANSWER, WHAT DO WE KNOW ABOUT INTERACTIONS BETWEEN BIOACTIVE INGREDIENTS AND CONTEXT OF ORAL EXPOSURE? WHAT INFORMATION IS NEEDED TO UNDERSTAND SUCH POTENTIAL INTERACTIONS? WHAT KINDS OF MODULATORY EFFECTS, SLIER ACTIONS COULD BE RELEVANT TO INFANT DEVELOPMENT? AND HOW WOULD THIS INFORMATION INFLUENCE EXPECTATIONS FOR DEVELOPMENTAL CONSEQUENCES OF AN ISOLATED BIOACTIVE INGREDIENT IN FORMULAS. SO, AGAIN, REPEATING WHAT WE HAVE HEARD THROUGHOUT MILK IS A COMPLEX FLUID AND THE NUTRIENTS ARE FOUND IN DISCRETE COMPARTMENTS WHICH MAY INFLUENCE FUNCTIONS. IT STARTED IN BOVINE MILK BUT STRUCTURES, COMPLEXES IN HUMAN MILK AND BOVINE HAVE BEEN DISRUPTED. HEAT TREATMENT MAY HAVE EFFECTS. REALLY HASHTAG, WE DON'T KNOW, EXCEPT FOR A COUPLE EXAMPLES DON'T UNDERSTAND FULLY HOW THESE COMPONENTS INTERACT, AND WE NEED THE EVIDENCE. I'VE HIGHLIGHTED A COUPLE. THE OTHER BIGGER PICTURE, OBVIOUSLY KEEP IN MIND, I MENTIONED YESTERDAY, THESE SYSTEMS INTERACT. WE FOUND LACK OF MICROBIOME, COGNITIVE DEVELOPMENT, ALL OF THESE ARE INTERACTING. IF WE STUDY PRE-CLINICAL OR CLINICAL STUDY WE WERE LOOKING AT ONE OUTCOME. WE'RE NOT FULLY ABLE TO UNDERSTAND COMPLEXITY OR EFFECTS AND ULTIMATELY UNDERLYING MECHANISMS. AND AGAIN TO MAKE IT MORE COMPLICATED, OTHERS ALLUDED TO THIS, AS WE LOOK, WE HAVE DIRECT EFFECT ON INTESTINAL CELLS INTERACTING WITH RECEPTOR, MAY BE ABSORBED INTO CIRCULATION, MAY INTERACT WITH MICROBIOME AS PRE-BIOTIC OR PROBIOTIC, OR MICROBES MAY MODIFY THOSE BIOACTIVES, PEPTIDES, WHICH INTERACT ON CELLS OR BE ABSORBED. WE KNOW THINKING ABOUT THE BIOLOGICAL MATRIX, BIOACTIVES INTERACT WITHIN THE MILK OR ON THE CELLS, AND AS I'LL TALK ABOUT, THIS PLOT DOES APPEAR TO BE PRESENT WITHIN HUMAN MILK. WE NOW HAVE PROTEINS INTERACTING WHICH IS CHANGING THEIR FUNCTIONS. AND THEN WE'VE HAD SEVERAL QUESTIONS ABOUT HOW DO WE STUDY THESE. I THINK THAT WE REALLY NEED ALL OF THEM. I THINK PARTICULARLY WE NEED ORGANOIDS TO ASK QUESTIONS THAT SINGLE CELL TYPES OF IN VITRO STUDIES WERE PROBABLY TOO LIMITED. IF YOU'RE INTERESTED IN SPECIFIC CELL TYPE, YOU CAN LOOK AT IMMUNE CELLS AND INTESTINAL CELLS, OTHER TYPES OF CELLS, BUT I WOULD LEAN TOWARD ORGANOIDS, FOR BRAIN AND OTHER TISSUES. THERE'S LIMITATIONS BUT IT CAN BE GOOD FOR UNDERSTANDING MECHANISMS. I THINK IT'S A HIGH-THROUGHPUT SCREENING. WE CAN MOVE TO ANIMAL MODELS. WE CAN HAVE GREATER COMPLEXITY, CONTROL THE GENETICS OF THE ENVIRONMENT, TO GREATER DEGREE, TEST FOR SAFETY AND EFFICACY. AND THEN ULTIMATELY WE NEED TO CONDUCT CLINICAL TRIALS TO DEMONSTRATE SAFETY AND EFFICACY AND REALLY CAPTURE REAL LIFE COMPLEXITY, GENETIC, ENVIRONMENTAL DIVERSITY AND MICROBIOME DIVERSITY. JOE TALKED ABOUT DIFFICULTY OF GETTING THEM, JUST GETTING BLOOD SAMPLES MUCH LESS OTHER TISSUES. I'M GOING TO MAKE A CASE FOR THE PIGLET AS A BIOMARKER OF BIOMEDICAL MODEL, NEARLY IDENTICAL DIGESTIVE PHYSIOLOGY, ACCELERATED GROWTH BUT THAT ALLOWS US TO SCREEN QUICKLY AND DETERMINE IF A COMPONENT IS (INDISCERNIBLE) WE'LL PICK THAT UP QUICKLY. PIGLETS WILL DOUBLE IN A WEEK. PIG IMMUNE SYSTEM IS 80% HOMOLOGOUS WITH HUMAN, 10% FOR RODENTS. IF YOU'RE ASKING QUESTIONS DIRECTLY ON THE IMMUNE SYSTEM, HOW THE MICROBIOME MAY INFLUENCE IMMUNE SYSTEM THE PIG IS A MUCH BETTER MODEL. THE MICROBIOME IS A BIT MORE SIMILAR WITH EXCEPTION THAT PIGLETS ARE MORE LACTOBACILLUS PREDOMINANT. WE CAN ALSO NOW MAINTAIN THEM GERM FREE TO IMPLANT A HUMAN MICROBIOME. PIGS AND HUMANS HAVE SIMILAR BRAIN AND SIMILAR GROWTH TRENDS. IF YOU LOOK AT PERINATAL, IT'S MORE SIMILAR IN HUMAN AND PIG VERSUS OTHER SPECIES. BOTH BRAIN, 20 TO 25% OF ADULT WEIGHT. PIG EXPERIENCE TWO PERIODS OF MYELINATION, PRE AND POST NATAL, AND IF WE LOOK SIMILAR TO ACCELERATED, WE CAN OVERLAY AND PIG AND HUMAN, ONE MONTH IN HUMAN IS ONE WEEK IN PIGLET. I'M GOING TO SWITCH GEARS AND TALK LACTOFERRIN AND OSTEOPONTIN. THERE'S DATA OUT THERE. THE MULTI-FUNCTIONAL PROTEINS INFLUENCE DEVELOPMENT OF MULTIPLE SYSTEMS. SOME DATA (INDISCERNIBLE) EVEN ADDING LACTOFERRIN, OUTSIDE OF THE CONTEXT OF HUMAN MILK WAS ABLE TO REDUCE DIARRHEA DURATION, INCREASE INFANTS ABLE TO ACHIEVE A SOLID STOOL. THIS WAS CLINICAL POPULATION. THERE'S BEEN A NUMBER OF SYSTEMATIC REVIEWS, META-ANALYSES. WHAT'S CONSISTENT OVER TIME HAS BEEN THAT LACTOFERRIN, BOVINE, CAN REDUCE RISK OF LATE ONSET SEPSIS, THERE MAY BE EFFECTS ON NEC BUT NOW THAT DOESN'T SEEM TO BE HOLDING. WE'V ADMINISTERED 1 OR 3.6 GRAMS TO FORMULA-FED PIGLETS, THIS COULD INCREASE CRYPT DEPTH AND CELLULAR PROLIFERATION. WE FOUND INCREASED SERUM IgG AND THEN IN EX VIVO ISOLATED IMMUNE CELLS FROM THE PIGLETS THAT THE PIGLETS COULD SEE BOVINE LACTOFERRIN IN THE DIET, SUGGESTING THEY COULD MOUNT BETTER RESPONSE TO BACTERIAL INFECTION. AND THEN BASED ON OBSERVATIONS LATE ONSET SEPSIS DEVELOPED A MODEL PIGLETS WERE INFECTED INTRAVENOUSLY WITH STAPH AUREUS, FED LACTOFERRIN OR A COMBINATION, REDUCING SEVERITY OF THE SEPTICEMIA AND BACTERIAL TRANSLOCATION, CYTOKINE SECRETION. OSTEOPONTIN, IN THE CLINICAL TRIAL THAT WAS CONDUCTED IN CHINA, I COLLABORATED ON THE STUDY, FEEDING INFANTS FORMULA WITH A LEVEL OF BOVINE OSTEOPONTIN SIMILAR TO HUMAN MILK WAS ABLE TO REDUCE SERUM TNF ALPHA, REDUCE FEVER, AND WE SHOWED INCREASED PROPORTION OF CIRCULATING T CELLS COMPARED TO STANDARD FORMULA, SO MORE SIMILAR TO BREASTFED. AND THEN RECENTLY SHOWED WITHIN THE INFANTS RECEIVING BOVINE OPN IN DIET ACTUALLY HAD HIGHER HUMAN OPN IN PLASMA COMPARED TO STANDARD FORMULA, REASON UNKNOWN BUT THIS IS AN ADVANTAGE OF BEING ABLE TO USE SPECIFIC FORMS OF PROTEIN. COLLABORATED, RHESUS MONKEYS, FEEDING OPN SAME CONCENTRATIONS SHIFTED? GENERAL EXPRESSION, SIMILAR TO MONKEYS MOTHER MED. AND THIS WAS BINDING TO INTEGRIN RECEPTORS, OSTEOPONTIN COMBINES RECEPTORS. MY COLLEAGUE DID A RECENT STUDY, SIMILAR LEVEL OF OPN IN PIGLET MODEL, FEEDING ALTERED BEHAVIOR IN RECOGNITION TASK SUSAN TALKED ABOUT EARLIER. OPN KNOCKOUT MICE, THERE ARE DIFFERENCES IN COGNITIVE DEVELOPMENT THAT PROVIDE OPN IN THE DIET COULD AMELIORATE SOME. YOU CAN SEE FOR BOTH IT'S HITTING ON IMMUNE FUNCTION OF CELLS, COGNITIVE FUNCTION, INTESTINAL GENE EXPRESSION. ONE OF THE OBSERVATIONS, THIS IS PRETTY MUCH WORK FROM BOWE'S LAB, HAS SHOWN BOVINE LACTOFERRIN AND OSTEOPONTIN FORM A COMPLEX. A BASIC PROTEIN, OPN IS ACID, PHOSPHORYLATED CALCIUM BINDING PROTEIN. WHAT THEY HAVE SHOWN IS 3 LF MOLECULES BIND TO 1 OPN, AND THE PREDOMINANT FORM BINDS TO CALCIUM-BOUND, WITH HIGH AFFINITY AND STARTED IN VITRO AND STANDARD CELL CULTURE USING 3 TO 1 RATIO, THIS IS A BIT STRONGER PROLIFERATIVE EFFECTS ON CELLS, EITHER DONE OPN ALONE OR LACTOFERRIN ALONE, MECHANISTIC RATIO MYELINATED THROUGH SIGNALING AND SHOWED THEY CO-LOCALIZED TO BOTH RECEPTORS, SO BARRIERS WERE NOT OVERLAPPING WITH THEIR RECEPTOR BINDING SITES. THEY THEN WENT MORE COMPLEX, STUDIED BOVINE COMPLEX TOGETHER WITH MILK PROTEIN, THEY FOUND COMPLEX WAS MORE RESISTANT TO DIGESTION THAN PROTEINS AND STIMULATED PROLIFERATION AND DIFFERENTIATION TO GREATER DEGREE THAN EITHER LACTOFERRIN ON ITS OWN. THE FUNCTIONS WERE IMMEDIATE. THIS INCREASES PROLIFERATION BUT LOOKED AT IMMUNE AND ANTIBACTERIAL IT WAS INTERMEDIATE. WE CAN'T ASSUME THAT THIS COMPLEX OR OTHER COMPLEXES ARE GOING TO ALWAYS BE ACTING IN ONE WAY OR ANOTHER SO WE REALLY NEED TO BE TESTING THIS ACROSS I THINK THE WHOLE SPECTRUM FROM IN VITRO TO ANIMAL MODELS TO HUMANS. I WANT TO FINISH UP WITH QUICKLY GOING THROUGH A STUDY WHETHER WE COMPARED FEEDING PIGLETS WITH HUMAN MILK OLIGOSACCHARIDES OR BMOS, MORE COMPLEX INGREDIENT, CONTAINS PREDOMINANTLY 3 AND 6 SL, ALSO LACTOSE AND GOS. IT'S NOT A PURE INGREDIENT. THE 2FL AND LARMN PRODUCED BY GLYCOME ARE PURE. I THINK IN THE FUTURE AS WE LOOK, WE SHOULD TRY TO ADD THESE IN PUREST FORMS, AS OPPOSED TO PICTURES THAT CARRY INGREDIENTS WE MAY NOT WANT. IN THE STUDY 2 DAY OLD PIGLETS WERE RANDOMIZED TO ONE OF THE FOUR DIETS. LEVELS WERE SELECTED BASED ON WHAT HAS BEEN SHOWN IN HUMAN STUDIES TO BE EFFICACIOUS OR ALREADY BEING ADDED TO FORMULAS. THEY WERE MAINTAINED FOR 33 DAYS, DID THE TESTING AND MRI. ONE OF THE NICE THINGS ABOUT USING PIGLET, TESTS OF COGNITION, NOVEL OBJECT RECOGNITION WHICH SUSAN SHOWED WE CAN TRANSLATE TO HUMANS AS WELL AS MONKEYS AND OTHER SPECIES. SO PIGLETS ARE PUTTING INTO AN AREA TO FAMILIARIZE, THEY ARE GIVEN TWO FAMILIAR OBJECTS, ONE HOUR, 48 HOURS, INTRODUCED TO NOVEL OBJECTS, THEY WOULD SPEND MORE TIME WITH THE MODEL OCTOBER. THIS SHOWS DATA. SO IT'S ABOUT A .5 RECOGNITION INDEX. AFTER THE ONE HOUR DELAY, LOOKING AT SHORT TERM MEMORY FED HMO DIET SHOWED IMPROVED PREFERENCE FOR NOVEL OBJECT. AGAIN, WE CAN USE HUMAN MRIs VERSUS JUST SUMMARIZING USING -- (INDISCERNIBLE) DIETS CONTAINING HMO ALONE OR WITH BMOS HAD INCREASED VOLUMES. THIS WAS A MAIN EFFECT FOR EACH MOUSE. WE LOOKED AT HIPPOCAMPAL, A WAY THAT MEASURED, HMO GROUPS SHOWED GREATER DOWNREGULATION OF GENE EXPRESSION. AND THERE WERE FOUR GENES IN PARTICULAR THAT WERE CORRELATED WITH RECOGNIZE AFTER ONE HOUR BUT NOT 48 HOURS OR WITH NOVEL OBJECT BY COMMISSION. THIS SHOWS THE EFFECTS OF FECAL MICROBIOTA, THESE ARE RECENTLY PUBLISHED SO YOU CAN GET MORE INFORMATION OR I CAN ANSWER QUESTIONS. IN TERMS OF MICROBIOTA THE MAIN EFFECT WAS BMOS, THIS IS A PRINCIPAL COMPONENT ANALYSIS, EFFECTS ON MICROBES. AND SO TO FINISH UP WE ALSO ARE INTERESTED IN TRYING TO UNDERSTAND THESE RELATIONSHIPS SO THIS WAS PUBLISHED AS A MEDIATION ANALYSIS SO WE WERE SPECIFICALLY INTERESTED IN RELATIONSHIP BETWEEN MICROBIOME AND RECOGNITION INDEX. THIS WOULD BE THE DIRECT PATH, WE ALSO LOOKED AT STRUCTURAL MRI HIPPOCAMPAL GENE EXPRESSION AND POTENTIAL MEDIATORS AND AGAIN THIS IS VERY COMPLEX. I WANT YOU TO GET THE BIG PICTURE. BUT THIS IS LOOKING AT RELATIONSHIP BETWEEN VARIOUS MICROBIOTA AND HIPPOCAMPAL GENE EXPRESSION AS WELL AS BRAIN VOLUMES. AND WHAT WE FOUND, ONE HOUR RECOGNITION, IT WAS DOWNREGULATION GABAergic. 48 HOUR RECOGNITION MEMORY AGAIN WERE ABLE TO START TO PICK UP MANY MORE GENES AND WHAT WAS REALLY FASCINATING IS WE WERE SEEING THESE. SOME QUESTIONS WE'VE BEEN HAVING HOW CAN WE UNDERSTAND THESE MECHANISMS AND INTERACTIONS, AND IN THIS CASE HMOs, DOING ONE THING, BMOs ANOTHER, SOME RELATIONSHIPS WERE IN THE CONTEXT OF THE BMOS FEEDING, HMO FEEDING, AND COMBINATION. WE CAN SEE, FOR EXAMPLE, THIS IS REALLY DISCOVERY BUT HELPING US TO UNDERSTAND POTENTIAL MECHANISMS OF ACTION AND IN ANIMAL MODEL WE COULD NEVER SEE IN CLINICAL TRIAL. KIND OF GOING BACK TO OUR QUESTIONS, WHAT DO WE KNOW ABOUT THE INTERACTIONS, I WOULD SAY NOT ENOUGH. COMPONENTS HAVE HAVE DISTINCT OR COMPLEMENTARY ACTIONS. WHAT INFORMATION IS NEEDED? I BELIEVE WE NEED TO UNDERSTAND MECHANISMS, NEED TO CONTINUE TO DO THE PRE-CLINICAL IN VITRO STUDIES AND AS WE BEGIN TO COMBINE INGREDIENTS AND LOOK AT THESE NOVEL INTERACTIONS IT'S JUST BEFORE WE CAN GO INTO HUMAN CLINICAL TRIALS. AGAIN, TO ADD METABOLIC. I WANT TO HEARKEN BACK, WE SHOULD MOVE BEYOND LOOKING AT A SINGLE OUTCOME, SINGLE SYSTEM, THAT'S NOT THE WAY THE HUMAN BODY IS WORKING AND RESPONDING TO HUMAN DIETARY COMPONENTS. AND EXPECTATIONS FOR CONSEQUENCES, AGAIN I THINK THESE PRE-CLINICALS, PARTICULARLY IN VITRO TO IN VIVO, WE'RE NOT GOING TO SEE EVERYTHING. WHAT ABOUT IN SILICO? THESE ARE ALL GOOD PLACES TO START, TO NARROW TARGETS, BUT ULTIMATELY WE NEED TO BE DOING ANIMAL STUDIES. WE NEED TO KNOW TARGETS AND UNDERSTAND MECHANISMS AND POTENTIAL FALLOUT AND ANTICIPATE BEFORE WE TAKE THIS INTO HIGHLY VULNERABLE POPULATION. AND, AGAIN, TO THANK MY COLLEAGUES IN THE LABORATORY. AND MY COLLABORATORS, FORMER GRADUATES AND FUNDING. SO THANK YOU. >> THIS IS KIMBERLY GIBBS. THANK YOU. I WANT TO EXTEND A THANK YOU TO DR. BODE. SORRY WE'RE WEREN'T ABLE TO TRANSITION SMOOTHLY. WE'RE GOING TO HOLD QUESTIONS UNTIL THE END OF THE SESSION. WE'RE GATHERING THEM HERE SO WE'RE LOOKING FORWARD TO ADDRESSING THE ONES THROUGH E-MAIL COMING IN. NOW I'D LIKE TO ASK OUR -- WELCOME OUR THIRD PRESENTER, DR. KIM. WHEN YOU'RE READY SHARE YOUR SLIDES. >> THANK YOU FOR THE INVITATION, I LEARNED A TON IN THE LAST DAY AND A HALF. I HAD THE EASY TASK TO INTEGRATE ALL THAT -- THESE ARE MY DISCLOSURES -- INTEGRATE EVERYTHING DISCUSSED SO FAR AROUND PUT A CLINICAL LENS ON THIS, HOW WE MAY INTERPRET FROM CLINICAL SIDE. THIS PARTICULAR SESSION ON INTERACTIONS I WANT TO HOW A CLINICIAN MIGHT WANT TO PERCEIVE THIS AREA. IT STARTS WITH THE CONCEPT INFANT FORMULA WHICH IS SIGNIFICANT AND LIFE SAVING FOR A LOT OF OUR BABIES BECAUSE OF THE COMPLEXITY OF THIS FORMULATION BUT BECAUSE OF THE NATURE OF IT BEING A SOLE NUTRITION FOR BABIES AT THIS STAGE IT BECOMES A POINT OF VULNERABILITY. THE GOAL IS STILL TO TRY TO SIMULATE OR TO GET CLOSE TO A LOT OF FEATURES THAT HUMAN MILK HAS. TALK ABOUT NOT JUST BASIC NUTRITION BUT OTHER FACTORS. WE KNOW THAT WITH TERM INFANTS AND PRE-TERM INFANTS MORE ASTOUNDEDLY THE IMMUNE SYSTEM IS NOT FULLY DEVELOPED, A HUGE FACTOR THAT WE'RE A SPECIES WHERE BABIES ARE BORN, AND ARE VULNERABLE IN MANY RESPECTS, DEPEND ON THE MOTHER. DEPEND ON THE MOTHER'S MILK TO CONFER BENEFITS. WHEN WE THINK ABOUT HOW INFANT FORMULA IS DERIVED, THE ASPECT OF VULNERABILITY WAS NOT THE FIRST STEP IN THE FORMATION OF HOW INFANT FORMULA CAME ABOUT. THE PARADIGM SHIFT WHEN WE STARTED THINKING HUMAN MILK IS A COMPLEX FLUID, IN FACT MEETS REQUIREMENTS OF BEING A LIQUID TISSUE LIKE BLOOD, SET THE STAGE WE'RE LOOKING AT A BIOLOGIC FLUID, VARIABLE, DISCUSSED SO FAR WITH A LOT OF COMPLEXITY THAT REALLY IS NOT A CONSTANT FROM MOTHER TO MOTHER, AND FROM TIME, SAMPLE TO SAMPLE. THE UNDERSTANDING IS STILL SOMETHING IN THE CLINICAL ENVIRONMENT NOT WELL APPRECIATED, THAT THE DISPARITY IN THE NOT JUST COMPOSITIONAL MAKEUP BUT IN PERFORMANCE OF THE FLUID IS NOT SOMETHING THAT TAKES TIME AND I KNOW THERE'S BEEN A LOT OF PEOPLE WHO EDUCATED THE FIELD TO DATE BUT I CAN TELL YOU THAT THE DEPTH AND DEGREE AND UNDERSTANDING THAT THE EXPERTS ON THIS PANEL HAVE SHOWN IS NOT REALLY TRANSLATED ACROSS THE CLINICAL ENVIRONMENT IN MANY WAYS. IT'S A MUCH MORE PRAGMATIC AND SIMPLISTIC VIEW OF HOW MILK OFFERS BENEFIT AND THAT INFANT FORMULA IS ABLE TO RECONSTITUTE SOME OF THESE BENEFITS BOTH NUTRITIONALLY AND FROM IMMUNE PERSPECTIVE. I'D SAY PARENTS PROBABLY SEE IT COMPLETELY EVEN AT DIFFERENT LEVEL. I THINK THAT'S THE SKEW THAT HAPPENS IN TERMS OF HOW TO DEAL WITH THE WHOLE CONCEPT OF ADVANCING INFANT FORMULA. SO IF WE WERE TO CREATE INFANT FORMULA NOW WE WOULD STILL START WITH NUTRITION AND SAYING LET'S COMPOSE THIS. I THINK PERSPECTIVE THAT'S UNIQUE WHEN WE LOOK AT COMPOSITION WHEN FORMULA IS MADE IT'S A FORMULATION OF VARIOUS COMPONENTS. THIS BECOMES IMPORTANT WHEN WE THINK ABOUT WHAT'S THE BACKGROUND MATRIX THAT'S THERE. WE KNOW THAT THE DIFFERENT MACRONUTRIENTS ARE BROUGHT TOGETHER FROM DIFFERENT SOURCES SO PREDOMINANTLY PLANT BASED SOURCES FOR THE FAT AND THEN THE BOVINE BASED SOURCES FOR THE PROTEIN. AS YOU'VE HEARD EARLIER, THAT, YOU KNOW, PROTEIN IS NOT JUST PROTEIN. THERE'S DIFFERENT COMPONENTS AND EVEN THE TREATMENT OF THE PROTEIN CAN ALTER ITS EFFECTS AND THEN CARBOHYDRATES WE DISCUSSED EXTENSIVELY MAKEUP CAN BE MORE COMPLEX THAN JUST LACTOSE. AND SO FROM CLINICAL PERSPECTIVE WE ARE REALLY LOOKING AT INFANT INFORMULA AS INFERIOR TO MOTHERS MILK AND KNOW THAT BECAUSE OF PERFORMANCE. PERFORMANCE THAT WE'RE LOOKING FOR, OUTCOMES THAT ARE EASY TO DIGEST FOR US, BABIES DIE, NOT JUST IN DEVELOPING COUNTRIES BUT IN FIRST WORLD COUNTRIES THAT WE SEE THE CHALLENGES OF MORTALITY IN THOSE BABIES THAT ARE FED INFANT FORMULA. THE WHOLE GAMUT OF OUTCOMES FROM INFECTION AND IMMUNE PERSPECTIVE THAT RELATE TO BOTH THE COMPOSITE OF ADDITIVE FACTORS IN HUMAN MILK THAT PROVIDE AND CONFER BENEFIT BUT ALSO POTENTIALLY NEGATIVE EFFECTS OF THOSE THINGS THAT ARE IN INFANT FORMULA, IN ITS CURRENT COMPOSITION, THAT MAY ALSO CAUSE HARM, IN THE PRE-TERM ARENA WITH MORE SENSITIZED HOST, THE INTACT BOVINE COMPONENTS OF FORMULAS WE HAVE AS WELL AS FORTIFIERS WE USE. SO THIS CONCEPT THAT INFANT FORMULA IS ADVANCING IN ORDER TO CLOSE THAT GAP AND ADDRESS THE MODEL OF NOT JUST NUTRITION, NOT JUST GROWTH AS THE OUTCOME MEASURE BUT REALLY TRYING ADD THESE ADDITIONAL FEATURES, I THINK ONE PARADIGM SHIFT IS TO NOT SEGREGATE NUTRITION AND BIOLOGIC ACTIVE FACTORS IN THE MILK BUT AS WE'VE HEARD ALREADY MANY OF THE NUTRITIONAL COMPONENTS ARE OF THEMSELVES BIOACTIVE. AND SO REALLY LOOKING AT THE ENTIRE MESH AS A BIOLOGIC SYSTEM, AS SHARON HAS SAID, AND IDENTIFYING THAT THE INTERACTIONS OCCUR ACROSS DOMAINS. NOT JUST WITHIN THE BIOLOGIC OR BIOACTIVE COMPARTMENT. I THINK THAT'S REALLY THE EVOLUTION THAT NEEDS TO HAPPEN FROM THE SCIENCE BUT ALSO FROM THE CLINICAL PERSPECTIVE, WE'RE TRYING TO EMBRACE ADVANCEMENTS IN FLUID THAT ACTUALLY IS, YES, MORE COMPLEX BUT IS ACTUALLY INTERACTING ON ALL DIFFERENT FRONTS, THERE MAY BE ARROWS CROSSING ACROSS THIS DIAGRAM FROM DIFFERENT BOXES. ONE ASPECT THAT WE AS CLINICIANS SEE AS BEING VERY CURRENT AND PROBABLY SIGNIFICANT IS SORT OF THE ADDITIONAL ORGAN OF THE MIKE ROW BIOME. THE MOST IMPORTANT BEING IN THE GUT. AND HOW THAT GUT MICROBIOME INFLUENCES SOME OF THE OUTCOMES THAT WE SEE WITH THE NORMAL HEALTHY HOST. SO, WE'VE HEARD ABOUT METABOLIC, NEUROLOGIC OUTCOMES, AND LONG TERM CARDIOVASCULAR HEALTH. WE KNOW THAT THE MODEL TO TEST BIOACTIVES AND LOOK AT THE INTERACTIONS AT LEAST AT THIS POINT NEEDS TO SEGREGATE THOSE COMPONENTS THAT REALLY HAVE A DIRECT ARROW TO THE HEALTHY GUT MICROBIOME, AND ONE OF THE CAVEATS WHICH EXTRACTED FROM MY READINGS AND CERTAINLY IN THIS SESSION IS CONCEPT THAT WE DON'T REALLY HAVE A STANDARD THAT SAYS THIS IS WHAT A NORMAL HEALTHY GUT MICROBIOME IS SUPPOSED TO LOOK LIKE. WE DON'T HAVE A STANDARD THAT THIS IS WHAT THE HEALTHY MILK MICROBIOME IS SUPPOSED TO LOOK LIKE. AS WE'VE HEARD ABOUT PRE-BIOTIC OR OLIGOSACCHARIDE ASPECT WE DON'T HAVE A COMPLETE SIGNATURE AS WELL THAT REFERENCES THAT SO THERE'S GREAT VARIABILITY IN TERMS OF WHAT IS NORMAL. SO I WONDER WHETHER THAT'S SOMETHING THAT WE HAVE TO PUT INTO THE MINDS OF WHEN WE'RE LOOKING AT WHAT IS STANDARD, MORE FOR THE SEER OUTLIERS IN THE SYSTEM AS OPPOSED TO SOMETHING THAT IS VERY SPECIFIC IN TERMS OF PROFILE. NEWER BIOACTIVES THAT COME INTO PLAY THEN HAVE A GAMUT OF POTENTIAL BENEFITS THAT ARE LISTED BELOW. AND WE NEED TO START TO DRAW SOME OF THOSE INTERACTIVE ARROWS WITH OTHER COMPONENTS IN THIS MODEL. ONE OF THE OBSERVATIONS I SEE WE HAVE A LOT OF CONTENT EXPERTS IN DIFFERENT COMPONENTS AND DIFFERENT FACTORS, AND I THINK A MODEL GOING FORWARD WHERE WE TRUST A GROUP OF PEOPLE CONTENT EXPERTS FOR EACH INDIVIDUAL COMPONENTS TO REALLY LIST THE BOUNDARIES UPON WHICH THEY THINK MINIMUM STANDARDS FOR CLEARANCE OF THESE COMPONENTS IN EVALUATING NEW ADDITIVES TO INFANT FORMULA SEEMS TO MAKE SENSE TO ME. I WANTED TO SAY WE SEE A LOT OF THINGS COME INTO THE CLINICAL ARENA THAT COME IN MANY DIFFERENT FRONTS, WHETHER DIETARY, SUBSTANCES, THINGS THAT COME IN TO THE PHARMACEUTICAL LEVEL. SO WE'RE PRETTY COMFORTABLE WITH THE FIRST SAFETY LEVELS TO SAY WHATEVER WE SEE IS PROBABLY CLEARED FOR SIMPLE PHYSICAL CHEMICAL PROPERTIES. AND THESE INCLUDE ACID BASED, OSMOLALITY, VISCOSITY, ET CETERA. WE HAVE HAD DIETARY PRODUCTS THAT HAVE COME IN THAT HAD VARYING NUANCES TO THESE, ONE IN PARTICULAR RECENTLY WITH A FORTIFIER WITH LOWER CLINICAL PH, NOT HAVE BEEN POSITIVE, HOW DOES THIS GET VETTED AND HOW MUCH OF THE SCIENCE DO WE KNOW, LIKE IN THIS CASE HOW MUCH ACID CAN PREMATURE BABY RECEIVED AND WHAT IS SORT OF THE MARGINS OF THE SAFETY AND WHAT ARE EFFECTS OF THAT ON THAT INFANT'S GUT AND WHAT DO WE UNDERSTAND ABOUT ACID LOAD, IN THE GUT. THAT'S ONE EXAMPLE. WE ALSO KNOW THAT WHEN WE'RE HAVING ADDITIVES THAT WE'RE MOTT JUST THINKING ABOUT CHEMICAL COMPOUNDS INTERACTING WITH OTHERS BUT ALSO LOOKING AT PROBIOTIC MIXTURES THAT ARE IN THE FORMULA BUT ALSO IN THE GUT OF THE HOST, AND I THINK THAT KNOWLEDGE TOO THERE ARE ACTIVE ENZYMES IN THE GUT THAT MAY ALSO BE INTERACTING IS IMPORTANT. THE PRODUCTS THAT WE SEE IN THE CLINICAL ENVIRONMENT, THIS IS WHERE THE REAL PRAGMATIC EXPERIENCE OCCURS, WE SEE PRODUCTS AND WE SEE PRODUCTS USED FROM A DIETARY POINT OF VIEW IN MAIN DIFFERENT WAYS, PROBABLY WAY OFF THE LABEL, WHETHER DILUTED OR CONCENTRATED OR MIXED AND INTERMIXED WITH EACH OTHER AND THAT REALLY ADDS TO SOME OF THE COMPLEXITY WHEN WE'RE TALKING ABOUT INTERACTIONS, IT'S NOT JUST WHAT ONE MAY PERCEIVE WITHIN THE INITIAL MIXTURE ITSELF OR THAT IT'S BEING MADE IN. AND I THINK I WANTED TO HIGHLIGHT ONE OTHER ASPECT, MY WITNESS TO HOW WE CAN GET THINGS WRONG IN TERMS OF THE MATRIX IS THIS APPROACH WHERE WE DEAL WITH AND JOE MENTIONED EARLIER ABOUT GASTROESOPHAGEAL REFLUX DISEASE. ONE OF THE TENTATIVE WAYS WE MANAGED IN SOME KIDS IS TO THICKEN THE FEEDS. MOST OF THESE ARE STARCH BASED, SOME GUM BASED THICKENERS HAVE COME ABOUT. AND WITH SOME LITERATURE THAT ACTUALLY SUPPORTED USE EVER GUM BASE AND STARCH BASE BECAUSE THEY MAY KEEP THE FEEDS DOWN. WE HAD SOME EVIDENCE SOME WITH UNTOWARD EFFECTS INCLUDING HOW IT EMPTIESES OUT OF THE STOMACH, ALTERS CALORIC DENSITY MAY ABSORB DIFFERENT MINERALS AND SO FORTH. EVEN COAGULATION IN THE GUM. XANTHAM GUM WAS A WAY TO THICKEN, IF WE ADDED A STARCH IT WOULD DIGEST QUICKLY AND WOULDN'T THICKEN HUMAN MILK. WE WENT THROUGH, IT SAME THROUGH PRACTICE, WE HAD A LOT OF PEOPLE USE THIS. SOME BABIES WERE ACTUALLY GETTING SEVERE CASES OF NECROTIZING ENTEROCOLITIS, IN SOME CASES DYING FROM THAT. WE FOUND THAT THIS DEGREE OF VISCOSITY CAN MAKE CHANGES IN THE GUT, AND THEY CAN LEAD TO POTENTIAL HARM. CHANGES INS ON NOTHING OSMOLOGY. WE SEE A LOT OF THINGS THAT CHANGE IN FORMULATION, IN POWDER AND LIQUID READY TO FEED, AND THOSE TWO MIXTURES MAY BE THE SAME PRODUCT HAVE VERY DIFFERENT CHEMISTRY IN ORDER TO MAKE THOSE DIFFERENT FORMATS. AND THEY MAY HAVE VERY DIFFERENT CONSEQUENCES DEPENDING ON DIFFERENT ADDITIVES THAT HAPPEN IN THE PRACTICAL ENVIRONMENT SO IT'S SOMETHING THAT ALSO NEEDS TO BE CONSIDERED WHEN WE'RE EVALUATING NEW ADDITIVES THAT COME INTO PLAY. WE TALKED ABOUT PRE-CLINICAL MODELS AND IMPORTANCE OF HAVING GOOD MODELS LIKE THE PIGLET TO HELP US UNDERSTAND EVIDENCE. BUT I DO THINK AS A CLINICIAN WE HAVE BEEN BURNED IN THE PAST WHERE SOME OF THE PRE-CLINICAL MODELS DON'T COMPLETELY REFLECT HUMAN EXPERIENCE. AND SO HAVING NOT JUST GROWTH INTOLERANCE AS OUTCOMES BUT LONG-TERM OUTCOMES WOULD BE VERY IMPORTANT. AS STATED BEFORE, TIMELINE TO GET THESE SIGNIFICANT TRIALS TO HAVE CLINICAL STUDIES EVEN IN A RANDOMIZED FASHION I THINK MAY BE PROHIBITIVE AND IS PROBABLY COUNTER TO WHAT WE WANT TO EXPERIENCE FROM CLINICAL PERSPECTIVE LARGELY BECAUSE WHAT WE'VE SEEN IN THE INFANT FORMULA ADVANCEMENT IS PROBABLY FASTER DEVELOPMENT IN SOME CASES TO REALLY TAKE ADVANTAGE OF EASIER PATHWAY, DRUG DEVELOPMENT PATHWAY, IN BRINGING IN ADVANCES IN INFANT FORMULA. SOMEONE MENTIONED ABOUT POST-MARKET DATA. I THINK STEVE MENTIONED THAT EARLIER. THAT THIS IS AN AREA THAT WE PROBABLY COULD DO A LOT BETTER IN, TRYING TO IDENTIFY WHEN CERTAIN AGENTS ARE BROUGHT IN HAVING DATA STRUCTURE THAT ACTUALLY IS ABLE TO CAPTURE A RICHER DEGREE OF REFLECTION OF THE PERFORMANCE OF THAT CHANGE IN A POPULATION. HOW MUCH CAN THE FDA SET THE STAGE FOR THAT. COMPARING BLOOD AGENTS, WHETHER DRUGS OR OTHER COMPOUNDS PUT IN, TO INTRAVENOUS PRODUCTS, WE HAVE EXPECTATIONS THEY PASS THE BASIC PHYSICAL CHEMICAL STRUCTURE, PASS PRE-CLINICAL AND CLINICAL STUDIES TO DEMONSTRATE ITS SAFE BUT WE'RE NOT LOOKING AND IDENTIFYING STUDIES THAT LOOK AT EVERY DIFFERENT INTERACTION BETWEEN THAT AGENT AND ALL ITS OTHER COMPONENTS WITHIN BLOOD TO GIVE KIND OF THE ANALOGY. WE EXPECT THAT SOME OF THE OUTCOMES THAT WE SEE ARE REALLY PERFORMANCE OUTCOMES OF WHAT HAPPENS TO THE HOST, WHAT'S THE PHYSIOLOGY OF THE HOST, IS THERE ORGAN DAMAGE THAT WE CAN MEASURE AS OPPOSED TO TRYING TO IDENTIFY EVERY PERMUTATION AND COMBINATION OVERALL. THAT'S THE BOUNDARY OF FOOD SUBSTANCE VERSUS INTRAVENOUS AND MORE RISK HERE IN TERMS OF INTERACTIONS IN THE CIRCULATING SYSTEM. THE CONCEPT OF WHAT THE MATRIX THAT WE'RE TRYING TO REFER TO, WE MAKE THE POINT THAT THE MATRIX SEEMS TO MATTER SIGNIFICANTLY, DEPENDING ON THE AGENT THAT YOU'RE LOOKING AT, IF YOU DILUTE SUBSTANCE MAY CHANGE THE WAY THE MATRIX FUNCTIONS,ER IS FORMANS OF INDIVIDUAL COMPONENTS IN THE MATRIX -- PERFORMANCE NEEDS TO BE TAKEN CARE OF AND HOW THE PRAGMATICS MIXTURES OF SOLUTIONS, OR ADDITIVES OR CONCENTRATIONS BEYOND LIMITS NEED TO BE TAKEN INTO FACTOR GIVEN THAT WE SEE THAT SCOPE OF PRACTICE IN REAL LIFE. AND SINCE DIETARY SORT OF CONTROLS LESS STRINGENT MAKES IT CHALLENGING. FROM A CLINICAL PERSPECTIVE WE EXPECT BASIC SAFETY AND EFFICACY TO BE PRESENT, SHORT AND LONG-TERM EFFECTS NEED TO BE CATALOGED TO SOME DEGREE AND THAT REALLY SAFETY FACTORS ARE AVOID SEVERE ADVERSE EFFECTS BUT DON'T WANT RESTRICTIONS TO BE SUCH THAT ADVANCEMENT CAN'T PROCEED BECAUSE OF EITHER COST BEING EXCESSIVE IVE OR REGULATORY ENVIRONMENT IS TOO STRANGENT. WE MAY GET FLOODED WITH ADDITIONS OF SIGNIFICANT NUMBER OF BIOACTIVES THAT MAY START TO HAVE UNTOWARD INTERACTIONS WITH ONE ANOTHER BUT ON THE OTHER HAND WE MAY REALLY STOP EVERYTHING COLD AND PROGRESS MAY ACTUALLY BE HALTED. AND I THINK THAT'S THE CHALLENGE. IN LISTENING TO EVERYONE'S DISCUSSION, HOW DO WE MANAGE THIS COMPLEX SYSTEM AND WHEN WE DON'T HAVE ALL THE ANSWERS, I THINK ABOUT HOW WE DEAL WITH THE SAME KIND OF BIOLOGIC PROBLEM IN THE CLINICAL ENVIRONMENT, WHEN WE DON'T HAVE ALL THE STUDIES TO SHOW WHAT'S THE BEST WAY TO MANAGE A PATIENT IN A DIFFERENT -- IN A SPECIFIC DOMAIN WHAT TREATMENT IS BEST, WE SEE PRACTICE VERY SIGNIFICANTLY IN THE ABSENCE OF EVIDENCE AND WHEN WE HAVE THAT VARIATION IN PRACTICE IN THE BEST WAY TO IMPROVE DELIVERLY IS STANDARDIZING APPROACH TO THAT AREA. I THINK IN A LOT OF WAYS WE'RE KIND OF BOOKMARKED BY THE ONE SIDE WHERE WE REALLY DON'T UNDERSTAND HUMAN MILK, DON'T UNDERSTAND HOW ALL THESE COMPONENTS INTERACT WITH ONE ANOTHER AND HOW THEY INFLUENCE BIOLOGY. BUT ON THE OTHER HAND WE NEED TO GET PROGRESS TO TAKE PLACE AND NEED TO MAKE A DECISION NOW AND ACT ON THINGS IN THE MOMENT. AND I THINK HAVING THE CONCEPT THAT THERE'S STILL SOMETHING WE CAN DO AND THAT SOMETHING RELATES TO COMING TOGETHER AND HAVING A PROCESS AND IDENTIFYING HOW WE CAN DEFINE SAFETY AND EFFICACY THAT IS SORT OF COLLECTED WISDOM AND STANDARDIZING THAT ACROSS THE SYSTEM BECAUSE AS A CLINICIAN AND I'D SAY AS A PARENT, YES, LANDSCAPE IS MESSY, YES SCIENCE IS MESSY, BUT IT'S EVEN MESSIER FROM A CONSUMER OR A PATIENT-FACING SIDE THAT THERE'S REALLY A CHALLENGE TO UNDERSTAND WHAT ARE WE SUPPOSED TO DO WITH ALL THESE PRODUCTS AND HOW NEW ADDITIVES CHANGE THE LANDSCAPE OF WHAT IS GOOD AND WHAT IS BAD. SO I THINK FRAMING THE INFANT FORMULA IS NO LONGER A NUTRITION PRODUCT AND IDENTIFYING IN A WAY TO APPLY RULES AND GUIDANCE THAT ALLOW US TO HAVE STANDARDIZED APPROACH TO REGULATION AND TO ALLOW FOR MORE PROGRESS I THANKS ARE THINK MAKES MORE SENSE THAN ALLOWING FOR THE CURRENT MODEL THAT'S PRESENT. COMMUNICATING THIS IN A WAY TO THE CLINICIAN AND TO THE PATIENTS IS REALLY IMPORTANT. I THINK THE FUTURE DOES NOT HAVE SCENARIO ANYTIME SOON THAT WE'RE GOING TO BE HAVING A LIFE WITHOUT INFANT FORMULA. I THINK WE DO SEE THE FUTURE MAY NOT BE THAT WE'RE STYMIED BYPRODUCTS BECAUSE OF COST AND ALL THESE ADDITIVES ARE JUST GOING TO LEAD TO A VERY EXPENSIVE PRODUCT BUT WE SOLVE TECHNOLOGY BY TAKING SOME LEAPS AND BOUNDS AND EXCITEMENT OF LOOKING AT ORGAN TECHNOLOGY,ING OR -- ORGANOID TECHNOLOGY MAY BE A WAY FORWARD. I'M SUMMARIZE, AS A CLINICIAN WE SEE AMAZING PROGRESS TO DATE IN INFANT FORMULA. WE SEE THERE'S A PARADIGM SHIFT THAT HAPPENED BUT STILL CONTINUES TO NEED TO HAPPEN IN ALL DOMAINS. AND THEN WE SEE A LOT OF EFFORT THAT NEEDS TO CONTINUE TO GO NOT JUST IN BIOACTIVE BUT ALSO TO FOCUS ON THE OLD NUTRITION COMPONENTS, IT'S HAPPENED HERE, SOME PROGRESS MENTIONED IN THE CONFERENCE SO FAR. AND REALLY TRYING TO SIMPLIFY THE APPROACH AND TAKING INTO ACCOUNT COLLECTIVE WISDOM AND LOOKING FOR WAYS TO STANDARDIZE THE APPROACH AS OVERALL SYSTEM AND COMMUNICATE THAT EFFECTIVELY TO ALL THE STAKEHOLDERS. I THINK WE CAN LEARN FROM ANIMAL MODELS BUT WE STILL ARE GOING TO REQUIRE HUMAN STUDIES TO MAKE GOOD. AND I THINK THE WAITING FOR EVERYTHING TO BE PERFECT AND TO SET THE STAGE HAVE ALWAYS SAID PERFECTION IS THE ENEMY OF GOOD AND I'LL FINISH WITH THE SAME THING THAT LARS SAID, KEEP KEEP THE MESSAGE SIMPLE, STILL A LOT TO LEARN IN OUR UNDERSTANDING OF THESE BIOACTIVES. THANK YOU. >> THAT WAS A WONDERFUL WAY TO WRAP UP OUR THREE SESSIONS. THERE WAS A LOT OF QUESTIONS THAT CAME IN SO I WILL KICK OFF THE QUESTION-AND-ANSWER SESSION BY ASKING A QUESTION TO DR. BODE. THE FIRST WAS REGARDING DSLMT AND NEC IS THIS MECHANISM KNOWN TO BE MICROBIOME INDEPENDENT? >> GREAT QUESTION. THE PREMISE WAS TO -- DO MICROBES ACTUALLY UTILIZE IT IF THAT'S THE CASE, DO WE WANT TO HAVE MICROBES THAT UTILIZE JUST ANY OLIGOSACCHARIDE BECAUSE THAT'S NOT WHAT WE SEE IN OUR STUDIES THAT THERE IS DIFFERENT OLIGOSACCHARIDE DOING THE SAME THING. STRUCTURE-SPECIFIC EFFECT, DROPPING IN A BOMB OF A PROBIOTIC THAT USES OLIGOSACCHARIDE INDISCRIMINATELY IS NOT WHAT WE WANT. NONETHELESS WE DO HAVE SOME EVIDENCE THERE IS A DIRECT EFFECT OF THE DSLNT ON THE HOST INDEPENDENT OF MICROBE AND WE'RE STILL AT AN EARLY STAGE OF TESTING IN ANIMAL MODEL BUT SEEMS TO BE NOT COMPLETELY DEPENDENT ON MICROBIAL DIGESTION. >> THIS QUESTION IS FROM THE E-MAIL FOR DR. DONOVAN. THE QUESTION IS ABOUT THE RANDOMIZATION OF LITTERMATES AS INDEPENDENT INDIVIDUALS. THE INDEPENDENT UNIT IS THE LITTER BECAUSE THE ENTIRE LITTER IS SUBJECTED TO THE SAME CONDITIONS DURING GESTATION. THEREFORE ISN'T TRULY STATISTICALLY INDEPENDENT AND CAN'T BE RANDOMIZED. CAN YOU ADDRESS THIS AND HOW TREATMENT OF LITTERMATES IS STATISTICALLY ACCURATE FOR PRE-CLINICAL SAFETY STUDIES? >> WELL, THAT'S A REALLY GOOD QUESTION. THE THANKS OF PIGLETS, WE CAN RANDOMIZE LITTERMATES ACROSS ALL TREATMENTS, THAT'S WHAT WE DO. THEY HAVE LARGE LITTERS. IT ALLOWS US TO CONTROL TO SOME DEGREE FOR THAT INTRAUTERINE ENVIRONMENT. ALSO IN OUR SETTING BASICALLY ALL OF THE SOWS ARE INSEMINATED WITH SEMEN FROM THE SAME BOAR, THE PIGLETS HAVE THE SAME DADDY, MANY ARE SISTERS, NOWHERE NEAR LIKE RODENTS IN TERMS OF BEING GENETICALLY SIMILAR BUT WE SEE THAT AS AN ADVANTAGE TO BE ABLE TO RANDOMIZE LITTERMATES AMONG DIETARY TREATMENT GROUPS. WE INCLUDE LITTER IN STATISTICAL MODEL. I CAN'T THINK MUCH A STUDY WHERE LITTER HAS COME OUT TO BE SIGNIFICANT. THERE MIGHT BE A DIFFERENCE IN HOW FIELDS APPROACH IT. IT'S HOW WE APPROACH IT EXPERIMENTALLY AND STATISTICALLY. >> THANK YOU. >> THIS NEXT QUESTION IS FOR DR. KIM. HOW CAN WE SUPPORT RESEARCHERS TO GET MORE INTERESTED IN HUMAN MILK AND INFANT FORMULA RESEARCH? WE THINK THERE'S MORE WE CAN -- AS FAR AS -- THIS IS FROM NIH PERSPECTIVE, WE CAN BE MORE INVOLVED WITH CLINICIAN RESEARCHERS AND THE MORE WE SPREAD INFORMATION WE CAN CONTINUE TO BUILD AND RECRUIT THE NEXT GENERATION IN THIS SPACE. >> I THINK THERE'S ALREADY BEEN A MOVEMENT TOWARDS IDENTIFYING THAT ONE, NUTRITION IS IMPORTANT, AND TWO, THAT HUMAN MILK NUTRITION IS IMPORTANT AND HUMAN MILK SCIENCE NEEDS TO BE RESOURCED BETTER FROM FEDERAL SOURCES SO I THINK THAT'S ONE THING THAT'S HAPPENING NOW. IT'S PROBABLY DECADES LATE BUT IT'S HAPPENING NOW. THE OTHER THING I THINK THAT COULD REALLY AID, SOMETHING THAT OTHER PLACES IN THE WORLD DO MORE, IS PARTNERSHIP WITH INDUSTRY AND TO TRY TO FOSTER THE GAMUT OF Ph.D. SCIENTISTS THAT COULD HELP SUPPORT THIS TYPE OF RESEARCH AND HAVING BOTH FEDERAL AND COMPANIES WORK TOGETHER TO FOSTER AREAS OF INTEREST LIKE THIS. >> IF I MAY ADD TO THAT, IT'S A GREAT QUESTION. WITH JAE, HAVING WORKED AT UCSD AS MY COLLEAGUE BEFORE HE MOVED ON, I THINK IT'S INTERESTING TO SEE THAT ON A DEPARTMENTAL LEVEL IT TOOK QUITE A WHILE TO GET HUMAN MILK RESEARCH AND INFANT FEEDING IN GENERAL ON THE AGENDA AND I WOULD REALLY BRING THIS BACK TO NIH AND NICHD AND COLLEAGUES ON THE CALL, DREW AND ASHLEY AND MANY OTHERS, PUTTING FUNDING MECHANISMS IN PLACE WHERE THERE IS A FOCUS ON HUMAN MILK HELPS THE CLINICAL RESEARCHERS AND RESEARCHERS IN GENERAL GO TO DEPARTMENTS AND SAY THERE IS INTEREST, THE NIH IS FUNDING THIS KIND OF STUFF. MONEY IS COMING ALONG, FUNDING COMING ALONG DEPARTMENT HEADS ARE MORE OPEN TO PUTTING MORE RESOURCES BEHIND THESE THINGS BECAUSE THEY UNDERSTAND THAT OTHERS SEE IT AS VALUABLE. SO REALLY SEEING THE MOVEMENT THERE FROM NICHD IN PARTICULAR TO MAKE THOSE FUNDING OPPORTUNITIES AVAILABLE SO WE CAN BRING IT TO DEPARTMENT HEADS AND SAY THERE'S SOME INTEREST IN HUMAN MILK RESEARCH HERE, THAT HELPS A GREAT DEAL AND THAT WILL AUTOMATICALLY SPUR MORE CLINICIAN RESEARCHERS ALSO TO JOIN THE TRAIN AND KEEP IT MOVING. >> THANK YOU BOTH FOR THAT FEEDBACK. I THINK THIS IS IT FOR OUR TIME FOR QUESTION AND ANSWER, UNFORTUNATELY. WE NEED TO MOVE ON. I'M GOING TO TRANSITION IT BACK TO DR. VARGAS FOR THE NEXT AGENDA ITEM. THANK YOU, PRESENTERS. >> I GET THE PLEASURE OF SAYING THE NEXT AGENDA ITEM IS LUNCH BUT BEFORE WE MOVE TO THAT, THANK YOU, ALL THE SPEAKERS, FOR SESSIONS 4 AND 5. WHAT WONDERFUL WALES TO CLOSE OUT THIS CONFERENCE. I REALLY AM CONSTANTLY IMPRESSED WITH THE RESEARCHERS IN THIS FIELD AND TODAY WAS ANOTHER DEMONSTRATION OF HOW THOUGHTFUL, WONDERFUL, AND COMPREHENSIVE YOU CAN BE. THANK YOU SO MUCH. WE WILL MOVE TO A 30-MINUTE LUNCH AND RETURN WITH QUESTIONS AND ANSWERS FOR EVERYBODY. THANK YOU. >> WELCOME BACK. WE'RE A LITTLE BEHIND SCHEDULE BUT WE BUILT IN PLENTY OF TIME TODAY FOR SOME Q&A AND DISCUSSION. WE'LL PLAY THIS BY EAR. IF WE NEED TO KEEP GOING AND TAKE A BREAK, WE WILL. IF IT SEEMS LIKE WE HAVE A LOT OF MOMENTUM AND CAN WORK THROUGH THE BREAK AND CLOSE UP EARLY, RECOGNIZING IT IS FRIDAY AFTERNOON, WE WILL DO THAT. IT WILL DEPEND HOW THE CONVERSATION GOES. FOR VIEWERS ONLINE, WE'VE TRIED TO SYNTHESIZE QUESTIONS THAT OVERLAP SO LISTEN FOR THOSE TODAY IN ADDITION TO QUESTIONS THAT OTHER SPEAKERS ASKED AND QUESTIONS WE FEDERAL STAFF OF OUR WONDERFUL SPEAKERS. WE'RE SCHEDULES FOR A BREAK AT 2:30, I MAY CALL AUDIBLES AS WE MOVE THROUGH THINGS. I WILL TURN IT OTHER TO DR. McKINNON AND DR. POTISCHMAN TO LEAD US THROUGH THE MODERATION IN THE FIRST PART AT LEAST. >> WE ALSO WANT TO THANK THE SPEAKERS FOR THEIR WONDERFUL PRESENTATIONS. WE LEARNED A LOT. I'M GOING TO JUST BE ASKING SOME QUESTIONS THAT CAME IN FROM E-MAIL AND WHAT NOT. BUT OTHERS IN THE GROUP WILL ASK MORE GLOBAL QUESTIONS. I'M FROM NIH, OFFICE OF DIETARY SUPPLEMENTS. I'LL PASS TO ROBIN. >> THANKS SO MUCH, NANCY. I'M ROBIN McKINNON, SENIOR ADVISER FOR NUTRITION POLICY OF CFSAN, AND DR. KOTARO FROM OFFICE OF FOOD SAFETY. I WANT TO ECHO AMAZE. AND THANKS TO THE SPEAKERS. WHAT AN EXTRAORDINARY JOB SYNTHESIZING THIS COMPLEX INFORMATION INTO SUCH A TIGHT PERIOD OF TIME, SO INCREDIBLY HELPFUL. AND SO AS NANCY MENTIONED, AS ASHLEY MENTIONED AS WELL, WE'LL JUST KIND OF PLAYTHINGS A LITTLE BIT BY EAR, FOLLOW WHERE THE ENERGY FLOWS AND THERE'S SO MANY WONDERFUL QUESTIONS, BY E-MAIL, SOME BY SPEAKERS, ADDITIONAL QUESTIONS POPPED UP. WE'LL SEE WHERE THE DISCUSSION TAKES US. AND IF WE NEED TO TAKE BREAKS AT DIFFERENT POINTS, WE'LL CERTAINLY DO THAT, AND IT'S POSSIBLE WE MAY COMBINE THE LAST SESSION AND WE'LL JUST SEE. KOTARO, INTRODUCE YOURSELF. AND NANCY HAS A QUESTION AS WELL. GO AHEAD, KOTARO. >> YES, HI. I'M KOTARO KANEKO, TOXICOLOGY REVIEWER FOR THE OFFICE OF FOOD SAFETY AT CFSAN. LET ME THANK FROM THE BOTTOM OF MY HEART ALL OF THE PARTICIPANTS AND VIEWERS, AN INCREDIBLE WORKSHOP. WE LEARNED A LOT. THIS IS A WONDERFUL START TO A LOT OF GREAT CONVERSATIONS IN THE NEAR FUTURE. BEFORE I GET TO THE FIRST SET OF QUESTIONS, I DO WANT TO KIND OF SET THIS UP BY SAYING THAT, YOU KNOW, IN ONE HAND WE COULD SAY HUMAN MILK IS COMPLICATED. THAT'S ONE VIEW. THE OTHER SIDE OF THE VIEW MIGHT BE THAT IF IT'S IN HUMAN MILK, IT'S ALL SAFE, WHO CARES. REALITY IN THE MIDDLE. AS JAE STATED IN THE LAST SESSION WE CAN'T JUST DO NOTHING BECAUSE WE DON'T UNDERSTAND EVERYTHING. IS THERE A WAY TO TAKE THE BIOACTIVES AND APPLY KNOWLEDGE IN HUMAN MILK AND HOW WE MIGHT THINK IN TERMS OF HOW WE MIGHT GET SAFETY AND WE DON'T WANT TO PUT UP ROAD BLOCKS FOR THE SAKE OF ROAD BLOCKS. LET ME LEAD WITH A QUESTION, TO START THIS OFF. WHAT CONSIDERATIONS SHOULD BE INVOLVED IN DECIDING WHAT AN ANTICIPATED EFFECT WHICH MAY BE BENEFICIAL UNDER CERTAIN CONDITIONS INDICATES THE NEED FOR FURTHER UNDERSTANDING OF INFORMATION SUCH AS MODE OF ACTION, EXPOSURE, RESPONSE RELATIONSHIP, ADME PROFILE OR FATE OF THE SUBSTANCE TO PROVIDE SUFFICIENT ASSURANCE OF THE REASONABLE CERTAINTY OF NO HARM FOR INFANTS WHO CONSUME THE ADDED INGREDIENT UNDER THE RANGE OF CONDITIONS OF USE RELATED TO INFANT FORMULA. SO, IT'S A VERY COMPLICATED QUESTION BUT BASICALLY WHAT WE'RE POSING IS WE KNOW A LOT OF BIOACTIVES HAVE ALL SORTS OF DIFFERENT FUNCTIONALITY, WE KNOW ABOUT SOME BIOACTIVE, A LOT LESS ABOUT OTHERS. CAN WE PUT THEM IN DIFFERENT BUCKETS, WELL, THESE SET OF BIOACTIVES IN THIS BUCKET WE KNOW ENOUGH ABOUT IT, SO WE DON'T NEED TO KNOW MORE, THERE MAY BE OTHER BIOACTIVES IN ANOTHER BUCKET BECAUSE THE WAY THE HYPOTHESIZED FUNCTION MIGHT BE WE MAY NEED TO KNOW ADDITIONAL INFORMATION. THAT'S THE WAY TO SIMPLIFY COMPLICATED, YOU KNOW, FORMULATION, HUMAN MILK, CAN WE THINK ABOUT THESE CATEGORIZATIONS? THIS COULD BE ANSWERED BY ANYONE BUT I'LL POSE TO DAVE DALLAS, LARS OR SHARON OR ANYONE ELSE STEP UP AND START THE DISCUSSION GOING. >> CAN YOU HEAR ME? >> YES. >> OKAY. ONE THOUGHT FROM KOTARO'S QUESTION, I TALKED ABOUT THE NEED FOR DIGESTIVE ANALYSIS, AND I THINK THAT COULD BE AN EXAMPLE OF SOMETHING WHERE THAT KIND OF NEED MAY NOT APPLY EQUALLY TO ALL DIFFERENT CLASSES OF NUTRIENTS. FOR EXAMPLE, FOR THE MOST PART, MILK OLIGOSACCHARIDES ARE NOT DEGRADED BY AT LEAST HUMAN-PRODUCED GLYCOSYLIDASES BY GAS, MORE BY BACTERIA, THE THE QUESTION OF DIGESTIBILITY IS NOT RELEVANT FOR OLIGOSACCHARIDES WHEREAS FOR PROTEINS IT'S REALLY RELEVANT. AND I DON'T KNOW ABOUT OTHER CLASSES, MAYBE COMPLEX TRIGLYCERIDES, FOR EXAMPLE, MIGHT NEED TO BE EVALUATED FOR DIGESTIVE OR IF WE GET INTO THE FUTURE OF THINGS LIKE EXOSOMES, MAYBE SIMPLER LIPIDS, MAYBE NOT AS MUCH. THAT'S ONE THOUGHT. >> THIS IS SHARON. I GUESS THINKING ABOUT THIS, YOU KNOW, OBVIOUSLY I'M A REGULATORY SCIENTIST, I THINK IT'S A QUESTION OF SAFETY VERSUS A QUESTION OF EFFICACY. AND A LOT OF -- WHAT I TALKED ABOUT WAS MORE EFFICACY BUT WE DO A NUMBER OF SAFETY STUDIES, AND GRANTED BEFORE THE INGREDIENT GETS TO US, THE PIGLET, THOUGH GO THROUGH BASIC TOXICOLOGY, YOU KNOW, OTHER THINGS BUT WE'VE DONE A NUMBER OF STUDIES FEED THE INGREDIENT, DO THE STANDARD SAFETY PARAMETERS, THE THING WE'VE BEEN SCREENING FOR SAFETY I CAN'T THINK OF ANYTHING THAT MAY HAVE SCREENED THAT HAS SUPPRESSED GROWTH OR, YOU KNOW, LED TO SOME STRANGE VALUE. AND OFTENTIMES WE DO STUDIES, AND WE BASICALLY SAY, OH, WE DIDN'T SEE ANY EFFECTS ON THE IMMUNE SYSTEM. SOMETIMES PEOPLE ARE DISAPPOINTED BY THAT BUT LOOKING THE OTHER WAY, FOR TARGET AS A HEALTHY HUMAN INFANT, I WOULD BE MORE WORRIED IF WE'RE SKEWING IMMUNE SYSTEM ONE WAY OR THE OTHER TOO MUCH. OUR WAY FOR SAFETY, THE STANDARD MEASUREMENT YOU MIGHT DO. WE'VE NEVER SEEN INGREDIENTS, AGAIN, AT THE LEVELS WE SCREEN BECAUSE THEY ARE TARGETED TO FORMULA, NOT FEEDING PHARMACOLOGICAL DOSE, SUGGESTING THAT MOST INGREDIENTS ARE IN GENERAL SAFE BUT WE HAVE TO DO DUE DILIGENCE. GETTING TO EFFICACY, THAT'S A DIFFERENT QUESTION. IT BRINGS IN ALL OF THE TOPICS THAT WE TALKED ABOUT, FIRST OF ALL, THERE'S SOME GAP WE'RE TRYING TO CLOSE BETWEEN OPTIMIZED DEVELOPMENT VERSUS SOMETHING WE MIGHT BE SEEING , IS IT WORTH IT IN TERMS OF COST, EQUITY, THERE'S ALSO WHEN WE -- MANY STUDIES WE DO FOR SPONSORS ARE FROM A PRAGMATIC PERSPECTIVE. SO IF THEY ARE LOOKING TO ADD A NOVEL INGREDIENT WE'LL FORMULATE THE BASE FORMULA AS WELL AS THE ONE THAT GETS THE NOVEL INGREDIENT, WITH THE COMPONENTS THAT ARE ALREADY IN THE FORMULA. I THINK THAT'S A MUCH BETTER APPROACH THAN JUST USING A BASIC FORMULA. FOR EXAMPLE, IF THEY HAVE NUCLEOTIDES, IF THEY HAVE A PRE-OR PROBIOTIC, ADDING THE NOVEL INGREDIENT IN THE MATRIX OF THE PRODUCT OF THE PRODUCT MAKES IT MORE TRANSLATABLE THAN DONE IN A REPLACEMENT FORMULA WITHOUT THE BELLS AND WHISTLES. WE HAVE TO PROVE SAFETY. I THINK THERE'S WAYS TO DO THAT. BUT I DO THINK WE HAVE TO ALSO HAVE STUDIES WHERE WE'RE LOOKING AT THESE FUNCTIONS, THAT'S WHERE WE MAY BE ABLE TO PICK UP, WE DIDN'T THINK IT WOULD AFFECT COGNITIVE DEVELOPMENT SIMILAR TO HUMAN DEVELOPMENT SO WE HAVE TO -- I HAVE TO AGREE WITH DAVID IN TERMS OF WE CAN -- BASED ON THE INGREDIENT, HOW IT'S UTILIZED IN THE BODY, WE CAN BE MUCH MORE DIRECTED IN TYPES OF ASSESSMENTS. >> I WOULD JUST, I AGREE WITH YOU, SHARON. HISTORICALLY, WHEN I FIRST STARTED WORKING WITH FORMULA COMPANIES, THEY WERE INTERESTED IN MEASURING GROWTH FOR FOUR WEEKS, (INDISCERNIBLE), I A CONVERSATION I WAS TOLD YOU INCREASED COST OF RESEARCH BUDGET WHEN I INSISTED FOLLOWING INSTANTS TO 12 MONTHS OF AGE SO I THINK GROWTH HAS BEEN AND STILL REMAINS THE PRIMARY SAFETY OUTCOME THAT IS LOOKED AT BY THE FORMULA COMPANIES. THAT'S NOT TO SAY WE CAN'T IMPROVE. IT GOT MORE COMPLICATED WHEN WE STARTED TO REALIZE THE AMOUNT OF PROTEIN THAT WAS PUT INTO INFANT FORMULA WAS ACTUALLY MAKING QUITE DIFFERENTLY, THAT GOT COMPLICATED, GIVING A HISTORICAL PERSPECTIVE ON THIS. >> LARS, DID YOU WANT TO ADD TO THIS? >> YEAH, A COUPLE THINGS REALLY. FIRST THING BASED ON KOTARO'S QUESTION CAN WE SEPARATE SAFETY AND EFFICACY, HOW MUCH DO WE NEED TO KNOW ABOUT DIGESTION, ABSORPTION, ADME IN GENERAL, MECHANISM OF ACTION, JUST LOOKING AT SAFETY BUT NOT LOOKING AT EFFICACY. IS IT REALLY THIS BLACK AND WHITE THING, IF YOU LOOK AT SAFETY YOU DON'T LOOK AT EFFICACY AND THE OTHER WAY AROUND. IF YOU SAY IT'S ONLY SAFE FIT DOESN'T -- IF IT DOESN'T DO ANYTHING WHY ADD IT? LOOKING AT THE ABSENCE OF EFFECTS AND ANY MECHANISM ON ANYTHING, AND CALL THAT SAFETY, IT RAISES THE QUESTION, WELL, WHY ADD IT IN THE FIRST PLACE? THAT'S SOMETHING THAT WE ALWAYS PUSH ASIDE BECAUSE WE'RE ASSESSING SAFETY BUT NOT EFFICACY. >> I'LL JUST ADD FUNCTION IS KIND OF A KEY STARTING POINT TO BE LOOK AC THE BOTH -- AS A SOURCE OF POTENTIAL BENEFIT AND POTENTIAL SAFETY. >> I WOULD SAY THE MORE WE KNOW ABOUT THE MECHANISM, THE BETTER WE CAN ADDRESS SAFETY AND BETTER WE CAN ADDRESS EFFICACY. THAT'S BOTTOM LINE. YES, THE MORE WE KNOW ABOUT THE VERY BASICS OF DIGESTION, ABSORPTION, PK, ADME, ALL THOSE DIFFERENT THINGS, WONDERFUL. THE REASON WE DON'T NEED TO CONSIDER DIGESTIBILITY FOR OLIGOSACCHARIDE IS SOMEONE DID THE WORK. AS WE INTRODUCE INDIVIDUAL OLIGOSACCHARIDES, THERE'S OTHER THINGS THAT WE NEED TO TAKE INTO CONSIDERATION, EITHER OLIGOSACCHARIDES THEMSELVES OR METABOLIC PRODUCTS AFTER DEGRADATION FROM BACTERIA, THAT PRODUCTS DON'T HAVE ADVERSE EFFECTS ON LIVER METABOLISM, IT'S MORE COMPLICATION THAN SAYING THEY DON'T HAVE AN EFFECT BECAUSE WE DON'T KNOW, WE HAVEN'T STUDIED. IT'S IMPORTANT TO HAVE IMPORTANT TO HAVE MECHANISTIC INSIGHTS AS WELL. >> GREAT, THANK YOU. >> ONE THING THAT WOULD BE HELPFUL SEEING HOW QUICKLY THIS SCIENCE MOVES IN EACH OF THE DIFFERENT DOMAINS IS FOR RESPONSIVENESS OF THE SYSTEM TO REACT SO THAT WHEN NEW CHANGES, NEW DISCOVERIES HAPPEN THERE'S ABILITY TO PLUG IN WHETHER SAFETY OR FUNCTION OR EFFICACY MEASURES TO BE PLACED IN THAT, YOU KNOW, ONE OF THE CHALLENGES THAT I SEE IS THAT THINGS MOVE SLOWLY, SO WE MAY HAVE A BETTER UNDERSTANDING AND THEN RULES DON'T CHANGE. AND THAT LAG TIME CAN BE FRUSTRATING ON BOTH SIDES, WHETHER IT'S THE CLINICAL OR INDUSTRY SIDE. >> SUSAN, IN YOUR ORIGINAL STUDIES LOOKING AT DHA WITHOUT ARA OR RATIOS, YOU SAW GROWTH, POINTING OUT THE IDEA THE INTERRELATIONSHIP OF BIOACTIVES MIGHT AFFECT EVEN FUNDAMENTAL THINGS LIKE GROWTH, ANY THOUGHTS ON THAT? >> WE PUBLISHED STUDIES IN PRE-TERM INFANTS, FIRST WAS DHA SOURCE MORE LIKE TRADITIONAL FISH OILS WITH RATHER HIGH EPA CONTENT. AND WE DID THINK WE HAD SOME REDUCTION IN GROWTH. AND THEN AGAIN WE USED A LOW EPA TUNA EYE SOCKET OIL WHICH WAS -- REALLY DID NOT HAVE THE SAME EFFECT BUT THE SLIDE I SHOWED THIS MORNING ON THE RELATIONSHIP BETWEEN ARACHIDONIC ACID CONCENTRATION AND GROWTH, ONE THING THAT DOES REDUCE ARACHIDONIC ACID HOW MUCH DHA THEY RECEIVED. SUBSEQUENTLY WERE AN OUTLIER, PEOPLE DIDN'T FIND ANY EFFECT ON GROWTH AND IN THE MEANTIME A SOURCE OF ARACHIDONIC ACID BECAME AVAILABLE AND EVERYONE STARTING USING ARACHIDONIC ACID SO I DON'T THINK MORE STUDIES WERE DONE BUT THERE WAS A META-ANALYSIS OF THE GROWTH IN VARIOUS PRE-TERM STUDIES AND WHAT CAME OUT OF THE THAT WAS THAT PROBABLY DOESN'T AFFECT GROWTH. IT WAS CONDUCTED BY I THINK THE GIBSON GROUP. >> THAT'S ALL FINE BUT NONETHELESS THE IDEA THERE CAN BE RELATIONSHIPS AMONGST THESE THAT COULD AFFECT SOME FUNDAMENTAL PARAMETERS IS STILL VALID. >> I AGREE WITH YOU AND I ALSO FEEL THAT WE ACTUALLY -- WE SAW LEGITIMATE REDUCTION IN LINEAR GROWTH AND I DO THINK IT WAS BECAUSE THERE WAS NO ARACHIDONIC ACID IN THE EARLY STUDIES. I DON'T DISCOUNT WHAT YOU'RE SAYING. >> I WANT TO SEE IF ANYBODY WANTS TO JUMP IN. >> MAYBE NANCY. WE COULD TURN TO YOU. YOU HAD ANOTHER QUESTION THAT CAME FROM E-MAIL. >> YES, I DID, BUT IT'S BEEN LARGELY ADDRESSED BY NOW. THERE WAS A QUESTION, LAST TWO TALKS, AFFECTING HMO PROFILES AND GLYCOSYLATION OF PROTEINS. AND THUS THEIR DIGESTION. JUST IGNORE IT. IT'S SPAM. SHOULD WE BE THINKING ABOUT MORE ABOUT SECRETORY STATUS BEYOND HMOS FOR MANY BIOACTIVES WE'LL BE CONSIDERING? >> I'LL TAKE THAT ONE, A QUESTION MEGAN RAISED DISCUSSING THIS TEXT IN THE MEANTIME AS WELL. SO, IT'S THE ALPHA-1- 2, N-GLYCANS, GLYCOLIPIDS, WHATEVER IT IS. HOWEVER, DIGESTIBILITY, CLEAVING, IS MAINLY INTERNAL FUCOSE, CORE FUCOSE CLOSER TO THE PROTEIN, CLOSER TO THE LIPID, NOT SURE HOW MUCH D IGESTABILITY IS AFFECTED. >> AND JUST TO JUMP IN ON THAT, I THINK IN GENERAL STUDIES DO SUGGEST THAT HAVING A DEGREE OF GLYCOSYLATION ON A PROTEIN MAY DECREASE ITS DIGESTABILITY, BUT I DON'T THINK THE SCIENCE IS VERY CLEAR YET. THERE'S MORE THAT NEEDS TO BE DONE THERE. >> YEAH, I THINK I'D LIKE TO PIPE IN ON THIS. WE'VE ACTUALLY STUDIED PROTEIN GLYCOSYLATION QUITE A BIT, PUBLISHED SEVERAL PAPERS ON IT. AND WE DIDN'T SEE ANY VARIATIONS IN PROTEINS WITH REGARD TO SECRETOR STATUS. I DON'T THINK THAT'S AN ISSUE WITH PROTEIN. THE BIGGER ISSUE WITH PROTEINS IS THE FACT THAT THEY BE ADDED NOW AND GLYCOSYLATION IS DIFFERENT FOR THESE PRODUCTS BEING PRODUCED. BOVINE LACTOFERRIN, THE CONCENTRATION IS HIGH MANNOSE GLYCAN, WHEREAS ON HUMAN LACTOFERRIN IT'S FULL OF SIALIC ACID AND FUCOSYLATION. THINK ABOUT HUMAN MILK LACTOFERRIN BEING EXPRESSED IN RICE, FOR EXAMPLE, THAT GLYCOSYLATION IS TOTALLY DIFFERENT. AND THE SAME WAY BEING EXPRESSED IN E. COLI FOR EXAMPLE. AND IN FACT PROTEIN GLYCOSYLATION IS A BIG ISSUE IN THE ANTIBODY DRUGS. THEY HAVE EXPRESSED ANTIBODIES WITH PROTEINS THAT CAUSED VERY BAD REACTION. WE SHOULD LOOK UP THE STORY OF THE LONE STAR TICK AND HOW THAT WAS DISCOVERED BECAUSE OF ANTI-CANCER DRUGS BEING EXPRESSED WITH THE WRONG GLYCOSYLATION. >> THANKS SO MUCH. DR. JEREMIAH FASANO MAY JUMP IN. I MODERATED AN EARLY SESSION AND WANTED TO FOLLOW UP ON SOMETHING HERE. IN THE SPIRIT OF IMPROV, GOING WITH THE FLOW, I THINK JEREMIAH MAY JOIN THE MODERATING GROUP FOR THIS LAST SESSION AS WELL. >> YEAH, THANK YOU, ROBIN. I JUST WANTED TO FOLLOW UP ON A COUPLE OF INTERESTING POINTS I HEARD ALREADY IN THIS Q&A SESSION. ONE POINT THAT I HEARD, AND LARS TOUCHED ON THIS, THIS IDEA THAT -- IT'S SOMETHING WE HAVE STRUGGLED WITH, THAT ON ONE HAND, YOU KNOW, SUBSTANCE MAY NOT EXHIBIT ANY PARTICULAR EFFECT, THUS NO SAFETY CONCERN. ON THE OTHER HAND CLEARLY IT'S INTENDED TO EXHIBIT SOME SORT OF EFFECT BECAUSE THAT'S PART OF THE INTEREST IN USING IT. AND SO TRYING TO KIND OF SQUARE THAT CIRCLE AND THINK ABOUT, YOU KNOW, FUNCTION AS A POINT OF DEPARTURE FOR SAFETY STUDIES AND FOR, YOU KNOW, EFFICACY STUDIES, I WANTED TO POSE THIS TO PARTICIPANTS, I FEEL LIKE ONE THEME I'VE HEARD IS THIS IDEA THAT THERE IS A LOT OF HOMEOSTATIC CONTROL IN INFANT DEVELOPMENT WITH RESPECT TO THESE BIOACTIVE MILK CONSTITUENTS, MAYBE PRESENCE OR ABSENCE IS IMPORTANT BUT THERE REALLY ISN'T WITHIN CERTAIN RANGES, THERE ISN'T MEANINGFUL SIGNIFICANCE TO A PARTICULAR LEVEL OR AMOUNT OF PARTICULAR SUBSTANCE. IS THAT SORT OF THE SENSE OF FOLKS IN THIS GROUP THAT THERE IS THIS LIKE FAIRLY STRONG HOMEOSTATIC CONTROL THAT MEANS ACTUAL LEVELS IN THE FORMULA WOULDN'T MATTER AND IF SO IS THERE SOME GOOD PLACES TO LOOK IN THE LITERATURE FOR BEING A BASIS FOR THIS? >> I HATE TO ANSWER WITH THE WORD "DEPENDS." WE THINK THE DOSE MATTERS, WE'VE IDENTIFIED THRESHOLDS IN MULTIPLE STUDIES CONSISTENT IN DIFFERENT CONTINENTS, THAT ONCE AGAIN IS THE STORY ABOUT DSN AND DENECROTIZING COLITIS, THERE IS A LEVEL OF 250-MICROGRAM PER ML THAT IF YOU'RE BELOW THAT THRESHOLD YOU'RE AT HIGHER RISK TO DEVELOP NEC, SEEN IN NORTH AMERICA COHORT THAT JAE WAS PART OF, IN THE U.K. COHORT AND IN SOUTH AFRICAN COHORT AS WELL THAT WE'VE DONE. SO THREE DIFFERENT COHORTS BUT VERY DIFFERENT -- SIMILAR THRESHOLD LEVELS IF YOU'RE LOW YOU'RE HIGHER RISK, ABOVE YOU'RE FINE. I WOULD ASSUME THAT APPLIES NOW IF I WANT TO ADD SPECIFIC COMPONENT TO HUMAN MILK. DOES THAT RELATE TO SAFETY? IF WE ADDED LOWER ENOUGH LEVEL WE'LL BE FINE, WE DON'T WORRY ABOUT IT, WELL, GREAT, BUT THEN WE ALSO DON'T HAVE ANY EFFECT. I'M ABSOLUTELY FOR, YOU KNOW, THIS DOSE-RESPONSE THAT DOSE DOES MATTER IN MANY CASES AND NOT JUST DOSE OF ONE COMPONENT BUT WE'VE SEEN THIS IN THE LAST SESSION, DOSE OF MULTIPLE DIFFERENT COMPONENTS AND RATIOS THEREOF IS INDEED IMPORTANT IN MANY CASES. IT'S NOT THAT SIMPLE EDIT AND HOW MUCH YOU ADD DOESN'T MATTER. I DON'T THINK THAT'S THE RIGHT ANSWER. >> I AGREE WITH LARS AND THINK WE SHOULD THINK ABOUT DOSE ESCALATION TYPE EXPERIMENTS FOR A LOT OF THESE THINGS WHERE WE START WITH THE LOW DOSE AND THEN WE KEEP INCREASING THE DOSE UNTIL WE SEE THE FUNCTION THAT WE WANT TO SEE. AND THEN WE COULD POTENTIALLY STOP THERE, WHERE, YOU KNOW, WE HAVE A HIGH ENOUGH DOSE TO FIND FUNCTION BUT WE'RE NOT SEEING ANY SORT OF ADVERSE EVENTS. THAT MIGHT BE A PRACTICAL STRATEGY FOR LOOKING AT THESE THINGS. >> THE PROBLEM OF COURSE IS THAT YOU DON'T KNOW WHAT TO MEASURE. SO IF YOU'RE PUTTING IN OLIGOSACCHARIDES, YOU KNOW, WHAT DO YOU MEASURE? SO, THE THING IS IT'S ALL JUST SAFETY BASED AT THE MOMENT. GET GRAS, AND THAT'S THE BEST YOU CAN DO. FINDING THE RIGHT CONCENTRATION IS GOING TO BE THE ISSUE BUT ON THE OTHER HAND I THINK IT'S JUST MAINLY SAFETY BECAUSE THE EFFICACY IS JUST SO HARD TO MEASURE. >> A CLARIFYING POINT, PART OF THE THING THAT WE STRUGGLE WITH THINKING ABOUT IS WELL-DESIGNED SAFETY STUDY SHOULD BE INFORMED BY THE PROPERTIES OF THE MATERIAL YOU'RE EVALUATING. SO, YOU KNOW, IN THAT SENSE FUNCTION CAN BE A POINT OF DEPARTURE, BOTH FOR SAFETY STUDIES AND FOR EFFICACY STUDIES. THAT, YOU KNOW, IS, AGAIN, SORT OF THE CHALLENGE OF ATTEMPTING TO THINK ABOUT MECHANISMS OF ACTION OR MODES OF ACTION AND HOW TO, YOU KNOW, UNLOCK THE BENEFITS BY, YOU KNOW, BUILDING THE SAFETY CASE. >> GO AHEAD. >> IT'S A NATURALLY OCCURRING COMPOUND LIKE HMO, THE BEST DIET IS TO SEE WHAT NATURE PRODUCES. WE'RE USING IT BECAUSE NATURE SUGGESTS IT'S THE BEST THING. OF COURSE IT'S A VARYING THING, BUT I THINK WITHIN THOSE PARAMETERS IT'S NOT -- IT'S PRETTY SAFE AND PRETTY GOOD. OTHERWISE WE WOULDN'T BE IN THOSE PARAMETERS. I THINK PERHAPS THERE'S A LITTLE BIT TOO MUCH ON -- YOU KNOW, WHETHER IT'S 10% OR 12%, I THINK. NATURE HAS GIVEN US WHAT THE BOUNDARY CONDITIONS ARE AND WITHIN THAT BOUNDARY CONDITION IT'S PROBABLY PRETTY GOOD. >> YEAH, BUT I WOULD ARGUE THERE THAT NATURE ISN'T ONE SIZE FITS ALL. WE SEE THIS IN STUDIES THE HUMAN MILK COMMUNITY IS DOING, YOU SEE ASSOCIATION WITH HIGHER RISK OF ASTHMA, ALLERGY, OBESITY, YOU GO THROUGH THE LIST, AND OLIGOSACCHARIDES IS ONE EXAMPLE, ARE THERE LEVELS TOO HIGH OR TOO LOW, POSSIBLE. AS LONG AS WE HAVE SAFETY ON VERY LOW LEVELS IT'S FINE BUT THAT DEFEATS THE PURPOSE. IF WE GET SAFETY APPROVAL AT .OF 2 GRAMS BUT IT DOESN'T DO ANYTHING WHAT'S THE OPPONENT. >> THE OTHER NUANCE, YES, THIS IS THE LEVEL WE SEE IN HUMAN MILK AND THIS IS THE DATA THAT SHOWS EFFICACY AND SAFETY AND WHAT EFFECT IT HAS ON THE HOST. THIS IS IN A NEW MATRIX IN INFANT FORMULA. EVERYTHING CHANGES. I WOULD WANT THERE TO BE SOME REASSURANCE THAT LEVEL, WITH THAT MATRIX IS ACHIEVING EITHER STRUCTURAL FUNCTION, PROPERTIES WE CAN MEASURE IN THE DISH AS WELL AS LOOKING FOR OUTCOMES THAT ARE CLINICALLY RELEVANT THAT CORRELATE THAT, YES, IN FACT THAT LEVEL IS GOOD IN NEW MATRIX. >> AM I WRONG ASSUMING WE'RE NOT CONSIDERING GOING TO PUT INGREDIENTS IN, I THINK THAT QUITE OFTEN COMES FROM PRE-CLINICAL STUDIES, THAT SHOW THAT MORE OF A CERTAIN COMPONENT THAT IS NATURALLY VARIABLE MIGHT BE BETTER OR ISN'T PRESENT IN INFANT FORMULA AT ALL. WE DON'T WANT TO DO STUDIES THAT ARE NO EFFECT EXPECTED, OTHER THAN WE'RE JUST PUTTING SOMETHING IN THERE, AND I GET THE SENSE FROM CONVERSATIONS BEFORE THIS MEETING MAYBE SOME FORMULA COMPANIES ARE DOING THAT OR ATTEMPTING TO DO THAT? THERE'S NOT A LOT OF FUNCTIONAL EVIDENCE THAT WHAT THEY ARE PUTTING IN IS IMPORTANT? I'M SORRY, I'VE BEEN DOING PREGNANCY STUDIES FOR THE LAST 20 YEARS SO I'M OUT OF THE INFANT FORMULA ARENA. BEFORE WHEN WE DID THOSE STUDIES WE HAD A PLAUSIBLE REASON TO CHANGE A COMPONENT AND TEST WHETHER THAT WAS FUNCTIONALLY IMPORTANT OR NOT. IS THAT NOT WHAT'S HAPPENING NOW? >> . >> LET ME CHIME IN. IN GENERAL WHAT WE'RE SEEING IS -- THIS IS SOMETHING STEVE ALLUDED TO IN THE FIRST DAY, YOU KNOW, IN SOME CASES, I WOULDN'T SAY ALL, THE IMPETUS TOWARDS PROPOSING COMES DOWN TO WHETHER WE -- THE ASSUMPTION WE WANT TO MAKE IN PERFORMING A CLOSE IN TERMS OF COMPOSITION TO HUMAN MILK AND SO THERE ARE A NUMBER OF BIOACTIVES THAT AT LEAST ARE THOUGHT UPON NOT NECESSARILY AS THE FUNCTIONAL FIRST, WHAT DOES IT DO, PER SE, BUT RATHER IT'S IN HUMAN MILK AND WE SHOULD MAKE IT LOOK LIKE HUMAN MILK AND THEREFORE THIS IS CONSTITUENT THAT PERHAPS COULD BE INFANT FORMULA, AGAIN, I THINK THE OVERALL GOAL OF COURSE I WOULD SUSPECT IS TO HAVE SOME KIND OF FUNCTIONAL OR BENEFICIAL EFFECT, PUTTING SOMETHING IN INFANT FORMULA BECAUSE WHAT'S THE POINT OF ADDING IF IT DOESN'T HAVE AN IMPACT? I DO ALSO THINK BECAUSE THERE'S A RELATIVELY LACK OF INFORMATION ON THE PHYSIOLOGIC EFFECTS OR FUNCTIONALITY OF PARTICULARLY BIOACTIVE INGREDIENT I THINK THAT THAT ASPECT IS NOT -- I DON'T WANT TO SAY SAY IGNORED BUT NOT THE FOREFRONT IN TERMS OF WHAT'S DRIVING WHY SOME OF THESE THINGS SHOULD BE ADDED. >> MAYBE TIMES HAVE CHANGED, I DON'T KNOW. >> YEAH, OR LET ME -- SOUNDS LIKE CARLITA WAS GOING TO JUMP IN. SHARON ALSO. >> I GUESS A COUPLE THOUGHTS I HAVE. WE NEED TO UNDERSTAND MORE ABOUT HUMAN MILK, TO INFORM TARGETS. WELL, FOR EXAMPLE WITHIN THE BEGIN PROJECT, TRYING TO ADDRESS HOW DO WE STUDY HUMAN MILK AS A COMPLEX BIOLOGICAL MATRIX. MEGAN AND OTHERS HAVE SHOWN IN SYSTEMS BIOLOGY, SOME COMPONENT ARE STABLE BUT OTHERS ARE VARIABLE AND YOU CAN SUES THAT VARIATION TO RELATE TO INFANT OUTCOMES BECAUSE I GO BACK TO WHAT LARS HAS SAID, EVEN WITHIN JUST THE HMO, WE KNOW THAT FOR SOME OUTCOMES IT'S NOT A SINGLE HMO, IT'S THE RATIOS OF HMOs OR COMBINATIONS, AND SAME THING COULD BE COMBINATIONS. TO HELP US BETTER UNDERSTAND HUMAN MILK AS A COMPLEX BIOLOGICAL MATRIX SHOULD INFORM HOW WE CAN MAKE HUMAN MILK MORE SIMILAR, FORMULA MORE SIMILAR THAN HUMAN MILK. WE SHOULD FOCUS ON FUNCTIONALITY AND OUTCOME RATHER THAN COMPOSITION AND TO ME WE'RE RUNNING INTO THE PROBLEM, THIS ISSUE OF TAKE JUST 2FL, ADDING THEM AND IT IS A MATRIX, BEING UNOPPOSED IN THE MATRIX OF HUMAN MILK IS WHERE WE MIGHT WORRY ABOUT, YOU KNOW, OFF-TARGET TYPES OF THINGS. SO I CAN -- SO MANY COMPANIES ARE ADDING COMBINATIONS OF THESE, SEEING THE COGNITIVE STUDY YESTERDAY, OH MY GOD, THEY ADDED 8 OR 9 INGREDIENTS AND, YOU KNOW, IT MADE ME NERVOUS TO SEE THAT. I'M JUST SAYING THAT ONE OF THE QUESTIONS IN THE CHAT IN TERMS OF IF WE'RE SEEING DIFFERENT HEALTH OUTCOMES, SUGGESTING SOMETHING IS MISSING FROM INFANT FORMULAS, IT COULD BE MISSING OR IT'S PRESENT IN -- PRESENT IN INFANT FORMULA, NOT IN HUMAN MILK, NOT JUST THAT FORMULAS ARE MISSING SOME MAGIC INGREDIENT BUT THINKING YESTERDAY ABOUT THE TALK, LOOK AT IMMUNOGLOBULINS, HMOs, HUMAN MILK IS A BROAD SPECTRUM, ANTIBIOTIC IS BROAD SPECTRUM, PROBIOTIC, BUT IT'S NOT JUST ONE OF THOSE INGREDIENTS SO I THINK WHAT I'M TRYING TO GET BACK TO, WE NEED TO UNDERSTAND MORE ABOUT HUMAN MILK, MACHINE LEARNING JOE BROUGHT UP YET THAT HOPEFULLY WILL GET US TO BETTER UNDERSTAND HOW WE CAN GET OUTCOMES AND MODIFY FORMULAS TO MINE THE GAP. SORRY FOR RAMBLING. >> WE DID HAVE QUESTIONS ABOUT COMPUTER MODELING AND HOW IT CAN BE USED TO HELP. YOU'RE AHEAD OF THE CURVE. >> WITH NEURODEVELOPMENTAL OUTCOMES WE HAVE TO REMEMBER THERE'S A BROADER ECOSYSTEM HERE BEYOND JUST THE FLUID, BIOLOGICAL FLUID. THERE ARE ALSO -- [ AUDIO DISTORTION ] BETWEEN PARENT AND INFANT THAT MAY DIFFER BETWEEN BREASTFED AND FORMULA INFANTS, JUST TO SAY THAT ALL OF THE DIFFERENCES WE SEE BETWEEN HUMAN MILK FED AND FORMULA FED ARE NOT NECESSARILY TRACEABLE TO A COMPONENT OR MIXTURE OF COMPONENTS IN THE MILK ITSELF BUT RATHER THERE ARE MANY FACTORS THAT DRIVE NEURODEVELOPMENT, IMMUNE HEALTH, G.I. HEALTH, ET CETERA. >> I'LL MAKE A POINT ABOUT INFORMATICS, DATA SCIENCE, WE'RE ALL LEANING ON DATA SCIENCE AND MANAGEMENT OF LARGE SYSTEM PROCESSES TO HANDLE COMPLEX SITUATIONS LIKE THIS. IT WOULD BE FAVORABLE TO HAVE STRUCTURE THAT IS CREATED THAT ADDRESSES SORT OF HOW TO APPROACH THE MODEL AS PEOPLE ADD NEW THINGS THAT THERE'S GOING TO BE CERTAIN LEVELS OF BIG DATA ANALYSIS TO CROSS-CHECK INTERACTIONS, CROSS-CHECK WITH ALL EXISTING KNOWN DATA. THAT WOULD BE REASSURING TO ME FROM A CLINICAL PERSPECTIVE THAT THAT'S GOING ON. IT MAY NOT BE PERFECT AND THINGS WILL STILL LEAK THROUGH THAT, BUT AT LEAST IT'S THE BEST WE CAN DO WITH CURRENT KNOWLEDGE. >> I WOULD ALMOST ARGUE TO SEPARATE THE HUMAN MILK DISCUSSION, AND WHILE WE'RE TRYING TO UNDERSTAND ALL THE BENEFITS OF HUMAN MILK AND THIS THIS WORKS AS A BIOLOGICAL SYSTEM, CRITICAL TO UNDERSTAND, IT'S NOT GOING TO HAPPEN TOMORROW. AT THE SAME TIME THERE IS INGREDIENTS ON THE LIST NOW THAT NIGHT TO BE APPROVED OR WANT TO BE APPROVED YESTERDAY, IDEALLY. THERE'S A TIME DISCONNECT HERE AS WELL. THE QUESTION IS HOW DO WE REALLY APPROACH THAT. HOW CAN WE COME UP WITH SOLUTIONS TODAY THAT WILL HELP THE REGULATORY PROCESS TO GET NEW INGREDIENTS INTO PRODUCTS AND BUILD ALL THAT -- CONTINUE TO BUILD THAT KNOWLEDGE AROUND HUMAN MILK AS A BIOLOGICAL SYSTEM AND HOW INDIVIDUAL COMPONENTS INTERACT AND HOW THIS ALL WORKS IN THE ENTIRE TRIAD ENVIRONMENT. AT THE SAME TIME, I WOULD ARGUE ONCE AGAIN NOT TO SEPARATE SAFETY AND BENEFIT OR EFFICACY TOO MUCH BECAUSE YOU CAN DO A LOT OF SAFETY STUDIES AND MIGHT MISS SOMETHING. THERE MIGHT BE RISK IF YOU DIDN'T THINK THAT SOMETHING IS LAPPING -- HAPPENING LATER DOWN THE LINE. WHY ADD THAT INGREDIENT IF THAT CAN'T CLEARLY SHOW THERE'S A BENEFIT TO ACTUALLY ADD IT? IF I DON'T SHOW THAT AS BENEFIT WHY GO THROUGH HASSLE AND THROUGH SAFETY EVALUATION? AND TAKE MINIMAL RISK IT MIGHT HAVE A NEGATIVE EFFECT IN THE END. I SEE THIS SIDE BY SIDE. IF YOU CAN SHOW STRONG DATA THERE'S A POTENTIAL BENEFIT OF ADDING THIS COMPONENT TO INFANT FORMULA, THEN THAT'S GREAT. THEN WE'LL EVALUATE IF THAT'S SAFE. IF THERE'S NO DATA ON EFFICACY, WHY ADD IT AND WHY TAKE THAT RESIDUAL RISK THAT THE INGREDIENT MIGHT DO SOMETHING DISADVANTAGEOUS. >> I THINK THAT'S THE TRADITIONAL WAY PEOPLE LOOK, INFANT FORMULA COMPANIES LOOKED, AND THE WAY REGULATORY LOOKED AT THIS. IF YOU'RE GOING TO PUT SOMETHING IN YOU HAVE TO JUSTIFY IN SOME WAY. IF IT'S NOT BEING JUSTIFIED, THEN IT'S INCOMPREHENSIBLE YOU CAN ADD SIX INGREDIENTS AND NOT HAVE A SINGLE REASON OR PIECE OF EVIDENCE WHY THAT DID ANYTHING. THAT'S JUST MARKETING TO ME. I THINK THAT'S PROBABLY WHAT YOU'RE DEALING WITH AT THE FDA. PUT SOMETHING NEW IN HERE AND WE CAN MAKE A NEW CLAIM. IT COMES TO DR. KIM'S LAST SLIDE WHICH I THINK IS REALLY SEARED IN MY MIND RIGHT NOW. WE'RE MAKING LOTS OF DIFFICULT CHOICES FOR PEOPLE FOR MAYBE NO REASON IN SOME CASES. >> I'LL NOTE WE HAD SOME QUESTIONS COME IN VIA E-MAIL BEFORE THAT WOULD KIND OF SYNTHESIZE AND COULD BEAR ON THIS PARTICULAR POINT THAT PEOPLE WHO SAID THAT THEY APPRECIATE THE DISCUSSION ON FUNCTION, BUT HOPED THERE WOULD BE MORE OF A SAFETY ASSESSMENT DISCUSSION, AS THE TITLE OF THE WORKSHOP IMPLIED. FUNCTIONAL MODE OF ACTION, OPPORTUNITIES TO CAPTURE BENEFIT BUT HOW CAN WE ENSURE THAT ASPECT OF THAT FUNCTIONALITY DOESN'T LEAD TO ADVERSE EVENTS IN SOME INDIVIDUALS THAT WOULD KEEP THE INGREDIENT OUT OF THE FOOD SUPPLY? AND THEN GETS TO THE MECHANISMS, FUNCTION OF BIOACTIVE MOLECULES FOR YEARS TO TIME. ARE THERE MODES OF ACTION WE CAN BE CERTAIN WILL NOT LEAD TO ADVERSE EVENTS AND -- I'LL JUST LEAVE THAT THERE. DOES THAT RAISE ANY ADDITIONAL TOPICS FOR DISCUSSION? OR THAT PEOPLE WOULD LIKE TO OPINE ON? >> YOU CAN'T PUT IN RANDOM COMPOUNDS. THE SLIDE, IT LOOKS LIKE STARTING TO PUT IN FIBER, YOU DON'T HAVE ADULT MICROBIOME TO DIGEST THE FIBER. SO THAT WOULD, TO ME, BE EXTREMELY DANGEROUS TO START DOING THAT. CERTAINLY YEAH SAFETY IS NUMBER ONE. EFFICACY HERE TOO IS QUESTIONABLE. HOWEVER, IF YOU'RE PUTTING IN THAN THE MAIN PRODUCT THAT'S BEEN -- FOR MOTHERS, YOU KNOW, IF SOMETHING INTERFERES WITH THAT, YOU TAKE THAT THING OUT THAT INTERFERES WITH IT BECAUSE CLEARLY YOU WANT MOTHERS'S MILK IN THERE. SO I WOULD WORK ON IT BACKWARDS. I WOULD GIVE PRIORITY TO THE COMPOUNDS THAT ARE FOUND IN MOTHERS'S MILK AS OPPOSED TO THOSE THAT, YOU KNOW, MAY REACT WITH IT OR WHATEVER. >> TO HOP ONTO YOUR POINT, CARLITO, I THINK THAT, YOU KNOW, FOR THINGS THAT ARE LIKE PROTEINS, MAYBE RECOMBINANT PROTEINS THAT ARE THE SAME AS THOSE FOUND IN HUMAN MILK YOU MADE THE POINT THEY COULD HAVE DIFFERENT GLYCOSYLATION BASED ON THE MODEL THEY ARE SYNTHESIZED IN. THEN I THINK WHEN THEY ARE ASKING ABOUT, YOU KNOW, SAFETY CONCERNS THAT DOES -- THAT IS IMPORTANT SO PERHAPS LIKE CLINICIANS LIKE JAE MIGHT BE ABLE TO TALK ABOUT WHAT SAFETY END POINTS YOU WOULD BE LOOKING FOR. OF THE. >> ONE THING THAT I GATHERED FROM ALL THE CONTENT EXPERTS, PROBABLY IF THEY HAD MORE TIME THEY COULD DEFINE THE SORT OF SAFETY TEST POINTS THAT WAS IN THEIR DOMAIN, AND IN ORDER TO -- IF YOU'RE A PROTEIN OR LIPID PERSON, WHATEVER, SAID THIS IS MINIMUM REQUIREMENTS FOR ESTABLISHING, YOU KNOW, A SAFETY LEVEL BASED ON PHYSICAL CHEMICAL NATURE OF THAT PARTICULAR AGENT. TO ME THAT COULD BE DONE PRETTY QUICKLY WITH A GROUP OF EXPERTS LIKE THIS. SO BITS AND PIECES ABOUT WHAT WAS CONSIDERED SAFETY WHEN YOU THINK ABOUT WHAT WOULD I WANT TO KNOW ABOUT PROTEIN, I LIKED YOUR TALKED, DAVID, ON THAT. YEAH, I REALLY THINK THERE ARE PROBABLY EXTRACTIBLE NUMBER OF THINGS AND IF THAT WAS TRANSPARENT TO US AS A CLINICIAN THAT ALL THESE SAFETY CHECKS WERE DONE INDIVIDUAL COMPONENTS BY EXPERTS AND THEN INTERACTION AS ANOTHER THING. SOMETIMES THERE'S AN AGENT THAT'S PUT IN TO LARS' POINT, COMPANIES ARE COMING OUT PUTTING SOMETHING IN, THE DATA SAYS THERE'S SOME BENEFIT. BENEFIT MAY BE AN ANTIBODY GOES UP OR LESS RUNNY NOSE IN SOME NUMBER OF KIDS, IS THAT -- HOW SIGNIFICANT IS THAT? THAT NEEDS TO BE DEFINED BETTER, WHAT DO WE THINK IS THE MINIMUM CLINICAL EFFECT BECAUSE IT CAN'T BE ANYTHING. IT REALLY NEEDS TO BE MUCH MORE STRUCTURED TO SAY THIS IS WHERE WE THINK THE FUNCTION IS GOOD ENOUGH, AND THEN ALSO TALK ABOUT SAFETY. BUT I THINK IT'S NOT JUST THE LOWEST BAR OF ANY SIGNAL THAT MAY BE CLINICALLY RELEVANT AND OFF THEY GO TO THE RACES. >> FOCUSING BACK ON THE IDEA OF POST-MARKETING SURVEILLANCE, THE FDA AND COMPANIES THAT MARKET THAT, IF YOU LOOK AT JAE'S EXAMPLE, THAT WASN'T PICKED UP IN THE INITIAL PRE-CLINICAL STUDIES. YOU THINK ABOUT THE USE OF DIFFERENT AGENTS TO PROMOTE (INDISCERNIBLE) NECROTIZING ENTEROCOLITIS WASN'T PICKED UP PRE-CLINICALLY, IT GOT PICKED UP IN THE ICU, MUCH OF THE PICKUP CAME BECAUSE A COUPLE PEOPLE NOTICES THE PROBLEM. ORGANIZED APPROACH TO SAYING IF WE PUT OUT THIS FORMULA WITH THIS BIOACTIVE, ARE WE SEEING MORE DIARRHEA, WHAT IS THE RESPONSIBILITY OF THE COMPANY TO PROVIDE THAT INFORMATION, LET INDEPENDENT PEOPLE SEE IF THERE'S A SAFETY SIGNAL. >> I LIKE THAT, STEVE. WE KNOW SAFETY REQUIRES A LARGER N THAN EFFICACY, TO THAT POINT THAT POST-MARKET STRUCTURE WOULD BE FANTASTIC. >> ROBIN, I WANTED TO HOP IN AND FOLLOW UP ON SOMETHING THAT LARS MENTIONED A FEW CONVERSATIONS BACK. I THINK THIS TOUCHES ON THE QUESTION I ASKED EARLIER, THIS IDEA OF, YOU KNOW, LOOKING AT INFANT FORMULA ON ONE HAND AND UNDERSTANDING THE BIOLOGY OF HUMAN MILK ON THE OTHER, AND I THINK THERE IS SOMETHING TO THAT IN THE SENSE THAT FOR SOMETHING TO ENTER THE FOOD SUPPLIES AS A FOOD INGREDIENT IT NEEDS TO MEET STANDARD OF THE SAFETY BECAUSE IT CAN BE IN FOOD AND CAPTURE BENEFITS. THAT DOES PRESENT US WITH A CHALLENGE OF SHARON SAID YOU'RE ADDING SOMETHING TO INFANT FORMULA IN ISOLATION, NOT IN THE FULL CONTEXT OR MATRIX. ALSO THE STANDARD FOR A FOOD INGREDIENT IS DIFFERENT STANDARD THAN FOR SOMETHING THAT OCCURS NATURALLY IN A FOOD. SO THIS RAISES AN INTERESTING POINT, A NUMBER OF FOLKS HAVE BEEN TALKING ABOUT THE UTILITY OR VALUE OF SOMETHING BEING PRESENT IN HUMAN MILK AS FAR AS INFORMING FOOD INGREDIENTS, SAFETY ASSESSMENT, I WANT TO POINT OUT FOR THOSE THOSE ARE DIFFERENT THINGS AND PART OF THE CHALLENGE GOING FROM THE LIQUID TISSUE OR COMPLEX BIOLOGICAL FLUID AND TAKING ISOLATED COMPONENTS FROM THAT AND TRYING TO SORT OF UNDERSTAND WHAT THE POTENTIAL IMPACT WOULD BE, BRINGS US BACK TO THAT NEXUS OF, YOU KNOW, FUNCTION FROM WHICH YOU CAN DERIVE QUESTIONS ABOUT SAFETY AS WELL AS YOUR ANTICIPATED BENEFIT. SO I DO THINK THAT IS A CHALLENGE AND REALLY ONE OF THE REASONS I HAD RAISED THIS QUESTION ABOUT HOMEOSTASIS, IS IT POTENTIALLY THIS IDEA THAT -- THIS IS SOMETHING LARS HAD MENTIONED ABOUT A LEVEL YOU NEED TO GET THE EFFECT, ABOVE THAT YOU'RE FINE, IS THAT A GENERAL PARADIGM WE CAN LOOK INTO LITERATURE TO SEE EVIDENCE WITHIN PARTICULAR LEVELS IT'S BIMODAL OR BINARY, OR WE HAVE TO THINK HARDER ABOUT DISTRIBUTIONS OF DIFFERENT LEVELS IN DIFFERENT MOTHERS AND WHAT IMPLICATIONS THAT MIGHT HAVE FOR THINKING ABOUT THE SAFETY ASSESSMENT. I'M NOT SURE IF THERE'S ANYTHING ACTIONABLE FOR THE FOLKS ON THE CALL BUT I WANTED TO POINT THAT OUT AS AN IMPORTANT PIECE. >> JEREMIAH, ONE THING -- WHAT YOU SAID MADE ME THINK OF, YOU KNOW, YES YOU NEED TO GIVE ENOUGH DOSE TO SEE A FUNCTION, BUT IT MAY BE THE CASE THAT YOU GIVE TOO HIGH OF A DOSE IT COULD BE PROBLEMATIC. LIKE I THINK WITH PROTEINS PEOPLE TEND TO DEVELOP ALLERGIC REACTIONS ARE MOST ABUNDANT, MOST COMMONLY ENCOUNTERED IN FOOD SOURCES. KIRSTI MAY BE ABLE TO TALK ABOUT YOU BUT YOU WANT TO AVOID EXCESSIVELY HIGH LEVELS OF PROTEINS FOR THAT REASON. >> THANK YOU. THAT'S A CONSIDERATION. THE OTHER PIECE, THE REASON I ASKED ABOUT THE DOSE-RESPONSE BEFORE WAS IS THERE -- COULD THERE BE MULTIPLE OUTCOMES OR CONSEQUENCES RELATED TO THE FUNCTION OF INTEREST AND NOT JUST A PURE ALLERGIC RESPONSE? THAT WOULD BE SOMETHING INTERESTING TO EVIDENCE IF THERE'S EVIDENCE TO SHOW THERE ARE INNATE HOMEOSTATIC MECHANISMS IN A PROTEIN SIGNAL TANS DEDUCTION BASED RESPONSE THERE ARE GUARD RAILS SUCH THAT EXPOSURE LEVEL WOULDN'T BE MEANINGFUL FOR SAFETY ASSESSMENT. >> I DON'T KNOW. I'M NOT AN IMMUNOLOGIST. VERY HIGH LEVELS MIGHT SHIFT THE BALANCE OF THE IMMUNE RESPONSE IN A WAY THAT MIGHT NOT BE BENEFICIAL AND NOT FROM AN ALLERGY PERSPECTIVE BUT FROM INTERACTIONS OF CERTAIN PROTEINS, CERTAIN KINDS OF IMMUNE CELLS. >> YOU HAVE TO CONSIDER IN THIS RESPECT WHETHER YOU'RE TALKING ABOUT A FOREIGN ANTIGEN, FOREIGN PROTEIN TO HUMANS OR SOMETHING THAT IS ACTUALLY ENDOGENOUSLY IN HUMAN MILK. YOU WOULD NOT NECESSARILY -- OR IT WOULD NOT BE LIKELY AT ALL TO REACT TO SOMETHING THAT IS ENDOGENOUSLY IN HUMAN MILK ALTHOUGH THERE ARE EXCEPTIONS TO THAT. THEY ARE EXTREMELY RARE. OBVIOUSLY ADDING PRO PROTEINS NOT ENDOGENOUSLY IN HUMAN MILK, SMALL OR LARGE AMOUNTS, YOU WOULD HAVE CONCERN FOR IMMUNOREACTIVITY OR ALLERGIC REACTIONS AND IT MAY NOT HAVE TO DO SO MUCH WITH THE LEVEL OF THOSE PROTEINS BUT A KEY ASPECT IS THAT WE HAVE ALL BECOME TOLERANT TO ENDOGENOUS HUMAN PROTEINS SUCH AS CASEINS OR PROTEINS THAT ARE FOUND IN HUMAN MILK, HUMAN CASEIN FOR EXAMPLE OR SOME OTHER PROTEINS LACTOFERRIN FOR EXAMPLE. WHEREAS ACTING PEANUT OBVIOUSLY YOU MIGHT BE REACTIVE TO THAT IS NOT NECESSARILY FOUND IN EVERY MOM'S MILK DEPENDING ON THEIR DIET, SO YOU HAVE TO CAR THE FOREIGNNESS OF THE PROTEIN IN THIS RESPECT AND THE OTHER EXAMPLE LARS BROUGHT UP YESTERDAY ADDING A PLANT-BASED OLIGOSACCHARIDE IN BREAST MILK AND HAVING ELICITED ALLERGIC REACTIONS. >> WHAT DO YOU THINK ABOUT A GLYCOPROTEIN HAS DIFFERENT GLYCOSYLATION BUT THE SAME SEQUENCE AS A HUMAN MILK PROTEIN IN TERMS OF ALLERGIC DEVELOPMENT PRO TENSION? >> THERE'S PROBABLY SOME LEVEL OF RISK THERE. BUT PROBABLY WE'RE NOT TALKING ABOUT THE SAME LEVEL OF RISK AS INTRODUCING A COMPLETELY FOREIGN PROTEIN THAT HAS NOT GONE UNDER TOLERANCE DEVELOPMENT AND, YOU KNOW, IS DEVELOPMENT OBVIOUSLY IN EARLY LIFE IN MOST CASES WHEN YOU BECOME TOLERANT TO YOUR OWN PROTEINS. >> THERE WAS A QUESTION FROM MANNEDRY IS WILL WELCOME OF ALLERGY WHEN FROM BOVINE? >> YES, THERE IS. IN FACT THIS IS THE EXAMPLE THAT I ALLUDED TO WITH RARE EXCEPTIONS. YOU COULD DEVELOP RESPONSES. WE KNOW, HAVE PUBLISHED A PAPER SELF YEARS AGO, MILK ALLERGIC INFANTS, IN SOME RARE CASES CHILDREN WHO HAVE REACTIVE PROTEINS, LACTIC OR ALLERGIC REACTION, THEY HAVE ACTUALLY AT LEAST THROUGH IgE RECOGNITION OF THE COUNTERPART HIGHLY HOMOLOGOUS HUMAN MILK PROTEINS SUCH AS CASE OF ALPHALACBUTIN. IF THAT MAKES SENSE. IT'S NOT THE PROTEIN THAT THE ANTIBODY IS RECOGNIZING AS A WHOLE SEQUENCE. IT'S GOING TO BE RECOGNIZING ONLY THE EPITOPES WHICH ARE 10, 15, 20 AMINO ACIDS IN LENGTH, IF THOSE PROTEIN OR THOSE EPITOPES ARE SHARED OR SIMILAR ENOUGH BETWEEN HUMAN PROTEINS AND BOVINE PROTEINS THAT'S WHEN REACTIVITY PROBLEM MAY BECOME AN ISSUE. >> I DO JUST WANT TO INTERJECT TO SAY THAT IN THEORY WE WERE SUPPOSED TO TAKE A BREAK BUT WE'RE IN A GOOD FLOW WITH DISCUSSION. ASHLEY OR DREW, I DON'T KNOW IF WE CAN MAKE A GAME DAY DECISION TO KEEP GOING OR WHAT ARE YOUR THOUGHTS? >> YEAH, I THINK WE SHOULD KEEP GOING. THERE'S BEEN WONDERFUL DIALOGUE WITH EVERYONE. WE WILL END EARLY BECAUSE OF THAT. SO THANK YOU, EVERYONE. >> THIS IS FANTASTIC. THANK YOU. >> IF THERE ARE SPECIFIC QUESTIONS, ASHLEY OR DREW OR ANYBODY ELSE, FEEL FREE TO EITHER TYPE THEM INTO THE CHAT OR POSE THEM RIGHT NOW. OR AS THE MOMENT ARISES. >> ROBIN CAN I CHIME IN FOR A SECOND? I JUST WANTED TO JUST FOLLOW UP ON SOME OF THE THINGS THAT KIRSI BROUGHT UP AND THINS I'M AN AMATEUR IMMUNOLOGIST, SO I WAS THINKING WHEN I THINK OF IMMUNE SYSTEM, THE PROCESS OF HOMEOSTASIS IS KIND OF IMPORTANT IN THE SENSE THAT IMMUNE SYSTEM SHOULD BE ABLE TO RESPOND AGGRESSIVELY TO FOREIGN PATHOGENS BUT ONCE REMOVED IN THEORY ANYWAY IMMUNE SYSTEM SHOULD BE ABLE TO RESET ITSELF TO WHATEVER LEVEL IT'S SUPPOSED TO. AND SO, YOU KNOW, PUT THAT IN A CONTEXT OF THE DEVELOPING IMMUNE SYSTEM IN INFANTS, WHERE A LOT OF STUFF HAS TO HAPPEN FOR THAT IMMUNE SYSTEM TO PROPERLY DEVELOP DURING ITS EARLY AGES. I WAS WONDERING WHAT ARE SOME OF THE REALLY GOOD BIOMARKERS TO MAKE SURE THAT NOT ONLY DO INFANTS MOUNT AGGRESSIVE IMMUNE RESPONSE TO PATHOGENS BUT A BIOMARKER EFFECT THAT SHOWS THAT THESE INFANTS EVEN THOUGH THEY ARE CHALLENGED CAN RESET THEIR IMMUNE SYSTEM DOWN TO THE LEVEL THEY ARE SUPPOSED TO AND I'M THINKING IN TERMS OF SAY A BIOACTIVE SUBSTANCE, IMMUNE MODULATOR, TESTING FOR FUNCTIONALITIES OR, YOU KNOW, THINKING OF WHAT THE POTENTIAL IMPACT MIGHT BE ON THE IMMUNE SYSTEM ARE THERE GOOD SET OF BIOMARKERS THAT WE COULD USE TO ENSURE THAT WE'RE NOT SCREWING UP SOMETHING THAT, YOU KNOW, SHOULD BE A NORMAL PART OF THE DEVELOPMENT FOR THE INFANT? >> I ACTUALLY INCLUDE IT IN MY PRESENTATION, THE LAST SLIDES, A LIST OF THE CLINICAL BIOMARKERS OR OUTCOMES THAT I WOULD MAKE AS A PRIORITY WHEN LOOKING AT SAFETY FROM CLINICAL PERSPECTIVE AS WELL AS A LIST OF SOME BASIC -- RELATIVELY BASIC IMMUNE ASSESSMENTS, T- AND B-CELL NUMBERS, T REGULATORY CELL NUMBERS, MONOCYTE NUMBERS, MAYBE LYMPHOCYTE RESPONSES, AND IMMUNOGLOBULIN LEVELS AS WELL AS SOME ANTIBODY ASSESSMENTS. THESE ARE TYPICALLY USED IN, YOU KNOW, WHEN ASSESSING, FOR EXAMPLE, FOR IMMUNE DEFICIENCY BUT THEY CAN BE ANALOGOUS TO THIS SITUATION. OBVIOUSLY AGAIN YOU MIGHT HAVE SOME RARE OFF-TARGET RESPONSES BY SOME BIOACTIVES THAT YOU WOULD HAVE TO BE ON THE LOOKOUT BUT THAT WOULD BE A TOO EXPANSIVE LIST TO BE DONE BY ANY CLINICAL TRIAL SO YOU WOULD PROBABLY WANT TO HAVE A CERTAIN SET OF MARKERS THAT YOU WANT TO LOOK AT IN ALL STUDIES, AND THEN BASED ON THE BIOACTIVE IN QUESTION, AND THINKING ABOUT THIS, IT'S ON TARGET AND POTENTIAL OFF-TARGET EFFECTS MIGHT WANTED TO ADD OTHER ASSESSMENTS SUCH AS AGAIN EXAMPLE OF PEANUT, I'M NOT FOR ADDING PEANUT BUT I USE THAT AS AN EXAMPLE BECAUSE IT APPLIES WELL. IF YOU'RE ADDING PEANUT IN FORMULA ASSESS RESPONSES OVER TIME. THERE MIGHT BE SPECIAL ASSESSMENTS THAT NEED TO BE DONE. OBVIOUSLY YOU WANT TO LOOK NO EXCESSIVE INFECTION OUTCOMES OBVIOUSLY AS WELL AS ANY AUTOIMMUNE OR ALLERGIC OUTCOMES. ANY CHRONIC INFLAMMATORY CONDITIONS. >> I WANTED TO FOLLOW UP. THAT WAS A REALLY INTERESTING ANSWER. MADE ME THINK OF SOMETHING SHARON MENTIONED EARLIER, AS AN OFFHAND EXAMPLE, IF YOU'RE LOOKING AT POTENTIAL EFFICACY STUDY, SEE ELEVATION OF PARTICULAR CYTOKINE, I THINK IL-8, MAYBE IL6. IF YOU HAVE THAT DATA FROM EFFICACY STUDIES, SEEING MODULATION OF THESE CYTOKINES, COULD THAT INFORM ENDPOINTS THAT YOU MIGHT DESIGN? WOULD THAT ADD TO OR EXPAND THE KIND OF ENDPOINTS YOU MIGHT LOOK AT TO MAKE SURE YOU WEREN'T SEEING PERTURBATION OF DEVELOPMENT IF YOU HAVE THAT DATA TO START WITH FROM EFFICACY STUDY? >> YEAH, I DO THINK SO, THAT THOSE COULD BE USED AS ADDITIONAL TOOLS TO, YOU KNOW, THINK ABOUT ASSESSMENTS IN A PHASE 2 TRIAL, FOR EXAMPLE. >> THANKS. >> I THINK WHEN I THINK ABOUT SAFETY IN THIS PERIOD OF TIME, I'M THINKING ACUTE SAFETY, WHICH OFTENTIMES IS WHAT WE'RE MEASURING BUT THEN, YOU KNOW, THERE'S A LOT OF DEVELOPMENTAL PLASTICITY IN PROGRAMMING THAT'S OCCURRING AND PARTICULARLY SOME IMMUNE OUTCOMES DURING THIS PERIOD OF TIME, INFANT LEARNING TOLERANCE, IT'S NOT SIMPLY JUST ALLERGIES OR ANTIGENS BEING EXPOSED BUT ALSO BEING DELIVERED IN THE MICROBIOME, THE ONE THING THAT'S UNIQUE ABOUT INFANCY AND THIS IS MY -- THINKING WHEN THE FDA REGULATES PRODUCTS FOR INFANTS I'M ASSUMING THERE'S A HIGHER LEVEL OF SCRUTINY THAN JUST BECAUSE OF VULNERABILITY OF THIS POPULATION, THE FACT WE CAN BE AFFECTING LONG-TERM PROGRAMMING OF A NUMBER OF SYSTEMS, BRAIN DEVELOPMENT, SO THAT'S ONE ASPECT. BUT THE OTHER ASPECT IS WE DON'T FOLLOW CHILDREN. IT'S VERY DIFFICULT AND VERY EXPENSIVE TO FOLLOW UP. I'M THINKING ABOUT THE STUDY CONDUCTED IN SWEDEN (INDISCERNIBLE) SHOWED HAVING THE OPM COULD IMPROVE DAILY SCORES, INFANTS WHO GOT OPM SIMILAR TO BREASTFED, THEY JUST PUBLISHED A STUDY 6 1/2 YEARS, NO DIFFERENCE, THERE'S NO DIFFERENCE IN THE OUTCOMES, COGNITIVE OUTCOMES THAT THEY LOOKED AT. DOES THAT MEAN IT'S NOT IMPORTANT, THAT THERE WASN'T SOMETHING GOING ON IN THE FIRST 6 TO 12 MONTHS OF LIFE? WE DON'T KNOW THAT. WE BASE MUCH OF OUR ASSUMPTION ABOUT EFFICACY AND SAFETY, SHORT TERM MEASURES, AND IT'S PROBABLY SHORT SIGHTED BUT A LOT OF QUESTIONS HOW DO WE DESIGN THOSE STUDIES, WHAT WOULD BE THE IMPORTANCE, THINKING ABOUT THE EXAMPLE LARS GAVE WITH THE DIFFERENCE WITH THE STUDIES, 2FL, INFECTION, DEFINITE DIFFERENCES IN INFANTS, SECRETOR MOMS, AND MEGAN'S WORK WITH BENEFIT, BUT THAT WAS -- THEY WERE MUCH OLDER SO IT WASN'T NECESSARILY ACUTE AFFECT IN THE LUMEN OF THE GUT INTERFERING WITH BINDING OF PATHOGENS BUT MAYBE BABIES WHO ARE MOM SECRETOR MILK ARE AMPLE UP, THEY WEREN'T HAVE THE 2FL THERE AND THAT ULTIMATELY IS LOCATED IN THE PROTECTION LATER ON, SO I CAN SEE BOTH AREAS COULD WORK IF YOU THINK ABOUT IT AS THE INFANT IS ALSO RESPONDING TO POTENTIALLY HAVING TO NOT HAVE AS MUCH PROTECTION FROM THE MILK. SO ONLY IF WE DON'T CAPTURE THAT, WE'RE A LITTLE BIT IN A BLACK BOX. AND SETTING REGULATORY HURDLES SO HIGH WE WOULDN'T ADD ANYTHING TO INFANT FORMULAS ANYMORE. >> SOMETHING I WOULD SAY I'VE SEEN COMMENTS, I THINK THAT WE PROBABLY NEED TO LOOK AT THIS AND NEED TO HAVE ALL THE INTERESTED PARTIES AT THE TABLE. WE NEED TO HAVE THE FDA, CONTENT EXPERTS, WE NEED THE COMPANIES THAT ARE ACTUALLY MAKING THESE FORMULAS AND WE NEED TO HAVE CLINICIANS THERE, YOU KNOW, BECAUSE AS MUCH AS I'M SUPPORTIVE OF THE POST MARKET SURVEILLANCE I'M ALSO THINKING, OKAY, WHAT KIND OF A PUBLIC HEALTH MESSAGE IS THAT SENDING TO A PARENT WHO MIGHT SAY WHY ARE WE DOING POST MARKET SURVEILLANCE ON MY BABY'S INFANT FORMULA? I THINK THAT GETS BACK TO COMMUNICATION. THIS IS AN INCREDIBLY IMPORTANT ISSUE. WE'RE NOT GOING TO SOLVE IT TODAY BUT TO ME, TO MOVE THE NEEDLE FORWARD WE NEED TO HAVE EVERYONE AT THE TABLE BECAUSE I THINK WE'RE ALL PROVIDING DIFFERENT INSIGHT. WE CAN HAVE GREAT RECOMMENDATIONS FROM ACADEMIC PERSPECTIVE THAT WOULD NEVER FLY FROM AN INFANT FORMULA MANUFACTURER, REGULATORY PERSPECTIVE. >> MANDY RAISED A COMMENT THAT I THINK IS PERTINENT TO WHAT YOU SAID, SHARON, ABOUT PARENT PERSPECTIVES IN THIS PICTURE. I WANT TO REFLECT WHAT'S HAPPENING RIGHT NOW IN THE PROBIOTIC ARENA WHICH I'M SURE THE FDA IS LOVING THAT SCENARIO IN THE PRE-TERM AREA. AND THAT IS THAT PROBIOTICS STUDIES HAVE BEEN HAVING ACROSS THE WORLD. THE U.S. HAD A FEW. THERE'S TWO CAMPS NOW THOSE WHO SAY WE DON'T HAVE FDA QUALITY PRODUCT AND THEREFORE WE CAN'T CROSS THAT LINE, AND OTHERS SAY THERE'S ENOUGH EVIDENCE THAT IT'S UNETHICAL NOT TO GO FORWARD. THE ANSWER IS PROBABLY IN BETWEEN. BUT THE PARENT RESPONSE HAS ALIGNMENT, PARENT GROUPS FOR NECROTIZING ENTEROCOLITIS CONCERN THERE'S NOT ENOUGH DIALOGUE AND PARENT PERSPECTIVE SO I THINK IT WOULD BE INTERESTING TO GET THE PARENT'S PERSPECTIVE HOW IMPORTANT IT IS TO ADVANCE INFANT FORMULA. IF WE LOOK AT PRE-TERM, MORE ENHANCED MODEL, INFANT FORMULA AGAINST HUMAN MILK THEY ARE VERY DIFFERENT IN TERMS OF PERFORMANCE. WE'RE CONCERNED ABOUT ADDING NEW THINGS AND SAFETY OF ADDING NEW THINGS WE ACTUALLY HAVE THE URGENCY THAT SOMETHING NEEDS TO CHANGE IF WE'RE GOING TO CONTINUE TO PROVIDE PRE-TERM FORMULA BECAUSE IT'S NOT GOOD ENOUGH. IT'S MISSING SO MANY THINGS AND MAY BE CAUSING EXCESSIVE HARM SO THINK ABOUT ALL THINGS EXPOSED TO PRE-TERM FORMULA NOW BEING HARMED BY THAT, AND WE ARE WONDERING ABOUT THE SAFETY OR EFFICACY OF SOMETHING THAT'S BEING ADDED SO IT'S ANOTHER WAY TO LOOK AT IT. THERE IS AN URGENCY, THAT'S WHY WE WANT TO HAVE PROGRESS BUT CERTAINLY BE MINDFUL. I THINK THAT'S ONE MODEL THAT WE SEE IN THE NICU ALL THE TIME IS THIS TENSION BETWEEN HUMAN MILK FED BABIES AND THOSE THAT GET EXPOSED TO PRE-TERM FORMULA. >> JUST LOOKING AT THE GROUP. STEVE, IF I COULD INTERRUPT. I SEE ASHLEY WAS GOING TO CHIME IN. >> I WAS GOING TO ASK A DIFFERENT QUESTION SO I WILL DEFER TO STEVE. >> I WANT TO SUPPORT WHAT JAE SAID ABOUT THE NEED TO ENGAGE THE PUBLIC IN THESE DISCUSSIONS. THIS IS NOT PURELY AN FDA ISSUE. OR AN NIH ISSUE. THERE ARE COST ISSUES, SOCIAL ISSUES, EQUITY ISSUES, ALL SORTS OF THINGS. I GET ASKED ALL THE TIME IF BIOACTIVES ARE SO VALUABLE, WHY AREN'T THEY IN ALL? WE HAVE A GOVERNMENT, CONGRESS HAS AN INTEREST, SO AS WE DEVELOP THINGS WE NEED A TRUE CONSENSUS. I DON'T THINK WE'RE ANYWHERE CLOSE TO LOOKING AT THESE ISSUES NOT JUST FROM FDA PERSPECTIVE, IS IT SAFE, BUT PUBLIC PERCEPTION AND CONSENSUS PERSPECTIVE. >> GOOD POINT. IT'S ALWAYS A GOOD REMINDER AT THE FEDERAL LEVEL, WE'RE STILL BIG BUT WE DO INTERACT WITH MANY PEOPLE ACROSS DIFFERENT AGENCIES. THAT'S A GOOD REMINDER TO MAKE SURE WE'RE ALSO TALKING TO OUR COLLEAGUES OVER IN WIC AND OTHER PLACES. I WANTED TO PIVOT A LITTLE BIT TO AN NIH-CENTRIC QUESTION, WE SEARCH AGENDAS AND RESEARCH INVESTMENTS, THOSE SORTS OF THINGS. SHARON DID A FABULOUS JOB DEMONSTRATING WORK IN PIGLETS AND I KNOW, SHARON, YOU'RE DEVELOPING A DATABASE ON PIGLET OUTCOME. I WONDER IF IT'S OKAY IF I PUT YOU ON THE SPOT AND OTHERS CAN JUMP IN ON SYSTEMS THAT NEED MORE TO MOVE THE AREA FORWARD. >> THIS IS WORK BEING LED ( INDISCERNIBLE) STEPHEN FLEMING, NOW HAS (INDISCERNIBLE) A SYSTEM, BUSINESSES INTERACTING CAN DATA ANALYSIS. THE CONCEPT TO GENERATE STANDARDIZED GROWTH CURVES FOR PIGLETS, SO THAT (INDISCERNIBLE) THIS IS INDUSTRY FUNDED BUT THIS IDEA IT WOULD BE AN OPEN DATASET SO AS PEOPLE WOULD BE WRITING THEIR OWN PIGLET STUDIES HAVE A REFERENCE STANDARD BUT COULD UPLOAD, THOUSANDS OF ANIMALS, WHAT NORMAL TRAJECTORIES LOOK LIKE, WE (INDISCERNIBLE) FALLING OFF THE GROWTH CURVE, SO A WAY TO MOVE FORWARD TO MAKE IT TRANSLATABLE AND WIDELY USED, NORMAL ORGAN DEVELOPMENT, AND THEN WORKING HARD TO DEVELOP BRAIN ATLASES FOR MRI, SCANNED PIGLETS FROM BIRTH ON. AGAIN, DIFFERENT COMPANY, INDUSTRY-FUNDED PROJECT, BUT REALLY EXPANDING THE DATABASE SO THAT YOU WOULD HAVE A PIG ATLAS FOR BRAIN STRUCTURE THAT IF YOU WANTED TO COME IN, IF OTHER PEOPLE WANTED TO COME IN THEY COULD SEE THIS INGREDIENT IS AFFECTING THIS AREA OF THE BRAIN AT A CERTAIN TIME. PART OF IT IS WHAT WE AS RESEARCHERS CAN DO TO BRING MORE DATA AND VALIDITY TO USING SOME OF THE PRE-CLINICAL MODELS BECAUSE AS I SAID NONE ARE PERFECT, NO PRE-CLINICAL MODEL IS PERFECT BUT ALLOWS ACCESS TO TISSUES AND MECHANISTIC WORK WE WOULD NEVER BE ABLE TO DO IN HUMAN INFANTS. AS LARS SAYS KNOWING ABOUT MECHANISMS HELPS US THINK ABOUT SAFETY AND EFFICACY. >> THANK YOU, SHARON. FABULOUS EXAMPLE. ALSO INTERMARRIES THE IDEA OF SHARING DATA WHICH WE ALWAYS -- SHARING EXISTING DATA WHICH WE LOVE TO HEAR AT NIH. ANY OTHERS WHO CAN THINK OF MODEL SYSTEM THAT MAY BE AT THE CUSP, MAYBE MORE WORK AND WE'LL BE READY FOR PRIME TIME? HEARING NONE. >> STUMPED PANEL, ASHLEY. >> I DID. I DID. >> THAT'S OKAY. IT'S THE END OF THE DAY. ROBIN, I'LL TURN IT BACK OVER TO YOU. >> OKAY. NO, THAT'S GREAT. I THINK WE MAY BE KIND OF STARTING A GRADUAL LAUNCH OR COMING IN TO LAND PLAN HERE BUT THINKING ABOUT THAT, FROM THE SPEAKERS' POINT OF VIEW MAYBE I'LL POSE THIS QUESTION AND THEN GO TO THE OTHER MODERATORS BUT JUST FOR THE SPEAKERS TO BE THINKING ABOUT ARE THERE ANY EITHER KEY QUESTIONS OR KEY POINTS THAT YOU REALLY WANTED TO RAISE, MAYBE IT WAS FROM YESTERDAY OR THAT YOU WANTED TO MAKE SURE WAS PRESENTED IN THE VIRTUAL TABLE HERE, VIRTUAL FORUM HERE AS WE'RE BEGINNING TO WIND DOWN, BUT BEFORE WE GET TO THAT, LET ME DOUBLE CHECK WITH MY -- WITH NANCY, KOTARO, JEREMIAH AND MODERATORS FROM DIFFERENT DAYS, KEY QUESTIONS YOU WOULD LIKE TO SEE WHILE WE HAVE THIS WEALTH OF RESOURCES HERE OF BRAINPOWER, AND EXPERTISE YOU WOULD LIKE TO POSE TO THE GROUP. >> THIS IS JOE. CAN I JUST BRING UP REALLY QUICKLY TO ADDRESS THE POINT THAT ASHLEY MADE. I TOTALLY AGREE THERE ARE CERTAIN MODELS THAT WILL HELP US, ENTEROID MODELS, ORGANOID MODELS, PIGLETS, BUT I WANT TO SORT OF POSE THAT WE CAN DO A LOT MORE WITH THE HUMAN AS OUR MODEL. AND WE ARE DEVELOPING NEW TECHNOLOGIES TO LOOK AT THE STOOLS. WE'RE LOOKING AT NEW TECHNOLOGIES TO LOOK AT URINE AND METABOLOMICS AND WE CAN TAKE PIECES OF COTTON AND PUT THEM INTO A DIAPER AND ELUTE THE URINE, LOOK AT METABOLOMICS, BREATH STUDIES, THERE ARE A LOT OF THINGS THAT WE COULD TAP INTO IN THE HUMAN THAT WE HAVE NOT REALLY LOOKED AT EXTENSIVELY. I WOULD LIKE TO SEE US REALLY DOING THAT A LITTLE BIT MORE. >> GREAT. THANKS SO MUCH FOR THAT, JOE. AND SO, YES, LET'S SEE IF THE MODERATORS HAD ANY OTHER QUESTIONS THAT THEY WANTED TO POSE TO THE GROUP, KOTARO, JEREMIAH, NANCY? >> I JUST WANTED TO COMMENT AT THE OFFERS OF DIETARY SUPPLEMENTS WE HAVE NO EXACT POST-MARKET SURVEILLANCE AND IT'S VERY HARD TO KEEP TRACK OF ADVERSE EVENTS. SO IT SEEMS WORTH THINKING ABOUT HAVING INDUSTRY DO MORE UP FRONT RESEARCH BEFORE SOMETHING GETS REQUESTED TO BE PUT IN TO INFANT FORMULA. JUST A DIFFICULT ISSUE. >> YEAH, WE HAVE PRE-MARKET AUTHORITY, REGULATORY AUTHORITY OVER INFANT FORMULA AND IT'S A COMPLICATED AREA. TOO COMPLICATED TO GO INTO DEPTH HERE BUT WE DO HAVE SOME PRE-SESSION INFORMATION THAT GOES INTO A LITTLE MORE INFORMATION ON THAT. KOTARO, DID YOU WANT TO -- I THINK YOU WERE -- >> YEAH, THIS ISN'T NECESSARILY A QUESTION BUT JUST SINCE WE'VE BEEN TALKING ABOUT POTENTIAL MODELS AND BIOMARKERS AND STUDY DESIGN AND EVERYTHING ELSE I THINK WE ENGAGE -- AS WE ENGAGE IN THE UPCOMING DAYS IT WOULD BE HELPFUL I THINK ALSO TO BE THINKING ABOUT HOW TO STANDARDIZE THESE STUDIES AS WELL, LIKE FOR EXAMPLE WHEN DALLAS WAS TALKING ABOUT THE ADJUSTABILITY STUDY, YOU KNOW, WE HAVE TO MAKE SURE THAT IN ORDER TO COMPARE ONE STUDY TO THE NEXT IT HAS TO BE FOLLOWING THE SAME TYPE OF PROTOCOL BECAUSE THE RESULTS MAY BE DIFFERENT. THESE ARE THE TYPE OF THINGS THAT WE DO IN TOXICITY STUDIES, MOST STUDIES ARE STANDARDIZED SO ONE CAN HAVE THE ABILITY TO COMPARE ONE STUDY VERSUS ANOTHER, AND SO AS WE THINK ABOUT MORE OF THE ANIMAL OR IN VITRO SYSTEM THAT COULD POTENTIALLY INFORM US IN TERMS OF SAFETY OR EFFICACY, I THINK IT'S IMPORTANT TO KEEP IN MIND THAT TOWARDS THE DESIGNING THEM SO THAT, YOU KNOW, WE -- OF COURSE'S DOING THE SAME THING SO WE CAN COMPARE AND CONTRAST DATA, I WANTED TO THROW THAT OUT THERE. >> THANKS SO MUCH, KOTARO. AND SO AT THIS POINT AS I MENTIONED BEFORE ARE THERE ANY OTHER KEY POINTS PEOPLE WANTED TO RAISE OR EVEN FROM YESTERDAY, THANKS, JOE, FOR YOUR EARLIER POINT, PARTICULARLY ON HUMAN STUDIES AND BUT ANYTHING YOU WOULD LIKE TO MAKE SURE IS REFLECTED IN THE MEETING TODAY THAT YOU MIGHT NOT HAVE HAD A CHANCE TO MENTION TO THIS POINT? SEEING NONE, I THINK AT THIS POINT THEN IF I'M NOT HEARING ANYTHING ADDITIONAL FROM THE SPEAKERS, I WOULD LIKE TO THANK MY CO-MODERATORS, NANCY JEREMIAH, THANK YOU TO THE SPEAKERS, WHAT A REMARKABLE JOB OVER THE LAST TWO DAYS. AND ALSO TO THE PARTICIPANTS. WE'VE HAD A SOLID CORE OF FOLKS THROUGHOUT, AND REALLY A LARGE NUMBER OF PARTICIPANTS ONLINE. SO AT THIS POINT I'D LIKE TO THANK EVERYBODY AND I THINK I AM TURNING IT BACK TO YOU, ASHLEY, TO CLOSE US OUT. >> YES, AND WE WILL MAKE THE CLOSEOUT QUICK. THANK YOU, EVERYONE. I'LL TURN IT OVER TO DREW FOR A FEW MINUTES AND THEN I'LL HAVE MAYBE FIVE MINUTES OF REMARKS ABOUT NEXT STEPS. DREW, OVER TO YOU. >> THANKS, ASHLEY. I'M GOING TO LET ASHLEY DO THE CLOSEOUT, FIRST ECHOING THANKS TO SPEAKERS FOR DIALOGUE, FOR TAKING TIME THE PAST TWO DAYS TO ENGAGE IN THE SUPER IMPORTANT TOPIC. I WORKED WITH AMAZING STAFF AT NICHD, AND THEIR COLLEAGUES AT THE FDA, AND OTHER AGENCIES THAT WANT TO DO THE RIGHT THING. WE WANT TO THINK BIG, DREAM BIG, AND MOVE THE FIELD FORWARD BUT WE RECOGNIZE TO DO THAT WE NEED YOU. AND SO TO ALL OF OUR SPEAKERS, AND PARTICIPANTS, WE HAD SEVERAL HUNDRED ONLINE, I PROFOUNDLY THANK YOU. WE APPRECIATE ALL THE COMMENTS. WE TAKE THEM TO HEART. WE KNOW THERE'S TOUGH QUESTIONS TO ASK AND ANSWER. AND WE'RE IN THIS JOURNEY WITH YOU. THAT'S, AGAIN, OUR HONOR TO BE ON THIS JOURNEY WITH YOU AND WE SEE GREAT THINGS AHEAD. SO I WANT TO THANK YOU. I'VE HAD THE PLEASURE OF MONITORING E-MAILS, TEXTS, SCREENS AND QUESTIONS, INPUT HAS BEEN GREAT. ASHLEY WILL WRAP UP BUT THIS IS NOT ENDING HERE. THIRLS THE START OF MANY DISCUSSIONS TO COME. AND WE'RE CAPTURING ALL THE INFORMATION. WE'LL SYNTHESIZE AND SOMETIMES WRESTLE WITH THE INFORMATION. THIS IS NOT THE END, JUST THE BEGINNING OF THE CONVERSATION. TO THE CREW THAT PUT THIS TOGETHER, ASHLEY AND HER TEAM, TREMENDOUS JOB PUTTING THIS TOGETHER. I'LL END WHERE I STARTED YESTERDAY, PROFOUND GRATITUDE, ALL THE INVESTIGATORS, EVERYONE WHO IS WORKING IN THIS AREA AND DEDICATION TO IMPROVING THE LIVES OF OUR MOST VULNERABLE. I CAN'T THINK OF A MORE NOBLE CAUSE. WE'RE HONORED TO BE ON THIS JOURNEY WITH YOU. WITH THAT, ASHLEY, I WANT IT ON THE RECORD THANKS TO YOU AND YOUR TEAM AND ROBIN, YOU AND YOUR TEAM. IT'S A GREAT PARTNERSHIP. I LOOK FORWARD TO OUR NEXT SET OF QUESTIONS. ASHLEY, BACK TO YOU. >> THANK YOU, DREW. >> BEFORE YOU START, I DID WANT TO SAY PARTICULARLY ON BEHALF OF MY FDA COLLEAGUES, THANK YOU TO YOU, TO DREW, ALL OF THE TEAM AT THE NIH AND THE NICHD WHO WORKED ON THIS TOGETHER BUT YOU HAVE REALLY TAKEN THE LEAD AND WE APPRECIATE THAT VERY MUCH. I WANTED TO REFLECT THAT FROM OUR TEAM. >> THANK YOU, ROBIN. AND THANK YOU TO YOUR TEAM OVER AT FDA. PARTICULARLY THANKS TO KOTARO WHO GOT ALL OF THE HARD QUESTIONS AGAIN TODAY. BUT THANK YOU TO YOU ALL FOR WORKING THROUGH THE PAST YEAR, WHAT'S BEEN A DIFFICULT SET OF TOPICS AND QUESTIONS TO NARROW THEM DOWN TO THE ONES YOU ULTIMATELY SAW. AND THEN ALSO TO THINK THROUGH HOW WE MIGHT BEST MOVE THIS FORWARD IN TWO DAYS. SO THANKS TO EVERYONE. I ALSO WANT TO THANK THE SPEAKERS AGAIN. WE WOULD NOT BE HERE WITHOUT YOU. WE HAVE ACCOMPLISHED WHAT WE SET OUT TO DO, TO TALK ABOUT THIS DATA, THE SCIENCE, THIS AREA. SO I'D LIKE TO DRAW A PARALLEL BETWEEN ONE OF THE THEMES WE'VE BEEN TALKING ABOUT TODAY, WHICH IS WE DON'T REALLY KNOW THE LONG-TERM EFFECTS OF EARLY LIFE BIOACTIVE EXPOSURES AND SO I WOULD PUT FORTH THAT WE DON'T REALLY KNOW WHAT THESE INCREDIBLE CONVERSATIONS AND PRESENTATIONS AND DATA SHARING TODAY WILL HAVE ON EFFECT OF FUTURE SCIENCE IN THIS SPACE. KOTARO SAID THIS IS A WONDERFUL START TO MANY FUTURE CONVERSATIONS. AND SO WE THANK YOU FOR YOUR TIME. WE THANK THE SPEAKERS AND ATTENDEES, BECAUSE I THINK YOU BOTH WERE ABLE TO WORK TOGETHER TO MOVE THROUGH A REALLY HARD AND COMPLEX AND REALLY VERY NEBULOUS RESEARCH AREA. BASED ON THE CONVERSATIONS THAT WE HAD IN THE CHAT WITH THE SPEAKERS AND ALSO THE QUESTIONS COMING IN FROM THE AUDIENCE, WE GOT SOME REALLY THOUGHTFUL REMARKS. SO WE'RE APPRECIATIVE OF THOSE AND AS DREW SAID WE HAVE THEM FOR REFERENCE. I KNOW ON THE FEDERAL SIDE WE NIGHT TIME TO DIGEST AND THINK ABOUT THE CONVERSATIONS THAT WE'VE SHARED OVER THE PAST TWO DAYS. WE REALLY APPRECIATE THE EXPERIENCE, DIFFERENT VIEWPOINTS THAT WERE PRESENTED, AND THE WILLINGNESS OF OUR SPEAKERS TO REALLY SPEAK UP WHEN WE DON'T KNOW THE ANSWER. THAT WAS VERY HELPFUL TO US. SO AS FAR AS NEXT STEPS FOR THIS GROUP, I'M NOT GOING TO WHEDELE OUT AGREEMENTS BUT WE'RE HOPING TO PUT TOGETHER PROCEEDINGS OF THE WORKSHOP. I DON'T NEED YOUR AGREEMENT TODAY THAT YOU'RE WILLING TO WORK ON THAT SO I'LL FOLLOW UP WITH YOU ALL VIA E-MAIL TO DETERMINE YOUR INTEREST IN WORKING ON THAT. FOR THE PUBLIC, THIS SESSION AS WE MENTIONED IN THE BEGINNING WILL BE RECORDED AND HAS BEEN RECORDED. WE ANTICIPATE IN A COUPLE WEEKS IT WILL BE AVAILABLE ON NIH VIDEOCAST. YOU SHOULD BE ABLE TO ACCESS IT THERE. AND WITH THAT, I WILL LET EVERYONE HAVE SOME TIME BACK IN THEIR FRIDAY AFTERNOON AND THANK YOU AGAIN TO EVERYONE. WE REALLY APPRECIATED YOUR TIME AND YOUR ATTENTION.