Targets, Metrics and Education for the future of Individualized Health
J. Bruce German University of California, Davis Foods for Health Institute
Foods for Health Institute Building the Science, Technologies and Education to Guide Diet and Health in the 21st Century The History: How did we get here? The 20th Century Science: Spectacular success! Chemistry –Reductionist Industrialization of Simple Chemicals Key = Purify
The Successes Reductionist Chemistry literally took humans to the stars.
Nutrition’s History Nutrient Deficiency Diseases Unpredictable – devastating Variable by geography, class
GOITER SCURVY RICKETS Essential Nutrients One of chemistry’s great achievements: Identifying all of the essential nutrients for humans Nutrition’s 1st Era Success of the 20th Century: Essential Nutrients and their Deficiencies Industrial ‘nutrified’ foods Population Solutions – ‘Overdose’
Result: Blissful Ignorance Consequences of Success
• Without fear of deficiency, nutrition and food became an education ‘elective’ • Result: a profoundly ignorant public • The Science of ‘Diet and Health’ divorced into the separate fields of Nutrition and Food Hostile Environment? But, we’re not healthy We should be enjoying the greatest health in history and some are, ………..but most are not
Jaring Roger Gentilhomme Timmerman strategic opportunity: Health and disease prevention – Prevention 1 Efficacy chronic 2 Safety total 3 Value $$$ The Challenge: How to do it! Targets What does diet act upon that improves the health of healthy individuals? Nutrition’s New Toolsets Biology guided R&D The 21st Century Biology - Evolution Integrative Industrialization of Organisms and Systems for Individuals
21st Century Chemistry Comprehensive – Entire classes of molecules Sensitive – Parts per trillion Accurate – Detailed complex structures
21st Century Mathematics Computational methods Massive Databases • Annotating Genomes to Neighborhood Maps Global networks • Economies to Ecosystems Industrialization of Research • Egalitarianism of Knowledge
Courtesy Matthias Friedrich -AND- Engineering
. Complex Systems measure – adjust – measure - adjust . Devices Fast, furious, cheap . Smart Processing Networked, controlled Genomics: the Footsteps of Evolution Humans: Plants: Animals Microorganisms:
What can they tell us about Diet and Health? Evolutionary Nutrition
What evolved under the Darwinian Pressure to be Nourishing? Lactation
The Darwinian Engine of Nutrition
Maternal Optima B Time Infant Optima B<(r)C Evolving a cost – benefit solution for Katie Hinde UCLA Health Proof of Principle: milk’s paradox Lactation The Darwinian Engine of Diet, Health & Sustainability Maternal Optima B Time Infant Optima B<(r)C Katie Hinde UCLA Functions of Milk? The 3rd most abundant class of biomolecule in human breast milk is un-digestible by humans! What are they? Milk Oligosaccharides Carlito Lebrilla •World’s Leading Analytical GlycoChemist Analytical tools for oligosaccharide analysis Biological sample to MS PNGase F Glycan Release 1990’s -10 days with Microwave Reactor 2000’s - 5 days Now - hours Microchip separation MALDI FTICR MS Automated SPE High performance MS Human Milk Glycans HMOs ProteinProteins Lipids Lactose Garrido et al Microbiology 2013 Human milk oligosaccharides Chain HMOs Length HMOs 4 ProteinProteins 5 Carlito Lebrilla UCD Chemistry 6 Lipids 7 8 Lactose 8 • Human indigestible and 9 highly variable 10 • Higher proportion of fucosylated (40-70%) than Other HMOs of longer lengths sialyated (4-38%) • Nearly 200 species in Nature 468 S5-S7 (23 December 2010) pooled human milk Garrido et al Microbiology (2013) Primate milk oligosaccharides Over 230 Species of Primates mammals Apes Siamang Orangutan Gorilla Chimpanzee Bonobo Human 15-20 Million New World Years ago Monkeys Squirrel Golden Lion Common Monkey Tamarin Marmoset Old World Monkeys -Rhesus -Mangabay 55 Million Years ago Functions of Milk? The 3rd most abundant class of biomolecule in human breast milk is un-digestible by humans! Why? Bacteria? David Mills Shields Endowed Chair Structure, Function and Health Benefits of Food Borne Bacteria Bifidobacterium Infantis 1 2.5 Mb B. infantis Glc 2,832,748 Mb 0.5 Mb Fucosidase Hexosaminidase Gal GlcNAc Sialidase galactosidase Fuc Neu5Ac 1.0 Mb ESB ?- HMO utilization by Bifidobacteria Bifidobacterial HMO Glycoprofiling HMO abundance in pooled breast milk 25 B. infantis 2.5 20 2 15 1.5 10 OD (600 nm) 5 1 B. breve 0 % HMO abundance in breast milk abundancein breast HMO % 0.5 B. longum HMO m/z . B. infantis 0 consumption Time(hours) 100 50 Several small MW oligosaccharides 0 consumed by B. infantis 50 Single HMO composition % HMO Consumed consumed by other 100 bifidobacteria HMO m/z Locascio et al JAFC 2007 Tripartite Evolutionary Relationship Milk Host Milk-Oriented Microbiota (MOM) Model for bifidobacterial enrichment in the infant GIT Model for bifidobacteria enrichment in the infant GIT Complex milk glycans enhance efficacy of specific bifidobacteria Caco-2 Growth on milk oligosaccharides helps some bifidobacteria bind intestinal cells HMO vs Lac grown cells: HT-29 • Induce TJ proteins • Induce anti- inflammatory cytokines (IL-10) Chichlowski et al JPGN 2012 Prebiotic milk oligosaccharides + B. infantis restore impaired gut barrier function and body weight Experimental Approach: Kristi Hamilton paracellular transcellular pathway pathway - Mice fed Western diet (high in fat) with or without supplementation with bovine milk oligosaccharides (BMO) + B. infantis. - Measure food intake, body weight, and Helen Raybould FD4 Horseradish intestinal barrier function peroxidase 40kDa (HRP) Paracellular permeability Transcellular permeability Mucosal inflammation Hamilton, Boudry, Mills et al, unpublished Infant microbial succession over breastfeeding USDA #2 Glycoprofiling of milk oligosaccharides in feces m/z Different oligosaccharide compositions in feces as determined by Mass Spec Infant microbial succession over breastfeeding USDA #2 Bacterial families Pyrosequencing of 16S rDNA present Other Staphylococcaceae Enterobacteriaceae Bifidobacteriaceae Coriobacteriaceae % % ofTotal Bacteroidaceae Streptococcaceae 0 1 2 12 Weeks What have we learned: We’re not alone! Opportunity: BioProfessionals Our minions! Bring to Practice: Personal Microbiota Management Milk oligos in action Infant transitioning to B. Infantis Infant failing to establish B. Infantis Neonatology: Translation Premature Infants Necrotizing Enterocolitis Combination of human milk oligosaccharides plus Bifidobacterium longum subsp. infantis: – Protection from infection – Growth Mark Underwood Chuck Bevins Med School Med Micro & Immunology Conflict of Interest Statement David Kyle PhD Co-Founder Martek Senior Executive Evolve Biosystems Inc. ’Bugs’ of Health Personal microbiome management: premature infants to weaning from athletes to hospitals Oligosaccharide Biology in Bovine Medrano Lab A4GNT B3GNT 1-9 ST3GAL 1-6 GCNT 1-4 ST6GAL 1,2 OGT ST6GALNAC 1-6 MFNG ST8SIA 1-6 LFNG B3GALNT 1,2 RFNG FUT 1-11 B4GALNT 1-4 POMGNT1 POFUT 1,2 GALNT 1-14 B3GALT 1-6 GBGT 1 C1GALT 1 B4GALT 1-7 A4GALT UGT8 POMT 1,2 MGAT 1,2,3 MGAT4A, 4B MGAT5, 5B GNE NANS NANP CMAS CMAH SLC35A1-A5 FUC A1,A2 SNP in coding SLC35B1 GLA SLC35C1 GLB1 FUK regions SLC35D2 GLB1L FPGT SLC17A5 HEXA GMDS ↓ HEXB TSTA3 HEXDC Genotyping array NEU1-4 GAA ↓ GANAB GBA Association study in GBA3 500 cows UCD Milk Processing Lab Daniela Barile Asst Prof FST •Pilot-scale filtration from MMS AG Systems •Fourier Transform Advanced IR MilkoScope •Speed vacuum MiVac Quattro Concentrator •Industrial freeze dryer The Breast Milk, Gut Microbiome and Immunity (BMMI) Project UC Davis Team David Mills (PI) Bruce German Carlito Lebrilla Ruslan Medzhitov Rob Knight Yale U. Colorado Jeff Gordon Wash U http://ffhi.ucdavis.edu/ Implications to Ag 2.0 Selective Polysaccharides will become a new component of human diets. Total opportunity ~ 1 trillion calories/day A new quality target for agriculture: structure/function polysaccharides Opportunity: ’Bugs’ of Delight From chocolate to coffee, wine to beer, yogurt to cheese, bread Metrics We are not the same We don’t all respond Health benefits must be DEMONSTRATED! Goal: Diagnostics of Health You cannot manage What You cannot measure 'Measure what is measurable, and make measurable what is not so', Galileo Galilei. Equation of Life Phenotype = Genotype + now Environment + ∫Genotype x Environment Not just Genetics 20 years 10,000,000 calories Is Genotyping Enough? • NO • Science: multi-genic conditions, age, environment • Economics: we will only pay for demonstrated improvements in health Genotype + Environment UCD Phenotyping People Nutrition Metabolism Vitamins Immunity Glucose Minerals Innate Lipids Amino acids Glycans Acquired Inflammation Sensation The Metrics of Taste Activity Olfaction Human Health Sleep Trigeminal Calories Microbiome Genetics Metabolites Anthropometry Conjugates Bone Signaling Muscle Endocrine Adipose Oxylipins Peptides Urinary Metabolites as Microbiome Diagnostics Monitor the development of appropriate microflora in infants Carolyn Slupsky Opportunity: Feed to ‘Target’ Prevention Strategy 1 6 Example: Fatty Liver Diseases The insidious accumulation of fat in non-adipose storage tissues is emerging as the core pathology of metabolic diseases. Can phenotyping determine if someone is developing this problem? Can phenotyping identify successful intervention? Hepatic VLDL Export Can we annotate the Lipid Export biochemistry (VLDL) of fat export and PC accumulation Lipids in the liver TG Can we measure it via plasma PEMT and Triglyceride Export Choline DG Liver Plasma Dependant PC PC PC x LP LP PEMT PE TAG TAG Choline Liver Plasma Triglyceride compositions Phosphatidylcholine Metabolism Choline DG Liver Plasma Dependant PC PC PC x LP LP PEMT PE TAG TAG Choline Liver Plasma Phosphatidyl choline compositions Opportunity: Metrics of Health Validating Food Efficacy needs measurement: fast, cheap, often, accurate! Different Decision Makers Disease Care Professional Clinician Health and Prevention Consumer Opportunity: Personal Health Education In Practice Personalizing Health and Diet Education A California Solution for Children’s Health [email protected] Health Assessment Activity and play in children Diet Children have no idea of the quality of the diets that they choose to eat! Diet Assessment Provide: Nutrients, calories and safety of personal diets Preference Assessment Personalize the ability of kids to taste foods Give children knowledge about themselves and their senses FFHI Education Program Getting Personal: The New Health Education GETUP Using a Gaming platform to excite, entertain and educate New Education Tools for Health Video games that improve health!! How do games facilitate identity, health learning and informed decision making? Health tracking devices feed health data into game experience Cynthia Carter Ching, PI Robin Hunicke Ariel Hauter Game Designer Play4Change Quantitative Data: Results Opportunity: Education of Health Personal health education from schools to blogs 2 billion users $500 billion budget Support and Partners Project Support and Collaborations UC Discovery CDRF – support DMI – support Nestle – Oligosaccharides & Support DSM – support and oligosaccharides Prolacta Inc. – human milk supplier Abbott - support Smithsonian – milk samples Evolution of Primates Agilent Technologies – Analytics – LC/MS of oligos Supelco – Analytics of oligosaccharide separation Lipomics Technologies – Analyses Joint Genomics Institute – Genomic Sequencing Cambridge University – samples WHNRC – Clinical trials NIH – Support NIEHS – Support USDA – Support NSF - support Hilmar, Sterling, Luprino – Oligosaccharides Teagasc Ireland Dairy – Oligosaccharides Support Gates Foundation - Support