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Of Men, Not Mice Comparative analysis of human diseases and mouse models Wenzhong Xiao Stanford Genome Technology Center Massachusetts General Hospital, Harvard Medical School Inflammation is a Common Mechanism of Human Disease Leading Causes of Deaths in the US (2015 CDC): • Heart disease: 614,348 • Cancer: 591,699 • Chronic lower respiratory diseases: 147,101 • Accidents (unintentional injuries): 136,053 • Stroke (cerebrovascular diseases): 133,103 • Alzheimer's disease: 93,541 • Diabetes: 76,488 • Influenza and pneumonia: 55,227 • Nephritis, nephrotic syndrome, and nephrosis: 48,146 • Intentional self-harm (suicide): 42,773 Challenges in Studying Patients • Ethical considerations and regulations • Heterogeneities of the individuals: nature and nurture • Diversity of the disease: etiologies & phenotypes • Variations in patient care Disease Models Patients New insights into disease mechanisms and treatments ? Molecular Studies on Model Organisms Cellular Phenotypical Inflammation in Injury To date, there have been >150 major clinical trials testing agents to block inflammatory response in critically ill patients and every one failed. Critical Evaluation of Disease Models: Reproducibility and Relevance to the Human Disease Inflammation and the Host Response to Injury consortium • >100 participating investigators from 17 academic institutions in the United States since 2001. • To study systemic inflammation in humans by monitoring multi-level information (genomics, proteomics, cell function, physiological and clinical) of trauma patients in intensive care units. • Comparisons with murine models. • http://igenomed.org/systemic_inflammation_of_hum ans How Well do Animal Models Reflect Human Diseases? Seok et al., PNAS, 2013 Comparisons of the Time Course Response between Human Disease and Mouse Models Gene HLA-DRA as an Example Correlations of Individual Pathways Genomic Response to Severe Acute Inflammatory Diseases in Human and Murine Models http://igenomed.org/immune/ Why Existing Murine Models Poorly Reflect Human Inflammatory Diseases? • Ways existing disease models were developed: phenotype(s) or genotype(s) • Divergence of evolution of the immune system between the species: resistance vs tolerance • Genetic distance between human and mouse Re-thinking the Animal Models: Are Mice Really Miniaturized Humans? from Shay et al., the Broad Institu Since every drug compound acts on gene product(s), disease studies in animal models need to show that the molecular behavior of key genes and pathways in the human disease is reproduced in the models used. New Approaches Needed to Improve Disease Models Study Patients Clinical trials based on animal model studies Model Systems Generate new hypotheses and better models ) Technologies for Host Resilience New Computational Opportunities in Patient Studies Genome: Inherited and Somatic Variations Epigenome and Transcriptome Proteome and Metabolome Cell biology Organ/Tissue physiology Microbiome Environmentome Clinical Information Acknowledgements • • • • • • • • • Junhee Seok Weihong Xu Amit Kaushal Hong Gao Claire Ryu Chia-Jung Chang Erik Miller Peng Li Gonghua Li • Wing H Wong, Stanford • Rob Tibshirani, Stanford • John Storey, Princeton • • • • • • Trauma (Ron Maier, Harborview) Burns (David Herndon, UTMB) Endotoxin (Stephen Lowry, UMDNJ) Cell Separation (Linc Moldawer, U Florida) Microfluidics (Mehmet Toner, MGH) Genomics (Ron Davis, Stanford, Henry Baker, U Florida) • Proteomics (Dick Smith, PNNL) • Functional analysis (Carol Miller-Graziano, U Rochester) • Ron Tompkins (PI, MGH) Questions &Comments? [email protected] http://igenomed.org/immune/ http://igenomed.org/immune/ http://igenomed.org/immune/ Comparisons of Publicly Available Studies of Severe Acute Inflammatory Diseases in Human and Murine models Species Disease Human Mouse GEO R Burns (reference) GSE37069 1. Trauma GSE36809 0. Endotoxemia GSE3284 0. Endotoxemia GSE3284 0. ARDS GSE10474 0. Sepsis GSE13904 0. Sepsis GSE9960 0. Sepsis GSE13015 0. Sepsis GSE28750 0. Acute Infection GSE6269 0. Burns GSE7404 0. Trauma GSE7404 0. Endotoxemia GSE7404 0. Endotoxemia GSE5663 0. ARDS GSE19030 -0. Sepsis GSE5663 0. Sepsis GSE5663 0. Sepsis GSE19668 0. Sepsis GSE26472 0. Infection GSE20524 0. Commonalities of Inflammatory Response to Different Injuries in Patients Time course studies of 167 patients up to 28 days after severe blunt trauma and 244 patients up to 1 year after burn injury. Burn R2=0.91 97% Trauma Gene MMP8 as an Example 0 Hour 1 Day 1 Week 1 Month 1 Year