1. Mind Body Genomics and Systems Biology: Underpinning the Mechanism of Relaxation Response Manoj K. Bhasin, Ph. D. Assistant Professor Of Medicine Harvard Medical School Director Bioinformatics & Systems Biology Co-Director, Genomics, Proteomics, Bioinformatics and Systems Biology Center Beth Israel Deaconess Medical Center Boston, MA mbhasin@bidmc.harvard.edu

2. Mission and Vision Our Mission Is To Innovate And Implement Novel Approaches For Deciphering The Molecular Mechanisms of Mind-Body InterventionsOur Mission Is To Innovate And Implement Novel Approaches For Deciphering The Molecular Mechanisms of Mind-Body Interventions Our vision is to use the power cutting edge omics and systems biology approaches to identify pathways and key master molecules associated with RR

3. TEMPORAL GENOMICS CHANGES OF RR IN H EALTHY S UBJECTS C ROSS - SECTIONAL AND L ONGITUDINAL TEMPORAL DESIGN

4. P ROGRESSIVELY U PREGULATED P ATHWAYS : Mitochondria and energy metabolismMitochondria and energy metabolism Electron transport chainElectron transport chain Insulin secretionInsulin secretion Higher Changes in N1 vs M as Compared to N1 vs N2 Bhasin et al, PLOS One, 2013

5. Systems Biology Network Analysis Of Upregulated Progressive RR Response Genes Interactive network analysis of significantly modulated pathways identified mitochondrial ATP synthase (ATP5C1) and Insulin (INS) as top upregulated progressive focus hub genes

6. Interactive network analysis of Long term, Short term and Progressive RR downregulated genes consists of many upstream and downstream targets of NF-  B Pseudo color scale from red to green represents Bottleneck ranks from 1 to 20. Bottleneck rank is a significance level with smaller rank indicating increasing confidence.

7. U NDERSTANDINGTHE MECHANISM OF R 3 P IN IBD/IBS U NDERSTANDING THE MECHANISM OF R 3 P IN IBD/IBS   Prospective single center study   Baseline and week 9 assessments after R 3 P   Changes in Biological and Psychological metrics associated with IBD/IBS (e.g. IBDQ, IBSQ) and gene expression profile   Peripheral Blood Mononuclear Cells (PBMCs) from 19 IBS and 29 IBD patients obtained before (Pre RR) and after (Post RR) 9 weeks of RR   Transcriptional profiling   Systems Biology analysis of Transcriptome changes to identify key molecules

8. RR INDUCED SYSTEM LEVEL ALTERATIONS IN C ELLULAR PROLIFERATION AND I MMUNE SYSTEM RELATED NETWORK IN IBD primary regulatory nodes/molecules= UBC, MAPK8, NFKB and ERK1/2 Kuo and Bhasin et al, PLOS One, 2015

9. A NALYSIS OF N ETWORK /P ATHWAYS IDENTIFIED NFKB DOWNSTREAM AND C ELL C YCLE LINKED MOLECULES AS K EY MOLECULES : Kuo and Bhasin et al, PLOS One, 2015

10. Review of Mind-Body interventions effects in Diseased & Healthy States :

11. S UMMARY S UMMARY : The systems level analysis of RR data in healthy subjects provided first insight into multimodal effect of RR to relay its beneficial effects. 1. 1.RR mediated upregulation of mitochondrial energy production through upregulation of ATPase and insulin function. 1. 1.RR blunt down inflammation by down regulating up- and Down- stream molecules of NFKB. Systems Biology analysis suggested NF-kB as key molecules for ascribing beneficial effects of RR in IBD patients. Meta-analysis of MBI indicated downregulation of pro- inflammatory molecules and NFKB interactants as primary mechanism to deliver beneficial effects.