“The Digital Transformation of Healthcare” Guest Lecture Pharmacy Informatics 2014 University of California San Diego June 2, 2014 Dr. Larry Smarr Director, California Institute for Telecommunications and Information Technology Harry E. Gruber Professor, Dept. of Computer Science and Engineering Jacobs School of Engineering, UCSD http://lsmarr.calit2.net

The Vision of Digitally Enabled Genomic Medicine is an Emerging Reality July/August 2011 February 2012

Systems Biology & Systems Medicine Consumer-Driven Social Networks The Emergence of P4 Medicine -- Predictive, Preventive, Personalized, Participatory Systems Biology & Systems Medicine Consumer-Driven Social Networks P4 MEDICINE Digital Revolution Big Data Converging Megatrends Driving the Transformation of Healthcare for Patients Source: Lee Hood, ISB

100 Pioneer Wellness Project: Started March 2014 –I Am One of The 100 Source: Lee Hood, ISB

How Did I Get Started? I Arrived in La Jolla in 2000 and Decided to Move Against the Obesity Epidemic By Measuring the State of My Body and “Tuning” It Using Nutrition and Exercise, I Became Healthier Age 41 Age 51 1999 2010 Age 61 1999 2000 1989 I Reversed My Body’s Decline By Quantifying and Altering Nutrition and Exercise http://lsmarr.calit2.net/repository/LS_reading_recommendations_FiRe_2011.pdf

Wireless Monitoring Helps Drive Exercise Goals

Quantifying My Sleep Pattern Using a Zeo - Increased My Average to 8 Hours/Night Stroke risk increased by sleeping less than six hours a night -M. Ruiter, Sleep 2012 REM is Normally 20% of Sleep Mine is Between 45-65% of Sleep An Infant Typically Has 50% REM

MyFitnessPal- Calories Ingested I Used a Variety of Emerging Personal Sensors To Quantify My Body & Drive Behavioral Change Withings/iPhone- Blood Pressure MyFitnessPal- Calories Ingested FitBit - Daily Steps & Calories Burned Azumio-Heart Rate Zeo-Sleep Withings WiFi Scale - Daily Weight

From Measuring Macro-Variables to Measuring Your Internal Variables www.technologyreview.com/biomedicine/39636

Visualizing Time Series of 150 LS Blood and Stool Variables, Each Over 5-10 Years Calit2 64 megapixel VROOM

Episodic Peaks in Inflammation Followed by Spontaneous Drops Only One of My Blood Measurements Was Far Out of Range--Indicating Chronic Inflammation 27x Upper Limit Episodic Peaks in Inflammation Followed by Spontaneous Drops Normal Range <1 mg/L Normal Complex Reactive Protein (CRP) is a Blood Biomarker for Detecting Presence of Inflammation

But by Using Stool Analysis Time Series, I Discovered I Had Oscillating Immune Variables Far Above Normal 124x Upper Limit Typical Lactoferrin Value for Active IBD Normal Range <7.3 µg/mL Lactoferrin is a Protein Shed from Neutrophils - An Immune System Antibacterial that Sequesters Iron

Colonoscopy Images Show Inflamed Pseudopolyps in 6 inches of Sigmoid Colon Jan 2012 Dec 2010

I Obtained the MRI Slices From UCSD Medical Services Confirming the IBD (Crohn’s) Hypothesis: Finding the “Smoking Gun” with MRI Imaging Liver I Obtained the MRI Slices From UCSD Medical Services and Converted to Interactive 3D Working With Calit2 Staff & DeskVOX Software Transverse Colon Small Intestine Descending Colon Sigmoid Colon Threading Iliac Arteries Major Kink Diseased Sigmoid Colon MRI Jan 2012 Cross Section

Why Did I Have an Autoimmune Disease like IBD? Despite decades of research, the etiology of Crohn's disease remains unknown. Its pathogenesis may involve a complex interplay between host genetics, immune dysfunction, and microbial or environmental factors. --The Role of Microbes in Crohn's Disease So I Set Out to Quantify All Three! Paul B. Eckburg & David A. Relman Clin Infect Dis. 44:256-262 (2007) 

This Has Enabled Sequencing of Both Human and Microbial Genomes The Cost of Sequencing a Megabase of DNA Has Fallen Over 10,000x in the Last Ten Years! This Has Enabled Sequencing of Both Human and Microbial Genomes

I Wondered if Crohn’s is an Autoimmune Disease, Did I Have a Personal Genomic Polymorphism? From www.23andme.com Polymorphism in Interleukin-23 Receptor Gene — 80% Higher Risk of Pro-inflammatory Immune Response ATG16L1 IRGM NOD2 SNPs Associated with CD I am Now an Advisor on the 23andme IBD Project

Imagine Crowdsourcing 23andme SNPs For Even a Small Portion of Crohnology! www.crohnology.com

Crowd-Sourcing the Effectiveness of Pharmaceutical Medications for Crohn’s Disease www.crohnology.com

Treating the Human Superorganism: Your Body Has Ten Microbes for Every Human Cell! Nature Reviews Microbiology v.9, p. 279 (2011)

To Map Out the Dynamics of My Microbiome Ecology I Partnered with the J. Craig Venter Institute JCVI Did Metagenomic Sequencing on Seven of My Stool Samples Over 1.5 Years Sequencing on Illumina HiSeq 2000 Generated 200 Million 100bp Reads JCVI Lab Manager, Genomic Medicine Manolito Torralba IRB PI Karen Nelson President JCVI Illumina HiSeq 2000 at JCVI Manolito Torralba, JCVI Karen Nelson, JCVI

We Downloaded Additional Gut Microbiomes from NIH HMP For Comparative Analysis From Sequences to Bacterial Species Relative Abundance Required 25 CPU-Years at San Diego Supercomputer Center “Healthy” Individuals IBD Patients 250 Subjects 1 Point in Time 2 Ulcerative Colitis Patients, 6 Points in Time Larry Smarr 6 Points in Time 5 Ileal Crohn’s Patients, 3 Points in Time Total of 27 Billion Reads Or 2.7 Trillion Bases Source: Jerry Sheehan, Calit2 Weizhong Li, Sitao Wu, CRBS, UCSD

We Found Major Shifts in Microbial Ecology Between Healthy and Two Forms of IBD On the IBD Spectrum Explosion of Proteobacteria Collapse of Bacteroidetes

Tracking How 1 Month Antibiotic, 2 Months Prednisone Therapy Alters the Gut Microbial Ecology Reduced 45x Reduced 90x Therapy Greatly Reduced Two Phyla, But Massive Reduction in Bacteroidetes And Large % Proteobacteria Remain Small Changes With No Therapy How Does One Get Back to a “Healthy” Gut Microbiome?

Time Points of Metagenomic Therapy: 1 Month Antibiotics Comparing Changes in Gut Microbiome Ecology with Oscillations of the Innate and Adaptive Immune System LS Data from Yourfuturehealth.com Stool Tests Time Points of Metagenomic Sequencing of LS Stool Samples Innate Immune System Normal Therapy: 1 Month Antibiotics +2 Month Prednisone Adaptive Immune System Normal

Time Series Reveals Autoimmune Dynamics of Gut Microbiome by Phyla Therapy Six Metagenomic Time Samples Over 16 Months

Toward Microbiome Disease Diagnosis UC 100x Healthy CD 100x Healthy

Inexpensive 16S Time Series of Microbiome Now Possible Through Ubiome Data source: LS (Yellow Lines Stool Samples); Sequencing and Analysis Ubiome

From War to Gardening: New Therapeutical Tools for Managing the Microbiome “I would like to lose the language of warfare,” said Julie Segre, a senior investigator at the National Human Genome Research Institute. ”It does a disservice to all the bacteria that have co-evolved with us and are maintaining the health of our bodies.”

Evidence for the Efficacy of Probiotics is IBD is Mixed - More Clinical Research Needed “...there is virtually no evidence of probiotic efficacy in Crohn’s disease.”

Problem of Alternative Stable States In Ecological System Dynamics From the Single “Bad” Microbe Medical Target to the Microbiome Ecology Paradigm Sci Transl Med 4, 137rv5 (2012); Science 336, 1255 (2012) Problem of Alternative Stable States In Ecological System Dynamics

Microbiome Transfer May Be a Radical New Treatment for IBD Procedures Starting With Natural Microbiome Next Steps: Create Synthetic Microbiomes Tuned to the Patient See Microbiome 1:3 (2013) Dr. Alexander Khoruts, NY Times www.nytimes.com/2010/07/13/science/13micro.html Not FDA Approved Yet; Increasing Number of Doctors Performing Procedure; Clinical Trials Under Way; Encouraging Results… www.gihealthfoundation.org/reuters/articles.cfm?article=20111102drgd011

Next Decade Will See New Microbiome “Gardening Tools” August 7, 2012 Journal of Nanotechnology (2012)

The Disruption of Consumer Health Data Gathering Is Growing Rapidly Blood Variable Time Series Stool Variable Time Series Human Genetic Variations MicrobiomeTime Series

Thanks to Our Great Team! UCSD Metagenomics Team Weizhong Li Sitao Wu Calit2@UCSD Future Patient Team Jerry Sheehan Tom DeFanti Kevin Patrick Jurgen Schulze Andrew Prudhomme Philip Weber Fred Raab Joe Keefe Ernesto Ramirez JCVI Team Karen Nelson Shibu Yooseph Manolito Torralba SDSC Team Michael Norman Mahidhar Tatineni Robert Sinkovits UCSD Health Sciences Team William J. Sandborn Elisabeth Evans John Chang Brigid Boland David Brenner