“The Deeply Quantified Self: A Case Study” Future Technology Keynote Minimally Invasive Surgery Week 2015 Society of Laparoendoscopic Surgeons New York City, NY September 5, 2015 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 1

By Measuring the State of My Body and “Tuning” It Using Nutrition and Exercise, I Became Healthier 2000 Age Age Age I Arrived in La Jolla in 2000 After 20 Years in the Midwest and Decided to Move Against the Obesity Trend I Reversed My Body’s Decline By Quantifying and Altering Nutrition and Exercise

Calit2 Has Been Had a Vision of “the Digital Transformation of Health” for 15 Years Next Step—Putting You On-Line! –Wireless Internet Transmission –Key Metabolic and Physical Variables –Model -- Dozens of Processors and 60 Sensors / Actuators Inside of our Cars Post-Genomic Individualized Medicine –Combine –Genetic Code –Body Data Flow –Use Powerful AI Data Mining Techniques The Content of This Slide from 2001 Larry Smarr Calit2 Talk on Digitally Enabled Genomic Medicine

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

Wireless Monitoring Produced Time Series That Helped Me Improve My Health Since Starting November 3, 2011 Total Distance Tracked 3,223 miles = San Diego to Bangor, ME Total Vertical Distance Climbed 107,000 ft. = 3.7 Mt. Everest Using Polar Chest Strap During Elliptical Workouts My Resting Heartrate Fell from 70 to 40!

Quantifying My Sleep Pattern Using Zeo - Surprisingly About Half My Sleep is REM! REM is Normally 20% of Sleep Mine is Between 45-65% of Sleep An Infant Typically Has 50% REM

From Measuring Macro-Variables to Measuring Your Internal Variables

Quantifying Your Inner Self: A Case Study An N=1 Case Study of Using Quantified Self To Discover and Track an Autoimmune Disease

I Have Turned My Body into a Genomic and Biomarker Observatory One Blood Draw For Me Calit2 64 Megapixel VROOM

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

Adding Stool Tests Revealed Oscillatory Behavior in an Immune Variable Which is Antibacterial Normal Range <7.3 µg/mL 124x Upper Limit for Healthy Lactoferrin is a Protein Shed from Neutrophils - An Antibacterial that Sequesters Iron Typical Lactoferrin Value for Active Inflammatory Bowel Disease (IBD)

Colonoscopy Images Show Persistent Inflamed Pseudopolyps in 6 inches of Sigmoid Colon Dec 2010 Jan 2012 “Inflammatory polyp versus inflamed fold in the distal sigmoid colon and apthous ulcers in the rectum, consistent with active Crohn’s colitis.” William J. Sandborn, MD UCSD Jan 3, 2012

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

MRE Reveals Inflammation in 6 Inches of Sigmoid Colon Thickness 15cm – 5x Normal Thickness “Long segment wall thickening in the proximal and mid portions of the sigmoid colon, extending over a segment of approximately 16 cm, with suggestion of intramural sinus tracts. Edema in the sigmoid mesentery and engorgement of the regional vasa recta.” – Cynthia Santillan, MD Radiologist MRI report Jan 2012 Clinical MRI Slice Program DeskVOX 3D Image 3D vs. 2D Visualization Of DICOM file of LS MRI Wall Thickness 5x Normal

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 Paul B. Eckburg & David A. Relman Clin Infect Dis. 44: (2007) I Have Been Quantifying All Three

The Cost of Sequencing a Human Genome Has Fallen Nearly 10,000x in the Last Ten Years This Has Enabled Sequencing of Both Human and Microbial Genomes

Person A Person B Single Nucleotide Polymorphisms (SNPs) Make Up About 90% of All Human Genetic Variation Tracks One Million SNPs SNPs Occur Every 100 to 300 Bases Along Human DNA

I Found I Had One of the Earliest Known SNPs Associated with Crohn’s Disease From SNPs Associated with CD Interleukin-23 Receptor Gene — 80% Higher Risk of Pro-inflammatory Immune Response NOD2 IRGM ATG16L1 23andme is Seeking 10,000 Volunteers with IBD to Determine SNP Distribution to Stratify Disease Spectrum

To Understand the Interaction of Genetics with Disease States We Must Consider the Human Microbiome and Not Just the Human Genome Your Microbiome is Your “Near-Body” Environment and its Cells Contain 300x as Many DNA Genes As Your Human Cells Your Body Has 10 Times As Many Microbe Cells As Human Cells

June 8, 2012 June 14, 2012 Interest in the Human Microbiome Has Moved Quickly From Frontier Science to Public Awareness August 18, 2012 June, 2012

When We Think About Biological Diversity We Typically Think of the Wide Range of Animals But All These Animals Are in One SubPhylum Vertebrata of the Chordata Phylum All images from Wikimedia Commons. Photos are public domain or by Trisha Shears & Richard Bartz

Think of These Phyla of Animals When You Consider the Biodiversity of Microbes Inside You All images from WikiMedia Commons. Photos are public domain or by Dan Hershman, Michael Linnenbach, Manuae, B_cool Phylum Annelida Phylum Echinodermata Phylum Cnidaria Phylum Mollusca Phylum Arthropoda Phylum Chordata

The Genetic Distance Between Microbes Vastly Exceeds That Among All Animals and Plants You Are Here Source: Carl Woese, et al Tree of Life Derived from 16S rRNA Sequences

To Map Out the Dynamics of Autoimmune Microbiome Ecology Couples Next Generation Genome Sequencers to Big Data Supercomputers Illumina HiSeq 2000 at JCVI SDSC Gordon Data Supercomputer Example: Inflammatory Bowel Disease (IBD) We used 25 CPU-years to compute comparative gut microbiomes starting from 7 trillion DNA bases of my samples, 255 healthy, and 20 IBD controls

We Found Major State Shifts in Microbial Ecology Phyla Between Healthy and Three Forms of IBD Most Common Microbial Phyla Average HE Average Ulcerative Colitis Average LS Colonic Crohn’s Disease Average Ileal Crohn’s Disease Collapse of Bacteroidetes Explosion of Actinobacteria Explosion of Proteobacteria Hybrid of UC and CD High Level of Archaea

This Year We Will Extend My Stool Time Series Collaborating with the UCSD Knight Lab Larry’s 40 Stool Samples Over 3.5 Years to Rob’s lab on April 30, 2015

We Must Move From Combating Single Microbe Diseases to Developing the Human/Microbiome System Approach to Public Health Bach (2002) N Engl J Med, Vol. 347, For Public Health It is Still About Microbes, But from Single Species to Entire Ecologies

The United States Population’s Human Gut Microbiome Has Diverged a Great Deal from Hunter-Gatherers “The microbiome of uncontacted Amerindians,” J. C. Clemente, et al. Science Advances 1, e (2015). [Amerindians in Venezuela/Columbia] [Africa] Human Microbiome Project Missing Microbes

The Coupled Neural, Immune, and Microbiome Systems Provide a Model Explaining How Nutrition Can Alter Neurodevelopment

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.”

Reports Are Being Published on The Birth of the Human Microbiome Market October 2014

Fecal Microbiome Transfer Is a Rapidly Growing New Treatment for IBD Dr. Bill Sandborn, Chief UCSD GI Dr. Brigid Boland, UCSD GI

Where I Believe We are Headed: Predictive, Personalized, Preventive, & Participatory Medicine Will Grow to 1000, Then 10,000, Then 100,000

Genetic Sequencing of the DNA of Humans and Their Microbes Is a Huge Growth Area and the Future Foundation of Medicine Twitter 9/27/2014

From One to a Billion Data Points Defining Me: The Exponential Rise in Body Data in Just One Decade Billion: My Full DNA, MRI/CT Images Million: My DNA SNPs, Zeo, FitBit Hundred: My Blood Variables One: My Weight Weight Blood Variables SNPs Microbial Genome Improving Body Discovering Disease

Thanks to Our Great Team! UCSD Metagenomics Team Weizhong Li Sitao Wu Future Patient Team Jerry Sheehan Tom DeFanti Kevin Patrick Jurgen Schulze Andrew Prudhomme Philip Weber Fred Raab Joe Keefe Ernesto Ramirez Ayasdi Devi Ramanan Pek Lum JCVI Team Karen Nelson Shibu Yooseph Manolito Torralba SDSC Team Michael Norman Mahidhar Tatineni Robert Sinkovits UCSD Health Sciences Team Rob Knight William J. Sandborn Elisabeth Evans John Chang Brigid Boland David Brenner Dell/R Systems Brian Kucic John Thompson