1. “Know Thyself: Quantifying Your Human Body and Its One Hundred Trillion Microbes” Understanding Cultures and Addressing Disparities in Society: Degrees of Health and Well-Being Public Lecture Series University of California, San Diego January 20, 2016 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

2. Abstract To truly understand the state of the human body in health or disease, we now realize that we must consider a much more complex system than medical science considered heretofore. This is because we now know that the human body is host to 100 trillion microorganisms, ten times the number of cells in the human body and these microbes contain 300 times the number of DNA genes that our human DNA does. The microbial component of our “superorganism” is comprised of hundreds of species with immense biodiversity. Exponential decrease in the cost of genetic sequencing has enabled scientists to finally "read out" the nature of the changes in the microbial ecology in people in health and with disease. In addition, researchers have traveled to remote sites to measure the difference between the microbiome of indigenous people and those of Western cultures. These differences turn out to be profound, pointing to a gap of "missing microbes" in our Westernized societies. To put a more personal face on the “patient of the future,” I have been collecting massive amounts of data from my own body over the last five years, which reveals detailed examples of the episodic evolution of this coupled immune-microbial system. As similar techniques become more widely applied, we can look forward to revolutionary changes in medical practice over the next decade.

3. “Know Thyself” From the Temple of Apollo to the Quantified Self From the Reichert-Haus in Ludwigshafen, Germany

4. Calit2 Has Been Had a Vision of How to Digitally “Know Thyself” 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 www.bodymedia.com The Content of This Slide from 2001 Larry Smarr Calit2 Talk on Digitally Enabled Genomic Medicine

5. 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 Human Genome SNPs Microbial Genome Improving Body Discovering Disease “Be the change that you wish to see in the world”

6. 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

7. Wireless Monitoring Produced Time Series That Helped Me Improve My Health Since Starting November 3, 2011 Total Distance Tracked 5495 miles = Round Trip San Diego to Bangor, ME Total Vertical Distance Climbed 176,560 ft. = 6x Mt. Everest My Resting Heartrate Fell from 70 to 40! Elliptical Walking Sunday January 17, 2016 137 42 I Increased Walking, Aerobic, and Resistance Training, All of Which Have Health Benefits

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

9. I Decided to Track My Internal Biomarkers Just As I Did My External Body One Blood Draw For Me Calit2 64 Megapixel VROOM

10. Only One of My Blood Measurements Was Far Out of Range--Indicating Chronic Inflammation Normal Range <1 mg/L 15x Upper Limit Complex Reactive Protein (CRP) is a Blood Biomarker for Detecting Presence of Inflammation

11. 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 15x Upper Limit

12. Adding Stool Tests Revealed Dramatic Episodic Spikes in Immune Variables Normal Range <7.3 µg/mL 124x Upper Limit for Healthy Lactoferrin is An Antibacterial that Sequesters Iron Typical Lactoferrin Value for Active Inflammatory Bowel Disease (IBD)

13. Descending Colon Sigmoid Colon Threading Iliac Arteries Major Kink Confirming the IBD (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 Transverse Colon Liver Small Intestine Diseased Sigmoid Colon Cross Section MRI Jan 2012 Severe Colon Wall Swelling

14. Why Did I Have an Autoimmune Disease like Crohn’s Disease? 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. 44:256-262 (2007) I Have Been Quantifying All Three

15. Person A Person B Single Nucleotide Polymorphisms (SNPs) in the Human Genome Make Up About 90% of All Human Genetic Variation www.23andme.com Tracks One Million SNPs SNPs Occur Every 100 to 300 Bases Along Human DNA

16. I Found I Had One of the Earliest Known SNPs Associated with Crohn’s Disease From www.23andme.com SNPs Associated with CD Polymorphism in Interleukin-23 Receptor Gene — 80% Higher Risk of Pro-inflammatory Immune Response NOD2 IRGM ATG16L1 23andme is Now Collecting 10,000 IBD Patient’s SNPs

17. I Reasoned That The Driver of My Gut Autoimmune Disease Was a Disturbance in My Gut Microbiome Ecology Inclusion of the “Dark Matter” of the Body Will Radically Alter Medicine 99% of Your DNA Genes Are in Microbe Cells Not Human Cells Your Body Has 10 Times As Many Microbe Cells As DNA-Bearing Human Cells

18. 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

19. 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

20. 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, & Matt Clancy

21. Think of These Phyla of Animals When You Consider the Biodiversity of Microbes Inside You Allimagesfrom WikiMediaCommons.Photosarepublicdomain orbyDan Hershman,MichaelLinnenbach,Manuae,B_cool,DlloydAllimagesfrom WikiMediaCommons.Photosarepublicdomain orbyDan Hershman,MichaelLinnenbach,Manuae,B_cool,Dlloyd Phylum Annelida Phylum Echinodermata Phylum Cnidaria Phylum Mollusca Phylum Arthropoda Phylum Chordata Phylum Porifera All images from WikiMedia Commons. Photos are public domain or by Dan Hershman, Michael Linnenbach, Manuae, B_cool, Nick Hobgood

22. 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

23. Just Genome Sequencing the Stool of 300 Patients Sorted Out Their Health or Disease Type Source: Thomas Hill, Ph.D. Executive Director Analytics Dell | Information Management Group, Dell Software Healthy Ulcerative Colitis Colonic Crohn’s Ileal Crohn’s

24. This Year We Sequencing and Computing My Stool Time Series Collaborating with the UCSD Knight Lab Larry’s 50 Stool Samples Over 3.5 Years to Rob’s lab on April 30, 2015

25. My Gut Microbiome Ecology Varying Over 3.5 Years: Sequencing by UCSD’s Knight Lab and Institute for Genomic Medicine LS Analysis, January 2016 Next Step: Comparing Time Series of Microbiome, Immune Biomarkers, & Symptoms to Guide Therapy

26. From N=1 to UC San Diego Undertaking a Major Clinical Study of IBD Using These Techniques Inflammatory Bowel Disease Biobank For Healthy and Disease Patients Drs. William J. Sandborn, John Chang, & Brigid Boland UCSD School of Medicine, Division of Gastroenterology Over 200 Enrolled Announced November 7, 2014! Knight and Smarr Have Been Awarded a CPU-Century of Supercomputer Time To Analyze 50 IBD Patients, LS Time Series, and 300 Healthy People’s Microbiome

27. Center for Microbiome Innovation Seminars Faculty Hiring Education UCSD Microbial Sciences Initiative InstrumentCores Seed Grants Fellowships Chancellor Khosla Launched the UC San Diego Microbiome and Microbial Sciences Initiative October 29, 2015

28. UC San Diego Microbiome and Microbial Sciences Initiative: Leadership Team Rob Knight Pediatrics/CSE Pieter Dorrestein Pharmacy Kit Pogliano Biol Sci Bernhard Palsson BioE/Pediatrics Bill Sandborn Gastroenterology Jeff Hasty Biol Sci Karsten Zengler Pediatrics Larry Smarr Calit2 /CSE Paul Jensen SIO Pavel Pevzner CSE Rachel Dutton Biol Sci Rommie Amaro Chem & Biochem Victor Nizet Pediatrics/Pharmacy Vineet Bafna CSE

29. 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, 911-920 2014 For Public Health It is Still About Microbes, But from Single Species to Entire Ecologies

30. 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, e1500183 (2015). [Amerindians in Venezuela/Columbia] [Africa] U.S. Human Microbiome Project Missing Microbes

31. We Have Much to Learn from Indigenous Peoples “Our work emphasizes the value of deep characterization of microbiomes of people living ancestral life-styles, particularly if practices in industrialized societies might eradicate potentially beneficial microbes and their encoded functions.” “The average Yanomami's microbiota had twice as many genes as that of the average US person.”

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

33. There is a Huge New Field of Products Coming Which Enable You to “Garden” Your 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.” Will Medical Foods Provide New Tools for Altering Gut Microbiome?

34. Massive Research is Underway to Discover A Wide Range of Methods for Gardening Your Microbiome http://vitals.lifehacker.com/beyond-probiotics-can-you-hack-your-microbiome-1689720231

35. Manipulating Your Microbiome Can Work -- Fecal Microbiome Transfer Is a Rapidly Growing New Treatment for Clostridia Difficile Dr. Bill Sandborn, Chief UCSD GI Dr. Brigid Boland, UCSD GI C. diff is the nation’s most common hospital-acquired infection, affecting 500,000 and killing 30,000 Americans/year. Fecal transplants are 90% curative. OpenBiome supplies to over 500 hospitals in all 50 states, so far 10,000 transplants. www.cidrap.umn.edu/news-perspective/2015/02/cdc-puts-c-difficile-burden-453000-cases-29000-deaths

36. Consumer Internal Self-Tracking Tools Are Growing Rapidly Blood Variable Time SeriesStool Variable Time Series Human Genetic Variations Integrated Wellness Human Microbiome

37. The Emergence of P4 Medicine -- Predictive, Preventive, Personalized, Participatory Systems Biology & Systems Medicine Consumer-Driven Social Networks P4 MEDICINE Digital Revolution Big Data How Will the Quantified Consumer Be Integrated into Healthcare Systems? Lee Hood, Director ISB

38. Genetic Sequencing of Humans and Their Microbes Is a Huge Growth Area and the Future Foundation of Medicine Source: @EricTopol Twitter 9/27/2014

39. The Looming Disruption In Integrated Healthcare Systems Citizens Create Vast Datasets Outside of Medical Records Doctors Must Partner with Super-Informed Patients From Pharmaceuticals to Medicinal Foods From Treating Sickness to Maintaining Wellness

40. 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 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