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Quantifying your Human Body & Its Trillions of Microbes

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Lecture Academy of Integrative Health and Medicine (AIHM)
Annual Conference San Diego, CA November 1, 2016

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Quantifying your Human Body & Its Trillions of Microbes

  1. 1. “Quantifying your Human Body & Its Trillions of Microbes” Lecture Academy of Integrative Health and Medicine (AIHM) Annual Conference San Diego, CA November 1, 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 1
  2. 2. Abstract The human body is host to 10s of trillions of microorganisms, ten times the number of DNA-bearing cells in the human body and these microbes contain over 100 times the number of DNA genes that our human DNA does. The microbial component of our “superorganism” is comprised of 100s of species with immense biodiversity. 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 the coupled immune-microbial system.
  3. 3. Lecture Objectives • 1) Tracking Your Microbiome Ecology in Health and Disease • 2) An Example of Measuring the Impact of Pharmaceutical Therapy on the Microbiome • 3) New Non-Pharmaceutical Therapies Emerging to Manipulate the Microbiome
  4. 4. “Know Thyself” From the Temple of Apollo to the Quantified Self From the Reichert-Haus in Ludwigshafen, Germany
  5. 5. Knowing Me: From One to a Trillion Data Points Defining Me in 15 Years Weight Blood Biomarker Time Series Human Genome SNPs Microbiome Metagenomic Time Series Improving Body Discovering Disease Human Genome Genomics Big Data Tsunami
  6. 6. 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
  7. 7. 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
  8. 8. Wireless Monitoring Produced Time Series That Helped Me Improve My Health Since Starting November 3, 2011 Total Distance Tracked 6180 miles = Round Trip San Diego to Nome, Alaska Total Vertical Distance Climbed 190,000 ft. = 6.5x 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
  9. 9. From Measuring Macro-Variables to Measuring Your Internal Variables www.technologyreview.com/biomedicine/39636
  10. 10. As a Model for the Precision Medicine Initiative, I Have Tracked My Internal Biomarkers To Understand My Body’s Dynamics My Quarterly Blood Draw Calit2 64 Megapixel VROOM
  11. 11. Only One of My Blood Measurements Was Far Out of Range Complex Reactive Protein (CRP) is a Blood Biomarker for Detecting Presence of Inflammation Doctor: “Come Back When You Have a Symptom” Normal Range <1 mg/L
  12. 12. First Peak Was an Early Warning Sign of a Developing Internal Disease State 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
  13. 13. Longitudinal Time Series Revealed Oscillatory Behavior in an Immune Variable That 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)
  14. 14. 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
  15. 15. Descending Colon Sigmoid Colon Threading Iliac Arteries Major Kink Confirming the IBD (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 Transverse Colon Liver Small Intestine Diseased Sigmoid Colon Cross Section MRI Jan 2012 Severe Colon Wall Swelling
  16. 16. Comparison of 3D Volumetric MRI Visualization with Clinical MRI Slice Program Confirms Inflammation “Long segment wall thickening in the proximal and mid portions of the sigmoid colon, extending over a segment of ~16 cm, with suggestion of intramural sinus tracts. Edema in the sigmoid mesentery and engorgement of the regional vasa recta.” – MRI report, Cynthia Santillan, M.D. UCSD Jan 2012 Clinical MRI Slice Program Crohn's disease affects the thickness of the intestinal wall. Reveals Inflammation in 6 Inches of Sigmoid Colon Image from Jurgen Schultz, Calit2 Image from Cynthia Santillan, UCSD Health Services Wall Thickness 5x Normal
  17. 17. Evolving Microbiome Environmental Pressures: Dynamical Innate and Adaptive Immune Oscillations in Colon Normal <600 Innate Immune System Normal 50 to 200 Adaptive Immune System These Must Be Coupled to A Dynamic Microbiome Ecology
  18. 18. To Understand the Interaction of Genetics and the Immune System We Must Consider the Human Microbiome Your Microbiome is Your “Near-Body” Environment and its Cells Contain 100x as Many DNA Genes As Your Human DNA-Bearing Cells Your Body Has 10 Times As Many Microbe Cells As DNA-Bearing Human Cells Inclusion of the “Dark Matter” of the Body Will Radically Alter Medicine
  19. 19. New Estimates In 2016 Estimate a Human Body Contains ~30 Trillion Human Cells and ~40 Trillion Microbes However, Red Blood Cells and Platelets Have No Nuclear DNA. Therefore, Ratio of DNA-Bearing Cells for Human vs. Microbiome is Still >10:1 DNA-Bearing Cells
  20. 20. We Gathered Raw Illumina Reads on 275 Humans and Generated a Time Series of My Gut Microbiome 5 Ileal Crohn’s Patients, 3 Points in Time 2 Ulcerative Colitis Patients, 6 Points in Time “Healthy” Individuals Source: Jerry Sheehan, Calit2 Weizhong Li, Sitao Wu, CRBS, UCSD Total of 27 Billion Reads Or 2.7 Trillion Bases Inflammatory Bowel Disease (IBD) Patients 250 Subjects 1 Point in Time 7 Points in Time Each Sample Has 100-200 Million Illumina Short Reads (100 bases) Larry Smarr (Colonic Crohn’s)
  21. 21. To Map Out the Dynamics of Autoimmune Microbiome Ecology Couples Next Generation Genome Sequencers to Big Data Supercomputers Source: Weizhong Li, UCSD Our Team Used 25 CPU-years to Compute Comparative Gut Microbiomes Starting From 2.7 Trillion DNA Bases of My Time Series, IBD Patients, & Healthy Controls Illumina HiSeq 2000 at JCVI SDSC Gordon Data Supercomputer
  22. 22. 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
  23. 23. Think of These Phyla of Animals When You Consider the Biodiversity of Microbes Inside You 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
  24. 24. Results Include Relative Abundance of Hundreds of Microbial Species Average Over 250 Healthy People From NIH Human Microbiome Project Note Log Scale Clostridium difficile
  25. 25. 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
  26. 26. We Found Major State Shifts in Microbial Ecology Phyla Between Healthy and Two Forms of IBD Most Common Microbial Phyla Average HE Average Ulcerative Colitis Average LS Colonic Crohn’s Average Ileal Crohn’s Collapse of Bacteroidetes Great Increase in Actinobacteria Explosion of Proteobacteria Hybrid of UC and CD High Level of Archaea
  27. 27. Exploring the Dynamics of the Human Microbiome Ecology
  28. 28. Time Series Reveals Autoimmune Dynamics of Gut Microbiome by Phyla Therapy Six Metagenomic Time Samples Over 16 Months
  29. 29. Lessons From Ecological Dynamics I: Invasive Species Dominate After Major Species Destroyed ”In many areas following these burns invasive species are able to establish themselves, crowding out native species.” Source: Ponderosa Pine Fire Ecology http://cpluhna.nau.edu/Biota/ponderosafire.htm
  30. 30. Almost All Abundant Species (≥1%) in Healthy Subjects Are Severely Depleted in Larry’s Gut Microbiome • Red Bars Are Relative Abundance of Top 20 Species in Healthy People • Blue Bars Are Relative Abundance of Same Species in Larry Smarr When CRP=27 (12/28/2011)
  31. 31. Invasive Species Take Over Gut Microbiome in Disease State 152x 765x 148x 849x 483x 220x 201x 522x 169x Source: Sequencing JCVI; Analysis Weizhong Li, UCSD LS December 28, 2011 Stool Sample • Blue Bars Are Relative Abundance of Top 20 Species in Larry Smarr When CRP=27 (12/28/2011) • Red Bars Are Relative Abundance of Same Species in Healthy People
  32. 32. Lessons from Ecological Dynamics II: Gut Microbiome Has Multiple Relatively Stable Equilibria “The Application of Ecological Theory Toward an Understanding of the Human Microbiome,” Elizabeth Costello, Keaton Stagaman, Les Dethlefsen, Brendan Bohannan, David Relman Science 336, 1255-62 (2012)
  33. 33. In 2016 We Are Extending My Stool Time Series by Collaborating with the UCSD Knight Lab Larry’s 40 Stool Samples Over 3.5 Years to Rob’s lab on April 30, 2015
  34. 34. LS Weekly Weight During Period of 16S Microbiome Analysis Abrupt Change in Weight and in Symptoms at January 1, 2014 Lialda Uceris Frequent IBD Symptoms Weight Loss Few IBD Symptoms Weight Gain Source: Larry Smarr, UCSD
  35. 35. My Microbiome Ecology Time Series Over 3 Years Source Justine Debelius, Knight Lab, UC San Diego
  36. 36. Coloring Samples Before (Blue) and After (Red) January 2014 Reveals Clustering Source Justine Debelius, Knight Lab, UC San Diego
  37. 37. An Apparent Sudden Phase Change Occurs Source Justine Debelius, Knight Lab, UC San Diego
  38. 38. My Gut Microbiome Ecology Shifted After Drug Therapy Between Two Time-Stable Equilibriums Correlated to Physical Symptoms Lialda & Uceris 12/1/13 to 1/1/14 12/1/13- 1/1/14 Frequent IBD Symptoms Weight Loss 7/1/12 to 12/1/14 Blue Balls on Diagram to the Right Principal Coordinate Analysis of Microbiome Ecology PCoA by Justine Debelius and Jose Navas, Knight Lab, UCSD Weight Data from Larry Smarr, Calit2, UCSD Weekly Weight Few IBD Symptoms Weight Gain 1/1/14 to 8/1/15 Red Balls on Diagram to the Right
  39. 39. From N=1 to a Population of People with Disease 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 300 Enrolled Announced November 7, 2014
  40. 40. Combining Deep Metagenomics and Supercomputing Time to Map the Differences Between Health and Disease • Controls: 100s of Healthy Subjects • Smarr Gut Microbiome Time Series – ~80 Samples Over 5 Years • Hundreds of IBD Patients – Phenotyped Patients Drawn from Sandborn BioBank Knight/Smarr Labs Using 100 CPU-Years of Supercomputer Time
  41. 41. 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
  42. 42. 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
  43. 43. 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.” Will Medical Foods Provide New Tools for Altering Gut Microbiome?
  44. 44. 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 (CDC) 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
  45. 45. Massive Research is Underway to Discover A Wide Range of New Techniques for Manipulating Your Microbiome www.huffingtonpost.com/entry/gut-bacteria-microbiome-disease_us_57068c55e4b053766188f383 www.synlogictx.com
  46. 46. Center for Microbiome Innovation Seminars Faculty Hiring Education UCSD Microbial Sciences Initiative Instrument Cores Seed Grants Fellowships Chancellor Khosla Launched the UC San Diego Microbiome and Microbial Sciences Initiative October 29, 2015
  47. 47. Thanks to Our Great Team! Calit2@UCSD Future Patient Team Jerry Sheehan Tom DeFanti Joe Keefe John Graham Kevin Patrick Mehrdad Yazdani Jurgen Schulze Andrew Prudhomme Philip Weber Fred Raab Ernesto Ramirez JCVI Team Karen Nelson Shibu Yooseph Manolito Torralba Ayasdi Devi Ramanan Pek Lum UCSD Metagenomics Team Weizhong Li Sitao Wu SDSC Team Michael Norman Mahidhar Tatineni Robert Sinkovits UCSD Health Sciences Team David Brenner Rob Knight Lab Justine Debelius Jose Navas Gail Ackermann Greg Humphrey William J. Sandborn Lab Elisabeth Evans John Chang Brigid Boland Dell/R Systems Brian Kucic John Thompson

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