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Discovering the 100 Trillion Bacteria Living Within Each of Us


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Guest Lecture
Pharmacy Informatics
University of California, San Diego
May 23, 2016

Published in: Data & Analytics
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Discovering the 100 Trillion Bacteria Living Within Each of Us

  1. 1. “Discovering the 100 Trillion Bacteria Living Within Each of Us” Guest Lecture Pharmacy Informatics University of California, San Diego May 23, 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 1
  2. 2. Lecture Objectives • What is the Human Microbiome? • The Explosion of Research and Public Interest in the Human Microbiome • The Impact of Pharmaceuticals on the Microbiome Ecology • Healthy Means Homeostasis and Stability in the Microbiome • How the Microbiome is Shaped in the First Three Years of Life - Critical for Future Health • Tracking Your Microbiome Ecology in Health and Disease • Measuring the Impact of Pharmaceutical Therapy on the Microbiome • New Non-Pharmaceutical Therapies Emerging • The Explosion of Big Data in Pharmacy Informatics
  3. 3. 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 300x 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
  4. 4. 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
  5. 5. Most of Evolutionary Time Was in the Microbial World You Are Here Source: Carl Woese, et al Tree of Life Derived from 16S rRNA Sequences
  6. 6. 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
  7. 7. 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
  8. 8. The Cost of Sequencing DNA Has Fallen Over 10,000x in the Last Ten Years This Has Enabled Sequencing of Both Human and Microbial Genomes
  9. 9. Treating the Human Superorganism: Your Body Has Ten Microbes for Every Human Cell! Nature Reviews Microbiology v.9, p. 279 (2011)
  10. 10. June 8, 2012 June 14, 2012 Interest in the Human Microbiome Has Moved Quickly From Frontier Science to Public Awareness August 18, 2012June, 2012
  11. 11. UCSD is Becoming a National Leader in the Human Microbiome
  12. 12. 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 Source: Rob Knight, UCSD
  13. 13. President Obama Announces National Microbiome Initiative May 13, 2016
  14. 14. The Human Gut Microbiome and Pharmacy The gut microbiota have been shown to have an important influence, direct and indirect, on the metabolism and toxicity of a wide range of drugs and xenobiotics. The major drug-metabolizing capability of the gut microbiota is reductive metabolism, but demethylation, dehydroxylation, deacylation, decarboxylation, and hydrolysis reactions have also been demonstrated as well as acetylation. Microbiome-driven drug metabolism can result positively in the activation of prodrugs to their pharmacologically active forms or alternatively result in adverse consequences such as toxicity. In addition, the gut microbiota can affect drug metabolism and toxicity indirectly via, e.g., competition of bacterial-derived metabolites for xenobiotic metabolism pathways or the modulation of host metabolic systems.
  15. 15. 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 2014For Public Health It is Still About Microbes, But from Single Species to Entire Ecologies
  16. 16. 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] Human Microbiome Project Missing Microbes
  17. 17. How Does Your First Three Years Set You on a Course of Health or Illness For the Rest of Your Life?
  18. 18. • Impact of Birth Mode: Vaginal or C-Section
  19. 19. Source: Rob Knight, UCSD
  20. 20. • Impact of Early Use of Antibiotics on Microbiome Development
  21. 21. Infant (Stool) Mouth Stool Vagina Skin Source: Rob Knight, UCSD
  22. 22. Source: Rob Knight, UCSD
  23. 23. Source: Rob Knight, UCSD
  24. 24. Source: Rob Knight, UCSD
  25. 25. Source: Rob Knight, UCSD
  26. 26. How stable is our microbiome over time (if we’re healthy)?
  27. 27. Source: Rob Knight, UCSD Mouth Stool Vagina Skin
  28. 28. Source: Rob Knight, UCSD
  29. 29. Can our microbiome ecology shift over time (if we’re not healthy)?
  30. 30. Larry’s 40 Stool Samples Over 3.5 Years to Rob’s lab on April 30, 2015
  31. 31. Larry Smarr 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 5/1/12 to 12/1/14 Blue Balls on Diagram to the Right Few IBD Symptoms Weight Gain 1/1/14 to 1/1/16 Red 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 Antibiotics Prednisone 1/1/12 to 5/1/12 5/1/12 Weekly Weight (Red Dots Stool Sample) Few IBD Symptoms Weight Gain 1/1/14 to 1/1/16 Red Balls on Diagram to the Right
  32. 32. 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.”
  33. 33. Fecal Microbiome Transfer Is a Rapidly Growing New Treatment for IBD Dr. Bill Sandborn, Chief UCSD GI Dr. Brigid Boland, UCSD GI
  34. 34. Source: Rob Knight, UCSD
  35. 35. Source: Rob Knight, UCSD
  36. 36. • ` Source: Rob Knight, UCSD
  37. 37. To Expand IBD Project the Knight/Smarr Labs Were Awarded ~ 1 CPU-Century Supercomputing Time • Smarr Gut Microbiome Time Series – From 7 Samples Over 1.5 Years – To 50 Samples Over 4 Years • IBD Patients: From 5 Crohn’s Disease and 2 Ulcerative Colitis Patients to ~100 Patients – 50 Carefully Phenotyped Patients Drawn from Sandborn BioBank – 43 Metagenomes from the RISK Cohort of Newly Diagnosed IBD patients • New Software Suite from Knight Lab – Re-annotation of Reference Genomes, Functional / Taxonomic Variations – Novel Compute-Intensive Assembly Algorithms from Pavel Pevzner 8x Compute Resources Over Prior Study
  38. 38. Massive Research is Underway to Discover A Wide Range of New Techniques for Manipulating Your Microbiome
  39. 39. Genetic Sequencing of Humans and Their Microbes Is a Huge Growth Area and the Future Foundation of Medicine Source: @EricTopol Twitter 9/27/2014
  40. 40. 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 Ilkay Altintas UCSD Health Sciences Team David Brenner Rob Knight Lab Justine Debelius Jose Navas Bryn Taylor Gail Ackermann Greg Humphrey William J. Sandborn Lab Elisabeth Evans John Chang Brigid Boland Dell/R Systems Brian Kucic John Thompson Thomas Hill