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The Human Microbiome, Supercomputers,and the Advancement of Medicine

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Keynote Presentation
Cavendish Global Health Impact Forum
San Diego, CA
June 22, 2016

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The Human Microbiome, Supercomputers,and the Advancement of Medicine

  1. 1. “The Human Microbiome, Supercomputers, and the Advancement of Medicine” Keynote Presentation Cavendish Global Health Impact Forum San Diego, CA June 22, 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. It’s a microbial world… …there are 100 million times as many bacteria on Earth as stars in the universe. Microbiology is the ultimate Big Data science! NASA: Hubble Deep Field
  3. 3. When the Earth’s Atmosphere Had No Oxygen Mineral Deposits Were Produced by Microbes James St. John, Wikimedia Commons
  4. 4. Microbes Transformed Planet Earth to a Home For Multicellular Life Photo by Josef Reischig via Wikipedia Cyanobacteria’s Waste Product was Oxygen
  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. Globally Connected Microbiome Genome Supercomputer and Repository $24.5M Grant in 2005 Larry Smarr, PI
  7. 7. Your Body Has 10 Times As Many Microbe Cells As DNA-Bearing Human Cells Your Microbiome is Your “Near-Body” Environment and its Cells Contain 300x as Many DNA Genes As Your Human DNA-Bearing Cells Inclusion of the “Dark Matter” of the Body Will Radically Alter Medicine
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. Treating the Human Superorganism: Your Body is an Ecology! Nature Reviews Microbiology v.9, p. 279 (2011)
  12. 12. 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
  13. 13. 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
  14. 14. I Decided to Track My Internal Biomarkers To Understand My Body’s Dynamics My Quarterly Blood DrawCalit2 64 Megapixel VROOM
  15. 15. 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
  16. 16. 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)
  17. 17. 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 Samples and Healthy and IBD Controls Illumina HiSeq 2000 at JCVI SDSC Gordon Data Supercomputer
  18. 18. 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)
  19. 19. Results Include Relative Abundance of Hundreds of Microbial Species Average Over 250 Healthy People From NIH Human Microbiome Project Note Log Scale Clostridium difficile
  20. 20. 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
  21. 21. 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
  22. 22. Invasive Species Take Over Gut Microbiome in Disease State 152x 765x 148x 849x 483x 220x 201x 522x 169x 20 Most Abundant Species Source: Sequencing JCVI; Analysis Weizhong Li, UCSD LS December 28, 2011 Stool Sample Relative Abundance In Gut Microbiome
  23. 23. 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)
  24. 24. 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 8/1/16 Red Balls on Diagram to the Right
  25. 25. Each Microbe Contains a Few Thousand Genes on Its DNA E. Coli Contains ~5000 Genes on its Circular Chromosome, Which is 1000x the Length of the Cell! Several Million Genes Can Occur in the Human Gut Microbiome
  26. 26. In a “Healthy” Gut Microbiome: Large Taxonomy Variation, Low Protein Family Variation Source: Nature, 486, 207-212 (2012) Over 200 People
  27. 27. We Discovered That Many Protein Families Are Very Over or Under-Abundant in the Disease State Source: Bryn Taylor, Justine Debelius, Rob Knight, Mehrdad Yazdani, Larry Smarr, UCSD; Weizhong Li, JCVI Note: Orders of Magnitude Increase or Decrease in Protein Families Between Health and Disease Next Step: Which Proteins (Functions) are Altered?
  28. 28. To Expand IBD Project the Knight/Smarr Labs Were Awarded ~ 1 Million Core-Hours on SDSC’s Comet Supercomputer • 8x Compute Resources Over Prior Study • Smarr Gut Microbiome Time Series – From 7 Samples Over 1.5 Years – To 70 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
  29. 29. Autoimmune Disease Overlap In Human Genome SNP Predisposition Gut Lees, et al. 60:1739-1753 (2011)
  30. 30. 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.”
  31. 31. Fecal Microbiome Transfer Is a Rapidly Growing New Treatment for IBD Dr. Bill Sandborn, Chief UCSD GI Dr. Brigid Boland, UCSD GI
  32. 32. 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
  33. 33. UCSD is Becoming a National Leader in the Human Microbiome
  34. 34. Building a UC San Diego High Performance Cyberinfrastructure to Support Distributed Integrative Omics FIONA 12 Cores/GPU 128 GB RAM 3.5 TB SSD 48TB Disk 10Gbps NIC Knight Lab 10Gbps Gordon Prism@UCSD Data Oasis 7.5PB, 200GB/s Knight 1024 Cluster In SDSC Co-Lo CHERuB 100Gbps Emperor & Other Vis Tools 64Mpixel Data Analysis Wall 120Gbps 40Gbps 1.3Tbps PRP/
  35. 35. 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
  36. 36. President Obama Announces National Microbiome Initiative May 13, 2016
  37. 37. 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

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