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“Inspired by Carl: Exploring the Microbial Dynamics Within”

“Inspired by Carl: Exploring the Microbial Dynamics Within”. Invited Talk Looking in the Right Direction: Carl Woese and the New Biology University of Illinois, Urbana-Champaign September 20, 2015. Dr. Larry Smarr

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“Inspired by Carl: Exploring the Microbial Dynamics Within”

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  1. “Inspired by Carl: Exploring the Microbial Dynamics Within” Invited Talk Looking in the Right Direction: Carl Woese and the New Biology University of Illinois, Urbana-Champaign September 20, 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 http://lsmarr.calit2.net

  2. Carl Woese Was My Mentor for Microbial Genomics To Larry Smarr: “I want to talk to you about setting up a megabase sequencing unit at the U of I I take this as necessary to the survival of good biology on this campus, for it is clear that megabase sequencing will be a major biological activity in the future. - Carl Woese, July 6, 1995 To Carl Woese: “What I have always understood is that you were responsible for ‘turning Larry Smarr on’ to biology, to evolution, to the adventures in living systems.”– John Wooley, July 26, 2006 Last visit to Carl and Gay at their house Sept 20, 2009

  3. There are 100 billion stars in the Andromeda galaxy… • …and 100 billion galaxies in the • known universe.

  4. 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!

  5. Carl’s Late Thoughts on the Critical Need for Research in Microbial Ecologies The second major direction involves the nature of the global ecosystem. . . . Bacteria are the major organisms on this planet—in numbers, in total mass, in importance to the global balances. Thus, it is microbial ecology that . . . is most in need of development, both in terms of facts needed to understand it, and in terms of the framework in which to interpret them.” -Carl WoeseCurrent Biology 15: R111–R112 (2005). I started intensively working on microbial ecologies in 2005

  6. PI Larry Smarr Grant Announced January 17, 2006

  7. Calit2 Microbial Metagenomics Cluster-Next Generation Optically Linked Science Data Server Source: Phil Papadopoulos, SDSC, Calit2 ~200TB Sun X4500 Storage 10GbE 512 Processors ~5 Teraflops ~ 200 Terabytes Storage 1GbE and 10GbE Switched/ Routed Core

  8. Calit2 CAMERA: 0ver 4000 Registered Users From Over 90 Countries

  9. The Human Gut Starting Showing Up as a Another Microbial Environment Being Metagenomically Sampled

  10. The Human Gut as a Super-Evolutionary Microbial Cauldron • Enormous Density • 1000x Ocean Water • Highly Dynamic Microbial Ecology • Hundreds to Thousands of Species • Horizontal Gene Transfer • Phages • Adaptive Selection Pressures (Immune System) • Innate Immune System • Adaptive Immune System • Macrophages and Antimicrobial proteins • Constantly Changing Environmental Pressures • Diet • Antibiotics • Pharmaceuticals

  11. To Better Understand the Human Gut DynamicsI Have Turned My Body into a Genomic and Biomarker Observatory One Blood Draw For Me • Calit2 64 Megapixel VROOM

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

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

  14. Evolving Microbiome Environmental Pressures: Dynamical Innate and Adaptive Immune Oscillations in Colon These Must Be Coupled to A Dynamic Microbiome Ecology Adaptive Immune System Normal 50 to 200 Innate Immune System Normal <600

  15. For Deep Analysis of Changes in the Gut Microbiome EcologyOur Team Compared a Healthy Population with 3 Types of IBD Each Sample Has 100-200 Million Illumina Short Reads (100 bases) “Healthy” Individuals Inflammatory Bowel Disease (IBD) Patients 250 Subjects 1 Point in Time 2 Ulcerative Colitis Patients, 6 Points in Time Larry Smarr (Colonic Crohn’s) 7 Points in Time 5 Ileal Crohn’s Patients, 3 Points in Time Total of 27 Billion Reads Or 2.7 Trillion Bases Source: Jerry Sheehan, Calit2 Weizhong Li, Sitao Wu, CRBS, UCSD

  16. To Map Out the Dynamics of Autoimmune Microbiome Ecology Couples Next Generation Genome Sequencers to Big Data Supercomputers Illumina HiSeq 2000 at JCVI Example: Inflammatory Bowel Disease (IBD) • We Used 25 CPU-Years • to Compute • Comparative Gut Microbiomes • of my 7 Time Samples, • 255 Healthy, • and 20 IBD Patients SDSC Gordon Data Supercomputer

  17. UCSD’s Integrated Digital Infrastructure (IDI) InitiativeEnhanced Cyberinfrastructure to Support Knight Lab for Microbial Genomics Knight 1024 Cluster In SDSC Co-Lo Data Oasis 7.5PB, 100GB/s Knight Lab CHERuB 100Gbps 120Gbps Emperor & Other Vis Tools 10Gbps 40Gbps FIONA 12 Cores/GPU 128 GB RAM 3.5 TB SSD 48TB Disk 10Gbps NIC Gordon 64Mpixel Data Analysis Wall Prism@UCSD

  18. Resulting Microbiome Profiles Allow Us to Quickly Find 1 Unhealthy Person Out of 155 HMP “Healthy” Subjects 75 Most Abundant Species

  19. Dell Analytics Separates The 4 Patient Types in Our DataUsing Our Microbiome Species Data Ulcerative Colitis Colonic Crohn’s Healthy Ileal Crohn’s Source: Thomas Hill, Ph.D. Executive Director Analytics Dell | Information Management Group, Dell Software

  20. I Built on Dell Analytics to Show Dynamic Evolution of My Microbiome Toward and Away from Healthy State – Colonic Crohn’s Seven Time Samples Over 1.5 Years Healthy Colonic Crohn’s Ileal Crohn’s

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

  22. We Find Large Changes in Gut Microbial Abundance: IlealCD Average Compared to Healthy Average by Family 30 Families >10x or <1/10x (Out of 76 Families with > 0.1% Abundance) 235x 1/320x

  23. Our Research Shows Even Larger Changes in Protein Family Abundance Between Health and Disease – IlealCrohns Ratio of Ileal CD Average to Healthy Average for Each Nonzero KEGG Note Hi/Low Symmetry KEGGs Greatly Increased In the Disease State Most KEGGs Are Within 10x In Healthy and Ileal Crohn’s Disease KEGGs Greatly Decreased In the Disease State Over 7000 KEGGs Which Are Nonzero in Health and Disease States

  24. Our Relative Abundance Results Across ~300 People Reveal Potential Diagnostic Species UC 100x Healthy Healthy 100x CD UC 100x CD We Produced Similar Results for ~2500 Microbial Species

  25. The Woese Effect:I Seem to Have a Large Amount of Archaea in my Gut 18% LS Average 175x Healthy Average

  26. Next Step: Discover How the Time Varying Immune System & PharmaDrives Adaptive Changes in the Microbiome Ecology Immune & Inflammation Variables 2012 2013 2015 2011 2014 2009 2010 Weekly Symptoms Pharma Therapies Stool Samples First 7

  27. To Expand IBD Project the Knight/Smarr Labs Were Just Awarded ~ 1 CPU-Century Supercomputing Time 8x Compute Resources Over Prior Study • 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 PavelPevzner

  28. Bringing the Lessons of Microbial Ecologyto Healthcare

  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 Coupled Neural, Immune, and Microbiome SystemsProvide a Model Explaining How Nutrition Can Alter Neurodevelopment

  31. Thanks to Our Great Team! UCSD MetagenomicsTeam 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 PekLum JCVI Team Karen Nelson ShibuYooseph ManolitoTorralba SDSC Team Michael Norman MahidharTatineni Robert Sinkovits Dell/R Systems Brian Kucic John Thompson UCSD Health Sciences Team Rob Knight Lab William J. Sandborn Elisabeth Evans John Chang Brigid Boland David Brenner

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