The Human Microbiome Supercomputers and the Advancement of

“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. calit 2. net 1

NASA: Hubble Deep Field 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!

When the Earth’s Atmosphere Had No Oxygen Mineral Deposits Were Produced by Microbes James St. John, Wikimedia Commons

Microbes Transformed Planet Earth to a Home For Multicellular Life Cyanobacteria’s Waste Product was Oxygen Photo by Josef Reischig via Wikipedia

Most of Evolutionary Time Was in the Microbial World You Are Here Tree of Life Derived from 16 S r. RNA Sequences Source: Carl Woese, et al

Globally Connected Microbiome Genome Supercomputer and Repository $24. 5 M Grant in 2005 Larry Smarr, PI

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 300 x as Many DNA Genes As Your Human DNA-Bearing Cells Inclusion of the “Dark Matter” of the Body Will Radically Alter Medicine

New Estimates In 2016 Estimate a Human Body Contains ~30 Trillion Human Cells and ~40 Trillion Microbes DNA-Bearing Cells However, Red Blood Cells and Platelets Have No Nuclear DNA. Therefore, Ratio of DNA-Bearing Cells for Human vs. Microbiome is Still >10: 1

When We Think About Biological Diversity We Typically Think of the Wide Range of Animals But All These Animals Are in One Sub. Phylum Vertebrata of the Chordata Phylum All images from Wikimedia Commons. Photos are public domain or by Trisha Shears & Richard Bartz

Think of These Phyla of Animals When You Consider the Biodiversity of Microbes Inside You Phylum Chordata Phylum Cnidaria Phylum Echinodermata Phylum Annelida Phylum Mollusca Phylum Arthropoda All images from Wiki. Media Commons. Photos are public domain or by Dan Hershman, Michael Linnenbach, Manuae, B_cool

Treating the Human Superorganism: Your Body is an Ecology! Nature Reviews Microbiology v. 9, p. 279 (2011)

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 For Public Health It is Still About Microbes, But from Single Species to Entire Ecologies 2014

The United States Population’s Human Gut Microbiome Has Diverged a Great Deal from Hunter-Gatherers [Amerindians in Venezuela/Columbia] [Africa] Missing Microbes Human Microbiome Project “The microbiome of uncontacted Amerindians, ” J. C. Clemente, et al. Science Advances 1, e 1500183 (2015).

I Decided to Track My Internal Biomarkers To Understand My Body’s Dynamics Calit 2 64 Megapixel VROOM My Quarterly Blood Draw

Only One of My Blood Measurements Was Far Out of Range--Indicating Chronic Inflammation 27 x 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

Adding Stool Tests Revealed Oscillatory Behavior in an Immune Variable Which is Antibacterial Typical Lactoferrin Value for Active Inflammatory Bowel Disease (IBD) 124 x Upper Limit for Healthy Normal Range <7. 3 µg/m. L Lactoferrin is a Protein Shed from Neutrophils An Antibacterial that Sequesters Iron

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 Hi. Seq 2000 at JCVI SDSC Gordon Data Supercomputer

We Gathered Raw Illumina Reads on 275 Humans and Generated a Time Series of My Gut Microbiome Each Sample Has 100 -200 Million Illumina Short Reads (100 bases) “Healthy” Individuals Inflammatory Bowel Disease (IBD) Patients 250 Subjects 1 Point in Time Larry Smarr (Colonic Crohn’s) 2 Ulcerative Colitis Patients, 6 Points in Time 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, Calit 2 Weizhong Li, Sitao Wu, CRBS, UCSD

Results Include Relative Abundance of Hundreds of Microbial Species Note Log Scale Average Over 250 Healthy People From NIH Human Microbiome Project Clostridium difficile

We Found Major State Shifts in Microbial Ecology Phyla Between Healthy and Three Forms of IBD Average HE Most Common Microbial Phyla Average Ulcerative Colitis Average LS Colonic Crohn’s Disease Average Ileal Crohn’s Disease

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

Invasive Species Take Over Gut Microbiome in Disease State 152 x 765 x 148 x Relative Abundance In Gut Microbiome 20 Most Abundant Species 849 x 483 x 220 x 201 x 169 x 522 x Source: Sequencing JCVI; Analysis Weizhong Li, UCSD LS December 28, 2011 Stool Sample

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)

My Gut Microbiome Ecology Shifted After Drug Therapy Between Two Time-Stable Equilibriums Correlated to Physical Symptoms Weekly Weight Frequent IBD Symptoms Weight Loss 7/1/12 to 12/1/14 Few IBD Symptoms Weight Gain 1/1/14 to 8/1/16 Blue Balls on Diagram to the Right 12/1/131/1/14 Lialda & Uceris 12/1/13 to 1/1/14 Red Balls on Diagram to the Right Principal Coordinate Analysis of Microbiome Ecology PCo. A by Justine Debelius and Jose Navas, Knight Lab, UCSD Weight Data from Larry Smarr, Calit 2, UCSD

Each Microbe Contains a Few Thousand Genes on Its DNA E. Coli Contains ~5000 Genes on its Circular Chromosome, Which is 1000 x the Length of the Cell! Several Million Genes Can Occur in the Human Gut Microbiome

In a “Healthy” Gut Microbiome: Large Taxonomy Variation, Low Protein Family Variation Over 200 People Source: Nature, 486, 207 -212 (2012)

We Discovered That Many Protein Families Are Very Over or Under-Abundant in the Disease State Note: Orders of Magnitude Increase or Decrease in Protein Families Between Health and Disease Next Step: Which Proteins (Functions) are Altered? Source: Bryn Taylor, Justine Debelius, Rob Knight, Mehrdad Yazdani, Larry Smarr, UCSD; Weizhong Li, JCVI

To Expand IBD Project the Knight/Smarr Labs Were Awarded ~ 1 Million Core-Hours on SDSC’s Comet Supercomputer • 8 x 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 Bio. Bank – 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

Autoimmune Disease Overlap In Human Genome SNP Predisposition Gut Lees, et al. 60: 1739 -1753 (2011)

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. ”

Fecal Microbiome Transfer Is a Rapidly Growing New Treatment for IBD Dr. Bill Sandborn, Chief UCSD GI Dr. Brigid Boland, UCSD GI

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_57068 c 55 e 4 b 053766188 f 383 www. synlogictx. com

UCSD is Becoming a National Leader in the Human Microbiome

Building a UC San Diego High Performance Cyberinfrastructure to Support Distributed Integrative Omics Knight 1024 Cluster In SDSC Co-Lo Gordon 1. 3 Tbps PRP/ Knight Lab Data Oasis 7. 5 PB, 200 GB/s CHERu. B 100 Gbps 120 Gbps 10 Gbps FIONA 12 Cores/GPU 128 GB RAM 3. 5 TB SSD 48 TB Disk 10 Gbps NIC Emperor & Other Vis Tools 40 Gbps Prism@UCSD 64 Mpixel Data Analysis Wall

Chancellor Khosla Launched the UC San Diego Microbiome and Microbial Sciences Initiative October 29, 2015 UCSD Microbial Sciences Initiative Center for Microbiome Innovation Seminars Instrument Cores Source: Rob Knight, UCSD Faculty Hiring Seed Grants Fellowships Education

President Obama Announces National Microbiome Initiative May 13, 2016

Thanks to Our Great Team! Calit 2@UCSD Future Patient Team Jerry Sheehan Tom De. Fanti 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 Dell/R Systems Brian Kucic John Thompson Thomas Hill 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