“The Human Microbiome, Supercomputers,and the Advancement of Medicine”

Keynote PresentationCavendish Global Health Impact Forum

San Diego, CAJune 22, 2016

Dr. Larry SmarrDirector, California Institute for Telecommunications and Information Technology

Harry E. Gruber Professor, Dept. of Computer Science and Engineering

Jacobs School of Engineering, UCSDhttp://lsmarr.calit2.net

1

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

When the Earth’s Atmosphere Had No OxygenMineral Deposits Were Produced by Microbes

James St. John, Wikimedia Commons

Microbes Transformed Planet Earth to a HomeFor Multicellular Life

Photo by Josef Reischig via Wikipedia

Cyanobacteria’s Waste Product

was Oxygen

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

Globally ConnectedMicrobiome Genome

Supercomputer and Repository

$24.5M Grant in 2005Larry 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 CellsContain 300x as Many DNA GenesAs Your Human DNA-Bearing Cells

Inclusion of the “Dark Matter” of the BodyWill Radically Alter Medicine

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

When We Think About Biological DiversityWe Typically Think of the Wide Range of Animals

But All These Animals Are in One SubPhylum Vertebrataof 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

All images from WikiMedia Commons. Photos are public domain or by Dan Hershman, Michael Linnenbach, Manuae, B_cool

PhylumAnnelida

PhylumEchinodermata

PhylumCnidaria

PhylumMollusca

Phylum Arthropoda

PhylumChordata

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, 911-9202014For Public Health It is Still About Microbes,

But from Single Species to Entire Ecologies

The United States Population’s Human Gut MicrobiomeHas 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]

HumanMicrobiomeProject

Missing Microbes

I Decided to Track My Internal BiomarkersTo Understand My Body’s Dynamics

My QuarterlyBlood DrawCalit2 64 Megapixel VROOM

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

Adding Stool Tests RevealedOscillatory 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

TypicalLactoferrin Value for Active Inflammatory

Bowel Disease (IBD)

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-yearsto Compute

Comparative Gut MicrobiomesStarting From

2.7 Trillion DNA Bases of My Samples

and Healthy and IBD Controls

Illumina HiSeq 2000 at JCVI

SDSC Gordon Data Supercomputer

We Gathered Raw Illumina Reads on 275 Humansand 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, Calit2Weizhong Li, Sitao Wu, CRBS, UCSD

Total of 27 Billion ReadsOr 2.7 Trillion Bases

Inflammatory Bowel Disease (IBD) Patients250 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)

Results Include Relative Abundance of Hundreds of Microbial Species

Average Over 250 Healthy PeopleFrom NIH Human Microbiome Project

Note Log Scale

Clostridium difficile

We Found Major State Shifts in Microbial Ecology PhylaBetween Healthy and Three Forms of IBD

Most Common Microbial

Phyla

Average HE

Average Ulcerative Colitis

Average LSColonic 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

152x

765x

148x

849x483x

220x201x

522x169x

20 Most Abundant Species

Source: Sequencing JCVI; Analysis Weizhong Li, UCSDLS December 28, 2011 Stool Sample

Relative AbundanceIn Gut Microbiome

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 RelmanScience 336, 1255-62 (2012)

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 SymptomsWeight 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 SymptomsWeight Gain 1/1/14 to 8/1/16

Red Balls on Diagram to the Right

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

In a “Healthy” Gut Microbiome:Large Taxonomy Variation, Low Protein Family Variation

Source: Nature, 486, 207-212 (2012)

Over 200 People

We Discovered That Many Protein FamiliesAre 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?

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

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 TransferIs 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_57068c55e4b053766188f383

www.synlogictx.com

UCSD is Becoming a National Leader in the Human Microbiome

Building a UC San Diego High Performance Cyberinfrastructureto Support Distributed Integrative Omics

FIONA12 Cores/GPU128 GB RAM3.5 TB SSD48TB Disk

10Gbps NIC

Knight Lab

10Gbps

Gordon

Prism@UCSD

Data Oasis7.5PB,

200GB/s

Knight 1024 ClusterIn SDSC Co-Lo

CHERuB100Gbps

Emperor & Other Vis Tools

64Mpixel Data Analysis Wall

120Gbps

40Gbps

1.3TbpsPRP/

Center for Microbiome Innovation

Seminars Faculty Hiring Education

UCSD Microbial Sciences Initiative

InstrumentCores

Seed GrantsFellowships

Chancellor Khosla Launched the UC San Diego Microbiome and Microbial Sciences Initiative October 29, 2015

Source: Rob Knight, UCSD

President Obama Announces National Microbiome InitiativeMay 13, 2016

Thanks to Our Great Team!

Calit2@UCSD Future Patient TeamJerry SheehanTom DeFanti Joe Keefe John GrahamKevin PatrickMehrdad YazdaniJurgen Schulze Andrew Prudhomme Philip Weber Fred RaabErnesto Ramirez

JCVI TeamKaren Nelson Shibu Yooseph Manolito Torralba

AyasdiDevi RamananPek Lum

UCSD Metagenomics TeamWeizhong Li Sitao Wu

SDSC TeamMichael Norman Mahidhar Tatineni Robert Sinkovits Ilkay Altintas

UCSD Health Sciences TeamDavid BrennerRob Knight Lab Justine Debelius Jose Navas Bryn Taylor Gail Ackermann Greg HumphreyWilliam J. Sandborn Lab Elisabeth Evans John Chang Brigid Boland

Dell/R SystemsBrian KucicJohn Thompson Thomas Hill