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

2. It’s a microbial world…
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!

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

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

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

6. Supercomputer and Repository
Globally Connected
Microbiome Genome
Supercomputer and Repository
$24.5M Grant in 2005
Larry Smarr, PI

7. Your Microbiome is Your “Near-Body” Environment and its Cells
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. However, Red Blood Cells and Platelets Have No Nuclear DNA.
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. But All These Animals Are in One SubPhylum Vertebrata
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. 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 WikiMedia Commons. Photos are public domain or by Dan Hershman, Michael Linnenbach, Manuae, B_cool

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

12. We Must Move From Combating Single Microbe Diseases to Developing the Human/Microbiome System Approach to Public Health
2014
Bach (2002) N Engl J Med, Vol. 347,
For Public Health It is Still About Microbes,
But from Single Species to Entire Ecologies

13. [Amerindians in Venezuela/Columbia]
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 (2015).

14. My Quarterly Blood Draw
I Decided to Track My Internal Biomarkers To Understand My Body’s Dynamics
My Quarterly Blood Draw
Calit2 64 Megapixel VROOM

15. Episodic Peaks in Inflammation Followed by Spontaneous Drops
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

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

17. Our Team Used 25 CPU-years to Compute Comparative Gut Microbiomes
To Map Out the Dynamics of Autoimmune Microbiome Ecology Couples Next Generation Genome Sequencers to Big Data Supercomputers
Source: Weizhong Li, UCSD
Illumina HiSeq 2000 at JCVI
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
SDSC Gordon Data Supercomputer

18. We Gathered Raw Illumina Reads on 275 Humans and Generated a Time Series of My Gut Microbiome
Each Sample Has 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

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

21. Source: Ponderosa Pine Fire Ecology
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

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

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, (2012)

24. Blue Balls on Diagram to the Right Red Balls on Diagram to the Right
My Gut Microbiome Ecology Shifted After Drug Therapy Between Two Time-Stable Equilibriums Correlated to Physical Symptoms
Frequent IBD Symptoms
Weight Loss
7/1/12 to 12/1/14
Blue Balls on Diagram to the Right
Weekly Weight
Few IBD Symptoms
Weight Gain
1/1/14 to 8/1/16
Red Balls on Diagram to the Right
12/1/13 to 1/1/14
12/1/13-1/1/14
Lialda & Uceris
Principal Coordinate Analysis of Microbiome Ecology
PCoA by Justine Debelius and Jose Navas, Knight Lab, UCSD
Weight Data from Larry Smarr, Calit2, UCSD

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

27. 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

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

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

32. Massive Research is Underway to Discover A Wide Range of New Techniques for Manipulating Your Microbiome

33. UCSD is Becoming a National Leader in the Human Microbiome

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
Data Oasis
7.5PB, 200GB/s
Knight 1024 Cluster
In SDSC Co-Lo
CHERuB
100Gbps
Emperor & Other Vis Tools
64Mpixel Data Analysis Wall
120Gbps
1.3Tbps
PRP/
40Gbps

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

36. President Obama Announces National Microbiome Initiative May 13, 2016

37. Thanks to Our Great Team!
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
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