The Human Microbiome, Supercomputers,and the Advancement of Medicine
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. 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. 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
Photo by Josef Reischig via Wikipedia
Cyanobacteria’s
Waste Product
was Oxygen
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
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. 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. 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
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. 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
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. 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. I Decided to Track My Internal Biomarkers
To Understand My Body’s Dynamics
My Quarterly
Blood DrawCalit2 64 Megapixel VROOM
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. 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. 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. 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. 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
Most
Common
Microbial
Phyla
Average HE
Average
Ulcerative Colitis
Average LS
Colonic Crohn’s Disease
Average
Ileal Crohn’s Disease
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. 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. 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. 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. 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
Source: Nature, 486, 207-212 (2012)
Over 200 People
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. 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
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
www.huffingtonpost.com/entry/gut-bacteria-microbiome-disease_us_57068c55e4b053766188f383
www.synlogictx.com
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/
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