measuring the human brain-gut microbiome-immune system dynamics: a big data challenge
TRANSCRIPT
“Measuring the Human Brain-Gut Microbiome-Immune System Dynamics: a Big Data Challenge”
Plenary Talk
45th Annual Meeting of the Behavior Genetics Association
San Diego, CA
June 18, 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.net1
June 8, 2012 June 14, 2012
Interest in the Human MicrobiomeHas Moved Quickly From Frontier Science to Public Awareness
August 18, 2012June, 2012
To Understand the Interaction of Genetics and Human BehaviorWe Must Consider the Human Microbiome
Your Microbiome is Your “Near-Body” Environment
and its CellsContain 300x
as Many DNA GenesAs Your Human Cells
Your Body Has 10 Times As Many Microbe Cells As Human Cells
The Microbiome–Gut–Brain AxisProvides New Systemic Insights into Shifts in Behavior and Disease
Source: Montiel-Castro, et al. Frontiers in Integrative Neuroscience 2013
Many New Research Studies are Demonstrating Deep Relationships Between the Gut Microbiome and Behavioral Disorders
Gut Microbes Regulate Serotonin Production,90% of Which is in the Large Intestine
“It's almost unthinkable that the gut is not playing a critical role in mind states,"
says gastroenterologist Emeran Mayer, MD, director of the Center for Neurobiology of Stress at UCLA
Cell 161 264-276 (2015)
How Can One Combine Human Genetic GWASWith Gut Microbiome Metagenomics and Immune System Dynamics?
An N=1 Case Study of an Autoimmune Disease
I Have Turned My Body into a Genomic and Biomarker Observatory
One Blood DrawFor MeCalit2 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)
I Turned to SNP Analysis and GWAS to Understand My Human Genomic Predispositions
I Found I Had One of the Earliest Known SNPsAssociated with Crohn’s Disease
From www.23andme.com
SNPs Associated with CD
Polymorphism in Interleukin-23 Receptor Gene
— 80% Higher Risk of Pro-inflammatoryImmune Response
rs1004819
NOD2
IRGM
ATG16L1
There May Be a Correlation Between CD SNPsand Where and When the Disease Manifests
Me-MaleCD Onset
At 60-Years Old
Female CD Onset
At 20-Years Old
NOD2 (1)Rs2066844
2.08x Increased Risk
Il-23RRs1004819
1.8x Increased Risk
Subject withIleal Crohn’s
Subject withColonic Crohn’s
Source: Larry Smarr and 23andme
I Also Had an Increased Risk for Ulcerative Colitis,But a SNP that is Also Associated with Colonic CD
I Have a 33% Increased Risk for Ulcerative Colitis
HLA-DRA (rs2395185)
I Have the Same Level of HLA-DRA Increased Risk
as Another Male Who Has HadUlcerative Colitis for 20 Years
“Our results suggest that at least for the SNPs investigated [including HLA-DRA],
colonic CD and UC have common genetic basis.”-Waterman, et al., IBD 17, 1936-42 (2011)
So IBD May be Stratified by a Personalized Combinationof the 163 Known SNP Loci Associated with IBD
The width of the bar is proportional to the variance explained by that locus
“Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease,” Jostins, et al. Nature 491, 119-124 (2012)
Could Changes in the Microbiome Ecology and Genetic StructureProvide Some of the Missing Variance?
However, the Total Disease Variance Explained Is Only:• 13.6% for Crohn’s• 7.5% for Ulcerative Colitis
Why Did I Have an Autoimmune Disease like IBD?
Despite decades of research, the etiology of Crohn's disease
remains unknown. Its pathogenesis may involve a complex interplay between
host genetics, immune dysfunction,
and microbial or environmental factors.--The Role of Microbes in Crohn's Disease
Paul B. Eckburg & David A. RelmanClin Infect Dis. 44:256-262 (2007)
I Have Been Quantifying All Three
The Genetic Distance Between MicrobesVastly Exceeds That Among All Animals and Plants
You Are
Here
Source: Carl Woese, et al
Tree of Life Derived from 16S rRNA Sequences
For Deep Analysis of Changes in the Gut Microbiome EcologyOur Team Compared a Healthy Population with 3 Types of IBD
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) Patients
250 Subjects1 Point in Time
7 Points in Time
Each Sample Has 100-200 Million Illumina Short Reads (100 bases)
Larry Smarr(Colonic Crohn’s)
From Swedish Twin Study
To Map Out the Dynamics of Autoimmune Microbiome Ecology Couples Next Generation Genome Sequencers to Big Data Supercomputers
Illumina HiSeq 2000 at JCVI
SDSC Gordon Data Supercomputer
Example: Inflammatory Bowel Disease (IBD)
We used 25 CPU-yearsto compute
comparative gut microbiomesstarting from
7 trillion DNA bases of my samples,
255 healthy, and 20 IBD controls
Computational NextGen Sequencing Pipeline:From Sequence to Taxonomy and Function
PI: (Weizhong Li, CRBS, UCSD): NIH R01HG005978 (2010-2013, $1.1M)
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
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
Collapse of BacteroidetesExplosion of Actinobacteria
Explosion of Proteobacteria
Hybrid of UC and CDHigh Level of Archaea
Dell Analytics Separates The 4 Patient Types in Our DataUsing Our Microbiome Species Data
Source: Thomas Hill, Ph.D.Executive Director Analytics
Dell | Information Management Group, Dell Software
Healthy
Ulcerative Colitis
Colonic Crohn’s
Ileal Crohn’s
I Built on Dell Analytics to Show Dynamic Evolution of My Microbiome Toward and Away from Healthy State – Colonic Crohn’s
Healthy
Ileal Crohn’s
Seven Time Samples Over 1.5 Years
Colonic Crohn’s
This Year We Will Extend My Stool Time SeriesCollaborating with the UCSD Knight Lab
Larry’s 40 Stool Samples Over 3.5 Years to Rob’s lab on April 30, 2015
Time Series Reveals Behavior Changes (Depression, Malaise)Associated with Time Progression of Autoimmune Disease
Immune &Inflammation
Variables
Weekly Symptoms
PharmaTherapies
StoolSamples
Mood Disorders
2009 20142013201220112010 2015
In a “Healthy” Gut Microbiome:Large Taxonomy Variation, Low Protein Family Variation
Source: Nature, 486, 207-212 (2012)
Over 200 People
We Computed the Relative Abundance of Microbial Gene Families -~10,000 KEGG Orthologous Genes, Across Healthy and IBD Subjects
How Large is the Microbiome’s Genetic ChangeBetween Health and Disease States?
Ratio of One of the Healthy Subjects to the Average KEGG for 35 Healthy:Test to see How Much Inter-Personal Variation There is Within Healthy
Most KEGGs Are Within 10xOf Healthy for a Random HE
Ratio of Random HE11529 to Healthy Average for Each Nonzero KEGG
Nonzero KEGGs
We Computed the Relative
Abundance of 10,000 KEGGsin 35 HealthyAnd 25 IBD
Patients
However, Our Research Shows Large Changes in Protein Families Between Health and Disease
Most KEGGs Are Within 10xIn Healthy and Ileal Crohn’s Disease
KEGGs Greatly IncreasedIn the Disease State
KEGGs Greatly DecreasedIn the Disease State
Over 7000 KEGGs Which Are Nonzero in Health and Disease States
Ratio of CD Average to Healthy Average for Each Nonzero KEGG
Note Hi/LowSymmetry
Note 700 KEGGsWith Ratio >10
Note 1000 KEGGsWith Ratio <0.1
Next Step: Compute Genes and Function For All ~300 People’s Gut Microbiome
Full Processing to Function:Genes & Protein Families
(COGs, KEGGs)
Would Require ~1-2 Million Core-Hours
UC San Diego Will Be Carrying Out a Major Clinical Study of IBD Using These Techniques
Inflammatory Bowel Disease BiobankFor Healthy and Disease Patients
Drs. William J. Sandborn, John Chang, & Brigid BolandUCSD School of Medicine, Division of Gastroenterology
Already 185 Enrolled
Announced November 7, 2014!
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
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
The Coupled Neural, Immune, and Microbiome SystemsProvide a Model Explaining How Nutrition Can Alter Neurodevelopment
Thanks to Our Great Team!
UCSD Metagenomics TeamWeizhong LiSitao Wu
Calit2@UCSD Future Patient TeamJerry SheehanTom DeFantiKevin PatrickJurgen SchulzeAndrew PrudhommePhilip WeberFred RaabJoe KeefeErnesto Ramirez
AyasdiDevi RamananPek Lum
JCVI TeamKaren NelsonShibu YoosephManolito Torralba
SDSC TeamMichael NormanMahidhar Tatineni Robert Sinkovits
UCSD Health Sciences TeamRob KnightWilliam J. SandbornElisabeth EvansJohn ChangBrigid BolandDavid Brenner
Dell/R SystemsBrian KucicJohn Thompson