Digitally Revealing the Dynamics of Your Superorganism Body

“Digitally Revealing the Dynamics
of Your Superorganism Body”
IEEE International Conference on
Healthcare Informatics 2013
Philadelphia, PA
September 10, 2013
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
1

Abstract
For over a decade, Calit2 has had a driving vision that healthcare is being
transformed into “digitally enabled genomic medicine.” To put a more personal
face on the "patient of the future," I have been increasingly quantifying my own
body. In addition to external markers I also currently track over 100 blood and
stool biomarkers every few months. Calit2 uses advanced interactive
visualization techniques to visually explore my organs. Using my saliva
23andme.com obtained 1 million single nucleotide polymorphisms (SNPs) in my
human DNA. My gut microbiome has been metagenomically sequenced by the
J. Craig Venter Institute, yielding 25 billion DNA bases. I will show how one can
use this Big Data approach to decipher the complex dynamic interactions
between the various components of my immune system and the human and
microbial DNA present in my “superorganism” body. Doing so in my case led to
the unexpected diagnosis of a chronic incurable disease. My hope is that by
"living in the future" I can provide some early insights into the digital
transformations of wellness and health care

Calit2 Has Been Had a Vision of
“the Digital Transformation of Health” for a Decade
• Next Step—Putting You On-Line!
– Wireless Internet Transmission
– Key Metabolic and Physical Variables
– Model -- Dozens of Processors and 60 Sensors /
Actuators Inside of our Cars
• Post-Genomic Individualized Medicine
– Combine
–Genetic Code
–Body Data Flow
– Use Powerful AI Data Mining Techniques
www.bodymedia.com
The Content of This Slide from 2001 Larry Smarr
Calit2 Talk on Digitally Enabled Genomic Medicine

The Calit2 Vision of Digitally Enabled Genomic Medicine
is an Emerging Reality
4
July/August 2011 February 2012

Where I Believe We are Headed: Predictive,
Personalized, Preventive, & Participatory Medicine
www.newsweek.com/2009/06/26/a-doctor-s-vision-of-the-future-of-medicine.html
I am Leroy Hood’s Lab Rat!

From One to a Billion Data Points Defining Me:
The Exponential Rise in Body Data in Just One Decade!
Billion: My Full DNA,
MRI/CT Images
Million: My DNA SNPs,
Zeo, FitBit
Hundred: My Blood VariablesOne:
My WeightWeight
Blood
Variables
SNPs
Microbial and
Human Genome
Improving Body
Discovering Disease

By Measuring the State of My Body and “Tuning” It
Using Nutrition and Exercise, I Became Healthier
2000
Age
41
2010
Age
61
1999
1989
Age
51
1999
I Arrived in La Jolla in 2000 After 20 Years in the Midwest
and Decided to Move Against the Obesity Trend
I Reversed My Body’s Decline By
Quantifying and Altering Nutrition and Exercise
http://lsmarr.calit2.net/repository/LS_reading_recommendations_FiRe_2011.pdf

Challenge-Develop Standards to Enable MashUps
of Personal Sensor Data Across Private Clouds
Withing/iPhone-
Blood Pressure
Zeo-Sleep
Azumio-Heart Rate
EM Wave PC-
Stress
MyFitnessPal-
Calories Ingested
FitBit -
Daily Steps &
Calories Burned

From Measuring Macro-Variables
to Measuring Your Internal Variables
www.technologyreview.com/biomedicine/39636

Invited Paper for Focus Issue of Biotechnology Journal,
Edited by Profs. Leroy Hood and Charles Auffray.
http://lsmarr.calit2.net/repository/Biotech_J.
_Supporting_Info_published.pdf
http://lsmarr.calit2.net/repository/Biotech_J.
_LS_published_article.pdf
Download Pdfs from my Portal:

Visualizing Time Series of
150 LS Blood and Stool Variables, Each Over 5 Years
Calit2 64 megapixel VROOM

Complex Reactive Protein
From Blood Samples
Normal Range
<1 mg/L
Normal
27x Upper Limit
Antibiotics
Antibiotics
Peak Sec IgA 1/30/12
Peak CRP, Calprotectin 12/28/11
Peak Lactoferrin 5/2/11
CRP is a Generic Measure of Inflammation in the Blood

Lactoferrin is Shed from Neutrophils
Into Stool Sample
Normal Range
<7.3 µg/mL
124x Upper Limit
Antibiotics
Peak Sec IgA 1/30/12
Peak CRP, Calprotectin 12/28/11
Peak Lactoferrin 5/2/11
Antibiotics
Lactoferrin is a Protein Shed from Neutrophils -
An Antibacterial that Sequesters Iron

High Lactoferrin Biomarker Led Me to Hypothesis
I Had Inflammatory Bowel Disease (IBD)
IBD is an Autoimmune Disease Which Comes in Two Subtypes:
Crohn’s and Ulcerative Colitis
High Level of Calprotectin
Confirmed Hypothesis
Scand J Gastroenterol.
42, 1440-4 (2007)
My Values 2009-10
My Values May 2011

Descending Colon
Sigmoid Colon
Threading Iliac Arteries
Major Kink
Confirming the IBD (Crohn’s) Hypothesis:
Finding the “Smoking Gun” with MRI Imaging
I Obtained the MRI Slices
From UCSD Medical Services
and Converted to Interactive 3D
Working With
Calit2 Staff & DeskVOX Software
Transverse Colon
Liver
Small Intestine
Diseased Sigmoid Colon
Cross Section
MRI Jan 2012

Converting MRI Slices Into 3D Interactive Virtual Reality
AND 3-D Printing
Research: Calit2 FutureHealth Team

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. Relman
Clin Infect Dis. 44:256-262 (2007)
So I Set Out to Quantify All Three!

I Wondered if Crohn’s is an Autoimmune Disease,
Did I Have a Personal Genomic Polymorphism?
From www.23andme.com
SNPs Associated with CD
Polymorphism in
Interleukin-23 Receptor Gene
— 80% Higher Risk
of Pro-inflammatory
Immune Response
NOD2
ATG16L1
IRGM
Now Comparing
163 Known IBD SNPs
with 23andme SNP Chip

I Had My Full Human Genome Sequenced in 2012 -
1 Million/Year by 2015
www.personalgenomes.org
My Anonymized Human Genome
is Available for Download
PGP Used Complete Genomics, Inc.
to Sequence my Human DNA
Next Step: Compare Full Genome With IBD SNPs

Fine Time-Resolution Sampling Reveals Dynamics of
Innate/Adaptive Immune System Dysfunction
Normal
Normal

LS Cultured Bacterial Abundance
Reveals Dynamic Microbiome Dysfunction

Next: Analyze the Dynamics of My Microbiome Ecology-
85% of the Species Can Not Be Cultured
Inclusion of the Microbiome
Will Radically Change Medicine
99% of Your
DNA Genes
Are in Microbe Cells
Not Human Cells
Your Body Has 10 Times
As Many Microbe Cells As Human Cells

To Map My Gut Microbes, I Sent a Stool Sample to
the Venter Institute for Metagenomic Sequencing
Gel Image of Extract from Smarr Sample-Next is Library Construction
Manny Torralba, Project Lead - Human Genomic Medicine
J Craig Venter Institute
January 25, 2012
Shipped Stool Sample
December 28, 2011
I Received
a Disk Drive April 3, 2012
With Two 35 GB FASTQ Files
Weizhong Li, UCSD
NGS Pipeline:
230M Reads
Only 0.2% Human
Required 1/2 cpu-yr
Per Person Analyzed!
Sequencing
Funding
Provided by
UCSD School of
Health Sciences

Additional Phenotypes Added from NIH HMP
For Comparative Analysis
5 Ileal Crohn’s, 3 Points in Time
6 Ulcerative Colitis, 1 Point in Time
35 “Healthy” Individuals
1 Point in Time

Gut Microbiome Metagenomic Datasets
One “Read” = 100 DNA Bases
Total of 1.2 Trillion Bases!
Source: Weizhong Li, CRBS, UCSD

Computational NextGen Sequencing Pipeline:
From “Big Equations” to “Big Data” Computing
PI: (Weizhong Li, CRBS, UCSD):
NIH R01HG005978 (2010-2013, $1.1M)

We Used SDSC’s Gordon Data-Intensive Supercomputer
to Analyze a Wide Range of Gut Microbiomes
• ~180,000 Core-Hrs on Gordon
– KEGG function annotation: 90,000 hrs
– Mapping: 36,000 hrs
– Used 16 Cores/Node
and up to 50 nodes
– Duplicates removal: 18,000 hrs
– Assembly: 18,000 hrs
– Other: 18,000 hrs
• Gordon RAM Required
– 64GB RAM for Reference DB
– 192GB RAM for Assembly
• Gordon Disk Required
– Ultra-Fast Disk Holds Ref DB for All Nodes
– 8TB for All Subjects
Enabled by
a Grant of Time
on Gordon from SDSC
Director Mike Norman

We Computationally Align 230M Illumina Short Reads
With a Reference Genome Set & Then Visually Analyze
~4500 Reference Genomes
with Strains and Viruses

We Still Don’t Know a Significant
Fraction of the Gut Genomes
Source: Weizhong Li, CRBS, UCSD
Illumina Short Reads Aligned Against
>5000 Complete or Draft Genomes

We Find Major Shifts in Microbial Ecology
Between Healthy and Two Forms of IBD
Collapse of
Bacteroidetes
Explosion of
Proteobacteria
Microbiome “Dysbiosis”
or “Mass Extinction”?
On the IBD Spectrum

Major Changes in LS Microbiome Before and After
1 Month Antibiotic & 2 Month Prednisone Therapy
Reduced 45x
Reduced 90x
Therapy Greatly Reduced Two Phyla,
But Massive Reduction in Bacteroidetes
And Large % Proteobacteria Remain
Small Changes
With No Therapy
How Does One Get Back
to a “Healthy” Gut Microbiome?

What Can We Learn About Early Disease Onset
As We Sequence the Microbiome More Deeply?

Does the Gut Microbiome Intermediate Between
Inflammation & the Development of Colorectal Cancer?
• Colon Cancer is the most common cancer among
Inflammatory Bowel Disease (IBD) patients
• IBD is one of the three leading high-risk factors for
Colon Cancer
The root cause of CRC is unclear,
but inflammation is a well-recognized risk factor
(Wu et al. 2009; McLean et al. 2011)

Inflammation Enables Anaerobic Respiration Which
Leads to Phylum-Level Shifts in the Gut Microbiome
Sebastian E. Winter, Christopher A. Lopez & Andreas J. Bäumler,
EMBO reports VOL 14, p. 319-327 (2013)

We Computed the Genes Which Define
761 E. coli Strains
90% Overlap of ~4000 Genes
Source: Weizhong Li, UCSD

Horizontal Gene Transfer Provides Pathogenic Strains:
Additional Fitness Factors Leading to Growth Advantage
Image from Zhang S., et al. Infect Immun 71: 1–12 (2003)
Sebastian E. Winter, Christopher A. Lopez & Andreas J. Bäumler,
EMBO reports VOL 14, p. 319-327 (2013)

LS Time Series Gut Microbiome Classes
vs. Healthy, Crohn’s, Ulcerative Colitis
Class
Gamma-
proteobacteria

E. coli/Shigella Phylogenetic Tree
Miquel, et al.
PLOS ONE, v. 5, p. 1-16 (2010)
Does Intestinal Inflammation Select for
Pathogenic Strains That Can Induce Further Damage?
“Adherent-invasive E. coli (AIEC)
are isolated more commonly
from the intestinal mucosa of
individuals with Crohn’s disease
than from healthy controls.”
“Thus, the mechanisms
leading to dysbiosis might also
select for intestinal colonization
with more harmful members of the
Enterobacteriaceae*
—such as AIEC—
thereby exacerbating inflammation
and interfering with its resolution.”
Sebastian E. Winter , et al.,
EMBO reports VOL 14, p. 319-327 (2013) *Family Containing E. coli
AIEC LF82

“Mucosa-associated pks+ E. coli [e.g. NC101]
were found in a significantly high percentage
of inflammatory bowel disease and CRC patients.
This suggests that in mice,
colitis can promote tumorigenesis
by altering microbial composition
and inducing the expansion
of microorganisms with genotoxic capabilities.”

Chronic Inflammation Can Accumulate
Cancer-Causing Bacteria in the Human Gut

Our New 2013
Reference Genome
Set contains
761 Ecoli strains
=6x our 2012 Set
Colored nodes
are the 38 strains in
the 2011 PNAS paper
D
A
B1
B2
E
S

We Divided the 761 E. coli Strains into 40 Groups,
Each of Which Had 80% Identical Genes
LS00
1
LS00
2
LS00
3
Median
CD
Median
UC
Median
HE
Group 0: D
Group 2: E
Group 3: A, B1
Group 4: B1
Group 5: B2
Group 7: B2
Group 9: S
Group 18,19,20: S
Group 26: B2
LF82NC101

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.”

Early Attempts at Modeling the Systems Biology of
the Gut Microbiome and the Human Immune System

Integrative Personal Omics Profiling
Using 100x My Quantifying Biomarkers
• Michael Snyder,
Chair of Genomics
Stanford Univ.
• Genome 140x
Coverage
• Blood Tests 20
Times in 14 Months
– tracked nearly
20,000 distinct
transcripts coding
for 12,000 genes
– measured the
relative levels of
more than 6,000
proteins and 1,000
metabolites in
Snyder's blood
Cell 148, 1293–1307, March 16, 2012

DELSA Mission
Accelerate the impact of data-enabled
life sciences research
on the pressing needs of our global
society.
Website: www.delsaglobal.org
Twitter: @DELSAglobal
Email: info@delsaglobal.org
DataData
KnowledgeKnowledge
ActionAction
OutcomesOutcomes
The Data-Enabled Life Sciences Alliance
(DELSA Global)
DELSA Vision
Through interdisciplinary research
and transdisciplinary engagement,
the life science community will move
from “one scientist—one project”
to collective innovation
in data-enabled science.
Source: Eugene Kolker

•The Quantified Human Initiative is an effort to combine our
natural curiosity about self with new research paradigms.
Rich datasets of two individuals, Drs. Smarr and Snyder,
serve as 21st
century personal data prototypes.
•A true picture requires multi-disciplinary analysis (genomic, proteomic,
metabolomic, microbiomic, phenotypic, and clinical data).
•The DELSA community will use these data to build
coherent datasets for studying the “normal condition” and
work toward an understanding of genotype-to-phenotype,
biological variability, environment as an influence,
and clinical outcomes.
•The Quantified Human Initiative is working to enable
each individual to make more informed and
effective decisions in their everyday lives.
The DELSA
Quantified Human Initiative
Source: Eugene Kolker

Data e-Platform to Leverage Multilevel
Personal Health Information (DELPHI)
• Integrate heterogeneous data into a “single” uniform database
• Approach this integration within a geospatial context
• Implement a machine learning analytics layer on top
• Open the data and analytics up to third party developers of
apps and services
Enable Personalized Population Health
Through the Creation of
a “Whole Health Information” Platform
that Takes into Account Everything
from the Genome to the Exposome
Source: Kevin Patrick, MD UCSD

DELPHI Integrates
Multiple Sources of Health-Relevant Data

Explore whether individual and population health
can be improved by promoting research on the patient
and person-generated data
that are increasingly captured via
consumer electronic devices, mobile apps
and the telecommunications industry
6-month Planning Grant (Commenced 5/1/13)
Calit2.net/hdexplore
Personal Data for the Public Good
Gaining Insight from Patient and
Person-Generated Real World/Real Time Data
Kevin Patrick, Jerry Sheehan, Matthew Bietz, Judith Gregory,
Michael Claffey, Scout Calvert, Lori Melichar, Steve Downs

Digitally Revealing the Dynamics of Your Superorganism Body

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