quantifying your dynamic human body (including its microbiome), will move us from a sickcare system...
TRANSCRIPT
“Quantifying Your Dynamic Human Body (Including Its Microbiome), Will Move Us
From a Sickcare System to a Healthcare System”
Invited Presentation Microbiology and the Microbiome and the Implications for Human Health
Analytic, Life Science & Diagnostic Association (ALDA) 2016 Senior Management ConferenceHalf Moon Bay, CA
October 3, 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
Conference Abstract
“For the past several years, Dr. Smarr has been engaged in a computer-aided study of his body. Larry has been charting his bodily input and output, as well as taking periodic blood and stool tests for five years as part of a new generation of medical research that is focusing on early detection of disease states. Studying the microbiome is part of this area of medical research since there are 100 times as many genes on the microbial DNA as your human DNA and yet this is currently outside of medical practice. Larry believes that over the next 10-20 years efforts like his will enable scientists to create computational models of your body, grounded in you and your microbiome's genome, and—using longitudinal time series of data refreshed continually with measurements from your body and collated with similar readings from millions of other similarly monitored bodies. Mining this enormous database, software will produce detailed guidance about diet, supplements, exercise, medication, or treatment—guidance based on a precise reading of your own body’s peculiarities and its status in real time. And, at that time, says Larry, you will have a scientific basis for medicine and the current US "Sickcare" system will be replaced by a true "Healthcare" system.
From One to a Trillion Data Points Defining Me in 15 Years:The Exponential Rise in Body Data
Weight
Blood BiomarkerTime Series
Human Genome SNPs
Microbiome MetagenomicTime Series
Improving Body
Discovering Disease
Human Genome
Genomics Big Data Tsunami
Imagine FollowingA Hundred MillionQuantified People
Calit2 Has Been Had a Vision of “the Digital Transformation of Health” for 15 Years
• 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
Over the Last Decade, I Have Used a Variety of Personal SensorsTo Quantify My Body & Drive Behavioral Change
Withings/iPhone-Blood Pressure
Zeo-SleepAzumio-Heart Rate
MyFitnessPal-Calories Ingested
FitBit -Daily Steps &
Calories Burned
Withings WiFi Scale -Daily Weight
Wireless Monitoring Produced Time Series That Helped Me Improve My Health
Since Starting November 3, 2011Total Distance Tracked 6180 miles = Round Trip San Diego to Nome, Alaska
Total Vertical Distance Climbed 190,000 ft. = 6.5x Mt. Everest
My Resting Heartrate Fell from 70 to 40!
Elliptical
Walking
Sunday January 17, 2016137
42
I Increased Walking,
Aerobic, and Resistance Training,
All of WhichHave Health
Benefits
From Measuring Macro-Variables to Measuring Your Internal Variables
www.technologyreview.com/biomedicine/39636
As a Model for the Precision Medicine Initiative, I Have Tracked My Internal Biomarkers To Understand My Body’s Dynamics
My Quarterly Blood DrawCalit2 64 Megapixel VROOM
Only One of My Blood Measurements Was Far Out of Range
Complex Reactive Protein (CRP) is a Blood Biomarker for Detecting Presence of Inflammation
Doctor: “Come Back When You Have a Symptom”
Normal Range <1 mg/L
First Peak Was an Early Warning Sign of Developing Internal Disease State
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
Longitudinal Time Series RevealedOscillatory Behavior in an Immune Variable That 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)
Time Series Reveals Oscillations in Immune BiomarkersAssociated with Time Progression of Autoimmune Disease
Immune &Inflammation
Variables
Weekly Symptoms
PharmaTherapies
StoolSamples
2009 20142013201220112010 2015
Monitoring Your BodyWould Have SuggestedIntervention Now!
Descending Colon
Sigmoid ColonThreading Iliac Arteries
Major Kink
Confirming the IBD (Colonic 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
Transverse ColonLiver
Small Intestine
Diseased Sigmoid ColonCross SectionMRI Jan 2012
Severe ColonWall Swelling
Why Did I Have an Autoimmune Disease like Crohn’s Disease?
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
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
NOD2
IRGM
ATG16L1
There May Be a Correlation Between CD SNPsand Where and When the Disease Manifests
Me-MaleCD Onset
At 60-Years Old
Il-23RRs1004819
1.8x Increased Risk
Female CD Onset
At 20-Years Old
NOD2 (1)Rs2066844
2.08x Increased Risk
Subject withIleal Crohn’s
Subject withColonic Crohn’s
Source: Larry Smarr and 23andme
IBD is a “Spectrum” Disorder Stratified by a Personal Combination of 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)
23andme Has Collected 10,000 IBD Patient’s SNPs
Using Supercomputers and Deep Metagenomicsto Discover the Shifts in Microbiome Ecology in Health and Disease
An Initial Study of the Variation of the Human Gut MicrobiomeAcross Populations and Within an Individual Over Time
5 Ileal Crohn’s Patients, 3 Points in Time
2 Ulcerative Colitis Patients, 6 Points in Time
“Healthy” Individuals
Larry Smarr, Weizhong Li, Sitao Wu, UCSDGraphic Source: Jerry Sheehan, Calit2
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)
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 Subjects
Illumina HiSeq 2000 at JCVI
SDSC Gordon Data Supercomputer
The Supercomputer Converts Tens of Billions of DNA Fragments Into 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 Two Forms of IBD
Most Common Microbial
Phyla
Average HE
Average Ulcerative ColitisAverage LS
Colonic Crohn’sAverage Ileal Crohn’s
Collapse of BacteroidetesGreat Increase in Actinobacteria
Explosion of Proteobacteria
Hybrid of UC and CDHigh Level of Archaea
Metagenomic Sequencing the Stool of 300 PatientsSorted Out Their Health or Disease Type
Source: Thomas Hill, Ph.D.Executive Director Analytics
Dell | Information Management Group, Dell Software
Healthy
Ulcerative Colitis
Colonic Crohn’s
Ileal Crohn’s
Exploring the Dynamicsof the Human Microbiome Ecology
The Human Gut as a Super-Evolutionary Microbial Cauldron
• Enormous Density– 1000x Ocean Water
• Highly Dynamic Microbial Ecology– Hundreds to Thousands of Species
• Horizontal Gene Transfer• Phages• Adaptive Selection Pressures (Immune System)
– Innate Immune System– Adaptive Immune System– Macrophages and Antimicrobial proteins
• Constantly Changing Environmental Pressures– Diet– Antibiotics– Pharmaceuticals
Time Series Reveals Autoimmune Dynamics of Gut Microbiome by Phyla
Therapy
Six Metagenomic Time Samples Over 16 Months
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
Almost All Abundant Species (≥1%) in Healthy SubjectsAre Severely Depleted in Larry’s Gut Microbiome
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)
We are Genomically Analyzing My Stool Time Series in a Collaboration with the UCSD Knight Lab
Larry’s 40 Stool Samples Over 3.5 Years to Rob’s lab on April 30, 2015
LS Weekly Weight During Period of 16S Microbiome AnalysisAbrupt Change in Weight and in Symptoms at January 1, 2014
Lialda
Uceris
Frequent IBD SymptomsWeight Loss
Few IBD SymptomsWeight Gain
Source: Larry Smarr, UCSD
My Microbiome Ecology Time Series Over 3 Years
Source Justine Debelius, Knight Lab, UC San Diego
Coloring Samples Before (Blue) and After (Red) January 2014Reveals Clustering
Source Justine Debelius, Knight Lab, UC San Diego
An Apparent Sudden Phase Change Occurs
Source Justine Debelius, Knight Lab, UC San Diego
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 8/1/15
Red Balls on Diagram to the Right
My Fasting Glucose Level Seems to Have Also Shifted in January 2014
Glucose Best Range70 to 100
Prediabetes Range100 to 125
Weight gain started
From N=1 to a Population of People with Disease
Inflammatory Bowel Disease BiobankFor Healthy and Disease Patients
Drs. William J. Sandborn, John Chang, & Brigid BolandUCSD School of Medicine, Division of Gastroenterology
Over 300 Enrolled
Announced November 7, 2014
To Expand IBD Project the Knight/Smarr Labs Were Awarded ~ 1 CPU-Century Supercomputing Time
• Smarr Gut Microbiome Time Series– From 7 Samples Over 1.5 Years – To 50 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
8x Compute Resources Over Prior Study
N=1 Microbiome Time Series Compared to Populations of Healthy and SickUsing Machine Learning and Data Analytics
Toward Computational Modelsof the Interaction of the Human Host and Its Microbiome
Forty Years of Computing Gravitational Waves From Colliding Black Holes – One Billion Times Increase in Supercomputer Speed!
1977
L. Smarr and K. EppleyGravitational Radiation Computed
from an Axisymmetric Black Hole Collision 40 Years
2016
LIGO ConsortiumSpiral Black Hole Collision
MegaFLOPS PetaFLOPSHolst, et al. Bull. Amer. Math. Soc 53, 513-554 (1916)
Complexity of Computing First Gut Microbiome DynamicsVersus First Dynamics of Colliding Black Holes
• My 1975 PhD Dissertation– Solving Einstein’s Equations of General Relativity for Colliding Black Holes and Grav Waves
– CDC 6600 Megaflop/s– Hundred Hours of Computing
• Rob Knight & Smarr Gut Microbiome Map Using 800,000 Core-Hours on SDSC’s Comet– Mapping From Illumina Sequencing to Taxonomy and Gene Abundance Dynamics
– Comet Petaflop/s – Comet Core is 40,000x CDC6600 Speed
– ~Million Core-Hours– 10,000x Supercomputer Time
• Gut Microbiome Takes ~ ½ Billion Times the Compute Power of Early Solutions of Dynamic General Relativity
NCSA Numerical Astrophysics GroupUsed NCSA Supercomputers to Explain Cosmic Phenomena
Mike Norman, Charles Evans, Roger Ove, John Hawley, Dean Sumi, Rob Wolff, Larry Smarr
Gas Accretion Onto a Black HoleCreates “Exhaust Channels”
Cosmic JetsEmerge from
Galactic CentersCollision of Neutron Stars
“A Whole-Cell Computational ModelPredicts Phenotype from Genotype”
A model of Mycoplasma genitalium, • 525 genes• Using 1,900
experimental observations
• From 900 studies, • They created the
software model, • Which requires 128
computers to run
Early Attempts at Modeling the Systems Biology of the Gut Microbiome and the Human Immune System
How Automobiles Went Froma Sickcare System to a Healthcare System
The Transformation in Automobile HealthcareGives Us Insight into the Human Healthcare Shift to Come
http://onlinelibrary.wiley.com/doi/10.1002/biot.201100495/abstract
Modern Cars Have Massive Sensor Arrays Which Record Time SeriesEnabling Computer Diagnostics For Early Warning
http://blog.asautoparts.com/5-common-symptoms-of-faulty-car-sensors/
Before the computer diagnostics technology,
most car owners did not know
something was wrong with the engine until something
drastic happened, such as overheating or
running out of gas. www.thepeoplehistory.com/carelectronics.html
The Transition from Car “Sickcare” to Car “Healthcare” Was Enabled by Pattern Recognition Using Big Data Analytics
“… using IBM big data and analytics technology, all available data sources can be analyzed
to discover patterns and anomalies to predict and anticipate maintenance needs.
From Reactive Repairs for “Chronic Disease”to Quantified Cars That “Keep Themselves Healthy”
“In the not-too-distant future, analytics will help organizations prevent incidents from occurring,
rather than just being a tool to rapidly react to incidents.” --Rich Radi, director, Driver Excellence for ARI, the world’s largest
privately held family-owned fleet management company
The Planetary Computer Fed by a Trillion SensorsWill Drive a Global Industrial Internet
www.tsensorssummit.org
www-bsac.eecs.berkeley.edu/frontpagefiles/BSACGrowingMEMS_Markets_%20SEMI.ORG.html
Next Decade
One Trillion
GE’s Industrial Internet is CurrentlyGenerating 10,000 TB/Day
Toward a Future Healthcare System
Big Data Analytics is a Key Componentof The Future of Supercomputing
Next Generation Telescopes Will Keep Track of the Entire Universe
On-Line in Five Years,Tracks ~40B Objects,
Creates 10M Alerts/NightWithin 1 Minute of Observing
2x40Gbps
NCSA Supercomputer
Artificial Intelligence (AI) is Advancing at a Amazing Pace:Deep Learning Algorithms Working on Massive Datasets
Training on 30M Moves, Then Playing Against Itself
Less Than 2 Years!
From Self-Driving Cars to Personalized Medical AssistantsDeep Learning Will Provide Artificial Intelligence to Coach Us to Wellness
Where Medicine Coaching is Now
Where Wellness Coaching is Going
January 10, 2014
Can a Planetary Supercomputer with Artificial IntelligenceTransform Our Sickcare System to a Healthcare System?
Using this data, the planetary computer will be able to build a computational model of your body
and compare your sensor stream with millions of others. Besides providing early detection of internal changes
that could lead to disease, cloud-powered voice-recognition wellness coaches
could provide continual personalized support on lifestyle choices, potentially staving off disease
and making health care affordable for everyone.
ESSAYAn Evolution Toward a Programmable UniverseBy LARRY SMARRPublished: December 5, 2011
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
UCSD Health Sciences TeamDavid BrennerRob Knight Lab Justine Debelius Jose Navas Gail Ackermann Greg HumphreyWilliam J. Sandborn Lab Elisabeth Evans John Chang Brigid Boland
Dell/R SystemsBrian KucicJohn Thompson