“Quantifying your Human Body & Its Trillions of Microbes”
LectureAcademy of Integrative Health and Medicine (AIHM)
Annual ConferenceSan Diego, CA
November 1, 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
Abstract
The human body is host to 10s of trillions of microorganisms, ten times the number of DNA-bearing cells in the human body and these microbes contain over 100 times the number of DNA genes that our human DNA does. The microbial component of our “superorganism” is comprised of 100s of species with immense biodiversity. I have been collecting massive amounts of data from my own body over the last five years, which reveals detailed examples of the episodic evolution of the coupled immune-microbial system.
Lecture Objectives
• 1) Tracking Your Microbiome Ecology in Health and Disease
• 2) An Example of Measuring the Impact of Pharmaceutical Therapy on the Microbiome
• 3) New Non-Pharmaceutical Therapies Emerging to Manipulate the Microbiome
“Know Thyself”From the Temple of Apollo to the Quantified Self
From the Reichert-Haus in Ludwigshafen, Germany
Knowing Me:From One to a Trillion Data Points Defining Me in 15 Years
Weight
Blood BiomarkerTime Series
Human Genome SNPs
Microbiome MetagenomicTime Series
Improving Body
Discovering Disease
Human Genome
Genomics Big Data Tsunami
Calit2 Has Been Had a Vision of How to Digitally “Know Thyself” 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
I Used a Variety of Emerging 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 a 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)
Colonoscopy Images Show PersistentInflamed Pseudopolyps in 6 inches of Sigmoid Colon
Dec 2010 Jan 2012
“Inflammatory polyp versus inflamed fold in the distal sigmoid colon and apthous ulcers in the rectum, consistent with active Crohn’s colitis.”
William J. Sandborn, MD UCSD Jan 3, 2012
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
Comparison of 3D Volumetric MRI Visualization with Clinical MRI Slice Program Confirms Inflammation
“Long segment wall thickening in the proximal and mid portions of the sigmoid colon, extending over a segment of ~16 cm,
with suggestion of intramural sinus tracts. Edema in the sigmoid mesentery
and engorgement of the regional vasa recta.” – MRI report, Cynthia Santillan, M.D. UCSD
Jan 2012
Clinical MRI Slice Program
Crohn's disease affects the thickness of the intestinal wall.
Reveals Inflammation in 6 Inches of Sigmoid Colon
Image from Jurgen Schultz, Calit2
Image from Cynthia Santillan, UCSD Health Services
Wall Thickness 5x Normal
Evolving Microbiome Environmental Pressures: Dynamical Innate and Adaptive Immune Oscillations in Colon
Normal <600
Innate Immune System
Normal 50 to 200
Adaptive Immune SystemThese Must Be Coupled to
A Dynamic Microbiome Ecology
To Understand the Interaction of Genetics and the Immune SystemWe Must Consider the Human Microbiome
Your Microbiome is Your “Near-Body” Environment
and its CellsContain 100x as Many DNA GenesAs Your Human DNA-Bearing Cells
Your Body Has 10 Times As Many Microbe Cells As DNA-Bearing
Human Cells
Inclusion of the “Dark Matter” of the BodyWill Radically Alter Medicine
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
We Gathered Raw Illumina Reads on 275 Humansand 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, Calit2Weizhong Li, Sitao Wu, CRBS, UCSD
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 Time Series,
IBD Patients, & Healthy Controls
Illumina HiSeq 2000 at JCVI
SDSC Gordon Data Supercomputer
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, & Matt Clancy
Think of These Phyla of Animals When You Consider the Biodiversity of Microbes Inside You
PhylumAnnelida
PhylumEchinodermata
PhylumCnidaria
PhylumMollusca
Phylum Arthropoda
PhylumChordata
PhylumPorifera
All images from WikiMedia Commons. Photos are public domain or by Dan Hershman, Michael Linnenbach, Manuae, B_cool, Nick Hobgood
Results Include Relative Abundance of Hundreds of Microbial Species
Average Over 250 Healthy PeopleFrom NIH Human Microbiome Project
Note Log Scale
Clostridium difficile
Genome 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
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
Exploring the Dynamicsof the Human Microbiome Ecology
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
• Red Bars Are Relative Abundance of Top 20 Species in Healthy People
• Blue Bars Are Relative Abundance of Same Species in Larry Smarr When CRP=27 (12/28/2011)
Invasive Species Take Over Gut Microbiome in Disease State
152x
765x
148x
849x483x
220x201x
522x169x
Source: Sequencing JCVI; Analysis Weizhong Li, UCSDLS December 28, 2011 Stool Sample
• Blue Bars Are Relative Abundance of Top 20 Species in Larry Smarr When CRP=27 (12/28/2011)
• Red Bars Are Relative Abundance of Same Species in Healthy People
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)
In 2016 We Are Extending My Stool Time Series byCollaborating 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
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
Combining Deep Metagenomics and Supercomputing Timeto Map the Differences Between Health and Disease
• Controls: 100s of Healthy Subjects
• Smarr Gut Microbiome Time Series– ~80 Samples Over 5 Years
• Hundreds of IBD Patients– Phenotyped Patients Drawn from Sandborn BioBank
Knight/Smarr Labs Using 100 CPU-Years of Supercomputer Time
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, 911-9202014
For 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]
U.S. HumanMicrobiome
Project
Missing Microbes
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.”
Will Medical Foods Provide New Tools for Altering Gut Microbiome?
Manipulating Your Microbiome Can Work -- Fecal Microbiome TransferIs a Rapidly Growing New Treatment for Clostridia Difficile
Dr. Bill Sandborn, Chief UCSD GI
Dr. Brigid Boland, UCSD GI
C. diff is the nation’s most common
hospital-acquired infection,
affecting 500,000 and killing 30,000 Americans/year
(CDC)
Fecal transplants are 90% curative.
OpenBiome supplies to over 500 hospitals
in all 50 states, so far 10,000 transplants.
www.cidrap.umn.edu/news-perspective/2015/02/cdc-puts-c-difficile-burden-453000-cases-29000-deaths
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
Center for Microbiome Innovation
Seminars Faculty Hiring Education
UCSD Microbial Sciences Initiative
InstrumentCores
Seed GrantsFellowships
Chancellor Khosla Launched the UC San Diego Microbiome and Microbial Sciences Initiative October 29, 2015
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
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