“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