“Know Thyself: Quantifying Your Human Body and Its One Hundred Trillion Microbes”

Understanding Cultures and Addressing Disparities in Society:Degrees of Health and Well-Being Public Lecture Series

University of California, San DiegoJanuary 20, 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

“Know Thyself”From the Temple of Apollo to the Quantified Self

From the Reichert-Haus in Ludwigshafen, Germany

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

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

BloodVariables

Human Genome SNPs

Microbial Genome

Improving Body

Discovering Disease

“Be the change that you wish to see in the world”

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 5495 miles = Round Trip San Diego to Bangor, ME

Total Vertical Distance Climbed 176,560 ft. = 6x 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

I Decided to Track My Internal BiomarkersJust As I Did My External Body

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

15x Upper Limit

Complex Reactive Protein (CRP) is a Blood Biomarker for Detecting Presence of Inflammation

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

15x Upper Limit

Adding Stool Tests RevealedDramatic Episodic Spikes in Immune Variables

Normal Range<7.3 µg/mL

124x Upper Limit for Healthy

Lactoferrin is An Antibacterial that Sequesters Iron

TypicalLactoferrin Value for Active Inflammatory

Bowel Disease (IBD)

Descending Colon

Sigmoid ColonThreading 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

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

Person A

Person B

Single Nucleotide Polymorphisms (SNPs) in the Human Genome Make Up About 90% of All Human Genetic Variation

www.23andme.com Tracks One Million SNPs

SNPs Occur Every 100 to 300 Bases

Along Human DNA

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

23andme is Now Collecting 10,000 IBD Patient’s SNPs

I Reasoned That The Driver of My Gut Autoimmune DiseaseWas a Disturbance in My Gut Microbiome Ecology

Inclusion of the “Dark Matter” of the BodyWill Radically Alter Medicine

99% of Your DNA Genes

Are in Microbe CellsNot Human Cells

Your Body Has 10 Times As Many Microbe Cells As DNA-Bearing

Human Cells

June 8, 2012 June 14, 2012

Interest in the Human MicrobiomeHas Moved Quickly From Frontier Science to Public Awareness

August 18, 2012June, 2012

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

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

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

Just 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

This Year We Sequencing and Computing My Stool Time SeriesCollaborating with the UCSD Knight Lab

Larry’s 50 Stool Samples Over 3.5 Years to Rob’s lab on April 30, 2015

My Gut Microbiome Ecology Varying Over 3.5 Years:Sequencing by UCSD’s Knight Lab and Institute for Genomic Medicine

LS Analysis, January 2016

Next Step: Comparing Time Series of Microbiome,Immune Biomarkers, & Symptoms to Guide Therapy

From N=1 to UC San Diego Undertakinga 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

Over 200 Enrolled

Announced November 7, 2014!

Knight and Smarr Have Been Awarded a CPU-Century of Supercomputer TimeTo Analyze 50 IBD Patients, LS Time Series, and 300 Healthy People’s Microbiome

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

UC San Diego Microbiome and Microbial Sciences Initiative: Leadership Team

Rob KnightPediatrics/CSE

Pieter DorresteinPharmacy

Kit PoglianoBiol Sci

Bernhard PalssonBioE/Pediatrics

Bill SandbornGastroenterology

Jeff HastyBiol Sci

Karsten ZenglerPediatrics

Larry SmarrCalit2 /CSE

Paul JensenSIO

Pavel PevznerCSE

Rachel DuttonBiol Sci

Rommie AmaroChem & Biochem

Victor NizetPediatrics/Pharmacy

Vineet BafnaCSE

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

We Have Much to Learn from Indigenous Peoples

“Our work emphasizes the value of deep characterization

of microbiomes of people living ancestral life-styles, particularly if practices in industrialized societies might

eradicate potentially beneficial microbes and their encoded functions.”

“The average Yanomami's microbiota had twice as many genes as that of the average US person.”

The Coupled Neural, Immune, and Microbiome SystemsProvide a Model Explaining How Nutrition Can Alter Neurodevelopment

There is a Huge New Field of Products ComingWhich Enable You to “Garden” Your 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?

Massive Research is Underway to Discover A Wide Range of Methods for Gardening Your Microbiome

http://vitals.lifehacker.com/beyond-probiotics-can-you-hack-your-microbiome-1689720231

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.

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

Consumer Internal Self-Tracking ToolsAre Growing Rapidly

Blood Variable Time Series Stool Variable Time Series

Human Genetic Variations

Integrated Wellness

Human Microbiome

The Emergence of P4 Medicine --Predictive, Preventive, Personalized, Participatory

Systems Biology & Systems Medicine

Consumer-Driven Social Networks

P4 MEDICINE

Digital RevolutionBig Data

How Will the Quantified ConsumerBe Integrated into Healthcare Systems?

Lee Hood, Director ISB

Genetic Sequencing of Humans and Their MicrobesIs a Huge Growth Area and the Future Foundation of Medicine

Source: @EricTopolTwitter 9/27/2014

The Looming Disruption In Integrated Healthcare Systems

• Citizens Create Vast Datasets Outside of Medical Records

• Doctors Must Partner with Super-Informed Patients

• From Pharmaceuticals to Medicinal Foods

• From Treating Sickness to Maintaining Wellness

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