“The Digital Transformation of Healthcare”

Guest Lecture

Pharmacy Informatics 2014

University of California San Diego

June 2, 2014

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

http://lsmarr.calit2.net 1

The Vision of Digitally Enabled Genomic Medicineis an Emerging Reality

2

July/August 2011 February 2012

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

Converging Megatrends Driving the Transformation of Healthcare for Patients

Systems Biology & Systems Medicine

Consumer-Driven Social Networks

P4 MEDICINE

Digital RevolutionBig Data

Source: Lee Hood, ISB

100 Pioneer Wellness Project: Started March 2014 –I Am One of The 100

Source: Lee Hood, ISB

By Measuring the State of My Body and “Tuning” ItUsing Nutrition and Exercise, I Became Healthier

2000

Age 41

2010

Age 61

1999

1989

Age 51

1999

How Did I Get Started? I Arrived in La Jolla in 2000and Decided to Move Against the Obesity Epidemic

I Reversed My Body’s Decline By Quantifying and Altering Nutrition and Exercise

http://lsmarr.calit2.net/repository/LS_reading_recommendations_FiRe_2011.pdf

Wireless Monitoring Helps Drive Exercise Goals

Quantifying My Sleep Pattern Using a Zeo -Increased My Average to 8 Hours/Night

REM is Normally 20% of SleepMine is Between 45-65% of Sleep

An Infant Typically Has 50% REM

Stroke risk increased by sleeping less than six hours a night-M. Ruiter, Sleep 2012

From Measuring Macro-Variables to Measuring Your Internal Variables

www.technologyreview.com/biomedicine/39636

Visualizing Time Series of 150 LS Blood and Stool Variables, Each Over 5-10 Years

Calit2 64 megapixel VROOM

Only One of My Blood Measurements Was Far Out of Range--Indicating Chronic Inflammation

Normal Range<1 mg/L

Normal

27x Upper Limit

Episodic Peaks in Inflammation Followed by Spontaneous Drops

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

But by Using Stool Analysis Time Series, I Discovered I Had Oscillating Immune Variables Far Above Normal

Normal Range<7.3 µg/mL

124x Upper Limit

Lactoferrin is a Protein Shed from Neutrophils -An Immune System Antibacterial that Sequesters Iron

TypicalLactoferrin Value for

Active IBD

Colonoscopy Images Show Inflamed Pseudopolyps in 6 inches of Sigmoid Colon

Dec 2010 Jan 2012

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 & DeskVOX Software

Transverse ColonLiver

Small Intestine

Diseased Sigmoid ColonCross Section

MRI Jan 2012

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. RelmanClin Infect Dis. 44:256-262 (2007) 

So I Set Out to Quantify All Three!

The Cost of Sequencing a Megabase of DNAHas Fallen Over 10,000x in the Last Ten Years!

This Has Enabled Sequencing of Both Human and Microbial Genomes

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-inflammatoryImmune Response

NOD2

ATG16L1

IRGM

I am Now an Advisoron the

23andme IBD Project

Imagine Crowdsourcing 23andme SNPsFor Even a Small Portion of Crohnology!

www.crohnology.com

Crowd-Sourcing the Effectivenessof Pharmaceutical Medications for Crohn’s Disease

www.crohnology.com

Treating the Human Superorganism:Your Body Has Ten Microbes for Every Human Cell!

Nature Reviews Microbiology v.9, p. 279 (2011)

To Map Out the Dynamics of My Microbiome Ecology I Partnered with the J. Craig Venter Institute

• JCVI Did Metagenomic Sequencing on Seven of My Stool Samples Over 1.5 Years

• Sequencing on Illumina HiSeq 2000 – Generated 200 Million

100bp Reads

• JCVI Lab Manager, Genomic Medicine– Manolito Torralba

• IRB PI Karen Nelson– President JCVI

Illumina HiSeq 2000 at JCVI

Manolito Torralba, JCVI Karen Nelson, JCVI

We Downloaded Additional Gut Microbiomesfrom NIH HMP For Comparative Analysis

5 Ileal Crohn’s Patients, 3 Points in Time

2 Ulcerative Colitis Patients, 6 Points in Time

“Healthy” Individuals

From Sequences to Bacterial Species Relative AbundanceRequired 25 CPU-Years at San Diego Supercomputer Center

Source: Jerry Sheehan, Calit2Weizhong Li, Sitao Wu, CRBS, UCSD

Total of 27 Billion ReadsOr 2.7 Trillion Bases

IBD Patients

250 Subjects1 Point in Time

Larry Smarr6 Points in Time

We Found Major Shifts in Microbial EcologyBetween Healthy and Two Forms of IBD

Collapse of Bacteroidetes

Explosion of Proteobacteria On the IBD Spectrum

Tracking How 1 Month Antibiotic, 2 Months Prednisone TherapyAlters the Gut Microbial Ecology

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?

Comparing Changes in Gut Microbiome Ecology with Oscillations of the Innate and Adaptive Immune System

Normal

Innate Immune System

Normal

Adaptive Immune System

Time Points of Metagenomic Sequencing

of LS Stool Samples

Therapy: 1 Month Antibiotics+2 Month Prednisone

LS Data from Yourfuturehealth.com Stool Tests

Time Series Reveals Autoimmune Dynamics of Gut Microbiome by Phyla

Therapy

Six Metagenomic Time Samples Over 16 Months

Toward Microbiome Disease Diagnosis

UC 100x Healthy

CD 100x Healthy

Inexpensive 16S Time Series of MicrobiomeNow Possible Through Ubiome

Data source: LS (Yellow Lines Stool Samples); Sequencing and Analysis Ubiome

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.”

Evidence for the Efficacy of Probiotics is IBD is Mixed -More Clinical Research Needed

“...there is virtually no evidence of probiotic efficacy in Crohn’s disease.”

From the Single “Bad” Microbe Medical Targetto the Microbiome Ecology Paradigm

Sci Transl Med 4, 137rv5 (2012);

Science 336, 1255 (2012)

Problem of Alternative Stable StatesIn Ecological System Dynamics

Microbiome TransferMay Be a Radical New Treatment for IBD

www.gihealthfoundation.org/reuters/articles.cfm?article=20111102drgd011

Dr. Alexander Khoruts, NY Timeswww.nytimes.com/2010/07/13/science/13micro.html

Not FDA Approved Yet;Increasing Number of Doctors Performing Procedure;

Clinical Trials Under Way;Encouraging Results…

ProceduresStarting With

Natural Microbiome

Next Steps:Create

Synthetic MicrobiomesTuned to the Patient

SeeMicrobiome 1:3 (2013)

Next Decade Will See New Microbiome“Gardening Tools”

Journal of Nanotechnology (2012)

August 7, 2012

The Disruption of Consumer Health Data GatheringIs Growing Rapidly

Blood Variable Time Series Stool Variable Time Series

MicrobiomeTime SeriesHuman Genetic Variations

Thanks to Our Great Team!

UCSD Metagenomics Team

Weizhong LiSitao Wu

Calit2@UCSD Future Patient Team

Jerry SheehanTom DeFantiKevin PatrickJurgen SchulzeAndrew PrudhommePhilip WeberFred RaabJoe KeefeErnesto Ramirez

JCVI Team

Karen NelsonShibu YoosephManolito Torralba

SDSC Team

Michael NormanMahidhar Tatineni Robert Sinkovits

UCSD Health Sciences Team

William J. SandbornElisabeth EvansJohn ChangBrigid BolandDavid Brenner