Calit2 Director Larry Smarr's presentation to pharmacy students at the Skaggs School on June 2, 2014.

1. “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

2. The Vision of Digitally Enabled Genomic Medicine
is an Emerging Reality
2
July/August 2011 February 2012

3. 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 Revolution
Big Data
Source: Lee Hood, ISB

4. 100 Pioneer Wellness Project:
Started March 2014 –I Am One of The 100
Source:
Lee Hood, ISB

5. By Measuring the State of My Body and “Tuning” It
Using 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 2000
and 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

6. Wireless Monitoring
Helps Drive Exercise Goals

7. Quantifying My Sleep Pattern Using a Zeo -
Increased My Average to 8 Hours/Night
REM is Normally 20% of Sleep
Mine 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

8. From Measuring Macro-Variables
to Measuring Your Internal Variables
www.technologyreview.com/biomedicine/39636

9. Visualizing Time Series of
150 LS Blood and Stool Variables, Each Over 5-10 Years
Calit2 64 megapixel VROOM

10. 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

11. 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
Typical
Lactoferrin
Value for
Active
IBD

12. Colonoscopy Images Show
Inflamed Pseudopolyps in 6 inches of Sigmoid Colon
Dec 2010 Jan 2012

13. Descending Colon
Sigmoid Colon
Threading 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 Colon
Liver
Small Intestine
Diseased Sigmoid Colon
Cross Section
MRI Jan 2012

14. 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. Relman
Clin Infect Dis. 44:256-262 (2007)
So I Set Out to Quantify All Three!

15. The Cost of Sequencing a Megabase of DNA
Has Fallen Over 10,000x in the Last Ten Years!
This Has Enabled Sequencing of
Both Human and Microbial Genomes

16. 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-inflammatory
Immune Response
NOD2
ATG16L1
IRGM
I am Now an Advisor
on the
23andme IBD Project

17. Imagine Crowdsourcing 23andme SNPs
For Even a Small Portion of Crohnology!
www.crohnology.com

18. Crowd-Sourcing the Effectiveness
of Pharmaceutical Medications for Crohn’s Disease
www.crohnology.com

19. Treating the Human Superorganism:
Your Body Has Ten Microbes for Every Human Cell!
Nature Reviews
Microbiology
v.9, p. 279 (2011)

20. 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

21. We Downloaded Additional Gut Microbiomes
from 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 Abundance
Required 25 CPU-Years at San Diego Supercomputer Center
Source: Jerry Sheehan, Calit2
Weizhong Li, Sitao Wu, CRBS, UCSD
Total of 27 Billion Reads
Or 2.7 Trillion Bases
IBD Patients
250 Subjects
1 Point in Time
Larry Smarr
6 Points in Time

22. We Found Major Shifts in Microbial Ecology
Between Healthy and Two Forms of IBD
Collapse of
Bacteroidetes
Explosion of
Proteobacteria On the IBD Spectrum

23. Tracking How 1 Month Antibiotic, 2 Months Prednisone Therapy
Alters 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?

24. 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

25. Time Series Reveals Autoimmune Dynamics
of Gut Microbiome by Phyla
Therapy
Six Metagenomic Time Samples Over 16 Months

26. Toward Microbiome Disease Diagnosis
UC 100x Healthy
CD 100x Healthy

27. Inexpensive 16S Time Series of Microbiome
Now Possible Through Ubiome
Data source: LS (Yellow Lines Stool Samples);
Sequencing and Analysis Ubiome

28. 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.”

29. 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.”

30. From the Single “Bad” Microbe Medical Target
to the Microbiome Ecology Paradigm
Sci Transl Med 4, 137rv5 (2012);
Science 336, 1255 (2012)
Problem of Alternative Stable States
In Ecological System Dynamics

31. Microbiome Transfer
May Be a Radical New Treatment for IBD
www.gihealthfoundation.org/reuters/articles.cfm?article=20111102drgd011
Dr. Alexander Khoruts, NY Times
www.nytimes.com/2010/07/13/science/13micro.html
Not FDA Approved Yet;
Increasing Number of Doctors Performing Procedure;
Clinical Trials Under Way;
Encouraging Results…
Procedures
Starting With
Natural Microbiome
Next Steps:
Create
Synthetic Microbiomes
Tuned to the Patient
See
Microbiome 1:3 (2013)

32. Next Decade Will See New Microbiome
“Gardening Tools”
Journal of Nanotechnology (2012)
August 7, 2012

33. The Disruption of Consumer Health Data Gathering
Is Growing Rapidly
Blood Variable Time Series Stool Variable Time Series
MicrobiomeTime SeriesHuman Genetic Variations

34. Thanks to Our Great Team!
UCSD Metagenomics Team
Weizhong Li
Sitao Wu
Calit2@UCSD
Future Patient Team
Jerry Sheehan
Tom DeFanti
Kevin Patrick
Jurgen Schulze
Andrew Prudhomme
Philip Weber
Fred Raab
Joe Keefe
Ernesto Ramirez
JCVI Team
Karen Nelson
Shibu Yooseph
Manolito Torralba
SDSC Team
Michael Norman
Mahidhar Tatineni
Robert Sinkovits
UCSD Health Sciences Team
William J. Sandborn
Elisabeth Evans
John Chang
Brigid Boland
David Brenner