Lecture Academy of Integrative Health and Medicine (AIHM) Annual Conference San Diego, CA November 1, 2016

1. “Quantifying your Human Body
& Its Trillions of Microbes”
Lecture
Academy of Integrative Health and Medicine (AIHM)
Annual Conference
San Diego, CA
November 1, 2016
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. 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.

3. 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

4. “Know Thyself”
From the Temple of Apollo to the Quantified Self
From the Reichert-Haus in Ludwigshafen, Germany

5. Knowing Me:
From One to a Trillion Data Points Defining Me in 15 Years
Weight
Blood Biomarker
Time Series
Human Genome
SNPs
Microbiome Metagenomic
Time Series
Improving Body
Discovering Disease
Human Genome
Genomics Big Data Tsunami

6. 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

7. I Used a Variety of Emerging Personal Sensors
To Quantify My Body & Drive Behavioral Change
Withings/iPhone-
Blood Pressure
Zeo-Sleep
Azumio-Heart Rate
MyFitnessPal-
Calories Ingested
FitBit -
Daily Steps &
Calories Burned
Withings WiFi Scale -
Daily Weight

8. Wireless Monitoring
Produced Time Series That Helped Me Improve My Health
Since Starting November 3, 2011
Total 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, 2016
137
42
I Increased
Walking,
Aerobic, and
Resistance
Training,
All of Which
Have Health
Benefits

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

10. As a Model for the Precision Medicine Initiative,
I Have Tracked My Internal Biomarkers To Understand My Body’s Dynamics
My Quarterly
Blood Draw
Calit2 64 Megapixel VROOM

11. 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

12. 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

13. Longitudinal Time Series Revealed
Oscillatory 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
Typical
Lactoferrin Value
for
Active
Inflammatory
Bowel Disease
(IBD)

14. Colonoscopy Images Show Persistent
Inflamed 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

15. Descending Colon
Sigmoid Colon
Threading 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 Colon
Liver
Small Intestine
Diseased Sigmoid Colon
Cross Section
MRI Jan 2012
Severe Colon
Wall Swelling

16. 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

17. Evolving Microbiome Environmental Pressures:
Dynamical Innate and Adaptive Immune Oscillations in Colon
Normal <600
Innate Immune System
Normal 50 to 200
Adaptive Immune System
These Must Be Coupled to
A Dynamic Microbiome Ecology

18. To Understand the Interaction of Genetics and the Immune System
We Must Consider the Human Microbiome
Your Microbiome is
Your “Near-Body” Environment
and its Cells
Contain 100x as Many DNA Genes
As 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 Body
Will Radically Alter Medicine

19. 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

20. We Gathered Raw Illumina Reads on 275 Humans
and 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, Calit2
Weizhong Li, Sitao Wu, CRBS, UCSD
Total of 27 Billion Reads
Or 2.7 Trillion Bases
Inflammatory Bowel Disease (IBD) Patients
250 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)

21. 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-years
to Compute
Comparative Gut Microbiomes
Starting From
2.7 Trillion DNA Bases
of My Time Series,
IBD Patients, & Healthy Controls
Illumina HiSeq 2000 at JCVI
SDSC Gordon Data Supercomputer

22. When We Think About Biological Diversity
We Typically Think of the Wide Range of Animals
But All These Animals Are in One SubPhylum Vertebrata
of the Chordata Phylum
All images from Wikimedia Commons.
Photos are public domain or by Trisha Shears, Richard Bartz, & Matt Clancy

23. Think of These Phyla of Animals When
You Consider the Biodiversity of Microbes Inside You
Phylum
Annelida
Phylum
Echinodermata
Phylum
Cnidaria
Phylum
Mollusca
Phylum
Arthropoda
Phylum
Chordata
Phylum
Porifera
All images from WikiMedia Commons.
Photos are public domain or by Dan Hershman, Michael Linnenbach, Manuae, B_cool, Nick Hobgood

24. Results Include Relative Abundance of Hundreds of Microbial Species
Average Over 250 Healthy People
From NIH Human Microbiome Project
Note Log Scale
Clostridium difficile

25. Genome Sequencing the Stool of 300 Patients
Sorted 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

26. We Found Major State Shifts in Microbial Ecology Phyla
Between Healthy and Two Forms of IBD
Most
Common
Microbial
Phyla
Average HE
Average Ulcerative Colitis
Average LS
Colonic Crohn’s
Average Ileal Crohn’s
Collapse of Bacteroidetes
Great Increase in Actinobacteria
Explosion of
Proteobacteria
Hybrid of UC and CD
High Level of Archaea

27. Exploring the Dynamics
of the Human Microbiome Ecology

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

29. 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

30. Almost All Abundant Species (≥1%) in Healthy Subjects
Are 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)

31. Invasive Species Take Over Gut Microbiome
in Disease State
152x
765x
148x
849x
483x
220x
201x
522x
169x
Source: Sequencing JCVI; Analysis Weizhong Li, UCSD
LS 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

32. 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 Relman
Science 336, 1255-62 (2012)

33. In 2016 We Are Extending My Stool Time Series by
Collaborating with the UCSD Knight Lab
Larry’s 40 Stool Samples Over 3.5 Years
to Rob’s lab on April 30, 2015

34. LS Weekly Weight During Period of 16S Microbiome Analysis
Abrupt Change in Weight and in Symptoms at January 1, 2014
Lialda
Uceris
Frequent IBD Symptoms
Weight Loss
Few IBD Symptoms
Weight Gain
Source: Larry Smarr, UCSD

35. My Microbiome Ecology
Time Series Over 3 Years
Source Justine Debelius, Knight Lab, UC San Diego

36. Coloring Samples Before (Blue) and After (Red) January 2014
Reveals Clustering
Source Justine Debelius, Knight Lab, UC San Diego

37. An Apparent Sudden Phase Change Occurs
Source Justine Debelius, Knight Lab, UC San Diego

38. 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 Symptoms
Weight 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 Symptoms
Weight Gain 1/1/14 to 8/1/15
Red Balls on
Diagram to the Right

39. From N=1
to a Population of People with Disease
Inflammatory Bowel Disease Biobank
For Healthy and Disease Patients
Drs. William J. Sandborn, John Chang, & Brigid Boland
UCSD School of Medicine, Division of Gastroenterology
Over 300 Enrolled
Announced November 7, 2014

40. Combining Deep Metagenomics and Supercomputing Time
to 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

41. 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, 911-920
2014
For Public Health It is Still About Microbes,
But from Single Species to Entire Ecologies

42. The United States Population’s Human Gut Microbiome
Has 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. Human
Microbiome
Project
Missing Microbes

43. 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?

44. Manipulating Your Microbiome Can Work -- Fecal Microbiome Transfer
Is 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

45. 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

46. Center for
Microbiome
Innovation
Seminars
Faculty
Hiring
Education
UCSD Microbial Sciences Initiative
Instrument
Cores
Seed Grants
Fellowships
Chancellor Khosla Launched the UC San Diego
Microbiome and Microbial Sciences Initiative October 29, 2015

47. Thanks to Our Great Team!
Calit2@UCSD
Future Patient Team
Jerry Sheehan
Tom DeFanti
Joe Keefe
John Graham
Kevin Patrick
Mehrdad Yazdani
Jurgen Schulze
Andrew Prudhomme
Philip Weber
Fred Raab
Ernesto Ramirez
JCVI Team
Karen Nelson
Shibu Yooseph
Manolito Torralba
Ayasdi
Devi Ramanan
Pek Lum
UCSD Metagenomics Team
Weizhong Li
Sitao Wu
SDSC Team
Michael Norman
Mahidhar Tatineni
Robert Sinkovits
UCSD Health Sciences Team
David Brenner
Rob Knight Lab
Justine Debelius
Jose Navas
Gail Ackermann
Greg Humphrey
William J. Sandborn Lab
Elisabeth Evans
John Chang
Brigid Boland
Dell/R Systems
Brian Kucic
John Thompson