Invited Lecture Harvard Club of San Diego San Diego, CA May 15, 2017

1. “Exploring your Inner Microbiome”
Invited Lecture
Harvard Club of San Diego
San Diego, CA
May 15, 2017
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
To truly understand the state of the human body in health or disease, we now realize that
we must consider a much more complex system than medical science considered
heretofore. This is because we now know that the human body is host to 40 trillion
microorganisms, ten times the number of DNA-bearing cells in the human body and these
microbes contain 100 times the number of DNA genes that our human DNA does. The
microbial component of our “superorganism” is comprised of hundreds of species with
immense biodiversity. Because of the exponential reduction in the cost of sequencing the
microbes DNA, we are in a period of rapid discovery about the differences in the
microbiome ecology in health and disease, including behavioral changes and
neurodegenerative diseases. To put a more personal face on the “patient of the future,” I
have been collecting massive amounts of data from my own body over the last five years.
Having discovered that I had an autoimmune disease, inflammatory bowel disease, this
data has revealed detailed examples of the episodic evolution of this coupled immune-
microbial system. As similar techniques become more widely applied, we can look forward
to revolutionary changes in medical practice over the next decade.

3. California’s Institutes for Science and Innovation
A Bold Experiment in Collaborative Research
UCSB
UCLA
California
NanoSystems Institute
UCSF
UCB
California Institute for Bioengineering,
Biotechnology,
and Quantitative Biomedical Research
UCI
UCSD
California Institute for
Telecommunications and
Information Technology
Center for
Information Technology Research
in the Interest of Society
UCSC
UCD
UCM
www.ucop.edu/california-institutes

4. The California Institute for Telecommunications and Information Technology
Provides Facilities for Cross-Disciplinary Research
• “Convergence” Laboratory Facilities
– Nanotech, BioMEMS, Chips, Radio, Photonics
– Virtual Reality, Digital Cinema, HDTV, Gaming
• Over 1000 Researchers in Two Buildings
– Linked via Dedicated Optical Networks
UC Irvine UC San Diego
Buildings Dedicated in 2005

5. Calit2 is a Framework for “Living in the Future”
of Digital Transformations of Health, Energy, Environment, and Culture

6. Independent Analysis of Calit2:
Harvard Business School’s Case Study on Calit2
June 10, 2014

7. My Voyage of Discovery to Understand the Microbial Universe Inside Us
Started 40 Years Ago At Harvard

8. While I was a Junior Fellow at Harvard
I Did Observational Research on Our Neighbor Galaxy

9. There are 100 billion stars in the
Andromeda galaxy…
…and 100 billion galaxies in the
known universe.

10. It’s a microbial world…
…there are 100 million times as many bacteria on Earth
as stars in the universe.
Microbiology is the ultimate Big Data science!

12. Most of Life’s Evolutionary Time
Was in the Microbial World
You
Are
Here
Source: Carl Woese, et al
Tree of Life Derived from 16S rRNA Sequences

13. Marine Microbial Ecology Genome Sequencing Project –
Anchor Dataset Launched March 13, 2007
Measuring the Genetic Diversity
of Ocean Microbes
Specify
Ocean Data
Each Sample
~2000
Microbial
Species

14. To Understand Health and Disease
We Must Consider the Human Microbiome
Inclusion of the “Dark Matter” of the Body
Will Radically Alter Medicine
99% of Your
DNA Genes
Are in Microbe Cells
Not Human Cells
Your Body Has
10 Times As Many Microbe Cells
As DNA-Bearing Human Cells

15. The Cost of Sequencing DNA
Has Fallen Over 100,000x in the Last Ten Years
This Has Enabled Sequencing of
Both Human and Microbial Genomes

16. June 8, 2012 June 14, 2012
Interest in the Human Microbiome
Has Moved Quickly From Frontier Science to Public Awareness
August 18, 2012June, 2012

17. 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

18. 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

19. Treating the Human Superorganism:
Your Body is an Ecology!
Nature Reviews
Microbiology
v.9, p. 279 (2011)

20. The Human Microbiome
Has Very Different Microbial Ecologies
Slide from Rob Knight, UCSD

21. As Different as
a Coral Reef’s and a Prairie's Microbiome
Slide from Rob Knight, UCSD

22. 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

23. President Obama Announces National Microbiome Initiative
May 13, 2016

24. The Microbiome–Gut–Brain Axis
Provides New Systemic Insights into Shifts in Behavior and Disease
Source: Montiel-Castro, et al.
Frontiers in Integrative Neuroscience 2013
Particularly Important for Healthy Aging

25. Many New Research Studies are Demonstrating Deep Relationships
Between the Gut Microbiome and Behavioral Disorders

26. Gut Microbes Regulate Serotonin Production,
90% of Which is in the Large Intestine
“It's almost unthinkable
that the gut is not playing a critical role in mind states,"
says gastroenterologist Emeran Mayer, MD,
director of the Center for Neurobiology of Stress at UCLA
Cell 161 264-276 (2015)

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

28. 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

29. 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

30. 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

31. First Peak Was an Early Warning Sign
of a Developing Internal Disease State
Normal Range <1 mg/L
27x Upper Limit for Healthy
Complex Reactive Protein (CRP) is a Blood Biomarker
for Detecting Presence of Inflammation
Episodic Peaks in Inflammation
Followed by Spontaneous Drops

32. 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)

33. 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

34. Human Stool Contains a Vast Amount of Information:
1 Gram Contains ~1 Billion Microbes, Each With >1 Million DNA Bases
1 Teaspoon Stool Has the Information Content of 1 ton of DVDs

35. I Have Been Collaborating with the UCSD Knight Lab
On Analyzing My Stool Time Series
Larry’s 40 Stool Samples Over 3.5 Years
to Rob’s lab on April 30, 2015

36. Microbiome Ecology Highly Disrupted
by Medical Interventions
Data from Dr. Embriette Hyde,
Rob Knight Group, UCSD
July 2015 Colonoscopy

37. Lessons from Ecological Dynamics:
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)

38. PCoA by Justine Debelius and Jose Navas,
Knight Lab, UCSD
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
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. My Fasting Glucose Level
Seems to Have Also Shifted in January 2014
Glucose Best Range
70 to 100
Prediabetes Range
100 to 125
Weight gain started

40. 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

41. Genome Sequencing the Stool of 300 Patients
Sorts 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

42. We Found Major State Shifts in Microbial Ecology Phyla
Between Healthy and Three 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

43. 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
Knight Lab is Sequencing
Biobank Stool Samples Now
Announced November 7, 2014

44. 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

45. 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

46. 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

47. Fecal Transplants
From Healthy Donor
To C. Diff Patients
Source: Knight Lab, UCSD
Mouth
Skin
Vagina
Stool

48. 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?

49. 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

50. The Coupled Neural, Immune, and Microbiome Systems
Provide a Model Explaining How Nutrition Can Alter Neurodevelopment

51. 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
Embriette Hyde
Jose Navas
Gail Ackermann
Greg Humphrey
William J. Sandborn Lab
Elisabeth Evans
John Chang
Brigid Boland
Dell/R Systems
Brian Kucic
John Thompson