From Me To We: Discovering the Trillions of Microorganisms That are a Part of Us
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Transcript of From Me To We: Discovering the Trillions of Microorganisms That are a Part of Us
“From Me To We:
Discovering the Trillions of Microorganisms That are a Part of Us,
and How the Information They Provide is Changing Medicine”
Lecture
UC San Diego Town and Gown
San Diego, CA
May 9, 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.net1
Abstract
To fully understand the state of the human body in health or disease, we must consider a
much more complex system than medical science considered before. This is because we
now know that the human body is host to trillions of micro-organisms on our skin and
throughout our GI tract. The microbial component of our “superorganism” is comprised of
hundreds of species with immense biodiversity. Exponential decrease in the cost of
genetic sequencing has enabled scientists to finally “read out” the nature of the changes
in the microbial ecology in people in health and with disease. To put a more personal face
on the patient of the future, Professor Smarr has been collecting massive amounts of data
from his own body over the last five years, which reveal detailed examples of the evolution
of this human-microbe system. As similar techniques become more widely applied, we will
see revolutionary changes in medical practice over the next decade.
There are 100 billion stars in the
Andromeda galaxy…
…and 100 billion galaxies in the
known universe.
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!
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
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
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
June 8, 2012 June 14, 2012
Interest in the Human Microbiome
Has Moved Quickly From Frontier Science to Public Awareness
August 18, 2012June, 2012
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
Think of These Phyla of Animals When
You Consider the Biodiversity of Microbes Inside You
Phylum
Annelida
Phylum
Echinodermata
Phylum
CnidariaPhylum
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
Treating the Human Superorganism:
Your Body is an Ecology!
Nature Reviews
Microbiology
v.9, p. 279 (2011)
Center for
Microbiome
Innovation
SeminarsFaculty
HiringEducation
UCSD Microbial Sciences Initiative
Instrument
Cores
Seed Grants
Fellowships
Chancellor Khosla Launched the UC San Diego
Microbiome and Microbial Sciences Initiative October 29, 2015
President Obama Announces National Microbiome Initiative
May 13, 2016
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
Many New Research Studies are Demonstrating Deep Relationships
Between the Gut Microbiome and Behavioral Disorders
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)
“Know Thyself”
From the Temple of Apollo to the Quantified Self
From the Reichert-Haus in Ludwigshafen, Germany
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
As a Model for the Precision Medicine Initiative,
I Have Tracked My Internal Biomarkers To Understand My Body’s Dynamics
My Quarterly
Blood DrawCalit2 64 Megapixel VROOM
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
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
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)
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 ColonLiver
Small Intestine
Diseased Sigmoid ColonCross Section
MRI Jan 2012
Severe Colon
Wall Swelling
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
Microbiome Ecology Highly Disrupted
by Medical Interventions
Data from Dr. Embriette Hyde,
Rob Knight Group, UCSD
July 2015 Colonoscopy
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)
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
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
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
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
We Found Major State Shifts in Microbial Ecology Phyla
Between Healthy and Three Forms of IBD
Most
Common
Microbial
Phyla
Average HE
Average Ulcerative ColitisAverage LS
Colonic Crohn’sAverage Ileal Crohn’s
Collapse of Bacteroidetes
Great Increase in ActinobacteriaExplosion of
Proteobacteria
Hybrid of UC and CD
High Level of Archaea
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
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
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
Manipulating Your Microbiome Can Work -- Fecal Microbiome Transfer
Is a Rapidly Growing New Treatment for Clostridia Difficile
Dr. Bill Sandborn,
Chief UCSD GIDr. 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
Fecal Transplants
From Healthy Donor
To C. Diff Patients
Source: Knight Lab, UCSD
Mouth
Skin
Vagina
Stool
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?
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
The Coupled Neural, Immune, and Microbiome Systems
Provide a Model Explaining How Nutrition Can Alter Neurodevelopment
Thanks to Our Great Team!
Calit2@UCSD
Future Patient TeamJerry Sheehan
Tom DeFanti
Joe Keefe
John Graham
Kevin Patrick
Mehrdad Yazdani
Jurgen Schulze
Andrew Prudhomme
Philip Weber
Fred Raab
Ernesto Ramirez
JCVI TeamKaren Nelson
Shibu Yooseph
Manolito Torralba
AyasdiDevi Ramanan
Pek Lum
UCSD Metagenomics TeamWeizhong Li
Sitao Wu
SDSC TeamMichael Norman
Mahidhar Tatineni
Robert Sinkovits
UCSD Health Sciences TeamDavid 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 SystemsBrian Kucic
John Thompson