“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