Guest Lecture Pharmacy Informatics University of California, San Diego May 23, 2016

1. “Discovering the 100 Trillion Bacteria
Living Within Each of Us”
Guest Lecture
Pharmacy Informatics
University of California, San Diego
May 23, 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. Lecture Objectives
• What is the Human Microbiome?
• The Explosion of Research and Public Interest in the Human Microbiome
• The Impact of Pharmaceuticals on the Microbiome Ecology
• Healthy Means Homeostasis and Stability in the Microbiome
• How the Microbiome is Shaped in the First Three Years of Life - Critical for Future Health
• Tracking Your Microbiome Ecology in Health and Disease
• Measuring the Impact of Pharmaceutical Therapy on the Microbiome
• New Non-Pharmaceutical Therapies Emerging
• The Explosion of Big Data in Pharmacy Informatics

3. 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 300x 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

4. 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

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

6. 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

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

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

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

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

11. UCSD is Becoming
a National Leader in the Human Microbiome

12. 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
Source: Rob Knight, UCSD

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

14. The Human Gut Microbiome and Pharmacy
The gut microbiota have been shown to have an important influence,
direct and indirect, on the metabolism and toxicity of a wide range of drugs
and xenobiotics. The major drug-metabolizing capability of the gut microbiota
is reductive metabolism, but demethylation, dehydroxylation, deacylation,
decarboxylation, and hydrolysis reactions have also been demonstrated as well
as acetylation. Microbiome-driven drug metabolism can result positively
in the activation of prodrugs to their pharmacologically active forms
or alternatively result in adverse consequences such as toxicity.
In addition, the gut microbiota can affect drug metabolism and toxicity indirectly
via, e.g., competition of bacterial-derived metabolites for xenobiotic
metabolism pathways or the modulation of host metabolic systems.
http://link.springer.com/chapter/10.1007/978-1-4471-6539-2_15

15. 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
2014For Public Health It is Still About Microbes,
But from Single Species to Entire Ecologies

16. 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]
Human
Microbiome
Project
Missing Microbes

17. How Does Your First Three Years
Set You on a Course
of Health or Illness
For the Rest of Your Life?

19. • Impact of Birth Mode: Vaginal or C-Section

20. Source: Rob Knight, UCSD

21. • Impact of Early Use of Antibiotics on Microbiome Development

22. Infant
(Stool)
Mouth
Stool
Vagina
Skin
Source: Rob Knight, UCSD

23. Source: Rob Knight, UCSD

24. Source: Rob Knight, UCSD

25. Source: Rob Knight, UCSD

26. Source: Rob Knight, UCSD

27. How stable is our microbiome over time
(if we’re healthy)?

28. Source: Rob Knight, UCSD
Mouth
Stool
Vagina
Skin

29. Source: Rob Knight, UCSD

30. Can our microbiome ecology shift over time
(if we’re not healthy)?

31. Larry’s 40 Stool Samples Over 3.5 Years
to Rob’s lab on April 30, 2015

32. Larry Smarr 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
5/1/12 to 12/1/14
Blue Balls on Diagram
to the Right
Few IBD Symptoms
Weight Gain
1/1/14 to 1/1/16
Red 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
Antibiotics
Prednisone
1/1/12 to 5/1/12
5/1/12
Weekly Weight (Red Dots Stool Sample)
Few IBD Symptoms
Weight Gain
1/1/14 to 1/1/16
Red Balls on Diagram
to the Right

33. 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.”

34. Fecal Microbiome Transfer
Is a Rapidly Growing New Treatment for IBD
Dr. Bill Sandborn,
Chief UCSD GI
Dr. Brigid Boland,
UCSD GI

35. Source: Rob Knight, UCSD

36. Source: Rob Knight, UCSD

37. • `
Source: Rob Knight, UCSD

38. To Expand IBD Project the Knight/Smarr Labs Were Awarded
~ 1 CPU-Century Supercomputing Time
• Smarr Gut Microbiome Time Series
– From 7 Samples Over 1.5 Years
– To 50 Samples Over 4 Years
• IBD Patients: From 5 Crohn’s Disease and 2 Ulcerative Colitis
Patients to ~100 Patients
– 50 Carefully Phenotyped Patients Drawn from Sandborn BioBank
– 43 Metagenomes from the RISK Cohort of Newly Diagnosed IBD patients
• New Software Suite from Knight Lab
– Re-annotation of Reference Genomes, Functional / Taxonomic Variations
– Novel Compute-Intensive Assembly Algorithms from Pavel Pevzner
8x Compute Resources
Over Prior Study

39. 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

40. Genetic Sequencing of Humans and Their Microbes
Is a Huge Growth Area and the Future Foundation of Medicine
Source: @EricTopol
Twitter 9/27/2014

41. 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
Ilkay Altintas
UCSD Health Sciences Team
David Brenner
Rob Knight Lab
Justine Debelius
Jose Navas
Bryn Taylor
Gail Ackermann
Greg Humphrey
William J. Sandborn Lab
Elisabeth Evans
John Chang
Brigid Boland
Dell/R Systems
Brian Kucic
John Thompson
Thomas Hill