This is a keynote lecture I gave at a scientific conference on how to translate discoveries about the genome into medical applications. ( http://jointsummits2011.amia.org/keynote-presentations ) I urged them to think of the human body as a lake, and to think of themselves as ecologists. For more information, visit http://carlzimmer.com
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The Human Jungle: Exploring the Microbiome
1. The Inner Jungle:
The Natural History of the Human Microbiome
Carl Zimmer
Joint Summits on Translational Science Keynote Lecture
San Francisco, CA, March 8, 2011
30. Cold Spring Harbor Archives http://www.flickr.com/photos/cshlarchives/4276595071/
31. “Molecular genetics, our latest
wonder, has taught us to spell
out the connectivity of the tree
of life in such palpable detail that
we may say in plain words, ‘This
riddle of life has been solved.’
The ideas of information
storage, of the replication of the
stored information and of its Max Delbruck,
programmed readout have Nobel Lecture, 1969
become commonplace and have
filtered down into the popular
magazines and grade school
textbooks.”
33. It will unlock new insights into our
origins and history as a species;
and it points to new ways of
combating disease. The people of
many countries have invested in
the Human Genome Project's
determination of the sequence, and
it is hard to see how that
investment could have received
better returns.
http://www.nature.com/nature/journal/v409/n6822/full/409745a0.html
49. Microbial abundance raises the
question: how human are we?
Human:
10 trillion human cells
20,000 human genes
Microbiota: Microbiota:
100 trillion microbial cells 20 million microbial genes
99.9% of our genomes the same, but our microbes...?
53. The microbiome kills invading pathogens
The skin bacteria
Staphylococcus
epidermis makes
δ-toxin and kills
S. aureus
Cogen et al, PLoS ONE 5(1): e8557. doi:10.1371/journal.pone.0008557
54. The microbiome heals wounds
Left ear: wound Right ear: wound
without S. epidermis with S. epidermis
Lai 2009 Nature Medicine 15, 1377 - 1382 (2009)
56. Diversity from nose to nose
Wos-Oxley et al, The ISME Journal (2010) 4, 839–851
57. Mouth to mouth: 818 bacterial species lives in three people’s
mouths, 387 shared by all three.
Zaura et al BMC Microbiol (2009) vol. 9 (1) pp. 259
58. What is the shape of the core microbiome?
Hamady M , Knight R Genome Res. 2009;19:1141-1152
59. Or is it a core of genes, not of species?
Hamady M , Knight R Genome Res. 2009;19:1141-1152
60. Diversity within
the core
Periphery
(not in all people)
Core
(in all people)
Costello et al, Science Vol. 326 no. 5960 pp. 1694-1697
61. r Hair
The body has many niches
Hair
ehead Forehead
Forehead
ernal ear (L) External nose
External nose
ernal ear (R) External ear (R)
External ear (R)
el External ear (L) External ear (L)
mpit (R) Palm (R)
Palm (R)
mpit (L) Index finger (R)
Index finger (R)
ernal nose Palm (L) Palm (L)
tril (R) Index finger (L) Index finger (L)
tril (L) Forearm (R) Forearm (R)
ex finger (R) Forearm (L) Forearm (L)
m (R) Nostril (R) Nostril (R)
ex finger (L) Nostril (L) Nostril (L)
earm (R) EAC (R) Armpit (R)
earm (L) EAC (L) Armpit (L)
m (L) Armpit (R) Sole of foot (R)
k of knee (R) Armpit (L) Sole of foot (L)
k of knee (L) Sole of foot (R) Back of knee (R)
e of foot (R) Sole of foot (L) Back of knee (L)
e of foot (L) Back of knee (R) Navel
C (R) Back of knee (L) EAC (R)
C (L) Navel EAC (L)
ns penis Glans penis Glans penis
ia minora Labia minora Labia minora
l cavity Oral cavity Oral cavity
sal tongue Dorsal tongue Dorsal tongue
(Sp) Gut (Sp) Gut (Sp)
(Sw) Gut (Sw) Gut (Sw)
0.02 0.05
weighted quantitative symmetric
UniFrac (Kulczynski)
Costello et al, Science Vol. 326 no. 5960 pp. 1694-1697
Fig. S11
64. Wang et al, Appl Microbiol Biotechnol (2010) 88:1333–1342
65. From The Art of Ecology, 2011
Time opens new niches
66. Time opens new niches
A 0.9
0.8
UniFrac distance
0.7
0.6 variation within people
(day-to-day)
variation between people
0.5 (on any given day)
0.4
Oral Gut Skin Nostril Hair EAC
cavity
Habitat
B 0.3
eighted UniFrac distance
0.2
variation within people
0.1 (day-to-day)
Costello et al, Science Vol. 326 no. 5960 pp. 1694-1697
variation between people
67. Diversity through co-dependence:
the case of the elusive mouth resident, Synergistetes
Vartoukian et al Environmental Microbiology (2010) 12(4), 916–928
68. Top: Synergistetes alone in culture grows
extremely slowly
Bottom: Parvimonas micra speeds up
growth of Synergistetes (streak)
Vartoukian et al Environmental Microbiology (2010) 12(4), 916–928
70. Four mouth microbes that cannot grow alone
Actinomyces Streptococcus
naeshindii oralis
Fusobacterium Porphyromonas
nucleatum gigivalis
Robinson et al, Microbiol Mol Biol Rev. 2010 Sep;74(3):453-76.
71. Four mouth microbes that cannot grow alone
supports the growth of
Actinomyces Streptococcus
naeshindii oralis
supports the growth of
Fusobacterium Porphyromonas
nucleatum gigivalis
Robinson et al, Microbiol Mol Biol Rev. 2010 Sep;74(3):453-76.
72. Four mouth microbes that cannot grow alone
supports the growth of
Actinomyces Streptococcus
naeshindii oralis
supports the growth of
supports the
growth of
Fusobacterium Porphyromonas
nucleatum gigivalis
Robinson et al, Microbiol Mol Biol Rev. 2010 Sep;74(3):453-76.
73. Four mouth microbes that cannot grow alone
supports the growth of
Actinomyces Streptococcus
naeshindii oralis
supports the growth of
supports the
growth of
supports the growth of
Fusobacterium Porphyromonas
nucleatum gigivalis
Robinson et al, Microbiol Mol Biol Rev. 2010 Sep;74(3):453-76.
74. Four mouth microbes that cannot grow alone
supports the growth of
Actinomyces Streptococcus
naeshindii oralis
supports the growth of
supports the cannot support the
growth of growth of
supports the growth of
Fusobacterium Porphyromonas
nucleatum gigivalis
Robinson et al, Microbiol Mol Biol Rev. 2010 Sep;74(3):453-76.
75. Four mouth microbes that cannot grow alone
supports the growth of
Actinomyces Streptococcus
naeshindii oralis
supports the growth of
supports the cannot support on its cannot support the
growth of own, but can speed growth of
growth if A. naeshindii is
also present
supports the growth of
Fusobacterium Porphyromonas
nucleatum gigivalis
Robinson et al, Microbiol Mol Biol Rev. 2010 Sep;74(3):453-76.
83. A lesson from ecology:
diversity is healthy
Salmonella invades more
successfully if mice are
treated with antibiotics, have
low-diversity microbiomes
(LCM), or are germ-free
Photo- http://flic.kr/p/3vhoNg Stecher and Hardt Current Opinion in Microbiology 2010, 14:1–10
84. Reid et al Nat Rev Micro (2011) vol. 9 (1) pp. 27-38
85. Reid et al Nat Rev Micro (2011) vol. 9 (1) pp. 27-38
86. Reid et al Nat Rev Micro (2011) vol. 9 (1) pp. 27-38
87. Reid et al Nat Rev Micro (2011) vol. 9 (1) pp. 27-38
88. Reid et al Nat Rev Micro (2011) vol. 9 (1) pp. 27-38
90. As Helicobacter hepaticus
becomes more common in
mouse cecae (A), microbiome
diversity falls (B)
KUEHL ET AL, INFECTION AND IMMUNITY, Oct. 2005, p. 6952–6961
96. Do My Bacteria Make Me Look Fat?
Ley RE, Backhed F, Turnbaugh P, et al. 2005. Proc Natl Acad Sci USA 102: 11070–5.
97. • Germ-free mice given
ob/ob or wild-type gut
microbes
• Chow consumption and
exercise the same for
both groups
• Both sets of mice had
similar starting weight
and percentage of body
fat
Turnbaugh, et al. Nature 2006; 444:1027
101. Khoruts’s dilemma:
61 year old patient
--Antibiotics for lung infection led to intestinal
C. difficile infection
Chronic Diarrhea - 8 months
Loose bowel movements every 15 minutes
Wore diapers at all times
Confined to a wheel chair
Lost 27 Kg
Antibiotic therapy for C. difficile uneffective
Khoruts, et al. J. Clin. Gastroenterol. 44, 354–360 (2010)
103. Patient had first solid bowel movement 2
days after treatment
On 6 month follow up visit, reported daily
stools that were well formed
Khoruts, et al. J. Clin. Gastroenterol. 44, 354–360 (2010)
104.
105.
106. Thanks to Jonathan Eisen, Karen Jansson, Rob Knight,
Sarkis Mazmanian, David Post, and David Skelly
For more information,
visit carlzimmer.com
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Models of a core microbiome. The circles represent the microbial communities in different individuals and can be thought of as either representing different taxa (species, genera, etc.) or representing different genes. (A) “Substantial core” model. Most individuals share most components of the microbiota. (B) “Minimal core” model. All individuals share a few components, and any individual shares many components with a few other individuals, but very little is shared across all individuals. (C) “No core” model. Nothing is shared by all individuals, and most diversity is unique to a given individual. (D) “Gradient” model. Individuals next to each other on a gradient, for example, age or obesity, share many components, but individuals at opposite ends share little or nothing. (E) “Subpopulation” model. Different subpopulations, for example, those defined by geography or disease, have different cores, but nothing is shared across subpopulations. Scenarios C–E would represent situations in which the strategy of identifying core species for sequencing, then using these as a scaffold for “omics” studies, would be problematic.\n
Models of a core microbiome. The circles represent the microbial communities in different individuals and can be thought of as either representing different taxa (species, genera, etc.) or representing different genes. (A) “Substantial core” model. Most individuals share most components of the microbiota. (B) “Minimal core” model. All individuals share a few components, and any individual shares many components with a few other individuals, but very little is shared across all individuals. (C) “No core” model. Nothing is shared by all individuals, and most diversity is unique to a given individual. (D) “Gradient” model. Individuals next to each other on a gradient, for example, age or obesity, share many components, but individuals at opposite ends share little or nothing. (E) “Subpopulation” model. Different subpopulations, for example, those defined by geography or disease, have different cores, but nothing is shared across subpopulations. Scenarios C–E would represent situations in which the strategy of identifying core species for sequencing, then using these as a scaffold for “omics” studies, would be problematic.\n