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Workshop Overview1
THE SOCIAL BIOLOGY OF MICROBIAL COMMUNITIES
Introduction
Beginning with the germ theory of disease in the 19th century and extending
through most of the 20th century, microbes2 were believed to live their lives as
solitary, unicellular, disease-causing organisms (Losick and Kaiser, 1997). This
perception stemmed from the focus of most investigators on organisms that could
be grown in the laboratory as cellular monocultures, often dispersed in liquid,
and under ambient conditions of temperature, lighting, and humidity (Kolter
and Greenberg, 2006). Most such inquiries were designed to identify microbial
pathogens by satisfying Koch's postulates.3 This pathogen-centric approach to the
study of microorganisms produced a metaphorical "war" against these microbial
invaders waged with antibiotic therapies, while simultaneously obscuring the
1 The planning committee's role was limited to planning the workshop, and the workshop summary
has been prepared by the workshop rapporteurs (with the assistance of Pamela Bertelson, Rebekah
Hutton, and Katherine McClure) as a factual summary of what occurred at the workshop. Statements,
recommendations, and opinions expressed are those of individual presenters and participants, and are
not necessarily endorsed or verified by the Institute of Medicine, and they should not be construed
as reflecting any group consensus.
2 Microscopic organisms, including bacteria, archaea, fungi, protists, and viruses.
3 Koch's postulates must be satisfied in order to state that a particular microbe causes a specific
infectious disease. They include the following: (i) The parasite occurs in every case of the disease in
question and under circumstances which can account for the pathological changes and clinical course
of the disease. (ii) The parasite occurs in no other disease as a fortuitous and nonpathogenic parasite.
(iii) After being fully isolated from the body and repeatedly grown in pure culture, the parasite can
induce the disease anew (Fredricks and Relman, 1996; Koch, 1891; Rivers, 1937).
1
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2 THE SOCIAL BIOLOGY OF MICROBIAL COMMUNITIES
dynamic relationships that exist among and between host organisms and their
associated microorganisms--only a tiny fraction of which act as pathogens.
A recent revolution in our collective understanding of microbes is that the
vast majority of these organisms live in communities and lead intensely interac-
tive lives, competing, cooperating, and forming associations with one another
and with their living and nonliving host environments. As the earth's first living
inhabitants, communities4 of microorganisms have had several billion years to
coevolve and adapt to one another and their environments, resulting in a world
of spectacular diversity and interdependence. Indeed, microbial communities are
intricately intertwined with all ecosystems on Earth--from the extreme environ-
ments of the human gut to deep-sea hydrothermal vents and the windswept plains
of Antarctica.
This ecological view of microbial life has enormous potential for transform-
ing our understanding of the world around us. Recent research on the communi-
ties of microorganisms that live in and on us (the human microbiome) suggests
that many traits once assumed to be "human"--such as the digestion of certain
foods or the ability to defend against disease--may result from human-microbe
interactions (Dethlefsen et al., 2007; IOM, 2006). Such findings have dispelled
the notion that "human beings are physiological islands, entirely capable of regu-
lating [our] own internal workings" and replaced it with the notion of the human
body as a complex ecosystem (Ackerman, 2012). This realization "promises to
radically alter the principles and practices of medicine, public health, and basic
science" (Relman, 2012).
Recognition of the ubiquity and importance of microbial communities not
only advances an ecological view of microbial life but also raises intriguing
questions about the formation of groups that behave collectively in ways that
have consequences for their individual members. There is mounting evidence to
suggest that molecular "conversations" take place among members of a broad
spectrum of microbial communities, and also between a variety of microbes and
host organisms. Having only recently become aware that such conversations ex-
ist at all, our ability to eavesdrop on them and to translate them into scientific
knowledge can be described as rudimentary at best. Yet, there is the emerging
sense that microbes interact in complex, diverse, and subtle ways that we have
yet to fully appreciate, much less understand.
Despite their obvious importance, very little is actually known about the
processes and factors that influence the assembly, function, and stability of mi-
crobial communities. Gaining this knowledge will require a seismic shift away
from the study of individual microbes in isolation to inquiries into the nature of
diverse and often complex microbial communities, the forces that shape them,
4 For the purposes of this overview, and as suggested by speaker Joan Strassmann of Washington
University at St. Louis, "microbial community" simply means "all the small forms of life occurring in
the same place and time, where same implies a shared place, with some possibility they will encounter
each other, or take resources the other might have used."
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WORKSHOP OVERVIEW 3
and their relationships with other communities and organisms, including their
multicellular hosts.
Statement of Task5
On March 6 and 7, 2012, the Institute of Medicine's (IOM's) Forum on Mi-
crobial Threats hosted a public workshop to explore the emerging science of the
"social biology" of microbial communities. Workshop presentations and discus-
sions embraced a wide spectrum of topics, experimental systems, and theoretical
perspectives representative of the current, multifaceted exploration of the micro-
bial frontier. Participants discussed ecological, evolutionary, and genetic factors
contributing to the assembly, function, and stability of microbial communities;
how microbial communities adapt and respond to environmental stimuli; theo-
retical and experimental approaches to advance this nascent field; and potential
applications of knowledge gained from the study of microbial communities for
the improvement of human, animal, plant, and ecosystem health and toward a
deeper understanding of microbial diversity and evolution.
Organization of the Workshop Summary
This workshop summary was prepared by the rapporteurs for the Forum's
members and includes a collection of individually authored papers and com-
mentary. Sections of the workshop summary not specifically attributed to an
individual reflect the views of the rapporteurs and not those of the members of
the Forum on Microbial Threats, its sponsors, or the IOM. The contents of the
unattributed sections of this summary report provide a context for the reader to
appreciate the presentations and discussions that occurred over the 2 days of this
workshop.
The summary is organized into sections as a topic-by-topic description of
the presentations and discussions that took place at the workshop. Its purpose is
5 The original Statement of Task stated the following: An ad hoc committee will plan and conduct
a public workshop that will feature invited presentations and discussions to explore the scientific
and policy implications of the microbiome in health and disease. Topics to be discussed may
include, but are not limited to, the social behavior of microorganisms to form and maintain stable
communities; how the use of antibiotics and other drugs can influence the community composition
of the microbiome; microbial evolution and co-adaptation; an exploration of the various microbiomes
in mammalian/terrestrial/aquatic environments; and the impacts of globalization on the introduction,
establishment and evolution of "novel" diseases in established microbial communities. In the course
of planning this workshop, the planning committee decided to focus the workshop's agenda on "the
ecological, evolutionary, and genetic factors contributing to the assembly, function, and stability of
microbial communities; how microbial communities adapt and respond to environmental stimuli;
theoretical and experimental approaches to advance this nascent field; and potential applications of
knowledge gained from the study of microbial communities for the improvement of human, animal,
plant, and ecosystem health and toward a deeper understanding of microbial diversity and evolution."
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4 THE SOCIAL BIOLOGY OF MICROBIAL COMMUNITIES
to present information from relevant experience, to delineate a range of pivotal
issues and their respective challenges, and to offer differing perspectives on the
topic as discussed and described by the workshop participants. Manuscripts and
reprinted articles submitted by workshop participants may be found, in alphabeti-
cal order, in Appendix A.
Although this workshop summary provides a description of the individual
presentations, it also reflects an important aspect of the Forum's philosophy. The
workshop functions as a dialogue among representatives from different sectors
and allows them to present their views about which areas, in their opinion, merit
further study. This report only summarizes the statements of participants at the
workshop over the course of 2 consecutive days. This workshop summary is not
intended to be an exhaustive exploration of the subject matter nor does it rep-
resent the findings, conclusions, or recommendations of a consensus committee
process.
Glimpses of Microbial Community Dynamics
"We have to get away from this monolithic, one-dimensional perspec-
tive of a one bugone-disease picture of health. The community is the
unit of study."
--David Relman (Buchen, 2010)
"One reason we may have a hard time remembering that all microbes
exist in communities is due to an early focus of scientists on microbes
that cause disease."
--Joan Strassmann (2012a)
Observations of bacteria grown in the artificially simple environments of the
Petri dish and the test tube have provided detailed knowledge of the physiology
and cellular processes of organisms amenable to such culturing techniques (Little
et al., 2008). With the recent development of "culture-independent" methods of
microbial characterization,6 researchers have determined that such culturable
species represent only a minuscule fraction of the microbial diversity around
us. These techniques have further revealed the dynamic communities that the
vast majority of microorganisms shape and inhabit--from simple communities
composed of one to two species to complex, spatially diversified, host-associated
communities comprising hundreds of species (Handelsman, 2004; Little et al.,
2008; Nee, 2004).
This workshop's focus on the community as the unit of study continues the
Forum's exploration of "a more realistic and detailed picture of the dynamic
6 Various "culture-independent" techniques are discussed in the section "The Structure and Func-
tion of Microbial Communities (see page 25)."
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WORKSHOP OVERVIEW 5
interactions among and between host organisms and their diverse populations of
microbes" (IOM, 2006, 2009). Newly recognized as social organisms, microbes
also provide a fresh lens through which to view interactions both among and
between species. Studies of such interactions among multicellular organisms in-
form the disciplines of social biology7 and ecology.8 While theoretical constructs
derived from observations of the macroscopic world offer ways to interpret mi-
crobial interactions, it is also possible that these phenomena will require novel
explanatory frameworks.
Microbial Communities in Biotic and Abiotic Environments
The following descriptions of microbial communities, adapted to several
distinct habitats, provide glimpses of microbes interacting with each other and
with their environments, and reveal collective functions that exceed the capabili-
ties of individual members.
Biofilms The vast majority of microbes form and inhabit biofilms: complex,
differentiated aggregations, typically of multiple species, that thrive on nearly
every surface (Hall-Stoodley et al., 2004; Kolter and Greenberg, 2006; Parsek and
Greenberg, 2005). Surrounded by a self-produced polymeric matrix,9 biofilms are
characterized by structural heterogeneity, genetic diversity, and complex commu-
nity interactions, as shown in Figure WO-1. For example, the microbial constitu-
ents of the biofilm known as dental plaque include hundreds of species and strains
of bacteria, as well as various methanogens (archaea) whose collective metabolic
activities are associated with tooth decay (Lepp et al., 2004; Relman, 2005). By
analogy to human communities, biofilms are organized into divisions of labor,
with individual cells taking on specific tasks (Kolter and Greenberg, 2006).
The structure of biofilms protects resident organisms from environmental
extremes such as ultraviolet light, toxins (including antibiotics), pH, and de-
hydration--advantages that may have allowed the first microbes to populate
Earth's surface--as well as from host immune defenses (e.g., phagocytosis) and
predation (Hall-Stoodley et al., 2004). The matrix polymer surrounding biofilms
can store water and nutrients, and some biofilms have networks of channels that
enable these resources to be distributed (IOM, 2011; Kolter and Greenberg, 2006;
Stewart and Franklin, 2008).
In medical settings, biofilms contribute to hospital-acquired infections,
most notably by colonizing in-dwelling medical devices such as catheters and
7 The study of interactions within communities of single species.
8 The study of organisms' interactions with each other and with their environment.
9 Cells in a biofilm secrete polymers of varying chemical composition that form an extracellular
polymeric substance (EPS) or a slime matrix that gives the biofilm stability and helps it to adhere to
a surface. Although generally assumed to be primarily composed of polysaccharides, the EPS can
also contain proteins and nucleic acids (Hall-Stoodley et al., 2004).
OCR for page 6
6
FIGURE WO-1
Microbial biofims:
Sticking together for
success. Single-celled
microbes readily form
communities in resilient
structures that provide
advantages of multi
cellular organization.
This schematic was
drawn by Peg Dirckx
from the Center for
Biofilm Engineering
to incorporate various
biofilm behaviors and
concepts based largely
on observations from
confocal and time-
lapse microscopy. An
interactive version
can be found at http://
www.erc.montana.edu/
MultiCellStrat/default.
html.
SOURCE: MSU Center
for Biofilm Engineering,
P. Dirckx.
Figure WO-1.eps
landscape, bitmap
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WORKSHOP OVERVIEW 7
prostheses (Hall-Stoodley et al., 2004; Kolter and Greenberg, 2006). According
to Freemont (IOM, 2011), bacteria within established biofilm communities have
been shown to tolerate antimicrobial agents at concentrations as high as 1,000
times the dosage needed to kill genetically equivalent bacteria in liquid culture.
Bacterial biofilms may also make certain infections, such as those found in
chronic wounds and the respiratory tract of individuals with cystic fibrosis, very
difficult to treat (Hall-Stoodley et al., 2004).
Multicellular structures for migration and dispersal The lifecycle of several
types of microbes--including algae of the order Volvocales, social amoebae 10 of
the order Dictyosteliida, and more than 50 species of Myxobacteria 11-- contain
stages in which these usually unicellular organisms aggregate to form multicel-
lular structures (Brock et al., 2011; Kaiser, 2006; Strassmann and Queller, 2011).
When the unicellular stage of the social amoeba Dictyostelium discoideum runs
out of bacteria to prey upon, tens of thousands of amoebae aggregate into a mul-
ticellular migratory slug (Brock et al., 2011; Kuzdzal-Fick et al., 2011). It moves
toward light and, once in a suitable location, the slug transforms into a fruiting
body, a process during which one in five cells die in order to form the structure's
sterile stalk. The stalk aids in the dispersal of the remaining cells, which differ-
entiate into spores. The social biology of D. discoideum is further discussed in
Control of cheating in the social amoeba and Farming of bacteria.
Myxobacteria xanthus undergoes a similar transformation when nutrients
are scarce, aggregating into groups of more than 100,000 cells that then form
elaborate fruiting bodies for spore dispersal as illustrated in Figure WO-2. Chemi-
cal and cell-contact signals have been found to coordinate developmental gene
expression with cellular movement, leading to the construction of fruiting bodies
in this bacterium (Kaiser, 2006).
The bacterium and the squid The Hawaiian squid Euprymna scolopes forms a
persistent association with the Gram-negative luminous bacterium Vibrio fischeri
(Nyholm and McFall-Ngai, 2004). Incorporated into the squid's light organ, the
bacterium emits luminescence that resembles moonlight and starlight filtering
through ocean waters, camouflaging the nocturnal squid from predators (Figure
WO-3) (Nyholm and McFall-Ngai, 2004). The forces supporting the formation
and stability of this association were discussed by several workshop speakers.
V. fischeri is the exclusive partner of the host squid in a special adaptation of
the squid's light organ. Colonization of the squid's light organ by the bacterium
10 Although they are amoeboid protists, not fungi, members of this order are commonly known as
"cellular slime molds."
11 Any of numerous Gram-negative, rod-shaped saprophytic bacteria (deriving nourishment from
dead or decaying organic matter) of the phylum Myxobacteria, typically found embedded in slime
in which they form complex colonies and noted for their ability to move by gliding along surfaces
without any known organ of locomotion.
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8 THE SOCIAL BIOLOGY OF MICROBIAL COMMUNITIES
FIGURE WO-2 Myxobacteria build multicellular fruiting bodies. Each of the 50 species
of myxobacteria inherits a plan to build a morphologically different fruiting body. Fruiting
Figure WO-2.eps
bodies are 100 to 400 microns high and contain about 100,000 terminally differentiated
spores. bitmap
SOURCE: Kaiser (2006).
begins within an hour after hatching and appears to occur in stages, as shown in
Figure WO-4, with each step enabling greater specificity between host and symbi-
ont. Once established, V. fischeri drives the development of the tissues with which
they associate, inducing the maturation of the squid's light organ from a morphol-
ogy that promotes colonization to one that promotes the maintenance of an exclu-
sive association with V. fischeri through the life of the host (McFall-Ngai et al.,
2012). Up to 95 percent of the resident symbiont population is expelled each day
at dawn, followed by daily regrowth of bacteria within the crypts (McFall-Ngai
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WORKSHOP OVERVIEW 9
A B
C D
FIGURE WO-3 The bacterium and the squid. A persistent, symbiotic association be-
tween the squid Euprymna scolopes (A) and its luminous bacterial symbiont Vibrio fischeri
(B) forms within the squid'sFigure WO-3
light organ (C and D). After colonization of the host's light
organ tissue, V. fischeri induces a series of irreversible developmental changes that trans-
form these tissues into a mature, functional light organ (Nyholm and McFall-Ngai, 2004).
SOURCE: (A) Images taken by C. Frazee, provided by M. McFall-Ngai and E. G. Ruby;
(B) Image provided courtesy of Marianne Engel; (C and D). Reprinted by permission from
Macmillan Publishers Ltd: Nature, Dusheck (2002), copyright 2002.
et al., 2012). This simple model of persistent colonization of animal epithelia
by Gram-negative bacteria provides a "valuable complement to studies of both
beneficial and pathogenic consortial interactions, such as in the mammalian in-
testine, and chronic disease that involve persistent colonization by Gram-negative
bacteria, such as cystic fibrosis" (Nyholm and McFall-Ngai, 2004).
Plant roots and their partners Plants establish associations with several micro-
organisms in a relationship somewhat analogous to that of mammals with their
gastrointestinal microbiota. The roots of most higher plant species form mycor-
rhizae, an association with specific fungal species that significantly improves
the plant's ability to acquire phosphorous, nitrogen, and water from the soil. 12
A few plant families, including legumes, associate with nitrogen-fixing bacteria.
They colonize the plant's roots and form specialized nodules, where the bacteria
12 See http://agronomy.wisc.edu/symbiosis.
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10 THE SOCIAL BIOLOGY OF MICROBIAL COMMUNITIES
FIGURE WO-4 The winnowing. This model depicts the progression of light-organ colo-
nization as a series of steps, each more specific for symbiosis-competent Vibrio fischeri.
(a) In response to Gram-positive Figure WO-4.eps
and Gram-negative bacteria (alive or dead) the bacterial
peptidoglycan signal causes the cells of bitmap
the ciliated surface epithelium to secrete mucus.
(b) Only viable Gram-negative bacteria form dense aggregations. (c) Motile or nonmotile
V. fischeri out-compete other Gram-negative bacteria for space and become dominant in the
aggregations. (d) Viable and motile V. fischeri are the only bacteria that are able to migrate
through the pores and into the ducts to colonize host tissue. (e) Following successful coloni-
zation, symbiotic bacterial cells become nonmotile and induce host epithelial cell swelling.
Only bioluminescent V. fischeri will sustain long-term colonization of the crypt epithelium.
SOURCE: Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews
Microbiology, Nyholm and McFall-Ngai (2004), copyright 2004.
receive energy from the plant and convert atmospheric nitrogen to ammonia,
which the plant can then assimilate into amino acids, nucleotides, and other cel-
lular constituents (Desbrosses and Stougaard, 2011). This partnership furnishes
much of Earth's biologically available nitrogen,13 a key contributor to agricultural
productivity that has long been achieved by growing legumes in rotation with
nonlegume crops.
13Nitrogen is a critical nutrient for plants, but often it is not readily available in soil, hence the
extensive use in agriculture of chemical fertilizers containing nitrogen.
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WORKSHOP OVERVIEW 11
Partnerships between plant roots and microbes are established through chem-
ical and genetic "cross-talk." During nodule formation, legume roots release
flavonoid compounds that trigger nitrogen-fixing Rhizobium bacteria to express
modified chitin oligomers known as nodulation (Nod) factors, which in turn
facilitate infection of the root by the bacteria, as well as nodule development
(Desbrosses and Stougaard, 2011; Ferguson et al., 2010; Long, 2001; Riely et al.,
2006) (see Figure WO-5).
Other plants produce chemical signals called strigolactones that increase their
contact with arbuscular mycorrhizal fungi; this triggers the fungi to release diffusible
factors that, when recognized by the plant, activate genes collectively known as Myc
factors (Parniske, 2008). Both Nod and Myc factors promote plant growth, which
may benefit microbes by increasing the availability of infection sites (IOM, 2009).
Microbial inhabitants of the human gut Just as microbes colonize the bobtail
squid's light organ shortly after hatching, microbes colonize the human body
internally and externally during its first weeks to years of life and establish
themselves in relatively stable communities in various microhabitats (Costello et
al., 2012; Dethlefsen et al., 2007). Research to date suggests that the site-specific
microbial communities--known as microbiota or microbiomes14--that inhabit
the skin, intestinal lumen, mouth, vagina, etc., contain characteristic microbial
FIGURE WO-5 An example of nitrogen-fixing symbiosis between legumes and rhizobia
bacteria.
SOURCE: Provided courtesy of Jean-Michel Ané, University of Wisconsin, Madison.
14The term microbiome is attributed to the late Joshua Lederberg, who suggested that a
comprehensive genetic view of the human as an organism should include the genes of the human
microbiome (Hooper and Gordon, 2001). Because most of the organisms that make up the microbiome
are known only by their genomic sequences, the microbiota and the microbiome are from a practical
standpoint largely one and the same (IOM, 2009).
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86 THE SOCIAL BIOLOGY OF MICROBIAL COMMUNITIES
this information, he and colleagues searched for and found beetle-associated,
antibiotic-producing Actinobacteria that mediate this fungal community, inhibit-
ing O. minus without similarly affecting Entomocorticium (Scott et al., 2008).
Another species of Actinobacteria they have isolated from honeybees produces
a small- molecule antagonist to Paenibacillus larvae, the bees' major bacterial
pathogen. In total, Currie and coworkers have identified seven novel small mol-
ecules from Actinobacteria associated with insects; some of which are currently
being tested as potential drug leads.
Microbial Roles in Health
Insights into microbial interactions--and ways to disrupt them--could lead
to new therapeutic approaches. Current approaches to infection, such as antibiot-
ics and other antimicrobials, are nonspecific and create strong selective pressures
for the development of resistance (Xavier, 2011). Targeting social strategies
that underlie virulence, or the mechanisms by which microorganisms become
pathogenic within certain environments may prove a more efficient and effective
means to treat disease (Brown et al., 2009; Rasko and Sperandio, 2010). Indeed,
a more ecologically-informed view of antibiotic production and resistance in
bacteria may lead to new approaches to treat bacterial infections. While antibiotic
resistance is generally thought to be driven by brief, cyclic invasions of popula-
tions by antibiotic-producing and antibiotic-resistant bacteria, recent research
suggests that non-clonal communities of bacteria in structured, wild habitats use
cooperation as a strategy in antibiotic-mediated competition with neighboring
populations (Cordero et al., 2012). Reflecting the concept of "ecological context
dependence," noted by Currie and many others throughout the workshop, this
research suggests that within a population, only a few members produce the
antibiotic to which all others are resistant, creating interaction networks within
and between populations that prevent invasion while also maintaining diversity
(Cordero et al., 2012; Morlon, 2012).
As noted by Dethlefsen et al. (2007), it is "crucial to consider the role of
microbial communities, and not just individual species, as pathogens and mu-
tualists." Recent investigations have revealed links between altered microbiota
ecology (dysbiosis) and infectious and noninfectious diseases alike. These obser-
vations have prompted calls to transition clinical practice from "the body-as-a-
battleground to the human-as-habitat perspective" and to consider system-level,
adaptive management approaches to managing health. Adaptive management
approaches are used to "manage biodiversity in a variety of habitats, including
communities in highly disturbed environments affected by overfishing and by
climate change" (Costello et al., 2012). This approach may better reflect health as
"a product of ecosystem services provided by microbial communities" and would
require the development of new diagnostic tools to inform health management
decisions (Costello et al., 2012).
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WORKSHOP OVERVIEW 87
Relman observed that "there are all sorts of promises that are dangling out
there in front of us in the way of diagnostics and predictive aspects of medicine.
There is a lot of as yet unrealized potential and as yet unrealized promise." Early
investigations have revealed that there is a great deal left to discover about the
patterns of microbial diversity in humans and the stability of these populations,
particularly in the face of perturbations (i.e., resilience). This ecological perspec-
tive will likely provide new leads for the management of disease. Indeed, as noted
by Lita Proctor, a program director of the Human Microbiome Project, "unlike the
human genome, the microbiome is changeable; and it is this changeability that
holds promise for prevention and treatment of disease" (Balter, 2012).
The increased recognition of the beneficial as well as benign host-microbe
relationships will further drive the paradigm shift--in the way we collectively
identify and think about the microbial world around us--first suggested by Joshua
Lederberg more than two decades ago. The familiar "war metaphor" in which the
only good bug is a dead bug will be replaced with a more ecologically informed
view of the dynamic relationships within and between hosts, their microbiomes,
and their environments (Lederberg, 2000). This perspective recognizes that mi-
crobes and their hosts ultimately depend upon one another for survival and en-
courages the exploration and exploitation of these ecological relationships in
order to improve human, animal, plant, and environmental health and well-being
(Lederberg, 2000).
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