A report from the American Academy of Microbiology

Systems Microbiology:
Beyond Microbial Genomics

By Merry R. Buckley

Copyright 2004
American Academy of Microbiology
1752 N Street, NW
Washington, DC 20052
http://www.asmusa.org

This report is based on a colloquium sponsored by the

American Academy of Microbiology held June 4-6,
2004, in Portland, Oregon.

The American Academy of Microbiology is the honorific

leadership group of the American Society for Microbiology. The mission of the American Academy
of Microbiology is to recognize scientific excellence
and foster knowledge and understanding in the microbiological sciences.

The American Academy of Microbiology is grateful for

the generous support of the following:
National Science Foundation
U.S. Department of Energy

The opinions expressed in this report are those solely of

the colloquium participants and may not necessarily
reflect the official positions of our sponsors or the
American Society for Microbiology.

BOARD OF GOVERNORS,
AMERICAN ACADEMY OF MICROBIOLOGY

COLLOQUIUM STEERING COMMITTEE

Eugene W. Nester, Ph.D. (Chair)

University of Washington

Timothy J. Donohue, Ph.D. (Co-Chair)

University of Wisconsin-Madison

Kenneth I. Berns, M.D., Ph.D.

University of Florida Genetics Institute

James K. Fredrickson, Ph.D. (Co-Chair)

Battelle Pacific Northwest National Laboratory

Arnold L. Demain, Ph.D.

Drew University

Penny Chisholm, Ph.D.

Massachusetts Institute of Technology

E. Peter Greenberg, Ph.D.

University of Iowa

Nancy L. Craig, Ph.D.

John Hopkins University School of Medicine

J. Michael Miller, Ph.D.

Centers for Disease Control and Prevention

Jeremy S. Edwards, Ph.D.

University of Delaware

Stephen A. Morse, Ph.D.

Centers for Disease Control and Prevention

Marvin E. Frazier, Ph.D.

U.S. Department of Energy

Harriet L. Robinson, Ph.D.

Emory University

Carol A. Colgan
Director, American Academy of Microbiology

Abraham L. Sonenshein, Ph.D.

Tufts University Medical School
George F. Sprague, Jr., Ph.D.
Institute for Molecular Biology, University of Oregon
David A. Stahl, Ph.D.
University of Washington
Judy D. Wall, Ph.D.
University of Missouri

COLLOQUIUM PARTICIPANTS
John F. Alderete, Ph.D.
University of Texas Health Sciences Center, San Antonio

Julie C. Mitchell, Ph.D.

University of Wisconsin-Madison

Judith P. Armitage, Ph.D.

University of Oxford, England

Hirotada Mori, Ph.D.

Nara Institute of Science and Technology, Nara, Japan

Jeffrey Blanchard, Ph.D.

University of Massachusetts-Amherst

Kenneth Nealson, Ph.D.

University of Southern California

Patrick P. Dennis, Ph.D.

National Science Foundation

Martin Polz, Ph.D.

Massachusetts Institute of Technology

Claire M. Fraser, Ph.D.

The Institute for Genomic Research

Virgil Rhodius, Ph. D.

University of California, San Francisco

Alf Game, Ph.D.

BBSRC, Swindon, England

Margaret Romine, Ph.D.

Battelle Pacific Northwest National Laboratory

Carol Giometti, Ph.D.

Argonne National Laboratory

Lucia Rothman-Denes, Ph.D.

University of Chicago

Yuri Gorby, Ph.D.

Battelle Pacific Northwest National Laboratory

Lucy Shapiro, Ph.D.

Stanford University School of Medicine

James Hu, Ph.D.

Texas A&M University

Thomas J. Silhavy, Ph.D.

Princeton University

Julius H. Jackson, Ph.D.

Michigan State University

Heidi Sofia, Ph.D.

Battelle Pacific Northwest National Laboratory

Eugene Kolker, Ph.D.

Biatech, Bothell, Washington

David A. Stahl, Ph.D.

University of Washington

Allan E. Konopka, Ph.D.

Purdue University

Jonathan Zehr, Ph.D.

University of California, Santa Cruz

Frank W. Larimer, Ph.D.

Oak Ridge National Laboratory
Robert A. LaRossa, Ph.D.
E.I. DuPont De Nemours & Co., Inc.
Michael T. Laub, Ph.D.
Bauer Center for Genomics Research, Harvard University
Jared R. Leadbetter, Ph.D.
California Institute of Technology
Harley McAdams, Ph.D.
Stanford University
George Michaels, Ph.D.
Battelle Pacific Northwest National Laboratory

EXECUTIVE SUMMARY

The American Academy of Microbiology convened a

colloquium June 4-6, 2004, in Portland, Oregon, to confer about the scientific promise of systems microbiology.
Participants discussed the power of applying a systems
approach to the study of biology and to microbiology in
particular, specifics about current research efforts, technical bottlenecks, requirements for data acquisition and
maintenance, educational needs, and communication
issues surrounding the field. A number of recommendations were made for removing barriers to progress in
systems microbiology and for improving opportunities
in education and collaboration.
Systems biology, as a concept, is not new, but the
recent explosion of genomic sequences and related
data has revived interest in the field. Systems microbiology, a subset of systems biology, represents a different
approach to investigating biological systems. It attempts
to examine the emergent properties of microorganisms
that arise from the interplay of genes, proteins, other
macromolecules, small molecules, organelles, and the
environment. It is these interactions, often nonlinear,
that lead to the emergent properties of biological systems that are generally not tractable by traditional
approaches. As a complement to the long-standing
trend toward reductionism, systems microbiology seeks
to treat the organism or community as a whole, integrating fundamental biological knowledge with genomics,
metabolomics, and other data to create an integrated
picture of how a microbial cell or community operates.
Systems microbiology promises not only to shed light
on the activities of microbes, but will also provide biology the tools and approaches necessary for achieving a
better understanding of life and ecosystems.
Microorganisms are ideal candidates for systems
biology research because they are relatively easy to
manipulate and because they play critical roles in health,
environment, agriculture, and energy production.
Potential applications of systems microbiology research
range from improvements in the management of bacterial infections to the development of commercial-scale
microbial hydrogen generation.
A number of technical challenges must be met to
realize the potential of systems microbiology. Development of a new, comprehensive systems microbiology
database that would be available to the entire research
community was identified as the single most critical
need. Other challenges include difficulties in measuring
single-cell parameters, limitations in identifying and
measuring metabolites and other products, the inability
to cultivate diverse microbes, limits on data accessibil-

ity, computational limitations associated with data integration, the lack of sufficient functional gene annotations,
needs for quantitative proteomics, and the inapplicability of current high throughput methods to all areas of
systems microbiology. Difficulties have also been
encountered in acquiring the necessary data, assuring
the quality of that data, and in making data available to
the community in a useful format.
Problems with data quality assurance and data availability could be partially offset by launching a dedicated
systems microbiology database. To be of greatest value
to the field, a database should include systems data
from all levels of analysis, including sequences, microarray data, proteomics data, metabolite measurements,
data on protein-protein or protein-nucleic interactions,
carbohydrate and small RNA profiles, information on
cell surface markers, and appropriate supporting data.
Regular updates of these databases and adherence to
agreed upon data format standards are critical to the
success of these resources.
It was recommended that educational requirements
for undergraduate and graduate students in microbiology be amended to better prepare the next generation
of researchers for the quantitative requirements of
applying systems microbiology methods in their work.
1

Systems microbiology research is too complex to be

the sole property of any single academic discipline. The
contributions of microbiologists, computer scientists,
control theorists, biostatisticians, and others are all
required to move the field forward. Since research in
systems microbiology demands the contributions of a
diverse array of professionals, collaboration across disciplines and national borders should be strongly
encouraged by research bodies and funding agencies.
Although the details of systems microbiology research
are probably not of interest to the average individual,
the potential applications and benefits of these types of
investigations should be conveyed to the lay public.

INTRODUCTION

Systems microbiology is changing the way we look at

the microbial world. There are as many definitions of
systems microbiology as there are researchers who
engage in it, but the essence of the discipline is this:
systems microbiology seeks to identify how microbial functions evolve and how emergent properties in
cells and communities arise from seemingly simple,
linear genetic sequences. The idea of applying systems
analysis to the study of biological entities is more than
50 years old, but recent advances in genome sequencing and other high throughput measurements have
turned the fanciful imaginings of the past into the ambitious goals of the present.

proteins in an organism ( as is often done in reductionist

approaches ) is analogous to creating a catalog of parts
in a car. Just having access to the parts catalog doesnt
tell you how to build the car, and it wont reveal the principles and operating mechanisms of the whole vehicle.
To proceed, one needs to know how the individual parts
interact to convert fuel into electricity and forward
motion. Similarly, achieving a real understanding of an
organism requires insight into how all the various parts
relate to each other and how their dynamic interactions
regulate the complex molecular cascades that make
life possible. Rather than describing and treating the
individual parts of a microbe, systems microbiology
treats the microbe or the microbial community as a
whole, seeking to understand the interplay of its
genes, proteins, and organelles, and how they respond
to external stimuli.

Since the inception of microbiology, the field has generally embraced reductionism, focusing on increasingly
smaller details of microorganisms over time. Systems
microbiology complements that trend, seeking to
explain the properties that arise from interactions of the
smaller parts of an organism or between members of a
microbial community. Identifying each of the genes and

Researchers investigating microbes and microbial

communities from a systems perspective may use
techniques from many fields, including microbiology,
biochemistry, genomics, bioinformatics, chemistry, and
computational science, among others. However, modeling cellular, organismal, and community dynamics is
what sets systems microbiology apart from these other

Systems Microbiology in Action:

Systems Analysis of Photosynthetic Bacteria

The capture of light energy by photosynthetic organisms is the foundation of the biosphere. Photosynthetic plants and microorganisms harvest the suns energy and convert it into the stuff of life: by
splitting water they create the oxygen that sustains the biosphere and by harvesting carbon dioxide
and nitrogen gas from the atmosphere they provide the nutrients at the base of the global food chain.
Research on photosynthetic bacteria has provided key insights into the critical processes that photosynthetic microbes and plants carry out in support of life on this planet.
Today, systems approaches are being used to analyze the photosynthetic bacterium Rhodobacter
sphaeroides. By scrutinizing the patterns of gene expression R. sphaeroides exhibits in the presence
of light energy, scientists have been able to identify previously undiscovered genes that are required
to carry out photosynthesis. Moreover, genes that have an impact on global climate have been identified by using systems concepts to analyze gene expression in R. sphaeroides in the presence of
greenhouse gases. Genes that degrade toxic compounds and produce renewable biofuels have been
discovered in a similar manner. Investigators have also used systems microbiology to catalog the
proteins in R. sphaeroides photosynthetic apparatus, providing new ways to test the functions of
many previously uncharacterized components of the light-gathering machinery.

fields. In the systems approach, models of the microbe

are constructed at every level, including molecular, subcellular, cellular, and community functions.
Because it encompasses many varied fields of expertise, the work of systems microbiology is, by nature,
interdisciplinary and is not the sole property of any single traditional academic discipline.
The larger field of systems biology has been defined
by Ideker, et al. ( 2001 ), as, studying biological systems
by systematically perturbing them ( biologically, genetically or chemically ); monitoring the gene, protein, and
informational pathway responses; integrating these data;
and ultimately formulating mathematical models that
describe the structure of the system and its responses to
individual perturbations. * Systems biology is unique in
its effort to identify the components of a living system,
understand how those parts fit together, and determine
how the parts function as a whole.
The cumulative knowledge produced by decades of
reductionist experimentation serves as the foundation upon which systems biology is built. By leveraging
the fundamental discoveries of the 19th and 20th
centuries, systems research is drawing on the accomplishments of the past to build a more complete
knowledge of living things. It is not a substitute for
conventional research, but, rather, represents an evolution of biological research building on previous
knowledge as well as on recent and future technological developments. In this way, the systems approach
adds to the past and current reductionist efforts to
understand biology. In the future, the systems approach
to addressing biological questions will provide answers
to some of the greatest outstanding questions in biology
and will provide the means by which we can predict and
manipulate the function and evolution of living systems.

will eventually be applied to the systems analysis of

non-microbial life.

Microbial systems are important and ideal models

Bacteria, archaea, eukaryotic microbes, and viruses
offer easier access to the workings of biology than do
multicellular organisms, a fact that systems microbiology can surely exploit. The technical details of cultivation
are undoubtedly less difficult for many microbes, which
can be grown in petri dishes, tubes, and flasks, than
they are for larger organisms, which require more complex growth conditions and more space. Microbes
can also be grown asexually, allowing researchers to
study clonal groups of cells, a feat that is often impossible with multicellular life forms. For decades these
characteristics have allowed researchers to perform

Systems Microbiology in Action:

Gene Regulatory Networks

and Designer Microbes
Systems microbiology is enabling scientists to
design novel microbes that can be used to
address environmental, agricultural, or medical
problems. Researchers are using systems
approaches to weave existing data on wellstudied organisms into an integrated picture of
how microbial cells function. By modeling the
metabolic and regulatory networks of common
lab inhabitants like Escherichia coli, scientists
can now build novel gene circuits that respond
to new signals in a predictable way. These
designer microbes have a number of potential

WHY SYSTEMS MICROBIOLOGY?

Systems microbiology is a specialization within systems biology, and to derive a parallel definition for
systems microbiology only requires changing studying
biological systems to read studying microbiological
systems in the Ideker description. However, if systems
microbiology is merely a subcategory of systems biology, then why does it deserve particular attention? Can
systems microbiology offer lessons about life that
inquiries into the biology of plants and animals cannot?
The answer is an unqualified yes. Clearly, studying
microbes from a systems perspective can yield longsought answers to questions about microbes and their
roles in human health and the function of the biosphere.
But perhaps more significantly, this approach can also
lead to the development of the tools and insights that

applications, including the degradation of persistent toxic chemicals that would otherwise
poison soils and water supplies. Engineered bacterial strains have also been used as microbial
factories for generating ethanol ( an important
biofuel), feed additives, and pharmaceuticals.
Microbial production of these materials can be
more cost-effective than production by traditional methods.

* Ideker, et al., 2001. Annu. Rev. Genom. Hum. Genet, 2: 343.

experiments under strictly controlled conditions. Systems microbiology is poised to capitalize on these
aspects of microbes in order to provide new insights
into their operation and to develop the platforms that
can be applied to other living systems.
With the exception of fungi and certain other eukaryotic microbes, microorganisms carry relatively small
genomes. The size of microbial genomes has enabled
researchers to sequence the entire genetic material of
thousands of viruses and hundreds of bacteria and
archaea, and many more are sequenced every year.
The ability to easily sequence major stretches of microbial genomes is particularly useful in studying the
molecular and genetic basis of evolution, a phenomenon that is amenable to an experimental approach in
microbial systems but is more difficult to explore in
multicellular organisms.

Microbes offer important lessons about all life forms

Although microbes are structurally simpler than larger

life forms, they are intricate organisms that collectively
harbor most of biochemical diversity on the plant and
have a great deal to teach us about life on earth. In
many ways, they are more dynamic than the individual
cells of multicellular organisms, which exist in relatively
protected, controlled environments. Because of their
exposure to the stresses and vagaries of life outside a
larger life form, microbes are forced to be more adaptable and responsive to their environments than are
metazoan cells. These are important features that systems microbiology can tackle and apply to improve our
understanding of these abilities in all organisms.
Microbes can offer lessons in the interdependence of
biological responses to changing environments. Since
they exhibit almost all the critical cellular features of
living cells in a relatively simple package, microbes can
also enable a predictive understanding of interrelationships across scales, such as the relationships between
molecular functions, sub-cellular functions, cellular
functions, and so forth. Microbes are good platforms
from which to study the emergent properties that come
from the interacting parts of all organisms and groups
of organisms. Microbes also offer insights into cellular
life in multiple contexts, both as individual organisms
and as members of a community.

POTENTIAL APPLICATIONS
MICROBIOLOGY

OF

to move past the basic study of biological components

( including molecules, enzymes, microbial species, etc.)
and into a synthesis that can be used to predict the
future state of biological systems, systems microbiology
promises to provide powerful new tools and insights
contributing to agricultural, medical, industrial, and environmental innovations.
The practice of agriculture stands to benefit in a number of ways from the information gathered through
systems microbiology. For example, the procedures surrounding meat production could benefit from improved
systems knowledge of microbial causes of cattle, chickens, and swine diseases, the epidemiology of those
diseases, and the influences of pathogen transport. Similarly, high-density aquaculture could be improved through
a parallel knowledge of the pathogens of fish and shellfish.
The beneficial aspects of soil microbes or communities
on plant productivity could be explored using systems
techniques and could decrease our dependence on
agricultural chemicals. Likewise, the impact of microbes
on diseases of agricultural crops could be better managed with a systems understanding of the interplay of
microbes, plants and pesticide application.
In medicine, systems approaches can offer strategies
for identifying drug targets, overcoming antibiotic resistance, and managing the emergence of new diseases.
A systems understanding of human pathogens will
likely enable society to design antibiotics that target the
weakest parts or Achilles heel of the organism. Alternatively, systems approaches could identify the
appropriate antibiotics for use in multi-drug strategies
that target pursue two or more steps simultaneously
an approach that promises to reduce the development
of antibiotic resistance. An improved understanding of
pathogens from a systems perspective will also facilitate management of hospital acquired infections. Using
these methods to study pathogen ecology can offer
insights into interventions that will prevent the emergence of new diseases from environmental sources.
Other applications where the predictive abilities of
systems microbiology could be put to use include:
Novel energy production systems. The develo p ment of commercial microbial hydrogen
generation, BIO-batteries, and other technologies for energy production could be optimized by
a better understanding of the microbial cell or
microbial community as an integrated system.

SYSTEMS

The broad aim of systems microbiology is to acquire

an understanding of the wiring diagrams of life to
grasp the relationships between the individual components that build an organism or a community. In seeking

Metabolic engineering. Existing commercial

bioreactors and the products derived from organisms inoculated into them could be optimized
through a systems approach.

 Biocontrol. The use of helper microbes to eliminate or control undesired microbial populations
could be made possible through a systems
understanding of their interactions in soil and
aquatic communities.
Pollution and bioremediation. Water and soil
quality management systems could be optimized
with systems approaches.

require a consortium of scientists. Some of the professionals that are needed for these investigations include:
Microbiologists,
Biochemists,
Evolutionary biologists
Mathematicians,
Computer scientists,
Physicists,

Bioterrorism and decontamination. By identifying

key steps in the function of potential bioterrorism
agents, systems microbiology can help detect the
release and prevent the spread of these microbes.
Microbiological detection systems. Novel, highly
specific, and sensitive detection systems and
diagnostics can be easily developed using systems methods.
Global monitoring. As the most numerous and
diverse life forms on this planet, the activities of
microbes and microbial communities can be
used as sensitive reporters of local or planetary
changes in temperature, greenhouse gases,
pollutants, etc.

Chemists,
Control theorists,
Systems engineers,
Geochemists,
Atmospheric chemists,
Chemical and physical oceanographers,
Earth scientists, and
Biostatisticians.
While specialists in each of these fields can make
contributions to developing a systems approach to
microbiology, interdisciplinary researchers familiar with
microbiology will be in an excellent position to advance
the field.
5

REGULATION

RESEARCH IN
SYSTEMS MICROBIOLOGY
A number of specific issues in systems microbiology
research merit discussion, including the scientific fields
that should be involved in projects of this type, how
systems microbiology can be applied to studying biological regulation and microbial communities, the role of
a systems approach in hypothesis-generating research,
and how the presence of noise in biological systems
will affect progress in systems microbiology.

DISCIPLINES THAT CAN CONTRIBUTE

MICROBIOLOGY

TO

SYSTEMS

What fields can contribute to systems microbiology?

Progress in this field needs the contributions of a diverse
range of professionals. That is not to say that all problems will require the input of many different fields of
expertise, as there are inevitably going to be goals that
can be accomplished by individuals and goals that will

OF

BIOLOGICAL SYSTEMS

Due to the number and complexity of interactions

involved in the biological pathways and regulatory networks, progress in understanding these systems has
often been made by studying one isolated circuit at a
time. As a result, limited progress has been made in
describing the interactions between different components of interconnected regulatory networks. Systems
microbiology may be the perfect approach for tackling
this crucial subject. Using the tools of systems biology,
researchers can begin to delve into the basic mechanisms of regulation, uncovering previously unknown
types of interactions. Other, broader questions can also
be addressed, including whether fundamental design
principles exist in biological regulation and whether
understanding these design principles offers insights
into the in situ behavior of organisms.
Although a number of systems methods for addressing questions about biological pathways and networks
already exist, new methods and approaches are
needed. Investigators and technology development
professionals need to consider which investments
of time and money will have the greatest payoff in
understanding these fundamental aspects of microbes
and other living systems.

APPLYING A SYSTEMS BIOLOGY APPROACH

MICROBIAL COMMUNITIES

TO

Current and future systems microbiology techniques

can provide approaches to understanding the complex
properties of microbial communities, their dynamics,
and their impacts on natural and human systems. Systems approaches to microbial communities could
answer the following fundamental questions: Which
species are present? What are they doing? Where are
they doing it? What is the environmental impact of the
community? And finally, what happens to the community and its impacts in the event of a natural or
society-generated disturbance?
As a first step in these investigations, it will be necessary to identify all the members of the community under
study as well as all the interactions in which they
engage. This is no small feat, and the ability to accomplish this kind of undertaking is likely to require new
analytical and computational tools. The systems approach
may at first find its greatest success by focusing on relatively simpler communities in which there is little
overlap between the niches occupied by different members of the community. Stochastic effects may obscure
the picture in communities in which there is a high
degree of redundancy.
6

Spatial organization is another confounding factor in

carrying out an analysis, but it may be avoided by studying laboratory communities in liquid suspension. In any
event, and whichever community is selected for study
using systems analysis, it is likely that single cell biochemical techniques will be needed as one of the key
dissecting tools ( see Technical Challenges in Systems
Microbiology section Single cell measurements ).
Systems microbiology approaches should avoid treating the sum of all the genomes from a given environment,
also known as the metagenome, as a single entity.
Researchers should instead develop methods for
assembling the individual genomes of the possible
thousands of community members. The cell and its
genome are critical units of organization in microbial
communities and they should not be dissolved in
research that hopes to achieve an understanding of
these associations.

HYPOTHESIS -GENERATING RESEARCH

By mining high throughput data, scientists can
achieve new insights and derive novel hypotheses that
would be time-consuming or impossible to develop
through traditional reductionist approaches. Many successful examples of applying hypothesis-generating
principles exist, including the genome mining work that
uncovered motility and chemotaxis genes in Geobacter

species. Prior to the genome mining work, these organisms were thought to be non-motile, but following the
discovery of motility genes, experiments were implemented that confirmed their motility. Both tactics,
hypothesis-generating research and hypothesis-driven
research, are required for successful application of systems approaches.

MEASURING NOISE

IN

BIOLOGICAL SYSTEMS

Noise is a problematic factor in all branches of experimental science, biology included. In biology, some of
the difficulty lies in separating measurement noise, the
irreproducible quantitative variation due to observational
factors, from true biological noise, the irreproducible
variation exhibited by biological systems. Moreover, stochastic processes have been shown to drive some
biological phenomena, so biological noise cannot be
dismissed from data analysis lest a significant underlying process be ignored. Hence, noise is an inescapable
part of biological science and must be addressed in
investigations that employ systems approaches. The
ability to measure noise in a given biological system will
depend upon the ability to quantify its relevant features.

TECHNICAL CHALLENGES IN
SYSTEMS MICROBIOLOGY
As an evolving field, most of the successes of systems microbiology lie in the future. However, to realize
this potential the technical challenges that riddle the
path ahead must be acknowledged, managed, and overcome. Technical bottlenecks range from difficulties in
identifying and quantifying cellular constituents to limitations in the ability to cultivate diverse microbes or
monitor the activity of complex microbial communities.
Difficulties also arise in acquiring and cataloging the
necessary information and research data and in assuring data quality.
A database of systems microbiology information
would facilitate the process of overcoming these difficulties in data acquisition and quality assurance and
would most likely prove to be hugely advantageous for
the field.

TECHNICAL BOTTLENECKS

Data accessibility

Since its inception, progress in microbiology has proceeded in lockstep with advances in technology. This
dependence on technology also extends to systems
microbiology, and a number of methodological difficulties must be resolved for the field to move forward.
Many of these bottlenecks are universal and apply to
multiple systems, but others are more system-specific.

Enormous quantities of biological data have been accumulated over the years, including genome sequences,
annotations, biochemical information, microarray profiles, and other types of information. These data could
serve as an invaluable resource for developing a systems
understanding of microbes, however, many important
data sets are unavailable to public databases and others
are not amenable to storage or comparison in a database format ( video images etc.). Ideally, these data sets
should be stored in searchable, cross-referenced databases that allow researchers ready access to
information pertaining to their individual research

Single cell measurements

The inability to measure biochemical parameters in
single cells poses a serious restriction on the power of
systems microbiology. Average measurements of tens,
hundreds, or even millions of cells have been useful to
microbiology research, but to better understand the
range of variation and the true dynamics of an organism, measurements of activity in single cells will be
necessary. Quantitative measures of gene expression,
protein levels, metabolites and other cellular constituents are needed to complete the picture of
biological systems. It is highly desirable to be able to
carry out these measurements non-destructively and
in real time. Tracking single cell measurements over
time would be particularly helpful in following components that are located at specific points in the cell or on
the cell membrane.

Identifying and accurately measuring metabolites

Difficulty in identifying and localizing metabolites and
in determining the pool sizes of these components
poses another obstacle to applying the systems
approach. The sensitivity and spatial resolution of the
currently available methods need to be improved in
order to model the behavior of metabolites with the proteins that use these compounds as substrates,
products, or ligands. Greater sensitivity and resolution
would also establish tighter links between observations
of community structure and function.

Cultivation
The inability to isolate and cultivate many types of
microbes has long limited the range of organisms that
are available for analysis. Although the vast majority of
microbes resist cultivation by traditional methods, it has
been proposed that many more strains would yield to
cultivation efforts if novel, imaginative approaches were
used. Systems microbiology would benefit greatly from
renewed efforts to cultivate diverse strains or consortia
of microbes from different environments, since the ability to study individual strains under lab conditions is
often a key to experimentation.

OTHER

TECHNICAL BOTTLENECKS IN SYSTEMS

MICROBIOLOGY INCLUDE:

Difficulties in sequencing DNA from microbial communities.

Difficulties in analyzing microbial communities in situ.
Generally low analytical sensitivity for
microbes that are hard to culture or
slow growing.
Limited facilities for controlled cultivation
of microbes.
Lack of a coordinated repository for
depositing analyzed microbial cultures
or communities.
Poor infrastructure available for imaging,
Difficulties in managing and archiving large
electronic files, particularly images.
The lack of available methods to visualize
the presence and activity of proteins or
protein complexes.
The dearth of user-friendly bioinformatics
applications.
The lack of modeling paradigms that can
accommodate broad applications in time
and spatial dimensions.
The lack of a collaboratory informatics
infrastructure that biologists can use, and
The inability to measure biological
responses that are close to the current
baseline of detection.

efforts. For example, with new microarray data in

hand, a researcher could access a relevant database
to discover the location and context of a gene of interest, its place on a metabolic map of that organism, its
relationship with or within regulatory networks, and
related genes or pathways in other organisms. In order
to make the best use of archival data and to move forward in the field, data of use in systems microbiology
must be publicly accessible and encoded in a format
that can easily be cross referenced. ( Further discussion of this and other requirements for data formatting
and databases are included in the section titled A Systems Microbiology Database.) The quantity of
biological data is expanding daily, and the current state
of disorder will only worsen if steps are not taken to
organize data relevant to systems microbiology into a
useful, convenient resource.

Computational limitations

Even given the unprecedented advancements in computing power that have been achieved over the past
decade, certain computational limitations still impose
restrictions on the type and dimension of systems modeling that can be accomplished. Although a
bottoms-up modeling approach, in which the activity
of a system is simulated from the known or suspected
activity of its components, may be too complicated to
tackle for a number of years to come, greater computing
power could enable a top-down microbial modeling
approach in the near future. In top-down models, measures of the end products of the system are used to
predict the activity of the system. In these models, it
may be most appropriate to focus on the role of those
proteins known as master regulators ( which direct the
responses of the cell and the cell cycle ) and the topdown regulatory architecture. The development of this
type of model could enable the subsequent modeling of
collections of interacting organisms in simple consortia
or complex communities.

Annotation and functional characterization of genes

Gaining an understanding of the function of a gene
product poses yet another barrier to progress in systems microbiology. Annotation and the comprehensive
functional characterization of proteins or RNA molecules remains difficult, error-prone processes, but
systems microbiology relies heavily on a thorough
understanding of the functions of gene products. Making more and better annotation and functional
information available to systems researchers would
enable improved gene and gene function predictions
( in newly sequenced organisms ), and allow evaluation
of context-dependent expression and function.

Proteomics
In order to promote the success of systems microbiology, the development of new proteomics approaches
needs to continue. To date, proteomics ( the study of
the full complement of proteins in the genome of an
organism ) has been slow to generate the types of quantitative data needed for use in systems applications.

High-throughput technologies
Although some high-throughput technologies are
relatively mature such as the use of microarrays for
gene expression measurements many of the data
needed for systems microbiology currently cannot
be obtained using high-throughput techniques, presenting a serious limitation on the rate at which the
field can proceed. Additional high-throughput technologies are needed. These include, but are not
limited to, the production and characterization of the
vast array of proteins encoded in microbial genomes,
identifying and characterizing the interactions among
the various proteins and other macromolecules,
determining the type and concentration of intracellular metabolites and extracellular signal molecules at a
given cell state, accurately monitoring the presence
of key regulatory RNA molecules, and determining
the suite of surface components that can often drive
microbe-microbe and microbe-surface interactions
in biofilms.

INFORMATION

AND

DATA GAPS

While there are idiosyncratic differences in the type

of type of information that needs to be gathered to
characterize different biological systems, certain general requirements can be identified that are needed to
characterize any given system. This information includes
the parts list : a comprehensive accounting of the
components of the system at many levels of organization, including the molecular, subcellular, taxonomic, and
environmental levels. However, in many cases the entire
list of components is not always needed to develop a
thorough understanding of the behavior of a biological
system. Even in the absence of complete knowledge,
the systems approach can still work well.
There is also a need to obtain global information, or
comprehensive measurements of cellular components,
for each system under study. This may include, for
example, the types and levels of regulation that occur in
the system or the types, activities, locations and fluxes
of cellular proteins, nucleic acids, metabolites, carbohydrates, and other cellular constituents. There is also a
need to understand how an organism lives in its natural
state. The evolutionary history of the system across
multiple temporal scales is also necessary.

Once the systems approach begins to yield results,

the information gathered is likely to feed back and
indicate the most critical data that are needed to move
forward in the analysis.

Needed data
A great deal of data that may be of use in systems
microbiology has already been generated. Genome
sequences from cultivated and non-cultivated organisms are a considerable resource for this effort, as are
the gene inventories that have characterized the genetic
diversity of a broad range of different environments.
Other information, including microarray data, exists but
is not readily available to the research community in the
form of an easily accessible public database. There is
also concern regarding the relative quality of these data.
Strategic decisions are needed in collecting the additional data necessary to pursue systems microbiology.
It may be advisable, for example, in the effort to define
microbial systems, to weigh the relative advantages of
studying one microbe under multiple different conditions rather than studying many different strains under
one condition.
Continued genome sequencing is crucial to the
efforts of systems biologists. In particular, more
sequences are needed from more organisms derived
from a greater range of habitats. Dense sequencing of
certain branches of the bacterial and archaeal phylogenetic trees can provide important information about the
mechanisms of cellular differentiation and evolution.
For example, many closely-related Proteobacteria have
widely diverse morphologies, niches, and metabolic
systems. Although certain regulatory molecules are
highly conserved in this branch of the tree, they have
been found to control widely different functions in each
of the different species. Systems analysis of genome
sequences and organization could determine how these
control systems evolved.
Genome sequences can only get systems biology so
far, however. It is also critical to obtain more data on
the functions of the proteins or nucleic acids encoded
by these sequences. Scientists currently rely too heavily
on homology mapping in inferring the functions of proteins and protein domains. Homology mapping involves
comparing a given protein sequence to the sequences
of proteins that have been characterized previously.
Unfortunately, not all protein functions assigned in public databases are accurate, creating a situation in which
the functions of many proteins remain unknown or are
possibly misconstrued. Such cases of misassignment
can hamper advances in the field. The results of
sequence homology analyses can also be vague; often,

proteins can only be given nonspecific descriptions, like

hypothetical kinase or transmembrane protein .
Moreover, many genes that are discovered today have
no homologs among the functionally described genes
and cannot even be assigned a tentative function.
Accurate gene annotation will be vital to progress
in systems microbiology. In many cases, considerable experimentation is necessary to confirm the
inferences of gene function that are suggested by homology mapping and other sequence-based approaches.
Experimental evidence about at least one protein in a
family of proteins would prove extremely helpful to systems efforts. Methods for updating annotations in
public databases are also needed so that researchers
can be made aware of new insights on the function of
related gene products.
Accurate quantitative information on a variety of
biological parameters is needed to model the function
of biological systems. Particularly necessary are data
that can describe a system sufficiently to allow treatment of that system as a black box component of larger
systems. These data can include flux measurements,
association characteristics (between components and
individuals ), three-dimensional architecture, context
dependent functional measurements ( including locational dependency of enzymatic functions ), physical and
chemical characteristics, and the spatial-temporal relationships between events in the system under study.
It has long been known that results of experiments
performed in vivo differ from those performed in vitro
and that laboratory type strains differ from wild type isolates. More extensive sampling of microbes in their
innate habitats, in vivo or in situ, is necessary to characterize microbial systems without the biases incurred
by growth in the laboratory environment. Also, natural
isolates change, sometime dramatically, with extended
culture in the laboratory; genome rearrangements, loss
of virulence, and loss of complexity in biological
processes have both been noted after lengthy culture.
For this reason, lab cultures may not provide appropriate
models for natural biological systems. As genomebased modeling of microbes in their natural state is
improved and metagenomic data are made available, it
may become easier to estimate the activities of those
microbes that cannot be cultivated or whose activities
are altered in cultivation, including their environmental
activity and their requirements for growth.
Other types of data that are needed for systems
microbiology efforts to proceed include:
Data that indicate spatiotemporal relationships

between system components,

 Data on community architecture,

in collective centers to the benefit of researchers and

the field in general.

Data that can reveal design principles and bio-

logical networks,
Data that expand the phenotypic characteriza-

tions of cells and communities,

Data on the natural variability of microbial sys-

tems, and
Data on cell cycle or spatial events.

ACQUIRING INFORMATION

10

AND

DATA

Difficulties have arisen in collecting the data necessary for systems microbiology investigations. Existing
disparities in formatting and data standardization
between databases, for example, can hinder the ability
of researchers trying to acquire information from prior
investigations. Often, the necessary information is
stored in a database or in the literature, but the representations or archive layout can prohibit easy access.
These data are seldom subjected to a quality assessment, and researchers access these resources at their
peril. Also, the representation of biological data in these
databases often reflects a cultural gap in understanding
between the computational scientists who design these
databases and the biologists who use the data. In general, there is not enough support for the databases and
other information sources critical to the advancement of
systems microbiology.
The documentation of metabolic pathways poses a
particular problem; there is a pressing need for standardization in these data sets. Scientific societies,
journals and/or funding agencies should move to set
standards for formatting of metabolic and regulatory
pathway information. These formatting guidelines
could apply to the type and organization of metabolic
pathway information provided in research publications
and submitted to public databases. It is also crucial
that these data are stored in a searchabl way that
allows researchers to explore pathways through a database interface.
Due to the high costs of many of the technologies
necessary for carrying out the work of systems microbiology, it may be advisable to develop central locations
of excellence to serve as a resource for the scientific
community. High resolution microscopy, other imaging
or modeling technologies, and high throughput data
production facilities, for example, which are too costly
for many labs or universities to provide, could be housed

ASSURING

DATA QUALITY

The problem of how to ensure and validate the quality of data available in public databases has become
more and more challenging with the genomics data
explosion of recent years. Physics and other fields have
grappled with large data sets in the past and the manner in which the dilemma was solved in those areas
may offer lessons to biology today. The contributions of
computer scientists and information specialists will be
crucial in resolving the issue of information management, but it is important that biologists work closely
with these professionals to ensure the utility of the
information systems that are developed.
Genomic data should not be treated as static; mechanisms need to be put into place to continuously
update the sequence and annotation data available in
public databases. One serious impediment to maintaining data timeliness is the inability or reluctance of most
scientists to commit to the long-term upkeep of their
publicly available data. When a student graduates, or
the funding for a project is exhausted, the impetus to
continue updating and actively curating small databases is often lost.
The manner in which genomics and other critical
data are generated should be standardized and
reported in both the archival databases and publications. For example, microarray data are more useful
only if the details of the experimental conditions and
analyses are recorded and documented in an accessible format. This type of information must be included
with genomics data sets to ensure the results are interpreted properly.
Quality assurance and reproducibility standards for
systems microbiology data that are consistent across all
the relevant journals and agencies need to be established. Once proper standards are developed they could
be implemented through peer review and incentives
from funding agencies.
In applying for funding, researchers are strongly
advised to allot money and personnel time to quality
assurance tasks.

MAKING SYSTEMS DATA APPLICABLE

AND

AVAILABLE

Efforts to standardize experiments, analyses, and biological materials across microbiological fields will aid in

efforts to develop the field of systems microbiology.

For example, defined cultivation practices can be standardized to enable the reproducibility of experiments
from lab to lab. The results from experiments carried
out under such standard conditions can be integrated
across many labs in a coherent framework. In addition,
the selection of model organisms or model communities for particular broad areas of research would help to
standardize the collection of information in a manner
that would be useful to a systems approach. Ideally,
model organisms would be selected to represent different evolutionary histories so that data obtained from
one phylogenetic branch could be applied to other lineages to determine the biological consistency and
universality of particular theories.
It is recommended that a commission on data
exchange be established to determine standards for
data analysis that would promote exchange of data
resources. Finally, a reference microorganism repository with original samples and libraries as well as
information on the field sites and environments from
which the microbes were derived would also enable
researchers from different labs to build effectively on
the work of others.
Properly designed databases are pivotal in making
the data of systems microbiology widely available. A
general standard should be instituted by the professional societies and scholarly journals that requires data
to be submitted to an appropriate public database.

A PROPOSAL
DATABASE

FOR A

SYSTEMS MICROBIOLOGY

How can researchers in systems microbiology, as a

community, make the most out of the data that has
already been collected? What is the best way to ensure
that data from one system can be applied to learn
something about other systems? The key to optimizing
the use of systems microbiology data lies in sharing
quality data openly. The value of a given investigation in
systems microbiology is trivialized if the resulting data
are not made available to the scientific community in a
standardized and accessible format.
Currently, however, protocols for ensuring that quality
systems microbiology data are widely disseminated
among researchers are absent and, as a result, data are
not effectively shared among researchers. Microarray
data, for example, are scattered among numerous different repositories, personal websites, and often partly
reported in publications and there are no mandatory standards or consistency in their analysis. Moreover, there is
no unified way in which to query these and other data.

The success of systems microbiology will be limited

unless the data of past and present is shared promptly
and structured in a way that it can be used effectively.
To accomplish these twin goals of dissemination and
organization, it is recommended that a central, curated
database for systems microbiology be established.
A number of unconnected data resources are available to researchers in systems microbiology, but they
are inadequate to address the needs of the field. Databases of raw data and personal data usually lack a
quality control framework. Other databases house data
that are out of date, are not indexed or searchable, or
are not available to the research community at large. A
new database is clearly needed. Assembling a database
for use by the systems microbiology community represents a central challenge for the field and for systems
biology in general.
To be effective, a systems microbiology database
should be all-inclusive, searchable, current, and authoritative. The accumulated data should include many
levels of information from the different analytical and
experimental techniques relevant to the field. To accomplish this goal, a coordinated effort will be required on
the part of researchers and those responsible for maintaining the existing data sets and databases to integrate
the available information into a logical configuration.
This configuration should be easily queried and
searched capabilities that would facilitate the optimal
use of the data resources. Efforts to ensure that the
data remains up to date would be critical to the success of the database. Also critical are the development
of data formatting standards that will streamline submission, searching and retrieval of data. Format
standardization must be made a high priority for the
field. It is critical that biologists, as the end-users be the
driving force behind the design and construction of the
database and the contributions of scientists from all
nations should be welcomed to the database effort. A
database that demands quality and accommodates data
from all quarters could serve as the gold standard
source of information for the field.
The appropriate dimensions of the database are open
to debate. Smaller databases that focus on single
organisms, for example, may better capture the attention and efforts of professionals who are invested in a
particular system. As a result, small databases may be
easier to maintain and keep up to date. On the other
hand, a larger database could be more efficient and
cost effective with respect to administration and hosting issues.

11

Systems microbiology data for the database

Data from all levels of analysis in systems microbiology should be targeted for inclusion in the database.
These include ( but are not limited to) the data associated with genomics and other techniques: sequence
data, microarray data, proteomics data, data from
metabolite studies, data on protein-protein interactions,
data on protein-nucleic acid complexes, carbohydrate
profiles and profiles of cell surface markers as well as
data from previous publications on traditional biochemical, genetic or physiological analyses. Supporting data
could also be included. For example, detailed information on the conditions used for cell growth, links to
relevant information on the genes and proteins of wellstudied organisms, imaging data, and the results of
biochemical and physiology analyses would be very
useful to researchers. That said, the amount of raw data
involved in systems microbiology investigations is staggering, and not all of it can be included in a single
database. Thus, it is likely that different data sets will
have to be included selectively and linked for the investigator to easily access as needed. The contributions of
computer scientists and information engineers will likely
be required in finding the solutions to managing and
storing these large data sets.

12

The storage and dissemination of genomics data is a

particular need in the systems community today.
Researchers need access to primary array data if the
lessons learned in a given experiment are to be applied
to other systems. Primary microarray, proteomics, and
metabolomics data and higher-level analyses should be
included in the database.
Naturally, a set of quality standards and rules for
cataloguing information will need to be conceived for
the database.

Updating the database

The systems microbiology database should be
updated regularly. The utility of any data resource in
biology diminishes if the information is not kept up to
date in a timely fashion. A number of existing biological
databases have shown how quickly a useful resource
can become obsolete if it is neglected. Mechanisms for
easy, continual updating of a database of this kind,
either automated or investigator-driven, are currently
lacking, however, and the development of an appropriate methodology poses a serious obstacle.
Conventions can change rapidly and, oftentimes, provisionally, in the field of microbiology. Genus and species
names, for example, may be revised many times over a
span of only a few years, wreaking havoc in finding and
curating appropriate information in databases and scholarly publications. Gene numbering can also change,

sometimes from day to day during the course of a sequencing project. The database will need to be updated with
respect to new species designations and gene numbering, but it should be carried out in a rational way that
minimizes confusion for database users.

EDUCATION, TRAINING,
AND COLLABORATION IN
SYSTEMS MICROBIOLOGY
Systems microbiology represents a new and powerful way of thinking that was necessitated by the
ever-increasing volumes of biological data becoming
available and the comprehensive nature of genome
sequencing, which provides exhaustive information on
the genetic contents of cells and organisms. As highthroughput technologies and access to large data sets
accelerate the pace of discovery the need for a systems
approach to interpret and exploit these volumes of data
becomes increasingly apparent. This new point of view
needs to be reflected in our approach to education and
training in microbiology at the undergraduate and graduate level. Of critical concern is the encouragement and
training of professionals who are interested in learning
how to integrate complex biological information using a
systems approach.

PREPARING MICROBIOLOGY STUDENTS

SYSTEMS APPROACHES

TO

USE

System biology holds great promise for the future of

microbiology. Considering the power of these approaches, microbiologists should be trained with an eye to
the skills that are necessary to understand and apply systems concepts to microbiological problems. To prepare
them for systems microbiology applications, the core curriculum for microbiology students should include:
Microbiology,
Quantitative biology and mathematics,
Biostatistics,
Biochemistry,
Physiology, and
Modeling of biological systems.

Quantitative training for undergraduates

For a number of reasons, undergraduate curricula in
the biological sciences have largely excluded intensive
quantitative training. For most students, this limits
their access to the fields of bioinformatics, computation, and statistics, making them ill-prepared for the
rigorous mathematical and statistical requirements of
applying systems techniques. Training for biology students in mathematics must be improved and
expanded to develop a new crop of numerically literate
microbiologists able to meet the challenges of systems microbiology.
Although quantitative training should be extended, systems biologists do not need the same skills as a typical
mathematician. Math for biologists should be couched in
the language of biology to emphasize the potential applications of math in the field. Specially designed courses in
applied mathematics that include a laboratory section to
demonstrate the principles discussed in class would be
particularly suitable for biologists. Other novel
approaches to training include the use of computerbased mathematics programs like Mathematica or
statistical programs like Statistica, which may enable students to apply sophisticated math and statistics to
biology with less training than would otherwise be
required. These approaches can greatly facilitate calculations but they are not a substitute for understanding.
Systems biologists need to understand the underlying
assumptions of different statistical methods, to know
when it is appropriate to apply a specific test.

Summer institutes for undergraduates and graduate students

Summer educational opportunities could be made
available to microbiology students to provide intense
training in systems microbiology to a select few. These
courses could cover such topics as mathematics, computer programming, or systems microbiology in
general. The aforementioned centers of excellence in
systems microbiology would be natural sites for hosting such institutes.

INSTRUMENTATION TRAINING
Progress in biology is paced by instrumentation; steps
forward are enabled by new technologies, and the field
can be stymied if new tools are not made available
or are unused. Broader training in the high throughput
techniques and new analytical, microscopic and modeling
instrumentation associated with systems microbiology
is highly recommended so that more microbiologists
can take advantage of the most current technological
advances. In their training, students should be exposed
to a number of techniques and approaches so that they

can learn to choose appropriate methods to address a

given hypothesis.
It is imperative for biologists to communicate with
the physicists and engineers who design and construct
instrumentation for use in systems microbiology.
Oftentimes, the different vocabularies of biology and
physical science can stand in the way of effective communication between these professionals. Engineers and
physicists who develop biology instrumentation need to
be exposed to more biology training to facilitate the
necessary collaborations and design the appropriate
user-friendly devices to support research activities.

COLLABORATION

IN

SYSTEMS MICROBIOLOGY

Collaboration is a key ingredient for success in systems microbiology. However, the details of collaboration,
including communication between distant institutions,
questions of where to situate collaborating scientists,
student co-mentoring, co-authorship, and issues to do
with funding, tenure or promotion can hamper effective
cooperation and career development of involved researchers. These challenges must be dealt with to enable
effective interdisciplinary research and collaboration.

Encouraging new collaborations

Steps must be taken to encourage collaborations
among the microbiologists, biochemists, computer scientists, engineers, and others who can contribute to
studies in systems microbiology. As in other arenas, the
best incentive for stimulating collaboration in systems
microbiology is a monetary incentive. Additional funding is needed to establish programs that include
incubator funds, start-up funds, planning grants or supplements to traditional investigator-driven awards in
order to facilitate the process of bringing disparate
groups of professionals together. The systems microbiology approach can also be encouraged through
funding a meeting or laboratory course of interested scientists that could take the approximate form of a
Gordon Conference or Specialized Laboratory Course (in
which roughly 50 participants hold poster sessions,
attend lectures or perform experiments in a live-in
setting ). Ensuring access to funding for students and
post-doctoral associates who engage in systems microbiology is also central to making progress in the field.
Support for collaboration between academic and industrial interests can yield fruitful collaborations in systems
microbiology provided proper controls are put in place
to ensure the timely publication of results.
Special attention should be given to choosing how
peer review is carried out in evaluating the merit of systems microbiology proposals as the breadth of these

13

proposals may exceed the expertise of individual assessors. It may be necessary do develop special panels to
evaluate these proposals.

International collaborations
Researchers in systems microbiology should take full
advantage of opportunities to engage in international
collaboration. The scientific community involved in this
particular topic is extremely cosmopolitan, and researchers from different nations have their own traditional
strengths to lend to a given project. In Europe, for example, researchers in Germany and the Netherlands are
known for their work in physiological diversity, Poland
and Hungary have strong credentials in marrying biology
to math and physics, and Romanian scientists have
maintained expertise in histological techniques that can
be applied to solving systems microbiology questions.

14

International work is also justified in light of the

global nature of the problems facing science today.
SARS and other infectious diseases readily cross international borders, over fishing and water quality are
problems that must be managed by cooperative teams
of nations, and climate change threatens every ecosystem on the planet. Finally, the equipment necessary for
carrying out the work of systems microbiology can be
extremely expensive, putting it out of the reach of many
research groups or individual countries. Collaboration
across borders can allow scientists to take advantage of
cutting-edge technologies without having to duplicate
costly equipment.
International collaboration is not always easy to
accomplish, however. A number of significant logistical
obstacles stand in the way of effective research.
Arranging and funding meetings among international
groups of collaborators can be difficult, as can the coordination of funding for collaborative research from grant
programs in different countries. Efforts to bring collaborators together from distant institutions would benefit
from implementing the newest technologies available in
web-based communications. Such systems provide a
cost-effective way to hold collaborator meetings and
host seminars, and could serve as an important complement to face-to-face communications. Microbiology
professional associations from all nations should work
in partnership to promote collaborations and to advance
the goals of systems microbiology.

COMMUNICATING SYSTEMS
MICROBIOLOGY TO THE PUBLIC

Systems microbiology is a complex field that is not

readily accessible to or understood by the public, but it
will certainly bring great benefits to society. Because of
the long-range importance of systems approaches, scientists must make a special effort to educate the public
about the benefits of investing in systems research.
One lesson to drive home to the public is that the
benefits of cutting edge research, including systems
microbiology, are eventually felt by ordinary citizens.
The space program, for example, brought the world a
number of technological advancements, including the
pocket calculator and the home computer. The same
will be true of investments in systems microbiology;
this research will inevitably benefit the public. The public should also be made aware of the necessity of
understanding natural phenomena in order to properly
manage these systems when something goes awry.
This goal could be achieved by encouraging or requiring
researchers receiving public funds to engage in outreach efforts or by encouraging professional societies,
institutions or supplementary grant programs to provide
financial support for disseminating systems microbiology messages to the public.
The applications of systems microbiology are numerous, but a few applications are more relatable to
non-scientists than others. The impacts of systems
microbiology on biomedical research, and hence, on
human health, should be conveyed to the public, as
should the import of the field in managing the health of
the global ecosystem. The impacts of the field on managing bacteria, increasing existing or creating new beneficial
activities in microbes, and controlling the hazards of agricultural antibiotic use should be communicated as well.

MODES

OF

COMMUNICATION

A number of modes of communication are open to

those interested in conveying systems microbiology lessons to non-scientists. For example, commercial space
on television would be an effective, albeit expensive,
vehicle for communicating with the public. Educational
programs that center on interviews with key scientists
in the field could be recorded on DVD and sold to
schools for use in the classroom, or targeted for use by
public radio and television. Childrens or young adult
books that convey the excitement of microbiology to
the lay population could be a useful vehicle, especially
when one considers the scientifically literacy of the
average citizen. Microbiology could also be integrated

into high school curricula; experimentation with microbial systems can offer relatively low-cost, high-impact
lessons for young people. A program that encourages
graduate students in microbiology to reach out to the
community could establish a long-term commitment to
conveying the importance and excitement of microbiology research to the public.

- The database should be structured so that

researchers studying one microbial system can
access parallel information on other organisms or
communities.

THE ROLE

- Efficient mechanisms to update publicly available

sequence and annotation data should be established.

OF THE

SCIENTIFIC COMMUNITY

Communication between the scientific community

and the general public needs improvement. Scientists
can be ineffective communicators when it comes to
reaching a lay audience. Hence, a greater emphasis on
coursework in writing and presentation is recommended
for microbiology students. Also, scientists and the relevant scientific societies need to be more proactive in
conveying important science to writers and journalists.

- Systems and guidelines need to be developed so

that existing and new data are made publicly accessible and available in formats that allow easy
cross-reference.

A number of additional recommendation were made that

would significantly enhance our ability to understand
microorganisms and microbial communities at the systems level. The power of systems microbiology is
seriously limited by the inability to measure biochemical
parameters in single cells, and technologies to enable
this capability should be a high priority. Average measurements of populations of cells are sufficient for some
applications, but the ability to measure expression, protein levels, and metabolites in individual cells is needed
to complete the picture of biological systems. New analytical techniques and approaches that can provide data at
the appropriate level of resolution need to be developed.

RECOMMENDATIONS
Systems microbiology requires a balance between
breadth and depth of knowledge in the professionals engaged in collaborative research. It is
necessary for each of the specialists involved to be
knowledgeable in their own field, but they must also
have sufficient knowledge of the other areas of the
project to contribute fully. Academic and research
programs should be aware of these issues as they
prepare professionals to function as leaders in their
field. Mathematics and computational training for
students of microbiology must also be improved
and expanded to encourage the development of the
numerical skills necessary to meet the challenges of
systems approaches.
A centralized database for systems microbiology
data is critical. The ability to use archival data will be
necessary to realize the full potential of systems
microbiology research.
- The database should enables rapid submission and
retrieval of high quality data in standardized formats.
This database should include: annotated genome
sequence data, metabolic pathway data, microarray
data, proteomics data, data from metabolite studies, data on protein-protein interactions, data on
protein-nucleic acid complexes, carbohydrate profiles, and profiles of cell surface markers.

Systems microbiology relies heavily on genomic

sequences; more sequences are needed from more
diverse organisms and habitats to ensure progress
in the field. Continued progress in the functional
annotation of the proteins encoded by genome
sequences is also crucial to the success of systems
microbiology. Experimental evidence on the function
of at least one protein in each family of proteins
would prove extremely helpful to systems efforts
and should be a high priority. Microbes are the most
abundant organisms on this planet and they have
immense impacts on ecological, agricultural, animal
and human ecosystems. More extensive in vivo and
in situ sampling and study of microbes is necessary
if systems microbiology is to accurately characterize
microbial systems that are unaffected by the physical and chemical forces of the lab environment.
New collaborations should be fostered among international scientists and across scientific disciplines.
The benefits of systems microbiology should be
communicated to the public through innovative and
creative means.
New educational programs should be established to
prepare students for the advances in microbiology
through studies in systems microbiology.

15