Systems Biology

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Preface

You hold in your hand a volume devoted to systems biology of infectious disease.
If you are new to the field, you may be asking ‘‘what is systems biology?’’ If you
think you already know the answer, you may be wondering how such an approach
can be applied to a problem as complex as infectious disease. Our goal is to
address both of these questions, and we anticipate that this volume will be of great
interest to investigators already engaged in systems biology research as well as to
those scientists and clinicians who may be seeking an introduction to the field.

What is Systems Biology?

As you read through this volume, it will become apparent that while there is no
single concise definition of systems biology, most authors will settle on several
key points. First, systems biology is an inter-disciplinary approach, requiring the
combined talents of biologists, mathematicians, and computer scientists. Second,
systems biology is holistic, with the goal of obtaining a comprehensive under-
standing of the workings of biological systems. This is achieved through the
acquisition of massive amounts of data by high-throughput technologies—oligo-
nucleotide microarrays, mass spectrometry, and next-generation sequencing—and
the analysis of this data through sophisticated mathematical algorithms (Fig. 1). It
is perhaps the use of mathematics, to integrate abundant and diverse types of data
and to generate models of interconnected molecular networks, that best charac-
terizes systems biology.
An additional characteristic often attributed to the approach is the use of an
iterative cycle of experimental perturbations. Once a model has been developed,
subsequent perturbations of the biological system are used to yield refinements to
the model and increase its predictive capacity. While the value of a clear
understanding of complex molecular networks may seem readily apparent, pro-
ponents of systems biology argue that the approach is also the only way to
understand the ‘‘emergent properties’’ of biological systems. As described in

v
vi Preface

Test s

Experimental
Systems
Predict ions

Integrated
SYSTEMS High-throughput

Dat a
Molecular BIOLOGY Profiling
Networks

Mathematical
Modeling

Models

Fig. 1 The systems biology paradigm viewed as an iterative cycle of events leading to the
generation of integrated models of molecular networks that serve to generate predictions for
subsequent testing, model refinement, and a deeper understanding of biological processes

‘‘Systems Approaches to Dissecting Immunity’’, these are properties—or bio-

logical outcomes—that cannot be predicted by an understanding of the individual
parts of a system alone. Finally, systems biology typically seeks to capture
information about changes in a biological system over time, providing unique
insights into the dynamic nature of the system, a property that has particular
relevance to infectious disease.

Why Focus on Infectious Disease?

Systems biology as we know it today was made possible by the human genome
project and the advent of high-throughput technologies to measure global changes
in gene transcription and protein and metabolite abundance. The first uses of this
approach just over a decade ago focused on the systematic perturbation of yeast
and the mathematical modeling of metabolic pathways (Ideker et al. 2001). Given
Preface vii

the complexity of even a single-cell organism, many would argue (and some still
do) that the approach is ill-suited for multi-cellular organisms or mammalian
systems. Yet the cancer field rapidly embraced the approach and has proven its
utility for network-based classification and prognosis of breast cancer, the iden-
tification of oncogenes in B-cell lymphomas, and improvements to radiation
therapy (Laubenbacher et al. 2009).
The infectious disease field, in contrast, has come rather late to the game.
Although our own group published the first genomic analysis of HIV-infected cells
in culture (Geiss 2000), and numerous reports of transcriptional profiling of virus-
infected cells and tissues have followed, the application of a true systems biology
approach to infectious disease has until only recently been considered too daunting.
What has brought about the change in attitude? Recent and dramatic improvements
to mathematical modeling (see ‘‘Studying Salmonellae and Yersiniae
Host–Pathogen Interactions Using Integrated ‘Omics and Modeling’’ and
‘‘Insights into Proteomic Immune Cell Signaling and Communication
via Data-Driven Modeling’’) and the success of the approach in other fields are
certainly contributing factors, but perhaps most important is the growing realization
that the infectious disease field desperately needs to take new approaches to solve
long unanswered challenges, particularly in the areas of vaccine and drug
development.
Trying to understand the countless and complex pathogen–host interactions and
intra- and inter-cellular signaling events that occur during the course of infectious
disease is indeed a formidable task. Historically, a reductionist approach was both
the most tractable and only available line of attack. But clearly a new approach is
needed. Vaccines against numerous deadly diseases, most notably AIDS, malaria,
and tuberculosis are still lacking. Drug-resistant viruses and bacteria continue to
emerge, a trend that is likely to endure as long as microbial targets remain the
focus of new drug development, and the focus on microbial targets also yields
drugs that are typically narrow in spectrum. As described throughout this volume,
systems biology offers a new and holistic approach to understanding pathogen–
host interactions, the innate immune response, and the mechanisms that lead to
disease, immunopathology, or protective immunity. The approach holds enormous
potential, but there are challenges as well.

Risks and Rewards

No doubt everyone engaged in systems biology research has heard the criticism that
the approach is nothing more than an expensive fishing expedition that takes
funding away from individual investigators. The relative merits of big versus small
science aside, if systems biology is a fishing expedition, the chapters in this volume
show that the approach is beginning to make some nice catches. For example,
systems biology is accelerating vaccine development by increasing our under-
standing of how protective immune responses are elicited ‘‘Systems Biology
viii Preface

of Vaccination in the Elderly’’. Similarly, by providing a better understanding of the

host response to infection, the approach is facilitating the development of drugs that
target the host side of the pathogen–host interaction ‘‘Systems Biology Analyses
to Define Host Responses to HCV Infection and Therapy’’, an approach that will
yield drugs that are broader in spectrum and less prone to microbial resistance.
Moreover, systems biology is beginning to deliver on its much touted potential for
yielding biomarkers for new diagnostic and prognostic applications ‘‘Systems
Biology Approach for New Target and Biomarker Identification’’.
Nevertheless, the approach is expensive, and with ever-tightening budgets,
more money for systems biology means less money elsewhere. Moreover, because
the approach has been extensively hyped as being revolutionary, expectations have
been set high, and many are understandably disappointed with the pace of
progress. The extent to which systems biology represents a true paradigm shift has
also been called into question (Bothwell 2006). And there are still plenty of
technical, scientific, and mathematical hurdles to overcome. Even the choice of
experimental systems can be a challenge. The jump from cell culture systems to
nonhuman primates, for example, represents an enormous leap in system com-
plexity that taxes every aspect of the approach, particularly computational and
modeling techniques. Yet, as discussed in ‘‘The Role and Contributions of
Systems Biology to the Non-Human Primate Model of Influenza Pathogenesis
and Vaccinology’’ and ‘‘‘Omics Investigations of HIV and SIV Pathogenesis
and Innate Immunity’’, significant progress is being made, and the analysis of
biologically relevant infection models is essential if we are to understand the
processes of disease and immunity and translate findings into rational drug design
and vaccine development.

In This Volume

We begin this volume with an engaging editorial by Dr. Valentina Di Francesco

and colleagues, who oversee a broad portfolio of systems biology research con-
tracts at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID
has made a substantial commitment to systems biology through the sponsorship of
genomic, proteomic, and bioinformatic resource centers, and more recently
through the funding of a systems biology for infectious disease research program.
This program is aimed at using experimental and computational approaches to
analyze, model, and predict the architecture and dynamics of the molecular net-
works underlying the initiation and progression of infectious disease (Aderem
et al. 2011). Each of the primary investigators associated with this program have
provided material for this volume.
The chapters of Systems Biology provide the reader with cutting-edge research
from leaders in the systems biology field. The initial chapter provides both a
concise overview of the systems biology paradigm as well as an excellent dis-
cussion of how this approach is being used to dissect the innate immune system.
Preface ix

Subsequent chapters are devoted to systems biology approaches to bacterial–host

interactions (including Salmonella, Yersinia, and Mycobacterium), where
molecular events within the pathogen are as important as the host response to the
invading microbe; the application of high-throughput and computational
approaches to nonhuman primate models of influenza and AIDS; and an over-
view of the emerging field of systems vaccinology, where systems biology is
changing the way we think about vaccine design and testing. Final chapters are
dedicated to defining the host response to hepatitis C virus infection and therapy,
to drug target and biomarker identification, and to new computational approa-
ches, including data-driven modeling. By assembling a diverse spectrum of
perspectives and expertise, it is hoped that the information provided here will
serve as a catalyst for additional innovative approaches that will continue to
drive the field forward and that will ultimately transform how we view, treat, and
protect against infectious disease.

Seattle, Washington, July 2012 Marcus J. Korth

Michael G. Katze

References

Aderem A, Adkins JN, Ansong C, Galagan J, Kaiser S, Korth MJ, Law GL,
Mcdermott JE, Proll SC, Rosenberger G, Schoolnik G, Katze MG (2011) A
systems biology approach to infectious disease research: innovating the path-
ogen-host research paradigm. mBio 2:e00325-00310
Bothwell JH (2006) The long past of systems biology. New Phytol 170:6-10
Geiss GK, Bumgarner RE, An MC, Agy MB, Van ’T Wout AB, Hammersmark E,
Carter VS, Upchurch D, Mullins JI, Katze MG (2000) Large-scale monitoring
of host cell gene expression during HIV-1 infection using cDNA microarrays.
Virology 266:8-16
Ideker T, Thorsson V, Ranish JA, Christmas R, Buhler J, Eng JK, Bumgarner R,
Goodlett DR, Aebersold R, Hood L (2001) Integrated genomic and proteomic
analyses of a systematically perturbed metabolic network. Science 292:929-
934
Laubenbacher R, Hower V, Jarrah A, Torti SV, Shulaev V, Mendes P, Torti FM,
Akman S (2009) A systems biology view of cancer. Biochim Biophys Acta
1796:129-139

Acknowledgments

We thank Cynthia Baker for her invaluable help in assembling this volume, Sean
Proll for assistance with figure production, and Patrick Lane for the final systems
x Preface

biology graphic. Research in the Katze laboratory is supported by Public Health

Service grants R2400011172, R2400011157, P30DA015625, P51RR00166, and
U54AI081680 and by federal funds from the National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Department of Health and
Human Services, under contract HHSN272200800060C.
Introduction: Embracing Complexity
in Infectious Disease Research

The concept of systems biology is not new, in fact reflecting on work done in the
1960s, British biologist Denis Noble described systems biology as ‘‘… putting
together rather than taking apart, integration rather than reduction. … It requires
that we develop ways of thinking about integration that are as rigorous as our
reductionist procedures, but different … it means changing our philosophy, in the
full sense of the term’’ (Noble 2006).
Infectious disease research seems an ideal target on which to apply a systems
biology approach to understand an infectious agent, its host biology in response to
infection, and the dynamic nature of the pathogen and host interactions over the
course of disease. Traditional experimental approaches to infectious disease
research have focused mostly on subsets of the virulence process or on particular
events that occur during infection limiting both the speed and ability to understand
the complex process as a whole. For example, the study of individual genes,
operons and regulons provides necessary insights into the workings of infection, but
it does not offer a comprehensive framework for the interaction of the regulatory
networks of the infectious agent and the host cells. Comprehensive identification of
the cellular and molecular components of the pathogen and its host, and
characterization of the functional role and mechanisms involved in the interaction
require the use of advanced high throughput (HTP) technologies. High-perfor-
mance computational resources and sophisticated analysis tools are now available
to make sense of the enormous datasets generated. In spite of the difficulties and
challenges, the complexity of biological systems can now finally be embraced.
The National Institute of Allergy and Infectious Diseases (NIAID), part of the
National Institutes of Health (NIH), supports research to better understand, treat, and
prevent infectious, immunologic, and allergic diseases. Given the potential of
microbial genomic research, in the last few years NIAID has made a significant
investment in genomic-related programs that provide to the scientific community
comprehensive, publicly accessible resources for genome sequencing, transcripto-
mics, proteomics and bioinformatics, as well as rapid release of data and reagents for

xi
xii Introduction: Embracing Complexity in Infectious Disease Research

basic and applied research, in support of the Institute’s mission (http://www.

niaid.nih.gov/topics/pathogenGenomics/research/Pages/relatedInitiatives.aspx). To
leverage the availability of advanced technologies for genomics research in 2008,
NIAID established the Systems Biology Program (SBP) for infectious diseases
research to encourage a shift in thinking toward a more global and high-throughput
approach to basic research on infectious diseases in order to gain insight into the
biology of microbes, their role in pathogenesis, and their molecular interactions with
the host. The SBP utilizes computational and experimental high-throughput meth-
odologies to identify, analyze, quantify, model, and predict the structure and
dynamics of molecular networks involved in host/pathogen interactions (Aderem
et al. 2011). High-throughput methodologies often include next generation
sequencing, transcriptomics, proteomics, metabolomics, and lipidomics. By
encouraging a systems biology approach, NIAID also fosters multidisciplinary
teams—including statistical modelers, computational biologists, experts in HTP
genomics technologies, microbiologists, and clinicians—to tackle the complexity of
infectious disease research in a more comprehensive fashion.
As in other systems biology programs, the NIAID SBP has been experiencing a
number of challenges and ideal solutions are yet to be found. Comprehensive data
analysis and biological interpretation of the experimental results appear to be the
largest hurdles. Contemporary HTP technologies generate unprecedented amounts
of experimental data. In a systems biology project, an efficient and well-designed
data management infrastructure is crucial for data analysis. Experimental data must
be organized and systematically maintained to allow for long-term storage, acces-
sibility, and fast retrieval by multiple research laboratories that may be disseminated
geographically while participating in joint projects.
Mathematical modeling of the behavior of biological systems in response to the
tested experimental conditions is indispensable to integrate and effectively sum-
marize the experimental data; to identify missing information (e.g. predicted
essential genes that seem to be missing from the annotated genomes); to predict the
systems’ response to perturbations; and to suggest the next experiment. However,
establishing accurate models with high confidence levels depends on enough
amounts of data to set parameters, constraints, and to cross-validate, hence
increasing the need for even more experimental data.
In addition, systems biology research is sometimes conducted primarily with in
vitro experimentation rather than with in vivo/ex vivo systems to allow for better
control of the experimental system (e.g. temperature, chemistry, infection time
course) and measurements that can be replicated more easily and economically.
Nevertheless, the most promising observations derived from in vitro systems are
generally tested and validated in the relevant animal and human tissues. Also,
whenever technically feasible, multiple HTP technologies should be applied con-
currently to the same biological samples. This can present a challenge because
sample preparation protocols for different genomic technologies may alter the
characteristics of the sample.
Introduction: Embracing Complexity in Infectious Disease Research xiii

The power of the systems biology approach can only be fully exploited by
ensuring that—in addition to publications—the generated data, associated metadata,
original experimental design and protocols, and resulting models are made easily
accessible to the broad scientific community of infectious disease researchers. This
is especially important given the abundance of data generated by typical systems
biology projects, the limitations of the current analysis and modeling approaches,
and the budgetary constraints that limit the number of validation studies that can be
performed within any funded project. For that reason, NIAID is requiring that
funded systems biology projects share with the broad scientific community all the
generated ‘omics’ data and metadata, resources, and novel reagents through publicly
accessible databases and reagent repositories. Still, it appears that infectious disease
researchers in general need to become more familiar with the advanced technolo-
gies, analysis tools, and computational approaches—of the systems biology
approach in order to take full advantage of the shared resources and further pursue
much needed validation studies.
The systems biology approach is gradually being adopted by infectious disease
researchers. The slow pace of adoption is not surprising, since it parallels what
happened in the past with the introduction of new research tools that are generally
refined over many years before they are adopted for widespread use. New methods
are typically more expensive and lack evidence of reliability, accuracy, and value.
However, new methods usually become more precise and economical over time and
that is proving to be the case with systems biology.
HTP experimental work, data analysis, and model development are performed by
technology experts, bioinformaticians, and computational scientists respectively.
Biologists and infectious disease scientists more often provide interpretation of the
data in the context of the biological systems being investigated and contribute to the
design of important follow-up validation studies with more traditional ‘reductionist’
approaches (e.g., phenotype characterization of gene knock-outs) to pursue the most
promising new hypotheses gleaned from the data. While the controversy in the
scientific community continues as to where the balance should lie between the
‘reductionist’ and the ‘systems’ approach in biomedical research, the controversy
should be settled as traditional methodologies are still needed to fill in the details of
specific biological events, with systems biology acting as a hypothesis generator
pointing to areas needing further investigation.
NIH supports a broad array of basic and clinical research. Systems biology ulti-
mately seeks to improve health by approaching disease not as a pathology in indi-
vidual biochemical pathways of a particular cell type in a single organ, but as the
result of complex and interdependent processes. The long-term expectation is that
systems biology will more quickly identify the biological processes involved in
disease and facilitate the development of therapeutic strategies, vaccines, and
diagnostics based on a more comprehensive and systems-wide understanding of the
xiv Introduction: Embracing Complexity in Infectious Disease Research

mechanisms implicated in the disease processes. Several chapters in this book

already demonstrate the promise and initial successes of the systems biology
approach.

William Alexander
Peter A. Dudley
Valentina Di Francesco
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD, USA
E-mail: [email protected]

References

Aderem A, Adkins JN, Ansong C et al (2011) A systems biology approach to

infectious diseases research: innovating the pathogen-host research paradigm.
MBio 2(1): e00325-10
Noble D (2006) The music of life: biology beyond the genome. Oxford University
Press, USA
Contents

Systems Approaches to Dissecting Immunity . . . . . . . . . . . . . . . . . . . 1

Alan Diercks and Alan Aderem

Studying Salmonellae and Yersiniae Host–Pathogen Interactions

Using Integrated ‘Omics and Modeling . . . . . . . . . . . . . . . . . . . . . . . 21
Charles Ansong, Brooke L. Deatherage, Daniel Hyduke, Brian Schmidt,
Jason E. McDermott, Marcus B. Jones, Sadhana Chauhan,
Pep Charusanti, Young-Mo Kim, Ernesto S. Nakayasu, Jie Li,
Afshan Kidwai, George Niemann, Roslyn N. Brown, Thomas O. Metz,
Kathleen McAteer, Fred Heffron, Scott N. Peterson, Vladimir Motin,
Bernhard O. Palsson, Richard D. Smith and Joshua N. Adkins

ChIP-Seq and the Complexity of Bacterial

Transcriptional Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
James Galagan, Anna Lyubetskaya and Antonio Gomes

The Role and Contributions of Systems Biology

to the Non-Human Primate Model of Influenza
Pathogenesis and Vaccinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Carole Baskin

‘Omics Investigations of HIV and SIV Pathogenesis

and Innate Immunity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Robert E. Palermo and Deborah H. Fuller

Systems Biology of Vaccination in the Elderly . . . . . . . . . . . . . . . . . . 117

Sai S. Duraisingham, Nadine Rouphael, Mary M. Cavanagh,
Helder I. Nakaya, Jorg J. Goronzy and Bali Pulendran

xv
xvi Contents

Systems Biology Analyses to Define Host Responses

to HCV Infection and Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Reneé C. Ireton and Michael Gale Jr.

Systems Biology Approach for New Target

and Biomarker Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
I-Ming Wang, David J. Stone, David Nickle, Andrey Loboda,
Oscar Puig and Christopher Roberts

Insights into Proteomic Immune Cell Signaling

and Communication via Data-Driven Modeling . . . . . . . . . . . . . . . . . 201
Kelly F. Benedict and Douglas A. Lauffenburger

Critical Dynamics in Host–Pathogen Systems . . . . . . . . . . . . . . . . . . . 235

Arndt G. Benecke
Contributors

Alan Aderem Seattle Biomedical Research Institute, 307 Westlake Ave N, Suite
500, Seattle, WA 98109, USA, e-mail: [email protected]
Joshua N. Adkins Pacific Northwest National Laboratory, Biological Separations
and Mass Spectroscopy Group, PO Box 999, MSIN: K8-98, Richland, WA 99352,
USA, e-mail: [email protected]
Charles Ansong Pacific Northwest National Laboratory, Biological Separations
and Mass Spectroscopy Group, PO Box 999, MSIN: K8-98, Richland, WA 99352,
USA
Carole Baskin Science Foundation Arizona, 400 East Van Buren Street, Phoenix,
AZ 85004, USA, e-mail: [email protected]
Arndt G. Benecke Centre National de la Recherche Scientifique, Institut des
Hautes Études Scientifiques, 35 route de Chartres, 91440 Bures sur Yvette, France,
e-mail: [email protected]
Kelly F. Benedict Department of Biological Engineering, Massachusetts Institute
of Technology, Room: 16-343, 77 Massachusetts Avenue, Cambridge, MA 02139,
USA
Roslyn N. Brown Pacific Northwest National Laboratory, Biological Separations
and Mass Spectroscopy Group, PO Box 999, MSIN: K8-98, Richland, WA 99352,
USA
Mary M. Cavanagh Department of Medicine, Stanford University, Stanford, CA
94305, USA
Pep Charusanti Department of Bioengineering, University of California-San
Diego, La Jolla, CA, USA
Sadhana Chauhan Departments of Pathology and Microbiology and Immunol-
ogy, University of Texas Medical Branch, Galveston, TX, USA

xvii
xviii Contributors

Brooke L. Deatherage Pacific Northwest National Laboratory, Biological Sep-

arations and Mass Spectroscopy Group, PO Box 999, MSIN: K8-98, Richland,
WA 99352, USA
Alan Diercks Seattle Biomedical Research Institute, 307 Westlake Ave N, Suite
500, Seattle, WA 98109, USA
Sai S. Duraisingham Emory Vaccine Center, Yerkes National Primate Research
Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA
Deborah H. Fuller Department of Microbiology, University of Washington,
Seattle, WA, USA; Washington National Primate Research Center, Seattle, WA,
USA, e-mail: [email protected]
James Galagan Department of Biomedical Engineering, Boston University,
Boston, MA 02215, USA; Department of Microbiology, Boston University,
Boston, MA 02215, USA; Bioinformatics Program, Boston University, Boston,
MA 02215, USA; The Eli and Edythe L. Broad Institute of Harvard, MIT,
Cambridge, MA 02142, USA
Michael Gale Jr. Department of Immunology, University of Washington
School of Medicine, 1959 NE Pacific Street, Box 357650, Seattle, WA 98195,
USA, e-mail: [email protected]
Antonio Gomes Bioinformatics Program, Boston University, Boston, MA 02215,
USA
Jorg J. Goronzy Department of Medicine, Stanford University, Stanford, CA
94305, USA; Department of Medicine, Palo Alto Veteran Administration Health
Care System, Palo Alto, CA 94304, USA
Fred Heffron Department of Molecular Microbiology and Immunology, Oregon
Health and Sciences University, Portland, OR, USA
Daniel Hyduke Department of Bioengineering, University of California-San
Diego, La Jolla, CA, USA
Reneé C. Ireton Department of Immunology, University of Washington School
of Medicine, 1959 NE Pacific Street, Box 357650, Seattle, WA 98195, USA
Marcus B. Jones J. Craig Venter Institute, Rockville, MD, USA
Afshan Kidwai Department of Molecular Microbiology and Immunology, Ore-
gon Health and Sciences University, Portland, OR, USA
Young-Mo Kim Pacific Northwest National Laboratory, Biological Separations
and Mass Spectroscopy Group, PO Box 999, MSIN: K8-98, Richland, WA 99352,
USA