Systems Biology

Robert A. Meyers

• Publisher: Wiley-Blackwell
• Year: 2012
• Print ISBN: 9783527326075
• eBook ISBN: 9783527668595
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Systems biology is a relatively new biological study field that focuses on the systematic study of complex interactions in biological systems, thus using a new perspective (integration instead of reduction) to study them. Particularly from year 2000 onwards, the term is used widely in the biosciences, and in a variety of contexts. Systems biology is the study of the interconnected aspect of molecular, cellular, tissue, whole animal and ecological processes, and comprises mathematical and mechanistic studies of dynamical, mesoscopic, open, spatiotemporally defined, nonlinear, complex systems that are far from thermodynamic equilibrium.

Part I

Biological Basis of Systems Biology

1

Systems Biology

Melanie Boerries¹, Roland Eils², and Hauke Busch¹

¹Freiburg Institute for Advanced Studies – LifeNet, School of Life Sciences, Albertstraße 19, 79104 Freiburg, Germany

²German Cancer Research Institute, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

1 Introduction

2 What Is Systems Understanding?

3 Why Are Biological Systems Different?

3.1 Biological Complexity

3.2 Global Properties of Biological Systems

3.2.1 Robustness of Biological Systems

3.2.2 System Adaptation and Control

3.2.3 Modules and Protocols

4 Systems Biology Modeling

4.1 Network Biology

4.2 Dynamic Network Models

4.3 Reaction–Diffusion Models

4.4 Holism versus Reductionism: The Global Dynamics of Networks

4.5 Modeling Resources and Standards

5 Future Prospects of Systems Biology

5.1 Synthetic Biology

5.2 Conclusions: Where Are We?

References

Keywords

Systems biology

A new field of biology that studies the functional structure and dynamics of intercellular and intracellular networks with the help signal- and systems-oriented methods.

Synthetic biology

Studies life as networks of biological objects such as DNA proteins RNA and metabolites.

Network biology

Studies the static organization of life as networks made up of biological entities such as DNA proteins RNA or metabolites.

System

A set of interacting parts functioning as a whole and distinguishable from its surroundings by identifiable boundaries.

Systems theory

This denotes the cross-disciplinary investigation of the abstract organization of systems irrespective of their substance type or spatiotemporal scale of existence. The goal is the study of emerging properties that arise from the interconnectedness of the individual parts making up the system.

Robustness

The robustness of biological systems denotes the maintenance of specific system functionalities in the presence of fluctuations or change in environmental parameters.

Control

Control is defined as the response action taken by a system to counteract parameter changes to maintain system functions at a certain predefined level.

Modularity

A design concept of complex systems to integrate simpler self-contained functional building-blocks into the framework of one larger system.

Model

The concept of representing causal relationships from real systems in the language of mathematics

Systems Biology is a new field of biology, which places the theoretical foundations of systems analysis of living matter into the context of modern high-throughput quantitative experimental data, mathematics, and in silico simulations. The aim is to analyze the organization and to gain engineering-control of metabolic and genetic pathways. The ultimate goal is to gain an “holistic” view of the complex workings of life. The need for a system level understanding of biology is reviewed in this chapter, and comments are provided on the current scientific progress in this field. The current and future directions of experimental design strategies and theoretical approaches are also highlighted.

1 Introduction

Systems Biology is a recently established field in life sciences that aims at promoting a global systems understanding of living matter through the integration of various scientific domains (see Refs [1–3] for special journal sections and Refs [4–7] for textbooks on the topic).

The considerate attention that Systems Biology receives is due to the fact that it currently causes a paradigmatic shift in many areas of biological research. Modern molecular biology has been mostly a descriptive science, devoting insight to small, isolated compartments of a system as a whole – for example, by investigating the influence of individual proteins within the behavior of a whole cell. Thus, the study of the interconnected nature of cellular processes has long been avoided in favor of a reductionist approach. On the one hand this is due to the sheer amount of new challenges that come about when tackling complex systems, whereas on the other hand it has been the common leitmotif in other natural sciences, such as physics, to shed light mostly on well-defined and controllable systems. Those systems are then either small and isolated, or large and homogeneous, so that they can be tackled by applying the laws of statistics. Novel challenges, however, lie in the description of dynamical, mesoscopic, open, spatiotemporally extended, nonlinear systems, operating far away from thermodynamic equilibrium, which are the most important type to understand, as these are the systems that support life.

Although reductionist approaches have been successful in elucidating key processes and key factors of many fundamentally important biological processes, contemporary science is now realizing the importance of wholeness by studying problems of organization. Emergent phenomena arise from the interaction of various units or modules, which are neither resolvable nor understandable through the study of local events or the respective parts in isolation. Hence, traditional reductionist models and methods of cell and molecular biology are not very well suited, and can be incomplete, misleading, or even completely wrong.

Historically, Jan Christiaan Smuts was among the first to formulate a theory of the whole that was hoped to fill the gap between science and philosophy. In his book Holism and Evolution, which was published in 1926 [8], Smuts argued that Nature consisted of discrete objects, or “wholes,” that are not entirely resolvable into their respective parts. The wholes and parts mutually depend on each other in their functionality, thus forming one organic, unified web of relations, which comprises matter, life, and mind, and which cannot be accounted for by a reductionistic analysis. Smuts saw his idea confirmed in evolution, regarding Holism as the active driving force towards more perfect wholes or species.

The theoretical foundations of systems engineering were laid some 60 years ago, when the concept of systems theory in biology was proposed during the 1940s by the biologist Ludwig von Bertalanffy [9]. The proposal was further developed during the 1950s by Ross Ashby [10], as a counter-movement against reductionism in science. In the sense of holism, von Bertalanffy emphasized the need for a study of the informational organization within real, open systems. The assembly of such inter-related elements then comprise a unified whole, which in turn can show new emergent properties.

In 1948, the mathematician Norbert Wiener established the field of cybernetics [11] as the science of communication and control of systems in regard to their environment. Cybernetics is closely related to systems theory, using the same concepts of information, control, or feedback. However, whereas the former focuses on systems function for providing regular and reproducible behavior, the latter deals more with system structure. Even so, both terms are often used in conjunction, for both structure and function cannot be understood as separate entities.

Today, biology embarks on systems thinking in two different ways. One way is to regard Systems Biology as a new way toward integrating information from different organizational levels, starting from DNA to proteins via signaling pathways to functional modules, into the context of a holistic organizational view [12]. The primary goal of the second view on Systems Biology is to establish a conceptual framework and working methodologies for the augmentation of knowledge on biological phenomena by combining systems theory and molecular biology: “Systems Biology is not a collection of facts but a way of thinking” [13]. This view has already been shared during the late 1960s by Mesarovi

, who predicted that Systems Biology would be an established field of science as soon as “… biologists start asking the right questions” [14]. Put differently, biologists need not recast facts already known from molecular biology in a different language, but they need to ask questions based on system-theoretic concepts [15].

Both approaches share the extensive need for high-quality, quantitative biological data obtained through extensive experimental measurements, and this is the reason why the use of systems theory in biology has gained momentum during recent years. New techniques can provide the necessary amount of quantitative data for the establishment of appropriate holistic models of cellular processes. Eventually, those new experimental techniques will lay the foundation for the integration of mathematics, engineering, physics, and computer science into biology, to permit an understanding of the range of complex biological regulatory systems at multiple hierarchical and spatiotemporal levels of cellular organization [16].

2 What Is Systems Understanding?

The word “system” derives from the Greek σνστημα, and is composed of the prefix syn, which means “together,” and the root of histanai, meaning “cause to stand.” A system is defined as “… the assembly or set of inter-related elements comprising a unified whole that is distinct from its environment,” and can be hierarchically organized and made up of other subsystems or modules, which allows the construction of a complex entity from simpler units. For example, organelles such as mitochondria constitute distinct subsystems within the organization of a cell. The subdivision of natural entities into systems is an abstract construct. Systems per se do not really exist in reality; rather, they are defined as a set of elements interacting over time and space.

Systems theory denotes the transdisciplinary investigation of the abstract organization of phenomena, independent of their substance, type, or spatiotemporal scale of existence [17]. The goal of systems theory is to study emerging properties arising from the interconnectedness and complexity of relationships between parts. Such theory argues that however complex or diverse a system is, there are always different types of organizational structures present, which can be represented as a network of information flow. Because these concepts and principles remain the same across different scientific disciplines such as biology, physics, or engineering, systems theory can provide a basis for their unification. The systems view distinguishes itself from the more traditional analytic approach by emphasizing the concepts of system–environment boundaries, signal input–output relationships, signal and information processing, system states, control, and hierarchies. Albeit systems theory is valid for all system types, it usually focuses on complex, adaptive, self-regulating systems which are termed “cybernetic.”

Elegant, simple, and globally valid models are rare in biology as compared to other fields of science. Few examples exist where a function can be attributed to the workings of a single small molecule or few proteins, as in the case of hemoglobin for the transport of gases in the bloodstream, or bacterial chemotaxis [18].

In general, many genes and proteins are involved in cellular responses to external stimuli. In general, biology follows a reductionist approach by investigating small, isolated parts of a cell, tissue, or organism; typically, biology tries to deduce biological phenomena from m...

Table of contents

• Cover
• Related Titles
• Title Page
• Copyright
• Preface and Commentary
• List of Contributors
• Part I: Biological Basis of Systems Biology
• Part II: Systems Biology of Evolution
• Part III: Modeling of Biological Systems
• Part IV: Systems Biology in Medicine and Disease
• Part V: Systems Biology of Organisms
• Index