Manual Systems Biology: Definitions and Perspectives

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Articles

  1. Practical Applications of Systems Biology
  2. Integrative Systems Biology Resources and Approaches in Disease Analytics
  3. Practical Applications of Systems Biology
  4. Related Articles

One example of pattern-detection within large datasets has received special attention from philosophers of science, namely research on so-called network motifs. By comparing the gene regulatory network of the bacterium E. Statistically significant circuits were defined as network motifs. The diagrams represent the regulation of a gene Z, via a direct path between a transcription factor X to Z, and an indirect connection from X via another gene or transcription factor Y to Z.

In a coherent feedforward loop cFFL , all connections are activating. Adapted from Alon Akin to common circuit types in electronic networks, it was hypothesized that the recurring wiring patterns may indicate generalizable functional behaviors. Mathematical analysis suggested that the cFFL may function as a sign-sensitive delay element that filters out noisy inputs for gene activation e.

In contrast, the regulatory function of the iFFL was hypothesized to be an accelerator that creates a rapid pulse of gene expression in response to an activation signal. These predicted functions have been experimentally demonstrated in living bacteria Mangan et al. Such results have sparked interesting debates on whether network motifs could be seen as design principles , whose functions are generalizable across different biological contexts see Section 2. Philosophers and scientists alike have debated the implications of research focusing on generic properties of biological networks, rather than the properties of specific molecular components e.

Among the controversial issues is how the enhanced focus on topological properties relates to more traditional mechanistic explanations in biology Section 4.

A related issue is whether functional capacities can be derived from an analysis of network architectures alone. Some systems biologists and philosophers have pointed to the limitations and possible biases associated with inferences of functions from automated pattern-detection in datasets Calvert ; Keller ; Krohs ; see also Prill et al.


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Specifically, some have called for a more dynamic approach that can account for the context of the whole network and how it changes over time. Network approaches have recently been extended to also study temporal aspects of coordinated protein-protein interactions in cell cycles and evolutionary dynamics de Lichtenberg et al. Of scientific as well as philosophical relevance is whether and how these approaches can extend mechanistic strategies in molecular biology by identifying how multiple biological processes are organized and coordinated in time Green et al.

The framework explores how inherent mathematical properties of the network architectures may constrain developmental and evolutionary processes, in a way analogous to how laws of motion constrain the possible planetary movements Goodwin et al. Controversies of this kind can reveal interesting differences in research aims as well as different standards for models and explanation present in systems biology Section 5.

Systems biologists often describe their approach as one occupied with functional , rather than evolutionary questions Boogerd et al. By stressing the autonomy of functional biology, philosophy of systems biology can help balance the extensive emphasis on evolutionary biology in philosophy of biology Pradeu At the same time, evolutionary systems biology has recently emerged as a new research approach aiming to extend both systems biology and evolutionary biology Section 3.

Another recent extension of systems biology is the emergence of systems medicine , the medical application of systems biology. Systems biology has from the outset been associated with ambitiouns to solve grand societal challenges. Examples are the aims to provide a better understanding of complex diseases like cancer, and the vision of developing patient-specific models that will allow for individualized disease prediction and prevention Section 5.

The aforementioned aims are often pursued through large-scale international collaborations where many research teams provide data and models to be integrated in complex models of whole cells e. Such projects raise new exciting questions for philosophy of science concerning strategies for model building and model validation Carusi Moreover, they provide new sources for philosophical discussions on reduction and explanation Section 4 and on the societal applications of big data biology Section 5.

In the wake of big data production around year , comprehensive gene regulatory networks could be constructed that allowed for more systematic and ambitious design projects. Also in this context, however, the ties to precursors are diverse, and there are different views on whether modular approaches are compatible with biological complexity see below.

But the relation to engineering is complex, and synthetic biology displays a plurality of epistemic aims, visions and methodological frameworks. A central research aim in synthetic biology is to modify metabolic pathways so as to control biochemical reactions and produce chemicals of societal value. Synthetic organisms may also be designed for bioremediation. Many efforts are also directed towards improvements of biomedical research and clinical practices, e.

Much of synthetic biology research can be characterized as application-oriented innovations that utilize and modify biological structures. But not all practices fit this description. Some synthetic biologists pursue a basic science approach to understand the origin of life or the conditions for minimal life Section 3. Examples are 3D printers that can print biological tissue structures and perhaps—with time—also replicate themselves. DNA-based device construction , or what Benner and Sismour characterize more broadly as the engineering trend, explores the extent to which interchangeable and functionally distinct components can be designed and implemented in a modular fashion.

The BioBrick Foundation is a paradigmatic example of this approach biobricks. The guiding principles for this approach are standardization, decoupling, and abstraction of parts and functional descriptions Endy The orientation towards functional devices and machine-like control is also explicit in the so-called iGEM competition Genetically Engineered Machine where student teams compete in the task of constructing genetically engineered biological systems to address societal problems.

Whether the ideal of constructing standardized and replaceable parts is compatible with biological complexity is an ongoing topic of debate Sections 2 and 3. The notion of a minimal genome highlights the idea that existing organisms may have genomes more complex than necessary for the basic functions of survival and reproduction.

The human parasite Mycoplasma genitalium has been considered a model organism for the exploration of such questions due to its small genome, and it has also been the target for the first whole-cell model in systems biology Karr et al. In , scientists at the J. From the synthetic DNA sequence, the researchers could partly control the production of new Mycoplasma mycoides cells. This genome was recently further reduced to a working approximation for the simplest synthetic minimal genome JCVI-syn 3. Researchers within this stream are often interested in the fundamental question of what life is, and the notion of applied science may not be an appropriate description of this research approach see Section 3.

Historically, the theoretical discussion of what life is has often been coupled to wet-lab synthesis of compounds associated with early or minimal life. This research practice connects to projects within genome-driven cell engineering investigating the minimal requirements for a living system to function, survive, and reproduce. Research on protocells may focus primarily on understanding the origin of life as we know it, or aim to create synthetic life forms in other and simpler ways Rasmussen et al.

Practical Applications of Systems Biology

Deplazes has suggested the following extended classification of practices within synthetic biology: i bioengineering, ii synthetic genomics, iii protocell synthetic biology, iv unnatural molecular biology, and v in silico approaches see Figure 3. Unnatural molecular biology aims to create systems with different components, e.

Figure 3: Schematic representation of the five categories of synthetic biology and their connections. As Figure 3 illustrates, computer simulations are central to all research practices in synthetic biology. Systems and synthetic biology offer new opportunities to reconsider the relative prospects and limitations of engineering approaches for biological research Braillard ; Calcott et al.

Engineering approaches are often considered inadequate to grasp biological complexity. Specifically, design thinking has often been associated with adaptationism, i. Accordingly, critics have argued that the engineering approach may lead to a simplified understanding of evolution as driven solely by natural selection Lynch But whereas some approaches in systems biology can be described as adaptationist Green , it cannot be assumed that design approaches always entail adaptationist implications. Because research in systems and synthetic biology often is often dissociated from evolutionary considerations, these research practices may force philosophers to reexamine the concepts of biological function and design beyond traditional aetiological accounts Holm ; Preston It is, however, still debatable whether the thin notion of design is compatible with biological complexity.

Integrative Systems Biology Resources and Approaches in Disease Analytics

Design approaches may implicitly enforce the view that operations and outputs of specific parts are stable and predictable across different contexts. Yet, as outlined in the following sections, the ties to engineering are multi-faceted in both systems and synthetic biology. Although synthetic biology is distinct from systems biology in the explicit aim to design synthetic systems, it is often described as a practice relying on systems biology as a theoretical foundation for design Barrett et al. Synthetic and systems biology are sometimes described through the complementary aims of forward and reverse engineering.

Forward engineering refers to the design of systems with novel functions, often by drawing on an existing high-level model e. Forward engineering, or re-engineering, can lead to more complex systems, but simplicity may also be pursued through implementation of a more abstract coding language or through reduction or rewiring of genetic circuits. The search for recurring network motifs Section 1. Because functional features such as robustness are not only important to the survival oforganisms but also to design problems in engineering, reverse engineering of organizational features that underpin such capacities is an important aim in both fields Hartwell et al.

In engineering, the notion of reverse engineering is often associated with the aim to identify generic features of system design, or design principles , that can be reused in new systems. The search for functional principles, with applications to different systems in biology and engineering, dates back to the ideals of cybernetics and biochemical systems theory Wiener ; Savageau Negative feedback control has long been a central principle in mechanical and electronic engineering to maintain stable concentrations and minimize fluctuations.

An important insight from cybernetics is that the same formalization can also describe biological processes, e.

Practical Applications of Systems Biology

Characteristic of the search for design principles in modern systems biology is that the strategy is enforced through automated pattern-detection in network models based on large biological datasets, as exemplified by the search for network motifs Section 1. The hope is that simple control principles, using e. Alon ; Tyson et al. One such example is the so-called toggle-switch, a simple regulatory circuit that is considered a design principle in both systems and synthetic biology.

systems biology explained

Like a toggle-switch that turns an electrical device ON or OFF, genetic toggle-switches have been found to regulate many biological processes such as the cell cycle of budding yeast and developmental processes in fruit flies Tyson et al. A genetic toggle-switch is a double-negative feedback loop that shifts the system between two distinct stable states of gene expression—allowing synthesis of one protein while another is repressed.

Synthetic biologists have succeeded in constructing a synthetic toggle switch in E. Because of the abstract nature of proposed design principles, an interesting philosophical question is how such strategies relate to discussions about the possibilities of laws in biology.

Biological systems are often taken to be too contingent, diverse, and context-dependent to allow for derivation of laws or general principles akin to those found in physics Burian et al. The quest for design principles in biology is therefore an interesting test case to explore whether more abstract descriptions of generic features of functional organization can be formulated also in the context of biology Green b.

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A related question is how the enhanced focus on generic principles and topological features of biological networks relates to mechanistic accounts of biological explanation Section 4. An important question for such debates is whether generalizable functions can be inferred from organizational structures, relatively independently of cellular, organismal, and environmental contexts.

The search for network motifs and other functional units make apparent that systems biology research does not necessarily give up assumptions of modularity. Whether systems biology presents more holistic approach to biological complexity is therefore an issue of debate in both philosophy of science and systems biology itself.