Search for organising principles: understanding in systems biology

Abstract

Due in large measure to the explosive progress in molecular biology, biology has become arguably the most exciting scientific field. The first half of the 21st century is sometimes referred to as the 'era of biology', analogous to the first half of the 20th century, which was considered to be the 'era of physics'. Yet, biology is facing a crisis--or is it an opportunity--reminiscent of the state of biology in pre-double-helix time. The principal challenge facing systems biology is complexity. According to Hood, 'Systems biology defines and analyses the interrelationships of all of the elements in a functioning system in order to understand how the system works.' With 30000+ genes in the human genome the study of all relationships simultaneously becomes a formidably complex problem. Hanahan and Weinberg raised the question as to whether progress will consist of 'adding further layers of complexity to a scientific literature that is already complex almost beyond measure' or whether the progress will lead to a 'science with a conceptual structure and logical coherence that rivals that of chemistry or physics.' At the core of the challenge is the need for a new approach, a shift from reductionism to a holistic perspective. However, more than just a pronouncement of a new approach is needed. We suggest that what is needed is to provide a conceptual framework for systems biology research. We propose that the concept of a complex system, i.e. a system of systems as defined in mathematical general systems theory (MGST), is central to provide such a framework. We further argue that for a deeper understanding in systems biology investigations should go beyond building numerical mathematical or computer models--important as they are. Biological phenomena cannot be predicted with the level of numerical precision as in classical physics. Explanations in terms of how the categories of systems are organised to function in ever changing conditions are more revealing. Non-numerical mathematical tools are appropriate for the task. Such a categorical perspective led us to propose that the core of understanding in systems biology depends on the search for organising principles rather than solely on construction of predictive descriptions (i.e. models) that exactly outline the evolution of systems in space and time. The search for organising principles requires an identification/discovery of new concepts and hypotheses. Some of them, such as coordination motifs for transcriptional regulatory networks and bounded autonomy of levccels in a hierarchy, are outlined in this article. Experimental designs are outlined to help verify the applicability of the interaction balance principle of coordination to transcriptional and posttranscriptional networks.

Fundamental issues in systems biology

“…It is crucial, they argue, 'to analyse systems as systems, and not as mere collections of parts' in order to understand the emergent properties of component interactions. (43,27,34) Systems are taken to constitute a fundamental ontological category, and differences between biological and human-made (engineered) systems are considered less important than their similarities. (44,34) Although this form of systems biology developed in response to the genomics 'revolution', it draws on much earlier systems theorists such as cyberneticists Norbert Wiener (45) and W. Ross Ashby (46) , general and organismal system theorist Ludwig von Bertalanffy, (47,48) mathematical biophysicists Nicolas Rashevsky (49) and Robert Rosen, (50) systems engineer Mihajlo Mesarović, (51) and (very occasionally) living systems theorist James…”

“…(33) Strong arguments are made that systems biology is more than just an extension of genomics and bioinformatics -it is indeed their necessary and 'natural' conclusion, but it is also something qualitatively different from what has already been achieved by the various 'omic' tools and findings. (34,35,36) A good question to ask, therefore, is whether systems biology sets itself apart from earlier genomics because of its object ('systems') or because of the way it does things ('systematically'). The objects of systems biology Under the systems biology rubric are two different (but not mutually exclusive) understandings of 'system'.…”

Systems level analysis of osteoclastogenesis reveals intrinsic and extrinsic regulatory interactions

“…In addition, several novel processes were identified. As is conventional in the systems biology approach, we used mining and modeling of the data set to infer and generate testable hypotheses (Kitano, 2002;Mesarovic et al, 2004). We present assay data for two such processes, the intrinsic regulation of apoptosis and the expression of pro-angiogenic factors.…”

MCR-ALS on metabolic networks: Obtaining more meaningful pathways

“…specific kinetics of the reaction system, unknown dynamics, values of the model parameters, objective functions) may not be valid for all the metabolic possible states of the network [13][14][15]. To face this limitation, hybrid (grey) models can be useful [16].…”