Thematic Minireview Series on Computational Systems Biology*

Introduction

This prologue introduces the thematic minireview series on computational systems biology. This series was inspired by the American Society for Biochemistry and Molecular Biology's special symposium “Systems Biology for Biochemists,” which took place in the fall of 2009 and sought to examine the following question: how can systems-level analyses be used to generate and test new hypotheses about the molecular features of living systems?

Three of the minireviews in the series expand on talks presented at the 2009 meeting, spanning questions ranging from the roles of trace elements in biological systems and analyses of drug action in living cells to computational approaches for the discovery of new knowledge in the biomedical texts, whereas the other three minireviews focus on computational and experimental strategies for studying protein-protein interaction and metabolic networks.

In the first minireview, Yan Zhang and Vadim N. Gladyshev show how analysis of genomic representation of enzymes whose activity is critically dependent on a particular trace element, as well as of the proteins involved in acquisition and insertion of these trace elements into the enzymes, can detect new pathways for trace element utilization and provide new mechanistic and evolutionary clues into the function of metalloenzymes.

The second and third minireviews take the quest for detailed knowledge of the chemical composition of living cells into the realm of metabolomics, defined by the Metabolomics Society as “the comprehensive characterization of the small molecule metabolites in biological systems.” Among the many challenges in metabolomics are the needs to develop strategies for detecting the enormous number and diversity of metabolites, for assessing the relevance of changes in metabolite concentrations in complex physiological settings, and for inferring pathways and regulatory mechanisms from analyses of metabolomic data. Guo-Fang Zhang, Sushabhan Sadhukhan, Gregory P. Tochtrop, and Henri Brunengraber discuss emerging solutions to these problems and show how metabolomics is beginning to help in the identification of promising new biomarkers and to illuminate metabolic pathways and their regulation. Also essential are strategies for organizing the results of such studies so that they can be mined to further our understanding of metabolic networks. Just as databases such as GenBank^TM and the Protein Data Bank allow mining of DNA and protein sequences and protein or nucleic acid structures, respectively, there are a growing number of databases focused on metabolites, metabolomes, and metabolic pathways. Such databases and how they can be used to illuminate novel pathways and enzymatic activities are the focus of the minireview by Oliver Fiehn, Dinesh K. Barupal, and Tobias Kind.

The fourth minireview examines ways to glean information about protein-protein interactions from high-throughput proteomic data, which record the peptide composition of various partially or highly purified fractions from eukaryotic cells. Although it is reasonably straightforward to use proteomic data to define stable components of multiprotein complexes, it has proved more difficult to deduce specific protein-protein interactions within a given complex or, alternatively, to detect weak or transient protein-protein interactions. With the arrival of new preparative methods, as well as improved approaches for quantitation of proteins in complex mixtures by protein mass spectrometry, such problems have grown more accessible. Mihaela E. Sardiu and Michael P. Washburn review computational and statistical approaches that exploit quantitative proteomic data to address questions of stoichiometry, assembly, and turnover in protein complexes.

The fifth minireview focuses on the computational analysis of large-scale screens of the effects of small molecules on living cells. A key issue in drug development is the need to create strategies for identifying specific drug targets to understand mechanisms underlying their desirable therapeutic effects and, just as important, to anticipate unintended “off-target” side effects. Hon Nian Chua and Frederick P. Roth illustrate how genome- or systems-wide analysis of the consequences of genetic and chemical perturbations even in simple model organisms can accelerate discovery of drug-target interactions.

The sixth and final minireview discusses the application of computational methods not directly to the results of biomedical experiments but to new ways of extracting these results from the scientific articles and books that describe them. An exciting feature of the new systems biology is its potential to generate new questions and hypotheses that drive research in unexpected directions, often in areas that are at the edge of the investigators' expertise. With the explosion of the scientific literature, however, scientists often find it difficult to cope with the flood of publications even within their own areas of expertise, let alone around the edges. James A. Evans and Andrey Rzhetsky discuss emerging strategies for mining the literature: not only to learn what has been reported but also to gain information about how a research area has developed and the history and/or biases that shape the way researchers think about a problem. Their minireview illustrates the power of text-mining strategies to identify inconsistencies as well as consistencies in the conclusions of large numbers of publications addressing related problems. Thus, they argue for the need for approaches to mine the literature that will go beyond just summarizing what has been reported to provide explicit computational reasoning that will help to assess the reliability of conclusions by considering their internal consistency, biases, and forgotten and neglected findings.

All in all, we believe the minireviews in this series highlight the promise of systems approaches for understanding complex biological processes, and we hope that they will be both informative and thought-provoking. We hope also that they will inspire attendance of the upcoming American Society for Biochemistry and Molecular Biology's special symposium “Chemical, Synthetic and Systems Biology: New Directions of Biochemistry in the 21st Century,” which will take place October 12–16, 2011, at the Snowbird Ski and Summer Resort in Utah.