Systems Biology Perspectives on Minimal and Simpler Cells

Abstract

SUMMARY The concept of the minimal cell has fascinated scientists for a long time, from both fundamental and applied points of view. This broad concept encompasses extreme reductions of genomes, the last universal common ancestor (LUCA), the creation of semiartificial cells, and the design of protocells and chassis cells. Here we review these different areas of research and identify common and complementary aspects of each one. We focus on systems biology, a discipline that is greatly facilitating the classical top-down and bottom-up approaches toward minimal cells. In addition, we also review the so-called middle-out approach and its contributions to the field with mathematical and computational models. Owing to the advances in genomics technologies, much of the work in this area has been centered on minimal genomes, or rather minimal gene sets, required to sustain life. Nevertheless, a fundamental expansion has been taking place in the last few years wherein the minimal gene set is viewed as a backbone of a more complex system. Complementing genomics, progress is being made in understanding the system-wide properties at the levels of the transcriptome, proteome, and metabolome. Network modeling approaches are enabling the integration of these different omics data sets toward an understanding of the complex molecular pathways connecting genotype to phenotype. We review key concepts central to the mapping and modeling of this complexity, which is at the heart of research on minimal cells. Finally, we discuss the distinction between minimizing the number of cellular components and minimizing cellular complexity, toward an improved understanding and utilization of minimal and simpler cells.

Design and synthesis of a minimal bacterial genome

“…4). With syn2.0, we achieved for the first time a minimized cell with a genome smaller than that of the smallest aad6253-4 25 . S7).…”

Large-scale reduction of the Bacillus subtilis genome: consequences for the transcriptional network, resource allocation, and metabolism

“…This genome is smaller than that of any independently replicating bacterium found in nature. The bottom-up approach also includes attempts to synthesize protocells that are well-suited to study basic cellular processes such as cell division and replication (Blain and Szostak 2014;Xavier et al 2014). …”

Small genomes and the difficulty to define minimal translation and metabolic machineries

“…Gabaldón et al (2007Gabaldón et al ( , 2008 described the correlation between the total number of CDS in the genome and several topological properties and graph-theory parameters of the corresponding inferred metabolic networks such as its size (number of nodes/metabolites, diameter) and node clustering. Xavier et al (2014) noted also the correlation between the number of CDS, and the number of reactions in networks. But what seems more interesting is their use of the number of chemical components in the minimal medium of a species as a proxy of the biosynthetic abilities and the metabolic complexity of the corresponding microorganism.…”

“…It would be of interest to model natural free-living cells with incomplete metabolisms to examine their relative position in this hierarchy. Xavier et al (2014) pointed out that genome size hardly correlates with some indirect measures of complexity, like the interactome size or the doubling time. A better approach to define complexity could be the measure of the metabolic network size.…”