Current Opinion in Systems Biology

Most life forms harbor multiple, diverse mobile genetic elements (MGE) that widely differ in their rates and mechanisms of mobility. Recent findings on two classes of MGE in prokaryotes revealed a novel mechanism, RNA-guided transposition, where a transposon-encoded guide RNA directs the transposase to a unique site in the host genome. Tn7-like transposons, on multiple occasions, recruited CRISPR systems that lost the capacity to cleave target DNA and instead mediate RNA-guided transposition via CRISPR RNA...

Engineering new functions in the microbiome requires understanding how host genetic control and microbe-microbe interactions shape the microbiome. One key genetic mechanism underlying host control is the immune system. The immune system can promote stability in the composition of the microbiome by reshaping the ecological dynamics of its members, but the degree of stability will depend on the interplay between ecological context, immune system development, and higher-order microbe-microbe interactions. The eco-evolutionary interplay affecting composition and stability should inform the strategies used to engineer new functions in the microbiome...

To reliably form and maintain structures with specific functions, many multicellular systems evolved to leverage the interplay between biochemical signaling, mechanics, and morphology. We review mechanochemical feedback loops in cases where cell-cell contact-based Notch signaling drives fate decisions, and the corresponding differentiation process leads to contact remodeling. We compare different mechanisms for initial symmetry breaking and subsequent pattern refinement, as well as discuss how patterning outcomes depend on the relationship between biochemical and mechanical timescales...

Decades of in vitro biochemical reconstitution, genetics and structural biology studies have established a vast knowledge base on the molecular mechanisms of chromatin regulation and transcription. A remaining challenge is to understand how these intricate biochemical systems operate in the context of the 3D genome organization and in the crowded and compartmentalized nuclear milieu. Here we review recent progress in this area based on high-resolution imaging approaches.

Models of transcriptional regulation that assume equilibrium binding of transcription factors have been less successful at predicting gene expression from sequence in eukaryotes than in bacteria. This could be due to the non-equilibrium nature of eukaryotic regulation. Unfortunately, the space of possible non-equilibrium mechanisms is vast and predominantly uninteresting. The key question is therefore how this space can be navigated efficiently, to focus on mechanisms and models that are biologically relevant...

In multicellular organisms, metabolism is compartmentalized at many levels, including tissues and organs, different cell types, and subcellular compartments. Compartmentalization creates a coordinated homeostatic system where each compartment contributes to the production of energy and biomolecules the organism needs to carrying out specific metabolic tasks. Experimentally studying metabolic compartmentalization and metabolic interactions between cells and tissues in multicellular organisms is challenging at a systems level...

A full understanding of cell signaling processes requires knowledge of protein structure/function relationships, protein-protein interactions, and the abilities of pathways to control phenotypes. Computational models offer a valuable framework for integrating that knowledge to predict the effects of system perturbations and interventions in health and disease. Whereas mechanistic models are well suited for understanding the biophysical basis for signal transduction and principles of therapeutic design, data-driven models are particularly suited to distill complex signaling relationships among samples and between multivariate signaling changes and phenotypes...

Metabolites are prone to damage, either via enzymatic side reactions, which collectively form the underground metabolism, or via spontaneous chemical reactions. The resulting non-canonical metabolites that can be toxic, are mended by dedicated "metabolite repair enzymes." Deficiencies in the latter can cause severe disease in humans, whereas inclusion of repair enzymes in metabolically engineered systems can improve the production yield of value-added chemicals. The metabolite damage and repair loops are typically not yet included in metabolic reconstructions and it is likely that many remain to be discovered...

Circadian rhythms are ∼24 h cycles of organismal and cellular activity ubiquitous to mammalian physiology. A prevailing paradigm suggests that timing information flows linearly from rhythmic transcription via protein abundance changes to drive circadian regulation of cellular function. Challenging this view, recent evidence indicates daily variation in many cellular functions arises through rhythmic post-translational regulation of protein activity. We suggest cellular circadian timing primarily functions to maintain proteome homeostasis rather than perturb it...

Billions of functionally distinct blood cells emerge from a pool of hematopoietic stem cells in our bodies every day. This progressive differentiation process is hierarchically structured and remarkably robust. We provide an introductory review to mathematical approaches addressing the functional aspects of how lineage choice is potentially implemented on a molecular level. Emerging from studies on the mutual repression of key transcription factors, we illustrate how those simple concepts have been challenged in recent years and subsequently extended...

Two-component systems (TCSs) are a ubiquitous family of signal transduction pathways that enable bacteria to sense and respond to diverse physical, chemical, and biological stimuli outside and inside the cell. Synthetic biologists have begun to repurpose TCSs for applications in optogenetics, materials science, gut microbiome engineering, and soil nutrient biosensing, among others. New engineering methods including genetic refactoring, DNA-binding domain swapping, detection threshold tuning, and phosphorylation cross-talk insulation are being used to increase the reliability of TCS sensor performance and tailor TCS signaling properties to the requirements of specific applications...

Metastases represent a major cause of cancer-associated deaths. Despite extensive research, targeting metastasis remains the main obstacle in cancer therapy. Therefore, it is of tremendous importance to elucidate the mechanisms that impinge on the different steps of the metastatic cascade. Metabolic plasticity is a cornerstone of the tumorigenic process that not only enables cancer cells to rapidly proliferate but also thrive and retain vitality. Plasticity of the metabolic networks that wire cancer cells is of utmost importance during the metastatic cascade when cancer cells are at their most vulnerable and have to survive in a panoply of inhospitable environments as they make their journey to form metastatic lesions...

Advances in synthetic biology have provided genetic tools to reprogram cells to obtain desired cellular functions that include tools to enable the customization of cells to sense an extracellular signal and respond with a desired output. These include a variety of engineered receptors capable of transmembrane signaling that transmit information from outside of the cell to inside when specific ligands bind to them. Recent advances in synthetic receptor engineering have enabled the reprogramming of cell and tissue behavior, controlling cell fate decisions, and providing new vehicles for therapeutic delivery...

Synthetic biology increasingly enables the construction of sophisticated functions in mammalian cells. A particularly promising frontier combines concepts drawn from industrial process control engineering-which is used to confer and balance properties such as stability and efficiency-with understanding as to how living systems have evolved to perform similar tasks with biological components. In this review, we first survey the state-of-the-art for both technologies and strategies available for genetic programming in mammalian cells...

Multiscale computational modeling aims to connect the complex networks of effects at different length and/or time scales. For example, these networks often include intracellular molecular signaling, crosstalk, and other interactions between neighboring cell populations, and higher levels of emergent phenomena across different regions of tissues and among collections of tissues or organs interacting with each other in the whole body. Recent applications of multiscale modeling across intracellular, cellular, and/or tissue levels are highlighted here...

Forefront techniques for molecular interrogation of mammalian tissues, such as multiplexed tissue imaging, intravital microscopy, and single-cell RNA sequencing (scRNAseq), can combine to quantify cell-type abundance, co-localization, and global levels of receptors and their ligands. Nonetheless, it remains challenging to translate these various quantities into a more comprehensive understanding of how cell-cell communication networks dynamically operate. Therefore, construction of computational models for network-level functions - including niche-dependent actions, homeostasis, and multi-scale coordination - will be valuable for productively integrating the battery of experimental approaches...

Computational modeling has become an established technique to encode mathematical representations of cellular processes and gain mechanistic insights that drive testable predictions. These models are often constructed using graphical user interfaces or domain-specific languages, with community standards used for interchange. Models undergo steady state or dynamic analysis, which can include simulation and calibration within a single application, or transfer across various tools. Here, we describe a novel programmatic modeling paradigm, whereby modeling is augmented with software engineering best practices...

Heterogeneity in cell signaling pathways is increasingly appreciated as a fundamental feature of cell biology and a driver of clinically relevant disease phenotypes. Understanding the causes of heterogeneity, the cellular mechanisms used to control heterogeneity, and the downstream effects of heterogeneity in single cells are all key obstacles for manipulating cellular populations and treating disease. Recent advances in genetic engineering, including multiplexed fluorescent reporters, have provided unprecedented measurements of signaling heterogeneity, but these vast data sets are often difficult to interpret, necessitating the use of computational techniques to extract meaning from the data...

As the single cell field races to characterize each cell type, state, and behavior, the complexity of the computational analysis approaches the complexity of the biological systems. Single cell and imaging technologies now enable unprecedented measurements of state transitions in biological systems, providing high-throughput data that capture tens-of-thousands of measurements on hundreds-of-thousands of samples. Thus, the definition of cell type and state is evolving to encompass the broad range of biological questions now attainable...

Rapid technological advances in transcriptomics and lineage tracing technologies provide new opportunities to understand organismal development at the single-cell level. Building on these advances, various computational methods have been proposed to infer developmental trajectories and to predict cell fate. These methods have unveiled previously uncharacterized transitional cell types and differentiation processes. Importantly, the ability to recover cell states and trajectories has been evolving hand-in-hand with new technologies and diverse experimental designs; more recent methods can capture complex trajectory topologies and infer short- and long-term cell fate dynamics...