Abstract Cells communicate with each other to jointly regulate cellular processes during cellular differentiation and tissue morphogenesis. This multiscale coordination arises through the spatiotemporal activity of morphogens to pattern cell signaling and transcriptional factor activity. This coded information controls cell mechanics, proliferation, and differentiation to shape the growth and morphogenesis of organs. While many of the molecular components and physical interactions have been identified in key model developmental systems, there are still many unresolved questions related to the dynamics involved due to challenges in precisely perturbing and quantitatively measuring signaling dynamics. Recently, a broad range of synthetic optogenetic tools have been developed and employed to quantitatively define relationships between signal transduction and downstream cellular responses. These optogenetic tools can control intracellular activities at the single cell or whole tissue scale to direct subsequent biological processes. In this brief review, we highlight a selected set of studies that develop and implement optogenetic tools to unravel quantitative biophysical mechanisms for tissue growth and morphogenesis across a broad range of biological systems through the manipulation of morphogens, signal transduction cascades, and cell mechanics. More generally, we discuss how optogenetic tools have emerged as a powerful platform for probing and controlling multicellular development.
more »
« less
Whole-Cell Models and Simulations in Molecular Detail
Comprehensive data about the composition and structure of cellular components have enabled the construction of quantitative whole-cell models. While kinetic network–type models have been established, it is also becoming possible to build physical, molecular-level models of cellular environments. This review outlines challenges in constructing and simulating such models and discusses near- and long-term opportunities for developing physical whole-cell models that can connect molecular structure with biological function.
more »
« less
- Award ID(s):
- 1817307
- PAR ID:
- 10152058
- Date Published:
- Journal Name:
- Annual Review of Cell and Developmental Biology
- Volume:
- 35
- Issue:
- 1
- ISSN:
- 1081-0706
- Page Range / eLocation ID:
- 191 to 211
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Genomically minimal cells, such as JCVI-syn3.0 and JCVI-syn3A, offer an empowering framework to study relationships between genotype and phenotype. With a polygenic basis, the fundamental physiological process of cell division depends on multiple genes of known and unknown function in JCVI-syn3A. A physical description of cellular mechanics can further understanding of the contributions of genes to cell division in this genomically minimal context. We review current knowledge on genes in JCVI-syn3A contributing to two physical parameters relevant to cell division, namely, the surface-area-to-volume ratio and membrane curvature. This physical view of JCVI-syn3A may inform the attribution of gene functions and conserved processes in bacterial physiology, as well as whole-cell models and the engineering of synthetic cells.more » « less
-
Beard, Daniel A (Ed.)Antibiotic resistance poses mounting risks to human health, as current antibiotics are losing efficacy against increasingly resistant pathogenic bacteria. Of particular concern is the emergence of multidrug-resistant strains, which has been rapid among Gram-negative bacteria such asEscherichia coli. A large body of work has established that antibiotic resistance mechanisms depend on phenotypic heterogeneity, which may be mediated by stochastic expression of antibiotic resistance genes. The link between such molecular-level expression and the population levels that result is complex and multi-scale. Therefore, to better understand antibiotic resistance, what is needed are new mechanistic models that reflect single-cell phenotypic dynamics together with population-level heterogeneity, as an integrated whole. In this work, we sought to bridge single-cell and population-scale modeling by building upon our previous experience in “whole-cell” modeling, an approach which integrates mathematical and mechanistic descriptions of biological processes to recapitulate the experimentally observed behaviors of entire cells. To extend whole-cell modeling to the “whole-colony” scale, we embedded multiple instances of a whole-cellE.colimodel within a model of a dynamic spatial environment, allowing us to run large, parallelized simulations on the cloud that contained all the molecular detail of the previous whole-cell model and many interactive effects of a colony growing in a shared environment. The resulting simulations were used to explore the response ofE.colito two antibiotics with different mechanisms of action, tetracycline and ampicillin, enabling us to identify sub-generationally-expressed genes, such as the beta-lactamase ampC, which contributed greatly to dramatic cellular differences in steady-state periplasmic ampicillin and was a significant factor in determining cell survival.more » « less
-
Abstract The biochemical and biophysical properties of the extracellular matrix (ECM) play a pivotal role in regulating cellular behaviors such as proliferation, migration, and differentiation. Engineered protein‐based hydrogels, with highly tunable multifunctional properties, have the potential to replicate key features of the native ECM. Formed by self‐assembly or crosslinking, engineered protein‐based hydrogels can induce a range of cell behaviors through bioactive and functional domains incorporated into the polymer backbone. Using recombinant techniques, the amino acid sequence of the protein backbone can be designed with precise control over the chain‐length, folded structure, and cell‐interaction sites. In this review, the modular design of engineered protein‐based hydrogels from both a molecular‐ and network‐level perspective are discussed, and summarize recent progress and case studies to highlight the diverse strategies used to construct biomimetic scaffolds. This review focuses on amino acid sequences that form structural blocks, bioactive blocks, and stimuli‐responsive blocks designed into the protein backbone for highly precise and tunable control of scaffold properties. Both physical and chemical methods to stabilize dynamic protein networks with defined structure and bioactivity for cell culture applications are discussed. Finally, a discussion of future directions of engineered protein‐based hydrogels as biomimetic cellular scaffolds is concluded.more » « less
-
null (Ed.)JCVI-syn3A is a genetically minimal bacterial cell, consisting of 493 genes and only a single 543 kbp circular chromosome. Syn3A’s genome and physical size are approximately one-tenth those of the model bacterial organism Escherichia coli ’s, and the corresponding reduction in complexity and scale provides a unique opportunity for whole-cell modeling. Previous work established genome-scale gene essentiality and proteomics data along with its essential metabolic network and a kinetic model of genetic information processing. In addition to that information, whole-cell, spatially-resolved kinetic models require cellular architecture, including spatial distributions of ribosomes and the circular chromosome’s configuration. We reconstruct cellular architectures of Syn3A cells at the single-cell level directly from cryo-electron tomograms, including the ribosome distributions. We present a method of generating self-avoiding circular chromosome configurations in a lattice model with a resolution of 11.8 bp per monomer on a 4 nm cubic lattice. Realizations of the chromosome configurations are constrained by the ribosomes and geometry reconstructed from the tomograms and include DNA loops suggested by experimental chromosome conformation capture (3C) maps. Using ensembles of simulated chromosome configurations we predict chromosome contact maps for Syn3A cells at resolutions of 250 bp and greater and compare them to the experimental maps. Additionally, the spatial distributions of ribosomes and the DNA-crowding resulting from the individual chromosome configurations can be used to identify macromolecular structures formed from ribosomes and DNA, such as polysomes and expressomes.more » « less
An official website of the United States government

