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1. Build-a-Cell: Engineering a Synthetic Cell Community

   https://doi.org/10.3390/life11111176  

   Frischmon, Caroline; Sorenson, Carlise; Winikoff, Michael; Adamala, Katarzyna P (November 2021, Life)

   Build-a-Cell is a global network of researchers that aims to develop synthetic living cells within the next decade. These cells will revolutionize the biotechnology industry by providing scientists and engineers with a more complete understanding of biology. Researchers can already replicate many cellular functions individually, but combining them into a single cell remains a significant challenge. This integration step will require the type of large-scale collaboration made possible by Build-a-Cell’s open, collective structure. Beyond the lab, Build-a-Cell addresses policy issues and biosecurity concerns associated with synthetic cells. The following review discusses Build-a-Cell’s history, function, and goals. 

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2. Evolution of a minimal cell

   https://doi.org/10.1038/s41586-023-06288-x  

   Moger-Reischer, R. Z.; Glass, J. I.; Wise, K. S.; Sun, L.; Bittencourt, D. M.; Lehmkuhl, B. K.; Schoolmaster, D. R.; Lynch, M.; Lennon, J. T. (August 2023, Nature)

   Abstract Possessing only essential genes, a minimal cell can reveal mechanisms and processes that are critical for the persistence and stability of life^1,2. Here we report on how an engineered minimal cell^3,4contends with the forces of evolution compared with theMycoplasma mycoidesnon-minimal cell from which it was synthetically derived. Mutation rates were the highest among all reported bacteria, but were not affected by genome minimization. Genome streamlining was costly, leading to a decrease in fitness of greater than 50%, but this deficit was regained during 2,000 generations of evolution. Despite selection acting on distinct genetic targets, increases in the maximum growth rate of the synthetic cells were comparable. Moreover, when performance was assessed by relative fitness, the minimal cell evolved 39% faster than the non-minimal cell. The only apparent constraint involved the evolution of cell size. The size of the non-minimal cell increased by 80%, whereas the minimal cell remained the same. This pattern reflected epistatic effects of mutations inftsZ, which encodes a tubulin-homologue protein that regulates cell division and morphology^5,6. Our findings demonstrate that natural selection can rapidly increase the fitness of one of the simplest autonomously growing organisms. Understanding how species with small genomes overcome evolutionary challenges provides critical insights into the persistence of host-associated endosymbionts, the stability of streamlined chassis for biotechnology and the targeted refinement of synthetically engineered cells^2,7–9. 

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3. Evolution of a minimal cell

   https://doi.org/10.1101/2021.06.30.450565  

   Moger-Reischer RZ, Glass JI (January 2021, bioRxiv)

   Possessing only essential genes, a minimal cell can reveal mechanisms and processes that are critical for the persistence and stability of life. Here, we report on how a synthetically constructed minimal cell contends with the forces of evolution compared to a non-minimized cell from which it was derived. Genome streamlining was costly, but 80% of fitness was regained in 2000 generations. Although selection acted upon divergent sets of mutations, the rates of adaptation in the minimal and non-minimal cell were equivalent. The only apparent constraint of minimization involved epistatic interactions that inhibited the evolution of cell size. Together, our findings demonstrate the power of natural selection to rapidly optimize fitness in the simplest autonomous organism, with implications for the evolution of cellular complexity. 

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4. A single-cell resolved cell-cell communication model explains lineage commitment in hematopoiesis

   https://doi.org/10.1242/dev.199779  

   Rommelfanger, Megan K.; MacLean, Adam L. (December 2021, Development)

   ABSTRACT Cells do not make fate decisions independently. Arguably, every cell-fate decision occurs in response to environmental signals. In many cases, cell-cell communication alters the dynamics of the internal gene regulatory network of a cell to initiate cell-fate transitions, yet models rarely take this into account. Here, we have developed a multiscale perspective to study the granulocyte-monocyte versus megakaryocyte-erythrocyte fate decisions. This transition is dictated by the GATA1-PU.1 network: a classical example of a bistable cell-fate system. We show that, for a wide range of cell communication topologies, even subtle changes in signaling can have pronounced effects on cell-fate decisions. We go on to show how cell-cell coupling through signaling can spontaneously break the symmetry of a homogenous cell population. Noise, both intrinsic and extrinsic, shapes the decision landscape profoundly, and affects the transcriptional dynamics underlying this important hematopoietic cell-fate decision-making system. This article has an associated ‘The people behind the papers’ interview. 

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5. Microfluidic single-cell measurements of oxidative stress as a function of cell cycle position

   https://doi.org/10.1007/s00216-023-04924-z  

   Allcroft, Tyler J; Duong, Jessica T; Skardal, Per Sebastian; Kovarik, Michelle L (November 2023, Analytical and Bioanalytical Chemistry)

   Single-cell measurements routinely demonstrate high levels of variation between cells, but fewer studies provide insight into the analytical and biological sources of this variation. This is particularly true of chemical cytometry, in which individual cells are lysed and their contents separated, compared to more established single-cell measurements of the genome and transcriptome. To characterize population level variation and its sources, we analyzed oxidative stress levels in 1278 individual Dictyostelium discoideum cells as a function of exogenous stress level and cell cycle position. Cells were exposed to varying levels of oxidative stress via singlet oxygen generation using the photosensitizer Rose Bengal. Single-cell data reproduced the dose-response observed in ensemble measurements by CE-LIF, superimposed with high levels of heterogeneity. Through experiments and data analysis, we explored possible biological sources of this heterogeneity. No trend was observed between population variation and oxidative stress level, but cell cycle position was a major contributor to heterogeneity in oxidative stress. Cells synchronized to the same stage of cell division were less heterogeneous than unsynchronized cells (RSD of 37-51% vs 93%), and mitotic cells had higher levels of reactive oxygen species than interphase cells. While past research has proposed changes in cell size during the cell cycle as a source of biological noise, the measurements presented here use an internal standard to normalize for effects of cell volume, suggesting that a more complex contribution of cell cycle in heterogeneity of oxidative stress. 

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