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Hierarchical organization in ecology, whereby interactions are nested in a manner that leads to a dominant species, naturally result in the exclusion of all but the dominant competitor. Alternatively, non-hierarchical competitive dynamics, such as cyclical interactions, can sustain biodiversity. Here, we designed a simple microbial community with three strains of E. coli that cyclically interact through (i) the inhibition of protein production, (ii) the digestion of genomic DNA, and (iii) the disruption of the cell membrane. We find that intrinsic differences in these three major mechanisms of bacterial warfare lead to an unbalanced community that is dominated by the weakest strain. We also use a computational model to describe how the relative toxin strengths, initial fractional occupancies, and spatial patterns affect the maintenance of biodiversity. The engineering of active warfare between microbial species establishes a framework for exploration of the underlying principles that drive complex ecological interactions., The maintenance of ecological diversity depends on the strength and direction of competitive interactions, but these interactions are difficult to study in microbial communities. Here the authors use engineered E. coli strains to show that competitively weak strains can persist when pairwise interactions are asymmetrical.

The last decade has seen bacteria at the forefront of biotechnological innovation, with applications including biomolecular computing, living therapeutics, microbiome engineering and microbial factories. These emerging applications are all united by the need to precisely control complex microbial dynamics in spatially extended environments, requiring tools that can bridge the gap between intracellular and population-level coordination. To address this need, we engineer an inducible quorum sensing system which enables precise tunability of bacterial dynamics both at the population and community level. As a proof-of-principle, we demonstrate the advantages of this system when genetically equipped for cargo delivery. In addition, we exploit the absence of cross-talk with respect to the majority of well-characterized quorum sensing systems to demonstrate inducibility of multi-strain communities. More broadly, this work highlights the unexplored potential of remotely inducible quorum sensing systems which, coupled to any gene of interest, may facilitate the translation of circuit designs into applications., Biotechnology innovations require the precise control over microbial dynamics. Here the authors engineer an inducible quorum sensing system to fine tune population and community level behaviour.

Background Bone metastases are common and devastating to cancer patients. Existing treatments do not specifically target the disease sites and are therefore ineffective and systemically toxic. Here we present a new strategy to treat bone metastasis by targeting both the cancer cells (“the seed”), and their surrounding niche (“the soil”), using stem cells engineered to home to the bone metastatic niche and to maximise local delivery of multiple therapeutic factors. Methods We used mesenchymal stem cells engineered using mRNA to simultaneously express P-selectin glycoprotein ligand-1 (PSGL-1)/Sialyl-Lewis X (SLEX) (homing factors), and modified versions of cytosine deaminase (CD) and osteoprotegerin (OPG) (therapeutic factors) to target and treat breast cancer bone metastases in two mouse models, a xenograft intratibial model and a syngeneic model of spontaneous bone metastasis. Findings We first confirmed that MSC engineered using mRNA produced functional proteins (PSGL-1/SLEX, CD and OPG) using various in vitro assays. We then demonstrated that mRNA-engineered MSC exhibit enhanced homing to the bone metastatic niche likely through interactions between PSGL-1/SLEX and P-selectin expressed on tumour vasculature. In both the xenograft intratibial model and syngeneic model of spontaneous bone metastasis, engineered MSC can effectively kill tumour cells and preserve bone integrity. The engineered MSC also exhibited minimal toxicity in vivo, compared to its non-targeted chemotherapy counterpart (5-fluorouracil). Interpretation Our combinatorial targeting of both the cancer cells and the niche represents a simple, safe and effective way to treat metastatic bone diseases, otherwise difficult to manage with existing strategies. It can also be applied to other cell types (e.g., T cells) and cargos (e.g., genome editing components) to treat a broad range of cancer and other complex diseases. Fund National Institutes of Health, National Cancer Institute of the National Institutes of Health, Department of Defense, California Institute of Regenerative Medicine, National Science Foundation, Baylx Inc., and Fondation ARC pour la recherche sur le cancer.

Stabilizing synthetic gene circuits Making synthetic gene circuits in bacteria is one thing, but making them stable under selective pressure with high mutation rates is another. Liao et al. addressed this problem with an ecological strategy in which they created three strains of bacteria, each of which could kill or be killed by one of the other strains (see the Perspective by Johnston and Collins). Once the first strain of bacteria hosting the engineered circuit underwent mutations that decreased function, the system could be “rebooted” by addition of another strain that killed the first but also contained the desired synthetic circuit, allowing its function to proceed unperturbed. This strategy provides a way to control synthetic ecosystems and maintain synthetic gene circuits without using traditional selection to maintain plasmids with antibiotics. Science , this issue p. 1045 ; see also p. 986