Balance is key: New strategies to boost protein production from engineered cells
University of Warwick research demonstrates how to engineer ‘cell factories’ that last longer and produce more chemicals, without needing antibiotics or complex engineering methods, paving the way for sustainable biotech that lasts.
Synthetic biology aims to engineer living cells, often bacteria, to become chemical factories, pumping out chemicals important to healthcare, industry, and the environment. To achieve this, genetic circuits (synthetic DNA programs) are inserted into bacteria to harness the internal machinery to produce the chemicals.
However, the existing efforts to create these ‘living factories’ have struggled because keeping genetically engineered cells working as intended is challenging. Under the stress of producing chemicals, they often stop functioning, mutate or lose out in competition to faster-growing mutant cells in the population, limiting their useful productive lifespan.
In this paper, published in Nature Communications, researchers from the University of Warwick have used detailed computational simulations that mimic how bacteria grow, mutate, and compete in the lab, to produce a new solution to optimize cell factories. Dozens of genetic engineering strategies have been evaluated to theoretically find a way to keep cell factories stable and produce high quantities of products over many generations.
Dr. Alexander Darlington, Royal Academy of Engineering Research Fellow and Assistant Professor, School of Engineering, University of Warwick said: “Engineered cells have a limited lifespan because they are under stress and prone to genetic errors, which results in mutations which destroy function. These mutants tend to grow quicker and come to quickly dominate the cell factory.
“The computational modelling that we have conducted here compared a number of different genetic strategies - “gene circuit controllers” – and found the best ones before we even got to the lab. We are now looking to engineer these strategies into bacteria to enhance longevity, production, and their robustness to mutation.
“We applied ideas from control engineering to design something-like a genetic thermostat which turns things up when it gets too cool or down when too hot. We found that the best results came from combining two self-adjusting feedback systems: one sensitive to production and one sensitive to growth rate. Acting together, these negative feedback systems are predicted to increase the function of our engineered cells by threefold. It turns out that balance is the key: our systems are predicted to balance function with growth so that there is a small chance of takeover by mutant cells.”
The optimal strategy, using negative-feedback systems, works through inserting genes that act like sensors and monitor cell growth rates and cell output and then automatically adjusting gene activity to keep everything running smoothly. The slight drawback is a reduction in the production rate of each cell but thanks to the significantly longer lifespans, cumulative chemical production over time is much higher.
Dr. Darlington added: “After a gene circuit is inserted into a cell, making the chemical product uses its energy and resources, which slows the cell’s growth and favours mutations that will shut down the engineered gene circuit that is producing the protein. We have developed a sophisticated mathematical model which captures cell growth, protein production, mutation and selection and coupled this with optimisation techniques to design multiple different genetic control strategies – now the exciting part is testing them in the lab”
The proposed approaches would not need antibiotics (reducing the potential for antibiotic resistance) or complex engineering efforts (requiring more expensive rounds of experimental tinkering). The team believe their approach simplifies engineering efforts and could reduce product development times.
The proposed methods can be easily applied to different systems without need for significant redesign, and can be incorporated alongside existing approaches, contributing towards the ultimate goal of synthetic biology applications that perform robustly and reliably in the long term.
ENDS
Notes to Editors
The paper ‘Genetic controllers for enhancing the evolutionary longevity of synthetic gene circuits in bacteria’ is published in Nature Communications. DOI: 10.1038/s41467-025-63627-4
Image: Artist Rendering of Re-engineered Bacteria - Image Credit: Thom Leach, Amoeba Studios
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30 September 2025