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Bacterial synthetic biology in cancer immunotherapy



With the advances in synthetic biology, previously unopened doors to different elements of science have been given a new opportunity to shine. Synthetic biology is a collaboration between many fields, such as engineering, physics, and chemistry, underpinning the success and evolution of this highly fruitful field (Sudhir P. Singh, et al., 2019). In the healthcare context, this field holds immense promise; it can be used to improve disease diagnoses and develop new treatments, aiding in the key goal in pharmaceuticals - the production of new drugs, or enhancement of existing ones, with fewer adverse effects, off-target events, and more selectivity. This article explores the fascinating world of synthetic biology in combination with bacteriology, delving into its principles, applications, and challenges.


Principles of Bacterial Synthetic Biology


At its core, synthetic biology aims to program novel artificial or native biological systems using advanced genetic techniques, while maintaining the complexity of the central dogma for the optimized production of desired biomolecules beneficial to society (Sudhir P. Singh, et al., 2019). This integration of interdisciplinary fields allows for the paradigm shift of what was previously perturbed by challenges associated with bacterial therapy to be executed, allowing for the bioengineered systems to be facilitated in healthcare settings and pharmacological biomanufacturing (Kathryn, 2021)


A fundamental component in bacterial synthetic biology is the utilization of engineering concepts - standardisation, modularity, and abstraction - for the rational design of biological systems for industrial application (Kathryn, 2021). One of the most important considerations before the development of synthetic biotics is the choice of the chassis organism, which is the host system for which the artificial genetic circuit will be wired. This is a critical step that must be proceeded with caution as it influences all the downstream modules developed: the engineering process; the clinical application; and therapeutic efficacy in in vitro experiments, animal models, and clinical trials (Arboleda-García et al., 2023). The insertion of an exogenous genetic circuit into the host system may be suppressed by the indigenous resistance mechanisms; therefore, the synthetic circuits should be designed and programmed in a way that can operate both effectively and independently. The ideal chassis would be able to grow on minimal media to reduce production costs, while maintaining robust growth and stability when faced with environmental stress, such as the toxins released by the intermediates during the biosynthesis of the target biomolecules (Arboleda-García et al., 2023). A prime example of a chassis microorganism is Escherichia coli, a widely studied microbe in this field and has been a model organism for molecular biology research for over 60 years due to its easy maintenance, genetic manipulation, and laboratory reproducibility (Sudhir P. Singh, et al., 2019). Currently, other strains are being developed and engineered by optimising their genome sizes (D. Choe et al., 2019) and mutation rates (B. Csörgő et al., 2012), and by altering their codon language (E. C. Fischer et al., 2020) to potentially improve bacterial therapy. 


Bacterial Synthetic Biology in Cancer

An exciting aspect of the application of bacterial synthetic biology is its potential in cancer research, which faces many issues in developing immunotherapy. The tumour microenvironment (TME) is an important bottleneck for tumour immunotherapy. However, by exploiting its unique characteristics - hypoxia, low glucose concentration, and acidic microenvironment - researchers can bioengineer condition-responsive genetic elements into bacteria that allow them to control drug release after reaching the TME (Feng et al., 2023). This reduces off-target phenomena in drug delivery and improves drug delivery accuracy of drug delivery. 


Figure 1: Condition-responsive bacteria have genes that are activated only when a certain stimulus is provided. These genes can be engineered to express antitumor pathways. Image taken from "Recent advances in bacterial therapeutics based on sense and response"  (Feng et al., 2023).


Bacterial synthetic biology also holds promise for the diagnosis of microscopic malignant lesions that would be otherwise undetectable with the current tomography resolution. Some facultative anaerobes, such as Salmonella, exhibit a tropism for replicating and accumulating in tumours. By combining both biomarker selectivity and specificity of tumour-replicating bacteria, the deliberate injection of synthetic bacteria expressing specific biomarkers when triggered by small inducing molecules can therefore aid in improved patient prognosis. However, despite its potential to non-invasively diagnose and monitor treatment, its feasibility depends on factors such as the protein expression rate, secretion efficiency, bacterial density, and the limit of detection (J. T. Panteli et al., 2015)


Challenges and future directions:


While the potential applications of bacterial synthetic biology in cancer research are exciting, there are still challenges to face. Safety concerns, including the potential for bacterial proliferation in off-target locations, must be carefully addressed through rigorous testing and containment strategies. Additionally, ethical considerations regarding the release of genetically modified organisms into the human body must be carefully navigated and considered.


The integration of different scientific fields to maximise the potential of synthetic biological systems with improved and novel traits has enabled the overcoming of cancer immunotherapy limitations and the creation of new ones to help mankind. This rapidly evolving discipline will continue to give newer perspectives to the design and construction of complex biological systems. As this field is still in its early stages, we are entering an incredibly exciting time for synthetic biotics in cancer immunotherapy. Further advancements of ‘-omic’ technology and continued interdisciplinary collaboration between different fields can propel its development and continue to drive greater efficiency in discovery and development as well as increase the breadth of the range of diseases that can be addressed. 

 

Article prepared by: Melisa Wong Siang Ming, Research and Development Associate of MBIOS 23/24


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References


  1. Sudhir P. Singh, et al. (2019) Basics and roots of Synthetic Biology, Current Developments in Biotechnology and Bioengineering. Available at: https://www.sciencedirect.com/science/article/pii/B9780444640857000010#bib1 (Accessed: 30 December 2023).

  2. Kathryn (2021) Principles of synthetic biology. Essays in Biochemistry. [Online] 65 (5), 791–811. Available from: doi:10.1042/ebc20200059.

  3. Arboleda-García, A. et al. (2023) ‘Advancements in synthetic biology-based bacterial cancer therapy: A modular design approach’, Critical Reviews in Oncology/Hematology, 190, p. 104088. doi:10.1016/j.critrevonc.2023.104088. 

  4. Choe, D., Lee, J.H., Yoo, M., Hwang, S., et al. (2019) Adaptive laboratory evolution of a genome-reduced Escherichia coli. Nature Communications. [Online] 10 (1). Available from: doi:10.1038/s41467-019-08888-6.

  5. Csörgő, B., Fehér, T., Tímár, E., Blattner, F.R., et al. (2012) Low-mutation-rate, reduced-genome Escherichia coli: an improved host for faithful maintenance of engineered genetic constructs. Microbial Cell Factories. [Online] 11 (1), 11. Available from: doi:10.1186/1475-2859-11-11.

  6. Fischer, E.C., Hashimoto, K., Zhang, Y., Feldman, A.W., et al. (2020) New codons for efficient production of unnatural proteins in a semisynthetic organism. Nature Chemical Biology. [Online] 16 (5), 570–576. Available from: doi:10.1038/s41589-020-0507-z.

  7. Feng, Z. et al. (2023) ‘Recent advances in bacterial therapeutics based on sense and response’, Acta Pharmaceutica Sinica B, 13(3), pp. 1014–1027. doi:10.1016/j.apsb.2022.09.015.

  8. Panteli, J.T., Forkus, B.A., Van Dessel, N. & Forbes, N.S. (2015) Genetically modified bacteria as a tool to detect microscopic solid tumor masses with triggered release of a recombinant biomarker. Integrative Biology. [Online] 7 (4), 423–434. Available from: doi:10.1039/c5ib00047e.


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