Advanced Biomolecular Controllers for Inflammation Regulation in Mammalian Systems
Embargoed until 2027-02-16
Author
Date
2024Type
- Doctoral Thesis
ETH Bibliography
yes
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Abstract
Homeostasis, a critical physiological process, enables living organisms to sustain stable internal environments, thereby ensuring their survival and optimal functioning amidst fluctuating external conditions. At its core, this dynamic equilibrium is crucially governed by the immune system, which deploys an extensive array of cellular and molecular entities to safeguard the organism from pathogenic threats, while concurrently maintaining internal stability. Cytokines, as central mediators, exemplify the intricate homeostatic balance, where their regulatory missteps can incite conditions ranging from detrimental systemic inflammations, as seen in cytokine storms to immune deficiencies that potentially pave the way for malignancies. Thus, they necessitate therapeutic interventions that carefully balance their dual-natured physiological impacts. Exploring the intersection of synthetic biology and control theory, this dissertation illuminates the critical role of negative feedback in maintaining stability and homeostasis in biological systems. Leveraging insights from previous work, which established the Antithetic Integral Controller (AIC) in bacteria to mitigate disturbances from protease-induced degradation and achieve Robust Perfect Adaptation (RPA), this study seeks to translate these findings to a mammalian context. This transition unlocks potential applications, notably in cell-based therapy. Comprehensive design, engineering, and optimization of both RNA and protein-based AICs are undertaken to regulate cytokine levels, thoroughly examining the promising opportunities and considerable challenges encountered. In Chapter 2, this work carefully dissects and evaluates sensor and actuator mechanisms that could regulate crucial immune mediators, spotlighting the STAT3 sensor mechanism for IL-6 and the NF-κB for IL-1β and TNF-α, along with rigorous exploration and assessment of various actuator mechanisms like Adalimumab and IL-1Ra. The ensuing chapters meticulously explore designs ranging from the RNA-based Controllers (Chapter 3 and 4), which hold the potential for robust adaptation amidst network perturbations, to protein-based AICs (Chapter 5 and 6) exploiting mechanisms such as protease mutual degradation and intein splicing, each unveiling its unique potentialities and challenges in practical biological systems. Chapter 7 marks a significant stride towards real-world applications, with a controller designed to regulate the crucial cytokine TNF-α, moving beyond merely modulating synthetic factors within the cell. Managing extracellular molecules added a layer of complexity, demanding the development of stable cell lines and a continuous multicell-type co-culture platform for a six-day testing period. Nevertheless, the successful regulation of TNF-α by cells utilizing the AIC signifies a pivotal initial step towards more expansive therapeutic applications. In conclusion, this dissertation navigates through the comprehensive and complex domain of cytokine control, encompassing sensor and actuator mechanisms, RNA-based control, and protein-based control approaches, all set against the vast backdrop of synthetic biology and immune modulation. It seeks to unravel, design, and manipulate the regulatory networks of the immune system, promising not just to illuminate cytokine control mechanisms but also to serve as a foundational piece in the wide-reaching field of synthetic biology and immunotherapeutics. This detailed exploration, aimed at connecting synthetic biology and clinical applications, possesses the potential to both decipher and harness the intricate regulatory networks within biology, steering us toward a future where medical therapeutics are intricately designed and controlled, paving the way for innovative treatments and potential cures. Show more
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https://doi.org/10.3929/ethz-b-000659936Publication status
publishedExternal links
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Publisher
ETH ZurichSubject
Homeostasis; Synthetic Biology; Cytokines; Antithetic Integral Controller (AIC)Organisational unit
03921 - Khammash, Mustafa / Khammash, Mustafa
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ETH Bibliography
yes
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