A Process Controls Approach to Cell Signalling

Abstract

Many biological questions can benefit from the diverse perspectives of multiple disciplines, including engineering. In the last several decades, biological research has been advanced from engineering approaches to delineate processes including stem cell differentiation, optimizing cancer therapies, and building physical and genetic tools to manipulate cell function. The collaboration between fields necessitates a common language to bridge concepts that have historically been developed for engineering and emergent properties of biological systems. By utilizing the expertise of both fields, greater advances can be reached in biological research through the application of large data sets and modelling of biological processes. Parallels between cellular signalling and engineering process controls include feedback and feed‐forward loops, amplification and thresholds; in both fields, these subprocesses contribute widely to the overall function of the cell and engineered system. Feedback and feed‐forward loops, amplification and thresholds, along with their importance in biology and process controls and their contributions to overall function.

Key Concepts

  • Parallels exist between the structure and function of cellular signal transduction architectures and engineering process control concepts.
  • Disruptions in signalling pathways and process control systems can have detrimental consequences, including health disorders and manufacturing casualties, respectively.
  • Understanding cell signalling mechanisms in a process control context can provide a novel perspective for understanding treatments and therapies of diseases stemming from dysregulation of cellular controls.
  • Similarities between everyday process controls like air conditioning can help unravel apparent complexities in cellular signaling.
  • Using extended analogy between process controls and cellular signaling may provide insights into mechanisms of manipulation not previously explored.

Keywords: cell signalling; process control; positive feedback; negative feedback; feed‐forward; threshold; amplification

Figure 1. A comparison between a signalling pathway, and a fermenter for producing beer with analogous regulation. (a) In the signalling pathway, feedback loops control the amount of receptor on the cell surface, resulting in differential levels of response (receptors are endocytosed via a β‐arrestin pathway, reflecting negative feedback; more receptors are exocytosed after a transcriptional response, reflecting positive feedback). Directly downstream of the receptor, amplification of the signal occurs through production of the secondary messenger cAMP, increasing the downstream transcriptional response. The efficiency of cAMP signalling is maintained through the presence of phosphodiesterases which restrict cAMP localisation. Feed‐forward signalling not only creates a transcriptional response (represented by pErk activation) but also stabilises the resulting messenger ribonucleic acid (mRNA) transcript. (b) Diagrams of control architectures as depicted in the signalling pathway and brewery process. (c) In the fermenter, analogous architectures are present. Feed‐forward control is implemented to re‐distribute stagnant yeast and add new yeast cells to account for idle and dying yeast. Amplification is achieved through the second valve, modified in response to feedback controls, to ultimately alter the amount of beer going into the storage tank. If the storage tank liquid level exceeds level threshold, feedback control will modify the aforementioned amplification step to prevent overflow.
Figure 2. A comparison of FFLs in (a) biology and (b) process controls. The colour‐coding of the boxes indicates analogous components: the upstream signal, intermediate, target and output. The controller and disturbance work together as the upstream signal in the analogy since the disturbance does not directly affect the measured variable.
Figure 3. Integration of control architectures in signal transduction. The concentration of ligand above or below a concentration threshold controls the switch‐like activation of two different signalling pathways originating from the same receptor. Further signal attenuation is achieved through feed‐forward control (dashed blue arrow), negative feedback (dashed yellow lines), and positive feedback and amplification (green and purple dashed arrow).
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Further Reading

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McGirr, Brooke A, Tubergen, Philip J, Hartz, Julie L, Myers, Paul J, Pitman, Mark A, Lazzara, Matthew J, and Deppmann, Christopher D(Sep 2018) A Process Controls Approach to Cell Signalling. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028189]