Biphasic response as a mechanism against mutant takeover in tissue homeostasis circuits

Abstract

Tissues use feedback circuits in which cells send signals to each other to control their growth and survival. We show that such feedback circuits are inherently unstable to mutants that misread the signal level: Mutants have a growth advantage to take over the tissue, and cannot be eliminated by known cell‐intrinsic mechanisms. To resolve this, we propose that tissues have biphasic responses in and the signal is toxic at both high and low levels, such as glucotoxicity of beta cells, excitotoxicity in neurons, and toxicity of growth factors to T cells. This gives most of these mutants a frequency‐dependent selective disadvantage, which leads to their elimination. However, the biphasic mechanisms create a new unstable fixed point in the feedback circuit beyond which runaway processes can occur, leading to risk of diseases such as diabetes and neurodegenerative disease. Hence, glucotoxicity, which is a dangerous cause of diabetes, may have a protective anti‐mutant effect. Biphasic responses in tissues may provide an evolutionary stable strategy that avoids invasion by commonly occurring mutants, but at the same time cause vulnerability to disease.

Endocrine autoimmune disease as a fragility of immune-surveillance against hypersecreting mutants

“…In addition to ASHM, tissues with the present regulatory motif often have another mechanism against mis-sensing mutants. This mechanism is cell-autonomous biphasic control, in which the signal promotes growth of cells at low levels but kills cells at very high signal levels (19). For example, glucose drives the growth of beta cells at low to medium concentrations, but drives their death through glucotoxicity at high concentrations.…”

“…At very high levels, glucose causes beta cell functional decline and death, in a process called glucotoxicity. This biphasic effect of glucose can act to protect against strong mis-sensing mutants (Karin 2017).…”

“…We argue that tissues that turn over and that secrete factors such as hormones must have feedback control of their cell proliferation, in order to maintain proper organ size and secretion rate (18). Such feedback inherently shows a fragility to mutant cells that mis-sense the feedback signal: such cells both hyper-secrete the hormone and begin to rapidly proliferate (19). The mutant proliferation poses a threat because once the hyper-secreting mutant clone reaches a large enough size, it can lead to physiological dysregulation.…”

Theoretical Design of Paradoxical Signaling-Based Synthetic Population Control Circuit inE. coli

“…However, the proper functioning of this feedback circuit architecture is dependent on the precise activity and expression of receptors and regulatory proteins involved within the circuit, which are susceptible to mutations. When a cell with a receptor loss-of-function mutation (exhibiting a dysregulated proliferative response) arises, it may invade the cell population and thus break the homeostatic control [6]. A paradoxical feedback input design has been shown to prevent such a takeover in natural occurring mammalian systems [6][7][8][9].…”

“…Conversely, if below the signal threshold, cells are driven to a low steady state cell population. Thus, this paradoxical feedback input design can yield a bi-stable cell population dynamic system, with one unstable and two stable equilibrium points [6][7][8][9]. The paradoxical feedback control circuit allows for cell intrinsic "safety mechanisms" against aberrant proliferation, due to receptor loss-of-function mutations.…”