A general hypothesis of multistable systems in pathophysiology

Abstract

Despite intensive investigations numerous diseases remain etiologically puzzling and recalcitrant to treatments. A hypothesis is proposed here assuming that these difficulties are due to an unsuitable approach to the mechanisms of life, which is subjugated by an apparent complexity and fails to grasp the uniformity that lays behind. The stability of metabolism, despite the enormous complex of chemical reactions, suggests that reciprocal control is a prerequisite of life. Negative feedback loops have been known for a long time to maintain homeostasis, while more recently, different life processes involved in transitions or changes have been modeled by positive loops giving rise to bistable switches, also including various diseases. The present hypothesis makes a generalization, by assuming that any functional element of a biological system is involved in a positive or a negative feedback loop. Consequently, the hypothesis holds that the starting mechanism of any disease that affects a healthy human can be conceptually reduced to a bistable or multistationary loop system, thus providing a unifying model leading to the discovery of critical therapeutic targets.

Fibromyalgia pathogenesis explained by a neuroendocrine multistable model

“…The system consists of positive and negative loops, and we have demonstrated that it can globally behave as a monostable system (see Box 1 ) (when the negative loop is dominant) for stronger GABAergic transmission, or as a bistable system (when the positive loop is dominant) for a weakening of GABAergic transmission [ 18 ]. Bistable switches are known to promote predictable functional changes in living systems [ 26 ], also including pathogenesis processes [ 27 ].…”

“…The mutual inhibition between HPG and HPA axes gives rise to a positive loop; therefore, the dynamic system is a candidate multistable system that can admit multiple equilibria [ 130 ]. Hence, similarly to the thalamocortical loop, this endocrine loop can behave as a switch driving pathogenesis [ 27 ]. Such double-inhibitory loop operates physiological functions [ 72 , 131 ], but under peculiar circumstances could lead to functional disorders.…”