ME/CFS, a Bistable Cell State?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) begins acutely, usually afterinfection, and then persists indefinitely after the trigger has cleared — resisting individualtherapeutic interventions and, after decades of searching, yielding neither a persistent triggernor a single reliable biomarker. This work proposes that both failures are expected, because theillness is a bistable state of a network of interacting biochemical feedback loops. A mechanistic dynamical-systems model was constructed: a system of differential equations encodingexperimentally supported interactions linking NAD⁺ metabolism, inflammation, mitochondrial oxidativestress, and stress-response signaling. The individual interactions are established in the literature;the hypothesis concerns their systems-level organization into coupled positive feedback loops.Nothing is fitted to patient data — the model is a formal plausibility argument, not a statisticalmodel or a treatment recommendation system. The simulations show this architecture is sufficient to generate two stable attractors, so that atransient trigger produces lasting illness. It reproduces persistence after trigger removal,threshold-like onset, the failure of single agents, and duration-dependent recovery. Extending thesingle cell into a one-dimensional tissue predicts spatially heterogeneous severity and recovery asa slow front advancing from well-perfused toward poorly perfused tissue — a potential explanationfor the modest biomarker changes seen in blood. Bistability survives simultaneous ±25% perturbationof all parameters, so the conclusion is structural rather than parameter-specific. The model yields one falsifiable prediction: durable recovery requires breaking the self-sustainingmitochondrial ROS loop and holding it broken long enough for the inner membrane to rebuild — andmust therefore be judged across a treatment-withdrawal (washout) phase, the readout that separatesdurable escape from transient symptomatic relief.