Model Organism Research Panel
Translating ME/CFS research into mechanistic understanding requires model systems that recapitulate key features of the disease. While no single model fully captures the complexity of ME/CFS, a panel approach—combining animal models, cellular systems, and organoid platforms—enables investigation of specific pathophysiological axes under controlled conditions.
2 Cellular Models of Metabolic Dysfunction
In vitro studies using peripheral blood mononuclear cells (PBMCs) and skeletal muscle cells from ME/CFS patients have revealed consistent bioenergetic abnormalities. Seahorse extracellular flux analysis of patient-derived PBMCs demonstrates reduced mitochondrial reserve capacity and impaired oxidative phosphorylation compared with healthy controls (Tomas et al. 2017) (Missailidis, Annesley, and Fisher 2019). These findings support a cell-intrinsic metabolic defect rather than a purely systemic phenomenon. Immortalized cell lines and primary cultures exposed to patient serum have been used to investigate circulating factors that may impair cellular bioenergetics. Studies exposing healthy cells to ME/CFS serum have reported reduced ATP production and altered mitochondrial membrane potential, suggesting the presence of inhibitory factors in the ME/CFS milieu (Fluge et al. 2016). Identifying these factors remains an active area of investigation with direct therapeutic implications. Induced pluripotent stem cell (iPSC) technology offers emerging opportunities to generate patient-specific neuronal, cardiac, and immune cells for disease modeling. While iPSC-derived models of ME/CFS are still in early development, they hold promise for studying tissue-specific manifestations—such as neuronal hypersensitivity or cardiomyocyte dysfunction—in a genetically defined background.
3 Organoid Systems for Tissue-Specific Effects
Three-dimensional organoid cultures represent the frontier of ME/CFS model systems. Gut organoids derived from patient biopsies can recapitulate epithelial barrier dysfunction and altered microbiome–host interactions relevant to the gastrointestinal symptoms frequently reported in ME/CFS (Chapter Gastrointestinal and Microbiome Dysfunction). Brain organoids may enable investigation of neuroinflammatory processes and blood–brain barrier integrity in a human-relevant system. Multi-organ-on-a-chip platforms, which connect microfluidic compartments representing different tissue types, offer the potential to model systemic interactions—for example, the gut–brain axis or immune–metabolic crosstalk—that characterize ME/CFS pathophysiology. These platforms are still maturing but represent a promising direction for studying how dysfunction in one organ system propagates to others.
4 Towards an Integrated Model Panel
Standardization of model systems is essential for reproducibility. The ME/CFS research community would benefit from consensus protocols for cell culture conditions, animal model endpoints, and organoid characterization, analogous to the standardization efforts that have advanced cancer and neurodegenerative disease research.