2017 WONOEP appraisal: Studying epilepsy as a network disease using systems biology approaches

Abstract

The revolution in high‐throughput omics technologies has dramatically expanded our understanding of the epilepsies as complex diseases. It is now clear that further progress in treating the full spectrum of seizure disorders requires a systems‐level framework for analyzing and integrating data from multiple omics technologies that moves beyond the search for single molecular alterations to an understanding of dysregulated pathways in epilepsy. Taking such a pathway‐centered view requires further integrating the tools of systems biology into epilepsy research. In this appraisal, we highlight and summarize systems biology approaches in basic epilepsy studies as they were discussed during the 2017 Workshop on the Neurobiology of Epilepsy (WONOEP). During the 3‐day event, participants exchanged emerging results and thoughts on developing the systems biology of epilepsy, and the promise and limitations of these approaches for the near term.

Gene networks and microRNAs: Promises and challenges for treating epilepsies and their comorbidities

“…They have their internal organization and produce emerging properties that affect the hierarchically higher levels, but these higher levels feedback on the organization of the molecular networks. Therefore, a gene mutation may cause a protein to function improperly and trigger a cascade of events that may lead to the development of a disease [8]. However, it may not necessarily lead to that disease, because the system as a whole may generate effective counter-mechanisms to oppose those generated by the pathological protein.…”

“…In the past few years, thousands of genetic variations have been identified in clinical and preclinical studies that associate with epileptic phenotypes. A major unresolved issue is why a single mutation can lead to many different outcomes: a gene variant in a single molecular pathway can in fact be associated with different types of epilepsy in different patients [8]. Even though it can be difficult to identify identical mutations across different patients affected by the same form of epilepsy, different mutations may affect the same functional pathway(s), which can be identified by mapping interactions of the different causal genes, that is, searching modules enriched with the altered genes.…”

Terminology for psychogenic nonepileptic seizures: Making the case for “functional seizures”

“…To anticipate the counter-arguments from neurologists, who may argue that epileptic seizures are, in many cases, "functional" or "network" as opposed to "structural" disorders 31 , we have to say that yes, epileptic seizures are indeed "functional" or "network" disorders as opposed to "structural" problems, in many patients; but, this does not refute that PNES are also a functional disorder 32,33 . In addition, for epileptic seizures, we have a more specific and more appropriate modifier to describe the term "seizure", that is "epileptic"; but, for PNES, we do not have a better and more specific modifier to adjoin with the term "seizure".…”

Precision Medicine: Academic dreaming or clinical reality?

“…The volume of longitudinal information in an individual is now so intensive, that researchers are proposing the concept of the “epidemiology of one” in which a single individual is viewed as an entire population of observations that can be analyzed for self‐monitoring and forecasting by adapting statistical methods to individual‐level data 14 . In addition, systems biology, which aims at comprehensively studying molecular diversity, identifying general principles and patterns and integrating biological knowledge in complex models, 15 is likely to become increasingly applied in epilepsy 16 . An illustration of this approach is the analysis in patients investigated for epilepsy surgery of complex correlations among brain tissue metabolomics (high‐resolution magnetic resonance spectroscopy), genomics (RNA microarray analysis), histopathology (cellular interactome, neovascularization, and newly found microlesions), and electrocorticographic data (spiking rate in different cortical regions) 17 .…”

“…14 In addition, systems biology, which aims at comprehensively studying molecular diversity, identifying general principles and patterns and integrating biological knowledge in complex models, 15 is likely to become increasingly applied in epilepsy. 16 An illustration of this approach is the analysis in patients investigated for epilepsy surgery of complex correlations among brain tissue metabolomics (high-resolution magnetic resonance spectroscopy), genomics (RNA microarray analysis), histopathology (cellular interactome, neovascularization, and newly found microlesions), and electrocorticographic data (spiking rate in different cortical regions). 17 Researchers derived accurate biomarkers of epileptogenesis, which, pending validation, could be used noninvasively.…”