FIGURE 5.

A proper understanding of NDDs complexity requires a holistic approach, since it is challenging to identify key cellular and molecular mechanisms that culminate in such phenotypes. (A) Systems biology approaches aim to understand biological interactions occurring within different biologic entities by utilizing mathematical models and network biology representing existing connections between cells and/or tissues. Integrating the data into biological networks, allow to understand interactions between signaling and regulatory pathways occur within the system. (B) Reaction-associated enzymes and encoded genes are represented in GEMs (Orth et al., 2010; Zhang and Hua, 2015) with stoichiometric (mass and energy) balance, which enables flux balance analysis (FBA), the study of systemic metabolic responses and analysis of the flow of metabolites through the network (Orth et al., 2010; Mardinoglu and Nielsen, 2012; Zhang and Hua, 2015). Essentiality analysis (EA), based on FBA, works at a single level and allows the identification of essential genes and reactions, the knockout or inhibition of which would interrupt a vital biological function. Complementary, synthetic lethality analysis (SLA) can identify combinations of genes or reactions that when simultaneously knocked out or inhibited can disrupt an essential biological function (Zhang and Hua, 2015).