Figure 1. Niches occupied by various experimental approaches.

Different models and approaches are complementary and will likely all need to be pursued and integrated to achieve the level of mechanistic understanding needed to develop new therapeutic approaches. Three axes are depicted, increasing human relevance (Y), increasing molecular or mechanistic insight (X) and increasing throughput (Z). The primate (most humanoid) systems are labeled in blue and the other vertebrate models are red. Studies in living patients provide high human relevance, but low molecular insights (e.g. functional imaging) and relatively low throughput. In contrast, mouse models provide high levels of mechanistic or molecular insight at varying levels of throughput and often unknown, but assumed, high human relevance. Zebrafish provide a higher throughput model system, whereas non-human primates are more relevant to humans, but lower throughput and less genetically manipulable. iPSCs promise high human relevance, likely high molecular and mechanistic insight, and relatively low throughput currently, although there is potential for higher throughput with automation and new methods. Primary human neural cells derived from progenitors harvested from human embryonic brain are higher throughput, but because they may not have all of the genetic background characteristics of specific patients (in contrast with IPSC-derived neurons), they may have slightly diminished human relevance and molecular predictive power. Human post-mortem tissue provides human relevance at intermediate throughput, but limited causality testing and hence lower mechanistic insight than the cell or animal models.