Figure 1.

The strengths and limitations of different models of the intact human brain. The strengths and limitations of six different model systems—human cells obtained peripherally from living donors (or immortalized versions of these cells, e.g., lymphoblast lines), neuroblastoma cells grown in standard cell culture, 2-dimensional (2D) and 3-dimensional induced pluripotent stem cell (iPSC) models (brain organoids), animal models, and ex vivo human brain tissue (obtained either postmortem or resected during surgery)—are presented. Each is rated for each of the factors listed left, with the intensity of the color bar indicating the relative fidelity of each model. For example, cells and tissues derived from humans (including iPSCs) carry the genome of the donor, while the genome of human neuroblastoma lines contains various structural rearrangements, and animal models carry their species’ genome (107). In contrast, animal models are the only system in which behavior can be dynamically linked to invasive measures of cellular and circuit function, although it is possible to correlate phenotypes observed in human cells and tissues with behavioral phenotypes observed in the donors from whom they were derived. The other factors are discussed in more detail in the main body of the review. Note that the color bars are intended to give a broad, rather than a definitive, indication of model fidelity: there is likely to be significant variation within categories, particularly in the case of iPSC models, given the diversity of methodological approaches [e.g., co-culturing iPSC-derived neural progenitors with astrocytes accelerates maturation (31)]. Created with BioRender.com.