Advancing the understanding of autism disease mechanisms through genetics

. Author manuscript; available in PMC: 2016 Oct 20.

Published in final edited form as: Nat Med. 2016 Apr;22(4):345–361. doi: 10.1038/nm.4071

Advantages and limitations of human in vitro models
Genomic conservation not an issue; allows for modeling of coding and non-coding variants. One of the few living systems in which human brain development can be studied. High experimental tractability, including genetic manipulation, neuronal physiology and the potential for high-throughput assays for phenotypic screening and drug discovery. Neurons derived directly from affected individuals (iPSCs) can be used to model disease without knowing the causal or contributory genetic variants.	Culture variability, heterogeneity and reproducibility issues arising from multiple sources, including culture methodology and differences in lines and clones used. Cultures to date produce immature fetal-like neurons, limiting their potential to properly model later developmental stages. Neuronal migration, cortical lamination, projection patterns and circuit-level organization are difficult to model in 2D cultures. Tissue engineering and 3D organoid cultures will enable the study of some of these phenotypes. So far, mostly limited to syndromic ASD or small cohorts of idiopathic ASD. As a fundamentally in vitro system, in vivo connectivity and external milieu are not preserved; thus findings may not precisely translate to in vivo biology.

Advantages and limitations of human in vitro models

Advantages

Limitations

Genomic conservation not an issue; allows for modeling of coding and non-coding variants.
One of the few living systems in which human brain development can be studied.
High experimental tractability, including genetic manipulation, neuronal physiology and the potential for high-throughput assays for phenotypic screening and drug discovery.
Neurons derived directly from affected individuals (iPSCs) can be used to model disease without knowing the causal or contributory genetic variants.

Culture variability, heterogeneity and reproducibility issues arising from multiple sources, including culture methodology and differences in lines and clones used.
Cultures to date produce immature fetal-like neurons, limiting their potential to properly model later developmental stages.
Neuronal migration, cortical lamination, projection patterns and circuit-level organization are difficult to model in 2D cultures. Tissue engineering and 3D organoid cultures will enable the study of some of these phenotypes.
So far, mostly limited to syndromic ASD or small cohorts of idiopathic ASD.
As a fundamentally in vitro system, in vivo connectivity and external milieu are not preserved; thus findings may not precisely translate to in vivo biology.