Human models are needed for studying human neurodevelopmental disorders

There is a need to understand human neurodevelopmental processes and disorders — including diseases caused by, or worsened by, exposure to environmental toxicants. Animal models (especially differences between inbred mouse strains or transgenic mouse lines) can be indispensable for determining molecular mechanisms of gene regulation in the brain. However, animal models are limited in revealing some of the most fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. These shortcomings are exaggerated in disorders that affect the brain, where the most significant differences between humans and animal models exist; these limitations could lead to failures in specific drug interventions in affected individuals.

Analysis of human-specific characteristics of the brain has been slowed down by the difficulty in acquiring developing brain tissue, as well as diseased human brain tissue. The various types of human pluripotent human stem cells (hPSCs) provide an important alternative for studying development and function of brain cells. To facilitate brain-disease modeling, human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) provide paradigms for defining human-specific biology and identifying disease mechanisms. By adding the “correct cocktail” to hESC cultures, one can differentiate these stem cells into (for example) myocytes (to make muscle), osteoblasts (to make cartilate or bone), keratinocytes (to make skin), endothelial cells (to make the lining of intestine), cardiomyocytes (heart muscle cells), and oligodendrocytes or astrocytes or other brain-specific cells.

Questions remain, however, about the utility and value of these cell-culture-based models and how best to move the technology forward. In the attached (excellent) review, authors summarize human-specific features of the process of neurodevelopment and neurodevelopmental diseases. Authors also present the gaps between animal models and human diseases, demonstrate how human stem cell models can bridge some of these gaps, and discuss the challenges for further improvement. This information argues for a more thoughtful approach to disease modeling through consideration of the valuable features and limitations of each model system, be they human or nonhuman animal — to mimic disease characteristics.

Am J Human Genet 6 Dec 2o18; 103, 829–857

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