Brain physiome: A concept bridging <i>in vitro</i> 3D brain models and <i>in silico</i> models for predicting drug toxicity in the brain.

Abstract

In the last few decades, adverse reactions to pharmaceuticals have been evaluated using 2D <i>in vitro</i> models and animal models. However, with increasing computational power, and as the key drivers of cellular behavior have been identified, <i>in silico</i> models have emerged. These models are time-efficient and cost-effective, but the prediction of adverse reactions to unknown drugs using these models requires relevant experimental input. Accordingly, the physiome concept has emerged to bridge experimental datasets with <i>in silico</i> models. The brain physiome describes the systemic interactions of its components, which are organized into a multilevel hierarchy. Because of the limitations in obtaining experimental data corresponding to each physiome component from 2D <i>in vitro</i> models and animal models, 3D <i>in vitro</i> brain models, including brain organoids and brain-on-a-chip, have been developed. In this review, we present the concept of the brain physiome and its hierarchical organization, including cell- and tissue-level organizations. We also summarize recently developed 3D <i>in vitro</i> brain models and link them with the elements of the brain physiome as a guideline for dataset collection. The connection between <i>in vitro</i> 3D brain models and <i>in silico</i> modeling will lead to the establishment of cost-effective and time-efficient <i>in silico</i> models for the prediction of the safety of unknown drugs.