From mice to clinical relevance: humanizing neuroscience with human-based model systems

Preclinical research in neuroscience has traditionally relied on animal models to investigate disease mechanisms and develop new therapeutic strategies. While these models are valuable to gain mechanistic insights, their translational power remains limited due to interspecific differences and, hence, frequent failures in clinical translation. The uniqueness of the human brain calls for alternative approaches in neuroscientific research that more faithfully capture human physiology and pathology. In recent years, a variety of human-based model systems have emerged, ranging from dissociated neuronal cultures and stem cell-derived platforms, including organoids, to micro-engineered devices and human brain slice approaches. Each model offers distinct advantages and limitations in recapitulating neural circuits, disease mechanisms, and therapeutic responses. In this review, we critically discuss the merits and drawbacks of animal models, outline the historic development and current applications of human-based systems, and highlight their potential to complement or replace animal-based models. We further explore current challenges in human brain research, including human variability, technical challenges, as well as ethical considerations and regulatory hurdles. Together, these advances represent a shift toward more predictive, human, and ethically responsible neuroscientific research that could aid in decreasing the translational gap.