Map of the developing brain opens pathways to treat Parkinson's

Scientists from Duke-NUS Medical School and their collaborators have created a comprehensive single-cell map of the developing human brain — one which captures nearly every cell type, their genetic fingerprints, and how they grow and interact. It also benchmarks best-in-class laboratory methods for producing high-quality neurons, marking a major step towards new therapies for Parkinson’s disease and other brain disorders.

Parkinson’s disease damages midbrain dopaminergic neurons — cells that release the chemical dopamine to control movement and learning. Restoring these cells could one day help alleviate symptoms such as tremors and mobility loss.

To better understand how these neurons develop when grown in a laboratory, the research team built a two-step mapping framework called BrainSTEM (Brain Single-cell Two tiEr Mapping). Working with partners, including The University of Sydney, they analysed nearly 680,000 cells from the fetal brain to map the entire cellular landscape. Their work was recently published in the journal Science Advances.

The second higher-resolution projection focuses on the midbrain — pinpointing dopaminergic neurons with greater precision. This comprehensive reference map now provides scientists worldwide with a standard to evaluate the accuracy of midbrain models, compared to the real human brain.

“Our data-driven blueprint helps scientists produce high-yield midbrain dopaminergic neurons that faithfully reflect human biology,” said Dr Hilary Toh from Duke-NUS Medical School, a first author on the paper. “Grafts of this quality are pivotal to increasing cell therapy efficacy and minimising side effects, paving the way to offer alternative therapies to people living with Parkinson’s disease.”

The study found that many methods used to grow midbrain cells also produced unwanted cells from other brain regions. This shows that both the lab techniques and the data analysis need improvement to detect and remove these off-target cells.

“By mapping the brain at single-cell resolution, BrainSTEM gives us the precision to distinguish even subtle off-target cell populations,” said Dr John Ouyang, a principal research scientist at Duke-NUS’s Centre for Computational Biology and senior author on the study. “This rich cellular detail provides a critical foundation for AI-driven models that will transform how we group patients and design targeted therapies for neurodegenerative diseases.”

Duke-NUS Assistant Professor Alfred Sun, also a senior author on the study, added, “BrainSTEM marks a significant step forward in brain modelling. By delivering a rigorous, data-driven approach, it will speed the development of reliable cell therapies for Parkinson’s disease. We’re setting a new standard to ensure the next generation of Parkinson’s models truly reflects human biology.”

The team plans to provide their brain atlases as an open-source reference and the multi-tier mapping process as a ready-to-use package. With BrainSTEM being a framework that can be applied to sieve out any cell type in the brain, labs worldwide can deploy it to deepen insights, refine workflows and accelerate discovery across neuroscience.

“This study redefines the benchmark — establishing multi-tier mapping as essential for capturing cellular detail in complex biological systems,” said Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS. “By revealing how the human midbrain develops in such detail, we will accelerate Parkinson’s research and cell therapy, delivering better care and offer hope to people living with the disease.”

Image caption: Midbrain dopaminergic neurons under a microscope. Image credit: Hilary Toh, Duke-NUS Medical School.