Research

The research at Qian Lab focuses on the development and disorders of the human cerebral cortex. We study it using two complementary approaches: direct analysis of human brain tissue through spatial transcriptomics, and modeling with human stem cell-derived brain organoids.

Why study the human cerebral cortex?

Because it’s what makes us human. It’s the seat of higher cognition, language and most importantly, imagination. It is the “crown jewel” of the brain. Compared to the more ancient, survival-focused regions like the brainstem or hypothalamus, the cortex is evolutionarily young and incredibly advanced in humans. But that same complexity makes it vulnerable. Disorders like autism and brain malformations often stem from disruptions in cortical development.

Yet our understanding of how the human cortex develops is still limited — largely because the field has relied so heavily on mouse models, which often fall short at capturing human-specific features of brain development. That’s why our work emphasizes the use of human-based approaches — studying the human brain on its own terms.

How do we study the human cerebral cortex?

Brain organoids provide a tractable experimental model to study human brain development.

Brain Organoids are tiny, self-organizing balls of cells, about 3 to 4 millimeters in diameter, each containing roughly 5 million cells. And they can be made from anyone’s cells — even yours or mine. Inside, they replicate many of the key features of the developing human cerebral cortex. Inside, they replicate many of the key features of the developing human cerebral cortex. Our previous work developed one of the first scalable and reproducible protocols to generate cerebral cortex–specific organoids, which led to one of the most highly cited papers in the field (Qian et al, Cell, 2016).

Nevertheless, organoids are still models — and like all models, they’re approximations. As the saying goes, “All models are wrong, but some are useful.” The key is knowing how to benchmark them.

To do that, we need reference maps based on actual human brain tissue profiled using Spatial Transcriptomics— techniques that preserve both gene expression and spatial context at single-cell resolution. Using single-cell spatial transcriptomics (MERFISH), we built an atlas of the developing human cortex from over 18 million cells (Qian et al., Nature 2025). We found that boundaries between cortical layers and areas form much earlier than previously recognized — long before they are visible under a microscope — underscoring the unique power of spatial transcriptomics.

Spatial transcriptomics reveals the cell type and cytoarchitecture of the developing human cortex at single-cell resolution.

Looking ahead, our lab will integrate these two approaches — organoids and human brain tissue — into a unified strategy. Postmortem brain tissue gives us molecular and spatial ground truth. It captures what’s really happening in human development and disease. But it’s also static — we can’t manipulate it, and we only get one snapshot in time. Organoids, by contrast, are dynamic and experimentally tractable. They allow us to observe development as it unfolds, manipulate genetic or environmental factors, and test potential interventions. Of course, they’re imperfect models — but that’s exactly why we need to benchmark them against real tissue.

What will we do next?

Here are some examples of the projects we’re excited to pursue — some already underway, others launching soon:

1. Expanding the developmental atlas of the human cortex.

While our current atlas is already massive, it’s still far from complete. We’ve focused so far on mid-gestation, but there’s so much more to explore: earlier developmental windows, later stages like the neonatal period, and additional cortical areas that haven’t yet been mapped. Filling in these gaps will provide a richer, more continuous view of cortical development.

2. Engineering next-generation organoids that mimic specific cortical areas.

For years, the field has focused on producing generic “cortical” organoids — but the cortex is not one uniform structure. Our spatial data offers a unique opportunity to benchmark and improve organoids so they resemble distinct cortical areas with much higher fidelity. This is important, because neurodevelopmental disorders often affect particular regions of the cortex. If we can recreate those areas in a dish, we’ll be in a much better position to study disease mechanisms.

3. Using organoids as platforms for disease modeling.

There’s a long list of genes associated with developmental brain disorders, but for many of them, we still don’t know how they work. With CRISPR and organoids, we can now build efficient, scalable models to interrogate these genes and dissect their function. These systems can even be used to test therapeutic interventions, helping to bridge the gap between discovery and application.

4. Analyze human disease tissue with spatial transcriptomics.

At CHOP and other institutions, neuropathology departments have stored decades’ worth of FFPE brain samples — preserved in paraffin blocks, just waiting to be revisited with new tools. With spatial transcriptomics, we can finally extract meaningful molecular insights from these “time capsules” by analyzing them alongside matching controls to uncover the underlying pathology and pathogenesis at precision not achievable by traditional methods. By pairing these analyses with organoid models, we can formulate and test mechanistic hypotheses that link pathology to development.