Podcast recap: Xin Jin on decoding brain disorders with in vivo Perturb-seq

In the last episode of the Genetics Podcast, Patrick speaks with Dr. Xin Jin, a pioneering neuroscientist at Scripps Research, about her team’s cutting-edge method for decoding the genetics of complex brain disorders. Their approach, in vivo Perturb-seq, combines CRISPR-based gene perturbations with single-cell sequencing to map how genetic risk factors affect specific cell types across the brain.

Bridging the gap between genes and mechanisms

Over decades, genomics research has uncovered hundreds of genes linked to neurodevelopmental and neurodegenerative disorders. However, it is difficult to ascertain which genes are actually causative, relevant, and lead to phenotypes.

Xin points out that neurodevelopmental disorders like autism spectrum disorder (ASD) are not the result of “one molecule going wrong,” but rather the emergent outcome of multiple mutations interacting across many cell types. If we want effective treatments, we first need to answer whether these diverse genetic causes produce similar biological consequences, or whether each one is essentially a distinct disorder in need of its own therapeutic approach.

From single perturbations to system-level insight

Xin pioneered the technique in vivo Perturb-seq years ago, and her research group is now developing it further. The method combines CRISPR-based gene perturbation with single-cell genomics inside a living organism, offering the following advantages: 

• One perturbation per cell – Each cell receives a single genetic edit, ensuring the effects of each gene knockout can be observed in isolation.
• Whole-organism context – By delivering edits directly into the mouse brain, cells maintain their natural connections, signaling, and microenvironment—features that in vitro cultures can’t fully replicate.
• Single-cell readouts – Sequencing each cell individually reveals both its identity (e.g., astrocyte, microglia) and how the perturbation changes its gene expression profile.
• Parallel analysis at scale – Dozens or even hundreds of gene edits can be tested simultaneously, dramatically speeding up the process compared to traditional one-mutation-at-a-time approaches.

This setup allows the team to build a vast “matrix” of results: which gene was altered, which cell type it was in, and how that cell responded. From there, convergence points can emerge, such as multiple autism-linked genes producing similar changes in the same subset of neurons or intracellular pathways. This can help identify key drivers of disease rather than downstream “followers” in the network.

Xin has applied this approach extensively to ASD, which is associated with both common variants with subtle effects and rare mutations with strong impact. Using in vivo Perturb-seq, she perturbed dozens of known ASD risk genes in parallel in the mouse brain, then used single-cell profiling to measure how each change affected different neuronal and glial populations. This intricate mapping process could inform therapeutic strategies—identifying common intervention points that might help patients with very different genetic profiles.

Beyond autism: Toward neurodegeneration and other systems

While the initial focus has been on neurodevelopmental disorders, Xin sees potential for applying the method to:

• Neurodegenerative diseases such as ALS, Parkinson’s, and frontotemporal dementia, where in vivo context is crucial for modeling aging and inflammation.
• Other organ systems like liver or heart, as viral delivery methods for gene perturbation improve.

The approach’s power lies in capturing the complexity of living tissue — including immune interactions, cellular diversity, and intact architecture — while maintaining experimental scale.

Accelerating therapeutic development

One of the most exciting possibilities is using in vivo Perturb-seq to identify shared molecular pathways across multiple genetic causes of a disease. If several mutations converge on the same downstream network or cell type, a single therapeutic strategy might address them all. This could dramatically shorten the path from genetic discovery to treatment, especially for rare diseases.

Xin also envisions using the platform for “rescue” screens — systematically testing potential interventions in genetically perturbed models to see which restore normal cell function.

From a botanical garden to the frontiers of neuroscience

Xin’s first encounter with science came in the botanic garden where her grandfather worked as a plant taxonomist. She learned early that two plants could look identical yet differ entirely in their chemistry—a lesson in the gap between form and function that stayed with her.

As a teenager, she excelled in the Chemistry Olympiad, sharpening her problem-solving skills and discovering the possibility of studying abroad. At 18, she moved from China to MIT, where research in Alice Ting’s chemistry lab gave her hands-on experience and taught her how to work and think like a scientist.

Listen to the full episode below.