Research and Technology Development

As we develop from a single cell into a thinking organism, the brain first builds and then continuously remodels itself through the dynamic interplay of programmed and experience-dependent gene regulation. These gene regulatory mechanisms underlie neurodevelopment, learning, and memory, and are frequently disrupted across diverse disorders of the nervous system.

Yet, studying gene regulation at scale remains a major challenge. In particular, we lack the ability to systematically identify, manipulate, and track the activity of the vast numbers of gene regulatory elements—especially enhancers—that orchestrate gene expression across the cell types of the brain. 

Enhancers are short DNA sequences that control when, where, and how strongly genes are expressed, often acting at a distance from their target genes. While thousands of disease-associated variants map to enhancers, the majority remain unlinked to their target genes and the cellular functions they control. In the rare cases where candidate enhancers have been validated and target-linked, they have already enabled immediate strategies for cell- and gene-based therapies, highlighting the enormous translational potential of systematically mapping and controlling these elements.

Our lab develops and applies scalable synthetic biology technologies to identify, manipulate, and record gene regulatory elements in the brain. We use these approaches to both understand gene regulation and engineer new cell and gene therapies for disorders of the nervous system.

Our Approach

Our research program is organized around two core, complementary arms:

1. Identifying gene regulatory elements and their targets

We are pioneering single-cell CRISPR screening technologies to identify enhancers and define the genes they regulate across diverse brain cell types. These approaches enable functional validation of candidate enhancers in human neurons and glia, mapping of enhancer–gene relationships at scale, and identification of cell type-specific regulatory elements to drive expression in basic research and therapeutics.

2. Recording gene regulation over time

We are developing molecular recording methods that write enhancer activation and other cellular events as permanent records in DNA. These approaches enable the reconstruction of past biological processes—including developmental programs, cellular responses, and disease-associated changes in gene regulation—at single-cell resolution.

Together, these technologies enable a new way of studying the nervous system: linking gene regulatory elements to their targets, and reconstructing the dynamic histories of their activity.

Goals

Our goal is to define the enhancer–gene regulatory circuitry across the cell types of the human brain, and to uncover the cascades of enhancer activation that underlie development, memory, and disease.

We use this knowledge to develop new gene and cell therapies, including strategies for cell type-specific and state-dependent therapeutic expression.

Genome Engineering and Translation

We are also human genome engineers, and develop tools and approaches to make genome engineering more efficient, versatile, and broadly applicable.

Recent work includes:

  • Development of promoter and gRNA scaffold “parts lists” for improved genome editing efficiency and reliability
  • Methods for building large, stable synthetic circuits for molecular recording and cellular programming

We collaborate extensively with academic and industry partners working with animal models and patient-derived systems to rapidly test therapeutic applications. For example, enhancers identified in our work are being used toward the development of gene therapies for neurodevelopmental disorders, including severe forms of autism and epilepsy.

Expertise and Systems

Our work integrates experimental and computational approaches across:

  • Stem cell and stem cell-derived brain models (e.g. neurons, astrocytes, microglia, and cerebral organoids)
  • Human genome engineering and synthetic biology
  • Single-cell genomic profiling
  • High-content CRISPR screens
  • Massively parallel reporter assays (MPRAs)
  • Molecular recording technologies (e.g. ENGRAM, DNA Typewriter)
  • Computational analysis of large-scale functional genomics datasets

Opportunities

There are substantial opportunities for creativity and innovation in our research program, including:

  • Identifying enhancers for cell type-specific or stimulus-responsive gene expression in basic research and therapeutics
  • Developing new molecular recording systems for diverse biological events
  • Recording cellular responses to perturbation and disease progression
  • Deciphering the impact of disease-associated genetic variation
  • Engineering next-generation cell therapies that trigger therapeutic expression based on recorded cellular history

We are always looking for curious and motivated trainees interested in developing new technologies and applying them to fundamental and translational problems in neuroscience and gene regulation.

You can read more about our work in our publications, or learn how to apply to join the lab here.