The Truong Laboratory treats the human genome as a programmable substrate for composing cellular behaviors, and develops technologies to write and control it at scale. Our goal is to understand how genome structure encodes cellular function and how these relationships can be systematically engineered.
Our work centers on human induced pluripotent stem cells (iPSCs) as a renewable and engineerable substrate for building programmable cell systems. By moving beyond single-gene editing toward the architectural engineering of multi-genic regions and synthetic genetic systems, we seek to define the principles governing how genetic elements combine to produce stable, functional cellular states — an approach we term Compositional Cell Engineering.
Immune and regenerative systems serve as biological instantiations of this framework, enabling us to study how genome-encoded programs give rise to complex, adaptive cellular behaviors in clinically relevant contexts. These capabilities provide a foundation for both fundamental discovery and the development of next-generation cell-based therapies.
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1. Foundational Platform - Genome Engineering
REWRITE (Recombinase Writing by Repeatable Integrations and Tag Excision): We developed a genome writing platform that enables the reconfiguration of large (>100 kb) regions of the human genome in human iPSCs. By integrating CRISPR/Cas9, site-specific recombinases, and synthetic DNA assembly, REWRITE enables the construction and installation of synthetic genomic architectures at native loci. This capability allows us to move beyond single-gene editing toward the engineering of multi-genic regions and integrated genetic programs, providing a foundation for both interrogating genome function and composing new cellular behaviors. Using this system, the genome becomes a programmable substrate through which complex cellular functions can be designed and implemented.
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SynTACS: (Synthetic Transcriptional Architecture of Condensates and Super-Enhancers).
In parallel, we investigate how genome organization and regulatory architecture give rise to stable gene expression and cellular identity. SynTACS focuses on understanding how elements such as super-enhancers, transcription factor networks, and chromatin structure interact to control transcriptional programs. This work aims to define the principles governing multi-genic genome organization and to establish a framework for designing synthetic regulatory architectures. These efforts contribute toward a long-term goal of developing a “programming language” for the genome, enabling predictive and scalable engineering of cellular function.
2. Applications: Immuno-Engineering
We use the immune system as a platform for programmable cell behavior, where genome-encoded diversity, selection, and environmental responsiveness can be engineered and studied in a controlled manner. Leveraging genome-scale rewriting and synthetic regulatory systems, we develop human cell platforms that reconfigure antigen presentation pathways, HLA architecture, and inflammatory signaling to probe how immune identity and function are specified.
Within this modular ecosystem, macrophages, dendritic cells, and thymic epithelial cells serve as programmable cellular chassis through which we investigate antigen presentation, immune recognition, and tolerance. These systems enable the controlled study of how engineered cells sense, process, and respond to complex biological environments, and provide a foundation for designing therapeutic and experimental immune cell behaviors .
3. Therapeutics: Regenerative Tissue Engineering
REPHRESH: (Regenerative Phagoctye Reboot for Self-Healing):
We develop programmable macrophages as a platform for regenerative cell systems, leveraging their intrinsic roles in tissue surveillance, phagocytosis, and immune modulation. Macrophages are highly adaptable cells that transition between inflammatory and reparative states and can access diverse tissues, including the central nervous system as microglia.
Using compositional cell engineering, we design genetic programs that control macrophage state, enhance their ability to sense and localize to diseased environments, and coordinate responses such as phagocytosis and secretion of therapeutic factors. These cells function as programmable chassis for interacting with damaged tissue and modulating local biological processes.
This system enables the development of engineered cell systems for regenerative applications, including the clearance of neurotoxic aggregates and the restoration of tissue homeostasis in neurodegenerative and other disease contexts.