Research

Current Research

CAR-T cell therapies have shown that immune cells can be reprogrammed to eliminate cancer—but their performance remains inconsistent, especially in solid tumors. Key challenges include limited persistence, unpredictable efficacy, and lack of precise control over how engineered cells behave. At the same time, tools from synthetic and systems biology now offer unprecedented power to interrogate and reshape immune function: massively parallel genetic screens, single-cell profiling, and machine-learning-guided protein design are transforming how we study and engineer cells.

The Goodman Lab develops and integrates these technologies to turn immune cell engineering into a rational design process. We build high-throughput experimental platforms and computational models to understand how genetic sequences control immune cell phenotypes—and to use that insight to create better therapies. Our work focuses on decoding intracellular signaling domains, dissecting clonal heterogeneity, and harnessing native gene regulation to precisely and safely control cell state.

Research Directions

1. Mapping and engineering intracellular signaling to control immune cell behavior.
   Synthetic receptors like CARs link antigen recognition to downstream responses, but the sequence rules governing their signaling activity are still largely unknown. We use large-scale pooled screens—guided by protein language models and machine learning—to test thousands of variants and discover short motifs and receptor architectures that govern activation, persistence, and memory. These insights guide the design of synthetic signaling tuned for enhanced therapeutic function.

2. Tracking clonal dynamics and transcriptional states to understand functional heterogeneity.
   Different autologously-produced cell products and even individual clones within a product can vary widely in their therapeutic efficacy. Using single-locus barcoding, we track thousands of engineered clones over time in vitro and in vivo. By pairing this with single-cell transcriptomic and epigenetic profiling, we identify molecular features that predict which clones persist, expand, and function best—and how to engineer or enrich for those states.

3. Harnessing endogenous gene regulation to create safer, state-aware cell therapies.
   Static genetic programs can limit therapeutic precision and can compromise safety. We’re developing strategies to link therapeutic payloads to native regulatory elements that respond to cell state—for example, loci activated during exhaustion or effector differentiation. By screening geomically-encoded circuits across many genomic contexts, we identify sites where context-aware expression enables cells to balance key functions dynamically and safely.

Vision

Together, these efforts aim to create a blueprint for programmable immune cell therapies—where design is informed by high-throughput functional and clinical data, guided by computational models, and optimized for safety, precision, and scalability. While our current focus is on CAR-T cells for cancer, the tools and principles we develop extend to other diseases and immune cell types. Our long-term vision is to make engineered cell therapies safer, more versatile, widely adopted, and integral to the future of medicine.