Decoding cell-fate decisions through molecular recording

The National Institutes of Health Office of the Director awarded $843,125 to Sloan-Kettering Institute For Cancer Research on September 30, 2026, under the Trans-NIH Research Support program (CFDA 93.310) to develop single-cell genomic recording technologies that encode cellular histories as retrievable DNA edits.

The recipient will design modular synthetic circuits that permanently capture diverse biological events—lineage history, signaling pathway activity, transient gene expression, microenvironmental interactions, and CRISPR-based genetic perturbations—enabling retrospective reconstruction of developmental trajectories at single-cell resolution. As proof of concept, the work will apply this recording system to directed differentiation of human pluripotent stem cells into pancreatic islets, a model relevant to treating type 1 diabetes. The platform will reveal how combinations of transient cellular events determine final cell fate and establish a broadly applicable approach for reconstructing sequences of cellular events that program developmental outcomes.

Work is performed in New York, New York, with a period of performance through July 31, 2031.

Abstract

Deciphering how combinations of intrinsic and extrinsic cues determine cell fates is a fundamental challenge in developmental biology, with broad implications for regenerative medicine and cancer. While single-cell genomics technologies can profile cell states in detail, current approaches cannot reconstruct how prior events-such as signaling pathway activations, transient gene expression changes, or cell-cell interactions-shape developmental outcomes. Here we propose to create a new class of single-cell genomic recording technologies that integrate past cellular histories with present states captured by single-cell profiling. We will design modular synthetic circuits that permanently encode diverse biological events-lineage history, signaling activity, transient transcript expression, microenvironmental interactions, and crispr-based genetic perturbations-as retrievable DNA edits. These records will enable the retrospective reconstruction of developmental trajectories at single-cell resolution, revealing how combinations of past cellular events program final cell type. As a proof of concept, we will apply this system to the directed differentiation of human pluripotent stem cells into pancreatic islets, a clinically relevant model for treating type 1 diabetes. This approach will reveal how transient cellular events affect cell-fate decisions and establish a broadly applicable platform for recording and reconstructing sequences of cellular events that determine the final cell fate.