In a recent issue of Science, Jay Shendure, Alexander Schier and colleagues present an extraordinarily powerful new approach to trace the lineage of cells as they divide within an organism.
In this paper, they outline the development of a synthetic genetic barcode that serves as a sort of notebook to record a cell’s history. They use genome editing (mediated by CRISPR/Cas9) to make edits to this barcode. With each successive cell generation, a cell inherits a copy of the barcode, including all of the prior edits, makes its own unique edits to the barcode, and passes it down to its daughter cells. The key feature in this approach is the progressive introduction and accumulation of barcode edits over time, allowing for each successive cell generation to have a unique but traceable combination of edits.
In a series of proof-of-concept experiments, they show how cell lineage relationships can be reconstructed by analyzing the sequences of the barcode edits. Impressively, they reconstructed the lineage trees of almost 200,000 cells in an adult zebrafish, all of the way back to a two-cell embryo.
While this recent innovation is exciting, a key limitation is the lack of any information on cell identity (e.g., skin, kidney, muscle, etc.). If one could incorporate marks of cell identity into this system, this would be a tremendous advance and change the field of stem cell and developmental biology.