CRISPR “Cell Recorder” Maps Mouse Embryo Development in Unprecedented Detail

A gene-editing “cell recorder” has captured mouse development in unprecedented detail, revealing how cells divide and form an embryo’s organs.

Two independent teams of scientists report their findings in Science and Cell. One team recorded the cell-by-cell growth of a two-week-old mouse embryo from a single fertilized egg.¹ The other captured most of the embryo’s cell divisions as its organs formed.²

Why mapping mammalian development is so difficult

Both studies were inspired by groundbreaking work from the early 1980s: the first, and still the only, complete map of animal development. British biologist John Sulston observed every cell of the nematode Caenorhabditis elegans using a microscope. The animal had exactly 959 somatic cells, or fully differentiated cells, and developed from an egg into an adult.

Tracing the lineage of most other animals is impossible, especially in mammals, says Jay Shendure, a genome scientist at the University of Washington in Seattle. C. elegans is transparent, and every worm develops in the same way, with the same 959 cells following an unchanging pattern of cell division.

Mammals such as mice are far more complex. Their development occurs inside the body, and cell numbers eventually reach billions. External cues, including growth factors, influence whether cells develop into tissues such as the lungs or liver.

A key question in biology, Shendure says, is how this apparent randomness can produce individuals of the same species with nearly identical body shapes.

“Twins look the same, and humans look the same, but even twins grow through completely different cell divisions,” he says.

CRISPR barcodes track a cell’s lineage

Shendure first approached this problem around 2016, when he and his team developed a method based on the gene-editing technology CRISPR. The researchers introduced genetic “barcodes” at specific locations in developing zebrafish cells, Danio rerio.³ They then used DNA sequencing to identify the barcodes in different cells and infer their relationships.

However, CRISPR-based “lineage recorders” can harm cells if they introduce too many edits during development, says Jonathan Wiseman, a molecular biologist at the Whitehead Institute in Cambridge, Massachusetts, who led the Cell study.

To address this problem, Shendure and Wiseman’s teams used a more precise and less damaging gene-editing technique called prime editing. The method introduced genetic edits as cells divided during embryonic development.

Recording the development of 1.3 million mouse cells

Shendure’s team collected fertilized mouse eggs and applied a technique called DNA typewriting. It adds a continuous, indelible genetic mark to a specific region of the genome as a cell divides.

The eggs were then transplanted into mice. Two weeks later, after the embryo had formed its major organ systems, the researchers read the DNA typewriter edits and reconstructed the relationships among 1.3 million edited cells—about 10% of the entire embryo.