Two HHMI Teams Map Cell Family Trees for Millions of Cells in Developing Mice, a First for a Mammal
Using DNA that records its own history, Jonathan Weissman's and Jay Shendure's groups traced how cells commit to their fates, a feat last done for a whole animal in roundworms in 1983.
Every one of the roughly 37 trillion cells in a human body descends from a single fertilized egg. Scientists have long wanted to draw that cellular family tree. For simple, transparent animals like roundworms they have. For a mammal, which grows from one cell to hundreds of millions in a few weeks inside its mother, it has been out of reach. Two teams at the Howard Hughes Medical Institute say they have now done it.
HHMI investigators Jonathan Weissman and Jay Shendure and their groups separately developed tools that reconstruct cellular family trees spanning millions of cells in developing mice. They are the most complete lineage maps yet made for a mammal, and they also show how cells commit to their fates as the animal develops. "It's really proof of principle that we can do what was done with the roundworm in 1983, but for mammals like you and me," Weissman said.
The roundworm comparison explains the challenge. A roundworm embryo is transparent, so researchers can watch every cell divide under a microscope. A mouse embryo develops hidden inside the mother, so no one can follow it in real time over long periods. The teams instead engineered cells that record their own history. Each time a cell divides, it adds a small, permanent mark to its genome. Those marks are inherited, so every cell carries a record of its ancestry that can be read out long after the divisions have happened.
In 2025, Weissman's team unveiled a version of this technique called PEtracer, which uses prime editing, a precise gene-editing method, to install marks at more than 100 sites in the genome. "The cell divides and each of the sisters gets a mark, and those are inherited by their daughters, and they get additional marks, and so on and so forth," Weissman said. "And so, by looking at the end at the marks in this DNA, we're able to reconstruct what this relationship is."
Because the marks are read by sequencing individual cells, a single experiment reveals both what a cell has become, including its type and the genes it is using, and where it came from. In the new work, Weissman's group at the Whitehead Institute engineered stem cells with the heritable marks and injected them into an embryo. As the embryo developed in the womb, the marks were passed into nearly every cell it produced. Analyzing each cell let the team build very large family trees showing the different cell types and how they arose.
Shendure's group took a parallel route with its own recording tool, called DNA Typewriter, which writes sequential edits into DNA. A figure released with the work shows an embryo at day 13.5 of development carrying robust levels of those sequential edits. The Shendure team's results are posted on the preprint server bioRxiv.
Lineage maps like these could help researchers see when and how cells in an embryo make irreversible choices, and where those choices go wrong in developmental disease. The work remains proof of principle in mice. But the maps show it is now possible to follow a mammal's cells from the first cell onward, something that was done for the first time in any animal for a roundworm more than four decades ago.
