Key Takeaways
- HHMI Investigators Jonathan Weissman and Jay Shendure separately developed new tools to trace cellular development.
- Their teams used these tools to create cell fate maps of a developing mouse, showing how single cells develop into the millions of cells that make up an animal.
- The work could help scientists better understand development and disease and help researchers create AI models of mammalian development.
Growing inside each of us is a cellular family tree.
Every one of the 37 trillion cells in our body is generated from another cell, going all the way back to a single fertilized egg. Much like we can draw a family tree tracking generations of our ancestors, scientists can also create family trees of cells, showing how they're related to each other.
While researchers have created these family trees for simple, transparent animals like roundworms, generating a comprehensive cell fate map for a mammal, which develops in utero from a single fertilized egg to hundreds of millions of cells in just a few weeks, has remained out of reach.
Now, HHMI Investigators Jonathan Weissman and Jay Shendure and their teams have each separately figured out how to do it. Using new tools they created, the researchers have reconstructed cellular family trees spanning millions of cells in developing mice — the most complete lineage maps yet made for a mammal — and traced how those 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 says.
Developing New Tools to Study Development
A roundworm embryo is transparent, allowing researchers to watch every cell divide under a microscope. In contrast, a mouse embryo develops inside the mother, hidden from view, so scientists cannot watch development in real time over long periods.
Instead of observing this development, researchers have learned to make cells that can record it. The idea is to engineer cells to write their own history into their DNA: 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 occurred.
In 2025, Weissman and his team unveiled a new version of this technique they call PEtracer , which uses prime editing to install these marks at more than a hundred 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 says. "And so, by looking at the end at the marks in these DNA, we're able to reconstruct what this relationship is."
Because the marks are read out by sequencing individual cells, the same experiment reveals both what a cell has become — its type and the genes it is expressing — and where it came from.
In new research, Weissman and his team at the Whitehead Institute applied PEtracer to study mouse development. The team engineered stem cells with these heritable genetic marks and injected them into an embryo. As the embryo developed in utero, these marks were incorporated into nearly every cell it produced. By analyzing each cell, the researchers were able to create massive cellular family trees that showed the different types of cells and their relationships to each other.
In separate research, Shendure and his team at the University of Washington developed a similar technology in 2022 called DNA Typewriter that also tracks cell lineage, using prime editing to log each cell division on a string of DNA. By reading the resulting ticker tape, scientists can also reconstruct cellular development. In the new research, Shendure's team injected the components of DNA Typewriter into a fertilized mouse egg, where the marks accumulated as the cells divided.
"Most biological measurements are based on either live imaging, which is limited by the fact that most animal tissues are not transparent, or genomics, which are destructive and only measure a single timepoint," Shendure says. "Recording techniques like the ones in these studies enable measurements over time including in settings that we can't directly visualize."
Understanding Development and Disease
The new maps and tools will allow researchers to better understand what happens during mammalian development, including how cells differentiate to grow tissues. They will also allow researchers to study disease, including where and when a developing embryo is most vulnerable to environmental or genetic stressors.
They can also be used to understand how tumors initiate, grow, spread, and become resistant to therapies.
"There are so many key things that happen during development or during the evolution of a tumor that are happening at a time when we can't observe them directly, so if we can record that information in the DNA, then we can infer and reconstruct exactly how it's happening," Weissman says.
Beyond the biological insights, the data will be used to train AI models of embryogenesis, with the ultimate goal of building a "virtual embryo" that can predict development outcomes.
Weissman says along with these practical uses, there are also a lot of "unknown unknowns" that could come from these tools, much like the map of the roundworm in the 1980s led to new biological discoveries no one could have anticipated.
"That was just by understanding the process and getting at the underlying molecular mechanisms that led to those discoveries," Weissman says.
