From a single cell to 1.2 million: Scientists successfully create the largest cellular “family tree” for a mammal
The new findings could provide valuable insights into birth defects and cancer
Allen Institute
image:
A circular lineage tree of a 13-day old mouse embryo, originating from a single cell at the center expanding outward over developmental time. Cells derived from the first cell division are marked in blue or red.
view moreCredit: Seattle Hub for Synthetic Biology
How does a single fertilized egg produce all the cells in an animal’s body? This question has hung over science for decades, and it’s critical to understanding how diseases like cancer take hold and spread in the body. A new study in the journal Science led by researchers from the Seattle Hub for Synthetic Biology (Seattle Hub)—comprised of the Allen Institute, UW Medicine, and Biohub—moves us closer to the answer.
Researchers successfully built a time-calibrated lineage tree showing how a single cell turned into 1.28 million—about 10% of the cells in a two-week-old mouse embryo. This is by far the largest lineage tree ever built for a mammal.
“This work brings us closer to understanding one of biology’s fundamental questions on how a single cell gives rise to the extraordinary complexity of a living organism,” said Garabet Yeretssian, director of extramural research and partnerships at Biohub, which has provided ongoing funding for the Seattle Hub. “We are proud to support the Seattle Hub team in developing technologies that make it possible to trace that process at an unprecedented scale and open new ways to understand how those trajectories change during development and disease."
Scientists used a technology called DNA Typewriter to reconstruct most of the cell lineage of a developing mouse, mapping how more than 1.28 million individual cells emerged from the first cell division to form tissues and organs. Their research could provide crucial insights into understanding birth defects and even cancer.
DNA Typewriter works by inserting sequential genetic stamps into a cell’s DNA as it divides. The stamps are copied into every daughter cell—a cell that results when a parent cell divides—and written in order, so they act like a journal within the genome, revealing how a cell divided and what happened to it when it did. Researchers injected the DNA Typewriter system into a fertilized mouse egg and let the embryo develop for 13.5 days, around two-thirds of the way through mouse gestation. They measured the genetic stamps in 1.58 million individual cell nuclei and reconstructed the “family tree” of cells composing the embryo.
"We were surprised by just how robustly marking happened right at the very first division," said Haedong Kim, co-first author of the study. "It gave us two naturally occurring, independent copies of the same experiment, within a single embryo, so we could check every finding twice."
Researchers identified multiple unique marks—genetic fingerprints that help scientists distinguish one cell from another—written by DNA Typewriter at the first cell division, when the fertilized egg split into two cells. And as they in turn continued to divide into more cells on two parallel but different tracks, researchers found that they contributed a different number of total cells to the embryo—about 57% to 42%—but provided the same proportion of every cell type.
“Our success in putting DNA Typewriter into a developing embryo, together with the resulting cell lineage, brings us closer to our dream of comprehensively mapping mammalian development,” said Jay Shendure, scientific director of the Seattle Hub for Synthetic Biology and professor of genome sciences at UW Medicine. “All cell types have their origins in development, and such maps may enable insights into the thousands of genetic disorders that arise during development.”
What this means for human health
This research is a critical first step because learning how cells divide and organize during development could help researchers better understand birth defects, cancer, and developmental disorders. By understanding the path of normal cellular development and how one cell becomes many, researchers have a reference model for comparison that can better identify when and where the normal path diverges into diseases. This knowledge can help researchers develop ways to prevent abnormal cellular development or intervene when cells go astray.
The DNA Typewriter technology could also be applied to determine how cancer cells spread, better understand how stem cell therapies work, and how aging affects cells in various organs. Recovering biological answers from lineage data could accelerate research that might otherwise take much longer.
Importantly, this study shows that it’s possible to record and read a dense cell lineage history of a complex mammal in a single experiment. The DNA Typewriter system embedded ordered molecular marks throughout mouse development that could be decoded to reconstruct which cell gave rise to which. The resulting tree is publicly available, along with an interactive browser called NextCell that allows anyone to explore this cellular family tree of mouse development.
About Allen Institute
Allen Institute is a 501(c)(3) nonprofit medical research organization dedicated to accelerating science for a healthier world. Through large-scale, multidisciplinary research initiatives, the Institute generates foundational knowledge, data, tools, and models that are shared openly with the world to advance our understanding of life and health. Founded by Jody Allen and the late Paul G. Allen, Allen Institute is supported primarily by Fund for Science and Technology.
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Zoom Out [VIDEO]
The cell lineage of a mouse embryo, from the fertilized egg to day 13.5 of development: 1,281,141 cells from one animal. The embryo recorded its own cell divisions in its genome as it developed, using a molecular recorder called DNA Typewriter. Distance from the center is developmental time, so pulling back is the same as running the clock forward.
Typewriter [VIDEO]
How can a mouse record its own family tree? DNA Typewriter uses a prime editor to write a short DNA "symbol" into one active site on an engineered stretch of DNA. Each insertion closes that site and opens the next one, so the symbols read left to right in the order they were written.
Credit
Seattle Hub for Synthetic Biology
Journal
Science
Method of Research
Experimental study
Subject of Research
Animals
Article Title
A DNA Typewriter records the cell lineage history of a mouse, from zygote to late organogenesis
Article Publication Date
8-Oct-2026
Mapping how a single cell becomes an entire mouse
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.
Journal
Science
Article Title
A DNA Typewriter records the cell lineage history of a mouse, from zygote to late organogenesis
Article Publication Date
8-Oct-2026
DNA Typewriter records cells’ history in early mouse embryo
Inserted into a fertilized mouse egg genome, the tape then tracked the lineage of 1.3 million embryonic cells up to late organ development
image:
DNA Typewriter is injected into the genetic material of a fertilized mouse egg. This technology taps into the genetic material in the fertilized egg and resulting embryonic cells as a recording device of the cells' histories. It tracks their relationships as the embryo develops.
view moreCredit: Kyle O'Conner/Seattle Hub for Synthetic Biology
Scientists have succeeded in reconstructing the family tree of cells in a developing mouse embryo. They recorded cells’ relationships, starting when the fertilized egg first split in two and ending after the body with organs took shape. That period lasted 13.5 days. (Full gestation in mice is 19 to 21 days.)
The study results will appear Thursday, Oct. 8, 2026 in Science.
“We are interested in tracking how cells’ early ancestry in an embryo influences their later fates. Exploring cell lineages helps decode normal development. Such research could eventually advance knowledge about congenital malformations, neurodevelopmental conditions, genetic disorders or cancer,” said Dr. Jay Shendure, professor of genome sciences at the University of Washington School of Medicine in Seattle and a Howard Hughes Medical Institute Investigator.
He and Dr. Chengxiang Qiu, a molecular and systems biologist at Dartmouth College in New Hampshire, are co-senior authors of the Science paper.
Their team’s most recent milestone was reached by using a tracking technology called DNA Typewriter, invented by Shendure and Junhong Choi, who is at Sloan Kettering Cancer Center.
The team inserted a newly redesigned tape into the fertilized mouse egg genome to tap into the mouse’s DNA as a recording medium. The redesign makes the tape’s record easier to read back out of individual cells. As cells divide and take on different characteristics to build the embryo, the DNA Typewriter remains inside each cell’s own genetic material. It serves like a keeper of a ship’s log.
“Think of it like an actual typewriter, except it types onto a cell's own DNA instead of paper,” explained Haedong Kim, a co-first author of the study and a postdoctoral scientist in genome sciences at UW Medicine, the Seattle Hub for Synthetic Biology and the Howard Hughes Medical Institute. “Every time a cell divides, it strikes one new character onto the next blank line — always in order, never overwriting what's already there. Because the characters are always filled in sequence, that sequence itself spells out the cell's division history.”
These codes can then be recovered in a cell’s progeny. Shared DNA Typewriter markings tell scientists which groups of cells had an ancestor cell in common.
"Writing the record is only half the problem. You also have to read it back out of each cell, so we redesigned the tape to make that easier," said Kim.
The complexity of a mammal’s body has challenged scientists who try to accurately trace the lineage of the vast numbers and types of cells in a developing mouse. Decades ago, other scientists accomplished such a feat in a tiny roundworm. But that transparent creature has a simple internal structure with comparatively few cells. Attempts to trace a mouse’s embryonic cell lineage with older technologies produced vital data but a more fragmentary view.
Also, the older methods that cut DNA can leave scars, according to researchers. In addition, they are harsher on the cells and often erase earlier records. They run out of recording capacity fast. Because they place marks in no particular order, the timeline must be guessed afterward.
“DNA Typewriter avoids all of this,” said Kim. “It writes without fully severing the DNA, keeps recording relatively steadily, and writes everything in strict order, so we can record cell lineages at much higher resolution for a longer time.”
The research team attempted this recording in 100 fertilized mouse eggs and ended up with 10 embryos to examine. In Embryo No. 3, the recording system was clearly switched on and had gathered the richest history, according to the scientists. They turned their full analysis to it.
Their study resulted in several new insights. One stemmed from a fortuitous catch immediately after the fertilized mouse egg split in half.
“Our recording captured a clear, permanent mark distinguishing the two very first cells, letting us trace nearly every cell we profiled from the embryo back to one or the other,” said Kim. “One of these two founding cells did go on to produce more descendants than the other, but they produced diverse cell types at almost equal ratios.”
Another finding: By analyzing the recordings, the scientists could pinpoint when, during development, each cell type first broke off on its own separate path.
The scientists showed that these kinds of family trees of development could help them understand when cells pick their jobs, with results consistent with findings accrued over decades of study, but here measured in a single mouse.
“Blood cells and the retina committed relatively early, while the skin's outer layer didn't commit until noticeably later,” they said. “Cell fate wasn't locked in all at once. Different cell types settled into their identity on their own separate schedules, some early and some late.
Looking at the overall study, Kim said: “This kind of large-scale developmental recording gives scientists a map of how one cell becomes a whole body — which helps explain how organs form correctly, how that process can go wrong in birth defects, and how abnormal cell growth drives cancer. As stem cell engineering advances, this kind of recording can also help guide how we engineer cells for therapeutic use.”
The other co-first authors on the study were Qi Yu and Sophie Seidel of the UW School of Medicine’s Department of Genome Sciences and at the Seattle Hub for Synthetic Biology, where Shendure is the lead scientific director. Shendure is also the scientific director of the UW Medicine Brotman Baty Institute for Precision Medicine and of the Allen Institute for Cell Lineage Tracing.
This work was supported by the Seattle Hub for Synthetic Biology, a collaboration between the Allen Institute, BioHub and University of Washington School of Medicine (CZIF2023-008738); Paul G. Allen Frontiers Group’s Allen Discovery Center for Cell Lineage Tracing; UW Medicine Brotman Baty Institute for Precision Medicine; Washington Research Foundation; National Institutes of Health (R00HG012973 and P30CA008748); Damon Runyon Cancer Research Foundation (DFS-64-24); Searle Scholars Award (SSP-2025-101); Dartmouth’s Center for Quantitative Biology National Institute of General Medical Sciences grant (P20GM130454) and Swiss National Science Foundation (239394).
Journal
Science
Method of Research
Experimental study
Subject of Research
Animals
Article Title
A DNA Typewriter records the cell lineage history of a mouse, from zygote to late organogenesis
Article Publication Date
8-Oct-2026
COI Statement
The University of Washington has filed a patent application related to DNA Typewriter, on which Junghong Choiand Jay Shendure are listed as inventors. Jay Shendure is on the scientific advisory board, a consultant, or a co-founder of 10x Genomics, Cellular Intelligence, Guardant Health, Pacific Biosciences and Phase Genomics. All other authors declare no competing interests. The scientists also disclose that data exploration, data analysis, coding and manuscript writing were supported by AI-based tools.
