Shortly after conception, a fertilised egg divides, becoming two. Then each of those cells splits, becoming four and on and on. Over time, those lineages of cells grow distinct, giving rise to all the different organs and tissues in the human body and comprising as many as 36 trillion cells.
Scientists would love to understand the trajectory of each of those cells over time. “It’s something that developmental biologists like me have dreamed of for over 100 years,” said Alex Schier of the University of Basel in Switzerland. But the best they have managed has been taking snapshots of cells at different stages.
Lacking that complete history, scientists still have much to learn about how, exactly, cells produce our organs or how they heal wounds later in life. “We really only understand bits and pieces,” said Tanja Stadler, a computational biologist at ETH in Zurich.
Stadler’s lab and others around the world are trying to turn cells into their own historians, as she and her colleagues described in the journal Nature Reviews Genetics recently. Their engineered cells can insert distinctive bits of genetic material into their DNA. As the cells divide, those genetic bits turn into distinctive bar codes.
The technology is also allowing cells to create a genetic record when they experience a notable event, such as receiving a signal from other cells or making a particular protein.
Schier speculated that doctors might even someday inject sentinel cells into our bodies to track our changing health. “I feel kind of sick now — did I have an infection three months ago? Did I have mercury poisoning seven months ago?” Schier said. The answers could be found in the cellular history recorded by sentinel cells.
“I’m pushing all my chips in on these technologies,” said Jay Shendure, a biologist at the University of Washington in the US and a DNA sequencing pioneer. “It’s a fundamentally new paradigm for how we measure biology over time.”
Shendure was among the first scientists to envision such history-recording cells. As a graduate student in 2000, he spent six months trying to build a cell that could periodically alter a tiny bit of its own DNA. After six months of failure, he abandoned the project.
Over the next decade, researchers invented a powerful new tool for editing DNA, called CRISPR. The technology could zero in on one spot in a cell’s genome, and then either snip out or insert new DNA.
Shendure and his colleagues set out to use CRISPR to record a cell’s history. They engineered cells in zebrafish, a species that is easy to study because its embryos are transparent. The researchers engineered the zebra-fish so that they could cut or add DNA at a dozen sites in their genomes.
Then the researchers grew fish embryos from the cells. Every now and then, a cell would randomly alter one of the sites. When it divided, its descendant cells inherited those genetic scars.
When the fish reached adulthood, the scientists sequenced their DNA. The altered bits of DNA acted like a bar code, with nearly identical codes revealing cells that were closely related.
Shendure and his colleagues traced the relationships of the cells in a family tree. The bar codes in blood cells, for example, indicated that almost all of a fish’s blood arose from just five progenitor cells.
After Shendure and his colleagues published these results in 2016, they realised they did not have a monopoly on the insight. “It turned out that about 10 people had the same idea,” he said.
Now the researchers are working together to create a new generation of cell recorders.
At the California Institute of Technology, US, for example, Michael Elowitz and his colleagues have developed a recorder that doesn’t require that scientists destroy cells to read their history. Instead, they can douse cells with chemicals that make them light up if they bear a certain bar code.
Elowitz and other researchers are also inventing ways for cells to record specific events. An immune cell might record sensing a virus, for example, or a skin cell could record when it made pigments in response to sunlight.
Recently, Shendure and his colleagues expanded the power of cell recorders by creating a “DNA typewriter”. After a cell adds a mark to its DNA, it can add a new mark directly next to the old one, like typing keys on a typewriter. The scientists have created dozens of different keys, which can record both a cell’s history of division along with many of its experiences.
So far, the researchers have tested the DNA typewriter only in clumps of mouse cells in a petri dish. But they are trying to create what they call the “recorder mouse”, in which all 10 billion of the animal’s cells carry individual records of their experiences since fertilisation.
Schier hopes that scientists will be able to use the mice to discover some of the rules of development. “How many ways are there to make a heart?” he asked. “I hope we find something new there.”
NYTNS
