Scientists develop new techniques to track how cells develop

August 24, 2016 by Peter Reuell, Harvard University
Scientists develop new techniques to track how cells develop
Alex Schier is the author of a recent study on the use of CRISPR to mark cells with a genetic barcode that can be used to track the development of cells and reconstruct their lineages. Credit: Stephanie Mitchell/Harvard Staff Photographer

Understanding how various cell types differentiate themselves during development is one of the fundamental questions in developmental biology. Using genome-editing tools, Harvard scientists are getting closer to finding answers.

A recent study authored by Alexander Schier, chair of the Department of Molecular and Cellular Biology and the Leo Erikson Life Sciences Professor of Molecular and Cellular Biology, James Gagnon, a postdoctoral fellow in Schier's lab, and Aaron McKenna and Greg Findlay, Ph.D. students in the lab of Jay Shendure at the University of Washington, developed a system that uses the CRISPR genome-editing tool to mark zebrafish cells with a genetic barcode that can later be used to reconstruct their lineage. The study was published earlier this year in Science.

"We would like to understand how cells go down different avenues during development and end up as specific cell types," Schier said. "With this new tool, we can take adult brain cells and … see how those cells are related to each other all the way back to the embryo.

"In this system CRISPR targets 10 short sequences and randomly cuts them, inducing either deletions or insertions as the cell repairs the cuts," he explained. "We can then sequence those areas, and understand how the cells relate to each other."

For example, Schier said, a single cell may have one sequence cut in a certain location, but as it divides, its daughter and granddaughter cells may be cut at additional locations. By tracing how those changes accumulate, researchers eventually can identify how cells relate to each other. The more closely related cells are, the more similar their mutated barcodes.

Though the idea of marking cells to track their development isn't new, the new technique offers far more versatility and specificity.

"One major way this has been done is by labeling cells with fluorescent proteins and then following the inheritance of the color," Schier said. "For example, one could deduce that cells that are purple might have come from a common progenitor that was purple."

The problem, Schier said, was that even the most advanced systems were limited to only about 100 distinct colors.

"The power of this method is that you can, essentially, get thousands of colors," Schier said. "In this paper, we demonstrated that we could produce 4,000 unique barcodes which we could trace to see how cells are related to one another."

Already, Schier said, the technique is providing new insights for researchers to investigate.

"There are some tantalizing hints we found," he said. "For example, we found that more than 98 percent of the blood in one fish came from just five , and in another fish it came from just two. This raises interesting questions of tissue dynamics that we would really like to understand—how relatively few progenitor cells give rise to a large number of or brain cells."

Schier's lab isn't alone in exploring the possibilities of using CRISPR to understand how cells develop. Researchers working in the lab of George Church, the Robert Winthrop Professor of Genetics at Harvard Medical School (HMS), developed a similar system in which the guide RNA sequence that instructs CRISPR where to cut was also the target.

The end result is a system that targets a specific genetic sequence and cuts it, but as that cut is repaired it creates a new guide RNA, telling the system where to cut next, and generating enough diversity to allow researchers to trace a cell's lineage. This study has been posted on the preprint server BioRxiv.

The next step, Church said, will be learning not only how cells develop into adulthood, but how and when cells change their identity during development.

"We want to know who begat whom," he said, but also "what the cells are thinking and what they're doing. We can stop the merry-go-round at any point in development and take a snapshot of their lineage and what the are doing."

Explore further: New technique helps researchers determine developmental origins of cells

Related Stories

'On' switches for cells

February 3, 2014

(Phys.org) —Whether human or animal, vertebrate or invertebrate, nearly every creature begins life as a tiny clump of cells. Before those cells can begin blossoming toward being a fully formed organism, however, they first ...

Unsilencing silenced genes by CRISPR/Cas9

July 1, 2016

The ability to control gene expression in cells allows scientists to understand gene function and manipulate cell fate. Recently, scientists have developed a revolutionary gene-editing tool, called CRIPSR/Cas9, which employs ...

Recommended for you

Venom shape untangles scorpion family tree

November 14, 2018

As a child growing up in Mexico, Carlos Santibanez-Lopez feared the scorpions that would often decorate the walls and ceilings of his home in search of a warm place with plenty of food.

Gene-edited food is coming, but will shoppers buy?

November 14, 2018

The next generation of biotech food is headed for the grocery aisles, and first up may be salad dressings or granola bars made with soybean oil genetically tweaked to be good for your heart.

Visualizing 'unfurling' microtubule growth

November 13, 2018

Living cells depend absolutely on tubulin, a protein that forms hollow tube-like polymers, called microtubules, that form scaffolding for moving materials inside the cell. Tubulin-based microtubule scaffolding allows cells ...

DNA structure impacts rate and accuracy of DNA synthesis

November 13, 2018

The speed and error rate of DNA synthesis is influenced by the three-dimensional structure of the DNA. Using "third-generation" genome-wide DNA sequencing data, a team of researchers from Penn State and the Czech Academy ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.