Scientists at the Wyss Institute and Harvard Medical School (HMS) developed a new method for tracing cell division back to its origin.

Developmental biologists have long struggled to track how and when the 26 billion cells that make up a newborn arise from one zygote (a fertilized ovum).

Now they can, using genetic barcodes that record the process of cell division.

The system requires a special type of DNA sequence that encodes a modified homing guide RNA (hgRNA) molecule. These molecules are engineered to guide the enzyme Cas9 (of CRISPR-Cas9 fame)—if present—to its own hgRNA sequence, which Cas9 cuts.

When the cell repairs the laceration, it can introduce genetic mutations in the hgRNA sequence, which accumulate over time to create a unique barcode.

Researchers tested their theory in developing mice. A “founder mouse,” its genome chock full of 60 different hgRNA sequences, was crossed with rodents that expressed the Cas9 protein.

Those critters then produced zygotes—the union of the sperm cell and egg cell—whose hgRNA sequences started being cut and mutated shortly after fertilization.

“Starting with the zygote and continuing through all of its pregnancy, every time a cell divides there’s a chance that its daughter cells’ hgRNAs will mutate,” first author Reza Kalhor, a postdoctoral research fellow at the Wyss Institute and HMS, explained.

By comparing the pattern of mutations between cells, scientists can determine when those parts developed (via Wyss Institute at Harvard University)

“In each generation, all the cells acquire their own unique mutations in addition to the ones they inherit from their mother cell,” he said in a statement. “So we can trace how closely related different cells are by comparing which mutations they have.”

Each hgRNA can produce hundreds of mutant alleles (for non-CSI watchers: a variant form of a given gene). Together, they generate a unique barcode that contains the full developmental lineage of each of the approximately 10 billion cells in an adult mouse.

“Current lineage-tracking methods can only show snapshots in time, because you have to physically stop the development process to see how the cells look at each stage, almost like looking at individual frames of a motion picture,” according to senior study author George Church, professor of genetics at HMS. “This barcode recording method allows us to reconstruct the complete history of every mature cell’s development,” he continued, “which is like playing the full motion picture backwards in real time.”

Moving forward, the team is focused on improving readout techniques, in an effort to analyze barcodes of individual cells and reconstruct the lineage tree.

So what does this “huge milestone,” as described by Wyss Institute director Donald Ingber, mean for you?

First of all, a better understanding of the process by which a single cell grows to form an adult animal is just absolutely rad. But when applied to disease models, it could provide “entirely new insights into how diseases, such as cancer, emerge,” Ingber said.

The research was published this week as a First Release article in the journal Science.

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