All humans begin life as a single cell that divides repeatedly to form two, then four, then eight cells, all the way up to the 26 billion or so that make up a newborn. Tracing how and when those 26 billion cells arise from one zygote is the grand challenge of developmental biology, a field that so far has only been able to capture and analyze snapshots of the development process.
Now, a new method developed by scientists at the Wyss Institute and Harvard Medical School (HMS) brings that task into the realm of possibility using evolving genetic barcodes that record the process of cell division in developing mice, enabling the lineage of every cell in a mouse’s body to be traced back to its single-celled origin.
The research is published today in Science as a First Release article.
“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,” said senior author George Church, who is a core faculty member at the Wyss Institute, professor of genetics at HMS, and professor of health sciences and technology at Harvard and MIT. “This barcode recording method allows us to reconstruct the complete history of every mature cell’s development, which is like playing the full motion picture backwards in real time.”
The genetic barcodes are created using a special type of DNA sequence that encodes a modified RNA molecule called a homing guide RNA (hgRNA), which was described in a previous paper. The hgRNA molecules are engineered such that when the enzyme Cas9 (of CRISPR-Cas9 fame) is present, the hgRNA will guide the Cas9 to its own hgRNA sequence in the genome, which Cas9 then cuts. When the cell repairs that cut, it can introduce genetic mutations in the hgRNA sequence, which accumulate over time to create a unique barcode.