Harvard researchers—using zebrafish and frog embryos as models—have traced the process by which a single cell builds a complete organism, according to three papers published April 26 in "Science" magazine.
The research was conducted by Molecular and Cellular Biology Professor Alexander F. Schier, Harvard Medical School Systems Biology Assistant Professor Allon M. Klein, Harvard Medical School Systems Biology Department Chair Marc W. Kirschner, members of their respective labs, and Harvard Medical School Associate Systems Biology Professor Sean G. Megason at the Broad Institute in Cambridge.
“The project, at the highest conceptual level, was asking the question, ‘What happens to gene expression in all of the cells in an embryo over time?’” said James A. Briggs, a member of Klein’s lab. “The state of affairs previously was that we knew a lot about gene expression in terms of what a couple of genes did, but we didn’t know what all of the genes were doing in each individual cell.”
Briggs said the researchers utilized an innovative single-cell RNA sequencing technology developed by Klein to map the process of cell differentiation in pluripotent cells, cells that have the potential to develop into specialized cells that, in turn, comprise specific tissues.
Jeffrey A. Farrell, a researcher in Schier’s lab, said that, in this technique, an embryo is first dissociated into individual cells, which are then suspended in solution. The solution of cells is combined with a solution of beads, each of which is encoded with a unique “barcode” and contains primers that can capture RNA. A buffer is then added to break open the cells and release their RNA content, which is captured by the beads.
“Each bead’s unique barcode, when you sequence the RNA, lets you know that those came from this cell versus the ones that came from a different bead,” Farrell said. “All of your RNAs are attached to things with unique barcodes, so you can then turn them into DNA and put them in a sequencer to get the sequence of all the things that are in that cell.”
Farrell said that, though the three projects utilized slightly different methodologies, the initiatives shared a common goal and sought to answer the same core question.
“Essentially, all three studies did something similar,” Farrell said. “They took embryos from different time points, dissociated them, sequenced a number of the different cells, and then came up with different computational ways of trying to arrange them into these paths from a pluripotent state to differentiated cell types.”
Farrell said the studies have numerous applications in the field of regenerative medicine. He said that—in one example—a comprehensive map of gene expression on the cellular level can help scientists better understand how cells decide their fate.
Schier Lab researcher Yiqun Wang added that other researchers can take new approaches to analyzing the data sets used in the three studies, potentially leading to more breakthroughs.
“Just simply by offering this data set to the field, other people can look into it and maybe extract more information and understand more about development,” Wang said. “And of course understanding more about the process of development would have some implications on treating developmental diseases.”
Briggs echoed Wang’s optimism.
“There are two things that we’re really excited about doing right now. One is applying the same kind of approaches to other organisms to learn about evolution,” he said. “The other thing we’re really excited about doing is using this really detailed map as kind of a reference, so now when we change how certain genes work, we can ask, on a really global level, what that means for development in an embryo.”
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