Ways to genetically alter stem cells just keep getting better

For science wonks the gene editing technique CRISPR appears in your email, Twitter feed, or journal reading daily, if not hourly. The incredibly easy and inexpensive way to edit the genes in cells has exploded in the past couple years and is increasingly being used to edit stem cells in the lab to study specific diseases. A team at the Gladstone Institutes in San Francisco, using funds from CIRM and others, reports today that a version of the technique not widely used can greatly improve the outcome.

Bruce-Conklin-&-Mo-Mandegar-16

Bruce Conklin and Mo Mandegar manipulated the genes of stem cells using a modified version of CRISPR

Instead of using CRISPR to slice out genes they used CRISPR Interference or CRISPRi to turn the gene off rather than removing them. As teams have learned to use the modification, first reported in 2013, its efficiency has risen to the point that the current team got the target gene silenced in 95 percent of the cells in a lab culture. With traditional CRISPR researchers often see only about 60 to 70 percent of the cells having the target gene sliced out. The silencing method also has the advantage of being reversible so if you are using stem cells to model a disease, you have many more options to manipulate cells and to determine the role that specific genes play in a disease.

heart cells using CRISPRi

Heart Cells created using CRISPRi

“We were amazed by the dramatic difference in performance between the two systems,” said senior author Bruce Conklin in an institute press release. “We thought that permanently cutting the genome would be the more effective way to silence a gene, but in fact, CRISPRi is so precise and binds so tightly to the genome that it is actually a better way to silence a gene.”

His team used the technique in both iPS type stem cells and in heart tissue grown from iPS cells. They then created a model of heart disease by silencing a gene essential for heart function.

Of course, with any technology as revolutionary at CRISPR, the fights have begun for discovery credit both in terms of intellectual responsibility and monetary due, aka patent rights. Two stories detailed these issues yesterday. Science Magazine published a piece on the increasingly nasty patent battle between the University of California, Berkeley and the Broad Institute of Harvard and MIT.  Then a story in the Independent, announced the technique had won this year’s prestigious $500,000 Alpert Prize given out each year by my former employer Harvard Medical School. The prize committee recognized the principal researcher at Berkeley, Jennifer Doudna, and four other researchers around the world they said were responsible for the early discoveries. They did not name Feng Zhang, the main researcher at the Broad.

Fair disclosure: I wrote the announcement when the Broad Institute was created, organized the speakers for the annual Alpert Symposium and am currently very thoroughly Californian. I am picking no sides here.

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