Scientists Edit Stem Cell–Derived Neurons Using CRISPR

Researchers can use the technology to investigate neurological diseases in ways not previously possible.


It is well known that genetic mutations and variants lead to an increased risk of neurological diseases. Studying these genetic causes has been challenging, however, because scientists have significantly limited access to human neurons. Neurons are donated by patients that undergo procedures involving removal of brain tissue, but the samples only survive for a few days. As a result, most research has been performed using animal models of brain diseases –– a poor substitute.


Since technology for the production of induced pluripotent stem cells (iPSCs) was developed in 2006, researchers have been able to convert adult stem cells into stem cells that can be transformed into neurons. But these cells do not have the genetic variations associated with brain diseases.


Neuroscientists haven’t been able to benefit from CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene-editing technology either. When iPSCs are subjected to even one or two DNA cuts using Cas9, the cells often die.

Researchers at UC San Francisco and the National Institutes of Health have now developed a solution to this problem. A new version of CRISPR, CRISPRi (i for interference) is at the heart of the new tool. In this version, the Cas9 enzyme is deactivated so that CRISPRi does not make any cuts to the targeted gene and thus avoids killing the cell.

The scientists have used the system to find genes that may contribute to brain diseases, including genes that extend the life span of neurons but do not affect iPSCs or cancer cells and genes that increase the number of neurites, projections that grow from neurons and transmit nerve signals.


Perhaps most interesting are the “housekeeping” genes identified by the researchers. These genes are known to be essential for survival and were thought to perform the same function in all cells. The scientists have shown, however, that they cause different behaviors in neurons and stem cells. In the two types of cells, the housekeeping genes were found to activate or inactivate very different sets of genes, suggesting that housekeeping genes did not operate in the same manner in all cell types.


The researchers are currently using their new CRISPRi tool to investigate different types of neurons with the hope of determining why certain diseases affect certain subsets of neurons and other types of brain cells including astrocytes and microglia. The ultimate goal is to identify molecular pathways involved in various neurological diseases that can be targeted by new drugs.


David Alvaro, Ph.D.

David is Scientific Editor in Chief of the Pharma’s Almanac content enterprise, responsible for directing and generating industry, scientific and research-based content, including client-owned strategic content, in addition to serving as Scientific Research Director for That's Nice. Before joining That’s Nice, David served as a scientific editor for the multidisciplinary scientific journal Annals of the New York Academy of Sciences. He received a B.A. in Biology from New York University in 1999 and a Ph.D. in Genetics and Development from Columbia University in 2008.