CRISPR method further developed by Swiss researchers

Researchers at ETH Zurich, Switzerland, further developed the well-known CRISPR/Cas method. For the first time, it is now possible to modify dozens, if not hundreds, of genes in a cell simultaneously.

Up to 25 sequences within a genome can be changed simultaneously

Researchers at ETH Zurich, Switzerland, further developed the well-known CRISPR/Cas method. For the first time, it is now possible to modify dozens, if not hundreds, of genes in a cell simultaneously.

With the CRISPR/Cas biotechnological method, individual genes in cells can be removed, replaced or altered with relative ease and speed. In addition, researchers have been able to use CRISPR/Cas-based technologies to increase or reduce the activity of individual genes. Within a very short period of time, these methods have established themselves worldwide both in basic biological research and in applied areas such as plant breeding.

In the past, researchers were usually only able to modify one gene at a time using this method. In rare cases, it was also possible to modify two, three or, in a single case, seven genes simultaneously. Randall Platt, a professor at the Department of Biosystems at ETH Zurich, and his team have now developed an approach that, as they have shown in experiments, allows 25 sites within the genome of a cell to be altered simultaneously. And that's not all. This number can be further increased to dozens or even hundreds of genes, said Platt. The method has huge potential for biomedical research and biotechnology. "Thanks to this new tool, we and other scientists can now implement what we used to dream of,'' explained Platt.

Targeted and massive reprogramming of cells

"Our method enables us for the first time to modify entire gene networks in one step," said Platt. It is also possible to program cells in a complex way and on a massive scale. This enables the activity of certain genes to be increased and that of other genes to be reduced. It is also possible to precisely control the time of such a change in activity.

This is interesting in basic research, for example, in order to find out why different cell types behave differently or to investigate complex genetic diseases. The same applies to cell replacement therapy, in which damaged cells are replaced with healthy ones. Researchers can use this method to transform stem cells into differentiated cells such as nerve cells or insulin-producing beta cells, or vice versa, to produce stem cells from differentiated skin cells.

Cas enzyme with dual function

The CRISPR/Cas method requires the enzyme Cas and a small RNA molecule. Its sequence of RNA building blocks serves as an "address label" in order to direct the enzyme precisely to its intended site of action on the chromosomes. The ETH scientists have created a plasmid on which the construction information of the Cas enzyme is located. Also, the construction information of a large number of RNA address molecules are located can be arranged in a row, and located in this plasmid. In their experiments, the researchers introduced this plasmid into human cells and thus showed that several genes can be modified and regulated at the same time.

The new technology did not use the enzyme Cas9, which was usually used in previous CRISPR /Cas methods, but used instead of the related enzyme Cas12a. The latter can modify genes, and also cut individual "address labels" from the long "RNA address list". Cas12a also uses shorter RNA address molecules than Cas9. "And the shorter these addressing sequences are, the more of them can be packed onto a plasmid," said Professor Platt.

Campa CC, Weisbach NR, Santinha AJ, Incarnato D, Platt RJ: Multiplexed genome engineering by Cas12a and CRISPR arrays encoded on single transcripts. Nature Methods, August 12, 2019, doi: 10,1038/s41592-019-0508-6 []

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