Genetically modifying individual cells in animals

One proven method for tracking down the genetic causes of diseases is to knock out a single gene in animals and study the consequences this has for the organism. The problem is that for many diseases, the pathology is determined by multiple genes. This makes it extremely difficult for scientists to determine the extent to which any one of the genes is involved in the disease. To do this, they would have to perform many animal experiments – one for each desired gene modification.

Researchers led by Randall Platt, Professor of Biological Engineering at the Department of Biosystems Science and Engineering at ETH Zurich in Basel, have now developed a method that will greatly simplify and speed up research with laboratory animals: using the CRISPR-​Cas gene scissors, they simultaneously make several dozen gene changes in the cells of a single animal, much like a mosaic. While no more than one gene is altered in each cell, the various cells within an organ are altered in different ways. Individual cells can then be precisely analysed. This enables researchers to study the ramifications of many different gene changes in a single experiment.

First time in adult animals

For the first time, the ETH Zurich researchers have now successfully applied this approach in living animals – specifically, in adult mice – as they report in the current issue of Nature. Other scientists had previously developed a similar approach for cells in culture or animal embryos.

To “inform” the mice’s cells as to which genes the CRISPR-​Cas gene scissors should destroy, the researchers used the adeno-​associated virus (AAV), a delivery strategy that can target any organ. They prepared the viruses so that each virus particle carried the information to destroy a particular gene, then infected the mice with a mixture of viruses carrying different instructions for gene destruction. In this way, they were able to switch off different genes in the cells of one organ. For this study, they chose the brain.

New pathogenic genes discovered

Using this method, the researchers from ETH Zurich, together with colleagues from the University of Geneva, obtained new clues to a rare genetic disorder in humans, known as 22q11.2 deletion syndrome. Patients affected by the disease show many different symptoms, typically diagnosed with other conditions such as schizophrenia and autism spectrum disorder. Before now, it was known that a chromosomal region containing 106 genes is responsible for this disease. It was also known that the disease was associated with multiple genes, however, it was not known which of the genes played which part in the disease.

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