With the new method, the cells in individual organs of animals can be genetically modified in a mosaic-like manner (symbol image generated with Midjourney). Credit: ETH Zurich
Key points:
- Using CRISPR-Cas, researchers have developed a way to simultaneously make several dozen gene changes in the cells of a single animal.
- This method eliminates the need to perform many animal experiments—one for each desired gene modification.
- In tests, the method successfully found three genes responsible for a rare genetic disorder in humans.
Researchers have now developed a method that will 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 analyzed. This enables researchers to study the ramifications of many different gene changes in a single experiment, rather than performing an animal experiment for each desired gene modification.
In a study published in Nature, researchers from ETH Zurich and the University of Geneva describe successfully applying the approach in living animals for the first time.
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.
The researchers focused on 29 genes of a chromosomal region linked 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.
In each individual mouse brain cell, they modified one of these 29 genes and then analyzed the RNA profiles of those brain cells. The scientists were able to show that three of these genes are largely responsible for the dysfunction of brain cells. In addition, they found patterns in the mouse cells that are reminiscent of schizophrenia and autism spectrum disorders. Among the three genes, one was already known, but the other two had not previously been the focus of much scientific attention.
“If we know which genes in a disease have abnormal activity, we can try to develop drugs that compensate for that abnormality,” said António Santinha, a doctoral student and lead author of the study.
Santinha says the new approach would also be suitable for studying other genetic disorders. ETH Zurich has applied for a patent on the technology, and the researchers now want to use it as part of a spin-off they are establishing.