Mosaic genetically modified laboratory animals

Mice with differently genetically modified body cells can be used to research the causes of certain diseases. Illustration © Midjourney, ETH Zurich

Researchers have developed a process that can create individual laboratory animals with several experimental gene changes. This means that fewer animal sacrifices are necessary in medical research and new research opportunities are opened up. The team has already been able to use the method to track down the causes of a hereditary disease. Such insights could ultimately lead to the development of treatments for diseases with genetic causes, the scientists say.

Lifestyle, infections and environmental pollution – in addition to these factors, predispositions also play an important role in many diseases. In basic medical research, scientists therefore investigate the question of which genes are involved in certain clinical pictures. For this purpose, relevant genetic traits are specifically eliminated in laboratory animals using genetic methods. How this affects these so-called knockout mutants can provide crucial information about the connections. In many diseases, however, several genes contribute to the clinical picture. This is why many animal experiments are necessary - one line of mice and co is used to examine only one gene function.

The newly developed process by researchers led by António Santinha from the Swiss Federal Institute of Technology in Zurich is now addressing this problem. The method they are now presenting allows body cells with different genetic changes to be created in a single animal at the same time. The effects can then be examined in more detail using molecular genetic methods. This means that the consequences of many different gene changes can be researched at once in a single experiment. The current results build on previous developments of the concept in cell cultures and organoids. Now, for the first time, the team has managed to successfully use the procedure on living animals – mice.

Viruses deliver genetic scissors

The system is based on the use of the Crispr/Cas genetic scissors, which can be programmed to cut at very specific genetic locations. In order to bring this tool into the body cells of the laboratory animals, the researchers use special viruses as suppliers: They prepare the so-called adeno-associated virus (AA virus) so that different units each carry the information to destroy a single target gene. A mixture of these viruses is then injected into the test animals. The system can use special forms of the AA virus that target specific cells or organs in the body, the scientists explain.

For their test study, they chose nerve cells from the brain. The focus was on investigating the basics of a hereditary disease called 22q11 microdeletion syndrome. Those affected often develop schizophrenia or autism spectrum disorders, among other things. It was previously known that several genes contribute to the disease, which are located in a specific chromosomal region, which, however, includes numerous genetic genes. It has therefore remained unclear which genes play what role in the disease.

Successful test on mice

When investigating with their new system, the researchers focused on 29 genes in this chromosomal region, which, like in humans, are also active in the mouse brain. As they report, they were able to successfully switch off all of these genes in different cells of the brain in individual animals. By examining them, the team was then able to gain new insights: It was shown that three of the genetic genes lead to functional disorders in the brain cells as a result of the manipulation. The team discovered molecular patterns that have already been identified in schizophrenia and autism spectrum disorders.

According to the researchers, the method now has considerable potential for basic medical research: the procedure could greatly simplify and accelerate studies to investigate the genetic causes of diseases - and the extent of animal suffering will also be significantly reduced. The scientists emphasize that alternative approaches without animal testing have disadvantages: “Cells behave differently in culture than in living organisms. “That’s why it’s a big advantage to be able to carry out analyzes on adult animals,” explains Santinha.

The results of such research can be very valuable medically: “In many hereditary diseases, several genes play a role, not just one. “If we know which genes have abnormal activity in a disease, we can try to develop drugs that compensate for this abnormality,” says Santinha.

Source: Swiss Federal Institute of Technology Zurich, specialist article: Nature, doi: 10.1038/s41586-023-06570-y

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