Thesis defense Maarten Geurts: CRISPR engineering in organoids for gene repair and disease modelling

With so-called CRISPR techniques, researchers can make a change in a specific location in the DNA. For example, CRISPR makes it possible to repair a mutation An error in the DNA. Mutations can, among other things, arise if the DNA is copied incorrectly or through external influences. For example, tumor cells often contain mutations that are beneficial for their growth. in the DNA. The variants of CRISPR that are now mainly used need to make a cut around the mutation to repair it. This cut causes damage to the DNA, which makes the techniques currently unsafe for use in humans.

Mini organs

During his PhD, Maarten Geurts studied a new generation of CRISPR tools that can directly modify DNA without damaging it. These tools are therefore promising for clinical application. Geurts focused on the efficacy and safety of the new generation CRISPR techniques, such as base and prime editing, in organoids Miniature organs that can be cultured in the laboratory. Organoids mimic the shape and function of  an actual organ. Researchers use the structures to, for example, study the effects of medication on diseased organs.. These miniature organs resemble real human organs in structure and function and are therefore a good model for research into the effects of DNA editing.

Better treatments

Among other things, Geurts and his colleagues discovered that the new CRISPR tools can successfully repair the mutations that cause cystic fibrosis without causing damage to the DNA. With his thesis, he shows that the same can be achieved with the new generation of techniques compared to the commonly used variants, but with fewer undesirable side effects as a result. The techniques therefore hold great promise for clinical application and could contribute to the development of better treatments for thousands of human diseases, including cystic fibrosis and cancer.

Organoid group

Geurts completed his PhD in the Organoid group (formerly the Clevers group) where – as the name suggests – a lot of research is carried out into, and with, organoids. “Being part of this group means I always had at least 10 fellow PhD students around me, who always knew exactly what I was going through,” he says. He could vent if his experiments failed, but they also provided distraction. “I forgot all disappointments when we went on crazy adventures together in the lab.”

Biological findings

A specific highlight during his PhD has to do with this research into cystic fibrosis. “The feeling I got when I first realized that the mutations that cause cystic fibrosis had been repaired in my organoids was amazing,” said Geurts. That discovery paved the way for all chapters in his thesis. Furthermore, he especially enjoyed all the pilot experiments he has done – the search for new biological discoveries. “But I have found that to get such an exciting initial discovery published, it takes hundreds of experiments that are a lot less exciting,” he says.

Think critically

Geurts would like to advise researchers at the start of their trajectory to take a step back from time to time during their PhD and to consider whether all the projects they have started are worth it. “Looking back, I may have spent too much time on projects that didn’t yield that much, while other projects that I never followed through with might have been more fruitful. Try to take some time during the busy days in the lab to think critically about your projects and goals,” he concludes.