How do you find a solution for a disease so rare that sometimes only one patient a year is diagnosed? During his PhD, Imre Schene addressed this question for hereditary metabolic diseases in children. He successfully defended his thesis on March 19, 2026.
Metabolic diseases are a large group of innate disorders caused by an error in the genetic material. Because of this error, a protein can no longer properly convert one substance into another. The symptoms that arise depend on the specific defect.
“There are hundreds of different conditions, and some are extremely rare,” Imre explains. “For some diseases we may see only one or two patients per year. As a result, there is often no commercial incentive to develop drugs, and only about 30% of these rare diseases have an effective treatment.”
During his PhD, Imre therefore worked on new ways to study these diseases and potentially treat them. He conducted this research under the supervision of Sabine Fuchs, Edward Nieuwenhuis, and Peter van Hasselt.
Because each metabolic disease is so unique, Imre focused on developing personalized therapy approaches. In this strategy, researchers take cells directly from patients and use them to recreate the disease in the laboratory. “We can then perform many different experiments on these cells, such as testing potential medicines,” Imre explains.
However, the type of cells needed differs for each metabolic disease. Some disorders affect very basal biological processes and are therefore visible in almost all cells in the body. “In those cases, we can sometimes simply take a skin biopsy,” Imre points out. “But other processes can only be studied in very specific cell types, such as liver cells, which are difficult to obtain from patient-derived material.”
Methods to generate liver-like cells from patient material already existed, but they were not reliable enough. “The cells we could grow did not perform all the important metabolic processes,” Imre notes. “That meant we could not always use them as reliable models to study different metabolic diseases.”
Imre therefore worked on two ways to improve these models. “First, we compared many different liver cell models with each other,” he says. “Based on that work, we developed a web application that helps researchers determine which model best matches the biological function they want to study.”
In addition, together with colleagues, he improved the liver cell model already used by his research group. “We developed a new culture medium that enables the cells to carry out many more metabolic functions.” With this new approach, the cells can now perform processes such as synthesizing sugars and breaking down fatty acids. This is essential for research into large groups of metabolic disorders.
A major advantage of the method is that it also works with liver biopsies that were previously collected from patients. “We already had around 300 patient samples stored,” Imre says. “It would have been a shame to be unable to use them, but fortunately we now can.”
The final part of Imre’s research focused on repairing the DNA errors that cause metabolic diseases. For this, he used a relatively new technique known as prime editing. Compared with other gene-editing techniques, prime editing cuts only one of the two strands of DNA, allowing more precise repair.
Prime editing relies on so-called prime editing guide RNAs (pegRNAs): molecules that act as navigators and guide the editing protein to the correct location in the DNA. “We created a method to rapidly test pegRNAs,” Imre explains. “As a result, we can now identify within a week which navigator molecules work well, and which do not.”
Using this approach, his research group was not only able to repair errors in DNA. The group was also among the first to show that this technique can restore the function of cells from patients with metabolic diseases. “And this repair method also appears to be safe, without unwanted changes elsewhere in the DNA,” Imre adds proudly
Looking ahead, Imre sees several remaining challenges. “The first question is how we deliver this tool precisely to the right cells,” he says. “For liver diseases, that is relatively straightforward, but for cells in organs such as the heart or brain it is much more difficult.” In addition, researchers still need to optimize the technique for each of the many different mutations that cause metabolic diseases.
Time is also an important factor, Imre emphasizes. “Some children already have a significant developmental delay by the time they receive a diagnosis. If DNA repair only starts then, part of the damage may already be irreversible.”
Looking back on his PhD journey, Imre says he is particularly proud of how he turned obstacles into new opportunities. “The liver models we used turned out to be much less capable than we had expected. But we always remained open to different ways of tackling the problem.”
That openness eventually led the group to quickly adapt prime editing. “We read the article in Nature and immediately thought: ‘this is exactly what we need.’ Within three months we already had our first results.”
According to Imre, research is most rewarding when things do not work immediately. “That process of failing, adjusting, and trying again is how you move closer to a new biological understanding or a treatment that might one day help a patient.”
Imre is currently training as a pediatrician. He emphasizes how much he learned from his supervisor, Sabine Fuchs. “In the future I want, like her, to keep one foot in the clinic and the other in research. That way you stay close to the latest developments and can translate these techniques to patients more quickly.”
