Microbiologist John van der Oost from Wageningen University & Research has been awarded an ERC Proof of Concept grant to advance research on a CRISPR-based cancer treatment. The €150,000 grant will support work by van der Oost and researcher Christian Südfeld over the next eighteen months as they develop a method to selectively kill cancer cells while minimizing harm to healthy tissue.
The research focuses on differences in DNA methylation between healthy and tumor cells. Tumor cells often lack certain chemical markers, called methyl groups, that are present in healthy cells. These markers help regulate gene activity. The researchers aim to use this distinction by employing a specialized form of the CRISPR-Cas9 enzyme, known as ThermoCas9, which can differentiate between DNA with and without methyl groups.
"Because some tumour cells have far fewer methyl groups on their DNA than healthy cells, they form an ideal target for our ThermoCas9," said John van der Oost, Emeritus Professor of Microbiology.
Initial laboratory experiments using human cells have shown that the CRISPR system damages DNA in cancer cells but not in healthy ones. The team’s next step is to determine whether increasing this damage will be enough to destroy tumor cells. "Sometimes a small amount of DNA damage leads to a scar that makes the genetic code unreadable," Van der Oost explained. "If this happens in genes that are essential for the cell's survival, it may lead to cell death. And the more of these essential genes we hit, the greater the chance that the tumour cell will die."
The project will begin with liver cancer due to its suitability for experimental genetic therapies. In recent years, methods using nanoparticles have been developed to deliver proteins and DNA directly into liver cells. "The liver plays a key role in waste processing in our body," Van der Oost stated. "Nanoparticles in the bloodstream are naturally transported there for breakdown." He added: "Before the liver actually breaks down the nanoparticles, CRISPR has time to do its job."
Clinical application remains distant because distinguishing between cancerous and non-cancerous cells based solely on methylation is complex; tumors are genetically diverse and some healthy tissues might also lack these chemical tags at certain sites. As Van der Oost noted: "But existing treatments such as chemotherapy and radiotherapy also damage healthy cells."
ThermoCas9’s effectiveness at body temperature is another challenge since it naturally operates best at higher temperatures (around 60°C). Using data from its recently determined 3D structure alongside artificial intelligence tools and laboratory evolution techniques, researchers plan to adapt ThermoCas9 for optimal performance at normal human body temperature.
Postdoctoral researcher Christian Südfeld will continue efforts to optimize the system over the coming year and a half. Plans include collaboration with clinical experts such as those at the Netherlands Cancer Institute.
The ERC Proof of Concept grant is designed by the European Research Council as additional funding for previous ERC grant recipients who wish to translate fundamental research into practical applications; thirteen Dutch researchers received PoC grants this year.
