Science in person
Puck Knipscheer is an Oncode Investigator at the Hubrecht Institute. Her group studies the molecular details of DNA repair routes. DNA repair acts as a double-edged sword. On the one hand, cancer may develop if DNA damage is not properly repaired. On the other hand, DNA damage may be exploited in therapies to specifically kill cancer cells.
Oncode Investigator - the Hubrecht Institute
Scrutinizing the molecular details of DNA repair
2020 was special for more than one reason. How did you experience this historic year?
“Obviously, 2020 will not exactly win the award for ‘best year ever’ due to the corona pandemic. It has been a very tough year for many people. However, it has not all been doom and gloom for me. My research group actually had an excellent year from a scientific point of view. We were finally able to reap the benefits of many years of hard work. For example, we published a Nature paper, in which we revealed the molecular pathways involved in the repair of alcohol-derived DNA crosslinks. Among other things, this is definitely something we want to further pursue in the future.”
Finding the answer to one question usually results in more questions, and finding answers to those requires new funding. You took some major steps there as well, right?
“Yes, I am proud that I received an ERC Consolidator Grant in 2020. This will enable me to expand my research group with four researchers for the next five years. The grant proposal has three main components. Firstly, we want to further investigate a number of known DNA repair mechanisms. Secondly, we want to continue our work on the repair of DNA damage caused by alcohol and other endogenous sources. Thirdly, we want to study DNA repair in the chromatin context. Chromatin is a complex of DNA and associated proteins. It ensures that DNA molecules are condensed into compact structures in the nucleus of the cell, preventing the long DNA strands from becoming tangled. Chromatin also plays an important role in repairing DNA damage.”
“In 2020, I also teamed up with eleven Dutch scientists to write a ‘Zwaartekracht’ proposal. This diverse group includes scientists from Delft, Leiden, Groningen and Rotterdam. We want to join forces to study replication stress, which is an important source of DNA mutations. The plan is to investigate the effects of replication stress on a biochemical, cellular, and genomic level in healthy and cancer cells. It is a very exciting and challenging project. Of course, these Zwaartekracht grants are very competitive, but it has been very rewarding to exchange thoughts with great scientists from various fields even if we do not get this one. We will collaborate one way or the other.”
“Base funding allows scientists to leave the beaten track. This is a unique way of funding that maximally fosters excellent science in my opinion. I cannot overemphasize the importance of the freedom to try new things.”
So there are actually quite some opportunities. Why is Oncode funding still very important in your research?
“Oncode Institute provides base funding, meaning that Oncode Investigators receive a research budget that they can spend as they deem fit. This creates the freedom to try new things and be creative. Some of these pilot projects lead to promising avenues. The preliminary data can then be used to attract additional funding. In fact, a substantial part of my ERC research proposal was based on data that I collected with base funding from Oncode.”
Can you give an example of such a pilot project?
“For example, our new research line on the chromatin context was a risky step out of our comfort zone. My lab has always focused on the proteins involved in DNA repair. We use the Xenopus egg extract experimental system to understand how these proteins work, supplemented with multiple other techniques. Extending our scope to investigate DNA repair in the chromatin context was not straightforward. We were not sure if we could study this properly in our experimental system. However, we knew that this approach could yield many valuable insights if it worked. We had to conduct many preliminary experiments to demonstrate that it did. Such preliminary studies might only take a month in some cases, but they could just as well take years. Oncode funding has enabled us to bridge this uncertain phase.”
What drives you to dive into the details of such molecular mechanisms every day?
“My drive is to understand DNA repair mechanisms at the biochemical level in the greatest detail. It fascinates me that we still know very little about the exact mechanism behind cancer-causing mutations. Which pathways and substances are involved in causing DNA damage? We think that we know a lot about DNA repair, but some topics only surfaced recently. For example, in the last ten years or so replication stress was revealed as a potential source of DNA mutations. I think there are many things we still don’t know about and it keeps surprising me that we know so little. There still is a world out there waiting to be explored and I am eager to continue exploring it.”
Sometimes it is hard to explain how fundamental insights can have impact for cancer patients. What is your view on this?
“Our research is strongly fundamental, but it has obvious relevance for clinical practice. The molecular processes that guard the integrity of our DNA not only protect us from cancer, they also determine how cancer cells respond to treatments. By studying these mechanisms, we might be able to reveal novel potential drug targets. My research focusses on better understanding these relevant and complex processes. It would be fantastic if this knowledge could someday inspire the development of better treatments for cancer patients.