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Timo is a DPhil student in Madalena Tarsounas' lab. Here, Timo talks about his research on the breast cancer genes BRCA1 and BRCA2 and the importance of this work. Having just submitted his thesis, Timo also offers some personal advice about the process and tells us about his life outside of work.

 

Tell us a little about your research

 The research in our lab focuses on the breast cancer genes BRCA1 and BRCA2 which gained global media attention after Hollywood actress Angelina Jolie’s diagnosis with an inherited mutation in BRCA1.

Inherited mutations in either of the two genes predispose to breast, ovarian, pancreatic and, in men, to prostate cancer. Whereas any British woman faces a chance of approximately 12.5% to develop breast cancer, chances for BRCA1 and BRCA2 mutation carriers are above a staggering 60% and 50%, respectively. Facing this probability and the loss of her mother to cancer, Angelina Jolie decided to have her breast surgically removed in order to prevent breast cancer formation.

Our research follows two lines of investigations. Firstly, we are interested in finding more effective therapeutic strategies against cancers associated with a BRCA mutation. This will also avoid the detrimental side effects of widely used chemotherapeutics. We take advantage of the fact, that we can distinguish between healthy tissue (normal BRCA) and cancerous tissue (mutated BRCA). This allows us to develop treatments which only kill cancer cells leaving healthy tissue unharmed. Scientists gave this approach a metaphorical name – targeted therapy.

Secondly, we investigate what BRCA does on a cellular level, why it is important and why it is linked to tumourigenesis. Fully understanding the features of these genes will provide us with the necessary know-how to fight this cancer and maybe eventually even prevent it from developing in the first place.

https://www.oncology.ox.ac.uk/research/research-group/genome-stability-and-tumourigenesis

In my research project, I focus on BRCA2 and particularly what happens to a human cell when its BRCA2 is not functional anymore. First of all, it is important to know that one key cellular function of BRCA2 is to repair DNA. If BRCA2 is mutated, damaged DNA is not repaired properly anymore.

During my project, I found that the damaged DNA triggers an innate immune response. The same mechanism is activated when a virus infects a human cell. For human cells to sense the invasion of a virus and to react appropriately, the viral DNA is detected by sensors within the cell. This, in turn, inflicts an immune response signalling infection by a pathogen. Subsequently, the immune system eliminates the infected cell ideally before the virus can spread to other cells. Similarly, I found that, after turning off BRCA2, accumulation of damaged DNA in the cell promotes an innate immune response. Furthermore, treating these cells pharmacologically with the right dose of a drug of a class called PARP inhibitors further potentiates this immune response selectively in BRCA2 mutated tumour cells.

https://www.nature.com/articles/s41467-019-11048-5

 Have there been any challenges?

Science is unpredictable and, unfortunately, the project I was working on during my 1st year turned out to be a dead-end. Nonetheless, it was an extremely valuable lesson at what point to end a project and on which basis. After that, I felt even more prepared to start the project described above in my 2nd year which turned out very successful. We published the results in a peer-reviewed journal. In the end, finding something novel is always challenging but this is exactly what makes the job as a scientist exciting and enjoyable. No day is like the other and there is always something new to discover (possibly no one else has seen or experienced before).

 What are the implications of your work? 

Cancer immunotherapy is a promising strategy to treat cancers. The idea behind it is to harness the power of the patient’s own immune system to fight off cancerous cells. However, cancers evolve mechanisms to evade these attempts by the immune system. In order to exploit the immune system therapeutically, its anti-cancer potential must be potentiated. The findings of my research project allow the assumption that the cell-intrinsic immune response in tumours with a BRCA2 mutation can be selectively potentiated by treatment with PARP inhibitors.

 You’ve just submitted your thesis; do you have any tips for those who are about to start writing?

First of all, it might be important to know that I genuinely enjoyed writing my thesis and also to reflect on my DPhil project. It is the perfect time for in depth reading on your research field and to integrate all ideas (including your own). I know others might find writing a thesis painful. Maybe my best advice is therefore to make it as enjoyable as possible. Maybe a change of location helps. Try the beautiful libraries scattered all over Oxford or even another city or country, wherever you feel more comfortable writing (the only thing you need is WIFI). Furthermore, writing a thesis is quite time consuming. So, I would recommend to start early and, at least 3 months before submission, to stop running experiments and to fully focus on the thesis.

 What are your plans now you’ve completed your DPhil?

 Well, I haven’t completed my DPhil yet. Submitting a thesis is the first step, the viva is the next one. Also, I signed up for an innovation and enterprise skills initiative run by the Saïd Business School. Here, I will learn how innovative findings we come across in the lab can be translated into a good or service. This will provide me with the right business acumen before I start applying for a role in the pharmaceutical industry. Nevertheless, before the next career step, I am planning a few months break to take a multi-country trip.

 Outside of work, what do you do to relax?

 As a scientist you must be able to juggle a variety of tasks simultaneously (on a daily basis). These range from reading (and understanding) the latest discoveries in scientific journals, to brainstorming about your own project, to testing your hypotheses in the lab and to presenting your ideas and results either to your team colleagues at small weekly meetings or to peers at large international conferences.

As a perfect balance, I find it very enjoyable to start the day with an early work out in the gym. After a run on the treadmill and lifting weights, I am ready to tackle all these challenges. Furthermore, I always enjoy learning something new. Compared to the scientific routine in the lab, a trip to the museum or a fascinating book requires different parts of your mind. It also attracts your attention away from your project for some time and, the next day, you might look at a problem you have found puzzling from a completely different point of view.