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Ellen Hubin

Influence of genetic variability and external regulating factors on amyloid-beta peptide aggregation

Promotion date: October 24.

Promotor: Prof. dr. Vinod Subramaniam (UT), Prof. dr. ir. Nico van Nuland (VUB, Belgium)

Assistant Promotor: Dr. Kerensa Broersen

Despite extensive testing of numerous drug compounds in clinical trials, there is still no means of halting or reverting progression of Alzheimer’s disease (AD). Current treatment is limited to the alleviation of disease symptoms.

One of the leading hypothesis states that amyloid-beta (Aβ) aggregation initiates a cascade of molecular events culminating in widespread neurodegeneration. Several drug discovery strategies have therefore been directed at interfering with Aβ production, aggregation, clearance or toxicity.

In this thesis the influence of genetic variability and external regulating factors on Aβ dynamics - in particular on the aggregation and structural properties of Aβ - is investigated in vitro. Here, a biophysical approach is used, complemented with cell culture studies.

Single and potential multi-target AD treatment strategies are discussed. It is suggested that combining network medicine with general ecosystem management principles is a new and holistic approach to better understand AD mechanisms and potentially design more successful therapies.

What were the main challenges in your PhD project?

Part of my research concerned looking at genetic variability leading to the presence of different Aβ peptide lengths and mutants. We found that an Aβ mutation, leading to AD at early age, alters the process of aggregation and the structural and inflammatory properties of Aβ. This finding may contribute to the design of more effective medication strategies.

The other part of my research was more unorthodox. We provide evidence that the dynamics and complex multifactorial nature of AD show many similarities with the basic principles of an ecosystem. By studying and interviewing ecologist experts, I tried to approach AD from a novel angle, by combining network medicine with ecosystem management principles. This resulted in an opinionated chapter in my thesis. This approach may be fruitful for the development of novel multi-target strategies to treat AD by combining medicine treatment with nutritional advice, lifestyle guidelines, and physical and mental therapies. The end goal however remains intact: finding a therapy that simultaneously targets various disease factors and mechanisms that play crucial roles in AD, such as Aβ aggregation, inflammation reactions in the brain, and oxidation stress reactions.

As my PhD was joint between two universities, I travelled a lot between the University of Twente and the Free University of Brussels. I stayed in Twente for about six months, working on various parts of my research. I believe it allowed me to develop as an independent researcher more quickly, and be flexible and adapt to different research labs and working policies.

What highlights can you recall, happening during your PhD thesis project?

The biophysical part of my research led to significant results, such as finding that different Aβ peptide lengths and mutations, due to genetic factors, profoundly affect the aggregative, structural and toxic properties of the peptide. These results were found and published in the first half of my PhD period.

I also enjoyed working on the more philosophical part of this work, trying to fill the gap between cell biologists and biophysics experts on the one hand, and ecological experts on the other hand. It was a challenge to bring both worlds into contact by clarifying, explaining and translating their mutual concepts into a new meaningful context.

In what way did you develop personally, as a researcher and scientist, during the PhD work?

In the startup stages of the PhD, I was in need of guidance and information on every level of the work. Step-by-step I grew in becoming an independent scientist finding my own way through the research processes. I learned to come up with new ideas, see opportunities, and start working from these with self-confidence. The first half of my PhD I experienced as very valuable years, learning skills and extending my knowledge on various topics. One also learns to cope with failure (experiments almost never go exactly as you planned) and persist.

Communicating one’s ideas is an important part of the job, I found out. You have to convince your colleagues, and even sometimes your supervisors, that your plan of research is relevant and promising. If you meet interesting people at conferences and want to engage in new collaborations, you have to be able to explain your research clearly and concisely.

Did you publish some good papers?

Articles were published in Cellular and Molecular Life Sciences and in FEBS Letters: Federation of European Biochemical Societies. Publications have been submitted to six other magazines and are under review at this very moment.

What are your future plans?

After a period of three months as a post-doc, I am planning to continue my career in the biotech and pharmaceutical industry. I hope to find a position in which research is a major part of the job. Hopefully in the future, I might be able to develop my managerial and communicational skills even further, contributing to policy processes and strategies of industrial partners in biophysics and biotechnology. But that is a long time from now, I suppose.

What, in your opinion, is important for Mesa+ to stay successful in future?

A cordial atmosphere is present at Mesa+, which I valued greatly. I was encouraged by the open atmosphere to go and ask for advice and support with colleagues. This open-mindedness and hospitality is a typical Dutch state of mind, I guess, working much in favor of Mesa+ as a successful institution.

Sometimes it pays off to take a step back in history, rethink the goals one aims for, and talk to people with different expertise. Then new connections with other research areas are open and new opportunities arise. It worked in my PhD and might lead to new ideas for the nanotechnological research areas within Mesa+ as well.