At the Frontier of Human Knowledge: The 2017 EMPIRIS Award Goes to the Young Researcher Tobias Wauer
The young academic Tobias Wauer conducts research at the MRC Laboratory of Molecular Biology in Cambridge. He has received the 2017 Award for Research in Brain Diseases of the Credit Suisse umbrella foundation EMPIRIS for his work on the molecular causes of Parkinson's disease. In our interview he explains his fascination for research.
Mr. Wauer, your PhD project focused on Parkinson's disease. Why did you decide to conduct research on this topic?
It has been known for quite some time that mutations in the protein Parkin are associated with Parkinson's disease. In the cell, Parkin marks damaged mitochondria – the powerhouses of the cell – with ubiquitin chains and this triggers their breakdown by the cell's waste disposal systems. If this process does not work properly anymore one can expect the neurons to undergo cell death, which probably leads to Parkinson's disease. Parkin transfers Ubiquitin, which is another protein. It can be added as long chains to proteins, and thus regulate cellular processes. However, the molecular details of this process and what goes wrong in the case of Parkinson's were not clear. So, initially I was interested in the academic question of how these molecular chains work. Starting from basic research and my interest in protein mechanisms I then ended up investigating Parkinson's. For me, it was clear that a better understanding of Parkin would not only lead to new insights into the protein system but would also answer questions about the disease.
How did you investigate Parkin and what insights did you gain?
We used a whole variety of different methods. If you want to find out what goes wrong in a particular disease, you first need to understand the molecular blueprint of the involved biological molecule. To do this we used a technique called X-ray crystallography. Firstly, we had to produce crystals of the protein, which were then bombarded with a focused X-ray beam at a particle accelerator. Based on the resulting diffraction pattern, we were able to discover what the molecular structure of Parkin looks like. This gave us insights which had previously been impossible to achieve, for example into how patient mutations trigger the disease. The structure also showed that Parkin does not take on an active form in the cell but is in fact trapped in a closed inactive conformation. However, one can expect that there must be an activator for Parkin in the cell, which allows Parkin to fulfill its neuroprotective duties by marking damaged mitochondria with ubiquitin chains and cause their subsequent degradation.
Research is a very rewarding kind of work.
How is Parkin activated then?
We used mass spectrometry to investigate the interaction between Parkin and PINK1, another protein which is relevant in Parkinson's. We and other groups found that as soon as mitochondria are damaged, PINK1 transfers a phosphate group to a specific position in ubiquitin. As a result of this chemical modification ubiquitin's function is influenced and it is now present in a so-called phosphorylated state. Phosphorylated ubiquitin then has the ability to activate Parkin. In the second part of the PhD, we focused on how the interaction between phosphorylated ubiquitin and Parkin occurs and how this molecular switch works to activate Parkin.
What were the biggest challenges in your research into Parkin?
When I originally told my PhD supervisor that I wanted to focus on Parkin, he had some reservations. The fact that Parkin is a key part in the puzzle to understand Parkinson's has been known for some time, and many research groups were already working in this area. At the beginning, it wasn't easy to gain a foothold in the field, and a lot of extra hours were necessary to catch up. This area of research was uncharted territory for me in terms of both the subject and the methods used. However, I had fantastic colleagues and a very supportive supervisor. Without their help and support, the project would have probably never succeeded in such a short period of time.
The human aspect of science is a wonderful thing.
What kind of opportunities do these findings open up?
Millions of people are affected by Parkinson's disease and so far there has been no prospect for a cure. Especially in Western countries, an age-associated disease can become a major issue due to the demographic change. New findings relating to genetic factors, and molecular processes provide a better understanding of the disease and make it possible to develop new therapeutic and diagnostic approaches. For example, our findings may enable the development of new drugs, which activate Parkin in a physiological manner and thus boost its neuroprotective effect to prevent Parkinson's.
What fascinates you about scientific research?
I've always been excited by the scientific endeavor. It is fascinating how microscopically small things are the foundation of everything that happens in our macroscopic world. Research is a very rewarding kind of work: you constantly discover things that no one has ever seen before. In particular I'm interested in disease mechanisms, since results in this area are not only exciting on their own, but might one day also prove beneficial for patients. However, researching complex issues of this kind – at the very frontier of human knowledge – can only be achieved when people from a range of different backgrounds work together. This human aspect of science is a wonderful thing.