Proteases have long been assumed to be exclusively used for the disposal of cellular waste. However, researchers now know that the protein-cleaving enzymes also fulfil important functions in cellular communication. The biologist Dr. Oliver Schilling from the University of Freiburg has co-developed methods that improve our understanding of the function of proteases in molecular processes. His research group is currently investigating cellular processes that are regulated by these proteolytic enzymes and looking into issues such as the key role they play in tumour development. Schilling, who was awarded a European Research Council (ERC) Starting Grant in August 2011, describes his scientific approach as a hybrid of two completely different approaches.
Many researchers follow predetermined roads by using experiments to test a previously formulated hypothesis. Other researchers are more like seafarers and discoverers who go in search of unknown lands. Methodologists who have the tools to explore with no idea of the outcome often fall into the second category. Dr. Oliver Schilling from the Institute of Molecular Medicine and Cell Research at the University of Freiburg has been focused on method development for a long time. However, he does not see his work in terms of a mere “fishing expedition” explaining that although he is open to accidental discoveries he still uses proteomics methods with a specific goal in mind. “We are able to identify the cellular targets of proteases and their proteolytic products in our laboratory. But, besides this identification, we also always look into the functional importance of the proteolytic events, for example in the context of cell-cell communication in tumour tissue,” said the biologist.
More than 550 human proteases are now known, and their sheer number therefore suggests that these enzymes must have an important function. The function could be, for example, in the interaction of cancer cells with their environment, i.e. the stroma which consists of fibroblasts, scavenger cells of the immune system and blood vessel-forming cells. Hundreds of signalling molecules are exchanged between the tumour cell and its environment in order to keep the growth and division rate of the tumour under control. “A large number of cellular proteases are secreted to the outside, both by tumour cells and stromal cells,” said Schilling. “What is the function of secreted proteases?” It is now assumed that these proteases control signalling cascades either by modifying signalling molecules by way of cleaving off appendages or by silencing overreactive signalling molecules by way of degradation. However, little is yet known about the specific targets of the individual proteases and the resulting products. In order to be able to control the signalling processes of cancer cells, it is important to gain an in-depth understanding of protease function.
Schilling was born in Osnabrück in 1975, grew up in Bremen, and went on to study biology in Braunschweig and Münster between 1994 and 2000. He was introduced to the methods that are now the core competence of his laboratory when he attended a practical course in Manchester to broaden his scientific and cultural experience. Prior to his stay in England, Schilling spent a year as an Erasmus exchange student in Tours (France) where he completed his biochemistry studies – in French. He did his degree thesis on the identification of the characteristic ends of proteolytically cleaved proteins in the laboratory of Prof. Dr. Walter Stöcker at the University of Münster. “I was given a lot of freedom, and was able to try out many things,” recalls Schilling.
Schilling did his doctorate in the Hamburg-based laboratory of the European Molecular Biology Laboratory (EMBL) on the German Synchrotron Research Centre (DESY) campus. He was part of a small team of biologists and physicists studying metallo-beta-lactamase-like proteins using the proteomics methods he had been using in his previous projects.“In contrast to my previous projects, this particular project not only involved the identification and the biophysical and structural characterisation of the proteins. We also selected a particular member of this protein family and focused on its specific function,” said the biologist. The researchers were able to show that the metallo-beta-lactamase-like protein was a phosphodiesterase. Closely related phosphodiesterases play a key role in the maturation of tRNA molecules. After finishing his doctorate, Schilling met his future boss, Prof. Dr. Chris Overall from Canada, at a conference in Tyrol in 2004 where the two scientists discovered that they had a common interest, namely proteases.
Schilling spent his postdoctoral period in Overall’s laboratory between 2005 and 2008, during which time he further developed methods that enabled him to investigate large quantities of different proteins and products resulting from proteolytic processes. One of these methods involved clarifying the structure of the proteolytic cleavage sites of proteins while he used other methods to investigate the biochemical specificity of different protease types (i.e. solving the question as to which amino acid sequences are recognised by the respective proteases).
Schilling’s research in Overall’s laboratory led to several important publications in journals of the renowned Nature Publishing Group and also to methodological know-how that is now used by researchers around the world and which he took with him when he moved to Freiburg in 2008. Whilst in Canada, Schilling met his future wife, a medical doctor with whom he likes to discuss the clinical implications of his research. These discussions are highly important to him as he does not want his independent research group, funded with an Emmy Noether research grant since 2009, to be just a service provider to other research groups.
Schilling and his team use many different cell and molecular biology methods. “We have previously worked with other research groups who were focusing more on the manipulation of cells rather than on proteomics,” said Schilling. Proteases are enzymes that are active in biological contexts, breaking down proteins and often changing their functions, and for Schilling it is not enough to investigate their function out of context. Funded by an ERC Starting Grant, Schilling will now work with international teams of researchers and carry out own biological experiments to study the function of proteases in cancer cell signalling in detail. “When I was a postdoc I was very much focused on the development of methods,” said Schilling going on to add, “now I am part of a medical institute and my wife is a doctor, which is a constant reminder that proteomics methods need to have a medical relevance.”
And what does Schilling do in his spare time? “I do not have much spare time,” said Schilling laughing. “I often spend evenings and weekends in the laboratory. You have to really love doing research if you want to come up with results.” Schilling admits that he often gets irritated with all the paperwork involved in being a research group leader, but he finds that the laboratory work and the direct contact with colleagues makes up for it. “Our research benefits from the fertile combination of the different ideas and talents in our team,” said Schilling who makes sure that his team has the same freedom he enjoyed when he did his degree thesis. Research is a question of testing out things, but is always also based on a concrete problem.
Further information:PD Dr. Oliver Schilling Institute of Molecular Medicine and Cell ResearchUniversity of FreiburgTel: +49 (0)761-203 9615 Fax: +49 (0)761-203 9620 E-mail: oliver.schilling(at)mol-med.uni-freiburg.de