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Rainer Wittig: oxygen biology opens up new paths

“When one talks about light in the field of biology, the crucial role played by oxygen often comes into it.” When Rainer Wittig says that he sees himself as an oxygen researcher, he is not just simplifying his job title because essentially, that is exactly what he is. A lot of the molecular biologist’s work revolves around oxygen, in particular its highly reactive forms. Wittig has been head of the biology department at the Ulm-based ILM since autumn 2008.

Dr. Rainer Wittig bases his work around oxygen. © Pytlik

The 41-year-old researcher puts his his long-standing expertise in cancer research to very good use in the further development of photodynamic therapy and basic research-oriented work on tissue repair. Although he has only been working at the ILM for one and a half years, Wittig is already involved in numerous important interdisciplinary projects at the institute. At the same time, the researcher has enough free time to pursue creative activities.

After completing his training as an industrial manager, Wittig went on to study and work in the field of biology. He did his biology studies in Münster before he continued his studies in the south of Germany. He spent his advanced study period in Freiburg and did his degree thesis on gene expression analyses at the German Cancer Research Centre (DKFZ) in 1998. He continued at the DKFZ where he developed and used gene array technology to investigate the chemoresistance of melanomas. He was awarded his PhD in 2002 and continued his research into the genes related to the chemoresistance of melanomas for another four years. He carried out functional studies to differentiate between causal and follower genes using a test system developed in cooperation with his colleagues from the DKFZ that enables genes for certain tumour types to be switched on and off using an antibiotic.

Wittig left the DKFZ after nine years of research. According to the German university regulations at the time, Wittig would normally have been obliged to leave the research institution after three years, but he was able to stay on for longer. In 2006, Wittig moved to a Darmstadt-based diagnostics company to supervise tumour diagnostics projects, develop an ELISA test for tumour markers and be part of a large cooperative project on fluorescence (video endoscopy) diagnostics. It was here that Wittig came indirectly, and unknowingly, into close contact with his future employer, the Ulm-based ILM, where a happy coincidence led to him accepting a position in October 2008. To his delight, this new job brought him back into contact with active research.

An animal experiment replacement model helps Wittig feel at home

Cross-section through tumour cells on CAM. The images show how blood vessels (red) grow into the tumour. © ILM

An animal experiment replacement model, which has been used for many years at the ILM, went a long way to helping Wittig quickly feel at home in his new environment: The chorioallantoic membrane (CAM), an extraembryonic organ of a fertilised chicken egg, enables the researchers to carry out experiments relating to vascularisation and the tumours' ability to metastasise using genetically modified tumour cells. These experiments enable potentially tumour-relevant genes to be validated in vivo.

Although the model can only be used for a specific period of time, it is nevertheless extremely suited for use as a "bridging technology" between high-throughput research to the detailed and therapy-oriented functional analysis of individual cancer-related genes. Applying this method enables the genetic and cellular investigations in Heidelberg to continue uninterrupted and also gives Wittig the opportunity to continue working in cooperation with his former colleagues.

Goal: a “light glue” for tissue

Many of Wittig’s projects are (still) based on basic research, but it is envisaged that they will form the basis for the expansion of the ILM’s portfolio. Although this investment in the future is not without its risks, it promises innovative approaches. Wittig plans to work with his former colleagues from Heidelberg to develop a photochemical tissue apparatus. The goal of this project is to “glue” tissue together with light, rather than using a needle and thread. Further projects involve the development of a three-dimensional cell culture method which will combine fluorescence imaging with biochemical aspects.

Cells before and after treatment with ROS superoxide dichloroacetate. The photo on the right shows the more intensive staining of mitochondria (red). The cell nuclei are stained blue. © Wittig/ILM

The idea of improving photodynamic therapy (PDT), i.e. tumour therapy using light in combination with photosensitisers, is also still a very new idea. It is based on the observation that many tumour cells have an altered metabolism; the tumour cells avoid mitochondrial respiration and activate glycolysis which provides most of the building blocks required for cell proliferation (this is known as the "Warburg effect").

In contrast to healthy cells, it appears that tumour cells develop a particular sensitivity to oxygen radicals (reactive oxygen species, ROS): on the one hand, they need ROS for growth; on the other hand, too many ROS cause them to undergo apoptosis. Therefore, the systems used by the tumour cells to detoxify ROS are particularly active. It also makes sense that the tumour cells shut down the mitochondria because they are involved in the cell's apoptosis programme. Several studies have shown that the experimental reactivation of mitochondrial respiration in tumour cells leads to the generation of ROS and to the death of the cells.

ROS are also produced during PDT, which is induced by the energy transmission of excited photosensitisers. The combination of PDT with the pharmacological modulation of the ROS quantities could potentially make PDT more effective. Wittig assumes that a modulated metabolism and the signalling processes associated with this is a good starting point for tumour cells to become susceptible to ROS-mediated cell death, which can be triggered by PDT. The first experiments focusing on the modelling of these mechanisms on the genetic and biochemical level have commenced. If Wittig's approach proves to be successful, he plans to test the method in vivo using a CAM model. This approach is fairly attractive as it attempts to optimise the local and targeted attack on tumour cells by PDT by combining it with a systemic sensibilisation of the cells that has as few side effects as possible.

Wittig’s biological expertise is also called for in a project relating to photochemical tissue repair. The project is based on the idea of replacing needle and thread in surgery at the same time as avoiding the disadvantages of photothermal tissue fusion, a method that is relatively invasive: Wittig is hoping to be able to trigger certain chemical reactions (covalent bindings) using light in order to make the cells adhere to each other, without the need for heat and foreign substances. However, a lot of basic research is still required before intestines, to take just one example, are able to grow together again neatly and effectively.

3D cell cultures designed to reflect the physiological reality

Tumour cell spheroids. The photo is a view of the cells that shows that the size of these three-dimensional models can be governed by the initial number of cells used. © Wittig/ILM

Wittig's plans to establish three-dimensional cell cultures could well gain in importance in the medium and long term. The pharmaceutical industry has already shown an interest in the cultures. Rainer Wittig has already defined standard growth conditions for a number of tumour cell lines. The advantage of so-called tumour cell spheroid cultures is the realistic physiology of the united cell structure that can only be achieved to a limited degree in two-dimensional tumour cell cultures in petri dishes. However, this difference has a considerable effect on the efficiency of a range of active substances. It is therefore expected that standardised three-dimensional cellular reporter systems will have a huge part to play in the pharmaceutical sector in the future.

Working in cooperation with Herbert Schneckenburger, a physicist from Aalen who is associated with the ILM, Wittig is focusing on three-dimensional imaging: The researchers hope to be able to incorporate a fluorescing sensor into the tumour cells in order to obtain information about the location of cells within the cell spheroids. This is of huge interest in oncological terms since, following the application of drugs, reactivities are expected to be different in central tumour regions from the reactivities in tumour areas that are well-supplied with blood (oxygen and nutrients).

How much light can cells tolerate?

As is common practice at the ILM, Wittig with his life science expertise is also involved in projects that are closer to application. He has fitted very quickly into the ILM’s profile. This becomes all too clear when Wittig mentions another cooperative project with his colleagues from Aalen that is a perfect mix of a basic and practically relevant research: how much light can cells tolerate? This question is of particular importance when using innovative high-resolution microscopic methods which expose living cells to high light intensities.

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