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Karin Scharffetter-Kochanek: research that gets under the skin

Prof. Karin Scharffetter-Kochanek has recently become a member of the renowned Leopoldina Academy of Sciences. She was delighted with the distinction at the same time as recognising that it does not directly add anything to research. With this, she meant that the truly important things only really happen in the laboratory, on the hospital ward and on the operating table.

The 50-year old researcher’s work is characterised by a competent and integrative approach. Scharffetter-Kochanek has been focusing on human skin for a long time. In her research, the skin has become a model system that serves as the basis for a trans-organ, systemic approach looking at the underlying mechanisms and the complex interactions with other organs.

Research issues arising from clinical work

Prof. Karin Scharffetter-Kochanek © University Hospital Ulm
The dermatologist spends two afternoons a week in the laboratory. She would like to spend more time in the laboratory, but her current position does not give her the necessary scope to do so. Prof. Scharffetter-Kochanek, who was born in Hildesheim, has been the Medical Director of the Department of Dermatology and Allergic Diseases at the University Hospital in Ulm since 2002, a position that offers her an excellent opportunity to do what is most important to her: build a bridge between patients and research and find answers to clinically important questions.

Scharffetter-Kochanek and some of her colleagues at Ulm University and Ulm University Hospital have recently established a new interdisciplinary group of clinical researchers focusing on molecular and cellular ageing. The group is partially funded by the German Research Foundation. The goal of the researchers is to investigate the molecular processes of ageing and their importance in the complex in vivo situation of different organs. In the long term, the researchers hope to develop preventive and therapeutic approaches to enable people to grow old and stay healthy.

Many paths to dermatology

Scharffetter-Kochanek’s academic career did not follow a rigid master plan, but involved the flexible and determined convergence of different experiences. The young medical doctor began her career in the field of pathology at the Max Planck Institute of Biochemistry and the Hospital of Dermatology in Munich before becoming senior physician in Professor Krieg’s Department of Dermatology at Cologne University Hospital in 1996. This position enabled her to continue her research and expand her laboratory. Supported by fellow scientists and doctors, she worked on skin ageing and the effect of UV radiation before moving to Ulm in 2002.

Research with transgenic mice

In 1993, her supervisor, Thomas Krieg, recommended Scharffetter-Kochanek, who had by then become a full-time professor, to spend some time abroad, a move that later turned out to be a very valuable one. Supported by a Heisenberg grant, she rejected a professorship offered by the University of Göttingen and spent two years at the Institute of Genetics at the Baylor College of Medicine in Houston where she was able to do research on conditional transgenic mice, something that was still new at the time. This complex model organism taught her how to find answers to clinical questions related to ineffective wound healing and the cell-cell interactions underlying this disturbance.

What prevents the healing of wounds?

Oxygen radical formation of old fibroblasts (fluorescent detection). © University Hospital Ulm
Scharffetter-Kochanek came to dermatological issues by way of acne, which she wanted to investigate in order to help acne sufferers. However, her interest soon shifted to connective tissue diseases, the basic as well as complex process of wound healing. She wanted to understand the development of wounds in different diseases and the importance of connective tissue in the regeneration of skin. Over time, Scharffetter-Kochanek became more and more interested in the tiniest details and sought to find out more about the underlying mechanisms. What is the role of free oxygen radicals, what leads to DNA damage and which signalling pathways are induced when the DNA is damaged, what are the causes of morbidity and mortality?

Her research in Texas increased her enthusiasm for genetics and formed the basis for future successful projects. In Texas, and later also in Germany, Scharffetter-Kochanek developed polygenic mouse models for autoimmune diseases such as psoriasis, which is now known to be a polygenic disease (i.e. involving several genes).

Discovery of psoriasis genes

Psoriasis is much more than a skin disease; it also increases patients’ cardiovascular risk. The photo shows a vessel lumen constricted by arteriosclerotic alterations. © University Hospital Ulm
Over the last ten years, Scharffetter-Kochanek and several young, talented researchers have focused on three psoriasis genes and succeeded in localising them on a specific chromosome fragment. Working hand in hand with immunogeneticists at the University of Lund in Sweden, Scharffetter-Kochanek hopes to identify these genes in advance of a group of researchers in the USA who are working on the same topic. She also hopes to use the psoriasis mouse model to considerably advance this research by gaining further insights into psoriasis, other autoimmune diseases and the genes involved.

During her research stay in Houston, Karin Scharffetter-Kochanek realised that innovative research is often the result of an unorthodox approach, i.e. having a different way of looking at things. In Houston, a failed experiment gave her some groundbreaking insights because “I did not have the specialist genetic knowledge” that would otherwise have clouded her way of looking at things. The geneticists involved in the experiment were very disappointed that they failed to completely switch off the CD18 molecule (integrin β2 subunit). The knock-out mice still expressed up to 10% of the CD18 molecule.

Luck through apparent failure

Unlike her colleagues, Scharffetter-Kochanek was not disappointed with the ‘failure’, because this specific transgenic mouse showed signs of psoriasis. The researchers later found that fully transgenic mice did not have psoriasis. The researcher then started to look for the genetic causes of psoriasis thus avoiding the need to carry out huge genetic association studies.

Psoriasis also involves macrophages

Together with her young and enthusiastic colleagues, Scharffetter-Kochanek succeeded in showing that beta-2 integrins enabled inflammation cells to move from the vessels to the antigens. They also found that the disease involved T-cells, antigen-presenting cells and especially macrophages. Her research group has been concentrating on the interaction between the different cells of the immune system. Scharffetter-Kochanek is fascinated by the fact that psoriasis is far more than a human skin disease, and that it also considerably increases the risk of cardiovascular diseases. For this reason, she finds interdisciplinary cooperation very important.

What makes inflammation chronic?

Scharffetter-Kochanek is especially interested in unregulated inflammatory reactions. Working with industrial partners, her research group was able to clarify the molecular mechanisms of action of defective wound healing processes (chronic, venous ulcus cruris) and to develop new therapeutic approaches. These wounds do not heal because defective macrophages produce inflammation-stimulating cytokines (TNF alpha) and oxygen radicals (ROS), thereby creating an aggressive microenvironment that favours chronic inflammation.

The role of mesenchymal stem cells in wound healing

Scharffetter-Kochanek also obtained important insights into the molecular mechanisms of skin ageing. She has just been granted funding for a project to gain further insights into skin ageing and hopes to clarify the role of mesenchymal stem cells in wound healing. She further hopes to substantiate her hypothesis that chronic skin ulcers damage the stem cells in skin and impede their regenerative potential. This would then successfully build a bridge between research and clinical application because such findings would explain why isolated stem cells, when injected into open wounds, remain ineffective for as long as the aggressive wound environment does not improve.

Heavily committed to clinical work and her goal to develop new therapies by gaining a better understanding of the biology of tumour cells – in particular for malignant melanomas for which no cure is currently available – Scharffetter-Kochanek supports young colleagues who are interested in the potential of interfering with the signalling cascades to affect black skin cancer.

Intellectual freedom for hospital doctors

She is very concerned that doctors are not “swallowed up” by clinical routine. Any loss of intellectual freedom would prevent young doctors from posing important questions such as the one she raised in the case of the knock-out mouse mentioned above. Maybe her membership in the Leopoldina Academy comes at the right time for her to propagate what Scharffetter-Kochanek regards as a “political goal”. The Academy must be heard; the German Research Minister recently upgraded the Academy to a national institution and advisor to the German government.

wp - 14 Oct. 2008
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