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Andreas Diefenbach: A molecular approach to disease mechanisms

Prof. Dr. Andreas Diefenbach began his academic career as a philosophy student. Nowadays, the immunologist at the Freiburg University Medical Centre investigates how cells of the innate immune system fight off cancer and infections. He believes that, in contrast to all other subjects, immunology is an area that very much focuses on concepts. Diefenbach’s research frequently gives rise to situations needing new paradigms.

Prof. Dr. Andreas Diefenbach, immunologist at the University of Freiburg © private

The innate immune system is found in almost all groups of organisms. In mammals, the innate immune system involves, for example, natural killer cells that carry specific molecular probes on their surface. These probes recognise body cells that have become infected by viruses and bacteria or that have transformed into cancer cells. In contrast to the adaptive immune system with its T- and B-lymphocytes, the innate immune system does not have to be trained, it is fully functioning the moment a baby is born. In early 2000, Prof. Dr. Andreas Diefenbach, who is now head of the Laboratory of Innate Immune Recognition at the Institute of Medical Microbiology and Hygiene at the Freiburg University Medical Centre, was exploring the way natural killer cells recognise their targets. Up to that point, very little was known about these molecular relationships. "During my period as a postdoc at the University of Berkeley, I discovered and characterised surface molecules which reveal cancer cells to immune cells," said the researcher. From 2000 onwards, Diefenbach has focused his research on the molecular mechanisms associated with the mammalian innate immune system.

Putting things into a wider context

Diefenbach did not start his academic career in the field of medical research. “Besides my interest in biology, I have also always been hugely interested in the fine arts,” said Diefenbach who was born in Aachen in 1965. Despite having chosen intensive biology classes at school, Diefenbach decided to study philosophy at the University of Erlangen. After six semesters he switched to medicine. His interest in the molecular approaches of uncovering disease mechanisms brought him to immunology. “Immunology is a science that deals with general principles and concepts, and which has always put things into their wider context,” said Diefenbach. “The subject is thus closer to philosophical thinking than it appears.” In the late 1980s and early 1990s, a medical student still had the time to prepare a good scientific doctoral thesis, which suited Diefenbach perfectly.

Colon section: the red spots represent cells that carry a gene typical of natural killer cells. © Prof. Dr. Andreas Diefenbach

His PhD thesis brought him into contact with natural killer cells and the innate immune system. It dealt with the role of these cells in fending off the human parasite Leishmania. After completing his doctoral thesis, Diefenbach spent a few months as an assistant at the University of Erlangen, before he moved to Berkeley in 1999. He received a grant from the DFG to finance his postdoctoral studies. The research group at Berkley already knew about some natural killer cell receptor proteins. These receptor proteins are the probes with which the killer cells are able to recognise cancer cells. Diefenbach chose to focus on the NKG2D receptor and found the counterparts of these receptors on the cancer cells. It is now known that these molecules constitute a protein family, and homologous molecules are also known in humans. This provided evidence as to how immunological recognition works. "But the next question we asked related to why cancer molecules carry such molecules on their surface," said Diefenbach. "What happens during the transformation process from healthy cells to tumour cells, the point at which the cells begin to carry these proteins on their surface?"

Part of a known signalling cascade?

This is not just a purely academic question. If the scientists are able to gain an understanding of the molecular mechanisms in the interior of cancer cells, they might be able to find ways to enhance this process in all cancer cells. Cancer cells that do not carry such alarm signals would then also be caught and destroyed by the natural killer cells. After his postdoctoral period in Berkeley, Diefenbach accepted a position as assistant professor at New York University where he led his own research group. He initiated a cooperation with the Institute of Medical Microbiology and Hygiene in Freiburg and moved to Freiburg in 2006. “What happens in tumour cells is still largely unknown,” said Diefenbach. “But we now have a rough idea as to how one of the mechanisms is able to work.” Diefenbach believes that a signalling cascade that normally reacts to cellular DNA damage and arrests cell division so that the DNA can be repaired, plays a role in this process. Diefenbach and his team have since found out that the traitorous molecules on the surface of tumour cells are generated in a branch of this cascade and they are currently working on clarifying the details and mechanisms that might also play a role.

Another issue being dealt with by Diefenbach’s team is: Is there a connection between the innate and the adaptive immune system? Many experiments show that T-cells of the adaptive immune system also possess NKG2D receptors and that an interaction between the natural killer cells and the so-called dendritic cells of the adaptive immune system is required to enable the killer cells to fully exert their defence function. It also seems that natural killer cells share similarities with the lymphocytes of the adaptive immune system. And furthermore, it appears that the natural killer cells adopt an intermediary position between these two systems. “We even believe that the adaptive immune system might have developed from natural killer cells,” said Diefenbach.

A completely new field is opening up

A colon section with its finger-like villi: blue: DAPI (all cell nuclei), green: Reg3 (protein induced by IL-22 and which guarantees epithelial homeostasis), red: lysozyme C (all so-called Paneth cells). The photo shows that Reg3-positive Paneth cells “protect” the stem cell niche (between the Paneth cells). © Prof. Dr. Andreas Diefenbach

However, there is another project of far greater interest to Diefenbach's team. Some time ago, the researchers found a type of innate immune system cell in the intestines of mice that was previously not known to have been involved in the development of lymph nodes. These so-called lymph tissue-inductor cells also possess NKG2D receptors and release a signalling substance that directly affects the epithelial cells. This substance, which is known as interleukin-22, contributes to making the epithelial cells able to fend off intruders found in the intestines, such as aggressive bacteria. This finding opens up a completely new field of research and raises many questions. "What is the role of these cells in terms of inflammatory intestinal diseases?" asks Diefenbach. "What happens on the molecular level? Do these cells also protect the stem cells in the intestines, which our results have shown are surrounded by the epithelial cells like guards?"

There is much to do in terms of new concepts and models. A lot remains to be discovered. Diefenbach is happy with his move to Freiburg where he has found excellent conditions for pursuing new paths of enquiry through cooperations with the Max Planck Institute of Immunobiology and the Freiburg University Medical Centre. And this environment also helps him to put his research into a wider context. 

Further information:
Prof. Dr. med. Andreas Diefenbach
Institute of Medical Microbiology and Hygiene
University of Freiburg
Tel.: +49 (0)761/203-6522
Fax: +49 (0)761/203-6651
E-mail : andreas.diefenbach(at)uniklinik-freiburg.de


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