ERC Advanced Grants for top researchers at the Charité

Funding for projects in human genetics and immunology

Berlin, 26.04.2022

Researchers at Charité – Universitätsmedizin Berlin have convinced the European Commission’s selection committee: How does the innate immune system react to greatly increased nutritional requirements during pregnancy and breastfeeding? How does the memory of natural killer cells work? And: Which mechanisms of gene regulation led to the development of wings in a mammal in the course of evolution? These are the questions they will be investigating over the next five years. ERC Advanced Grants are among the most highly endowed European awards. Each project has around 2.5 million euros at its disposal for implementation.

The aim is to pursue groundbreaking ideas that are, however, fraught with uncertainty. With its Advanced Grants, the European Research Council (ERC) therefore supports outstanding, established scientists in venturing into as yet unknown and at the same time promising areas of their field. The sole selection criterion is the scientific excellence of the applicants and the projects.

Prof. Dr. Andreas Diefenbach, Director of the Institute for Microbiology and Infection Immunology at the Charité, is concerned with the development of the immune system. His work focuses on the question of which mechanisms the innate immune system uses to recognise infectious agents or even cancer cells. He intensively studied so-called natural killer cells (NK cells) and was able to show that these and other lymphocytes of the innate immune system, called Innate Lymphoid Cells (ILC), not only take on central tasks in the defence against infection, but also important functions in non-immunological processes such as metabolism. One focus of his work is the role of the innate immune system in environmental adaptation processes and the influence of microbiome, radiation or nutrition on these processes.

ERC Advanced Grant ILCADAPT: How cells of the innate immune system react to metabolic changes in tissues

Successful, demand-driven adaptation to a continuously changing environment is a prerequisite for all healthy life. However, the molecular basis of these processes is only understood in fragments. For example, the absorption of food components in the intestine is a central physiological process that influences all aspects of the organism and is subject to complex regulation. Misregulation, on the other hand, leads to deficiency syndromes or metabolic diseases such as obesity and diabetes. Prof. Diefenbach and his team at the Charité and the Leibniz Institute German Rheumatism Research Center Berlin (DRFZ) have already been able to show that ILC, lymphocytes of the innate immune system, play an important regulatory role in the absorption of nutrients by the epithelial cells of the intestine – cells that line the inside of the intestine. The ILCs act as sensors of changing nutrient requirements and respond to changes in food input. They specifically release messenger substances that change the function of the intestinal epithelium in order to adjust the absorption of nutrients. The ERC project ILCADAPT will analyse the role of ILC in an exceptional situation, the greatly increased demand for nutrients during pregnancy and lactation. Both physiological states are associated with greatly increased metabolic demand. The aim is to understand the molecular networks through which lymphocytes of the innate immune system regulate the utilisation of nutrients by controlling programmes of epithelial cells and hormone-producing cells of the epithelium. The long-term perspective of the investigations is to identify fundamental regulatory mechanisms and make them accessible for therapies in metabolic diseases.

Prof. Dr Stefan Mundlos, Director of the Institute of Medical Genetics and Human Genetics at Charité and Research Group Leader at the Max Planck Institute for Molecular Genetics (MPIMG), investigates the causes of genetic diseases and researches how information is stored and passed on in the genome. He is also concerned with genetically caused malformations of the skeleton and rare bone diseases. In particular, Prof. Mundlos focuses on the question of how the regulation of gene activity controls human development and how, in detail, this can lead to diseases and malformations. To this end, the human geneticist uses new methods of genome engineering and questions the influence of non-coding parts of the genome on gene regulation during embryonic development. Another focus is the comparative genomics of evolutionary adaptation processes.

ERC Advanced Grant GenRenov (Genetic Engineering of Regulatory Evolution): How the bat learned to fly – a prime example of evolutionary adaptation

How does the external form of an organism come about? And how is this process controlled by non-coding elements of the genetic material? Prof. Mundlos has been asking these questions for many years. It is known that the regulation of genes plays a key role in shaping phenotypes, the external appearance of an organism. The exact influences of regulatory sequences, on the other hand, those areas of the genetic material that are not themselves read, are still unknown. Regulatory sequences make up a large part of the non-coding genetic material. They do not contain building instructions for proteins. Instead, they control gene expression, i.e. whether and when a gene is read and how much protein is produced as a result. It is important to understand how enhancers, promoters and other regulatory components work together to control and fine-tune gene expression. Enhancer sequences can be located far from their target gene. The promoter region, on the other hand, is always in close proximity to the actual gene. In addition, there are epigenetic regulators – factors that chemically modify the “packaging” of the genetic material, providing it with a read barrier, but do not change the DNA sequence itself. Prof. Mundlos and his team have already succeeded in showing how DNA changes in non-coding areas can lead to diseases. Thus, deviations in the DNA sequence can cause changes in the three-dimensional structure of the genome. If, for example, a DNA thread in the cell nucleus no longer fits into the correct loops, this can result in faulty gene regulation.

One of the greatest challenges at present is to uncover the sequence code that controls gene expression and ultimately the phenotype. In the ERC project GenRevo, Prof. Mundlos has set out to study the genomics of an extreme example of evolutionary adaptation, the wing of bats, as a model system. The aim is to find out and functionally analyse how in detail the regulatory sequence determines the appearance of the wings, i.e. the front limbs of the flying mammal. Together with a team at the Charité and the Max Planck Institute for Molecular Genetics, the human geneticist plans to identify the non-coding genetic regulatory elements that control this extraordinary evolutionary adaptation. The mouse, in which the anterior and posterior extremities have relatively the same structure, serves as a comparison. Since these control elements are relatively large, the researchers want to artificially produce and test the genome segments themselves using synthetic biology technologies. Subsequent analyses should reveal which genetic switches are required for the formation of wings instead of paws, and according to which laws they work together. In addition to clarifying fundamental questions, the newly developed technology should decisively facilitate the functional analysis of mammalian genomes in the future. It could also enable studies of non-coding DNA segments that influence the development of the body or the emergence of genetic diseases.