SyNergy Cluster of Excellence: fighting diseases of the brain

“The cluster runs extremely smoothly and the team is exceptionally well coordinated,” says Professor Martin Dichgans, Director of the Institute for Stroke and Dementia Research (ISD) at LMU University Hospital. Research has already chalked up major successes. Dichgans is a future spokesperson for SyNergy (Munich Cluster for Systems Neurology). Another new spokesperson is Professor Magdalena Götz, Head of the Division of Physiological Genomics at LMU’s Biomedical Center and Head of the Institute of Stem Cell Research at Helmholtz Munich. Both have been involved in SyNergy from day one and, together with the third spokesperson, Professor Thomas Misgeld from the Institute of Neuronal Cell Biology at the Technical University of Munich (TUM) and the German Center for Neurodegenerative Diseases (DZNE) are eager to drive cross-disciplinary collaboration forward.

Making pioneering breakthroughs together

The scientific breakthroughs they are aiming for can only be achieved in collaboration. More than twenty years ago, for example, Magdalena Götz invented a method for reprogramming glial cells, the brain’s support cells, that allows new neurons to be generated. “Together with colleagues in the Cluster of Excellence, we want to push this approach all the way to clinical application,” she explains - in other words, repairing neural tissue destroyed by stroke or dementia.

Götz knows that without the research alliance, this would not be possible. Such pioneering achievements can be realized only when outstanding minds from different disciplines come together. “SyNergy gives neurological research a massive boost,” the developmental biologist adds. Thanks to the cluster, she explains, neuroscientists can work with researchers and clinicians who have their own specific knowledge of brain injuries, strokes, and Alzheimer’s disease.

This is the basic idea behind SyNergy: bringing together researchers from different fields related to brain disease, finding interfaces and synergies, and thus opening up completely new possibilities. Martin Dichgans has also benefited from this concept in the past: “Diseases of small blood vessels in the brain cause stroke, but also dementia, often in combination with Alzheimer’s disease.” His group searches for genes that predispose to neurovascular diseases and stroke, and then uncovers the underlying mechanisms in experimental studies. “From there, we feed therapeutic approaches back into the clinic.” For example, he discovered changes in a gene active in endothelial cells – the cells that line blood vessels. “We identified the molecular signaling pathways involved and new options for pharmacological intervention.”

Based on this discovery, a colleague in the cluster developed innovative 3D models of the blood-brain barrier with human induced pluripotent stem cells, in which he recapitulated and further advanced the results that Dichgans and his team obtained in mice. “He also tested our therapeutic approach, so we now believe we can move toward a clinical trial.”

New approaches thanks to SyNergy Tandem Projects and SyNergy teams

According to Götz and Dichgans, the research alliance offers a unique opportunity to collaborate with experts with very different areas of specialization, who bring with them fresh impetus and scientific concepts at the interface between the various diseases. To facilitate this form of innovation and exchange, the SyNergy members engage in Tandem Projects – a key feature of the cluster since the beginning. This involves bringing together two researchers from different areas, who leave their comfort zone and jointly attempt something new. Over the years, this has generated many new ideas and research approaches have been generated at SyNergy in this way.

One Tandem Project, for example, seeks to find out how damaged neurons lose their functionality, how newly formed neurons become functional, and how neural networks work. The participating LMU research group carries out neurobiological research for the project, and then a TUM team from the field of computer-aided and theoretical neuroscience creates computer models of the corresponding networks with the help of artificial intelligence.

In another project, researchers from the Institute for Stroke and Dementia Research at LMU University Hospital are collaborating with stem cell biology researchers from TUM on an approach for transplanting human neuro-organoids – that is to say, “mini-brains” cultivated in the laboratory. In this way, recipient brains that have been damaged by a stroke can be made functional again. Initial successes have already been achieved in a mouse model: The transplants grow into the brain and make connections, and there are signs that the mice exhibit functional improvements after a stroke as a result. As the next step, the LMU-TUM Tandem Project plans to find out why this is so.

Viral toolbox and AI data analysis

Technology Hubs are another SyNergy model to have proven their worth: Wherever new research fields open up, the Hubs ensure that the required technological approaches are established. “At SyNergy, we don’t just use this technology, but are always further developing it,” says Martin Dichgans. In the new funding phase, SyNergy plans to invest in new imaging techniques – highly innovative microscopy that can be combined with molecular techniques such as single-cell sequencing.

It also wants to expand its work on so-called gene shuttles – viral vectors that researchers can use to introduce certain regulatory proteins, known as transcription factors, into cells. “The world of viruses is a great toolbox,” explains Magdalena Götz, “that expands constantly with identification of vectors with specific properties we can exploit.” Moreover, this viral vector toolbox is extremely versatile and can be employed in highly targeted ways.

Another focus in the future will be on managing the data that arises during research in the cluster. Take the cutting-edge “omics” approaches, for instance, which now record not only the entire genome, but also the translation of the genes and proteomics – and do so at the single-cell level. As such, the cluster members have to deal with the complex data of thousands, or tens of thousands, of cells. To ensure that these huge data volumes are handled in a responsible, efficient, and sensible manner, SyNergy has recruited data managers, but also increased its ranks for exploiting the newest computational technologies its third phase. “We’ve got Professor Fabian Theis from Helmholtz Munich on board, a world-leading expert in AI and the modeling of gene expression networks and single-cell analysis,” says Götz.

Investing in the next generation

A major milestone that is of great importance for SyNergy is bringing the exciting results of previous research to therapeutic practice. Specific clinical studies had already been initiated during the second funding phase, and now the research alliance wants to build on this success. The journey from basic research to the development of clinical treatments is not a sprint, however, and can take as long as 15 years. This is another reason for investing in the next generation of researchers: “We must keep moving and develop our network of students, postdocs and principle investigator and welcome younger, up-and-coming researchers into our community and nurturing their careers,” emphasizes Martin Dichgans. “The SyNergy family benefits greatly from diversity and excellence.”

The cluster is like a magnet, attracting excellent students from all over the world via the Graduate School of Neuroscience. “We need this new blood and must retain it to continue the long-term projects we’ve undertaken,” says Dichgans. Thanks to the excellent research work it has carried out, SyNergy has long established itself in the international scientific landscape. This has extremely positive effects on the researchers in the team: “Doctoral students and postdocs want to stay, further develop their skills in the cluster, and become a group leader at SyNergy.”

What are the new cluster spokespersons most looking forward to over the coming years? “To collaborations! New interactions and exciting research findings, giving rise to new ideas.”