In the balancing act between detail and overall concept

Synapses determine our perception of how we move and what we remember. They are the contact points through which our nerve cells communicate. Little is known about how synapses are formed and how our brains form the complex molecular machinery by which neurons transmit certain information. This is exactly what Professor Dr Volker Haucke, Director at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Professor of Molecular Pharmacology at the Freie Universität Berlin (FU Berlin), and his team are investigating. For his "SynapseBuild" project, he was awarded one of the coveted ERC Advanced Grants by the European Research Council (ERC) at the end of March. The grant is endowed with a budget of up to €2.5 million. In his interview with Brain City Berlin, the biochemist tells us more about the project, doing research in Berlin as a centre for science, and the "Berlin Spirit".     

Synapses are the billion-fold switching points of the nervous system through which signals are passed from one nerve cell to another. We know a lot about their function today, but almost nothing about how they are formed. The problem in the past was that it was almost impossible to follow these processes live in living systems while simultaneously analysing them at a molecular level. We are pursuing a new approach that includes human nerve cells derived from stem cells and the CRISPR/Cas technology for genome editing. This enables us to follow in real time how synapses form while the nerve cell differentiates. At the same time, we get access to the molecular components of human nerve cells and the genes that control them.

We've already watched synapses being made in lab mice. And we can make synapse proteins light up so that they're visible in developing fruit flies or roundworms, but this is limited in the analysis of the molecules, because there is practically no biochemical access to the material. At FMP, we're using human stem cells to produce excitatory neurotransmitters, i.e. those that send messages, in cell cultures. We can manipulate these stem cells using CRISPR/Cas technology, the so-called "gene scissors". This allows us to introduce glowing proteins into the cells which make certain synapse components visible. And we can genetically modify the stem cells. This enables us to follow in real time as the components of the synapse that forms are transported from the cell body along the axon and assembled there. We can also see which components are involved in this process and how it is controlled.

We primarily want to understand how synapses are formed. We'd also like to answer key questions, such as: Where does the material come from that is needed to form a functional synapse that release neurotransmitters from the nerve cell? How is this material then built into the resulting synapse? Are the same mechanisms active when synapses become stronger or weaker over the long term? What are the key processes in learning and storing memories? How does the nerve cell know when the formation of the synapse is complete? And how is the programme controlled in the formation of the nervous system, in which many different types of synapses cooperate? Answering such questions could be central to a better understanding of neurological disorders. And then there's the topic of regeneration: if nerves get cut or individual synapses perish, for example as a result of neurodegeneration, could we use this new approach to develop new synapses to fix these problems? In other words: understanding synapse formation could open up completely new approaches to combating neurological and neurodegenerative diseases. But that's still very much in the future. We are talking about a period of at least ten years.

The brain is extremely complex and the evolutionary biological origin of the nervous system is extremely interesting. It is a tremendous task to build a synapse without knowing what it's supposed to look like. From a cell biology perspective, this is a fascinating problem that is even more complex on the next level. Not only do different types of nerve cells exist, synapses can also be strengthened or weakened. Nerve cells also have to build many different types of synapses. For the system, this means: it must always adapt in interaction with itself and with the neighbouring cells. For us researchers, it is therefore important to ask the following critical question over and over: What does this result mean for the big picture? And what can I learn from it? These are crucial questions that people tend to forget when working on one detail or another.

Absolutely. The balancing act between the depth of detail and the view of the overarching concept behind it is difficult, but very important. Every scientist certainly has strengths in one direction or another. It is all the more important to have a team that integrates both types of scientists.

We have neuroscientists, cell biologists, molecular biologists, and optical biophysicists. We bring together all of the relevant specialities. This helps a lot because, for example, a physicist will ask different questions than a neurobiologist would.

We will finance four additional scientific positions on our research team and a part-time technical assistant. In addition to the nerve cells derived from human stem cells, we also need other models such as organoids, which are mini-brains from nerve cell bundles, and genetically modified mice to be able to verify findings in vivo and view them in the complex organism.

It is important and satisfying for a scientist to go out and inspire enthusiasm for one's own research. In addition, you are repeatedly faced with questions in teaching that help you to focus on your research work. These are often the simple questions.  In principle, there is no qualitative difference between research at universities and non-university institutions. At external institutions, we may be a little more focused on research and we have funds for large devices that we then provide to universities as infrastructure. At the FMP we have a very close relationship with the colleagues at the universities with whom we work. The working atmosphere is very open and collegial and corresponds entirely to the “Berlin spirit”.

Let me delve deeper into that: when I was appointed professor at FU Berlin in 2003, the city was in a financially difficult situation. As a consequence, the universities often competed against each other. At the FU Berlin, people tended to see themselves as ready for the chopping block and assumed that the university would be merged into the [older] Humboldt-Universität zu Berlin (HU Berlin) in Mitte [formerly East Berlin]. At HU Berlin, there was probably no less mistrust. This was especially true for the university management at that time. From the research point of view, such suspicions were never much of a problem. At that time, many young faculty were being newly appointed to the city's universities. There were no "top dogs" yet as may have been the case at other larger research centres in Germany. On the research level, an extremely fruitful and trusting coexistence has developed, which at some point has also inspired the university management to call a truce. As a result and with the support of many, including the new university directors and Berlin's government, the Berlin University Alliance has emerged. A great idea. Because such a science-driven university network was what the scientists in Berlin have always wanted. I think it's paid off.

The Berlin University Alliance catalyses new initiatives for collaborative research funding. In addition, it bundles resources and thus enables maximum access for all researchers to equipment and expertise across Berlin. The non-university research institutions must also have contact persons who bundle the whole thing. That's why they have come together under the umbrella of BR 50, as a contact for the BUA. We can discuss and solve problems together. As far as I know, we're the only city in Germany to have two such associations.

Every neuroscientist now knows NeuroCure. The cluster of excellence stands for quality and interdisciplinarity. Unlike many other clusters of excellence, NeuroCure has put almost all of its financial resources into recruiting scientists from outside. This has led to NeuroCure becoming a trademark worldwide. As an instrument, NeuroCure has significantly increased the attractiveness of Berlin as a place to conduct research. We use NeuroCure to work with many great colleagues in a great range of fields including clinical. It also helps us attract people. Young researchers in our field are specifically seeking out Berlin.

Above all, the Berlin Spirit I already mentioned. Berlin is now also internationally attractive as a centre for scientific research. It has developed extremely dynamically over the past 15 to 20 years and has made a big leap, both quantitatively and qualitatively. It's fun to work here. But there is still a lot to do: at the moment we are not quite at the same level as Boston, San Francisco or Zurich. But we have to get there and we will.

Berlin is a cosmopolitan city that lets you do what you want. A city that promotes freedom of thought. Berlin has a lot of green space and style. I come from a village where societal control was very important. You couldn't order a cup of coffee for Sunday breakfast without incurring disapproval from others. It's different in Berlin. Like all cities, Berlin also has its problems, of course. For example, it is a bit too spread out. Research campuses such as Berlin-Buch should be better connected via public transport.

Listen to your inner voice! It also includes letting it speak. I really have to give something a chance so that it can grab me. If I just scratch the surface, it will remain difficult. Research as a career often comes with great risks. It can take a long time to get a permanent position and be reasonably convinced that your career is really going to take hold. Only a few doctoral students will ultimately become professors or remain in academic research. Nevertheless, don't just look at the numbers. If you really want something, you can do it. So my advice is: Follow your interests, not fashion and chose the best lab you can think of! (vd0)