What’s your research about?
’Our daily thoughts and actions depend on the flow of information through neural circuits, mediated by the specialized cell-cell contacts called synapses that relay signals between contacting neurons. Impaired synaptic function underlies several neurodevelopmental and psychiatric disorders e.g. autism and schizophrenia. Synapse pathology and loss are also hallmark features of common neurodegenerative diseases. The formation and maturation of synaptic connections depend on interactions between synaptic cell adhesion proteins that span the synaptic cleft to form a physical bridge between contacting neurons. A well-known example is that of pre-synaptic neurexins and its interaction with diverse post-synaptic partners, which shape the properties of a synapse by defining its molecular architecture. Mutations in the gene encoding neurexin-1 have also repeatedly been found to confer genetic risk for autism and schizophrenia.
’We are interested in the protein-protein and protein-glycan interactions, such as that of neurexins and their ligands, sculpt synaptic connections. The aim is to expand our understanding of the fundamental building blocks of our brains, and thereby also better understand the diseases that result from their dysfunction.
What questions are your research based on?
’Fundamentally we work to understand how our brains normally functions by determining the role of its molecular building blocks. More specifically we focus on how specific proteins contribute to the formation and function of synapses. We believe that this approach is essential to genetic defects in some of the genes encoding these proteins cause human disease.
What is your vision?
Our work fundamentally serves to identify means to treat disorders by correcting their underlying cause rather than simply addressing their symptoms. We believe that this will be possible by targeting underlying genetic imbalances and by relying on the brain’s capacity for life-long plasticity, also for severe diseases that affect the brain.
Why did you start with research?
’I was always interested to understand diseases from a molecular perspective. Still today, many diseases are not well understood and many largely defined by their symptoms rather than their underlying cause. To me it made more sense to direct therapies at the underlying cause, which require research, also to better understand the normal physiology of our cells and organs. Research is also fun and I enjoy my work – in particular the freedom to independently come up with new ideas, test them and discover new things. Science is exiting and sometimes rewarding, but sometimes also challenging.
What is your scientific background?
’I became fascinated by molecular biology when reading about genetics and the early elegant experiments that pioneered the field. I went for medical studies. It was not an obvious choice at the time, but one that I have not regretted as it is a broad education that provides many opportunities later on. I knew I wanted to do research and rotated in several labs. Eventually, I got into contact with Nils Göran Larsson at the Karolinska Institute, who provided an interesting opportunity. Together with Lars Olson, a neuroscientist working on Parkinson’s disease, I pursued a project to develop and study genetically modified mice to study mitochondrial dysfunctions in mouse models. It turned out to be a good mix between experimental genetics, basic biochemistry and neuroscience.
'After my PhD, I shifted more to the neuroscience field and went for a post-doc in Tom Südhof’s lab at the Stanford University. I entered his lab during the same year that he was awarded first the Lasker Prize and later the Nobel Prize so it was a fun time to be there. My initial post-doc project turned out to be a dead end so instead I got to explore numerous alternative ideas and techniques; nothing substantive came out of it but I learnt a lot from these “failures”. At this time, I became interested in the fundamental question of how synapses are formed, and through proteomics we identified a couple of proteins that may play a role in this process and that we are still studying. I also picked up other techniques, for example a protocol developed in the Südhof lab to reprogram human stem cells into neurons that we now use both to study basic mechanisms and patient lines. This method becomes particularly useful combined with CRISPR/Cas9, which emerged at the same time.
'Today I work part time clinically in Clinical Chemistry at the Sahlgrenska University Hospital, performing biochemical and genetic diagnostics of disorders caused by deleterious genetic variants affecting cellular metabolism and physiology. Although all of these disorders are rare, they are relatively common as a group as there are thousands of unique conditions. Occasionally we discover diseases that have never previously been described. We try to utilize our network and research methodologies to bridge the clinical diagnostics and basic science For example, we study patient-derived cells to strengthen the diagnosis and to investigate mechanisms of the disease.
Who do you collaborate with?
’We collaborate a lot! We basically have to as neuroscience is so broad and to publish well today you need a breadth of techniques that only the biggest labs can accommodate. We collaborate on a project-to-project basis with several groups here in Gothenburg to get access to expertise and techniques for protein biochemistry, mouse behavior and electrophysiology. We also have close collaborations with groups in Germany. The Core Facilities here at the University of Gothenburg are also very useful.
’On the clinical side, we collaborate within a network of pediatrician neurologists and clinical geneticists at the Sahlgrenska University Hospital, which gives us the opportunity to work translationally with patient-derived cells and models.
’I am also part of Wallenberg Centre for Molecular and Translational Medicine (WCMTM), which provides a good network and facilitates opportunities to collaborate.
May, 2022
Interview by Niclas Lundh
More information on Fredriks Sterky's research page at gu.se.
Sidansvarig: webb@biomedicine.gu.se
