Unleashing splicing to understand biology and eventually tackle ‘untreatable’ diseases
Cells use editing tools to skip or rearrange information stored in DNA. Thanks to a 10-million-euro ERC Synergy Grant co-financed by ERC and UKRI, researchers have launched a new project to study how this machinery can be controlled with molecular precision, which has the potential to revolutionize biomedical research and eventually treat human disease.
Imagine sitting down to watch a film for a second time, but the story takes a surprising turn, for example a new scene or a particular voiceover. You might realize that rather than the theatrical version you saw in the first place, this is a Director’s Cut. The movie producers have created not just one, but two versions of the same film, each with its own unique scenes and storyline.
The same thing is happening – at the molecular scale – inside every human cell. Cells are like eccentric filmmakers, using a process known as alternative splicing as their creative tool. Just how movie producers use an editing toolbar to rewind, speed up or cut a scene entirely, cells use their editing tools to swap, skip or include specific DNA segments in the messenger RNA. This ability allows cells to alter gene expression or create slightly different versions of a protein with unique functions.
Humans have roughly 20 thousand genes within our genomes, but thanks to alternative splicing, cells can make more than 100 thousand. This expanded catalogue of proteins helps cells both adapt to changing environments and carry out more complex functions. It is thought that almost 95 % of human genes undergo alternative splicing of some sort.
Knowledge of alternative splicing can be used to reveal new therapeutic targets and treat diseases that were previously considered incurable, for example, spinal muscular atrophy as one of the leading causes of infant mortality. Despite the emerging success of splicing-based therapies, the mechanistic understanding of how small molecule drugs can modulate alternative splicing remains very limited. Small molecule drugs have distinct advantages as therapeutics as they can be administered orally and pass-through cell membranes to reach the cell nucleus, where alternative splicing takes place. To accelerate the discovery of therapeutic targets for other diseases previously considered untreatable, researchers require new experimental tools and methods to study the underlying biological mechanisms as well as the splice code involved.
This is the objective of UNLEASH, a new collaborative research project that started on June 1st, 2023. Supported by a 10.2 million euro Synergy Grant jointly funded by the European Research Council (ERC) and UK Research and Innovation (UKRI), the UNLEASH project aims to identify and develop new small molecules that can eventually function as drugs and control which types of alternative splicing events take place in cells. The project is expected to last for a period of six years.
UNLEASH will combine the complementary expertise in the research groups of Prof Michael Sattler (Helmholtz Munich), Prof David Gray and Prof Angus Lamond (University of Dundee), and Prof Juan Valcárcel (Center for Genomic Regulation, Barcelona), employing an interdisciplinary approach that combines chemical, structural, cellular, and systems biology methods, along with deep learning and AI-based approaches.
In the long term, the researchers will identify, develop and improve small molecules that can selectively alter alternative splicing events, characterizing compounds bound to splice site complexes, and testing mechanistic models of splice site selection. The resulting data will be used to train neural networks to predict changes in alternative splicing patterns and the effects of small molecule modulators. “With our project we hope to unleash the unique potential of small molecules as splicing modulators to eventually enable the development of novel drugs for treating diseases with unmet medical need” explains Michael Sattler, senior researcher at Helmholtz Munich.
Helmholtz Munich will primarily contribute its outstanding expertise in integrative structural biology to investigate the structure and dynamics of protein-RNA complexes and structure-based drug development, particularly through the use of NMR spectroscopy in combination with X-ray structural analysis and cryo-electron microscopy. The project aligns with Helmholtz Munich's vision of enabling innovative approaches for the development of new drugs by exploring fundamental biological processes.
About the Scientist
Prof Dr Michael Sattler, Department Head at the Molecular Targets & Therapeutics Center, Director at the Institute of Structural Biology at Helmholtz Munich, Professor for Biomolecular NMR-Spectroscopy at the Technical University Munich (TUM) and Director at the Bavarian NMR Center (www.bnmrz.org)
About the ERC Synergy Grant
The very prestigious Synergy Grants support small groups of two to four Principal Investigators to jointly address ambitious research problems that could not be addressed by the individual principal investigators and their teams working alone. The projects enable substantial advances at the frontiers of knowledge, stemming, for example, from the cross-fertilisation of scientific fields, from new productive lines of enquiry, or new methods and techniques, including unconventional approaches and investigations at the interface between established disciplines. The transformative research funded by Synergy Grants has the potential of becoming a benchmark on a global scale.