The European Research Council (ERC) announced the recipients of the 2021 Starting Grants today. Drs. Alejo Rodríguez-Fraticelli and Cristina Mayor-Ruiz from the BIST centre IRB Barcelona, and Drs. Lars Velten, Eva Novoa, and Renée Beekman from the BIST centre CRG were among the recipients, which included 13 researchers working at institutes in Catalonia.
The ERC Starting Grants will help the scientists build their own teams and conduct pioneering research. In total, 397 group leaders were awarded throughout Europe, 23 of them in Spain, 13 of which are in Catalonia, with five going to researchers at BIST centres. The ERC has awarded 619 million euros in this call, with over 5 million euros going to the BIST centre researchers.
Monovalent degraders: drugs for the destruction of proteins of therapeutic interest
Headed by Dr. Cristina Mayor-Ruiz, a “la Caixa” Foundation – BIST Chemical Biology Programme group leader in the IRB Barcelona Targeted Protein Degradation and Drug Discovery lab, the TrickE3 project will focus on the development and systematic discovery of a novel type of drug, namely “monovalent degraders”. These drugs comprise a single piece but they have a double mechanism of action: they can bind to a protein of therapeutic interest and, in turn, recruit the natural cellular degradation machinery (E3 ligases) to remove it. This technique makes it possible to eliminate proteins that were previously considered inaccessible and thus provides new perspectives for the treatment of a wide range of diseases. Monovalent degraders also have highly desirable physicochemical properties, which will help them reach clinical practice.
Despite the enormous potential of these types of drugs, the few that are available have been discovered by chance, without following a rational strategy. The TrickE3 project has the ambitious goal of changing this paradigm and systematising both the design of and search for these drugs. Although applicable to many diseases, the project will focus on useful degraders for pancreatic cancer.
“We hope that the methods we want to implement help to turn protein degradation into a therapeutic strategy. Pancreatic cancer is one of the cancers with worse prognosis and this is why it is a priority focus for us,” says Dr. Mayor-Ruiz.
Stem cell diversity and its implications in different diseases
Through the MemOriStem project, IRB Barcelona’s Quantitative Stem Cell Dynamics lab, headed by Dr. Alejo Rodríguez-Fraticelli, will address the complexity of stem cell diversity. Specifically, it will attempt to answer two key questions: how does stem cell diversity arise and what implications does this diversity have on inflammatory diseases, cancer, and processes such as ageing?
The MemOriStem project will focus on the study of hematopoiesis, the process that gives rise to the formation of blood cells, including immune system cells, that are associated with many diseases. Previous studies by the researcher point to the establishment of various epigenetic memories that last over time and that determine the characteristics of the stem cells themselves, as well as those of the cells derived from them.
“Understanding how stem cell diversity arises and its consequences will allow us to decipher how we might manipulate this diversity for therapeutic purposes. It will also bring about an important step forward in the field of synthetic cell biology, with implications for both the prevention and treatment of diseases,” says Dr. Rodríguez-Fraticelli.
The role of sperm RNA in passing on paternal hereditary information
Dr. Eva Novoa, Group Leader of the Epitranscriptomics and RNA Dynamics lab at the CRG, will study the role of RNA in sperm in passing paternal hereditary information through diet for example. Dr. Novoa’s group will use nanopore sequencing in conjunction with newly developed methods to reveal how sperm RNA may influence the metabolisms of future generations of mammals.
“For decades, researchers have been fascinated by the inheritance of environmental exposures across generations, but the processes by which this information is transmitted via the germline remain unclear. After years searching for this information in DNA, two seminal works showed that diet-induced paternal phenotypes could be passed to subsequent generations via RNAs”, says Dr. Novoa.
“In this project, we propose to decipher which RNA molecules and RNA modifications are responsible for transmitting this information across generations, how dietary information gets converted into changes in sperm RNA populations, and what is the diversity of RNA populations across individual sperm cells”.
Impact of translocations on tumour formation
Dr. Renée Beekman, Group Leader of the Single Cell Epigenomics and Cancer Development lab at the CRG with double affiliation at CNAG-CRG and IDIBAPS, will study the impact of translocations, a phenomenon where a chromosome breaks and a portion of it reattaches to a different chromosome, on the formation of tumours. Dr. Beekman’s group will study this in Non-Hodgkin lymphoma to identify potential new vulnerabilities in the disease.
“Very little is known about the earliest stages of tumour formation,” says Dr. Beekman. “This project will obtain ground-breaking new insights into this process by developing tumour model systems that allow us to discover new biological mechanisms that contribute to the initiation of the long-term process of cancer formation. In doing so, we will unravel the early molecular processes marking the onset of a healthy cell becoming a tumor.”
New models of gene regulation in the human blood-forming system
Dr. Lars Velten, Group Leader of the Single Cell Genomics of Tissue Regeneration lab at the CRG, will combine deep learning and single-cell screening techniques to create new models of gene regulation in the human blood-forming system. The project’s aim is to introduce a new AI-guided concept for biological engineering.
“We are at a crucial turning point for bioscience. Thanks to artificial intelligence, bioscientists are becoming able to engineer and newly design complex biological systems without extensive trial and error,” explains Dr. Velten. “In my project, we will use these tools to build new genetic switches and networks to control the behavior of blood stem cells. We hope that this will one day be useful to synthetically generate, for example, the massive amounts of blood stem cells needed for bone marrow transplants.”