DRIVE

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Behind our cells’ recycling system Autophagy can be thought of as a cell’s internal recycling system, through which damaged or unnecessary components are destroyed and their basic constituents recycled. Manipulating this system could represent an effective way of treating a wide range of diseases, a topic central to the work of the DRIVE initial training network (ITN) project, as Professor Fulvio Reggiori explains. The cells in our body have an internal system called autophagy to remove components that the cell doesn’t want, components which may be unnecessary, damaged or potentially harmful. In a way, autophagy can be thought of as analogous to the role played by recycling trucks in removing domestic waste. “A recycling truck will pass and take the rubbish that you leave outside your house to a plant where some things will be dismounted and recycled. In a cell, these components are taken to the lysosome, the cell’s plant, by autophagy,” says Professor Fulvio Reggiori, coordinator of the DRIVE project. When problems develop with autophagy, damaged components may be left behind in a cell, which can have wider health consequences. “What may happen in a cell when autophagy goes wrong is that you may have damaged mitochondria or other dysfunctional organelles, which can then be cytotoxic,” explains Professor Reggiori.

The common theme across these different sub-projects is a focus on autophagy, with the wider aim of translating research advances into improved treatment, which must be built on a detailed understanding of the system itself. While autophagy has been known about for a long time, understanding of it was limited until around 20 years ago. “People could observe autophagy, but nobody could follow it or manipulate it, because the genes involved were not known,” explains Professor Reggiori. It was not until the end of the ‘90s that autophagy-related (ATG) genes were identified, which represented a major breakthrough in the field, and researchers discovered that autophagy is conserved in all eukaryotic organisms. “Researchers devised screens in baker’s yeast to identify the genes that, when mutated, were blocking autophagy,” outlines Professor Reggiori. “As soon as they identified these genes, they saw that the rest of the eukaryotes have homologues of these genes.”

the truck to recognise the different types of rubbish, such as dysfunctional mitochondria, or bacteria, or other things that are damaged in a cell,” he explains. The truck has to be able to identify the components that the cell doesn’t want. “A cell needs a system which recognises what the cell does not want. And sometimes that’s a bacterium, sometimes a mitochondria, and sometimes something else,” outlines Professor Reggiori.

The wider aim here is to manipulate autophagy in certain ways, an idea which holds rich potential as a way to improve the treatment of a variety of conditions. This idea has shown a degree of promise in the treatment of certain types of muscular dystrophy and neurodegenerative diseases for example, where the aim is to remove or eliminate specific structures of a cell, like protein aggregates or dysfunctional organelles. “The idea in these cases is to activate autophagy, or enhance it,” says Professor Reggiori. Manipulating autophagy also holds potential as a way of treating cancer, yet Professor Reggiori says the approach here would be different. “Cancer cells need nutrients and to protect themselves from

damage caused by anticancer treatments. They use autophagy to survive. So in the case of cancer, you want to inhibit autophagy,” he explains. “There are already trials. Typically it’s much easier to find an inhibitor – a molecule that blocks the function of enzymes – than it is to find drugs that activate a protein.” Numerous pharmaceutical companies have the knowledge, expertise and financial power to develop effective inhibitors, but further fundamental research is required for the development especially of activators, which is where DRIVE plays a role. One project Professor Reggiori is supervising involves looking at the role of autophagy in regulating cell metabolism. “Autophagy, per

se, is part of the metabolism – it degrades cell’s constituents, and for example out of proteins, you get amino-acids. These aminoacids are then recycled to make new proteins, or they can be used as a source of energy,” he explains. A cell without energy dies, and under stress conditions the cell partially eats itself (this is where the word autophagy originates from), to keep essential activity going, much like in the body as a whole. “Your brain always needs to be active – some other parts can stop working for a time to preserve energy – and it’s similar in cells,” continues Professor Reggiori. “You degrade parts of your cells to provide the energy to keep the essential functions of the cell active.”

Some researchers are looking at how autophagy works, to try and understand it and investigate how you can modulate it. Some are also looking at how it goes wrong. The DRIVE project An effective and reliable means of manipulating autophagy could open up new possibilities in the treatment of a variety of conditions, including certain cancers and neurodegenerative diseases, a topic at the heart of the DRIVE project. There are 15 early stage researchers (ESRs) working on different sub-projects in DRIVE, a Marie SkłodowskaCurie innovative training network (ITN) that brings together partners from across Europe, aiming to both build a deeper understanding of mechanism of autophagy and translate this into therapeutic developments. “Some of the ESRs are looking at how autophagy works, to try and understand it and investigate how you can modulate it. Some are also looking at how it goes wrong,” continues Professor Reggiori. “ESRs in the project are also looking at diseases caused by mutations of genes involved in autophagy.”

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A core set of approximately 20 ATG genes comprise the core machinery of autophagy, which are highly conserved across species and organisms. While other genes involved in the process have been identified, they have more peripheral roles, says Professor Reggiori. “The ATG genes, the core machinery, generate the truck that passes by. Other ATG genes have been found to be able to allow

The ESRs of DRIVE

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DRIVE

Translational research

Driving next generation autophagy researchers towards translation

Project Main Objective

The goal of DRIVE was to train through research 15 early stage scientists (ESRs) on applied autophagy research. Ultimately, DRIVE has the ambition to foster the European-wide growth of applied and translational autophagy research, and accelerate the establishment of clinical-grade solutions for the benefit of millions of patients.

Project Funding

This project is receiving funding from the European Union’s Horizon 2020 research and innovation programme, Innovative Training Networks (ITN) Call: H2020-MSCA-ITN-2017. Overall budget€ 3 890 064,96

Project Partners

• University Medical Center Groningen, NL (ESR1 and ESR15) • Institut Necker Enfants-Malades, Paris, F (ESR2) • University of Turku, FI (ESR3) • The Weizmann Institute of Science, Rehovot, IS (ESR4) • University of Oslo, N (ESR5) • Medical Center – University of Freiburg, D (ESR6) • Consejo Superior de Investigaciones Científicas (CSIC), E (ESR7 and ESR13) • Eberhard Karls University Tübingen, D (ESR8) • The Institute of Cancer Research (ICR), London, UK (ESR9) • Kings College London, UK (ESR10) • Anaxomics Biotech SL, Barcelona, E (ESR11) • Fraunhofer IME ScreeningPort, Hambourg, D (ESR12) • Adjuvantis SAS, Lyon, F (ESR14)

Contact Details

Fulvio Reggiori, Prof. Ph.D Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen T: +31 50 361 6163 E: f.m.reggiori@umcg.nl W: http://bscs.umcg.nl/en/groups/ reggiorigroup/

This changes the metabolism of the cell, a topic which Professor Reggiori and his colleague are investigating in the project, while there are also sub-projects on a variety of other topics. While each of the ESRs within DRIVE are working on a specific, highly specialised research project, Professor Reggiori says they also gain a deeper awareness of challenges in the drug development process. “The students have gained knowledge of all the different phases in translational research, the entire drug development pipeline. But they specialised in autophagy,” he explains. While the Covid-19 pandemic has limited the amount of time the ESRs could spend at other laboratories or with the project’s associated partners, they have been able to build strong bonds both with their peers and supervisors. “The students are all pulling in the same direction and they met in the first year of the project, while they also have a connection with the different supervisors,” says Professor Reggiori. These connections will stand the ESRs in good stead for their future careers, whether that lies in academia, the commercial sector, or somewhere else entirely. As an

ITN, the project has focused primarily on training students and investigating how research advances can be translated into therapeutic improvements. “We want the students to have the ability to enter industry with the competencies they need to work in drug discovery,” outlines Professor Reggiori. Whatever direction they choose to take, the skills the ESRs have gained and the connections they have established in the project will be very beneficial, believes Professor Reggiori. “They will have a network of people who they can turn to for help, support and collaboration, to ask questions about certain assays and biomarkers, which is invaluable,” he says. The project partners have also established strong collaborative relationships, and Professor Reggiori says there is interest in establishing a successor project. “We’ve had preliminary discussions. We would like to continue and to push it more towards translation - maybe we could look to narrow the research focus,” he continues. “Maybe by combining our different types of expertise, we can establish a new ITN where we focus on solving, or challenging one or two specific diseases.”

DRIVE Early Stage Researchers

Prof. Fulvio Reggiori PhD

Fulvio Reggiori studied biochemistry at University of Fribourg (CH), where he also obtained his PhD in Biochemistry. Subsequently, he had postdoctoral experiences at the MRC Laboratory of Molecular Biology in Cambridge (UK), and the Life Sciences Institute of the University of Michigan (USA). As an independent researcher, he was first at University Medical Center Utrecht (NL) and then at the University Medical Center Groningen(NL). His research interests are connected with the mechanism and functions of autophagy.

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There were fifteen early stage researchers (ESRs) in DRIVE (https://drive-autophagy. eu/), working on a wide variety of projects, from fundamental research on autophagy, to investigations into the physiological aspects of autophagy, through to the development of treatments for specific conditions. The ESRs were hosted by project beneficiaries from across Europe, with the shared goal of moving autophagy research towards translation. These projects can be divided into four major areas characterizing translational research. Four of the projects (ESRs 1, 5, 6 and 15) were investigating fundamental aspects of autophagy by studying the mechanism underlying this pathway, while three were centered on the physiological aspects of autophagy, namely its specific roles in determined cells and tissues (ESRs 7, 8 and 9). One project (ESR 7), for example, involved looking at autophagy in the development of the retina, research which

holds wider relevance to our understanding of glaucoma. A further four projects (ESRs 2, 3, 4 and 10) were about autophagy in a pathological context, with researchers using models to gain deeper insights into defects in autophagy that lead to specific diseases. This included mouse models for hereditary spastic paraparesis (SPG49) and the VICI syndrome, two pathologies associated with dysfunctional autophagy. Finally, there were also four projects in DRIVE (ESRs 11, 12, 13 and 14) in which the aim was to develop improved treatments, with researchers looking to find modulators for autophagy and also mitophagy, the selective type of autophagy involved in the turnover of dysfunctional or superfluous mitochondria. With this broad scope, researchers ultimately aim to bring the prospect of improved treatments based on autophagy a step closer.

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