GIGA - Annual report 2022

GIGA 22 annual report

Editor Michel Georges Graphic design Aurélie Gouverneur Pictures ©Geoffrey Meuli - Photography & Images Shutterstock ULiège GIGA


2 EDITORIAL Michel Moutschen Vice-director for research ULiège

3 «It is my great privilege to write the editorial of this 2022 edition of the GIGA’s activity report, as a GIGA researcher, as a physician at the CHU de Liège and as vice-rector for research at ULiège. You will find in this document what one usually finds in activity reports: key figures. They are impressive and demonstrate the vitality of the GIGA as well as its global perspective: thirty percent of GIGA researchers are non-Belgians. When you walk through the elevators and corridors of the GIGA, you can feel this international atmosphere, this precious ground for creativity. You will also read much more, such as the flagship publications of last year and the very inspiring interview with Liesbet Geris where she explains her vision of the European Research Council (ERC) grants (she knows what she is talking about). Reading this report prompts me to share some thoughts with you. The four letters of the acronym GIGA have been part of the campus landscape for so many years that we forget how gigantic what has been accomplished is. The community of the GIGA, of CHU de Liège and of the entire university should be proud of what has been built. We must preserve this heritage and leverage its immense potential. Over the last twenty years, the GIGA has always shown the way. Very logically then, the questions and challenges facing the GIGA today summarize and anticipate those of all our university research such as the definition of an optimal size of research units, the relations of research units with faculties, the balance between transdisciplinarity and thematic focus and the adoption of new modes of evaluationwithout compromising the quest for excellence. Not to mention of course the, the dilemmas between central vs. distributedmanagement of vital functions of our university, such as doctoral training, management of technological platforms, innovation exploration and support in research project proposal preparation. By arbitrating these apparent dualities, by creating new paths, new operating models, the GIGA will continue to play its role as a laboratory for the transformation of our university». Michel Moutschen Vice-director for research, ULiège «The four letters of the acronym GIGA have been part of the campus landscape for so many years that we forget how gigantic what has been accomplished is».

4 GIGA GIGA-Research GIGA-Platforms GIGA-Education GIGA-Innovation DIRECTION Michel Georges Director Brigitte Malgrange Vice-Director

5 ADMINISTRATION SITUATION GIGA is located on the Sart-Tilman Campus, University of Liège (Belgium). The GIGA tower is adjacent to the site of the University Hospital (CHU). Finances/Accounting Sandrina Evrard, Manager Team Donatienne Boxus Marie Castronovo Marc Jacquemotte Sandrine L’Heureux Axelle Lio Eva Mashyaka Teresa Orsini Infrastructure Isabelle Danese, Manager Team Audrey Hoffmann Gaëlle Massart Sihem Moudjed Fabienne Simart Welcome desk Gaëlle Massart Communication Aurélie Gouverneur

6 608 MEMBERS 58% / 42% 41 Nationalities 30% foreigners 18% EU 12% outside EU 479 Publications 41 PhD theses defended women men AT A GLANCE

7 490 active research projects 149 new research projects in 2022 55 partner countries in the ongoing projects FUNDINGS Federal 2% Walloon Region 21,8% Wallonie/Bxl Federation 21,8% ULiège 15,9% EU 13% Donation/contracts 12% FEDER/ERDF 2,2% Others 2% 32,3 Mio €

8 GIGA-RESEARCH yGIGA-CANCER yGIGA-CARDIOVASCULAR yGIGA-CONSCIOUSNESS yGIGA-CRC IN VIVO IMAGING yGIGA-I3 yGIGA-IN SILICO MEDICINE yGIGA-MEDICAL GENOMICS yGIGA-MBD yGIGA-NEUROSCIENCES yGIGA-STEM CELLS HEAD : Agnès Noël LABORATORIES Laboratory of Cellular and Molecular Epigenetics Luc Willems Laboratory of Connective Tissue Biology Alain Colige, Christophe Deroanne Laboratory of Experimental Pathology Michaël Herfs, Pascale Hubert Metastases Research Laboratory Akeila Bellahcène, Olivier Peulen Laboratory of Molecular Angiogenesis Ingrid Struman Laboratory of Tumours and Development Biology Agnès Noël, Didier Cataldo, Nor-Eddine Sounni, Erik Maquoi, Christel Péqueux, Carine Munaut, Christine Gilles HEAD : Patrizio Lancellotti LABORATORIES Laboratory of Cardiology Cécile Oury, Patrizio Lancellotti Laboratory of Translational Research in Nephrology François Jouret Surgical Research Center Natzi Sakalihasan, Jean-Olivier Defraigne Laboratory of Molecular Biomimetic Patricia Lassaux GIGA-CANCER GIGA-CARDIOVASCULAR

9 HEAD : Steven Laureys LABORATORIES Coma Science Group Olivia Gosseries, Aurore Thibaut Sensation and Perception Research Group Audrey Vanhaudenhuyse Anesthesia and Perioperative Neurosciences Lab Vincent Bonhomme, Didier Ledoux HEAD : Fabienne Collette & Gilles Vandewalle LABORATORIES Group R&D in Radiochemistry Patrick Riss, Sylvestre Dammicco Group Preclinical Alain Plenevaux, Mohamed Ali Bahri Group Nuclear Medicine Roland Hustinx, Nadia Withof, Pierre Lovinfosse Group Development in data acquisitions Christophe Phillips, Laurent Lamalle, Alain Seret, Christian Degueldre Group Movere Gaëtan Garraux Group Sleep & chronobiology Pierre Maquet, Gilles Vandewalle, Christina Schmidt Group Aging & Memory Fabienne Collette, Christine Bastin, Eric Salmon Group Cognitive Neurosciences Steve Majerus, Arnaud D’Argembeau Group Physiology of Cognition Athena Demertzi HEAD : Catherine Sadzot LABORATORIES Laboratory of Cellular and Molecular Immunology Fabrice Bureau, Nathalie Jacobs, Christophe Desmet Laboratory of Hematology Yves Beguin, Frédéric Baron, Jo Caers, Sophie Servais Laboratory of Immunoendocrinology Vincent Geenen Laboratory of Immunology & Infectious Diseases Michel Moutschen Laboratory of Immunometabolism and Nutrition Sylvie Legrand, Nathalie Esser, Nicolas Paquot Laboratory of Immunophysiology Thomas Marichal Laboratory for Organogenesis and Regeneration Marc Muller Laboratory of Molecular Immunology and Signal Transduction Emmanuel Dejardin Laboratory of Rheumatology Michel Malaise, Dominique de Seny Laboratory of Translational Gastroenterology Edouard Louis, Marie-Alice Meuwis Laboratory of Virology and Immunology Catherine Sadzot, Marielle Lebrun Laboratory of Pneumology Renaud Louis, Florence Schleich, Julien Guiot, Catherine Moermans, Céline Kempeneers HEAD : Thomas Desaive LABORATORIES Biomechanics Research Unit Liesbet Geris Neuroimaging, data acquisition and processing Christophe Phillips Critical care basic science Philippe Morimont, Bernard Lambermont Model-based therapeutics Thomas Desaive, Pierre Dauby GIGA-CONSCIOUSNESS GIGA-CRC GIGA-I3 GIGA-IN SILICOMEDICINE

10 HEAD : Tom Druet LABORATORIES Laboratory of Human Genetics Vincent Bours, Aimé Lumaka Unit of Animal Genomics Michel Georges, Souad Rahmouni, Carole Charlier, Tom Druet, Anne Van den Broeke Laboratory of Systems and Modelisation (BIO3) Kristel Van Steen HEAD : Franck Dequiedt LABORATORIES Laboratory of Gene Expression and Cancer Franck Dequiedt, Yvette Habraken, Denis Mottet Laboratory of Functional Genetics Stéphane Schurmans Laboratory of Molecular Pharmacology Julien Hanson Laboratory of Viral Interactomes Networks Jean-Claude Twizere HEAD : Julie Bakker LABORATORIES Laboratory of Nervous System Bernard Rogister, Rachelle Franzen, Pierre Leprince, Didier Martin, Félix Scholtes Laboratory of Neuroendocrinology Julie Bakker, Charlotte Cornil, Anne-Simone Parent Laboratory of Neurophysiology Vincent Seutin, Lucien Bettendorff, Guillaume Drion, Vincent Engel HEAD : Laurent Nguyen LABORATORIES Laboratory of Molecular Regulation of Neurogenesis Laurent Nguyen, Bernard Lakaye, Ira Espuny-Camacho, Sophie Laguesse Laboratory of Medical Chemistry Alain Chariot Laboratory of Cancer Signaling Pierre Close Laboratory of Developmental Neurobiology Brigitte Malgrange, Laurence Delacroix, Renaud Vandenbosch Laboratory of Zebrafish Development and Disease Model Bernard Peers, Marianne Voz, Isabelle Manfroid Laboratory of Cancer Stemness Francesca Rapino GIGA-MEDICAL GENOMICS GIGA-MBD GIGA-NEUROSCIENCES GIGA-STEM CELLS


12 HIGHLIGHTS Overview of 12 of the best 2022 publications

13 HIGHLIGHTED PUBLICATION Consciousness can be defined by two components: arousal (wakefulness) and awareness (subjective experience). However, neurophysiological consciousness metrics able to disentangle between these components have not been reported. Researchers of the Coma Science Group propose an explainable consciousness indicator (ECI) using deep learning to disentangle the components of consciousness. They employ electroencephalographic (EEG) responses to transcranial magnetic stimulation under various conditions, including sleep, general anesthesia, and severe brain injury. They also test their framework using resting-state EEG under general anesthesia and severe brain injury. ECI simultaneously quantifies arousal and awareness under physiological, pharmacological, and pathological conditions. Particularly, ketamine-induced anesthesia and rapid eye movement sleep with low arousal and high awareness are clearly distinguished from other states. In addition, parietal regions appear most relevant for quantifying arousal and awareness. This indicator provides insights into the neural correlates of altered states of consciousness. QUANTIFYING AROUSAL AND AWARENESS IN ALTERED STATES OF CONSCIOUSNESS USING INTERPRETABLE DEEP LEARNING Lee M, Sanz LRD, Barra A, Wolff A, Nieminen JO, Boly M, Rosanova M, Casarotto S, Bodart O, Annen J, Thibaut A, Panda R, Bonhomme V, Massimini M, Tononi G, Laureys S, Gosseries O, Lee SW. Nat Commun. 2022 Feb 25;13(1):1064.

14 A multidisciplinary study conducted by researchers from the Laboratory of Experimental Pathology (GIGA-Cancer) and their partners (local and international) highlights that some innate peptides secreted by the cervical/vaginal mucosa are used by the predominant Lactobacillus species (L. crispatus, L. jensenii, L. iners) as an amino acid source. As part of a broad effort to escape the immune responses, human papillomaviruses (HPV) drastically inhibit the expression of these antimicrobial peptides, ultimately promoting an imbalance in the vaginal flora. The replacement of the normally dominant lactic acid bacteria (constituting over 95% of the vaginal flora) by a more diverse bacterial mixture (dominated by Gardnerella vaginalis and other anaerobic bacteria) has been considered as a risk factor for both the persistence and progression of HPV-dependent (pre)neoplastic lesions for many years. Conversely, the potential influence of HPV infections on the vaginal microbiota remained largely unexplored. This study conducted by Michael Herfs and his team (more particularly Alizee Lebeau and Diane Bruyere) first showed that persistent (for several months/years) viral infections significantly increase the risk of bacterial vaginosis. Related to an inhibition of both NF-κB and Wnt/β-catenin signaling pathways (dependent on the interaction of E7 viral oncoprotein with NEMO, CK1 and β-TrCP), this phenomenon is associated with a drastic reduction in secretion of innate peptides by the host mucosa. Unexpectedly, these peptides display no antimicrobial activity on Lactobacillus species but rather, are cleaved, internalized and used as amino acid source by these lactic acid bacteria, sustaining their growth/survival. Commonly treated with broad-spectrum antibiotics, bacterial vaginosis is well-known to have a very high recurrence rate (>50%). Therefore, some innate peptides (e.g. elafin and S100A7) physiologically secreted by the host mucosa could constitute prebiotics of choice and prove to be allies in the treatment of this pathology affecting between 15 and 30% of women. HPV INFECTION ALTERS VAGINAL MICROBIOME THROUGH DOWN-REGULATING HOST MUCOSAL INNATE PEPTIDES USED BY LACTOBACILLI AS AMINO ACID SOURCES Lebeau A, Bruyere D, Roncarati P, Peixoto P, Hervouet E, Cobraiville G, Taminiau B, Masson M, Gallego C, Mazzucchelli G, Smargiasso N, Fleron M, Baiwir D, Hendrick E, Pilard C, Lerho T, Reynders C, Ancion M, Greimers R, Twizere JC, Daube G, Schlecht-Louf G, Bachelerie F, Combes JD, Melin P, Fillet M, Delvenne P, Hubert P, Herfs M. Nat Commun. 2022 Feb 28;13(1):1076.

15 Breast cancer is the most frequent cancer in Belgium. It concerns about 11,000 new cases detected each year. During her postdoc in Italy, Stéphanie Herkenne discovered that the OPA1 protein is overexpressed in breast cancer cases with a poor prognosis of the patients. Furthermore, genetic or pharmacological inhibition of OPA1 reduces proliferation, migration, adhesion and invasion of breast cancer cells in vitro and in vivo. Although the mitochondrion is the energy powerhouse of the cell, it has many additional functions. Indeed, it has recently been shown that mitochondria are involved in the regulation of cell death, cell differentiation, immune responses or during autophagy. The mitochondria alone can regulate all these functions because it is not a static organelle but is highly dynamic. Indeed, mitochondria are able to fuse and fragment allowing an exchange of mitochondrial material according to the needs of the cell. Mitochondrial fission is regulated by the cytoplasmic protein DRP1 (Dynamin related protein 1) while fusion requires the intervention of several actors such as Mitofusins 1 and 2 as well as OPA1 (Optic Atrophy Protein 1). The researchers found that inhibition of OPA1 in breast cancer cells, including triple-negative breast cancer, does not disrupt mitochondrial functions but instead increases the level of miRNAs belonging to the 148/152 family (148a, 148b and 152). The miRNAs are small non-coding RNAs that have the particularity of preventing the expression of different proteins and these three miRNAs have the particularity of being under-expressed during the development of breast cancer. They are also considered to be inhibitors of tumor growth and invasion. In conclusion, these data show that targeted inhibition of the OPA1 protein reduces the growth of breast cancers and thus names OPA1 as a potential new target for treating breast cancers, and in particular triple-negative breast cancer, which does not respond to other treatments. INHIBITION OF THE MITOCHONDRIAL PROTEIN OPA1 CURTAILS BREAST CANCER GROWTH Zamberlan M, Boeckx A, Muller F, Vinelli F, Ek O, Vianello C, Coart E, Shibata K, Christian A, Grespi F, Giacomello M, Struman I, Scorrano L, Herkenne S. J Exp Clin Cancer Res. 2022 Mar 12;41(1):95.

16 The team from Laurent Nguyen discovered a new function for oligodendrocyte precursors. These cells, which are responsible for the myelination of neurons in the adult nervous system, are also involved in guiding interneurons that settle in the cerebral cortex during embryonic development. The formation of the cerebral cortex requires the migration and settlement of some neural cells that are born in distant cerebral regions. This is the case for interneurons and some precursors of oligodendrocytes which are born in the ventral part of the developing brain. Once installed in the cortex, the interneurons tune cortical network activity and the oligodendrocytes produce the myelin which covers the axons of the neurons in order to facilitate the propagation of action potentials. Thus, the migration of these cells from their place of birth is important for their functional insertion within the cerebral cortex. However, cell migration could also contribute to the transmission of morphogenetic information to neighboring cells along the migration path. This hypothesis was tested by researchers from the molecular regulation of neurogenesis laboratory, directed by Pr Laurent Nguyen. They discovered the existence of a molecular crosstalk between interneurons and oligodendrocyte precursors during their migration, which is responsible for the unidirectional repulsion of interneurons via the semaphorin/plexin molecular system. This new mode of cell repulsion contributes to the guidance of interneurons in the cortex by preventing them from aggregating around blood vessels. The researchers’ results also suggest that a dysfunction in this molecular dialogue between oligodendrocyte precursors and interneurons could underlie the emergence of neurodevelopmental diseases such as autism and epilepsy. This work demonstrates the existence of a new non-canonical function of oligodendrocyte precursors (independent of axon myelination) which is important for the construction of the cerebral cortex. New perspectives open up following these results. “This finding likely represents only the tip of the iceberg since there are many cell populations migrating simultaneously in the developing cortex. It therefore paves the way for a better understanding of the molecular dialogues that are established between these moving cells and their environment to shape the cerebral cortex,” explains Laurent Nguyen. The analysis of these cellular interactions is in progress and is the topic of a new research project funded by Welbio. OLIGODENDROCYTE PRECURSORS GUIDE INTERNEURON MIGRATION BY UNIDIRECTIONAL CONTACT REPULSION Lepiemme F, Stoufflet J, Javier-Torrent M, Mazzucchelli G, Silva CG, Nguyen L. Science. 2022 May 20;376(6595):eabn6204.

17 As part of a Chinese Thousand Talents Program Award, Michel Georges and Carole Charlier collaborated with the laboratory of Professor Lusheng Huang (Nanchang, China) to study the effect of the host genome on the composition of its intestinal microbiota. To that end, the unit of Animal Genomics tooks advantage of an exceptional mosaic pig population with exacerbated genetic diversity yet reduced environmental variation established in a >10 years effort by Professor Huang. It allowed them to demonstrate the he- ritable nature of the abundance of at least some bacterial taxa, and - most importantly – to identify a locus with major effect on the abundance of specific Erysipelotrichaceae ge- nera. The researchers showed that the causative variant is a null allele in the porcine gene corresponding to the ABO blood group in human. They showed that this allele acts by reducing the abundance of GalNAc in the intestinal mucus. This affects the growth of bacteria that use GalNAC as car- bon source using a non-inducible GalNAc operon. Preliminary results point towards the fact that the balanced AO blood group polymorphism in the pig host sustains a ba- lanced polymorphism of the GalNAc operon in the p.75.a5 Erysipelotrichaceae. ABO GENOTYPE ALTERS THE GUT MICROBIOTA BY REGULATING GALNAC LEVELS IN PIGS Yang H, Wu J, Huang X, Zhou Y, Zhang Y, Liu M, Liu Q, Ke S, He M, Fu H, Fang S, Xiong X, Jiang H, Chen Z, Wu Z, Gong H, Tong X, Huang Y, Ma J, Gao J, Charlier C, Coppieters W, Shagam L, Zhang Z, Ai H, Yang B, Georges M, Chen C, Huang L. Nature. 2022 Jun;606(7913):358-367.

18 A collaboration between several GIGA teams has led to the discovery of a new function for exosomes in cancer progression. Exosomes, or extracellular vesicles (EVs) released by cells, are intercellular messengers that modify the tumor environment to promote breast cancer progression. The evolution of a cancer, as well as the response to treatment, are strongly influenced by the microenvironment in which the tumor develops. Tumor cells interact with blood vessel cells (endothelial cells) but also with stromal cells such as fibroblasts or immune cells. Ingrid Struman’s laboratory is interested in the strategies used by these cells to communicate. Her team shows that the cancer cell modifies the communication with the surrounding cells to its own advantage. Specifically, during tumor growth, endothelial cells release exosomes that in turn alter tumor immunity. Exosomes are small extracellular vesicles (EVs) that are about 100 nanometers in size; they are inter-cellular messengers. In the context of cancer, tumor-derived EVs participate in tumor progression by deregulating various physiological processes, including angiogenesis and inflammation. The authors report that EVs released from endothelial cells in the environment of a breast tumor participate in the recruitment of macrophages to the tumor, leading to an immunomodulatory phenotype favorable to tumor growth. Using sequencing approaches, they identified several microRNAs present in endothelial cell EVs that share common targets involved in the regulation of the immune system. The goal of this project was to better understand how breast cancer cells modify host cells to better progress. Beyond the understanding of the mechanism of action, this study opens new perspectives as it highlights new therapeutic targets to develop new treatments for this disease. Ingrid Struman’s team will continue this work to better understand the mechanism involved in the export of microRNAs. She is also interested in the impact of this discovery on the spread of metastasis. This study is the result of a collaboration funded by an ARC of the ULiège and the FNRS between the teams of Pr. Franck Dequiedt and Dr. Ingrid Struman (Senior Research Fellow FNRS). This study was also carried out in collaboration with other GIGA researchers - the team of Souad Rahmouni (GIGA-Medical Genomics) and Dr. Julien Guiot (GIGA-I3 - Pneumology Department of the CHU). ENDOTHELIAL EXTRACELLULAR VESICLES PROMOTE TUMOUR GROWTH BY TUMOUR-ASSOCIATEDMACROPHAGE REPROGRAMMING Njock MS, O’Grady T, Nivelles O, Lion M, Jacques S, Cambier M, Herkenne S, Muller F, Christian A, Re macle C, Guiot J, Rahmouni S, Dequiedt F, Struman I. J Extracell Vesicles. 2022 Jun;11(6):e12228

19 The Metastasis Research Laboratory (Olivier Peulen and Akeila Bellahcène - GIGA-Cancer), has been studying the myoferlin protein and its role in pancreatic cancer for many years. Their efforts have led to the discovery that pharmacological targeting of this protein induces cancer cell death by iron accumulation. This accumulation also sensitises these cells to other inducers of ferroptosis. Researchers at the Metastasis Research Laboratory have discovered that myoferlin, physiologically involved in membrane biology, has a tumour-promoting function that has not been fully understood. The in-depth study of this function now allows them to consider myoferlin as a potential therapeutic target. Research at the Metastasis Research Laboratory has previously suggested a link between myoferlin and the function of mitochondria in pancreatic cancer cells. Further investigation of this link allowed Gilles Rademaker and Yasmine Boumahd, working under the supervision of Olivier Peulen, to observe that a small molecule binding to myoferlin was toxic to the cancer cells and caused destruction of their mitochondrial network. They also showed that this observation was accompanied by a specific degradation of mitochondria, mitophagy, and by an accumulation of reactive oxygen species in the cytoplasm. In an attempt to understand the origin of these reactive oxygen species, they demonstrated that the intracellular iron concentration increased a few hours after targeting myoferlin. This increase in iron concentration was responsible for the formation of reactive oxygen species and for the cytotoxic effects of pharmacological targeting of myoferlin. The researchers then sought to better understand the reasons that led to the death of the cancer cells. It appeared that the cancer cell could not activate a defense system against reactive oxygen species, resulting in damage to the cell membranes. The cells thus underwent ferroptosis. Inspired by this discovery, the research team combined the pharmacological agent directed against myoferlin with molecules (erastin, RSL3) whose analogues (e.g. PRLX93936) are currently in the clinical trials. They have shown that there is synergy between the different molecules and that it is therefore possible to envisage more effective treatments or treatments using lower concentrations, thus limiting possible side effects.These results open up interesting therapeutic perspectives but nevertheless require several verifications, including in models closer to the patient. MYOFERLIN TARGETING TRIGGERS MITOPHAGY AND PRIMES FERROPTOSIS IN PANCREATIC CANCER CELLS Rademaker G, Boumahd Y, Peiffer R, Anania S, Wissocq T, Liégeois M, Luis G, Sounni NE, Agirman F, Maloujahmoum N, De Tullio P, Thiry M, Bellahcène A, Castronovo V, Peulen O. Redox Biol. 2022 Jul;53:102324

20 Alain Chariot’s team (Laboratory of Medical Chemistry – GIGA Stem Cells) describes how macrophages provide the right cocktail of proteins to trigger inflammation in order to fight pathogens or to resolve inflammation and promote tissue repair. Macrophages are critical in anti-microbial and inflammatory activity in host defense as well as in the resolution of inflammation and wound healing. Their response to microenvironmental cues allows them to acquire distinct effector states in order to carry out multiple functions. Their plasticity helps macrophages to acquire tailored activities within tissues and is often addressed through the concept of macrophage polarization. Interferon-gamma is the canonical type 1 cytokine which, together with bacterial lipopolysaccharide (LPS) is associated with a type 1 immune environment and triggers a proinflammatory profile that is referred to as “M1” or “classical” macrophage polarization. In contrast, IL-4 and IL-13, which are cytokines typically associated with type 2 immune responses, trigger different responses in macrophages, resulting in what is often referred to as M2 macrophage polarization. M2 macrophages downplay inflammation, promote tissue repair and remodeling through the secretion of anti-inflammatory cytokines (IL-10), scavenging receptors and a variety of remodeling factors. Processes linked to M2 macrophage are involved in tumor growth and metastasis, in the cellular response to helminth infections as well as in insulin sensitivity in adipocytes. Researchers reported that translational reprogramming linked to macrophage polarization relies on Elp3, a tRNA-modifying enzyme involved in mRNA translation of mostly unknown candidates. Elp3 deficiency enhances M1 polarization, which potentiates inflammation in a mouse model of experimental colitis. On the other hand, Elp3 deficiency blocks M2 polarization in vivo, which delays Wnt-driven tumor initiation in the intestine. Mechanistically, Elp3 promotes mRNA translation of multiples candidates, including Ric8b, a mTORC2 activator. Elp3 also promotes the synthesis of several mitochondrial proteins, with important consequences in metabolic reprogramming linked to macrophage polarization. Therefore, this study highlights the key role of some tRNA modifications in the biology of immune cells. ELP3-MEDIATED CODON-DEPENDENT TRANSLATION PROMOTES MTORC2 ACTIVATION AND REGULATES MACROPHAGE POLARIZATION Chen D, Nemazanyy I, Peulen O, Shostak K, Xu X, Tang SC, Wathieu C, Turchetto S, Tielens S, Nguyen L, Close P, Desmet C, Klein S, Florin A, Büttner R, Petrellis G, Dewals B, Chariot A. EMBO J. 2022 Sep 15;41(18):e109353.

21 “Sleep is health”. Yes, but probably even more if we sleep at the right time! Christina Schmidt and her team (Sleep and Chronology Lab - GIGA-CRC in vivo Imaging) used this statement as the basis for their questioning on the practice of chronic napping in a project, funded by the European Research Council and the National Funds for Scientific Research, initiated in 2018. Their first results indicate that the frequent intrusion of periods of daytime rest during aging is not only associated with an altered temporal organization of our rest-activity cycle, but also with lower episodic memory performance. This memory component appears indeed particularly affected by the aging process. Moreover, placing rest periods at key times of the day (e.g. “late naps”) was associated with a desynchronization between the sleep-wake cycle and the internal biological clock. The latter shapes the temporal organization of our sleep-wake cycle to achieve a consolidated period of sleep at night and a period of activity during the day. In this study, the timing of this clock was derived by extracting the melatonin profiles of the volunteers, thus making it possible to situate each individual and their sleep habits with respect to their biological clock. Melatonin is produced by the pineal gland and follows a modulation of about 24 hours, thereby allowing the extraction of the endogenous circadian phase. The alignment between the latter and the sleep-wake cycle in daily life seems to be associated with more consolidated periods of nighttime rest, which may be even more important during aging, which is usually associated with an increased occurrence of sleep complaints and for which the underlying regulation processes are not yet fully elucidated. In a next step, the team aims to explore the brain correlates of napping phenotypes, its impact on sleep regulation, but also the potential predictive value of sleep temporality for the cognitive trajectory during aging. DAYTIME REST: ASSOCIATIONWITH 24-H REST-ACTIVITY CYCLES, CIRCADIAN TIMING AND COGNITION IN OLDER ADULTS Reyt M, Deantoni M, Baillet M, Lesoinne A, Laloux S, Lambot E, Demeuse J, Calaprice C, LeGoff C, Collette F, Vandewalle G, Maquet P, Muto V, Hammad G, Schmidt C. J Pineal Res. 2022 Oct;73(3):e12820.

22 Researchers from the GIGA CRC In vivo Imaging, the EPF Lausanne and the University of Geneva published a study that shows that the phenomenology of «mind blanking» challenges the belief that the humanmind is always thinking. We generally consider that our mind is full of thoughts when we are awake. Like a river stream always running, similarly we entertain our own dynamic mental stream: a thought can lead to another, relevant to what we do or not, ebbing between our inner life and the outer environment. How can the brain sustain such a thought-related mode constantly, though? This study indicates that it actually cannot, and that our brains also need to “go offline” for some moments, which we can experience as blanks in the mind. Researchers from the University of Liège and EPF Lausanne & University of Geneva re-analyzed a previously collected dataset where healthy participants were reporting their mental state as this was before hearing an auditory probe (beep) while resting in the MRI scanner. The choices were among perceptions of the environment, stimulus-dependent thoughts, stimulus-independent thoughts, and mental absences. Functional images were being collected during this experience-sampling method. The researchers found that mind blanking episodes were reported quite rarely compared to the other states, and that they were re-appearing also scarcely across time. Using machine learning, the researchers further found that our brains during mind-blanking episodes organized in a way where all brain regions were communicating with each other at the same time. This ultra-connected brain pattern was further characterized by high amplitude of the fMRI global signal, which is a proxy of low cortical arousal. In other words, when reporting mind blanking our brains seem to be in a mode similar to that of deep sleep, only that we are awake. The researchers claim that the rigid neurofunctional profile of mind blanking could account for the inability to report mental content due to the brain’s inability to differentiate signals in an informative way. While waiting for the underlying mechanisms to be illuminated, this work suggests that instantaneous non-reportable mental events can happen during wakefulness, setting mind blanks as a prominent mental state during ongoing experience. MIND BLANKING IS A DISTINCT MENTAL STATE LINKED TO A RECURRENT BRAIN PROFILE OF GLOBALLY POSITIVE CONNECTIVITY DURING ONGOINGMENTATION Mortaheb S, Van Calster L, Raimondo F, Klados MA, Boulakis PA, Georgoula K, Majerus S, Van De Ville D, Demertzi A. Proc Natl Acad Sci U S A. 2022 Oct 11;119(41):e2200511119.

23 A collaboration between several teams from the GIGA of the University of Liege and the Department of Microbiology and Infectious Diseases of the University of Sherbrooke in Canada has led to the identification of a new molecular pathway involved in the response of cancer cells to genotoxic agents. In cancer therapy, the success of chemotherapy relies on the induction of a cell death program, specifically triggered in tumor cells following their exposure to chemical agents and allowing their elimination. Cisplatin is a chemotherapeutic agent used to treat many types of cancer, including ovarian and breast cancer. Despite its effectiveness, the recurrent problem with the use of cisplatin is the appearance of resistant cancer cells and sometimes severe side effects. The teams of Dr. Yvette Habraken and Prof. Franck Dequiedt (GIGA-Molecular Biology of Diseases) have identified a new molecular pathway involved in the response of cancer cells to cisplatin. The scientists have shown that following treatment with cisplatin, c-Jun, a molecular factor usually involved in transcription (the first steps in gene expression), also impacts mRNA splicing (an important step during gene expression that defines the final structure of mRNA). Via this new function, c-Jun induces the expression of a short isoform of the mitochondrial enzyme COASY, which is responsible for cisplatin-induced cell death. These discoveries could ultimately contribute to improving the efficacy of genotoxic anticancer treatments and limiting their deleterious effects. This study is the result of multiple collaborations between GIGA researchers (Yvette Habraken, Franck Dequiedt, Alain Colige, Olivier Peulen) and the technology platforms (GIGA-Imaging and GIGA-Genomics). THE TRANSCRIPTION FACTOR C-JUN INHIBITS RBM39 TO REPROGRAM PRE-MRNA SPLICING DURING GENOTOXIC STRESS Lemaitre F, Chakrama F, O’Grady T, Peulen O, Rademaker G, Deward A, Chabot B, Piette J, Colige A, Lambert C, Dequiedt F, Habraken Y. Nucleic Acids Res. 2022 Dec 9;50(22):12768-12789.

24 OTHER RELEVANT PUBLICATIONS GIGA-Cancer ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in adults for pro-VEGFC activation and lymphatic homeostasis. Dupont L, Joannes L, Morfoisse F, Blacher S, Monseur C, Deroanne CF, Noël A, Colige AC. JCI Insight. 2022 Apr 22;7(8):e151509. Periostin in lymph node pre-metastatic niches governs lymphatic endothelial cell functions and metastatic colonization. Gillot L, Lebeau A, Baudin L, Pottier C, Louis T, Durré T, Longuespée R, Mazzucchelli G, Nizet C, Blacher S, Kridelka F, Noël A. Cell Mol Life Sci. 2022 May 14;79(6):295. HDAC Inhibition with Valproate Improves Direct Cytotoxicity of Monocytes against Mesothelioma Tumor Cells. Hoyos C, Fontaine A, Jacques JR, Heinen V, Louis R, Duysinx B, Scherpereel A, Wasielewski E, Jamakhani M, Hamaidia M, Willems L. Cancers (Basel). 2022 Apr 26;14(9):2164. Paladin, overexpressed in colon cancer, is required for actin polymerisation and liver metastasis dissemination. Rademaker G, Costanza B, Pyr Dit Ruys S, Peiffer R, Agirman F, Maloujahmoum N, Vertommen D, Turtoi A, Bellahcène A, Castronovo V, Peulen O. Oncogenesis. 2022 Jul 26;11(1):42. Lipin-1, a Versatile Regulator of Lipid Homeostasis, Is a Potential Target for Fighting Cancer. Brohée L, Crémer J, Colige A, Deroanne C. Int J Mol Sci. 2021 Apr 23;22(9):4419. A safe and effective vaccine against bovine leukemia virus. Suárez Archilla G, Gutiérrez G, Camussone C, Calvinho L, Abdala A, Alvarez I, Petersen M, Franco L, Destefano G, Monti G, Jacques JR, Joris T, Willems L, Trono K. Front Immunol. 2022 Aug 10;13:980514. GIGA-Cardiovascular Differential Biological Effects of Dietary Lipids and Irradiation on the Aorta, Aortic Valve, and the Mitral Valve. Donis N, Jiang Z, D’Emal C, Hulin A, Debuisson M, Dulgheru R, Nguyen ML, Postolache A, Lallemand F, Coucke P, Martinive P, Herzog M, Pamart D, Terrell J, Pincemail J, Drion P, Delvenne P, Nchimi A, Lancellotti P, Oury C. Front Cardiovasc Med. 2022 Feb 28;9:839720. doi: 10.3389/ fcvm.2022.839720. eCollection 2022. Kidney-targeted irradiation triggers renal ischemic preconditioning in mice. Khbouz B, Lallemand F, Cirillo A, Rowart P, Legouis D,Sounni NE, Noël A, De Tullio P, de Seigneux S, Jouret F. Am J Physiol Renal Physiol. 2022 Aug 1;323(2):F198-F211. Prognostic Value of Non-Invasive Global Myocardial Work in Asymptomatic Aortic Stenosis. Ilardi F, Postolache A, Dulgheru R, Trung MN, de Marneffe N, Sugimoto T, Go YY, Oury C, Esposito G, Lancellotti P. J Clin Med. 2022 Mar 11;11(6):1555. Successful heart transplantation from donation after euthanasia with distant procurement using normothermic regional perfusion and cold storage. Tchana-Sato V, Hans G, Brouckaert J, Detry O, Van Cleemput J, Rex S, Jaquet O, De Troy E, Trung MN, Ancion A, Van den Eynde R, Lievens I, Lagny MG, Delbouille MH, Defraigne JO, Ledoux D, Rega F. Am J Transplant. 2022 Dec;22(12):3146-3149. Towards Precritical Medical Therapy of the Abdominal Aortic Aneurysm. Musumeci L, Eilenberg W, Pincemail J, Yoshimura K, Sakalihasan N. Biomedicines. 2022 Nov 29;10(12):3066. GIGA-Consciousness A neurophenomenological approach to non-ordinary states of consciousness: hypnosis, meditation, and psychedelics. Timmermann C*, Bauer PR*, Gosseries O*, Vanhaudenhuyse A*, Vollenweider F, Laureys S, Singer T; Mind and Life Europe (MLE) ENCECON Research Group; Antonova E*, Lutz A*. Trends Cogn Sci. 2023 Feb;27(2):139-159. Disruption in structural- functional network repertoire and time-resolved subcortical fronto- temporoparietal connectivity in disorders of consciousness. Panda R, Thibaut A, Lopez-Gonzalez A, Escrichs A, Bahri MA, Hillebrand A, Deco G, Laureys S, Gosseries O, Annen J, Tewarie P. Elife. 2022 Aug 2;11:e77462. Evaluation of the effect of analgesic treatment on signs of nociception-related behaviors during physiotherapy in patients with disorders of consciousness: a pilot crossover randomized controlled trial. Bonin EAC, Binda Fossati ML, Filippini MM, Bornheim S, Lejeune N, O’Brien AT, Bodart O, Laureys S, Thibaut A, Chatelle C. Pain. 2022 Feb 1;163(2):e349-e356. Effect of suprainguinal fascia iliaca compartment block on postoperative opioid consumption and functional recovery in posterolateral-approached total hip arthroplasty: a single-blind randomized controlled trial. Carella M, Beck F, Piette N, Denys S, Kurth W, Lecoq JP, Bonhomme V. Reg Anesth Pain Med. 2022 Jun 15:rapm-2021-103427. Virtual reality hypnosis in the management of pain: Self-reported and neurophysiological measures in healthy subjects. Rousseaux F, Panda R, Toussaint C, Bicego A, Niimi M, Faymonville ME, Nyssen AS, Laureys S, Gosseries O, Vanhaudenhuyse A. Eur J Pain. 2023 Jan;27(1):148-162. IF 6,6 Psycho-oncology interventions focusing on fatigue and sleep disturbances. Grégoire C, Faymonville ME, Jerusalem G, Gosseries O, Vanhaudenhuyse A. Curr Opin Oncol. 2022 Jul 1;34(4):270-278. IF 5,5

25 GIGA-CRC Timely coupling of sleep spindles and slow waves linked to early amyloid-β burden and predicts memory decline. Chylinski D, Van Egroo M, Narbutas J, Muto V, Bahri MA, Berthomier C, Salmon E, Bastin C, Phillips C, Collette F, Maquet P, Carrier J, Lina JM, Vandewalle G. Elife. 2022 May 31;11:e78191. doi: 10.7554/eLife.78191. Effect of an 18-Month Meditation Training on Regional Brain Volume and Perfusion in Older Adults: The Age-Well Randomized Clinical Trial. Chételat G, Lutz A, Klimecki O, Frison E, Asselineau J, Schlosser M, Arenaza-Urquijo EM, Mézenge F, Kuhn E, Moulinet I, Touron E, Dautricourt S, André C, Palix C, Ourry V, Felisatti F, Gonneaud J, Landeau B, Rauchs G, Chocat A, Quillard A, Devouge EF, Vuilleumier P, de La Sayette V, Vivien D, Collette F, Poisnel G, Marchant NL; Medit-Ageing Research Group. JAMA Neurol. 2022 Nov 1;79(11):1165-1174. Age-related differences in the neural correlates of vivid remembering. Folville A, Bahri MA, Delhaye E, Salmon E, D’Argembeau A, Bastin C. Neuroimage. 2020 Feb 1;206:116336. doi: 10.1016/j.neuroimage.2019.116336. Epub 2019 Nov 5. GIGA-I3 Neutrophil Extracellular Traps Are Found in Bronchoalveolar Lavage Fluids of Horses With Severe Asthma and Correlate With Asthma Severity. Janssen P, Tosi I, Hego A, Maréchal P, Marichal T, Radermecker C. Front Immunol. 2022 Jul 13;13:921077. Anti-IL5 mepolizumab minimally influences residual blood eosinophils in severe asthma. Van Hulst G, Jorssen J, Jacobs N, Henket M, Louis R, Schleich F, Bureau F, Desmet CJ. Eur Respir J. 2022 Mar 17;59(3):2100935. Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle. Sanchez Gil J, Dubois M, Neirinckx V, Lombard A, Coppieters N, D’Arrigo P, Isci D, Aldenhoff T, Brouwers B, Lassence C, Rogister B, Lebrun M, Sadzot-Delvaux C. Mol Ther Oncolytics. 2022 Jun 6;26:35-48. Combined obstructive airflow limitation associated with interstitial lung diseases (O-ILD): the bad phenotype ? Guiot J, Henket M, Frix AN, Gester F, Thys M, Giltay L, Desir C, Moermans C, Njock MS, Meunier P, Corhay JL, Louis R. Respir Res. 2022 Apr 11;23(1):89. Antibody response against SARS-CoV-2 Delta and Omicron variants after third-dose BNT162b2 vaccination in allo-HCT recipients. Canti L, Ariën KK, Desombere I, Humblet-Baron S, Pannus P, Heyndrickx L, Henry A, Servais S, Willems E, Ehx G, Goriely S, Seidel L, Michiels J, Willems B, Goossens ME, Beguin Y, Marchant A, Baron F. Cancer Cell. 2022 Apr 11;40(4):335-337. Mesenchymal Stem Cell Injection in Crohn’s Disease Strictures: A Phase I-II Clinical Study. Vieujean S, Loly JP, Boutaffala L, Meunier P, Reenaers C, Briquet A, Lechanteur C, Baudoux E, Beguin Y, Louis E. J Crohns Colitis. 2022 Mar 14;16(3):506-510. GIGA-In Silico Medicine Shamo: A Tool for Electromagnetic Modeling, Simulation and Sensitivity Analysis of the Head. Grignard M, Geuzaine C, Phillips C. Neuroinformatics. 2022 Jul;20(3):811824. Enhanced electrical conductivity and stretchability of ionic-liquid PEDOT:PSS air-cathodes for aluminium-air batteries with long lifetime and high specific energy. Machrafi H, Iermano F, Temsamani S, Bobinac I, Iorio CS. Sci Rep. 2022 Dec 21;12(1):22107. Modelling patient specific cardiopulmonary interactions. Cushway J, Murphy L, Chase JG, Shaw GM, Desaive T. Comput Biol Med. 2022 Dec;151(Pt A):106235. In Vitro, In Vivo, and In Silico Models of Lymphangiogenesis in Solid Malignancies. Bekisz S, Baudin L, Buntinx F, Noël A, Geris L. Cancers (Basel). 2022 Mar 16;14(6):1525. Ribosome exit tunnel electrostatics. Joiret M, Kerff F, Rapino F, Close P, Geris L. Phys Rev E. 2022 Jan;105(1-1):014409. GIGA-Medical Genomics Kinetics and Persistence of the Cellular and Humoral Immune Responses to BNT162b2 mRNA Vaccine in SARS-CoV-2-Naive and -Experienced Subjects: Impact of Booster Dose and Breakthrough Infections. Desmecht S, Tashkeev A, El Moussaoui M, Marechal N, Perée H, Tokunaga Y, Fombellida-Lopez C, Polese B, Legrand C, Wéry M, Mni M, Fouillien N, Toussaint F, Gillet L, Bureau F, Lutteri L, Hayette MP, Moutschen M, Meuris C, Vermeersch P, Desmecht D, Rahmouni S*, Darcis G*. Front Immunol. 13:863554 (2022) Deeper insights into long-term survival heterogeneity of Pancreatic Ductal Adenocarcinoma (PDAC) patients using integrative individual-and group-level transcriptome network analyses. Bhardwaj A, Josse C, Van Daele D, Poulet C, Chavez M, Struman I, Van Steen K. Sci Rep. 12(1):11027 (2022) Interpretable network-guided epistasis detection. Duroux D, Climente-González H, Azencott C-A, Van Steen K. GigaScience. 11 giab093 (2022) Novel Loss of Function Variant in BCKDK Causes a Treatable Developmental and Epileptic EncephalopathyBoemer F, Josse C, Luis G, Di Valentin E, Thiry J, Cello C, Caberg JH, Dadoumont C, Harvengt J, Lumaka A, Bours V, Debray FG. Int J Mol Sci. 23(4):2253 (2022) Association Between Human Gut Microbiome and N-Glycan Composition of Total Plasma Proteome. Petrov VA, Sharapov SZ, Shagam L, Nostaeva AV, Pezer M, Li D, Hanić M, McGovern D, Louis E, Rahmouni S, Lauc G, Georges M, Aulchenko YS. Front Microbiol. 13:811922 (2022)

26 GIGA-MBD INPP5E controls ciliary localization of phospholipids and the odor response in olfactory sensory neurons. Ukhanov K, Uytingco C, Green W, Zhang L, Schurmans S, Martens JR. J Cell Sci. 2022 Mar 1;135(5):jcs258364. Unveiling the Metal-Dependent Aggregation Properties of the C-terminal Region of Amyloidogenic Intrinsically Disordered Protein Isoforms DPF3b and DPF3a. Leyder T, Mignon J, Mottet D, Michaux C. Int J Mol Sci. 2022 Dec 4;23(23):15291. Superconserved receptors expressed in the brain: Expression, function, motifs and evolution of an orphan receptor family. Stäubert C, Wozniak M, Dupuis N, Laschet C, Pillaiyar T, Hanson J. Pharmacol Ther. 2022 Dec;240:108217. Sorting and packaging of RNA into extracellular vesicles shape intracellular transcript levels. O’Grady T, Njock MS, Lion M, Bruyr J, Mariavelle E, Galvan B, Boeckx A, Struman I, Dequiedt F. BMC Biol. 2022 Mar 24;20(1):72. GIGA-Neurosciences Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis. Sambon M, Pavlova O, Alhama-Riba J, Wins P, Brans A, Bettendorff L. Biochim Biophys Acta Gen Subj. 2022 Mar;1866(3):130071. Recent insights into gap junction biogenesis in the cochlea. Defourny J, Thiry M (2023). Dev Dyn. Feb;252(2):239-246. Loss of function of the maternal membrane oestrogen receptor ERα alters expansion of trophoblast cells and impacts mouse fertility. Rusidzé M, Faure MC, Sicard P, Raymond-Letron I, Giton F, Vessieres E, Prevot V, Henrion D, Arnal JF, Cornil CA, Lenfant F. Development. 2022 Oct 1;149(19):dev200683. Cyclin-dependent kinase 7 contributes to myelin maintenance in the adult central nervous system and promotes myelin gene expression. Dion V, Schumacher N, Masar N, Pieltain A, Tocquin P, Lesoinne P, Malgrange B, Vandenbosch R, Franzen R. Glia. 2022 Sep;70(9):1652-1665. Neuroendocrine regulation of female aggression. Oliveira VEM, Bakker J. Front Endocrinol (Lausanne). 2022 Aug 10;13:957114. doi: 10.3389/fendo.2022.957114. eCollection 2022. Induction of oxidative stress and alteration of synaptic gene expression in newborn hippocampal granule cells after developmental exposure to Aroclor 1254. Pinson A, Sevrin E, Chatzi C, Le Gac B, Thiry M, Westbrook GL, Parent AS. Neuroendocrinology. 2022 Oct 18:10.1159/000527576. GIGA-Stem Cells A δ-cell subpopulation with a pro-β-cell identity contributes to efficient age-independent recovery in a zebrafish model of diabetes. Carril Pardo CA, Massoz L, Dupont MA, Bergemann D, Bourdouxhe J, Lavergne A, Tarifeño-Saldivia E, Helker CS, Stainier DY, Peers B, Voz MM, Manfroid I. Elife. 2022 Jan 21;11:e67576. doi: 10.7554/ eLife.67576. Identification of an evolutionarily conserved domain in Neurod1 favouring enteroendocrine versus goblet cell fate. Reuter AS, Stern D, Bernard A, Goossens C, Lavergne A, Flasse L, Von Berg V, Manfroid I, Peers B, Voz ML. PLoS Genet. 2022 Mar 14;18(3):e1010109. Scaling brain neurogenesis across evolution. Malgrange B, Nguyen L. Science. 2022 Sep 9;377(6611):1155-1156. The E3 ligase COP1 promotes ERα signaling and suppresses EMT in breast cancer. Tang SC, Lion Q, Peulen O, Chariot P, Lavergne A, Mayer A, Fuster PA, Close P, Klein S, Florin A, Büttner R, Nemazanyy I, Shostak K, Chariot A. Oncogene. 2022 Jan;41(2):173-190. doi: 10.1038/s41388021-02038-3. Epub 2021 Oct 29.


28 INTERVIEW L I ESBET GERI S Liesbet Geris (LG) just got her third ERC grant. Michel Georges (MG), GIGA director, met her to discuss her career, her projects and her point of view on the ERC. MG: Congratulations! A 3rd ERC is a major accomplishment! Do you know if you are the only one to have managed it? LG: I’ve done some checking on the website and I know Peter Carmeliet, Conny Aerts and Patrik Verstreken at KU Leuvne have all received 3 ERC as well. They’ve had 3 advanced grants. So there are some people. MG: It is quite an exclusive club! LG: Yes, it feels a bit unreal to see my name in the list. However, the ERC scheme only started in 2007. I’ve submitted my first one in 2010 so I have been submitting ERCs practically from the beginning. Some of my younger colleagues have had a starting grant and have also already obtained a consolidator grant. I’m sure that short list will become much longer when time goes by. MG: In a nutshell, could you tell us what you are working on? LG: The main field of research of the team is in silico medicine or in silico regenerative medicine. Our main applications are centered around bone and cartilage pathologies and tissue engineering, with a strong focus on the development of enabling technologies in general and in silico enabling technologies in particular. The starting grant was about using developmental biology or the way nature designs bone and cartilage as an inspiration to develop in silico models that would then help us increase the efficiency of tissue engineering approaches in the lab. That took a while and, in fact, we are still working on some of the aspects of that concept. The first consolidator grant was more about developing the combination of in vitro - mesofluidics - and in silico tools to have devices that

29 we could use in the lab to mimic the physical native environment after implantation to test our constructs in vitro before we would implant them. Examples are the testing of new biomaterials or tissue engineered constructs and their interaction with macrophages, or the testing of the influence of vascularization speed through application of different flow regimes in the device. This new consolidator grant focusses again much more on in silico models but it is centered around osteoarthritis and addresses the entire therapy development pipeline up until in silico clinical trials. In those virtual patients cohorts we will investigate both drug related therapeutic approaches and tissue engineering approaches. Each of them of course will be accompanied with the appropriate in vitro and in vivo models that we have to perform the validation. For the first consolidator, I did not get it the first time I submitted it. One of the panel members during the interview commented on the fact that there was again a lot of in silico modeling In a bone tissue engineering application, questioning the novelty of that grant. Of course it was not the same but it made me aware that the information I had put in the abstract was too generic. There is so much work still to be done in the development of computational models as well as in the development of regenerative strategies for bone and cartilage pathologies. Looking at the grants I obtained, there is a continuum. Some elements stay the same but new pieces of the puzzle get added every time. MG: Can you tell us about the composition of your group now? Also in term of what the background is for the people and how you bridge Leuven and Liège? LG: The team is quite diverse in its composition, we have biomedical engineers and chemical engineers, mathematicians, biomedical scientists, an orthopedic surgeon, dentistry MDs and lab technicians. I think it’s very important to have that variety in the group because that way people get really trained on all the aspects of the interdisciplinary field we are working in. I’m very lucky that I have a very good group that works very well together; that are always willing to help the others out and that understand the added value of the other disciplines for their own personal work. Everybody benefits when we all work together. The work in Leuven and Liège is not split very clearly. The advantage of in silico work is that a lot can be done online. We use Slack (app) a lot within the team - also to avoid mail boxes that are already overflowing. Additionally, some people in Leuven are located in the engineering school and some in the hospital so also there they’re not on the same site. We have regular physical meetings for smaller groups and twice a year we organise a team day to bring everyone together. MG: How big is the group now? LG: I have 15 PhD students and 10 postdocs. There are a bit more people in Leuven at the moment because some personal grants were easier to obtain there. 8 to 10 people are working at the GIGA, the rest is in Leuven. MG: What is your background? LG: My background is mechanical engineering, in mechatronics and products design to be precise. There was no biomedical engineering option when I was studying, so I had to wait until my last year of engineering to choose more bio-oriented courses. However, I had known even from before starting my studies that biomedical engineering was where I wanted to go. I went to Leuven for the “info days” and there were some PhD students giving demo’s of their research in biomechanics. That was when I realized that this was the perfect way for me to combine my interests in the sciences, mathematics and biology. I also realized quite early that I wanted to do a PhD to further move towards biomedical engineering. By the time I graduated my master’s, I was really hooked on the computational part and looked for a topic that allowed me to combine the computational work with an application in biomedicine. MG: What is your opinion about the ERC and its meaning? European research in general first and then what do you think it means for a University like ours. In general, the funding for research in Europe LG: I think ERC is really important in the European lands- «The main field of research of the team is in silico medicine or in silico regenerative medicine. Our main applications are centered around bone and cartilage pathologies and tissue engineering, with a strong focus on the development of enabling technologies in general and in silico enabling technologies in particular» «The team is quite diverse in its composition, we have biomedical engineers and chemical engineers, mathematicians, biomedical scientists, an orthopedic surgeon, dentistry MDs and lab technicians»