Multiple Sclerosis (MS) is the most frequent neuroinflammatory disease. Despite new treatments that slow the progression of the disease, patients with MS (PwMS) frequently evolve towards major disability. The pathogenesis of MS is controversially debated, but the recent discovery that infection with the Epstein-Barr virus (EBV) is a major risk factor will radically change research avenues. The BEHIND-MS consortium ambitions to understand how EBV promotes MS development. To this end, we have established a multidisciplinary team that will for the first time draw a comprehensive map of the interactions between the virus and all arms of the immune system in the blood and brain of PwMS and how they ultimately lead to neural damage, in the context of genetic risk factors. We will also develop an in vitro model of MS that integrates the virus, the immune system and brain cells reprogrammed from the blood of the same PwMS. Thus, for the first time, we will study in the laboratory the complex molecular mechanisms that give rise to MS. Finally, we will develop an animal model of prodromal MS that would be a ‘game changer’ for our understanding of MS pathogenesis and allow testing of promising new treatments. The pivotal knowledge developed in this project will empower the entire healthcare value chain to work towards better clinical management of MS. A detailed understanding of EBV-MS interactions, combined with newly identified biomarkers, and study models will open the doors for researchers, clinicians and industry to capitalize on the mechanisms underlying EBV-MS interactions, and develop new diagnostic, preventive and therapeutic tools and guidelines. Throughout the project, an open dialogue with the main stakeholder representatives will ensure a mutual understanding of patient needs and project results. Ultimately, by contributing to improved risk analysis, stratification and treatment strategies, BEHIND-MS has the potential to reduce the burden of MS on society.

The pathological alterations of neurological function (e.g. stroke, trauma, neurodegeneration, epilepsy, neuropsychiatric diseases, chronic pain) are commonly associated with alterations in brain rhythms and activity patterns. There is an urgent clinical need for treatments that can precisely control and restore neural activity, taking advantage of state-of-the-art technological developments in a variety of fields including nanotechnology, nano- and microelectronics, novel materials, brain science, clinical neurology, and computational modelling. META-BRAIN (MagnetoElectric and Ultrasonic Technology for Advanced BRAIN modulation) brings together seven expert partners in these fields with the aim of achieving precise spatiotemporal control of brain activity using magnetoelectric nanoarchitectures that can be polarized by non-invasive, remote magnetic fields. This novel principle of brain activity control will minimize the amplitude of the required magnetic fields, be wireless, and have enhanced spatial resolution from single neurons to cortical areas. We will develop a model-driven fabrication of the coils and monitor the effects on brain function with arrays of graphene microtransistors that uniquely allow full-band recording, integrating all elements in a closed loop. As an alternative to remote brain stimulation we will also use novel ultrasonic technologies. The META-BRAIN control paradigm will be systematically studied in pre-clinical systems from individual neurons to the full brain. All developments and experiments will be carried out in conjunction with theoretical models that will simulate, quantify, and predict optimal arrangements and patterns for the desired output. Translation to humans will be evaluated with our clinical partners, and a detailed dissemination and exploitation plan will be developed by two expert company partners, one of which has extensive expertise in the fabrication of brain interface devices with a worldwide distribution capability.

Starting from a unique collection of paleo-environmental samples (frozen Arctic soils and sediments) already at AWI and their corresponding ancient DNA (aDNA) metagenomes that stretch back up to a million years, we will retrieve information on how rhizosphere biodiversity and functionality responded to climate changes and extreme events. Preliminary metagenomic data from the collection suggests it is a gold mine of archaic DNA that represents a timeline of adaptions to climate change in the rhizosphere. By reconstructing and analyzing these ancient metagenomes and correlating with available historical climatic change data, we will identify molecular adaptions that impart climate tolerance (specifically resistance to increased temperature and drought). This will be used to i) produce and test engineered root-colonizing bacteria (Pseudomonas fluorescens and Pseudomonas chlororaphis) that will improve climate tolerance of plants (production of humidifying polysaccharides around the root) facilitating the ability to grow on marginal agricultural land (MAL), ii) inform ancestral reconstruction of thermostable and/or cold tolerant enzymes for industrial application and iii) produce engineered Pseudomonas putida strains tailored for bioproduction. For the latter application, we will select genes that encode biomolecules relevant for climate-tolerant phenotypes (humidifying polysaccharides and the biosurfactant betaines). The production of these molecules using biotechnology will be targeted in the project and their application in selected industrial products verified. Target end-user applications will include polysaccharides and betaines for the development of 3D printed organ-on-chip and drug delivery systems as well as the formulation of metalworking fluids, lubricants and industrial cleaning products.