Five leading European supercomputing centres are committed to develop, within their respective national programs and service portfolios, a set of services that will be federated across a consortium. The work will be undertaken by the following supercomputing centres, which form the High Performance Analytics and Computing (HPAC) Platform of the Human Brain Project (HBP): ▪ Barcelona Supercomputing Centre (BSC) in Spain, ▪ The Italian supercomputing centre CINECA, ▪ The Swiss National Supercomputing Centre CSCS, ▪ The Jülich Supercomputing Centre in Germany, and ▪ Commissariat à l'énergie atomique et aux énergies alternatives (CEA), France (joining in April 2018). The new consortium will be called Fenix and it aims at providing scalable compute and data services in a federated manner. The neuroscience community is of particular interest in this context and the HBP represents a prioritised driver for the Fenix infrastructure design and implementation. The Interactive Computing E-Infrastructure for the HBP (ICEI) project will realise key elements of this Fenix infrastructure that are targeted to meet the needs of the neuroscience community. The participating sites plan for cloud-like services that are compatible with the work cultures of scientific computing and data science. Specifically, this entails developing interactive supercomputing capabilities on the available extreme computing and data systems. Key features of the ICEI infrastructure are: ▪ Scalable compute resources; ▪ A federated data infrastructure; and ▪ Interactive Compute Services providing access to the federated data infrastructure as well as elastic access to the scalable compute resources. The ICEI e-infrastructure will be realised through a coordinated procurement of equipment and R&D services. Furthermore, significant additional parts of the infrastructure and R&D services will be realised within the ICEI project through in-kind contributions from the participating supercomputing centres.

The last of four multi-year work plans will take the HBP to the end of its original incarnation as an EU Future and Emerging Technology Flagship. The plan is that the end of the Flagship will see the start of a new, enduring European scientific research infrastructure, EBRAINS, hopefully on the European Strategy Forum on Research Infrastructures (ESFRI) roadmap. The SGA3 work plan builds on the strong scientific foundations laid in the preceding phases, makes structural adaptations to profit from lessons learned along the way (e.g. transforming the previous Subprojects and Co-Design Projects into fewer, stronger, well-integrated Work Packages) and introduces new participants, with additional capabilities. The SGA3 work plan is built around improved integration and a sharpening of focus, to ensure a strong HBP legacy at the end of this last SGA. In previous phases, the HBP laid the foundation for empowering empirical and theoretical neuroscience to approaching the different spatial and temporal scales using state-of-the-art neuroinformatics, simulation, neuromorphic computing, neurorobotics, as well as high-performance analytics and computing. While these disciplines have been evolving for some years, we now see a convergence in this field and a dramatic speeding-up of progress. Data is driving a scientific revolution that relies heavily on computing to analyse data and to provide the results to the research community. Only with strong computer support, is it possible to translate information into knowledge, into a deeper understanding of brain organisation and diseases, and into technological innovation. In this respect, the underlying Fenix HPC and data e-infrastructure, co-designed with the HBP, will be key. The services offered by EBRAINS will be grouped in six Service Categories: SC1: Curated and shared data: EBRAINS FAIR data services - neuroscience data publishing SC2: Brain atlas services: navigate the brain in 3D - find, contribute and analyse brain data, based on location SC3: Brain modelling and simulation workflows: integrated tools to create and investigate models of the brain SC4: Closed loop AI and robotics workflows: design, test and implement robotic and AI solutions SC5: Medical Data Analytics SC6: Interactive workflows on HPC or NMC: Europe-wide access to scalable and interactive compute services Their users are to be supported with High-Level Support Teams and Vouchers, as well as Engagement and Facility Hubs located around Europe, at which additional services, unique equipment and compute infrastructure will be offered by local HBP Partners. Significant outcomes in relevant scientific communities are expected to materialise rapidly. Association with new Partnering Projects is still sought, along with wider international cooperation. The SGA3 objectives can be summarised as: 1) Establish a sustainable European scientific research infrastructure, EBRAINS, leading to an increased use and adoption of FAIR data, web-based analyses, model building, simulation, atlasing, and virtual experiments for brain research and brain-inspired sciences. 2) Provide a multi-level atlas of the human brain - the first of its kind that links microstructural detail and inter-subject variability. 3) Increase the capacity of neuroscientists for multiscale neural activity modelling of the human brain network. 4) Increase the availability of integrated multiscale data and computational models supporting brain states transitions, network complexity and cognitive functions. 5) Enhance real-world task performance through biologically plausible adaptive cognitive architectures running on neuromorphic hardware and a closed-loop Neurorobotics Platform. 6) Ensure that neuroscientific insights at the interface of neuro-inspired computing and technology are being translated into a benefit for patients with brain diseases. 7) Ensure an ethically and legally compliant infrastructure and promote embedding of Responsible Research and Innovation, a

Diabetes mellitus is a chronic disease characterised by high blood glucose due to inadequate insulin production and/or insulin resistance which affects 382 million people worldwide. Pancreatic islet transplantation is an extremely promising cure for insulin-sensitive diabetes mellitus (ISDM), but side effects of lifelong systemic immunosuppressive therapy, short supply of donor islets and their poor survival and efficacy in the portal vein limit the application of the current clinical procedure to the most at-risk brittle Type I diabetes (T1D) sufferers. The DRIVE consortium will develop a novel suite of bio-interactive hydrogels (β-Gel) and on-demand drug release systems to deliver islets in a protective macrocapsule (β-Shell) to the peritoneum with targeted deposition using a specialised injection catheter (β-Cath). Pancreatic islets will be microencapsulated in β-Gels; biofunctionalised injectable hydrogels containing immunosuppressive agents and polymeric microparticles with tuneable degradation profiles for localised delivery of efficacy cues. These β-Gels will be housed in a porous retrievable macrocapsule, β-Shell, for added retention, engraftment, oxygenation, vascularisation and immunoprotection of the islets. A minimally invasive laparoscopic procedure (O-Fold) will be used to create an omental fold and at the same time deliver β-Shell. An extended residence time in β-Gel will enhance long-term clinical efficacy of the islets and result in improved glycemic control. The novel β-Gels will also be developed as human three-dimensional in-vitro models of in-vivo behaviour. Islet harvesting and preservation technologies will be developed to facilitate their optimised yield, safe handling and transport, and ease of storage. DRIVE will also enable the future treatment of a broader range of T1 and insulin-sensitive T2 diabetics by working with induced pluripotent stem cell experts to ensure the compatibility of our system with future stem cell sources of β-cells.

Colorectal cancer (CRC) is increasingly being recognized as a heterogeneous disease with distinct molecular subtypes. These subtypes have different biological processes at the basis of their disease and consequently their prognosis and responses to therapy are also different. We have previously developed molecular diagnostic assays using a single platform on routine FFPE tumour biopsies. These assays identify gene expression profiles with distinct prognosis and drug response phenotypes (CMS4/c-type, BRAF mutant-like, and MSI-like). Our overall objective is to develop targeted therapies more effective than the current therapies that do not take advantage of molecular classification of the disease to select patients for therapy. We therefore propose to perform 3 two-stage single arm multi-centre open-label phase II studies based on solid preclinical evidence and a sound scientific rationale for these subgroups of CRC patients: 1) combination of chemotherapy and a TGF-βR inhibitor (LY2157299) in patients presenting a C-type signature; 2) vinorelbine in patients with a BRAFm-like signature; and 3) an immunotherapeutic anti-PD-L1 drug (MPDL3280A) in combination with bevacizumab in patients with a MSI-like signature. The primary objectives of these studies are to determine the clinical efficacy (progression-free survival as primary endpoint), safety and tolerability of the experimental treatments in these molecularly selected populations. Mutation analysis at the beginning of treatment and monitoring by liquid biopsies might reveal further biomarkers that predict response in retrospective analysis. The project outcomes may have a significant impact in CRC patients with poor-risk prognosis worldwide as 40-50% of them present gene expression profiles matching one of the 3 approaches. Around 40,000 European CRC patients may potentially benefit from the results. Also, these may be translated to other cancer types with equivalent gene expression patterns/deregulated signalling pathways.

Understanding the human brain is one of the greatest scientific challenges of our time. Such an understanding can provide profound insights into our humanity, leading to fundamentally new computing technologies, and transforming the diagnosis and treatment of brain disorders. Modern ICT brings this prospect within reach. The HBP Flagship Initiative (HBP) thus proposes a unique strategy that uses ICT to integrate neuroscience data from around the world, to develop a unified multi-level understanding of the brain and diseases, and ultimately to emulate its computational capabilities. The goal is to catalyze a global collaborative effort. During the HBP’s first Specific Grant Agreement (SGA1), the HBP Core Project will outline the basis for building and operating a tightly integrated Research Infrastructure, providing HBP researchers and the scientific Community with unique resources and capabilities. Partnering Projects will enable independent research groups to expand the capabilities of the HBP Platforms, in order to use them to address otherwise intractable problems in neuroscience, computing and medicine in the future. In addition, collaborations with other national, European and international initiatives will create synergies, maximizing returns on research investment. SGA1 covers the detailed steps that will be taken to move the HBP closer to achieving its ambitious Flagship Objectives.