One of the major challenges in understanding the complex immune system is the question when and why this defense system attacks endogenous proteins (i.e. self-proteins). Currently, there are no reliable methods to predict what induces such an immune response, despite it has a major impact in medicine by causing autoimmune diseases, and in biotechnology by inducing adverse reactions towards new drugs. PredicTOOL will concentrate on antibody-mediated immune reactions to endogenous proteins. By high sensitivity nanotechnological tools based on spectroscopic and imaging techniques (e.g. Circular Dichroism Spectroscopy, Single Molecule Force Spectroscopy, Isothermal Titration Calorimetry, Fluorescence Microscopy), PredicTOOL will identify common patterns that characterize the interaction of autoantibodies with their antigens and further interaction with cells of the immune system. We will use well characterized human model diseases (cardiovascular). The proposed technologies will allow applying the rules of classic mechanics to identify the pattern of autoantibody-antigen interactions and will lead to better understand why an endogenous protein induces an immune response. The project aims to: i) identify patterns expressed in proteins to which autoantibodies bind on a nanometer scale; ii) investigate whether certain mutations or post-translational changes in the proteins facilitate conformational changes leading to expression of such patterns; iii) assess the binding of human autoantibodies to such modified proteins and compare this with the binding to the wild type/native protein; and iv) develop a platform of microstructured arrays to investigate immunogenic proteins. The results of this highly interdisciplinary and translational project will allow to better understand autoimmunity and to develop new ways for prevention and treatment in medicine, and to optimize the production of safer biotherapeutic drugs. The vision of PredicTOOL is that physics has the potential to substantially change the view on the pathogenesis of autoimmunity. It is highly interdisciplinary and bridges in a translational approach, immunology, physics, biotechnology and medicine. It targets to identify patterns driving antibody-mediated cardiovascular diseases. The project bears two major areas of application. In medicine, it can lead to better understand autoimmunity and to develop new ways for prevention and treatment. In the development of biotherapeutics, it can help to finally produce safer biotherapeutic drugs. The biggest strength of the project is to directly work in the human system (proteins and antibodies) applying state-of-the-art nanotechnological techniques and physical methods. We have already established the proof-of-principle of our approach using PF4/heparin model system, which now allows transferring our findings to other proteins to identify common patterns.

The greenerRPP project aims to markedly enhance the EU’s capacity for the production of secreted high-quality recombinant proteins, especially industrial enzymes and therapeutic proteins (biotherapeutics). The combined markets are in excess of $330 billion p.a., and the products are of massive significance for healthcare and a sustainable bio-based economy. greenerRPP will address urgent problems in these industries, such as difficult-to-express proteins and the rapidly-emerging issue of 'sustainability' in the European biotechnology industry. It will deliver improvements in yield and process design that increase the industry's effectiveness while simultaneously reducing high current levels of waste. It will deliver industrial enzymes that reduce energy and raw material costs in countless industrial and domestic settings. To achieve this, we will develop powerful new microbial and mammalian cell platforms that produce recombinant proteins in unusually high quantities and in unparalleled quality, and bring to market a suite of super-producing platforms. A comprehensive training programme will equip greenerRPP ESRs with the interdisciplinary and intersectoral skills required to be future leaders in these industries, while emphasising sustainability and gender-diversity dimension principles at every level. Finally, the programme addresses the stark global inequality in this biotechnology sector: recombinant protein production is largely carried out in (or outsourced by) high-income countries, placing low/middle income countries at a massive disadvantage. greenerRPP includes a series of South East Asian Institutions as Associated Partners, to develop a global network with a knowledge exchange-secondment programme that boosts these countries' own manufacturing programmes. greenerRPP ESRs will thus enhance a European industrial sector that has never been more important to society, while making it 'greener' and reaching out to lower income countries.

The iodine status is a primary determinant of thyroid disorders, which are a major cause of morbidity, particularly in women. In addition, even mild-to-moderate iodine deficiency during pregnancy is related to neurocognitive impairment in the offspring. Iodine deficiency imposes tremendous costs on the health-care systems of affected regions, but can easily be prevented by iodine fortification programmes. In many countries, iodine deficiency receives surprisingly little publicity. The initial EUthyroid consortium evaluated European prevention programmes against iodine deficiency and uncovered major limitations including the low awareness on the importance of iodine for healthy living. EUthyroid2 will now fill important gaps in the prevention of iodine deficiency in Europe and beyond. The main objective of EUthyroid2 is to improve the low awareness with respect to iodine deficiency-related risks in adolescents and young women. The major aim is to find best practice models for accessing and informing them to increase their awareness and to improve their iodine status in order to lay the foundation for their own thyroid and general health and that of their offspring. Implementation studies and community-based randomised-controlled trials will be conducted with the objective of increasing iodine-related awareness in adolescents and young women up to age of 24 before pregnancy. The interventions are multimodal and performed in the two settings educational system and ambulatory care in eight study regions. As public health project EUthyroid2 is not only science, but will also serve our societies. Therefore, dissemination of findings to various sectors of our countries and the EU will be of utmost importance. By finding best practice models to raise the awareness on the importance of iodine for a healthy life of their own and their offspring in young people, EUthyroid2 will lay the foundation for a cost-effective way to eradicate iodine deficiency-related disorders.

DEFENDER will address the need for innovative intervention strategies against viruses with epidemic potential, by adopting a comprehensive and integrative platform approach. DEFENDER’s revolutionary Research and Innovation pipeline will focus on preventing virus entry through a host-directed bottom-up approach based on functional genetics in parallel to a top-down virus glycoprotein-centered approach. We will identify novel host dependency and restriction factors, including receptors and proteins involved in viral attachment and binding, endosomal uptake and virus genome uncoating, as targets for antiviral therapy. In parallel, we will use recombinant viral glycoproteins to identify broadly neutralizing nanobodies and novel epitopes for the AI-based design of next generation immunogens and the improvement of therapeutic antibodies. The host bottom-up functional genetic approach will be applied to Nipah, Lassa, Zika, Dengue, Yellow fever, and Chikungunya viruses. Host factors will be identified using a unique arrayed CRISPR perturbation platform, combined with advanced statistical and machine learning approaches and mathematical modelling, mechanistic experiments, and cutting-edge imaging techniques. In parallel, the virus top-down glycoprotein-centered approach will lead to the identification and structural characterization of broadly neutralizing nanobodies targeting conserved epitopes of the glycoproteins of Nipah and Lassa viruses in pre-fusion conformation. DEFENDER will deliver innovative antiviral candidates that induce target degradation, next generation immunogens, and a novel concept to improve the activity of therapeutic antibodies, with proof-of-concept preclinical evaluation in mice. It will define the most vulnerable virus-host interactions, to deliver a robust development pipeline for novel antivirals, therapeutic antibodies, and immunogens and increase antiviral options against a wide range of priority (re-) emerging viruses.

Developing new antiviral treatment against viruses and particularly high-priority emerging and re-emerging viruses as listed by the WHO, remains crucial as, among other aspects, the viruses evolve under selection. Broad spectrum host-directed antiviral drugs (HDA) are promising therapeutic options, however the robust identification of relevant host factors by genome-wide knockout screens is challenging due to low consistency in the resulting hits. Our project aims to (1) establish a computational and experimental pipeline to identify and validate an antiviral for these viruses, and (2) identify at least one broad spectrum antiviral drug against potential emerging and re-emerging viruses as listed by the WHO. To address these, we will implement a drug selection pipeline following several strategies: We will employ (i) machine learning, based on data from knockout screens, proteomics, protein interaction, transcriptomics of infected cells with pandemic-related viruses, Genome-Wide Association Studies, and generic gene descriptors, (ii) High Density Cell Arrays, which provide much more detailed readouts compared to state of the art pooled knockout screens, (iii) primary cell cultures obtained from a diverse array of human tissues, as they are more appropriate to study the host cell physiology during infection, compared to cancer cell lines, and (iv) use the pipeline to identify host restriction factors, which, when activated, challenge the virus; followed by innovative drug development and delivery based on small activating RNA. The pipeline comprises an Expedited Arm for which broad spectrum antiviral drugs for repurposing will be selected followed by in vitro and in vivo efficacy testing, and a clinical trial as a proof of concept. The elaborated Arm includes all strategies (i)-(iv) and will provide a sustainable pandemic preparedness pipeline ready-to-operate to identify the appropriate treatment against the emerging virus at the early time of a new outbreak.