Final Report Summary - ISBE (Infrastructure for Systems Biology - Europe)
Executive Summary:
The modern life sciences are making big steps in analysing living organisms. This is fuelled by the development of powerful technologies, such as genomics, proteomics, metabolomics, imaging and many more resulting in important new insight and a true data deluge. Despite these successes our understanding of how living systems function is still remarkably limited. Here, ‘understanding’ is defined as being able to correctly predict the functioning of systems after changing their components or their environment.
Systems biology is a branch of the life sciences that can create understanding through integrating multiple and diverse data sets in quantitative computational models. These models are able to predict the behaviour of biological systems based on experimental data about the interplay of molecules, cells and tissues in time and space. This level of understanding can make a huge impact on health, biotechnology and sustainability, whilst fuelling the bioeconomy. As such, national governments and the European Commission have recognised the importance of systems biology, investing considerably in the past decade. In ISBE, European countries are joining forces to create a research infrastructure for systems biology by building on national strengths to meet European needs.
Infrastructure for Systems Biology Europe (ISBE) will be a knowledge-based research infrastructure that will add value to national and European investments by empowering European researchers across academia, medicine and industry to implement systems biology approaches. It will enable easy access to expertise, resources and training and offer hands-on support in building and using computational models based on model-compliant high quality data. To be effective, ISBE will take responsibility for the development and implementation of community standards to make data, models and tools re-usable over prolonged periods of time. This is essential for progress in the life sciences and, importantly, makes research more efficient and cost-effective.
ISBE’s offerings to the scientific community are based on surveys of the needs of different user communities and potential provider institutions in Europe. ISBE will consist of a collaborative and synergistic matrix of national systems biology centres with overlapping and complementary expertise, each centre being tightly linked to its national systems biology research community. Activities of the centres will be coordinated and overseen at the European level by a central ISBE office, headed by an ISBE director and a supervisory board of stakeholders.
Project Context and Objectives:
The ISBE preparatory phase project had 3 major objectives:
• Identification of existing activities and consultation with stakeholders regarding the technical requirements of the infrastructure.
• A proposal outlining the recommendations for the technical specifications of the physical infrastructure, required technologies and access policies
• Development and negotiation of a business plan and sustainable funding model for the construction and operational phase of ISBE
The proposed model for ISBE is built on extensive project work carried out by the individual work packages as well as consultations with future user and provider communities during the ISBE preparatory phase. Surveys and interviews have been carried out with stakeholder groups in academia, hospitals and clinics and industry, including SMEs, as well as with national funders and scientific journals, to inform the ISBE strategy. The ISBE strategy has also been informed by the developing landscape of European Research Infrastructures in the life sciences.
The ongoing challenge in the life sciences is to convert the huge amount of biological data that we produce into an understanding of how living systems function to a level that enables successful prediction of their operations and of changing their components or networks - see ISBE publication Success Stories in Systems Biology, 2015 (http://project.isbe.eu/systems-biology/case-studies/). Intelligent, computational model-driven approaches are essential to deal with the extreme complexity of biological systems. This is a game-changing goal for the life sciences for the next ten years and is made possible by recent rapid technological developments, such as genomics, proteomics, metabolomics, advanced imaging, bioinformatics and our rapidly increasing understanding of tissues and organs. This has been recognised by national funding organisations and the European Commission, resulting in significant investments and many major research programmes dedicated to systems biology in the past 10 years.
European investment in systems biology initially focussed on the development and use of predictive models, so far mostly at the molecular level, such as metabolic networks within cells. More recently, there has been a clear shift towards the implementation of systems biology approaches within biomedical research (known as ‘systems medicine’) and across the biotech industry. Recent examples include the transnational programme Coordinating Action Systems Medicine (CASyM), the ERANet projects ERACoSysMed and ERASysApp and various EU programmes that are part of the Bio-Based Industries (BBI) funding scheme.
Recent developments include the use of multi-scale modelling, which aims at understanding the functioning of complete organs and organisms as the result of the dynamic interplay in time and space of molecules, cells, tissues. Here, molecular and cellular biology meet physiology. Such integrative efforts are already creating a strong basis for new avenues in biomedical and pharmaceutical research. Examples include the virtual human heart ( http://thevirtualheart.org/ ), the Virtual Liver Network (http://www.virtual-liver.de/ ), the Human Metabolic Atlas (www.metabolicatlas.org) and other projects within the international Virtual Physiological Human (VPH) programme( http://www.vph-institute.org/ ).
Whilst prior investments have created a solid knowledge base for systems biology in a number of European countries, dissemination and uptake is still slow. Reasons include:
• Protocols for properly planning and executing experiments and acquisition of high quality, quantitative data that can be integrated in computational models are not yet widely used.
• Expertise required to build and use high quality predictive computational models is limited and will not grow without widespread integration into biological and biomedical academic curricula, while lack of suitable for training for industry is also inhibiting take up.
• Integrated stewardship of results is still in its infancy. This includes annotation and curation of model-compliant data sets and making them findable and re-usable over prolonged periods of time.
• Slow translation of systems biology approaches into clinically and commercially usable application.
ISBE’s vision is that systems level approaches should be within reach of the majority of European life scientists to accelerate a fast adoption and translation into new research findings and industrial applications. This will increase the competitiveness of the European Research Area as well as in health and the bio-economy industry. ISBE therefore intends to make the necessary expertise, services, tools and resources easily and openly accessible to scientists in academia, hospitals and clinics and for industry, in particular SMEs. This process will be enhanced by European education and training programmes and a range of community activities, such as the development and implementation of standards.
ISBE’s strategy is to support the European Research Area by building on existing national investments, expertise and strengths and harnessing the experience of national and transnational initiatives in systems biology, such as the ERANET programmes. ISBE will not have a research programme itself. Rather, it will support research projects and programmes of its users, i.e. individual researchers, research groups and research consortia.
ISBE will consist of a European matrix of national systems biology centres that offer expertise, services and resources. The activities of the centres will be coordinated at the European level by a central office. Each centre will be tightly linked to national systems biology research groups and therefore well-embedded within the local research community. The collaborating national ISBE centres will offer a broad range of expertise, services and resources to life scientists in academia, clinics and industry across Europe through a single ISBE web-based portal.
The 2010 ESFRI Roadmap lists 13 research infrastructures in the life sciences, including ISBE. They complement each other, together forming a strong basis for the development and dissemination of knowledge and the provision of services. The essence of systems biology is to integrate diverse data and technologies to obtain a complete picture of biological systems. Building on this vision, ISBE is already collaborating with the 12 other biomedical ESFRI research infrastructures to harmonise and optimise their procedures and offerings, through the Horizon 2020 funded programmes COordinated Research Infrastructures Building Enduring Life-science Services (CORBEL) and RItrain.
Project Results:
Contents:
1. Rationale
2. The Research Infrastructure
3. Stewardship and Standardisation
4. Modelling of biological systems based on integration of diverse data sets
5. Facilitating model-compliant data generation
6. Community Activities
7. Training and Education
8. Organisational structure
9. Access to ISBE
10. Providers of ISBE services
11. Legal and Governance (from 2018)
12. The ISBE Funding Strategy
13. Financial model for the national level (nSBCs)
14. Financial model for European operations (CIO)
15. Further expansion of ISBE
16. Services and community activities
17. The interim phase - building the infrastructure
17.1. Interim Phase Stage 1 (2015-2016)
17.2. Interim Phase Stage 2 (2016-2018)
18. Legal Basis for ISBE
19. Measuring Wider Impact
The results of the preparatory phase culminated in, and were integrated through, the publication of the ISBE Business Plan in July 2015. The Business Plan, itself, is an update and expansion of the ISBE Business Case published in November 2014. The Business Plan outlines the rationale for ISBE, the physical infrastructure, the plans for services and access, the legal and governance structure and financial aspects of the research infrastructure. It also sets out how ISBE will be built during the interim phase from 2015 till 2018, with the commencement of “ISBE-light”. The ISBE Business Plan is the result of the collaborative activity of 23 research institutions and funding agencies in 11 European member states in the context of the European Strategy Forum on Research Infrastructures (ESFRI) Roadmap.
1.Rationale:
Over the past sixty years the life sciences have developed at an ever increasing pace. The discovery of the double helix structure of DNA in the early 1950s may be taken as the starting point of the molecular biology revolution, which radically changed our understanding of living systems. Scientific and technological progress in molecular and cell biology in the years that followed has included cloning, sequencing of the human genome, and the ever growing power of -omics technologies and other methodologies that allow genome-wide analysis of the molecular components of life. This has led to the dawning of a new biological age that is now beginning to give us deep insight into how living systems function, with a rapidly growing impact on human health, food, sustainability and the economy.
The traditional approach to research in the life sciences has been one of reductionism. However, the data explosion in the life sciences, including health-related research, means that biological data can no longer be analysed and interpreted in a useful way without taking into account the broader context of the living organism. Because of exponentially growing volumes of data and the complexity of biological systems, new approaches had to be developed to integrate the diverse data sets of molecules, cells and tissues and convert this ‘information’ to ‘understanding’. Here, ‘understanding’ means the ability to successfully predict how biological systems behave after changing environmental conditions or altering molecular components.
Converting data to understanding is systems biology, which addresses the emergence of biological function from the dynamic interactions of the components of biological systems. It embraces systems theory, an approach that is fully incorporated in other areas of science and in engineering. Biological systems are highly dynamic, with many components and interactions. Thus their functioning can only be understood by building quantitative and predictive computational models based on experimental data. This is at the heart of systems biology and it is this knowledge-based approach that is the central offering of the Infrastructure for Systems Biology Europe (ISBE) to the life sciences community.
Our rapidly growing capacity to understand and rationally alter living systems is beginning to have a major impact on human health, food and feed production and sustainability. Metabolic engineering of microorganisms and the integrated model of the beating human heart, which predicts the - often counter intuitive - effects of potential drugs, are just two examples. The economic effects of these developments in the life sciences cannot be overestimated. The importance of the bioeconomy in Europe is growing rapidly. The EU's bioeconomy sectors in 2012 were worth € 2,000 billion in annual turnover and account for more than 22 million jobs representing approximately 9% of the EU workforce (reference: Innovating for Sustainable Growth: A Bioeconomy for Europe; COM (2012) final; European Commission: Brussels, Belgium, 2012). The systems biology approach is a strong research base that translates into industrial products and processes and in healthcare. This is a primary reason for recent significant investment in systems biology for the European life sciences community. This has also been reflected more widely by significant international investments, such as the Institute of Systems Biology in Seattle and the Systems Biology Institute in Tokyo to support their considerable and growing research effort in this area.
To make this effort both effective and efficient requires the creation of an environment, an infrastructure, for systems biology in Europe that is capable of coordinating and leveraging the science base.
The aim of ISBE is to make resources, expertise and training in systems biology readily accessible to European researchers, clinicians and industry, including SMEs, and to actively support their research efforts. ISBE builds on over a decade of national and EU support in systems biology and will coordinate and synergise future investment. It will actively support researchers in:
• addressing how the dynamic interactions between biological components (molecules, cells, tissues, organs) leads to the functioning of living organisms in a constantly changing environment,
• creating predictive computational multi-scale models of living systems, up to complete organisms, representing these interactions,
• exploiting such models to generate major socio-economic benefits in areas including pharmaceuticals and healthcare, agricultural science, energy and the environment.
The ISBE research infrastructure will consist of a matrix of interconnected national centres of excellence in systems biology, coordinated and managed at the European level.
Building understanding of the functioning of hugely complex biological systems is a process that takes time, in which predictive models improve and expand stepwise. Therefore, it is essential that data, procedures and models can be re-used and are accessible over long periods of time. A primary function of ISBE will be to harness the community in the development and implementation of standards and operating procedures that enable and promote re-usability. Through the ISBE infrastructure, European researchers from across the life sciences will have access to the best systems biology research expertise, tools, services and training via a single portal.
2.The research infrastructure:
The ISBE infrastructure is designed to meet the needs of three broad and interlinking life science research communities in academia, clinical research and industry. ISBE will offer services and resources that are valuable for all branches of the life sciences, independent of the type of organism or biological system studied. Systems biology creates a strong unifying and theory-based foundation in the life sciences.
ISBE will provide efficient access to core research assets of systems biology, i.e. maps, models, data, and tools. Assets will include (i) user research assets that are managed and curated by ISBE to ensure quality and reproducibility and (ii) publicly available model-compliant research assets that have been selected by ISBE. These will be made available in a cataloguing resource which contextualises information according to biological phenomena rather than data type. For example, assets describing the human liver will be organised together, along a hierarchical map of the liver. This method of organising resources will not transfer data, maps, models and tool physically, but will work with links, pointers and web services, leaving the items at a repository managed locally or by collaborating research infrastructures (such as ELIXIR, the European life science data management research infrastructure) with whom ISBE has developed a number of guiding principles for effective management and sharing of data.
Offering systematic asset management tools to ISBE users will enhance the ‘findability’ and ‘integratability’ of data, models, SOPs, maps, software and tools. This will considerably enhance the efficiency of life sciences research and increase its impact on society. It is stressed that this aspect of ISBE’s activities is generic, i.e. not restricted to specific fields or levels of complexity in biology, biotechnology and health-related research.
Research assets will be attributed to their authors’ profiles, which will be made available in a catalogued resource. This constitutes a valuable source for life scientists who want to complement their research efforts with high quality results from other studies. It is an additional way of creating impact by easy deposition into specialised data sources provided by other research infrastructures such as ELIXIR. In this context ISBE will offer expertise for direct curation of models, standard operating procedures (SOPs) and data, tools and protocols linked to them, with persistent identifiers (for example digital object identifiers (DOIs)) for easy access, attribution and citation. Centralisation of access to assets in ISBE will increase the breadth of audience and, as a result, the impact that published assets can have. This will incentivise researchers to deposit their data, tools, models and maps.
ISBE will ensure sustained and dedicated public resources for research asset management over the long-term. Helping establish sustainable funding models for all resources is considered key for systems biology research asset management. The resources will also provide, in conjunction with research infrastructures such as BBMRI and ELIXIR, provisions for commercially and personally sensitive data.
3.Stewardship and Standardisation:
ISBE will offer an online ‘Knowledge Hub‘ providing best practice material and tutorials to assist researchers in making their research assets FAIR compliant, that is findable, accessible, interoperable, and reproducible. The material will include identifying the most suitable formats, ontologies for annotation, and best practice usage of them, for a wide variety of research assets. Importantly, this will make maps, data, tools and models re-usable over prolonged periods of time, in follow-up research projects and by other researchers, adding significant value to research investment. In this context, a key activity of ISBE will be advocacy for the development and adoption of best practice, community standards, and minimum description models, setting in motion their habitual use by the community. ISBE’s support to make research assets of its users re-usable over prolonged periods will make research more efficient and considerably improve its cost-effectiveness.
Supporting the experimental design phase with expert knowledge ensures suitable data is collected for downstream use. After this, advice on integration of data into models, followed by model validation is important. The framework which supports the scientific process, the collaborative data infrastructure, needs to support storage and access to the data and models, as well as access to infrastructure services that assist with data and model analysis including simulation software for models, and data analysis software. A mediating layer is needed that simplifies the accessibility and usability of the software for the users, allowing smoother interoperating of the research assets in different analysis software, and also makes the storage and availability of research assets in multiple platforms simpler for the user.
Data curation, in this context, refers to the skills and due process that would be required to format and annotate data, models and SOPs to a suitable standard, their storage, maintenance, and eventual disposal over their lifetime. This might include direct curation by centre experts, training of producers/users to curate their own data and models, and would also involve clear management plans for length of storage and privacy requirements. Data curation components involve:
(i) the development of community standards and best practices for maps, data, tools, models and SOPS;
(ii) the provision of brokerage services to bring researchers in contact with external research infrastructures or institutes with experimental design and data generation capabilities in compliance with ISBE standards;
(iii) Training to disseminate better data management practices throughout the community.
The single most important aspect is trust. Service providers must trust researchers to format, annotate and make their data and models available according to a base level of requirements. Providers must trust the infrastructure to store and maintain their data, models, and SOPs for the lifetime of their data management agreement – including the security of sensitive research assets, and the ability to maintain intellectual property rights where appropriate. Providers also must trust that they can get adequate acknowledgement and credit if their research assets are reused in other projects – much like with paper citations at present.
4.Modelling of biological systems based on integration of diverse data sets:
Modelling is at the heart of systems biology. ISBE will support life scientists, either proficient or unskilled in systems biology, to develop and use quantitative and predictive computational models to understand the functioning of complex biological systems. These services will include model-supported data integration and data analysis, model analysis and validation, model-based simulation and analysis of system behaviour, and model construction. Increasingly, this involves integration of highly diverse data sets and a variety of pre-existing models, in multi-scale models that span large time scales and length scales.
ISBE will offer a wide range of modelling methodologies for systems ranging from subcellular molecular networks through to cells, tissues, and organs up to complete organisms in their dynamic environment. In this, ISBE will draw on a broad range of genome wide maps, Boolean, Bayesian, and Petrinet models, all the way up to multi-scale models that harbour mixtures of multidimensional, stochastic and partial differential equation models and integrate the molecular, cellular and physiological levels.
As scientists that are not experienced in modelling of biological systems are a major target of its services, ISBE will enable a wide range of researchers to use computational modelling to integrate diverse data sets and explore, predict and test the behaviour of complex biological systems in biotechnology and health research. This will support the conversion of information about systems into system level understanding.
5.Facilitating model-compliant data generation:
Most existing biological data sets are unsuitable for systems biology modelling: they are incomplete, unannotated, or have been acquired for other purposes. Researchers active in the systems biology field generally require precise data obtained under defined experimental conditions which must be described adequately if they are to be validly reused. Improving the generation of model-compliant data is not simple. It requires, firstly, systems biology compliant experimental design and then a strong framework of activities that support a smooth pathway from data, model, SOP and other research asset generation, through to storage, followed by search, access, and reuse by downstream users.
To address this, ISBE will facilitate the generation of data suitable for systems biology through: (i) the development of community standards and best practices for maps, data, tools, models and SOPS; (ii) the provision of brokerage services to bring researchers in contact with external research infrastructures or institutes with experimental design and data generation capabilities in compliance with ISBE standards; and (iii) support in the experimental design phase and throughout the data generation, integration, modelling and model validation process, in order to obtain model-compliant data.
6.Community activities:
The ISBE user and provider communities are the infrastructure’s greatest resource. ISBE will harness their expertise in a range of community-led activities across its systems biology and life science stakeholders:
• integral map, model and data curation
• development and implementation of community standards, in collaboration with the life science community and international systems biology journals
• foster the maintenance and development of systems biology formatting and annotation standards, such as Systems Biology Markup Language (SBML), Simulation Experiment Description Markup Language (SED-ML), and Minimum Information Required In the Annotation of Models (MIRIAM)
• promote the development of standards for the exchange of information between models dealing with time varying but spatially lumped processes, such as CellML, and spatially and time varying processes, such as FieldML.
• serve as a contact for worldwide initiatives and collaborations in systems biology-related fields
• be a key player in the collaboration between and the harmonisation of activities of the thirteen life sciences ESFRI research infrastructures in the context of the CORBEL programme
• cooperate with and contribute to harmonisation between European systems biology-oriented research programmes and activities, such as Virtual Physiological Human, ERASysApp, Coordinating Action Systems Medicine (CASYM), ERACoSysMed and ERASynBio
• promote, support and contribute to the organisation of international congresses in the field of systems biology
• develop and maintain the European Systems Biology Community website (community.isbe.eu) as a portal for networking and community engagement
7.Training and education:
Education and training in systems biology is vital for ensuring the effective adoption of systems biology approaches to tackle today’s societal challenges. ISBE’s ambition is to train a new generation of systems biologists equipped with the cross-disciplinary skills. This will be important not just for systems biology, but it will also have applications in many areas of academia, government, industry, consultancy and other non-governmental organisations.
ISBE’s multi-faceted training strategy consists of the following key elements:
• User training and continued professional development
ISBE’s national Systems Biology Centres will provide bespoke training to ensure effective utilisation of its tools, services and resources. This training will range from starter courses for novices to specialised training for experts and tailored courses for industrial users. ISBE will work with, and learn from, other research infrastructures to develop a training strategy which encompasses a range of learning methods to ensure maximum efficacy.
• Education
Together with ERASysApp, ISBE has developed a core curriculum for Masters level students in systems biology which will be disseminated through various communication channels (publication, website and conferences) and implemented as a pilot project through interested universities.
• Dissemination of information on education and training
ISBE will maintain a comprehensive and up-to-date database of systems biology-related education, courses, workshops and conferences and make this information openly available. If ISBE identifies major gaps in knowledge dissemination or development, it will lobby national and European organisations to take the initiative, or will develop courses itself.
• Training of staff managing and operating research infrastructures
The complexity of research infrastructures and the exploitation of their full potential requires suitably trained managers and technical operators. As a key participant in the recently funded Horizon 2020 CORBEL and RItrain projects, ISBE is working with other European research infrastructures to develop and support the training of staff managing and operating research infrastructures including the exchange of staff and best practices between facilities. The development and establishment of a Masters in Research Infrastructure Management within the RItrain project will contribute to the supply of human resources with the requisite skills.
ISBE will build on existing European resources and draw on the national technological and scientific strengths of its providers to offer a comprehensive portfolio of services and resources. ISBE will map onto existing national structures and coordinate and synergise facilities under a single banner, creating ease of access for its users. This will stimulate growth in the user-base of existing resources, providing a return on existing investments while keeping coordination costs minimal.
The core of ISBE will be a distributed knowledge-based infrastructure of national Systems Biology Centres (nSBCs) across Europe, offering interconnected and complementary services and resources both nationally and transnationally.
This will create a European infrastructure that:
• aims to cover all facets of the rapidly developing field of systems biology
• synergises past, present and future national and European investments in systems biology
• has a highly flexible capacity to provide an integrated range of services
• provides coordinated services with other European research infrastructures
8.Organisational structure:
National Systems Biology Centres (nSBCs) are the cornerstone of the ISBE research infrastructure. Embedded in their national life science community, each will deliver the portfolio of standard ISBE services and resources, as well as bespoke services based on the expertise of institutions in their country. nSBCs will serve (i) their national user-base including academia and industry, (ii) transnational users, as well as (iii) multinational projects. Trans- and multinational activities will run through collaborations of two or more nSBCs that are coordinated through the Central ISBE Office (CIO) and the coordinating SBC (cSBC). Managing individual nSBCs within the context of the ISBE infrastructure will be the responsibility of the relevant national authority.
In principle, a country will maintain one nSBC which will constitute the primary vehicle for providing services to the national community. This nSBC may be a single national institution or a distributed centre drawing expertise from a number of different institutions in a country.
The Central ISBE Office (CIO) will be responsible for central management, administration and executing the Governing Board’s decisions of ISBE as well as working with the Management Group to undertake delivery. It will integrate, coordinate, monitor and oversee:
• overall operations and strategy development of ISBE, including nominations and selection of new nSBCs
• functional links between nSBCs, including commissioning of novel services, resources and activities
• quality control of nSBCs and the European matrix of centres
• liaison with national and European funding organisations, external cooperation, partnerships with other research infrastructures, including other ESFRIs, and international organisations in or outside Europe
To give the CIO rapid and easy access to scientific competencies in the field of systems biology, it will be physically linked to one of the nSBCs, which fulfils the role of coordinating Systems Biology Centre (cSBC). The role of the cSBC is to advise the CIO on matters relating to the coordination of user support, stewardship and teaching and training. Also, with the help of the cSBC, the CIO will maintain an overview of the scientific and technical capabilities of all nSBCs. This enables the CIO to identify gaps in expertise as early as possible.
The scientific expertise of the cSBC will support the CIO to manage complex and extensive user requests that require cooperation of two or more nSBCs working together. The CIO will support pan-European community activities including training and development of community standards. The function of cSBC will be performed by a nominated nSBC.
Given the present and near-future developments in the life sciences, the need for the kinds of services offered by ISBE will increase steadily. This requires an infrastructure with services that are scalable and can be adapted rapidly to changing needs of its users. Therefore, the nSBCs should be flexible, both with respect to the volume of support activities and their range of expertise. This is one of the aspects that must be agreed upon in the covenants that ISBE will have with each of the national funders that finance an nSBC. The development of the volume and the types of support that ISBE offers will be coordinated by the CIO.
9. Access to ISBE:
ISBE will be openly accessible to all researchers from European academia, hospitals, clinics and industry, including SMEs. It will not have a research programme itself. Rather, it will support the research projects and programmes of its users, i.e. individual researchers, research groups and research consortia. Access to the infrastructure will be easy and efficient through a central web portal. ISBE will support users that are proficient in systems biology, as well as those that are inexperienced in the field. This will enhance the dissemination and implementation of systems biology in all branches of the life sciences and the impact of systems biology for the benefit of society. After first contact through the ISBE web portal, users will be linked to one of the nSBCs that is able to provide the requested services, or to a number of nSBCs for more complex services. In all cases the user will have a single ISBE officer as contact person.
Access to the majority of ISBE’s web-based resources will be free of charge. Services that are more elaborate, such as modelling, model validation and data collection, will require a fee, based on a contract between ISBE (or the relevant nSBC) and the user. It is expected that in most cases costs will be covered through national or European grants. In many cases user projects will already have undergone peer review through a funding organisation. If so, ISBE will accept the user without further screening. If not, ISBE will carry out its own quality check based on a simple peer review process.
Cost models for the above will be developed together with national funders and the nSBCs. Training and education activities will be developed and offered through the nSBCs. Costs for ISBE clients will depend on the user-type, activity and the tariff defined by the nSBC.
ISBE will be a gateway to services provided by linked research infrastructures and provide brokerage services to introduce users to services outside of the remit of ISBE including systems biology compliant data generation and experimental design that is not performed within the infrastructure.
10. Providers of ISBE services:
A range of national research programmes in many countries has resulted in a broad and substantial systems biology base in Europe, including those established on support from a series of transnational ERA-Net programmes, or supported by FP6, FP7 and Horizon 2020 awards. ISBE will serve as the coordinator of this expertise, fostering new user-bases and providing a single entry point.
Leading systems biology centres in most European member and associated states have been identified during ISBE’s Preparatory Phase. Within each of the national communities, ISBE has pinpointed the leading centres and addressed a number of them to audit their capacity and interest in providing systems biology services and resources to a broad audience. Prominent researchers in more than 40 institutions across Europe have been consulted, and more than 80 available systems biology resources have been identified with this exercise.
Almost all of the institutions surveyed (90%) recognised the value of offering their expertise and services to a broader community of users via a pan-European infrastructure, and thus manifested interest for being part of ISBE as a provider. A portion of these resources are already available to very variable numbers of users (from between 5 and 15,000 per month), but their sustainability and interoperability is often at risk. In fact, most of the resources surveyed by ISBE were funded primarily on short-term, unspecific grants, with less than 10% operating with stable funding arrangements. In this context, a broadening of user bases through ISBE will be beneficial and improve sustainability.
11. Legal and governance (from 2018):
ISBE requires its own legal personality in order to obtain funding, manage budgets and establish legal agreements with the national Systems Biology Centres (nSBCs). This legal entity can coherently engage with users, providers, national ministries, funding agencies and the European Commission. The Preparatory Phase has identified the European Research Infrastructure Consortium (ERIC) mechanism as being the most appropriate legal model for ISBE. This allows ISBE to become a legal entity with a European identity and to benefit from tax exemptions. The ERIC framework has already been ratified by many EU member states and allows membership for countries outside the EU. While the nature and mechanisms for coordination of nSBCs would be outlined in the ERIC, direct agreements between ISBE and the nSBC will be required to ensure efficient coordination of services across centres. All nSBCs will be established by entering into a pre-agreed Service Level Agreements (SLA) with ISBE that will define, in a fair and transparent manner, the commissioning of services, resources and other activities that will be offered. The SLAs will formally define those services and resources that are to be offered through ISBE and define the levels of services expected by users, as well as the obligations for the nSBCs in maintaining their availability. An nSBC may be a single institution or a single institution may act in a capacity to represent several other nationally-located institutions responsible for providing aspects of the nSBC services. The ISBE governance structure will provide for effective and timely management and monitoring of operations across the nSBCs. It will provide suitable external scientific and technical advice and operate with transparency and clarity in its procedures, including the nomination and election of members .
The location of the host institution for the CIO for the Legal Phase has yet to be identified. The host country will be identified during the Interim Phase (2015-2018). The procedure and eligibility criteria for approving further nSBCs will also be developed in the Interim Phase, with evaluation processes set out in the ERIC. While the CIO may be situated at the same institution as an nSBC, there will be clear mechanisms that separate their responsibility and functions to allow independent operation and avoid conflict of interest.
The Governing Board will be the central decision making body with high-level oversight, supervising the CIO on behalf of the member states. It will be responsible for ISBE’s strategy and budgets, as well as approval of prospective nSBCs. Representatives will be drawn from and nominated by national funding bodies, together with scientific experts identified by the national funder and tasked with representing the interests of their national communities.
The Heads of Centres Committee will provide operational coordination across the nSBCs and will be responsible for maintaining effective operations across the nSBCs and developing strategic plans, for agreement by the Governing Board. Members will be the directors of the nSBCs, together with the director of ISBE.
The ISBE director is expected to have significant experience coordinating collaborative programmes, notably those with significant elements community outreach and industrial involvement. As head of the CIO, the Director will be appointed by the Governing Board. The Director will be responsible for executing the Governing Board’s decisions, and management of the central budget. The CIO will organise the scientific evaluation and monitoring of nSBCs, as well as managing SLAs and the interface with other ESFRIs. The CIO will also coordinate internal communications and outreach aspects on behalf of the centres.
In support of this, cross-centre Technical Working Groups will lead the delivery of the specific technical and training work streams. These boards will coordinate the delivery of community-led activities.
Understanding user needs is crucial to the success of ISBE. ISBE will draw from the widest possible international expertise to gain insight in how best to meet emerging community needs and opportunities across all sectors, combined with ensuring the continued delivery of cutting edge technologies.
ISBE will establish three main advisory panels, described below, giving independent external advice to enable:
• effective and efficient operations
• suitable oversight and monitoring
• independent audit
• prioritisation of ethical considerations
• a flexibly managed portfolio of expanding resources services by adapting activities within nSBCs as well as bringing in new nSBCs, including the amendment and termination of existing activities at nSBCs, and proposals for novel services to address emerging challenges.
A Scientific Advisory Board (SAB) will be the main sources of external advice from academia for both the Governing Board and executive. A key role is SAB’s evaluation of nSBC applications against a pre-agreed evaluation process, and their subsequent monitoring to advise the Governing Board on decisions such as to renew or terminate nSBCs.
An Industry Liaison Board (ILB) will be the main source for wider coordinated consultation of stakeholders within the commercial sector. Its separate identity from the SAB underlines the importance of addressing industrial interest in working collaboratively with academic systems biology researchers. The SAB also will draw from the ILB membership.
An Ethical Board (EB) will consider the ethical implications of ISBE’s activities such as managing information from plant, animal and human experimentation, together with the related issues of data security and access. It will draw expertise from the nSBCs as well as the SAB and ILB. ISBE will build on links being established within the CORBEL project across ESFRIs for the consideration of legal and ethical issues for data exchange and protection in transnational research collaborations.
This will include ensuring appropriate collection and storage of patient samples; regulations on working with genetically modified organisms, and guidelines for accommodation and care of lab animals.
ISBE User Boards will engage representatives from different user sectors to ensure effective feedback on services and activities, and their involvement in developing novel targeted activities.
ISBE will work closely with other research infrastructures building on existing activities, such as those currently supported through CORBEL and RItrain, to deliver joint activities and avoid redundancy of operations. Representatives of other research infrastructures will also be invited to attend meetings of standing and advisory bodies. Where longer term agreements are needed, ISBE will work with other research infrastructures to develop appropriate Memoranda of Understanding.
12. The ISBE Funding Strategy:
The financial model for ISBE is similar to that implemented by or proposed for other European research infrastructures, including BBMRI, ECRIN and ELIXIR. The proposed financial model of ISBE has five main components:
• national Systems Biology Centres (nSBCs)
• the Central ISBE Office (CIO)
• further expansion of ISBE
• services and community activities
• funding through third parties
13. Financial model for the national level (nSBCs):
The operational costs of each nSBCs will be covered at the national level, with many of these services and resources often already receiving national support. Further national support, in the context of ISBE, will enhance national investments and uptake by their growing national user base. ISBE will make national investments more cost-effective by providing access to a broader user and provider base at the European level.
14 Financial model for European operations (CIO):
The CIO, headed by the ISBE director, will coordinate the development and maintenance of the portfolio of services, resources and community activities and take responsibility for ISBE’s finance, governance and outreach. In practice, levels of national member state contributions should reflect their relative size. To support the CIO, ISBE therefore proposes to use a similar Gross Domestic Product (GDP) based subscription model to that currently employed by other ESFRIs. It is anticipated that additional contributions such as ‘in-kind’ support of indirect costs may come from the country that hosts the CIO.
15. Further expansion of ISBE:
ISBE will expand its budget in two ways, i.e. through stepwise increased national budgets of its nSBCs and by acquiring funding at the European level through the CIO. Once established, ISBE is designed to grow with expanding user demand, as well as new countries joining over time. The ISBE infrastructure model allows for its subsequent expansion over time, in a manner that can respond to evolving user demands be developing the scope of services and resources it supplies. There are increasing opportunities in the Horizon 2020 scheme for developing European research infrastructures. Examples are the recently awarded grants for the CORBEL (harmonizing activities of life sciences research infrastructures) and RItrain (training research infrastructure personnel) programmes in which ISBE participates. Another example is the transnationally funded FAIRDOM programme, which will be integrated in the ISBE activities. Together, this presently represents a European level budget for ISBE of ~€4.6M. The CIO will, together with the nSBCs, make a continuous effort in expanding European funding of ISBE.
16. Services and community activities:
A detailed cost model for ISBE services for all user types will be developed in conjunction with nSBCs and relevant national funders based more exactly on the specific services a centre will provide.
17. The Interim Phase - building the infrastructure:
By the end of the ISBE Interim Phase (2015-2018) a fully functional ISBE will be established as a legal identity. This section describes the mechanisms and timeframe of how ISBE will be rolled out up until its formal start in 2018.
The Interim Phase has five major objectives:
• reach formal agreement with national funding organisations about ISBE’s legal structure and budget for the Legal Phase
• make available an initial portfolio of services and resources to European scientists: ISBE-light
• establish ISBE’s governance and management structure
• establish the European distributed knowledge-based infrastructure of interconnected nSBCs
• harmonise ISBE’s operations with those of other research infrastructures in the life sciences, primarily through the CORBEL and RItrain programmes
The Interim Phase will consist of two distinct stages. Interim Phase Stage 1 will begin in August 2015, immediately after the end of the Preparatory Phase. The aim of Stage 1 is to have at least three national funding organisations signing a Memorandum of Understanding (MoU) within the first year of the interim phase. This stage will establish an interim governance and management structure capable of commencing delivery of the ‘ISBE-light’ operational portfolio. Negotiations with funders will continue to establish commitment for financial support. This should ensure an adequate budget for the construction of ISBE during Interim Phase Stage 2. The start of Stage 2 will commence with the appointment of the founding director, who takes responsibility for building the research infrastructure.
17.1 Interim Phase Stage 1 (2015-2016):
The major objectives of Stage 1 are (i) to continue activities on the national and European level, initiated during the Preparatory Phase, and (ii) secure Stage 2 budget, and (iii) start delivering ISBE-light services.
This comprises the following processes:
• establish an interim governance structure
• formally involve at least three national funding organisations on the basis of a MoU
• identify and pursue further European funding opportunities
• negotiate with national funders and key stakeholders to establish the budget for Stage 2
• select a founding director as soon as the Stage 2 budget is secured
• identify the host country for the Central ISBE Office (CIO) and the coordinating Systems Biology Centre (cSBC)
• start the procedure to identify and select nSBCs that will be formally established in Stage 2
• commence delivery of a portfolio of web-based services and resources called ’ISBE-light’
• operate ISBE-branded activities through the CORBEL, RItrain H2020 projects and FAIRDOM, with continuing partnership with other ESFRI research infrastructures and national infrastructural programmes
The management at the outset of the Interim Phase will reflect the commencement of the operations of ‘ISBE-light’ web-based services and resources with the formation of the ISBE Interim Committee (IC). The ISBE Interim Committee (IC) will (i) ensure inclusive negotiations with both national funders and key stakeholders that are required to establish the budget for Stage 2, (ii) select the founding director, and (iii) start the procedure to identify and select nSBCs that will be formally established in Stage 2. The IC will consist of all members of the Management Team (MT) and Intergovernmental Working Group (IWG) and draw on members of the Preparatory Phase Steering Committee who have expressed their interest in further engagement. This IC will identify further European funding opportunities for ISBE, as well as coordinate strategic interactions with other ESFRIs. In addition, steps will be taken to form user community forums and an Industry Liaison Board. The IC and the MT will be chaired by a full time Interim Coordinator, who will be responsible for the development of ISBE during Stage 1. The MT is a sub-committee of the IC, which will consist of those involved in the delivery of ISBE-light’s portfolio of services, and coordination across ISBE-branded activities through the CORBEL and RItrain H2020 projects and FAIRDOM. The IWG is another sub-committee of the IC, which will draw together representatives of national funding organisations who have expressed an interest in supporting ISBE.
The costs of Stage 1 are estimated to be minimally € 250k for 12 months (see Table 6.1and Appendix 9, Table 1). Contributions are expected via financial and in-kind contributions through ISBE stakeholders and national funders. Negotiations with national funding agencies should result in the signing of a MoU and associated financial support, or another type of agreement, in which they declare interest in participating in building ISBE and contribute to a budget for Stage 2. The selection of nSBCs in Interim Phase Stage 2 requires an open and transparent procedure, which will be agreed with national funding organisations and research communities. The same holds for the host country of the CIO. To expand awareness of ISBE in the scientific communities and maintain the momentum and interest developed during the Preparatory Phase, ISBE will offer in Stage 1 and Stage 2 a portfolio of four types of web-based services and resources.
Most ISBE-light services will be available free of charge to users. They will be operated and supervised by systems biology centres of excellence that have an interest in continued involvement in ISBE. ISBE-light will commence as soon as possible after the start of Interim Phase Stage 1. Services will continue in Stage 2, forming a solid basis for a complete portfolio in ISBE’s Legal Phase.
ISBE-light will offer three types of services:
1. Modelling services and resources
ISBE’s modelling services aim to lower the threshold for biologists to incorporate computational modelling in their research. In this early stage of ISBE development, clients will be directed to a ready-to-use web-based modelling platform, linked to relevant model resources. Target communities for these services are researchers in academia and industry with varying levels of training in mathematics and statistics and in computer and information science.
For the initial ISBE-light services, ISBE will focus first on modelling frameworks that have (i) a large potential user base, and (ii) standardised ways of asking research questions. By doing so, one can span a large space of questions with a well-defined set of query parameters. In addition, users can pose a wide range of questions by filling in a form and uploading their own data or models, similar to what is already common place in bioinformatics.
2. Access to tools, standards and model-compliant data and maps
For ISBE-light, ISBE will engage with the existing FAIRDOM initiative , a joint action of the ERANet ERASysApp with ISBE. FAIRDOM aims to establish a data and model management service facility for systems biology. This is intended to operate under the ISBE-light umbrella. ISBE-light services will aim for web-based access to tools, archives, model-compliant data and maps which will focus on:
• making software available with user guides that support and improve research asset management from instrument to publication
• supporting the establishment of research asset management planning for grants
• developing an online ’knowledge hub’ which: a) identifies and characterises different tools and standards that can be used within projects, b) identifies public repositories and characterises them according to the type of data that they contain, and what standards are used in conjunction with the repository, c) identifies and categorises minimum information models for different research-asset types, and d) provides data-templates that are semantically capable for a range of different data-assay types.
3. Education and training
Services will aim at dissemination of information on training and education in systems biology and will include:
• dissemination of information on training and postgraduate education in systems biology (in collaboration with ERASysApp), through the ISBE community portal
• dissemination and implementation of a core curriculum through the ISBE website, publication, Erasmus+ and low cost networking meetings
• dissemination of courses (summer and winter schools, workshops, advanced training) that ISBE partners are involved in
In addition, ISBE is currently exploring a synergistic role between ISBE and scientific journals with respect to ISBE being a rich source of multidisciplinary expertise in systems biology, spanning a broad range of biological fields, disciplines and skills, and ISBE taking initiatives in developing and disseminating community standards and standard operation procedures (SOPs) in the systems biology field.
During Interim Phase Stage 1, ISBE will be embedded in European-level systems biology initiatives and national systems biology communities and it will actively contribute to the harmonisation of ESFRI research infrastructures in the life sciences field.
17.2 Interim Phase Stage 2 (2016-2018):
Stage 2 will commence on the appointment of the founding director and will end with the establishment of ISBE as a legal entity. The major responsibility of the founding director is therefore to develop ISBE’s legal identity and operational processes. The objective of Stage 2 is to develop a legally-based and fully functional ISBE. This includes the following:
• establish the Central ISBE office (CIO), the coordinating SBC (cSBC) and ISBE’s governance structure
• continue empowering ISBE-light and organise the transition of ISBE-light towards a fully operational ISBE by developing a broad portfolio of services, resources, community activities and training and education programmes together with the nSBCs and in dialogue with user communities
• establish a collaborative federation of nSBCs that will be fully operational in the Legal Phase
• negotiate the operational budget of ISBE Legal Phase
• develop the legal basis for ISBE, preferentially an ERIC
• continue developing partnerships with other European research infrastructures, primarily through the CORBEL and RItrain projects.
The management structure from Stage 1 for the ISBE Interim Committee and the ISBE-light Management Team will be modified at the start of Stage 2 as part of the stepwise migration of the Interim Phase governance structure towards that described for the Legal Phase (2018 onwards). Stage 2 requires a budget of approximately € 1.6 M for two years (2016-2018) comprising:
• salary of the founding director and CIO staff
• operation costs of the Central ISBE Office (CIO)
• activities to develop and coordinate the European matrix of collaborating nSBCs and ISBE’s portfolio of services and resources.
ISBE will negotiate with national funding agencies that are MoU signatories, as well as other national funders, to agree on conditions for sustainable funding of ISBE in its Legal Phase. ISBE will seek their contribution to the central budget to support the CIO and coordinating and community activities. In parallel, agreement should be reached about national funding of the individual nSBCs and the coordinating SBC. The open and transparent nomination and selection process for nSBCs will be executed along the lines agreed on in Stage 1. Provisions will be made to give users in European countries without an nSBC access to ISBE’s resources and services.
Negotiations in Stage 1 will identify the host country of the interim CIO. The founding director will head the interim CIO and establish the governance structure for the legal phase. At present it is anticipated that the IC sub-committees will be fully integrated into the Interim Committee, in anticipation of migration to the full ESFRI bodies in the Legal Phase. Finally, groups expecting to form nSBCs will be invited to form a “Candidate nSBC working group” (anticipated to grow into the legal phase ‘Heads of Centres Committee’). Negotiations in Stage 1 will identify the host country of the interim CIO. The founding director will head the interim CIO and establish the governance structure for the legal phase.
18. Legal basis for ISBE:
An important aim of Stage 2 is to agree on the legal status of ISBE. The current preference is for an ERIC. However, we expect that the development of the ISBE structure for the legal phase will continue and therefore the suitability of ERIC, including the potential for a transitional legal structure to facilitate to foundation of ISBE will be kept under dynamic review. Decisions will be made based on discussions with national funding organisations and governments. Establishing ISBE’s legal status marks the transition of the Interim Phase to the Legal Phase.
Together with the nSBCs and relevant research communities, ISBE will develop and establish its portfolio of services, resources and community activities within the framework outlined in this Business Plan. This will build on the activities of ISBE-light that started in Stage 1. The portfolio will grow steadily in Stage 2 and in the subsequent Legal Phase, constantly adapting to the developing needs of ISBE’s users.
A major task of the founding director will be to develop relationships with different user communities, including academia, hospitals/clinics and industry/SMEs. This will build on the expertise in translational research for those centres providing ISBE activities to enhance translation and create a coherence forward look for systems approaches from a joint academia-industry perspective. A vital part of this will involve establishing user committees and advisory boards.
Coordination with ELIXIR on ensuring synergies to address community needs:
In developing its portfolio ISBE recognises the key links it has already forged with ELIXIR as part of developing the CORBEL and RItrain proposals. In addition the FAIRDOM project addresses the overlapping data standards requirement across both Research Infrastructures. ISBE and ELIXIR will continue to work closely in ensuring a common strategic framework for delivery of services and resources that avoids duplication and redundancy of provision. As a first stage, both RIs are committed to formalising their relationship and further defining their interface, be developing a common strategic document on joint working early in 2016.
19. Measuring Wider Impact:
In addition to understanding and measuring the direct outputs of ISBE and its services, it is also important to develop appropriate metrics to understand how ISBE has supported the delivery of the research of those communities using ISBE. During the Interim Phase ISBE will consider the needs for longer term monitoring of services and their users. ISBE plans to demonstrate to its funders how its activities and services:
• have influenced the development of a highly skilled work force
• have fostered the usage of data and model standards, and appropriate tools
• have aided in development of collaborations of provider and users at scientific institutions in Europe and worldwide
• have encouraged closer collaboration between academia and industry to the benefit of the EU bioeconomy
• have enhanced the application and integration of systems approaches in the biosciences by acting as a ‘knowledge broker’ of choice
• have facilitated the rapid uptake of novel and innovative technologies across all biomedical sectors
Potential Impact:
Systems biology has the potential to contribute greatly to addressing the major societal grand challenges in health, agriculture and bio-economy.
Health:
While twentieth century scientific advances succeeded in protecting people from diseases that caused them to die young, with developments in antibiotics and drugs, the challenges of European healthcare in the twenty-first century will be to cope with ageing populations with complex diseases such as cancer and Alzheimer’s, or increasingly where patients present with more than one condition.
Europe is faced with an ageing population, with affiliated challenges in healthcare provision. Recent European Commission reports have highlighted the correlation between increasing population age and increased public spending on healthcare . The EC, through its Healthy Ageing programme, is seeking to adapt EU policies and strategies to meet the demands associated with this significant demographic shift.
Systems biology’s emphasis on combining knowledge from multiple biological processes makes it uniquely placed to combat diseases and the multi-factorial mechanisms that underlie them. The model-based approach of systems biology is essential to unravelling the complex molecular, cellular and organ basis of such diseases, allowing more effective and rational approaches to prevention, diagnosis and personalised treatment schemes. It is through the power of these models to integrate diverse data sets that we can now begin to properly predict responses to specific interventions and provide new and personalised therapies.
Systems biology is also key to overcoming the problem that many existing drugs and therapies have no, or even an adverse, effect on patients. Individualised genome sequencing, transcriptomics, proteomics and metabolomics combined with systems biology based analyses, begin to allow a much more successful, rationalised and personalised treatment plans for the patient.
Agriculture:
In agricultural sciences, systems biology approaches are widely used to tackle issues that relate to sustainable food production. Varieties of drought and salt resistant crops, are needed to overcome the world-wide shortage of fresh water to expand overall outputs. Understanding of the relevant processes in plants has opened new avenues to modify molecular and cellular networks and thereby the creation of crops that provide commercially viable yields under previously unfavourable conditions.
Control of flowering time is another area being tackled by a systems biology approach. This is an exceptionally important economic issue because it allows farmers to optimise yields by defining the best time of the year for crops to be harvested.
Finally, an area underpinning sustainable energy production is to develop a better understanding of the light harvesting and photosynthetic systems of plants and green algae that will facilitate enhancements to their butanol producing metabolic networks. Linking such complex systems and fine tuning their functioning is now typically addressed through systems biology approaches. A considerable number of European research groups are active in these and related agricultural fields.
Industrial biotechnology:
The food industry is one of the largest and most important manufacturing sectors in Europe, and systems biology approaches are giving cutting edge producers an international competitive advantage. Understanding molecular, cellular networks of microorganisms, plants and animals, which have been defined and integrated by systems research, enables a predictable and rational approach to their genetic and metabolic engineering. For instance, systems biology research groups across Europe are utilising computational models in the development of new food products and new plant and animal breeding regimes.
Bioeconomy:
The Organisation of Economic Co-operation and Development (OECD) has placed strong emphasis on the fact that biological resource centres (such as ISBE) are an essential part of the infrastructural requirements for the proper development of bio resources and their explicit role for industry . In parallel, the European Union has substantially invested in programmes such as IMI , EMTRAIN , EIT and the development of platforms such as KIC to stimulate public-private research and training initiatives. A prerequisite for industry to participate in these programmes is the willingness to promote an open innovation model and exploitation of results. In this context the collaboration and coordination between research infrastructures, including ISBE, in the Horizon 2020 funded programmes CORBEL and RItrain should play a key role in increasing the output of these programs.
Despite these and other public-private efforts, commercial parties and particularly SMEs face the same problems as the academic sector: they have difficulties in finding and involving the necessary expertise and resources in systems biology. Large companies may have the possibility to invest in (often costly) solutions to tackle some aspects of this problem. SMEs, that lack both budget and manpower, cannot easily overcome this hurdle. Other obstacles hindering industrial research and innovative capacity are the duplication of efforts, difficulty of integrating private and public data and lack of standards. A positive development in solving this problem is that a collaborative landscape is developing, with a range of pre-competitive coalitions in research areas such as human health, environment, energy, and food technology. Here ISBE services and resources, and also matchmaking, would boost collaborations between private and public research efforts.
Community activities:
The ISBE user and provider communities are the infrastructure’s greatest resource. ISBE will harness their expertise in a range of community-led activities across its systems biology and life science stakeholders:
• integral map, model and data curation
• development and implementation of community standards, in collaboration with the life science community and international systems biology journals
• foster the maintenance and development of systems biology formatting and annotation standards, such as Systems Biology Markup Language (SBML), Simulation Experiment Description Markup Language (SED-ML), and Minimum Information Required In the Annotation of Models (MIRIAM)
• promote the development of standards for the exchange of information between models dealing with time varying but spatially lumped processes, such as CellML, and spatially and time varying processes, such as FieldML.
• serve as a contact for worldwide initiatives and collaborations in systems biology-related fields
• be a key player in the collaboration between and the harmonisation of activities of the thirteen life sciences ESFRI research infrastructures in the context of the CORBEL programme
• cooperate with and contribute to harmonisation between European systems biology-oriented research programmes and activities, such as Virtual Physiological Human, ERASysApp, Coordinating Action Systems Medicine (CASYM), ERACoSysMed and ERASynBio
• promote, support and contribute to the organisation of international congresses in the field of systems biology
• develop and maintain the European Systems Biology Community website (community.isbe.eu) as a portal for networking and community engagement
Education and training:
ISBE services will aim at dissemination of information on training and education in systems biology and will include:
• dissemination of information on training and postgraduate education in systems biology (in collaboration with ERASysApp), through the ISBE community portal
• dissemination and implementation of a core curriculum through the ISBE website, publication, Erasmus+ and low cost networking meetings
• dissemination of courses (summer and winter schools, workshops, advanced training) that ISBE partners are involved in
Liaison with scientific journals
ISBE is currently exploring a synergistic role between ISBE and scientific journals with respect to:
• ISBE being a rich source of multidisciplinary expertise in systems biology, spanning a broad range of biological fields, disciplines and skills
• ISBE taking initiatives in developing and disseminating community standards and standard operation procedures (SOPs) in the systems biology field
Measuring Wider Impact:
In addition to understanding and measuring the direct outputs of ISBE and its services, it is also important to develop appropriate metrics to understand how we have supported the delivery of the research of those communities using ISBE. ISBE will therefore consider the needs for longer term monitoring of services and their users. ISBE plans to demonstrate to its funders how its activities and services:
• have influenced the development of a highly skilled work force
• have fostered the usage of data and model standards, and appropriate tools
• have aided in development of collaborations of provider and users at scientific institutions in Europe and worldwide
• have encouraged closer collaboration between academia and industry to the benefit of the EU bioeconomy.
• have enhanced the application and integration of systems approaches in the biosciences by acting as the ‘knowledge broker’ of choice
• have facilitated the rapid uptake of novel and innovative technologies across all biomedical sector
List of Websites:
www.isbe.eu
Names and email addresses of ISBE Consortium members:
UK
Richard Kitney, Imperial College, r.kitney@imperial.ac.uk
Barbara Skene, Imperial College, b.skene@imperial.ac.uk
Sara Butcher, Imperial College, s.butcher@imperial.ac.uk
Carole Goble, The University of Manchester, carole.goble@manchester.ac.uk
Natalie Stanford – The University of Manchester, natalie.stanford@manchester.ac.uk
Gabriela Pastori, Biotechnology and Biological Sciences Research Council, gabriela.pastori@bbsrc.ac.uk
Adrian Pugh, Biotechnology and Biological Sciences Research Council, adrian.pugh@bbsrc.ac.uk
Netherlands
Roel Van Driel, Universiteit van Amsterdam (UvA), r.vandriel@uva.nl
Vitor Martins Dos Santos, Wageningen University, vitor.martinsdossantos@wur.nl
Babette Regierer, Wageningen University, regierer@lifeglimmer.com
Martijn Mone, Wageningen University, martijn.mone@wur.nl
Hans Westerhoff, VU University Amsterdam, h.v.westerhoff@vu.nl
Martijn Mone, VU University Amsterdam (currently at Wageningen University)
Bea Pauw, Netherlands Organisation for Scientific research –Earth and Life Sciences, b.pauw@nwo.nl
Greece
Dimitris Thanos, Biomedical Research Foundation Academy of Athens (BRFAA), thanos@bioacademy.gr
Sissy Kolyva, Biomedical Research Foundation Academy of Athens (BRFAA), s.kolyva@pasteur.gr
Ireland
Eadaoin Mc Kiernan, University College Dublin, eadaoin.mckiernan@ucd.ie
William Fitzmaurice, University College Dublin, william.fitzmaurice@ucd.ie
Germany
Jutta Steinkoetter, Max Delbrück Centrum for Molecular Medicine (MDC), jutta.steinkoetter@mdc-berlin.de
Thomas Hoeffer, Deutsches Krebsforschungszentrum (DKFZ), T.Hoefer@Dkfz-Heidelberg.de
Cornelia Depner, Deutsches Krebsforschungszentrum (DKFZ), c.depner@dkfz-heidelberg.de
Angela Oberthuer, Ruprecht-Karls-Universität Heidelberg- BioQuant Centre (UHEI), angela.oberthuer@bioquant.uni-heidelberg.de
Wolfgang Mueller, Heidelberg Institute for Theoretical Studies (HITS), wolfgang.mueller@h-its.org
Martin Golebiewski, Heidelberg Institute for Theoretical Studies (HITS), Martin.Golebiewski@h-its.org
Renate Kania, Heidelberg Institute for Theoretical Studies (HITS), Renate.Kania@h-its.org
Norway
Stig Omholt, Norges miljø- og biovitenskapelige universitet (NMBU), stig.omholt@ntnu.no
Jon Olav Vik, Norges miljø- og biovitenskapelige universitet (NMBU; jonovik@gmail.com
Czech Republic
Rudiger Etrrich, Centrum vyzkumu globalni zmeny Akademie ved Ceske republiky v.v.i. (C4SYS), ettrich@nh.cas.cz
Marcela Kotrcova, Centrum vyzkumu globalni zmeny Akademie ved Ceske republiky v.v.i. (C4SYS), kotrcova@nh.cas.cz
Spain
James Sharpe, Centre for Genomic Regulation (CRG), James.Sharpe@crg.eu
Joaquim Calbo, Centre for Genomic Regulation (CRG), Joaquim.Calbo@crg.eu
Slovenia
Kristina Gruden National Institute of Biology – Slovenia (NIB), kristina.gruden@nib.si
Damjana Rozman, Univerza v Ljubljani (UL), damjana.rozman@mf.uni-lj.si
Jure Acimovic, Univerza v Ljubljani (UL), jure.acimovic@mf.uni-lj.si
Marta Sabec, Ministrstvo za izobraževanje, znanost in šport (MIZS), Marta.Sabec@gov.si
EMBL-EBI
Henning, Hermjakob, EMBL-European Bioinformatics Institute (EMBL-EBI), hhe@ebi.ac.uk
Nicolas Le Novere, EMBL-European Bioinformatics Institute (EMBL-EBI), lenov@ebi.ac.uk'
Nick Juty, EMBL-European Bioinformatics Institute (EMBL-EBI), juty@ebi.ac.uk
Sweden
Stefan Hohman, University of Gothenburg (UGOT), stefan.hohmann@gu.se
Marija Cvijovic, University of Gothenburg (UGOT), marija.cvijovic@chalmers.se
Jens Nielsen, Chalmers University of Technology, nielsenj@chalmers.se
Finland
Garry Corthals, University of Turku, Garry Corthals left Turku in May 2014 to take up a position at Universiteit van Amsterdam (UvA) - G.L.Corthals@uva.nl
The modern life sciences are making big steps in analysing living organisms. This is fuelled by the development of powerful technologies, such as genomics, proteomics, metabolomics, imaging and many more resulting in important new insight and a true data deluge. Despite these successes our understanding of how living systems function is still remarkably limited. Here, ‘understanding’ is defined as being able to correctly predict the functioning of systems after changing their components or their environment.
Systems biology is a branch of the life sciences that can create understanding through integrating multiple and diverse data sets in quantitative computational models. These models are able to predict the behaviour of biological systems based on experimental data about the interplay of molecules, cells and tissues in time and space. This level of understanding can make a huge impact on health, biotechnology and sustainability, whilst fuelling the bioeconomy. As such, national governments and the European Commission have recognised the importance of systems biology, investing considerably in the past decade. In ISBE, European countries are joining forces to create a research infrastructure for systems biology by building on national strengths to meet European needs.
Infrastructure for Systems Biology Europe (ISBE) will be a knowledge-based research infrastructure that will add value to national and European investments by empowering European researchers across academia, medicine and industry to implement systems biology approaches. It will enable easy access to expertise, resources and training and offer hands-on support in building and using computational models based on model-compliant high quality data. To be effective, ISBE will take responsibility for the development and implementation of community standards to make data, models and tools re-usable over prolonged periods of time. This is essential for progress in the life sciences and, importantly, makes research more efficient and cost-effective.
ISBE’s offerings to the scientific community are based on surveys of the needs of different user communities and potential provider institutions in Europe. ISBE will consist of a collaborative and synergistic matrix of national systems biology centres with overlapping and complementary expertise, each centre being tightly linked to its national systems biology research community. Activities of the centres will be coordinated and overseen at the European level by a central ISBE office, headed by an ISBE director and a supervisory board of stakeholders.
Project Context and Objectives:
The ISBE preparatory phase project had 3 major objectives:
• Identification of existing activities and consultation with stakeholders regarding the technical requirements of the infrastructure.
• A proposal outlining the recommendations for the technical specifications of the physical infrastructure, required technologies and access policies
• Development and negotiation of a business plan and sustainable funding model for the construction and operational phase of ISBE
The proposed model for ISBE is built on extensive project work carried out by the individual work packages as well as consultations with future user and provider communities during the ISBE preparatory phase. Surveys and interviews have been carried out with stakeholder groups in academia, hospitals and clinics and industry, including SMEs, as well as with national funders and scientific journals, to inform the ISBE strategy. The ISBE strategy has also been informed by the developing landscape of European Research Infrastructures in the life sciences.
The ongoing challenge in the life sciences is to convert the huge amount of biological data that we produce into an understanding of how living systems function to a level that enables successful prediction of their operations and of changing their components or networks - see ISBE publication Success Stories in Systems Biology, 2015 (http://project.isbe.eu/systems-biology/case-studies/). Intelligent, computational model-driven approaches are essential to deal with the extreme complexity of biological systems. This is a game-changing goal for the life sciences for the next ten years and is made possible by recent rapid technological developments, such as genomics, proteomics, metabolomics, advanced imaging, bioinformatics and our rapidly increasing understanding of tissues and organs. This has been recognised by national funding organisations and the European Commission, resulting in significant investments and many major research programmes dedicated to systems biology in the past 10 years.
European investment in systems biology initially focussed on the development and use of predictive models, so far mostly at the molecular level, such as metabolic networks within cells. More recently, there has been a clear shift towards the implementation of systems biology approaches within biomedical research (known as ‘systems medicine’) and across the biotech industry. Recent examples include the transnational programme Coordinating Action Systems Medicine (CASyM), the ERANet projects ERACoSysMed and ERASysApp and various EU programmes that are part of the Bio-Based Industries (BBI) funding scheme.
Recent developments include the use of multi-scale modelling, which aims at understanding the functioning of complete organs and organisms as the result of the dynamic interplay in time and space of molecules, cells, tissues. Here, molecular and cellular biology meet physiology. Such integrative efforts are already creating a strong basis for new avenues in biomedical and pharmaceutical research. Examples include the virtual human heart ( http://thevirtualheart.org/ ), the Virtual Liver Network (http://www.virtual-liver.de/ ), the Human Metabolic Atlas (www.metabolicatlas.org) and other projects within the international Virtual Physiological Human (VPH) programme( http://www.vph-institute.org/ ).
Whilst prior investments have created a solid knowledge base for systems biology in a number of European countries, dissemination and uptake is still slow. Reasons include:
• Protocols for properly planning and executing experiments and acquisition of high quality, quantitative data that can be integrated in computational models are not yet widely used.
• Expertise required to build and use high quality predictive computational models is limited and will not grow without widespread integration into biological and biomedical academic curricula, while lack of suitable for training for industry is also inhibiting take up.
• Integrated stewardship of results is still in its infancy. This includes annotation and curation of model-compliant data sets and making them findable and re-usable over prolonged periods of time.
• Slow translation of systems biology approaches into clinically and commercially usable application.
ISBE’s vision is that systems level approaches should be within reach of the majority of European life scientists to accelerate a fast adoption and translation into new research findings and industrial applications. This will increase the competitiveness of the European Research Area as well as in health and the bio-economy industry. ISBE therefore intends to make the necessary expertise, services, tools and resources easily and openly accessible to scientists in academia, hospitals and clinics and for industry, in particular SMEs. This process will be enhanced by European education and training programmes and a range of community activities, such as the development and implementation of standards.
ISBE’s strategy is to support the European Research Area by building on existing national investments, expertise and strengths and harnessing the experience of national and transnational initiatives in systems biology, such as the ERANET programmes. ISBE will not have a research programme itself. Rather, it will support research projects and programmes of its users, i.e. individual researchers, research groups and research consortia.
ISBE will consist of a European matrix of national systems biology centres that offer expertise, services and resources. The activities of the centres will be coordinated at the European level by a central office. Each centre will be tightly linked to national systems biology research groups and therefore well-embedded within the local research community. The collaborating national ISBE centres will offer a broad range of expertise, services and resources to life scientists in academia, clinics and industry across Europe through a single ISBE web-based portal.
The 2010 ESFRI Roadmap lists 13 research infrastructures in the life sciences, including ISBE. They complement each other, together forming a strong basis for the development and dissemination of knowledge and the provision of services. The essence of systems biology is to integrate diverse data and technologies to obtain a complete picture of biological systems. Building on this vision, ISBE is already collaborating with the 12 other biomedical ESFRI research infrastructures to harmonise and optimise their procedures and offerings, through the Horizon 2020 funded programmes COordinated Research Infrastructures Building Enduring Life-science Services (CORBEL) and RItrain.
Project Results:
Contents:
1. Rationale
2. The Research Infrastructure
3. Stewardship and Standardisation
4. Modelling of biological systems based on integration of diverse data sets
5. Facilitating model-compliant data generation
6. Community Activities
7. Training and Education
8. Organisational structure
9. Access to ISBE
10. Providers of ISBE services
11. Legal and Governance (from 2018)
12. The ISBE Funding Strategy
13. Financial model for the national level (nSBCs)
14. Financial model for European operations (CIO)
15. Further expansion of ISBE
16. Services and community activities
17. The interim phase - building the infrastructure
17.1. Interim Phase Stage 1 (2015-2016)
17.2. Interim Phase Stage 2 (2016-2018)
18. Legal Basis for ISBE
19. Measuring Wider Impact
The results of the preparatory phase culminated in, and were integrated through, the publication of the ISBE Business Plan in July 2015. The Business Plan, itself, is an update and expansion of the ISBE Business Case published in November 2014. The Business Plan outlines the rationale for ISBE, the physical infrastructure, the plans for services and access, the legal and governance structure and financial aspects of the research infrastructure. It also sets out how ISBE will be built during the interim phase from 2015 till 2018, with the commencement of “ISBE-light”. The ISBE Business Plan is the result of the collaborative activity of 23 research institutions and funding agencies in 11 European member states in the context of the European Strategy Forum on Research Infrastructures (ESFRI) Roadmap.
1.Rationale:
Over the past sixty years the life sciences have developed at an ever increasing pace. The discovery of the double helix structure of DNA in the early 1950s may be taken as the starting point of the molecular biology revolution, which radically changed our understanding of living systems. Scientific and technological progress in molecular and cell biology in the years that followed has included cloning, sequencing of the human genome, and the ever growing power of -omics technologies and other methodologies that allow genome-wide analysis of the molecular components of life. This has led to the dawning of a new biological age that is now beginning to give us deep insight into how living systems function, with a rapidly growing impact on human health, food, sustainability and the economy.
The traditional approach to research in the life sciences has been one of reductionism. However, the data explosion in the life sciences, including health-related research, means that biological data can no longer be analysed and interpreted in a useful way without taking into account the broader context of the living organism. Because of exponentially growing volumes of data and the complexity of biological systems, new approaches had to be developed to integrate the diverse data sets of molecules, cells and tissues and convert this ‘information’ to ‘understanding’. Here, ‘understanding’ means the ability to successfully predict how biological systems behave after changing environmental conditions or altering molecular components.
Converting data to understanding is systems biology, which addresses the emergence of biological function from the dynamic interactions of the components of biological systems. It embraces systems theory, an approach that is fully incorporated in other areas of science and in engineering. Biological systems are highly dynamic, with many components and interactions. Thus their functioning can only be understood by building quantitative and predictive computational models based on experimental data. This is at the heart of systems biology and it is this knowledge-based approach that is the central offering of the Infrastructure for Systems Biology Europe (ISBE) to the life sciences community.
Our rapidly growing capacity to understand and rationally alter living systems is beginning to have a major impact on human health, food and feed production and sustainability. Metabolic engineering of microorganisms and the integrated model of the beating human heart, which predicts the - often counter intuitive - effects of potential drugs, are just two examples. The economic effects of these developments in the life sciences cannot be overestimated. The importance of the bioeconomy in Europe is growing rapidly. The EU's bioeconomy sectors in 2012 were worth € 2,000 billion in annual turnover and account for more than 22 million jobs representing approximately 9% of the EU workforce (reference: Innovating for Sustainable Growth: A Bioeconomy for Europe; COM (2012) final; European Commission: Brussels, Belgium, 2012). The systems biology approach is a strong research base that translates into industrial products and processes and in healthcare. This is a primary reason for recent significant investment in systems biology for the European life sciences community. This has also been reflected more widely by significant international investments, such as the Institute of Systems Biology in Seattle and the Systems Biology Institute in Tokyo to support their considerable and growing research effort in this area.
To make this effort both effective and efficient requires the creation of an environment, an infrastructure, for systems biology in Europe that is capable of coordinating and leveraging the science base.
The aim of ISBE is to make resources, expertise and training in systems biology readily accessible to European researchers, clinicians and industry, including SMEs, and to actively support their research efforts. ISBE builds on over a decade of national and EU support in systems biology and will coordinate and synergise future investment. It will actively support researchers in:
• addressing how the dynamic interactions between biological components (molecules, cells, tissues, organs) leads to the functioning of living organisms in a constantly changing environment,
• creating predictive computational multi-scale models of living systems, up to complete organisms, representing these interactions,
• exploiting such models to generate major socio-economic benefits in areas including pharmaceuticals and healthcare, agricultural science, energy and the environment.
The ISBE research infrastructure will consist of a matrix of interconnected national centres of excellence in systems biology, coordinated and managed at the European level.
Building understanding of the functioning of hugely complex biological systems is a process that takes time, in which predictive models improve and expand stepwise. Therefore, it is essential that data, procedures and models can be re-used and are accessible over long periods of time. A primary function of ISBE will be to harness the community in the development and implementation of standards and operating procedures that enable and promote re-usability. Through the ISBE infrastructure, European researchers from across the life sciences will have access to the best systems biology research expertise, tools, services and training via a single portal.
2.The research infrastructure:
The ISBE infrastructure is designed to meet the needs of three broad and interlinking life science research communities in academia, clinical research and industry. ISBE will offer services and resources that are valuable for all branches of the life sciences, independent of the type of organism or biological system studied. Systems biology creates a strong unifying and theory-based foundation in the life sciences.
ISBE will provide efficient access to core research assets of systems biology, i.e. maps, models, data, and tools. Assets will include (i) user research assets that are managed and curated by ISBE to ensure quality and reproducibility and (ii) publicly available model-compliant research assets that have been selected by ISBE. These will be made available in a cataloguing resource which contextualises information according to biological phenomena rather than data type. For example, assets describing the human liver will be organised together, along a hierarchical map of the liver. This method of organising resources will not transfer data, maps, models and tool physically, but will work with links, pointers and web services, leaving the items at a repository managed locally or by collaborating research infrastructures (such as ELIXIR, the European life science data management research infrastructure) with whom ISBE has developed a number of guiding principles for effective management and sharing of data.
Offering systematic asset management tools to ISBE users will enhance the ‘findability’ and ‘integratability’ of data, models, SOPs, maps, software and tools. This will considerably enhance the efficiency of life sciences research and increase its impact on society. It is stressed that this aspect of ISBE’s activities is generic, i.e. not restricted to specific fields or levels of complexity in biology, biotechnology and health-related research.
Research assets will be attributed to their authors’ profiles, which will be made available in a catalogued resource. This constitutes a valuable source for life scientists who want to complement their research efforts with high quality results from other studies. It is an additional way of creating impact by easy deposition into specialised data sources provided by other research infrastructures such as ELIXIR. In this context ISBE will offer expertise for direct curation of models, standard operating procedures (SOPs) and data, tools and protocols linked to them, with persistent identifiers (for example digital object identifiers (DOIs)) for easy access, attribution and citation. Centralisation of access to assets in ISBE will increase the breadth of audience and, as a result, the impact that published assets can have. This will incentivise researchers to deposit their data, tools, models and maps.
ISBE will ensure sustained and dedicated public resources for research asset management over the long-term. Helping establish sustainable funding models for all resources is considered key for systems biology research asset management. The resources will also provide, in conjunction with research infrastructures such as BBMRI and ELIXIR, provisions for commercially and personally sensitive data.
3.Stewardship and Standardisation:
ISBE will offer an online ‘Knowledge Hub‘ providing best practice material and tutorials to assist researchers in making their research assets FAIR compliant, that is findable, accessible, interoperable, and reproducible. The material will include identifying the most suitable formats, ontologies for annotation, and best practice usage of them, for a wide variety of research assets. Importantly, this will make maps, data, tools and models re-usable over prolonged periods of time, in follow-up research projects and by other researchers, adding significant value to research investment. In this context, a key activity of ISBE will be advocacy for the development and adoption of best practice, community standards, and minimum description models, setting in motion their habitual use by the community. ISBE’s support to make research assets of its users re-usable over prolonged periods will make research more efficient and considerably improve its cost-effectiveness.
Supporting the experimental design phase with expert knowledge ensures suitable data is collected for downstream use. After this, advice on integration of data into models, followed by model validation is important. The framework which supports the scientific process, the collaborative data infrastructure, needs to support storage and access to the data and models, as well as access to infrastructure services that assist with data and model analysis including simulation software for models, and data analysis software. A mediating layer is needed that simplifies the accessibility and usability of the software for the users, allowing smoother interoperating of the research assets in different analysis software, and also makes the storage and availability of research assets in multiple platforms simpler for the user.
Data curation, in this context, refers to the skills and due process that would be required to format and annotate data, models and SOPs to a suitable standard, their storage, maintenance, and eventual disposal over their lifetime. This might include direct curation by centre experts, training of producers/users to curate their own data and models, and would also involve clear management plans for length of storage and privacy requirements. Data curation components involve:
(i) the development of community standards and best practices for maps, data, tools, models and SOPS;
(ii) the provision of brokerage services to bring researchers in contact with external research infrastructures or institutes with experimental design and data generation capabilities in compliance with ISBE standards;
(iii) Training to disseminate better data management practices throughout the community.
The single most important aspect is trust. Service providers must trust researchers to format, annotate and make their data and models available according to a base level of requirements. Providers must trust the infrastructure to store and maintain their data, models, and SOPs for the lifetime of their data management agreement – including the security of sensitive research assets, and the ability to maintain intellectual property rights where appropriate. Providers also must trust that they can get adequate acknowledgement and credit if their research assets are reused in other projects – much like with paper citations at present.
4.Modelling of biological systems based on integration of diverse data sets:
Modelling is at the heart of systems biology. ISBE will support life scientists, either proficient or unskilled in systems biology, to develop and use quantitative and predictive computational models to understand the functioning of complex biological systems. These services will include model-supported data integration and data analysis, model analysis and validation, model-based simulation and analysis of system behaviour, and model construction. Increasingly, this involves integration of highly diverse data sets and a variety of pre-existing models, in multi-scale models that span large time scales and length scales.
ISBE will offer a wide range of modelling methodologies for systems ranging from subcellular molecular networks through to cells, tissues, and organs up to complete organisms in their dynamic environment. In this, ISBE will draw on a broad range of genome wide maps, Boolean, Bayesian, and Petrinet models, all the way up to multi-scale models that harbour mixtures of multidimensional, stochastic and partial differential equation models and integrate the molecular, cellular and physiological levels.
As scientists that are not experienced in modelling of biological systems are a major target of its services, ISBE will enable a wide range of researchers to use computational modelling to integrate diverse data sets and explore, predict and test the behaviour of complex biological systems in biotechnology and health research. This will support the conversion of information about systems into system level understanding.
5.Facilitating model-compliant data generation:
Most existing biological data sets are unsuitable for systems biology modelling: they are incomplete, unannotated, or have been acquired for other purposes. Researchers active in the systems biology field generally require precise data obtained under defined experimental conditions which must be described adequately if they are to be validly reused. Improving the generation of model-compliant data is not simple. It requires, firstly, systems biology compliant experimental design and then a strong framework of activities that support a smooth pathway from data, model, SOP and other research asset generation, through to storage, followed by search, access, and reuse by downstream users.
To address this, ISBE will facilitate the generation of data suitable for systems biology through: (i) the development of community standards and best practices for maps, data, tools, models and SOPS; (ii) the provision of brokerage services to bring researchers in contact with external research infrastructures or institutes with experimental design and data generation capabilities in compliance with ISBE standards; and (iii) support in the experimental design phase and throughout the data generation, integration, modelling and model validation process, in order to obtain model-compliant data.
6.Community activities:
The ISBE user and provider communities are the infrastructure’s greatest resource. ISBE will harness their expertise in a range of community-led activities across its systems biology and life science stakeholders:
• integral map, model and data curation
• development and implementation of community standards, in collaboration with the life science community and international systems biology journals
• foster the maintenance and development of systems biology formatting and annotation standards, such as Systems Biology Markup Language (SBML), Simulation Experiment Description Markup Language (SED-ML), and Minimum Information Required In the Annotation of Models (MIRIAM)
• promote the development of standards for the exchange of information between models dealing with time varying but spatially lumped processes, such as CellML, and spatially and time varying processes, such as FieldML.
• serve as a contact for worldwide initiatives and collaborations in systems biology-related fields
• be a key player in the collaboration between and the harmonisation of activities of the thirteen life sciences ESFRI research infrastructures in the context of the CORBEL programme
• cooperate with and contribute to harmonisation between European systems biology-oriented research programmes and activities, such as Virtual Physiological Human, ERASysApp, Coordinating Action Systems Medicine (CASYM), ERACoSysMed and ERASynBio
• promote, support and contribute to the organisation of international congresses in the field of systems biology
• develop and maintain the European Systems Biology Community website (community.isbe.eu) as a portal for networking and community engagement
7.Training and education:
Education and training in systems biology is vital for ensuring the effective adoption of systems biology approaches to tackle today’s societal challenges. ISBE’s ambition is to train a new generation of systems biologists equipped with the cross-disciplinary skills. This will be important not just for systems biology, but it will also have applications in many areas of academia, government, industry, consultancy and other non-governmental organisations.
ISBE’s multi-faceted training strategy consists of the following key elements:
• User training and continued professional development
ISBE’s national Systems Biology Centres will provide bespoke training to ensure effective utilisation of its tools, services and resources. This training will range from starter courses for novices to specialised training for experts and tailored courses for industrial users. ISBE will work with, and learn from, other research infrastructures to develop a training strategy which encompasses a range of learning methods to ensure maximum efficacy.
• Education
Together with ERASysApp, ISBE has developed a core curriculum for Masters level students in systems biology which will be disseminated through various communication channels (publication, website and conferences) and implemented as a pilot project through interested universities.
• Dissemination of information on education and training
ISBE will maintain a comprehensive and up-to-date database of systems biology-related education, courses, workshops and conferences and make this information openly available. If ISBE identifies major gaps in knowledge dissemination or development, it will lobby national and European organisations to take the initiative, or will develop courses itself.
• Training of staff managing and operating research infrastructures
The complexity of research infrastructures and the exploitation of their full potential requires suitably trained managers and technical operators. As a key participant in the recently funded Horizon 2020 CORBEL and RItrain projects, ISBE is working with other European research infrastructures to develop and support the training of staff managing and operating research infrastructures including the exchange of staff and best practices between facilities. The development and establishment of a Masters in Research Infrastructure Management within the RItrain project will contribute to the supply of human resources with the requisite skills.
ISBE will build on existing European resources and draw on the national technological and scientific strengths of its providers to offer a comprehensive portfolio of services and resources. ISBE will map onto existing national structures and coordinate and synergise facilities under a single banner, creating ease of access for its users. This will stimulate growth in the user-base of existing resources, providing a return on existing investments while keeping coordination costs minimal.
The core of ISBE will be a distributed knowledge-based infrastructure of national Systems Biology Centres (nSBCs) across Europe, offering interconnected and complementary services and resources both nationally and transnationally.
This will create a European infrastructure that:
• aims to cover all facets of the rapidly developing field of systems biology
• synergises past, present and future national and European investments in systems biology
• has a highly flexible capacity to provide an integrated range of services
• provides coordinated services with other European research infrastructures
8.Organisational structure:
National Systems Biology Centres (nSBCs) are the cornerstone of the ISBE research infrastructure. Embedded in their national life science community, each will deliver the portfolio of standard ISBE services and resources, as well as bespoke services based on the expertise of institutions in their country. nSBCs will serve (i) their national user-base including academia and industry, (ii) transnational users, as well as (iii) multinational projects. Trans- and multinational activities will run through collaborations of two or more nSBCs that are coordinated through the Central ISBE Office (CIO) and the coordinating SBC (cSBC). Managing individual nSBCs within the context of the ISBE infrastructure will be the responsibility of the relevant national authority.
In principle, a country will maintain one nSBC which will constitute the primary vehicle for providing services to the national community. This nSBC may be a single national institution or a distributed centre drawing expertise from a number of different institutions in a country.
The Central ISBE Office (CIO) will be responsible for central management, administration and executing the Governing Board’s decisions of ISBE as well as working with the Management Group to undertake delivery. It will integrate, coordinate, monitor and oversee:
• overall operations and strategy development of ISBE, including nominations and selection of new nSBCs
• functional links between nSBCs, including commissioning of novel services, resources and activities
• quality control of nSBCs and the European matrix of centres
• liaison with national and European funding organisations, external cooperation, partnerships with other research infrastructures, including other ESFRIs, and international organisations in or outside Europe
To give the CIO rapid and easy access to scientific competencies in the field of systems biology, it will be physically linked to one of the nSBCs, which fulfils the role of coordinating Systems Biology Centre (cSBC). The role of the cSBC is to advise the CIO on matters relating to the coordination of user support, stewardship and teaching and training. Also, with the help of the cSBC, the CIO will maintain an overview of the scientific and technical capabilities of all nSBCs. This enables the CIO to identify gaps in expertise as early as possible.
The scientific expertise of the cSBC will support the CIO to manage complex and extensive user requests that require cooperation of two or more nSBCs working together. The CIO will support pan-European community activities including training and development of community standards. The function of cSBC will be performed by a nominated nSBC.
Given the present and near-future developments in the life sciences, the need for the kinds of services offered by ISBE will increase steadily. This requires an infrastructure with services that are scalable and can be adapted rapidly to changing needs of its users. Therefore, the nSBCs should be flexible, both with respect to the volume of support activities and their range of expertise. This is one of the aspects that must be agreed upon in the covenants that ISBE will have with each of the national funders that finance an nSBC. The development of the volume and the types of support that ISBE offers will be coordinated by the CIO.
9. Access to ISBE:
ISBE will be openly accessible to all researchers from European academia, hospitals, clinics and industry, including SMEs. It will not have a research programme itself. Rather, it will support the research projects and programmes of its users, i.e. individual researchers, research groups and research consortia. Access to the infrastructure will be easy and efficient through a central web portal. ISBE will support users that are proficient in systems biology, as well as those that are inexperienced in the field. This will enhance the dissemination and implementation of systems biology in all branches of the life sciences and the impact of systems biology for the benefit of society. After first contact through the ISBE web portal, users will be linked to one of the nSBCs that is able to provide the requested services, or to a number of nSBCs for more complex services. In all cases the user will have a single ISBE officer as contact person.
Access to the majority of ISBE’s web-based resources will be free of charge. Services that are more elaborate, such as modelling, model validation and data collection, will require a fee, based on a contract between ISBE (or the relevant nSBC) and the user. It is expected that in most cases costs will be covered through national or European grants. In many cases user projects will already have undergone peer review through a funding organisation. If so, ISBE will accept the user without further screening. If not, ISBE will carry out its own quality check based on a simple peer review process.
Cost models for the above will be developed together with national funders and the nSBCs. Training and education activities will be developed and offered through the nSBCs. Costs for ISBE clients will depend on the user-type, activity and the tariff defined by the nSBC.
ISBE will be a gateway to services provided by linked research infrastructures and provide brokerage services to introduce users to services outside of the remit of ISBE including systems biology compliant data generation and experimental design that is not performed within the infrastructure.
10. Providers of ISBE services:
A range of national research programmes in many countries has resulted in a broad and substantial systems biology base in Europe, including those established on support from a series of transnational ERA-Net programmes, or supported by FP6, FP7 and Horizon 2020 awards. ISBE will serve as the coordinator of this expertise, fostering new user-bases and providing a single entry point.
Leading systems biology centres in most European member and associated states have been identified during ISBE’s Preparatory Phase. Within each of the national communities, ISBE has pinpointed the leading centres and addressed a number of them to audit their capacity and interest in providing systems biology services and resources to a broad audience. Prominent researchers in more than 40 institutions across Europe have been consulted, and more than 80 available systems biology resources have been identified with this exercise.
Almost all of the institutions surveyed (90%) recognised the value of offering their expertise and services to a broader community of users via a pan-European infrastructure, and thus manifested interest for being part of ISBE as a provider. A portion of these resources are already available to very variable numbers of users (from between 5 and 15,000 per month), but their sustainability and interoperability is often at risk. In fact, most of the resources surveyed by ISBE were funded primarily on short-term, unspecific grants, with less than 10% operating with stable funding arrangements. In this context, a broadening of user bases through ISBE will be beneficial and improve sustainability.
11. Legal and governance (from 2018):
ISBE requires its own legal personality in order to obtain funding, manage budgets and establish legal agreements with the national Systems Biology Centres (nSBCs). This legal entity can coherently engage with users, providers, national ministries, funding agencies and the European Commission. The Preparatory Phase has identified the European Research Infrastructure Consortium (ERIC) mechanism as being the most appropriate legal model for ISBE. This allows ISBE to become a legal entity with a European identity and to benefit from tax exemptions. The ERIC framework has already been ratified by many EU member states and allows membership for countries outside the EU. While the nature and mechanisms for coordination of nSBCs would be outlined in the ERIC, direct agreements between ISBE and the nSBC will be required to ensure efficient coordination of services across centres. All nSBCs will be established by entering into a pre-agreed Service Level Agreements (SLA) with ISBE that will define, in a fair and transparent manner, the commissioning of services, resources and other activities that will be offered. The SLAs will formally define those services and resources that are to be offered through ISBE and define the levels of services expected by users, as well as the obligations for the nSBCs in maintaining their availability. An nSBC may be a single institution or a single institution may act in a capacity to represent several other nationally-located institutions responsible for providing aspects of the nSBC services. The ISBE governance structure will provide for effective and timely management and monitoring of operations across the nSBCs. It will provide suitable external scientific and technical advice and operate with transparency and clarity in its procedures, including the nomination and election of members .
The location of the host institution for the CIO for the Legal Phase has yet to be identified. The host country will be identified during the Interim Phase (2015-2018). The procedure and eligibility criteria for approving further nSBCs will also be developed in the Interim Phase, with evaluation processes set out in the ERIC. While the CIO may be situated at the same institution as an nSBC, there will be clear mechanisms that separate their responsibility and functions to allow independent operation and avoid conflict of interest.
The Governing Board will be the central decision making body with high-level oversight, supervising the CIO on behalf of the member states. It will be responsible for ISBE’s strategy and budgets, as well as approval of prospective nSBCs. Representatives will be drawn from and nominated by national funding bodies, together with scientific experts identified by the national funder and tasked with representing the interests of their national communities.
The Heads of Centres Committee will provide operational coordination across the nSBCs and will be responsible for maintaining effective operations across the nSBCs and developing strategic plans, for agreement by the Governing Board. Members will be the directors of the nSBCs, together with the director of ISBE.
The ISBE director is expected to have significant experience coordinating collaborative programmes, notably those with significant elements community outreach and industrial involvement. As head of the CIO, the Director will be appointed by the Governing Board. The Director will be responsible for executing the Governing Board’s decisions, and management of the central budget. The CIO will organise the scientific evaluation and monitoring of nSBCs, as well as managing SLAs and the interface with other ESFRIs. The CIO will also coordinate internal communications and outreach aspects on behalf of the centres.
In support of this, cross-centre Technical Working Groups will lead the delivery of the specific technical and training work streams. These boards will coordinate the delivery of community-led activities.
Understanding user needs is crucial to the success of ISBE. ISBE will draw from the widest possible international expertise to gain insight in how best to meet emerging community needs and opportunities across all sectors, combined with ensuring the continued delivery of cutting edge technologies.
ISBE will establish three main advisory panels, described below, giving independent external advice to enable:
• effective and efficient operations
• suitable oversight and monitoring
• independent audit
• prioritisation of ethical considerations
• a flexibly managed portfolio of expanding resources services by adapting activities within nSBCs as well as bringing in new nSBCs, including the amendment and termination of existing activities at nSBCs, and proposals for novel services to address emerging challenges.
A Scientific Advisory Board (SAB) will be the main sources of external advice from academia for both the Governing Board and executive. A key role is SAB’s evaluation of nSBC applications against a pre-agreed evaluation process, and their subsequent monitoring to advise the Governing Board on decisions such as to renew or terminate nSBCs.
An Industry Liaison Board (ILB) will be the main source for wider coordinated consultation of stakeholders within the commercial sector. Its separate identity from the SAB underlines the importance of addressing industrial interest in working collaboratively with academic systems biology researchers. The SAB also will draw from the ILB membership.
An Ethical Board (EB) will consider the ethical implications of ISBE’s activities such as managing information from plant, animal and human experimentation, together with the related issues of data security and access. It will draw expertise from the nSBCs as well as the SAB and ILB. ISBE will build on links being established within the CORBEL project across ESFRIs for the consideration of legal and ethical issues for data exchange and protection in transnational research collaborations.
This will include ensuring appropriate collection and storage of patient samples; regulations on working with genetically modified organisms, and guidelines for accommodation and care of lab animals.
ISBE User Boards will engage representatives from different user sectors to ensure effective feedback on services and activities, and their involvement in developing novel targeted activities.
ISBE will work closely with other research infrastructures building on existing activities, such as those currently supported through CORBEL and RItrain, to deliver joint activities and avoid redundancy of operations. Representatives of other research infrastructures will also be invited to attend meetings of standing and advisory bodies. Where longer term agreements are needed, ISBE will work with other research infrastructures to develop appropriate Memoranda of Understanding.
12. The ISBE Funding Strategy:
The financial model for ISBE is similar to that implemented by or proposed for other European research infrastructures, including BBMRI, ECRIN and ELIXIR. The proposed financial model of ISBE has five main components:
• national Systems Biology Centres (nSBCs)
• the Central ISBE Office (CIO)
• further expansion of ISBE
• services and community activities
• funding through third parties
13. Financial model for the national level (nSBCs):
The operational costs of each nSBCs will be covered at the national level, with many of these services and resources often already receiving national support. Further national support, in the context of ISBE, will enhance national investments and uptake by their growing national user base. ISBE will make national investments more cost-effective by providing access to a broader user and provider base at the European level.
14 Financial model for European operations (CIO):
The CIO, headed by the ISBE director, will coordinate the development and maintenance of the portfolio of services, resources and community activities and take responsibility for ISBE’s finance, governance and outreach. In practice, levels of national member state contributions should reflect their relative size. To support the CIO, ISBE therefore proposes to use a similar Gross Domestic Product (GDP) based subscription model to that currently employed by other ESFRIs. It is anticipated that additional contributions such as ‘in-kind’ support of indirect costs may come from the country that hosts the CIO.
15. Further expansion of ISBE:
ISBE will expand its budget in two ways, i.e. through stepwise increased national budgets of its nSBCs and by acquiring funding at the European level through the CIO. Once established, ISBE is designed to grow with expanding user demand, as well as new countries joining over time. The ISBE infrastructure model allows for its subsequent expansion over time, in a manner that can respond to evolving user demands be developing the scope of services and resources it supplies. There are increasing opportunities in the Horizon 2020 scheme for developing European research infrastructures. Examples are the recently awarded grants for the CORBEL (harmonizing activities of life sciences research infrastructures) and RItrain (training research infrastructure personnel) programmes in which ISBE participates. Another example is the transnationally funded FAIRDOM programme, which will be integrated in the ISBE activities. Together, this presently represents a European level budget for ISBE of ~€4.6M. The CIO will, together with the nSBCs, make a continuous effort in expanding European funding of ISBE.
16. Services and community activities:
A detailed cost model for ISBE services for all user types will be developed in conjunction with nSBCs and relevant national funders based more exactly on the specific services a centre will provide.
17. The Interim Phase - building the infrastructure:
By the end of the ISBE Interim Phase (2015-2018) a fully functional ISBE will be established as a legal identity. This section describes the mechanisms and timeframe of how ISBE will be rolled out up until its formal start in 2018.
The Interim Phase has five major objectives:
• reach formal agreement with national funding organisations about ISBE’s legal structure and budget for the Legal Phase
• make available an initial portfolio of services and resources to European scientists: ISBE-light
• establish ISBE’s governance and management structure
• establish the European distributed knowledge-based infrastructure of interconnected nSBCs
• harmonise ISBE’s operations with those of other research infrastructures in the life sciences, primarily through the CORBEL and RItrain programmes
The Interim Phase will consist of two distinct stages. Interim Phase Stage 1 will begin in August 2015, immediately after the end of the Preparatory Phase. The aim of Stage 1 is to have at least three national funding organisations signing a Memorandum of Understanding (MoU) within the first year of the interim phase. This stage will establish an interim governance and management structure capable of commencing delivery of the ‘ISBE-light’ operational portfolio. Negotiations with funders will continue to establish commitment for financial support. This should ensure an adequate budget for the construction of ISBE during Interim Phase Stage 2. The start of Stage 2 will commence with the appointment of the founding director, who takes responsibility for building the research infrastructure.
17.1 Interim Phase Stage 1 (2015-2016):
The major objectives of Stage 1 are (i) to continue activities on the national and European level, initiated during the Preparatory Phase, and (ii) secure Stage 2 budget, and (iii) start delivering ISBE-light services.
This comprises the following processes:
• establish an interim governance structure
• formally involve at least three national funding organisations on the basis of a MoU
• identify and pursue further European funding opportunities
• negotiate with national funders and key stakeholders to establish the budget for Stage 2
• select a founding director as soon as the Stage 2 budget is secured
• identify the host country for the Central ISBE Office (CIO) and the coordinating Systems Biology Centre (cSBC)
• start the procedure to identify and select nSBCs that will be formally established in Stage 2
• commence delivery of a portfolio of web-based services and resources called ’ISBE-light’
• operate ISBE-branded activities through the CORBEL, RItrain H2020 projects and FAIRDOM, with continuing partnership with other ESFRI research infrastructures and national infrastructural programmes
The management at the outset of the Interim Phase will reflect the commencement of the operations of ‘ISBE-light’ web-based services and resources with the formation of the ISBE Interim Committee (IC). The ISBE Interim Committee (IC) will (i) ensure inclusive negotiations with both national funders and key stakeholders that are required to establish the budget for Stage 2, (ii) select the founding director, and (iii) start the procedure to identify and select nSBCs that will be formally established in Stage 2. The IC will consist of all members of the Management Team (MT) and Intergovernmental Working Group (IWG) and draw on members of the Preparatory Phase Steering Committee who have expressed their interest in further engagement. This IC will identify further European funding opportunities for ISBE, as well as coordinate strategic interactions with other ESFRIs. In addition, steps will be taken to form user community forums and an Industry Liaison Board. The IC and the MT will be chaired by a full time Interim Coordinator, who will be responsible for the development of ISBE during Stage 1. The MT is a sub-committee of the IC, which will consist of those involved in the delivery of ISBE-light’s portfolio of services, and coordination across ISBE-branded activities through the CORBEL and RItrain H2020 projects and FAIRDOM. The IWG is another sub-committee of the IC, which will draw together representatives of national funding organisations who have expressed an interest in supporting ISBE.
The costs of Stage 1 are estimated to be minimally € 250k for 12 months (see Table 6.1and Appendix 9, Table 1). Contributions are expected via financial and in-kind contributions through ISBE stakeholders and national funders. Negotiations with national funding agencies should result in the signing of a MoU and associated financial support, or another type of agreement, in which they declare interest in participating in building ISBE and contribute to a budget for Stage 2. The selection of nSBCs in Interim Phase Stage 2 requires an open and transparent procedure, which will be agreed with national funding organisations and research communities. The same holds for the host country of the CIO. To expand awareness of ISBE in the scientific communities and maintain the momentum and interest developed during the Preparatory Phase, ISBE will offer in Stage 1 and Stage 2 a portfolio of four types of web-based services and resources.
Most ISBE-light services will be available free of charge to users. They will be operated and supervised by systems biology centres of excellence that have an interest in continued involvement in ISBE. ISBE-light will commence as soon as possible after the start of Interim Phase Stage 1. Services will continue in Stage 2, forming a solid basis for a complete portfolio in ISBE’s Legal Phase.
ISBE-light will offer three types of services:
1. Modelling services and resources
ISBE’s modelling services aim to lower the threshold for biologists to incorporate computational modelling in their research. In this early stage of ISBE development, clients will be directed to a ready-to-use web-based modelling platform, linked to relevant model resources. Target communities for these services are researchers in academia and industry with varying levels of training in mathematics and statistics and in computer and information science.
For the initial ISBE-light services, ISBE will focus first on modelling frameworks that have (i) a large potential user base, and (ii) standardised ways of asking research questions. By doing so, one can span a large space of questions with a well-defined set of query parameters. In addition, users can pose a wide range of questions by filling in a form and uploading their own data or models, similar to what is already common place in bioinformatics.
2. Access to tools, standards and model-compliant data and maps
For ISBE-light, ISBE will engage with the existing FAIRDOM initiative , a joint action of the ERANet ERASysApp with ISBE. FAIRDOM aims to establish a data and model management service facility for systems biology. This is intended to operate under the ISBE-light umbrella. ISBE-light services will aim for web-based access to tools, archives, model-compliant data and maps which will focus on:
• making software available with user guides that support and improve research asset management from instrument to publication
• supporting the establishment of research asset management planning for grants
• developing an online ’knowledge hub’ which: a) identifies and characterises different tools and standards that can be used within projects, b) identifies public repositories and characterises them according to the type of data that they contain, and what standards are used in conjunction with the repository, c) identifies and categorises minimum information models for different research-asset types, and d) provides data-templates that are semantically capable for a range of different data-assay types.
3. Education and training
Services will aim at dissemination of information on training and education in systems biology and will include:
• dissemination of information on training and postgraduate education in systems biology (in collaboration with ERASysApp), through the ISBE community portal
• dissemination and implementation of a core curriculum through the ISBE website, publication, Erasmus+ and low cost networking meetings
• dissemination of courses (summer and winter schools, workshops, advanced training) that ISBE partners are involved in
In addition, ISBE is currently exploring a synergistic role between ISBE and scientific journals with respect to ISBE being a rich source of multidisciplinary expertise in systems biology, spanning a broad range of biological fields, disciplines and skills, and ISBE taking initiatives in developing and disseminating community standards and standard operation procedures (SOPs) in the systems biology field.
During Interim Phase Stage 1, ISBE will be embedded in European-level systems biology initiatives and national systems biology communities and it will actively contribute to the harmonisation of ESFRI research infrastructures in the life sciences field.
17.2 Interim Phase Stage 2 (2016-2018):
Stage 2 will commence on the appointment of the founding director and will end with the establishment of ISBE as a legal entity. The major responsibility of the founding director is therefore to develop ISBE’s legal identity and operational processes. The objective of Stage 2 is to develop a legally-based and fully functional ISBE. This includes the following:
• establish the Central ISBE office (CIO), the coordinating SBC (cSBC) and ISBE’s governance structure
• continue empowering ISBE-light and organise the transition of ISBE-light towards a fully operational ISBE by developing a broad portfolio of services, resources, community activities and training and education programmes together with the nSBCs and in dialogue with user communities
• establish a collaborative federation of nSBCs that will be fully operational in the Legal Phase
• negotiate the operational budget of ISBE Legal Phase
• develop the legal basis for ISBE, preferentially an ERIC
• continue developing partnerships with other European research infrastructures, primarily through the CORBEL and RItrain projects.
The management structure from Stage 1 for the ISBE Interim Committee and the ISBE-light Management Team will be modified at the start of Stage 2 as part of the stepwise migration of the Interim Phase governance structure towards that described for the Legal Phase (2018 onwards). Stage 2 requires a budget of approximately € 1.6 M for two years (2016-2018) comprising:
• salary of the founding director and CIO staff
• operation costs of the Central ISBE Office (CIO)
• activities to develop and coordinate the European matrix of collaborating nSBCs and ISBE’s portfolio of services and resources.
ISBE will negotiate with national funding agencies that are MoU signatories, as well as other national funders, to agree on conditions for sustainable funding of ISBE in its Legal Phase. ISBE will seek their contribution to the central budget to support the CIO and coordinating and community activities. In parallel, agreement should be reached about national funding of the individual nSBCs and the coordinating SBC. The open and transparent nomination and selection process for nSBCs will be executed along the lines agreed on in Stage 1. Provisions will be made to give users in European countries without an nSBC access to ISBE’s resources and services.
Negotiations in Stage 1 will identify the host country of the interim CIO. The founding director will head the interim CIO and establish the governance structure for the legal phase. At present it is anticipated that the IC sub-committees will be fully integrated into the Interim Committee, in anticipation of migration to the full ESFRI bodies in the Legal Phase. Finally, groups expecting to form nSBCs will be invited to form a “Candidate nSBC working group” (anticipated to grow into the legal phase ‘Heads of Centres Committee’). Negotiations in Stage 1 will identify the host country of the interim CIO. The founding director will head the interim CIO and establish the governance structure for the legal phase.
18. Legal basis for ISBE:
An important aim of Stage 2 is to agree on the legal status of ISBE. The current preference is for an ERIC. However, we expect that the development of the ISBE structure for the legal phase will continue and therefore the suitability of ERIC, including the potential for a transitional legal structure to facilitate to foundation of ISBE will be kept under dynamic review. Decisions will be made based on discussions with national funding organisations and governments. Establishing ISBE’s legal status marks the transition of the Interim Phase to the Legal Phase.
Together with the nSBCs and relevant research communities, ISBE will develop and establish its portfolio of services, resources and community activities within the framework outlined in this Business Plan. This will build on the activities of ISBE-light that started in Stage 1. The portfolio will grow steadily in Stage 2 and in the subsequent Legal Phase, constantly adapting to the developing needs of ISBE’s users.
A major task of the founding director will be to develop relationships with different user communities, including academia, hospitals/clinics and industry/SMEs. This will build on the expertise in translational research for those centres providing ISBE activities to enhance translation and create a coherence forward look for systems approaches from a joint academia-industry perspective. A vital part of this will involve establishing user committees and advisory boards.
Coordination with ELIXIR on ensuring synergies to address community needs:
In developing its portfolio ISBE recognises the key links it has already forged with ELIXIR as part of developing the CORBEL and RItrain proposals. In addition the FAIRDOM project addresses the overlapping data standards requirement across both Research Infrastructures. ISBE and ELIXIR will continue to work closely in ensuring a common strategic framework for delivery of services and resources that avoids duplication and redundancy of provision. As a first stage, both RIs are committed to formalising their relationship and further defining their interface, be developing a common strategic document on joint working early in 2016.
19. Measuring Wider Impact:
In addition to understanding and measuring the direct outputs of ISBE and its services, it is also important to develop appropriate metrics to understand how ISBE has supported the delivery of the research of those communities using ISBE. During the Interim Phase ISBE will consider the needs for longer term monitoring of services and their users. ISBE plans to demonstrate to its funders how its activities and services:
• have influenced the development of a highly skilled work force
• have fostered the usage of data and model standards, and appropriate tools
• have aided in development of collaborations of provider and users at scientific institutions in Europe and worldwide
• have encouraged closer collaboration between academia and industry to the benefit of the EU bioeconomy
• have enhanced the application and integration of systems approaches in the biosciences by acting as a ‘knowledge broker’ of choice
• have facilitated the rapid uptake of novel and innovative technologies across all biomedical sectors
Potential Impact:
Systems biology has the potential to contribute greatly to addressing the major societal grand challenges in health, agriculture and bio-economy.
Health:
While twentieth century scientific advances succeeded in protecting people from diseases that caused them to die young, with developments in antibiotics and drugs, the challenges of European healthcare in the twenty-first century will be to cope with ageing populations with complex diseases such as cancer and Alzheimer’s, or increasingly where patients present with more than one condition.
Europe is faced with an ageing population, with affiliated challenges in healthcare provision. Recent European Commission reports have highlighted the correlation between increasing population age and increased public spending on healthcare . The EC, through its Healthy Ageing programme, is seeking to adapt EU policies and strategies to meet the demands associated with this significant demographic shift.
Systems biology’s emphasis on combining knowledge from multiple biological processes makes it uniquely placed to combat diseases and the multi-factorial mechanisms that underlie them. The model-based approach of systems biology is essential to unravelling the complex molecular, cellular and organ basis of such diseases, allowing more effective and rational approaches to prevention, diagnosis and personalised treatment schemes. It is through the power of these models to integrate diverse data sets that we can now begin to properly predict responses to specific interventions and provide new and personalised therapies.
Systems biology is also key to overcoming the problem that many existing drugs and therapies have no, or even an adverse, effect on patients. Individualised genome sequencing, transcriptomics, proteomics and metabolomics combined with systems biology based analyses, begin to allow a much more successful, rationalised and personalised treatment plans for the patient.
Agriculture:
In agricultural sciences, systems biology approaches are widely used to tackle issues that relate to sustainable food production. Varieties of drought and salt resistant crops, are needed to overcome the world-wide shortage of fresh water to expand overall outputs. Understanding of the relevant processes in plants has opened new avenues to modify molecular and cellular networks and thereby the creation of crops that provide commercially viable yields under previously unfavourable conditions.
Control of flowering time is another area being tackled by a systems biology approach. This is an exceptionally important economic issue because it allows farmers to optimise yields by defining the best time of the year for crops to be harvested.
Finally, an area underpinning sustainable energy production is to develop a better understanding of the light harvesting and photosynthetic systems of plants and green algae that will facilitate enhancements to their butanol producing metabolic networks. Linking such complex systems and fine tuning their functioning is now typically addressed through systems biology approaches. A considerable number of European research groups are active in these and related agricultural fields.
Industrial biotechnology:
The food industry is one of the largest and most important manufacturing sectors in Europe, and systems biology approaches are giving cutting edge producers an international competitive advantage. Understanding molecular, cellular networks of microorganisms, plants and animals, which have been defined and integrated by systems research, enables a predictable and rational approach to their genetic and metabolic engineering. For instance, systems biology research groups across Europe are utilising computational models in the development of new food products and new plant and animal breeding regimes.
Bioeconomy:
The Organisation of Economic Co-operation and Development (OECD) has placed strong emphasis on the fact that biological resource centres (such as ISBE) are an essential part of the infrastructural requirements for the proper development of bio resources and their explicit role for industry . In parallel, the European Union has substantially invested in programmes such as IMI , EMTRAIN , EIT and the development of platforms such as KIC to stimulate public-private research and training initiatives. A prerequisite for industry to participate in these programmes is the willingness to promote an open innovation model and exploitation of results. In this context the collaboration and coordination between research infrastructures, including ISBE, in the Horizon 2020 funded programmes CORBEL and RItrain should play a key role in increasing the output of these programs.
Despite these and other public-private efforts, commercial parties and particularly SMEs face the same problems as the academic sector: they have difficulties in finding and involving the necessary expertise and resources in systems biology. Large companies may have the possibility to invest in (often costly) solutions to tackle some aspects of this problem. SMEs, that lack both budget and manpower, cannot easily overcome this hurdle. Other obstacles hindering industrial research and innovative capacity are the duplication of efforts, difficulty of integrating private and public data and lack of standards. A positive development in solving this problem is that a collaborative landscape is developing, with a range of pre-competitive coalitions in research areas such as human health, environment, energy, and food technology. Here ISBE services and resources, and also matchmaking, would boost collaborations between private and public research efforts.
Community activities:
The ISBE user and provider communities are the infrastructure’s greatest resource. ISBE will harness their expertise in a range of community-led activities across its systems biology and life science stakeholders:
• integral map, model and data curation
• development and implementation of community standards, in collaboration with the life science community and international systems biology journals
• foster the maintenance and development of systems biology formatting and annotation standards, such as Systems Biology Markup Language (SBML), Simulation Experiment Description Markup Language (SED-ML), and Minimum Information Required In the Annotation of Models (MIRIAM)
• promote the development of standards for the exchange of information between models dealing with time varying but spatially lumped processes, such as CellML, and spatially and time varying processes, such as FieldML.
• serve as a contact for worldwide initiatives and collaborations in systems biology-related fields
• be a key player in the collaboration between and the harmonisation of activities of the thirteen life sciences ESFRI research infrastructures in the context of the CORBEL programme
• cooperate with and contribute to harmonisation between European systems biology-oriented research programmes and activities, such as Virtual Physiological Human, ERASysApp, Coordinating Action Systems Medicine (CASYM), ERACoSysMed and ERASynBio
• promote, support and contribute to the organisation of international congresses in the field of systems biology
• develop and maintain the European Systems Biology Community website (community.isbe.eu) as a portal for networking and community engagement
Education and training:
ISBE services will aim at dissemination of information on training and education in systems biology and will include:
• dissemination of information on training and postgraduate education in systems biology (in collaboration with ERASysApp), through the ISBE community portal
• dissemination and implementation of a core curriculum through the ISBE website, publication, Erasmus+ and low cost networking meetings
• dissemination of courses (summer and winter schools, workshops, advanced training) that ISBE partners are involved in
Liaison with scientific journals
ISBE is currently exploring a synergistic role between ISBE and scientific journals with respect to:
• ISBE being a rich source of multidisciplinary expertise in systems biology, spanning a broad range of biological fields, disciplines and skills
• ISBE taking initiatives in developing and disseminating community standards and standard operation procedures (SOPs) in the systems biology field
Measuring Wider Impact:
In addition to understanding and measuring the direct outputs of ISBE and its services, it is also important to develop appropriate metrics to understand how we have supported the delivery of the research of those communities using ISBE. ISBE will therefore consider the needs for longer term monitoring of services and their users. ISBE plans to demonstrate to its funders how its activities and services:
• have influenced the development of a highly skilled work force
• have fostered the usage of data and model standards, and appropriate tools
• have aided in development of collaborations of provider and users at scientific institutions in Europe and worldwide
• have encouraged closer collaboration between academia and industry to the benefit of the EU bioeconomy.
• have enhanced the application and integration of systems approaches in the biosciences by acting as the ‘knowledge broker’ of choice
• have facilitated the rapid uptake of novel and innovative technologies across all biomedical sector
List of Websites:
www.isbe.eu
Names and email addresses of ISBE Consortium members:
UK
Richard Kitney, Imperial College, r.kitney@imperial.ac.uk
Barbara Skene, Imperial College, b.skene@imperial.ac.uk
Sara Butcher, Imperial College, s.butcher@imperial.ac.uk
Carole Goble, The University of Manchester, carole.goble@manchester.ac.uk
Natalie Stanford – The University of Manchester, natalie.stanford@manchester.ac.uk
Gabriela Pastori, Biotechnology and Biological Sciences Research Council, gabriela.pastori@bbsrc.ac.uk
Adrian Pugh, Biotechnology and Biological Sciences Research Council, adrian.pugh@bbsrc.ac.uk
Netherlands
Roel Van Driel, Universiteit van Amsterdam (UvA), r.vandriel@uva.nl
Vitor Martins Dos Santos, Wageningen University, vitor.martinsdossantos@wur.nl
Babette Regierer, Wageningen University, regierer@lifeglimmer.com
Martijn Mone, Wageningen University, martijn.mone@wur.nl
Hans Westerhoff, VU University Amsterdam, h.v.westerhoff@vu.nl
Martijn Mone, VU University Amsterdam (currently at Wageningen University)
Bea Pauw, Netherlands Organisation for Scientific research –Earth and Life Sciences, b.pauw@nwo.nl
Greece
Dimitris Thanos, Biomedical Research Foundation Academy of Athens (BRFAA), thanos@bioacademy.gr
Sissy Kolyva, Biomedical Research Foundation Academy of Athens (BRFAA), s.kolyva@pasteur.gr
Ireland
Eadaoin Mc Kiernan, University College Dublin, eadaoin.mckiernan@ucd.ie
William Fitzmaurice, University College Dublin, william.fitzmaurice@ucd.ie
Germany
Jutta Steinkoetter, Max Delbrück Centrum for Molecular Medicine (MDC), jutta.steinkoetter@mdc-berlin.de
Thomas Hoeffer, Deutsches Krebsforschungszentrum (DKFZ), T.Hoefer@Dkfz-Heidelberg.de
Cornelia Depner, Deutsches Krebsforschungszentrum (DKFZ), c.depner@dkfz-heidelberg.de
Angela Oberthuer, Ruprecht-Karls-Universität Heidelberg- BioQuant Centre (UHEI), angela.oberthuer@bioquant.uni-heidelberg.de
Wolfgang Mueller, Heidelberg Institute for Theoretical Studies (HITS), wolfgang.mueller@h-its.org
Martin Golebiewski, Heidelberg Institute for Theoretical Studies (HITS), Martin.Golebiewski@h-its.org
Renate Kania, Heidelberg Institute for Theoretical Studies (HITS), Renate.Kania@h-its.org
Norway
Stig Omholt, Norges miljø- og biovitenskapelige universitet (NMBU), stig.omholt@ntnu.no
Jon Olav Vik, Norges miljø- og biovitenskapelige universitet (NMBU; jonovik@gmail.com
Czech Republic
Rudiger Etrrich, Centrum vyzkumu globalni zmeny Akademie ved Ceske republiky v.v.i. (C4SYS), ettrich@nh.cas.cz
Marcela Kotrcova, Centrum vyzkumu globalni zmeny Akademie ved Ceske republiky v.v.i. (C4SYS), kotrcova@nh.cas.cz
Spain
James Sharpe, Centre for Genomic Regulation (CRG), James.Sharpe@crg.eu
Joaquim Calbo, Centre for Genomic Regulation (CRG), Joaquim.Calbo@crg.eu
Slovenia
Kristina Gruden National Institute of Biology – Slovenia (NIB), kristina.gruden@nib.si
Damjana Rozman, Univerza v Ljubljani (UL), damjana.rozman@mf.uni-lj.si
Jure Acimovic, Univerza v Ljubljani (UL), jure.acimovic@mf.uni-lj.si
Marta Sabec, Ministrstvo za izobraževanje, znanost in šport (MIZS), Marta.Sabec@gov.si
EMBL-EBI
Henning, Hermjakob, EMBL-European Bioinformatics Institute (EMBL-EBI), hhe@ebi.ac.uk
Nicolas Le Novere, EMBL-European Bioinformatics Institute (EMBL-EBI), lenov@ebi.ac.uk'
Nick Juty, EMBL-European Bioinformatics Institute (EMBL-EBI), juty@ebi.ac.uk
Sweden
Stefan Hohman, University of Gothenburg (UGOT), stefan.hohmann@gu.se
Marija Cvijovic, University of Gothenburg (UGOT), marija.cvijovic@chalmers.se
Jens Nielsen, Chalmers University of Technology, nielsenj@chalmers.se
Finland
Garry Corthals, University of Turku, Garry Corthals left Turku in May 2014 to take up a position at Universiteit van Amsterdam (UvA) - G.L.Corthals@uva.nl
