CORDIS

Executive Summary:
CASYM AND THE ROAD TOWARDS A EUROPEAN SYSTEMS MEDICINE APPROACH
From 2012 until 2017 the multidisciplinary consortium CASyM with representatives from academia, research institutes, clinical centres as well as funding bodies, Industry and SMEs joined forces to build a vision and a practical strategy (roadmap) for the implementation of Systems Medicine across Europe. During this time CASyM functioned as managing, coordination and support platform that brought together a critical mass of relevant stakeholders to develop a strong European Systems Medicine community and to work towards a long-term and sustained implementation of Systems Medicine across Europe – with the aim to bring Systems Medicine into everyday clinical research and practice for the benefit of public health in the near future.
The CASyM roadmap, initially published in 2014, and released as revised version in 2017 identified four core priority actions (community building, proof of concept/pilot study, cross-disciplinary training and data access, sharing and standardization) and ten key areas necessary to the successful implementation of Systems Medicine in Europe. These areas are outlined along with cross-cutting actions and specific recommendations over a period of 2, 5 and 10 years. Based on the recommendations of the CASyM roadmap, the European Commission (EC) launched the first Systems Medicine ERA-NET under Horizon 2020 – a consortium of 13 European funding bodies with support by the EC under the co-fund scheme, which agreed on a common agenda to further develop a European Systems Medicine approach. The ERA-NET “Systems Medicine to address clinical needs” started in January 2015 with the aim to specifically fund demonstrator projects – as recommended by the CASyM roadmap – that identify areas where a systems approach addresses a clinical question and provides solution strategies to clinical problems with clear emphasis on using Systems Medicine to make a real, lasting benefit for personalized care and the understanding of the cause of complex diseases.
In parallel, and to foster further support the formation of a Systems Medicine community through dissemination of specific information, CASyM launched the Systems Medicine Web Hub – the only central web based European platform related to Systems Medicine that also integrates a range of social media channels with the aim to support scientists, projects and initiatives in communicating their efforts. Since CASyM had no requirement to continue after the project´s life span, its achievements, however, needed to be sustained in order to ensure that the considerable investment of the EC makes a real, long lasting benefit on health, understanding of disease, funding policy and health economics. A CASyM key deliverable was thus to safeguard the legacy of bringing Systems Medicine to all relevant key players and to push for real life examples that make a difference. To achieve these goals in a sustainable fashion and beyond the life time of the project, CASyM, in 2016, founded the European Association of Systems Medicine (EASyM) that will fulfil the long-term strategy and vision for Systems Medicine in Europe in the future.
By building on current national and international efforts using Systems Medicine as toolbox to deliver personalised care, and the coalescing of the many stakeholder groups, the goals already achieved in CASyM & EASyM laid the future foundation that –eventually– will bring more significant and sustained benefits to the European citizen, both in sickness and in health.

Project Context and Objectives:
COORDINATING A EUROPEAN APPROACH TO SYSTEMS MEDICINE TO DEVELOP AN IMPLEMENTATION STRATEGY
Systems Medicine is ideally placed to contribute to the development of a pro-active personalised medicine and healthcare towards more efficacious, precise and cost-effective diagnostics, re-purposing of drugs and more precise treatments of the direct causes of complex diseases. In the last decade this field has been developing rapidly, though often into a range of disparate strands, thereby potentially undermining the benefits which science, society and health care systems could derive from the implementation of Systems Medicine approaches in clinical research and practice.
Very early the EC recognized the potential of Systems Medicine and supported research teams with a competitive edge for this innovative approach. This led to many successful projects with focus on medical aspects and the potential for tangible applications in clinical research and practice. In order to further develop this field and to provide a sound strategic foundation as well as a large-scale community building process for Systems Medicine, in 2012 the EC funded the coordinating action for the implementation of Systems Medicine across Europe – CASyM (www.casym.eu) with the aim to strengthen the European Systems Medicine community, to avoid fragmentation and to build a vision and practical implementation strategy (roadmap) for this approach. In this sense CASyM functioned as an overarching strategic platform project for promotion, networking and support of a coordinated approach to promote and integrate Systems Medicine in Europe.
During the projects´ duration CASyM worked successfully towards a sustained and overarching European Systems Medicine concept. CASyM put a clear focus on the identification of challenges and how to overcome them as well as on chances and possibilities that, in the medium- and long-term, will improve patient health through systems approaches. Initially started as a consortium with 23 partners from 14 member states, CASyM now represents a large and open integrative European network with more than 120 associated partners that is well recognized within the scientific and medical communities but also within funding bodies, SME´s and patient organizations. A vital feature of CASyM was a broad and coordinated consultation process of all European stakeholders, to network relevant communities, highlight successful projects and initiatives, disseminate relevant information and closely bring together those that are essential for the development of a sustained and far reaching Systems Medicine approach. To put this into practice the CASyM work plan defines seven major objectives that are summarized in the following section:

A ROADMAP FOR SYSTEMS MEDICINE
The development of a strategic roadmap represents a core objective of the CASyM project. Clinical needs are the main driver of this roadmap, that functions as an overarching conceptual framework and guide for citizens, policy-makers, funders, scientists, clinicians and industry. The underlying foundation of the CASyM roadmap is a framework of research priorities for developing and structuring Systems Medicine in Europe.
To obtain valuable input for this undertaking, a large and cross-disciplinary stakeholder consultation process was initiated by CASyM during which the consortium closely interacted with and networked key players of different communities including medical doctors, systems biologists, national funders, regulatory agencies and patient organizations. The main objective of this consultation process was the identification of technological needs as well as the most promising areas for a successful implementation of Systems Medicine in Europe. A major outcome, as published in the CASyM roadmap, was the identification of 4 core priority actions and 10 key areas for a successful implementation of Systems Medicine across Europe. The tool for this consultation process was a coordinated series of Europe-wide focused conferences, meetings and strategic workshops during which the invited participants reflected on selected key topics in structured round table discussions. The output of these events, summarized in specific reports, and published on the CASyM website or as peer-review articles in scientific journals, laid the theoretical framework and strategic orientation of the roadmap as a central task and deliverable of the CASyM project.

DEVELOPING MULTIDISCIPLINARY TRAINING CONCEPTS IN SYSTEMS APPROACHES FOR THE NEXT GENERATION OF SCIENTISTS AND MDS
The development of cross-disciplinary training concepts that target young professionals, especially with a medical background, is key to ensuring a long-term and sustainable implementation of Systems Medicine. A core feature of CASyM was thus to plan, develop and implement a variety of interdisciplinary training concepts. These training concepts aim at integrating pre-clinical disciplines such as molecular biology or biochemistry with systems-based approaches such as disease networks or mathematical and computational modelling and aim at integrating Systems Medicine as an open interdisciplinary approach to the medical curriculum in the future.
Based on existing and successful training approaches a goal of the CASyM training strategy was to create opportunities for sustainable education, to define needs and to design feasible as well as practical interdisciplinary activities in systems approaches. During the lifetime of the project CASyM thus analysed the needs for specific training modules, and developed concepts as well as strategies including specific implementation examples to foster a broad dissemination, acceptance and incorporation of interdisciplinary Systems Medicine training across Europe. Main features were:
-Tailored interdisciplinary programmes and training implementation actions that target students at master’s, doctoral and/or postdoctoral level, as well as clinicians at different stages of their careers.
-To identify the need and specifications for course modules in Systems Medicine that can be incorporated in curricula for medical and biology students with the aim to start the development of a “Systems Medicine” curriculum.
-To organize meetings, expert-guided workshops and targeted lecture series including the design of European Summer/Winter Schools in Systems Medicine to more broadly dissemination Systems Medicine training approaches.
-To develop EACCME accredited CPD (Continuous Professional Development) courses for clinicians and researchers available as blended online and face-to-face opportunities across the community with the aim to establish an educational agenda in medical research and practice.

DEFINING THE TECHNOLOGICAL AND METHODOLOGICAL BASIS OF SYSTEMS MEDICINE
Heterogeneous and complex sets of data that are produced in a modern clinical setting and the life sciences need robust concepts and policies for integration, standards and sharing procedures. The main goal was to identify the technological and infrastructure needs for data management & standardization, integration & sharing and analysis that are necessary for a Europe-wide implementation approach for Systems Medicine.
At the core of Systems Medicine and CASyM is the close interaction between clinicians, basic scientists and mathematical/computational modelling researchers. A priority was thus to foster an integrative approach on data handling, storage and sharing and promote means to access the quality of knowledge utilized for the formulation of mathematical and computational models in Systems Medicine. CASyM assessed the ample knowledge available in the different disciplines and prepared a series of recommendations to advance a mutual understanding and effective communication.

STRENGTHENING INNOVATION ACTIVITIES, TECHNOLOGY TRANSFER AND EXPLOITATION
Systems Medicine is still a rather young approach that has potential for innovations and industrial exploitations such as healthcare applications, decision support systems or mathematical and computer-assisted predictive clinical disease models. The main objective was to assess opportunities and barriers for the application of Systems Medicine approaches towards new industries.
CASyM focused on strengthening innovation activities, technology transfer and exploitation. A central aim was to evaluate the potentials and barriers towards new industries concerned with the medical and healthcare application of Systems Medicine. A goal was thus to inspire scientists and investors (e.g. venture capital firms) to create new industries, in particular SMEs. Such new businesses will have to deal with interdisciplinary approaches, such as the advanced analyses and integration of complex and heterologous data sets (see above), the development of mathematical and computational models to tackle disease complexity, or the prediction of responses to selective drugs, as well as the development of novel therapeutic approaches. To overcome this, CASyM fostered a broader application of Systems Medicine in pharmaceutical research emphasizing Systems Medicine as a tool to unravel disease mechanisms, portfolio optimization, and identification of new technologies.

INTEGRATION OF NATIONAL EFFORTS IN SYSTEMS MEDICINE AND WITHIN THE EU
National funding bodies such as ministries and agencies and their research and technological development agenda play a vital role for an effective implementation of Systems Medicine in Europe.
Key was to identify, in close interaction with ministries and funding agencies all over Europe, the existing programs in Systems Medicine, relations to programs in Systems Biology/Medicine and personalized medicine as well as to explore the best ways of setting up and launching new pan-European programs in Systems Medicine.

NETWORKING AND DISSEMINATING THE CASYM CONCEPT AND ITS ACHIEVED RESULTS
Networking through an open concept of integration as well as dissemination of relevant information to relevant stakeholder communities are central aspects of this objective. From the beginning CASyM functioned as an open network with the aim to integrate all relevant stakeholders in a broad cross-disciplinary consultation process. In parallel, the continuous collation of the outputs of the CASyM work packages as well as the dissemination of the CASyM roadmap and the Systems Medicine concept including outreach activities were core priorities essential for an unbiased exchange of information between relevant stakeholder communities.
Establishing a central web-based platform (the Systems Medicine Web Hub) as the community trusted source of information for Systems Medicine was a key objective & deliverable in CASyM´s communication strategy. Major aim of this portal is to collect information from different and heterogeneous sources – such as events, project descriptions, people, positions, resources and publications – and to efficiently supply this information for broad dissemination & outreach. The additional integration of a range of social media channels was utilized to provide further support for scientists, projects and initiatives with the aim of communicating their (project) efforts more efficiently to help forming a community, thereby preventing fragmentation and duplication of efforts. By integrating a wide range of information, the portal contributes to the development of integrative approaches that can address the challenges of Systems Medicine more efficiently, thereby taking the community further towards a modern pro-active medicine that is predictive, preventive, personalised and participatory (P4 medicine ). Through its outreach and community building activities during the last years, CASyM established a critical momentum in favor of a coherent European Systems Medicine approach that now needs to be secured, expanded and sustained. To achieve a sustained impact of the long-term goals of the project, a key strategic aim was to lay the foundation for the implementation of the European Association of Systems Medicine (EASyM) as the project´s legacy and the organization of a joint CASyM/EASyM international conference on Systems Medicine.

ESTABLISHING AN EFFICIENT FINANCIAL AND ADMINISTRATIVE MANAGEMENT
Since the CASyM consortium is large and represents many stakeholders with different backgrounds, the project also required a great amount of financial and administrative management in order to properly deliver the desired results of the work plan. The establishment of an efficient and adequate financial and administrative management concept was central to this objective to create a trustful and reliable working atmosphere that enables the consortium to put the whole concentration on the task implementation and to find appropriate and practical solutions for upcoming challenges.

Project Results:
Please see document attached.
Potential Impact:
INITIATING A PARADIGM SHIFT IN CLASSICAL MEDICINE
An overarching aim of Systems Medicine is to provide a modern systems-based approach to medical research and clinical practice. This has great potential to lead to early stage medical intervention with focus on prevention rather than disease treatment, the reduction in disease severity, and the ability to apply resources more strategically and wisely. In parallel, the implementation of Systems Medicine will eventually lead to a paradigm shift and a re-thinking in the way diseases are classified: In traditional medicine diseases are still classified according to (i) specific organs (e.g. heart failure, nephropathy, etc.), (ii) by symptom (e.g. hypertension, depression, etc.) or (iii) clinicians who described a specific disease (e.g. Parkinson, Alzheimer, etc.). With the implementation of Systems Medicine, the classical disease classification will eventually shift from a single organ-based, symptomatic description to a more in depth, precise and mechanistically description based on underlying pathways, regulatory networks and disease relevant (molecular)factors. This will ultimately lead to a more precise description of the origins of disease and is fundamentally different from the prevailing practice of classical medicine that is typically characterized by a reactive approach (intervention only occurs once a disease has already manifested itself). Hence, Systems Medicine will lead to a more differentiated view of how to understand disease and well-being – namely as complex interplay of biological networks on multiple levels (e.g. cells, tissues, organs and organism as well as environmental factors) and dimensions (e.g. spatiotemporal/over time and space).
With CASyM as a pan-European project the above described paradigm shift from the classical /reactive to a modern/proactive medicine has been fostered and further advanced. The CASyM roadmap with its four core priority actions, 10 key implementation areas and proof of concept/pilot studies puts a clear focus and forward looking implementation strategy on these topics that already influenced national funding organizations (as shown in the assembly of the ERACoSysMed consortium) and the scientific communities (as shown in the above described demonstrator projects). One of the long term objectives of the CASyM consortium and its successor, the European Association of Systems Medicine EASyM, is to keep this momentum alive and to further contribute to a sustained European Systems Medicine approach in medical practice and clinical research according to the strategic timeline and content of the road map.

With regard to the scientific development, the implementation of systems-based approaches has already started and many areas that are labelled with precision-, personalized- or 4P-medicine are utilizing multiple -omics technologies to produce patient specific data. However, in all these disciplines the bottom line will be how to integrate big data into predictive models of disease and well-being and how to extract meaningful information that can be used to better treat or prevent disease. Here, the CASyM roadmap and, hence, Systems Medicine will offer the conceptual approach to make significant progress in clinical research and practice in the future.

Currently a reliable assessment of the long-term impact of the work of CASyM, EASyM and the Systems Medicine implementation across Europe is somewhat difficult, since the field is still at a relatively early developmental stage. In addition success stories will need a proper performance evaluation with regard to their socio-economic impact, which will take additional time. But Systems Medicine seems to be one of the most promising approaches able to tackle major societal challenges associated with an ageing society and increasing costs for healthcare in Europe. Systems Medicine as a toolbox — as described in the CASyM roadmap of 2017 — has the power to explain the emergence and progression of disease phenotypes with molecular, cellular, physiological and environmental data. By using such a toolbox clinicians will eventually be able to integrate the huge amounts of data that modern life sciences is able to produce – even with a simple blood analysis – and assess and interpret these data in a meaningful way. This will bring a future benefit to the daily lives of patients.

Acceptance through success stories that demonstrate feasibility
Success has already been made in that CASyM fostered the development of a joint research and technological development agenda between national and European stakeholders that resulted in the initiation of the first ERA-NET on Systems Medicine under Horizon 2020 - ERACoSysMed. Here, 13 funding organizations from 11 EU countries joined forces to fund demonstrator projects of Systems Medicine that prove the feasibility of this approach in clinical research and practice.

An important final outcome will be the identification of new areas for clinical research to deliver improved preventive and personalized therapies and an increased knowledge of health and disease focused on improving clinical decision making. From the stakeholder consultation activities in CASyM, especially with regard to the currently funded Systems Medicine demonstrator projects of ERACoSysMed, it is obvious that Systems Medicine research successfully addressed many clinically relevant areas such as systems mathematical modelling, systems pharmacology or drug repurposing. In the short- and medium-term perspective the scientific achievements in these areas and in particular in the field of cancer pathology have the potential for translation into routine clinical applications (e.g. predictive modelling of tumour remission/recurrence behaviour under chemotherapy treatment). Routine mathematical and quantitative tumour prediction in clinical practice will be a tremendous improvement of cancer prognosis and a step towards a more precise and personalized medicine with a true benefit for the daily lives of patients.

Currently ERACoSysMed has launched its second call that, again, puts a clear focus on demonstrator projects to (...) “improve current knowledge of health and disease, leading to new paths for clinical research aimed at delivering better and more efficient and personalized prevention, diagnostics and treatments of human diseases (...) ”. This indicates that the national funders constituting the ERACoSysMed consortium have a clear perception on the future demand in further promoting Systems Medicine through additional proof of concept studies that will demonstrate the impact on future clinical, public health and socio-economic relevant applications. Thus, the second and forthcoming third call of ERACoSysMed will further promote and strengthen the translation of Systems Medicine research findings into clinically relevant areas in the future.
Foundations for future medical training of scientists and MDs in Systems Medicine

A hallmark of CASyM is the legacy of System Medicine training that was highly appreciated by the community and represents a sustainable deliverable of CASyM also for the future. This accounts on actions regarding the formal training of medical students and professionals, as well as for life-long training with accredited courses and workshops of Systems Medicine in Europe and beyond. The realisation and needs of Systems Medicine interdisciplinary training that were underlined in the project proposal of 2011 as tailored programs, course modules, workshops, etc. goes well beyond this initial plan. CASyM became recognised as a major policy maker and provider of Systems Medicine education and training and as a European leader that collects all the expertise requested in this highly inter-disciplinary field, underlined by the clinical needs. The training legacy of CASyM will remain a sustainable effort within EASyM. After 4 years there is a major improvement in training the next generation of scientists and MDs that is reflected in the results from multiple questionnaires, thus the initial goal has been reached. However, what is even more important is that this need has been recognized as „must“ for training the next generation of scientists and MDs also for the future.
Another hallmark was the identification of the needs and specifications for course modules in Systems Medicine. As a result of the CASyM training activities, multiple Systems Medicine topics have been incorporated into the medical curricula at European Universities, which is a great success. On the other side, we must admit that it was not yet possible to reach a pan-European agreement that all medical schools in Europe should adopt Systems Medicine topics. Just at the end of CASyM the first communication with the European Medical School Association (AMSE) and the medical student associations (EMSA and IFMSA) finally took place, offering clear future to achieve this pan-European goal.

Overall, the Systems Medicine education and training in the CASyM period met all the initial goals and actually achieved much more. It set the standards of Systems Medicine education and training, showed how it can be done and where are the remaining hurdles, provided the feedback from the relevant communities and formed a core group of educators and professors who will promote and practice Systems Medicine topics also in the future.

Assessment of the future potential for Systems Medicine – Systems vs. Personalized Medicine
The goal in the future is to establish Systems Medicine as an important innovation platform and toolbox for personalised medicine. Systems Medicine is an enabler for personalised medicine and a toolkit through which the goals of personalized care can be delivered. At present, the communities are overlapping just for a small part. Many activities identified as important prerequisite are the same (e.g. provision of longitudinal data, data harmonisation, new types of clinical trials etc.). A comparison of the Systems Medicine Roadmap developed by CASyM and the Strategic Research and Innovation Agenda (SRIA ) for Personalised Medicine developed by the CSA PerMed shows needs for a better awareness, for high quality, harmonised and accessible longitudinal data as well as IT tools have been identified by both. However, the PerMed Agenda is much broader, tackling also the translational gap, regulatory, health-economic and legal issues. On the other hand, the envisaged IT tools are more focussed: the PerMed Agenda has an emphasis on machine learning methodologies and decision support systems. However, Systems Medicine also comprises mechanistic computational models as an essential element to tackle the complexity of diseases as a prerequisite to realise personalised medicine. These models help to advance diagnosis, identify new treatment targets, improve existing treatment regimens and develop preventive strategies or aid in drug repurposing strategies. The development of these models, based on molecular and clinical data, on in vivo and in vitro models, are highly challenging. An understanding is achieved based on underlying molecular pathways and networks as well as biochemical reactions. As such, Systems Medicine delivers a basis and a toolbox for personalised medicine.

The CASyM roadmap to Systems Medicine demonstrates also a deeper analysis of the hurdles in the development and implementation of Systems Medicine based tools. In addition to the aspects identified similarly to PerMed, the need for community building across disciplines, training and the need to convince people outside the field of the usefulness and relevant input of such computation based methodologies. Therefore there will also in the mid- to long-term future be a need to fund dedicated activities in Systems Medicine with the aim to:
-Develop and improve predictive mathematical models.
-Support projects for clinical applications of Systems Medicine that demonstrate the value for personalised medicine.
-Enable training and community building.

It is important that the awareness of challenges and the innovation potential of Systems Medicine for personalised medicine remain “on the radar” of all stakeholders. Consequently the term “Systems Medicine” should be continually used as a crucial technology that delivers a toolbox for personalised medicine. This will allow dedicated calls and community education.
As the overall goal of personalised medicine is the same as in the International Consortium for Personalised Medicine (IC PerMed ), a separate community building of funders and policy makers with a focus on personalised medicine is not necessarily needed. The Systems Medicine stakeholders could eventually be merged with IC PerMed and both communities should seek proximity and close exchange. An immediate aim should be to establish a bi-directional communication and where possible and appropriate joint meetings to seek exchange and discussion fora. The continued and specific needs of Systems Medicine for the development of in silico models and community education will require on-going strategy developments and support. This should still be possible in an integrated approach of Systems Medicine within IC PerMed, e.g. through a focused subgroup and the organization of dedicated calls to further improve the toolbox of computational models. A continued organization within ERA-Nets and bi- or multi-lateral calls can be suitable instruments. Here, EASyM with its clinicians and researchers working in Systems Medicine should serve as a scientific advisor on Systems Medicine and its further evolution as a pan-European approach to a modern pro-active medicine.


List of Websites:
www.casym.eu

Marc Kirschner
Forschungszentrum Jülich GmbH
Project Management Jülich (PtJ)
52425 Jülich, Germany
Phone: +49 2461 61 6863
E-mail:m.kirschner@fz-juelich.de