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FP7

SERBORDISINN Report Summary

Project ID: 316088
Funded under: FP7-REGPOT
Country: Serbia

Final Report Summary - SERBORDISINN (Strengthening the Research Potential of IMGGE through Reinforcement of Biomedical Science of Rare Diseases in Serbia – en route for innovation)

Executive Summary:
Molecular genetics is the doorway to diagnosis and sustainable therapy for human diseases. Serbia is now home to an expanding institute of excellence in cutting-edge genetic testing and analysis thanks to EU funding. The Institute of Molecular Genetics and Genetic Engineering, University of Belgrade (IMGGE) (http://www.imgge.bg.ac.rs) has become the most recognized molecular genetics centre and has a major focus on rare diseases (RD). The SERBORDISinn (Strengthening the research potential of IMGGE through reinforcement of biomedical science of rare diseases in Serbia – en route for innovation) (http://www.serbordisinn.rs/) Project has significantly upgraded IMGGE research capacities in the study of molecular basis of RD.
Acquisition of sophisticated equipment, especially the next generation sequencing platform, followed by introduction of modern methodology, radically changed the capacity of IMGGE researchers to perform cutting edge basic and translational research, diagnostics of rare diseases as well as innovative research in this biomedical field.
Fruitful exchange of know-how and experience has immensely contributed to reinforcement of IMGGE research potential. It has been realized through 76 visits of eminent European experts and 87 trainings of IMGGE staff in the EU partnering organizations.
The biological samples′ storage and database facilities for information collection are at the heart of any genetic testing. IMGGE biobanks house several thousand samples in 35 collections of different RD. Access is available online through the http://serbordisinn.rs/category/biobanks/. Also, a Serbian National Genetic Database http://ethnos.findbase.org/home-rs/, has been established.
Strategic partnerships with national medical institutions involved in rare diseases have resulted in implementation of achievements of SERBORDISinn into Serbian medical practice and has established IMGGE as a key player in the Serbian public health sector. As a result, Serbian Health Insurance Fund has offered IMGGE a contract to be a centre for molecular diagnosis of RD.
Furthermore, IMGGE has engaged its scientific knowledge to raise public awareness of rare diseases in Serbia and Balkan and has become a trustful partner of rare disease patients in the whole region.
Dissemination activities included 22 various events at local, regional and European level, with more than two thousands participations of researchers and medical practitioners. The
"1000 Balkan genomes" Project is one of the most important results of SERBORDISinn initiatives, leading to increased research collaborations between Balkan countries.
In the course of the SERBORDISinn Project, IMGGE has raised the awareness of IP rights among its researchers. Major IMGGE strategic documents have been developed - IP protection Manual and IMGGE Strategic Scientific and Development Action Plan. As a result, first IMGGE patents have been registered.
At the end of SERBORDISinn Project, IMGGE is recognized as an Expert Centre for molecular genetic of rare diseases, a leader in the field of biomedical science of rare diseases in Serbia and Balkan, as well as "innovation engine" capable of contributing actively to the national, regional and European sustainable development.
SERBORDISinn has pushed IMGGE through the doorstep of ERA and has enabled IMGGE scientists to be actively involved in European scientific community. This gives IMGGE opportunity to contribute to overall scientific progress in Europe.

Project Context and Objectives:
Rare diseases (RD) are diseases with a low prevalence in the general population; the European Union considers diseases to be rare when they affect not more than 5 per 10000 persons. It is estimated that there are between 5000 and 8000 different RD. From the medical perspective, RD are characterized by the large number and broad diversity of disorders and symptoms that vary not only from disease to disease, but also within the same disease. It is worth noting that most cancers, including all cancers affecting children, are RD. Although rare, the impact of RD on society as a whole is large; these diseases should not be underestimated since they pose serious difficulties for the entire families.
Infrequent occurrence of RD leads to prolonged time needed to make an accurate diagnosis. Furthermore, the market for affected patients is so narrow that research and development of new treatments is not sufficiently developed.
Biomedical science is the application of biology-based science to medical use, basic research, health monitoring or treatment. It is the engine room of modern medicine. Without biomedical scientists, the diagnosis of disease, the evaluation of the effectiveness of treatment, and research into the causes and cures of disease would not be possible.
Molecular genetics (MGs) is probably the most powerful tool in biomedical science today. Fascinating development and accumulation of knowledge in the field of MGs made a great impact on medical practice. It has been shown that the majority of human diseases are determined by genetic factors. Modern molecular genetic (MG) approaches are indispensable for improvement of diagnosis and follow-up of numerous RD. Research dedicated to MG markers of RD is the basis for the designing molecular-targeted therapeutics, and, consequently, more effective treatment of RD.
Biobanks are a critical resources and an important way to accelerate such molecular-based biomedical research. The data and patients′ biospecimens (tissue, blood and molecular components: DNA, RNA, cDNA) that are collected, tested for quality, and then distributed to researchers, are absolute requirements in the pathway to develop modern biomedical science, diagnosis and cures for human diseases.
In Serbia, until recently, rare diseases were on the margins of a healthcare system, which has constantly been facing serious problems, due to limited funding and gaps in technologies created after prolonged period of isolation. The process of upgrading equipment, as well as updating diagnostic procedures and related products has been slow and inadequate.
SERBORDISinn is a European Commission-funded Project (REGPOT-CT-2013-316088-SERBORDISinn; www.serbordisinn.rs), awarded to the Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia (IMGGE), aiming to enrich research potential of Serbia and Balkan region in genomics of rare diseases.
IMGGE has been established 30 years ago and it is the leading Serbian research institution, employing scientists with the highest expertise in molecular biology and molecular genetics. Research in the field of biomedical science of rare diseases is one of the major interests of IMGGE.
The main objectives of SERBORDISinn Project Proposal are:
1. Building up an Expert Centre (ExCe) for molecular genetics (MGs) of rare diseases (RD) in IMGGE.
2. Reinforcement of material resources and implementation of new approaches for IMGGE research progress (reinforcement of material potential through acquisition and upgrading of equipment, implementation of biosafety measures to comply with EU guidelines, improvement of methodological approaches for study of molecular markers in RD, application of bioinformatics tools and reinforcement of computational biology at IMGGE, as well as building up capacities to establish national biobanks for selected RD).
3. Reinforcement of human resources (reinforcement of human potential that can contribute to implementation of new methodologies related to ExCe for MGs of RD, reinforcement of the scientific management of the IMGGE).
4. Exchange of know-how and experience (networking with EU institutions and other European and regional groups or networks in order to increase personnel mobility and exchange of know-how and experience related to RD, intensifying the transfer of knowledge and information of the latest MG approaches for study of RD from distinguished EU centres to IMGGE, strengthening training programmes related to newly acquired equipment, facilitating knowledge transfer and network building at regional level).
5. Dissemination and promotion (the increase in awareness of the researchers, health care practitioners – medical doctors and laboratory specialists, pharmaceutical industry, rare disease patients’ organizations, representatives of the republic health insurance body etc., regarding ExCe for MGs of RD activities; increase in the public awareness regarding ExCe for MGs of RD activities; dissemination of know-how, promotion of local and regional networking with research and health care institutions as well as pharmaceutical industry involved in biomedical science for RD; increasing visibility of SERBORDISinn / IMGGE at all levels).

The main objectives of the SERBORDISinn Project have been to reinforce IMGGE’s research and innovation capacity and thus to enable IMGGE to become the most recognizable molecular genetic centre for RD research and related diagnostics in the Balkans. This has been fully accomplished through:

• upgrading and acquiring sophisticated research equipment;
• introduction and implementation of cutting-edge methodological approaches in the field of molecular genetics of RD;
• reinforcement of human resources by employing experienced researchers and technicians, as well as research managers;
• networking with local and regional medical centres;
• exchange of know-how and experience with EU partnering organizations, experienced in the field of RD (trans-national two-way mobility has been realized through visits of eminent European experts, trainings of IMGGE’s staff in the EU partnering organizations and technology-related trainings for newly acquired equipment);
• establishment of Serbian and Balkan RD-specific databases and biobanks;
• gaining expertise on IP issues; and
• organization of workshops and regional conferences, dissemination and promotional activities with the purpose of increasing the visibility of Project achievements.

The implementation of SERBORDISinn Project enabled fulfilment of long-lasting IMGGE efforts dedicated to implement new MG methodologies for diagnosis and follow-up of RD, to convey the new knowledge to hospitals and clinics in Serbia where the patients with RD are treated and thus to improve the public health. In line with that, the local and regional patients′ samples (biobanks) and databases have been established as essential resources to support prosperous biomedical research of RD at IMGGE. The significance of the establishment of IMGGE as an Expert Centre for MGs of RD is enhanced by the foreseeing future integration of Serbia into European Union. The Institute already participates in various European actions related to RD and thanks to the full realization of SERBORDISinn Project it will continue to actively contribute to EU efforts to harmonize prevention, diagnosis and treatment of RD.

Project Results:
The proposed Action Plan of SERBORDISinn project was realized by the IMGGE as a whole and especially its four Laboratories (Laboratory for Molecular Biomedicine, Laboratory for Molecular Biology, Laboratory for Human Molecular Genetics and Laboratory for Molecular Genetics of Industrial Microorganisms). All activities, organized in five work packages were successfully conducted in the timely manner.

Here are presented the most important SERBORDISinn achievements recognized after termination of project.

(WP1) Building up an Expert Centre (ExCe) for molecular genetics (MGs) of rare diseases (RD) in IMGGE

IMGGE is the first research institution in Serbia who rose awareness of IP rights among its researchers. Several trainings and workshops conducted by experts in the IP field enabled better comprehension of innovation and technology transfer and established background for implementation of good IP practice in IMGGE. This newly acquired knowledge facilitated creation of strategy for management of IP generated by IMGGE researchers. To enable support of IP protection culture, IP protection Manual was developed and approved by the IMGGE Scientific Advisory Board in November 2015. IP policy was introduced to IMGGE research staff through interactive lectures and workshops. The Manual describes in detail roles and responsibilities of the IMGGE researchers and steps which should be taken in the identification, protection, managing and exploitation of IP. The Manual establishes internal procedures for IP, as well as procedures for registering IP with the authorized official bodies both Serbian and international. The IP protection Manuel, as well as Patent Application form and Invention disclosure form are posted on IMGGE web site. The sustainability of IP protection and exploitation environment were set up by establishment of IP committee. IP committee consists of trained researchers who have previous experience in IP protection and exploitation and are coming from each IMGGE laboratory.
During the course of the SERBORDISinn project IMGGE researchers were involved in realization of three innovative projects which resulted in two registered patents. IMGGE also established strategic partnership with a small enterprise company Veterinary Station "Koker" from Adaševci, Sebia in order to enable co-exploitation of research results. These achievements are illustration of IMGGE successful efforts to adopt IP policies and to orient part of its activities to innovations.
In the course of the SERBORDISinn project major IMGGE strategic document have been developed and fully completed: IMGGE Strategic Scientific and Development Action Plan. Internal capability for developing a Strategic Scientific and Development Action Plan for IMGGE was built throughout seven training workshops of 12 IMGGE research associates. Workshop topics consisted of strategic analysis and planning, outlining strategic areas, creation of action plan and defining the performance indicators and resulted in IMGGE strategy for period of five years (2016–2021). Built upon upgraded SWOT analysis of the IMGGE, the Strategic Scientific and Development Action Plan lays the foundation for the development of innovations and determine guidelines for strategic directions in a short-term and a long-term period with concrete actions that will ensure the implementation of defined strategies and measurable indicators of the achieved development. The distinctive feature in the current strategy document is that it is more technology oriented and focused towards project applications in a more systematic way. It has metrics for monitoring progress in IP and in its exploitation, as well as assists in development of sustainable relationship with other regional institutions regarding share of the best IP practice.
In addition, involvement of Serbian health care sector is indispensable for achievements of SERBORDISinn goals. In order to build up an Expert Centre for molecular genetics of rare diseases, IMGGE developed collaboration with clinical centres and hospitals in which rare diseases are treated to better organize collection of biological samples, informed consents, biobanks and clinical studies. As a result, two networks, namely NIRBOS and NMD SerbNet, were founded during implementation of SERBORDISinn.
NIRBOS (Research Initiative for RD in Serbia or Naucna Inicijativa za Retke Bolesti u Srbiji) established collaboration with all medical institutions in Serbia relevant to RD. Local partners of SERBORDISinn are: University Children’s Hospital, Belgrade; The Clinical Center of Serbia, Belgrade – Institute of Hematology, Institute of Gastroenterology; Clinical Center of Vojvodina, Novi Sad; The Clinic for Neurology and Psychiatry for Children and Youth – Medical Faculty, University of Belgrade; Institute of Orthopedic Surgery "BANJICA", Belgrade and Mother and Child Health Care Institute, Belgrade.
NMD-SerbNet (Serbian Neuromuscular Disease Network) was inaugurated on 1 November 2014 during SERBORDISinn and the 2014 GoldenHelix Symposium "Genomics of Rare Diseases" held in Belgrade, Serbia. Several institutions have joined forces to collaborate in the network including, Clinic for Neurology and Psychiatry for Children and Youth (Faculty of Medicine, University of Belgrade), Neurology Clinic (Clinical Center of Serbia, Faculty of Medicine, University of Belgrade), Clinical Hospital Center Zemun, Center for Human Molecular Genetics (Faculty of Biology, University of Belgrade), Institute of Human Genetics (Faculty of Medicine, University of Belgrade) and Institute for Molecular Genetics and Genetic Engineering (University of Belgrade). In this network adult and pediatric clinicians, along with basic science researchers commit themselves to improve diagnosis, research and therapy of neuromuscular disorders in Serbia.
At the end of SERBORDISinn project IMGGE is recognized as an Expert Centre for molecular genetic of rare diseases, a leader in the field of biomedical science of rare diseases in Serbia and Balkan, as well as "innovation engine" capable of contributing actively to the national, regional and European sustainable development.

(WP2) Reinforcement of material resources and implementation of new approaches for IMGGE research progress
A. Acquisition and upgrading of equipment
One of the most significant results of the implementation of SERBORDISinn Project is the reinforcement of material potential of IMGGE, which has been accomplished through the upgrading of already existing and acquiring new, state-of-the-art research equipment.
The following equipment has been purchased and works at full capacity at IMGGE:
1. Flow cytometer and cell sorting system - allows simultaneous multi-parametric analysis of the physical and chemical characteristics of individual cells within heterogeneous populations.
2. Next Generation Sequencing Platform - enables to analyze minimum tenths of genes simultaneously, having better inside of the genes rearrangements, which is particularly important for diagnostics of rare diseases.
3. Next Generation Sequencing Sample Preparation Unit - enables functioning of NGS Platform and consists of: PCR Plate, DYNAMAG-96 SIDE SKIRTED, Microsample Incubator, Micro Centrifuge, Centrifuge with cooling and Termocycler.
4. Primary Cell culture and Biobank Workstations and Sample Preparation Units -enables creation of new model systems for study of molecular mechanisms of selected RD and host-microbe interactions, which consist of: two CO2 incubators and automated cell counter.

5. Sterile Workstation Unit - enables appropriate handling of biological specimens and consists of: two biological safety cabinets, one PCR Cabinet and three aspiration systems for safe disposal of liquids.

6. Data Storage System - enables the implementation of up-to-date computational biology tools in RD research and consists of: 20 Notebooks with Windows OS and MS Office, Desktop workstation and three MFC Units.

7. Biobank Workstation Sample Preservation Unit - enables appropriate storage of biological specimens and consists of: two deep freezers, two freezers and three liquid nitrogen containers.

8. Multimode Reader Modular System - supports a wide spectrum of applications such as reporter gene assays, apoptosis assays, cell viability and cell proliferation, DNA/DNA, DNA/protein or protein/protein binding assays.

9. Tissue Sample Preparation and Imaging Unit - enables preparation of frozen tissues sections for histochemical and immunochemical analyses, enables additional imaging and analysis capabilities of the Olympus fluorescent BX51 microscope which was already in use in IMGGE, introduction of FISH based detection of various chromosomal rearrangements, introduction of immunohistochemistry on muscle cells/tissue, FISH-based detection of specific microorganisms in natural (e.g. environmental) samples. This Unit consists of: Cryostat for clinical application, Inverted phase contrast Microscope and
Upgrade of existing CytoVision system.
10. Processor for treatment of biological wastes - enables safe disposal of hazardous biological material and consists of: washer of laboratory dishes, dry sterilizer and two vertical autoclaves.
11. Fluorometer - Qubit 3.0 - allows precise DNA and RNA quantification, essential for functioning of NGS technology.
Acquisition of sophisticated, capital equipment, especially the equipment for next generation sequencing, followed by introduction and optimization of modern MG methods, complemented and significantly upgraded IMGGE research capacities. That radically changed the possibilities of IMGGE researchers to perform cutting edge basic and translational research, diagnostics of rare diseases as well as innovative research in this biomedical field. Thanks to the SERBORDISinn Project IMGGE is the first Institution in Serbia and in majority of Balkan countries that has such an up-to-date, fully operational equipment. This exclusiveness established IMGGE as an Expert Centre for molecular genetics of rare diseases.
The opportunity to routinely use listed novel equipment, together with enhanced professional skills and established links with European colleagues, led to the overall increase in IMGGE R&D potential, made the IMGGE visible and attractive partner for collaborative actions within various local, regional and EU initiatives.

B. Improvement of methodological approaches and Reinforcement of computational biology and bioinformatics
Promotion of the quality and validity of results obtained by IMGGE researchers and improvement of the international acceptance of data generated at IMGGE was achieved by establishment of GLP working group. Initially, this group addressed several critical issues such as adoption of SOPs related to biobanking, application of EQA schemes for selected RD, organization of primary cell culture facility according to GLP standards. Implementation of GLP policies permits that future activities of IMGGE fulfill the needs for quality standards. Realization of these activities led to establishment of pipeline of actions which have to be undertaken when organizing similar activities at IMGGE, upon completion of SERBORDISinn. Adoption of GLP policy and incorporation of GLP principles into everyday practice significantly contributed to reinforcement of biomedical science of rare diseases at IMGGE and helped us to obtain results that are reliable, repeatable, auditable and recognized by scientists worldwide.

Methods used for characterization of molecular markers relevant for diagnosis and prognosis of rare diseases currently employed at IMGGE (amplification of DNA by polymerase chain reaction (PCR), real-time PCR, digestion of DNA with restriction enzymes, analysis of DNA by agarose and acrylamide gel electrophoresis, denaturing gradient gel electrophoresis (DGGE), Sanger sequencing, fluorescent in situ hybridization) were standardized and validated. For each of the methods consensus has been achieved and common protocols have been established and distributed to all Laboratories involved in molecular genetic testing of rare diseases. We standardized and accredited these methods, in accordance with the requirements of SRPS ISO/IEC 17025:2006 standard, periodically validated in the European Quality Control Program/EQA schemes or by inter-laboratory comparisons (detection of mutations in CFTR gene, detection of mutations in MTHFR, Factor II, Factor V and PAI-1 genes found in coagulopathies, analysis of polymorphisms affecting individual response to anticoagulant therapy, molecular analysis of A1AT (a1-proteinase-inhibitor) gene mutations, detection of mutations in the PAH gene, detection of mutations in TPMT gene, detection of microdeletions 22q11 22q11.2 (DiGeorge/Velo-Cardio-Facial syndrome) and 15q11 (Prader-Willi/Angelman syndrome). These standardized and validated methods are performed within the Sector for Laboratory Investigations formed as a body competent to perform testing in the scope of accreditation. All standardized and validated methodologies have been implemented both into IMGGE research activities, and into rare disease diagnosis.

In order to fully exploit novel and upgraded equipment a number of modern molecular genetics methods and approaches for research and diagnosis and follow-up of rare diseases were introduced and optimized in IMGGE according to the standards of European professional community. In accordance to the research capacities determined by acquisition of novel equipment, upgrade of already existing equipment and recently procured state of the art equipment the spectrum of currently routinely used methods for study of molecular biomarkers was expanded. As well, they were standardized and validated in order to upgrade IMGGE research activities. Moreover, new molecular genetics methodologies for diagnosis and follow-up of rare diseases, with the aim to support hospitals and clinics in Serbia where the patients with RD are treated, were also implemented. Methods that were introduced were selected to fully exploit available IMGGE equipment: FACS system (cell viability assays, determination of transfection efficiency, cell cycle analysis, autophagy assays, apoptosis assays, cell proliferation assays, sorting of CD34 positive cells, sorting of neutrophils from sputum or blood, isolation of stem cells from the cell lines and tissues using cell surface pluripotency markers, cell proliferation and cytokine production, microbe – host cell interaction), confocal microscope (FRAP (fluorescence recovery after photobleaching), host – microbe interactions, pathogen exclusion assay, in vivo imaging), plate reader (detection of intracellular ROS production (DCFH-DA based assay), luminometric determination peroxidase class III activity, cell viability assays (MTT cytotoxicity test, crystal violet assays), DPPH radical scavenging assay, determination of total phenolic content, ferrozine method - Ferrous ion chelating capacity assay, ferricyanide method – determination of sample reducing power, superoxide anion radical scavenging assay, determinaton of bacterial lactase activity, quantification of bacterial lipase activity, determination of total SH group content in plant tissue isolates (DTNB spectrophotometric method), ELISA, assessment of the kinetics of enzymatic reactions, determination of cytotoxicity of bio-compounds, drugs and other agents, host-pathogen interaction assays, quorum sensing assays) and MiSeq and new generation sequencing (sequencing of molecular markers related to selected rare malignancies, detection of molecular markers related to selected rare diseases, microbiome analysis, genome sequencing of microorganisms). As well, several IMGGE researchers were trained to introduce and use zebrafish animal model system which recently emerged as a valuable system for modeling human diseases, in particular for defining disease pathways and for discovering new therapies. A new efficient and reliable tool to make precise, targeted changes to the genome of living cells, CRISPR/Cas9 technology, was also introduced in IMGGE.
Implementation of up to date methodology enables IMGGE researchers to perform cutting edge basic and translational research, as demonstrated by increase of impact factor of journals in which we published results obtained during realization of SERBORDISinn. For the IMGGE researchers, use of novel standardized procedures enables exchange and acceptance of new knowledge generated through implementation of the SERBORDISinn project.
As an Expert Centre for molecular genetics of rare diseases oriented towards research and innovation, we designed the first prototypes of two cost-effective multiplex diagnostic test kits for Serbian and Balkan populations (Kit for detection of the most frequent Balkan beta-globin mutations and Kit for the prediction of multiple myeloma development in the patients with Gaucher disease).
The Serbian National Mutation Database has been established to merge and systematize genetic data from various reliable national resources, on different mutations found in inherited disorders in the Serbian population. The Serbian National Genetic database currently has 64 data records for causative genomic variants allele frequencies and 6 records for genetic disease summaries. In August 2015, as a part of WP5 dissemination activities, the database had also been launched on-line (http://ethnos.findbase.org/home-rs).
Implementation of Next Generation Sequencing (NGS) technology has generated large amount of data. To tackle the challenge of the next generation sequencing data analysis, researchers from IMGGE in collaboration with Seven Bridges Genomics (biomedical data analyses company) have developed unique pipeline for amplicon-based next generation sequencing with the application in cancer genomics. In addition, researchers attended bioinformatics trainings and had the opportunity to be trained in expertise related to application of various bioinformatics tools. Therefore, one of the results of SERBORDISinn activities is a well educated bioinformatics team in IMGGE capable of performing bioinformatics analysis necessary for research and diagnostics of rare diseases.

C. Building up capacities to establish national biobanks for selected RD

One of the main goals of this project was the establishment of national biobanks for rare diseases in Serbia. We approached the task of establishing and introducing biobank facilities in IMGGE by following different aspects like setting-up capacities through procurement of storage facilities and efficient data storage facility, as well as implementing standard operating procedures for collection and storing biological samples. Our efforts resulted in remarkable number of collections of rare diseases (35) containing several thousands of samples that have been established in the IMGGE biobank. Information on RD biobanks is available through SERBORDISinn and IMGGE web-sites. Throughout the project our biobanks were improving through enrichment of sample collection and through communication with experts from other biobanks.
In this regards, SERBORDISinn has undergone several ethics reviews related to specific rare diseases. The following approvals of Ethics Committees were obtained:
1. Approval of the Ethics Committee of the Clinical Center of Serbia, no. 1086/4 for chronic lymphocytic leukemia.
2. Approval of the Ethics Committee of the Clinical Center of Serbia, no.1393/12, for Crohn's disease and ulcerative colitis.
3. Approval of the Ethics Committee of the Clinical Center of Serbia, no. 1393/13, for inflammatory bowel disease.
4. Approval of the Ethics Committee of the Clinical Center of Serbia, no. 1435/10- (Ev. No. 11-102-102) for molecular and immunophenotypic markers in hematopoietic stem cells transformation.
5. Approval of the Ethics Committee of the Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic" no. 8/8, for glycogen storage disease.
6. Approval of the Ethics Committee of the Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic" no. 8/21 for hyperphenylalaninemia.
7. Approval of the Ethics Committee of the Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic" no. 1805/3 for thalassemia
8. Approval of the Ethics Committee of the University Childrens' Hospital, no. 017/6-990/67 for pharmacogenomics in children acute lymphoblastic leukemia.
9. Approval of the Ethics Committee of the University Children's Hospital, no. 017/6-26/71 for Maturity Onset Diabetes of the Young (MODY).

Expansion of our biobank collection was achieved through constant promoting of IMGGE biobank and networking activities. By organizing the Workshop: “Balkan rare disease biobanks, databases and research collaborations – SERBORDISinn initiative” at the Balkan Congress of Human Genetic in September 2015 in Belgrade, we informed the regional scientific community about the establishment of biobanks within IMGGE. We encouraged researchers from numerous institutions to join us in sharing information of collections of biological samples and patients’ repositories in their possession. We have also set up link on the website of our SERBORDISinn project dedicated to biobanks (http://serbordisinn.rs/category/biobanks/). In this way our biobanks became available to scientific community worldwide. In addition we made the platform for other researchers from the region to promote their biobanks through the SERBORDISinn website.
Transfer of knowledge and experience through contact with biobank experts from other institutions who are involved in different projects was of immense support. For instance, attendance at RD-Connect project Annual meeting, was very helpful mainly regarding the issues of linking patterns between patient samples and their adequate clinical and genetic characteristics that are required for the research. We also recognized the importance of applying SOPs methods in the preparation and storage samples and the importance of confidentiality of information relating to the patient.
In order to improve biobank management and to connect with other European biobank collection centres, we approached the BBMRI-ERIC (The Biobanking and BioMolecular resources Research Infrastructure – European Research Infrastructure Consortium) and became a partner in the Project proposal with the objective of establishing a roadmap to a competitive, collaborative hub of genetics and biobanking in the Mediterranean and neighbouring countries.
In order to establish molecular genetic databases to complement national patients’ registries for RD we introduced new database storage system. We actively participated in the development of the software, managed the implementation of specifics changes and thus, we have developed the data storage system which is appropriate to our requirements. Data storage system enabled us to have an integrated system for running biobanking tasks as well as for organizing adequate storage facilities. Our data storage system is synchronized with the Cloud Storage. All the data can be accessed online, enabling our biobanks’ databases to contact biobank networks.
Establishing integrated biobanking data system allowed us to be recognized as a reliable partner by the networks such as EuroBioBank, BBMRI, BioMolecular Resources Research Infrastructure and RD-Connect and broader scientific community. IMGGE’s biobank for rare diseases has already been used by larger biobank systems and networks in order to perform high-quality research on sufficient number of patients. Several papers in the best journals for genetics (e.g. Nature Genetics) have been published, in which researchers from IMGGE were co-authors thanks to the analysis of samples from IMGGE RD biobank.

(WP3) Reinforcement of human resources

Reinforcement of human potential facilitated successful implementation of novel approaches for improvement of basic and applied biomedical science of rare diseases in IMGGE.
Three Research Managers with longstanding expertise in different fields supported SERBORDISinn activities and with their engagement IMGGE implemented the Project more efficiently. They have strengthened IMGGE innovation building capacities, IP activities and administrative coordination.
Employed experienced researches and experienced technicians facilitated the realization of the Project’s specific objectives and technical goals. Experienced researches enabled successful activation and running of the diverse newly acquired and upgraded equipment such as Illumina MiSeq next-generation sequencing platform, flow cytometer with cell sorter, the multimode reader Infinite M200pro, cryotome and Applied imaging workstation for cytogenetic imaging and analysis. Furthermore, they participated in establishment of Primary Cell culture and Biobanks. The efficient usage of new and upgraded equipment was accomplished through engagement of experienced technicians. Employed experienced researches and experienced technicians have expertise in different fields which facilitated testing and implementation of new and updated methodologies in biology, molecular biology, biochemistry and immunology. Hired experts facilitated the acquisition of knowledge necessary for interpretation of NGS data to researchers from IMGGE involved in performing NGS. Nowadays, IMGGE researchers can analyze and understand obtained NGS data at the full extent.
In total, eight experienced researchers were hired during the Project SERBORDISInn: two experts in bioinformatics, four experts in molecular biology and biochemistry, one expert in biology and immunology and one expert in biology and biochemistry.
In total, ten experienced technicians were hired during the Project SERBORDISInn: seven experienced technician with expertise in molecular biology, one experienced technician with expertise in computational biology/statistics, one experienced technician with expertise in medicine and one experienced technician with expertise in biology.
Majority of experienced researchers and technicians continued their work at IMGGE as researchers on the projects of Ministry of Education, Science and Technological Development, Republic of Serbia.
Hiring more experienced researchers and experienced technicians was extremely important for improving the IMGGE research potential Engagement of experts enabled that IMGGE researchers get knowledge necessary for efficient usage of the newly acquired or upgraded equipment and for implementation of new and upgraded methodologies for improvement of basic and applied biomedical science of rare diseases in IMGGE.
(WP4) Exchange of know-how and experience
The activities related to exchange of know-how and experience, and facilitation of IMGGE’s personnel mobility became intensive from the very beginning of SERBORDISinn Project. These activities were focused onto 1) networking with renowned EU institutions and other European and regional groups, 2) intensification of the knowledge and information transfer of the latest trends, methodologies and approaches in RD research from most prominent European research centres, as well as on 3) trainings related to equipment acquired during SERBORDISinn Project and 4) facilitating knowledge transfer and network building at regional level.
All those intertwining activities were performed as planned or very often before scheduled time allowing implementation of gained knowledge at IMGGE and giving an opportunity to exploit obtained equipment fully even during the course of SERBORDISinn Project. The knowledgeable usage of the equipment and implementation of modern methodologies is becoming more intensive since other Laboratories at IMGGE that have not been directly involved in SERBORDISinn Project are also interested in research opportunities they provide. Therefore, SERBORDISinn Project will have impact on IMGGE’s research capacity development as a whole well beyond its completion.
Trainings of IMGGE researchers (trainings in novel methodologies, technology-related training and on-site technology training for the equipment acquired during SERBORDISInn Project) have been conducted successfully and on time. In total, 87 trainings have been realized not just at initial EU collaborative centers, but also in other European institution that during a course of the Project have become IMGGE’s partnering organizations. Received trainings significantly improved research capacities of all staff at IMGGE, and it is expected to further influence research capacity development since exchanged of know-how and experience set a basis for future IMGGE’s growth.
Participation of IMGGE’s researchers at international and regional conferences and workshops was intense and fruitful, and gave them opportunity not just to listen and to meet the best European and world scientists in the field of rare diseases research but also to present their results. During the Project staggering 219 participation of IMGGE’s researchers at international and regional conferences/symposia/workshops have been completed. At the same period 76 visits (at 12 occasions) of EU experts to IMGGE or events organized by SERBORDSinn were accomplished.
Successful organisation of conference with regional participation and internationally recognized scientists as lecturers facilitated knowledge transfer at regional level and regional network building. Clearly, the impact of the Project on IMGGE research capacity will be felt long after Project has been finished. Exchange of know-how and experience, and facilitated personnel mobility, together with all other Project’s objectives actually enabled long expected quantum leap at IMGGE.
The most significant results are:
1. Planned trainings in novel methodologies, technology-related training and on-site technology training for the equipment acquired during SERBORDISinn Project have successfully been organized and accomplished;
2. IMGGE’s researchers are trained in modern methodologies and cutting edge technologies, and thus fully capable to preform basic and translational research and diagnostics of rare diseases, as well as implement them in other areas of research interests;
3. Effects of exchange of know-how and experience are clearly visible through evident increase of publication record – number and quality, of IMGGE’s researchers;
4. Participation of IMGGE’s researchers at international and regional conferences/symposia and workshops have been organized and they successfully presented their scientific achievements and SERBORDISinn Project;
5. All experts’ visits form renowned EU institutions have been effective and productive.
6. Symposium on Rare Diseases (“Genomics of Rare Diseases”) has successfully been organized. Conference with regional participation has been organized as a part of the Symposium (Day 2).
Activity First 18 months Second 18 months Total
Trainings 39+5+1=45 38+4=42 87
Conferences 63+37=100 84+35=119 147+72=219
Experts’ Visits 32 (5 visits) 44 (7 visits) 76 (12 visits)

Networking with our EU partner organizations was very productive and exceeded what was planned. In second 18 months of the Project 42 trainings in the EU collaborative centres have been realized. It is worth noting that the long-term visits/trainings were not realized only in the initial partners’ institutions, as the list of EU partners has been enlarged with new partner institutions.
(WP5) Dissemination and promotion

During three years of SERBORDISinn project realization, IMGGE organized 22 promotion and dissemination events. Taking into account that during the three years preceding the start of the project, IMGGE organized only three events, we had more than 700% increase in promotional activities. Nineteen different attractive locations in Belgrade, one in Novi Sad and two outside Serbia (Portoroz and Bled in Slovenia), adjusted different programs and expert speakers attracted significant number of participants (researchers, healthcare representatives, industry representatives, governmental representatives and patient organizations).
It is worth noting that SERBORDISinn enabled IMGGE to develop a strong and productive collaboration with National Organization for Rare Diseases of Serbia (NORBS). Majority of our events, like three Rare Disease Days, Open Days such as “From Mysteries to Medicines of a Rare Disease: Fibrodysplasia Ossificans Progressiva” and “XXI Century – Time without rare diseases?” as well as two workshops at the First and the Second National Conferences on Rare Diseases were all organized together with NORBS and for the patients with rare diseases. On the European Researchers Night, children with rare diseases were invited to IMGGE to participate in experiments: “Understanding of the cell” and “DNA isolation” and learn what researchers do. Also, IMGGE provided a free booth for NORBS at our major event “Genomics of Rare Disease” thus enabling patients to actively participate in the Symposium. During last three years we engaged our scientific knowledge to raise public awareness of rare diseases in Serbia and to become trustful partner willing to solve diagnostics problems of rare disease patients in the whole region.
Regarding the potential of IMGGE to provide diagnostic services, SERBORDISinn promotional events were highly successful. Local and regional medical doctors who attended SERBORDISinn events became fully aware of capacities and capabilities of IMGGE to provide sophisticated molecular genetic tests for rare diseases. These events also enabled broad public promotion of rare diseases and IMGGE’ expertise in the field. Repetitive TV appearances and press releases positioned IMGGE as an Expert Centre for molecular genetics of rare diseases in the eye of Serbian general population. Together with other SERBORDISinn activities, these promotional events were incentive for the Serbian Health Insurance Fond to recognize IMGGE as a scientific institution who could bring medical, micro-economic and social benefit to citizens of Republic of Serbia.
To increase the visibility of the project to the whole Balkan region, several SERBORDISinn events were joint with the Balkan Congresses on Human Genetics - the most important meetings on human genetics which gather researchers from all Balkan countries. By organizing round table “Balkan Network for Rare Diseases: FP7 SERBORDISinn Project Goals” (Bled, Slovenia, 2013) and three workshops “Balkan Region’s opportunities in Horizon 2020”, “Balkan Genome Initiative” and “Balkan rare disease biobanks, databasis and research collaborations – SERBORDISinn initiative” (Belgrade, Serbia, 2015), IMGGE launched several initiatives and collaborations across the Balkan region.
By inviting our EU partners to be the key speakers at our events we continued to build strong research oriented relationships with them. Furthermore, we used events to promote IMGGE’s dedication to research and innovation in the field of rare diseases, IMGGE’s expertise and cutting edge equipment. As a result we were able to recruit new local and regional partners for future collaborations (such as Seven Bridges Genomics – a bioinformatics company from Serbia). Soon after Symposium “Genomics of Rare Disease” in November 2014, IMGGE became member of the esteemed European research collaboration network “RD-CONNECT”. This membership is one of the main indicators of successful promotion of IMGGE which led to its scientific recognition at European level and its inclusion into ERA. Furthermore, with the Conference on “Structure and Dynamics of the Sarcomere” in May 2015, we showed the capability to attract all important world experts on neuromuscular diseases and be recognized as leaders in the area.
Ample variety of SERBORDISinn promotional events put the research, diagnostics and innovation activities performed in the IMGGE in the spotlight of all stakeholders (representatives of the Government, National Health Insurance Fond, medical doctors and other healthcare practitioners, biomedical researchers, pharmaceutical and biotechnology industries and rare disease patient organizations) not only in Serbia, but also across the Western Balkan region and Europe. Taken all together, the most significant results of the WP5 promotional and dissemination activities are:
1. Recognition of IMGGE as an Expert Centre for molecular genetics of rare diseases in Serbia and the Western Balkan region
3. Established collaborations between IMGGE and Balkan institutes with MG expertise related to RD
4. Established collaborations between IMGGE and European institutes and networks with MG expertise related to RD
5. Raised visibility of IMGGE as a whole

Leaflets and website acted in concert with organization of SERBORDISinn events. All leaflets, both in English and Serbian languages were continuously distributed at various promotional events organized by SERBORDISinn project. Also, IMGGE researchers who participated at various local and international conferences and meetings further distributed leaflets in order to widely promote SERBORDISinn activities related to rare disease research, diagnostics and networking. Thus, leaflets were continuous source of information that reached all stakeholders, travelled across Serbia and outside country borders and depicted IMGGE as the Expert Centre for molecular genetics of rare diseases as well as the focal point of research and innovation in the field of rare diseases.
Project website (http://www.serbordisinn.rs/) was one of the main communication platforms to disseminate the results of the SERBORDISinn project and to promote the research carried out by the IMGGE. As a result of the regularly updated website, all events organized by IMGGE were well announced, attended by many participants and therefore very successful.
Due to the substantial shift from classical molecular genetic technologies to the cutting-edge genetic technologies which were introduced during SERBORDISinn project, our strategy for web Balkan national databases changed and evolved into “1000 Balkan Genomes” project which has already been launched. The “1000 Balkan genomes” project, the most important initiative of the SERBORDISinn, will increase research collaborations between Balkan countries and reassure IMGGE as a focal point in the Western Balkan region. Genomes of at least 1000 persons originating from all parts of Balkan Peninsula will be sequenced in order to create a comprehensive and detailed catalogue of human genetic variations characteristic for this region. This data will be stored at our established web platform (http://ethnos.findbase.org/home-rs), and become available for all Balkan research and clinical teams to submit their data and make them publicly available. Such web databases with rare variants proven to cause genetic diseases will be important source for human genetic diagnostic laboratories and clinical geneticist across Europe.
All SERBORDISinn WP5 promotional activities were designed to seize media attention about research performed on rare disease at the IMGGE. The increase of number of independent mentions of SERBORDISinn / IMGGE in the media was accomplished. Majority of SERBORDISinn events were covered in Serbian media with several live TV appearances and press releases.
Considering the increased number of independent mentions of SERBORDISinn / IMGGE in the media, continuous invitations for collaboration from international researcher groups (such as RD-connect) and companies (Seven Bridges Genomics) as well as the opened opportunity for a long-term contract with the National Health Insurance Fond to perform genetic testing for rare diseases for the whole country, we are confident that our promotional activities firmly positioned IMGGE as the Expert Centre for molecular genetics of rare diseases in the Western Balkan region. Moreover, WP5 activities which were in line with the progress of SERBORDISinn project and the increasement of research and innovation potential of the IMGGE as a whole will assure sustainability of the achieved position and enable further progress of IMGGE in years to come.

Potential Impact:
SERBORDISinn Project has mobilized, strengthened and developed scientific and innovation potential of IMGGE. Modern equipment, expertise in applying cutting-edge MG methodologies and RD-specific biobanks, as a source of biological material for future basic research, has establish IMGGE as an Expert Centre for MGs related to RD. Increase in potential has made IMGGE visible and attractive partner for collaborative actions within various local, regional and EU initiatives.
The result of implemented SERBORDISinn has significantly upgraded the IMGGE's RTD capacity and capability in terms of material resources and implementation of novel MG methodologies. Consequently, once given the opportunity to use sophisticated equipment, together with enhanced professional skills and established links with their European colleagues, researchers in IMGGE have obtained promising career conditions.
Through SERBORDISinn, IMGGE has upgraded the ongoing and implement new, cutting-edge MG methodologies, as well as novel approaches essential for high quality biomedical research and applications in the field of RD. Biobanks, as a resource that supports a diverse range of research intended to improve the prevention, diagnosis and treatment of RD, have substantially accelerated research on RD in IMGGE. New database storage system as an integrated system for running biobanks and facilities for adequate storage of samples have been introduced. Our data storage system is synchronized with the Cloud Storage. All the data can be accessed via internet, enabling our biobanks’ databases to contact biobank networks, such as EuroBioBank, BBMRI-ERIC and RD-Connect. Our 35 collections with several thousands of samples will help achieving one of the goals of EuroBioBank, which is to build a critical mass of RD sample collections.
Furthermore, establishment of molecular genetic databases to complement national patients’ registries for RD has been accomplished through SERBORDISinn. The advantages of the patients` registries are numerous: the recruitment of patients for clinical trials is much easier, patients are informed about new treatments that might be relevant to them, scientists are informed about the prevalence of distinct rare disorders, etc.
In parallel with equipment acquisition, implementation of new MG methodologies and building RD biobanks, activities such as hiring experienced researchers and exchange of know-how with distinguished EU partnering organizations has enabled an increase in invited participations of IMGGE researchers at international conferences as well as in the number and quality of published papers with IMGGE affiliation. The IMGGE has become not only the Institution where state-of-the-art approaches in biomedical studies are performed, but also a role model for the national scientific community.
Strategic partnerships with national medical institutions involved in rare diseases has resulted in implementation of achievements of SERBORDISinn into Serbian medical practice and has established IMGGE as a key player in the Serbian public health sector. SERBORDISinn impact on healthcare in Serbia has resulted in significant increase in the quality and the number of services provided (molecular genetic analysis of RDs). As a result, Serbian Health Insurance Agency has offered IMGGE a contract to be a national centre for molecular diagnosis of RDs. Furthermore, building up the local network, NIRBOS (Research Initiative for RD in Serbia or Naucna Inicijativa za Retke Bolesti u Srbiji, in Serbian) provides long-term sustainability of SERBORDISinn objectives and achievements.
Balkan regional databases for different genetic diseases did not exist. SERBORDISinn achievements have paved the way for the development of joint Balkan genetic databases. Our strategy for web Balkan national databases has evolved into “1000 Balkan Genomes” Project which has already been launched. The “1000 Balkan genomes” Project, the most important initiative of the SERBORDISinn, will increase research collaborations between Balkan countries and reassure IMGGE as a focal point in the Western Balkan region. Genomes of at least 1000 persons originating from all parts of Balkan Peninsula will be sequenced in order to create a comprehensive and detailed catalogue of human genetic variations characteristic for this region. This data will be stored at the web platform established within SERBORDISinn (http://ethnos.findbase.org/home-rs), and become available for all Balkan research and clinical teams to submit their data and make them publicly available. Such web databases with rare variants proven to cause genetic diseases are important source for human genetic diagnostic laboratories and clinical geneticists across Europe.
Through numerous SERBORDISinn activities IMGGE has established collaboration and collaborative projects with Balkan institutes with MG expertise related to RD. Also, SERBORDISinn has made the local and regional research community aware about the importance, opportunities, and short- and long-term benefits of the Framework Programs.
Altogether SERBORDISinn achievements has upgraded IMGGE’s research potential to study molecular basis of different human pathologies in order to understand how diseases can be controlled, treated and prevented. In addition, SERBORDISinn has made IMGGE’s researchers move forward towards implementation of the results of their research in national biotechnological industry. Once we had established new, cutting-edge MG methodologies and RD-specific biobanks we were able to widen our research activity that led to a significant improvement of our participation in Horizon 2020 and long-lasting sustainability.

SERBORDISinn List of Impact Indicators

The impact of SERBORDISinn assessed by quantitative indicators

1. The increase in the number of requests to access new capital equipment in IMGGE during and after realization of the Project. (expected increase: 10% per year, realized: a several fold increase overall). IMGGE has introduced NGS technology for the first time in Serbia and neighbouring countries as well. Therefore, a number of researchers and medical institutions have requested to use NGS technology. IMGGE staff helped with the analysis and joint papers have been published. The institutions are: Vinca Institute of Nuclear Sciences University of Belgrade, Institute of Human Genetics, Faculty of Medicine University of Belgrade, University Children’s Hospital, Belgrade, The Clinical Center of Serbia, Belgrade – Clinic for Hematology, Clinic for Pulmonary Diseases, Clinic for Neurology, Faculty of Medicine, University of Belgrade; Mother and Child Health Care Institute Belgrade and Division for Metabolic Diseases, Department of Pediatrics University Hospital Center Zagreb, Croatia.

2. Setting up national biobanks for RD and becoming a member of EuroBioBank organization. There were some not well organized collections of samples of RD in IMGGE before SERBORDISinn Project. Today, there is a national biobank for RD in IMGGE, containing 35 collections with several thousands of samples. Our biobank data storage system is synchronized with the Cloud Storage. All the data can be accessed via internet, enabling our biobank’s databases to contact biobank networks, such as EuroBioBank, BBMRI-ERIC and RD-Connect.

3. Establishment of molecular genetic databases to complement national patients’ registries for RD. Molecular genetic databases did not exist before SERBORDISinn Project. The first Serbian Genetic Web Database (http://ethnos.findbase.org/home-rs) has been established as a result of the SERBORDISinn Project. Merging and systematization of genetic data from various reliable national resources have been started and will be continuous in the future. Once established, the Serbian National Genetic Web database will continue to getter genetic data and ensure prolonged visibility and impact of SERBORDISinn Project in years after its termination. It will represent the crucial dissemination effort which will have boundless and timeless effects.

4. Establishment of joint Balkan molecular genetic databases for RD. Balkan institutions involved in molecular genetics of RD were not connected at all. Through SERBPRDISinn activities relevant institutions, researchers and medical practitioners have get to know each other and have started a joint Project “1000 Balkan Genomes”. Thus our strategy for web Balkan national databases changed and evolved into Project which has already been launched. The “1000 Balkan genomes” Project, the most important initiative of the SERBORDISinn, will increase research collaborations between Balkan countries and reassure IMGGE as a focal point in the Western Balkan region. Genomes of at least 1000 persons originating from all parts of Balkan Peninsula will be sequenced in order to create a comprehensive and detailed catalogue of human genetic variations characteristic for this region. This data will be stored at our established web platform (http://ethnos.findbase.org/home-rs), and become available for all Balkan research and clinical teams to submit their data and make them publicly available. Such web databases with rare variants proven to cause genetic diseases will be important source for human genetic diagnostic laboratories and clinical geneticists across Europe.

5. Building up the local network, NIRBOS (Research Initiative for RD in Serbia or Naucna Inicijativa za Retke Bolesti u Srbiji, in Serbian). (expected increment: 10% per year, realized: 30% per year). Several research and medical institutions have joined NIRBOS in past three years: Clinic for Pulmonary Diseases (Clinical Center of Serbia), Institute for Rheumatology (Clinical Center of Serbia), Clinic for Otology (Clinical Center of Serbia), Clinic for Neurology and Psychiatry for Children and Youth (Faculty of Medicine, University of Belgrade), Neurology Clinic (Clinical Center of Serbia, Faculty of Medicine, University of Belgrade), Clinical Hospital Center Zemun, Center for Human Molecular Genetics (Faculty of Biology, University of Belgrade), Institute of Human Genetics (Faculty of Medicine, University of Belgrade). Additionally, NMD-SerbNet (Serbian Neuromuscular Disease Network) was inaugurated in November 2014 during SERBORDISinn Symposium "Genomics of Rare Diseases" held in Belgrade, Serbia.

6. The increase in the number of students writing MSc/PhD thesis in IMGGE on the topics connected with RD during and after realization of the Project. (expected increment: 50% per year, realized: a several fold increase overall). Few MSc and PhD thesis on the topics related to RD were done in Serbia. However, SERBORDISinn has promoted the topic. During the realization of the Project 6 PhD theses were done in IMMGE on RD topic, and 10 more are in progress. Additionally, 23 PhD theses were done by PhD students on the Faculty of Medicine University of Belgrade, who used IMGGE RD biobanks and new equipment acquired through SERBORDISinn. Two theses were done by PhD student of law and bioethics on the RD topic. IMGGE researchers actively participated in their realization too. Moreover, in IMGGE two PhD theses of geneticists from Medical Center Banja Luka, Republic of Srpska, Bosnia and Herzegovina related to RD are in progress. Also, realization of one PhD thesis of the researcher from Clinical Hospital Centre Rijeka, Department of Pediatrics, University of Rijeka, Rijeka, Croatia related to RD is in progress.

7. The increase in the number of local/regional/EU experienced researchers interested to be trained or work in IMGGE during and after realization of the Project. (expected increment: 30% per year, realized: a several fold increase overall). There were several group and individual trainings organized in IMGGE related to NGS technology. As a result, two institutions have acquired NGS technology and have started to use it for research and diagnostics. Also, SERBORDISsinn was a co-organizer of the workshop “Are we on the right track towards accreditation? How to measure and improve quality?”, with the participation of 15 researchers from Serbia and other Balkan countries.

8. The increase in invited participations of IMGGE researchers at international conferences during and after realization of the Project. (expected increment: 50% per year, realized: a several fold increase overall). IMGGE researchers, participants of SERBORDISinn Project, have been invited speakers at several international conferences and meetings, mostly as a result of the research done using new methodology. Some of those conferences are: Pharmacogenomics Day, Ljubljana, Slovenia 2013; Summer School Pharmacogenomics and Genomic Medicine, Aegina, Greece, 2014; Conference on NGS in Medicine, Skopje, Macedonia, 2014; Pharmacogenomics Day, Sarajevo, Bosnia and Herzegovina, 2014; International Conference: Tumor biomarkers: From discovery to clinical applications, Athens, Greece, 2014; “Genes and genome”, Serbian Academy of Science and Art, 2015; Congress of Paediatricians of Republic Srpska, Bosnia and Herzegovina, Jahorina 2015; Symposium Rare Metabolic Diseases, Rijeka, Croatia 2016, etc.

9. The increase in the number and quality of published papers with IMGGE affiliation during and after realization of the Project. (expected increment: 20% per year, realized: 60% overall). In the period preceding the SERBORDISinn, the three-year average number of publications was 50, while, during the Project, the three-year average number of publications was 80 (mostly on RD related topics, but also related to other topics, but realized using new methodologies and equipment). Also, the cumulative impact factor of these publications raised by 35%.

10. The increase in the quality and the number of services provided (molecular genetic analysis of RDs) during and after realization of the Project. (expected increment: 10% per year, realized: 200% overall). The most of newly introduced molecular analysis are related to diagnosis and follow up of RD, as well as pharmacogenomics and nutrigenomics. The main result is that Serbian Health Insurance Agency has offered IMGGE a contract to be a national centre for molecular diagnosis of RDs.

11. The increase in the number of SERBORDISinn and IMGGE websites hits during and after realization of the Project. (expected increment: 40% per year, realized: a several fold increase overall). SERBORDISinn website (www.serbordisinn.rs) has been a powerful tool for promotion and dissemination of the Project. It was launched at the very beginning of the
Project, in December 2013. The average annual number of hits is: more than three thousands from Serbia and more than six hundreds from other countries (mostly Europe and USA).

12. The increase in the number of independent mentions of SERBORDISinn/IMGGE in the media during and after realization of the Project. (expected increment: 50% per year, realized: 700% overall). During three years of SERBORDISinn Project realization, IMGGE organized 22 promotion and dissemination events. Taking into account that during the three years preceding the start of the Project, IMGGE organized only three events, we had more than 700% increase in promotional activities. Nineteen different attractive locations in Belgrade, one in Novi Sad and two outside Serbia (Portoroz and Bled in Slovenia), adjusted different programs and expert speakers attracted significant number of participants (researchers, healthcare representatives, industry representatives, governmental representatives and patient organizations). All SERBORDISinn promotional activities were designed to seize media attention about research performed on rare disease at the IMGGE. The increase in the number of independent mentions of SERBORDISinn / IMGGE in the media was accomplished. Majority of SERBORDISinn events were covered in Serbian media with several live TV appearances and press releases.

13. The increase in the number of collaborations between IMGGE and Balkan institutes with MG expertise related to RD during and after realization of the Project. (expected increment: 25% per year, realized: a several fold increase overall). New collaborations have been established through new projects and contracts on collaboration. IMGGE has established collaboration during SERBORDISinn Project with following institutions from Balkan region and EU: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Pharmacogenetics Laboratory Ljubljana, Slovenia; CECAD Institute for Genetics, Cologne, Germany; Karlsrue Institute of Technology (KIT), Karlsrue, Germany; Institute for Genetic Engineering and Biotechnology, Sarajevo, Bosnia and Herzegovina; University of Trieste, Department of Medical, Surgical and Health Sciences, Trieste, Italy; Clinical Hospital Centre Rijeka, Department of Paediatrics, University of Rijeka, Rijeka, Croatia; University Children's Hospital, Department of Hematology, Oncology with Haemophilia Center, Faculty of Medicine Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina.

Further Research and Innovation for Sustainability

1. The increase in the number of requests by enterprises, private and public bodies to engage IMGGE in new collaborative actions with commercialization effect during and after realization of the Project. (expected increment: 5% per year, realized: a several fold increase overall). During the course of the SERBORDISinn Project IMGGE researchers were involved in realization of three innovative Projects which resulted in two registered patents. IMGGE also established strategic partnership with a small enterprise company Veterinary Station "Koker" Adaševci in order to enable co-exploitation of research results. These achievements are illustration of IMGGE successful efforts to adopt IP policies and to orient part of its activities to innovations. Also, collaborative Projects with Karlsrue Institute of Technology (KIT), Karlsrue, Germany and Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Pharmacogenetics Laboratory Ljubljana, Slovenia, are expected to have commercialization effect.

2. Designing and producing cost-effective diagnostic test kit(s) for RD specific for Balkan populations in cooperation with SME. Currently we have two prototypes (Kit for detection of the most frequent Balkan beta-globin mutations and Kit for the prediction of multiple myeloma development in the patients with Gaucher disease) for which we received support from the World Bank and Genzyme pharmaceutical industry. Our future intentions will be oriented towards next generation technology which will be used to develop diagnostics, prognostics and pharmacogenetic cost-effective panels.

3. The increase in participation in Horizon 2020 during and after realization of the Project. (expected increment: 5% per year; realized: a several fold increase overall). Researchers from all IMGGE laboratories have been applying to significant number of various European projects. The list of applications is as follows:

Horizon 2020 - Teaming Project: CERD (Centre of Excellence for Next Generation Biomedicine of Rare Diseases)
Horizon 2020 - COST Action: “Integrating Mediterranean and Eastern European Biobanking in European Science”.
Horizon 2020 - ERC Starting Grant: “Of Centrosomes and Cilia (CenCilia): Combining genomics and deep phenotyping to understand effects of “centriole dysfunction” using C. elegans”.
Horizon 2020 - Twinning Project: “Centre of Excellence for Next Generation Biomedicine of Rare Diseases“.
Horizon 2020 - Fast Track to Innovation Project: “Scale-up and initial commercialization of novel probiotic for intestinal infections of non-human mammals”.
Horizon 2020: “GEnome and MIcrobiome are Nested in IBS”.
Horizon 2020 - ERC Consolidator grant: “Deciphering the role of proteases of gut microbiota in autism spectrum disorders development and prevention”.
Horizon 2020: “Biomass Biorefinement and Biotransformation for Bioactive Terpenoids - Bio4mations”.
Horizon 2020 - Twinning Project: “Mining microbial resources from novel niches for medicinal leads using integrated sequence-structure platform – microMEDICUSS”.
Horizon 2020 - COST Action: “Defeating Antibiotic Resistance via Integrated, Interdisciplinary Networking and Novel Technological Pipeline Development”.
Horizon 2020 - COST action: “Application of next generation sequencing for the study and diagnosis of plant viral diseases in agriculture”.

QUALITATIVE INDICATORS

• Additional fund raising obtained following the results of SERBORDISinn. A great number of grants have been obtained during SERBORDISinn. Some of them are funded by the Ministry of Education, Science and Technological Development Republic of Serbia: “Rare Diseases: Molecular Pathophysiology, Diagnostic and Therapeutic Modalities and Social, Ethical and Legal Aspects“, an interdisciplinary project whose coordinator is Dr Sonja Pavlovic, coordinator of SERBORDISinn; “Complex Diseases as a Model System for Phenotype Modulation - Structural and Functional Analysis of Molecular Biomarkers“; “Studying Signal Transduction Pathways and Epigenetic Mechanisms that Control Human SOX Genes Expression: Further Insight into their Roles in Cell Fate Determination and Differentiation”; “Genes and Molecular Mechanisms Promoting Probiotic Activity of Lactic Acid Bacteria from Western Balkan”. Researchers from all IMGGE laboratories have been applying to a significant number of various projects besides Horizon 2020, such as: NIH Project: “Exploration of platinum distribution and speciation in neural cells exposed to Pt chemotherapeuticals in combination with Pt sequestering treatments for investigation of CIPN”; ICGEB Collaborative Research Programme: “Illuminating SOX14 target genes in models of cervical cancer”; Glenn Memorial Grant: “Neutrophil elastase promoter genotype as biomarker for response to antiinflammatory therapy in bronchiectasis”; Congenital heart diseases - Medical Grant: “MicroRNAs expression profiling in myocardium and peripheral blood from children with Tetralogy of Fallot and 22q11.2 microdeletion – searching for regulators of cardiac development and disease”; Antibody Resource Research Grant: “Elucidating the role of SOXB1 genes in glioblastoma multiforme tumor cells and cancer stem cells”; Bilateral cooperation Project Serbia - Slovenia: “Genetic variability of adenosine receptors: pharmacogenomic and nutrigenomic implications”; Bilateral cooperation Project Serbia – Croatia: “The role of prothrombin in colon cancer”; Bilateral cooperation Project Serbia - Federal Republic of Germany: “MicroRNAs inlungresponse to asthma therapy”; Danube Transnational Programme: “The innovative and sustainable use of the bacterial flora of the Danube river system”; DAAD Project: “Mining microbial resources for novel antifungal drug leads”; Bilateral cooperation Project Serbia – Croatia: “Exploration of bacterial diversity from soda lakes Rusanda and Palic”; NineSigma Call: “Mechanisms of Ulcer Pharmacology Evaluation”.

• Engagement of IMGGE with local SME(s) for further commercialization actions. The partnership with two SMEs has been established. Partnership with Seven Bridges Genomics, a bioinformatics company, has been established for the purpose of education of IMGGE staff and advanced interpretation of big data obtained by newly implemented technology. Partnership with the Veterinary Station "Koker" Adaševci resulted in the patent application.

• Trained IMGGE staff in IP and innovation issues and creation of strategic IMGGE IP development plan. Training of all researchers employed in IMMGGE (100) regarding IP issue enabled better understanding and awareness of IP protection and established background for implementation of good IP practise in IMGGE. Two major strategic documents have been developed and fully completed: IMGGE IP protection Manual and IMGGE Strategic Scientific and Development Action Plan. Two patents of IMGGE researchers have been submitted to the Intellectual Property of the Republic of Serbia and to the International Patent System.

Spreading excellence and disseminating knowledge

The significance and benefits of the SERBORDISinn Project results have become visible and exploited through dissemination activities. Proper maintenance and update of the web site (www.serbordisinn.rs) have increased the transparency of the Project’s achievements to the public and to professionals, and has improved IMMGE's recognition within Serbia, the Balkan region, the EU and worldwide. In order to spread excellence and disseminate knowledge gained through SERBORDISinn Project we have organized 22 various events at local, regional and European level. Their impact is significant since the number of attracted participants was more than two thousands.
The wide dissemination of knowledge and research excellence gained through SERBORDISinn has been achieved by distribution of leaflets, organization of open days, Rare Disease Days, European Researchers’ Nights, local/regional workshops for target groups (researchers, health care practitioners, pharmaceutical industry representatives, health policy-makers, patients groups, media and public at large). The impact of these activities is the increase in awareness of the mentioned target groups on the ExCe for MGs of RD established at IMGGE. It is worth noting that SERBORDISinn enabled IMGGE to develop a strong and productive collaboration with National Organization for Rare Diseases of Serbia (NORBS). During the last three years we have engaged our scientific knowledge to raise public awareness of rare diseases in Serbia and to become trustful partner willing to solve diagnostics problems of rare disease patients in the whole region.
Regarding the potential of IMGGE to provide diagnostic services, SERBORDISinn promotional events were highly successful. Local and regional medical doctors who attended SERBORDISinn events became fully aware of capacities and capabilities of IMGGE to provide sophisticated molecular genetic tests for rare diseases. These events also enabled broad public promotion of rare diseases and IMGGE’s expertise in the field. Repetitive TV appearances and press releases positioned IMGGE as an Expert Centre for Molecular Genetics of Rare Diseases in the eye of Serbian general population. Remarkable increase in the number of independent mentions of SERBORDISinn / IMGGE in the media was accomplished. Majority of SERBORDISinn events were covered in Serbian media with several live TV appearances and press releases. Together with other SERBORDISinn activities, these promotional events were incentive for the Serbian Health Insurance Fund to recognize IMGGE as a scientific institution who could bring medical, micro-economic and social benefit to citizens of Republic of Serbia.
To increase the visibility of the Project to the whole Balkan region, several SERBORDISinn events were joint with the Balkan Congresses on Human Genetics - the most important meetings on human genetics which gather researchers from all Balkan countries. By organizing round table “Balkan Network for Rare Diseases: FP7 SERBORDISinn Project Goals” (Bled, Slovenia, 2013) and three workshops “Balkan Region’s opportunities in Horizon 2020”, “Balkan Genome Initiative” and “Balkan rare disease biobanks, databasis and research collaborations – SERBORDISinn initiative” (Belgrade, Serbia, 2015), IMGGE launched several initiatives and collaborations across the Balkan region.
The most important promotional and dissemination activity of SERBORDISinn was the Symposium “Genomics of Rare Disease”. It was one of the most important meetings dedicated to rare disease in 2014 in Europe. After that event, IMGGE became a member of the esteemed European research collaboration network “RD-CONNECT”. This membership is one of the main indicators of successful promotion of IMGGE which led to its scientific recognition at European level and its inclusion into ERA. Furthermore, with the Conference on “Structure and Dynamics of the Sarcomere” in 2016, we showed the capability to attract all important world experts on neuromuscular diseases and to be recognized as leaders in the area.
Some very important activities contributed to the dissemination of the information on the Project achievements - the IMGGE profile was posted on H2020 web site (www.horizon2020projects.com) and the article “Science in service of rare diseases in Serbia” was published in European Parliament Magazine (March 2014, Issue 385/3, page 14).
All those activities have increased visibility of IMGGE’s excellence and know-how, have promoted the achievements of SERBORDISinn Project, and have established IMGGE as a main driving force for bringing up RD specific problems into focus of health care, biotechnological and pharmaceutical industries and health policy-makers in Serbia.

Innovation impacts

SERBORDISinn has resulted in embedding the exploitation of acquired and created knowledge and technology into IMGGE structure. Deliverables of the Project are: trained IMGGE staff in IP and innovation issues, creation of strategic IP development plan, as well as established work group for innovation and IP within IMGGE. This will provide sustainability of IMGGE’s commitment to innovation.
Realization of SERBORDISinn Project has promoted excellence in IMGGE research that sets up the innovation dimension at IMGGE. This is particularly important for economically weak regions, such as Serbia, that lack continuity in this approach.
Two major strategic documents important for building up IMGGE innovation capacity have been developed and fully completed: IMGGE IP protection Manual and IMGGE Strategic Scientific and Development Action Plan. As a result of SERBORDISin activities, two patents of IMGGE researchers have been submitted to the Intellectual Property of the Republic of Serbia and to the International Patent System. Also, two prototypes (Kit for detection of the most frequent Balkan beta-globin mutations and Kit for the prediction of multiple myeloma development in the patients with Gaucher disease) have been developed with the support from the World Bank and Genzyme pharmaceutical industry.
Another achievement of SERBORDISinn is the contract of Serbian Health Insurance Agency that offered IMGGE to be a national centre for molecular diagnosis of RDs.
IMGGE is recognized as an expert centre and a leader in the field of biomedical science of rare diseases in Serbia and Balkan, as well as "innovation engine" capable of contributing actively to the national, regional and European sustainable development needs in this field of research and management of rare diseases.
Altogether, improvement of IMGGE's research capacity has given new impulses to stabilization and reinforcement of S&T potential in Serbia. Consequently, that has led to IMGGE's increased contribution to national economic and social development.
Furthermore, IMGGE has used SERBORDISinn as an opportunity to become excellent enough for full integration in EU networks and EU collaborative research projects. SERBORDISinn has pushed IMGGE through the doorstep of ERA and has enabled IMGGE scientists to be actively involved in European scientific community. This gives IMGGE opportunity to contribute to overall scientific progress in Europe.

List of Websites:
www.serbordisinn.rs

Sonja Pavlovic,PhD
Principal Investigator
Laboratory for Molecular Biomedicine
Institute of Molecular Genetics and Genetic Engineering
University of Belgrade
Vojvode Stepe 444a
11010 Belgrade
Serbia
tel: +381 11 3976 445
fax: +381 11 3975 808
e-mail: sonya@sezampro.rs
www.imgge.bg.ac.rs

Related information

Contact

Sonja Pavlovic, (Head of Laboratory for Molecular Hematology)
Tel.: +381113976445
E-mail
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