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Enhancing University of Crete Medical School Scientific Excellence and Translational Research Potential in Human Diseases

Final Report Summary - TRANSPOT (Enhancing University of Crete Medical School Scientific Excellence and Translational Research Potential in Human Diseases)

Executive Summary:
At the University of Crete Medical School, in the convergence region of Crete, Greece, there have been concerted efforts to establish a multidisciplinary scientific environment which will foster excellence in research in areas of major biomedical importance, such as stem cell biology, autoimmune, cardiovascular, malignant and degenerative diseases. The TransPOT support program aims to accelerate these efforts by enhancing the technological capability of the Institution through the establishment of state-of-the-art infrastructure, attracting high-calibre scientists and by networking with major research entities in Europe.
During the period of the grant, TransPOT researchers have utilized REGPOT-funded human resources and state-of-the-art infrastructure to address fundamental biological questions relevant to a spectrum of human diseases and the application of cell- or molecule-based therapeutic strategies in pre-clinical models. The successful outcome of these efforts is highlighted by the impressive number of publications and reports in scientific conferences achieved by TransPOT scientists. The program also worked to ensure spreading of scientific excellence and dissemination of knowledge through the organization of focused symposia and by raising public understanding of scientific and health issues.

Project Context and Objectives:
The greatest disease burden in Europe is represented by non-communicable diseases, a group of conditions that includes metabolic, malignant, autoimmune/inflammatory and degenerative diseases. Despite the progress in unraveling their causes and molecular mechanisms, translation of research findings into innovative strategies for the prevention, diagnosis and treatment of these diseases is slow and represents one of the biggest challenges and priorities for European medical research. Indeed, translating research for human health represents a main objective for the Horizon 2020 program of the EC. Promising ideas for novel therapeutic interventions may encounter roadblocks in bench-to-bedside testing. While translation is sometimes facilitated by public-private partnerships, therapies for uncommon disorders or novel ideas frequently do not attract private sector investment. Where private sector capacity is limited or not available, public resources can bridge the gap between discovery and clinical testing so that more efficient translation of promising discoveries may take place. A stronger public research infrastructure could thus strengthen and accelerate this critical part of the clinical research enterprise.

The success of translational research in Europe can be accelerated by the improvement of the research capacity in EU regions of convergence. Geographically isolated areas with low mobility of the inhabitants and relative genetic homogeneity, such as the island of Crete, Greece, provide the opportunity to establish unique patient cohorts and facilitate translational research for the benefit of EU citizens and beyond. The TransPOT program mobilizes the available expertise and resources of the University of Crete Medical School (UoC-Med) with a view to establish infrastructure necessary to accelerate translation of research findings into the development of innovative strategies for the prevention, diagnosis and treatment of diseases which have a high health and economic burden for Europe such as dyslipidemias, neurological and cardiovascular disorders, inflammation / autoimmunity and malignancy. The successful outcome of these efforts could be amplified by the operation of a core Translational Medical Research Facility within the UoC Medical School, which will provide the local biomedical community with centralized resources necessary for the conduct of high quality translational research and technology development.

Assisted by the FP7 Capacities programme, TransPOT aimed to enrich the infrastructure of the Institution with state-of-the-art equipment and experienced researchers and to network with European Centers of excellence in medical research. This could act as a catalyst to strengthen the Institutional R&D capacity, reinforce its competitiveness at international level and allow it to become dynamic actor of the ERA within the enlarged Union. Based on this concept, TransPOT set the following objectives:

1. To expand the research capability of the Institution in the fields of Genomics and Cell Therapy by the acquisition of state-of-the-art equipment.
2. To protect and enrich human capital for translational medical research and technological development with emphasis on repatriation of established Greek scientists.
3. To exchange know-how and acquire new expertise through twinning with Mentor Labs in EU developed regions.
4. To develop strategic partnerships with centers of excellence in Europe.
5. To increase the visibility of the Institution by disseminating knowledge in translational medical research at local, regional and international level.

By promoting scientific excellence and strengthening the technological capacities at Institutional level, TransPOT served as a strategic investment for the region by bringing multiple scientific, healthcare, economic and social benefits, accelerating its convergence with the rest of EU.

Project Results:
The FP7 project TransPOT was designed to strengthen the research and technological potential of the University of Crete Medical School (UoC-Med), through the acquisition of advanced equipment and the hiring of qualified scientific personnel, thereby helping to offset the potential “brain drain” in the region. The UoC-Med strives for excellence in research in areas of major biomedical importance, such as stem cell biology, as well as autoimmune, cardiovascular, malignant and degenerative diseases.

Objective 1. To expand the research capability of the Institution in the fields of Genomics and Cell Therapy by the acquisition of state-of-the-art equipment.
State-of-the-art infrastructure has been established through TransPOT:
A Good Manufacturing Practices (GMP) Lab has been successfully built according to the EU GMP regulations and it features positive-pressure modular clean-rooms of different grades, e.g. gowning and storage rooms in addition to the higher-grade working laboratory space. The processing and cell culture rooms have specific clean-room benches and stands for the equipment supplied, which includes biological safety cabinets, CO2 incubators, controlled-rate freezer and liquid nitrogen supply, microscopes, centrifuges, and storage equipment. The GMP Lab is already involved in the production of mesenchymal stem cells (MSCs) and dendritic cells (DCs) for preclinical research purposes.

The GMP Cell Therapy Unit has served as a primer for the establishment of the “Center for Collection of Cord Blood” at UoC-Med (KESOPA; www.kesopa.gr). KESOPA is the second national biobank for the collection of cord blood and the provision of cord blood MSCs for regenerative medicine applications and as the only facility of its type in Crete, it has received wide publicity. KESOPA operates under NetCord/FACT accreditation and in compliance with international standards.

A Genomics Set-Up consisting of a Laser Capture Microdissector (LCM) platform and Real-Time PCR machine has also been established and used by many groups for genomic applications. It also supports the activities of the GMP unit.

Several major benefits have been derived from the equipment purchased and the facilities built as part of the TransPOT project, including that: (i) the acquired TransPOT infrastructure is now strategically placed to assist a wide spectrum of translational research activities and to position the UoC at the forefront of translational medical research; (ii) more than 37 high-quality publications authored by TransPOT researchers have emerged from this REGPOT support action; (iii) the TransPOT facility has been included in the infrastructure roadmap of EATRIS-GR which, if fully funded by the national funding agency, the facility will be financially supported for the period 2015–2020; and (iv) the TransPOT facility has attracted financial support from the UoC for purchasing a microscopy system and software for karyotyping, which will support both Genomics and Cell Therapy applications.

Objective 2. To protect and enrich human capital for translational medical research and technological development with emphasis on repatriation of established Greek scientists.
A major objective of the project was to sustain and enhance the human resources available for translational medical research and technological development, with the emphasis on repatriation of established Greek scientists. This goal has largely been accomplished in that two senior scientists at the Assistant Professor level have been recruited from abroad to work for TransPOT. While working in the TransPOT project, both researchers obtained tenured positions at the UoC, which can be considered as a major contribution of TransPOT to the enhancement of the University’s human capital, which otherwise has been reduced by nearly 30% since 2009.

In addition, 23 junior research and support personnel have been hired through TransPOT and have become highly trained through specific research projects, participation in international conferences, seminars and workshops, as well as through short-term visits to mentor laboratories. They have significantly contributed to the scientific output of TransPOT. Whereas the current funding situation in Greece, coupled with the on-going economic crisis have severely impacted on our capacity to offer renewed contracts to the majority of these researchers, success stories have emerged. As an example, a TransPOT researcher has initiated her own company, Embiodiagnostics ( http://embiodiagnostics.gr/ ), which offers a comprehensive range of genomic services towards the improvement of human health and who at the same time maintains good contacts with UoC-Med. Additional, albeit limited success in Horizon 2020 grant proposals have allowed the continuation of some research projects. Moreover, we pursue financial support by UoC to maintain a technician to run the Genomics Laboratory.

The successful implementation of support infrastructure and recruitment of personnel to the S&T objectives of TransPOT required close interaction between clinical and basic scientists, technology experts and support personnel. We supported 17 specific projects aiming to enhance interactions between clinicians and basic scientists in forefront translational research thereby expanding the Institutional research potential on:
(a) experimental cardiology; (2 projects supported).
(b) infectious diseases; (2 projects supported).
(c) Inflammatory and autoimmune pathologies; (6 projects supported).
(d) Malignant diseases; (3 projects supported).
(f) Neurodegeneration; (1 project supported).
(g) Metabolic diseases; (1 project supported).
(h) Stem cell biology and therapy; (3 projects supported).
Core support personnel in genomics, bioinformatics and cell therapy applications were also recruited to run the facilities.

Objective 3. To exchange know-how and acquire new expertise through twinning with Mentor Labs in EU developed regions.

TransPOT scientists have been active towards twinning with major research centres in Europe. Exchanges of personnel with Mentor Labs assisted these efforts and increased know-how. There has been strong and valuable advanced training of the TransPOT Translational Facility research staff at network institutions namely Geneva Medical School (Switzerland), the University of Zurich (Switzerland), the University of Copenhagen (Denmark), and the National Hellenic Research Foundation (Greece), which were highly successful in transferring skills and knowledge to the UoC, with emphasis on genomics and GMP cord blood and stem cell applications, and in establishing research links that will have long-term impacts. Importantly, these visits have yielded a number of joint publications that would not have been possible without the TransPOT support.

The program has also been successful in achieving valuable training of research personnel (including Professors) through short visits to Mentor laboratories and through attendance of courses organised by TransPOT and international organizations. In total, 10 visits have been performed, including those to: Almac Diagnostics, Belfast, UK to gain expertise in microarray gene expression technologies; Hellenic Cord Blood Bank (HCBB), Academy of Athens, to gain expertise for the accreditation of the “Center for Collection of Cord Blood” (KESOPA) at UoC based on the TransPOT GMP Cell Therapy Unit; and to the mentor laboratory at the Cancer Research Centre of the University of Liverpool, to receive training in genomics applications and to establish research links that have led to joint publications.

Twenty-six (26) scientists from Europe and the USA representing the academic and biotech/pharma sectors were invited to give lectures in modern aspects of biomedicine covering diverse fields, such as inflammatory/autoimmune and malignant diseases, aging, neurological, psychiatric and cardiovascular pathologies, and treatment advances.

Practical skills, such as in-house training in qPCR, bioinformatics, Intellectual Property and manuscript writing and preparation, were also provided and were highly attended. In several instances, the invited speakers gave additional lectures to students of the Medical School Graduate Program “Molecular Basis of Human Diseases”, thereby amplifying the impact of this deliverable to junior scientists. Several research collaborations initiated between TransPOT scientists and invited speakers have already yielded joined publications, projects, submission of research proposals, and exchanges of reagents necessary to improve the research and innovation capacity of TransPOT members.

Objective 4. To develop strategic partnerships with centres of excellence in Europe.

Valuable collaborations with several groups have been established both in Greece and rest of Europe, including: in genomics technologies, the Cancer Research Centre, University of Liverpool and Almac Diagnostics (UK); in genomic analyses, Geneva Medical School, Switzerland; in bioinformatics the University of Copenhagen, Denmark, and in stem cell culture and clinical applications, the National Hellenic Research Foundation (Athens), the Biomedical Research Foundation of the Academy of Athens and the Paul Sabatier University of Toulouse, Etablissement Français du Sang (EFS). These collaborations are expected to have strong long-term impacts on the capacity and quality of UoC and to yield high-impact publications.

Objective 5. To increase the visibility of the Institution by disseminating knowledge in translational medical research at local, regional and international level.

Various activities related to the dissemination and communication of the TransPOT achievements have been executed successfully:
1. The TransPOT webpage (http://transpot.med.uoc.gr/english/) has been running since the beginning of the programme.
2. Three TransPOT e-Newsletters were published. The fourth Newsletter will be circulated to summarise the TransPOT achievements.
3. Several well-attended conferences were co-organised by TransPOT and three symposia took place at the UoC in the fields of Inflammation, Applications of Bioinformatics in Molecular Biology and Endocrine Aspects in Andrology. The latter was endorsed by the European Society of Endocrinology and the European Academy of Andrology; we consider this as a major success towards increasing the visibility of TransPOT and UoC-Med in this research field.
4. Publications in scientific journals are a measure of the quality and success of scientific research. For TransPOT, this dissemination activity comprised an impressive total of 37 published papers to date (with others in preparation). This reveals the extent of collaborations within the UoC and point to the synergistic effect of well-funded scientific groups with different interests coming together under the umbrella of TransPOT. Collaborations have extended to other entities associated with TransPOT, including mentor laboratories and advisory board members. The infrastructure obtained through TransPOT has enormously assisted in the work that led to these publications.
5. Team members presented TransPOT results in major scientific conferences and biotechnology forums.
6. A booklet advertising TransPOT-funded infrastructure and know-how has been generated and has been/is distributed to academic institutions, SMEs and pharmaceutical companies in Greece and rest of Europe.
7. Researchers from the UoC-Med have a broad network of international collaborative linkages, and several employees have visited laboratories abroad as part of the exchange activities of the project. The enthusiasm of the visiting professors who were invited as part of the project to visit UoC is testament to the high esteem in which the UoC is held at the international level. The visiting professorship programme brought more than 26 renowned foreign researchers to give lectures at in various fields of interest.
8. Researchers from the UoC-Med have engaged in valuable outreach activities to the public including talks at schools, public lectures etc.
Potential Impact:
Strategic and Social Impact:

(1) Improving human resources and reversing the ‘brain-drain’: In the convergence region of Crete there has been a concerted effort to create a scientific environment which will foster the ‘renaissance’ of science in Greece, based on merit and scientific excellence. The University of Crete Medical School, together with the near-by Institute for Molecular Biology & Biotechnology (IMBB) of Foundation of Research & Technology Hellas, perform some of the best molecular biology and biomedical research in the country. The pursuit of scientific excellence in UoC is demonstrated by regular publications in prestigious scientific journals, despite the difficulties that scientists face as a result of being geographically located at the periphery of Europe and having scarce national funding. Central to the success of UoC is the ability to attract talented researchers and offer state-of-the-art facilities and modern equipment.

The unanticipated changes in the Greek economy over the last 5 years which took place after the submission of the TransPOT proposal, have hindered the full exploitation of the opportunities offered by REGPOT support to improve human resources by, for example, attracting senior scientists back to the region who could enrich the research capacity of UoC-Med. In fact, there is still a tremendous, on-going exit of skilled scientists from Greece which has also been commented on in multiple occasions by the premier scientific journal Nature (see for example: http://www.nature.com/news/austerity-led-brain-drain-is-killing-greek-science-12813 and http://www.nature.com/nmat/journal/v12/n8/full/nmat3735.html ) and by media in Europe including BBC and Spiegel. The promise by the former General Secretariat of Research & Technology of Greece to earmark approx. € 300 million per year for research for the period 2010-2013 using a reserve of EU structural funds (see Nature news article in: http://www.nature.com/news/2010/100504/full/465022a.html) collapsed under the deepening of economic crisis. The situation has worsened the last 2 years with near- absence of funding and the centralized management of Universities reserve money by the government (http://www.nature.com/news/outcry-over-greek-plan-to-borrow-cash-from-universities-1.17416 ). Of relevance, the budget provided to the UoC by the government for the academic year 2015-2016 amounts to 3,5 million euro to cover all running expenses, educational and research activities of the entire University; the successive cuts in UoC central funding now amount to a 70% reduction compared to 2009.

Under this extremely adverse climate, the opportunity to recruit senior and experienced scientists and improve infrastructure through TransPOT had a profound effect on maintaining the research capacity of UoC-Med, evident by the significant number of publications and announcements in international conferences during the last 4 years. Of note, we have been able to appoint 2 senior researchers from the US for whom tenure positions have been offered by the UoC. We would like to highlight the fact that to our knowledge, this has not been possible with other ongoing REGPOT-funded programmes in Greece and we thus consider it as a major success, representing the outcome of intensive efforts of the TransPOT steering committee. In addition, the recruitment of experienced researchers (post-doctoral level) and technicians, translated into increased productivity and contributed to holding back the ‘brain-drain’ from Greece, at a time when unprecedented numbers of qualified young scientists are leaving the country in order to find work elsewhere. We have advocated that investment in research & technology is a key factor to exit from the economic crisis.

(2) Improving research potential and healthcare capacity through state-of-the-art infrastructure: The acquired TransPOT infrastructure has strategically been placed to assist a wide spectrum of biomedical research activities, including target gene identification, pre-clinical testing, drug discovery, development and application of cell-based therapies, biobanking, concept discovery and modelling (reverse translation) in various diseases, which contributes to bringing the Institution at the forefront of translational medical research.
The establishment of core facilities and infrastructure coupled with the recruitment of key investigators have improved the regional research potential and will enable the Institution to increase its competitiveness at the European level by participating in or leading research projects under Horizon 2020 in various disease areas. The TransPOT facility will evolve to a Translational Medical Research Facility, which will develop opportunities for collaborative studies with the European biotechnology sector and pharmaceutical industry in molecular diagnosis and translational research. There is already interest from 2 SMEs in using these facilities.

A strong user orientation in the offered services is a major goal of TransPOT as it will assist its sustainability. Thus, the TransPOT infrastructure has been strategically planned to enhance interactions of the Program with a number of clinics (cardiology, orthopaedics, vascular surgery, haematology etc.) in the University Hospital of Heraklion as well as other private or public hospitals in Greece which require high quality genomic / post-genomics services or mesenchymal stem cells appropriate for therapeutic application. The Good Manufacturing Practices (GMP) Cell Therapy Laboratory has also been instrumental to the establishment of a regional public Cord Blood Bank (CBB) for allogenic transplantations in the UoC Medical School under the auspices of the University Hospital of Heraklion and the Greek Ministry of Health. CBB supports all GMP cell processing, quality testing and cryopreservation stages of cord blood units (CBUs) and related hemopoietic stem cells. In partnership with the other two public CBBs of Greece, it can actively contribute to the treatment and therapy of patients with hematological malignancies across Europe. CBUs that do not meet the criteria for clinical use are processed for stem cell research purposes.
The TransPOT infrastructure may also provide expert diagnostic services to the local private and public health sector. Among the team’s expertise are diseases such as Familial Mediterranean Fever (FMF), an orphan disease endemic in Crete, and chronic idiopathic neutropenia (CIN), a hematologic disorder seen with high frequency in the south of Greece. Therefore, the TransPOT infrastructure may directly impact on the quality of healthcare in the region of Crete.

The TransPOT infrastructure therefore benefited the region at multiple levels by: (a) improving translational research capacity; (b) increasing the number and improving the training of scientists at all career levels; (c) improving the quality of healthcare; (d) enhancing interactions with the pharmaceutical industry and biotechnology sector.

(3) Impact on training and education: A major bottleneck identified by the European technology platform IMI (Innovative Medicine Initiative) in the area of translational research is training and education. The UoC Medical School takes pride in its intensive post-graduate programs which integrate basic and clinical sciences and give major emphasis on translational research training. These post-graduate programs recruit some of the best graduates in Biology & Medicine in the country and offer advanced instruction in biomedical sciences. It is the aim of these Programs to create a new generation of outstanding scientists who can further promote excellence in research and education in Greece.
Along with TransPOT personnel, the post-graduate students have directly been benefited from the TransPOT activities through admission to practical training courses (intellectual property, qPCR, bioinformatics) and lectures given by invited speakers in forefront research subjects.

(4) Impact on Networking: As a result of its geographical location, research in the converging region of Crete struggles with the potential problem of isolation. TransPOT facilitated strategic partnerships with other research groups within the EU through exchange visits and collaborative projects and joint organisation of conferences or meetings which, coupled with the enrichment of infrastructure, had a significant impact on the development of the research potential of the institution by:
(a) Exposing the UoC-Med scientific community at all levels (faculty, senior and junior scientists) to the most recent advances in biomedicine and state-of-the-art technological breakthroughs thereby enriching their research and innovation capacity.
(b) Enhancing networking. As an indication, a number of research collaborations has been initiated between TransPOT scientists and invited speakers which have already impacted on the quality of the research output of the institution. These include joined publications, projects, submission of research proposals and/or exchange of reagents necessary to improve the research and innovation capacity of TransPOT members. These partnerships have thus significant impact on facilitating the integration of both the research team and UoC in the wider European research community thus supporting the harmonisation of scientific knowledge across Europe.
(c) Contributing to the long term research potential by training scientists at all levels in both advanced scientific concepts and practical skills. The latter included IPR training (the first ever of its kind in UoC-Med), manuscript preparation (provided by the Nature Immunology senior editor), a 2-day real time PCR course and a 1-day hands-on bioinformatics course. Visits to expert laboratories have brought in the institution important new technological knowledge in key areas of biomedical importance, especially genomics applications.
(d) Disseminating the most recent results of the research entity and increasing visibility and recognition of our research and technological capacity to the National and international scientific community.

Scientific Impact:
The recruitment of experienced researchers to UoC Medical School through REGPOT support increase the research potential and strengthen the technological capacity of the Institution. In particular, TransPOT supported projects on (a) experimental cardiology; (b) infectious diseases; (c) Inflammatory and autoimmune pathologies; (d) Malignant diseases; (f) Neurodegeneration; (g) Metabolic diseases; and (h) Stem cell biology and therapy. The distribution of these posts reflects the Program’s commitment to sustainable scientific excellence and competitiveness in forefront research areas funded by Horizon 2020.

Testimony to the impact that TransPOT has made on the research capacity of the institution is the large number of publications (>37), including in the prestigious journals PNAS and Cell Host & Microbe, presentations in conferences and awards by TransPOT personnel. TransPOT has been successful in bringing together clinicians and basic scientists by supporting joined research endeavours and building a solid base for future efforts for funding. We believe this is a major achievement that will have a long term scientific impact on the institution.

Spreading excellence, exploiting results, disseminating knowledge:
TransPOT have worked towards improving the perception and understanding of science and research by the public. TransPOT faculty and experienced scientists participated in tutorials in local schools and planned visits of pupils from local schools to the UoC-Med labs as well as in seminars for the general public to disseminate the knowledge about the importance and benefits of Cord Blood donation and advocate the REGPOT-funded infrastructure available at UoC-Med.

As part of the disseminating activities, the TransPOT web page distributed information to both the scientific community and the public at large. The available infrastructure has been advertised to increase access by the broader scientific community of Europe and associated countries. Additionally, TransPOT organised workshops and conferences on the island of Crete to facilitate knowledge transfer and develop new interplay between scientists and clinicians working on differing aspects of human disease. These workshops have also played an important role in promoting the region as a focus for translational research to the scientific community as a whole.

In summary, the scientific, strategic and social impact of TransPOT extended beyond UoC and brought health, social, educational and economic benefits to the region.

List of Websites:
http://transpot.med.uoc.gr