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Translating basic research findings in major human diseases

Final Report Summary - TRANSMED (Translating basic research findings in major human diseases)

Executive Summary:
TransMed, a project funded by EU, involves a multidisciplinary team of investigators who took advantage of the Regpot FP7 activity and joined efforts to support development of a center of excellence for high-quality translational science in the area of Attica. Thus, TransMed supported the establishment of the scientific foundation for a strong preclinical translational research activity in the Biomedical Research Foundation of the Academy of Athens (BRFAA).
The expertise of the team span a wide area including neuroscience, cell biology, imaging analysis, physiology, pharmacology, proteomics, genetics, bioinformatics and systems biology. The involve scientists had proven that have the commitment, training, expertise and experience to conduct successful research in neurodegenerative and metabolic/inflammatory disease areas. Hence, it was critical to develop in these directions in order to fully integrate the already available tools and expertise of the group and generate a center of excellence in translational research in metabolic and brain-related pathologies. As per the requirements of the program the specific actions taken for the implementation of the project include:
Strengthening of the human potential by recruitment of expert scientists that increased the current work force of the groups. Emphasis was given in repatriation and we have succesfully reversed the brain drain via the hired scientists
Upgrade of the infrastructure by acquisition of new equipment that led to the development of several new core facilities for preclinical translational studies at BRFAA

Promotion of the transfer of knowledge by establishment of strategic partnerships not only with European colleagues from collaborating centers of excellence but from other international institutes organisation of two way exchanges (twinning) between BRFAA and European centers - introduction of translational research approaches to investigators of the region by conferences, workshops, seminars.
Establishment of alliances with industrial partners eventually needed to exploit research discoveries and organisation of Open House events with industry representatives or the general public.
The benefits of TransMed are bidirectional. The TranSMed team has been strengthened by integrative approaches to crucial questions relevant to major human diseases with high prevalence in EU countries that facilitated the integration of the region within the main directions of ERA. On the other side, our actions outlasted the scope of TransMed and established excellent quality of training for early and late stage scientists, while promoting ties with other European academic centers, industrial outputs and the general public.
Although TransMed concluded its funding period, the group has put in place a plan and continues its activities not only via the focused research in neurodegeneration and obesity but also, via targeted actions to integrate all similar activities in the area of Attica. These activities are of potentially high-impact in the economic development of the area by providing a fertile ground for attracting money from the public and private sectors. This can support the R&D, innovation and entrepreneurship, all absolutely necessary for further development at a regional and national level. Given the success of TransMed in achieving its goals under the unique financial and social crisis we are optimistic we will be able to continue the expansion of our center of excellence in relevant areas. The latter will be further supported by the integration of all similar activities in Attica, its development to a major node for preclinical translational research for major diseases of our times.

Project Context and Objectives:
The main goal of TransMed was to support an interdisciplinary group of investigators, faculty in a recently established Institute in Greece, the Biomedical Research Foundation of the Academy of Athens (BRFAA), to build a Center of Excellence in preclinical translational research. These investigators, all trained in Institutes ranked in the top positions worldwide, and with prior faculty appointments in Europe and/or USA, have joined the newly established (early 2000) BRFAA to provide their expertise and experience in different, although complementary, scientific fields. Their acceptance of the job offered at the BRFAA, provides an excellent example of reversal of brain-drain from established scientists that have the training, the scientific knowledge and the professional experience to support the “jump start” of a new academic facility in a developing country. Along these lines TransMed, funded under the FP7 Regpot activity, provided the financial support towards achieving a major goal, the development of a center of excellence for preclinical, translational research. As we described in the original proposal, despite the excellence of the faculty and the significant existing infrastructure, progress towards the development of a center for translational research at BRFAA was hindered by the following factors:

The lack of in vivo imaging facilities to follow disease development and therapeutic efficacy of pharmacological interventions
The lack of dedicated animal behaviour facilities to study cognitive and motor tasks in the animal models used
The lack of appropriate electrophysiology tools to move beyond individual synaptic function, to more widespread wiring parameters and neuronal networks
The lack of tools to conclusively characterise the metabolic profile over time and its association to disease development following genetic and /or pharmacologic interventions.
The lack of molecular mapping of animal tissue (e.g. brain) and localisation and special arrangement of drug and/or biomarker (e.g. proteins/peptides)
The lack of proper data analysis of biological read-outs and its integration in modelled systems to facilitate therapeutic interventions via identification of specific biomarkers and major pathways involved.

TransMed aimed to bypass the inherent difficulties to “correct” the above deficiencies due to the limited financial resources (at the time the proposal was submitted the financial crisis had started in Greece resulting in drastic cuts in available national funds for research). Taking advantage of the scientific excellence of the repatriated scientists/ faculty at BRFAA and the Regpot activity of FP7, proposed to establish the foundation for the development of a self-sustained center for preclinical translational research in the neurodegenerative and metabolic/inflammatory disease areas.

The main objectives of TransMed, as dictated by the frame of Regpot and the specific aims of the project were to:
Develop the required infrastructure to achieve the scientific goals.
Hire scientist, experts in the areas to be developed and capable to set up and achieve the full potential of the newly developed infrastructure for the needs of the team and the wider scientific community.
Provide training for junior scientists and students in preclinical translational research and thus, guarantee the sustainability of expertise and continuous development of the center
Liaise with established centers of excellence in Europe and through collaborative projects and training schemes achieve the full potential of the proposed actions
Disseminate its activities not only in the scientific community but also in the industry and the general public, as it is clear that translational research to be successfully implemented requires a consensus between all involved parties.

Project Results:
The specific actions taken by TransMed are dictated by the scope of Regpot activities and addressed one-by-one the objectives described above. The results and foregrounds of TransMed, the first organized effort for preclinical translational research in neurodegeneration and obesity/metabolic diseases in Greece, as per the order of the objectives of the program are:

Upgrade of the infrastructure by acquisition of new equipment
i. We have developed the units for mouse behavioural function and metabolism assessment
ii. In addition we have expanded the capabilities of the cardiovascular function unit already existing at BRFAA. All these together provide a well-equipped mouse physiology core facility that can support research and discovery but also can provide the services necessary for the move of newly developed compounds to the clinic. Furthermore, they can be used for new uses of already established drugs, a faster, beneficial to the patients and rewarding activity. The details on the equipment acquired and its functional potential is shown in attached files.
iii. Imaging
iv. Neuroscience-related (stereology/ electrophysiology/ et al)
v. Biomarker identification, including proteomics and mass spectrometry equipment
vi. Set-up for modelling of biological systems based on large data files

Strengthening of the human potential by recruitment of expert scientists to increase the current work force of the groups (emphasis will be given in repatriation).
Thus, we have hired experts in behaviour, electrophysiology, metabolism and regulation of adiposity, cardiovascular physiology and pathophysiology, image processing and analysis, systems biology/medicine). They were all in charge of set up the new equipment, explore the potential applications and understand how the needs of the projects could be best addressed using this new technology, train students and other researchers and run some of he projects establishing new collaborations and areas of investigation. Core facilities have been developed for behavioural, metabolism and electrophysiology studies, our hired experts are The outcome of their work is reflected in the progress of their projects (as shown in the detailed report of dissemination activities below) and their career development: four were offered research associate positions - 3 of them at BRFAA and 1 in the biotechnology department in the University in Athens (unfortunately during this period due to the crisis there is freeze in tenure track faculty hiring and there are no openings in the universities and academic institutions) and 1 in the private sector, an international data analysis company. Interestingly, no one chose to leave the country despite very challenging offers abroad. This has been so far a major success of the program in addressing one of the primary goal of Regpot activities, the strengthening of the scientific human force in a developing country and the reverse of the brain drain.

Promote transfer of knowledge
i.We established strategic partnerships with European scientists from centers of excellence in the areas of obesity and neurodegeneration. More specifically, we interacted with scientists from all the associated institutes from developed countries through the proposed twinning activities between BRFAA and the European sites of reference.
* Long standing collaborations with University of Lund and Dresden Meical School, have been very successful so far in terms of establishment of common scientific projects and bidirectional training and other disseminating activities
* Interaction with TUM has been critical in supporting the development of imaging at BRFAA to an excellent facility that supports the “high” demands of approximately 150 faculty, students and postdoctoral and other associated scientists.
Our interaction with the Edinburgh Medical School has been instrumental for the behavioural/electrophysiology aspects of the project and for the aspects of TransMed involving the impact of the stress response in disease development. The latter is an area of emerging significance for a spectrum of diseases developed in adult life although stemming from earlier life events and represents a major area of investigation in the efforts to understand metabolic disturbances leading to obesity and neurodegenerative processes. In view of HORIZON 2020 our teams aim to join efforts in common proposals.

ii.We introduced translational research approaches and tools, while discussing the challenges of these approaches, to investigators of the region by targeted workshops and a series of seminars

Synergize existing research efforts,across the basic research laboratories to enhance translational research capacities in obesity, metabolic syndrome and neurodegeneration at the regional and national level.
* The infrastructures developed at the BRFAA have been already used by investigators other than those of the TransMed team. These include the group of Dr Capetanaki working on cardiovascular research and heart failure, Dr Georgopoulos working on Alzheimer’ disease and Dr Xanthou on allergic inflammation. It is very rewarding we were able to provide the means for development of new scientific targets and vey encouraging for the sustainability of the Center and the outcome of new proposals and collaborations.

We promoted alliances with industrial partners and we organized an Open House event, for further interaction between researchers, local regulatory agencies and industry representatives. To date the outcome of these actions include collaboration with Marine Polymers Inc, Burlington, MA and BiogenIdec, Cambridge, MA, while we are in the process of discussing on collaborative projects with Novartis and Sanofi in Athens, greece and Bionian, a cluster of start-ups, small and larger companies recently co-funded by Greek government and EU funds.

We supported the development of fields necessary for solidification of preclinical Translational research, such as formation of patient data bases (for Parkinson’s disease and patients with non-alcoholic fatty liver disease), bioinformatics and systems biology, image analysis, development of small molecules and others.

Potential Impact:
TransMed has a significant impact in several ways since it has funded a major part of the equipment necessary for the establishment of a distinct preclinical translational research core at BRFAA and the recruitment of early stage researchers to set-up this equipment and make the center functional, whereas it has supported a steady interaction between BRFAA researchers and colleagues from developed EU and other international Centers of excellence and it provided all that is required for the organization of workshops, conferences, seminars and other dissemination events.
The above actions as a whole would be of great importance for any scientific institute around the world with implications we will discuss below. In the particular time TransMed was funded its positive impact was multiplied by several factors given the very serious economical and social crisis in Greece.

A major important outcome of TransMed with immediate socio-economic impact, include support of scientific development of researchers at BRFAA and their teams, support of companies selling/servicing biomedical equipment and creation of new job positions. The wider and long term implications address a variety of areas and groups with interconnected interests. The development of new core facilities provided the basis for new research studies that increased the visibility of BRFAA researchers in the scientific community and their participation in new collaborative research efforts. The above brought funds that supported graduate students and additional early stage researchers to advance their careers, at at time a significant number of their colleagues considered to quit research due to lack of funding. Along these lines TransMed provided perspectives for sustainability in the efforts of early stage researchers, a major effect beyond strict financial benefits. We estimate that the number of new positions we offered due to the activities supported by TransMed are in the range of 12-15, excluding the hired scientists/experts directly supported by TransMed. The implications of this action will be fully revealed in several years that, provided the sustainability of the center of excellence we developed, we will have a group of fully trained scientists in new (not previously supported by BRFAA) areas of research with state-of-the art technical support. In conjunction with the above we plan to establish additinal interdisciplinary training programs in collaborations with University departments, similar to the Bioinformatics program of the UoA in collaboration with BRFAA and other Research Institutes directed by Dr Manolakos. As we have discussed several times in this report TransMed has successfully achieved the aim to reverse the brain drain, substantiated by the repatriation of hired expert scientists. Most importantly, all of the hired experts continue with their careers in Greece, in the area of Attica.

The establishment of steady collaborations with centers of excellence outside of the geographical area of Greece has driven the significant expansion of our projects and of successful applications for funding by national and international agencies. This creates new job positions but, furthermore, allows for development of new infrastructures with profound impact for the area. A promising sign for further development, hopefully via application and support for creation of a spin-off company, is our collaboration with the industry, such as international companies such as Biogen Idec, Regeneron and Marine Polymers. We have the “ambitious” plan to expand these activities and be able to provide a central facility for preclinical translational services for testing new compounds, that provides also possibilities for additional research studies for new targets identification. Along these lines, following our final open event addressing the industry representatives in Attica, we have started discussions for new collaborative projects with industrial partners. Successful implementation of these plans will have impact on all the above discussed areas and will provide a path for financial sustainability of our center.

Another positive outcome of TransMed with unique socio-economic impact for Greece is the support of a unit for testing generic drugs’ bioavailability and efficacy. As per the recent legislation, genomics will replace to a great extent the currently marketed pharmaceuticals in Greece and BRFAA will be the national center for evaluation of efficacy of these compounds, helped partially by infrastructure developed under TransMed. Apparently, this infrastructure may support necessity of additional animal or cell studies on a compound-based need. Direct, local and wider, national and possibly international, for the greater geographical area, implications are linked to this activity.

The range of seminars, workshop and conference organization activities supported by TransMed had a dual effect, i.e. increasing the exposure of our scientists, policy makers and industrial community to state-of-the art presentations and training in their respective fields. Furthermore, they have benefited the specific patient groups, such as those with Parkinson’s disease, as evidenced by recent studies revealed the specific genetic causes of disease in the Greek population. The open event for the public was very rewarding and greatly enjoyed by both scientists and the public. It involved demonstration of infrastructures and the potential of the research taking place at BRFAA and several targeted presentations on neurodegeneration and obesity. It also involved discussion on obesity with major focus on healthy nutrition, the greek products with beneficial effect on energy consumption and support of health with positive effects on healthy aging. Special demonstration for children of early ages was also organized together with discussion with older citizens on early signs of neurodegeneration and life style adjustments to accommodate these effects of aging.

Overall, we believe that TransMed had major socio-economic impact and demonstrable societal implications. We hope the center of excellence supported by transMed will manage not only to keep up with its activities but, furthermore, to expand and address additional areas of preclinical translational research. We aim to build capacities for common projects with industrial partners and we have proposed a plan to the local regulatory bodies for close interaction between the Regpot supported new facilities of Attica to achieve the maximum of the added value of this EU activity. Hopefully, this will provide the basis for additional EU originated and industrial support for a sustainable and productive center of Excellence in preclinical translational research, that will take advantage of the expertise and experience of our faculty to provide training, and an active node for research and development in the biomedical field, in the area of Attica.

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