Project group

The Concept
Germany and Slovenia have been cooperating in molecular life sciences since many years within the frame of several research activities, including the ERASYSBIO and PathoGenoMiks ERA NETs. The announcement of the "Industrially Relevant Molecular Life Sciences"(lNREMOS) framework in 2005 resulted from the effort to strengthen the transfer of technology and to encourage spin-off companies in this field of biotechnology. The selection of the project on "Systems Biology Tools development for Cell Therapy and Drug Development"- SYSTHER - as a Slovenian-German Virtual Research Institute was also aimed to foster translational research in cancer with the strong emphasis on new aspect in therapy - personalised medicine. Such aspect can only be approached by the new tools provided by systems biology and bioinformatics. The Project has joined several research and clinical groups in Germany and in Slovenia. The project was financed by the Slovenian Ministry of Higher Education, Science and Technology and the German Ministry for Education and Research.

The Structure
Duration: 5 years (2006-2011)
Total finances: 5.6 mio EUR; Slovenia: 1.6 mio EUR and Germany: 4 mio EUR (25% co-financing by partners)
Institutions: Slovenia: 2 Public research institutes, 2 Public health institutions, 1 New private company                                                             
Germany: 2 Universities, 1 Public health institution, 1 Private company

The Key Players
The coordination and management was divided between two coordinators: Prof. Joachim Selbig and Assist. Prof. Miomir Knežević.

In Slovenia the lead partner was National Institute of Biology with the two strong teams in the field of cancer biology and systems biology, lead by Prof. Tamara Lah Turnšek (with Dr. Helena Motaln) and Prof. Maja Ravnikar (with Prof. Kristina Gruden), respectively, who also cooperated with the team of Prof. Nada Lavrač at Josef Stefan Institute. The link between stem cell research and clinical application in Slovenia was established via Profs. Matjaž Jeras and Primož Rožman from the Blood Transfusion Centre and clinicians from University Medical Centre in Ljubljana.

In Germany, the coordinator Prof. Selbig (with Dr. Kathrin Juerchott) from University of Potsdam (Max Planck Institute for Plant Physiology, Potsdam-Golm), provided strong expertise in systems biology, matched by Michal Or-Guil at the Humboldt University in Berlin. The cancer research and clinics were lead by Prof. Joerg Tonn and Dr. Christian Schichor from Grosshadern Clinic of Ludwig Maximillian University in Munich. The bidirectional technology transfer was supported by Dr. Johannes Schuchhardt in Germany (Microdiscovery GmbH) and in Slovenia, the new biotech company BioSistemika was established by young entrepreneur and researcher Klemen Zupančič and partners (http://www.biosistemika.com). This spin-out company of NIB represents the transfer of knowledge from research into application.

The content is available on: http://www.svsther.eu and http://svsther.biologie.hu-berlin.del

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The Task of the Virtual Institute
was to prove the validity of systems biology-approach, using bioinformatics and mathematical

(I) Define cancer cell and normal mesenchymal stem cells (MSC) interactions at the transcriptomic, proteomic and metabolomic ("omics") levels and the integration of thee data
using system biology approach.

(II) Design of new experimental approaches and protocols for the improvement of cancer
diagnosis by following the pattern of blood markers, focusing on immune related potential,
starting with:
- Normal framework of omics data & data analyses using novel mathematical modelling tools on healthy volunteers.
- Data acquisition and management tools for complex data, related to diagnosis, prediction
and therapeutic application in cancer.

(III) Establish the biotechnology company for exploiting the research results.


The Achievements
(I) Despite modern treatment concepts, prognosis of patients harbouring a brain tumour is still dismal. Stem cell therapy could only be based on improved knowledge of differentially gene expression and protein signalling pathways in normal bone marrow derived stem cells, which are recruited by the tumour. In the SYSTHER project, we proved that newly developed bioinformatics' tools could well explain the observed phenotype of cellular interactions, resulting in significant effects of normal mesenchymal stem cells (MSC) to impair the proliferation and invasion of brain tumour - glioblastoma cell (U87MG) in vitro. By metabolomics, we proved that these two cell lines do, and how they significantly differ in their metabolism. We also pointed on relatively higher genetic stability of normal MSC than previously thought, as we were the first to prove that the spontaneous malignant transformation of normal MSC in vitro was due to the contamination with tumour cells. This data provide the needed molecular basis for future use of the stem cells alone and/or as vectors for cell therapy of glioblastoma and other tumours. Also, the amount and type of recruited stem cells in the tumour can be used as a diagnostic tool, and to estimate prognosis in adjuvant treatment plans.

(II) To assess the clinical significance of SYSTHER findings, translational studies were aimed to investigate whether there is a response to malignancy in the blood of tumour patients that could be used for diagnostic purposes. We are testing an interesting concept that also brain tumours - GBMs - leave a fingerprint in the blood-borne antibody repertoire, although they rarely metastasise. However, to establish base line levels, we finished the first clinical studies in healthy individuals, focusing on serum metabolites, peptide-antibody profiles and miRNA, as well as and on the tanscriptome profiles of white blood cells. The investigation of the impact of a single dose of dexamethasone, a part of standard therapy for glioblastoma patients, and other treatments is still in progress, leading to possible predictions of therapy response. Here we expect significant variations among patients, as were found in healthy individuals, so each patient would respond differently. All this data justify the personalised medical treatment, based on gathering sufficient molecular information, clustered and sorted by systems biology tools, to choose the most efficient and least harmful treatment.

(III) The final results of in vitro analyses and translational studies of SYSTHER will be validated for their potential to be translated into clinical practice and management of tumour patients. New systems biology based approaches applied in our biological systems can easily be transferred to study other pathological conditions. The dissemination and commercialization of the knowledge and expertise will be achieved by newly established biotech company BioSistemika, acting alone and in cooperation with other SYSTHER partners worldwide.


Significance

SCIENCE Systher team published over 30 original articles, and 10 more are expected in the near future based on joint research. At least ten of them appeared in the journals with highest impact in the field. Many lectures and seminars were given, all over the world, increasing the visibility of the novel findings.

PATIENTS Anti-malignant cancer effects of normal adult – mesenchymal stem cells promise that the cell therapy as a part of advanced therapies, will be a realistic option for adjuvant treatment in resistant tumours.

HEALTH CARE SYSTEM Personalized medicine - multiple molecular testing of patients, by the systems biology tools will rescue from harmful side effects and high costs of unnecessary treatments, and on the other hand justify the expenses for the most efficient patient-tailored therapy.

BUSINESS SECTOR New services, provided by systems biology application, assisting complex diagnosis, prognosis and prediction of tumour therapy response will become more easily available for numerous customers. Personalized molecular networks will be used to structure an individual portfolio for specific treatment of cancer patients.

 

Research work

One of the research work areas within SYSTHER is the research of gene expression (transcriptome) in individual types of lymphocytes  isolated from healthy volunteers. This data are presenting a foundation for the clinical trial (cancer treatment). Additionally, transcriptome is being studied in human mesenchymal stem cells (Figure 4), in senescent mesenchymal stem cells and transformed mesenchymal stem cells  isolated from bone marrow of healthy volunteers. This will enable us to characterize individual cell lines of stem cells and their applicability for use in therapy.

Gene expression of all known genes in human genome can be followed with DNA-microarrays. Large amount of gathered data needs to be inspected, normalized and quality checked.

Only after these steps the data can be analysed in such a way that biological questions of hMSC quality and genome stability can be addressed. Resolving those issues shall provide us with the standards of safe use of human mesenchymal stem cells in cell-based therapies for treating diseases like cancer that cannot be cured efficiently with conventional medicine. One of the tools that helps us visualize the experimental data and connect them with already known biological knowledge is Biomine.