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You are here: ICE-HT > About > RA3: Biosciences / Biotechnology
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RA3: Biosciences / Biotechnology

The RA źBiosciences/Biotechnology╗ aims at providing the framework for the integration of physical sciences and engineering with life sciences. In the post-genomic era, which is characterized by the revolution of nanotechnology, systems biology and microelectronics, FORTH/ICE-HT has the expertise in nanotechnology and materials science, analytical and physical chemistry, surface chemistry and characterization, fermentation technology, metabolic engineering, quantitative systems biology and biotechnology and complex systems analysis and engineering, to pursue projects for: (a) analytical technology development and advancement for the accurate, systemic and systematic analysis and design of biological systems and processes, (b) development of computational tools for the analysis and characterization of biological systems and processes, (c) development of novel materials, which could be used in the context of aim (a) or constitute part of microdevices for nanobiotechnology applications. The current expertise of FORTH/ICE-HT with existing and pursued collaborations with the schools of Natural Sciences, Health Sciences and Engineering of the adjacent University of Patras, the National University of Athens and the other relevant Institutes of FORTH in Crete and Ioannina expand the pursued applications in diverse areas, such as biotechnology and metabolic engineering, bioprocess development, strain selection, disease prognosis and diagnosis, medical therapies, bio-energy and bio-environment applications. FORTH/ICE-HT was the first and presently among very few research Institutes in Greece that hosts in the same institutional body and facilities state-of-the-art research in both nanotechnology and life sciences/biotechnology. This combination provides the basis for the training of the new generation of researchers that can work, interact and produce in a highly-interdisciplinary environment at the interface of traditionally "distant" disciplines.

Specifically, the activities of RA3 źBiosciences/Biotechnology╗ may be divided in three main application - oriented areas of research, spanning all colors of biotechnology:
(a) industrial biotechnology/bioengineering & synthetic biology,
(b) environmental biotechnology/bioengineering (in conjunction with RA2)
(c) biomedical research, including the investigation of toxicity effects of novel nanomaterials

In the context of these applications, the research groups of FORTH/ICE-HT, who are active in this RA and at its interface with the other two RAs of the Institute, produce new knowledge and expertise in the following scientific subjects: (a) development of novel technologies and methodologies of biomolecular analysis, with emphasis in high-throughput approaches; FORTH/ICE-HT is a pioneer in Greece and South-Eastern Europe in research in mass spectrometry metabolomics and the high-throughput analysis of metabolic networks, (b) analysis, simulation and mathematical modeling of biological processes, systems and networks, (c) metabolic/biochemical engineering and systems & synthetic biology, which comprise the integrated application of novel, mainly high-throughput (omic) methodologies for biomolecular analysis and the development of novel informatics and computational tools for biological network analysis for the comprehensive study and optimization of biological systems and (d) nanobiotechnology, in conjunction with RA1:Nanotechnology/Advanced Materials, having also included recently the toxicological risk assessment of new materials for human health and safety (see following schematic representation).

Figure1

In this context, there has been extensive activity in the following areas:
Metabolic Engineering and Quantitative Systems/Synthetic Biology

  • Development and application of methodologies for the analysis of metabolic network activity, with emphasis in metabolomics and metabolic flux analysis
  • Integrated analysis of cellular physiology dynamics through the combination of high-throughput biomolecular -omic- data from various levels of cellular function
  • Development of informatics and computational tools for the reconstruction, analysis and mathematical modeling of biological networks

Development of high accuracy and sensitivity analytical methods for DNA, RNA, proteins, small molecules
Development of nanoparticle-based biosensors for molecular diagnosis (in conjunction with RA1: ═anotechnology / Advanced ╠aterials)
Development of targeted-multifunctional nanotechnologies(nanoliposomes, or hybrid polymer/lipid systems) for theragnostic applications (in conjunction with RA1: ═anotechnology / Advanced ╠aterials)
Development, characterization and toxicological assessment of new histocompatible biomaterials (in conjunction with RA1: ═anotechnology / Advanced ╠aterials)
Non-destructive characterization of biogenic materials and drug polymorphs (in conjunction with RA1: ═anotechnology / Advanced ╠aterials)
Analysis of the mechanisms of biological mineralization (in conjunction with RA1: ═anotechnology / Advanced ╠aterials)
Development of non-invasive spectroscopic methods for in-time diagnosis of ophthalmic diseases & pharmacokinetics analysis
Assessment of toxicity and potential negative effects on health for novel nanomaterials (in conjunction with RA1: ═anotechnology / Advanced ╠aterials).
Mathematical modelling of brain activity
Mathematical modelling of tumour growth
Development of efficient bioprocesses for the production of biopolymers and biofuels from organic wastes and biomass (in conjunction with RA2: Energy/Environment)
Integrated experimental and computational study of biodegradation of organic pollutants in soil (in conjunction with RA2: Energy/Environment)
Each of these activities is described below:

Metabolic Engineering and Quantitative Systems/Synthetic Biology

  • Development and application of methodologies for the analysis of metabolic network activity, with emphasis in metabolomics and metabolic flux analysis Figure2
    Metabolism being a significant part of cellular physiology, obtaining an accurate and extensive metabolic network activity map under any physiological conditions is of great importance for understanding cellular regulation and dynamics. The modern high-throughput biomolecular analyses fluxomics and metabolomics provide fingerprints of the cellular metabolic state, with metabolomics having been characterized as the "apogee" of genomic analyses. The Metabolic Engineering and Systems Biology Laboratory at FORTH/ICE-HT was the pioneer in South-Eastern Europe to establish research in metabolomics in the context of quantitative systems biology and metabolic engineering/synthetic biology and has extensive expertise in mass spectrometry (especially hyphenated with gas chromatography) metabolomics. Its research collaboration with Bayer HealthCare, USA was the first investigating and demonstrating the usefulness of metabolomics in industrial cell culture engineering.
  • Integrated analysis of cellular physiology dynamics through the combination of high-throughput biomolecular -omic- data from various levels of cellular function
    Figure3It is becoming increasingly clear that a comprehensive analysis of biological systems requires the integration of all molecular fingerprints of cellular function: genome sequence, transcriptional, proteomic, and metabolic profiles and flux distributions. It is the combined study of all of these molecular profiles for a systematically perturbed cellular system that can provide insight about the function of unknown genes, the relationship between gene and metabolic regulation and even the reconstruction of the gene regulation network. To-date, the number of integrated analyses is rather limited as it requires the standardization of omic methodologies at each molecular level, the educated selection of physiological conditions and samplings, along with integrated databases and computational tools, which could infer the cause-effect relationship between the various profiles. The Metabolic Engineering and Systems Biology Laboratory at FORTH/ICE-HT was among the first in Greece to establish research in integrated omic analyses enhancing both the analytical and computational systems biology toolbox in the context of applications in all colours of biotechnology.
  • Development of informatics and computational tools for the reconstruction, analysis and mathematical modeling of biological networks
    The accurate reconstruction of the structure and regulation of the biomolecular networks at all levels of cellular function individually and in combination is among the major challenges of the post-genomic era. Network Biology & Medicine are Figure4revolutionizing functional genomics, systems biology and biotechnology, drug design and development and biomedical research. Relevant research at FORTH/ICE-HT focuses mainly on the metabolic and protein interaction network reconstruction, analysis and optimization, including the reconstruction of the metabolic network of the brain, of bacteria of industrial interest and of mammalian cell lines based on omic data and relevant literature, and contribution to the development of a metadatabase for the experimentally-supported human protein interactome.
Development of high accuracy and sensitivity analytical methods for DNA, RNA, proteins, small molecules
Microfabricated analytical systems enable parallel sample processing, reduced analysis-times, low consumption of sample and reagents, portability, integration of various analytical procedures and automation. In this area, our achievements are summarized as follows:
  • Development of microfluidic devices (chips) that enable reverse transcription andFigure5 polymerase chain reaction of DNA with cycle number selection;
  • Coupling of the DNA/RNA amplification chip with a laser-induced fluorescence detection system for rapid and automatable analysis of amplification products;
  • Development of microfluidic devices that enable capillary electrophoresis of DNA coupled with laser-induced fluorescence detection;
  • Development of an integrated microarray system that couples a microarray spotter with a 3-laser confocal fluorometric scanner for the construction and 'reading' of microarrays in the same instrument;
  • Development multiplex quantitative competitive polymerase chain reaction performed on spectrally encoded microspheres.

Development of nanoparticle-based biosensors for molecular diagnosis
Figure6This research activity exploits the unique optical properties of nanoparticles for the development of high sensitivity dipstick-type biosensors that allow simple visual detection of DNA sequences and polymorphisms without the use of specialized and costly instrumentation (in conjunction with RA1: ═anotechnology / Advanced ╠aterials)

Development of targeted-multifunctional nanotechnologies (nanoliposomes, or hybrid polymer/lipid systems) for theragnostic applications
Such nanotechnologies may be used to target specific cells (as cancer cells) or Figure7pathologies (as amyloid deposits in Alzheimer's disease) and/or alter associated drug pharmacokinetics by overcoming biological barriers (as the blood-brain barrier). Several administration routes are being considered as i.v, i.p., ocular, pulmonary and vaginal. Alternatively, the nanosystems may be immobilized (by various chemical methodologies) on surfaces for construction of controlled-rate drug (or bioactive substance) eluting biomaterials with enhanced biocompatibility and performance (in conjunction with RA1: ═anotechnology / Advanced ╠aterials).

Development, characterization and toxicological assessment of new histocompatible biomaterials (in conjunction with RA1: ═anotechnology / Advanced ╠aterials)

  • Synthesis and characterization of calcium phosphate bone cements and calcium phosphate ceramics, used as alloplastic bone graft materials. Figure8
  • Preparation of bioactive silicate glasses, used as scaffolds in bone tissue engineering, based on sol-gel method and a containerless melting technique employing a CO2 laser melting a levitated glass droplet, along with textural, structural and bioactivity characterization of these materials. The preparation method offers numerous advantages, including varying material porosity and high purity at non glassifiable compositions with conventional melt quenching methods.
  • Controlled drug delivery systems based on biopolymers: Synthesis and characterization of alginate hydrogels as delivery agents of protein/peptide and small molecule drugs.

Non-destructive characterization of biogenic materials and drug polymorphs
The development of methods for the non-destructive characterization of biogenic materials, e.g. bones, urinary stones, cystoliths, is of significance for the diagnosis and progress monitoring of related degenerative and metabolic diseases, such as osteoporosis and osteoarthritis. The development of non-destructive techniques for online qualitative and quantitative determination of active ingredients in drug formulations, with emphasis in polymorphic activity compounds, is of great interest for the pharmaceutical companies (in conjunction with RA1: ═anotechnology / Advanced ╠aterials).

Analysis of the mechanisms of biological mineralization
Knowledge of the mechanism of formation of biominerals (calcium phosphates, oxalatesFigure9 and carbonates) on biopolymers (e.g. collagen and polysaccharides) and artificial polymers (as polymethyl or polyhydroxy methacrylate used in intraocular lens replacement in cataract surgery) is of key importance to obtain understanding not only for the development of innovative cure methods, but also for the design of biomaterials for use in the replacement of target tissues. For reliable mechanistic data, highly reproducible and precise methods for the measurement of biomineralization processes in vitro are required (in conjunction with RA1: ═anotechnology / Advanced ╠aterials).

Development of non-invasive spectroscopic methods for in-time diagnosis of ophthalmic diseases & pharmacokinetics analysis
Figure10Lens protein aggregation and/or phase separation of the lens cytoplasm into protein-rich and protein-poor liquid phases have been considered as possible sources of cataract, which is considered today as the most important cause of preventable blindness worldwide. Currently, cataract diagnosis is made clinically at the mature level of the disease, thus tools for early, non-invasive diagnosis are of great significance. FORTH/ICE-HT activities towards this goal concern the use of a multi-faceted approach employing optical methodologies based on elastic and inelastic light scattering spectroscopies for the investigation of protein dynamics and their interactions to gain insight of the molecular basis of cataract and other ophthalmic diseases.

Assessment of toxicity and potential negative effects on health for novel nanomaterials (in conjunction with RA1: ═anotechnology / Advanced ╠aterials)
Evaluation of the biological effect of nanomaterials (functional cell properties, matrix cellFigure11 effectors) and validation of processes involving nanomaterials according to their type and form of use, taking into consideration that nanomaterials are of similar or much smaller size than the biological entities, are able to reach even the nucleus of the cell and, due to their unique reactive properties, may interact with molecules on the cell surface as well as within the cell. The same properties, which give nanomaterials unique advantages for their use in biotechnology, food and drug industry and biomedical applications, create also unique toxicity issues and the need for the development and validation of specific toxicology assays. To this end, we employ a fast multi-screening of several toxicological endpoints involving cell viability, oxidative stress and cell cycle dynamics assays combined with fluorescent microscopy with specialized markers to evaluate cell cytoskeleton and microtubule network as well as DNA damage.

Mathematical modelling of brain activity
Figure12State-of-the-art mathematical modelling of brain provides significant insight on the extent of overlapping information from electroencephalography (EEG) and magnetoencephalography (MEG) measurements. The definitive non-uniqueness result we obtained states that even we acquired synchronous data from both EEG and MEG modalities a 33% of the active neuronal current is impossible to be identified. Further study of the sensitivity of the recorded brain activity on geometric variations is under investigation.

Mathematical modelling of tumour growth
As of today, there are many mathematical models describing the growth of tumors, reflecting our restricted knowledge of the actual mechanism that guides the growth of a tumor. Almost every such model is analyzed representing the tumor by a sphere. A much more realistic shape incorporating the anatomical peculiarities of the human body is that of an ellipsoid, which allows for a three independent directions of growth. We initiate an analytic study of ellipsoidal tumor growth based on the pioneering model of Greenspan and we compare our results with the more commonly studied spherical models.

Development of efficient bioprocesses for the production of biopolymers and biofuels from organic wastes and biomass (in conjunction with RA2: Energy/Environment)
Different processes based on pure and mixed microbial cultures have been developed for the valorization of various types of organic wastes, eg. agro-industrial or municipal, and biomass, such as sweet sorghum, aiming mainly at the recovery of biofuels. Bioprocesses such as anaerobic digestion for methane generation, dark fermentative hydrogen production, alcoholic fermentation and direct electricity generation via microbial fuel cells have been optimized based on the development of novel reactor configurations, bioreactor operational development, process control and mathematical modeling. The efficiency of most of the developed bioprocesses have also been validated at pilot scale.

Integrated experimental and computational study of biodegradation of organic pollutants in soil (in conjunction with RA2: Energy/Environment)
Our activities focus on the optimization and control of conditions and parameters governing the bioremediation of soils (bio-venting, bio-piles, slurry reactors) polluted by persistent organic pollutants (POPs). The possibility of enhancing the bioavailability and biodegradability of pollutants by pre-treating the soil with plasma discharges (advanced oxidation process) is currently being investigated.

 


 

 
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