The Role of Universities in the Triple Helix model of innovation management within the biotechnology industry, Case example: Turku Science Park Network

Biotechnology has been recognized as the key strategic technology for industrial growth. The industry is heavily dependent on basic research. Finland continues to rank in the top 10 of Europe's most innovative countries in terms of tax-policy, education system, infrastructure and the number of patents issued. Regardless of the excellent statistical results, the output of this innovativeness is below acceptable. Research on the issues hindering the output creation has already been done and the identifiable weaknesses in the Finland's National Innovation system are the non-existent growth of entrepreneurship and the missing internationalization. Finland is proven to have all the enablers of the innovation policy tools, but is lacking the incentives and rewards to push the enablers, such as knowledge and human capital, forward. Science Parks are the biggest operator in research institutes in the Finnish Science and Technology system. They exist with the purpose of speeding up the commercialization process of biotechnology innovations which usually include technological uncertainty, technical inexperience, business inexperience and high technology cost. Innovation management only internally is a rather historic approach, current trend drives towards open innovation model with strong triple helix linkages. The evident problems in the innovation management within the biotechnology industry are examined through a case study approach including analysis of the semi-structured interviews which included biotechnology and business expertise from Turku School of Economics. The results from the interviews supported the theoretical implications as well as conclusions derived from the pilot survey, which focused on the companies inside Turku Science Park network. One major issue that the Finland's National innovation system is struggling with is the fact that it is technology driven, not business pulled. Another problem is the university evaluation scale which focuses more on number of graduates and short-term factors, when it should put more emphasis on the cooperation success in the long-term, such as the triple helix connections with interaction and knowledge distribution. The results of this thesis indicated that there is indeed requirement for some structural changes in the Finland's National innovation system and innovation policy in order to generate successful biotechnology companies and innovation output. There is lack of joint output and scales of success, lack of people with experience, lack of language skills, lack of business knowledge and lack of growth companies.

Training system for conceptual design and evaluation for wastewater treatment

Rising population, rapid urbanisation and growing industrialisation have severely stressed water quality and its availability in Malawi. In addition, financial and institutional problems and the expanding agro industry have aggravated this problem. The situation is worsened by depleting water resources and pollution from untreated sewage and industrial effluent. The increasing scarcity of clean water calls for the need for appropriate management of available water resources. There is also demand for a training system for conceptual design and evaluation for wastewater treatment in order to build the capacity for technical service providers and environmental practitioners in the country. It is predicted that Malawi will face a water stress situation by 2025. In the city of Blantyre, this situation is aggravated by the serious pollution threat from the grossly inadequate sewage treatment capacity. This capacity is only 23.5% of the wastewater being generated presently. In addition, limited or non-existent industrial effluent treatment has contributed to the severe water quality degradation. This situation poses a threat to the ecologically fragile and sensitive receiving water courses within the city. This water is used for domestic purposes further downstream. This manuscript outlines the legal and policy framework for wastewater treatment in Malawi. The manuscript also evaluates the existing wastewater treatment systems in Blantyre. This evaluation aims at determining if the effluent levels at the municipal plants conform to existing standards and guidelines and other associated policy and regulatory frameworks. The raw material at all the three municipal plants is sewage. The typical wastewater parameters are Biochemical Oxygen Demand (BOD5), Chemical Oxygen Demand (COD), and Total Suspended Solids (TSS). The treatment target is BOD5, COD, and TSS reduction. Typical wastewater parameters at the wastewater treatment plant at MDW&S textile and garments factory are BOD5 and COD. The treatment target is to reduce BOD5 and COD. The manuscript further evaluates a design approach of the three municipal wastewater treatment plants in the city and the wastewater treatment plant at Mapeto David Whitehead & Sons (MDW&S) textile and garments factory. This evaluation utilises case-based design and case-based reasoning principles in the ED-WAVE tool to determine if there is potential for the tool in Blantyre. The manuscript finally evaluates the technology selection process for appropriate wastewater treatment systems for the city of Blantyre. The criteria for selection of appropriate wastewater treatment systems are discussed. Decision support tools and the decision tree making process for technology selection are also discussed. Based on the treatment targets and design criteria at the eight cases evaluated in this manuscript in reference to similar cases in the ED-WAVE tool, this work confirms the practical use of case-based design and case-based reasoning principles in the ED-WAVE tool in the design and evaluation of wastewater treatment 6 systems in sub-Sahara Africa, using Blantyre, Malawi, as the case study area. After encountering a new situation, already collected decision scenarios (cases) are invoked and modified in order to arrive at a particular design alternative. What is necessary, however, is to appropriately modify the case arrived at through the Case Study Manager in order to come up with a design appropriate to the local situation taking into account technical, socio-economic and environmental aspects. This work provides a training system for conceptual design and evaluation for wastewater treatment.

Structural studies on enzymes of biotechnological and biomedical interest

Structural studies of proteins aim at elucidating the atomic details of molecular interactions in biological processes of living organisms. These studies are particularly important in understanding structure, function and evolution of proteins and in defining their roles in complex biological settings. Furthermore, structural studies can be used for the development of novel properties in biomolecules of environmental, industrial and medical importance. X-ray crystallography is an invaluable tool to obtain accurate and precise information about the structure of proteins at the atomic level. Glutathione transferases (GSTs) are amongst the most versatile enzymes in nature. They are able to catalyze a wide variety of conjugation reactions between glutathione (GSH) and non-polar components containing an electrophilic carbon, nitrogen or sulphur atom. Plant GSTs from the Tau class (a poorly characterized class) play an important role in the detoxification of xenobiotics and stress tolerance. Structural studies were performed on a Tau class fluorodifen-inducible glutathione transferase from Glycine max (GmGSTU4-4) complexed with GSH (2.7 Å) and a product analogue Nb-GSH (1.7 Å). The three-dimensional structure of the GmGSTU4-4-GSH complex revealed that GSH binds in different conformations in the two subunits of the dimer: in an ionized form in one subunit and a non-ionized form in the second subunit. Only the ionized form of the substrate may lead to the formation of a catalytically competent complex. Structural comparison between the GSH and Nb-GSH bound complexes revealed significant differences with respect to the hydrogen-bonding, electrostatic interaction pattern, the upper part of -helix H4 and the C-terminus of the enzyme. These differences indicate an intrasubunit modulation between the G-and Hsites suggesting an induced-fit mechanism of xenobiotic substrate binding. A novel binding site on the surface of the enzyme was also revealed. Bacterial type-II L-asparaginases are used in the treatment of haematopoietic diseases such as acute lymphoblastic leukaemia (ALL) and lymphomas due to their ability to catalyze the conversion of L-asparagine to L-aspartate and ammonia. Escherichia coli and Erwinia chrysanthemi asparaginases are employed for the treatment of ALL for over 30 years. However, serious side-effects affecting the liver and pancreas have been observed due to the intrinsic glutaminase activity of the administered enzymes. Structural studies on Helicobacter pylori L-asparaginase (HpA) were carried out in an effort to discover novel L-asparaginases with potential chemotherapeutic utility in ALL treatment. Detailed analysis of the active site geometry revealed structurally significant differences between HpA and other Lasparaginases that may be important for the biological activities of the enzyme and could be further exploited in protein engineering efforts.

DPS-Like Peroxide Resistance Protein: Structural and Functional Studies on a Versatile Nanocontainer

Oxidative stress is a constant threat to almost all organisms. It damages a number of biomolecules and leads to the disruption of many crucial cellular functions. It is caused by reactive oxygen species (ROS), such as hydrogen peroxide (H2O₂), superoxide (•O₂ -), and hydroxyl radical (•OH). The most harmful of these compounds is •OH, which is only formed in cells in the presence of redox-cycling transition metals, such as iron and copper. Bacteria have developed a number of mechanisms to cope with ROS. One of the most widespread means employed by bacteria is the DNA-binding proteins from starved cells (Dps). Dps proteins protect the cells by binding and oxidizing Fe2+, thus greatly reducing the production of •OH. The oxidized iron is stored inside the protein as an iron core. In addition, Dps proteins bind directly to DNA forming a protective coating that shields DNA from harmful agents. Moreover, Dps proteins have been found to elicit other protective functions in cells and to participate in bacterial virulence. Dps proteins are of special importance to Streptococci owing to the lack of catalase in this genus of bacteria.This study was focused on structural and functional characterization of streptococcal Dpslike peroxide resistance (Dpr) proteins. Initially, crystal structures of Streptococcus pyogenes Dpr were determined. The data confirmed the presence of a di-metal ferroxidase center (FOC) in Dpr proteins and revealed the presence of a novel N-terminal helix as well as a surface metal-binding site. The crystal structures of Streptococcus suis Dpr complexed with transition metals demonstrated the metal specificity of the FOC. Solution binding studies also indicated the presence of a di-metal FOC. These results suggested a possible role for Dpr in the detoxification of various metals. Iron was found to mineralize inside the protein as ferrihydrite based on X-ray absorption spectroscopy data. The iron core was found to exhibit clear superparamagnetic behaviour using magnetic and Mössbauer measurements. The results from this study are expected to further increase our understanding on the binding, oxidation, and mineralization of iron and other metals in Dpr proteins. In particular, the structural and magnetic properties of the iron core can form a basis for potential new applications in nanotechnology. From the streptococcal viewpoint, the results would help in understanding better the complicated picture of bacterial pathogenesis. Dpr proteins may also provide a novel target for drug design due to their tight involvement in bacterial virulence.

Teknologiansiirto vuorovaikutuksena yliopistojen ja yritysten välillä - Systemaattinen kirjallisuuskatsaus

Tutkielman tavoitteena oli selvittää teknologiansiirrosta vuorovaikutusnäkökulmasta tehdyt empiiriset tutkimukset systemaattisen kirjallisuuskatsauksen avulla. Teoreettinen näkökulma perustui vuorovaikutteisten innovaatioverkostojen rakentamista yliopistojen, yritysten ja valtion välille korostavaan Triple Helix -viitekehykseen. Valtion ohjaava rooli rajattiin tutkielman ulkopuolelle. Tutkimuskysymykset olivat miten teknologiansiirtoa on empiirisesti tutkittu yliopistojen ja yritysten välisenä vuorovaikutuksena, mitkä ovat yliopistojen ja yritysten väliset vuorovaikutusmuodot ja miten teknologiansiirtoa kannattaisi tutkia. Tutkimuksista koostuva aineisto hankittiin systemaattisella kirjallisuushaulla. Aineisto rajattiin teknologiansiirtoa vuorovaikutusnäkökulmasta tutkineisiin empiirisiin tutkimuksiin. Analysointimenetelmänä käytettiin sisällönanalyysiä. Tulosten perusteella teknologiansiirron tutkimisen teoreettisia lähestymistapoja olivat yrittäjyyssuuntautuneisuuteen yliopistoissa kannustava ”entrepreneurial university” -suuntaus, innovaatiot ja innovaatiojärjestelmät, tutkijoiden ominaisuudet ja sosiaalinen pääoma, vuorovaikutus- ja tiedonsiirtoprosessit, organisationaalinen oppiminen ja yliopiston teknologiansiirtopolitiikat. Teknologiansiirtoa oli tutkittu enemmän yliopisto- kuin yritysnäkökulmasta. Tutkimuksista puolet otti huomioon hiljaisen tiedon siirrettävyyden vain vuorovaikutuksen avulla. Tutkielman tuloksena tunnistettiin 34 erilaista vuorovaikutusmuotoa teknologiansiirrossa yliopistojen ja yritysten välillä. Tutkituimmat vuorovaikutusmuodot olivat patentit ja lisenssit, asiantuntija-apu ja konsultointi, epämuodolliset kontaktit ja verkostot, yliopistojen spin-off-yritykset ja sopimustutkimus. Tutkimusyhteistyötä oli tutkittu suhteellisen vähän. Teknologiansiirron tehokkuutta kannattaisi tutkia yritysnäkökulmasta selvittämällä tutkimusyhteistyön ja innovaatioiden välinen yhteys. Teknologiansiirtoa vuorovaikutusprosessina kannattaisi tutkia kaikkien siihen osallistuvien sidosryhmien näkökulmista. Teknologiansiirtoprojektien onnistumiseen vaikuttavia tekijöitä voisi selvittää vertailevien tapaustutkimusten avulla. Tiedonsiirtoprosessiin liittyvää vuorovaikutusta ei prosessina kannattaisi tutkia irrallisena ilmiönä siihen liittyvistä tiedonsiirto-olosuhteista. Vuorovaikutusmuotojen määrä suomalaisessa teknologiansiirrossa olisi tutkimisen arvoinen asia. Vuorovaikutusmuotojen lukumäärän selvittämisellä voisi arvioida yhteistyösuhteen syvyyttä yliopistojen ja yritysten välillä. Yritykset tulisi nähdä aktiivisina toimijoina teknologiansiirrossa, ja teknologiansiirtoa tulisi tutkia myös yritysten näkökulmasta.

The Impact of National Innovation System on Entrepreneurial Venture Creation Process

The important role of entrepreneurship in countries’ economic development and overall society well-being is widely recognized by researchers, experts as well as policy makers. Every phase of the process of starting a new business is related to the interaction with at least one player of country innovation system and therefore the efficiency of this interaction may have an influence on the success of whole entrepreneurial process and consequently on the willingness of potential entrepreneurs to engage into this process. The study proposes a System Dynamics model for studying the impact of National Innovation System (NIS) on the entrepreneurial venture creation process. The developed model also takes country population aspect into account and provides results for estimation the effect various demographic tendencies on the process performance. The special impact is made on possible ways to facilitate the development of entrepreneurial framework conditions. Business incubators are seen as one of the effective tool for accomplishing such task. The study also provides the result for estimation of possible impact arising from properly functioned Business Incubators.

Open innovation: university-industry interaction in Russia

Innovation nowadays is one of the key elements of counties’ competitiveness. In the face of continuous world economic changes, open innovation business model implementation allows many companies to improve and accelerate their innovation processes through collaboration. Universities as traditional sources of knowledge might be involved in such kind of collaboration. In developing countries, which are in transition towards innovation-based economy, as Russia, open innovation business model can serve as a tool to speed up this transition. The Master’s Thesis explores the implementation of open innovation model in collaboration between companies and universities in global scale and particularly in Russia. The study is qualitative and it is based on integrative analysis of literature, secondary data and results of the survey, conducted among Russian universities. In the thesis a model for implementation of open innovation into Triple Helix model is elaborated. The study also explores not very common practice of reverse-directional interaction - from industry to university. The findings of this research show a necessity of solving the identified problems in parallel with implementation of open innovation concept in university-industry collaboration.

Vesicular Trafficking in Osteoclasts

Osteoclasts are multinucleated bone-degrading cells that undergo large changes in their polarisation and vesicular trafficking during the bone resorption cycle. Rab proteins are small GTPases that offer both temporal and spatial regulation to the transport between membranous organelles. Previously the presence and function of only few of the currently known 60 Rab proteins in osteoclasts have been reported. In this study, the expression of 26 Rab genes in bone-resorbing osteoclasts was demonstrated with gene-specific primer pairs. The further analysis of three Rab genes during human osteoclast differentiation revealed that Rab13 gene is highly induced during osteoclastogenesis. The presence of Rab13 protein in the secretory vesicles directed towards the ruffled border and in the endocytotic or transcytotic pathways in resorbing osteoclasts was excluded. The localisation of Rab13 suggests that that it is associated with a previously unknown vesicle population travelling between the trans-Golgi network and the basolateral membrane in bone resorbing osteoclasts. Rab proteins convey their functions by binding to specific effector proteins. We found a novel Rab13 interaction with endospanins-1 and -2 that are yet poorly characterised small transmembrane proteins. The Rab13 subfamily member Rab8 also bound to endospanins, while Rab10 and unrelated Rabs did not. Rab13 and endospanin-2 co-localised in perinuclear vesicles in transfected cells, demonstrating the interaction also in vivo. The inhibition of Rab13 did not interfere with the localisation of endospanin-2 nor did it affect the cell surface expression of growth hormone receptor, as has been previously described for endospanins. The physiological role of this novel protein-protein interaction thus remains to be clarified. The analysis of the transcytotic route in bone resorbing osteoclasts revealed that multiple vesicle populations arise from the ruffled border and transport the bone degradation products for exocytosis. These vesicles are directed to the functional secretory domain that is encircled by an actin-based molecular barrier. Furthermore, the transcytotic vesicles contain abundant Helix pomatia lectin binding sites and represent lipid raft concentrates. Finally, autophagosomal compartments may also be involved in the transcytosis.

Identification of characteristics for successful university-company partnership development

The importance of university-company collaboration has increased during the last decades. The drivers for that are, on the one hand, changes in business logic of companies and on the other hand the decreased state funding of universities. Many companies emphasize joint research with universities as an enabling input to their development processes, which aim at creating new innovations, products and wealth. These factors have changed universities’ operations and they have adopted several practices of dynamic business organizations, such as strategic planning, monitoring and controlling methods of internal processes etc. The objective of this thesis is to combine different characteristics of successful university-company partnership and its development. The development process starts with identifying potential partners in the university’s interest group, which requires understanding the role of different partners in the innovation system. Next, in order to find a common development basis, matching the policy and strategy between partners is needed. The third phase is to combine the academic and industrial objectives of a joint project, which is a typical form of university-company collaboration. The optimum is a win-win situation where both partners, universities and companies, can get addedvalue. For the companies added value typically means access to new research results before their competitors. For the universities added value offers a possibility to carry on high level scientific work. The research output in the form of published scientific articles is evaluated by the international science community. Because the university-company partnership is often executed by joint projects, the different forms of this kind of projects is discussed in this study. The most challenging form of collaboration is a semi-open project model, which is not based on bilateral activities between universities and companies but on a consortium of several universities, research institutes and companies. The universities and companies are core actors in the innovation system. Thus the discussion of their roles and relations to public operators like publicly funded financiers is important. In the Finnish innovation system there are at least the following doers executing strategies and policies: EU, Academy of Finland and TEKES. In addition to these, Strategic Centres for Science, Technology and Innovation which are owned jointly by companies, universities and research organizations have a very important role in their fields of business. They transfer research results into commercial actions to generate wealth. The thesis comprises two parts. The first part consists of an overview of the study including introduction, literature review, research design, synthesis of findings and conclusions. The second part introduces four original research publications.

Nanoclustering augmentation : a novel mechanism of Ras activation in cancer

Proteins of the Ras family are central regulators of crucial cellular processes, such as proliferation, differentiation and apoptosis. Their importance is emphasized in cancer, in which the isoforms H-ras, N-ras and K-ras are misregulated by mutations in approximately 20 – 30 % of cases. Thus, they represent major cancer oncogenes and one of the most important targets for cancer drug development. Ras proteins are small GTPases, which cycle between the GTP-bound active and GDP-bound inactive state. Despite the tremendous research conducted in the last three decades, many fundamental properties of Ras proteins remain poorly understood. For instance, although new concepts have recently emerged, the understanding of Ras behavior in its native environment, the membrane, is still largely missing. On the membrane Ras organizes into nanoscale clusters, also called nanoclusters. They differ between isoforms, but also between activation states of Ras. It is considered that nanoclusters represent the basic Ras signaling units. Recently, it was demonstrated that on the membrane Ras adopts distinct conformations, the so-called orientations, which are dependent on the Ras activations state. The membrane-orientation of H-ras is stabilized by the helix α4 and the C-terminal hypervariable region (hvr). The novel switch III region was proposed to be involved in mediating the change between different H-ras orientations. When the regions involved in this mechanism are mutated, H-ras activity is changed by an unknown mechanism. This thesis has explained the connection between the change of Ras orientation on the membrane and Ras activity. We demonstrated that H-ras orientation mutants exhibit altered diffusion properties on the membrane, which reflect the changes in their nanoclustering. The altered nanoclustering consequently rules the activity of the mutants. Moreover, we demonstrated that specific cancer-related mutations, affecting the switch III region of different Ras isoforms, exhibit increased nanoclustering, which consequently leads to stronger Ras signaling and tumorigenicity. Thus, we have discovered nanoclustering increase as a novel mechanism of Ras activity modulation in cancer. The molecular architecture of complexes formed on the membrane upon Ras activation is another poorly understood property of Ras. The following work has provided novel details on the regulation of Ras nanoclustering by a known H-ras-GTP nanoclustering stabilizer galectin-1 (Gal-1). Our study demonstrated that Gal-1 is not able to bind Ras directly, as it was previously proposed. Instead, its effect on H-ras-GTP nanoclustering is indirect, through binding of the effector proteins. Collectively, our findings represent valuable novel insights in the behavior of Ras, which will help the future research to eventually develop new strategies to successfully target Ras in cancer.

Recognition of nucleic acids by metal ion complexes

Metal-ion-mediated base-pairing of nucleic acids has attracted considerable attention during the past decade, since it offers means to expand the genetic code by artificial base-pairs, to create predesigned molecular architecture by metal-ion-mediated inter- or intra-strand cross-links, or to convert double stranded DNA to a nano-scale wire. Such applications largely depend on the presence of a modified nucleobase in both strands engaged in the duplex formation. Hybridization of metal-ion-binding oligonucleotide analogs with natural nucleic acid sequences has received much less attention in spite of obvious applications. While the natural oligonucleotides hybridize with high selectivity, their affinity for complementary sequences is inadequate for a number of applications. In the case of DNA, for example, more than 10 consecutive Watson-Crick base pairs are required for a stable duplex at room temperature, making targeting of sequences shorter than this challenging. For example, many types of cancer exhibit distinctive profiles of oncogenic miRNA, the diagnostics of which is, however, difficult owing to the presence of only short single stranded loop structures. Metallo-oligonucleotides, with their superior affinity towards their natural complements, would offer a way to overcome the low stability of short duplexes. In this study a number of metal-ion-binding surrogate nucleosides were prepared and their interaction with nucleoside 5´-monophosphates (NMPs) has been investigated by 1H NMR spectroscopy. To find metal ion complexes that could discriminate between natural nucleobases upon double helix formation, glycol nucleic acid (GNA) sequences carrying a PdII ion with vacant coordination sites at a predetermined position were synthesized and their affinity to complementary as well as mismatched counterparts quantified by UV-melting measurements.