Methods for construction and analysis of computational models in systems biology : applications to the modelling of the heat shock response and the self-assembly of intermediate filaments

Systems biology is a new, emerging and rapidly developing, multidisciplinary research field that aims to study biochemical and biological systems from a holistic perspective, with the goal of providing a comprehensive, system- level understanding of cellular behaviour. In this way, it addresses one of the greatest challenges faced by contemporary biology, which is to compre- hend the function of complex biological systems. Systems biology combines various methods that originate from scientific disciplines such as molecu- lar biology, chemistry, engineering sciences, mathematics, computer science and systems theory. Systems biology, unlike “traditional” biology, focuses on high-level concepts such as: network, component, robustness, efficiency, control, regulation, hierarchical design, synchronization, concurrency, and many others. The very terminology of systems biology is “foreign” to “tra- ditional” biology, marks its drastic shift in the research paradigm and it indicates close linkage of systems biology to computer science. One of the basic tools utilized in systems biology is the mathematical modelling of life processes tightly linked to experimental practice. The stud- ies contained in this thesis revolve around a number of challenges commonly encountered in the computational modelling in systems biology. The re- search comprises of the development and application of a broad range of methods originating in the fields of computer science and mathematics for construction and analysis of computational models in systems biology. In particular, the performed research is setup in the context of two biolog- ical phenomena chosen as modelling case studies: 1) the eukaryotic heat shock response and 2) the in vitro self-assembly of intermediate filaments, one of the main constituents of the cytoskeleton. The range of presented approaches spans from heuristic, through numerical and statistical to ana- lytical methods applied in the effort to formally describe and analyse the two biological processes. We notice however, that although applied to cer- tain case studies, the presented methods are not limited to them and can be utilized in the analysis of other biological mechanisms as well as com- plex systems in general. The full range of developed and applied modelling techniques as well as model analysis methodologies constitutes a rich mod- elling framework. Moreover, the presentation of the developed methods, their application to the two case studies and the discussions concerning their potentials and limitations point to the difficulties and challenges one encounters in computational modelling of biological systems. The problems of model identifiability, model comparison, model refinement, model inte- gration and extension, choice of the proper modelling framework and level of abstraction, or the choice of the proper scope of the model run through this thesis.

Sustainable Computer Science Education

As the world becomes more technologically advanced and economies become globalized, computer science evolution has become faster than ever before. With this evolution and globalization come the need for sustainable university curricula that adequately prepare graduates for life in the industry. Additionally, behavioural skills or “soft” skills have become just as important as technical abilities and knowledge or “hard” skills. The objective of this study was to investigate the current skill gap that exists between computer science university graduates and actual industry needs as well as the sustainability of current computer science university curricula by conducting a systematic literature review of existing publications on the subject as well as a survey of recently graduated computer science students and their work supervisors. A quantitative study was carried out with respondents from six countries, mainly Finland, 31 of the responses came from recently graduated computer science professionals and 18 from their employers. The observed trends suggest that a skill gap really does exist particularly with “soft” skills and that many companies are forced to provide additional training to newly graduated employees if they are to be successful at their jobs.

Computational models for and from biology : simple gene assembly and reaction systems

The advancement of science and technology makes it clear that no single perspective is any longer sufficient to describe the true nature of any phenomenon. That is why the interdisciplinary research is gaining more attention overtime. An excellent example of this type of research is natural computing which stands on the borderline between biology and computer science. The contribution of research done in natural computing is twofold: on one hand, it sheds light into how nature works and how it processes information and, on the other hand, it provides some guidelines on how to design bio-inspired technologies. The first direction in this thesis focuses on a nature-inspired process called gene assembly in ciliates. The second one studies reaction systems, as a modeling framework with its rationale built upon the biochemical interactions happening within a cell. The process of gene assembly in ciliates has attracted a lot of attention as a research topic in the past 15 years. Two main modelling frameworks have been initially proposed in the end of 1990s to capture ciliates’ gene assembly process, namely the intermolecular model and the intramolecular model. They were followed by other model proposals such as templatebased assembly and DNA rearrangement pathways recombination models. In this thesis we are interested in a variation of the intramolecular model called simple gene assembly model, which focuses on the simplest possible folds in the assembly process. We propose a new framework called directed overlap-inclusion (DOI) graphs to overcome the limitations that previously introduced models faced in capturing all the combinatorial details of the simple gene assembly process. We investigate a number of combinatorial properties of these graphs, including a necessary property in terms of forbidden induced subgraphs. We also introduce DOI graph-based rewriting rules that capture all the operations of the simple gene assembly model and prove that they are equivalent to the string-based formalization of the model. Reaction systems (RS) is another nature-inspired modeling framework that is studied in this thesis. Reaction systems’ rationale is based upon two main regulation mechanisms, facilitation and inhibition, which control the interactions between biochemical reactions. Reaction systems is a complementary modeling framework to traditional quantitative frameworks, focusing on explicit cause-effect relationships between reactions. The explicit formulation of facilitation and inhibition mechanisms behind reactions, as well as the focus on interactions between reactions (rather than dynamics of concentrations) makes their applicability potentially wide and useful beyond biological case studies. In this thesis, we construct a reaction system model corresponding to the heat shock response mechanism based on a novel concept of dominance graph that captures the competition on resources in the ODE model. We also introduce for RS various concepts inspired by biology, e.g., mass conservation, steady state, periodicity, etc., to do model checking of the reaction systems based models. We prove that the complexity of the decision problems related to these properties varies from P to NP- and coNP-complete to PSPACE-complete. We further focus on the mass conservation relation in an RS and introduce the conservation dependency graph to capture the relation between the species and also propose an algorithm to list the conserved sets of a given reaction system.

Embedding sustainability into the new computer science curriculum for English schools

The primary goals of this study are to: embed sustainable concepts of energy consumption into certain part of existing Computer Science curriculum for English schools; investigate how to motivate 7-to-11 years old kids to learn these concepts; promote responsive ICT (Information and Communications Technology) use by these kids in their daily life; raise their awareness of today’s ecological challenges. Sustainability-related ICT lessons developed aim to provoke computational thinking and creativity to foster understanding of environmental impact of ICT and positive environmental impact of small changes in user energy consumption behaviour. The importance of including sustainability into the Computer Science curriculum is due to the fact that ICT is both a solution and one of the causes of current world ecological problems. This research follows Agile software development methodology. In order to achieve the aforementioned goals, sustainability requirements, curriculum requirements and technical requirements are firstly analysed. Secondly, the web-based user interface is designed. In parallel, a set of three online lessons (video, slideshow and game) is created for the website GreenICTKids.com taking into account several green design patterns. Finally, the evaluation phase involves the collection of adults’ and kids’ feedback on the following: user interface; contents; user interaction; impacts on the kids’ sustainability awareness and on the kids’ behaviour with technologies. In conclusion, a list of research outcomes is as follows: 92% of the adults learnt more about energy consumption; 80% of the kids are motivated to learn about energy consumption and found the website easy to use; 100% of the kids understood the contents and liked website’s visual aspect; 100% of the kids will try to apply in their daily life what they learnt through the online lessons.

Quantitative refinement of reaction-based biomodels

In the field of molecular biology, scientists adopted for decades a reductionist perspective in their inquiries, being predominantly concerned with the intricate mechanistic details of subcellular regulatory systems. However, integrative thinking was still applied at a smaller scale in molecular biology to understand the underlying processes of cellular behaviour for at least half a century. It was not until the genomic revolution at the end of the previous century that we required model building to account for systemic properties of cellular activity. Our system-level understanding of cellular function is to this day hindered by drastic limitations in our capability of predicting cellular behaviour to reflect system dynamics and system structures. To this end, systems biology aims for a system-level understanding of functional intraand inter-cellular activity. Modern biology brings about a high volume of data, whose comprehension we cannot even aim for in the absence of computational support. Computational modelling, hence, bridges modern biology to computer science, enabling a number of assets, which prove to be invaluable in the analysis of complex biological systems, such as: a rigorous characterization of the system structure, simulation techniques, perturbations analysis, etc. Computational biomodels augmented in size considerably in the past years, major contributions being made towards the simulation and analysis of large-scale models, starting with signalling pathways and culminating with whole-cell models, tissue-level models, organ models and full-scale patient models. The simulation and analysis of models of such complexity very often requires, in fact, the integration of various sub-models, entwined at different levels of resolution and whose organization spans over several levels of hierarchy. This thesis revolves around the concept of quantitative model refinement in relation to the process of model building in computational systems biology. The thesis proposes a sound computational framework for the stepwise augmentation of a biomodel. One starts with an abstract, high-level representation of a biological phenomenon, which is materialised into an initial model that is validated against a set of existing data. Consequently, the model is refined to include more details regarding its species and/or reactions. The framework is employed in the development of two models, one for the heat shock response in eukaryotes and the second for the ErbB signalling pathway. The thesis spans over several formalisms used in computational systems biology, inherently quantitative: reaction-network models, rule-based models and Petri net models, as well as a recent formalism intrinsically qualitative: reaction systems. The choice of modelling formalism is, however, determined by the nature of the question the modeler aims to answer. Quantitative model refinement turns out to be not only essential in the model development cycle, but also beneficial for the compilation of large-scale models, whose development requires the integration of several sub-models across various levels of resolution and underlying formal representations.

Surface Studies of Thiolate Adsorbates on Some Metals

The results and discussions in this thesis are based on my studies about selfassembled thiol layers on gold, platinum, silver and copper surfaces. These kinds of layers are two-dimensional, one molecule thick and covalently organized at the surface. They are an easy way to modify surface properties. Self-assembly is today an intensive research field because of the promise it holds for producing new technology at nanoscale, the scale of atoms and molecules. These kinds of films have applications for example, in the fields of physics, biology, engineering, chemistry and computer science. Compared to the extensive literature concerning self-assembled monolayers (SAMs) on gold, little is known about the structure and properties of thiolbased SAMs on other metals. In this thesis I have focused on thiol layers on gold, platinum, silver and copper substrates. These studies can be regarded as a basic study of SAMs. Nevertheless, an understanding of the physical and chemical nature of SAMs allows the correlation between atomic structure and macroscopic properties. The results can be used as a starting point for many practical applications. X-ray photoelectron spectroscopy (XPS) and synchrotron radiation excited high resolution photoelectron spectroscopy (HR-XPS) together with time-offlight secondary ion mass spectrometry (ToF-SIMS) were applied to investigate thin organic films formed by the spontaneous adsorption of molecules on metal surfaces. Photoelectron spectroscopy was the main method used in these studies. In photoelectron spectroscopy, the sample is irradiated with photons and emitted photoelectrons are energy-analyzed. The obtained spectra give information about the atomic composition of the surface and about the chemical state of the detected elements. It is widely used in the study of thin layers and is a very powerful tool for this purpose. Some XPS results were complemented with ToF-SIMS measurements. It provides information on the chemical composition and molecular structure of the samples. Thiol (1-Dodecanethiol, CH3(CH2)11SH) solution was used to create SAMs on metal substrates. Uniform layers were formed on most of the studied metal surfaces. On platinum, surface aligned molecules were also detected in investigations by XPS and ToF-SIMS. The influence of radiation on the layer structure was studied, leading to the conclusion that parts of the hydrocarbon chains break off due to radiation and the rest of the layer is deformed. The results obtained showed differences depending on the substrate material. The influence of oxygen on layer formation was also studied. Thiol molecules were found to replace some of the oxygen from the metal surfaces.

Kahden merkkijonon pisimmän yhteisen alijonon ongelma ja sen ratkaiseminen

Tämä tutkielma kuuluu merkkijonoalgoritmiikan piiriin. Merkkijono S on merkkijonojen X[1..m] ja Y[1..n] yhteinen alijono, mikäli se voidaan muodostaa poistamalla X:stä 0..m ja Y:stä 0..n kappaletta merkkejä mielivaltaisista paikoista. Jos yksikään X:n ja Y:n yhteinen alijono ei ole S:ää pidempi, sanotaan, että S on X:n ja Y:n pisin yhteinen alijono (lyh. PYA). Tässä työssä keskitytään kahden merkkijonon PYAn ratkaisemiseen, mutta ongelma on yleistettävissä myös useammalle jonolle. PYA-ongelmalle on sovelluskohteita – paitsi tietojenkäsittelytieteen niin myös bioinformatiikan osa-alueilla. Tunnetuimpia niistä ovat tekstin ja kuvien tiivistäminen, tiedostojen versionhallinta, hahmontunnistus sekä DNA- ja proteiiniketjujen rakennetta vertaileva tutkimus. Ongelman ratkaisemisen tekee hankalaksi ratkaisualgoritmien riippuvuus syötejonojen useista eri parametreista. Näitä ovat syötejonojen pituuden lisäksi mm. syöttöaakkoston koko, syötteiden merkkijakauma, PYAn suhteellinen osuus lyhyemmän syötejonon pituudesta ja täsmäävien merkkiparien lukumäärä. Täten on vaikeaa kehittää algoritmia, joka toimisi tehokkaasti kaikille ongelman esiintymille. Tutkielman on määrä toimia yhtäältä käsikirjana, jossa esitellään ongelman peruskäsitteiden kuvauksen jälkeen jo aikaisemmin kehitettyjä tarkkoja PYAalgoritmeja. Niiden tarkastelu on ryhmitelty algoritmin toimintamallin mukaan joko rivi, korkeuskäyrä tai diagonaali kerrallaan sekä monisuuntaisesti prosessoiviin. Tarkkojen menetelmien lisäksi esitellään PYAn pituuden ylä- tai alarajan laskevia heuristisia menetelmiä, joiden laskemia tuloksia voidaan hyödyntää joko sellaisinaan tai ohjaamaan tarkan algoritmin suoritusta. Tämä osuus perustuu tutkimusryhmämme julkaisemiin artikkeleihin. Niissä käsitellään ensimmäistä kertaa heuristiikoilla tehostettuja tarkkoja menetelmiä. Toisaalta työ sisältää laajahkon empiirisen tutkimusosuuden, jonka tavoitteena on ollut tehostaa olemassa olevien tarkkojen algoritmien ajoaikaa ja muistinkäyttöä. Kyseiseen tavoitteeseen on pyritty ohjelmointiteknisesti esittelemällä algoritmien toimintamallia hyvin tukevia tietorakenteita ja rajoittamalla algoritmien suorittamaa tuloksetonta laskentaa parantamalla niiden kykyä havainnoida suorituksen aikana saavutettuja välituloksia ja hyödyntää niitä. Tutkielman johtopäätöksinä voidaan yleisesti todeta tarkkojen PYA-algoritmien heuristisen esiprosessoinnin lähes systemaattisesti pienentävän niiden suoritusaikaa ja erityisesti muistintarvetta. Lisäksi algoritmin käyttämällä tietorakenteella on ratkaiseva vaikutus laskennan tehokkuuteen: mitä paikallisempia haku- ja päivitysoperaatiot ovat, sitä tehokkaampaa algoritmin suorittama laskenta on.

Data analysis tools and methods for DNA microarray and high-throughput sequencing data

The recent rapid development of biotechnological approaches has enabled the production of large whole genome level biological data sets. In order to handle thesedata sets, reliable and efficient automated tools and methods for data processingand result interpretation are required. Bioinformatics, as the field of studying andprocessing biological data, tries to answer this need by combining methods and approaches across computer science, statistics, mathematics and engineering to studyand process biological data. The need is also increasing for tools that can be used by the biological researchers themselves who may not have a strong statistical or computational background, which requires creating tools and pipelines with intuitive user interfaces, robust analysis workflows and strong emphasis on result reportingand visualization. Within this thesis, several data analysis tools and methods have been developed for analyzing high-throughput biological data sets. These approaches, coveringseveral aspects of high-throughput data analysis, are specifically aimed for gene expression and genotyping data although in principle they are suitable for analyzing other data types as well. Coherent handling of the data across the various data analysis steps is highly important in order to ensure robust and reliable results. Thus,robust data analysis workflows are also described, putting the developed tools andmethods into a wider context. The choice of the correct analysis method may also depend on the properties of the specific data setandthereforeguidelinesforchoosing an optimal method are given. The data analysis tools, methods and workflows developed within this thesis have been applied to several research studies, of which two representative examplesare included in the thesis. The first study focuses on spermatogenesis in murinetestis and the second one examines cell lineage specification in mouse embryonicstem cells.