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.

Clinical and genetic markers in disease progression – a study among subjects with obstructive lung diseases

Asthma, COPD, and asthma and COPD overlap syndrome (ACOS) are chronic pulmonary diseases with an obstructive component. In COPD, the obstruction is irreversible and the disease is progressive. The aim of the study was to define and analyze factors that affected disease progression and patients’ well-being, prognosis and mortality in Chronic Airway Disease (CAD) cohort. The main focus was on COPD and ACOS patients. Retrospective data from medical records was combined with genetic and prospective follow-up data. Smoking is the biggest risk factor for COPD and even after the diagnosis of the disease, smoking plays an important role in disease development and patient’s prognosis. Sixty percent of the COPD patients had succeeded in smoking cessation. Patients who had managed to quit smoking had lower mortality rates and less psychiatric diseases and alcohol abuse although they were older and had more cardiovascular diseases than patients who continued smoking. Genetic polymorphism rs1051730 in the nicotinic acethylcholine receptor gene (CHRNA3/5) associated with heavy smoking, cancer prevalence and mortality in two Finnish independent cohorts consisting of COPD patients and male smokers. Challenges in smoking cessation and higher mortality rates may be partly due to individual patient’s genetic composition. Approximately 50% of COPD patients are physically inactive and the proportion was higher among current smokers. Physically active and inactive patients didn’t differ from each other in regard to age, gender or comorbidities. Bronchial obstruction explained inactivity only in severe disease. Subjective sensation of dyspnea, however, had very strong association to inactivity and was also associated to low health related quality of life (HRQoL). ACOS patients had a significantly lower HRQoL than either the patients with asthma or with COPD even though they were younger than COPD patients, had better lung functions and smaller tobacco exposure.

Involving employees in six sigma

Six sigma is a quality improvement philosophy with systematic and formal approach. In order to successfully implement and utilize six sigma the basic disciplines of it should be adopted by the entire organization. Furthermore, employee involvement is crucial in six sigma implementation. This thesis addresses the challenges of long-lasting involvement in the case company. It focuses on gaps of involving six sigma trained employees, Black Belts. Theoretical framework of the thesis illustrates different factors influencing employee involvement. Influencing factors can be divided into ten categories: organizational culture, managerial commitment, leadership style, employee empowerment, employees’ perceptions, communication, training, goals, performance measurement and incentives. Factors and categories overlap and are related to each other. The framework provides holistic view of employee involvement in six sigma context but can be used also with other quality management philosophies. This thesis was conducted as a case study and written on an assignment to a power and automation technology company. Due to the nature of research problem, the data collection was conducted by interviewing case company personnel. In order to study involvement from employees’ point of view interview questions were designed to be open-ended and to allow the interviewees to tell freely about the phenomenon. This thesis provides empirical support on previous studies in organizational support, management commitment and employee empowerment. In addition, it indicates the importance of separate function for Black Belts in the organization. The gaps in Black Belt involvement can be categorized under two categories: Management driven gaps are related to management commitment, organizational structure and culture and information systems. Black Belt driven gaps are related to practice and effort of using six sigma. This thesis finds solutions for bridging these gaps in the case company by applying findings from literature research and suggestions given by the interviewees. For each gap, actions are suggested for bridging the discrepancy between current and desired situations. The thesis states that in order to embed six sigma in the organization the most crucial gaps, lack of management commitment, six sigma vision and possibilities to use six sigma, should be diminished.

Involving employees in six sigma

Six sigma is a quality improvement philosophy with systematic and formal approach. In order to successfully implement and utilize six sigma the basic disciplines of it should be adopted by the entire organization. Furthermore, employee involvement is crucial in six sigma implementation. This thesis addresses the challenges of long-lasting involvement in the case company. It focuses on gaps of involving six sigma trained employees, Black Belts. Theoretical framework of the thesis illustrates different factors influencing employee involvement. Influencing factors can be divided into ten categories: organizational culture, managerial commitment, leadership style, employee empowerment, employees’ perceptions, communication, training, goals, performance measurement and incentives. Factors and categories overlap and are related to each other. The framework provides holistic view of employee involvement in six sigma context but can be used also with other quality management philosophies. This thesis was conducted as a case study and written on an assignment to a power and automation technology company. Due to the nature of research problem, the data collection was conducted by interviewing case company personnel. In order to study involvement from employees’ point of view interview questions were designed to be open-ended and to allow the interviewees to tell freely about the phenomenon. This thesis provides empirical support on previous studies in organizational support, management commitment and employee empowerment. In addition, it indicates the importance of separate function for Black Belts in the organization. The gaps in Black Belt involvement can be categorized under two categories: Management driven gaps are related to management commitment, organizational structure and culture and information systems. Black Belt driven gaps are related to practice and effort of using six sigma. This thesis finds solutions for bridging these gaps in the case company by applying findings from literature research and suggestions given by the interviewees. For each gap, actions are suggested for bridging the discrepancy between current and desired situations. The thesis states that in order to embed six sigma in the organization the most crucial gaps, lack of management commitment, six sigma vision and possibilities to use six sigma, should be diminished.