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## Computational Biomodeling Laboratory (Combio Lab)

The research of the laboratory centers on computational methods for modelling biochemical systems. The general interest of the laboratory is gaining an understanding of the fundamental computational and information-processing principles behind the functioning of bio-systems. We have considerable expertise in building discrete models, based on combinatorics, graph theory, and stochastic processes. We are also experts in evaluating such models against experimental data, discovering their control structure, quantitative model comparison and quantitative model refinement.

The laboratory has hosted in the last 5 years 5 postdoctoral students and has graduated 3 TUCS PhD students, 2 of them receiving their degrees with honors. The scientific volume of the unit has been consistently very good, both in quality and in quantity. The laboratory is actively involved in the editorial boards of several journals and the program committees of the most relevant conference in its field of research.

Research Unit Web Page: http://combio.abo.fi/

### Leader of the unit

Ion Petre### Researchers

Cristian Gratie Vladimir Rogojin Eugen Czeizler Dwitiya Tyagi### Doctoral Students

Bogdan Iancu Sepinoud Azimi Diana-Elena Gratie Charmi Panchal Muhammad Usman Krishna Kanhaiya### Undergraduate Students

Tolou Shadbahr Fatimah Shokri Nebiat Ibssa### Projects

#### Quantitative strategies for the self-assembly of intermediate filaments

In our research we concentrate on the process of in vitro self-assembly of intermediate filaments from tetrameric vimentin. We investigate different plausible strategies for filament elongation through mathematical modelling, model fitting, model validation and sensitivity analysis. In the assessment of the potential variants the focus is on properties such as scalability, robustness and ability to explain experimental data. This systematic approach enables the formulation of certain hypotheses about how the still little-known process of filament self-assembly is executed. Based on this hypotheses future biological experiments that would verify them are proposed. This project is an example of a hypothesis-driven research in the field of systems biology.

#### Network Controllability (Academy of Finland, 2013–2017)

Networks are all around us. The first example crossing one’s mind might be the World Wide Web, but probably not the only one. Our world is full of social structures, networks, where individuals are connected with each other by different means such as mobile phones or transportation. A network can be represented by nodes and by edges, where edges describe connections between the nodes. Imagine airports with flight connections. There is continuous flow of people travelling through the cities, and the biggest airports are the system hubs. Networks can also be microscopic, for example metabolic networks or gene regulatory networks in a cell. Common to all is that the state of the system typically changes with time. Hence, we call them dynamic networks. With many systems, it would be in our interest to steer them or even control them toward some desired state. However, this has turned out to be a very challenging task.

Within this project we aim to better understand the fundamental principles of network controllability. We develop novel and extend the existing methods on controlling networks. In particular, we are interested in large and complex biological networks, which are extremely difficult to control. Therefore, parallel to full control we are investigating also how such systems could be controlled partially. This kind of approach might, indeed, enable many practical applications, which otherwise would be infeasible simply from engineering perspective.

We exploit the control principles in order to predict the best way to engineer the networks, which we aim to control. In particular, we apply the methodology on two biological systems, cancer and renewable energy production. Malignant growth tends to arise when there is ‘too much energy in a system’. Hence, controlling cancer would mean steering the tumor towards non-growing state. Our ambition is to re-program cancer networks by identifying cell’s own pathogenic addictions and other vulnerabilities. Multi-targeting those identified nodes can improve anti-cancer therapeutics. In renewable energy production we optimize the metabolic flux to obtain maximal fuel yield. While the practical goals with energy aspect are rather opposite, the ultimate goal in both systems is to be able to control them. Obviously, the generic approaches and tools can be used in other applications. They also serve as a complement to traditional micro-scale engineering.

*Funding instrument:* Academy of Finland, Synthetic Biology Programme (FinSynBio) 2013-2017.

#### Quantitative model refinement (Academy of Finland, 2013–2017)

Much effort is currently invested in developing larger, more finely-grained computational models in many branches of science, supported by developments in computing infrastructure and by advances in quantitative experimental measuring techniques. This is supported by developments in the computing infrastructure and by advances in quantitative experimental techniques.

We focus in this project on computational techniques allowing the quantitative refinement of a model without altering its numerical fit and validation. Our research addresses two main problems in the design of mathematical models in systems biology: (i) the quantitative fit and validation of a large model is a computationally difficult problem; (ii) changing a model (e.g., adding details to it) implies redoing the work on the numerical fit and validation of the model. Our proposed methodology builds on the expertise gained in computer science in (qualitative) program refinement, extending it in a fundamental way to the realm of quantitative biomodels.

*Funding instrument:* Academy of Finland 2013-2017.

#### Quantitativa modeling of protein self-assembly

In our research we concentrate on the process of in vitro self-assembly of intermediate filaments from tetrameric vimentin. We investigate different plausible strategies for filament elongation through mathematical modelling, model fitting, model validation and sensitivity analysis. In the assessment of the potential variants the focus is on properties such as scalability, robustness and ability to explain experimental data. This systematic approach enables the formulation of certain hypotheses about how the still little-known process of filament self-assembly is executed. Based on this hypotheses future biological experiments that would verify them are proposed.

#### Boolean and multi-value logic for biological network analysis

The aim is to develop a methodology for the functional analysis of biological networks with a focus on describing the contribution of their various modules to the global quantitative behavior of the networks. The formalism we develop aims to describe how a (quantitative) property of a biological network in terms of combinations of modules being knocked-in or –out (through Boolean logic) or in terms of combination of different levels of activity for the modules (through multi-valued logic). The approach is highly relevant for reverse engineering of biological networks, in an effort to identify their functional motifs, as well as for synthetic biology, for engineering a desired behavior from a given library of modules. Our analysis will first consider two case studies: (i) EGFR (Epidermal growth factor receptor) signaling pathway which is essential for normal cell growth and development; (ii) a computational platform for high-throughput vaccine development.

#### Computational gene assembly

The process of gene assembly has the attention of the Biocomputing community for several years already. It is by now clear that the process of gene assembly in ciliates is highly computational: it turns out that ciliates "know" one of the basic data structures of Computer Science - the linked list - and use it in a very elegant pattern matching manner in the process of gene assembly! We are investigating a set of three molecular operations that accomplishes the gene assembly through the "fold and recombine" paradigm. We introduced the mathematical model of pointer reduction systems to formalize the micronuclear gene patterns (through permutations, strings and graphs) and the gene assembly process. Our investigation of these systems resulted in a uniform explanation of all known experimental results concerning gene assembly in ciliates.

#### Computational modelling with reaction systems

A biochemical network consists of a great number of reactions that cooperate with one another with the fundamental goal of keeping the cell alive. Reaction systems consider only two possible regulatory mechanisms: facilitation and inhibition. A biochemical reaction concerns a finite set of reactants provided that all the reactants involved in that particular reaction are present in a given state and all of its inhibitors are absent. We demonstrate that reaction systems are rich enough to capture the essential characteristics of quantitative models (e.g., ODE-based models) and also show the expressive power of reaction systems when dealing with wide range of problems from biology to computer science (e.g., exact pattern matching in strings). Our aim is also to introduce a methodology that enables us to translate a quantitative model to a qualitative reaction system based one without losing any essential characteristics of the former one.

#### Large-scale modelling

It is common practice in the field of biomodelling to represent different aspects of the same biological phenomena with different formalisms and at different abstraction levels. The choice of a particular modeling approach and abstraction level depends on the initial understanding of the phenomena, availability of the relevant initial and experimental data, scale, mathematical and computational complexity of the model, the researcher’s own competence, etc. On the other hand, individual research teams usually focus in depth at some particular aspects of a cellular biology, while leaving the “great picture” mostly untouched. This is due to the fact that building a comprehensive model for a living cell would require a tremendous amount of experimental data, deep and extremely versatile knowledge of the cell’s biology and processes, serious theoretical and computational challenges and large interdisciplinary research team. In our project, rather than attempting to build large and detailed computational model for a living cell from scratch, we are developing approaches to integrate various modelling/simulating techniques into a comprehensive modeling framework and implement it as a public software platform.

### Publications

#### Click here to see the full list of publications from the TUCS Publication Database

#### The latest updated publications:

Gheorghe Paun, Ion Petre, Grzegorz Rozenberg, Arto Salomaa (Eds.), At the Intersection of Computer Science with Biology, Chemistry and Physics – In Memory of Solomon Marcus. *Theoretical Computer Science* 701, 2017.

Mikhail Barash, Ion Petre, A Foundational Framework for Step-by-Step Model Construction. *Fundamenta Informaticae* 154, 1–10, 2017.

Sepinoud Azimi, Steady States of Constrained Reaction Systems. *Theoretical Computer Science* , 1–7, 2017.

Krishna Kanhaiya, Eugen Czeizler, Cristian Gratie, Ion Petre, Controlling Directed Protein Interaction Networks in Cancer. *Scientific Reports* 7(1), 10327, 2017.

Cecilia Sahlgren, Annika Meinander, Hongbo Zhang, Fang Cheng, Maren Preis, Chunlin Xu, Tiina Salminen, Diana Toivola, Daniel Abankwa, Didem Karaman, Outi Salo, Ronald Österbacka, John Eriksson, Stefan Willför, Ion Petre, Jouko Peltonen, Reko Leino, Mark Johnson, Jessica Rosenholm, Niklas Sandler, Tailored Approaches in Drug Development and Diagnostics – From Molecular Design to Biological Model Systems. *Advanced Healthcare Materials* , 1700258, 2017.

Usman Sanwal, Luigia Petre, Ion Petre, Stepwise Construction of a Metabolic Network in Event-B: The Heat Shock Response. *Computers in Biology and Medicine* (91), 1–12, 2017.

Usman Sanwal, Umair Siddique, Combining Refinement and Signal-Temporal Logic for Biological Systems. In: Herman Geuvers, Matthew England, Osman Hasan, Florian Rabe, Olaf Teschke (Eds.), *Intelligent Computer Mathematics*, LNAI 10383, 333–3398, Springer, 2017.

Andrzej Ehrenfeucht, Ion Petre, Grzegorz Rozenberg, Reaction systems: a model of computation inspired by the functioning of the living cell. In: Stavros Konstantinidis, Nelma Moreira, Rogério Reis, Jeffrey Shallit (Eds.), *The Role of Theory in Computer Science*, 1–32, World Scientific, 2017.

Sepinoud Azimi, Joonas Jalonen, Jarkko Kari, Ion Petre (Eds.), *Computability in Europe 2017*, TUCS General Publication, 2017.

Sepinoud Azimi, Hendrik Jan Hoogeboom, Jetty Kleijn, Marloes van der Nat, Ion Petre, Arto Salomaa (Eds.), *A Magician in Science: Liber Amicorum Grzegorz Rozenberg*, TUCS General Publication, TUCS, 2017.

Dwitiya Tiyagi-Tiwari, Krishna Kanhaiya, Ion Petre, Controllability and Identifying Drug Targets of Metabolic Networks in Cancer. TUCS Technical Reports 1185, 2017.

Bogdan Iancu, Usman Sanwal, Cristian Gratie, Ion Petre, Fit-Preserving Refinement of the ErbB Signalling Pathway. TUCS Technical Reports 1187, TUCS, 2017.

Charmi Panchal, Vladimir Rogojin, Generating the Logicome from Microarray Data. TUCS Technical Reports 1175, TUCS, 2017.

Artiom Alhazov, Rudolf Freund, Vladimir Rogozhin, Yurii Rogozhin, Computational Completeness of Complete, Star-Like, and Linear Hybrid Networks of Evolutionary Processors with a Small Number of Processors. *Natural Computing* 15(1), 51–68, 2016.

Sepinoud Azimi, Cristian Gratie, Sergiu Ivanov, Luca Manzoni, Ion Petre, Antonio E. Porreca, Complexity of Model Checking for Reaction Systems. *Theoretical Computer Science* 623, 103–113, 2016.

Diana-Elena Gratie, Cristian Gratie, Composition Colored Petri Nets for the Refinement of Reaction-based Models. *Electronic Notes in Theoretical Computer Science* 326, 51–72, 2016.

Cristian Gratie, Ion Petre, Complete Characterization for the Fit-Preserving Data Refinement of Mass-Action Reaction Networks. *Theoretical Computer Science* 641, 11–24, 2016.

Vladimir Rogojin, Ion Petre, Large-Scale Executable Biology Using Rapid Integration of Computational Models. *Computer Science Journal of Moldova* 24(1 (70)), 118 – 135, 2016.

Sepinoud Azimi, Charmi Panchal, Andrzej Mizera, Ion Petre, Multi-Stability, Limit Cycles, and Period-Doubling Bifurcation with Reaction Systems. *TUCS Technical Reports* 1167, 20–25, 2016.

Eugen Czeizler, Cristian Gratie, Wu Kai Chiu, Krishna Kanhaiya, Ion Petre, Target Controllability of Linear Networks. In: Ezio Bartocci, Pietro Lio, Nicola Paoletti (Eds.), *Computational Methods in Systems Biology*, Lecture Notes in Bioinformatics 9859, 67–81, Springer, 2016.

Charmi Panchal, Sepinoud Azimi, Ion Petre, Generating the Logicome of a Biological Network. In: Botón-Fernández María,, Martín-Vide Carlos,, Santander-Jiménez Sergio,, Miguel A. Vega-Rodríguez (Eds.), *Algorithms for Computational Biology*, Lecture Notes in Bioinformatics (Subseries of Lecture Notes in Computer Science), 38–49, Springer, 2016.

Vladimir Rogojin, Keivan Kazemi, Krishna Kanhaiya, Eugen Czeizler, Ion Petre, Automatic Discovery of Combined Drug Therapy. In: Andrea Bracciali, David Gilbert, Gilbert MacKenzie (Eds.), *Thirteenth International Meeting on Computational Intelligence Methods for Bioinformatics and Biostatistics*, University of Stirling, UK, 2016.

Diana-Elena Gratie, Bogdan Iancu, Sepinoud Azimi, Ion Petre, Quantitative Model Refinement in Four Different Frameworks, with Applications to the Heat Shock Response. In: Luigia Petre, Emil Sekerinski (Eds.), *From Action Systems to Distributed Systems*, 201–2014, Taylor & Francis, 2016.

Diana-Elena Gratie, *Refinement of Biomodels Using Petri Nets*. TUCS Dissertations 216. 2016.

Sepinoud Azimi, Charmi Panchal, Andrzej Mizera, Ion Petre, Multi-Stability, Limit Cycles, and Period-Doubling Bifurcation with Reaction Systems. TUCS Technical Reports 1167, TUCS, 2016.

Eugen Czeizler, Cristian Gratie, Kai Chiu Wu, Krishna Kanhaiya, Ion Petre, Target Controllability of Linear Networks. TUCS Technical Reports 1157, TUCS, 2016.

Andrzej Ehrenfeucht, Ion Petre, Grzegorz Rozenberg, Reaction Systems: A Model of Computation Inspired by the Functioning of the Living Cell. TUCS Technical Reports 1161, TUCS, 2016.

Krishna Kanhaiya, Eugen Czeizler, Christian Gratie, Ion Petre, Controlling Directed Protein Interaction Networks in Cancer. TUCS Technical Reports 1155, TUCS, 2016.

Krishna Kanhaiya, Vladimir Rogojin, Keivan Kazemi, Eugen Czeizler, Ion Petre, NetControl4BioMed: A Pipeline for Biomedical Data Acquisition and Analysis of Network Controllability. TUCS Technical Reports 1163, TUCS, 2016.

Dumitru Iulian Nastac, Irina-Maria Dragan, Alexandru Isaic-Maniu, A Practical Classification Model for Small and Medium Sized Enterprises According to Their Profitability. TUCS Technical Reports 1165, Turku Centre for Computer Science, 2016.

Vladimir Rogojin, Keivan Kazemi, Krishna Kanhaiya, Eugen Czeizler, Ion Petre, NetControl4BioMed – Automatic Discovery of Combined Drug Therapy. TUCS Technical Reports 1162, TUCS, 2016.

Usman Sanwal, Luigia Petre, Ion Petre, Stepwise Construction of a Metabolic Network in Event-B: the Heat Shock Response. TUCS Technical Reports 1160, TUCS, 2016.