Andrzej Mizera Methods for Construction and Analysis of Computational Models in Systems Biology

297 Pages·2011·7.57 MB·English

Andrzej Mizera
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
Turku Centre for Computer Science
TUCS Dissertations
No 138, August 2011

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
Andrzej Mizera
To be presented, with the permission of the Division for Natural Sciences
and Technology of Åbo Akademi University, for public criticism in
Auditorium Gamma on August 26, 2011, at 12 noon.
Åbo Akademi University
Department of Information Technologies
Joukahaisenkatu 3-5A, FIN-20520 Turku, Finland
2011
Supervisors
Prof. Ion Petre
Department of Information Technologies
Åbo Akademi University
Joukahaisenkatu 3-5A, FIN-20520 Turku
Finland
Dr hab. Barbara Gambin
Department of Ultrasound
Institute of Fundamental Technological Research
Polish Academy of Sciences
Pawińskiego 5B, 02-106 Warsaw
Poland
Reviewers
Prof. Erik de Vink
Department of Mathematics and Computer Science
Technische Universiteit Eindhoven
Den Dolech 2, 5600 MB Eindhoven
The Netherlands
Prof. Corrado Priami
Centre for Computational and Systems Biology
The Microsoft Research - University of Trento
Piazza Manci 17, 38123 Povo (Trento)
Italy
Opponent
Prof. Erik de Vink
Department of Mathematics and Computer Science
Technische Universiteit Eindhoven
Den Dolech 2, 5600 MB Eindhoven
The Netherlands
ISBN 978-952-12-2616-8
ISSN 1239-1883
Abstract
Systemsbiologyisanew,emergingandrapidlydeveloping,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
modellingof lifeprocessestightly linked toexperimentalpractice. Thestud-
ies contained in this thesis revolve arounda numberof 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,
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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.
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Sammanfattning
(abstract in Swedish)
Systembiologi är ett nytt, emergent och snabbt växande, tvärvetenskaplig
forskningsområdesomfokuserarpåsystematiskt studiumavbiokemiska och
biologiska system ur ett heltäckande perspektiv, med syftet att uppnå allsi-
dig förståelse av cellulära beteenden på systemnivå. På detta sätt angriper
systembiologinenavdestörstautmaningarnasommodernbiologistårinför,
dvs. att förstå funktionen hos komplexa biologiska system. Systembiologin
sammanfogar olika metoder vilka har sitt ursprung i vetenskapliga disci-
pliner, såsom molekylärbiologi, kemi, ingenjörsvetenskap, matematik, data-
vetenskap och systemteori. Systembiologin, till skillnad från “traditionell”
biologi,fokuserarpåhögnivåbegreppsåsom:nätverk,komponent,robusthet,
effektivitet, kontroll, reglering, hierarkisk design, synkronisering,samverkan
och många andra. Själva terminologin i systembiologin är “främmande” för
“traditionell” biologi; den markerar en drastisk förändring i forskningspara-
digmet och tyder på en nära koppling mellan systembiologin och dataveten-
skap.
Ett av de basala verktygen som används i systembiologin är matema-
tisk modellering av livsprocesser i samband med experimentell forskning.
De undersökningar som ingår i denna avhandling kretsar kring ett antal
utmaningar som ofta förekommer i beräkningsmodellering inom systembio-
login. Den presenterade forskningen består av utveckling och tillämpning av
ett brett sortiment av metoder vilka har sitt ursprung i datavetenskap och
matematik för konstruktion och analys av datormodeller i systembiologin.
I synnerhet är den forskningen utförd i kontexten av två biologiska fenomen
utvalda som fallstudier: 1) eukaryotiskt värme-chock respons och 2) in vitro
självorganisering av intermediära filament, en av huvudbeståndsdelarna av
cytoskelettet. Sortimentetavpresenteradetillvägagångssätt sträckersigfrån
heuristiska metoder, via numeriska och statistiska metoder till analytiska
metoder, tillämpade i strävan att formellt beskriva de två biologiska proces-
serna. Vi konstaterar att de presenterade metoderna, fastän utnyttjade i de
enskilda fallstudierna, inte är begränsade till dessa utan kan tillämpas vid
analys av andra biologiska mekanismer samt komplexa system i allmänhet.
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Hela sortimentet av utvecklade och tillämpade modelleringstekniker samt
metodologier för modellanalys utgör ett rikt modelleringsramverk. Presen-
tationenavdeutvecklademetoderna,derastillämpningidetvåfallstudierna
och diskussionerna om deras möjligheter och begränsningar, visar därtill på
svårigheter och utmaningar man stöter på i beräkningsmodellering av bi-
ologiska system. Identifierbarhet av modeller, jämförelse mellan modeller,
precisering, integration och utvidgning av modeller, urval av rätt modelle-
ringsramverk och abstraktionsnivå samt urval av ett lämpligt omfång för en
modell är problem som diskuteras genom hela denna avhandling.
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Acknowledgements
My experience with scientific research started in 2005 when I was in the last
stageofmymaster’sdegreestudiesattheFacultyofMathematics, Informat-
ics and Mechanics at the University of Warsaw. I was then encouraged by
Dr hab. Anna Gambin to continue learning and broadening my knowledge
as a PhD student. Following her advice, I enrolled in a PhD programme
at the Institute of Fundamental Technological Research, Polish Academy of
Sciences. The first one and a half years of my studies I spent on studying
mechanics and getting to know the field of biomechanics under the supervi-
sion of Dr hab. Barbara Gambin. In the meantime, in September 2006 I got
in touch with Prof. Ion Petre from Åbo Akademi University, Finland and
decided to focus my research on computational modelling in systems biol-
ogy. In consequence, I joined the Computational Biomodelling Laboratory
at Åbo Akademi University in January 2007.
Firstand foremost, I want to expressmy tremendousand deepgratitude
to my both supervisors. I am extremely thankfulto my supervisorProf. Ion
Petre for the enormous, comprehensive and wise support I have obtained
from him. I wish to thank him for all the time and effort he has dedicated
to me, for always being available whenever I had a problem concerning both
scientific as well as non-scientific matters, for the patience and understand-
ing with which he treated me, for the great passion with which he has been
guiding and advising me ever since we met for the first time, and the con-
fidence that I could always rely on him. I am immensely grateful to my
supervisor Dr hab. Barbara Gambin for her extensive, all-embracing and
thoughtful assistance. I would especially like to thank her for all the time
and energy she has devoted to me, for her constant readiness to support me
in all aspects of my studies, for giving me the reassurance that I can turn
to her for help with all kinds problems, as well as for the enthusiasm and
commitment with which she has been assisting me during all the years of
myPhDstudies. Itis ingeneral difficulttoencounter peopleof suchperson-
alities in general, so I feel extremely lucky that I was given the opportunity
to work with them and have them as my supervisors. Thank you!
I am very thankful to Prof. Erik de Vink that he kindly agreed to be
a reviewer of my dissertation and that he accepted to act as the opponent
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at my doctoral defence. I am very grateful to Prof. Corrado Priami for
accepting to be a reviewer of my doctoral thesis. I would like to thank
both of them for all the time and effort they dedicated to a thorough review
of my dissertation, their helpful, valuable and accurate remarks as well as
encouraging comments.
I am especially grateful to Elena Czeizler and Eugen Czeizler for our
many inspiring and fruitful scientific discussions as well as efficient and pro-
ductive work which resulted in a number of publications. I am extremely
thankful to Anna Gambin for her advice, many discussions, valuable com-
ments and all the support I received from her during my stay in Poland
during the academic year 2008/2009.
I would like to thank Prof. Jerzy Tiuryn from the Faculty of Mathe-
matics, Informatics and Mechanics at the University of Warsaw, who gave
me the first taste of what scientific research means as my master thesis
supervisor. I would like to list and thank all the other members of his Com-
putational Biology Group who advised and assisted me during the work on
my master thesis as well as are the coauthors of my first scientific article:
Norbert Dojer, Anna Gambin, and Bartosz Wilczyński.
I want to list here and express my gratitude to all my coauthors and
people with whom I collaborated during my PhD studies. I am thank-
ful to Ralph-Johan Back, Elena Czeizler, Eugen Czeizler, Norbert Dojer,
John E. Eriksson, Małgorzata Figurska, Anna Gambin, Barbara Gambin,
Claire L. Hyder, Eleonora Kruglenko, Tamara Kujawska, Annika Meinan-
der, Andrey Mikhailov, Richard I. Morimoto, Andrzej Nowicki, Ion Petre,
Diana Preoteasa, Lea Sistonen, Maciej Stańczyk, Jerzy Tiuryn,and Bartosz
Wilczyński.
These acknowledgements would be incomplete without expressing my
gratitude to each of the former and present members of the Computational
Biomodelling Laboratory at Åbo Akademi University (Combio). I am par-
ticularlygratefultomyfriendVladimirRogojin,thefirstmemberofCombio
whom I met and without whom my stay in Finland would certainly not be
this rich and joyful. I would like to thank Artiom Alhazov, Sepinoud Azimi,
Ralph-Johan Back, Elena Czeizler, Eugen Czeizler, Vladimir Grigor, Bog-
dan Iancu, Tseren-Onolt Ishdorj, Miika Langille, Chang Li, and Ion Petre
for all the great time I spent with them at work as well as during our less
formal meetings and activities.
I would like to thank Åbo Akademi University and the Turku Centre
for Computer Science for the excellent conditions they provided me with as
well as for the friendly atmosphere that I could enjoy during my doctoral
studies. IamtrulygratefultotheadministrationoftheDepartmentofInfor-
mation Technologies attheÅboAkademiUniversity andtheadministration
of Turku Centre for Computer Science for their substantial assistance in all
organizational matters.
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