Natural Computing Series

Series Editors: G. Rozenberg Th. Bäck A.E. Eiben J.N. Kok H.P. Spaink Leiden Center for Natural Computing

Advisory Board: S. Amari G. Brassard K.A. De Jong C.C.A.M. Gielen T. Head L. Kari L. Landweber T. Martinetz Z. Michalewicz M.C. Mozer E. Oja G. Paun˘ J. Reif H. Rubin A. Salomaa M. Schoenauer H.-P. Schwefel C. Torras D. Whitley E. Winfree J.M. Zurada

For further volumes: http://www.springer.com/series/4190 Anne Condon  David Harel  Joost N. Kok   Erik Winfree Editors

Algorithmic Bioprocesses Editors Dr. Anne Condon Prof. Dr. Arto Salomaa Department of Computer Science Centre for Computer Science University of British Columbia and Mathematics Department Vancouver, BC V6T1Z4, [email protected] Turku 20014, asalomaa@utu.fi Prof. David Harel Department of Computer Science Dr. Erik Winfree and Applied Mathematics Computer Science, Computation and Neural The Weizmann Institute of Science Systems and Bioengineering Rehovot 76100, Israel Caltech [email protected] Pasadena, CA 91125, USA [email protected] Prof. Dr. Joost N. Kok Leiden Institute of Advanced Computer Science (LIACS) 2333 Leiden, The Netherlands [email protected]

Series Editors G. Rozenberg (Managing Editor) A.E. Eiben [email protected] Vrije Universiteit Amsterdam The Netherlands Th. Bäck, Joost N. Kok, H.P. Spaink Leiden Center for Natural Computing Leiden University 2333 Leiden, The Netherlands

ISSN 1619-7127 ISBN 978-3-540-88868-0 e-ISBN 978-3-540-88869-7 DOI 10.1007/978-3-540-88869-7 Springer Dordrecht Heidelberg London New York

Library of Congress Control Number: 2008944308

ACM Computing Classification (1998): J.3, F.2

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Springer is part of Springer Science+Business Media (www.springer.com) This book is dedicated to This image was created by DADARA Preface

This Festschrift celebrates the 65th birthday of Grzegorz Rozenberg, one of the world leaders in research on theoretical computer science and natural computing. Grzegorz had—and still has—enormous influence on the development of both dis- ciplines. He has published over 500 research papers, 6 books, and coedited about 90 books. His papers shaped research in a whole range of areas, including formal language and automata theory, the theory of concurrent systems, the theory of graph transformations, mathematical structures in computer science, and natural comput- ing. He is often referred to as a guru of natural computing, as he was promoting the vision of natural computing as a coherent scientific discipline already back in the 1970s. He is especially fond of—and very successful in—interdisciplinary research. As a matter of fact, his education and research career is interdisciplinary in a quite symbolic way: His first degree was as an electronics engineer; he got his master’s degree in computer science and his Ph.D. in mathematics, and for over 30 years he has worked closely with biologists on information processing in biological systems. Grzegorz is well known for his work for the scientific community. Apparently, this has its roots at the beginning of his career in , as he felt that scientists there were quite isolated and forgotten by their colleagues in the West. He promised himself that if he ever got out of Eastern Europe he would spend a considerable part of his life working for the community. His current or past functions for the academic community include: president of the European Association for Theoretical Computer Science (EATCS); a cofounder and president of the International Society for Nanoscale Science, Computation, and Engineering (ISNSCE); chair of the steering committee of the DNA Computing Conference; chair of the steering committee of the International Conference on Ap- plication and Theory of Petri Nets; chair of the steering committee of the European Educational Forum; a cofounder and chair of the steering committee of the Inter- national Conference on Developments in Language Theory; and a cochair of the steering committee of the International Conference on Unconventional Computa- tion. He is on the editorial boards of many journals and book series. As a matter of fact, he was a cofounder of some well-known journals and book series, most notably the journal Natural Computing, the journal Theoretical Computer Science C (Theory of Natural Computing), the book series Monographs and Texts in Theoretical Com- puter Science, the book series Natural Computing, and the book series Advances in

vii viii Preface

Petri Nets. For over 20 years, he was the editor of the Bulletin of the European Asso- ciation for Theoretical Computer Science, and is a coeditor of four handbooks—on formal languages, on graph grammars and computing by graph transformations, on membrane computing, and on natural computing. He also made valuable contributions on the national scene in The Netherlands. For example, he was the founder and the first president of the Dutch Association for Theoretical Computer Science. Also, he initiated the Dutch Theory Day, which is today the main meeting forum for researchers working on theoretical computer science in The Netherlands. His life in science is only one of his several lives. He is a professional magician— often performing at scientific conferences. Also, he spends a considerable part of his intellectual life studying the paintings of Hieronymus Bosch. [Apparently, he is writing a book on the art of Bosch.] But, most of all, he is a family man, and an ad- mirer of the art of his son, DADARA. The phrase “family man” must be seen here in a broader context, as he calls his Ph.D. students and postdocs, and many of the scientists who come to work with him, “his children.” For more insight into Grze- gorz’s life and personality, please see the tribute “Grzegorz Rozenberg: A Magical Scientist and Brother” by his close friend and collaborator Arto Salomaa in Part I of this book. To celebrate the 65th birthday of Grzegorz, we organized in December 2007 a workshop on Algorithmic Bioprocesses at the Lorentz Center of Leiden University. The theme of the workshop is one of Grzegorz’s research areas, and it falls within the general field of natural computing which is certainly his favorite research field now. As a matter of fact, we wanted the workshop to reflect Grzegorz’s views of computer science and natural computing, which in a nutshell, can be explained as follows. The spectacular progress in information and communications technology (ICT) is very much supported by the evolution of computer science which designs and develops the instruments needed for this progress: computers, computer networks, software methodologies, etc. Since ICT has a tremendous impact on our everyday life, so too does computer science. However, there is much more to computer science than ICT: It is the science of information processing, and, as such, it is a fundamental science for other scientific disciplines. On the one hand, the only common denominator among the many, diverse re- search areas in computer science is that they require us to think about various aspects of information processing. Therefore, the frequently used term “informatics”—most commonly used in Europe—is much better than “computer science”; the latter stip- ulates that a specific instrument, namely the computer, is the main research topic of our discipline. On the other hand, one of the important developments of the last century for a number of other scientific disciplines is the adoption of information and information processing as central notions and frameworks of thought—biology and physics are prime examples here. For these scientific disciplines, informatics provides not only instruments but also a way of thinking. One of the grand chal- lenges of informatics is to understand the world around us in terms of information processing. Preface ix

Informatics (computer science) is now undergoing an important transformation which is stimulated to a great extent by all kinds of interactions with the natural sciences. It is adapting and extending its traditional notions of computation and computational techniques to account for computation taking place in nature around us. Natural computing is concerned with computing taking place in nature as well as human-designed computing inspired by nature. Using the terminology of natural sciences, specifically biochemistry, one can say that natural computing is an im- portant catalyst for the interactions between informatics and natural sciences, and hence an important catalyst for the ongoing, exciting development of informatics. The main idea of the “Algorithmic Bioprocesses” workshop was to reflect the above point of view, and most importantly to reflect the power and excitement of interdisciplinary research, which forms the core of natural computing. We have cho- sen the name “Algorithmic Bioprocesses” because the workshop did not cover the whole spectrum of natural computing research, but rather it was mostly focused on the interactions between computer science on the one hand and biology, chemistry, and DNA-oriented nanoscience on the other. The workshop turned out to be a great success due—among other reasons – to the fact that many world leaders of research in natural computing participated. It was also a very pleasant social event. Grzegorz was visibly happy with the work- shop, obviously because of its high scientific level, but also because so many of the speakers were really his “children.” The idea of a book based on the workshop had already occurred to us before the event, and participants suggested additional contributors to the book, especially scientists whose work is related to Grzegorz’s research interests. As a result, this book contains some contributions that were not presented at the workshop. We be- lieve that the resulting book provides a valuable perspective on an important part of current research in natural computing. The book is divided into parts which, with the exception of Part I, reflect various research areas related to algorithmic bioprocesses. Part I is a tribute to Grzegorz written by his very close friend and collaborator Arto Salomaa. Part II, “Sequence Discovery, Generation, and Analysis,” is concerned with many aspects of funda- mental studies of biological systems. Part III, “Gene Assembly in Ciliates,” covers theoretical, computational, and experimental research on the process of gene assem- bly, including the hypothesis on the biological realization of this process. Part IV, “Nanoconstructions and Self-assembly,” discusses many aspects of nanoconstruc- tions and self-assembly including theoretical and computational aspects as well as pragmatic considerations on implementations of physical chemistry processes. Part V, “Membrane Computing,” discusses the membrane computing model inspired by the compartmentalization of cells by biological membranes. It also surveys research on a more recent model of spiking neural P systems which is motivated by the behav- ior of spiking neural networks. Part VI, “Formal Models and Analysis,” surveys gen- eral computer science-inspired approaches to modeling and analysis of biological processes, such as the use of Petri nets, and the use of probabilistic model checking. It also presents models for specific biological phenomena such as recombination, the x Preface eukaryotic heat shock response, the MAP kinase cascade, and the behavior of the calyx of Held synapse. Part VII, “Process Calculi and Automata,” deals with the re- lationship between automata and process calculi on the one hand and biochemistry on the other. It considers molecules as automata, biochemical implementation of automata, process calculi as a general framework for studying biological processes, and translations from process algebra models into differential equations—a more traditional framework used by biologists. Part VIII, “Biochemical Reactions,” con- siders problems of stochastic simulation and modeling in relation to dynamic de- scription of biochemical reactions. Finally, Part IX, “Broader Perspective,” provides a more general setting for the book by adding a number of additional topics from natural computing. They include molecular evolution, regulation of gene expression, light-based computing, cellular automata, realistic modeling of biological systems, and evolutionary computing. Thus, the book covers a wide spectrum of research topics from natural comput- ing. Since it is a Festschrift, it is fitting to note here that Grzegorz made valuable research contributions to the research themes of all parts of this book. We hope that this book will contribute to the further development of research in the very exciting and important area of natural computing, by providing valuable perspective and knowledge to researchers in natural computing, and by motivating and encouraging others to join this research field. Most of all, we hope that the book is really a worthy tribute to Grzegorz. We want to thank all the contributors for helping us to achieve these goals.

Vancouver, Canada Anne Condon Rehovot, Israel David Harel Leiden, The Netherlands Joost N. Kok Turku, Finland Arto Salomaa Pasadena, USA Erik Winfree Contents

Part I Tribute

Grzegorz Rozenberg: A Magical Scientist and Brother ...... 3 Arto Salomaa

Part II Sequence Discovery, Generation, and Analysis

Monotony and Surprise ...... 15 Alberto Apostolico

Information Content of Sets of Biological Sequences Revisited ...... 31 Alessandra Carbone and Stefan Engelen

Duplication in DNA Sequences ...... 43 Masami Ito, Lila Kari, Zachary Kincaid, and Shinnosuke Seki

Sequence and Structural Analyses for Functional Non-coding RNAs ... 63 Yasubumi Sakakibara and Kengo Sato

Part III Gene Assembly in Ciliates

Strategies for RNA-Guided DNA Recombination ...... 83 Angela Angeleska, Nataša Jonoska, Masahico Saito, and Laura F. Landweber

Reality-and-Desire in Ciliates ...... 99 Robert Brijder and Hendrik Jan Hoogeboom

Template-Guided Recombination: From Theory to Laboratory ...... 117 Mark Daley and Michael Domaratzki

Part IV Nanoconstructions and Self-assembly

DNA Cages with Icosahedral Symmetry in Bionanotechnology ...... 141 Nataša Jonoska, Anne Taormina, and Reidun Twarock

Applying Symmetric Enumeration Method to One-Dimensional Assembly of Rotatable Tiles ...... 159 Satoshi Kobayashi

xi xii Contents

A Self-assembly Model of Time-Dependent Glue Strength ...... 185 Sudheer Sahu, Peng Yin, and John H. Reif

The Perils of Polynucleotides Revisited ...... 205 Nadrian C. Seeman

Algorithmic Control: The Assembly and Operation of DNA Nanostructures and Molecular Machinery ...... 215 Andrew J. Turberfield

Part V Membrane Computing

On Nonuniversal Symport/Antiport P Systems ...... 229 Oscar H. Ibarra and Sara Woodworth

Spiking Neural P Systems. Recent Results, Research Topics ...... 273 Gheorghe Paun˘ and Mario J. Pérez-Jiménez

Membrane Computing Schema: A New Approach to Computation Using String Insertions ...... 293 Mario J. Pérez-Jiménez and Takashi Yokomori

Part VI Formal Models and Analysis

Finite Splicing: Generative Capacity, New Models and Complexity Aspects ...... 313 Paola Bonizzoni and Remco Loos

Formal Models of the Calyx of Held ...... 331 Andrea Bracciali, Marcello Brunelli, Enrico Cataldo, and Pierpaolo Degano

Understanding Network Behavior by Structured Representations of Transition Invariants ...... 367 Monika Heiner

Quantitative Verification Techniques for Biological Processes ...... 391 Marta Kwiatkowska, Gethin Norman, and David Parker

A New Mathematical Model for the Heat Shock Response ...... 411 Ion Petre, Andrzej Mizera, Claire L. Hyder, Andrey Mikhailov, John E. Eriksson, Lea Sistonen, and Ralph-Johan Back

Part VII Process Calculi and Automata

Artificial Biochemistry ...... 429 Luca Cardelli Contents xiii

Process Calculi Abstractions for Biology ...... 463 Maria Luisa Guerriero, Davide Prandi, Corrado Priami, and Paola Quaglia

Deriving Differential Equations from Process Algebra Models in Reagent-Centric Style ...... 487 Jane Hillston and Adam Duguid

Programmable DNA-Based Finite Automata ...... 505 Tamar Ratner and Ehud Keinan

Part VIII Biochemical Reactions

A Multi-volume Approach to Stochastic Modeling with Membrane Systems ...... 519 Daniela Besozzi, Paolo Cazzaniga, Dario Pescini, and Giancarlo Mauri

Programmability of Chemical Reaction Networks ...... 543 Matthew Cook, David Soloveichik, Erik Winfree, and Jehoshua Bruck

Log-gain Principles for Metabolic P Systems ...... 585 Vincenzo Manca

Hybrid Method for Simulating Small-Number Molecular Systems ....607 Kazufumi Mizunuma and Masami Hagiya

Part IX Broader Perspective

On Involutions Arising from Graphs ...... 623 Jurriaan Hage and Tero Harju

Parallel Computing by Xeroxing on Transparencies ...... 631 Tom Head

Some Undecidable Dynamical Properties for One-Dimensional Reversible Cellular Automata ...... 639 Jarkko Kari and Ville Lukkarila

On Using Divide and Conquer in Modeling Natural Systems ...... 661 Yaki Setty, Irun R. Cohen, Avi E. Mayo, and David Harel

No Molecule Is an Island: Molecular Evolution and the Study of Sequence Space ...... 675 Erik A. Schultes, Peter T. Hraber, and Thomas H. LaBean

Niching Methods: Speciation Theory Applied for Multi-modal Function Optimization ...... 705 Ofer M. Shir and Thomas Bäck xiv Contents

On the Concept of Cis-regulatory Information: From Sequence Motifs to Logic Functions ...... 731 Ryan Tarpine and Sorin Istrail Contributors

Angela Angeleska University of South Florida, Florida, FL, USA, [email protected] Alberto Apostolico Dipartimento di Ingegneria dell’ Informazione, Università di Padova, Padova, Italy, [email protected] and College of Computing, Georgia Institute of Technology, 801 Atlantic Drive, Atlanta, GA 30318, USA Thomas Bäck Natural Computing Group, Leiden University, Leiden, The Netherlands, [email protected] and NuTech Solutions, Dortmund, Germany Ralph-Johan Back Department of Information Technologies, Åbo Akademi University, Turku 20520, Finland, backrj@abo.fi Daniela Besozzi Dipartimento di Informatica e Comunicazione, Università degli Studi di Milano, Via Comelico 39, 20135 Milano, Italy, [email protected] Paola Bonizzoni Dipartimento di Informatica Sistemistica e Comunicazione, Università degli Studi di Milano—Bicocca, Viale Sarca 336, 20126 Milano, Italy, [email protected] Andrea Bracciali Dipartimento di Informatica, Università di Pisa, Pisa, Italy, [email protected] Robert Brijder Leiden Institute of Advanced Computer Science, Universiteit Leiden, Niels Bohrweg 1, 2333 CA Leiden, The Netherlands, [email protected] Jehoshua Bruck California Institute of Technology, Pasadena, CA, USA, [email protected] Marcello Brunelli Dipartimento di Biologia, Università di Pisa, Pisa, Italy, [email protected] Alessandra Carbone Génomique Analytique, Université Pierre et Marie Curie, INSERM UMRS511, 91, Bd de l’Hôpital, 75013 Paris, France, [email protected]

xv xvi Contributors

Luca Cardelli Microsoft Research, Cambridge, UK, [email protected] Enrico Cataldo Dipartimento di Biologia, Università di Pisa, Pisa, Italy, [email protected] Paolo Cazzaniga Dipartimento di Informatica, Sistemistica e Comunicazione, Università degli Studi di Milano—Bicocca, Viale Sarca 336, 20126 Milano, Italy, [email protected] Irun R. Cohen Weizmann Institute of Science, Rehovot 76100, Israel, [email protected] Matthew Cook Institute of Neuroinformatics, UZH, ETH Zürich, Zürich, Switzerland, [email protected] Mark Daley Departments of Biology and Computer Science, University of Western Ontario, London, ON, N6A 5B7, Canada, [email protected] Pierpaolo Degano Dipartimento di Informatica, Università di Pisa, Pisa, Italy, [email protected] Michael Domaratzki Department of Computer Science, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada, [email protected] Adam Duguid School of Informatics, The University of Edinburgh, Edinburgh, Scotland, UK, [email protected] Stefan Engelen Génomique Analytique, Université Pierre et Marie Curie, INSERM UMRS511, 91, Bd de l’Hôpital, 75013 Paris, France, [email protected] John E. Eriksson Turku Centre for Biotechnology, Turku, Finland and Department of Biochemistry, Åbo Akademi University, Turku 20520, Finland, john.eriksson@btk.fi Maria Luisa Guerriero Laboratory for Foundations of Computer Science, The University of Edinburgh, Informatics Forum, 10 Crichton Street, EH8 9AB, Edinburgh, UK, [email protected] Jurriaan Hage Department of Information and Computing Sciences, Universiteit Utrecht, P.O. Box 80.089, 3508 TB Utrecht, The Netherlands, [email protected] Masami Hagiya Graduate School of Information Science and Technology, University of Tokyo, Tokyo, Japan, [email protected] David Harel Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel, [email protected] Tero Harju Department of Mathematics, University of Turku, 20014 Turku, Finland, harju@utu.fi Tom Head Mathematical Sciences, Binghamton University, Binghamton, NY 13902-6000, USA, [email protected] Contributors xvii

Monika Heiner Department of Computer Science, Brandenburg University of Technology, Postbox 101344, 03013 Cottbus, Germany, [email protected] Jane Hillston School of Informatics, The University of Edinburgh, Edinburgh, Scotland, UK, [email protected] Hendrik Jan Hoogeboom Leiden Institute of Advanced Computer Science, Universiteit Leiden, Niels Bohrweg 1, 2333 CA Leiden, The Netherlands, [email protected] Peter T. Hraber Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA, [email protected] Claire L. Hyder Turku Centre for Biotechnology, Turku, Finland and Department of Biochemistry, Åbo Akademi University, Turku 20520, Finland, chyder@btk.fi Oscar H. Ibarra Department of Computer Science, University of California, Santa Barbara, CA 93106, USA, [email protected] Sorin Istrail Department of Computer Science and Center for Computational Molecular Biology, Brown University, 115 Waterman Street, Box 1910, Providence, RI 02912, USA, [email protected] Masami Ito Department of Mathematics, Faculty of Science, Kyoto Sangyo University, Kyoto 603-8555, Japan, [email protected] Nataša Jonoska Department of Mathematics, University of South Florida, Tampa, FL 33620, USA, [email protected] Jarkko Kari Department of Mathematics, University of Turku, 20014 Turku, Finland, jkari@utu.fi and Turku Centre for Computer Science, 20520 Turku, Finland Lila Kari Department of Computer Science, University of Western Ontario, London, Ontario, N6A 5B7, Canada, [email protected] Ehud Keinan Department of Chemistry, Technion—Israel Institute of Technology, Technion City, Haifa 32000, Israel, [email protected] and Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Zachary Kincaid Department of Computer Science, University of Western Ontario, London, Ontario, N6A 5B7, Canada, [email protected] and Department of Mathematics, University of Western Ontario, London, Ontario, N6A 5B7, Canada Satoshi Kobayashi Department of Computer Science, University of Electro-Communications, 1-5-1, Chofugaoka, Chofu, Tokyo 182-8585, Japan, [email protected] xviii Contributors

Marta Kwiatkowska Oxford University Computing Laboratory, Wolfson Building, Parks Road, Oxford OX1 3QD, UK, [email protected] Thomas H. LaBean Department of Computer Science, Duke University, Durham, NC 27708, USA, [email protected] Laura F. Landweber Ecology and Evolutionary Biology, , Princeton, NJ, USA, lfl@princeton.edu Remco Loos EMBL-EBI, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK, [email protected] Ville Lukkarila Department of Mathematics, University of Turku, 20014 Turku, Finland and Turku Centre for Computer Science, 20520 Turku, Finland, vinilu@utu.fi Vincenzo Manca Department of Computer Science, Strada Le Grazie, 15-37134 Verona, Italy, [email protected] Giancarlo Mauri Dipartimento di Informatica, Sistemistica e Comunicazione, Università degli Studi di Milano—Bicocca, Viale Sarca 336, 20126 Milano, Italy, [email protected] Avi E. Mayo Weizmann Institute of Science, Rehovot 76100, Israel, [email protected] Andrey Mikhailov Turku Centre for Biotechnology, Turku, Finland and Department of Biochemistry, Åbo Akademi University, Turku 20520, Finland, andrey.mikhailov@btk.fi Andrzej Mizera Department of Information Technologies, Åbo Akademi University, Turku 20520, Finland, amizera@abo.fi Kazufumi Mizunuma IBM, Tokyo, Japan, [email protected] Gethin Norman Oxford University Computing Laboratory, Wolfson Building, Parks Road, Oxford, OX1 3QD, UK, [email protected] Mario J. Pérez-Jiménez Research Group on Natural Computing, Department of Computer Science and Artificial Intelligence, University of Sevilla, Avda. Reina Mercedes s/n, 41012 Sevilla, Spain, [email protected] Gheorghe Paun˘ Institute of Mathematics of the Romanian Academy, PO Box 1-764, 014700 Bucure¸sti, Romania, [email protected] and Department of Computer Science and Artificial Intelligence, University of Sevilla, Avda. Reina Mercedes s/n, 41012 Sevilla, Spain, [email protected] David Parker Oxford University Computing Laboratory, Wolfson Building, Parks Road, Oxford, OX1 3QD, UK, [email protected] Contributors xix

Dario Pescini Dipartimento di Informatica, Sistemistica e Comunicazione, Università degli Studi di Milano—Bicocca, Viale Sarca 336, 20126 Milano, Italy, [email protected] Ion Petre Department of Information Technologies, Åbo Akademi University, Turku 20520, Finland, ipetre@abo.fi Davide Prandi Dipartimento di Medicina Sperimentale e Clinica, Università “Magna Graecia” di Catanzaro, Catanzaro, Italy, [email protected] Corrado Priami Dipartimento di Ingegneria e Scienza dell’Informazione, Università di Trento, Trento, Italy and The Microsoft Research, University of Trento Centre for Computational and Systems Biology, Trento, Italy, [email protected] Paola Quaglia Dipartimento di Ingegneria e Scienza dell’Informazione, Università di Trento, Trento, Italy, [email protected] Tamar Ratner Department of Chemistry, Technion—Israel Institute of Technology, Technion City, Haifa 32000, Israel, [email protected] John H. Reif Department of Computer Science, Duke University, Box 90129, Durham, NC 27708, USA, [email protected] Sudheer Sahu Department of Computer Science, Duke University, Box 90129, Durham, NC 27708, USA, [email protected] Masahico Saito Department of Mathematics, University of South Florida, Florida, FL, USA, [email protected] Yasubumi Sakakibara Department of Biosciences and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223–8522, Japan, [email protected] Arto Salomaa Turku Centre for Computer Science, Joukahaisenkatu 3-5 B, 20520 Turku, Finland, asalomaa@utu.fi Kengo Sato Japan Biological Informatics Consortium 2-45 Aomi, Koto-ku, Tokyo 135-8073, Japan, [email protected] Erik A. Schultes Department of Computer Science, Duke University, Durham, NC 27708, USA, [email protected] Nadrian C. Seeman Department of Chemistry, New York University, New York, NY 10003, USA, [email protected] Shinnosuke Seki Department of Computer Science, University of Western Ontario, London, Ontario, N6A 5B7, Canada, [email protected] Yaki Setty Computational Biology Group, Microsoft Research, Cambridge CB3 0FB, UK, [email protected] Ofer M. Shir Natural Computing Group, Leiden University, Leiden, The Netherlands, [email protected] xx Contributors

Lea Sistonen Turku Centre for Biotechnology, Turku, Finland and Department of Biochemistry, Åbo Akademi University, Turku 20520, Finland, lea.sistonen@btk.fi David Soloveichik California Institute of Technology, Pasadena, CA, USA, [email protected] Anne Taormina Department of Mathematical Sciences, University of Durham, Durham DH1 3LE, UK, [email protected] Ryan Tarpine Department of Computer Science and Center for Computational Molecular Biology, Brown University, 115 Waterman Street, Box 1910, Providence, RI 02912, USA, [email protected] Andrew J. Turberfield Department of Physics, University of Oxford, Parks Road, Oxford OX1 3PU, UK, a.turberfi[email protected] Reidun Twarock Department of Mathematics and Department of Biology, University of York, York YO10 5DD, UK, [email protected] Erik Winfree California Institute of Technology, Pasadena, CA, USA, [email protected] Sara Woodworth Department of Computer Science, University of California, Santa Barbara, CA 93106, USA, [email protected], [email protected] Peng Yin Department of Computer Science, Department of Bioengineering, Center for Biological Circuit Design, Caltech, Pasadena, CA 91125, USA, [email protected] Takashi Yokomori Department of Mathematics, Faculty of Education and Integrated Arts and Sciences, Waseda University, 1-6-1 Nishiwaseda, Shinjuku-ku, Tokyo 169-8050, Japan, [email protected] Part I Tribute Grzegorz Rozenberg: A Magical Scientist and Brother

Arto Salomaa

Abstract This is a personal description of Grzegorz Rozenberg. There is some- thing magical in the fact that one man, Grzegorz, has been able to obtain so many and such good results in so numerous and diverse areas of science. This is why I have called him a “magical scientist.” He is also a very interdisciplinary scientist. In some sense this is due to his educational background. His first degree was in electronics engineering, the second a master’s in computer science, and the third a Ph.D. in mathematics. However, in the case of Grzegorz, the main drive for new disciplines comes from his tireless search for new challenges in basic science, rather than following known tracks. Starting with fundamental automata and language the- ory, he soon extended his realm to biologically motivated developmental languages, and further to concurrency, Petri nets, and graph grammars. During the past decade, his main focus has been on natural computing, a term coined by Grzegorz him- self to mean either computing taking place in nature or human-designed computing inspired by nature.

1 General

Everyone who has worked with or otherwise followed closely Grzegorz Rozenberg has been profoundly impressed by his overwhelming enthusiasm in doing research. One can do great science and have fun doing it is one of his thoughts often ex- pressed. Grzegorz has contemplated thoroughly the qualities of good science, and is ready to discuss and give advice about questions such as the choice of your research area or topic, what is important and what is not, or what is applicable and what is not. Sometimes a widely investigated research area begins to stagnate. Often an in- vigorating new idea, perhaps from a different field of science, changes the situation. These and related thoughts usually come up in discussions with Grzegorz. While some science writers talk about the “end of science,” meaning that one already has walked through all significant roads, Grzegorz has quite an opposite view: we are in many respects only at the beginning of the road. In particular, this is true of com- puter science and natural computing. I will next outline some of Grzegorz’s thoughts about these areas.

A. Salomaa () Turku Centre for Computer Science, Joukahaisenkatu 3-5 B, 20520 Turku, Finland e-mail: asalomaa@utu.fi

A. Condon et al. (eds.), Algorithmic Bioprocesses, Natural Computing Series, 3 DOI 10.1007/978-3-540-88869-7_1, © Springer-Verlag Berlin Heidelberg 2009 4 A. Salomaa

Computer science develops tools needed for ICT, information, and communica- tions technology. Such tools include computer networks and software methodolo- gies, the theoretical basis being essential. Computer science is more than ICT, it is the general science of information and information processing. The European term informatics is much better than computer science. The former term does not refer to any device or instrument for information processing. Such instruments always presuppose a paradigm of thinking about information processing, whereas if one speaks of “informatics”, no devices or paradigms are stipulated. In particular, informatics should study computing and information processing taking place in nature, and develop paradigms based on it. Research in natural com- puting, as Grzegorz understands it, is genuinely interdisciplinary and bridges infor- matics to natural sciences. Evolutionary computing and neural computing are older examples of such bridges. Human-designed computing inspired by nature includes such paradigms as molecular computing and quantum computing. This is no place to overview Grzegorz’s huge scientific production (hundreds of papers, some eighty books or edited books), or to discuss his contributions to the scientific community. (For instance, he was EATCS President much longer than anyone else, not to mention his more than twenty years as the editor of the EATCS Bulletin.) I will still return to our scientific cooperation in terms of three glimpses of it, in Sect. 3. Next, I will discuss other matters.

2 Personal Recollections

2.1 Grzegorz and Bolgani

You get a good picture about Grzegorz as a human being by reading [7]: what is important for him, what he likes to do, where he has been, and whom he has been with. He has surely had a many-faceted, even adventurous life, centered around fam- ily (most importantly Maja, Daniel, and Mundo), science, and also magic. Before I add some personal comments to the matters in [7], I mention a couple of things, covered very little or not at all in [7]. Life changed for Grzegorz when his grandson Mundo came into the world in Au- gust 2005. After that, much of his conversation has consisted of telling people about recent happenings with Mundo. Our email has piles of pictures of Mundo. I have a big picture of Grzegorz and myself, standing in snow during a sauna intermission in 1980. It has the text Happiness is being a Grandfather. I am glad that this is now true also for Grzegorz. Owls are briefly mentioned in [7]. Grzegorz has a huge collection of owl fig- urines, real stuffed owls, and material dealing with owls. This exhibition is a real wonder to a visitor in Bilthoven. Grzegorz calls owls magicians of nature. His inter- est in owls was initiated by some pictures taken by Juhani Karhumäki in the 1970s. Also, Hieronymus Bosch is only briefly mentioned in [7]. During the past decade, Grzegorz has become a real expert on Bosch. He has a comprehensive library of Grzegorz Rozenberg: A Magical Scientist and Brother 5 books on Bosch, in numerous languages. I was sorry to tell him that I have found no such book in Finnish. Grzegorz likes to go to “Boschian” lectures and meetings. My favorite Bosch site is www.abcgallery.com/B/bosch/bosch.html I do not know whether Grzegorz has seen it or likes it. I will tell at the beginning of the next subsection about my first meeting with Grzegorz. Some years after that Grzegorz started to visit Turku. In 1976, one pur- pose of the visit was the Ph.D. defense of Juhani Karhumäki. Grzegorz has had many excellent Ph.D. students of his own, and has been an external examiner or opponent in many other Ph.D. defenses. The reaction of the candidates has been overwhelmingly positive. How helpful, constructive, and friendly he has been, can be seen from many contributions to [1]. Grzegorz stayed with my family many times in the 1970s and became famous, among many other things, for eating huge amounts of blueberry pie. I was called “Tarzan,” and Grzegorz wanted to become a member of the Tarzan family. We de- cided that he will be Bolgani. Later on, “Bolgani” became his official name as a magician, and it also appears on his visiting card. In the following, I will use the two names interchangeably. Although most of the time a scientist, Bolgani has also periods when he lives with magic. He has developed the performing art of close-up magic to a high pro- fessional level. I have watched him in numerous shows, both in private homes and at conference gatherings. I have long given up trying to explain or understand the illusions. I just enjoy the show. When Bolgani gave a performance in my home, one of the guests came up later with the “explanation” that he was wearing contact lenses of a special type. Illusions have no explanation. Undoubtedly, Bolgani is a born magician. The maiden name of his mother is Zauberman. The name of his wife Maja means “illusion” in Hindi. His hands are very sensitive; I have not seen anyone handle a deck of cards as gently as Bolgani. A magician likes to give a performance. Grzegorz is a great lecturer. The commu- nity knows this: he always has numerous invitations. It is difficult to match his sense of humor, and probably impossible to match his capability to include magical illu- sions in his lectures. Many people make easy things difficult in their lectures. Grze- gorz has the talent of making difficult things easy. As has said, Grze- gorz is always enthusiastic, always optimistic, always amusing, and never boring. Bolgani often presents a sequence of illusions within the framework of a story, such as the following. Bolgani explains that in Chinese the names of the suits hung tao (heart) and hei tao (spade) are similar and, therefore, some confusion may arise. But now we try to be careful. He then shows the audience some hearts and puts them on the table, as well as some spades and puts them also on the table, far from the hearts. “So this pile is hung tao?” The audience agrees. “And this is hei tao?” Again consensus. Bolgani then entertains the audience and talks about various matters; about owls, and about the sauna. That laughter and for him, nowadays Mundo is the best medicine. That one should never assume anything. That the only place where success comes before work is in the dictionary. Then Bolgani goes back to 6 A. Salomaa the cards. “So this is hung tao and this hei tao?” General agreement. But when he shows the cards, it is the other way round. “Too bad, let us see what happens if we put everybody in the same pile.” He first puts the pile of hearts on the table and the spades on top. Again, there is some entertainment. “Now let us see if they interchanged again.” Bolgani picks up the cards and shows them. “This is absolutely crazy. They are all zhao hua (club, grass flower)!”

2.2 Brother

Grzegorz had been1 in Holland about one and a half years, and was running a coun- trywide seminar in Utrecht, where foreign speakers were also invited. I got an invi- tation (by ordinary mail, not by phone) from G. Rozenberg in May 1971. I was not familiar with the name previously. He waited for me at the airport and arranged our meeting through loudspeakers. He looked much younger than I had anticipated. He drove a small Volkswagen. We got immediately into a very hectic discussion about parallel rewriting and L systems. This was contrary to all principles about driving, expressed by Grzegorz later. After about one hour, I started to wonder why we had not yet arrived at my hotel in Utrecht, well known for the model railroad upstairs. It turned out that we were still on some side streets of Amsterdam. The same day Grzegorz told me more about L systems, at the university and dur- ing dinner at an Indonesian restaurant. This turned out to be an area where our scien- tific cooperation has been most vivid. The most important outcome is the book [8], but L systems play an important role also in [10, 11]. I had four lectures during the seminar, and Grzegorz also arranged a big party in their Marco Pololaan apartment. Although the twenty people present were quite noisy, the baby Daniel slept all the time. There I got to know many of my friends for the first time, notably Aristid Lindenmayer. L systems seemed to be a really fresh idea. I got carried away, and already decided to include a chapter about them in my forthcoming book on formal languages. During the next few weeks, I exchanged numerous letters with Grzegorz about the topic. At this stage, I would like to tell two stories about our joint books. In some way, they illustrate very well Grzegorz’s friendliness, efficiency, and professionalism. When working on the book [8], we had many specific deadlines, depending on mutual trips, etc. Once, I got very nervous that Grzegorz was too involved in other research topics, and could not possibly make the deadline. I wrote a very angry letter to him. His answer was very brief. “Tarzan has never before written such an angry letter. The reason is simple. In your letter you mention that you did not go to sauna in two days.” That was it, and he made the deadline.

1To justify the word brother appearing in the title of this paper, I quote Grzegorz from [7]where he describes his “wonderful family.” Then I have two brothers of choice, Andrzej and Arto. It is difficult to imagine better brothers (an interesting aspect of this brotherhood is that Andrzej and Arto have never met). Grzegorz Rozenberg: A Magical Scientist and Brother 7

In March 1994, Grzegorz suggested to me: “Let us make a handbook on formal languages.” We started planning it immediately. In less than three years, a copy of [11] (three volumes, more than 2000 pages, 3.6 kilos altogether, more than 50 authors) was in the library of Turku University. Are there similar examples of such speedy editing of such an extensive handbook-type of scientific work? Very soon Bolgani became a close family member. My wife tells him everything about our cats and often wears blouses given by him as presents. He is a coau- thor in my son’s first scientific publication. My daughter always liked to travel to Utrecht because “it is the town with the Orange Julius.” My grandchildren call him Äijä-Bolgani (grandpa-Bolgani). My grandson was very impressed because Bolgani drew many coins from his ears, and my granddaughter because of his expanding command of Finnish. On the other hand, Bolgani’s late mother treated me as her own son. I myself have, more and more during the years, learned to ask his advice in difficult decisions and situations. Bolgani always brings carefully selected gifts, not only to me but also to every- body in my “clan.” In 1975, he gave me a very special memory device. It was with me everywhere for thirty years, until it finally wore out. No substitute was available, and I had to be satisfied with miserable alternatives. But in 2007, Bolgani gave me a substitute, even better than the original! My brother has an immense supply of jokes and anecdotes, always suitable to the occasion. Often a fatiguing situation entirely changes with his comments. When I came, exhausted in the airport bus, together with some other conference participants to Waterloo in 1977, Bolgani was there to meet us. Instead of greeting me, he went to the driver, pointing toward me, “Did that fellow behave well in the bus?” Sometimes, I have experienced real surprise. I had forgotten my slippers in Bilthoven. The next time I was there they were not to be found, and Bolgani just remarked that maybe the cleaning lady had somehow misplaced them. Sometime afterwards, I was staying in Hermann Maurer’s (a close friend of both of us and a marvelous scientific collaborator) house in Graz. When I entered my room, my slippers were there! Bolgani claims that I have a good memory, whereas he has a bad one. I am not sure of this; it could be the other way round. For instance, in Bolgani’s writings to me, the expressions “Rabbit Ph.D. Story” and “Dog Paper Story” appear many times. I do not remember what they refer to. Some of our best times together have been in the sauna. Bolgani has a special sauna certificate and many sauna records, for instance, the shortest time between the plane landing and him sitting in the sauna, or seeing special animals from the sauna window. I let Bolgani himself speak (“löyly” is the Finnish word for sauna heat, and “supikoira” for raccoon dog): When you come to Tarzan nest You get sauna at its best Where you can admire Löyly and birch wood on fire A lot of flora and fauna Can be seen from Salosauna 8 A. Salomaa

But with Bolgani and nice weather You can see two supikoiras together

3 Case Studies of Scientific Cooperation

3.1 Quasi-uniform Events and Mostowski

One of the early papers on automata by Grzegorz [6] deals with quasi-uniform events. “Languages” were often in the early days called “events,” but I will now speak of languages. A language L over an alphabet Σ is quasi-uniform if, for some m ≥ 0, = ∗ ∗ ∗ L B0 b1B2 b3 ...b2m−1B2m, where each bi is a letter of the alphabet Σ, and each Bi is a subset (possibly empty) ∗ of Σ. Observe that Bi reduces to the empty word when Bi is empty. Thus, there may be several consecutive letters in the regular expression, but the subsets are always separated by at least one letter. Grzegorz shows, for instance, that it is decid- able whether or not a given finite automaton accepts a quasi-uniform language. The reader might want to prove this, especially because the reference [6] is not so easily available. Much later, when studying subword occurrences and subword histories, I noticed that the language defined by a subword history of a very natural form always is a finite union of quasi-uniform languages (and hence, star-free). This is an example where we have worked separately on similar questions. Indeed, because Grzegorz and I never have time to cover all topics, I have never had a chance to explain to him the connection between quasi-uniform events and subword histories. The paper [6] was communicated for publication by the famous logician Andrzej Mostowski on August 7, 1967. Grzegorz tells about him [7] as follows. Mostowski was a very kind man of very good manners. He always had time whenever I wanted to talk to him. I still remember the interview when he offered me a job. Looking through the papers he said at some point: “I see that you will be the youngest member of the Institute,” he paused and then he continued “but this problem will resolve itself with time.” I also met Mostowski a few times, long before I met Grzegorz. He wore very ele- gant suits, quite unlike the casual attire now common. He was polite and considerate to me. For instance, he was chairing a session in a big logic conference in Helsinki in 1962, where I gave a talk about infinite-valued truth functions. I was somewhat nervous, and this was apparently noticed by Mostowski. There were some simple questions after my talk, but Mostowski did not want to embarrass me with his in- volved question. Instead, he came to me later asking, “How do you actually obtain the decidability?” Then it was no problem for me to explain to him the details. Grzegorz Rozenberg: A Magical Scientist and Brother 9

3.2 Developing Cells and Lindenmayer

My cooperation with Grzegorz was centered around developmental languages and L systems for about two decades. I already told about my first meeting with Aristid Lindenmayer. Grzegorz had gotten to know him somewhat earlier [7], after studying a paper by Dirk van Daalen. Aristid became a close friend of ours. Apart from biological matters, we used to consult him about many other things, for instance, the English language. We edited a book [9], for Aristid’s 60th birthday. It also contains information about the early stages of L systems and the people involved. Aristid did not know about our plan. One evening in November 1985, Grzegorz phoned him, inviting him for a cup of coffee. Aristid was surprised to see me also in Bilthoven. Grzegorz told him that we knew about his birthday and bought him a book as a present, giving Aristid a parcel containing [9]. After that, the representatives of Springer-Verlag and other friends who had been hiding upstairs came to congratulate Aristid. After Aristid’s untimely passing away, we wanted to organize a conference ded- icated to his memory. It was originally planned to take place in Lapland. But there were many practical difficulties. The conference, the first DLT, took place in Turku. All participants signed a special greeting to Jane Lindenmayer. The letter “L” in “DLT” was originally intended to refer also to L systems. One of our early joint papers on L systems was the widely referenced article [3, 4], where Mogens Nielsen and Sven Skyum were also coauthors. Much of the work was done during the Oberwolfach conference in 1973 in my family apartment. Sometimes, Grzegorz was shouting so enthusiastically that my family thought we were fighting. The paper has a strange editorial history: part II appeared several months before part I. One of the technical contributions of [3, 4] and related papers was to show how to get rid of the erasing rules, that is cell death. I mention one example. A D0Lsystem consists of a word and a morphism (rules for the development of each letter). We get the language of the system by iterating the morphism on the word. For instance, starting with the single-letter word a and the morphism a → aba, b → b3, we get the words a, aba, abab3aba, abab3abab9abab3aba, .... (A knowledgeable reader will notice the connection with Cantor’s dust.) A general D0L system may have arbitrarily many letters, and some of the rules may be erasing. How to get rid of the erasing rules? It was shown in [3, 4] (a very detailed proof appears in [2]) that this is always possible if one allows finitely many starting words and applies a letter-to-letter morphism to the end result.

3.3 Twin-Shuffle and Unisono Duet

Simultaneously with the Handbook [11], Grzegorz and I worked with Gheorghe Paunˇ on a book on DNA-based computing [5]. This was in accordance with Grze- 10 A. Salomaa gorz’s enthusiasm about natural computing. We had already noticed that a property shared by most of the models of DNA computing is that they produce all recursively enumerable sets, that is, are universal in the sense of Turing machines. This property seems to be completely independent, for instance, of a model being grammatical or a machine model. One morning in the summer 1996 Grzegorz called me. We talked for about one hour. He spoke very fast, telling me that there is something déjà vu in WatsonÐCrick complementarity which leads to Turing universality. Roughly, the matter can be described as follows. Consider the binary alphabet {0, 1}, as well as its “complement” {0¯, 1¯}.Fora word x over {0, 1}, we denote by x¯ thewordover{0¯, 1¯}, where every letter of x is replaced by its “barred version.” For instance, if x = 001100, then x¯ = 0¯0¯1¯1¯0¯0.¯ The shuffle of two words x and y is the set of words obtained by “shuffling” x and y, without changing the order of letters in x or y. For instance, each of the words

000¯ 01¯ 11¯ 10¯ 00¯ 0¯, 0¯0¯1¯1¯0¯0001100¯ , 0001¯ 010¯ 1¯1¯00¯ 0¯ is obtained by shuffling x and x¯ with x = 001100. The twin-shuffle language TS consists of all words obtained by taking an arbitrary word over {0, 1} and shuffling it with its complement. It was known before that TS is universal: every recursively enumerable language is obtained from it by a generalized sequential machine map- ping. This means that TS stays invariant for each specific “task,” only the input– output format has to be specified differently, according to the particular needs. By viewing the four bases of DNA as the letters 0, 1 and their barred versions, the inter- connection between Watson–Crick complementarity and the twin-shuffle language becomes clear. These matters were discussed in [12], and later in [5] and in many other publica- tions. They were also discussed during ICALP’99 in Prague [13]. This was some- thing special. Grzegorz and I were both invited speakers. But for the first time in ICALP history, the invitation was presented to us jointly. We took the matter very seriously. Both of us were speaking separately; Grzegorz about the wonders of his favorite ciliate Tom. But there was also a joint part where we both spoke unisono. This duet had required much practice. Fortunately, the hotel was luxurious, and I had a big apartment. So, there were no complaints from the neighbors.

4Conclusion Grzegorz writes in [7]: I have a wonderful family. I have written many papers. I have shuffled many decks of cards. Life has been good to me. Let us hope that it will continue to be so in the years to come.

References

1. Brauer W et al (1992) Grzegorz: many happy returns. EATCS Bull 46:391–413 Grzegorz Rozenberg: A Magical Scientist and Brother 11

2. Kari L, Rozenberg G, Salomaa A (1997) L systems. In: Rozenberg G, Salomaa A (eds) Hand- book of formal languages, vol 1. Springer, Berlin 3. Nielsen M, Rozenberg G, Salomaa A, Skyum S (1974) Nonterminals, homomorphisms and codings in different variations of OL-systems, part I. Acta Inform 3:357–364 4. Nielsen M, Rozenberg G, Salomaa A, Skyum S (1974) Nonterminals, homomorphisms and codings in different variations of OL-systems, part II. Acta Inform 4:87–106 5. Paun˘ G, Rozenberg G, Salomaa A (1998) DNA computing. New computing paradigms. Springer, Berlin 6. Rozenberg G (1967) Decision problems for quasi-uniform events. Bull Acad Pol Sci XV:745– 752 7. Rozenberg G (1999) The magic of theory and the theory of magic. In: Calude C (ed) People and ideas in theoretical computer science. Springer, Singapore, pp 227–252 8. Rozenberg G, Salomaa A (1980) The mathematical theory of L systems. Academic Press, New York 9. Rozenberg G, Salomaa A (1986) The book of L. Springer, Berlin 10. Rozenberg G, Salomaa A (1994) Cornerstones of undecidability. Prentice Hall, New York 11. Rozenberg G, Salomaa A (eds) (1997) Handbook of formal languages, vols 1–3. Springer, Berlin 12. Rozenberg G, Salomaa A (eds) (1996) Watson–Crick complementarity, universal computa- tions and genetic engineering. Leiden University, Department of Computer Science Technical Report 96–28 13. Rozenberg G, Salomaa A (1999) DNA computing: new ideas and paradigms. In: Wiedermann J, van Emde P (eds) Automata, languages and programming, ICALP’99 proceedings. Springer lecture notes in computer science, vol 1644. Springer, Berlin, pp 106–118 Part II Sequence Discovery, Generation, and Analysis