21 st Century is Life Science Century Emergence

今世紀の課題 21 st Century is Life Science Century Emergence of New Science for Understanding Life as System Fusion of Biology, Computer Science, Artificial Intelligence, Physics, Chemistry, Mathematics, etc. Copyright 2010 Masao Nagasaki

システム生物学とは？ System Component Identification System Prediction System Control System Design Copyright 2010 Masao Nagasaki

システム生物学とは？ System Component Identification System Prediction System Control System Design Copyright 2010 Masao Nagasaki 生体内の制御関係（パス ウェイ）を理解する。

パスウェイとは？ • パスウェイ (Pathway) – 代謝系 (Metabolic Pathway) – 遺伝子制御ネットワーク (Gene Regulatory Network) – シグナル伝達経路 (Signal Transduction Pathway) 　を指す。 Copyright 2010 Masao Nagasaki

Pathway (1/3) Metabolic Pathway おおまかには細胞内での 化学物質の反応のパスウ ェイ Copyright 2010 Masao Nagasaki

Pathway (2/3) Signaling Pathway Fas ligand Apoptosis induced by Fas receptor complex Cytoplasm caspase Signal cascade Copyright 2010 Masao Nagasaki おおまかには細胞内での たんぱく質の反応のパス ウェイ

Pathway (3/3) Gene Regulatory Network Nucleus PER TIM activate おおまかに、細胞内の、 遺伝子の転写や、翻訳 activate が関係する反応のパス ウェイ activate ｄCLK CYC tim TIM pｅｒ PER dｂｔ d. Clk DBT PER Rapid degradation ｄCLK cyc CYC Drosophila Circadian Feedback Loop Cytoplasm Copyright 2010 Masao Nagasaki PER TIM ｄCLK CYC

Why important ? Case Study: Combinations of Drugs 1. Anticancer Drug - Fluorouracil (5 -FU) 2. Antiviral Drug - Sorivudine zzzza z By combining the above two drugs, in 1993, 15 peoples died in Japan. Copyright 2010 Masao Nagasaki

→Main Effects →Side Effects sorivudine monophosphate sorivudine diphosphate sorivudine triphosphate Antiviral Drug d. TMP kinase thymidine kinase Enzymes only in Virus nucleoside-phosphate kinase Degradation of sugar chain virus DNA polymerase inhibition If we know thebymore exact pathway level understandings of intestinal bacteria two drugs…. Pathway level sorivudine bromovinyluracil understanding is very ④ Depletion of leukocytopenia important!! and platelet ③ Elevate the blood concentration Death ① binding Anticancer Drug dihydrouracil dehydrogenase ② fluorouracil antitumor effect fluorodihydrouracil

→Main Effects sorivudine monophosphate sorivudine diphosphate sorivudine triphosphate →Side Effects Antiviral Drug d. TMP kinase thymidine kinase Enzymes only in Virus nucleoside-phosphate kinase Degradation of sugar chain by intestinal bacteria sorivudine virus DNA polymerase inhibition bromovinyluracil Someone: We can do simulation in my the ④ Depletion of ③ Elevatebrain by combining the regulations of blood leukocytopenia them! concentration Death and platelet ① binding Anticancer Drug dihydrouracil dehydrogenase ② fluorouracil antitumor effect fluorodihydrouracil

Can you do them? Endothelial cell (Angiogenesis) models on Cell Illustrator

Pathway　Database - Basic - Copyright 2010 Masao Nagasaki

パスウェイデータベース 有名なデータベース • KEGG　 • Bio. Cyc • Transpath • Ingenuity Pathway Knowledge Base • Resnet Pathway Database • STKE • Reactome Copyright 2010 Masao Nagasaki

KEGG • • • URL: http: //www. kegg. org/ Developer: 金久教授ら＠京都大学 代謝系の情報が強い シグナル伝達系のデータも充実の予定？ License: Academicは無償 商用は有料 Pathways Reactions Drugs(+Enzyme) Compound Genes Copyright 2010 Masao Nagasaki 362 7, 546 6, 850 15, 072 1, 498, 697 http: //www. genome. ad. jp/ja/info_kegg_ja. html 2008年 4月現在

KEGG MAP Copyright 2010 Masao Nagasaki

Bio. Cyc • • URL: http: //www. biocyc. org/ Developer: Peter Karpら(U. S. ) Eco. Cyc(E. coliのデータベース) 代謝系(Meta. Cyc　600種以上の代謝系データ を収集) 2008年 4月現在 • License: AcademicはFree, 商用は有償 Eco. Cyc http: //biocyc. org/ecocyc/release-notes. shtml Copyright 2010 Masao Nagasaki Pathways 224 Reactions 1658 Enzymes 1361 Transporters 227 Genes 4464 Transcription Units 3277 Citations 16297

Eco. Cyc: http: //biocyc. org/ MAP Copyright 2010 Masao Nagasaki

Copyright 2010 Masao Nagasaki

Ingenuity Pathway Knowledge. Base • URL: http: //www. ingenuity. com/ • Developer: Ingenuity Systems Inc. (Boston, U. S. ) • License: 商用 Copyright 2010 Masao Nagasaki

Ingenuity Pathway Knowlege. Base • ３２種のJournalから１件１件人が読んでデータを抽 出 American J. Pathology Arteriosclerosis, Thrombosis and Vascular Biology Biochemistry Blood Cancer Research Cell Current Biology Development EMBO European J. of Immunology FASEB Journal Genes and Development Hypertension Immunity J. Biological Chemistry Copyright 2010 Masao Nagasaki J. Cell Biology J. Experimental Medicine J. Immunology J. Lipid Research J. National Cancer Institute J. Neuroscience Molecular and Cellular Biology Molecular Biology of the Cell Molecular Cell Nature Cell Biology Nature Genetics Nature Medicine Neuron Oncogene Proc. National Acad. Sciences USA Science

Ingenuity Pathway Knowlege. Base • 登録されている遺伝子数(2008年 5月現在) 13, 600個 ヒト遺伝子 • マウス遺伝子 11, 100個 ラット遺伝子 6, 600個 対応している遺伝子データ Affymetrix Uni. Gene Gen. Bank Copyright 2010 Masao Nagasaki Entrez Gene Swiss. Protein Accession Number Gen. PERT

Ingenuity Pathway Knowlege. Base DEMO Copyright 2010 Masao Nagasaki

Transpath • URL: http: //www. biobase-international. com/ • Developer: BIOBASE Corp. @Germany • License: 商用 Copyright 2010 Masao Nagasaki

TRANSPATH • さまざまなJournalから１件１件人が読んでデータを 抽出 American J. Pathology Arteriosclerosis, Thrombosis and Vascular Biology Biochemistry Blood Cancer Research Cell Current Biology Development EMBO European J. of Immunology FASEB Journal Genes and Development Hypertension Immunity J. Biological Chemistry Copyright 2010 Masao Nagasaki J. Cell Biology J. Experimental Medicine J. Immunology J. Lipid Research J. National Cancer Institute J. Neuroscience Molecular and Cellular Biology Molecular Biology of the Cell Molecular Cell Nature Cell Biology Nature Genetics Nature Medicine Neuron Oncogene Proc. National Acad. Sciences USA Science

TRANSPATH • 登録されている遺伝子数/タンパク数(2008年 4月現在) 主にHuman, Mouse, Rat • 対応している遺伝子データ(2006年 3月現在) Affymetrix Uni. Gene Gen. Bank Ref. Seq Copyright 2010 Masao Nagasaki Entrez Gene HGNC OMIM Ensemble

BIOBASE Copyright 2010 Masao Nagasaki

TRANSPATH DEMO Copyright 2010 Masao Nagasaki

Resnet • URL: http: //www. ariadnegenomics. com/products/resnet/ • Developer: Ariadone Genomics Inc. (Corolado, U. S. ) • License: 商用 • パスウェイデータベース – Pub. Medに登録されている14, 000件のabstract(注)と 47のjournal全文からNLP( 自然言語処理）の技術を用いて(Med. Scanというソフトを独自開発＆使用)生体内の反 応を抽出。 – 現在の最新はVer. 5. 0 – Yeastのデータも扱っている。 ResnetにはResnet Coreがあって、Human Curationもしているらしいがその数はあまり 多くない。 Copyright 2010 Masao Nagasaki

Reactome • URL: http: //www. reactome. org/ • Developer: Reactome Team – Cold Spring Harbor lab. , EBI, GO • Curated database of biological processes in humans – Basically using experiments performed on human systems – Using indirect evidence, by inferring in humans based on the finding of putative human orthologs for the proteins Copyright 2010 Masao Nagasaki

Reactome: history • • • Sep. 2002: Genome Knowledgebase started Jan. 2003: ver. 1 June 2004: Reactome launched, ver. 10 Jan, 2006: ver. 16 Mar, 2008: ver. 24 Date March, 2008: Version 24 (Human) Copyright 2010 Masao Nagasaki # of proteins 2499 # of complexes 2016 # of reactions 2530 # of pathways 818

Reactome Reaction map -Clustered -Navigator Copyright 2010 Masao Nagasaki

パスウェイ表示ソフトウェア Copyright 2010 Masao Nagasaki

パスウェイ表示ソフトウェア 有名なソフトウェア • Pathway Builder • Pathway Studio • Cytoscape • Ingenuity Pathway Analysis • Connection Maps in STKE Copyright 2010 Masao Nagasaki

Pathway. Builder • 商用：Transpath Databaseとセット販売 Copyright 2010 Masao Nagasaki

Pathway. Studio • URL: http: //www. ariadnegenomics. com/products/pathway/ • Developer: Ariadne Genomics Inc. (Colorado, U. S. ) • License: 商用 旧Pathway. Assist (特徴) 1. Resnet Databaseを 表示できる。 Copyright 2010 Masao Nagasaki

Cytoscape • URL: http: //www. cytoscape. org/ • Developer: Institute for Systems Biology, the University of California San Diego, Memorial Sloan-Kettering Cancer Center and Institut Pasteur • License: 無償 LGPL – 生体内パスウェイデータを統合して表示することができる ソフトウェア Copyright 2010 Masao Nagasaki

Cytoscape • History – – • Apr 11 2008: version 2. 6 Dec 17 2005: version 2. 2 Apr 16 2005: version 2. 1 Around 2003: version 1. 1 Publication – Paul Shannon 1, Andrew Markiel 1, Owen Ozier 2, Nitin S. Baliga 1, Jonathan T. Wang 2, Daniel Ramage 2, Nada Amin 2, Benno Schwikowski 1, 5 and Trey Ideker 2, 3, 4, 5, Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks, Genome Research 13: 2498 -2504, 2003 • 1 Institute for Systems Biology, Seattle, Washington 98103, USA , 2 Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA , 3 Department of Bioengineering, University of California-San Diego, La Jolla, California 92093, USA Copyright 2010 Masao Nagasaki

Ingenuity Pathway Analysis(IPA) • Developer: Ingenuity Systems Inc. (Boston, U. S. ) • URL: http: //www. ingenuity. com • Ingenuity Pathway Knowledge Baseの情報を表 示できる Copyright 2010 Masao Nagasaki

Connections Map - STKE • • URL: http: //stke. sciencemag. org/ オンライン STKEで管理されているパスウェイ情報を見るソフトウェア 東京大学はScienceのオンラインジャーナルにアクセスできるのでみれた はず？ Copyright 2010 Masao Nagasaki High Osmolarity Glycerol(HOG) Pathway in Yeast

生体内パスウェイシミュレーション Copyright 2010 Masao Nagasaki

シミュレーション可能な パスウェイソフト • パスウェイソフト全般について重要な事項 – Architecture (Simulation Engine) – Modeling Method (ＧＵＩ Interface) Copyright 2010 Masao Nagasaki

確率的？ • GD(Gillespie’s Direct Method) • GB(the Gibson-Bruck Next Reaction Method) • FB(the Firth-Bray multi-state stochastic method) • SPN(a stochastic Petri net method) などの方法がある。 （利点） • 確率的なモデル化が可能。 （欠点） • 遅い。 • 反応パラメータがさほど細かくわかっていないモデル化では わざわざやる必要があるのか？ • 解析が難しい。 Copyright 2010 Masao Nagasaki

ハイブリッド(決定的＆確率的） • TL (the Gillespie Tau-Leap method) • VB (the Vasudeva-Bhalla method) • HR (the Haseltine-Rawlings method) • Hybrid Functional Petri net (利点） • 決定的、確率的を組み合わせたモデル化が可能。 （欠点） • ますますもって解析が難しい。 Copyright 2010 Masao Nagasaki

有名なソフトウェア • • Cell Illustrator E-Cell JDesigner Cell. Designer Virtual Cell Dizzy COPASI などなどその他大勢（９０種以上） Copyright 2010 Masao Nagasaki

Cell Designer • • URL: http: //systems-biology. org/ Developer: 北野教授らによって開発 Architecture: なし(SBWを利用) OS: Windows/Unix/Mac OS X GUI: 高い Latest: Ver 4. 0. 0 License: Free License Copyright 2010 Masao Nagasaki

JDesigner • • • URL: http: //sbw. kgi. edu/software/jdesigner. htm Developer: Keck Graduate Institute (U. S. ) GUI: 高 Architecture: なし(SBWを利用) OS: Windows版 License: LGPL Copyright 2010 Masao Nagasaki

E-Cell • • URL: http: //www. e-cell. org/ Developer: 慶応の富田研究室 Latest: Ver. 3. 1 Architecture: ハイブリッド(HR) ＧＵＩ: 結果のみ OS: Windows, Linux, Mac OS X License: 無償: GPL (例外付) Copyright 2010 Masao Nagasaki

Dizzy • URL: http: //magnet. systemsbiology. net/software/Dizzy/ • Developer: Prof. Hamid Bolouri at Institute for Systems Biology (Seattle, Washington, U. S. ) • Latest: Ver 1. 11. 4 • Architecture: 確率的(Gillespie, Gibson-Bruck, Tau-Leap) • GUI: 結果のみ • OS: Windows, Linux, Mac OS X • License: LGPL Copyright 2010 Masao Nagasaki

COPASI - Complex Pathway Simulator • URL: http: //www. copasi. org/ • Developer: Collaboration project between Mendes group@Virginia Bioinformatics Institute and Kummer group@European Media Lab Research • Latest: Release 4. 3 (Build 25) • Architecture: 決定的(DE) • GUI: 結果のみ • License: 非商用は無償 Copyright 2010 Masao Nagasaki

COPASI Copyright 2010 Masao Nagasaki

Cell Illustrator • • • URL: http: //www. cellillustrator. com/ http: //cionline. hgc. jp/ Developer: Institute of Medical Science, the University of Tokyo Latest: Ver. 4. 0 Architecture: ハイブリッド(HFPNe) GUI: 高度 License: 商用（共同研究の場合 無償） Copyright 2010 Masao Nagasaki

XML Format Copyright 2010 Masao Nagasaki

ＸＭＬとは？ • e. Xtensible Markup LanguageをXMLと呼ぶ • データ形式の 1つ • コンピュータでも読めるし、人も(一応)理解できる (例) <? xml version=“ 1. 0” encoding=“UTF-8” ? > <lecture id=“ 7”> Attribute <date>2010 -04 -23</date> <name>システム生物学入門</name> <person>masao nagasaki</person> Element </lecture> Copyright 2010 Masao Nagasaki

XMLとは • 文書フォーマットの定義： – Document Type Definition (DTD) – XML Schema – Relax NG • 文書の変換: – XSL Transformations (XSLT) Copyright 2010 Masao Nagasaki

XML Format for Pathway Simulation and (or? ) Pathway Modeling Copyright 2010 Masao Nagasaki

Systems Biology Markup Language (SBML) • • URL: http: //www. sbml. org/ 生体内の反応を記述するためのXMLフォーマット Latest: Ver. 2. 4 定義: XML Schema Copyright 2010 Masao Nagasaki

Cell Markup Language (Cell. ML) • • URL: http: //www. cellml. org/ Developer: University of Auckland (NZ) Latest: Ver 1. 1 文書定義: DTD Copyright 2010 Masao Nagasaki

Cell System Markup Language (CSML) • URL: http: //www. csml. org/ • Developer: Institute of Medical Science, the University of Tokyo (UT) • Latest: Ver. 3. 0 • 文書定義: Relax NG Copyright 2010 Masao Nagasaki

Bio. PAX • URL: http: //www. biopax. org/ • Developer: Prof. Chris Sanderらによって推進。Bio. PAX is community project with open participation. • Ontologyを表現するためのXML形式の言語(OWL)でフォー マットを定義 Copyright 2010 Masao Nagasaki

Bio. PAX • The goal – the integration of diverse pathway resources by defining an open file format specification for the exchange of biological pathway data • Bio. PAX level 1 for representation of metabolic pathways • Bio. PAX level 2 for representation of molecular interactions – molecular binding interactions • sequence features: a phosphorylation site or other post-translational modification – protein post-translational modifications, – basic experimental descriptions, • evidence: detailed descriptions of experiments – hierarchical pathways • the pathway class to allow participation of pathways as well as interactions. – now, include PSI-MI Level 2 format for better support of signal transduction and molecular states • For future level, coverage for additional types of pathway data, such as signal transduction pathways and genetic regulatory networks Copyright 2010 Masao Nagasaki

Bio. PAX Roadmap Cited from: http: //www. biopax. org/Docs/Bio. PAX_Roadmap. html Copyright 2010 Masao Nagasaki

Pathway Database -Simulatable Pathway- Copyright 2010 Masao Nagasaki

Bio. Models • -URL: http: //www. ebi. ac. uk/biomodels/ • Developer: EMBL-EBI & SBML Team　Launched at 4/2005. • ダイナミックパスウェイデータベースを共有するためのウェブサイト • SBMLフォーマットのXMLファイルを保存 -登録数は 335個(Apr/2009現在） Copyright 2010 Masao Nagasaki

Cell. ML Repository • • • URL: http: //www. cellml. org/examples/repository/index. html Developer: Bioenginnering Instiutute, The University of Auckland 380程度のシミュレーション可能なパスウェイが登録されている。 Copyright 2010 Masao Nagasaki

CSML Repository • • • URL: http: //www. csml. org/models/csml-models/ Developer: Institute of Medical Science, the University of Tokyo 他形式からの変換モデルも含め300程度のシミュレーション可能なパスウェイを登録。 Copyright 2010 Masao Nagasaki

DNA情報解析分野でやってること Copyright 2010 Masao Nagasaki

あともう１つやっていること Copyright 2010 Masao Nagasaki

セルイラストレータで作成した パスウェイモデル（１） 1. Gene regulatory mechanism in l phage 2. Pathway of Fas induced apotosis 4. Regulation mechanism of lac operon • 遺伝子制御ネット シグナル伝達経路 3. Pathway of lateral regulation by Notch-Delta 遺伝子制御ネットワーク Copyright 2010 Masao Nagasaki 細胞間ネットワーク ワーク＋代謝経路 5. Hem metabolic pathway 代謝経路 • ▽ 遺伝子制御ネットワーク

セルイラストレータで作成した パスウェイモデル（２） 6. CDK related pathway of p 53 • シグナル伝達経 路 9. ARF Stabilization pathway of p 53 シグナル伝達経路 Copyright 2010 Masao Nagasaki 7. Circadian Clock in Drosophila シグナル伝達経路＋遺 伝子制御ネットワーク 10. EGFR Signal pathway シグナル伝達経路 8. Circadian clock in Mouse シグナル伝達経路＋遺 伝子制御ネットワーク • 11. Micro RNA micro. RNAの制御 ネットワーク

セルイラストレータ関連の文献 Li C*, Nagasaki M*, Saito A and Miyano S, Time-dependent structural transformation analysis to high-level Petri net model with active state transition diagram, BMC Syst Biol. , 4: 39, 2010 Apr. (*Equal contributor). Nagasaki M, Saito A, Jeong E, Li C, Kojima K, Ikeda E, Miyano S, Cell Illustrator 4. 0: A computational platform for systems biology, In Silico Biol. , 10, 0002, 2010 Li C*, Nagasaki M*, Ueno K, Miyano S. Simulation-based model checking approach to cell fate specification during Caenorhabditis elegans vulval development by hybrid functional Petri net with extension. BMC Systems Biology 2009; 3: 42 Jeong E, Nagasaki M, Miyano S. Rule-based reasoning for system dynamics in cell systems. Genome Informatics 20: 25 -36 (2008). Nagasaki M, Saito A, Li C, Jeong E, Miyano S. Systematic reconstruction of TRANSPATH data into Cell System Markup Language. BMC Systems Biology. 2008; 2: 53. Kojima K, Nagasaki M, Miyano S. Fast grid layout algorithm for biological networks with sweep calculation. Bioinformatics. 2008; 24(12): 1433 -41. Jeong E, Nagasaki M, Saito A, Miyano S. Cell System Ontology: Representation for modeling, visualizing, and simulating biological pathways. In Silico Biology. 2007; 7: 0055. Jeong E, Nagasaki M, Miyano S. Conversion from Bio. PAX to CSO for System Dynamics and Visualization of Biological Pathway. Genome Informatics. 2007; 18: 225 -236. Kojima K, Nagasaki M, Jeong E, Kato M, Miyano S. An efficient grid layout algorithm for biological networks utilizing various biological attributes. BMC Bioinformatics. 2007; 8: 76. (Pub. Med_17338825 Doi A. Modeling and simulation of biological pathways with Hybrid Functional Petri Net. Ph. D Thesis, The University of Tokyo. 2006 Tasaki S, Nagasaki M, Oyama M, Hata H, Ueno K, Yoshida R, Higuchi T, Sugano S, Miyano S. Modeling and estimation of dynamic EGFR pathway by data assimilation approach using time series proteomic data. Genome Informatics. 2006; 17(2): 226 -238. Matsuno H, Li C, Miyano S. Petri Net based description for systematic understanding of biological pathways. IEICE Transactions on Fundamentals of Electronics, Communications and Computer Sciences. 2006; 89 -A: 3166 -74. Nagasaki M, Yamaguchi R, Yoshida R, Imoto S, Doi A, Tamada Y, Matsuno H, Miyano S, Higuchi T. Genomic data assimilation for estimating hybrid functional Petri net from time-course gene expression data. Genome Informatics. 2006; 17(1): 46 -61. Doi A, Nagasaki M, Ueno K, Matsuno H, Miyano S. A combined pathway to simulate CDK-dependent phosphorylation and ARF-dependent stabilization for p 53 transcriptional activity. Genome Informatics. 2006; 17(1): 112 -23. Saito A, Nagasaki M, Doi A, Ueno K, Miyano S. Cell fate simulation model of gustatory neurons with micro. RNAs double-negative feedback loop by hybrid function Petri net with extension. Genome Informatics. 2006; 17(1): 100 -11. Matsuno H, Inouye ST, Okitsu Y, Fujii Y, Miyano S. A new regulatory interaction suggested by simulations for circadian genetic control mechanism in mammals. Journal of bioinformatics and computational biology. 2006; 4(1): 139 -53. Doi A, Nagasaki M, Matsuno H, Miyano S. Simulation-based validation of the p 53 transcriptional activity with hybrid functional Petri net. In Silico Biology. 2006; 6(1 -2): 0001. Nagasaki M, Doi A, Matsuno H, Miyano S. Petri Net Based Description and Modeling of Biologinal Pathways. Algebraic Biology 2005 - Computer Algebra in Biology, H. Anai and K. Horimoto, eds. , Universal Academy Press, Inc. , Tokyo. 2005; 19 -31. Kato M, Nagasaki M, Doi A , Miyano S. Automatic Drawing of Biological Networks Using Cross Cost and Subcomponent Data. Genome Informatics. 2005; 16(2): 22 -31. Kitakaze H, Matsuno H, Ikeda N. Prediction of debacle points for robustness of biological pathways by using recurrent neural networks. Genome Informatics. 2005; 16(1): 192 -202. Li C, Suzuki S, Ge Qi-Wei, Nakata M, Matsuno H, Miyano S. On modeling and analyzing signaling pathways with inhibitory interactions based on Petri net, Proc. The 2005 Internatinal Joint Conference of In. Co. B, AASBi and KSBI (BIOINFO 2005). 2005; 348 -53. Nagasaki M, Doi A, Matsuno H, Miyano S. A versatile Petri net based architecture for modeling and simulation of complex biological processes. Genome Informatics. 2004; 15(1): 180 -97. Nagasaki M. A Platform for Biopathway Modeling/Simulation and Recreating biopathway databases towards simulation. Ph. D Thesis, The University of Tokyo. 2004. Nagasaki M, Doi A, Matsuno H, Miyano S. Integrating biopathway databases for large-scale modeling and simulation. The Second Asia-Pacific Bioinformatics Conferences, Volume 29 of Conferences in Research and Practice in Information Technology, Australian Computer Society. 2004; 43 -52. Doi A, Fujita S, Matsuno H, Nagasaki M, Miyano S. Constructing biological pathway models with hybrid functional Petri nets. In Silico Biology. 2004; 4(3): 271 -91 Matsui M, Fujita S, Suzuki S, Matsuno H, Miyano S. Simulated Cell Division Processes of the Xenopus Cell Cycle Pathway by Genomic Object Net. Journal of Integrative Bioinformatics. 2004; 0001. Fujita S, Matsui M, Matsuno H, Miyano S. Modeling and simulation of fission yeast cell cycle on hybrid functional Petri net. IEICE Transactions on Fundamentals of Electronics, Communications and Computer Sciences. 2004; E 87 -A(11): 2919 -28. Matsuno H, Murakami R, Yamane R, Yamasaki N, Fujita S, Yoshimori H, Miyano S. Boundary formation by notch signaling in Drosophila multicellular systems: experimental observations and a gene network modeling by Genomic Object Net. Pacific Symposium on Biocomputing. 2003: 152 -63. Nagasaki M, Doi A, Matsuno H, Miyano S. Recreating biopathway databases towards simulation. In: Computational Methods in Systems Biology. Lecture Notes in Computer Science. 2003; 2602: 191 -2. Matsuno H, Tanaka Y, Aoshima H, Doi A, Matsui M, Miyano S. Biopathways Representation and Simulation on Hybrid Functional Petri Net. In Silico Biology. 2003; 3(3): 389 -404. Nagasaki M, Doi A, Matsuno H, Miyano S. Genomic Object Net: I. A platform for modeling and simulating biopathways. Applied Bioinformatics. 2003; 2: 181 -4. Doi A, Nagasaki M, Fujita S, Matsuno H, Miyano S. Genomic Object Net: II. Modeling biopathways by hybrid functional Petri net with extension. Applied Bioinformatics. 2003; 2: 185 -8. Matsuno H, Fujita S, Doi A, Nagasaki M, Miyano S. Towards biopathway modeling and simulation. Lecture Notes in Computer Science. 2003; 2679; 3 -22. Doi A, Matsuno H, Matsui M, Hirata Y, Miyano S. Simulation of biological systems by hybrid Petri net with an enhancement. Proc. The International Conference on Fundamentals of Electronics, Communications and Computer Science 2002; S 5: 13 -8 Matsuno H, Doi A, Hirata Y, Miyano S. XML Documentation of Biopathways and Their Simulations in Genomic Object Net. Genome Informatics. 2001; 12: 54 -62. Matsuno H, Doi A, Nagasaki M, Miyano S. Hybrid Petri net representation of gene regulatory network. Pacific Symposium on Biocomputing 5. 2000; 341 -52. Copyright 2010 Masao Nagasaki

In Silico によるモデルが役に立つ例 事例１ p 53 A. Doi, H. Matsuno, M. Nagasaki, S. Miyano, Simulation Based Validation of p 53 Transcriptional Activity with Hybrid Functional Petri Net, In Silico Biology, 2006; 6(1 -2): 0001. Copyright 2010 Masao Nagasaki

他のパスウェイ表現 KEGG データベース Copyright 2010 Masao Nagasaki Kohnによるマップ (Kohn, 1999. )

文献に記述された生物学的な事実 1 2 3 4 5. . . biological phenomena on the literature (obtained by experiments) #1 #2 p 53(N) is bound to MDM 2(N), forming complex p 53_MDM 2(N). T 1 m 1*m 2*0. 01 binding [3, 7] MDM 2(N) is bound to p 19 ARF(N), forming complex MDM 2_p 19 ARF. T 2 m 2*m 4*0. 01 binding [3, 5, 7] T 3 m 4*m 5*0. 01 binding [3, 7] T 4 m 1*m 6*0. 01 binding [3, 7] T 5 1 transcription - p 53_MDM 2(N) is bound to p 19 ARF(N), forming complex p 53_MDM 2(N)_p 19 ARF. MDM 2_p 19 ARF is bound to p 53(N), forming complex p 53_MDM 2(N)_p 19 ARF. Transcription of injected gene p 53, producing p 53 m. RNA. type of biological literature process . . . 以下省略（計21個） Copyright 2010 Masao Nagasaki #1トランジションの番号 #2トランジションの速度

仮説 a) 複合体(p 53_MDM 2_p 19 ARF)が転写活性を 持たない。 Copyright 2010 Masao Nagasaki

仮説 b) 複合体(p 53_MDM 2_p 19 ARF)が転写活性を 持つ。 Copyright 2010 Masao Nagasaki

In Silico In Vitro Pomerantz et al. , 1998. In Vitroの実験からし て、仮説bのモデル が正しそうだ。 Copyright 2010 Masao Nagasaki 仮説 a) 仮説 b)

In Silico によるモデルが役に立つ例 事例2 概日リズム Hiroshi Matsuno, Shin-Ichi T. Inouye, Yasuki Okitsu, Yasushi Fujii, Satoru Miyano, A new regulatory interactions suggested by simulations for circadian genetic control mechanism in mammals, APBC, 171 -180, Imperial College Press (2005) Copyright 2010 Masao Nagasaki

マウス概日リズム遺伝子制御機構 Copyright 2010 Masao Nagasaki

一方、ショウジョウバエでは？ Copyright 2010 Masao Nagasaki

マウス概日リズム遺伝子制御機構 ※PER/CRYがPER/TIMに該当 Copyright 2010 Masao Nagasaki

実際には Copyright 2010 Masao Nagasaki

(In Vivo/Vitro) Sato, T. K. , et al. , A functional genomics strategy reveals Rora as a component of the mammalian circadian clock, Neuron, 43, pp. 527 -537, 2004. (In Silico) Hiroshi Matsuno, Shin-Ichi T. Inouye, Yasuki Okitsu, Yasushi Fujii, Satoru Miyano, A new regulatory interactions suggested by simulations for circadian genetic control mechanism in mammals, APBC, 171 -180, Imperial College Press January 2005. (In Vivo/Vitro) Akashi, M. , Takumi, T. , The orphan nuclear receptor RORα regulates circadian transcription of the mammalian core-clock Bmal 1, Nature Structural Molecular Biology, Published online: 10 April 2005, http: //www. nature. com/nsmb/journal /vaop/ncurrent/abs/nsmb 925. html. Copyright 2010 Masao Nagasaki

デモ Copyright 2010 Masao Nagasaki

今日の話の内容は 書籍　「システム生物学がわかる！　セルイラストレー タを使ってみよう」 　土井・長崎・斎藤・宮野編　共立出版　 2007年７月発売 書籍「Foundations of Systems Biology」 Using Cell Illustrator and Pathway Databases」 Masao Nagasaki, Ayumu Saito, Atsushi Doi, Hiroshi Matsuno, Satoru Miyano 2009年 5月発売 東京大学医科学研究所　総合研究棟８ F DNA情報解析分野 助教 長崎 masao@ims. u-tokyo. ac. jp Copyright 2010 Masao Nagasaki

おしまい Copyright 2010 Masao Nagasaki

• Modeling and Simulation with Hybrid Functional Petri Nets of the Role of Interleukin-6 in Human Early Haematopoiesis, Troncale et al. , Pac. Symp. Biocompt. , (2006). • Sato Y, Hashiguchi Y, Nishida M. Evolution of multiple phosphodiesterase isoforms in stickleback involved in c. AMP signal transduction pathway. BMC Systems Biology 2009; 3: 23 Copyright 2010 Masao Nagasaki