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SBML Level 3: an extensible format for the exchange and reuse of biological models

Keating, Sarah M. and Waltemath, Dagmar and König, Matthias and Zhang, Fengkai and Dräger, Andreas and Chaouiya, Claudine and Bergmann, Frank T. and Finney, Andrew and Gillespie, Colin S. and Helikar, Tomáš and Hoops, Stefan and Malik‐Sheriff, Rahuman S. and Moodie, Stuart L. and Moraru, Ion I. and Myers, Chris J. and Naldi, Aurélien and Olivier, Brett G. and Sahle, Sven and Schaff, James C. and Smith, Lucian P. and Swat, Maciej J. and Thieffry, Denis and Watanabe, Leandro and Wilkinson, Darren J. and Blinov, Michael L. and Begley, Kimberly and Faeder, James R. and Gómez, Harold F. and Hamm, Thomas M. and Inagaki, Yuichiro and Liebermeister, Wolfram and Lister, Allyson L. and Lucio, Daniel and Mjolsness, Eric and Proctor, Carole J. and Raman, Karthik and Rodriguez, Nicolas and Shaffer, Clifford A. and Shapiro, Bruce E. and Stelling, Joerg and Swainston, Neil and Tanimura, Naoki and Wagner, John and Meier‐Schellersheim, Martin and Sauro, Herbert M. and Palsson, Bernhard. and Bolouri, Hamid and Kitano, Hiroaki and Funahashi, Akira and Hermjakob, Henning and Doyle, John C. and Hucka, Michael and Adams, Richard R. and Allen, Nicholas A. and Angermann, Bastian R. and Antoniotti, Marco and Bader, Gary D. and Červený, Jan and Courtot, Mélanie and Cox, Chris D. and Dalle Pezze, Piero and Demir, Emek and Denney, William S. and Dharuri, Harish and Dorier, Julien and Drasdo, Dirk and Ebrahim, Ali and Eichner, Johannes and Elf, Johan and Endler, Lukas and Evelo, Chris T. and Flamm, Christoph and Fleming, Ronan M. T. and Fröhlich, Martina and Glont, Mihai and Gonçalves, Emanuel and Golebiewski, Martin and Grabski, Hovakim and Gutteridge, Alex and Hachmeister, Damon and Harris, Leonard A. and Heavner, Benjamin D. and Henkel, Ron and Hlavacek, William S. and Hu, Bin and Hyduke, Daniel R. and Jong, Hidde and Juty, Nick and Karp, Peter D and Karr, Jonathan R. and Kell, Douglas B. and Keller, Roland and Kiselev, Ilya and Klamt, Steffen and Klipp, Edda and Knüpfer, Christian and Kolpakov, Fedor and Krause, Falko and Kutmon, Martina and Laibe, Camille and Lawless, Conor and Li, Lu and Loew, Leslie M. and Machne, Rainer and Matsuoka, Yukiko and Mendes, Pedro and Mi, Huaiyu and Mittag, Florian and Monteiro, Pedro T and Natarajan, Kedar Nath and Nielsen, Poul M. F. and Nguyen, Tramy and Palmisano, Alida and Pettit, Jean‐Baptiste and Pfau, Thomas and Phair, Robert D. and Radivoyevitch, Tomas and Rohwer, Johann M. and Ruebenacker, Oliver A. and Saez‐Rodriguez, Julio and Scharm, Martin and Schmidt, Henning and Schreiber, Falk and Schubert, Michael and Schulte, Roman and Sealfon, Stuart C. and Smallbone, Kieran and Soliman, Sylvain and Stefan, Melanie I. and Sullivan, Devin P. and Takahashi, Koichi and Teusink, Bas and Tolnay, David and Vazirabad, Ibrahim and Kamp, Axel and Wittig, Ulrike and Wrzodek, Clemens and Wrzodek, Finja and Xenarios, Ioannis and Zhukova, Anna and Zucker, Jeremy (2020) SBML Level 3: an extensible format for the exchange and reuse of biological models. Molecular Systems Biology, 16 (8). Art. No. e9110. ISSN 1744-4292.

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Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction‐based models and packages that extend the core with features suited to other model types including constraint‐based models, reaction‐diffusion models, logical network models, and rule‐based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single‐cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution.

Item Type:Article
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URLURL TypeDescription
Keating, Sarah M.0000-0002-3356-3542
Waltemath, Dagmar0000-0002-5886-5563
König, Matthias0000-0003-1725-179X
Zhang, Fengkai0000-0001-7112-9328
Dräger, Andreas0000-0002-1240-5553
Chaouiya, Claudine0000-0003-2350-0756
Bergmann, Frank T.0000-0001-5553-4702
Gillespie, Colin S.0000-0003-1787-0275
Helikar, Tomáš0000-0003-3653-1906
Hoops, Stefan0000-0001-8503-8371
Malik‐Sheriff, Rahuman S.0000-0003-0705-9809
Moodie, Stuart L.0000-0001-6191-5595
Moraru, Ion I.0000-0002-3746-9676
Myers, Chris J.0000-0002-8762-8444
Naldi, Aurélien0000-0002-6495-2655
Olivier, Brett G.0000-0002-5293-5321
Schaff, James C.0000-0003-3286-7736
Smith, Lucian P.0000-0001-7002-6386
Thieffry, Denis0000-0003-0271-1757
Watanabe, Leandro0000-0001-7030-8690
Wilkinson, Darren J.0000-0003-0736-802X
Blinov, Michael L.0000-0002-9363-9705
Begley, Kimberly0000-0002-1642-7493
Faeder, James R.0000-0001-8127-609X
Hamm, Thomas M.0000-0001-9579-7267
Inagaki, Yuichiro0000-0003-4011-8487
Liebermeister, Wolfram0000-0002-2568-2381
Lister, Allyson L.0000-0002-7702-4495
Lucio, Daniel0000-0002-8912-7213
Mjolsness, Eric0000-0002-9085-9171
Proctor, Carole J.0000-0002-1366-1399
Raman, Karthik0000-0002-9311-7093
Rodriguez, Nicolas0000-0002-9290-7894
Shaffer, Clifford A.0000-0003-0001-0295
Stelling, Joerg0000-0002-1145-891X
Swainston, Neil0000-0001-7020-1236
Meier‐Schellersheim, Martin0000-0002-8754-6377
Sauro, Herbert M.0000-0002-3659-6817
Palsson, Bernhard.0000-0003-2357-6785
Kitano, Hiroaki0000-0002-3589-1953
Funahashi, Akira0000-0003-0605-239X
Hermjakob, Henning0000-0001-8479-0262
Doyle, John C.0000-0002-1828-2486
Hucka, Michael0000-0001-9105-5960
Natarajan, Kedar Nath0000-0002-9264-1280
Additional Information:© 2020 California Institute of Technology. Published under the terms of the CC BY 4.0 license. Received 11 July 2019; Revised 24 June 2020; Accepted 9 July 2020. We sincerely thank all current and past SBML users, developers, contributors, supporters, advisors, administrators, and community members. We give special thanks to the following people for contributions and support: Jim Anderson, Nadia Anwar, Gordon Ball, Duncan Bérenguier, Upinder Bhalla, Frédéric Y. Bois, Benjamin Bornstein, Richard Boys, Ann Chasson, Thomas Cokelaer, Marco Donizelli, Alexander Dörr, Marine Dumousseau (Sivade), Lisa Falk, David Fange, Ed Frank, Ralph Gauges, Martin Ginkel, Nail Gizzatkulov, Victoria Gor, Igor Goryanin, Ryan N. Gutenkunst, Arnaud Henry, Stefanie Hoffmann, Duncan Hull, Dagmar Iber, Gael Jalowicki, Henrik Johansson, Akiya Jouraku, Devesh Khandelwal, Thomas B. L. Kirkwood, Victor Kofia, Benjamin L. Kovitz, Bryan Kowal, Andreas Kremling, Ursula Kummer, Hiroyuki Kuwahara, Anuradha Lakshminarayana, Nicolas Le Novère, Thomas S. Ligon, Adrian Lopez, Timo Lubitz, Peter Lyster, Natalia Maltsev, Jakob Matthes, Joanne Matthews, Tommaso Mazza, Eric Minch, Sebastian Nagel, Maki Nakayama, Poul M. F. Nielsen, German Nudelman, Anika Oellrich, Nobuyuki Ohta, Michel Page, Victoria Petri, Ranjit Randhawa, Veerasamy Ravichandran, Elisabeth Remy, Isabel Rojas, Ursula Rost, Jan D. Rudolph, Takayuki Saito, Takeshi Sakurada, Howard Salis, Maria J. Schilstra, Marvin Schulz, Shalin Shah, Daryl Shanley, Tom Shimizu, Jacky Snoep, Hugh D. Spence, Yves Sucaet, Linda Taddeo, Jose Juan Tapia, Alex Thomas, Jannis Uhlendorf, Martijn P. van Iersel, Marc Vass, Jonathan Webb, Katja Wengler, Benjamin Wicks, Sarala Wimalaratne, Haoran Yu, Thomas J. Zajac, W. Jim Zheng, and Jason Zwolak. The principal authors thank many funding agencies for their support of this work. F.B., A.D., M.H., T.M.H., S.M.K., B.O., and L.S., as well as and its online resources, were supported by the National Institute of General Medical Sciences (NIGMS, US), grant R01‐GM070923 (PI: Hucka). In addition, F.B. has been supported by the Bundesministerium für Bildung und Forschung (BMBF, DE), grant de.NBI ModSim1, 031L0104A (PI: Ursula Kummer). M.L.B. has been supported by NIH (US) grant P41‐GM103313 and R01‐GM095485. A.D. has been supported by infrastructural funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, and by the German Center for Infection Research (DZIF). A.F. was supported by the Grant‐in‐Aid for Young Scientists (B), grant 21700328 from JSPS KAKENHI (JP) to Keio University. J.F. was supported by National Institutes of Health (NIH, US) grant P41‐GM103712 to the National Center for Multiscale Modeling of Biological Systems (MMBioS). H.H. was supported by the Biotechnology and Biological Sciences Research Council (BBSRC, UK) “MultiMod” project (grant BB/N019482/1). T.H. was supported by NIH (US) grant 5R35‐GM119770‐03 to the University of Nebraska–Lincoln. S.H. was supported by NIGMS (US) grant R01‐GM080219. M.K. was supported by the Federal Ministry of Education and Research (BMBF, DE), research network Systems Medicine of the Liver (LiSyM), grant 031L0054, Humboldt‐University Berlin (PI: König). A.L. was supported by the BBSRC (UK) while working at the Centre for Integrated Systems Biology of Ageing and Nutrition (CISBAN), Newcastle University. C.M. was supported by the National Science Foundation (NSF, USA) under grant CCF‐1748200 and CCF‐1856740. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the NSF. I.M. was supported by NIH grant P41‐EB023912 and P41‐GM103313. K.R. was supported by the Department of Biotechnology, Government of India (grant BT/PR4949/BRB/10/1048/2012). M.M.‐S. was supported by the Intramural Research Program of NIAID, NIH (US). R.M.‐S. was supported by the BBSRC (UK) “MultiMod” project (grant BB/N019482/1). B.P.'s was supported by NIH (US) grant GM57089 to the University of California, San Diego, and by the Novo Nordisk Foundation Grant NNF10CC1016517. H.M.S. was supported by NIGMS (US) grant R01‐GM123032 (PI: Sauro) and by the National Institute of Biomedical Imaging and Bioengineering (NIBIB, US) grant P41‐EB023912 (PI: Sauro). J.C.S. was supported by NIGMS (US) grant P41‐GM103313. M.S. was supported by the DDMoRe program (EU), Innovative Medicines Initiative Joint Undertaking under grant agreement 115156. N.S. was supported by BBSRC (UK) grant “Centre for Synthetic Biology of Fine and Speciality Chemicals (SYNBIOCHEM) ”, grant BB/M017702/1 (PI: Nigel S. Scrutton). F.Z. was supported by the Intramural Research Program of NIAID, NIH (US). We also thank the Google Summer of Code program for support of SBML software development. Author contributions: SMK, DW, MK, FZ, AD, CC, and MH wrote the bulk of the manuscript. Together with FTB, AF, CSG, TH, SH, RM‐S, SLM, IIM, CJM, AN, BGO, SS, JCS, LPS, MJS, DT, LW, and DJW, they also wrote and/or edited specifications for SBML Level 3 Core and the Level 3 packages. MLB, KB, JRF, HFG, TMH, YI, WL, ALL, DL, EM, CJP, KR, NR, CAS, BES, JS, JCS, NS, NT, and JW contributed proposals for SBML Level 3 and/or are past or current members of the SBML Team. MM‐S, HMS, BP, HB, HK, AF, HH, JCD, and MH were principal investigators (or the equivalent, depending on the institution) for grants supporting SBML development. The SBML community members listed in the Appendix supported the development of SBML Level 3 through participation in discussions, commentary on specification documents, and/or implementation of SBML‐using software. Conflict of interest: TH has served as a shareholder and/or has consulted for Discovery Collective, Inc. Acknowledgments by SBML community members: B.A.'s work on SBML Level 3 was supported by the National Institutes of Health (NIH, US) and he is currently employed by AstraZeneca. G.B. was supported by National Resource for Network Biology (NRNB, US), award 5P41‐GM103504. M.L.B. was supported by grant P41‐GM103313 and R01‐GM095485 from the NIH (US) to the University of Connecticut School of Medicine. J.Č. was supported by the Czech Research Infrastructure Infrastructure for Systems Biology C4SYS, project LM2015055; GA ČR, grant 18‐24397S; and the MEYS of the Czech Republic under OP RDE grant CZ.02.1.01/0.0/0.0/16_026/0008413 “Strategic Partnership for Environmental Technologies and Energy Production”. D.D. was supported by grant iLite (Innovations for LIver and Tissue Engineering) from Agence nationale de la recherche (ANR, France) to INRIA, Paris, France; by grant LiSyM (Liver Systems Medicine) from Bundesministerium für Bildung und Forschung (BMBF, Germany) to IfADo, Dortmund, Germany; by grant VLN (Virtual Liver Network) from Bundesministerium für Bildung und Forschung (BMBF, Germany) to IfADo, Dortmund, Germany; by grant Physicancer from Institut national de la santé et de la recherche médicale (INSERM, France) to INRIA, Paris, France; and by grant NOTOX (Predicting long‐term toxic effects using computer models based on systems characterisations of organotypic cultures) from EU 7th Framework Programme to INRIA, Paris, France. C.E. was supported by CHARME, COST, Action CA15110 MoU (PI: Chris Evelo) to Maastricht University. R.F. was supported by the U.S. Department of Energy, Offices of Advanced Scientific Computing Research and the Biological and Environmental Research as part of the Scientific Discovery Through Advanced Computing program, grant DE‐SC0010429. A.G. was supported by the Japanese Society for the Promotion of Science. M.G. was supported by funding to HITS from the German Federal Ministry of Education and Research (BMBF) as part of the Liver Systems Medicine Network LiSyM (FKZ 031L0056) and through the MulticellML project (FKZ 01ZX1707B), as well as from the European Union Horizon2020 framework programme of the European Commission under Grant Agreement 825843 and from the Klaus Tschira Foundation (KTS). M.G.G. was supported by European Molecular Biology Laboratory (EMBL) core funding. W.S.H. was supported by grant R01‐GM111510 from the National Institute of General Medical Sciences (NIGMS, US) of the NIH. D.K. was supported by Novo Nordisk Foundation grant NNF10CC1016517. E.K. was supported by Deutsche Forschungsgemeinschaft (DFG, GRK1772, GRK 2290 and TRR175) and by People Programme (Marie Skłodowska‐Curie Actions H2020‐MSCA‐ITN‐2015‐675585). F.K. was supported by the Russian Foundation for Basic Research, 17‐00‐00296, Institute of Computational Technologies of SB RAS, Novosibirsk, 630090, Russian Federation (PI: Fedor Kolpakov). J.K. was supported by grants R35‐GM119771 and P41‐EB023912 from the NIH (US) to the Icahn School of Medicine. P.K. was supported by NIH grant GM075742 from the NIH (US) to SRI International. S.K. was supported by grant 031L104B (de.NBI partner project “ModSim”) by the German Federal Ministry of Education and Research to MPI Magdeburg. L.M.L. was supported by grant P41‐GM103313 from the NIH (US) to the University of Connecticut School of Medicine. P.M. was supported by grant GM080219 from the NIH (US). P.T.M was supported by grant PTDC/EEI‐CTP/2914/2014 from Fundação para a Ciência e a Tecnologia (FCT) to INESC‐ID. A.P.'s contribution to this manuscript is a follow‐up of the work done while employed at Virginia Tech. (VA, US). The opinions expressed in this manuscript are the authors’ own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States Government. S.C.S. was supported by grant U19‐AI117873 from the NIH (US).
Funding AgencyGrant Number
Bundesministerium für Bildung und Forschung (BMBF)de.NBI ModSim1
Bundesministerium für Bildung und Forschung (BMBF)031L0104A
Deutsche Forschungsgemeinschaft (DFG)EXC 2124
German Center for Infection Research (DZIF)UNSPECIFIED
Japan Society for the Promotion of Science (JSPS)21700328
Biotechnology and Biological Sciences Research Council (BBSRC)BB/N019482/1
Bundesministerium für Bildung und Forschung (BMBF)031L0054
Department of Biotechnology (India)BT/PR4949/BRB/10/1048/2012
Novo Nordisk FoundationNNF10CC1016517
European Union115156
Biotechnology and Biological Sciences Research Council (BBSRC)BB/M017702/1
Czech Research Infrastructure Infrastructure for Systems BiologyLM2015055
Czech Science Foundation18‐24397S
Ministry of Education, Youth and Sports (Czech Republic)CZ.02.1.01/0.0/0.0/16_026/0008413
Agence Nationale pour la Recherche (ANR)UNSPECIFIED
Institut national de la santé et de la recherche médicale (INSERM)UNSPECIFIED
European Cooperation in Science and Technology (COST)CA15110 MoU
Department of Energy (DOE)DE‐SC0010429
Bundesministerium für Bildung und Forschung (BMBF)FKZ 031L0056
Bundesministerium für Bildung und Forschung (BMBF)FKZ 01ZX1707B
European Research Council (ERC)825843
Klaus Tschira FoundationUNSPECIFIED
European Molecular Biology Organization (EMBO)UNSPECIFIED
Deutsche Forschungsgemeinschaft (DFG)GRK1772
Deutsche Forschungsgemeinschaft (DFG)GRK 2290
Deutsche Forschungsgemeinschaft (DFG)TRR175
Marie Curie FellowshipH2020‐MSCA‐ITN‐2015‐675585
Russian Foundation for Basic Research17‐00‐00296
Russian FederationUNSPECIFIED
Bundesministerium für Bildung und Forschung (BMBF)031L104B
Fundação para a Ciência e a Tecnologia (FCT)PTDC/EEI‐CTP/2914/2014
Subject Keywords:computational modeling; file format; interoperability; reproducibility; systems biology
Issue or Number:8
Record Number:CaltechAUTHORS:20200827-073238775
Persistent URL:
Official Citation:SBML Level 3: an extensible format for the exchange and reuse of biological models. Sarah M Keating, Dagmar Waltemath, Matthias König, Fengkai Zhang, Andreas Dräger, Claudine Chaouiya, Frank T Bergmann, Andrew Finney, Colin S Gillespie, Tomáš Helikar, Stefan Hoops, Rahuman S Malik‐Sheriff, Stuart L Moodie, Ion I Moraru, Chris J Myers, Aurélien Naldi, Brett G Olivier, Sven Sahle, James C Schaff, Lucian P Smith, Maciej J Swat, Denis Thieffry, Leandro Watanabe, Darren J Wilkinson, Michael L Blinov, Kimberly Begley, James R Faeder, Harold F Gómez, […], SBML Level 3 Community members. Mol Syst Biol. (2020) 16: e9110;
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105126
Deposited By: Tony Diaz
Deposited On:27 Aug 2020 15:54
Last Modified:27 Aug 2020 15:54

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