Multiscale Systems Biology

Working group co-leads:

Mark Alber, UC Riverside,

Feilim Mac GabhannJohns Hopkins University,

Ronan M.T. Fleming, University of Luxembourg.


Goals and Objectives: 

This working group is devoted to multiple-scale analysis and simulation of biological systems, with a special emphasis on cellular phenomena. Our first goal is to maintain a repository of up-to-date information on available tools, novel concepts, and major relevant review papers in the field, available here This resource aims to capture the state of the art in multi-scale systems biology, for purposes of advancing research, education, and training. Secondary goals include identifying and articulating current challenges and opportunities in the field, as well as fostering scientific collaborations.


New: Draft white paper on Multiscale Modelling of Molecular Systems Biology:

The scope of this white paper is reconstruction, mathematical modelling, and computational modelling of multiscale biomolecular networks. Modelling the coupling of biomolecular networks with biophysical models on lesser and greater spatiotemporal scales. All computational modelling methods must be demonstrably reducible to a mathematical model. Here is the link to the google doc: Contributions are welcome.


NOVEMBER 2017 MEETINGS - Meetings of interest to MSB members, described below:

1. Multiscale Systems Biology Methods for Studying Biomedical Processes in Patients Under Stress or with Chronic or Acute Diseases, Nov 15-16 2017 (Riverside CA)

2. Workshop on Immuno-Oncology Modeling—From Molecular Biology to Clinical Efficacy, Nov 12 2017 at the AAPS meeting (San Diego CA)


NEW: November Conference in Riverside (see next item); on September 19th 2017 we hosted a preparatory webinar to discuss topics for the conference. These are the minutes of the meeting PDF iconNotes from Webinar 2017-09.pdf.

[Webinar Announcement: September 19th, 1:30-3:00pm, Link. Webinar to discuss topics for the November conference (see next item).]


Past conference announcement (Presentation videos:

Multi-Scale Systems Biology Methods for Studying Biomedical Processes in Patients Under Stress or with Chronic or Acute Disease Conference

University of California, RiversideGenomics AuditoriumNovember 15th &16th, 2017

Sponsored by:


Co-organizers: Mark Alber, University of California, Riverside, USARonan MT Fleming, Université du Luxembourg, University of Leiden, The NetherlandsFeilim Mac Gabhann, Johns Hopkins University, USA 

Participants of the Conference will present talks and discuss interactions of methods developed for addressing three main challenges to bridging scales from molecular to clinical by catalyzing collaborations with clinicians. Clinicians will lead discussions on establishing interdisciplinary collaborations on development of new patient specific treatment strategies. Researchers from pharmaceutical companies will be also invited to participate in discussions.

1. Multi-scale modeling of cell behavior and tissue growth in patients under stress conditions or with chronic or acute diseases including, among others, cancer, thrombosis and sepsis. For example, modeling blood clot formation in cancer patients or patients with diabetes. Data for patients with acute stage of a disease or with untreated chronic disease are often not available making calibration of models difficult. Discussions will address specific topics including whether a model calibrated under normal conditions be used for simulating cellular and tissue behavior in a patient with several health problems by just shifting parameter ranges, or new model extensions need to be developed? Which models are to be used for simulating chronic diseases in patients treated with a combination of medications?

2. Multi-scale modeling of therapeutic interventions, including pharmaceuticals as well as gene therapy, cell therapy, and physiological therapy. Development of multi-scale models of the key molecular biology, cellular biology, heterogeneous tissue architecture, and physiology, could lead to detailed comparison of many different treatments, including different drugs, routes of administration, doses and schedules by virtual clinical trials that incorporate models of many patients. Due to the multi-scale nature of the models, clinicians could identify emergent therapeutic or toxic effects of treatments, as well as conditions under which therapies fail. These models can translate knowledge from in vitro cell culture to in vivo preclinical and clinical studies, which is important because it is known that observed mechanisms in vitro do not always hold in vivo. These models can help researchers and clinicians translate therapies from animals to humans, or from microphysiological systems (‘body-on-a-chip’) to patients.

3. Multi-scale modelling of biochemical networks personalized with omics data. Combining -omics data, machine learning approaches and other statistical methods with multi-scale modeling approaches to human disease. For example: Integration of statistics, optimization and multi-scale mechanistic modelling of brain metabolism to try to stratify Parkinson's disease patients based on distinct aetiopathegenic origins.

For further details, see:


NEW: Sasha Popel is co-organizing a relevant workshop at the AAPS (American Association of Pharmaceutical Scientists) in November.

AAPS Workshop on Immuno-Oncology Modeling—From Molecular Biology to Clinical Efficacy
8:30 AM–4:00 PM Nov 12, 2017
San Diego Convention Center - Room 25A
Bing Wang Ph.D.
Aleksander S. Popel Ph.D.
For additional information on that meeting, contact Sasha Popel



MSM 2017 (10th Anniversary) meeting

Notes from Breakout Session 2017-03-22


1. Discussion of steering committee goals and questions, and the history of the MSB WG


2. Discussion of Goals of MSB WG


  - Members of MSB WG have varied interests (scales, diseases, approaches)


  - Many people belong to MSB and another WG


  - Some other WGs are focussed on specific challenges/goals of the original MSB WG


  - This overlap - in people and topics - with several other WGs gives MSB a purpose:

            to integrate across the WGs, look at issues that are common across the WGs,

           and consider collaborative activities such as perspective papers, special issues, and meetings.


  - Example areas: 'gene-to-cell'; 'molecule-to-tissue'; 'molecules & mechanics'; drug delivery. The application areas in each are as diverse as the membership.

           Example 1: One of the topics is connection between chemical and mechanical stimuli determining size and shape of a tissue,

          with possible applications to early development, wound healing, blood clot formation, deformation and embolization,

          cancer invasion, Cell-ECM interactions, and remodeling. 


           Example 2: Another connective topic is drug delivery and response to therapeutics; many models incorporate a therapeutic component.

          Approaches that enable multiscale modeling of pharmacology has applications for therapeutics at different scales:

          gene therapy, small molecules, proteins, cell therapy, organ transplant, and more, across multiple diseases


           Example 3: Discussion of general principles of development of models of cellular and tissue behavior under stress,

           including trauma and chronic disease conditions. This would include discussion of model calibration and uncertainty quantification

           under healthy and stress conditions. Can a model calibrated under normal conditions be used for simulating

           cellular and tissue behavior under stress by just shifting parameter ranges or new model extension needs to be developed?

           Which models are to be used for simulating chronic diseases in a specific  patient treated with a combination of medications?

           In chronic diseases, data for acute and untreated disease is often not available - does this hurt model calibration? 

           Biomedical applications would include cancer, blood clotting, bacterial drug resistance and others.


  - Additional topics raised at the meeting include: model reduction; machine learning; incorporation of -omics data,


3. Plan for position papers, special issues, and meetings


  - Using this discussion as a basis, create a list of topics (including the examples listed above)


  - Approaches include: building primers; collating success stories; current challenges in the field

    (each of these has different audiences)


  - Editor in Chief of the Bulletin of Mathematical Biology, Reinhard C. Laubenbacher, described interest of the journal in special issues related to multi-scale modeling. PLoS Computational Biology editors have also previously expressed interest in special issues related to multi-scale modeling. 


  - Distribute lists/ideas to the members for discussion and refinement


  - Build collaborative teams to work on specific topics


  - Use this and other efforts to increase discussion of topics between IMAG meetings


  - Collaborate on organizing special sessions at the annual meetings of the professional societies including AAAS, Biophysical Society, Society for Mathematical Biology, American Physical Society, SIAM, Biomedical Engineering Society, ... 


  - Collaborate on preparing Special Issues, Position Papers, and Reviews for the PLoS Computational Biology, Biophysical Journal, Bulletin of Mathematical Biology, and Journal of the Royal Society Interface.



Discussion Items for Breakout Session (Wednesday March 22nd, 12:30-2:30pm, Kirschstein Auditorium)

A. Working Group Activities - Current/Planned

A1. Review of MSM-oriented community activities by MSB WG members in the past 18 months (see draft below; send additional material to

A2. Review of plans for future MSM-oriented community activities (note items 4 and 5 below, planning future collaborative efforts)

  1. journal special issues
  2. conferences/workshops on multiscale modeling
  3. special sessions at other conferences
  4. perspectives/editorials/reviews
  5. Biophysical Journal has a new collection/section, 'Computational Tools'; we could assemble a review for this.Papers for the CTs section, in addition to following the usual review criteria of novelty and importance, reviewers of CTs are asked to test drive the software and judge its usability. These papers are limited to five pages in length and describe software for analysis of experimental data, modeling and/or simulation, or database services.
  6. Webinars and other within-WG/MSM activities

B. Topics of interest for Future Working Group Activities

B1. Emerging topics in multiscale systems biology:

  1. "Gene-to-Cell": Connecting genetics to changes in cellular action
  2. "Molecule-to-Cell-to-Tissue": Multi-scale modeling of Tissue Growth and mechanisms determining Form and Size of Tissue. This could include cardiovascular systems, blood clot formation, early development, wound healing and cancer invasion as well as cellular interactions with/remodeling of the blood vessel wall and ECM. 
  3. "Molecules and Mechanics": Coupling molecular signaling and mechanical stimuli/mechanotransduction

B2. Discussion of collaboration on organizing special sessions at conferences on these topics (see upcoming meetings listed below, including Annual Meetings of the Society for Mathematical Biology, Biophysical Society, AMS, APS, SIAM, Bioengineering Meetings; please suggest others)

B3. Discussion of collaboration on organizing special issues of journals on these topics. Target journals include: PLoS Computational Biology; Bulleting of Mathematical Biology; Biophysical Journal; Soft Matter (R.Chem.Soc.); Interface J.R.Soc.L. Contact has been made with several of these already.

C. Questions from the Steering Committee 

     - Have the goals or objectives changed (from what is posted on the wiki)?

     - What obstacles, if any, have hindered your achieving them?
     - What has been accomplished?
     - How active have the members of the WG been, on average?
     - How can the WG improve?
     - Is there a need to evolve, subdivide, or merge the WG (merging, separating, etc.)?
     - What are the target journals of published papers in this area?
     - Have any special issues been completed or planned?
     - Would it be possible or useful to create a database / bibliography of MSM papers on the wiki?
     - Are there a few seminal review articles that document past successes or future needs related to your WG?
     - Finally, the Executive Committee is considering the development of two position papers to encompass the entirety of the MSM activity / future. From the perspective of the ImuBEAM, what would you recommend regarding target audiences and salient messages?

List of MSM-oriented community activities by MSB WG members in the past 18 months (draft; send additional material to


Modelling of Tissue Growth and FormMathematical Biology Institute (NSF MBI) Workshop 2 (co-organized by Mark Alber)March 6-10, 2017.

Interdisciplinary Workshop On Multi-scale Modeling of Complex System in Developmental & Plant Biology: UCR  (co-organized by Mark Alber)
The 8th International Bio-Fluid Symposium, Caltech.
The Bio-Fluid symposium led to a Journal of Biomechanics special issue on Biofluid mechanics of multitude pathways: From cellular to organ

MEETINGS - upcoming

Workshop on “PDE models of motility and invasion in active biosystems” at the Mathematical Research Institute, Oberwolfach, Germany. October 22-28, 2017.

SPECIAL SESSIONS at which MSM/MSB topics were discussed:

Special Session on Multiscale Systems Biology at the 2017 AIChE Annual Meeting, San Francisco. 
Workshop "Computing Tissue" at the 15th European Conference on Computational Biology, The Hague, Netherlands.
Minisymposium "Multiscale models of tissue mechanics, as tools to interpret experimental data"  (co-organized by Mark Alber)at the 2017 Annual Meeting of the Society of Mathematical Biology, Salt Lake City, July 17-21, 2017.
Special Session "Stochastic and Multi-scale Models in Mathematical Biology, Analysis and Simulations"  (co-organized by Mark Alber)
at the American Mathematical Society Western Section meeting to be held at UC Riverside on Nov. 4 and 5, 2017.


Mark Alber is organizing special issues of the Bulletin of Mathematical Biology and of PLoS Computational Biology as a follow up to the MBI and UCR meetings above. 
MSM/IMAG 2015 Meeting 

Collection of MSM communitiy oriented activities in the past year by MSB WG members 

  • Conferences (co)organised
    • Denise Kirchner
      • Signaling across Scales: Life Sciences to Social Systems, University of Michigan, 2014.
      • Computational Discovery in Complex Systems Biology, University of Michigan, 2015.
    • Ross Carlson
      • Metabolic Pathways Analysis, Braga, Portugal, 2015.
    • Ines Thiele, Jason Papin.
      • 4th Conference on Constraint-Based Reconstruction and Analysis (COBRA 2015), September 16-18, 2015. Including topical focus on multi-scale modeling (whole cell models, host pathogen interactions and microbial communities)
    • Michael Henson
      • Foundations of Systems Biology in Engineering, August 2015, Cambridge MA.
  • Model/Tool sharing
    • Ronan Fleming
      • Jan 2015- took over the leadership of the COBRA toolbox, the most widely used software package for constraint-based modeling of biochemical networks.
    • Michael Saunders
      • New software for multi-scale flux balance analysis released via the COBRA toolbox
  • Position paper entitled “Do Genome-scale Models Need Exact Solvers or Clearer Standards?” to appear shortly in Molecular Systems Biology.
    • 42 Authors, including MSM participants Bernhard Palsson, Michael Saunders, Ronan Fleming, Ines Thiele, Michael Saunders.
    • Response to: Chindelevitch L, Trigg J, Regev A & Berger B (2014) An exact arithmetic toolbox for a consistent and reproducible structural analysis of metabolic network models. Nat. Commun. 5: 4893
    • Refutation of inaccurate results reported by Chindelevitch et al, largely due to inaccurate parsing of published metabolic models, combined with a call for clear standards in model formulation.

Breakout Session A (8th Sept. 1:20 – 2:10pm)

  • What are the most important open challenges in Multiscale Systems Biology (from a technical perspective, not restricted to one particular biological domain)?
    • Suggestions for open challenges (WG participants please suggest new challenges with your name)
      • Linear modelling techniques vs intrinsic nonlinearity of biological processes
      • Translation of equivalent mathematical modelling results between fields (e.g. chemical engineering vs statistical physics vs hypergraph theory etc)
      • Integration of multiscale modelling (prior information) with big data (new information)
        • Model data dynamic whereas experimental data static
        • Model generated big data
      • Bridging scales from molecular to clinical by catalyzing collabortions with clinicians
        • not data poor, not methods poor, just need to go ahead and do it)
        • Successfully engaging with clinicians, developing a forum where that can be catalysed
      • Building the multiscale modeling community
        • Need for multiscale data for modeling purposes
        • Need for a working definition of Multiscale Systems Biology
  • What should the objectives be for the Multiscale Systems Biology WG in the coming year?
    • Suggestions for objectives (WG participants please suggest new objectives with your name)
      • Outreach to biologists
      • Webinars
      • Workshop sessions
    • Building Multiscale Systems Biology WG
      • Decentralized summer schools, embed students into labs for periods of time, more transfer of knowledge than technical segment of a talk
      • Meetings with a focus on brainstorming on problems
      • Workshop sessions at existing conferences
      • Special issues in journals
        • Plos Comp Bio
      • Webinars with modeler and experimentalist point of view
      • Membership
        • Attracting new membership
    • Meetings
      • Summer schools for communication of techniques
        • e.g. computational multiscale methods
        • Special sessions at other meetings
        • 3rd Day at annual MSM meeting, technical talks, training day before the meeting. For this, we would need to finalise the date of the next MSM meeting with at least 9 months notice.
    • Workshops
    • Training
      • Training grants (e.g. R25)
    • White papers
    • Communities emerging around authorship of white papers
    • Reaching out to actuarial communities
    • List of web databases with data for validation
    • Centralized benchmark of the modeling techniques, e.g., a DREAM like challenge or hackathon.
    • A bibliography of all of the relevant papers in different technical areas related to MSM and that can be a resource 
Past Presentations: 

Wednesday, November 14, 2012 at 12:30pm ET

Modeling cardiac function and dysfunction
Natalia Trayanova, PhD, Johns Hopkins University
Simulating cardiac electrophysiological function is one of the most striking examples of a successful integrative multi-scale modeling approach applied to a living system directly relevant to human disease. This presentation showcases specific examples of the state-of-the-art in cardiac integrative modeling, including 1) improving ventricular ablation procedure by using MRI reconstructed heart geometry and structure to investigate the reentrant circuits formed in the presence of an infarct scar; 2) developing a new out-of-the box high-frequency defibrillation methodology; 3) understanding the contributions of non-myocytes to cardiac function and dysfunction, and others.
Archived Recording:

Monday, September 17, 2012 at 1pm ET

Multi-Scale Modeling of Sickle Cell Anemia
George Karniadakis, PhD, Brown University
Presentation Slides
Sickle cells exhibit abnormal morphology and membrane mechanics in the deoxygenated state due to the polymerization of the interior sickle hemoglobin (HbS). We study the dynamics of self-assembly behavior of HbS in solution and corresponding induced cell morphologies by dissipative particle dynamics approach. A coarse-grained HbS model, which contains hydrophilic and hydrophobic particles, is constructed to match the structural properties and physical description (including crowding effects) of HbS. The hydrophobic interactions are shown to be necessary with chirality being the main driver for the formation of HbS fibers. In the absence of chain chirality, only the self-assembled small aggregates are observed whereas self-assembled elongated step-like bundle microstructures appear when we consider the chain chirality. Several typical cell morphologies (sickle, granular, elongated shapes), induced by the growth of HbS fibers, are revealed and their deviations from the biconcave shape are quantified by the asphericity and elliptical shape factors.We then use these sickle cells to study the rheological properties of sickle blood and the adhesive dynamics between red blood cells, white cells, and the arterial wall in small arterioles.
Archived Recording:

Friday June 8, 2012 at 1:00pm ET

Specification, Construction, and Exact Reduction of State Transition System Models of Biochemical Processes
Scott M. Bugenhagen and Daniel A. Beard, PhD
In this presentation, we introduce methods for the high-level specification of a system using hypergraphs, for the automated generation of a state-level model from a high-level model, and for the exact reduction of a state-level model using information (viz. symmetries and invariant manifolds) from the high-level model. We then give a tutorial demonstration of the practical application of the methods to the modeling of biochemical reaction systems using several examples constructed using Vernan, a MATLAB tool implementing the methods.

Friday October 28, 2011 1-2pm ET

Kasia A. Rejniak, PhD, H. Lee Moffitt Cancer Center & Research Institute
Title: Computational Bridging of Epithelial Morphogenesis and Tumor Mutations
A major challenge in biology is the mapping of genotypic changes to phenotypic outcomes. I will present how a computational model of epithelial morphogenesis (IBCell) can address this problem by linking molecular alterations to epithelial morphology through cellular core traits. In particular, I will show an example in which IBCell interrogated with 3-dimensional experimental acinar morphologies of breast epithelial cells expressing a mutant HER2 receptor leads to identification of previously unknown core trait alterations, i.e., loss of negative feedback from autocrine secreted ECM. I will also briefly show other applications of the IBCell model.
Lance L. Munn, PhD, Massachusetts General Hospital & Harvard Medical School
Title: Imaging vascular dynamics
Although therapies targeting the vasculature have had growing popularity in the past decade, we still know surprisinlgy little about how vasculature is formed or remodeled in plastic tissues such as wound beds or tumors. Intravital microscopy in transparent windows has the potential to reveal how cells organize and cooperate to accomplish critical processes such as morphogenesis and anastomosis. Facilitated by the recent availability of in vivo reporters and time-lapse imaging which allow tracking of specific cell populations, intravital microscopy is a powerful tool for determining cellular mechanisms of vascularization and tumor growth.

Tuesday May 31, 2011 11am-12pm ET: The Cardiovascular System and Disease

Nic Smith, Kings College London. Translating multi-scale modelling to the Heart of the clinic: developing personalised cardiac models

Michael King, Cornell University. Multiscale model of platelet adhesion and thrombus formation: validation with the humanized mouse


Goals and Objectives: 

This working group is devoted to multiple-scale analysis and simulation of biological systems, with a special emphasis on cellular phenomena. Our first goal is to maintain a repository of up-to-date information on available tools, novel concepts, and major relevant review papers in the field, available here This resource aims to capture the state of the art in multi-scale sytems biology, for purposes of advancing research, education, and training. Secondary goals include identifying and articulating current challenges and opportunities in the field, as well as fostering scientific collaborations.

Additional Information: 

Challenges and opportunities

High-throughput genomic, proteomic and epigenomic data are rapidly accumulating. Current models of physiological systems rarely take advantage of the availability of such data, in part because they inform process that operate on different time and space scales. Thus, a challenge and opportunity for multiscale systems biology is utilize statistical modeling and analyses dealing with high-throughput data to inform mechanistic multiscale modeling.

Another challenge for the physics-based models is for computationally intensive simulations to reach to laboratory and experimental timescales to enable direct comparison between models and experimental data. There is a trade-off between efficient course-graining, and retaining connection to meaningful physical parameters that correspond to independently measurable quantities.


Participation in Working Group

Participation in this working group (WG) is open to all who are interested; to join please contact one of the WG co-leads listed above. WG participants will be kept appraised of WG, Multiscale Modeling (MSM) Consortium, and IMAG discussions. Responsibilities of this working group include: (i) defining the WG title, goals and objectives, (ii) determining the current state of the art in multiscale systems biology, and identifying new challenges and opportunities, and (iii) suggesting and attending webinar presentations, contributing to WG white papers, workshops and publications. Participants will be expected to actively engage in WG activities, including managing content on the site, participating in online presentations, and other relevant activities (MSM participants are assigned IMAG wiki logins by IMAG staff). The activities of the WG should not reflect someone’s personal agenda, but should represent the consensus of the group.

Working Group Activities: 


MSM/IMAG 2014 Meeting Breakout Session on Modular Model Construction

We are holding a breakout session during the 2014 MSM meeting (1:00-1:45pm Sept. 3) on the topic of "Modular construction of multi-scale models". Details and discussion can be found here:


Multiscale Systems Biology: A Special Issue Devoted to Understanding Biology and Medicine Across Multiple Scales, Annals of Biomedical Engineering, November 2012

IEEE Transactions on Biomedical Engineering, Special Issue on Multiscale Modeling and Analysis in Computational Biology and Medicine Volume: 58, Issue: 10, Part:2

Multiscale Modeling of Particle Interactions: Applications in Biology and Nanotechnology. M.R. King and D.J. Gee, editors, Wiley, 2010

Engineering in Medicine and Biology Magazine, IEEE Vol 28 , Issues:2- 3, 2009

Table sorting checkbox: