PhysiCell: an Open Source Physics-Based Cell Simulator for 3-D Multicellular Systems

Versions: 1.12.0 -

Release dates: 15 May 2023 -

• 1.12.0 : 15 May 2023

Overview:

PhysiCell is a flexible open source framework for building agent-based multicellular models in 3-D tissue environments.

Reference: A Ghaffarizadeh, R Heiland, SH Friedman, SM Mumenthaler, and P Macklin, PhysiCell: an Open Source Physics-Based Cell Simulator for Multicellular Systems, PLoS Comput. Biol. 14(2): e1005991, 2018. DOI: 10.1371/journal.pcbi.1005991

Visit http://MathCancer.org/blog for the latest tutorials and help.

Notable recognition:

• 2019 PLoS Computational Biology Research Prize for Public Impact

Key makefile rules:

make: compiles the current project. If no project has been defined, it first populates the cancer heterogeneity 2D sample project and compiles it

make project-name: populates the indicated sample project. Use "make" to compile it.

• project-name choices:
  • template
  • biorobots-sample
  • cancer-biorobots-sample
  • cancer-immune-sample
  • celltypes3-sample
  • heterogeneity-sample
  • pred-prey-farmer
  • virus-macrophage-sample
  • worm-sample
  • ode-energy-sample
  • physiboss-cell-lines-sample
  • cancer-metabolism-sample
  • interaction-sample
  • mechano-sample
  • rules-sample

make list-projects : list all available sample projects

make clean : removes all .o files and the executable, so that the next "make" recompiles the entire project

make data-cleanup : clears out all simulation data

make reset : de-populates the sample project and returns to the original PhysiCell state. Use this when switching to a new PhysiCell sample project.

make save PROJ=name: save the current project (including the Makefile, main.cpp, and everything in ./config and ./custom_modules/) in ./user_projects/name, where name is your choice for the project. If the project already exists, overwrite it.

make load PROJ=name: load the user project name from ./user_projects/name (including the Makefile, main.cpp, and everything in ./config and ./custom_modules/).

make list-user-projects: list all user projects in ./user_projects/. (Use these names without the trailing / in make load PROJ=name.)

make jpeg : uses ImageMagick to convert the SVG files in the output directory to JPG (with appropriate sizing to make movies). Supply OUTPUT=foldername to select a different folder.

make movie : uses ffmpeg to convert the JPG files in the output directory an mp4 movie. Supply OUTPUT=foldername to select a different folder, or FRAMERATE=framerate to override the frame rate.

make upgrade : fetch the latest release of PhysiCell and overwrite the core library and sample projects.

Key Links

Homepage: http://PhysiCell.MathCancer.org

Downloads: http://PhysiCell.sf.net

Support: https://sourceforge.net/p/physicell/tickets/

Quick Start: Look at QuickStart.md in the documentation folder.

User Guide: Look at UserGuide.pdf in the documentation folder.

Setup and Training: See last year's workshop and hackathon at https://github.com/PhysiCell-Training/ws2021

Older Tutorials: http://www.mathcancer.org/blog/physicell-tutorials/

Latest info: follow @PhysiCell on Twitter (http://twitter.com/PhysiCell)

See changes.md for the full change log.

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Release summary:

Version 1.12.0 introduces rules-based modeling: human-interpretable statements of the form

In cell type T, signal S increases/decreases behavior B

are represented with a CSV format that can directly and uniquely map onto a Hill response function to auto-generate simulation code. T is any cell type in the simulation, S can be any signal in the signal dictionary, and B any supported behavior in the behavior dictionary. For example:

• In malignant epithelial cells, pressure decreases cycle entry.
• In M0 macrophages, necrotic debris increases transformation to M1 macrophage.
• In effector T cells, contact with malignant epithelial cell decreases migration speed.
• In effector T cells, IFN-gamma increases attack of malignant epithelial cells.

The CSV version of these statements can be parsed and transformed into code dynamically at runtime, without additional user-written C++ or recompiling. This will be the basis of a pre-compiled PhysiCell Studio (model design, execution, and visualization in one package) and similar PhysiCell Cloud (install-free, browser-based model design, execution, and visualization). This allows modelers to focus on choosing their hypotheses--how signals (stimuli) change cell behavior--and less on coding and debugging. It is our hope that this language is sufficiently expressive to write most models without additional user code. However, users can still write custom phenotype functions that can be integrated with rules-based modeling, allowing further fine-tuning of individual cell behavior.

NOTE 1: MacOS users need to define a PHYSICELL_CPP environment variable to specify their OpenMP-enabled g++. See the Quickstart for details.

NOTE 2: Windows users need to follow an updated (from v1.8) MinGW64 installation procedure. This will install an updated version of g++, plus libraries that are needed for some of the intracellular models. See the Quickstart for details.

Major new features and changes in the 1.12.z versions

1.12.0

• Rules-based modeling: See introduction above.

• Automated annotation of the model hypotheses: Upon parsing the rules, PhysiCell auto-generates HTML-formatted text annotating all model hypotheses, for use in a paper's method section. This is to encourage better model interoperability and reproducibility.

• CSV-based specification of model rules:

  • Version 1: cell_type , signal , direction , behavior , base_value , max_response_value , half_max , Hill_power , applies_to_dead

    • cell_type: The (human-readable) name of any cell type in the simulation, matching their declarations in the XML configuration file.
      • Allowed values: Any named cell type in the simulation.
    • signal: Any signal in the simulation's signal dictionary that can be queried to modulate a behavior.
      • Allowed values: Any signal that is known to the signal dictionary.
    • direction: Tells whether the signal increases or decreases the behavior.
      • Allowed values: increases or decreases
    • behavior: Any behavioral parameter in the simulation's behavior dictionary that can be edited to modulate a behavior.
      • Allowed values: Any behavioral parameter that is known in the behavior dictionary.
    • base_value: The value of the behavioral parameter in the absence of any signals
      • Allowed value: Must match the behavior's parameter value in the cell definition
    • max_response_value: The maximally changed behavior when acting under high values of signal
      • Allowed values (for rules that increase the behavior): Any positive value equalling or exceeding the base_value. E.g., ten times the base value.
      • Allowed values (for rules that decrease the behavior): Any positive value equal to or less than the base_value. E.g., one tenth the base value.
    • half_max: Value of the signal at which the behavior undergoes half of its maximal change.
      • Allowed values: Non-zero positive numbers.
    • Hill_power: The Hill coefficient in a Hill response function.
      • Allowed values: Any non-zero positive number. Integer values are MUCH more computationally efficient.
    • 'applies_to_dead': Indicates if the rule should also be applied to dead cells.
      • Allowed values: 0 (for false) or 1 (for true).

  • Version 2: cell_type , signal , direction , behavior , max_response_value , half_max , Hill_power , applies_to_dead This version always copies the base_values from the corresponding cell definition.

    • cell_type: The (human-readable) name of any cell type in the simulation, matching their declarations in the XML configuration file.
      • Allowed values: Any named cell type in the simulation.
    • signal: Any signal in the simulation's signal dictionary that can be queried to modulate a behavior.
      • Allowed values: Any signal that is known to the signal dictionary.
    • direction: Tells whether the signal increases or decreases the behavior.
      • Allowed values: increases or decreases
    • behavior: Any behavioral parameter in the simulation's behavior dictionary that can be edited to modulate a behavior.
      • Allowed values: Any behavioral parameter that is known in the behavior dictionary.
    • max_response_value: The maximally changed behavior when acting under high values of signal
      • Allowed values (for rules that increase the behavior): Any positive value equalling or exceeding the base_value. E.g., ten times the base value.
      • Allowed values (for rules that decrease the behavior): Any positive value equal to or less than the base_value. E.g., one tenth the base value.
    • half_max: Value of the signal at which the behavior undergoes half of its maximal change.
      • Allowed values: Non-zero positive numbers.
    • Hill_power: The Hill coefficient in a Hill response function.
      • Allowed values: Any non-zero positive number. Integer values are MUCH more computationally efficient.
    • applies_to_dead: Indicates if the rule should also be applied to dead cells.
      • Allowed values: 0 (for false) or 1 (for true).

• Support for both rules-based behavior and traditional phenotype functions: If both are specified, then rules-based phenotype are applied first, followed by user-supplied phenotype functions that can further fine-tune cell behavior (as needed).

• Code-free model specification by PhysiCell Studio.

• Updated PhysiBoSS to remove cell definition "inheritance," (with "flat", self-standing cell definitions), to make it compatible with PhysiCell Studio. Hereafter, all properties of each cell definition must be explicitely defined.

• New section in PhysiCell_settings.xml to indicate a rules CSV file file:

<cell_rules>
    <rulesets>
        <ruleset protocol="CBHG" version="2.0" format="csv" enabled="true">
            <folder>./config</folder>
            <filename>cell_rules.csv</filename>
        </ruleset>
    </rulesets>
    <settings />
</cell_rules>

• protocol: This value should always be CBHG (cell behavior hypothesis grammar)
• version: Use 0.0 (or none for pre-beta files, but migrate away from this.) Use 1.0 for v1 rules as specified above. Use 2.0 for v2 rules as specified above.
• format: For now, only csv is supported.
• enabled: Set true to apply the rules, and false otherwise.

• folder: Set the folder containing the rules file. This should typically be ./config.
• filename: Set the name of the rules file. e.g., cell_rules.csv.

Minor new features and changes:

1.12.0

• Added new functions to PhysiCell_basic_signaling:

  • multivariate_Hill_response_function combines multiple signals (std::vector<double> signals) with individual half-maxes (std::vector<double> half_maxes) and Hill powers (std::vector<double> hill_powers) into a multivariate Hill response function, such that if only supplied with a single nonzero signal, then it returns the regular single-variable Hill function for that corresponding signal.

  • multivariate_linear_response_function combines multiple signals (std::vector<double> signals) with independent minimal thresholds (std::vector<double> min_thresholds: values below which individual linear responses are zero) and maximum thresholds (std::vector<double> max_thresholds ): values above which individual linear responses are one) into a multivariate linear response, such that if only supplied with a single nonzero signal, then it returns the regular single-variable linear response function for that corresponding signal. This function is "capped" between 0 and 1.

  • linear_response_to_Hill_parameters determines a half-maximum and Hill power to approximate a linear response function (with minimum threshold s0 and maximum threshold s1) with a Hill response function.

  • Hill_response_to_linear_parameters determins minimum and maximum thresholds to approximate a Hill response function (with half-maximum half_max and Hill power double Hill_power) with a linear response function.

• Added double get_single_base_behavior( Cell_Definition* pCD , std::string name ) to PhysiCell_signal_behavior to extract single base behaviors directly from a Cell_Definition.

• Added double get_single_base_behavior( Cell* pCD , std::string name ) to PhysiCell_signal_behavior to extract single base behaviors directly from a cell's corresponding Cell_Definition.

• PhysiCell outputs dictionary.txt at runtime with the current list of known signals and behaviors (for use in rules-based modeling).

• BioFVM_vector now includes double dot_product( std::vector<double>& a , std::vector<double>& b ); for a standardized dot product.

• BioFVM_vector now includes std::vector<double> cross_product( std::vector<double>& a , std::vector<double>& b ); for a standardized cross product.

• Added new rules-sample sample project to demonstrate rules-based modeling. It's a "toy model" with tumor cells, macrophages, and T cells.

• Updated sample projects for compatibility.

• Added make list-user-projects rule to Makefile to list all user projects available for loading

Beta features (not fully supported):

1.12.0

• None in this release.

Bugfixes:

1.12.0

• None in this release.

Notices for intended changes that may affect backwards compatibility:

• We intend to deprecate the unused phenotype variables relative_maximum_attachment_distance, relative_detachment_distance, and maximum_attachment_rate from phenotype.mechanics.

• We intend to merge Custom_Variable and Custom_Vector_Variable in the future.

• We may change the role of operator() and operator[] in Custom_Variable to more closely mirror the functionality in Parameters<T>.

• Additional search functions (e.g., to find a substrate or a custom variable) will start to return -1 if no matches are found, rather than 0.

• We will change the timing of when entry_functions are executed within cycle models. Right now, they are evaluated immediately after the exit from the preceding phase (and prior to any cell division events), which means that only the parent cell executes it, rather than both daughter cells. Instead, we'll add an internal Boolean for "just exited a phase", and use this to execute the entry function at the next cycle call. This should make daughter cells independently execute the entry function.

• We might make trigger_death clear out all the cell's functions, or at least add an option to do this.

• We might change the behavior of copied Custom Data when a cell changes type (changes to a new cell definition). Currently, all custom data elements in a cell are overwritten based on those in the new cell definition. This is not the best behavior for custom data elements that represent state variables instead of type-dependent parameters.

Planned future improvements:

• Further XML-based simulation setup.

• Read saved simulation states (as MultiCellDS digital snapshots)

• Add a new standard phenotype function that uses mechanobiology, where high pressure can arrest cycle progression. (See https://twitter.com/MathCancer/status/1022555441518338048.)

• Create an angiogenesis sample project

• Create a small library of angiogenesis and vascularization codes as an optional standard module in ./modules (but not as a core component)

• Improved plotting options in SVG

• Further update sample projects to make use of more efficient interaction testing available

• Major refresh of documentation.