Combining intracellular models with a single model by vincent-noel · Pull Request #415 · MathCancer/PhysiCell

vincent-noel · 2026-03-31T20:00:18Z

Hi all !

This is a PR on something I've been thinking about for some time: the possibility of having multiple types of intracellular models, and to have them interact. To achieve this, we need to modify a bit the implementation of Intracellular, mainly to change the variable in Phenotype, from an Intracellular pointer to a vector of Intracellular pointers.

This leads to a few more changes, such as having the pre/post intracellular update function belonging to the Intracellular object, and to add the Intracellular to a few method parameters (to be sure to have the "good" one).

Here I'm providing a quick example I build in the last days, which has an SBML ODE model for the TNF receptor binding and endocytosis and a Boolean model for the cell fate. To build it, use make spheroid_tnf.

For the ODE model, I'm using what I think is the latest implementation of roadrunner, based on #362 and #406. I had to modify a few things, such as introducing the Intracellular* parameter in many places, and I also changed the way the species values are modified before the update. So before thinking about merging this, we should focus on #362 and #406, and I can make a separate PR to have my changes too.

I am also working on example using the latest version of dFBA which is being developed at BSC by @marcorusc and @migp11, but I'll wait for them to submit their PR.

Let me know what you think !

drbergman · 2026-04-01T11:56:38Z

I think this is really cool! We should have a conversation around next updates to Intracellular together since, as you pointed out, this interacts in non-trivial ways with other open PRs. This feels like a use-case for a GitHub project...

migp11 · 2026-04-01T15:10:14Z

This sounds great! Together with @marcorusc and @othmya, we are finishing the physicell-dfba paper, which includes several different use cases that can be
@vincent-noel have you reimplemented the TNF receptor model in SBML from this publication?

https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2022.836794/full
That is a very nice test case!
Regarding the implementation of a hybrid model, including a Boolean model and an FBA-based metabolic model, I've been thinking and got some ideas based on @othmya last paper
https://www.nature.com/articles/s41540-026-00669-4
and another paper we did on AGS metabolism
https://www.nature.com/articles/s41540-025-00586-y
The nice thing about this potential use case is that there is already a Boolean model and a metabolic one.
Open to discuss the topic :)
Best

vincent-noel · 2026-04-02T01:11:23Z

@migp11 Indeed, this is your TNF receptor model. That was the simplest example I could think of, and it worked.

About the AGS model, that's a nice idea. I have some reading to do, and then let's talk about this.

…libroadrunner

drbergman

Looks 90% ready! Last 10% for me is just clarifying a couple changes. See individual comments.

For some of these comments, I'm unclear on the distinctions between start, clone, and inherit. If someone who knows how those work approves, I will approve regarding those comments, too.

drbergman · 2026-08-21T17:05:54Z

-		child->phenotype.intracellular->inherit(this);
+	for (size_t i=0; i < child->phenotype.intracellulars.size(); i++)
+	{
+		child->phenotype.intracellulars[i]->start();


just noting here that if we need to decide how to proceed with #425. the call to start() here would not be necessary. and I think we could make the inherit call unnecessary.

drbergman · 2026-08-21T17:07:25Z

+	for (auto* intracellular: pNew->phenotype.intracellulars)
+		intracellular->start();


We're confident we don't need to inherit here? I honestly don't know.

drbergman · 2026-08-21T17:16:30Z

-			if (pParent != NULL && pParent->phenotype.intracellular != NULL) {
-				pCD->phenotype.intracellular->initialize_intracellular_from_pugixml(node);
+			if (pParent != NULL && pParent->phenotype.intracellulars.size() > 0) {
+				pCD->phenotype.intracellulars[0]->initialize_intracellular_from_pugixml(node);

 			// Otherwise we need to create a new one
 			} else {
 				MaBoSSIntracellular* pIntra = new MaBoSSIntracellular(node);
-				pCD->phenotype.intracellular = pIntra->getIntracellularModel();
+				pCD->phenotype.intracellulars.push_back(pIntra->getIntracellularModel());


This code diff is hard for me to understand.

If the parent has an intracellular model, initialize the first intracellular of this cell def from the node. else push a new one onto the end

Assuming that pCD inherits its intracellulars from pParent, we can't guarantee they share the same intracellular type. Also, why are we only updating the first entry here? I'll look for where we update further entries below.

Found where further entries are updated below. I'm wondering now if this here is dead code.

drbergman · 2026-08-21T17:18:36Z

+#ifdef ADDON_PHYSIBOSS
+			if (model_type == "maboss") {
+				// If it has already be copied
+				if (pParent != NULL && pParent->phenotype.intracellulars.size() >= intracellular_count) {
+					pCD->phenotype.intracellulars[intracellular_count]->initialize_intracellular_from_pugixml(intracellular);
+
+				// Otherwise we need to create a new one
+				} else {
+					MaBoSSIntracellular* pIntra = new MaBoSSIntracellular(intracellular);
+					pCD->phenotype.intracellulars.push_back(pIntra->getIntracellularModel());
+				}
+			}
+#endif
+
+#ifdef ADDON_ROADRUNNER
+		if (model_type == "roadrunner") 
+        {
+			// If it has already be copied
+			if (pParent != NULL && pParent->phenotype.intracellulars.size() >= intracellular_count) 
+            {
+                // std::cout << "------ " << __FUNCTION__ << ": copying another\n";
+				pCD->phenotype.intracellulars[intracellular_count]->initialize_intracellular_from_pugixml(node);
+            }	
+			// Otherwise we need to create a new one
+			else 
+            {
+                std::cout << "\n------ " << __FUNCTION__ << ": creating new RoadRunnerIntracellular\n";
+				RoadRunnerIntracellular* pIntra = new RoadRunnerIntracellular(intracellular);
+				pIntra->validate_PhysiCell_tokens(pCD->phenotype);
+                pIntra->validate_SBML_species();
+				pCD->phenotype.intracellulars.push_back(pIntra->getIntracellularModel());
+
+			}
+		}
+#endif
+
+#ifdef ADDON_PHYSIDFBA
+		if (model_type == "dfba") {
+			// If it has already be copied
+			if (pParent != NULL && pParent->phenotype.intracellulars.size() > intracellular_count) {
+				pCD->phenotype.intracellulars[intracellular_count]->initialize_intracellular_from_pugixml(intracellular);
+			// Otherwise we need to create a new one
+			} else {
+				PhysiCelldFBA::dFBAIntracellular* pIntra = new PhysiCelldFBA::dFBAIntracellular(intracellular);
+				pCD->phenotype.intracellulars.push_back(pIntra->getIntracellularModel());
+			}
+		}
+#endif


ah! This is what I was looking for. so what's the part above meant for then?

drbergman · 2026-08-21T17:26:56Z

+Intracellular::Intracellular(const Intracellular *intracellular)
+{
+	this->pre_update_intracellular = intracellular->pre_update_intracellular;
+	this->post_update_intracellular = intracellular->post_update_intracellular;
+}
+
+Intracellular* Intracellular::operator=(const Intracellular *intracellular ) { 
+
+	this->pre_update_intracellular = intracellular->pre_update_intracellular;
+	this->post_update_intracellular = intracellular->post_update_intracellular;
+	return this;
+}


do we not want these to do inherit or clone? I'm speaking from ignorance here, but that seems to be something that we expect to happen every time we copy around Intracellular objects

vincent-noel requested review from drbergman and rheiland March 31, 2026 20:00

vincent-noel changed the base branch from master to development March 31, 2026 20:00

vincent-noel force-pushed the feat/intracellulars branch 2 times, most recently from 742e7ae to 90d4278 Compare April 1, 2026 01:19

vincent-noel added the work in progress label Aug 14, 2026

drbergman and others added 8 commits August 21, 2026 12:47

daniel's librr

4bbf7b2

phenotype->intracellular is now a vector of Intracellular models

bca9738

Updated PhysiBoSS to support intracellulars

bf7571a

Updated libroadrunner to work with intracellulars

adcad28

Now using setFloatingSpeciesByIndex and getFloatingSpeciesByIndex in …

a49328c

…libroadrunner

Updated PhysiBoSS sample projects

49a2185

Added spheroid_tnf sample project

564dacf

Added desctructor for RoadRunnerIntracellular

9d03cfa

vincent-noel force-pushed the feat/intracellulars branch from 90d4278 to 9d03cfa Compare August 21, 2026 16:09

drbergman reviewed Aug 21, 2026

View reviewed changes

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Combining intracellular models with a single model - #415

Combining intracellular models with a single model#415
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vincent-noel commented Mar 31, 2026

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		for (auto* intracellular: pNew->phenotype.intracellulars)
		intracellular->start();

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vincent-noel commented Mar 31, 2026

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