WntCellCycleOdeSystem.cpp

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#include "WntCellCycleOdeSystem.hpp"
#include "CellwiseOdeSystemInformation.hpp"
#include "IsNan.hpp"

// These #includes are needed for the constructor and EvaluateYDerivatives()
#include "ApcOneHitCellMutationState.hpp"
#include "ApcTwoHitCellMutationState.hpp"
#include "BetaCateninOneHitCellMutationState.hpp"

WntCellCycleOdeSystem::WntCellCycleOdeSystem(double wntLevel,
                                             boost::shared_ptr<AbstractCellMutationState> pMutationState,
                                             std::vector<double> stateVariables)
    : AbstractOdeSystem(9),
      mpMutationState(pMutationState),
      mWntLevel(wntLevel)
{
    mpSystemInfo.reset(new CellwiseOdeSystemInformation<WntCellCycleOdeSystem>);

    Init(); // set up parameter values

    // Set up a Wnt signalling pathway in a steady state
    double destruction_level = ma5d/(ma4d*wntLevel+ma5d);
    double beta_cat_level_1 = -1.0;
    double beta_cat_level_2 = -1.0;

    if (!mpMutationState)
    {
        // No mutations specified
    }
    else if (mpMutationState && mpMutationState->IsType<ApcOneHitCellMutationState>())
    {
        // APC +/- : only half are active
        beta_cat_level_1 = 0.5*ma2d/(ma2d+0.5*ma3d*destruction_level);
        beta_cat_level_2 = 0.5*ma2d/(ma2d+0.5*ma3d*destruction_level);
    }
    else if (mpMutationState && mpMutationState->IsType<ApcTwoHitCellMutationState>())
    {
        // APC -/-
        destruction_level = 0.0; // no active destruction complex
        beta_cat_level_1 = 0.5; // fully active beta-catenin
        beta_cat_level_2 = 0.5; // fully active beta-catenin
    }
    else if (mpMutationState && mpMutationState->IsType<BetaCateninOneHitCellMutationState>())
    {
        // Beta-cat delta 45
        beta_cat_level_1 = 0.5*ma2d/(ma2d+ma3d*destruction_level);
        beta_cat_level_2 = 0.5;
    }
    else
    {
        // healthy cells
        beta_cat_level_1 = 0.5*ma2d/(ma2d+ma3d*destruction_level);
        beta_cat_level_2 = 0.5*ma2d/(ma2d+ma3d*destruction_level);
    }

    // Cell-specific initial conditions
    SetDefaultInitialCondition(5, destruction_level);
    SetDefaultInitialCondition(6, beta_cat_level_1);
    SetDefaultInitialCondition(7, beta_cat_level_2);
    SetDefaultInitialCondition(8, wntLevel);

    if (stateVariables != std::vector<double>())
    {
        SetStateVariables(stateVariables);
    }
}

void WntCellCycleOdeSystem::SetMutationState(boost::shared_ptr<AbstractCellMutationState> pMutationState)
{
    mpMutationState = pMutationState;
}

WntCellCycleOdeSystem::~WntCellCycleOdeSystem()
{
    // Do nothing
}

void WntCellCycleOdeSystem::Init()
{
    // Initialise model parameter values
    // Swat (2004) Parameters
    double k1 = 1.0;
    double k2 = 1.6;
    double k3 = 0.05;
    double k16 = 0.4;
    double k34 = 0.04;
    double k43 = 0.01;
    double k61 = 0.3;
    double k23 = 0.3;
    double a = 0.04;
    double J11 = 0.5;
    double J12 = 5.0;
    double J61 = 5.0;
    double J62 = 8.0;
    double J13 = 0.002;
    double J63 = 2.0;
    double Km1 = 0.5;
    double Km2 = 4.0;
    double Km4 = 0.3;
    double kp = 0.05;
    double phi_pRb = 0.005;
    double phi_E2F1 = 0.1;
    double phi_CycDi = 0.023;
    double phi_CycDa = 0.03;
    double phi_pRbp = 0.06;

    // Mirams et al. parameter values
    double a1 = 0.423;
    double a2 = 2.57e-4;
    double a3 = 1.72;
    double a4 = 10.0;
    double a5 = 0.5;
    double WntMax = 10.0;
    double mitogenic_factorF = 6.0e-4;
    double APC_Total = 0.02;

    // Non-dimensionalise...
    mk2d = k2/(Km2*phi_E2F1);
    mk3d = k3*a1*mitogenic_factorF/(Km4*phi_E2F1*a2);
    mk34d = k34/phi_E2F1;
    mk43d = k43/phi_E2F1;
    mk23d = k23*Km2/(Km4*phi_E2F1);
    mad = a/Km2;
    mJ11d = J11*phi_E2F1/k1;
    mJ12d = J12*phi_E2F1/k1;
    mJ13d = J13*phi_E2F1/k1;
    mJ61d = J61*phi_E2F1/k1;
    mJ62d = J62*phi_E2F1/k1;
    mJ63d = J63*phi_E2F1/k1;
    mKm1d = Km1/Km2;
    mkpd = kp/(Km2*phi_E2F1);
    mphi_r = phi_pRb/phi_E2F1;
    mphi_i = phi_CycDi/phi_E2F1;
    mphi_j = phi_CycDa/phi_E2F1;
    mphi_p = phi_pRbp/phi_E2F1;
    ma2d = a2/phi_E2F1;
    ma3d = a3*APC_Total/phi_E2F1;
    ma4d = a4*WntMax/phi_E2F1;
    ma5d = a5/phi_E2F1;
    mk16d = k16*Km4/phi_E2F1;
    mk61d = k61/phi_E2F1;
    mPhiE2F1 = phi_E2F1;
}

void WntCellCycleOdeSystem::EvaluateYDerivatives(double time, const std::vector<double>& rY, std::vector<double>& rDY)
{
    double r = rY[0];
    double e = rY[1];
    double i = rY[2];
    double j = rY[3];
    double p = rY[4];
    double c = rY[5];
    double b1 = rY[6];
    double b2 = rY[7];
    double wnt_level = rY[8];

    double dx1 = 0.0;
    double dx2 = 0.0;
    double dx3 = 0.0;
    double dx4 = 0.0;
    double dx5 = 0.0;
    double dx6 = 0.0;
    double dx7 = 0.0;
    double dx8 = 0.0;

    /*
     * The variables are
     * 1. r = pRb
     * 2. e = E2F1
     * 3. i = CycD (inactive)
     * 4. j = CycD (active)
     * 5. p = pRb-p
     * 6. c = APC (Active)
     * 7. b = Beta-Catenin
    */

    // Bit back-to-front, but work out the Wnt section first...

    // Mutations take effect by altering the level of beta-catenin
    if (!mpMutationState)
    {
        // No mutations specified
    }
    else if (mpMutationState->IsType<ApcOneHitCellMutationState>()) // APC +/-
    {
        dx6 = ma5d*(1.0-c) - ma4d*wnt_level*c;
        dx7 = ma2d*(0.5-b1) - 0.5*ma3d*b1*c;
        dx8 = ma2d*(0.5-b2) - 0.5*ma3d*b2*c;
    }
    else if (mpMutationState->IsType<ApcTwoHitCellMutationState>()) // APC -/-
    {
        dx6 = 0.0;
        dx7 = ma2d*(0.5-b1);
        dx8 = ma2d*(0.5-b2);
    }
    else if (mpMutationState->IsType<BetaCateninOneHitCellMutationState>()) // Beta-Cat D45
    {
        dx6 = ma5d*(1.0-c) - ma4d*wnt_level*c;
        dx7 = ma2d*(0.5-b1) - ma3d*b1*c;
        dx8 = ma2d*(0.5-b2);
    }
    else
    {
        // da
        dx6 = ma5d*(1.0-c) - ma4d*wnt_level*c;
        // db
        dx7 = ma2d*(0.5-b1) - ma3d*b1*c;
        dx8 = ma2d*(0.5-b2) - ma3d*b2*c;
    }

    // Now the cell cycle stuff...

    // dr
    dx1 = e/(mKm1d+e)*mJ11d/(mJ11d+r)*mJ61d/(mJ61d+p) - mk16d*r*j+mk61d*p-mphi_r*r;
    // de
    dx2 = mkpd+mk2d*(mad*mad+e*e)/(1+e*e)*mJ12d/(mJ12d+r)*mJ62d/(mJ62d+p) - e;
    // di
    dx3 = mk3d*(b1+b2) + mk23d*e*mJ13d/(mJ13d+r)*mJ63d/(mJ63d+p) + mk43d*j - mk34d*i*j/(1+j) - mphi_i*i;
    // dj
    dx4 = mk34d*i*j/(1+j) - (mk43d+mphi_j)*j;
    // dp
    dx5 = mk16d*r*j - mk61d*p - mphi_p*p;

    double factor = mPhiE2F1*60.0;  // convert non-dimensional d/dt s to d/dt in hours

    rDY[0] = dx1*factor;
    rDY[1] = dx2*factor;
    rDY[2] = dx3*factor;
    rDY[3] = dx4*factor;
    rDY[4] = dx5*factor;
    rDY[5] = dx6*factor;
    rDY[6] = dx7*factor; // beta-cat allele 1
    rDY[7] = dx8*factor; // beta-cat allele 2
    rDY[8] = 0.0; // do not change the Wnt level
}

const boost::shared_ptr<AbstractCellMutationState> WntCellCycleOdeSystem::GetMutationState() const
{
    return mpMutationState;
}

bool WntCellCycleOdeSystem::CalculateStoppingEvent(double time, const std::vector<double>& rY)
{
    double r = rY[0];
    double e = rY[1];
    double p = rY[4];
    double dY1 = mkpd+mk2d*(mad*mad+e*e)/(1+e*e)*mJ12d/(mJ12d+r)*mJ62d/(mJ62d+p) - e;
    double factor = mPhiE2F1*60.0;  // Convert non-dimensional d/dt s to d/dt in hours.
    dY1 = dY1*factor;

    assert(!std::isnan(rY[1]));
    assert(!std::isnan(dY1));
    return (rY[1] > 1.0 && dY1 > 0.0);
}

double WntCellCycleOdeSystem::CalculateRootFunction(double time, const std::vector<double>& rY)
{
    return rY[1] - 1.0;
}

template<>
void CellwiseOdeSystemInformation<WntCellCycleOdeSystem>::Initialise()
{
    this->mVariableNames.push_back("pRb");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(7.357000000000000e-01);

    this->mVariableNames.push_back("E2F1");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(1.713000000000000e-01);

    this->mVariableNames.push_back("CycD_i");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(6.900000000000001e-02);

    this->mVariableNames.push_back("CycD_a");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(3.333333333333334e-03);

    this->mVariableNames.push_back("pRb_p");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(1.000000000000000e-04);

    this->mVariableNames.push_back("APC");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Beta_Cat1");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Beta_Cat2");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Wnt");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mInitialised = true;
}

double WntCellCycleOdeSystem::GetWntLevel() const
{
    return mWntLevel;
}

// Serialization for Boost >= 1.36
#include "SerializationExportWrapperForCpp.hpp"
CHASTE_CLASS_EXPORT(WntCellCycleOdeSystem)