VanLeeuwen2009WntSwatCellCycleOdeSystem.cpp

/*

Copyright (c) 2005-2012, University of Oxford.
All rights reserved.

University of Oxford means the Chancellor, Masters and Scholars of the
University of Oxford, having an administrative office at Wellington
Square, Oxford OX1 2JD, UK.

This file is part of Chaste.

Redistribution and use in source and binary forms, with or without
modification, are permitted provided that the following conditions are met:
 * Redistributions of source code must retain the above copyright notice,
   this list of conditions and the following disclaimer.
 * Redistributions in binary form must reproduce the above copyright notice,
   this list of conditions and the following disclaimer in the documentation
   and/or other materials provided with the distribution.
 * Neither the name of the University of Oxford nor the names of its
   contributors may be used to endorse or promote products derived from this
   software without specific prior written permission.

THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS "AS IS"
AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE
IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE
ARE DISCLAIMED. IN NO EVENT SHALL THE COPYRIGHT HOLDER OR CONTRIBUTORS BE
LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR
CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT LIMITED TO, PROCUREMENT OF SUBSTITUTE
GOODS OR SERVICES; LOSS OF USE, DATA, OR PROFITS; OR BUSINESS INTERRUPTION)
HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT
LIABILITY, OR TORT (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT
OF THE USE OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.

*/

#include "VanLeeuwen2009WntSwatCellCycleOdeSystem.hpp"
#include "CellwiseOdeSystemInformation.hpp"

VanLeeuwen2009WntSwatCellCycleOdeSystem::VanLeeuwen2009WntSwatCellCycleOdeSystem(unsigned hypothesis,
                                                                                 double wntLevel,
                                                                                 boost::shared_ptr<AbstractCellMutationState> pMutationState,
                                                                                 std::vector<double> stateVariables)
    : AbstractOdeSystem(22),
      mpMutationState(pMutationState),
      mHypothesis(hypothesis),
      mWntLevel(wntLevel)
{
    if (hypothesis!=1 && hypothesis!=2)
    {
        EXCEPTION("You must set up this cell cycle ODE system with hypothesis one or two.");
    }

    mpSystemInfo.reset(new CellwiseOdeSystemInformation<VanLeeuwen2009WntSwatCellCycleOdeSystem>);

    Init(); // set up parameter values

    double d_d_hat = mDd + mXiD*wntLevel;
    double d_d_x_hat = mDdx + mXiDx*wntLevel;
    double d_x_hat = mDx + mXiX*wntLevel;
    double p_c_hat = mPc + mXiC*wntLevel;

    double sigma_D = 0.0; // for healthy cells
    //double sigma_B = 0.0; // for healthy cells - never used!

    if (!mpMutationState)
    {
        // No mutations specified
    }
    else if (mpMutationState->IsType<ApcOneHitCellMutationState>())
    {
        sigma_D = 0.5;
    }
    else if (mpMutationState->IsType<ApcTwoHitCellMutationState>())
    {
        sigma_D = 1.0;
    }
    else if (mpMutationState->IsType<BetaCateninOneHitCellMutationState>())
    {
        //sigma_B = 0.5; // never used!
    }
    // Other mutations have no effect.

    // Cell-specific initial conditions
    double steady_D = ((1.0-sigma_D)*mSd*mSx)/((1.0-sigma_D)*mSd*d_d_hat + d_x_hat*(d_d_hat + d_d_x_hat));
    SetDefaultInitialCondition(5, steady_D); // Destruction complex (APC/Axin/GSK3B)

    double temp = (mSx*(d_d_hat+d_d_x_hat))/((1.0-sigma_D)*mSd*d_d_hat+d_x_hat*(d_d_hat+d_d_x_hat));
    SetDefaultInitialCondition(6, temp);  // Axin

    double steady_Cf = ((mSc-mDc*mKd - mPu*steady_D)+sqrt(SmallPow((mSc-mDc*mKd - mPu*steady_D),2) + (4.0*mSc*mDc*mKd)))/(2.0*mDc);
    temp = (mPu*steady_D*steady_Cf)/(mDu*(steady_Cf+mKd));
    SetDefaultInitialCondition(7, temp); // beta-catenin to be ubiquitinated

    double theta = mDc + (mPu*steady_D)/(steady_Cf + mKd);

    double steady_Co = ( mSc - p_c_hat - theta*mKc + sqrt(4.0*mSc*theta*mKc + SmallPow((mSc - p_c_hat - theta*mKc),2)) )/(2.0*theta);
    SetDefaultInitialCondition(8, steady_Co); // Open form beta-catenin

    double steady_Cc = steady_Cf - steady_Co;

    if ((steady_Cc < 0) && (steady_Cc+100*DBL_EPSILON > 0) ) // stop protein values going -ve
    {
        steady_Cc = 0.0;
    }
    SetDefaultInitialCondition(9, steady_Cc); // Closed form beta-catenin

    SetDefaultInitialCondition(12, mSa/mDa);  // 'Free' adhesion molecules

    SetDefaultInitialCondition(13, mSa*mSca*steady_Co/(mDa*mDca)); // Co-A Adhesion complex

    SetDefaultInitialCondition(15, mSt/mDt); // `Free' transcription molecules (TCF)

    SetDefaultInitialCondition(16, mSct*mSt*steady_Co/(mDt*mDct)); // Co-T open form beta-catenin/TCF

    SetDefaultInitialCondition(17, mSct*mSt*steady_Cc/(mDt*mDct)); // Cc-T closed beta-catenin/TCF

    temp = (mSct*mSt*mSy*steady_Cf)/(mDy*(mSct*mSt*steady_Cf + mDct*mDt*mKt));
    SetDefaultInitialCondition(20, temp); // Wnt target protein

    SetDefaultInitialCondition(21, wntLevel); // Wnt stimulus

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

void VanLeeuwen2009WntSwatCellCycleOdeSystem::SetMutationState(boost::shared_ptr<AbstractCellMutationState> pMutationState)
{
    mpMutationState = pMutationState;
}

VanLeeuwen2009WntSwatCellCycleOdeSystem::~VanLeeuwen2009WntSwatCellCycleOdeSystem()
{
    // Do nothing
}

void VanLeeuwen2009WntSwatCellCycleOdeSystem::Init()
{
    // 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;

    // Value of the mitogenic factor to make the van Leeuwen model influence cell cycle just the same
    double mitogenic_factorF = 1.0/25.0;

    // Non-dimensionalise parameters
    mk2d = k2/(Km2*phi_E2F1);
    mk3d = k3*mitogenic_factorF/(Km4*phi_E2F1);
    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;
    mk16d = k16*Km4/phi_E2F1;
    mk61d = k61/phi_E2F1;
    mPhiE2F1 = phi_E2F1;

    // Initialize van Leeuwen model parameters
    mSa = 20;   //  nM/h
    mSca = 250; //  (nMh)^-1
    mSc = 25;   //  nM/h
    mSct = 30;  //  (nMh)^-1
    mSd = 100;  //  h^-1
    mSt = 10;   //  nM/h
    mSx = 10;   //  nM/h
    mSy = 10;   //  h^-1
    mDa = 2;    //  h^-1
    mDca = 350; //  h^-1
    mDc = 1;    //  h^-1
    mDct = 750; //  h^-1
    mDd = 5;    //  h^-1
    mDdx = 5;   //  h^-1
    mDt = 0.4;  //  h^-1
    mDu = 50;   //  h^-1
    mDx = 100;  //  h^-1
    mDy = 1;    //  h^-1
    mKc = 200;  //  nM
    mKd = 5;    //  nM
    mKt = 50;   //  nM
    mPc = 0.0;  //  h^-1
    mPu = 100;  //  h^-1
    mXiD = 5;   //  h^-1
    mXiDx = 5;  //  h^-1
    mXiX = 200; //  h^-1
    if (mHypothesis==1)
    {
        mXiC = 0.0; //  h^-1 (FOR HYPOTHESIS ONE)
    }
    else
    {
        mXiC = 5000.0;   //  h^-1 (FOR HYPOTHESIS TWO)
    }
}

void VanLeeuwen2009WntSwatCellCycleOdeSystem::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 dx1 = 0.0;
    double dx2 = 0.0;
    double dx3 = 0.0;
    double dx4 = 0.0;
    double dx5 = 0.0;

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

    // Variables
    double D = rY[5];
    double X = rY[6];
    double Cu = rY[7];
    double Co = rY[8];
    double Cc = rY[9];
    double Mo = rY[10];
    double Mc = rY[11];
    double A = rY[12];
    double Ca = rY[13];
    double Ma = rY[14];
    double T = rY[15];
    double Cot = rY[16];
    double Cct = rY[17];
    double Mot = rY[18];
    double Mct = rY[19];
    double Y = rY[20];
    double stimulus_wnt = rY[21];

    // Totals
    double Cf = Cc+Co;
    double Ct = Cct+Cot;
    double Mf = Mc+Mo;
    double Mt = Mct+Mot;

    double d_d_hat = mDd + mXiD*stimulus_wnt;
    double d_d_x_hat = mDdx + mXiDx*stimulus_wnt;
    double d_x_hat = mDx + mXiX*stimulus_wnt;
    double p_c_hat = mPc + mXiC*stimulus_wnt;

    double sigma_D = 0.0;   // for healthy cells
    double sigma_B = 0.0;   // for healthy cells

    if (!mpMutationState)
    {
        // No mutations specified
    }
    else if (mpMutationState->IsType<ApcOneHitCellMutationState>())
    {
        sigma_D = 0.5;
    }
    else if (mpMutationState->IsType<ApcTwoHitCellMutationState>())
    {
        sigma_D = 1.0;
    }
    else if (mpMutationState->IsType<BetaCateninOneHitCellMutationState>())
    {
        sigma_B = 0.5;
    }
    // Other mutations have no effect.

    // 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 - changed to include Ct+Mt - transcriptional beta-catenin
    dx3 = mk3d*(Ct+Mt) + 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;

    // The van Leeuwen ODE system
    rDY[5] = (1.0-sigma_D)*mSd*X - (d_d_hat + d_d_x_hat)*D;
    rDY[6] = mSx - (1.0-sigma_D)*mSd*X - d_x_hat*X + d_d_x_hat*D;
    rDY[7] = (mPu*D*Cf)/(Cf+mKd) - mDu*Cu;

    rDY[8] = (1.0-sigma_B)*mSc + mDca*Ca + mDct*Cot - (mSca*A + mSct*T + mDc)*Co
             - (p_c_hat*Co)/(Co + Mo + mKc) - (mPu*D*Co)/(Cf+mKd);

    rDY[9] = (p_c_hat*Co)/(Co + Mo + mKc) + mDct*Cct - (mSct*T + mDc)*Cc
             - (mPu*D*Cc)/(Cf+mKd);

    rDY[10] = sigma_B*mSc + mDca*Ma + mDct*Mot - (mSca*A + mSct*T + mDc)*Mo
             - (p_c_hat*Mo)/(Co + Mo + mKc);

    rDY[11] = (p_c_hat*Mo)/(Co + Mo + mKc) + mDct*Mct - (mSct*T + mDc)*Mc;
    rDY[12] = mSa + mDca*(Ca+Ma) - (mSca*(Co+Mo) + mDa)*A;
    rDY[13] = mSca*Co*A - mDca*Ca;
    rDY[14] = mSca*Mo*A - mDca*Ma;
    rDY[15] = mSt + mDct*(Ct+Mt) - mSct*(Cf+Mf)*T - mDt*T;
    rDY[16] = mSct*Co*T - mDct*Cot;
    rDY[17] = mSct*Cc*T - mDct*Cct;
    rDY[18] = mSct*Mo*T - mDct*Mot;
    rDY[19] = mSct*Mc*T - mDct*Mct;
    rDY[20] = (mSy*(Ct+Mt))/(Ct + Mt + mKt) - mDy*Y;
    rDY[21] = 0.0;  // don't interfere with Wnt stimulus
}

const boost::shared_ptr<AbstractCellMutationState> VanLeeuwen2009WntSwatCellCycleOdeSystem::GetMutationState() const
{
    return mpMutationState;
}

bool VanLeeuwen2009WntSwatCellCycleOdeSystem::CalculateStoppingEvent(double time, const std::vector<double>& rY)
{
    std::vector<double> dy(rY.size());
    EvaluateYDerivatives(time, rY, dy);

    return (rY[1] > 1.0 && dy[1] > 0.0);
}

double VanLeeuwen2009WntSwatCellCycleOdeSystem::CalculateRootFunction(double time, const std::vector<double>& rY)
{
    return rY[1] - 1.0;
}

template<>
void CellwiseOdeSystemInformation<VanLeeuwen2009WntSwatCellCycleOdeSystem>::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("D");  // Destruction complex (APC/Axin/GSK3B)
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("X");  // Axin
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Cu"); // beta-catenin to be ubiquitinated
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Co"); // Open form beta-catenin
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Cc"); // Closed form beta-catenin
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Mo"); // Open form mutant beta-catenin
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(0.0);

    this->mVariableNames.push_back("Mc"); // Closed form mutant beta-catenin
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(0.0);

    this->mVariableNames.push_back("A");  // 'Free' adhesion molecules
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Ca"); // Co-A Adhesion complex
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Ma"); // Mo-A Mutant adhesion complex
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(0.0);

    this->mVariableNames.push_back("T"); // `Free' transcription molecules (TCF)
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Cot"); // Co-T open form beta-catenin/TCF
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Cct"); // Cc-T closed beta-catenin/TCF
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Mot"); // Mo-T open form mutant beta-catenin/TCF
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(0.0);

    this->mVariableNames.push_back("Mct"); // Mc-T closed form mutant beta-catenin/TCF
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(0.0);

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

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

    this->mInitialised = true;
}

double VanLeeuwen2009WntSwatCellCycleOdeSystem::GetWntLevel() const
{
    return mWntLevel;
}

unsigned VanLeeuwen2009WntSwatCellCycleOdeSystem::GetHypothesis() const
{
    return mHypothesis;
}

// Serialization for Boost >= 1.36
#include "SerializationExportWrapperForCpp.hpp"
CHASTE_CLASS_EXPORT(VanLeeuwen2009WntSwatCellCycleOdeSystem)