Damped genetic oscillator

The simplest GRN exhibiting oscillatory behaviors can be modeled through two variables $x_1$ and $x_2$ with opposite mutual effects: $x_1$ catalyzes the production of $x_2$, that in turn inhibits the production of $x_1$. We suppose that the system can be externally controlled by a chemical inducer that targets only one of the genes. The model is defined as

\[\left\{ \begin{array}{l} \dot{x}_1 = -\gamma_1 x_1 + u(t) k_1 s^{-}(x_2,\theta_2) , \\ \dot{x}_2 = -\gamma_2 x_2 + k_2 s^{+}(x_1,\theta_1). \end{array}\right.\]

where a detail of each term can be found in Introduction.

For any initial condition, the openloop system (i.e, $u \equiv 1$) converges to the equilibrium point $(\theta_1, \theta_2)$ when $t \rightarrow \infty$, producing a damped oscillatory behavior^[1]:

The control objective is to induce a sustained oscillation. Thus, we can state the problem of producing a single cycle, which can be written through the initial and terminal constraints:

\[ x(0) = x(t_f) = (x_1^c, \theta_2 )\]

for free final time $t_f > 0$ and for $x_1^c > \theta_1$.

Problem definition

using Plots
using Plots.PlotMeasures
using OptimalControl
using NLPModelsIpopt

We define the regularization functions, where the method is decided through the argument regMethod.

# Regularization of the PWL dynamics
function s⁺(x, θ, regMethod)
    if regMethod == 1 # Hill
        out = x^k/(x^k + θ^k)
    elseif regMethod == 2 # Exponential
        out = 1 - 1/(1 + exp(k*(x-θ)))
    end
    return out
end

# Regularization of |u(t) - 1|
function abs_m1(u, regMethod)
    if regMethod == 1 # Hill
        out = (u^k - 1)/(u^k + 1)
    elseif regMethod == 2 # Exponential
        out = 1 - 2/(1 + exp(k*(u-1)))
    end
    return out*(u - 1)
end

Definition of the OCP:

# Constant definition
k₁    = 2;    k₂    = 3     # Production rates
γ₁    = 0.2;  γ₂    = 0.3   # Degradation rates
θ₁    = 4;    θ₂    = 3     # Transcriptional thresholds
uₘᵢₙ  = 0.6;  uₘₐₓ  = 1.4   # Control bounds
x₁ᶜ   = 4.7                 # Cycle point (initial and final)
λ     = 0.5                 # Trade-off fuel/time

# Initial guest for the NLP
tf    = 1
u(t)  = 1
sol = (control=u, variable=tf)

# Optimal control problem definition
ocp = @def begin

    tf ∈ R,                variable
    t ∈ [ 0, tf ],         time
    x = ( x₁, x₂ ) ∈ R²,   state
    u ∈ R,                 control

    x₁(0) == x₁ᶜ
    x₂(0) == θ₂
    x₁(tf) == x₁ᶜ
    x₂(tf) == θ₂

    uₘᵢₙ ≤ u(t) ≤ uₘₐₓ
    tf ≥ 1 # Force the state out of the confort zone

    ẋ(t) == [ - γ₁*x₁(t) + k₁*u(t)*(1 - s⁺(x₂(t),θ₂,regMethod))  ,
              - γ₂*x₂(t) + k₂*s⁺(x₁(t),θ₁,regMethod) ]

    ∫(λ*abs_m1(u(t),regMethod) + 1-λ) → min

end

Resolution through Hill regularization

In order to ensure convergence of the solver, we solve the OCP by iteratively increasing the parameter $k$ while using the $i-1$-th solution as the initialization of the $i$-th iteration.

regMethod = 1       # Hill regularization
ki = 10             # Value of k for the first iteration
N = 400
maxki = 30          # Value of k for the last iteration
while ki < maxki
    global ki += 10  # Iteration step
    local print_level = (ki == maxki) # Only print the output on the last iteration
    global k = ki
    global sol = solve(ocp; grid_size=N, init=sol, print_level=4*print_level)
end

Total number of variables............................:     1605
                     variables with only lower bounds:        1
                variables with lower and upper bounds:      401
                     variables with only upper bounds:        0
Total number of equality constraints.................:     1205
Total number of inequality constraints...............:        0
        inequality constraints with only lower bounds:        0
   inequality constraints with lower and upper bounds:        0
        inequality constraints with only upper bounds:        0


Number of Iterations....: 45

                                   (scaled)                 (unscaled)
Objective...............:   2.2765512009279618e+00    2.2765512009279618e+00
Dual infeasibility......:   1.0597656607954186e-09    1.0597656607954186e-09
Constraint violation....:   1.0342837697407958e-11    1.0342837697407958e-11
Variable bound violation:   1.3738012283326384e-08    1.3738012283326384e-08
Complementarity.........:   1.0012132457540830e-11    1.0012132457540830e-11
Overall NLP error.......:   1.0597656607954186e-09    1.0597656607954186e-09


Number of objective function evaluations             = 48
Number of objective gradient evaluations             = 46
Number of equality constraint evaluations            = 48
Number of inequality constraint evaluations          = 0
Number of equality constraint Jacobian evaluations   = 46
Number of inequality constraint Jacobian evaluations = 0
Number of Lagrangian Hessian evaluations             = 45
Total seconds in IPOPT                               = 0.530

EXIT: Optimal Solution Found.

Plotting of the results:

plt1 = plot()
plt2 = plot()

tf    = variable(sol)
tspan = range(0, tf, N)   # time interval
x₁(t) = state(sol)(t)[1]
x₂(t) = state(sol)(t)[2]
u(t)  = control(sol)(t)

xticks = ([0, θ₁, x₁ᶜ], ["0", "θ₁", "x₁ᶜ"])
yticks = ([0, θ₂], ["0", "θ₂"])

plot!(plt1, x₁.(tspan), x₂.(tspan), label="optimal trajectory", xlabel="x₁", ylabel="x₂", xlimits=(θ₁/1.5, 1.1*x₁ᶜ), ylimits=(θ₂/2, 1.75*θ₂))
xticks!(xticks)
yticks!(yticks)
plot!(plt2, tspan, u, label="optimal control", xlabel="t")
plot(plt1, plt2; layout=(1,2), size=(800,300))

Resolution through exponential regularization

The same procedure for iteratively increasing $k$ is used.

regMethod = 2       # Exponential regularization
ki = 100             # Value of k for the first iteration
N = 400
maxki = 400          # Value of k for the last iteration
while ki < maxki
    global ki += 100  # Iteration step
    local print_level = (ki == maxki) # Only print the output on the last iteration
    global k = ki
    global sol = solve(ocp; grid_size=N, init=sol, print_level=4*print_level)
end

Total number of variables............................:     1605
                     variables with only lower bounds:        1
                variables with lower and upper bounds:      401
                     variables with only upper bounds:        0
Total number of equality constraints.................:     1205
Total number of inequality constraints...............:        0
        inequality constraints with only lower bounds:        0
   inequality constraints with lower and upper bounds:        0
        inequality constraints with only upper bounds:        0


Number of Iterations....: 153

                                   (scaled)                 (unscaled)
Objective...............:   1.9639867482958062e+00    1.9639867482958062e+00
Dual infeasibility......:   1.4269852197426100e-09    1.4269852197426100e-09
Constraint violation....:   1.6378010059270309e-12    1.6378010059270309e-12
Variable bound violation:   1.3731138226447115e-08    1.3731138226447115e-08
Complementarity.........:   1.9744395290108560e-11    1.9744395290108560e-11
Overall NLP error.......:   1.4269852197426100e-09    1.4269852197426100e-09


Number of objective function evaluations             = 160
Number of objective gradient evaluations             = 154
Number of equality constraint evaluations            = 160
Number of inequality constraint evaluations          = 0
Number of equality constraint Jacobian evaluations   = 154
Number of inequality constraint Jacobian evaluations = 0
Number of Lagrangian Hessian evaluations             = 153
Total seconds in IPOPT                               = 1.670

EXIT: Optimal Solution Found.

Plotting of the results:

plt1 = plot()
plt2 = plot()

tf    = variable(sol)
tspan = range(0, tf, N)   # time interval
x₁(t) = state(sol)(t)[1]
x₂(t) = state(sol)(t)[2]
u(t)  = control(sol)(t)

xticks = ([0, θ₁, x₁ᶜ], ["0", "θ₁", "x₁ᶜ"])
yticks = ([0, θ₂], ["0", "θ₂"])

plot!(plt1, x₁.(tspan), x₂.(tspan), label="optimal trajectory", xlabel="x₁", ylabel="x₂", xlimits=(θ₁/1.5, 1.1*x₁ᶜ), ylimits=(θ₂/2, 1.75*θ₂))
xticks!(xticks)
yticks!(yticks)
plot!(plt2, tspan, u, label="optimal control", xlabel="t")
plot(plt1, plt2; layout=(1,2), size=(800,300))

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