Optimal control of bioproduction in the presence of population heterogeneity.

Cell-to-cell variability, born of stochastic chemical kinetics, persists even in large isogenic populations. In the study of single-cell dynamics this is typically accounted for. However, on the population level this source of heterogeneity is often sidelined to avoid the inevitable complexity it introduces. The homogeneous models used instead are more tractable but risk disagreeing with their heterogeneous counterparts and may thus lead to severely suboptimal control of bioproduction. In this work, we introduce a comprehensive mathematical framework for solving bioproduction optimal control problems in the presence of heterogeneity. We study population-level models in which such heterogeneity is retained, and propose order-reduction approximation techniques. The reduced-order models take forms typical of homogeneous bioproduction models, making them a useful benchmark by which to study the importance of heterogeneity. Moreover, the derivation from the heterogeneous setting sheds light on parameter selection in ways a direct homogeneous outlook cannot, and reveals the source of approximation error. With view to optimally controlling bioproduction in microbial communities, we ask the question: when does optimising the reduced-order models produce strategies that work well in the presence of population heterogeneity? We show that, in some cases, homogeneous approximations provide remarkably accurate surrogate models. Nevertheless, we also demonstrate that this is not uniformly true: overlooking the heterogeneity can lead to significantly suboptimal control strategies. In these cases, the heterogeneous tools and perspective are crucial to optimise bioproduction.

Revisiting moment-closure methods with heterogeneous multiscale population models.

Stochastic chemical kinetics at the single-cell level give rise to heterogeneous populations of cells even when all individuals are genetically identical. This heterogeneity can lead to nonuniform behaviour within populations, including different growth characteristics, cell-fate dynamics, and response to stimuli. Ultimately, these diverse behaviours lead to intricate population dynamics that are inherently multiscale: the population composition evolves based on population-level processes that interact with stochastically distributed single-cell states. Therefore, descriptions that account for this heterogeneity are essential to accurately model and control chemical processes. However, for real-world systems such models are computationally expensive to simulate, which can make optimisation problems, such as optimal control or parameter inference, prohibitively challenging. Here, we consider a class of multiscale population models that incorporate population-level mechanisms while remaining faithful to the underlying stochasticity at the single-cell level and the interplay between these two scales. To address the complexity, we study an order-reduction approximations based on the distribution moments. Since previous moment-closure work has focused on the single-cell kinetics, extending these techniques to populations models prompts us to revisit old observations as well as tackle new challenges. In this extended multiscale context, we encounter the previously established observation that the simplest closure techniques can lead to non-physical system trajectories. Despite their poor performance in some systems, we provide an example where these simple closures outperform more sophisticated closure methods in accurately, efficiently, and robustly solving the problem of optimal control of bioproduction in a microbial consortium model.

Beyond the chemical master equation: Stochastic chemical kinetics coupled with auxiliary processes.

The chemical master equation and its continuum approximations are indispensable tools in the modeling of chemical reaction networks. These are routinely used to capture complex nonlinear phenomena such as multimodality as well as transient events such as first-passage times, that accurately characterise a plethora of biological and chemical processes. However, some mechanisms, such as heterogeneous cellular growth or phenotypic selection at the population level, cannot be represented by the master equation and thus have been tackled separately. In this work, we propose a unifying framework that augments the chemical master equation to capture such auxiliary dynamics, and we develop and analyse a numerical solver that accurately simulates the system dynamics. We showcase these contributions by casting a diverse array of examples from the literature within this framework and applying the solver to both match and extend previous studies. Analytical calculations performed for each example validate our numerical results and benchmark the solver implementation.

Minimizing deformation of a thin fluid film driven by fluxes of momentum and heat.

We consider a thin fluid film flowing down an inclined substrate subjected to localized external sources of momentum and heat flux that induce deformations of the fluid's free surface. This scenario is encountered in several industrial processes and of particular interest is the case where these deformations are undesirable. When the substrate is thin and the temperature along its underside is freely imposed by an active cooling mechanism, temperature gradients are generated at the fluid surface which drive a thermocapillary flow and influence the deformations. This naturally leads us to pose the optimal control problem of choosing the temperature profile that minimizes the unwanted free-surface deformations. Numerical computations reveal that the external forces generate deflections in a region near their peak beyond which all deflections are suppressed by the optimal control. Where nonzero deflections occur, the control is of bang-bang type (taking either its upper or lower bound), while the control is obtained in closed form for regions where the deflections are suppressed. Strikingly, in switching between these regions the optimal control chatters, that is, it switches infinitely many times over a finite interval. By appealing to Pontryagin's maximum principle and leveraging a symmetry embedded in the adjoint problem we uncover the underlying fractal structure of the chattering. Finally, we present practical approaches to avoid the infinite switching while retaining significantly reduced free-surface deformations.

On rapid oscillations driving biological processes at disparate timescales.

We consider a generic biological process described by a dynamical system, subject to an input signal with a high-frequency periodic component. The rapid oscillations of the input signal induce inherently multiscale dynamics, motivating order-reduction techniques. It is intuitive that the system behaviour is well approximated by its response to the averaged input signal. However, changes to the high-frequency component that preserve the average signal are beyond the reach of such intuitive reasoning. In this study, we explore system response under the influence of such an input signal by exploiting the timescale separation between high-frequency input variations and system response time. Employing the asymptotic method of multiple scales, we establish that, in some circumstances, the intuitive approach is simply the leading-order asymptotic contribution. We focus on higher-order corrections that capture the response to the details of the high-frequency component beyond its average. This approach achieves a reduction in system complexity while providing valuable insight into the structure of the response to the oscillations. We develop the general theory for nonlinear systems, while highlighting the important case of systems affine in the state and the input signal, presenting examples of both discrete and continuum state spaces. Importantly, this class of systems encompasses biochemical reaction networks described by the chemical master equation and its continuum approximations. Finally, we apply the framework to a nonlinear system describing mRNA translation and protein expression previously studied in the literature. The analysis shines new light on several aspects of the system quantification and both extends and simplifies results previously obtained.

To quarantine, or not to quarantine: A theoretical framework for disease control via contact tracing.

Contact tracing via smartphone applications is expected to be of major importance for maintaining control of the COVID-19 pandemic. However, viable deployment demands a minimal quarantine burden on the general public. That is, consideration must be given to unnecessary quarantining imposed by a contact tracing policy. Previous studies have modeled the role of contact tracing, but have not addressed how to balance these two competing needs. We propose a modeling framework that captures contact heterogeneity. This allows contact prioritization: contacts are only notified if they were acutely exposed to individuals who eventually tested positive. The framework thus allows us to address the delicate balance of preventing disease spread while minimizing the social and economic burdens of quarantine. This optimal contact tracing strategy is studied as a function of limitations in testing resources, partial technology adoption, and other intervention methods such as social distancing and lockdown measures. The framework is globally applicable, as the distribution describing contact heterogeneity is directly adaptable to any digital tracing implementation.