| Publications about 'tracking' |
| Articles in journal or book chapters |
| Cells respond to biochemical and physical internal as well as external signals. These signals can be broadly classified into two categories: (a) ``actionable'' or ``reference'' inputs that should elicit appropriate biological or physical responses such as gene expression or motility, and (b) ``disturbances'' or ``perturbations'' that should be ignored or actively filtered-out. These disturbances might be exogenous, such as binding of nonspecific ligands, or endogenous, such as variations in enzyme concentrations or gene copy numbers. In this context, the term robustness describes the capability to produce appropriate responses to reference inputs while at the same time being insensitive to disturbances. These two objectives often conflict with each other and require delicate design trade-offs. Indeed, natural biological systems use complicated and still poorly understood control strategies in order to finely balance the goals of responsiveness and robustness. A better understanding of such natural strategies remains an important scientific goal in itself and will play a role in the construction of synthetic circuits for therapeutic and biosensing applications. A prototype problem in robustly responding to inputs is that of ``robust tracking'', defined by the requirement that some designated internal quantity (for example, the level of expression of a reporter protein) should faithfully follow an input signal while being insensitive to an appropriate class of perturbations. Control theory predicts that a certain type of motif, called integral feedback, will help achieve this goal, and this motif is, in fact, a necessary feature of any system that exhibits robust tracking. Indeed, integral feedback has always been a key component of electrical and mechanical control systems, at least since the 18th century when James Watt employed the centrifugal governor to regulate steam engines. Motivated by this knowledge, biological engineers have proposed various designs for biomolecular integral feedback control mechanisms. However, practical and quantitatively predictable implementations have proved challenging, in part due to the difficulty in obtaining accurate models of transcription, translation, and resource competition in living cells, and the stochasticity inherent in cellular reactions. These challenges prevent first-principles rational design and parameter optimization. In this work, we exploit the versatility of an Escherichia coli cell-free transcription-translation (TXTL) to accurately design, model and then build, a synthetic biomolecular integral controller that precisely controls the expression of a target gene. To our knowledge, this is the first design of a functioning gene network that achieves the goal of making gene expression track an externally imposed reference level, achieves this goal even in the presence of disturbances, and whose performance quantitatively agrees with mathematical predictions. |
| The problem of stabilization of equilibria is one of the central issues in control. In addition to its intrinsic interest, it represents a first step towards the solution of more complicated problems, such as the stabilization of periodic orbits or general invariant sets, or the attainment of other control objectives, such as tracking, disturbance rejection, or output feedback, all of which may be interpreted as requiring the stabilization of some quantity (typically, some sort of ``error'' signal). A very special case, when there are no inputs, is that of stability. This short and informal article provides an introduction to the subject. |
| During normal kidney function, there are are routinely wide swings in proximal tubule fluid flow and proportional changes in Na+ reabsorption across tubule epithelial cells. This "glomerulotubular balance" occurs in the absence of any substantial change in cell volume, and is thus a challenge to coordinate luminal membrane solute entry with peritubular membrane solute exit. In this work, linear optimal control theory is applied to generate a configuration of regulated transporters that could achieve this result. A previously developed model of rat proximal tubule epithelium is linearized about a physiologic reference condition; the approximate linear system is recast as a dynamical system; and a Riccati equation is solved to yield optimal linear feedback that stabilizes Na+ flux, cell volume, and cell pH. This optimal feedback control is largely consigned to three physiologic variables, cell volume, cell electrical potential, and lateral intercellular hydrostatic pressure. Transport modulation by cell volume stabilizes cell volume; transport modulation by electrical potential or interspace pressure act to stabilize Na+ flux and cell pH. This feedback control is utilized in a tracking problem, in which reabsorptive Na+ flux varies over a factor of two. The resulting control parameters consist of two terms, an autonomous term and a feedback term, and both terms include transporters on both luminal and peritubular cell membranes. Overall, the increase in Na+ flux is achieved with upregulation of luminal Na+/H+ exchange and Na+-glucose cotransport, with increased peritubular Na+-3HCO_3- and K+-Cl- cotransport, and with increased Na+,K+-ATPase activity. The configuration of activated transporters emerges as testable hypothesis of the molecular basis for glomerulotubular balance. It is suggested that the autonomous control component at each cell membrane could represent the cytoskeletal effects of luminal flow. |
| The problem of stabilization of equilibria is one of the central issues in control. In addition to its intrinsic interest, it represents a first step towards the solution of more complicated problems, such as the stabilization of periodic orbits or general invariant sets, or the attainment of other control objectives, such as tracking, disturbance rejection, or output feedback, all of which may be interpreted as requiring the stabilization of some quantity (typically, some sort of ``error'' signal). A very special case, when there are no inputs, is that of stability. This short and informal article provides an introduction to the subject. |
| Conference articles |
| Integral feedback can help achieve robust tracking independently of external disturbances. Motivated by this knowledge, biological engineers have proposed various designs of biomolecular integral feedback controllers to regulate biological processes. In this paper, we theoretically analyze the operation of a particular synthetic biomolecular integral controller, which we have recently proposed and implemented experimentally. Using a combination of methods, ranging from linearized analysis to sum-of-squares (SOS) Lyapunov functions, we demonstrate that, when the controller is operated in closed-loop, it is capable of providing integral corrections to the concentration of an output species in such a manner that the output tracks a reference signal linearly over a large dynamic range. We investigate the output dependency on the reaction parameters through sensitivity analysis, and quantify performance using control theory metrics to characterize response properties, thus providing clear selection guidelines for practical applications. We then demonstrate the stable operation of the closed-loop control system by constructing quartic Lyapunov functions using SOS optimization techniques, and establish global stability for a unique equilibrium. Our analysis suggests that by incorporating effective molecular sequestration, a biomolecular closed-loop integral controller that is capable of robustly regulating gene expression is feasible. |
| Combining in-vivo experiments with system identification methods, we determine a simple model of aerotaxis in B. subtilis, and we subsequently employ this model in order to compute the sequence of oxygen gradients needed in order to achieve set-point regulation with respect to a signal tracking the center of mass of the bacterial population. We then successfully validate both the model and the control scheme, by showing that in-vivo positioning control can be achieved via the application of the precomputed inputs in-vivo in an open-loop configuration. |
| This paper adopts a contraction approach to the analysis of the tracking properties of dynamical systems under high gain feedback when subject to inputs with bounded derivatives. It is shown that if the tracking error dynamics are contracting, then the system is input to output stable with respect to the input signal derivatives and the output tracking error. As an application, it iss hown that the negative feedback connection of plants composed of two strictly positive real LTI subsystems in cascade can follow external inputs with tracking errors that can be made arbitrarily small by applying a sufficiently large feedback gain. We utilize this result to design a biomolecular feedback for a synthetic genetic sensor to make it robust to variations in the availability of a cellular resource required for protein production. |
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