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 Publications by Eduardo D. Sontag in year 2021
 Books and proceedings
1. E.D. Sontag. Notes on Mathematical Systems Biology. 2021. [WWW] Keyword(s): systems biology, mathematical biology.

 Articles in journal or book chapters
1. M.A. Al-Radhawi, M. Margaliot, and E. D. Sontag. Maximizing average throughput in oscillatory biochemical synthesis systems: an optimal control approach. Royal Society Open Science, 8(9):210878, 2021. [PDF]
Abstract:
 A dynamical system entrains to a periodic input if its state converges globally to an attractor with the same period. In particular, for a constant input, the state converges to a unique equilibrium point for any initial condition. We consider the problem of maximizing a weighted average of the system's output along the periodic attractor. The gain of entrainment is the benefit achieved by using a non-constant periodic input relative to a constant input with the same time average. Such a problem amounts to optimal allocation of resources in a periodic manner. We formulate this problem as a periodic optimal control problem, which can be analyzed by means of the Pontryagin maximum principle or solved numerically via powerful software packages. We then apply our framework to a class of nonlinear occupancy models that appear frequently in biological synthesis systems and other applications. We show that, perhaps surprisingly, constant inputs are optimal for various architectures. This suggests that the presence of non-constant periodic signals, which frequently appear in biological occupancy systems, is a signature of an underlying time-varying objective functional being optimized.

2. T. Chen, M. A. Al-Radhawi, C.A. Voigt, and E.D. Sontag. A synthetic distributed genetic multi-bit counter. iScience, 24:103526, 2021. [PDF] Keyword(s): counters, synthetic biology, transcriptional networks, gene networks, boolean circuits, boolean gates, systems biology.
Abstract:
 A design for genetically-encoded counters is proposed via repressor-based circuits. An N-bit counter reads sequences of input pulses and displays the total number of pulses, modulo $2^N$. The design is based on distributed computation, with specialized cell types allocated to specific tasks. This allows scalability and bypasses constraints on the maximal number of circuit genes per cell due to toxicity or failures due to resource limitations. The design starts with a single-bit counter. The N-bit counter is then obtained by interconnecting (using diffusible chemicals) a set of N single-bit counters and connector modules. An optimization framework is used to determine appropriate gate parameters and to compute bounds on admissible pulse widths and relaxation (inter-pulse) times, as well as to guide the construction of novel gates. This work can be viewed as a step toward obtaining circuits that are capable of finite-automaton computation, in analogy to digital central processing units.

3. J. Hanson, M. Raginsky, and E.D. Sontag. Learning recurrent neural net models of nonlinear systems. Proc. of Machine Learning Research, 144:1-11, 2021. [PDF] Keyword(s): machine learning, empirical risk minimization, recurrent neural networks, dynamical systems, continuous time, system identification, statistical learning theory, generalization bounds.
Abstract:
 This paper considers the following learning problem: given sample pairs of input and output signals generated by an unknown nonlinear system (which is not assumed to be causal or time-invariant), one wishes to find a continuous-time recurrent neural net, with activation function tanh, that approximately reproduces the underlying i/o behavior with high confidence. Leveraging earlier work concerned with matching derivatives up to a finite order of the input and output signals the problem is reformulated in familiar system-theoretic language and quantitative guarantees on the sup-norm risk of the learned model are derived, in terms of the number of neurons, the sample size, the number of derivatives being matched, and the regularity properties of the inputs, the outputs, and the unknown i/o map.

4. H. Hong, J. Kim, M.A. Al-Radhawi, E.D. Sontag, and J. K. Kim. Derivation of stationary distributions of biochemical reaction networks via structure transformation. Communications Biology, 4:620-, 2021. [PDF] Keyword(s): stationary distribution, chemical reaction networks, network translation, biochemical reaction networks, chemical master equation, stochastic, probabilistic, systems biology.
Abstract:
 Long-term behaviors of biochemical reaction networks (BRNs) are described by steady states in deterministic models and stationary distributions in stochastic models. Unlike deterministic steady states, stationary distributions capturing inherent fluctuations of reactions are extremely difficult to derive analytically due to the curse of dimensionality. Here, we develop a method to derive analytic stationary distributions from deterministic steady states by transforming BRNs to have a special dynamic property, called complex balancing. Specifically, we merge nodes and edges of BRNs to match in- and out-flows of each node. This allows us to derive the stationary distributions of a large class of BRNs, including autophosphorylation networks of EGFR, PAK1, and Aurora B kinase and a genetic toggle switch. This reveals the unique properties of their stochastic dynamics such as robustness, sensitivity, and multimodality. Importantly, we provide a user-friendly computational package, CASTANET, that automatically derives symbolic expressions of the stationary distributions of BRNs to understand their long-term stochasticity.

5. K. Johnson, G. Howard, D. Morgan, E. Brenner, A. Gardner, R. Durrett, W. Mo, A. Al'Khafaji, E.D. Sontag, A. Jarrett, T. Yankeelov, and A. Brock. Integrating transcriptomics and bulk time course data into a mathematical framework to describe and predict therapeutic resistance in cancer. Physical Biology, 18:016001, 2021. [PDF] Keyword(s): oncology, cancer, chemoresistance, resistance, intratumor heterogeneity, population dynamics, DNA barcoding, evolution, systems biology.
Abstract:
 The development of resistance to chemotherapy is a major cause of treatment failure in cancer. Intratumoral heterogeneity and phenotypic plasticity play a significant role in therapeutic resistance. Individual cell measurements such as flow and mass cytometry and single cell RNA sequencing (scRNA-seq) have been used to capture and analyze this cell variability. In parallel, longitudinal treatment-response data is routinely employed in order to calibrate mechanistic mathematical models of heterogeneous subpopulations of cancer cells viewed as compartments with differential growth rates and drug sensitivities. This work combines both approaches: single cell clonally-resolved transcriptome datasets (scRNA-seq, tagging individual cells with unique barcodes that are integrated into the genome and expressed as sgRNA's) and longitudinal treatment response data, to fit a mechanistic mathematical model of drug resistance dynamics for a MDA-MB-231 breast cancer cell line. The explicit inclusion of the transcriptomic information in the parameter estimation is critical for identification of the model parameters and enables accurate prediction of new treatment regimens.

6. M. Sadeghi, J.M. Greene, and E.D. Sontag. Universal features of epidemic models under social distancing guidelines. Annual Reviews in Control, 51:426-440, 2021. Note: Also in bioRxiv, 2020, https://www.biorxiv.org/content/10.1101/2020.06.21.163931v2.[WWW] [PDF] [doi:https://doi.org/10.1016/j.arcontrol.2021.04.004] Keyword(s): epidemiology, COVID-19, COVID, systems biology.
Abstract:
 Different epidemiological models, from the classical SIR system to more sophisticated ones involving population compartments for socially distanced, quarantined, infection aware, asymptomatic infected, and other individuals, share some remarkable dynamic characteristics when contact rates are subject to periodic or one-shot changes. In simple pulsed isolation policies, a linear relationship is found among optimal start time and duration for reduction of the infected peak. If a single interval social distancing starts too early or too late it will be ineffective with respect to decreasing the peak of infection. On the other hand, the nonlinearity of epidemic models leads to non-monotone behavior of the peak of infected population under periodic relaxation policies. This observation led us to hypothesize that an additional single interval social distancing at a proper time can significantly decrease the infected peak of periodic policies, and we verified this improvement.

7. E.D. Sontag. An explicit formula for minimizing the infected peak in an SIR epidemic model when using a fixed number of complete lockdowns. International Journal of Robust and Nonlinear Control, Special Issue on Control-Theoretic Approaches for Systems in the Life Sciences, pp 1-24, 2021. [PDF] Keyword(s): epidemiology, COVID-19, COVID, systems biology.
Abstract:
 Careful timing of NPIs (non-pharmaceutical interventions) such as social distancing may avoid high second waves'' of infections of COVID-19. This paper asks what should be the timing of a set of K complete-lockdowns of prespecified lengths (such as two weeks) so as to minimize the peak of the infective compartment. Perhaps surprisingly, it is possible to give an explicit and easily computable rule for when each lockdown should commence. Simulations are used to show that the rule remains fairly accurate even if lockdowns are not perfect.

8. A.P. Tran, M.A. Al-Radhawi, E. Ernst, and E.D. Sontag. Optimization of heuristic logic synthesis by iteratively reducing circuit substructures using a database of optimal implementations. 2021. Note: Submitted. Keyword(s): Heuristic logic minimizer, Boolean circuit reduction, optimal synthesis, logic optimization, synthetic biology.
Abstract:
 Minimal synthesis of Boolean functions is an NP-hard problem, and heuristic approaches typically give suboptimal circuits. However, in the emergent field of synthetic biology, genetic logic designs that use even a single additional Boolean gate can render a circuit unimplementable in a cell. This has led to a renewed interest in the field of optimal multilevel Boolean synthesis. For small numbers (1-4) of inputs, an exhaustive search is possible, but this is impractical for large circuits. In this work, we demonstrate that even though it is challenging to build a database of optimal implementations for anything larger than 4-input Boolean functions, a database of 4-input optimal implementations can be used to greatly reduce the number of logical gates required in larger heuristic logic synthesis implementations. The proposed algorithm combines the heuristic results with an optimal implementation database and yields average improvements of 5.16% for 5-input circuits and 4.54% for 6-input circuits on outputs provided by the logic synthesis tool extit{ABC}. In addition to the gains in the efficiency of the implemented circuits, this work also attests to the importance and practicality of the field of optimal synthesis, even if it cannot directly provide results for larger circuits. The focus of this work is on circuits made exclusively of 2-input NOR gates but the presented results are readily applicable to 2-input NAND circuits as well as (2-input) AND/NOT circuits. In addition, the framework proposed here is likely to be adaptable to other types of circuits. An implementation of the described algorithm, HLM (Hybrid Logic Minimizer), is available at https://github.com/sontaglab/HLM/.

9. A.P. Tran, J.H. Meldon, and E.D. Sontag. Transient diffusion into a bi-layer membrane with mass transfer resistance: Exact solution and time lag analysis. Frontiers in Chemical Engineering, 2:25, 2021. [PDF] Keyword(s): Bi-layer membrane, transient diffusion, heat conduction, mass transfer resistance.
Abstract:
 Exact analytical and closed-form solutions to a problem involving transient diffusion in a bi-layer membrane with external transfer resistance are presented. In addition to the solutions of the transient response, the lead and lag times that are often of importance in the characterization of membranes and arise from the analysis of the asymptotic behavior of the mass permeated through the membrane are also provided. The solutions presented here are also compared to previously derived limiting cases of the diffusion in a bi-layer with an impermeable wall and constant concentrations at the upstream and downstream boundaries. Analysis of the time lag shows that this membrane property is independent of the direction of flow. Finally, an outline is provided of how these solutions, which characterize the response to a step function increase in concentration, can be also used to derive more complex input conditions. Adequately handling boundary layer effects has a wide array of potential applications such as the study of bi-layer undergoing phenomena of heat convection, gas film resistance, and absorption/desorption.

10. N. Trendel, P. Kruger, S. Gaglione, J. Nguyen, J. Pettmann, E.D. Sontag, and O. Dushek. Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation. Science Signaling, 14:eaay9363, 2021. [PDF] Keyword(s): immunology, cell signaling, T cells, systems biology.
Abstract:
 Maintaining and limiting T cell responses to constant antigen stimulation is critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) induces signalling that activates T cells to produce cytokines and also leads to the downregulation of surface TCRs. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation that requires complete downregulation of the receptor or the ligand. However, this is not the case for the TCR, and therefore, precisely how TCR downregulation maintains or limits T cell responses is controversial. Here, we observed that in vitro expanded primary human T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR downregulation. By directly fitting a mechanistic model to the data, we show that TCR downregulation produces imperfect adaptation, but when coupled to a switch produces perfect adaptation in cytokine production. A pre diction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings highlight that even partial TCR downregulation can limit T cell responses by producing perfect adaptation rendering T cells dependent on costimulation for sustained responses.

11. A.L. Williams, J.E. Fitzgerald, F. Ivich, E.D. Sontag, and M. Niedre. Comment on In vivo flow cytometry reveals a circadian rhythm of circulating tumor cells. npg Light: Science & Applications, 10:188, 2021. [PDF] Keyword(s): circulating tumor cells, liquid biopsy, cancer, oncology, multiple myeloma, systems biology.
Abstract:
 Correspondence regarding circulating tumor cell detection

 Conference articles
1. J. Miller, M.A. Al-Radhawi, and E.D. Sontag. Mediating ribosomal competition by splitting pools. In Proc. 2021 Automatic Control Conference, pages 1897-1902, 2021. [PDF] Keyword(s): systems biology, synthetic biology, ribosomes, RFM, ribosome flow model.
Abstract:
 Conference version of paper published in IEEE Control Systems Letters, 2020

2. A.C.B de Olivera, M. Siami, and E.D. Sontag. Bilinear dynamical networks under malicious attack: an efficient edge protection method. In Proc. 2021 Automatic Control Conference, pages 1210-1216, 2021. [PDF] Keyword(s): Bilinear systems, adversarial attacks, robustness measures, supermodular optimization.
Abstract:
 In large-scale networks, agents and links are often vulnerable to attacks. This paper focuses on continuous-time bilinear networks, where additive disturbances model attacks or uncertainties on agents/states (node disturbances), and multiplicative disturbances model attacks or uncertainties on couplings between agents/states (link disturbances). It investigates network robustness notion in terms of the underlying digraph of the network, and structure of exogenous uncertainties and attacks. Specifically, it defines a robustness measure using the $\mathcal H_2$-norm of the network and calculates it in terms of the reachability Gramian of the bilinear system. The main result is that under certain conditions, the measure is supermodular over the set of all possible attacked links. The supermodular property facilitates the efficient solution finding of the optimization problem. Examples illustrate how different structures can make the system more or less vulnerable to malicious attacks on links.

3. A.C.B de Olivera, M. Siami, and E.D. Sontag. Eminence in noisy bilinear networks. In Proc. 2021 60th IEEE Conference on Decision and Control (CDC), pages 4835-4840, 2021. [PDF] Keyword(s): Bilinear systems, H2 norm, centrality, adversarial attacks, robustness measures.
Abstract:
 When measuring importance of nodes in a network, the interconnections and dynamics are often supposed to be perfectly known. In this paper, we consider networks of agents with both uncertain couplings and dynamics. Network uncertainty is modeled by structured additive stochastic disturbances on each agent's update dynamics and coupling weights. We then study how these uncertainties change the network's centralities. Disturbances on the couplings between agents resul in bilinear dynamics, and classical centrality indices from linear network theory need to be redefined. To do that, we first show that, similarly to its linear counterpart, the squared H2 norm of bilinear systems measures the trace of the steady-state error covariance matrix subject to stochastic disturbances. This makes the H2 norm a natural candidate for a performance metric of the system. We propose a centrality index for the agents based on the H2 norm, and show how it depends on the network topology and the noise structure. Finally, we simulate a few graphs to illustrate how uncertainties on different couplings affect the agents' centrality rankings compared to a linearized model of the same system.

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