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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 and E.D. Sontag. Analysis of a reduced model of epithelial-mesenchymal fate determination in cancer metastasis as a singularly-perturbed monotone system. In C.A. Beattie, P. Benner, M. Embree, S. Gugercin, and S. Lefteriu, editors, Realization and Model Reduction of Dynamical Systems. Springer-Verlag, 2021. Note: To appear (see preprint in arXiv:1910.11311). [PDF] Keyword(s): epithelial-mesenchymal transition, miRNA, singular perturbations, monotone systems, oncology, cancer, metastasis, chemical reaction networks, systems biology.
Abstract:
 Metastasis can occur after malignant cells transition from the epithelial phenotype to the mesenchymal phenotype. This transformation allows cells to migrate via the circulatory system and subsequently settle in distant organs after undergoing the reverse transition. The core gene regulatory network controlling these transitions consists of a system made up of coupled SNAIL/miRNA-34 and ZEB1/miRNA-200 subsystems. In this work, we formulate a mathematical model and analyze its long-term behavior. We start by developing a detailed reaction network with 24 state variables. Assuming fast promoter and mRNA kinetics, we then show how to reduce our model to a monotone four-dimensional system. For the reduced system, monotone dynamical systems theory can be used to prove generic convergence to the set of equilibria for all bounded trajectories. The theory does not apply to the full model, which is not monotone, but we briefly discuss results for singularly-perturbed monotone systems that provide a tool to extend convergence results from reduced to full systems, under appropriate time separation assumptions.

2. M.A. Al-Radhawi, M. Sadeghi, and E.D. Sontag. Long-term regulation of prolonged epidemic outbreaks in large populations via adaptive control: a singular perturbation approach. IEEE Control Systems Letters, pp 10.1109/LCSYS.2021.3083983, 2021. [PDF] Keyword(s): epidemiology, COVID-19, COVID, systems biology.
Abstract:
 Initial hopes of quickly eradicating the COVID-19 pandemic proved futile, and the goal shifted to controlling the peak of the infection, so as to minimize the load on healthcare systems. To that end, public health authorities intervened aggressively to institute social distancing, lock-down policies, and other Non-Pharmaceutical Interventions (NPIs). Given the high social, educational, psychological, and economic costs of NPIs, authorities tune them, alternatively tightening up or relaxing rules, with the result that, in effect, a relatively flat infection rate results. For example, during the summer in parts of the United States, daily infection numbers dropped to a plateau. This paper approaches NPI tuning as a control-theoretic problem, starting from a simple dynamic model for social distancing based on the classical SIR epidemics model. Using a singular-perturbation approach, the plateau becomes a Quasi-Steady-State (QSS) of a reduced two-dimensional SIR model regulated by adaptive dynamic feedback. It is shown that the QSS can be assigned and it is globally asymptotically stable. Interestingly, the dynamic model for social distancing can be interpreted as a nonlinear integral controller. Problems of data fitting and parameter identifiability are also studied for this model. The paper also discusses how this simple model allows for a meaningful study of the effect of population size, differences in the policy between countries, vaccinations, and the emergence of second waves.

3. D. Angeli, M.A. Al-Radhawi, and E.D. Sontag. A robust Lyapunov criterion for non-oscillatory behaviors in biological interaction networks. IEEE Transactions on Automatic Control, 2021. Note: Revised version under review (preprint in arXiv.2009.10702, 2020). Keyword(s): oscillations, dynamical systems, enzymatic cycles, systems biology.
Abstract:
 We introduce the notion of non-oscillation, propose a constructive method for its robust verification, and study its application to biological interaction networks (also known as, chemical reaction networks). We begin by revisiting Muldowney's result on non-existence of periodic solutions based on the study of the variational system of the second additive compound of the Jacobian of a nonlinear system. We show that exponential stability of the latter rules out limit cycles, quasi-periodic solutions, and broad classes of oscillatory behavior. We focus then on nonlinear equations arising in biological interaction networks with general kinetics, and we show that the dynamics of the aforementioned variational system can be embedded in a linear differential inclusion. We then propose algorithms for constructing piecewise linear Lyapunov functions to certify global robust non-oscillatory behavior. Finally, we apply our techniques to study several regulated enzymatic cycles where available methods are not able to provide any information about their qualitative global behavior.

4. 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): empirical risk minimization, recurrent neural nets, 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.

5. 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.

6. 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.

7. M. Sadeghi, J.M. Greene, and E.D. Sontag. Universal features of epidemic models under social distancing guidelines. Annual Reviews in Control, 2021. Note: To appear (preprint in bioRxiv, 2020, https://www.biorxiv.org/content/10.1101/2020.06.21.163931v2). [PDF] 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.

8. Eduardo D. Sontag. An explicit formula for minimizing the infected peak in an SIR epidemic model when using a fixed number of complete lockdowns. medRxiv, 2021. Note: Submitted to a journal for peer review.[WWW] Keyword(s): epidemiology, COVID-19, COVID, systems biology.
Abstract:
 A too-early start of NPIs (non-pharmaceutical interventions) such as social distancing may lead to 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.

9. A.P. Tran, M. Ali 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/.

10. 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.

11. 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.

 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, 2021. Note: To appear.Keyword(s): systems biology, synthetic biology, ribosomes, RFM.
Abstract:
 Conference version of paper published in IEEE Control Systems Letters, 2020

2. A.C. Branco de Oliveira, M. Siami, and E.D. Sontag. Edge selection in bilinear dynamical networks. In Proc. 2021 Automatic Control Conference, 2021. Note: To appear.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.

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