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1. Essential metabolism for a minimal cell

   https://doi.org/10.7554/eLife.36842  

   Breuer, Marian; Earnest, Tyler M; Merryman, Chuck; Wise, Kim S; Sun, Lijie; Lynott, Michaela R; Hutchison, Clyde A; Smith, Hamilton O; Lapek, John D; Gonzalez, David J; et al (January 2019, eLife)

   One way that researchers can test whether they understand a biological system is to see if they can accurately recreate it as a computer model. The more they learn about living things, the more the researchers can improve their models and the closer the models become to simulating the original. In this approach, it is best to start by trying to model a simple system. Biologists have previously succeeded in creating ‘minimal bacterial cells’. These synthetic cells contain fewer genes than almost all other living things and they are believed to be among the simplest possible forms of life that can grow on their own. The minimal cells can produce all the chemicals that they need to survive – in other words, they have a metabolism. Accurately recreating one of these cells in a computer is a key first step towards simulating a complete living system. Breuer et al. have developed a computer model to simulate the network of the biochemical reactions going on inside a minimal cell with just 493 genes. By altering the parameters of their model and comparing the results to experimental data, Breuer et al. explored the accuracy of their model. Overall, the model reproduces experimental results, but it is not yet perfect. The differences between the model and the experiments suggest new questions and tests that could advance our understanding of biology. In particular, Breuer et al. identified 30 genes that are essential for life in these cells but that currently have no known purpose. Continuing to develop and expand models like these to reproduce more complex living systems provides a tool to test current knowledge of biology. These models may become so advanced that they could predict how living things will respond to changing situations. This would allow scientists to test ideas sooner and make much faster progress in understanding life on Earth. Ultimately, these models could one day help to accelerate medical and industrial processes to save lives and enhance productivity. 

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2. A Simple Dynamic Controller for Emulating Human Balance Control

   https://doi.org/10.1007/978-3-031-39504-8_16  

   McNeal, J Stu; Hunt, Alexander (August 2023, Springer, Cham.)

   This paper presents a biologically inspired control system developed for maintaining balance in a simulated human atop an oscillating platform. This work advances our previous research by adapting a human balance controller to an inverted pendulum and controlled by linear-Hill muscle models. To expedite neuron/synapse parameter value selection, we employ a novel two-stage process that pairs a previously developed analytic method with particle swarm optimization. Using the parameter values found analytically as inputs for particle swarm optimization (PSO), we take advantage of the benefits of each method while avoiding their pitfalls. Our results show that PSO optimization allowed improved balance control from modest (<10%) changes to the synaptic parameters. The improved performance was accompanied by muscle coactivations, however, and further refinement is needed to better align overall behavior of the neural controller with biological systems. 

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3. Designing biological network motif-based controllers by reverse engineering Hill function-type models from linear models

   https://doi.org/10.1098/rsif.2024.0811  

   Spurgeon, Matthew; Clark, Tea; Spartalis, Thales Rossi; Darlington, Alexander; Tang, Xun; Foo, Mathias (April 2025, Journal of The Royal Society Interface)

   Perfect adaptation, the ability to regulate and maintain gene expression to its desired value despite disturbances, is important in the development of organisms. Building biological controllers to endow engineered biological systems with such perfect adaptation capability is a key goal in synthetic biology. Model-guided exploration of such synthetic circuits has been effective in designing such systems. However, theoretical analysis to guarantee controller properties with nonlinear models, such as Hill functions, remains challenging, while use of linear models fails to capture the inherent nonlinear dynamics of gene expression systems. Here, we propose a reverse engineering approach to infer the kinetic parameters for nonlinear Hill function-type models from analysis of linear models and apply our method to design controllers, which achieve perfect adaptation. Focusing on three biological network motif-based controllers, we demonstrate via simulation the efficacy of the proposed approach in combining linear system theories with nonlinear modelling, to design multiple gene circuits that could deliver perfect adaptation. Given the ubiquitous use of Hill functions in describing the dynamics of biological regulatory networks, we anticipate the proposed reverse engineering approach to benefit a wide range of systems and synthetic biology applications. 

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4. Quantifying cooperative multisite binding in the hub protein LC8 through Bayesian inference

   https://doi.org/10.1371/journal.pcbi.1011059  

   Estelle, Aidan B.; George, August; Barbar, Elisar J.; Zuckerman, Daniel M. (April 2023, PLOS Computational Biology)

   Keskin, Ozlem (Ed.)

   Multistep protein-protein interactions underlie most biological processes, but their characterization through methods such as isothermal titration calorimetry (ITC) is largely confined to simple models that provide little information on the intermediate, individual steps. In this study, we primarily examine the essential hub protein LC8, a small dimer that binds disordered regions of 100+ client proteins in two symmetrical grooves at the dimer interface. Mechanistic details of LC8 binding have remained elusive, hampered in part by ITC data analyses employing simple models that treat bivalent binding as a single event with a single binding affinity. We build on existing Bayesian ITC approaches to quantify thermodynamic parameters for multi-site binding interactions impacted by significant uncertainty in protein concentration. Using a two-site binding model, we identify positive cooperativity with high confidence for LC8 binding to multiple client peptides. In contrast, application of an identical model to the two-site binding between the coiled-coil NudE dimer and the intermediate chain of dynein reveals little evidence of cooperativity. We propose that cooperativity in the LC8 system drives the formation of saturated induced-dimer structures, the functional units of most LC8 complexes. In addition to these system-specific findings, our work advances general ITC analysis in two ways. First, we describe a previously unrecognized mathematical ambiguity in concentrations in standard binding models and clarify how it impacts the precision with which binding parameters are determinable in cases of high uncertainty in analyte concentrations. Second, building on observations in the LC8 system, we develop a system-agnostic heat map of practical parameter identifiability calculated from synthetic data which demonstrates that the ability to determine microscopic binding parameters is strongly dependent on both the parameters themselves and experimental conditions. The work serves as a foundation for determination of multi-step binding interactions, and we outline best practices for Bayesian analysis of ITC experiments. 

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5. Predicting the future is hard and other lessons from a population time series data science competition.

   Humphries, G.R.W. (October 2018, Ecological informatics)

   Population forecasting, in which past dynamics are used to make predictions of future state, has many real-world applications. While time series of animal abundance are often modeled in ways that aim to capture the underlying biological processes involved, doing so is neither necessary nor sufficient for making good predictions. Here we report on a data science competition focused on modelling time series of Antarctic penguin abundance. We describe the best performing submitted models and compare them to a Bayesian model previously developed by domain experts and build an ensemble model that outperforms the individual component models in prediction accuracy. The top performing models varied tremendously in model complexity, ranging from very simple forward extrapolations of average growth rate to ensembles of models integrating recently developed machine learning techniques. Despite the short time frame for the competition, four of the submitted models outperformed the model previously created by the team of domain experts. We discuss the structure of the best performing models and components therein that might be useful for other ecological applications, the benefit of creating ensembles of models for ecological prediction, and the costs and benefits of including detailed domain expertise in ecological modelling. Additionally, we discuss the benefits of data science competitions, among which are increased visibility for challenging science questions, the generation of new techniques not yet adopted within the ecological community, and the ability to generate ensemble model forecasts that directly address model uncertainty. 

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