Algorithm for cellular reprogramming.

The day we understand the time evolution of subcellular events at a level of detail comparable to physical systems governed by Newton's laws of motion seems far away. Even so, quantitative approaches to cellular dynamics add to our understanding of cell biology. With data-guided frameworks we can develop better predictions about, and methods for, control over specific biological processes and system-wide cell behavior. Here we describe an approach for optimizing the use of transcription factors (TFs) in cellular reprogramming, based on a device commonly used in optimal control. We construct an approximate model for the natural evolution of a cell-cycle-synchronized population of human fibroblasts, based on data obtained by sampling the expression of 22,083 genes at several time points during the cell cycle. To arrive at a model of moderate complexity, we cluster gene expression based on division of the genome into topologically associating domains (TADs) and then model the dynamics of TAD expression levels. Based on this dynamical model and additional data, such as known TF binding sites and activity, we develop a methodology for identifying the top TF candidates for a specific cellular reprogramming task. Our data-guided methodology identifies a number of TFs previously validated for reprogramming and/or natural differentiation and predicts some potentially useful combinations of TFs. Our findings highlight the immense potential of dynamical models, mathematics, and data-guided methodologies for improving strategies for control over biological processes.

Reservoir observers: Model-free inference of unmeasured variables in chaotic systems.

Deducing the state of a dynamical system as a function of time from a limited number of concurrent system state measurements is an important problem of great practical utility. A scheme that accomplishes this is called an "observer." We consider the case in which a model of the system is unavailable or insufficiently accurate, but "training" time series data of the desired state variables are available for a short period of time, and a limited number of other system variables are continually measured. We propose a solution to this problem using networks of neuron-like units known as "reservoir computers." The measurements that are continually available are input to the network, which is trained with the limited-time data to output estimates of the desired state variables. We demonstrate our method, which we call a "reservoir observer," using the Rössler system, the Lorenz system, and the spatiotemporally chaotic Kuramoto-Sivashinsky equation. Subject to the condition of observability (i.e., whether it is in principle possible, by any means, to infer the desired unmeasured variables from the measured variables), we show that the reservoir observer can be a very effective and versatile tool for robustly reconstructing unmeasured dynamical system variables.