Cell reprogramming design by transfer learning of functional transcriptional networks.

Recent developments in synthetic biology, next-generation sequencing, and machine learning provide an unprecedented opportunity to rationally design new disease treatments based on measured responses to gene perturbations and drugs to reprogram cell behavior. The main challenges to seizing this opportunity are the incomplete knowledge of the cellular network and the combinatorial explosion of possible interventions, both of which are insurmountable by experiments. To address these challenges, we develop a transfer learning approach to control cell behavior that is pre-trained on transcriptomic data associated with human cell fates to generate a model of the functional network dynamics that can be transferred to specific reprogramming goals. The approach additively combines transcriptional responses to gene perturbations (single-gene knockdowns and overexpressions) to minimize the transcriptional difference between a given pair of initial and target states. We demonstrate the flexibility of our approach by applying it to a microarray dataset comprising over 9,000 microarrays across 54 cell types and 227 unique perturbations, and an RNASeq dataset consisting of over 10,000 sequencing runs across 36 cell types and 138 perturbations. Our approach reproduces known reprogramming protocols with an average AUROC of 0.91 while innovating over existing methods by pre-training an adaptable model that can be tailored to specific reprogramming transitions. We show that the number of gene perturbations required to steer from one fate to another increases as the developmental relatedness decreases. We also show that fewer genes are needed to progress along developmental paths than to regress. Together, these findings establish a proof-of-concept for our approach to computationally design control strategies and demonstrate their ability to provide insights into the dynamics of gene regulatory networks.

Cell reprogramming design by transfer learning of functional transcriptional networks.

Recent developments in synthetic biology, next-generation sequencing, and machine learning provide an unprecedented opportunity to rationally design new disease treatments based on measured responses to gene perturbations and drugs to reprogram cells. The main challenges to seizing this opportunity are the incomplete knowledge of the cellular network and the combinatorial explosion of possible interventions, both of which are insurmountable by experiments. To address these challenges, we develop a transfer learning approach to control cell behavior that is pre-trained on transcriptomic data associated with human cell fates, thereby generating a model of the network dynamics that can be transferred to specific reprogramming goals. The approach combines transcriptional responses to gene perturbations to minimize the difference between a given pair of initial and target transcriptional states. We demonstrate our approach's versatility by applying it to a microarray dataset comprising >9,000 microarrays across 54 cell types and 227 unique perturbations, and an RNASeq dataset consisting of >10,000 sequencing runs across 36 cell types and 138 perturbations. Our approach reproduces known reprogramming protocols with an AUROC of 0.91 while innovating over existing methods by pre-training an adaptable model that can be tailored to specific reprogramming transitions. We show that the number of gene perturbations required to steer from one fate to another increases with decreasing developmental relatedness and that fewer genes are needed to progress along developmental paths than to regress. These findings establish a proof-of-concept for our approach to computationally design control strategies and provide insights into how gene regulatory networks govern phenotype.

Prevalence of multistability and nonstationarity in driven chemical networks.

External flows of energy, entropy, and matter can cause sudden transitions in the stability of biological and industrial systems, fundamentally altering their dynamical function. How might we control and design these transitions in chemical reaction networks? Here, we analyze transitions giving rise to complex behavior in random reaction networks subject to external driving forces. In the absence of driving, we characterize the uniqueness of the steady state and identify the percolation of a giant connected component in these networks as the number of reactions increases. When subject to chemical driving (influx and outflux of chemical species), the steady state can undergo bifurcations, leading to multistability or oscillatory dynamics. By quantifying the prevalence of these bifurcations, we show how chemical driving and network sparsity tend to promote the emergence of these complex dynamics and increased rates of entropy production. We show that catalysis also plays an important role in the emergence of complexity, strongly correlating with the prevalence of bifurcations. Our results suggest that coupling a minimal number of chemical signatures with external driving can lead to features present in biochemical processes and abiogenesis.

Whom is real science for?The Biggest Ideas in the Universe Sean Carroll Dutton, 2022. 304 pp.

Skip the metaphors-physics needn't be diluted for nonexperts to achieve real understanding.

Prevalence and scalable control of localized networks.

The ability to control network dynamics is essential for ensuring desirable functionality of many technological, biological, and social systems. Such systems often consist of a large number of network elements, and controlling large-scale networks remains challenging because the computation and communication requirements increase prohibitively fast with network size. Here, we introduce a notion of network locality that can be exploited to make the control of networks scalable, even when the dynamics are nonlinear. We show that network locality is captured by an information metric and is almost universally observed across real and model networks. In localized networks, the optimal control actions and system responses are both shown to be necessarily concentrated in small neighborhoods induced by the information metric. This allows us to develop localized algorithms for determining network controllability and optimizing the placement of driver nodes. This also allows us to develop a localized algorithm for designing local feedback controllers that approach the performance of the corresponding best global controllers, while incurring a computational cost orders-of-magnitude lower. We validate the locality, performance, and efficiency of the algorithms in Kuramoto oscillator networks, as well as three large empirical networks: synchronization dynamics in the Eastern US power grid, epidemic spreading mediated by the global air-transportation network, and Alzheimer's disease dynamics in a human brain network. Taken together, our results establish that large networks can be controlled with computation and communication costs comparable to those for small networks.

Network structural origin of instabilities in large complex systems.

A central issue in the study of large complex network systems, such as power grids, financial networks, and ecological systems, is to understand their response to dynamical perturbations. Recent studies recognize that many real networks show nonnormality and that nonnormality can give rise to reactivity-the capacity of a linearly stable system to amplify its response to perturbations, oftentimes exciting nonlinear instabilities. Here, we identify network structural properties underlying the pervasiveness of nonnormality and reactivity in real directed networks, which we establish using the most extensive dataset of such networks studied in this context to date. The identified properties are imbalances between incoming and outgoing network links and paths at each node. On the basis of this characterization, we develop a theory that quantitatively predicts nonnormality and reactivity and explains the observed pervasiveness. We suggest that these results can be used to design, upgrade, control, and manage networks to avoid or promote network instabilities.

Functional observability and target state estimation in large-scale networks.

The quantitative understanding and precise control of complex dynamical systems can only be achieved by observing their internal states via measurement and/or estimation. In large-scale dynamical networks, it is often difficult or physically impossible to have enough sensor nodes to make the system fully observable. Even if the system is in principle observable, high dimensionality poses fundamental limits on the computational tractability and performance of a full-state observer. To overcome the curse of dimensionality, we instead require the system to be functionally observable, meaning that a targeted subset of state variables can be reconstructed from the available measurements. Here, we develop a graph-based theory of functional observability, which leads to highly scalable algorithms to 1) determine the minimal set of required sensors and 2) design the corresponding state observer of minimum order. Compared with the full-state observer, the proposed functional observer achieves the same estimation quality with substantially less sensing and fewer computational resources, making it suitable for large-scale networks. We apply the proposed methods to the detection of cyberattacks in power grids from limited phase measurement data and the inference of the prevalence rate of infection during an epidemic under limited testing conditions. The applications demonstrate that the functional observer can significantly scale up our ability to explore otherwise inaccessible dynamical processes on complex networks.

Heterogeneity-stabilized homogeneous states in driven media.

Understanding the relationship between symmetry breaking, system properties, and instabilities has been a problem of longstanding scientific interest. Symmetry-breaking instabilities underlie the formation of important patterns in driven systems, but there are many instances in which such instabilities are undesirable. Using parametric resonance as a model process, here we show that a range of states that would be destabilized by symmetry-breaking instabilities can be preserved and stabilized by the introduction of suitable system asymmetry. Because symmetric states are spatially homogeneous and asymmetric systems are spatially heterogeneous, we refer to this effect as heterogeneity-stabilized homogeneity. We illustrate this effect theoretically using driven pendulum array models and demonstrate it experimentally using Faraday wave instabilities. Our results have potential implications for the mitigation of instabilities in engineered systems and the emergence of homogeneous states in natural systems with inherent heterogeneities.

Synchronizing Chaos with Imperfections.

Previous research on nonlinear oscillator networks has shown that chaos synchronization is attainable for identical oscillators but deteriorates in the presence of parameter mismatches. Here, we identify regimes for which the opposite occurs and show that oscillator heterogeneity can synchronize chaos for conditions under which identical oscillators cannot. This effect is not limited to small mismatches and is observed for random oscillator heterogeneity on both homogeneous and heterogeneous network structures. The results are demonstrated experimentally using networks of Chua's oscillators and are further supported by numerical simulations and theoretical analysis. In particular, we propose a general mechanism based on heterogeneity-induced mode mixing that provides insights into the observed phenomenon. Since individual differences are ubiquitous and often unavoidable in real systems, it follows that such imperfections can be an unexpected source of synchronization stability.

Random heterogeneity outperforms design in network synchronization.

A widely held assumption on network dynamics is that similar components are more likely to exhibit similar behavior than dissimilar ones and that generic differences among them are necessarily detrimental to synchronization. Here, we show that this assumption does not generally hold in oscillator networks when communication delays are present. We demonstrate, in particular, that random parameter heterogeneity among oscillators can consistently rescue the system from losing synchrony. This finding is supported by electrochemical-oscillator experiments performed on a multielectrode array network. Remarkably, at intermediate levels of heterogeneity, random mismatches are more effective in promoting synchronization than parameter assignments specifically designed to facilitate identical synchronization. Our results suggest that, rather than being eliminated or ignored, intrinsic disorder in technological and biological systems can be harnessed to help maintain coherence required for function.

Mechanism for Strong Chimeras.

Chimera states have attracted significant attention as symmetry-broken states exhibiting the unexpected coexistence of coherence and incoherence. Despite the valuable insights gained from analyzing specific systems, an understanding of the general physical mechanism underlying the emergence of chimeras is still lacking. Here, we show that many stable chimeras arise because coherence in part of the system is sustained by incoherence in the rest of the system. This mechanism may be regarded as a deterministic analog of noise-induced synchronization and is shown to underlie the emergence of strong chimeras. These are chimera states whose coherent domain is formed by identically synchronized oscillators. Recognizing this mechanism offers a new meaning to the interpretation that chimeras are a natural link between coherence and incoherence.

Asymmetry underlies stability in power grids.

Behavioral homogeneity is often critical for the functioning of network systems of interacting entities. In power grids, whose stable operation requires generator frequencies to be synchronized-and thus homogeneous-across the network, previous work suggests that the stability of synchronous states can be improved by making the generators homogeneous. Here, we show that a substantial additional improvement is possible by instead making the generators suitably heterogeneous. We develop a general method for attributing this counterintuitive effect to converse symmetry breaking, a recently established phenomenon in which the system must be asymmetric to maintain a stable symmetric state. These findings constitute the first demonstration of converse symmetry breaking in real-world systems, and our method promises to enable identification of this phenomenon in other networks whose functions rely on behavioral homogeneity.

Extreme Antagonism Arising from Gene-Environment Interactions.

Antagonistic interactions in biological systems, which occur when one perturbation blunts the effect of another, are typically interpreted as evidence that the two perturbations impact the same cellular pathway or function. Yet, this interpretation ignores extreme antagonistic interactions wherein an otherwise deleterious perturbation compensates for the function lost because of a prior perturbation. Here, we report on gene-environment interactions involving genetic mutations that are deleterious in a permissive environment but beneficial in a specific environment that restricts growth. These extreme antagonistic interactions constitute gene-environment analogs of synthetic rescues previously observed for gene-gene interactions. Our approach uses two independent adaptive evolution steps to address the lack of experimental methods to systematically identify such extreme interactions. We apply the approach to Escherichia coli by successively adapting it to defined glucose media without and with the antibiotic rifampicin. The approach identified multiple mutations that are beneficial in the presence of rifampicin and deleterious in its absence. The analysis of transcription shows that the antagonistic adaptive mutations repress a stringent response-like transcriptional program, whereas nonantagonistic mutations have an opposite transcriptional profile. Our approach represents a step toward the systematic characterization of extreme antagonistic gene-drug interactions, which can be used to identify targets to select against antibiotic resistance.

Coherent Dynamics Enhanced by Uncorrelated Noise.

Synchronization is a widespread phenomenon observed in physical, biological, and social networks, which persists even under the influence of strong noise. Previous research on oscillators subject to common noise has shown that noise can actually facilitate synchronization, as correlations in the dynamics can be inherited from the noise itself. However, in many spatially distributed networks, such as the mammalian circadian system, the noise that different oscillators experience can be effectively uncorrelated. Here, we show that uncorrelated noise can in fact enhance synchronization when the oscillators are coupled. Strikingly, our analysis also shows that uncorrelated noise can be more effective than common noise in enhancing synchronization. We first establish these results theoretically for phase and phase-amplitude oscillators subject to either or both additive and multiplicative noise. We then confirm the predictions through experiments on coupled electrochemical oscillators. Our findings suggest that uncorrelated noise can promote rather than inhibit coherence in natural systems and that the same effect can be harnessed in engineered systems.

Spontaneous oscillations and negative-conductance transitions in microfluidic networks.

The tendency for flows in microfluidic systems to behave linearly poses challenges for designing integrated flow control schemes to carry out complex fluid processing tasks. This hindrance precipitated the use of numerous external control devices to manipulate flows, thereby thwarting the potential scalability and portability of lab-on-a-chip technology. Here, we devise a microfluidic network exhibiting nonlinear flow dynamics that enable new mechanisms for on-chip flow control. This network is shown to exhibit oscillatory output patterns, bistable flow states, hysteresis, signal amplification, and negative-conductance transitions, all without reliance on dedicated external control hardware, movable parts, flexible components, or oscillatory inputs. These dynamics arise from nonlinear fluid inertia effects in laminar flows that we amplify and harness through the design of the network geometry. These results, which are supported by theory and simulations, have the potential to inspire development of new built-in control capabilities, such as on-chip timing and synchronized flow patterns.

Distinguishing cell phenotype using cell epigenotype.

The relationship between microscopic observations and macroscopic behavior is a fundamental open question in biophysical systems. Here, we develop a unified approach that-in contrast with existing methods-predicts cell type from macromolecular data even when accounting for the scale of human tissue diversity and limitations in the available data. We achieve these benefits by applying a k-nearest-neighbors algorithm after projecting our data onto the eigenvectors of the correlation matrix inferred from many observations of gene expression or chromatin conformation. Our approach identifies variations in epigenotype that affect cell type, thereby supporting the cell-type attractor hypothesis and representing the first step toward model-independent control strategies in biological systems.

Braess's paradox and programmable behaviour in microfluidic networks.

Microfluidic systems are now being designed with precision as miniaturized fluid manipulation devices that can execute increasingly complex tasks. However, their operation often requires numerous external control devices owing to the typically linear nature of microscale flows, which has hampered the development of integrated control mechanisms. Here we address this difficulty by designing microfluidic networks that exhibit a nonlinear relation between the applied pressure and the flow rate, which can be harnessed to switch the direction of internal flows solely by manipulating the input and/or output pressures. We show that these networks- implemented using rigid polymer channels carrying water-exhibit an experimentally supported fluid analogue of Braess's paradox, in which closing an intermediate channel results in a higher, rather than lower, total flow rate. The harnessed behaviour is scalable and can be used to implement flow routing with multiple switches. These findings have the potential to advance the development of built-in control mechanisms in microfluidic networks, thereby facilitating the creation of portable systems and enabling novel applications in areas ranging from wearable healthcare technologies to deployable space systems.

Topological Control of Synchronization Patterns: Trading Symmetry for Stability.

Symmetries are ubiquitous in network systems and have profound impacts on the observable dynamics. At the most fundamental level, many synchronization patterns are induced by underlying network symmetry, and a high degree of symmetry is believed to enhance the stability of identical synchronization. Yet, here we show that the synchronizability of almost any symmetry cluster in a network of identical nodes can be enhanced precisely by breaking its structural symmetry. This counterintuitive effect holds for generic node dynamics and arbitrary network structure and is, moreover, robust against noise and imperfections typical of real systems, which we demonstrate by implementing a state-of-the-art optoelectronic experiment. These results lead to new possibilities for the topological control of synchronization patterns, which we substantiate by presenting an algorithm that optimizes the structure of individual clusters under various constraints.

Predicting growth rate from gene expression.

Growth rate is one of the most important and most complex phenotypic characteristics of unicellular microorganisms, which determines the genetic mutations that dominate at the population level, and ultimately whether the population will survive. Translating changes at the genetic level to their growth-rate consequences remains a subject of intense interest, since such a mapping could rationally direct experiments to optimize antibiotic efficacy or bioreactor productivity. In this work, we directly map transcriptional profiles to growth rates by gathering published gene-expression data from Escherichia coli and Saccharomyces cerevisiae with corresponding growth-rate measurements. Using a machine-learning technique called k-nearest-neighbors regression, we build a model which predicts growth rate from gene expression. By exploiting the correlated nature of gene expression and sparsifying the model, we capture 81% of the variance in growth rate of the E. coli dataset, while reducing the number of features from >4,000 to 9. In S. cerevisiae, we account for 89% of the variance in growth rate, while reducing from >5,500 dimensions to 18. Such a model provides a basis for selecting successful strategies from among the combinatorial number of experimental possibilities when attempting to optimize complex phenotypic traits like growth rate.

State observation and sensor selection for nonlinear networks.

A large variety of dynamical systems, such as chemical and biomolecular systems, can be seen as networks of nonlinear entities. Prediction, control, and identification of such nonlinear networks require knowledge of the state of the system. However, network states are usually unknown, and only a fraction of the state variables are directly measurable. The observability problem concerns reconstructing the network state from this limited information. Here, we propose a general optimization-based approach for observing the states of nonlinear networks and for optimally selecting the observed variables. Our results reveal several fundamental limitations in network observability, such as the trade-off between the fraction of observed variables and the observation length on one side, and the estimation error on the other side. We also show that, owing to the crucial role played by the dynamics, purely graph-theoretic observability approaches cannot provide conclusions about one's practical ability to estimate the states. We demonstrate the effectiveness of our methods by finding the key components in biological and combustion reaction networks from which we determine the full system state. Our results can lead to the design of novel sensing principles that can greatly advance prediction and control of the dynamics of such networks.