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The tendency for cell fate to be robust to most perturbations, yet sensitive to certain perturbations raises intriguing questions about the existence of a key path within the underlying molecular network that critically determines distinct cell fates. Reprogramming and trans-differentiation clearly show examples of cell fate change by regulating only a few or even a single molecular switch. However, it is still unknown how to identify such a switch, called a master regulator, and how cell fate is determined by its regulation. Here, we present CAESAR, a computational framework that can systematically identify master regulators and unravel the resulting canalizing kernel, a key substructure of interconnected feedbacks that is critical for cell fate determination. We demonstrate that CAESAR can successfully predict reprogramming factors for de-differentiation into mouse embryonic stem cells and trans-differentiation of hematopoietic stem cells, while unveiling the underlying essential mechanism through the canalizing kernel. CAESAR provides a system-level understanding of how complex molecular networks determine cell fates.

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Output stabilizing control of biological systems is of utmost importance in systems biology since key phenotypes of biological networks are often encoded by a small subset of their phenotypic marker nodes. This study addresses the challenge of output stabilizing control for complex biological systems modeled by Boolean networks (BNs). The objective is to identify a set of constant control inputs capable of driving the BN toward a desirable long-term behavior with respect to specified output nodes. Leveraging the algebraic properties of Boolean logic, we develop a novel control algorithm that reformulates the output stabilizing control problem into a simple graph theoretic problem involving auxiliary BNs, the scale of which significantly decreases compared to the original BN. The proposed method ensures superiority over previous results in terms of both the number of control inputs and computational loads, since it searches for the solution within the reduced BNs while retaining essential structures needed for output stabilization. The efficacy of the proposed control scheme is demonstrated through extensive numerical experiments with complex random BNs and real biological networks. To support the reproducible research initiative, detailed results of numerical experiments are provided in the supplementary material, and all the implementation codes are made accessible at https://github.com/choonlog/OutputStabilization.

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Boolean networks have been widely used in systems biology to study the dynamical characteristics of biological networks such as steady-states or cycles, yet there has been little attention to the dynamic properties of network structures. Here, we systematically reveal the core network structures using a recursive self-composite of the logic update rules. We find that all Boolean update rules exhibit repeated cyclic logic structures, where each converged logic leads to the same states, defined as kernel states. Consequently, the period of state cycles is upper bounded by the number of logics in the converged logic cycle. In order to uncover the underlying dynamical characteristics by exploiting the repeating structures, we propose leaping and filling algorithms. The algorithms provide a way to avoid large string explosions during the self-composition procedures. Finally, we present three examples-a simple network with a long feedback structure, a T-cell receptor network and a cancer network-to demonstrate the usefulness of the proposed algorithm.

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Environmental effects in excitation energy transfer have mostly been modeled by baths of harmonic oscillators, but to what extent such modeling provides a reliable description of actual interactions between molecular systems and environments remains an open issue. We address this issue by investigating fluctuations in the excitation energies of the light harvesting 2 complex using a realistic all-atomistic simulation of the potential energy surface. Our analyses reveal that molecular motions exhibit significant anharmonic features, even for underdamped intramolecular vibrations. In particular, we find that the anharmonicity contributes to the broadening of spectral densities and substantial overlaps between neighboring peaks, which complicates the meaning of mode frequencies constituting a bath model. Thus, we develop a strategy to construct a minimally underdamped harmonic bath that has a clear connection to all-atomistic dynamics by utilizing actual normal modes of molecules but optimizing their frequencies such that the resulting bath model can best reproduce the all-atomistic simulation results. By subtracting the underdamped contribution from the entire fluctuations, we also show that identifying a residual spectral density representing all other contributions with overdamped behavior is possible. We find that this can be fitted well with a well-established analytic form of a spectral density function or, alternatively, modeled as explicit time dependent fluctuations with muti-exponential or power law type correlation functions. We provide an assessment and the implications of these possibilities. The approach presented here can also serve as a general strategy to construct a simplified bath model that can effectively represent the underlying all-atomistic bath dynamics.

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Predicting cellular responses to perturbations requires interpretable insights into molecular regulatory dynamics to perform reliable cell fate control, despite the confounding non-linearity of the underlying interactions. There is a growing interest in developing machine learning-based perturbation response prediction models to handle the non-linearity of perturbation data, but their interpretation in terms of molecular regulatory dynamics remains a challenge. Alternatively, for meaningful biological interpretation, logical network models such as Boolean networks are widely used in systems biology to represent intracellular molecular regulation. However, determining the appropriate regulatory logic of large-scale networks remains an obstacle due to the high-dimensional and discontinuous search space. To tackle these challenges, we present a scalable derivative-free optimizer trained by meta-reinforcement learning for Boolean network models. The logical network model optimized by the trained optimizer successfully predicts anti-cancer drug responses of cancer cell lines, while simultaneously providing insight into their underlying molecular regulatory mechanisms.

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Understanding and manipulating cell fate determination is pivotal in biology. Cell fate is determined by intricate and nonlinear interactions among molecules, making mathematical model-based quantitative analysis indispensable for its elucidation. Nevertheless, obtaining the essential dynamic experimental data for model development has been a significant obstacle. However, recent advancements in large-scale omics data technology are providing the necessary foundation for developing such models. Based on accumulated experimental evidence, we can postulate that cell fate is governed by a limited number of core regulatory circuits. Following this concept, we present a conceptual control framework that leverages single-cell RNA-seq data for dynamic molecular regulatory network modeling, aiming to identify and manipulate core regulatory circuits and their master regulators to drive desired cellular state transitions. We illustrate the proposed framework by applying it to the reversion of lung cancer cell states, although it is more broadly applicable to understanding and controlling a wide range of cell-fate determination processes.

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Inducing apoptosis in cancer cells is a primary goal in anti-cancer therapy, but curing cancer with a single drug is unattainable due to drug resistance. The complex molecular network in cancer cells causes heterogeneous responses to single-target drugs, thereby inducing an adaptive drug response. Here, we showed that targeted drug perturbations can trigger state conflicts between multi-stable motifs within a molecular regulatory network, resulting in heterogeneous drug responses. However, we revealed that properly regulating an interconnecting molecule between these motifs can synergistically minimize the heterogeneous responses and overcome drug resistance. We extracted the essential cellular response dynamics of the Boolean network driven by the target node perturbation and developed an algorithm to identify a synergistic combinatorial target that can reduce heterogeneous drug responses. We validated the proposed approach using exemplary network models and a gastric cancer model from a previous study by showing that the targets identified with our algorithm can better drive the networks to desired states than those with other control theories. Of note, our approach suggests a new synergistic pair of control targets that can increase cancer drug efficacy to overcome adaptive drug resistance.

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BACKGROUND: A central challenge in biology is to discover a principle that determines individual phenotypic differences within a species. The growth rate is particularly important for a unicellular organism, and the growth rate under a certain condition is negatively associated with that of another condition, termed fitness trade-off. Therefore, there should exist a common molecular mechanism that regulates multiple growth rates under various conditions, but most studies so far have focused on discovering those genes associated with growth rates under a specific condition. RESULTS: In this study, we found that there exists a recurrent gene expression signature whose expression levels are related to the fitness trade-off between growth preference and stress resistance across various yeast strains and multiple conditions. We further found that the genomic variation of stress-response, ribosomal, and cell cycle regulators are potential causal genes that determine the sensitivity between growth and survival. Intriguingly, we further observed that the same principle holds for human cells using anticancer drug sensitivities across multiple cancer cell lines. CONCLUSIONS: Together, we suggest that the fitness trade-off is an evolutionary trait that determines individual growth phenotype within a species. By using this trait, we can possibly overcome anticancer drug resistance in cancer cells.

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Tumor suppressor p53 plays a pivotal role in suppressing cancer, so various drugs has been suggested to upregulate its function. However, drug resistance is still the biggest hurdle to be overcome. To address this, we developed a deep learning model called AnoDAN (anomalous gene detection using generative adversarial networks and graph neural networks for overcoming drug resistance) that unravels the hidden resistance mechanisms and identifies a combinatorial target to overcome the resistance. Our findings reveal that the TGF-ß signaling pathway, alongside the p53 signaling pathway, mediates the resistance, with THBS1 serving as a core regulatory target in both pathways. Experimental validation in lung cancer cells confirms the effects of THBS1 on responsiveness to a p53 reactivator. We further discovered the positive feedback loop between THBS1 and the TGF-ß pathway as the main source of resistance. This study enhances our understanding of p53 regulation and offers insights into overcoming drug resistance.

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The nature of the electron-binding forces in the dipole-bound states (DBS) of anions is interrogated through experimental and theoretical means by investigating the autodetachment dynamics from DBS Feshbach resonances of ortho-, meta-, and para-bromophenoxide (BrPhO-). Though the charge-dipole electrostatic potential has been widely regarded to be mainly responsible for the electron binding in DBS, the effect of nonclassical electron correlation has been conceived to be quite significant in terms of its static and/or dynamic contributions toward the binding of the excess electron to the neutral core. State-specific real-time autodetachment dynamics observed by picosecond time-resolved photoelectron velocity-map imaging spectroscopy reveal that the autodetachment processes from the DBS Feshbach resonances of BrPhO- anions cannot indeed be rationalized by the conventional charge-dipole potential. Specifically, the autodetachment lifetime is drastically lengthened depending on differently positioned Br-substitution, and this rate change cannot be explained within the framework of Fermi's golden rule based on the charge-dipole assumption. High-level ab initio quantum chemical calculations with EOM-EA-CCSD, which intrinsically takes into account electron correlations, generate more reasonable predictions on the binding energies than density functional theory (DFT) calculations, and semiclassical quantum dynamics simulations based on the EOM-EA-CCSD data excellently predict the trend in the autodetachment rates. These findings illustrate that static and dynamic properties of the excess electron in the DBS are strongly influenced by correlation interactions among electrons in the nonvalence orbital of the dipole-bound electron and highly polarizable valence orbitals of the bromine atom, which, in turn, dictate the interesting chemical fate of exotic anion species.

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Accumulated genetic alterations in cancer cells distort cellular stimulus-response (or input-output) relationships, resulting in uncontrolled proliferation. However, the complex molecular interaction network within a cell implicates a possibility of restoring such distorted input-output relationships by rewiring the signal flow through controlling hidden molecular switches. Here, a system framework of analyzing cellular input-output relationships in consideration of various genetic alterations and identifying possible molecular switches that can normalize the distorted relationships based on Boolean network modeling and dynamics analysis is presented. Such reversion is demonstrated by the analysis of a number of cancer molecular networks together with a focused case study on bladder cancer with in vitro experiments and patient survival data analysis. The origin of reversibility from an evolutionary point of view based on the redundancy and robustness intrinsically embedded in complex molecular regulatory networks is further discussed.

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The underlying genetic networks of cells give rise to diverse behaviors known as phenotypes. Control of this cellular phenotypic diversity (CPD) may reveal key targets that govern differentiation during development or drug resistance in cancer. This work establishes an approach to control CPD that encompasses practical constraints, including model limitations, the number of simultaneous control targets, which targets are viable for control, and the granularity of control. Cellular networks are often limited to the structure of interactions, due to the practical difficulty of modeling interaction dynamics. However, these dynamics are essential to CPD. In response, our statistical control approach infers the CPD directly from the structure of a network, by considering an ensemble average function over all possible Boolean dynamics for each node in the network. These ensemble average functions are combined with an acyclic form of the network to infer the number of point attractors. Our approach is applied to several known biological models and shown to outperform existing approaches. Statistical control of CPD offers a new avenue to contend with systemic processes such as differentiation and cancer, despite practical limitations in the field.

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Cancer is caused by the accumulation of genetic alterations and therefore has been historically considered to be irreversible. Intriguingly, several studies have reported that cancer cells can be reversed to be normal cells under certain circumstances. Despite these experimental observations, conceptual and theoretical frameworks that explain these phenomena and enable their exploration in a systematic way are lacking. In this review, we provide an overview of cancer reversion studies and describe recent advancements in systems biological approaches based on attractor landscape analysis. We suggest that the critical transition in tumorigenesis is an important clue for achieving cancer reversion. During tumorigenesis, a critical transition may occur at a tipping point, where cells undergo abrupt changes and reach a new equilibrium state that is determined by complex intracellular regulatory events. We introduce a conceptual framework based on attractor landscapes through which we can investigate the critical transition in tumorigenesis and induce its reversion by combining intracellular molecular perturbation and extracellular signaling controls. Finally, we present a cancer reversion therapy approach that may be a paradigm-changing alternative to current cancer cell-killing therapies.

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Clinical effect of donor-derived natural killer cell infusion (DNKI) after HLA-haploidentical hematopoietic cell transplantation (HCT) was evaluated in high-risk myeloid malignancy in phase 2, randomized trial. Seventy-six evaluable patients (aged 21-70 years) were randomized to receive DNKI (N = 40) or not (N = 36) after haploidentical HCT. For the HCT conditioning, busulfan, fludarabine, and anti-thymocyte globulin were administered. DNKI was given twice 13 and 20 days after HCT. Four patients in the DNKI group failed to receive DNKI. In the remaining 36 patients, median DNKI doses were 1.0 × 108/kg and 1.4 × 108/kg on days 13 and 20, respectively. Intention-to-treat analysis showed a lower disease progression for the DNKI group (30-month cumulative incidence, 35% vs 61%, P = 0.040; subdistribution hazard ratio, 0.50). Furthermore, at 3 months after HCT, the DNKI patients showed a 1.8- and 2.6-fold higher median absolute blood count of NK and T cells, respectively. scRNA-sequencing analysis in seven study patients showed that there was a marked increase in memory-like NK cells in DNKI patients which, in turn, expanded the CD8+ effector-memory T cells. In high-risk myeloid malignancy, DNKI after haploidentical HCT reduced disease progression. This enhanced graft-vs-leukemia effect may be related to the DNKI-induced, post-HCT expansion of NK and T cells. Clinical trial number: NCT02477787.

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MOTIVATION: Cellular behavior is determined by complex non-linear interactions between numerous intracellular molecules that are often represented by Boolean network models. To achieve a desired cellular behavior with minimal intervention, we need to identify optimal control targets that can drive heterogeneous cellular states to the desired phenotypic cellular state with minimal node intervention. Previous attempts to realize such global stabilization were based solely on either network structure information or simple linear dynamics. Other attempts based on non-linear dynamics are not scalable. RESULTS: Here, we investigate the underlying relationship between structurally identified control targets and optimal global stabilizing control targets based on non-linear dynamics. We discovered that optimal global stabilizing control targets can be identified by analyzing the dynamics between structurally identified control targets. Utilizing these findings, we developed a scalable global stabilizing control framework using both structural and dynamic information. Our framework narrows down the search space based on strongly connected components and feedback vertex sets then identifies global stabilizing control targets based on the canalization of Boolean network dynamics. We find that the proposed global stabilizing control is superior with respect to the number of control target nodes, scalability, and computational complexity. AVAILABILITY AND IMPLEMENTATION: We provide a GitHub repository that contains the DCGS framework written in Python as well as biological random Boolean network datasets (https://github.com/sugyun/DCGS). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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Tolaasin, a pore-forming bacterial peptide toxin secreted by Pseudomonas tolaasii, causes brown blotch disease in cultivated mushrooms by forming membrane pores and collapsing the membrane structures. Tolaasin is a lipodepsipeptide, MW 1985, and pore formation by tolaasin molecules is accomplished by hydrophobic interactions and multimerizations. Compounds that inhibit tolaasin toxicity have been isolated from various food additives. Food detergents, sucrose esters of fatty acids, and polyglycerol esters of fatty acids can effectively inhibit tolaasin cytotoxicity. These chemicals, named tolaasin-inhibitory factors (TIF), were effective at concentrations ranging from 10-4 to 10-5 M. The most effective compound, TIF 16, inhibited tolaasin-induced hemolysis independent of temperature and pH, while tolaasin toxicity increased at higher temperatures. When TIF 16 was added to tolaasin-pretreated erythrocytes, the cytotoxic activity of tolaasin immediately stopped, and no further hemolysis was observed. In the artificial lipid bilayer, the single-channel activity of the tolaasin channel was completely and irreversibly blocked by TIF 16. When TIF 16 was sprayed onto pathogen-treated oyster mushrooms growing on the shelves of cultivation houses, the development of disease was completely suppressed, and normal growth of oyster mushrooms was observed. Furthermore, the treatment with TIF 16 did not show any adverse effect on the growth of oyster mushrooms. These results indicate that TIF 16 is a good candidate for the biochemical control of brown blotch disease.

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The epithelial-to-mesenchymal transition (EMT) of primary cancer contributes to the acquisition of lethal properties, including metastasis and drug resistance. Blocking or reversing EMT could be an effective strategy to improve cancer treatment. However, it is still unclear how to achieve complete EMT reversal (rEMT), as cancer cells often transition to hybrid EMT states with high metastatic potential. To tackle this problem, we employed a systems biology approach and identified a core-regulatory circuit that plays the primary role in driving rEMT without hybrid properties. Perturbation of any single node was not sufficient to completely revert EMT. Inhibition of both SMAD4 and ERK signaling along with p53 activation could induce rEMT in cancer cells even with TGFß stimulation, a primary inducer of EMT. Induction of rEMT in lung cancer cells with the triple combination approach restored chemosensitivity. This cell-fate reprogramming strategy based on attractor landscapes revealed potential therapeutic targets that can eradicate metastatic potential by subverting EMT while avoiding hybrid states. SIGNIFICANCE: Network modeling unravels the highly complex and plastic process regulating epithelial and mesenchymal states in cancer cells and discovers therapeutic interventions for reversing epithelial-to-mesenchymal transition and enhancing chemosensitivity.

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Cancer tissue samples contain cancer cells and non-cancer cells with each biopsied site containing distinct proportions of these populations. Consequently, assigning useful tumor subtypes based on gene expression measurements from clinical samples is challenging. We applied a blind source separation approach to extract cancer cell-intrinsic gene expression patterns within clinical tumor samples of colorectal cancer. After a blind source separation, we found that a cancer cell-intrinsic gene expression program unique to each patient exists in the "residual" expression profile remaining after separation of the gene expression data. We performed a consensus clustering analysis of the extracted gene expression profiles to identify novel and robust cancer cell-intrinsic subtypes. We validated the identified subtypes using an independent clinical gene expression dataset. The cancer cell-intrinsic subtypes are independent of biopsy site and provided prognostic information in addition to currently available clinical and molecular variables. After validating this approach in colorectal cancer, we further identified novel tumor subtypes with unique clinical information across multiple types of cancer. These cancer cell-intrinsic molecular subtypes provide novel prognostic value for clinical assessment of cancer.

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The response variation to anti-cancer drugs originates from complex intracellular network dynamics of cancer. Such dynamic networks present challenges to determining optimal drug targets and stratifying cancer patients for precision medicine, although several cancer genome studies provided insights into the molecular characteristics of cancer. Here, we introduce a network dynamics-based approach based on attractor landscape analysis to evaluate the therapeutic window of a drug from cancer signaling networks combined with genomic profiles. This approach allows for effective screening of drug targets to explore potential target combinations for enhancing the therapeutic window of drug responses. We also effectively stratify patients into desired/undesired response groups using critical genomic determinants, which are network-specific origins of variability to drug response, and their dominance relationship. Our methods provide a viable and quantitative framework to connect genotype information to the phenotypes of drug response with regard to network dynamics determining the therapeutic window.

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Recently, FGFR inhibitors have been highlighted as promising targeted drugs due to the high prevalence of FGFR1 amplification in cancer patients. Although various potential biomarkers for FGFR inhibitors have been suggested, their functional effects have been shown to be limited due to the complexity of the cancer signaling network and the heterogenous genomic conditions of patients. To overcome such limitations, we have reconstructed a lung cancer network model by integrating a cell line genomic database and analyzing the model in order to understand the underlying mechanism of heterogeneous drug responses. Here, we identify novel genomic context-specific candidates that can increase the efficacy of FGFR inhibitors. Furthermore, we suggest optimal targets that can induce more effective therapeutic responses than that of FGFR inhibitors in each of the FGFR-resistant lung cancer cells through computational simulations at a system level. Our findings provide new insights into the regulatory mechanism of differential responses to FGFR inhibitors for optimal therapeutic strategies in lung cancer.

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