Connecting the dots: Computational network analysis for disease insight and drug repurposing.

Network biology is a powerful framework for studying the structure, function, and dynamics of biological systems, offering insights into the balance between health and disease states. The field is seeing rapid progress in all of its aspects: data availability, network synthesis, network analytics, and impactful applications in medicine and drug development. We review the most recent and significant results in network biomedicine, with a focus on the latest data, analytics, software resources, and applications in medicine. We also discuss what in our view are the likely directions of impactful development over the next few years.

MRI-Targeted Prostate Biopsy Introduces Grade Inflation and Overtreatment.

Purpose: The use of MRI-targeted biopsies has led to lower detection of Gleason Grade Group 1 (GG1) prostate cancer and increased detection of GG2 disease. Although this finding is generally attributed to improved sensitivity and specificity of MRI for aggressive cancers, it might also be explained by grade inflation. Our objective was to determine the likelihood of definitive treatment and risk of post-treatment recurrence for patients with GG2 cancer diagnosed using targeted biopsies relative to men with GG1 cancer diagnosed using systematic biopsies. Methods: We performed a retrospective study on a large tertiary centre registry (HUS Acamedic Datalake) to retrieve data on prostate cancer diagnosis, treatment, and cancer recurrence. We included patients with either GG1 with systematic biopsies (3317 men) or GG2 with targeted biopsies (554 men) from 1993 to 2019. We assessed the risk of curative treatment and recurrence after treatment. Kaplan-Meier survival curves were computed to assess treatment- and recurrence-free survival. Cox proportional hazards regression analysis was performed to assess the risk of posttreatment recurrence. Results: Patients with systematic biopsy detected GG1 cancer had a significantly longer median time-to-treatment (31 months) than those with targeted biopsy detected GG2 cancer (4 months, p<0.0001). The risk of recurrence after curative treatment was similar between groups with the upper bound of 95% CI, excluding an important difference (HR: 0.94, 95% CI [0.71-1.25], p=0.7). Conclusion: GG2 cancers detected by MRI-targeted biopsy are treated more aggressively than GG1 cancers detected by systematic biopsy, despite having similar oncologic risk. To prevent further overtreatment related to the MRI pathway, treatment guidelines from the pre-MRI era need to be updated to consider changes in the diagnostic pathway.

Network controllability solutions for computational drug repurposing using genetic algorithms.

Control theory has seen recently impactful applications in network science, especially in connections with applications in network medicine. A key topic of research is that of finding minimal external interventions that offer control over the dynamics of a given network, a problem known as network controllability. We propose in this article a new solution for this problem based on genetic algorithms. We tailor our solution for applications in computational drug repurposing, seeking to maximize its use of FDA-approved drug targets in a given disease-specific protein-protein interaction network. We demonstrate our algorithm on several cancer networks and on several random networks with their edges distributed according to the Erdos-Rényi, the Scale-Free, and the Small World properties. Overall, we show that our new algorithm is more efficient in identifying relevant drug targets in a disease network, advancing the computational solutions needed for new therapeutic and drug repurposing approaches.

Network analytics for drug repurposing in COVID-19.

To better understand the potential of drug repurposing in COVID-19, we analyzed control strategies over essential host factors for SARS-CoV-2 infection. We constructed comprehensive directed protein-protein interaction (PPI) networks integrating the top-ranked host factors, the drug target proteins and directed PPI data. We analyzed the networks to identify drug targets and combinations thereof that offer efficient control over the host factors. We validated our findings against clinical studies data and bioinformatics studies. Our method offers a new insight into the molecular details of the disease and into potentially new therapy targets for it. Our approach for drug repurposing is significant beyond COVID-19 and may be applied also to other diseases.

NetControl4BioMed: a web-based platform for controllability analysis of protein-protein interaction networks.

MOTIVATION: There is an increasing amount of data coming from genome-wide studies identifying disease-specific survivability-essential proteins and host factors critical to a cell becoming infected. Targeting such proteins has a strong potential for targeted, precision therapies. Typically however, too few of them are drug targetable. An alternative approach is to influence them through drug targetable proteins upstream of them. Structural target network controllability is a suitable solution to this problem. It aims to discover suitable source nodes (e.g. drug targetable proteins) in a directed interaction network that can control (through a suitable set of input functions) a desired set of targets. RESULTS: We introduce NetControl4BioMed, a free open-source web-based application that allows users to generate or upload directed protein-protein interaction networks and to perform target structural network controllability analyses on them. The analyses can be customized to focus the search on drug targetable source nodes, thus providing drug therapeutic suggestions. The application integrates protein data from HGNC, Ensemble, UniProt, NCBI and InnateDB, directed interaction data from InnateDB, Omnipath and SIGNOR, cell-line data from COLT and DepMap, and drug-target data from DrugBank. AVAILABILITYAND IMPLEMENTATION: The application and data are available online at https://netcontrol.combio.org/. The source code is available at https://github.com/Vilksar/NetControl4BioMed under an MIT license.

NetControl4BioMed: a pipeline for biomedical data acquisition and analysis of network controllability.

BACKGROUND: Network controllability focuses on discovering combinations of external interventions that can drive a biological system to a desired configuration. In practice, this approach translates into finding a combined multi-drug therapy in order to induce a desired response from a cell; this can lead to developments of novel therapeutic approaches for systemic diseases like cancer. RESULT: We develop a novel bioinformatics data analysis pipeline called NetControl4BioMed based on the concept of target structural control of linear networks. Our pipeline generates novel molecular interaction networks by combining pathway data from various public databases starting from the user's query. The pipeline then identifies a set of nodes that is enough to control a given, user-defined set of disease-specific essential proteins in the network, i.e., it is able to induce a change in their configuration from any initial state to any final state. We provide both the source code of the pipeline as well as an online web-service based on this pipeline http://combio.abo.fi/nc/net_control/remote_call.php . CONCLUSION: The pipeline can be used by researchers for controlling and better understanding of molecular interaction networks through combinatorial multi-drug therapies, for more efficient therapeutic approaches and personalised medicine.

Structural Target Controllability of Linear Networks.

Computational analysis of the structure of intra-cellular molecular interaction networks can suggest novel therapeutic approaches for systemic diseases like cancer. Recent research in the area of network science has shown that network control theory can be a powerful tool in the understanding and manipulation of such bio-medical networks. In 2011, Liu et al. developed a polynomial time algorithm computing the size of the minimal set of nodes controlling a linear network. In 2014, Gao et al. generalized the problem for target control, minimizing the set of nodes controlling a target within a linear network. The authors developed a Greedy approximation algorithm while leaving open the complexity of the optimization problem. We prove here that the target controllability problem is NP-hard in all practical setups, i.e., when the control power of any individual input is bounded by some constant. We also show that the algorithm provided by Gao et al. fails to provide a valid solution in some special cases, and an additional validation step is required. We fix and improve their algorithm using several heuristics, obtaining in the end an up to 10-fold decrease in running time and also a decrease in the size of solutions.

Controlling Directed Protein Interaction Networks in Cancer.

Control theory is a well-established approach in network science, with applications in bio-medicine and cancer research. We build on recent results for structural controllability of directed networks, which identifies a set of driver nodes able to control an a-priori defined part of the network. We develop a novel and efficient approach for the (targeted) structural controllability of cancer networks and demonstrate it for the analysis of breast, pancreatic, and ovarian cancer. We build in each case a protein-protein interaction network and focus on the survivability-essential proteins specific to each cancer type. We show that these essential proteins are efficiently controllable from a relatively small computable set of driver nodes. Moreover, we adjust the method to find the driver nodes among FDA-approved drug-target nodes. We find that, while many of the drugs acting on the driver nodes are part of known cancer therapies, some of them are not used for the cancer types analyzed here; some drug-target driver nodes identified by our algorithms are not known to be used in any cancer therapy. Overall we show that a better understanding of the control dynamics of cancer through computational modelling can pave the way for new efficient therapeutic approaches and personalized medicine.

DNA rendering of polyhedral meshes at the nanoscale.

It was suggested more than thirty years ago that Watson-Crick base pairing might be used for the rational design of nanometre-scale structures from nucleic acids. Since then, and especially since the introduction of the origami technique, DNA nanotechnology has enabled increasingly more complex structures. But although general approaches for creating DNA origami polygonal meshes and design software are available, there are still important constraints arising from DNA geometry and sense/antisense pairing, necessitating some manual adjustment during the design process. Here we present a general method of folding arbitrary polygonal digital meshes in DNA that readily produces structures that would be very difficult to realize using previous approaches. The design process is highly automated, using a routeing algorithm based on graph theory and a relaxation simulation that traces scaffold strands through the target structures. Moreover, unlike conventional origami designs built from close-packed helices, our structures have a more open conformation with one helix per edge and are therefore stable under the ionic conditions usually used in biological assays.

The phosphorylation of the heat shock factor as a modulator for the heat shock response.

The heat shock response is a well-conserved defence mechanism against the accumulation of misfolded proteins due to prolonged elevated heat. The cell responds to heat shock by raising the levels of heat shock proteins (hsp), which are responsible for chaperoning protein refolding. The synthesis of hsp is highly regulated at the transcription level by specific heat shock (transcription) factors (hsf). One of the regulation mechanisms is the phosphorylation of hsf's. Experimental evidence shows a connection between the hyper-phosphorylation of hsfs and the transactivation of the hsp-encoding genes. In this paper, we incorporate several (de)phosphorylation pathways into an existing well-validated computational model of the heat shock response. We analyze the quantitative control of each of these pathways over the entire process. For each of these pathways we create detailed computational models which we subject to parameter estimation in order to fit them to existing experimental data. In particular, we find conclusive evidence supporting only one of the analyzed pathways. Also, we corroborate our results with a set of computational models of a more reduced size.

Quantitative analysis of the self-assembly strategies of intermediate filaments from tetrameric vimentin.

In vitro assembly of intermediate filaments from tetrameric vimentin consists of a very rapid phase of tetramers laterally associating into unit-length filaments and a slow phase of filament elongation. We focus in this paper on a systematic quantitative investigation of two molecular models for filament assembly, recently proposed in (Kirmse et al. J. Biol. Chem. 282, 52 (2007), 18563-18572), through mathematical modeling, model fitting, and model validation. We analyze the quantitative contribution of each filament elongation strategy: with tetramers, with unit-length filaments, with longer filaments, or combinations thereof. In each case, we discuss the numerical fitting of the model with respect to one set of data, and its separate validation with respect to a second, different set of data. We introduce a high-resolution model for vimentin filament self-assembly, able to capture the detailed dynamics of filaments of arbitrary length. This provides much more predictive power for the model, in comparison to previous models where only the mean length of all filaments in the solution could be analyzed. We show how kinetic observations on low-resolution models can be extrapolated to the high-resolution model and used for lowering its complexity.

Geometrical tile design for complex neighborhoods.

Recent research has showed that tile systems are one of the most suitable theoretical frameworks for the spatial study and modeling of self-assembly processes, such as the formation of DNA and protein oligomeric structures. A Wang tile is a unit square, with glues on its edges, attaching to other tiles and forming larger and larger structures. Although quite intuitive, the idea of glues placed on the edges of a tile is not always natural for simulating the interactions occurring in some real systems. For example, when considering protein self-assembly, the shape of a protein is the main determinant of its functions and its interactions with other proteins. Our goal is to use geometric tiles, i.e., square tiles with geometrical protrusions on their edges, for simulating tiled paths (zippers) with complex neighborhoods, by ribbons of geometric tiles with simple, local neighborhoods. This paper is a step toward solving the general case of an arbitrary neighborhood, by proposing geometric tile designs that solve the case of a "tall" von Neumann neighborhood, the case of the f-shaped neighborhood, and the case of a 3 x 5 "filled" rectangular neighborhood. The techniques can be combined and generalized to solve the problem in the case of any neighborhood, centered at the tile of reference, and included in a 3 x (2k + 1) rectangle.