Functional genomics and systems biology in human neuroscience.

Neuroscience research has entered a phase of key discoveries in the realm of neurogenomics owing to strong financial and intellectual support for resource building and tool development. The previous challenge of tissue heterogeneity has been met with the application of techniques that can profile individual cells at scale. Moreover, the ability to perturb genes, gene regulatory elements and neuronal activity in a cell-type-specific manner has been integrated with gene expression studies to uncover the functional underpinnings of the genome at a systems level. Although these insights have necessarily been grounded in model systems, we now have the opportunity to apply these approaches in humans and in human tissue, thanks to advances in human genetics, brain imaging and tissue collection. We acknowledge that there will probably always be limits to the extent to which we can apply the genomic tools developed in model systems to human neuroscience; however, as we describe in this Perspective, the neuroscience field is now primed with an optimal foundation for tackling this ambitious challenge. The application of systems-level network analyses to these datasets will facilitate a deeper appreciation of human neurogenomics that cannot otherwise be achieved from directly observable phenomena.

Building patient-specific models for receptor tyrosine kinase signaling networks.

Cancer progresses due to changes in the dynamic interactions of multidimensional factors associated with gene mutations. Cancer research has actively adopted computational methods, including data-driven and mathematical model-driven approaches, to identify causative factors and regulatory rules that can explain the complexity and diversity of cancers. A data-driven, statistics-based approach revealed correlations between gene alterations and clinical outcomes in many types of cancers. A model-driven mathematical approach has elucidated the dynamic features of cancer networks and identified the mechanisms of drug efficacy and resistance. More recently, machine learning methods have emerged that can be used for mining omics data and classifying patient. However, as the strengths and weaknesses of each method becoming apparent, new analytical tools are emerging to combine and improve the methodologies and maximize their predictive power for classifying cancer subtypes and prognosis. Here, we introduce recent advances in cancer systems biology aimed at personalized medicine, with focus on the receptor tyrosine kinase signaling network.

Editor Profile: Nektarios Tavernarakis.

In this special interview series, we profile members of The FEBS Journal editorial board to highlight their research focus, perspectives on the journal and future directions in their field. Nektarios Tavernarakis is Chairman of the Board of Directors at the Foundation for Research and Technology-Hellas (FORTH), and Professor of Molecular Systems Biology at the University of Crete Medical School, Greece. In 2020, he was elected Vice President of the European Research Council (ERC). He has served as Editorial Board Member of The FEBS Journal since 2018.

The ancillary effects of nanoparticles and their implications for nanomedicine.

Nanoparticles are often engineered as a scaffolding system to combine targeting, imaging and/or therapeutic moieties into a unitary agent. However, mostly overlooked, the nanomaterial itself interacts with biological systems exclusive of application-specific particle functionalization. This nanoparticle biointerface has been found to elicit specific biological effects, which we term 'ancillary effects'. In this Review, we describe the current state of knowledge of nanobiology gleaned from existing studies of ancillary effects with the objectives to describe the potential of nanoparticles to modulate biological effects independently of any engineered function; evaluate how these effects might be relevant for nanomedicine design and functional considerations, particularly how they might be useful to inform clinical decision-making; identify potential clinical harm that arises from adverse nanoparticle interactions with biology; and, finally, highlight the current lack of knowledge in this area as both a barrier and an incentive to the further development of nanomedicine.

Hypothesis of macroscopic quantum state in biological systems and discussion on the possibility of its experimental verification.

Earlier it was noted that the functioning of biological systems is accompanied by a very low level of energy dissipation, and it was assumed that a physical mechanism similar to that which works in superconductivity can operate here. The paper proposes a hypothesis that the phenomenon of life is not based on superconductivity, but on some so far unexplored macroscopic quantum state of organic structures making up the cell. It is assumed that this state is also characterized by the presence of an energy gap in the electronic spectrum, which makes the state stable and provides a low level of energy dissipation. The possibility of using optical spectroscopy methods for identifying the energy gap in biological objects is analyzed. It is assumed that the virus is alive inside the host cell, but not alive outside the host cell. It is proposed to use Raman spectroscopy of the process of bacterial infection with phages to search for the energy gap. This should confirm or refute the main hypothesis, as well as provide an opportunity to answer the question: "Are viruses alive?"

A Petri nets-based framework for whole-cell modeling.

Whole-cell modeling aims to incorporate all main genes and processes, and their interactions of a cell in one model. Whole-cell modeling has been regarded as the central aim of systems biology but also as a grand challenge, which plays essential roles in current and future systems biology. In this paper, we analyze whole-cell modeling challenges and requirements and classify them into three aspects (or dimensions): heterogeneous biochemical networks, uncertainties in components, and representation of cell structure. We then explore how to use different Petri net classes to address different aspects of whole-cell modeling requirements. Based on these analyses, we present a Petri nets-based framework for whole-cell modeling, which not only addresses many whole-cell modeling requirements, but also offers a graphical, modular, and hierarchical modeling tool. We think this framework can offer a feasible modeling approach for whole-cell model construction.

VANESA: An open-source hybrid functional Petri net modeling and simulation environment in systems biology.

Petri nets are a common method for modeling and simulation of systems biology application cases. Usually different Petri net concepts (e.g. discrete, hybrid, functional) are demanded depending on the purpose of the application cases. Modeling complex application cases requires a unification of those concepts, e.g. hybrid functional Petri nets (HFPN) and extended hybrid Petri nets (xHPN). Existing tools have certain limitations which motivated the extension of VANESA, an existing open-source editor for biological networks. The extension can be used to model, simulate, and visualize Petri nets based on the xHPN formalism. Moreover, it comprises additional functionality to support and help the user. Complex (kinetic) functions are syntactically analyzed and mathematically rendered. Based on syntax and given physical unit information, modeling errors are revealed. The numerical simulation is seamlessly integrated and executed in the background by the open-source simulation environment OpenModelica utilizing the Modelica library PNlib. Visualization of simulation results for places, transitions, and arcs are useful to investigate and understand the model and its dynamic behavior. The impact of single parameters can be revealed by comparing multiple simulation results. Simulation results, charts, and entire specification of the Petri net model as Latex file can be exported. All these features are shown in the demonstration case. The utilized Petri net formalism xHPN is fully specified and implemented in PNlib. This assures transparency, reliability, and comprehensible simulation results. Thus, the combination of VANESA and OpenModelica shape a unique open-source Petri net environment focusing on systems biology application cases. VANESA is available at: http://agbi.techfak.uni-bielefeld.de/vanesa.

The Trifecta of Single-Cell, Systems-Biology, and Machine-Learning Approaches.

Together, single-cell technologies and systems biology have been used to investigate previously unanswerable questions in biomedicine with unparalleled detail. Despite these advances, gaps in analytical capacity remain. Machine learning, which has revolutionized biomedical imaging analysis, drug discovery, and systems biology, is an ideal strategy to fill these gaps in single-cell studies. Machine learning additionally has proven to be remarkably synergistic with single-cell data because it remedies unique challenges while capitalizing on the positive aspects of single-cell data. In this review, we describe how systems-biology algorithms have layered machine learning with biological components to provide systems level analyses of single-cell omics data, thus elucidating complex biological mechanisms. Accordingly, we highlight the trifecta of single-cell, systems-biology, and machine-learning approaches and illustrate how this trifecta can significantly contribute to five key areas of scientific research: cell trajectory and identity, individualized medicine, pharmacology, spatial omics, and multi-omics. Given its success to date, the systems-biology, single-cell omics, and machine-learning trifecta has proven to be a potent combination that will further advance biomedical research.

The lower threshold as a unifying principle between Code Biology and Biosemiotics.

Whether we emphasize the notion of 'sign' or the notion of 'code', either way the main interest of biosemiotics and Code Biology is the same, and we argue that the idea of the lower threshold is what still unifies these two groups. Code Biology concentrates on the notion of code: living organisms are defined as code-users or code-makers, and so it may be called the 'lower coding threshold' in this case. The semiotic threshold on the other hand is a concept without a specific definition. There are many possible ways of understanding this term. In order to maintain the lower threshold as the unifying concept between Code Biology and biosemiotics, it is important to be very clear about where this threshold is located and how it is defined. We focus on establishing the lower semiotic threshold at protein biosynthesis, and we propose basing the semiotic understanding of the lowest life forms on the following criteria: arbitrariness, representation, repetition, historicity and self-replication. We also offer that this definition of the lower threshold need not include the notion of interpretation, in the hope that this newly specified common principle of the lower threshold be accepted as a way forward in the conversation between Code Biology and biosemiotics.

Code biology and the problem of emergence.

It should now be recognized that codes are central to life and to understanding its more complex forms, including human culture. Recognizing the 'conventional' nature of codes provides solid grounds for rejecting efforts to reduce life to biochemistry and justifies according a place to semantics in life. The question I want to consider is whether this is enough. Focussing on Eigen's paradox of how a complex code could originate, I will argue that along with Barbieri's efforts to account for the origins of life based on the ribosome and then to account for the refined codes through a process of ambiguity reduction, something more is required. Barbieri has not provided an adequate account of emergence, or the basis for providing such an account. I will argue that Stanley Salthe has clarified to some extent the nature of emergence by conceptualizing it as the interpolation of new enabling constraints. Clearly, codes can be seen as enabling constraints. How this actually happens, though, is still not explained. Stuart Kauffman has grappled with this issue and shown that it radically challenges the assumptions of mainstream science going back to Newton. He has attempted to reintroduce real possibilities or potentialities into his ontology, and argued that radically new developments in nature are associated with realizing adjacent possibles. This is still not adequate. What is also involved, I will suggest, utilizing concepts developed by the French natural philosopher Gilbert Simondon, is 'transduction' as part of 'ontogenesis' of individuals in a process of 'individuation', that is, the emergence of 'individuals' from preindividual fields or milieux.

Metacode: One code to rule them all.

The code of codes or metacode is a microcosm where biological layers, as well as their codes, interact together allowing the continuity of information flow in organisms by increasing biological entities' complexity. Through this novel organic code, biological systems scale towards niches with higher informatic freedom building structures that increase the entropy in the universe. Code biology has developed a novel informational framework where biological entities strive themselves through the information flow carried out through organic codes consisting of two molecular or functional landscapes intertwined through arbitrary linkages via an adaptor whose nature is autonomous from molecular determinism. Here we will integrate genomic and epigenomic codes according to the evidence released in ENCODE (phase 3), psychENCODE and GTEx project, outlining the principles of the metacode, to address the continuous nature of biological systems and their inter-layered information flow. This novel complex metacode maps from very constrained sets of elements (i.e., regulation sites modulating gene expression) to new ones with greater freedom of decoding (i.e., a continuous cell phenotypic space). This leads to a new domain in code biology where biological systems are informatic attractors that navigate an energy metaspace through a complexity-noise balance, stalling in emergent niches where organic codes take meaning.

Biological computation running on quantum computation.

Biological computation supporting biological phenomena functionally practices the underlying quantum computation indexically, rather than symbolically. An advantage of the indexical operation of quantum computation rests upon a significant reduction of the computational complexity compared with the corresponding classical counterpart running exclusively upon the symbol manipulation. The reduction of the complexity is sought in allowing for the participation of multiple processors running concurrently in a parallel manner. The concurrent distribution of multiple processors operating mutually in an inseparable manner lets each processor regard the rest of the distribution as its own environment. The environment thus formed and detected by each processor may differ from the similar ones appropriated to the other individual participants nearby. Both the individual processor and the corresponding environment turn out to be agential. Quantum computation practiced indexically may serve as a precursor agency apt for both forming Jakob von Uexküll's umwelt towards the environment and making use of James J. Gibson's affordance from the environment. The individual environment to each material participant there is already indexically agential in pulling that participant in.

A biochemically-realisable relational model of the self-manufacturing cell.

As shown by Hofmeyr, the processes in the living cell can be divided into three classes of efficient causes that produce each other, so making the cell closed to efficient causation, the hallmark of an organism. They are the enzyme catalysts of covalent metabolic chemistry, the intracellular milieu that drives the supramolecular processes of chaperone-assisted folding and self-assembly of polypeptides and nucleic acids into functional catalysts and transporters, and the membrane transporters that maintain the intracellular milieu, in particular its electrolyte composition. Each class of efficient cause can be modelled as a relational diagram in the form of a mapping in graph-theoretic form, and a minimal model of a self-manufacturing system that is closed to efficient causation can be constructed from these three mappings using the formalism of relational biology. This fabrication-assembly or (F,A)-system serves as an alternative to Robert Rosen's replicative metabolism-repair or (M,R)-system, which has been notoriously problematic to realise in terms of real biochemical processes. A key feature of the model is the explicit incorporation of formal cause, which arrests the infinite regress that plagues all relational models of the cell. The (F,A)-system is extended into a detailed relational model of the self-manufacturing cell that has a clear biochemical realisation. This (F,A) cell model allows the interpretation and visualisation of concepts such as the metabolism and repair components of Rosen's (M,R)-system, John von Neumann's universal constructor, Howard Pattee's symbol-function split via the symbol-folding transformation, Marcello Barbieri's genotype-ribotype-phenotype ontology, and Tibor Gánti's chemoton.

Incorporating Machine Learning into Established Bioinformatics Frameworks.

The exponential growth of biomedical data in recent years has urged the application of numerous machine learning techniques to address emerging problems in biology and clinical research. By enabling the automatic feature extraction, selection, and generation of predictive models, these methods can be used to efficiently study complex biological systems. Machine learning techniques are frequently integrated with bioinformatic methods, as well as curated databases and biological networks, to enhance training and validation, identify the best interpretable features, and enable feature and model investigation. Here, we review recently developed methods that incorporate machine learning within the same framework with techniques from molecular evolution, protein structure analysis, systems biology, and disease genomics. We outline the challenges posed for machine learning, and, in particular, deep learning in biomedicine, and suggest unique opportunities for machine learning techniques integrated with established bioinformatics approaches to overcome some of these challenges.

Model-based robustness and bistability analysis for methylation-based, epigenetic memory systems.

In recent years, epigenetic memory systems have been developed based on DNA methylation and positive feedback systems. Achieving a robust design for these systems is generally a challenging and multifactorial task. We developed and validated a novel mathematical model to describe methylation-based epigenetic memory systems that capture switching dynamics of methylation levels and methyltransferase amounts induced by different inputs. A bifurcation analysis shows that the system operates in the bistable range, but in its current setup is not robust to changes in parameters. An expansion of the model captures heterogeneity of cell populations by accounting for distributed cell division rates. Simulations predict that the system is highly sensitive to variations in temperature, which affects cell division and the efficiency of the zinc finger repressor. A moderate decrease in temperature leads to a highly heterogeneous response to input signals and bistability on a single-cell level. The predictions of our model were confirmed by flow cytometry experiments conducted in this study. Overall, the results of our study give insights into the functional mechanisms of methylation-based memory systems and demonstrate that the switching dynamics can be highly sensitive to experimental conditions.

Metabolomics: small molecules that matter more.

Metabolomics, an analytical study with high-throughput profiling, helps to understand interactions within a biological system. Small molecules, called metabolites or metabolomes with the size of <1500 Da, depict the status of a biological system in a different manner. Currently, we are in need to globally analyze the metabolome and the pathways involved in healthy, as well as diseased conditions, for possible therapeutic applications. Metabolome analysis has revealed high-abundance molecules during different conditions such as diet, environmental stress, microbiota, and disease and treatment states. As a result, it is hard to understand the complete and stable network of metabolites of a biological system. This review helps readers know the available techniques to study metabolomics in addition to other major omics such as genomics, transcriptomics, and proteomics. This review also discusses the metabolomics in various pathological conditions and the importance of metabolomics in therapeutic applications.

Systems Neuroscience of Natural Behaviors in Rodents.

Animals evolved in complex environments, producing a wide range of behaviors, including navigation, foraging, prey capture, and conspecific interactions, which vary over timescales ranging from milliseconds to days. Historically, these behaviors have been the focus of study for ecology and ethology, while systems neuroscience has largely focused on short timescale behaviors that can be repeated thousands of times and occur in highly artificial environments. Thanks to recent advances in machine learning, miniaturization, and computation, it is newly possible to study freely moving animals in more natural conditions while applying systems techniques: performing temporally specific perturbations, modeling behavioral strategies, and recording from large numbers of neurons while animals are freely moving. The authors of this review are a group of scientists with deep appreciation for the common aims of systems neuroscience, ecology, and ethology. We believe it is an extremely exciting time to be a neuroscientist, as we have an opportunity to grow as a field, to embrace interdisciplinary, open, collaborative research to provide new insights and allow researchers to link knowledge across disciplines, species, and scales. Here we discuss the origins of ethology, ecology, and systems neuroscience in the context of our own work and highlight how combining approaches across these fields has provided fresh insights into our research. We hope this review facilitates some of these interactions and alliances and helps us all do even better science, together.

Future avenues for Alzheimer's disease detection and therapy: liquid biopsy, intracellular signaling modulation, systems pharmacology drug discovery.

When Alzheimer's disease (AD) disease-modifying therapies will be available, global healthcare systems will be challenged by a large-scale demand for clinical and biological screening. Validation and qualification of globally accessible, minimally-invasive, and time-, cost-saving blood-based biomarkers need to be advanced. Novel pathophysiological mechanisms (and related candidate biomarkers) - including neuroinflammation pathways (TREM2 and YKL-40), axonal degeneration (neurofilament light chain protein), synaptic dysfunction (neurogranin, synaptotagmin, α-synuclein, and SNAP-25) - may be integrated into an expanding pathophysiological and biomarker matrix and, ultimately, integrated into a comprehensive blood-based liquid biopsy, aligned with the evolving ATN + classification system and the precision medicine paradigm. Liquid biopsy-based diagnostic and therapeutic algorithms are increasingly employed in Oncology disease-modifying therapies and medical practice, showing an enormous potential for AD and other brain diseases as well. For AD and other neurodegenerative diseases, newly identified aberrant molecular pathways have been identified as suitable therapeutic targets and are currently investigated by academia/industry-led R&D programs, including the nerve-growth factor pathway in basal forebrain cholinergic neurons, the sigma1 receptor, and the GTPases of the Rho family. Evidence for a clinical long-term effect on cognitive function and brain health span of cholinergic compounds, drug candidates for repositioning programs, and non-pharmacological multidomain interventions (nutrition, cognitive training, and physical activity) is developing as well. Ultimately, novel pharmacological paradigms, such as quantitative systems pharmacology-based integrative/explorative approaches, are gaining momentum to optimize drug discovery and accomplish effective pathway-based strategies for precision medicine. This article is part of the special issue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

Mouse Genetic Reference Populations: Cellular Platforms for Integrative Systems Genetics.

Interrogation of disease-relevant cellular and molecular traits exhibited by genetically diverse cell populations enables in vitro systems genetics approaches for uncovering the basic properties of cellular function and identity. Primary cells, stem cells, and organoids derived from genetically diverse mouse strains, such as Collaborative Cross and Diversity Outbred populations, offer the opportunity for parallel in vitro/in vivo screening. These panels provide genetic resolution for variant discovery and functional characterization, as well as disease modeling and in vivo validation capabilities. Here we review mouse cellular systems genetics approaches for characterizing the influence of genetic variation on signaling networks and phenotypic diversity, and we discuss approaches for data integration and cross-species validation.