References of "Balling, Rudi 50000566"
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See detailFrom Systems Biology to Systems Biomedicine
Antony, Paul UL; Balling, Rudi UL; Vlassis, Nikos UL

in Current Opinion in Biotechnology (2012), 23(4), 604-8

Systems Biology is about combining theory, technology, and targeted experiments in a way that drives not only data accumulation but knowledge as well. The challenge in Systems Biomedicine is to ... [more ▼]

Systems Biology is about combining theory, technology, and targeted experiments in a way that drives not only data accumulation but knowledge as well. The challenge in Systems Biomedicine is to furthermore translate mechanistic insights in biological systems to clinical application, with the central aim of improving patients’ quality of life. The challenge is to find theoretically well-chosen models for the contextually correct and intelligible representation of multiscale biological systems. In this review, we discuss the current state of Systems Biology, highlight the emergence of Systems Biomedicine, and highlight some of the topics and views that we think are important for the efficient application of Systems Theory in Biomedicine. [less ▲]

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See detailUnderstanding complexity in neurodegenerative diseases: in silico reconstruction of emergence.
Kolodkin, Alexey UL; Simeonidis, Evangelos UL; Balling, Rudi UL et al

in Frontiers in Physiology (2012), 3

Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction) is also an emergent ... [more ▼]

Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction) is also an emergent property, emerging from a perturbation of the network. On the one hand, the biomolecular network of every individual is unique and this is evident when similar disease-producing agents cause different individual pathologies. Consequently, a personalized model and approach for every patient may be required for therapies to become effective across mankind. On the other hand, diverse combinations of internal and external perturbation factors may cause a similar shift in network functioning. We offer this as an explanation for the multi-factorial nature of most diseases: they are "systems biology diseases," or "network diseases." Here we use neurodegenerative diseases, like Parkinson's disease (PD), as an example to show that due to the inherent complexity of these networks, it is difficult to understand multi-factorial diseases with simply our "naked brain." When describing interactions between biomolecules through mathematical equations and integrating those equations into a mathematical model, we try to reconstruct the emergent properties of the system in silico. The reconstruction of emergence from interactions between huge numbers of macromolecules is one of the aims of systems biology. Systems biology approaches enable us to break through the limitation of the human brain to perceive the extraordinarily large number of interactions, but this also means that we delegate the understanding of reality to the computer. We no longer recognize all those essences in the system's design crucial for important physiological behavior (the so-called "design principles" of the system). In this paper we review evidence that by using more abstract approaches and by experimenting in silico, one may still be able to discover and understand the design principles that govern behavioral emergence. [less ▲]

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See detailPLAU inferred from a correlation network is critical for suppressor function of regulatory T cells.
He, Feng UL; Chen, Hairong; Probst-Kepper, Michael et al

in Molecular Systems Biology (2012), 8

Human FOXP3(+)CD25(+)CD4(+) regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and ... [more ▼]

Human FOXP3(+)CD25(+)CD4(+) regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. Here, we describe a strategy to identify the key genes directly from an undirected correlation network which we reconstruct from a very high time-resolution (HTR) transcriptome during the activation of human Tregs/CD4(+) T-effector cells. We show that a predicted top-ranked new key gene PLAU (the plasminogen activator urokinase) is important for the suppressor function of both human and murine Tregs. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study demonstrates the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on HTR data, and reveals a critical role for PLAU in Treg suppressor function. [less ▲]

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See detailEmergence of the silicon human and network targeting drugs
Kolodkin, Alexey UL; Boogerda, Fred C.; Plantb, Nick et al

in European Journal of Pharmaceutical Sciences (2012), 46(4), 190-197

The development of disease may be characterized as a pathological shift of homeostasis; the main goal of contemporary drug treatment is, therefore, to return the pathological homeostasis back to the ... [more ▼]

The development of disease may be characterized as a pathological shift of homeostasis; the main goal of contemporary drug treatment is, therefore, to return the pathological homeostasis back to the normal physiological range. From the view point of systems biology, homeostasis emerges from the interactions within the network of biomolecules (e.g. DNA, mRNA, proteins), and, hence, understanding how drugs impact upon the entire network should improve their efficacy at returning the network (body) to physiological homeostasis. Large, mechanism-based computer models, such as the anticipated human whole body models (silicon or virtual human), may help in the development of such network-targeting drugs. Using the philosophical concept of weak and strong emergence, we shall here take a more general look at the paradigm of network-targeting drugs, and propose our approaches to scale the strength of strong emergence. We apply these approaches to several biological examples and demonstrate their utility to reveal principles of bio-modeling. We discuss this in the perspective of building the silicon human. [less ▲]

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See detailAnalysis of critical transitions in Parkinson's disease
Trefois, Christophe UL; Antony, Paul UL; Baumuratov, Aidos UL et al

Poster (2011, December 12)

Background Parkinson’s disease is the most common neurodegenerative movement disorder and is clinically characterized by resting tremor, bradykinesia and cogwheel rigidity. The disease affects 1-2% of the ... [more ▼]

Background Parkinson’s disease is the most common neurodegenerative movement disorder and is clinically characterized by resting tremor, bradykinesia and cogwheel rigidity. The disease affects 1-2% of the global population with prevalence in the people above 65 years of age. The main pathological hallmark of Parkinson’s disease is a progressive loss of dopaminergic neurons in the substantia nigra. Therefore, one important challenge is to improve the understanding of regime shifts between health and disease states. Improving predictions of critical transitions triggering the onset of parkinsonian phenotypes could contribute to the improvement of preventive treatments. Methods Based on cellular models, we will use the mathematical concept of critical transitions to create a toolbox for potentially predicting tipping points towards cellular Parkinson’s disease phenotypes, e.g. mitochondrial dysfunction. Experimentally, we will induce and analyze potential critical transitions in the SH-SY5Y cell line. To do this, we will apply Parkinson’s disease relevant chemical and genetic perturbations and analyze multiple scales of the resulting temporal system behavior. We will combine high content imaging with genetic and biochemical data. A significant informatics challenge arises from the aim to perform the analysis of high time-resolved 3D imaging data. We are therefore developing an automated image analysis pipeline that relies on latest technologies and techniques, such as 3D deconvolution and 3D particle tracking. This pipeline will be applied to study parameters, such as mitochondrial dynamics, which include for instance velocity, morphology, and spatial organization. [less ▲]

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See detailCandidate mutations for early-onset lung cancer by family genome sequencing
Simeonidis, Vangelis UL; Roach, Jared; Brunkow, Mary et al

Poster (2011, July)

Early-onset lung cancer has been studied as a rare, but distinct, sub-type of lung cancer. Genome-wide association studies (GWAS) have linked several genes with this form of malignancy. We sequenced the ... [more ▼]

Early-onset lung cancer has been studied as a rare, but distinct, sub-type of lung cancer. Genome-wide association studies (GWAS) have linked several genes with this form of malignancy. We sequenced the genomes of a family quartet in which one of the offspring was diagnosed with early-onset lung cancer at about 48 years of age. The family has a history of heavy smoking and the father had in the past been diagnosed with head and neck cancer. The DNA source was blood, which leads us to concentrate our analysis on Mendelian inheritance models. To make the inheritance pattern explicit, we establish the parental origin of the offspring’s genomes through phasing of their chromosomes. This helps identify whether mutations in the proband came from the father or the mother. More than 18 million sequence variants were initially identified in the proband through comparison to the hg19 reference genome. We reduce this list to fewer than 200 potentially functional variants (e.g. single nucleotide variations and short indels) present in the genomes of the proband and at least one parent, by applying a series of filters. We refine the list of candidate mutations further by comparison to gene candidates from GWAS studies and genes that are mutated in lung cancer tissue as recorded by The Cancer Genome Atlas. The results of our analysis are discussed and conclusions about possible causative mutations for early-onset lung cancer are drawn. [less ▲]

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See detailParkinson’s disease mouse models in translational research
Antony, Paul UL; Diederich, Nico UL; Balling, Rudi UL

in Mammalian Genome : Official Journal of the International Mammalian Genome Society (2011), 22(7-8), 401-19

Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson's disease (PD), the higher is the predictive value for clinical ... [more ▼]

Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson's disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to address all PD-related questions, is yet to be developed. However, many of the existing models are useful in answering specific questions. An appropriate model should be chosen after considering both the context of the research and the model properties. This review addresses the validity, strengths, and limitations of current PD mouse models for translational research. [less ▲]

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See detail4D Biology for health and disease
Abrahams, J. P.; Apweiler, R.; Balling, Rudi UL et al

in New Biotechnology (2011), 28(4), 291-293

The "4D Biology Workshop for Health and Disease", held on 16-17th of March 2010 in Brussels, aimed at finding the best organising principles for large-scale proteomics, interactomics and structural ... [more ▼]

The "4D Biology Workshop for Health and Disease", held on 16-17th of March 2010 in Brussels, aimed at finding the best organising principles for large-scale proteomics, interactomics and structural genomics/biology initiatives, and setting the vision for future high-throughput research and large-scale data gathering in biological and medical science. Major conclusions of the workshop include the following. (i) Development of new technologies and approaches to data analysis is crucial. Biophysical methods should be developed that span a broad range of time/spatial resolution and characterise structures and kinetics of interactions. Mathematics, physics, computational and engineering tools need to be used more in biology and new tools need to be developed. (ii) Database efforts need to focus on improved definitions of ontologies and standards so that system-scale data and associated metadata can be understood and shared efficiently. (iii) Research infrastructures should play a key role in fostering multidisciplinary research, maximising knowledge exchange between disciplines and facilitating access to diverse technologies. (iv) Understanding disease on a molecular level is crucial. System approaches may represent a new paradigm in the search for biomarkers and new targets in human disease. (v) Appropriate education and training should be provided to help efficient exchange of knowledge between theoreticians, experimental biologists and clinicians. These conclusions provide a strong basis for creating major possibilities in advancing research and clinical applications towards personalised medicine. [less ▲]

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See detailSystems medicine and integrated care to combat chronic noncommunicable diseases
Bousquet, J.; Anto, J. M.; Sterk, P. J. et al

in Genome Medicine (2011), 3(7), 43-47

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic ... [more ▼]

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems. [less ▲]

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See detailFighting the Diseases of the Future
Balling, Rudi UL

in Our Common Future Conference Summary Report (2011)

Infectious disease is one of the greatest threats facing the world in the decades to come: unpredictable, fast-moving, difficult to track, and potentially more deadly than anything we’ve ever seen before ... [more ▼]

Infectious disease is one of the greatest threats facing the world in the decades to come: unpredictable, fast-moving, difficult to track, and potentially more deadly than anything we’ve ever seen before. Rudi Balling, a German geneticist and director of the Luxembourg Centre for Systems Biomedicine, says the solutions to the epidemics of the future are cooperation be- tween scientists and a holistic approach to biology that accounts for the complexities of today’s world. [less ▲]

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See detailEATRIS Infrastructure Accelerates Translation
Balling, Rudi UL; Becker, Regina UL

in BIOforum Europe (2010), (1-2), 14-16

Efficient translation of research discoveries into clinical application is essential to improve human health and maintain Europe’s competitiveness in biomedical research and in health industry. A major ... [more ▼]

Efficient translation of research discoveries into clinical application is essential to improve human health and maintain Europe’s competitiveness in biomedical research and in health industry. A major bottleneck is the lack and the frag- mented nature of research infrastructure and know-how, leading to unacceptable delays or preventing of the development of new innovative medicines. The aim of EATRIS, European Advanced Translational Research InfraStructure in Medicine, is to fill this gap by developing a pan-European research infrastructure. [less ▲]

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See detailA non-functioning vitamin D receptor predisposes to leukaemoid reactions in mice
Erben, R. G.; Zeitz, U.; Weber, K. et al

in Hematological Oncology (2010), 28(4), 185-191

The vitamin D hormone 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the biologically active form of vitamin D, is not only essential for mineral metabolism but may have important functions beyond calcium ... [more ▼]

The vitamin D hormone 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the biologically active form of vitamin D, is not only essential for mineral metabolism but may have important functions beyond calcium homoeostasis. By gene targeting, we have recently generated mice expressing a functionally inactive mutant vitamin D receptor (VDR). After a change in environmental conditions from specific pathogen free (SPF) conditions to a modified barrier system, a high percentage of aged mutant, but not wild-type, mice developed a haematological disorder characterized by splenomegaly, granulocytosis, thrombocytosis and dysplastic changes with displacement of erythropoiesis in bone marrow during the following months. All cases were associated with very high serum levels of the acute phase reaction protein serum amyloid A (SAA). Serological testing of affected mice revealed antibodies against murine hepatitis virus (MHV). However, electron microscopy of spleen and bone marrow cells did not reveal virus particles, and clinical signs of infectious diseases were absent. We hypothesize that a non-functioning VDR is associated with a latent defect in the regulation of myeloid cell differentiation and proliferation. Under the conditions of environmental stress, this latent defect may predispose to a deregulation of myelopoiesis in the form of a leukaemoid reaction accompanied by dysplastic changes. Thus, 1,25(OH)(2)D(3) may be an important inhibitory factor in the onset and progression of myeloproliferative and myelodysplastic diseases [less ▲]

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See detailFinding and sharing: new approaches to registries of databases and services for the biomedical sciences
Smedley, D.; Schofield, P.; Chen, C. K. et al

in Database: the Journal of Biological Databases and Curation (2010), Jul 6

The recent explosion of biological data and the concomitant proliferation of distributed databases make it challenging for biologists and bioinformaticians to discover the best data resources for their ... [more ▼]

The recent explosion of biological data and the concomitant proliferation of distributed databases make it challenging for biologists and bioinformaticians to discover the best data resources for their needs, and the most efficient way to access and use them. Despite a rapid acceleration in uptake of syntactic and semantic standards for interoperability, it is still difficult for users to find which databases support the standards and interfaces that they need. To solve these problems, several groups are developing registries of databases that capture key metadata describing the biological scope, utility, accessibility, ease-of-use and existence of web services allowing interoperability between resources. Here, we describe some of these initiatives including a novel formalism, the Database Description Framework, for describing database operations and functionality and encouraging good database practise. We expect such approaches will result in improved discovery, uptake and utilization of data resources. Database URL: http://www.casimir.org.uk/casimir_ddf. [less ▲]

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See detailSYSGENET: a meeting report from a new European network for systems genetics
Schughart, K.; Arends, D.; Andreux, P. et al

in Mammalian Genome : Official Journal of the International Mammalian Genome Society (2010), 21(7-8), 331-6

The first scientific meeting of the newly established European SYSGENET network took place at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, April 7-9, 2010. About 50 researchers ... [more ▼]

The first scientific meeting of the newly established European SYSGENET network took place at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, April 7-9, 2010. About 50 researchers working in the field of systems genetics using mouse genetic reference populations (GRP) participated in the meeting and exchanged their results, phenotyping approaches, and data analysis tools for studying systems genetics. In addition, the future of GRP resources and phenotyping in Europe was discussed. [less ▲]

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See detailEuroPhenome: a repository for high-throughput mouse phenotyping data
Morgan, Hugh; Beck, Tim; Blake, Andrew et al

in Nucleic Acids Research (2010), 38(1), 577-585

The broad aim of biomedical science in the postgenomic era is to link genomic and phenotype information to allow deeper understanding of the processes leading from genomic changes to altered phenotype and ... [more ▼]

The broad aim of biomedical science in the postgenomic era is to link genomic and phenotype information to allow deeper understanding of the processes leading from genomic changes to altered phenotype and disease. The EuroPhenome project (http://www.EuroPhenome.org) is a comprehensive resource for raw and annotated highthroughput phenotyping data arising from projects such as EUMODIC. EUMODIC is gathering data from the EMPReSSslim pipeline (http://www.empress .har.mrc.ac.uk/) which is performed on inbred mouse strains and knock-out lines arising from the EUCOMM project. The EuroPhenome interface allows the user to access the data via the phenotype or genotype. It also allows the user to access the data in a variety of ways, including graphical display, statistical analysis and access to the raw data via web services. The raw phenotyping data captured in EuroPhenome is annotated by an annotation pipeline which automatically identifies statistically different mutants from the appropriate baseline and assigns ontology terms for that specific test. Mutant phenotypes can be quickly identified using two EuroPhenome tools: PhenoMap, a graphical representation of statistically relevant phenotypes, and mining for a mutant using ontology terms. To assist with data definition and cross-database comparisons, phenotype data is annotated using combinations of terms from biological ontologies. [less ▲]

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See detailDiseases as network perturbations
del Sol Mesa, Antonio UL; Balling, Rudi UL; Hood, Leroy UL et al

in Current Opinion in Biotechnology (2010), 21(4), 566-571

The tremendous amount of the data obtained from the study of complex biological systems changes our view on the pathogenesis of human diseases. Instead of looking at individual components of biological ... [more ▼]

The tremendous amount of the data obtained from the study of complex biological systems changes our view on the pathogenesis of human diseases. Instead of looking at individual components of biological processes, we focus our attention more on the interaction and dynamics of biological systems. A network representation and analysis of the physiology and pathophysiology of biological systems is an effective way to study their complex behavior. Specific perturbations can trigger cascades of failures, which lead to the malfunctioning of cellular networks and as a result to the development of specific diseases. In this review we discuss recent developments in the field of disease network analysis and highlight some of the topics and views that we think are important for understanding network-based disease mechanisms. [less ▲]

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See detailFOXP3: required but not sufficient. the role of GARP (LRRC32) as a safeguard of the regulatory phenotype.
Probst-Kepper, M.; Balling, Rudi UL; Buer, J.

in Current Molecular Medicine (2010), 10(6), 533-539

FOXP3 is essential for the development and function of regulatory CD4(+)CD25(hi) T (T(reg)) cells. However, recent evidence suggests that FOXP3 alone is not sufficient to completely explain the regulatory ... [more ▼]

FOXP3 is essential for the development and function of regulatory CD4(+)CD25(hi) T (T(reg)) cells. However, recent evidence suggests that FOXP3 alone is not sufficient to completely explain the regulatory phenotype of these key players in autoimmunity and inflammation: after being activated, conventional human CD4(+) T cells transiently up-regulate FOXP3 without acquiring a regulatory function. Researchers have recently found that glycoprotein A repetitions predominant (GARP, or LRRC32) is a T(reg)-specific receptor that binds latent TGF-beta and dominantly controls FOXP3 and the regulatory phenotype via a positive feedback loop. This finding provides a missing link in our molecular understanding of FOXP3 in T(reg) cells. This viewpoint focuses on GARP as safeguard of FOXP3 and the regulatory phenotype [less ▲]

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See detailThe bumpy road to personalized healthcare.
Phillips, R. A.; Balling, Rudi UL

in European Biotechnology Science & Industry News (2010), 9(7-8),

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See detailHumanized mice for modeling human infectious disease: challenges, progress, and outlook.
Legrand, Nicolas; Ploss, Alexander; Balling, Rudi UL et al

in Cell Host & Microbe (2009), 6(1), 5-9

Over 800 million people worldwide are infected with hepatitis viruses, human immunodeficiency virus (HIV), and malaria, resulting in more than 5 million deaths annually. Here we discuss the potential and ... [more ▼]

Over 800 million people worldwide are infected with hepatitis viruses, human immunodeficiency virus (HIV), and malaria, resulting in more than 5 million deaths annually. Here we discuss the potential and challenges of humanized mouse models for developing effective and affordable therapies and vaccines, which are desperately needed to combat these diseases. [less ▲]

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See detailReverse engineering and verification of gene networks: principles, assumptions, and limitations of present methods and future perspectives.
He, Feng UL; Balling, Rudi UL; Zeng, An-Ping

in Journal of Biotechnology (2009), 144(3), 190-203

Reverse engineering of gene networks aims at revealing the structure of the gene regulation network in a biological system by reasoning backward directly from experimental data. Many methods have recently ... [more ▼]

Reverse engineering of gene networks aims at revealing the structure of the gene regulation network in a biological system by reasoning backward directly from experimental data. Many methods have recently been proposed for reverse engineering of gene networks by using gene transcript expression data measured by microarray. Whereas the potentials of the methods have been well demonstrated, the assumptions and limitations behind them are often not clearly stated or not well understood. In this review, we first briefly explain the principles of the major methods, identify the assumptions behind them and pinpoint the limitations and possible pitfalls in applying them to real biological questions. With regard to applications, we then discuss challenges in the experimental verification of gene networks generated from reverse engineering methods. We further propose an optimal experimental design for allocating sampling schedule and possible strategies for reducing the limitations of some of the current reverse engineering methods. Finally, we examine the perspectives for the development of reverse engineering and urge the need to move from revealing network structure to the dynamics of biological systems. [less ▲]

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