• Antibodies inside of a cell can change its outside: Can intrabodies provide a new therapeutic paradigm?

      Marschall, Andrea L J; Dübel, Stefan; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2016)
      Challenges posed by complex diseases such as cancer, chronic viral infections, neurodegenerative disorders and many others have forced researchers to think beyond classic small molecule drugs, exploring new therapeutic strategies such as therapy with RNAi, CRISPR/Cas9 or antibody therapies as single or as combination therapies with existing drugs. While classic antibody therapies based on parenteral application can only reach extracellular targets, intracellular application of antibodies could provide specific advantages but is so far little recognized in translational research. Intrabodies allow high specificity and targeting of splice variants or post translational modifications. At the same time off target effects can be minimized by thorough biochemical characterization. Knockdown of cellular proteins by intrabodies has been reported for a significant number of disease-relevant targets, including ErbB-2, EGFR, VEGFR-2, Metalloproteinase MMP2 and MMP9, β-amyloid protein, α-synuclein, HIV gp120, HCV core and many others. This review outlines the recent advances in ER intrabody technology and their potential use in therapy.
    • The biology and mathematical modelling of glioma invasion: a review.

      Alfonso, J C L; Talkenberger, K; Seifert, M; Klink, B; Hawkins-Daarud, A; Swanson, K R; Hatzikirou, H; Deutsch, A; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2017-11)
      Adult gliomas are aggressive brain tumours associated with low patient survival rates and limited life expectancy. The most important hallmark of this type of tumour is its invasive behaviour, characterized by a markedly phenotypic plasticity, infiltrative tumour morphologies and the ability of malignant progression from low- to high-grade tumour types. Indeed, the widespread infiltration of healthy brain tissue by glioma cells is largely responsible for poor prognosis and the difficulty of finding curative therapies. Meanwhile, mathematical models have been established to analyse potential mechanisms of glioma invasion. In this review, we start with a brief introduction to current biological knowledge about glioma invasion, and then critically review and highlight future challenges for mathematical models of glioma invasion.
    • Cancer therapeutic potential of combinatorial immuno- and vasomodulatory interventions.

      Hatzikirou, H; Alfonso, J C L; Mühle, S; Stern, C; Weiss, S; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38124 Braunschweig, Germany. (2015-11-06)
      Currently, most of the basic mechanisms governing tumour-immune system interactions, in combination with modulations of tumour-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumour growth, where the main novelty is the modelling of the interplay between functional tumour vasculature and effector cell recruitment dynamics. Parameters are calibrated on the basis of different in vivo immunocompromised Rag1(-/-) and wild-type (WT) BALB/c murine tumour growth experiments. The model analysis supports that tumour vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immunostimulations. We find that improved levels of functional tumour vasculature, potentially mediated by normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumour burden reduction and growth control. Normalization of tumour blood vessels opens a therapeutic window of opportunity to augment the antitumour immune responses, as well as to reduce intratumoral immunosuppression and induced hypoxia due to vascular abnormalities. The potential success of normalizing tumour-associated vasculature closely depends on the effector cell recruitment dynamics and tumour sizes. Furthermore, an arbitrary increase in the initial effector cell concentration does not necessarily imply better tumour control. We evidence the existence of an optimal concentration range of effector cells for tumour shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immuno- and vasomodulatory interventions.
    • Cellular automaton models for time-correlated random walks: derivation and analysis.

      Nava-Sedeño, J M; Hatzikirou, H; Klages, R; Deutsch, A; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2017-12-05)
      Many diffusion processes in nature and society were found to be anomalous, in the sense of being fundamentally different from conventional Brownian motion. An important example is the migration of biological cells, which exhibits non-trivial temporal decay of velocity autocorrelation functions. This means that the corresponding dynamics is characterized by memory effects that slowly decay in time. Motivated by this we construct non-Markovian lattice-gas cellular automata models for moving agents with memory. For this purpose the reorientation probabilities are derived from velocity autocorrelation functions that are given a priori; in that respect our approach is "data-driven". Particular examples we consider are velocity correlations that decay exponentially or as power laws, where the latter functions generate anomalous diffusion. The computational efficiency of cellular automata combined with our analytical results paves the way to explore the relevance of memory and anomalous diffusion for the dynamics of interacting cell populations, like confluent cell monolayers and cell clustering.
    • Commentary: "Can Selective MHC Downregulation Explain the Specificity and Genetic Diversity of NK Cell Receptors?".

      Robert, Philippe A; Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. (2015)
    • Computational Study to Determine When to Initiate and Alternate Therapy in HIV Infection.

      Haering, Matthias; Hördt, Andreas; Meyer-Hermann, Michael; Hernandez-Vargas, Esteban A (2014)
      HIV is a widespread viral infection without cure. Drug treatment has transformed HIV disease into a treatable long-term infection. However, the appearance of mutations within the viral genome reduces the susceptibility of HIV to drugs. Therefore, a key goal is to extend the time until patients exhibit resistance to all existing drugs. Current HIV treatment guidelines seem poorly supported as practitioners have not achieved a consensus on the optimal time to initiate and to switch antiretroviral treatments. We contribute to this discussion with predictions derived from a mathematical model of HIV dynamics. Our results indicate that early therapy initiation (within 2 years postinfection) is critical to delay AIDS progression. For patients who have not received any therapy during the first 3 years postinfection, switch in response to virological failure may outperform proactive switching strategies. In case that proactive switching is opted, the switching time between therapies should not be larger than 100 days. Further clinical trials are needed to either confirm or falsify these predictions.
    • Deceleration of fusion-fission cycles improves mitochondrial quality control during aging.

      Figge, Marc Thilo; Reichert, Andreas S; Meyer-Hermann, Michael; Osiewacz, Heinz D; Applied Systems Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute and Friedrich Schiller University, Jena, Germany. (2012-06)
      Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the 'mitochondrial infectious damage adaptation' (MIDA) model according to which a deceleration of fusion-fission cycles reflects a systemic adaptation increasing life span.
    • Discrete-time neural observer for HIV infection dynamic

      Hernandez-Vargas, Esteban A.; Alanis, Alma Y.; Sanchez, Edgar N.; Systems Immunology, Helmholtz-Zentrum für Infecktionsforschung, Inhoffenstraße 7, D-38124, Braunschweig, Germany (Institute of Electrical and Electronics Engineers, 2013-04-19)
    • The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response.

      He, Jin-Shu; Meyer-Hermann, Michael; Xiangying, Deng; Zuan, Lim Yok; Jones, Leigh Ann; Ramakrishna, Lakshmi; de Vries, Victor C; Dolpady, Jayashree; Aina, Hoi; Joseph, Sabrina; Narayanan, Sriram; Subramaniam, Sharrada; Puthia, Manoj; Wong, Glenn; Xiong, Huizhong; Poidinger, Michael; Urban, Joseph F; Lafaille, Juan J; Curotto de Lafaille, Maria A; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7, 30625 Hannover, Germany. (2013-11-18)
      The mechanisms involved in the maintenance of memory IgE responses are poorly understood, and the role played by germinal center (GC) IgE(+) cells in memory responses is particularly unclear. IgE(+) B cell differentiation is characterized by a transient GC phase, a bias toward the plasma cell (PC) fate, and dependence on sequential switching for the production of high-affinity IgE. We show here that IgE(+) GC B cells are unfit to undergo the conventional GC differentiation program due to impaired B cell receptor function and increased apoptosis. IgE(+) GC cells fail to populate the GC light zone and are unable to contribute to the memory and long-lived PC compartments. Furthermore, we demonstrate that direct and sequential switching are linked to distinct B cell differentiation fates: direct switching generates IgE(+) GC cells, whereas sequential switching gives rise to IgE(+) PCs. We propose a comprehensive model for the generation and memory of IgE responses.
    • Diversity of coupled oscillators can enhance their synchronization.

      Montaseri, Ghazal; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2016-10)
      The heterogeneity of coupled oscillators is important for the degree of their synchronization. According to the classical Kuramoto model, larger heterogeneity reduces synchronization. Here, we show that in a model for coupled pancreatic β-cells, higher diversity of the cells induces higher synchrony. We find that any system of coupled oscillators that oscillates on two time scales and in which heterogeneity causes a transition from chaotic to damped oscillations on the fast time scale exhibits this property. Thus, synchronization of a subset of oscillating systems can be enhanced by increasing the heterogeneity of the system constituents.
    • Ebola virus infection modeling and identifiability problems.

      Nguyen, Van Kinh; Binder, Sebastian C; Boianelli, Alessandro; Meyer-Hermann, Michael; Hernandez-Vargas, Esteban A; Helmholtz Center for Infection Research (2015)
      The recent outbreaks of Ebola virus (EBOV) infections have underlined the impact of the virus as a major threat for human health. Due to the high biosafety classification of EBOV (level 4), basic research is very limited. Therefore, the development of new avenues of thinking to advance quantitative comprehension of the virus and its interaction with the host cells is urgently needed to tackle this lethal disease. Mathematical modeling of the EBOV dynamics can be instrumental to interpret Ebola infection kinetics on quantitative grounds. To the best of our knowledge, a mathematical modeling approach to unravel the interaction between EBOV and the host cells is still missing. In this paper, a mathematical model based on differential equations is used to represent the basic interactions between EBOV and wild-type Vero cells in vitro. Parameter sets that represent infectivity of pathogens are estimated for EBOV infection and compared with influenza virus infection kinetics. The average infecting time of wild-type Vero cells by EBOV is slower than in influenza infection. Simulation results suggest that the slow infecting time of EBOV could be compensated by its efficient replication. This study reveals several identifiability problems and what kind of experiments are necessary to advance the quantification of EBOV infection. A first mathematical approach of EBOV dynamics and the estimation of standard parameters in viral infections kinetics is the key contribution of this work, paving the way for future modeling works on EBOV infection.
    • Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas.

      Jain, Harsh Vardhan; Richardson, Alan; Meyer-Hermann, Michael; Byrne, Helen M (2014)
      Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics.
    • Functional modules of sigma factor regulons guarantee adaptability and evolvability.

      Binder, Sebastian C; Eckweiler, Denitsa; Schulz, Sebastian; Bielecka, Agata; Nicolai, Tanja; Franke, Raimo; Häussler, Susanne; Meyer-Hermann, Michael; Helmholtz Centre for infection research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany. (2016)
      The focus of modern molecular biology turns from assigning functions to individual genes towards understanding the expression and regulation of complex sets of molecules. Here, we provide evidence that alternative sigma factor regulons in the pathogen Pseudomonas aeruginosa largely represent insulated functional modules which provide a critical level of biological organization involved in general adaptation and survival processes. Analysis of the operational state of the sigma factor network revealed that transcription factors functionally couple the sigma factor regulons and significantly modulate the transcription levels in the face of challenging environments. The threshold quality of newly evolved transcription factors was reached faster and more robustly in in silico testing when the structural organization of sigma factor networks was taken into account. These results indicate that the modular structures of alternative sigma factor regulons provide P. aeruginosa with a robust framework to function adequately in its environment and at the same time facilitate evolutionary change. Our data support the view that widespread modularity guarantees robustness of biological networks and is a key driver of evolvability.
    • Immunology. Antigen feast or famine.

      Dustin, Michael L; Meyer-Hermann, Michael; Skirball Institute for Molecular Medicine, New York University School of Medicine, New York, NY 10016, USA. michael.dustin@med.nyu.edu (2012-01-27)
    • Implications of Intravital Imaging of Murine Germinal Centers on the Control of B Cell Selection and Division.

      Binder, Sebastian C; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2016)
      Intravital imaging of antibody optimization in germinal center (GC) reactions has set a new dimension in the understanding of the humoral immune response during the last decade. The inclusion of spatio-temporal cellular dynamics in the research on GCs required analysis using the agent-based mathematical models. In this study, we integrate the available intravital imaging data from various research groups and incorporate these into a quantitative mathematical model of GC reactions and antibody affinity maturation. Interestingly, the integration of data concerning the spatial organization of GCs and B cell motility allows to draw conclusions on the strength of the selection pressure and the control of B cell division by T follicular helper cells.
    • In silico analysis of cell cycle synchronisation effects in radiotherapy of tumour spheroids.

      Kempf, Harald; Hatzikirou, Haralampos; Bleicher, Marcus; Meyer-Hermann, Michael; Department of Systems Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany ; Frankfurt Institute for Advanced Studies, Frankfurt, Germany. (2013-11)
      Tumour cells show a varying susceptibility to radiation damage as a function of the current cell cycle phase. While this sensitivity is averaged out in an unperturbed tumour due to unsynchronised cell cycle progression, external stimuli such as radiation or drug doses can induce a resynchronisation of the cell cycle and consequently induce a collective development of radiosensitivity in tumours. Although this effect has been regularly described in experiments it is currently not exploited in clinical practice and thus a large potential for optimisation is missed. We present an agent-based model for three-dimensional tumour spheroid growth which has been combined with an irradiation damage and kinetics model. We predict the dynamic response of the overall tumour radiosensitivity to delivered radiation doses and describe corresponding time windows of increased or decreased radiation sensitivity. The degree of cell cycle resynchronisation in response to radiation delivery was identified as a main determinant of the transient periods of low and high radiosensitivity enhancement. A range of selected clinical fractionation schemes is examined and new triggered schedules are tested which aim to maximise the effect of the radiation-induced sensitivity enhancement. We find that the cell cycle resynchronisation can yield a strong increase in therapy effectiveness, if employed correctly. While the individual timing of sensitive periods will depend on the exact cell and radiation types, enhancement is a universal effect which is present in every tumour and accordingly should be the target of experimental investigation. Experimental observables which can be assessed non-invasively and with high spatio-temporal resolution have to be connected to the radiosensitivity enhancement in order to allow for a possible tumour-specific design of highly efficient treatment schedules based on induced cell cycle synchronisation.
    • In-silico insights on the prognostic potential of immune cell infiltration patterns in the breast lobular epithelium.

      Alfonso, J C L; Schaadt, N S; Schönmeyer, R; Brieu, N; Forestier, G; Wemmert, C; Feuerhake, F; Hatzikirou, H; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2016-10-12)
      Scattered inflammatory cells are commonly observed in mammary gland tissue, most likely in response to normal cell turnover by proliferation and apoptosis, or as part of immunosurveillance. In contrast, lymphocytic lobulitis (LLO) is a recurrent inflammation pattern, characterized by lymphoid cells infiltrating lobular structures, that has been associated with increased familial breast cancer risk and immune responses to clinically manifest cancer. The mechanisms and pathogenic implications related to the inflammatory microenvironment in breast tissue are still poorly understood. Currently, the definition of inflammation is mainly descriptive, not allowing a clear distinction of LLO from physiological immunological responses and its role in oncogenesis remains unclear. To gain insights into the prognostic potential of inflammation, we developed an agent-based model of immune and epithelial cell interactions in breast lobular epithelium. Physiological parameters were calibrated from breast tissue samples of women who underwent reduction mammoplasty due to orthopedic or cosmetic reasons. The model allowed to investigate the impact of menstrual cycle length and hormone status on inflammatory responses to cell turnover in the breast tissue. Our findings suggested that the immunological context, defined by the immune cell density, functional orientation and spatial distribution, contains prognostic information previously not captured by conventional diagnostic approaches.
    • Inoculation density and nutrient level determine the formation of mushroom-shaped structures in Pseudomonas aeruginosa biofilms.

      Ghanbari, Azadeh; Dehghany, Jaber; Schwebs, Timo; Müsken, Mathias; Häussler, Susanne; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2016-09-09)
      Pseudomonas aeruginosa often colonises immunocompromised patients and the lungs of cystic fibrosis patients. It exhibits resistance to many antibiotics by forming biofilms, which makes it hard to eliminate. P. aeruginosa biofilms form mushroom-shaped structures under certain circumstances. Bacterial motility and the environment affect the eventual mushroom morphology. This study provides an agent-based model for the bacterial dynamics and interactions influencing bacterial biofilm shape. Cell motility in the model relies on recently published experimental data. Our simulations show colony formation by immotile cells. Motile cells escape from a single colony by nutrient chemotaxis and hence no mushroom shape develops. A high number density of non-motile colonies leads to migration of motile cells onto the top of the colonies and formation of mushroom-shaped structures. This model proposes that the formation of mushroom-shaped structures can be predicted by parameters at the time of bacteria inoculation. Depending on nutrient levels and the initial number density of stalks, mushroom-shaped structures only form in a restricted regime. This opens the possibility of early manipulation of spatial pattern formation in bacterial colonies, using environmental factors.
    • In Vivo Killing Capacity of Cytotoxic T Cells Is Limited and Involves Dynamic Interactions and T Cell Cooperativity.

      Halle, Stephan; Keyser, Kirsten Anja; Stahl, Felix Rolf; Busche, Andreas; Marquardt, Anja; Zheng, Xiang; Galla, Melanie; Heissmeyer, Vigo; Heller, Katrin; Boelter, Jasmin; Wagner, Karen; Bischoff, Yvonne; Martens, Rieke; Braun, Asolina; Werth, Kathrin; Uvarovskii, Alexey; Kempf, Harald; Meyer-Hermann, Michael; Arens, Ramon; Kremer, Melanie; Sutter, Gerd; Messerle, Martin; Förster, Reinhold; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016-02-16)
      According to in vitro assays, T cells are thought to kill rapidly and efficiently, but the efficacy and dynamics of cytotoxic T lymphocyte (CTL)-mediated killing of virus-infected cells in vivo remains elusive. We used two-photon microscopy to quantify CTL-mediated killing in mice infected with herpesviruses or poxviruses. On average, one CTL killed 2-16 virus-infected cells per day as determined by real-time imaging and by mathematical modeling. In contrast, upon virus-induced MHC class I downmodulation, CTLs failed to destroy their targets. During killing, CTLs remained migratory and formed motile kinapses rather than static synapses with targets. Viruses encoding the calcium sensor GCaMP6s revealed strong heterogeneity in individual CTL functional capacity. Furthermore, the probability of death of infected cells increased for those contacted by more than two CTLs, indicative of CTL cooperation. Thus, direct visualization of CTLs during killing of virus-infected cells reveals crucial parameters of CD8(+) T cell immunity.
    • A mathematical model of immune activation with a unified self-nonself concept.

      Khailaie, Sahamoddin; Bahrami, Fariba; Janahmadi, Mahyar; Milanez-Almeida, Pedro; Huehn, Jochen; Meyer-Hermann, Michael (2013)
      The adaptive immune system reacts against pathogenic nonself, whereas it normally remains tolerant to self. The initiation of an immune response requires a critical antigen(Ag)-stimulation and a critical number of Ag-specific T cells. Autoreactive T cells are not completely deleted by thymic selection and partially present in the periphery of healthy individuals that respond in certain physiological conditions. A number of experimental and theoretical models are based on the concept that structural differences discriminate self from nonself. In this article, we establish a mathematical model for immune activation in which self and nonself are not distinguished. The model considers the dynamic interplay of conventional T cells, regulatory T cells (Tregs), and IL-2 molecules and shows that the renewal rate ratio of resting Tregs to naïve T cells as well as the proliferation rate of activated T cells determine the probability of immune stimulation. The actual initiation of an immune response, however, relies on the absolute renewal rate of naïve T cells. This result suggests that thymic selection reduces the probability of autoimmunity by increasing the Ag-stimulation threshold of self reaction which is established by selection of a low number of low-avidity autoreactive T cells balanced with a proper number of Tregs. The stability analysis of the ordinary differential equation model reveals three different possible immune reactions depending on critical levels of Ag-stimulation: a subcritical stimulation, a threshold stimulation inducing a proper immune response, and an overcritical stimulation leading to chronic co-existence of Ag and immune activity. The model exhibits oscillatory solutions in the case of persistent but moderate Ag-stimulation, while the system returns to the homeostatic state upon Ag clearance. In this unifying concept, self and nonself appear as a result of shifted Ag-stimulation thresholds which delineate these three regimes of immune activation.