dr hab. Michał Komorowski 

Doktorat
20091130  Statistical methods for estimation of biochemical kinetic parameters (DS,UW)
 1242 
Habilitacja
20181023  Rozwój metod analizy stochastycznych modeli reakcji biochemicznych 
Ostatnie publikacje
1.  Komorowski M., Tawfik D.S.^{♦}, The Limited Information Capacity of CrossReactive Sensors Drives the Evolutionary Expansion of Signaling, Cell Systems, ISSN: 24054712, DOI: 10.1016/j.cels.2018.12.006, Vol.8, No.1, pp.7685.e6, 2019 Streszczenie: Signaling systems expand by duplications of various components, be it receptors or downstream effectors. However, whether and how duplicated components contribute to higher signaling capacity is unclear, especially because in most cases, their specificities overlap. Using information theory, we found that augmentation of capacity by an increase in the copy number is strongly limited by logarithmic diminishing returns. Moreover, counter to conventional biochemical wisdom, refinements of the response mechanism, e.g., by cooperativity or allostery, do not increase the overall signaling capacity. However, signaling capacity nearly doubles when a promiscuous, noncognate ligand becomes explicitly recognized via duplication and partial divergence of signaling components. Our findings suggest that expansion of signaling components via duplication and enlistment of promiscuously acting cues is virtually the only accessible evolutionary strategy to achieve overall highsignaling capacity despite overlapping specificities and molecular noise. This mode of expansion also explains the highly crosswired architecture of signaling pathways. Słowa kluczowe: paralog expansion, gene duplication, allostery, cooperativity, biochemical signal processing, information capacity Afiliacje autorów:
 200p.  
2.  Jetka T., Nienałtowski K., Winarski T., Błoński S., Komorowski M., Informationtheoretic analysis of multivariate singlecell signaling responses, PLOS COMPUTATIONAL BIOLOGY, ISSN: 15537358, DOI: 10.1371/journal.pcbi.1007132, Vol.15, No.7, pp.e1007132123, 2019 Streszczenie: Mathematical methods of information theory appear to provide a useful language to describe how stimuli are encoded in activities of signaling effectors. Exploring the informationtheoretic perspective, however, remains conceptually, experimentally and computationally challenging. Specifically, existing computational tools enable efficient analysis of relatively simple systems, usually with one input and output only. Moreover, their robust and readily applicable implementations are missing. Here, we propose a novel algorithm, SLEMI—statistical learning based estimation of mutual information, to analyze signaling systems with highdimensional outputs and a large number of input values. Our approach is efficient in terms of computational time as well as sample size needed for accurate estimation. Analysis of the NFκB single—cell signaling responses to TNFα reveals that NFκB signaling dynamics improves discrimination of high concentrations of TNFα with a relatively modest impact on discrimination of low concentrations. Provided Rpackage allows the approach to be used by computational biologists with only elementary knowledge of information theory. Afiliacje autorów:
 140p.  
3.  Billing U.^{♦}, Jetka T., Nortmann L.^{♦}, Wundrack N.^{♦}, Komorowski M., Waldherr S.^{♦}, Schaper F.^{♦}, Dittrich A.^{♦}, Robustness and Information Transfer within IL6induced JAK/STAT Signalling, Communications Biology, ISSN: 23993642, DOI: 10.1038/s4200301802594, Vol.2, No.27, pp.114, 2019 Streszczenie: Cellular communication via intracellular signalling pathways is crucial. Expression and activation of signalling proteins is heterogenous between isogenic cells of the same celltype. However, mechanisms evolved to enable sufficient communication and to ensure cellular functions. We use information theory to clarify mechanisms facilitating IL6induced JAK/STAT signalling despite celltocell variability. We show that different mechanisms enabling robustness against variability complement each other. Early STAT3 activation is robust as long as cytokine concentrations are low. Robustness at high cytokine concentrations is ensured by high STAT3 expression or serine phosphorylation. Later the feedbackinhibitor SOCS3 increases robustness. Channel Capacity of JAK/STAT signalling is limited by celltocell variability in STAT3 expression and is affected by the same mechanisms governing robustness. Increasing STAT3 amount increases Channel Capacity and robustness, whereas increasing STAT3 tyrosine phosphorylation reduces robustness but increases Channel Capacity. In summary, we elucidate mechanisms preventing dysregulated signalling by enabling reliable JAK/STAT signalling despite celltocell heterogeneity. Afiliacje autorów:
 
4.  Jetka T., Nienałtowski K., Filippi S.^{♦}, Stumpf M.P.H.^{♦}, Komorowski M., An informationtheoretic framework for deciphering pleiotropic and noisy biochemical signaling, Nature Communications, ISSN: 20411723, DOI: 10.1038/s41467018070851, Vol.9, pp.459119, 2018 Streszczenie: Many components of signaling pathways are functionally pleiotropic, and signaling responses are marked with substantial celltocell heterogeneity. Therefore, biochemical descriptions of signaling require quantitative support to explain how complex stimuli (inputs) are encoded in distinct activities of pathways effectors (outputs). A unique perspective of information theory cannot be fully utilized due to lack of modeling tools that account for the complexity of biochemical signaling, specifically for multiple inputs and outputs. Here, we develop a modeling framework of information theory that allows for efficient analysis of models with multiple inputs and outputs; accounts for temporal dynamics of signaling; enables analysis of how signals flow through shared network components; and is not restricted by limited variability of responses. The framework allows us to explain how identity and quantity of type I and type III interferon variants could be recognized by cells despite activating the same signaling effectors. Afiliacje autorów:
 45p.  
5.  Martincuks A.^{♦}, Andryka K., Küster A.^{♦}, SchmitzVan de Leur H.^{♦}, Komorowski M., MüllerNewen G.^{♦}, Nuclear translocation of STAT3 and NFκB are independent of each other but NFκB supports expression and activation of STAT3, Cellular Signalling, ISSN: 08986568, DOI: 10.1016/j.cellsig.2017.01.006, Vol.32, pp.3647, 2017 Streszczenie: NFκB and STAT3 are essential transcription factors in immunity and act at the interface of the transition from chronic inflammation to cancer. Different functional crosstalks between NFκB and STAT3 have been recently described arguing for a direct interaction of both proteins. During a systematic analysis of NFκB/STAT3 crosstalk we observed that appearance of the subcellular distribution of NFκB and STAT3 in immunofluorescence heavily depends on the fixation procedure. Therefore, we established an optimized fixation protocol for the reliable simultaneous analysis of the subcellular distributions of both transcription factors. Using this protocol we found that cytokineinduced nuclear accumulation of NFκB or STAT3 did not alter the subcellular distribution of the other transcription factor. Both knockout and overexpression of STAT3 does not have any major effect on canonical TNFαNFκB signalling in MEF or HeLa cells. Similarly, knockout of p65 did not alter nuclear accumulation of STAT3 in response to IL6. However, p65 expression correlates with elevated total cellular levels of STAT3 and STAT1 and supports activation of these transcription factors. Our findings in MEF cells argue against a direct physical interaction of free cellular NFκB and STAT3 but point to more intricate functional interactions. Słowa kluczowe: STAT3, NFκB, Signal transduction, Nuclear translocation, Crosstalk Afiliacje autorów:
 30p.  
6.  Nienałtowski K., Włodarczyk M.^{♦}, Lipniacki T., Komorowski M., Clustering reveals limits of parameter identifiability in multiparameter models of biochemical dynamics, BMC SYSTEMS BIOLOGY, ISSN: 17520509, DOI: 10.1186/s1291801502058, Vol.9, pp.6519, 2015 Streszczenie: Background Afiliacje autorów:
 35p.  
7.  Jetka T., Charzyńska A.^{♦}, Gambin A.^{♦}, Stumpf M.P.H.^{♦}, Komorowski M., StochDecomp—Matlab package for noise decomposition in stochastic biochemical systems, BIOINFORMATICS, ISSN: 13674803, DOI: 10.1093/bioinformatics/btt631, Vol.30, No.1, pp.137138, 2014 Streszczenie: Motivation: Stochasticity is an indispensable aspect of biochemical processes at the cellular level. Studies on how the noise enters and propagates in biochemical systems provided us with nontrivial insights into the origins of stochasticity, in total, however, they constitute a patchwork of different theoretical analyses. Afiliacje autorów:
 40p.  
8.  Woodcock D.J.^{♦}, Vance K.W.^{♦}, Komorowski M., Koentges G.^{♦}, Finkenstädt B.^{♦}, Rand D.A.^{♦}, A hierarchical model of transcriptional dynamics allows robust estimation of transcription rates in populations of single cells with variable gene copy number, BIOINFORMATICS, ISSN: 13674803, DOI: 10.1093/bioinformatics/btt201, Vol.29, pp.15191525, 2013 Streszczenie: Motivation: cisregulatory DNA sequence elements, such as enhancers and silencers, function to control the spatial and temporal expression of their target genes. Although the overall levels of gene expression in large cell populations seem to be precisely controlled, transcription of individual genes in single cells is extremely variable in real time. It is, therefore, important to understand how these cisregulatory elements function to dynamically control transcription at singlecell resolution. Recently, statistical methods have been proposed to back calculate the rates involved in mRNA transcription using parameter estimation of a mathematical model of transcription and translation. However, a major complication in these approaches is that some of the parameters, particularly those corresponding to the gene copy number and transcription rate, cannot be distinguished; therefore, these methods cannot be used when the copy number is unknown. Afiliacje autorów:
 45p.  
9.  Liepe J.^{♦}, Filippi S.^{♦}, Komorowski M., Stumpf M.P.H.^{♦}, Maximising the information content of experiments in systems biology, PLOS COMPUTATIONAL BIOLOGY, ISSN: 15537358, DOI: 10.1371/journal.pcbi.1002888, Vol.9, No.1, pp.e1002888113, 2013 Streszczenie: Our understanding of most biological systems is in its infancy. Learning their structure and intricacies is fraught with challenges, and often sidestepped in favour of studying the function of different gene products in isolation from their physiological context. Constructing and inferring global mathematical models from experimental data is, however, central to systems biology. Different experimental setups provide different insights into such systems. Here we show how we can combine concepts from Bayesian inference and information theory in order to identify experiments that maximize the information content of the resulting data. This approach allows us to incorporate preliminary information; it is global and not constrained to some local neighbourhood in parameter space and it readily yields information on parameter robustness and confidence. Here we develop the theoretical framework and apply it to a range of exemplary problems that highlight how we can improve experimental investigations into the structure and dynamics of biological systems and their behavior. Afiliacje autorów:
 45p.  
10.  Finkenstädt B.^{♦}, Woodcock D.J.^{♦}, Komorowski M., Harper C.V.^{♦}, Davis J.R.E.^{♦}, White M.R.H.^{♦}, Rand D.A.^{♦}, Quantifying intrinsic and extrinsic noise in gene transcription using the linear noise approximation: An application to single cell data, Annals of Applied Statistics, ISSN: 19326157, DOI: 10.1214/13AOAS669, Vol.7, No.4, pp.19601982, 2013 Streszczenie: A central challenge in computational modeling of dynamic biological systems is parameter inference from experimental time course measurements. However, one would not only like to infer kinetic parameters but also study their variability from cell to cell. Here we focus on the case where singlecell fluorescent protein imaging time series data are available for a population of cells. Based on van Kampen’s linear noise approximation, we derive a dynamic state space model for molecular populations which is then extended to a hierarchical model. This model has potential to address the sources of variability relevant to singlecell data, namely, intrinsic noise due to the stochastic nature of the birth and death processes involved in reactions and extrinsic noise arising from the celltocell variation of kinetic parameters. In order to infer such a model from experimental data, one must also quantify the measurement process where one has to allow for nonmeasurable molecular species as well as measurement noise of unknown level and variance. The availability of multiple singlecell time series data here provides a unique testbed to fit such a model and quantify these different sources of variation from experimental data. Słowa kluczowe: Linear noise approximation, kinetic parameter estimation, intrinsic and extrinsic noise, state space model and Kalman filter, Bayesian hierarchical modeling Afiliacje autorów:
 40p.  
11.  Schumacher J.^{♦}, Behrends V.^{♦}, Pan Z.^{♦}, Brown D.R.^{♦}, Heydenreich F.^{♦}, Lewis M.R.^{♦}, Bennett M.H.^{♦}, Razzaghi B.^{♦}, Komorowski M., Barahona M.^{♦}, Stumpf M.P.H.^{♦}, Wigneshweraraj S.^{♦}, Bundy J.G.^{♦}, Buck M.^{♦}, Nitrogen and carbon status are integrated at the transcriptional level by the nitrogen regulator NtrC in vivo, mBio, ISSN: 21507511, DOI: 10.1128/mBio.0088113, Vol.4, pp.00881113, 2013 Streszczenie: Nitrogen regulation in Escherichia coli is a model system for gene regulation in bacteria. Growth on glutamine as a sole nitrogen source is assumed to be nitrogen limiting, inferred from slow growth and strong NtrB/NtrCdependent gene activation. However, we show that under these conditions, the intracellular glutamine concentration is not limiting but 5.6fold higher than in ammoniumreplete conditions; in addition, αketoglutarate concentrations are elevated. We address this glutamine paradox from a systems perspective. We show that the dominant role of NtrC is to regulate glnA transcription and its own expression, indicating that the glutamine paradox is not due to NtrCindependent gene regulation. The absolute intracellular NtrC and GS concentrations reveal molecular control parameters, where NtrCspecific activities were highest in nitrogenstarved cells, while under glutamine growth, NtrC showed intermediate specific activity. We propose an in vivo model in which αketoglutarate can derepress nitrogen regulation despite nitrogen sufficiency. Afiliacje autorów:
 40p.  
12.  Komorowski M., Miękisz J.^{♦}, Stumpf M.P.H.^{♦}, Decomposing Noise in Biochemical Signalling Systems Highlights the Role of Protein Degradation, BIOPHYSICAL JOURNAL, ISSN: 00063495, DOI: 10.1016/j.bpj.2013.02.027, Vol.104, pp.17831793, 2013 Streszczenie: Stochasticity is an essential aspect of biochemical processes at the cellular level. We now know that living cells take advantage of stochasticity in some cases and counteract stochastic effects in others. Here we propose a method that allows us to calculate contributions of individual reactions to the total variability of a system’s output. We demonstrate that reactions differ significantly in their relative impact on the total noise and we illustrate the importance of protein degradation on the overall variability for a range of molecular processes and signaling systems. With our flexible and generally applicable noise decomposition method, we are able to shed new, to our knowledge, light on the sources and propagation of noise in biochemical reaction networks; in particular, we are able to show how regulated protein degradation can be employed to reduce the noise in biochemical systems. Afiliacje autorów:
 35p.  
13.  Komorowski M.^{♦}, Zurauskiene J.^{♦}, Stumpf M.P.H.^{♦}, StochSens  matlab package for sensitivity analysis of stochastic chemical systems, BIOINFORMATICS, ISSN: 13674803, DOI: 10.1093/bioinformatics/btr714, Vol.28, No.5, pp.731733, 2012 Streszczenie: Motivation: The growing interest in the role of stochasticity in biochemical systems drives the demand for tools to analyse stochastic dynamical models of chemical reactions. One powerful tool to elucidate performance of dynamical systems is sensitivity analysis. Traditionally, however, the concept of sensitivity has mainly been applied to deterministic systems, and the difficulty to generalize these concepts for stochastic systems results from necessity of extensive Monte Carlo simulations. Afiliacje autorów:
 40p.  
14.  Harrington H.A.^{♦}, Komorowski M.^{♦}, Beguerisse Díaz M.^{♦}, Ratto G.M.^{♦}, Stumpf M.P.H.^{♦}, Mathematical modeling reveals the functional implications of the different nuclear shuttling rates of Erk1 and Erk2, PHYSICAL BIOLOGY, ISSN: 14783967, DOI: 10.1088/14783975/9/3/036001, Vol.9, pp.036001112, 2012 Streszczenie: The mitogenactivated protein kinase (MAPK) family of proteins is involved in regulating cellular fates such as proliferation, differentiation and apoptosis. In particular, the dynamics of the Erk/Mek system, which has become the canonical example for MAPK signaling systems, have attracted considerable attention. Erk is encoded by two genes, Erk1 and Erk2, that until recently had been considered equivalent as they differ only subtly at the sequence level. However, these proteins exhibit radically different trafficking between cytoplasm and nucleus and this fact may have functional implications. Here we use spatially resolved data on Erk1/2 to develop and analyze spatiotemporal models of these cascades, and we discuss how sensitivity analysis can be used to discriminate between mechanisms. Our models elucidate some of the factors governing the interplay between signaling processes and the Erk1/2 localization in different cellular compartments, including competition between Erk1 and Erk2. Our approach is applicable to a wide range of signaling systems, such as activation cascades, where translocation of molecules occurs. Our study provides a first model of Erk1 and Erk2 activation and their nuclear shuttling dynamics, revealing a role in the regulation of the efficiency of nuclear signaling. Afiliacje autorów:
 30p.  
15.  Komorowski M.^{♦}, Costa M.J.^{♦}, Rand D.A.^{♦}, Stumpf M.P.H.^{♦}, Sensitivity, robustness, and identifiability in stochastic chemical kinetics models, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, ISSN: 00278424, DOI: 10.1073/pnas.1015814108, Vol.108, No.21, pp.86458650, 2011 Streszczenie: We present a novel and simple method to numerically calculate Fisher information matrices for stochastic chemical kinetics models. The linear noise approximation is used to derive model equations and a likelihood function that leads to an efficient computational algorithm. Our approach reduces the problem of calculating the Fisher information matrix to solving a set of ordinary differential equations. This is the first method to compute Fisher information for stochastic chemical kinetics models without the need for Monte Carlo simulations. This methodology is then used to study sensitivity, robustness, and parameter identifiability in stochastic chemical kinetics models. We show that significant differences exist between stochastic and deterministic models as well as between stochastic models with timeseries and timepoint measurements. We demonstrate that these discrepancies arise from the variability in molecule numbers, correlations between species, and temporal correlations and show how this approach can be used in the analysis and design of experiments probing stochastic processes at the cellular level. The algorithm has been implemented as a Matlab package and is available from the authors upon request. Afiliacje autorów:
 45p.  
16.  Komorowski M.^{♦}, Finkenstädt B.^{♦}, Rand D.^{♦}, Using a single fluorescent reporter gene to infer halflife of extrinsic noise and other parameters of gene expression, BIOPHYSICAL JOURNAL, ISSN: 00063495, DOI: 10.1016/j.bpj.2010.03.032, Vol.98, pp.27592769, 2010 Streszczenie: Fluorescent and luminescent proteins are often used as reporters of transcriptional activity. Given the prevalence of noise in biochemical systems, the timeseries data arising from these is of significant interest in efforts to calibrate stochastic models of gene expression and obtain information about sources of nongenetic variability. We present a statistical inference framework that can be used to estimate kinetic parameters of gene expression, as well as the strength and halflife of extrinsic noise from single fluorescentreportergene timeseries data. The method takes into account stochastic variability in a fluorescent signal resulting from intrinsic noise of gene expression, kinetics of fluorescent protein maturation, and extrinsic noise, which is assumed to arise at transcriptional level. We use the linear noise approximation and derive an explicit formula for the likelihood of observed fluorescent data. The method is embedded in a Bayesian paradigm, so that certain parameters can be informed from other experiments allowing portability of results across different studies. Inference is performed using Markov chain Monte Carlo. Fluorescent reporters are primary tools to observe dynamics of gene expression and the correct interpretation of fluorescent data is crucial to investigating these fundamental processes of cellular life. As both magnitude and frequency of the noise may have a dramatic effect on the cell fitness, the quantification of stochastic fluctuation is essential to the understanding of how genes are regulated. Our method provides a framework that addresses this important question. Afiliacje autorów:
 32p. 
Lista rozdziałów w ostatnich monografiach
1. 587  Nienałtowski K., Jetka T., Komorowski M., Quantitative Biology. Theory, Computational Methods, and Models, rozdział: Sensitivity analysis, Edited by Brian Munsky, William S. Hlavacek and Lev S. Tsimring, pp.293319, 2018  
2. 588  Jetka T., Nienałtowski K., Komorowski M., Quantitative Biology. Theory, Computational Methods, and Models, rozdział: Experimental design, Edited by Brian Munsky, William S. Hlavacek and Lev S. Tsimring, pp.321337, 2018 
Abstrakty konferencyjne
1.  Topolewski P., Komorowski M., Cell cycle does not contribute to celltocell heterogeneity of interferon responses, Cytokine, ISSN: 10434666, DOI: 10.1016/j.cyto.2017.09.011, No.MoP711, pp.100, 2017  25p.  
2.  Zakrzewska K.E., Jetka T., Nienałtowski K., Szymańska K., Andryka K., Topolewski P., Głów E., Komorowski M., Sensing and remembering IFNs concentrations, Cytokine, ISSN: 10434666, DOI: 10.1016/j.cyto.2017.09.011, No.MoP712, pp.100, 2017  25p.  
3.  Andryka K., Głów E., Nienałtowski K., Jetka T., Komorowski M., Sensing accuracy of interferons' concentrations, Cytokine, ISSN: 10434666, DOI: 10.1016/j.cyto.2015.08.238, Vol.76, pp.108, 2015 Streszczenie: Interferons exhibit their key role of immune modulators through activation of the JakStat signalling pathway. We know substantial amount of molecular details regarding functioning of the pathway. However, to what extend the action of the pathway is dose dependent at the single cell level remains largely unclear. Specifically it is not know if single cells respond in a digital fashion or their output is continuously dependent on the stimulant’s concentration. We have combined an informationtheoretic framework with highthroughput confocal imaging of mouse embryonic fibroblasts to provide a thorough, singlecell analysis of the JakStat signalling in response to interferon beta and interferon gamma. We showed that in a baseline state single cells have information hardly sufficient to distinguish between presence or absence of interferons. However they can be put in an alert state by an action of interferons, which allows them to respond more in an analogous fashion. Our results show that the accuracy with which signalling pathways transmit information is not fixed but can be modulated on the contextual basis. Afiliacje autorów:
 25p.  
4.  Jetka T., Komorowski M., How can we quantify ligand sensitivity for singlecell heterogenous dynamical responses?, FEBS Journal, ISSN: 1742464X, Vol.281, No.Supplement: 1, Special Issue: SI, pp.625, 2014 Słowa kluczowe: Information Processing, Sensitivity Analysis, Signal Transduction Afiliacje autorów:
 
5.  Głów E., Jetka T., Komorowski M., Sensitisation in the IFNalpha/b, IFNgamma crosstalk reveals mechanisms for enhanced information processing capacity of the STAT1, STAT2 signalling pathway, FEBS Journal, ISSN: 1742464X, Vol.281, No.Supplement: 1, Special Issue: SI, pp.640, 2014 Słowa kluczowe: Interferon, Jak/Stat, Stimulation Afiliacje autorów:
